PMID- 26957818 TI - What's new in emergencies, trauma and shock? The tortuous path in the management of necrotizing fasciitis: Is early surgical intervention critical? PMID- 26957819 TI - Abdominal injuries in communal crises: The Jos experience. AB - BACKGROUND: Abdominal injuries contribute significantly to battlefield trauma morbidity and mortality. This study sought to determine the incidence, demographics, clinical features, spectrum, severity, management, and outcome of abdominal trauma during a civilian conflict. MATERIALS AND METHODS: A prospective analysis of patients treated for abdominal trauma during the Jos civil crises between December 2010 and May 2012 at the Jos University Teaching Hospital. RESULTS: A total of 109 victims of communal conflicts with abdominal injuries were managed during the study period with 89 (81.7%) males and 20 (18.3%) females representing about 12.2% of the total 897 combat related injuries. The peak age incidence was between 21 and 40 years (range: 3-71 years). The most frequently injured intra-abdominal organs were the small intestine 69 (63.3%), colon 48 (44%), and liver 41 (37.6%). Forty-four (40.4%) patients had extra-abdominal injuries involving the chest in 17 (15.6%), musculoskeletal 12 (11%), and the head in 9 (8.3%). The most prevalent weapon injuries were gunshot 76 (69.7%), explosives 12 (11%), stab injuries 11 (10.1%), and blunt abdominal trauma 10 (9.2%). The injury severity score varied from 8 to 52 (mean: 20.8) with a fatality rate of 11 (10.1%) and morbidity rate of 29 (26.6%). Presence of irreversible shock, 3 or more injured intra-abdominal organs, severe head injuries, and delayed presentation were the main factors associated with mortality. CONCLUSION: Abdominal trauma is major life-threatening injuries during conflicts. Substantial mortality occurred with loss of nearly one in every 10 hospitalized victims despite aggressive emergency room resuscitation. The resources expenditure, propensity for death and expediency of timing reinforce the need for early access to the wounded in a concerted trauma care systems. PMID- 26957820 TI - Does community emergency care initiative improve the knowledge and skill of healthcare workers and laypersons in basic emergency care in India? AB - BACKGROUND: Due to lack of training in emergency care, basic emergency care in India is still in its infancy. We designed All India Institute of Medical Sciences basic emergency care course (AIIMS BECC) to address the issue. AIM: To improve the knowledge and skill of healthcare workers and laypersons in basic emergency care and to identify impact of the course. MATERIALS AND METHODS: Prospective study conducted over a period of 4 years. The target groups were medical and nonmedical personnel. Provider AIIMS BECC is of 1 day duration including lectures on cardio-pulmonary resuscitation, choking, and special scenarios. Course was disseminated via lectures, audio-visual aids, and mannequin training. For analysis, the participants were categorized on the basis of their education and profession. A pre- and a post-course evaluation were done and individual scores were given out of 20 and compared among all the groups and P value was calculated. RESULTS: A total of 1283 subjects were trained. 99.81% became providers and 2.0% were trained as instructors. There was a significant improvement in knowledge among all the participants irrespective of their education level including medicos/nonmedicos. However, participants who had higher education (graduates and postgraduates) and/or belonged to medical field had better knowledge gain as compared to those who had low level of education (<=12(th) standard) and were nonmedicos. CONCLUSION: BECC is an excellent community initiative to improve knowledge and skill of healthcare and laypersons in providing basic emergency care. PMID- 26957821 TI - Cross-border firing and injury patterns. AB - INTRODUCTION: Cross-border firing are increasingly being common in the modern era. The injuries resulting from these low intensity conflicts are a source of anxiety among treating physicians and their respective governments. The provisions are required to minimise the suffering of the victims viz. Mode of injuries, mortality patterns, adequacy of treatment at pre-hospital and tertiary care hospital and provisions to decrease morbidity and mortality for the people living in these areas. MATERIALS AND METHODS: A retrospective study was conducted in GMCH, Jammu who suffered injuries due to cross border firing in the month of October, 2014. 68 patients were reported in the causality wing. All the patients were referred from level 2 trauma centre. There were 51 males and 17 females out of which 5 were children. The cause of injury, involvement of organ system, cause of mortality and morbidity and loopholes in prehospital management were identified. RESULTS: Sharpnel were the most common cause of injury followed by indirect trauma. The common cause of mortality was abdominal and thoracic injuries. There were 4 deaths at hospital 2 of which were brought dead and 2 died during the course of treatment. There were twenty patients with extremity injuries, fourteen with chest trauma, eleven with abdomen including parineal injuries, three with head injuries, eight with ENT injuries, three with eye injuries and nine with splinters in the back out of which two were in the spinal canal. CONCLUSION: Prehospital stabilisation, early transport, in-transit resuscitation, immediate surgery if required and implementation of triage model and ATLS protocol has been the key to reduce mortality and morbidity. PMID- 26957822 TI - Early surgical intervention and its impact on patients presenting with necrotizing soft tissue infections: A single academic center experience. AB - OBJECTIVES: Early diagnosis and emergent surgical debridement of necrotizing soft tissue infections (NSTIs) remains the cornerstone of care. We aimed to study the effect of early surgery on patients' outcomes and, in particular, on hospital length of stay (LOS) and Intensive Care Unit (ICU) LOS. MATERIALS AND METHODS: Over a 6-year period (January 2003 through December 2008), we analyzed the records of patients with NSTIs. We divided patients into two groups based on the time of surgery (i.e., the interval from being diagnosed and surgical intervention): Early (<6 h) and late (>=6 h) intervention groups. For these two groups, we compared baseline demographic characteristics, symptoms, and outcomes. For our statistical analysis, we used the Student's t-test and Pearson Chi-square (chi(2)) test. To evaluate the clinical predictors of early diagnosis of NSTIs, we performed multivariate logistic regression analysis. RESULTS: In the study population (n = 87; 62% males and 38% females), age, gender, wound locations, and comorbidities were comparable in the two groups. Except for higher proportion of crepitus, the clinical presentations showed no significant differences between the two groups. There were significantly shorter hospital LOS and ICU LOS in the early than late intervention group. The overall mortality rate in our study patients with NSTIs was 12.5%, but early intervention group had a mortality of 7.5%, but this did not reach statistical significance. CONCLUSIONS: Our findings show that early surgery, within the first 6 h after being diagnosed, improves in hospital outcomes in patients with NSTIs. PMID- 26957823 TI - Tweeting the meeting: A comparative analysis of an Australian emergency medicine conference over four years. AB - OBJECTIVE: Social media allows user-generated content and dialog between users and has also entered into the domain of healthcare. The purpose of this study was to compare the use of Twitter at the Australasian College of Emergency Medicine Annual Scientific Meeting (ACEM ASM) from 2011 to 2014 and analyze its ability to spread emergency medicine education. MATERIALS AND METHODS: Retrospectively, TweetReach was utilized to analyze relevant tweets. Each Annual Scientific Meeting (ASM) had an associated Twitter account/s from, which data were collected. Duplicate tweets were excluded from the analysis. Information on the number of total tweets (regular tweets, retweets, and replies) and contributors was gathered. The potential audience, the reach, was calculated. RESULTS: From 2011 to 2014 the number of tweets rose from 460 to 4694, a 920% increase. Only 54 Twitter users contributed to the 2011 ASM. This rose to 252 (2012), 291 (2013) and 572 (2014). The average number of tweets per contributor ranged from 8.2 to 10.9. The reach, the potential number of Twitter users exposed to posts, rose >30 times from 2011 (15,502 users) to 2014 (471,166). CONCLUSION: The use of Twitter at the ACEM ASM rose significantly from 2011 to 2014. It is a highly useful tool for the dissemination of emergency medicine education. Twitter has been harnessed by the ASM to enhance the conference experience by further generating interaction between delegates as well as those worldwide. PMID- 26957824 TI - Laparotomy for blunt abdominal trauma-some uncommon indications. AB - Trauma laparotomy after blunt abdominal trauma is conventionally indicated for patients with features of hemodynamic instability and peritonitis to achieve control of hemorrhage and control of spillage. In addition, surgery is clearly indicated for the repair of posttraumatic diaphragmatic injury with herniation. Some other indications for laparotomy have been presented and discussed. Five patients with blunt abdominal injury who underwent laparotomy for nonroutine indications have been presented. These patients were hemodynamically stable and had no overt signs of peritonitis. Three patients had solid organ (spleen, kidney) infarction due to posttraumatic occlusion of the blood supply. One patient had mesenteric tear with internal herniation of bowel loops causing intestinal obstruction. One patient underwent surgery for traumatic abdominal wall hernia. In addition to standard indications for surgery in blunt abdominal trauma, laparotomy may be needed for vascular thrombosis of end arteries supplying solid organs, internal or external herniation through a mesenteric tear or anterior abdominal wall musculature, respectively. PMID- 26957825 TI - Cerebral venous sinus thrombosis in closed head trauma: A call to look beyond fractures and hematomas! PMID- 26957826 TI - Successful resuscitation after splenic artery aneurysm rupture. PMID- 26957827 TI - Luxatio erecta humeri in the swimmer's shoulder: A combination of ligamentous laxity and motion dyskinesis. PMID- 26957828 TI - Fulminant pneumatosis coli: A rare presentation of hollow viscus injury after blunt abdominal trauma. PMID- 26957829 TI - Left ventricular thrombus diagnosed by point-of-care ultrasonography. PMID- 26957830 TI - Clinical profile of patients with traumatic cervical spine injury in the emergency department of a tertiary care hospital. PMID- 26957831 TI - A fatal anal impalement. PMID- 26957832 TI - Fatal vascular air embolism during fluid resuscitation as a complication of pressure infuser bag. PMID- 26957833 TI - Update on Clinical Trials in Retinal Diseases. PMID- 26957834 TI - Updates on the Clinical Trials in Diabetic Macular Edema. AB - In this era of evidence-based medicine, significant progress has been made in the field of pharmacotherapeutics for the management of diabetic macular edema (DME). A. number of landmark clinical trials have provided strong evidence of the safety and efficacy of agents such as anti-vascular endothelial growth factors for the treatment of DME. Decades of clinical research, ranging from the early treatment of diabetic retinopathy study to the present-day randomized clinical trials (RCTs) testing novel agents, have shifted the goal of therapy from preventing vision loss to ensuring a maximum visual gain. Systematic study designs have provided robust data with an attempt to optimize the treatment regimens including the choice of the agent and timing of therapy. However, due to a number of challenges in the management of DME with approved agents, further studies are needed. For the purpose of this review, an extensive database search in English language was performed to identify prospective, RCTs testing pharmacological agents for DME. In order to acquaint the reader with the most relevant data from these clinical trials, this review focuses on pharmacological agents that are currently approved or have widespread applications in the management of DME. An update on clinical trials presently underway for DME has also been provided. PMID- 26957835 TI - Update on Clinical Trials in Dry Age-related Macular Degeneration. AB - This review article summarizes the most recent clinical trials for dry age related macular degeneration (AMD), the most common cause of vision loss in the elderly in developed countries. A literature search through websites https://www.pubmed.org and https://www.clinicaltrials.gov/, both accessed no later than November 04, 2015, was performed. We identified three Phase III clinical trials that were completed over the recent 5 years Age-Related Eye Disease Study 2 (AREDS2), implantable miniature telescope and tandospirone, and several other trials targeting a variety of mechanisms including, oxidative stress, complement inhibition, visual cycle inhibition, retinal and choroidal blood flow, stem cells, gene therapy, and visual rehabilitation. To date, none of the biologically oriented therapies have resulted in improved vision. Vision improvement was reported with an implantable mini telescope. Stem cells therapy holds a potential for vision improvement. The AREDS2 formulas did not add any further reduced risk of progression to advanced AMD, compared to the original AREDS formula. Several recently discovered pathogenetic mechanisms in dry AMD have enabled development of new treatment strategies, and several of these have been tested in recent clinical trials and are currently being tested in ongoing trials. The rapid development and understanding of pathogenesis holds promise for the future. PMID- 26957836 TI - Management of Neovascular Age-related Macular Degeneration: A Review on Landmark Randomized Controlled Trials. AB - In the last decade, a number of prospective clinical trials with carefully designed study protocols have been conducted for the treatment of neovascular age related macular degeneration (AMD). These landmark clinical trials such as ANCHOR and MARINA and, more recently, the Comparison of AMD Treatment Trials and VIEW studies have revolutionized the management of neovascular AMD. While AMD continues to remain a leading cause of severe visual loss worldwide, advances in pharmacotherapeutics have led to substantial improvements in the outcome of these patients. The introduction of anti-vascular endothelial growth factor agents has resulted in improvement of visual outcomes and has had a positive impact on the quality of life among elderly population. While the contemporary management of neovascular AMD has been successful in tremendously reducing the visual morbidity, the financial burden of therapy has increased exponentially. To overcome these challenges, newer pharmacologic agents are evaluated for their efficacy and safety in AMD. Ground-breaking advances in bench to bedside research have led to discovery of new pathways that appear to be viable targets for preventing visual loss in AMD. In this review, study designs and results of landmark clinical trials in AMD from the past decade have been summarized. PMID- 26957837 TI - Clinical Trials in Branch Retinal Vein Occlusion. AB - Branch retinal vein occlusion (BRVO) is the second most common retinal vascular disorder. The management of macular edema has changed considerably over time. The laser is considered the gold standard treatment for over two decades. However, visual recovery with laser is usually slow and incomplete. The advent of intravitreal agents, specifically anti-vascular endothelial growth factors (VEGF) have heralded a new era which promises rapid recovery of vision and quality of vision. Randomized clinical trials have reported optimal results with anti-VEGF agents (ranibizumab, bevacizumab, and aflibercept) compared to laser therapy or steroids. However, nearly 50% of the patients require repeat intravitreal anti VEGF therapy up to 4 years after initiating therapy to sustain the visual gains. The adverse events (systemic and ocular) of these agents are minimal. Monotherapy with anti-VEGF agents have been found to provide better results than any combination with laser. This review article summarizes evidence from randomized controlled trials evaluating treatment options for the treatment of macular edema secondary to BRVO with a special focus on anti-VEGF therapy. PMID- 26957838 TI - Central Retinal Vein Occlusion: A Review of Current Evidence-based Treatment Options. AB - A central retinal vein occlusion (CRVO) can induce an ischemic and hypoxic state with resulting sequelae of macular edema and neovascularization. Many treatment options have been studied. Our review aims to investigate the safety and efficacy of the multiple treatment options of CRVO. A PubMed and Cochrane literature search was performed. Well-controlled randomized clinical trials that demonstrated strong level 1 evidence-based on the rating scale developed by the British Centre for Evidence-Based Medicine were included. Seven clinical trials met inclusion criteria to be included in this review. These included studies that investigated the safety and efficacy of retinal photocoagulation (1 study), intravitreal steroid treatment (2 studies), and antivascular endothelial growth factor treatment (4 studies) for the treatment of CRVO. In addition, studies evaluating surgical treatment options for CRVO were also included. Many treatment modalities have been demonstrated to be safe and efficacious in the treatment of CRVO. These treatment options offer therapeutic benefits for patients and clinically superior visual acuity and perhaps the quality of life after suffering from a CRVO. PMID- 26957839 TI - Clinical Trials in Retinal Dystrophies. AB - Research development is burgeoning for genetic and cellular therapy for retinal dystrophies. These dystrophies are the focus of many research efforts due to the unique biology and accessibility of the eye, the transformative advances in ocular imaging technology that allows for in vivo monitoring, and the potential benefit people would gain from success in the field - the gift of renewed sight. Progress in the field has revealed the immense complexity of retinal dystrophies and the challenges faced by researchers in the development of this technology. This study reviews the current trials and advancements in genetic and cellular therapy in the treatment of retinal dystrophies and also discusses the current and potential future challenges. PMID- 26957840 TI - Incidence of Endophthalmitis after Intravitreal Anti-vascular Endothelial Growth Factor: Experience in Saudi Arabia. AB - PURPOSE: To report the incidence of endophthalmitis, the clinical and microbiological aspects, after intravitreal (IVT) injection of anti-vascular endothelial growth factor. METHODS: A chart review was performed of patients diagnosed with endophthalmitis after receiving IVT injections of bevacizumab (Avastin) and ranibizumab (Lucentis) presenting to King Khaled Eye Specialist Hospital (KKESH) from May 2006 to December 2012. Endophthalmitis was diagnosed clinically as an intraocular infection with vitreous involvement that required treatment with IVT antibiotics or had undergone pars plana vitrectomy (PPV) to remove the suspected microorganism. Main outcome measures were the incidence of endophthalmitis and the clinical and microbiological features. RESULTS: Seven cases of endophthalmitis were identified, there was 1 (0.004%) case of endophthalmitis of 22674 IVT injections performed at KKESH. All cases were after IVT bevacizumab. Three (42.85%) cases were culture-positive and caused by Staphylococcus epidermidis. The initial management was vitreous tap and IVT injection of antibiotics followed by PPV in 6 (85.7%) cases. One (14.3%) case underwent evisceration. Visual acuity improved at last visit in only 2 (28.6%) cases. The rate of endophthalmitis was 0.0004% for bevacizumab. CONCLUSIONS: The rate of endophthalmitis after IVT bevacizumab and ranibizumab was very low. We recommend following a standardized injection protocol, adherence to sterile techniques, and proper patient follow-up are determinant factors for low incidence rates. In addition, endophthalmitis after IVT bevacizumab and ranibizumab have poor visual outcomes despite prompt treatment. PMID- 26957841 TI - Incidence of Endophthalmitis after Intravitreal Bevacizumab using Aliquots Prepared On-site in 2 Operating Rooms in Kuwait. AB - PURPOSE: To report the incidence of endophthalmitis after intravitreal injection of bevacizumab and the outcomes of treatment of endophthalmitis at two centers in Kuwait. SUBJECTS AND METHODS: The aliquots of bevacizumab were prepared under aseptic precautions and administered in the operating theater on the same day at both centers. All patients received antibiotic drops after injection of bevacizumab. Data were collected on the number of cases that received intravitreal bevacizumab (IVB) and those that developed endophthalmitis were identified at the two centers. All cases of endophthalmitis received an intravitreal antibiotic injection and additional treatments as warranted. Data were collected on the outcomes of endophthalmitis treatment. RESULTS: There were 5 cases of endophthalmitis among a total of 5429 injections (0.09%: Confidence interval: 0.084-0.1). The incidence was 3 cases among 4690 (0.06%) and 2 cases among 739 injections (0.027%) at each center, respectively (P = 0.08). Four cases of endophthalmitis were culture-positive and organisms isolated were, coagulase negative Staphylococcus in 2 cases, Staphylococcus lugdunensis and Streptococcus pneumoniae in 1 case each. The final visual acuity was better than pre-IVB in 3 cases, same as pre-IVB in 1 case and worse in 1 case with streptococcal infection. No eyes developed phthisis bulbi or required enucleation. CONCLUSIONS: The incidence of endophthalmitis after intravitreal injection of bevacizumab using aliquots prepared in the operating room is comparable to other studies. There were no clusters of endophthalmitis cases. PMID- 26957842 TI - Knowledge, Attitude, and Perception of Barriers for Eye Care among Diabetic Persons Registered at Employee Health Department of a Tertiary Eye Hospital of Central Saudi Arabia. AB - PURPOSE: To evaluate the level of knowledge, attitudes, and barriers to diabetic retinopathy (DR) screening among diabetic healthcare staff at a tertiary eye hospital in central Saudi Arabia. METHODS: This was a descriptive survey using a closed-ended questionnaire. A. 5-grade. Likert scale was used for responses to each question. Data were collected on patient demographics and the status of diabetes. Survey responses related to knowledge, attitude, and barriers were grouped. RESULTS: The study sample was comprised of 45 diabetics employed at the hospital. The mean age was 49 +/- 11 years and 33 diabetics were males. One-third of the study population was referred to the eye clinic for DR screening. DR screening was performed in 25% of diabetics over the previous year. Twenty-nine (64%; 95% confidence intervals: 50-78) participants had excellent knowledge of eyecare for diabetic complications. Thirteen percent of participants had a positive attitude toward periodic eye checkups. Travel distance to an eyecare unit, no referral from family physicians for annual eye checkups and the lack of availability of gender-specific eyecare professionals were the main perceived barriers. CONCLUSION: Annual DR screening needs to be promoted to primary healthcare providers and diabetic patients. Barriers should be addressed to improve the uptake of DR screening. PMID- 26957843 TI - Vascular Endothelial Growth Factor Gene Polymorphism is not Associated with Diabetic Retinopathy in Egyptian Patients. AB - PURPOSE: Vascular endothelial growth factor (VEGF) was implicated as a major contributor to the development of diabetic retinopathy (DR). This study investigated whether single nucleotide polymorphisms of A allele of rs699947 or G allele of rs10434 in the VEGF gene were associated with DR in Egyptian patients with type 2 diabetes mellitus (DM). METHODS: This is a case-controlled study which was performed at Cairo University Hospital in 2012 on Egyptian patients with type 2 DM with and without DR. Healthy adults without diabetes comprised the comparison group. Patients underwent an ophthalmological examination and fundus photography. Genotyping was performed for the A allele of rs699947 and the G allele of rs10434 polymorphisms using real-time polymerase chain reaction. RESULTS: A total of 128 patients were enrolled in this study and divided into three groups: Group A included 46 patients with type 2 DM and DR; Group B included 41 patients with type 2 DM without DR; and Group C included 41 healthy controls. There was no significant association between rs699947 or rs10434 and any of the three groups (P = 0.5, P = 0.7, respectively). Allelic frequency in the three groups was not statistically significant for rs699947 or rs10434 (P = 0.6, P = 0.6, respectively). CONCLUSION: Rs699947 or rs10434 polymorphism was not associated with the presence of DR in Egyptian patients. Further studies are required before genetic testing for polymorphism can be used clinically to correlate with DR. PMID- 26957844 TI - Cross-Sectional Analysis of Neurocognitive Function, Retinopathy, and Retinal Thinning by Spectral-Domain Optical Coherence Tomography in Sickle Cell Patients. AB - PURPOSE: The purpose was to examine the relationship between neurocognitive function and two distinct forms of retinopathy in sickle cell disease. MATERIALS AND METHODS: Patients with sickle cell disease (n = 44, age range: 19-56 years, 70% female) were prospectively recruited for this cross-sectional study. Retinopathy was characterized by: (1) Presence of focal retinal thinning on spectral domain optical coherence tomography and (2) determination of the sickle retinopathy stage on funduscopic exam based on Goldberg classification. Neurocognitive function was assessed using the Philadelphia Brief Assessment of Cognition (PBAC), a validated test of cognition. Univariate and multivariate analyses for PBAC score outcomes were performed. Retinal thinning and retinopathy stage were primary variables of interest and age, gender, genotype, education, and history of stroke were covariates. RESULTS: Univariate analysis revealed associations with total PBAC score and age (P = 0.049), history of stroke (P = 0.04), and genotype (P < 0.001). Focal retinal thinning and Goldberg retinopathy stage were not associated with each other in this sample. Neither the presence of focal retinal thinning nor degree of retinopathy was associated with total PBAC score in univariate or multivariate analyses. CONCLUSIONS: We find an association between lower cognitive function and older age, history of stroke and sickle cell genotype SS in patients with sickle cell disease. Our data do not provide evidence to support an association between cognitive function and retinopathy in sickle cell patients. PMID- 26957845 TI - Retinal Vessel Caliber, Choroidal Thickness and Ocular Pulse Amplitude Measurements in Essential Thrombocythemia. AB - PURPOSE: The choroid and retina receive most of the blood that enter to the eye, and this uptake may be affected by essential thrombocythemia (ET) in which thrombosis and hemorrhage is common. This study compares choroidal thickness, retinal vascular caliber, and ocular pulse amplitude (OPA) measurements between patients with ET and healthy adults. MATERIALS AND METHODS: Thirty-seven patients with ET and 37 age-sex-matched healthy adults were recruited in this cross sectional and comparative study. Spectral-domain optical coherence tomography was used to measure the subfoveal choroidal thickness (SFCT) and retinal vascular caliber measurements. The Pascal dynamic contour tonometer was used for OPA and intraocular pressure (IOP) measurements. The independent samples t-test was used for comparison of measurements between the groups. Pearson's correlation coefficient analysis was used to detect correlations between the variables. A P < 0.05 was statistically significant. RESULTS: SFCT, OPA, and IOP measurements were not statistically significant differences between the study group and the control group (P > 0.05, all comparisons). Blood platelet counts were not associated with choroidal thickness, OPA, and IOP (P > 0.05). Retinal arteriolar and venular calibers were statistically, significantly thicker in healthy controls when compared to the study group (P < 0.05). CONCLUSIONS: Our results indicate that choroidal thickness and pulsatile blood flow are not significantly affected in ET and under high blood platelet counts. Retinal arteriolar and venular calibers are thinner in ET when compared to age-sex matched healthy controls. PMID- 26957846 TI - National Burden of Eye Diseases in Iran, 1990-2010; Findings from the Global Burden of Diseases Study 2010. AB - PURPOSE: The disability-adjusted life-years (DALYs) lost due to eye diseases and trends in DALYs in Iran has not been previously reported. The object of this study is to report the burden of eye diseases in Iran and to compare changes from 1990 to 2010 based on age and gender. METHODS: Data from the Global Burden of Disease Study 2010 (GBD 2010) are used to report DALYs for cataract, refraction/accommodation (functional) disorders, macular degeneration, and glaucoma. RESULTS: Cataract, refraction/accommodation (functional) disorders, macular degeneration, and glaucoma were the 84(th), 87(th), 138(th), and 151(st) causes of DALY in 1990 and the 89(th), 72(nd), 99(th), and 137(th) in 2010, respectively. Cataract accounted for 0.085% of national DALY in 1990 and 0.09% in 2010, refraction/accommodation (functional) disorders accounted for 0.42% in 1990 and 0.47% in 2010, macular degeneration accounted for 0.017% in 1990 and 0.071% in 2010 and glaucoma accounted for 0.0099% in 1990 and 0.025% in 2010. There was a steady increase in DALY with age for each eye disease for both genders and dichotomized for males and females from 1990 to 2010. CONCLUSIONS: Epidemiologic transition is reflected in major ophthalmic and blinding diseases in the GBD data for Iran. The burden of macular degeneration is rising, followed by glaucoma. The burden of presbyopia affected individuals past their middle age. The burden of cataract manifested as a slower increase that could be attributable to better access to treatment. PMID- 26957847 TI - Determinants of Utilization of Eye Care Services in a Rural Adult Population of a Developing Country. AB - PURPOSE: To describe the factors that determine the utilization of eye care services in a rural community in South-Western Nigeria. METHODS: A descriptive cross-sectional survey using a multistage sampling technique was conducted. The main outcome measure was self-reported previous consultation of an orthodox medical facility for eye care. RESULTS: The study sample included 643 participants. Only 122 (19%) respondents had previously visited orthodox facilities in search of eye care and 24% of those with presenting visual acuity <6/18 had sought eye care. Characteristics associated with previous utilization of eye care services were age of =70 years (odds ratio [OR] >= 1.7, P = 0.02); male gender (OR = 1.5, P = 0.04); literacy (OR = 1.7, P = 0.007); and residing close to an eye care facility (OR = 2.8, P < 0.001). Blind respondents were three times more likely to seek eye care (P < 0.001). Regression analysis revealed that factors associated with increased likelihood of utilization of eye care services included age >= 70 years; literacy; residence close to an eye facility; being diabetic or hypertensive; history of ocular symptoms, and blindness. CONCLUSIONS: These findings suggest that a significant proportion (75%) of adults in the study area are not utilizing eye care services and that blindness is an important determinant of utilization of eye care services. Health education and awareness campaigns about the importance and benefits of seeking eye care early, and the provision of community-based eye care programs are essential to boost the uptake of eye care services in this community as well as other rural areas of West Africa. PMID- 26957848 TI - Long-term Outcomes of Ahmed Glaucoma Valve Implantation in Refractory Glaucoma at Farabi Eye Hospital, Tehran, Iran. AB - PURPOSE: To describe long-term outcomes and complications of Ahmed glaucoma valve (AGV) implantation in subjects with refractory glaucoma at Farabi Eye Hospital, Tehran, Iran. MATERIALS AND METHODS: This retrospective cohort study evaluated patient records of all subjects with refractory glaucoma who had undergone AGV implantation up to January 2013. The main outcome measure was the surgical success rate. Complete success was defined as intraocular pressure (IOP) <22 mmHg, without anti-glaucoma medications or additional surgery. Qualified success was IOP <22 mmHg regardless of number of anti-glaucoma medications. In all cases, loss of vision (no light perception) was considered an independent indicator of failure. Data were also collected on intraoperative and postoperative complications. RESULTS: Twenty-eight eyes were included in the study. With a mean follow-up of 48.2 +/- 31.7 months (median: 40.50 months; range: 3-124 months), the IOP decreased from a mean preoperative value of 30.8 +/- 5.6 mmHg to 20.0 +/- 6.4 mmHg at last visit. The number of medications decreased from 3.7 +/- 0.4 preoperatively to 2.5 +/- 1.1 postoperatively. Cumulative qualified success was achieved in 69% of eyes. Mean time to failure according to qualified success criteria was 92.3 +/- 9.4 months. Postoperative complications were recorded in 16 (57.1%) eyes. The most common complication was focal endothelial corneal decompensation at the site of tube-cornea touch. CONCLUSION: AGV implantation with adjunctive topical anti-glaucoma drops controlled IOP in approximately 70% of eyes with refractory glaucoma with a median of 40.5 months of follow-up. However, complication rates were higher. PMID- 26957849 TI - EX-PRESS(r) Implant Position and Function: Comparative Evaluation with Ultrasound Biomicroscopy and Optical Coherence Tomography. AB - PURPOSE: This study evaluated the feasibility of anterior segment optical coherence tomography (OCT) and ultrasound biomicroscopy (UBM) for the imaging of EX-PRESS((r)) implant. MATERIALS AND METHODS: This nonrandomized comparative case series was performed at the Department of Ophthalmology of the University Hospital of Heraklion, Crete, Greece. The Ellex Eye Cubed (40 MHz) UBM and the Zeiss Visante OCT systems were used. The filtering bleb morphology (BL), aqueous outflow (AS), and tube position (TB) were evaluated by two independent observers using a quality scale of 1 (worst) to 4 (best). Data were also collected on corneal and iris clearance from the tip of the tube (CC and IC, respectively). Data from both the devices were statistically analyzed. P < 0.05 was considered as statistically significant. RESULTS: Ten eyes of 10 patients (6 males) with EX PRESS((r)) implant were examined. TB, AS, and BL scores using UBM were 2.40 +/- 0.39, 3.45 +/- 0.72, and 2.45 +/- 0.64, respectively. TB, AS, and BL scores for OCT were 3.35 +/- 0.41, 1.55 +/- 0.43, and 2.55 +/- 0.55, respectively. AS was significantly higher with UBM whereas the opposite was true for TB. Differences in BL between OCT and UBM were not statistically significant (P > 0.05). CONCLUSION: Imaging of the EX-PRESS((r)) implant is feasible with both UBM and OCT. Both modalities allow visualization of the position of the implant tube in relation to the iris or cornea and delineate the internal structure of the filtering bleb. PMID- 26957850 TI - Comparison of Ocular Monochromatic Higher-order Aberrations in Normal Refractive Surgery Candidates of Arab and South Asian Origin. AB - PURPOSE: To compare the ocular monochromatic higher-order aberration. (HOA) profile in normal refractive surgery candidates of Arab and South Asian origin. METHODS: This cross-sectional, observational, comparative study was performed in the cornea department of a specialty hospital. Normal refractive surgery candidates with no ocular morbidity except refractive error were recruited. Refractive surgery candidates underwent a preoperative evaluation, including wavefront aberrometry with the iDesign aberrometer (AMO, Inc., Santa Ana, California, United States). The HOA from right eyes were analyzed for HOA signed, absolute, and polar Zernike coefficients. RESULTS: Two hundred Arab participants (group 1) and 200 participants of South-Asian origin (group 2) comprised the study sample. The age and refractive status were comparable between groups. The mean of the HOA root mean square (RMS) was 0.36 +/- 17 MU and 0.38 +/- 18 MU for Arab and South-Asian eyes, respectively (P < 0.05, rank sum test [RST]). Of the 22 higher order signed Zernike modes, only Z3 (-3), Z3 (-1),3 (1), Z4 (-4), Z4 ( 2), Z4 (0), Z4 (4), and Z5 (-5) were significantly different from zero (one sample t-test, P < 0.002, with a Bonferroni correction of 0.05/22). All the signed and absolute Zernike terms were comparable between groups (RST, P > 0.002 [0.05/22]). The polar coefficients for coma, trefoil, spherical aberration, and tetrafoil were comparable between groups (P > 0.05, RST). Combined RMS values of third, fourth, fifth, and sixth order also were comparable between groups (P > 0.05, RST). CONCLUSIONS: Preoperative whole eye HOA were similar for refractive surgery candidates of Arab and South-Asian origin. The values were comparable to historical data for Caucasian eyes and were lower than Asian (Chinese) eyes. These findings may aid in refining refractive nomograms for wavefront ablations. PMID- 26957851 TI - Accuracy of Corneal Power Measurements for Intraocular Lens Power Calculation after Myopic Laser In situ Keratomileusis. AB - PURPOSE: To evaluate the accuracy of corneal power measurements for intraocular lens (IOL) power calculation after myopic laser in situ keratomileusis (LASIK). METHODS: The study evaluated 45 eyes with a history of myopic LASIK. Corneal power was measured using manual keratometry, automated keratometry, optical biometry, and Scheimflug tomography. Different hypothetical IOL power calculation formulas were performed for each case. RESULTS: The steepest mean K value was measured with manual keratometry (37.48 +/- 2.86 D) followed by automated keratometry (37.31 +/- 2.83 D) then optical biometry (37.06 +/- 2.98 D) followed by Scheimflug tomography (36.55 +/- 3.08). None of the K values generated by Scheimflug tomography were steeper than the measurements from the other 3 instruments. Using equivalent K reading (EKR) 4 mm with the Double-K SRK/T formula, the refractive outcome generated 97.8% of cases within +/- 2 D, 80.0% of cases within +/- 1 D, and 42.2% of cases within +/- 0.5 D. The best combination of formulas was "Shammas-PL + Double-K SRK/T formula using EKR 4 mm." CONCLUSION: Scheimflug tomography imaging using the Holladay EKR 4 mm improved the accuracy of IOL power calculation in post-LASIK eyes. The best option is a combination of formulas. We recommended the use the combined "Shammas-PL +/- Double-K SRK/T formula using EKR 4 mm"h for optical outcomes. PMID- 26957852 TI - Corneal Biomechanical and Anterior Chamber Parameters Variations after 1-year of Transepithelial Corneal Collagen Cross-linking in Eyes of Children with Keratoconus. AB - AIM: To assess the changes in corneal hysteresis (CH) and corneal resistance factor (CRF) 1-year following transepithelial corneal collagen cross-linking (CXL) treatment in eyes of children with keratoconus. METHODS: This case series was conducted in 22 eyes of 22 children. Children aged < 18 years with progressive keratoconus were included. They were treated with transepithelial CXL. Corneal biomechanical and anterior chamber parameters such as CH, CRF, and peak 1 were noted using ocular response analyzer, Pentacam, intraocular lens master, and anterior segment optical coherence tomography before and 1, 3, 6, and 12 months after treatment. RESULTS: Our series had 22 eyes of 22 children with a mean age 15.7 +/- 2.1 years. The CH and CRF 1-year after treatment declined (difference of mean 0.1 mmHg (95% confidence interval [CI] 0.04-0.24), P = 0.2] and (difference of mean 0.1 mmHg [95% CI 0.04-0.30], P = 0.3), respectively. Peak 1 and peak 2 increased (difference of mean 0.1 mmHg [95% CI 0.006-0.008], P = 0.2) and (difference of mean 0.1 mmHg [95% CI 0.007-0.006], P = 0.3), respectively. The uncorrected distance visual acuity improved from 0.95 +/- 0.34 logMAR to 0.68 +/- 0.45 logMAR (P < 0.05). No statistically significant changes during 12 months follow-up were observed in axial length, corneal volume, anterior chamber volume, and anterior chamber depth (P > 0.05). CONCLUSION: Transepithelial CXL in keratoconus in pediatric age group seems to have good stability in corneal biomechanical parameters after 1-year. Further studies with a larger sample and better study design are recommended to confirm our findings. PMID- 26957853 TI - Tacrolimus Ointment for Treatment of Vernal Keratoconjunctivitis. AB - PURPOSE: To evaluate the safety and efficacy of tacrolimus 0.1% ointment for the treatment of refractory vernal keratoconjunctivitis (VKC). MATERIALS AND METHODS: This prospective, nonrandomized case series enrolled 20 patients (40 eyes) with severe VKC, who were treated with tacrolimus 0.1% ointment. The mean age of the patients was 18.25 +/- 4.2 years (range, 9-31 years). Each patient completed a follow-up period of at least 24 months. The main outcome measure was the clinical response to treatment. RESULTS: Significant improvements in clinical signs and symptoms were achieved in all patients 6 weeks after starting treatment with topical tacrolimus. Treatment was gradually reduced, with increasing intervals between applications. VKC recurred in all patients who attempted to discontinue treatment. No additional medications were required and no significant changes in visual acuity or refraction were documented. Five patients discontinued treatment due to a severe burning sensation and were excluded from the study. CONCLUSIONS: Tacrolimus, 0.1% ointment, is a safe and effective treatment for VKC refractory to standard treatment and may be used as a substitute for steroid treatments used to controlled disease activity. However, adverse effects could cause poor patient compliance. PMID- 26957854 TI - Novel Mutations in Two Saudi Patients with Congenital Retinal Dystrophy. AB - To report novel mutations in two Saudi children with clinical features of Leber congenital amaurosis (LCA) and Alstrom syndrome. CASE REPORTS: Case 1 was a child with phenotypic features of LCA including oculodigital sign, bilateral enophthalmos, nystagmus, pale disc, and retinal changes. Direct sequencing of the coding sequence of GUCY2D revealed a missense mutation affecting highly conserved position (c. 743C > T; p.S248 L). Case 2 describes a girl with marked nystagmus, photophobia, and retinal changes in both eyes with short and stubby fingers tapering at the distal phalanges. The electroretinograms were nonrecordable in each eye. She had a hearing aid in the left ear, mid-facial hypoplasia, bilateral enophthalmos, and insulin dependent diabetes. Mutation screening of candidates genes revealed a pathogenic mutation in ALMS1 gene (c. 8441C > A, p.S2814). Two novel mutations causing phenotypic LCA and Alstrom syndrome in Saudi patients from consanguineous families expand the genotypic spectrum of congenital retinal dystrophies. PMID- 26957855 TI - Cobbler's Technique for Iridodialysis Repair. AB - We describe a novel "Cobbler's technique" for iridodialysis repair in the right eye of a patient aged 18 years, with a traumatic iridodialysis secondary to open globe injury with an iron rod. Our technique is simple with easy surgical maneuvers, that is, effective for repairing iridodialysis. The "Cobbler's technique" allows a maximally functional and cosmetic result for iridodialysis. PMID- 26957856 TI - Barriers to Cataract Surgery in Africa: A Systematic Review. AB - Cataract remains the leading cause of blindness in Africa. We performed a systematic literature search of articles reporting barriers to cataract surgery in Africa. PubMed and Google Scholar databases were searched with the terms "barriers, cataract, Africa, cataract surgery, cataract surgical coverage (CSC), and rapid assessment of avoidable blindness (RAAB)." The review covered from 1999 to 2014. In RAAB studies, barriers related to awareness and access were more commonly reported than acceptance. Other type of studies reported cost as the most common barrier. Some qualitative studies tended to report community and family dynamics as barriers to cataract surgery. CSC was lower in females in 88.2% of the studies. The variability in outcomes of studies of barriers to cataract surgery could be due to context and the type of data collection. It is likely that qualitative data will provide a deeper understanding of the complex social, family, community, financial and gender issues relating to barriers to uptake of cataract surgery in Africa. PMID- 26957857 TI - Atypical Presentation of Ocular Toxoplasmosis: A Case Report of Exudative Retinal Detachment and Choroidal Ischemia. AB - A 24-year-old healthy male presented with a chief complaint of blurred vision in the right eye for 1-week. Fundus examination indicated right exudative retinal detachment and choroidal ischemia. The patient responded well to anti toxoplasmosis medications and steroids. Exudative retinal detachment and choroidal ischemia are atypical presentations of ocular toxoplasmosis. However, both conditions responded well to anti.parasitic therapy with steroid. PMID- 26957858 TI - Ocular Leishmaniasis Treated by Intralesional Amphotericin B. AB - Leishmaniasis is a group of diseases with varied clinical manifestations. Ocular involvement is an unusual presentation of leishmaniasis, and the eyelid is not a common site of cutaneous lesions, likely due to the mobility of the lids. Some case reports of conjunctival involvement are either a contiguous dissemination from lid margin or in the setting of disseminated leishmaniasis in an immunocompromised host. To our knowledge, isolated involvement of the bulbar conjunctiva has not been reported. We present the first case in the literature of a patient with an erythematous fibrovascular lesion in the interpalpebral zone that was clinically diagnosed as pterygium, but recurred at the site of surgical excision. After histopathologic diagnosis, the lesion was treated with intralesional injection of amphotericin B and improved completely within a few weeks. An accurate diagnosis of leishmaniasis in the eye may be challenging in many clinical settings. To our knowledge, an isolated pterygium.like lesion has not been reported in literature. In addition, intralesional injection of amphotericin B is a novel treatment method in this setting. PMID- 26957859 TI - Acute Corneal Hydrops 3 Years after Intra-corneal Ring Segments and Corneal Collagen Cross-linking. AB - This case report describes a 15-year-old male with allergic conjunctivitis and keratoconus, who underwent uneventful intra-corneal ring segment (ICRS) implantation and corneal collagen cross-linking (CXL) in the right eye. During the follow-up periods, the patient was noted to have several episodes of allergic conjunctivitis that were treated accordingly. At the 2 years postoperatively, he presented with another episode of allergic conjunctivitis and progression of keratoconus was suspected on topography. However, the patient was lost to follow up, until he presented with acute hydrops at 3 years postoperatively. There are no reported cases of acute corneal hydrops in cross-linked corneas. We suspect the young age, allergic conjunctivitis and eye rubbing may be a risk factors associated with possible progression of keratoconus after CXL. Prolonged follow up and aggressive control of the allergy might be necessary in similar cases. PMID- 26957860 TI - A Rare Case of Puberty Onset Congenital Erythropoietic Porphyria with Ophthalmological Manifestations. AB - A 27-year-old male patient was presented with foreign body sensation in both the eyes for 2 years duration and blisters followed by scarring and pigmentation in the photo-exposed areas of the body over the previous 12 years. His urine was reddish colored for the previous year. On examination, there was scarring, hyper pigmentation of photo-exposed parts of the body along with resorption of the distal phalanges of fingers in both hands except the smallest digit which had onycholysis. Ocular examination indicated scleral necrosis in the interpalpebral areas in both eyes and bilateral dry eye. Hematological examination indicated a picture suggestive of hemolytic anemia. Abdominal ultrasonography indicated an enlarged spleen. These clinical features are suggestive of puberty onset congenital erythropoietic porphyria with ophthalmological manifestations. PMID- 26957861 TI - Journal of Pharmacy and Bioallied Sciences. PMID- 26957862 TI - Current status of pyrazole and its biological activities. AB - Pyrazole are potent medicinal scaffolds and exhibit a full spectrum of biological activities. This review throws light on the detailed synthetic approaches which have been applied for the synthesis of pyrazole. This has been followed by an in depth analysis of the pyrazole with respect to their medical significance. This follow-up may help the medicinal chemists to generate new leads possessing pyrazole nucleus with high efficacy. PMID- 26957863 TI - Laboratory approach for diagnosis of toluene-based inhalant abuse in a clinical setting. AB - The steady increase of inhalant abuse is a great challenge for analytical toxicologists. This review describes an overview of inhalant abuse including the extent of the problem, types of products abused, modes of administration, pharmacology and effects of inhalants, the role of laboratory, interpretation of laboratory results and clinical considerations. Regular laboratory screening for inhalant abuse as well as other substance abuse and health risk behaviors must be a part of standard clinical care. PMID- 26957864 TI - Statins and its hepatic effects: Newer data, implications, and changing recommendations. AB - Hepatic adverse effects are one of the most commonly known adverse effects reported with statins. Frequently, fear of serious hepatic effects contributes to underutilization of statins as well as unnecessary discontinuation of its use among those indicated. There are changing data on the occurrence of these negative hepatic effects, recommendations on their actual risk, monitoring required, and safety of use in those with preexisting hepatic disorders. Based on reviewed literature, statins appear to be associated with a very low risk of true and serious liver injury. Unprecedented fears regarding hepatic adverse effects of statins among prescribers and patients can deny patients of the significant benefits of these agents. Routine periodic monitoring of liver function does not appear to detect or prevent serious liver injury and hence may not be indicated. But the potential of statins to cause significant and serious hepatic effects should not be overlooked in daily clinical practice. Statin use need not be avoided in patients with preexisting liver dysfunction such as nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, compensated cirrhosis, and compensated chronic liver disease if its use is clearly indicated. Physician's judgment based on the risk and benefit for an individual patient does matter when a strategy is chosen regarding the use of statins and monitoring patients while on statins. PMID- 26957865 TI - Virulence and antimicrobial resistance of common urinary bacteria from asymptomatic students of Niger Delta University, Amassoma, Bayelsa State, Nigeria. AB - BACKGROUND: Asymptomatic bacteriuria frequently occurs among all ages with the possibility of developing into urinary tract infections, and the antimicrobial resistance patterns of the etiologic organisms are essential for appropriate therapy. Thus, we investigated the virulence and antimicrobial resistance patterns of common urinary bacteria in asymptomatic students of Niger Delta University, Amassoma, Bayelsa State, Nigeria in a cross-sectional study. MATERIALS AND METHODS: Clean catch mid-stream early morning urine samples collected from 200 asymptomatic University students of aged ranges 15-30 years were cultured, screened and common bacteria were identified using standard microbiological procedures. The isolates were screened for hemolysin production and their susceptibility to antibiotics was determined using standard disc assay method. RESULTS: A total prevalence rate of 52.0% significant bacteriuria was detected and it was significantly higher among the female with a weak association (chi (2) = 6.01, phi = 0.173, P = 0.014). The Klebsiella pneumoniae and Staphylococcus aureus isolates were most frequently encountered among the isolated bacteria and 18 (12.7%) of all the bacterial isolates produced hemolysins. All the bacterial isolates exhibited 50-100% resistance to the tested beta-lactam antibiotics, tetracycline and co-trimoxazole. The isolated bacteria were 85-100% multi-drug resistant. However, most of the isolates were generally susceptible to gentamicin and ofloxacin. The phenotypic detection of extended spectrum beta-lactamases was 9 (9.6%) among the tested Gram-negative bacterial isolates. CONCLUSIONS: The observed high proportions of multidrug resistant urinary bacteria among asymptomatic University students call for the need of greater control of antibiotic use in this study area. PMID- 26957866 TI - Knowledge, perceptions, and attitudes toward complementary and alternative medicines among pharmacy students of a Malaysian Public University. AB - BACKGROUND: The use of complementary and alternative medicine (CAM) is consistently on the rise worldwide. Consumers often consider pharmacists as a major source of information about CAM products and their safety. Due to the limitation of data, it is worth exploring the knowledge, perceptions, and attitudes of pharmacy students toward CAM. OBJECTIVE: The objective of this study was to explore the knowledge, perceptions, and attitudes of pharmacy students regarding the use of CAM in Malaysia. MATERIALS AND METHODS: A cross-sectional study was conducted for 3 months among Bachelor of Pharmacy students in a public sector University of Malaysia. A pretested, self-administered questionnaire, comprised four sections, was used to collect the data from 440 participants. Descriptive analysis was used, and Chi-square test was used to test the association between dependent and independent variables. RESULTS: Of 440 questionnaire distributed, 287 were returned giving a response rate of (65.2%). The results showed that 38.6% participants gave correct answers when asked about the use of herbal products with digoxin. Majority of the participants were knowledgeable about supplementary therapy (25.3%) while the lack of knowledge was mostly evident in traditional Chinese medicines (73.7%). Majority of the students were either neutral (49.5%) or disagreed that (42.8%) CAM use is unsafe. Females were more in disagreement to the statements than males (P = 0.007). Majority of students also agreed to use CAM therapies for their health and well-being (51.2%). CONCLUSION: The study revealed that pharmacy students did not have adequate knowledge of CAM though their attitudes and perceptions were relatively positive. PMID- 26957867 TI - Evaluation of anti-malarial drugs' use in Fitche Hospital, North Shoa, Oromia Region, Ethiopia. AB - OBJECTIVE: Retrospective evaluation of anti-malarial drugs' use in Fitche Hospital, North Shoa, Oromia Region, Ethiopia. METHODS: Retrospective cross sectional study design was conducted using selected patients cards of 1-year (January 2012-January 2013 G.C) with anti-malarial agents from January 18 to 30, 2013. The sample size was calculated by using Joint Commission on the Accreditation of Health care Organization criteria and sampling was done by using a systematic random sampling technique. RESULTS: One hundred and twenty-five patient cards with anti-malarial drugs were reviewed of which 32.8%, 21.6%, 15.2% belongs to age range of 20-29, 10-19, and 30-39, respectively. Chloroquine prescription accounts for 50.4% from total anti-malarial drugs. 71.2% and 78.4% of patients received antibiotics and analgesics, respectively, with anti-malarial drugs. 77.6% of drugs were prescribed by generic name while the brand name was 22.39%. CONCLUSIONS: The study done in Fitche Hospital revealed that the use of anti-malarial agent was not in complete agreement with the current guideline of Ethiopia despite good practice. PMID- 26957868 TI - New fatty acid and acyl glycoside from the aerial parts of Phyllanthus fraternus Webster. AB - BACKGROUND: Phyllanthus fraternus Webster (Euphorbiaceae) is used to treat dyspepsia, indigestion, jaundice, dysentery, diabetes, influenza, kidney stones, urinary tract diseases, vaginitis, and skin eruptions in traditional systems of medicine. MATERIALS AND METHODS: The methanol extract of aerial parts of P. fraternus was obtained by soxhlation method. Isolation of compounds was done by silica gel column chromatography. Analytical thin layer chromatography was used to check the homogeneity of eluted fractions. The structures of isolated compounds were established on the basis of spectral studies and chemical reactions. RESULTS: Phytochemical investigation of a methanolic extract of the aerial parts yielded a new fatty acid characterized as cis-n-octacos-17-enoic acid (5) and a new acyl tetraglycoside formulated as n-dodecanoyl-O-beta-D glucopyranosyl-(2'->1'')-O-beta-D-glucopyranosyl-(2''->1''')-O-beta-D glucopyranosyl-(2'''->1'''')-O-beta-D-glucopyranoside (7) along with known compounds 1-pentacosanol (1), beta-sitosteryl oleate (2), beta-sitosteryl linoleate (3), stigmasterol (4) and palmityl glucuronoside (6). PMID- 26957869 TI - A study on the interactions of doctors with medical representatives of pharmaceutical companies in a Tertiary Care Teaching Hospital of South India. AB - BACKGROUND: The promotional activities by medical representatives (MRs) of the pharmaceutical companies can impact the prescribing pattern of doctors. Hence, the interaction between doctors and the pharmaceutical industry is coming under increasing scrutiny. OBJECTIVE: The primary objective was to assess the attitude of the doctors toward the interaction with the MRs of the pharmaceutical company. The secondary objective was to assess the awareness of the doctors about regulations governing their interaction with the pharmaceutical company. MATERIALS AND METHODS: This was a cross-sectional study. This study was carried out using a pretested questionnaire containing 10 questions between June and September 2014. The doctors working in the Dhanalakshmi Srinivasan Medical College and Hospital, Perambalur (Tamil Nadu) during the study period was included. RESULTS: A total of 100 pretested questionnaires were distributed, and 81 doctors responded (response rate 81%). 37% doctors responded that they interacted with MR once a week whereas 25.9% told that they interact with MRs twice a month. About 69.1% doctors think that MR exaggerate the benefits of medicines and downplays the risks and contraindications of medicine(P = 0.000). 61.7% doctors think that MR has an impact on their prescribing (P = 0.000). 63% doctors stated that they had received promotional tools such as stationery items, drug sample, textbooks or journal reprints from MR in last 12 months (P = 0.0012). Unfortunately, 70.4% doctors have not read the guidelines about interacting with the pharmaceutical industry or its representative (P = 0.000). CONCLUSION: Rather than forbidding any connection between doctors and industry, it is better to establish ethical guidelines. The Medical Council of India code is a step in the right direction, but the majority of doctors in this study have not read the guidelines about interacting with the pharmaceutical industry or its representative. PMID- 26957870 TI - Usage of complementary and alternative medicine among patients with chronic kidney disease on maintenance hemodialysis. AB - AIM: To determine the prevalence and the type of complementary and alternative medicine (CAM) use among chronic kidney disease (CKD) patients on maintenance hemodialysis (MHD). MATERIALS AND METHODS: The study was conducted in 200 CKD patients who were on MHD. The patients were subjected to a validated interviewer administered questionnaire adopted from the National Health Interview Survey Adult CAM. The knowledge on CAM and its usage by the patients were assessed based on the responses given by the patients. RESULTS: Of the 200 patients, 52 (26%) patients were identified to be using CAM therapy. The most commonly used CAM modality by these patients was Ayurveda both alone (30.4%) and in combination with other CAM modalities (23.2%), followed by acupuncture in 17.3% patients. CAM usage was high in the age range of 50-64 years (67%). Of the CAM users, 21% of patients were from a rural area; 16.5% of patients were from upper middle class, and 24% were on dialysis for 1-4 years. There was a statistically significant association between CAM usage and age, gender, place of living, socioeconomic status, and duration of dialysis (P < 0.01). CONCLUSION: The present survey provides the data on the usage of CAM among dialysis patients and adds to the increasing evidence about CAM use. Because many products are at risk to either accumulate or cause interactions with medication, a better education on the risks and benefits of the CAM therapy by the health care providers to the end stage renal disease patients is needed. PMID- 26957871 TI - Stress relaxant and antioxidant activities of acid glycoside from Spondias mangifera fruit against physically and chemically challenged albino mice. AB - AIM: Stress relaxant and antioxidant activities of ethanolic extract of fruit Spondias mangifera (EEFSM) and its isolated compound (Sm-01) were evaluated. The structure of Sm-01 was also elucidated. MATERIALS AND METHODS: EEFSM at two different doses of 100 and 200 mg/kg (bw)/day and Sm-01 at dose of 10 mg/kg (bw)/day were screened for in vivo stress relaxant activity using anoxia stress tolerance, swimming endurance and cyclophosphamide-induced immune suppression model and in vitro antioxidant activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH) model. The levels of Hb, red blood cell (RBC) and white blood cell (WBC) along with organ and body weights suppressed by cyclophosphamide were estimated. The structure of Sm-01 was elucidated by spectroscopy (ultraviolet, infrared, (1)H-nuclear magnetic resonance [NMR],(13) C-NMR and mass spectrometry) and chemical analyses. RESULTS: Sm-01 was structurally elucidated as propan-1,2-dioic acid-3-carboxyl-beta-D-glucopyranosyl-(6'->1")-beta-D-glucofuranoside. It was found that EEFSM and Sm-01 significantly increased the anoxia stress tolerance, swimming endurance and duration of stay on rotarod and normalized the levels of Hb, RBC, and WBC along with altered organ and body weights suppressed by cyclophosphamide. EEFSM and Sm-01 also exhibited significant antioxidant activity against DPPH free radical at the concentrations of 0.05, 0.5, and 1.0 mg/mL with obtained IC50 of 0.32 and 0.15 mg/mL, respectively. CONCLUSIONS: These findings demonstrated that extract and Sm-01 both possess significant stress relaxant and antioxidant activities favoring its use as adaptogens. The activities of the extract may be due to the Sm-01. PMID- 26957872 TI - A cross-sectional assessment of health-related quality of life among type 2 diabetic patients in Pakistan. AB - OBJECTIVE: This study aims to describe the health-related quality of life (HRQoL) profile of Type 2 diabetes mellitus (T2DM) population attending outpatient clinics in Sargodha City, Pakistan. METHODS: The study was designed as a cross sectional descriptive survey. T2DM patients attending a tertiary care institute in Sargodha, Pakistan were targeted for the study. The EuroQol EQ-5D was used for the assessment of HRQoL and was scored using values derived from the UK general population survey. Descriptive statistics were used for the elaboration of sociodemographic characteristics. The Chi-square test was used to depict the possible association between study variables and HRQoL. Where significant associations were noted, Phi/Cramer's V was used for data interpretation accordingly. SPSS version 21 (SPSS Inc., Chicago, IL, USA) was used for data analysis and P < 0.05 was taken as significant. RESULTS: Three hundred and ninety two patients were approached for the study. The cohort was dominated by males (n = 222, 56.60%) with 5.58 +/- 4.09 years of history of T2DM. The study highlighted poor HRQoL among the study participants (0.471 +/- 0.336). Gender, marital status, education, monthly income, occupation, location and duration of the disease were reported to be significantly associated with HRQoL (P < 0.001). CONCLUSION: T2DM imposes a negative effect on HRQoL of the patients. Attention is needed to highlight determinants of HRQoL and to implement policies for better management of T2DM, particularly in early treatment phases where improving HRQoL is still possible. PMID- 26957873 TI - Identification and prevalence of tetracycline resistance in enterococci isolated from poultry in Ilishan, Ogun State, Nigeria. AB - BACKGROUND: Tetracycline is one of the most frequently used antibiotics in Nigeria both for human and animal infections because of its cheapness and ready availability. The use of tetracycline in animal husbandry could lead to horizontal transfer of tet genes from poultry to human through the gut microbiota, especially enterococci. Therefore, this study is designed to identify different enterococcal species from poultry feces in selected farms in Ilishan, Ogun State, Nigeria, determine the prevalence of tetracycline resistance/genes and presence of IS256 in enterococcal strains. MATERIALS AND METHODS: Enterococci strains were isolated from 100 fresh chicken fecal samples collected from seven local poultry farms in Ilishan, Ogun State, Nigeria. The strains were identified by partial sequencing of 16S rRNA genes. Antibiotic susceptibility of the isolates to vancomycin, erythromycin, tetracycline, gentamicin, amoxycillin/claulanate, and of loxacin were performed by disc diffusion method. Detection of tet, erm, and van genes and IS256 insertion element were done by polymerase chain reaction amplification. RESULTS: Sixty enterococci spp. were identified comprising of Enterococcus faecalis 33 (55%), Enterococcus casseliflavus 21 (35%), and Enterococcus gallinarium 6 (10%). All the isolates were resistant to erythromycin (100%), followed by tetracycline (81.67%), amoxicillin/clavulanic acid (73.33%), ofloxacin (68.33%), vancomycin (65%), and gentamicin (20%). None of the enterococcal spp. harbored the van and erm genes while tet(M) was detected among 23% isolates and is distributed mostly among E. casseliflavus. IS256 elements were detected only in 33% of E. casseliflavus that were also positive for tet(M) gene. CONCLUSION: This study provides evidence that tetracycline resistance gene is present in the studied poultry farms in Ilishan, Ogun State, Nigeria and underscores the need for strict regulation on tetracycline usage in poultry farming in the studied location and consequently Nigeria. PMID- 26957874 TI - Effectiveness of posthemodialysis administration of pregabalin (75 mg) in treatment resistance uremia pruritus. AB - Uremic pruritus (UP) is one of the complications faced by majority of the patients with end stage renal disease (ESRD). Due to complex pathophysiology of UP, most of the anti-inflammatory and tropical lubricants often not provide a long lasting control over pruritus. Recently the uses of certain anti-epileptics are found to demonstrate promising relief to UP. To test the effect of 75 mg pregabalin in patients with treatment resistance pruritus. Data was prospectively collected from a patient with ESRD and suffering from treatment resistance pruritus. Intensity of pruritus was recorded using 5D-itching scale (5D-IS) and visual analogue scale (VAS). Pre and post assessment was done for this patient, on initial assess the parathyroid hormone level of the patient was 70.5 pg/ml with a serum phosphate level of 2.61 mmol/L. Upon initial assess the VAS score was 8 and 5D-IS score was twenty. After the duration of four weeks of pregabalin 75 mg post hemodialysis, 5D-IS score reduced to 8 and VAS score move down to 3. Pregabalin 75 mg post hemodialysis was found to reduce the intensity of UP. Pregabalin 75 mg post hemodialysis can be another option to treat UP. PMID- 26957875 TI - Personalized medicine: A paradigm shift towards promising health care. PMID- 26957876 TI - Biostatistics teaching to the undergraduate medical students through research oriented medical education posting program in a Teaching Medical Institute in Coastal Area of Pondicherry: An experience of a biostatistician. PMID- 26957877 TI - Nanotechnology in medicine: Leads from Ayurveda. PMID- 26957878 TI - Understanding and Managing Intravenous Container Overfill. AB - Understanding IV container overfill promotes safety. PMID- 26957880 TI - New Medical Devices. PMID- 26957879 TI - Confusion From the FDA on Compounding: Agency Tries to Expand List of Useable "Bulk Drug Substances". AB - Confusion, ire follow FDA interim policy on compounding. PMID- 26957881 TI - Pharmaceutical Approval Update. AB - Elbasvir/grazoprevir (Zepatier) for chronic hepatitis C virus; sumatriptin nasal powder (Onzetra Xsail) for migraine; eribulin mesylate (Halaven), now for liposarcoma; and extended-release amphetamine (Adzenys XR-ODT) for ADHD. PMID- 26957882 TI - Correction. AB - [This corrects the article on p. 64 in vol. 41, PMID: 26766892.]. PMID- 26957883 TI - Naltrexone/Bupropion ER (Contrave): Newly Approved Treatment Option for Chronic Weight Management in Obese Adults. AB - Naltrexone/bupropion ER (Contrave): newly approved treatment option for chronic weight management in obese adults. PMID- 26957884 TI - Formulary Policies a Battleground In HHS Proposal on Nondiscrimination: Are Tiering and Cost Sharing Civil Rights Issues? AB - The Department of Health and Human Services' proposed rule on Section 1557 of the Patient Protection and Affordable Care Act bans discrimination in health care. How the rule would affect formularies and P&T committees has prompted varying concerns. PMID- 26957885 TI - Value of the Pharmacist in the Medication Reconciliation Process. AB - Involving pharmacists in the process of comparing the medications that should be ordered for a patient with the new medications that are currently ordered and resolving differences improves accuracy, decreases mortality, and improves transitions of care. PMID- 26957886 TI - Benzocaine-Induced Methemoglobinemia: A Case Report. AB - Topical anesthetics, such as benzocaine, have been reported to cause methemoglobinemia, in which hemoglobin is unable to release oxygen effectively to body tissues. The pathophysiology, symptoms, and treatment of a 46-year-old patient are examined. PMID- 26957887 TI - The Checkpoint Immunotherapy Revolution: What Started as a Trickle Has Become a Flood, Despite Some Daunting Adverse Effects; New Drugs, Indications, and Combinations Continue to Emerge. AB - What started as a trickle of new agents that help the body's immune system fight cancer has now become a flood, despite some daunting adverse effects. This report discusses the new drugs, indications, and combinations that continue to emerge. PMID- 26957888 TI - American Academy of Ophthalmology 2015 Annual Meeting. AB - The 119th annual meeting of the American Academy of Ophthalmology attracted 28,000 attendees. The authors review key scientific sessions on endophthalmitis, new patient education videos, and ongoing research activities. PMID- 26957889 TI - Midwifery-Led Maternity Care: Back to Basics. AB - In this column, the editor of The Journal of Perinatal Education discusses Britain's National Health Service's updated evidence-based guidelines stating that women with uncomplicated pregnancies are better off in the hands of midwives than hospital physicians during birth. The editor also describes the contents of this issue, which offer a broad range of resources, research, and inspiration for childbirth educators in their efforts to promote, support, and protect natural, safe, and healthy birth. Women with uncomplicated pregnancies are better off in the hands of midwives than hospital physicians during birth. PMID- 26957890 TI - Doula, Sister, Aunt, Storyteller: A Midwife's Retelling of Birth. AB - As a midwife, delivering hundreds of babies a year in a busy city hospital, I rarely have the opportunity to reconnect with what made me pursue the path of midwifery. This is the story of the birth of my niece. PMID- 26957892 TI - Childbirth Education Prior to Pregnancy? Survey Findings of Childbirth Preferences and Attitudes Among Young Women. AB - The childbirth preferences and attitudes of young women prior to pregnancy (N = 758) were explored in a cross-sectional survey. Sources of influential childbirth information and self-reported childbirth learning needs were described. Young women's attitudes about childbirth, including the degree of confidence in coping with a vaginal birth, whether birth is considered a natural event, and expectations of labor pain were associated with their mode of birth preference. Conversations with friends and family were the most influential source of childbirth information. Gaps in knowledge about pregnancy and birth were identified. An improved understanding of women's preferences and attitudinal profiles can inform the structure and content of educational strategies that aim to help the next generation of maternity care consumers participate in informed decision making. PMID- 26957891 TI - The Broken Thread of Health Promotion and Disease Prevention for Women During the Postpartum Period. AB - Postpartum maternal health affects maternal functional status, future pregnancy outcomes, maternal chronic disease development, and infant health. After pregnancy, however, many mothers may find that they face gaps in care related to their health and caregiving roles. Research shows that they were unprepared, uninformed, and unsupported during the postpartum period as they struggle with physical and emotional symptoms, infant caregiving, breastfeeding concerns, and lifestyle adjustments. Limited follow-up after a diagnosis of gestational hypertension or gestational diabetes and screening for postpartum depression are additional gaps in preventive and supportive care. Integrative reviews revealed modest efficacy and limitations of recent postpartum health promotion and disease prevention interventions. System, clinical, and community strategies are identified to address these gaps in women's postpartum health services. PMID- 26957893 TI - Health Professionals' Attitudes and Beliefs About Breastfeeding. AB - The aim of this descriptive study was to investigate how health-care providers perceived their role in breastfeeding and maternal support. Data was collected via interviews of 53 health-care professionals that provided care to breastfeeding women. The emerging themes included (a) understanding the benefits of breastfeeding: often lacking current knowledge, (b) lacking consistency: gaps between knowledge of benefits and actual clinical practice, (c) not knowing how to help: lack of assessment and therapeutic skills, and (d) understanding the barriers to breastfeeding: how health-care providers can make a difference. Data analysis suggests inconsistencies between the health-care provider's perceived support and behaviors, lack of knowledge, and significant lack of skill in the assessment and management of breastfeeding couples. PMID- 26957894 TI - The Development and Implementation of a Prenatal Education Program for Expectant Parents of Multiples. AB - Preparing expectant parents of multiples required a unique prenatal education program. A thorough explanation of the course layout, curriculum, and content the faculty developed for this unique 9-hour program is presented. The unique implications for parenting multiples was highlighted throughout the program, which included expectations for late pregnancy, preparation for labor and birth, assuring infant safety, learning how to provide infant care, identifying sources of support, breastfeeding information and support, potential for neonatal intensive care, postpartum depression, and providing a multiple parent's personal perspective. All classes were interactive and used active learner-based teaching strategies. PMID- 26957895 TI - An Integrative Review of Factors Influencing Breastfeeding in Adolescent Mothers. AB - The purpose of this integrative review was to describe factors that influence breastfeeding behaviors in adolescent mothers. Twenty-two articles met inclusion criteria. Findings showed that most adolescent mothers intended to breastfeed during pregnancy. Yet, breastfeeding initiation ranged from 39% to 69%. Almost half of adolescent mothers stopped within 1 month. Less than 25% continued to breastfeeding behaviors to 6 months. Factors that influenced breastfeeding decisions in adolescent mothers included social and cultural norms. Personal beliefs about being a good mother were important to intention and initiation of breastfeeding. Promoting maternal competence was found to be essential to breastfeeding initiation and continuation for adolescent mothers. Support from partners and professionals also led to positive attitudes toward breastfeeding initiation and continuation. PMID- 26957896 TI - Comparison of the Bradley Method and HypnoBirthing Childbirth Education Classes. AB - The purpose of this article is to compare and contrast two forms of childbirth education: HypnoBirthing (the Mongan Method) and the Bradley Method (husband coached natural childbirth). Evidence was obtained using a formal literature review, reading published books and workbooks on the two methods, and attending classes to document content delivered. Similarities and differences in content are reported along with birth outcomes from evaluations of the two methods. Tables with this content were formatted so that they can be used by educators and providers. PMID- 26957897 TI - Effects of a Workplace Intervention on Parent-Child Relationships. AB - This study tested whether effects of a workplace intervention, aimed at promoting employees' schedule control and supervisor support for personal and family life, had implications for parent-adolescent relationships; we also tested whether parent-child relationships differed as a function of how many intervention program sessions participants attended. Data came from a group randomized trial of a workplace intervention, delivered in the information technology division of a Fortune 500 company. Analyses focused on 125 parent-adolescent dyads that completed baseline and 12-month follow-up home interviews. Results revealed no main effects of the intervention, but children of employees who attended 75% or more program sessions reported more time with their parent and more parent education involvement compared to adolescents whose parents attended less than 75% of sessions, and they tended to report more time with parent and more parental solicitation of information about their experiences compared to adolescents whose parents were randomly assigned to the usual practice condition. PMID- 26957898 TI - Next-generation sequencing-based comprehensive molecular analysis of 43 Japanese patients with cone and cone-rod dystrophies. AB - PURPOSE: To investigate the efficacy of targeted exome sequencing for mutational screening of Japanese patients with cone dystrophy (CD) or cone-rod dystrophy (CRD). METHODS: DNA samples from 43 Japanese patients with CD or CRD were sequenced using an exome-sequencing panel targeting all 193 known inherited eye disease genes and next-generation sequencing methodologies. Subsequently, candidate variants were screened using systematic data analyses, and their potential pathogenicity was assessed using distinct filtering approaches, which included the frequency of the variants in normal populations, in silico prediction tools, and cosegregation. RESULTS: Causative mutations were detected in 12 patients with CD or CRD (27.9%). In total, 14 distinct mutations were identified in the genes ABCA4, CDHR1, CRB1, CRX, GUCY2D, KCNV2, PROM1, PRPH2, and RDH5, including four novel mutations, c.3050+1G>A in ABCA4, c.386A>G in CDHR1, c.652+1_652+4del in CRB1, and c.454G>A in KCNV2. Moreover, a putative pathogenic mutation was identified in RGS9BP, a gene recognized as the source of bradyopsia. CONCLUSIONS: Targeted exome sequencing effectively identified causative mutations in Japanese patients with CD or CRD. The results confirmed the heterogeneity of the genes responsible for CD and CRD in Japanese populations, as well as the efficacy of targeted exome sequencing-based screening of patients with inherited retinal degeneration. PMID- 26957899 TI - Exome sequencing identified null mutations in LOXL3 associated with early-onset high myopia. AB - PURPOSE: To identify null mutations in novel genes associated with early-onset high myopia using whole exome sequencing. METHODS: Null mutations, including homozygous and compound heterozygous truncations, were selected from whole exome sequencing data for 298 probands with early-onset high myopia. These data were compared with those of 507 probands with other forms of eye diseases. Null mutations specific to early-onset high myopia were considered potential candidates. Candidate mutations were confirmed with Sanger sequencing and were subsequently evaluated in available family members and 480 healthy controls. RESULTS: A homozygous frameshift mutation (c.39dup; p.L14Afs*21) and a compound heterozygous frameshift mutation (c.39dup; p.L14Afs*21 and c.594delG; p.Q199Kfs*35) in LOXL3 were separately identified in two of the 298 probands with early-onset high myopia. These mutations were confirmed with Sanger sequencing and were not detected in 1,974 alleles of the controls from the same region (507 individuals with other conditions and 480 healthy control individuals). These two probands were singleton cases, and their parents had only heterozygous mutations. A homozygous missense mutation in LOXL3 was recently reported in a consanguineous family with Stickler syndrome. CONCLUSIONS: Our results suggest that null mutations in LOXL3 are likely associated with autosomal recessive early-onset high myopia. LOXL3 is a potential candidate gene for high myopia, but this possibility should be confirmed in additional studies. LOXL3 null mutations in human beings are not lethal, providing a phenotype contrary to that in mice. PMID- 26957900 TI - A unique lineage gives rise to the meibomian gland. AB - PURPOSE: To identify the lineage that contributes to the morphogenesis of the meibomian gland. METHODS: To examine which cell lineage gives rise to the meibomian gland, the expression of Pax6 as well as that of various cytokeratin markers, including keratin 14 (Krt14), Krt15, Krt4, and Krt10, was examined with immunofluorescent staining of C57BL/6J mouse eyelids from P2 to P11 pups and adult mice. RESULTS: Pax6 was localized to the cytoplasm within the acinar region of the meibomian glands during morphogenesis but was absent in the fully developed gland. Keratin 14 was expressed throughout the gland at all stages whereas keratin 15 was absent at all stages. Keratin 4, a marker of mucosal lineage, was present throughout the gland and was colocalized with keratin 10 (epidermal lineage marker) in the developing duct at P4. This colocalization region decreased as the gland developed becoming restricted to the central duct near the opening to the acini in the fully developed gland. CONCLUSIONS: We identified a unique cell lineage that expresses markers characteristic of mucosal and epidermal epithelia during meibomian gland morphogenesis. This unique group of cells was located in the central duct with a concentration near the ductule orifice. The expression of these cells reduced during meibomian gland morphogenesis and may play a role in the development and homeostasis of the gland. PMID- 26957901 TI - Analysis of tear inflammatory mediators: A comparison between the microarray and Luminex methods. AB - PURPOSE: Inflammatory mediators have been shown to modulate dry eye (DE) disease and may correlate with disease severity, yet the methods used and the associated findings vary significantly in the literature. The goal of this research was to compare two methods, the quantitative microarray and the magnetic bead assay, for detecting cytokine levels in extracted tear samples across three subject groups. METHODS: Tears were collected from Schirmer strips of the right and left eyes of 20 soft contact lens wearers (CL), 20 normal non-contact lens wearers (NOR), and 20 DE subjects and stored at -80 degrees C. Tear proteins were eluted and precipitated using ammonium bicarbonate and acetone. The right and left eye samples were combined for each subject. Following the Bradford protein quantitation method, 10 ug of total protein was used for each of the two analyses, Quantibody(r) Human Inflammation Array 3 (RayBiotech) and High Sensitivity Human Cytokine Magnetic Bead Kit (Millipore). The assays were run using the GenePix(r) 4000B Scanner (Molecular Devices) or the Luminex MagPix(r) plate reader (Luminex), respectively. The data were then compared between the two instruments and the three subject groups. RESULTS: Of the 40 proteins on the Quantibody(r) microarray, seven had average expression levels above the lower limit of detection: ICAM-1, MCP-1, MIG, MCSF, TIMP-1, TIMP-2, and TNF-RI. Significant differences in expression levels (p<0.05) were detected between the CL and DE groups for MCSF, TIMP-1, and TNF R1, between the NOR and DE groups for ICAM-1, and between the CL and NOR groups for ICAM-1, MCP-1, MCSF, TIMP-1, TIMP 2, and TNF-R1 when using the Student t test. Of the 13 proteins tested with Luminex, IL-1beta, IL-4, IL-6, IL-7, and IL-8 had expression levels above the minimum detectable level, and these were most often detected using the Luminex assay compared to the Quantibody(r) microarray. Contrarily, IL-2, IL-12, IL-13, INF-g, and GM-CSF were detected more frequently using the Quantibody(r) microarray than the Luminex assay. Significant differences in expression levels (p<0.05) were only detected between the CL and DE groups for IL-7 and IL-8 and between the CL and NOR subjects for IL-8. CONCLUSIONS: In addition to detecting more significant differences between the subject groups, the Quantibody(r) microarray detected more inflammatory cytokines in total within the range of detection than the Luminex assay. Differences were also noted in the types of cytokines each assay could detect from the limited protein samples. Both methods offer advantages and disadvantages; therefore, these factors should be considered when determining the appropriate assay for analyzing tear protein samples. PMID- 26957902 TI - Asian Radiology Forum 2015 for Building an Asian Friendship: A Step toward the Vigorous Intersociety Collaboration in Asia. AB - According to the reports presented at the Asian Radiology Forum 2015, organized by the Korean Society of Radiology (KSR) during the Korean Congress of Radiology (KCR) in September 2015 in Seoul, there is an increasing need to promote international exchange and collaboration amongst radiology societies in Asian countries. The Asian Radiology Forum was first held by KSR and the national delegates of Asian radiological partner societies, who attended this meeting with the aim of discussing selected subjects of global relevance in radiology. In 2015, current stands, pros and cons, and future plans for inter-society collaboration between each Asian radiological partner societies were primarily discussed. The Asian radiology societies have international collaborations with each other through various activities, such as joint symposia, exchange programs, social exchange, and international membership. The advantages of continuing inter society collaboration in most of the Asian radiology societies include international speakers, diverse clinical research, and cutting edge technology; while limited range of financial and human resources, language barrier, differences in goals and expectations are claimed as disadvantages. With regard to the future, most of the Asian radiology societies focus on expanding partner societies and enhancing globalization and collaboration programs through various international meetings and exchange programs. PMID- 26957903 TI - Three-Dimensional Printing: Basic Principles and Applications in Medicine and Radiology. AB - The advent of three-dimensional printing (3DP) technology has enabled the creation of a tangible and complex 3D object that goes beyond a simple 3D-shaded visualization on a flat monitor. Since the early 2000s, 3DP machines have been used only in hard tissue applications. Recently developed multi-materials for 3DP have been used extensively for a variety of medical applications, such as personalized surgical planning and guidance, customized implants, biomedical research, and preclinical education. In this review article, we discuss the 3D reconstruction process, touching on medical imaging, and various 3DP systems applicable to medicine. In addition, the 3DP medical applications using multi materials are introduced, as well as our recent results. PMID- 26957904 TI - Advances in Multidetector CT Diagnosis of Pediatric Pulmonary Thromboembolism. AB - Although pediatric pulmonary thromboembolism is historically believed to be rare with relatively little information available in the medical literature regarding its imaging evaluation, it is more common than previously thought. Thus, it is imperative for radiologists to be aware of the most recent advances in its imaging information, particularly multidetector computed tomography (MDCT), the imaging modality of choice in the pediatric population. The overarching goal of this article is to review the most recent updates on MDCT diagnosis of pediatric pulmonary thromboembolism. PMID- 26957905 TI - Intra-Individual, Inter-Vendor Comparison of Diffusion-Weighted MR Imaging of Upper Abdominal Organs at 3.0 Tesla with an Emphasis on the Value of Normalization with the Spleen. AB - OBJECTIVE: To compare the apparent diffusion coefficient (ADC) values of upper abdominal organs with 2 different 3.0 tesla MR systems and to investigate the usefulness of normalization using the spleen. MATERIALS AND METHODS: Forty-one patients were enrolled in this prospective study, of which, 35 patients (M:F, 27:8; mean age +/- standard deviation, 62.3 +/- 12.3 years) were finally analyzed. In addition to the routine liver MR protocol, single-shot spin-echo echo-planar diffusion-weighted imaging using b values of 0, 50, 400, and 800 s/mm(2) in 2 different MR systems was performed. ADC values of the liver, spleen, pancreas, kidney and liver lesion (if present) were measured and analyzed. ADC values of the spleen were used for normalization. The Pearson correlation, Spearman correlation, paired sample t test, Wilcoxon signed rank test and Bland Altman method were used for statistical analysis. RESULTS: For all anatomical regions and liver lesions, both non-normalized and normalized ADC values from 2 different MR systems showed significant correlations (r = 0.5196-0.8488). Non normalized ADC values of both MR systems differed significantly in all anatomical regions and liver lesions (p < 0.001). However, the normalized ADC of all anatomical regions and liver lesions did not differ significantly (p = 0.065 0.661), with significantly lower coefficient of variance than that of non normalized ADC (p < 0.009). CONCLUSION: Normalization of the abdominal ADC values using the spleen as a reference organ reduces differences between different MR systems, and could facilitate consistent use of ADC as an imaging biomarker for multi-center or longitudinal studies. PMID- 26957906 TI - Assessment of Placental Stiffness Using Acoustic Radiation Force Impulse Elastography in Pregnant Women with Fetal Anomalies. AB - OBJECTIVE: We aimed to evaluate placental stiffness measured by acoustic radiation force impulse (ARFI) elastography in pregnant women in the second trimester with a normal fetus versus those with structural anomalies and non structural findings. MATERIALS AND METHODS: Forty pregnant women carrying a fetus with structural anomalies diagnosed sonographically at 18-28 weeks of gestation comprised the study group. The control group consisted of 34 healthy pregnant women with a sonographically normal fetus at a similar gestational age. Placental shear wave velocity (SWV) was measured by ARFI elastography and compared between the two groups. Structural anomalies and non-structural findings were scored based on sonographic markers. Placental stiffness measurements were compared among fetus anomaly categories. Doppler parameters of umbilical and uterine arteries were compared with placental SWV measurements. RESULTS: All placental SWV measurements, including minimum SWV, maximum SWV, and mean SWV were significantly higher in the study group than the control group ([0.86 +/- 0.2, 0.74 +/- 0.1; p < 0.001], [1.89 +/- 0.7, 1.59 +/- 0.5; p = 0.04], and [1.26 +/- 0.4, 1.09 +/- 0.2; p = 0.01]), respectively. CONCLUSION: Placental stiffness evaluated by ARFI elastography during the second trimester in pregnant women with fetuses with congenital structural anomalies is higher than that of pregnant women with normal fetuses. PMID- 26957907 TI - Efficacy and Safety of Balloon-Occluded Retrograde Transvenous Obliteration with Sodium Tetradecyl Sulfate Liquid Sclerotherapy. AB - OBJECTIVE: To evaluate the efficacy and safety of balloon-occluded retrograde transvenous obliteration (BRTO) with sodium tetradecyl sulfate (STS) liquid sclerotherapy of gastric varices. MATERIALS AND METHODS: Between February 2012 and August 2014, STS liquid sclerotherapy was performed in 17 consecutive patients (male:female = 8:9; mean age 58.6 years, range 44-86 years) with gastric varices. Retrograde venography was performed after occlusion of the gastrorenal shunt using a balloon catheter and embolization of collateral draining veins using coils or gelfoam pledgets, to evaluate the anatomy of the gastric varices. We prepared 2% liquid STS by mixing 3% STS and contrast media in a ratio of 2:1. A 2% STS solution was injected into the gastric varices until minimal filling of the afferent portal vein branch was observed (mean 19.9 mL, range 6-33 mL). Patients were followed up using computed tomography (CT) or endoscopy. RESULTS: Technical success was achieved in 16 of 17 patients (94.1%). The procedure failed in one patient because the shunt could not be occluded due to the large diameter of gastrorenal shunt. Complete obliteration of gastric varices was observed in 15 of 16 patients (93.8%) with follow-up CT or endoscopy. There was no rebleeding after the procedure. There was no procedure-related mortality. CONCLUSION: BRTO using STS liquid can be a safe and useful treatment option in patients with gastric varices. PMID- 26957908 TI - Plug-Assisted Retrograde Transvenous Obliteration for the Treatment of Gastric Variceal Hemorrhage. AB - OBJECTIVE: To evaluate the feasibility, safety, and clinical outcomes of plug assisted retrograde transvenous obliteration (PARTO) to treat gastric variceal hemorrhage in patients with portal hypertension. MATERIALS AND METHODS: From May 2012 to June 2014, 19 patients (11 men and 8 women, median age; 61, with history of gastric variceal hemorrhage; 17, active bleeding; 2) who underwent PARTO using a vascular plug and a gelfoam pledget were retrospectively analyzed. Clinical and laboratory data were examined to evaluate primary (technical and clinical success, complications) and secondary (worsening of esophageal varix [EV], change in liver function) end points. Median follow-up duration was 11 months, from 6.5 to 18 months. The Wilcoxon signed-rank test was used to compare laboratory data before and after the procedure. RESULTS: Technical success (complete occlusion of the efferent shunt and complete filling of gastric varix [GV] with a gelfoam slurry) was achieved in 18 of 19 (94.7%) patients. The embolic materials could not reach the GV in 1 patient who had endoscopic glue injection before our procedure. The clinical success rate (no recurrence of gastric variceal bleeding) was the same because the technically failed patient showed recurrent bleeding later. Acute complications included fever (n = 2), fever and hypotension (n = 2; one diagnosed adrenal insufficiency), and transient microscopic hematuria (n = 3). Ten patients underwent follow-up endoscopy; all exhibited GV improvement, except 2 without endoscopic change. Five patients exhibited aggravated EV, and 2 of them had a bleeding event. Laboratory findings were significantly improved after PARTO. CONCLUSION: PARTO is technically feasible, safe, and effective for gastric variceal hemorrhage in patients with portal hypertension. PMID- 26957909 TI - Interposition of the Posterior Cruciate Ligament into the Medial Compartment of the Knee Joint on Coronal Magnetic Resonance Imaging. AB - OBJECTIVE: The purpose of our study was to evaluate the overall prevalence and clinical significance of interposition of the posterior cruciate ligament (PCL) into the medial compartment of the knee joint in coronal magnetic resonance imaging (MRI). MATERIALS AND METHODS: We retrospectively reviewed 317 consecutive patients referred for knee MRI at our institution between October 2009 and December 2009. Interposition of the PCL into the medial compartment of the knee joint on proton coronal MRI was evaluated dichotomously (i.e., present or absent). We analyzed the interposition according to its prevalence as well as its relationship with right-left sidedness, gender, age, and disease categories (osteoarthritis, anterior cruciate ligament tear, and medial meniscus tear). RESULTS: Prevalence of interposition of PCL into the medial compartment of the knee joint was 47.0% (149/317). There was no right (50.0%, 83/166) to left (43.7%, 66/151) or male (50.3%, 87/173) to female (43.1%, 62/144) differences in the prevalence. There was no significant association between the prevalence and age, or the disease categories. CONCLUSION: Interposition of the PCL into the medial compartment of the knee joint is observed in almost half of patients on proton coronal MRI of the knee. Its presence is not associated with any particular factors including knee pathology and may be regarded as a normal MR finding. PMID- 26957910 TI - Sonographic Findings of Common Musculoskeletal Diseases in Patients with Diabetes Mellitus. AB - Diabetes mellitus (DM) can accompany many musculoskeletal (MSK) diseases. It is difficult to distinguish the DM-related MSK diseases based on clinical symptoms alone. Sonography is frequently used as a first imaging study for these MSK symptoms and is helpful to differentiate the various DM-related MSK diseases. This pictorial essay focuses on sonographic findings of various MSK diseases that can occur in diabetic patients. PMID- 26957911 TI - Risk of Thyroid Cancer in Euthyroid Asymptomatic Patients with Thyroid Nodules with an Emphasis on Family History of Thyroid Cancer. AB - OBJECTIVE: To determine the factors associated with thyroid cancer, focusing on first-degree family history and ultrasonography (US) features, in euthyroid asymptomatic patients with thyroid nodules. MATERIALS AND METHODS: This retrospective study included 1310 thyroid nodules of 1254 euthyroid asymptomatic patients who underwent US-guided fine-needle aspiration biopsy between November 2012 and August 2013. Nodule size and clinical risk factors-such as patient age, gender, first-degree family history of thyroid cancer, multiplicity on US and serum thyroid stimulating hormone (TSH) levels-were considered together with US features to compare benign and malignant nodules. Multiple logistic regression analysis was performed to assess the risk of thyroid malignancy according to clinical and US characteristics. RESULTS: Although all of the clinical factors and US findings were significantly different between patients with benign and malignant nodules, a solitary lesion on US (p = 0.041-0.043), US features and male gender (p < 0.001) were significant independent risk factors for thyroid malignancy in a multivariate analysis. Patient age, a first-degree family history of thyroid cancer and high normal serum TSH levels did not independently significantly increase the risk of thyroid cancer. However, multicollinearity existed between US assessment and patient age, first-degree family history of thyroid cancer and serum TSH values. CONCLUSION: Ultrasonography findings should be the primary criterion used to decide the management of euthyroid asymptomatic patients with thyroid nodules. The concept of first-degree family history as a risk factor for thyroid malignancy should be further studied in asymptomatic patients. PMID- 26957912 TI - Plunging Ranulas Revisited: A CT Study with Emphasis on a Defect of the Mylohyoid Muscle as the Primary Route of Lesion Propagation. AB - OBJECTIVE: The purpose of this study was to clarify the pathogenesis of plunging ranulas in regard of the pathway of lesion propagation using CT scans. MATERIALS AND METHODS: We retrospectively reviewed CT scans of 41 patients with plunging ranula. We divided plunging ranulas into two types: type 1 was defined as those directly passing through a defect of the mylohyoid muscle with the presence (type 1A) or absence (type 1B) of the tail sign and type 2 as those through the traditional posterior route along the free edge of the mylohyoid muscle. Images were also analyzed for the extent of the lesion in respect to the spaces involved. As for type 1 lesions, we recorded the location of the defect of the mylohyoid muscle and the position of the sublingual gland in relation to the defect. RESULTS: CT scans demonstrated type 1 lesion in 36 (88%), including type 1A in 14 and type 1B in 22, and type 2 lesion in 5 (12%). Irrespective of the type, the submandibular space was seen to be involved in all cases either alone or in combination with one or more adjacent spaces. Of the 36 patients with type 1 lesions, the anterior one-third was the most common location of the defect of the mylohyoid muscle, seen in 22 patients. The sublingual gland partially herniated in 30 patients. CONCLUSION: Our results suggest that the majority of plunging ranulas take an anterior shortcut through a defect of the mylohyoid muscle. PMID- 26957913 TI - Morphometric Evaluation of Bony Nasolacrimal Canal in a Caucasian Population with Primary Acquired Nasolacrimal Duct Obstruction: A Multidetector Computed Tomography Study. AB - OBJECTIVE: The bony nasolacrimal duct (BNLD) morphology as a contributory factor in primary acquired nasolacrimal duct obstruction (PANDO) is still controversial. The objectives of this study were to evaluate the morphometric differences of BNLDs in unilateral PANDO patients between PANDO and non-PANDO sides, as compared with the control group using multidetector computed tomography (CT). MATERIALS AND METHODS: Bilateral BNLDs in 39 unilateral PANDO patients and 36 control subjects were retrospectively reviewed. CT images with 0.5-mm thickness were obtained with a 64-slice scanner. The length, volume, coronal orientation type, sagittal orientation angle of BNLD, and relative lacrimal sac-BNLD angle were assessed. The entrance, minimum and distal end transverse diameters (TD) of BNLD was investigated. RESULTS: The mean minimum and distal end BNLD TDs measurements were significantly narrower in PANDO patients, both in PANDO and non-PANDO sides, as compared with the control group (p < 0.001 and p = 0.040, respectively); however, there were no significant differences between PANDO and non-PANDO sides within PANDO patients. The length, entrance TD, volume, coronal orientation type, sagittal orientation angle of BNLD, and relative lacrimal sac-BNLD angle were not significantly different between PANDO patients and control subjects, as well as between PANDO and non-PANDO sides within PANDO patients. CONCLUSION: The narrow mean minimum and distal end BNLD TD in PANDO patients, in both PANDO and non PANDO sides, may be associated with PANDO development. The lack of difference between PANDO and non-PANDO sides within PANDO patients and some overlap between PANDO patients and control subjects suggest that narrow BNLD is not the sole factor. PMID- 26957914 TI - Chlorfenapyr-Induced Toxic Leukoencephalopathy with Radiologic Reversibility: A Case Report and Literature Review. AB - Chlorfenapyr is a widely used, moderately hazardous pesticide. Previous reports have indicated that chlorfenapyr intoxication can be fatal in humans. We reported the first non-fatal case of chlorfenapyr-induced toxic leukoencephalopathy in a 44-year-old female with resolution of extensive and abnormal signal intensities in white matter tracts throughout the brain, brain stem, and spinal cord on serial magnetic resonance imaging. PMID- 26957916 TI - Uterine Intravenous Leiomyomatosis with Intracardiac Extension and Pulmonary Benign Metastases on FDG PET/CT: A Case Report. AB - A 48-year-old woman presented with a 50-day history of irregular vaginal bleeding and lower abdominal pain. Ultrasound indicated an extremely large occupying lesion in the pelvic cavity that was highly suggestive of malignancy. Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) was performed to further assess the nature of pelvic abnormality. PET/CT images demonstrated a diffusely lobulated mass ranging from cervix up to the inferior pole of kidneys with mild FDG uptake. Simultaneously, multiple nodules in bilateral lungs and a hypodense lesion in the right ventricle were shown without FDG-avidity. Based on the imaging results, the presumptive diagnosis was uterine intravenous leiomyomatosis with intracardiac extension and pulmonary benign metastases, which was subsequently confirmed by MRI and the lesion biopsy. PMID- 26957915 TI - F-18 Sodium Fluoride Positron Emission Tomography/Computed Tomography for Detection of Thyroid Cancer Bone Metastasis Compared with Bone Scintigraphy. AB - OBJECTIVE: The aim of the study was to compare the diagnostic performances of F 18 sodium fluoride positron emission tomography/computed tomography (bone PET/CT) and bone scintigraphy (BS) for the detection of thyroid cancer bone metastasis. MATERIALS AND METHODS: We retrospectively enrolled 6 thyroid cancer patients (age = 44.7 +/- 9.8 years, M:F = 1:5, papillary:follicular = 2:4) with suspected bone metastatic lesions in the whole body iodine scintigraphy or BS, who subsequently underwent bone PET/CT. Pathologic diagnosis was conducted for 4 lesions of 4 patients. RESULTS: Of the 17 suspected bone lesions, 10 were metastatic and 7 benign. Compared to BS, bone PET/CT exhibited superior sensitivity (10/10 = 100% vs. 2/10 = 20%, p = 0.008), and accuracy (14/17 = 82.4% vs. 7/17 = 41.2%, p < 0.025). The specificity (4/7 = 57.1%) of bone PET/CT was not significantly different from that of BS (5/7 = 71.4%, p > 0.05). CONCLUSION: Bone PET/CT may be more sensitive and accurate than BS for the detection of thyroid cancer bone metastasis. PMID- 26957917 TI - Broncho-Pleural Fistula with Hydropneumothorax at CT: Diagnostic Implications in Mycobacterium avium Complex Lung Disease with Pleural Involvement. AB - OBJECTIVE: To determine the patho-mechanism of pleural effusion or hydropneumothorax in Mycobacterium avium complex (MAC) lung disease through the computed tomographic (CT) findings. MATERIALS AND METHODS: We retrospectively collected data from 5 patients who had pleural fluid samples that were culture positive for MAC between January 2001 and December 2013. The clinical findings were investigated and the radiological findings on chest CT were reviewed by 2 radiologists. RESULTS: The 5 patients were all male with a median age of 77 and all had underlying comorbid conditions. Pleural fluid analysis revealed a wide range of white blood cell counts (410-100690/uL). The causative microorganisms were determined as Mycobacterium avium and Mycobacterium intracellulare in 1 and 4 patients, respectively. Radiologically, the peripheral portion of the involved lung demonstrated fibro-bullous changes or cavitary lesions causing lung destruction, reflecting the chronic, insidious nature of MAC lung disease. All patients had broncho-pleural fistulas (BPFs) and pneumothorax was accompanied with pleural effusion. CONCLUSION: In patients with underlying MAC lung disease who present with pleural effusion, the presence of BPFs and pleural air on CT imaging are indicative that spread of MAC infection is the cause of the effusion. PMID- 26957918 TI - A Pulmonary Sequestered Segment with an Aberrant Pulmonary Arterial Supply: A Case of Unique Anomaly. AB - We presented a rare case of a 64-year-old man with a combined anomaly of the bronchus and pulmonary artery that was detected incidentally. Computed tomography showed a hyperlucent, aerated sequestered segment of the right lower lung with an independent ectopic bronchus, which had no connection to the other airway. The affected segment was supplied by its own aberrant pulmonary artery branch from the right pulmonary trunk. This anomaly cannot be classified with any of the previously reported anomalies. PMID- 26957919 TI - Erratum: Noninvasive Diagnosis of Hepatocellular Carcinoma: Elaboration on Korean Liver Cancer Study Group-National Cancer Center Korea Practice Guidelines Compared with Other Guidelines and Remaining Issues. PMID- 26957920 TI - Effects of Prophylactic Ankle Supports on Vertical Ground Reaction Force During Landing: A Meta-Analysis. AB - There has been much debate on how prophylactic ankle supports (PASs) may influence the vertical ground reaction force (vGRF) during landing. Therefore, the primary aims of this meta-analysis were to systematically review and synthesize the effect of PASs on vGRF, and to understand how PASs affect vGRF peaks (F1, F2) and the time from initial contact to peak loading (T1, T2) during landing. Several key databases, including Scopus, Cochrane, Embase, PubMed, ProQuest, Medline, Ovid, Web of Science, and the Physical Activity Index, were used for identifying relevant studies published in English since inception to April 1, 2015. The computerized literature search and cross-referencing the citation list of the articles yielded 3,993 articles. Criteria for inclusion required that 1) the study was conducted on healthy adults; 2) the subject number and trial number were known; 3) the subjects performed landing with and without PAS; 4) the landing movement was in the sagittal plane; 5) the comparable vGRF parameters were reported; and 6) the F1 and F2 must be normalized to the subject's body weight. After the removal of duplicates and irrelevant articles, 6, 6, 15 and 11 studies were respectively pooled for outcomes of F1, T1, F2 and T2. This study found a significantly increased F2 (.03 BW, 95% CI: .001, .05) and decreased T1 (-1.24 ms, 95% CI: -1.77, -.71) and T2 (-3.74 ms, 95% CI: -4.83, 2.65) with the use of a PAS. F1 was not significantly influenced by the PAS. Heterogeneity was present in some results, but there was no evidence of publication bias for any outcome. These changes represented deterioration in the buffering characteristics of the joint. An ideal PAS design should limit the excessive joint motion of ankle inversion, while allowing a normal range of motion, especially in the sagittal plane. Key pointsPAS can effectively protect the ligamentous structure from spraining by providing mechanical support and cutaneous proprioceptive benefits.Using of PAS can significantly elevate F2 and reduce T1 and T2 during landing. These changes represented deterioration in the buffering characteristics of the joint.An ideal PAS design should limit the excessive joint motion of the ankle inversion, while allow normal range of motion, especially in the sagittal plane. PMID- 26957921 TI - Differences in Sensation Seeking Between Alpine Skiers, Snowboarders and Ski Tourers. AB - Despite different injury rates and injury patterns previous personality related research in the field of downhill winter sports did not subdivide between different alpine slope users. In this study, we tried to find out whether the personality trait sensation seeking differs between skiers, snowboarders and ski tourers. In a cross-sectional survey 1185 persons (726 alpine skiers, 321 snowboarders and 138 ski tourers comparable in age and sex) were electronically questioned with the sensation seeking scale (SSS-V) comprising the four factors thrill and adventure seeking, experiences seeking, disinhibition and boredom susceptibility. Kruskal-Wallis Tests revealed a significantly higher total score of the SSS-V for snowboarders in comparison to alpine skiers and ski tourers (H(2) = 41.5, p < 0.001). Ski tourers and snowboarders scored significantly higher in the dimensions "thrill- and adventure-seeking" and "experience-seeking" than alpine skiers. Furthermore, snowboarders showed higher scores in "disinhibition" related to alpine skiers and ski tourers and "boredom susceptibility" compared to alpine skiers. Data show differences in the personality trait sensation seeking in people practising different winter sports. As snowboarders showed higher SS-scores compared to alpine skiers and ski tourers prevention and information programs might benefit from a selective approach focusing on special characteristics of the respective group. Key pointsIt is the very first research trying to identify differences between different types of winter sport slope usersObtained results show higher sensation seeking scores in snowboardersThese results might stimulate new approaches in educational campaigns to reduce accident rates in winter sports. PMID- 26957922 TI - Daily Overfeeding from Protein and/or Carbohydrate Supplementation for Eight Weeks in Conjunction with Resistance Training Does not Improve Body Composition and Muscle Strength or Increase Markers Indicative of Muscle Protein Synthesis and Myogenesis in Resistance-Trained Males. AB - This study determined the effects of heavy resistance training and daily overfeeding with carbohydrate and/or protein on blood and skeletal muscle markers of protein synthesis (MPS), myogenesis, body composition, and muscle performance. Twenty one resistance-trained males were randomly assigned to either a protein + carbohydrate [HPC (n = 11)] or a carbohydrate [HC (n = 10)] supplement group in a double-blind fashion. Body composition and muscle performance were assessed, and venous blood samples and muscle biopsies were obtained before and after eight weeks of resistance training and supplementation. Data were analyzed by two-way ANOVA (p <= 0.05). Total body mass, body water, and fat mass were significantly increased in both groups in response to resistance training, but not supplementation (p < 0.05); however, lean mass was not significantly increased in either group (p = 0.068). Upper- (p = 0.024) and lower-body (p = 0.001) muscle strength and myosin heavy chain (MHC) 1 (p = 0.039) and MHC 2A (p = 0.027) were also significantly increased with resistance training. Serum IGF-1, GH, and HGF were not significantly affected (p > 0.05). Muscle total DNA, total protein, and c-Met were not significantly affected (p > 0.05). In conjunction with resistance training, the peri-exercise and daily overfeeding of protein and/or carbohydrate did not preferentially improve body composition, muscle performance, and markers indicative of MPS and myogenic activation. Key pointsIn response to 56 days of heavy resistance training and HC or HPC supplementation, similar increases in muscle mass and strength in both groups occurred; however, the increases were not different between supplement groups.The supplementation of HPC had no preferential effect on augmenting serum IGF-1 GH, or HGF.The supplementation of HPC had no preferential effect on augmenting increases in total muscle protein content or the myogenic markers, total DNA and muscle cMet content.In response to 56 days of a daily supplemental dose of 94 g of protein and 196 g of carbohydrate, the HPC group was no more effective than 312 g of carbohydrate in the HC group in increasing muscle strength and mass due to its ability to elevate serum anabolic hormones and growth factors and markers of myogenic activation of satellite cells. PMID- 26957923 TI - Effects of Loaded Squat Exercise with and without Application of Superimposed EMS on Physical Performance. AB - The aim of the present study was to investigate the effects of a multiple set squat exercise training intervention with superimposed electromyostimulation (EMS) on strength and power, sprint and jump performance. Twenty athletes from different disciplines participated and were divided into two groups: strength training (S) or strength training with superimposed EMS (S+E). Both groups completed the same training program twice a week over a six week period consisting of four sets of the 10 repetition maximum of back squats. Additionally, the S+E group had EMS superimposed to the squat exercise with simultaneous stimulation of leg and trunk muscles. EMS intensity was adjusted to 70% of individual pain threshold to ensure dynamic movement. Strength and power of different muscle groups, sprint, and vertical jump performance were assessed one week before (pre), one week after (post) and three weeks (re) following the training period. Both groups showed improvements in leg press strength and power, countermovement and squat jump performance and pendulum sprint (p < 0.05), with no changes for linear sprint. Differences between groups were only evident at the leg curl machine with greater improvements for the S+E group (p < 0.05). Common squat exercise training and squat exercise with superimposed EMS improves maximum strength and power, as well as jumping abilities in athletes from different disciplines. The greater improvements in strength performance of leg curl muscles caused by superimposed EMS with improvements in strength of antagonistic hamstrings in the S+E group are suggesting the potential of EMS to unloaded (antagonistic) muscle groups. Key pointsSimilar strength adaptations occurred after a 6 week 10 RM back squat exercise program with superimposed EMS (S+E) and 10 RM back squat exercise (S) alone.Specific adaptations for S+E at the leg curl muscles were evident.S and S+E improved SJ, CMJ and pendulum sprint performance.No improvement occurred in linear sprint performance. PMID- 26957924 TI - The Effects of Multiple-Joint Isokinetic Resistance Training on Maximal Isokinetic and Dynamic Muscle Strength and Local Muscular Endurance. AB - The transfer of training effects of multiple-joint isokinetic resistance training to dynamic exercise performance remain poorly understood. Thus, the purpose of the present study was to investigate the magnitude of isokinetic and dynamic one repetition-maximum (1RM) strength and local muscular endurance increases after 6 weeks of multiple-joint isokinetic resistance training. Seventeen women were randomly assigned to either an isokinetic resistance training group (IRT) or a non-exercising control group (CTL). The IRT group underwent 6 weeks of training (2 days per week) consisting of 5 sets of 6-10 repetitions at 75-85% of subjects' peak strength for the isokinetic chest press and seated row exercises at an average linear velocity of 0.15 m s(-1) [3-sec concentric (CON) and 3-sec eccentric (ECC) phases]. Peak CON and ECC force during the chest press and row, 1RM bench press and bent-over row, and maximum number of modified push-ups were assessed pre and post training. A 2 x 2 analysis of variance with repeated measures and Tukey's post hoc tests were used for data analysis. The results showed that 1RM bench press (from 38.6 +/- 6.7 to 43.0 +/- 5.9 kg), 1RM bent-over row (from 40.4 +/- 7.7 to 45.5 +/- 7.5 kg), and the maximal number of modified push-ups (from 39.5 +/- 13.6 to 55.3 +/- 13.1 repetitions) increased significantly only in the IRT group. Peak isokinetic CON and ECC force in the chest press and row significantly increased in the IRT group. No differences were shown in the CTL group for any measure. These data indicate 6 weeks of multiple joint isokinetic resistance training increases dynamic muscle strength and local muscular endurance performance in addition to specific isokinetic strength gains in women. Key pointsMultiple-joint isokinetic resistance training increases dynamic maximal muscular strength, local muscular endurance, and maximal isokinetic strength in women.Multiple-joint isokinetic resistance training increased 1RM strength in the bench press (by 10.2%), bent-over barbell row (by 11.2%), and maximal modified push-up performance (by 28.6%) indicating a carryover of training effects to dynamic exercise performance.The carryover effects may be attractive to strength training and conditioning professionals seeking to include alternative modalities such as multiple-joint isokinetic dynamometers to resistance training programs. PMID- 26957925 TI - Effects of Cycling Versus Running Training on Sprint and Endurance Capacity in Inline Speed Skating. AB - The purpose of this study was to compare the effects of running versus cycling training on sprint and endurance capacity in inline speed skating. Sixteen elite athletes (8 male, 8 female, 24 +/- 8 yrs) were randomly assigned into 2 training groups performing either 2 session per week of treadmill running or ergometer cycling in addition to 3 skating specific sessions (technique, plyometrics, parkour) for 8 weeks. Training intensity was determined within non-specific (cycling or running) and effects on specific endurance capacity within a specific incremental exercise test. Before and after the intervention all athletes performed a specific (300m) and one non-specific (30s cycling or 200m running) all-out sprint test according to the group affiliation. To determine the accumulation of blood lactate (BLa) and glucose (BGL) 20 MUl arterialized blood was drawn at rest, as well as in 1 min intervals for 10 min after the sprint test. The sport-specific peak oxygen uptake (VO2 peak) was significantly increased (+17%; p = 0.01) in both groups and highly correlated with the sprint performance (r = -0.71). BLa values decreased significantly (-18%, p = 0.02) after the specific sprint test from pre to post-testing without any group effect. However, BGL values only showed a significant decrease (-2%, p = 0.04) in the running group. The close relationship between aerobic capacity and sprint performance in inline speed skating highlights the positive effects of endurance training. Although both training programs were equally effective in improving endurance and sprint capacities, the metabolic results indicate a faster recovery after high intensity efforts for all athletes, as well as a higher reliance on the fat metabolism for athletes who trained in the running group. Key pointsIn addition to a highly developed aerobic performance inline speed skaters also require a highly trained anaerobic capacity to be effective in the sprint sections such as the mass start, tactical attacks and finish line sprint.An 8 week low-intensity endurance training program of either cycling or running training combined with additional routine training improves classical aerobic characteristics (17% increase of VO2 peak), as well as values for acceleration and speed.Athletes who trained in the running group demonstrated a higher reliance on the fat metabolism in the sport-specific post-testing.The significant reduction in anaerobic ATP turnover during repeated sprints appears to be partially compensated by an increase in VO2 in subsequent sprint. The results revealed a close relationship between the aerobic capacity and sprint performance in inline speed skating. PMID- 26957926 TI - Acute Effects of Foot Rotation in Healthy Adults during Running on Knee Moments and Lateral-Medial Shear Force. AB - As runners age, the likelihood of developing osteoarthritis (OA) significantly increases as 10% of people 55+ have symptomatic knee OA while 70% of people 65+ have radiographic signs of knee OA. The lateral-medial shear force (LMF) and knee adduction moment (KAM) during gait have been associated with cartilage loading which can lead to OA. Foot rotation during gait has been shown to alter the LMF and KAM, however it has not been investigated in running. The purpose of this study was to investigate changes in the KAM and LMF with foot rotation during running. Twenty participants volunteered and performed five running trials in three randomized conditions (normal foot position [NORM], external rotation [EXT], and internal rotation [INT]) at a running speed of 3.35m.s(-1) on a 20 meter runway. Kinematic and kinetic data were gathered using a 9-camera motion capture system and a force plate, respectively. Repeated measures ANOVAs determined differences between conditions. The KAM and LMF were lower in both EXT and INT conditions compared to the NORM, but there were no differences between EXT and INT conditions. The decreases in KAM and LMF in the EXT condition were expected and concur with past research in other activities. The reductions in the INT condition were unexpected and contradict the literature. This may indicate that participants are making mechanical compensations at other joints to reduce the KAM and LMF in this abnormal internal foot rotation condition. Key pointsExternal rotation of the foot during running reduced the loads on the medial compartment of the kneeInternal rotation of the foot also reduced the medial loads, but is a more unnatural interventionExternal and internal rotation reduced the shear forces on the knee, which may help slow the degeneration of knee joint cartilage. PMID- 26957927 TI - Professional Soccer Player Neuromuscular Responses and Perceptions to Acute Whole Body Vibration Differ from Amateur Counterparts. AB - Acute whole body vibration (WBV) is an increasingly popular training technique amongst athletes immediately prior to performance and during scheduled breaks in play. Despite its growing popularity, evidence to demonstrate its effectiveness on acute neuromuscular responses is unclear, and suggestions that athlete ability impacts effectiveness warrant further investigation. The purpose of this study was to compare the neuromuscular effects of acute WBV and perceptions of whether WBV is an effective intervention between amateur and professional soccer players. Participants were 44 male soccer players (22 professional and 22 amateur; age: 23.1 +/- 3.7 years, body mass: 75.6 +/- 8.8 kg and height: 1.77 +/- 0.05 m). Participants in each group were randomly assigned to either an intervention of 3 x 60 s of WBV at 40 Hz (8mm peak-to-peak displacement) or control group. Peak knee isometric force, muscle activation and post activation potentiation (PAP) of the knee extensors along with self-report questionnaire of the perceived benefits of using the intervention were collected. A three-way ANOVA with repeated measures revealed professional players demonstrated a significant 10.6% increase (p < 0.01, Partial Eta(2) = 0.22) in peak knee isometric force following acute WBV with no significant differences among amateur players. A significant difference (p < 0.01, Partial Eta(2) = 0.16) in PAP amongst professional players following acute WBVT was also reported. No significant differences amongst amateur players were reported across measurements. Results also indicated professional players reported significantly stronger positive beliefs in the effectiveness of the WBV intervention (p < 0.01, Partial Eta(2) = 0.27) compared to amateur players. Acute WBV elicited a positive neuromuscular response amongst professional players identified by PAP and improvements in knee isometric peak force as well as perceived benefits of the intervention, benefits not found among amateur players. Key pointsAcute WBV improves knee extensor peak isometric force output and PAP amongst professional and not amateur soccer playersProfessional players perceived acute WBV as more beneficial to performance than amateur playersIsometric strength,vibration intensity and duration appear to influence results amongst players of different playing levels. PMID- 26957928 TI - Effects of a Stretching Development and Maintenance Program on Hamstring Extensibility in Schoolchildren: A Cluster-Randomized Controlled Trial. AB - The main purpose of the present study was to examine the effects of a physical education-based stretching development and maintenance program on hamstring extensibility in schoolchildren. A sample of 150 schoolchildren aged 7-10 years old from a primary school participated in the present study (140 participants were finally included). The six classes balanced by grade were cluster randomly assigned to the experimental group 1 (n = 51), experimental group 2 (n = 51) or control group (n = 49) (i.e., a cluster randomized controlled trial design was used). During the physical education classes, the students from the experimental groups 1 and 2 performed a four-minute stretching program twice a week for nine weeks (first semester). Then, after a five-week period of detraining coinciding with the Christmas holidays, the students from the experimental groups 1 and 2 completed another stretching program twice a week for eleven weeks (second semester). The students from the experimental group 1 continued performing the stretching program for four minutes while those from the experimental group 2 completed a flexibility maintenance program for only one minute. The results of the two-way analysis of variance showed that the physical education-based stretching development program significantly improved the students' hamstring extensibility (p < 0.001), as well as that these gains obtained remained after the stretching maintenance program (p < 0.001). Additionally, statistically significant differences between the two experimental groups were not found (p > 0.05). After a short-term stretching development program, a physical education based stretching maintenance program of only one-minute sessions twice a week is effective in maintaining hamstring extensibility among schoolchildren. This knowledge could help and guide teachers to design programs that allow a feasible and effective development and maintenance of students' flexibility in the physical education setting. Key pointsA physical education-based stretching maintenance program of only one-minute sessions twice a week is effective in maintaining hamstring extensibility among schoolchildren.A four-minute maintenance program shows similar effects that the one-minute maintenance program on hamstring extensibility among schoolchildren.Physical education teachers and other practitioners could carry out one-minute programs for a feasible and effective maintenance of students' flexibility. PMID- 26957929 TI - Use of Ultrasound to Monitor Biceps Femoris Mechanical Adaptations after Injury in a Professional Soccer Player. AB - This study examined the use of ultrasound to monitor changes in the long head of the biceps femoris (BF) architecture of aprofessional soccer player with acute first-time hamstring strain. The player followed a 14 session physiotherapy treatment until return to sport. The pennation angle and aponeurosis strain of the long head of the biceps femoris (BF) were monitored at 6 occasions (up until 1 year) after injury. The size of the scar / hematoma was reduced by 63.56% (length) and 67.9% (width) after the intervention and it was almost non-traceable one year after injury. The pennation angle of the fascicles underneath the scar showed a decline of 51.4% at the end of the intervention while an increase of 109.2% of the fascicles which were closer to deep aponeurosis was observed. In contrast, pennation angle of fascicles located away from the injury site were relatively unaffected. The treatment intervention resulted in a 57.9% to 77.3% decline of maximum strain per unit of MVC moment and remained similar one year after the intervention. This study provided an example of the potential use of ultrasound-based parameters to link the mechanical adaptations of the injured muscle to specific therapeutic intervention. Key pointsChanges in fascicle orientation after biceps femoris mild tear were reduced after a 28 day intervention and remained similar one year after injury.Tendon/aponeurosis strain per unit of moment of force decreased during the course of the therapeutic intervention.Future studies could utilize ultrasonography to monitor mechanical responses after various types of hamstring injury and interventions in order to improve criteria for a safe return to sport. PMID- 26957930 TI - Acute Physiological Responses to Short- and Long-Stage High-Intensity Interval Exercise in Cardiac Rehabilitation: A Pilot Study. AB - Despite described benefits of aerobic high-intensity interval exercise (HIIE), the acute responses during different HIIE modes and associated health risks have only been sparsely discovered in heart disease patients. Therefore, the aim of this study was to investigate the acute responses for physiological parameters, cardiovascular and inflammatory biomarkers, and catecholamines yielded by two different aerobic HIIE protocols compared to continuous exercise (CE) in phase III cardiac rehabilitation. Eight cardiac patients (7 with coronary heart disease, 1 with myocarditis; 7 males, 1 female; age: 63.0 +/- 9.4 years; height: 1.74 +/- 0.05 m; weight: 83.6 +/- 8.7 kg), all but one treated with beta-blocking agents, performed a maximal symptom-limited incremental exercise test (IET) and three different exercise tests matched for mean load (Pmean) and total duration: 1) short HIIE with a peak workload duration (tpeak) of 20 s and a peak workload (Ppeak) equal to the maximum power output (Pmax) from IET; 2) long HIIE with a tpeak of 4 min, Ppeak was corresponding to the power output at 85 % of maximal heart rate (HRmax) from IET; 3) CE with a target workload equal to Pmean of both HIIE modes. Acute metabolic and peak cardiorespiratory responses were significantly higher during long HIIE compared to short HIIE and CE (p < 0.05) except HRpeak which tended to be higher in long HIIE than in short HIIE (p = 0.08). Between short HIIE and CE, no significant difference was found for any parameter. Acute responses of cardiovascular and inflammatory biomarkers and catecholamines didn't show any significant difference between tests (p > 0.05). All health-related variables remained in a normal range in any test except NT proBNP, which was already elevated at baseline. Despite a high Ppeak particularly in short HIIE, both HIIE modes were as safe and as well tolerated as moderate CE in cardiac patients by using our methodological approach. Key pointsHigh intensity interval exercise (HIIE) with short peak workload durations (tpeak) induce a lower acute metabolic and peak cardiorespiratory response compared to intervals with long tpeak despite higher peak workload intensities and identical mean load. No significant difference for any physiological parameter was found between short HIIE and CE.Between short HIIE, long HIIE, and CE, no significant difference was found in the increase (or decrease, respectively,) of health related markers such as cardiovascular biomarkers, catecholamines, or inflammatory parameters during exercise.During all exercise modes, all risk markers remained in a normal range except for NT-proBNP which was, however, already elevated at baseline.Short HIIE, long HIIE, and CE were safely performed by patients with CHD or myocarditis in cardiac rehabilitation by using our methodological approach to exercise prescription. This approach included the prescription of exercise intensities with respect to LTP1, LTP2, and Pmax as well as a conscious setting of Pmean at a moderate level (80 % of PLTP2). Importantly, all exercise modes were matched for Pmean and exercise duration in order to enable a comparison of the three protocols. PMID- 26957931 TI - A Kinematic Analysis of the Jumping Front-Leg Axe-Kick in Taekwondo. AB - The jumping front-leg axe-kick is a valid attacking and counterattacking technique in Taekwondo competition (Streif, 1993). Yet, the existing literature on this technique is sparse (Kloiber et al., 2009). Therefore, the goal of this study was to determine parameters contributing significantly to maximum linear speed of the foot at impact. Parameters are timing of segment and joint angular velocity characteristics and segment lengths of the kicking leg. Moreover, we were interested in the prevalence of proximal-to-distal-sequencing. Three dimensional kinematics of the kicks of 22 male Taekwondo-athletes (age: 23.3 +/- 5.3 years) were recorded via a motion capturing system (Vicon Motion Systems Limited, Oxford, UK). The participants performed maximum effort kicks onto a rack held kicking pad. Only the kick with the highest impact velocity was analysed, as it was assumed to represent the individual's best performance. Significant Pearson correlations to impact velocity were found for pelvis tilt angular displacement (r = 0.468, p < 0.05) and for hip extension angular velocity (r = 0.446, p < 0.05) and for the timing of the minima of pelvis tilt velocity (r = 0.426, p < 0.05) and knee flexion velocity (r = -0.480, p < 0.05). Backward step linear regression analysis suggests a model consisting of three predictor variables: pelvis tilt angular displacement, hip flexion velocity at target contact and timing of pelvic tilt angular velocity minimum (adjusted R(2) = 0.524). Results of Chi-Squared tests show that neither for the leg-raising period (chi(2) = 2.909) of the technique, nor for the leg-lowering period a pattern of proximal-to-distal sequencing is prevalent (chi(2) = 0.727). From the results we conclude that the jumping front-leg axe-kick does not follow a proximal-to-distal pattern. Raising the leg early in the technique and apprehending the upper body to be leant back during the leg-lowering period seems to be beneficial for high impact velocity. Furthermore, striking by extending the hip rather than by flexing the knee could raise impact velocity. Key pointsAngular velocity characteristics of the pelvis segment and the kicking leg's hip and knee joint show no proximal-to-distal sequencing, neither for the leg-raising or leg lowering period in a jumping front-leg axe-kick.Anthropometric parameters of taekwondo athlete's do not influence their impact velocities.In order to raise the impact velocity in the jumping front-leg axe-kick an athlete should avoid tilting back with the torso. Instead, an upright position should be maintained.In the leg-lowering period, we suggest hitting the target by using hip extension with a rather straight knee, instead of flexing the knee. PMID- 26957932 TI - Assessing Motor Skill Competency in Elementary School Students: A Three-Year Study. AB - This study was to examine how well fourth- and fifth-grade students demonstrated motor skill competency assessed with selected PE Metrics assessment rubrics (2009). Fourth- and fifth-grade students (n = 1,346-1,926) were assessed on their performance of three manipulative skills using the PE Metrics Assessment Rubrics during the pre-intervention year, the post-intervention year 1, and the post intervention year 3. Descriptive statistics, independent t-test, ANOVA, and follow-up comparisons were conducted for data analysis. The results indicated that the post-intervention year 2 cohort performed significantly more competent than the pre-intervention cohort and the post-intervention year 1 cohort on the three manipulative skill assessments. The post-intervention year 1 cohort significantly outperformed the pre-intervention cohort on the soccer dribbling, passing, and receiving and the striking skill assessments, but not on the throwing skill assessment. Although the boys in the three cohorts performed significantly better than the girls on all three skills, the girls showed substantial improvement on the overhand throwing and the soccer skills from baseline to the post-intervention year 1 and the post-intervention year 2. However, the girls, in particular, need to improve striking skill. The CTACH PE was conducive to improving fourth- and fifth-grade students' motor skill competency in the three manipulative skills. This study suggest that PE Metrics assessment rubrics are feasible tools for PE teachers to assess levels of students' demonstration of motor skill competency during a regular PE lesson. Key pointsCATCH PE is an empirically-evidenced quality PE curricular that is conducive to improving students' manipulative skill competency.Boys significantly outperformed than girls in all three manipulative skills.Girls need to improve motor skill competency in striking skill. PE Metrics are feasible assessment rubrics that can be easily used by trained physical education teachers to assess students' manipulative skill competency. PMID- 26957933 TI - Comparison Between Pre-Exhaustion and Traditional Exercise Order on Muscle Activation and Performance in Trained Men. AB - The purpose of this study was to measure the acute effects of pre-exhaustion vs. traditional exercise order on neuromuscular performance and sEMG in trained men. Fourteen young, healthy, resistance trained men (age: 25.5 +/- 4.0 years, height: 174.9 +/- 4.1 cm, and total body mass: 80.0 +/- 11.1 kg) took part of this study. All tests were randomized and counterbalanced for all subjects and experimental conditions. Volunteers attended one session in the laboratory. First, they performed ten repetition maximum (10RM) tests for each exercise (bench press and triceps pushdown) separately. Secondly, they performed all three conditions at 10RM: pre-test (bench press and triceps pushdown, separately), pre-exhaustion (triceps pushdown+bench press, PE) and traditional (bench press+triceps pushdown, TR), and rested 30 minutes between conditions. Results showed that pre-test was significantly greater than PE (p = 0.031) but not different than TR, for total volume load lifted. There was a significant difference between the pre-test and the time-course of lactate measures (p = 0.07). For bench press muscle activity of the pectoralis major, the last repetition was significantly greater than the first repetition (pre-test: p = 0.006, PE: p = 0.016, and TR: p = 0.005). Also, for muscle activity of the triceps brachii, the last repetition was significantly greater than the first repetition (pre-test: p = 0.001, PE: p = 0.005, and TR: p = 0.006). For triceps pushdown, muscle activity of the triceps brachii, the last repetition was significantly greater than the first repetition (pre-test: p = 0.006, PE: p = 0.016, and TR: p = 0.005). For RPE, there were no significant differences between PE and TR (p = 0.15). Our results suggest that exercise order decreases repetitions performed, however, neuromuscular fatigue, lactate, and RPE are not impacted. The lack of difference in total volume load lifted between PE and TR might explain, at least in part, the similar metabolic and perceptual responses. Key pointsThe effects of different exercise order schemes (e.g. PE and TR) on muscle activity and strength performance indicated that similar responses were observed when comparing these schemes.Strength and conditioning coaches should consider these results when prescribing resistance training programs.The primary target (e.g. muscle group) of the training session should trained first, when fatigue level low, in order to maximize training outcomes. PMID- 26957934 TI - Short Duration Heat Acclimation in Australian Football Players. AB - This study examined if five sessions of short duration (27 min), high intensity, interval training (HIIT) in the heat over a nine day period would induce heat acclimation in Australian football (AF) players. Fourteen professional AF players were matched for VO2peak (mL.kg(-1).min(-1)) and randomly allocated into either a heat acclimation (Acc) (n = 7) or Control (Con) group (n = 7). The Acc completed five cycle ergometer HIIT sessions within a nine day period on a cycle ergometer in the heat (38.7 +/- 0.5 degrees C; 34.4 +/- 1.3 % RH), whereas Con trained in thermo-neutral conditions (22.3 +/- 0.2 degrees C; 35.8 +/- 0. % RH). Four days prior and two days post HIIT participants undertook a 30 min constant load cycling test at 60% VO2peak in the heat (37.9 +/- 0.1 degrees C; 28.5 +/- 0.7 % RH) during which VO2, blood lactate concentration ([Lac(-)]), heart rate (HR), rating of perceived exertion (RPE), thermal comfort, core and skin temperatures were measured. Heat acclimation resulted in reduced RPE, thermal comfort and [Lac(-)] (all p < 0.05) during the submaximal exercise test in the heat. Heart rate was lower (p = 0.007) after HIIT, in both groups. Heat acclimation did not influence any other measured variables. In conclusion, five short duration HIIT sessions in hot dry conditions induced limited heat acclimation responses in AF players during the in-season competition phase. In practice, the heat acclimation protocol can be implemented in a professional team environment; however the physiological adaptations resulting from such a protocol were limited. Key pointsSome minor heat acclimation adaptations can be induced in professional AF players with five 27 min non-consecutive, short duration HIIT sessions in the heat.The heat acclimation protocol employed in this study was able to be implemented in a professional team sport environment during an actual competitive season.Elevating and maintaining a high core temperature sufficient for heat acclimation likely requires a longer heat training session or some pre-heating prior to exercise. PMID- 26957935 TI - The Total Work Measured During a High Intensity Isokinetic Fatigue Test Is Associated With Anaerobic Work Capacity. AB - The purpose of the study was to determine whether total work measured during a high intensity isokinetic fatigue test (TWFAT) could be considered as a valid measure of anaerobic work capacity (AWC), such as determined by total work measured during a Wingate Anaerobic Test (TWWAnT). Twenty well-trained cyclists performed 2 randomly ordered sessions involving a high intensity isokinetic fatigue test consisting in 30 reciprocal maximal concentric contractions of knee flexors and extensors at 180 degrees .s(-1), and a Wingate Anaerobic Test. We found that TWFAT of knee extensors was largely lower than TWWAnT (4151 +/- 691 vs 22313 +/- 2901 J, respectively, p < 0.05, Hedge's g = 4.27). Both measures were highly associated (r = 0.83), and the 95% limits of agreement (LoA) represented 24.5% of TWWAnT. TWFAT of knee flexors (2151 +/- 540 J) was largely lower than TWWAnT (p < 0.05, g = 9.52). By contrast, both measures were not associated (r = 0.09), and the 95% LoA represented 31.1% of TWWAnT. Combining TWFAT of knee flexors and knee extensors into a single measure (6302 +/- 818 J) did not changed neither improved these observations. We still found a large difference with TWWAnT (p < 0.05, g = 5.26), a moderate association (r = 0.65) and 95% LoA representing 25.5% of TWWAnT. We concluded that TWFAT of knee extensors could be considered as a valid measure of AWC, since both measure were highly associated. However, the mean difference between both measures and their 95% LoA were too large to warrant interchangeability. Key pointsTotal work performed during a high intensity isokinetic fatigue test can be considered as a valid measure of anaerobic work capacity (as determined by total work performance during a 30-s Wingate anaerobic test).The 95% limits of agreement are two large to allow a direct comparison between both measures. In other words, it is not possible to estimate the magnitude of performance improvement during a 30-s Wingate anaerobic test from that observed during a high intensity isokinetic fatigue test.In addition to provide sport scientists and coaches with measures of peak torque and ratios between agonists and antagonists muscles in a perspective of injury prevention, isokinetic dynamometry can also be used in the physiological assessment of athletes. However, some precautions should be taken in the interpretation of data. PMID- 26957936 TI - Using Mean Absolute Relative Phase, Deviation Phase and Point-Estimation Relative Phase to Measure Postural Coordination in a Serial Reaching Task. AB - The objectives of this communication are to present the methods used to calculate mean absolute relative phase (MARP), deviation phase (DP) and point estimate relative phase (PRP) and compare their utility in measuring postural coordination during the performance of a serial reaching task. MARP and DP are derived from continuous relative phase time series representing the relationship between two body segments or joints during movements. MARP is a single measure used to quantify the coordination pattern and DP measures the stability of the coordination pattern. PRP also quantifies coordination patterns by measuring the relationship between the timing of maximal or minimal angular displacements of two segments within cycles of movement. Seven young adults practiced a bilateral serial reaching task 300 times over 3 days. Relative phase measures were used to evaluate inter-joint relationships for shoulder-hip (proximal) and hip-ankle (distal) postural coordination at early and late learning. MARP, PRP and DP distinguished between proximal and distal postural coordination. There was no effect of practice on any of the relative phase measures for the group, but individual differences were seen over practice. Combined, MARP and DP estimated stability of in-phase and anti-phase postural coordination patterns, however additional qualitative movement analyses may be needed to interpret findings in a serial task. We discuss the strengths and limitations of using MARP and DP and compare MARP and DP to PRP measures in assessing coordination patterns in the context of various types of skillful tasks. Key pointsMARP, DP and PRP measures coordination between segments or joint anglesAdvantages and disadvantages of each measure should be considered in relationship to the performance taskMARP and DP may capture coordination patterns and stability of the patterns during discrete tasks or phases of movements within a taskPRP and SD or PRP may capture coordination patterns and stability during continuous oscillating movement tasks. PMID- 26957937 TI - The Acute Effect of Local Vibration As a Recovery Modality from Exercise-Induced Increased Muscle Stiffness. AB - Exercise involving eccentric muscle contractions is known to decrease range of motion and increase passive muscle stiffness. This study aimed at using ultrasound shear wave elastography to investigate acute changes in biceps brachii passive stiffness following intense barbell curl exercise involving both concentric and eccentric contractions. The effect of local vibration (LV) as a recovery modality from exercise-induced increased stiffness was further investigated. Eleven subjects performed 4 bouts of 10 bilateral barbell curl movements at 70% of the one-rep maximal flexion force. An arm-to-arm comparison model was then used with one arm randomly assigned to the passive recovery condition and the other arm assigned to the LV recovery condition (10 min of 55 Hz vibration frequency and 0.9-mm amplitude). Biceps brachii shear elastic modulus measurements were performed prior to exercise (PRE), immediately after exercise (POST-EX) and 5 min after the recovery period (POST-REC). Biceps brachii shear elastic modulus was significantly increased at POST-EX (+53 +/- 48%; p < 0.001) and POST-REC (+31 +/- 46%; p = 0.025) when compared to PRE. No differences were found between passive and LV recovery (p = 0.210). LV as a recovery strategy from exercise-induced increased muscle stiffness was not beneficial, probably due to an insufficient mechanical action of vibrations. Key pointsBouts of barbell curl exercise induce an immediate increased passive stiffness of the biceps brachii muscle, as evidenced by greater shear elastic modulus measured by supersonic shear imaging.The administration of a vibratory massage did not reduce this acute exercise-induced increased stiffness. PMID- 26957938 TI - Limitations of Spectral Electromyogramic Analysis to Determine the Onset of Neuromuscular Fatigue Threshold during Incremental Ergometer Cycling. AB - Recently, a new method has been proposed to detect the onset of neuromuscular fatigue during an incremental cycling test by assessing the changes in spectral electromyographic (sEMG) frequencies within individual exercise periods of the test. The method consists on determining the highest power output that can be sustained without a significant decrease in spectral frequencies. This study evaluated the validity of the new approach by assessing the changes in spectral indicators both throughout the whole test and within individual exercise periods of the test. Fourteen cyclists performed incremental cycle ergometer rides to exhaustion with bipolar surface EMG signals recorded from the vastus lateralis. The mean and median frequencies (Fmean and Fmedian, respectively) of the sEMG power spectrum were calculated. The main findings were: (1) Examination of spectral indicators within individual exercise periods of the test showed that neither Fmean nor Fmedian decreased significantly during the last (most fatiguing) exercise periods. (2) Examination of the whole incremental test showed that the behaviour of Fmean and Fmedian with increasing power output was highly inconsistent and varied greatly among subjects. (3) Over the whole incremental test, half of the participants exhibited a positive relation between spectral indicators and workload, whereas the other half demonstrated the opposite behavior. Collectively, these findings indicate that spectral sEMG indexes do not provide a reliable measure of the fatigue state of the muscle during an incremental cycling test. Moreover, it is concluded that it is not possible to determine the onset of neuromuscular fatigue during an incremental cycling test by examining spectral indicators within individual exercise periods of the test. Key pointsThe behaviour of spectral EMG indicators during the incremental test exhibited a high heterogeneity among individuals, with approximately half of the participants showing a positive relation between spectral indicators and workload and the other half showing the opposite behaviour.None of the spectral EMG indicators examined (Fmean nor Fmedian) decreased significantly between the ventilatory threshold and the highest power output.Examination of spectral indicators within individual exercise periods of the test showed that neither Fmean nor Fmedian decreased significantly during the last (most fatiguing) exercise periods. PMID- 26957939 TI - Reliability of Three-Dimensional Angular Kinematics and Kinetics of Swimming Derived from Digitized Video. AB - The purpose of this study was to explore the reliability of estimating three dimensional (3D) angular kinematics and kinetics of a swimmer derived from digitized video. Two high-level front crawl swimmers and one high level backstroke swimmer were recorded by four underwater and two above water video cameras. One of the front crawl swimmers was digitized at 50 fields per second with a window for smoothing by a 4(th) order Butterworth digital filter extending 10 fields beyond the start and finish of the stroke cycle (FC1), while the other front crawl (FC2) and backstroke (BS) swimmer were digitized at 25 frames per second with the window extending five frames beyond the start and finish of the stroke cycle. Each camera view of one stroke cycle was digitized five times yielding five independent 3D data sets from which whole body centre of mass (CM) yaw, pitch, roll, and torques were derived together with wrist and ankle moment arms with respect to an inertial reference system with origin at the CM. Coefficients of repeatability ranging from r = 0.93 to r = 0.99 indicated that both digitising sampling rates and extrapolation methods are sufficiently reliable to identify real differences in net torque production. This will enable the sources of rotations about the three axes to be explained in future research. Errors in angular kinematics and displacements of the wrist and ankles relative to range of motion were small for all but the ankles in the X (swimming) direction for FC2 who had a very vigorous kick. To avoid large errors when digitising the ankles of swimmers with vigorous kicks it is recommended that a marker on the shank could be used to calculate the ankle position based on the known displacements between knee, shank, and ankle markers. Key pointsUsing the methods described, an inverse dynamics approach based on 3D position data digitized manually from multiple camera views above and below the water surface is sufficiently reliable to yield insights regarding torque production in swimming additional to those of other approaches.The ability to link the torque profiles to swimming actions and technique is enhanced by having additional data such as wrist and ankle displacements that can be obtained readily from the digitized data.An additional marker on the shank should be used to improve accuracy and reliability of calculating the ankle motion for swimmers with a vigorous kick. PMID- 26957940 TI - Investigating the Contextual Interference Effect Using Combination Sports Skills in Open and Closed Skill Environments. AB - This study attempted to present conditions that were closer to the real-world setting of team sports. The primary purpose was to examine the effects of blocked, random and game-based training practice schedules on the learning of the field hockey trap, close dribble and push pass that were practiced in combination. The secondary purpose was to investigate the effects of predictability of the environment on the learning of field hockey sport skills according to different practice schedules. A game-based training protocol represented a form of random practice in an unstable environment and was compared against a blocked and a traditional random practice schedule. In general, all groups improved dribble and push accuracy performance during the acquisition phase when assessed in a closed environment. In the retention phase, there were no differences between the three groups. When assessed in an open skills environment, all groups improved their percentage of successful executions for trapping and passing execution, and improved total number of attempts and total number of successful executions for both dribbling and shooting execution. Between-group differences were detected for dribbling execution with the game based group scoring a higher number of dribbling successes. The CI effect did not emerge when practicing and assessing multiple sport skills in a closed skill environment, even when the skills were practiced in combination. However, when skill assessment was conducted in a real-world situation, there appeared to be some support for the CI effect. Key pointsThe contextual interference effect was not supported when practicing several skills in combination when the sports skills were assessed in a closed skill environment.There appeared to be some support for the contextual interference effect when sports skills were assessed in an open skill environment, which were similar to a real game situation.A game based training schedule can be used as an alternative practice schedule as it displayed superior learning compared to a blocked practice schedule when assessed by the game performance test (real-world setting). The game-based training schedule also matched the blocked and random practice schedules in the other tests. PMID- 26957941 TI - Effects of Short-Term Docosahexaenoic Acid Supplementation on Markers of Inflammation after Eccentric Strength Exercise in Women. AB - The omega-3 fatty acid docosahexaenoic acid (DHA) has anti-inflammatory and anti nociceptive (pain inhibiting) effects. Because strenuous exercise often results in local inflammation and pain, we hypothesized that DHA supplementation attenuates the rise in markers of local muscle inflammation and delayed onset muscle soreness (DOMS) that occur after eccentric strength exercise. Twenty seven, healthy women (33 +/- 2 y, BMI 23.1+/-1.0 kg.m(-2)) were randomized to receive 9d of 3000 mg/d DHA or placebo in a double-blind fashion. On day 7 of the supplementation period, the participants performed 4 sets of maximal-effort eccentric biceps curl exercise. Before and 48h after the eccentric exercise, markers of inflammation were measured including measures of muscle soreness (10 point visual analog pain scale, VAS), swelling (arm circumference), muscle stiffness (active and passive elbow extension), skin temperature, and salivary C reactive protein (CRP) concentrations. As expected, muscle soreness and arm circumference increased while active and passive elbow extension decreased. The increase in soreness was 23% less in the DHA group (48h increase in VAS soreness ratings: 4.380.4 vs. 5.600.5, p=0.02). Furthermore, the number of subjects who were able to achieve full active elbow extension 48h after eccentric exercise was greater in the DHA group (71% vs. 15%, p = 0.006), indicating significantly less muscle stiffness. No between-group differences were observed for passive elbow extension (p = 0.78) or arm swelling (p = 0.75). Skin temperature and salivary CRP concentrations did not change from baseline to 48h after exercise in either group. These findings indicate that short-term DHA supplementation reduces exercise-induced muscle soreness and stiffness. Therefore, in addition to other health benefits that n-3 fatty acids have been associated with, DHA supplementation could be beneficial for improving tolerance to new and/or strenuous exercise programs and thereby might facilitate better training adaptations and exercise adherence. Key pointsSeven days of 3000 mg/day supplementation with algae-derived docosahexaenoic acid (DHA) attenuates the delayed onset muscle soreness and stiffness, and protects against the loss of joint range of motion that is caused by strenuous eccentric exercise.This benefit was observed in women, and supports the findings from other studies that were conducted on men or a combination of men and womenThe benefits from algae-derived DHA appear to be similar to those reported in other studies that used a combination of DHA and eicosapentaenoic acid (EPA) derived from fish oilThe findings of better recovery from strenuous exercise with DHA supplementation, paired with other research which demonstrated that DHA and EPA protect against chronic diseases suggest that DHA is an attractive optionThese findings have relevance to athletic populations, in that DHA would be expected to facilitate recovery and allow for better performance during training and competition. However, DHA supplementation might also benefit non-athletic populations, such as individuals starting new exercise programs and patient populations that are prone to muscle soreness (e.g. physical therapy patients). PMID- 26957942 TI - A Comparison between Alpine Skiing, Cross-Country Skiing and Indoor Cycling on Cardiorespiratory and Metabolic Response. AB - Since physical inactivity especially prevails during winter months, we set out to identify outdoor alternatives to indoor cycling (IC) by comparing the metabolic and cardiorespiratory responses during alpine skiing (AS), cross-country skiing (XCS) and IC and analyse the effects of sex, age and fitness level in this comparison. Twenty one healthy subjects performed alpine skiing (AS), cross country skiing (XCS), and IC. Oxygen uptake (VO2), total energy expenditure (EE), heart rate (HR), lactate, blood glucose and rate of perceived exertion (RPE) were determined during three 4-min stages of low, moderate and high intensity. During XCS and IC VO2max and EE were higher than during AS. At least 21/2 hours of AS are necessary to reach the same EE as during one hour of XCS or IC. HR, VO2, lactate, and RPEarms were highest during XCS, whereas RPEwhole-body was similar and RPElegs lower than during AS and IC, respectively. Weight adjusted VO2 and EE were higher in men than in women while fitness level had no effect. Male, fit and young participants were able to increase their EE and VO2 values more pronounced. Both AS and XCS can be individually tailored to serve as alternatives to IC and may thus help to overcome the winter activity deficit. XCS was found to be the most effective activity for generating a high EE and VO2 while AS was the most demanding activity for the legs. Key pointsDuring cross-country skiing and indoor cycling VO2max and energy expenditure were higher than during alpine skiingApproximately 21/2 hours of alpine skiing are necessary to reach the same energy expenditure of one hour of cross-country skiing or indoor cycling.Alpine skiing and cross-country skiing can be individually tailored to serve as sports alternatives in winter to activity deficit.By applying different skiing modes as parallel ski steering, carving long radii and short turn skiing, metabolic and cardiorespiratory response can be increased during alpine skiing.Male, fit and young participants were able to increase their energy expenditure and VO2 more pronounced with an increase in intensity compared with their counterparts. PMID- 26957943 TI - Coenzyme Q10 Supplementation Modulates NFkappaB and Nrf2 Pathways in Exercise Training. AB - This study reports the effects of Q10, coenzyme Q10 or ubiquinone, a component of the electron transport chain in mitochondria, on nuclear factor kappa-light-chain enhancer of activated B cells (NFkappaB), inhibitors of kappa B (IkappaB), nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and hemeoxygenase 1 (HO-1) in rats after chronic exercise training for 6 weeks. 8-week old male Wistar rats were assigned randomly to one of four treatments planned in a 2 x 2 factorial arrangement of two condition (sedentary vs. exercise training), and two coenzyme Q10 levels (0 and 300 mg/kg per day for 6 weeks). The expression levels of the target proteins were determined in the heart, liver and muscle, and biochemical parameters including creatinine, urea, glucose and lipid profile were investigated in plasma. When compared with sedentary group, significant decreases in heart, liver and muscle NFkappaB levels by 45%, 26% and 44% were observed in Q10 supplemented rats after exercise training, respectively, while the inhibitory protein IkappaB increased by 179%, 111% and 127% in heart, liver and muscle tissues. Q10 supplementation caused an increase in Nrf2 (167%, 165% and 90%) and HO-1 (107%, 156% and 114%) after exercise training in heart, liver and muscle tissues (p < 0.05). No significant change was observed in any of the parameters associated with protein, carbohydrate and lipid metabolism, except that exercise caused a decrease in plasma triglyceride, which was further decreased by Q10. In conclusion, these results suggest that Q10 modulates the expression of NFkappaB, IkappaB, Nrf2 and HO-1 in exercise training, indicating an anti-inflammatory effect of Q10 and emphasizes its role in antioxidant defense. Key pointsCoenzyme Q10 is a component of the electron transport chain in mitochondria which is linked to the generation of energy in the cell.Coenzyme Q10 may inhibit the peroxidation of lipids, thus acting as an antioxidant and protects tissue against oxidative injury.Using of coenzyme Q10 can significantly elevate IkappaB, Nrf2 and HO-1 and reduce NFkappaB during exercise training. PMID- 26957944 TI - Iron Supplementation and Altitude: Decision Making Using a Regression Tree. PMID- 26957945 TI - Elastic Knee Sleeves Limit Anterior Tibial Translation in Healthy Females. PMID- 26957946 TI - Putting Laughter in Context: Shared Laughter as Behavioral Indicator of Relationship Well-Being. AB - Laughter is a pervasive human behavior that most frequently happens in a social context. However, data linking the behavior of laughter with psychological or social outcomes is exceptionally rare. Here, we draw attention to shared laughter as a useful objective marker of relationship well-being. Spontaneously-generated laughs of 71 heterosexual romantic couples were coded from a videorecorded conversation about how the couple first met. Multilevel models revealed that, while controlling for all other laughter present, the proportion of the conversation spent laughing simultaneously with the romantic partner was uniquely positively associated with global evaluations of relationship quality, closeness, and social support. Results are discussed with respect to methodological considerations and theoretical implications for relationships and behavioral research more broadly. PMID- 26957947 TI - Minimal second language exposure, SES, and early word comprehension: New evidence from a direct assessment. AB - Although the extant literature provides robust evidence of the influence of language exposure and socioeconomic status (SES) on language acquisition, it is unknown how sensitive the early receptive vocabulary system is to these factors. The current study investigates effects of minimal second language exposure and SES on the comprehension vocabulary of 16-month-old children in the language in which they receive the greatest exposure. Study 1 revealed minimal second language exposure and SES exert significant and independent effects on a direct measure of vocabulary comprehension in English-dominant and English monolingual children (N = 72). In Study 2, we replicated the effect of minimal second language exposure in Spanish-dominant and Spanish monolingual children (N = 86), however no effect of SES on vocabulary was obtained. Our results emphasize the sensitivity of the language system to minimal changes in the environment in early development. PMID- 26957948 TI - Analysis of the immune response of human dendritic cells to Mycobacterium tuberculosis by quantitative proteomics. AB - BACKGROUND: The cellular immune response for Mycobacterium tuberculosis (M. tuberculosis) infection remained incompletely understood. To uncover membrane proteins involved in this infection mechanism, an integrated approach consisting of an organic solvent-assisted membrane protein digestion, stable-isotope dimethyl labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was used to comparatively profile the membrane protein expression of human dendritic cells upon heat-killed M. tuberculosis (HKTB) treatment. RESULTS: Organic solvent-assisted trypsin digestion coupled with stable-isotope labeling and LC-MS/MS analysis was applied to quantitatively analyze the membrane protein expression of THP-1 derived dendritic cells. We evaluated proteins that were upregulated in response to HKTB treatment, and applied STRING website database to analyze the correlations between these proteins. Of the investigated proteins, aminopeptidase N (CD13) was found to be largely expressed after HKTB treatment. By using confocal microscopy and flow cytometry, we found that membranous CD13 expression was upregulated and was capable of binding to live mycobacteria. Treatment dendritic cell with anti-CD13 antibody during M. tuberculosis infection enhanced the ability of T cell activation. CONCLUSIONS: Via proteomics data and STRING analysis, we demonstrated that the highly-expressed CD13 is also associated with proteins involved in the antigen presenting process, especially with CD1 proteins. Increasing expression of CD13 on dendritic cells while M. tuberculosis infection and enhancement of T cell activation after CD13 treated with anti-CD13 antibody indicates CD13 positively involved in the pathogenesis of M. tuberculosis. PMID- 26957949 TI - Adherence to Traditionally Masculine Norms and Condom-Related Beliefs: Emphasis on African American and Hispanic Men. AB - Although studies have shown that adherence to traditional masculine norms (i.e., Status, Toughness, Antifemininity) affect men's attitudes toward sexual health, there is little research on how men's adherence to these norms affect them in the context of heterosexual, dyadic relationships. Among 296 young pregnant couples, we investigated the extent to which adherence to traditional masculine norms affected male and female partners' own condom-related beliefs (i.e., condom self efficacy, positive condom attitudes) and that of their partners. We tested an interdependence model using a dyadic-analytic approach to path analysis. We also tested for differences across gender and race-ethnicity (i.e., African American, Hispanic). Results showed that adherence to the Antifemininity and Toughness masculine norms predicted negative condom-related beliefs, whereas, overall, adherence to the Status norm predicted positive condom-related beliefs. Men's and women's adherence to traditional norms about masculinity were associated with their partner's condom self-efficacy, and moderated associations based on gender and race-ethnicity were detected. In contrast, each dyad member's traditional masculine norms were not associated with his or her partner's positive condom attitudes. Taken together, findings indicated that the roles of traditional masculinity and condom-related beliefs in sexual health should be addressed within the context of relationships and associations between masculine norms and condom-related beliefs are not uniformly negative. PMID- 26957950 TI - The Development of Selective Attention Orienting is an Agent of Change in Learning and Memory Efficacy. AB - The present study examined whether the developmental transition from facilitation based orienting mechanisms available very early in life to selective attention orienting (e.g., inhibition of return, IOR) promotes better learning and memory in infancy. We tested a single age group (4-month-olds) undergoing rapid development of attention orienting mechanisms. Infants completed a spatial cueing task designed to elicit IOR, in which cat or dog category exemplars consistently appeared in either the cued or noncued locations. Infants were subsequently tested on a visual paired comparison of exemplars from these cued and noncued animal categories. As expected, infants showed either facilitation-based orienting or the more mature IOR-based orienting during spatial cueing/encoding. Infants who demonstrated IOR-based orienting showed memory for both specific exemplars and broader category learning, whereas those who showed facilitation based orienting showed weaker evidence of learning. Attention orienting also interacted with previous pet experience, such that the number of pets at home influenced learning only when infants engaged facilitation-based orienting during encoding. Learning in the context of IOR-based orienting was stable regardless of pet experience, suggesting that selective attention serves as an online learning mechanism during visual exploration that is less sensitive to prior experience. PMID- 26957951 TI - First on the List: Effectiveness at Self-Regulation and Prioritizing Difficult Exercise Goal Pursuit. AB - Identifying and understanding the goal pursuit strategies that distinguish effective self-regulators from less effective self-regulators is important for elucidating how individuals achieve their goals. We suggest that the timing of plans for difficult goal pursuits is one differentiation. A pilot study shows that effective self-regulators tend to believe they are best suited to pursue difficult goals earlier in the day, and two studies provide evidence that effective and less effective self-regulators differ in the timing of their plans for difficult goal pursuits. Results indicate that when exercising is perceived as difficult goal pursuit, effective self-regulators prioritize that difficult goal pursuit by planning to exercise earlier in the day whereas less effective self-regulators plan exercise for later in the day. PMID- 26957952 TI - Muscle contraction velocity, strength and power output changes following different degrees of hypohydration in competitive olympic combat sports. AB - BACKGROUND: It is habitual for combat sports athletes to lose weight rapidly to get into a lower weight class. Fluid restriction, dehydration by sweating (sauna or exercise) and the use of diuretics are among the most recurrent means of weight cutting. Although it is difficult to dissuade athletes from this practice due to the possible negative effect of severe dehydration on their health, athletes may be receptive to avoid weight cutting if there is evidence that it could affect their muscle performance. Therefore, the purpose of the present study was to investigate if hypohydration, to reach a weight category, affects neuromuscular performance and combat sports competition results. METHODS: We tested 163 (124 men and 39 woman) combat sports athletes during the 2013 senior Spanish National Championships. Body mass and urine osmolality (UOSM) were measured at the official weigh-in (PRE) and 13-18 h later, right before competing (POST). Athletes were divided according to their USOM at PRE in euhydrated (EUH; UOSM 250-700 mOsm . kgH2O(-1)), hypohydrated (HYP; UOSM 701-1080 mOsm . kgH2O( 1)) and severely hypohydrated (S-HYP; UOSM 1081-1500 mOsm . kgH2O(-1)). Athletes' muscle strength, power output and contraction velocity were measured in upper (bench press and grip) and lower body (countermovement jump - CMJ) muscle actions at PRE and POST time-points. RESULTS: At weigh-in 84 % of the participants were hypohydrated. Before competition (POST) UOSM in S-HYP and HYP decreased but did not reach euhydration levels. However, this partial rehydration increased bench press contraction velocity (2.8-7.3 %; p < 0.05) and CMJ power (2.8 %; p < 0.05) in S-HYP. Sixty-three percent of the participants competed with a body mass above their previous day's weight category and 70 of them (69 % of that sample) obtained a medal. CONCLUSIONS: Hypohydration is highly prevalent among combat sports athletes at weigh-in and not fully reversed in the 13-18 h from weigh-in to competition. Nonetheless, partial rehydration recovers upper and lower body neuromuscular performance in the severely hypohydrated participants. Our data suggest that the advantage of competing in a lower weight category could compensate the declines in neuromuscular performance at the onset of competition, since 69 % of medal winners underwent marked hypohydration. PMID- 26957953 TI - Validation of the Self Reporting Questionnaire 20-Item (SRQ-20) for Use in a Low- and Middle-Income Country Emergency Centre Setting. AB - Common mental disorders are highly prevalent in emergency centre (EC) patients, yet few brief screening tools have been validated for low- and middle-income country (LMIC) ECs. This study explored the psychometric properties of the SRQ-20 screening tool in South African ECs using the Mini Neuropsychiatric Interview (MINI) as the gold standard comparison tool. Patients (n=200) from two ECs in Cape Town, South Africa were interviewed using the SRQ-20 and the MINI. Internal consistency, screening properties and factorial validity were examined. The SRQ 20 was effective in identifying participants with major depression, anxiety disorders or suicidality and displayed good internal consistency. The optimal cutoff scores were 4/5 and 6/7 for men and women respectively. The factor structure differed by gender. The SRQ-20 is a useful tool for EC settings in South Africa and holds promise for task-shifted approaches to decreasing the LMIC burden of mental disorders. PMID- 26957955 TI - Experimental Lachesis muta rhombeata envenomation and effects of soursop (Annona muricata) as natural antivenom. AB - BACKGROUND: In the Atlantic forest of the North and Northeast regions of Brazil, local population often uses the fruit juice and the aqueous extract of leaves of soursop (Annona muricata L.) to treat Lachesis muta rhombeata envenomation. Envenomation is a relevant health issue in these areas, especially due to its severity and because the production and distribution of antivenom is limited in these regions. The aim of the present study was to evaluate the relevance of the use of soursop leaf extract and its juice against envenomation by Lachesis muta rhombeata. METHODS: We evaluated the biochemical, hematological and hemostatic parameters, the blood pressure, the inflammation process and the lethality induced by Lachesis muta rhombeata snake venom. We also assessed the action of the aqueous extract of leaves (AmL) and juice (AmJ) from A. muricata on the animal organism injected with L. m. rhombeata venom (LmrV) in the laboratory environment. RESULTS: LmrV induced a decrease of total protein, albumin and glucose; and increase of creatine kinase, aspartate aminotransferase, and urea concentrations. It provoked hemoconcentration followed by reduction of hematocrit, an increase in prothrombin time and partial thromboplastin time and a decrease of the blood pressure. LmrV induced the release of interleukin-6, an increase in neutrophils and changes in the serum protein profile, characteristic of the acute inflammatory process. LD50 values were similar for the groups injected with LmrV and treated or untreated with AmJ and AmL. Both treatments play a role on the maintenance of blood glucose, urea and coagulation parameters and exert a protective action against the myotoxicity. However, they seem to worsen the hypotension caused by LmrV. CONCLUSION: The treatments with AmJ and AmL present some beneficial actions, but they might intensify some effects of the venom. Therefore, additional studies on A. muricata are necessary to enable its use as natural antivenom for bushmaster snakebite. PMID- 26957954 TI - Bridged Analogues for p53-Dependent Cancer Therapy Obtained by S-Alkylation. AB - A small library of anticancer, cell-permeating, stapled peptides based on potent dual-specific antagonist of p53-MDM2/MDMX interactions, PMI-N8A, was synthesized, characterized and screened for anticancer activity against human colorectal cancer cell line, HCT-116. Employed synthetic modifications included: S alkylation-based stapling, point mutations increasing hydrophobicity in key residues as well as improvement of cell-permeability by introduction of polycationic sequence(s) that were woven into the sequence of parental peptide. Selected analogue, ArB14Co, was also tested in vivo and exhibited potent anticancer bioactivity at the low dose (3.0 mg/kg). Collectively, our findings suggest that application of stapling in combination with rational design of polycationic short analogues may be a suitable approach in the development of physiologically active p53-MDM2/MDMX peptide inhibitors. PMID- 26957956 TI - Seroprevalence and risk factors of Hepatitis B and Hepatitis C infections among pregnant women in the Asante Akim North Municipality of the Ashanti region, Ghana; a cross sectional study. AB - BACKGROUND: Viral hepatitis is a serious public health problem affecting billions of people globally with maternal-fetal transmission on the rise. OBJECTIVES: This study sought to determine the prevalence and factors associated with hepatitis B virus (HBV) and hepatitis C virus (HCV) infections among pregnant women in the Asante Akim North Municipality, in the Ashanti region of Ghana. METHODS: In this cross-sectional study 168 pregnant women were recruited from the Agogo Presbyterian hospital. Blood samples were collected for the detection of Hepatitis B Surface Antigen (HBsAg) and anti-HCV antibodies. A pretested questionnaire was used to obtain demographic data and identify the risk factors associated with the two infections. RESULTS: Of the 168 participants studied, 16 (9.5%) tested positive for HBV and 13 (7.7%) tested positive for HCV representing 9.5% and 7.7% respectively. A participant tested positive for both HBV and HCV co infection representing 0.6%. Undertaking blood transfusion, tattooing and sharing of needles were associated with hepatitis C infection (P=0.001). HBV was not associated with any of the risk factors (P>0.05). CONCLUSION: Our findings suggest a high prevalence of hepatitis B and hepatitis C among pregnant women; blood transfusion, tattooing and sharing of hypodermic needles were associated with hepatitis C infection. Measures to reduce the disease and transmission burden must be introduced. PMID- 26957957 TI - Chronic hepatitis B associated with hepatic steatosis, insulin resistance, necroinflammation and fibrosis. AB - BACKGROUND: The effect of hepatitis B virus (HBV) infection on fatty liver disease is unclear. OBJECTIVES: The aim of this study was to investigate the viral and host causes of fatty liver in chronic hepatitis B (CHB) patients. This study included 88 CHB patients of which 17 were not treated. Liver biopsy was performed in each patient. Group 1 included those with hepatic steatosis (n=28) and group 2 those without hepatic steatosis. The groups were compared in terms of age, body mass index (BMI), Homeostasis Model Assessment- Insulin Resistance (HOMA-IR), viral load, biochemical parameters and histological findings. Patients in group 1 were subdivided according to the degree of steatosis as follows: grade 1 (15 patients, 53.6%), grade 2 (6 patients, 21.4%), and grade 3 (7 patients, 25%). RESULTS: In group 1 (n=28), mean age, BMI, cholesterol, and HOMA-IR were found to be significantly higher than in group 2 (n=60). There were no significant differences in the positivity of viral load, HbeAg, treatment, fibrosis and other laboratory parameters between the two groups. HOMA-IR was the only independent predictive factor of liver steatosis in patients with CHB in logistic regression analysis. CONCLUSION: Hepatic steatosis in CHB patients was associated with host metabolic factors. PMID- 26957958 TI - Triple positivity of HBsAg, anti-HCV antibody, and HIV and their influence on CD4+ lymphocyte levels in the highly HIV infected population of Abeokuta, Nigeria. AB - BACKGROUND: Few studies exist on hospital-based seroprevalence of triple positivity of HIV/HBV/HCV in Nigeria. OBJECTIVES: The study aimed at determining the triple positivity of HIV, HBsAg and HCV among HIV-infected individuals in Abeokuta, Nigeria and defining the influence of these triple infections on CD4+ counts of HIV-infected individuals as antiretroviral therapy improves in Nigeria. METHODS: Enumeration of CD4+ levels in 183 HIV-infected persons was done with Partec Flow Cytometer. Seropositivity of HBsAg and anti-HCV antibody was detected with rapid kits. RESULTS: From the result obtained, significance variance (p<0.05) existed between HIV positive persons and persons who tested positive to HIV/HBV/HCV triple infection before and after the commencement of HAART. Of these infections, 31(16.9%) had HBV/HCV/HIV triple infection, while 152(83.1%) had HIV mono infection only, 56(30.6%) had HBV/HIV dual infection only and 43(23.5%) had HCV/HIV dual infection only. Significant variance (p<0.05) also existed between subjects with CD4 counts of <200 cells/ul, 200-499 cells/ul and >500 cells/ul. Highest seroprevalence of HIV (35.0%) was found in age groups 35-44 years and >65 years had the least (2.7%). Significant variance (p<0.05) also existed in the progression of CD4+ lymphocytes cells between subjects with persistent decrease (32.3%) in CD4+ lymphocytes cells and those with fluctuation in their CD4+ lymphocytes cells (12.9%) after the commencement of ART. CONCLUSION: The study further confirms that triple positivity of HIV/HBV/HCV infection is common in Abeokuta, Nigeria. Testing of these triple infections should be a big concern in the best choice and commencement of ART. Also, the study showed that consistent and prolonged use of HAART had a positive impact on the CD4 count of HIV-infected individuals. PMID- 26957959 TI - Anti-HCV antibody among newly diagnosed HIV patients in Ughelli, a suburban area of Delta State Nigeria. AB - BACKGROUND: Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) share common routes of infection and as such, co-infection is expected. Co-infection of the two viruses is of great medical importance as it determines the effect of drugs used for treatment at various stages. OBJECTIVE: This interplay between HIV and HCV sets the tone for the objective of this study which is to ascertain the seroprevalence of HCV among newly diagnosed HIV patients in Ughelli, a suburban area of Delta State, Nigeria. METHODS: A total of 200 newly diagnosed HIV positive patients were recruited for this study. Each of the sera was tested for anti-HCV antibody using SWE-life HCV ultra rapid test strip. Appropriate questionnaires were used to ascertain other important information which include social behaviour such as whether the patients were MSM (males), IDU, tattoo and/or have received blood transfusion in the past. RESULTS: The prevalence of HCV among the study population was determined to be 15.0%. A higher seroprevalence was observed among females (16.5%) than in males (13.0%). A higher seroprevalence was also observed among age groups >26 years (16.0%) than in age groups 14-25 years (13.0%) and 2-13 years (0.0%). Of the 7 patients with tattoos, 1(14.3%) tested positive for HCV compared to 29(15.0%) with no tattoos. We found no significant correlation with transfusion, intravenous drug use (IDU), men that have sex with men (MSM), tattooing and the seroprevalence of HCV. However, significant correlation existed with age, sex and HCV prevalence. CONCLUSION: This study reports a 15.0% seroprevalence of HCV among newly diagnosed HIV patients and that is alarmingly well above several other studies done in the past in Nigeria and other countries of sub-Saharan Africa. Planned preven tion, screening, and treatment are needed to reduce further transmission and morbidity. Future studies involving HCV-RNA assays are needed. PMID- 26957960 TI - Seropositivity and determinants of immunoglobulin-G (IgG) antibodies against Herpes simplex virus (HSV) types -1 and -2 in pregnant women in Port Harcourt, Nigeria. AB - BACKGROUND: This study is the first documented prevalence of IgG antibody against HSV-1&-2 in Port Harcourt, Nigeria and thus provides baseline data for future in depth studies on HSV infection in South-South, Nigeria. OBJECTIVE: This study determined the seropositivity and determinants of serum IgG antibody against HSV 1 & HIV-2 among pregnant women attending BMSH, Port Harcourt, Rivers State, Nigeria. METHODS: Serum samples from 180 pregnant women attending antenatal clinic at Braithwaite Memorial Specialist Hospital (BMSH) in Port Harcourt, Nigeria. Serum samples were analysed with commercial HSV type-1&-2 specific IgG Enzyme Linked Immunosorbent Assay (ELISA) kits. Chi-square analysis was used to determine the association of infection with socio-demographic variables. RESULTS: Of the 180 pregnant women, 179 (99.4%) were seropositive and 1(0.6%) was seronegative for HSV 1&2 IgG antibody. No statistical association existed between the prevalence of HSV-1&-2 IgG antibodies and the socio-demographic variables studied (p>0.05) except for marital status which was significantly associated (p<0.05). CONCLUSION: Our data shows that HSV-1 & 2 seropositivity among pregnant women in Port Harcourt is high; thus serological screening for HSV-1&-2 might be advisable for antenatal attendees. PMID- 26957961 TI - Polymerase chain reaction to search for Herpes viruses in uveitic and healthy eyes: a South African perspective. AB - OBJECTIVE: To analyse aqueous polymerase chain reaction (PCR) results in patients diagnosed with undifferentiated uveitis and determine prevalence of herpesviridae in non-uveitic patients undergoing routine cataract extraction. DESIGN: Retrospective comparative case series and prospective cross-sectional study. SUBJECTS: 72 patients with idiopathic uveitis and 57 surgical patients. METHODS: Diagnostic aqueous paracentesis with PCR testing for 6 herpes viridae in uveitic patients. Anterior chamber paracentesis immediately pre-operative in the prospective arm, with PCR testing. RESULTS: In the retrospective review we had a 47.2% positive PCR yield. Data analysis revealed a statistically significant correlation between a positive yield and being HIV+ (p=0.018); between an EBV+ yield and being HIV+ (p= 0.026) and a CMV+ result and being HIV+ (p=0.032). Posterior uveitis (p=0.014) and symptoms <30 days (p= 0.0014) had a statistically significant yield. In the prospective arm of the study: all 57 patients were HIV- and all aqueous samples were negative for the 6 herpesviridae. CONCLUSION: We recommend PCR testing for Herpesviridae as a safe second line test for patients with undifferentiated uveitis. We were unable to establish prevalence and suggest that the idea of a commensal herpes virus is unlikely if the blood-ocular barrier is intact. PMID- 26957962 TI - Acceptability of self-collected vaginal samples for HPV testing in an urban and rural population of Madagascar. AB - OBJECTIVE: To evaluate the acceptability of self-collected vaginal samples for HPV testing in women living in rural and urban areas of Madagascar. MATERIALS AND METHODS: Participants were recruited in a health care center (urban group) and smaller affiliated dispensaries (rural group). They were invited to perform unsupervised self-sampling for HPV testing and to answer a questionnaire on socio demographic information, cervical cancer knowledge and self-sampling acceptability. RESULTS: A total of 300 women were recruited. Median age was 44.1 years (range 29-65 years) in the urban group and 40.9 years (range 29-65 years) in the rural group. Urban women had improved knowledge on HPV, cervical cancer and cervical cancer screening (p<0.05) as compared to rural women. Urban women lived closer to a health care center (P<0.05), had fewer different sexual partners (P<0.05) and later first sexual intercourse (p=0.07). Unlike urban women, most rural women were married (p<0.05). CONCLUSION: Acceptability of self sampling for HPV testing was similarly excellent in both groups despite their difference in terms of socio-demographic factors and knowledge about cervical cancer. PMID- 26957963 TI - Inventory of potential vectors of trypanosoma and infection rate of the Tsetse fly in the National Park of Ivindo, Gabon. AB - BACKGROUND: Trypanosoma's vectors distribution is poorly investigated in Gabon, where Trypanosomiasis historical foci exist. Thus, an active detection of Trypanosoma sp transmission needs to be assessed. OBJECTIVES: The present study aims to identify potential vectors of Trypanosoma sp and to evaluate the infection rate of the Tsetse fly in an area of Gabon. METHODS: An entomological survey was conducted in the National Park of Ivindo in May 2012 using Vavoua traps. All captured insects were identified. Tsetse were dissected and organs were microscopically observed to detect the presence of Trypanosoma sp. RESULTS: 247 biting flies known as vectors of Trypanosomiasis were caught including 189 tsetse flies, 32 Tabanid and 26 Stomoxys. Tsetse flies had the highest bulk densities per trap per day (ADT = 3 tsetse / trap / day), while the lowest density was found among Stomoxys (ADT= 0.41 Stomoxys / trap / day). The infection rate of flies was 6.3%. Infectious organs were midguts and to a lesser extent salivary glands and proboscis. CONCLUSION: The presence of Tsetse infected by Trypanosoma highlights an existing risk of trypanosomiasis infection in the National Park of Ivindo. PMID- 26957964 TI - Occupational skin diseases and prevention among sanitation workers in China. AB - BACKGROUND: Little research has been focused on the health status or the occupational protection awareness of sanitation workers. The policy recommendations on the occupational safety and health of sanitation workers based on the scientific research are also insufficient in developing countries like China. OBJECTIVE: To study the incidence of dermatoses and the relevance with occupational exposure, protection awareness and protective measures among sanitation workers for better management and protection of the sanitation workers. METHODS: 273 sanitation workers and 113 administrative staff from 11 streets of Wuhan were recruited. Dermatological problems were evaluated and recorded by physical examination. Occupational exposure, protection awareness, the use of protective equipments and personal history of skin disease were assessed by questionnaires. RESULTS: Compared with administrative staff, sanitation workers had much more occupational dermatological problems and had a much higher rate of harmful ultraviolet ray exposure. Young sanitation workers were more aware of occupational self-protection and a relatively higher rate of them using protective equipments compared with old ones. CONCLUSION: Exposure to multiple health hazards and the poor use of protective equipments are related to skin diseases in sanitation workers. Prejob training of self-protection and the use of protective equipments are recommended. PMID- 26957965 TI - Trends in HIV prevalence from 2008 to 2012 among young adults in Port Harcourt, Nigeria. AB - BACKGROUND: The pandemic of HIV lines amongst the utmost infectious disease menaces in antiquity. HIV remains a problem worldwide and it's a grave health snags in developing nations particularly in Nigeria. OBJECTIVE: This study focused on "trends in HIV reporting from 2008 to 2012 among young adults in Port Harcourt, Nigeria. METHODS: Secondary data were collected from BMSH, Port Harcourt using a Performa specifically intended for this determination. Socio demographic data for the subjects were recovered from coded patients' medical records kept at BMSH. The data generated was exposed to Fisher's Exact Test. RESULTS: The study showed that a total of 3081 HIV-positive cases were reported between 2008 and 2012. The HIV trend were not well defined, it peaked in 2009(36.6%) and 2008(32.8%) and a decrease in 2011(16.6%), 2012(8.3%) and 2010(5.7%). A 3.8% increase was observed between 2008 and 2009 and 30.9% decrease between 2009 and 2010. However, the prevalence seemed to stabilize between 2009 and 2012. HIV patterns among various age-groups is not well-defined, it rose with increasing age and peaked at 26-30 years (35.7%) after which it declined. Sex differences (P<0.05) in the trend was observed. Males ages 26-30 years showed uniform pattern with an increasing trend while 36-40 years showed decreasing trend except in 2009(34.1%). Females ages 26-30 years showed uniform pattern with an increasing trend from 2008(21.7%) to 2010(41.9%) and decreased from 41.9% (2010) to 36.5%(2012). The low HIV prevalence in 2010 could be attributed to the fact that the proportion of centers giving ART enlarged from 2005 to date. Health care facilities providing HIV/AIDS counselling and testing services also increased. CONCLUSION: The long decades fight against HIV especially in Rivers State is making progress, though an unstable one. The observed increase in years with high HIV prevalences calls for an intensified focus of intervention. PMID- 26957966 TI - Evaluation of the anti-candidal activity of methanolic leaf extract of cleistopholis patens (fam. Annonaceae) on candida species isolated from stage II HIV patients. AB - BACKGROUND: Candida species (sp) is implicated in causing opportunistic disseminated mycotic complications in stage II HIV patients. Cleistopholis patens is a West African medicinal tree reported to have significant antifungal activity against C. albicans. OBJECTIVES: This study aimed to determine the anti-candidal activity of methanolic leaf extract of Cleistopholis patens against Candida species isolated from stage II HIV patients. METHODS: The minimum inhibitory concentration (MIC) of the extract and Nystatin(r)(r) was determined by agar dilution method. The killing rate studies of the plant extract and Nystatin(r) were also determined. RESULTS: The extract had activity against all Candida isolates, with the MIC against the five isolates ranging from 6.0 - 9.8 mg/ml. Nystatin(r) also demonstrated plausible activity against the isolates with MICs ranging from 0.3125 - 25 mg/ml. Candida albicans strain 2 was the most sensitive to both extract and Nystatin(r) with MIC values of 6 and 0.3125 mg/ml respectively. Candida krusei was the least sensitive with MIC values of 9.8 and 25 mg/ml for the extract and Nystatin(r) respectively. The killing rate values for the extract ranged from -0.029 to -0.091 min(-1) and that of Nystatin(r) ranged from -0.076 to -0.11216 min(-1). CONCLUSIONS: The results indicate that the methanolic extract of Cleistopholis patens is a promising clinical alternative besides Nystatin(r) in the treatment of infections caused by Candida species in stage II HIV patients. PMID- 26957967 TI - Evaluating the use of cell phone messaging for community Ebola syndromic surveillance in high risked settings in Southern Sierra Leone. AB - BACKGROUND: Most underdeveloped countries do not meet core disease outbreak surveillance because of the lack of human resources, laboratory and infrastructural facilities. The use of cell phone technology for disease outbreak syndromic surveillance is a new phenomenon in Sierra Leone despite its successes in other developing countries like Sri Lanka. In this study we set to evaluate the effectiveness of using cell phone technology for Ebola hemorrhagic fever syndromic surveillance in a high risked community in Sierra Leone. OBJECTIVES: This study evaluated the effectiveness of using cell phone messaging (text and calls) for community Ebola hemorrhagic fever syndromic surveillance in high risked community in southern Sierra Leone. METHOD: All cell phone syndromic surveillance data used for this study was reported as cell phone alert messages texts and voice calls; by the Moyamba District Health Management Team for both Ebola hemorrhagic fever suspect and mortalities. We conducted a longitudinal data analysis of the monthly cumulative confirmed Ebola hemorrhagic fever cases and mortalities collected by both the traditional sentinel and community cell phone syndromic surveillance from August 2014 to October 2014. RESULTS: A total of 129 and 49 Ebola hemorrhagic fever suspect and confirmed cases respectively were recorded using the community Ebola syndromic surveillance cell phone alert system by the Moyamba District Health Management Team in October 2014. The average number of Ebola hemorrhagic fever suspects and confirmed cases for October 2014 were 4.16 (Std.dev 3.76) and 1.58 (Std.dev 1.43) respectively. Thirty-four percent (n=76) of the community Ebola syndromic surveillance cell phone alerts that were followed-up within 24 hours reported Ebola hemorrhagic fever suspect cases while 65.92% (n=147) reported mortality. CONCLUSION: Our study suggests some form of underreporting by the traditional sentinel Ebola hemorrhagic fever disease surveillance system in Moyamba District southern Sierra Leone for August September 2014. Cell phone messaging technology can be effectively use as a tool for community epidemic surveillance from peripheral health care facilities to higher levels. PMID- 26957968 TI - Seroprevalence of West Nile Virus specific IgG and IgM antibodies in North Western and Western provinces of Zambia. AB - BACKGROUND: West Nile Virus (WNV) infection has been reported worldwide, including in Africa but its existence in Zambia is unknown. Symptoms for the virus include headache, myalgia, arthralgia and rash. OBJECTIVES: This study aimed to determine the seroprevalence of WNV and its correlates. METHODS: A cross sectional study was conducted in North-Western and Western provinces of Zambia. Samples were subjected to IgG and IgM antibodies testing against WNV. Logistic regression analyses were conducted to determine magnitudes of association. RESULTS: A total of 3,625 of persons participated in the survey out of which 10.3% had WNV infection. Farmers were 20% (AOR=0.80; 95% CI [0.64, 0.99]) less likely to have infection compared to students. Meanwhile participants who lived in grass roofed houses were 2.97 (AOR=2.97; 95% CI [1.81, 4.88]) times more likely to be infected than those who lived in asbestos roofed houses. IRS was associated with reduced risk of infection (AOR=0.81; 95% CI [0.69, 0.94]). Travelling to Angola was associated with the infection [AOR=1.40; 95% CI [1.09, 1.81]. CONCLUSION: Spraying houses with insecticide residual spray would minimize mosquito-man contact. Furthermore, surveillance at the border with Angola should be enhanced in order to reduce importation of the virus into the country. PMID- 26957969 TI - Risk factors for placental malaria and associated adverse pregnancy outcomes in Rufiji, Tanzania: a hospital based cross sectional study. AB - BACKGROUND: Prevention and treatment of malaria during pregnancy is crucial for reduction of malaria in pregnancy and its adverse outcomes. The spread of parasite resistance to Sulphadoxine-Pyrimethamine (SP) used for Intermittent Preventive Treatment for malaria in pregnancy (IPTp), particularly in East Africa has raised concerns about the usefulness and the reliability of the IPTp regimen. We aimed to assess the effectiveness of two doses of SP in treating and preventing occurrence of adverse pregnancy outcomes. METHODOLOGY: The study was an analytical cross sectional study which enrolled 350 pregnant women from Kibiti Health Centre, South Eastern Tanzania. Structured questionnaires were used to obtain previous obstetrics and medical history of participants and verified by reviewing antenatal clinic cards. Maternal placental blood samples for microscopic examination of malaria parasites were collected after delivery. Data was analyzed for associations between SP dosage, risk for PM and pregnancy outcome. Sample size was estimated based on precision. RESULTS: Prevalence of placental maternal (PM) was 8% among pregnant women (95%CI, 4.4-13.1%). Factors associated with increased risk of PM were primigravidity (P<0.001) and history of fever during pregnancy (P= 0.02). Use of at least 2 doses of SP for IPTp during pregnancy was insignificantly associated with reducing the risk PM (P=0.08), low birth weight (P=0.73) and maternal anemia (P=0.71) but associated significantly with reducing the risk of preterm birth (P<0.001). CONCLUSION: Two doses of SP for IPTp regime are ineffective in preventing and treating PM and adverse pregnancy outcome. Hence a review to the current IPTp regimen should be considered with possibility of integrating it with other malaria control strategies. PMID- 26957970 TI - Potential of household environmental resources and practices in eliminating residual malaria transmission: a case study of Tanzania, Burundi, Malawi and Liberia. AB - BACKGROUND: The increasing protection gaps of insecticide-treated nets and indoor residual spraying methods against malaria have led to an emergence of residual transmission in sub-Saharan Africa and thus, supplementary strategies to control mosquitoes are urgently required. OBJECTIVE: To assess household environmental resources and practices that increase or reduce malaria risk among children under five years of age in order to identify those aspects that can be adopted to control residual transmission. METHODS: Household environmental resources, practices and malaria test results were extracted from Malaria Indicators Survey datasets for Tanzania, Burundi, Malawi and Liberia with 16,747 children from 11,469 households utilised in the analysis. Logistic regressions were performed to quantify the contribution of each factor to malaria occurrence. RESULTS: Cattle rearing reduced malaria risk between 26%-49% while rearing goats increased the risk between 26%-32%. All piped-water systems reduced malaria risk between 30%-87% (Tanzania), 48%-95% (Burundi), 67%-77% (Malawi) and 58%-73 (Liberia). Flush toilets reduced malaria risk between 47%-96%. Protected-wells increased malaria risk between 19%-44%. Interestingly, boreholes increased malaria risk between 19%-75%. Charcoal use reduced malaria risk between 11%-49%. CONCLUSION: Vector control options for tackling mosquitoes were revealed based on their risk levels. These included cattle rearing, installation of piped-water systems and flush toilets as well as use of smokeless fuels. PMID- 26957971 TI - Variations in antimalarial components of Artemisia annua Linn from three regions of Uganda. AB - INTRODUCTION: Artemisia annua plant from the family Asteracea is a powerful antimalarial plant introduced to Uganda around 2003. In addition to the artemisinin component, the plant also contains flavonoids which work in synergy to artemisinin against malaria parasites. The plant also contains aromatic oils which repel mosquitoes. In this paper we report the variations in antimalarial components of A. annua samples from the regions cultivating it in Uganda. METHODS: Artemisia annua samples were obtained from three regions that cultivated the plant at the time of this study. The samples were brought to laboratory, authenticated and processed. The levels of artemisinin, total flavonoids and aromatic components were quantified using high performance thin layer chromatography, ultra violet spectrophotometry and gas chromatography respectively. RESULTS: Artemisinin and total flavonoids levels were higher in samples obtained from high land areas (western and south western region) compared to that obtained from lowland regions (central) i.e 0.8% Vs 0.4% and 2.6% Vs 1.5% respectively. The aromatic oils (mosquito repellent components) were similar with camphor component being highest and levels ranging from 75.4% to 79.0%. CONCLUSION: Our findings show that the active components in Artemisia annua cultivated and used in the Uganda vary with geographical regions and this calls for standardisation by source. PMID- 26957972 TI - Antiplasmodial activity of some phenolic compounds from Cameroonians Allanblackia. AB - BACKGROUND: Plasmodium falciparum, one of the causative agents of malaria, has high adaptability through mutation and is resistant to many types of anti malarial drugs. This study presents an in vitro assessment of the antiplasmodial activity of some phenolic compounds isolated from plants of the genus Allanblackia. METHODS: Tests were performed on well plates filled with a fixed parasitized erythrocytes volume. Compounds to be tested were then added in wells. After incubation, tritiated hypoxanthine is added and the plates were returned to the incubator. After thawing, the nucleic acids are collected. Inhibitory Concentration 50 (IC50) was determined by linear interpolation. RESULTS: From Allanblackia floribunda, have been isolated and characterized 1,7 dihydroxyxanthone 1, macluraxanthone 4, morelloflavone 9, Volkensiflavone 10 and morelloflavone 7-O-glucoside 11; from Allanblackia monticola, alpha-mangosine 2, rubraxanthone 3, allaxanthone C 5, norcowanine 6, tovophiline A 7, allaxanthone B 8 and from Allanblackia gabonensis, 1,7-dihydroxyxanthone 1. Six of them were evaluated for their antimalarial properties. The most active compound, macluraxanthone, presented a very interesting activity, with an IC50 of 0.36 and 0.27 ug/mL with the F32 and FcM29 strains respectively. CONCLUSION: This work confirms that species of Allanblackia genus are medicinally important plants containing many biologically active compounds that can be used effectively as antiplasmodial. PMID- 26957973 TI - Potential antimalarial activity of Methyl Jasmonate and its effect on lipid profiles in Plasmodium Berghei infected mice. AB - BACKGROUND: The antimalarial activity and lipid profiles of Methyl Jasmonate (MJ) were investigated against established malaria infection in vivo using BALB/c mice. METHODS: Arteether (AE) and chloroquine (CQ) were used as reference drugs while ethanol was used as the vehicle for drug delivery for MJ. RESULTS: Mice treated with 10 and 25 mg/kg MJ showed a remarkable reduction in percentage parasitemia by 68.3% and 78.2% on day 10(post treatment) respectively while 45.4% and 87.2% reduction in percentage parasitemia were observed in the group treated with 50 mg/kg on day 3 and 10 (post treatment) respectively. The highest mean survival time was observed in CQ followed by AE and MJ in dose-dependent manner. A progressive decrease in packed cell volume (PCV) was observed in infected untreated mice which led to the death of all the mice by day 9 (post treatment). Infected mice treated with MJ showed reduced level of HDL and LDL compared with infected untreated group. As the dose of MJ increased in infected mice cholesterol levels increased while there was reduction in triglyceride. CONCLUSION: Overall there was marked decrease in parasitemia in Plasmodium berghei infected mice treated with graded doses of MJ but appears to have reduced antimalarial activity compared with CQ and AE. PMID- 26957974 TI - Prevalence and risk factors of latent Tuberculosis among adolescents in rural Eastern Uganda. AB - BACKGROUND: Latent Tuberculosis treatment is a key tuberculosis control intervention. Adolescents are a high risk group that is not routinely treated in low income countries. Knowledge of latent Tuberculosis (TB) burden among adolescents may influence policy. OBJECTIVES: We determined the prevalence and risk factors of latent TB infection among adolescents in rural Uganda. METHODS: We analyzed baseline data from a study that assessed the prevalence and incidence of Tuberculosis disease among adolescents. We extracted socio-demographics, medical assessment information, and tuberculin skin test results and estimated prevalence ratios (PR) of latent TB infection risk factors by binomial regression. RESULTS: The prevalence of latent TB was 16.1%, 95% CI (15.1 - 17.2). Significant risk factors were: a BCG scar, APR 1.29 (95% CI 1.12 - 1.48); male gender, APR 1.37 (95% CI 1.21 - 1.56); age 17 -18 years, APR 1.46 (95% CI 1.24 - 1.71) and 15-16 years, APR 1.25 (95% CI 1.07 - 1.46) compared to 12-14 years; being out of school, APR 1.31 (95% CI 1.05 - 1.62); and a known history of household TB contact in last 2 years, APR 1.91 (95% CI 1.55 - 2.35). CONCLUSION: Targeted routine latent TB treatment among adolescents out of school may be crucial for TB disease control in low income countries. PMID- 26957975 TI - Inducible clindamycin resistance and nasal carriage rates of Staphylococcus aureus among healthcare workers and community members. AB - BACKGROUND: Nasal carriage of Staphylococcus aureus is becoming an increasing problem among healthcare workers and community individuals. OBJECTIVES: To determine the prevalence of methicillin-resistant S. aureus (MRSA) nasal colonization and inducible clindamycin resistance (ICR) of S. aureus among healthcare workers at Soba University Hospital and community members in Khartoum State, Sudan. METHODS: Five hundred nasal swabs samples were collected during March 2009 to April 2010. Isolates were identified using conventional laboratory assays and MRSA determined by the disk diffusion method. The D-test was performed for detection of ICR isolates with Clinical Laboratory Standard Institute guidelines. RESULTS: Of the 114 S. aureus isolated, 20.2% represented MRSA. The occurrence of MRSA was significantly higher among healthcare worker than community individuals [32.7% (18/55) vs. 6.9% (5/59)] (p=0.001). Overall the 114 S. aureus isolates tested for ICR by D-test, 29 (25.4%) yielded inducible resistance. Significantly higher (p=0.026) ICR was detected among MRSA (43.5%) than methicillin-susceptible S. aureus (MSSA) (20.9%). CONCLUSION: MRSA nasal carriage among healthcare workers needs infection control practice in hospitals to prevent transmission of MRSA. The occurrence of ICR in S. aureus is of a great concern, D- test should be carried out routinely in our hospitals to avoid therapeutic failure. PMID- 26957976 TI - New pneumococcal conjugate vaccine introductions in four sub-Saharan African countries: a cross-country analysis of health systems' impacts. AB - BACKGROUND: Pneumonia is a main cause of under-five mortality in low-income settings. The pneumococcal conjugate vaccine (PCV) has been introduced in many countries as a tool in the disease's prevention. Although PCV's effectiveness has been established, less is known about the effects of introducing additional injectable vaccines into routine immunisation programmes, particularly in the context of resource-constrained settings. OBJECTIVES: To explore the effects of PCV introduction on the immunisation programmes and health systems in four low income countries. METHODS: This study was carried out in Cameroon, Ethiopia, Kenya and Mali. Three to four regions and nine to 10 districts were selected within each country. Semi-structured interviews were carried out at national, regional and district levels (n=173). Researcher-administered questionnaires were completed with facility staff (n=124). Routine data on monthly vaccination activities were collected at district and facility levels. RESULTS: PCV was generally well integrated into existing routine immunisation. Little or no impact was found in most areas of the health systems. Some minor effects were found on immunisation programmes, particularly in areas with either planning activities or investments e.g. staff skills were strengthened and there were limited improvements in surveillance. Although health sector workers perceived increases in the coverage of other vaccines following the introduction of PCV, routine service data did not confirm this claim. No substantial impacts were seen in health system management, service delivery or performance. CONCLUSIONS: The introduction of PCV had marginal impacts on the Expanded Programme for Immunisation and little to none on broader health systems. PMID- 26957977 TI - Tackling sexually transmitted infection burden in Ugandan communities living in the United Kingdom: a qualitative analysis of the socio-cultural interpretation of disease and condom use. AB - BACKGROUND: Despite being in a different country and social environment, Ugandans living in the UK still reportedly have the lowest rates of condom usage and one of the highest incidences of STIs in UK. In Uganda, STIs and HIV prevalence has been reported to be on the increase. Understanding peoples' beliefs and the attitudes that influence their behavior is a key factor to effectively designing control programs. METHODS: A qualitative study that interviewed 37 purposively selected Ugandans living in the UK was conducted. Lay theories and interpretations were derived using thematic analysis. RESULTS: Condoms generally carried a lot of stigma and were perceived for use primarily in extramarital affairs and pregnancy control. HIV/AIDS was most feared due to its perceived socio-psychological or physical effects unlike other STIs described as "non threatening" due to wide availability of "quality" treatment in UK. Notions of trust, the purpose of relationships, symptom recognition and partner selection greatly influenced decisions to undertake consistent condom use. CONCLUSIONS: The socio-cultural understanding of STIs, sex, trust and relationships are symbolic in influencing consistent condom use among Ugandans. This indicates a need to acknowledge community beliefs and values about sexual health and design messages about STIs and condoms that would help eliminate these serious condom-related misconceptions. PMID- 26957978 TI - Antibacterial activities of lactic acid bacteria isolated from cow faeces against potential enteric pathogens. AB - BACKGROUND: The addition of sub therapeutic doses of antibiotics to cattle feed for growth promotion is a contributory factor to antibiotic resistance, thus an alternative to antibiotics is needed in animal feed additives. OBJECTIVE: To determine the antimicrobial activity of cow's intestinal Lactic acid bacteria (LAB) against enteric commensals. METHOD: Escherichia coli, Klebsiella species (spp) and LAB were isolated from thirty different cow faecal samples and the LAB identified by partial sequencing of 16S rRNA. The antimicrobial activity of the LAB was determined against the test Escherichia coli and Klebsiella spp. RESULTS: Five species of LAB were isolated from thirty cow faecal samples and identified as Enterococcus hirae (8), Enterococcus durans (6), Enterococcus faecium (1), Enterococcus faecalis (1) and Weissella confusa (1). Viable cells and cell free supernatant (CFS) of the LAB were able to inhibit the growth of the test organisms with the largest zone of inhibition by the viable cells being 26mm against Escherichia coli CB6 produced by Enterococcus hirae CO6A while Weissella confusa CO29M and Enterococcus hirae CO2A produced the largest zones of inhibition (26mm) against Klebsiella CB2. CONCLUSION: This study shows that LAB from cow faeces possess considerable antimicrobial activity against resistant Escherichia coli from the same environment. PMID- 26957979 TI - Bone metabolism and hand grip strength response to aerobic versus resistance exercise training in non-insulin dependent diabetic patients. AB - BACKGROUND: Diabetes mellitus has been shown in many studies to be associated with reduced bone mass and an increased risk of fracture. Currently, our understanding of how to use exercise effectively in diabetic patients in prevention of osteoporosis is incomplete and has prompted our interest to identify the type of effective osteogenic exercise. OBJECTIVE: The aim of this study was to compare the changes in handgrip strength and bone metabolism after 6 months between aerobic and resistance exercise training in non-insulin dependent diabetic patients in Jeddah area. MATERIALS AND METHODS: One hundred non-insulin dependent diabetic male patients participated in this study and were divided into two equal groups; the first group (A) received aerobic exercise training, where the second group (B) received resistance exercise training. The program consisted of three sessions per week for six months. RESULTS: The mean values of serum calcium and Hand grip strength were significantly increased, while the mean values of parathyroid hormone were significantly decreased in both groups .Also, there were significant differences between mean levels of the investigated parameters in group (A) and group (B) after treatment. CONCLUSION: Aerobic exercise training on treadmill is appropriate to improve markers of bone metabolism and hand grip strength in non-insulin dependent diabetic patients. PMID- 26957980 TI - Implementation of POCT in the diabetic clinic in a large hospital. AB - AIM: Point-of-care testing (POCT) is gaining renewed interest, especially in resource-limiting primary health care, due to rise in prevalence of communicable and non-communicable diseases hence POCT needscontinuous appraisal. METHODS: Random glucose and glycated haemoglobin (HbA1c) were measured in 104 diabetic patients using standard laboratory multichannel analyzer 917. The utility of venous blood compared to capillary blood in measuring HbA1c was evaluated in a subset of 20 patients using a POCT device, DCA Vantage. Lastly, the POCT was validated against the laboratory multichannel analyser 917, in measurement of HbA1c in a second subset of 46 patients. RESULTS: Random blood glucose levels and HbA1c levels moderately correlated (r2 = 0.56; p < 0.0001). Random glucose tests showed that 41% of the patients had poor glycaemic control while HbA1c showed 74%. Venous and capillary blood in HbA1c showed strong correlation (r2 = 0.89440; p < 0.001. There was also strong correlation (r = 0.9802; p < 0.0001) in HbA1c measured using the DCA Vantage and the standard laboratory analyser, Multichannel Analyser 917. CONCLUSION: Venous or capillary blood can be used in POCT for HbA1c. POCT is ideal for monitoring glucose control and management of diabetes in resource-limited countries such as South Africa. PMID- 26957981 TI - Association of waist and hip circumferences with the presence of hypertension and pre-hypertension in young South African adults. AB - BACKGROUND: Obesity is one of the most important risk factors for cardiovascular diseases (CVDs) including hypertension (HT) which is itself a risk factor for CVDs. Recent studies suggest that waist circumference (WC) may be more sensitive than Body Mass Index (BMI) in determining individual risk scores for CVDs. OBJECTIVES: The current study aimed at investigating the influence of various anthropometric variables on blood pressure status in a group of students from Walter Sisulu University. METHODS: Informed consent was obtained from 216 male and female students from Walter Sisulu University with a mean age of 22.1+/-0.2 years. Anthropometric measurements were performed for each participant. Blood pressure was measured in triplicates after 10 minutes of rest and the average computed. RESULTS: Just over 46% of the subjects were diagnosed with hypertension (HT) and pre-HT. The gender specific prevalence of HT/pre-HT was higher in the male (76.7%) compared to the female (30.5%) group. Waist circumference (WC) and total body fat (TBF) correlated significantly with blood pressure and HT/pre-HT in females but not males. ROC analysis showed that with the exception of waist-to hip (WHR), all other anthropometric measurements and ratios studied can be used to discriminate blood pressure in young adult females not males. CONCLUSION: Increased WC and HC were associated with HT and pre-HT in young adult females in the Walter Sisulu University. PMID- 26957982 TI - Activity limitations and participation restrictions experienced by people with stroke in Musanze district in Rwanda. AB - BACKGROUND: Stroke is a major cause of long-term disability. Information regarding the limitations in activity and participation experienced by patients with stroke in a specific setting such as Musanze district in Rwanda would assist to develop the rehabilitation programmes that would take into consideration the functional challenges experienced post stroke. OBJECTIVE: To explore the activity limitations and participation restrictions experienced by people with stroke in Musanze district in Rwanda. METHODS: A qualitative phenomenological approach using in-depth face-to-face interviews with 10 participants was employed to gather the data that was analyzed using a qualitative thematic approach. RESULTS: The themes that arose as activity limitations included limitations in walking, self care, and domestic life activities. The themes related to participation restrictions as expressed by the participants were inability to return to previous occupation, decreased social interactions and inability to participate in religious activities. CONCLUSION: The current study findings highlight the need for interventions to improve the functional status of stroke survivors. PMID- 26957983 TI - The comparison of high and standard definition computed tomography techniques regarding coronary artery imaging. AB - OBJECTIVE: The aim was to compare coronary high-definition CT (HDCT) with standard-definition CT (SDCT) angiography as to radiation dose, image quality and accuracy. MATERIAL AND METHODS: 28 patients with history of coronary artery disease scanned by HDCT (Discovery CT750 HD) and SDCT (Somatom Definition AS). The scan modes were both axial prospective ECG-triggered. The vessel diameters and vessel attenuation values of totally 280 measurements from 140 coronary arteries were analyzed by two experienced radiologists. All data was analyzed by intraclass correlation test. Image quality graded by motion and stair step artifacts (grade 1, poor, to grade 4, excellent), accuracy of vessel inner and outer diameters were compared between the two CT units using the independent samples t-test and Mann-Whitney U test. RESULTS: The intraclass correlation coefficient (ICC) of measured vessel attenuation values in SDCT between the two radiologists was exceedingly good. The ICC was higher in HDCT. The radiation dose of HDCT was higher than that of SDCT. The mean tube current was 180 (mA) in HDCT and 147(mA) in SDCT with the same tube voltage (kVp). There was no significant difference between image quality. CONCLUSION: HDCT has a higher radiation dose but has much more atenuation and the spatial resolution which improve measurement accuracy for imaging coronary arteries. PMID- 26957984 TI - A systematic review and appraisal of methods of developing and validating lifestyle cardiovascular disease risk factors questionnaires. AB - BACKGROUND: Well developed and validated lifestyle cardiovascular disease (CVD) risk factors questionnaires is the key to obtaining accurate information to enable planning of CVD prevention program which is a necessity in developing countries. We conducted this review to assess methods and processes used for development and content validation of lifestyle CVD risk factors questionnaires and possibly develop an evidence based guideline for development and content validation of lifestyle CVD risk factors questionnaires. MATERIALS/METHODS: Relevant databases at the Stellenbosch University library were searched for studies conducted between 2008 and 2012, in English language and among humans. Using the following databases; pubmed, cinahl, psyc info and proquest. Search terms used were CVD risk factors, questionnaires, smoking, alcohol, physical activity and diet. RESULTS: Methods identified for development of lifestyle CVD risk factors were; review of literature either systematic or traditional, involvement of expert and /or target population using focus group discussion/interview, clinical experience of authors and deductive reasoning of authors. For validation, methods used were; the involvement of expert panel, the use of target population and factor analysis. CONCLUSION: Combination of methods produces questionnaires with good content validity and other psychometric properties which we consider good. PMID- 26957985 TI - Prevalence of CKD-MBD in pre-dialysis patients using biochemical markers in Enugu, South-East Nigeria. AB - BACKGROUND: As kidney function declines, there is a progressive deterioration in mineral homeostasis with disruption of normal serum and tissue concentration of phosphorus and calcium, and changes in circulating levels of hormones-parathyroid hormone (PTH), calcitriol (1,25(OH)2 D), and Fibroblast growth factor-23 (FGF 23). OBJECTIVE: This study was aimed at determining the prevalence of markers of CKD-MBD in pre-dialysis patients. METHODS: We evaluated consecutively 168 subjects made up of 85 CKD patients and 83 healthy controls, who were attending the renal clinics and medical outpatient of University of Nigeria Teaching Hospital, Enugu. GFR was estimated and serum calcium, phosphorus, alkaline phosphatase, PTH, and 25(OH) D levels assayed. RESULTS: The prevalence of various mineral bone disease abnormalities were 70% hyper-phosphatemia, 85% hyper parathyroidism, and 100% low levels of 25 (OH) D among the patients. Estimated GFR correlated negatively with both serum phosphorus, and PTH. Age of the patients ranged from18-76 years with a male to female ratio of 1.7:1. Chronic Glomerulonephritis (CGN), hypertension and diabetes mellitus caused CKD in 75% of the patients. There was no significant decrease in serum calcium levels of patients compared to controls. The patients did not have pathologically raised alkaline phosphatase, although their mean level was significantly higher than that of the control group. CONCLUSION: Low 25 (OH) D levels (insufficiency/deficiency), hyperparathyroidism, and hyper-phosphatemia were the obvious markers of CKD-MBD in our pre-dialysis patients. These should be evaluated at presentation in these patients. PMID- 26957986 TI - Sonographic evaluation of the spleen among sickle cell disease patients in a teaching hospital in Nigeria. AB - BACKGROUND: Regional variations in size and parenchyma echo-texture of the spleen among sickle cell disease (SCD) patients have been documented in various publications. The objectives of this study were to assess the size and parenchyma echo-texture of the spleen of SCD patients and ascertain the relationship of age, height and weight with the spleen sizes. METHODS: This was a cross sectional study involving 103 each of SCD and age matched control subjects. Aloka ST- 550 3500 ultrasound machine with 3.5 and 5 MHz convex transducers was used to scan the subjects over a 15 months period (September, 2012 to November, 2013). The age, height and weight of each subject were recorded. RESULTS: The spleen sizes of SCD patients were generally larger than those of the controls (p < 0.05). Abnormal spleen parenchyma of varied appearances was found among the SCD subjects. There were negative correlations between mean spleen sizes and height, weight and age in SCD patients but positive correlations were found between them in the controls. CONCLUSION: Routine sonographic assessment of spleen size and echo-texture is useful in the management of SCD patients. PMID- 26957987 TI - Upper gastrointestinal diseases in patients for endoscopy in South-Western Uganda. AB - BACKGROUND: There is a paucity of published data regarding upper gastrointestinal diseases in Ugandans with upper gastrointestinal symptoms referred for endoscopy. OBJECTIVES: To study the presenting complaints, pathology and Helicobacter pylori prevalence among patients with upper gastrointestinal symptoms in South-Western Uganda. METHODS: Patients presenting with upper gastrointestinal symptoms underwent upper endoscopy and a urease test for Helicobacter Pylori, all suspicious lesions were biopsied for histopathology review as appropriate. RESULTS: The most common presenting complaints were epigastric pain (51.6%), dysphagia (13.6%) and odynophagia (7.1%). The most common endoscopy finding was gastritis (40.2%), followed by normal examination (15.2%), oesophageal cancer (13.6%), gastric ulcer (7.6%) and gastric cancer (7.1%). Patients older than 40 years (n=110) had significant findings including gastritis (50.9%), oesophageal cancer (22.7%) and gastric cancer (11.8%). However in younger patients, with the age range of 18-40 years (n=74), most examinations were normal (92.9%). Of the 176 patients able to undergo Helicobacter pylori testing 75.6% were positive. Helicobacter pylori infection was associated with statistically significant increase in gastritis, oesophageal cancer, gastric ulcer, gastric cancer, and duodenal ulcers (p-values< 0.05). CONCLUSION: Gastritis, ulcerative disease, and upper gastrointestinal malignancies are common in South-Western Ugandans and are associated with a high prevalence of Helicobacter pylori. PMID- 26957988 TI - Risk of obstructive sleep apnoea syndrome among in-patients at a neuropsychiatric hospital in Nigeria: a short report. AB - BACKGROUND/OBJECTIVES: Sleep problems are commonly reported by persons with severe mental illness. Obstructive sleep apnoea syndrome (OSA) is commonly co morbid with mental illness. Screening for OSA and its subsequent management may improve outcomes in this patient population. We screened for risk of OSA among in patients with severe mental illness to determine its prevalence as well as its correlates using a socio-demographic questionnaire and the Berlin questionnaire. METHODS: A cross sectional descriptive exploratory survey of in-patients (n=89) at a regional Neuro- Psychiatric hospital using a socio-demographic questionnaire and the Berlin questionnaire. RESULTS: Eighteen patients (18/89; 20.9%) were classed as high risk for OSA. High risk for OSA was significantly associated with a higher body mass index; BMI (p<0.01), but not gender (p=0.53), diagnoses (p=0.84), co-morbidity (p=0.73) or use of atypical antipsychotics (p=0.48). CONCLUSION: Patients with severe mental illness are at high risk for OSA with being overweight higher BMI significantly associated with this high risk. PMID- 26957989 TI - Assessment of the biomass related indoor air pollution in Kwale district in Kenya using short term monitoring. AB - BACKGROUND: Indoor air pollution remains an important health problem in some countries. Although research data on this issue is available, routine monitoring in affected areas is limited. The aims of this study were to quantify exposure to biomass-related indoor air pollution; assess the respiratory health of subjects; and explore the feasibility of routine monitoring in Kwale district, Kenya. METHODS: We sampled 125 rural houses using short-term monitoring for levels of CO, CO2 and TSP. Additional exposure information was obtained using a checklist. Respiratory health was also assessed using a questionnaire, and electronic spirometer in 172 inhabitants. RESULTS: The overall median levels of CO in the sampled houses on all study sites ranged from 5.9 (IQR 3-14.5) to 10 (5.5-21.2) mg/m3, levels of CO2 ranged from 774 (IQR 724-846) to 839 (IQR 749-961) mg/m3) and the levels of TSP ranged from 295 (IQR 79-853 to 1384 (IQR 557-3110) ug/m(3) which indicates that safe levels recommended by WHO and USEPA could be exceeded. Relatively high incidences of respiratory illness or symptoms were reported and the spirometry readings suggested impaired lung function in over 80% of respondents. CONCLUSION: Our results quantify that the use of biomass fuel can give rise to high levels of indoor air pollution. Given that poor lung function contributes to public health problems in rural regions of East Africa, such as Kwale in Kenya, our findings create grounds for more detailed investigations of the problem and may provide motivation for community based interventions. PMID- 26957990 TI - Tryptophan-induced pathogenesis of breast cancer. AB - BACKGROUND: The pathogenesis of breast cancer remains unclear. AIMS: To investigate the pathogenesis of breast cancer through targeted metabolomics of amino acids components in serum of patients with breast cancer. METHODS: Patients with breast cancers were enrolled in our hospital between year January 1(st), 2013 and December 31(st), 2014. Targeted analysis of amino acids was performed using ESI-QTOF-MS instrument. In vitro experiment was performed to determine the influence of tryptophan towards interleukin-10 (IL-10) secretion by CD4+ T cell. RESULTS: Targeted metabolomics of amino acids showed that the level of tryptophan significantly (p<0.05) increased in patients with breast cancer. Furthermore, the biological function of tryptophan was determined through determining the influence of tryptophan towards IL-10 secretion using in vitro method. The addition of tryptophan (100 uM) in the cell medium can significantly inhibited the secretion of IL-10 by CD4+ T cells, as indicated by the mRNA level and protein concentration. CONCLUSION: The inhibition of IL-10 secretion by CD4+ T cells is a potential pathogenesis of breast cancer. PMID- 26957991 TI - The effect of parity on maternal body mass index, plasma mineral element status and new-born anthropometrics. AB - BACKGROUND: Adverse pregnancy outcome is an important public health problem that has been partly associated with increasing maternal parity. AIM: To determine the effect of parity on maternal body mass index (BMI), mineral element status and newborn anthropometrics. METHODS: Data for 349 pregnant women previously studied for the impacts of maternal plasma mineral element status on pregnancy and its outcomes was analysed. Obstetric and demographic data and 5mls of blood samples were obtained from each subject. Blood lead, plasma copper, iron and zinc were determined using atomic absorption spectrophotometer. RESULTS: Maternal BMI increases with parity. Women with parity two had significantly higher plasma zinc but lower plasma copper with comparable levels of the elements in nulliparous and higher parity groups. Although plasma iron was comparable among the groups, blood lead was significantly higher in parity > three. Newborn birth length increases with parity with a positive correlation between parity and maternal BMI (r = 0.221; p = 0.001) and newborn birth length (r = 0.170; p = 0.002) while plasma copper was negatively correlated with newborn's head circumference (r = -0.115; p = 0.040). CONCLUSION: It is plausible that parity affects maternal BMI and newborn anthropometrics through alterations in maternal plasma mineral element levels. While further studies are desired to confirm the present findings, there is need for pregnant and would-be pregnant women to diversify their diet to optimize their mineral element status. PMID- 26957992 TI - Relationship between soil cobalt and vitamin B12 levels in the liver of livestock in Saudi Arabia: role of competing elements in soils. AB - OBJECTIVE: This study aimed to analyze the agricultural soils from different regions in Saudi Arabia for cobalt and related metals as Cu(2+), Ni(2+), Cr(3+), Zn(2+) and Pb(2+). MATERIALS AND METHODS: Liver and muscle tissues of livestock grazing on the selected areas were analyzed for the content of Co and vitamin B12. RESULTS: Our results indicated that the levels of Co in surface soil (0-15 cm) were higher than in sub-surface soil (>15 cm-45 cm). In contrast, Pb and Zn were higher in sub-surface soil than in surface soil. A significant positive correlation existed between the levels of Co and vitamin B12 in the liver of livestock. However, Co was not detected in muscle tissues while vitamin B12 was present at very low levels in comparison with the levels found in the liver. The results indicated that Zn(2+), Pb(2+) compete with Co in soil, which eventually affected the levels of vitamin B12 in liver. CONCLUSION: It was recommended that survey of heavy metals in grazing fields of cattle should consider inclusion of multiple elements that compete with the bioavailability of essential elements in plants and animals for the prevention of deficiency of essential elements such as Co. PMID- 26957993 TI - An assessment of university students and staff perceptions regarding the use of human urine as a valuable soil nutrient in South Africa. AB - BACKGROUND: The declines in soil fertility associated with insufficient commercial fertilizers have resulted in the use of organic manure (human urine and faeces) as a source of fertilizers for production and cultivation of crop plants. The aim of this study was to assess perceptions of students and workers at the University of Limpopo (Medunsa Campus) regarding the fertilizing effect of urine. METHODS: A total of 225 questionnaires were administered to staff and students. The questionnaire sought to establish the knowledge, attitude and behavioural changes as regards the use of urine as a fertilizer for the cultivation of vegetables. RESULTS: Descriptive statistical analysis of the data indicated that 86.8% of the respondents were unaware of any human urine use as a fertilizer, 82.7% and 81.1% would not eat spinach and maize fertilized with urine respectively. Only 38.3% said they would eat vegetables fertilized with animal urine making it more tolerable as compared to human urine. Health reasons were given as the main reasons why respondents were unwilling to eat crops fertilized with human urine. However, 69.9% of the respondents [74.3% females, 69.9% students, 75.0% (27-36) age group] were willing to change their attitudes and unwillingness if they were better informed about the safety of human urine use for agricultural purposes. CONCLUSION: Education, awareness and reassurance on the importance and safety of urine would have to be done so that urine for agricultural purposes could become more acceptable to people. PMID- 26957994 TI - Comparison of the inhibition capability of oleanolic acid and betulinic acid towards drug-metabolizing enzymes. AB - BACKGROUND: Human UDP-glucuronosyltransferases (UGTs) are important membrane proteins located in endoplasmic reticulum, and play important roles in metabolism of a variety of endogenous and exogenous compounds. AIMS: To determine the influence of subtle difference in the structure of oleanolic acid and betulinic acid towards the inhibition towards the activity of UGT isoforms. METHODS: In vitro glucuronidation of 4-methylumbelliferone (4-MU) reaction was employed as the probe reaction to determine the inhibition of these two compounds towards UGTs' activity. RESULTS: The inhibition of capability of oleanolic acid towards UGT1A6 and UGT1A8 were higher than betulinic acid. However, no significant difference was observed for the inhibition of oleanolic acid and betulinic acid towards UGT1A7. Furthermore, concentration-dependent behaviour was determined for the inhibition of oleanolic acid and betulinic acid towards UGT1A6 and UGT1A8. At various concentrations of oleanolic acid and betulinic acid, the inhibition of oleanolic acid towards UGT1A6 and UGT1A8 was higher than betulinic acid. CONSLUSION: Given that UGT1A6 and UGT1A8 play key role in the the inhibition of oleanolic acid towards UGT1A6 and UGT1A8 will induce drug-drug interaction and the risk of diseases. PMID- 26957995 TI - The scourge of head injury among commercial motorcycle riders in Kampala; a preventable clinical and public health menace. AB - BACKGROUND: Trauma is an increasingly important cause of disease globally. Half of this trauma is from road traffic injuries with motorcycles contributing 21 58%. Low protective gear use, lack of regulation and weak traffic law enforcement contribute to unsafe nature of commercial motorcycles also known as "boda boda" in Uganda. OBJECTIVES: To determine the prevalence of protective gear use, the occurrence of head injury and the relationship between the two among commercial motorcycle riders in Kampala. METHODS: Following ethical approval we recruited consecutive consenting participants to this analytical cross-sectional study. Data was collected using pretested interviewer administered questionnaires, double entered in Epidata and analyzed with STATA. Proportions and means were used to summarize data. Odds ratios were calculated for association between wearing helmets and occurrence and severity of head injury. RESULTS: All 328 participants recruited were male. Of these, 18.6% used Protective gear and 71.1 % sustained head injury. Helmets protected users from head injury (OR 0.43, 95% CI, 0.23-0.8) and significantly reduced its severity when it occurred. CONCLUSION: Protective gear use was low, with high occurrence of head injury among commercial motorcycle riders in Uganda. More effective strategies are needed to promote protective gear use among Uganda's commercial motorcycle riders. PMID- 26957996 TI - The protection of glycyrrhetinic acid (GA) towards acetaminophen (APAP)-induced toxicity partially through fatty acids metabolic pathway. AB - BACKGROUND: Acetaminophen (APAP)-induced liver toxicity remains the key factor limiting the clinical application of APAP, and herbs are the important sources for isolation of compounds preventing APAP-induced toxicity. AIMS: To investigate the protection mechanism of glycyrrhetinic acid towards APAP-induced liver damage using metabolomics method. METHODS: APAP-induced liver toxicity model was made through intraperitoneal injection (i.p.) of APAP (400 mg/kg). Glycyrrhetinic acid was dissolved in corn oil, and intraperitoneal injection (i.p.) of glycyrrhetinic acid (500 mg/kg body weight) was performed for 20 days before the injection of APAP. UPLC-ESI-QTOF MS was employed to analyze the metabolomic profile of serum samples. RESULTS: The pre-treatment of glycyrrhetinic acid significantly protected APAP-induced toxicity, indicated by the histology of liver, the activity of ALT and AST. Metabolomics showed that the level of palmtioylcarnitine and oleoylcarnitine significantly increased in serum of APAP-treated mice, and the pre-treatment with GA can prevent this elevation of these two fatty acid carnitines. CONCLUSION: Reversing the metabolism pathway of fatty acid is an important mechanism for the protection of glycyrrhetinic acid towards acetaminophen-induced liver toxicity. PMID- 26957997 TI - Assessing unmet anaesthesia need in Sierra Leone: a secondary analysis of a cluster-randomized, cross-sectional, countrywide survey. AB - OBJECTIVES: To determine the unmet anaesthesia need in a low resource region. INTRODUCTION: Surgery and anaesthesia services in low- and middle-income countries (LMICs) are under-equipped, under-staffed, and unable to meet current surgical need. There is little objective measure as to the true extent and nature of unmet need. Without such an understanding it is impossible to formulate solutions. Therefore, we re-examined Surgeons OverSeas (SOSAS) unmet surgical need data to extrapolate unmet anaesthesia need. METHODS: For the untreated surgical conditions identified by SOSAS, we assigned anaesthetic technique required to carry out the procedure. The chosen anaesthetic was based on common practice in the region. Procedures were categorized into minimal anaesthesia, spinal anaesthesia, regional anaesthesia, ketamine/monitored anaesthesia care (MAC), and general endotracheal anaesthesia (GETA). DISCUSSIONS: Ninety-two per cent (687 of 745) of untreated surgical conditions in Sierra Leone would require some form of anaesthesia. Seventeen per cent (125 of 745) would require MAC, 22% (167 of 745) would require spinal anaesthesia, and 53% (395 of 745) would require GETA. CONCLUSION: Analyses such as this can provide guidance as to the rational and efficient production and distribution of personnel, drugs and equipment. PMID- 26957998 TI - Retroesophageal right subclavian artery: a case report and review of the literature. AB - BACKGROUND: Variations of vessels arising from the aortic arch are numerous. One of the common anatomical variations is the right subclavian artery originating as the last branch of the aortic arch. This is a report of a case of an adult male cadaver with a retroesophageal right subclavian artery. OBJECTIVE: To highlight the significance of a retroesophageal right subclavian artery, especially its clinical and surgical implications. METHOD: Is a report of a case of an anomalous vessel found during routine student dissection of the chest region in a male cadaver. RESULT: The retroesophageal subclavian artery was seen originating as the last branch from the postero-lateral aspect of the thoracic aorta at the vertebral level T4. The heart was normal with no other vascular variations seen in this region. CONCLUSION: Anatomists and pathologists mainly encounter a retroesophageal right subclavian artery by chance and is usually described as asymptomatic, but several clinical conditions have been associated with its occurrence. This is a clear example of when knowledge of an anatomical variation is helpful in clinical practice. PMID- 26957999 TI - A case report on near manual strangulation and glasgow coma scale. AB - BACKGROUND: Glasgow Coma Scale (GCS) is considered as a gold standard in estimating the prognosis of the comatose patient. The management of the patient relies heavily on this scale. The mechanism of injury must also be included in scoring of the GCS. Survival from strangulation is uncommon, and if it occurs, it is often associated with various complications such as neurological consequences. OBJECTIVE: To highlight a poor correlation with low GCS and ultimate outcome in cases of manual strangulation. CASE REPORT: This is a case report of young female adult who was raped and manually strangulated by a colleague during a training course for traditional healers. She was admitted with very low (3/15) Glasgow Coma Scale (GCS) and presumed to have a poor prognosis. She was rigorously ventilated in Intensive Care Unit (ICU), and was discharged from hospital after a week without any complications. The neck and genital injuries are described. This report discusses. CONCLUSION: A low Glasgow Coma Scale is not a predictive of poor prognosis in cases of manual strangulation. PMID- 26958000 TI - Blindness and scalp haematoma in a child following a snakebite. AB - BACKGROUND: Snake envenomation is a major public health problem of the Savannah regions of West Africa. Ocular manifestations of snakebites are rare with few reports documenting blindness as a complication. OBJECTIVE: To highlight an unusual manifestation of snake bites and its attendant problems. METHODS: A report of scalp haematoma and blindness in a 10 year old child presenting 2 weeks after a snake bite (presumably carpet viper) is a rare manifestation. Local swelling, epistaxis, bilateral proptosis, exposure keratopathy and use of traditional eye medications were associated findings. Anti-venom though administered late saved the child's life but blindness could not be reversed. RESULTS: Ocular ultrasonography revealed layered retrobulbar collection in the left eye, presumably due to hemorrhage. The skull x-ray showed a soft tissue swelling and aspirate from scalp swelling was bloody. Cranial Computed Tomography (CT) scan done late detected no abnormalities. CONCLUSION: Snakebite is associated with lifelong morbidity. Ocular manifestations must be treated as emergency. This case highlights the effect of ignorance and poverty in a setting of a common medical emergency leading to blindness and reduced quality of life. PMID- 26958001 TI - Multiple intracerebral lesions in a young male. AB - BACKGROUND: As the incidence of HIV infection has increased its neurological complications are being encountered in our clinical practice. Toxoplasmosis is a common cerebral opportunistic infection seen in HIV-infected patients, even though the incidence has declined with the use of antiretroviral therapy. Establishing a definitive diagnosis of cerebral toxoplasmosis is difficult in resource limited settings. CLINICAL CASE: A 20 year old gentleman was referred to our institute as a case of stroke. Magnetic resonance imaging (MRI) of his brain showed multiple ill-defined and nodular enhancing lesions in bilateral supratentorial and infratentorial neuroparenchyma. Test for HIV-1 was reactive. Toxoplasma serology revealed raised IgG antibody levels. Based on the MRI features and positive toxoplasma serology a diagnosis of cerebral toxoplasmosis was made. He was treated with trimethoprim/sulfamethoxazole and pyrimethamine/ Sulfadoxine for 3 weeks. After 2 weeks of treatment, repeat MRI of brain was done which showed significant resolution of the lesions. CONCLUSION: We are presenting this case to highlight the fact that cerebral toxoplasmosis should be considered in the differential diagnosis of multiple neuroparenchymal lesions in young individuals who present with neurological deficits. PMID- 26958003 TI - Hepatitis, HIV and Ebola: light at the end of the tunnel. PMID- 26958002 TI - The role of non-governmental organizations in providing curative health services in North Darfur State, Sudan. AB - BACKGROUND: Conflict in North Darfur state, Western Sudan started in 2003, and the delivering of curative health services was becoming a greater challenge for the country's limited resources. NGOs have played an important role in providing curative health services. OBJECTIVES: To examine the role that Non-Governmental Organizations (NGOs) have played in providing curative health services, as well as to identify the difficulties and challenges that affect NGOs in delivering curative health services. METHODS: Secondary data was collected from different sources, including government offices and medical organizations in Sudan and in North Darfur state. Primary data was obtained through interviews with government and NGOs representatives. The interviews were conducted with (1) expatriates working for international NGOs (N=15) (2) health professionals and administrators working in health sector (N= 45) in the period from November 2010 to January 2011. RESULTS: The government in North Darfur state spent 70% of its financial budget on security, while it spent it less than 1% on providing health services. The international NGOs have been providing 70% of curative health services to the State's population by contributing 52.9% of the health budget and 1 390 health personnel. Since 2003 NGOs have provided technical assistance to the health staff. As a result, more than fifty nurses have been trained to provide care and treatment, more than twenty-three doctors have been trained in laboratory equipment operation, and approximately six senior doctors and hospital directors have received management training. NGOs have been managing and supporting 89 public health facilities, and established 24 health centres in IDP camps, and 20 health centres across all the districts in North Darfur state. CONCLUSION: The NGOs have played an important role in providing curative health services and in establishing good health facilities, but a future problem is how the government will run these health facilities after a peaceful settlement has been reached which might cause NGOs to leave the region. PMID- 26958004 TI - Contraceptive non-use and associated factors among university students in 22 countries. AB - BACKGROUND: The aim of this study was to investigate contraceptive non-use and associated factors (socio-demographics, sexual behaviour, internal assets and mental health) among undergraduate university students in 22 countries. METHODS: Using anonymous questionnaires, data was collected from 16979 undergraduate university students (mean age 20.8, SD=2.8) from 23 universities in 22 countries. RESULTS: Of the total sample of 16979 undergraduate university students, 7032 (41.9%) reported to have been sexually active in the past 12 months. Of those who had been sexually active, 42.6% reported never (42.7% among male and 42.6% among female students) using contraceptives in the past 12 months. In multivariate regression analysis, among both men and women, younger age, religious affiliation (Hindu; and among women only being Muslim), intrinsic religiosity, and sexually protective behaviour were associated with contraceptive non-use. Lack of internal assets (among men, low life satisfaction and lack of personal control, and among women low personal mastery) ; among women not having depressive symptoms and among men having PTSD symptoms were associated with contraceptive non-use. CONCLUSION: Low contraceptive use was found and several factors identified as associated with contraceptive non-use may help guide intervention efforts. PMID- 26958005 TI - Sexual orientation and quality of life among students of Obafemi Awolowo University (OAU), Nigeria. AB - BACKGROUND: Sexual orientation is an individual's pattern of physical and emotional arousal toward members of the same and/or opposite gender. OBJECTIVE: To determine the pattern of sexual orientation and the relationship between sexual orientation and quality of life among a sample of OAU students. METHODS: A descriptive cross sectional study among 481 students of OAU using a multistage sampling technique. They completed a Socio-demographic data schedule, questions on sexual orientation and the World Health Organization Quality of Life Scale - Brief version (WHO QOL-BREF). RESULTS: 4.9% of the sample self-identified as bisexual while 0.1% self-identified as gay/lesbian. 11.8% of the respondents reported varying degrees of attraction to the opposite gender. The mean age of sexual debut was 17.62 (+/-4.05). Those who self-identified as gay/lesbian/bisexual had a lower average score on all domains of the WHO QOL BREF. CONCLUSION: Same sex sexual attraction and practice occur among young people in Nigeria and this has sexual and reproductive health implications. GLB youth report a lower QOL compared to heterosexual counterparts and this may suggest some distress among this vulnerable group. More studies should be undertaken to explore issues raised in planning interventions and health services that would improve safe sexual practices within this group. PMID- 26958006 TI - "The fairer the better?" Use of potentially toxic skin bleaching products. AB - BACKGROUND: Skin bleaching is a widespread phenomenon in spite of their potentially toxic health effects. OBJECTIVES: This study aimed to determine if such products are used in Sweden in particular by pregnant women, furthermore to explore immigrant women's view skin bleaching. METHODS: 455 pregnant women completed a questionnaire, which were statistically analysed. Focus groups and individual interviews were conducted with immigrant women, content analysis was used to assess the data. RESULTS: Skin bleaching products were used by 2.6% of pregnant women, significantlly more by women born in non-European countries. Motivating factors were associated with the concept of beauty together with social and economic advantages. The women had low awareness of the potential health risks of the products. Regulations on the trade of skin bleaching products have not effectively reduced the availability of the products in Sweden nor the popularity of skin bleaching. CONCLUSION: There is need for further research especially among pregnant women and possible effects on newborns. Products should be tested for toxicity. Public health information should be developed and health care providers educated and aware of this practice, due to their potential negative health implications. PMID- 26958007 TI - Hydatidiform moles among patients with incomplete abortion in Mwanza City, North western Tanzania. AB - BACKGROUND: Prevalence of hydatidiform mole is not clearly defined, partly because most studies have reported different prevalence rates from different regions. However, there is no previous study that has determined the prevalence and associated risk factors of HM among patients with incomplete abortion evacuated at Bugando Medical Centre (BMC) and Sekou Toure Regional Hospital (STRH). METHODS: A total of 180 patients with incomplete abortion were enrolled between February 2013 and April 2013. The products of conception were collected and analyzed using Haemotoxylin and Eosin staining technique for hydatidiform moles. RESULTS: One hundred and eighty patients with incomplete abortion scheduled for uterine evacuation agreed to participate in this study. The overall prevalence of HM was 12.8%. Majority of patients (27.5%) with HM were those aged below 20 years. No significant association was observed with risk factors such as parity, contraceptive use, previous abortion and blood group. CONCLUSION: The prevalence of HM (12.8%) was high and age between 15-20 years was the only significant associated risk factor with the presence of HM among patients with incomplete abortion. Therefore, we recommend submission of evacuated products of conception for histopathological analysis to minimize missed opportunity. PMID- 26958008 TI - Prevalence of intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) use during pregnancy and other associated factors in Sekondi-Takoradi, Ghana. AB - BACKGROUND: Intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) has been adopted as policy by most countries in sub-Saharan Africa. This cross-sectional study assessed the prevalence of IPTp-SP usage for prevention of malaria among pregnant women as well as evaluated factors associated with IPTp-SP use during pregnancy in Sekondi-Takoradi region of Ghana. METHODS: Pregnant women attending their antenatal-care with either clinical/ultrasound evidence of pregnancy were recruited. Venous blood was screened for malaria using RAPID response antibody kit and Giemsa staining. Haemoglobin estimations were done by cyanmethemoglobin method while Human Immunodeficiency Virus (HIV) screening was performed by the national diagnostic algorithm of two rapid antibody test and western blot confirmation. RESULTS: Of the 754 consented pregnant women interviewed in this study, 57.8% had received IPTp-SP while 42.2% had not at their first contact with the study personnel. Furthermore, 18.6% (81/436) of those that received IPTp-SP were malaria positive while 81.4% (355/436) were malaria negative. The results also indicated that 47.7% (51/107) of the pregnant women in their third trimester who were meant to have received at least two-doses of SP had received >=2 doses while 35.5% (38/107) had received 1 dose. In multivariable logistic regression analysis, pregnant women in their third trimester who received >=2 doses of SP showed decreased likelihoods of malaria (adjusted OR, 0.042; 95% CI, 0.003-0.51; P = 0.013). CONCLUSION: IPTp-SP usage among pregnant women in Sekondi-Takoradi reduces malaria and its use for malaria prevention should be strengthened with proper dosage completion and coverage. PMID- 26958009 TI - Effect of early amniotomy on the outcome of spontaneous labour: a randomized controlled trial of pregnant women in Enugu, South-east Nigeria. AB - BACKGROUND: Early amniotomy is common in obstetric practice but, its effectiveness has not been proven. OBJECTIVES: To determine the effects of early amniotomy on the duration of labour, and other maternal / neonatal outcomes of uncomplicated pregnancies in Enugu, South-east Nigeria. METHODS: A randomized controlled study of 214 consenting term pregnant women at the University of Nigeria Teaching Hospital Enugu, Nigeria. Intervention group received amniotomy early in active labour while the control group had their membranes conserved. RESULTS: Mean duration of labour for the amniotomy group (279.4 +/- 53.7 minutes) was significantly lower than that of control group (354.4 +/- 67.5 minutes), (t = -8.988, p <0.001). Three (3.8%) women in amniotomy group needed oxytocin augmentation as against 21 (19.6%) women in the control group RR = 0.14, (CI 95%: 0.04 - 0.46), NNT = 16. The two groups did not vary with respect to cesarean section rate, newborn Apgar scores, and need for new born special care unit admission. CONCLUSION: Early amniotomy when compared to fetal membrane conservation reduced the duration of labour and need for oxytocin augmentation among term singleton pregnant women in Enugu, Nigeria. Its routine use in well selected cases may reduce prolonged labour and its complications. PMID- 26958010 TI - Obstetric vesico-vaginal fistulae seen in the Northern Democratic Republic of Congo: a descriptive study. AB - BACKGROUND: The Democratic Republic of Congo (DRC) is a developing country with poor obstetric indicators. Despite ongoing efforts to improve care, women continue to suffer multiple complications of child birth including vesico-vaginal fistulae (VVF). OBJECTIVE: To describe socio-demographic and clinical characteristics of VVF patients in Northern DRC. METHODS: Women presenting at two VVF mobile surgical campaign missions in the province of Equateur in Northern DRC in August 2012 and October 2013 were examined and treated for VVF. We collected socio-demographic data, including marital status, education, and accompaniment by husbands for treatment, as a proxy for marital support, and clinical data related to characteristics of VVF in patients, duration of illness, and the outcome of treatment surgery. RESULTS: Out of 163 VVF patients, 100 (61.3%) were less than 35 years old, 102 had no formal education ( 62.6%), and 100 were married ( 61.3%). The mean duration of illness before surgery was 8.4 years. Successful surgery rate for VVF was 87.1% (142/163). A majority of patients who were married, were accompanied to the hospital by their husbands for treatment (56/100; 56.00%). Association analysis revealed age was the only variable that maintained significant association with duration of illness after multivariate analysis (p-value <0.0001). Marital status was the only variable associated with surgical outcome (0.334, 95% CI 0.125- 0.847, p-value = 0.021). CONCLUSION: We found that most VVF patients were young adults, not educated, and married. Marital status and age may have important roles in outcome of VVF surgery and duration of illness, respectively. PMID- 26958011 TI - Correlation of ultrasonographic estimated fetal weight with actual birth weight in a tertiary hospital in Lagos, Nigeria. AB - BACKGROUND: Sonographic fetal weight estimation is an important component of antenatal care. AIM: To sonographically estimate fetal weight at term and to compare estimated with actual birth weights to determine the validity of estimated fetal weights. SUBJECTS AND METHODS: In the prospective study, a convenience sample of 282 women was recruited. Ethical approval and informed consent of patients were obtained. An experienced sonographer estimated fetal weights by measuring BPD, HC, AC and FL using a scanner with Hadlock 3 weight estimation model. Actual birth weights were measured with a Crown weighing scale by a midwife. Data was analyzed with SPSS software version 17.0 while descriptive and inferential statistics were used to interpret results. Results were tested at error level set at p<= 0.05. RESULTS: Mean estimated and actual birth weights were 3378+/-40g and 3393+/-60g respectively. Difference between the two means was not significant. Eleven percent of fetuses were sonographically estimated to be microsomic while 14.5% were microsomic at birth; 12.1% were sonographically estimated to be macrosomic but 15.2% were macrosomic at birth. Most macrosomic fetuses were delivered through cesarean section(CS) and fetal weights increased with maternal age and parity. CONCLUSION: Sonographically estimated fetal weight using Hadlock 3 weight estimation model without validation correlated positively with actual birth weight in a Nigerian population. PMID- 26958012 TI - Prevalence and determinants of low birth weight: the situation in a traditional birth home in Benin City, Nigeria. AB - BACKGROUND: The traditional birth attendant delivers majority of pregnant women in Nigeria. OBJECTIVE: This study aimed at determining the prevalence and associated risk factors for delivery of low birth weight (LBW) neonates in a Traditional Birth Home (TBH)in Benin City, Nigeria. METHODS: A total of 780 pregnant women who received ante-natal care at a TBH and live singletons born to them were recruited for this study. Venous blood was collected from all pregnant women at onset of labour, and haemogblobin concentration determined using standard method. RESULTS: The prevalence of low birth weight was 6.3%, and was significantly affected by maternal age (P =0.039), gestational age (P=0.019), maternal height (P = 0.001), marital status (P = 0.015), and time of registration (P = 0.016). Being in a polygamous union, was significantly associated with the prevalence of LBW (OR = 13.640; 95%CI: = 6.148, 30.261; P = < 0.0001). Maternal anaemia was identified as a risk factor for the delivering of LBW neonates (OR = 2.797; 95% CI = 1.555, 5.029; P = 0.0001). CONCLUSION: The prevalence of low birth weight was 6.3%. Intervention by appropriate agencies is advocated to reduce LBW in TBHs in Nigeria. PMID- 26958013 TI - Magnitude and factors associated with delayed initiation of breastfeeding among mothers who deliver in Mulago hospital, Uganda. AB - BACKGROUND: Breastfeeding as a determinant of infant health and nutrition saves up to 1.5 million infant lives annually. Though breastfeeding is mostly universal in sub-Saharan Africa, early initiation of breastfeeding is rarely practiced. OBJECTIVE: To determine magnitude and factors associated with delayed initiation of breastfeeding among mother-infant pairs who deliver in Mulago hospital. METHODS: We carried out a descriptive cross sectional study, where 665 mother infant pairs were interviewed within 24 hours following delivery; with additional qualitative data collected using focus group discussions to understand reasons for delaying initiation. The data was analysed by identification and coding of themes. RESULTS: In this study, 31.4% mothers delayed initiation of breastfeeding. This was associated with maternal HIV positive status (AOR 2.3; 95% CI 1.3-4.2), inadequate prenatal guidance, (AOR 3.6; 95% CI 1.9-6.8), inadequate professional assistance to initiate breastfeeding (AOR 1.8; 95% CI 1.2 2.8) and caesarean section delivery (AOR 8.6; 95% CI 4.7-16.0). Other reasons were perceived lack of breast milk, need of rest for both mother and baby after labor, and negative cultural beliefs. CONCLUSION: In Mulago Hospital 1:3 mothers delayed initiation of breastfeeding. The reasons for delayed initiation include; inadequate information during ANC, HIV positive serostatus, caesarian section delivery and negative cultural ideas. PMID- 26958014 TI - Burden and pattern of micro vascular complications in type 2 diabetes in a tertiary health institution in Nigeria. AB - INTRODUCTION: Diabetes mellitus (DM) afflicts at least 5 million people in Nigeria, with more than 80% having type 2 diabetes mellitus (T2DM). Microvascular complications increase both morbidity and mortality inpatients with T2DM. The aims of this study were to report the burden of various microvascular complications in T2DM and to identify various factors associated with these complications in patients with T2DM attending the diabetes outpatients' clinic. METHODS: Ninety (90) patients with T2DM who have attended diabetes clinic for at least 3 months were recruited for this study. Detailed history, physical examination and biochemical analysis was done in each of the patients. All patients underwent a detailed standard evaluation to detect diabetic retinopathy (fundoscopy), neuropathy (10g monofilament and/or diabetes neuropathy scores), and nephropathy (microalbuminuria, macroalbuminuria, serum creatinine and estimated glomerular filtration rate). RESULTS: There was high prevalence of microvascular complications among patients with T2DM. Almost half of patients with T2DM had some form of microvascular complications; diabetic neuropathy being the commonest (69.6%),followed by nephropathy (54.5%) and retinopathy (48.9%). The factors associated with developing these complications were increasing age, duration of diabetes, hypertension and dyslipidaemia for nephropathy and neuropathy. CONCLUSION: There is a high burden of microvascular complications in patients with type 2 diabetes. Age, male gender, hypertension, glycaemic control, BMI and duration of diabetes, and glycaemic control were factors associated with microvasular complications. PMID- 26958015 TI - Aerobic exercises alleviate symptoms of fatigue related to inflammatory cytokines in obese patients with type 2 diabetes. AB - BACKGROUND: Non-insulin dependent diabetic patients frequently suffer from fatigue symptoms that result from chronic systemic inflammation. Aerobic exercise was proved to modulate systemic inflammation. OBJECTIVE: This study was an attempt to measure the impact of aerobic exercises on fatigue symptoms related to systemic inflammation in obese patients with type 2 diabetes. METHODS: Eighty obese patients with type 2 diabetes participated in the present study, their age ranged from 40-58 years and their BMI ranged from 31-36 kg/m2 and were assigned to two subgroups; group (A) received aerobic exercise training for 12 weeks and group (B) received no exercise training for 3 months. Measurements of fatigue symptoms and markers of systemic inflammation were assessed before and at the end of the study for all participants in both groups. RESULTS: The mean values of inflammatory markers (IL-6 and TNF-alpha) and Multidimensional Fatigue Inventory (MFI) was significantly decreased in group (A), while changes were not significant in group (B). Moreover, there were significant differences between mean levels of the investigated parameters in group (A) and group (B) at the end of the study. CONCLUSION: Treadmill walking exercise training is an effective treatment policy to improve symptoms of fatigue related to inflammatory cytokines in obese patients with type 2 diabetes. PMID- 26958016 TI - Contribution of ENPP1, TCF7L2, and FTO polymorphisms to type 2 diabetes in mixed ancestry ethnic population of South Africa. AB - BACKGROUND: Transcription factor 7-like 2 gene (TCF7L2), fat mass and obesity associated gene (FTO), and ectonucleotide pyrophosphatase/phosphodiesterase gene (ENPP1) are known risk loci for type 2 diabetes (T2DM) mostly in European populations. OBJECTIVES: To assess the association of these genes with T2DM risk in a South African mixed-ancestry population. METHODS: Five hundred and sixty six participants were genotyped for ENPP1-rs997509 and -rs1044498, FTO-9941349 and rs3751812, TCF7L2-rs12255372 and -rs7903146 polymorphisms using Taqman genotyping assays and validated by automated sequencing to assess the association of the polymorphisms with cardiometabolic traits. RESULTS: In logistic regression models adjusted for age, sex, body mass index (BMI) and insulin resistance, minor allele of rs997509 was associated with a higher risk of prevalent T2DM under a recessive model [odd ratio 4.60 (95% confidence interval: 1.07 to 19.86); p = 0.040].Under additive model, the rs7903146 [1.43 (1.00 to 2.04); p= 0.053] and rs9941349 [1.43 (1.00 to 2.04); p = 0.052] minor alleles showed marginally significant associations with a high risk of T2DM. However, only the rs7903146 alleles (p=0.011) and genotypes (p=0.025) distributions were statistically significantly different between diabetic and non-diabetic individuals. CONCLUSION: Our findings demonstrate that ENPP1, TCF7L2, and FTO may predispose to T2DM in the mixed ancestry population. PMID- 26958017 TI - Low serum 25(OH)D levels are associated to higher BMI and metabolic syndrome parameters in adult subjects in Turkey. AB - BACKGROUND: The aim of this study was to investigate the association of 25(OH)D levels with biochemical, anthropometric, and metabolic data obtained from normal and obese people. METHODS: This study was carried out on 90 individuals between the ages of 18 to 63 that had various body mass indexes. Blood samples and anthropometric measurements were taken. RESULTS: Waist circumferences, fat mass, LDL cholesterol levels, HDL cholesterol levels, 25(OH)D levels, and triglyceride levels were significantly different according to the body mass index groups of the participants (p<0.05). When compared to the normal body mass index group, both other groups (overweight and obese) had higher waist circumferences, triglyceride levels, LDL cholesterol levels, fasting insulin levels, HOMA-IR ratios, parathyroid hormone levels, and fat mass, and had lower 25(OH)D levels (p<0.05). The overweight group participants had higher 25(OH)D levels than the obese group, and had lower waist circumferences, fat mass, fasting insulin level, HOMA-IR ratios, and HbA1C and PTH levels than those in the obese group (p<0.05). CONCLUSION: In conclusion, the mean level of 25(OH)D is very low in overweight and obese individuals and low serum 25(OH)D levels appear to be associated with obesity, visceral obesity, hypertriglyceridemia, insulin resistance, and metabolic syndrome in obese patients. PMID- 26958018 TI - Effect of low-intensity continuous training on lung function and cardiorespiratory fitness in both cigarette and hookah smokers. AB - BACKGROUND: The decline in cardiorespiratory fitness and lung function was higher in smokers. Training method could mitigate some of the negative consequences of smoking among smokers unable or unwilling to quit. OBJECTIVE: To examine the effects of continuous training on lungs functional capability and cardiorespiratory fitness in smokers. METHODS: Fifteen cigarette smokers, 14 hookah smokers, and 14 nonsmokers were assigned to low-intensity continuous training (20-30 minutes of running at 40% of maximum oxygen uptake (O2max)). Lung function and cardiorespiratory fitness parameters were determined using respectively spirometer and treadmill maximal exercise test. RESULTS: Continuous training improved forced expiratory volume in one second (FEV1) and forced expiratory flow at 50% of FVC (FEF50 %) in all participants, smokers and nonsmokers (p < 0.05). In contrast, forced vital capacity (FVC) improvement was significant only among cigarette smokers (CS) (+1.7+/-2.21%, p < 0.01) and hookah smokers (HS) (+1.3+/-1.7 %, p < 0.05). Likewise, an improvement in cardiorespiratory fitness in both smokers groups without significant changes in diastolic blood pressure (DBP) for CS group and in velocity at maximum oxygen uptake (vO2max) for HS group. CONCLUSION: The low-intensity continuous training improves cardiorespiratory fitness and reduces lung function decline in both cigarette and hookah smokers. It seems to be beneficial in the prevention programs of hypertension. It could have important implications in prevention and treatment programs in smokers unable or unwilling to quit. PMID- 26958019 TI - Proportion of patients in the Uganda rheumatic heart disease registry with advanced disease requiring urgent surgical interventions. AB - INTRODUCTION: Since the establishment of the Uganda Rheumatic Heart Registry, over 900 patients have been enrolled. We sought to stratify the patients in the registry according to disease severity and optimal management strategy. METHODS: We reviewed data of 618 patients who had enrolled in the Registry between March 2010 and February 2013. The 67 patients who had died were excluded leaving 551 patients who were recruited. The optimum management strategy was determined according to the 2012 European Society of Cardiology guidelines on the management of valvular heart disease. RESULTS: Out of the 551 patient's records evaluated, 398 (72.3%) required invasive intervention, with 332(60.3%) patients requiring surgery and 66 (12.0%) requiring percutaneous mitral commissurotomy (PMC). This leaves only 27.7% of patients who required only medical management. Currently, majority of the patients (498, 90.4%) in the registry are on medical treatment. Of the 60.3% requiring surgical intervention, only 8.0% (44 patients) underwent valvular surgery and 5(1.0%) patients of the 66 (12.0%) underwent PMC successfully. CONCLUSION: There is a high proportion of patients with severe disease that require surgical treatment yet they cannot access this therapy due to absence of local expertise. PMID- 26958020 TI - Guidance on the diagnosis and management of asthma among adults in resource limited settings. AB - BACKGROUND: Optimal management of asthma in resource limited settings is hindered by lack of resources, making it difficult for health providers to adhere to international guidelines. The purpose of this review is to identify steps for asthma diagnosis and management in resource limited settings. METHODS: Review of international asthma guidelines and other published studies on diagnosis and management of asthma. RESULTS: We establish that clinical diagnosis of asthma can be made if recurrent respiratory symptoms especially current wheeze or wheeze in the last 12 months are present. Presence of a trigger, other allergic diseases, personal or family history of asthma; clinical improvement and increase in the peak flow and forced expiratory volume in one second of >=12% after salbutamol administration increases the likelihood of asthma. At diagnosis severity grading, patient education, removal or reduction of trigger should be done. Follow up 2-6 weeks and assessment of control during therapy is essential. Therapy should be adjusted up or down depending on control levels. Patients should be instructed to increase the frequency of their bronchodilators and/or steroids therapy when they start to experience worsening symptoms. CONCLUSION: Good quality asthma care can be achieved in resource limited settings by use of clinical data and simple tests. PMID- 26958021 TI - Bile acids cycle disruption in patients with nasopharyngeal carcinoma promotes the elevation of interleukin-10 secretion. AB - BACKGROUND: Unclear pathogenesis existed for nasopharyngeal carcinoma. AIMS: to analyze the role of bile acids in the pathogenesis of nasopharyngeal carcinoma. METHODS: 20 healthy volunteers and 20 patients with nasopharyngeal carcinoma were enrolled between January 1(st), 2013 and December 31(st), 2014. ESI-QTOF-MS analysis of serum was performed to find altered bile acids components. The biological function of changed bile acids was investigated using in vitro experiment. RESULTS: Compared with healthy volunteers, the level of DCA and GDCA exhibited higher abundance in patients with nasopharyngeal carcinoma (p<0.01). Furthermore, the biological function was investigated for the inhibition of DCA and GDCA towards the secretion of IL-10 by CD4+CD25- T cells. Both DCA and GDCA significantly inhibited the secretion of IL-10 by CD4+CD25- T cells. Furthermore, DCA+GDCA can show stronger inhibition towards the secretion of IL-10 than DCA and GDCA. CONCLUSION: The inhibition of IL-10 secretion by elevated DCA and GDCA components in nasopharyngeal carcinoma patients is the inducer for nasopharyngeal carcinoma. PMID- 26958022 TI - No relation between EFHC2 gene polymorphism and Idiopathic generalized epilepsy. AB - BACKGROUND: Idiopathic generalized epilepsy (IGE) is an epilepsy form without an underlying brain lesion or neurological indication or symptom. Recent investigations on the genetic origins of IGE and its subtypes report that certain mutations of various ion and non-ion channels genes in the central nervous system may be associated with IGE. PURPOSE: In this study we evaluated the relation between IGE and S430Y polymorphism in EFHC2 gene in a Turkish population. MATERIAL/METHODS: The study enrolled 96 healthy volunteers (47 male, 49 female), served as controls, and 96 IGE patients (41 male, 55 female), IGE diagnosis was confirmed in the neurology department. DNA extractions were performed. The presence of S430Y polymorphism in the exon 9 of EFHC2 gene were analyzed by Real Time PCR. The findings obtained from the control and patient groups were compared. RESULTS: In the patient group there was one heterozygous male with 685 T>C mutation. In the control group, there were two objects with 685 T>C mutation; one heterozygous male, one heterozygous female. 662 G>A mutation was determined in neither controls nor patients. CONCLUSION: In our series of 96 IGE patients and 96 healthy controls, there was no relation between S430Y polymorphism in EFHC2 gene and IGE presence. PMID- 26958023 TI - Perceived stigma and associated factors among people with epilepsy at Gondar University Hospital, Northwest Ethiopia: a cross-sectional institution based study. AB - BACKGROUND: Epilepsy is the world's most common neurological disorder, affecting approximately 69 million people worldwide. Perceived stigma affects many domains of the lives of people with epilepsy. However, in Ethiopia there is dearth of study on perceived stigma specifically among people with epilepsy. OBJECTIVE: To assess the prevalence of perceived stigma and associated factors among people with epilepsy (PWE) attending the outpatient department of the University of Gondar hospital, Northwest Ethiopia, 2014. METHODS: Institution based quantitative cross - sectional study was employed among 408 individuals people with epilepsy. Single population proportion formula was used utilized to calculate sample size. The participants were selected using systematic random sampling technique. Perceived stigma was measured using by the modified Family Interview Schedule (FIS) tool. Binary logistic regression analysis and adjusted odds ratio with 95% confidence interval were used to identify the associated factors with perceived stigma.. RESULTS: Overall, the prevalence of perceived stigma was found to be 71.6%. Marital status [single (AOR = 0.23, CI: 0.25, 0.90), widowed ( AOR = 0.37, CI: 0.15, 0.90) duration of illness [2-5 years (AOR = 4.38, CI:1.98,9.62, 6-10 years (AOR =4.29, CI:1.90,9.64, >=11 years (AOR = 4.31,CI:1.84,10.00) and seizure frequency of [1-11per year (AOR=2.34, CI:2.21,3.56), >=1per month (AOR = 5.63, CI:3.42,10.32)] were factors associated with perceived stigma. CONCLUSION: Overall, the prevalence of perceived stigma was found to be high. Marital status, long duration of illness and seizure frequency were factors associated with perceived stigma. PMID- 26958024 TI - Post-stroke depression among stroke survivors attending two hospitals in Kampala Uganda. AB - BACKGROUND: The burden of stroke worldwide is increasing rapidly. There is paucity of data on post-stroke depression (PSD) among stroke survivors in Uganda, despite the high prevalence of PSD reported elsewhere. METHODS: In a cross sectional study, we assessed adult participants with confirmed first stroke with a standardized questionnaire. The Patient Health Questionnaire-9 was used to assess for depression among non-aphasic patients while the Aphasic Depression Rating Scale was administered to aphasic patients. Univariable and multivariable analyses performed to describe associations with PSD. RESULTS: Forty three females (58.9%) and 30 males (41.1%) who had a stroke participated. Fifty eight (79.5%) had ischemic strokes and 12 participants (16.4%) were aphasic. The prevalence of PSD among the study participants was 31.5%. PSD was higher among patients assessed within 6 months after the onset of stroke. PSD was strongly associated with the total Barthel index of activities of daily living (BIADL) score; p=0.001. There was no significant association between demographic characteristics and PSD. CONCLUSION: There is a high prevalence of unrecognized post-stroke depression. Post-stroke depression was strongly associated with the patient's inability to undertake activities of daily life. There is urgent need for integration of screening for and management of post-stroke depression among stroke survivors. PMID- 26958025 TI - Clinical and genetic data of Huntington disease in Moroccan patients. AB - BACKGROUND: Huntington's disease (HD) occurs worldwide with prevalence varying from 0.1 to 10/100,000 depending of the ethnic origin. Since no data is available in the Maghreb population, the aim of this study is to describe clinical and genetic characteristics of Huntington patients of Moroccan origin. METHODS: Clinical and genetics data of 21 consecutive patients recruited from 2009 to 2014 from the outpatient clinic of six medical centers were analyzed. Statistical analysis was performed using descriptive statistics. RESULTS: Twenty one patients from 17 families were diagnosed positive for the IT15 gene CAG expansion. Clinical symptoms were predominantly motor (19/21). Twelve patients had psychiatric and behavioral disorders, and 11 patients had cognitive disorders essentially of memory impairment. Analysis of genetic results showed that 5 patients had reduced penetrant (RP) alleles and 16 had fully penetrant (FP) alleles. The mean CAG repeat length in patients with RP alleles was 38.4 +/- 0.54, and 45.37 +/- 8.30 in FP alleles. The age of onset and the size of the CAG repeat length showed significant inverse correlation (p <0.001, r = -0.754). CONCLUSION: Clinical and genetic data of Moroccan patients are similar to those of Caucasian populations previously reported in the literature. PMID- 26958026 TI - A systematic review of published literature describing factors associated with tuberculosis recurrence in people living with HIV in Africa. AB - BACKGROUND: A summary of factors associated with recurrent tuberculosis (TB) in the African HIV-infected population is lacking. We performed a systematic review to address this. METHODS: We performed a literature search within PubMed and The WHO Global Library with specific inclusion and exclusion criteria to identify manuscripts emanating from the African continent which potentially described factors associated with recurrent TB in persons living with HIV. RESULTS: The literature search yielded 52 unique manuscripts, of which only 4 manuscripts were included in the final systematic review following application of the inclusion and exclusion criteria. Baseline CD4 count, baseline HIV viral load, a positive tuberculin skin test, prior active TB disease, cutaneous hypersensitivity reaction to treatment, having < 3 lung zones affected by prior TB disease, and anaemia were associated with recurrent TB in HIV-infected individuals, whilst age and antiretroviral status were not. CONCLUSION: The lack of studies describing recurrent TB in Africa which stratify results by HIV-status is a hindrance to understanding risk factors for recurrent TB in this population. This might be overcome by implementing guidelines related to the publishing of data from observational studies in peer-reviewed medical journals reporting recurrent TB in populations with a high-burden of HIV infection. PMID- 26958027 TI - Prevalence of positive tuberculin skin test and associated factors among Makerere medical students, Kampala, Uganda. AB - BACKGROUND: Tuberculosis infection among medical students is thought to be higher than that among comparable groups. OBJECTIVES: To determine the prevalence of positive Tuberculin Skin Test (TST) and associated factors among medical students at Makerere University. METHODS: A-cross-sectional study among randomly selected medical students. Using intra-dermal technique, TST was performed by administering 0.1ml of purified protein derivative. Readings performed after 72 hours and positive TST based on an induration of >=10mm. RESULTS: Of 302 students selected to participate, 292 received TST and 288 were analyzed. Of 288 students, 173(60%) were pre-clinical (years 1-3) and 115(40%) clinical (years 4&5). Overall 130 students [45.1%(C.I.39.3-51.1)] had positive TST, not different from one derived from mixture analysis [46.3%(95% Bayesian credibility interval 36.5% 55.8%)]. Positive TST prevalence among pre-clinical was 39.9%(67/173) compared to 53.0%(61/115) among clinical students, OR=1.70,C.I.(1.06-2.74) and increases in a linear pattern with increasing years of study (p=0.002,OR=5.04). CONCLUSION: The prevalence of TB infection among medical students was twice higher than that of adults living in the suburbs and higher among those in clinical relative to pre clinical years suggesting that exposure and infection might be related to clinical work. We recommend urgent institution of infection control measures. PMID- 26958028 TI - Effects of treatment on free radicals in patients with pulmonary tuberculosis in South Western Nigeria. AB - BACKGROUND: Formation of Malondialdehyde (MDA), a free radical, in Tuberculosis patients does occur when Tubercule bacilli induces reactive oxygen species as a result of phagocytic respiratory burst. OBJECTIVES: This study evaluated the effect of treatment on plasma level of Malondialdehyde among patients infected with Mycobacterium Tuberculosis in Osogbo South Western Nigeria. METHODOLOGY: Descriptive cross sectional study among 110 patients, grouped into four categories (three TB patient categories and controls). All patients were screened for presence or absence of Mycobacterium tuberculosis in their sputum and HIV 1 & 2 in their blood using standard techniques. The level of free radical (Malondialdehyde, MDA) was determined by Thiobabituric acid reacting method. Data was analyzed using the SPSS software version 17.0. RESULTS: Serum Malondialdehyde (MDA) levels were significantly lower in TB patients on drugs (TBD) compared with the new cases on treatment (NCT). (0.17+0.88mol/L Vs 0.27+0.08mol/L, p<0.05). Varying degrees of correlations were also found between free radicals and electrolytes. CONCLUSION: Reduced serum MDA levels in TBD suggested a reduction in the levels of free radical injury once treatment was commenced. Therefore serum free radical may be an index of monitoring response to treatment in tuberculosis management. PMID- 26958029 TI - In vivo anti-plasmodial activities and toxic impacts of lime extract of a combination of Picralima nitida, Alstonia boonei and Gongronema latifolium in mice infected with Chloroquine-sensitive Plasmodium berghei. AB - BACKGROUND: Lime extracts of powdered combination of seeds of Picralima nitida, stem bark of Alstonia boonei and leaves of Gongronema latifolium is a common remedy used in the treatment of malaria in South Western Nigeria. OBJECTIVE: To determine the antiplasmodial activities of the combined herbal extracts and its impact on the haematological, hepatological and renological parameters in mice. METHODS: The 4-day suppressive and curative tests were used to assess the antiplasmodial activities of the extract in mice infected with chloroquine sensitive Plasmodium berghei at concentration of 200mg/kg, 400mg/kg and 800mg/kg body weight. The haematological parameters including red blood cells, white blood cells, packed cell volume and haemoglobin count were analysed with an auto analyser. The activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were determined, while urea, protein and creatinine were analysed by standard procedural methods. RESULTS: The 4-day suppressive test revealed that the test extract achieved percentage suppression of 39.0%, 41.6% and 54.68% for the 200mg/kg, 400mg/kg and 800mg/kg concentration respectively. Additionally, the curative test achieved a high percentage suppression of 80.97%, 83.84% and 86.16% at the 200mg/kg, 400mg/kg and 800mg/kg concentration respectively. The extracts did not induce significant change on haematological parameters (P>0.05), while significant elevation in the values of the ALT and AST (P<0.05) was observed and elevation of creatinine (P<0.05) at 800mg/kg. CONCLUSIONS: The results support the traditional use of the herbal combination in the treatment of malaria, however the liver cells were impacted by the extracts in bioassay conducted with mice. PMID- 26958030 TI - Ketolide agents HMR 3004 and HMR 3647 (telithromycin) inhibit the growth of Plasmodium falciparum in vitro. AB - BACKGROUND: Malaria is on the increase due to emergence of parasite drug resistance and there is thus an urgent need for the development of new antiparasitic drugs effective at low concentrations. Ketolides antibiotics are used for treatment of various ailments and are relevant candidates to establish antiparasitic activity. OBJECTIVES: The present study investigates the activity of ketolide compounds HMR 3004 and HMR 3647 (telithromycin) (0.025-12.5 uM) for activity against chloroquine-sensitive and resistant strains of Plasmodium falciparum in vitro. METHODS: The antiplasmodial activity of the two ketolide agents were determined using microscopic and colorimetric [lactate dehydrogenase assay] procedures. RESULTS: Both HMR 3004 and HMR 3647 caused a dose-dependent inhibition of growth of both parasite strains with IC50 values 3 and 15 nM, respectively. Suppression of parasite growth was evident after 8 hours of exposure to both agents at 12.5 uM with total parasite clearance achieved at 40 hours. CONCLUSION: The results indicate lack of cross-resistance between the ketolide compounds and chloroquine, implying presence of a drug target different from that of chloroquine. The particular drug target has still to be investigated but the stage-specific results indicate that it is expressed in all parasite growth phases. These observations demonstrate the anti-malarial potential of the ketolide antimicrobial agents. PMID- 26958031 TI - Occurrence of aminoglycoside-modifying enzymes genes (aac(6')-I and ant(2")-I) in clinical isolates of Pseudomonas aeruginosa from Southwest Nigeria. AB - BACKGROUND: Enzymatic modification of aminoglycosides is the primary mechanism of resistance by Pseudomonas aeruginosa. OBEJECTIVES: We investigated the occurrence and mechanism of aminoglycosides resistance in P. aeruginosa isolates from hospitals in SouthWest Nigeria. METHODS: A total of 54 consecutive, non-duplicate clinical isolates of P. aeruginosa were studied for the presence of aminoglycosides -modifying enzymes (AMEs) by PCR amplification and sequencing of genes encoding AMEs. RESULTS AND CONCLUSION: Two types of AME genes [aac (6') - I and ant (2") - I] were found in 12 isolates out of 54. Seven strains harboured one or more types of enzymes of which aac (6') - I was the most frequently found gene (10/54 isolates, 18.5%). None of the isolates investigated in this study were positive for aph, aac (3) and aac (6") - II genes. Prevalence of P. aeruginosa producing AME genes in this study may suggest aminoglycosides use in Nigeria. This study highlights need for functional antimicrobial surveillance system in Nigeria. PMID- 26958032 TI - Comparison of identification and antimicrobial resistance pattern of Staphylococcus aureus isolated from Amassoma, Bayelsa state, Nigeria. AB - BACKGROUND: Staphylococcus aureus is often responsible for fatal infections and recent upsurge of resistant strains has resulted in therapeutic failure. The identification of this microorganism is a major challenge to medical microbiologists in developing countries. METHODS: One hundred and eighty five isolates which had been previously isolated from the nares of 185 healthy college students' volunteers in Amassoma, Bayelsa State, South Nigeria were identified by MALDI TOF mass spectrometry, and PCR amplification of the spa gene. The identified isolates were compared with presumptive identities obtained by growth on MSA, tube coagulation and slide agglutination tests. Antimicrobial susceptibility testing of S. aureus isolates was performed by Kirby Bauer technique while MRSA was screened for by growth on chromlDTM MRSA plate and confirmed by PCR-amplification of mecA/mecC genes. RESULTS: From the 185 staphylococci that grew with yellow colonies on MSA, 24 were positive in the slide coagulase test, while 17 were positive in the tube coagulase test; MALDI TOF mass spectrometry and PCR amplification of the spa gene showed excellent concordance with the tube test, as all tube coagulase-positive strains were identified as S. aureus, while tube coagulase-test negative isolates in all cases were designated as other staphylococcal species by MALDI-TOF mass spectrometry and were spa PCR test negative. All S. aureus isolates were susceptible to clindamycin, vancomycin, fusidic acid, rifampicin and linezolid, while observed resistance to penicillin and trimethoprim were high. Only one MRSA strain was detected. CONCLUSION: The study confirms that the tube coagulase test is an accurate diagnostic method for identification of S. aureus, while growths on MSA and slide agglutination tests are inaccurate. We found a low prevalence of MRSA and a high rate of trimethroprim-resistance in the studied population. PMID- 26958033 TI - Prevalence and risk factors for methicillin resistant Staphylococcus aureus carriage among emergency department workers and bacterial contamination on touch surfaces in Erciyes University Hospital, Kayseri, Turkey. AB - OBJECTIVE: The aim of this study was to determine Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) nasal carriage among emergency department (ED) workers, and bacterial contamination on hand-touch surfaces at ED. METHODS: This single-centered study enrolled 105 ED workers and 190 hand-touch surfaces at ED in June 2014. Nasal and environmental samples for S. aureus carriage and for bacterial contamination were obtained. For isolation swabs were cultured on ChromAgar S. aureus and environmental samples first cultured in broth and antibiogram obtained by clinical and Laboratory Standards Institute guidelines. A questionnaire was completed for each subject. RESULTS: The S. aureus carriage rate was 18.1% (n=19), with 2.9% (n=3) MRSA positivity. There were two (1.9%) mobile phone positivities for S. aureus, one of them was MRSA, and a computer keyboard contamination for MRSA was also detected. All MRSA isolates were susceptible for the tested antibiotics. There was significant difference between gender (p=0.044) in terms of nasal carriage of S. aureus and MRSA, all three MRSA isolates were from females. CONCLUSION: Our study showed that the carriage of MRSA was not affected by clinical exposure in the hospital because of the existing infection control policy in our hospital. PMID- 26958034 TI - Study on the isolation of active constituents in Lonicera japonica and the mechanism of their anti-upper respiratory tract infection action in children. AB - BACKGROUND: Lonicera japonica has been studied extensively by scholars at home and abroad, a number of compounds have been isolated from it, which mainly include organic acids and flavonoids. Pharmacological studies have shown that Lonicera japonica has antibacterial and gall bladder-protective effects. OBJECTIVE: To study the active constituents in Lonicera japonica and the mechanism of their anti-upper respiratory tract infection action in children. METHODS: Compounds were identified by chromatographic methods, and the mechanism of anti-pediatric upper respiratory tract infection action of Lonicera japonica decoction was studied using experimental animals. RESULTS: A total of four compounds were isolated, after injection of egg white, toe edema in rats in the control group was very obvious, different test concentrations of Lonicera japonica decoction all inhibited toe edema in rats to some extents, the edema was the mildest in the Lonicera japonica decoction high-dose group, which had the strongest inhibitory effect on the development of inflammation, the Lonicera japonica decoction showed certain dose-effect relationship with toe edema in rats. In the rat body temperature control experiment, while body temperature of rats in the blank group had already risen, other groups were still able to lower the body temperature of rats under the action of test drugs. The severity of ear edema in mice in the blank control group was obvious, with increased thickness which showed significant difference between left and right ears. Under test doses, three Lonicera japonica decoction groups all inhibited xylene-induced ear edema in mice. CONCLUSION: Lonicera japonica has an anti-upper respiratory tract infection action in children. PMID- 26958035 TI - Prevalence and factors associated with dental caries among children and adults in selected districts in Uganda. AB - OBJECTIVE: The aim was to determine the prevalence and factors associated with dental caries among adults and children in seven districts of Uganda. METHODS: Participants aged 11-13 (n=1230) and 35-44 years (n=648) were randomly selected from urban and rural areas of Gulu, Soroti, Jinja, Masaka, Kabale, Kabarole and Hoima districts. They were examined by 4 trained and calibrated dentists for dental caries using Decayed, Missing and Filled teeth index as described by World Health Organisation. RESULTS: Overall mean DMFT score was 0.73 for children and 4.71 for adults. Generally, there was a higher mean DMFT score in the rural (2.19) compared to urban areas (1.97). In all the districts, except Hoima, there was a higher mean DMFT score of children in rural compared to urban. In adults, similar trend was mainly registered in Masaka, Hoima and Gulu districts. Most participants (79.9%, n=1309) occasionally ate sugared snacks. Overall, 95% (n=1795) of the participants cleaned their teeth with plastic tooth brushes (71.7%) and chewing sticks (8.3%). CONCLUSION: Although the severity of dental caries was low, the disease was widespread in the study population. A high proportion of participants reported consumption of sugared snacks and drinks, which calls for oral health education. PMID- 26958036 TI - Adverse drug reaction reporting among health care workers at Mulago National Referral and Teaching hospital in Uganda. AB - BACKGROUND: Adverse Drug Reactions (ADRs) are an important contributor to patient morbidity and hospitalisation in Uganda. Under-reporting of ADRs may increase medicine-induced morbidity and mortality among patients. This study determined the extent of ADR reporting, and associated factors, among healthcare workers in Uganda. METHODS: A quantitative, cross-sectional, study was conducted. Pretested, semi-structured questionnaires were administered to 289 randomly sampled healthcare workers over a three-month period in Mulago National Referral Hospital, Uganda. The primary outcome was the proportion of healthcare workers who had ever reported an ADR. Data was double-entered in Epidata version 3.0, cleaned and exported to STATA version 10.1 for analysis. RESULTS: The overall response rate was 77.2% (n=223). The majority of the respondents were females (139, 62.3%). The median age of all respondents was 32.6 years (min-23; max-65). Only about 16.6% (n=37) of healthcare workers had ever reported an ADR. Very few (n= 84, 37.7%) healthcare workers knew the tools used in ADR reporting. Less than a quarter (n=41, 18.4%) of the healthcare workers knew where to report ADRs. Lack of training was reported as the major (56.5%, 126) deterrent to reporting ADRs by healthcare workers. CONCLUSION: Adverse drug reactions are under-reported in Uganda, and healthcare workers have insufficient knowledge of existing pharmacovigilance systems, including ADR reporting systems. To address these challenges, there is need to sensitize and train healthcare workers in patient centred aspects of medicine surveillance, so as to provide appropriate care while optimising patient safety. PMID- 26958037 TI - Evaluation of prescription pattern and patients' opinion on healthcare practices in selected primary healthcare facilities in Ibadan, South-Western Nigeria. AB - BACKGROUND: Inappropriate prescribing negatively impacts on health and economy of individual and the society. OBJECTIVES: To evaluate the prescribing patterns and patients' opinions on healthcare practices in selected primary healthcare centres (PHC) in Ibadan, South-Western Nigeria. METHODS: A prospective cross-sectional study was carried out among patients and healthcare workers in selected PHCs using semi-structured questionnaires. Also, patients' prescription records were reviewed using the WHO-prescribing indicators. RESULTS: About one-half (210; 52.5%) were very satisfied with convenience of obtaining prescribed medicines in the PHCs, accessibility of PHC to abode (158;39.5%) and affordable medications (136;34.0%). Patients were dissatisfied with follow-up of care (191; 47.8%), courtesy of workers (184; 46.3%) and non-availability of medicines (138;34.5%). Number of drugs per encounter was 5.8+/-2.3 and % encounter with an antibiotic was >26.8% in each facility. Hematinics accounted for (814; 35.0%), analgesics (544; 23.4%), antimicrobials (303;13.0%) and antihypertensives (5; 0.2%). CONCLUSION: Primary healthcare attendees were satisfied with medication costs affordability and accessibility of PHC to abode but expressed dissatisfaction with follow-up of care and courtesy of workers. Also, inappropriate prescriptions characterized by polypharmacy and overuse of antibiotics were common underscoring the need for regular training of PHC workers on rational drug use and instituting appropriate measures for improvement. PMID- 26958038 TI - Poverty and inequality - but of what - as social determinants of health in Africa? AB - BACKGROUND: Many African economies have achieved substantial economic growth over the past recent years, yet several of the Millennium Development Goals (MDGs) including those concerned with health, remain considerably behind target. This paper examines whether progress towards these goals is being hampered by existing levels of poverty and income inequality. It also considers whether the inequality hypothesis of Wilkinson and Pickett1 applies to population health outcomes in African states. METHODS: Correlation analysis and scatter plots were used to assess graphically the link between variations in health outcomes, level of poverty and income inequality in different countries. Health status outcomes were measured by using four indicators: infant and under-five (child) mortality rates; maternal mortality ratios; and life expectancy at birth. In each of the 52 African nations, the proportion of the population living below the poverty line is used as an indicator of the level of poverty and Gini coefficient as a measure of income inequality. The study used a comprehensive review of secondary and relevant literature that are pertinent in the subject area. The data datasets obtained online from UNICEF2 and UNDP3 (2009) used to test the research questions. World Health Organization the three broad dimensions to consider when moving towards better population health outcome through Universal Health Coverage and the Social Determinants of Health framework reviewed to establish the poverty and income inequality link in African countries population health outcomes. RESULTS: The study shows that poverty is strongly associated with all health outcome differences in Africa (IMR, cc = 0.63; U5MR, cc = 0.64; MMR, cc = 0.49; life expectancy at birth, cc = -0.67); income inequality with only one of the four indicators (IMR, cc = 0.14; U5MR, cc = 0.07; MMR, cc = 0.22; life expectancy at birth, cc = -0.49), whereas income inequality is associated with one of the four indicators. CONCLUSION: The study shows that tackling poverty should be the immediate concern in Africaas a means of promoting better health for all. There is a question mark over whether the findings of Wilkinson and Pickett1 on the relationship between income inequality and health apply to Africa. The reasons for this question mark are discussed. More research is needed to investigate whether the inequality results found in this study are replicated in other studies of African health. PMID- 26958039 TI - Permanent neonatal diabetes mellitus - a case report of a rare cause of diabetes mellitus in East Africa. AB - Diabetes mellitus is a metabolic disease characterised by chronically high glucose levels. Genetic factors have been implicated in the aetiology following mutations in a single gene. An extremely rare form of diabetes mellitus is monogenic diabetes, a subset of which is permanent neonatal diabetes, and is usually suspected if a child is diagnosed with diabetes at less than 6 months of age. We present the first case reported from East Africa of a child diagnosed with permanent neonatal diabetes resulting from a mutation in the KCNJ11 gene encoding the Kir6.2 subunit. Despite the rarity of permanent neonatal diabetes, this diagnosis should be considered in infants with persistent hyperglycaemia requiring insulin therapy. Children with an ATP-sensitive potassium channel defect in the pancreatic beta cell have an overall good prognosis when treated with oral sulphonylurea therapy. PMID- 26958040 TI - A case report: the first successful cochlear implant in Uganda. AB - Hearing impairment is a significant disability. According to the World Health Organization (WHO), more than 80% of the world's approximately 120 million people with hearing impairment live in developing countries. Cochlear implant is the only therapeutic intervention for those with severe-profound sensorineural hearing loss. We are reporting an interesting case of the very first cochlear implant operation carried out in Uganda. The patient was a 23 year old male whose presenting complaint was inability to hear in the left ear for three and a half years and in the right ear for one year. He had been treated for TB(Tuberculosis) mastoiditis. After the 8 months of treatment, the otorrhea persisted and he underwent a tympanomastoidectomy on the same ear. He reported no familial history of hearing loss. On examination, ENT examination revealed a small pars flaccida retration pocket of the right tympanic membrane with cholesteatoma. The left ear had an intact tympanic membrane. Pure tone audiometry revealed profound sensorineural hearing loss in both ears (see attached PTA results), CT scan of the temporal bone showed normal inner ear anatomy bilaterally and mild sclerotic changes in both mastoid bones. He then had surgery on his right ear which included cochlear implantation. The cochlear implant (CI) was activated on the first postoperative day remotely via internet with the help of the cochlear implant team at New York University Cochlear Implant Center and the patient was immediately able to appreciate some sounds. He received a pneumococcal vaccine on the first postoperative day and was discharged the following day. PMID- 26958041 TI - Tako-tsubo cardiomyopathy after a quarrel. AB - OBJECTIVE: To report a case of Tako-tsubo cardiomyopathy in a blind woman. CASE PRESENTATION: We report a confirmed case of Tako-tsubo cardiomyopathy in a 55 year-old blind woman with past medical history of ocular trauma. The patient suffered from sudden chest pain after a quarrel. Transthoracic echocardiogram (TTE) showed regional wall motion abnormalities. Coronary angiogram showed no significant coronary stenosis, but ventriculogram demonstrated apical ballooning akinesis and hypercontraction in the basal segments. The follow-up TTE revealed a recovery of systolic function 6 weeks later. CONCLUSION: We report a case of Tako tsubo cardiomyopathy after a quarrel, implicating that severe emotional or physical stress could trigger myocardial stunning. PMID- 26958042 TI - Epicardial fat thickness and cardiovascular involvements. PMID- 26958044 TI - University students' sexual orientation, contraception and toxic skin bleaching products. PMID- 26958043 TI - From sexual orientation to cochlear transplants in a tropical environment. PMID- 26958045 TI - Risk factors for lung diseases after renal transplantation. AB - BACKGROUND: Lung diseases are one of the major causes of morbidity and mortality after renal transplantation. The aim of the study is to define the risk factors for infectious and noninfectious pulmonary complications in kidney transplant patients. MATERIALS AND METHODS: We prospectively studied 267 patients after renal transplantation. The kidney recipients were followed-up for the development of pulmonary complications for a period of 7 years. Different noninvasive and invasive diagnostic tests were used in cases suspected of lung disease. RESULTS: The risk factors associated with the development of pulmonary complications were diabetes mellitus (odds ratio [OR] = 4.60; P = 0.001), arterial hypertension (OR = 1.95; P = 0.015), living related donor (OR = 2.69; P = 0.004), therapy for acute graft rejection (OR = 2.06; P = 0.038), immunosuppressive regimens that includes mycophenolate (OR = 2.40; P = 0.011), azathioprine (OR = 2.25; P = 0.023), and tacrolimus (OR = 1.83; P = 0.041). The only factor associated with the lower risk of complications was a positive serology test for Cytomegalovirus of the recipient before transplantation (OR = 0.1412; P = 0.001). CONCLUSION: The risk factors can be used to identify patients at increased risk for posttransplant lung diseases. Monitoring of higher-risk patients allow timely diagnosis and early adequate treatment and can reduce the morbidity and mortality after renal transplantation. PMID- 26958046 TI - Comparison of open surgical discectomy versus plasma-laser nucleoplasty in patients with single lumbar disc herniation. AB - BACKGROUND: Intervertebral disc herniation is a major cause of low back pain. Several treatment methods are available for lumbar disc herniation including Chemonucleolysis, open surgery, nucleoplasty, laser disc decompression, and intradiscal electrothermal therapy. The high prevalence of lumbar disc herniation necessitates a minimally invasive yet effective treatment method. In this study, we compared the outcomes of open surgery and nucleoplasty method in patients with single lumbar disc herniation. MATERIALS AND METHODS: This study was a noninferiority randomized clinical trial conducted in one of the University Hospitals of Isfahan Medical University; The Alzahra Hospital. About 200 patients with the diagnosis of lumbar disc herniation were recruited and were assigned to either the treatment or control groups using block randomization. One group received open surgery and the other group received nucleoplasty as the method of treatment. Patients were revisited at 14 days, 1, 2, 3 months, and 1-year after surgery and were assessed for the following variables: Lower back pain, lower limb pain, common complications of surgery (e.g., discitis, infection and hematoma) and recurrence of herniation. RESULTS: The mean (standard deviation) severity of low back pain was reduced from 6.92 (2.5) to 3.43 (2.3) in the nucleoplasty group (P = 0.04) and from 7.5 (2.2) to 3.04 (1.61) in the discectomy group (P = 0.73). Between group difference was not statistically significant (P = 0.44), however, time and treatment interaction was significant (P = 0.001). The level of radicular pain evaluated 1 year after treatment was reduced from 8.1 (1.2) to 2.9 (1.2) (P = 0.004) and from 7.89 (2.1) to 3.6 (2.5) (P =0.04) in the discectomy and the nucleoplasty groups respectively, significant interaction between time and treatment options was observed (P < 0.001) while there was no significant difference between two treatment groups (P = 0.82). CONCLUSION: Our results show that while nucleoplasty is as effective as open discectomy in the treatment of lumbar disc herniation, it is also less invasive with higher patient compliance. Taking factor such as decreased cost and duration of the surgery, as well as faster recovery in patients into account; we suggest considering nucleoplasty as an effective method of treatment in patients with single-level disc herniation. PMID- 26958047 TI - Roles of osteopontin and matrix metalloproteinase-7 in occurrence, progression, and prognosis of nonsmall cell lung cancer. AB - BACKGROUND: This study detected osteopontin (OPN) and matrix metalloproteinase-7 (MMP-7) expressions to explore the roles of OPN and MMP-7 in the occurrence, progression, and prognosis of nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: A retrospective study was conducted on NSCLC tissues (n = 152; case group) and adjacent nonneoplastic lung parenchyma (adjacent to tumor >5 cm; n = 152; control group) collected from 152 NSCLC patients. The protein expressions of OPN and MMP-7 were detected by immunohistochemistry. OPN and MMP-7 messenger RNA (mRNA) expressions were detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The protein and mRNA expressions of OPN and MMP-7 in NSCLC tissues were evidently higher than those in adjacent nonneoplastic lung parenchyma (all P < 0.05). OPN protein and mRNA expression were associated with the degree of differentiation, tumor node metastasis (TNM) staging, and lymph node metastasis in NSCLC (all P < 0.05). MMP-7 protein expression was associated with TNM staging and lymph node metastasis (both P < 0.05) while MMP-7 mRNA expression was associated with the degree of differentiation, TNM staging, and lymph node metastasis (all P < 0.05). A significantly positive relativity was revealed between OPN expression and MMP-7 expression (protein: r = 0.789, P < 0.001; mRNA: r = 0.377, P < 0.001). Lymph node metastasis, TNM staging, OPN, and MMP-7 protein expressions were independent risk factors for the prognosis of NSCLC (all P < 0.05). CONCLUSION: High MMP-7 and OPN protein expressions are closely related to the occurrence, progression, and prognosis of NSCLC, and can be served as unfavorable prognostic factors for NSCLC. PMID- 26958048 TI - Study of 2 years follow-up of referral patients with abnormal Pap smear. AB - BACKGROUND: Abnormal Pap smear consists of premalignant or malignant cervical lesions. Many of premalignant cervical lesions will never progress to invasive malignancy, or even may regress over the time. Thus, there is always a risk of overtreatment of patients with an abnormal Pap smear. A long-term follow-up of these patients can reveal final events associated with each subtype of abnormal Pap smear, and, therefore, help us to prevent unnecessary interventions. The aim of our study was to present 2 years follow-up of referral patients with abnormal Pap smear. MATERIALS AND METHODS: A total of 334 consecutive women aged more than 16 who were referred with an abnormal Pap smear were entered into the study. Patients were followed with biannual Pap smear and annual colposcopy and biopsy for 2 years. RESULTS: At baseline, the majority of patients with abnormal Pap smear were normal on colposcopy and biopsy (68% and 86%, respectively). Six months after first abnormal Pap smear majority of patients in each group showed a significant regress to normal or less invasive lesion (P < 0.001). Twelve patients (4%) had no change in Pap smear, whereas 313 (94%) had at least one stage improvement. Only nine (3%) patients had deteriorated Pap smear after 6 months. All 308 patients who underwent colposcopy and biopsy had normal Pap smear 24 months after the first abnormal Pap smear. CONCLUSION: Pap smear is associated with a high rate of false-positive results. In addition, the majority of low grade cervical lesions can spontaneously regress. A long-term follow-up of a patient with abnormal Pap smear can help us to avoid needless interventions. PMID- 26958050 TI - A comparative study of vaginal estrogen cream and sustained-release estradiol vaginal tablet (Vagifem) in the treatment of atrophic vaginitis in Isfahan, Iran in 2010-2012. AB - BACKGROUND: Atrophic vaginitis is a disease, which affects up to 50% of postmenopausal women. This study compared the effectiveness and user-friendliness of Vagifem (an estradiol vaginal tablet) and vaginal estrogen cream in the treatment of atrophic vaginitis. MATERIALS AND METHODS: One hundred and sixty postmenopausal women with symptoms of atrophic vaginitis were randomly divided into two groups of treatment with Vagifem or with vaginal estrogen cream for 12 weeks. Patients used the medication daily for the first 2 weeks of the study, and twice weekly. Severity of vaginal atrophy and four main symptoms of atrophic vaginitis including dysuria, dyspareunia, vaginal itching, and dryness were evaluated and compared before and after treatment. In addition, patients were asked regarding user-friendliness and hygienic issues of medications. RESULTS: Both vaginal estrogen cream and Vagifem significantly improved symptoms of atrophic vaginitis but in terms of effectiveness for the treatment symptoms of atrophic vaginitis, there was no significant difference between the two medications. Vagifem compared to estrogen cream resulted in significantly lower rate of hygienic problems (0% versus 23%, P < 0.001), and was reported by the patients as a significantly easier method of treatment (90% versus 55%, P < 0.0001). CONCLUSION: This investigation showed that Vagifem is an appropriate medication for the treatment of atrophic vaginitis, which is as effective as vaginal estrogen creams and is more user-friendly. PMID- 26958049 TI - Single-incision laparoscopic cholecystectomy versus mini-laparoscopic cholecystectomy: A randomized clinical trial study. AB - BACKGROUND: Surgical technique using small-diameter instruments and single incision laparoscopy are two new options for less invasive laparoscopic cholecystectomy (LC). In this study, we have compared mini-LC (MLC) with single incision LC (SILC). MATERIALS AND METHODS: This study is a randomized clinical trial conducted on the patients diagnosed with symptomatic cholelithiasis who underwent LC. Forty patients were randomized to two equal groups of MLC and SILC. They were compared in terms of demographic data, operation time, and surgical complications. RESULTS: Baseline characteristics were similar in two groups. Operation time in MLC was significantly shorter than that in SILC (45.1 +/- 69 min vs 63.75 +/- 7.57 min, P-value < 0.001). Also, the total length of the wound in SILC group was shorter than that in MLC group (P-value < 0.003). Postoperative pain scores were similar in two groups. Hospital stay was shorter in MLC (1.2 +/- 0.6 days vs 1.6 +/- 0.8 days, P < 0.021). There was no difference in postoperative complications in two groups. CONCLUSION: MLC because of less operation time is preferred than SILC. Also, by subjective measures, it was a more comfortable method compared to SILC. PMID- 26958051 TI - Hyperglycemia is a predictor of prognosis in traumatic brain injury: Tertiary intensive care unit study. AB - BACKGROUND: Hyperglycemia is frequently encountered in critically ill patients and has been shown to contribute to both morbidity and mortality. We aimed to study the predictive role of blood glucose level in clinical outcomes of mechanically ventilated patients with traumatic brain injury during intensive care unit (ICU) stay and to explore its relationship with Glasgow coma scale (GCS) and acute physiology and chronic health examination (APACHE) II scores that are used in the evaluation of ICU patients as predictor. MATERIALS AND METHODS: A total of 185 patients with craniocerebral trauma who were hospitalized in the ICU were included in the study. Comparisons of mean glucose values (MGVs) and APACHE II scores between survivors and nonsurvivors were made with Student's t-test and chi-square test. Survival analysis was performed with log rank (Mantel-Cox) test and Cox regression was used for mortality risk factors analysis. RESULTS: MGVs at the initial, last, and all measurements were significantly higher for nonsurvivors than for survivors. Hazard rate at any given time point for patients with mean glucose value (MGV) between 150 and 179 was found to be 3.691 times that of patients with MGV values between 110 and 149. The hazard rate at any given time point for patients with MGV values >=180 was found to be 6.571 times that of patients with MGV values between 110 and 149. CONCLUSION: High glucose level is an independent risk factor for mortality in mechanically ventilated ICU patients with traumatic brain injury. PMID- 26958052 TI - Outcomes of pediatric inguinal hernia repair with or without opening the external oblique muscle fascia. AB - BACKGROUND: Considering that complications and outcome of each method of pediatric inguinal hernia repair are one of the determinants for pediatric surgeons for selection of the appropriate surgical technique, we compared the early and late complications of two inguinal repair techniques, with and without opening the external oblique muscle fascia. MATERIALS AND METHODS: In this double blind clinical trial study, boy children aged 1-month to 6 years with diagnosed inguinal hernia were included and randomly allocated into two groups for undergoing two types of hernia repair techniques, with and without opening the external oblique muscle fascia. Surgical complications such as fever, scrotal edema and hematoma, and wound infections classified as early complication and recurrence, testis atrophy and sensory impairment of inguinal area classified as late complications. The rates of mentioned early and late complications were compared in the two interventional groups. RESULTS: In this study, 66 patients were selected and allocated to the two interventional groups. The prevalence of early and late complications in two studied groups were not different significantly in two interventional groups (P > 0.05). Operation time was significantly shorter in inguinal repair techniques without opening the external oblique muscle fascia than the other studied technique (P = 0.001). CONCLUSION: The findings of our study indicated that though early and late complications of the two repair methods were similar, but the time of procedure was shorter in herniotomy without opening the external oblique muscle, which considered the superiority of this method than inguinal hernia repair with opening the external oblique muscle. PMID- 26958054 TI - The value of otoendoscopy in the management of middle ear cholesteatoma. AB - BACKGROUND: The surgical management of cholesteatoma is a controversial issue, particularly regarding intact-canal-wall mastoidectomy (ICWM) versus canal-wall down mastoidectomy (CWDM). The current experiment compared the quality of visualization in different middle ear structures using ICWM with otoendoscopy with findings of CWDM by microscopy. MATERIALS AND METHODS: The patients diagnosed with cholesteatoma underwent tympanomastoidectomy, and then the patients selected for CWDM were included in the study (25 patients: 11 females and 14 males). After removing the cholesteatoma from the involved areas, otoendoscopic examination was done with a 4 mm, 0 degrees endoscope by a neurootologist. All five middle ear structures (lateral epitympanum, sinus tympani, posterior crus of the stapes, round window niche, and Eustachian tube orifice) suspected of occult cholesteatoma were evaluated in terms of having or lacking the pathology. Then, CWDM was performed and all of the mentioned sites were reevaluated for diagnosing occult cholesteatoma. RESULTS: The symmetric measures were 73%, 92%, 63%, 81%, and 100% for lateral epitympanum, sinus tympani, posterior crus of the stapes, round window niche, and Eustachian tube orifice, respectively. CONCLUSION: Otoendoscopy was confirmed to have a great potential to be adopted by surgeons as a less invasive procedure in the surgical management of middle ear cholesteatoma. PMID- 26958053 TI - Effect of vitamin E succinate on inflammatory cytokines induced by high-intensity interval training. AB - AIM AND SCOPE: The anti-inflammatory effect of vitamin E under moderate exercises has been evaluated. However, the effect of vitamin E succinate, which has more potent anti-inflammatory effect than other isomers of vitamin E has not been evaluated. Therefore, the aim of the present study was to evaluate the effects of vitamin E succinate on tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) production induced by high-intensity interval training (HIIT). MATERIALS AND METHODS: In the present study, 24 rats were randomly divided into control (C), supplementation (S), HIIT, and HIIT + supplementation (HIIT+S) groups. HIIT training protocol on a treadmill (at a speed of 40-54 m/min) and vitamin E succinate supplementation (60 mg/kg/day) was conducted for 6 weeks. RESULTS: Serum IL-6 in the HIIT group significantly increased compared with the C group (350.42 +/- 123.31 pg/mL vs 158.60 +/- 41.96 pg/mL; P = 0.002). Also, serum TNF alpha concentrations significantly enhanced (718.15 +/- 133.42 pg/mL vs 350.87 +/ 64.93 pg/mL; P = 0.001) in the HIIT group compared with the C group. Treatment of the training group with vitamin E numerically reduced IL-6 and TNF-alpha when compared with the HIIT group (217.31 +/- 29.21 and 510.23 +/- 217.88, respectively, P > 0.05). However, no significant changes were observed in serum TNF-alpha (P = 0.31) and IL-6 (P = 0.52) concentrations in the HIIT + S group compared with the C group. CONCLUSION: HIIT-induced IL-6 and TNF-alpha decreased by administration of Vitamin E succinate. PMID- 26958056 TI - A systematic review and meta-analysis on screening lipid disorders in the pediatric age group. AB - BACKGROUND: Different viewpoints exist about lipid screening in all children or only in children with positive family history (FH) of premature cardiovascular diseases (CVDs) or hypercholesterolemia. This systematic review and meta-analysis aim to assess the effectiveness of lipid screening in children and adolescents according to the existence of positive FH of CVD risk factors. MATERIALS AND METHODS: PubMed, Scopus, and Google scholar were searched to identify relevant papers that were published from November 1980 until 30 November 2013. Irrelevant studies were set aside after studying their title, abstract, and full text. Then, the relevant studies were assessed by using a quality appraisal checklist. We used random effect model for meta-analysis and calculating the total estimation of sensitivity, specificity, and the positive predictive value (PPV) of FH in predicting dyslipidemia among children and adolescents. RESULTS: Overall, 17,214 studies were identified in the primary search, out of which 19 primary studies were qualified for study entry. The sensitivity of positive FH of premature CVD or dyslipidemia for predicting dyslipidemia among children varied between 15 and 93. Moreover, the effectiveness of screening children for dyslipidemia according to premature CVD or dyslipidemia in their relatives was low in 86.9% of the primary studies. The total estimation of sensitivity, specificity, and predictive value was 42.6, 59, and 20.7, respectively, according to the meta-analysis results. CONCLUSION: The present meta-analysis indicated that selecting target population for screening children and adolescents for dyslipidemia according to their FH has low sensitivity. PMID- 26958055 TI - Management of ovarian cysts in infants. AB - BACKGROUND: To discuss the experience of diagnosis and treatment of ovarian cyst in infants. MATERIALS AND METHODS: A retrospective review was conducted on 20 infants who suffered from ovarian cyst. RESULTS: There were no dysplasia ovarian was found in children which were preoperatively diagnosed simplex cyst. Within thirteen children preoperatively detected mixed cystic-solid lesion, six cases ovarian cysts disappeared and two cases underwent poor blood supply in the following time. CONCLUSION: Adverse effects for ovarian cyst in infants can be prevented by agressive surgical intervention. Harmful effects of ovarian cyst can be prevented by positive surgical intervention despite the diagnostic difficulties in children with clinical symptoms of this condition. PMID- 26958057 TI - Gastric varices: Classification, endoscopic and ultrasonographic management. AB - Gastric varices (GV) are responsible for 10-30% of all variceal hemorrhage. However, they tend to bleed more severely with higher mortality. Around 35-90% rebleed after spontaneous hemostasis. Approximately 50% of patients with cirrhosis of liver harbor gastroesophageal varices. In this review, new treatment modalities in the form of endoscopic treatment options and interventional radiological procedures have been discussed besides discussion on classification and pathophysiology of GV. PMID- 26958058 TI - Features and application of wearable biosensors in medical care. AB - One of the new technologies in the field of health is wearable biosensor, which provides vital signs monitoring of patients, athletes, premature infants, children, psychiatric patients, people who need long-term care, elderly, and people in impassable regions far from health and medical services. The aim of this study was to explain features and applications of wearable biosensors in medical services. This was a narrative review study that done in 2015. Search conducted with the help of libraries, books, conference proceedings, through databases of Science Direct, PubMed, Proquest, Springer, and SID (Scientific Information Database). In our searches, we employed the following keywords and their combinations; vital sign monitoring, medical smart shirt, smart clothing, wearable biosensors, physiological monitoring system, remote detection systems, remote control health, and bio-monitoring system. The preliminary search resulted in 54 articles, which published between 2002 and 2015. After a careful analysis of the content of each paper, 41 sources selected based on their relevancy. Although the use of wearable in healthcare is still in an infant stage, it could have a magic effect on healthcare. Smart wearable in the technology industry for 2015 is one that is looking to be a big and profitable market. Wearable biosensors capable of continuous vital signs monitoring and feedback to the user will be significantly effective in timely prevention, diagnosis, treatment, and control of diseases. PMID- 26958059 TI - WHO and UNICEF: Updates on immunization coverage and how can we improve upon? PMID- 26958060 TI - Science growth and human development index in Iran. PMID- 26958061 TI - Chromogenic agar medium for rapid detection of extended-spectrum beta-lactamases and Klebsiella pneumoniae carbapenemases producing bacteria from human immunodeficiency virus patients. PMID- 26958063 TI - Comparison between Kawasaki disease with lymph-node-first presentation and Kawasaki disease without cervical lymphadenopathy. AB - PURPOSE: We evaluated the characteristics of patients with Kawasaki disease (KD) who presented with only fever and cervical lymphadenopathy on admission, and compared them with the characteristics of those who presented with typical features but no cervical lymphadenopathy. METHODS: We enrolled 98 patients diagnosed with KD. Thirteen patients had only fever and cervical lymphadenopathy on the day of admission (group 1), 31 had typical features with cervical lymphadenopathy (group 2), and 54 had typical features without cervical lymphadenopathy (group 3). RESULTS: The mean age (4.3+/-2.1 years) and duration of fever (7.5+/-3.6 days) before the first intravenous immunoglobulin (IVIG) administration were highest in group 1 (P=0.001). Moreover, this group showed higher white blood cell and neutrophil counts, and lower lymphocyte counts after the first IVIG administration as compared to the other groups (P=0.001, P=0.001, and P=0.003, respectively). Group 1 also had a longer duration of hospitalization and higher frequency of second-line treatment as compared to groups 2 and 3 (group 1 vs. group 2, P=0.000 and P=0.024; group 1 vs. group 3, P=0.000 and P=0.007). A coronary artery z score of >2.5 was frequently observed in group 1 than in group 3 (P=0.008). CONCLUSION: KD should be suspected in children who are unresponsive to antibiotics and have prolonged fever and cervical lymphadenopathy, which indicates that KD is associated with the likelihood of requiring second-line treatment and risk of developing coronary artery dilatation. PMID- 26958062 TI - A practical view of immunotherapy for food allergy. AB - Food allergy is common and sometimes life threatening for Korean children. The current standard treatment of allergen avoidance and self-injectable epinephrine does not change the natural course of food allergy. Recently, oral, sublingual, and epicutaneous immunotherapies have been studied for their effectiveness against food allergy. While various rates of desensitization (36% to 100%) and tolerance (28% to 75%) have been induced by immunotherapies for food allergy, no single established protocol has been shown to be both effective and safe. In some studies, immunologic changes after immunotherapy for food allergy have been revealed. Adverse reactions to these immunotherapies have usually been localized, but severe systemic reactions have been observed in some cases. Although immunotherapy cannot be recommended for routine practice yet, results from recent studies demonstrate that immunotherapies are promising for the treatment of food allergy. PMID- 26958064 TI - Infantile Marfan syndrome in a Korean tertiary referral center. AB - PURPOSE: Infantile Marfan syndrome (MFS) is a rare congenital inheritable connective tissue disorder with poor prognosis. This study aimed to evaluate the cardiovascular manifestations and overall prognosis of infantile MFS diagnosed in a tertiary referral center in Korea. METHODS: Eight patients diagnosed with infantile MFS between 2004 and 2014 were retrospectively evaluated. RESULTS: Their median age at the time of diagnosis was 2.5 months (range, 0-20 months). The median follow-up period was 25.5 months (range, 0-94 months). The median length at birth was 50.0 cm (range, 48-53 cm); however, height became more prominent over time, and the patients were taller than the 97th percentile at the time of the study. None of the patients had any relevant family history. Four of the 5 patients who underwent DNA sequencing had a fibrillin 1 gene mutation. All the patients with echocardiographic data of the aortic root had a z score of >2. All had mitral and tricuspid valve prolapse, and various degrees of mitral and tricuspid regurgitation. Five patients underwent open-heart surgery, including mitral valve replacement, of whom two required multiple operations. The median age at mitral valve replacement was 28.5 months (range, 5-69 months). Seven patients showed congestive heart failure before surgery or during follow-up, and required multiple anti-heart failure medications. Four patients died of heart failure at a median age of 12 months. CONCLUSION: The prognosis of infantile MFS is poor; thus, early diagnosis and timely cautious treatment are essential to prevent further morbidity and mortality. PMID- 26958065 TI - Impact of lifestyle factors on trends in lipid profiles among Korean adolescents: the Korea National Health and Nutrition Examination Surveys study, 1998 and 2010. AB - PURPOSE: Only a few studies have explored nationwide trends in lipid profiles among Asian adolescents. We aimed to assess trends in lipid profiles and the associated lifestyle factors among Korean children. METHODS: We analyzed data for 2,094 adolescents who were aged 10-18 years and had participated in the Korea National Health and Nutrition Examination Surveys in 1998 and 2010. RESULTS: During 1998-2010, the prevalence of obesity significantly increased in boys, but no changes were observed in girls. Over this period, there was a small but significant decrease in the mean low-density lipoprotein (LDL)-cholesterol level in boys (1998, 87.5 mg/dL; 2010, 83.6 mg/dL; P=0.019) and mean triglyceride levels in girls (1998, 90.8 mg/dL; 2010, 85.8 mg/dL; P=0.020). There were no significant changes in the prevalence of dyslipidemia in boys, but a modest decrease was noted in girls (1998, 25.1%; 2010, 18.3%; P=0.052). During the study period, the prevalence of breakfast skipping decreased, whereas that of regular exercise increased in both groups. Daily total energy intake did not change between these years. In multivariable logistic regression analyses, breakfast skipping was associated with increased risk of hyper-LDL-cholesterolemia in boys (odds ratio [OR], 5.77) and hypertriglyceridemia (OR, 2.27) in girls. Regular exercise was associated with decreased risk of hypo-HDL-cholesterolemia (OR, 0.40) in boys. CONCLUSION: Although the prevalence of obesity in boys increased, favorable or constant trends in lipid profiles were observed among Korean adolescents during 1998-2010. Decrease in breakfast skipping and increase in regular exercise may have contributed to these trends. PMID- 26958067 TI - Meta-analysis of factors predicting resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. AB - PURPOSE: Studies have been conducted to identify predictive factors of resistance to intravenous immunoglobulin (IVIG) for Kawasaki disease (KD). However, the results are conflicting. This study aimed to identify laboratory factors predictive of resistance to high-dose IVIG for KD by performing meta-analysis of available studies using statistical techniques. METHODS: All relevant scientific publications from 2006 to 2014 were identified through PubMed searches. For studies in English on KD and IVIG resistance, predictive factors were included. A meta-analysis was performed that calculated the effect size of various laboratory parameters as predictive factors for IVIG-resistant KD. RESULTS: Twelve studies comprising 2,745 patients were included. Meta-analysis demonstrated significant effect sizes for several laboratory parameters: polymorphonuclear leukocytes (PMNs) 0.698 (95% confidence interval [CI], 0.469-0.926), C-reactive protein (CRP) 0.375 (95% CI, 0.086-0.663), pro-brain natriuretic peptide (pro-BNP) 0.561 (95% CI, 0.261-0.861), total bilirubin 0.859 (95% CI, 0.582-1.136), alanine aminotransferase (AST) 0.503 (95% CI, 0.313-0.693), aspartate aminotransferase (ALT) 0.436 (95% CI, 0.275-0.597), albumin 0.427 (95% CI, -0.657 to -0.198), and sodium 0.604 (95% CI, -0.839 to -0.370). Particularly, total bilirubin, PMN, sodium, pro-BNP, and AST, in descending numerical order, demonstrated more than a medium effect size. CONCLUSION: Based on the results of this study, laboratory predictive factors for IVIG-resistant KD included higher total bilirubin, PMN, pro-BNP, AST, ALT, and CRP, and lower sodium and albumin. The presence of several of these predictive factors should alert clinicians to the increased likelihood that the patient may not respond adequately to initial IVIG therapy. PMID- 26958068 TI - A new mosaic der(18)t(1;18)(q32.1;q21.3) with developmental delay and facial dysmorphism. AB - We report the case of a 22-month-old boy with a new mosaic partial unbalanced translocation of 1q and 18q. The patient was referred to our Pediatric Department for developmental delay. He showed mild facial dysmorphism, physical growth retardation, a hearing disability, and had a history of patent ductus arteriosus. White matter abnormality on brain magnetic resonance images was also noted. His initial routine chromosomal analysis revealed a normal 46,XY karyotype. In a microarray-based comparative genomic hybridization (aCGH) analysis, subtle copy number changes in 1q32.1-q44 (copy gain) and 18q21.33-18q23 (copy loss) suggested an unbalanced translocation of t(1;18). Repeated chromosomal analysis revealed a low-level mosaic translocation karyotype of 46,XY,der(18)t(1;18)(q32.1;q21.3)[12]/46,XY[152]. Because his parents had normal karyotypes, his translocation was considered to be de novo. The abnormalities observed in aCGH were confirmed by metaphase fluorescent in situ hybridization. We report this patient as a new karyotype presenting developmental delay, facial dysmorphism, cerebral dysmyelination, and other abnormalities. PMID- 26958066 TI - Epilepsy in children with a history of febrile seizures. AB - PURPOSE: Febrile seizure, the most common type of pediatric convulsive disorder, is a benign seizure syndrome distinct from epilepsy. However, as epilepsy is also common during childhood, we aimed to identify the prognostic factors that can predict epilepsy in children with febrile seizures. METHODS: The study comprised 249 children at the Korea University Ansan Hospital who presented with febrile seizures. The relationship between the subsequent occurrence of epilepsy and clinical factors including seizure and fever-related variables were analyzed by multivariate analysis. RESULTS: Twenty-five patients (10.0%) had additional afebrile seizures later and were diagnosed with epilepsy. The subsequent occurrence of epilepsy in patients with a history of febrile seizures was associated with a seizure frequency of more than 10 times during the first 2 years after seizure onset (P<0.001). Factors that were associated with subsequent occurrence of epilepsy were developmental delay (P<0.001), preterm birth (P=0.001), multiple seizures during a febrile seizure attack (P=0.005), and epileptiform discharges on electroencephalography (EEG) (P=0.008). Other factors such as the age at onset of first seizure, seizure duration, and family history of epilepsy were not associated with subsequent occurrence of epilepsy in this study. CONCLUSION: Febrile seizures are common and mostly benign. However, careful observation is needed, particularly for prediction of subsequent epileptic episodes in patients with frequent febrile seizures with known risk factors, such as developmental delay, history of preterm birth, several attacks during a febrile episode, and epileptiform discharges on EEG. PMID- 26958069 TI - Successfully treated infective endocarditis caused by methicillin-resistant Staphylococcus Aureus in extremely low birth weight infant. AB - Survival rates of preterm infants have improved in the past few decades, and central venous catheters play an important role in the intensive medical treatment of these neonates. Unfortunately, these indwelling catheters increase the risk of intracardiac thrombosis, and they provide a nidus for microorganisms during the course of septicemia. Herein, we report a case of persistent bacteremia due to methicillin-resistant Staphylococcus aureus in an extremely low birth weight (ELBW) infant, along with vegetation observed on an echocardiogram, the findings which are compatible with a diagnosis of endocarditis. The endocarditis was successfully treated with antibiotic therapy, and the patient recovered without major complications. We suggest a surveillance echocardiogram for ELBW infants within a few days of birth, with regular follow-up studies when clinical signs of sepsis are observed. PMID- 26958070 TI - Recombinant Human Erythropoietin Therapy for a Jehovah's Witness Child With Severe Anemia due to Hemolytic-Uremic Syndrome. AB - Patients with hemolytic-uremic syndrome (HUS) can rapidly develop profound anemia as the disease progresses, as a consequence of red blood cell (RBC) hemolysis and inadequate erythropoietin synthesis. Therefore, RBC transfusion should be considered in HUS patients with severe anemia to avoid cardiac or pulmonary complications. Most patients who are Jehovah's Witnesses refuse blood transfusion, even in the face of life-threatening medical conditions due to their religious convictions. These patients require management alternatives to blood transfusions. Erythropoietin is a glycopeptide that enhances endogenous erythropoiesis in the bone marrow. With the availability of recombinant human erythropoietin (rHuEPO), several authors have reported its successful use in patients refusing blood transfusion. However, the optimal dose and duration of treatment with rHuEPO are not established. We report a case of a 2-year-old boy with diarrhea-associated HUS whose family members are Jehovah's Witnesses. He had severe anemia with acute kidney injury. His lowest hemoglobin level was 3.6 g/dL, but his parents refused treatment with packed RBC transfusion due to their religious beliefs. Therefore, we treated him with high-dose rHuEPO (300 IU/kg/day) as well as folic acid, vitamin B12, and intravenous iron. The hemoglobin level increased steadily to 7.4 g/dL after 10 days of treatment and his renal function improved without any complications. To our knowledge, this is the first case of successful rHuEPO treatment in a Jehovah's Witness child with severe anemia due to HUS. PMID- 26958071 TI - Predictors of perceived male partner concurrency among women at risk for HIV and STI acquisition in Durban, South Africa. AB - BACKGROUND: Women in sub-Saharan Africa continue to be at greater risk for HIV acquisition than men. Concurrency, viz. multiple sexual partnerships that overlap over time, has been studied as a possible risk factor for HIV transmission. The aim of this study was to identify predictors of perceived male partner concurrency among sexually active, HIV negative women. METHODS: Socio-demographic and behavioural data from women enrolled in a biomedical HIV prevention clinical trial were assessed in relation to perceived male partner concurrency using the Chi squared test. Univariate and multivariate logistic regression was performed to assess the independent predictors of perceived male partner concurrency. Kaplan-Meier survival estimates were obtained for HIV and STI incidence in relation to male partner concurrency. A Cox Proportional Hazards model was used to assess the association between perceived male partner concurrency and HIV and STI incidence. RESULTS: The results revealed that 29 % of women reported their male partners to be in concurrent sexual relationships, 22 % reported partners that were not engaging in concurrency, whilst 49 % reported not knowing their partners concurrency status. Older women, having never married, experiencing economic abuse, and women reporting individual concurrency, were found to be significant predictors of perceived male partner concurrency in the studied population. Perceived male partner concurrency was not found to be a significantly associated with incident HIV and STI infections in this analysis. CONCLUSIONS: The study provides insight into predictors of perceived male partner concurrency among women at high risk for STI and HIV acquisition. These results may inform the design of behavioural and biomedical interventions, to address the role of multiple sexual partnerships in HIV prevention. PMID- 26958072 TI - Purpose in Life in Emerging Adulthood: Development and Validation of a New Brief Measure. AB - Accruing evidence points to the value of studying purpose in life across adolescence and emerging adulthood. Research though is needed to understand the unique role of purpose in life in predicting well-being and developmentally relevant outcomes during emerging adulthood. The current studies (total n = 669) found support for the development of a new brief measure of purpose in life using data from American and Canadian samples, while demonstrating evidence for two important findings. First, purpose in life predicted well-being during emerging adulthood, even when controlling for the Big Five personality traits. Second, purpose in life was positively associated with self-image and negatively associated with delinquency, again controlling for personality traits. Findings are discussed with respect to how studying purpose in life can help understand which individuals are more likely to experience positive transitions into adulthood. PMID- 26958073 TI - Novel phthalide derivatives identified from Ligusticum chuanxiong (Chuanxiong). AB - BACKGROUND: Ligusticum chuanxiong Hort. (Chuanxiong) is a well-known Chinese medicine, and studies on its chemical constituents are important for explaining its mechanism of action and quality control. This study aims to investigate the chemical constituents of the dried rhizome of. L. chuanxiong. METHODS: The dried rhizome of L. chuanxiong was extracted with 60 % ethanol, and the concentrated extract was isolated by silica gel, octadecyl silane, and Sephadex LH-20 columns, followed by preparative/semipreparative high-performance liquid chromatography (HPLC) to obtain the pure chemical constituents. The structures of the constituents were elucidated by HR-ESI-MS, UV, IR, 1D NMR, and 2D NMR methods. Enantiomeric separation was achieved by a chiral HPLC method. The absolute configuration was determined by the modified Mosher's method. RESULTS: Six novel phthalide derivatives, (+)/(-)-chuanxiongins A-F (1-6), together with four known phthalides (7-10) were isolated from Chuanxiong. All of the new compounds (1-6) were present as pairs of enantiomers. Enantiomeric separation of 1 was successfully achieved by HPLC on a chiral column. The absolute configuration of ( )-1 was determined by a modified Mosher's method. CONCLUSION: The six novel phthalide derivatives (1-6) isolated from Chuanxiong were phthalide fatty acid esters that were structurally analogous and characterized by fatty acid acylation at 6-OH or 7-OH. PMID- 26958074 TI - Burst nucleation by hot injection for size controlled synthesis of epsilon-cobalt nanoparticles. AB - BACKGROUND: Reproducible growth of narrow size distributed epsilon-Co nanoparticles with a specific size requires full understanding and identification of the role of essential synthesis parameters for the applied synthesis method. For the hot injection methodology, a significant discrepancy with respect to obtained sizes and applied reaction conditions is reported. Currently, a systematic investigation controlling key synthesis parameters as injection temperature and time, metal to surfactant ratio and reaction holding time in terms of their impact on mean ([Formula: see text]mean) and median ([Formula: see text]median) particle diameter using dichlorobenzene (DCB), Co2(CO)8 and oleic acid (OA) as the reactant matrix is lacking. METHODS: A series of solution-based epsilon-Co nanoparticles were synthesized using the hot injection method. Suspensions and obtained particles were analyzed by DLS, ICP-OES, (synchrotron)XRD and TEM. Rietveld refinements were used for structural analysis. Mean ([Formula: see text]mean) and median ([Formula: see text]median) particle diameters were calculated with basis in measurements of 250-500 particles for each synthesis. 95 % bias corrected confidence intervals using bootstrapping were calculated for syntheses with three or four replicas. RESULTS: epsilon-Co NPs in the size range ~4-10 nm with a narrow size distribution are obtained via the hot injection method, using OA as the sole surfactant. Typically the synthesis yield is ~75 %, and the particles form stable colloidal solutions when redispersed in hexane. Reproducibility of the adopted synthesis procedure on replicate syntheses was confirmed. We describe in detail the effects of essential synthesis parameters, such as injection-temperature and time, metal to surfactant ratio and reaction holding time in terms of their impact on mean ([Formula: see text]mean) and median ([Formula: see text]median) particle diameter. CONCLUSIONS: The described synthesis procedure towards epsilon-Co nanoparticles (NPs) is concluded to be robust when controlling key synthesis parameters, giving targeted particle diameters with a narrow size distribution. We have identified two major synthesis parameters which control particle size, i.e., the metal to surfactant molar ratio and the injection temperature of the hot OA-DCB solution into which the cobalt precursor is injected. By increasing the metal to surfactant molar ratio, the mean particle diameter of the epsilon-Co NPs has been found to increase. Furthermore, an increase in the injection temperature of the hot OA-DCB solution into which the cobalt precursor is injected, results in a decrease in the mean particle diameter of the epsilon-Co NPs, when the metal to surfactant molar ratio [Formula: see text] is fixed at ~12.9. PMID- 26958075 TI - Novel implementation research designs for scaling up global mental health care: overcoming translational challenges to address the world's leading cause of disability. AB - Despite established knowledge that Low and Middle Income Countries (LMICs) bear the majority of the world's burden of mental disorders, and more than a decade of efficacy research showing that the most common disorders, such as depression and anxiety, can be treated using readily available local personnel in LMICs to apply evidence-based treatments, there remains a massive mental health treatment gap, such that 75 % of those in LMICs never receive care. Here, we discuss the use of a new type of implementation science study design, the effectiveness implementation hybrids, to speed the translation and scale up of mental health care in LMICs. We use our current study of Interpersonal Psychotherapy (IPT) delivered by local personnel for depression and trauma-related disorders among HIV+ women in Kenya as an example of effectiveness-implementation hybrid design for mental health services research in LMICs. PMID- 26958076 TI - Involuntary psychiatric admission: how the patients are detected and the general practitioners' expectations for hospitalization. An interview-based study. AB - BACKGROUND: In Norway, it is usually GPs that refer patients to involuntary admission. A high proportion of such referrals come from out-of-hours clinics. Little is known about who first initiate the contact between the patients and the referring doctors and which expectations the referring doctors have with respect to the involuntary admissions. The aim of the study was to examine who first detected the patients who were subsequently involuntarily admitted, and to examine the referring doctors' expectations for the admissions. METHODS: Semi structured interviews with 74 doctors that had referred patients for involuntary admission at a psychiatric hospital. RESULTS: Patients who were involuntarily admitted were detected by other branches of the health service (52 %, n = 39), family (25 %, n = 19), and the police (17 %, n = 13). The doctors mentioned these expectations for the admission (more than one expectation could be given): start treatment with neuroleptics: 58 % (n = 43), take care of the patient: 45 % (n = 34), extensive changes to the treatment regime: 37 % (n = 28), solve an acute situation: 35 % (n = 26), and clarify the diagnosis: 22 % (n = 17). Female doctors significantly more often expected that the patients would be examined and treated, while the male doctors significantly more often expected that the patients would be cared for. CONCLUSIONS: Involuntary admissions are typically complex processes involving different people and services and patients with various needs. More knowledge about the events preceding hospitalization is needed in order to develop alternatives to involuntary admissions. PMID- 26958079 TI - Tissue-independent and tissue-specific patterns of DNA methylation alteration in cancer. AB - BACKGROUND: There is growing evidence that DNA methylation alterations contribute to carcinogenesis. While cancer tissue exhibits widespread DNA methylation changes, the proportion of tissue-specific versus tissue-independent DNA methylation alterations in cancer is unclear. In addition, it is unknown which factors determine the patterns of aberrant DNA methylation in cancer. RESULTS: Using HumanMethylation450 BeadChips (450k), we here analyze genome-wide DNA methylation patterns of ten types of fetal tissue, in addition to matched normal cancer data for corresponding tissue types, encompassing over 3000 samples. We demonstrate that the level of aberrant cancer DNA methylation in gene promoters and gene bodies is highly correlated between cancer types. We estimate that up to 60 % of the DNA methylation variation in a cancer genome of a given tissue type is explained by the corresponding variation in a cancer genome of another type, implying that much of the cancer DNA methylation landscape is tissue independent. We further show that histone marks in normal cells are better predictors of aberrant cancer DNA methylation than the corresponding signals in human embryonic stem cells. We build predictors of cancer DNA methylation patterns and show that although inclusion of three histone marks (H3K4me3, H3K27me3 and H3K36me3) improves model accuracy, the bivalent marks are the most predictive. Finally, we show that chromatin accessibility of gene promoters in normal tissue dictates the promoter's propensity to acquire aberrant DNA methylation in cancer in so far as it determines its level of DNA methylation in normal tissue. CONCLUSIONS: Our data show that a considerable fraction of the aberrant cancer DNA methylation landscape results from a mechanism that is largely tissue specific. Histone marks as specified in the normal cell of origin provide highly predictive models of aberrant cancer DNA methylation and outperform those derived from the same marks in hESCs. PMID- 26958077 TI - Dissection of early transcriptional responses to water stress in Arundo donax L. by unigene-based RNA-seq. AB - BACKGROUND: Arundo donax L. (Poaceae) is considered one of the most promising energy crops in the Mediterranean region because of its high biomass yield and low input requirements, but to date no information on its transcriptional responses to water stress is available. RESULTS: We obtained by Illumina-based RNA-seq the whole root and shoot transcriptomes of young A. donax plants subjected to osmotic/water stress with 10 and 20 % polyethylene glycol (PEG; 3 biological replicates/organ/condition corresponding to 18 RNA-Seq libraries), and identified a total of 3034 differentially expressed genes. Blast-based mining of stress-related genes indicated the higher responsivity of roots compared to shoots at the early stages of water stress especially under the milder PEG treatment, with a majority of genes responsive to salt, oxidative, and dehydration stress. Analysis of gene ontology terms underlined the qualitatively different responses between root and shoot tissues. Among the most significantly enriched metabolic pathways identified using a Fisher's exact test with FDR correction, a crucial role was played in both shoots and roots by genes involved in the signaling cascade of abscisic acid. We further identified relatively large organ-specific differences in the patterns of drought-related transcription factor AP2-EREBP, AUX/IAA, MYB, bZIP, C2H2, and GRAS families, which may underlie the transcriptional reprogramming differences between organs. Through comparative analyses with major Poaceae species based on Blast, we finally identified a set of 53 orthologs that can be considered as a core of evolutionary conserved genes important to mediate water stress responses in the family. CONCLUSIONS: This study provides the first characterization of A. donax transcriptome in response to water stress, thus shedding novel light at the molecular level on the mechanisms of stress response and adaptation in this emerging bioenergy species. The inventory of early-responsive genes to water stress identified could constitute useful markers of the physiological status of A. donax and be a basis for the improvement of its productivity under water limitation. The full water stressed A. donax transcriptome is available for Blast-based homology searches through a dedicated web server (http://ecogenomics.fmach.it/arundo/). PMID- 26958078 TI - Hyper-accumulation of starch and oil in a Chlamydomonas mutant affected in a plant-specific DYRK kinase. AB - BACKGROUND: Because of their high biomass productivity and their ability to accumulate high levels of energy-rich reserve compounds such as oils or starch, microalgae represent a promising feedstock for the production of biofuel. Accumulation of reserve compounds takes place when microalgae face adverse situations such as nutrient shortage, conditions which also provoke a stop in cell division, and down-regulation of photosynthesis. Despite growing interest in microalgal biofuels, little is known about molecular mechanisms controlling carbon reserve formation. In order to discover new regulatory mechanisms, and identify genes of interest to boost the potential of microalgae for biofuel production, we developed a forward genetic approach in the model microalga Chlamydomonas reinhardtii. RESULTS: By screening an insertional mutant library on the ability of mutants to accumulate and re-mobilize reserve compounds, we isolated a Chlamydomonas mutant (starch degradation 1, std1) deficient for a dual specificity tyrosine-phosphorylation-regulated kinase (DYRK). The std1 mutant accumulates higher levels of starch and oil than wild-type and maintains a higher photosynthetic activity under nitrogen starvation. Phylogenetic analysis revealed that this kinase (named DYRKP) belongs to a plant-specific subgroup of the evolutionarily conserved DYRK kinase family. Furthermore, hyper-accumulation of storage compounds occurs in std1 mostly under low light in photoautotrophic condition, suggesting that the kinase normally acts under conditions of low energy status to limit reserve accumulation. CONCLUSIONS: The DYRKP kinase is proposed to act as a negative regulator of the sink capacity of photosynthetic cells that integrates nutrient and energy signals. Inactivation of the kinase strongly boosts accumulation of reserve compounds under photoautotrophic nitrogen deprivation and allows maintaining high photosynthetic activity. The DYRKP kinase therefore represents an attractive target for improving the energy density of microalgae or crop plants. PMID- 26958081 TI - Erratum to: Expression of REG Ialpha gene in type 2 diabetics in Pakistan. AB - [This corrects the article DOI: 10.1186/s13098-015-0092-6.]. PMID- 26958082 TI - Factors associated with glucose tolerance, pre-diabetes, and type 2 diabetes in a rural community of south India: a cross-sectional study. AB - BACKGROUND: India's national rural prevalence of type 2 diabetes has quadrupled in the past 25 years. Despite the growing rural burden, few studies have examined putative risk factors and their relationship with glucose intolerance and diabetes in rural areas. We undertook a cross-sectional study to determine the prevalence of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes in a rural area of south India. In addition, we determined which factors were associated with type 2 diabetes. METHODS: We sampled 2 % of the adult population from 17 villages using a randomized household-level sampling technique. Each participant undertook a questionnaire that included basic descriptive information and an assessment of socioeconomic status, physical activity, and dietary intake. Height, weight, waist and hip circumference, and blood pressure measurements were taken. An oral glucose tolerance test was used to determine diabetes status. We used stepwise logistic model building techniques to determine associations between several putative factors and type 2 diabetes. RESULTS: 753 participants were included in the study. The age- and sex standardized prevalence of IFG was 3.9 %, IGT was 5.6 %, and type 2 diabetes was 10.8 %. Factors associated with type 2 diabetes after adjusting for confounders included physical activity [OR 0.81], rurality [OR 0.76], polyunsaturated fat intake [OR 0.94], body mass index [OR 1.85], waist to hip ratio [OR 1.62], and tobacco consumption [OR 2.82]. CONCLUSION: Our study contributes to the growing body of research suggesting that diabetes is a significant concern in rural south India. Associated risk factors should be considered as potential targets for reducing health burdens in India. PMID- 26958080 TI - Cutaneous stimulation at the ankle: a differential effect on proprioceptive postural control according to the participants' preferred sensory strategy. AB - BACKGROUND: Ankle movements can be partially encoded by cutaneous afferents. However, little is known about the central integration of these cutaneous signals, and whether individual differences exist in this integration. The aim of this study was to determine whether the effect of cutaneous stimulation at the ankle would differ depending on the participants' preferred sensory strategy appraised by relative proprioceptive weighting (RPw). METHODS: Forty-seven active young individuals free of lower-limb injury stood on a force platform either barefoot or wearing a custom-designed bootee. Vibrations (60 Hz, 0.5 mm) were applied either to the peroneal tendons or to the lumbar paraspinal muscles. RESULTS: The barefoot RPw was strongly negatively correlated to the absolute change in RPw measured in the bootee condition (r = -0.81, P < 0.001). Participants were then grouped depending on their barefoot RPw value. The RPw was significantly higher in the bootee condition than in the barefoot condition only for participants with low barefoot RPw. CONCLUSIONS: The external cutaneous stimulation given by the bootee increased the weight of ankle proprioceptive signals only for participants with low barefoot RPw. This result confirmed that optimization of the ankle proprioceptive signals provided by cutaneous afferent stimulation has a differential effect depending on the participants' preferred sensory strategy. PMID- 26958083 TI - The Impact of PD-L1 Expression in Patients with Metastatic GEP-NETs. AB - Programmed death-ligand 1 (PD-L1), which is expressed on many cancer cells, interacts with PD1 expressed on the surface of T cells, inhibiting the T cells and blocking the antitumor immune response. Expression of PD-L1 in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has not been studied. We investigated the impact of PD-L1 expression in 32 patients with metastatic GEP NET. The expression of PD-L1 was evaluated using an anti-PD-L1 immunohistochemistry (IHC) antibody optimized for staining of formalin-fixed paraffin-embedded (FFPE) tissue samples. The correlation between PD-L1 and clinicopathological data including survival and response to systemic treatments was analyzed. Primary sites were 24 foregut-derived GEP-NETs, including stomach (n=1), duodenum (n=2), biliary tract (n=7), and pancreas (n=14), and 8 hindgut derived GEP-NETs of the distal colon and rectum. Among the 32 patients with metastatic GEP-NET analyzed in this study, 7 (21.9%) had expression of PD-L1 in tumor tissues. Expression of PD-L1 was significantly associated with high-grade WHO classification (grade 3) (p=0.008) but not with gender, primary site, and number of metastatic sites (p>0.05). The status of PD-L1 expression was statistically associated with progression-free survival (PFS) for first-line systemic treatment (p=0.047). Moreover, the status of PD-L1 expression could significantly predict overall survival (p=0.037). The expression of PD-L1 was associated with higher WHO tumor grade (grade 3) in metastatic GEP-NETs. PD-L1 expression had both predictive and prognostic value for survival of patients with metastatic GEP-NETs. PMID- 26958084 TI - Evaluation of Plasma miR-21 and miR-152 as Diagnostic Biomarkers for Common Types of Human Cancers. AB - Stable blood based miRNA species have allowed for the differentiation of patients with various types of cancer. Therefore, specific blood-based miRNA might be considered as a methodology which could be informative of the presence of cancer potentially from multiple distinct organ sites. Recently, miR-21 has been identified as an "oncomir" in various tumors while miR-152 as a tumor suppressor. In this study, we investigated whether circulating miR-21 and miR-152 can be used for early detection of lung cancer (LuCa), colorectal carcinoma (CRC), breast cancer (BrCa) and prostate cancer (PCa), with distinguishing cancer from various benign lesions on these organ sites. We measured the two miRNA levels by using real-time RT-PCR in plasma samples from a total of 204 cancer patients, 159 various benign lesions, and 228 normal subjects. We observed significantly elevated expression of miR-21 and miR-152 in LuCa, CRC, and BrCa when compared with normal controls. We also found upregulation of plasma miR-21 and miR-152 levels in patients with benign lesions of lung and breast, as compared to normal controls, respectively. No significant expression variation of the two miRNAs was observed in PCa or prostatic benign lesions as compared to healthy controls. Receiver operating characteristic (ROC) analyses revealed that miR-21 and/or miR 152 can discriminate LuCa, CRC and BrCa from normal controls. Our results suggest that plasma miR-21 and miR-152 may serve as non-specific noninvasive biomarkers for early screening of LuCa, CRC, and BrCa, but not PCa. PMID- 26958085 TI - Ganoderma lucidum Combined with the EGFR Tyrosine Kinase Inhibitor, Erlotinib Synergize to Reduce Inflammatory Breast Cancer Progression. AB - The high incidence of resistance to Tyrosine Kinase Inhibitors (TKIs) targeted against EGFR and downstream pathways has increased the necessity to identify agents that may be combined with these therapies to provide a sustained response for breast cancer patients. Here, we investigate the therapeutic potential of Ganoderma lucidum extract (GLE) in breast cancer, focusing on the regulation of the EGFR signaling cascade when treated with the EGFR TKI, Erlotinib. SUM-149, or intrinsic Erlotinib resistant MDA-MB-231 cells, and a successfully developed Erlotinib resistant cell line, rSUM-149 were treated with increasing concentrations of Erlotinib, GLE, or their combination (Erlotinib/GLE) for 72h. Treatment effects were tested on cell viability, cell proliferation, cell migration and invasion. To determine tumor progression, severe combined immunodeficient mice were injected with SUM-149 cells and then treated with Erlotinib/GLE or Erlotinib for 13 weeks. We assessed the protein expression of ERK1/2 and AKT in in vitro and in vivo models. Our results show that GLE synergizes with Erlotinib to sensitize SUM-149 cells to drug treatment, and overcomes intrinsic and developed Erlotinib resistance. Also, Erlotinib/GLE decreases SUM-149 cell viability, proliferation, migration and invasion. GLE increases Erlotinib sensitivity by inactivating AKT and ERK signaling pathways in our models. We conclude that a combinatorial therapeutic approach may be the best way to increase prognosis in breast cancer patients with EGFR overexpressing tumors. PMID- 26958086 TI - Loss of MKK3 and MK2 Copy Numbers in Non-Small Cell Lung Cancer. AB - Identification of genetic alterations in members of the p38 mitogen-activated protein kinase (MAPK) pathway is important as these proteins have dynamic roles in tumor progression and may serve as potential therapeutic targets in cancer. We analyzed tumor and non-tumorous lung tissue of 233 non-small cell lung cancer (NSCLC) patients for the presence of copy number alterations (CNAs) in the MAPK kinase 3 (MKK3) and MAPK-activated kinase 2 (MK2) genes. We report frequent CNAs in MKK3 and MK2 genes in NSCLC. Copy number losses were detected in 31% of NSCLC tumors (odds ratio: 7.08, 95% confidence interval: 3.2-15.6, P<0.001) for the MKK3 gene and in 28% of tumors for the MK2 gene (odds ratio: 3.68, 95% confidence interval: 1.9-7.2, P<0.001). Several of the non-tumorous tissues showed an elevated MKK3 copy number, with a concurrent loss of this in 89% of the paired tumors. MKK3 gene deletions were significantly more frequent in squamous and large cell carcinoma than in adenocarcinoma. These data demonstrate a novel loss of MKK3 and MK2 genomic copy numbers in NSCLC tumors, and suggest these genes as interesting therapeutic candidates in NSCLC. PMID- 26958087 TI - Metabolic Determinants and Anthropometric Indicators Impact Clinical-pathological Features in Epithelial Ovarian Cancer Patients. AB - BACKGROUND: Over the last twenty years, the efforts of the scientific community devoted to the comprehension and treatment of ovarian cancer have remained poorly remunerative, with the case-fatality ratio of this disease remaining disappointedly high. Limited knowledge of the basic principles regulating ovarian carcinogenesis and factors impacting the course of disease may significantly impair our ability to intervene in early stages and lessen our expectations in terms of treatment outcomes. In the present study, we sought to assess whether metabolic factors and anthropometric indicators, i.e., pre-treatment fasting glucose and body mass index, are associated with renown cancer related prognostic factors such as tumour stage and grade at diagnosis. MATERIALS AND METHODS: Study participants were 147 women diagnosed with epithelial ovarian cancer and treated with platinum based regimens and/or surgery at the Regina Elena National Cancer Institute of Rome, Italy. Glucose levels were assessed at the institutional laboratories on venous blood collected in overnight fasting conditions and prior to any therapeutic procedure. Stage was coded according to the FIGO staging system based on the results of the diagnostic workup, while tumour grade was locally assessed by an expert pathologist. Participants' characteristics were descriptively analyzed for the overall study population and in a subgroup of 70 patients for whom data on body mass index (BMI) were available. FIGO stage and grade were compared by categories of pre-treatment fasting glucose defined upon the median value, i.e., 89 mg/dl. The association of interest was tested in regression models including BMI. RESULTS: For the overall study population, patients in the lowest category of fasting glucose were significantly more likely to exhibit a FIGO stage III-IV at diagnosis compared with their counterpart in the highest glucose category (81.3 vs 66.7%, p: 0.021). Subgroup analysis in 70 patients with BMI data confirmed this association (81.5 vs 55.8, p: 0.049), which remained significant when tested in regression models including BMI (OR: 0.28 95% CI 0.086-0.89, p: 0.031). No relevant evidence emerged when testing the association between fasting glucose and tumour grade. CONCLUSIONS: In patients diagnosed with epithelial ovarian cancer, pre-treatment glucose levels appear to be inversely associated with FIGO stage. Further studies are warranted to eventually confirm and correctly interpret the implications of this novel finding. PMID- 26958089 TI - Assessing the Key Attributes of Low Utilization of Mammography Screening and Breast-self Exam among African-American Women. AB - PURPOSE: African-American (AA) women living in four Black Belt Counties (BBC) of Alabama; consisting of Barbour, Macon, Green and Wilcox are known to have lower mammogram utilization and breast self-exam rates when compared to their white female counterparts. The influence of socioeconomic and demographic factors on these disparities has not been clearly defined so far. Our study was designed to determine whether these observed disparities can be predicted with the socioeconomic and other demographic attributes. METHODS: Health Disparity Questionnaires data (n = 516) for BBC of Alabama was analyzed using a logistic regression model to examine the association of breast cancer screening rates and breast self-exam with income, the level of education, family doctor, type of health insurance, obesity, and age. RESULTS: Income, education, family doctor, age and health insurance were independent predictors for the low utilization rate of mammography and breast self-exam (BSE). CONCLUSION: Improving socioeconomic conditions such as level of education and availability of health care are essential to increase the rates of breast cancer screening test and breast self exam in the BBC of Alabama. PMID- 26958088 TI - Immunochemical Assays and Nucleic-Acid Detection Techniques for Clinical Diagnosis of Prostate Cancer. AB - Prostate cancer (PCa) is a significant cause of morbidity and mortality and the most common cancer in men in Europe, North America, and some parts of Africa. The established methods for detecting PCa are normally based on tests using Prostate Specific Antigen (PSA) in blood, Prostate cancer antigen 3 (PCA3) in urine and tissue Alpha-methylacyl-CoA racemase (AMACR) as tumour markers in patient samples. Prior to the introduction of PSA in clinics, prostatic acid phosphatase (PAP) was the most widely used biomarker. An early diagnosis of PCa through the detection of these biomarkers requires the availability of simple, reliable, cost effective and robust techniques. Immunoassays and nucleic acid detection techniques have experienced unprecedented growth in recent years and seem to be the most promising analytical tools. This growth has been driven in part by the surge in demand for near-patient-testing systems in clinical diagnosis. This article reviews immunochemical assays, and nucleic-acid detection techniques that have been used to clinically diagnose PCa. PMID- 26958090 TI - Draft Genome Sequence of Colletotrichum falcatum - A Prelude on Screening of Red Rot Pathogen in Sugarcane. AB - Colletotrichum falcatum, a concealed fungal ascomycete causes red rot, which is a serious disease in sugarcane. It infects economically important stalk tissues, considered as store house of sugar in sugarcane. The study is to find genetic complexities of C. falcatum in establishing this as a stalk infecting pathogen and to decipher the unique lifestyle of this pathogen using NGS technology. We report the draft genome of C. falcatum of about 48.16 Mb in size with 12,270 genes. The genome sequences were compared with other fungal species which revealed that C. falcatum is closely related to C. graminicola and C.sublineola the causal organisms of anthracnose in maize and sorghum. These results brought a new revelation to explore the lifestyle of this unique pathogen which is specialized to infect sugarcane stalk tissues in detail. PMID- 26958091 TI - Draft Genome Sequence of Brevibacillus borstelensis cifa_chp40, a Thermophilic Strain Having Biotechnological Importance. AB - Brevibacillus borstelensis cifa_chp40 is a thermophilic, strictly aerobic gram positive motile bacteria isolated from the alkaline hot water spring located in the Eastern Ghats zone of India. It could grow in a wide range of temperature and degrade low-density polythene at 37 degrees C. The strain cifa_chp40 produces essential enzymes like protease, lipase, esterase and amidase at 50 degrees C. Here, we report the draft genome sequence of B. borstelensis cifa_chp40 which will provide further insight into the metabolic capabilities, function and evolution of this important organism. PMID- 26958092 TI - Draft Genome Sequences of Two Pathogenic Corynebacterial Species Isolated from Cows. AB - The species Corynebacterium renale, Corynebacterium pilosum, and Corynebacterium cystitidis were initially thought to be the same species C. renale, but with different immunological types. These bacteria are the causative agent of cystitis, urethritis and pyelonephritis and are found usually as constituents of the normal flora in the lower urogenital tract of cattle. Therefore, we present the draft genome sequences of two pathogenic Corynebacterium species: C. renale CIP 52.96 and C. pilosum CIP 103422. The genome sequences of these species have 2,322,762 bp with 2,218 protein encoding genes and 2,548,014 bp with 2,428 protein encoding genes, respectively. These genomes can help clarify the virulence mechanisms of these unknown bacteria and enable the development of more effective methods for control. PMID- 26958093 TI - Local influence of cell viability on stretch-induced permeability of alveolar epithelial cell monolayers. AB - Ventilator induced lung injury (VILI), often attributed to over-distension of the alveolar epithelial cell layer, can trigger loss of barrier function. Alveolar epithelial cell monolayers can be used as an idealized in vitro model of the pulmonary epithelium, with cell death and tight junction disruption and permeability employed to estimate stretch-induced changes in barrier function. We adapted a method published for vascular endothelial permeability, compare its sensitivity with our previously published method, and determine the relationship between breeches in barrier properties after stretch and regions of cell death After 4-5 days in culture, primary rat alveolar epithelial cells seeded on plasma treated polydimethylsiloxane membrane coated with biotin-labeled fibronectin, or fibronectin alone were stretched in the presence of FITC-tagged streptavidin (biotin-labeled membrane) or BODIPY-ouabain. We found that the FITC-labeling method was a more sensitive indicator of permeability disruption, with significantly larger positively stained areas visible in the presence of stretch and with ATP production inhibitor Antimycin-A. Triple-stained images with Hoescht (nuclei), Ethidium Homodimer (EthD, damaged cell nuclei) and FITC (permeable regions) were used to determine that within permeable regions intact cells were positioned closer to damaged cells than in non-permeable regions. We concluded that local cell death may be an important contributor to barrier integrity. PMID- 26958094 TI - Limited impact of Cntn4 mutation on autism-related traits in developing and adult C57BL/6J mice. AB - BACKGROUND: Mouse models offer an essential tool to unravel the impact of genetic mutations on autism-related phenotypes. The behavioral impact of some important candidate gene models for autism spectrum disorder (ASD) has not yet been studied, and existing characterizations mostly describe behavioral phenotypes at adult ages, disregarding the developmental nature of the disorder. In this context, the behavioral influence of CNTN4, one of the strongest suggested ASD candidate genes, is unknown. Here, we used our recently established developmental test battery to characterize the consequences of disruption of contactin 4 (Cntn4) on neurological, sensory, cognitive, and behavioral phenotypes across different developmental stages. METHODS: C57BL/6J mice with heterozygous and homozygous disruption of Cntn4 were studied through an extensive, partially longitudinal, test battery at various developmental stages, including various paradigms testing social and restricted repetitive behaviors. RESULTS: Developmental neurological and cognitive screenings revealed no significant differences between genotypes, and ASD-related behavioral domains were also unchanged in Cntn4-deficient versus wild-type mice. The impact of Cntn4 deficiency was found to be limited to increased startle responsiveness following auditory stimuli of different high amplitudes in heterozygous and homozygous Cntn4-deficient mice and enhanced acquisition in a spatial learning task in homozygous mice. CONCLUSIONS: Disruption of Cntn4 in the C57BL/6J background does not affect specific autism-related phenotypes in developing or adult mice but causes subtle non-disorder specific changes in sensory behavioral responses and cognitive performance. PMID- 26958095 TI - Erratum to: Imprinting disorders: a group of congenital disorders with overlapping patterns of molecular changes affecting imprinted loci. AB - [This corrects the article DOI: 10.1186/s13148-015-0143-8.]. PMID- 26958096 TI - Effect of calcitonin gene-related peptide antagonist on the cardiovascular events, mortality, and prostaglandin E2 production by nitrate-induced tolerant rats with acute myocardial infarction. AB - BACKGROUND: Anti-ischemic effects of NO releasing by nitroglycerin (NTG) and the release of calcitonin gene-related peptide (CGRP) are involved in the decrease of vascular remodeling in different cardiovascular diseases. Using a nitrate-free period is still generally required to prevent nitrate tolerance and should be used as the first-line option to maintain adequate symptom control and on an individual basis. Personalized anti-ischemic concerns require the urgent change of paradigm from interventional measures to predictive, preventive, and personalized treatment with organic nitrates and its combination with drugs that may improve prognosis and drugs that can be added for patients who remain symptomatic despite therapy with the other classes of agents. The purpose of this study was to evaluate the influence of human calcitonin gene-related peptide antagonist (CGRP8-37) on cardiohemodynamic events, prostaglandin E2 (PGE2) plasma concentration, the severity of ventricular arrhythmias, and mortality occurring during acute myocardial infarction (AMI) in NTG-tolerant and nontolerant rats. METHODS: In the pilot study of efficacy of calcitonin gene-related peptide antagonist (CGRP8-37), 58 male Wistar rats were included. All procedures were performed according to protocols approved by the General Animal Care and Use Committee. Adult male rats underwent surgery to induce AMI by ligating the left anterior descending coronary artery or SHAM. ECG was used to confirm myocardial ischemia. In each experiment, a rat was maintained under anesthesia for the duration of the experiment. At the end of the experiment, the rat was killed by an overdose of pentobarbital. All animals in accordance with the received pharmacological agent were randomized into three groups: I-received only NTG, 50 mg/kg daily, s.c. injections b.i.d. 3 days prior to AMI; II-received NTG by the same dose, route, and frequency of administration + CGRP antagonist (CGRP8-37), 10 MUg/kg two times daily by a similar period of administration; and III-served as control (C) group without preliminary tolerance to NTG. RESULTS: Subcutaneous injections of NTG (50 mg/kg) 30 min prior to AMI in NTG-tolerant animals (group I) and in NTG-tolerant rats + CGRP antagonist (group II) caused minor changes in blood pressure and heart period that was accompanied before NTG s.c. administration with blunted baroreflex sensitivity in response to i.v. administration of sodium nitroprusside in these groups of rats (0.66 +/- 0.05 and 0.56 +/- 0.04 ms/mmHg, P < 0.05, respectively) in comparison to C (group III) animals (0.9 +/- 0.1 ms/mmHg). AMI 1 h duration was associated with a high incidence of ventricular arrhythmia and significant mortality in group I (70 %) and especially in group II (90 %) animals at 72 h after reperfusion as compared with group III rats (56 %), that correlated to a decrease of PGE2 plasma content in group II (2.2 +/- 0.4 ng/ml, P < 0.001) and group I (3.6 +/- 0.2 ng/ml, P < 0.01) vs. control group of rats (4.8 +/- 0.3 ng/ml). CONCLUSIONS: CGRP could be involved in the mechanism of nitrate tolerance via the inhibition of release of the potent vasodilator CGRP leading to exacerbation of acute myocardial ischemia. The influence of CGRP antagonist could enhance this condition. PMID- 26958097 TI - A continuous glucose monitoring device by graphene modified electrochemical sensor in microfluidic system. AB - This paper presents a continuous glucose monitoring microsystem consisting of a three-electrode electrochemical sensor integrated into a microfluidic chip. The microfluidic chip, which was used to transdermally extract and collect subcutaneous interstitial fluid, was fabricated from five polydimethylsiloxane layers using micromolding techniques. The electrochemical sensor was integrated into the chip for continuous detection of glucose. Specifically, a single-layer graphene and gold nanoparticles (AuNPs) were decorated onto the working electrode (WE) of the sensor to construct a composite nanostructured surface and improve the resolution of the glucose measurements. Graphene was transferred onto the WE surface to improve the electroactive nature of the electrode to enable measurements of low levels of glucose. The AuNPs were directly electrodeposited onto the graphene layer to improve the electron transfer rate from the activity center of the enzyme to the electrode to enhance the sensitivity of the sensor. Glucose oxidase (GOx) was immobilized onto the composite nanostructured surface to specifically detect glucose. The factors required for AuNPs deposition and GOx immobilization were also investigated, and the optimized parameters were obtained. The experimental results displayed that the proposed sensor could precisely measure glucose in the linear range from 0 to 162 mg/dl with a detection limit of 1.44 mg/dl (S/N = 3). The proposed sensor exhibited the potential to detect hypoglycemia which is still a major challenge for continuous glucose monitoring in clinics. Unlike implantable glucose sensors, the wearable device enabled external continuous monitoring of glucose without interference from foreign body reaction and bioelectricity. PMID- 26958098 TI - A flexible device for ocular iontophoretic drug delivery. AB - In this work, a flexible ocular iontophoretic device, which can be fabricated by batch processing, is reported. In vivo experiments were conducted on rabbit eyes, and the results demonstrated this device could realize ocular iontophoresis effectively, simply, and conveniently. Compared to conventional eye cups, it can be placed under the eyelid and can deliver ions through a small area on the eyeball, reducing tissue damage caused by the drug during ion penetration. Owing to the flexibility of the device, the device can be easily seated under the eyelid stably during iontophoresis. Manganese ions as a tracer for detection of optic nerve damage were delivered into rabbit eyes by this iontophoretic device. Under 1 mA for 600 s, the average Mn(2+) concentration in the eye ball after iontophoresis was 102 ng/ml, while the one in the control group was 23 ng/ml. Using 2 mA for 600 s, the average concentration was 271 ng/ml, while it was 38 ng/ml in the control group. Thermal injury during iontophoresis was not observed under an applied current of no more than 2 mA for no longer than 10 min, with the local temperature less than 38 degrees C, measured by an infrared thermal imager. PMID- 26958099 TI - A microfluidic device for automated, high-speed microinjection of Caenorhabditis elegans. AB - The nematode worm Caenorhabditis elegans has been widely used as a model organism in biological studies because of its short and prolific life cycle, relatively simple body structure, significant genetic overlap with human, and facile/inexpensive cultivation. Microinjection, as an established and versatile tool for delivering liquid substances into cellular/organismal objects, plays an important role in C. elegans research. However, the conventional manual procedure of C. elegans microinjection is labor-intensive and time-consuming and thus hinders large-scale C. elegans studies involving microinjection of a large number of C. elegans on a daily basis. In this paper, we report a novel microfluidic device that enables, for the first time, fully automated, high-speed microinjection of C. elegans. The device is automatically regulated by on-chip pneumatic valves and allows rapid loading, immobilization, injection, and downstream sorting of single C. elegans. For demonstration, we performed microinjection experiments on 200 C. elegans worms and demonstrated an average injection speed of 6.6 worm/min (average worm handling time: 9.45 s/worm) and a success rate of 77.5% (post-sorting success rate: 100%), both much higher than the performance of manual operation (speed: 1 worm/4 min and success rate: 30%). We conducted typical viability tests on the injected C. elegans and confirmed that the automated injection system does not impose significant adverse effect on the physiological condition of the injected C. elegans. We believe that the developed microfluidic device holds great potential to become a useful tool for facilitating high-throughput, large-scale worm biology research. PMID- 26958100 TI - An optofluidic system with volume measurement and surface plasmon resonance sensor for continuous glucose monitoring. AB - The traditional technology of glucose monitoring is painful and invasive because of the frequent blood collection. Nowadays, the enzyme electrode sensor is mainly used for continuous glucose monitoring in clinic, but it has inherent disadvantages of significant signal drift of current due to bioelectricity in body and the missing of hypoglycemia resulting from the irreversible consumption of glucose at the process of enzyme catalytic reaction. Interstitial fluid (ISF) transdermal extraction can be nearly unsensible which effectively reduces the pain caused by invasive detection so that it may provide a new way to monitor glucose. MEMS technology has been used to produce devices for transdermal ISF extraction, but there is a lack of on-chip ISF volume measurement capabilities, which are required to compensate skin permeability variations. This paper presents a lab-on-a-chip system for ISF transdermal extraction, ISF volume measurement, and optical glucose sensing towards the application of continuous glucose monitoring. The device significantly incorporates a MEMS volume sensor, which measures extracted ISF volume via conductance monitoring, and integrates a fiber-optic surface plasmon resonance sensor to measure glucose concentration in microchannel. The fiber-based technique provides an excellent approach to overcome the above two drawbacks of the enzyme electrode based glucose sensing. Six different volumes were tested, and the standard deviation of every sample is less than 0.05 MUl, The resonance wavelength moves from 549.081 nm to 592.914 nm while the concentration ranges from 0 to 200 mg/dl. The feasibility of the single chip device for accurate and continuous monitoring of subcutaneous ISF glucose concentrations is verified. PMID- 26958101 TI - Quantitative analysis of the chemotaxis of a green alga, Chlamydomonas reinhardtii, to bicarbonate using diffusion-based microfluidic device. AB - There is a growing interest in the photosynthetic carbon fixation by microalgae for the production of valuable products from carbon dioxide (CO2). Microalgae are capable of transporting bicarbonate (HCO3 (-)), the most abundant form of inorganic carbon species in the water, as a source of CO2 for photosynthesis. Despite the importance of HCO3 (-) as the carbon source, little is known about the chemotactic response of microalgae to HCO3 (-). Here, we showed the chemotaxis of a model alga, Chlamydomonas reinhardtii, towards HCO3 (-) using an agarose gel-based microfluidic device with a flow-free and stable chemical gradient during the entire assay period. The device was validated by analyzing the chemotactic responses of C. reinhardtii to the previously known chemoattractants (NH4Cl and CoCl2) and chemotactically neutral molecule (NaCl). We found that C. reinhardtii exhibited the strongest chemotactic response to bicarbonate at the concentration of 26 mM in a microfluidic device. The chemotactic response to bicarbonate showed a circadian rhythm with a peak during the dark period and a valley during the light period. We also observed the changes in the chemotaxis to bicarbonate by an inhibitor of bicarbonate transporters and a mutation in CIA5, a transcriptional regulator of carbon concentrating mechanism, indicating the relationship between chemotaxis to bicarbonate and inorganic carbon metabolism in C. reinhardtii. To the best of our knowledge, this is the first report of the chemotaxis of C. reinhardtii towards HCO3 (-), which contributes to the understanding of the physiological role of the chemotaxis to bicarbonate and its relevance to inorganic carbon utilization. PMID- 26958102 TI - Biomimetic microchannels of planar reactors for optimized photocatalytic efficiency of water purification. AB - This paper reports a biomimetic design of microchannels in the planar reactors with the aim to optimize the photocatalytic efficiency of water purification. Inspired from biology, a bifurcated microchannel has been designed based on the Murray's law to connect to the reaction chamber for photocatalytic reaction. The microchannels are designed to have a constant depth of 50 MUm but variable aspect ratios ranging from 0.015 to 0.125. To prove its effectiveness for photocatalytic water purification, the biomimetic planar reactors have been tested and compared with the non-biomimetic ones, showing an improvement of the degradation efficiency by 68%. By employing the finite element method, the flow process of the designed microchannel reactors has been simulated and analyzed. It is found that the biomimetic design owns a larger flow velocity fluctuation than that of the non-biomimetic one, which in turn results in a faster photocatalytic reaction speed. Such a biomimetic design paves the way for the design of more efficient planar reactors and may also find applications in other microfluidic systems that involve the use of microchannels. PMID- 26958103 TI - Particle migration and sorting in microbubble streaming flows. AB - Ultrasonic driving of semicylindrical microbubbles generates strong streaming flows that are robust over a wide range of driving frequencies. We show that in microchannels, these streaming flow patterns can be combined with Poiseuille flows to achieve two distinctive, highly tunable methods for size-sensitive sorting and trapping of particles much smaller than the bubble itself. This method allows higher throughput than typical passive sorting techniques, since it does not require the inclusion of device features on the order of the particle size. We propose a simple mechanism, based on channel and flow geometry, which reliably describes and predicts the sorting behavior observed in experiment. It is also shown that an asymptotic theory that incorporates the device geometry and superimposed channel flow accurately models key flow features such as peak speeds and particle trajectories, provided it is appropriately modified to account for 3D effects caused by the axial confinement of the bubble. PMID- 26958104 TI - A Study of Internal Thoracic Arteriovenous Principal Perforators by Using Multi detector Row Computed Tomography Angiography. AB - OBJECTIVE: There are numerous reports of perforating branches from the intercostal spaces of the internal thoracic vessels. These branches have varying diameters, and a main perforating branch, the principal perforator, most often found in the second or third intercostal space. We report different results based on multi-detector row computed tomography. METHODS: We evaluated 121 sides from 70 women scheduled for breast reconstruction with free lower abdominal skin flaps who underwent preoperative multi-detector row computed tomographic scan between June 2008 and June 2015. For primary reconstruction, we analyzed both sides, and for 1-sided secondary reconstruction, we analyzed only the unaffected side. We evaluated both early arterial phase and late venous phase 5-mm horizontal, cross sectional, and volume-rendering images for perforation sites and internal thoracic arteriovenous perforating branches' intercostal space thickness. We analyzed differences in thickness between the internal thoracic arteries and veins and symmetry in cases involving both sides. RESULTS: Venous principal perforators nearly always perforated the same intercostal spaces as accompanying veins of arterial principal perforators (99.2%), forming arteriovenous principal perforators. We found 49 principal perforators in the first intercostal space (37.4%), 52 in the second intercostal space (39.7%), 23 in the third intercostal space (17.6%), 6 in the fourth intercostal space (4.6%), and 1 in the fifth intercostal space (0.7%). Of the 51 cases in which we studied both sides, 25 cases (49%) had principal perforators with bilateral symmetry. CONCLUSIONS: In contrast to findings from past reports, we found that internal thoracic arteriovenous principal perforators were often present in almost the same numbers in the first and second intercostal spaces. PMID- 26958105 TI - Perfusion and Oxygenation of Random Advancement Skin Flaps Depend More on the Length and Thickness of the Flap Than on the Width to Length Ratio. AB - OBJECTIVE: The aim was to investigate the relationship between the dimensions (length, width, and thickness) of random advancement skin flaps and retained tissue perfusion and oxygenation. METHODS: Flaps were raised on the flanks of pigs. The flaps were either 0.5 or 1.0 cm wide, thin (dissected halfway through the subcutaneous tissue) or thick (dissected down to the muscle fascia). Tissue perfusion was measured by laser Doppler velocimetry, and tissue oxygenation (pO2) was measured using a Licox system, every 0.5 cm along the flaps' length. Tissue temperature was visualized by high-resolution infrared camera. RESULTS: Perfusion and oxygenation decreased gradually from the base to the tip of the flap, reaching approximately 40% of presurgical values (2.0 cm) and approximately 20% (2.5 cm) from the base of the flap. There was virtually no blood flow, nor oxygen tension, 3.0 cm from the base of the flap. The width to length ratio of the flap did not determine blood flow or oxygenation, being approximately 30% in a 0.5 cm wide and 2 cm long flap, and 0% in a 1.0 cm wide and 4 cm long flap, both with a width to length ratio of 1:4. Blood flow and oxygenation were preserved to a greater extent in the thick flaps (~40%) than in the thin flaps (~20%), in a 0.5 cm wide and 2 cm long flap. CONCLUSIONS: The dissection of a random advancement flap results in hypoperfusion and oxygenation that cannot be predicted by the width to length ratio but depend on the length and thickness of the flap. PMID- 26958106 TI - Surgical management of acute quadriceps tendon rupture (a case report with literature review). AB - Quadriceps tendon rupture is uncommon and often overlooked in emergency. Tearing affects weakening tendon by systemic diseases or some medications. The mechanism is generally indirect. Inability to actively extend the knee associated to a supra-patellar defect evoke easily the diagnosis without other investigations. Surgical repair is realized in emergency to completely restore the extension. We report a case of a patient who has sustained of complete quadriceps tendon tear after a long period of tendon weakening by statin therapy, hypertension and diabetes. The repair has consisted on end-to-end Krackow sutures associated with bone suture to the proximal pole of the patella. Surgeons and emergency physicians must think to this form of extensor apparatus rupture, because early diagnosis leads to early treatment and to best outcomes. PMID- 26958107 TI - Prenatal intraventricular hemorrhage in a term infant with congenital CMV infection. PMID- 26958108 TI - [Intra and suprasellar arachnoid cyst: contribution of MRI]. PMID- 26958109 TI - Kienbock's disease: a case report. AB - Kienbock disease is a condition characterized by avascular necrosis of the lunate bone. Advanced imaging can aid in the diagnosis and staging of Kienbock disease. Magnetic resonance imaging (MRI) is an important adjunct to diagnosis. In particular, MRI is helpful early in the disease when plain radiographs may not reveal abnormalities. A 17-year-old man with Kienbock disease who underwent radiography and MR is described in this article. PMID- 26958110 TI - Cervical cancer control and prevention in Malawi: need for policy improvement. AB - INTRODUCTION: Malawi has the highest incidents of cervical cancer followed by Mozambique and Comoros thus according to the 2014 Africa cervical cancer multi indicator incidence and mortality score card. Despite having an established cervical cancer prevention program, there is low screening coverage. Studies have been carried out to determine socio-cultural and economical barriers to cervical cancer prevention services utilization and very few have concentrated on health system and policy related barriers to cervical cancer prevention and control. The paper presents finding on a qualitative study which carried out to determine the suitability of the national sexual and reproductive health and rights [SRHR] in mitigating challenges in cervical cancer control and prevention. METHODS: a desk review of the Malawi National Sexual and Reproductive Health and Rights [SRHR] policy 2009 was done with an aim of understanding its context, goal and objectives. Analysis of the policy history provided insight into the conditions that led to the policy. Policies from countries within the region were referred in the review. Government officials were interviewed to solicit information on the policy. RESULTS: Malawi does not have a standalone policy on cervical cancer; however, cervical cancer is covered under reproductive cancer theme in the SRHR. Unlike some policies within the region, the Malawian SRHR policy does not mention the age at which the women should be screened, the frequency and who is to do the screening. The policy does not stipulate policy implications on the ministry of health, the SRH programs and health service providers on cervical cancer. Furthermore the policy does not include HPV vaccination as a key component of cervical cancer control and prevention. CONCLUSION: the policy does not reflect fairly the best attempt to reduce the incidence and mortality of cervical cancer as such we recommend that the Reproductive Health Directorate to consider developing a standalone policy on cervical cancer control and prevention. PMID- 26958111 TI - Determinants of exclusive breastfeeding: a study of two sub-districts in the Atwima Nwabiagya District of Ghana. AB - INTRODUCTION: Optimal breastfeeding rates have not been encouraging globally with sub-optimal feeding being customized in Sub-Saharan Africa. However, in the Atwima Nwabiagya district of Ghana, the message of Exclusive Breastfeeding (EBF) has caught up well with many nursing mothers. we examined the determinants of EBF vis-a-vis performance of a community based growth promotion strategy in the Atwima Nwabiagya district of the Ashanti region of Ghana. METHODS: The study employed a cross-sectional comparative study design to analyze the impact of a community based growth promotion strategy on exclusive breast feeding in Abuakwa and Barekese, both in the Atwima Nwabiagya district of Ghana. Simple random sampling was used to select three communities each from the two sub-districts. Data collection tool employed was a standard questionnaire consisting of closed ended questions. The variables were EBF knowledge level of mothers, cultural practices affecting EBF practice, occupational hindrances and the level of community participation in EBF activities. RESULTS: In all three hundred (300) nursing mothers of babies (0-12 months) were purposively interviewed. Results showed that mother's level of knowledge about EBF was good as such the practice was high. In addition, cultural practices in the area did not deter mothers from practicing exclusive breastfeeding. Two factors were associated with EBF in the univariate logistic model. Unmarried mothers were less likely to practice EB compared with mothers who were married (OR = 0.46, 95% 0.28, 0.77). Also the duration of breast feeding was associated wit EBF. The adjusted odds ratio was 0.41(95% CI: 0.32, 0.54) in favor of three months compared with six months. CONCLUSION: The Community Based Growth Promotion strategy has had a positive impact on the practice of EBF in the district. It is recommended that the collapsed initiative be reawaken if the stakes are to be maintained. There is also the need to address mothers' occupational needs and effective breastfeeding practices as this emerged as a major set-back to the practice of EBF among the participants. PMID- 26958112 TI - [Stercoral the perforation of the colon: report of a case and review of literature]. PMID- 26958113 TI - Ischemic cardiomyopathy revealed by central retinal artery occlusion (CRAO). AB - Here we report a case of central retinal artery occlusion revealing an ischemic cardiomyopathy. A 54-year old smoker man presented at the hospital because of sudden visual loss in his left eye. There was cherry-red spot in the macula in his left eye. We performed a fluorescein angiogram and cervical color Doppler. Later investigations revealed an ischemic cardiomyopathy undiagnosed until then. PMID- 26958114 TI - [Compression of the external iliac artery by Kerboull frame: report of a case]. PMID- 26958115 TI - Therapeutic efficacy of different brands of albendazole against soil transmitted helminths among students of Mendera Elementary School, Jimma, Southwest Ethiopia. AB - INTRODUCTION: Different brands Albendazole are commercially available and the efficacious brand/s is/are required for effective control of STHs infection. Thus, this study is aimed at determining the therapeutic efficacy of different brands of albendazole against soil transmitted helminths among school children of Jimma town. METHODS: A cross sectional survey for prevalence of geohelminths and a randomized trial for efficacy study of different brands of albendazole was conducted among students Mendera Elementary School from March 29 to April 29, 2010. Positive subjects were randomized into three treatment arms using lottery method. The collected stool samples were examined by the McMaster method. CRs were calculated using SPSS windows version 16 and ERRs were calculated using appropriate formula. RESULTS: Of the 715 school children who had their stools examined, 326 were positive for STHs with a prevalence rate of 45.6%. The cure rates (CR) for A. lumbricoides, T. trichiura and Hookworm were 99.4, 59.9 and 93.7%, respectively. Similarly, the egg reduction rates (ERR) were 97, 99.9 and 99.9% respectively. A statistical significant mean STH egg count difference were observed between pre and post-intervention study (p <0.001). But no statistical significant curing effect difference were observed among the three brands used against the three STHs (p >0.05). CONCLUSION: All the three brands of Albendazole tested regardless of the brand type were therapeutically efficacious for Ascariasis, Trichuriasis and Hookworm infections irrespective of the infection status whether it was single or multiple. PMID- 26958116 TI - Determinants of death among tuberculosis patients in a semi urban diagnostic and treatment centre of Bafoussam, West Cameroon: a retrospective case-control study. AB - INTRODUCTION: Tuberculosis (TB) remains a worldwide public health problem with 8.6 millions of new cases and 1.3 millions of death annually. Despite the progress recorded in fighting against this disease in the recent years, Africa is still not on the track to achieve the objective to reduce by half the death rate due to this disease by 2015. METHODS: A case-control study was conducted on data of patients admitted for tuberculosis between 1996 and 2011 in the Diagnostic and Treatment Center of Baleng. Cases were patients who died from any cause during anti tuberculosis treatment. Logistic regression model was used to identify factors associated to death. RESULTS: In 4201 patients treated during the study period, 3245 (77.24%) were included in the study. The mean age was 35.9 (SD 14.2) and male represent 62.2% (CI 60.6- 63.9) of them. At the end of the follow up, 2883 patients were successfully treated, 362 died during treatment and 132 (36.5%) deaths occurred during the first two months of TB treatment. HIV positive status, Extra-pulmonary TB, sputum smear-negative pulmonary TB and male sex were significant independent risk factors of death with adjusted odds ratio of 4.8 (CI 3.2- 7.4); 3.0 (CI 1.6- 5.4); 2.7 (CI 1.7- 4.4) and 1.5 (CI 1.0- 2.3) respectively. CONCLUSION: The mortality rate of TB patients undergoing TB treatment remains high. Studies are needed to identify and test efficient interventions of mortality reduction among TB patients in resource limiting settings. PMID- 26958118 TI - Effect of community level intervention on nutritional status and feeding practices of under five children in Ile Ife, Nigeria. AB - INTRODUCTION: Childhood malnutrition remains a widespread problem in developing world like Nigeria. The country ranks second among the ten countries contributing to sixty percent of the world's wasted under-five children. Community Integrated Management of Childhood illness (CIMCI) is a programme that employs the use of community based counsellors to address child health and nutritional challenges of the under-five and has the potential to reduce the morbidity and mortality resulting from poor nutritional and feeding practices. The study assessed the effect of community level intervention on nutritional status and feeding practices of children in Ile-Ife, Nigeria. METHODS: A cross-sectional comparative study that employed the use of multi stage cluster sampling techniques in selecting 722 mothers of index under five children. The study was done in two Local Government Areas of Osun State, Nigeria. Quantitative techniques were used in data collection. Data analysis was done using SPSS version 20.0. Descriptive and bivariate analyses was performed. RESULTS: The two Local Government Area (LGA) did not differ significantly in their wealth index (p = 0.344). However, more children in the non-implementing LGA (16.1%) had low weight for age compared with 3.6% in the CIMCI implementing LGA (p = 0.000). A statistically significant difference exist in the MUAC measurement of children 12-23 months between the CIMCI implementing and non-implementing communities (p = 0.007). A higher percentage of caregivers (19.3%) introduced complementary feeding earlier than 6 months in the non-implementing area (p < 0.001). CONCLUSION: Using community level nutritional counseling can greatly improve nutritional status and feeding practices of under five children. PMID- 26958117 TI - [Ocular decompression retinopathy: a rare complication of trabeculectomy]. PMID- 26958119 TI - [Merkel cell carcinoma: a new observation]. PMID- 26958120 TI - [Aberrant course of the internal carotid artery]. PMID- 26958121 TI - Surgical management of acute distal biceps tendon rupture associated with contralateral radial palsy. AB - Acute distal biceps tendon rupture constitute a rare lesion of biceps injuries, typically, easy to diagnosis after lifting a heavy object. Treatment is controversial, nonoperative for sedentary and elderly patients; surgical for young and active individuals. Many operative techniques are described, they all aim to restore an excellent strength of flexion and supination. We opted for one incision method and fixation using trans-osseous anchoring for our patient, because we are convinced that is a simpler and safer technique. Postoperative rehabilitation, after a period of elbow immobilization, must be operated for returning to full activity. Biceps tendon repair has permitted to our patient who suffer from right upper limb handicap due to radial nerve palsy, recuperating the lost strength and force in his dominant limb and maintaining some quality of life. PMID- 26958123 TI - [Ewing sarcoma of petrous bone location]. PMID- 26958122 TI - [Duodenal diverticulitis: unusual complication not always easy to manage]. PMID- 26958124 TI - Second trimester abortion as a cause of maternal death: a case report. AB - Each year, an estimated 529 000 maternal deaths occur worldwide. In literature, it is known that maternal mortality can occur during pregnancy, peripartum and also in postpartum period. Although very rare, maternal deaths may occur after spontaneous abortion. In present case, 37 year old G5P4 (Caesarean Section) women was admitted to Adnan Menderes University, Obstetrics and Gynecology clinic with diagnosis of missed abortion at 18 weeks' gestation. She had been hospitalized in the public maternity hospital for five days due to abortus incipience and prolapse of amnion membranes but had no contractions. Fetal heart beats ceased at the second day of hospitalization. Medically induced abortion was recommended but not accepted by the patient. At the fifth day of hospitalization, she was referred to our clinic due to deterioration of general health condition, low blood pressure and tachycardia. In emergency department, it was determined that she was not oriented, had confusion, had blood pressure of 49/25 mmHg and tachycardia. In ultrasonographic examination, 18 week in utero ex fetus was determined and there was free fluid in abdominopelvic cavity. The free fluid was suspected to be amniotic fluid due to rupture of uterus. Laparotomy was performed, no uterine rupture, hematoma or atony was observed. However during laparotomy, a very bad smelling odor, might be due to septicemia, was felt in the operation room. Cardiac arrest occurred during that operation. In autopsy report, it was concluded that maternal death was because of remaining of inutero ex fetus for a long time. In conclusion, although very rare, maternal deaths after spontaneous abortion may occur. Because spontaneous abortion is a common outcome of pregnancy, continued careful, strict monitoring and immediate treatment of especially second trimester spontaneous abortion is recommended to prevent related, disappointing, unexpected maternal deaths. PMID- 26958125 TI - [Mandibular tumor? Think of a lung metastasis]. PMID- 26958126 TI - A clinical challenging situation of intra oral fibroma mimicking pyogenic granuloma. PMID- 26958127 TI - Comparison of hysterosalpingograms with laparoscopy in the diagnostic of tubal factor of female infertility at the Yaounde General Hospital, Cameroon. AB - INTRODUCTION: The objectives were to assess the diagnostic value of hysterosalpingography (HSG) with laparoscopy as gold standard in the evaluation of tubal patency and pelvic adhesions in women suffering from infertility. METHODS: We conducted a comparative cross sectional study on 208 medical files of infertile women followed up at the Yaounde General Hospital during a period of five years (December 2007 to December 2012). Tubal patency, hydrosalpinx and pelvic adhesions detected at HSG were compared with laparoscopic findings as the gold standard. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy of HSG were calculated with 95% confidence interval (CI). RESULTS: Mean age of the patients was 31.4 +/- 6.45 years. Secondary infertility was the most frequent type of infertility (66.82%). HSG had a moderate sensitivity (51.0%; 95% IC. 37.5-64.4), high specificity (90.0%; 95% IC.74.4-96.5), high PPV (89.3%; 95% IC. 72.8-96.3) and a moderate NPV (52.9%; 95% IC. 39.5-65.9) in the diagnosis of bilateral proximal tubal occlusion. Concerning, distal tubal patency, HSG had a high sensitivity (86.8%; 95% IC. 76.7-92.9), low specificity (42.2%; 95% CI. 29.0-56.7), moderate PPV (69.4%; 95% IC. 58.9-78.2) and a moderate NPV (67.9%; 95% IC. 49.3-82.0) in the diagnosis of bilateral or unilateral distal tubal occlusion. However, HSG had a low diagnostic value (27.8%; 95%IC.18.8-39.0) in the pelvic adhesions. CONCLUSION: HSG is of limited diagnostic value in tubal factor infertility and is of low diagnostic value for pelvic adhesions. PMID- 26958128 TI - Torsion of the appendix testis in an undescended testicle. PMID- 26958129 TI - Exceptional laceration of flexor digitorum tendons proximal to a severe palmar hand wound: a case report with literature review. AB - Hand wounds are common, poor functional outcomes are marked because of sequelae inherent to posttraumatic and postoperative complications. Suitable surgery repair in emergency can ensure best results. Classically, tendon's injuries occur near the injured area and their repair depend on traumatized zone, sutures techniques, associated lesions and surgeon's abilities. We report a case of a farmer who has sustained of a severe hand wound due to blades of a combine harvester. Clinical examination showed exceptional laceration of 2(nd) and 3(rd) flexor digitorum tendons from musculo-tendinous junction, without any lesion in their palmar section. We proceeded; after extensive debridement, abundant lavage and removal of foreign body; to modified Kessler sutures using PDS 4.0 followed by dorsal splint for protecting tendons repair, and progressive rehabilitation program. Final result was interesting after 12 weeks. Thinking to tendon laceration is important, when manipulating machines with rotational movements. PMID- 26958130 TI - [Atypical ocular toxoplasmosis in a Congolese woman of 72 years: report of a case]. PMID- 26958131 TI - [Sleeve resection of the cervical trachea on posttraumatic tracheal crush]. PMID- 26958132 TI - [Sister Mary Joseph nodule revealing digestive and ovarian carcinoma: report of 4 cases]. PMID- 26958133 TI - [Skin metastases of vulvar carcinoma]. PMID- 26958134 TI - [Clinical aspects of primary lung cancers in the cancer ward of CHUA-HUJRA Antananarivo]. PMID- 26958135 TI - Endometrial carcinoma located in the right septate uterus cavity: a case report. AB - Endometrial cancer in patients with uterine congenital malformations is exceptional and there are only a few rare cases published in the literature. We report the case of a 67 years-old patient with an endometrial cancer located in the right cavity of a complete septate uterus. PMID- 26958136 TI - Non invasive assessment of liver fibrosis in chronic hemodialysis patients with viral hepatitis C. AB - The liver biopsy has long been the "gold standard" for assessing liver fibrosis in patients with hepatitis C. It's an invasive procedure which is associated with an elevated bleeding, especially in chronic hemodialysis patients. Main goal is to assess liver fibrosis in chronic hemodialysis with HCV by Fibroscan and by biological scores (APRI, Forns and Fib-4), and to measure the correlation between these tests. Cross-sectional study including all chronic hemodialysis patients with hepatitis C virus, in two public hemodialysis centers of Fez. All patients were evaluated for liver fibrosis using noninvasive methods (FibroScan and laboratory tests). Subsequently, the correlation between different tests has been measured. 95 chronic hemodialysis were studied, twenty nine patients (30.5%) with chronic hepatitis C. The average age was 52.38 +/- 16.8 years. Nine liver fibrosis cases have been concluded by forns score. Fibroscan has objectified significant fibrosis in 6 cases. On the other side APRI has objectified sgnifivant fibrosis only in 3 cases. The Fib-4 showed severe fibrosis in five cases. The results have been most consistent between APRI and Fib-4, followed by Fibroscan and Forns, then APRI and FibroScan. PMID- 26958137 TI - [Complications of Meckel diverticulum (MD) in adults: report of 11 cases CHU Yalgado Ouedraogo in Burkina Faso]. PMID- 26958139 TI - Williams-Beuren syndrome associated with single kidney and nephrocalcinosis: a case report. AB - Williams-Beuren syndrome is a rare neurodevelopmental disorder, characterized by congenital heart defects, abnormal facial features, mental retardation with specific cognitive and behavioral profile, growth hormone deficiency, renal and skeletal anomalies, inguinal hernia, infantile hypercalcaemia. We report a case with Williams-Beuren syndrome associated with a single kidney and nephrocalcinosis complicated by hypercalcaemia. A male infant, aged 20 months presented growth retardation associated with a psychomotor impairment, dysmorphic features and nephrocalcinosis. He had also hypercalciuria and hypercalcemia. Echocardiography was normal. DMSA renal scintigraphy showed a single functioning kidney. The FISH generated one ELN signal in 20 metaphases read and found the presence of ELN deletion, with compatible Williams-Beuren syndrome. PMID- 26958138 TI - Prevalence and predictors of HIV sero-discordance among cohabiting couples tested in northern Tanzania. AB - INTRODUCTION: In sub-Saharan Africa where HIV/AIDS epidemic is predominantly generalized, majority of HIV infections occur among heterosexual couples. The majority of people do not know their sero-status. Thus, utilisation of Couples' HIV Counselling and Testing (CHCT) services remain to be critical in preventing new infections. The objective was to establish prevalence and predictors of HIV sero-discordance among cohabiting couples presenting for CHCT services in northern Tanzania. METHODS: A cross-sectional study inteveviewed 1,333 couples aged 18-49 years tested from 2005 to 2007 in Kilimanjaro and Arusha regions. A CHCT checklist was used to collect data from couples. Data were analyzed using STATA 10. RESULTS: Generally, 220(16%) out of 1,333 couples were HIV sero discordant. In sero-discordance unions, women were likely to be HIV positive than men (71% versus 29% respectively p<0.001). HIV sero-discordant relationship was associated with age (35-45 years) for both men and women (Adjusted Odds Ratio (AOR): 2.3, 95% Confidence Interval (CI): 1.7-3.2) and (AOR: 2.6, 95% CI 1.9-3.7) respectively. Women with older men partners were less likely to be in HIV sero discordance relationships (AOR: 0.5 95% CI 0.3-09). Arusha couples were likely to be HIV sero-discordant than those of Kilimanjaro (AOR: 2.3 95% CI 1.7-3.2). Couples living far away from CHCT centres were less likely to be sero-discordant than those live nearby (AOR: 0.4 95% CI 0.2-0.9). CONCLUSION: HIV sero discordance prevalence is high among our participants. Thus, we recommend CHCT utilization should widely be promoted as entry point in treatment as prevention strategy in order to protect uninfected partners in HIV sero-discordance relationships. PMID- 26958140 TI - [Inhalation of scarf pin: emerging respiratory emergency]. PMID- 26958141 TI - Angio-embolization of a renal pseudoaneurysm complicating a percutaneous renal biopsy: a case report. AB - We report the treatment of a bleeding renal pseudoaneurysm by angio-embolization. A 21 years old woman developed macroscopic haematuria following renal biopsy. Renal angio-scan showed a 1.4 cm renal pseudoaneurysm in the left kidney. The presence of pseudoaneurysm was confirmed by selective renal angiography. Successful embolization was performed using gelatine sponge particles. PMID- 26958142 TI - [Kaposi sarcoma in bronchopulmonary localization revealing HIV infection]. PMID- 26958143 TI - Right-heart infective endocarditis: a propos of 10 cases. AB - The prevalence and characteristics of right heart endocarditis in Africa are not well known. The aim of this study was to describe the epidemiological, clinical and laboratory profiles of patients with right-heart infective endocarditis. This was a 10-year retrospective study conducted in 2 cardiology departments in Dakar, Senegal. All patients who met the diagnosis of right heart infective endocarditis according to the Duke's criteria were included. We studied the epidemiological, clinical as well as their laboratory profiles. There were 10 cases of right-heart infective endocarditis representing 3.04% of cases of infective endocarditis. There was a valvulopathy in 3 patients, an atrial septal defect in 1 patient, parturiency in 2 patients and the presence of a pacemaker in one patient. Anaemia was present in 9 patients whilst leukocytosis in 6 patients. The port of entry was found to be oral in three cases, ENT in one case and urogenital in two cases. Apart from one patient with vegetations in the tricuspid and pulmonary valves, the rest had localized vegetation only at the tricuspid valve. However, blood culture was positive in only three patients. There was a favorable outcome after antibiotic treatment in 4 patients with others having complications; three cases of renal impairment, two cases of heart failure and one case of pulmonary embolism. There was one mortality. Right heart infective endocarditis is rare but associated with potentially fatal complications. PMID- 26958144 TI - Pleomorphic adenoma of the soft palate: major tumor in a minor gland. AB - Salivary gland tumors are a relatively rare and morphologically diverse group of lesions. Pleomorphic adenoma is a benign tumor of the salivary gland that consists of a combination of epithelial and mesenchymal elements. The tumor most commonly arises from the parotid (60-70%) or submandibular glands. It develops less frequently in a minor salivary gland, presenting as an intraoral mass depend on the soft palate. We describe a case of benign pleomorphic adenoma of soft palate in a 45 year old female with computed tomography and histopathological findings. This patient presented in ENT department with history of gradually increasing mass lesion in the palatal region over a period of few months. PMID- 26958145 TI - What should medical students do to choose their specialty? PMID- 26958146 TI - Middle Cerebral Artery Occlusion Model of Stroke in Rodents: A Step-by-Step Approach. AB - Stroke is one of the leading causes of morbidity and mortality in developed countries and an immense amount of medical care resources are devoted to combat the poststroke debilitating consequences. The key to develop effective and clinically applicable treatment methodologies is a better understanding of the pathophysiology of the disease, including the root causes and targets for pharmacology. Developing these foundations requires the use of standard animal models that mimic the physicochemical process of the diseases that can reliably replicate results in order to test and fine-tune therapeutic modalities. Middle cerebral artery occlusion (MCAO), endothelin-1-induced ischemic stroke, photothrombosis, devascularization, embolization, and spontaneous infarction using hemorrhage are some examples of different animal models. Reliability of MCAO has been proved and due to the ability to induce reperfusion similar to tissue plasminogen activator (tPA) therapy, this model is widely used in preclinical studies. Here, we describe a detailed methodology on how to develop MCAO stroke in rodents using intra-arterial insertion of filament to occlude the middle cerebral artery. This approach allows for the study of a wide array of basic pathophysiology mechanisms, regenerative medicine and rehabilitation therapy. PMID- 26958147 TI - Analysis of Spinal Cord Infarction Associated with Aortic Stent Graft Placement Using Nationwide Inpatient Sample (2002-2011). AB - PURPOSE: We performed this study to identify the rate and determinants of and associated outcomes with spinal cord infarction among patients treated with aortic stent graft placement at a national level. METHODS: We analyzed the data files from Nationwide Inpatient Sample (NIS) from 2002 to 2011. We performed multivariate logistic regression analysis to assess the rates of moderate to severe disability or death in patients with and without spinal cord infarction after adjusting for age, gender, and comorbidities that were significant in univariate analysis. We also determined change in annual rates of spinal cord infarction associated with aortic stent graft placement from 2002 through 2011. RESULTS: Spinal cord infarction occurred in 761 (0.2%) of 305,788 patients who underwent aortic stent graft placement. There was an increase in the annual rate of spinal cord infarction among patients who underwent aortic stent graft placement from 2002 (0.03%) to 2011 (0.4%) (p <0.001). The patients who developed spinal cord infarction had significantly higher odds of in hospital mortality ([odd ratio] OR: 3.0; 95% confidence interval [CI]: 2.4-3.8) after adjusting for age, gender, race/ethnicity, aortic aneurysms, thoracic graft, hypertension, ischemic strokes or transient ischemic attacks, coagulopathy, congestive heart failure, deficiency or chronic blood loss anemia, atrial fibrillation, renal failure, elective admission, and teaching hospital status. Among those who were discharged alive, patients who developed spinal cord infarction had significantly higher odds of moderate to severe disability (OR: 2.8; 95% CI: 2.5-3.2). CONCLUSIONS: The occurrence of spinal cord infarction in patients undergoing aortic stent graft placement appears to be increasing. Spinal cord infarction is associated with prominently higher rates of death and moderate to severe disability. PMID- 26958148 TI - Preserved Visual Acuity in Anterior Ischemic Optic Neuropathy Secondary to Giant Cell (temporal) Arteritis. AB - OBJECTIVE: To evaluate the prevalence and clinical profile of patients with biopsy-proven arteritic anterior ischemic optic neuropathy presenting with preserved visual acuity of 20/40 or better and those with an initial poor visual acuity of 20/50 or worse through a retrospective chart review. RESULTS: Nine of 37 patients with arteritic anterior ischemic optic neuropathy presented with a preserved visual acuity of 20/40 or better in the affected eye. All patients with preserved visual acuity had initial visual field defects that spared the central field. All 37 patients immediately received high-dose corticosteroid therapy. Visual acuity worsened by > 2 lines in one of nine patients (11%) with preserved visual acuity, with a corresponding progression of visual field constriction. CONCLUSION: Although preserved visual acuity of 20/40 or better has traditionally been associated with the nonarteritic form of anterior ischemic optic neuropathy, giant cell arteritis should still be strongly considered, especially if they have giant cell arteritis systemic symptoms. PMID- 26958149 TI - Cerebellar Hemangioblastoma. PMID- 26958150 TI - Stent-Assisted Clip Placement for Complex Internal Carotid Artery Intracranial Aneurysms. AB - BACKGROUND: We report two procedures using a stent-assisted microsurgical clip placement to treat complex intracranial aneurysms originating from supraclinoid segment of the internal carotid artery. CASE DESCRIPTIONS: In both procedures, primary clip placement was considered technically difficult due to either complex morphology or inferior protrusion of aneurysm fundus within the interclinoid space. A nitinol self-expanding stent was placed across the neck of the aneurysm either preoperatively or intraoperatively. Obliteration of aneurysm and patency of the artery was confirmed by angiography after clip placement. CONCLUSION: Description of an integrated open microsurgical and endovascular approach and review of literature pertaining to considerations for treatment approach are discussed. PMID- 26958151 TI - Stem Cells as a Potential Adjunctive Therapy in Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Despite advances in the management of subarachnoid hemorrhage, a considerable proportion of patients are still left with severe and disabling long term consequences. Unfortunately, there are limited therapeutic options to counteract the sequelae following the initial insult. The role of stem cells has been studied in the treatment of various diseases. The goal of this study was to provide a literature review regarding the potential advantages of stem-cell therapy to counteract or minimize the sequelae of aneurysmal subarachnoid hemorrhage. METHODS: PubMed, Google Scholar, and ClinicalTrials.gov searches were conducted to incorporate pertinent studies that discussed stem cell use in the management of subarachnoid hemorrhage. Included articles were subjected to data extraction for the synthesis of the efficacy of stem-cell therapy. RESULTS: Four preclinical studies with 181 animal model subjects (44 mice, 137 rats) were incorporated in our review. Endovascular punctures (65%) and blood injections in subarachnoid spaces (17%) were used to induce hemorrhage models. Stem cells were administered intravenously (3.0 * 10(6) cells) or intranasally (1.5 * 10(6) cells). According to literature, mesenchymal cell therapy significantly (p<0.05) induces stem-cell migration to lesion sites, decreases associated neural apoptosis and inflammation, improves ultrastructural integrity of cerebral tissue, and aids in improving sensorimotor function post subarachnoid hemorrhage. CONCLUSION: Stem cells, particularly mesenchymal stem cells, have shown promising cellular, morphological, and functional benefits in animal models suffering from induced subarachnoid hemorrhages. However, further studies are warranted to elucidate the full effects of stem-cell therapy for aneurysmal subarachnoid hemorrhage. PMID- 26958152 TI - Histopathological Characteristics of IV Recombinant Tissue Plasminogen -Resistant Thrombi in Patients with Acute Ischemic Stroke. PMID- 26958153 TI - Identical Choroid Plexus Cysts in Monozygotic Monochorionic Twins. AB - Choroid plexus cysts have been infrequently reported with chromosomal abnormalities.Isolated choroid plexus cysts in a monozygotic twin pair hints to a genetically determined pathway as a possible cause. PMID- 26958154 TI - Temporary Lumbar Subcutaneous Cerebrospinal Fluid Shunt Placement in Pediatric Patient: A Technical Note. AB - BACKGROUND: We report the technical aspects of lumbar subcutaneous cerebrospinal fluid (CSF) shunt for temporary CSF drainage that may be an alternative strategy to lumbar catheter placement with external drainage system. CASE DESCRIPTION: A 7 years and nine-month old boy with developmental delay, intermittent episodes of agitation, and combination of myoclonic and generalized tonic clonic seizures, associated with communicating hydrocephalus was evaluated. A temporary CSF drainage trial was contemplated to determine whether a permanent CSF shunt would be beneficial. A temporary lumbar subcutaneous CSF shunt was performed to avoid catheter dislodgement or drainage system disruption due to child's agitative behavior and seizures. The catheter was inserted into the subarachnoid space at L3-L4 vertebral level and advanced approximately 20 cm above site of insertion and approximately 4 cm was imbedded into the subcutaneous tissue. An ultrasound two days later demonstrated CSF collection in subcutaneous tissue measuring 3.48 cm * 0.84 cm surrounding the catheter tip. The patient's parents reported improvement in clinical symptoms after four days of CSF drainage. CONCLUSIONS: Lumbar subcutaneous CSF shunt may be used for temporary CSF drainage for diagnostic purposes without the need for in patient admission and monitoring required for standard lumbar catheter with external CSF drainage system. PMID- 26958155 TI - Recurrent Transcortical Motor Aphasia-Another CNS Infectious Syndrome Associated with Herpes Virus Infection. AB - Herpes simplex encephalitis is an acute/subacute illness that causes both general and focal signs of cerebral dysfunction with fever, headache, and confusion as cardinal features. Recurrent herpes simplex meningitis, also known as Mollaret's meningitis, is another manifestation of central nervous system herpetic infection with recurrent episodes of fever, headache, and nuchal rigidity associated with cerebrospinal fluid (CSF) evidence of active herpes simplex infection. Bell's palsy is yet another manifestation of a herpes virus infection in at least some reported cases documented by CSF analysis. We report a case of a 70-year-old male who presented with acute transcortical motor aphasia initiating a stroke work-up that was negative. Physical examination revealed genital vesicles, and the CSF was consistent with active herpes simplex infection. PMID- 26958156 TI - Lumbar Catheter Placement Using Paramedian Approach Under Fluoroscopic Guidance. AB - BACKGROUND: Lumbar catheter placement under fluoroscopic guidance may reduce the rate of technical failures and associated complications seen with insertion guided by manually palpable landmarks. METHODS: We reviewed our experience with 43 attempted lumbar catheter placements using paramedian approach under fluoroscopic guidance and ascertained rates of technical success, and clinical events. RESULTS: Among the 43 patients, 18, 1, and 1 patients were on aspirin (with dipyrimadole in 2), clopidogrel, and combination of both, respectively. Lumbar catheter placement was successful in 42 of 43 attempted placements. Floroscopic guidance was critical in three patients; one patient had severe cerebrospinal fluid (CSF) depletion (empty thecal sac phenomenon) following pituitary surgery leading to no cerebrospinal fluid return despite correct placement confirmation under fluoroscopy. Two patients had spinal needle placement at the junction between epidural and cerebrospinal fluid spaces (junctional position) leading to cerebrospinal fluid return but inability to introduce the lumbar catheter. After confirmation of position by the injection of contrast or radiographic landmarks the needle was advanced by indenting the subcutaneous tissue or reinserting at a spinal level above the first insertion. The lumbar catheter remained in position over a mean period (+/-standard deviation) of 4.1(+/-2.3) days. Improvement in hydrocephalus was seen in two patients with intracranial mass lesions. One patient developed cerebrospinal fluid leakage through the insertion track following removal of catheter and required skin suturing at the site of insertion. CONCLUSIONS: We observed a high technical success rate with low rate of complications even in patients with intracranial mass lesions, those on ongoing antiplatelet medications or in whom insertion would not be possible guided by manually palpable landmarks. PMID- 26958157 TI - A Probabilistic Graphical Model for Individualizing Prognosis in Chronic, Complex Diseases. AB - Making accurate prognoses in chronic, complex diseases is challenging due to the wide variation in expression across individuals. In many such diseases, the notion of subtypes-subpopulations that share similar symptoms and patterns of progression-have been proposed. We develop a probabilistic model that exploits the concept of subtypes to individualize prognoses of disease trajectories. These subtypes are learned automatically from data. On a new individual, our model incorporates static and time-varying markers to dynamically update predictions of subtype membership and provide individualized predictions of disease trajectory. We use our model to tackle the problem of predicting lung function trajectories in scleroderma, an autoimmune disease, and demonstrate improved predictive performance over existing approaches. PMID- 26958158 TI - An Interactive User Interface for Drug Labeling to Improve Readability and Decision-Making. AB - FDA-approved prescribing information (also known as product labeling or labels) contain critical safety information for health care professionals. Drug labels have often been criticized, however, for being overly complex, difficult to read, and rife with overwarning, leading to high cognitive load. In this project, we aimed to improve the usability of drug labels by increasing the 'signal-to-noise ratio' and providing meaningful information to care providers based on patient specific comorbidities and concomitant medications. In the current paper, we describe the design process and resulting web application, known as myDrugLabel. Using the Structured Product Label documents as a base, we describe the process of label personalization, readability improvements, and integration of diverse evidence sources, including the medical literature from PubMed, pharmacovigilance reports from FDA adverse event reporting system (FAERS), and social media signals directly into the label. PMID- 26958159 TI - Content and Usability Evaluation of Patient Oriented Drug-Drug Interaction Websites. AB - Drug-Drug Interactions (DDI) are an important source of preventable adverse drug events and a common reason for hospitalization among patients on multiple drug therapy regimens. DDI information systems are important patient safety tools with the capacity to identify and warn health professionals of clinically significant DDI risk. While substantial research has been completed on DDI information systems in professional settings such as community, hospital, and independent pharmacies; there has been limited research on DDI systems offered through online websites directly for use by ambulatory patients. The focus of this project is to test patient oriented website capacity to correctly identify drug interactions among well established and clinically significant medication combinations and convey clinical risk data to patients. The patient education capability was assessed by evaluating website Information Capacity, Patient Usability and Readability. The study results indicate that the majority of websites identified which met the inclusion and exclusion criteria operated similarly, but vary in risk severity assessment and are not optimally patient oriented to effectively deliver risk information. The limited quality of information and complex medical term content complicate DDI risk data conveyance and the sites may not provide optimal information delivery to allow medication consumers to understand and manage their medication regimens. PMID- 26958160 TI - OpenHealth Platform for Interactive Contextualization of Population Health Open Data. AB - The financial incentives for data science applications leading to improved health outcomes, such as DSRIP (bit.ly/dsrip), are well-aligned with the broad adoption of Open Data by State and Federal agencies. This creates entirely novel opportunities for analytical applications that make exclusive use of the pervasive Web Computing platform. The framework described here explores this new avenue to contextualize Health data in a manner that relies exclusively on the native JavaScript interpreter and data processing resources of the ubiquitous Web Browser. The OpenHealth platform is made publicly available, and is publicly hosted with version control and open source, at https://github.com/mathbiol/openHealth. The different data/analytics workflow architectures explored are accompanied with live applications ranging from DSRIP, such as Hospital Inpatient Prevention Quality Indicators at http://bit.ly/pqiSuffolk, to The Cancer Genome Atlas (TCGA) as illustrated by http://bit.ly/tcgascopeGBM. PMID- 26958161 TI - An Associative Memory Model for Integration of Fragmented Research Data and Identification of Treatment Correlations in Breast Cancer Care. AB - A major challenge in advancing scientific discoveries using data-driven clinical research is the fragmentation of relevant data among multiple information systems. This fragmentation requires significant data-engineering work before correlations can be found among data attributes in multiple systems. In this paper, we focus on integrating information on breast cancer care, and present a novel computational approach to identify correlations between administered drugs captured in an electronic medical records and biological factors obtained from a tumor registry through rapid data aggregation and analysis. We use an associative memory (AM) model to encode all existing associations among the data attributes from both systems in a high-dimensional vector space. The AM model stores highly associated data items in neighboring memory locations to enable efficient querying operations. The results of applying AM to a set of integrated data on tumor markers and drug administrations discovered anomalies between clinical recommendations and derived associations. PMID- 26958162 TI - The Nurse Watch: Design and Evaluation of a Smart Watch Application with Vital Sign Monitoring and Checklist Reminders. AB - Computerized wearable devices such as smart watches will become valuable nursing tools. This paper describes a smart-watch system developed in close collaboration with a team of nurses working in a Swedish ICU. The smart-watch system provides real-time vital-sign monitoring, threshold alarms, and to-do reminders. Additionally, a Kanban board, visualized on a multitouch screen provides an overview of completed and upcoming tasks. We describe an approach to implement automated checklist systems with smart watches and discuss aspects of importance when implementing such memory and attention support. The paper is finalized with an in-development formative evaluation of the system. PMID- 26958163 TI - Utilizing Multidimensional Computer Adaptive Testing to Mitigate Burden With Patient Reported Outcomes. AB - Utilization of patient-reported outcome measures (PROs) had been limited by the lack of psychometrically sound measures scored in real-time. The Patient Reported Outcomes Measurement Information System (PROMIS) initiative developed a broad array of high-quality PRO measures. Towards reducing the number of items administered in measuring PROs, PROMIS employs Item Response Theory (IRT) and Computer Adaptive Testing (CAT). By only administering questions targeted to the subject's trait level, CAT has cut testing times in half(1). The IRT/CAT implementation in PROMIS is unidimensional in that there is a separate set of questions administered for each measured trait. However, there are often correlations among traits. Multidimensional IRT (MIRT) and multidimensional CAT (MCAT) provide items concerning several correlated traits, and should ameliorate patient burden. We developed an MIRT model using existing PROMIS item banks for depression and anxiety, developed MCAT software, and compared the efficiency of the MCAT approach to the unidimensional approach. Note: Research reported in this publication was supported in part by the National Library of Medicine of the National Institutes of Health under Award Number R01LM011962. PMID- 26958164 TI - A Low-Cost Method for Multiple Disease Prediction. AB - Recently, in response to the rising costs of healthcare services, employers that are financially responsible for the healthcare costs of their workforce have been investing in health improvement programs for their employees. A main objective of these so called "wellness programs" is to reduce the incidence of chronic illnesses such as cardiovascular disease, cancer, diabetes, and obesity, with the goal of reducing future medical costs. The majority of these wellness programs include an annual screening to detect individuals with the highest risk of developing chronic disease. Once these individuals are identified, the company can invest in interventions to reduce the risk of those individuals. However, capturing many biomarkers per employee creates a costly screening procedure. We propose a statistical data-driven method to address this challenge by minimizing the number of biomarkers in the screening procedure while maximizing the predictive power over a broad spectrum of diseases. Our solution uses multi-task learning and group dimensionality reduction from machine learning and statistics. We provide empirical validation of the proposed solution using data from two different electronic medical records systems, with comparisons to a statistical benchmark. PMID- 26958165 TI - Physician handoffs: opportunities and limitations for supportive technologies. AB - Shift-to-shift handoffs refer to the process of transferring role and responsibility for providing care from one person to another, thus insuring continuity of care. Through focus groups of residents and supervising physicians, we studied how physicians select patient cases to discuss during handoffs. We also compared the selection across level of experience. Understanding the patient selection criteria can give us insight into how to improve handoffs, in particular using supportive technologies that are integrated into the clinical information system. Studying the actual handoff process and note-taking also generated suggestions for handoff improvement. PMID- 26958166 TI - Model Checking for Verification of Interactive Health IT Systems. AB - Rigorous methods for design and verification of health IT systems have lagged far behind their proliferation. The inherent technical complexity of healthcare, combined with the added complexity of health information technology makes their resulting behavior unpredictable and introduces serious risk. We propose to mitigate this risk by formalizing the relationship between HIT and the conceptual work that increasingly typifies modern care. We introduce new techniques for modeling clinical workflows and the conceptual products within them that allow established, powerful modeling checking technology to be applied to interactive health IT systems. The new capability can evaluate the workflows of a new HIT system performed by clinicians and computers to improve safety and reliability. We demonstrate the method on a patient contact system to demonstrate model checking is effective for interactive systems and that much of it can be automated. PMID- 26958167 TI - Employing complex polyhierarchical ontologies and promoting interoperability of i2b2 data systems. AB - I2b2 is in widespread use for managing research data warehouses. It employs reference ontologies as a record index and supports searching for aggregate cases using a pattern match operator on ASCII strings representing the node traversal from root to concept(PATHs). This creates complexities in dissemination and deployment for large polyhierarchical ontologies such as SNOMED CT. We hypothesized that an alternative approach employing transitive closure tables (TC) could lead to more accurate, efficient and interoperable search tools for i2b2. We evaluated search speed, accuracy and interoperability of queries employing each approach. We found both TC-based and PATH-based queries to produce accurate results. However, we observed that TC-based queries involving concepts included in large numbers of paths ran substantially faster than PATH-based queries for the same concept. Oracle query plan resource estimates differed by one to three orders of magnitude for these queries. We conclude that a simplification of dissemination tools for SNOMED CT and revision in the metadata build for i2b2 can effectively employ SNOMED CT with increased efficiency and comparable accuracy. Use of transitive closure tables in metadata can promote network query interoperability. PMID- 26958168 TI - Implementation and evaluation of a tele-education system for the diagnosis of ophthalmic disease by international trainees. AB - Tele-education systems are increasingly being utilized in medical education worldwide. Due to limited human resources in healthcare in low and middle-income countries, developing online systems that are accessible to medical trainees in underserved areas potentially represents a highly efficient and effective method of improving the quantity and quality of the health care workforce. We developed, implemented, and evaluated an interactive web-based tele-education system (based on internationally accepted, image-based guidelines) for the diagnosis of retinopathy of prematurity among ophthalmologists-in-training in Brazil, Mexico, and the Philippines. We demonstrate that participation in this tele-education program improved diagnostic accuracy and reliability, and was preferred to standard pedagogical methods. This system may be employed not only in training, but also in international certification programs, and the process may be generalizable to other image-based specialties, such as dermatology and radiology. PMID- 26958169 TI - Representation of Drug Use in Biomedical Standards, Clinical Text, and Research Measures. AB - Drug misuse is a prominent cause of morbidity and mortality in the United States. Recent focus on behavioral and social domains in the electronic health record (EHR) has highlighted the need for comprehensive examination of social history information, such as drug use. In this study, representation of drug use was examined in three types of sources: (1) standards from HL7 and openEHR, (2) clinical text from publicly accessible clinical notes and a local EHR, and (3) research measures from the PhenX Toolkit and CDE Browser. In total, 27 elements were identified across the examined sources, revealing a diverse set of values that were found to be associated with drug use type, frequency, method, time frame, and amount. The findings of this study provide insight into the representation of drug use information that may contribute to efforts for standardizing collection and use of these data to support clinical care and research. PMID- 26958170 TI - Similarity-Based Recommendation of New Concepts to a Terminology. AB - Terminologies can suffer from poor concept coverage due to delays in addition of new concepts. This study tests a similarity-based approach to recommending concepts from a text corpus to a terminology. Our approach involves extraction of candidate concepts from a given text corpus, which are represented using a set of features. The model learns the important features to characterize a concept and recommends new concepts to a terminology. Further, we propose a cost-effective evaluation methodology to estimate the effectiveness of terminology enrichment methods. To test our methodology, we use the clinical trial eligibility criteria free-text as an example text corpus to recommend concepts for SNOMED CT. We computed precision at various rank intervals to measure the performance of the methods. Results indicate that our automated algorithm is an effective method for concept recommendation. PMID- 26958171 TI - Mining and Visualizing Family History Associations in the Electronic Health Record: A Case Study for Pediatric Asthma. AB - Asthma is the most common chronic childhood disease and has seen increasing prevalence worldwide. While there is existing evidence of familial and other risk factors for pediatric asthma, there is a need for further studies to explore and understand interactions among these risk factors. The goal of this study was to develop an approach for mining, visualizing, and evaluating association rules representing pairwise interactions among potential familial risk factors based on information documented as part of a patient's family history in the electronic health record. As a case study, 10,260 structured family history entries for a cohort of 1,531 pediatric asthma patients were extracted and analyzed to generate family history associations at different levels of granularity. The preliminary results highlight the potential of this approach for validating known knowledge and suggesting opportunities for further investigation that may contribute to improving prediction of asthma risk in children. PMID- 26958172 TI - Cloud-based Predictive Modeling System and its Application to Asthma Readmission Prediction. AB - The predictive modeling process is time consuming and requires clinical researchers to handle complex electronic health record (EHR) data in restricted computational environments. To address this problem, we implemented a cloud-based predictive modeling system via a hybrid setup combining a secure private server with the Amazon Web Services (AWS) Elastic MapReduce platform. EHR data is preprocessed on a private server and the resulting de-identified event sequences are hosted on AWS. Based on user-specified modeling configurations, an on-demand web service launches a cluster of Elastic Compute 2 (EC2) instances on AWS to perform feature selection and classification algorithms in a distributed fashion. Afterwards, the secure private server aggregates results and displays them via interactive visualization. We tested the system on a pediatric asthma readmission task on a de-identified EHR dataset of 2,967 patients. We conduct a larger scale experiment on the CMS Linkable 2008-2010 Medicare Data Entrepreneurs' Synthetic Public Use File dataset of 2 million patients, which achieves over 25-fold speedup compared to sequential execution. PMID- 26958173 TI - Inferring Clinical Workflow Efficiency via Electronic Medical Record Utilization. AB - Complexity in clinical workflows can lead to inefficiency in making diagnoses, ineffectiveness of treatment plans and uninformed management of healthcare organizations (HCOs). Traditional strategies to manage workflow complexity are based on measuring the gaps between workflows defined by HCO administrators and the actual processes followed by staff in the clinic. However, existing methods tend to neglect the influences of EMR systems on the utilization of workflows, which could be leveraged to optimize workflows facilitated through the EMR. In this paper, we introduce a framework to infer clinical workflows through the utilization of an EMR and show how such workflows roughly partition into four types according to their efficiency. Our framework infers workflows at several levels of granularity through data mining technologies. We study four months of EMR event logs from a large medical center, including 16,569 inpatient stays, and illustrate that over approximately 95% of workflows are efficient and that 80% of patients are on such workflows. At the same time, we show that the remaining 5% of workflows may be inefficient due to a variety of factors, such as complex patients. PMID- 26958174 TI - Modeling a Nursing Guideline with Standard Terminology and Unified Modeling Language for a Nursing Decision Support System: A Case Study. AB - In recent years, Decision Support Systems (DSSs) have been developed and used to achieve "meaningful use". One approach to developing DSSs is to translate clinical guidelines into a computer-interpretable format. However, there is no specific guideline modeling approach to translate nursing guidelines to computer interpretable guidelines. This results in limited use of DSSs in nursing. Unified modeling language (UML) is a software writing language known to accurately represent the end-users' perspective, due to its expressive characteristics. Furthermore, standard terminology enabled DSSs have been shown to smoothly integrate into existing health information systems. In order to facilitate development of nursing DSSs, the UML was used to represent a guideline for medication management for older adults encode with the International Classification for Nursing Practice (ICNP(r)). The UML was found to be a useful and sufficient tool to model a nursing guideline for a DSS. PMID- 26958175 TI - LORD: a phenotype-genotype semantically integrated biomedical data tool to support rare disease diagnosis coding in health information systems. AB - Characterizing a rare disease diagnosis for a given patient is often made through expert's networks. It is a complex task that could evolve over time depending on the natural history of the disease and the evolution of the scientific knowledge. Most rare diseases have genetic causes and recent improvements of sequencing techniques contribute to the discovery of many new diseases every year. Diagnosis coding in the rare disease field requires data from multiple knowledge bases to be aggregated in order to offer the clinician a global information space from possible diagnosis to clinical signs (phenotypes) and known genetic mutations (genotype). Nowadays, the major barrier to the coding activity is the lack of consolidation of such information scattered in different thesaurus such as Orphanet, OMIM or HPO. The Linking Open data for Rare Diseases (LORD) web portal we developed stands as the first attempt to fill this gap by offering an integrated view of 8,400 rare diseases linked to more than 14,500 signs and 3,270 genes. The application provides a browsing feature to navigate through the relationships between diseases, signs and genes, and some Application Programming Interfaces to help its integration in health information systems in routine. PMID- 26958176 TI - Characterization of the Context of Drug Concepts in Research Protocols: An Empiric Study to Guide Ontology Development. AB - We examined a large body of research study documents (protocols) to identify mentions of drug concepts and established base concepts and roles needed to characterize the semantics of these instances. We found these concepts in three general situations: background knowledge about the drug, study procedures involving the drug, and other roles of the drug in the study. We identified 18 more specific contexts (e.g., adverse event information, administration and dosing of the drug, and interactions between the study drug and other drugs). The ontology was validated against a test set of protocol documents from NIH and ClinicalTrial.gov. The goal is to support the automated extraction of drug information from protocol documents to support functions such as study retrieval, determination of subject eligibility, generation of order sets, and creation of logic for decision support alerts and reminders. Further work is needed to formally extend existing ontologies of clinical research. PMID- 26958177 TI - Improving EHR Capabilities to Facilitate Stage 3 Meaningful Use Care Coordination Criteria. AB - Primary care practices have been limited in their ability to leverage electronic health records (EHRs) and health information exchange (HIE) to improve care coordination, but will soon be incentivized to do so under proposed Stage 3 meaningful use criteria. We use mixed methods to understand how primary care practices manage, share and reconcile electronic patient information across care settings, and identify innovations in EHR design to support enhanced care coordination. Opportunities identified by practices focused on availability and usability of features that facilitate (1) generation of customized summary of care records, (2) team-based care approaches, and (3) management of the increased volume of electronic information generated and exchanged during care transitions. More broadly, vendors and policymakers need to continue to work together to improve interoperability as the key to effective care coordination. If these EHR innovations were widespread, the value of meeting the proposed Stage 3 care coordination criteria would be substantially enhanced. PMID- 26958178 TI - COHeRE: Cross-Ontology Hierarchical Relation Examination for Ontology Quality Assurance. AB - Biomedical ontologies play a vital role in healthcare information management, data integration, and decision support. Ontology quality assurance (OQA) is an indispensable part of the ontology engineering cycle. Most existing OQA methods are based on the knowledge provided within the targeted ontology. This paper proposes a novel cross-ontology analysis method, Cross-Ontology Hierarchical Relation Examination (COHeRE), to detect inconsistencies and possible errors in hierarchical relations across multiple ontologies. COHeRE leverages the Unified Medical Language System (UMLS) knowledge source and the MapReduce cloud computing technique for systematic, large-scale ontology quality assurance work. COHeRE consists of three main steps with the UMLS concepts and relations as the input. First, the relations claimed in source vocabularies are filtered and aggregated for each pair of concepts. Second, inconsistent relations are detected if a concept pair is related by different types of relations in different source vocabularies. Finally, the uncovered inconsistent relations are voted according to their number of occurrences across different source vocabularies. The voting result together with the inconsistent relations serve as the output of COHeRE for possible ontological change. The highest votes provide initial suggestion on how such inconsistencies might be fixed. In UMLS, 138,987 concept pairs were found to have inconsistent relationships across multiple source vocabularies. 40 inconsistent concept pairs involving hierarchical relationships were randomly selected and manually reviewed by a human expert. 95.8% of the inconsistent relations involved in these concept pairs indeed exist in their source vocabularies rather than being introduced by mistake in the UMLS integration process. 73.7% of the concept pairs with suggested relationship were agreed by the human expert. The effectiveness of COHeRE indicates that UMLS provides a promising environment to enhance qualities of biomedical ontologies by performing cross-ontology examination. PMID- 26958179 TI - Using Workflow Modeling to Identify Areas to Improve Genetic Test Processes in the University of Maryland Translational Pharmacogenomics Project. AB - Delivering genetic test results to clinicians is a complex process. It involves many actors and multiple steps, requiring all of these to work together in order to create an optimal course of treatment for the patient. We used information gained from focus groups in order to illustrate the current process of delivering genetic test results to clinicians. We propose a business process model and notation (BPMN) representation of this process for a Translational Pharmacogenomics Project being implemented at the University of Maryland Medical Center, so that personalized medicine program implementers can identify areas to improve genetic testing processes. We found that the current process could be improved to reduce input errors, better inform and notify clinicians about the implications of certain genetic tests, and make results more easily understood. We demonstrate our use of BPMN to improve this important clinical process for CYP2C19 genetic testing in patients undergoing invasive treatment of coronary heart disease. PMID- 26958180 TI - A hybrid manifold learning algorithm for the diagnosis and prognostication of Alzheimer's disease. AB - The diagnosis of Alzheimer's disease (AD) requires a variety of medical tests, which leads to huge amounts of multivariate heterogeneous data. Such data are difficult to compare, visualize, and analyze due to the heterogeneous nature of medical tests. We present a hybrid manifold learning framework, which embeds the feature vectors in a subspace preserving the underlying pairwise similarity structure, i.e. similar/dissimilar pairs. Evaluation tests are carried out using the neuroimaging and biological data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) in a three-class (normal, mild cognitive impairment, and AD) classification task using support vector machine (SVM). Furthermore, we make extensive comparison with standard manifold learning algorithms, such as Principal Component Analysis (PCA), Principal Component Analysis (PCA), Multidimensional Scaling (MDS), and isometric feature mapping (Isomap). Experimental results show that our proposed algorithm yields an overall accuracy of 85.33% in the three-class task. PMID- 26958181 TI - Extracting Characteristics of the Study Subjects from Full-Text Articles. AB - Characteristics of the subjects of biomedical research are important in determining if a publication describing the research is relevant to a search. To facilitate finding relevant publications, MEDLINE citations provide Medical Subject Headings that describe the subjects' characteristics, such as their species, gender, and age. We seek to improve the recommendation of these headings by the Medical Text Indexer (MTI) that supports manual indexing of MEDLINE. To that end, we explore the potential of the full text of the publications. Using simple recall-oriented rule-based methods we determined that adding sentences extracted from the methods sections and captions to the abstracts prior to MTI processing significantly improved recall and F1 score with only a slight drop in precision. Improvements were also achieved in directly assigning several headings extracted from the full text. These results indicate the need for further development of automated methods capable of leveraging the full text for indexing. PMID- 26958182 TI - PHAST: A Collaborative Machine Translation and Post-Editing Tool for Public Health. AB - This paper describes a novel collaborative machine translation (MT) plus post editing system called PHAST (Public Health Automatic System for Translation, phastsystem.org), tailored for use in producing multilingual education materials for public health. Its collaborative features highlight a new approach in public health informatics: sharing limited bilingual translation resources via a groupware system. We report here on the design methods and requirements used to develop PHAST and on its evaluation with potential public health users. Our results indicate such a system could be a feasible means of increasing the production of multilingual public health materials by reducing the barriers of time and cost. PHAST's design can serve as a model for other communities interested in assuring the accuracy of MT through shared language expertise. PMID- 26958183 TI - Semi-supervised Learning for Phenotyping Tasks. AB - Supervised learning is the dominant approach to automatic electronic health records-based phenotyping, but it is expensive due to the cost of manual chart review. Semi-supervised learning takes advantage of both scarce labeled and plentiful unlabeled data. In this work, we study a family of semi-supervised learning algorithms based on Expectation Maximization (EM) in the context of several phenotyping tasks. We first experiment with the basic EM algorithm. When the modeling assumptions are violated, basic EM leads to inaccurate parameter estimation. Augmented EM attenuates this shortcoming by introducing a weighting factor that downweights the unlabeled data. Cross-validation does not always lead to the best setting of the weighting factor and other heuristic methods may be preferred. We show that accurate phenotyping models can be trained with only a few hundred labeled (and a large number of unlabeled) examples, potentially providing substantial savings in the amount of the required manual chart review. PMID- 26958184 TI - POETenceph - Automatic identification of clinical notes indicating encephalopathy using a realist ontology. AB - Identifying inpatients with encephalopathy is important. The disorder is prevalent, often missed, and puts patients at risk. We describe POETenceph, natural language processing pipeline, which ranks clinical notes on the extent to which they indicate the patient had encephalopathy. We use a realist ontology of the entities and relationships indicative of encephalopathy in clinical notes. POETenceph includes a passage rank algorithm, which takes identified disorders; matches them to the ontology; calculates the diffuseness, centrality, and length of the matched entry; adds the scores; and returns the ranked documents. We evaluate it against a corpus of clinical documents annotated for evidence of delirium. Higher POETenceph are associated with increasing numbers of reviewer annotations. Detailed examination found that 65% of the bottom scoring documents contained little or no evidence and 70% of the top contained good evidence. POETenceph can effectively rank clinical documents for their evidence of encephalopathy as characterized by delirium. PMID- 26958186 TI - Effects of HIE/HIT Implementation and Coordination of Care on Health Outcomes and Quality. PMID- 26958185 TI - Strategies for Managing Mobile Devices for Use by Hospitalized Inpatients. AB - Despite the potential advantages, implementation of mobile devices and ongoing management pose challenges in the hospital environment. Our team implemented the PROSPECT (Promoting Respect and Ongoing Safety through Patient-centeredness, Engagement, Communication and Technology) project at Brigham and Women's Hospital. The goal of PROSPECT is to transform the hospital environment by providing a suite of e-tools to facilitate teamwork among nurses, physicians, patients and to engage patients and care partners in their plan of care. In this paper, we describe the device-related decisions and challenges faced including device and accessory selection, integration, information and device security, infection control, user access, and ongoing operation and maintenance. We relate the strategies that we used for managing mobile devices and lessons learned based on our experiences. PMID- 26958187 TI - A Flexible Simulation Architecture for Pandemic Influenza Simulation. AB - Simulation is an important resource for studying the dynamics of pandemic influenza and predicting the potential impact of interventions. However, there are several challenges for the design of such simulator architectures. Specifically, it is difficult to develop simulators that combine flexibility with run-time performance. This tradeoff is problematic in the pandemic-response setting because it makes it challenging to extend and adapt simulators for ongoing situations where rapid results are indispensable. Simulation architectures based on aspect-oriented programming can model specific concerns of the simulator and can allow developers to rapidly extend the simulator in new ways without sacrificing run-time performance. It is possible to use such aspects in conjunction with separate simulation models, which define community, disease, and intervention properties. The implication of this research for pandemic response is that aspects can add a novel layer of flexibility to simulation environments, which enables modelers to extend the simulator run-time component to new requirements that go beyond the original modeling framework. PMID- 26958188 TI - Designing Asynchronous Communication Tools for Optimization of Patient-Clinician Coordination. AB - Asynchronous communication outside the clinical setting has both enriched and complicated patient-clinician interactions. Many patients can now interact with a patient portal 24 hours a day, asking questions of their clinicians via secure message, checking lab results, ordering medication refills, or making appointments. However, the mode of communication (asynchronous) and the nature of the interaction (lacking tone or body language) strip valuable information from each side of patient-clinician asynchronous communication. Using interviews with 34 individuals who actively manage a chronic illness of their own, or for a child or partner, we elicited narratives about patients' experiences and expectations for using asynchronous communication to address medical issues with their clinicians. Based on these perspectives, we present opportunities for designing asynchronous communication tools to better facilitate understanding of and coordination around care activities between patients and clinicians. PMID- 26958189 TI - Reviewing 741 patients records in two hours with FASTVISU. AB - The secondary use of electronic health records opens up new perspectives. They provide researchers with structured data and unstructured data, including free text reports. Many applications been developed to leverage knowledge from free text reports, but manual review of documents is still a complex process. We developed FASTVISU a web-based application to assist clinicians in reviewing documents. We used FASTVISU to review a set of 6340 documents from 741 patients suffering from the celiac disease. A first automated selection pruned the original set to 847 documents from 276 patients' records. The records were reviewed by two trained physicians to identify the presence of 15 auto-immune diseases. It took respectively two hours and two hours and a half to evaluate the entire corpus. Inter-annotator agreement was high (Cohen's kappa at 0.89). FASTVISU is a user-friendly modular solution to validate entities extracted by NLP methods from free-text documents stored in clinical data warehouses. PMID- 26958190 TI - Supporting Clinical Cognition: A Human-Centered Approach to a Novel ICU Information Visualization Dashboard. AB - Advances in intensive care unit bedside displays/interfaces and electronic medical record (EMR) technology have not adequately addressed the topic of visual clarity of patient data/information to further reduce cognitive load during clinical decision-making. We responded to these challenges with a human-centered approach to designing and testing a decision-support tool: MIVA 2.0 (Medical Information Visualization Assistant, v.2). Envisioned as an EMR visualization dashboard to support rapid analysis of real-time clinical data-trends, our primary goal originated from a clinical requirement to reduce cognitive overload. In the study, a convenience sample of 12 participants were recruited, in which quantitative and qualitative measures were used to compare MIVA 2.0 with ICU paper medical-charts, using time-on-task, post-test questionnaires, and interviews. Findings demonstrated a significant difference in speed and accuracy with the use of MIVA 2.0. Qualitative outcomes concurred, with participants acknowledging the potential impact of MIVA 2.0 for reducing cognitive load and enabling more accurate and quicker decision-making. PMID- 26958191 TI - Automated mutual exclusion rules discovery for structured observational codes in echocardiography reporting. AB - Structured reporting in medicine has been argued to support and enhance machine assisted processing and communication of pertinent information. Retrospective studies showed that structured echocardiography reports, constructed through point-and-click selection of finding codes (FCs), contain pair-wise contradictory FCs (e.g., "No tricuspid regurgitation" and "Severe regurgitation") downgrading report quality and reliability thereof. In a prospective study, contradictions were detected automatically using an extensive rule set that encodes mutual exclusion patterns between FCs. Rules creation is a labor and knowledge-intensive task that could benefit from automation. We propose a machine-learning approach to discover mutual exclusion rules in a corpus of 101,211 structured echocardiography reports through semantic and statistical analysis. Ground truth is derived from the extensive prospectively evaluated rule set. On the unseen test set, F-measure (0.439) and above-chance level AUC (0.885) show that our approach can potentially support the manual rules creation process. Our methods discovered previously unknown rules per expert review. PMID- 26958192 TI - Patient Engagement in Cancer Survivorship Care through mHealth: A Consumer centered Review of Existing Mobile Applications. AB - With improvements in early detection and treatment, the number of cancer survivors has been on the rise. Studies suggest that cancer survivors do not often receive proper follow-up care despite existing guidelines. Patient engagement is key to healthy survivorship, and mHealth provides a viable platform to empower survivors with just- in-time personalized support. However, our understanding of existing mHealth solutions in cancer survivorship is limited. In this paper, we use Patient Engagement Framework to investigate existing apps to bridge this knowledge gap. App features are mapped to the framework components to determine the level of engagement facilitated. Ability to record treatment summaries has been found in five out of seven apps examined. While collaborative care and social engagement are found minimally, the majority of features (95%) are limited to information and way finding, e-tools, and interactive forms. Limitations of the existing apps and possible improvements to the framework are discussed. PMID- 26958193 TI - Using Big Data to Evaluate the Association between Periodontal Disease and Rheumatoid Arthritis. AB - An association between periodontal disease and rheumatoid arthritis is believed to exist. Most investigations into a possible relationship have been case-control studies with relatively low sample sizes. The advent of very large clinical repositories has created new opportunities for data-driven research. We conducted a retrospective cohort study to measure the association between periodontal disease and rheumatoid arthritis in a population of 25 million patients. We demonstrated that subjects with periodontal disease were roughly 1.4 times more likely to have rheumatoid arthritis. These results compare favorably with those of previous studies on smaller cohorts. Additional work is needed to identify the mechanisms behind this association and to determine if aggressive treatment of periodontal disease can alter the course of rheumatoid arthritis. PMID- 26958194 TI - Simulation-based Evaluation of the Generalizability Index for Study Traits. AB - The Generalizability Index for Study Traits (GIST) has been proposed recently for assessing the population representativeness of a set of related clinical trials using eligibility features (e.g., age or BMI), one each time. However, GIST has not yet been evaluated. To bridge this knowledge gap, this paper reports a simulation-based validation study for GIST. Using the National Health and Nutrition Examination Survey (NHANES) data, we demonstrated the effectiveness of GIST at quantifying the population representativeness of a set of related trials that differ in disease domains, study phases, sponsor types, and study designs, respectively. We also showed that among seven example medical conditions, the GIST of age increases from Phase I trials to Phase III trials in the seven disease domains and is the lowest in asthma trials. We concluded that GIST correlates with simulation-based generalizability results and is a valid metric for quantifying population representativeness of related clinical trials. PMID- 26958195 TI - JuFiT: A Configurable Rule Engine for Filtering and Generating New Multilingual Umls Terms. AB - We here describe JuFiT, an easily adjustable rule engine which allows to filter non-natural terms (i.e., ones usually not occurring in running citation texts) from the Umls metathesaurus and even adds new terms to the UMLS (by rewriting non natural terms). Unlike previous attempts (with MetaMap or Casper), JuFiT serves multilingual purposes in that it runs for English, Spanish, French, German and Dutch documents, as well - the most prominent European languages in terms of UMLS coverage. We evaluated JuFiT under a variety of experimental conditions and found evidence that it increases annotation quality for English, and most likely also for German and Spanish. PMID- 26958196 TI - Mining Twitter as a First Step toward Assessing the Adequacy of Gender Identification Terms on Intake Forms. AB - The Institute of Medicine (IOM) recommends that health care providers collect data on gender identity. If these data are to be useful, they should utilize terms that characterize gender identity in a manner that is 1) sensitive to transgender and gender non-binary individuals (trans* people) and 2) semantically structured to render associated data meaningful to the health care professionals. We developed a set of tools and approaches for analyzing Twitter data as a basis for generating hypotheses on language used to identify gender and discuss gender related issues across regions and population groups. We offer sample hypotheses regarding regional variations in the usage of certain terms such as 'genderqueer', 'genderfluid', and 'neutrois' and their usefulness as terms on intake forms. While these hypotheses cannot be directly validated with Twitter data alone, our data and tools help to formulate testable hypotheses and design future studies regarding the adequacy of gender identification terms on intake forms. PMID- 26958197 TI - mobile Digital Access to a Web-enhanced Network (mDAWN): Assessing the Feasibility of Mobile Health Tools for Self-Management of Type-2 Diabetes. AB - The mobile Digital Access to a Web-enhanced Network (mDAWN) program was implemented as an online, mobile self-management system to support patients with type-2 diabetes and their informal caregivers. Patients used wireless physiological sensors, received text messages, and had access to a secure web platform with health resources and semi-facilitated discussion forum. Outcomes were evaluated using (1) pre and post self-reported health behavior measures, (2) physiological outcomes, (3) program cost, and (4) in-depth participant interviews. The group had significantly decreased health distress, HbA1c levels, and systolic blood pressure. Participants largely saw the mDAWN as providing good value for the costs involved and found the program to be empowering in gaining control over their diabetes. mHealth programs have the potential to improve clinical outcomes through cost effective patient-led care for chronic illness. Further evaluation needs to examine integration of similar mHealth programs into the patient-physician relationship. PMID- 26958198 TI - Uncertainty, Case Complexity and the Content of Verbal Handoffs at the Emergency Department. AB - Handoffs are known to increase the risk of medical error and adverse events. Few electronic tools can support this process effectively, however. Our objective was to describe the relationship between clinical complexity, diagnostic uncertainty, fit with illness script and the content of case presentations by physicians. We observed the handoff of care for150 patients during eleven shift changes at a large urban emergency department (ED). Results indicate that as uncertainty about diagnosis and perceived illness script increased, more descriptive detail was conveyed to the incoming physicians. Physicians were concerned primarily with creating a shared mental model of a patient's clinical state and with describing the expected path to disposition rather than simply passing on data and findings. Electronic tools for ED handoffs should allow adjustment of structure and content to capture complexity and uncertainty appropriately without requiring extra effort for more routine cases that better fit to more standard narratives. PMID- 26958199 TI - Surgical Duration Estimation via Data Mining and Predictive Modeling: A Case Study. AB - Operating rooms (ORs) are one of the most expensive and profitable resources within a hospital system. OR managers strive to utilize these resources in the best possible manner. Traditionally, surgery durations are estimated using a moving average adjusted by the scheduler (adjusted system prediction or ASP). Other methods based on distributions, regression and data mining have also been proposed. To overcome difficulties with numerous procedure types and lack of sufficient sample size, and avoid distributional assumptions, the main objective is to develop a hybrid method of duration prediction and demonstrate using a case study. PMID- 26958200 TI - Medical Inpatient Journey Modeling and Clustering: A Bayesian Hidden Markov Model Based Approach. AB - Modeling and clustering medical inpatient journeys is useful to healthcare organizations for a number of reasons including inpatient journey reorganization in a more convenient way for understanding and browsing, etc. In this study, we present a probabilistic model-based approach to model and cluster medical inpatient journeys. Specifically, we exploit a Bayesian Hidden Markov Model based approach to transform medical inpatient journeys into a probabilistic space, which can be seen as a richer representation of inpatient journeys to be clustered. Then, using hierarchical clustering on the matrix of similarities, inpatient journeys can be clustered into different categories w.r.t their clinical and temporal characteristics. We evaluated the proposed approach on a real clinical data set pertaining to the unstable angina treatment process. The experimental results reveal that our method can identify and model latent treatment topics underlying in personalized inpatient journeys, and yield impressive clustering quality. PMID- 26958201 TI - Quality Assurance of Cancer Study Common Data Elements Using A Post-Coordination Approach. AB - Domain-specific common data elements (CDEs) are emerging as an effective approach to standards-based clinical research data storage and retrieval. A limiting factor, however, is the lack of robust automated quality assurance (QA) tools for the CDEs in clinical study domains. The objectives of the present study are to prototype and evaluate a QA tool for the study of cancer CDEs using a post coordination approach. The study starts by integrating the NCI caDSR CDEs and The Cancer Genome Atlas (TCGA) data dictionaries in a single Resource Description Framework (RDF) data store. We designed a compositional expression pattern based on the Data Element Concept model structure informed by ISO/IEC 11179, and developed a transformation tool that converts the pattern-based compositional expressions into the Web Ontology Language (OWL) syntax. Invoking reasoning and explanation services, we tested the system utilizing the CDEs extracted from two TCGA clinical cancer study domains. The system could automatically identify duplicate CDEs, and detect CDE modeling errors. In conclusion, compositional expressions not only enable reuse of existing ontology codes to define new domain concepts, but also provide an automated mechanism for QA of terminological annotations for CDEs. PMID- 26958202 TI - In Search of Social Translucence: An Audit Log Analysis of Handoff Documentation Views and Updates. AB - Communication and information sharing are critical parts of teamwork in the hospital; however, achieving open and fluid communication can be challenging. Finding specific patient information within documentation can be difficult. Recent studies on handoff documentation tools show that resident handoff notes are increasingly used as an alternative information source by non-physician clinicians. Previous findings also show that residents have become aware of this unintended use. This study investigated the alignment of resident note updating patterns and team note viewing patterns based on usage log data of handoff notes. Qualitative interviews with clinicians were used to triangulate findings based on the log analysis. The study found that notes that were frequently updated were viewed significantly more frequently than notes updated less often (p < 2.2 * 10( 16)). Almost 44% of all notes had aligned frequency of views and updates. The considerable percentage (56%) of mismatched note utilization suggests an opportunity for improvement. PMID- 26958203 TI - Causal Phenotype Discovery via Deep Networks. AB - The rapid growth of digital health databases has attracted many researchers interested in using modern computational methods to discover and model patterns of health and illness in a research program known as computational phenotyping. Much of the work in this area has focused on traditional statistical learning paradigms, such as classification, prediction, clustering, pattern mining. In this paper, we propose a related but different paradigm called causal phenotype discovery, which aims to discover latent representations of illness that are causally predictive. We illustrate this idea with a two-stage framework that combines the latent representation learning power of deep neural networks with state-of-the-art tools from causal inference. We apply this framework to two large ICU time series data sets and show that it can learn features that are predictively useful, that capture complex physiologic patterns associated with critical illnesses, and that are potentially more clinically meaningful than manually designed features. PMID- 26958204 TI - Initial Readability Assessment of Clinical Trial Eligibility Criteria. AB - Various search engines are available to clinical trial seekers. However, it remains unknown how comprehensible clinical trial eligibility criteria used for recruitment are to a lay audience. This study initially investigated this problem. Readability of eligibility criteria was assessed according to (i) shallow and lexical characteristics through the use of an established, generic readability metric; (ii) syntactic characteristics through natural language processing techniques; and (iii) health terminological characteristics through an automated comparison to technical and lay health texts. We further stratified clinical trials according to various study characteristics (e.g., source country or study type) to understand potential factors influencing readability. Mainly caused by frequent use of technical jargons, a college reading level was found to be necessary to understand eligibility criteria text, a level much higher than the average literacy level of the general American population. The use of technical jargons should be minimized to simplify eligibility criteria text. PMID- 26958205 TI - Automatic Assignment of Non-Leaf MeSH Terms to Biomedical Articles. AB - Assigning labels from a hierarchical vocabulary is a well known special case of multi-label classification, often modeled to maximize micro F1-score. However, building accurate binary classifiers for poorly performing labels in the hierarchy can improve both micro and macro F1-scores. In this paper, we propose and evaluate classification strategies involving descendant node instances to build better binary classifiers for non-leaf labels with the use-case of assigning Medical Subject Headings (MeSH) to biomedical articles. Librarians at the National Library of Medicine tag each biomedical article to be indexed by their PubMed information system with terms from the MeSH terminology, a biomedical conceptual hierarchy with over 27,000 terms. Human indexers look at each article's full text to assign a set of most suitable MeSH terms for indexing it. Several recent automated attempts focused on using the article title and abstract text to identify MeSH terms for the corresponding article. Despite these attempts, it is observed that assigning MeSH terms corresponding to certain non leaf nodes of the MeSH hierarchy is particularly challenging. Non-leaf nodes are very important as they constitute one third of the total number of MeSH terms. Here, we demonstrate the effectiveness of exploiting training examples of descendant terms of non-leaf nodes in improving the performance of conventional classifiers for the corresponding non-leaf MeSH terms. Specifically, we focus on reducing the false positives (FPs) caused due to descendant instances in traditional classifiers. Our methods are able to achieve a relative improvement of 7.5% in macro-F1 score while also increasing the micro-F1 score by 1.6% for a set of 500 non-leaf terms in the MeSH hierarchy. These results strongly indicate the critical role of incorporating hierarchical information in MeSH term prediction. To our knowledge, our effort is the first to demonstrate the role of hierarchical information in improving binary classifiers for non-leaf MeSH terms. PMID- 26958206 TI - Challenges and Insights in Using HIPAA Privacy Rule for Clinical Text Annotation. AB - The Privacy Rule of Health Insurance Portability and Accountability Act (HIPAA) requires that clinical documents be stripped of personally identifying information before they can be released to researchers and others. We have been manually annotating clinical text since 2008 in order to test and evaluate an algorithmic clinical text de-identification tool, NLM Scrubber, which we have been developing in parallel. Although HIPAA provides some guidance about what must be de-identified, translating those guidelines into practice is not as straightforward, especially when one deals with free text. As a result we have changed our manual annotation labels and methods six times. This paper explains why we have made those annotation choices, which have been evolved throughout seven years of practice on this field. The aim of this paper is to start a community discussion towards developing standards for clinical text annotation with the end goal of studying and comparing clinical text de-identification systems more accurately. PMID- 26958207 TI - Clinical Predictive Modeling Development and Deployment through FHIR Web Services. AB - Clinical predictive modeling involves two challenging tasks: model development and model deployment. In this paper we demonstrate a software architecture for developing and deploying clinical predictive models using web services via the Health Level 7 (HL7) Fast Healthcare Interoperability Resources (FHIR) standard. The services enable model development using electronic health records (EHRs) stored in OMOP CDM databases and model deployment for scoring individual patients through FHIR resources. The MIMIC2 ICU dataset and a synthetic outpatient dataset were transformed into OMOP CDM databases for predictive model development. The resulting predictive models are deployed as FHIR resources, which receive requests of patient information, perform prediction against the deployed predictive model and respond with prediction scores. To assess the practicality of this approach we evaluated the response and prediction time of the FHIR modeling web services. We found the system to be reasonably fast with one second total response time per patient prediction. PMID- 26958208 TI - An Ensemble Method for Spelling Correction in Consumer Health Questions. AB - Orthographic and grammatical errors are a common feature of informal texts written by lay people. Health-related questions asked by consumers are a case in point. Automatic interpretation of consumer health questions is hampered by such errors. In this paper, we propose a method that combines techniques based on edit distance and frequency counts with a contextual similarity-based method for detecting and correcting orthographic errors, including misspellings, word breaks, and punctuation errors. We evaluate our method on a set of spell corrected questions extracted from the NLM collection of consumer health questions. Our method achieves a F1 score of 0.61, compared to an informed baseline of 0.29, achieved using ESpell, a spelling correction system developed for biomedical queries. Our results show that orthographic similarity is most relevant in spelling error correction in consumer health questions and that frequency and contextual information are complementary to orthographic features. PMID- 26958210 TI - Supporting Multi-sourced Medication Information in i2b2. AB - Postmarketing drug surveillance is critical to assessing adverse events associated with medications, because prelaunch clinical trials frequently miss negative drug effects. The Informatics for Integrating Biology and the Bedside platform (i2b2) has been used effectively for this. However, previous work suffers from incomplete medical data present in electronic health record (EHR) systems. Here, we develop a system to integrate non-traditional data sources with EHR data: pharmacy dispensing information and patient-reported data. We implement and validate a toolset to gather medication data from a Pharmacy Benefit Manager network, import it into an i2b2 EHR repository using a standard data format, merge it with the EHR data, and present it to for annotation with results returned to i2b2. This toolkit is enabling studies on medication list data quality, adherence, and adverse event detection. PMID- 26958209 TI - A Study of Concept Extraction Across Different Types of Clinical Notes. AB - Our research investigates methods for creating effective concept extractors for specialty clinical notes. First, we present three new "specialty area" datasets consisting of Cardiology, Neurology, and Orthopedics clinical notes manually annotated with medical concepts. We analyze the medical concepts in each dataset and compare with the widely used i2b2 2010 corpus. Second, we create several types of concept extraction models and examine the effects of training supervised learners with specialty area data versus i2b2 data. We find substantial differences in performance across the datasets, and obtain the best results for all three specialty areas by training with both i2b2 and specialty data. Third, we explore strategies to improve concept extraction on specialty notes with ensemble methods. We compare two types of ensemble methods (Voting/Stacking) and a domain adaptation model, and show that a Stacked ensemble of classifiers trained with i2b2 and specialty data yields the best performance. PMID- 26958211 TI - Long-Term Engagement with Health-Management Technology: a Dynamic Process in Diabetes. AB - Diabetes management is a complex, dynamic process that is largely incumbent on patient choices and behavior. We explore how health-management needs-and the needs for technological support-change over time for individuals with diabetes. Through interviews and a focus group, we found that after initial diagnosis, individuals face acute information needs and chiefly turn to mobile applications and Internet resources to help understand the diabetes-specific factors that affect their health. Over time their focus shifts from highly regimented routines to more flexible ones that enable them to maintain a quality of life. Our results suggest that long-term engagement with health technology does not necessarily require continuous, sustained use: routine disease management could lead to a decrease in use, until a new event occurs. Our findings point to a need for tools that help patients with diabetes to effectively manage their health as their bodies, treatment and circumstances change over time. PMID- 26958212 TI - Evolving Patient Compliance Trends: Integrating Clinical, Insurance, and Extrapolated Socioeconomic Data. AB - Efforts toward improving patient compliance in medication focus on either identifying trends in patient features or studying changes through an intervention. Our study seeks to provide an important link between these two approaches through defining trends of evolving compliance. In addition to using clinical covariates provided through insurance claims and health records, we also extracted census based data to provide socioeconomic covariates such as income and population density. Through creating quadrants based on periods of medicine intake, we derive several novel definitions of compliance. These definitions revealed additional compliance trends through considering refill histories later in a patient's length of therapy. These results suggested that the link between patient features and compliance includes a temporal component, and should be considered in policymaking when identifying compliant subgroups. PMID- 26958213 TI - Automated Reconciliation of Radiology Reports and Discharge Summaries. AB - We study machine learning techniques to automatically identify limb abnormalities (including fractures, dislocations and foreign bodies) from radiology reports. For patients presenting to the Emergency Room (ER) with suspected limb abnormalities (e.g., fractures) there is often a multi-day delay before the radiology report is available to ER staff, by which time the patient may have been discharged home with the possibility of undiagnosed fractures. ER staff, currently, have to manually review and reconcile radiology reports with the ER discharge diagnosis; this is a laborious and error-prone manual process. Using radiology reports from three different hospitals, we show that extracting detailed features from the reports to train Support Vector Machines can effectively automate the identification of limb fractures, dislocations and foreign bodies. These can be automatically reconciled with a patient's discharge diagnosis from the ER to identify a number of cases where limb abnormalities went undiagnosed. PMID- 26958214 TI - Interpretable Probabilistic Latent Variable Models for Automatic Annotation of Clinical Text. AB - We propose Latent Class Allocation (LCA) and Discriminative Labeled Latent Dirichlet Allocation (DL-LDA), two novel interpretable probabilistic latent variable models for automatic annotation of clinical text. Both models separate the terms that are highly characteristic of textual fragments annotated with a given set of labels from other non-discriminative terms, but rely on generative processes with different structure of latent variables. LCA directly learns class specific multinomials, while DL-LDA breaks them down into topics (clusters of semantically related words). Extensive experimental evaluation indicates that the proposed models outperform Naive Bayes, a standard probabilistic classifier, and Labeled LDA, a state-of-the-art topic model for labeled corpora, on the task of automatic annotation of transcripts of motivational interviews, while the output of the proposed models can be easily interpreted by clinical practitioners. PMID- 26958215 TI - Representation of Functional Status Concepts from Clinical Documents and Social Media Sources by Standard Terminologies. AB - Patient-reported functional status is widely recognized as an important patient centered outcome that adds value to medical care, research, and quality improvement. Functional status outcomes are, however, not routinely or uniformly collected in the medical record, except in certain small patient populations (e.g. geriatrics, nursing home residents). To utilize patient reported functional status for clinical research and practice, we manually collected 2,763 terms from clinical records and social media sites and modeled them on the widely used Short Form-36 Health Survey. We then examined the coverage of the Unified Medical Language System (UMLS) for these functional status terms through automated mapping. Most terms (85.9%) did not have exact matches in the UMLS. The partial matches were prevalent, however, they typically did not capture the terms' exact semantics. Our study suggests that there is a need to extend existing standard terminologies to incorporate functional status terms used by patients and clinicians. PMID- 26958216 TI - Reproducing a Prospective Clinical Study as a Computational Retrospective Study in MIMIC-II. AB - In this paper we sought to reproduce, as a computational retrospective study in an EHR database (MIMIC-II), a recent large prospective clinical study: the 2013 publication, by the Japanese Association for Acute Medicine (JAAM), about disseminated intravascular coagulation, in the journal Critical Care (PMID: 23787004). We designed in SQL and Java a set of electronic phenotypes that reproduced the study's data sampling, and used R to perform the same statistical inference procedures. All produced source code is available online at https://github.com/fabkury/paamia2015. Our program identified 2,257 eligible patients in MIMIC-II, and the results remarkably agreed with the prospective study. A minority of the needed data elements was not found in MIMIC-II, and statistically significant inferences were possible in the majority of the cases. PMID- 26958217 TI - Computer-Supported Feedback Message Tailoring for Healthcare Providers in Malawi: Proof-of-Concept. AB - Although performance feedback has the potential to help clinicians improve the quality and safety of care, healthcare organizations generally lack knowledge about how this guidance is best provided. In low-resource settings, tools for theory-informed feedback tailoring may enhance limited clinical supervision resources. Our objectives were to establish proof-of-concept for computer supported feedback message tailoring in Malawi, Africa. We conducted this research in five stages: clinical performance measurement, modeling the influence of feedback on antiretroviral therapy (ART) performance, creating a rule-based message tailoring process, generating tailored messages for recipients, and finally analysis of performance and message tailoring data. We retrospectively generated tailored messages for 7,448 monthly performance reports from 11 ART clinics. We found that tailored feedback could be routinely generated for four guideline-based performance indicators, with 35% of reports having messages prioritized to optimize the effect of feedback. This research establishes proof of-concept for a novel approach to improving the use of clinical performance feedback in low-resource settings and suggests possible directions for prospective evaluations comparing alternative designs of feedback messages. PMID- 26958218 TI - Contrasting Association Results between Existing PheWAS Phenotype Definition Methods and Five Validated Electronic Phenotypes. AB - Phenome-Wide Association Studies (PheWAS) comprehensively investigate the association between genetic variation and a wide array of outcome traits. Electronic health record (EHR) based PheWAS uses various abstractions of International Classification of Diseases, Ninth Revision (ICD-9) codes to identify case/control status for diagnoses that are used as the phenotypic variables. However, there have not been comparisons within a PheWAS between results from high quality derived phenotypes and high-throughput but potentially inaccurate use of ICD-9 codes for case/control definition. For this study we first developed a group of high quality algorithms for five phenotypes. Next we evaluated the association of these "gold standard" phenotypes and 4,636,178 genetic variants with minor allele frequency > 0.01 and compared the results from high-throughput associations at the 3 digit, 5 digit, and PheWAS codes for defining case/control status. We found that certain diseases contained similar patient populations across phenotyping methods but had differences in PheWAS. PMID- 26958219 TI - Building Structured Personal Health Records from Photographs of Printed Medical Records. AB - Personal health records (PHRs) provide patient-centric healthcare by making health records accessible to patients. In China, it is very difficult for individuals to access electronic health records. Instead, individuals can easily obtain the printed copies of their own medical records, such as prescriptions and lab test reports, from hospitals. In this paper, we propose a practical approach to extract structured data from printed medical records photographed by mobile phones. An optical character recognition (OCR) pipeline is performed to recognize text in a document photo, which addresses the problems of low image quality and content complexity by image pre-processing and multiple OCR engine synthesis. A series of annotation algorithms that support flexible layouts are then used to identify the document type, entities of interest, and entity correlations, from which a structured PHR document is built. The proposed approach was applied to real world medical records to demonstrate the effectiveness and applicability. PMID- 26958220 TI - Design, Development, and Initial Evaluation of a Terminology for Clinical Decision Support and Electronic Clinical Quality Measurement. AB - When coupled with a common information model, a common terminology for clinical decision support (CDS) and electronic clinical quality measurement (eCQM) could greatly facilitate the distributed development and sharing of CDS and eCQM knowledge resources. To enable such scalable knowledge authoring and sharing, we systematically developed an extensible and standards-based terminology for CDS and eCQM in the context of the HL7 Virtual Medical Record (vMR) information model. The development of this terminology entailed three steps: (1) systematic, physician-curated concept identification from sources such as the Health Information Technology Standards Panel (HITSP) and the SNOMED-CT CORE problem list; (2) concept de-duplication leveraging the Unified Medical Language System (UMLS) MetaMap and Metathesaurus; and (3) systematic concept naming using standard terminologies and heuristic algorithms. This process generated 3,046 concepts spanning 68 domains. Evaluation against representative CDS and eCQM resources revealed approximately 50-70% concept coverage, indicating the need for continued expansion of the terminology. PMID- 26958221 TI - Analysis of empty responses from electronic resources in infobutton managers. AB - Infobuttons provide context-aware educational materials to both providers and patients and are becoming an important element in modern electronic health records (EHR) and patient health records (PHR). However, the content from different electronic resources (e-resource) as responses from infobutton manager has not been fully analyzed and evaluated. In this paper, we propose a method for automatically analyzing responses from infobutton manager. A tool is implemented to retrieve and analyze responses from infobutton manager. To test the tool, we extracted and sampled common and uncommon concepts from EHR usage data in Intermountain Healthcare's enterprise data warehouse. From the output of the tool, we evaluate infobutton performance by multiple categories, including against the most and less common used concepts, grouped by different modules in patient portal, by different e-resources, and by type of access (standardized Health Level Seven (HL7) vs not). Based on the results of our evaluation, we provide suggestions for further enhancements of infobuttons to the current implementation, including suggesting accessing priorities of e-resources and encouraging the use of the HL7 standard. PMID- 26958222 TI - A Novel Multiple Choice Question Generation Strategy: Alternative Uses for Controlled Vocabulary Thesauri in Biomedical-Sciences Education. AB - Multiple choice questions play an important role in training and evaluating biomedical science students. However, the resource intensive nature of question generation limits their open availability, reducing their contribution to evaluation purposes mainly. Although applied-knowledge questions require a complex formulation process, the creation of concrete-knowledge questions (i.e., definitions, associations) could be assisted by the use of informatics methods. We envisioned a novel and simple algorithm that exploits validated knowledge repositories and generates concrete-knowledge questions by leveraging concepts' relationships. In this manuscript we present the development and validation of a prototype which successfully produced meaningful concrete-knowledge questions, opening new applications for existing knowledge repositories, potentially benefiting students of all biomedical sciences disciplines. PMID- 26958223 TI - Veterans Health Administration Experience with Data Quality Surveillance of Continuity of Care Documents: Interoperability Challenges for eHealth Exchange Participants. AB - As part of ongoing data quality efforts authors monitored health information retrieved through the United States Department of Veterans Affairs' (VA) Virtual Lifetime Electronic Record (VLER) Health operation. Health data exchanged through the eHealth Exchange (managed by Healtheway, Inc.) between VA and external care providers was evaluated in order to test methods of data quality surveillance and to identify key quality concerns. Testing evaluated transition of care data from 20 VLER Health partners. Findings indicated operational monitoring discovers issues not addressed during onboarding testing, that many issues result from specification ambiguity, and that many issues require human review. We make recommendations to address these issues, specifically to embed automated testing tools within information exchange transactions and to continuously monitor and improve data quality, which will facilitate adoption and use. PMID- 26958224 TI - Towards data integration automation for the French rare disease registry. AB - Building a medical registry upon an existing infrastructure and rooted practices is not an easy task. It is the case for the BNDMR project, the French rare disease registry, that aims to collect administrative and medical data of rare disease patients seen in different hospitals. To avoid duplicating data entry for health professionals, the project plans to deploy connectors with the existing systems to automatically retrieve data. Given the data heterogeneity and the large number of source systems, the automation of connectors creation is required. In this context, we propose a methodology that optimizes the use of existing alignment approaches in the data integration processes. The generated mappings are formalized in exploitable mapping expressions. Following this methodology, a process has been experimented on specific data types of a source system: Boolean and predefined lists. As a result, effectiveness of the used alignment approach has been enhanced and more good mappings have been detected. Nonetheless, further improvements could be done to deal with the semantic issue and process other data types. PMID- 26958225 TI - Diagnostic Characteristics of Patient Self-Assessment of Preoperative Cardiac Risk for Non-Cardiac Surgery - Foundations for Patient Driven Decision Support. PMID- 26958226 TI - Expanding a First-Order Logic Mitigation Framework to Handle Multimorbid Patient Preferences. AB - The increasing prevalence of multimorbidity is a challenge for physicians who have to manage a constantly growing number of patients with simultaneous diseases. Adding to this challenge is the need to incorporate patient preferences as key components of the care process, thanks in part to the emergence of personalized and participatory medicine. In our previous work we proposed a framework employing first order logic to represent clinical practice guidelines (CPGs) and to mitigate possible adverse interactions when concurrently applying multiple CPGs to a multimorbid patient. In this paper, we describe extensions to our methodological framework that (1) broaden our definition of revision operators to support required and desired types of revisions defined in secondary knowledge sources, and (2) expand the mitigation algorithm to apply revisions based on their type. We illustrate the capabilities of the expanded framework using a clinical case study of a multimorbid patient with stable cardiac artery disease who suffers a sudden onset of deep vein thrombosis. PMID- 26958227 TI - Design of a Community-Engaged Health Informatics Platform with an Architecture of Participation. AB - Community-engaged health informatics (CEHI) applies information technology and participatory approaches to improve the health of communities. Our objective was to translate the concept of CEHI into a usable and replicable informatics platform that will facilitate community-engaged practice and research. The setting is a diverse urban neighborhood in New York City. The methods included community asset mapping, stakeholder interviews, logic modeling, analysis of affordances in open-source tools, elicitation of use cases and requirements, and a survey of early adopters. Based on synthesis of data collected, GetHealthyHeigths.org (GHH) was developed using open-source LAMP stack and Drupal content management software. Drupal's organic groups module was used for novel participatory functionality, along with detailed user roles and permissions. Future work includes evaluation of GHH and its impact on agency and service networks. We plan to expand GHH with additional functionality to further support CEHI by combining informatics solutions with community engagement to improve health. PMID- 26958228 TI - Knowledge Extraction from MEDLINE by Combining Clustering with Natural Language Processing. AB - The identification of relevant predicates between co-occurring concepts in scientific literature databases like MEDLINE is crucial for using these sources for knowledge extraction, in order to obtain meaningful biomedical predications as subject-predicate-object triples. We consider the manually assigned MeSH indexing terms (main headings and subheadings) in MEDLINE records as a rich resource for extracting a broad range of domain knowledge. In this paper, we explore the combination of a clustering method for co-occurring concepts based on their related MeSH subheadings in MEDLINE with the use of SemRep, a natural language processing engine, which extracts predications from free text documents. As a result, we generated sets of clusters of co-occurring concepts and identified the most significant predicates for each cluster. The association of such predicates with the co-occurrences of the resulting clusters produces the list of predications, which were checked for relevance. PMID- 26958229 TI - Intelligent Simulation Model To Facilitate EHR Training. AB - Despite the rapid growth of EHR use, there are currently no standardized protocols for EHR training. A simulation EHR environment may offer significant advantages with respect to EHR training, but optimizing the training paradigm requires careful consideration of the simulation model itself, and how it is to be deployed during training. In this paper, we propose Six Principles that are EHR-agnostic and provide the framework for the development of an intelligent simulation model that can optimize EHR training by replicating real-world clinical conditions and appropriate cognitive loads. PMID- 26958230 TI - Developing the Pathologists' Monthly Assignment Schedule: A Case Study at the Division of Anatomical Pathology of The Ottawa Hospital. AB - In the Division of Anatomical Pathology of a teaching hospital at the beginning of each month, clinical managers assign expected daily pathology requests to the pathologists on duty. Since the number of these requests is usually large and a division employs a number of pathologists with different sub-specialties, the size of the problem is significant and finding a feasible assignment schedule manually is time-consuming. Moreover, every time there is a need to change, a new assignment schedule needs to be developed taking into account all the pre-defined constraints including pathologists' availability, sub-specialty mix, teaching/research releases, etc. In this paper we describe an analytics optimization model embedded in a decision support tool that helps the clinical managers of the division determine the optimal monthly assignment schedule. The decision support tool has been validated using data from the Division of Anatomical Pathology at The Ottawa Hospital in Ottawa, Ontario, Canada. PMID- 26958231 TI - Reading and Writing: Qualitative Analysis of Pharmacists' Use of the EHR when Preparing for Team Rounds. AB - In the collaborative hospital environment, pharmacists are important members of the healthcare team, yet compared to physicians and nurses, little is known about pharmacists' information needs or how they interact with the electronic health record (EHR). We directly observed seven clinical inpatient pharmacists as they interacted with the EHR preparing for clinical rounds using an eye-tracking camera and contextual inquiry. Pharmacists spent 50% of their time reading information from the EHR, such as notes and medication lists, and 27% of their time copying EHR data onto paper, such as patient history and laboratory results. In an environment where minutes count, the results of this study can help inform the development of CDS tools and/or EHR designs to facilitate the information needs of the pharmacists in providing care for their patients. PMID- 26958232 TI - Assessing the Utility of Automatic Cancer Registry Notifications Data Extraction from Free-Text Pathology Reports. AB - Cancer Registries record cancer data by reading and interpreting pathology cancer specimen reports. For some Registries this can be a manual process, which is labour and time intensive and subject to errors. A system for automatic extraction of cancer data from HL7 electronic free-text pathology reports has been proposed to improve the workflow efficiency of the Cancer Registry. The system is currently processing an incoming trickle feed of HL7 electronic pathology reports from across the state of Queensland in Australia to produce an electronic cancer notification. Natural language processing and symbolic reasoning using SNOMED CT were adopted in the system; Queensland Cancer Registry business rules were also incorporated. A set of 220 unseen pathology reports selected from patients with a range of cancers was used to evaluate the performance of the system. The system achieved overall recall of 0.78, precision of 0.83 and F-measure of 0.80 over seven categories, namely, basis of diagnosis (3 classes), primary site (66 classes), laterality (5 classes), histological type (94 classes), histological grade (7 classes), metastasis site (19 classes) and metastatic status (2 classes). These results are encouraging given the large cross-section of cancers. The system allows for the provision of clinical coding support as well as indicative statistics on the current state of cancer, which is not otherwise available. PMID- 26958233 TI - Nutrition Informatics Applications in Clinical Practice: a Systematic Review. AB - Nutrition care and metabolic control contribute to clinical patient outcomes. Biomedical informatics applications represent a way to potentially improve quality and efficiency of nutrition management. We performed a systematic literature review to identify clinical decision support and computerized provider order entry systems used to manage nutrition care. Online research databases were searched using a specific set of keywords. Additionally, bibliographies were referenced for supplemental citations. Four independent reviewers selected sixteen studies out of 364 for review. These papers described adult and neonatal nutrition support applications, blood glucose management applications, and other nutrition applications. Overall, results indicated that computerized interventions could contribute to improved patient outcomes and provider performance. Specifically, computer systems in the clinical setting improved nutrient delivery, rates of malnutrition, weight loss, blood glucose values, clinician efficiency, and error rates. In conclusion, further investigation of informatics applications on nutritional and performance outcomes utilizing rigorous study designs is recommended. PMID- 26958234 TI - Drug-drug Interaction Discovery Using Abstraction Networks for "National Drug File - Reference Terminology" Chemical Ingredients. AB - The National Drug File - Reference Terminology (NDF-RT) is a large and complex drug terminology. NDF-RT provides important information about clinical drugs, e.g., their chemical ingredients, mechanisms of action, dosage form and physiological effects. Within NDF-RT such information is represented using tens of thousands of roles. It is difficult to comprehend large, complex terminologies like NDF-RT. In previous studies, we introduced abstraction networks to summarize the content and structure of terminologies. In this paper, we introduce the Ingredient Abstraction Network to summarize NDF-RT's Chemical Ingredients and their associated drugs. Additionally, we introduce the Aggregate Ingredient Abstraction Network, for controlling the granularity of summarization provided by the Ingredient Abstraction Network. The Ingredient Abstraction Network is used to support the discovery of new candidate drug-drug interactions (DDIs) not appearing in First Databank, Inc.'s DDI knowledgebase. PMID- 26958235 TI - Machine Learning Approaches for Detecting Diabetic Retinopathy from Clinical and Public Health Records. AB - INTRODUCTION: Annual eye examinations are recommended for diabetic patients in order to detect diabetic retinopathy and other eye conditions that arise from diabetes. Medically underserved urban communities in the US have annual screening rates that are much lower than the national average and could benefit from informatics approaches to identify unscreened patients most at risk of developing retinopathy. METHODS: Using clinical data from urban safety net clinics as well as public health data from the CDC's National Health and Nutrition Examination Survey, we examined different machine learning approaches for predicting retinopathy from clinical or public health data. All datasets utilized exhibited a class imbalance. RESULTS: Classifiers learned on the clinical data were modestly predictive of retinopathy with the best model having an AUC of 0.72, sensitivity of 69.2% and specificity of 55.9%. Classifiers learned on public health data were not predictive of retinopathy. DISCUSSION: Successful approaches to detecting latent retinopathy using machine learning could help safety net and other clinics identify unscreened patients who are most at risk of developing retinopathy and the use of ensemble classifiers on clinical data shows promise for this purpose. PMID- 26958236 TI - Understanding patients' health and technology attitudes for tailoring self management interventions. AB - Healthcare providers are moving towards tailoring self-management interventions to include the communication technologies patients use in daily life. Accurate understanding of patients' attitudes towards both technology and involvement in managing chronic conditions will be critical for informing effective self management strategies. The tailoring of these interventions, however, could be undermined by providers' implicit biases based on patient age, race, and education level that have been shown to negatively affect care. To inform the design and tailoring of self-management interventions, we elicited attitudes toward technology use and participation in care of 40 participants in a maximum variation sample. The analysis revealed three participant clusters-"Proactive Techies," "Indie Self-Managers," and "Remind Me! Non-Techies"-that represent varying attitudes toward health behaviors and technologies that were independent of race, education level, and age. Our approach provides insight into how people prioritize important values related to health participation and technology. PMID- 26958237 TI - Understanding the acceptance factors of an Hospital Information System: evidence from a French University Hospital. AB - The goal of this study was to examine the perceived usefulness, the perceived ease of use and the perceived behavioral control of a Hospital Information System (HIS) for the care staff. We administrated a questionnaire composed of open-end and closed questions, based on the main concepts of Technology Acceptance Model. As results, the perceived usefulness, ease of use and behavioral control (self efficacy and organizational support) are correlated with medical occupations. As an example, we found that a half of the medical secretaries consider the HIS is ease of use, at the opposite to the anesthesiologists, surgeons and physicians. Medical secretaries reported also the highest rate of PBC and a high rate of PU. Pharmacists reported the highest rate of PU but a low rate of PBC, which is similar to the rate of the surgeons and physicians. Content analysis of open questions highlights factors influencing these constructs: ergonomics, errors in the documenting process, insufficient compatibility with the medical department or the occupational group. Consequently, we suggest that the gap between the perceptions of the different occupational groups may be explained by the use of different modules and by interdependency of the care stare staff. PMID- 26958238 TI - USER FRUSTRATION IN HIT INTERFACES: EXPLORING PAST HCI RESEARCH FOR A BETTER UNDERSTANDING OF CLINICIANS' EXPERIENCES. AB - User frustration research has been one way of looking into clinicians' experience with health information technology use and interaction. In order to understand how clinician frustration with Health Information Technology (HIT) use occurs, there is the need to explore Human-Computer Interaction (HCI) literature that addresses both frustration and HIT use. In the past three decades, HCI frustration research has increased and expanded. Researchers have done a lot of work to understand emotions, end-user frustration and affect. This paper uses a historical literature review approach to review the origins of emotion and frustration research and explore the research question; Does HCI research on frustration provide insights on clinicians' frustration with HIT interfaces? From the literature review HCI research on emotion and frustration provides additional insights that can indeed help explain user frustration in HIT. Different approaches and HCI perspectives also help frame HIT user frustration research as well as inform HIT system design. The paper concludes with a suggested directions on how future design and research may take. PMID- 26958239 TI - Identifying the Clinical Laboratory Tests from Unspecified "Other Lab Test" Data for Secondary Use. AB - Clinical laboratory results are stored in electronic health records (EHRs) as structured data coded with local or standard terms. However, laboratory tests that are performed at outside laboratories are often simply labeled "outside test" or something similar, with the actual test name in a free-text result or comment field. After being aggregated into clinical data repositories, these ambiguous labels impede the retrieval of specific test results. We present a general multi-step solution that can facilitate the identification, standardization, reconciliation, and transformation of such test results. We applied our approach to data in the NIH Biomedical Translational Research Information System (BTRIS) to identify laboratory tests, map comment values to the LOINC codes that will be incorporated into our Research Entities Dictionary (RED), and develop a reference table that can be used in the EHR data extract transform-load (ETL) process. PMID- 26958240 TI - Homophily of Vocabulary Usage: Beneficial Effects of Vocabulary Similarity on Online Health Communities Participation. AB - Online health communities provide popular platforms for individuals to exchange psychosocial support and form ties. Although regular active participation (i.e., posting to interact with other members) in online health communities can provide important benefits, sustained active participation remains challenging for these communities. Leveraging previous literature on homophily (i.e., "love of those who are like themselves"), we examined the relationship between vocabulary similarity (i.e., homophily of word usage) of thread posts and members' future interaction in online health communities. We quantitatively measured vocabulary similarity by calculating, in a vector space model, cosine similarity between the original post and the first reply in 20,499 threads. Our findings across five online health communities suggest that vocabulary similarity is a significant predictor of members' future interaction in online health communities. These findings carry practical implications for facilitating and sustaining online community participation through beneficial effects of homophily in the vocabulary of essential peer support. PMID- 26958241 TI - Approaches to Supporting the Analysis of Historical Medication Datasets with RxNorm. AB - OBJECTIVE: To investigate approaches to supporting the analysis of historical medication datasets with RxNorm. METHODS: We created two sets of National Drug Codes (NDCs). One is based on historical NDCs harvested from versions of RxNorm from 2007 to present. The other comprises all sources of NDCs in the current release of RxNorm, including proprietary sources. We evaluated these two resources against four sets of NDCs obtained from various sources. RESULTS: In two historical medication datasets, 14-19% of the NDCs were obsolete, but 91-96% of these obsolete NDCs could be recovered and mapped to active drug concepts. CONCLUSION: Adding historical data significantly increases NDC mapping to active RxNorm drugs. A service for mapping historical NDC datasets leveraging RxNorm was added to the RxNorm API and is available at https://rxnav.nlm.nih.gov/. PMID- 26958242 TI - Just One More Patient: Optimizing EMR Documentation in Ambulatory Care. AB - The adoption of electronic medical records (EMRs) in primary care settings is on the rise in the United States and many are feeling the stress. The introduction of the EMR or transition to a new EMR is known to create workflow challenges for primary care providers and their office staff, as was the case in our health system. This study evolved out of an attempt to alleviate stress by defining the best practice or most optimal way to document office visits, allowing providers to see just one more patient each day. We leveraged a change management model that encourages looking for what is working vs. throwing resources at problem areas. By doing so we identified several distinguishing behaviors among providers who were doing exceptionally well with the EMR. We deployed an intervention aimed at enhancing the identified behaviors in a group of providers and it resulted marked improvement in efficiency. PMID- 26958243 TI - Casting a Wider Net: Data Driven Discovery of Proxies for Target Diagnoses. AB - BACKGROUND: The Hospital Readmissions Reduction Program (HRRP) introduced in October 2012 as part of the Affordable Care Act (ACA), ties hospital reimbursement rates to adjusted 30-day readmissions and mortality performance for a small set of target diagnoses. There is growing concern and emerging evidence that use of a small set of target diagnoses to establish reimbursement rates can lead to unstable results that are susceptible to manipulation (gaming) by hospitals. METHODS: We propose a novel approach to identifying co-occurring diagnoses and procedures that can themselves serve as a proxy indicator of the target diagnosis. The proposed approach constructs a Markov Blanket that allows a high level of performance, in terms of predictive accuracy and scalability, along with interpretability of obtained results. In order to scale to a large number of co-occuring diagnoses (features) and hospital discharge records (samples), our approach begins with Google's PageRank algorithm and exploits the stability of obtained results to rank the contribution of each diagnosis/procedure in terms of presence in a Markov Blanket for outcome prediction. RESULTS: Presence of target diagnoses acute myocardial infarction (AMI), congestive heart failure (CHF), pneumonia (PN), and Sepsis in hospital discharge records for Medicare and Medicaid patients in California and New York state hospitals (2009-2011), were predicted using models trained on a subset of California state hospitals (2003 2008). Using repeated holdout evaluation, we used ~30,000,000 hospital discharge records and analyzed the stability of the proposed approach. Model performance was measured using the Area Under the ROC Curve (AUC) metric, and importance and contribution of single features to the final result. The results varied from AUC=0.68 (with SE<1e-4) for PN on cross validation datasets to AUC=0.94, with (SE<1e-7) for Sepsis on California hospitals (2009 - 2011), while the stability of features was consistently better with more training data for each target diagnosis. Prediction accuracy for considered target diagnoses approaches or exceeds accuracy estimates for discharge record data. CONCLUSIONS: This paper presents a novel approach to identifying a small subset of relevant diagnoses and procedures that approximate the Markov Blanket for target diagnoses. Accuracy and interpretability of results demonstrate the potential of our approach. PMID- 26958244 TI - Impact of Robotic Surgery on Decision Making: Perspectives of Surgical Teams. AB - There has been rapid growth in the purchase of surgical robots in both North America and Europe in recent years. Whilst this technology promises many benefits for patients, the introduction of such a complex interactive system into healthcare practice often results in unintended consequences that are difficult to predict. Decision making by surgeons during an operation is affected by variables including tactile perception, visual perception, motor skill, and instrument complexity, all of which are changed by robotic surgery, yet the impact of robotic surgery on decision making has not been previously studied. Drawing on the approach of realist evaluation, we conducted a multi-site interview study across nine hospitals, interviewing 44 operating room personnel with experience of robotic surgery to gather their perspectives on how robotic surgery impacts surgeon decision making. The findings reveal both potential benefits and challenges of robotic surgery for decision making. PMID- 26958245 TI - AMIA members' "vital signs": what the HIT implementation listserv says about goals for AMIA and for medical informatics. AB - The health information technology (HIT) implementation listserv was conceived as a way to combine a substantial portion of American Medical Informatics Association (AMIA) members who belonged to four working groups (WGs): CIS, Evaluation, ELSI, and POI. Other AMIA members joined in significant numbers. It immediately became a major forum for discussing medical informatics, informatics policies, and discussion of the purpose of AMIA itself. The listserv membership approximates 25% of AMIA's members and has generated over 6,000 posts. We report on a survey of the listserv's members: what members think about the listserv; what participants want for medical informatics; how they think those goals should be achieved, and what AMIA's role should be in this process. The listserv provides vital signs about AMIA and hopes for informatics. We combine qualitative analysis of members' comments and responses about the listserv using ATLAS.ti qualitative text analysis tool and a word cloud generator. PMID- 26958246 TI - Public Perspectives of Mobile Phones' Effects on Healthcare Quality and Medical Data Security and Privacy: A 2-Year Nationwide Survey. AB - Given growing interest in mobile phones for health management (mHealth), we surveyed consumer perceptions of mHealth in security, privacy, and healthcare quality using national random-digit-dial telephone surveys in 2013 and 2014. In 2013, 48% thought that using a mobile phone to communicate data with a physician's electronic health record (EHR) would improve the quality of health care. By 2014, the proportion rose to 57% (p < .001). There were no similar changes in privacy concerns yet nearly two-thirds expressed privacy concerns. In 2013 alone, respondents were more likely to express privacy concerns about medical data on mobile phones than they were to endorse similar concerns with EHRs or health information exchange (HIE). Consumers increasingly believe that mHealth improves healthcare quality, but security and privacy concerns need to be addressed for quality improvement to be fully realized. PMID- 26958247 TI - Automatic Extraction and Post-coordination of Spatial Relations in Consumer Language. AB - To incorporate ontological concepts in natural language processing (NLP) it is often necessary to combine simple concepts into complex concepts (post coordination). This is especially true in consumer language, where a more limited vocabulary forces consumers to utilize highly productive language that is almost impossible to pre-coordinate in an ontology. Our work focuses on recognizing an important case for post-coordination in natural language: spatial relations between disorders and anatomical structures. Consumers typically utilize such spatial relations when describing symptoms. We describe an annotated corpus of 2,000 sentences with 1,300 spatial relations, and a second corpus of 500 of these relations manually normalized to UMLS concepts. We use machine learning techniques to recognize these relations, obtaining good performance. Further, we experiment with methods to normalize the relations to an existing ontology. This two-step process is analogous to the combination of concept recognition and normalization, and achieves comparable results. PMID- 26958248 TI - Automatic Classification of Structured Product Labels for Pregnancy Risk Drug Categories, a Machine Learning Approach. AB - With regular expressions and manual review, 18,342 FDA-approved drug product labels were processed to determine if the five standard pregnancy drug risk categories were mentioned in the label. After excluding 81 drugs with multiple risk categories, 83% of the labels had a risk category within the text and 17% labels did not. We trained a Sequential Minimal Optimization algorithm on the labels containing pregnancy risk information segmented into standard document sections. For the evaluation of the classifier on the testing set, we used the Micromedex drug risk categories. The precautions section had the best performance for assigning drug risk categories, achieving Accuracy 0.79, Precision 0.66, Recall 0.64 and F1 measure 0.65. Missing pregnancy risk categories could be suggested using machine learning algorithms trained on the existing publicly available pregnancy risk information. PMID- 26958249 TI - Validating free-text order entry for a note-centric EHR. AB - Electronic Health Records (EHRs) have increased the utility and portability of health information by storing it in structured formats. However, EHRs separate this structured data from the rich, free-text descriptions of clinical notes. The ultimate objective of our research is to develop an interactive progress note that unifies entry, access, and retrieval of structured and unstructured health information. In this study we present the design and subsequent testing with eight clinicians of a core element of this envisioned note: free-text order entry. Clinicians saw this new order-entry paradigm as a way to save time and preserve data quality by reducing double-documentation. However, they wanted the prototype to recognize more diverse types of shorthand and apply default values to fields that remain fairly constant across orders, such as number of refills and pickup location. Future work will test more complex orders, such as cascading orders, with a broader range of clinicians. PMID- 26958250 TI - Improving Continuity of Care via the Discharge Summary. AB - Discharge summaries (DCS) frequently fail to improve the continuity of care. A chart review of 188 DCS was performed to identify specific components that could be improved through health information technology. Medication reconciliations were analyzed for completeness and for medical reasoning. Documentation of pending results and follow-up details were analyzed. Patient preferences, patient goals, and the handover tone were noted. Patients were discharged on an average of 9.8 medications, only 3% of medication reconciliations were complete and medical reasoning was frequently absent. There were 358 pending results in 188 hospital discharges though only 14% were mentioned in the DCS. Documentation of clear, timely follow-up was present for less than 50% of patients. Patient preferences, patient goals, and lessons learned were rarely included. A handover tone was in only 17% of the DCS. Evaluating the DCS as a clinical handover is novel but information for safe handovers is frequently missing. PMID- 26958251 TI - Determinants of Consumer eHealth Information Seeking Behavior. AB - Patients are increasingly using the Internet and other technologies to engage in their own healthcare, but little research has focused on the determinants of consumer eHealth behaviors related to Internet use. This study uses data from 115,089 respondents to four years of the National Health Interview Series to identify the associations between one consumer eHealth behavior (information seeking) and demographics, health measures, and Personal Health Information Management (PHIM) (messaging, scheduling, refills, and chat). Individuals who use PHIM are 7.5 times more likely to search the internet for health related information. Just as health has social determinants, the results of this study indicate there are potential social determinants of consumer eHealth behaviors including personal demographics, health status, and healthcare access. PMID- 26958252 TI - Smartphone Data in Rheumatoid Arthritis - What Do Rheumatologists Want? AB - OBJECTIVE: To create a relevant and clinically informative visualization of passively collected patient mobility data from smartphones of rheumatoid arthritis (RA) patients for rheumatologists. METHODS: (1) Pilot analysis of smartphone mobility data in RA; (2) Assessment of rheumatologists' needs for patient data through semi-structured interviews; and (3) Evaluation of the visual format of the RA data using scenario-based usability methods. RESULTS: We created a color-scale mobility index superimposed on a calendar to summarize the passive mobility measures from the smartphone that the rheumatologists confirmed would be clinically relevant. CONCLUSION: This assessment of clinician data needs and preferences demonstrates the potential value of passively collected smartphone data to resolve an important data question in RA. Efforts such as these are necessary to ensure that any smartphone data that patients share with their doctors will not exacerbate clinician information overload, but actually facilitate clinical decisions. PMID- 26958253 TI - Vessel Delineation in Retinal Images using Leung-Malik filters and Two Levels Hierarchical Learning. AB - Blood vessel segmentation is important for the analysis of ocular fundus images for diseases affecting vessel caliber, occlusion, leakage, inflammation, and proliferation. We introduce a novel supervised method to evaluate performance of Leung-Malik filters in delineating vessels. First, feature vectors are extracted for every pixel with respect to the response of Leung-Malik filters on green channel retinal images in different orientations and scales. A two level hierarchical learning framework is proposed to segment vessels in retinal images with confounding disease abnormalities. In the first level, three expert classifiers are trained to delineate 1) vessels, 2) background, and 3) retinal pathologies including abnormal pathologies such as lesions and anatomical structures such as optic disc. In the second level, a new classifier is trained to detect vessels and non-vessel pixels based on results of the expert classifiers. Qualitative evaluation shows the effectiveness of the proposed expert classifiers in modeling retinal pathologies. Quantitative results on two standard datasets STARE (AUC = 0.971, Acc=0.927) and DRIVE (AUC = 0.955, Acc =0.903) are comparable with other state-of-the-art vessel segmentation methods. PMID- 26958254 TI - Application of a Consumer Health Information Needs Taxonomy to Questions in Maternal-Fetal Care. AB - Pregnancy is a time when expectant mothers may have numerous questions about their unborn children, especially when congenital anomalies are diagnosed prenatally. We sought to characterize information needs of pregnant women seen in the Vanderbilt Children's Hospital Fetal Center. Participants recorded questions from diagnosis through delivery. Questions were categorized by two researchers using a hierarchical taxonomy describing consumer health information needs. Consensus category assignments were made, and inter-rater reliability was measured with Cohen's Kappa. Sixteen participants reported 398 questions in 39 subcategories, of which the most common topics were prognosis (53 questions; 13.3%) and indications for intervention (31 questions; 7.8%). Inter-rater reliability of assignments showed moderate (kappa=0.57) to substantial (kappa=0.75) agreement for subcategories and primary categories, respectively. Pregnant women with prenatal diagnoses have diverse unmet information needs; a taxonomy of consumer health information needs may improve the ability to meet such needs through content and system design. PMID- 26958255 TI - Adaptation of a Published Risk Model to Point-of-care Clinical Decision Support Tailored to Local Workflow. AB - Electronic clinical decision support can bring newly published knowledge to the point of care. However, local organizational buy-in, support for team workflows, IT system ease of use and other sociotechnical factors are needed to promote adoption. We successfully implemented a multi-variate cardiac risk stratification model from another institution into ours. We recreated the model and integrated it into our workflow, accessing it from our EHR with patient-specific data and facilitating clinical documentation if the user accepts the model results. Our clinical leaders championed the change and led educational dissemination efforts. We describe the ad-hoc social and technical collaboration needed to build and deploy the tool. The tool complements a clinical initiative within a community of practice, and is correlated with appropriate use of nuclear imaging. PMID- 26958256 TI - Data-driven Temporal Prediction of Surgical Site Infection. AB - Analysis of data from Electronic Health Records (EHR) presents unique challenges, in particular regarding nonuniform temporal resolution of longitudinal variables. A considerable amount of patient information is available in the EHR - including blood tests that are performed routinely during inpatient follow-up. These data are useful for the design of advanced machine learning-based methods and prediction models. Using a matched cohort of patients undergoing gastrointestinal surgery (101 cases and 904 controls), we built a prediction model for post operative surgical site infections (SSIs) using Gaussian process (GP) regression, time warping and imputation methods to manage the sparsity of the data source, and support vector machines for classification. For most blood tests, wider confidence intervals after imputation were obtained in patients with SSI. Predictive performance with individual blood tests was maintained or improved by joint model prediction, and non-linear classifiers performed consistently better than linear models. PMID- 26958257 TI - Ginkgo and Warfarin Interaction in a Large Veterans Administration Population. AB - Ginkgo biloba is a widely used herbal product that could potentially have a severe interaction with warfarin, which is the most frequently prescribed anticoagulant agent in North America. Literature, however, provides conflicting evidence on the presence and severity of the interaction. In this study, we developed text processing methods to extract the ginkgo usage and combined it with prescription data on warfarin from a very large clinical data respository. Our statistical analysis suggests that taking concurrently with warfarin, gingko does significantly increase patients' risk of a bleeding adverse event (hazard ratio = 1.38, 95%CI: 1.20 to 1.58, p<.001). This study also is the first attempt of using a large medical record databaseto confirm a suspected herb-drug interaction. PMID- 26958258 TI - Recognizing Disjoint Clinical Concepts in Clinical Text Using Machine Learning based Methods. AB - Clinical concept recognition (CCR) is a fundamental task in clinical natural language processing (NLP) field. Almost all current machine learning-based CCR systems can only recognize clinical concepts of consecutive words (called consecutive clinical concepts, CCCs), but can do nothing about clinical concepts of disjoint words (called disjoint clinical concepts, DCCs), which widely exist in clinical text. In this paper, we proposed two novel types of representations for disjoint clinical concepts, and applied two state-of-the-art machine learning methods to recognizing consecutive and disjoint concepts. Experiments conducted on the 2013 ShARe/CLEF challenge corpus showed that our best system achieved a "strict" F-measure of 0.803 for CCCs, a "strict" F-measure of 0.477 for DCCs, and a "strict" F-measure of 0.783 for all clinical concepts, significantly higher than the baseline systems by 4.2% and 4.1% respectively. PMID- 26958259 TI - Challenges and Solutions in Optimizing Execution Performance of a Clinical Decision Support-Based Quality Measurement (CDS-QM) Framework. AB - Given the close relationship between clinical decision support (CDS) and quality measurement (QM), it has been proposed that a standards-based CDS Web service could be leveraged to enable QM. Benefits of such a CDS-QM framework include semantic consistency and implementation efficiency. However, earlier research has identified execution performance as a critical barrier when CDS-QM is applied to large populations. Here, we describe challenges encountered and solutions devised to optimize CDS-QM execution performance. Through these optimizations, the CDS-QM execution time was optimized approximately three orders of magnitude, such that approximately 370,000 patient records can now be evaluated for 22 quality measure groups in less than 5 hours (approximately 2 milliseconds per measure group per patient). Several key optimization methods were identified, with the most impact achieved through population-based retrieval of relevant data, multi-step data staging, and parallel processing. These optimizations have enabled CDS-QM to be operationally deployed at an enterprise level. PMID- 26958260 TI - Scaling Out and Evaluation of OBSecAn, an Automated Section Annotator for Semi Structured Clinical Documents, on a Large VA Clinical Corpus. AB - "Identifying and labeling" (annotating) sections improves the effectiveness of extracting information stored in the free text of clinical documents. OBSecAn, an automated ontology-based section annotator, was developed to identify and label sections of semi-structured clinical documents from the Department of Veterans Affairs (VA). In the first step, the algorithm reads and parses the document to obtain and store information regarding sections into a structure that supports the hierarchy of sections. The second stage detects and makes correction to errors in the parsed structure. The third stage produces the section annotation output using the final parsed tree. In this study, we present the OBSecAn method and its scale to a million document corpus and evaluate its performance in identifying family history sections. We identify high yield sections for this use case from note titles such as primary care and demonstrate a median rate of 99% in correctly identifying a family history section. PMID- 26958261 TI - Completing Death Certificates from an EMR: Analysis of a Novel Public-Private Partnership. AB - With the objective of increasing electronic death registration, Intermountain Healthcare and the Utah Office of Vital Records and Statistics have developed a system enabling death certification from within Intermountain's electronic medical record (EMR), consisting of an EMR module and an HL7 interface. Comparison of post-intervention death certification at Intermountain Healthcare against a baseline study found a slight increase in the percentage of deaths certified electronically (73% pre vs. 77% post). Analysis of deaths certified using the EMR-module found that they were completed significantly sooner than those certified on paper or using the state's web-based electronic death registration system (EDRS) (Mean time: Paper = 114.72 hours, EDRS = 81.84 hours, EMR = 43.92 hours; p < 0.0001). EMR-certified deaths also contained significantly more causes of deaths than either alternative method (Mean number of causes: Paper = 3.9 causes, EDRS = 4.0 causes, EMR = 5.5 causes; p < 0.0001). PMID- 26958262 TI - A Method to Compare ICF and SNOMED CT for Coverage of U.S. Social Security Administration's Disability Listing Criteria. AB - We developed a method to evaluate the extent to which the International Classification of Function, Disability, and Health (ICF) and SNOMED CT cover concepts used in the disability listing criteria of the U.S. Social Security Administration's "Blue Book." First we decomposed the criteria into their constituent concepts and relationships. We defined different types of mappings and manually mapped the recognized concepts and relationships to either ICF or SNOMED CT. We defined various metrics for measuring the coverage of each terminology, taking into account the effects of inexact matches and frequency of occurrence. We validated our method by mapping the terms in the disability criteria of Adult Listings, Chapter 12 (Mental Disorders). SNOMED CT dominates ICF in almost all the metrics that we have computed. The method is applicable for determining any terminology's coverage of eligibility criteria. PMID- 26958264 TI - The State and Trends of Barcode, RFID, Biometric and Pharmacy Automation Technologies in US Hospitals. AB - The standard of safe medication practice requires strict observance of the five rights of medication administration: the right patient, drug, time, dose, and route. Despite adherence to these guidelines, medication errors remain a public health concern that has generated health policies and hospital processes that leverage automation and computerization to reduce these errors. Bar code, RFID, biometrics and pharmacy automation technologies have been demonstrated in literature to decrease the incidence of medication errors by minimizing human factors involved in the process. Despite evidence suggesting the effectivity of these technologies, adoption rates and trends vary across hospital systems. The objective of study is to examine the state and adoption trends of automatic identification and data capture (AIDC) methods and pharmacy automation technologies in U.S. hospitals. A retrospective descriptive analysis of survey data from the HIMSS Analytics(r) Database was done, demonstrating an optimistic growth in the adoption of these patient safety solutions. PMID- 26958263 TI - Use of Patient Portals for Personal Health Information Management: The Older Adult Perspective. AB - The personal health information management (PHIM) practices and needs of older adults are poorly understood. We describe initial results from the UW SOARING project (Studying Older Adults & Researching Information Needs and Goals), a participatory design investigation of PHIM in older adults (60 years and older). We conducted in-depth interviews with older adults (n=74) living in a variety of residential settings about their management of personal health information. A surprising 20% of participants report using patient portals and another 16% reported prior use or anticipated use of portals in the future. Participants cite ease of access to health information and direct communication with providers as valuable portal features. Barriers to the use of patient portals include a general lack of computer proficiency, high internet costs and security concerns. Design features based on consideration of needs and practices of older adults will facilitate appeal and maximize usability; both are elements critical to adoption of tools such as patient portals that can support older adults and PHIM. PMID- 26958265 TI - Towards a Generalizable Time Expression Model for Temporal Reasoning in Clinical Notes. AB - Accurate temporal identification and normalization is imperative for many biomedical and clinical tasks such as generating timelines and identifying phenotypes. A major natural language processing challenge is developing and evaluating a generalizable temporal modeling approach that performs well across corpora and institutions. Our long-term goal is to create such a model. We initiate our work on reaching this goal by focusing on temporal expression (TIMEX3) identification. We present a systematic approach to 1) generalize existing solutions for automated TIMEX3 span detection, and 2) assess similarities and differences by various instantiations of TIMEX3 models applied on separate clinical corpora. When evaluated on the 2012 i2b2 and the 2015 Clinical TempEval challenge corpora, our conclusion is that our approach is successful - we achieve competitive results for automated classification, and we identify similarities and differences in TIMEX3 modeling that will be informative in the development of a simplified, general temporal model. PMID- 26958266 TI - Organizational Uses of Health Information Exchange to Change Cost and Utilization Outcomes: A Typology from a Multi-Site Qualitative Analysis. AB - Health information exchange (HIE) systems facilitate access to patient information for a variety of health care organizations, end users, and clinical and organizational goals. While a complex intervention, organizations' usage of HIE is often conceptualized and measured narrowly. We sought to provide greater specificity to the concept of HIE as an intervention by formulating a typology of organizational HIE usage. We interviewed representatives of a regional health information organization and health care organizations actively using HIE information to change patient utilization and costs. The resultant typology includes three dimensions: user role, usage initiation, and patient set. This approach to categorizing how health care organizations are actually applying HIE information to clinical and business tasks provides greater clarity about HIE as an intervention and helps elucidate the conceptual linkage between HIE an organizational and patient outcomes. PMID- 26958267 TI - A Graph Based Methodology for Temporal Signature Identification from HER. AB - Data driven technology is believed to be a promising technique for transforming the current status of healthcare. Electronic Health Records (EHR) is one of the main carriers for conducting the data driven healthcare research, where the goal is to derive insights from healthcare data and utilize such insights to improve the quality of care delivery. Due to the progression nature of human disease, one important aspect for analyzing healthcare data is temporality, which suggests the temporal relationships among different healthcare events and how their values evolve over time. Sequential pattern mining is a popular tool to extract time invariant patterns from discrete sequences and has been applied in analyzing EHR before. However, due to the complexity of EHR, those approaches usually suffers from the pattern explosion problem, which means that a huge number of patterns will be detected with improper setting of the support threshold. To address this challenge, in this paper, we develop a novel representation, namely the temporal graph, for event sequences like EHR, wherein the nodes are medical events and the edges indicate the temporal relationships among those events in patient EHRs. Based on the temporal graph representation, we further develop an approach for temporal signature identification to identify the most significant and interpretable graph bases as temporal signatures, and the expressing coefficients can be treated as the embeddings of the patients in such temporal signature space. Our temporal signature identification framework is also flexible to incorporate semi-supervised/supervised information. We validate our framework on two real-world tasks. One is predicting the onset risk of heart failure. The other is predicting the risk of heart failure related hospitalization for patients with COPD pre-condition. Our results show that the prediction performance in both tasks can be improved by the proposed approaches. PMID- 26958268 TI - DenguePredict: An Integrated Drug Repositioning Approach towards Drug Discovery for Dengue. AB - Dengue is a viral disease of expanding global incidence without cures. Here we present a drug repositioning system (DenguePredict) leveraging upon a unique drug treatment database and vast amounts of disease- and drug-related data. We first constructed a large-scale genetic disease network with enriched dengue genetics data curated from biomedical literature. We applied a network-based ranking algorithm to find dengue-related diseases from the disease network. We then developed a novel algorithm to prioritize FDA-approved drugs from dengue-related diseases to treat dengue. When tested in a de-novo validation setting, DenguePredict found the only two drugs tested in clinical trials for treating dengue and ranked them highly: chloroquine ranked at top 0.96% and ivermectin at top 22.75%. We showed that drugs targeting immune systems and arachidonic acid metabolism-related apoptotic pathways might represent innovative drugs to treat dengue. In summary, DenguePredict, by combining comprehensive disease- and drug related data and novel algorithms, may greatly facilitate drug discovery for dengue. PMID- 26958269 TI - Mortality Prediction in ICUs Using A Novel Time-Slicing Cox Regression Method. AB - Over the last few decades, machine learning and data mining have been increasingly used for clinical prediction in ICUs. However, there is still a huge gap in making full use of the time-series data generated from ICUs. Aiming at filling this gap, we propose a novel approach entitled Time Slicing Cox regression (TS-Cox), which extends the classical Cox regression into a classification method on multi-dimensional time-series. Unlike traditional classifiers such as logistic regression and support vector machines, our model not only incorporates the discriminative features derived from the time-series, but also naturally exploits the temporal orders of these features based on a Cox like function. Empirical evaluation on MIMIC-II database demonstrates the efficacy of the TS-Cox model. Our TS-Cox model outperforms all other baseline models by a good margin in terms of AUC_PR, sensitivity and PPV, which indicates that TS-Cox may be a promising tool for mortality prediction in ICUs. PMID- 26958270 TI - Finding Cervical Cancer Symptoms in Swedish Clinical Text using a Machine Learning Approach and NegEx. AB - Detection of early symptoms in cervical cancer is crucial for early treatment and survival. To find symptoms of cervical cancer in clinical text, Named Entity Recognition is needed. In this paper the Clinical Entity Finder, a machine learning tool trained on annotated clinical text from a Swedish internal medicine emergency unit, is evaluated on cervical cancer records. The Clinical Entity Finder identifies entities of the types body part, finding and disorder and is extended with negation detection using the rule-based tool NegEx, to distinguish between negated and non-negated entities. To measure the performance of the tools on this new domain, two physicians annotated a set of clinical notes from the health records of cervical cancer patients. The inter-annotator agreement for finding, disorder and body part obtained an average F-score of 0.677 and the Clinical Entity Finder extended with NegEx had an average F-score of 0.667. PMID- 26958271 TI - Machine Learning for Treatment Assignment: Improving Individualized Risk Attribution. AB - Clinical studies model the average treatment effect (ATE), but apply this population-level effect to future individuals. Due to recent developments of machine learning algorithms with useful statistical guarantees, we argue instead for modeling the individualized treatment effect (ITE), which has better applicability to new patients. We compare ATE-estimation using randomized and observational analysis methods against ITE-estimation using machine learning, and describe how the ITE theoretically generalizes to new population distributions, whereas the ATE may not. On a synthetic data set of statin use and myocardial infarction (MI), we show that a learned ITE model improves true ITE estimation and outperforms the ATE. We additionally argue that ITE models should be learned with a consistent, nonparametric algorithm from unweighted examples and show experiments in favor of our argument using our synthetic data model and a real data set of D-penicillamine use for primary biliary cirrhosis. PMID- 26958272 TI - Collecting Family Health History using an Online Social Network: a Nationwide Survey among Potential Users. AB - Family health history (FHx) is one of the most important risk factors for disease. Unfortunately, collection and use of FHx is under-utilized in the clinical setting. Efforts to improve collection of FHx have had minimal impact. A novel approach to collect FHx using social networking capabilities is being explored. We conducted a nationwide survey of 5,258 respondents to 1- assess the interest in using an online social network for FHx, 2- identify if such a tool would have clinical utility, and 3- identify notable trends and potential concerns. We found survey respondents to be very supportive of the proposed approach and interesting trends related to age, education, and race were identified. Results from this survey will be used to guide future research and development of a proposed FHx social network application. PMID- 26958273 TI - A Study of Neural Word Embeddings for Named Entity Recognition in Clinical Text. AB - Clinical Named Entity Recognition (NER) is a critical task for extracting important patient information from clinical text to support clinical and translational research. This study explored the neural word embeddings derived from a large unlabeled clinical corpus for clinical NER. We systematically compared two neural word embedding algorithms and three different strategies for deriving distributed word representations. Two neural word embeddings were derived from the unlabeled Multiparameter Intelligent Monitoring in Intensive Care (MIMIC) II corpus (403,871 notes). The results from both 2010 i2b2 and 2014 Semantic Evaluation (SemEval) data showed that the binarized word embedding features outperformed other strategies for deriving distributed word representations. The binarized embedding features improved the F1-score of the Conditional Random Fields based clinical NER system by 2.3% on i2b2 data and 2.4% on SemEval data. The combined feature from the binarized embeddings and the Brown clusters improved the F1-score of the clinical NER system by 2.9% on i2b2 data and 2.7% on SemEval data. Our study also showed that the distributed word embedding features derived from a large unlabeled corpus can be better than the widely used Brown clusters. Further analysis found that the neural word embeddings captured a wide range of semantic relations, which could be discretized into distributed word representations to benefit the clinical NER system. The low-cost distributed feature representation can be adapted to any other clinical natural language processing research. PMID- 26958274 TI - Citation Sentiment Analysis in Clinical Trial Papers. AB - In scientific writing, positive credits and negative criticisms can often be seen in the text mentioning the cited papers, providing useful information about whether a study can be reproduced or not. In this study, we focus on citation sentiment analysis, which aims to determine the sentiment polarity that the citation context carries towards the cited paper. A citation sentiment corpus was annotated first on clinical trial papers. The effectiveness of n-gram and sentiment lexicon features, and problem-specified structure features for citation sentiment analysis were then examined using the annotated corpus. The combined features from the word n-grams, the sentiment lexicons and the structure information achieved the highest Micro F-score of 0.860 and Macro-F score of 0.719, indicating that it is feasible to use machine learning methods for citation sentiment analysis in biomedical publications. A comprehensive comparison between citation sentiment analysis of clinical trial papers and other general domains were conducted, which additionally highlights the unique challenges within this domain. PMID- 26958275 TI - tcTKB: an integrated cardiovascular toxicity knowledge base for targeted cancer drugs. AB - Targeted cancer drugs are often associated with unexpectedly high cardiovascular (CV) adverse events. Systematic approaches to studying CV events associated with targeted anticancer drugs have high potential for elucidating the complex pathways underlying targeted anti-cancer drugs. In this study, we built tcTKB, a comprehensive CV toxicity knowledge base for targeted cancer drugs, by extracting drug-CV pairs from five large-scale and complementary data sources. The data sources include FDA drug labels (44,979 labels), the FDA Adverse Event Reporting System (FAERS) (4,285,097 records), the Canada Vigilance Adverse Reaction Online Database (CVAROD) (1,107,752 records), published biomedical literature (21,354,075 records), and published full-text articles from the Journal of Oncology (JCO) (13,855 articles). tcTKB contains 14,351 drug-CV pairs for 45 targeted anticancer drugs and 1,842 CV events. We demonstrate that CV events positively correlate with drug target genes and drug metabolism genes, demonstrating that tcTKB in combination with other data resources, could facilitate our understanding of targeted anticancer drugs and their associated CV toxicities. PMID- 26958276 TI - Barriers and Facilitators to Patient-Provider Communication When Discussing Breast Cancer Risk to Aid in the Development of Decision Support Tools. AB - The purpose of this study was to identify barriers and facilitators to patient provider communication when discussing breast cancer risk to aid in the development of decision support tools. Four patient focus groups (N=34) and eight provider focus groups (N=10) took place in Northern Manhattan. A qualitative analysis was conducted using Atlas.ti software. The coding yielded 62.3%-94.5% agreement. The results showed that 1) barriers are time constraints, lack of knowledge, low health literacy, and language barriers, and 2) facilitators are information needs, desire for personalization, and autonomy when communicating risk in patient-provider encounters. These results will inform the development of a patient-centered decision aid (RealRisks) and a provider-facing breast cancer risk navigation (BNAV) tool, which are designed to facilitate patient-provider risk communication and shared decision-making about breast cancer prevention strategies, such as chemoprevention. PMID- 26958277 TI - Evaluating Term Coverage of Herbal and Dietary Supplements in Electronic Health Records. AB - Herbal and dietary supplement consumption has rapidly expanded in recent years. Due to pharmacological and metabolic characteristics of some supplements, they can interact with prescription medications, potentially leading to clinically important and potentially preventable adverse reactions. Electronic health record (EHR) system provides a valuable source from which drug-supplement interactions can be mined and assessed for their clinical effects. A fundamental prerequisite is a functional understanding of supplement documentation in EHR and associated supplement coverage in major online databases. To address this, clinical notes and corresponding medication lists from an integrated healthcare system were extracted and compared with online databases. Overall, about 40% of listed medications are supplements, most of which are included in medication lists as nutritional or miscellaneous products. Gaps were found between supplement and standard medication terminologies, creating documentation difficulties in fully achieving robust supplement documentation in EHR systems. In addition, in the clinical notes we identified supplements which were not mentioned in the medication lists. PMID- 26958278 TI - Handling Temporality of Clinical Events for Drug Safety Surveillance. AB - Using longitudinal data in electronic health records (EHRs) for post-marketing adverse drug event (ADE) detection allows for monitoring patients throughout their medical history. Machine learning methods have been shown to be efficient and effective in screening health records and detecting ADEs. How best to exploit historical data, as encoded by clinical events in EHRs is, however, not very well understood. In this study, three strategies for handling temporality of clinical events are proposed and evaluated using an EHR database from Stockholm, Sweden. The random forest learning algorithm is applied to predict fourteen ADEs using clinical events collected from different lengths of patient history. The results show that, in general, including longer patient history leads to improved predictive performance, and that assigning weights to events according to time distance from the ADE yields the biggest improvement. PMID- 26958279 TI - Using a Clinical Knowledge Base to Assess Comorbidity Interrelatedness Among Patients with Multiple Chronic Conditions. AB - Decision support tools increasingly integrate clinical knowledge such as medication indications and contraindications with electronic health record (EHR) data to support clinical care and patient safety. The availability of this encoded information and patient data provides an opportunity to develop measures of clinical decision complexity that may be of value for quality improvement and research efforts. We investigated the feasibility of using encoded clinical knowledge and EHR data to develop a measure of comorbidity interrelatedness (the degree to which patients' co-occurring conditions interact to generate clinical complexity). Using a common clinical scenario-decisions about blood pressure medications in patients with hypertension-we quantified comorbidity interrelatedness by calculating the number of indications and contraindications to blood pressure medications that are generated by patients' comorbidities (e.g., diabetes, gout, depression). We examined properties of comorbidity interrelatedness using data from a decision support system for hypertension in the Veterans Affairs Health Care System. PMID- 26958280 TI - Three-dimensional Content-Based Cardiac Image Retrieval using global and local descriptors. AB - The increase in volume of medical images generated and stored has created difficulties in accurate image retrieval. An alternative is to generate three dimensional (3D) models from such medical images and use them in the search. Some of the main cardiac illnesses, such as Congestive Heart Failure (CHF), have deformation in the heart's shape as one of the main symptoms, which can be identified faster in a 3D object than in slices. This article presents techniques developed to retrieve 3D cardiac models using global and local descriptors within a content-based image retrieval system. These techniques were applied in pre classified 3D models with and without the CHF disease and they were evaluated by using Precision vs. Recall metric. We observed that local descriptors achieved better results than a global descriptor, reaching 85% of accuracy. The results confirmed the potential of using 3D models retrieval in the medical context to aid in the diagnosis. PMID- 26958281 TI - Analyzing Self-Help Forums with Ontology-Based Text Mining: An Exploration in Kidney Space. AB - The Internet has emerged as a popular source for health-related information. More than eighty percent of American Internet users have searched for health topics online. Millions of patients use self-help online forums to exchange information and support. In parallel, the increasing prevalence of chronic diseases has become a financial burden for the healthcare system demanding new, cost-effective interventions. To provide such interventions, it is necessary to understand patients' preferences of treatment options and to gain insights into their experiences as patients. We introduce a text-processing algorithm based on semantic ontologies to allow for finer-grained analyses of online forums compared to standard methods. We have applied our method in an analysis of two major Chronic Kidney Disease (CKD) forums. Our results suggest that the analysis of forums may provide valuable insights on daily issues patients face, their choice of different treatment options and interactions between patients, their relatives and clinicians. PMID- 26958282 TI - Dynamic Estimation of the Probability of Patient Readmission to the ICU using Electronic Medical Records. AB - In this paper, we propose a framework to dynamically estimate the probability that a patient is readmitted after he is discharged from the ICU and transferred to a lower level care. We model this probability as a latent state which evolves over time using Dynamical Linear Models (DLM). We use as an input a combination of numerical and text features obtained from the patient Electronic Medical Records (EMRs). We process the text from the EMRs to capture different diseases, symptoms and treatments by means of noun phrases and ontologies. We also capture the global context of each text entry using Statistical Topic Models. We fill out the missing values using a Expectation Maximization based method (EM). Experimental results show that our method outperforms other methods in the literature terms of AUC, sensitivity and specificity. In addition, we show that the combination of different features (numerical and text) increases the prediction performance of the proposed approach. PMID- 26958283 TI - Modelling Risk of Cardio-Respiratory Instability as a Heterogeneous Process. AB - Cardio-respiratory instability (CRI) occurs frequently in acutely ill. If not identified and treated early, it leads to significant morbidity and mortality. Current practice primarily relies on vigilance of the clinical personnel for early recognition of CRI. Given limited monitoring resources available in critical care environment, it can be suboptimal. Thus, an "Early Warning Scoring" mechanism is desirable to alert medical team when a patient is approaching instability. It is widely recognized that critically ill may show subtle changes prior to the onset of CRI, but it is not well known how their risk evolves before the onset. Using large amounts of physiological data routinely gathered from continuous noninvasive monitoring of Step-Down Unit patients, we demonstrate a data-driven approach that: (1) Characterizes patient's individual CRI risk process; (2) Identifies groups of patients that progress along similar risk evolution trajectories; (3) Utilizes grouping information to help forecast the emergence of CRI. PMID- 26958284 TI - Combining Human Disease Genetics and Mouse Model Phenotypes towards Drug Repositioning for Parkinson's disease. AB - Parkinson's disease (PD) is a severe neurodegenerative disorder without effective treatments. Here, we present a novel drug repositioning approach to predict new drugs for PD leveraging both disease genetics and large amounts of mouse model phenotypes. First, we identified PD-specific mouse phenotypes using well-studied human disease genes. Then we searched all FDA-approved drugs for candidates that share similar mouse phenotype profiles with PD. We demonstrated the validity of our approach using drugs that have been approved for PD: 10 approved PD drugs were ranked within top 10% among 1197 candidates. In predicting novel PD drugs, our approach achieved a mean average precision of 0.24, which is significantly higher (p50%) of Col4 in the PCM significantly decreased in damaged cartilage (P = 0.004) and clinically failed repair tissue (P < 0.001). Laminin was only found with high expression (>50%) in 4/8 of the normal samples, which was not statistically significantly different from damaged cartilage (P = 0.15) or failed cartilage repair (P = 0.054). CONCLUSIONS: Col4 in cartilage contain antiangiogenic domains and may play a role in the hypoxic environment in articular cartilage. Col4 and laminin was not found in the PCM of damaged and clinically failed repair. PMID- 26958318 TI - Electromechanical Assessment of Human Knee Articular Cartilage with Compression Induced Streaming Potentials. AB - PURPOSE: To assess the electromechanical properties of human knee articular cartilage with compression-induced streaming potentials for reliability among users and correlation with macroscopic and histological evaluation tools and sulfated glycosaminoglycan (sGAG) content. METHODS: Streaming potentials are induced in cartilage in response to loading when mobile positive ions in the interstitial fluid temporarily move away from negatively charged proteoglycans. Streaming potential integrals (SPIs) were measured with an indentation probe on femoral condyles of 10 human knee specimens according to a standardized location scheme. Interobserver reliability was measured using an interclass correlation coefficient (ICC). The learning curves of 3 observers were evaluated by regression analysis. At each SPI measurement location the degradation level of the tissue was determined by means of the International Cartilage Repair Society (ICRS) score, Mankin score, and sGAG content. RESULTS: The computed ICC was 0.77 (0.70-0.83) indicating good to excellent linear agreement of SPI values among the 3 users. A significant positive linear correlation of the learning index values was observed for 2 of the 3 users. Statistically significant negative correlations between SPI and both ICRS and Mankin scores were observed (r = 0.502, P < 0.001, and r = 0.255, P = 0.02, respectively). No correlation was observed between SPI and sGAG content (r = 0.004, P = 0.973). CONCLUSIONS: SPI values may be used as a quantitative means of cartilage evaluation with sufficient reliability among users. Due to the significant learning curve, adequate training should be absolved before routine use of the technique. PMID- 26958316 TI - High-Resolution Methods for Diagnosing Cartilage Damage In Vivo. AB - Advances in current clinical modalities, including magnetic resonance imaging and computed tomography, allow for earlier diagnoses of cartilage damage that could mitigate progression to osteoarthritis. However, current imaging modalities do not detect submicrometer damage. Developments in in vivo or arthroscopic techniques, including optical coherence tomography, ultrasonography, bioelectricity including streaming potential measurement, noninvasive electroarthrography, and multiphoton microscopy can detect damage at an earlier time point, but they are limited by a lack of penetration and the ability to assess an entire joint. This article reviews current advancements in clinical and developing modalities that can aid in the early diagnosis of cartilage injury and facilitate studies of interventional therapeutics. PMID- 26958319 TI - Glucosamine Hydrochloride but Not Chondroitin Sulfate Prevents Cartilage Degradation and Inflammation Induced by Interleukin-1alpha in Bovine Cartilage Explants. AB - OBJECTIVE: Glucosamine hydrochloride (GH) and chondroitin sulfate (CS) are commonly used for the treatment of osteoarthritis (OA). The aim of this study was to assess their effects, alone and in combination, on preventing aggrecan degradation and inflammation in an in vitro model of OA. DESIGN: To test the effects of GH and/or CS as a preventative treatment, cartilage explants were pretreated with the compound(s) using concentrations that showed no detrimental effect on chondrocyte viability. Interleukin-1alpha (IL-1alpha) was added to induce cartilage degradation, supernatant and explants were analyzed for proteoglycan degradation products, aggrecanase mRNA expression and activity, and for the release of inflammatory markers. RESULTS: Following treatment with IL 1alpha, 2 mg/mL dose of GH pretreatment was associated with a reduction of glycosaminoglycan release, reduced generation of the pathological interglobular domain aggrecan catabolites, decreased mRNA levels of ADAMTS-4 and -5 and reduced activity of ADAMTS-4. In contrast, CS alone did not have a significant effect on IL-1alpha-induced cartilage degradation and the addition of 0.4 mg/mL CS to 2 mg/mL GH did not further inhibit IL-1alpha-induced activity. Pretreatment with 2 mg/mL GH also reduced the release of inflammatory markers, prostaglandin E2 and nitric oxide induced by IL-1alpha while CS did not have a significant effect. CONCLUSIONS: The results suggest that GH prevents cartilage degradation mediated by aggrecanases ADAMTS-4 and -5, and may also reduce inflammation. This could be part of the mechanisms by which GH is effective in maintaining joint integrity and function, and preventing or delaying early symptoms of OA. PMID- 26958320 TI - Efficient, Low-Cost Nucleofection of Passaged Chondrocytes. AB - Nucleofection of chondrocytes has been shown to be an adequate method of transfection. Using Amaxa's nucleofection system, transfection efficiencies up to 89% were achievable for vector (pmaxGFP) and 98% for siRNA (siGLO) into passaged chondrocytes. However, such methods rely on costly commercial kits with proprietary reagents limiting its use in basic science labs and in clinical translation. Bovine-passaged chondrocytes were plated in serum reduced media conditionsand then nucleofected using various in laboratory-produced buffers. Cell attachment, confluency, viability, and transfection efficiency was assessed following nucleofection. For each parameter the buffers were scored and a final rank for each buffer was determined. Buffer denoted as 1M resulted in no significant difference for cell attachment, confluency, and viability as compared to non-nucleofected controls. Nucleofection in 1M buffer, in the absence of DNA vectors, resulted in increased col2, ki67, ccnd1 mRNA levels, and decreased col1 mRNA levels at 4 days of culture. Flow cytometry revealed that the transfection efficiency of 1M buffer was comparable to that obtained using the Amaxa commercial kit. siRNA designed against lamin A/C resulted in an average reduction of lamin A and C proteins to 19% and 8% of control levels, respectively. This study identifies a cost-effective, efficient method of nonviral nucleofection of bovine-passaged chondrocytes using known buffer formulations. Human-passaged chondrocytes could also be successfully nucleofected in 1M buffer. Thus this method should facilitate cost-efficient gene targeting of cells used for articular cartilage repair in a research setting. PMID- 26958321 TI - Effects of Dexamethasone Concentration and Timing of Exposure on Chondrogenesis of Equine Bone Marrow-Derived Mesenchymal Stem Cells. AB - OBJECTIVE: Dexamethasone is known to support mesenchymal stem cell (MSC) chondrogenesis, although the effects of dose and timing of exposure are not well understood. The objective of this study was to investigate these variables using a laboratory model of MSC chondrogenesis. DESIGN: Equine MSCs were encapsulated in agarose and cultured in chondrogenic medium with 1 or 100 nM dexamethasone, or without dexamethasone, for 15 days. Samples were analyzed for extracellular matrix (ECM) accumulation, prostaglandin E2 and alkaline phosphatase secretion, and gene expression of selected collagens and catabolic enzymes. Timing of exposure was evaluated by ECM accumulation after dexamethasone was withdrawn over the first 6 days, or withheld for up to 3 or 6 days of culture. RESULTS: ECM accumulation was not significantly different between 1 and 100 nM dexamethasone, but was suppressed ~40% in dexamethasone-free cultures. Prostaglandin E2 secretion, and expression of catabolic enzymes, including matrix metalloproteinase 13, and type X collagen was generally lowest in 100 nM dexamethasone and not significantly different between 1 nM and dexamethasone-free cultures. Dexamethasone could be withheld for at least 2 days without affecting ECM accumulation, while withdrawal studies suggested that dexamethasone supports ECM accumulation beyond day 6. CONCLUSION: One nanomolar dexamethasone supported robust cartilage-like ECM accumulation despite not having an effect on markers of inflammation, although higher concentrations of dexamethasone may be necessary to suppress undesirable hypertrophic differentiation. While early exposure to dexamethasone was not critical, sustained exposure of at least a week appears to be necessary to maximize ECM accumulation. PMID- 26958322 TI - Platelet-Rich Plasma May Improve Osteochondral Donor Site Healing in a Rabbit Model. AB - PURPOSE: The purpose of this study was to assess the effect(s) of platelet-rich plasma (PRP) on osteochondral donor site healing in a rabbit model. METHODS: Osteochondral donor sites 3 mm in diameter and 5 mm in depth were created bilaterally on the femoral condyles of 12 New Zealand White rabbits. Knees were randomized such that one knee in each rabbit received an intra-articular injection of PRP and the other received saline (placebo). Rabbits were euthanized at 3, 6, and 12 weeks following surgery. Repair tissue was evaluated using the International Cartilage Repair Society (ICRS) macroscopic and histological scores. RESULTS: No complications occurred as a result of the interventions. There was no significant difference in macroscopic scores between the 2 groups (5.5 +/- 3.8 vs. 3.8 +/- 3.5; P = 0.13). Subjective macroscopic assessment determined greater tissue infill with fewer fissures and a more cartilage-like appearance in PRP-treated knees. Overall ICRS histological scores were better in the PRP group compared with the placebo (9.8 +/- 2.0 vs. 7.8 +/- 1.8; P = 0.04). Histological scores were also higher in the PRP group compared with the placebo group at each time point. Greater glycosaminoglycan and type II collagen content were noted in the repair tissue of the PRP group compared with the placebo group. CONCLUSION: The results of this study indicate that PRP used as an intra articular injection may improve osteochondral healing in a rabbit model. PMID- 26958323 TI - Letter to the Editor for "Management of Osteoarthritis with Avocado/Soybean Unsaponifiables". PMID- 26958324 TI - Erratum: Response to the Letter to the Editor for "Management of Osteoarthritis with Avocado/Soybean Unsaponifiables". PMID- 26958325 TI - An overview of treatment options for urinary stones. AB - Urolithiasis has become a worldwide problem with the prevalence of the disease increasing over the past few decades. While various treatment modalities have evolved over the years, discrepancies exist regarding the clinical indications and the efficacy of each of these treatment options. In the present review, we aim to review the current treatment modalities for urinary tract stones to provide a better understanding on the therapeutic approaches as well as their clinical indications. PMID- 26958326 TI - The course and outcome of renal failure due to human leptospirosis referred to a hospital in North of Iran; A follow-up study. AB - BACKGROUND: Renal complication of leptospirosis is common and its clinical manifestations vary from urinary sediment changes to acute renal failure. The aim of this study was to determine the final outcome of renal involvement in leptospirosis. METHODS: This longitudinal prospective study included all serologically confirmed cases of leptospirosis with evidence of renal failure. All patients were followed for three months while all patients with renal failure were followed-up for one year. RESULTS: Fifty-one patients, 53.5+/-14.8 years (82.4% males) with acute renal failure were studied. Over the hospitalization period, 28 patients recovered, and seven (13.72%) patients died of multiple organ failure. At the time of discharge, 16 patients had mild renal failure. Over the follow-up period, all patients recovered but in two patients renal failure persisted at creatinine level of 1.5 mg/dl. CONCLUSION: Development of renal failure in leptospirosis is not rare. Recovery of renal function may last several months. However, most patients recover completely at least after one year. PMID- 26958327 TI - Salivary oxidant/ antioxidant status and hematological parameters in patients with recurrent aphthous stomatitis. AB - BACKGROUND: Recurrent aphthous stomatitis (RAS) is the most common inflammatory ulcerative condition of oral cavity. The aim of this study was to compare the levels of the salivary Malondialdehyde (MDA) and total antioxidant capacity (TAC) and blood parameter in RAS versus healthy controls. METHODS: This case-control study consisted of 28 patients with RAS and 28 age and sex -matched control without RAS. Cell blood count was assessed by sysmex system, serum iron and total iron binding capacity was measured by standard laboratory kit and for ferritin ELISA kit was utilized. Salivary TAC and MDA level determined using FRAP and TBARS method respectively. Statistical analysis was performed using SPSS Version 21, chi-square test was used to compare proportions, and student's t-test and Mann Whitney U-test were used for the comparison of quantitative variables. RESULTS: Salivary MDA level was significantly higher (p<0.001) and TAC level was significantly lower (p<0.042) in RAS as compared with the control group. Also, serum ferritin level was significantly higher in RAS patients (p<0.008). CONCLUSION: These findings indicate the alteration of oxidant/antioxidant status was observed in recurrent aphthous stomatitis, may be also associated with changing several hematinic parameters in this study. The finding maybe helpful to clarify the etiologies of RAS and possibely to improve the management or preventive options. PMID- 26958328 TI - Comparison of pyridostigmine and bisacodyl in the treatment of refractory chronic constipation. AB - BACKGROUND: Treatment of chronic constipation is creating one of the major problems for doctors and patients. Pyridostigmine increases the gastrointestinal motility through the effects on cholinesterase. It seems that this mechanism can reduce chronic constipation. The aim of this study was to compare the effects of pyridostigmine and bisacodyl on chronic constipation. METHODS: This study was conducted on 68 patients who suffered from chronic constipation. Patients were randomly divided into two groups of Pyridostigmine and bisacodyl in which each consisted of 34 patients, respectively. Bristol stool form score, straining defecation, the time of defecation, the number of defecation per week, sense of incomplete evacuation and self-digitation were collected by means of questionnaires and the data were compared. RESULTS: Sixty-eight patients with the mean age of 68.12+/-84.49 were studied. The mean difference in the frequency of defecation per week, VAS score, the time to defecation and the Bristol Stool form Scale in pre and post-treatment were 4.33+/-1.88, 5.96+/-2.29, 12.30+/-7.95 min and 2.10+/-0.95 in pyridostigmine group and 2.96+/-1.81, 4.06+/-2.22, 6.67+/-5.23 min and 1.41+/-0.84 in bisacodyl group, respectively. The significant difference was observed in both pyridostigmine and bisacodyl groups (P=0.005, P=0.002, P=0.002 and P=0.005, respectively). 60% and 32.3 of patients in pyridostigmine and bisacodyl groups recovered from self-digitations, respectively. In pyridostigmine and bisacodyl groups, 66.7% and 32.3 of them had improvement in the sense of incomplete defecation, respectively. CONCLUSION: Pyridostigmine and bisacodyl significantly improved the symptoms of chronic constipation similarly. PMID- 26958329 TI - Time Trend Analysis of Cancer? Incidence in Caspian Sea, 2004 - 2009: A Population-based Cancer Registries Study (northern Iran). AB - BACKGROUND: Cancer is a major public health problem in the world. In Iran especially after a transition to a dynamic and urban community, the pattern of cancer has changed significantly. An important change occurred regarding the incidence of cancer at the southern shores of the Caspian Sea, including Gilan, Mazandaran and Golestan province. This study was designed it investigate the epidemiology and changes in trend of cancer incidence in the geographic region of the Caspian Sea (North of Iran). METHODS: Data were collected from Cancer Registry Center report of Iran health deputy. Trends of incidence were analyzed by joinpoint regression analysis. RESULTS: During the study period year (2004 2009), 33,807 cases of cancer had been recorded in three provinces of Gilan, Mazandran and Golstan. Joinpoint analysis indicated a significant increase in age standardized incidence rates (ASR) with an average annual percentage change (AAPC) 10.3, 8.5 and 5.2 in Gilan, Mazandaran and Golestan, respectively. The most common cancer in these provinces were correspondingly cancer of stomach, breast, skin, colorectal and bladder, respectively. CONCLUSION: The incidence of cancer tends to be increasing in North of Iran. These findings warrant the epidemiologic studies are helpful in planning preventive programs and recognition of risk factors. PMID- 26958330 TI - The status of antioxidants, malondialdehyde and some trace elements in serum of patients with breast cancer. AB - BACKGROUND: There are studies that indicated dyshomeostasis of oxidant/antioxidant and trace elements in breast cancer patients, but the data regarding the status of these parameters in various stages of breast cancer are limited. The aim of this study was to highlight the status of these biochemical factors in various stages of breast cancer. METHODS: Fifty-eight breast cancers patients participated in this study and underwent staging work up for the assessment of disease stage. Serum total antioxidant capacity and lipid peroxidation were determined spectrophotometically. Glutathione peroxidase (GPX), catalase (CAT) and superoxide dismutase (SOD) levels were analyzed by ELISA method. The serum level of Cu, Mn and Zn was measured by atomic absorption spectrophotometer. Student t-test and one-way analysis of variance (ANOVA) were used to compare group means. RESULTS: All the patients included in the study classified as mild (stages I+II) and advanced stages (stages III+IV). Patients in advanced stage had lower serum antioxidant capacity and higher lipid peroxidation levels, but the differences were not statistically differet (P=0.690 and 0.666, respectively). Patients in advanced stage had higher, but not statistically different serum levels of CAT, GPX and SOD levels (p>0.05). Patients in both groups had to some extent similar serum Cu, Mn and Zn levels. CONCLUSION: There was no evidence of remarkable discrepancy in the status of analyzed factors in various stages of breast cancer. It seems that the severity of oxidative stress in different stages of breast cancer is similar to some extent. PMID- 26958331 TI - Serum C-reactive protein in asthma and its ability in predicting asthma control, a case-control study. AB - BACKGROUND: Increased serum high sensitive C-reactive protein (hs-CRP) in asthma and its association with disease severity has been investigated in many studies. This study aimed to determine serum hs-CRP status in asthma versus healthy controls and to examine its ability in predicting asthma control. METHODS: Serum CRP was measured by ELISA method using a high sensitive CRP kit. Severity of asthma was determined using Asthma Control Test. Spearman and chi square tests were used for association and correlation respectively. The predictive ability was determined by receiver operating characteristics (ROC) analysis. Accuracy was determined by determination of area under the ROC curve (AUC). RESULTS: A total of 120 patients and 115 controls were studied. Median serum hs-CRP in asthma was higher than control (P=0.001. In well controlled asthma the hs-CRP decreased significantly compared with poorly controlled (P=0.024) but still was higher than control (P=0.017). Serum hs-CRP at cutoff level of 1.45 mg/L differentiated the patients and controls with accuracy of 63.5 % (AUC= 0.635+/-0.037, P=0.001). Serum hs-CRP <= 2.15 mg/L predicted well controlled asthma with accuracy of 62.5% (AUC= 0.625+/-0.056, p=0.025). After adjusting for age, sex, weight and smoking, there was an independent association between serum hs-CRP >1.45 mg/L and asthma by adjusted OR=2.49, p=0.018). CONCLUSION: These findings indicate that serum hs CRP in asthma is higher than healthy control and increases with severity of asthma and decreases with. Thus, serum hs-CRP measurement can be helpful in predicting asthma control and treatment response. PMID- 26958332 TI - Peripheral blood lymphocytes are able to maintain their viability and basic function in normal urine. AB - BACKGROUND: Similar to inflammatory cells, peripheral blood mononuclear cells (PBMCs) can also infiltrate in to kidney and urinary tracts and subsequently excreted by urine. In this study we determined the viability rate and response to phytohemagglutinin-A (PHA) of human PBMCs in normal urine. METHODS: A number of 1*10(6) ficoll-hypaque isolated PBMCs were dispensed in 1 ml normal urine and 6 molar urea and RPMI-1640+FBS10 % were considered as negative and positive control, respectively. After 20, 60 and 120 minutes the viability of these cells was measured by trypan blue dye exclusion assay. 1*10(5) of PBMCs were isolated from urine and cultured as triplicate in RPMI-1640'supplemented with FBS 10% and PHA for 96hr. MTT assay was performed to determine the PBMCs response to PHA. These experiments were repeated three times independently. RESULTS: There was no significant difference between the viability rates of the PBMCs incubated in urine and positive control after 20, 60 and 120 minutes. Overall, there was a significant difference in trends of viability rate across the three groups (p<0.05). CONCLUSION: Our results showed that not only PBMCs remained remarkably alive in urine after 120 minutes, but can also respond to PHA up to 60 minutes after incubation in urine. These data open a new avenue in the designation for cell culture-based techniques in urine cell analysis. PMID- 26958333 TI - A study of the incidence of BCG vaccine complications in infants of Babol, Mazandaran (2011-2013). AB - BACKGROUND: BCG vaccination which is administered to prevent tuberculosis is sometimes associated with serious complications. This study aimed to determine the incidence of complications of BCG vaccination in Babol. METHODS: All infants who received BCG vaccination between 2011-2013 in health centers of Babol entered the study. Data regarding complications of vaccine were extracted according to the National Inventory of babies. All complicated cases were confirmed by the Academic Committee to review the adverse consequences of the vaccine. RESULTS: Among the 15984 vaccinated neonates, 150 (0.93%) cases presented lymphadenitis. 46.5% were females and 53.5% were males; 43% were rural residents and 57% were urban residents. No cases of lymphadenitis including 1% of lymphadenitis with abscess formation were recovered without treatment. Disseminated infection occurred in 3 cases of immune deficient patients who responded to the treatment. Most complications occurred during 4 months after vaccination. CONCLUSION: According to the results of this study, the prevalence of lymphadenitis in Babol was higher than the standard of WHO. This may be attributed to type and vaccine storage and injection technique. These findings justify further training of health-center workers. PMID- 26958334 TI - Difficulties in the diagnosis and management of alveolar hydatid disease: A case series. AB - BACKGROUND: Alveolar echinococcosis (AE) is a chronic, rare and sometimes lethal parasitic infection in humans, caused by the larval stage of the fox tapeworm Echinococcus multilocularis. This study aimed to investigate the clinical aspects and treatment outcomes of patients with alveolar hydatid disease. METHODS: The medical records of patients with alveolar echinococcosis admitted between 1997 and 2012 were reviewed. Diagnosis was confirmed by physical examination, ultrasonography and CT scanning and MRI. Various treatment techniques were used such as complete liver resection in seven (38.89%) patients, biliary bypass in two (11.11%) patients, laparotomy and tumor biopsy in eight (44.44%) patients and long term medical treatment in one (5.56%) patient. After discharge, all patients were followed to determine the effect of treatment, complications, recurrences and survival. RESULTS: A total of 18 patients with mean age of 46.11+/-15.14 years (range 23-74 years) were studied. The disease was more prevalent in women than men (78.9% vs 4, 21.1%, P=0.021). Fourteen (77.78%) patients live in Chenaran, a town located in Khorasan, Iran). Death occurred in (22.22%) patients after an average period of 45.70+/-7.50 months after disease onset. 14 remaining patients survived after a mean follow-up duration of 54.60+/-29.17 months. CONCLUSION: Diagnosis of alveolar echinococcosis should be considered in endemic area. Early diagnosis and treatment is associated with excellent outcome. PMID- 26958335 TI - Literature review in the treatment of calciphylaxis: A case with uncontrolled and severe secondary hyperparathyroidism. AB - BACKGROUND: Calciphylaxis is a serious disorder often observed in dialysis patients and less frequently in chronic renal failure patients with secondary hyperparathyroidism. Mortality rate increases following the development of calciphylaxis, immediate application of parathyroidectomy along with other treatment options may be lifesaving. CASE PRESENTATION: A 44-year-old male patient had been on regular hemodialysis three times per week, with 4-hour sessions since December 2003. The etiology of his renal failure was unknown and the patient had no systemic disease when hemodialysis was started, painful, erythematous skin lesions were detected over and around the external malleolus of the right foot. In the next two months, erythematous skin lesions gained a necrosed character and spread into the malleolar and posterior tibial region and back of the ankle in both extremities. The patient showed no clinical signs of recovery and despite anti-biotherapy, debridement and protective measures, the skin lesions got infected and presented as intolerable, painful wounds. The patient was diagnosed with calcific uremic arteriolopathy (CUA) and hospitalized for parathyroidectomy. All parathyroid glands were removed after having checked quick PTH intraoperatively. A small amount of parathyroid tissue was intramuscularly auto-implanted into the right forearm .Skin lesions showed fast improvement in further follow-ups. Three months after parathyroidectomy, iPTH value was measured as 1197 pg/ml. After 6 months of medical treatment, iPTH was found as 970 ng/L and we decided to remove the implanted parathyroid tissue from the right forearm. CONCLUSION: In this article, we present a case of calciphylaxis accompanied by severe secondary hyperparathyroidism. PMID- 26958336 TI - A case report of peritoneal tuberculosis with multiple miliary peritoneal deposits mimicking advanced ovarian carcinoma. AB - BACKGROUND: Peritoneal tuberculosis accounts 1-2% of all forms of tuberculosis. Peritoneal tuberculosis is an important differential diagnosis for ovarian cancer in women with ascites, adnexal mass and elevated cancer antigen 125 (CA125) levels. We report a case of a 32- year -old woman with multiple miliary peritoneal deposits mimicking advanced ovarian carcinoma. CASE PRESENTATION: A 32 year-old drug addicted woman presented with menometrorrhagia, fever and shivering, ascites and pelvis mass. Ultrasonography revealed a 53*65 mm cyst in left ovary and ascites. Multiple miliary peritoneal deposits were observed during laparatomy without any mass, histologic examination confirmed tuberculosis of uterus, tubes, omentum, liver and external surfaces of small intestine. Finally, the patient recovered with anti-tuberculosis treatment. CONCLUSION: These findings highlight considering tuberculosis in the differential diagnosis of any patients with adnexal mass, ascitis and elevated serum CA125 even with negative cytology and bacteriology test results. PMID- 26958337 TI - The ontogeny of choanocyte chambers during metamorphosis in the demosponge Amphimedon queenslandica. AB - BACKGROUND: The aquiferous body plan of poriferans revolves around internal chambers comprised of choanocytes, a cell type structurally similar to choanoflagellates. These choanocyte chambers perform a range of physiological and developmental functions, including the capture of food and the generation of stem cells. Despite the increasing interest for choanocytes as sponge stem cells, there is limited knowledge on the development of choanocyte chambers. Using a combination of cell lineage tracing, antibody staining and EdU labeling, here we examine the development of choanocytes and the chambers they comprise during metamorphosis in the marine demosponge Amphimedon queenslandica. RESULTS: Lineage tracing experiments show that larval epithelial cells transform into mesenchymal pluripotent stem cells, resembling archeocytes, within 24 h of initiating metamorphosis. By 36 h, some of these labeled archeocyte-like cells have differentiated into choanocytes that will form the first postlarval choanocyte chambers. Non-labeled cells also contribute to these primary choanocyte chambers, consistent with these chambers being a chimera of multiple transdifferentiated larval cell types and not the proliferation of a single choanocyte precursor. Moreover, cell proliferation assays demonstrate that, following the initial formation of choanocyte chambers, chambers grow at least partially by the proliferation of choanocytes within the chamber, although recruitment of individual cells into established chambers also appears to occur. EdU labeling of postlarvae and juveniles reveals that choanocyte chambers are the primary location of cell proliferation during metamorphosis. CONCLUSION: Our results show that multiple larval cell lineages typically contribute to formation of individual choanocyte chambers at metamorphosis, contrary to previous reports in other species that show sponge choanocyte chambers form clonally. Choanocytes in postlarval and juvenile A. queenslandica chambers can also divide, with choanocyte chambers being the primary location of cell proliferation. Interestingly, the level of cell proliferation varies greatly between chambers and appears to be contingent on the size, location and developmental state of the chamber. Small chambers on the periphery of the body tend to possess more dividing cells. As choanocytes can also dedifferentiate into archeocyte-like cells, cell proliferation in chambers may not only contribute to chamber growth and self-renewal but also increase the number of pluripotent archeocytes. PMID- 26958339 TI - Understanding clinical reasoning in osteopathy: a qualitative research approach. AB - BACKGROUND: Clinical reasoning has been described as a process that draws heavily on the knowledge, skills and attributes that are particular to each health profession. However, the clinical reasoning processes of practitioners of different disciplines demonstrate many similarities, including hypothesis generation and reflective practice. The aim of this study was to understand clinical reasoning in osteopathy from the perspective of osteopathic clinical educators and the extent to which it was similar or different from clinical reasoning in other health professions. METHODS: This study was informed by constructivist grounded theory. Participants were clinical educators in osteopathic teaching institutions in Australia, New Zealand and the UK. Focus groups and written critical reflections provided a rich data set. Data were analysed using constant comparison to develop inductive categories. RESULTS: According to participants, clinical reasoning in osteopathy is different from clinical reasoning in other health professions. Osteopaths use a two-phase approach: an initial biomedical screen for serious pathology, followed by use of osteopathic reasoning models that are based on the relationship between structure and function in the human body. Clinical reasoning in osteopathy was also described as occurring in a number of contexts (e.g. patient, practitioner and community) and drawing on a range of metaskills (e.g. hypothesis generation and reflexivity) that have been described in other health professions. CONCLUSIONS: The use of diagnostic reasoning models that are based on the relationship between structure and function in the human body differentiated clinical reasoning in osteopathy. These models were not used to name a medical condition but rather to guide the selection of treatment approaches. If confirmed by further research that clinical reasoning in osteopathy is distinct from clinical reasoning in other health professions, then osteopaths may have a unique perspective to bring to multidisciplinary decision-making and potentially enhance the quality of patient care. Where commonalities exist in the clinical reasoning processes of osteopathy and other health professions, shared learning opportunities may be available, including the exchange of scaffolded clinical reasoning exercises and assessment practices among health disciplines. PMID- 26958338 TI - Tolerability of the SQ-standardised grass sublingual immunotherapy tablet in patients treated with concomitant allergy immunotherapy: a non-interventional observational study. AB - BACKGROUND: The majority of allergic patients are poly-sensitized. For causal treatment by allergy immunotherapy (AIT) a single or few allergen products containing the clinically most relevant allergens are applied, but few data on tolerability of multiple application of AIT is available. The aim of our study was to investigate safety and tolerability in patients who started treatment by sublingual immunotherapy (SLIT) with the standardised SQ((r)) grass SLIT-tablet and were treated with concomitant AIT products. METHODS: In a non-interventional, open-label, observational study in Germany treatment of patients with the SQ((r)) grass SLIT-tablet and concomitant AIT (SCIT or SLIT) was documented between January 2012 and January 2014. Patients were followed at visits at first administration of the SQ((r)) grass SLIT-tablet and after 1-3 months of treatment. Tolerability of the treatment with the SQ((r)) grass SLIT-tablet and concomitant AIT were assessed by the physician and administration of AIT and adverse events (AEs) were recorded by the patients in diaries. AEs and adverse drug reactions (ADRs) were coded by using the Medical Dictionary for Regulatory Activities. RESULTS: In total, 181 patients were documented by 48 allergists and 160 patients treated with a concomitant AIT (SCIT 130, SLIT 30). AEs were reported in 58 (36.3 %) patients with concomitant AIT, and AEs considered related with the SQ((r)) grass SLIT-tablet in 49 (30.6 %) and with concomitant AIT in 18 (11.3 %) patients. Treatment was discontinued due to ADRs in 12 (7.5 %) patients and severity of ADRs was assessed mild or moderate in 29 (18.1 %), and severe in 20 (12.5 %) patients. Most common reactions were localised at the application site of the SQ((r)) grass SLIT-tablet as oral pruritus, throat irritation, oedema mouth and paraesthesia oral; no serious ADRs were reported. Overall tolerability of the SQ((r)) grass SLIT-tablet if given with concomitant AIT was assessed as "good" or "very good" by 91.0 % of patients and 91.6 % of physicians. CONCLUSIONS: In comparison to data from previous studies no increase in frequency of AEs or change in the tolerability profile was observed when SLIT with the SQ((r)) grass SLIT-tablet was administered with concomitant SCIT or SLIT. PMID- 26958340 TI - Some considerations on the current debate about typing resolution in solid organ transplantation. AB - BACKGROUND: The shortage of suitable organs and achieved tolerance are uncontested main concerns in transplantation. Long waiting lists for deceased donors and limited numbers of living donors are the current scenarios. Kidney grafts from living donors have better overall survival compared to cadaveric and require less aggressive immunosuppressive regimens. The human leukocyte antigen (HLA) labs have the key role to test the recipient and donors compatibility based on typing and antibody profile. The current standard molecular procedure in solid organ transplantation is low-resolution typing, at the antigen level. MAIN TEXT: In this commentary, the merits of high versus low degree of typing resolution in solid organ transplantation are discussed. Critical questions and reasons to bring high-resolution typing as a routine test in health system are considered. Specifically, with the introduction of the next-generation sequencing (NGS) in HLA, the pros and cons in living donation and benefits after deceased donation are critically evaluated. CONCLUSION: NGS has the potential to improve the transplant rates and the overall graft survival. Alternative strategies to increase in demanding the number of transplants are briefly highlighted. PMID- 26958341 TI - Automatically explaining machine learning prediction results: a demonstration on type 2 diabetes risk prediction. AB - BACKGROUND: Predictive modeling is a key component of solutions to many healthcare problems. Among all predictive modeling approaches, machine learning methods often achieve the highest prediction accuracy, but suffer from a long standing open problem precluding their widespread use in healthcare. Most machine learning models give no explanation for their prediction results, whereas interpretability is essential for a predictive model to be adopted in typical healthcare settings. METHODS: This paper presents the first complete method for automatically explaining results for any machine learning predictive model without degrading accuracy. We did a computer coding implementation of the method. Using the electronic medical record data set from the Practice Fusion diabetes classification competition containing patient records from all 50 states in the United States, we demonstrated the method on predicting type 2 diabetes diagnosis within the next year. RESULTS: For the champion machine learning model of the competition, our method explained prediction results for 87.4 % of patients who were correctly predicted by the model to have type 2 diabetes diagnosis within the next year. CONCLUSIONS: Our demonstration showed the feasibility of automatically explaining results for any machine learning predictive model without degrading accuracy. PMID- 26958342 TI - Occult pulmonary lymphangitic carcinomatosis presenting as 'chronic cough' with a normal HRCT chest. AB - A diagnosis of 'chronic cough' (CC) requires the exclusion of sinister pulmonary pathology, including infection and malignancy. We present a patient with a 3 month history of CC who had an extensive workup including a normal high resolution computed tomography of the chest (HRCT) 6 weeks prior to consultation at our center. He subsequently developed constitutional symptoms including weight loss and loss of appetite 5 weeks after initial consultation. A repeat HRCT chest and a subsequent whole body PET scan found that he had developed extensive pulmonary lymphangitic carcinomatosis (PLC) from a colon primary. Treatment of the colon cancer resulted in significant decrease in metastatic disease burden and cough resolution. PLC is a very rare cause of 'chronic cough' and incipient/occult PLC presenting with chronic cough and a normal initial HRCT chest has not been previously reported. PMID- 26958343 TI - Comparing the surgical timelines of military and civilians traumatic lower limb amputations. AB - The care and challenges of injured service have been well documented in the literature from a variety of specialities. The aim of this study was to analyse the surgical timelines of military and civilian traumatic amputees and compare the surgical and resuscitative interventions. A retrospective review of patient notes was undertaken. Military patients were identified from the Joint Theatre Trauma Registry (JTTR) in 2009. Civilian patients were identified using the hospital informatics database. Patient demographics, treatment timelines as well as surgical and critical care interventions were reviewed. In total 71 military patients sustained traumatic amputations within this time period. This represented 11% of the total injury demographic in 2009. Excluding upper limb amputees 46 patients sustained lower extremity amputations. These were investigated further. In total 21 civilian patients were identified in a 7-year period. Analysis revealed there was a statistically significant difference between patient age, ITU length of stay, blood products used and number of surgical procedures between military and civilian traumatic amputees. This study identified that military patients were treated for longer in critical care and required more surgical interventions for their amputations. Despite this, their time to stump closure and length of stay were not statistically different compared to civilian patients. Such observations reflect the importance of an Orthoplastic approach, as well as daily surgical theatre co-ordination and weekly multi-disciplinary meetings in providing optimal care for these complex patients. This study reports the epidemiological observed differences between two lower limb trauma groups. PMID- 26958344 TI - Hospitalization for pulmonary embolism associated with antecedent testosterone or estrogen therapy in patients found to have familial and acquired thrombophilia. AB - BACKGROUND: In patients hospitalized over a 4 year period for pulmonary embolism (PE), we assessed relationships of testosterone (TT) and estrogen therapy (ET) anteceding PE in patients found to have familial-acquired thrombophilia. METHODS: From 2011 through 2014, 347 patients were hospitalized in Cincinnati Mercy Hospitals with PE. Retrospective chart review was used to identify patients receiving TT or ET before PE; coagulation studies were done prospectively if necessary. RESULTS: Preceding hospitalization for PE, 8 of 154 men (5 %) used TT, and 24 of 193 women (12 %) used ET. The median number of months from the initiation of TT or ET to development of PE was 7 months in men and 18 months in women. Of the 6 men having coagulation measures, all had >= 1 thrombophilia, and of the 18 women having measures of coagulation, 16 had >= 1 thrombophilia. The sensitivity of a previous history of thrombosis to predict PE was low, 25 % (2/8 men), 4 % (1/24 women). CONCLUSIONS: Of 154 men hospitalized for PE, 8 (5 %) used TT, and of 193 women, 24 (12 %) used ET. Our data suggests that PE is an important complication of TT in men and ET in women, in part reflecting an interaction between familial and acquired thrombophilia and exogenous hormone use. PMID- 26958345 TI - High-quality genome sequence and description of Paenibacillus dakarensis sp. nov. AB - Strain FF9T was isolated in Dakar (Senegal) from a blood-culture taken from a 16 month-old child. MALDI-TOF analysis did not allow for identification. After sequencing, strain FF9T exhibited 98.18% similarity with the 16SrRNA sequence of Paenibacillus uliginis. A polyphasic study of phenotypic and genomic analyses showed that strain FF9T is Gram variable, catalase-positive, and presents a genome of 4,569,428 bp (one chromosome but no plasmid) with 4,427genes (4,352 protein-coding and 75 RNA genes (including 3 rRNA operons). The G+C content is 45.7%. On the basis of these genomic and phenotypic data analyses, we propose the creation of Paenibacillus dakarensis strain FF9T. PMID- 26958346 TI - Noncontiguous finished genome sequence and description of Paenibacillus ihumii sp. nov. strain AT5. AB - Paenibacillus ihumii sp. nov. strain AT5 (= CSUR 1981 = DSM 100664) is the type strain of P. ihumii. This bacterium was isolated from a stool sample from a morbidly obese French patient using the culturomics approach. The genome of this Gram-negative, facultative anaerobic, motile and spore-forming bacillus is 5 924 686 bp long. Genomic analysis identified 253 (5%) of 3812 genes as ORFans and at least 2599 (50.03%) of 5194 orthologous proteins not shared with the closest phylogenetic species. PMID- 26958347 TI - Citrobacter amalonaticus human urinary tract infections, Marseille, France. AB - Citrobacter amalonaticus is a bacterium that has rarely been reported as a human pathogen. Here we report four cases of C. amalonaticus infections occurring in patients hospitalized in Marseille, France, and review all cases described in the published literature. PMID- 26958348 TI - Implementation of routine foot check in patients with diabetes on hemodialysis: associations with outcomes. AB - OBJECTIVE: Patients with diabetes are at increased risk of foot ulcers, which may result in limb amputations. While regular foot care prevents ulcerations and amputation in those patients with diabetes not on dialysis, evidence is limited in diabetic hemodialysis patients. We investigated the association between the implementation of a routine foot check program in diabetic incident hemodialysis patients, and major lower limb amputations. METHODS: In 1/2008, monthly intradialytic foot checks were implemented as part of standard clinic care in all Fresenius Medical Care North America hemodialysis facilities. Patients with diabetes who initiated hemodialysis between 1/2004 and 12/2007 constituted the preimplementation cohort, and patients starting hemodialysis between 1/2008 and 12/2011 comprised the postimplementation cohort. In addition, we conducted a sensitivity analysis where we excluded patients from the clinics with <10 patients in the postimplementation period and where percent difference in patient with diabetes number between postimplementation and preimplementation period was <20%. We compared lower limb amputation rates employing Poisson regression models with offset of exposure time in these two cohorts. RESULTS: We studied 35 513 patients in the preimplementation and 25 779 patients in the postimplementation cohort. In the postimplementation cohort, amputation rate decreased by 17% (p=0.0034). The major lower limb amputation rate was 1.30 per 100 patient years in preimplementation and 1.07 in postimplementation cohort. These beneficial results were corroborated in the multivariate analysis (p=0.0175) and were even more pronounced in the sensitivity analysis (p=0.0083). CONCLUSION: Monthly foot checks are associated with reduction of major lower limb amputations in diabetic incident hemodialysis patients. PMID- 26958349 TI - Performance characteristics between TDx(r)FLx and TBATM-25FR for the therapeutic drug monitoring of methotrexate. AB - BACKGROUND: High-dose methotrexate (HDMTX) is used in the treatment of certain malignancies, including leptomeningeal metastases, systemic non-Hodgkin lymphoma, acute lymphoblastic leukemia, and osteosarcoma. High circulating levels of methotrexate can cause severe myelosuppression. The present study aimed to examine the differences in plasma MTX concentrations measured by two immunoassay systems currently available in the Japanese market, a TDX/FLX analyzer and a TBA 25FR analyzer. METHODS: A total of 69 plasma samples from 16 patients were assayed by a fluorescence polarization immunoassay technique using a TDx/FLx analyzer (Abbott Diagnostics, Chicago, Illinois, U.S.A.) and a homogeneous enzyme immunoassay technique using a TBA-25FR analyzer (Toshiba Medical Systems, Tokyo, Japan). RESULTS: Assay results were very consistent between the two systems, with good correlation 24 h after the start of treatment (TBA-25FR = 1.06?TDX/FLX, 1.31, r = 0.99), 48 h after the start of treatment (TBA-25FR = 1.00?TDX/FLX, +0.027, r > 0.99), and 72 h after the start of treatment (TBA-25FR = 1.09?TDX/FLX, +0.011, r > 0.99). CONCLUSIONS: The calibration curve spanned one order of magnitude with a linear working range from the lowest to the highest standard. The standard deviations show the excellent reproducibility of repeated measurements at each standard level for both immunoassay systems. However, when using the TBA-25FR, it is necessary to perform measurements in the low concentration range with care. PMID- 26958350 TI - Characterization of airag collected in Ulaanbaatar, Mongolia with emphasis on isolated lactic acid bacteria. AB - BACKGROUND: Airag, alcoholic sour-tasting beverage, has been traditionally prepared by Mongolian nomads who naturally ferment fresh mares' milk. Biochemical and microbiological compositions of airag samples collected in Ulaanbaatar, Mongolia and physiological characteristics of isolated lactic acid bacteria were investigated. METHODS: Protein composition and biochemical composition were determined using sodium dodecyl sulfate-gel electrophoresis and high performance liquid chromatography, respectively. Lactic acid bacteria were identified based on nucleotide sequence of 16S rRNA gene. Carbohydrate fermentation, acid survival, bile resistance and acid production in skim milk culture were determined. RESULTS: Equine whey proteins were present in airag samples more than caseins. The airag samples contained 0.10-3.36 % lactose, 1.44-2.33 % ethyl alcohol, 1.08-1.62 % lactic acid and 0.12-0.22 % acetic acid. Lactobacillus (L.) helveticus were major lactic acid bacteria consisting of 9 isolates among total 18 isolates of lactic acid bacteria. L. helveticus survived strongly in PBS, pH 3.0 but did not grow in MRS broth containing 0.1 % oxgall. A couple of L. helveticus isolates lowered pH of skim milk culture to less than 4.0 and produced acid up to more than 1.0 %. CONCLUSION: Highly variable biochemical compositions of the airag samples indicated inconsistent quality due to natural fermentation. Airag with low lactose content should be favorable for nutrition, considering that mares' milk with high lactose content has strong laxative effect. The isolates of L. helveticus which produced acid actively in skim milk culture might have a major role in production of airag. PMID- 26958351 TI - 'Locked rehabilitation': a need for clarification. AB - Recently, the term 'locked rehabilitation' has spread from commissioning to now also clinical parlance. This is without any clear service description or category of patient which this service manages. Differences between this new term and an established definition of low secure services are examined and reasons for the introduction of this terminology are discussed. This is contextualised within service development, payment by results and measures of quality. It is argued that there is a need for ongoing measurements of types of patients admitted to, and treatments offered by, this 'new' ward, as well as those within psychiatric intensive and low secure care services. PMID- 26958352 TI - Maintaining Adherence Programme: evaluation of an innovative service model. AB - Aims and method The Maintaining Adherence Programme (MAP) is a new model of care for patients with schizophrenia, schizoaffective disorder and bipolar affective disorder which aims to encourage adherence and prevent relapse. This evaluation, conducted by retrospective and prospective data collection (including patient questionnaires and staff interviews), aimed to describe MAP's impact on healthcare resource use, clinical measures and patient and staff satisfaction, following its implementation in a university National Health Service (NHS) foundation trust in England. We included 143 consenting patients who entered MAP before 31 March 2012. Results In-patient bed days and non-MAP NHS costs reduced significantly in the 18 months post-MAP entry. At 15-18 months post-MAP, Medication Adherence Rating Scale scores had improved significantly from baseline and there was a shift towards less severe clinician-rated disease categories. Based on patient surveys, 96% would recommend MAP to friends, and staff were also overwhelmingly positive about the service. Clinical implications MAP was associated with reduced cost of treatment, improvements in clinical outcomes and very high patient and staff satisfaction. PMID- 26958354 TI - Reasons for choosing to specialise in psychiatry: differences between core psychiatry trainees and consultant psychiatrists. AB - Aims and method This questionnaire study aimed to investigate the reasons for choosing to specialise in psychiatry in a sample of consultant psychiatrists and core trainee psychiatrists from within the West Midlands. Results Five reasons were significantly different between the core trainees and consultant psychiatrists. 'Emphasis on the patient as a whole' was identified as the most important reason for choosing to specialise for both core trainees and consultants. Six additional reasons were shared within the top ten 'very important' reasons, although their actual ranking varies. Clinical implications Some of the reasons for choosing to specialise in psychiatry were shown to significantly differ between core trainees and consultants. Numerous key driving factors have remained important over time for both groups, whereas other reasons have been replaced with a shift of importance towards lifestyle and humanitarian factors for core trainees. Consequently, it may be advisable not to use the reasons that consultants gave for choosing psychiatry when thinking about how to attract today's prospective psychiatrists. PMID- 26958353 TI - Development of a compassion-focused and contextual behavioural environment and validation of the Therapeutic Environment Scales (TESS). AB - Aims and method The aims of the study were to develop a scale sensitive enough to measure the interpersonal processes within a therapeutic environment, and to explore whether the new scale was sensitive enough to detect differences between settings, including a community based on compassionate mind and contextual behaviourism. The Therapeutic Environment Scales (TESS) were validated with 81 participants in three different settings: a specialist service for anxiety disorders, a specialist in-patient ward and a psychodynamic therapeutic community. Results TESS was found to be reliable and valid. Significant differences were seen between the services on the dimensions of compassion, belongingness, feeling safe, positive reinforcement of members' acts of courage, extinction and accommodation of unhelpful behaviours, inconsistency and high expressed emotion. These processes were over time associated with improved outcomes on a specialist service for anxiety disorders. Clinical implications The TESS offers a first step in exploring important interpersonal relationships in therapeutic environments and communities. An environment based on a compassionate mind and contextual behaviourism offers promise for the running of a therapeutic community. PMID- 26958355 TI - In-patient rehabilitation: clinical outcomes and cost implications. AB - Aims and method A retrospective evaluation was undertaken of the clinical and economic effectiveness of three in-patient rehabilitation units across one London National Health Service trust. Information on admission days and costs 2 years before and 2 years after the rehabilitation placement, length of rehabilitation placement and the discharge pathway was collected on 22 service users. Results There were statistically significant reductions in hospital admission days in the 2 years following rehabilitation compared with the 2 years before, further reflected in significantly lower bed costs. Longer length of rehabilitation placement was correlated with fewer admission days after the placement. A substantial proportion of the sample went into more independent living, some with no further admissions at follow-up. Clinical implications The findings suggest that in-patient rehabilitation is both clinically and cost effective: if benefits are sustained they will offset the cost of the rehabilitation placement. PMID- 26958356 TI - BJPsych Bulletin author mentoring scheme - helping trainees become published authors. AB - The publishing world is changing rapidly. Innovations include the move to open access, the rise of social media and the transition to digitalisation. In the light of these developments and with ever-increasing pressures on early career psychiatrists and trainees to publish papers in journals with a recognised pedigree, the BJPsych Bulletin is piloting an author mentoring scheme. Mentors will help clinicians and aspiring academics develop articles from a pedestrian manuscript to one that will hopefully provoke important debate and aid changes in current practices. The scheme will run on a trial basis for approximately 12 months and will then be reviewed. Mentoring has been found to have an important effect of research output including publication and grant success; the hope is that this new initiative at the BJPsych Bulletin will result in such dividends to all involved. PMID- 26958357 TI - Ending political abuse of psychiatry: where we are at and what needs to be done. AB - The number of reports of political activists falling victim to the political abuse of psychiatry is increasing. When the USSR first disintegrated, this practice virtually ceased to occur. What came in its place, however, was a disturbing collection of other forms of abuses, including human rights abuses, caused by a lack of resources, outdated treatment methods, a lack of understanding of individual human rights and a growing lack of tolerance in society. The number of cases of political abuse of psychiatry has increased since the 21st century began, particularly over the past few years in Russia, Belarus and Kazakhstan. PMID- 26958358 TI - Debating personal health budgets. AB - Personal health budgets (PHBs) were piloted in the National Health Service (NHS) in England between 2009 and 2012 and were found to have greater positive effects on quality of life and psychological well-being for those with mental health problems than commissioned service, as well as reducing their use of unplanned care. The government intends to extend PHBs in England for long-term conditions, including mental health, from April 2015. Given the importance of engaging clinicians in the next phase of PHB development, we provide an overview of the approach, synthesise the evidence from the national pilot and debate some of the opportunities and challenges. Balancing individual choice and recovery with concerns for risk, equity and the sustainability of existing community services is the central tension underpinning this innovation in mental health service delivery. PMID- 26958359 TI - End-of-life care in psychiatry: 'one chance to get it right'. AB - End-of-life care has been given increasing importance within healthcare settings. In June 2014, the Leadership Alliance for the Care of Dying People published One Chance to Get it Right. This nationally accepted guidance replaces previous end of-life care pathways such as the Liverpool Care Pathway and outlines how dying patients should be managed irrespective of setting. Increasingly, patients with mental health problems are entering their final days of life within psychiatric in-patient or acute hospital settings, and psychiatrists need to be aware of the new guidance and ready to implement it within psychiatric practice. PMID- 26958360 TI - Medical certification of incapacity in guardianship applications: conceptualising capacity. AB - Aims and method To examine how capacity is recorded in practice and compare this with the statutory definition, medical reports accompanying a random 10% sample (183 applications; 360 reports) of guardianship applications granted in 2011-2012 were examined. Results Clinicians did not explicitly use the statutory definition of capacity in 47.5% of reports. Over half of applications (56.4%) did not explicitly link the powers sought with the patient's vulnerabilities; such a link was less common in older adults (P = 0.0175). Clinical implications Guardianship orders can justify deprivation of liberty. Therefore it is important that such cases involve a thorough assessment of the person and that due process is followed, including adherence to the statutory definition of capacity. Practice could be improved by altering the paperwork required of medical practitioners, in line with mental health legislation. In addition, these findings should inform current legislation reform. PMID- 26958361 TI - How psychiatric trainees keep up to date: survey of psychiatric trainees' use of journals and other information sources. AB - Aims and method To gather information about psychiatric trainees' use of different information sources and academic materials, a questionnaire was distributed at the London Deanery Annual Psychiatry Trainee Conference and the training programmes of two teaching trusts. Results Participants returned 202 out of a total of 300 completed questionnaires (67%). Websites were the most commonly accessed information source ahead of textbooks, abstracts and journals. Year of training correlated positively with journal use and negatively with textbook use. Year of training also correlated positively with frequency of reading three journals published by the Royal College of Psychiatrists and with specific reasons for consulting journals, namely to improve clinical practice and inform trainees' own research. Clinical implications Respondents reported consulting websites more frequently than more traditional information sources but journals are still a widely used source of information for trainee clinicians. It is important that trainees continue to be equipped with skills to identify and access high-quality information at the point of clinical uncertainty. PMID- 26958362 TI - The exit examination should not function as a selection criterion. PMID- 26958363 TI - Correction. PMID- 26958365 TI - Crystal structure of aqua-(nitrato-kappaO)dioxido{2-[3-(pyridin-2-yl-kappaN)-1H 1,2,4-triazol-5-yl-kappaN (4)]phenolato-kappaO}uranium(VI) aceto-nitrile monosolvate monohydrate. AB - In the title compound, [U(C13H9N4O)(NO3)O2(H2O)].CH3CN.H2O, the U(VI) atom is seven-coordinated in a distorted penta-gonal-bipyramidal N2O5 manner by one tridentate triazole ligand, one monodentate nitrate anion and one water mol-ecule in the equatorial plane and by two uran-yl(VI) O atoms in the axial positions. In the crystal, the U(VI) complex mol-ecule is linked to the water and aceto-nitrile solvent mol-ecules through N-H?N, O-H?O and O-H?N hydrogen bonds, forming a sheet structure parallel to the bc plane. The sheets are further linked by an additional O-H?O hydrogen bond, forming a three-dimensional network. PMID- 26958364 TI - Association of a multibiomarker disease activity score at multiple time-points with radiographic progression in rheumatoid arthritis: results from the SWEFOT trial. AB - OBJECTIVES: In rheumatoid arthritis (RA), predictive biomarkers for subsequent radiographic progression (RP) could improve therapeutic choices for individual patients. We previously showed that the multibiomarker disease activity (MBDA) score in patients with newly diagnosed RA identified patients at risk for RP. We evaluated the MBDA score at multiple time-points as a predictor of RP during 2 years of follow-up. METHODS: A subset of patients with RA (N=220) from the Swedish Farmacotherapy (SWEFOT) trial were analysed for MBDA score, disease activity score of 28 joints (DAS28), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) at baseline (BL), month 3 and year 1, for predicting RP based on modified Sharp/van der Heijde scores at BL, year 1 and year 2. RESULTS: Patients with persistently low MBDA (<30) scores or those with a decrease from moderate (30-44) to low MBDA scores, did not develop RP during 2 years of follow up. The highest risk for RP during 2 years of follow-up (42%) was observed among patients with persistently high (>44) MBDA scores. Among methotrexate non responders with a high MBDA score at BL or month 3, significantly more of those who received triple therapy had RP at year 2 compared with those who received antitumour necrosis factor therapy. CONCLUSIONS: Measuring the MBDA score both before and during treatment in RA was useful for the assessment of individual patient risk for RP during 2 years of follow-up. In comparison with low CRP, ESR or DAS28, a low MBDA score at any time-point was associated with numerically lower proportions of RP. TRIAL REGISTRATION NUMBER: NCT00764725. PMID- 26958366 TI - Crystal structure of fac-tricarbon-yl(quinoline-2-carboxyl-ato-kappa(2) N,O)(tri phenyl-arsane-kappaAs)rhenium(I). AB - In the title compound, [Re(C10H6NO2)(CO)3{As(C6H5)3}], the coordination environment of Re(I) is that of a distorted octa-hedron. Three coordination sites are occupied by three carbonyl groups in a facial arrangement and the remaining three sites by tri-phenyl-arsane and deprotonated quinaldic acid in As-mono- and N,O-bidentate fashions, respectively. In the crystal, the complexes are linked through weak C-H?O hydrogen bonds, forming a three-dimensional network. It worth noting that, as far as we know, this complex is the first Re(I) tri-phenyl-arsane tricarbonyl compound to be reported. PMID- 26958367 TI - Crystal structure of N-hy-droxy-picolinamide monohydrate. AB - The crystal structure of the title compound, C6H6N2O2.H2O, consists of N-hy-droxy picolinamide and water mol-ecules connected through O-H?O and N-H?N hydrogen bonds. The O-H?O inter-actions and pi-pi stacking inter-actions between the pyridine rings [centroid-centroid distance = 3.427 (1) A] organize the components into columns extending along the b axis and the N-H?N hydrogen bonds link these columns into a two-dimensional framework parallel to (100). The N-hy-droxy picolinamide mol-ecule adopts a strongly flattened conformation and only the O-H group H atom deviates significantly from the mol-ecule best plane. The dihedral angle between the hydroxamic group and the pyridine ring is 5.6 (2) degrees . The conformation about the hydroxamic group C-N bond is Z and that about the C-C bond between the pyridine and hydroxamic groups is E. PMID- 26958368 TI - Crystal structure of a Pd4 carbonyl tri-phenyl-phosphane cluster [Pd4(CO)5(PPh3)4].2C4H8O, comparing solvates. AB - Attempts to synthesize Au-Pd heterometallic compounds from homonuclear palladium or gold complexes, [Pd(PtBu2)2] and [Au(PPh3)Cl] in a tetra-hydro-furan (THF) solution under a CO atmosphere resulted in a homonuclear Pd cluster, namely penta kis-(MU-carbonyl-kappa(2) C:C)tetra-kis-(tri-phenyl-phosphane kappaP)tetrapalladium(5 Pd-Pd) tetra-hydro-furan disolvate, [Pd4(CO)5(C18H15P)4].2C4H8O. The complex mol-ecule lies on a twofold rotation axis. The crystal structure is described in relation to the CH2Cl2 solvate previously determined by our group [Willocq et al. (2011 ?). Inorg. Chim. Acta, 373, 233-242], and in particular to the desolvated structure [Feltham et al. (1985 ?). Inorg. Chem. 24, 1503-1510]. It is assumed that the title compound transforms into the latter structure, upon gradual loss of solvent mol-ecules. In the title compound, the symmetry-unique THF solvent mol-ecule is linked to the complex mol-ecule by a weak C-H?O hydrogen bond. Contributions of disordered solvent molecules to the diffraction intensities, most likely associated with methanol, were removed with the SQUEEZE [Spek (2015). Acta Cryst. C71, 9-18] algorithm. PMID- 26958369 TI - Crystal structure of an organic-inorganic supra-molecular salt based on a 4,4' methyl-enebis(3,5-dimethyl-1H-pyrazol-2-ium) cation and a beta-octa-molybdate anion. AB - The asymmetric unit of the title compound, bis-[4,4'-methyl-enebis(3,5-dimethyl 1H-pyrazol-2-ium)] beta-octa-molybdate, (C11H18N4)2[Mo8O26] or (H4mbdpz)2[Mo8O26], is composed of an H4mbdpz(2+) cation and half of the beta octa-molybdate anion which is completed by inversion symmetry. The organic mol ecular units are engaged in a series of N-H?O hydrogen bonds with neighbouring anions, with N?O distances and N-H?O angles in the ranges 2.730 (2)-2.941 (2) A and 122-166 degrees , respectively. These inter-actions lead to the formation of a supra-molecular two-dimensional network parallel to the (010) plane. PMID- 26958370 TI - Crystal structure of 5-tert-but-yl-10,15,20-tri-phenyl-porphyrin. AB - In the title free base porphyrin, C42H34N4, the neighbouring N?N distances in the center of the ring vary from 2.818 (8) to 2.998 (8) A and the phenyl rings are tilted from the 24-atom mean plane at angles varying between 62.42 (2)-71.63 (2) degrees . The NH groups are involved in intra-molecular bifurcated N-H?(N,N) hydrogen bonds. The Ca-Cm-Ca angles vary slightly for the phenyl rings, between 124.19 (18)-126.17 (18) degrees . The largest deviation from the mean plane of the 24-atom macrocycle is associated with the meso carbon at the substituted tert butyl position, which is displaced from the mean plane by 0.44 (2) A. The free base porphyrin is characterized by a significant degree of ruffled (B 1u ) distortion with contributions from domed (A 2u ) and wave [Eg (y) and Eg (x)] modes. In the crystal, mol-ecules are linked by a number of weak C-H?pi inter actions, forming a three-dimensional framework. The structure was refined as a two-component inversion twin. PMID- 26958371 TI - Crystal structure of 1-benzyl-4-formyl-1H-pyrrole-3-carb-oxamide. AB - In the title compound, C13H12N2O2 (I), the mean planes of the pyrrole and benzyl rings are approximately perpendicular, forming a dihedral angle of 87.07 (4) degrees . There is an intra-molecular N-H?O hydrogen bond forming an S(7) ring motif. In the crystal, mol-ecules are linked via a pair of N-H?O hydrogen bonds forming inversion dimers. C-H?O hydrogen bonds link the dimers into chains along direction [10-1]. The chains are further linked by weak C-H?pi inter-actions forming layers parallel to the ac plane. PMID- 26958372 TI - Crystal structure of N-(3-oxo-butano-yl)-l-homoserine lactone. AB - The structure and absolute configuration of the title compound, C8H11NO4, which is a known quorum-sensing modulator, have been determined. The mol-ecule exhibits signs of an intra-molecular attractive carbon-yl-carbonyl n->pi* inter-action between the amide and lactone ester groups, specifically - a short contact of 2.709 (2) A between the amide oxygen atom and ester carbon atom, approach of the amide oxygen atom to the ester carbonyl group along the Burgi-Dunitz trajectory, at 99.1 (1) degrees , and pyramidalization of the ester carbonyl group by 1.1 (1) degrees . Moreover, a similar n->pi* inter-action is observed for the amide carbonyl group approached by the ketone oxygen donor. These inter-actions apparently affect the conformation of the uncomplexed mol-ecule, which adopts a different shape when bound to protein receptors. In the crystal, the mol-ecules form translational chains along the a axis via N-H?O hydrogen bonds. PMID- 26958373 TI - Supra-molecular hydrogen-bonding patterns in the N(9)-H protonated and N(7)-H tautomeric form of an N(6) -benzoyl-adenine salt: N (6)-benzoyl-adeninium nitrate. AB - In the title molecular salt, C12H10N5O(+).NO3 (-), the adenine unit has an N (9) protonated N(7)-H tautomeric form with non-protonated N(1) and N(3) atoms. The dihedral angle between the adenine ring system and the phenyl ring is 51.10 (10) degrees . The typical intra-molecular N(7)-H?O hydrogen bond with an S(7) graph set motif is also present. The benzoyl-adeninium cations also form base pairs through N-H?O and C-H?N hydrogen bonds involving the Watson-Crick face of the adenine ring and the C and O atoms of the benzoyl ring of an adjacent cation, forming a supra-molecular ribbon with R 2 (2)(9) rings. Benzoyl-adeninum cations are also bridged by one of the oxygen atoms of the nitrate anion, which acts as a double acceptor, forming a pair of N-H?O hydrogen bonds to generate a second ribbon motif. These ribbons together with pi-pi stacking inter-actions between the phenyl ring and the five- and six-membered adenine rings of adjacent mol ecules generate a three-dimensional supra-molecular architecture. PMID- 26958374 TI - Crystal structure of Sr2CdPt2 containing linear platinum chains. AB - The ternary inter-metallic title phase, distrontium cadmium diplatinum, was prepared from stoichiometric amounts of the elements at 1123 K for one day. The crystal structure adopts the ortho-rhom-bic Ca2GaCu2 structure type in space group Immm. Its main features are characterized by linear (Pt-Pt?Pt-Pt) n chains that are aligned along [010] and condensed through cadmium atoms forming Cd centred Pt2Cd2/2 rectangles to build up sheets parallel to (001). These sheets are connected to each other via alternating (001) sheets of strontium atoms along [001]. The strontium sheets consists of corrugated Sr4 units that are condensed to each other through edge-sharing parallel to [100]. PMID- 26958375 TI - Crystal structure of MU-oxalodi-hydroxamato-bis-[(2,2'-bipyrid-yl)(di-methyl sulfoxide-kappaO)copper(II)] bis-(perchlorate). AB - The centrosymmetric binuclear complex, [Cu2(C2H2N2O4)(C10H8N2)2(C2H6OS)2](ClO4)2, contains two copper(II) ions, connected through an N-deprotonated oxalodi hydroxamic acid dianion, two terminal 2,2'-bi-pyridine ligands, and two apically coordinating dimethylsulfoxide mol-ecules. Two non-coordinating perchlorate anions assure electrical neutrality. The copper(II) ions in the complex dication [Cu2(C10H8N2)2(MU-C2H2N2O4)(C2H6SO)2](2+) are in an O2N3 square-pyramidal donor environment, the Cu-Cu separation being 5.2949 (4) A. Two hydroxamate groups in the deprotonated oxalodi-hydroxamic acid are located trans to one each other. In the crystal, O-H?O and C-H?O hydrogen bonds link the complex cations to the perchlorate anions. Further C-H?O hydrogen bonds combine with pi-pi contacts with a centroid-to-centroid separation of 3.6371 (12) A to stack the mol-ecules along the a-axis direction. PMID- 26958376 TI - Crystal structure of catena-poly[[[trans-bis(aceto-nitrile kappaN)diaquacobalt(II)]-MU-pyrazine-kappa(2) N:N'] dinitrate]. AB - The central structural motif of the title coordination polymer, [Co(NO3)2(C4H4N2)(CH3CN)2(H2O)2] n , is a chain composed of Co(II) ions linked by bis-monodentate bridging pyrazine ligands through their N atoms. The Co(II) ion is located on an inversion center and is additionally coordinated by two O atoms of water mol-ecules and two N atoms of aceto-nitrile mol-ecules. The resultant N4O2 coordination sphere is distorted octa-hedral. The linear cationic chains extend parallel to the a axis and are aligned into layers parallel to the ac plane. Nitrate anions are situated in the space between the Co(II) chains and form O-H?O hydrogen bonds with the coordinating water mol-ecules, leading to a three-dimensional network structure. Weak C-H?O hydrogen bonds are also present between pyrazine or aceto-nitrile mol-ecules and the nitrate anions. PMID- 26958377 TI - Crystal structure of (2Z,5Z)-3-(4-meth-oxy-phen-yl)-2-[(4-meth-oxy-phenyl)-imino] 5-[(E)-3-(2-nitro-phen-yl)allyl-idene]-1,3-thia-zolidin-4-one. AB - In the title compound, C26H21N3O5S, the thia-zole ring is nearly planar with a maximum deviation of 0.017 (2) A, and is twisted with respect to the three benzene rings, making dihedral angles of 25.52 (12), 85.77 (12) and 81.85 (13) degrees . In the crystal, weak C-H?O hydrogen bonds and C-H?pi inter-actions link the mol-ecules into a three-dimensional supra-molecular architecture. Aromatic pi pi stacking is also observed between the parallel nitro-benzene rings of neighbouring mol-ecules, the centroid-to-centroid distance being 3.5872 (15) A. PMID- 26958378 TI - Bis[N-(2-hy-droxy-eth-yl)-N-iso-propyl-dithio-carbamato-kappa(2) S,S'](piperazine kappaN)cadmium: crystal structure and Hirshfeld surface analysis. AB - The title compound, [Cd(C6H12NOS2)2(C4H10N2)], features a distorted square pyramidal coordination geometry about the central Cd(II) atom. The di-thio carbamate ligands are chelating, forming similar Cd-S bond lengths and define the approximate basal plane. One of the N atoms of the piperazine mol-ecule, which adopts a chair conformation, occupies the apical site. In the crystal, supra molecular layers propagating in the ac plane are formed via hy-droxy-O-H?O(hy droxy), hy-droxy-O-H?N(terminal-piperazine) and coordinated-piperazine-N-H?O(hy droxy) hydrogen bonds; the layers also feature methine-C-H?S inter-actions and S?S [3.3714 (10) A] short contacts. The layers stack along the b-axis direction with very weak terminal-piperazine-N-H?O(hy-droxy) inter-actions between them. An evaluation of the Hirshfeld surfaces confirms the importance of inter-molecular inter-actions involving oxygen and sulfur atoms. PMID- 26958379 TI - Crystal structure of (4-cyano-pyridine-kappaN){5,10,15,20-tetrakis[4 (benzoyloxy)phenyl]porphyrinato-kappa(4) N}zinc-4-cyano-pyridine (1/1). AB - In the title compound, [Zn(C72H44N4O8)(C6H4N2)].C6H4N2 or [Zn(TPBP)(4-CNpy].(4 CNpy) [where TPBP and 4-CNpy are 5,10,15,20-(tetra-phenyl-benzoate)porphyrinate and 4-cyano-pyridine, respectively], the Zn(II) cation is chelated by four pyrrole-N atoms of the porphyrinate anion and coordinated by a pyridyl-N atom of the 4-CNpy axial ligand in a distorted square-pyramidal geometry. The average Zn N(pyrrole) bond length is 2.060 (6) A and the Zn-N(4-CNpy) bond length is 2.159 (2) A. The zinc cation is displaced by 0.319 (1) A from the N4C20 mean plane of the porphyrinate anion toward the 4-cyano-pyridine axial ligand. This porphyrinate macrocycle exhibits major saddle and moderate ruffling and doming deformations. In the crystal, the [Zn(TPBP)(4-CNpy)] complex mol-ecules are linked together via weak C-H?N, C-H?O and C-H?pi inter-actions, forming supra molecular channels parallel to the c axis. The non-coordinating 4-cyano-pyridine mol-ecules are located in the channels and linked with the complex mol-ecules, via weak C-H?N inter-actions and pi-pi stacking or via weak C-H?O and C-H?pi inter-actions. The non-coordinating 4-cyano-pyridine mol-ecule is disordered over two positions with an occupancy ratio of 0.666 (4):0.334 (4). PMID- 26958380 TI - Sodium potassium hydrogen citrate, NaKHC6H5O7. AB - The crystal structure of sodium potassium hydrogen citrate has been solved and refined using laboratory X-ray powder diffraction data, and optimized using density functional theory techniques. The Na(+) cation is six-coordinate, with a bond-valence sum of 1.17. The K(+) cation is also six-coordinate, with a bond valence sum of 1.08. The distorted [NaO6] octahedra share edges, forming chains along the a axis. The likewise distorted [KO6] octahedra share edges with the [NaO6] octahedra on either side of the chain, and share corners with other [KO6] octahedra, resulting in triple chains along the a axis. The most prominent feature of the structure is the chain along [111] of very short, very strong hydrogen bonds; the O?O distances are 2.414 and 2.400 A. The Mulliken overlap populations in these hydrogen bonds are 0.138 and 0.142 e, which correspond to hydrogen-bond energies of 20.3 and 20.6 kcal mol(-1). PMID- 26958381 TI - Crystal structure of (n-but-yl)[2-(2,6-di-meth-oxy-phen-yl)-6-methyl-phen-yl](2 meth-oxy-phen-yl)phospho-nium chloride monohydrate. AB - The title hydrated salt, C26H32O3P(+).Cl(-).H2O, contains four different substit uents (H, alkyl, aryl, and biar-yl) on the P atom. The P-H hydrogen atom of the phospho-nium ion was located in a difference Fourier map and refined without imposing additional restraints. In the crystal, the Cl(-) ions and water mol ecules are linked by pairs of Owater-H?Cl(-) hydrogen bonds and further linked to the phospho-nium cation by P-H(+)?Cl(-) and CAr/OMe-H?Owater hydrogen bonds to form an infinite one-dimensional chain along the [010] direction. PMID- 26958383 TI - Crystal structures of (S)-(+)-5-(3-bromo/chloro-4-isopropoxyphen-yl)-5-methyl imidazolidine-2,4-dione. AB - In (S)-(+)-5-(3-bromo-4-isopropoxyphen-yl)-5-methyl-imidazolidine-2,4-dione, C13H15BrN2O3, (I), the hydantoin groups are connected via inter-molecular N-H?O hydrogen bonds, forming a terraced sheet structure. In the chloro analogue, (S) (+)-5-(3-chloro-4-isopropoxyphen-yl)-5-methyl-imidazolidine-2,4-dione, C13H15ClN2O3, (II), the inter-molecular N-H?O hydrogen-bonding network forms a flat sheet. Comparison of the crystal structures reveals that (II) is more loosely packed than (I). PMID- 26958382 TI - Two new polytypes of 2,4,6-tri-bromo-benzo-nitrile. AB - Three polymorphs of 2,4,6-tri-bromo-benzo-nitrile (RCN), C7H2Br3N, two of which are novel and one of which is a redetermination of the original structure first determined by Carter & Britton [(1972). Acta Cryst. B28, 945-950] are found to be polytypic. Each has a layer structure which differs only in the stacking of the layers. Each layer is composed of mol-ecules associated through C N?Br contacts which form R (2) 2(10) rings. Two such rings are associated with each N atom; one with each ortho-Br atom. No new polytypes of 1,3,5-tri-bromo-2-iso-cyano-benzene (RNC) were found but a re-determination of the original structure by Carter et al. [(1977). Cryst. Struct. Commun. 6, 543-548] is presented. RNC was found to be isostructural with one of the novel polytypes of RCN. Unit cells were determined for 23 RCN samples and 11 RNC samples. Polytypes could not be distinguished based on crystal habits. In all four structures, each mol-ecule of the asymmetric unit lies across a mirror plane. PMID- 26958384 TI - Crystal structure and conformational analysis of 2-hy-droxy-3-(2-methyl-prop-1-en 1-yl)naphthalene-1,4-dione. AB - In the structure of the title compound, C14H12O3, the substituent side chain, in which the H atoms of both methyl groups are disordered over six equivalent sites, lies outside of the plane of the naphthalene-dione ring. The ring-to-chain C-C-C C torsion angles are 50.7 (3), -176.6 (2) and 4.9 (4) degrees . An intra molecular meth-yl-hy-droxy C-H?O hydrogen bond is present. In the crystal, mol ecules are primarily connected by inter-molecular O-H?O hydrogen bonds, forming a centrosymmetric cyclic dimer motif [graph set R 2 (2)(10)]. Also present is a weak inter-molecular C-H?O hydrogen bond linking the dimers and a weak pi-pi ring inter-action [ring centroid separation = 3.7862 (13) A], giving layers parallel to (10-3). PMID- 26958385 TI - Two mixed-ligand lanthanide-hydrazone complexes: [Pr(NCS)3(pbh)2].H2O and [Nd(NCS)(NO3)(pbh)2(H2O)]NO3.2.33H2O [pbh is N'-(pyridin-2-ylmethylidene)benzo hydrazide, C13H11N3O]. AB - The gel-mediated syntheses and crystal structures of [N'-(pyridin-2-ylmethylidene kappaN)benzohydrazide-kappa(2) N',O]tris(thiocyanato-kappaN)praseodymium(III) mono-hydrate, [Pr(NCS)3(C13H11N3O)2].H2O, (I), and aqua(nitrato-kappa(2) O,O')[N' (pyri-din-2-ylmethylidene-kappaN)benzohydrazide-kappa(2) N',O](thiocyanato kappaN)neo-dym-ium(III) nitrate 2.33-hydrate, [Nd(NCS)(NO3)(C13H11N3O)2(H2O)]NO3.2.33H2O, (II), are reported. The Pr(3+) ion in (I) is coordinated by two N,N,O-tridentate N'-(pyridin-2 ylmethylidene)benzohydrazide (pbh) ligands and three N-bonded thio-cyanate ions to generate an irregular PrN7O2 coordination polyhedron. The Nd(3+) ion in (II) is coordinated by two N,N,O-tridentate pbh ligands, an N-bonded thio-cyanate ion, a bidentate nitrate ion and a water mol-ecule to generate a distorted NdN5O5 bicapped square anti-prism. The crystal structures of (I) and (II) feature numerous hydrogen bonds, which lead to the formation of three-dimensional networks in each case. PMID- 26958386 TI - Poly[MU2-aqua-aqua-[MU3-N-butyl-N-(2-hy-droxy-ethyl)di-thio-carbamato-kappa(3) O,O':S]sodium]. AB - In the title compound, [Na(C7H14NOS2)(H2O)2] n , the Na(I) cation is coordinated by five O atoms [Na-O = 2.3142 (11)-2.4677 (10) A] from three aqua and two N butyl-N-(2-hy-droxy-eth-yl)di-thio-carbamate (L) ligands and one S atom [Na-S = 3.0074 (6) A] from a third L ligand in a highly distorted octa-hedral geometry. Two aqua ligands related by an inversion center bridge two Na(I) cations, and each L ligand coordinates three Na(I) cations, leading to a layered arrangement aligned parallel to the bc plane. Inter-molecular O-H?S hydrogen bonds are observed in the inner part of each polymeric layer; these are packed along the a axis and held together by weak van der Waals forces. PMID- 26958387 TI - Crystal structures of (1E,4E)-1,5-bis-(5-bromo-thio-phen-2-yl)-2,4-di-methyl penta-1,4-dien-3-one and (E)-4-(5-bromo-thio-phen-2-yl)-1,3-di-phenyl-but-3-en-2 one. AB - The title compounds, C15H12Br2OS2, (I), and C20H15BrOS, (II), were synthesized by employing Claisen-Schmidt condensation of pentan-3-one and di-benzyl-acetone with 5-bromo-thio-phene-2-carbaldehyde in the presence of methano-lic KOH. Even though 1:2 products were expected in both of the reactions, 1:2 and 1:1 products were obtained as (I) and (II), respectively. In (I), the two methyl groups are trans to each other, 29.5 (7) and 28.7 (7) degrees away from the central carbonyl bond between them, whereas the two phenyl rings of di-benzyl-acetone subtend a dihedral angle of 53.09 (18) degrees . In the crystal of (I), C-H?O hydrogen bonds define mol-ecular chains along c. A second type of mol-ecular chain is formed along b by means of C-Br?pi inter-actions. These two families of mol ecular chains are stacked by pi-pi inter-actions, forming a three-dimensional supra-molecular architecture. In (II), similar C-H?O hydrogen bonds as in (I) define inversion dimers, whilst C-H?.pi inter-actions build a staircase structure along the a axis. PMID- 26958388 TI - Crystal structures of (2,2'-bipyridyl-kappa(2) N,N')bis-[N,N-bis-(2-hydroxy-eth yl)di-thio-carbamato-kappa(2) S,S']zinc dihydrate and (2,2'-bipyridyl-kappa(2) N,N')bis-[N-(2-hydroxy-eth-yl)-N-iso-propyl-dithio-carbamato-kappa(2) S,S']zinc. AB - The common feature of the title compounds, [Zn(C5H10NO2S2)2(C10H8N2)].2H2O, (I), and [Zn(C6H12NOS2)2(C10H8N2)], (II), is the location of the Zn(II) atoms on a twofold rotation axis. Further, each Zn(II) atom is chelated by two symmetry equivalent and symmetrically coordinating di-thio-carbamate ligands and a 2,2'-bi pyridine ligand. The resulting N2S4 coordination geometry is based on a highly distorted octa-hedron in each case. In the mol-ecular packing of (I), supra molecular ladders mediated by O-H?O hydrogen bonding are found whereby the uprights are defined by {?HO(water)?HO(hy-droxy)?} n chains parallel to the a axis and with the rungs defined by 'Zn[S2CN(CH2CH2)2]2'. The water mol-ecules connect the ladders into a supra-molecular layer parallel to the ab plane via water-O-H?S and pyridyl-C-H?O(water) inter-actions, with the connections between layers being of the type pyridyl-C-H?S. In (II), supra-molecular layers parallel to the ab plane are sustained by hy-droxy-O-H?S hydrogen bonds with connections between layers being of the type pyridyl-C-H?S. PMID- 26958389 TI - Crystal structure of apatite type Ca2.49Nd7.51(SiO4)6O1.75. AB - The title compound, Ca2+x Nd8-x (SiO4)6O2-0.5x (x = 0.49), was synthesized at 1873 K and rapidly quenched to room temperature. Its structure has been determined using single-crystal X-ray diffraction and compared with results reported using neutron and X-ray powder diffraction from samples prepared by slow cooling. The single-crystal structure from room temperature data was found to belong to the space group P63/m and has the composition Ca2.49Nd7.51(SiO4)6O1.75 [dicalcium octa-neodymium hexa-kis-(ortho-silicate) dioxide], being isotypic with natural apatite and the previously reported Ca2Nd8(SiO4)6O2 and Ca2.2Nd7.8(SiO4)6O1.9. The solubility limit of calcium in the equilibrium state at 1873 K was found to occur at a composition of Ca2+x Nd8-x (SiO4)6O2-0.5x , where x = 0.49. PMID- 26958390 TI - catena-Poly[bis(1,3-benzo-thia-zol-3-ium) [[di-chlorido-anti-monate(III)]-di-MU chlorido-MU-oxido-[chlorido-anti-monate(III)]-MU-chlorido]]. AB - The title compound, {(C7H6NS)2[Sb2Cl6O]} n , contains two benzo-thia-zolidium cations and one tri-MU-chlorido-tri-chlorido-MU-oxido-di-anti-monate(III) anion. The structure of the inorganic cation may be described as as being built up from two polyhedra, i.e. a square-pyramidal SbCl4O and a distorted octa-hedral SbOCl5 unit, sharing a common face (comprising the O atom and two Cl atoms). The two benzo-thia-zole cations are quasi-planar and subtend a dihedral angle of 19.93 (5) degrees . The crystal packing can be described by alternating (100) layers and [001] chains of the organic cations and inorganic anions connected through an extensive three-dimensional network of N-H?Cl, C-H?O and C-H?Cl hydrogen bonds. This is consolidated by slipped pi-pi stacking, with centroid-to-centroid distances between the benzo-thia-zole rings of 3.7111 (18)-3.8452 (16) A. These inter-actions link the mol-ecules within the layers and also link the layers together and reinforce the cohesion of the ionic structure. PMID- 26958392 TI - Crystal structure of (Na0.70)(Na0.70,Mn0.30)(Fe(3+),Fe(2+))2Fe(2+)(VO4)3, a sodium-, iron- and manganese-based vanadate with the alluaudite-type structure. AB - The title compound, sodium (sodium,manganese) triiron(II,III) tris[vana-date(V)], (Na0.70)(Na0.70,Mn0.30)(Fe(3+),Fe(2+))2Fe(2+)(VO4)3, was prepared by solid-state reactions. It crystallizes in an alluaudite-like structure, characterized by a partial cationic disorder. In the structure, four of the 12 sites in the asymmetric unit are located on special positions, three on a twofold rotation axis (Wyckoff position 4e) and one on an inversion centre (4b). Two sites on the twofold rotation axis are entirely filled by Fe(2+) and V(5+), whereas the third site has a partial occupancy of 70% by Na(+). The site on the inversion centre is occupied by Na(+) and Mn(2+) cations in a 0.7:0.3 ratio. The remaining Fe(2+) and Fe(3+) atoms are statistically distributed on a general position. The three dimensional framework of this structure is made up of kinked chains of edge sharing [FeO6] octa-hedra stacked parallel to [10-1]. These chains are held together by VO4 tetra-hedral groups, forming polyhedral sheets perpendicular to [010]. Within this framework, two types of channels extending along [001] are present. One is occupied by (Na(+)/Mn(2+)) while the second is partially occupied by Na(+). The mixed site containing (Na(+)/Mn(2+)) has an octa-hedral coordination sphere, while the Na(+) cations in the second channel are coordinated by eight O atoms. PMID- 26958391 TI - Crystal structure of (MU-1,4-di-carb-oxy-butane-1,4-di-carboxyl-ato)bis-[bis-(tri phenyl-phosphane)silver(I)] di-chloro-methane tris-olvate. AB - The mol-ecular structure of the tetra-kis(tri-phenyl-phosphan-yl)disilver salt of butane-1,1,4,4-tetra-carb-oxy-lic acid, [Ag2(C8H8O8)(C18H15P)4].3CH2Cl2, crystallizes with one and a half mol-ecules of di-chloro-methane in the asymmetric unit. The coordination complex exhibits an inversion centre through the central CH2-CH2 bond. The Ag(I) atom has a distorted trigonal-planar P2O coordination environment. The packing is characterized by inter-molecular T shaped pi-pi inter-actions between the phenyl rings of the PPh3 substituents in neighbouring mol-ecules, forming a ladder-type superstructure parallel to [010]. These ladders are arranged in layers parallel to (101). Intra-molecular hydrogen bonds between the OH group and one O atom of the Ag-bonded carboxyl-ate group results in an asymmetric bidendate coordination of the carboxyl-ate moiety to the Ag(I) ion. PMID- 26958393 TI - Crystal structure of trans-(1,8-dibutyl-1,3,6,8,10,13-hexa-aza-cyclo-tetra-decane kappa(4) N (3),N (6),N (10),N (13))bis-(isonicotinato-kappaO)nickel(II) determined from synchrotron data. AB - The title compound, [Ni(C6H4NO2)2(C16H38N6)], was prepared through self-assembly of a nickel(II) aza-macrocyclic complex with isonicotinic acid. The Ni(II) atom is located on an inversion center and exhibits a distorted octa-hedral N4O2 coordination environment, with the four secondary N atoms of the aza-macrocyclic ligand in the equatorial plane [average Ni-Neq = 2.064 (11) A] and two O atoms of monodentate isonicotinate anions in axial positions [Ni-Oax = 2.137 (1) A]. Intra molecular N-H?O hydrogen bonds between one of the secondary amine N atoms of the aza-macrocyclic ligand and the non-coordinating carboxyl-ate O atom of the anion stabilize the mol-ecular structure. Inter-molecular N-H?N hydrogen bonds, as well as pi-pi inter-actions between neighbouring pyridine rings, give rise to the formations of supra-molecular ribbons extending parallel to [001]. PMID- 26958394 TI - Crystal structure of bis-(1,3-di-amino-propane-kappa(2) N,N')bis-[2-(4-nitro-phen yl)acetato-kappaO]cadmium. AB - In the structure of the title compound, [Cd(C8H6NO4)2(C3H10N2)2], the Cd(II) atom is located on a center of symmetry with one independent Cd-O distance of 2.3547 (17) A and two Cd-N distances of 2.3265 (18) and 2.3449 (19) A. The Cd(II) atom has an overall octa-hedral coordination environment. Several types of hydrogen bonding inter-actions are evident. Both intra- and inter-molecular inter-actions occur between the amino groups and the O atoms of the acetate group. These N-H?O hydrogen bonds lead to a layered structure extending parallel to the bc plane. In addition, weak inter-molecular C-H?O inter-actions involving the nitro groups exist, leading to the formation of a three-dimensional network structure. PMID- 26958395 TI - Crystal structure of zwitterionic 2-[bis-(2-meth-oxy-phen-yl)phosphanium-yl]-4 methyl-benzene-sulfonate monohydrate di-chloro-methane monosolvate. AB - In the title compound, C21H21O5PS.H2O.CH2Cl2, the phospho-nium-sulfonate zwitterion has the acidic H atom located on the P atom rather than the sulfonate group. The S-O bond lengths [1.4453 (15)-1.4521 (14) A] are essentially equal. In the crystal, the water mol-ecules bridge two zwitterions via Owater-H?Osulfonate hydrogen bonds into a centrosymmetric dimer. The dimers are further linked by weak CAr-yl-H?Osulfonate hydrogen bonds into chains extending along [100]. The PH(+) group is not involved in inter-molecular inter-actions. PMID- 26958396 TI - Dimethyl and diethyl esters of 5,6-bis-(pyridin-2-yl)pyrazine-2,3-di-carb-oxy-lic acid: a comparison. AB - In dimethyl 5,6-bis-(pyridin-2-yl)pyrazine-2,3-di-carboxyl-ate, C18H14N4O4, (I), and diethyl 5,6-bis-(pyridin-2-yl)pyrazine-2,3-di-carboxyl-ate, C20H18N4O4, (II), the dimethyl and diethyl esters of 5,6-bis-(pyridin-2-yl)pyrazine-2,3-di-carb-oxy lic acid, the orientation of the two pyridine rings differ. In (I), pyridine ring B is inclined to pyrazine ring A by 44.8 (2) degrees and the pyridine and pyrazine N atoms are trans to one another, while pyridine ring C is inclined to the pyrazine ring by 50.3 (2) degrees , with the pyridine and pyrazine N atoms cis to one another. In compound (II), the diethyl ester, which possesses twofold rotation symmetry, the pyridine ring is inclined to the pyrazine ring by 40.7 (1) degrees , with the pyridine and pyrazine N atoms trans to one another. In the crystal of (I), mol-ecules are linked by C-H?N hydrogen bonds, forming chains along [001]. The chains are linked by C-H?pi inter-actions, forming a three dimensional structure. In the crystal of (II), mol-ecules are linked via C-H?O hydrogen bonds, forming a three-dimensional framework. There are C-H?pi inter actions present within the framework. PMID- 26958397 TI - 6-[6-(Pyridin-2-yl)-1,2,4,5-tetra-zin-3-yl]pyridin-3-amine monohydrate. AB - The packing of the title compound, C12H9N7.H2O, is dominated by hydrogen bonding and pi-stacking. Layers parallel to [010] are established by hydrogen bonds involving all amine donor functions and one of the water donor functions, while the remaining water donor function enables the stacking of the layers along [10 1], which is accompanied by pi-stacking. In the molecule, the plane of the central tetra-zine ring forms angles of 5.33 (7) and 19.84 (8) degrees with the adjacent 3-amine-pyridine and pyridine rings, respectively. PMID- 26958398 TI - 2-({[(Pyridin-1-ium-2-ylmeth-yl)carbamo-yl]form-amido}-meth-yl)pyridin-1-ium bis (3,5-di-carb-oxy-benzoate): crystal structure and Hirshfeld surface analysis. AB - The asymmetric unit of the title salt, C14H16N4O2 (2+).2C9H5O6 (-), comprises half a dication, being located about a centre of inversion, and one anion, in a general position. The central C4N2O2 group of atoms in the dication are almost planar (r.m.s. deviation = 0.009 A), and the carbonyl groups lie in an anti disposition to enable the formation of intra-molecular amide-N-H?O(carbon-yl) hydrogen bonds. To a first approximation, the pyridinium and amide N atoms lie to the same side of the mol-ecule [Npy-C-C-Namide torsion angle = 34.8 (2) degrees ], and the anti pyridinium rings are approximately perpendicular to the central part of the mol-ecule [dihedral angle = 68.21 (8) degrees ]. In the anion, one carboxyl-ate group is almost coplanar with the ring to which it is connected [Cben-Cben-Cq-O torsion angle = 2.0 (3) degrees ], whereas the other carboxyl-ate and carb-oxy-lic acid groups are twisted out of the plane [torsion angles = 16.4 (3) and 15.3 (3) degrees , respectively]. In the crystal, anions assemble into layers parallel to (10-4) via hy-droxy-O-H?O(carbon-yl) and charge-assisted hy droxy-O-H?O(carboxyl-ate) hydrogen bonds. The dications are linked into supra molecular tapes by amide-N-H?O(amide) hydrogen bonds, and thread through the voids in the anionic layers, being connected by charge-assisted pyridinium-N O(carboxyl-ate) hydrogen bonds, so that a three-dimensional architecture ensues. An analysis of the Hirshfeld surface points to the importance of O-H?O hydrogen bonding in the crystal structure. PMID- 26958399 TI - Rietveld refinement of the crystal structures of Rb2 XSi5O12 (X = Ni, Mn). AB - The synthetic leucite silicate framework mineral analogues Rb2 XSi5O12 {X = Ni [dirubidium nickel(II) penta-silicate] and Mn [dirubidium manganese(II) penta silicate]} have been prepared by high-temperature solid-state synthesis. The results of Rietveld refinements, using X-ray powder diffraction data collected using Cu Kalpha X-rays, show that the title compounds crystallize in the space group Pbca and adopt the cation-ordered structure of Cs2CdSi5O12 and other leucites. The structures consist of tetra-hedral SiO4 and XO4 units sharing corners to form a partially substituted silicate framework. Extraframework Rb(+) cations sit in channels in the framework. All atoms occupy the 8c general position for this space group. In these refined structures, silicon and X atoms are ordered onto separate tetra-hedrally coordinated sites (T-sites). However, the Ni displacement parameter and the Ni-O bond lengths suggest that for the X = Ni sample, there may actually be some T-site cation disorder. PMID- 26958400 TI - Crystal structure of diethyl 3-(3-chloro-phen-yl)-2,2-di-cyano-cyclo-propane-1,1 di-carboxyl-ate. AB - In the racemic title compound, C17H15ClN2O4, which has been synthesized and the crystal structure of the solvent-free mol-ecule determined, the angle between the planes of the benzene and cyclo-propane rings is 54.29 (10) degrees . The mol ecular conformation is stabilized by two weak intra-molecular C-H?Ocarbox-yl inter-actions. In the crystal, C-H?O hydrogen bonds form centrosymmetric cyclic R 2 (2)(10) dimers which are linked into chain substructures extending along c. Further C-H?Nnitrile hydrogen bonding, including a centrosymmetric cyclic R 2 (2)(14) association, link the chain substructures, forming a two-dimensional layered structure extending across the approximate ab plane. No significant pi-pi or halogen-halogen inter-molecular inter-actions are present in the crystal. PMID- 26958401 TI - Crystal structure of diethyl 2-acet-oxy-2-[3-(4-nitro-phen-yl)-3-oxo-1-phenyl prop-yl]malonate. AB - In the racemic title compound, C24H25NO9, the dihedral angle between the planes of the two benzene-ring systems is 80.16 (6) degrees , while the side-chain conformation is stabilized by a methyl-ene-carboxyl C-H?O hydrogen bond. Weak inter-molecular C-H?O hydrogen bonds form inversion dimers [graph set R 2 (2)(16)] which are linked into chains extending along a. Further C-H?O hydrogen bonding extends the structure along b through cyclic R 2 (2)(10) motifs. Although no pi-pi aromatic ring inter-actions are present in the structure, C-H?pi ring inter-actions across c generate an overall three-dimensional supra-molecular structure. PMID- 26958402 TI - Crystal structures of methyl (E)-3-(2-chloro-phen-yl)-2-({2-[(E)-2-nitro-vin yl]phen-oxy}meth-yl)acrylate and methyl (E)-2-({4-chloro-2-[(E)-2-nitro-vin yl]phen-oxy}meth-yl)-3-(2-chloro-phen-yl)acrylate. AB - The title compounds, C19H16ClNO5, (I), and C19H15Cl2NO5, (II), both crystallize in the monoclinic space group P21/n. They differ essentially in the orientation of the methyl acetate group, with the C=O bond directed towards the NO2 group in (I) but away from it in (II). In compound (I), the mean plane of the methyl acrylate unit is planar, with a maximum deviation of 0.0044 (2) A for the methyl C atom, while in (II) this deviation is 0.0147 A. The inter-planar angles between the two aromatic rings are 74.87 (9) and 75.65 (2) degrees for compounds (I) and (II), respectively. In both compounds, the methyl acrylate and nitro-vinyl groups each adopt an E conformation about the C=C bond. In the crystal of (I), mol ecules are linked by C-H?O hydrogen bonds forming chains along the b axis. The chains are linked via C-H?Cl hydrogen bonds, forming sheets parallel to the ab plane. The sheets are linked via C-H?pi inter-actions, forming a three dimensional structure. In the crystal of (II), mol-ecules are linked by pairs of C-H?O hydrogen bonds, forming inversion dimers with an R 2 (2)(30) ring motif. The dimers are linked via C-H?O hydrogen bonds, forming sheets parallel to the ac plane and enclosing R 4 (4)(28) ring motifs. The sheets are linked via parallel slipped pi-pi inter-actions (inter-centroid distances are both ca 3.86 A), forming a three-dimensional structure. PMID- 26958403 TI - Crystal structure of (1S,2R)-6,6-dimethyl-4,8-dioxo-2-phenyl-spiro-[2.5]octane-1 carbaldehyde. AB - In the title compound, C17H18O3, the two non-spiro C atoms of the cyclo-propane ring bear a formyl and a phenyl substituent which are trans-oriented. In the crystal, mol-ecules are linked by weak C-H?O and C-H?pi contacts resulting in a three-dimensional supra-molecular structure. PMID- 26958404 TI - Crystal structure of 3-{[4-(2-meth-oxy-phen-yl)piperazin-1-yl]meth-yl}-5-(thio phen-2-yl)-1,3,4-oxa-diazole-2(3H)-thione. AB - The title compound, C18H20N4O2S2, is a new 1,3,4-oxa-diazole and a key pharmacophore of several biologically active agents. It is composed of a meth yl(thio-phen-2-yl)-1,3,4-oxa-diazole-2(3H)-thione moiety linked to a 2-meth-oxy phenyl unit via a piperazine ring that has a chair conformation. The thio-phene ring mean plane lies almost in the plane of the oxa-diazole ring, with a dihedral angle of 4.35 (9) degrees . The 2-meth-oxy-phenyl ring is almost normal to the oxa-diazole ring, with a dihedral angle of 84.17 (10) degrees . In the crystal, mol-ecules are linked by weak C-H?S hydrogen bonds and C-H?pi inter-actions, forming layers parallel to the bc plane. The layers are linked via weak C-H?O hydrogen bonds and slipped parallel pi-pi inter-actions [inter-centroid distance = 3.6729 (10) A], forming a three-dimensional structure. The thio-phene ring has an approximate 180 degrees rotational disorder about the bridging C-C bond. PMID- 26958405 TI - Medical Problems during Participation of Medical Congress - A Long Trip to Val D'Isere from Korea. AB - Since the 3rd WIN meeting in 1982 more than 500 participants join the meeting in Val D'Isere every year [1]. One of our authors has attended the meeting more than 10 times. He experienced many physical illnesses while travelling from South Korea to Val D'Isere in France, which is located in the Alps mountain near the border between France and Italy. In order to get there, it is necessary to take airplane, train, and/or bus with a heavy suitcase. During the trip which usually takes more than 15 hours, he experienced headache, gastrointestinal trouble, sleep disturbance and other additional physical illnesses. Therefore, we reviewed the itinerary to Val D'Isere and presented physical illnesses which occurred during a long trip for an academic activity by specialized professionals such as university hospital professors. In addition, we discussed the mechanism of such illnesses and offered possible solutions including medical treatment. PMID- 26958406 TI - Promotion of Neurointervention to International Journal Based on Journal Metrics. AB - PURPOSE: The aim is to provide evidence of the internationalization of Neurointervention based on journal metrics for articles published from 2011 to 2015. MATERIALS AND METHODS: The following metrics and data were collected and analyzed with descriptive statistics: number of citable and non-citable articles; number of research articles (original papers) supported by grants; editorial board members' countries; authors' countries; citing authors' countries; source title of citing articles; two-year impact factor; total citations; and Hirsch index (h-index). Data were retrieved and analyzed from the journal homepage and Web of Science Core Collection in January 24, 2016. RESULTS: There were 80 citable and eight non-citable articles from 2011 to 2015. Out of 31 original articles, nine had research funds (29.0%). Editorial board members are from five countries. The authors are from six countries. The top-ranking countries of citing authors were USA, Korea, and China. The two-year impact factors were 1.125, 0.923, and 0.931 from 2013 to 2015. H-index was 7. CONCLUSION: It was possible to confirm the internationalization of Neurointervention based on journal metrics. New digital standards should be adopted for more rapid dissemination of journal content. PMID- 26958407 TI - Pipeline Embolization Device for Large/Giant or Fusiform Aneurysms: An Initial Multi-Center Experience in Korea. AB - PURPOSE: The purpose of this study was to assess the safety and early outcomes of the Pipeline device for large/giant or fusiform aneurysms. MATERIALS AND METHODS: The Pipeline was implanted in a total of 45 patients (mean age, 58 years; M:F=10:35) with 47 large/giant or fusiform aneurysms. We retrospectively evaluated the characteristics of the treated aneurysms, the periprocedural events, morbidity and mortality, and the early outcomes after Pipeline implantation. RESULTS: The aneurysms were located in the internal carotid artery (ICA) cavernous segment (n=25), ICA intradural segment (n=11), vertebrobasilar trunk (n=8), and middle cerebral artery (n=3). Procedure-related events occurred in 18 cases, consisting of incomplete expansion (n=8), shortening-migration (n=5), transient occlusion of a jailed branch (n=3), and in-stent thrombosis (n=2). Treatment-related morbidity occurred in two patients, but without mortality. Both patients had modified Rankin scale (mRS) scores of 2, but had an improved mRS score of 0 at 1-month follow-up. Of the 19 patients presenting with mass effect, 16 improved but three showed no changes in their presenting symptoms. All patients had excellent outcomes (mRS, 0 or 1) during the follow-up period (median, 6 months; range, 2-30 months). Vascular imaging follow-up (n=31, 65.9%; median, 3 months, range, 1-25 months) showed complete or near occlusion of the aneurysm in 24 patients (77.4%) and decreased sac size in seven patients (22.6%). CONCLUSION: In this initial multicenter study in Korea, the Pipeline seemed to be safe and effective for large/giant or fusiform aneurysms. However, a learning period may be required to alleviate device-related events. PMID- 26958408 TI - Arterial Wall Imaging in Symptomatic Carotid Stenosis: Delayed Enhancement on MDCT Angiography. AB - OBJECTIVE: To evaluate progressive enhancement in the carotid arterial wall overlying plaque in the symptomatic side for patients with cerebrovascular symptoms until delayed phase using MDCTA. MATERIALS AND METHODS: Twenty-one patients (all men; ages, 49-82 years; mean, 67.8 +/- 8.4 years) with recent stroke and severe extracranial carotid stenosis were retrospectively analyzed. Pre-, early- and delayed phase images of MDCTA were obtained, and Hounsfield units (HU) of carotid walls were measured. We also measured HU of the asymptomatic contralateral carotid arterial wall for comparison. Friedman's test and Wilcoxon signed-rank test were used to evaluate the differences between groups. RESULTS: The averaged HU of the carotid wall in the symptomatic side was higher on the delayed phase (65.8 +/- 14.2 HU) compared to early arterial phase (54.2 +/- 12.6 HU). The averaged HU difference of wall enhancement between pre contrast and delayed phase (28.0 +/- 14.8 HU) was significantly higher than the between pre-contrast and early arterial phase (16.4 +/- 12.1 HU) with P < 0.05. In analysis of the contralateral asymptomatic side, the HU difference between pre contrast and delayed phase (15.5 +/- 12.0 HU) showed no significant higher value than between pre-contrast and early arterial phase (14.9 +/- 10.9 HU). CONCLUSION: The pronounced enhancement of the carotid wall in the delayed phase on MDCTA was demonstrated in symptomatic patients with severe internal carotid artery stenosis. In the future, we need more comparative studies to verify this finding as one of risk stratification. PMID- 26958409 TI - Easy Advancement of a Large-Profile Microcatheter (Excelsior XT27TM) by Parallel Use of Two Microguidewires For Stent Delivery. AB - PURPOSE: In the endovascular treatment of cerebral aneurysms, navigating a large bore microcatheter for delivery of an open-cell stent can be challenging, especially in wide-necked bifurcation aneurysms. We were able to overcome this difficulty by parallel use of two microguidewires through the stent-delivery microcatheter. MATERIALS AND METHODS: From December 2014 to April 2015, we treated 15 patients with wide-necked bifurcation aneurysms. For stent delivery, we used a 300-cm 0.014-in microguidewire (Transend), which was placed into the target branch using an exchange technique. A 0.027-in microcatheter (Excelsior XT 27), which was designed for the stent, was advanced over the exchange microguidewire. If we had trouble in advancing the microcatheter over the exchange microguidewire, we inserted a regular microguidewire (Traxcess), into the microcatheter lumen in a parallel fashion. We also analyzed the mechanism underlying microcatheter positioning failure and the success rate of the 'parallel-wire technique'. RESULTS: Among the 15 cases, we faced with navigation difficulty in five patients. In those five cases, we could advance the microcatheter successfully by applying the parallel-wire technique. There were no procedure-related complications. CONCLUSION: Simply by using another microguidewire together with pre-existing microguidewire in a parallel fashion, the stent-delivery microcatheter can be easily navigated into the target location in case of any advancement difficulty. PMID- 26958410 TI - Hemodynamic Characteristics Regarding Recanalization of Completely Coiled Aneurysms: Computational Fluid Dynamic Analysis Using Virtual Models Comparison. AB - PURPOSE: Hemodynamic factors are considered to play an important role in initiation and progression of the recurrence after endosaccular coiling of the intracranial aneurysms. We made paired virtual models of completely coiled aneurysms which were subsequently recanalized and compared to identify hemodynamic characteristics related to the recurred aneurysmal sac. MATERIALS AND METHODS: We created paired virtual models of computational fluid dynamics (CFD) in five aneurysms which were initially regarded as having achieved complete occlusion and then recurred during follow-up. Paired virtual models consisted of the CFD model of 3D rotational angiography obtained in the recurred aneurysm and the control model of the initial, parent artery after artificial removal of the coiled and recanalized aneurysm. Using the CFD analysis of the virtual model, we analyzed the hemodynamic characteristics on the neck of each aneurysm before and after its recurrence. RESULTS: High wall shear stress (WSS) was identified at the cross-sectionally identified aneurysm neck at which recurrence developed in all cases. A small vortex formation with relatively low velocity in front of the neck was also identified in four cases. The aneurysm recurrence locations corresponded to the location of high WSS and/or small vortex formation. CONCLUSION: Recanalized aneurysms revealed increased WSS and small vortex formation at the cross-sectional neck of the aneurysm. This observation may partially explain the hemodynamic causes of future recanalization after coil embolization. PMID- 26958411 TI - Outpatient Day-care Neuroangiography and Neurointervention of Unruptured Intracranial Aneurysms. AB - PURPOSE: Day-care management of unruptured intracranial aneurysms can shorten hospital stay, reduce medical cost and improve outcome. We present the process, outcome and duration of hospital stay for the management of unruptured intracranial aneurysms via a neurointervention clinic in a single center during the past four years. MATERIALS AND METHODS: We analyzed 403 patients who were referred to Neurointervention Clinic at Asan Medical Center for aneurysm evaluation between January 1, 2011 and December 31, 2014. There were 141 (41%) diagnostic catheter angiographies, 202 (59%) neurointerventional procedures and 2 (0.6%) neurointerventional procedures followed by operation. We analyzed the process, outcome of angiography or neurointervention, and duration of hospital stay. RESULTS: There was no aneurysm in 58 patients who were reported as having an aneurysm in MRA or CTA (14 %). Among 345 patients with aneurysm, there were 283 patients with a single aneurysm (82%) and 62 patients with multiple aneurysms (n=62, 18%). Aneurysm coiling was performed in 202 patients (59%), surgical clipping in 14 patients (4%), coiling followed by clipping in 2 patients (0.6%) and no intervention was required in 127 patients (37%). The hospital stay for diagnostic angiography was less than 6 hours and the mean duration of hospital stay was 2.1 days for neurointervention. There were 4 procedure-related adverse events (2%) including 3 minor and 1 major ischemic strokes. CONCLUSION: Our study revealed that day-care management of unruptured intracranial aneurysms could be performed without an additional risk. It could enable rapid patient flow, shorten hospital stay and thus reduce hospital costs. PMID- 26958412 TI - Delayed Intracerebral Hemorrhage from a Pseudoaneurysm Following a Depressed Skull Fracture. AB - A 26-year-old male presented with delayed intracerebral hemorrhage from a ruptured distal middle cerebral artery pseudoaneurysm that followed a compound depressed skull fracture from years ago. The brain protrusion through the skull defect likely resulted in stretching and subsequent tearing of the arterial wall resulting in the pseudoaneurysm formation. No prior report of such a clinical occurrence exists in the literature. We highlight an unusual but treatable cause for intracerebral hemorrhage following surgery for traumatic brain injury. PMID- 26958413 TI - Progressive Deconstruction of a Distal Posterior Cerebral Artery Aneurysm Using Competitive Flow Diversion. AB - Progressive deconstruction is an endovascular technique for aneurysm treatment that utilizes flow diverting stents to promote progressive thrombosis by diverting blood flow away from the aneurysm's parent vessel. While the aneurysm thromboses, collateral blood vessels develop over time to avoid infarction that can often accompany acute parent vessel occlusion. We report a 37-year-old woman with a left distal posterior cerebral artery aneurysm that was successfully treated with this strategy. The concept and rationale of progressive deconstruction are discussed in detail. PMID- 26958414 TI - Duplicated Origin of the Left Vertebral Artery: A Case Report and Embryological Review. AB - The duplicated origin of vertebral artery (VA) is a very rare condition. It could be easily misdiagnosed as an arterial dissection on selective catheter angiography, especially in a patient with acute cerebellar infarction of unknown etiology. We report a patient with an acute cerebellar infarction and duplicated origin of the left VA, which was found during the selective catheter angiography. PMID- 26958415 TI - Successful Cross-circulation Stent-Retriever Embolectomy Through Posterior Communicating Artery for Acute MCA Occlusion by Using Trevo XP ProVue. AB - Acute ischemic stroke due to embolic occlusion of the middle cerebral artery (MCA) in patients with chronic ipsilateral internal carotid artery (ICA) occlusion is quite rare. Several previous reports demonstrated that intra arterial (IA) thrombolytic therapy or aspiration thrombectomy using the cross circulation technique via an alternative collateral pathway is feasible in acute stroke patients with an unfavorable direct route to the occluded sites. However, stent-retriever embolectomy via the cross-circulation approach has not been reported in the literature. The present paper reports the first case of successful stent-retriever embolectomy for acute MCA occlusion via the patent posterior communicating artery (PComA) by using Trevo XP ProVue stent-retriever in a patient with acute MCA stroke and chronic occlusion at the origin site of the ipsilateral ICA. PMID- 26958416 TI - A tiny bleb at Junctional Dilatation of the Posterior Communicating Artery as a Predisposing Factor for Development of a De Novo Aneurysm. AB - Formation of de novo aneurysm from a junctional dilatation at the origin site of the posterior communicating artery (PcomA) has been rarely reported. In this case report, three females in sixth decades of age developed a de novo aneurysm from the junctional dilatation of the PComA with a tiny bleb-like lesion over 5 years after initial presentation. PMID- 26958417 TI - Polyvictimization: Latent profiles and mental health outcomes in a clinical sample of adolescents. AB - OBJECTIVE: Exposure to multiple traumatic events (polyvictimization) is a reliable predictor of deleterious health outcomes and risk behaviors in adolescence. The current study extends the literature on the prevalence and consequences of adolescent trauma exposure by (a) empirically identifying and characterizing trauma exposure profiles in a large, ethnically diverse, multi site, clinical sample of adolescents, and (b) evaluating relations among identified profiles with demographic characteristics and clinical correlates. METHOD: Data from the National Child Traumatic Stress Network Core Data Set were used to identify and characterize victimization profiles using latent class analysis in a sample of 3,485 adolescents (ages 13-18, 63% female, 35.7% White, 23.2% Black/African American, 35.0% Hispanic/Latino). Multiple measures of psychological distress and risk behaviors were evaluated as covariates of trauma exposure classes. RESULTS: Five trauma exposure classes, or profiles, were identified. Four classes-representing approximately half the sample-were characterized by polyvictimization. Polyvictimization classes were differentiated on number of trauma types, whether emotional abuse occurred, and whether emotional abuse occurred over single or multiple developmental epochs. Unique relations with demographic characteristics and mental health outcomes were observed. DISCUSSION: Results suggest polyvictimization is not a unidimensional phenomenon but a diverse set of trauma exposure experiences with unique correlates among youth. Further research on prevention of polyvictimization and mechanisms linking chronic trauma exposure, gender, and ethnicity to negative outcomes is warranted. PMID- 26958418 TI - Racemose neurocysticercosis. AB - BACKGROUND: Neurocysticercosis (NCC) is an invasive parasitic infection of the central nervous system caused by the larval stage of the tapeworm Taenia solium. The clinical manifestations of NCC depend on the parasitic load and location of infection, as well as the developmental stage of the cysticerci and host immune response, with symptoms ranging from subclinical headaches to seizures, cerebrovascular events, and life-threatening hydrocephalus. Racemose NCC represents a particularly severe variant of extraparenchymal NCC characterized by the presence of multiple confluent cysts within the subarachnoid space and is associated with increased morbidity and mortality, as well as a decreased response to treatment. Albendazole is the preferred drug for the treatment of racemose NCC due to its superior cerebrospinal fluid penetration compared to praziquantel and the ability to be used concomitantly with steroids. CASE DESCRIPTION: In this report, we describe a 39-year-old man recently emigrated from Mexico with racemose NCC and hydrocephalus successfully treated with prolonged albendazole treatment, high-dose dexamethasone, and ventriculoperitoneal shunt placement for the relief of obstructive hydrocephalus. CONCLUSIONS: Treatment of racemose NCC represents a significant clinical challenge requiring multimodal intervention to minimize infectious- and treatment related morbidity. We review the clinical, diagnostic, and therapeutic features relevant to the management of this aggressive form of NCC. PMID- 26958419 TI - Resting state functional connectivity magnetic resonance imaging integrated with intraoperative neuronavigation for functional mapping after aborted awake craniotomy. AB - BACKGROUND: Awake craniotomy is currently the gold standard for aggressive tumor resections in eloquent cortex. However, a significant subset of patients is unable to tolerate this procedure, particularly the very young or old or those with psychiatric comorbidities, cardiopulmonary comorbidities, or obesity, among other conditions. In these cases, typical alternative procedures include biopsy alone or subtotal resection, both of which are associated with diminished surgical outcomes. CASE DESCRIPTION: Here, we report the successful use of a preoperatively obtained resting state functional connectivity magnetic resonance imaging (MRI) integrated with intraoperative neuronavigation software in order to perform functional cortical mapping in the setting of an aborted awake craniotomy due to loss of airway. CONCLUSION: Resting state functional connectivity MRI integrated with intraoperative neuronavigation software can provide an alternative option for functional cortical mapping in the setting of an aborted awake craniotomy. PMID- 26958420 TI - Effect of repeated transsphenoidal surgery in recurrent or residual pituitary adenomas: A systematic review and meta-analysis. AB - BACKGROUND: Recurrent or residual pituitary adenomas previously treated by transsphenoidal surgery are not uncommon. There are no strongly established guidelines to perform treatment of such cases. The objective of this study is to elucidate the effect of transsphenoidal reoperation in residual or recurrent pituitary adenomas. METHODS: We made a systematic review of the literature to elucidate this effect through electronic search in MEDLINE/PubMed and Cochrane Central database. PRISMA statement was used as a basis for this systematic review and analysis of the risk of bias was made according to the Grading of Recommendations, Assessment, Development and Evaluation recommendations. RESULTS: In this review, fifteen studies were finally pooled analyzed. Although remission rates (RRs) and follow-up periods varied widely, from 149 patients with growth hormone-secreting tumors the mean RR was 44.5%, from 273 patients with adrenocorticotropic hormone-secreting tumors the mean RR was 55.5% and among 173 patients with nonsecreting tumors, RR was 76.1%. There was significant higher RR in nonsecreting tumors. Mean follow-up was 32.1 months. No difference was found between microscopic and endoscopic techniques. CONCLUSIONS: A second transsphenoidal surgery is accompanied by a chance of remission in approximately half of cases with secreting tumors. In nonsecreting ones, success is higher. PMID- 26958421 TI - Spontaneous thrombosis of giant intracranial aneurysm and posterior cerebral artery followed by also spontaneous recanalization. AB - BACKGROUND: Spontaneous complete thrombosis of a giant aneurysm and its parent artery is a rare event. Their spontaneous recanalization is even rarer, with few reports. CASE DESCRIPTION: A 17-year-old male patient presenting blurred vision and headache, with a history of seizures, was referred to our service. After further investigation with cranial computed tomography, magnetic resonance imaging (MRI), and cerebral angiography (CAG), it was diagnosed a thrombosed aneurysm of the posterior cerebral artery (PCA) and also complete thrombosis of the PCA. Three years later, he experienced visual worsening. A new MRI scan indicated flow both through the aneurysm and the left PCA, which was further confirmed by CAG. We decided for a noninterventional treatment combined with strict clinical follow-up. The patient continues to present with the previous neurological deficit, without recurrence of headaches. CONCLUSIONS: Thrombosis is not the final event in the natural history of giant aneurysms, and partial thrombosis does not preclude the risk of rupture. Thrombosed aneurysms may display additional growth brought about by wall dissections or intramural hemorrhages. Their treatment may be either surgical or involve endovascular procedures such as embolization. Thrombosed giant aneurysms are dynamic and unstable lesions. A noninterventional treatment is feasible, but aneurysmal growth or recanalization may suggest the need for a more active intervention. PMID- 26958422 TI - Fenestration of bone flap during decompressive craniotomy for subdural hematoma. AB - BACKGROUND: Persistent/recurrent extra-axial hemorrhage may occur after decompression of a subdural hematoma (SDH) followed by an immediate replacement of bone flap. A fenestration of the bone flap may encourage extra-axial fluid absorption; however, the literature has not explored this technique. METHODS: Forty-four consecutive patients who underwent surgical decompression of SDH with immediate replacement of bone flap were divided into two groups: Fenestration (F), n = 33, and no fenestration (NF), n = 11. Fenestration involves placement of twist drill holes 1-2 cm apart throughout the bone flap. Clinical data (age, sex, history of antiplatelet/anticoagulation [AA], and presence of drains) were collected. The size of bone flap, postoperative volume, and midline shift (MLS) were measured. A univariate analysis was performed for continuous variables; Fisher's exact test was performed for categorical variables. RESULTS: For postoperative volume, NF group exhibited 94.4 +/- 15.5 cm(3), while F group exhibited 47.3 +/- 15.5 cm(3) (P = 0.04); no AA exhibited 62.9 +/- 12.3 cm(3), while AA exhibited 100.5 +/- 19.0 cm(3) (P = 0.07); no drains exhibited 110.1 +/- 29.6 cm(3), while drains exhibited 63.0 +/- 9.1 cm(3) (P = 0.14). For postoperative MLS, NF group exhibited 4.8 +/- 1.1 mm, while F group exhibited 2.5 +/- 1.1 mm (P = 0.16); no AA exhibited 2.3 +/- 1.0 mm, while AA exhibited 5.8 +/- 1.4 mm (P = 0.048); no drains exhibited 4.6 +/- 2.2 mm, while drains exhibited 3.8 +/- 0.7 mm (P = 0.70). Accounting for fenestration status and AA status: For F group, AA status did not correlate with postoperative volume or MLS significantly; for NF group, history of AA exhibited higher postoperative value 129.2 +/- 26.5 cm(3), compared to no history of AA at 59.5 +/- 16.2 cm(3) (P = 0.03). CONCLUSION: Our results suggest that fenestration prior to the immediate replacement of bone flap after surgical decompression of SDH has the potential to reduce extra-axial fluid accumulation. PMID- 26958423 TI - Urgent discectomy: Clinical features and neurological outcome. AB - BACKGROUND: To evaluate the clinical features and outcome of patients with progressive neurological deficits due to disc herniation who were treated surgically within 24 h. METHODS: We conducted a retrospective analysis of consecutive patients who were admitted between 2004 and 2013 via the Emergency Department. Records were screened for presenting symptoms, neurological status at admission, discharge, and 6-week follow-up. RESULTS: About 72 of 526 patients underwent surgery within 24 h. Magnetic resonance imaging showed lumbar disc herniation in 72 patients. The most common presenting symptoms included radiculopathy (n = 69), the Lasegue sign (n = 60), sensory deficits (n = 57), or motor deficits (n = 47). In addition, 11 patients experienced perineal numbness and 12 had bowel and bladder dysfunction. At discharge, motor and sensory deficits and bowel and bladder dysfunction had improved significantly (P < 0.001, P = 0.029, and P = 0.015, respectively). CONCLUSION: Motor deficits, sensory deficits, and cauda equina dysfunction were significantly improved immediately after urgent surgery. After 6 weeks, motor and sensory deficits were also significantly improved compared to the neurological status at discharge. Thus, we advocate immediate surgery of disc herniation in patients with acute onset of motor deficits, perineal numbness, or bladder or bowel dysfunction indicative of cauda equina syndrome. PMID- 26958424 TI - Do we need to establish guidelines for patients with neuromodulation implantable devices, including spinal cord stimulators undergoing nonspinal surgeries? AB - BACKGROUND: Spinal cord stimulation is currently approved to treat chronic intractable pain of the trunk and limbs. However, such implantable electronic devices are vulnerable to external electrical currents and magnetic fields. Within the hospitals and modern operating rooms (ORs), there is an abundance of electrical devices and other types of equipment that could interfere with such devices. Despite the increasing number of patients with neuromodulation implantable devices, there are no written guidelines available or consensus of cautions for such patients undergoing unrelated surgery. CASE DESCRIPTIONS: A 60 year-old female with a permanent St. Jude's spinal cord stimulator (SCS) presented for open total abdominal hysterectomy. Both the anesthesia and gynecology staffs were aware of the device presence, but were unaware of any precautions regarding intraoperative management. The device was found to be nonmagnetic resonance imaging compatible, and bipolar cautery was used instead of monopolar cautery. A 59-year-old female with a 9-year-old permanent Medtronic SCS, presented for right total hip arthroplasty. The device was switched off prior to entering the OR, bipolar cautery was used, and grounding pads were placed away from her battery site. In each case, the manufacturer's representative was contacted preoperative. Both surgeries proceeded uneventfully. CONCLUSIONS: The Food and Drug Administration safety information manual warns about the use of diathermy, concomitant implanted stimulation devices, lithotripsy, external defibrillation, radiation therapy, ultrasonic scanning, and high-output ultrasound, all of which can lead to permanent implant damage if not turned off prior to undertaking procedures. Lack of uniform guidelines makes intraoperative management, as well as remote anesthesia care of patients with previously implanted SCSs unsafe. PMID- 26958425 TI - Camptocormia and deep brain stimulation: The interesting overlapping etiologies and the therapeutic role of subthalamic nucleus-deep brain stimulation in Parkinson disease with camptocormia. AB - BACKGROUND: Camptocormia is known as "bent spine syndrome" and defined as a forward hyperflexion. The most common etiologic factor is related with the movement disorders, mainly in Parkinson's disease (PD). CASE DESCRIPTION: We present the case of a 51-year-old woman who has been followed with PD for the last 10 years, and also under the therapy for PD. An unappreciated correlation low back pain with camptocormia developed. She underwent deep brain stimulation (DBS) in the subthalamic nucleus bilaterally and improved her bending posture. CONCLUSION: The relationship between the DBS and camptocormia is discussed in this unique condition. PMID- 26958426 TI - Radiotherapy-induced tumors of the spine, peripheral nerve, and spinal cord: Case report and literature review. AB - BACKGROUND: The development of a secondary malignancy in the field of radiation is a rare but well-recognized hazard of cancer treatment. The radiotherapy induced (RT-I) tumors are even more aggressive and potentially lethal than the primary tumor. To goal of this article is to report a case of RT-I neural tumor located in the peripheral nerve and spinal cord and to perform a literature review of the subject. CASE REPORTS: Thirty-year male with symptoms of hypoesthesia and dysesthesia of the L5 nerve root distribution and previous treatment of a testicular seminoma 20 years previously. The lumbar magnetic resonance imaging showed the growth of a nerve root tumor. Surgery was performed, and a fusiform tumor was resected with clear margins. The anatomopathological and immunohistochemical studies were compatible with a malignant peripheral nerve sheath tumor. A total of 30 cases were included in the review. The mean age of the patients at diagnosis of the induced tumor was 39.36 (+/-16.74) years. Most were male (63.3%). The main type of primary disease was neural tumors (30%). The most common type of histology was fibrosarcoma (20.0%). No difference was found in age, gender, and time of diagnosis between neural and nonneural tumors. The mean survival after the diagnosis of the secondary tumor was 10.7 months (+/ 13.27), and neural tumors had a longer survival period (P = 0.031). CONCLUSION: The current gold standard therapy is complete resection with clear margins, since most tumors do not respond to chemotherapy and RT. The neural type of RT-I tumor presented a longer survival period. PMID- 26958427 TI - Treatment of epidermoid tumors with gamma knife radiosurgery: Case series. AB - BACKGROUND: Epidermoid tumors (ETs) are benign lesions that are treated mainly by means of surgical resection, with overall good results. External beam radiotherapy is an alternative treatment for those recurrent tumors, in which a second surgery might not be the best choice for the patient. A little information exists about the effectiveness of gamma knife radiosurgery for the treatment of newly diagnosed and recurrent ETs. We present three cases of ETs treated with gamma knife radiosurgery. CASE DESCRIPTION: Case 1 is a 21-year-old female with an ET located in the left cerebellopontine angle (CPA) with symptoms related to VIII cranial nerve dysfunction. Symptom control was achieved and maintained after single session radiosurgery with gamma knife. Case 2 is a 59-year-old female patient with the history of trigeminal neuralgia secondary to a recurrent ET located in the left CPA. Significant pain improvement was achieved after treatment with gamma knife radiosurgery. Case 3 is a 29-year-old male patient with a CPA ET causing long lasting trigeminal neuralgia, pain relief was achieved in this patient after gamma knife radiosurgery. CONCLUSION: Long-term symptom relief was achieved in all three cases proving that gamma knife radiosurgery is a good and safe alternative for patients with recurrent or nonsurgically treated ETs. PMID- 26958428 TI - Dilemmas surrounding the diagnosis of deep brain stimulation electrode infection without associated wound complications: A series of two cases. AB - BACKGROUND: When wounds are benign, diagnosis of deep brain stimulation (DBS) electrode infection and associated intraparenchymal infection can be challenging. Only a couple, such cases exist in literature. Since infections of the central nervous system can be life-threatening, prompt diagnosis is necessary to prevent neurological injury. Employed within the appropriate context, magnetic resonance imaging (MRI) of the brain, as well as laboratory data and clinical presentation, may help guide diagnosis. CASE DESCRIPTIONS: Case 1 - A 55-year-old male with bilateral DBS electrodes and generators (49 days from last procedure), who presented with confusion and fever. Pertinent positive laboratory was white blood cell 20.5K. MRI of the brain showed edema with enhancement along the right DBS electrode. Wound exploration revealed gross purulence in the subgaleal space. The entire system was removed; cultures from subgaleal space revealed Propionibacterium acnes; cultures from electrode were negative. The patient was sent home on antibiotics. Case 2 - A 68-year-old male with a right DBS electrode (11 days from placement), who presented after an unwitnessed fall, followed by confusion and amnesia. Pertinent laboratory examinations were negative. MRI of the brain showed edema with enhancement along the DBS electrode. Wound exploration revealed no infection. The DBS system was left in place; final cultures were negative; no antibiotics were prescribed. Repeat MRI showed resolving fluid-attenuated inversion recovery (FLAIR) signal and contrast enhancement. CONCLUSIONS: Contrast enhancement, T2 FLAIR, and diffusion weighted imaging are influenced by postoperative changes. Caution is stressed regarding dependence on these features for acute diagnosis of infection and indication for electrode removal. Timing of the imaging after surgery must be considered. Other factors, such as systemic signs and abnormal laboratory data, should be evaluated. Based on these guidelines, retrospectively, the patient in Case 2 should not have been rushed for a wound exploration; close observation with serial imaging and laboratory data may have prevented an unnecessary procedure. PMID- 26958429 TI - Tinnitus: Is there a place for brain stimulation? AB - Tinnitus is the perception of a "phantom sound" and has a high prevalence. Although many therapies have been investigated within the last decades, there is still no effective standard therapy. Animal studies and human functional imaging studies revealed that tinnitus perception is associated with many complex changes in multiple brain structures. There is growing evidence that brain stimulation might be able to interrupt the local altered neuronal activity and hereby inhibit tinnitus perception. In this editorial review, an update is given on the most promising targets for brain stimulation. Promising structures for stimulation are the dorsal cochlear nucleus, the inferior colliculus and the medial geniculate body of the thalamus. For cortical stimulation, the auditory cortex is considered as a target. Nevertheless, the field is waiting for evidence from well-designed clinical trials, based on supporting evidence from experimental/mechanistic research, to support or discourage the application of brain stimulation in tinnitus. PMID- 26958430 TI - Adaptive hypofractionated gamma knife radiosurgery for a large brainstem metastasis. AB - BACKGROUND: To demonstrate how adaptive hypofractionated radiosurgery by gamma knife (GK) can be successfully utilized to treat a large brainstem metastasis - a novel approach to a challenging clinical situation. CASE DESCRIPTION: A 42-year old woman, diagnosed with metastatic nonsmall cell lung cancer in July 2011, initially treated with chemotherapy and tyrosine kinase inhibitors, developed multiple brain metastases March 2013, with subsequent whole brain radiotherapy, after which a magnetic resonance imaging (MRI) showed a significant volume regression of all brain metastases. A follow-up MRI in October 2013 revealed a growing brainstem lesion of 26 mm. Linear accelerator-based radiotherapy and microsurgery were judged contraindicated, why the decision was made to treat the patient with three separate radiosurgical sessions during the course of 1 week, with an 18% tumor volume reduction demonstrated after the last treatment. Follow up MRI 2.5 months after her radiosurgical treatment showed a tumor volume reduction of 67% compared to the 1(st) day of treatment. Later on, the patient developed a radiation-induced perilesional edema although without major clinical implications. An MRI at 12 months and 18-fluoro-deoxyglucose positron emission tomography of the brain at 13 months showed decreased edema with no signs of tumor recurrence. Despite disease progression during the last months of her life, the patient's condition remained overall acceptable. CONCLUSION: GK-based stereotactic adaptive hypofractionation proved to be effective to achieve tumor control while limiting local adverse reactions. This surgical modality should be considered when managing larger brain lesions in critical areas. PMID- 26958432 TI - Intracranial Pial Arteriovenous Fistulae: Diagnosis and Treatment Techniques in Pediatric Patients with Review of Literature. AB - Pial arteriovenous fistulae (AVF) are rare vascular lesions comprising single or multiple arterial feeders draining directly into the venous channel without intervening tangle of blood vessels as in brain AV malformations. In our present paper, we describe three cases of pial AVF in the pediatric age group with different presentations treated successfully with endovascular and surgical methods. Two patients underwent treatment for pial AVF by the endovascular technique and one by surgical clipping. The treatments were successful with good clinical outcome. We did not encounter any peri-procedural complications in any of the cases. Pial AVF is a rare entity and high degree of suspicion and adequate clinical and imaging knowledge is required to make the diagnosis. Exclusion of the fistula from the cerebral circulation should be done at the earliest to prevent devastating complications that result during the natural course of the disease. PMID- 26958431 TI - Renal Collecting System Anatomy in Living Kidney Donors by Computed Tomographic Urography: Protocol Accuracy Compared to Intravenous Pyelographic and Surgical Findings. AB - OBJECTIVES: To evaluate the accuracy of triple-bolus computed tomography urography (CTU) as a surrogate of intravenous pyelography (IVP) for determining the anatomy of the urinary collecting system in living kidney donors. MATERIALS AND METHODS: In an analytic descriptive cross-sectional study, 36 healthy kidney donors were recruited during 12 months. Preoperative IVP and CTU were utilized to evaluate kidneys' anatomy; major and minor calyces and variation were used as anatomical indices to compare the accuracy of CTU and IVP; the images were then compared to surgical findings. RESULTS: Thirty-six kidney donors (92% male; mean age: 28 +/- 6 years) were enrolled in this study. The kappa coefficient value was significant and almost perfect for the CTU and IVP findings in detecting the pattern of calyces (kappa coefficient 0.92, asymptotic 95% confidence interval 0.86-0.97). Anatomic variations or anomalies of the urinary collecting system included the bifid pelvis (5.6%), duplication (8.3%), and extra-renal pelvis (2.8%). Both the sensitivity and specificity of CTU in the detection of the anatomy and variations were 100%; the sensitivity and specificity of IVP were 83.3% and 100%, respectively. CONCLUSIONS: The triple-bolus preoperative CTU can be considered an alternative to IVP for assessing the anatomy of the urinary collecting system. PMID- 26958433 TI - Silicone-induced Penile Sclerosing Lipogranuloma: Magnetic Resonance Imaging Findings. AB - Sclerosing lipogranuloma is a rare benign disease, representing a peculiar granulomatous reaction of fatty tissue. The majority of cases are secondary to injection of exogenous foreign bodies, such as silicone, paraffin, mineral, or vegetable oils. To the best of our knowledge, we present the first case of a silicone-induced penile lipogranuloma in a 52-year-old man evaluated with a multiparametric magnetic resonance imaging (MRI) protocol, including diffusion weighted imaging, magnetization transfer imaging, and dynamic contrast-enhanced MRI. MRI of the penis by combining both conventional and functional information represents an important imaging tool in the preoperative workup of silicone induced penile lipogranuloma. PMID- 26958434 TI - Processing and Characterization of Nanoparticle Coatings for Quartz Crystal Microbalance Measurements. AB - The quartz-crystal microbalance is a sensitive and versatile tool for measuring adsorption of a variety of compounds (e.g. small molecules, polymers, biomolecules, nanoparticles and cells) to surfaces. While the technique has traditionally been used for measuring adsorption to flat surfaces and thin ridged films, it can also be extended to study adsorption to nanoparticle surfaces when the nanoparticles are fixed to the crystal surface. The sensitivity and accuracy of the measurement depend on the users' ability to reproducibly prepare a thin uniform nanoparticle coating. This study evaluated four coating techniques, including spin coating, spray coating, drop casting, and electrophoretic deposition, for two unique particle chemistries [nanoscale zero valent iron (nZVI) and titanium dioxide (TiO2)] to produce uniform and reproducible nanoparticle coatings for real-time quartz-crystal microbalance measurements. Uniform TiO2 coatings were produced from a 50 mg/mL methanol suspension via spin coating. Nanoscale zero-valent iron was best applied by spray coating a low concentration 1.0 mg/mL suspended in methanol. The application of multiple coatings, rather than an increase in the suspension concentration, was the best method to increase the mass of nanoparticles on the crystal surface while maintaining coating uniformity. An upper mass threshold was determined to be approximately 96 ug/cm(2); above this mass, coatings no longer maintained their uniform rigid characteristic, and a low signal to noise ratio resulted in loss of measurable signal from crystal resonances above the fundamental. PMID- 26958435 TI - Report on Pairing-based Cryptography. AB - This report summarizes study results on pairing-based cryptography. The main purpose of the study is to form NIST's position on standardizing and recommending pairing-based cryptography schemes currently published in research literature and standardized in other standard bodies. The report reviews the mathematical background of pairings. This includes topics such as pairing-friendly elliptic curves and how to compute various pairings. It includes a brief introduction to existing identity-based encryption (IBE) schemes and other cryptographic schemes using pairing technology. The report provides a complete study of the current status of standard activities on pairing-based cryptographic schemes. It explores different application scenarios for pairing-based cryptography schemes. As an important aspect of adopting pairing-based schemes, the report also considers the challenges inherent in validation testing of cryptographic algorithms and modules. Based on the study, the report suggests an approach for including pairing-based cryptography schemes in the NIST cryptographic toolkit. The report also outlines several questions that will require further study if this approach is followed. PMID- 26958436 TI - Findings and Recommendations from the NIST Workshop on Alternative Fuels and Materials: Biocorrosion. AB - In 2013, the Applied Chemicals and Materials Division of the National Institute of Standards and Technology (NIST) hosted a workshop to identify and prioritize research needs in the area of biocorrosion. Materials used to store and distribute alternative fuels have experienced an increase in corrosion due to the unique conditions caused by the presence of microbes and the chemistry of biofuels and biofuel precursors. Participants in this workshop, including experts from the microbiological, fuel, and materials communities, delved into the unique materials and chemical challenges that occur with production, transport, and storage of alternative fuels. Discussions focused on specific problems including: a) the changing composition of "drop-in" fuels and the impact of that composition on materials; b) the influence of microbial populations on corrosion and fuel quality; and c) state-of-the-art measurement technologies for monitoring material degradation and biofilm formation. PMID- 26958437 TI - Revision of the NIST Standard for (223)Ra: New Measurements and Review of 2008 Data. AB - After discovering a discrepancy in the transfer standard currently being disseminated by the National Institute of Standards and Technology (NIST), we have performed a new primary standardization of the alpha-emitter (223)Ra using Live-timed Anticoincidence Counting (LTAC) and the Triple-to-Double Coincidence Ratio Method (TDCR). Additional confirmatory measurements were made with the CIEMAT-NIST efficiency tracing method (CNET) of liquid scintillation counting, integral gamma-ray counting using a NaI(Tl) well counter, and several High Purity Germanium (HPGe) detectors in an attempt to understand the origin of the discrepancy and to provide a correction. The results indicate that a -9.5 % difference exists between activity values obtained using the former transfer standard relative to the new primary standardization. During one of the experiments, a 2 % difference in activity was observed between dilutions of the (223)Ra master solution prepared using the composition used in the original standardization and those prepared using 1 mol.L(-1) HCl. This effect appeared to be dependent on the number of dilutions or the total dilution factor to the master solution, but the magnitude was not reproducible. A new calibration factor ("K-value") has been determined for the NIST Secondary Standard Ionization Chamber (IC "A"), thereby correcting the discrepancy between the primary and secondary standards. PMID- 26958438 TI - Design and Operation of an Optically-Accessible Modular Reactor for Diagnostics of Thermal Thin Film Deposition Processes. AB - The design and operation of a simple, optically-accessible modular reactor for probing thermal thin film deposition processes, such as atomic layer deposition processes (ALD) and chemical vapor deposition (CVD), is described. This reactor has a nominal footprint of 225 cm(2) and a mass of approximately 6.6 kg, making it small enough to conveniently function as a modular component of an optical train. The design is simple, making fabrication straightforward and relatively inexpensive. Reactor operation is characterized using two infrared absorption measurements to determine exhaust times for tetrakis(dimethylamino)titanium and water, proto-typical ALD precursors, in a pressure and flow regime commonly used for ALD. PMID- 26958439 TI - An Areal Isotropic Spline Filter for Surface Metrology. AB - This paper deals with the application of the spline filter as an areal filter for surface metrology. A profile (2D) filter is often applied in orthogonal directions to yield an areal filter for a three-dimensional (3D) measurement. Unlike the Gaussian filter, the spline filter presents an anisotropic characteristic when used as an areal filter. This disadvantage hampers the wide application of spline filters for evaluation and analysis of areal surface topography. An approximation method is proposed in this paper to overcome the problem. In this method, a profile high-order spline filter serial is constructed to approximate the filtering characteristic of the Gaussian filter. Then an areal filter with isotropic characteristic is composed by implementing the profile spline filter in the orthogonal directions. It is demonstrated that the constructed areal filter has two important features for surface metrology: an isotropic amplitude characteristic and no end effects. Some examples of applying this method on simulated and practical surfaces are analyzed. PMID- 26958440 TI - On the Stability of Rotating Drops. AB - We consider the equilibrium and stability of rotating axisymmetric fluid drops by appealing to a variational principle that characterizes the equilibria as stationary states of a functional containing surface energy and rotational energy contributions, augmented by a volume constraint. The linear stability of a drop is determined by solving the eigenvalue problem associated with the second variation of the energy functional. We compute equilibria corresponding to both oblate and prolate shapes, as well as toroidal shapes, and track their evolution with rotation rate. The stability results are obtained for two cases: (i) a prescribed rotational rate of the system ("driven drops"), or (ii) a prescribed angular momentum ("isolated drops"). For families of axisymmetric drops instabilities may occur for either axisymmetric or non-axisymmetric perturbations; the latter correspond to bifurcation points where non-axisymmetric shapes are possible. We employ an angle-arc length formulation of the problem which allows the computation of equilibrium shapes that are not single-valued in spherical coordinates. We are able to illustrate the transition from spheroidal drops with a strong indentation on the rotation axis to toroidal drops that do not extend to the rotation axis. Toroidal drops with a large aspect ratio (major radius to minor radius) are subject to azimuthal instabilities with higher mode numbers that are analogous to the Rayleigh instability of a cylindrical interface. Prolate spheroidal shapes occur if a drop of lower density rotates within a denser medium; these drops appear to be linearly stable. This work is motivated by recent investigations of toroidal tissue clusters that are observed to climb conical obstacles after self-assembly [Nurse et al., Journal of Applied Mechanics 79 (2012) 051013]. PMID- 26958441 TI - An Improved Algorithm of Congruent Matching Cells (CMC) Method for Firearm Evidence Identifications. AB - The Congruent Matching Cells (CMC) method was invented at the National Institute of Standards and Technology (NIST) for firearm evidence identifications. The CMC method divides the measured image of a surface area, such as a breech face impression from a fired cartridge case, into small correlation cells and uses four identification parameters to identify correlated cell pairs originating from the same firearm. The CMC method was validated by identification tests using both 3D topography images and optical images captured from breech face impressions of 40 cartridge cases fired from a pistol with 10 consecutively manufactured slides. In this paper, we discuss the processing of the cell correlations and propose an improved algorithm of the CMC method which takes advantage of the cell correlations at a common initial phase angle and combines the forward and backward correlations to improve the identification capability. The improved algorithm is tested by 780 pairwise correlations using the same optical images and 3D topography images as the initial validation. PMID- 26958442 TI - SAGRAD: A Program for Neural Network Training with Simulated Annealing and the Conjugate Gradient Method. AB - SAGRAD (Simulated Annealing GRADient), a Fortran 77 program for computing neural networks for classification using batch learning, is discussed. Neural network training in SAGRAD is based on a combination of simulated annealing and Moller's scaled conjugate gradient algorithm, the latter a variation of the traditional conjugate gradient method, better suited for the nonquadratic nature of neural networks. Different aspects of the implementation of the training process in SAGRAD are discussed, such as the efficient computation of gradients and multiplication of vectors by Hessian matrices that are required by Moller's algorithm; the (re)initialization of weights with simulated annealing required to (re)start Moller's algorithm the first time and each time thereafter that it shows insufficient progress in reaching a possibly local minimum; and the use of simulated annealing when Moller's algorithm, after possibly making considerable progress, becomes stuck at a local minimum or flat area of weight space. Outlines of the scaled conjugate gradient algorithm, the simulated annealing procedure and the training process used in SAGRAD are presented together with results from running SAGRAD on two examples of training data. PMID- 26958443 TI - A Simple and Fast Spline Filtering Algorithm for Surface Metrology. AB - Spline filters and their corresponding robust filters are commonly used filters recommended in ISO (the International Organization for Standardization) standards for surface evaluation. Generally, these linear and non-linear spline filters, composed of symmetric, positive-definite matrices, are solved in an iterative fashion based on a Cholesky decomposition. They have been demonstrated to be relatively efficient, but complicated and inconvenient to implement. A new spline filter algorithm is proposed by means of the discrete cosine transform or the discrete Fourier transform. The algorithm is conceptually simple and very convenient to implement. PMID- 26958444 TI - Development of an Ultra-Pure, Carrier-Free (209)Po Solution Standard. AB - Ultra-pure, carrier-free (209)Po solution standards have been prepared and standardized for their massic alpha-particle emission rate. The standards, which will be disseminated by the National Institute of Standards and Technology (NIST) as Standard Reference Material SRM 4326a, have a mean mass of (5.169 +/- 0.003) g of a solution of polonium in nominal 2.0 mol?L(-1) HCl (having a solution density of (1.032 +/- 0.002) g? mL(-1) at 20 degrees C) that are contained in 5 mL, flame-sealed, borosilicate glass ampoules. They are certified to contain a (209)Po massic alpha-particle emission rate of (39.01 +/- 0.18) s(-1)?g(-1) as of a reference time of 1200 EST, 01 December 2013. This new standard series replaces SRM 4326 that was issued by NIST in 1994. The standardization was based on 4pialpha liquid scintillation (LS) spectrometry with two different LS counting systems and under wide variations in measurement and counting source conditions. The methodology for the standardization, with corrections for detection of the low-energy conversion electrons from the delayed 2 keV isomeric state in (205)Pb and for the radiations accompanying the small 0.45 % electron-capture branch to (209)Bi, involves a unique spectral analysis procedure that is specific for the case of (209)Po decay. The entire measurement protocol is similar, but revised and improved from that used for SRM 4326. Spectroscopic impurity analyses revealed that no photon-emitting or alpha-emitting radionuclidic impurities were detected. The most common impurity associated with (209)Po is (208)Po and the activity ratio of (208)Po/(209)Po was < 10(-7). PMID- 26958445 TI - Long-Term Stability of One-Inch Condenser Microphones Calibrated at the National Institute of Standards and Technology. AB - The devices calibrated most frequently by the acoustical measurement services at the National Institute of Standards and Technology (NIST) over the 50-year period from 1963 to 2012 were one-inch condenser microphones of three specific standard types: LS1Pn, LS1Po, and WS1P. Due to its long history of providing calibrations of such microphones to customers, NIST is in a unique position to analyze data concerning the long-term stability of these devices. This long history has enabled NIST to acquire and aggregate a substantial amount of repeat calibration data for a large number of microphones that belong to various other standards and calibration laboratories. In addition to determining microphone sensitivities at the time of calibration, it is important to have confidence that the microphones do not typically undergo significant drift as compared to the calibration uncertainty during the periods between calibrations. For each of the three microphone types, an average drift rate and approximate 95 % confidence interval were computed by two different statistical methods, and the results from the two methods were found to differ insignificantly in each case. These results apply to typical microphones of these types that are used in a suitable environment and handled with care. The average drift rate for Type LS1Pn microphones was -0.004 dB/year to 0.003 dB/year. The average drift rate for Type LS1Po microphones was 0.016 dB/year to 0.008 dB/year. The average drift rate for Type WS1P microphones was -0.004 dB/year to 0.018 dB/year. For each of these microphone types, the average drift rate is not significantly different from zero. This result is consistent with the performance expected of condenser microphones designed for use as transfer standards. In addition, the values that bound the confidence intervals are well within the limits specified for long-term stability in international standards. Even though these results show very good long-term stability historically for these microphone types, it is expected that periodic calibrations will always be done to track the calibration history of individual microphones and check for anomalies indicative of shifts in sensitivity. PMID- 26958446 TI - The Optics and Alignment of the Divergent Beam Laboratory X-ray Powder Diffractometer and its Calibration Using NIST Standard Reference Materials. AB - The laboratory X-ray powder diffractometer is one of the primary analytical tools in materials science. It is applicable to nearly any crystalline material, and with advanced data analysis methods, it can provide a wealth of information concerning sample character. Data from these machines, however, are beset by a complex aberration function that can be addressed through calibration with the use of NIST Standard Reference Materials (SRMs). Laboratory diffractometers can be set up in a range of optical geometries; considered herein are those of Bragg Brentano divergent beam configuration using both incident and diffracted beam monochromators. We review the origin of the various aberrations affecting instruments of this geometry and the methods developed at NIST to align these machines in a first principles context. Data analysis methods are considered as being in two distinct categories: those that use empirical methods to parameterize the nature of the data for subsequent analysis, and those that use model functions to link the observation directly to a specific aspect of the experiment. We consider a multifaceted approach to instrument calibration using both the empirical and model based data analysis methods. The particular benefits of the fundamental parameters approach are reviewed. PMID- 26958447 TI - Smart Electronic Laboratory Notebooks for the NIST Research Environment. AB - Laboratory notebooks have been a staple of scientific research for centuries for organizing and documenting ideas and experiments. Modern laboratories are increasingly reliant on electronic data collection and analysis, so it seems inevitable that the digital revolution should come to the ordinary laboratory notebook. The most important aspect of this transition is to make the shift as comfortable and intuitive as possible, so that the creative process that is the hallmark of scientific investigation and engineering achievement is maintained, and ideally enhanced. The smart electronic laboratory notebooks described in this paper represent a paradigm shift from the old pen and paper style notebooks and provide a host of powerful operational and documentation capabilities in an intuitive format that is available anywhere at any time. PMID- 26958448 TI - An Implementation of the Fundamental Parameters Approach for Analysis of X-ray Powder Diffraction Line Profiles. AB - This work presents an open implementation of the Fundamental Parameters Approach (FPA) models for analysis of X-ray powder diffraction line profiles. The original literature describing these models was examined and code was developed to allow for their use within a Python based least squares refinement algorithm. The NIST interest in the FPA method is specific to its ability to account for the optical aberrations of the powder diffraction experiment allowing for an accurate assessment of lattice parameter values. Lattice parameters are one of the primary certified measurands of NIST Standard Reference Materials (SRMs) for powder diffraction. Lattice parameter values obtained from analysis of data from SRMs 640e and 660c using both the NIST FPA Python code and the proprietary, commercial code Topas, that constitutes the only other actively supported, complete implementation of FPA models within a least-squares data analysis environment, agreed to within 2 fm. This level of agreement demonstrates that both the NIST code and Topas constitute an accurate implementation of published FPA models. PMID- 26958450 TI - A Journey in Standard Development: The Core Manufacturing Simulation Data (CMSD) Information Model. AB - This report documents a journey "from research to an approved standard" of a NIST led standard development activity. That standard, Core Manufacturing Simulation Data (CMSD) information model, provides neutral structures for the efficient exchange of manufacturing data in a simulation environment. The model was standardized under the auspices of the international Simulation Interoperability Standards Organization (SISO). NIST started the research in 2001 and initiated the standardization effort in 2004. The CMSD standard was published in two SISO Products. In the first Product, the information model was defined in the Unified Modeling Language (UML) and published in 2010 as SISO-STD-008-2010. In the second Product, the information model was defined in Extensible Markup Language (XML) and published in 2013 as SISO-STD-008-01-2012. Both SISO-STD-008-2010 and SISO STD-008-01-2012 are intended to be used together. PMID- 26958449 TI - Rapid Prototyping of Nanofluidic Slits in a Silicone Bilayer. AB - This article reports a process for rapidly prototyping nanofluidic devices, particularly those comprising slits with microscale widths and nanoscale depths, in silicone. This process consists of designing a nanofluidic device, fabricating a photomask, fabricating a device mold in epoxy photoresist, molding a device in silicone, cutting and punching a molded silicone device, bonding a silicone device to a glass substrate, and filling the device with aqueous solution. By using a bilayer of hard and soft silicone, we have formed and filled nanofluidic slits with depths of less than 400 nm and aspect ratios of width to depth exceeding 250 without collapse of the slits. An important attribute of this article is that the description of this rapid prototyping process is very comprehensive, presenting context and details which are highly relevant to the rational implementation and reliable repetition of the process. Moreover, this process makes use of equipment commonly found in nanofabrication facilities and research laboratories, facilitating the broad adaptation and application of the process. Therefore, while this article specifically informs users of the Center for Nanoscale Science and Technology (CNST) at the National Institute of Standards and Technology (NIST), we anticipate that this information will be generally useful for the nanofabrication and nanofluidics research communities at large, and particularly useful for neophyte nanofabricators and nanofluidicists. PMID- 26958451 TI - Toward Continuous GPS Carrier-Phase Time Transfer: Eliminating the Time Discontinuity at an Anomaly. AB - The wide application of Global Positioning System (GPS) carrier-phase (CP) time transfer is limited by the problem of boundary discontinuity (BD). The discontinuity has two categories. One is "day boundary discontinuity," which has been studied extensively and can be solved by multiple methods [1-8]. The other category of discontinuity, called "anomaly boundary discontinuity (anomaly-BD)," comes from a GPS data anomaly. The anomaly can be a data gap (i.e., missing data), a GPS measurement error (i.e., bad data), or a cycle slip. Initial study of the anomaly-BD shows that we can fix the discontinuity if the anomaly lasts no more than 20 min, using the polynomial curve-fitting strategy to repair the anomaly [9]. However, sometimes, the data anomaly lasts longer than 20 min. Thus, a better curve-fitting strategy is in need. Besides, a cycle slip, as another type of data anomaly, can occur and lead to an anomaly-BD. To solve these problems, this paper proposes a new strategy, i.e., the satellite-clock-aided curve fitting strategy with the function of cycle slip detection. Basically, this new strategy applies the satellite clock correction to the GPS data. After that, we do the polynomial curve fitting for the code and phase data, as before. Our study shows that the phase-data residual is only ~3 mm for all GPS satellites. The new strategy also detects and finds the number of cycle slips by searching the minimum curve-fitting residual. Extensive examples show that this new strategy enables us to repair up to a 40-min GPS data anomaly, regardless of whether the anomaly is due to a data gap, a cycle slip, or a combination of the two. We also find that interference of the GPS signal, known as "jamming", can possibly lead to a time-transfer error, and that this new strategy can compensate for jamming outages. Thus, the new strategy can eliminate the impact of jamming on time transfer. As a whole, we greatly improve the robustness of the GPS CP time transfer. PMID- 26958452 TI - Morphological and Electrical Characterization of MWCNT Papers and Pellets. AB - Six types of commercially available multiwall carbon nanotube soot were obtained and prepared into buckypapers by pellet pressing and by filtration into a paper. These samples were evaluated with respect to thickness, compressibility and electrical conductivity. DC conductivity results by two-point and four-point (van der Pauw) measurement methods as a function of preparation parameters are presented. Topology was investigated qualitatively by way of scanning electron microscopy and helium ion microscopy and from this, some generalizations about the nanotube structural properties and manufacturing technique with respect to conductivity are given. PMID- 26958453 TI - Certification of NIST Room Temperature Low-Energy and High-Energy Charpy Verification Specimens. AB - The possibility for NIST to certify Charpy reference specimens for testing at room temperature (21 degrees C +/- 1 degrees C) instead of -40 degrees C was investigated by performing 130 room-temperature tests from five low-energy and four high-energy lots of steel on the three master Charpy machines located in Boulder, CO. The statistical analyses performed show that in most cases the variability of results (i.e., the experimental scatter) is reduced when testing at room temperature. For eight out of the nine lots considered, the observed variability was lower at 21 degrees C than at -40 degrees C. The results of this study will allow NIST to satisfy requests for room-temperature Charpy verification specimens that have been received from customers for several years: testing at 21 degrees C removes from the verification process the operator's skill in transferring the specimen in a timely fashion from the cooling bath to the impact position, and puts the focus back on the machine performance. For NIST, it also reduces the time and cost for certifying new verification lots. For one of the low-energy lots tested with a C-shaped hammer, we experienced two specimens jamming, which yielded unusually high values of absorbed energy. For both specimens, the signs of jamming were clearly visible. For all the low-energy lots investigated, jamming is slightly more likely to occur at 21 degrees C than at -40 degrees C, since at room temperature low-energy samples tend to remain in the test area after impact rather than exiting in the opposite direction of the pendulum swing. In the evaluation of a verification set, any jammed specimen should be removed from the analyses. PMID- 26958454 TI - Potential Stable Low-Permeation Rate Standard Based on Micro-machined Silicon. AB - Silicon wafers with micro-machined holes were evaluated for use as low-permeation rate standard artifacts. Accuracy, stability, and reliability were assessed. Two independent experimental techniques for evaluating permeation were used: chilled mirror hygrometer and mass loss. The wafers exhibited a well-defined linear relationship between hole area and resultant water partial pressure for both techniques, although the mass loss curve exhibited a constant vertical offset from the hygrometer curve, attributed to water loss through the O-ring seal. In contrast to polymer permeation standards, Si wafers provided long-term reproducible permeation rates. However, they were also highly fragile, with most of them cracking during the course of the investigation. PMID- 26958455 TI - Interaction of CD38 Variant and Chronic Interpersonal Stress Prospectively Predicts Social Anxiety and Depression Symptoms Over Six Years. AB - Variation in the CD38 gene, which regulates secretion of the neuropeptide oxytocin, has been associated with several social phenotypes. Specifically, rs3796863 A allele carriers have demonstrated increased social sensitivity. In 400 older adolescents, we used trait-state-occasion modeling to investigate how rs3796863 genotype, baseline ratings of chronic interpersonal stress, and their gene-environment (GxE) interaction predicted trait social anxiety and depression symptoms over six years. We found significant GxE effects for CD38 A-carrier genotypes and chronic interpersonal stress at baseline predicting greater social anxiety and depression symptoms. A significant GxE effect of smaller magnitude was also found for C/C genotype and chronic interpersonal stress predicting greater depression; however, this effect was small compared to the main effect of chronic interpersonal stress. Thus, in the context of chronic interpersonal stress, heightened social sensitivity associated with the rs3796863 A allele may prospectively predict risk for social anxiety and (to a lesser extent) depression. PMID- 26958456 TI - Microbiological evaluation of different reprocessing methods for cuffed and un cuffed tracheostomy tubes in home-care and hospital setting. AB - BACKGROUND: Manufacturers' recommendations on cleaning of tracheostomy tubes focus on general warning information and non-specific manual cleaning procedures. The aim of this experimental study was to evaluate different reprocessing methods and to determine the mechanical integrity and functionality of tracheostomy tubes following reprocessing. METHODS: Sixteen cuffed or un-cuffed tracheostomy tubes obtained from hospital in-patients were reprocessed using one of the following reprocessing methods: a) manual brushing and rinsing with tap water, b) manual brushing followed by disinfection with a glutaraldehyde solution, c) manual brushing followed machine-based cleaning in a dishwasher, and d) manual brushing followed by ultrasound cleaning in a commercially available ultrasound device. Microbial burden of the tubes before and after reprocessing was assessed by measurement of microbial colony-forming units per mL (CFU/mL) of rinsing fluid. After cleaning, tracheostomy tubes were investigated for loss of functionality. FINDINGS: Manual brushing and rinsing with tap water reduced microbial colonization in average by 10(2) CFU/mL, but with poor reproducibility and reliability. Complete microbial reduction was achieved only with additional chemical or machine-based thermal disinfection. Ultrasound sonification yielded no further microbial reduction after manual brushing. CONCLUSION: Manual brushing alone will not result in complete eradication of microorganism colonising cuffed or un-cuffed tracheostomy tubes. However, manual cleaning followed by chemical or thermal disinfection may be regarded as safe and reproducible reprocessing method. If a machine-based reprocessing method is used for cuffed tubes, the cuffs' ventilation hose must be secured in a safe position prior to thermal disinfection. PMID- 26958457 TI - Hygiene guideline for the planning, installation, and operation of ventilation and air-conditioning systems in health-care settings - Guideline of the German Society for Hospital Hygiene (DGKH). AB - Since the publication of the first "Hospital Hygiene Guideline for the implementation and operation of air conditioning systems (HVAC systems) in hospitals" (http://www.krankenhaushygiene.de/informationen/fachinformationen/leitlinien/12) in 2002, it was necessary due to the increase in knowledge, new regulations, improved air-conditioning systems and advanced test methods to revise the guideline. Based on the description of the basic features of ventilation concepts, its hygienic test and the usage-based requirements for ventilation, the DGKH section "Ventilation and air conditioning technology" attempts to provide answers for the major air quality issues in the planning, design and the hygienically safe operation of HVAC systems in rooms of health care. PMID- 26958459 TI - Surveillance for parasites in unaccompanied minor refugees migrating to Germany in 2015. AB - In 2015, most of the refugees arriving in Germany originated from countries with poor hygienic and sanitary conditions. Stool samples of 1,230 minor refugees unaccompanied by adults were investigated for possible parasites. Giardia lamblia was by far the most frequently detected parasite (n=165); all other parasites were considerably less frequent and encountered in the following order: Hymenolepis nana (n=23), Entamoeba histolytica (n=17), Trichuris trichiura (n=8), and Blastocystis hominis (n=1). Ascaris lumbricoides was not detected among any of the screened refugees. Considerable differences in prevalence rates in refugees originating from different countries could be observed. PMID- 26958458 TI - Presence of exoY, exoS, exoU and exoT genes, antibiotic resistance and biofilm production among Pseudomonas aeruginosa isolates in Northwest Iran. AB - BACKGROUND: Pseudomonas aeruginosa, as Gram-negative rod bacilli, has an important role in human infection. In the present study we aimed to investigate the presence of exo genes and biofilm production among Pseudomonas aeruginosa isolates in Northwest Iran. MATERIAL AND METHODS: 160 isolates of P. aeruginosa were collected and identified by biochemical tests and were characterized for antibiotic resistance. Biofilm production was evaluated by microtiter plate assay and the presence of exo genes was evaluated by allele-specific PCR (polymerase chain reaction). Chi-square test was used for statistical analysis. RESULTS: The most effective antibiotics against isolates were colistin and polymyxin B. 87% of the isolates were biofilm producers of which 69% were strongly biofilm producers. 55% of the isolates carried exoY, 52% of the isolates carried exoU, and 26.3% and 5% carried exoS and exoT, respectively. CONCLUSION: Our findings showed different distribution of exo genes in clinical isolates of P. aeruginosa in Northwest Iran. ExoS and exoU were more prevalent in non-biofilm producers and exoY was more prevalent in biofilm producer isolates. These results might indicate the importance of exoY in biofilm production of Pseudomonas aeruginosa. PMID- 26958460 TI - Differences in the rheological properties and mixing compatibility with heparinoid cream of brand name and generic steroidal ointments: The effects of their surfactants. AB - Most steroidal ointments contain propylene glycol (PG) and surfactants, which improve the solubility of corticosteroids in white petrolatum. Surfactants aid the uniform dispersal of PG within white petrolatum. Since the surfactants used in generic ointments are usually different from those used in brand name ointments, we investigated the effects of surfactants on the rheological properties of three brand name ointments and six equivalent generic ointments. We detected marked differences in hardness, adhesiveness, and spreadability among the ointments. Further examinations of model ointments consisting of white petrolatum, PG, and surfactants revealed that the abovementioned properties, especially hardness and adhesiveness, were markedly affected by the surfactants. Since steroidal ointments are often admixed with moisturizing creams prior to use, we investigated the mixing compatibility of the ointments with heparinoid cream and how this was affected by their surfactants. We found that the ointments containing glyceryl monostearate demonstrated good mixing compatibility, whereas those containing non-ionic surfactants with polyoxyethylene chains exhibited phase separation. These results were also consistent with the findings for the model ointments, which indicates that the mixing compatibility of steroidal ointments with heparinoid cream is determined by the emulsifying capacity of the surfactants in their oily bases. PMID- 26958461 TI - Tinea pedis due to Cylindrocarpon lichenicola beginning onycholysis. AB - A 33 year old woman presented with both feet, humid and white Tinea pedis at the second, third and fourth inter-toes areas associated with a beginning onycholysis of the nails lasting for 18 months. KOH mount of the samples was positive for fungal hyphae. The fungus was isolated on Sabouraud-chlorampphenicol agar and identified as Cylindrocarpon lichenicola. The patient was treated with an association of terbinafine tablet and terbinafine cream and presented clinical cure after three months. PMID- 26958462 TI - Correlation between amygdala BOLD activity and frontal EEG asymmetry during real time fMRI neurofeedback training in patients with depression. AB - Real-time fMRI neurofeedback (rtfMRI-nf) is an emerging approach for studies and novel treatments of major depressive disorder (MDD). EEG performed simultaneously with an rtfMRI-nf procedure allows an independent evaluation of rtfMRI-nf brain modulation effects. Frontal EEG asymmetry in the alpha band is a widely used measure of emotion and motivation that shows profound changes in depression. However, it has never been directly related to simultaneously acquired fMRI data. We report the first study investigating electrophysiological correlates of the rtfMRI-nf procedure, by combining the rtfMRI-nf with simultaneous and passive EEG recordings. In this pilot study, MDD patients in the experimental group (n = 13) learned to upregulate BOLD activity of the left amygdala using an rtfMRI-nf during a happy emotion induction task. MDD patients in the control group (n = 11) were provided with a sham rtfMRI-nf. Correlations between frontal EEG asymmetry in the upper alpha band and BOLD activity across the brain were examined. Average individual changes in frontal EEG asymmetry during the rtfMRI-nf task for the experimental group showed a significant positive correlation with the MDD patients' depression severity ratings, consistent with an inverse correlation between the depression severity and frontal EEG asymmetry at rest. The average asymmetry changes also significantly correlated with the amygdala BOLD laterality. Temporal correlations between frontal EEG asymmetry and BOLD activity were significantly enhanced, during the rtfMRI-nf task, for the amygdala and many regions associated with emotion regulation. Our findings demonstrate an important link between amygdala BOLD activity and frontal EEG asymmetry during emotion regulation. Our EEG asymmetry results indicate that the rtfMRI-nf training targeting the amygdala is beneficial to MDD patients. They further suggest that EEG-nf based on frontal EEG asymmetry in the alpha band would be compatible with the amygdala-based rtfMRI-nf. Combination of the two could enhance emotion regulation training and benefit MDD patients. PMID- 26958463 TI - Klinefelter syndrome has increased brain responses to auditory stimuli and motor output, but not to visual stimuli or Stroop adaptation. AB - Klinefelter syndrome (47, XXY) (KS) is a genetic syndrome characterized by the presence of an extra X chromosome and low level of testosterone, resulting in a number of neurocognitive abnormalities, yet little is known about brain function. This study investigated the fMRI-BOLD response from KS relative to a group of Controls to basic motor, perceptual, executive and adaptation tasks. Participants (N: KS = 49; Controls = 49) responded to whether the words "GREEN" or "RED" were displayed in green or red (incongruent versus congruent colors). One of the colors was presented three times as often as the other, making it possible to study both congruency and adaptation effects independently. Auditory stimuli saying "GREEN" or "RED" had the same distribution, making it possible to study effects of perceptual modality as well as Frequency effects across modalities. We found that KS had an increased response to motor output in primary motor cortex and an increased response to auditory stimuli in auditory cortices, but no difference in primary visual cortices. KS displayed a diminished response to written visual stimuli in secondary visual regions near the Visual Word Form Area, consistent with the widespread dyslexia in the group. No neural differences were found in inhibitory control (Stroop) or in adaptation to differences in stimulus frequencies. Across groups we found a strong positive correlation between age and BOLD response in the brain's motor network with no difference between groups. No effects of testosterone level or brain volume were found. In sum, the present findings suggest that auditory and motor systems in KS are selectively affected, perhaps as a compensatory strategy, and that this is not a systemic effect as it is not seen in the visual system. PMID- 26958464 TI - Electrical source imaging of interictal spikes using multiple sparse volumetric priors for presurgical epileptogenic focus localization. AB - Electrical source imaging of interictal spikes observed in EEG recordings of patients with refractory epilepsy provides useful information to localize the epileptogenic focus during the presurgical evaluation. However, the selection of the time points or time epochs of the spikes in order to estimate the origin of the activity remains a challenge. In this study, we consider a Bayesian EEG source imaging technique for distributed sources, i.e. the multiple volumetric sparse priors (MSVP) approach. The approach allows to estimate the time courses of the intensity of the sources corresponding with a specific time epoch of the spike. Based on presurgical averaged interictal spikes in six patients who were successfully treated with surgery, we estimated the time courses of the source intensities for three different time epochs: (i) an epoch starting 50 ms before the spike peak and ending at 50% of the spike peak during the rising phase of the spike, (ii) an epoch starting 50 ms before the spike peak and ending at the spike peak and (iii) an epoch containing the full spike time period starting 50 ms before the spike peak and ending 230 ms after the spike peak. To identify the primary source of the spike activity, the source with the maximum energy from 50 ms before the spike peak till 50% of the spike peak was subsequently selected for each of the time windows. For comparison, the activity at the spike peaks and at 50% of the peaks was localized using the LORETA inversion technique and an ECD approach. Both patient-specific spherical forward models and patient-specific 5 layered finite difference models were considered to evaluate the influence of the forward model. Based on the resected zones in each of the patients, extracted from post-operative MR images, we compared the distances to the resection border of the estimated activity. Using the spherical models, the distances to the resection border for the MSVP approach and each of the different time epochs were in the same range as the LORETA and ECD techniques. We found distances smaller than 23 mm, with robust results for all the patients. For the finite difference models, we found that the distances to the resection border for the MSVP inversions of the full spike time epochs were generally smaller compared to the MSVP inversions of the time epochs before the spike peak. The results also suggest that the inversions using the finite difference models resulted in slightly smaller distances to the resection border compared to the spherical models. The results we obtained are promising because the MSVP approach allows to study the network of the estimated source-intensities and allows to characterize the spatial extent of the underlying sources. PMID- 26958465 TI - Temporal filtering of longitudinal brain magnetic resonance images for consistent segmentation. AB - Longitudinal analysis of magnetic resonance images of the human brain provides knowledge of brain changes during both normal aging as well as the progression of many diseases. Previous longitudinal segmentation methods have either ignored temporal information or have incorporated temporal consistency constraints within the algorithm. In this work, we assume that some anatomical brain changes can be explained by temporal transitions in image intensities. Once the images are aligned in the same space, the intensities of each scan at the same voxel constitute a temporal (or 4D) intensity trend at that voxel. Temporal intensity variations due to noise or other artifacts are corrected by a 4D intensity-based filter that smooths the intensity values where appropriate, while preserving real anatomical changes such as atrophy. Here smoothing refers to removal of sudden changes or discontinuities in intensities. Images processed with the 4D filter can be used as a pre-processing step to any segmentation method. We show that such a longitudinal pre-processing step produces robust and consistent longitudinal segmentation results, even when applying 3D segmentation algorithms. We compare with state-of-the-art 4D segmentation algorithms. Specifically, we experimented on three longitudinal datasets containing 4-12 time-points, and showed that the 4D temporal filter is more robust and has more power in distinguishing between healthy subjects and those with dementia, mild cognitive impairment, as well as different phenotypes of multiple sclerosis. PMID- 26958468 TI - Epilepsy with myoclonic-atonic seizures (Doose syndrome): When video-EEG polygraphy holds the key to syndrome diagnosis. AB - An electroclinical epilepsy syndrome diagnosis enables physicians to predict outcomes as well as select appropriate treatment options. We report a child who presented with reflex myoclonus at the age of 9 months and was initially diagnosed with myoclonic epilepsy in infancy. After 9 years of medically resistant myoclonic seizures, extensive investigations, and emerging learning difficulties, she was referred for video-telemetry to characterize her seizures in an attempt to make a syndromic diagnosis. A three-day video-telemetry assessment was performed to document seizures. Neck and deltoid EMG channels were applied from the onset of the recording. Frequent generalized bursts of 3- to 5 Hz spike/polyspike and slow wave discharges, associated with clinical manifestations, mostly myoclonic seizures, were noted. In addition, definite atonic components were noted on the neck EMG as well as the deltoids associated with the slow component of the ictal discharges. The EEG and polygraphy findings are suggestive of a generalized epilepsy characterized by predominantly myoclonic seizures with atonic components. This raises the possibility whether a variant of epilepsy with myoclonic-atonic seizures (Doose syndrome) may be the underlying diagnosis for this girl. A trial of the ketogenic diet would therefore be considered as an option in her future management in view of its beneficial effect in this condition. PMID- 26958469 TI - Stereotactic Body Radiotherapy for the Treatment of Renal Tumors. AB - The purpose of this study was to evaluate the response of actively growing renal masses to stereotactic body radiation therapy (SBRT). We retrospectively reviewed our institutional review board-approved kidney database and identified 4 patients who underwent SBRT, 15 Gy dose, for their rapidly growing renal masses. Three patients had a decreased tumor size after radiation treatment by 20.8%, 38.1%, and 20%. The other patient had a size gain of 5.6%. This patient maintained a similar tumor growth rate before and after SBRT. Mean follow-up time was 13.8 months. SBRT represents an effective management option in select patients with larger rapidly growing kidney masses. PMID- 26958466 TI - Unlearning chronic pain: A randomized controlled trial to investigate changes in intrinsic brain connectivity following Cognitive Behavioral Therapy. AB - Chronic pain is a complex physiological and psychological phenomenon. Implicit learning mechanisms contribute to the development of chronic pain and to persistent changes in the central nervous system. We hypothesized that these central abnormalities can be remedied with Cognitive Behavioral Therapy (CBT). Specifically, since regions of the anterior Default Mode Network (DMN) are centrally involved in emotional regulation via connections with limbic regions, such as the amygdala, remediation of maladaptive behavioral and cognitive patterns as a result of CBT for chronic pain would manifest itself as a change in the intrinsic functional connectivity (iFC) between these prefrontal and limbic regions. Resting-state functional neuroimaging was performed in patients with chronic pain before and after 11-week CBT (n = 19), as well as a matched (ages 19 59, both sexes) active control group of patients who received educational materials (n = 19). Participants were randomized prior to the intervention. To investigate the differential impact of treatment on intrinsic functional connectivity (iFC), we compared pre-post differences in iFC between groups. In addition, we performed exploratory whole brain analyses of changes in fractional amplitude of low frequency fluctuations (fALFF). The course of CBT led to significant improvements in clinical measures of pain and self-efficacy for coping with chronic pain. Significant group differences in pre-post changes in both iFC and fALFF were correlated with clinical outcomes. Compared to control patients, iFC between the anterior DMN and the amygdala/periaqueductal gray decreased following CBT, whereas iFC between the basal ganglia network and the right secondary somatosensory cortex increased following CBT. CBT patients also had increased post-therapy fALFF in the bilateral posterior cingulate and the cerebellum. By delineating neuroplasticity associated with CBT-related improvements, these results add to mounting evidence that CBT is a valuable treatment option for chronic pain. PMID- 26958470 TI - Complete Response to Bicalutamide Withdrawal Prolonged for Almost 2 Years in Patients With Metastatic Prostate Cancer. AB - This is the first case report describing a complete response to bicalutamide withdrawal that lasted for almost 2 years in a patient with metastatic prostate cancer. An 80-year-old man who had prostate-specific antigen (PSA) level elevation (168.1 ng/mL) visited our hospital in February 2010. Bone scintigraphy showed pelvic metastases. We started hormonal therapy with leuprorelin and bicalutamide. The PSA concentration decreased to <0.1 ng/mL but started increasing again and reached 1.64 ng/mL in October 2012, at which time bicalutamide administration was discontinued. The PSA concentration decreased again and has remained below the limit of sensitivity for almost 2 years. PMID- 26958471 TI - Primary Renal Synovial Sarcoma: An Oncologic Surprise. AB - Primary renal synovial sarcoma is a rare tumor having a specific chromosomal translocation t(X; 18) (p11.2; q11.2). The clinical features of this tumor and radiologic appearances are quite similar to those of renal cell carcinoma. Confirmatory diagnosis requires fluorescent in situ hybridization or reverse transcriptase polymerase chain reaction validation for differentiating the tumors from sarcomatoid renal cell carcinoma. We present a case of primary renal synovial sarcoma that was diagnosed in a middle-aged man. PMID- 26958467 TI - The effect of alcohol consumption on the adolescent brain: A systematic review of MRI and fMRI studies of alcohol-using youth. AB - BACKGROUND: A large proportion of adolescents drink alcohol, with many engaging in high-risk patterns of consumption, including binge drinking. Here, we systematically review and synthesize the existing empirical literature on how consuming alcohol affects the developing human brain in alcohol-using (AU) youth. METHODS: For this systematic review, we began by conducting a literature search using the PubMED database to identify all available peer-reviewed magnetic resonance imaging (MRI) and functional magnetic resonance imaging (fMRI) studies of AU adolescents (aged 19 and under). All studies were screened against a strict set of criteria designed to constrain the impact of confounding factors, such as co-occurring psychiatric conditions. RESULTS: Twenty-one studies (10 MRI and 11 fMRI) met the criteria for inclusion. A synthesis of the MRI studies suggested that overall, AU youth showed regional differences in brain structure as compared with non-AU youth, with smaller grey matter volumes and lower white matter integrity in relevant brain areas. In terms of fMRI outcomes, despite equivalent task performance between AU and non-AU youth, AU youth showed a broad pattern of lower task-relevant activation, and greater task-irrelevant activation. In addition, a pattern of gender differences was observed for brain structure and function, with particularly striking effects among AU females. CONCLUSIONS: Alcohol consumption during adolescence was associated with significant differences in structure and function in the developing human brain. However, this is a nascent field, with several limiting factors (including small sample sizes, cross-sectional designs, presence of confounding factors) within many of the reviewed studies, meaning that results should be interpreted in light of the preliminary state of the field. Future longitudinal and large-scale studies are critical to replicate the existing findings, and to provide a more comprehensive and conclusive picture of the effect of alcohol consumption on the developing brain. PMID- 26958472 TI - Bladder Hamartoma in a Fetus: Case Report. AB - We present the case of the youngest reported patient with a bladder hamartoma detected prenatally by ultrasonography. Bladder tumors in newborns are rare, but a hamartoma should not be discarded among the diagnostic possibilities when evaluating a fetus or a newborn with a polypoid bladder lesion. PMID- 26958473 TI - Double Trouble: A Rare Case of Bilateral Upper Pole Ureteropelvic Junction Obstruction. AB - A 16-year-old girl presented with bilateral back pain caused by bilateral upper pole ureteropelvic junction obstructions; an extremely rare phenomenon. Bilateral robotically assisted upper pole pyeloplasties were preformed at the same setting with an excellent clinical response. Although rare, upper pole ureteropelvic junction obstruction is a defined entity that urologists should be aware of. PMID- 26958474 TI - Epithelioid Angiomyolipoma in a Pediatric Patient: Case Report and Review of Literature. AB - We report a case of a 17-year-old girl with tuberous sclerosis complex who underwent partial nephrectomy for a newly discovered 7.5-cm renal mass subsequently determined to be an epithelioid angiomyolipoma, a rare variant of angiomyolipoma that can be confused clinically, radiographically, and pathologically for renal cell carcinoma. Proper diagnosis and treatment are critical, especially in the pediatric patient. This case report and review of literature serve at increasing the awareness of this renal tumor, with its somewhat unpredictable outcome, reviewing the pertinent literature on the topic of epithelioid angiomyolipoma in the clinical setting of tuberous sclerosis complex. PMID- 26958475 TI - Supernumerary Kidney With a Horseshoe Component. AB - We report a case of supernumerary kidney consisting of 4 renal moieties and including a horseshoe kidney. A 40-year-old woman presented complaining of intermittent vague abdominal pain and heaviness for a few years. Ultrasonography of the urinary tract revealed 2 kidneys on the left side and horseshoe kidneys located distal to them. The right horseshoe kidney was of small size. Further imaging revealed 4 renal moieties. Three moieties were on the left side and the other was attached to the most distal moiety on the left, forming a horseshoe kidney. PMID- 26958476 TI - Imaging Misdiagnosis Analysis of a Rare Case of Renal Subcapsular Hematoma Located in the Renal Hilum and Collecting Area. AB - We report a rare case of renal subcapsular hematoma, which was located in the renal hilum and collecting area. Preoperative ultrasonography, retrograde urethrography, and computed tomographic examinations misdiagnosed the patient with simple hydronephrosis, without finding a lesion causing the hydronephrosis. We retrospectively summarized the imaging features and analyzed the reasons leading to the misdiagnosis. PMID- 26958477 TI - Ectopic Adrenocortical Tissue in the Spermatic Cord in a 44-Year-old Man. AB - We report on a 44-year-old man who underwent microsurgical inguinal repair for symptomatic varicocele. As an incidental finding during surgery, a yellowish tumor (9 * 5 * 4 mm) was found in the spermatic cord. Histologic examination revealed ectopic adrenocortical tissue. Ectopic adrenocortical tissue in the spermatic cord is known to appear in children and adolescents but is extremely rare in adults. Surgical removal of the tissue is recommended, although malignant transformation or functional hormonal disorders are very unlikely. PMID- 26958478 TI - Postcoital Hemorrhage of a Recurrent Seminal Vesicle Cyst Requiring Embolization. AB - Herein is a case of a 23-year-old man with recurrence of a seminal vesicle cyst after percutaneous drainage and laparoscopic excision complicated by hemorrhage requiring embolization. He presented to the emergency department for pain after ejaculation. Computed tomographic scan of his pelvis revealed extravasation of contrast near his cyst and pelvic fluid collection suspicious for a hematoma. The patient had steadily decreasing hemoglobin and hematocrit levels. An interventional radiologist performed an embolization of the left seminal vesicle cystic arteries. Hemoglobin and hematocrit values improved and he was discharged. Hemorrhage resolved with embolization procedure and pain dissipated over the course of follow up care. PMID- 26958479 TI - Inflammatory Myofibroblastic Tumor: A Case Study. AB - Inflammatory myofibroblastic tumor (IMT) is a rare benign lesion found in many locations throughout the body and genitourinary tract. Endoscopically and radiographically, these solid lesions cannot be distinguished from malignant bladder tumors. We present the case of a 21-year-old woman who presented with painful obstructive and irritative voiding symptoms of short duration. After extensive preoperative evaluation failed to reveal a definitive diagnosis, the patient underwent partial cystectomy. Final pathology revealed IMT. A high index of suspicion is required for diagnosis of IMT as it is often difficult to distinguish from its malignant counterparts. PMID- 26958480 TI - Tuberculosis of the Spermatic Cord: Case Report. AB - The spermatic cord tuberculoma is uncommon, especially in its lower portion. Most cases were described in Japanese literature. We report a case of tuberculosis of the spermatic cord in a sexually active young man, revealed by a scrotal mass mimicking a tumor of the testicle and discuss the suitable diagnostic and therapeutic procedures, with preservation of the testes and the other sexual organs. PMID- 26958481 TI - A Case of Pulmonary Pleomorphic Carcinoma With Renal Metastasis. AB - A 62-year-old man was referred to our hospital for an axillary mass. Computed tomography (CT) revealed a right axillary tumor and a left renal tumor. Needle biopsies of lung tumor and renal tumor were performed, but a definite diagnosis was impossible. Because his performance status worsened and the lung tumor grew day by day, chemotherapy with gemcitabine and cisplatin was started without definite diagnosis. However, the chemotherapy could not be continued because of interstitial pneumonia and the patient died because of the progression of disease. The final histopathologic diagnosis was pulmonary pleomorphic carcinoma based on immunohistochemical staining. PMID- 26958482 TI - Case of Subcutaneous Leiomyosarcoma of the Scrotum Presenting as a Sebaceous Cyst in a 71-Year-old Man: A Case Report and Review of the Literature. AB - Leiomyosarcoma of the scrotum is a rare genital malignancy with approximately 35 reported cases in literature. We present a case of leiomyosarcoma of the scrotum in a 71-year-old man appearing as a sebaceous cyst that later developed ulcerations. However, because the irregular mass developed ulcerations, this should trigger one to consider that lesion is potentially malignant. The pathology report demonstrated malignant spindle cell neoplasm consistent with leiomyosarcoma, which tested positive for desmin and actin stains. On literature review, a study reported a 5-year survival rate of 50%-80%. The clinical features, diagnosis, histopathologic images, and treatment are reviewed. PMID- 26958483 TI - Renal Bleeding Due to Extramedullary Hematopoiesis in a Patient With Chronic Myelogenous Leukemia. AB - Chronic myelogenous leukemia (CML) is a myeloproliferative disorder that normally presents in middle-aged adults. Renal infiltration and extramedullary hematopoiesis in renal tissue has been rarely reported. This case report presents a patient with CML and renal insufficiency who developed gross hematuria. Efforts at controlling the hematuria led to a cascade of events propelled by the underlying disorder that ultimately led to a radical nephrectomy, multiorgan failure, and prolonged hospitalization. We suggest that management of gross hematuria in clinically stable patients with CML, suspected of having extramedullary hematopoiesis, should prioritize treatment of the myeloproliferative disorder over efforts to control bleeding. PMID- 26958484 TI - Lithium-induced Nephrotoxicity: A Case Report of Renal Cystic Disease Presenting as a Mass Lesion. AB - Lithium is an effective therapeutic agent used in the management of bipolar disorder. However, lithium is also associated with several side effects, including renal toxicity. We present a case of a symptomatic cystic mass lesion in the kidney of a patient who had a history of lithium therapy for the management of bipolar disorder. PMID- 26958485 TI - Episodic Hypertension With an Adrenal Mass: A Red Herring. AB - A 66-year-old man with symptomatic hypertensive episodes was found to have a 9-mm adrenal mass and elevated metanephrine levels. He was scheduled for an adrenalectomy for suspected pheochromocytoma. Subsequent workup revealed a large bladder mass which was found to be a paraganglioma. There is no consensus on what should be considered the standard management of primary bladder paraganglioma, including surgical technique, assessment of malignancy, and appropriate follow up, owing to the rarity of the diagnosis. PMID- 26958486 TI - Accessory Scrotum With Perineal Lipoma: Pathologic Evaluation Including Androgen Receptor Expression. AB - Accessory scrotum is an unusual developmental anomaly defined as additional scrotal tissue in addition to a normally developed scrotum. The accessory scrotum arises posterior to the normally located scrotum and does not contain a testis. We report a case of an 18-month-old boy with an accessory scrotum attached to a perineal lipoma. We resected both and determined histologically that they were of the same tissue as the scrotum, including the presence of androgen receptor expression. To the best of our knowledge, this is the first case to assess androgen receptor expression in an accessory scrotum using immunostaining. PMID- 26958488 TI - Preface on small cell lung cancer. PMID- 26958487 TI - Nonspecific Presentation of a Multiloculated Prostatic Abscess After Transurethral Prostatic Biopsy for Elevated Prostate-specific Antigen Level. AB - Prostate postbiopsy infectious complications typically present in the form of prostatitis and uncommonly urosepsis. Prostatic abscesses are generally found after multiple bouts of prostatitis and are associated with a clinically septic picture requiring intensive care unit admission and resuscitation. We report the case of a 65-year-old man who presented with prostatic abscess in the setting of nonspecific urinary symptoms after transrectal ultrasonography-guided prostate biopsy. At 4-month follow-up, he is currently free of disease with undetectable prostate-specific antigen level and negative imaging. PMID- 26958489 TI - Cellular and molecular biology of small cell lung cancer: an overview. AB - Although the incidence of small cell lung cancer (SCLC) has declined during the past 30 years, it remains a frustrating disease to research and treat. Numerous attempts to enhance the anti-tumor effects of traditional chemotherapy for SCLC have not been successful. For any tumor to become cancerous, various genetic mutations and biologic alterations must occur in the cell that, when combined, render it a malignant neoplasm. New and novel therapies based on understanding these mechanisms of transformation are needed. Herein we provide an in-depth view of some of the genomic alterations in SCLC that have emerged as potential targets for therapeutic intervention. PMID- 26958490 TI - Cancer stem cells in small cell lung cancer. AB - Small cell lung cancer (SCLC) is one of the most aggressive lung tumors, with poor survival rates. Although patients may initially respond to treatment, this is followed by rapid development of drug resistance and disease progression. SCLC patients often present with metastasis at time of diagnosis, ruling out surgery as a treatment option. Currently, treatment options for this disease remain limited and platinum-based chemotherapy is the treatment of choice. A better understanding of the biology of SCLC could allow us to identify new therapeutic targets. Cancer stem cell (CSC) theory is currently crucial in cancer research and could provide a viable explanation for the heterogeneity, drug resistance, recurrence and metastasis of several types of tumors. Some characteristics of SCLC, such as aggressiveness, suggest that this kind of tumor could be enriched in CSCs, and drug resistance in SCLC could be attributable to the existence of a CSC subpopulation in SCLC. Herein we summarize current understanding of CSC in SCLC, including the evidence for CSC markers and signaling pathways involved in stemness. We also discuss potential ongoing strategies and areas of active research in SCLC, such as immunotherapy, that focus on inhibition of signaling pathways and targeting molecules driving stemness. Understanding of signaling pathways and the discovery of new therapeutic markers specific to CSCs will lead to new advances in therapy and improvements in prognosis of SCLC patients. Therefore, evaluation of these CSC-specific molecules and pathways may become a routine part of SCLC diagnosis and therapy. PMID- 26958491 TI - Treatment for small cell lung cancer, where are we now?-a review. AB - Small cell lung cancer (SCLC) represents between 13% and 15% of all diagnosed lung cancers worldwide. It is an aggressive neoplasia, with a 5-year mortality of 90% or more. It has historically been classified as limited disease (LD) and extensive disease (ED) in most study protocols. The cornerstone of treatment for any stage of SCLC is etoposide-platinum based chemotherapy; in limited stage (LS), concomitant radiotherapy to thorax and mediastinum. Prophylactic radiotherapy to the central nervous system (CNS) [prophylactic cerebral irradiation (PCI)] has diminished the incidence of brain metastasis as the site for relapse in LD and ED patients, therefore it should be offered to patients with complete response to induction first-line treatment. Regarding second-line treatment, results are more modest and topotecan is accepted as treatment for this scenario offering a modest benefit. PMID- 26958492 TI - Small cell lung cancer (SCLC): no treatment advances in recent years. AB - Small cell lung cancer (SCLC) is an aggressive malignancy with a distinct natural history and dismal prognosis. Given its predisposition for early dissemination, patients are commonly diagnosed with metastatic disease and chemotherapy is regarded as the cornerstone of approved treatment strategies. However, over the last 30 years there has been a distinct paucity of significant breakthroughs in SCLC therapy. Thus, SCLC is characterized as a recalcitrant neoplasm with limited therapeutic options. By employing well-established research approaches, proven to be efficacious in non-small cell lung cancer (NSCLC), a growing amount of data has shed light on the molecular biology of SCLC and enhanced our knowledge of the "drivers" of tumor cell survival and proliferation. New therapeutic targets have emerged, but no significant improvement in patients' survival has been demonstrated thus far. In a sense, the more we know, the more we fail. Nowadays this is starting to change and methodical research efforts are underway. It is anticipated that the next decade will see a revolution in the treatment of SCLC patients with the application of effective precision medicine and immunotherapy strategies. PMID- 26958494 TI - Second-line therapy for small cell lung cancer: exploring the potential role of circulating tumor cells. AB - BACKGROUND: Small cell lung cancer (SCLC) is an aggressive and invasive variant of lung tumors. SCLC, especially in advanced stages, is distinguished by extremely high numbers of circulating tumor cells (CTCs) in comparison to other malignancies. CTCs are operative in tumor spread and are currently enumerated to assess prognosis and response to cytotoxic therapy. Chemosensitivity of SCLC CTCs compared to primary tumors and metastases is not known. METHODS: Establishment of two SCLC CTC cell lines, namely BHGc7 and BHGc10, allowed the in vitro characterization of their chemosensitivity to the second-line chemotherapeutics topotecan and epirubicin in comparison to a range of SCLC cell lines. RESULTS: The SCLC CTC cell lines exhibited an approximately 7- and 12-fold increased chemosensitivity to epirubicin compared to topotecan, respectively, in in vitro cytotoxicity assays. In comparison to a panel of six SCLC cell lines, the two CTC lines showed a significantly higher chemosensitivity to epirubicin (range, 3- to 16-fold) and topotecan (range, 2.2- to 14.4-fold), respectively. CONCLUSIONS: CTC cell lines derived from SCLC patients with recurrent disease exhibit high chemosensitivity to epirubicin vs. topotecan and show considerable more cytotoxicity in response to both compounds in comparison to a panel of SCLC cell lines. Thus, a decrease in the number of CTCs in response to second-line chemotherapy in SCLC patients may overestimate the effect on resident SCLC lesions and metastases. PMID- 26958496 TI - Surgical controversies in mesothelioma: MesoVATS addresses the role of surgical debulking. AB - Contemporary multi-modality treatment of malignant mesothelioma remains challenging. The merits of surgical resection and the particular extent of resection continue to be debated topics. To date few randomized surgical trials have been completed to address many lingering issues concerning surgery in mesothelioma. Recently, the MesoVATS trial shows us that a minimally invasive thoracoscopic procedure for curative resection in mesothelioma is of limited benefit. Results of ongoing clinical trials are awaited. PMID- 26958493 TI - Targeted drugs in small-cell lung cancer. AB - In contrast to non-small-cell lung cancer (NSCLC), few advances have been made in systemic treatment of small-cell lung cancer (SCLC) in recent years. Most patients are diagnosed with extensive stage disease and are commonly treated with platinum-based chemotherapy which, although attaining high initial objective responses, has a limited impact on survival. Due to the dismal prognosis of SCLC, novel and more effective treatment strategies are urgently needed. A deeper characterization of the genomic landscape of SCLC has led to the development of rational and promising targeted agents. However, despite a large number of clinical trials, results have been disappointing and there are still no approved targeted drugs for SCLC. Recent comprehensive genomic studies suggest SCLC is a heterogeneous disease, characterized by genomic alterations targeting a broad variety of genes, including those involved in transcription regulation and chromatin modification which seem to be a hallmark of this specific lung cancer subtype. Current research efforts are focusing on further understanding of the cellular and molecular abnormalities underlying SCLC development, progression and resistance to chemotherapy. Unraveling the genomic complexity of SCLC could be the key to optimize existing treatments, including chemotherapy and radiotherapy, and for identifying those patients most likely to benefit from selected targeted therapeutic approaches. PMID- 26958495 TI - Anti-vascular endothelial growth factor therapies at the crossroads: linifanib for non-small cell lung cancer. AB - Activated vascular endothelial growth factor receptors (VEGFR) 1, 2 and 3, and platelet-derived growth factor receptor (PDGFR) work together to guide the microvasculature into tumor lesions, and have been shown to be involved in tumor growth, invasion and metastasis. In non-small cell lung cancer (NSCLC), tumor angiogenesis mediated by vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) is known to be associated with a poor disease free survival and poor overall survival. A randomized phase II trial was carried out to compare the efficacy/safety of three doses of linifanib with that of CBDCD + paclitaxel (PTX), as the largest and first placebo-controlled trial of linifanib for NSCLC. The result revealed modest, but not robust improvement of the progression-free and overall survival. A number of negative results and number of positive results without robust clinical benefit have been reported from trials of treatments targeting tumor angiogenesis, and anti-angiogenesis therapies seem to be at the crossroads between a prosperous future and a downhill path. Appropriate predictive markers to select right the drugs for the right patients need to be developed to obtain clinical benefit from anti-VEGF therapies. PMID- 26958497 TI - AZD9291 in TKI EGFR resistance in non-small cell lung cancer and the new concept of phase I trials. AB - Epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) constitute the standard of care for stage IV EGFR mutated non-small cell lung cancer (NSCLC) patients initiating first-line systemic treatment. Despite the initial remarkable activity of targeted treatment in these patients rendering objective response rates (ORR) of 50-80% and progression-free survivals (PFS) of 9-12 months, most patients present disease progression during the first 12 to 24 months. Although the activity of platinum-based doublets has been shown in EGFR mutated NSCLC patients after progression to first-line TKIs, PFS is rather short. Drug development companies have more recently focused their attention on the molecular basis of EGFR TKIs acquired resistance. Secondary resistance mutations have proven to be the most frequent cause of acquired resistance. Among them, T790M mutation in exon 20 seems to be the leading responsible for that resistance. Several agents have shown preliminary preclinical and clinical activity in overcoming acquired resistance to firstline EGFR TKIs. To date, however, only AZD9291, an oral, potent, irreversible EGFR TKI that is selective for EGFR tyrosine kinase inhibitor-sensitizing mutations and the T790M resistance mutation has shown to be not only highly active but also fairly tolerable in a large cohort of patients. Here we present a critical analysis of this trial in its clinical setting and propose some future directions. PMID- 26958498 TI - Raising the bar for enthusiasm when looking at results of randomized phase II trials-the case of sunitinib in small-cell lung cancer. AB - With the advent of targeted agents, randomized phase II trials designed with explicit comparative intent, to allow a better interpretation of the results obtained with experimental treatment, have become a common approach for anti cancer drug development. In the Cancer and Leukemia Group B (CALGB) 30504 randomized phase II trial, patients with extensive-stage small-cell lung cancer (SCLC), without progression after four to six cycles of standard chemotherapy with cisplatin or carboplatin plus etoposide, were randomized to sunitinib or placebo, until disease progression. Primary endpoint of the study was progression free survival (PFS), and the results were formally positive [hazard ratio (HR) 0.62; one-sided P=0.02]. However, the prognosis of patients with extensive-stage SCLC is particularly bad, and even a relevant relative benefit (i.e., an encouraging HR) will likely correspond to a debatable absolute benefit: the difference in median PFS between patients treated with sunitinib and patients assigned to control arm was slightly higher than 1.5 months. Is this difference in median PFS big enough to predict a clinically relevant benefit in overall survival? Unfortunately, we do not know. From a "clinical" point of view, is this small absolute improvement in PFS relevant enough to further invest in the strategy? Probably not, also considering the absence of known predictive factors. If the results of the phase II trial had been really promising, the subsequent phase III study should have been promptly conducted, but this was not the case. It seems that, this time, the bar for enthusiasm was already raised in the phase II setting. PMID- 26958499 TI - AZD9291 in epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer. AB - Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced EGFR mutant non-small cell lung cancer have an objective response rate (ORR) of approximately 60-70% and a median progression free-survival (PFS) of approximately 10-13 months. Studies of tumor biopsies performed after progression on EGFR TKI revealed that 50-60% of EGFR mutant NSCLC developed an EGFR exon 20 T790M mutation as a mechanism of acquired resistance. AZD9291 is a third generation irreversible EGFR TKI with activity against the activating EGFR mutation, the T790M acquired resistance mutation, and relative sparing of the wild-type EGFR. AZD9291 was investigated in a phase I trial with expansion cohorts in patients with disease progression after EGFR TKI. Patients with and without detectable T790M mutations were enrolled in the trial. The ORR in patients with centrally confirmed and without detectable T790M mutations was 61% (95% CI, 52-70%) and 21% (95% CI, 12-34%), respectively. The PFS observed in patients with centrally confirmed and without detectable T790M mutations was 9.6 months (95% CI, 8.3 to not reached) and 2.8 months (95% CI, 2.1-4.3 months), respectively. At the dose for further investigation, 80 mg daily, the rate of all grade 3-5 drug related adverse events was 11%, and the rates of grade 3 diarrhea and rash were 1% and 0%, respectively. The identification of the T790M resistance mutation and the subsequent development of an agent against the mechanism of resistance provide a template for future drug development for acquired resistance to targeted therapy. PMID- 26958500 TI - Necitumumab for first-line treatment of advanced, squamous, non-small-cell lung cancer: a relevant step forward? PMID- 26958501 TI - Is epidermal growth factor receptor tyrosine kinase inhibitor in combination with cytotoxic chemotherapy a better treatment option for patients with EGFR-mutated non-small-cell lung cancer? AB - Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) combined with cytotoxic chemotherapy achieved a high disease control rate and favorable progression-free survival (PFS) for EGFR-mutated non-small-cell lung cancer (NSCLC) patients. This combination therapy might circumvent de novo resistance to EGFR-TKI. Randomized phase III studies are required to confirm the survival benefit of this combination therapy in NSCLC patients. In addition, there are some other promising strategies including the combination of EGFR-TKI plus bevacizumab, third-generation EGFR-TKIs, and immune checkpoint inhibitors that remain a future challenge for lung cancer treatment. PMID- 26958502 TI - Stereotactic ablative radiotherapy for early stage non-small cell lung cancer: a word of caution. AB - Recently published data from pooled randomised trials conclude that stereotactic ablative radiotherapy (SABR) can be considered the treatment of choice in operable lung cancer patients fit for lobectomy. This conclusion comes for comparable 3-year survival and much lower risk of early severe morbidity and mortality. In this editorial comment we discuss the validity of the conclusions due to the prematurity of the survival analysis and to the poor accuracy of patients' staging leading to higher rates of regional relapse in the SABR arm. Besides, therapy-related mortality and morbidity in the pooled cohort is much higher that the internationally accepted standards maybe because surgery was not performed according to the best approaches and procedures currently available. The effectiveness of SABR as the sole therapy for resectable lung cancer is still awaiting for sound evidences. It could be adopted for individual cases only in two situations: (I) the patient does not accept surgical treatment; and (II) in cases were the risk of surgical related mortality is considered to exceed the probability of long-term survival after lung resection. For this, a multidisciplinary team (MDT) assessment, including surgeons and oncologists, is mandatory. PMID- 26958503 TI - The continuing role of epidermal growth factor receptor tyrosine kinase inhibitors in advanced squamous cell carcinoma of the lung. AB - Squamous cell carcinoma (SCC) of the lung represents about 20-30% of non-small cell lung cancers (NSCLC) and is associated with a poorer prognosis with limited treatment options. Erlotinib is an approved, standard second-line therapy in this setting, besides docetaxel. The LUX-Lung 8 study has shown superior overall survival (OS), progression-free survival (PFS), as well as disease control rates for treatment with afatinib compared to erlotinib in this head-to-head trial in patients with previously treated advanced SCC of the lung, with manageable side effect profile. This is the first and largest prospective phase III trial comparing two different tyrosine kinase inhibitors in patients with advanced SCC of the lung. Whether the results would be practice-changing remains to be seen, especially with the advent of novel immunotherapeutic agents such as nivolumab, which is recently approved for advanced lung SCC. PMID- 26958504 TI - Afatinib in the treatment of squamous non-small cell lung cancer: a new frontier or an old mistake? AB - Lung squamous cell carcinoma represents approximately 20% of all non-small cell lung cancer (NSCLC) and is associated with a very poor prognosis. In the randomized phase III LUX-Lung 8 trial afatinib showed a statistical significant efficacy advantage compared to erlotinib as second-line treatment of advanced/metastatic squamous NSCLC. Despite its well-built design and the statistical significant results, in our opinion the study is still far from being clinically relevant for this subset of patients. Moreover, during the last years other drugs have shown encouraging activity with low toxicity in pretreated lung squamous cell carcinomas. In particular, nivolumab in the treatment of platinum pretreated squamous NSCLC has recently radically changed the treatment paradigms in this histology. Sure, LUX-Lung 8 trial achieved its primary endpoint progression-free survival showing some afatinib activity in one of the most difficult-to treat and genetically complex neoplasm but we haven't found the most active drug in this subset of patients yet. The purpose of this editorial is to discuss some of the most controversial aspects of the LUX-Lung 8 trial focusing especially on its rational and design. PMID- 26958505 TI - Overall survival in non-small cell lung cancer-what is clinically meaningful? AB - The development of molecularly targeted therapies [tyrosine kinase inhibitors (TKIs) and monoclonal antibodies] has significantly improved outcomes for patients with advanced or metastatic non-small cell lung cancer (NSCLC) resulting in improved progression-free survival (PFS), overall survival (OS) and quality of life (QoL). In addition, targeting the immune axis (CTLA-4, PD-1/PD-L1) has also shown promising results. Major goals of almost all clinical trials based on histology and molecular markers for NSCLC patients are improvements of OS and QoL. However, in the majority of these trials only small incremental improvements in OS were seen. Food and Drug Administration (FDA) and other health authorities have recommended to consider OS to be the standard clinical benefit endpoint that should be used to establish the efficacy of a treatment for NSCLC patients, however, the question remains what is clinically meaningful and how can this outcome be measured. According to suggestions of the American Society of Clinical Oncology (ASCO) Cancer Research Committee a relative improvement in median OS of at least 20% (3-4 months) is regarded to define a clinically meaningful improvement in outcome of NSCLC patients. However, this should not diminish PFS as a valid endpoint since a PFS improvement can also result in a meaningful palliation (e.g., painful bone metastases). Other factors (e.g., QoL) may also be involved to measure and to define the clinical importance of a given trial result. Using the "Quality-adjusted Time Without Symptoms of Toxicity" (Q-TWiST) analysis method it has been demonstrated that a clinically important and meaningful difference for Q-TWiST is 10-15% of OS in a study. Trials that are designed with less ambitious goals, however, may still be of benefit to individual NSCLC patients if the trial endpoints are met. Since there is no single factor which will make a trial clinically meaningful, these recommendations, however, are not intended to set standards for regulatory approval or insurance coverage but rather to encourage patients and investigators to demand more from clinical trials. PMID- 26958506 TI - PiggyBac transposon vectors: the tools of the human gene encoding. AB - A transposon is a DNA segment, which is able to change its relative position within the entire genome of a cell. The piggyBac (PB) transposon is a movable genetic element that efficiently transposes between vectors and chromosomes through a "cut-and-paste" mechanism. During transposition, the PB transposase recognizes transposon-specific inverted terminal repeats (ITRs) sequences located on both ends of the transposon vector and eight efficiently moves the contents from its original positions and efficiently integrates them into TTAA chromosomal sites. PB has drawn much attention because of its transposition efficiency, safety and stability. Due to its priorities, PB can be used as a new genetic vehicle, a new tool for oncogene screening and a new method for gene therapy. PB has created a new outlook for human gene encoding. PMID- 26958507 TI - Dose escalation for unresectable locally advanced non-small cell lung cancer: end of the line? AB - Radiation Therapy Oncology Group (RTOG) 0617 was a randomized trial that investigated both the impact of radiation dose-escalation and the addition of cetuximab on the treatment of non-small cell lung cancer (NSCLC). The results of RTOG 0617 were surprising, with the dose escalation randomization being closed prematurely due to futility stopping rules, and cetuximab ultimately showing no overall survival benefit. Locally advanced unresectable NSCLC has conventionally been treated with concurrent chemoradiation. Though advances in treatment technology have improved the ability to deliver adequate treatment dose, the foundation for radiotherapy (RT) has remained the same since the 1980s. Since then, progressive studies have sought to establish the safety and efficacy of escalating radiation dose to loco-regional disease. Though RTOG 0617 did not produce the anticipated result, much interest remains in dose escalation and establishing an explanation for the findings of this study. Cetuximab was also not found to provide a survival benefit when applied to an unselected population. However, planned retrospective analysis suggests that those patients with high epidermal growth factor receptor (EGFR) expression may benefit, suggesting that cetuximab should be applied in a targeted fashion. We discuss the results of RTOG 0617 and additional findings from post-hoc analysis that suggest that dose escalation may be limited by normal tissue toxicity. We also present ongoing studies that aim to address potential causes for mortality in the dose escalation arm through adaptive or proton therapy, and are also leveraging additional concurrent systemic agents such as tyrosine kinase inhibitors (TKIs) for EGFR activating mutations or EML4-ALK rearrangements, and poly (ADP-ribose) polymerase (PARP) inhibitors. PMID- 26958508 TI - Cranial irradiation in patients with EGFR-mutant non-small cell lung cancer brain metastases. AB - The most effective treatment approach for brain metastases in patients with non small cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations is a current subject of investigation. Cranial irradiation is the standard treatment for brain metastases, but tyrosine kinase inhibitors (TKIs) such as erlotinib have also activity against brain metastases in this subset of patients. The combination of TKI and radiotherapy is a promising one, but data is lacking to indicate whether this is superior to erlotinib or whole brain radiation therapy (WBRT) alone. Retrospective data suggest that WBRT achieves more durable intracranial control compared to erlotinib alone. Randomized, prospective studies will be necessary to determine whether TKI, cranial irradiation, or both is the optimal initial treatment for brain metastases in EGFR-mutant NSCLC. PMID- 26958509 TI - Immunotherapy in locally-advanced non-small cell lung cancer: releasing the brakes on consolidation? AB - Locally-advanced non-small cell lung cancer (LA-NSCLC) is optimally treated with definitive chemoradiation or surgery in combination with chemotherapy or chemoradiation. Prognosis, however, remains poor, and attempts to improve outcomes using consolidation or maintenance chemotherapy have not improved overall survival. Given the limited success of traditional cytotoxic chemotherapies as maintenance therapy for LA-NSCLC, recent studies have investigated the role of novel agents such as maintenance or consolidation, including antiangiogenic agents and molecular targeted therapy. With multiple newly reported trials demonstrating improved outcomes with immunotherapy over cytotoxic chemotherapy for stage IV NSCLC, integrating immunotherapy with definitive chemoradiation regimens or as consolidative therapy for LA-NSCLC is an attractive option. The recently published START trial is the first to test immunotherapy in LA-NSCLC in a randomized, phase III setting. In that trial, the administration of maintenance tecemotide (L-BLP25), which induces a T-cell response to the mucin 1 (MUC1) glycoprotein, was found to be well tolerated and improve overall survival compared with placebo among patients receiving concurrent, but not sequential, chemoradiation. Despite the promising findings of this trial, numerous questions regarding immunotherapy for LA-NSCLC remain, and several additional immunotherapy trials are underway or planned in this patient population. PMID- 26958510 TI - Concomitant EGFR mutations/ALK rearrangements: beyond a simple dual target. PMID- 26958511 TI - Metachronous primary uterine cancer surgically resected during Crizotinib treatment in a ALK-rearranged advanced lung adenocarcinoma. AB - Rearrangements of the anaplastic lymphoma kinase (ALK) gene are present in 3% to 7% of non-small-cell lung cancers (NSCLCs). Patients harboring ALK rearrangements show very favourable outcomes if treated with targeted agents, among which crizotinib is the first and best studied. Crizotinib, an oral small-molecule tyrosine kinase inhibitor of ALK, MET, and ROS1 kinases, is a very active and well tolerated drug. Nevertheless, the optimal therapy management with this new drug is still partially unknown, especially with regard to the safety of combined treatments. Recently, the integration of locoregional treatments has been proposed as a feasible multimodality strategy in selected patients with good clinical conditions and slow-growing or oligoprogressive disease. In this report, a case of advanced lung adenocarcinoma, progressed after first line chemotherapy and re-biopsied detecting ALK rearrangement, is described. During crizotinib treatment the primary lung tumor showed an excellent regression; meanwhile a major surgery for a metachronous uterine cancer was safely and successfully carried out. PMID- 26958512 TI - Cancer generated lactic acid: Novel therapeutic approach. PMID- 26958513 TI - The post-analytical phase of histopathology practice: Storage, retention and use of human tissue specimens. AB - There are several aspects to a histopathology practice besides the acquisition of biopsy specimens and histopathological diagnosis. Pathology Departments are home to an abundant source of knowledge in the form of stored specimens and slides. We attempt to highlight the importance of regulation of storage, retention, and appropriate use of human tissue material in research and ownership rights to the same. We also discuss requirement and waiver of informed consent for scientific work involving the use of such tissues, which in the absence of defined laws come under the purview of Institution Review Boards. Pathology Departments, under the binding of the parent institution, are conceded the responsibility of maintenance and retention of pathology specimens. This communication highlights some of the important aspects in human tissue material handling and research, underscoring the necessity for established regulations regarding the same. PMID- 26958514 TI - Serum prolactin in patients with liver disease in comparison with healthy adults: A preliminary cross-sectional study. AB - INTRODUCTION: Studies from the west have shown raised prolactin levels in patients with liver disease. Considering the lacunae on Indian context, we conducted the present study with an objective to assess the prolactin levels in patients with cirrhosis and viral hepatitis with or without features of encephalopathy. The data presented here are the results of the preliminary analysis. MATERIALS AND METHODS: The present study was a prospective, cohort study among patients diagnosed as either viral hepatitis or cirrhosis liver. A cohort of normal healthy adults was selected based on history and laboratory investigations (complete blood count, liver and renal function tests). Serum prolactin was measured for all the study participants, and Kruskal-Wallis H-test with post-hoc Dunn's test was used to analyze the significance of the differences in the levels between various groups. Tests of diagnostic accuracy were used to assess the prediction capability of serum prolactin with a cut-off level of 50 ng/ml. RESULTS: A total of 70 patients (10 - normal healthy; 25 - acute viral hepatitis; 35 - cirrhosis liver) were recruited in the present study with the median (range) age in years of 56 (34-68) and male: female ratio of 2:1. A statistically significant (P < 0.05) increase in the serum prolactin was observed in patients with cirrhosis with or without encephalopathy. But, among the patients with viral hepatitis, a significant elevation was observed only in patients with encephalopathy. Additionally, a statistically significant association was observed between serum prolactin levels with serum bilirubin (rho =0.67, P = 0.04) and aspartate aminotransferase (rho =0.72, P = 0.05). A cut-off value of 50 ng/ml of serum prolactin was found to predict the mortality. A total of 4/12 (33.3%) with prolactin value of <50 ng/ml died while 11/23 (47.8%) died with values >50 ng/ml (P < 0.05). Similarly, in patients with viral hepatitis with encephalopathy features, 1/4 (25%) with prolactin value of <50 ng/ml died while among those without any such features (n = 21), 9 (42.9%) died (P < 0.05). CONCLUSION: Serum prolactin has a significant association with patients with liver disease and predicts mortality. PMID- 26958515 TI - Analytical study of intrauterine fetal death cases and associated maternal conditions. AB - INTRODUCTION: Intrauterine fetal death is an important indicator of maternal and perinatal health of a given population. This study was undertaken to study the maternal and fetal factors associated with intrauterine fetal death. MATERIALS AND METHODS: This was a retrospective single center study. The details were entered in a preformed proforma. The details of complaints at admission, obstetrics history, menstrual history, examination findings, per vaginal examination findings, mode of delivery and fetal outcomes, placental examination, condition of cord and investigation reports were recorded. RESULTS: A total of 250 intrauterine fetal deaths were reported amongst 6942 deliveries conducted during the study period. The incidence rate of intrauterine fetal death was 36/1000 live births. Two hundred and twenty-two deliveries were unbooked and unsupervised. The other observations were rural population (58%), low socioeconomic group (71.2%), previous stillbirth (9.2%), gestational hypertension (32.8%), anemia (74.4%), antepartum hemorrhage (18.8%), and congenital malformations (CMFs) (8.8%). CONCLUSIONS: The incidence of intrauterine fetal deaths in our population is higher than that reported from developed countries. This is associated with anemia, pregnancy-induced hypertension, illiteracy, low socioeconomic status, and higher incidence of undiagnosed CMFs. PMID- 26958516 TI - Antibiotic sensitivity pattern in blaNDM-1-positive and carbapenemase-producing Enterobacteriaceae. AB - BACKGROUND: Some studies published in recent time revealed that many bacteria from Enterobacteriaceae group are multi-antibiotic-resistant because of the production enzymes carbapenemase particularly New Delhi metallo-beta-lactamase encoded by gene called blaNDM-1. Looking at public health importance of this issue there is a need for studies at other centers to confirm or refute published findings. OBJECTIVES: This study was designed with the aim of exploring antibiotic resistance in Enterobacteriaceae group of bacteria and also to explore gene and enzyme responsible for it. MATERIALS AND METHODS: Samples of Enterobacteriaceae were collected from wards and outpatient departments. Antibiotic sensitivity was checked by an automated system (VITEK 2 COMPACT). Carbapenemase production was assessed by Modified Hodge Test. Presence of blaNDM 1 was assessed by polymerase chain reaction. STATISTICS: Frequency and percentage were used to describe the data. Frequency of sensitivity was compared between carbapenemase producers and noncarbapenemase producers by Fisher's exact test. RESULTS: Forty-seven percent bacteria were found to be producing carbapenemase enzyme. These bacteria were significantly less sensitive to cefoperazone, cefepime, and amikacin. Among carbapenemase-producing organisms, 3% and 6% were resistant to tigecycline and colistin, respectively. Forty percent bacteria were found to be having blaNDM-1 gene. There was a significant difference between blaNDM-1-positive and blaNDM-1-negative for sensitivity toward cefoperazone + sulbactam, imipenem, meropenem, amikacin, tobramycine, ciprofloxacin, and levofloxacin. CONCLUSION: Presence of carbapenemase enzyme and blaNDM-1 gene is associated with high level of resistance in Enterobacteriaceae group of bacteria and only few antibiotics have good sensitivity for these organisms. PMID- 26958517 TI - The diagnostic accuracy of rapid urease biopsy test compared to histopathology in implementing "test and treat" policy for Helicobacter pylori. AB - BACKGROUND: Helicobacter pylori is one of the most important causes of the varied spectrum of gastroduodenal diseases. It is important to have a rapid diagnostic method to detect the organism so as to initiate the treatment early and check its progression to malignancy. AIMS: To evaluate the diagnostic accuracy of rapid urease biopsy test in detecting H. pylori infection and implementation of "test and treat" policy. MATERIALS AND METHODS: All patients of chronic dyspepsia not responding to conventional treatment were subjected to endoscopy, and mucosal biopsy samples were collected. A rapid urease test (RUT) and histopathology was performed on these samples and taking histopathology as gold standard for H. pylori demonstration, the diagnostic accuracy of RUT was evaluated. RESULTS: The specificity, sensitivity, positive predictive value, negative predictive value, and diagnostic accuracy of RUT were 97.22%, 94.04%, 98.75%, 87.5%, and 95%, respectively. CONCLUSION: Use of a rapid diagnostic test viz., rapid urease biopsy test to confirm H. pylori infection is recommended for early diagnosis and treatment of H. pylori associated gastroduodenal diseases. PMID- 26958518 TI - The effect of bone growth factor in the tendon to bone healing in anterior cruciate ligament reconstruction: An experimental study in rabbits. AB - BACKGROUND: Reconstruction of the anterior cruciate ligament (ACL) involves use of semintendinosis and gracilis tendons graft that is transplanted into bone tunnels at the femoral and tibial insertion sites and the sites and the bone tendon interface is a weak link in the early healing period due to slow rate of healing. We hypothesized that an addition of bone growth factor like Sadat-Habdan mesenchymal stimulating peptide (SHMSP) could enhance bone tendon healing rate so that re-rupture of the tendon does not take place. METHODOLOGY: Twenty skeletally mature rabbits underwent ACL reconstruction of the right knee. In 10 of the rabbits at the site of the tendon-graft 5 mg/kg body weight of SHMSP was put in the bone tunnel. In 10 other animals, nothing was added. At eight and 12 weeks 5 animals from each group were sacrificed. The tendon-graft site was harvested and sent for histopathological examination to assess the healing at the tendon-bone graft to the tibial tunnel. RESULTS: There were no deaths in both the groups. One rabbit of the control group developed an infection. In all the animals of the study group from 4 weeks onward showed bone formation, wherein the control group only granulation tissue was observed. By 8 weeks in the study group, the canal was totally obliterated with the new bone formation which extended onto the periosteal area. In the control, there was minimal change in the formation of the new bone formation. CONCLUSION: Addition of a growth factor like SHMSP would enhance the osteo-integration of the tendon-graft in the bony tunnel after ACL reconstruction in vivo. PMID- 26958519 TI - Oral exfoliative cytology as a screening tool for iron overload in beta thalassemia patients. AB - BACKGROUND: Increased iron overload is frequent problem in thalassemia patients, and this is monitored by serum ferritin levels or chemical assessment of the iron levels in liver tissue. However, repeated monitoring of serum ferritin levels to assess the iron overload is an invasive procedure associated with practical problems. AIMS: To use Perl's Prussian blue reaction to evaluate the iron overload in beta-thalassemia patients by staining the oral cytosmears. MATERIALS AND METHODS: The study comprised 35 patients diagnosed with beta-thalassemia. Cytosmears were prepared from exfoliated oral epithelial cells, fixed in 70% ethanol and stained with Perl's Prussian blue stain for detection of blue colored granules in the cytoplasm. RESULTS: 29/35 (82.9%) cases showed a positive reaction for Perl's Prussian blue reaction while 6/35 (17%) cases did not show the presence of blue colored granules in the oral cytosmears. The presence of iron detected by Perl's Prussian blue reaction correlated with serum ferritin level (P < 0.05). CONCLUSION: Perl's Prussian blue reaction can be used to evaluate the iron overload in beta-thalassemia patients by staining the oral cytosmears. It is a simple and noninvasive method for assessment of iron overload in such patients. PMID- 26958520 TI - Association of polymorphisms in angiotensin-converting enzyme gene with gestational diabetes mellitus in Indian women. AB - BACKGROUND: Numerous genes have been reported in relation with gestational diabetes mellitus (GDM), but the findings were not consistently replicated across populations, or there have been no detailed studies on them. Previous literatures suggested that, out of all angiotensin converting enzyme (ACE) gene polymorphisms, only ACE insertion/deletion (I/D) gene polymorphism has a strong association with GDM in Asian Indian women. AIM: This study was devoted to evaluate the association of four single nucleotide polymorphisms (SNPs) ACE A240T, C1237T, G2350A and I/D with GDM and Type 2 diabetes mellitus. MATERIALS AND METHODS: This study recruited 105 GDM cases, 119 Type 2 diabetes mellitus subjects and 120 controls. PCR-RFLP was used for identifying genotypes of ACE A240T, C1237T and G2350A and PCR was performed in the case of ACE I/D. RESULTS: Significant associations of ACE SNP's, C1237T, and G2350A with GDM were observed. Haplotype analysis revealed the remarkably significant evidence of association with SNP combination ACE A240T, C1237T, G2350A, and I/D with GDM patients (P = 0.024). Individuals possessing haplotype "TTAI" (frequency 30% in GDM and 0 in controls) derived from these SNPs had 185 fold increased risk of developing GDM (95% of confidence interval: 11.13-3102.15), which was highest when compared with other 15 haplotypes. CONCLUSION: Shorter-range haplotypes were also significant, but the only consistently associated alleles were found to be in ACE C1237T, G2350A, and I/D. These results suggested that the variant in close proximity to ACE C1237T, G2350A and/or I/D modulates susceptibility to GDM and noninsulin dependent diabetes mellitus in Indian women. PMID- 26958521 TI - Evaluation of carotid arteries in stroke patients using color Doppler sonography: A prospective study conducted in a tertiary care hospital in South India. AB - AIMS AND OBJECTIVES: Cerebral ischemic stroke is life-threatening and debilitating neurological disease, it is the third leading cause of death in the world. Studies have shown that there is a close relationship between carotid artery stenosis and ischemic cerebral vascular disease. This study is done to assess the carotid arteries with the help of color Doppler sonography and to correlate cerebrovascular accidents. MATERIALS AND METHODS: The prospective study was carried out on 50 patients using purposive sampling technique. Risk factors such as hypertension, diabetes mellitus, smoking, and family history were documented. The data gathered from color Doppler examination consisted of peak systolic velocity of common carotid artery (CCA) and internal carotid artery (ICA), velocity ratios between CCA and ICA and plaque characteristics as seen on real-time image. STATISTICAL ANALYSIS USED: The collected data were analyzed and presented in the form of tables, figures, graphs, and diagrams wherever necessary. As this study deals with the only frequency distribution of various factors, so no tests of significance were applied. RESULTS: The highest incidence of stroke was found in the male population in the age group of 60-69 years. Various risk factors included hypertension, diabetes mellitus, smoking, and family history. Of 50 patients, 12 patients showed significant stenosis (>60%). Atherosclerotic plaques were seen in 39 patients (78%). CONCLUSION: Color Doppler examination is an economic, safe, reproducible, and less time-consuming method of demonstrating the cause of cerebrovascular insufficiency in extracranial carotid artery system and will guide in instituting treatment modalities. PMID- 26958522 TI - Short-term acute effects of gutkha chewing on heart rate variability among young adults: A cross-sectional study. AB - BACKGROUND AND OBJECTIVES: An increase in the consumption of smokeless tobacco has been noticed among high school, college students, and adults. Despite the antiquity and popularity of chewing tobacco in India, its effects have not been investigated systematically in humans. The aim of this study was to investigate acute effects of gutkha chewing on heart rate variability (HRV) among healthy young adults. MATERIALS AND METHODS: A total of 60 young adult males were included in the study. Each individual was asked to chew tobacco and subjected to HRV analysis. HRV analysis using short-term electrocardiogram recording was used to measure HRV parameters before gutkha chewing and at 5, 15, and 30 min after chewing tobacco. One-way analysis of variance and paired t-test was used to assess changes over time. RESULTS: There was a significant increase in heart rate (HR) during tobacco chewing. Mean HR at baseline measured 73.0 +/- 6.2 bpm. There was a rise in mean HR to 83.7 +/- 9.1 bpm at 5 min during tobacco chewing and gradual reduction to baseline observed after 15 min followed by no significant change till 30 min. The normalized low-frequency power and LF/high-frequency (HF) power ratio were elevated after 5 min; however, normalized HF power was reduced after 5 min tobacco chewing. CONCLUSION: Gutkha is closely associated with traditional cardiovascular risk factors as detected by a transient enhancing sympathetic activity during tobacco chewing in the form of increased HRV parameters or an imbalance between sympathetic and parasympathetic neural activity among healthy young adults. PMID- 26958523 TI - A study to compare the plasma glucose levels obtained in sodium fluoride and citrate buffer tubes at a tertiary care hospital in Punjab. AB - OBJECTIVES: Recent guidelines for estimation of glucose recommend the use of citrate buffer tubes to inhibit glycolysis if the sample cannot be cooled immediately and separated within 30 min. These tubes are currently not available in India. We prepared the citrate tubes and compared the glucose results obtained with sodium fluoride tubes. METHODS: Random blood samples of 44 apparently healthy volunteers were collected in three pairs of citrate buffer and sodium fluoride tubes during September to October 2013. They were labeled as 0 h, 1 h and 2 h samples indicating a delay in centrifugation to separate plasma. Glucose was analyzed on the fully auto analyzer in duplicates using glucose oxidase peroxidase method. RESULTS: The mean glucose concentrations at 0 h in citrate tubes were 105.8 +/- 19.5 mg/dl compared to 99.6 +/- 18.3 mg/dl in sodium fluoride tube. There was statistically significant difference in the glucose levels measured in plasma separated from citrate buffer tube and sodium fluoride tube at 0 h, 1 h, and 2 h. The difference between citrate and sodium fluoride tube results ranged from 6.1 mg/dl at 0 h to 7.4 mg/dl at 2 h. Glucose levels decreased significantly at 2 h in both citrate and sodium fluoride tubes. CONCLUSION: There is a significant decrease in glucose levels in sodium fluoride tubes even with immediate separation of plasma. There is urgent need to standardize the preanalytical conditions for glucose estimation so that effective inhibition of glycolysis can be done. PMID- 26958524 TI - Oral teratoma. AB - For congenital teratomas, oropharyngeal cavity is one of the rarest sites (2% of all teratomas). They are rarely picked up by prenatal ultrasonography. Postnatally, newborns present with respiratory distress and at this point role of pediatricians is very crucial in establishing secure airway after which they need to be carefully evaluated and surgically managed. We present a female neonate with palatal teratoma which was treated successfully with surgery. PMID- 26958525 TI - Dyke-Davidoff-Masson syndrome. AB - Dyke-Davidoff-Masson syndrome (DDMS) refers to atrophy or hypoplasia of one cerebral hemisphere, due to an insult to the developing brain in fetal or early childhood period. Age of presentation depends on the time of neurologic insult, and characteristic changes may be seen only in adolescence. Male gender and left hemisphere are more frequently involved. A 17-year-old female adolescent with a history of recurrent refractory seizures, hemiplegia and mental retardation reported to Department of Radiology for computed tomography (CT) assessment of brain. On examination, she had facial asymmetry, delayed milestones, and spastic hemiplegia. The CT brain showed right cortical atrophy with ventricular dilatation, prominent sulci, and shifting of falx to the right side. Bone window image showed asymmetry in skull vault thickness, the width of diploic space, the size of paranasal air sinuses and inclination of the petrous ridge between the affected and normal sides. As the above case deviates from the usual presentation of male left sided DDMS, hence the report. PMID- 26958526 TI - Tuberous sclerosis with oral manifestations: A rare case report. AB - Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome, inherited as an autosomal dominant trait with a high incidence of sporadic cases and protean clinical expression, with a incidence of prevalence between 1 in 10,000 and 1 in 170,000. The cardinal features of TSC are skin lesions, convulsive seizures, and mental retardation. We report a sporadically occurring case of definite TSC in a young female who presented with oral and cutaneous manifestations without mental retardation or history of convulsive seizures, which to the best of our knowledge has not been reported so far. PMID- 26958527 TI - Primary pulmonary synovial sarcoma: A case report and review of literature. AB - Primary pulmonary synovial sarcoma is a very rare, but highly aggressive tumor. Metastatic pulmonary sarcoma due to hematogenous dissemination is much more common. Hence why in any case of pulmonary sarcoma, whole body survey is necessary to exclude a primary tumor elsewhere. No clinical or radiological presentations are specific for pulmonary sarcoma hence; it is often confused with bronchogenic carcinoma. On the other hand, image-guided fine needle aspiration cytology (FNAC) is very much helpful in diagnosis of bronchogenic carcinoma, whereas, it may be inclusive in cases pulmonary sarcomas including primary synovial sarcoma, especially in cases of huge pulmonary masses. So why image guided tru-cut core biopsy or open lung biopsy and their histopathological examination, supplemented by immunohistochemistry are preferable for the tissue diagnosis of pulmonary synovial sarcoma, although FNAC and immunocytochemistry may be used for the diagnosis. Surgical resection is treatment of choice, if it is not possible, palliative chemotherapy may be an option. Here, we report a rare case of primary synovial sarcoma which occupied almost whole of the right hemithorax in a 60-year-old male farmer. PMID- 26958528 TI - Delayed migration of a bullet from loin to scrotum. AB - Here, we report a rare case of migration of a foreign body has occurred from loin to scrotum. A 35-year-old male patient presented with right sided scrotal mass, on exploration it was found to be a metallic bullet. The patient had a history of gunshot injury in his loin 8 years back and was treated conservatively that time. The probable explanation to this mysterious incident may be that, the bullet might have entered the peritoneal cavity through the loin, but did not cause any extensive damage, so the patient well responded to the initial conservative management. With time, due to changes in abdominal pressure or may be due to gravitational force, it had migrated to the dependent scrotum through the patent processus vaginalis. So, this case signifies that a foreign body can migrate through the body planes and get settled far from the primary place. PMID- 26958529 TI - Unusual communications of the brachial plexus. AB - The knowledge of innervation of pectoral muscles is important to surgeons performing breast surgeries, axillary lymph node dissection, harvesting pectoralis major/minor for flaps, and during neurotization procedures where the pectoral nerves are particularly at risk. The present case describes the innervation of the pectoral muscles solely by a nerve trunk arising from the ansa pectoralis (AP) - the loop of medial and lateral pectoral nerves. Interestingly, there was also a communication between the AP and roots forming the median nerve. It is imperative for the operating surgeons to be aware of these rare variations in order to prevent denervation and subsequent atrophy of the pectoral musculature. PMID- 26958530 TI - Twist to matricing: Restoration of adjacent proximal defects in a novel manner. AB - The quality treatment in an efficient way is the road map to successful clinical practice. Various methods are employed to achieve goals. Refurbishment of the adequate marginal ridge, proximal contact, and contour are the prime challenges in restoring two adjacent proximal defects. This paper presents an overview of achieving satisfactory proximal restorations in a time saving innovative manner. PMID- 26958531 TI - Isolated pulmonary mucormycosis presenting as cavitary lesion in an immunocompetent adult: A rare case report. AB - Cavitary lung lesions have a specific array of differential diagnosis. Among rare causes is mucormycosis that should not be overlooked. A high index of suspicion is necessary for a correct diagnosis and aggressive management. It usually occurs in immunosupressed patients. It is a life-threatening, rapidly progressive, and angioinvasive fungal infection. We present a case of pulmonary mucormycosis presenting as a cavity in an immunocompetent middle aged male. PMID- 26958533 TI - Hyaluronic acid and tendon lesions. AB - INTRODUCTION: recently, the viscoelastic properties of hyaluronic acid (HA) on liquid connective tissue have been proposed for the treatment of tendinopathies. Some fundamental studies show encouraging results on hyaluronic acid's ability to promote tendon gliding and reduce adhesion as well as to improve tendon architectural organisation. Some observations also support its use in a clinical setting to improve pain and function. This literature review analyses studies relating to the use of hyaluronic acid in the treatment of tendinopathies. METHODS: this review was constructed using the Medline database via Pubmed, Scopus and Google Scholar. The key words hyaluronic acid, tendon and tendinopathy were used for the research. RESULTS: in total, 28 articles (in English and French) on the application of hyaluronic acid to tendons were selected for their relevance and scientific quality, including 13 for the in vitro part, 7 for the in vivo animal part and 8 for the human section. CONCLUSIONS: preclinical studies demonstrate encouraging results: HA permits tendon gliding, reduces adhesions, creates better tendon architectural organisation and limits inflammation. These laboratory observations appear to be supported by limited but encouraging short term clinical results on pain and function. However, controlled randomised studies are still needed. PMID- 26958534 TI - Clinical evidence in the treatment of rotator cuff tears with hyaluronic acid. AB - PURPOSE: the aim of this quantitative review is to document potential benefit and adverse effects of hyaluronic acid (HA) injection into the shoulder with rotator cuff tears. METHODS: a systematic literature search was performed in english PubMed, Medline, Ovid, Google Scholar and Embase databases using the combined key words "hyaluronic acid", "rotator cuff tear", "hyaluronate", "shoulder", "viscosupplementation", with no limit regarding the year of publication. Articles were included if they reported data on clinical and functional outcomes, complications in series of patients who had undergone HA injection for management of rotator cuff tears. Two Authors screened the selected articles for title, abstract and full text in accordance with predefined inclusion and exclusion criteria. The papers were accurately analyzed focusing on objective rating scores reported. RESULTS: a total of 11 studies, prospective, 7 were randomized were included by full text. A total of 1102 patients were evaluated clinically after different HA injection compare with corticosteroid injection, physically therapies, saline solution injection and control groups. The use of HA in patients with rotator cuff tears improve VAS and functional score in all trials that we have analyzed. CONCLUSION: intra-articular injection with HA is effective in reducing pain and improving function in shoulder with rotator cuff tears and without severe adverse reaction. LEVEL OF EVIDENCE: Level I. PMID- 26958535 TI - Rates of surgery for frozen shoulder: an experience in England. AB - AIM: the aim of this study was to identify the incidence of surgical treatment for frozen shoulder in a western population. METHODS: patients included in this study all resided within a well-defined area in the North West of England, all had surgery for frozen shoulder over a 3-year period and were identified from theatre logbooks of two local hospitals. Cases having surgery for shoulder stiffness other than frozen shoulder were excluded. Local and national population size estimates were based on data obtained from the UK Office for National Statistics. RESULTS: 117 patients underwent surgery for frozen shoulder during the period examined; of these 101 had arthroscopic arthrolysis and 16 had manipulation under anaesthesia. The overall incidence of frozen shoulder surgery was calculated at 2.67 procedures per 10,000 general population per year, and at 7.55 for those aged 40-60. CONCLUSION: surgical intervention for frozen shoulder is common, estimated at over 14,180 cases per year in England. Given the variation in costs associated with arthroscopic arthrolysis and manipulation under anaesthesia, comparative studies of the cost effectiveness of the two procedures would be of great value. LEVEL OF EVIDENCE: 2C (outcome research). PMID- 26958536 TI - Percutaneous needling of Morton's complex: a technical note. AB - BACKGROUND: the Morton's complex, i.e. fibrotic mass enfolding the medial plantar nerve, the bursa and the interdigital transverse ligament in the web space, is a common cause of pain and functional disability. Conservative and operative treatments are investigated but currently the best approach to treat the Morton's complex is unknown. METHODS: we describe a non-invasive, straight forward intervention consisting on multiple percutaneous punctures, shearing the fibrotic tissue in lateromedial and anteroposterior directions. The goal is to break up fibrosis occupying the intermetatarsal space thus releasing the affected nerve from the adjacent structures, there by stimulating tissue remodelling. RESULTS: slow tissue remodelling occurs following sequential fibrosis cleavage through multiple needling. Needling of the intermetatarsal fibrosis is performed every eight weeks until pain resolution. Echographic changes are associated to pain reduction as measured by Visual Analogue Score (VAS). CONCLUSION: we present an original idea that may improve Morton's management. Upcoming prospective clinical studies have to demonstrate the symptomatic benefits and the usefulness of this novel echographic intervention. PMID- 26958532 TI - I.S.Mu.L.T - Rotator Cuff Tears Guidelines. AB - Despite the high level achieved in the field of shoulder surgery, a global consensus on rotator cuff tears management is lacking. This work is divided into two main sessions: in the first, we set questions about hot topics involved in the rotator cuff tears, from the etiopathogenesis to the surgical treatment. In the second, we answered these questions by mentioning Evidence Based Medicine. The aim of the present work is to provide easily accessible guidelines: they could be considered as recommendations for a good clinical practice developed through a process of systematic review of the literature and expert opinion, in order to improve the quality of care and rationalize the use of resources. PMID- 26958537 TI - Platelet-rich plasma (PRP) treatment of sports-related severe acute hamstring injuries. AB - PURPOSE: hamstring injury is the most common musculoskeletal disorder and one of the main causes of missed sporting events. Shortening the time to return to play (TTRTP) is a priority for athletes and sports medicine practitioners. HYPOTHESIS: platelet-rich plasma (PRP) injection at the site of severe acute hamstring injury increases the healing rate and shortens the TTRTP. STUDY DESIGN: Cohort study. METHODS: all patients with ultrasonography and MRI evidence of severe acute hamstring injury between January 2012 and March 2014 were offered PRP treatment. Those who accepted received a single intramuscular PRP injection within 8 days post-injury; the other patients served as controls. The same standardized rehabilitation program was used in both groups. A physical examination and ultrasonography were performed 10 and 30 days post-injury, then a phone interview 120 days post-injury, to determine the TTRTP at the pre-injury level. RESULTS: of 34 patients, 15 received PRP and 19 did not. Mean TTRTP at the pre-injury level was 50.9+/-10.7 days in the PRP group and 52.8+/-15.7 days in the control group. The difference was not statistically significant. CONCLUSION: a single intramuscular PRP injection did not shorten the TTRTP in sports people with severe acute hamstring injuries. PMID- 26958538 TI - Objective assessment of corticosteroid effect in plantar fasciitis: additional utility of ultrasound. AB - BACKGROUND: although plantar fascia thickening is well documented as a sonographic criterion for the diagnosis of plantar fasciitis (PF), however it was less evaluated as an objective measure of response to treatment. It is unknown to what extent if any different responses to different treatments are related to the ultrasound (US) morphology changes. We aimed to evaluate changes in US findings in correlation to pain reported. METHODS: this prospective observational trial included 21 plantar fasciitis patients (26 feet), resistant to conservative treatment for at least 2 months. Plantar fascia thickness and echogenicity were evaluated, compared to asymptomatic feet and correlated with visual analogue scale (VAS) and Heel Tenderness Index (HTI), before and after dexam-ethasone (DXM) iontophoresis in group I, and DXM injection in group II. RESULTS: increased thickness and reduced echogenicity were constant in symptomatic feet, with high statistical significant difference compared to asymptomatic side. Correlation between plantar fascia thickness with VAS and HTI before and after treatment showed statistically significant positive correlation (p<0.05). ROC curve test showed that reduction of plantar fascia thickness by US in response to DXM had 100% sensitivity, 65.2% specificity and 69% accuracy, with higher specificity and accuracy than VAS. CONCLUSION: US changes showed concurrent validity correlated with self-reported clinical improvement. Accordingly, ultrasound can be considered an objective useful tool for monitoring response to corticosteroid in patients with plantar fasciitis. PMID- 26958539 TI - Platelet-rich plasma (PRP) to treat chronic patellar tendinopathies: comparison of a single versus two closely-timed injections. PMID- 26958540 TI - Tears of the fascia cruris demonstrate characteristic sonographic features: a case series analysis. AB - BACKGROUND: fascia cruris (FC) tears have recently been recognised in the literature, although little is known about their characteristic ultrasound findings. The aim was to describe the echo-graphic features of FC tears in order to improve recognition and diagnosis. METHODS: the ultrasound reports and images of >600 patients attending a specialist musculoskeletal clinic for Achilles tendon ultrasound scans between October 2010-May 2014 were reviewed. Any patient diagnosed with a FC tear had a structured data set extracted. All ultrasound images were performed by one consultant radiologist. Bilateral Achilles images were available for analysis. RESULTS: sixteen patients from >600 subjects were diagnosed with a FC tear. Fourteen subjects were male and two female (mean age 37.8; range 23-61), with seven elite level sports men. Nine tears were right sided and seven left, with eight situated laterally and seven medially. Seven of the tears were situated in the musculotendinous junction. Symptomatic Achilles tendinopathy co-existed in ten of sixteen subjects (average transverse diameter of Achilles tendon = 7.1+/-2.0 mm). CONCLUSION: FC tears should be considered in the differential diagnoses for Achillodynia, diagnosed using their characteristic ultrasound findings, with a hypoechoic area at the medial or lateral attachment to the Achilles tendon in the transverse plane. PMID- 26958541 TI - Collagen content in the vastus lateralis and the soleus muscle following a 90-day bed rest period with or without resistance exercises. AB - INTRODUCTION: spaceflight seems associated with deterioration of the function of the skeletal muscles. Since muscle collagen is critical for muscle function, an improved understanding of the content of the muscle collagen during long-term inactivity seems important. Bed-rest with in-bed resistance training serves as a proxy for the conditions in space. Therefore, ground-based studies may improve the understanding of the consequences of long-term inactivity. PURPOSE: the purpose is to compare the change in collagen protein in the vastus lateralis (VL) and the soleus (SOL) muscle amongst persons exposed to a 90-day bed rest with or without resistance exercise. METHODS: an explorative analysis was completed based on data from a randomized, controlled trial. The intervention group (BRE, SOL n=4, VL n=8) performed supine-based squat exercises, whereas the controls (BE, SOL n=6, VL n=12) remained inactive during follow-up. Muscle biopsies from vastus lateralis and soleus were taken at baseline (pre) and after 90-days' follow-up (post). Muscle collagen (MUg collagen/mg protein) was quantified. Two-way repeated measurements ANOVA was used to compare the interaction between the intervention (BRE/BR) and time (pre/post) for each muscle. RESULTS: the collagen content of VL was similar between pre and post in the BRE group (-3.8 MUg collagen/mg protein [95% CI: -22.0; 14.4], p=0.68) while it rose amongst individuals in the BR group (14.9 MUg collagen/mg protein [95% CI: -0.01; 29.7], p=0.05). The difference of 18.66 [95% CI: -6.5; 43.9] between BRE and BR across time was, however, not significant (p=0.14). No significant reduction in SOL muscle collagen content was observed from pre to post in the BR group (-9.3 MUg collagen/mg protein [95% CI: -24.9; 6.4], p=0.25) or in the BRE group (-6.5 MUg collagen/mg protein [95% CI: -25.6; 12.6], p=0.50). There was no difference in the effect of BR versus BRE over time (mean difference -2.78 MUg collagen/mg protein [95% CI: -29.7; 24.1], p=0.82). CONCLUSION: muscle collagen content in the VL or SOL muscle does not seem to differ after a 90-day bed rest period with or without squat exercises. PMID- 26958542 TI - Effects of training on postural stability in young basketball players. AB - BACKGROUND: in basketball, balance ability is important to reduce non-contact injuries. The purpose of the present study was to investigate the effect of training on balance. METHODS: thirty-two healthy male volunteers were recruited from amateur basketball teams. They were asked to perform the Balance Error Scoring System BESS test in order to measure the number of stability errors in six conditions. The test was performed at the beginning of the season (T0) and after 12 weeks (T1). In both cases the test was carried out before (pre-session) and after a training session (post-session). RESULTS: the comparison of the total BESS scores both pre- and post-session showed a statistically significant increase of stability errors at both T0 and T1 (T0: pre-session 8.6+/-6.1 errors, post-session 10.7+/-6.3 errors; t=-4.03; p=0.002) (T1: pre-session 7.2+/-3.8 errors, post-session 9.1+/-5.4 errors; t=-1.93; p=0.03). Between T0 and T1 we noticed a reduction of errors which reached a statistical significance during the pre-session time (t=2.75; p=0.0049). CONCLUSION: stability improved after 12 weeks of training, even for those conditions for which no specific training was done to improve, such as on the soft surface and feet aligned in a tandem stance. PMID- 26958543 TI - In vivo bone tunnel remodeling in symptomatic patients after ACL reconstruction: a retrospective comparison of articular and extra-articular fixation. AB - BACKGROUND: there is only a paucity of studies dealing with bone remodeling within the tunnels after anterior cruciate ligament (ACL) reconstruction. The objective of this study was to evaluate the influence of tendon graft type and surgical fixation technique on bone tunnel remodeling in patients with symptomatic knees after ACL reconstruction. METHODS: in a retrospective study 99mTc-HDP bone tracer uptake (BTU) in SPECT/CT of 57 knees with symptoms of pain and/or instability after ACL reconstruction was investigated. All 57 knees were subdivided according their anatomy (femur and tibia), fixation (articular versus extra-articular fixation) and graft types into eight groups: femoral-articular versus extra-articular fixation using bone-patellar tendon-bone (BPTB) and hamstring autografts; tibial-articular versus extra-articular fixation using patellar tendon and hamstring autografts; BTU grading for each area of the localisation scheme were recorded. Tunnel diameter and length was measured in the CT scans. RESULTS: BTU was higher for the articular fixation in the femur and for the extra-articular fixation in the tibial tunnel. Patellar tendon graft fixation showed a significantly higher BTU in the superior-lateral and posterior-central area of the tibia, meaning the areas of the tibial tunnel near the entrance into the joint. Tunnel enlargement correlated significantly with increased BTU (p<0.05). CONCLUSION: assessment of in vivo bone tunnel remodelling in symptomatic patients after ACL reconstruction revealed different patterns of BTU with regards to graft and fixation method. PMID- 26958544 TI - Sonoelastography in the diagnosis of tendinopathies: an added value. AB - BACKGROUND: sonoelastography helps in the detection of abnormalities not yet evident on B-mode exam. METHODS: in this observational study, we report a collection of cases of symptomatic patients without alterations at ultrasound imaging but with evidence of pathological findings at sonoelastography. Patients, with clinical history suggestive for tendinopathies or surgically treated, and negative at the ultrasound exam, were submitted to sonoelastography. Out of 846, 632 patients with positive ultrasound exam were excluded. Sonoelastography was therefore performed in the remaining 214. RESULTS: the examination was positive in 168 cases: 78 patients were affected with shoulder diseases, while elbow pathology was observed in 31 subjects; patellar, Achilles and plantar fascia disorders were reported in 19, 27, and 13 patients, respectively. CONCLUSION: sonoelastography can reveal tendon abnormalities of clinical relevance in a high percentage of cases, where the ultrasound exam was negative, making the method a complementary tool to ultrasound evaluation. PMID- 26958545 TI - Double layer repair of tibialis anterior muscle hernia in a soccer player: a case report and review of the literature. AB - BACKGROUND: muscle herniations usually present in athletes especially in the lower legs; occurring through defects in the deep fascial layer of the muscles and typically seen following local blunt trauma or muscle hypertrophy after strenuous exercise. Management of muscle hernias varies from conservative therapy to surgical repair and usually needs multidisciplinary collaboration for differential diagnosis. METHODS: herein tibialis anterior muscle hernia in 17 year-old male soccer player was presented. The diagnosis was confirmed with dynamic ultrasonographic views changing with the different movements of the ankle. Since the symptoms were not relieved with conservative methods, surgical repair of the defect was offered. RESULTS: we preferred to repair fascial defect with double layer and Mesh graft that were placed over primary suture repair. No complications were reported such as wound or mesh infection postoperatively. The patient was clinically satisfied and returned his previous activity level after 3 months of surgery. After 2 years of follow-up the feature of the bulge was dissolved and player was satisfied with the operation. CONCLUSION: knowledge of the lower extremity muscle herniation is essential for both proper management and/or surgical referral. The importance of protective devices in prevention, dynamic ultrasonography in diagnosis and double layer repair of the fascial defect with Mesh graft in treatment of muscle herniations were highlighted. PMID- 26958547 TI - Choosing a Post-Fellowship Path. PMID- 26958548 TI - Reflecting on Physician "Burnout". PMID- 26958546 TI - Guided-Mode Resonance Grating with Self-Assembled Silver Nanoparticles for Surface-Enhanced Raman Scattering Spectroscopy. AB - We designed and fabricated guided-mode resonance (GMR) gratings on indium-tin oxide (ITO) thin film to generate a significantly enhanced local electric field for surface-enhanced Raman scattering (SERS) spectroscopy. Ag nanoparticles (NPs) were self-assembled onto the surface of the grating, which can provide a large amount of "hot-spots" for SERS sensing. The ITO gratings also exhibit excellent tolerance to fabrication deviations due to the large refractive index contrast of the ITO grating. Quantitative experimental results of 5,5'-dithiobis(2 nitrobenzoic acid) (DTNB) demonstrate the best enhancement factor of ~14* on ITO gratings when compared with Ag NPs on a flat ITO film, and the limit of detection (LOD) of DTNB is as low as 10 pM. PMID- 26958549 TI - Endoscopic Band Ligation: A Safe And Effective Treatment For Active Diverticular Bleeding. PMID- 26958550 TI - Intrarectal Mesh Migration with Recurrence After Transabdominal Mesh Rectopexy. PMID- 26958551 TI - Mature Cystic Teratoma of the Pancreas. PMID- 26958552 TI - Dumbbell Gallbladder Diagnosed by ERCP. PMID- 26958553 TI - Anaplastic Large Cell Lymphoma and Vanishing Bile Duct Syndrome. PMID- 26958554 TI - Liver Involvement in Erythropetic Protoporphyria. PMID- 26958555 TI - The Black Esophagus: A Rare But Deadly Disease. AB - We present a series of cases of acute esophageal necrosis along with a video demonstration. The video captures a case showing the severity of necrosis of the esophageal mucosa; an orogastric tube easily passed through the esophageal lumen and into the right hemithorax. The series also demonstrates the severity of this illness, with an associated high mortality rate. PMID- 26958556 TI - Massive Esophageal Variceal Bleeding as a Rare Complication of Sickle Cell Anemia. AB - A 24-year-old man with sickle cell anemia presented with fatigue, dark stool, and coffee ground emesis. He was found to have large esophageal varices and experienced massive variceal hemorrhage in the hospital. The varices were caused by diffuse splanchnic venous thrombosis, and his only risk factor for hypercoagulability was sickle cell anemia. Splanchnic venous thrombosis due to sickle cell anemia is exceedingly rare. PMID- 26958557 TI - Esophageal Eosinophilia Treated With Long-Duration Proton Pump Inhibitor Therapy. AB - We present a case of proton pump inhibitor-responsive eosinophilic esophagitis (PPI-REE) in a patient with severe dysphagia and markedly elevated baseline esophageal eosinophilia that was previously deemed unresponsive to PPI. Upon reintroduction to PPI therapy with monthly endoscopy and dilation over the course of 4 months, the patient improved clinically and resolved her mucosal eosinophilia. Our case suggests that a longer duration of PPI therapy may be required for histologic improvement, especially in patients with very high mucosal eosinophil count. PMID- 26958558 TI - Successful Treatment of a Persistent Esophageal Lichen Planus Stricture With a Fully Covered Metal Stent. AB - We report a case of a 51-year-old woman with an esophageal lichen planus (ELP) stricture refractory to medical therapy and endoscopic stricture dilation. A multidisciplinary decision was made to place an esophageal fully covered metal stent. The stent was removed 6 weeks later and the patient is doing well on 3 month follow up. We show that a removable esophageal stent is an option after standard medical therapy and endoscopic dilations fail. This is the first reported use of an esophageal stent for therapy of an ELP stricture. PMID- 26958559 TI - Severe Enteropathy From Mycophenolate Mofetil. AB - The adverse effects of mycophenolate mofetil on the colon are well known. However, isolated small intestinal involvement resulting in diarrhea and severe weight loss is infrequently reported in the literature. We present the case of a 45-year-old woman on mycophenolate mofetil following renal transplant, who presented with abdominal pain and weight loss. An esophagogastroduodenoscopy and colonoscopy with biopsies were normal. A small bowel capsule study revealed extensive enteropathy of jejunum and ileum that was confirmed on a push enteroscopy with biopsies. Her symptoms completely resolved after being switched to enteric-coated mycophenolic acid. PMID- 26958560 TI - Perisigmoid Abscess Leading to a Diagnosis of Ehlers-Danlos Syndrome Type IV. AB - The Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders characterized by triad of joint hypermobility, skin extensibility, and tissue fragility. Ehlers-Danlos syndrome type IV places patients at risk for life threatening, spontaneous, vascular or visceral rupture due to reduced or abnormal secretion of type III collagen. We present an adolescent male who was found to have a perisigmoid abscess with a fistula connecting to adjacent sigmoid colon secondary to undiagnosed EDS type IV. Conservative management with antibiotics and bowel rest was pursued to allow for elective resection for his acute complicated diverticulitis at a safer time. PMID- 26958561 TI - Ustekinumab for Successful Treatment of Refractory Esophageal Crohn's Disease. AB - Esophageal involvement in Crohn's disease is rare. We present a case of refractory esophageal Crohn's disease that responded to ustekinumab, which has shown promise in the treatment of refractory, typically intestinal Crohn's disease. There are no prior reports on the successful use of ustekinumab in esophageal Crohn's disease, but should be considered as a possible management strategy in patients with this condition. PMID- 26958562 TI - Somatostatinoma of the Ampulla: An Incidental Postoperative Finding Following Colorectal Cancer Resection. AB - Somatostatinoma of the gastrointestinal tract is a rare finding, especially arising from the ampulla of Vater. We present a man recently diagnosed with rectal adenocarcinoma who was found on imaging to have an ampullary mass. Histology and immunohistochemical staining of the biopsied tissue were consistent with a nonfunctioning somatostatinoma. The patient had neurofibromatosis, which have been reported in patients with ampullary somatostatinomas. Our case highlights the importance of gastrointestinal findings in those with underlying genetic conditions. PMID- 26958563 TI - Pneumobilia Resulting From Choledochoduodenal Fistula Secondary to Metastatic Colon Adenocarcinoma. AB - Pneumobilia, or air within the biliary tree, is a poor prognostic indicator in a patient without prior biliary sphincterotomy. Differential diagnosis includes infection with gas-forming organisms, choledochoenteric fistula in the setting of gallstones or penetrating ulcer disease, malignant invasion from a primary liver or biliary tract tumor, or metastatic disease. Treatment depends on etiology and patient factors, but often requires surgical intervention. We report a patient with gastrointestinal bleeding in whom pneumobilia was incidentally noted on abdominal plain film. Computed tomography and endoscopy revealed the biliary enteric fistula to be caused by metastatic colon adenocarcinoma invading the biliary tree. PMID- 26958564 TI - Granular Cell Tumor of the Common Hepatic Duct as an Unusual Cause of Jaundice in a Hepatitis C Patient. AB - A 33-year-old woman with a history of intravenous cocaine abuse presented with fatigue, nausea, and jaundice. Serologic testing revealed a positive hepatitis C virus (HCV) antibody and HCV RNA. Ultrasound and magnetic resonance imaging/magnetic resonance cholangiopancreatography showed a partially obstructing lesion in the common hepatic duct, which was confirmed by endoscopic retrograde cholangiopancreatography. Surgical excision revealed a granular cell tumor of the common hepatic duct, with immunohistochemical staining of tumor cells positive for S-100. PMID- 26958565 TI - No Stone Left Unturned: Using Choledocholithiasis to Open a Papillary Stenosis via a Choledochodudenal Fistula. AB - In a patient found to have cholelithiasis and choledocholithiasis, a choledochoduodenal fistula was used to gain access to the bile duct. Due to severe stenosis and atrophy of the major papilla, cannulation was not possible. Stones were purposely impacted in the native ampulla to cause bulging and stretching of the stenosis. Once the stenosis was stretched, the bile and pancreatic duct were accessed via the native ampulla, allowing for stone removal. PMID- 26958566 TI - Severe Thrombotic Complication of Eltrombopag in a Cirrhotic Patient. AB - We present a patient with hepatitis C virus (HCV) and cirrhosis who was treated with eltrombopag for idiopathic thrombocytopenic purpura and was incidentally found to have a right atrial thrombus with extension into the left internal jugular vein. Eltrombopag was discontinued and the patient was treated with thrombectomy and anticoagulation. Given the proposed use of eltrombopag in HCV associated thrombocytopenia, we advise caution when treating cirrhotics who are at higher intrinsic risk of thrombosis. PMID- 26958567 TI - Decompensated Liver Cirrhosis Presenting as a Spontaneous Left-Sided Bacterial Empyema. AB - Decompensation of cirrhosis presents with ascites, encephalopathy, variceal bleeding, or spontaneous bacterial peritonitis. Infrequently, decompensation can result from spontaneous bacterial empyema. A 38-year-old man presented with fevers, chills, and dyspnea. Labs were significant for leukocytosis, transaminitis, and coagulopathy. Imaging showed liver cirrhosis with ascites and a left pleural effusion. Treatment of the effusion consisted of chest tube drainage and antibiotics. Spontaneous bacterial empyema was diagnosed after pleural fluid cultures were positive for Escherichia coli. Our case demonstrates that spontaneous bacterial empyemas can be left-sided, and the first sign of decompensation. PMID- 26958568 TI - Dysferlin-Deficient Muscular Dystrophy Identified Through Laboratory Testing for Elevated Aminotransferases. AB - We present a 24-year-old combat veteran who underwent extensive work-up for elevated aminotransferases, including liver biopsy, with no underlying pathology identified. Subsequent investigations showed elevated creatinine kinase and aldolase. The patient was later diagnosed with biopsy-proven dysferlin-deficient muscular dystrophy. Persistent transaminase elevation despite negative liver work up should prompt clinicians to consider extrahepatic sources of enzyme elevation. Promptly correlating aminotransferase elevation with musculoskeletal pathology may present an opportunity for clinicians to detect myopathies such as muscular dystrophy in their preclinical stages. PMID- 26958569 TI - Acute Hepatitis and Pneumonitis Caused by Disseminated Bacillus Calmette-Guerin Infection. AB - Intravesical instillation of Bacillus Calmette-Guerin (BCG) is the treatment of choice for superficial bladder carcinoma. We report a case of disseminated BCG infection in an early stage bladder cancer patient that initially presented with hepatitis followed by pneumonitis and sepsis. A complete clinical response was achieved in 14 days with anti-mycobacterial therapy and prednisolone. Disseminated BCG is a rare treatment complication and is likely a combination of direct infection and hypersensitivity. PMID- 26958570 TI - Severe Cholestasis and Bile Acid Nephropathy From Anabolic Steroids Successfully Treated With Plasmapheresis. AB - Severe cholestasis with anabolic androgenic steroids is well-known to cause acute liver injury. Treatment is usually supportive after withdrawal of the offending agent. Acute kidney injury (AKI) frequently occurs in acute liver injury and may complicate management and prognosis. We highlight the use of plasmapheresis resulting in rapid improvement in cholestatic jaundice with resolution of AKI. Plasmapheresis should be considered in special cases in which there is progressive clinical decline despite supportive care. PMID- 26958571 TI - Splenic Artery Embolization for Treatment of Refractory Ascites After Liver Transplantation. AB - Post-transplantation refractory ascites is uncommon; however, it can be a serious problem, increasing both morbidity and mortality in patients. Despite scant literature available, splenic artery embolization (SAE) has been shown to be an effective treatment for refractory ascites after cadaveric orthotopic liver transplantation (OLT). We report a successful use of therapeutic SAE for refractory ascites post-OLT. PMID- 26958572 TI - Giant Solitary Fibrous Tumor of the Buttock. PMID- 26958573 TI - Lead Poisoning From a Ceramic Jug Presenting as Recurrent Abdominal Pain and Jaundice. AB - Lead poisoning may present with non-specific symptoms that may result in unnecessary investigations. We report a case of acute lead poisoning in a previously healthy 28-year-old man who presented with recurrent abdominal pain, jaundice, constipation, and weight loss. An extensive diagnostic work-up was completed with inconclusive results. A detailed history revealed an unusual source of lead exposure. Chelation therapy resulted in substantial clinical and biochemical improvement. PMID- 26958574 TI - The impact of minimally oversized adeno-associated viral vectors encoding human factor VIII on vector potency in vivo. AB - Recombinant adeno-associated viral (rAAV) vectors containing oversized genomes provide transgene expression despite low efficiency packaging of complete genomes. Here, we characterized the properties of oversized rAAV2/8 vectors (up to 5.4 kb) encoding human factor VIII (FVIII) under the transcriptional control of three liver promoters. All vectors provided sustained production of active FVIII in mice for 7 months and contained comparable levels of vector genomes and complete expression cassettes in liver. Therefore, for the 5.4 kb genome size range, a strong expression cassette was more important for FVIII production than the vector genome size. To evaluate the potency of slightly oversized vectors, a 5.1 kb AAVrh8R/FVIII vector was compared to a 4.6 kb (wild-type size) vector with an identical expression cassette (but containing a smaller C1-domain deleted FVIII) for 3 months in mice. The 5.1 kb vector had twofold to threefold lower levels of plasma FVIII protein and liver vector genomes than that obtained with the 4.6 kb vector. Vector genomes for both vectors persisted equally and existed primarily as high molecular weight concatemeric circular forms in liver. Taken together, these results indicate that the slightly oversized vectors containing heterogeneously packaged vector genomes generated a functional transgene product but exhibited a twofold to threefold lower in vivo potency. PMID- 26958575 TI - Multilineage polyclonal engraftment of Cal-1 gene-modified cells and in vivo selection after SHIV infection in a nonhuman primate model of AIDS. AB - We have focused on gene therapy approaches to induce functional cure/remission of HIV-1 infection. Here, we evaluated the safety and efficacy of the clinical grade anti-HIV lentiviral vector, Cal-1, in pigtailed macaques (Macaca nemestrina). Cal 1 animals exhibit robust levels of gene marking in myeloid and lymphoid lineages without measurable adverse events, suggesting that Cal-1 transduction and autologous transplantation of hematopoietic stem cells are safe, and lead to long term, multilineage engraftment following myeloablative conditioning. Ex vivo, CD4+ cells from transplanted animals undergo positive selection in the presence of simian/human immunodeficiency virus (SHIV). In vivo, Cal-1 gene-marked cells are evident in the peripheral blood and in HIV-relevant tissue sites such as the gastrointestinal tract. Positive selection for gene-marked cells is observed in blood and tissues following SHIV challenge, leading to maintenance of peripheral blood CD4+ T-cell counts in a normal range. Analysis of Cal-1 lentivirus integration sites confirms polyclonal engraftment of gene-marked cells. Following infection, a polyclonal, SHIV-resistant clonal repertoire is established. These findings offer strong preclinical evidence for safety and efficacy of Cal-1, present a new method for tracking protected cells over the course of virus mediated selective pressure in vivo, and reveal previously unobserved dynamics of virus-dependent T-cell selection. PMID- 26958576 TI - Multichannel continuous electroencephalography-functional near-infrared spectroscopy recording of focal seizures and interictal epileptiform discharges in human epilepsy: a review. AB - Functional near-infrared spectroscopy (fNIRS) has emerged as a promising neuroimaging technique as it allows noninvasive and long-term monitoring of cortical hemodynamics. Recent work by our group and others has revealed the potential of fNIRS, combined with electroencephalography (EEG), in the context of human epilepsy. Hemodynamic brain responses attributed to epileptic events, such as seizures and interictal epileptiform discharges (IEDs), are routinely observed with a good degree of statistical significance and in concordance with clinical presentation. Recording done with over 100 channels allows sufficiently large coverage of the epileptic focus and other areas. Three types of seizures have been documented: frontal lobe seizures, temporal lobe seizures, and posterior seizures. Increased oxygenation was observed in the epileptic focus in most cases, while rapid but similar hemodynamic variations were identified in the contralateral homologous region. While investigating IEDs, it was shown that their hemodynamic effect is observable with fNIRS, that their response is associated with significant (inhibitive) nonlinearities, and that the sensitivity and specificity of fNIRS to localize the epileptic focus can be estimated in a sample of 40 patients. This paper first reviews recent EEG-fNIRS developments in epilepsy research and then describes applications to the study of focal seizures and IEDs. PMID- 26958577 TI - Near-infrared measurements of brain oxygenation in stroke. AB - We investigated the feasibility of using frequency-domain near-infrared spectroscopy (fdNIRS) to study brain oxygenation in the first few hours of stroke onset. The OxiplexTS((r)) fdNIRS system was used in this study. Using a standard probing protocol based on surface landmarks, we measured brain tHb and [Formula: see text] in healthy volunteers, cadavers, and acute stroke patients within 9 h of stroke onset and 3 days later. We obtained measurements from 11 controls, 5 cadavers, and 5 acute stroke patients. [Formula: see text] values were significantly lower in cadavers compared to the controls and stroke patients. Each stroke patient had at least one area with reduced [Formula: see text] on the stroke side compared to the contralateral side. The evolution of tHb and [Formula: see text] at 3 days differed depending on whether a large infarct occurred. This study shows the proof of principle that quantified measurements of brain oxygenation using NIRS could be used in the hectic environment of acute stroke management. It also highlights the current technical limitations and future challenges in the development of this unique bedside monitoring tool for stroke. PMID- 26958578 TI - Automated pericardial fat quantification from coronary magnetic resonance angiography: feasibility study. AB - Pericardial fat volume (PFV) is emerging as an important parameter for cardiovascular risk stratification. We propose a hybrid approach for automated PFV quantification from water/fat-resolved whole-heart noncontrast coronary magnetic resonance angiography (MRA). Ten coronary MRA datasets were acquired. Image reconstruction and phase-based water-fat separation were conducted offline. Our proposed algorithm first roughly segments the heart region on the original image using a simplified atlas-based segmentation with four cases in the atlas. To get exact boundaries of pericardial fat, a three-dimensional graph-based segmentation is used to generate fat and nonfat components on the fat-only image. The algorithm then selects the components that represent pericardial fat. We validated the quantification results on the remaining six subjects and compared them with manual quantifications by an expert reader. The PFV quantified by our algorithm was [Formula: see text], compared to [Formula: see text] by the expert reader, which were not significantly different ([Formula: see text]) and showed excellent correlation ([Formula: see text],[Formula: see text]). The mean absolute difference in PFV between the algorithm and the expert reader was [Formula: see text]. The mean value of the paired differences was [Formula: see text] (95% confidence interval: [Formula: see text] to 6.21). The mean Dice coefficient of pericardial fat voxels was [Formula: see text]. Our approach may potentially be applied in a clinical setting, allowing for accurate magnetic resonance imaging (MRI)-based PFV quantification without tedious manual tracing. PMID- 26958579 TI - Visual saliency-based active learning for prostate magnetic resonance imaging segmentation. AB - We propose an active learning (AL) approach for prostate segmentation from magnetic resonance images. Our label query strategy is inspired from the principles of visual saliency that have similar considerations for choosing the most salient region. These similarities are encoded in a graph using classification maps and low-level features. Random walks are used to identify the most informative node, which is equivalent to the label query sample in AL. To reduce computation time, a volume of interest (VOI) is identified and all subsequent analysis, such as probability map generation using semisupervised random forest classifiers and label query, is restricted to this VOI. The negative log-likelihood of the probability maps serves as the penalty cost in a second-order Markov random field cost function, which is optimized using graph cuts for prostate segmentation. Experimental results on the Medical Image Computing and Computer Assisted Intervention (MICCAI) 2012 prostate segmentation challenge show the superior performance of our approach to conventional methods using fully supervised learning. PMID- 26958580 TI - Fabrication and control of CT number through polymeric composites based on coronary plaque CT phantom applications. AB - Biomedical phantoms are commonly used for various medical imaging modalities to improve imaging quality and procedures. Current biomedical phantoms fabricated commercially are high in cost and limited in the specificity of human environments and structures that can be mimicked. This study aimed to control the measurable computed tomography (CT) number in Hounsfield units through polymeric biomedical phantom materials using controlled amounts of hydroxyapatite (hA). The purpose was to fabricate CT phantoms capable of mimicking various coronary plaque types while introducing a fabrication technique and basis for a numerical model to which the technique may be applied. The CT number is tunable based on the controlled material properties of electron density and atomic numbers. Three different polymeric matrices of polyethylene (PE), thermoplastic polyurethane (TPU), and polyvinylidene fluoride (PVDF) were selected due to their varied specific densities and ease of fabrication acting as integral properties for CT phantom fabrication. These polymers were processed together with additions of hA in mass percentages of 2.5, 5, 10, and 20% hA as well as a 0% hA as a control for each polymeric material. By adding hA to PE, TPU, and PVDF an increasing trend was exhibited between CT number and weight percent of hA. PMID- 26958581 TI - Ligand and interfacial dynamics in a homodimeric hemoglobin. AB - The structural dynamics of dimeric hemoglobin (HbI) from Scapharca inaequivalvis in different ligand-binding states is studied from atomistic simulations on the MUs time scale. The intermediates are between the fully ligand-bound (R) and ligand-free (T) states. Tertiary structural changes, such as rotation of the side chain of Phe97, breaking of the Lys96-heme salt bridge, and the Fe-Fe separation, are characterized and the water dynamics along the R-T transition is analyzed. All these properties for the intermediates are bracketed by those determined experimentally for the fully ligand-bound and ligand-free proteins, respectively. The dynamics of the two monomers is asymmetric on the 100 ns timescale. Several spontaneous rotations of the Phe97 side chain are observed which suggest a typical time scale of 50-100 ns for this process. Ligand migration pathways include regions between the B/G and C/G helices and, if observed, take place in the 100 ns time scale. PMID- 26958582 TI - Loop dynamics of thymidine diphosphate-rhamnose 3'-O-methyltransferase (CalS11), an enzyme in calicheamicin biosynthesis. AB - Structure analysis and ensemble refinement of the apo-structure of thymidine diphosphate (TDP)-rhamnose 3'-O-methyltransferase reveal a gate for substrate entry and product release. TDP-rhamnose 3'-O-methyltransferase (CalS11) catalyses a 3'-O-methylation of TDP-rhamnose, an intermediate in the biosynthesis of enediyne antitumor antibiotic calicheamicin. CalS11 operates at the sugar nucleotide stage prior to glycosylation step. Here, we present the crystal structure of the apo form of CalS11 at 1.89 A resolution. We propose that the L2 loop functions as a gate facilitating and/or providing specificity for substrate entry or promoting product release. Ensemble refinement analysis slightly improves the crystallographic refinement statistics and furthermore provides a compelling way to visualize the dynamic model of loop L2, supporting the understanding of its proposed role in catalysis. PMID- 26958583 TI - Large scale rigidity-based flexibility analysis of biomolecules. AB - KINematics And RIgidity (KINARI) is an on-going project for in silico flexibility analysis of proteins. The new version of the software, Kinari-2, extends the functionality of our free web server KinariWeb, incorporates advanced web technologies, emphasizes the reproducibility of its experiments, and makes substantially improved tools available to the user. It is designed specifically for large scale experiments, in particular, for (a) very large molecules, including bioassemblies with high degree of symmetry such as viruses and crystals, (b) large collections of related biomolecules, such as those obtained through simulated dilutions, mutations, or conformational changes from various types of dynamics simulations, and (c) is intended to work as seemlessly as possible on the large, idiosyncratic, publicly available repository of biomolecules, the Protein Data Bank. We describe the system design, along with the main data processing, computational, mathematical, and validation challenges underlying this phase of the KINARI project. PMID- 26958584 TI - A modified PATH algorithm rapidly generates transition states comparable to those found by other well established algorithms. AB - PATH rapidly computes a path and a transition state between crystal structures by minimizing the Onsager-Machlup action. It requires input parameters whose range of values can generate different transition-state structures that cannot be uniquely compared with those generated by other methods. We outline modifications to estimate these input parameters to circumvent these difficulties and validate the PATH transition states by showing consistency between transition-states derived by different algorithms for unrelated protein systems. Although functional protein conformational change trajectories are to a degree stochastic, they nonetheless pass through a well-defined transition state whose detailed structural properties can rapidly be identified using PATH. PMID- 26958585 TI - Stochastic stimulated electronic x-ray Raman spectroscopy. AB - Resonant inelastic x-ray scattering (RIXS) is a well-established tool for studying electronic, nuclear, and collective dynamics of excited atoms, molecules, and solids. An extension of this powerful method to a time-resolved probe technique at x-ray free electron lasers (XFELs) to ultimately unravel ultrafast chemical and structural changes on a femtosecond time scale is often challenging, due to the small signal rate in conventional implementations at XFELs that rely on the usage of a monochromator setup to select a small frequency band of the broadband, spectrally incoherent XFEL radiation. Here, we suggest an alternative approach, based on stochastic spectroscopy, which uses the full bandwidth of the incoming XFEL pulses. Our proposed method is relying on stimulated resonant inelastic x-ray scattering, where in addition to a pump pulse that resonantly excites the system a probe pulse on a specific electronic inelastic transition is provided, which serves as a seed in the stimulated scattering process. The limited spectral coherence of the XFEL radiation defines the energy resolution in this process and stimulated RIXS spectra of high resolution can be obtained by covariance analysis of the transmitted spectra. We present a detailed feasibility study and predict signal strengths for realistic XFEL parameters for the CO molecule resonantly pumped at the [Formula: see text] transition. Our theoretical model describes the evolution of the spectral and temporal characteristics of the transmitted x-ray radiation, by solving the equation of motion for the electronic and vibrational degrees of freedom of the system self consistently with the propagation by Maxwell equations. PMID- 26958586 TI - A beam branching method for timing and spectral characterization of hard X-ray free-electron lasers. AB - We report a method for achieving advanced photon diagnostics of x-ray free electron lasers (XFELs) under a quasi-noninvasive condition by using a beam splitting scheme. Here, we used a transmission grating to generate multiple branches of x-ray beams. One of the two primary diffracted branches (+1st-order) is utilized for spectral measurement in a dispersive scheme, while the other ( 1st-order) is dedicated for arrival timing diagnostics between the XFEL and the optical laser pulses. The transmitted x-ray beam (0th-order) is guided to an experimental station. To confirm the validity of this timing-monitoring scheme, we measured the correlation between the arrival timings of the -1st and 0th branches. The observed error was as small as 7.0 fs in root-mean-square. Our result showed the applicability of the beam branching scheme to advanced photon diagnostics, which will further enhance experimental capabilities of XFEL. PMID- 26958588 TI - Molecular features in complex environment: Cooperative team players during excited state bond cleavage. AB - Photoinduced bond cleavage is often employed for the generation of highly reactive carbocations in solution and to study their reactivity. Diphenylmethyl derivatives are prominent precursors in polar and moderately polar solvents like acetonitrile or dichloromethane. Depending on the leaving group, the photoinduced bond cleavage occurs on a femtosecond to picosecond time scale and typically leads to two distinguishable products, the desired diphenylmethyl cations (Ph2CH(+)) and as competing by-product the diphenylmethyl radicals ([Formula: see text]). Conical intersections are the chief suspects for such ultrafast branching processes. We show for two typical examples, the neutral diphenylmethylchloride (Ph2CH-Cl) and the charged diphenylmethyltriphenylphosphonium ions ([Formula: see text]) that the role of the conical intersections depends not only on the molecular features but also on the interplay with the environment. It turns out to differ significantly for both precursors. Our analysis is based on quantum chemical and quantum dynamical calculations. For comparison, we use ultrafast transient absorption measurements. In case of Ph2CH-Cl, we can directly connect the observed signals to two early three-state and two-state conical intersections, both close to the Franck-Condon region. In case of the [Formula: see text], dynamic solvent effects are needed to activate a two-state conical intersection at larger distances along the reaction coordinate. PMID- 26958587 TI - Identification of the dominant photochemical pathways and mechanistic insights to the ultrafast ligand exchange of Fe(CO)5 to Fe(CO)4EtOH. AB - We utilized femtosecond time-resolved resonant inelastic X-ray scattering and ab initio theory to study the transient electronic structure and the photoinduced molecular dynamics of a model metal carbonyl photocatalyst Fe(CO)5 in ethanol solution. We propose mechanistic explanation for the parallel ultrafast intra molecular spin crossover and ligation of the Fe(CO)4 which are observed following a charge transfer photoexcitation of Fe(CO)5 as reported in our previous study [Wernet et al., Nature 520, 78 (2015)]. We find that branching of the reaction pathway likely happens in the (1)A1 state of Fe(CO)4. A sub-picosecond time constant of the spin crossover from (1)B2 to (3)B2 is rationalized by the proposed (1)B2 -> (1)A1 -> (3)B2 mechanism. Ultrafast ligation of the (1)B2 Fe(CO)4 state is significantly faster than the spin-forbidden and diffusion limited ligation process occurring from the (3)B2 Fe(CO)4 ground state that has been observed in the previous studies. We propose that the ultrafast ligation occurs via (1)B2 -> (1)A1 -> (1)A' Fe(CO)4EtOH pathway and the time scale of the (1)A1 Fe(CO)4 state ligation is governed by the solute-solvent collision frequency. Our study emphasizes the importance of understanding the interaction of molecular excited states with the surrounding environment to explain the relaxation pathways of photoexcited metal carbonyls in solution. PMID- 26958590 TI - A de novo microdeletion involving PAFAH1B (LIS1) related to lissencephaly phenotype. AB - Lissencephaly is a type of the congenital malformation of the brain. Due to the impairments of neuronal migration, patients show absence of brain convolution manifesting smooth brain surfaces. One of the human genes responsible for lissencephaly is the platelet-activating factor acetylhydrolase 1b gene (PAFAH1B; also known as LIS1) located on 17p13.3. Patients with heterozygous deletion of this chromosomal region exhibit lissencephaly. Recently, we encountered a male patient who showed typical lissencephaly. Using a microarray analysis, we identified a 1.3 Mb submicroscopic deletion in 17p13.3. This deletion included PAFAH1B. Both of the parents showed no deletion in this region. Therefore, this was determined to be derived from de novo origin. After obtaining the written informed consent, skin fibroblasts were provided from this patient and disease specific induced pluripotent stem (iPS) cells were generated and used for medical research (Shimojima K, Okumura A, Hayashi M, Kondo T, Inoue H, and Yamamoto T. CHCHD2 is down-regulated in neuronal cells differentiated from iPS cells derived from patients with lissencephaly. Genomics, in press). PMID- 26958589 TI - Carrier-envelope phase dependence of the directional fragmentation and hydrogen migration in toluene in few-cycle laser fields. AB - The dissociative ionization of toluene initiated by a few-cycle laser pulse as a function of the carrier envelope phase (CEP) is investigated using single-shot velocity map imaging. Several ionic fragments, CH3 (+), H2 (+), and H3 (+), originating from multiply charged toluene ions present a CEP-dependent directional emission. The formation of H2 (+) and H3 (+) involves breaking C-H bonds and forming new bonds between the hydrogen atoms within the transient structure of the multiply charged precursor. We observe appreciable intensity dependent CEP-offsets. The experimental data are interpreted with a mechanism that involves laser-induced coupling of vibrational states, which has been found to play a role in the CEP-control of molecular processes in hydrocarbon molecules, and appears to be of general importance for such complex molecules. PMID- 26958591 TI - Human Cytomegalovirus variant peptides adapt by decreasing their total coordination upon binding to a T cell receptor. AB - The tertiary structure of the native Cytomegalovirus peptide (NLV) presented by HLA-A2 and bound to the RA14 T cell receptor was used as a reference for the calculation of atomic coordination differences of both the NLV as well as of a number of singly substituted NLV variants in the absence of TCR. Among the pMHC complexes, the native peptide was found to exhibit the highest total coordination difference in respect to the reference structure, suggesting that it experienced the widest structural adaptation upon recognition by the TCR. In addition, the peptide on the isolated NLV-MHC complex was over-coordinated as compared to the rest of the variants. Moreover, the trend was found to account for a set of measured dissociation constants and critical concentrations for target-cell lysis for all variants in complexation with RA14: functionally, all variant peptides were established to be either weak agonists or null peptides, while, at the same time, our current study established that they were also under-coordinated in respect to NLV. It could, thus, be argued that the most 'efficient' structural adaptation upon pMHC recognition by the TCR requires of the peptide to undergo the widest under-coordination possible. The main structural characteristic which differentiated the NLV in respect to the variants was a the presence of 16 oxygen atoms (waters) in the former's second coordination shell which accounted for over coordination of roughly 100% and 30% in the O-O and C-O partials respectively. In fact, in the absence of second shell oxygens, the NLV peptide was decidedly under coordinated in respect to all of the variants, as also suggested by the C-C partial. PMID- 26958593 TI - Amino acid sequence alignment of vertebrate CAPN3/calpain-3/p94. AB - CAPN3 is a calpain superfamily member that is predominantly expressed in skeletal muscle. So far, clear CAPN3 orthologs were found only in vertebrates. CAPN3 is a unique protease in that it undergoes extremely rapid and exhaustive autolysis and that autolyzed fragments spontaneously associate each other to reconstitute the proteolytic activity. These unique properties of CAPN3 are dependent on IS1 and IS2, two CAPN3-characterizing sequences that do not exist in other calpains or any other proteases. To understand how IS1 and IS2 are conserved among vertebrates, this data article provides amino acid sequence alignment of representative vertebrate CAPN3s. For further analysis and discussion, see Ono et al. [1]. PMID- 26958592 TI - Data for proteomic profiling of Anthers from a photosensitive male sterile mutant and wild-type cotton (Gossypium hirsutum L.). AB - Cotton is an important economic crop, used mainly for the production of textile fiber. Using a space mutation breeding technique, a novel photosensitive genetic male sterile mutant CCRI9106 was isolated from the wild-type upland cotton cultivar CCRI040029. To study the male sterile mechanisms of CCRI9106, histological and iTRAQ-facilitated proteomic analyses of anthers were performed. This data article contains data related to the research article titled iTRAQ Facilitated Proteomic Profiling of Anthers From a Photosensitive Male Sterile Mutant and Wild-type Cotton (Gossypium hirsutum L.)[1]. This research article describes the iTRAQ-facilitated proteomic analysis of the wild-type and a photosensitive male sterile mutant in cotton. The report indicated that exine formation defect is the key reason for male sterility in mutant plant. The information presented here represents the tables and figures that detail the processing of the raw data obtained from iTRAQ analysis. PMID- 26958594 TI - Protein functional analysis data in support of comparative proteomics of the pathogenic black yeast Exophiala dermatitidis under different temperature conditions. AB - In the current study a comparative proteomic approach was used to investigate the response of the human pathogen black yeast Exophiala dermatitidis toward temperature treatment. Protein functional analysis - based on cellular process GO terms - was performed on the 32 temperature-responsive identified proteins. The bioinformatics analyses and data presented here provided novel insights into the cellular pathways at the base of the fungus temperature tolerance. A detailed analysis and interpretation of the data can be found in "Proteome of tolerance fine-tuning in the human pathogen black yeast Exophiala dermatitidis" by Tesei et al. (2015) [1]. PMID- 26958595 TI - Benchmark data for identifying N(6)-methyladenosine sites in the Saccharomyces cerevisiae genome. AB - This data article contains the benchmark dataset for training and testing iRNA Methyl, a web-server predictor for identifying N(6)-methyladenosine sites in RNA (Chen et al., 2015 [15]). It can also be used to develop other predictors for identifying N(6)-methyladenosine sites in the Saccharomyces cerevisiae genome. PMID- 26958596 TI - Analytical purification of a 60-kDa target protein of artemisinin detected in Trypanosoma brucei brucei. AB - Here we describe the isolation and purity determination of Trypanosoma brucei (T. b.) brucei candidate target proteins of artemisinin. The candidate target proteins were detected and purified from their biological source (T. b. brucei lysate) using the diazirine-free biotinylated probe 5 for an affinity binding to a streptavidin-tagged resin and, subsequently, the labeled target proteins were purified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). We herein showed the electrophoresis gel and the immunoblotting film containing the 60-kDa trypanosomal candidate target protein of artemisinin as a single band, which was visualized on-gel by the reverse-staining method and on a Western blotting film by enhanced chemiluminescence. The data provided in this article are related to the original research article "Biotinylated probes of artemisinin with labeling affinity toward Trypanosoma brucei brucei target proteins", by Konziase (Anal. Biochem., vol. 482, 2015, pp. 25-31. http://dx.doi.org/10.1016/j.ab.2015.04.020). PMID- 26958597 TI - Data supporting Arf6 regulation of Schwann cell differentiation and myelination. AB - The data is related to the research article entitled "Arf6 mediates Schwann cell differentiation and myelination" [1]. To further investigate the role of Arf6 in promoting myelination by Schwann cells in vivo, we have characterized an another line (#2) of small-hairpin (sh)RNA transgenic mice targeting Arf6. The number of transgenes per one allele in this line was very low (2 transgenes), comparing with high copies in the previous line (#1, 20 transgenes) [1]. In 4 days of neonatal age, transgenic mice exhibited decreased myelin thickness; however, decreased levels were not as much as those in the line #1, likely depending on transgene copy number. In 60-day-old mice, the difference became smaller. On the other hand, transgene's effect was not related to cell proliferation and apoptosis. These data support the key role of Arf6 in Schwann cell myelination, especially in the initiation. PMID- 26958598 TI - Abnormal number cell division of human thyroid anaplastic carcinoma cell line, SW 1736. AB - Cell division, during which a mother cell usually divides into two daughter cells during one cell cycle, is the most important physiological event of cell biology. We observed one-to-four cell division during imaging of live SW1736 human thyroid anaplastic carcinoma cells transfected with a plasmid expressing the hybrid protein of green fluorescent protein and histone 2B (plasmid eGFP-H2B). Analysis of the images revealed a mother cell divided into four daughter cells. And one of the abnormally divided daughter cells subsequently formed a dinucleate cell. PMID- 26958599 TI - Global proteomic characterization of microdissected estrogen receptor positive breast tumors. AB - We here describe two proteomic datasets deposited in ProteomeXchange via PRIDE partner repository [1] with dataset identifiers PXD000484 (defined as "training") and PXD000485 (defined as "test") that have been used for the development of a tamoxifen outcome predictive signature [2]. Both datasets comprised 56 fresh frozen estrogen receptor (ER) positive primary breast tumor specimens derived from patients who received tamoxifen as first line therapy for recurrent disease. Patient groups were defined based on time to progression (TTP) after start of tamoxifen therapy (6 months cutoff): 32 good and 24 poor treatment outcome patients were comprised in the training set, respectively. The test set included 41 good and 15 poor treatment outcome patients. All specimens were subjected to laser capture microdissection (LCM) to enrich for epithelial tumor cells prior to high resolution mass spectrometric (MS) analysis. Protein identification and label-free quantification (LFQ) were performed with MaxQuant software package [3]. A total of 3109 and 4061 proteins were identified and quantified in the training and test set, respectively. We here present the first public proteomic dataset analyzing ER positive recurrent breast cancer by LCM coupled to high resolution MS. PMID- 26958600 TI - Data in support of optimized production of angiotensin-I converting enzyme inhibitory peptides derived from proteolytic hydrolysate of bitter melon seed proteins. AB - VY-7 has been demonstrated as a potent ACE inhibitory peptide in the previous study [1]. In this article, we provide accompanying data about the identification of bitter melon seed proteins (BMSPs), and quantitative analysis and optimized production of VY-7 in BMSPs hydrolysate. PMID- 26958601 TI - Data on energy, exergy analysis and optimisation for a sugar factory. AB - A huge amount of energy is consumed during sugar production in the food industry. The large amount of steam used and the power of the turbine power plant are key factors. This makes energy and exergy analysis important in sugar factories. The data given in the following paper are related to input and output information of the paper entitled Energy - exergy analysis and optimisation of a model sugar factory in Turkey by Taner and Sivrioglu (2015) [1]. Factory total energy efficiency and exergy efficiency are found to be eta enT=72.2% and eta exT=37.4%, respectively, and according to these results, the total energy quality ? T=0.64. These results indicate higher efficiency than similar studies (Vuckovic et al., 2014; Pellegrini and Oliviera Junior, 2011; Deshmukh et al., 2013; Palacios Bereche et al., 2015) [2], [3], [4], [5]. This study can be a model for these similar factories by Taner and Sivrioglu (2015) [1]. PMID- 26958602 TI - Adhesion and spreading of osteoblast-like cells on surfaces coated with laminin derived bioactive core peptides. AB - Functional peptides are attractive as novel therapeutic reagents because their amino acid sequences are flexible in adopting and mimicking the local functional features of proteins. These peptides are of low molecular weight, synthetically versatile and inexpensive to produce, suggesting that they can be used as drug targeting, potent, stable and bioavailable agents. A short bioactive peptide is expected to be more beneficial in regenerative medicine than an entire protein because of the lower antigenicity of short amino acid sequences. We detected core peptides from human laminin that are involved in adhesion and spreading, which are the first steps of various cells including osteogenic cells, in becoming functional. In this experiment, we detected adhesion and spreading of osteoblast like cells seeded on the core peptide-coated surface. These in vitro data are related to the research article, entitled "Identification of a bioactive core sequence from human laminin and its applicability to tissue engineering" (Yeo et al., 2015) [1]. PMID- 26958603 TI - Differential expression patterns of Nqo1, AKR1B8 and Ho-1 in the liver and small intestine of C57BL/6 mice treated with sulforaphane. AB - This data article contains complementary figures and results related to the research article entitled "butylated hydroxyanisole induces distinct expression patterns of Nrf2 and detoxification enzymes in the liver and small intestine of C57BL/6 mice" (Luo et al., 2015 [1]), which defined the basal and butylated hydroxyanisole (BHA)-induced expression patterns of Phase II enzymes Nqo1, AKR1B8, and Ho-1 in the liver and small intestine of C57BL/6 mice. Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane] (SFN), a naturally occurring isothiocyanate derived from cruciferous vegetables, is a highly potent inducer of phase II cytoprotective enzymes. This dataset reports the histological changes of Nqo1, AKR1B8, and Ho-1 in wild-type (WT) and Nrf2 (-/-) mice induced by SFN. The mice were given a 25 mg/kg single oral dose of SFN for 24 h and 48 h. Immunohistochemistry revealed that, in the liver from WT mice, SFN increased Nqo1 staining in hepatocytes with slight higher staining in the pericentral region. The induction of AKR1B8 appeared mostly in hepatocytes in the periportal region. The basal and inducible Ho-1 was located predominately in Kupffer cells. In the small intestine from WT mice, the inducible expression of Nqo1 and AKR1B8 appeared more obvious in the villus than that in the crypt. PMID- 26958604 TI - Wind tunnel data of the analysis of heat pipe and wind catcher technology for the built environment. AB - The data presented in this article were the basis for the study reported in the research articles entitled 'Climate responsive behaviour heat pipe technology for enhanced passive airside cooling' by Chaudhry and Hughes [10] which presents the passive airside cooling capability of heat pipes in response to gradually varying external temperatures and related to the research article "CFD and wind tunnel study of the performance of a uni-directional wind catcher with heat transfer devices" by Calautit and Hughes [1] which compares the ventilation performance of a standard roof mounted wind catcher and wind catcher incorporating the heat pipe technology. Here, we detail the wind tunnel test set-up and inflow conditions and the methodologies for the transient heat pipe experiment and analysis of the integration of heat pipes within the control domain of a wind catcher design. PMID- 26958605 TI - Data of a fluorescent imaging-based analysis of anti-cancer drug effects on three dimensional cultures of breast cancer cells. AB - Three-dimensional (3D) cell culture is a powerful tool to study cell growth under 3D condition. To perform a simple test for anti-cancer drugs in 3D culture, visualization of non-proliferated cells is required. We propose a fluorescent imaging-based assay to analyze cancer cell proliferation in 3D culture. We used a pulse-labeling technique with a photoconvertible fluorescent protein Kaede to identify non-proliferated cells. This assay allows us to observe change in cell proliferation in 3D culture by simple imaging. Using this assay, we obtained the data of the effects of anti-cancer drugs, 5-fluorouracil and PD0332991 in a breast cancer cell line, MCF-7. PMID- 26958606 TI - Housing land transaction data and structural econometric estimation of preference parameters for urban economic simulation models. AB - This paper describes a dataset of 6284 land transactions prices and plot surfaces in 3 medium-sized cities in France (Besancon, Dijon and Brest). The dataset includes road accessibility as obtained from a minimization algorithm, and the amount of green space available to households in the neighborhood of the transactions, as evaluated from a land cover dataset. Further to the data presentation, the paper describes how these variables can be used to estimate the non-observable parameters of a residential choice function explicitly derived from a microeconomic model. The estimates are used by Caruso et al. (2015) to run a calibrated microeconomic urban growth simulation model where households are assumed to trade-off accessibility and local green space amenities. PMID- 26958607 TI - Data on antioxidant activity in grapevine (Vitis vinifera L.) following cryopreservation by vitrification. AB - Cryopreservation is used for the long-term conservation of plant genetic resources. This technique very often induces lethal injury or tissue damage. In this study, we measured indicators of viability and cell damage following cryopreservation and vitrification-cryopreservation in Vitis vinifera L. axillary buds cv. "Flame seedless" stored in liquid nitrogen (LN) for: three seconds, one hour, one day, one week and one month; after LN thawed at 38 degrees C for three minutes. The enzymatic activity of catalase (CAT) and superoxide dismutase (SOD), as well as the amount of malondialdehyde (MDA), total protein and viability were assayed. PMID- 26958608 TI - Survey of microbial populations within Lake Michigan nearshore waters at two Chicago public beaches. AB - Lake Michigan is a critical resource for the residents of Chicago, providing drinking water to its 9+ million area residents. Along Chicago's 26 miles of public beaches the populous urban environment and this freshwater environment meet. While city-led monitoring initiatives investigate pathogenic bacteria in these nearshore waters, very little is known about other microbial species present. We collected surface water samples from two Chicago public beaches - Montrose Beach and 57th Street Beach - every ten days from June 5 through August 4, 2013 as well as once in early Fall (October 4, 2013). Sixteen bacterial communities in total were surveyed through targeted sequencing of the V4 16S rRNA gene. Taxa were identified using Mothur. Raw sequence data is available via NCBI's SRA database (part of BioProject PRJNA245802). OTU calls for each read are also available at our online repository: www.lakemichiganmicrobes.com/bacteria/. PMID- 26958609 TI - Supporting data for analysis of the Helicobacter pylori exoproteome. AB - The goal of this research was to analyze the composition of the Helicobacter pylori exoproteome at multiple phases of bacterial growth (Snider et al., 2015) [1]. H. pylori was grown in a serum-free medium and at serial time points, aliquots were centrifuged and fractionated to yield culture supernatant, a soluble cellular fraction, and a membrane fraction. Samples were analyzed by single dimensional LC-MS/MS analyses and multidimensional protein identification technology (MudPIT). Here we present data showing the numbers of assigned spectra and proportional abundance of individual proteins in each of the samples analyzed, along with a calculation of the level of enrichment of individual proteins in the supernatant compared to the soluble cellular fraction. PMID- 26958610 TI - Data characterizing flexural properties of Al/Al2O3 syntactic foam core metal matrix sandwich. AB - Microstructural observations and flexural property datasets are provided for aluminum alloy matrix syntactic foam core sandwich composites. The tests are conducted in three-point bending configuration. The data supplied includes methods used for conducting microscopy and mechanical testing. Raw load displacement data, which is used to plot stress-strain graphs, obtained during the flexural test is also included. Images from a DSLR camera are stitched together to form a detailed failure sequencing video. Failure of specimens is captured in sequential images using a digital camera. These images are stitched together to develop a video for visualization of failure mechanisms. Calculations are also included for a theoretical model that is used to estimate the flexural properties of the syntactic foam core sandwich. PMID- 26958611 TI - Structural dataset for the fast-exchanging KRAS G13D. AB - Cancers bearing the KRAS G13D mutation are notable for their distinct clinical behavior relative to other oncogenic KRAS mutations. We hypothesized that primary biochemical or biophysical properties of KRAS G13D might contribute to these clinical observations and as part of our study undertook structural studies using x-ray crystallography. In this data article we discuss several x-ray diffraction datasets that yielded structures of oncogenic KRAS mutants including a high resolution (1.13 A) structure of KRAS G13D. The datasets are typical for high resolution x-ray diffraction data and allow the construction of atomic resolution, three dimensional structural models with high confidence. This data can be correlated with biochemical information such as defects in substrate binding kinetics, GTPase activities and interactions with the RAS effector RAF kinase. PMID- 26958612 TI - Data in support of the comparative genome analysis of Lysinibacillus B1-CDA, a bacterium that accumulates arsenics. AB - This study is a part of our long term project on bioremediation of toxic metals and other pollutants for protection of human health and the environment from severe contamination. The information and results presented in this data article are based on both in vitro and in silico experiments. in vitro experiments were used to investigate the presence of arsenic responsive genes in a bacterial strain B1-CDA that is highly resistant to arsenics. However, in silico studies were used to annotate the function of the metal responsive genes. By using this combined study consisting of in vitro and in silico experiments we have identified and characterized specific genes from B1-CDA that can be used as a potential tool for removal of arsenics as well as other heavy metals from the contaminated environment. PMID- 26958613 TI - Observation of Chinese Hamster Ovary Cells retained inside the non-woven fiber matrix of the CellTank bioreactor. AB - This data article shows how the recombinant Chinese Hamster Ovary (CHO) cells are located in the interstices of the matrix fibers of a CellTank bioreactor after completion of a perfusion culture, supporting the article entitled "Very high cell density perfusion of CHO cells anchored in a non-woven matrix-based bioreactor" by Zhang et al. [1]. It provides a visualization of the cell distribution in the non-woven fiber matrix in a deeper view. PMID- 26958614 TI - Location of plant species in Norway gathered as a part of a survey vegetation mapping programme. AB - Georeferenced species data have a wide range of applications and are increasingly used for e.g. distribution modelling and climate change studies. As an integrated part of an on-going survey programme for vegetation mapping, plant species have been recorded. The data described in this paper contains 18.521 registrations of plants from 1190 different circular plots throughout Norway. All species localities are georeferenced, the spatial uncertainty is provided, and additional ecological information is reported. The published data has been gathered from 1991 until 2015. The entries contain all higher vascular plants and pteridophytes, and some cryptogams. Other ecological information is also provided for the species locations, such as the vegetation type, the cover of the species and slope. The entire material is stored and available for download through the GBIF server. PMID- 26958615 TI - Benchmark data for sulcal pits extraction algorithms. AB - This article contains data related to the research article Auzias et al. (2015) [1]. This data can be used as a benchmark for quantitative evaluation of sulcal pits extraction algorithm. In particular, it allows a quantitative comparison with our method, and the assessment of the consistency of the sulcal pits extraction across two well-matched populations. PMID- 26958616 TI - Data in support of DPF2 regulates OCT4 protein level and nuclear distribution. AB - DPF2, also named ubi-d4/requiem (REQU), interacts with a protein complex containing OCT4. This paper provides data in support of the research article entitled "DPF2 regulates OCT4 protein level and nuclear distribution". The highlights include: (1) Denature-immunoprecipitation assay revealed ubiquitination of OCT4 in pluripotent H9 cells, which was enhancedby MG132, a proteasome inhibitor. (2) Well colocalization of ectopic OCT4 and FLAG-Ub was found in HeLa cells, which was also increased by MG132. (3) MG132 treatment decreased DPF2 cytoplasmic expression in vivo. These data give insights into how proteasome inhibition contributes to studying ubiquitnation of OCT4. PMID- 26958617 TI - Data in support of UbSRD: The Ubiquitin Structural Relational Database. AB - This article provides information to support the database article titled "UbSRD: The Ubiquitin Structural Relational Database" (Harrison et al., 2015) [1] . The ubiquitin-like homology fold (UBL) represents a large family that encompasses both post-translational modifications, like ubiquitin (UBQ) and SUMO, and functional domains on many biologically important proteins like Parkin, UHRF1 (ubiquitin-like with PDB and RING finger domains-1), and Usp7 (ubiquitin-specific protease-7) (Zhang et al., 2015; Rothbart et al., 2013; Burroughs et al., 2012; Wauer et al., 2015) [2], [3], [4], [5]. The UBL domain can participate in several unique protein-protein interactions (PPI) since protein adducts can be attached to and removed from amino groups of lysine side chains and the N-terminus of proteins. Given the biological significance of UBL domains, many have been characterized with high-resolution techniques, and for UBQ and SUMO, many protein complexes have been characterized. We identified all the UBL domains in the PDB and created a relational database called UbSRD (Ubiquitin Structural Relational Database) by using structural analysis tools in the Rosetta (Leaver et al., 2013; O'Meara et al., 2015; Leaver-fay et al., 2011) [1], [6], [7], [8]. Querying UbSRD permitted us to report many quantitative properties of UBQ and SUMO recognition at different types interfaces (noncovalent: NC, conjugated: CJ, and deubiquitanse: DB). In this data article, we report the average number of non-UBL neighbors, secondary structure of interacting motifs, and the type of inter molecular hydrogen bonds for each residue of UBQ and SUMO. Additionally, we used PROMALS3D to generate a multiple sequence alignment used to construct a phylogram for the entire set of UBLs (Pei and Grishin, 2014) [9]. The data described here will be generally useful to scientists studying the molecular basis for recognition of UBQ or SUMO. PMID- 26958618 TI - Data for the analysis of PolyHIPE scaffolds with tunable mechanical properties for bone tissue engineering. AB - This article presents data related to the research article titled, 'Emulsion templated scaffolds with tunable mechanical properties for bone tissue engineering' (Owen et al., in press) [1]. This data article contains excel files with the results obtained during the mechanical characterisation of 20 acrylate based PolyHIPE compositions, giving the Young's modulus, ultimate tensile stress and strain at failure for each specimen tested. Also included are the measurements taken to determine the degree of openness (DOO) of each composition, and the data for the cell viability and alkaline phosphatase (ALP) activity on the emulsion templated scaffolds. PMID- 26958619 TI - Data analysis and other considerations concerning the study of precipitation in Al-Mg-Si alloys by Atom Probe Tomography. AB - Atom Probe Tomography (APT) analysis and hardness measurements were used to characterize the early stages of precipitation in an Al-0.51 at%Mg-0.94 at%Si alloy as reported in the accompanying Acta Materialia paper [1]. The changes in microstructure were investigated after single-stage or multi-stage heat treatments including natural ageing at 298 K (NA), pre-ageing at 353 K (PA), and automotive paint-bake ageing conditions at 453 K (PB). This article provides and a detailed report on the experimental conditions and the data analysis methods used for this investigation. Careful design of experimental conditions and analysis methods was carried out to obtain consistent and reliable results. Detailed data on clustering for prolonged NA and PA treatments have been reported. PMID- 26958620 TI - Dataset for genotyping validation of cytochrome P450 2A6 whole-gene deletion (CYP2A6*4) by real-time polymerase chain reaction platforms. AB - This data article contains a supplementary figure and validation data relating to the research article entitled "Genotyping of wild-type cytochrome P450 2A6 and whole-gene deletion using human blood samples and a multiplex real-time polymerase chain reaction method with dual-labeled probes" (Shimizu et al., Clinica Chimica Acta 441, 71-74, 2015), which presents a multiplex real-time polymerase chain reaction method with dual-labeled probes for human P450 2A6 wild type and whole-gene deletion. Real-time methods have dramatically improved the speed of complex genetic diagnostics compared to conventional assays based on restriction enzyme digestion. Here, we show the basic assay validation data by single and multiplex determinations in comparison with commercial TaqMan copy number assays for P450 2A6. PMID- 26958621 TI - Odor impact of volatiles emitted from marijuana, cocaine, heroin and their surrogate scents. AB - Volatile compounds emitted into headspace from illicit street drugs have been identified, but until now odor impact of these compounds have not been reported. Data in support of identification of these compounds and their odor impact to human nose are presented. In addition, data is reported on odor detection thresholds for canines highlighting differences with human ODTs and needs to address gaps in knowledge. New data presented here include: (1) compound identification, (2) gas chromatography (GC) column retention times, (3) mass spectral data, (4) odor descriptors from 2 databases, (5) human odor detection thresholds from 2 databases, (6) calculated odor activity values, and (7) subsequent ranking of compounds by concentration and ranking of compounds by odor impact (reported as calculated odor activity values). For further interpretation and discussion, see Rice and Koziel [1] and Rice [2]. PMID- 26958622 TI - Proteomic and glycomic analyses of a lung-specific protein surfactant protein-D. AB - In order to verify the protein enriched from pooled human sera to be a lung specific protein surfactant protein-D (SP-D), we performed peptide mass fingerprinting (PMF)-based protein identification. MASCOT search results of the obtained PMF unequivocally demonstrated that it is identical to human SP-D. Meanwhile, we performed MALDI-QIT-TOF mass spectrometry-based N-glycomic analysis of the recombinant human SP-D produced in murine myeloma cells. The obtained mass spectra of N-glycans from the recombinant SP-D demonstrated that the recombinant protein is almost exclusively modified with core-fucosylated N-glycans [1]. PMID- 26958623 TI - Data on synthesis and characterization of new diglycerol based environmentally friendly non-isocyanate poly(hydroxyurethanes). AB - This article contains original experimental data, figures and methods to the preparation of non-isocyanate poly(hydroxyurethanes) by an environmentally friendly method without the use of toxic phosgene and isocyanates from bis(2,3 dihydroxypropyl)ether dicarbonate and various diamines (Tryznowski et al., Submitted for publication) [1]. Bis(2,3-dihydroxypropyl)ether dicarbonate was obtained from a one-step procedure from commercially available diglycerol. The product was characterized by (1)H NMR, (13)C NMR, and FTIR spectroscopies and for the first time by X-Ray diffraction measurements. Then, the bis(cyclic carbonate) monomer was used as a precursor for the synthesis of various NIPUs. The NIPUs were prepared in a non-solvent process. Spectral and thermal properties of the NIPUs are compered. Here we give the procedure in order to perform bis(2,3 dihydroxypropyl)ether dicarbonate with high yield and the procedure NIPU synthesis and the complete set of monomer and NIPU analysis ((1)H NMR, (13)C NMR, FTIR, X-Ray). PMID- 26958624 TI - Data analysis of "krokodil" samples obtained by street-like synthesis. AB - The data described in this work is related to be the subject of an article in the Forensic Science International, titled: "The harmful chemistry behind "krokodil": street-like synthesis and product analysis" (http://dx.doi.org/10.1016/j.forsciint.2015.07.042) [1]. The data presented here provides additional description of the chemical profile of "krokodil". Physicochemical and organoleptic characteristics, TLC profile, UV/Vis, (1)H NMR and FTIR spectrum are presented. These data validate the proposed synthetic procedure and pathway and give further information about the contaminants present in "krokodil". PMID- 26958625 TI - Nucleotide sequence alignment of hdcA from Gram-positive bacteria. AB - The decarboxylation of histidine -carried out mainly by some gram-positive bacteria- yields the toxic dietary biogenic amine histamine (Ladero et al. 2010 <10.2174/157340110791233256> [1], Linares et al. 2016 > [2]). The reaction is catalyzed by a pyruvoyl-dependent histidine decarboxylase (Linares et al. 2011 <10.1080/10408398.2011.582813> [3]), which is encoded by the gene hdcA. In order to locate conserved regions in the hdcA gene of Gram-positive bacteria, this article provides a nucleotide sequence alignment of all the hdcA sequences from Gram-positive bacteria present in databases. For further utility and discussion, see > [4]. PMID- 26958626 TI - Characterisation of the mechanical and fracture properties of a uni-weave carbon fibre/epoxy non-crimp fabric composite. AB - A complete database of the mechanical properties of an epoxy polymer reinforced with uni-weave carbon fibre non-crimp fabric (NCF) is established. In-plane and through-the-thickness tests were performed on unidirectional laminates under normal loading and shear loading. The response under cyclic shear loading was also measured. The material has been characterised in terms of stiffness, strength, and failure features for the different loading cases. The critical energy release rates associated with different failure modes in the material were measured from interlaminar and translaminar fracture toughness tests. The stress strain data of the tensile, compressive, and shear test specimens are included. The load-deflection data for all fracture toughness tests are also included. The database can be used in the development and validation of analytical and numerical models of fibre reinforced plastics (FRPs), in particular FRPs with NCF reinforcements. PMID- 26958627 TI - Effects of hTERT immortalization on osteogenic and adipogenic differentiation of dental pulp stem cells. AB - These data relate to the differentiation of human dental pulp stem cells (DPSC) and DPSC immortalized by constitutively expressing human telomerase reverse transcriptase (hTERT) through both osteogenic and adipogenic lineages (i.e. to make bone producing and fat producing cells from these dental pulp stem cells). The data augment another study to characterize immortalized DPSC for the study of neurogenetic "Characterization of neurons from immortalized dental pulp stem cells for the study of neurogenetic disorders" [1]. Two copies of one typical control cell line (technical replicates) were used in this study. The data represent the differentiation of primary DPSC into osteoblast cells approximately 60% more effectively than hTERT immortalized DPSC. Conversely, both primary and immortalized DPSC are poorly differentiated into adipocytes. The mRNA expression levels for both early and late adipogenic and osteogenic gene markers are shown. PMID- 26958628 TI - Safety profile of the intravenous administration of brain-targeted stable nucleic acid lipid particles. AB - In a clinical setting, where multiple administrations of the therapeutic agent are usually required to improve the therapeutic outcome, it is crucial to assess the immunogenicity of the administered nanoparticles. In this data work, we investigated the safety profile of the repeated intravenous administration of brain-targeted stable nucleic acid lipid particles (RVG-9r-targeted SNALPs). To evaluate local activation of the immune system, we performed analysis of mouse tissue homogenates and sections from cerebellum. To investigate peripheral activation of the immune system, we used serum of mice that were intravenously injected with RVG-9r-targeted SNALPs. These data are related and were discussed in the accompanying research article entitled "Intravenous administration of brain-targeted stable nucleic acid lipid particles alleviates Machado-Joseph disease neurological phenotype" (Conceicao et al., in press) [1]. PMID- 26958629 TI - Data set in support of neurotoxicity of trimethyltin chloride by morphological and protein analysis. AB - Trimethyltin chloride (TMT) is a neurotoxicant widely present in the aquatic environment. Chronic exposure of embryos to TMT for 4 days post-fertilization (dpf) elicited a concentration-related decrease in head & eye size and increase in axial malformation. In addition, Rohon-Beard sensory neurons and motor neurons showed decreased patterns of protein expression. These data coincide with previous research about the neurotoxicity of TMT on mRNA expression (Kim et al., 2016 [1]). These data demonstrates that TMT inhibits specific neurodevelopmental stages in zebrafish embryos and suggests a possible mechanism for the toxicity of TMT in vertebrate neurodevelopment. This paper contains data related to research concurrently published in Kim et al. (2016) [1]. PMID- 26958630 TI - Data on the DNA damaging and mutagenic potential of the BH3-mimetics ABT 263/Navitoclax and TW-37. AB - Unfortunately, the mutagenic activities of chemotherapy and radiotherapy can provoke development of therapy-induced malignancies in cancer survivors. Non mutagenic anti-cancer therapies may be less likely to trigger subsequent malignant neoplasms. Here we present data regarding the DNA damaging and mutagenic potential of two drugs that antagonize proteins within the Bcl-2 family: ABT-263/Navitoclax and TW-37. Our data reveal that concentrations of these agents that stimulated Bax/Bak-dependent signaling provoked little DNA damage and failed to trigger mutations in surviving cells. The data supplied in this article is related to the research work entitled "Inhibition of Bcl-2 or IAP proteins does not provoke mutations in surviving cells" [1]. PMID- 26958631 TI - Liver metal levels and expression of genes related to iron homeostasis in rhesus monkeys after inhalational manganese exposure. AB - Here we present data on liver metal levels and expression of genes related to iron homeostasis in rhesus monkeys after inhalational manganese exposure. Archived liver samples from rhesus monkeys exposed to 0 (n=6), 0.06 (n=6), 0.3 (n=4) and 1.5 (n=4) mg/m(3) manganese inhalation for 65 days were obtained from a published study ("Tissue manganese concentrations in young male rhesus monkeys following subchronic manganese sulfate inhalation" [1]). Samples were analyzed by spectroscopy, immunoblotting and quantitative PCR to assess metal levels and gene expression. Liver manganese and iron levels were linearly correlated although only the intermediate manganese exposure level (0.3 mg Mn/m(3)) led to a statistically significant increase in liver iron levels. PMID- 26958632 TI - Delayed early developmental trajectories of white matter tracts of functional pathways in preterm-born infants: Longitudinal diffusion tensor imaging data. AB - Probabilistic maps of white matter pathways related to motor, somatosensory, auditory, visual, and limbic functions, and major white matter tracts (the corpus callosum, the inferior fronto-occipital fasciculus, and the middle cerebellar peduncle) were applied to evaluate the developmental trajectories of these tracts, using longitudinal diffusion tensor imaging (DTI) obtained in term-born and preterm-born healthy infants. Nineteen term-born and 30 preterm-born infants completed MR scans at three time points: Time-point 1, 41.6+/-2.7 postmenstrual weeks; Time-point 2, 46.0+/-2.9 postmenstrual weeks; and Time-point 3, 50.8+/-3.7 postmenstrual weeks. The DTI-derived scalar values (fractional anisotropy, eigenvalues, and radial diffusivity) of the three time points are available in this Data article. PMID- 26958633 TI - High-throughput imaging method for direct assessment of GM1 ganglioside levels in mammalian cells. AB - GM1-gangliosidosis is an inherited autosomal recessive disorder caused by mutations in the gene GLB1, which encodes acid beta-galactosidase (beta-gal). The lack of activity in this lysosomal enzyme leads to accumulation of GM1 gangliosides (GM1) in cells. We have developed a high-content-imaging method to assess GM1 levels in fibroblasts that can be used to evaluate substrate reduction in treated GLB1(-/-) cells [1]. This assay allows fluorescent quantification in a multi-well system which generates unbiased and statistically significant data. Fluorescently labeled Cholera Toxin B subunit (CTXB), which specifically binds to GM1 gangliosides, was used to detect in situ GM1 levels in a fixed monolayer of fibroblasts. This sensitive, rapid, and inexpensive method facilitates in vitro drug screening in a format that allows a high number of replicates using low working volumes. PMID- 26958634 TI - Data supporting the shedding of larger extracellular vesicles by multidrug resistant tumour cells. AB - To date, there are no simple and minimally invasive methods to diagnose MDR. Extracellular vesicles (EVs) are shed by all cells, carry a specific cargo from the donor cells and are present in several body fluids, which means that they can potentially be easily collected from cancer patients and become the source of biomarkers to diagnose cancer. This data article contains a full list of the proteins identified in the EVs shed by an isogenic pair of chronic myeloid leukaemia cells (MDR cells and their drug-sensitive counterparts) by LC/MS/MS analysis, together with their GeneOntology analysis. In addition, it also contains data from protein content analysis and Dynamic light scattering count rate events of the referred EVs as well as of the EVs shed from an isogenic pair of non-small cell lung cancer cells (MDR cells and their drug-sensitive counterparts). The interpretation of the data presented in this article and further extensive insights can be found in "Multidrug resistant tumour cells shed more microvesicles-like EVs and less exosomes than their drug-sensitive counterpart cells" [1]. PMID- 26958635 TI - Data on interaction between adeno-associated virus and U87 cell via cRGD chemical modification. AB - RGD tripeptide is a specific, high-affinity ligand for integrin, which is highly expressed in cancer cells. We previously reported that cRGD chemically modified AAV2 (AAV2(N587+1/azido+RGD)) showed significantly enhanced infectivity compared to RGD genetically inserted AAV2 (AAV2(N587+RGD)) (10.1016/j.biomaterials.2015.11.066) [1]. Herein we provide the binding ability analysis of RGD modified AAV2 and U87 cell by flow cytometry and the theoretical working model of RGD-alphavbeta3 integrin interaction. PMID- 26958636 TI - Data of the molecular dynamics simulations of mutations in the human connexin46 docking interface. AB - The structure of hCx26 derived from the X-ray analysis was used to generate a homology model for hCx46. Interacting connexin molecules were used as starting model for the molecular dynamics (MD) simulation using NAMD and allowed us to predict the dynamic behavior of hCx46wt and the cataract related mutant hCx46N188T as well as two artificial mutants hCx46N188Q and hCx46N188D. Within the 50 ns simulation time the docked complex composed of the mutants dissociate while hCx46wt remains stable. The data indicates that one hCx46 molecule forms 5 7 hydrogen bonds (HBs) with the counterpart connexin of the opposing connexon. These HBs appear essential for a stable docking of the connexons as shown by the simulation of an entire gap junction channel and were lost for all the tested mutants. The data described here are related to the research article entitled "The cataract related mutation N188T in human connexin46 (hCx46) revealed a critical role for residue N188 in the docking process of gap junction channels" (Schadzek et al., 2015) [1]. PMID- 26958637 TI - Mass spectrometry data from proteomic analysis of human skin keratins after exposure to UV radiation. AB - A mass spectrometry (MS)-based proteomic methodology was employed to monitor oxidative modifications in keratins, the main constituents of human skin ("Non invasive proteomic analysis of human skin keratins: screening of methionine oxidation in keratins by mass spectrometry" [1], "UV irradiation-induced methionine oxidation in human skin keratins: mass spectrometry-based non-invasive proteomic analysis" [2]). Human skin proteins were obtained non-invasively by tape stripping and solubilized in sodium dodecyl sulfate (SDS) buffer, followed by purification and digestion using the filter-aided sample preparation method. The tryptic peptides were then analyzed by liquid chromatography (LC)/electrospray ionization (ESI)-MS, tandem MS (MS/MS), and LC/ESI-selected reaction monitoring (SRM)/MS. The MS/MS data were generated to confirm amino acid sequences and oxidation sites of tryptic peptides D(290)VDGAYMTK(298) (P1) and N(258)MQDMVEDYR(267) (P2), which contain the most susceptible oxidation sites (Met(259), Met(262), and Met(296) in K1 keratin) upon UVA irradiation [2]. Subsequently, quantitative determination of the relative oxidation levels of P1 and P1 [2] was achieved by LC/ESI-SRM/MS analyses of P1 and P2 together with their oxidized forms after exposure to UVA radiation or treatment with hydrogen peroxide (H2O2). PMID- 26958638 TI - Data on cell cycle in breast cancer cell line, MDA-MB-231 with ferulic acid treatment. AB - Inhibition to repair DNA metabolism to respond to damaged DNA can lead to genetic instability, resulting in cancer cell death (Audeh et al., 2010; Bryant et al., 2005; Farmer et al., 2005; Lukas et al., 2003; Tutt et al., 2010) [1], [2], [6], [8], [11]. Despite of various studies demonstrating efficiency of combination therapy through down-regulation of DNA repair pathway, the suppression effects of DNA repair pathway by chemotherapeutic agents from natural bioactive compounds are less understood (Eitsuka et al., 2014; Kastan et al., 2004; Kawabata et al., 2000; Mancuso et al., 2014) [5], [7], [9]. Here, the data shows that ferulic acid reduced the S-phases post to UV treatment in breast cancer cells and was hypersensitive in breast cancer cells, MDA-MB-231. PMID- 26958639 TI - A first dataset toward a standardized community-driven global mapping of the human immunopeptidome. AB - We present the first standardized HLA peptidomics dataset generated by the immunopeptidomics community. The dataset is composed of native HLA class I peptides as well as synthetic HLA class II peptides that were acquired in data dependent acquisition mode using multiple types of mass spectrometers. All laboratories used the spiked-in landmark iRT peptides for retention time normalization and data analysis. The mass spectrometric data were deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD001872. The generated data were used to build HLA allele-specific peptide spectral and assay libraries, which were stored in the SWATHAtlas database. Data presented here are described in more detail in the original eLife article entitled 'An open-source computational and data resource to analyze digital maps of immunopeptidomes'. PMID- 26958640 TI - Data defining markers of human neural stem cell lineage potential. AB - Neural stem cells (NSCs) and neural progenitor cells (NPCs) are self-renewing and multipotent cells, however, NPCs are considered to be more lineage-restricted with a reduced self-renewing capacity. We present data comparing the expression of 21 markers encompassing pluripotency, self-renewal (NSC) as well as neuronal and glial (astrocyte and oligodendrocyte) lineage specification and 28 extracellular proteoglycan (PG) genes and their regulatory enzymes between embryonic stem cell (ESC)-derived human NSCs (hNSC H9 cells, Thermo Fisher) and human cortex-derived normal human NPCs (nhNPCs, Lonza). The data demonstrates expression differences of multiple lineage and proteoglycan-associated genes between hNSC H9 cells and nhNPCs. Data interpretation of markers and proteoglycans defining NSC and neural cell lineage characterisation can be found in "Cell surface heparan sulfate proteoglycans as novel markers of human neural stem cell fate determination" (Oikari et al. 2015) [1]. PMID- 26958641 TI - CFD and experimental data of closed-loop wind tunnel flow. AB - The data presented in this article were the basis for the study reported in the research articles entitled 'A validated design methodology for a closed loop subsonic wind tunnel' (Calautit et al., 2014) [1], which presented a systematic investigation into the design, simulation and analysis of flow parameters in a wind tunnel using Computational Fluid Dynamics (CFD). The authors evaluated the accuracy of replicating the flow characteristics for which the wind tunnel was designed using numerical simulation. Here, we detail the numerical and experimental set-up for the analysis of the closed-loop subsonic wind tunnel with an empty test section. PMID- 26958642 TI - Data in support of the identification of neuronal and astrocyte proteins interacting with extracellularly applied oligomeric and fibrillar alpha-synuclein assemblies by mass spectrometry. AB - alpha-Synuclein (alpha-syn) is the principal component of Lewy bodies, the pathophysiological hallmark of individuals affected by Parkinson disease (PD). This neuropathologic form of alpha-syn contributes to PD progression and propagation of alpha-syn assemblies between neurons. The data we present here support the proteomic analysis used to identify neuronal proteins that specifically interact with extracellularly applied oligomeric or fibrillar alpha syn assemblies (conditions 1 and 2, respectively) (doi: 10.15252/embj.201591397[1]). alpha-syn assemblies and their cellular partner proteins were pulled down from neuronal cell lysed shortly after exposure to exogenous alpha-syn assemblies and the associated proteins were identified by mass spectrometry using a shotgun proteomic-based approach. We also performed experiments on pure cultures of astrocytes to identify astrocyte-specific proteins interacting with oligomeric or fibrillar alpha-syn (conditions 3 and 4, respectively). For each condition, proteins interacting selectively with alpha syn assemblies were identified by comparison to proteins pulled-down from untreated cells used as controls. The mass spectrometry data, the database search and the peak lists have been deposited to the ProteomeXchange Consortium database via the PRIDE partner repository with the dataset identifiers PRIDE: PXD002256 to PRIDE: PXD002263 and doi: 10.6019/PXD002256 to 10.6019/PXD002263. PMID- 26958644 TI - Data in support of the detection of genetically modified organisms (GMOs) in food and feed samples. AB - Food and feed samples were randomly collected from different sources, including local and imported materials from the Syrian local market. These included maize, barley, soybean, fresh food samples and raw material. GMO detection was conducted by PCR and nested PCR-based techniques using specific primers for the most used foreign DNA commonly used in genetic transformation procedures, i.e., 35S promoter, T-nos, epsps, cryIA(b) gene and nptII gene. The results revealed for the first time in Syria the presence of GM foods and feeds with glyphosate resistant trait of P35S promoter and NOS terminator in the imported soybean samples with high frequency (5 out of the 6 imported soybean samples). While, tests showed negative results for the local samples. Also, tests revealed existence of GMOs in two imported maize samples detecting the presence of 35S promoter and nos terminator. Nested PCR results using two sets of primers confirmed our data. The methods applied in the brief data are based on DNA analysis by Polymerase Chain Reaction (PCR). This technique is specific, practical, reproducible and sensitive enough to detect up to 0.1% GMO in food and/or feedstuffs. Furthermore, all of the techniques mentioned are economic and can be applied in Syria and other developing countries. For all these reasons, the DNA-based analysis methods were chosen and preferred over protein-based analysis. PMID- 26958643 TI - Detailed analysis of association between common single nucleotide polymorphisms and subclinical atherosclerosis: The Multi-ethnic Study of Atherosclerosis. AB - Previously identified single nucleotide polymorphisms (SNPs) in genome wide association studies (GWAS) of cardiovascular disease (CVD) in participants of mostly European descent were tested for association with subclinical cardiovascular disease (sCVD), coronary artery calcium score (CAC) and carotid intima media thickness (CIMT) in the Multi-Ethnic Study of Atherosclerosis (MESA). The data in this data in brief article correspond to the article Common Genetic Variants and Subclinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis [1]. This article includes the demographic information of the participants analyzed in the article as well as graphical displays and data tables of the association of the selected SNPs with CAC and of the meta-analysis across ethnicities of the association of CIMT-c (common carotid), CIMT-I (internal carotid), CAC-d (CAC as dichotomous variable with CAC>0) and CAC-c (CAC as continuous variable, the log of the raw CAC score plus one) and CVD. The data tables corresponding to the 9p21 fine mapping experiment as well as the power calculations referenced in the article are also included. PMID- 26958645 TI - Proteomic dataset of the organohalide-respiring bacterium Dehalococcoides mccartyi strain CBDB1 grown on hexachlorobenzene as electron acceptor. AB - The proteome of the anaerobic organohalide-respiring bacterium Dehalococcoides mccartyi strain CBDB1 was analyzed by nano liquid chromatography coupled to mass spectrometry (LC-MS/MS). Two different preparation methods, (i) in-solution and (ii) in-gel proteolytic digestion were assessed to elucidate the core and the functional proteome of bacterial cultures grown in synthetic anaerobic medium with hexachlorobenzene as sole electron acceptor. A detailed analysis of the data presented is available (Schiffmann et al., 2014) [1]. PMID- 26958646 TI - In depth analysis of the Sox4 gene locus that consists of sense and natural antisense transcripts. AB - SRY (Sex Determining Region Y)-Box 4 or Sox4 is an important regulator of the pan neuronal gene expression during post-mitotic cell differentiation within the mammalian brain. Sox4 gene locus has been previously characterized with multiple sense and overlapping natural antisense transcripts [1], [2]. Here we provide accompanying data on various analyses performed and described in Ling et al. [2]. The data include a detail description of various features found at Sox4 gene locus, additional experimental data derived from RNA-Fluorescence in situ Hybridization (RNA-FISH), Western blotting, strand-specific reverse-transcription quantitative polymerase chain reaction (RT-qPCR), gain-of-function and in situ hybridization (ISH) experiments. All the additional data provided here support the existence of an endogenous small interfering- or PIWI interacting-like small RNA known as Sox4_sir3, which origin was found within the overlapping region consisting of a sense and a natural antisense transcript known as Sox4ot1. PMID- 26958647 TI - The Learning Objective Catalogue for Patient Safety in Undergraduate Medical Education--A Position Statement of the Committee for Patient Safety and Error Management of the German Association for Medical Education. AB - BACKGROUND: Since the report "To err is human" was published by the Institute of Medicine in the year 2000, topics regarding patient safety and error management are in the focal point of interest of science and politics. Despite international attention, a structured and comprehensive medical education regarding these topics remains to be missing. GOALS: The Learning Objective Catalogue for Patient Safety described below the Committee for Patient Safety and Error Management of the German Association for Medical Education (GMA) has aimed to establish a common foundation for the structured implementation of patient safety curricula at the medical faculties in German-speaking countries. METHODS: The development the Learning Objective Catalogue resulted via the participation of 13 faculties in two committee meetings, two multi-day workshops, and additional judgments of external specialists. RESULTS: The Committee of Patient Safety and Error Management of GMA developed the present Learning Objective Catalogue for Patient Safety in Undergraduate Medical Education, structured in three chapters: Basics, Recognize Causes as Foundation for Proactive Behavior, and Approaches for Solutions. The learning objectives within the chapters are organized on three levels with a hierarchical organization of the topics. Overall, the Learning Objective Catalogue consists of 38 learning objectives. All learning objectives are referenced with the National Competency-based Catalogue of Learning Objectives for Undergraduate Medical Education. DISCUSSION: The Learning Objective Catalogue for Patient Safety in Undergraduate Medical Education is a product that was developed through collaboration of members from 13 medical faculties. In the German-speaking countries, the Learning Objective Catalogue should advance discussion regarding the topics of patient safety and error management and help develop subsequent educational structures. The Learning Objective Catalogue for Patient Safety can serve as a common ground for an intensified, constructive, subject-specific discussion about these topics at the medical faculties, and guide the implementation of hopefully multiple patient safety curricula in undergraduate medical education. PMID- 26958648 TI - Physician-assisted suicide, euthanasia and palliative sedation: attitudes and knowledge of medical students. AB - OBJECTIVES: In November 2015, the German Federal Parliament voted on a new legal regulation regarding assisted suicide. It was decided to amend the German Criminal Code so that any "regular, repetitive offer" (even on a non-profit basis) of assistance in suicide would now be considered a punishable offense. On July 2, 2015, a date which happened to be accompanied by great media interest in that it was the day that the first draft of said law was presented to Parliament, we surveyed 4th year medical students at the Technical University Munich on "physician-assisted suicide," "euthanasia" and "palliative sedation," based on a fictitious case vignette study. METHOD: The vignette study described two versions of a case in which a patient suffered from a nasopharyngeal carcinoma (physical suffering subjectively perceived as being unbearable vs. emotional suffering). The students were asked about the current legal norms for each respective course of action as well as their attitudes towards the ethical acceptability of these measures. RESULTS: Out of 301 students in total, 241 (80%) participated in the survey; 109 answered the version 1 questionnaire (physical suffering) and 132 answered the version 2 questionnaire (emotional suffering). The majority of students were able to assess the currently prevailing legal norms on palliative sedation (legal) and euthanasia (illegal) correctly (81.2% and 93.7%, respectively), while only a few students knew that physician-assisted suicide, at that point in time, did not constitute a criminal offense. In the case study that was presented, 83.3% of the participants considered palliative sedation and the simultaneous withholding of artificial nutrition and hydration as ethically acceptable, 51.2% considered physician-assisted suicide ethically legitimate, and 19.2% considered euthanasia ethically permissible. When comparing the results of versions 1 and 2, a significant difference could only be seen in the assessment of the legality of palliative sedation: it was considered legal more frequently in the physical suffering version (88.1% vs. 75.8%). CONCLUSION: The majority of the students surveyed wrongly assumed that physician-assisted suicide is a punishable offense in Germany. However, a narrow majority considered physician assisted suicide ethically acceptable in the case study presented. Compared to euthanasia, more than twice as many participants considered physician-assisted suicide acceptable. There was no significant difference between personal attitudes towards palliative sedation, physician-assisted suicide or euthanasia in light of physical or emotional suffering. Educational programs in this field should be expanded both qualitatively and quantitatively, especially considering the relevance of the subject matter, the deficits within the knowledge of legal norms and the now even higher complexity of the legal situation due to the new law from December 2015. PMID- 26958649 TI - Quo vadis?--Medical education 2020 between politics and science. PMID- 26958650 TI - Development and implementation of the Clinical Tooth Shade Differentiation Course -an evaluation over 3 years. AB - OBJECTIVE: Tooth shade differentiation concerns the identification and classification of tooth shades. The objective of this project was to implement the Clinical Tooth Shade Differentiation Course in the preclinical stage of studies and to evaluate the students' perspective over a period of 3 years. METHODOLOGY: The course is planned for a duration of 10 weeks with two 45-minute sessions per semester week. The entire attendance time was 10:15 h. 2 lectures of 90 minutes each, 2 seminars of 60 min each and 2 teaching units with the phantom head and role playing took place. In addition to the various parameters of tooth shade, changes in tooth shade and the basics of dental esthetics, clinical procedures for manual and digital tooth shade determination were explained and practiced. 96% (69 of 72) of the students participated in the first evaluation in 2012/2013 (T1), and 68% of these were women. In the following year, 2013/2014 (T2), 92% (45 of 48 students) took part; 62% of these were women and 38% men. The 2014/2015 evaluation (T3) comprised 94% (45 of 48 students). Of these, 67% were women. RESULTS: In the evaluation, the students gave the course a positive grade. The questions in "General/Organization" were given a mean (M) of 1.5 (SD=0.7) in T1 and T2, and 1.2 (SD=0.3) in T3. The "Overall Assessment" yielded M(T1)=1.6 (SD=0.6), M(T2)=1.5 (SD=0.5) and M(T3)=1.1 (SD=0.3). In T1 and T2, the item "The instructor actively involved the students in the course" was given a mean of 2.1 (SD=0.9), and in T3 a mean of 1.2 (SD=0.5). CONCLUSIONS: The course presented here conceptually shows how practical dental skills can be taught in a theoretical and clinical context. Educational objectives from the role of a dental expert were taken from the national competence-based catalog of educational objectives for dentistry and can also be supplemented. The objectives can be transferred to other dental faculties. PMID- 26958651 TI - Peer-led Stress Prevention Seminars in the First Year of Medical School--A Project Report. AB - INTRODUCTION: From the beginning of the first year of medical studies, increased psychological stress and elevated burnout prevalence rates can be registered compared to sample populations. Characterized by learning "on an equal footing", the principle of peer-assisted learning (PAL) is widely used in medical education. This report aims to showcase the development and evaluation of peer led stress prevention seminars for first year medical students after one year of implementation. PROJECT DESCRIPTION: With each of the three sessions lasting 90 min., the stress prevention seminars took place in small groups (6-10 students) in the period from November 2013 to January 2014 and from November 2014 to December 2014 at the Medical Faculty of Heidelberg. Led by trained peers, the seminar content ranged from psycho-educational elements, i.e. time management strategy development and test anxiety assistance, to relaxation techniques. All seminar sessions were evaluated via questionnaire. All questions were answered on a Likert scale ranging from 1 to 7 (1=strongly agree; 7=strongly disagree). RESULTS: 75 students consented to participate in seminars (65% female; aged 20.5+/-3.3 years). The series of seminars was averagely given the school grade of 1.2+/-0.4 (1=very good to 6=unsatisfactory) in WS 2013/14 and 1.5+/-0.5 in the following year and the peer tutors' competence was evaluated as very high (1.4 to 1.5 approval rate on the Likert scale). DISCUSSION: The seminar sessions' importance to the students is underlined by their very positive evaluations. This offer seems to have benefited students especially during the demanding transitional phase at the start of their studies. Both the implementation of the preventive measure at an early stage as well as the use of PAL seem to have proven effective. CONCLUSION: PAL seems to be effective in the field of stress prevention. However, specific efficacy studies are still lacking. PMID- 26958652 TI - The FAMULATUR PLUS as an innovative approach for teaching physical examination skills. AB - The FAMULATUR PLUS is an innovative approach to teaching physical examination skills. The concept is aimed at medical students during the clinical part of their studies and includes a clinical traineeship (English for "Famulatur") extended to include various courses ("PLUS"). The courses are divided into clinical examination courses and problembased-learning (PBL) seminars. The concept's special feature is the full integration of these courses into a 30-day hospital traineeship. The aim is to facilitate the transfer of knowledge from the courses into daily practice. Each week of the FAMULATUR PLUS is structured in line with the courses and focuses on a particular part of the body (e.g., abdomen). A physical examination course under the supervision of a physician is offered at the beginning of the week. Here, medical students learn the relevant examination techniques by practicing on each other (partner exercises). Subsequently, the techniques taught are applied independently during everyday work on the ward, corrected by the supervisor, if necessary, and thereby reinforced. The final POL seminar takes place towards the end of the week. Possible differential diagnoses are developed based on a clinical case study. The goal is to check these by taking a fictitious medical history and performing a physical examination, as well as to make a preliminary diagnosis. Finally, during the PBL seminar, medical students will be shown how physical examination techniques can be efficiently applied in the diagnosis of common cardinal symptoms (e.g., abdominal pain). The initial implementation of the FAMULATUR PLUS proved the practical feasibility of the concept. In addition, the accompanying evaluation showed that the participants of the pilot project improved with regard to their practical physical examination skills. PMID- 26958653 TI - Vaccination: Developing and implementing a competency-based-curriculum at the Medical Faculty of LMU Munich. AB - BACKGROUND: In Germany medical students should gain proficiency and specific skills in the vaccination field. Especially important is the efficient communication of scientific results about vaccinations to the community, in order to give professional counseling with a complete overview about therapeutic options. AIM OF THE PROJECT: The aim of this project is to set up a vaccination related curriculum in the Medical Faculty at the Ludwig-Maximilians-University in Munich. The structure of the curriculum is based on the National catalogue for competency-based learning objectives in the field of vaccination (Nationaler Kompetenzbasierter Lernzielekatalog Medizin NKLM). Through this curriculum, the students will not only acquire the classical educational skills concerning vaccination in theory and practice, but they will also learn how to become independent in the decision-making process and counseling. Moreover, the students will become aware of consequences of action related to this specific topic. METHODS: According to defined guidelines, an analysis was performed on courses, which are currently offered by the university. A separate analysis of the NKLM was carried out. Both analyses identified the active courses related to the topic of vaccination as well as the NKLM learning objectives. The match between the topics taught in current courses and the NKLM learning objectives identified gaps concerning the teaching of specific content. Courses were modified in order to implement the missing NKLM learning objectives. RESULTS: These analyses identified 24 vaccination-related courses, which are currently taught at the University. Meanwhile, 35 learning objectives on vaccination were identified in the NKLM catalogue. Four of which were identified as not yet part of the teaching program. In summary, this interdisciplinary work enabled the development of a new vaccination-related curriculum, including 35 learning objectives, which are now implemented in regular teaching courses by the Medical Faculty. CONCLUSIONS: This project successfully describes a method to develop and implement a competency based teaching program on the topic of vaccination. Importantly, the process presented here can serve as a guide to develop and implement similar teaching programs on other subjects and Universities. PMID- 26958654 TI - A study on effects of and stance over tuition fees. AB - AIM: Regarding tuition fees (that in Germany already have been abrogated) putative drawbacks like prolonged study duration have been suspected while benefits are not clearly proven. We investigated whether tuition fees (500 Euro per semester) affected the course of studies of Cologne medical students and asked for students' stance over tuition fees. METHODS: Of 1,324 students we analyzed the rate of those passing their first medical exam ("Physikum") within minimum time and students' discontinuation rate, respectively. Regression analysis tested for putative influences of tuition fees and demographic factors. In an additional online survey 400 students answered questions regarding the load by and their stance over tuition fees. RESULTS: We find that fees did not affect rate of Cologne students passing their first medical exam within minimum time or students' discontinuation rate. According to the online survey, at times of tuition fees significantly more students did not attend courses as scheduled. Time spent on earning money was significantly increased. 51% of students who had to pay tuition fees and 71% of those who never had to stated tuition fees to be not justified. More than two thirds of students did not recognize any lasting benefit from tuition fees. CONCLUSION: Tuition fees did not affect discontinuation rate or study duration of Cologne medical students. However, they obviously influenced the study course due to an increased need to pursue a sideline. Cologne medical students rather refused tuition fees and did not recognize their advantages in terms of enhanced quality of studies. PMID- 26958655 TI - Academic Performance of Students with the Highest and Mediocre School-leaving Grades: Does the Aptitude Test for Medical Studies (TMS) Balance Their Prognoses? AB - BACKGROUND: Admission to undergraduate medical training in Germany occurs by central and local pathways. Central admission includes two distinct groups: Students with top school-leaving grades (best-SLG group) and students with inferior school-leaving grades who are admitted with a delay of up to seven years (delayed admission group). Students with academic difficulties and early dropouts are present in both groups. Local admission at our university involves the German Test for Medical Studies (TMS) and allows the admission by merit of students with a wide range of school-leaving grades. AIMS: To examine the justification of a TMS-based strategy to reduce the admission of potentially weak best school leavers and enhance the admission of potentially able candidates with mediocre school-leaving grades. METHOD: The prognostic contribution of the school-leaving (SL) GPA and the TMS to academic performance and to continuity in the pre clinical part of the undergraduate medical program was examined in two study groups: best school leavers (SL grade 1.0, SL-GPA 823-900 points) and mediocre school leavers (SL grades 2.0-2.3, SL-GPA 689-660 points). The outcomes in both groups were compared in relation to their TMS results. The prospective study included four consecutive cohorts. RESULTS: In each study group the TMS predicted the academic performance (beta=0.442-0.446) and the continuity of studies (OR=0.890-0.853) better than the SL-GPA (beta=0.238-0.047; OR=1.009-0.998). Attrition was most strongly associated with failing to take the TMS (OR=0.230 0.380). Mediocre school leavers with TMS scores >=125 performed as well as the best school leavers. Mediocre school leavers with TMS scores between 110-124 performed on average less well but within the required standards. Best school leavers with mediocre TMS scores and 30% of the best school leavers who hadn't taken the TMS performed less well than most mediocre school leavers with high TMS scores. DISCUSSION: The TMS appears to differentiate between potentially successful and less successful students in both GPA categories. Mediocre school leavers (SLG 2.0-2.3) with exceptionally high TMS results reach better pre clinical examination results than best school leavers (SLG 1.0) with mediocre TMS results. Thus, the present data justify the use of the TMS to facilitate the participation of mediocre school leavers in the competition for admission slots. PMID- 26958656 TI - Importance and benefits of the doctoral thesis for medical graduates. AB - INTRODUCTION: The majority of medical graduates in Germany complete a doctorate, even though a doctoral degree is not necessary for the practice of medicine. So far, little is known about doctoral candidates' view on the individual benefit a doctoral thesis has for them. Consequently, this is the subject of the present investigation. METHOD: Data from surveys with graduates of the five medical faculties of Baden-Wurttemberg from the graduation years 2007/2008 (N=514) and 2010/2011 (N=598) were analysed. RESULTS: One and a half years after graduating 53% of those interviewed had completed their doctorate. When asked about their motivation for writing a doctoral thesis, participants answered most frequently "a doctorate is usual" (85%) and "improvement of job opportunities" (75%), 36% said that an academic career has been their primary motive. Less than 10% responded that they used their doctoral thesis as a means to apply for a job. The proportion of graduates working in health care is equally large among those who have completed a thesis and those who have not. Graduates who pursued a thesis due to scientific interest are also currently more interested in an academic career and recognise more opportunities for research. An implicit benefit of a medical thesis emerged with regard to the self-assessment of scientific competences as those who completed a doctorate rated their scientific competencies higher than those who have not. DISCUSSION: Although for the majority of physicians research interest is not the primary motivation for completing a doctorate, they might nevertheless achieve some academic competencies. For graduates pursuing an academic career the benefit of completing a medical thesis is more obvious. PMID- 26958657 TI - Stressed out or subjective acquisition of competence--how do veterinary students see their curative work placement? AB - Veterinary studies in Germany are regulated by the Veterinary Certification Act (TAppV). The practical part of the education consists of 1,170 hours, whereby up to 850 hours can be spent on the curative work placement. A curative work placement can result in physical and psychological stress in the sense of a professional overload. It is the aim of this study to find out in what areas and to what extent competence is acquired and psychological stress exists in students during their work placement. Veterinary students (n=142) from all German education institutes participated in a voluntary online-study based on Burnout Screening Scales (BOSS) as well as a questionnaire regarding the acquisition of competence and excessive stress during the work placement (FKUP). The distribution of values for work placement related stress show that such work placement related stress is generally slightly increased (T=60) and lies above that of occupational stresses within the normal population. Work placement related physical complaints also show a significant slight increase (T=61). A value (T=42) within the normal range was determined for the resource values. Few of the students questioned considered themselves to be excessively stressed in favour of a high subjective acquisition of competences. The largest increase regarding the acquisition of competence was noted for the areas of animal handling/restraint and application and injection techniques. In the sense of a perceived excessive demand regarding practical capabilities the areas of emergency management, surgery and medication dispensation were mentioned. With regard to the load structure and the acquisition of competence by veterinary students during their work placement, more support of the individual and a balancing of teaching/learning goals would be desirable and represents a promising approach. PMID- 26958658 TI - Dual-emissive fluorescence measurements of hydroxyl radicals using a coumarin activated silica nanohybrid probe. AB - This work reports a novel dual-emissive fluorescent probe based on dye hybrid silica nanoparticles for ratiometric measurement of the hydroxyl radical (OH). In the probe sensing system, the blue emission of coumarin dye (coumarin-3 carboxylic acid, CCA) immobilized on the nanoparticle surface is selectively enhanced by OH due to the formation of a coumarin hydroxylation product with strong fluorescence, whereas the emission of red fluorescent dye encapsulated in the silica nanoparticle is insensitive to OH as a self-referencing signal, and so the probe provides a good quantitative analysis based on ratiometric fluorescence measurement with a detection limit of 1.65 MUM. Moreover, the probe also shows high selectivity for OH determination against metal ions, other reactive oxygen species and biological species. More importantly, it exhibits low cytotoxicity and high biocompatibility in living cells, and has been successfully used for cellular imaging of OH, showing its promising application for monitoring of intracellular OH signaling events. PMID- 26958659 TI - Chip-based platform for dynamic analysis of NK cell cytolysis mediated by a triplebody. AB - Cancer therapy via redirected lysis mediated by antibodies and antibody-derived agents relies on the availability of substantial numbers of sufficiently active immune effector cells. To monitor antitumor responses before and during therapy, sensitive methods are needed, capable of quantitating specific lysis of target cells. Here we present a chip-based single-cell cytometric assay, which uses adherent human target cells arrayed in structured micro-fields. Using a fluorescent indicator of cell death and time-lapse microscopy in an automated high-throughput mode, we measured specific target cell lysis by activated human NK cells, mediated by the therapeutic single chain triplebody SPM-2 (33-16-123). This antibody-derived tri-specific fusion protein carries binding sites for the myeloid antigens CD33 and CD123 and recruits NK cells via a binding site for the Fc-receptor CD16. Specific lysis increased with increasing triplebody concentration, and the single-cell assay was validated by direct comparison with a standard calcein-release assay. The chip-based approach allowed measurement of lysis events over 16 hours (compared to 4 hours for the calcein assay) and required far smaller numbers of primary cells. In addition, dynamic properties inaccessible to conventional methods provide new details about the activation of cytolytic effector cells by antibody-derived agents. Thus, the killing rate exhibited a dose-dependent maximum during the reaction interval. In clinical applications ex vivo monitoring of NK activity of patient's endogenous cells will likely help to choose appropriate therapy, to detect impaired or recovered NK function, and possibly to identify rare subsets of cancer cells with particular sensitivity to effector-cell mediated lysis. PMID- 26958660 TI - Lateral resolution of desorption nanoelectrospray: a nanospray tip without nebulizing gas as a source of primary charged droplets. AB - Desorption nanoelectrospray (nanoDESI) was described in 2007 and it represents a miniaturized version of desorption electrospray without the assistance of the nebulizing gas. Compared to DESI, a nanoelectrospray tip (2 +/- 1 MUm I.D.) generates primary charged droplets of smaller sizes and lower spray liquid flow rates. This is the first report on utilization of nanoDESI for mass spectrometry imaging (MSI). Its new coupling with a Q-TOF instrument allowed faster mass spectra acquisition (4 Hz) essential for MSI of fine surface details. To evaluate nanoDESI potential for mass spectrometry imaging, etched glass substrates with Rhodamine B patterns of different dimensions were prepared. The Rhodamine B lines were analysed in 1D scanning mode and their width was determined experimentally by nanoDESI measurement. The experimental data revealed that the lateral resolution of nanoDESI is close to 30 MUm along the x-axis (orthogonal to the inlet). 2D scanning mode confirmed good resolution along both axes as dye squares with dimensions about 60 MUm * 60 MUm were easily distinguished. The low flow rate of the spray liquid reduced undesirable analyte washing effects, which allowed repeated scanning analysis of the surface. The presented results demonstrate the applicability of nanoDESI for high surface resolution mass spectrometry imaging. PMID- 26958661 TI - High performance perovskite solar cell via multi-cycle low temperature processing of lead acetate precursor solutions. AB - A lead acetate-based precursor, as a lead source in CH3NH3PbI3 perovskite, showed potential in rapidly (<60 seconds) forming homogeneous films with a very smooth interface and large grain growth at relatively low temperatures via multi-step coating. Cells based on this method exhibited high power conversion efficiency beyond 17% with good reproducibility. PMID- 26958662 TI - Evaporation-induced self-structuring of organised silica nanohybrid films through cooperative physical and chemical interactions. AB - In this work, we develop the concept of evaporation-induced self-structuring as a novel approach for producing organised films by exploiting cooperative physical and chemical interactions under far-from-equilibrium conditions (spin-coating), using sol-gel precursors with multiple functional groups. Thin films of self structured silsesquioxane nanohybrids have been deposited by spin coating through the sol-gel hydrolysis and condensation of a bridged organosilane bearing self assembling urea groups. The resulting nanostructure, investigated by FTIR, AFM and SEM, is shown to be highly dependent on the catalyst used (nucleophilic or acidic), and can be further modulated by varying the spinning rate. FTIR studies revealed the presence of highly organised structures under acidic catalysis due to strong hydrogen bonding between urea groups and hydrophobic interactions between long alkylene chains. The preferential orientation of the urea cross links parallel to the substrate is shown using polarized FTIR experiments. PMID- 26958663 TI - Aqueous solvation of amphiphilic molecules by extended depolarized light scattering: the case of trimethylamine-N-oxide. AB - Hydrophilic and hydrophobic interactions strongly affect the solvation dynamics of biomolecules. To understand their role, small model systems are generally employed to simplify the investigations. In this study the amphiphile trimethylamine N-oxide (TMAO) is chosen as an exemplar, and studied by means of extended frequency range depolarized light scattering (EDLS) experiments as a function of solute concentration. This technique proves to be a suitable tool for investigating different aspects of aqueous solvation, being able at the same time to provide information about relaxation processes and vibrational modes of solvent and solute. In the case study of TMAO, we find that the relaxation dynamics of hydration water is moderately retarded compared to the bulk, and the perturbation induced by the solute on surrounding water is confined to the first hydration shell. The results highlight the hydrophobic character of TMAO in its interaction with water. The number of molecules taking part in the solvation process decreases as the solute concentration increases, following a trend consistent with the hydration water-sharing model, and suggesting that aggregation between solute molecules is negligible. Finally, the analysis of the resonant modes in the THz region and the comparison with the corresponding results obtained for the isosteric molecule tert-butyl alcohol (TBA) allow us to provide new insights into the different solvating properties of these two biologically relevant molecules. PMID- 26958664 TI - [Headaches in the elderly can be caused by many different conditions]. PMID- 26958665 TI - Clinical insights: Understanding the link between nutrition and pressure ulcer prevention. PMID- 26958667 TI - OSHA expands push on health care facilities: Assisted lifting facilities included in the hot zone. PMID- 26958666 TI - Bridging politics, policy, and practice: Transforming health care in Massachusetts through the creation of a statewide commission on LGBT aging. PMID- 26958668 TI - 2015 updated AGS Beers Criteria offer guide for safer medication use among older adults. PMID- 26958669 TI - NICHE Solutions--Next in the series: Transitions. PMID- 26958670 TI - Reply from the Author. PMID- 26958671 TI - Response. PMID- 26958672 TI - Response. PMID- 26958673 TI - Response. PMID- 26958674 TI - [Miguel Uriguen Saiz (1948-2014)]. PMID- 26958675 TI - A Conceptual Advance--Two Faces of Neoliberalism. PMID- 26958676 TI - New European HIV Test Finder launched during European HIV-Hepatitis Testing Week. PMID- 26958677 TI - Reply to R Draijer and GS Duchateau. PMID- 26958678 TI - [ETIOLOGY OF ACUTE PANCREATITIS--UNDERESTIMATED PROBLEM IN PEDIATRICS]. AB - Pediatric pancreatitis has received much attention during the past few years. The incidence of acute pancreatitis in children has increased over the past 20 years. Therefore, acute pancreatitis should be considered during the differential diagnosis of abdominal pain in children. The etiological factors are different than in adults and, in recent reports, a wide range of potential causes has been associated with acute pancreatitis in children. The most common etiology of acute pancreatitis in children are biliary duct disorders, drugs, systemic diseases, trauma and also genetic factors. More than one third of the cases is idiopathic. The good knowledge of etiological factors is very useful in the planning of the adequate diagnostic procedures. The finding of the proper cause allow us to start appropriate treatment. PMID- 26958679 TI - CHRONIC PANCREATITIS IN A PATIENT WITH THE p.Asn34Ser HOMOZYGOUS SPINK1 MUTATION- OWN EXPERIENCE. AB - Chronic pancreatitis (CP) is characterized by progressive damage to the exocrine and endocrine cell structures and pancreatic ducts with subsequent fibrosis of the organ. Patients with no apparent etiological factor are classified as having idiopathic CP (ICP). Genetic studies indicate the importance of mutations in the serine protease inhibitor, Kazal type 1 gene (SPINK1) in the pathogenesis of CP This report describes a case of a 29-year-old Polish-Vietnamese patient with the p.Asn34Ser (p.N34S) homozygous mutation in the SPINK1 gene. The patient was hospitalized due to pain of average intensity in the epigastric area which occurred for the first time in his life. Imaging examination showed the atrophy of the pancreatic parenchyma with the presence of numerous small calcifications and a single calcified lodgement with a diameter of 22 mm in the distal segment of Wirsung 's duct. Clinical interview did not reveal any obvious etiological pancreatitis risk factors implying the causative role of the p.Asn34Ser homozygous mutation of SPINK1 in this case as proven in our investigation. PMID- 26958681 TI - BONE MINERAL DENSITY IN CHILDREN WITH IDIOPATHIC HYPERCALCIURIA. AB - The aim of the study was to evaluate bone mineral density (BMD) in the lumbar spine in children with idiopathic hypercalciuria. PATIENTS AND METHODS: The study group included 31 children (14 boys, 17 girls) aged 5 to 17 years (mean age 9.8 +/- 4.0 years) with idiopathic hypercalciuria. All children remained on normal calcium diet, without vitamin D and citrate supplementation. We evaluated lumbar spine (L1-L4) BMD (L1-L4 BMD) (expressed as Z-score) and blood serum levels of 25 hydroxyvitamin D3 (250HD3), calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and intact parathormone (iPTH). We also evaluated 24-hour urinary Ca, P, and sodium (Na) excretion. RESULTS: Reduced L1-L4 BMD Z-score <-1 was found in 25.8% of children, Z-score values from -1 to 1 in 64.5% of children, and Z-score > 1 in 9.7% of children. Reduced 250HD3 level (< 20 ng/mL) was found in 71% of children, levels in the range of 20-30 ng/mL in 22.6% of children, and levels > 30 ng/mL in 6.4% of children. Seven out of 8 children with L1-L4 BMD Z-score <-1 were found to have 250HD3 deficiency (level < 20 ng/mL). Among children with reduced lumbar spine BMD, most were girls at the mean age of 13.8 years. Ca and P levels were normal in all children. We did not find significant differences in 25OHD3, Ca, and P levels in relation to gender and age. We found a positive correlation between L1-L4 BMD Z-score and serum 250HD3 level. Concomitant nephrolithiasis was found in 50% of patients with reduced lumbar spine BMD. CONCLUSIONS: Reduced lumbar spine BMD in patients with idiopathic hypercalciuria seems to be related to vitamin D3 deficiency. PMID- 26958680 TI - VIT. B12 DEFICIENCY IN CHILDREN (IMERSLUND-GRASBECK SYNDROME IN TWO PAIRS OF SIBLINGS). AB - Improvement in the quality of life in Europe and North America in last decades caused that economical and social aspects of living conditions of the population have less effect and genetic defects of malabsorption of vitamin B12 became the main reason for cobalamin deficiency in children. Imerslund-Grasbeck syndrome (IGS) is characterized by vitamin B12 deficiency that leads usually to megaloblastic anemia and mild proteinuria. We described two pairs of siblings in two families with IGS. The diagnosis in first family (two brothers) was established at 33 and 22 months of age. The reason for diagnostic tests were proteinuria and anemia. Apart from respiratory tract infections, they didn't present other symptoms of cobalamin deficiency. In the second family IGS was diagnosed in children at 5 and 8 years of age. Diagnostic evaluation procedures wereperformedbecause ofneurologicalsigns, including weakness, loss of appetite, dysmorphia, psychomotor retardation. Laboratory tests revealed megaloblastic anemia, low concentration of vitamin B12 in serum and mild proteinuria. In the first pair low concentration of vitamin B12 was validated by the Schilling test, in the second pair methylomalonate acid was detected in the urinary metabolic test. All children were successfully treated with vitamin B12 and anemia and neurological signs disappeared. Long-term follow up showed failure to thrive in the girl and physical and mental retardation, microcephaly in her brother. Proteinuria in the range: 0.3-1.2 g/24 h was detected in each child, and the other laboratory tests were normal. Clinical symptoms, laboratory tests and good reaction to parenteral treatment with vitamin B12 allowed us to diagnose Imerslund-Grasbeck syndrome, even without genetic tests. CONCLUSION: A delayed diagnosis of congenital malabsorption of cobalamin can lead to physical and mental retardation in children. Children with megaloblastic anemia and proteinuria resistant to classical treatment should be tested for congenital malabsorbtion of cobalamin. PMID- 26958682 TI - BODY SOMATIC TYPE INFLUENCE ON THE SPINAL CURVATURES IN EARLY AGE SCHOOL CHILDREN: PRELIMINARY REPORT. AB - INTRODUCTION: Sedentary lifestyle and its consequences are becoming a serious problem not only among the elderly but also relate to children. Reduced muscle mass, disorder of normal spinal curves or problems related to the percentage of body fat are part of physical activity limitation. The aim of this study was to assess the relationship between somatic type of the body and spinal curvatures in school children. MATERIAL AND METHODS: This study included 94 randomly selected children from 1-3 elementary schools grades, 49 girls and 45 boys. The subjects were divided into 3 groups: a group of children with a BMI indicating underweight (BMI <14.5, n=25), a group of children with normal BMI (BMI = 14.5-17.5, n = 33) and children BMI indicating overweight (BMI > 17.5, n = 36). The Posturometr-S was a device used for measurement and evaluation of the formation of the spine in the sagittal plane. There were three angles of inclination of anterior-posterior curvature of the spine identified: the alpha angle-upper thoracic spine, the beta angle-thoraco-lumbar spine and the gamma angle-lumbosacral spine. RESULTS: Analysing the results of the different angles of curvature of the spine in the sagittal plane we can notice a statistically significant difference between the groups only in the a angle. CONCLUSION: The own investigations have showed that the somatic type of the body does not affect the shape of the spine in school children assessed using Posturometr-S. Ther investigations are needed. PMID- 26958683 TI - [RATE OF PHYSICAL DEVELOPMENT IN BOYS AGED 10-11 YEARS AND THE EFFECTS OF TRAINING LOADS DURING A 12-MONTH SOCCER PROGRAM]. AB - AIM: The aim of the study was to evaluate the rate of physical development in prepubertal boys in response to training at different loads. MATERIAL AND METHODS: The study involved two groups of soccer players, experimental groups E1 (n = 26, age 10.4 +/- 0.6 years) and E2 (n = 27, age 10.3 +/- 0.8 years) who were involved in a 12-month soccer training program, and a control group (C) of age matched untrained boys (n = 22). The training protocol of E1 involved a greater share of coordination-based exercises, in E2 more focus was placed on conditioning fitness and strength. Body height, mass, fat percentage, and body mass index were measured pre-, peri-, and post-training. Chronological and developmental age were used to calculate a Biological State Maturity Index (BSMI). RESULTS: Between-group differences were observed in body fat percentage, which was higher in the control group by 6.8% at post-training compared with E1 (p < 0.05). E1 showed the most congruence between chronological and developmental age. Developmental age was most retarded in E2 by an average of 4.3 months. Greatest between-group differences were observed in E1 and the control group for the BSMI of body height (49.9%) at pre-training. BSMI of height and mass in the control group were different (p < 0.01) from both experimental groups at pre-, peri-, and post-training. CONCLUSIONS: 1. The experimental soccer training programs were conducive to the physical development of boys aged 10-11 years as evidenced by the absence of disturbances in the range of observed variables characterizing the body built and biological development. 2. Body mass index did not accurately reflect changes in body composition. A more detailed analysis of body composition is required in the recruitment and selection of young soccer players in order to better control the effects of training and diet. 3. The adopted BSMI measure indicated a delay in growth according to developmental age norms in the entire sample. However, the accelerated physical development in E1 during the study duration may be indicative of the stimulative effect of this group's training program and the adopted training load on physical development. PMID- 26958684 TI - PARENTAL PERCEPTION OF BODY WEIGHT IN PRESCHOOL CHILDREN AND AN ANALYSIS OF THE CONNECTION BETWEEN SELECTED PARENT-RELATED FACTORS AND THE ASSESSMENT OF THEIR CHILDREN'S WEIGHT. AB - INTRODUCTION: The efforts parents make to maintain the correct body weight in children indicates parental awareness of overweight and obesity-related health risks. AIM: The objective of the analysis was to define the accuracy of the appraisal of weight-to-height proportions in preschool children, as assessed by their parents and to analyse the connection of selected parental factors with the assessment conducted. MATERIAL AND METHODS: Data were collected from 230 children (121 males and 109 females aged 6.28 +/- 0.56 years) attending preschools in the city of Wroclaw, Poland. Body height and weight were measured to calculate BMI; cut-offs referenced by the International Obesity Task Force were used to determine weight status (underweight, overweight, obese). The participants' parents completed a weight-height assessment of their child and provided information on how often the child's body weight was checked. Cohen's kappa coefficient was used as a statistical measure of inter-rater agreement between actual child weight and parental perception of child weight. Selected parental factors influencing the correctness of assessing child body weight was tested using the chi-square test. RESULTS: This study showed that 42.1% of underweight children and 60.9% overweight and obese children are perceived as having normal weight. In the group of children with normal weight-to-height proportions, 13.3% of the parents declared their normal-weight children to be underweight. No relationship was found in the study between the correct assessment of body weight and the parents' own body weight, their education, or such factors as sex and the frequency of checking the child's body weight. CONCLUSIONS: The incompatibility between actual and perceived weight status indicates the need for health education among parents in assessing and monitoring the child's body weight during the developmental period. PMID- 26958685 TI - ATYPICAL DISLOCATION OF IMPACTED PERMANENT TEETH IN CHILDREN. OWN EXPERIENCE. AB - INTRODUCTION: Disturbances in forming of the hard tissue of teeth and bones can be a cause of their malformation and translocation. The impact of permanent teeth is one of them. It can occur with translocation of the tooth germ. The aim of the study was to present an atypical translocation of impacted permanent teeth in children. MATERIAL AND METHODS: 3.5 year clinical observation was carried out in 14 children (5 girls and 9 boys), aged between 9 and 12 years old. Patients were referred to our Department by orthodontists, paedodontists and General Dental Practitioners, due to impacted permanent teeth. According to the interview, in 8 cases children suffered from a trauma of a facial part of the skull, caused by a fall. On admitance patients were generally healthy. Basing on the clinical and radiological examination, translocation of the impacted permanent teeth has been diagnosed. In 9 cases it concerned medial maxillary incisors, whereas in remaining children--maxillary premolars. The extraction of such teeth has been performed as a part of the one day surgery procedures. CONCLUSION: In the cases where basing on the radiogram, the position of the tooth allows to predict the latter translocation, the germ has to be extracted. PMID- 26958686 TI - PRACTICAL ASPECTS OF THERAPEUTIC HYPOTHERMIA IN NEONATES WITH HYPOXIC ISCHEMIC ENCEPHALOPATHY--QUESTIONS AND ANSWERS. PART I. PROVIDING NEWBORN CARE BEFORE AND DURING TRANSFER TO THE REFERENCE CENTER. AB - The first decade of the 21st century saw the worldwide spread of therapeutic hypothermia as a beneficial therapeutic procedure in neonates with hypoxic ischemic encephalopathy. New guidelines for the resuscitation of newborns confirm that therapeutic hypothermia should be the standard method of treatment offered to neonates with acute perinatal hypoxia. The quality of care which an asphyxiated newborn receives during and immediately after resuscitation, as well as the mode of preparation for transport, can have a significant impact on improving the outcome, but it can also result in the deterioration of neonates treated with hypothermia. Since to a considerable degree the therapeutic effect depends on the time of beginning the cooling procedure, there is no reason to unnecessarily delay treatment. For this purpose, neonatologists or pediatricians from referring hospitals who do not have the equipment for hypothermia can and even should begin the cooling process while waiting for the arrival of the neonatal transport team. In that short period a number of concerns arise regarding the optimal methods of child care and preparation for transport to the hypothermia center. The authors discuss the possibility of initiating cooling before transportation using simple, so called low-tech cooling methods, the possible risks associated with the incidence of hyperthermia, difficulties in the interpretation of the eligibility criteria, supportive therapy, and the problems connected with the communication process between the medical team and the parents. The aspects that have been analyzed should be helpful for professionals in neonatal wards, outside hypothermia centers. PMID- 26958687 TI - THE CONSEQUENCES OF FAILING ELECTIVE NONINVASIVE RESPIRATORY SUPPORT AS COMPARED TO IMMEDIATE INTUBATION: A POPULATION STUDY OF VERY LOW BIRTH WEIGHT NEONATES. AB - INTRODUCTION: Elective noninvasive respiratory support has become common. However, many neonates fail this procedure and they may require intubation. The aim of this study was to determine the relative outcome of very low birth weight neonates who failed noninvasive respiratory support compared to those that were initially intubated and mechanically ventilated. MATERIAL AND METHODS: We accessed the database of every neonate who received respiratory support in 18 hospitals in the central region of Poland and examined the records for a 7-year period. The evaluation encompassed 1667 neonates with very low birth weight who were potential candidates for elective noninvasive respiratory support. Three prospective primary outcome measures were assessed using logistic regression to control for differences in baseline risk. We also examined the length of respiratory support corrected for EGA. RESULTS: After controlling for significant baseline factors, we found that there was no statistically significant difference in mortality, severe retinopathy of prematurity (ROP) orsevere bronchopulmonary dysplasia (BPD) between infants failing noninvasive respiratory support and those electively intubated. However, their mortality and severe ROP were significantly higher than in those successfully treated with noninvasive respiratory support. Additionally, there was no difference in the length of mechanical ventilation or the length of all respiratory support between those that failed noninvasive support and those that were electively intubated. CONCLUSION: Our study suggests that in those preterm infants who are at a higher risk of failing noninvasive ventilation there is no compelling reason to administer elective intubation and mechanical ventilation immediately after birth. It seems that efforts should rather be made towards the implementation of the optimal non-invasive respiratory support. PMID- 26958688 TI - USING THE AUTOMATED FIO2- SPO2 CONTROL IN NEONATAL INTENSIVE CARE UNITS IN POLAND. A PRELIMINARY REPORT. AB - AIM: Analysis of the way in which a new method of implementing the automated control of oxygen therapy during respiratory support is applied in newborns with respiratory failure. MATERIAL, METHODS AND RESULTS: The AVEA-CLiO2 ventilator with automated FiO2- SpO2 control was used in our study of 121 newborns conducted between February 2014 and January 2015 in five neonatal intensive care units. A web-based database was used to gather information entered concurrently with using the FiO2- SpO2 control system. This included demographics, clinical status, clinical indications, as well as objective and subjective experience. Among the 121 newborns 94 were preterm and 27 were near-term (33-36 hbd). The primary indication for using the system was "routine management" of FiO2 during respiratory support and it was generally initiated within the first 2 days of life. Many of the newborns were managed with the system for more than a week. The control range was usually 90%-95% SpO2, though sometimes it was lower or wider. The control range was not related to the newborn's maturity or indication for use. The perception of more "frequent and persistent" SpO2 alarms was lower when the alarms were set loosely. There were no reports of the system not working effectively. CONCLUSIONS: We expect this first report of the routine use of automated FiO2- SpO2 control to be useful not only to other centers in Poland but also to all those adopting this important new technology. Our registry continues and we expect to have an update when we have experience with 1000 infants. Carefully controlled trials are also needed to refine the optimum use of automated FiO2- SpO2 control and to quantify its impact on neonatal outcomes. PMID- 26958689 TI - STRATEGIES OF USING SURFACTANT: RESULTS OF THE FIRST POLISH NATIONAL SURVEY OF DAILY PRACTICE. AB - BACKGROUND: The efficiency of routine practices in the management of neonatal respiratory distress syndrome (RDS) have never been systematically investigated in Poland. OBJECTIVE: To evaluate RDS treatment policies and short-term outcomes in neonatal intensive care units (NICUs). MATERIAL AND METHODS: We retrospectively analyzed medical records of premature neonates <= 32 weeks' gestation, diagnosed with RDS in level-2 and level-3 referral centers. Collected data: comprised clinical variables, antenatal corticosteroids, respiratory support, surfactant (SFT) policies and short-term outcomes. RESULTS: Data of 987 infants from 53 NICUs were analyzed. The median gestational age was 29 weeks (range 22-32) and birth weight 1190 g (range 340-2860). Infants requiring SFT had significantly lower exposure to antenatal corticosteroids (75%) vs. those managed without SFT (83%, p = 0.006). SFT was given to 59% infants in level-3 NICUs and 40% in level-2. There was significant variability of SFT use between level 2 and level 3 NICU. (9% to 100%). Poractant alfa was most commonly used (97%) in the median initial dose of 170 mg/kg (IQR 120-200). Single application was most frequent (79.8%). SFT administration methods were endotracheal instillation in babies maintained on mechanical ventilation (68.0%), INSURE (27.6%) and minimally invasive delivery (MIST) 4.4%. Early rescue treatment remained core SFTstrategy (57.4% cases), while prophylaxis accounted for only 13.3% cases. CONCLUSIONS: There is considerable variation in the frequency of use of surfactant in Polish neonatal centers. Traditional intratracheal instillation with subsequent mechanical ventilation dominates, although newer methods INSURE and MIST are becoming increasingly popular. Early rescue SFT is a predominant strategy, which conforms to current standards. The rate of antenatal corticosteroids remains too low. PMID- 26958690 TI - SUBGALEAL HEMATOMA AS A PERINATAL PRESENTATION OF RARE HEMATOLOGIC PROBLEMS IN NEWBORNS. OWN EXPERIENCE. AB - INTRODUCTION: Bleeding to the subgaleal space is a rare and often serious complication of childbirth. Delivery with the use of vacuum or forceps is considered as the main risk factor of subgaleal hemorrhage. Reports of other possible causes (including fetal ones) appear rarely. OBJECTIVES: The aim of this study is to present and analyze two unusual cases of bleeding to subgaleal space in neonates delivered through caesarean section, in whom two different concomitant hematologic problems were diagnosed. The authors demonstrate also the mechanisms leading to the formation of subgaleal hematoma as well as discuss the impact of the final diagnosis on the course of the perinatal period and the need to modify medical practice in a variety of clinical situations in both newborns and their mothers. MATERIAL AND METHODS: Authors present two consecutive cases of severe subgaleal hemorrhage. RESULTS: In the first newborn hemophilia was finally diagnosed. The second neonate was diagnosed with neonatal alloimmune thrombocytopenia. CONCLUSIONS: Subgaleal hemorrhage is a rare complication of delivery. In severe cases, other possible risks should be considered apart from the traumatic delivery only. An early identification of potential hematological risk factors can influence the effectiveness of the treatment and help to modify the follow-up of both the infant and its mother. PMID- 26958691 TI - THE VALUE OF THE OXYGENATION INDEX IN THE PREDICTION OF POSTNATAL OUTCOME IN NEONATES WITH CONGENITAL DIAPHRAGMATIC HERNIA. PRELIMINARY REPORT. AB - The predicitive values of fetal ultrasonography and magnetic resonance imaging are well established as antenatal outcome predictors in neonates with congenital diaphragmatic hernia (CHD). Postnatal outcome predictors remain elusive. THE AIM: To evaluate the value of the oxygenation index (OI) as a predictor of postnatal survival. MATERIAL AND METHODS: 58 newborns with congenital diaphragmatic hernia, treated in the same centre (a university hospital) between February 2006 and March 2014 were involved in the retrospective study. Standardized preoperative stabilization involved: sedation without muscle paralysis, high frequency oscillation ventilation (HFOV) and inhaled nitric oxide (iNO, used as required). Oxygenation index OI = FiO2 x 100 x M AP/PaO2, where FiO2 is the fraction of inspired oxygen, MAP is the mean airway pressure, and PaO2 is the partial pressure of oxygen in arterial blood, calculated at the end of the first day of standardized preoperative stabilization, and evaluated as a predictor of survival. RESULTS: The overall survival rate on the hospital discharge was 74.1%. As far as the oxygenation index (OI) at the end of the first day of the preoperative stabilisation is concerned, in 40/43 survivors it was below or equal to 12, in one infant it equalled 12.7, and in two remaining survivors OI was much higher (18 and 56, respectively). The prognostic value of the oxygenation index was high, with the area under the curve (AUC) 0.943, sensitivity 0.930, and specificity 0.876. CONCLUSIONS: The oxygenation index (OI) calculated at the end of the first day of standardized preoperative stabilization with high frequency oscillation ventilation (HFOV) and nitric oxide (iNO) is a simple and sensitive predictor of the survival of neonates with a congenital diaphragmatic hernia. It may be a valuable tool to select high-risk neonates who might require more invasive therapeutic modalities, i.e. extracorporeal membrane oxygenation (ECMO). PMID- 26958692 TI - PROCEEDING IN ACUTE KIDNEY INJURY IN ASPHYXIATED NEONATES--DIFFICULTIES AND SUCCESS. AB - Acute kidney injury (AKI) is a common consequence of perinatal asphyxia reported in 30 to 70% cases. We present 4 full-term neonates with oliguric/anuric AKI caused by perinatal asphyxia requiring renal replacement therapy (RRT) and their long-term outcomes. Patient No. 1 was dialyzed for 12 days (continuous ambulatory peritoneal dialysis (CAPD)/continuous venovenous hemodiafiltration (CWHDF)), then was treated conservatively, and received pre-emptive kidney transplantation (KTx) at the age of 3 3/12 years. Patient No. 2 was treated with CAPD/automated peritoneal dialysis (APD) for 15 months, due to recovery of renal function, dialysis was withdrawn. He is now 8 5/12 years old and has chronic kidney disease (CKD) stage III. Patient No. 3 after 5 days of continuous arteriovenous hemofiltration (CAVH) required CAPD for 17 days. The child is now 8 4/12 years old and has CKD stage III. Patient No. 4, dialyzed from 3rd day of life for 51 months (CAVH followed by CAPD/APD), was given cadaver KTx at the age of 4 3/12 years. Psychomotor development is good in 2 patients, whereas patients No. 3 and 4 have tetraplegic spastic infantile cerebral palsy, severe mental retardation, and epilepsy. CONCLUSIONS: Severe perinatal asphyxia with oliguric/anuric AKI is a risk factor for chronic kidney disease sometimes end-stage renal disease. PMID- 26958693 TI - ASSESSMENT OF BODY COMPOSITION USING BIOELECTRICAL IMPEDANCE ANALYSIS IN PRETERM NEONATES RECEIVING INTENSIVE CARE. AB - AIM: Evaluation of bioelectrical impedance values and body composition during early infancy in groups of preterm newborns and full-term newborns. MATERIAL AND METHODS: A total of 38 newborns was enrolled in the study: 26 very low birth weight preterm newborns with the mean birth weight of 1236 g (SD: 161) as the study group and 12 term newborns with birth weight of 2500-4000 g as the control group. Anthropometric measurements and body composition using bioimpedance analysis at the age of 1 week and at the age of 3 months were assessed. RESULTS: At the age of 1 week we noted higher resistance with the impedance variables R5, R50 R100 in the group of preterm newborns compared to the full-term newborns' group (923(144) vs. 647(78) p < 0.01; 870 (140) vs. 615 (73) p < 0.01; 844 (141) vs. 599 (72) p < 0.01). Moreover, the bioimpedance index and fat mass (%) were significantly lower in the group of preterm infants at the age of 3 months (3.81 (0.9) vs. 5.72 (1.1) p < 0.01; 16.1% (1.7) vs. 18.9% (2.7) p = 0.006). We observed a decreased amount of the percentage of total body water (TBW%) in both of the analyzed infant groups throughout the observational period. At the age of 3 months the amount of TBW % was similar in both groups (71.5% (7.03) vs. 70.8% (8.8) p = 0.8). CONCLUSIONS: Bioimpedance analysis is a simple, non-invasive, repeatable method to estimate total body water, fat-free mass, and fat mass, both in term and preterm newborns. The study confirms differences in body composition between preterm newborns and full-term newborns. Moreover, we have shown that the differences are present until the end of the 3rd month of life, with the exception of the amount of water percentage (TBW %), which are similar in both groups. PMID- 26958694 TI - THE INCIDENCE OF HYPERGLYCAEMIA IN VERY LOW BIRTH WEIGHT PRETERM NEWBORNS. RESULTS OF A CONTINUOUS GLUCOSE MONITORING STUDY--PRELIMINARY REPORT. AB - AIM: To determine the incidence of hyperglycaemia in very low birth weight preterm newborns. To assess risk factors in hyperglycemia and outcome in groups of children with and without clinically significant hyperglycaemia. MATERIAL AND METHODS: The prospective study included newborns with very low birth weight in whom the continuous glucose monitoring system was used for glucose measurements. A standardized hyperglycaemia treatment schedule was implemented and a uniform nutrition strategy introduced. The patients were divided into groups: group A- patients with under 5% of the readings over 150 mg/dL of glucose (control group), group B--patients with more than 5% of the readings over 150 mg/dL of glucose and under 5% of the readings over 180 mg/dL of glucose (mild hyperglycaemia), and group C--patients with over 5% of the readings > 180 mg/dL or on insulin treatment (moderate or severe hyperglycaemia). RESULTS: 63 patients were included in the study. Their mean gestational age was 27.7 weeks (SD:2.4), the mean birth weight was 1059g (SD: 262 g). Hyperglycaemia was detected in 27 (42.9%), including mild hyperglycaemia in 19 (30.2%), and moderate or severe hyperglycaemia in 8 (12.7%) neonates. Lower gestational age (p = 0.02) and higher CRIB IIscore (p < 0.01) were positively associated with hyperglycaemia. Early onset sepsis (p < 0.01) was associated with higher glucose levels as well. A significantly higher mortality rate on the 28th day of life (p = 0.02), depending on the severity of hyperglycemia, was noted. No adverse effects related to the continuous glucose monitoring system were observed. CONCLUSIONS: The study confirmed the usefulness and safety of the continuous glucose monitoring system in VLBW neonates. A continuous glucose monitoring system should be used in neonatal intensive care units as a standard method. PMID- 26958695 TI - MONITORED SUPPLEMENTATION OF VITAMIN D IN PRETERM NEONATES--A PRIMARY REPORT. AB - AIM: To evaluate vitamin D (vitD) monitored therapy effectiveness and safety in preterm neonates. PATIENTS AND METHODS: Our observational study was carried out in 80 neonates born before 33 weeks' gestational age (GA) hospitalized in the Clinical Department of Neonatology and Neonatal and Intensive Care Department Medical University of Warsaw from July 2013 to July 2014. Daily vitamin D oral supplementation was provided from 1 to 3 weeks of age at the dose of 500-1000 IU/24 h. The dosage was modified according of 25-hydroxyvitamin-D blood serum concentration. Both blood serum 25(OH) D concentration and calcium-phosphate metabolism were assessed at 4 weeks of age, at 34-37 weeks' post-conceptual age (on discharge) and at 39-41 weeks PCA. RESULTS: Mean serum 25(OH)D level was 40 ng/ml at 4 weeks of age, 61 ng/ml at 34-37 weeks PCA, and 53 ng/ml at 39-41 weeks PCA. Higher concentrations were observed in ELBW neonates. Deficiency was noted most often at the first measurement. 52.5% of neonates received 500IU vitD before discharge, 19% had stopped supplementation due to overdosing. High dose vitD supplementation was provided in 34% cases. Disturbance of calcium-phosphate metabolism due to vitD deficiency was observed in one patient. Hypervitaminosis was associated with higher calcium-creatinine ratio. Very high individual heterogeneity of 25(OH)D concentration changes were observed (from 70 ng/ml/4 weeks decrease to 92 ng/ml/4 weeks increase). CONCLUSIONS: Supplementation of vitamin D in preterm neonates needs monitoring. A safe time interval to monitor vitamin D supplementation seems to be 1 month. The schedule of the therapy requires further studies. PMID- 26958696 TI - WHY IS NEONATAL ANAESTHESIA SUCH A CHALLENGE? AB - Approximately 1.5 million neonates receive general anaesthesia each year for surgical procedures. Providing anaesthesia to neonates is not easy. Surgical procedures are often difficult and extensive, and the physiology of neonates makes respiratory and cardiovascular problems more frequent and life-threatening. The paper covers the changing concepts in neonatal anaesthesia, including recent studies that indicate that anaesthetic exposure could cause neuronal apoptosis in the developing brain. This could potentially influence the long-term developmental outcome, especially in infants requiring multiple surgical procedures. Respiratory and cardiovascular critical events, age-related differences of the pharmacokinetics of the drugs used for anaesthesia, as well as technical problems are also covered. PMID- 26958697 TI - HOW TO DETERMINE THE NUTRITIONAL STATUS OF PRETERM BABIES?--REVIEW OF THE LITERATURE. AB - Prematurity is a high risk factor threatening the well-being of newborns and their somatic and psychological development in the future. Preterm babies need special medical care in which proper nutrition and metabolic control play an evident role. Our review presents the current knowledge concerning the clinical value of different methods investigated in the neonatal unit setting, including: protein markers of nutritional status (albumin,prealbumin, transferrin, and Retinol Binding Protein (RBP) and hormonal markers of nutritional status (somatomedin C, visfatin and ghrelin). Moreover, there is a discussion of the methods used for evaluating body composition. A variety of different techniques based on the physical properties of organisms was tested on neonates, e.g. the Dual Energy X-ray Absorptiometry (DEXA) method and Bioelectrical Impedance Analysis (BIA). Based on the review of the literature, we can speculate that none of the above methods represents a good single marker of the babies' nutritional status, or a prognostic factor for the future development of premature infants and infants born with IUGR. A combination of several methods from different groups seems to be a promising possibility. It is critical to continue looking for markers that will in a simple and efficient way help to optimize the correct nutritional therapy in infants with IUGR and those who were born prematurely. PMID- 26958698 TI - Quantum Chemical Studies of Light Harvesting. AB - The design of optimal light-harvesting (supra)molecular systems and materials is one of the most challenging frontiers of science. Theoretical methods and computational models play a fundamental role in this difficult task, as they allow the establishment of structural blueprints inspired by natural photosynthetic organisms that can be applied to the design of novel artificial light-harvesting devices. Among theoretical strategies, the application of quantum chemical tools represents an important reality that has already reached an evident degree of maturity, although it still has to show its real potentials. This Review presents an overview of the state of the art of this strategy, showing the actual fields of applicability but also indicating its current limitations, which need to be solved in future developments. PMID- 26958700 TI - Strain Control: Reversible H2 Activation and H2/D2 Exchange in Pt Complexes. AB - Experiments have indicated that bulky ligands are required for efficient H2 activation by Pt-Sn complexes. Herein, we unravel the mechanisms for a Pt-Sn complex, Pt(Sn(t)Bu3)2(CN(t)Bu)2 (1a), catalyzed reversible H2 activation. Among a number of Pt-Sn catalysts used to model H2 activation and H2/D2 exchange reactions, only 1a with large strain was found to be suitable because the addition of H2 to 1a requires lowest distortion energy, minimal structural changes, and smallest entropy of activation. The activity of this Pt-Sn complex was compared vis-a-vis its Pt-Ge and Pt-Si analogues, and we predicted that strained Pt-Ge complex can efficiently activate H2 reversibly. Direct dynamics calculations for the rate of reductive elimination of H2, HD, and D2 from Pt(Sn(t)Bu3)(CN(t)Bu)2H3 (4a) and Pt(Sn(t)Bu3)(CN(t)Bu)2HD2 (4a([2D])) shows that H/D atom tunneling contributes significantly, which leads to an enhanced kinetic isotope effect. Strain control is suggested as a design concept in H2 activation. PMID- 26958699 TI - Magnetic Hydrogels from Alkyne/Cobalt Carbonyl-Functionalized ABA Triblock Copolymers. AB - A series of alkyne-functionalized poly(4-(phenylethynyl)styrene)-block poly(ethylene oxide)-block-poly(4-(phenylethynyl)styrene) (PPES-b-PEO-b-PPES) ABA triblock copolymers was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. PESn[Co2(CO)6]x-EO800-PESn[Co2(CO)6]x ABA triblock copolymer/cobalt adducts (10-67 wt % PEO) were subsequently prepared by reaction of the alkyne-functionalized PPES block with Co2(CO)8 and their phase behavior was studied by TEM. Heating triblock copolymer/cobalt carbonyl adducts at 120 degrees C led to cross-linking of the PPES/Co domains and the formation of magnetic cobalt nanoparticles within the PPES/Co domains. Magnetic hydrogels could be prepared by swelling the PEO domains of the cross-linked materials with water. Swelling tests, rheological studies and actuation tests demonstrated that the water capacity and modulus of the hydrogels were dependent upon the composition of the block copolymer precursors. PMID- 26958701 TI - The safety of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure. AB - INTRODUCTION: Mineralocorticoid receptor antagonists (MRAs) have been accorded a class 1 indication for patients with chronic heart failure and a reduced left ventricular ejection fraction (HFREF) in both European and American guidelines. Uptake, however, has been less than optimal largely due to concerns about their safety, in particular the risk of hyperkalemia and renal dysfunction. AREAS COVERED: This review presents the current state of affairs regarding the safety of MRAs in heart failure with reduced ejection fraction. EXPERT OPINION: Careful patient selection and adherence to guideline-recommended inclusion and exclusion criteria, dosing, and serial monitoring of serum potassium and renal function, along with patient education regarding the potassium content of common foods, should minimize these risks and allow increased use of MRAs. Additionally, this may also result in a further reduction in cardiovascular mortality and hospitalizations for heart failure. The development of new non-steroidal MRAs, and especially new potassium binding molecules that are well tolerated and effective, hold the promise for increased safety and, therefore, increased and more prolonged use of MRAs in patients with heart failure, especially those with chronic kidney disease, diabetes mellitus, and the elderly. PMID- 26958702 TI - Amide Rotation Hindrance Predicts Proteolytic Resistance of Cystine-Knot Peptides. AB - Cystine-knot peptides have remarkable stability against protease degradation and are attractive scaffolds for peptide-based therapeutic and diagnostic agents. In this work, by studying the hydrolysis reaction of a cystine-knot inhibitor MCTI-A and its variants with ab initio QM/MM molecular dynamics simulations, we have elucidated an amide rotation hindrance mechanism for proteolysis resistance: The proteolysis of MCTI-A is retarded due to the higher free energy cost during the rotation of NH group around scissile peptide bond at the tetrahedral intermediate of acylation, and covalent constraint provided by disulfide bonds is the key factor to hinder this rotation. A nearly linear correlation has been revealed between free energy barriers of the peptide hydrolysis reaction and the amide rotation free energy changes at the protease-peptide Michaelis complex state. This suggests that amide rotation hindrance could be one useful feature to estimate peptide proteolysis stability. PMID- 26958704 TI - Highly Efficient Flexible Perovskite Solar Cells Using Solution-Derived NiOx Hole Contacts. AB - A solution-derived NiOx film was employed as the hole contact of a flexible organic-inorganic hybrid perovskite solar cell. The NiOx film, which was spin coated from presynthesized NiOx nanoparticles solution, can extract holes and block electrons efficiently, without any other post-treatments. An optimal power conversion efficiency (PCE) of 16.47% was demonstrated in the NiOx-based perovskite solar cell on an ITO-glass substrate, which is much higher than that of the perovskite solar cells using high temperature-derived NiOx film contacts. The low-temperature deposition process made the NiOx films suitable for flexible devices. NiOx-based flexible perovskite solar cells were fabricated on ITO-PEN substrates, and a preliminary PCE of 13.43% was achieved. PMID- 26958703 TI - Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1). AB - WD repeat-containing protein 5 (WDR5) is an important component of the multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1). Rearrangement of the MLL1 gene is associated with onset and progression of acute myeloid and lymphoblastic leukemias, and targeting the WDR5-MLL1 interaction may result in new cancer therapeutics. Our previous work showed that binding of small molecule ligands to WDR5 can modulate its interaction with MLL1, suppressing MLL1 methyltransferase activity. Initial structure-activity relationship studies identified N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides as potent and selective antagonists of this protein-protein interaction. Guided by crystal structure data and supported by in silico library design, we optimized the scaffold by varying the C-1 benzamide and C-5 substituents. This allowed us to develop the first highly potent (Kdisp < 100 nM) small molecule antagonists of the WDR5-MLL1 interaction and demonstrate that N-(4-(4-methylpiperazin-1-yl)-3' (morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6 dihydropyridine-3-carboxamide 16d (OICR-9429) is a potent and selective chemical probe suitable to help dissect the biological role of WDR5. PMID- 26958705 TI - Physiological and Behavioral Responses of Horses to Wither Scratching and Patting the Neck When Under Saddle. AB - Riding is considered to be an arousing activity for horses. It has been suggested that wither scratching may be a more useful tool for relaxation compared with the common practice of neck patting. In the current study, 18 horses were exposed to 3 treatments, including control or no interaction, neck patting, and wither scratching, for 1 min each following a short obstacle course. Heart rate, heart rate variability, and a variety of behaviors were measured in the horses. Wither scratching produced a significantly longer duration of relaxed-type behaviors. Wither scratching could be a useful tool to help a horse relax while under saddle. Additionally, the study identified 2 ear positions that may be useful for future research in horse behavior. PMID- 26958706 TI - Solution-Processed p-Dopant as Interlayer in Polymer Solar Cells. AB - We report here an original approach to dope the semiconducting polymer-metal interface in an inverted bulk-heterojunction (BHJ) organic solar cell. Solution processed 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4-TCNQ), is deposited on top of a P3HT:PC61BM layer before deposition of the top electrode. Doping of P3HT by F4-TCNQ occurs after thermally induced diffusion at 100 degrees C of the latter into the BHJ. Diffusion and doping are evidenced by XPS and UV-vis-NIR absorption. XPS highlights the decrease in Fluorine concentration on top of the BHJ after annealing. In the same time, a charge transfer band attributed to doping is observed in the UV-vis-NIR absorption spectrum. Inverted polymer solar cells using solution-processed F4-TCNQ exhibit power conversion efficiency of nearly 3.5% after annealing. This simple and efficient approach, together with the low annealing temperature required to allow diffusion and doping, leads to standard efficiency P3HT:PC61BM polymer solar cells, which are suitable for printing on plastic flexible substrate. PMID- 26958707 TI - Mental Toughness Moderates Social Loafing in Cycle Time-Trial Performance. AB - PURPOSE: The purpose of this study was to determine if mental toughness moderated the occurrence of social loafing in cycle time-trial performance. METHOD: Twenty seven men (Mage = 17.7 years, SD = 0.6) completed the Sport Mental Toughness Questionnaire prior to completing a 1-min cycling trial under 2 conditions: once with individual performance identified, and once in a group with individual performance not identified. Using a median split of the mental toughness index, participants were divided into high and low mental toughness groups. Cycling distance was compared using a 2 (trial) * 2 (high-low mental toughness) analysis of variance. We hypothesized that mentally tough participants would perform equally well under both conditions (i.e., no indication of social loafing) compared with low mentally tough participants, who would perform less well when their individual performance was not identifiable (i.e., demonstrating the anticipated social loafing effect). RESULTS: The high mental toughness group demonstrated consistent performance across both conditions, while the low mental toughness group reduced their effort in the non-individually identifiable team condition. CONCLUSIONS: The results confirm that (a) clearly identifying individual effort/performance is an important situational variable that may impact team performance and (b) higher perceived mental toughness has the ability to negate the tendency to loaf. PMID- 26958708 TI - Dual-Energy CT of Urate Deposits in Costal Cartilage and Intervertebral Disks of Patients With Tophaceous Gout and Age-Matched Controls. AB - OBJECTIVE: The purpose of this study was to investigate whether monosodium urate (MSU) deposits could be identified within the abdomen and axial skeleton of patients with tophaceous gout using dual-energy CT (DECT). CONCLUSION: DECT of the abdomen, chest wall, and spine revealed extensive MSU deposits in costal cartilages and, to a lesser extent, intervertebral disks in the male patients with gout in our study. These were quantified volumetrically. However, age matched control subjects showed similar deposits, indicating this was not a disease-specific finding. Thus, MSU deposition in the axial skeleton may be physiologic in middle-aged men. PMID- 26958709 TI - The Significance and Challenges of Monocyte Impairment: For the Ill Patient and the Surgeon. AB - BACKGROUND: Trauma, major elective surgery, and overt sepsis can lead to a cascade of immunological change. A subset of these patients will have a degree of immune suppression that leads to hyporesponsive innate defenses, increasing the risk of infective co-morbidity and death. This article is an overview of monocyte impairment in the high-risk surgical patient. Specifically, our primary focus is on observations made pertaining to monocyte function and pathophysiological mechanisms underpinning this impairment. Clinical factors influencing monocyte function are also discussed. METHODS: A Pubmed search was conducted to review aspects of monocyte impairment in the surgical patient. Search terms included "monocyte impairment," "immunoparalysis," and "endotoxin tolerance" cross referenced against terms including "trauma," "major surgery," and "sepsis." RESULTS: Findings revealed a broad variety of monocyte defects reported in surgical patients. They ranged from altered cytokine responses, particularly ex vivo TNF-alpha production, to impaired antigen presentation such as depressed HLA DR expression. The latter is the most commonly described marker of secondary infection and death. Studies of underlying mechanisms have commonly utilized a model of endotoxin tolerance with in vitro monocytes, revealing a complex array of dysregulated pathways. For our purposes, endotoxin tolerance and monocyte impairment are sufficiently similar entities to permit further study as a single subject. In the high risk patient, microRNAs (also referred to as miRNA or miR) are emerging as potential biomarkers that may modify such pathways. Creation of a reliable impaired human monocyte model could be important to all such considerations. CONCLUSION: Impairment of monocyte function continues to be predictive of nosocomial infection, multi-organ failure, and death in some surgical patients. However, the optimal marker that could identify a patient as high risk early enough, and whether it might guide potential therapy, still is yet to be proven. PMID- 26958710 TI - GPCR-Bench: A Benchmarking Set and Practitioners' Guide for G Protein-Coupled Receptor Docking. AB - Virtual screening is routinely used to discover new ligands and in particular new ligand chemotypes for G protein-coupled receptors (GPCRs). To prepare for a virtual screen, we often tailor a docking protocol that will enable us to select the best candidates for further screening. To aid this, we created GPCR-Bench, a publically available docking benchmarking set in the spirit of the DUD and DUD-E reference data sets for validation studies, containing 25 nonredundant high resolution GPCR costructures with an accompanying set of diverse ligands and computational decoy molecules for each target. Benchmarking sets are often used to compare docking protocols; however, it is important to evaluate docking methods not by "retrospective" hit rates but by the actual likelihood that they will produce novel prospective hits. Therefore, docking protocols must not only rank active molecules highly but also produce good poses that a chemist will select for purchase and screening. Currently, no simple objective machine scriptable function exists that can do this; instead, docking hit lists must be subjectively examined in a consistent way to compare between docking methods. We present here a case study highlighting considerations we feel are of importance when evaluating a method, intended to be useful as a practitioners' guide. PMID- 26958712 TI - Forty Years with Emerging Viruses. AB - I was raised in a middle-class family in West Texas and was lucky in my preparation through high school faculty, short government programs arising from the politics of Sputnik, inspiring high school mentors, and university training at a first-rate institution. My educational background led me to apply to medical school. With some financial aid, I managed to graduate and then obtain a first class internal medicine residency at Parkland Hospital, where I acquired skills in discerning evaluation and treatment of patients with complicated diseases. In spite of a liking for and ability in clinical medicine, I entered the Public Health Service and worked for 5 years at the National Institutes of Health laboratory in Panama; there, I began to see the fascination of ecological impacts on virus transmission in nature and its spillover into human populations. I shifted my interests to these themes and their interaction with viral pathogenesis. At each stage of my career, I picked an institution to work where there were strong leaders and other inspiring scientists. I think the young scientist should choose the best available institution and one that offers a career direction that leads to a life where he or she awakens and cannot wait to arrive at his or her job-regardless of the details of each choice, the outcome will be a satisfied person who will contribute greatly to his or her chosen field. PMID- 26958713 TI - Inventing Viruses. AB - In the nineteenth century, "virus" commonly meant an agent (usually unknown) that caused disease in inoculation experiments. By the 1890s, however, some disease causing agents were found to pass through filters that retained the common bacteria. Such an agent was called "filterable virus," the best known being the virus that caused tobacco mosaic disease. By the 1920s there were many examples of filterable viruses, but no clear understanding of their nature. However, by the 1930s, the term "filterable virus" was being abandoned in favor of simply "virus," meaning an agent other than bacteria. Visualization of viruses by the electron microscope in the late 1930s finally settled their particulate nature. This article describes the ever-changing concept of "virus" and how virologists talked about viruses. These changes reflected their invention and reinvention of the concept of a virus as it was revised in light of new knowledge, new scientific values and interests, and new hegemonic technologies. PMID- 26958714 TI - PHIRE and TWiV: Experiences in Bringing Virology to New Audiences. AB - Virology encompasses a broad spectrum of topics touching upon many aspects of our everyday lives. However, appreciation of this impact is too often restricted to those who have specialized training and participate in virology research. The Phage Hunters Integrating Research and Education (PHIRE) program and the This Week in Virology (TWiV) podcast seek to bring virology to new audiences through two different approaches-direct involvement of undergraduates in discovering and genomically characterizing bacteriophages (PHIRE) and clear, accessible, and free discussions among experts of all topics in virology (TWiV). Here we discuss these two high-impact programs, the audiences that they serve, their broader impacts, and their future potential. PMID- 26958715 TI - Role of the Vector in Arbovirus Transmission. AB - Many arboviral diseases are uncontrolled, and the viruses that cause them are globally emerging or reemerging pathogens that produce significant disease throughout the world. The increased spread and prevalence of disease are occurring during a period of substantial scientific growth in the vector-borne disease research community. This growth has been supported by advances in genomics and proteomics, and by the ability to genetically alter disease vectors. For the first time, researchers are elucidating the molecular details of vector host-seeking behavior, the susceptibility of disease vectors to arboviruses, the immunological control of infection in disease vectors, and the determinants that facilitate transmission of arboviruses from a vector to a host. These discoveries are facilitating the development of novel strategies to combat arboviral disease, including the release of transgenic mosquitoes harboring dominant lethal genes, the introduction of arbovirus-blocking microbes into mosquito populations, and the development of acquisition- and transmission-blocking therapeutics. Understanding the role of the vector in arbovirus transmission has provided critical practical and theoretical tools to control arboviral disease. PMID- 26958716 TI - Balance and Stealth: The Role of Noncoding RNAs in the Regulation of Virus Gene Expression. AB - In the past two decades, our knowledge of gene regulation has been greatly expanded by the discovery of microRNAs (miRNAs). miRNAs are small (19-24 nt) noncoding RNAs (ncRNAs) found in metazoans, plants, and some viruses. They have been shown to regulate many cellular processes, including differentiation, maintenance of homeostasis, apoptosis, and the immune response. At present, there are over 300 known viral miRNAs encoded by diverse virus families. One well characterized function of some viral miRNAs is the regulation of viral transcripts. Host miRNAs can also regulate viral gene expression. We propose that viruses take advantage of both host and viral ncRNA regulation to balance replication and infectious state (for example, latent versus lytic infection). As miRNA regulation can be reversed upon certain cellular stresses, we hypothesize that ncRNAs can serve viruses as barometers for cellular stress. PMID- 26958717 TI - Thinking Outside the Triangle: Replication Fidelity of the Largest RNA Viruses. AB - When judged by ubiquity, adaptation, and emergence of new diseases, RNA viruses are arguably the most successful biological organisms. This success has been attributed to a defect of sorts: high mutation rates (low fidelity) resulting in mutant swarms that allow rapid selection for fitness in new environments. Studies of viruses with small RNA genomes have identified fidelity determinants in viral RNA-dependent RNA polymerases and have shown that RNA viruses likely replicate within a limited fidelity range to maintain fitness. In this review we compare the fidelity of small RNA viruses with that of the largest RNA viruses, the coronaviruses. Coronaviruses encode the first known viral RNA proofreading exoribonuclease, a function that likely allowed expansion of the coronavirus genome and that dramatically increases replication fidelity and the range of tolerated variation. We propose models for regulation of coronavirus fidelity and discuss the implications of altered fidelity for RNA virus replication, pathogenesis, and evolution. PMID- 26958718 TI - The Placenta as a Barrier to Viral Infections. AB - Throughout pregnancy, the placenta acts as a physical and immunological barrier against the hematogenous transmission of viruses from mother to fetus. Despite this, very little is known regarding the specific mechanisms by which the placenta shields the developing fetus from viral infections or about the strategies utilized by select viruses to bypass and/or weaken the placental barrier. In this review, we summarize studies regarding virus-host interactions at the placental interface and explore key areas for future investigation. We focus our review on placental trophoblasts, which form the barrier between maternal and fetal circulations and thus govern the cross talk between the maternal and fetal microenvironments. PMID- 26958720 TI - Mechanisms of Virus Membrane Fusion Proteins. AB - Enveloped viruses infect host cells by a membrane fusion reaction that takes place at the cell surface or in intracellular compartments following virus uptake. Fusion is mediated by the membrane interactions and conformational changes of specialized virus envelope proteins termed membrane fusion proteins. This article discusses the structures and refolding reactions of specific fusion proteins and the methods for their study and highlights outstanding questions in the field. PMID- 26958721 TI - Herpesvirus Genome Integration into Telomeric Repeats of Host Cell Chromosomes. AB - It is well known that numerous viruses integrate their genetic material into host cell chromosomes. Human herpesvirus 6 (HHV-6) and oncogenic Marek's disease virus (MDV) have been shown to integrate their genomes into host telomeres of latently infected cells. This is unusual for herpesviruses as most maintain their genomes as circular episomes during the quiescent stage of infection. The genomic DNA of HHV-6, MDV, and several other herpesviruses harbors telomeric repeats (TMRs) that are identical to host telomere sequences (TTAGGG). At least in the case of MDV, viral TMRs facilitate integration into host telomeres. Integration of HHV-6 occurs not only in lymphocytes but also in the germline of some individuals, allowing vertical virus transmission. Although the molecular mechanism of telomere integration is poorly understood, the presence of TMRs in a number of herpesviruses suggests it is their default program for genome maintenance during latency and also allows efficient reactivation. PMID- 26958722 TI - Viral Manipulation of Plant Host Membranes. AB - Plant viruses, like animal viruses, induce the formation of novel intracellular membranous structures that provide an optimum environment for coordinating diverse viral processes such as viral RNA synthesis and virus egress. Membrane reshaping is accomplished by the expression of specific membrane-associated viral proteins that interact with host proteins involved in membrane trafficking processes. Plant virus-induced membranous structures are motile, and this intracellular motility is required for the transport of viral RNA from sites of synthesis to plasmodesmata, which are used to move viral RNA from cell to cell. Cellular movement of these virus-induced bodies requires myosin motor activity and is dependent on the secretory pathway. The coupling of membrane-associated replication complexes with virus intra- and intercellular trafficking may explain why viral infection of neighboring cells is established rapidly and efficiently. PMID- 26958723 TI - Glycan Engagement by Viruses: Receptor Switches and Specificity. AB - A large number of viruses, including many human pathogens, bind cell-surface glycans during the initial steps of infection. Viral glycan receptors such as glycosaminoglycans and sialic acid-containing carbohydrates are often negatively charged, but neutral glycans such as histo-blood group antigens can also function as receptors. The engagement of glycans facilitates attachment and entry and, consequently, is often a key determinant of the host range, tissue tropism, pathogenicity, and transmissibility of viruses. Here, we review current knowledge about virus-glycan interactions using representative crystal structures of viral attachment proteins in complex with glycans. We illuminate the determinants of specificity utilized by different glycan-binding viruses and explore the potential of these interactions for switching receptor specificities within or even between glycan classes. A detailed understanding of these parameters is important for the prediction of binding sites where structural information is not available, and is invaluable for the development of antiviral therapeutics. PMID- 26958719 TI - Cytoplasmic RNA Granules and Viral Infection. AB - RNA granules are dynamic cellular structures essential for proper gene expression and homeostasis. The two principal types of cytoplasmic RNA granules are stress granules, which contain stalled translation initiation complexes, and processing bodies (P bodies), which concentrate factors involved in mRNA degradation. RNA granules are associated with gene silencing of transcripts; thus, viruses repress RNA granule functions to favor replication. This article discusses the breadth of viral interactions with cytoplasmic RNA granules, focusing on mechanisms that modulate the functions of RNA granules and that typically promote viral replication. Currently, mechanisms for virus manipulation of RNA granules can be loosely grouped into three nonexclusive categories: (a) cleavage of key RNA granule factors, (b) regulation of PKR activation, and (c) co-opting of RNA granule factors for new roles in viral replication. Viral modulation of RNA granules supports productive infection by inhibiting their gene-silencing functions and counteracting their role in linking stress sensing with innate immune activation. PMID- 26958724 TI - Remarkable Mechanisms in Microbes to Resist Phage Infections. AB - Bacteriophages (phages) specifically infect bacteria and are the most abundant biological entities on Earth. The constant exposure to phage infection imposes a strong selective pressure on bacteria to develop viral resistance strategies that promote prokaryotic survival. Thus, this parasite-host relationship results in an evolutionary arms race of adaptation and counteradaptation between the interacting partners. The evolutionary outcome is a spectrum of remarkable strategies used by the bacteria and phages as they attempt to coexist. These approaches include adsorption inhibition, injection blocking, abortive infection, toxin-antitoxin, and CRISPR-Cas systems. In this review, we highlight the diverse and complementary antiphage systems in bacteria, as well as the evasion mechanisms used by phages to escape these resistance strategies. PMID- 26958725 TI - Polydnaviruses: Nature's Genetic Engineers. AB - Virus-host associations are usually viewed as parasitic, but several studies in recent years have reported examples of viruses that benefit host organisms. The Polydnaviridae are of particular interest because these viruses are all obligate mutualists of insects called parasitoid wasps. Parasitoids develop during their immature stages by feeding inside the body of other insects, which serve as their hosts. Polydnaviruses are vertically transmitted as proviruses through the germ line of wasps but also function as gene delivery vectors that wasps rely upon to genetically manipulate the hosts they parasitize. Here we review the evolutionary origin of polydnaviruses, the organization and function of their genomes, and some of their roles in parasitism. PMID- 26958726 TI - Human Cytomegalovirus: Coordinating Cellular Stress, Signaling, and Metabolic Pathways. AB - Viruses face a multitude of challenges when they infect a host cell. Cells have evolved innate defenses to protect against pathogens, and an infecting virus may induce a stress response that antagonizes viral replication. Further, the metabolic, oxidative, and cell cycle state may not be conducive to the viral infection. But viruses are fabulous manipulators, inducing host cells to use their own characteristic mechanisms and pathways to provide what the virus needs. This article centers on the manipulation of host cell metabolism by human cytomegalovirus (HCMV). We review the features of the metabolic program instituted by the virus, discuss the mechanisms underlying these dramatic metabolic changes, and consider how the altered program creates a synthetic milieu that favors efficient HCMV replication and spread. PMID- 26958727 TI - Vaccine Development as a Means to Control Dengue Virus Pathogenesis: Do We Know Enough? AB - Dengue virus (DENV) is a mosquito-transmitted RNA virus responsible for 390 million infections each year and significant morbidity and mortality throughout tropical and subtropical regions of the world. Efforts to develop a DENV vaccine span 70 years and include the work of luminaries of the virus vaccine field. Although vaccines have been used to reduce the global health burden of other flaviviruses, the unique requirement for a single vaccine to protect against four different groups of dengue viruses, and the link between secondary infections and DENV disease pathogenesis, has limited success to date. In this review, we discuss several promising DENV vaccine candidates in clinical trials and assess how recent advances in understanding of DENV biology and immunity may expedite efforts toward the development of safe and effective vaccines. PMID- 26958728 TI - Archaeal Viruses: Diversity, Replication, and Structure. AB - The Archaea-and their viruses-remain the most enigmatic of life's three domains. Once thought to inhabit only extreme environments, archaea are now known to inhabit diverse environments. Even though the first archaeal virus was described over 40 years ago, only 117 archaeal viruses have been discovered to date. Despite this small number, these viruses have painted a portrait of enormous morphological and genetic diversity. For example, research centered around the various steps of the archaeal virus life cycle has led to the discovery of unique mechanisms employed by archaeal viruses during replication, maturation, and virion release. In many instances, archaeal virus proteins display very low levels of sequence homology to other proteins listed in the public database, and therefore, structural characterization of these proteins has played an integral role in functional assignment. These structural studies have not only provided insights into structure-function relationships but have also identified links between viruses across all three domains of life. PMID- 26958729 TI - AAV-Mediated Gene Therapy for Research and Therapeutic Purposes. AB - Adeno-associated virus (AAV) is a small, nonenveloped virus that was adapted 30 years ago for use as a gene transfer vehicle. It is capable of transducing a wide range of species and tissues in vivo with no evidence of toxicity, and it generates relatively mild innate and adaptive immune responses. We review the basic biology of AAV, the history of progress in AAV vector technology, and some of the clinical and research applications where AAV has shown success. PMID- 26958730 TI - Three-Dimensional Imaging of Viral Infections. AB - Three-dimensional (3D) imaging technologies are beginning to have significant impact in the field of virology, as they are helping us understand how viruses take control of cells. In this article we review several methodologies for 3D imaging of cells and show how these technologies are contributing to the study of viral infections and the characterization of specialized structures formed in virus-infected cells. We include 3D reconstruction by transmission electron microscopy (TEM) using serial sections, electron tomography, and focused ion beam scanning electron microscopy (FIB-SEM). We summarize from these methods selected contributions to our understanding of viral entry, replication, morphogenesis, egress and propagation, and changes in the spatial architecture of virus-infected cells. In combination with live-cell imaging, correlative microscopy, and new techniques for molecular mapping in situ, the availability of these methods for 3D imaging is expected to provide deeper insights into understanding the structural and dynamic aspects of viral infection. PMID- 26958731 TI - Live Cell Imaging of Retroviral Entry. AB - Cellular entry of retroviruses is the first critical stage of retroviral replication. Live cell imaging has been utilized to visualize the dynamics, localization, and kinetics of the viral fusion process. Here, we review the different methodologies used for live cell imaging and how the use of these techniques has better elucidated the viral entry process of avian sarcoma and leukosis virus (ASLV) and human immunodeficiency virus type 1 (HIV-1) as well as cell-to-cell transmission of retroviruses. Although some controversies remain, further development of these techniques will provide new insights into the process and dynamics of retroviral fusion in vivo. PMID- 26958732 TI - Parvoviruses: Small Does Not Mean Simple. AB - Parvoviruses are small, rugged, nonenveloped protein particles containing a linear, nonpermuted, single-stranded DNA genome of ~5 kb. Their limited coding potential requires optimal adaptation to the environment of particular host cells, where entry is mediated by a variable program of capsid dynamics, ultimately leading to genome ejection from intact particles within the host nucleus. Genomes are amplified by a continuous unidirectional strand-displacement mechanism, a linear adaptation of rolling circle replication that relies on the repeated folding and unfolding of small hairpin telomeres to reorient the advancing fork. Progeny genomes are propelled by the viral helicase into the preformed capsid via a pore at one of its icosahedral fivefold axes. Here we explore how the fine-tuning of this unique replication system and the mechanics that regulate opening and closing of the capsid fivefold portals have evolved in different viral lineages to create a remarkably complex spectrum of phenotypes. PMID- 26958733 TI - Naked Viruses That Aren't Always Naked: Quasi-Enveloped Agents of Acute Hepatitis. AB - Historically, viruses were considered to be either enveloped or nonenveloped. However, recent work on hepatitis A virus and hepatitis E virus challenges this long-held tenet. Whereas these human pathogens are shed in feces as naked nonenveloped virions, recent studies indicate that both circulate in the blood completely masked in membranes during acute infection. These membrane-wrapped virions are as infectious as their naked counterparts, although they do not express a virally encoded protein on their surface, thus distinguishing them from conventional enveloped viruses. The absence of a viral fusion protein implies that these quasi-enveloped virions have unique mechanisms for entry into cells. Like true enveloped viruses, however, these phylogenetically distinct viruses usurp components of the host ESCRT system to hijack host cell membranes and noncytolytically exit infected cells. The membrane protects these viruses from neutralizing antibodies, facilitating dissemination within the host, whereas nonenveloped virions shed in feces are stable in the environment, allowing for epidemic transmission. PMID- 26958734 TI - In Vitro Assembly of Retroviruses. AB - Assembly, part of the late stages of the retroviral life cycle, begins when the structural polyprotein Gag associates with viral genomic RNA. Ultimately, more than a thousand Gag molecules form a spherical immature virion. Maturation takes place soon after or concomitantly with virus budding and is initiated as Gag is cleaved by the retroviral protease into its constituent protein domains. The immature core is thought to disassemble and the liberated CA proteins to reassemble into a morphologically distinct mature capsid. In vitro assembly with derivatives of Gag and CA has been used to study retroviruses for over two decades. In this review, we examine the discovery and development of three major model systems [human immunodeficiency virus type 1 (HIV-1), Rous sarcoma virus (RSV), and Mason-Pfizer monkey virus (MPMV)] and discuss structural features and aspects of the retroviral assembly pathway that have been uncovered using in vitro assembly. We also put forward two major unresolved questions in the field and propose future avenues of research. PMID- 26958735 TI - The Impact of Mass Spectrometry-Based Proteomics on Fundamental Discoveries in Virology. AB - In recent years, mass spectrometry has emerged as a core component of fundamental discoveries in virology. As a consequence of their coevolution, viruses and host cells have established complex, dynamic interactions that function either in promoting virus replication and dissemination or in host defense against invading pathogens. Thus, viral infection triggers an impressive range of proteome changes. Alterations in protein abundances, interactions, posttranslational modifications, subcellular localizations, and secretion are temporally regulated during the progression of an infection. Consequently, understanding viral infection at the molecular level requires versatile approaches that afford both breadth and depth of analysis. Mass spectrometry is uniquely positioned to bridge this experimental dichotomy. Its application to both unbiased systems analyses and targeted, hypothesis-driven studies has accelerated discoveries in viral pathogenesis and host defense. Here, we review the contributions of mass spectrometry-based proteomic approaches to understanding viral morphogenesis, replication, and assembly and to characterizing host responses to infection. PMID- 26958736 TI - Viruses and the DNA Damage Response: Activation and Antagonism. AB - Viruses must interact with their hosts in order to replicate; these interactions often provoke the evolutionarily conserved response to DNA damage, known as the DNA damage response (DDR). The DDR can be activated by incoming viral DNA, during the integration of retroviruses, or in response to the aberrant DNA structures generated upon replication of DNA viruses. Furthermore, DNA and RNA viral proteins can induce the DDR by promoting inappropriate S phase entry, by modifying cellular DDR factors directly, or by unintentionally targeting host DNA. The DDR may be antiviral, although viruses often require proximal DDR activation of repair and recombination factors to facilitate replication as well as downstream DDR signaling suppression to ensure cell survival. An unintended consequence of DDR attenuation during infection is the long-term survival and proliferation of precancerous cells. Therefore, the molecular basis for DDR activation and attenuation by viruses remains an important area of study that will likely provide key insights into how viruses have evolved with their hosts. PMID- 26958737 TI - Hydroxymethylation beyond Carbonylation: Enantioselective Iridium-Catalyzed Reductive Coupling of Formaldehyde with Allylic Acetates via Enantiotopic pi Facial Discrimination. AB - Chiral iridium complexes modified by SEGPHOS catalyze the 2-propanol-mediated reductive coupling of branched allylic acetates 1a-1o with formaldehyde to form primary homoallylic alcohols 2a-2o with excellent control of regio- and enantioselectivity. These processes, which rely on enantiotopic pi-facial discrimination of sigma-allyliridium intermediates, represent the first examples of enantioselective formaldehyde C-C coupling beyond aldol addition. PMID- 26958738 TI - Zika Virus Associated with Meningoencephalitis. PMID- 26958739 TI - Stepwise endoscopic resection of a large gastric lipoma causing gastric outlet obstruction and GI bleeding. PMID- 26958740 TI - An assessment of the ship drag penalty arising from light calcareous tubeworm fouling. AB - A test coupon coated with light calcareous tubeworm fouling was scanned, scaled and reproduced for wind-tunnel testing to determine the equivalent sand grain roughness ks. It was found that this surface had a ks = 0.325 mm, substantially less than the previously reported values for light calcareous fouling. This result was used to predict the drag on a fouled full scale ship. To achieve this, a modified method for predicting the total drag of a spatially developing turbulent boundary layer (TBL), such as that on the hull of a ship, is presented. The method numerically integrates the skin friction over the length of the boundary layer, assuming an analytical form for the mean velocity profile of the TBL. The velocity profile contains the roughness (fouling) information, such that the prediction requires only an input of ks, the free-stream velocity (ship speed), the kinematic viscosity and the length of the boundary layer (the hull length). Using the equivalent sandgrain roughness height determined from experiments, a FFG-7 Oliver Perry class frigate is predicted to experience a 23% increase in total resistance at cruise, if its hull is coated in light calcareous tubeworm fouling. A similarly fouled very large crude carrier would experience a 34% increase in total resistance at cruise. PMID- 26958741 TI - Transition-Metal-Free Cyclopropanation of 2-Aminoacrylates with N Tosylhydrazones: A General Route to Cyclopropane alpha-Amino Acid with Contiguous Quaternary Carbon Centers. AB - Cyclopropanation of 2-aminoacrylates with N-tosylhydrazones could proceed smoothly under transition-metal-free conditions via a [3 + 2] cycloaddition process. This robust protocol exhibits excellent generality, delivering a wide spectrum of cyclopropane alpha-amino acid esters bearing contiguous quaternary carbon centers in high yields and diastereoselectivities. With these readily available products, the steric convergence of cyclopropane alpha-amino acids could be readily obtained. PMID- 26958742 TI - A Study to Determine the Most Popular Lifestyle Smartphone Applications and Willingness of the Public to Share Their Personal Data for Health Research. AB - INTRODUCTION: Smartphone lifestyle applications (apps) and wearable fitness tracking devices collect a wealth of data that could provide research insights to support prevention and treatment of obesity and chronic diseases. The aim of this study was to pilot a survey to explore patterns of behavioral tracking using smartphone lifestyle apps and individuals' willingness to share their app generated data. METHODS: A cross-sectional Web-based survey was conducted within a university setting. The 35-item survey asked participants about their self tracking patterns; use of lifestyle apps and wearable devices; how their self tracked health data could be useful to them; and any restrictions they would impose on sharing personal data. Responses were tabulated and analyzed for trends. RESULTS: The survey was completed by 101 participants. On average, 3.1 (standard deviation [SD] +/-1.9) health and fitness apps were installed by current app users (n = 85), with MyFitnessPal, MapMyRun, Nike+, and Fitbit being most popular. Most participants were willing to share their personal health data for research (77%). Those who did not normally share their health-tracking data were more likely than sharers to be concerned about privacy (odds ratio [OR] = 5.93; 95% confidence interval [95% CI] = 2.09-16.78), as were those not identifying with the quantified-self movement compared with those who were (OR = 5.04; 95% CI = 1.64-15.50). DISCUSSION: Participants were generally willing to share personal data, thus increasing the potential for these data to inform public health research and for use in targeted personalized program and intervention development. CONCLUSIONS: Opportunities for partnerships between researchers and commercial app developers or industry could improve public health research and practice. PMID- 26958743 TI - Changes in Gait with Anteriorly Added Mass: A Pregnancy Simulation Study. AB - During pregnancy, the female body experiences structural changes, such as weight gain. As pregnancy advances, most of the additional mass is concentrated anteriorly on the lower trunk. The purpose of this study is to analyze kinematic and kinetic changes when load is added anteriorly to the trunk, simulating a physical change experienced during pregnancy. Twenty healthy females walked on a treadmill while wearing a custom made pseudo-pregnancy sac (1 kg) under 3 load conditions: sac-only condition, 10-lb condition (4.535 kg added anteriorly), and 20-lb condition (9.07 kg added anteriorly), used to simulate pregnancy in the second trimester and at full-term pregnancy, respectively. The increase in anterior mass resulted in kinematic changes at the knee, hip, pelvis, and trunk in the sagittal and frontal planes. In addition, ankle, knee, and hip joint moments normalized to baseline mass increased with increased load; however, these moments decreased when normalized to total mass. These kinematic and kinetic changes may suggest that women modify gait biomechanics to reduce the effect of added load. Furthermore, the increase in joint moments increases stress on the musculoskeletal system and may contribute to musculoskeletal pain. PMID- 26958744 TI - Detection of CTX-M-15-Producing Escherichia coli Isolates of Lineages ST131-B2 and ST167-A in Environmental Samples of a Tunisian Hospital. AB - To investigate the possible role of the hospital environment in the dissemination of extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli isolates, 300 samples were taken during 2013 from abiotic surfaces (n = 250), healthcare worker hands (n = 27), and hands of patients (n = 23) in a Tunisian Hospital. ESBL-producing E. coli isolates were recovered in 3.7% of analyzed samples (4% abiotic surfaces; 4.3% hands of patients; 0% in healthcare worker hands), and one isolate/sample was further studied. The characterization of beta-lactamase genes, as well as the genetic environment of blaCTX-M gene, was performed by PCR and sequencing. The ESBL genes found were as follows: blaCTX-M-15 (eight isolates), blaCTX-M-15+blaSHV-12 (two isolates), and blaSHV-12 (one isolate). The blaTEM-1b gene was detected in seven ESBL-positive isolates. The orf477 was found downstream of blaCTX-M-15 gene in 10 strains, whereas the ISEcp1 sequence was identified upstream of this gene in two isolates. The analysis of class 1 integrons by PCR and sequencing revealed five positive isolates with the following gene cassette arrangements: dfrA1-aadA1 (two isolates), aadA1 (two isolates), and aadA2 (one isolate). The virulence-encoding genes aer, eae, bfp, and hly were detected by PCR in six, four, four, and three isolates, respectively. The following sequence types and associated phylogroups were detected among ESBL-producing strains: ST167-phylogroup-A (six isolates) and ST131-phylogroup-B2 (two isolates). In conclusion, the hospital environment could be a reservoir of multiresistant bacteria, including ESBL-positive E. coli isolates, which could be acquired by the patient population, and strict control measures should be established to minimize this problem. PMID- 26958745 TI - 4-Phenylbutyric Acid Reveals Good Beneficial Effects on Vital Organ Function via Anti-Endoplasmic Reticulum Stress in Septic Rats. AB - OBJECTIVES: Sepsis and septic shock are the common complications in ICUs. Vital organ function disorder contributes a critical role in high mortality after severe sepsis or septic shock, in which endoplasmic reticulum stress plays an important role. Whether anti-endoplasmic reticulum stress with 4-phenylbutyric acid is beneficial to sepsis and the underlying mechanisms are not known. DESIGN: Laboratory investigation. SETTING: State Key Laboratory of Trauma, Burns and Combined Injury. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: Using cecal ligation and puncture-induced septic shock rats, lipopolysaccharide-treated vascular smooth muscle cells, and cardiomyocytes, effects of 4-phenylbutyric acid on vital organ function and the relationship with endoplasmic reticulum stress and endoplasmic reticulum stress-mediated inflammation, apoptosis, and oxidative stress were observed. MEASUREMENTS AND MAIN RESULTS: Conventional treatment, including fluid resuscitation, vasopressin, and antibiotic, only slightly improved the hemodynamic variable, such as mean arterial blood pressure and cardiac output, and slightly improved the vital organ function and the animal survival of septic shock rats. Supplementation of 4-phenylbutyric acid (5 mg/kg; anti-endoplasmic reticulum stress), especially administered at early stage, significantly improved the hemodynamic variables, vital organ function, such as liver, renal, and intestinal barrier function, and animal survival in septic shock rats. 4-Phenylbutyric acid application inhibited the endoplasmic reticulum stress and endoplasmic reticulum stress-related proteins, such as CCAAT/enhancer binding protein homologous protein in vital organs, such as heart and superior mesenteric artery after severe sepsis. Further studies showed that 4 phenylbutyric acid inhibited endoplasmic reticulum stress-mediated cytokine release, apoptosis, and oxidative stress via inhibition of nuclear factor-kappaB, caspase-3 and caspase-9, and increasing glutathione peroxidase and superoxide dismutase expression, respectively. CONCLUSIONS: Anti-endoplasmic reticulum stress with 4-phenylbutyric acid is beneficial to septic shock. This beneficial effect of 4-phenylbutyric acid is closely related to the inhibition of endoplasmic reticulum stress-mediated oxidative stress, apoptosis, and cytokine release. This finding provides a potential therapeutic measure for clinical critical conditions, such as severe sepsis. PMID- 26958747 TI - A Review of the Perceptions of Healthcare Providers and Family Members Toward Family Involvement in Active Adult Patient Care in the ICU. AB - OBJECTIVE: The objective of this article is to provide a summary of the perceptions of healthcare providers and family members toward their role in active patient care in the ICU and compare the views of healthcare providers with those of relatives of critically ill patients. DATA SOURCES: The search was conducted using PubMed as the primary search engine and EMBASE as a secondary search engine. STUDY SELECTION: Studies were included if they were conducted in the ICU, had an adult patient population, and contained a discussion of active patient care, including perspective or actions of family members or healthcare providers about the active participation. DATA EXTRACTION: Titles and abstracts of articles identified through PubMed and EMBASE were assessed for relevancy of family involvement. The full article was reviewed of titles and abstracts involving family involvement of care in the ICU to assess if the topic was active care and if the article involved perceptions of healthcare providers or family members. The references of all selected articles were then evaluated for the inclusion of additional studies. DATA SYNTHESIS: Articles including perceptions of healthcare providers were grouped separately from articles including attitudes of family members. Articles that contained the perceptions of both healthcare providers and family members were considered in both groups but were evaluated with each perspective separately. Examples of specific patient care tasks that were mentioned in each article were identified. CONCLUSIONS: A positive attitude exists among both family members and providers toward the involvement of family members in active care tasks. Providers and family members share the attitude that a partnership is necessary and that encouragement for family members to participate is essential. The findings in this review support the need for more objective research regarding how families are caring for their loved ones and how family involvement in care is affecting patient and family outcomes. PMID- 26958748 TI - How Long Does (S)He Have? Retrospective Analysis of Outcomes After Palliative Extubation in Elderly, Chronically Critically Ill Patients. AB - OBJECTIVE: For chronically critically ill elderly patients on mechanical ventilation, prognosis for significant recovery may be minimal. These individuals, or their surrogates, may decide for "palliative extubation." A common prognostic question arises: "How long does she/he have?" This study describes demographics, mortality, time to death, and factors associated with death after palliative extubation. DESIGN, SETTING, AND PATIENTS: Retrospective 3 year study in community hospital with ethnically diverse elderly population. Chronically critically ill patients followed from palliative extubation to death or survival to discharge. MEASURES: Mortality/survival following palliative extubation, time to death or discharge, factors associated with death. RESULTS: Hundred and forty-eight subjects underwent palliative extubation. Mean age: 78 years, 60% female, ethnically diverse with 46% white, and 54% others. Top diagnostic categories: sepsis (47%) and respiratory failure (22%). After extubation, 114 patients (77%) died in hospital and 34 (23%) were discharged. Of those who died, median time to death 8.9 hours (range, 4 min to 7 d). Mortality proportion was 56% at 24 hours and increased with time. Factors associated with early death: Systolic blood pressure less than 90 (p = 0.002) and Charlson Comorbidity Index that is above 6 or 0 (p = 0.002). CONCLUSIONS: Palliative extubation at end of life was an option selected by an ethnically diverse elderly population. Approximately three-fourths of subjects died in hospital, and one fourth was discharged alive. Over 50% who died did so within 24 hours, making this useful information for counseling and anticipatory planning. Subjects with systolic blood pressure less than 90 and Charlson Comorbidity Index that is very low or very high had higher mortality. PMID- 26958749 TI - Pharmacological Therapy for the Prevention and Treatment of Weakness After Critical Illness: A Systematic Review. AB - OBJECTIVES: ICU-acquired weakness is a common complication of critical illness and can have significant effects upon functional status and quality of life. As part of preliminary work to inform the design of a randomized trial of a complex intervention to improve recovery from critical illness, we sought to identify pharmacological interventions that may play a role in this area. DATA SOURCES: We systematically reviewed the published literature relating to pharmacological intervention for the treatment and prevention of ICU-acquired weakness. STUDY SELECTION: We searched MEDLINE, EMBASE, CINAHL+, Web of Science, and both U.S. and European trial registries up to July 2014 alongside reviews and reference lists from populations with no age or language restrictions. We included studies that reported a measure of muscle structure or physical function as an outcome measure. DATA EXTRACTION: We estimated pooled odds ratios and 95% CI using data extracted from published articles or where available, original data provided by the authors. Assessment of bias was performed using the Cochrane Collaboration's risk of bias tool. DATA SYNTHESIS: Ten studies met the inclusion criteria. The current body of evidence does not support the use of any pharmacological agent in this setting, although maintaining euglycemia may reduce the prevalence of critical illness polyneuropathy. CONCLUSIONS: At present, no pharmacological intervention can be recommended to prevent or treat ICU-acquired weakness. Further research is required into this field to include more novel agents such as myostatin inhibitors. Challenges in the conduct of research in this area are highlighted. PMID- 26958750 TI - Prediction of Large Vessel Occlusions in Acute Stroke: National Institute of Health Stroke Scale Is Hard to Beat. AB - OBJECTIVES: Endovascular treatment for acute ischemic stroke with a large vessel occlusion was recently shown to be effective. We aimed to develop a score capable of predicting large vessel occlusion eligible for endovascular treatment in the early hospital management. DESIGN: Retrospective, cohort study. SETTING: Two tertiary, Swiss stroke centers. PATIENTS: Consecutive acute ischemic stroke patients (1,645 patients; Acute STroke Registry and Analysis of Lausanne registry), who had CT angiography within 6 and 12 hours of symptom onset, were categorized according to the occlusion site. Demographic and clinical information was used in logistic regression analysis to derive predictors of large vessel occlusion (defined as intracranial carotid, basilar, and M1 segment of middle cerebral artery occlusions). Based on logistic regression coefficients, an integer score was created and validated internally and externally (848 patients; Bernese Stroke Registry). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Large vessel occlusions were present in 316 patients (21%) in the derivation and 566 (28%) in the external validation cohort. Five predictors added significantly to the score: National Institute of Health Stroke Scale at admission, hemineglect, female sex, atrial fibrillation, and no history of stroke and prestroke handicap (modified Rankin Scale score, < 2). Diagnostic accuracy in internal and external validation cohorts was excellent (area under the receiver operating characteristic curve, 0.84 both). The score performed slightly better than National Institute of Health Stroke Scale alone regarding prediction error (Wilcoxon signed rank test, p < 0.001) and regarding discriminatory power in derivation and pooled cohorts (area under the receiver operating characteristic curve, 0.81 vs 0.80; DeLong test, p = 0.02). CONCLUSIONS: Our score accurately predicts the presence of emergent large vessel occlusions, which are eligible for endovascular treatment. However, incorporation of additional demographic and historical information available on hospital arrival provides minimal incremental predictive value compared with the National Institute of Health Stroke Scale alone. PMID- 26958751 TI - Prevalence and Characteristics of Chronic Intensive Care-Related Pain: The Role of Severe Sepsis and Septic Shock. AB - OBJECTIVE: There is only limited knowledge about chronic pain conditions resulting from critical care. Experimental and clinical data suggest a close relationship between inflammation and pain perception. Since sepsis is the most severe form of systemic inflammation, the primary objective was to evaluate chronic pain states and functional impairment of septic and nonseptic patients 6 months after discharge from ICU. Second, we aimed to obtain the total prevalence and characteristics of chronic ICU-related pain. DESIGN: Case-control study. SETTING: Observational study in long-term survivors of mixed surgical and medical ICUs. PATIENTS: Septic and nonseptic survivors of critical care (n = 207) and healthy controls (n = 46). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We collected comprehensive information on patients' past and present pain 6 months after ICU discharge by means of the German pain questionnaire. Pain intensity levels and pain interference ratings were compared between septic and nonseptic patients and healthy controls. We found no differences in prevalence, severity, and interference of pain between septic and nonseptic patients. However, both patient groups differed significantly from controls. In secondary analysis, a third of all patients reported chronic clinically relevant pain associated with the ICU stay 6 months after ICU discharge. Half of these patients experienced chronic pain conditions before ICU admission and reported additional sources of pain. Most important, 16% of all patients had no preexisting pain condition and now experience chronic ICU-related pain. The majority of patients with chronic ICU-related pain reported a high degree of disabling pain, limiting daily activities. CONCLUSIONS: A high percentage of former ICU patients develop chronic pain conditions associated with critical care. These patients differ significantly from control data in terms of pain intensity and show high levels of interference with pain. The presence of sepsis per se seems to play a marginal role for the development of chronic ICU-related pain. PMID- 26958752 TI - Admission Hyperglycemia in Critically Ill Sepsis Patients: Association With Outcome and Host Response. AB - OBJECTIVES: To investigate whether admission hyperglycemia is associated with the presentation and/or outcome of sepsis, what the influence of hyperglycemia is on key host responses to sepsis, and whether hyperglycemia differentially affects patients with diabetes mellitus. DESIGN AND SETTING: A substudy of a prospective observational cohort study was conducted in the intensive care of two tertiary hospitals between January 2011 and July 2013. PATIENTS: Of all consecutive critically ill sepsis patients, admission glucose was used to stratify patients in euglycemia (71-140 mg/dL), mild hyperglycemia (141-199 mg/dL), and severe hyperglycemia (>= 200 mg/dL), and patients with hypoglycemia were excluded. Fifteen plasma biomarkers providing insight in key host responses implicated in sepsis pathogenesis were measured on admission. MEASUREMENTS AND MAIN RESULTS: Of 987 sepsis patients with admission glucose levels greater than 70 mg/dL, 519 (52.6%) had normal glucose levels, 267 (27.1%) had mild, and 201 (20.4%) severe hyperglycemia. Admission hyperglycemia was accompanied by mitigated alterations in plasma host response biomarker levels indicative of activation of the cytokine network, the vascular endothelium, and the coagulation system in patients without a history of diabetes. Severe, but not mild, admission hyperglycemia was associated with increased 30-day mortality (adjusted hazard ratio, 1.66 [95% CI, 1.24-2.23]), in both patients without diabetes (adjusted hazard ratio, 1.65 [95% CI, 1.12-2.42]) and with diabetes (adjusted hazard ratio, 1.91 [95% CI, 1.01 3.62]). CONCLUSION: Admission hyperglycemia is associated with adverse outcome of sepsis irrespective of the presence or absence of preexisting diabetes by a mechanism unrelated to exaggerated inflammation or coagulation. PMID- 26958783 TI - The effect of age on peripheral stem cell mobilization in healthy donors, single center experience. AB - PURPOSE: Peripheral stem cell transplantation is used as a life-saving therapeutic option in hematological malignancies. As previously established, most hematological malignancies are seen in the elderly population. Therefore, possible HLA-identical sibling donors of elderly patients are generally of an advanced age. In this study, we aimed to evaluate the effect of old age on stem cell mobilization and quality in older adult healthy sibling donors. MATERIALS AND METHODS: Between 2006 and 2014, we evaluated 38 healthy donors aged >=55 years. The granulocyte-colony stimulating factor (G-CSF) analogs were used at a dose of 5 ug/kg/day and administered subcutaneously twice a day for five days. CD34+ cells were estimated in the peripheral blood before collection of the apheresis product. The National Marrow Donor Program selects healthy unrelated donors if they are younger than 60 years. Therefore, we compared the product quality in donors over the age of 60 to that in donors aged 60 years or less. RESULTS: We collected sufficient products from all the donors with one to three apheresis procedures. No serious complication was detected in all donors. Reaching the target CD34+ cell count in one day were detected in 83% of younger and 79% of older donors (P = NS). Collected CD34+ cells x10e6/recipient body weight (kg) was same and 5.1 in the groups (P = NS). There were no correlation between the donor age and these parameters. CONCLUSION: Healthy donor apheresis in older adults can be performed effectively and possible donors should be evaluated regardless of their age. J. Clin. Apheresis 32:16-20, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26958784 TI - Mutagenicity of N-acyloxy-N-alkoxyamides as an indicator of DNA intercalation part 1: evidence for naphthalene as a DNA intercalator. AB - N-Acyloxy-N-alkoxyamides are direct-acting mutagens in S. typhimurium TA100 with a linear dependence upon log P that maximises at log P0 = 6.4. Eight N-acyloxy-N alkoxyamides (2-9) bearing a naphthalene group on any of the three side-chains and with log P0 < 6.4 have been demonstrated to be significantly and uniformly more mutagenic towards S. typhimurium TA100 than 50 mutagens without naphthalene. The activity enhancement of 2-9 is likely due to intercalative binding of naphthalene to bacterial DNA as a number are also active in TA98, a frame-shift strain of S. typhimurium, which is modified by intercalators. DNA damage profiles for naphthalene-bearing mutagens confirm enhanced reactivity with DNA when naphthalene is incorporated and a different binding mode when compared to mutagens without naphthalene. The effect is independent of whether the naphthalene is attached to an electron-donating alkyl or electron-withdrawing acyl group, alkyl tether length or, in the case of 6 and 7, the point of attachment to naphthalene. A new quantitative structure activity relationship has been constructed for all 58 congeners incorporating log P and an indicator variable, I, for the presence (I = 1) or absence (I = 0) of naphthalene and from which the activity enhancing effect of a naphthalene has been quantified at between three and four log P units. Contrary to conventional views, simple naphthalene groups could target molecules to DNA through intercalation. PMID- 26958785 TI - Observation of the nearly constant loss in super rigid saccharides: in search of a hidden crossover in dynamics deep in the glassy state. AB - The molecular dynamics of three saccharides: D-glucose, 1,6-anhydro-D-glucose (levoglucosan) and 1,6:2,3-dianhydro-beta-D-mannopyranose of various degrees of freedom, number of hydroxyl groups and internal structures was investigated over a wide range of temperatures and frequencies by means of Broadband Dielectric Spectroscopy (BDS). Despite the pronounced variety in the physicochemical properties of the carbohydrates, no change in the shape of the structural relaxation process was observed in the vicinity of the glass transition temperature (beta(KWW) = 0.5). On the other hand further studies of the Debye Stokes-Einstein relationship between dc conductivity and structural dynamics revealed some significant changes connected with the ability to form strong H bonded structures. Moreover the presence of nearly constant loss (NCL) at moderate frequencies and just below the T(g) in the glassy state of levoglucosan and 1,6:2,3-dianhydro-beta-D-mannopyranose was noticeable. We followed the temperature evolution of epsilon'' located at frequencies f = 0.1 kHz and f = 1 kHz, where the NCL is detected. Interestingly, a clear change in the dynamics far below the glass transition was observed in both compounds. This crossover (T(c)), found in different materials, and studied by various experimental techniques, is usually interpreted as being caused by the freezing of the Johari-Goldstein (JG) relaxation process. Alternatively it can also be due to the increasing anharmonicity in the density of vibrational states. Interestingly, it was shown that the slope of epsilon''(T) measured above the T(c) slightly changes while below the T(c) stays constant after physical aging. This is related to the densification of the sample that might result in steric hindrance and suppression of some kind of motion occurring in the glassy state, involving the larger parts of the molecules. PMID- 26958786 TI - Acute Effects of Drop-Jump Protocols on Explosive Performances of Elite Handball Players. AB - Dello Iacono, A, Martone, D, and Padulo, J. Acute effects of drop-jump protocols on explosive performances of elite handball players. J Strength Cond Res 30(11): 3122-3133, 2016-This study aimed to assess the acute effects of vertical and horizontal drop jump-based postactivation potentiation (PAP) protocols on neuromuscular abilities in tasks such as jumping, sprinting, and change of direction (COD). Eighteen handball players were assessed before and after PAP regimens, consisting of either vertical single-leg drop-jumps (VDJ) or horizontal single-leg drop-jumps (HDJ) single-leg drop-jumps, on countermovement jump (CMJ), linear sprint, shuttle sprint, and agility performance. The HDJ led to greater improvement of the COD performance in comparison with the VDJ (-6.8 vs. -1.3%; p <= 0.05), whereas the VDJ caused greater improvement in the CMJ task compared with the HDJs (+6.5 vs. +1%; p <= 0.05). Moreover, the VDJ regimens compared with HDJ induced greater changes in most of the kinetic variables associated with vertical jumping performance, such as peak ground reaction forces (+9.6 vs. +1.3%), vertical displacement (-13.4 vs. -5.3%), leg-spring stiffness (+18.6 vs. +3.6%), contact time (-9.2 vs. -1.3%), and reactive strength index (+7.3 vs. +2.4%) (all comparisons with p <= 0.05). Conversely, the HDJ regimens were able to improve the COD performance only by reducing the contact time on COD more than the VDJ (-13.3 vs. -2.4% with p <= 0.05). The results showed that both PAPs were able to improve the performances that specifically featured similar force orientation production. This investigation showed the crucial role that different and specific PAP regimens play in optimizing related functional performances. Specifically oriented vertical and horizontal single-leg drop-jump protocols represent viable means for achieving enhanced explosive-based tasks such as jumping and COD. PMID- 26958787 TI - A Bio-Inspired, Heavy-Metal-Free, Dual-Electrolyte Liquid Battery towards Sustainable Energy Storage. AB - Wide-scale exploitation of renewable energy requires low-cost efficient energy storage devices. The use of metal-free, inexpensive redox-active organic materials represents a promising direction for environmental-friendly, cost effective sustainable energy storage. To this end, a liquid battery is designed using hydroquinone (H2BQ) aqueous solution as catholyte and graphite in aprotic electrolyte as anode. The working potential can reach 3.4 V, with specific capacity of 395 mA h g(-1) and stable capacity retention about 99.7% per cycle. Such high potential and capacity is achieved using only C, H and O atoms as building blocks for redox species, and the replacement of Li metal with graphite anode can circumvent potential safety issues. As H2BQ can be extracted from biomass directly and its redox reaction mimics the bio-electrochemical process of quinones in nature, using such a bio-inspired organic compound in batteries enables access to greener and more sustainable energy-storage technology. PMID- 26958788 TI - Endovascular treatment of symptomatic Budd-Chiari syndrome - in favour of early transjugular intrahepatic portosystemic shunt. AB - INTRODUCTION: Treatment of Budd-Chiari syndrome (BCS) has shifted from mainly medical treatment, with surgical shunt and orthotopic liver transplantation (OLT) as rescue, to medical treatment combined with an early endovascular intervention in the past two decades. PURPOSE: To assess the safety and efficiency of endovascular treatment of symptomatic patients with BCS and to compare mortality with symptomatic BCS patients in the same region treated with only sporadic endovascular techniques. METHODS: This was a retrospective review of clinical data, treatment and survival in 14 patients diagnosed with BCS and treated with endovascular methods from 2003 to 2015. A national epidemiology study of BCS from 1986 to 2003 was used for comparison. RESULTS: Thirteen of the 14 patients eventually had transjugular intrahepatic portosystemic shunt (TIPS), four after previous liver vein angioplasty. TIPS were performed with polytetrafluoroethylene covered stents and technical success was 100%. Calculated preinterventional prognostic indices indicated a high risk of TIPS dysfunction, OLT and death. However, only one patient died and one had an OLT, and the 1- and 2-year primary TIPS-patency was 85 and 67%, respectively. Episodes of de-novo hepatic encephalopathy occurred in three patients. Overall 1- and 5-year transplantation free survival was 100 and 93% compared with 47 and 28%, respectively, in 1986 to 2003. CONCLUSION: TIPS seems to be a safe and effective treatment for symptomatic BCS and there is an obvious improvement in transplantation-free survival compared with conservatory medical treatment. It should, therefore, be considered early, as first-line intervention, in patients with insufficient response to medical treatment. PMID- 26958789 TI - A novel low-profile ER-REBOA catheter is not fluoroscopy-free. PMID- 26958790 TI - Racial disparities in emergency general surgery: Do differences in outcomes persist among universally insured military patients? AB - BACKGROUND: Racial disparities in surgical care are well described. As many minority patients are also uninsured, increasing access to care is thought to be a viable solution to mitigate inequities. The objectives of this study were to determine whether racial disparities in 30-/90-/180- day outcomes exist within a universally insured population of military-/civilian-dependent emergency general surgery (EGS) patients and ascertain whether differences in outcomes differentially persist in care received at military versus civilian hospitals and among sponsors who are enlisted service members versus officers. It also considered longer-term outcomes of EGS care. METHODS: Five years (2006-2010) of TRICARE data, which provides insurance to active/reserve/retired members of the US Armed Services and dependents, were queried for adults (>=18 years) with primary EGS conditions, defined by the AAST. Risk-adjusted survival analyses assessed race-associated differences in mortality, major acute care surgery related morbidity, and readmission at 30/90/180 days. Models accounted for clustering within hospitals and possible biases associated with missing race using reweighted estimating equations. Subanalyses considered restricted effects among operative interventions, EGS diagnostic categories, and effect modification related to rank and military- versus civilian-hospital care. RESULTS: A total of 101,011 patients were included: 73.5% white, 14.5% black, 4.4% Asian, and 7.7% other. Risk-adjusted survival analyses reported a lack of worse mortality and readmission outcomes among minority patients at 30, 90, and 180 days. Major morbidity was higher among black versus white patients (hazard ratio [95% confidence interval): 30 days, 1.23 [1.13-1.35]; 90 days, 1.18 [1.09-1.28]; and 180 days, 1.15 [1.07-1.24], a finding seemingly driven by appendiceal disorders (hazard ratio, 1.69-1.70). No other diagnostic categories were significant. Variations in military- versus civilian-managed care and in outcomes for families of enlisted service members versus officers altered associations, to some extent, between outcomes and race. CONCLUSIONS: While an imperfect proxy of interventions is directly applicable to the broader United States, the contrast between military observations and reported racial disparities among civilian EGS patients merits consideration. Apparent mitigation of disparities among military-/civilian dependent patients provides an example for which we as a nation and collective of providers all need to strive. The data will help to inform policy within the Department of Defense and development of disparities interventions nationwide, attesting to important differences potentially related to insurance, access to care, and military culture and values. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III. PMID- 26958791 TI - Laparotomy: The conquering of the abdomen and the historical journey of pancreatic and duodenal injuries. PMID- 26958792 TI - Perioperative risk factors impact outcomes in emergency versus nonemergency surgery differently: Time to separate our national risk-adjustment models? AB - BACKGROUND: Emergency surgery (ES) is acknowledged to be riskier than nonemergency surgery (NES). Yet, little is known about the relative impact of individual perioperative risk factors on 30-day outcomes in ES versus NES. METHODS: Using the 2011-2012 American College of Surgeons National Surgical Quality Improvement Program nationwide database, the 20 most common ES procedures were identified by Current Procedural Terminology code. Current Procedural Terminology codes with less than 300 observations in either ES or NES were excluded. Emergency surgery cases were defined as "emergent" and "nonelective" per American College of Surgeons National Surgical Quality Improvement Program criteria. Multivariable regression models were constructed to identify predictors of 30-day major morbidity and mortality (MMM) in each group, controlling for demographics, American Society of Anesthesiologists class, comorbidities, preoperative laboratory values, and procedure type. The odds ratios of independent predictors of MMM in ES and NES were derived then individually compared between the two groups; "effect modification" of procedure status (ES vs. NES) on each risk factor was subsequently calculated. RESULTS: Of 986,034 patients, 170,131 met inclusion criteria (59,949 ES; 110,182 NES). The overall risk of MMM was significantly higher in ES versus NES (16.75% vs. 9.73%, p < 0.001; odds ratio, 1.18; 95% confidence interval, 1.12-1.24; p < 0.001). Of 40 ES and 38 NES-identified independent risk factors, preoperative transfusion and white blood cell count of 4.5 * 10/MUL or less carried significantly higher relative risk of MMM in ES versus NES. Conversely, ascites, preoperative anemia, and white blood cell count of 11 * 10/MUL to 25 * 10/MUL carried greater relative risk for MMM in NES. Four procedures (laparoscopic cholecystectomy, laparotomy, and umbilical and incisional herniorrhaphy) were inherently riskier in ES versus NES. The effect modification of ES (vs. NES) ranged between 0.68 (0.52-0.88) for ascites and 2.56 (1.67-3.92) for umbilical hernia repair. CONCLUSIONS: Perioperative risk factors and procedure type impact postoperative morbidity and mortality differently in ES versus NES. Instead of using the same risk-adjustment model for both ES and NES, as currently practiced, our findings strongly suggest the need to benchmark emergent and elective surgeries separately. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III. PMID- 26958793 TI - The role of the sensor kinase, QseC, an adrenergic receptor of Escherichia coli, in bacterial translocation during hemorrhagic shock. AB - BACKGROUND: Hemorrhagic shock results in ileal mucosa damage and intestinal bacterial translocation. Additionally, during hemorrhagic shock, norepinephrine levels increase. Past research has shown that the QseC sensor kinase of Escherichia coli modulates the quorum-sensing response to epinephrine and norepinephrine. Therefore, the aim of our study was to examine whether the absence of the ability of E. coli to sense epinephrine/norepinephrine would attenuate the bacterial translocation to extraintestinal organs in a rat model of hemorrhagic shock. METHODS: An E. coli MC1000 qseC mutant was constructed, and E. coli MC1000 and MC1000DeltaqseC with streptomycin resistance were used to track bacterial translocation after gavage in rats. A rat model of nonlethal hemorrhagic shock was used. The rats were divided into six groups: controls (SS), rats that received a sham shock and MC1000 (M-SS), rats that received a sham shock and MC1000DeltaqseC (Delta-SS), rats that received a hemorrhagic shock alone (HS), rats that received a hemorrhagic shock and MC1000 (M-HS), and rats that received a hemorrhagic shock and MC1000DeltaqseC (Delta-HS). RESULTS: We found the incidence of bacterial translocation in the M-HS rats was higher than in the Delta-HS rats. The observed effects seem to be largely dependent on the inability to sense epinephrine/norepinephrine and the decreased motility of E. coli MC1000DeltaqseC. CONCLUSION: Therefore, a role for E. coli sensing epinephrine/norepinephrine in the pathophysiology of bacterial translocation following hemorrhagic shock is proposed. The demonstration of such an effect would suggest a new mechanism for the development of shock-induced sepsis. PMID- 26958795 TI - Prevention of fall-related injuries in the elderly: An Eastern Association for the Surgery of Trauma practice management guideline. AB - BACKGROUND: Fall-related injuries among the elderly (age 65 and older) are the cause of nearly 750,000 hospitalizations and 25,000 deaths per year in the United States, yet prevention research is lagging. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, the Eastern Association for the Surgery of Trauma produced this practice management guideline to answer the following injury prevention-related population, intervention, comparator, outcomes (PICO) questions:PICO 1: Should bone mineral-enhancing agents be used to prevent fall-related injuries in the elderly?PICO 2: Should hip protectors be used to prevent fall-related injuries in the elderly?PICO 3: Should exercise programs be used to prevent fall-related injuries in the elderly?PICO 4: Should physical environment modifications be used to prevent fall-related injuries in the elderly?PICO 5: Should risk factor screening be used to prevent fall-related injuries in the elderly?PICO 6: Should multiple interventions tailored to the population or individual be used to prevent fall-related injuries in the elderly? METHODS: A comprehensive search and review of all the available literature was performed. We used the GRADE methodology to assess the breadth and quality of the data specific to our PICO questions. RESULTS: We reviewed 50 articles that met our inclusion and exclusion criteria as they applied to our PICO questions. CONCLUSION: Given the data constraints, we offer the following suggestions and recommendations:PICO 1: We conditionally recommend vitamin D and calcium supplementation for frail elderly individuals.PICO 2: We conditionally recommend hip protectors for frail elderly individuals, in the appropriate environment.PICO 3: We conditionally recommend evidence-based exercise programs for frail elderly individuals.PICO 4: We conditionally recommend physical environment modification for frail elderly people.PICO 5: We conditionally recommend frailty screening for the elderly.PICO 6: We strongly recommend risk stratification with targeted comprehensive risk-reduction strategies tailored to particular high-risk groups. LEVEL OF EVIDENCE: Systematic review, level III. PMID- 26958794 TI - Safety of minimizing preoperative starvation in critically ill and intubated trauma patients. AB - BACKGROUND: Cessation of enteral nutrition prior to an operation/procedure is the most common reason for feeding interruption in critically ill trauma patients and contributes to substantial calorie deficits. This study reports on a strategy to increase calorie intake by continuing feeds until transfer for operations/procedures. METHODS: Nutrition guidelines were modified in 2006 to allow continuation of feeding in intubated patients up until transfer to the operating room. Prior to 2006, enteral feeding was stopped at least 6 hours prior to surgery. A retrospective cohort design from 2003 to 2010 compared clinical outcomes in groups of adult trauma subjects before and after guideline changes and in subjects at other centers without guideline changes. RESULTS: During the first week, subjects in the preimplementation cohort (n = 245) received a median of 3,787 kcal per person per week, while subjects in the postimplementation cohort (n = 368) received a median of 6,662 kcal per person per week (p < 0.001). There was no change in calorie intake for subjects at other centers (n = 1,002). The risks of acute respiratory distress syndrome, pneumonia, and mortality were decreased after implementation relative to the preimplementation cohort (acute respiratory distress syndrome: relative risk ratio [RR], 0.69; 95% confidence interval [CI], 0.59-0.81; pneumonia: RR, 0.82; 95% CI, 0.65-1.00; mortality: RR, 0.67; 95% CI, 0.46-0.99). Ventilator-free days increased by 1.4 days (95% CI, 0.1 2.7), while intensive care unit stay and hospital length of stay were unchanged. These outcomes showed similar trends over time at other participating centers. CONCLUSIONS: Allowing intubated trauma patients to continue enteral nutrition until transfer for operations or procedures was associated with increased caloric intake without evidence of increased pulmonary complications. This represents an important strategy to reduce calorie deficits in the trauma intensive care unit. LEVEL OF EVIDENCE: Therapeutic study/care management, level III. PMID- 26958796 TI - Antibiotics for appendicitis! Not so fast. AB - BACKGROUND: Emerging literature in acute appendicitis favors the nonoperative management of acute appendicitis. However, the actual use of this practice on a national level is not assessed. The aim of this study was to assess the changing trends in nonoperative management of acute appendicitis and its effects on patient outcomes. METHODS: We did an 8-year (2004-2011) retrospective analysis of the National Inpatient Sample database. We included all inpatients with the diagnosis of acute appendicitis. Patients with a diagnosis of appendiceal abscess or patients who underwent surgery for any other pathology were excluded from the analysis. Jonckheere-Terpstra trend analysis was performed for operative versus nonoperative management and outcomes. RESULTS: A total of 436,400 cases of acute appendicitis were identified. Mean age of the population was 33 +/- 19.5 years, and 54.5% were male. There was no significant change in the number of acute appendicitis diagnosed over the study period (p = 0.2). During the study period, nonoperative management of acute appendicitis increased significantly from 4.5% in 2004 to 6% in 2011 (p < 0.001). When compared with operatively managed patients, conservatively managed patients had a significantly longer hospital length of stay (3 [2-6] vs. 2 [1-3] days, p < 0.001), and in-hospital complications (27.8% vs. 7%, p < 0.001). On comparison of open and laparoscopic appendectomy, both had shorter hospital length of stay and rate of in-hospital complications. Overall hospital charges were lower in patients managed conservatively (15,441 [8,070-31,688] vs. 20,062 [13,672-29,928] USD, p < 0.001). CONCLUSIONS: Nonoperative management of appendicitis has increased over time; however, outcomes of nonoperative management did not improve over the study period. A more in-depth analysis of patient and system demographics may reveal this disparity in trends. LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level III. PMID- 26958797 TI - The Military Injury Severity Score (mISS): A better predictor of combat mortality than Injury Severity Score (ISS). AB - BACKGROUND: The Military Injury Severity Score (mISS) was developed to better predict mortality in complex combat injuries but has yet to be validated. METHODS: US combat trauma data from Afghanistan and Iraq from January 1, 2003, to December 31, 2014, from the US Department of Defense Trauma Registry (DoDTR) were analyzed. Military ISS, a variation of the ISS, was calculated and compared with standard ISS scores.Receiver operating characteristic curve, area under the curve, and Hosmer-Lemeshow statistics were used to discriminate and calibrate between mISS and ISS. Wilcoxon-Mann-Whitney, t test and chi tests were used, and sensitivity and specificity calculated. Logistic regression was used to calculate the likelihood of mortality associated with levels of mISS and ISS overall. RESULTS: Thirty thousand three hundred sixty-four patients were analyzed. Most were male (96.8%). Median age was 24 years (interquartile range [IQR], 21-29 years). Battle injuries comprised 65.3%. Penetrating (39.5%) and blunt (54.2%) injury types and explosion (51%) and gunshot wound (15%) mechanisms predominated. Overall mortality was 6.0%.Median mISS and ISS were similar in survivors (5 [IQR, 2-10] vs. 5 [IQR, 2-10]) but different in nonsurvivors, 30 (IQR, 16-75) versus 24 (IQR, 9-23), respectively (p < 0.0001). Military ISS and ISS were discordant in 17.6% (n = 5,352), accounting for 56.2% (n = 1,016) of deaths. Among cases with discordant severity scores, the median difference between mISS and ISS was 9 (IQR, 7-16); range, 1 to 59. Military ISS and ISS shared 78% variability (R = 0.78).Area under the curve was higher in mISS than in ISS overall (0.82 vs. 0.79), for battle injury (0.79 vs. 0.76), non-battle injury (0.87 vs. 0.86), penetrating (0.81 vs. 0.77), blunt (0.77 vs. 0.75), explosion (0.81 vs. 0.78), and gunshot (0.79 vs. 0.73), all p < 0.0001. Higher mISS and ISS were associated with higher mortality. Compared with ISS, mISS had higher sensitivity (81.2 vs. 63.9) and slightly lower specificity (80.2 vs. 85.7). CONCLUSION: Military ISS predicts combat mortality better than does ISS. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III. PMID- 26958798 TI - Hemobilia due to a portal vein to common bile duct fistula from a seatbelt injury. PMID- 26958746 TI - Prognostic Significance of Hyponatremia in Acute Intracerebral Hemorrhage: Pooled Analysis of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial Studies. AB - OBJECTIVES: To determine the association of hyponatremia at presentation with clinical and imaging outcomes in patients with acute intracerebral hemorrhage. DESIGN: Retrospective pooled analysis of prospectively collected data from 3,243 participants of the pilot and main phases of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials 1 and 2 (international, multicenter, open, blinded endpoint, randomized controlled trials designed to assess the effects of early intensive blood pressure lowering in patients with acute intracerebral hemorrhage). SETTING: Clinical hospital sites in 21 countries. PATIENTS: Patients with predominantly mild-moderate severity of spontaneous intracerebral hemorrhage within 6 hours of onset and elevated systolic blood pressure (150-220 mm Hg) were included in the study. INTERVENTIONS: Patients were assigned to receive intensive (target systolic blood pressure, < 140 mm Hg within 1 hr) or guideline-recommended (target systolic blood pressure, < 180 mm Hg) blood pressure-lowering therapy. MEASUREMENTS AND MAIN RESULTS: Presentation hyponatremia was defined as serum sodium less than 135 mEq/L. The primary outcome was death at 90 days. Multivariable logistic regression was used to assess the association of hyponatremia with important clinical events. Of 3,002 patients with available data, 349 (12%) had hyponatremia. Hyponatremia was associated with death (18% vs 11%; multivariable adjusted odds ratio, 1.81; 95% CI, 1.28-2.57; p < 0.001) and larger baseline intracerebral hemorrhage volume (multivariable adjusted, p = 0.046) but not with baseline perihematomal edema volume nor with growth of intracerebral hemorrhage or perihematomal edema during the initial 24 hours. CONCLUSIONS: Hyponatremia at presentation is associated with increased mortality in patients with predominantly deep and modest volume intracerebral hemorrhage through mechanisms that seem independent of growth in intracerebral hemorrhage or perihematomal edema. PMID- 26958799 TI - Current management of hemorrhage from severe pelvic fractures: Results of an American Association for the Surgery of Trauma multi-institutional trial. AB - BACKGROUND: There is no consensus as to the optimal treatment paradigm for patients presenting with hemorrhage from severe pelvic fracture. This study was established to determine the methods of hemorrhage control currently being used in clinical practice. METHODS: This prospective, observational multi-center study enrolled patients with pelvic fracture from blunt trauma. Demographic data, admission vital signs, presence of shock on admission (systolic blood pressure < 90 mm Hg or heart rate > 120 beats per minute or base deficit < -5), method of hemorrhage control, transfusion requirements, and outcome were collected. RESULTS: A total of 1,339 patients with pelvic fracture were enrolled from 11 Level I trauma centers. Fifty-seven percent of the patients were male, with a mean +/- SD age of 47.1 +/- 21.6 years, and Injury Severity Score (ISS) of 19.2 +/- 12.7. In-hospital mortality was 9.0 %. Angioembolization and external fixator placement were the most common method of hemorrhage control used. A total of 128 patients (9.6%) underwent diagnostic angiography with contrast extravasation noted in 63 patients. Therapeutic angioembolization was performed on 79 patients (5.9%). There were 178 patients (13.3%) with pelvic fracture admitted in shock with a mean +/- SD ISS of 28.2 +/- 14.1. In the shock group, 44 patients (24.7%) underwent angiography to diagnose a pelvic source of bleeding with contrast extravasation found in 27 patients. Thirty patients (16.9%) were treated with therapeutic angioembolization. Resuscitative endovascular balloon occlusion of the aorta was performed on five patients in shock and used by only one of the participating centers. Mortality was 32.0% for patients with pelvic fracture admitted in shock. CONCLUSION: Patients with pelvic fracture admitted in shock have high mortality. Several methods were used for hemorrhage control with significant variation across institutions. The use of resuscitative endovascular balloon occlusion of the aorta may prove to be an important adjunct in the treatment of patients with severe pelvic fracture in shock; however, it is in the early stages of evaluation and not currently used widely across trauma centers. LEVEL OF EVIDENCE: Prognostic study, level II; therapeutic study, level III. PMID- 26958801 TI - The profile of wounding in civilian public mass shooting fatalities. AB - BACKGROUND: The incidence and severity of civilian public mass shootings (CPMS) continue to rise. Initiatives predicated on lessons learned from military woundings have placed strong emphasis on hemorrhage control, especially via use of tourniquets, as means to improve survival. We hypothesize that both the overall wounding pattern and the specific fatal wounds in CPMS events are different from those in military combat fatalities and thus may require a new management strategy. METHODS: A retrospective study of autopsy reports for all victims involved in 12 CPMS events was performed. Civilian public mass shootings was defined using the FBI and the Congressional Research Service definition. The site of injury, probable site of fatal injury, and presence of potentially survivable injury (defined as survival if prehospital care is provided within 10 minutes and trauma center care within 60 minutes of injury) was determined independently by each author. RESULTS: A total 139 fatalities consisting of 371 wounds from 12 CPMS events were reviewed. All wounds were due to gunshots. Victims had an average of 2.7 gunshots. Relative to military reports, the case fatality rate was significantly higher, and incidence of potentially survivable injuries was significantly lower. Overall, 58% of victims had gunshots to the head and chest, and only 20% had extremity wounds. The probable site of fatal wounding was the head or chest in 77% of cases. Only 7% of victims had potentially survivable wounds. The most common site of potentially survivable injury was the chest (89%). No head injury was potentially survivable. There were no deaths due to exsanguination from an extremity. CONCLUSION: The overall and fatal wounding patterns following CPMS are different from those resulting from combat operations. Given that no deaths were due to extremity hemorrhage, a treatment strategy that goes beyond use of tourniquets is needed to rescue the few victims with potentially survivable injuries. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level IV; therapeutic/care management study, level V. PMID- 26958800 TI - The effects of antioxidants on a porcine model of liver hemorrhage. AB - PURPOSE: The aim of this study is to assess the efficacy of the combination of N acetylcysteine (NAC) and deferoxamine (DFO) in the resuscitation from hemorrhagic shock in a porcine model of bleeding during hepatectomy. METHODS: Twenty-one pigs were divided randomly to three groups: Sham (S) group, n = 5; fluid (F) resuscitation group, n = 8; and fluid plus NAC plus DFO (NAC&DFO) resuscitation group, n = 8. The animals of groups F and NAC&DFO were subjected to left hepatectomy and controlled hemorrhage from the traumatic liver surface. Shock was established within 10 minutes and maintained for 30 minutes at mean arterial pressure (MAP) of 30 to 40 mm Hg. Resuscitation followed the shock period with crystalloids and colloids. Group NAC&DFO received additionally NAC and DFO in doses of 200 mg/kg and 65 mg/kg, respectively. The total time of the experiment was 6 hours. RESULTS: Animal weight, blood loss, excised liver mass, and MAP at the end of the shock period were comparable between experimental groups. Group NAC&DFO received significantly lower volume of both crystalloids and colloids (35% and 42% less, respectively) compared to group F. Hepatocellular proliferation (proliferating cell nuclear antigen) was higher in the antioxidant group. Apoptosis, measured by caspase-3, was restored to sham group levels when NAC and DFO were administered. CONCLUSIONS: Our experimental study showed that coadministration of NAC and DFO during liver hemorrhage can decrease the amounts of fluids needed for resuscitation. Moreover, the antioxidant combination restores the energy dependent apoptosis and proliferation of the hepatocytes. PMID- 26958802 TI - Disparities in Substance Abuse Treatment Utilization Among Women with Intellectual Disability. AB - Despite concerns about health disparities among women with intellectual disabilities, little is known about substance abuse treatment access in this population. Using standardized performance measures, treatment initiation and engagement were examined retrospectively for women aged 18 to 64 (N = 3,752), men with (N = 5,732) and women without intellectual disability (N = 493,446). Logistic regression models of utilization were conducted. Women in the sample were less likely than men in the sample or women without intellectual disability to utilize treatment, suggesting both gender-related and disability-related barriers. Policy and practice implications for improving the health and welfare of women with intellectual disabilities are discussed. PMID- 26958803 TI - A computational framework for mapping the timing of vegetative phase change. AB - Phase change plays a prominent role in determining the form of growth and development. Although considerable attention has been focused on identifying the regulatory control mechanisms of phase change, a detailed understanding of the genetic architecture of this phenomenon is still lacking. We address this issue by deriving a computational model. The model is founded on the framework of functional mapping aimed at characterizing the interplay between quantitative trait loci (QTLs) and development through biologically meaningful mathematical equations. A multiphasic growth equation was implemented into functional mapping, which, via a series of hypothesis tests, allows the quantification of how QTLs regulate the timing and pattern of vegetative phase transition between independently regulated, temporally coordinated processes. The model was applied to analyze stem radial growth data of an interspecific hybrid family derived from two Populus species during the first 24 yr of ontogeny. Several key QTLs related to phase change have been characterized, most of which were observed to be in the adjacent regions of candidate genes. The identification of phase transition QTLs, whose expression is regulated by endogenous and environmental signals, may enhance our understanding of the evolution of development in changing environments. PMID- 26958804 TI - Three-dimensional imaging MS of lipids in atherosclerotic plaques: Open-source methods for reconstruction and analysis. AB - Three-dimensional MALDI imaging MS (IMS) is a growing branch of IMS still requiring developments in methodology and technology to make the technique routinely accessible. Many challenges are simply a matter of producing 3D reconstructions and interpreting them in a timely fashion. In this aim and using analysis of lipids from atherosclerotic plaques from a human carotid and mouse aortic sinuses, we describe 3D reconstruction methods using open-source software that provides high-quality visualization and rapid interpretation through multivariate segmentation of the 3D IMS data. Multiple datasets were generated for each sample and we provide insight into simple means to correlate the separate datasets. PMID- 26958805 TI - Treatment with oestrogen-receptor agonists or oxytocin in conjunction with exercise protects against myocardial infarction in ovariectomized rats. AB - NEW FINDINGS: What is the central question of this study? Could the activation of oxytocin or oestrogen receptors be protective against myocardial injury after ovariectomy? If so, would exercising have an additional ameliorating effect? What is the main finding and its importance? The results revealed that when accompanied by exercise, both oestrogen receptor agonists and oxytocin improved cardiac dysfunction, inhibited the generation of pro-inflammatory cytokines and reduced myocardial injury in ovariectomized female rats, suggesting a new approach for protecting postmenopausal women against ischaemia-induced myocardial injury. To investigate the putative protective effects of oxytocin or oestrogen receptor agonists against myocardial injury of ovariectomized sedentary or exercised rats, female Sprague-Dawley rats assigned to sham-operated control and ovariectomized (OVX) groups were kept sedentary or undertook swimming exercise for 4 weeks and were treated with saline, an oestrogen receptor (ER) beta (DPN) or ERalpha agonist (PPT) or oxytocin. Ovariectomy increased weight gain and anxiety in sedentary rats, whereas exercise prevented weight gain. When accompanied by exercise, both ER agonists and oxytocin inhibited weight gain and anxiety; oxytocin, in the absence or presence of exercise, increased the left ventricular diastolic dimensions and ejection fraction, whereas ER agonists also increased left ventricular diameter when given to exercised rats. Upon the induction of myocardial ischaemia-reperfusion in the OVX rats, plasma creatine kinase-(muscle-brain) was depressed by PPT and oxytocin, whereas DPN, PPT and OT reduced plasminogen activator inhibitor-1 concentrations. The increased tumour necrosis factor-alpha concentration in OVX rats was also suppressed by exercise or DPN, PPT or oxytocin treatments, whereas the interleukin-6 concentration was diminished by all the treatments when given in conjunction with exercise. Disorganization of cardiac muscle fibres was reduced in all exercised rats. Oestrogen receptor agonists, as well as oxytocin, in conjunction with exercise may be effective new therapeutics to protect against myocardial ischaemia in postmenopausal women. PMID- 26958806 TI - Rescue of protein expression defects may not be enough to abolish the pro arrhythmic phenotype of long QT type 2 mutations. AB - KEY POINTS: Most missense long QT syndrome type 2 (LQTS2) mutations result in Kv11.1 channels that show reduced levels of membrane expression. Pharmacological chaperones that rescue mutant channel expression could have therapeutic potential to reduce the risk of LQTS2-associated arrhythmias and sudden cardiac death, but only if the mutant Kv11.1 channels function normally (i.e. like WT channels) after membrane expression is restored. Fewer than half of mutant channels exhibit relatively normal function after rescue by low temperature. The remaining rescued missense mutant Kv11.1 channels have perturbed gating and/or ion selectivity characteristics. Co-expression of WT subunits with gating defective missense mutations ameliorates but does not eliminate the functional abnormalities observed for most mutant channels. For patients with mutations that affect gating in addition to expression, it may be necessary to use a combination therapy to restore both normal function and normal expression of the channel protein. ABSTRACT: In the heart, Kv11.1 channels pass the rapid delayed rectifier current (IKr ) which plays critical roles in repolarization of the cardiac action potential and in the suppression of arrhythmias caused by premature stimuli. Over 500 inherited mutations in Kv11.1 are known to cause long QT syndrome type 2 (LQTS2), a cardiac electrical disorder associated with an increased risk of life threatening arrhythmias. Most missense mutations in Kv11.1 reduce the amount of channel protein expressed at the membrane and, as a consequence, there has been considerable interest in developing pharmacological agents to rescue the expression of these channels. However, pharmacological chaperones will only have clinical utility if the mutant Kv11.1 channels function normally after membrane expression is restored. The aim of this study was to characterize the gating phenotype for a subset of LQTS2 mutations to assess what proportion of mutations may be suitable for rescue. As an initial screen we used reduced temperature to rescue expression defects of mutant channels expressed in Xenopus laevis oocytes. Over half (~56%) of Kv11.1 mutants exhibited functional gating defects that either dramatically reduced the amount of current contributing to cardiac action potential repolarization and/or reduced the amount of protective current elicited in response to premature depolarizations. Our data demonstrate that if pharmacological rescue of protein expression defects is going to have clinical utility in the treatment of LQTS2 then it will be important to assess the gating phenotype of LQTS2 mutations before attempting rescue. PMID- 26958807 TI - Autocrine epiregulin activates EGFR pathway for lung metastasis via EMT in salivary adenoid cystic carcinoma. AB - Salivary adenoid cystic carcinoma (SACC) is characterized by invasive local growth and a high incidence of lung metastasis. Patients with lung metastasis have a poor prognosis. Treatment of metastatic SACC has been unsuccessful, largely due to a lack of specific targets for the metastatic cells. In this study, we showed that epidermal growth factor receptors (EGFR) were constitutively activated in metastatic lung subtypes of SACC cells, and that this activation was induced by autocrine expression of epiregulin (EREG), a ligand of EGFR. Autocrine EREG expression was increased in metastatic SACC-LM cells compared to that in non-metastatic parental SACC cells. Importantly, EREG neutralizing antibody, but not normal IgG, blocked the autocrine EREG-induced EGFR phosphorylation and the migration of SACC cells, suggesting that EREG induced EGFR activation is essential for induction of cell migration and invasion by SACC cells. Moreover, EREG-activated EGFR stabilized Snail and Slug, which promoted EMT and metastatic features in SACC cells. Of note, targeting EGFR with inhibitors significantly suppressed both the motility of SACC cells in vitro and lung metastasis in vivo. Finally, elevated EREG expression showed a strong correlation with poor prognosis in head and neck cancer. Thus, targeting the EREG EGFR-Snail/Slug axis represents a novel strategy for the treatment of metastatic SACC even no genetic EGFR mutation. PMID- 26958808 TI - Prevention of irradiation-induced salivary hypofunction by rapamycin in swine parotid glands. AB - Radiotherapy is commonly used in patients with oral cavity and pharyngeal cancers, usually resulting in irreversible salivary hypofunction. Currently management of radiation damage to salivary glands still remains a great challenge. Recent studies show that activation of mammalian target of rapamycin (mTOR) occurs in salivary gland lesions, making it possible to apply mTOR inhibitor for treatment. Our results indicate inhibition of mTOR by rapamycin significantly alleviated irradiation-induced salivary hypofunction by restoring 46% salivary flow rate and protecting histological structures in swine. Furthermore, rapamycin protected human submandibular gland cell line (HSG) from irradiation-induced cell depletion and loss of cell proliferation capacity. These findings lay the foundation for a new clinical application of rapamycin to prevent irradiation-induced salivary hypofunction. PMID- 26958810 TI - Repeated observation of immune gene sets enrichment in women with non-small cell lung cancer. AB - There are different biological and clinical patterns of lung cancer between genders indicating intrinsic differences leading to increased sensitivity to cigarette smoke-induced DNA damage, mutational patterns of KRAS and better clinical outcomes in women while differences between genders at gene-expression levels was not previously reported. Here we show an enrichment of immune genes in NSCLC in women compared to men. We found in a GSEA analysis (by biological processes annotated from Gene Ontology) of six public datasets a repeated observation of immune gene sets enrichment in women. "Immune system process", "immune response", "defense response", "cellular defense response" and "regulation of immune system process" were the gene sets most over-represented while APOBEC3G, APOBEC3F, LAT, CD1D and CCL5 represented the top-five core genes. Characterization of immune cell composition with the platform CIBERSORT showed no differences between genders; however, there were differences when tumor tissues were compared to normal tissues. Our results suggest different immune responses in NSCLC between genders that could be related with the different clinical outcome. PMID- 26958809 TI - MMP-13 is involved in oral cancer cell metastasis. AB - The oral cancer cell line OC3-I5 with a highly invasive ability was selected and derived from an established OSCC line OC3. In this study, we demonstrated that matrix metalloproteinases protein MMP-13 was up-regulated in OC3-I5 than in OC3 cells. We also observed that expression of epithelial-mesenchymal transition (EMT) markers including Twist, p-Src, Snail1, SIP1, JAM-A, and vinculin were increased in OC3-I5 compared to OC3 cells, whereas E-cadherin expression was decreased in the OC3-I5 cells. Using siMMP-13 knockdown techniques, we showed that siMMP-13 not only reduced the invasion and migration, but also the adhesion abilities of oral cancer cells. In support of the role of MMP-13 in metastasis, we used MMP-13 expressing plasmid-transfected 293T cells to enhance MMP-13 expression in the OC3 cells, transplanting the MMP-13 over expressing OC3 cells into nude mice led to enhanced lung metastasis. In summary, our findings show that MMP-13 promotes invasion and metastasis in oral cancer cells, suggesting altered expression of MMP-13 may be utilized to impede the process of metastasis. PMID- 26958812 TI - ZCWPW1 is associated with late-onset Alzheimer's disease in Han Chinese: a replication study and meta-analyses. AB - Recently, a large genome-wide association study (GWAS) has identified a novel variant (rs1476679) within ZCWPW1 showing strong association with late-onset Alzheimer's disease (LOAD) in Caucasian. However, the effect of rs1476679 on other populations remains unclear. In order to explore whether rs1476679 is also associated with the LOAD risk in other ethnic groups, we recruited 2350 unrelated Northern Han Chinese subjects, which include 992 LOAD patients and 1358 healthy controls. Analysis of data from these subjects suggests that the rs1476679 polymorphism is significantly associated with the LOAD (genotype P = 0.017, allele P = 0.044). The logistic regression reveals the C allele at rs1476679 is a protective factor for LOAD in the dominant model (OR = 0.779, 95%CI = 0.659 0.921, Pc = 0.009) adjusting for gender, age and APOE epsilon4 status. Furthermore, rs1476679 can decrease the AD risk (Dominant: OR = 0.733, 95%CI = 0.607-0.884, Pc = 0.006; Additive: OR = 0.820, 95%CI = 0.708-0.950, Pc = 0.048) in APOE epsilon4 non-carriers after stratification. Furthermore, meta-analysis of 82525 individuals confirmed that rs1476679 within ZCWPW1 decreased the risk of LOAD (OR = 0.91, 95%CI = 0.89-0.94). To summarize, the rs1476679 polymorphism in ZCWPW1 is associated with LOAD in Northern Han Chinese population. PMID- 26958811 TI - A combination of trastuzumab and BAG-1 inhibition synergistically targets HER2 positive breast cancer cells. AB - Treatment of HER2+ breast cancer with trastuzumab is effective and combination anti-HER2 therapies have demonstrated benefit over monotherapy in the neoadjuvant and metastatic settings. This study investigated the therapeutic potential of targeting the BAG-1 protein co-chaperone in trastuzumab-responsive or -resistant cells. In the METABRIC dataset, BAG-1 mRNA was significantly elevated in HER2+ breast tumors and predicted overall survival in a multivariate analysis (HR = 0.81; p = 0.022). In a breast cell line panel, BAG-1 protein was increased in HER2+ cells and was required for optimal growth as shown by siRNA knockdown. Overexpression of BAG-1S in HER2+ SKBR3 cells blocked growth inhibition by trastuzumab, whereas overexpression of a mutant BAG-1S protein (BAG-1S H3AB), defective in binding HSC70, potentiated the effect of trastuzumab. Injection of a Tet-On SKBR3 clone, induced to overexpress myc-BAG-1S into the mammary fat pads of immunocompromised mice, resulted in 2-fold larger tumors compared to uninduced controls. Induction of myc-BAG-1S expression in two Tet-On SKBR3 clones attenuated growth inhibition by trastuzumab in vitro. Targeting endogenous BAG-1 by siRNA enhanced growth inhibition of SKBR3 and BT474 cells by trastuzumab, while BAG-1 protein-protein interaction inhibitor (Thio-S or Thio-2) plus trastuzumab combination treatment synergistically attenuated growth. In BT474 cells this reduced protein synthesis, caused G1/S cell cycle arrest and targeted the ERK and AKT signaling pathways. In a SKBR3 subpopulation with acquired resistance to trastuzumab BAG-1 targeting remained effective and either Thio-2 or BAG-1 siRNA reduced growth more compared to trastuzumab-responsive parental cells. In summary, targeting BAG-1 function in combination with anti-HER2 therapy might prove beneficial. PMID- 26958814 TI - A novel composite type I collagen scaffold with micropatterned porosity regulates the entrance of phagocytes in a severe model of spinal cord injury. AB - Traumatic spinal cord injury (SCI) is a damage to the spinal cord that results in loss or impaired motor and/or sensory function. SCI is a sudden and unexpected event characterized by high morbidity and mortality rate during both acute and chronic stages, and it can be devastating in human, social and economical terms. Despite significant progresses in the clinical management of SCI, there remain no effective treatments to improve neurological outcomes. Among experimental strategies, bioengineered scaffolds have the potential to support and guide injured axons contributing to neural repair. The major aim of this study was to investigate a novel composite type I collagen scaffold with micropatterned porosity in a rodent model of severe spinal cord injury. After segment resection of the thoracic spinal cord we implanted the scaffold in female Sprague-Dawley rats. Controls were injured without receiving implantation. Behavioral analysis of the locomotor performance was monitored up to 55 days postinjury. Two months after injury histopathological analysis were performed to evaluate the extent of scar and demyelination, the presence of connective tissue and axonal regrowth through the scaffold and to evaluate inflammatory cell infiltration at the injured site. We provided evidence that the new collagen scaffold was well integrated with the host tissue, slightly ameliorated locomotor function, and limited the robust recruitment of the inflammatory cells at the injury site during both the acute and chronic stage in spinal cord injured rats. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1040 1053, 2017. PMID- 26958815 TI - Secondary metabolites of seven Hypericum species growing in Turkey. AB - Context The genus Hypericum (Hypericaceae) has attracted remarkable scientific interest as its members have yielded many bioactive compounds. Objective The current study presents investigations on the accumulation of hypericin, pseudohypericin, hyperforin, adhyperforin, chlorogenic acid, neochlorogenic acid, caffeic acid, 2,4-dihydroxybenzoic acid, 13,118-biapigenin, hyperoside, isoquercitrin, quercitrin, quercetin, avicularin, rutin, (+)-catechin and (-) epicatechin in seven Hypericum (Hypericaceae) species growing wild in Turkey, namely, H. aviculariifolium Jaup. and Spach subsp. aviculariifolium (Freyn and Bornm.) Robson var. albiflorum (endemic), H. bithynicum Boiss., H. calycinum L., H. cardiophyllum Boiss., H. elongatum L. subsp. microcalycinum (Boiss. and Heldr.) Robson, H. hirsutum L. and H. xylosteifolium (Spach) N. Robson. Materials and methods The plant materials were collected at flowering period and dissected in different tissues. Air-dried plant material including stems, leaves and flowers was mechanically powdered with a laboratory mill and samples (0.1 g) were extracted in 10 mL of 100% methanol by ultrasonication at 40 degrees C for 30 min for HPLC-PDA analyses. Results Accumulation levels of the investigated compounds varied greatly depending on species and plant part. Discussion For the first time, the detailed chemical profiles of corresponding Turkish Hypericum species were reported and the results were discussed from a phytochemical point of view. Conclusions The present data have importance in evaluation of plant resources of Hypericum genus in selecting the new potential sources of bioactive compounds. PMID- 26958813 TI - Association of helicobacter pylori infection and chronic atrophic gastritis with risk of colonic, pancreatic and gastric cancer: A ten-year follow-up of the ESTHER cohort study. AB - OBJECTIVES: To assess the association of H. pylori and chronic atrophic gastritis (AG) with colonic, pancreatic and gastric cancer in a population-based prospective cohort. METHODS: Serum antibodies against H. pylori in general and specific to cytotoxin-associated gene A (CagA), as well as serum pepsinogen I and II were analyzed in 9,506 men and women, aged 50-75 years in a cohort study from Saarland, Germany. Incident cases of colonic, pancreatic and gastric cancer were ascertained by record linkage with data from the Saarland Cancer Registry. RESULTS: During an average follow-up of 10.6 years, 108 colonic, 46 pancreatic and 27 gastric incident cancers were recorded. There was no association between H. pylori infection and colonic cancer (HR = 1.07; 95% CI 0.73-1.56) or pancreatic cancer (HR = 1.32; 0.73-2.39), regardless of either CagA seropositivity or AG status. In contrast, CagA+ infection was associated with a strongly increased risk of gastric cancer, especially non-cardia gastric cancer, and this association was particularly pronounced in the presence of AG. Compared to people without AG and without CagA+ infection, people with both risk factors had a significantly increased risk of non-cardia gastric cancer (HR = 32.4; 7.6 137.6). CONCLUSIONS: This large cohort study did not observe an association of H. pylori infection or AG with colonic or pancreatic cancer, but underlines that the vast majority of non-cardia gastric cancers arise from AG and infection with CagA+ H. pylori strains. PMID- 26958816 TI - The business of the media and health communication. PMID- 26958817 TI - [Personal experiences with induced abortions in private clinics in Northeast Brazil]. AB - Based on a qualitative study conducted in 2012, the article analyzes middle-class individuals' experiences with induced abortions performed in private clinics. Thirty-four stories of induced abortions were narrated by 19 women and five men living in two state capitals in Northeast Brazil. Thematic analysis revealed differences in types of clinics and care provided by the physicians. The article shows that abortion in private clinics fails to guarantee safe or humane care. The narratives furnish descriptions of diverse situations and practices, ranging from flaws such as lack of information on medicines to others involving severe abuses like procedures performed without anesthesia. The article concludes that criminalization of abortion in Brazil allows clinics to operate with no state regulation; it does not prevent women from having abortions, but exposes them to total vulnerability and violation of human rights. PMID- 26958818 TI - Association between order of birth and chronic malnutrition of children: a study of nationally representative Bangladeshi sample. AB - This paper examines the net effect of birth order on child nutritional status in Bangladesh using data from the Bangladesh Demographic Health Survey, 2011 (BDHS). Analyses were restricted to 4,120 surviving, lastborn singleton children who were younger than 36 months at the time of the survey. Logistic regression was used to assess the association between birth order and child nutritional status. Results indicate 38.1% children are stunted and 8.2% children are fifth or higher order birth. Order of birth is one of the significant predictors of child being stunted. Third order, fourth order, and fifth or higher order children are 24%, 30%, and 72%, respectively, more likely to be stunted after adjusting for all other variables. Besides birth order, results also indicate that child age, size at birth, birth intention, maternal education, maternal body mass index, wealth index, place of residence and mass media access exert strong influences over child malnutrition. Reducing birth rates which limit number of births and birth order as well may reduce child malnutrition in Bangladesh. PMID- 26958819 TI - Perception of the value of generic drugs in Sao Paulo, Brazil. AB - The objective of this study was to assess the perceptions of opinion-leaders, patients and their accompanying family members or carers about generic drugs. Three groups of participants were surveyed: (i) 50 customers while they were visiting commercial pharmacies located in Sao Paulo city, Brazil, (ii) 25 patients and 25 companions while they were waiting at the university outpatient clinic, and (iii) 50 healthcare opinion-leaders from government, hospitals, health plans, academia, and pharmaceutical companies. The questions explored socio-demographic characteristics and perceptions regarding value attributes of generic drugs compared to brand name drugs. Respondents had an average age of 52 years and 53% were women. Respondents believed generic drugs to be cheaper than brand name drugs (97%), and 31% thought generic drugs to be less effective than brand name drugs. Also, generic drugs were perceived by 54% of respondents to be as safe as brand name drugs and 74% would prefer brand name drugs if there was no price difference. In conclusion, multiple factors may contribute to the decision to buy generic drugs; among these, perceived effectiveness, safety and price appear to be the most important factors. PMID- 26958820 TI - The impact of the reduction of sodium content in processed foods in salt intake in Brazil. AB - This study aimed at assessing the potential impact of the reduction of sodium content in processed foods in the average salt intake in the Brazilian population. A total of 32,900 participants of the first National Dietary Survey (NDS 2008-2009), age 10 years and older who provided information about food intake over two days were evaluated. The sodium reduction targets established by the Brazilian Ministry of Health in 2010 and 2013 were used as the reference to determine the maximum content of sodium in 21 groups of processed food. The results show that sodium reduction targets in processed food have small impact in mean Brazilian population intake of salt. For 2017, the expected mean reduction is of 1.5%, the average sodium intake being still above the recommended 2,000mg/day maximum. Therefore, it will hardly be possible to reach the necessary reduction in salt intake in Brazil from volunteer agreements like the ones made so far. PMID- 26958821 TI - Apolipoprotein E polymorphism and functional disability in Brazilian elders: the Bambui Health and Aging Study. AB - Numerous studies have associated the apolipoprotein E (apoE) epsilon4 allele with worse health status, but few have assessed the existence of genotype-dependent variations in functional performance. Among participants in the Bambui Health and Aging Study, Minas Gerais State, Brazil, 1,408 elderly underwent apoE genotyping. Functionality was assessed with a questionnaire, and individuals were classified as dependent in basic activities of daily living (BADLs), instrumental activities of daily living (IADLs), and mobility. The association between apoE genotype and functional status was assessed by logistic regression, taking confounding factors into account. Presence of epsilon4 allele was associated with lower odds of mobility deficit (OR = 0.65; 95%CI: 0.47-0.92) in the adjusted analysis. There were no significant differences in relation to presence of dependency in BADLs and IADLs. The reasons are not entirely understood, but they may involve the role of epsilon4 allele as a "thrifty gene" in a sample exposed to high risk of infectious and nutritional diseases in the past. PMID- 26958822 TI - [Not Available]. PMID- 26958823 TI - [Not Available]. PMID- 26958824 TI - [Epidemiological survey in schoolchildren: determinants and prevalence of cardiovascular risk factors]. AB - This study focused on the prevalence of dyslipidemia, high blood glucose, and high blood pressure in scho-olchildren and the associations with demographic, socioeconomic, biological, and behavior factors using a cross-sectional design with 1,139 schoolchildren from six to 18 years of age in Amargosa, Bahia State, Brazil. Prevalence ratio (PR) was used as the measure of association. Prevalence rates for dyslipidemia, high blood glucose, and high blood pressure were 62.1%, 6.6%, and 27%, respectively. Dyslipidemia was associated with the school's geographic location (PR = 1.52) and child's waist circumference (PR = 1.20), and high blood glucose with the school's geographic location (PR = 3.41) and child's peripheral adiposity (PR = 3.13). High blood pressure was associated with age bracket (PR = 2.34), waist-for-height ratio (PR = 1.62), sexual ma-turation (PR = 2.06), and physical activity (PR = 1.32). Intervention programs are needed to change life habits in schoolchildren. PMID- 26958825 TI - Antimicrobial activity of extracts from macroalgae Ulva lactuca against clinically important Staphylococci is impacted by lunar phase of macroalgae harvest. AB - Staphylococcus aureus is a common human bacterial pathogen that causes skin and soft tissue infections. Methicillin-resistant Staph. aureus (MRSA) are increasingly drug-resistant, and thus there is great need for new therapeutics to treat Staph. aureus infections. Attention has focused on potential utility of natural products, such as extracts of marine macroalgae, as a source of novel antimicrobial compounds. The green macroalgae Ulva lactuca produces compounds inhibitory to human pathogens, although the effectiveness of U. lactuca extracts against clinically relevant strains of Staph. aureus is poorly understood. In addition, macroalgae produce secondary metabolites that may be influenced by exogenous factors including lunar phase, but whether lunar phase affects U. lactuca antimicrobial capacity is unknown. We sought to evaluate the antibacterial properties of U. lactuca extracts against medically important Staphylococci, and to determine the effect of lunar phase on antimicrobial activity. We report that U. lactuca methanolic extracts inhibit a range of Staphylococci, and that lunar phase of macrolagae harvest significantly impacts antimicrobial activity, suggesting that antimicrobial properties can be maximized by manipulating time of algal harvest. These findings provide useful parameters for future studies aimed at isolating and characterizing U. lactuca anti Staphylococcal agents. SIGNIFICANCE AND IMPACT OF THE STUDY: The growing prevalence of antibiotic-resistant human pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) has intensified efforts towards discovery and development of novel therapeutics. Marine macroalgae like Ulva lactuca are increasingly recognized as potential sources of antimicrobials, but the efficacy of U. lactuca extracts against common, virulent strains of Staph. aureus is poorly understood. We demonstrate that U. lactuca methanolic extracts inhibit a variety of clinically relevant Staphylococcus strains, and that the antimicrobial activity can be maximized by optimizing time of algal harvest. These findings provide potentially useful parameters for future work of isolating and identifying novel antimicrobial agents from macroalgae. PMID- 26958826 TI - Fusarium species and fumonisins in subsistence maize in the former Transkei region, South Africa: a multi-year study in rural villages. AB - Fumonisin occurrence was investigated in subsistence maize in four rural villages in each of Mbizana and Centane areas, South Africa. Samples (total 211) were analysed morphologically for Fusarium species and by high performance liquid chromatography for fumonisins. The mean incidence levels of Fusarium verticillioides in Centane good maize were 16% for both 1997 and 2000, but increased to 32% in 2003, whereas Mbizana good maize contained levels of 17% and 11% (2000 and 2003 seasons, respectively). The mean total fumonisin level in good maize in Centane for 1997 and 2000 was 575 and 975 ug/kg and 2150 ug/kg in 2003. In Mbizana, the mean total fumonisin level in good maize for 2000 was 950 ug/kg, but decreased to 610 ug/kg in 2003. The 2003 drought conditions led to a substantial increase in fumonisin levels in dry subhumid Centane, compared to humid subtropical Mbizana. This study emphasises the seasonal fluctuation in fumonisin levels. PMID- 26958828 TI - Long-Range Electrostatics-Induced Two-Proton Transfer Captured by Neutron Crystallography in an Enzyme Catalytic Site. AB - Neutron crystallography was used to directly locate two protons before and after a pH-induced two-proton transfer between catalytic aspartic acid residues and the hydroxy group of the bound clinical drug darunavir, located in the catalytic site of enzyme HIV-1 protease. The two-proton transfer is triggered by electrostatic effects arising from protonation state changes of surface residues far from the active site. The mechanism and pH effect are supported by quantum mechanics/molecular mechanics (QM/MM) calculations. The low-pH proton configuration in the catalytic site is deemed critical for the catalytic action of this enzyme and may apply more generally to other aspartic proteases. Neutrons therefore represent a superb probe to obtain structural details for proton transfer reactions in biological systems at a truly atomic level. PMID- 26958829 TI - Respiratory disorders: Ironing out smoking-related airway disease. PMID- 26958827 TI - Variations in rates of severe perineal tears and episiotomies in 20 European countries: a study based on routine national data in Euro-Peristat Project. AB - INTRODUCTION: Rates of severe perineal tears and episiotomies are indicators of obstetrical quality of care, but their use for international comparisons is complicated by difficulties with accurate ascertainment of tears and uncertainties regarding the optimal rate of episiotomies. We compared rates of severe perineal tears and episiotomies in European countries and analysed the association between these two indicators. MATERIAL AND METHODS: We used aggregate data from national routine statistics available in the Euro-Peristat project. We compared rates of severe (third- and fourth-degree) tears and episiotomies in 2010 by mode of vaginal delivery (n = 20 countries), and investigated time trends between 2004 and 2010 (n = 9 countries). Statistical associations were assessed with Spearman's ranked correlations (rho). RESULTS: In 2010 in all vaginal deliveries, rates of severe tears ranged from 0.1% in Romania to 4.9% in Iceland, and rates of episiotomies from 3.7% in Denmark to 75.0% in Cyprus. A negative correlation between the rates of episiotomies and severe tears was observed in all deliveries (rho = -0.66; p = 0.001), instrumental deliveries (rho = -0.67; p = 0.002) and non-instrumental deliveries (rho = -0.72; p < 0.001). However there was no relation between time trends of these two indicators (rho = 0.43; p = 0.28). CONCLUSIONS: The large variations in severe tears and episiotomies and the negative association between these indicators in 2010 show the importance of improving the assessment and reporting of tears in each country, and evaluating the impact of low episiotomy rates on the perineum. PMID- 26958830 TI - Intrinsic honesty and the prevalence of rule violations across societies. AB - Deception is common in nature and humans are no exception. Modern societies have created institutions to control cheating, but many situations remain where only intrinsic honesty keeps people from cheating and violating rules. Psychological, sociological and economic theories suggest causal pathways to explain how the prevalence of rule violations in people's social environment, such as corruption, tax evasion or political fraud, can compromise individual intrinsic honesty. Here we present cross-societal experiments from 23 countries around the world that demonstrate a robust link between the prevalence of rule violations and intrinsic honesty. We developed an index of the 'prevalence of rule violations' (PRV) based on country-level data from the year 2003 of corruption, tax evasion and fraudulent politics. We measured intrinsic honesty in an anonymous die-rolling experiment. We conducted the experiments with 2,568 young participants (students) who, due to their young age in 2003, could not have influenced PRV in 2003. We find individual intrinsic honesty is stronger in the subject pools of low PRV countries than those of high PRV countries. The details of lying patterns support psychological theories of honesty. The results are consistent with theories of the cultural co-evolution of institutions and values, and show that weak institutions and cultural legacies that generate rule violations not only have direct adverse economic consequences, but might also impair individual intrinsic honesty that is crucial for the smooth functioning of society. PMID- 26958832 TI - Impact of meat and Lower Palaeolithic food processing techniques on chewing in humans. AB - The origins of the genus Homo are murky, but by H. erectus, bigger brains and bodies had evolved that, along with larger foraging ranges, would have increased the daily energetic requirements of hominins. Yet H. erectus differs from earlier hominins in having relatively smaller teeth, reduced chewing muscles, weaker maximum bite force capabilities, and a relatively smaller gut. This paradoxical combination of increased energy demands along with decreased masticatory and digestive capacities is hypothesized to have been made possible by adding meat to the diet, by mechanically processing food using stone tools, or by cooking. Cooking, however, was apparently uncommon until 500,000 years ago, and the effects of carnivory and Palaeolithic processing techniques on mastication are unknown. Here we report experiments that tested how Lower Palaeolithic processing technologies affect chewing force production and efficacy in humans consuming meat and underground storage organs (USOs). We find that if meat comprised one third of the diet, the number of chewing cycles per year would have declined by nearly 2 million (a 13% reduction) and total masticatory force required would have declined by 15%. Furthermore, by simply slicing meat and pounding USOs, hominins would have improved their ability to chew meat into smaller particles by 41%, reduced the number of chews per year by another 5%, and decreased masticatory force requirements by an additional 12%. Although cooking has important benefits, it appears that selection for smaller masticatory features in Homo would have been initially made possible by the combination of using stone tools and eating meat. PMID- 26958831 TI - Lens regeneration using endogenous stem cells with gain of visual function. AB - The repair and regeneration of tissues using endogenous stem cells represents an ultimate goal in regenerative medicine. To our knowledge, human lens regeneration has not yet been demonstrated. Currently, the only treatment for cataracts, the leading cause of blindness worldwide, is to extract the cataractous lens and implant an artificial intraocular lens. However, this procedure poses notable risks of complications. Here we isolate lens epithelial stem/progenitor cells (LECs) in mammals and show that Pax6 and Bmi1 are required for LEC renewal. We design a surgical method of cataract removal that preserves endogenous LECs and achieves functional lens regeneration in rabbits and macaques, as well as in human infants with cataracts. Our method differs conceptually from current practice, as it preserves endogenous LECs and their natural environment maximally, and regenerates lenses with visual function. Our approach demonstrates a novel treatment strategy for cataracts and provides a new paradigm for tissue regeneration using endogenous stem cells. PMID- 26958833 TI - Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons. AB - Inhibitory neurons regulate the adaptation of neural circuits to sensory experience, but the molecular mechanisms by which experience controls the connectivity between different types of inhibitory neuron to regulate cortical plasticity are largely unknown. Here we show that exposure of dark-housed mice to light induces a gene program in cortical vasoactive intestinal peptide (VIP) expressing neurons that is markedly distinct from that induced in excitatory neurons and other subtypes of inhibitory neuron. We identify Igf1 as one of several activity-regulated genes that are specific to VIP neurons, and demonstrate that IGF1 functions cell-autonomously in VIP neurons to increase inhibitory synaptic input onto these neurons. Our findings further suggest that in cortical VIP neurons, experience-dependent gene transcription regulates visual acuity by activating the expression of IGF1, thus promoting the inhibition of disinhibitory neurons and affecting inhibition onto cortical pyramidal neurons. PMID- 26958834 TI - Biomedicine: Visionary stem-cell therapies. PMID- 26958835 TI - Co-ordinated ocular development from human iPS cells and recovery of corneal function. AB - The eye is a complex organ with highly specialized constituent tissues derived from different primordial cell lineages. The retina, for example, develops from neuroectoderm via the optic vesicle, the corneal epithelium is descended from surface ectoderm, while the iris and collagen-rich stroma of the cornea have a neural crest origin. Recent work with pluripotent stem cells in culture has revealed a previously under-appreciated level of intrinsic cellular self organization, with a focus on the retina and retinal cells. Moreover, we and others have demonstrated the in vitro induction of a corneal epithelial cell phenotype from pluripotent stem cells. These studies, however, have a single, tissue-specific focus and fail to reflect the complexity of whole eye development. Here we demonstrate the generation from human induced pluripotent stem cells of a self-formed ectodermal autonomous multi-zone (SEAM) of ocular cells. In some respects the concentric SEAM mimics whole-eye development because cell location within different zones is indicative of lineage, spanning the ocular surface ectoderm, lens, neuro-retina, and retinal pigment epithelium. It thus represents a promising resource for new and ongoing studies of ocular morphogenesis. The approach also has translational potential and to illustrate this we show that cells isolated from the ocular surface ectodermal zone of the SEAM can be sorted and expanded ex vivo to form a corneal epithelium that recovers function in an experimentally induced animal model of corneal blindness. PMID- 26958836 TI - Soft surfaces of nanomaterials enable strong phonon interactions. AB - Phonons and their interactions with other phonons, electrons or photons drive energy gain, loss and transport in materials. Although the phonon density of states has been measured and calculated in bulk crystalline semiconductors, phonons remain poorly understood in nanomaterials, despite the increasing prevalence of bottom-up fabrication of semiconductors from nanomaterials and the integration of nanometre-sized components into devices. Here we quantify the phononic properties of bottom-up fabricated semiconductors as a function of crystallite size using inelastic neutron scattering measurements and ab initio molecular dynamics simulations. We show that, unlike in microcrystalline semiconductors, the phonon modes of semiconductors with nanocrystalline domains exhibit both reduced symmetry and low energy owing to mechanical softness at the surface of those domains. These properties become important when phonons couple to electrons in semiconductor devices. Although it was initially believed that the coupling between electrons and phonons is suppressed in nanocrystalline materials owing to the scarcity of electronic states and their large energy separation, it has since been shown that the electron-phonon coupling is large and allows high energy-dissipation rates exceeding one electronvolt per picosecond (refs 10-13). Despite detailed investigations into the role of phonons in exciton dynamics, leading to a variety of suggestions as to the origins of these fast transition rates and including attempts to numerically calculate them, fundamental questions surrounding electron-phonon interactions in nanomaterials remain unresolved. By combining the microscopic and thermodynamic theories of phonons and our findings on the phononic properties of nanomaterials, we are able to explain and then experimentally confirm the strong electron-phonon coupling and fast multi-phonon transition rates of charge carriers to trap states. This improved understanding of phonon processes permits the rational selection of nanomaterials, their surface treatments, and the design of devices incorporating them. PMID- 26958837 TI - Observing cellulose biosynthesis and membrane translocation in crystallo. AB - Many biopolymers, including polysaccharides, must be translocated across at least one membrane to reach their site of biological function. Cellulose is a linear glucose polymer synthesized and secreted by a membrane-integrated cellulose synthase. Here, in crystallo enzymology with the catalytically active bacterial cellulose synthase BcsA-BcsB complex reveals structural snapshots of a complete cellulose biosynthesis cycle, from substrate binding to polymer translocation. Substrate- and product-bound structures of BcsA provide the basis for substrate recognition and demonstrate the stepwise elongation of cellulose. Furthermore, the structural snapshots show that BcsA translocates cellulose via a ratcheting mechanism involving a 'finger helix' that contacts the polymer's terminal glucose. Cooperating with BcsA's gating loop, the finger helix moves 'up' and 'down' in response to substrate binding and polymer elongation, respectively, thereby pushing the elongated polymer into BcsA's transmembrane channel. This mechanism is validated experimentally by tethering BcsA's finger helix, which inhibits polymer translocation but not elongation. PMID- 26958839 TI - Behavioural economics: Corruption corrupts. PMID- 26958840 TI - Corrigendum: Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia. PMID- 26958838 TI - Crystal structures of the M1 and M4 muscarinic acetylcholine receptors. AB - Muscarinic M1-M5 acetylcholine receptors are G-protein-coupled receptors that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have emerged as attractive drug targets for treatments of neurological disorders, such as Alzheimer's disease and schizophrenia, but the high conservation of the acetylcholine-binding pocket has spurred current research into targeting allosteric sites on these receptors. Here we report the crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium. Comparison of these structures with each other, as well as with the previously reported M2 and M3 receptor structures, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. We also report identification of a cluster of residues that form a network linking the orthosteric and allosteric sites of the M4 receptor, which provides new insight into how allosteric modulation may be transmitted between the two spatially distinct domains. PMID- 26958841 TI - Prostate Cancer Associated Lipid Signatures in Serum Studied by ESI-Tandem Mass Spectrometryas Potential New Biomarkers. AB - Prostate cancer (PCa) is one amongst the most common cancersin western men. Incidence rate ofPCa is on the rise worldwide. The present study deals with theserum lipidome profiling of patients diagnosed with PCa to identify potential new biomarkers. We employed ESI-MS/MS and GC-MS for identification of significantly altered lipids in cancer patient's serum compared to controls. Lipidomic data revealed 24 lipids are significantly altered in cancer patinet's serum (n = 18) compared to normal (n = 18) with no history of PCa. By using hierarchical clustering and principal component analysis (PCA) we could clearly separate cancer patients from control group. Correlation and partition analysis along with Formal Concept Analysis (FCA) have identified that PC (39:6) and FA (22:3) could classify samples with higher certainty. Both the lipids, PC (39:6) and FA (22:3) could influence the cataloging of patients with 100% sensitivity (all 18 control samples are classified correctly) and 77.7% specificity (of 18 tumor samples 4 samples are misclassified) with p-value of 1.612*10-6 in Fischer's exact test. Further, we performed GC-MS to denote fatty acids altered in PCa patients and found that alpha-linolenic acid (ALA) levels are altered in PCa. We also performed an in vitro proliferation assay to determine the effect of ALA in survival of classical human PCa cell lines LNCaP and PC3. We hereby report that the altered lipids PC (39:6) and FA (22:3) offer a new set of biomarkers in addition to the existing diagnostic tests that could significantly improve sensitivity and specificity in PCa diagnosis. PMID- 26958842 TI - Biodiversity and Biogeography of Chthamalid Barnacles from the North-Eastern Pacific (Crustacea Cirripedia). AB - The biogeography and ecology of the species of Chthamalus present on the west coast of America are described, using data from 51 localities from Alaska to Panama, together with their zonation on the shore with respect to that of other barnacles. The species present were C. dalli, Pilsbry 1916, C. fissus, Darwin, 1854, C. anisopoma Pilsbry 1916 and four species in the C. panamensis complex. The latter are C. panamensis Pilsbry, 1916, C. hedgecocki, Pitombo & Burton, 2007, C. alani nom. nov. (formerly C. southwardorum Pitombo & Burton, 2007) and C. newmani sp. nov.). These four species were initially separated by enzyme electrophoresis. They could only be partially separated by DNA bar coding but may be separated using morphological characters. PMID- 26958843 TI - Selection of a Relevant In Vitro Blood-Brain Barrier Model to Investigate Pro Metastatic Features of Human Breast Cancer Cell Lines. AB - Around 7-17% of metastatic breast cancer patients will develop brain metastases, associated with a poor prognosis. To reach the brain parenchyma, cancer cells need to cross the highly restrictive endothelium of the Blood-Brain Barrier (BBB). As treatments for brain metastases are mostly inefficient, preventing cancer cells to reach the brain could provide a relevant and important strategy. For that purpose an in vitro approach is required to identify cellular and molecular interaction mechanisms between breast cancer cells and BBB endothelium, notably at the early steps of the interaction. However, while numerous studies are performed with in vitro models, the heterogeneity and the quality of BBB models used is a limitation to the extrapolation of the obtained results to in vivo context, showing that the choice of a model that fulfills the biological BBB characteristics is essential. Therefore, we compared pre-established and currently used in vitro models from different origins (bovine, mice, human) in order to define the most appropriate tool to study interactions between breast cancer cells and the BBB. On each model, the BBB properties and the adhesion capacities of breast cancer cell lines were evaluated. As endothelial cells represent the physical restriction site of the BBB, all the models consisted of endothelial cells from animal or human origins. Among these models, only the in vitro BBB model derived from human stem cells both displayed BBB properties and allowed measurement of meaningful different interaction capacities of the cancer cell lines. Importantly, the measured adhesion and transmigration were found to be in accordance with the cancer cell lines molecular subtypes. In addition, at a molecular level, the inhibition of ganglioside biosynthesis highlights the potential role of glycosylation in breast cancer cells adhesion capacities. PMID- 26958844 TI - Importance of N2-Fixation on the Productivity at the North-Western Azores Current/Front System, and the Abundance of Diazotrophic Unicellular Cyanobacteria. AB - To understand the impact of the northwestern Azores Current Front (NW-AzC/AzF) system on HCO3--and N2-fixation activities and unicellular diazotrophic cyanobacteria (UCYN) distribution, we combined geochemical and biological approaches from the oligotrophic surface to upper mesopelagic waters. N2-fixation was observed to sustain 45-85% of the HCO3--fixation in the picoplanktonic fraction performing 47% of the total C-fixation at the deep chlorophyll maximum north and south of the AzF. N2-fixation rates as high as 10.9 MUmol N m-3 d-1 and surface nitrate delta15N as low as 2.70/00 were found in the warm (18-24 degrees C), most saline (36.5-37.0) and least productive waters south of the AzF, where UCYN were the least abundant. However, picoplanktonic UCYN abundances up to 55 cells mL-1 were found at 45-200m depths in the coolest nutrient-rich waters north of the AzF. In this area, N2-fixation rates up to 4.5 MUmol N m-3 d-1 were detected, associated with depth-integrated H13CO3--fixation rates at least 50% higher than observed south of the AzF. The numerous eddies generated at the NW AzC/AzF seem to enhance exchanges of plankton between water masses, as well as vertical and horizontal diapycnal diffusion of nutrients, whose increase probably enhances the growth of diazotrophs and the productivity of C-fixers. PMID- 26958845 TI - Impact of Pre-Dialysis Care on Clinical Outcomes in Peritoneal Dialysis Patients. AB - BACKGROUND: Structured pre-dialysis care is associated with an increase in peritoneal dialysis (PD) utilization, but not with peritonitis risk, technical and patient survival. This study aimed at analyzing the impact of pre-dialysis care on these outcomes. METHODS: All incident patients starting PD between 2004 and 2011 in a Brazilian prospective cohort were included in this analysis. Patients were divided into 2 groups: early pre-dialysis care (90 days of follow up by a nephrology team); and late pre-dialysis care (absent or less than 90 days follow-up). The socio-demographic, clinical and biochemical characteristics between the 2 groups were compared. Risk factors for the time to the first peritonitis episode, technique failure and mortality based on Cox proportional hazards models. RESULTS: Four thousand one hundred seven patients were included. Patients with early pre-dialysis care presented differences in gender (female - 47.0 vs. 51.1%, p = 0.01); race (white - 63.8 vs. 71.7%, p < 0.01); education (<4 years - 61.9 vs. 71.0%, p < 0.01), respectively, compared to late care. Patients with early pre-dialysis care presented a higher prevalence of comorbidities, lower levels of creatinine, phosphorus, and glucose with a significantly better control of hemoglobin and potassium serum levels. There was no impact of pre dialysis care on peritonitis rates (hazard ratio (HR) 0.88; 95% CI 0.77-1.01) and technique survival (HR 1.12; 95% CI 0.92-1.36). Patient survival (HR 1.20; 95% CI 1.03-1.41) was better in the early pre-dialysis care group. CONCLUSION: Earlier pre-dialysis care was associated with improved patient survival, but did not influence time to the first peritonitis nor technique survival in this national PD cohort. PMID- 26958846 TI - A comparison of AMPV subtypes A and B full genomes, gene transcripts and proteins led to reverse-genetics systems rescuing both subtypes. AB - Avian metapneumovirus (AMPV) infection of poultry causes serious disease in most countries and subtype A reverse-genetic (RG) systems have allowed a generation of viruses of known sequence, and proved useful in developments towards better control by live vaccines. While subtype B viruses are more prevalent, bacterial cloning issues made subtype B RG systems difficult to establish. A molecular comparison of subtype A and B viruses was undertaken to assess whether subtype A RG components could be partially or fully substituted. AMPV subtype A and B gene end sequences leading to polyadenylation are, to our knowledge, reported for the first time, as well as several leader and trailer sequences. After comparing these alongside previously reported gene starts and protein sequences, it was concluded that subtype B genome copies would be most likely rescued by a subtype A support system, and this assertion was supported when individual subtype A components were successfully substituted. Application of an advanced cloning plasmid permitted eventual completion of a fully subtype B RG system, and proved that all subtype-specific components could be freely exchanged between A and B systems. PMID- 26958847 TI - The Combined Effect of Hydrophobic Mismatch and Bilayer Local Bending on the Regulation of Mechanosensitive Ion Channels. AB - The hydrophobic mismatch between the lipid bilayer and integral membrane proteins has well-defined effect on mechanosensitive (MS) ion channels. Also, membrane local bending is suggested to modulate MS channel activity. Although a number of studies have already shown the significance of each individual factor, the combined effect of these physical factors on MS channel activity have not been investigated. Here using finite element simulation, we study the combined effect of hydrophobic mismatch and local bending on the archetypal mechanosensitive channel MscL. First we show how the local curvature direction impacts on MS channel modulation. In the case of MscL, we show inward (cytoplasmic) bending can more effectively gate the channel compared to outward bending. Then we indicate that in response to a specific local curvature, MscL inserted in a bilayer with the same hydrophobic length is more expanded in the constriction pore region compared to when there is a protein-lipid hydrophobic mismatch. Interestingly in the presence of a negative mismatch (thicker lipids), MscL constriction pore is more expanded than in the presence of positive mismatch (thinner lipids) in response to an identical membrane curvature. These results were confirmed by a parametric energetic calculation provided for MscL gating. These findings have several biophysical consequences for understanding the function of MS channels in response to two major physical stimuli in mechanobiology, namely hydrophobic mismatch and local membrane curvature. PMID- 26958850 TI - Impact of Market Competition on Continuity of Care and Hospital Admissions for Asthmatic Children: A Longitudinal Analysis of Nationwide Health Insurance Data 2009-2013. AB - BACKGROUND: Ambulatory care-sensitive conditions, including asthma, can be managed with timely and effective outpatient care, thereby reducing the need for hospitalization. OBJECTIVE: This study assessed the relationship between market competition, continuity of care (COC), and hospital admissions in asthmatic children according to their health care provider. METHODS: A longitudinal design was employed with a 5-year follow-up period, between 2009 and 2013, under a Korean universal health insurance program. A total of 253 geographical regions were included in the analysis, according to data from the Korean Statistical Office. Data from 9,997 patients, aged <= 12 years, were included. We measured the COC over a 5-year period using the Usual Provider Continuity (UPC) index. Random intercept models were calculated to assess the temporal and multilevel relationship between market competition, COC, and hospital admission rate. RESULTS: Of the 9,997 patients, 243 (2.4%) were admitted to the hospital in 2009. In the multilevel regression analysis, as the Herfindahl-Hirschman Index increased by 1,000 points (denoting decreased competitiveness), UPC scores also increased (beta = 0.001; p < 0.0001). In multilevel logistic regression analysis, the adjusted odds ratio (OR) for hospital admissions for individuals with lower COC scores (>= 2 ambulatory visits and a UPC index score of < 1) was 3.61 (95% CI: 2.98-4.38) relative to the reference group (>= 2 ambulatory visits and a UPC index score of 1). CONCLUSIONS: Market competition appears to reduce COC; decreased COC was associated with a higher OR for hospital admissions. PMID- 26958849 TI - Incidence of Hospitalization for Respiratory Syncytial Virus Infection amongst Children in Ontario, Canada: A Population-Based Study Using Validated Health Administrative Data. AB - IMPORTANCE: RSV is a common illness among young children that causes significant morbidity and health care costs. OBJECTIVE: Routinely collected health administrative data can be used to track disease incidence, explore risk factors and conduct health services research. Due to potential for misclassification bias, the accuracy of data-elements should be validated prior to use. The objectives of this study were to validate an algorithm to accurately identify pediatric cases of hospitalized respiratory syncytial virus (RSV) from within Ontario's health administrative data, estimate annual incidence of hospitalization due to RSV and report the prevalence of major risk factors within hospitalized patients. STUDY DESIGN AND SETTING: A retrospective chart review was performed to establish a reference-standard cohort of children from the Ottawa region admitted to the Children's Hospital of Eastern Ontario (CHEO) for RSV related disease in 2010 and 2011. Chart review data was linked to Ontario's administrative data and used to evaluate the diagnostic accuracy of algorithms of RSV-related ICD-10 codes within provincial hospitalization and emergency department databases. Age- and sex-standardized incidence was calculated over time, with trends in incidence assessed using Poisson regression. RESULTS: From a total of 1411 admissions, chart review identified 327 children hospitalized for laboratory confirmed RSV-related disease. Following linkage to administrative data and restriction to first admissions, there were 289 RSV patients in the reference-standard cohort. The best algorithm, based on hospitalization data, resulted in sensitivity 97.9% (95%CI: 95.5-99.2%), specificity 99.6% (95%CI: 98.2 99.8%), PPV 96.9% (95%CI: 94.2-98.6%), NPV 99.4% (95%CI: 99.4-99.9%). Incidence of hospitalized RSV in Ontario from 2005-2012 was 10.2 per 1000 children under 1 year and 4.8 per 1000 children aged 1 to 3 years. During the surveillance period, there was no identifiable increasing or decreasing linear trend in the incidence of hospitalized RSV, hospital length of stay and PICU admission rates. Among the Ontario RSV cohort, 16.3% had one or more major risk factors, with a decreasing trend observed over time. CONCLUSION: Children hospitalized for RSV-related disease can be accurately identified within population-based health administrative data. RSV is a major public health concern and incidence has not changed over time, suggesting a lack of progress in prevention. PMID- 26958851 TI - Activation of Acetone and Other Simple Ketones in Anaerobic Bacteria. AB - Acetone and other ketones are activated for subsequent degradation through carboxylation by many nitrate-reducing, phototrophic, and obligately aerobic bacteria. Acetone carboxylation leads to acetoacetate, which is subsequently activated to a thioester and degraded via thiolysis. Two different types of acetone carboxylases have been described, which require either 2 or 4 ATP equivalents as an energy supply for the carboxylation reaction. Both enzymes appear to combine acetone enolphosphate with carbonic phosphate to form acetoacetate. A similar but more complex enzyme is known to carboxylate the aromatic ketone acetophenone, a metabolic intermediate in anaerobic ethylbenzene metabolism in denitrifying bacteria, with simultaneous hydrolysis of 2 ATP to 2 ADP. Obligately anaerobic sulfate-reducing bacteria activate acetone to a four carbon compound as well, but via a different process than bicarbonate- or CO2 dependent carboxylation. The present evidence indicates that either carbon monoxide or a formyl residue is used as a cosubstrate, and that the overall ATP expenditure of this pathway is substantially lower than in the known acetone carboxylase reactions. PMID- 26958852 TI - Promoters Architecture-Based Mechanism for Noise-Induced Oscillations in a Single Gene Circuit. AB - It is well known that single-gene circuits with negative feedback loop can lead to oscillatory gene expression when they operate with time delay. In order to generate these oscillations many processes can contribute to properly timing such delay. Here we show that the time delay coming from the transitions between internal states of the cis-regulatory system (CRS) can drive sustained oscillations in an auto-repressive single-gene circuit operating in a small volume like a cell. We found that the cooperative binding of repressor molecules is not mandatory for a oscillatory behavior if there are enough binding sites in the CRS. These oscillations depend on an adequate balance between the CRS kinetic, and the synthesis/degradation rates of repressor molecules. This finding suggest that the multi-site CRS architecture can play a key role for oscillatory behavior of gene expression. Finally, our results can also help to synthetic biologists on the design of the promoters architecture for new genetic oscillatory circuits. PMID- 26958854 TI - Crippling Violence: Conflict and Incident Polio in Afghanistan. AB - BACKGROUND: Designing effective public health campaigns in areas of armed conflict requires a nuanced understanding of how violence impacts the epidemiology of the disease in question. METHODS: We examine the geographical relationship between violence (represented by the location of detonated Improvised Explosive Devices) and polio incidence by generating maps of IEDs and polio incidence during 2010, and by comparing the mean number of IED detonations in polio high-risk districts with non polio high-risk districts during 2004-2009. RESULTS: We demonstrate a geographic relationship between IED violence and incident polio. Districts that have high-risk for polio have highly statistically significantly greater mean numbers of IEDs than non polio high-risk districts (p values 0.0010-0.0404). CONCLUSIONS: The geographic relationship between armed conflict and polio incidence provides valuable insights as to how to plan a vaccination campaign in violent contexts, and allows us to anticipate incident polio in the regions of armed conflict. Such information permits vaccination planners to engage interested armed combatants to co-develop strategies to mitigate the effects of violence on polio. PMID- 26958853 TI - Wound-Induced Polyploidization: Regulation by Hippo and JNK Signaling and Conservation in Mammals. AB - Tissue integrity and homeostasis often rely on the proliferation of stem cells or differentiated cells to replace lost, aged, or damaged cells. Recently, we described an alternative source of cell replacement- the expansion of resident, non-dividing diploid cells by wound-induced polyploidization (WIP). Here we show that the magnitude of WIP is proportional to the extent of cell loss using a new semi-automated assay with single cell resolution. Hippo and JNK signaling regulate WIP; unexpectedly however, JNK signaling through AP-1 limits rather than stimulates the level of Yki activation and polyploidization in the Drosophila epidermis. We found that polyploidization also quantitatively compensates for cell loss in a mammalian tissue, mouse corneal endothelium, where increased cell death occurs with age in a mouse model of Fuchs Endothelial Corneal Dystrophy (FECD). Our results suggest that WIP is an evolutionarily conserved homeostatic mechanism that maintains the size and synthetic capacity of adult tissues. PMID- 26958857 TI - Early Surgical Intervention for a Large Newborn Cephalohematoma. AB - Cephalohematomas in newborns are often managed nonsurgically and resolve within the first month of life. In cases of large hematomas (>7 cm) with delayed resorption and persistence over 4 weeks, these masses can often lead to complications of calcification, infection, or hyperbilirubinemia. We report a case of a 14-day-old child with a persistent, large, noncalcified cephalohematoma. After observation alone showed that the cephalohematoma increased in size, 100 ml of old blood was surgically evacuated on day 15 of life. The procedure required a small 1-cm incision and, unlike most large cephalohematomas evacuated after 1 month of observation, there were no signs of skull-deforming calcification observed. This case report presents the earliest evacuation of large noncalcified cephalohematomas in newborns ever reported in the literature, and suggests benefits of early surgical evacuation before 1 month of life. PMID- 26958856 TI - T1 Relaxation Time in Lungs of Asymptomatic Smokers. AB - PURPOSE: Interest in using T1 as a potential MRI biomarker of chronic obstructive pulmonary disease (COPD) has recently increased. Since tobacco smoking is the major risk factor for development of COPD, the aim for this study was to examine whether tobacco smoking, pack-years (PY), influenced T1 of the lung parenchyma in asymptomatic current smokers. MATERIALS AND METHODS: Lung T1 measurements from 35 subjects, 23 never smokers and 12 current smokers were retrospectively analyzed from an institutional review board approved study. All 35 subjects underwent pulmonary function test (PFT) measurements and lung T1, with similar T1 measurement protocols. A backward linear model of T1 as a function of FEV1, FVC, weight, height, age and PY was tested. RESULTS: A significant correlation between lung T1 and PY was found with a negative slope of -3.2 ms/year (95% confidence interval [CI] [-5.8, -0.6], p = 0.02), when adjusted for age and height. Lung T1 shortens with ageing among all subjects, -4.0 ms/year (95%CI [-6.3, -1.7], p = 0.001), and among the never smokers, -3.7 ms/year (95%CI [-6.0, -1.3], p = 0.003). CONCLUSIONS: A correlation between lung T1 and PY when adjusted for both age and height was found, and T1 of the lung shortens with ageing. Accordingly, PY and age can be significant confounding factors when T1 is used as a biomarker in lung MRI studies that must be taken into account to detect underlying patterns of disease. PMID- 26958855 TI - Epidemiology, Seasonality and Treatment of Hospitalized Adults and Adolescents with Influenza in Jingzhou, China, 2010-2012. AB - BACKGROUND: After the 2009 influenza A (H1N1) pandemic, we conducted hospital based severe acute respiratory infection (SARI) surveillance in one central Chinese city to assess disease burden attributable to influenza among adults and adolescents. METHODS: We defined an adult SARI case as a hospitalized patient aged >= 15 years with temperature >=38.0 degrees C and at least one of the following: cough, sore throat, tachypnea, difficulty breathing, abnormal breath sounds on auscultation, sputum production, hemoptysis, chest pain, or chest radiograph consistent with pneumonia. For each enrolled SARI case-patient, we completed a standardized case report form, and collected a nasopharyngeal swab within 24 hours of admission. Specimens were tested for influenza viruses by real time reverse transcription polymerase chain reaction (rRT-PCR). We analyzed data from adult SARI cases in four hospitals in Jingzhou, China from April 2010 to April 2012. RESULTS: Of 1,790 adult SARI patients enrolled, 40% were aged >= 65 years old. The median duration of hospitalization was 9 days. Nearly all were prescribed antibiotics during their hospitalization, less than 1% were prescribed oseltamivir, and 28% were prescribed corticosteroids. Only 0.1% reported receiving influenza vaccination in the past year. Of 1,704 samples tested, 16% were positive for influenza. Influenza activity in all age groups showed winter spring and summer peaks. Influenza-positive patients had a longer duration from illness onset to hospitalization and a shorter duration from hospital admission to discharge or death compared to influenza negative SARI patients. CONCLUSIONS: There is substantial burden of influenza-associated SARI hospitalizations in Jingzhou, China, especially among older adults. More effective promotion of annual seasonal influenza vaccination and timely oseltamivir treatment among high risk groups may improve influenza prevention and control in China. PMID- 26958859 TI - Comparing the Performance of NoSQL Approaches for Managing Archetype-Based Electronic Health Record Data. AB - This study provides an experimental performance evaluation on population-based queries of NoSQL databases storing archetype-based Electronic Health Record (EHR) data. There are few published studies regarding the performance of persistence mechanisms for systems that use multilevel modelling approaches, especially when the focus is on population-based queries. A healthcare dataset with 4.2 million records stored in a relational database (MySQL) was used to generate XML and JSON documents based on the openEHR reference model. Six datasets with different sizes were created from these documents and imported into three single machine XML databases (BaseX, eXistdb and Berkeley DB XML) and into a distributed NoSQL database system based on the MapReduce approach, Couchbase, deployed in different cluster configurations of 1, 2, 4, 8 and 12 machines. Population-based queries were submitted to those databases and to the original relational database. Database size and query response times are presented. The XML databases were considerably slower and required much more space than Couchbase. Overall, Couchbase had better response times than MySQL, especially for larger datasets. However, Couchbase requires indexing for each differently formulated query and the indexing time increases with the size of the datasets. The performances of the clusters with 2, 4, 8 and 12 nodes were not better than the single node cluster in relation to the query response time, but the indexing time was reduced proportionally to the number of nodes. The tested XML databases had acceptable performance for openEHR-based data in some querying use cases and small datasets, but were generally much slower than Couchbase. Couchbase also outperformed the response times of the relational database, but required more disk space and had a much longer indexing time. Systems like Couchbase are thus interesting research targets for scalable storage and querying of archetype-based EHR data when population-based use cases are of interest. PMID- 26958858 TI - Dynamical Allocation of Cellular Resources as an Optimal Control Problem: Novel Insights into Microbial Growth Strategies. AB - Microbial physiology exhibits growth laws that relate the macromolecular composition of the cell to the growth rate. Recent work has shown that these empirical regularities can be derived from coarse-grained models of resource allocation. While these studies focus on steady-state growth, such conditions are rarely found in natural habitats, where microorganisms are continually challenged by environmental fluctuations. The aim of this paper is to extend the study of microbial growth strategies to dynamical environments, using a self-replicator model. We formulate dynamical growth maximization as an optimal control problem that can be solved using Pontryagin's Maximum Principle. We compare this theoretical gold standard with different possible implementations of growth control in bacterial cells. We find that simple control strategies enabling growth-rate maximization at steady state are suboptimal for transitions from one growth regime to another, for example when shifting bacterial cells to a medium supporting a higher growth rate. A near-optimal control strategy in dynamical conditions is shown to require information on several, rather than a single physiological variable. Interestingly, this strategy has structural analogies with the regulation of ribosomal protein synthesis by ppGpp in the enterobacterium Escherichia coli. It involves sensing a mismatch between precursor and ribosome concentrations, as well as the adjustment of ribosome synthesis in a switch-like manner. Our results show how the capability of regulatory systems to integrate information about several physiological variables is critical for optimizing growth in a changing environment. PMID- 26958860 TI - P450 3A-Catalyzed O-Dealkylation of Lapatinib Induces Mitochondrial Stress and Activates Nrf2. AB - Lapatinib (LAP), an oral tyrosine kinase inhibitor for the treatment of metastatic breast cancer, has been associated with idiosyncractic hepatotoxicity. Recent investigations have implicated the importance of P450 3A4/5 enzymes in the formation of an electrophilic quinone imine (LAPQI) metabolite generated through further oxidation of O-dealkylated lapatinib (OD-LAP). In the current study, hepatic stress was observed via mitochondrial impairment. OD-LAP caused a time- and concentration-dependent decrease in oxygen consumption in HepG2 cells, whereas LAP did not alter the oxygen consumption rate. Interestingly, however, HepG2 cells transfected with human P450 3A4 did exhibit mitochondrial dysfunction via P450 3A4-mediated metabolism of LAP to OD-LAP. OD-LAP-induced mitochondrial toxicity was enhanced upon depletion of intracellular GSH levels, demonstrating that cellular GSH levels are important in the protection of mitochondrial function against LAPQI. Given the nature of LAPQI and the importance of GSH levels in LAP-induced mitochondrial stress, the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) was evaluated, as this transcription factor induces the expression of NAD(P)H quinone oxidoreductase 1, glutathione S transferase, UDP-glucuronosyltransferases, and glutathione synthetase, all of which might be expected to decrease the toxicity of LAP. Using a FRET-based target gene assay in HepG2 cells, OD-LAP was indeed found to activate Nrf2. Follow-up assays showed increased mRNA levels of Nrf2 target genes after a 4 h treatment with OD-LAP but not with LAP. LAP activation of Nrf2 was observed only when HepG2 cells were transduced with P450 3A4. The significance of Nrf2 protection was established in vivo in Nrf2-KO mice. Increased transaminase levels were found after a single LAP dose in both Nrf2-KO and control mice, indicating elevated hepatic necrosis, although transaminase levels reverted to baseline levels in the control mice upon repeat dosing. They continued to rise in Nrf2-KO mice, however, indicating the likelihood that Nrf-2 plays a significant role in combatting the hepatotoxicity triggered by LAP. PMID- 26958861 TI - Modulation of Domain Size in Polycrystalline n-Type Dicyanoperylene Mono- and Bilayer Transistors. AB - A single molecular layer (monolayer) of organic semiconductors is proven to be sufficient to create a conducting channel for charge carriers in field-effect transistors, which is an ideal platform to investigate the correlation between molecular self-assembly and device performance. Herein, ultrathin films including mono- and bilayers of an n-type dicyanoperylene (PDI8-CN2) are solution-processed by dip-coating. The domain size of the polycrystalline layers is modulated via the surface roughness of the dielectric within an extremely narrow window from 0.15 to 0.39 nm. When the surface roughness is varied from smooth to rough, the domain size and molecular order in the monolayer are significantly decreased, leading to the reduction in electron mobility by 3 orders of magnitude. On the contrary, a lower roughness dependence is observed in the case of the bilayers, with only a slight difference in domain size and charge carrier transport. On the smooth surface, the bilayers exhibit a transistor performance identical to that of the bulk film, confirming that the first few layers near the dielectric dominate the charge carrier transport. Additionally, these results provide insights into the intrinsic role of the interfacial microstructure of small molecular organic semiconductors. PMID- 26958862 TI - Effect of Structural Transformation of Nanoparticulate Zero-Valent Iron on Generation of Reactive Oxygen Species. AB - While it has been recognized for some time that addition of nanoparticlate zerovalent iron (nZVI) to oxygen-containing water results in both corrosion of Fe(0) and oxidation of contaminants, there is limited understanding of either the relationship between transformation of nZVI and oxidant formation or the factors controlling the lifetime and extent of oxidant production. Using Fe K-edge extended X-ray absorption fine structure (EXAFS) spectroscopy, we show that while nZVI particles are transformed to ferrihydrite then lepidocrocite in less than 2 h, oxidant generation continues for up to 10 h. The major products (Fe(II) and H2O2) of the reaction of nZVI with oxygenated water are associated, for the most part, with the surface of particles present with these surface-associated Fenton reagents inducing oxidation of a target compound (in this study, (14)C-labeled formate). Effective oxidation of formate only occurred after formation of iron oxides on the nZVI surface with the initial formation of high surface area ferrihydrite facilitating rapid and extensive adsorption of formate with colocation of this target compound and surface-associated Fe(II) and H2O2 apparently critical to formate oxidation. Ongoing formate oxidation long after nZVI is consumed combined with the relatively slow consumption of Fe(II) and H2O2 suggest that these reactants are regenerated during the nZVI-initiated heterogeneous Fenton process. PMID- 26958863 TI - Dynamic Octahedral Breathing in Oxygen-Deficient Ba(0.9)Co(0.7)Fe(0.2)Nb(0.1)O(3 delta) Perovskite Performing as a Cathode in Intermediate-Temperature SOFC. AB - Ba(0.9)Co(0.7)Fe(0.2)Nb(0.1)O(3-delta) outperforms as a cathode in solid-oxide fuel cells (SOFC), at temperatures as low as 700-750 degrees C. The microscopical reason for this performance was investigated by temperature dependent neutron powder diffraction (NPD) experiments. In the temperature range of 25-800 degrees C, Ba(0.9)Co(0.7)Fe(0.2)Nb(0.1)O(3-delta) shows a perfectly cubic structure (a = a0), with a significant oxygen deficiency in a single oxygen site, that substantially increases at the working temperatures of a SOFC. The anisotropic thermal motion of oxygen atoms considerably rises with T, reaching B(eq) ~ 5 A(2) at 800 degrees C, with prolate cigar-shaped, anisotropic vibration ellipsoids that suggest a dynamic breathing of the octahedra as oxygen ions diffuse across the structure by a vacancies mechanism, thus implying a significant ionic mobility that could be described as a molten oxygen sublattice. The test cell with a La(0.8)Sr(0.2)Ga(0.83)Mg(0.17)O(3-delta) electrolyte (~300 MUm in thickness)-supported configuration yields a peak power density of 0.20 and 0.40 W cm(-2) at temperatures of 700 and 750 degrees C, respectively, with pure H2 as fuel and ambient air as oxidant. The electrochemical impedance spectra (EIS) evolution with time of the symmetric cathode fuel cell measured at 750 degrees C shows that the Ba(0.9)Co(0.7)Fe(0.2)Nb(0.1)O(3-delta) cathode possesses a superior ORR catalytic activity and long-term stability. The mixed electronic ionic conduction properties of Ba(0.9)Co(0.7)Fe(0.2)Nb(0.1)O(3-delta) account for its good performance as an oxygen-reduction catalyst. PMID- 26958864 TI - Poly(vinyl alcohol) Physical Hydrogels: Matrix-Mediated Drug Delivery Using Spontaneously Eroding Substrate. AB - Poly(vinyl alcohol) hydrogels have a long and successful history of applications in biomedicine. Historically, these matrices were developed to be nondegradable limiting their utility to applications as permanent implants. For tissue engineering and drug delivery, herein we develop spontaneously eroding physical hydrogels based on PVA. We characterize in detail a mild, noncryogenic method of producing PVA physical hydrogels using poly(ethylene glycol) as a gelating agent, and investigate PVA molar mass as a means to define the kinetics of erosion of these biomaterials. PVA hydrogels are characterized for associated inflammatory response in adhering macrophages, antiproliferative effects mediated through delivery of cytotoxic drugs to myoblasts, and pro-proliferative activity achieved via presentation of conjugated growth factors to endothelial cells. Together, these data present a multiangle characterization of these novel multifunctional matrices for applications in tissue engineering and drug delivery mediated by implantable biomaterials. PMID- 26958865 TI - Probing the Druggability Limits for Enzymes of the NAD Biosynthetic Network in Glioma. AB - The biosynthesis of NAD constitutes an important metabolic module in the cell, since NAD is an essential cofactor involved in several metabolic reactions. NAD concentrations are known to be significantly increased in several cancers, particularly in glioma, consistent with the observation of up-regulation of several enzymes of the network. Modulating NAD biosynthesis in glioma is therefore an attractive therapeutic strategy. Here we report reconstruction of a biochemical network of NAD biosynthesis consisting of 22 proteins, 36 metabolites, and 86 parameters, tuned to mimic the conditions in glioma. Kinetic simulations of the network provide comprehensive insights about the role of individual enzymes. Further, quantitative changes in the same network between different states of health and disease enable identification of drug targets, based on specific alterations in the given disease. Through simulations of enzyme inhibition titrations, we identify NMPRTase as a potential drug target, while eliminating other possible candidates NMNAT, NAPRTase, and NRK. We have also simulated titrations of both binding affinities as well as inhibitor concentrations, which provide insights into the druggability limits of the target, a novel aspect that can provide useful guidelines for designing inhibitors with optimal affinities. Our simulations suggest that an inhibitor affinity of 10 nM used in a concentration range of 0.1 to 10 MUM achieves a near maximal inhibition response for NMPRTase and that increasing the affinity any further is not likely to have a significant advantage. Thus, the quantitative appreciation defines a maximal extent of inhibition possible for a chosen enzyme in the context of its network. Knowledge of this type enables an upper affinity threshold to be defined as a goal in lead screening and refinement stages in drug discovery. PMID- 26958866 TI - Impact of D2O/H2O Solvent Exchange on the Emission of HgTe and CdTe Quantum Dots: Polaron and Energy Transfer Effects. AB - We have studied light emission kinetics and analyzed carrier recombination channels in HgTe quantum dots that were initially grown in H2O. When the solvent is replaced by D2O, the nonradiative recombination rate changes highlight the role of the vibrational degrees of freedom in the medium surrounding the dots, including both solvent and ligands. The contributing energy loss mechanisms have been evaluated by developing quantitative models for the nonradiative recombination via (i) polaron states formed by strong coupling of ligand vibration modes to a surface trap state (nonresonant channel) and (ii) resonant energy transfer to vibration modes in the solvent. We conclude that channel (i) is more important than (ii) for HgTe dots in either solution. When some of these modes are removed from the relevant spectral range by the H2O to D2O replacement, the polaron effect becomes weaker and the nonradiative lifetime increases. Comparisons with CdTe quantum dots (QDs) served as a reference where the resonant energy loss (ii) a priori was not a factor, also confirmed by our experiments. The solvent exchange (H2O to D2O), however, is found to slightly increase the overall quantum yield of CdTe samples, probably by increasing the fraction of bright dots in the ensemble. The fundamental study reported here can serve as the foundation for the design and optimization principles of narrow bandgap quantum dots aimed at applications in long wavelength colloidal materials for infrared light emitting diodes and photodetectors. PMID- 26958867 TI - Self-Setting Calcium Phosphate Cements with Tunable Antibiotic Release Rates for Advanced Antimicrobial Applications. AB - Osteomyelitis, an infectious disease predominantly tied to poor sanitary conditions in underdeveloped regions of the world, is in need of inexpensive, easily in situ synthesizable and administrable materials for its treatment. The results of this study stem from the attempt to create one such affordable and minimally invasive therapeutic platform in the form of a self-setting, injectable cement with a tunable drug release profile, composed of only nanoparticulate hydroxyapatite, the synthetic version of the bone mineral. Cements comprised two separately synthesized hydroxyapatite powders, one of which, HAP2, was precipitated abruptly, retaining the amorphous nature longer, and the other one of which, HAP1, was precipitated at a slower rate, more rapidly transitioning to the crystalline structure. Cements were made with four different weight ratios of the two hydroxyapatite components: 100/0, 85/15, 50/50, and 0/100 with respect to HAP1 and HAP2. Both the setting and the release rates measured on two different antibiotics, vancomycin and ciprofloxacin, were controlled using the weight ratio of the two hydroxyapatite components. Various inorganic powder properties were formerly used to control drug release, but here we demonstrate for the first time that the kinetics of the mechanism of formation of a solid compound can be controlled to produce tunable drug release profiles. Specifically, it was found that the longer the precursor calcium phosphate component of the cement retains the amorphous nature of the primary precipitate, the more active it was in terms of speeding up the diffusional release of the adsorbed drug. The setting rate was, in contrast, inversely proportional to the release rate and to the content of this active hydroxyapatite component, HAP2. The empirical release profiles were fitted to a set of equations that could be used to tune the release rate to the therapeutic occasion. All of the cements loaded with vancomycin or ciprofloxacin inhibited the growth of Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli and Pseudomonas aeruginosa in both agar diffusion assays and broth dilution tests with intensities either comparable to the antibiotic per se, as in the case of ciprofloxacin, or even larger than the antibiotic alone, as in the case of vancomycin. Interestingly, even the pure cements exhibited an antibacterial effect ranging from moderate to strong, while demonstrating high levels of biocompatibility with osteoclastic RAW264.7 cells and only slightly affecting the viability of the osteoblastic MC3T3-E1 cells, in direct proportion with the amount of the more active hydroxyapatite component in the cements. This antibacterial effect was especially noticeable against Gram negative bacteria, where the growth inhibition by the cements was comparable to or even stronger than that of the pure antibiotics. The antibiofilm assay against P. aeruginosa biofilms reiterated the antibiotic effectiveness of pure, antibiotic-free cements. That the carrier per se, composed of a nontoxic, easily prepared, bone mineral composite, can exhibit a strong antibacterial effect even in the absence of an antibiotic drug is an insight highly relevant in view of the rising resistance of an array of pathogens to traditional antibiotic therapies and the demands for the timely development of suitable alternatives. PMID- 26958868 TI - Post-Translational Regulation of the Glucose-6-Phosphatase Complex by Cyclic Adenosine Monophosphate Is a Crucial Determinant of Endogenous Glucose Production and Is Controlled by the Glucose-6-Phosphate Transporter. AB - The excessive endogenous glucose production (EGP) induced by glucagon participates in the development of type 2 diabetes. To further understand this hormonal control, we studied the short-term regulation by cyclic adenosine monophosphate (cAMP) of the glucose-6-phosphatase (G6Pase) enzyme, which catalyzes the last reaction of EGP. In gluconeogenic cell models, a 1-h treatment by the adenylate cyclase activator forskolin increased G6Pase activity and glucose production independently of any change in enzyme protein amount or G6P content. Using specific inhibitors or protein overexpression, we showed that the stimulation of G6Pase activity involved the protein kinase A (PKA). Results of site-directed mutagenesis, mass spectrometry analyses, and in vitro phosphorylation experiments suggested that the PKA stimulation of G6Pase activity did not depend on a direct phosphorylation of the enzyme. However, the temperature-dependent induction of both G6Pase activity and glucose release suggested a membrane-based mechanism. G6Pase is composed of a G6P transporter (G6PT) and a catalytic unit (G6PC). Surprisingly, we demonstrated that the increase in G6PT activity was required for the stimulation of G6Pase activity by forskolin. Our data demonstrate the existence of a post-translational mechanism that regulates G6Pase activity and reveal the key role of G6PT in the hormonal regulation of G6Pase activity and of EGP. PMID- 26958870 TI - Angular Impulse and Balance Regulation During the Golf Swing. AB - Our aim was to determine how skilled players regulate linear and angular impulse while maintaining balance during the golf swing. Eleven highly-skilled golf players performed swings with a 6-iron and driver. Components contributing to linear and angular impulse generated by the rear and target legs (resultant horizontal reaction force [RFh], RFh-angle, and moment arm) were quantified and compared across the group and within a player (alpha = .05). Net angular impulse generated by both the rear and target legs was greater for the driver than the 6 iron. Mechanisms used to regulate angular impulse generation between clubs varied across players and required coordination between the legs. Increases in net angular impulse with a driver involved increases in target leg RFh. Rear leg RFh angle was maintained between clubs whereas target leg RFh became more aligned with the target line. Net linear impulse perpendicular to the target line remained near zero, preserving balance, while net linear impulse along the target line decreased in magnitude. These results indicate that the net angular impulse was regulated between clubs by coordinating force generation of the rear and target legs while sustaining balance throughout the task. PMID- 26958869 TI - Grisemycin, a Bridged Angucyclinone with a Methylsulfinyl Moiety from a Marine Derived Streptomyces sp. AB - Grisemycin (1), the first sulfur angucyclinone with an unusual ether-bridged system, was isolated from a marine-derived Streptomyces griseus strain M268. Its novel, here cage-like, structure was determined by spectroscopic analysis and single-crystal X-ray diffraction. Compound 1 exhibited modestly selective activity against the HL-60 cell line with an IC50 value of 31.54 MUM. Futhermore, the absolute stereochemistry of kiamycin (2), an 1,12-epoxybenz[a]anthracene, previously obtained from the same strain, was established by X-ray diffraction analysis. PMID- 26958871 TI - Cellular Biophysics. PMID- 26958872 TI - Optogenetics: Turning the Microscope on Its Head. PMID- 26958873 TI - Probing Nature's Nanomachines One Molecule at a Time. PMID- 26958874 TI - The Current Revolution in Cryo-EM. PMID- 26958875 TI - Making Sense of Intrinsically Disordered Proteins. PMID- 26958876 TI - Inherited Arrhythmias: Of Channels, Currents, and Swimming. PMID- 26958877 TI - Systems Biophysics: Multiscale Biophysical Modeling of Organ Systems. PMID- 26958878 TI - How Viruses Invade Cells. PMID- 26958879 TI - K-Ras at Anionic Membranes: Orientation, Orientation...Orientation. Recent Simulations and Experiments. PMID- 26958880 TI - Spatiotemporal Control of Transmembrane Proteins through the Cytoskeleton: An Evolving Story. PMID- 26958881 TI - Models and Simulations as a Service: Exploring the Use of Galaxy for Delivering Computational Models. AB - We describe the ways in which Galaxy, a web-based reproducible research platform, can be used for web-based sharing of complex computational models. Galaxy allows users to seamlessly customize and run simulations on cloud computing resources, a concept we refer to as Models and Simulations as a Service (MaSS). To illustrate this application of Galaxy, we have developed a tool suite for simulating a high spatial-resolution model of the cardiac Ca(2+) spark that requires supercomputing resources for execution. We also present tools for simulating models encoded in the SBML and CellML model description languages, thus demonstrating how Galaxy's reproducible research features can be leveraged by existing technologies. Finally, we demonstrate how the Galaxy workflow editor can be used to compose integrative models from constituent submodules. This work represents an important novel approach, to our knowledge, to making computational simulations more accessible to the broader scientific community. PMID- 26958882 TI - Untangling the Influence of a Protein Knot on Folding. AB - Entanglement and knots occur across all aspects of the physical world. Despite the common belief that knots are too complicated for incorporation into proteins, knots have been identified in the native fold of a growing number of proteins. The discovery of proteins with this unique backbone characteristic has challenged the preconceptions about the complexity of biological structures, as well as current folding theories. Given the intricacies of the knotted geometry, the interplay between a protein's fold, structure, and function is of particular interest. Interestingly, for most of these proteins, the knotted region appears critical both in folding and function, although full understanding of these contributions is still incomplete. Here, we experimentally reveal the impact of the knot on the landscape, the origin of the bistable nature of the knotted protein, and broaden the view of knot formation as uniquely decoupled from folding. PMID- 26958883 TI - Molecular Basis of S100A1 Activation at Saturating and Subsaturating Calcium Concentrations. AB - The S100A1 protein mediates a wide variety of physiological processes through its binding of calcium (Ca(2+)) and endogenous target proteins. S100A1 presents two Ca(2+)-binding domains: a high-affinity "canonical" EF (cEF) hand and a low affinity "pseudo" EF (pEF) hand. Accumulating evidence suggests that both Ca(2+) binding sites must be saturated to stabilize an open state conducive to peptide recognition, yet the pEF hand's low affinity limits Ca(2+) binding at normal physiological concentrations. To understand the molecular basis of Ca(2+) binding and open-state stabilization, we performed 100 ns molecular dynamics simulations of S100A1 in the apo/holo (Ca(2+)-free/bound) states and a half-saturated state, for which only the cEF sites are Ca(2+)-bound. Our simulations indicate that the pattern of oxygen coordination about Ca(2+) in the cEF relative to the pEF site contributes to the former's higher affinity, whereas Ca(2+) binding strongly reshapes the protein's conformational dynamics by disrupting beta-sheet coupling between EF hands. Moreover, modeling of the half-saturated configuration suggests that the open state is unstable and reverts toward a closed state in the absence of the pEF Ca(2+) ion. These findings indicate that Ca(2+) binding at the cEF site alone is insufficient to stabilize opening; thus, posttranslational modification of the protein may be required for target peptide binding at subsaturating intracellular Ca(2+) levels. PMID- 26958884 TI - Photoactivation Reduces Side-Chain Dynamics of a LOV Photoreceptor. AB - We used neutron-scattering experiments to probe the conformational dynamics of the light, oxygen, voltage (LOV) photoreceptor PpSB1-LOV from Pseudomonas putida in both the dark and light states. Global protein diffusion and internal macromolecular dynamics were measured using incoherent neutron time-of-flight and backscattering spectroscopy on the picosecond to nanosecond timescales. Global protein diffusion of PpSB1-LOV is not influenced by photoactivation. Observation time-dependent global diffusion coefficients were found, which converge on the nanosecond timescale toward diffusion coefficients determined by dynamic light scattering. Mean-square displacements of localized internal motions and effective force constants, , describing the resilience of the proteins were determined on the respective timescales. Photoactivation significantly modifies the flexibility and the resilience of PpSB1-LOV. On the fast, picosecond timescale, small changes in the mean-square displacement and are observed, which are enhanced on the slower, nanosecond timescale. Photoactivation results in a slightly larger resilience of the photoreceptor on the fast, picosecond timescale, whereas in the nanosecond range, a significantly less resilient structure of the light-state protein is observed. For a residue-resolved interpretation of the experimental neutron-scattering data, we analyzed molecular dynamics simulations of the PpSB1-LOV X-ray structure. Based on these data, it is tempting to speculate that light-induced changes in the protein result in altered side-chain mobility mostly for residues on the protruding Jalpha helix and on the LOV-LOV dimer interface. Our results provide strong experimental evidence that side-chain dynamics play a crucial role in photoactivation and signaling of PpSB1 LOV via modulation of conformational entropy. PMID- 26958885 TI - Free-Energy Landscape of the Amino-Terminal Fragment of Huntingtin in Aqueous Solution. AB - The first exon of Huntingtin-a protein with multiple biological functions whose misfolding is related to Huntington's disease-modulates its localization, aggregation, and function within the cell. It is composed of a 17-amino-acid amphipathic segment (Htt17), an amyloidogenic segment of consecutive glutamines (QN), and a proline-rich segment. Htt17 is of fundamental importance: it serves as a membrane anchor to control the localization of huntingtin, it modulates huntingtin's function through posttranslational modifications, and it controls the self-assembly of the amyloidogenic QN segment into oligomers and fibrils. Experimentally, the conformational ensemble of the Htt17 monomer, as well as the impact of the polyglutamine and proline-rich segments, remains, however, mostly uncharacterized at the atomic level due to its intrinsic flexibility. Here, we unveil the free-energy landscape of Htt17, Htt17Q17, and Htt17Q17P11 using Hamiltonian replica exchange combined with well-tempered metadynamics. We characterize the free-energy landscape of these three fragments in terms of a few selected collective variables. Extensive simulations reveal that the free energy of Htt17 is dominated by a broad ensemble of configurations that agree with solution NMR chemical shifts. Addition of Q17 at its carboxy-terminus reduces the extent of the main basin to more extended configurations of Htt17 with lower helix propensity. Also, the aliphatic carbons of Q17 partially sequester the nonpolar amino acids of Htt17. For its part, addition of Q17P11 shifts the overall landscape to a more extended and helical Htt17 stabilized by interactions with Q17 and P11, which almost exclusively form a PPII-helix, as well as by intramolecular H-bonds and salt bridges. Our characterization of Huntingtin's amino-terminus provides insights into the structural origin of its ability to oligomerize and interact with phospholipid bilayers, processes closely linked to the biological functions of this protein. PMID- 26958886 TI - The Voltage Activation of Cortical KCNQ Channels Depends on Global PIP2 Levels. AB - The slow afterhyperpolarization (sAHP) is a calcium-activated potassium conductance with critical roles in multiple physiological processes. Pharmacological and genetic data suggest that KCNQ channels partly mediate the sAHP. However, these channels are not typically open within the observed voltage range of the sAHP. Recent work has shown that the sAHP is gated by increased PIP2 levels, which are generated downstream of calcium binding by neuronal calcium sensors such as hippocalcin. Here, we examined whether changes in PIP2 levels could shift the voltage-activation range of KCNQ channels. In HEK293T cells, expression of the PIP5 kinase PIPKIgamma90, which increases global PIP2 levels, shifted the KCNQ voltage activation to within the operating range of the sAHP. Further, the sensitivity of this effect on KCNQ3 channels appeared to be higher than that on KCNQ2. Therefore, we predict that KCNQ3 plays an essential role in maintaining the sAHP under low PIP2 conditions. In support of this notion, we find that sAHP inhibition by muscarinic receptors that increase phosphoinositide turnover in neurons is enhanced in Kcnq3-knockout mice. Likewise, the presence of KCNQ3 is essential for maintaining the sAHP when hippocalcin is ablated, a condition that likely impairs PIP2 generation. Together, our results establish the relationship between PIP2 and the voltage dependence of cortical KCNQ channels (KCNQ2/3, KCNQ3/5, and KCNQ5), and suggest a possible mechanism for the involvement of KCNQ channels in the sAHP. PMID- 26958887 TI - Glutathionylation-Dependence of Na(+)-K(+)-Pump Currents Can Mimic Reduced Subsarcolemmal Na(+) Diffusion. AB - The existence of a subsarcolemmal space with restricted diffusion for Na(+) in cardiac myocytes has been inferred from a transient peak electrogenic Na(+)-K(+) pump current beyond steady state on reexposure of myocytes to K(+) after a period of exposure to K(+)-free extracellular solution. The transient peak current is attributed to enhanced electrogenic pumping of Na(+) that accumulated in the diffusion-restricted space during pump inhibition in K(+)-free extracellular solution. However, there are no known physical barriers that account for such restricted Na(+) diffusion, and we examined if changes of activity of the Na(+) K(+) pump itself cause the transient peak current. Reexposure to K(+) reproduced a transient current beyond steady state in voltage-clamped ventricular myocytes as reported by others. Persistence of it when the Na(+) concentration in patch pipette solutions perfusing the intracellular compartment was high and elimination of it with K(+)-free pipette solution could not be reconciled with restricted subsarcolemmal Na(+) diffusion. The pattern of the transient current early after pump activation was dependent on transmembrane Na(+)- and K(+) concentration gradients suggesting the currents were related to the conformational poise imposed on the pump. We examined if the currents might be accounted for by changes in glutathionylation of the beta1 Na(+)-K(+) pump subunit, a reversible oxidative modification that inhibits the pump. Susceptibility of the beta1 subunit to glutathionylation depends on the conformational poise of the Na(+)-K(+) pump, and glutathionylation with the pump stabilized in conformations equivalent to those expected to be imposed on voltage clamped myocytes supported this hypothesis. So did elimination of the transient K(+)-induced peak Na(+)-K(+) pump current when we included glutaredoxin 1 in patch pipette solutions to reverse glutathionylation. We conclude that transient K(+)-induced peak Na(+)-K(+) pump current reflects the effect of conformation dependent beta1 pump subunit glutathionylation, not restricted subsarcolemmal diffusion of Na(+). PMID- 26958888 TI - Calculating Transition Energy Barriers and Characterizing Activation States for Steps of Fusion. AB - We use continuum mechanics to calculate an entire least energy pathway of membrane fusion, from stalk formation, to pore creation, and through fusion pore enlargement. The model assumes that each structure in the pathway is axially symmetric. The static continuum stalk structure agrees quantitatively with experimental stalk architecture. Calculations show that in a stalk, the distal monolayer is stretched and the stored stretching energy is significantly less than the tilt energy of an unstretched distal monolayer. The string method is used to determine the energy of the transition barriers that separate intermediate states and the dynamics of two bilayers as they pass through them. Hemifusion requires a small amount of energy independently of lipid composition, while direct transition from a stalk to a fusion pore without a hemifusion intermediate is highly improbable. Hemifusion diaphragm expansion is spontaneous for distal monolayers containing at least two lipid components, given sufficiently negative diaphragm spontaneous curvature. Conversely, diaphragms formed from single-component distal monolayers do not expand without the continual injection of energy. We identify a diaphragm radius, below which central pore expansion is spontaneous. For larger diaphragms, prior studies have shown that pore expansion is not axisymmetric, and here our calculations supply an upper bound for the energy of the barrier against pore formation. The major energy-requiring deformations in the steps of fusion are: widening of a hydrophobic fissure in bilayers for stalk formation, splay within the expanding hemifusion diaphragm, and fissure widening initiating pore formation in a hemifusion diaphragm. PMID- 26958889 TI - Oncogenic K-Ras Binds to an Anionic Membrane in Two Distinct Orientations: A Molecular Dynamics Analysis. AB - K-Ras is a membrane-associated GTPase that cycles between active and inactive conformational states to regulate a variety of cell signaling pathways. Somatic mutations in K-Ras are linked to 15-20% of all human tumors. K-Ras attaches to the inner leaflet of the plasma membrane via a farnesylated polybasic domain; however, the structural details of the complex remain poorly understood. Based on extensive (7.5 MUs total) atomistic molecular dynamics simulations here we show that oncogenic mutant K-Ras interacts with a negatively charged lipid bilayer membrane in multiple orientations. Of these, two highly populated orientations account for ~54% of the conformers whose catalytic domain directly interacts with the bilayer. In one of these orientation states, membrane binding involves helices 3 and 4 of the catalytic domain in addition to the farnesyl and polybasic motifs. In the other orientation, beta-strands 1-3 and helix 2 on the opposite face of the catalytic domain contribute to membrane binding. Flexibility of the linker region was found to be important for the reorientation. The biological significance of these observations was evaluated by initial experiments in cells overexpressing mutant K-Ras as well as by an analysis of Ras-effector complex structures. The results suggest that only one of the two major orientation states is capable of effector binding. We propose that the different modes of membrane binding may be exploited in structure-based drug design efforts for cancer therapy. PMID- 26958890 TI - MreB-Dependent Organization of the E. coli Cytoplasmic Membrane Controls Membrane Protein Diffusion. AB - The functional organization of prokaryotic cell membranes, which is essential for many cellular processes, has been challenging to analyze due to the small size and nonflat geometry of bacterial cells. Here, we use single-molecule fluorescence microscopy and three-dimensional quantitative analyses in live Escherichia coli to demonstrate that its cytoplasmic membrane contains microdomains with distinct physical properties. We show that the stability of these microdomains depends on the integrity of the MreB cytoskeletal network underneath the membrane. We explore how the interplay between cytoskeleton and membrane affects trans-membrane protein (TMP) diffusion and reveal that the mobility of the TMPs tested is subdiffusive, most likely caused by confinement of TMP mobility by the submembranous MreB network. Our findings demonstrate that the dynamic architecture of prokaryotic cell membranes is controlled by the MreB cytoskeleton and regulates the mobility of TMPs. PMID- 26958891 TI - Endothelial Surface Protrusion by a Point Force. AB - During leukocyte rolling on the endothelium, surface protrusion and membrane tether extraction occur consecutively on leukocytes. Both surface protrusion and tether extraction of leukocytes stabilize leukocyte rolling. Tethers can also be extracted from endothelial cells (ECs), but surface protrusion of ECs has never been confirmed to exist. In this study, we examined EC surface protrusion with the micropipette aspiration technique. We found that, like leukocytes, surface protrusion on an EC did exist when a point force was imposed. Both the protrusional stiffness and the crossover force of EC surface protrusion were dependent on the force loading rate and the cytoskeletal integrity, but neither of them was dependent on tumor necrosis factor alpha stimulation. Temperature (37 degrees C) affected the protrusional stiffness only at small force loading rates. When a neutrophil was employed to directly impose the pulling force on the EC, simultaneous surface protrusion from both cells occurred, and it can be modeled as two springs connected in series, although the spring constants should be adjusted according to the force loading rate. Therefore, EC surface protrusion is an important aspect of leukocyte rolling, and it should not be ignored when leukocyte rolling stability is studied systematically. PMID- 26958892 TI - Characterization of Ternary Protein Systems In Vivo with Tricolor Heterospecies Partition Analysis. AB - Tools and assays that characterize protein-protein interactions are of fundamental importance to biology, because protein assemblies play a critical role in the control and regulation of nearly every cellular process. The availability of fluorescent proteins has facilitated the direct and real-time observation of protein-protein interactions inside living cells, but existing methods are mostly limited to binary interactions between two proteins. Because of the scarcity of techniques capable of identifying ternary interactions, we developed tricolor heterospecies partition analysis. The technique is based on brightness analysis of fluorescence fluctuations from three fluorescent proteins that serve as protein labels. We identified three fluorescent proteins suitable for tricolor brightness experiments. In addition, we developed the theory of identifying interactions in a ternary protein system using tricolor heterospecies partition analysis. The theory was verified by experiments on well-characterized protein systems. A graphical representation of the heterospecies partition data was introduced to visualize interactions in ternary protein systems. Lastly, we performed fluorescence fluctuation experiments on cells expressing a coactivator and two nuclear receptors and applied heterospecies partition analysis to explore the interactions of this ternary protein system. PMID- 26958893 TI - Intracellular Pressure Dynamics in Blebbing Cells. AB - Blebs are pressure-driven protrusions that play an important role in cell migration, particularly in three-dimensional environments. A bleb is initiated when the cytoskeleton detaches from the cell membrane, resulting in the pressure driven flow of cytosol toward the area of detachment and local expansion of the cell membrane. Recent experiments involving blebbing cells have led to conflicting hypotheses regarding the timescale of intracellular pressure propagation. The interpretation of one set of experiments supports a poroelastic model of the cytoplasm that leads to slow pressure equilibration when compared to the timescale of bleb expansion. A different study concludes that pressure equilibrates faster than the timescale of bleb expansion. To address this discrepancy, a dynamic computational model of the cell was developed that includes mechanics of and the interactions among the cytoplasm, the actin cortex, the cell membrane, and the cytoskeleton. The model results quantify the relationship among cytoplasmic rheology, pressure, and bleb expansion dynamics, and provide a more detailed picture of intracellular pressure dynamics. This study shows the elastic response of the cytoplasm relieves pressure and limits bleb size, and that both permeability and elasticity of the cytoplasm determine bleb expansion time. Our model with a poroelastic cytoplasm shows that pressure disturbances from bleb initiation propagate faster than the timescale of bleb expansion and that pressure equilibrates slower than the timescale of bleb expansion. The multiple timescales in intracellular pressure dynamics explain the apparent discrepancy in the interpretation of experimental results. PMID- 26958896 TI - Introduction to Biophysics Week: What is Biophysics? PMID- 26958894 TI - Limiting Energy Dissipation Induces Glassy Kinetics in Single-Cell High-Precision Responses. AB - Single cells often generate precise responses by involving dissipative out-of thermodynamic-equilibrium processes in signaling networks. The available free energy to fuel these processes could become limited depending on the metabolic state of an individual cell. How does limiting dissipation affect the kinetics of high-precision responses in single cells? I address this question in the context of a kinetic proofreading scheme used in a simple model of early-time T cell signaling. Using exact analytical calculations and numerical simulations, I show that limiting dissipation qualitatively changes the kinetics in single cells marked by emergence of slow kinetics, large cell-to-cell variations of copy numbers, temporally correlated stochastic events (dynamic facilitation), and ergodicity breaking. Thus, constraints in energy dissipation, in addition to negatively affecting ligand discrimination in T cells, can create a fundamental difficulty in determining single-cell kinetics from cell-population results. PMID- 26958895 TI - Dynamics of Mouth Opening in Hydra. AB - Hydra, a simple freshwater animal famous for its regenerative capabilities, must tear a hole through its epithelial tissue each time it opens its mouth. The feeding response of Hydra has been well-characterized physiologically and is regarded as a classical model system for environmental chemical biology. However, due to a lack of in vivo labeling and imaging tools, the biomechanics of mouth opening have remained completely unexplored. We take advantage of the availability of transgenic Hydra lines to perform the first dynamical analysis, to our knowledge, of Hydra mouth opening and test existing hypotheses regarding the underlying cellular mechanisms. Through cell position and shape tracking, we show that mouth opening is accompanied by changes in cell shape, but not cellular rearrangements as previously suggested. Treatment with a muscle relaxant impairs mouth opening, supporting the hypothesis that mouth opening is an active process driven by radial contractile processes (myonemes) in the ectoderm. Furthermore, we find that all events exhibit the same relative rate of opening. Because one individual can open consecutively to different amounts, this suggests that the degree of mouth opening is controlled through neuronal signaling. Finally, from the opening dynamics and independent measurements of the elastic properties of the tissues, we estimate the forces exerted by the myonemes to be on the order of a few nanoNewtons. Our study provides the first dynamical framework, to our knowledge, for understanding the remarkable plasticity of the Hydra mouth and illustrates that Hydra is a powerful system for quantitative biomechanical studies of cell and tissue behaviors in vivo. PMID- 26958897 TI - Safety of non-vitamin K antagonist oral anticoagulants - coronary risks. AB - INTRODUCTION: Since the approval and commercialization of non-vitamin K antagonist oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban, and rivaroxaban) several studies and meta-analyses have raised safety concerns regarding myocardial infarction (MI) risk among NOAC-treated patients, particularly with dabigatran. Uncertainty remains regarding the coronary risk associated with dabigatran, and whether this putative risk also applies to the other NOACs. AREAS COVERED: In this review, the coronary risks of NOACs based on findings from placebo-controlled trials are discussed, and randomized controlled trials and major cohort studies in AF patients are also appraised. We performed a random-effect meta-analysis, including both interventional trials and observational studies ("real-world" data). Further estimates were retrieved from the meta-analysis of coronary risk among NOAC-treated patients with concomitant AF and coronary disease. EXPERT OPINION: Currently, the best available data from both clinical trials and observational studies do not support the claim that patients treated with NOACs, including dabigatran, are at increased coronary risk. However, a definitive conclusion cannot be made (especially regarding dabigatran) and further data are required to address the coronary risks, mostly of high-risk patients. As with any therapeutic intervention, the possible complications should be balanced against the potential benefits at an individual patient level. PMID- 26958898 TI - Acute Effects of 30 Minutes Resistance and Aerobic Exercise on Cognition in a High School Sample. AB - PURPOSE: The purpose of this study was to determine differences in cognition between acute bouts of resistance exercise, aerobic exercise, and a nonexercise control in an untrained youth sample. METHOD: Ninety-four participants performed 30 min of aerobic exercise, resistance exercise, or nonexercise separated by 7 days each in a randomized crossover design. After each exercise intervention, participants were assessed using 2 cognitive tests. The Dot, Word, and Color elements of the Stroop Test (Victoria version) and Parts A and B of the Trail Making Test were used to measure cognition. RESULTS: Acute resistance and aerobic exercise resulted in similar improvements over nonexercise in all forms of the Stroop Test. Acute aerobic exercise led to improved performance over nonexercise and resistance exercise in Part B of the Trail-Making Test. Neither exercise intervention showed significant changes in time to complete Part A of the Trail Making Test. Boys outperformed girls on the Stroop Dot and Color Test following acute aerobic exercise, in the Stroop Dot, Word, and Color Test following acute resistance exercise, and in the Stroop Color Test and Trail-Making Test Part B following nonexercise. CONCLUSIONS: Both acute resistance and aerobic exercise increased measures of cognition over a nonexercise control in untrained high school youth. These findings suggest the merits of acute resistance exercise as an alternative or complement to aerobic activity for educators aiming to increase youth physical activity and cognitive function concurrently. PMID- 26958899 TI - Pregnancy snapshot: a retrospective, observational case-control study to evaluate the potential effects of maternal diabetes treatment during pregnancy on macrosomia. AB - OBJECTIVE: Pregnancy in women with diabetes is associated with increased incidence of macrosomia (high birth weight) versus women without diabetes. Macrosomia increases the risk of complications during delivery and neonatally. The potential effect on macrosomia incidence certain diabetes treatments may have is not fully established. This study aims to identify whether specific components of the prenatal care of mothers with diabetes are associated with increased macrosomia risk in a real-world U.S. RESEARCH DESIGN AND METHODS: Retrospective, observational case-controlled study of mothers either without diabetes, or with type 1 (T1D), type 2 (T2D), or gestational diabetes mellitus (G.D.M.), using data from a U.S. insurance claims database. Treatment selection was at physician discretion. MAIN OUTCOME MEASURE: Incidence of macrosomia. RESULTS: For mothers with T2D, use of neutral protamine Hagedorn (N.P.H.) insulin and glyburide increased during pregnancy, from 3.4% to 33.3%, and 3.7% to 16.5%, respectively. The most common G.D.M. treatments during pregnancy were glyburide (15.5%), N.P.H. (12.9%), basal-bolus therapy (10.0%), and metformin (8.1%). Endocrinologist care during pregnancy was associated with insulin use - but not glyburide use - for mothers with G.D.M., and with insulin use for mothers with T1D and T2D (compared with mothers not visiting an endocrinologist). Glyburide was associated with higher odds for macrosomia: G.D.M. (odds ratio [O.R.] 1.53, 95% confidence interval [C.I.] 1.38-1.69, p < 0.0001); T2D (O.R. 1.93, 95% C.I. 1.51-2.47, p < 0.0001). Endocrinologist care was associated with lower odds for macrosomia overall (O.R. 0.86, 95% C.I. 0.81-0.92) and for mothers with G.D.M. (O.R. 0.85, 95% C.I. 0.75-0.97, p = 0.0156) when the sub-populations were examined in separate models. CONCLUSIONS: Healthcare utilization and endocrinologist care were related to positive birth outcomes, especially with G.D.M. Further research into the safety and efficacy of glyburide in pregnancy is warranted. This study cannot infer causality and may not be representative of current U.S. healthcare practice. PMID- 26958901 TI - A Viability Approach for Robustness Measurement, Organizational Autopoiesis, and Cell Turnover in a Multicellular System. AB - In this article, we use the potential of computational biology to highlight the key role of cell apoptosis for studying some tissue's properties through in silico experiments of morphogenesis. Our morphogenesis model is a new approach focusing on the deterministic program within cells that controls their placement and their differentiation at the beginning of the embryogenesis. Indeed, when the tissue is made by just a few pair of cells, we consider that cellular mechanisms are related neither to the influence of mechanical forces nor to the spread of chemicals. Dynamics are based on spatial and logical choices, the other factors being involved when the tissue contains a large number of cells. We had established a mathematical formulation of such a model and had enlightened the link between phenotype (cell placement and cell differentiation) and genotype (cell program) at the early embryogenesis. Indeed, that work allowed for generating any early tissue and the associated program that designs it. We propose now to study and assess some properties of these tissues for further selection and classification purposes. More precisely, we present in this article novel methods to measure tissue robustness based on the backward morphogenesis of our model. We also show some implementations of their self-maintenance properties, on the one hand to deal with environment disturbances through autopoiesis and on the other hand to achieve a dynamical steady state which ensures tissue renewal. PMID- 26958902 TI - Variability in the Cross-Sectional Area and Narrowing of the Internal Jugular Vein in Patients Without Multiple Sclerosis. AB - OBJECTIVE: Chronic cerebrospinal vascular insufficiency is a proposed condition of intraluminal stenosis of the internal jugular vein (IJV) that impedes venous flow from the brain. Calculations of IJV stenosis are vague and described in veins with at least a 50% reduction in IJV caliber at a specific level. The purpose of this study was to assess normal changes in anatomic caliber of the course of the IJV in a generalized population. MATERIALS AND METHODS: Images from 500 consecutive contrast-enhanced neck CT studies performed in January-July 2011 were reviewed. Cross-sectional areas of the IJV were calculated at the jugular foramen, C1-C7 levels, and jugular angles bilaterally. Patients were excluded if they had severely motion-limited studies; limited clinical data; a history of multiple sclerosis, neck mass, or neck dissection; or known IJV occlusion. Normalized IJV cross-sectional areas at each level were compared with an averaged normalized cross-sectional area from all patients at each level. RESULTS: Greater than 50% narrowing compared with a normalized average was found in 133 of 363 patients (36.6%) and was seen at all IJV levels. In 36.1% of patients this narrowing occurred at the C1 level. Most of the areas of narrowing greater than 50% occurred above the C4 level. CONCLUSION: The IJV has marked variability in its course in the neck. Areas of narrowing greater than 50% occur most commonly in the upper cervical and skull base regions. Given the normal anatomic variations in IJV caliber, caution should be used when making the diagnosis of and treating IJV stenosis. PMID- 26958903 TI - Complicating causality: patient and professional perspectives on obstetric fistula in Nigeria. AB - Obstetric fistula, a preventable maternal morbidity characterised by chronic bladder and/or bowel incontinence, is widespread in Nigeria. This qualitative, multi-site study examined the competing narratives on obstetric fistula causality in Nigeria. Research methods were participant observation and in-depth interviews with 86 fistula patients and 43 healthcare professionals. The study found that both patient and professional narratives identified limited access to medical facilities as a major factor leading to obstetric fistula. Patients and professionals beliefs regarding the access problem, however, differed significantly. The majority of fistula patients reported either delivering or attempting to deliver in medical facilities and most patients attributed fistula to a lack of trained medical staff and mismanagement at medical facilities. Conversely, a majority of health professionals believed that women developed obstetric fistula because they chose to deliver at home due to women's traditional beliefs about womanhood and childbirth. Both groups described financial constraints and inadequate transport to medical facilities during complicated labour as related to obstetric fistula onset. Programmatic insights derived from these findings should inform fistula prevention interventions both with healthcare professionals and with Nigerian women. PMID- 26958904 TI - The Maturation of a Scientist: An Autobiography. AB - I was shaped by World War II, years of near starvation as a war refugee, postwar chaos, life in several countries, and relative affluence in later life. The truth is that as I was growing up I wanted to be a writer. My aspirations came to an end when, in order to speed up my graduation from college, I took courses in microbiology. It was my second love at first sight-that of my wife preceded it. I view science as an opportunity to discover the designs in the mosaics of life. What initiates my search of discovery is an observation that makes no sense unless there exists a novel design. Once the design is revealed there is little interest in filling all the gaps. I was fortunate to understand that what lasts are not the scientific reports but rather the generations of scientists whose education I may have influenced. PMID- 26958905 TI - The Legacy of Nat Sternberg: The Genesis of Cre-lox Technology. AB - Cre-lox of bacteriophage P1 has become one of the most widely used tools for genetic engineering in eukaryotes. The origins of this tool date to more than 30 years ago when Nat L. Sternberg discovered the recombinase, Cre, and its specific locus of crossover, lox, while studying the maintenance of bacteriophage P1 as a stable plasmid. Recombinations mediated by Cre assist in cyclization of the DNA of infecting phage and in resolution of prophage multimers created by generalized recombination. Early in vitro work demonstrated that, although it shares similarities with the well-characterized bacteriophage lambda integration, Cre lox is in many ways far simpler in its requirements for carrying out recombination. These features would prove critical for its development as a powerful and versatile tool in genetic engineering. We review the history of the discovery and characterization of Cre-lox and touch upon the present direction of Cre-lox research. PMID- 26958906 TI - Biogeography of Viruses in the Sea. AB - Viral ecology is a rapidly progressing area of research, as molecular methods have improved significantly for targeted research on specific populations and whole communities. To interpret and synthesize global viral diversity and distribution, it is feasible to assess whether macroecology concepts can apply to marine viruses. We review how viral and host life history and physical properties can influence viral distribution in light of biogeography and metacommunity ecology paradigms. We highlight analytical approaches that can be applied to emerging global data sets and meta-analyses to identify individual taxa with global influence and drivers of emergent properties that influence microbial community structure by drawing on examples across the spectrum of viral taxa, from RNA to ssDNA and dsDNA viruses. PMID- 26958907 TI - Role of the Insect Supervectors Bemisia tabaci and Frankliniella occidentalis in the Emergence and Global Spread of Plant Viruses. AB - Emergence of insect-transmitted plant viruses over the past 10-20 years has been disproportionately driven by two so-called supervectors: the whitefly, Bemisia tabaci, and the Western flower thrips, Frankliniella occidentalis. High rates of reproduction and dispersal, extreme polyphagy, and development of insecticide resistance, together with human activities, have made these insects global pests. These supervectors transmit a diversity of plant viruses by different mechanisms and mediate virus emergence through local evolution, host shifts, mixed infections, and global spread. Associated virus evolution involves reassortment, recombination, and component capture. Emergence of B. tabaci-transmitted geminiviruses (begomoviruses), ipomoviruses, and torradoviruses has led to global disease outbreaks as well as multiple paradigm shifts. Similarly, F. occidentalis has mediated tospovirus host shifts and global dissemination and the emergence of pollen-transmitted ilarviruses. The plant virus-supervector interaction offers exciting opportunities for basic research and global implementation of generalized disease management strategies to reduce economic and environmental impacts. PMID- 26958908 TI - Coronavirus Host Range Expansion and Middle East Respiratory Syndrome Coronavirus Emergence: Biochemical Mechanisms and Evolutionary Perspectives. AB - Coronaviruses have frequently expanded their host range in recent history, with two events resulting in severe disease outbreaks in human populations. Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2003 in Southeast Asia and rapidly spread around the world before it was controlled by public health intervention strategies. The 2012 Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak represents another prime example of virus emergence from a zoonotic reservoir. Here, we review the current knowledge of coronavirus cross-species transmission, with particular focus on MERS-CoV. MERS CoV is still circulating in the human population, and the mechanisms governing its cross-species transmission have been only partially elucidated, highlighting a need for further investigation. We discuss biochemical determinants mediating MERS-CoV host cell permissivity, including virus spike interactions with the MERS CoV cell surface receptor dipeptidyl peptidase 4 (DPP4), and evolutionary mechanisms that may facilitate host range expansion, including recombination, mutator alleles, and mutational robustness. Understanding these mechanisms can help us better recognize the threat of emergence for currently circulating zoonotic strains. PMID- 26958909 TI - Koala Retroviruses: Evolution and Disease Dynamics. AB - A retroviral etiology for malignant neoplasias in koalas has long been suspected. Evidence for retroviral involvement was bolstered in 2000 by the isolation of a koala retrovirus (KoRV), now termed KoRV-A. KoRV-A is an endogenous retrovirus-a retrovirus that infects germ cells-a feature that makes it a permanent resident of the koala genome. KoRV-A lacks the genetic diversity of an exogenous retrovirus, a quality associated with the ability of a retrovirus to cause neoplasias. In 2013, a second KoRV isolate, KoRV-B, was obtained from koalas with lymphomas in the Los Angeles Zoo. Unlike KoRV-A, which is present in the genomes of all koalas in the United States, KoRV-B is restricted in its distribution and is associated with host pathology (neoplastic disease). Here, our current understanding of the evolution of endogenous and exogenous KoRVs, and the relationship between them, is reviewed to build a perspective on the future impact of these viruses on koala sustainability. PMID- 26958910 TI - Endogenous Retroviruses in the Genomics Era. AB - Endogenous retroviruses comprise millions of discrete genetic loci distributed within the genomes of extant vertebrates. These sequences, which are clearly related to exogenous retroviruses, represent retroviral infections of the deep past, and their abundance suggests that retroviruses were a near-constant presence throughout the evolutionary history of modern vertebrates. Endogenous retroviruses contribute in myriad ways to the evolution of host genomes, as mutagens and as sources of genetic novelty (both coding and regulatory) to be acted upon by the twin engines of random genetic drift and natural selection. Importantly, the richness and complexity of endogenous retrovirus data can be used to understand how viruses spread and adapt on evolutionary timescales by combining population genetics and evolutionary theory with a detailed understanding of retrovirus biology (gleaned from the study of extant retroviruses). In addition to revealing the impact of viruses on organismal evolution, such studies can help us better understand, by looking back in time, how life-history traits, as well as ecological and geological events, influence the movement of viruses within and between populations. PMID- 26958911 TI - Matters of Size: Genetic Bottlenecks in Virus Infection and Their Potential Impact on Evolution. AB - For virus infections of multicellular hosts, narrow genetic bottlenecks during transmission and within-host spread appear to be widespread. These bottlenecks will affect the maintenance of genetic variation in a virus population and the prevalence of mixed-strain infections, thereby ultimately determining the strength with which different random forces act during evolution. Here we consider different approaches for estimating bottleneck sizes and weigh their merits. We then review quantitative estimates of bottleneck size during cellular infection, within-host spread, horizontal transmission, and finally vertical transmission. In most cases we find that bottlenecks do regularly occur, although in many cases they appear to be virion-concentration dependent. Finally, we consider the evolutionary implications of genetic bottlenecks during virus infection. Although on average strong bottlenecks will lead to declines in fitness, we consider a number of scenarios in which bottlenecks could also be advantageous for viruses. PMID- 26958912 TI - The Phage-Inducible Chromosomal Islands: A Family of Highly Evolved Molecular Parasites. AB - The phage-inducible chromosomal islands (PICIs) are a family of highly mobile genetic elements that contribute substantively to horizontal gene transfer, host adaptation, and virulence. Initially identified in Staphylococcus aureus, these elements are now thought to occur widely in gram-positive bacteria. They are molecular parasites that exploit certain temperate phages as helpers, using a variety of elegant strategies to manipulate the phage life cycle and promote their own spread, both intra- and intergenerically. At the same time, these PICI encoded mechanisms severely interfere with helper phage reproduction, thereby enhancing survival of the bacterial population. In this review we discuss the genetics and the life cycle of these elements, with special emphasis on how they interact and interfere with the helper phage machinery for their own benefit. We also analyze the role that these elements play in driving bacterial and viral evolution. PMID- 26958913 TI - Deep Recombination: RNA and ssDNA Virus Genes in DNA Virus and Host Genomes. AB - Viruses are notorious for rapidly exchanging genetic information between close relatives and with the host cells they infect. This exchange has profound effects on the nature and rapidity of virus and host evolution. Recombination between dsDNA viruses is common, as is genetic exchange between dsDNA viruses or retroviruses and host genomes. Recombination between RNA virus genomes is also well known. In contrast, genetic exchange across viral kingdoms, for instance between nonretroviral RNA viruses or ssDNA viruses and host genomes or between RNA and DNA viruses, was previously thought to be practically nonexistent. However, there is now growing evidence for both RNA and ssDNA viruses recombining with host dsDNA genomes and, more surprisingly, RNA virus genes recombining with ssDNA virus genomes. Mechanisms are still unclear, but this deep recombination greatly expands the breadth of virus evolution and confounds virus taxonomy. PMID- 26958914 TI - Hunting Viral Receptors Using Haploid Cells. AB - Viruses have evolved intricate mechanisms to gain entry into the host cell. Identification of host proteins that serve as viral receptors has enabled insights into virus particle internalization, host and tissue tropism, and viral pathogenesis. In this review we discuss the most commonly employed methods for virus receptor discovery, specifically highlighting the use of forward genetic screens in human haploid cells. The ability to generate true knockout alleles at high saturation provides a sensitive means to study virus-host interactions. To illustrate the power of such haploid genetic screens, we highlight the discovery of the lysosomal proteins NPC1 and LAMP1 as intracellular receptors for Ebola virus and Lassa virus, respectively. From these studies emerges the notion that receptor usage by these viruses is highly dynamic, involving a programmed switch from cell surface receptor to intracellular receptor. Broad application of genetic knockout approaches will chart functional landscapes of receptors and endocytic pathways hijacked by viruses. PMID- 26958917 TI - Flaviviridae Replication Organelles: Oh, What a Tangled Web We Weave. AB - Replication of positive-strand RNA viruses occurs in tight association with reorganized host cell membranes. In a concerted fashion, viral and cellular factors generate distinct organelle-like structures, designated viral replication factories. These virus-induced compartments promote highly efficient genome replication, allow spatiotemporal coordination of the different steps of the viral replication cycle, and protect viral RNA from the hostile cytoplasmic environment. The combined use of ultrastructural and functional studies has greatly increased our understanding of the architecture and biogenesis of viral replication factories. Here, we review common concepts and distinct differences in replication organelle morphology and biogenesis within the Flaviviridae family, exemplified by dengue virus and hepatitis C virus. We discuss recent progress made in our understanding of the complex interplay between viral determinants and subverted cellular membrane homeostasis in biogenesis and maintenance of replication factories of this virus family. PMID- 26958915 TI - Retroviral Integrase: Then and Now. AB - The retroviral integrases are virally encoded, specialized recombinases that catalyze the insertion of viral DNA into the host cell's DNA, a process that is essential for virus propagation. We have learned a great deal since the existence of an integrated form of retroviral DNA (the provirus) was first proposed by Howard Temin in 1964. Initial studies focused on the genetics and biochemistry of avian and murine virus DNA integration, but the pace of discovery increased substantially with advances in technology, and an influx of investigators focused on the human immunodeficiency virus. We begin with a brief account of the scientific landscape in which some of the earliest discoveries were made, and summarize research that led to our current understanding of the biochemistry of integration. A more detailed account of recent analyses of integrase structure follows, as they have provided valuable insights into enzyme function and raised important new questions. PMID- 26958919 TI - Ribosome Profiling as a Tool to Decipher Viral Complexity. AB - Viral genomes harbor a variety of unusual translational phenomena that allow them to pack coding information more densely and evade host restriction mechanisms imposed by the cellular translational apparatus. Annotating translated sequences within these genomes thus poses particular challenges, but identifying the full complement of proteins encoded by a virus is critical for understanding its life cycle and defining the epitopes it presents for immune surveillance. Ribosome profiling is an emerging technique for global analysis of translation that offers direct and experimental annotation of viral genomes. Ribosome profiling has been applied to two herpesvirus genomes, those of human cytomegalovirus and Kaposi's sarcoma-associated herpesvirus, revealing translated sequences within presumptive long noncoding RNAs and identifying other micropeptides. Synthesis of these proteins has been confirmed by mass spectrometry and by identifying T cell responses following infection. Ribosome profiling in other viruses will likely expand further our understanding of viral gene regulation and the proteome. PMID- 26958916 TI - Continuous and Discontinuous RNA Synthesis in Coronaviruses. AB - Replication of the coronavirus genome requires continuous RNA synthesis, whereas transcription is a discontinuous process unique among RNA viruses. Transcription includes a template switch during the synthesis of subgenomic negative-strand RNAs to add a copy of the leader sequence. Coronavirus transcription is regulated by multiple factors, including the extent of base-pairing between transcription regulating sequences of positive and negative polarity, viral and cell protein RNA binding, and high-order RNA-RNA interactions. Coronavirus RNA synthesis is performed by a replication-transcription complex that includes viral and cell proteins that recognize cis-acting RNA elements mainly located in the highly structured 5' and 3' untranslated regions. In addition to many viral nonstructural proteins, the presence of cell nuclear proteins and the viral nucleocapsid protein increases virus amplification efficacy. Coronavirus RNA synthesis is connected with the formation of double-membrane vesicles and convoluted membranes. Coronaviruses encode proofreading machinery, unique in the RNA virus world, to ensure the maintenance of their large genome size. PMID- 26958918 TI - Modulation of the Translational Landscape During Herpesvirus Infection. AB - Herpesviral mRNAs are produced and translated by cellular machinery, rendering them susceptible to the network of regulatory events that impact translation. In response, these viruses have evolved to infiltrate and hijack translational control pathways as well as to integrate specialized host translation strategies into their own repertoire. They are robust systems to dissect mechanisms of mammalian translational regulation and continue to offer insight into cis-acting mRNA features that impact assembly and activity of the translation apparatus. Here, I discuss recent advances revealing the extent to which the three herpesvirus subfamilies regulate both host and viral translation, thereby dramatically impacting the landscape of protein synthesis in infected cells. PMID- 26958922 TI - Novel Functions of the Human Papillomavirus E6 Oncoproteins. AB - Human papillomaviruses (HPVs) infect the epidermis as well as mucous membranes of humans. They are the causative agents of anogenital tract and some oropharyngeal cancers. Infections begin in the basal epithelia, where the viral genome replicates slowly along with its host cell. As infected cells begin to differentiate and progress toward the periphery, the virus drives proliferation in cells that would otherwise be quiescent. To uncouple differentiation from continued cellular propagation, HPVs express two oncoproteins, HPV E6 and E7. This review focuses on high-risk alpha-HPV E6, which in addition to supporting viral replication has transforming properties. HPV E6 promotes p53 degradation and activates telomerase, but the multifaceted oncoprotein has numerous other functions that are highlighted here. PMID- 26958920 TI - Mechanisms of DNA Packaging by Large Double-Stranded DNA Viruses. AB - Translocation of viral double-stranded DNA (dsDNA) into the icosahedral prohead shell is catalyzed by TerL, a motor protein that has ATPase, endonuclease, and translocase activities. TerL, following endonucleolytic cleavage of immature viral DNA concatemer recognized by TerS, assembles into a pentameric ring motor on the prohead's portal vertex and uses ATP hydrolysis energy for DNA translocation. TerL's N-terminal ATPase is connected by a hinge to the C-terminal endonuclease. Inchworm models propose that modest domain motions accompanying ATP hydrolysis are amplified, through changes in electrostatic interactions, into larger movements of the C-terminal domain bound to DNA. In phage phi29, four of the five TerL subunits sequentially hydrolyze ATP, each powering translocation of 2.5 bp. After one viral genome is encapsidated, the internal pressure signals termination of packaging and ejection of the motor. Current focus is on the structures of packaging complexes and the dynamics of TerL during DNA packaging, endonuclease regulation, and motor mechanics. PMID- 26958923 TI - Parvovirus Family Conundrum: What Makes a Killer? AB - Parvoviruses infect a wide variety of hosts, and their ancestors appear to have emerged tens to hundreds of millions of years ago and to have spread widely ever since. The diversity of parvoviruses is therefore extensive, and although they all appear to descend from a common ancestor and share common structures in their capsid and nonstructural proteins, there is often low homology at the DNA or protein level. The diversity of these viruses is also seen in the widely differing impacts they have on their hosts, which range from severe and even lethal disease to subclinical or nonpathogenic infections. In the past few years, deep sequencing of DNA samples from animals has shown just how widespread the parvoviruses are in nature, but most of the newly discovered viruses have not yet been associated with any disease. However, variants of some parvoviruses have altered their host ranges to create new epidemic or pandemic viruses. Here, we examine the properties of parvoviruses and their interactions with their hosts that are associated with these disparate pathogenic outcomes. PMID- 26958924 TI - Everything You Always Wanted to Know About Rabies Virus (But Were Afraid to Ask). AB - The cultural impact of rabies, the fatal neurological disease caused by infection with rabies virus, registers throughout recorded history. Although rabies has been the subject of large-scale public health interventions, chiefly through vaccination efforts, the disease continues to take the lives of about 40,000 70,000 people per year, roughly 40% of whom are children. Most of these deaths occur in resource-poor countries, where lack of infrastructure prevents timely reporting and postexposure prophylaxis and the ubiquity of domestic and wild animal hosts makes eradication unlikely. Moreover, although the disease is rarer than other human infections such as influenza, the prognosis following a bite from a rabid animal is poor: There is currently no effective treatment that will save the life of a symptomatic rabies patient. This review focuses on the major unanswered research questions related to rabies virus pathogenesis, especially those connecting the disease progression of rabies with the complex dysfunction caused by the virus in infected cells. The recent applications of cutting-edge research strategies to this question are described in detail. PMID- 26958921 TI - Virus-Based Nanoparticles as Versatile Nanomachines. AB - Nanoscale engineering is revolutionizing the way we prevent, detect, and treat diseases. Viruses have played a special role in these developments because they can function as prefabricated nanoscaffolds that have unique properties and are easily modified. The interiors of virus particles can encapsulate and protect sensitive compounds, while the exteriors can be altered to display large and small molecules in precisely defined arrays. These properties of viruses, along with their innate biocompatibility, have led to their development as actively targeted drug delivery systems that expand on and improve current pharmaceutical options. Viruses are naturally immunogenic, and antigens displayed on their surface have been used to create vaccines against pathogens and to break self tolerance to initiate an immune response to dysfunctional proteins. Densely and specifically aligned imaging agents on viruses have allowed for high-resolution and noninvasive visualization tools to detect and treat diseases earlier than previously possible. These and future applications of viruses have created an exciting new field within the disciplines of both nanotechnology and medicine. PMID- 26958925 TI - Pathophysiological Consequences of Calcium-Conducting Viroporins. AB - Eukaryotic cells have evolved a myriad of ion channels, transporters, and pumps to maintain and regulate transmembrane ion gradients. As intracellular parasites, viruses also have evolved ion channel proteins, called viroporins, which disrupt normal ionic homeostasis to promote viral replication and pathogenesis. The first viral ion channel (influenza M2 protein) was confirmed only 23 years ago, and since then studies on M2 and many other viroporins have shown they serve critical functions in virus entry, replication, morphogenesis, and immune evasion. As new candidate viroporins and viroporin-mediated functions are being discovered, we review the experimental criteria for viroporin identification and characterization to facilitate consistency within this field of research. Then we review recent studies on how the few Ca(2+)-conducting viroporins exploit host signaling pathways, including store-operated Ca(2+) entry, autophagy, and inflammasome activation. These viroporin-induced aberrant Ca(2+) signals cause pathophysiological changes resulting in diarrhea, vomiting, and proinflammatory diseases, making both the viroporin and host Ca(2+) signaling pathways potential therapeutic targets for antiviral drugs. PMID- 26958926 TI - Virus-Host Interactions: From Unbiased Genetic Screens to Function. AB - Deciphering the many interactions that occur between a virus and host cell over the course of infection is paramount to understanding mechanisms of pathogenesis and to the future development of antiviral therapies. Over the past decade, researchers have started to understand these complicated relationships through the development of methodologies, including advances in RNA interference, proteomics, and the development of genetic tools such as haploid cell lines, allowing high-throughput screening to identify critical contact points between virus and host. These advances have produced a wealth of data regarding host factors hijacked by viruses to promote infection, as well as antiviral factors responsible for subverting viral infection. This review highlights findings from virus-host screens and discusses our thoughts on the direction of screening strategies moving forward. PMID- 26958928 TI - No Love Lost Between Viruses and Interferons. AB - The interferon system protects mammals against virus infections. There are several types of interferons, which are characterized by their ability to inhibit virus replication and resultant pathogenesis by triggering both innate and cell mediated immune responses. Virus infection is sensed by a variety of cellular pattern-recognition receptors and triggers the synthesis of interferons, which are secreted by the infected cells. In uninfected cells, cell surface receptors recognize the secreted interferons and activate intracellular signaling pathways that induce the expression of interferon-stimulated genes; the proteins encoded by these genes inhibit different stages of virus replication. To avoid extinction, almost all viruses have evolved mechanisms to defend themselves against the interferon system. Consequently, a dynamic equilibrium of survival is established between the virus and its host, an equilibrium that can be shifted to the host's favor by the use of exogenous interferon as a therapeutic antiviral agent. PMID- 26958927 TI - Viruses in Rodent Colonies: Lessons Learned from Murine Noroviruses. AB - Noroviruses (NoVs) are highly prevalent, positive-sense RNA viruses that infect a range of mammals, including humans and mice. Murine noroviruses (MuNoVs) are the most prevalent pathogens in biomedical research colonies, and they have been used extensively as a model system for human noroviruses (HuNoVs). Despite recent successes in culturing HuNoVs in the laboratory and a small animal host, studies of human viruses have inherent limitations. Thus, owing to its versatility, the MuNoV system-with its native host, reverse genetics, and cell culture systems will continue to provide important insights into NoV and enteric virus biology. In the current review, we summarize recent findings from MuNoVs that increase our understanding of enteric virus pathogenesis and highlight similarities between human and murine NoVs that underscore the value of MuNoVs to inform studies of HuNoV biology. We also discuss the potential of endemic MuNoV infections to impact other disease models. PMID- 26958930 TI - Bacteriophage Therapy: Advances in Formulation Strategies and Human Clinical Trials. AB - Recently, a number of phage therapy phase I and II safety trials have been concluded, showing no notable safety concerns associated with the use of phage. Though hurdles for efficient treatment remain, these trials hold promise for future phase III clinical trials. Interestingly, most phage formulations used in these clinical trials are straightforward phage suspensions, and not much research has focused on the processing of phage cocktails in specific pharmaceutical dosage forms. Additional research on formulation strategies and the stability of phage-based drugs will be of key importance, especially with phage therapy advancing toward phase III clinical trials. PMID- 26958931 TI - Wheelchair seating: A study on the healthy elderly. AB - BACKGROUND: Many frail elderly and disabled persons have to use a manual wheelchair to remain mobile and active. Apart from a well-fitted wheelchair, an appropriate wheelchair cushion is considered crucial for postural support and to prevent complications. AIM: To examined the effect of two types of seat cushions in two types of wheelchairs with regard to pelvic rotation, respiratory function, and interface pressure. MATERIAL AND METHODS: Forty healthy elderly between 67 and 85 years of age participated. Two types of commonly used manual wheelchairs and two types of seat cushions were tested. Interface pressure, pelvic position, and respiratory function were measured using a sensor array mat, a study-specific inclinometer, and a spirometer. RESULTS: Differences in interface pressure and pelvic rotation between cushions were found in both wheelchairs. Compared with sitting on a standard cushion, sitting on the positioning cushion increased peak pressure. The posterior pelvic tilt increased with the positioning cushion in the Etac Cross wheelchair and for both cushions in the Etac Cross wheelchair compared with the HD Balance wheelchair. No difference was observed in respiratory function. CONCLUSIONS: This study highlights the importance of a thorough evaluation of the effects of wheelchair interventions, especially for the elderly and disabled. PMID- 26958932 TI - Conditions of Use, Reliability, and Quality of Audio/Video-Mediated Communications During In-Home Rehabilitation Teletreatment for Postknee Arthroplasty. AB - BACKGROUND: Audio/video-mediated communication between patients and clinicians using videoconferencing over telecommunication networks is a key component of providing teletreatments in rehabilitation. OBJECTIVE: The objectives of this study were to (1) document the conditions of use, performance, and reliability of videoconferencing-based communication in the context of in-home teletreatment (TELE) following total knee arthroplasty (TKA) and (2) assess from the perspective of the providers, the quality attributes of the technology used and its impact on clinical objectives. MATERIALS AND METHODS: Descriptive embedded study in a randomized controlled trial using a sample of 97 post-TKA patients, who received a total of 1,431 TELE sessions. Technical support use, service delivery reliability, performance, and use of network connection were assessed using self-report data from a costing grid and automated logs captured from videoconferencing systems. Physical therapists assessed the quality and impact of video-mediated communications after each TELE session on seven attributes. RESULTS: Installation of a new Internet connection was required in 75% of the participants and average technician's time to install test and uninstall technology (including travel time) was 308.4 min. The reliability of service delivery was 96.5% of planned sessions with 21% of TELE session requiring a reconnection during the session. Remote technical support was solicited in 43% of the sessions (interventions were less than 3-min duration). Perceived technological impacts on video-mediated communications were minimal with quality of the overall technical environment evaluated as good or acceptable in 96% of the sessions and clinical objectives reached almost completely or completely in 99% of the sessions. CONCLUSIONS: In-home rehabilitation teletreatments can be delivered reliably but requires access to technical support for the initial setup and maintenance. Optimization of the processes of reliably connecting patients to the Internet, getting the telerehabilitation platform in the patient's home, installing, configuring, and testing will be needed to generalize this approach of service delivery. PMID- 26958933 TI - Parents' Stress and Coping Related to Children's Use of a Cochlear Implant: A Qualitative Study. AB - The aim was to increase understanding of parents' experiences of having a child with a cochlear implant (CI) and to explore how these related to children's use of CI. Twelve parents of children, full-time users or limited users of CIs, participated in the study. Qualitative content analysis showed that the parents of children who used their CI differed from the parents with limited users in how they handled stressors. Support from health care professionals was seen as insufficient. Parents need to get involved in dynamic processes in which health care resources promote parental coping. PMID- 26958935 TI - The Paradox of Increased Trimethylamine-N-Oxide Levels Following Bariatric Surgery. PMID- 26958936 TI - Partnerships, Not Parachutists, for Zika Research. PMID- 26958929 TI - Innate and Adaptive Immune Regulation During Chronic Viral Infections. AB - Chronic viral infections represent a unique challenge to the infected host. Persistently replicating viruses outcompete or subvert the initial antiviral response, allowing the establishment of chronic infections that result in continuous stimulation of both the innate and adaptive immune compartments. This causes a profound reprogramming of the host immune system, including attenuation and persistent low levels of type I interferons, progressive loss (or exhaustion) of CD8(+) T cell functions, and specialization of CD4(+) T cells to produce interleukin-21 and promote antibody-mediated immunity and immune regulation. Epigenetic, transcriptional, posttranscriptional, and metabolic changes underlie this adaptation or recalibration of immune cells to the emerging new environment in order to strike an often imperfect balance between the host and the infectious pathogen. In this review we discuss the common immunological hallmarks observed across a range of different persistently replicating viruses and host species, the underlying molecular mechanisms, and the biological and clinical implications. PMID- 26958937 TI - Oroxylin A modulates mitochondrial function and apoptosis in human colon cancer cells by inducing mitochondrial translocation of wild-type p53. AB - Oroxylin A is a flavonoid extracted from the root of Scutellaria baicalensis Georgi. We previously demonstrated that oroxylin A induced apoptosis in human colon cancer cells via the mitochondrial pathway. In the present study, we investigated the underlying mechanisms responsible for the mitochondrial apoptotic pathway triggered by oroxylin A. p53 regulates mitochondrial survival, mitochondrial DNA integrity, and protection from oxidative stress. We determined that oroxylin A induces p53 mitochondrial translocation and inhibits SOD2 activity. Additionally, our studies demonstrate that oroxylin A promotes the formation and mitochondrial translocation of the p53-Recql4 complex in HCT-116 cells. Finally, we showed that oroxylin A triggers cytosolic p53 activation, thereby promoting apoptosis. Mitochondrial translocation of p53 was also validated in vivo. Thus, oroxylin A induces mitochondrial translocation of p53 and leads to mitochondrial dysfunction in human colon cancer cells. PMID- 26958938 TI - Bufalin suppresses hepatocellular carcinoma invasion and metastasis by targeting HIF-1alpha via the PI3K/AKT/mTOR pathway. AB - It has been reported that there are multiple mechanisms by which bufalin could exert its antimetastatic effect. HIF-1alpha has been reported to be involved in tumor migration and invasion by regulating EMT. However, it is not known whether bufalin could exert the antimetastatic effect by modulating HIF-1alpha expression in hepatocellular carcinoma. In the present study, we aimed to evaluate the antimetastatic potential of bufalin in vivo and in vitro. Our results demonstrated that the liver/lung metastases were significantly reduced in bufalin treated mice, as tested in the orthotopic transplanted and tail vein injection tumor models. Furthermore, the epithelial-to-mesenchymal transition (EMT) was inhibited in bufalin-treated tumors, as reflected the upregulation of E-cadherin, and downregulation of N-cadherin, vimentin, Snail. Similar results were observed in SMMC7721 cells treated with bufalin. Moreover, the transforming growth factor beta1 (TGF-beta1)-induced EMT was also abrogated by bufalin. Mechanistically, our study demonstrated that hypoxia-inducible factor-1alpha (HIF-1alpha) played an important role in the antimetastatic effect of bufalin in hepatocellular carcinoma. Importantly, HIF-1alpha expression may be regulated through the inhibition of the PI3K/AKT/mTOR pathway. Taken together, our results suggest that bufalin suppresses hepatic tumor invasion and metastasis and that this process may be related to the PI3K/AKT/mTOR/ HIF-1alpha axis. PMID- 26958939 TI - Adipocytes WNT5a mediated dedifferentiation: a possible target in pancreatic cancer microenvironment. AB - A significant epidemiological association between obesity and pancreatic ductal adenocarcinoma (PDAC) has previously been described, as well as a correlation between the degree of pancreatic steatosis, PDAC risk and prognosis. The underlying mechanisms are still not completely known.After co-culture of 3T3-L1 adipocytes and MiaPaCa2 with an in vitro transwell system we observed the appearance of fibroblast-like cells, along with a decrease in number and size of remaining adipocytes. RT-PCR analyses of 3T3-L1 adipocytes in co-culture showed a decrease in gene expression of typical markers of mature adipocytes, in parallel with an increased expression of fibroblast-specific and reprogramming genes. We found an increased WNT5a gene and protein expression early in MiaPaCa2 cells in co-culture. Additionally, EMSA of c-Jun and AP1 in 3T3-L1 demonstrated an increased activation in adipocytes after co-culture. Treatment with WNT5a neutralizing antibody completely reverted the activation of c-Jun and AP1 observed in co-cultured adipocytes.Increasing doses of recombinant SFRP-5, a competitive inhibitor for WNT5a receptor, added to the co-culture medium, were able to block the dedifferentiation of adipocytes in co-culture.These data support a WNT5a-mediated dedifferentiation process with adipocytes reprogramming toward fibroblast-like cells that might profoundly influence cancer microenvironment. PMID- 26958940 TI - Tumor-promoting function and prognostic significance of the RNA-binding protein T cell intracellular antigen-1 in esophageal squamous cell carcinoma. AB - T-cell intracellular antigen-1 (TIA1) is an RNA-binding protein involved in many regulatory aspects of mRNA metabolism. Here, we report previously unknown tumor promoting activity of TIA1, which seems to be associated with its isoform specific molecular distribution and regulation of a set of cancer-related transcripts, in esophageal squamous cell carcinoma (ESCC). Immunohistochemical overexpression of TIA1 ectopically localized in the cytoplasm of tumor cells was an independent prognosticator for worse overall survival in a cohort of 143 ESCC patients. Knockdown of TIA1 inhibited proliferation of ESCC cells. By exogenously introducing each of two major isoforms, TIA1a and TIA1b, only TIA1a, which was localized to both the nucleus and cytoplasm, promoted anchorage-dependent and anchorage-independent ESCC cell proliferation. Ribonucleoprotein immunoprecipitation, followed by microarray analysis or massive-parallel sequencing, identified a set of TIA1-binding mRNAs, including SKP2 and CCNA2. TIA1 increased SKP2 and CCNA2 protein levels through the suppression of mRNA decay and translational induction, respectively. Our findings uncover a novel oncogenic function of TIA1 in esophageal tumorigenesis, and implicate its use as a marker for prognostic evaluation and as a therapeutic target in ESCC. PMID- 26958941 TI - N52 monodeamidated Bcl-xL shows impaired oncogenic properties in vivo and in vitro. AB - Bcl-xL is a member of the Bcl-2 family, playing a critical role in the survival of tumor cells. Here, we show that Bcl-xL oncogenic function can be uncoupled from its anti-apoptotic activity when it is regulated by the post-translational deamidation of its Asn52.Bcl-xL activity can be regulated by post-translational modifications: deamidation of Asn52 and 66 into Asp residues was reported to occur exclusively in response to DNA damage, and to cripple its anti-apoptotic activity. Our work reports for the first time the spontaneous occurrence of monodeamidated Asp52Bcl-xL in control conditions, in vivo and in vitro. In the normal and cancer cell lines tested, no less than 30% and up to 56% of Bcl-xL was singly deamidated on Asn52. Functional analyses revealed that singly deamidated Bcl-xL retains anti-apoptotic functions, and exhibits enhanced autophagic activity while harboring impaired clonogenic and tumorigenic properties compared to native Bcl-xL. Additionally, Asp52Bcl-xL remains phosphorylatable, and thus is still an eligible target of anti-neoplasic agents. Altogether our results complement the existing data on Bcl-xL deamidation: they challenge the common acceptance that Asn52 and Asn66 are equally eligible for deamidation, and provide a valuable improvement of our knowledge on the regulation of Bcl-xLoncogenic functions by deamidation. PMID- 26958942 TI - An image guided small animal stereotactic radiotherapy system. AB - Small animal radiotherapy studies should be performed preferably on irradiators capable of focal tumor irradiation and healthy tissue sparing. In this study, an image guided small animal arc radiation treatment system (iSMAART) was developed which can achieve highly precise radiation targeting through the utilization of onboard cone beam computed tomography (CBCT) guidance. The iSMAART employs a unique imaging and radiation geometry where animals are positioned upright. It consists of a stationary x-ray tube, a stationary flat panel detector, and a rotatable and translational animal stage. System performance was evaluated in regards to imaging, image guidance, animal positioning, and radiation targeting using phantoms and tumor bearing animals. The onboard CBCT achieved good signal, contrast, and sub-millimeter spatial resolution. The iodine contrast CBCT accurately delineated orthotopic prostate tumors. Animal positioning was evaluated with ~0.3 mm vertical displacement along superior-inferior direction. The overall targeting precision was within 0.4 mm. Stereotactic radiation beams conformal to tumor targets can be precisely delivered from multiple angles surrounding the animal. The iSMAART allows radiobiology labs to utilize an image guided precision radiation technique that can focally irradiate tumors while sparing healthy tissues at an affordable cost. PMID- 26958976 TI - Profiling analysis of amino acids from hyperlipidaemic rats treated with Gynostemma pentaphyllum and atorvastatin. AB - Context Gynostemma pentaphyllum (Thunb.) Makino has been used in traditional medicine for the treatment of hyperlipidaemic with a long history. OBJECTIVE: The objective of this study was to evaluate the influence of Gynostemma pentaphyllum (GP) and atorvastatin on amino acids from the plasma and liver tissue of hyperlipidaemic rats. Materials and methods The rats were fed a high-fat diet continuously for 11 weeks for the construction of hyperlipidaemic model. The hyperlipidaemic rats were treated with Gynostemma pentaphyllum (120 mg/kg) and atorvastatin (1.8 mg/kg) for 4 weeks, and the rats were intragastric administration one time every day. Chromatographic separation was performed on a Shim-pack XR-ODSIII C18 analytical column (75 mm * 2.0 mm i.d., 1.6 MUm, Shmadazu Corp., Tokyo, Japan). The biomarkers of amino acids were identified by principal component analysis (PCA) and partial least squares discriminant analysis (PLS DA). Results After feeding with a high-fat diet, the TC and LDL-C values of the hyperlipidaemic mode rats increased dramatically (p < 0.01). The established method allowed a target analysis of 12 kinds of amino acids. PCA studies showed that the plasma amino acids had not returned to normal after GP treatment, but those had recovered slightly after atorvastatin treatment. GP has almost no impact on the metabolism of amino acids, while atorvastatin can modify the metabolism of amino acids via self-regulatory mechanisms. Discussion and conclusion UPLC/DAD combined with SCX-SPE can be successfully used for profiling analysis of amino acids. By the comparison of biomarkers following treatment with GP and atorvastatin, the influence of the two drugs on biomarkers is revealed. PMID- 26958977 TI - A pictorial presentation of 3.0 Chicago Classification for esophageal motility disorders. AB - High resolution manometry changed several esophageal motility paradigms. The 3.0 Chicago Classification defined manometric criteria for named esophageal motility disorders. We present a pictorial atlas of motility disorders. Achalasia types, esophagogastric junction obstruction, absent contractility, distal esophageal spasm, hypercontractile esophagus (jackhammer), ineffective esophageal motility, and fragmented peristalsis are depicted with high-resolution manometry plots. RESUMO A manometria de alta resolucao mudou varios paradigmas da motilidade digestiva. A Classificacao de Chicago, na versao 3.0, definiu criterios manometricos para as doencas da motilidade esofagiana. O presente artigo e um atlas das dismotilidades descritas. Tipos de acalasia, obstrucao ao nivel da juncao esofagogastrica, contracoes ausentes, espasmo esofagiano distal, esofago hipercontratil, motilidade esofagiana ineficaz e peristalse fragmentada sao mostradas em tracados de manometria de alta resolucao. PMID- 26958978 TI - Intra-abdominal pressure: an integrative review. AB - There is a growing request for measuring intra-abdominal pressure in critically ill patients with acute abdominal pain to be clarified. Summarizing the research results on measurement of vesical intra-abdominal pressure and analyzing the level of evidence were the purposes of this integrative literature review, carried out based on the databases LILACS, MEDLINE and PubMed, from 2005 to July 2012. Twenty articles were identified, in that, 12 literature reviews, 4 descriptive and exploratory studies, 2 expert opinions, one prospective cohort study and one was an experience report. The vesical intra-abdominal pressure measurement was considered gold standard. There are variations in the technique however, but some common points were identified: complete supine position, in absence of abdominal contracture, in the end of expiration and expressed in mmHg. Most research results indicate keeping the transducer zeroed at the level of the mid-axillary line at the iliac crest level, and instill 25mL of sterile saline. Strong evidence must be developed. RESUMO Em pacientes criticos com quadros abdominais agudos a esclarecer e crescente a solicitacao da afericao da pressao intra-abdominal. Sintetizar resultados de pesquisas sobre a mensuracao da pressao intra-abdominal pela via vesical e analisar o nivel de evidencia foram os objetivos desta revisao integrativa da literatura, realizada nas bases LILACS, MEDLINE e PubMed, no periodo de 2005 a julho de 2012. Identificaram-se 20 artigos, sendo 12 revisoes de literatura, 4 estudos exploratorio-descritivos, 2 opinioes de especialistas, 1 estudo de coorte prospectivo e 1 relato de experiencia. O metodo vesical para mensuracao da pressao intra-abdominal foi considerado padrao-ouro. Existem variacoes na tecnica, entretanto pontos em comum foram identificados: posicao supina completa, na ausencia de contratura abdominal, ao final da expiracao e expressa em mmHg. A maioria indica posicionar o ponto zero do transdutor na linha axilar media, ao nivel da crista iliaca e instilar 25ml de solucao salina esteril. Evidencias fortes precisam ser desenvolvidas. PMID- 26958979 TI - Immunophenotypic evolution of blast populations in pediatric acute myeloid leukemia. PMID- 26958980 TI - Facial subcutaneous emphysema of late onset after frontal sinus fracture. PMID- 26958981 TI - Toxicological Perspective on Climate Change: Aquatic Toxins. AB - In recent years, our group and several others have been describing the presence of new, not previously reported, toxins of high toxicity in vectors that may reach the human food chain. These include tetrodotoxin in gastropods in the South of Europe, ciguatoxin in fish in the South of Spain, palytoxin in mussels in the Mediterranean Sea, pinnatoxin all over Europe, and okadaic acid in the south of the U.S. There seem to be new marine toxins appearing in areas that are heavy producers of seafood, and this is a cause of concern as most of these new toxins are not included in current legislation and monitoring programs. Along with the new toxins, new chemical analogues are being reported. The same phenomenom is being recorded in freshwater toxins, such as the wide appearance of cylindrospermopsin and the large worldwide increase of microcystin. The problem that this phenomenon, which may be linked to climate warming, poses for toxicologists is very important not only because there is a lack of chronic studies and an incomplete comprehension of the mechanism driving the production of these toxins but also because the lack of a legal framework for them allows many of these toxins to reach the market. In some cases, it is very difficult to control these toxins because there are not enough standards available, they are not always certified, and there is an insufficient understanding of the toxic equivalency factors of the different analogues in each group. All of these factors have been revealed and grouped through the massive increase in the use of LC-MS as a monitoring tool, legally demanded, creating more toxicological problems. PMID- 26958982 TI - Structure-Based Engineering of Lithium-Transport Capacity in an Archaeal Sodium Calcium Exchanger. AB - Members of the Ca(2+)/cation exchanger superfamily (Ca(2+)/CA) share structural similarities (including highly conserved ion-coordinating residues) while exhibiting differential selectivity for Ca(2+), Na(+), H(+), K(+), and Li(+). The archaeal Na(+)/Ca(2+) exchanger (NCX_Mj) and its mammalian orthologs are highly selective for Na(+), whereas the mitochondrial ortholog (NCLX) can transport either Li(+) or Na(+) in exchange with Ca(2+). Here, structure-based replacement of ion-coordinating residues in NCX_Mj resulted in a capacity for transporting either Na(+) or Li(+), similar to the case for NCLX. This engineered protein may serve as a model for elucidating the mechanisms underlying ion selectivity and ion-coupled alternating access in NCX and similar proteins. PMID- 26958983 TI - Intact Endogenous Metabolite Analysis of Mice Liver by Probe Electrospray Ionization/Triple Quadrupole Tandem Mass Spectrometry and Its Preliminary Application to in Vivo Real-Time Analysis. AB - Probe electrospray ionization (PESI) is a recently developed ionization technique that enables the direct detection of endogenous compounds like metabolites without sample preparation. In this study, we have demonstrated the first combination use of PESI with triple quadrupole tandem mass spectrometry (MS/MS), which was then applied to intact endogenous metabolite analysis of mice liver, achieving detection of 26 metabolites including amino acids, organic acids, and sugars. To investigate its practicality, metabolic profiles of control and CCl4 induced acute hepatic injury mouse model were measured by the developed method. Results showed clear separation of the two groups in score plots of principal component analysis and identified taurine as the primary contributor to group separation. The results were further validated by the established gas chromatography/MS/MS method, demonstrating the present method's usefulness. In addition, we preliminarily applied the method to real-time analysis of an intact liver of a living mouse. We successfully achieved monitoring of the real-time changes of two tricarboxylic acid cycle intermediates, alpha-ketoglutaric acid and fumaric acid, in the liver immediately after pyruvic acid injection via a cannulated tube to the portal vein. The present method achieved an intact analysis of metabolites in liver without sample preparation, and it also demonstrates future possibility to establish in vivo real-time metabolome analysis of living animals by PESI/MS/MS. PMID- 26958984 TI - Tryptic Stability of Synthetic Bactenecin Derivatives Is Determined by the Side Chain Length of Cationic Residues and the Peptide Conformation. AB - Synthetic bactenecins 1 (HHC-10) and 10 (HHC-36), with excellent activities against bacterial superbugs, display low tryptic stability. To investigate factors influencing this stability, a series of 1/10 derived peptides bearing arginine and lysine analogues with varied methylene chains as well as all-d isomers were synthesized. Whereas incorporation of d-/l-nonproteinogenic amino acids into the turn-forming peptides did not dramatically affect the antimicrobial activities, the degree of peptide cleavage decreased significantly in peptides with the shortest length of cationic side chain and was influenced by the relative conformational stabilities of the turn structure and the stereoselectivity of tryptic digestion. The site of enzymatic cleavage was located at the less conformationally hindered position distant from the turn motif. Isothermal titration calorimetry showed strong and weak constant increments in the generated heat of enzymatic reaction of unstable and slowly degradable peptides with trypsin, respectively, and suggested a one-site binding model for the enthalpy-driven all-d-peptide-trypsin interactions. PMID- 26958985 TI - Composite Membrane with Underwater-Oleophobic Surface for Anti-Oil-Fouling Membrane Distillation. AB - In this study, we fabricated a composite membrane for membrane distillation (MD) by modifying a commercial hydrophobic polyvinylidene fluoride (PVDF) membrane with a nanocomposite coating comprising silica nanoparticles, chitosan hydrogel and fluoro-polymer. The composite membrane exhibits asymmetric wettability, with the modified surface being in-air hydrophilic and underwater oleophobic, and the unmodified surface remaining hydrophobic. By comparing the performance of the composite membrane and the pristine PVDF membrane in direct contact MD experiments using a saline emulsion with 1000 ppm crude oil (in water), we showed that the fabricated composite membrane was significantly more resistant to oil fouling compared to the pristine hydrophobic PVDF membrane. Force spectroscopy was conducted for the interaction between an oil droplet and the membrane surface using a force tensiometer. The difference between the composite membrane and the pristine PVDF membrane in their interaction with an oil droplet served to explain the difference in the fouling propensities between these two membranes observed in MD experiments. The results from this study suggest that underwater oleophobic coating can effectively mitigate oil fouling in MD operations, and that the fabricated composite membrane with asymmetric wettability can enable MD to desalinate hypersaline wastewater with high concentrations of hydrophobic contaminants. PMID- 26958986 TI - Stereochemically Distinct Cyclotetrasiloxanes Containing 3-Pyridyl Moieties and Their Functional Coordination Polymers. AB - Synthesis of new cyclotetrasiloxane scaffolds containing peripherally functionalized 3-pyridyl moieties, [MeSiO(CH?CH(3)Py)]4 (L(1)) and [MeSiO(CH2CH2(3)Py)]4 (L(2)), and their reactivity studies with certain d(10) metal ions are reported. The ligand L(1) is obtained by the Heck-coupling reaction of tetramethyl tetravinyl tetrasiloxane (D4(vi)) and 3-bromopyridine in the presence of the Pd(0) catalysts. The as-synthesized ligand L(1) shows the presence of three stereoisomers, cis-trans-cis (L(1A)), cis-cis-trans (L(1B)), and all-trans (L(1C)), which are quantitatively separated by column chromatography. Subsequent reduction of L(1A), L(1B), and L(1C) with triethylsilane in the presence of catalytic amounts of Pd/C leads to the formation of the ligands L(2A), L(2B), and L(2C) with retention of stereochemistry due to the precursor moieties. Treatment of ZnI2 with L(1A) gives a one-dimensional coordination framework [(L(1A))4(ZnI2)2]infinity, 1. These 1D chains are further connected by pi-pi stacking interactions between the pyridyl groups of the adjacent chains leading to the formation of a three-dimensional network with the topology of a PtS net. The reaction of silver nitrate with ligand L(1B) gives a chain like one-dimensional cationic coordination polymer {[(L(1B))4Ag2].2NO3.H2O.CH3OH }infinity, 2, consisting of two different kinds of 32-membered macrocycles. Treatment of the all-trans ligand L(2C) with copper(I) iodide salt results in the formation of a cubane-type Cu4I4 cluster MOF [(L(2C))4Cu4I4]infinity, 3, in a two-dimensional 4-connected uninodal sql/Shubnikov tetragonal plane net topology represented by the Schlafli symbol {4(4).6(2)}. This MOF displays a thermochromic luminescence behavior due to Cu4I4 clusters showing an orange emission at 298 K and a blue emission at 77 K. PMID- 26958987 TI - Immunological evaluation of the entirely carbohydrate-based Thomsen-Friedenreich PS B conjugate. AB - PS B, a naturally occurring CD4(+) T-cell simulating zwitterionic polysaccharide from Bacteroides fragilis ATCC 25285/NCTC 9343, was conjugated with aminooxy Thomsen Friedenreich (TF or T) [alpha-d-Gal-(1,3)-beta-d-GalNAc-ONH2] tumor antigen. Immunization in Jax C57BL/6, followed by ELISA revealed IgM and IgG antibody TF specificity. FACS data noted preferential binding to TF-laced MCF-7 cells but not to HCT-116 cells. PMID- 26958989 TI - New perspectives in organolanthanide chemistry from redox to bond metathesis: insights from theory. AB - A fifteen year contribution of computational studies carried out in close synergy with experiments is summarized. This interplay has allowed some important breakthroughs in the field of organolanthanide chemistry. The variety of different reaction mechanisms in lanthanide chemistry appear to be broader than the simple bond metathesis. PMID- 26958988 TI - Bowel Ultrasonography in the Management of Crohn's Disease. A Review with Recommendations of an International Panel of Experts. AB - BACKGROUND: Bowel ultrasonography (US) is considered a useful technique for assessing mural inflammation and complications in Crohn's disease (CD). The aim of this review is to appraise the evidence on the accuracy of bowel US for CD. In addition, we aim to provide recommendations for its optimal use. METHODS: Publications were identified by literature search from 1992 to 2014 and selected based on predefined criteria: 15 or more patients; bowel US for diagnosing CD, complications, postoperative recurrence, activity; adequate reference standards; prospective study design; data reported to allow calculation of sensitivity, specificity, agreement, or correlation values; articles published in English. RESULTS: The search yielded 655 articles, of which 63 were found to be eligible and retrieved as full-text articles for analysis. Bowel US showed 79.7% sensitivity and 96.7% specificity for the diagnosis of suspected CD, and 89% sensitivity and 94.3% specificity for initial assessment in established patients with CD. Bowel US identified ileal CD with 92.7% sensitivity, 88.2% specificity, and colon CD with 81.8% sensitivity, 95.3% specificity, with lower accuracy for detecting proximal lesions. The oral contrast agent improves the sensitivity and specificity in determining CD lesions and in assessing sites and extent. CONCLUSIONS: Bowel US is a tool for evaluation of CD lesions in terms of complications, postoperative recurrence, and monitoring response to medical therapy; it reliably detects postoperative recurrence and complications, as well as offers the possibility of monitoring disease progression. PMID- 26958990 TI - Associations Between Step Duration Variability and Inertial Measurement Unit Derived Gait Characteristics. AB - Inertial measurement units (IMU) provide a convenient tool for gait stability assessment. However, it is unclear how various gait characteristics relate to each other and whether gait characteristics can be obtained from resultant acceleration. Therefore, step duration variability was measured in treadmill walking from 39 young ambulant volunteers (age 24.2 [+/- 2.5] y; height 1.79 [+/- 0.09] m; mass 71.6 [+/- 12.0] kg) using motion capture. Accelerations and gyrations were simultaneously recorded with an IMU. Harmonic ratio, maximum Lyapunov exponents, and multiscale sample entropy (MSE) were calculated. Step duration variability was positively associated with MSE with coarseness levels = 3-6 (r = -.33 to -.42, P <= .045). Harmonic ratio and MSE with all coarseness levels were negatively associated (r = -.45 to -.57, P <= .004). The MSE with coarseness level = 2 was negatively associated with short-term maximum Lyapunov exponents (r = -.32, P = .047). The agreement between resultant and vertical acceleration derived gait characteristics was excellent (ICC = 0.97-0.99). In conclusion, MSE with varying coarseness levels was associated with the other gait characteristics evaluated in the study. Resultant and vertical acceleration derived results had excellent agreement, which suggests that resultant acceleration is a viable alternative to considering the acceleration dimensions independently. PMID- 26958992 TI - Case Study: Semantic Annotation of a Pediatric Critical Care Research Study. PMID- 26958991 TI - Treatment patterns of adjuvant interferon-alpha2b for high-risk melanoma: a retrospective study of the Grupo Espanol Multidisciplinar de Melanoma - Prima study. AB - Adjuvant interferon-alpha2b (IFN-alpha2b) has been studied extensively in clinical trials, but there have been few studies of real-world use. The aim of this study is to describe the IFN-alpha2b real-world patterns in patients with high-risk melanoma in Spain. This was a retrospective and multicentre chart review study of an unselected cohort of patients with melanoma at high risk for relapse (stage IIB/IIC/III) treated with IFN-alpha2b. Patterns were assessed in terms of dose and compliance to planned treatment. A survival analysis was carried out for the full population and according to Kirkwood scheme compliance and the presence of ulceration. Of 327 patients treated with IFN-alpha2b, 318 received a high-dose regimen following the standard Kirkwood scheme; thus, patterns are described for this regimen. A total of 121 (38%) and 88 (28%) patients had at least one dose reduction during the induction and maintenance phases, respectively. Dose delay was required in fewer than 10% of patients. A total of 78, 40 and 38% of the patients completed the induction phase, maintenance phase and completed treatment, respectively. The median progression free and overall survival for the full population were 3.2 and 10.5 years, respectively. There were no differences in progression-free survival and overall survival according to Kirkwood scheme compliance and the presence of ulceration. The most frequent adverse events were neutropenia (31%) and fatigue (30%). High dose IFN-alpha2b is the most frequently used regimen in Spain as an adjuvant systemic treatment for high-risk melanoma. Despite poor compliance, in this retrospective study, IFN-alpha2b treatment provided a benefit consistent with that described previously. PMID- 26958993 TI - Nursing Summit: Improving Transitions in Care Through Collaboration and Technology. PMID- 26958995 TI - Anti-deformed Polyacrylonitrile/Polysulfone Composite Membrane with Binary Structures for Effective Air Filtration. AB - Airborne particle filtration proposed for fibers requires their assembly into porous structures with small pore size and low packing density. The ability to maintain structural stability upon deformation stress in service is essential to ensure a highly porous packing material that functions reliably; however, it has proven extremely challenging. Here, we report a strategy to create anti-deformed poly(ethylene oxide)@polyacrylonitrile/polysulfone (PEO@PAN/PSU) composite membranes with binary structures for effective air filtration by combining multijet electrospinning and physical bonding process. Our approach allows the ambigenous fiber framework including thin PAN nanofibers and fluffy PSU microfibers, through which run interpenetrating PEO bonding structures, to assemble into stable filtration medium with tunable pore size and packing density by facilely optimizing the bimodal fiber construction and benefiting from the PEO inspiration. With the integrated features of small pore size, high porosity, and robust mechanical properties (8.2 MPa), the resultant composite membrane exhibits high filtration efficiency of 99.992%, low pressure drop of 95 Pa, and desirable quality factor of 0.1 Pa(-1); more significantly, it successfully gets rid of the potential safety hazards caused by unexpected structural collapsing under service stress. The synthesis of PEO@PAN/PSU medium would not only make it a promising candidate for PM2.5 governance but also provide a versatile strategy to design and develop stable porous membranes for various applications. PMID- 26958996 TI - Recyclable Colorimetric Detection of Trivalent Cations in Aqueous Media Using Zwitterionic Gold Nanoparticles. AB - This report describes a colorimetric assay for trivalent metal cations (M(3+)) using gold nanoparticles (AuNPs)-modified with oppositely charged thiols that can form intermolecular zwitterionic surfaces. Zwitterionic AuNPs (Zw-AuNPs) are stable in high-salt solutions and well-dispersed in a wide range of pH values. M(3+) including Fe(3+), Al(3+), and Cr(3+) can effectively trigger the aggregation of Zw-AuNPs by interfering with their surface potential, and aggregated AuNPs can be regenerated and recycled by removing M(3+). In our approach, the output signal can be observed by the naked eye within a micromolar (MUM) concentration range. Uniquely, our assay is capable of discriminating Fe(3+) from Fe(2+), which is challenging using traditional approaches. More importantly, Zw-AuNPs can be stored stably at room temperature for a long period (3 months) with constant detection performance. Both the cost-effectiveness and the long shelf life make Zw-AuNPs ideal for detecting M(3+) in resource-poor and remote areas. PMID- 26958997 TI - Intrinsic Selectivity and Structure Sensitivity of Rhodium Catalysts for C(2+) Oxygenate Production. AB - Synthesis gas (CO + H2) conversion is a promising route to converting coal, natural gas, or biomass into synthetic liquid fuels. Rhodium has long been studied as it is the only elemental catalyst that has demonstrated selectivity to ethanol and other C2+ oxygenates. However, the fundamentals of syngas conversion over rhodium are still debated. In this work a microkinetic model is developed for conversion of CO and H2 into methane, ethanol, and acetaldehyde on the Rh (211) and (111) surfaces, chosen to describe steps and close-packed facets on catalyst particles. The model is based on DFT calculations using the BEEF-vdW functional. The mean-field kinetic model includes lateral adsorbate-adsorbate interactions, and the BEEF-vdW error estimation ensemble is used to propagate error from the DFT calculations to the predicted rates. The model shows the Rh(211) surface to be ~6 orders of magnitude more active than the Rh(111) surface, but highly selective toward methane, while the Rh(111) surface is intrinsically selective toward acetaldehyde. A variety of Rh/SiO2 catalysts are synthesized, tested for catalytic oxygenate production, and characterized using TEM. The experimental results indicate that the Rh(111) surface is intrinsically selective toward acetaldehyde, and a strong inverse correlation between catalytic activity and oxygenate selectivity is observed. Furthermore, iron impurities are shown to play a key role in modulating the selectivity of Rh/SiO2 catalysts toward ethanol. The experimental observations are consistent with the structure sensitivity predicted from theory. This work provides an improved atomic-scale understanding and new insight into the mechanism, active site, and intrinsic selectivity of syngas conversion over rhodium catalysts and may also guide rational design of alloy catalysts made from more abundant elements. PMID- 26958998 TI - Fluorous-Tag Assisted Syntheses of Sulfated Keratan Sulfate Oligosaccharide Fragments. AB - The first block iteration strategy for iterative solution-phase synthesis of protected keratan sulfate (KS)-like fragments is reported. Obstacles in a strategy using galactose-glucosamine (Gal-GlcNAc) modules led to the discovery of a differentially protected GlcNAc-Gal module that could be used to synthesize KS like fragments using a fluorous tag that maintained solubility in organic solvents for purification of all intermediates via fluorous solid-phase extraction. PMID- 26958999 TI - Targeted MS Assay Predicting Tamoxifen Resistance in Estrogen-Receptor-Positive Breast Cancer Tissues and Sera. AB - We recently reported on the development of a 4-protein-based classifier (PDCD4, CGN, G3BP2, and OCIAD1) capable of predicting outcome to tamoxifen treatment in recurrent, estrogen-receptor-positive breast cancer based on high-resolution MS data. A precise and high-throughput assay to measure these proteins in a multiplexed, targeted fashion would be favorable to measure large numbers of patient samples to move these findings toward a clinical setting. By coupling immunoprecipitation to multiple reaction monitoring (MRM) MS and stable isotope dilution, we developed a high-precision assay to measure the 4-protein signature in 38 primary breast cancer whole tissue lysates (WTLs). Furthermore, we evaluated the presence and patient stratification capabilities of our signature in an independent set of 24 matched (pre- and post-therapy) sera. We compared the performance of immuno-MRM (iMRM) with direct MRM in the absence of fractionation and shotgun proteomics in combination with label-free quantification (LFQ) on both WTL and laser capture microdissected (LCM) tissues. Measurement of the 4 proteins by iMRM showed not only higher accuracy in measuring proteotypic peptides (Spearman r: 0.74 to 0.93) when compared with MRM (Spearman r: 0.0 to 0.76) but also significantly discriminated patient groups based on treatment outcome (hazard ratio [HR]: 10.96; 95% confidence interval [CI]: 4.33 to 27.76; Log-rank P < 0.001) when compared with LCM (HR: 2.85; 95% CI: 1.24 to 6.54; Log rank P = 0.013) and WTL (HR: 1.16; 95% CI: 0.57 to 2.33; Log-rank P = 0.680) LFQ based predictors. Serum sample analysis by iMRM confirmed the detection of the four proteins in these samples. We hereby report that iMRM outperformed regular MRM, confirmed our previous high-resolution MS results in tumor tissues, and has shown that the 4-protein signature is measurable in serum samples. PMID- 26959000 TI - Synthesis of Isoxazole and 1,2,3-Triazole Isoindole Derivatives via Silver- and Copper-Catalyzed 1,3-Dipolar Cycloaddition Reaction. AB - The CuI- or Ag2CO3-catalyzed [3+2] cycloaddition of propargyl-substituted dihydroisoindolin-1-one (3) with arylnitrile oxides 1a-d (Ar = Ph, p-MeC6H4, p MeOC6H4, p-ClC6H4) produces in good yields novel 3,5-disubstituted isoxazoles 4 of the ethyl-2-benzyl-3-oxo-1-((3-arylisoxazol-5yl)methyl)-2,3-dihydro-1H isoindole-1-carboxylate type. With aryl azides 2a-d (Ar = Ph, p-MeC6H4, p OMeC6H4, p-ClC6H4), a series of 1,4-disubstituted 1,2,3-triazoles 6 (ethyl-2 benzyl-3-oxo-1-((1-aryl-1H-1,2,3-triazol-4-yl)methyl)-2,3-dihydro-1H-isoindole-1 carboxylates) was obtained. The reactions proceed in a regioselective manner affording exclusively racemic adducts 4 and 6. Compared to the uncatalyzed cycloaddition, the yields are significantly improved in the presence of CuI as catalyst, without alteration of the selectivity. The regio- and stereochemistry of the cycloadducts has been corroborated by an X-ray diffraction study of 4a, and in the case of 6a by XH-correlation and HMBC spectra. PMID- 26959001 TI - Anti-Metastatic Properties of a Marine Bacterial Exopolysaccharide-Based Derivative Designed to Mimic Glycosaminoglycans. AB - Osteosarcoma is the most frequent malignant primary bone tumor characterized by a high potency to form lung metastases. In this study, the effect of three oversulfated low molecular weight marine bacterial exopolysaccharides (OS-EPS) with different molecular weights (4, 8 and 15 kDa) were first evaluated in vitro on human and murine osteosarcoma cell lines. Different biological activities were studied: cell proliferation, cell adhesion and migration, matrix metalloproteinase expression. This in vitro study showed that only the OS-EPS 15 kDa derivative could inhibit the invasiveness of osteosarcoma cells with an inhibition rate close to 90%. Moreover, this derivative was potent to inhibit both migration and invasiveness of osteosarcoma cell lines; had no significant effect on their cell cycle; and increased slightly the expression of MMP-9, and more highly the expression of its physiological specific tissue inhibitor TIMP-1. Then, the in vivo experiments showed that the OS-EPS 15 kDa derivative had no effect on the primary osteosarcoma tumor induced by osteosarcoma cell lines but was very efficient to inhibit the establishment of lung metastases in vivo. These results can help to better understand the mechanisms of GAGs and GAG-like derivatives in the biology of the tumor cells and their interactions with the bone environment to develop new therapeutic strategies. PMID- 26959002 TI - Extraction, Preconcentration and Isolation of Flavonoids from Apocynum venetum L. Leaves Using Ionic Liquid-Based Ultrasonic-Assisted Extraction Coupled with an Aqueous Biphasic System. AB - BACKGROUND: Ionic liquids (ILs) are considered as green solvents, and widely applied for the extraction of various compounds. METHODS: The present research focuses on the extraction of flavonoids from Apocynum venetum L. leaves by ultrasound-assisted extraction (UAE). Several major influencing factors were optimized. Then, an aqueous biphasic system (ABS) was applied for further isolation of flavonoids. RESULTS: The flavonoids were mainly distributed in the top phase, while impurities were extracted to the bottom phase. The parameters influencing the extraction, namely type and concentration of salt, temperature, and pH, were studied in detail. Under optimized conditions (72.43% IL extract, 28.57% (NH4)2SO4, 25 degrees C temperature, pH 4.5), the preconcentration factor and extraction efficiency were found to be 3.78% and 93.35%, respectively. CONCLUSIONS: This simple and efficient methodology is expected to see great use in the extraction and isolation of pharmaceutically active components from medicinal plant resources. PMID- 26959003 TI - bis-Nitrile and bis-Dialkylcyanamide Platinum(II) Complexes as Efficient Catalysts for Hydrosilylation Cross-Linking of Siloxane Polymers. AB - cis- and trans-Isomers of the platinum(II) nitrile complexes [PtCl2(NCR)2] (R = NMe2, N(C5H10), Ph, CH2Ph) were examined as catalysts for hydrosilylation cross linking of vinyl-terminated polydimethylsiloxane and trimethylsilyl-terminated poly(dimethylsiloxane-co-ethylhydrosiloxane) producing high quality silicone rubbers. Among the tested platinum species the cis-complexes are much more active catalysts than their trans-congeners and for all studied platinum complexes cis [PtCl2(NCCH2Ph)2] exhibits the best catalytic activity (room temperature, c = 1.0 * 10(-4) mol/L, taupot-life 60 min, taucuring 6 h). Although cis [PtCl2(NCCH2Ph)2] is less active than the widely used Karstedt's catalyst, its application for the cross-linking can be performed not only at room temperature (c = 1.0 * 10(-4) mol/L), but also, more efficiently, at 80 degrees C (c = 1.0 * 10(-4)-1.0 * 10(-5) mol/L) and it prevents adherence of the formed silicone rubbers to equipment. The usage of the cis- and trans-[PtCl2(NCR)2] complexes as the hydrosilylation catalysts do not require any inhibitors and, moreover, the complexes and their mixtures with vinyl- and trimethylsilyl terminated polysiloxanes are shelf-stable in air. Tested catalysts do not form colloid platinum particles after the cross-linking. PMID- 26959004 TI - Inulin and Fibersol-2 Combined Have Hypolipidemic Effects on High Cholesterol Diet-Induced Hyperlipidemia in Hamsters. AB - The resistant carbohydrates, inulin, and Fibersol-2, belong to soluble dietary fibers and are considered important prebiotics that maintain biological functions, including glucose homeostasis, lipid regulation, colon disease prevention, and prebiotics characteristics. However, few studies have investigated Fibersol-2 alone or in combination with inulin to assess a pooled effect on modulation of hyperlipidemia. We aimed to investigate the effects of this combined supplement (defined as InF) on hamsters fed a 0.2% cholesterol and 10% lard diet (i.e., high-cholesterol diet, HCD) to induce hyperlipidemia. A total of 40 male hamsters were randomly assigned to five groups (n = 8 per group) for treatment: standard diet, vehicle (control); or vehicle or InF supplementation by oral gavage at 0, 864, 1727, or 2591 mg/kg/day for eight weeks, designated HCD, InF-1X, InF-2X, and InF-3X groups, respectively. The hypolipidemic efficacy and safety of InF supplementation was assessed by serum lipid indexes, hepatic and fecal lipid content, and histology. InF supplementation significantly improved serum levels of triacylglycerol (TG) and low-density lipoprotein cholesterol (LDL-C) and the ratio of LDL-C/HDL-C after two-week treatment, and reduced serum total cholesterol (TC) levels after four week administration. After eight-week supplementation, InF supplementation dose dependently improved serum levels of TC, TG, HDL-C, and LDL-C; LDL-C/HDL-C ratio; and hepatic TC and TG levels. It inhibited TC absorption by feces elimination. Our study provides experiment-based evidence to support that this prebiotics remedy may be useful in preventing or treating hyperlipidemia. PMID- 26959005 TI - Pharmacokinetic-Pharmacodynamic Modeling to Study the Antipyretic Effect of Qingkailing Injection on Pyrexia Model Rats. AB - Qingkailing injection (QKLI) is a modern Chinese medicine preparation derived from a well-known classical formulation, An-Gong-Niu-Huang Wan. Although the clinical efficacy of QKLI has been well defined, its severe adverse drug reactions (ADRs) were extensively increased. Through thorough attempts to reduce ADR rates, it was realized that the effect-based rational use plays the key role in clinical practices. Hence, the pharmacokinetic-pharmacodynamic (PK-PD) model was introduced in the present study, aiming to link the pharmacokinetic profiles with the therapeutic outcomes of QKLI, and subsequently to provide valuable guidelines for the rational use of QKLI in clinical settings. The PK properties of the six dominant ingredients in QKLI were compared between the normal treated group (NTG) and the pyrexia model group (MTG). Rectal temperatures were measured in parallel with blood sampling for NTG, MTG, model control group (MCG), and normal control group (NCG). Baicalin and geniposide exhibited appropriate PK parameters, and were selected as the PK markers to map the antipyretic effect of QKLI. Then, a PK-PD model was constructed upon the bacalin and geniposide plasma concentrations vs. the rectal temperature variation values, by a two-compartment PK model with a Sigmoid Emax PD model to explain the time delay between the drug plasma concentration of PK markers and the antipyretic effect after a single dose administration of QKLI. The findings obtained would provide fundamental information to propose a more reasonable dosage regimen and improve the level of individualized drug therapy in clinical settings. PMID- 26959006 TI - Continuous-Flow Synthesis of Deuterium-Labeled Antidiabetic Chalcones: Studies towards the Selective Deuteration of the Alkynone Core. AB - Flow chemistry-based syntheses of deuterium-labeled analogs of important antidiabetic chalcones were achieved via highly controlled partial C=C bond deuteration of the corresponding 1,3-diphenylalkynones. The benefits of a scalable continuous process in combination with on-demand electrolytic D2 gas generation were exploited to suppress undesired over-reactions and to maximize reaction rates simultaneously. The novel deuterium-containing chalcone derivatives may have interesting biological effects and improved metabolic properties as compared with the parent compounds. PMID- 26959007 TI - Withaferin-A--A Natural Anticancer Agent with Pleitropic Mechanisms of Action. AB - Cancer, being the second leading cause of mortality, exists as a formidable health challenge. In spite of our enormous efforts, the emerging complexities in the molecular nature of disease progression limit the real success in finding an effective cancer cure. It is now conceivable that cancer is, in fact, a progressive illness, and the morbidity and mortality from cancer can be reduced by interfering with various oncogenic signaling pathways. A wide variety of structurally diverse classes of bioactive phytochemicals have been shown to exert anticancer effects in a large number of preclinical studies. Multiple lines of evidence suggest that withaferin-A can prevent the development of cancers of various histotypes. Accumulating data from different rodent models and cell culture experiments have revealed that withaferin-A suppresses experimentally induced carcinogenesis, largely by virtue of its potent anti-oxidative, anti inflammatory, anti-proliferative and apoptosis-inducing properties. Moreover, withaferin-A sensitizes resistant cancer cells to existing chemotherapeutic agents. The purpose of this review is to highlight the mechanistic aspects underlying anticancer effects of withaferin-A. PMID- 26959010 TI - From Olive Fruits to Olive Oil: Phenolic Compound Transfer in Six Different Olive Cultivars Grown under the Same Agronomical Conditions. AB - Phenolic compounds are responsible of the nutritional and sensory quality of extra-virgin olive oil (EVOO). The composition of phenolic compounds in EVOO is related to the initial content of phenolic compounds in the olive-fruit tissues and the activity of enzymes acting on these compounds during the industrial process to produce the oil. In this work, the phenolic composition was studied in six major cultivars grown in the same orchard under the same agronomical and environmental conditions in an effort to test the effects of cultivars on phenolic composition in fruits and oils as well as on transfer between matrices. The phenolic fractions were identified and quantified using high-performance liquid chromatography-diode array detector-time-of-flight-mass spectrometry. A total of 33 phenolic compounds were determined in the fruit samples and a total of 20 compounds in their corresponding oils. Qualitative and quantitative differences in phenolic composition were found among cultivars in both matrices, as well as regarding the transfer rate of phenolic compounds from fruits to oil. The results also varied according to the different phenolic groups evaluated, with secoiridoids registering the highest transfer rates from fruits to oils. Moreover, wide-ranging differences have been noticed between cultivars for the transfer rates of secoiridoids (4.36%-65.63% of total transfer rate) and for flavonoids (0.18%-0.67% of total transfer rate). 'Picual' was the cultivar that transferred secoiridoids to oil at the highest rate, whereas 'Changlot Real' was the cultivar that transferred flavonoids at the highest rates instead. Principal component analysis confirmed a strong genetic effect on the basis of the phenolic profile both in the olive fruits and in the oils. PMID- 26959009 TI - The Functions of Metallothionein and ZIP and ZnT Transporters: An Overview and Perspective. AB - Around 3000 proteins are thought to bind zinc in vivo, which corresponds to ~10% of the human proteome. Zinc plays a pivotal role as a structural, catalytic, and signaling component that functions in numerous physiological processes. It is more widely used as a structural element in proteins than any other transition metal ion, is a catalytic component of many enzymes, and acts as a cellular signaling mediator. Thus, it is expected that zinc metabolism and homeostasis have sophisticated regulation, and elucidating the underlying molecular basis of this is essential to understanding zinc functions in cellular physiology and pathogenesis. In recent decades, an increasing amount of evidence has uncovered critical roles of a number of proteins in zinc metabolism and homeostasis through influxing, chelating, sequestrating, coordinating, releasing, and effluxing zinc. Metallothioneins (MT) and Zrt- and Irt-like proteins (ZIP) and Zn transporters (ZnT) are the proteins primarily involved in these processes, and their malfunction has been implicated in a number of inherited diseases such as acrodermatitis enteropathica. The present review updates our current understanding of the biological functions of MTs and ZIP and ZnT transporters from several new perspectives. PMID- 26959008 TI - Amyloid-beta and Astrocytes Interplay in Amyloid-beta Related Disorders. AB - Amyloid-beta (Abeta) pathology is known to promote chronic inflammatory responses in the brain. It was thought previously that Abeta is only associated with Alzheimer's disease and Down syndrome. However, studies have shown its involvement in many other neurological disorders. The role of astrocytes in handling the excess levels of Abeta has been highlighted in the literature. Astrocytes have a distinctive function in both neuronal support and protection, thus its involvement in Abeta pathological process may tip the balance toward chronic inflammation and neuronal death. In this review we describe the involvement of astrocytes in Abeta related disorders including Alzheimer's disease, Down syndrome, cerebral amyloid angiopathy, and frontotemporal dementia. PMID- 26959011 TI - Molecular Cloning and Expression Analysis of Eight PgWRKY Genes in Panax ginseng Responsive to Salt and Hormones. AB - Despite the importance of WRKY genes in plant physiological processes, little is known about their roles in Panax ginseng C.A. Meyer. Forty-eight unigenes on this species were previously reported as WRKY transcripts using the next-generation sequencing (NGS) technology. Subsequently, one gene that encodes PgWRKY1 protein belonging to subgroup II-d was cloned and functionally characterized. In this study, eight WRKY genes from the NGS-based transcriptome sequencing dataset designated as PgWRKY2-9 have been cloned and characterized. The genes encoding WRKY proteins were assigned to WRKY Group II (one subgroup II-c, four subgroup II d, and three subgroup II-e) based on phylogenetic analysis. The cDNAs of the cloned PgWRKYs encode putative proteins ranging from 194 to 358 amino acid residues, each of which includes one WRKYGQK sequence motif and one C2H2-type zinc-finger motif. Quantitative real-time PCR (qRT-PCR) analysis demonstrated that the eight analyzed PgWRKY genes were expressed at different levels in various organs including leaves, roots, adventitious roots, stems, and seeds. Importantly, the transcription responses of these PgWRKYs to methyl jasmonate (MeJA) showed that PgWRKY2, PgWRKY3, PgWRKY4, PgWRKY5, PgWRKY6, and PgWRKY7 were downregulated by MeJA treatment, while PgWRKY8 and PgWRKY9 were upregulated to varying degrees. Moreover, the PgWRKY genes increased or decreased by salicylic acid (SA), abscisic acid (ABA), and NaCl treatments. The results suggest that the PgWRKYs may be multiple stress-inducible genes responding to both salt and hormones. PMID- 26959012 TI - Local Anesthetic-Induced Neurotoxicity. AB - This review summarizes current knowledge concerning incidence, risk factors, and mechanisms of perioperative nerve injury, with focus on local anesthetic-induced neurotoxicity. Perioperative nerve injury is a complex phenomenon and can be caused by a number of clinical factors. Anesthetic risk factors for perioperative nerve injury include regional block technique, patient risk factors, and local anesthetic-induced neurotoxicity. Surgery can lead to nerve damage by use of tourniquets or by direct mechanical stress on nerves, such as traction, transection, compression, contusion, ischemia, and stretching. Current literature suggests that the majority of perioperative nerve injuries are unrelated to regional anesthesia. Besides the blockade of sodium channels which is responsible for the anesthetic effect, systemic local anesthetics can have a positive influence on the inflammatory response and the hemostatic system in the perioperative period. However, next to these beneficial effects, local anesthetics exhibit time and dose-dependent toxicity to a variety of tissues, including nerves. There is equivocal experimental evidence that the toxicity varies among local anesthetics. Even though the precise order of events during local anesthetic-induced neurotoxicity is not clear, possible cellular mechanisms have been identified. These include the intrinsic caspase-pathway, PI3K-pathway, and MAPK-pathways. Further research will need to determine whether these pathways are non-specifically activated by local anesthetics, or whether there is a single common precipitating factor. PMID- 26959014 TI - Dried Saliva Spots: A Robust Method for Detecting Streptococcus pneumoniae Carriage by PCR. AB - The earliest studies in the late 19th century on Streptococcus pneumoniae (S. pneumoniae) carriage used saliva as the primary specimen. However, interest in saliva declined after the sensitive mouse inoculation method was replaced by conventional culture, which made isolation of pneumococci from the highly polymicrobial oral cavity virtually impossible. Here, we tested the feasibility of using dried saliva spots (DSS) for studies on pneumococcal carriage. Saliva samples from children and pneumococcus-spiked saliva samples from healthy adults were applied to paper, dried, and stored, with and without desiccant, at temperatures ranging from -20 to 37 degrees C for up to 35 days. DNA extracted from DSS was tested with quantitative-PCR (qPCR) specifically for S. pneumoniae. When processed immediately after drying, the quantity of pneumococcal DNA detected in spiked DSS from adults matched the levels in freshly spiked raw saliva. Furthermore, pneumococcal DNA was stable in DSS stored with desiccant for up to one month over a broad range of temperatures. There were no differences in the results when spiking saliva with varied pneumococcal strains. The collection of saliva can be a particularly useful in surveillance studies conducted in remote settings, as it does not require trained personnel, and DSS are resilient to various transportation conditions. PMID- 26959013 TI - Computational Study on New Natural Compound Inhibitors of Pyruvate Dehydrogenase Kinases. AB - Pyruvate dehydrogenase kinases (PDKs) are key enzymes in glucose metabolism, negatively regulating pyruvate dehyrogenase complex (PDC) activity through phosphorylation. Inhibiting PDKs could upregulate PDC activity and drive cells into more aerobic metabolism. Therefore, PDKs are potential targets for metabolism related diseases, such as cancers and diabetes. In this study, a series of computer-aided virtual screening techniques were utilized to discover potential inhibitors of PDKs. Structure-based screening using Libdock was carried out following by ADME (adsorption, distribution, metabolism, excretion) and toxicity prediction. Molecular docking was used to analyze the binding mechanism between these compounds and PDKs. Molecular dynamic simulation was utilized to confirm the stability of potential compound binding. From the computational results, two novel natural coumarins compounds (ZINC12296427 and ZINC12389251) from the ZINC database were found binding to PDKs with favorable interaction energy and predicted to be non-toxic. Our study provide valuable information of PDK-coumarins binding mechanisms in PDK inhibitor-based drug discovery. PMID- 26959018 TI - A High-Efficiency Wind Energy Harvester for Autonomous Embedded Systems. AB - Energy harvesting is currently a hot research topic, mainly as a consequence of the increasing attractiveness of computing and sensing solutions based on small, low-power distributed embedded systems. Harvesting may enable systems to operate in a deploy-and-forget mode, particularly when power grid is absent and the use of rechargeable batteries is unattractive due to their limited lifetime and maintenance requirements. This paper focuses on wind flow as an energy source feasible to meet the energy needs of a small autonomous embedded system. In particular the contribution is on the electrical converter and system integration. We characterize the micro-wind turbine, we define a detailed model of its behaviour, and then we focused on a highly efficient circuit to convert wind energy into electrical energy. The optimized design features an overall volume smaller than 64 cm3. The core of the harvester is a high efficiency buck boost converter which performs an optimal power point tracking. Experimental results show that the wind generator boosts efficiency over a wide range of operating conditions. PMID- 26959017 TI - Effect of Pyridine on the Mesophase of Teraryl Liquid Crystals: A New Series of Nematic Liquid Crystals Named 2-(4-Alkoxybiphen-4'-yl)-5-methylpyridines. AB - A new series of teraryl 2-(4-alkoxybiphen-4'-yl)-5-methylpyridines (nO-PPPyMe, n = 3-8) nematic liquid crystal compounds, bearing a biphenylene core and a picoline terminus, were synthesized using a short two-step reaction, and overall yields between 34% and 38% were obtained. Spectral analysis results were in accordance with the expected structures. The thermotropic behavior of the teraryl liquid crystal compounds was investigated through polarized optical microscopy and differential scanning calorimetry. All compounds exhibited a solely enantiotropic nematic phase at the medium-high temperature range of 162.4-234.2 degrees C. Furthermore, the results for the nO-PPPyMe series were analyzed relative to three other compound series, mO-PPPyCN (m = 2-8), iO-PPQMe (i = 3-8) and xO-PPyPMe (x = 1-10). Consequently, the effect of pyridine on the mesophase of teraryl liquid crystals was demonstrated. PMID- 26959019 TI - A Digitalized Gyroscope System Based on a Modified Adaptive Control Method. AB - In this work we investigate the possibility of applying the adaptive control algorithm to Micro-Electro-Mechanical System (MEMS) gyroscopes. Through comparing the gyroscope working conditions with the reference model, the adaptive control method can provide online estimation of the key parameters and the proper control strategy for the system. The digital second-order oscillators in the reference model are substituted for two phase locked loops (PLLs) to achieve a more steady amplitude and frequency control. The adaptive law is modified to satisfy the condition of unequal coupling stiffness and coupling damping coefficient. The rotation mode of the gyroscope system is considered in our work and a rotation elimination section is added to the digitalized system. Before implementing the algorithm in the hardware platform, different simulations are conducted to ensure the algorithm can meet the requirement of the angular rate sensor, and some of the key adaptive law coefficients are optimized. The coupling components are detected and suppressed respectively and Lyapunov criterion is applied to prove the stability of the system. The modified adaptive control algorithm is verified in a set of digitalized gyroscope system, the control system is realized in digital domain, with the application of Field Programmable Gate Array (FPGA). Key structure parameters are measured and compared with the estimation results, which validated that the algorithm is feasible in the setup. Extra gyroscopes are used in repeated experiments to prove the commonality of the algorithm. PMID- 26959016 TI - Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism. AB - Pyrrolizidine Alkaloids (PAs) are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH) metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types) in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1) and glutathione peroxidase 1 (GPX1) targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins. PMID- 26959020 TI - A Real-Time Interference Monitoring Technique for GNSS Based on a Twin Support Vector Machine Method. AB - Interferences can severely degrade the performance of Global Navigation Satellite System (GNSS) receivers. As the first step of GNSS any anti-interference measures, interference monitoring for GNSS is extremely essential and necessary. Since interference monitoring can be considered as a classification problem, a real-time interference monitoring technique based on Twin Support Vector Machine (TWSVM) is proposed in this paper. A TWSVM model is established, and TWSVM is solved by the Least Squares Twin Support Vector Machine (LSTWSVM) algorithm. The interference monitoring indicators are analyzed to extract features from the interfered GNSS signals. The experimental results show that the chosen observations can be used as the interference monitoring indicators. The interference monitoring performance of the proposed method is verified by using GPS L1 C/A code signal and being compared with that of standard SVM. The experimental results indicate that the TWSVM-based interference monitoring is much faster than the conventional SVM. Furthermore, the training time of TWSVM is on millisecond (ms) level and the monitoring time is on microsecond (MUs) level, which make the proposed approach usable in practical interference monitoring applications. PMID- 26959015 TI - Oncostatic-Cytoprotective Effect of Melatonin and Other Bioactive Molecules: A Common Target in Mitochondrial Respiration. AB - For several years, oncostatic and antiproliferative properties, as well as thoses of cell death induction through 5-methoxy-N-acetiltryptamine or melatonin treatment, have been known. Paradoxically, its remarkable scavenger, cytoprotective and anti-apoptotic characteristics in neurodegeneration models, such as Alzheimer's disease and Parkinson's disease are known too. Analogous results have been confirmed by a large literature to be associated to the use of many other bioactive molecules such as resveratrol, tocopherol derivatives or vitamin E and others. It is interesting to note that the two opposite situations, namely the neoplastic pathology and the neurodegeneration, are characterized by deep alterations of the metabolome, of mitochondrial function and of oxygen consumption, so that the oncostatic and cytoprotective action can find a potential rationalization because of the different metabolic and mitochondrial situations, and in the effect that these molecules exercise on the mitochondrial function. In this review we discuss historical and general aspects of melatonin, relations between cancers and the metabolome and between neurodegeneration and the metabolome, and the possible effects of melatonin and of other bioactive molecules on metabolic and mitochondrial dynamics. Finally, we suggest a common general mechanism as responsible for the oncostatic/cytoprotective effect of melatonin and of other molecules examined. PMID- 26959021 TI - Modeling the Insertion Mechanics of Flexible Neural Probes Coated with Sacrificial Polymers for Optimizing Probe Design. AB - Single-unit recording neural probes have significant advantages towards improving signal-to-noise ratio and specificity for signal acquisition in brain-to-computer interface devices. Long-term effectiveness is unfortunately limited by the chronic injury response, which has been linked to the mechanical mismatch between rigid probes and compliant brain tissue. Small, flexible microelectrodes may overcome this limitation, but insertion of these probes without buckling requires supporting elements such as a stiff coating with a biodegradable polymer. For these coated probes, there is a design trade-off between the potential for successful insertion into brain tissue and the degree of trauma generated by the insertion. The objective of this study was to develop and validate a finite element model (FEM) to simulate insertion of coated neural probes of varying dimensions and material properties into brain tissue. Simulations were performed to predict the buckling and insertion forces during insertion of coated probes into a tissue phantom with material properties of brain. The simulations were validated with parallel experimental studies where probes were inserted into agarose tissue phantom, ex vivo chick embryonic brain tissue, and ex vivo rat brain tissue. Experiments were performed with uncoated copper wire and both uncoated and coated SU-8 photoresist and Parylene C probes. Model predictions were found to strongly agree with experimental results (<10% error). The ratio of the predicted buckling force-to-predicted insertion force, where a value greater than one would ideally be expected to result in successful insertion, was plotted against the actual success rate from experiments. A sigmoidal relationship was observed, with a ratio of 1.35 corresponding to equal probability of insertion and failure, and a ratio of 3.5 corresponding to a 100% success rate. This ratio was dubbed the "safety factor", as it indicated the degree to which the coating should be over-designed to ensure successful insertion. Probability color maps were generated to visually compare the influence of design parameters. Statistical metrics derived from the color maps and multi-variable regression analysis confirmed that coating thickness and probe length were the most important features in influencing insertion potential. The model also revealed the effects of manufacturing flaws on insertion potential. PMID- 26959022 TI - Efficient Banknote Recognition Based on Selection of Discriminative Regions with One-Dimensional Visible-Light Line Sensor. AB - Banknote papers are automatically recognized and classified in various machines, such as vending machines, automatic teller machines (ATM), and banknote-counting machines. Previous studies on automatic classification of banknotes have been based on the optical characteristics of banknote papers. On each banknote image, there are regions more distinguishable than others in terms of banknote types, sides, and directions. However, there has been little previous research on banknote recognition that has addressed the selection of distinguishable areas. To overcome this problem, we propose a method for recognizing banknotes by selecting more discriminative regions based on similarity mapping, using images captured by a one-dimensional visible light line sensor. Experimental results with various types of banknote databases show that our proposed method outperforms previous methods. PMID- 26959023 TI - Per-Pixel Coded Exposure for High-Speed and High-Resolution Imaging Using a Digital Micromirror Device Camera. AB - High-speed photography is an important tool for studying rapid physical phenomena. However, low-frame-rate CCD (charge coupled device) or CMOS (complementary metal oxide semiconductor) camera cannot effectively capture the rapid phenomena with high-speed and high-resolution. In this paper, we incorporate the hardware restrictions of existing image sensors, design the sampling functions, and implement a hardware prototype with a digital micromirror device (DMD) camera in which spatial and temporal information can be flexibly modulated. Combined with the optical model of DMD camera, we theoretically analyze the per-pixel coded exposure and propose a three-element median quicksort method to increase the temporal resolution of the imaging system. Theoretically, this approach can rapidly increase the temporal resolution several, or even hundreds, of times without increasing bandwidth requirements of the camera. We demonstrate the effectiveness of our method via extensive examples and achieve 100 fps (frames per second) gain in temporal resolution by using a 25 fps camera. PMID- 26959024 TI - SVD-Based Technique for Interference Cancellation and Noise Reduction in NMR Measurement of Time-Dependent Magnetic Fields. AB - A nuclear magnetic resonance (NMR) experiment for measurement of time-dependent magnetic fields was introduced. To improve the signal-to-interference-plus-noise ratio (SINR) of NMR data, a new method for interference cancellation and noise reduction (ICNR) based on singular value decomposition (SVD) was proposed. The singular values corresponding to the radio frequency interference (RFI) signal were identified in terms of the correlation between the FID data and the reference data, and then the RFI and noise were suppressed by setting the corresponding singular values to zero. The validity of the algorithm was verified by processing the measured NMR data. The results indicated that, this method has a significantly suppression of RFI and random noise, and can well preserve the FID signal. At present, the major limitation of the proposed SVD-based ICNR technique is that the threshold value for interference cancellation needs to be manually selected. Finally, the inversion waveform of the applied alternating magnetic field was given by fitting the processed experimental data. PMID- 26959025 TI - Piezoresistive Soft Condensed Matter Sensor for Body-Mounted Vital Function Applications. AB - A soft condensed matter sensor (SCMS) designed to measure strains on the human body is presented. The hybrid material based on carbon black (CB) and a thermoplastic elastomer (TPE) was bonded to a textile elastic band and used as a sensor on the human wrist to measure hand motion by detecting the movement of tendons in the wrist. Additionally it was able to track the blood pulse wave of a person, allowing for the determination of pulse wave peaks corresponding to the systole and diastole blood pressures in order to calculate the heart rate. Sensor characterization was done using mechanical cycle testing, and the band sensor achieved a gauge factor of 4-6.3 while displaying low signal relaxation when held at a strain levels. Near-linear signal performance was displayed when loading to successively higher strain levels up to 50% strain. PMID- 26959026 TI - Developing an Ear Prosthesis Fabricated in Polyvinylidene Fluoride by a 3D Printer with Sensory Intrinsic Properties of Pressure and Temperature. AB - An ear prosthesis was designed in 3D computer graphics software and fabricated using a 3D printing process of polyvinylidene fluoride (PVDF) for use as a hearing aid. In addition, the prosthesis response to pressure and temperature was observed. Pyroelectric and piezoelectric properties of this ear prosthesis were investigated using an astable multivibrator circuit, as changes in PVDF permittivity were observed according to variations of pressure and temperature. The results show that this prosthesis is reliable for use under different conditions of pressure (0 Pa to 16,350 Pa) and temperature (2 degrees C to 90 degrees C). The experimental results show an almost linear and inversely proportional behavior between the stimuli of pressure and temperature with the frequency response. This 3D-printed ear prosthesis is a promising tool and has a great potentiality in the biomedical engineering field because of its ability to generate an electrical potential proportional to pressure and temperature, and it is the first time that such a device has been processed by the additive manufacturing process (3D printing). More work needs to be carried out to improve the performance, such as electrical stimulation of the nervous system, thereby extending the purpose of a prosthesis to the area of sensory perception. PMID- 26959027 TI - Online Kinematic and Dynamic-State Estimation for Constrained Multibody Systems Based on IMUs. AB - This article addresses the problems of online estimations of kinematic and dynamic states of a mechanism from a sequence of noisy measurements. In particular, we focus on a planar four-bar linkage equipped with inertial measurement units (IMUs). Firstly, we describe how the position, velocity, and acceleration of all parts of the mechanism can be derived from IMU signals by means of multibody kinematics. Next, we propose the novel idea of integrating the generic multibody dynamic equations into two variants of Kalman filtering, i.e., the extended Kalman filter (EKF) and the unscented Kalman filter (UKF), in a way that enables us to handle closed-loop, constrained mechanisms, whose state space variables are not independent and would normally prevent the direct use of such estimators. The proposal in this work is to apply those estimators over the manifolds of allowed positions and velocities, by means of estimating a subset of independent coordinates only. The proposed techniques are experimentally validated on a testbed equipped with encoders as a means of establishing the ground-truth. Estimators are run online in real-time, a feature not matched by any previous procedure of those reported in the literature on multibody dynamics. PMID- 26959028 TI - Assessment of Reinforced Concrete Surface Breaking Crack Using Rayleigh Wave Measurement. AB - An improved single sided Rayleigh wave (R-wave) measurement was suggested to characterize surface breaking crack in steel reinforced concrete structures. Numerical simulations were performed to clarify the behavior of R-waves interacting with surface breaking crack with different depths and degrees of inclinations. Through analysis of simulation results, correlations between R-wave parameters of interest and crack characteristics (depth and degree of inclination) were obtained, which were then validated by experimental measurement of concrete specimens instigated with vertical and inclined artificial cracks of different depths. Wave parameters including velocity and amplitude attenuation for each case were studied. The correlations allowed us to estimate the depth and inclination of cracks measured experimentally with acceptable discrepancies, particularly for cracks which are relatively shallow and when the crack depth is smaller than the wavelength. PMID- 26959029 TI - Quaternion-Based Signal Analysis for Motor Imagery Classification from Electroencephalographic Signals. AB - Quaternions can be used as an alternative to model the fundamental patterns of electroencephalographic (EEG) signals in the time domain. Thus, this article presents a new quaternion-based technique known as quaternion-based signal analysis (QSA) to represent EEG signals obtained using a brain-computer interface (BCI) device to detect and interpret cognitive activity. This quaternion-based signal analysis technique can extract features to represent brain activity related to motor imagery accurately in various mental states. Experimental tests in which users where shown visual graphical cues related to left and right movements were used to collect BCI-recorded signals. These signals were then classified using decision trees (DT), support vector machine (SVM) and k-nearest neighbor (KNN) techniques. The quantitative analysis of the classifiers demonstrates that this technique can be used as an alternative in the EEG-signal modeling phase to identify mental states. PMID- 26959030 TI - Robot Guidance Using Machine Vision Techniques in Industrial Environments: A Comparative Review. AB - In the factory of the future, most of the operations will be done by autonomous robots that need visual feedback to move around the working space avoiding obstacles, to work collaboratively with humans, to identify and locate the working parts, to complete the information provided by other sensors to improve their positioning accuracy, etc. Different vision techniques, such as photogrammetry, stereo vision, structured light, time of flight and laser triangulation, among others, are widely used for inspection and quality control processes in the industry and now for robot guidance. Choosing which type of vision system to use is highly dependent on the parts that need to be located or measured. Thus, in this paper a comparative review of different machine vision techniques for robot guidance is presented. This work analyzes accuracy, range and weight of the sensors, safety, processing time and environmental influences. Researchers and developers can take it as a background information for their future works. PMID- 26959031 TI - An Anchor-Based Pedestrian Navigation Approach Using Only Inertial Sensors. AB - In inertial-based pedestrian navigation, anchors can effectively compensate the positioning errors originating from deviations of Inertial Measurement Units (IMUs), by putting constraints on pedestrians' motions. However, these anchors often need to be deployed beforehand, which can greatly increase system complexity, rendering it unsuitable for emergency response missions. In this paper, we propose an anchor-based pedestrian navigation approach without any additional sensors. The anchors are defined as the intersection points of perpendicular corridors and are considered characteristics of building structures. In contrast to these real anchors, virtual anchors are extracted from the pedestrian's trajectory and are considered as observations of real anchors, which can accordingly be regarded as inferred building structure characteristics. Then a Rao-Blackwellized particle filter (RBPF) is used to solve the joint estimation of positions (trajectory) and maps (anchors) problem. Compared with other building structure-based methods, our method has two advantages. The assumption on building structure is minimum and valid in most cases. Even if the assumption does not stand, the method will not lead to positioning failure. Several real-scenario experiments are conducted to validate the effectiveness and robustness of the proposed method. PMID- 26959032 TI - Worst-Case Cooperative Jamming for Secure Communications in CIoT Networks. AB - The Internet of Things (IoT) is a significant branch of the ongoing advances in the Internet and mobile communications. The use of a large number of IoT devices makes the spectrum scarcity problem even more serious. The usable spectrum resources are almost entirely occupied, and thus, the increasing radio access demands of IoT devices cannot be met. To tackle this problem, the Cognitive Internet of Things (CIoT) has been proposed. In a CIoT network, secondary users, i.e., sensors and actuators, can access the licensed spectrum bands provided by licensed primary users (such as telephones). Security is a major concern in CIoT networks. However, the traditional encryption method at upper layers (such as symmetric cryptography and asymmetric cryptography) may be compromised in CIoT networks, since these types of networks are heterogeneous. In this paper, we address the security issue in spectrum-leasing-based CIoT networks using physical layer methods. Considering that the CIoT networks are cooperative networks, we propose to employ cooperative jamming to achieve secrecy transmission. In the cooperative jamming scheme, a certain secondary user is employed as the helper to harvest energy transmitted by the source and then uses the harvested energy to generate an artificial noise that jams the eavesdropper without interfering with the legitimate receivers. The goal is to minimize the signal to interference plus noise ratio (SINR) at the eavesdropper subject to the quality of service (QoS) constraints of the primary traffic and the secondary traffic. We formulate the considered minimization problem into a two-stage robust optimization problem based on the worst-case Channel State Information of the Eavesdropper. By using semi-definite programming (SDP), the optimal solutions of the transmit covariance matrices can be obtained. Moreover, in order to build an incentive mechanism for the secondary users, we propose an auction framework based on the cooperative jamming scheme. The proposed auction framework jointly formulates the helper selection and the corresponding energy allocation problems under the constraint of the eavesdropper's SINR. By adopting the Vickrey auction, truthfulness and individual rationality can be guaranteed. Simulation results demonstrate the good performance of the cooperative jamming scheme and the auction framework. PMID- 26959033 TI - Deriving the Characteristic Scale for Effectively Monitoring Heavy Metal Stress in Rice by Assimilation of GF-1 Data with the WOFOST Model. AB - Accurate monitoring of heavy metal stress in crops is of great importance to assure agricultural productivity and food security, and remote sensing is an effective tool to address this problem. However, given that Earth observation instruments provide data at multiple scales, the choice of scale for use in such monitoring is challenging. This study focused on identifying the characteristic scale for effectively monitoring heavy metal stress in rice using the dry weight of roots (WRT) as the representative characteristic, which was obtained by assimilation of GF-1 data with the World Food Studies (WOFOST) model. We explored and quantified the effect of the important state variable LAI (leaf area index) at various spatial scales on the simulated rice WRT to find the critical scale for heavy metal stress monitoring using the statistical characteristics. Furthermore, a ratio analysis based on the varied heavy metal stress levels was conducted to identify the characteristic scale. Results indicated that the critical threshold for investigating the rice WRT in monitoring studies of heavy metal stress was larger than 64 m but smaller than 256 m. This finding represents a useful guideline for choosing the most appropriate imagery. PMID- 26959034 TI - Improving Pulse Rate Measurements during Random Motion Using a Wearable Multichannel Reflectance Photoplethysmograph. AB - Photoplethysmographic (PPG) waveforms are used to acquire pulse rate (PR) measurements from pulsatile arterial blood volume. PPG waveforms are highly susceptible to motion artifacts (MA), limiting the implementation of PR measurements in mobile physiological monitoring devices. Previous studies have shown that multichannel photoplethysmograms can successfully acquire diverse signal information during simple, repetitive motion, leading to differences in motion tolerance across channels. In this paper, we investigate the performance of a custom-built multichannel forehead-mounted photoplethysmographic sensor under a variety of intense motion artifacts. We introduce an advanced multichannel template-matching algorithm that chooses the channel with the least motion artifact to calculate PR for each time instant. We show that for a wide variety of random motion, channels respond differently to motion artifacts, and the multichannel estimate outperforms single-channel estimates in terms of motion tolerance, signal quality, and PR errors. We have acquired 31 data sets consisting of PPG waveforms corrupted by random motion and show that the accuracy of PR measurements achieved was increased by up to 2.7 bpm when the multichannel switching algorithm was compared to individual channels. The percentage of PR measurements with error <= 5 bpm during motion increased by 18.9% when the multichannel switching algorithm was compared to the mean PR from all channels. Moreover, our algorithm enables automatic selection of the best signal fidelity channel at each time point among the multichannel PPG data. PMID- 26959035 TI - An Open Source "Smart Lamp" for the Optimization of Plant Systems and Thermal Comfort of Offices. AB - The article describes the design phase, development and practical application of a smart object integrated in a desk lamp and called "Smart Lamp", useful to optimize the indoor thermal comfort and energy savings that are two important workplace issues where the comfort of the workers and the consumption of the building strongly affect the economic balance of a company. The Smart Lamp was built using a microcontroller, an integrated temperature and relative humidity sensor, some other modules and a 3D printer. This smart device is similar to the desk lamps that are usually found in offices but it allows one to adjust the indoor thermal comfort, by interacting directly with the air conditioner. After the construction phase, the Smart Lamp was installed in an office normally occupied by four workers to evaluate the indoor thermal comfort and the cooling consumption in summer. The results showed how the application of the Smart Lamp effectively reduced the energy consumption, optimizing the thermal comfort. The use of DIY approach combined with read-write functionality of websites, blog and social platforms, also allowed to customize, improve, share, reproduce and interconnect technologies so that anybody could use them in any occupied environment. PMID- 26959036 TI - Eutypenoids A-C: Novel Pimarane Diterpenoids from the Arctic Fungus Eutypella sp. D-1. AB - Eutypenoids A-C (1-3), pimarane diterpenoid alkaloid and two ring A rearranged pimarane diterpenoids, were isolated from the culture of Eutypella sp. D-1 obtained from high-latitude soil of the Arctic. Their structures, including absolute configurations, were authenticated on the basis of the mass spectroscopy (MS), nuclear magnetic resonance (NMR), X-ray crystallography, and electronic circular dichroism (ECD) analysis. The immunosuppressive effects of eutypenoids A C (1-3) were studied using a ConA-induced splenocyte proliferation model, which suggested that 2 exhibited potent immunosuppressive activities. PMID- 26959038 TI - Toxicity of Smokeless Tobacco Extract after 184-Day Repeated Oral Administration in Rats. AB - The use of smokeless tobacco (ST) is growing rapidly and globally. The consumption of ST is associated with an increased risk for developing chronic diseases, such as diabetes, hypercholesterolemia, and myocardial infarction, and has led to many public health problems. It is very important to access the toxicity of ST. This experiment presents data from 184-day toxicology studies in Sprague-Dawley (SD) rats designed to characterize the chronic effects of a smokeless tobacco extract (STE). The control group and treatment groups were matched for a range of nicotine levels. Animals were given STE by oral gavage with doses of 3.75 (low-dose), 7.50 (mid-dose) and 15.00 (high-dose) mg . nicotine/kg body weight/day for 184 days, followed by 30 days for recovery. Variables evaluated included body weights, feed consumption, clinical observations, clinical and anatomic pathology (including organ weights), and histopathology. Decreased body weights and organ weights (heart, liver and kidney) were found in animals in the mid-dose and high-dose groups. STE also showed moderate and reversible toxicity in esophagus, stomach, liver, kidney and lung. PMID- 26959037 TI - Understanding Inequalities of Maternal Smoking--Bridging the Gap with Adapted Intervention Strategies. AB - Women who are generally part of socially disadvantaged and economically marginalized groups are especially susceptible to smoking during pregnancy but smoking rates are underreported in both research and interventions. While there is evidence to support the short-term efficacy of nicotine replacement therapy (NRT) use in pregnancy, long-term abstinence rates are modest. Current health strategies and interventions designed to diminish smoking in pregnancy have adopted a simplified approach to maternal smoking-one that suggests that they have a similar degree of choice to non-pregnant smokers regarding the avoidance of risk factors, and overlooks individual predictors of non-adherence. As a result, interventions have been ineffective among this high-risk group. For this reason, this paper addresses the multiple and interacting determinants that must be considered when developing and implementing effective strategies that lead to successful smoking cessation: socioeconomic status (SES), nicotine dependence, social support, culture, mental health, and health services. Based on our review of the literature, we conclude that tailoring cessation programs for pregnant smokers may ultimately optimize NRT efficacy and reduce the prevalence of maternal smoking. PMID- 26959039 TI - Impact of Integrated Watershed Management on Complex Interlinked Factors Influencing Health: Perceptions of Professional Stakeholders in a Hilly Tribal Area of India. AB - Lack of access to water has a significant impact on the health of people in tribal areas, where water in households as well as for productive purposes is essential for life. In resource-limited settings such as hilly tribal areas, implementation of an integrated watershed management programme (IWMP) can have a significant impact on public health by providing a solution to water scarcity and related problems. The professional stakeholders in rural healthcare and development administration are important pillars of the system that implements various programmes and policies of government and non-government organizations, and act as facilitators for the improvement of public health in tribal areas. Information about the perceptions of these stakeholders on public health implications of the integrated watershed management programme is important in this context. A qualitative study was conducted using face to face semi structured interviews and focus group discussions (FGDs) with stakeholders involved in healthcare provision, education and development administration. The transcripts of interviews and FGDs were analyzed using manifest and latent content analysis. The perceptions and experiences shared by healthcare and development administration stakeholders suggest that implementation of IWMP in tribal areas helps efficient water and agriculture management, which results in improved socio-economic conditions that lead to positive health outcomes. PMID- 26959041 TI - Sports Facilities, Shopping Centers or Homes: What Locations are Important for Adults' Physical Activity? A Cross-Sectional Study. AB - Physical activity (PA) is influenced by the built environment. However, little is known about the types of built environment where adults spend their time, and at what levels of PA they engage in those environments. Understanding the effect of the built environment on PA requires insight into PA behavior at different types of locations (e.g., home, work, shopping centers, and sports facilities). Therefore, this study describes where adults aged 45-65 years were active with moderate-to-vigorous intensity (MVPA), and examines associations of socio demographic factors and neighborhood with MVPA at these locations. Participants' (N = 308) PA was measured for seven days using accelerometers and GPS-devices. Adults spent most minutes of MVPA at home and work. Highest MVPA-ratios of total time spent at a location were achieved in sports facilities and during transport. Neighborhood characteristics and socio-demographic factors such as work status, health status and household structure, had significant effects on MVPA at various locations and on total MVPA. Understanding PA behavior at various locations may provide insights that allow professionals in different domains (e.g., health, landscaping, urban planning) to develop strategies to stimulate PA. PMID- 26959040 TI - SNP-SNP Interaction between TLR4 and MyD88 in Susceptibility to Coronary Artery Disease in the Chinese Han Population. AB - The toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88) dependent signaling pathway plays a role in the initiation and progression of coronary artery disease (CAD). We investigated SNP-SNP interactions between the TLR4 and MyD88 genes in CAD susceptibility and assessed whether the effects of such interactions were modified by confounding risk factors (hyperglycemia, hyperlipidemia and Helicobacter pylori (H. pylori) infection). Participants with CAD (n = 424) and controls (n = 424) without CAD were enrolled. Polymerase chain restriction-restriction fragment length polymorphism was performed on genomic DNA to detect polymorphisms in TLR4 (rs10116253, rs10983755, and rs11536889) and MyD88 (rs7744). H. pylori infections were evaluated by enzyme-linked immunosorbent assays, and the cardiovascular risk factors for each subject were evaluated clinically. The significant interaction between TLR4 rs11536889 and MyD88 rs7744 was associated with an increased CAD risk (p value for interaction = 0.024). In conditions of hyperglycemia, the interaction effect was strengthened between TLR4 rs11536889 and MyD88 rs7744 (p value for interaction = 0.004). In hyperlipidemic participants, the interaction strength was also enhanced for TLR4 rs11536889 and MyD88 rs7744 (p value for interaction = 0.006). Thus, the novel interaction between TLR4 rs11536889 and MyD88 rs7744 was related with an increased risk of CAD, that could be strengthened by the presence of hyperglycemia or hyperlipidemia. PMID- 26959042 TI - E-Cigarettes for Immediate Smoking Substitution in Women Diagnosed with Cervical Dysplasia and Associated Disorders. AB - The aim of this study was to determine if 31 women with cervical dysplasia and associated conditions exacerbated by smoking would be successful substituting cigarettes with their choice of either nicotine replacement therapy (NRT) or electronic cigarettes (EC). Women received motivational interviewing and tried both NRT and ECs, choosing one method to use during a six-week intervention period. Daily cigarette consumption was measured at baseline, six, and 12 weeks, with differences analyzed by the Wilcoxon signed-rank test. Study analysis consisted only of women choosing to use ECs (29/31), as only two chose NRT. At the 12-week follow-up, the seven day point prevalence abstinence from smoking was 28.6%, and the median number of cigarettes smoked daily decreased from 18.5 to 5.5 (p < 0.0001). The median number of e-cigarette cartridges used dropped from 21 at the six-week follow-up to 12.5 at the 12-week follow-up. After initiating EC use, women at risk for cervical cancer were able to either quit smoking or reduce the number of cigarettes smoked per day. Although a controlled trial with a larger sample size is needed to confirm these initial results, this study suggests that using ECs during quit attempts may reduce cigarette consumption. PMID- 26959043 TI - Accumulation of Heavy Metals in Vegetable Species Planted in Contaminated Soils and the Health Risk Assessment. AB - The objectives of the present study were to investigate heavy metal accumulation in 22 vegetable species and to assess the human health risks of vegetable consumption. Six vegetable types were cultivated on farmland contaminated with heavy metals (Pb, Cd, Cu, Zn, and As). The target hazard quotient (THQ) method was used to assess the human health risks posed by heavy metals through vegetable consumption. Clear differences were found in the concentrations of heavy metals in edible parts of the different vegetables. The concentrations of heavy metals decreased in the sequence as leafy vegetables > stalk vegetables/root vegetables/solanaceous vegetables > legume vegetables/melon vegetables. The ability of leafy vegetables to uptake and accumulate heavy metals was the highest, and that of melon vegetables was the lowest. This indicated that the low accumulators (melon vegetables) were suitable for being planted on contaminated soil, while the high accumulators (leafy vegetables) were unsuitable. In Shizhuyuan area, China, the total THQ values of adults and children through consumption of vegetables were 4.12 and 5.41, respectively, suggesting that the residents may be facing health risks due to vegetable consumption, and that children were vulnerable to the adverse effects of heavy metal ingestion. PMID- 26959044 TI - Spatial Patterns of Heat-Related Cardiovascular Mortality in the Czech Republic. AB - The study examines spatial patterns of effects of high temperature extremes on cardiovascular mortality in the Czech Republic at a district level during 1994 2009. Daily baseline mortality for each district was determined using a single location-stratified generalized additive model. Mean relative deviations of mortality from the baseline were calculated on days exceeding the 90th percentile of mean daily temperature in summer, and they were correlated with selected demographic, socioeconomic, and physical-environmental variables for the districts. Groups of districts with similar characteristics were identified according to socioeconomic status and urbanization level in order to provide a more general picture than possible on the district level. We evaluated lagged patterns of excess mortality after hot spell occurrences in: (i) urban areas vs. predominantly rural areas; and (ii) regions with different overall socioeconomic level. Our findings suggest that climatic conditions, altitude, and urbanization generally affect the spatial distribution of districts with the highest excess cardiovascular mortality, while socioeconomic status did not show a significant effect in the analysis across the Czech Republic as a whole. Only within deprived populations, socioeconomic status played a relevant role as well. After taking into account lagged effects of temperature on excess mortality, we found that the effect of hot spells was significant in highly urbanized regions, while most excess deaths in rural districts may be attributed to harvesting effects. PMID- 26959045 TI - A Brief Up-Date of the Use of Sodium Oxybate for the Treatment of Alcohol Use Disorder. AB - The treatment of alcohol use disorder (AUD) with sodium oxybate (SMO) or gamma hydroxybutyric acid (GHB) was introduced in Italy and Austria more than 20 years and 15 years ago, respectively, and it is now widely employed to treat alcohol withdrawal syndrome (AWS) and to maintain alcohol abstinence. These indications derive from its similar structure to the inhibitory neurotransmitter gamma-amino butyric acid (GABA), exerting an ethanol-mimicking effect, because it binds to GABAB receptors. Craving for, and abuse of, SMO remain a controversial issue; even though these unfavorable effects are evident in poly-drug addicted patients and in those with psychiatric diagnosis of borderline personality disorder. In addition, despite cases of severe intoxication and deaths being widely documented when GHB is used as "street drug"; its clinical use remains safe. Thus, the aim of the present review is to examine the role of SMO in the treatment of AUD, its possible implications in reducing alcohol consumption, and cases of abuse, and severe intoxication due to SMO during its clinical use in the treatment of AUD. PMID- 26959046 TI - Estimation of the Human Extrathoracic Deposition Fraction of Inhaled Particles Using a Polyurethane Foam Collection Substrate in an IOM Sampler. AB - Extrathoracic deposition of inhaled particles (i.e., in the head and throat) is an important exposure route for many hazardous materials. Current best practices for exposure assessment of aerosols in the workplace involve particle size selective sampling methods based on particle penetration into the human respiratory tract (i.e., inhalable or respirable sampling). However, the International Organization for Standardization (ISO) has recently adopted particle deposition sampling conventions (ISO 13138), including conventions for extrathoracic (ET) deposition into the anterior nasal passage (ET1) and the posterior nasal and oral passages (ET2). For this study, polyurethane foam was used as a collection substrate inside an inhalable aerosol sampler to provide an estimate of extrathoracic particle deposition. Aerosols of fused aluminum oxide (five sizes, 4.9 um-44.3 um) were used as a test dust in a low speed (0.2 m/s) wind tunnel. Samplers were placed on a rotating mannequin inside the wind tunnel to simulate orientation-averaged personal sampling. Collection efficiency data for the foam insert matched well to the extrathoracic deposition convention for the particle sizes tested. The concept of using a foam insert to match a particle deposition sampling convention was explored in this study and shows promise for future use as a sampling device. PMID- 26959047 TI - Association of Maternal and Child Health Center (Posyandu) Availability with Child Weight Status in Indonesia: A National Study. AB - Little is known about the childhood obesity prevention and treatment practices of Maternal and Child Health services (Posyandu) in Indonesia or in other countries. The present study aims to assess the association of the availability of Posyandu with overweight and obesity in children of different household wealth levels. This was a secondary analysis of data collected in the 2013 Riskesdas (or Basic Health Research) survey, a cross-sectional study, representative population-based data. Height and weight, the availability of Posyandu, and basic characteristics of the study population were collected from parents with children aged 0 to 5 years (n = 63,237). Non-availability of Posyandu significantly raised the odds of being obese (OR = 1.13, 95% CI: 1.06-1.21) and did not show a significant relationship in the odds for overweight (OR = 0.99, 95% CI: 0.93-1.07). This relationship persisted after a full adjustment (OR = 1.16, 95% CI: 1.07-1.25 and OR = 1.04, 95% CI: 0.96-1.13, respectively). There was effect modification by household wealth, which was stronger for obese children. The availability of Posyandu has a protective association with childhood obesity in Indonesia. Posyandu services are well placed to play an important role in obesity prevention and treatment in early life. PMID- 26959048 TI - Spatio-Temporal Distribution Characteristics and Trajectory Similarity Analysis of Tuberculosis in Beijing, China. AB - Tuberculosis (TB) is an infectious disease with one of the highest reported incidences in China. The detection of the spatio-temporal distribution characteristics of TB is indicative of its prevention and control conditions. Trajectory similarity analysis detects variations and loopholes in prevention and provides urban public health officials and related decision makers more information for the allocation of public health resources and the formulation of prioritized health-related policies. This study analysed the spatio-temporal distribution characteristics of TB from 2009 to 2014 by utilizing spatial statistics, spatial autocorrelation analysis, and space-time scan statistics. Spatial statistics measured the TB incidence rate (TB patients per 100,000 residents) at the district level to determine its spatio-temporal distribution and to identify characteristics of change. Spatial autocorrelation analysis was used to detect global and local spatial autocorrelations across the study area. Purely spatial, purely temporal and space-time scan statistics were used to identify purely spatial, purely temporal and spatio-temporal clusters of TB at the district level. The other objective of this study was to compare the trajectory similarities between the incidence rates of TB and new smear-positive (NSP) TB patients in the resident population (NSPRP)/new smear-positive TB patients in the TB patient population (NSPTBP)/retreated smear-positive (RSP) TB patients in the resident population (RSPRP)/retreated smear-positive TB patients in the TB patient population (RSPTBP) to detect variations and loopholes in TB prevention and control among the districts in Beijing. The incidence rates in Beijing exhibited a gradual decrease from 2009 to 2014. Although global spatial autocorrelation was not detected overall across all of the districts of Beijing, individual districts did show evidence of local spatial autocorrelation: Chaoyang and Daxing were Low-Low districts over the six-year period. The purely spatial scan statistics analysis showed significant spatial clusters of high and low incidence rates; the purely temporal scan statistics showed the temporal cluster with a three-year period from 2009 to 2011 characterized by a high incidence rate; and the space-time scan statistics analysis showed significant spatio temporal clusters. The distribution of the mean centres (MCs) showed that the general distributions of the NSPRP MCs and NSPTBP MCs were to the east of the incidence rate MCs. Conversely, the general distributions of the RSPRP MCs and the RSPTBP MCs were to the south of the incidence rate MCs. Based on the combined analysis of MC distribution characteristics and trajectory similarities, the NSP trajectory was most similar to the incidence rate trajectory. Thus, more attention should be focused on the discovery of NSP patients in the western part of Beijing, whereas the northern part of Beijing needs intensive treatment for RSP patients. PMID- 26959049 TI - Efficient Co-Replication of Defective Novirhabdovirus. AB - We have generated defective Viral Hemorrhagic Septicemia Viruses (VHSV) which express either the green fluorescent protein (GFP) or a far-red fluorescent protein (mKate) by replacing the genes encoding the nucleoprotein N or the polymerase-associated P protein. To recover viable defective viruses, rVHSV DeltaN-Red and rVHSV-DeltaP-Green, fish cells were co-transfected with both deleted cDNA VHSV genomes, together with plasmids expressing N, P and L of the RNA-dependent RNA polymerase. After one passage of the transfected cell supernatant, red and green cell foci were observed. Viral titer reached 107 PFU/mL after three passages. Infected cells were always red and green with the very rare event of single red or green cell foci appearing. To clarify our understanding of how such defective viruses could be so efficiently propagated, we investigated whether (i) a recombination event between both defective genomes had occurred, (ii) whether both genomes were co-encapsidated in a single viral particle, and (iii) whether both defective viruses were always replicated together through a complementation phenomenon or even as conglomerate. To address these hypotheses, genome and viral particles have been fully characterized and, thus, allowing us to conclude that rVHSV-DeltaN-Red and rVHSV-DeltaP-Green are independent viral particles which could propagate only by simultaneously infecting the same cells. PMID- 26959050 TI - CRISPR-Cas9 as a Powerful Tool for Efficient Creation of Oncolytic Viruses. AB - The development of oncolytic viruses has led to an emerging new class of cancer therapeutics. Although the safety profile has been encouraging, the transition of oncolytic viruses to the clinical setting has been a slow process due to modifications. Therefore, a new generation of more potent oncolytic viruses needs to be exploited, following our better understanding of the complex interactions between the tumor, its microenvironment, the virus, and the host immune response. The conventional method for creation of tumor-targeted oncolytic viruses is based on homologous recombination. However, the creation of new mutant oncolytic viruses with large genomes remains a challenge due to the multi-step process and low efficiency of homologous recombination. The CRISPR-associated endonuclease Cas9 has hugely advanced the potential to edit the genomes of various organisms due to the ability of Cas9 to target a specific genomic site by a single guide RNA. In this review, we discuss the CRISPR-Cas9 system as an efficient viral editing method for the creation of new oncolytic viruses, as well as its potential future applications in the development of oncolytic viruses. Further, this review discusses the potential of off-target effects as well as CRISPR-Cas9 as a tool for basic research into viral biology. PMID- 26959051 TI - A Healthy Dietary Pattern Reduces Lung Cancer Risk: A Systematic Review and Meta Analysis. AB - BACKGROUND: Diet and nutrients play an important role in cancer development and progress; a healthy dietary pattern has been found to be associated with several types of cancer. However, the association between a healthy eating pattern and lung cancer risk is still unclear. OBJECTIVE: Therefore, we conducted a systematic review with meta-analysis to evaluate whether a healthy eating pattern might reduce lung cancer risk. METHODS: We identified relevant studies from the PubMed and Embase databases up to October 2015, and the relative risks were extracted and combined by the fixed-effects model when no substantial heterogeneity was observed; otherwise, the random-effects model was employed. Subgroup and publication bias analyses were also performed. RESULTS: Finally, eight observational studies were included in the meta-analysis. The pooled relative risk of lung cancer for the highest vs. lowest category of healthy dietary pattern was 0.81 (95% confidence interval, CI: 0.75-0.86), and no significant heterogeneity was detected. The relative risks (RRs) for non-smokers, former smokers and current smokers were 0.89 (95% CI: 0.63-1.27), 0.74 (95% CI: 0.62-0.89) and 0.86 (95% CI: 0.79-0.93), respectively. The results remained stable in subgroup analyses by other confounders and sensitivity analysis. CONCLUSIONS: The results of our meta-analysis suggest that a healthy dietary pattern is associated with a lower lung cancer risk, and they provide more beneficial evidence for changing the diet pattern in the general population. PMID- 26959052 TI - Effect of Flaxseed Intervention on Inflammatory Marker C-Reactive Protein: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - Functional food-flaxseed and its derivatives (flaxseed oil or lignans) are beneficial for human health, possibly because of their anti-inflammatory effects. C-reactive protein (CRP), a sensitive marker of inflammation was chosen to evaluate the anti-inflammatory effects of flaxseed. We searched randomized controlled trials from PubMed and the Cochrane Library in October 2015 and conducted a meta-analysis to evaluate the effectiveness of flaxseed and its derivatives on CRP. The mean differences (net change) in CRP (mg/L) concentrations were pooled with a random- or a fixed-effects model depending on the results of heterogeneity tests. Overall, flaxseed interventions had no effects on reduction of CRP (p = 0.428). The null effects were consistent in the subgroup analysis with multiple studies and population characteristics. Significant heterogeneity was observed in most of the analyses. Meta-regression identified baseline body mass index (BMI) as a significant source of heterogeneity (P-interaction = 0.032), with a significant reduction in CRP of 0.83 mg/L (95% confidence interval -1.34 to -0.31; p = 0.002) among subjects with a BMI of >=30 kg/m2. In conclusion, our meta-analysis did not find sufficient evidence that flaxseed and its derivatives have a beneficial effect on reducing circulating CRP. However, they may significantly reduce CRP in obese populations. PMID- 26959053 TI - Vitamin D and Sunlight Exposure in Newly-Diagnosed Parkinson's Disease. AB - Circulating vitamin D has previously been found to be lower in patients with Parkinson's disease (PD), while the effects of sunlight exposure have not yet been fully investigated. Therefore, we evaluated the associations between serum vitamin D, vitamin D intake, sunlight exposure, and newly-diagnosed PD patients in a Chinese population. This case-control study measured serum 25-hydroxyvitamin D (25(OH)D) levels and sunlight exposure in 201 patients with newly-diagnosed PD and 199 controls without neurodegenerative diseases. Data on vitamin D intake and sunlight exposure were obtained using a self-report questionnaire. Multivariable logistic regressions were employed to evaluate the associations between serum 25(OH)D levels, sunlight exposure, and PD. Adjustments were made for sex, age, smoking, alcohol use, education, BMI, and vitamin D intake. There were significantly lower levels of serum 25(OH)D (20.6 +/- 6.5 ng/mL), daily vitamin D intake (8.3 +/- 3.7 g/day), and sunlight exposure (9.7 +/- 4.1 h/week) in patients with PD compared to healthy controls (p < 0.05). Crude odds ratios (ORs) for PD in the quartiles of serum 25(OH)D were 1 (reference), 0.710 (0.401, 1.257), 0.631 (0.348, 1.209), and 0.483 (0.267, 0.874), respectively. Crude ORs for PD in quartiles of sunlight exposure were 1 (reference), 0.809 (0.454, 1.443), 0.623 (0.345, 1.124) and 0.533 (0.294, 0.966), respectively. A significant positive correlation between serum 25(OH)D and sunlight exposure was found, but serum 25(OH)D was not correlated with daily vitamin D intake. This study indicates that lower levels of serum 25(OH)D and sunlight exposure are significantly associated with an increased risk for PD. PMID- 26959055 TI - Nutrition and Dementia: Evidence for Preventive Approaches? AB - In recent years, the possibility of favorably influencing the cognitive trajectory through promotion of lifestyle modifications has been increasingly investigated. In particular, the relationship between nutritional habits and cognitive health has attracted special attention. The present review is designed to retrieve and discuss recent evidence (published over the last 3 years) coming from randomized controlled trials (RCTs) investigating the efficacy of nutritional interventions aimed at improving cognitive functioning and/or preventing cognitive decline in non-demented older individuals. A systematic review of literature was conducted, leading to the identification of 11 studies of interest. Overall, most of the nutritional interventions tested by the selected RCTs were found to produce statistically significant cognitive benefits (defined as improved neuropsychological test scores). Nevertheless, the clinical meaningfulness of such findings was not adequately discussed and appears controversial. In parallel, only 2 studies investigated between-group differences concerning incident dementia and mild cognitive impairment cases, reporting conflicting results. Results of the present review suggest that several dietary patterns and nutritional components may constitute promising strategies in postponing, slowing, and preventing cognitive decline. However, supporting evidence is overall weak and further studies are needed. PMID- 26959054 TI - Phylloquinone and Menaquinone-4 Tissue Distribution at Different Life Stages in Male and Female Sprague-Dawley Rats Fed Different VK Levels Since Weaning or Subjected to a 40% Calorie Restriction since Adulthood. AB - Whether through the vitamin K-dependent proteins or the individual K vitamers, vitamin K (VK) is associated with a number of age-related conditions (e.g., osteoporosis, atherosclerosis, insulin resistance, cognitive decline). In light of this, we investigated the influence of lifetime dietary VK exposure on the tissue distribution of phylloquinone (K1) and menaquinone-4 (MK-4) vitamers in 3 , 12- and 22-month-old male and female rats fed different K1 diets since weaning or subjected to a 40% calorie restricted diet (CR) since adulthood. Dietary K1 intakes around the minimal amount required for normal blood coagulation had no significant influence on body weights of both male and female rats at different life stages. Tissue contents of the K vitamers differed according to organs, were generally higher in females than in males, and increased with K1 intake. The MK 4/total VK ratios tended to be increased in old age possibly reflecting an increased physiological demand for MK-4 during aging. Our study also confirmed the greater susceptibility of male rats to low VK containing diet, notably at a younger age. Despite lifelong higher K1 intakes per unit body weight, tissue K1 and MK-4 contents at 20 months were generally lower in CR rats compared to their ad libitum (AL) counterparts. Whether the lower tissue MK-4 content is the result of lower synthesis from K1 or greater tissue utilization remains to be determined. However, the more youthful coagulation profile observed in old CR rats (vs. AL rats) tends to support the notion that CR is associated with greater utilization of the K vitamers to sustain physiological functions. PMID- 26959056 TI - The Effects of Creatine Supplementation on Explosive Performance and Optimal Individual Postactivation Potentiation Time. AB - Creatine plays an important role in muscle energy metabolism. Postactivation potentiation (PAP) is a phenomenon that can acutely increase muscle power, but it is an individualized process that is influenced by muscle fatigue. This study examined the effects of creatine supplementation on explosive performance and the optimal individual PAP time during a set of complex training bouts. Thirty explosive athletes performed tests of back squat for one repetition maximum (1RM) strength and complex training bouts for determining the individual optimal timing of PAP, height and peak power of a counter movement jump before and after the supplementation. Subjects were assigned to a creatine or placebo group and then consumed 20 g of creatine or carboxymethyl cellulose per day for six days. After the supplementation, the 1RM strength in the creatine group significantly increased (p < 0.05). The optimal individual PAP time in the creatine group was also significant earlier than the pre-supplementation and post-supplementation of the placebo group (p < 0.05). There was no significant difference in jump performance between the groups. This study demonstrates that creatine supplementation improves maximal muscle strength and the optimal individual PAP time of complex training but has no effect on explosive performance. PMID- 26959057 TI - Sirt1 Is Required for Resveratrol-Mediated Chemopreventive Effects in Colorectal Cancer Cells. AB - Sirt1 is a NAD+-dependent protein-modifying enzyme involved in regulating gene expression, DNA damage repair, metabolism and survival, as well as acts as an important subcellular target of resveratrol. The complex mechanisms underlying Sirt1 signaling during carcinogenesis remain controversial, as it can serve both as a tumor promoter and suppressor. Whether resveratrol-mediated chemopreventive effects are mediated via Sirt1 in CRC growth and metastasis remains unclear; which was the subject of this study. We found that resveratrol suppressed proliferation and invasion of two different human CRC cells in a dose-dependent manner, and interestingly, this was accompanied with a significant decrease in Ki 67 expression. By transient transfection of CRC cells with Sirt1-ASO, we demonstrated that the anti-tumor effects of resveratrol on cells was abolished, suggesting the essential role of this enzyme in the resveratrol signaling pathway. Moreover, resveratrol downregulated nuclear localization of NF-kappaB, NF-kappaB phosphorylation and its acetylation, causing attenuation of NF-kappaB regulated gene products (MMP-9, CXCR4) involved in tumor-invasion and metastasis. Finally, Sirt1 was found to interact directly with NF-kappaB, and resveratrol did not suppress Sirt1-ASO-induced NF-kappaB phosphorylation, acetylation and NF kappaB-regulated gene products. Overall, our results demonstrate that resveratrol can suppress tumorigenesis, at least in part by targeting Sirt1 and suppression of NF-kappaB activation. PMID- 26959058 TI - Heat-Killed Enterococcus faecalis EF-2001 Ameliorates Atopic Dermatitis in a Murine Model. AB - Recent reports have shown the immunomodulatory effect of heat-killed lactic acid bacteria. Atopic dermatitis (AD) is an allergic skin disease, caused by immune dysregulation among other factors. The aim of this study was to assess the effect of heat-killed Enterococcus faecalis EF-2001 (EF-2001) on AD. We established an in vivo AD model by repeated local exposure of Dermatophagoides farinae extract (DFE; house dust mite extract) and 2,4-dinitrochlorobenzene (DNCB) to the ears of mice. After oral administration of EF-2001 for four weeks, the epidermal and dermal ear thickness, mast cell infiltration, and serum immunoglobulin levels were measured. In addition, the gene expression levels of pathogenic cytokines in the ears, lymph nodes, and splenocytes were assayed. EF-2001 attenuated AD symptoms based on the ear thickness, histopathological analysis, and serum immunoglobulin levels. Moreover, EF-2001 decreased the DFE/DNCB-induced expression of various pathogenic cytokines in the ears, lymph nodes, and splenocytes. These results suggest that EF-2001 has therapeutic potential in the treatment of AD owing to its immunomodulatory effects. PMID- 26959059 TI - The Potential Protective Action of Vitamin D in Hepatic Insulin Resistance and Pancreatic Islet Dysfunction in Type 2 Diabetes Mellitus. AB - Vitamin D deficiency (i.e., hypovitaminosis D) is associated with increased insulin resistance, impaired insulin secretion, and poorly controlled glucose homeostasis, and thus is correlated with the risk of metabolic diseases, including type 2 diabetes mellitus (T2DM). The liver plays key roles in glucose and lipid metabolism, and its dysregulation leads to abnormalities in hepatic glucose output and triglyceride accumulation. Meanwhile, the pancreatic islets are constituted in large part by insulin-secreting beta cells. Consequently, islet dysfunction, such as occurs in T2DM, produces hyperglycemia. In this review, we provide a critical appraisal of the modulatory actions of vitamin D in hepatic insulin sensitivity and islet insulin secretion, and we discuss the potential roles of a local vitamin D signaling in regulating hepatic and pancreatic islet functions. This information provides a scientific basis for establishing the benefits of the maintenance, or dietary manipulation, of adequate vitamin D status in the prevention and management of obesity-induced T2DM and non-alcoholic fatty liver disease. PMID- 26959060 TI - The Effects of an Oil and Wheat Flour Fortification Program on Pre-School Children and Women of Reproductive Age Living in Cote d'Ivoire, a Malaria-Endemic Area. AB - Anemia and micronutrient deficiencies are widespread in sub-Saharan Africa, but the impact of food fortification is still debated. The objective of this study was to estimate the iron and vitamin A status of preschool children (PSC) and women of reproductive age (WRA) in households consuming fortified oil and wheat flour. The survey was cross-sectional in a rural and an urban area. Data on demographics, socioeconomic status, and fortified foods were collected at households. Hemoglobin (Hb), retinol binding protein (RBP), ferritin, soluble transferrin receptors (sTfR), subclinical inflammation, and Plasmodium spp. infection data were collected. In PSC, vitamin A deficiency (VAD) was prevalent, but for each 1 mg retinol equivalents (RE)/kg of oil consumed, RBP increased by 0.37 MUmol/L (p = 0.03). In WRA, there was no significant VAD in the population (0.7%). Anemia was found in 92.2% of rural and 56.3% of urban PSC (p < 0.001). PSC with access to adequately fortified flour had Hb concentrations 15.7 g/L higher than those who did not (p < 0.001). Hb levels increased by +0.238 g/L per mg/kg increase in iron fortification levels (p < 0.001). The national program fortifying vegetable oil with vitamin A and wheat flour with iron and folic acid may have contributed to improved micronutrient status of PSC from two areas in Cote d'Ivoire. PMID- 26959061 TI - Conversion Ratio between Botox(r), Dysport(r), and Xeomin(r) in Clinical Practice. AB - Botulinum neurotoxin has revolutionized the treatment of spasticity and is now administered worldwide. There are currently three leading botulinum neurotoxin type A products available in the Western Hemisphere: onabotulinum toxin-A (ONA) Botox((r)), abobotulinum toxin-A (ABO), Dysport((r)), and incobotulinum toxin A (INCO, Xeomin((r))). Although the efficacies are similar, there is an intense debate regarding the comparability of various preparations. Here we will address the clinical issues of potency and conversion ratios, as well as safety issues such as toxin spread and immunogenicity, to provide guidance for BoNT-A use in clinical practice. INCO was shown to be as effective as ONA with a comparable adverse event profile when a clinical conversion ratio of 1:1 was used. The available clinical and preclinical data suggest that a conversion ratio ABO:ONA of 3:1-or even lower-could be appropriate for treating spasticity, cervical dystonia, and blepharospasm or hemifacial spasm. A higher conversion ratio may lead to an overdosing of ABO. While uncommon, distant spread may occur; however, several factors other than the pharmaceutical preparation are thought to affect spread. Finally, whereas the three products have similar efficacy when properly dosed, ABO has a better cost-efficacy profile. PMID- 26959062 TI - DNA Aptamers against Taiwan Banded Krait alpha-Bungarotoxin Recognize Taiwan Cobra Cardiotoxins. AB - Bungarus multicinctus alpha-bungarotoxin (alpha-Bgt) and Naja atra cardiotoxins (CTXs) share a common structural scaffold, and their tertiary structures adopt three-fingered loop motifs. Four DNA aptamers against alpha-Bgt have been reported previously. Given that the binding of aptamers with targeted proteins depends on structural complementarity, in this study, we investigated whether DNA aptamers against alpha-Bgt could also recognize CTXs. It was found that N. atra cardiotoxin 3 (CTX3) reduced the electrophoretic mobility of aptamers against alpha-Bgt. Analysis of the changes in the fluorescence intensity of carboxyfluorescein-labeled aptamers upon binding toxin molecules revealed that CTX3 and alpha-Bgt could bind the tested aptamers. Moreover, the aptamers inhibited the membrane-damaging activity and cytotoxicity of CTX3. In addition to CTX3, other N. atra CTX isotoxins also bound to the aptamer against alpha-Bgt. Taken together, our data indicate that aptamers against alpha-Bgt show cross reactivity with CTXs. The findings that aptamers against alpha-Bgt also suppress the biological activities of CTX3 highlight the potential utility of aptamers in regard to the broad inhibition of snake venom three-fingered proteins. PMID- 26959064 TI - Support Values for Genome Phylogenies. AB - We have recently developed a distance metric for efficiently estimating the number of substitutions per site between unaligned genome sequences. These substitution rates are called "anchor distances" and can be used for phylogeny reconstruction. Most phylogenies come with bootstrap support values, which are computed by resampling with replacement columns of homologous residues from the original alignment. Unfortunately, this method cannot be applied to anchor distances, as they are based on approximate pairwise local alignments rather than the full multiple sequence alignment necessary for the classical bootstrap. We explore two alternatives: pairwise bootstrap and quartet analysis, which we compare to classical bootstrap. With simulated sequences and 53 human primate mitochondrial genomes, pairwise bootstrap gives better results than quartet analysis. However, when applied to 29 E. coli genomes, quartet analysis comes closer to the classical bootstrap. PMID- 26959065 TI - Auto Diagnostics of Lung Nodules Using Minimal Characteristics Extraction Technique. AB - Computer-aided detection (CAD) systems provide useful tools and an advantageous process to physicians aiming to detect lung nodules. This paper develops a method composed of four processes for lung nodule detection. The first step employs image acquisition and pre-processing techniques to isolate the lungs from the rest of the body. The second stage involves the segmentation process using a 2D algorithm to affect every layer of a scan eliminating non-informative structures inside the lungs, and a 3D blob algorithm associated with a connectivity algorithm to select possible nodule shape candidates. The combinations of these algorithms efficiently eliminate the high rates of false positives. The third process extracts eight minimal representative characteristics of the possible candidates. The final step utilizes a support vector machine for classifying the possible candidates into nodules and non-nodules depending on their features. As the objective is to find nodules bigger than 4mm, the proposed approach demonstrated quite encouraging results. Among 65 computer tomography (CT) scans, 94.23% of sensitivity and 84.75% in specificity were obtained. The accuracy of these two results was 89.19% taking into consideration that 45 scans were used for testing and 20 for training. The rate of false positives was 0.2 per scan. PMID- 26959066 TI - Pepper Weevil (Coleoptera: Curculionidae) Preferences for Specific Pepper Cultivars, Plant Parts, Fruit Colors, Fruit Sizes, and Timing. AB - Peppers (Capsicum spp.) are an important crop in the USA, with about 32,000 ha cultivated in 2007, which resulted in $588 million in farm revenue. The pepper weevil, Anthonomus eugenii Cano (Coleoptera: Curculionidae), is the most troublesome insect pest of peppers in the southern United States. It is therefore urgent to find different vulnerabilities of pepper cultivars, fruit and plants parts, fruit colors and sizes, and timing to infestation by A. eugenii. Also relevant is testing whether fruit length and infestation state affect fruit numbers, weights, and proportions of fruit that are infested. Counts of A. eugenii adults and marks from oviposition and feeding suggested that C. chinense Jacquin "Habanero" was least susceptible, and C. annuum L. cultivars "SY" and "SR" were most susceptible. Comparison of plant parts and fruit sizes revealed that A. eugenii preferred the peduncle, calyx, and top of pepper fruits over the middle, bottom, leaves, or remainder of flowers. Anthonomus eugenii does not discriminate between green or yellow fruit color nor vary diurnally in numbers. Based on adult counts, medium to extra-large fruits (>=1.5 cm long) attracted more weevils than small fruits (<1.5 cm). However based on proportions of fruit numbers or fruit weights that were infested, there were no differences between large and small fruits. Choice of pepper cultivar can thus be an important part of an IPM cultural control program designed to combat A. eugenii by reduced susceptibility or by synchronous fruit drop of infested fruits. Our results are potentially helpful in developing scouting programs including paying particular attention to the preferred locations of adults and their sites of feeding and oviposition on the fruit. The results also suggested the potential value of spraying when the fruits are still immature to prevent and control infestation. PMID- 26959063 TI - South Asian Medicinal Compounds as Modulators of Resistance to Chemotherapy and Radiotherapy. AB - Cancer is a hyperproliferative disorder that involves transformation, dysregulation of apoptosis, proliferation, invasion, angiogenesis and metastasis. During the last 30 years, extensive research has revealed much about the biology of cancer. Chemotherapy and radiotherapy are the mainstays of cancer treatment, particularly for patients who do not respond to surgical resection. However, cancer treatment with drugs or radiation is seriously limited by chemoresistance and radioresistance. Various approaches and strategies are employed to overcome resistance to chemotherapy and radiation treatment. Many plant-derived phytochemicals have been investigated for their chemo- and radio-sensitizing properties. The peoples of South Asian countries such as India, Pakistan, Sri Lanka, Nepal, Bangladesh and Bhutan have a large number of medicinal plants from which they produce various pharmacologically potent secondary metabolites. The medicinal properties of these compounds have been extensively investigated and many of them have been found to sensitize cancer cells to chemo- and radio therapy. This review focuses on the role of South Asian medicinal compounds in chemo- and radio-sensitizing properties in drug- and radio-resistant cancer cells. Also discussed is the role of South Asian medicinal plants in protecting normal cells from radiation, which may be useful during radiotherapy of tumors to spare surrounding normal cells. PMID- 26959067 TI - Up-Regulation of Mitochondrial Antioxidant Superoxide Dismutase Underpins Persistent Cardiac Nutritional-Preconditioning by Long Chain n-3 Polyunsaturated Fatty Acids in the Rat. AB - Reactive oxygen species paradoxically underpin both ischaemia/reperfusion (I/R) damage and ischaemic preconditioning (IPC) cardioprotection. Long-chain omega-3 polyunsaturated fatty acids (LCn-3 PUFA) are highly susceptible to peroxidation, but are paradoxically cardioprotective. This study tested the hypothesis that LCn 3 PUFA cardioprotection is underpinned by peroxidation, upregulating antioxidant activity to reduce I/R-induced lipid oxidation, and the mechanisms of this nutritional preconditioning contrast to mechanisms of IPC. Rats were fed: fish oil (LCn-3 PUFA); sunflower seed oil (n-6 PUFA); or beef tallow (saturated fat, SF) enriched diets for six weeks. Isolated hearts were subject to: 180 min normoxic perfusion; a 30 min coronary occlusion ischaemia protocol then 120 min normoxic reperfusion; or a 3 * 5 min global IPC protocol, 30 min ischaemia, then reperfusion. Dietary LCn-3 PUFA raised basal: membrane docosahexaenoic acid (22:6n-3 DHA); fatty acid peroxidisability index; concentrations of lipid oxidation products; and superoxide dismutase (MnSOD) activity (but not CuZnSOD or glutathione peroxidase). Infarct size correlated inversely with basal MnSOD activity (r2 = 0.85) in the ischaemia protocol and positively with I/R-induced lipid oxidation (lipid hydroperoxides (LPO), r2 = 0.475; malondialdehyde (MDA), r2 = 0.583) across ischaemia and IPC protocols. While both dietary fish oil and IPC infarct-reduction were associated with reduced I/R-induced lipid oxidation, fish oil produced nutritional preconditioning by prior LCn-3 PUFA incorporation and increased peroxidisability leading to up-regulated mitochondrial SOD antioxidant activity. PMID- 26959068 TI - The Application of Genetic Risk Scores in Age-Related Macular Degeneration: A Review. AB - Age-related macular degeneration (AMD), a highly prevalent and impactful disease of aging, is inarguably influenced by complex interactions between genetic and environmental factors. Various risk scores have been tested that assess measurable genetic and environmental contributions to disease. We herein summarize and review the ability and utility of these numerous models for prediction of AMD and suggest additional risk factors to be incorporated into clinically useful predictive models of AMD. PMID- 26959069 TI - Acute Myeloid Leukemia: A Concise Review. AB - Acute myeloid leukemia (AML) is a heterogeneous clonal disorder characterized by immature myeloid cell proliferation and bone marrow failure. Cytogenetics and mutation testing remain a critical prognostic tool for post induction treatment. Despite rapid advances in the field including new drug targets and increased understanding of the biology, AML treatment remains unchanged for the past three decades with the majority of patients eventually relapsing and dying of the disease. Allogenic transplant remains the best chance for cure for patients with intermediate or high risk disease. In this review, we discuss the landmark genetic studies that have improved outcome prediction and novel therapies. PMID- 26959071 TI - Fabrication of Gelatin/PCL Electrospun Fiber Mat with Bone Powder and the Study of Its Biocompatibility. AB - Fabricating ideal scaffolds for bone tissue engineering is a great challenge to researchers. To better mimic the mineral component and the microstructure of natural bone, several kinds of materials were adopted in our study, namely gelatin, polycaprolactone (PCL), nanohydroxyapatite (nHA), and bone powder. Three types of scaffolds were fabricated using electrospinning; gelatin/PCL, gelatin/PCL/nHA, and gelatin/PCL/bone powder. Scaffolds were examined using scanning electron microscopy (SEM) and transmission electron microscopy (TEM) observations. Then, Adipose-derived Stem Cells (ADSCs) were seeded on these scaffolds to study cell morphology, cell viability, and proliferation. Through this study, we found that nHA and bone powder can be successfully united in gelatin/PCL fibers. When compared with gelatin/PCL and gelatin/PCL/nHA, the gelatin/PCL/bone powder scaffolds could provide a better environment to increase ADSCs' growth, adhesion, and proliferation. Thus, we think that gelatin/PCL/bone powder has good biocompatibility, and, when compared with nHA, bone powder may be more effective in bone tissue engineering due to the bioactive factors contained in it. PMID- 26959073 TI - The prognostic role of FIGO stage in patients with vulvar cancer: a systematic review and meta-analysis. AB - OBJECTIVE: To perform a meta-analysis examining the survival of patients with vulvar cancer based on the 2009 International Federation of Gynecology and Obstetrics (FIGO) staging system. METHODS: Medline, PubMed, and Cochrane databases were searched until 20 March 2015 for prospective or retrospective studies using the terms vulvar cancer, prognostic/prognosis, survival, recurrence, lymph nodes (LNs), inguinal lymphadenectomy/excision, and staging. The primary outcome was 5 year overall survival (OS), and secondary outcomes were 5 year disease-free survival (DFS) and progression-free survival (PFS). RESULTS: Fourteen retrospective studies were included. The 5 year OS rate decreased with increasing 2009 FIGO stage and number of LN metastasis. FIGO stage I, II, III, and IV patients had 5 year OS rates of 84.0%, 74.6%, 47.8%, and 9.4%, respectively. Pooled estimates showed that the 5 year OS was 84.5% for patients without LN metastasis, and for patients with >=3 LN metastases the 5 year OS rate was 30.1%. Similarly, the overall 5 year DFS and PFS decreased with the increasing number of LN metastases. The 5 year DFS rate was 87.2% for patients with no LN metastasis and for patients with >=3 LN metastases was 35.4%. The 5 year PFS rate was 86.6% for patients with no LN metastasis and for patients with >=3 LN metastases was 27.6%. LIMITATIONS: All studies were retrospective studies. DFS and PFS rates in patients with different 2009 FIGO stages and with different mean tumor sizes were not examined due to a limited number of reports. CONCLUSIONS: More advanced 2009 FIGO stage and greater number of LN metastases are associated with worse outcomes in patients with vulvar cancer. PMID- 26959074 TI - The usefulness of microsurgical pedicle lengthening in free anterolateral thigh flaps. AB - BACKGROUND: A microsurgical pedicle-lengthening technique can be used when a pedicle length longer than that usually provided by an anterolateral thigh (ALT) flap is required. The purpose of this report is description of pedicle lengthening method from original pedicle length for free ALT flaps and presentation of the results of application of this technique in reconstruction from a series of cases. PATIENTS AND METHODS: The microsurgical pedicle lengthening procedure was used in 10 patients who received free ALT flaps from January 2012 to June 2015. The location of reconstruction was the heel in 3 patients, foot in 3 patients, flank in 2 patients, forehead in 1 patient, and lower leg in 1 patient. The technique was categorized as two distinct 2 types according to the branching pattern of the perforator. The transected segments of the extra vessel lengths were translocated anterogradely, and used to perform pedicle extensions. RESULTS: The average length of the original pedicle was 13.1 cm (range 10.1-16.4 cm), and the average gain in length using the pedicle lengthening method was 6.5 cm (range 5.0-8.1 cm). All the flaps survived well postoperatively. Of the 10 patients, three experienced complications that included partial flap necrosis in one patient, wound dehiscence in one patient, and seroma in the third patient. No major complications occurred. CONCLUSION: The microsurgical pedicle-lengthening technique described here offers a solution for pedicles that are shorter than expected, with additional surgery required. This method may help overcome emergency situations that can arise during ALT flap surgery. (c) 2016 Wiley Periodicals, Inc. Microsurgery 36:559-566, 2016. PMID- 26959070 TI - Omega-3 Fatty Acids in Modern Parenteral Nutrition: A Review of the Current Evidence. AB - Intravenous lipid emulsions are an essential component of parenteral nutrition regimens. Originally employed as an efficient non-glucose energy source to reduce the adverse effects of high glucose intake and provide essential fatty acids, lipid emulsions have assumed a larger therapeutic role due to research demonstrating the effects of omega-3 and omega-6 polyunsaturated fatty acids (PUFA) on key metabolic functions, including inflammatory and immune response, coagulation, and cell signaling. Indeed, emerging evidence suggests that the effects of omega-3 PUFA on inflammation and immune response result in meaningful therapeutic benefits in surgical, cancer, and critically ill patients as well as patients requiring long-term parenteral nutrition. The present review provides an overview of the mechanisms of action through which omega-3 and omega-6 PUFA modulate the immune-inflammatory response and summarizes the current body of evidence regarding the clinical and pharmacoeconomic benefits of intravenous n-3 fatty acid-containing lipid emulsions in patients requiring parenteral nutrition. PMID- 26959076 TI - Exchange of Coordinated Solvent During Crystallization of a Metal-Organic Framework Observed by In Situ High-Energy X-ray Diffraction. AB - Using time-resolved monochromatic high energy X-ray diffraction, we present an in situ study of the solvothermal crystallisation of a new MOF [Yb2(BDC)3(DMF)2]?H2O (BDC=benzene-1,4-dicarboxylate and DMF=N,N-dimethylformamide) under solvothermal conditions, from mixed water/DMF solvent. Analysis of high resolution powder patterns obtained reveals an evolution of lattice parameters and electron density during the crystallisation process and Rietveld analysis shows that this is due to a gradual topochemical replacement of coordinated solvent molecules. The water initially coordinated to Yb(3+) is replaced by DMF as the reaction progresses. PMID- 26959078 TI - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's disease in zebrafish. AB - Parkinson's disease (PD) is the most common age associated neurodegenerative disease, which has been extensively studied for its etiology and phenotype. PD has been widely studied in alternate model system such as rodents towards understanding the role of neurotoxin by inducing PD. This study is aimed to understand the biomechanism of PD in zebrafish model system induced by 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP). The phenotype and role of various genes and proteins for Parkinsonism were tested and evaluated in this study using behavior, molecular and proteomic approaches. Zebrafish PD model induced by 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine showed a significant level of decrease in the movement with erratic swimming pattern and increased freezing bouts. CHCHD2, EEF2B, LRRK2, PARK7, PARK2, POLG, SNCGB and SYNB genes were differentially regulated at the transcript level in PD zebrafish. Similarly a total of 73 proteins were recognized as differentially expressed in the nervous system of zebrafish due to Parkinsonism based on quantitative proteomics approach. Proteins such as NEFL, MUNC13-1, NAV2 and GAPVD1 were down regulated in the zebrafish brain for the PD phenotype, which were associated with the neurological pathways. This zebrafish based PD model can be used as a potential model system for screening prospective drug molecules for PD. PMID- 26959079 TI - Host finding of the pigeon tick Argas reflexus. AB - The medically and veterinary important feral pigeon tick Argas reflexus (Ixodida: Argasidae) Fabricius usually feeds on pigeons, but if its natural hosts are not available, it also enters dwellings to bite humans that can possibly react with severe allergic reactions. Argas reflexus is ecologically extremely successful as a result of some outstanding morphological, physiological, and ethological features. Yet, it is still unknown how the pigeon tick finds its hosts. Here, different host stimuli such as living nestlings as well as begging calls, body heat, smell, host breath and tick faeces, were tested under controlled laboratory conditions. Of all stimuli tested, only heat played a role in host-finding. The heat stimulus was then tested under natural conditions within a pigeon loft. The results showed that A. reflexus is able to find a host over short distances of only a few centimetres. Furthermore, it finds its host by random movements and recognizes a host only right before direct contact is made. The findings are useful for the control of A. reflexus in infested apartments, both to diagnose an infestation and to perform a success monitoring after disinfestation. PMID- 26959080 TI - Origin and mechanism of crassulacean acid metabolism in orchids as implied by comparative transcriptomics and genomics of the carbon fixation pathway. AB - Crassulacean acid metabolism (CAM) is a CO2 fixation pathway that maximizes water use efficiency (WUE), compared with the C3/C4 CO2 pathway, which permits CAM plants to adapt to arid environments. The CAM pathway provides excellent opportunities to genetically design plants, especially bioenergy crops, with a high WUE and better photosynthetic performance than C3/C4 in arid environments. The information available on the origin and evolution of CAM is scant, however. Here, we analyzed transcriptomes from 13 orchid species and two existing orchid genomes, covering CAM and C3 plants, with an emphasis on comparing 13 gene families involved in the complete carbon fixation pathway. The dosage of the core photosynthesis-related genes plays no substantial role in the evolution of CAM in orchids; however, CAM may have evolved primarily by changes at the transcription level of key carbon fixation pathway genes. We proposed that in both dark and light, CO2 is primarily fixed and then released through two metabolic pathways via known genes, such as PPC1, PPDK and PPCK. This study reports a comprehensive comparison of carbon fixation pathway genes across different photosynthetic plants, and reveals the importance of the level of expression of key genes in the origin and evolution of CAM. PMID- 26959081 TI - Gap Filling as Exact Path Length Problem. AB - One of the last steps in a genome assembly project is filling the gaps between consecutive contigs in the scaffolds. This problem can be naturally stated as finding an s-t path in a directed graph whose sum of arc costs belongs to a given range (the estimate on the gap length). Here s and t are any two contigs flanking a gap. This problem is known to be NP-hard in general. Here we derive a simpler dynamic programming solution than already known, pseudo-polynomial in the maximum value of the input range. We implemented various practical optimizations to it, and compared our exact gap-filling solution experimentally to popular gap-filling tools. Summing over all the bacterial assemblies considered in our experiments, we can in total fill 76% more gaps than the best previous tool, and the gaps filled by our method span 136% more sequence. Furthermore, the error level of the newly introduced sequence is comparable to that of the previous tools. The experiments also show that our exact approach does not easily scale to larger genomes, where the problem is in general difficult for all tools. PMID- 26959082 TI - A Two-Dimensional Zirconium Carbide by Selective Etching of Al3C3 from Nanolaminated Zr3Al3C5. AB - The room-temperature synthesis of a new two-dimensional (2D) zirconium-containing carbide, Zr3C2T(z) MXene is presented. In contrast to traditional preparation of MXene, the layered ternary Zr3Al3C5 material instead of MAX phases is used as source under hydrofluoric acid treatment. The structural, mechanical, and electronic properties of the synthesized 2D carbide are investigated, combined with first-principles density functional calculations. A comparative study on the structrual stability of our obtained 2D Zr3C2T(z) and Ti3C2T(z) MXenes at elevated temperatures is performed. The obtained 2D Zr3C2T(z) exhibits relatively better ability to maintain 2D nature and strucural integrity compared to Ti-based Mxene. The difference in structural stability under high temperature condition is explained by a theoretical investigation on binding energy. PMID- 26959077 TI - Role of the vagus nerve in the development and treatment of diet-induced obesity. AB - This review highlights evidence for a role of the vagus nerve in the development of obesity and how targeting the vagus nerve with neuromodulation or pharmacology can be used as a therapeutic treatment of obesity. The vagus nerve innervating the gut plays an important role in controlling metabolism. It communicates peripheral information about the volume and type of nutrients between the gut and the brain. Depending on the nutritional status, vagal afferent neurons express two different neurochemical phenotypes that can inhibit or stimulate food intake. Chronic ingestion of calorie-rich diets reduces sensitivity of vagal afferent neurons to peripheral signals and their constitutive expression of orexigenic receptors and neuropeptides. This disruption of vagal afferent signalling is sufficient to drive hyperphagia and obesity. Furthermore neuromodulation of the vagus nerve can be used in the treatment of obesity. Although the mechanisms are poorly understood, vagal nerve stimulation prevents weight gain in response to a high-fat diet. In small clinical studies, in patients with depression or epilepsy, vagal nerve stimulation has been demonstrated to promote weight loss. Vagal blockade, which inhibits the vagus nerve, results in significant weight loss. Vagal blockade is proposed to inhibit aberrant orexigenic signals arising in obesity as a putative mechanism of vagal blockade-induced weight loss. Approaches and molecular targets to develop future pharmacotherapy targeted to the vagus nerve for the treatment of obesity are proposed. In conclusion there is strong evidence that the vagus nerve is involved in the development of obesity and it is proving to be an attractive target for the treatment of obesity. PMID- 26959084 TI - Facilitation contributes to Mediterranean woody plant diversity but does not shape the diversity-productivity relationship along aridity gradients. AB - The diversity-productivity relationship (humped-back model (HBM)) and the stress gradient (SGH) hypotheses may be connected when productivity is limited primarily by aridity. We analytically connect both hypotheses and assess the contribution of facilitation to woody plant richness along the aridity gradient of the Western Mediterranean floristic region. We monitored regeneration niches of woody plants, obtaining rarefied species richness and plant relative interaction indices in 54 forests and scrublands in a 1750-km geographical range across Spain, Morocco and the Canary Islands. We verified the monotonic increase in facilitation with aridity postulated by SGH and the humped-shape pattern of species richness expected from HBM, which became manifest after expanding the aridity gradient or crossing vegetation types. Along the gradient, interaction balance turned into facilitation earlier in forest than in scrublands. The effects of aridity and interaction balance on species diversity were additive rather than interdependent. Facilitation is an important driver of woody species richness at macroecological scales because it added up to diversity in most sites, with enhanced contribution with increased stress. The HBM was not shaped by species interactions. Results suggest that facilitation may act in Mediterranean vegetation buffering against critical transitions between states allowing woody plant communities to cope with the rise in aridity expected with global warming. PMID- 26959083 TI - Association between psoriasis and inflammatory bowel disease: a Danish nationwide cohort study. AB - BACKGROUND: Psoriasis, Crohn disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders with overlapping genetic architecture. However, data on the frequency and risk of CD and UC in psoriasis are scarce and poorly understood. OBJECTIVES: To investigate the association between CD and UC in patients with psoriasis. METHODS: All Danish individuals aged >= 18 years between 1 January 1997 and 31 December 2012 were linked in nationwide registers. Psoriasis severity was defined in two models: hospital visits and medication. Incidence rates per 10 000 person-years were calculated, and incidence rate ratios (IRRs) were estimated by Poisson regression. RESULTS: In the total cohort (n = 5 554 100) there were 75 209 incident cases of psoriasis, 11 309 incident cases of CD and 30 310 incident cases of UC, during follow-up. The adjusted IRRs (95% confidence intervals) of CD were 1.28 (1.03-1.59), 2.56 (1.87-3.50), 2.85 (1.72-4.73) and 3.42 (2.36-4.95) in patients with mild psoriasis, severe psoriasis (hospital), severe psoriasis (medication) and psoriatic arthritis, respectively. Similarly, the adjusted IRRs of UC were 1.49 (1.32-1.68), 1.56 (1.22-2.00), 1.96 (1.36-2.83) and 2.43 (1.86-3.17), respectively. The 10-year incidence of CD was 2-5 per 1000 patients and of UC 7-11 per 1000 patients, depending on psoriasis severity and the presence of psoriatic arthritis. Additionally, an increased risk of incident psoriasis was found following CD or UC. CONCLUSIONS: We observed a psoriasis-associated increased risk of CD and UC, which was higher in severe psoriasis, and an increased risk of psoriasis in patients with inflammatory bowel disease. Increased focus on gastrointestinal symptoms in patients with psoriasis may be warranted. PMID- 26959085 TI - Unraveling the multivalent binding of a marine family 6 carbohydrate-binding module with its native laminarin ligand. AB - Laminarin is an abundant brown algal storage polysaccharide. Marine microorganisms, such as Zobellia galactanivorans, produce laminarinases for its degradation, which are important for the processing of this organic matter in the ocean carbon cycle. These laminarinases are often modular, as is the case with ZgLamC which has an N-terminal GH16 module, a central family 6 carbohydrate binding module (CBM) and a C-terminal PorSS module. To date, no studies have characterized a true marine laminarin-binding CBM6 with its natural carbohydrate ligand. The crystal structure of ZgLamCCBM6 indicates that this CBM has two clefts for binding sugar (variable loop site, VLS; and concave face site, CFS). The ZgLamCCBM6 VLS binds in an exo-manner and the CFS interacts in an endo-manner with laminarin. Isothermal titration calorimetry (ITC) experiments on native and mutant ZgLamCCBM6 confirm that these binding sites have different modes of recognition for laminarin, in agreement with the 'regional model' postulated for CBM6-binding modules. Based on ITC data and structural data, we propose a model of ZgLamCCBM6 interacting with different chains of laminarin in a multivalent manner, forming a complex cross-linked protein-polysaccharide network. DATABASE: PDB code 5FUI. PMID- 26959095 TI - The ABCs (Airway, Blood Vessels, and Compartments) of Pediatric Neck Infections and Masses. AB - OBJECTIVE: The radiologist plays several important roles in the diagnosis and management of pediatric neck infections and masses. Although the clinical diagnosis of an infection is often clear, the radiologist should evaluate for an underlying cause and for drainable collections. With neck masses, the radiologist's role is to form a differential diagnosis and evaluate for biopsy of a potentially neoplastic lesion. With both clinical scenarios, the radiologist should also evaluate for complications. CONCLUSION: The mnemonic device ABCs (airway, blood vessels, and compartments) serves as a useful reminder for potentially critical complications of pediatric neck infections and masses. PMID- 26959096 TI - The Economic Impact for Farm Injury in Minnesota, 2004-2010. AB - Only 2% of Minnesota's employed population worked in agriculture between the years 2005 and 2012. However, this small portion of the state's employed population accounted for 31% of total work-related deaths in the state during that same time period. During a similar time period, 2007-2013, the contribution of agriculture to Minnesota's gross domestic product increased from approximately 1.5% to about 2.3%. This article describes the economic impact of injuries related to farm work between the years 2004 and 2010. Using hospital discharge data and the Census of Fatal Occupational Injuries (CFOI), estimates of the number of injuries and fatalities related to agricultural work were compiled. A cost of illness model was applied to these injury and fatality estimates to calculate the related indirect and direct costs in 2010 dollars. Estimated total costs, in 2010 dollars, ranged between $21 and $31 million annually over the 7 year study period. The majority of the costs were attributable to indirect costs, such as lost productivity at work and home. Fatal injuries accrued the largest proportion of the estimated costs followed by hospitalized and nonhospitalized injuries. A sensitivity analysis was performed to evaluate the impact each selected data source had upon the cost estimate. The magnitude of the costs associated with these injuries argues for better surveillance of injury related to agriculture to prioritize resources and evaluate intervention and prevention programs. PMID- 26959097 TI - Changes in cognitive functioning in sick-listed participants in occupational rehabilitation: A feasibility study. AB - BACKGROUND: Individuals on long-term sick leave attending occupational rehabilitation often complain about impairments in cognitive functions such as memory and attention. Knowledge of cognitive functioning in these individuals is limited. Such knowledge is clinically relevant for improving occupational rehabilitation programmes. OBJECTIVE: The aims of this feasibility study were to assess the methodological design and to investigate changes in memory and attention on participants during occupational rehabilitation. METHODS: Individuals attending occupational rehabilitation (n = 28) and individuals working full time (n = 25) matched for age, gender, and education participated. The two groups were administered cognitive tests targeting memory and attention and self-reported questionnaires at pre-test and post-test. Outcome measures were speed and accuracy of responses on the cognitive tests and self-reported work ability, subjective health complaints, and symptoms of depression and anxiety. RESULTS: In total, 35% of all invited participants agreed to take part and 93% of these also completed the second test. The mean gain scores in the intervention group were significantly higher than in the control group in response latency on simple and choice reaction time and errors in spatial working memory. CONCLUSION: The results of this study indicate that the motivation of participants to complete testing was high. Improvements in memory and attention were evident in rehabilitation participants indicating that rehabilitation may have an effect on cognitive functions. PMID- 26959099 TI - The Subjective Well-Being of Parents of Children with Developmental Disabilities: The Role of Hope as Predictor and Fosterer of Well-Being. AB - The purpose of this study was to identify factors that can improve the subjective well-being (SWB) of parents of children with a developmental disability, expand the knowledge relating to the role of hope in their lives, and improve the extent to which parent appraisals of the influence of the disability (on the couple's relationship, family functioning, and personal development) moderate this association. The results revealed that parental SWB was below the societal average; however, it differed significantly across levels of parent appraisals of their child's disability. Findings from this study point to the importance of hope to improve parental SWB. PMID- 26959098 TI - Primary Care Team Members Report Greater Individual Benefits from Long- Versus Short-Term Specialty Telemedicine Mentorship. AB - BACKGROUND: Primary care providers who participate in structured specialty telemedicine mentorship report improvements in clinical content mastery, professional satisfaction, and specialist communication. INTRODUCTION: Although these programs require investments of infrastructure resources and time, the duration of participation required to accrue optimal benefits is not known. We aimed to assess whether duration of participation is related to improved benefits of a longitudinal telemedicine-based mentorship program, specifically regarding perceived specialty care access, acquisition of new knowledge and skills, team integration, and overall job satisfaction. MATERIALS AND METHODS: We conducted an e-mail survey of Veterans Affairs-based primary care team members in the United States' Pacific Northwest region who engaged in a longitudinal telemedicine mentorship program (n = 78). RESULTS: After adjustment for potential confounding factors, respondents who engaged in telemedicine mentorship for >=1 year were significantly more likely to strongly agree that telemedicine mentorship improved patient access to specialty care (adjusted odds ratio [AOR] = 9.3, p < 0.005) and was useful in treating other patients on their panels (AOR = 3.7, p = 0.04). Participation >=1 year was also associated with higher self-reported knowledge and competencies (AOR = 4.0, p = 0.03) and with perception of integration into a clinical team (AOR = 5.6, p = 0.01), but not with overall job satisfaction. CONCLUSION: Telemedicine-based specialty mentorship programs are highly valued by primary care-based participants, and self-reported benefits accumulate beyond 1 year of participation. PMID- 26959108 TI - Metabolic Syndrome and Cognitive Performance Among Chinese >=50 Years: A Cross Sectional Study with 3988 Participants. AB - BACKGROUND: To date, the relationship between metabolic syndrome (MetS) and cognitive performance has not been well defined. This study aimed to explore the relationship between MetS and cognitive performance among Chinese elderly population. METHODS: A cross-sectional study was performed, with data collected in seven clinical centers from five provinces of Northern China. All recruited participants were >=50 years of age and complained with cognitive impairment or were reported with cognitive impairment by his/her caregiver(s). MetS was diagnosed according to the criteria issued by Chinese Medical Association Diabetes Association. Cognitive function was scored by Montreal Cognitive Assessment (MoCA). RESULTS: Three thousand nine hundred eighty-eight participants (in an average of 66.4 +/- 8.8 years of age, male 53.1%) were included in the analysis. Six hundred seventy-three (16.9%) participants were diagnosed with MetS, and 3013 (75.6%) participants had mild cognitive impairment (MCI) (MoCA score <26). There was no statistically significant difference in the MoCA scores between participants with MetS (21.0 +/- 5.4) and without MetS (21.3 +/- 5.3). In the logistic regression, after adjusting factors of age, education, marital status, smoking, and physical activity, diabetes and dyslipidemia were associated with MCI, whereas hypertension and overweight or obesity were not. Participants with diabetes had a higher risk of MCI (OR = 1.24, 95% CI: 1.03-1.50). Participants with dyslipidemia had a lower risk of MCI (OR = 0.81, 95% CI: 0.68 0.97). CONCLUSION: In our study, MetS is not associated with cognitive performance in elderly Chinese population. However, elderly Chinese with diabetes would have lower cognition function, and the dyslipidemia might be reversely associated with the cognitive function. PMID- 26959109 TI - Finding Value in Unexpected Places--Fixing the Medicare Physician Fee Schedule. PMID- 26959110 TI - Clinical management of pulmonary sarcoidosis. AB - Sarcoidosis is a multisystem disease for which diagnosis relies on the integration of clinical, radiologic, laboratory, and pathologic information. Assessment of clinical features is an important part of the disease evaluation. Computer Tomography provides information not available on routine chest roentgenogram which can assist diagnosing and establishing extent of disease. Monitoring for pulmonary and extra-pulmonary disease facilitates disease management. Patients with quality of life affecting symptoms or threatened end organ damage require systemic treatment which can be recommended in a stepwise fashion. Here, we provide guidance for the initial assessment, disease monitoring, and treatment recommendations for pulmonary and extra pulmonary disease. PMID- 26959111 TI - Knock-down of Hdj2/DNAJA1 co-chaperone results in an unexpected burst of tumorigenicity of C6 glioblastoma cells. AB - The chaperone system based on Hsp70 and proteins of the DnaJ family is known to protect tumor cells from a variety of cytotoxic factors, including anti-tumor therapy. To analyze whether this also functions in a highly malignant brain tumor, we knocked down the expression of Hsp70 (HSPA1A) and its two most abundant co-chaperones, Hdj1 (DNAJB1) and Hdj2 (DNAJA1) in a C6 rat glioblastoma cell line. As expected, tumor depletion of Hsp70 caused a substantial reduction in its growth rate and increased the survival of tumor-bearing animals, whereas the reduction of Hdj1 expression had no effect. Unexpectedly, a reduction in the expression of Hdj2 led to the enhanced aggressiveness of the C6 tumor, demonstrated by its rapid growth, metastasis formation and a 1.5-fold reduction in the lifespan of tumor-bearing animals. The in vitro reduction of Hdj2 expression reduced spheroid density and simultaneously enhanced the migration and invasion of C6 cells. At the molecular level, a knock-down of Hdj2 led to the relocation of N-cadherin and the enhanced activity of metalloproteinases 1, 2, 8 and 9, which are markers of highly malignant cancer cells. The changes in the actin cytoskeleton in Hdj2-depleted cells indicate that the protein is also important for prevention of the amoeboid-like transition of tumor cells. The results of this study uncover a completely new role for the Hdj2 co-chaperone in tumorigenicity and suggest that the protein is a potential drug target. PMID- 26959112 TI - Radiation therapy generates platelet-activating factor agonists. AB - Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID- 26959113 TI - Integrin-linked kinase activity modulates the pro-metastatic behavior of ovarian cancer cells. AB - Epithelial ovarian cancer (EOC) is the most fatal gynecologic cancer in the U.S., resulting in >14,000 deaths/year. Most women are diagnosed at late stage with widely disseminated intra-peritoneal metastatic disease, resulting in a 5-year survival rate of <30%. EOCs spread via direct extension and exfoliation into the peritoneal cavity, adhesion to peritoneal mesothelial cells, mesothelial cell retraction to expose sub-mseothelial matrix and anchoring in the type I collagen rich matrix to generate secondary lesions. As a molecular-level understanding of EOC metastasis may identify novel therapeutic targets, the current study evaluated the expression and activity of integrin-linked kinase (ILK), a Ser/Thr protein kinase activated upon integrin-mediated adhesion. Results show that ILK is co-expressed in EOC with the pro-metastatic enzyme membrane type 1 matrix metalloproteinase (MT1-MMP) and catalyzed phosphorylation of the cytoplasmic tail of the proteinase. Downregulation of ILK expression or activity reduced adhesion to and invasion of collagen gels and organotypic meso-mimetic cultures. As an initial early event in EOC metastasis is integrin-mediated adhesion, these results suggest that further evaluation of ILK inhibitors as anti-metastatic agents in EOC is warranted. PMID- 26959114 TI - Reciprocal positive selection for weakness - preventing olaparib resistance by inhibiting BRCA2. AB - Human tumor heterogeneity promotes therapeutic failure by increasing the likelihood of resistant cell subpopulations. The PARP-1 inhibitor olaparib is approved for use in BRCA-mutated ovarian cancers but BRCA2-reversion mutations lead to functional homologous recombination repair (HRR) and olaparib resistance. To overcome that resistance and expand use of PARP1 inhibition to cancers with functional HRR, we developed an antisense strategy to render the majority of tumor cells in a population BRCA2-deficient. We predicted that this strategy would render HRR-proficient tumor cells sensitive to olaparib and prevent emergence of resistance in a tumor cell population heterogeneous for HRR proficiency. We report that BRCA2 downregulation sensitized multiple human tumor cell lines (but not non-cancer human kidney cells) to olaparib and, combined with olaparib, increased aneuploidy and chromosomal translocations in human tumor cells. In a mixed HRR-proficient and HRR-deficient cell population, olaparib monotherapy allowed outgrowth of HRR-proficient cells resistant to subsequent olaparib treatment. Combined BRCA2 inhibition and olaparib treatment prevented selection of HRR-proficient cells and inhibited proliferation of the entire population. Treatment with BRCA2 siRNA and olaparib decreased ovarian xenograft growth in mice more effectively than either treatment alone. In vivo use of BRCA2 antisense oligonucleotides may be a viable option to expand clinical use of olaparib and prevent resistance. PMID- 26959115 TI - Protective role of p53 in skin cancer: Carcinogenesis studies in mice lacking epidermal p53. AB - p53 is a protein that causes cell cycle arrest, apoptosis or senescence, being crucial in the process of tumor suppression in several cell types. Different in vitro and animal models have been designed for the study of p53 role in skin cancer. These models have revealed opposing results, as in some experimental settings it appears that p53 protects against skin cancer, but in others, the opposite conclusion emerges. We have generated cohorts of mice with efficient p53 deletion restricted to stratified epithelia and control littermates expressing wild type p53 and studied their sensitivity to both chemically-induced and spontaneous tumoral transformation, as well as the tumor types originated in each experimental group. Our results indicate that the absence of p53 in stratified epithelia leads to the appearance, in two-stage skin carcinogenesis experiments, of a higher number of tumors that grow faster and become malignant more frequently than tumors arisen in mice with wild type p53 genotype. In addition, the histological diversity of the tumor type is greater in mice with epidermal p53 loss, indicating the tumor suppressive role of p53 in different epidermal cell types. Aging mice with p53 inactivation in stratified epithelia developed spontaneous carcinomas in skin and other epithelia. Overall, these results highlight the truly protective nature of p53 functions in the development of cancer in skin and in other stratified epithelia. PMID- 26959116 TI - Cinobufagin inhibits tumor growth by inducing intrinsic apoptosis through AKT signaling pathway in human nonsmall cell lung cancer cells. AB - The cinobufagin (CB) has a broad spectrum of cytotoxicity to inhibit cell proliferation of various human cancer cell lines, but the molecular mechanisms still remain elusive. Here we observed that CB inhibited the cell proliferation and tumor growth, but induced cell cycle arrest and apoptosis in a dose-dependent manner in non-small cell lung cancer (NSCLC) cells. Treatment with CB significantly increased the reactive oxygen species but decreased the mitochondrial membrane potential in NSCLC cells. These effects were markedly blocked when the cells were pretreated with N-acetylcysteine, a specific reactive oxygen species inhibitor. Furthermore, treatment with CB induced the expression of BAX but reduced that of BCL-2, BCL-XL and MCL-1, leading to an activation of caspase-3, chromatin condensation and DNA degradation in order to induce programmed cell death in NSCLC cells. In addition, treatment with CB reduced the expressions of p-AKTT308 and p-AKTS473 and inhibited the AKT/mTOR signaling pathway in NSCLC cells in a time-dependent manner. Our results suggest that CB inhibits tumor growth by inducing intrinsic apoptosis through the AKT signaling pathway in NSCLC cells. PMID- 26959118 TI - Chemical chaperon 4-phenylbutyrate protects against the endoplasmic reticulum stress-mediated renal fibrosis in vivo and in vitro. AB - Renal tubulointerstitial fibrosis is the common and final pathologic change of kidney in end-stage renal disease. Interesting, endoplasmic reticulum (ER) stress is known to contribute to the pathophysiological mechanisms during the development of renal fibrosis. Here, we investigated the effects of chemical chaperon sodium 4-phenylbutyrate (4-PBA) on renal fibrosis in vivo and in vitro. In a rat unilateral ureteral obstruction (UUO) model, 4-PBA mimicked endogenous ER chaperon in the kidneys and significantly reduced glucose regulated protein 78 (GRP78), CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP), activating transcription factor 4 (ATF4), and phosphorylated JNK protein expressions as well as restored spliced X-box-binding protein 1 (XBP1) expressions in the kidneys of UUO rats. 4-PBA also attenuated the increases of alpha-smooth muscle actin (alpha-SMA), connective tissue growth factor (CTGF) protein expressions, tubulointerstitial fibrosis, and apoptosis in the kidneys of UUO rats. Moreover, transforming growth factor (TGF)-beta markedly increased ER stress-associated molecules, profibrotic factors, and apoptotic markers in the renal tubular cells (NRK-52E), all of which could be significantly counteracted by 4-PBA treatment. 4-PBA also diminished TGF-beta-increased CTGF promoter activity and CTGF mRNA expression in NRK-52E cells. Taken together, our results indicated that 4-PBA acts as an ER chaperone to ameliorate ER stress-induced renal tubular cell apoptosis and renal fibrosis. PMID- 26959117 TI - Western diet enhances benzo(a)pyrene-induced colon tumorigenesis in a polyposis in rat coli (PIRC) rat model of colon cancer. AB - Consumption of Western diet (WD), contaminated with environmental toxicants, has been implicated as one of the risk factors for sporadic colon cancer. Our earlier studies using a mouse model revealed that compared to unsaturated dietary fat, the saturated dietary fat exacerbated the development of colon tumors caused by B(a)P. The objective of this study was to study how WD potentiates B(a)P-induced colon carcinogenesis in the adult male rats that carry a mutation in the Apc locus - the polyposis in the rat colon (PIRC) rats. Groups of PIRC rats were fed with AIN-76A standard diet (RD) or Western diet (WD) and received 25, 50, or 100 MUg B(a)P/kg body weight (wt) via oral gavage for 60 days. Subsequent to exposure, rats were euthanized; colons were retrieved and preserved in 10% formalin for counting the polyp numbers, measuring the polyp size, and histological analyses. Blood samples were collected and concentrations of cholesterol, triglycerides, glucose, insulin and leptin were measured. Rats that received WD + B(a)P showed increased levels of cholesterol, triglycerides, and leptin in comparison to RD + B(a)P groups or controls. The colon tumor numbers showed a B(a)P dose-response relationship. Adenomas with high grade dysplasia were prominent in B(a)P + WD rats compared to B(a)P + RD rats and controls (p < 0.05). The larger rat model system used in this study allows for studying more advanced tumor phenotypes over a longer duration and delineating the role of diet - toxicant interactions in sporadic colon tumor development. PMID- 26959119 TI - Mitochondrial ribosomal protein S18-2 is highly expressed in endometrial cancers along with free E2F1. AB - Endometrial cancer (EC) is one of the most frequent causes of cancer death among women in developed countries. Histopathological diagnosis and imaging techniques for EC are limited, thus new prognostic markers are needed to offer patients the best treatment and follow-up.In the present paper we showed that the level of mitochondrial ribosomal protein MRPS18-2 (S18-2) increased in EC compared with the normal endometrium and hyperplasia, based on a study of 42 patient biopsies. Importantly, high expression of free E2F1 in EC correlates well with high S18-2 expression. The EC cell line HEC-1-A, which overexpresses S18-2 constitutively, showed an increased proliferation capacity in vitro and in vivo (in SCID mice). Moreover, pan-keratin, beta-catenin and E-cadherin signals are diminished in these cells, compared to the parental HEC-1-A line, in contrast to vimentin signal that is increased. This may be associated with epithelial-mesenchymal cell transition (EMT).We conclude that high expression of S18-2 and free E2F1, and low pan-keratin, beta-catenin, and E-cadherin signals might be a good set of prognostic markers for EC. PMID- 26959120 TI - Icmt inhibition exerts anti-angiogenic and anti-hyperpermeability activities impeding malignant pleural effusion. AB - Small GTPases are pivotal regulators of several aspects of tumor progression. Their implication in angiogenesis, vascular permeability and tumor-associated inflammatory responses is relevant to the pathobiology of Malignant Pleural Effusion (MPE). Inhibition of isoprenylcysteine carboxylmethyltransferase (Icmt) abrogates small GTPase activation. We therefore hypothesized that cysmethynil, an Icmt inhibitor would limit pleural fluid accumulation in two models, a lung adenocarcinoma and a mesothelioma-induced MPE. Cysmethynil significantly reduced MPE volume in both models and tumor burden in the adenocarcinoma model. It inhibited pleural vascular permeability and tumor angiogenesis in vivo and reduced endothelial cell proliferation, migration and tube formation in vitro. Cysmethynil also promoted M1 anti-tumor macrophage homing in the pleural space in vivo, and inhibited tumor-induced polarization of macrophages towards a M2 phenotype in vitro. In addition, the inhibitor promoted adenocarcinoma cell apoptosis in vivo. Inhibition of small GTPase might thus represent a valuable strategy for pharmacotherapy of MPE. PMID- 26959122 TI - Essential oil constituents, phenolic content and antioxidant activity of Lavandula stricta Delile growing wild in southern Iran. AB - Lavandula stricta belongs to the Lamiaceae family and is considered as an endemic medicinal plant in southern Iran. Essential oil composition, total phenolic content and antioxidant activity from two different populations of L. stricta were studied for the first time. A GC and GC/MS analysis of essential oil isolated from the aerial part of L. stricta identified 31 constituents; the major constituents were alpha-pinene (58.34-63.52%), linalool (8.85-9.36%), 3-methyl butyl 2-methyl butanoate (7.45-7.70%), sabinene (2.84-3.56%), limonene (2.87 3.21%) and myrcene (2.25%). The total phenolic content of methanolic extracts was determined with the Folin-Ciocalteu reagent and the antioxidant activity of methanolic extract and essential oil were determined with the 2, 2-diphenyl-1 picryl hydrazyl free radical scavenging assay, respectively. Total phenols varied from 61.05 to 64.45 mg GAE/g dry weight, and IC50 values in the radical scavenging assay ranged from 334.11 to 395.23 MUg/mL in methanolic extracts and 420-475 MUg/mL in essential oil. PMID- 26959121 TI - Everolimus exhibits anti-tumorigenic activity in obesity-induced ovarian cancer. AB - Everolimus inhibits mTOR kinase activity and its downstream targets by acting on mTORC1 and has anti-tumorigenic activity in ovarian cancer. Clinical and epidemiologic data find that obesity is associated with worse outcomes in ovarian cancer. In addition, obesity leads to hyperactivation of the mTOR pathway in epithelial tissues, suggesting that mTOR inhibitors may be a logical choice for treatment in obesity-driven cancers. However, it remains unclear if obesity impacts the effect of everolimus on tumor growth in ovarian cancer. The present study was aimed at evaluating the effects of everolimus on cytotoxicity, cell metabolism, apoptosis, cell cycle, cell stress and invasion in human ovarian cancer cells. A genetically engineered mouse model of serous ovarian cancer fed a high fat diet or low fat diet allowed further investigation into the inter relationship between everolimus and obesity in vivo. Everolimus significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, reduced invasion and caused cellular stress via inhibition of mTOR pathways in vitro. Hypoglycemic conditions enhanced the sensitivity of cells to everolimus through the disruption of glycolysis. Moreover, everolimus was found to inhibit ovarian tumor growth in both obese and lean mice. This reduction coincided with a decrease in expression of Ki-67 and phosphorylated-S6, as well as an increase in cleaved caspase 3 and phosphorylated-AKT. Metabolite profiling revealed that everolimus was able to alter tumor metabolism through different metabolic pathways in the obese and lean mice. Our findings support that everolimus may be a promising therapeutic agent for obesity-driven ovarian cancers. PMID- 26959124 TI - Lipids and Diabetic Retinopathy. AB - The relationship between lipids and the development and/or severity of diabetic retinopathy (DR) is complex. Large epidemiologic studies suggest an inconsistent and overall modest association between serum triglycerides or major cholesterol species and the severity of DR; however, certain specific lipoprotein species may have stronger associations with DR severity, suggesting a pathophysiological role for lipoproteins analogous to that seen in atherosclerosis. In this lipoprotein mediated DR pathogenesis model, damage to the blood-retinal barrier allows extravasation of lipoprotein species, which are modified in the intraretinal environment, creating substantial local damage. Additionally, hypolipidemic therapy with statins and fibrates--particularly the latter--have been shown to modulate DR in large-scale studies. Since serum lipid profile changes do not necessarily correlate with DR modulation, the efficacy of these agents may be due to their tissue-specific changes in lipoproteins and/or their anti-inflammatory, antioxidative, antiangiogenic, and antiapoptotic functions. PMID- 26959123 TI - Drug Delivery Nanoparticles: Toxicity Comparison in Retinal Pigment Epithelium and Retinal Vascular Endothelial Cells. AB - Multiple synthetic polymer nanoparticles (NPs) have been widely used as drug delivery systems. However, their toxicity to the retinal pigment epithelium and retinal endothelium remains unclear. In this study, we analyze the cytotoxic effects of three different kinds of NPs, made of poly lactic-co-glycolic acid (PLGA), polycaprolactone (PCL), and PEGylated PLGA (PEG-PLGA), in a retinal pigment epithelium cell line (ARPE-19) and in primary human retinal vascular endothelial cells (RVEC). PEG-PLGA NPs presented the lowest cytotoxicity on ARPE 19 cells and RVEC as assessed by MTT viability assay. While PLGA and PCL exhibited variable amounts of toxicity, no significant toxicity was observed when incubating cells with high PEG-PLGA concentrations (100 ug/ml), for up to 6 days. On both transmission electron microscopy and confocal microscopy, Rhodamine 6G loaded PEG-PLGA NPs were observed intracellularly in multiple subcellular organelles. PEG-PLGA NPs are a potentially viable option for the treatment of eye diseases. PMID- 26959125 TI - The Role of Plasma Kallikrein-Kinin Pathway in the Development of Diabetic Retinopathy: Pathophysiology and Therapeutic Approaches. AB - Diabetic retinal disease is characterized by a series of retinal microvascular changes and increases in retinal vascular permeability that lead to development of diabetic retinopathy (DR) and diabetic macular edema (DME), respectively. Current treatment strategies for DR and DME are mostly limited to vascular endothelial growth factor (VEGF) inhibitors and laser photocoagulation. These treatment modalities are not universally effective in all patients, and potential side effects persist in a significant portion of patients. The plasma kallikrein kinin system (KKS) is one of the pathways that has been identified in the vitreous in proliferative DR and DME. Preclinical studies have shown that the activation of intraocular KKS induces retinal vascular permeability, vasodilation, and retinal thickening. Proteomic analysis from vitreous of eyes with DME has shown that KKS and VEGF pathways are potentially independent biologic pathways. Furthermore, proteins associated with DME in the vitreous were significantly more correlated with the KKS pathway compared to VEGF pathway. Preclinical experiments on diabetic animals showed that inhibition of KKS components was found to be an effective approach to decrease retinal vascular permeability. An initial phase I human trial of a novel plasma kallikrein inhibitor for the treatment of DME is currently ongoing to test the safety of this approach and serves as an initial step in the translation of basic science discovery into an innovative clinical intervention. PMID- 26959126 TI - Stem Cell-Based Therapy for Diseases of the Retinal Pigment Epithelium: From Bench to Bedside. AB - Age-related macular degeneration (AMD) represents a leading cause of blindness in the elderly, and Stargardt's macular dystrophy (SMD) is the most common form of juvenile-onset macular degeneration. Dry AMD and SMD share an underlying pathophysiology, namely dysfunction and ultimately loss of the retinal pigment epithelium (RPE), suggesting that RPE transplantation may offer a potential treatment strategy for both patient populations. Stem cells have emerged as a promising source of replacement RPE. During the past 15 years, extraordinary strides have been made in the identification, characterization, and differentiation of stem cells. Recently, this large body of basic science and preclinical research has been translated to patient care with the publication of results from Phase 1/2 trials demonstrating safety of transplantation of human embryonic stem cell (hESC)-derived RPE into patients with AMD and SMD. While significant challenges remain before dry AMD and SMD become treatable diseases, the goal has become more tangible. PMID- 26959127 TI - Subthreshold Diode Micropulse Laser: A Review. AB - The subthreshold diode micropulse laser is a form of non-damaging thermal laser therapy which has shown efficacy in multiple retinal conditions. The purpose of this article is to review the use of subthreshold diode micropulse laser as an emerging treatment modality for the treatment of retinal disease. The proposed mechanisms of action, safety, efficacy, recommended laser treatment parameters, and clinical applications for which the use of subthreshold diode micropulse laser has been studied will be reviewed. PMID- 26959128 TI - Vascular Endothelial Growth Factor and Diabetic Retinal Disease. AB - Diabetic retinal disease remains a leading cause of blindness among working-aged adults around the world. Until this decade, laser photocoagulation for both proliferative diabetic retinopathy and diabetic macular edema had been the standard of care for millions of patients. The introduction of vascular endothelial growth factor inhibitors (anti-VEGF) and subsequent clinical trials demonstrating their efficacy for treatment of diabetic eye disease have established a new standard in treatment of center-involved diabetic macular edema that is highly specific to the pathologic process and highly effective in preserving and improving vision. This review focuses on clinically relevant developments that led to the shift from focal/grid laser photocoagulation to anti VEGF injections in the treatment of center-involved diabetic macular edema (DME), with an overview of the disease pathophysiology, clinical disease course, and available anti-VEGF agents. This article also reviews the scientific evidence exploring the use of anti-VEGF agents in nonproliferative and proliferative diabetic retinopathy. PMID- 26959129 TI - Course of Ocular Function in PRPF31 Retinitis Pigmentosa. AB - Mutations in pre-mRNA splicing factors are the second most common cause of autosomal dominant retinitis pigmentosa, and a major cause of vision loss. The development of gene augmentation therapy for disease caused by mutations in PRPF31 necessitates defining pretreatment characteristics and disease progression of patients with PRPF31-related retinitis pigmentosa. We show rates of decline of visual field area -6.9% per year and 30-Hz flicker cone response of -9.2% per year, which are both similar to observed rates for retinitis pigmentosa. We hypothesize that RNA splicing factor retinitis pigmentosa will be amenable to treatment by AAV-mediated gene therapy, and that understanding the clinical progression rates of PRPF31 retinitis pigmentosa will help with the design of gene therapy clinical trials. PMID- 26959130 TI - New Translational Research in the Medical Management of Orbital Melanoma. AB - New translational research has paved the way for more optimistic management of melanoma. Medications targeting oncogenic signaling cascades and immune regulatory molecules have significantly improved overall survival for patients with metastatic melanoma. While isolated, operable orbital melanoma may still benefit from surgery, there potentially is an opportunity to provide patients with neoadjuvant systemic therapy with sustainable long-term effects. Additionally, patients with non-resectable orbital melanoma can benefit from systemic treatment. PMID- 26959132 TI - Fungal Infections in Boston Keratoprosthesis Patients: Lessons Learned and Novel Developments on the Horizon. AB - The Boston Keratoprosthesis (B-KPro) is a widely accepted modality of corneal restoration in eyes where traditional penetrating keratoplasty has little chance of success. It is the most commonly used keratoprosthesis worldwide. While the introduction of broad-spectrum antibiotic prophylaxis has virtually eliminated cases of bacterial endophthalmitis, fungal colonization and infections are a growing concern. This review of the literature summarizes risk factors for fungal infections in KPro eyes, rates of fungal infection and colonization, clinical presentation, causative organisms, management, and outcomes. We also focus on current recommendations for antifungal prophylaxis, and highlight the role of translational research at the Massachusetts Eye and Ear Infirmary (MEEI, Boston, USA) with its aim of developing novel strategies for reducing rates of fungal infections in KPro patients. PMID- 26959133 TI - Immunologic Mediators in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are a spectrum of T-cell mediated immune disorders. While the contributory mechanisms leading to the apoptosis of epidermal cells in SJS/TEN remain unproven, the keratinocyte apoptosis seen in SJS/TEN is thought to occur through the T-cell mediated Fas-Fas ligand (FasL), perforin/granzyme B, and other immune mediators. Most recently, emphasis has been placed on the granulysin pathway as being the primary mediator of apoptosis and widespread epidermal necrosis in SJS/TEN. This article aims to review the proposed mechanisms by which these pathways work and the immunomodulatory therapies that have been developed in an attempt to target them. PMID- 26959134 TI - Autologous Limbal Stem Cell Transplantation: The Progression of Diagnosis and Treatment. AB - Though the corneoscleral limbus has been studied for more than 150 years, our ability to successfully treat those with limbal stem cell deficiency (LSCD) is still a work in progress. Today, the only definitive cure for LSCD is stem cell transplantation. This review briefly discusses the evolution of our understanding of limbal stem cell function, provides an outline of the history of autologous limbal stem cell (LSC) transplantation, and discusses current techniques and future strategies for LSCD treatment. PMID- 26959135 TI - Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION): A Review and Update on Animal Models. AB - Non-arteritic anterior ischemic optic neuropathy (NAION) is a relatively common optic neuropathy in adults over the age of 50, typically causing sudden, painless, unilateral vision loss and always resulting in swelling of the optic nerve head. Though several anatomic and vascular risk factors have been identified, much remains unknown about its pathophysiology and there is no proven treatment. This article reviews the risk factors, clinical presentation, and therapies that have been investigated for NAION. In addition, we provide an update from recent rodent and primate models, which offer new insight into the pathophysiology of this disease and provide a platform for treatment trials. PMID- 26959131 TI - Understanding Neuropathic Corneal Pain--Gaps and Current Therapeutic Approaches. AB - The richly innervated corneal tissue is one of the most powerful pain generators in the body. Corneal neuropathic pain results from dysfunctional nerves causing perceptions such as burning, stinging, eye-ache, and pain. Various inflammatory diseases, neurological diseases, and surgical interventions can be the underlying cause of corneal neuropathic pain. Recent efforts have been made by the scientific community to elucidate the pathophysiology and neurobiology of pain resulting from initially protective physiological reflexes, to a more persistent chronic state. The goal of this clinical review is to briefly summarize the pathophysiology of neuropathic corneal pain, describe how to systematically approach the diagnosis of these patients, and finally summarizing our experience with current therapeutic approaches for the treatment of corneal neuropathic pain. PMID- 26959136 TI - Leber Hereditary Optic Neuropathy: Bringing the Lab to the Clinic. AB - Leber hereditary optic neuropathy (LHON) was the first clinically characterized mitochondrial disorder. Since its first description in 1871, much has been discovered regarding the genetics and pathophysiology of the disease. This has enabled the development of in vitro cell and animal models that can be used to try to determine not only the effects of the genetic mutation upon the clinical phenotype but to also test potential novel therapies. Treatments for LHON have ranged from vitamins and minerals to immunosuppressants and, more recently, targeted gene therapy. This article reviews the pathophysiology and clinical features of LHON with a focus on translational research. PMID- 26959137 TI - Investigation-Directed Approach to Inflammatory Optic Neuropathies. AB - Any presentation of an optic neuropathy with features that suggest inflammation should be addressed promptly because of blindness and the potential for effective treatment in some cases. A step-wise approach, including laboratory testing and imaging, is often informative, although the diagnosis may remain elusive despite detailed investigation. PMID- 26959138 TI - Translating the Low Translaminar Cribrosa Pressure Gradient Hypothesis into the Clinical Care of Glaucoma. AB - Glaucoma is an optic neuropathy with multiple known risk factors, including age, race, family history, and intraocular pressure. Unfortunately, the only currently modifiable risk factor in treating the disease is intraocular pressure (IOP). Recent studies have investigated intracranial pressure (ICP) and the translaminar cribrosa pressure gradient as a potential explanation for glaucomatous optic nerve vulnerability across a range of IOP values. The difference between these two pressures across the lamina cribrosa may have an effect on the optic nerve, which could provide another modifiable parameter in the battle against glaucoma. In order for modification of the translaminar pressure gradient to be considered in the treatment of glaucoma, noninvasive methods to accurately measure ICP need to be developed. The translaminar pressure gradient could be therapeutically adjusted by either further lowering the IOP or raising the ICP when it is pathologically low, if possible. PMID- 26959140 TI - The Role of the Immune System in Glaucoma: Bridging the Divide Between Immune Mechanisms in Experimental Glaucoma and the Human Disease. AB - Glaucoma is one of the leading causes of visual impairment worldwide. Classically, clinicians have evaluated patients through a full ophthalmological examination including gonioscopy, measurement of intraocular pressure (IOP), and assessment of the optic nerve. New imaging modalities have further enhanced our ability to evaluate glaucoma; however, our treatments have not evolved as much. Whether one uses medical treatment with topical ocular antihypertensives, laser trabeculoplasty, or filtering surgery, the mainstay of treatment is to lower IOP. However, as our understanding of the disease evolves, mechanisms other than elevated IOP have been implicated in glaucoma pathogenesis. Recent animal model studies have shown a possible role of the immune system in the pathophysiology of glaucoma. This article explores the current understanding of immune reactions in glaucoma, which could lead to a new paradigm of treatment for human disease. PMID- 26959141 TI - Medical Therapies of Amblyopia: Translational Research to Expand Our Treatment Armamentarium. AB - Amblyopia is a developmental brain disorder in which vision is lost due to asymmetric or inadequate visual stimulation early in life. Although amblyopia is responsive to treatment if therapy is initiated early, treatment of older children and adults is usually unsuccessful due to closure of a window of cortical brain plasticity. Extensive basic research has been devoted to understanding modulators in shaping the visual cortex during the critical period of plasticity, and to providing potential clinical applications of neurotransmitters in the treatment of amblyopia. Current pharmacological treatments are reviewed from basic science research extending into clinical use, focusing on the acetylcholinesterase inhibitor donezepil, serotonin receptor inhibitor fluoxetine, dopamine precursors carbidopa-levodopa, and catecholamine modulator citicoline. PMID- 26959139 TI - Is Estrogen a Therapeutic Target for Glaucoma? AB - This article's objective is to provide an overview of the association between estrogen and glaucoma. A literature synthesis was conducted of articles published in peer-reviewed journals screened through May 5, 2015, using the PubMed database. Keywords used were "estrogen and glaucoma," "reproductive factors and glaucoma," and "estrogen, nitric oxide and eye." Forty-three journal articles were included. Results indicated that markers for lifetime estrogen exposure have been measured by several studies and show that the age of menarche onset, oral contraceptive (OC) use, bilateral oophorectomy, age of menopause onset and duration between menarche to menopause are associated with primary open-angle glaucoma (POAG) risk. The Blue Mountain Eye Study found a significantly increased POAG risk with later (>13 years) compared with earlier (<=12 years) age of menarche. Nurses' Health Study (NHS) investigators found that OC use of greater than 5 years was associated with a 25% increased risk of POAG. The Mayo Clinic Cohort Study of Oophorectomy and Aging found that women who underwent bilateral oophorectomy before age 43 years had an increased risk of glaucoma. The Rotterdam Study found that women who went through menopause before reaching the age of 45 years had a higher risk of open-angle glaucoma (2.6-fold increased risk), while the NHS showed a reduced risk of POAG among women older than 65 who entered menopause after age >= 54 years. Increased estrogen states may confer a reduced risk of glaucoma or glaucoma-related traits such as reduced intraocular pressure (IOP). Pregnancy, a hyperestrogenemic state, is associated with decreased IOP during the third trimester. Though the role of postmenopausal hormone (PMH) use in the reduction of IOP is not fully conclusive, PMH use may reduce the risk of POAG. From a genetic epidemiologic perspective, estrogen metabolic pathway single nucleotide polymorphisms (SNPs) were associated with POAG in women and polymorphisms in endothelial nitric oxide synthase, a gene receptive to estrogen regulation, are associated with glaucoma. The study concluded that increasing evidence suggests that lifetime exposure to estrogen may alter the pathogenesis of glaucoma. Estrogen exposure may have a neuroprotective effect on the progression of POAG but further studies need to confirm this finding. The role of sex-specific preventive and therapeutic treatment may be on the horizon. PMID- 26959142 TI - Computer-Assisted Digital Image Analysis of Plus Disease in Retinopathy of Prematurity. AB - The objective of this study is to review the current state and role of computer assisted analysis in diagnosis of plus disease in retinopathy of prematurity. Diagnosis and documentation of retinopathy of prematurity are increasingly being supplemented by digital imaging. The incorporation of computer-aided techniques has the potential to add valuable information and standardization regarding the presence of plus disease, an important criterion in deciding the necessity of treatment of vision-threatening retinopathy of prematurity. A review of literature found that several techniques have been published examining the process and role of computer aided analysis of plus disease in retinopathy of prematurity. These techniques use semiautomated image analysis techniques to evaluate retinal vascular dilation and tortuosity, using calculated parameters to evaluate presence or absence of plus disease. These values are then compared with expert consensus. The study concludes that computer-aided image analysis has the potential to use quantitative and objective criteria to act as a supplemental tool in evaluating for plus disease in the setting of retinopathy of prematurity. PMID- 26959143 TI - Role of VEGF Inhibition in the Treatment of Retinopathy of Prematurity. AB - Retinopathy of prematurity (ROP) is a potentially blinding disease characterized by retinal neovascularization, which eventually can lead to tractional retinal detachment. Improvements have been made regarding the management of retinopathy of prematurity (ROP) since it was described in the Cryotherapy for Retinopathy of Prematurity study. A more appropriate time for therapeutic intervention was defined by the Early Treatment for Retinopathy of Prematurity (ETROP) trial. Advances in screening strategies with the use of digital imaging systems are now available. All of this and the use of laser photocoagulation and vitreoretinal surgery have contributed to significant increases in favorable outcomes and decreases in child blindness secondary to ROP. Recently the use of vascular endothelial growth factor (VEGF) inhibitors has been introduced to the armamentarium for the treatment of ROP. The purpose of this review article is to evaluate the role of VEGF inhibition in the treatment of ROP. PMID- 26959144 TI - Translational Vision Rehabilitation: From Eccentric Fixation to Reading Rehabilitation. AB - Eccentric fixation is a commonly used adaptive strategy in patients with central vision loss. A common complaint in patients with central vision loss is reading difficulty. The mechanisms as to how and why eccentric fixation develops comprise an exciting area of research. As we better understand this phenomenon, we may apply these findings to the clinical setting and in particular to reading rehabilitation. Biofeedback is a new technique that can be applied to eccentric fixation and may have a role in reading rehabilitation. PMID- 26959145 TI - Chronic Ocular Complications of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: The Role of Systemic Immunomodulatory Therapy. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but potentially blinding diseases that affect the skin and mucous membranes. Although the cutaneous manifestations tend to be self-limited and resolve without sequelae, the chronic ocular complications associated with SJS/TEN can persist despite local therapy. Poor understanding of the underlying pathophysiology and lack of a standardized clinical approach have resulted in a paucity of data in regards to suitable treatment options. Inflammatory cellular infiltration and elevated levels of ocular surface cytokines in the conjunctival specimens of affected patients give credence to an underlying immunogenic etiology. Furthermore, the presence of ongoing ocular surface inflammation and progressive conjunctival fibrosis in the absence of exogenous aggravating factors suggest a possible role for systemic immunomodulatory therapy (IMT). We review in detail the proposed immunogenesis underlying chronic ocular SJS/TEN and the possible utility of systemic IMT. PMID- 26959147 TI - Research in Human Resources for Health. PMID- 26959146 TI - Updates on the Molecular Pathology of Selected Ocular and Ocular Adnexal Tumors: Potential Targets for Future Therapy. AB - Ophthalmic pathologic studies of retinoblastoma first definitively elucidated a genetic etiology for cancer three decades ago. Advances in DNA sequencing, protein expression profiling, and the exploration of epigenetics have since led to categorization of tumors and clinical prognostication based on genetic aberrancy. There are now many neoplasms that are defined by a characteristic genetic signature. In the past several years alone, much has been discovered in regard to the original tumor-suppressor gene initially defined in retinoblastoma as well as in other intraocular tumors such as medulloepithelioma. Our further understanding of ocular adnexal tumors that result in substantial morbidity and mortality, such as sebaceous carcinoma, has also benefited from a genetic approach. In this article, we review the clinicopathologic features of the foregoing three entities--retinoblastoma, medulloepithelioma, and sebaceous carcinoma--in order to highlight discoveries in their underlying abnormal molecular genetic functioning. PMID- 26959148 TI - Cross-cultural adaptation of the Readiness for Interprofessional Learning Scale in Brazil. AB - Objective Conduct a cross-cultural adaptation of the expanded version of the 29 items Readiness for Interprofessional Learning Scale (RIPLS) into Brazilian Portuguese. Method Five steps were adopted: three translations, synthesis, three back-translations, assessment by an expert committee, and pre-test. Validation comprised 327 students from 13 undergraduate health courses from a public university. Parallel analyses were conducted using the R software and factor analysis using Exploratory Structural Equation Modeling. Results 1 9 12 16 10 11 17 19 21 24 25 29 Conclusion Evidences were found relating to the validity of the RIPLS version in Brazilian Portuguese in its application in the national context. PMID- 26959149 TI - Interprofessional education and collaborative practice in Primary Health Care. AB - Objective To understand the perceptions of professors, health care providers and students about the articulation of interprofessional education with health practices in Primary Health Care. Method To understand and interpret qualitative data collection, carried out between 2012 and 2013, through semi-structured interviews with 18 professors and four sessions of homogeneous focus groups with students, professors and health care providers of Primary Health Care. Results A triangulation of the results led to the construction of two categories: user centered collaborative practice and barriers to interprofessional education. The first perspective indicates the need to change the model of care and training of health professionals, while the second reveals difficulties perceived by stakeholders regarding the implementation of interprofessional education. Conclusion The interprofessional education is incipient in the Brazil and the results of this analysis point out to possibilities of change toward collaborative practice, but require higher investments primarily in developing teaching-health services relationship. PMID- 26959150 TI - Tool to measure workload of health professionals in Primary Health Care: development and validation. AB - Objective To develop and validate an instrument that addresses the interventions/activities carried out by the family health team as reference for staff planning. Method Methodological research developed in stages: instrument development, content validation, and pilot test in three units located in the southeastern region of Brazil. Results 39 interventions were validated in a single instrument to measure workload for clinician, dental surgeon, oral health technician/assistant, nurse, nurse assistant, and community health agent. In the pilot test, the instrument contained 100% of the interventions observed and the observers reached 93.7% agreement. Conclusion The proposed instrument is an innovating tool because of its configuration for health team and supports staff planning in primary health care. PMID- 26959151 TI - Absenteeism of nursing staff: decisions and actions of nurse managers. AB - Objective Measure absenteeism among nurses and nursing technicians/aides in three hospitals and explore possible management decisions by nursing managers to deal with it. Method Quantitative, qualitative study. In the qualitative stage, monthly rates, annual average and overall rates of absenteeism were measured among nurses and nursing technicians/aides from 12 service units in the hospitals, over 12 months, according to the equation proposed by the Support Center for Hospital Management (NAGEH - Nucleo de Apoio a Gestao Hospitalar). In the qualitative stage, 12 nursing managers from 12 units were interviewed. Results The quantitative stage revealed important differences in each institution and between institutions, with various monthly rates exceeding the monthly rate of 6.7% recommended by the Federal Council of Nursing (COFEN - Conselho Federal de Enfermagem). The qualitative stage examined positive impact decisions taken by these institutions, where relationships with managers, dialogue, and meeting the physical and emotional demands of professionals were considered important factors. Conclusion Absenteeism was a reality in day-to-day nursing staff management. It varied according to the month of the year and in different service units, and it was possible to classify these units according to the degree of the problem. In addition, the results showed that employee illness, dissatisfaction with institutional conditions, and inadequate interpersonal relationships were key factors, enabling management decisions based on each hospital's particular reality. PMID- 26959152 TI - Humanization of health care in the perception of nurses and physicians of a private hospital. AB - Objective Exploratory, descriptive, qualitative study aimed at checking the meaning of the term humanization for nurses and physicians at a private hospital in the city of Sao Paulo and identify factors that hinder and facilitate humanization in care. Method Exploratory, descriptive, and qualitative study conducted with 19 health care professionals. After data collection, the reports were categorized according to the method proposed by Bardin and analyzed within the theoretical framework of humanization. Results Humanization is related to respect, caring, and empathy. In professional practice, the actions aimed at humanization can be facilitated by organizational culture, but hampered by overwork. Conclusion It is necessary to adopt management policies and actions that provide professionals to meet the expectations of patients and their families in search of humanized care. PMID- 26959153 TI - Nursing staff in the internal medicine and surgical units of teaching hospitals: composition and cost. AB - Objective Evaluate the mean quantitative and qualitative nursing staff working in the internal medicine and surgical units of three public general teaching hospitals in the city of Sao Paulo, compared to projected mean staff according to the parameters of Cofen Resolution No. 293/04, as well as measure the mean cost of current and projected nursing staff. Method Quantitative, descriptive, exploratory study using prospective data collection. Results In most of the units studied, the number of nursing professionals was adequate. In two of the institutions, the percentage of nurses was lower than that recommended by Cofen. Qualitative and quantitative adjustment of the staff would represent a monthly cost increase of R$141,326 for Hospital A, R$138,989 for Hospital B, and a reduction of R$99,028 for Hospital C. Conclusion The main contribution of this study was the proposed method for qualitative and quantitative evaluation of nursing staff, in addition to determining the average cost for adjustments. PMID- 26959154 TI - Pressure ulcers prevalence indicators and patient falls incidence in teaching hospitals in the city of Sao Paulo. AB - Objective To measure the prevalence of pressure ulcers and the incidence of patient falls in three teaching hospitals in the city of Sao Paulo. Method Quantitative, exploratory and descriptive study. Data were collected from August 2012 to July 2013 using a form. They were analyzed according to descriptive and inferential statistics. Results The annual mean of pressure ulcers overall prevalence (PU) was of 10.1%, and the incidence of patient falls was of 13.8%. Conclusion Patients of Hospital 3 were the most vulnerable to pressure ulcers and falls, probably due to the aggressiveness of the disease and the complex treatments these patients were undergoing. Implementation of such indicators has enabled benchmarking and review of both assistance and management institutional protocols. PMID- 26959155 TI - Nursing Training in the Brazilian Red Cross in the 1940s: a Foucaultian approach. AB - Objectives To identify and analyze the discursive statements that characterizes the training of human resources in nursing in the 1940s by the Brazilian Red Cross. Method The approach of the documentary sources was through the assumptions of the Historical Method and they were questioned by using the thought of Michel Foucault. Results Historically, a peculiar model, the military teaching model, influenced the training of human resources in nursing, especially in the 1940s. The Brazilian Red Cross was linked to the Ministry of War and its nursing education had an emphasis on moral conduct, discipline, and respect for hierarchy, culminating in the production of nurses' "docile bodies". The attributes expected of nurses constituted the triad in the professional formation identity at that time: dedication, discipline and obedience. Conclusion The military model still reverberates practices in training of nurses in the present, as in the management, care and education in nursing. PMID- 26959156 TI - Webquest and Comics in the Formation of Human Resources in Nursing. AB - Objective To describe the process of constructing and implementation of Webquest as pedagogical strategy as guiding the study about the pedagogical concepts using Comic. Method The first stage of the study was outlined applied research of technological production. The second stage was characterized as research exploratory, descriptive documentary for the analysis of Comic. in the teaching diploma in Nursing of EEUSP in 2013. Results The proposed Webquest was implemented, resulting in 18 Comic. All Pedagogical Concepts studied were addressed; used the software indicated and the power point, the plots developed in different scenarios and most Comic contemplated mandatory items. Conclusion The use of different technological resources provide learning, by mobilizing multiple potentialities, abilities and interests of students, favoring the construction of collective and collaborative learning, strengthening important and necessary features in training that will influence the human resource profile in tune with the aspirations of the labor market. PMID- 26959157 TI - The I Professor Formation in the Wallonian approach. AB - Objectives Analyze how teachers perceive the construction of their I Professor from the perspective of Wallon and learn about their everyday experiences in school in the condition of being self and other. Method Qualitative, with 13 participants from the Bachelor of Nursing Program. Data collection was carried out in 2013 using interviews that were subjected to thematic analysis. Results Three categories emerged: Construction of the I Professor; living daily life supported by oneself and the other; and the components for constructing the I Professor, highlighting consciousness and valuing of oneself and the other. Conclusion The teachers traveled a path that allowed them to recognize themselves in different movements of the internalization of the I. PMID- 26959158 TI - Nursing interventions in pediatric care: a contribution to measuring workload. AB - Objective To identify and validate interventions/activities developed by a nursing team in a Brazilian pediatric unit. Method A descriptive, cross sectional, and observational study was developed in the pediatric clinic of the university hospital of University of Sao Paulo, Sao Paulo, Brazil. It was organized in the following stages: identifying activities carried out by the team (from records in patient charts and from direct observation); mapping out and validating activities identified in interventions according to the Nursing Intervention Classification (NIC). Results The 275 identified activities were mapped out into 63 interventions, 22 NIC classes and 7 NIC domains, and 25 associated and 13 personal activities. After validation, the number of activities decreased to 244, corresponding to 53 interventions, 20 NIC classes and 6 NIC domains, and 30 associated activities and 9 personal activities. Conclusion Identifying the interventions/activities performed by the nursing team can help measure workload and is an important contribution to overcoming difficulties when it comes to operationalizing the process of sizing professional teams in the field of pediatrics. PMID- 26959159 TI - Evaluation of the online management course from the perspective of former students. AB - Objective To evaluate the online course from the perspective of e-learners as well as the relation between variables. Method A quantitative, descriptive and exploratory study. Results After three years, the satisfaction rates in the three listed categories presented an average rate higher than 75%. The coefficients indicated a high consistency of the questionnaire. Considering the overall rates in the three years period, the Instructor Performance category presented the highest rate. Strong associations between Self-Assessment and Instructor Performance, Self-Evaluation and Program of the Course and Instructor performance and Program of the course were identified. There was no association between the three categories mentioned with any other variables existing in the study. Conclusion E-learners expressed satisfaction with the course that means favored the interaction and the promotion of collective knowledge in nursing management. Also aspects need to be improved, especially the training of the instructor to mediate discussions and encourage student involvement throughout the course. PMID- 26959160 TI - Exposure of nursing workers to workloads and their consequences. AB - Objective Measure the exposure of nursing workers to workloads and strain processes and their consequences, by means of indicators. Method Epidemiological, descriptive, cross-sectional quantitative study, conducted in 12 units of three teaching hospitals in the city of Sao Paulo. The study population consisted of 452 nursing workers and the data was collected from hospital medical records using the software System for Monitoring the Health of Nursing Workers (SIMOSTE). The data was analyzed on the basis of indicators that provided information about organizational dynamics, occupational health problems and their consequences. Results The health problem indicators revealed 879 exposures to worloads and 1,355 strain processes. The consequences indicators showed 2,709 lost days per year. Conclusions Exposure to different workloads subjects workers to numerous strain processes, which should be monitored in order to implement preventive measures. PMID- 26959161 TI - The educational environment of the undergraduate nursing course from the student perspective. AB - Objective Evaluate the educational environment of the School of Nursing at the University of Sao Paulo from the student perspective. Method Quantitative approach with exploratory design. The 176 students who participated in the study answered questions ona Likert scale from 1 to 5 to evaluate the educational environment. The data underwent an exploratory factor analysis and inferential statistical tests, while the reliability of the instrument was verified by Cronbach's Alpha. Results The dimensionality analysis established four factors: support for hands-on learning, with a mean score of 3.64; attitudes during learning, mean score of 2.92; learning atmosphere, mean 3.58; and learning weaknesses,mean 3.04. Conclusion The most favorable factor of the environment was support for learning. The attitudinal competencies received lower scores, suggesting the need to strengthen these aspects during the undergraduate course. PMID- 26959162 TI - Performance analysis of nursing students in teaching by skills and for understanding. AB - Objective To analyze the performance of students of the course Supervised Curricular Internship based on skills (curriculum A) and teaching for understanding (curriculum B). Method Exploratory descriptive, quantitative and documentary study. The location of the research was a private university of the city of Sao Paulo and for data collection were used 312 performance assessment tools for students of the course being studied. Results The assessment of the performance of curriculum A students had no difference compared to the overall average of curriculum B students. The A students showed better performance in relation to B in the intensive care unit and in pedagogical practices, and B showed better performance in attitudinal bases topics and management. Students who are nursing technicians have better performance and, those working in the afternoon have better grades. Conclusion It was not proven that students of the course Supervised Curricular Internship of the understanding curriculum (B) had better performance than the students of the skills curriculum (A). The technical training of nursing and work shift were variables that interfered in student performance regardless of the type of curriculum. During the study there was the possibility of analyzing the performance assessment tools for students, as well as the filling by professors, noting that there is need for better structuring of the evaluation of student performance and, above all, a process of training of professors for the execution of this activity. PMID- 26959163 TI - Nursing workers health and patient safety: the look of nurse managers. AB - Objective To understand the perception of nurse managers about the relationship between nursing workers health and patient safety. Method A qualitative survey was conducted using the social phenomenology approach of Alfred Schutz, accomplished through individual interviews with nine nurse managers from five Brazilian university hospitals. Results Nurse managers' perception of the relationship between nursing workers health and patient safety was evidenced in the following categories: "The suffering to balance workers health and patient safety" and "Interventions in everyday work life". Conclusion Managers' experience showed an everyday work life marked by suffering and concern, due to high rates of absenteeism and presenteeism resulting from illness and incapability of workers, and the need to ensure patient safety through qualified nursing care. PMID- 26959164 TI - Experiences and expectations of nurses in caring for organ donors and their families. AB - Objective Understand the experiences and expectations of intensive care unit nurses in caring for organ donors and their families. Method Qualitative research, with a social phenomenological approach, conducted in 2013 with 20 nurses. Results The experiences of the nurses with the families of donors were represented by two categories: obstacles encountered and interventions performed in the care of the donors' families. The expectations of these professionals in caring for organ donors and their families were described in the category: care to save lives. Conclusion The study showed that the day-to-day work of intensive care nurses in their care of organ donors and their families is permeated with obstacles that interfere in the donation process. In light of this, their goal is to provide intensive care to deceased donors and humanized care to the families, to help family members agree to organ donation and enable organs to be made available for transplants. PMID- 26959165 TI - The American Nurses of the Special Public Health Service and the Formation of Human Resources in Brazilian Nursing. AB - Objective To historicize the changes in training human resources in nursing in Brazil during the period from 1942 to 1961 based on the presence of 35 American nurses assigned to work in cooperation with Special Public Health Service. Method The sources used for the study were reports written by American nurses who described their impressions, suggestions, and the activities they carried out in the country. These were analyzed based on the discourse analysis of Michel Foucault. Results The period mentioned was marked by an American presence in nursing projects developed by the Special Public Health Service. The discourses indicated that the period was marked by many changes in Brazilian nursing, particularly with respect to attracting and training human resources for the profession. Conclusion The results indicate that the American nurses, through what they said and their influence, were central to the consolidation of a new paradigm in the training of nursing professionals in Brazil. PMID- 26959166 TI - Teacher identity formation in nursing teacher training: reflection mediated by digital technologies. AB - Objective Analyze the teacher identity formation process from the perspective of the past, present and future in the training of nursing teachers through the integration of digital technologies. Method Descriptive, exploratory study, with a qualitative approach, conducted in the on-site class "Teacher Identity Formation" in 2012. Of the synchronous and asynchronous activities, four were analyzed using content analysis. Results In chat, positive and negative impressions and reflections on the formation of one's own identity were identified (six categories); in the "Time tunnel," the projection of future identity (four categories); in the "Portfolio," the perception of one's own identity (four categories); and in the evaluation of the class, the perception of the experiences lived in the class (two categories). Conclusion The integration of digital technologies promoted, in a collaborative way, discussion and understanding by students of how their identity is formed and the projection of their future identity, aligned with the profile and role of teachers demanded in the world of today. PMID- 26959167 TI - Educational technology in care management: technological profile of nurses in Portuguese hospitals. AB - Objective To identify the technological profile of nurses in Portuguese hospitals. Method A quantitative exploratory study conducted in two hospitals in the northern region and one in the central region of Portugal. The sample was randomly selected and included 960 nurses. Results Of the participants, 420 (46.1%) used computers, 196 (23.4%) reported having knowledge about using computers for teaching, 174 (21.1%) used computers to teach, 112 (15.1%) recognized that using computers can be a technological means to supplement classroom training, 477 (61.6%) would like to receive training on using computers, and 382 (40.9%) reported self-learning of information technology. In relation to distance education, 706 (74.9%) reported they were familiar with it and 752 (76.4%) indicated an interest in participating in training using this modality. Conclusion Organizations should be mindful of the technological profile shown by this group of nurses and look for ways to introduce educational technologies in the management of care. PMID- 26959168 TI - Application of research and information to human resources policies: regional goals for the Americas. AB - Objective Report experiences involving the use of research and information systems to support national human resources policies through benchmarking between different countries, with comparisons over time and between similar countries or regions. Method In 2007, the Pan American Health Organization (PAHO) promoted a set of goals for all the countries in the Americas to improve the situation of health human resources, using a uniform methodology and research process carried out by Observatories of Human Resources. Results The analysis focused on the progress made in relation to the main challenges in the Southern Cone countries, with a special emphasis on Brazil, noting improvements in the distribution of professionals in the regions. Conclusion These experiences showed how research and the use of information systems can stimulate the expansion of good practices in the training, retention and development of the health workforce in the Americas. PMID- 26959169 TI - Development of an online nursing management course: successful experience between Brazil and Portugal. AB - Objective To describe the experience of planning and developing online refresher courses in nursing management for nurses in the contexts of Brazil and Portugal. Method The instructional design was based on meaningful learning theory, andragogy, and dialectical methodology, so it valued interaction between the actors, emphasizing the scenarios of practice and applying the concepts covered. The course structure is divided into nine theoretical units, four case studies, and an essay exam. Results The course was positively evaluated by the participants, who reported opportunities for acquisition of new knowledge, interaction and exchange of experiences, motivation to study the topics, and self learning. Conclusion It is expected that description of this experience will stimulate proposals for new courses and programs in distance education modalities, improving the processes of teaching and learning so as to give support to future analyses of their impact on the development and enhancement of management skills in nursing. PMID- 26959170 TI - Computational Study of Binding of MU-Conotoxin GIIIA to Bacterial Sodium Channels NaVAb and NaVRh. AB - Structures of several voltage-gated sodium (NaV) channels from bacteria have been determined recently, but the same feat might not be achieved for the mammalian counterparts in the near future. Thus, at present, computational studies of the mammalian NaV channels have to be performed using homology models based on the bacterial crystal structures. A successful homology model for the mammalian NaV1.4 channel was recently constructed using the extensive mutation data for binding of MU-conotoxin GIIIA to NaV1.4, which was further validated through studies of binding of other MU-conotoxins and ion permeation. Understanding the similarities and differences between the bacterial and mammalian NaV channels is an important issue, and the NaV1.4-GIIIA system provides a good opportunity for such a comparison. To this end, we study the binding of GIIIA to the bacterial channels NaVAb and NaVRh. The complex structures are obtained using docking and molecular dynamics simulations, and the dissociation of GIIIA is studied through umbrella sampling simulations. The results are compared to those obtained from the NaV1.4-GIIIA system, and the differences in the binding modes arising from the changes in the selectivity filters are highlighted. PMID- 26959171 TI - Solid state thermal degradation behaviour of graft copolymers of carboxymethyl cellulose with vinyl monomers. AB - The graft copolymer of sodium carboxymethyl cellulose (CMC) with acrylamide (ACM), dimethylacrylamide (DMA), N-vinyl pyrrolidone (NVP), 2-acrylamido-2-methyl 1-propane sulphonic acid (AMPS) and vinyl caprolactum (VCL) were synthesized in nitrogen atmosphere by employing redox initiators. The integral procedural decomposition temperature (IPDT) of CMC and its graft copolymer with ACM, DMA, AMPS, NVP and VCL have been found to be 274 degrees C, 375 degrees C, 421 degrees C, 404 degrees C, 466 degrees C and 331 degrees C, respectively. The higher value of IPDT showed more thermal stability. Among all five graft copolymers, the graft copolymer of CMC with NVP is thermally more stable and VCL grafted copolymer was found least thermally stable. The higher char yield and final decomposition temperature (FDT) were obtained in the case of more thermally stable graft copolymer. All five graft copolymers have shown more than one Tmax, which suggests that degradations were multistep process. PMID- 26959172 TI - Covalent immobilization of alpha-amylase on magnetic particles as catalyst for hydrolysis of high-amylose starch. AB - Enzyme immobilized on magnetic particles can be used as efficient recoverable biocatalysts under strong magnetic response. To enable re-use of enzyme, modified Fe3O4 particles were used as carrier to immobilize alpha-amylase in this paper. Firstly, the surface of Fe3O4 particles were coated with amino groups by direct using TEOS (tetraethoxysilane) followed by treatment with APTES (3 aminopropyltriethoxysilane) and then carboxylated by reacting it with succinic anhydride. In addition, the effect of the immobilization condition on enzyme activity recovery and immobilization efficiency were investigated. The results showed that the optimal immobilization occurred under following conditions: pH 5.5, 40 degrees C, enzyme concentration of 20mgmL(-1), reaction time for 36h. Using immobilized alpha-amylase as biocatalyst, the optimum pH and temperature for hydrolysis were observed to be 6.5 and 60 degrees C. The kinetics of hydrolysis reaction were studied using Michaelis-Menten equation. The affinity constant (Km) and maximum reaction rate (vmax) of magnetic particles immobilization alpha-amylase (MPIA) was 0.543mgmL(-1) and 1.321mgmin(-1) compared to those of 0.377mgmL(-1) and 6.859mgmin(-1) of free enzyme. After immobilization, enzymatic activity, storage stability, thermo-stability, and reusability of MPIA were found superior to those of the free one. MPIA maintained 86% enzyme activity after 30 days and maintained 78% enzyme activity after recycling six times. PMID- 26959174 TI - Evolution of Slow Magnetic Relaxation: from Diamagnetic Matrix Y(OH)CO3 to Dy(0.06)Y(0.94)(OH)CO3 with High Spin-Reversal Barrier and Blocking Temperature. AB - A stable Dy(III)-dispersed compound with single-molecule magnet behavior, Dy(0.06)Y(0.94)(OH)CO3, was isolated by a general strategy targeted at the doping of paramagnetic Dy(3+) into a diamagnetic 3D inorganic network of Y(OH)CO3. The single-ion origin of slow magnetic relaxation was gradually released as variations of the dysprosium/yttrium ratio and finally gave a relatively large spin-reversal barrier around 200 K and high hysteresis temperature of 8 K. This study opens up new opportunities to investigate the slow magnetic relaxation and magnetostructural correlation by choosing a suitable inorganic architecture with strong axial anisotropy. PMID- 26959175 TI - E-cadherin is important for cell differentiation during osteoclastogenesis. AB - E-cadherin, a protein responsible for intercellular adhesion between epithelial cells, is also expressed in the monocyte/macrophage lineage. In this study we have explored the involvement of E-cadherin during receptor activator of nuclear factor-kappaB ligand (RANKL)-stimulated osteoclast differentiation. Osteoclastogenesis involves a period of precursor expansion followed by multiple fusion events to generate a multinuclear osteoclast that is capable of bone resorption. We asked whether E-cadherin participated in early precursor interactions and recognition or was a component of the osteoclast fusion machinery. Here, we show that endogenous E-cadherin expression is the highest during early stages of osteoclast differentiation, with surface expression visible on small precursor cells (fewer than four nuclei per cell) in both RAW 264.7 cells and primary macrophages. Blocking E-cadherin function with neutralizing antibodies prior to the onset of fusion delayed the expression of TRAP, Cathepsin K, DC-STAMP and NFATc1 and significantly diminished multinucleated osteoclast formation. Conversely, E-cadherin-GFP overexpressing macrophages displayed earlier NFATc1 nuclear translocation along with faster formation of multinucleated osteoclasts compared to control macrophages. Through live imaging we identified that disrupting E-cadherin function prolonged the proliferative phase of the precursor population while concomitantly decreasing the proportion of migrating precursors. The lamellipodium and polarized membrane extensions appeared to be the principal sites of fusion, indicating precursor migration was a critical factor contributing to osteoclast fusion. These findings demonstrate that E-cadherin-mediated cell-cell contacts can modulate osteoclast specific gene expression and prompt differentiating osteoclast precursors toward migratory and fusion activities. PMID- 26959173 TI - An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers. AB - Pharmacological probes for the melanocortin receptors have been utilized for studying various disease states including cancer, sexual function disorders, Alzheimer's disease, social disorders, cachexia, and obesity. This study focused on the design and synthesis of bivalent ligands to target melanocortin receptor homodimers. Lead ligands increased binding affinity by 14- to 25-fold and increased cAMP signaling potency by 3- to 5-fold compared to their monovalent counterparts. Unexpectedly, different bivalent ligands showed preferences for particular melanocortin receptor subtypes depending on the linker that connected the binding scaffolds, suggesting structural differences between the various dimer subtypes. Homobivalent compound 12 possessed a functional profile that was unique from its monovalent counterpart providing evidence of the discrete effects of bivalent ligands. Lead compound 7 significantly decreased feeding in mice after intracerebroventricular administration. To the best of our knowledge, this is the first report of a melanocortin bivalent ligand's in vivo physiological effects. PMID- 26959176 TI - Issues with the Specificity of Immunological Reagents for Murine IDO1. PMID- 26959177 TI - The Nurture of Tumors Can Drive Their Metabolic Phenotype. AB - Many commonly accepted principles in tumor metabolism rely on in vitro studies performed under conditions which cannot faithfully recapitulate tumor heterogeneity. Davidson et al. (2016), in this issue of Cell Metabolism, and Hensley et al. (2016) find that the in vivo environment dictates the metabolic phenotype of lung tumors in patients and mouse models. PMID- 26959178 TI - It's in the Milk: Feeding the Microbiome to Promote Infant Growth. AB - Malnutrition is a global health burden affecting the development of millions of children worldwide, but the effects of current treatment strategies are modest. Charbonneau et al. (2016) identify sialylated oligosaccharides in breast milk as microbiota-dependent growth-promoting metabolites, paving the way for a new rational treatment of severe infant stunting. PMID- 26959179 TI - Deconstructing Dietary Restriction: A Case for Systems Approaches in Aging. AB - Dietary restriction is a robust and conserved intervention to slow aging and extend lifespan. In this issue of Cell Metabolism, Hou et al. (2016) use a systems biology approach in C. elegans to uncover key molecular nodes underlying the transcriptomic response to dietary restriction and predict novel regulators of lifespan. PMID- 26959180 TI - Toward a Molecular Definition of Leucine-Dependent mTORC1 Activation. AB - The mechanistic target of rapamycin complex 1 (mTORC1) coordinates nutrient availability with cell growth. Recent reports by Sabatini and coworkers (Saxton et al., 2016; Wolfson et al., 2016) characterize a cytoplasmic amino acid receptor that couples the binding of leucine to the activation of mTORC1. PMID- 26959181 TI - AMPK Promotes Autophagy by Facilitating Mitochondrial Fission. AB - AMPK senses decreased cellular energy levels, triggering mitochondrial autophagy or mitophagy through activating ULK1 and inhibiting mTORC1. In a recent report, Toyama et al. (2016) show that activated AMPK phosphorylation of MFF is critical for mitochondrial fission. Unphosphorylatable MFF mutants block mitophagy, connecting AMPK to mitochondrial fission and to mitophagy. PMID- 26959182 TI - Transferring Fragments of Paternal Metabolism to the Offspring. AB - Paternal diet influences offspring metabolism, yet the underlying epigenetic mechanisms are unclear. Recently, Chen et al. (2016) and Sharma et al. (2016) identified tRNA fragments in sperm and the male reproductive tract as possible inherited factors altered by paternal diet that lead to gene misexpression and altered metabolism in offspring. PMID- 26959183 TI - Of FOXes and Forgetful Worms. AB - Age-related cognitive decline is one of the most haunting aspects of human aging. In a recent publication, Coleen Murphy and colleagues (Kaletsky et al., 2016) describe the transcriptional program that maintains youthful function of aging neurons in the nematode worm. PMID- 26959184 TI - A Long-Acting FGF21 Molecule, PF-05231023, Decreases Body Weight and Improves Lipid Profile in Non-human Primates and Type 2 Diabetic Subjects. AB - FGF21 plays a central role in energy, lipid, and glucose homeostasis. To characterize the pharmacologic effects of FGF21, we administered a long-acting FGF21 analog, PF-05231023, to obese cynomolgus monkeys. PF-05231023 caused a marked decrease in food intake that led to reduced body weight. To assess the effects of PF-05231023 in humans, we conducted a placebo-controlled, multiple ascending-dose study in overweight/obese subjects with type 2 diabetes. PF 05231023 treatment resulted in a significant decrease in body weight, improved plasma lipoprotein profile, and increased adiponectin levels. Importantly, there were no significant effects of PF-05231023 on glycemic control. PF-05231023 treatment led to dose-dependent changes in multiple markers of bone formation and resorption and elevated insulin-like growth factor 1. The favorable effects of PF 05231023 on body weight support further evaluation of this molecule for the treatment of obesity. Longer studies are needed to assess potential direct effects of FGF21 on bone in humans. PMID- 26959187 TI - Taming tosyl azide: the development of a scalable continuous diazo transfer process. AB - Heat and shock sensitive tosyl azide was generated and used on demand in a telescoped diazo transfer process. Small quantities of tosyl azide were accessed in a 'one pot' batch procedure using shelf stable, readily available reagents. For large scale diazo transfer reactions tosyl azide was generated and used in a telescoped flow process, to mitigate the risks associated with handling potentially explosive reagents on scale. The in situ formed tosyl azide was used to rapidly perform diazo transfer to a range of acceptors, including beta ketoesters, beta-ketoamides, malonate esters and beta-ketosulfones. An effective in-line quench of sulfonyl azides was also developed, whereby a sacrificial acceptor molecule ensured complete consumption of any residual hazardous diazo transfer reagent. The telescoped diazo transfer process with in-line quenching was used to safely prepare over 21 g of an alpha-diazocarbonyl in >98% purity without any column chromatography. PMID- 26959186 TI - A Systems Approach to Reverse Engineer Lifespan Extension by Dietary Restriction. AB - Dietary restriction (DR) is the most powerful natural means to extend lifespan. Although several genes can mediate responses to alternate DR regimens, no single genetic intervention has recapitulated the full effects of DR, and no unified system is known for different DR regimens. Here we obtain temporally resolved transcriptomes during calorie restriction and intermittent fasting in Caenorhabditis elegans and find that early and late responses involve metabolism and cell cycle/DNA damage, respectively. We uncover three network modules of DR regulators by their target specificity. By genetic manipulations of nodes representing discrete modules, we induce transcriptomes that progressively resemble DR as multiple nodes are perturbed. Targeting all three nodes simultaneously results in extremely long-lived animals that are refractory to DR. These results and dynamic simulations demonstrate that extensive feedback controls among regulators may be leveraged to drive the regulatory circuitry to a younger steady state, recapitulating the full effect of DR. PMID- 26959185 TI - The Circadian Clock in the Ventromedial Hypothalamus Controls Cyclic Energy Expenditure. AB - Organismal homeostasis relies on coherent interactions among tissues, specifically between brain-driven functions and peripheral metabolic organs. Hypothalamic circuits compute metabolic information to optimize energetic resources, but the role of the circadian clock in these pathways remains unclear. We have generated mice with targeted ablation of the core-clock gene Bmal1 within Sf1-neurons of the ventromedial hypothalamus (VMH). While this mutation does not affect the central clock in the suprachiasmatic nucleus (SCN), the VMH clock controls cyclic thermogenesis in brown adipose tissue (BAT), a tissue that governs energy balance by dissipating chemical energy as heat. VMH-driven control is exerted through increased adrenergic signaling within the sympathetic nervous system, without affecting the BAT's endogenous clock. Moreover, we show that the VMH circadian clock computes light and feeding inputs to modulate basal energy expenditure. Thus, we reveal a previously unsuspected circuit where an SCN independent, hypothalamic circadian clock controls BAT function, energy expenditure, and thermogenesis. PMID- 26959188 TI - Brief Report: HIV-1 Tropism During Primary Infections in France: 1996-2014. AB - HIV-1 was mainly CCR5 tropic in recent seroconverters. We analyzed the coreceptor use in 239 primary HIV-1 infections (PHIs) between 1996 and 2014 using a validated recombinant virus phenotypic entry assay. CXCR4-using viruses were detected in 8.3%, 3.8%, and 6.1% of PHIs from 1996 to 2004, 2005 to 2009, and 2010 to 2014, respectively. The presence of CXCR4-using viruses was associated with the virological failure of antiretroviral treatment initiated during PHI (odds ratio, 7.9; 95% confidence interval, 1.1 to 56.5). The phenotypic tropism assay data show that the prevalence of X4 tropic transmitted viruses was stable in this French cohort of PHIs between 1996 and 2014. PMID- 26959189 TI - Implementation and Operational Research: Effectiveness and Patient Acceptability of a Sexually Transmitted Infection Self-Testing Program in an HIV Care Setting. AB - BACKGROUND: Rates of screening for bacterial sexually transmitted infections (STI) among men who have sex with men in HIV care settings remain low despite high prevalence of these infections. STI self-testing may help increase screening rates in clinical settings. METHODS: We implemented an STI self-testing program at a large, urban HIV care clinic and evaluated its effectiveness and acceptability. We compared measures obtained during the first year of the STI self-testing program (Intervention Year, April 1, 2013-March 31, 2014) to Baseline Year (January 1, 2012-December 31, 2012) to determine: (1) overall clinic change in STI testing coverage and diagnostic yield and; (2) program specific outcomes including appropriate anatomic site screening and patient reported acceptability. RESULTS: Overall, testing for gonorrhea and chlamydia increased significantly between Baseline and Intervention Year, and 50% more gonococcal and 47% more chlamydial infections were detected. Syphilis testing coverage remained unchanged. Nearly 95% of 350 men who participated in the STI self-testing program completed site-specific testing appropriately based on self reported exposures, and 92% rated their self-testing experience as "good" or "very good." CONCLUSIONS: STI self-testing in HIV care settings significantly increases testing coverage and detection of gonorrhea and chlamydia, and the program is acceptable to patients. Additional interventions to increase syphilis screening rates are needed. PMID- 26959190 TI - Antiretroviral Therapy Adherence Enhancing Interventions for Adolescents and Young Adults 13-24 Years of Age: A Review of the Evidence Base. AB - INTRODUCTION: Youth living with HIV are highly under-represented in the evidence base for adherence interventions, despite their diverse and unique needs and barriers. OBJECTIVE: This systematic review aimed to identify antiretroviral therapy (ART) adherence interventions specifically targeting adolescents and young adults (defined as ages 13-24) with the goal of characterizing the evidence base. METHODS: Articles were identified using the PubMed database and cover work published through September 14, 2015. INCLUSION CRITERIA: (1) average age 13 to 24, (2) HIV positive, (3) on or beginning ART, (4) intervention targeted ART adherence in full or in part, (5) reported adherence, viral load, and/or CD4 count outcomes. Strength of evidence was defined as level 1 [randomized controlled trial (RCT) with significance testing on outcomes], 2 (within group studies with statistical testing on outcomes), 3 (RCTs with descriptive results), or 4 (within group studies with descriptive results). RESULTS: Of 151 articles, 10 met inclusion criteria. Published between 2003 and 2014, these studies evaluated diverse intervention approaches. Most were conducted in the US and were small pilots that have yet to be replicated despite promising results. Only 3 studies met criteria for highest level strength of evidence; 2 supported a phone based counseling approach with adherence monitors and 1 for weekly individual and family counseling. CONCLUSIONS: Despite nearly 20 years passing since the wide scale availability of ART, and clear recognition that adolescents and youth adults fair worse on the cascade of HIV care, the evidence base remains sparse and underdeveloped. Promising approaches need replication and more rigorous studies are desperately needed. PMID- 26959191 TI - The Importance of Context: Neighborhood Drinking Norms and Heavy Drinking Among HIV Patients. PMID- 26959192 TI - Diagnostic Accuracy of the Point-of-Care Xpert HIV-1 Viral Load Assay in a South African HIV Clinic. PMID- 26959193 TI - Photocatalytic hydrogen evolution by Cu(II) complexes. AB - [Cu(TMPA)Cl]Cl (1) and [Cu(Cl-TMPA)Cl2] (2) exhibited efficient photocatalytic H2 evolution with a TON of 6108 and 10014 (6 h), respectively, in CH3CN/H2O solution (9 : 1, v/v) containing an Ir complex as the photosensitizer and triethylamine as the sacrificial reductant, representing the first example of photocatalytic Cu complex-based water reduction catalysts. PMID- 26959194 TI - Linking Equilibrium and Nonequilibrium Dynamics in Glass-Forming Systems. AB - Understanding nonequilibrium glassy dynamics is of great scientific and technological importance. However, prediction of the temperature, thermal history, and composition dependence of nonequilibrium viscosity is challenging due to the noncrystalline and nonergodic nature of the glassy state. Here, we show that the nonequilibrium glassy dynamics are intimately connected with the equilibrium liquid dynamics. This is accomplished by deriving a new functional form for the thermal history dependence of nonequilibrium viscosity, which is validated against experimental measurements of industrial silicate glasses and computed viscosities for selenium over a wide range of conditions. Since the temperature and composition dependence of liquid viscosity can be predicted using temperature-dependent constraint theory, our work also opens the possibility to improve understanding of the physics of nonequilibrium viscosity. PMID- 26959195 TI - The Effect of Polar Fluctuation and Lattice Mismatch on Carrier Mobility at Oxide Interfaces. AB - Since the discovery of two-dimensional electron gas (2DEG) at the oxide interface of LaAlO3/SrTiO3 (LAO/STO), improving carrier mobility has become an important issue for device applications. In this paper, by using an alternate polar perovskite insulator (La0.3Sr0.7) (Al0.65Ta0.35)O3 (LSAT) for reducing lattice mismatch from 3.0% to 1.0%, the low-temperature carrier mobility has been increased 30 fold to 35,000 cm(2) V(-1) s(-1). Moreover, two critical thicknesses for the LSAT/STO (001) interface are found, one at 5 unit cells for appearance of the 2DEG and the other at 12 unit cells for a peak in the carrier mobility. By contrast, the conducting (110) and (111) LSAT/STO interfaces only show a single critical thickness of 8 unit cells. This can be explained in terms of polar fluctuation arising from LSAT chemical composition. In addition to lattice mismatch and crystal symmetry at the interface, polar fluctuation arising from composition has been identified as an important variable to be tailored at the oxide interfaces to optimize the 2DEG transport. PMID- 26959196 TI - Validity and Reliability of Two Field-Based Leg Stiffness Devices: Implications for Practical Use. AB - Leg stiffness is an important performance determinant in several sporting activities. This study evaluated the criterion-related validity and reliability of 2 field-based leg stiffness devices, Optojump NextR (Optojump) and Myotest ProR (Myotest) in different testing approaches. Thirty-four males performed, on 2 separate sessions, 3 trials of 7 maximal hops, synchronously recorded from a force platform (FP), Optojump and Myotest. Validity (Pearson's correlation coefficient, r; relative mean bias; 95% limits of agreement, 95%LoA) and reliability (coefficient of variation, CV; intraclass correlation coefficient, ICC; standard error of measurement, SEM) were calculated for first attempt, maximal attempt, and average across 3 trials. For all 3 methods, Optojump correlated highly to the FP (range r = .98-.99) with small bias (range 0.91-0.92, 95%LoA 0.86-0.98). Myotest demonstrated high correlation to FP (range r = .81 .86) with larger bias (range 1.92-1.93, 95%LoA 1.63-2.23). Optojump yielded a low CV (range 5.9% to 6.8%), high ICC (range 0.82-0.86), and SEM ranging 1.8-2.1 kN/m. Myotest had a larger CV (range 8.9% to 13.0%), moderate ICC (range 0.64 0.79), and SEM ranging from 6.3 to 8.9 kN/m. The findings present important information for these devices and support the use of a time-efficient single trial to assess leg stiffness in the field. PMID- 26959197 TI - Current Therapies for the Medical Management of Diabetes. AB - Diabetes affects a large and diverse number of individuals who share in common its risks for complications but who differ greatly from one another in age, health, and a number of circumstances influential to successful treatment. Because type 2 diabetes comprises the majority of diabetes cases, a number of agents have been developed for its treatment. Their unique properties offer opportunities to overcome some of the treatment limitations of older medicines and enable a more individualized and flexible approach to glucose-lowering. At the same time, new medications are accompanied by greater costs and uncertainties about their long-term benefits or safety, and thus the present state of care for type 2 diabetes places focus on a process of shared decision-making between the clinician and patient as to which treatments can optimize health while minimizing harms. We review the major classes of diabetes agents and provide some guidance for how one might approach decision-making in choosing among them. PMID- 26959198 TI - Complications and Safety of Preconception Low-Dose Aspirin Among Women With Prior Pregnancy Losses. AB - OBJECTIVE: To evaluate complications and safety of preconception low-dose aspirin in 1,228 U.S. women (2007-2011). METHODS: Evaluation of the safety of low-dose aspirin in the participants and their fetuses was a planned secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial, a multicenter, block randomized, double-blind, placebo-controlled trial investigating the effect of low-dose aspirin on the incidence of live birth. Women aged 18-40 years with a history of one to two pregnancy losses trying to conceive were randomized to daily low-dose aspirin (81 mg, n=615) or placebo (n=613) and were followed for up to six menstrual cycles or through gestation if they became pregnant. Emergency care visits and possible aspirin-related symptoms were assessed at each study follow-up using standardized safety interviews. In addition, complications for both the participant and her fetus or neonate were captured prospectively using case report forms, interviews conducted during pregnancy and postpartum, and medical records. RESULTS: The proportion of women with at least one possible aspirin-related symptom during the trial was similar between treatment arms (456 [74%] low-dose aspirin compared with 447 [73%] placebo, P=.65) as was the proportion with at least one emergency care visit (104 [17%] low-dose aspirin compared with 99 [16%] placebo, P=.76). Maternal complications were evenly distributed by treatment arm with the exception of vaginal bleeding, which was more commonly reported in the low-dose aspirin arm (22% compared with 17%, P=.02). The distribution of fetal and neonatal complications-which included three stillbirths, three neonatal deaths, and 10 neonates with birth defect(s)-was similar between treatment arms. CONCLUSION: Although rare but serious complications resulting from low-dose aspirin cannot be ruled out, preconception low-dose aspirin appears to be well tolerated by women trying to conceive, women who become pregnant, and by their fetuses and neonates. PMID- 26959199 TI - Twin Pregnancy and Severe Maternal Outcomes: The World Health Organization Multicountry Survey on Maternal and Newborn Health. AB - OBJECTIVE: To evaluate maternal complications (potentially life-threatening conditions, maternal near miss, and maternal death) that are mutually exclusive and severe maternal outcomes (maternal near miss or maternal death) associated with twin pregnancies. METHODS: We performed a secondary analysis of a cross sectional World Health Organization Multicountry Survey, which was implemented in 29 countries. Data from 4,756 twin deliveries were compared with 308,111 singleton deliveries. Factors associated with maternal morbidity and twin pregnancies were reported with adjusted prevalence ratio (95% confidence interval). RESULTS: Potentially life-threatening conditions, maternal near miss, severe maternal outcomes, and maternal deaths were 2.14 (1.99-2.30), 3.03 (2.39 3.85), 3.19 (2.58-3.94), and 3.97 (2.47-6.38) times higher, respectively, among twin pregnancies. Maternal age older than 20 years, having a partner, multiparity, and elective cesarean delivery were associated with twin pregnancies. Postpartum hemorrhage and chronic hypertension were more frequently associated with severe maternal outcomes among twin pregnancies. Conditions indicating organ dysfunction (maternal near miss) were twofold to fivefold higher for twins. Poisson multiple regression analysis identified several factors independently associated with a severe maternal outcome, but not twin pregnancies. CONCLUSION: Twin pregnancy is associated with greater severe maternal morbidity and a higher rate of maternal death than singleton pregnancy. PMID- 26959200 TI - Antenatal Corticosteroid Therapy Before 24 Weeks of Gestation: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To evaluate the effectiveness of antenatal corticosteroids compared with placebo or no treatment in neonates born before 24 weeks of gestation. DATA SOURCES: We searched MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Cochrane Central Register of Controlled Trials databases from 1990 to March 13, 2015, and ClinicalTrials.gov. METHODS OF STUDY SELECTION: Studies considered were published randomized or quasirandomized controlled trials and observational studies that compared outcomes between neonates who received or did not receive antenatal corticosteroids born before 24 weeks of gestation. TABULATION, INTEGRATION, AND RESULTS: We performed duplicate independent assessment of the title and abstracts, full-text screening, inclusion of articles, and data abstraction. We performed meta-analyses using random effects models and quality assessment with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. There were 17 observational studies, and our primary outcome, mortality to discharge in neonates receiving active intensive treatment, had a total of 3,626 neonates. The adjusted odds of mortality to discharge were reduced by 52% in the antenatal corticosteroid group compared with the control group (crude adjusted odds ratio [OR] 0.45, 95% confidence interval [CI] 0.36-0.56; adjusted OR 0.48, 95% CI 0.38 0.61; mortality to discharge 58.1% [intervention] compared with 71.8% [control]) with a "moderate" quality of evidence based on the GRADE system. There were no significant differences between the groups for severe morbidity. CONCLUSION: The available data, all observational, show reduced odds of mortality to discharge in neonates born before 24 weeks of gestation who received antenatal corticosteroids and active intensive treatment. Antenatal corticosteroids should be considered for women at risk of imminent birth before 24 weeks of gestation who choose active postnatal resuscitation. PMID- 26959202 TI - Cervical Pessary and Vaginal Progesterone in Twin Pregnancies With a Short Cervix. AB - OBJECTIVE: To evaluate cervical pessary as an intervention to prevent preterm birth in twin pregnancies with a short cervix. METHODS: This was a retrospective cohort study of twin pregnancies managed by a single maternal-fetal medicine practice from 2005 to 2015. We included patients at 28 weeks of gestation or less who were diagnosed with a cervical length less than 20 mm. At the time of diagnosis, all patients were prescribed vaginal progesterone. Starting in 2013, they were also offered pessary placement in addition to vaginal progesterone. We compared outcomes between patients who received a pessary and matched women in a control group in a one-to-three ratio. Women in the control group were matched to women in the case group according to cervical length and gestational age (within 5 mm and 1 week, respectively, of the case patient at the time of pessary placement). We excluded patients with cerclage, monochorionic-monoamniotic placentation, major fetal congenital anomalies discovered before or after birth, patients with twin-twin transfusion syndrome, and patients for whom there were no appropriate controls. Chi-square, Fisher exact, and Student's t tests were used, as appropriate. Regression analysis was performed to control for significant differences at baseline. RESULTS: Twenty-one patients received a cervical pessary, and they were compared with 63 matched women in the control group. As expected (as a result of matching), baseline gestational age (25.7+/-2.1 compared with 25.9+/-2.1 weeks of gestation, P=.671) and cervical length (10.9+/-3.6 mm compared with 11.9+/-4.5 mm, P=.327) were similar between the groups. Patients with a pessary had a significantly lower incidence of delivery at less than 32 weeks of gestation (1/21 [4.8%] compared with 18/63 [28.6%], adjusted P=.05), longer interval to delivery (65.2+/-16.8 compared with 52.1+/-24.3 days, adjusted P=.025), and a lower incidence of severe neonatal morbidity (2/21 [9.5%] compared with 22/63 [34.9%], adjusted P=.04). CONCLUSION: For twin pregnancies with a short cervix, the addition of a cervical pessary to vaginal progesterone is associated with prolonged pregnancy and reduced risk of adverse neonatal outcomes. A large randomized trial should be performed to verify these retrospective findings. PMID- 26959201 TI - Ultrasound Measurement of the Fetal Adrenal Gland as a Predictor of Spontaneous Preterm Birth. AB - OBJECTIVE: To estimate whether ultrasound measurement of the fetal adrenal gland remote from delivery in asymptomatic women can accurately predict spontaneous preterm birth. METHODS: We conducted a prospective multicenter observational nested cohort study of asymptomatic nulliparous women with a singleton pregnancy to study adverse pregnancy outcomes. Between 22 0/7 and 30 6/7 weeks of gestation, credentialed ultrasonographers measured the width (width), length (length), and, when able, depth (depth) of the "fetal zone" of the fetal adrenal gland as well as the width (Width), length (Length), and depth (Depth) of the total gland. We used the ratios of each measurement (width/Width, length/Length, and depth/Depth) to control for variation in adrenal size by gestational age. The accuracy of each ratio measurement in predicting spontaneous preterm birth at less than 37 0/7 weeks of gestation and spontaneous preterm birth at less than 34 0/7 weeks of gestation was assessed by receiver operating characteristic curves using area under the curve. RESULTS: Pregnancy outcomes were available for 1,697 women with one or more fetal adrenal gland measurements. Spontaneous preterm birth at less than 37 0/7 weeks of gestation and spontaneous preterm birth at less than 34 0/7 weeks of gestation occurred in 82 (4.8%) and six women (0.4%), respectively. None of the fetal adrenal gland measurements distinguished spontaneous preterm birth from term birth. The areas under the curve (95% confidence intervals) for spontaneous preterm birth at less than 37 0/7 weeks of gestation were 0.51 (0.45-0.58), 0.50 (0.44-0.56), and 0.52 (0.41-0.63) for width/Width, length/Length, and depth/Depth ratios, respectively. The areas under the curve for spontaneous preterm birth at less than 34 0/7 weeks of gestation were 0.52 (0.25-0.79) and 0.55 (0.31-0.79) for width/Width and length/Length ratios, respectively. Additionally, none of the means of the gland measurements were statistically different between those delivering at term and spontaneous at preterm (P>.05). CONCLUSION: Fetal adrenal size, as measured by ultrasonography between 22 0/7 and 30 6/7 weeks of gestation, is not predictive of spontaneous preterm birth in asymptomatic nulliparous women. PMID- 26959203 TI - Fetal Meconium Peritonitis and Maternal Liver Disease. AB - BACKGROUND: There are five reported cases of fetal meconium peritonitis developing after episodes of maternal hepatitis. These cases demonstrate a potential association between severe maternal liver injury and subsequent fetal meconium peritonitis. CASE: A 26-year-old primigravid woman developed acute liver failure 4 days after unilateral oophorectomy for ovarian torsion at 24 weeks of gestation. Her liver function gradually normalized with conservative management. She was readmitted for acute abdominal pain with elevated blood pressure at 29 weeks of gestation. An emergency cesarean delivery was performed for severe preeclampsia. Her neonate was noted to have a distended abdomen. Laparotomy and bowel resection were performed for meconium peritonitis and bowel perforation. CONCLUSION: Fetal meconium peritonitis may develop after severe maternal liver disease. Thus, the latter may warrant heightened fetal surveillance. PMID- 26959204 TI - Catecholaminergic Polymorphic Ventricular Tachycardia in Pregnancy. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia is a genetic disorder in which ventricular tachycardia occurs in the absence of structural heart disease or a prolonged QT interval. If untreated, there is a high incidence of sudden cardiac death. Management of this cardiac condition during pregnancy merits a multidisciplinary approach. CASE: A nulliparous woman with catecholaminergic polymorphic ventricular tachycardia presented at 15 weeks of gestation. Her care involved a multidisciplinary team including cardiology, maternal-fetal medicine, obstetric nursing, cardiac nursing, and anesthesia. A simulation scenario was designed to prepare for cardiac events during labor. A term intrapartum cesarean delivery was performed for fetal indications. CONCLUSION: A multidisciplinary approach to the antepartum, intrapartum, and postpartum care of women with catecholaminergic polymorphic ventricular tachycardia is critical to a team-based successful pregnancy outcome. PMID- 26959205 TI - The Role of Social Networks, Medical-Legal Climate, and Patient Advocacy on Surgical Options: A New Era. AB - The dissemination of information online and resultant public discourse through social media and other online channels has influenced the practice of medicine in dramatic ways. Physicians have historically worked to develop new techniques and devices for the benefit of their patients. It is only a more recent phenomenon, however, that these tools are either removed or their use is curtailed largely driven by anecdotal reports; passionate, vocal, often media-savvy advocates; and plaintiff attorneys. The use of power morcellation, hysteroscopic tubal sterilization, and mesh in urogynecologic procedures all have been victims of these societal pressures. It is important for health care professionals to be involved in the debate to ensure that public outcry does not unduly influence what we, as clinicians, are able to safely offer our patients. By being better advocates for our field, our instruments, and our patients, we can ensure medical decision-making is driven by good science and not public fervor. PMID- 26959206 TI - Pregnancy-Related Venous Thromboembolism Risk in Asymptomatic Women With Antithrombin Deficiency: A Systematic Review. AB - OBJECTIVE: To evaluate the risk of pregnancy-associated venous thromboembolism in women with asymptomatic antithrombin deficiency. DATA SOURCES: The search was performed on MEDLINE (Ovid and PubMed databases) for the period 1966 to June 2012 and ClinicalTrials.gov as of December 15, 2015. METHODS OF STUDY SELECTION: A systematic review including randomized controlled trials, cohort studies, and case-control studies was conducted. Selection criteria included objectively diagnosed venous thromboembolism or venous thromboembolism treated with 3 months of anticoagulation before the availability of objective testing. The study population consisted of pregnant women with asymptomatic antithrombin deficiency. TABULATION, INTEGRATION, AND RESULTS: Seven publications were included in the review. No randomized controlled trials were identified. The best available data consist of three retrospective cohort studies and four case-control studies. Pooled results from case-control studies yielded an estimated odds ratio for venous thromboembolism of 6.09 (95% confidence interval 1.58-23.43). No pooled estimates could be obtained for cohort studies. Data on use of thromboprophylaxis were scarce. CONCLUSION: Despite the small number of patients included, and the variation in study designs, pooled results from case-control studies show a significant association between asymptomatic antithrombin deficiency and pregnancy-associated venous thromboembolism. Thromboprophylaxis during pregnancy and postpartum should be considered in these women. PMID- 26959207 TI - Infant Outcomes After Elective Early-Term Delivery Compared With Expectant Management. AB - OBJECTIVE: To compare the risk of neonatal morbidity and infant mortality between elective early-term deliveries and those expectantly managed and delivered at 39 weeks of gestation or greater. METHODS: We conducted a population-based retrospective cohort study of 675,302 singleton infants born alive at 37-44 weeks of gestation from 2005 to 2009 in more than 125 birthing facilities in Florida. Data were collected from a validated, longitudinally linked maternal and infant database. The study population was categorized into exposure groups based on the timing and reason for delivery initiation-four subtypes of deliveries at 37-38 weeks of gestation and a comparison group of expectantly managed infants delivered at 39-40 weeks of gestation. Primary outcomes included neonatal respiratory morbidity, sepsis, feeding difficulties, admission to the neonatal intensive care unit (NICU), and infant mortality. RESULTS: Neonatal outcome rates ranged from 6.0% for respiratory morbidities to 1.3% for both sepsis and feeding difficulties, and the infant mortality rate was 1.5 per 1,000 live births. When compared with infants expectantly managed and delivered at 39-40 weeks of gestation, those delivered after elective induction at 37-38 weeks of gestation did not have increased odds of neonatal respiratory morbidity, sepsis, or NICU admission but did experience slightly higher odds of feeding difficulty (odds ratio 1.18, 99% confidence interval 1.02-1.36). In contrast, infants delivered by elective cesarean at 37-38 weeks of gestation had 13-66% increased odds of adverse outcomes. Survival experiences were similar when comparing early inductions and early cesarean deliveries with the expectant management group. CONCLUSION: The issues that surround the timing and reasons for delivery initiation are complicated and each pregnancy unique. This study cautions against a general avoidance of all elective early-term deliveries. PMID- 26959209 TI - Prognostic Factors for Morcellation During Vaginal Hysterectomy. AB - OBJECTIVE: To determine prognostic factors associated with cold-knife morcellation during vaginal hysterectomy. METHODS: We conducted a retrospective cohort study evaluating all consecutive patients undergoing a vaginal hysterectomy between January 1, 2009, and August 31, 2014. The primary outcome was the utilization of uncontained vaginal morcellation performed using cold knife wedge resection at the time of vaginal hysterectomy. Secondary outcomes included perioperative data. Significant factors were included in a multivariate logistic regression model to the binary variable vaginal morcellation at the time of vaginal hysterectomy. RESULTS: A total of 743 women met study inclusion criteria and underwent vaginal hysterectomy with intact uterine removal (n=383) or with uterine morcellation (n=360) with and without other vaginal procedures. A nonparametric Wilcoxon-rank-sum test and chi test were used to compare the cohorts of patients with and without morcellation. Characteristics associated with significantly increased likelihood of morcellation included younger age, non Caucasian race, American Society of Anesthesiologists class 1 or 2, lower parity, lower number of prior vaginal deliveries, absence of prolapse, presence of leiomyoma, and an enlarged uterus. A multivariate logistic model utilizing factors most likely associated with morcellation revealed lack of prolapse (adjusted odds ratio [OR] 3.87, P<.001), leiomyoma (adjusted OR 2.77, P=.035), and larger uterine weight (adjusted OR 7.25, P<.001) increased the likelihood of morcellation. Prior vaginal delivery was associated with a decreased likelihood of morcellation (adjusted OR 0.79, P=.005). CONCLUSION: Vaginal hysterectomy with morcellation is associated with the following factors: absence of prior vaginal delivery, absence of prolapse, presence of leiomyoma, and a uterus larger than normal size. PMID- 26959208 TI - Pregnancy-Associated Hypertension in Glucose-Intolerant Pregnancy and Subsequent Metabolic Syndrome. AB - OBJECTIVE: To evaluate whether pregnancy-associated hypertension (preeclampsia or gestational hypertension) among women with varying degrees of glucose intolerance during pregnancy is associated with maternal metabolic syndrome 5-10 years later. METHODS: This was an observational cohort study of women previously enrolled in a treatment trial of mild gestational diabetes mellitus or an observational study of lesser degrees of glucose intolerance evaluated 5-10 years after their index pregnancy. At follow-up, women underwent anthropometric and blood pressure measurements and analysis of fasting glucose and serum lipids. RESULTS: A total of 825 women (47% of eligible women from the original study) were included in this analysis and evaluated at a median 7 years after their index pregnancy at a median age of 35 years. Overall, 239 (29%) had subsequent metabolic syndrome. The frequency of metabolic syndrome and its components was highest in the women who had pregnancy-associated hypertension and delivered preterm. After adjusting for confounding factors, pregnancy-associated hypertension in women who delivered preterm was associated with subsequent hypertension (130/85 mm Hg or greater; relative risk 3.06, 95% confidence interval [CI] 1.95-4.80, P<.001), high triglycerides (150 mg/dL or greater; relative risk 1.82, 95% CI 1.06-3.14, P=.03), and metabolic syndrome (per the American Heart Association and National Heart Lung and Blood Institute Scientific Statement; relative risk 1.78, 95% CI 1.14-2.78, P=.01) compared with women who remained normotensive throughout their index pregnancy and were delivered at term. CONCLUSION: Women with varying degrees of glucose intolerance who experienced pregnancy-associated hypertension and then delivered preterm had a higher frequency of subsequent hypertension, high triglycerides, and metabolic syndrome 5-10 years later. PMID- 26959210 TI - Obstetric Health Care Providers' Counseling Responses to Pregnant Patient Disclosures of Marijuana Use. AB - OBJECTIVE: To describe obstetric health care providers' responses and counseling approaches to patients' disclosures of marijuana use during first prenatal visits. METHODS: We performed a content analysis of audio-recorded patient-health care provider first prenatal visits for obstetrics health care providers' responses to patients' disclosure of marijuana use. The study was conducted at five urban outpatient clinics located in Pittsburgh, Pennsylvania. RESULTS: Among 468 audio-recorded first obstetric encounters, 90 patients (19%) disclosed marijuana use to 47 health care providers; mean number of recoded encounters containing marijuana disclosures for participating health providers was 1.8+/ 1.4. In 48% of these 90 visits, obstetric health care providers did not respond to marijuana use disclosures or offer counseling. When counseling was offered, it consisted of general statements without specific information on the risks or outcomes related to marijuana use in pregnancy, discussions regarding the need for urine toxicology testing, and warnings that use detected at the time of delivery would initiate child protective services involvement. CONCLUSION: Obstetric health care provider responses to disclosure of marijuana use occurred in approximately half of patient encounters when marijuana use was disclosed and focused on legal and procedural consequences with less focus on health or medical implications. Our results suggest a need for health care provider training on potential consequences of perinatal marijuana use and communication skills for counseling patients about perinatal marijuana. PMID- 26959211 TI - Child Brides, Forced Marriage, and Partner Violence in America: Tip of an Iceberg Revealed. AB - Forced marriage is a violation of human rights and thwarts personal safety and well-being. Child brides are at higher risk of intimate partner violence (IPV) and often are unable to effectively negotiate safe sex, leaving them vulnerable to sexually transmitted infections, including human immunodeficiency virus, and early pregnancy. The prevalence of forced marriage and child marriage in the United States is unknown. The intersection of forced marriage and child marriage and IPV is equally unknown. When 277 mothers who reported IPV to shelter or justice services were asked about a forced marriage attempt, frequency and severity of IPV, mental health status, and behavioral functioning of their child, 47 (17%) reported a forced marriage attempt with 45% of the women younger than 18 years of age at the time of the attempt. Among the 47 women, 11 (23%) reported death threats, 20 (43%) reported marriage to the person, and 28 (60%) reported a pregnancy. Women younger than 18 years reported more threats of isolation and economic deprivation associated with the attempt as well as pressure from parents to marry. Regardless of age, women experiencing a forced marriage attempt reported more intimate partner sexual abuse, somatization, and behavior problems for their children. Forced marriage attempts occurred to one in six women (17%) reporting IPV and are associated with worse functioning for mother and child. The frequent occurrence and associated effect of forced marriage attempts to maternal child functioning indicates routine assessment for a forced marriage attempt as part of comprehensive care for women reporting IPV. PMID- 26959212 TI - Umbilical Cord Venous Lactate for Predicting Arterial Lactic Acidemia and Neonatal Morbidity at Term. AB - OBJECTIVE: To estimate the utility of umbilical venous lactate, more readily available than umbilical cord arterial lactate, for predicting arterial lactic acidemia and neonatal outcomes at term. METHODS: This was a prospective cohort study of consecutive, nonanomalous, singleton, term births after labor in a large academic medical center (2009-2014). Umbilical arterial and venous lactate were measured immediately after delivery, before knowledge of neonatal outcomes. The outcome measures were arterial lactic acidemia (greater than 3.9 mmol/L) and a composite neonatal outcome consisting of neonatal death and any of a number of neonatal morbidities including intubation, mechanical ventilation, meconium aspiration syndrome, hypoxic-ischemic encephalopathy, and therapeutic hypothermia. Predictive ability of venous lactate was estimated using the area under the receiver operating characteristic curve. RESULTS: Among 7,741 births, venous lactate was strongly predictive of arterial lactic acidemia (area under the curve 0.958). The "optimal" cut point of venous lactate for predicting both arterial lactic acidemia and the composite neonatal outcome was 3.4 mmol/L. This predicted arterial lactic acidemia with sensitivity of 87.0% and specificity of 91.3%. Positive and negative predictive values were 79.9% and 94.7%, respectively. The composite neonatal outcome occurred in 104 neonates (1.3%). Compared with arterial lactate, venous lactate predicted the composite neonatal outcome with comparable sensitivity (75.0% compared with 74.0%, P>.99) but slightly lower specificity (69.7% compared with 72.2%, P<.01). CONCLUSION: Umbilical venous lactate strongly predicts arterial lactic acidemia and is comparable with arterial lactate for predicting neonatal morbidity at term. It could be used as a measure of neonatal morbidity when arterial blood is not available. PMID- 26959214 TI - Local Access to Family Planning Services and Female High School Dropout Rates. AB - OBJECTIVE: To assess whether geographic access to family planning services is associated with a reduced female high school dropout rate. METHODS: We conducted a retrospective cross-sectional study. We merged the location of Planned Parenthood and Title X clinics with microdata from the 2012-2013 American Community Surveys. The association between female high school dropout rates and local clinic access was assessed using nearest-neighbor matching estimation. Models included various covariates to account for sociodemographic differences across communities and male high school dropout rates to account for unmeasured community characteristics affecting educational outcomes. RESULTS: Our sample included 284,910 16- to 22-year-old females. The presence of a Planned Parenthood clinic was associated with a decrease (4.08% compared with 4.83%; relative risk ratio 0.84, P<.001) in female high school dropout rates. This association was consistent across several model specifications. The presence of a Title X clinic was associated with a decrease (4.79% compared with 5.07%; relative risk ratio 0.94, P=.03) in female high school dropout rates, an association that did not remain significant across model specifications. CONCLUSION: Local access to Planned Parenthood is associated with lower high school dropout rates in young women. PMID- 26959213 TI - Association of the Duration of Active Pushing With Obstetric Outcomes. AB - OBJECTIVE: To estimate the associations between the duration of active pushing during the second stage of labor and maternal and neonatal outcomes. METHODS: We performed an observational study in which data were obtained by trained abstractors from maternal and neonatal charts of deliveries at 25 hospitals over a 3-year period. In this secondary analysis, women with no prior cesarean delivery who had a term, singleton, cephalic gestation and reached complete dilation were analyzed. The duration of pushing, defined as the time from initiation of pushing to either vaginal delivery or the decision to proceed with a cesarean delivery, was determined. The primary maternal outcome was cesarean delivery and the primary neonatal outcome was a composite that included: mechanical ventilation, proven sepsis, brachial plexus palsy, clavicular fracture, skull fracture, other fracture, seizures, hypoxic-ischemic encephalopathy, or death. Nulliparous and parous women were analyzed separately in univariable and then multivariable analyses. RESULTS: A total of 53,285 women were analyzed. In both nulliparous and parous women, longer duration of pushing was associated with increased odds of both cesarean delivery and the neonatal adverse outcome composite. Nevertheless, even after 4 hours of pushing, approximately 78% of nulliparous women who continued with active pushing had a vaginal delivery and more than 97% did not have the composite adverse neonatal outcome. Similarly, after more than 2 hours of pushing, approximately 82% of parous women who continued active pushing delivered vaginally and more than 97% did not have the adverse neonatal outcome. CONCLUSION: A longer duration of pushing is associated with an increased relative risk, but small absolute difference in risk, of neonatal complications. Approximately 78% of nulliparous women delivered vaginally even after 4 hours of pushing. PMID- 26959215 TI - Transforming Clinical Education in Obstetrics and Gynecology: Gone Is the Day of the Sage on the Stage. AB - Many traditional approaches to clinical education today are outdated and inefficient with disruptive changes on the horizon. Millennials are the new wave of learners in health care and do not learn the same way as their older faculty. Merging health care systems are moving to standardizations of care and reduction of errors, and health care providers are going to be increasingly held more accountable for their clinical outcomes. Computers, digitalization, and connectivity are revolutionizing learning environments, and simulation learning in the form of trainers, mannequins, and team training is already widespread. Newer technologies like virtual and augmented reality are beginning to be used for clinical education and will be a more efficient and standardized way of providing simulation learning. Emerging technologies like holograms and head mounted displays will follow soon after and be even more disruptive. Faculty and mentors will always be crucial to learning in health care but will be empowered to teach in more focused and comprehensive ways. The educational model of the future will be a hybrid model of experienced faculty, interactive learning, and innovative and emerging technology. It is time we start to train health care providers for their future, not our past. PMID- 26959216 TI - The Case of Mr. George. PMID- 26959218 TI - What Is New in Prevention of Ovarian Cancer?: Best Articles From the Past Year. AB - This month we focus on current research in preventing ovarian cancer. Dr. Schorge discusses four recent publications, which are concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 26959219 TI - Pessary for Twins: If Ever, Not Yet. PMID- 26959220 TI - Super-Robust Polylactide Barrier Films by Building Densely Oriented Lamellae Incorporated with Ductile in Situ Nanofibrils of Poly(butylene adipate-co terephthalate). AB - Remarkable combination of excellent gas barrier performance, high strength, and toughness was realized in polylactide (PLA) composite films by constructing the supernetworks of oriented and pyknotic crystals with the assistance of ductile in situ nanofibrils of poly(butylene adipate-co-terephthalate) (PBAT). On the basis that the permeation of gas molecules through polymer materials with anisotropic structure would be more frustrated, we believe that oriented crystalline textures cooperating with inerratic amorphism can be favorable for the enhancement of gas barrier property. By taking full advantage of intensively elongational flow field, the dispersed phase of PBAT in situ forms into nanofibrils, and simultaneously sufficient row-nuclei for PLA are induced. After appropriate thermal treatment with the acceleration effect of PBAT on PLA crystallization, oriented lamellae of PLA tend to be more perfect in a preferential direction and constitute into a kind of network interconnecting with each other. At the same time, the molecular chains between lamellae tend to be more extended. This unique structure manifests superior ability in ameliorating the performance of PLA film. The oxygen permeability coefficient can be achieved as low as 2 * 10(-15) cm(3) cm cm(-2) s(-1) Pa(-1), combining with the high strength, modulus, and ductility (104.5 MPa, 3484 MPa, and 110.6%, respectively). The methodology proposed in this work presents an industrially scalable processing method to fabricate super robust PLA barrier films. It would indeed push the usability of biopolymers forward, and certainly prompt wider application of biodegradable polymers in the fields of environmental protection such as food packaging, medical packaging, and biodegradable mulch. PMID- 26959221 TI - The Honey Bee Pathosphere of Mongolia: European Viruses in Central Asia. AB - Parasites and pathogens are apparent key factors for the detrimental health of managed European honey bee subspecies, Apis mellifera. Apicultural trade is arguably the main factor for the almost global distribution of most honey bee diseases, thereby increasing chances for multiple infestations/infections of regions, apiaries, colonies and even individual bees. This imposes difficulties to evaluate the effects of pathogens in isolation, thereby creating demand to survey remote areas. Here, we conducted the first comprehensive survey for 14 honey bee pathogens in Mongolia (N = 3 regions, N = 9 locations, N = 151 colonies), where honey bee colonies depend on humans to overwinter. In Mongolia, honey bees, Apis spp., are not native and colonies of European A. mellifera subspecies have been introduced ~60 years ago. Despite the high detection power and large sample size across Mongolian regions with beekeeping, the mite Acarapis woodi, the bacteria Melissococcus plutonius and Paenibacillus larvae, the microsporidian Nosema apis, Acute bee paralysis virus, Kashmir bee virus, Israeli acute paralysis virus and Lake Sinai virus strain 2 were not detected, suggesting that they are either very rare or absent. The mite Varroa destructor, Nosema ceranae and four viruses (Sacbrood virus, Black queen cell virus, Deformed wing virus (DWV) and Chronic bee paralysis virus) were found with different prevalence. Despite the positive correlation between the prevalence of V. destructor mites and DWV, some areas had only mites, but not DWV, which is most likely due to the exceptional isolation of apiaries (up to 600 km). Phylogenetic analyses of the detected viruses reveal their clustering and European origin, thereby supporting the role of trade for pathogen spread and the isolation of Mongolia from South-Asian countries. In conclusion, this survey reveals the distinctive honey bee pathosphere of Mongolia, which offers opportunities for exciting future research. PMID- 26959222 TI - Medical Student Perceptions of the Learning Environment at the End of the First Year: A 28-Medical School Collaborative. AB - PURPOSE: Accreditation and professional organizations have recognized the importance of measuring medical students' perceptions of the learning environment, which influences well-being and professional competency development, to optimize professional development. This study was conducted to explore interactions between students' perceptions of the medical school learning environment, student demographic variables, and students' professional attributes of empathy, coping, tolerance of ambiguity, and patient-centeredness to provide ideas for improving the learning environment. METHOD: Twenty-eight medical schools at 38 campuses recruited 4,664 entering medical students to participate in the two-cohort longitudinal study (2010-2014 or 2011-2015). The authors employed chi-square tests and analysis of variance to examine the relationship between Medical School Learning Environment Survey (MSLES) scores and student characteristics. The authors used mixed-effects models with random school and campus effects to test the overall variances accounted for in MSLES scores at the end of the first year of medical school. RESULTS: Student attributes and demographic characteristics differed significantly across schools but accounted for only 2.2% of the total variance in MSLES scores. Medical school campus explained 15.6% of the variance in MSLES scores. CONCLUSIONS: At year's end, students' perceptions toward the learning environment, as reported on the MSLES, differed significantly according to the medical school campus where they trained. Further studies are needed to identify specific factors, such as grading policies, administrative support, and existence of learning communities, which may influence perceptions of the learning environment at various schools. Identifying such variables would assist schools in developing a positive learning environment. PMID- 26959223 TI - Reflections From the Intersection of Health Professions Education and Clinical Practice: The State of the Science of Interprofessional Education and Collaborative Practice. AB - This informed reflection, from the intersection of health professions education and clinical practice, takes stock of the state of the field of interprofessional education (IPE) and collaborative practice (CP) (together IPECP) by answering the following three questions: (1) As a field of study, where is IPECP? (2) As a research enterprise, what are the current analytical gaps? (3) Scientifically, what needs to be done going forward? While IPE and CP, as well as IPECP, have been areas of scholarly inquiry for nearly 50 years, they have collectively and individually had a limited sphere of influence. Analytical gaps identified include little research dealing with big picture health-related outcomes; mixed results on the effectiveness of health care teams; increasing recognition that additional IPECP competencies might be needed; a gap between the identification and application of educational best practices; and the need for sound, reliable, and validated tools for measuring IPECP. The authors outline the work of the National Center for Interprofessional Practice and Education at the University of Minnesota, which is focused on filling the identified analytical gaps by way of strategic actions organized around three domains-(1) developing an IPECP research agenda, (2) nurturing IPECP intervention research grounded in comparative effectiveness research study designs and the assumptions of critical realism, and (3) the creation of a sound informatics platform. The authors argue that filling these gaps is important because if the effectiveness of IPE on CP and of CP on health outcomes is ever to be ascertained, generalizable findings are paramount. PMID- 26959224 TI - The Role for Virtual Patients in the Future of Medical Education. AB - The medical education community is working-across disciplines and across the continuum-to address the current challenges facing the medical education system and to implement strategies to improve educational outcomes. Educational technology offers the promise of addressing these important challenges in ways not previously possible. The authors propose a role for virtual patients (VPs), which they define as multimedia, screen-based interactive patient scenarios. They believe VPs offer capabilities and benefits particularly well suited to addressing the challenges facing medical education. Well-designed, interactive VP based learning activities can promote the deep learning that is needed to handle the rapid growth in medical knowledge. Clinically oriented learning from VPs can capture intrinsic motivation and promote mastery learning. VPs can also enhance trainees' application of foundational knowledge to promote the development of clinical reasoning, the foundation of medical practice. Although not the entire solution, VPs can support competency-based education. The data created by the use of VPs can serve as the basis for multi-institutional research that will enable the medical education community both to better understand the effectiveness of educational interventions and to measure progress toward an improved system of medical education. PMID- 26959225 TI - Building a Framework of Entrustable Professional Activities, Supported by Competencies and Milestones, to Bridge the Educational Continuum. AB - The transition to competency-based medical education (CBME) and adoption of the foundational domains of competence by the Accreditation Council for Graduate Medical Education, Association of American Medical Colleges (AAMC), and American Board of Medical Specialties' certification and maintenance of certification (MOC) programs provided an unprecedented opportunity for the pediatrics community to create a model of learning and assessment across the continuum. Two frameworks for assessment in CBME have been promoted: (1) entrustable professional activities (EPAs) and (2) milestones that define a developmental trajectory for individual competencies. EPAs are observable and measureable units of work that can be mapped to competencies and milestones critical to performing them safely and effectively.The pediatrics community integrated the two frameworks to create a potential pathway of learning and assessment across the continuum from undergraduate medical education (UME) to graduate medical education (GME) and from GME to practice. The authors briefly describe the evolution of the Pediatrics Milestone Project and the process for identifying EPAs for the specialty and subspecialties of pediatrics. The method of integrating EPAs with competencies and milestones through a mapping process is discussed, and an example is provided. The authors illustrate the alignment of the AAMC's Core EPAs for Entering Residency with the general pediatrics EPAs and, in turn, the alignment of the latter with the subspecialty EPAs, thus helping build the bridge between UME and GME. The authors propose how assessment in GME, based on EPAs and milestones, can guide MOC to complete the bridge across the education continuum. PMID- 26959226 TI - Voltage-Controlled Interfacial Layering in an Ionic Liquid on SrTiO3. AB - One prominent structural feature of ionic liquids near surfaces is formation of alternating layers of anions and cations. However, how this layering responds to an applied potential is poorly understood. We focus on the structure of 1-butyl-1 methylpyrrolidinium tris(pentafluoroethyl) trifluorophosphate (BMPY-FAP) near the surface of a strontium titanate (SrTiO3) electric double-layer transistor. Using X-ray reflectivity, we show that at positive bias the individual layers in the ionic liquid double layer thicken and the layering persists further away from the interface. We model the reflectivity using a modified distorted crystal model with alternating cation and anion layers, which allows us to extract the charge density and the potential near the surface. We find that the charge density is strongly oscillatory with and without applied potential and that with an applied gate bias of 4.5 V the first two layers become significantly more cation rich than at zero bias, accumulating about 2.5 * 10(13) cm(-2) excess charge density. PMID- 26959227 TI - TGN1412 Induces Lymphopenia and Human Cytokine Release in a Humanized Mouse Model. AB - Therapeutic monoclonal antibodies (mAbs) such as the superagonistic, CD28 specific antibody TGN1412, or OKT3, an anti-CD3 mAb, can cause severe adverse events including cytokine release syndrome. A predictive model for mAb-mediated adverse effects, for which no previous knowledge on severe adverse events to be expected or on molecular mechanisms underlying is prerequisite, is not available yet. We used a humanized mouse model of human peripheral blood mononuclear cell reconstituted NOD-RAG1-/-Abeta-/-HLADQ(tg+ or tg-)IL-2Rgammac-/- mice to evaluate its predictive value for preclinical testing of mAbs. 2-6 hours after TGN1412 treatment, mice showed a loss of human CD45+ cells from the peripheral blood and loss of only human T cells after OKT3 injection, reminiscent of effects observed in mAb-treated humans. Moreover, upon OKT3 injection we detected selective CD3 downmodulation on T cells, a typical effect of OKT3. Importantly, we detected release of human cytokines in humanized mice upon both OKT3 and TGN1412 application. Finally, humanized mice showed severe signs of illness, a rapid drop of body temperature, and succumbed to antibody application 2-6 hours after administration. Hence, the humanized mouse model used here reproduces several effects and adverse events induced in humans upon application of the therapeutic mAbs OKT3 and TGN1412. PMID- 26959228 TI - Hierarchy Low CD4+/CD8+ T-Cell Counts and IFN-gamma Responses in HIV-1+ Individuals Correlate with Active TB and/or M.tb Co-Infection. AB - OBJECTIVE: Detailed studies of correlation between HIV-M.tb co-infection and hierarchy declines of CD8+/CD4+ T-cell counts and IFN-gamma responses have not been done. We conducted case-control studies to address this issue. METHODS: 164 HIV-1-infected individuals comprised of HIV-1+ATB, HIV-1+LTB and HIV-1+TB- groups were evaluated. Immune phenotyping and complete blood count (CBC) were employed to measure CD4+ and CD8+ T-cell counts; T.SPOT.TB and intracellular cytokine staining (ICS) were utilized to detect ESAT6, CFP10 or PPD-specific IFN-gamma responses. RESULTS: There were significant differences in median CD4+ T-cell counts between HIV-1+ATB (164/MUL), HIV-1+LTB (447/MUL) and HIV-1+TB- (329/MUL) groups. Hierarchy low CD4+ T-cell counts (<200/MUL, 200-500/MUL, >500/MUL) were correlated significantly with active TB but not M.tb co-infection. Interestingly, hierarchy low CD8+ T-cell counts were not only associated significantly with active TB but also with M.tb co-infection (P<0.001). Immunologically, HIV-1+ATB group showed significantly lower numbers of ESAT-6-/CFP-10-specific IFN-gamma+ T cells than HIV-1+LTB group. Consistently, PPD-specific IFN-gamma+CD4+/CD8+ T effector cells in HIV-1+ATB group were significantly lower than those in HIV 1+LTB group (P<0.001). CONCLUSIONS: Hierarchy low CD8+ T-cell counts and effector function in HIV-1-infected individuals are correlated with both M.tb co-infection and active TB. Hierarchy low CD4+ T-cell counts and Th1 effector function in HIV 1+ individuals are associated with increased frequencies of active TB, but not M.tb co-infection. PMID- 26959230 TI - Identification of Analytical Factors Affecting Complex Proteomics Profiles Acquired in a Factorial Design Study with Analysis of Variance: Simultaneous Component Analysis. AB - Complex shotgun proteomics peptide profiles obtained in quantitative differential protein expression studies, such as in biomarker discovery, may be affected by multiple experimental factors. These preanalytical factors may affect the measured protein abundances which in turn influence the outcome of the associated statistical analysis and validation. It is therefore important to determine which factors influence the abundance of peptides in a complex proteomics experiment and to identify those peptides that are most influenced by these factors. In the current study we analyzed depleted human serum samples to evaluate experimental factors that may influence the resulting peptide profile such as the residence time in the autosampler at 4 degrees C, stopping or not stopping the trypsin digestion with acid, the type of blood collection tube, different hemolysis levels, differences in clotting times, the number of freeze-thaw cycles, and different trypsin/protein ratios. To this end we used a two-level fractional factorial design of resolution IV (2(IV)(7-3)). The design required analysis of 16 samples in which the main effects were not confounded by two-factor interactions. Data preprocessing using the Threshold Avoiding Proteomics Pipeline (Suits, F.; Hoekman, B.; Rosenling, T.; Bischoff, R.; Horvatovich, P. Anal. Chem. 2011, 83, 7786-7794, ref 1) produced a data-matrix containing quantitative information on 2,559 peaks. The intensity of the peaks was log-transformed, and peaks having intensities of a low t-test significance (p-value > 0.05) and a low absolute fold ratio (<2) between the two levels of each factor were removed. The remaining peaks were subjected to analysis of variance (ANOVA)-simultaneous component analysis (ASCA). Permutation tests were used to identify which of the preanalytical factors influenced the abundance of the measured peptides most significantly. The most important preanalytical factors affecting peptide intensity were (1) the hemolysis level, (2) stopping trypsin digestion with acid, and (3) the trypsin/protein ratio. This provides guidelines for the experimentalist to keep the ratio of trypsin/protein constant and to control the trypsin reaction by stopping it with acid at an accurately set pH. The hemolysis level cannot be controlled tightly as it depends on the status of a patient's blood (e.g., red blood cells are more fragile in patients undergoing chemotherapy) and the care with which blood was sampled (e.g., by avoiding shear stress). However, its level can be determined with a simple UV spectrophotometric measurement and samples with extreme levels or the peaks affected by hemolysis can be discarded from further analysis. The loadings of the ASCA model led to peptide peaks that were most affected by a given factor, for example, to hemoglobin-derived peptides in the case of the hemolysis level. Peak intensity differences for these peptides were assessed by means of extracted ion chromatograms confirming the results of the ASCA model. PMID- 26959229 TI - AUXIN RESPONSE FACTOR 2 Intersects Hormonal Signals in the Regulation of Tomato Fruit Ripening. AB - The involvement of ethylene in fruit ripening is well documented, though knowledge regarding the crosstalk between ethylene and other hormones in ripening is lacking. We discovered that AUXIN RESPONSE FACTOR 2A (ARF2A), a recognized auxin signaling component, functions in the control of ripening. ARF2A expression is ripening regulated and reduced in the rin, nor and nr ripening mutants. It is also responsive to exogenous application of ethylene, auxin and abscisic acid (ABA). Over-expressing ARF2A in tomato resulted in blotchy ripening in which certain fruit regions turn red and possess accelerated ripening. ARF2A over expressing fruit displayed early ethylene emission and ethylene signaling inhibition delayed their ripening phenotype, suggesting ethylene dependency. Both green and red fruit regions showed the induction of ethylene signaling components and master regulators of ripening. Comprehensive hormone profiling revealed that altered ARF2A expression in fruit significantly modified abscisates, cytokinins and salicylic acid while gibberellic acid and auxin metabolites were unaffected. Silencing of ARF2A further validated these observations as reducing ARF2A expression let to retarded fruit ripening, parthenocarpy and a disturbed hormonal profile. Finally, we show that ARF2A both homodimerizes and interacts with the ABA STRESS RIPENING (ASR1) protein, suggesting that ASR1 might be linking ABA and ethylene-dependent ripening. These results revealed that ARF2A interconnects signals of ethylene and additional hormones to co-ordinate the capacity of fruit tissue to initiate the complex ripening process. PMID- 26959232 TI - HPV Serology Testing Confirms High HPV Immunisation Coverage in England. AB - BACKGROUND: Reported human papillomavirus (HPV) vaccination coverage in England is high, particularly in girls offered routine immunisation at age 12 years. Serological surveillance can be used to validate reported coverage and explore variations within it and changes in serological markers over time. METHODS: Residual serum specimens collected from females aged 15-19 years in 2010-2011 were tested for anti-HPV16 and HPV18 IgG by ELISA. Based on these results, females were classified as follows: seronegative, probable natural infection, probable vaccine-induced seropositivity, or possible natural infection/possible vaccine-induced seropositivity. The proportion of females with vaccine-induced seropositivity was compared to the reported vaccination coverage. RESULTS: Of 2146 specimens tested, 1380 (64%) were seropositive for both types HPV16 and HPV18 and 159 (7.4%) positive for only one HPV type. The IgG concentrations were far higher for those positive for both HPV types than those positive for only one HPV type. 1320 (62%) females were considered to have probable vaccine-induced seropositivity. Among vaccine-induced seropositives, antibody concentrations declined with increasing age at vaccination and increasing time since vaccination. CONCLUSIONS: The proportion of females with vaccine-induced seropositivity was closest to the reported 3-dose coverage in those offered the vaccination at younger ages, with a greater discrepancy in the older females. This suggests either some under-reporting of immunisations of older females and/or that partial vaccination (i.e. one- or two-doses) has provided high antibody responses in 13-17 year olds. PMID- 26959231 TI - Detection of Prokaryotic Genes in the Amphimedon queenslandica Genome. AB - Horizontal gene transfer (HGT) is common between prokaryotes and phagotrophic eukaryotes. In metazoans, the scale and significance of HGT remains largely unexplored but is usually linked to a close association with parasites and endosymbionts. Marine sponges (Porifera), which host many microorganisms in their tissues and lack an isolated germ line, are potential carriers of genes transferred from prokaryotes. In this study, we identified a number of potential horizontally transferred genes within the genome of the sponge, Amphimedon queenslandica. We further identified homologs of some of these genes in other sponges. The transferred genes, most of which possess catalytic activity for carbohydrate or protein metabolism, have assimilated host genome characteristics and are actively expressed. The diversity of functions contributed by the horizontally transferred genes is likely an important factor in the adaptation and evolution of A. queenslandica. These findings highlight the potential importance of HGT on the success of sponges in diverse ecological niches. PMID- 26959233 TI - Multisensory Tracking of Objects in Darkness: Capture of Positive Afterimages by the Tactile and Proprioceptive Senses. AB - This paper reports on three experiments investigating the contribution of different sensory modalities to the tracking of objects moved in total darkness. Participants sitting in the dark were exposed to a brief, bright flash which reliably induced a positive visual afterimage of the scene so illuminated. If the participants subsequently move their hand in the darkness, the visual afterimage of that hand fades or disappears; this is presumably due to conflict between the illusory visual afterimage (of the hand in its original location) and other information (e.g., proprioceptive) from a general mechanism for tracking body parts. This afterimage disappearance effect also occurs for held objects which are moved in the dark, and some have argued that this represents a case of body schema extension, i.e. the rapid incorporation of held external objects into the body schema. We demonstrate that the phenomenon is not limited to held objects and occurs in conditions where incorporation into the body schema is unlikely. Instead, we propose that the disappearance of afterimages of objects moved in darkness comes from a general mechanism for object tracking which integrates input from multiple sensory systems. This mechanism need not be limited to tracking body parts, and thus we need not invoke body schema extension to explain the afterimage disappearance. In this series of experiments, we test whether auditory feedback of object movement can induce afterimage disappearance, demonstrate that the disappearance effect scales with the magnitude of proprioceptive feedback, and show that tactile feedback alone is sufficient for the effect. Together, these data demonstrate that the visual percept of a positive afterimage is constructed not just from visual input of the scene when light reaches the eyes, but in conjunction with input from multiple other senses. PMID- 26959234 TI - Risk of Gastrointestinal Cancers among Patients with Appendectomy: A Large-Scale Swedish Register-Based Cohort Study during 1970-2009. AB - BACKGROUND: Removal of the appendix might induce physiological changes in the gastrointestinal tract, and subsequently play a role in carcinogenesis. Therefore, we conducted a nationwide register-based cohort study in Sweden to investigate whether appendectomy is associated with altered risks of gastrointestinal cancers. METHODS: A population-based cohort study was conducted using the Swedish national registries, including 480,382 eligible patients followed during the period of 1970-2009 for the occurrence of site-specific gastrointestinal cancer (esophageal/gastric/colon/rectal cancer). Outcome and censoring information was collected by linkage to health and demography registers. We examined the incidence of appendectomy in Sweden using data from 1987-2009. We also calculated standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) to estimate the relative gastrointestinal cancer risk through comparison to the general population. RESULTS: We noted an overall decrease in the age-standardized incidence of appendectomy among the entire Swedish population from 189.3 to 105.6 per 100,000 individuals between 1987 and 2009. Grouped by different discharge diagnosis, acute appendicitis, incidental appendectomy, and entirely negative appendectomy continuously decreased over the study period, while the perforation ratio (18%-23%) stayed relatively constant. Compared to the general population, no excess cancer risk was observed for gastrointestinal cancers under study with the exception of a marginally elevated risk for esophageal adenocarcinoma (SIR 1.32, 95% CI 1.09-1.58). CONCLUSIONS: In Sweden, the incidence of appendectomy and acute appendicitis has decreased during 1987-2009. No excess gastrointestinal cancer risks were observed among these appendectomized patients, with the possible exception of esophageal adenocarcinoma. PMID- 26959235 TI - Marine Mammal Brucella Reference Strains Are Attenuated in a BALB/c Mouse Model. AB - Brucellosis is a zoonosis of worldwide distribution with numerous animal host species. Since the novel isolation of Brucella spp. from marine mammals in 1994 the bacteria have been isolated from various marine mammal hosts. The marine mammal reference strains Brucella pinnipedialis 12890 (harbour seal, Phoca vitulina) and Brucella ceti 12891 (harbour porpoise, Phocoena phocoena) were included in genus Brucella in 2007, however, their pathogenicity in the mouse model is pending. Herein this is evaluated in BALB/c mice with Brucella suis 1330 as a control. Both marine mammal strains were attenuated, however, B. ceti was present at higher levels than B. pinnipedialis in blood, spleen and liver throughout the infection, in addition B. suis and B. ceti were isolated from brains and faeces at times with high levels of bacteraemia. In B. suis-infected mice serum cytokines peaked at day 7. In B. pinnipedialis-infected mice, levels were similar, but peaked predominantly at day 3 and an earlier peak in spleen weight likewise implied an earlier response. The inflammatory response induced pathology in the spleen and liver. In B. ceti-infected mice, most serum cytokine levels were comparable to those in uninfected mice, consistent with a limited inflammatory response, which also was indicated by restricted spleen and liver pathology. Specific immune responses against all three strains were detected in vitro after stimulation of splenocytes from infected mice with the homologous heat-killed brucellae. Antibody responses in vivo were also induced by the three brucellae. The immunological pattern of B. ceti in combination with persistence in organs and limited pathology has heretofore not been described for other brucellae. These two marine mammal wildtype strains show an attenuated pattern in BALB/c mice only previously described for Brucella neotomea. PMID- 26959236 TI - The Quest for Comparability: Studying the Invariance of the Teachers' Sense of Self-Efficacy (TSES) Measure across Countries. AB - Teachers' self-efficacy is an important motivational construct that is positively related to a variety of outcomes for both the teachers and their students. This study addresses challenges associated with the commonly used 'Teachers' Sense of Self-Efficacy (TSES)' measure across countries and provides a synergism between substantive research on teachers' self-efficacy and the novel methodological approach of exploratory structural equation modeling (ESEM). These challenges include adequately representing the conceptual overlap between the facets of self efficacy in a measurement model (cross-loadings) and comparing means and factor structures across countries (measurement invariance). On the basis of the OECD Teaching and Learning International Survey (TALIS) 2013 data set comprising 32 countries (N = 164,687), we investigate the effects of cross-loadings in the TSES measurement model on the results of measurement invariance testing and the estimation of relations to external constructs (i.e., working experience, job satisfaction). To further test the robustness of our results, we replicate the 32 countries analyses for three selected sub-groups of countries (i.e., Nordic, East and South-East Asian, and Anglo-Saxon country clusters). For each of the TALIS 2013 participating countries, we found that the factor structure of the self efficacy measure is better represented by ESEM than by confirmatory factor analysis (CFA) models that do not allow for cross-loadings. For both ESEM and CFA, only metric invariance could be achieved. Nevertheless, invariance levels beyond metric invariance are better achieved with ESEM within selected country clusters. Moreover, the existence of cross-loadings did not affect the relations between the dimensions of teachers' self-efficacy and external constructs. Overall, this study shows that a conceptual overlap between the facets of self efficacy exists and can be well-represented by ESEM. We further argue for the cross-cultural generalizability of the corresponding measurement model. PMID- 26959238 TI - Initiation of cyp26a1 Expression in the Zebrafish Anterior Neural Plate by a Novel Cis-Acting Element. AB - Early patterning of the vertebrate neural plate involves a complex hierarchy of inductive interactions orchestrated by signalling molecules and their antagonists. The morphogen retinoic acid, together with the Cyp26 enzymes which degrade it, play a central role in this process. The cyp26a1 gene expressed in the anterior neural plate thus contributes to the fine modulation of the rostrocaudal retinoic acid gradient. Despite this important role of cyp26a1 in early brain formation, the mechanisms that control its expression in the anterior neural plate are totally unknown. Here, we present the isolation of a 310-base pair DNA element adjacent to cyp26a1 promoter, displaying enhancer activity restricted to the anterior neural plate of the zebrafish gastrula. We show that unlike that of cyp26a1, expression driven by this cyp26a1 anterior neural plate element (cANE) is independent of retinoic acid. Through deletion analysis, we identify a 12-nucleotide motif essential for cANE activity. A consensus bipartite binding site for SoxB:Oct transcription factors overlaps with this motif. Mutational analysis suggests that SoxB binding is essential for its activity. We discuss the contribution of this study to the elucidation of the regulatory hierarchy involved in early neural plate patterning. PMID- 26959237 TI - Chemical and Hormonal Effects on STAT5b-Dependent Sexual Dimorphism of the Liver Transcriptome. AB - The growth hormone (GH)-activated transcription factor signal transducer and activator of transcription 5b (STAT5b) is a key regulator of sexually dimorphic gene expression in the liver. Suppression of hepatic STAT5b signaling is associated with lipid metabolic dysfunction leading to steatosis and liver cancer. In the companion publication, a STAT5b biomarker gene set was identified and used in a rank-based test to predict both increases and decreases in liver STAT5b activation status/function with high (>= 97%) accuracy. Here, this computational approach was used to identify chemicals and hormones that activate (masculinize) or suppress (feminize) STAT5b function in a large, annotated mouse liver and primary hepatocyte gene expression compendium. Exposure to dihydrotestosterone and thyroid hormone caused liver masculinization, whereas glucocorticoids, fibroblast growth factor 15, and angiotensin II caused liver feminization. In mouse models of diabetes and obesity, liver feminization was consistently observed and was at least partially reversed by leptin or resveratrol exposure. Chemical-induced feminization of male mouse liver gene expression profiles was a relatively frequent phenomenon: of 156 gene expression biosets from chemically-treated male mice, 29% showed feminization of liver STAT5b function, while <1% showed masculinization. Most (93%) of the biosets that exhibited feminization of male liver were also associated with activation of one or more xenobiotic-responsive receptors, most commonly constitutive activated receptor (CAR) or peroxisome proliferator-activated receptor alpha (PPARalpha). Feminization was consistently associated with increased expression of peroxisome proliferator-activated receptor gamma (Pparg) but not other lipogenic transcription factors linked to steatosis. GH-activated STAT5b signaling in mouse liver is thus commonly altered by diverse chemicals, and provides a linkage between chemical exposure and dysregulated gene expression associated with adverse effects on the liver. PMID- 26959239 TI - Tolerability and Pharmacokinetic Evaluation of Inhaled Dry Powder Tobramycin Free Base in Non-Cystic Fibrosis Bronchiectasis Patients. AB - RATIONALE: Bronchiectasis is a condition characterised by dilated and thick walled bronchi. The presence of Pseudomonas aeruginosa in bronchiectasis is associated with a higher hospitalisation frequency and a reduced quality of life, requiring frequent and adequate treatment with antibiotics. OBJECTIVES: To assess local tolerability and the pharmacokinetic parameters of inhaled excipient free dry powder tobramycin as free base administered with the Cyclops dry powder inhaler to participants with non-cystic fibrosis bronchiectasis. The free base and absence of excipients reduces the inhaled powder dose. METHODS: Eight participants in the study were trained in handling the device and inhaling correctly. During drug administration the inspiratory flow curve was recorded. Local tolerability was assessed by spirometry and recording adverse events. Serum samples were collected before, and 15, 30, 45, 60, 75, 90, 105, 120 min; 4, 8 and 12 h after inhalation. RESULTS AND DISCUSSION: Dry powder tobramycin base was well tolerated and mild tobramycin-related cough was reported only once. A good drug dose-serum concentration correlation was obtained. Relatively small inhaled volumes were computed from the recorded flow curves, resulting in presumably substantial deposition in the central airways-i.e., at the site of infection. CONCLUSIONS: In this first study of inhaled dry powder tobramycin free base in non-cystic fibrosis bronchiectasis patients, the free base of tobramycin and the administration with the Cyclops dry powder device were well tolerated. Our data support further clinical studies to evaluate safety and efficacy of this compound in this population. PMID- 26959240 TI - High-Resolution Gene Flow Model for Assessing Environmental Impacts of Transgene Escape Based on Biological Parameters and Wind Speed. AB - Environmental impacts caused by transgene flow from genetically engineered (GE) crops to their wild relatives mediated by pollination are longstanding biosafety concerns worldwide. Mathematical modeling provides a useful tool for estimating frequencies of pollen-mediated gene flow (PMGF) that are critical for assessing such environmental impacts. However, most PMGF models are impractical for this purpose because their parameterization requires actual data from field experiments. In addition, most of these models are usually too general and ignored the important biological characteristics of concerned plant species; and therefore cannot provide accurate prediction for PMGF frequencies. It is necessary to develop more accurate PMGF models based on biological and climatic parameters that can be easily measured in situ. Here, we present a quasi mechanistic PMGF model that only requires the input of biological and wind speed parameters without actual data from field experiments. Validation of the quasi mechanistic model based on five sets of published data from field experiments showed significant correlations between the model-simulated and field experimental-generated PMGF frequencies. These results suggest accurate prediction for PMGF frequencies using this model, provided that the necessary biological parameters and wind speed data are available. This model can largely facilitate the assessment and management of environmental impacts caused by transgene flow, such as determining transgene flow frequencies at a particular spatial distance, and establishing spatial isolation between a GE crop and its coexisting non-GE counterparts and wild relatives. PMID- 26959241 TI - Combinatorial Generation of Chemical Diversity by Redox Enzymes in Chaetoviridin Biosynthesis. AB - Chaetoviridins constitute a large family of structurally related secondary metabolites isolated from Chaetomium fungi. To elucidate the biosynthesis pathway and understand how the chemical diversity of chaetoviridins is generated, gene deletion and in vitro characterization of the four post-PKS modifications enzymes were undertaken. CazL and CazP were identified to have substrate promiscuity that facilitates the formation of nonchlorinated analogues. In addition, enzymatic oxidation and reduction combined with spontaneous dehydration and lactonization of the intermediates further expand the chemical diversity. PMID- 26959242 TI - Efficient Heat-Bath Sampling in Fock Space. AB - We introduce an algorithm for sampling many-body quantum states in Fock space. The algorithm efficiently samples states with probability approximately proportional to an arbitrary function of the second-quantized Hamiltonian matrix element connecting the sampled state to the current state. We apply the new sampling algorithm to the recently developed semistochastic full configuration interaction quantum Monte Carlo (S-FCIQMC) method, a semistochastic implementation of the power method for projecting out the ground state energy in a basis of Slater determinants. Our new sampling method requires modest additional computational time and memory compared to uniform sampling but results in newly spawned weights that are approximately of the same magnitude, thereby greatly improving the efficiency of projection. A comparison in efficiency between our sampling algorithm and uniform sampling is performed on the all electron nitrogen dimer at equilibrium in Dunning's cc-pVXZ basis sets with X ? {D, T, Q, 5}, demonstrating a large gain in efficiency that increases with basis set size. In addition, a comparison in efficiency is performed on three all electron first-row dimers, B2, N2, and F2, in a cc-pVQZ basis, demonstrating that the gain in efficiency compared to uniform sampling also increases dramatically with the number of electrons. PMID- 26959243 TI - Trends and Outcomes of Severe Sepsis in Patients on Maintenance Dialysis. AB - BACKGROUND: Though the incidence of severe sepsis is rising, there is a lack of contemporary information regarding the epidemiology and outcomes of severe sepsis in those on maintenance dialysis. The objectives of this study were to measure the incidence and outcomes of severe sepsis in those on maintenance dialysis. METHODS: Using data from Nationwide Inpatient Sample database from 2005 to 2010, we included all hospitalizations of adults with severe sepsis based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Those on maintenance dialysis were identified by ICD-9-CM codes. We calculated incidence of severe sepsis and mortality. We used logistic regression to assess independent effect of maintenance dialysis status on mortality. RESULTS: Of the estimated 5,000,152 hospitalizations with severe sepsis, 322,734 (6.4%) were on maintenance dialysis. The unadjusted incidence of severe sepsis was 145.4 per 1,000 in those on maintenance dialysis in comparison to 3.5 per 1,000 in the general population. Mortality was higher in those with severe sepsis (30.3 vs. 26.2%; p < 0.001). Maintenance dialysis is an independent predictor of death in those with severe sepsis (OR 1.26; 95% CI 1.23-1.29). CONCLUSIONS: Hospitalizations with severe sepsis are more prevalent and associated with poor outcomes in those on maintenance dialysis. PMID- 26959244 TI - Mutated Huntingtin Causes Testicular Pathology in Transgenic Minipig Boars. AB - BACKGROUND: Huntington's disease is induced by CAG expansion in a single gene coding the huntingtin protein. The mutated huntingtin (mtHtt) primarily causes degeneration of neurons in the brain, but it also affects peripheral tissues, including testes. OBJECTIVE: We studied sperm and testes of transgenic boars expressing the N-terminal region of human mtHtt. METHODS: In this study, measures of reproductive parameters and electron microscopy (EM) images of spermatozoa and testes of transgenic (TgHD) and wild-type (WT) boars of F1 (24-48 months old) and F2 (12-36 months old) generations were compared. In addition, immunofluorescence, immunohistochemistry, Western blot, hormonal analysis and whole-genome sequencing were done in order to elucidate the effects of mtHtt. RESULTS: Evidence for fertility failure of both TgHD generations was observed at the age of 13 months. Reproductive parameters declined and progressively worsened with age. EM revealed numerous pathological features in sperm tails and in testicular epithelium from 24- and 36-month-old TgHD boars. Moreover, immunohistochemistry confirmed significantly lower proliferation activity of spermatogonia in transgenic testes. mtHtt was highly expressed in spermatozoa and testes of TgHD boars and localized in all cells of seminiferous tubules. Levels of fertility-related hormones did not differ in TgHD and WT siblings. Genome analysis confirmed that insertion of the lentiviral construct did not interrupt any coding sequence in the pig genome. CONCLUSIONS: The sperm and testicular degeneration of TgHD boars is caused by gain-of-function of the highly expressed mtHtt. PMID- 26959245 TI - Comparison of Peritoneal Low-Molecular-Weight-Protein-Removal in CCPD and CAPD Patients Based on C-Terminal Agrin Fragment Clearance. AB - BACKGROUND/AIMS: This study compares the peritoneal elimination of the low molecular-weight-protein (LMWP) C-terminal agrin fragment (tCAF, size 22 kDa), a promising biomarker for kidney function, in continuous cycling peritoneal dialysis (CCPD) and continuous ambulatory peritoneal dialysis (CAPD). METHODS: 103 sets of serum, 24h-urine and dialysate samples were obtained in 15 CCPD (63 sets) and 11 CAPD (40 sets) patients. Total, renal and peritoneal substrate removals/clearances were measured/calculated for tCAF, creatinine, blood-urea nitrogen (BUN), cystatin C and albumin and correlated with the peritoneal transport type. RESULTS: Serum und urine concentrations of all biomarkers did not differ between both groups, urinary substrate removal was higher in CAPD patients for all biomarkers due to better residual renal function. Peritoneal substrate removal of tCAF and albumin were significantly higher in CAPD (tCAF: 35.3 vs. 19.3 ug/d, p<0.001; albumin: 4.3 vs. 3.7 g/d, p=0.001), whereas cystatin C and creatinine did not differ between CAPD and CCPD (cystatin: 7.7 vs. 6.1 mg/d, p=0.08, creatinine: 423.9 vs. 456.7 mg/d, p=0.241). BUN was better removed by CCPD (4846.6 vs. 3393.4 mg/d, p<0.001). CAPD patients with high-transporter characteristics had a higher peritoneal tCAF removal compared to high-average transporters (49.8 vs. 28.4 ug/d, p<0.001), no differences could be detected in CCPD patients between these groups. CAPD patients using icodextrin twice/day had higher peritoneal clearance of tCAF compared to once daily (4.4 vs. 2.8 l/wk/1.73 m2 body-surface-area, p<0.001). CONCLUSIONS: CAPD was superior to CCPD concerning peritoneal tCAF removal. This finding was pronounced in high-transporters and CAPD patients using icodextrin twice daily. PMID- 26959246 TI - Structure and Function of Benzylsuccinate Synthase and Related Fumarate-Adding Glycyl Radical Enzymes. AB - The pathway of anaerobic toluene degradation is initiated by a remarkable radical type enantiospecific addition of the chemically inert methyl group to the double bond of a fumarate cosubstrate to yield (R)-benzylsuccinate as the first intermediate, as catalyzed by the glycyl radical enzyme benzylsuccinate synthase. In recent years, it has become clear that benzylsuccinate synthase is the prototype enzyme of a much larger family of fumarate-adding enzymes, which play important roles in the anaerobic metabolism of further aromatic and even aliphatic hydrocarbons. We present an overview on the biochemical properties of benzylsuccinate synthase, as well as its recently solved structure, and present the results of an initial structure-based modeling study on the reaction mechanism. Moreover, we compare the structure of benzylsuccinate synthase with those predicted for different clades of fumarate-adding enzymes, in particular the paralogous enzymes converting p-cresol, 2-methylnaphthalene or n-alkanes. PMID- 26959247 TI - The spectrum of transcatheter mitral valve replacement devices. AB - Mitral regurgitation is the most common valvular heart disease. The gold standard for patients not suitable for valve repair is a surgical valve replacement. A significant proportion of patients, however are not referred for surgery due to comorbidities, advanced age or severe LV dysfunction. Transcatheter mitral valve replacement may be a viable therapeutic option for these high risk patients. With improvements in technology and data on the durability of the transcatheter mitral valve, this technology has the potential to be used in a lower risk population. A number of transcatheter systems have emerged recently and are at different stages of investigation. In this review, we outline the key elements and challenges of the transcatheter mitral valve design as well as the status of devices that have reached First in Man status. PMID- 26959248 TI - Zika: The Tragedy and the Opportunities. PMID- 26959251 TI - Insuring Women in the United States Before, During, and After Pregnancies. PMID- 26959253 TI - Preventing Zika Virus Infections in Pregnant Women: An Urgent Public Health Priority. PMID- 26959254 TI - Mounting Evidence of the Effectiveness and Versatility of Community Health Workers. PMID- 26959255 TI - A Public Health of Consequence: Review of the April 2016 Issue of AJPH. PMID- 26959256 TI - A Call for Global Discussion on Universal Coverage. PMID- 26959257 TI - Aedes Rides Again: Mosquitoes and Flaviviruses in the Americas. PMID- 26959258 TI - Initial Description of the Presumed Congenital Zika Syndrome. AB - OBJECTIVES: To provide an initial description of the congenital syndrome presumably associated with infection by Zika virus compared with other syndromes including congenital infections of established etiologies. METHODS: We provide an overview of a published case series of 35 cases, a clinical series of 104 cases, and published and unpublished reports of clinical and laboratory findings describing cases diagnosed since the beginning of the epidemic of microcephaly in Brazil. RESULTS: About 60% to 70% of mothers report rash during pregnancy; mainly in the first trimester. Principal features are microcephaly, facial disproportionality, cutis girata, hypertonia/spasticity, hyperreflexia, and irritability; abnormal neuroimages include calcifications, ventriculomegaly, and lissencephaly. Hearing and visual abnormalities may be present. CONCLUSIONS: Preliminary data suggest that severe congenital abnormalities are linked to Zika virus infection. Cases have severe abnormalities, and although sharing many characteristics with congenital abnormalities associated with other viral infections, abnormalities presumably linked to the Zika virus may have distinguishing characteristics. These severe neurologic abnormalities may result in marked mental retardation and motor disabilities for many surviving offspring. POLICY IMPLICATIONS: Affected nations need to prepare to provide complex and costly multidisciplinary care that children diagnosed with this new congenital syndrome will require. PMID- 26959259 TI - The Epidemic of Zika Virus-Related Microcephaly in Brazil: Detection, Control, Etiology, and Future Scenarios. AB - We describe the epidemic of microcephaly in Brazil, its detection and attempts to control it, the suspected causal link with Zika virus infection during pregnancy, and possible scenarios for the future. In October 2015, in Pernambuco, Brazil, an increase in the number of newborns with microcephaly was reported. Mothers of the affected newborns reported rashes during pregnancy and no exposure to other potentially teratogenic agents. Women delivering in October would have been in the first trimester of pregnancy during the peak of a Zika epidemic in March. By the end of 2015, 4180 cases of suspected microcephaly had been reported. Zika spread to other American countries and, in February 2016, the World Health Organization declared the Zika epidemic a public health emergency of international concern. This unprecedented situation underscores the urgent need to establish the evidence of congenital infection risk by gestational week and accrue knowledge. There is an urgent call for a Zika vaccine, better diagnostic tests, effective treatment, and improved mosquito-control methods. PMID- 26959261 TI - A Three-Dimensional Action Plan to Raise the Quality of Care of US Correctional Health and Promote Alternatives to Incarceration. PMID- 26959262 TI - On the Distinction--or Lack of Distinction--Between Population Health and Public Health. PMID- 26959260 TI - History, Epidemiology, and Clinical Manifestations of Zika: A Systematic Review. AB - OBJECTIVES: To describe salient epidemiological characteristics of Zika virus outbreaks across the world and to examine the clinical presentations, complications, and atypical manifestations related to their occurrence in recent history. METHODS: We conducted a systematic review of the literature by searching through MEDLINE, Embase, and Global Health Library, as well as the epidemiological bulletins and alerts from the World Health Organization, the Pan American Health Organization, and the European Centre for Disease Prevention and Control over the period 1954 to 2016. RESULTS: The search yielded 547 records. We retained 333 for further analysis, to which we added 11 epidemiological bulletins from various sources. Of these, we systematically reviewed 52 articles and reports, revealing some epidemiological features and patterns of spread of the Zika virus worldwide, as well as pathological outcomes suspected to be linked to Zika outbreaks. Neurologic disorders among zika patients were similar in Brazil and French Polynesia but a causal link is not established. Incidence of zika infection in pregnant women is not known. In Brazil, during the zika outbreak the incidence of microcephaly increased more than 20 times. Among 35 infants with microcephaly, born from women suspected to have Zika infection during pregnancy in northeast Brazil, 74% of the mothers reported rash during the first and second trimester. CONCLUSIONS: On February 1, 2016, The World Health Organization declared the ongoing Zika crisis an emergency and that, although not yet scientifically proven, the link between the virus and growing numbers of microcephaly cases was "strongly suspected." However, the causal relationship between zika and microcephaly is not universally accepted. Public Health Implications. The current situation with regard to Zika is not encouraging, because there is no vaccine, no treatment, and no good serological test, and vector control remains a challenge. PMID- 26959263 TI - Public Health 3.0: Time for an Upgrade. PMID- 26959264 TI - My Walk to Water. PMID- 26959265 TI - Setting the Agenda for a New Discipline: Population Health Science. PMID- 26959266 TI - Affordable Housing: A Key Lever to Community Health for Older Americans. PMID- 26959267 TI - Addressing Health Disparities Is a Place-Based Issue. PMID- 26959268 TI - Keep the Whole City in Mind. PMID- 26959269 TI - Overcrowding and Mortality During the Influenza Pandemic of 1918. AB - The influenza pandemic of 1918 killed more than 50 million people. Why was 1918 such an outlier? I. W. Brewer, a US Army physician at Camp Humphreys, Virginia, during the First World War, investigated several factors suspected of increasing the risk of severe flu: length of service in the army, race, dirty dishes, flies, dust, crowding, and weather. Overcrowding stood out, increasing the risk of flu 10-fold and the risk of flu complicated with pneumonia five-fold. Calculations made with Brewer's data show that the overall relationship between overcrowding and severe flu was highly significant (P < .001). Brewer's findings suggest that man-made conditions increased the severity of the pandemic flu illness. PMID- 26959270 TI - Community Vision and Interagency Alignment: A Community Planning Process to Promote Active Transportation. AB - In 2010, the Brooklyn Active Transportation Community Planning Initiative launched in 2 New York City neighborhoods. Over a 2-year planning period, residents participated in surveys, school and community forums, neighborhood street assessments, and activation events-activities that highlighted the need for safer streets locally. Consensus among residents and key multisectoral stakeholders, including city agencies and community-based organizations, was garnered in support of a planned expansion of bicycling infrastructure. The process of building on community assets and applying a collective impact approach yielded changes in the built environment, attracted new partners and resources, and helped to restore a sense of power among residents. PMID- 26959274 TI - Patterns of Health Insurance Coverage Around the Time of Pregnancy Among Women With Live-Born Infants--Pregnancy Risk Assessment Monitoring System, 29 States, 2009. PMID- 26959275 TI - Garfield Responds. PMID- 26959276 TI - Nepal's Crises Threaten Gains in Public Health. PMID- 26959277 TI - Hypoglycemia and diabetes: increased need for awareness. AB - Hypoglycemia is an abnormally low plasma glucose concentration that may expose individuals to potential harm. It is associated with treatment of type 1 diabetes and type 2 diabetes. Diabetes-related hypoglycemia may result in various complications, reduced quality of life, and increased costs. Hypoglycemia, therefore, impacts patient management and must be considered by primary healthcare practitioners at the forefront of diabetes care. This paper reviews the impact of hypoglycemia on patients and healthcare practitioners in the clinical setting. Recognizing hypoglycemia and its risk factors and identifying high-risk patients can assist with prevention and management. Prevention rather than treatment of hypoglycemia is preferable by individualizing glycemic goals, considering hypoglycemia risk factors, and continuing professional support. Education of patients and healthcare practitioners is also a key factor in hypoglycemia prevention. Although several newer-generation therapies and treatment strategies for type 2 diabetes have a lower risk of hypoglycemia than established agents, long-term safety data are currently lacking. Thus, choice of therapy is important, with hypoglycemic risk varying according to drug selection. PMID- 26959278 TI - Magnetization transfer from inhomogeneously broadened lines (ihMT): Improved imaging strategy for spinal cord applications. AB - PURPOSE: Inhomogeneous magnetization transfer (ihMT) shows great promise for specific imaging of myelinated tissues. Whereas the ihMT technique has been previously applied in brain applications, the current report presents a strategy for cervical spinal cord (SC) imaging free of cerebrospinal fluid (CSF) pulsatility artifacts. METHODS: A pulsed ihMT preparation was combined with a single-shot HASTE readout. Electrocardiogram (ECG) synchronization was used to acquire all images during the quiescent phase of SC motion. However ihMT signal quantification errors may occur when a variable recovery delay is introduced in the sequence as a consequence of variable cardiac cycle. A semiautomatic retrospective correction algorithm, based on repetition time (TR) -matching, is proposed to correct for signal variations of long T1 -components (e.g., CSF). RESULTS: The proposed strategy combining ECG synchronization and retrospective data pairing led to clean SC images free of CSF artifacts. Lower variability of the ihMT metrics were obtained with the correction algorithm, and allowed for shorter TR to be used, hence improving signal-to-noise ratio efficiency. CONCLUSION: The proposed methodology enabled faster acquisitions, while offering robust ihMT quantification and exquisite SC image quality. This opens great perspectives for widening the in vivo characterization of SC physiopathology using MRI, such as studying white matter tracts microstructure or impairment in degenerative pathologies. Magn Reson Med 77:581-591, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26959280 TI - Visualizing fungal metabolites during mycoparasitic interaction by MALDI mass spectrometry imaging. AB - Studying microbial interactions by MALDI mass spectrometry imaging (MSI) directly from growing media is a difficult task if high sensitivity is demanded. We present a quick and robust sample preparation strategy for growing fungi (Trichoderma atroviride, Rhizoctonia solani) on glass slides to establish a miniaturized confrontation assay. By this we were able to visualize metabolite distributions by MALDI MSI after matrix deposition with a home-built sublimation device and thorough recrystallization. We present for the first time MALDI MSI data for secondary metabolite release during active mycoparasitism. PMID- 26959279 TI - Optogenetic and pharmacological evidence that somatostatin-GABA neurons are important regulators of parasympathetic outflow to the stomach. AB - KEY POINTS: The dorsal motor nucleus of the vagus (DMV) in the brainstem consists primarily of vagal preganglionic neurons that innervate postganglionic neurons of the upper gastrointestinal tract. The activity of the vagal preganglionic neurons is predominantly regulated by GABAergic transmission in the DMV. The present findings indicate that the overwhelming GABAergic drive present at the DMV is primarily from somatostatin positive GABA (Sst-GABA) DMV neurons. Activation of both melanocortin and MU-opioid receptors at the DMV inhibits Sst-GABA DMV neurons. Sst-GABA DMV neurons may serve as integrative targets for modulating vagal output activity to the stomach. ABSTRACT: We have previously shown that local GABA signalling in the brainstem is an important determinant of vagally mediated gastric activity. However, the neural identity of this GABA source is currently unknown. To determine this, we focused on the somatostatin positive GABA (Sst-GABA) interneuron in the dorsal motor nucleus of the vagus (DMV), a nucleus that is intimately involved in regulating gastric activity. Also of particular interest was the effect of melanocortin and MU-opioid agonists on neural activity of Sst-GABA DMV neurons because their in vivo administration in the DMV mimics GABA blockade in the nucleus. Experiments were conducted in brain slice preparation of transgenic adult Sst-IRES-Cre mice expressing tdTomato fluorescence, channelrhodopsin-2, archaerhodopsin or GCaMP3. Electrophysiological recordings were obtained from Sst-GABA DMV neurons or DiI labelled gastric-antrum projecting DMV neurons. Our results show that optogenetic stimulation of Sst-GABA neurons results in a robust inhibition of action potentials of labelled premotor DMV neurons to the gastric-antrum through an increase in inhibitory post-synaptic currents. The activity of the Sst-GABA neurons in the DMV is inhibited by both melanocortin and MU-opioid agonists. These agonists counteract the pronounced inhibitory effect of Sst-GABA neurons on vagal pre-motor neurons in the DMV that control gastric motility. These observations demonstrate that Sst-GABA neurons in the brainstem are crucial for regulating the activity of gastric output neurons in the DMV. Additionally, they suggest that these neurons serve as targets for converging CNS signals to regulate parasympathetic gastric function. PMID- 26959282 TI - Structural and functional analysis of tomato beta-galactosidase 4: insight into the substrate specificity of the fruit softening-related enzyme. AB - Plant beta-galactosidases hydrolyze cell wall beta-(1,4)-galactans to play important roles in cell wall expansion and degradation, and turnover of signaling molecules, during ripening. Tomato beta-galactosidase 4 (TBG4) is an enzyme responsible for fruit softening through the degradation of beta-(1,4)-galactan in the pericarp cell wall. TBG4 is the only enzyme among TBGs 1-7 that belongs to the beta-galactosidase/exo-beta-(1,4)-galactanase subfamily. The enzyme can hydrolyze a wide range of plant-derived (1,4)- or 4-linked polysaccharides, and shows a strong ability to attack beta-(1,4)-galactan. To gain structural insight into its substrate specificity, we determined crystal structures of TBG4 and its complex with beta-d-galactose. TBG4 comprises a catalytic TIM barrel domain followed by three beta-sandwich domains. Three aromatic residues in the catalytic site that are thought to be important for substrate specificity are conserved in GH35 beta-galactosidases derived from bacteria, fungi and animals; however, the crystal structures of TBG4 revealed that the enzyme has a valine residue (V548) replacing one of the conserved aromatic residues. The V548W mutant of TBG4 showed a roughly sixfold increase in activity towards beta-(1,6)-galactobiose, and ~0.6 fold activity towards beta-(1,4)-galactobiose, compared with wild-type TBG4. Amino acid residues corresponding to V548 of TBG4 thus appear to determine the substrate specificities of plant beta-galactosidases towards beta-1,4 and beta 1,6 linkages. PMID- 26959281 TI - Concurrent TMPRSS2-ERG and SLC45A3-ERG rearrangements plus PTEN loss are not found in low grade prostate cancer and define an aggressive tumor subset. AB - BACKGROUND: SLC45A3 is the second most common ERG partner in prostate cancer (PrCa). Coexisting TMPRSS2 and SLC45A3 rearrangements are found in a subset of cases, but the meaning is still unknown. METHODS: SLC45A3-ERG and TMPRSS2-ERG rearrangements and their association with ERG and PTEN expression and with clinical and pathological features have been analyzed in 80 PrCa (PSMAR-Biobank, Barcelona, Spain). ERG and PTEN mRNA were assessed by qRT-PCR; TMPRSS2-ERG and SLC45A3-ERG by RT-PCR, FISH, and direct sequencing; and ERG expression by IHC. The endpoints were Gleason score (GS), stage, and PSA progression-free survival. RESULTS: Single TMPRSS2-ERG was found in 51.6% GS <= 7 and 22.2% GS >= 8 tumors (P = 0.027). SLC45A3-ERG was found in 25 cases, 20 of them with concurrent TMPRSS2-ERG rearrangement: 11.5% GS = 6, 22.2% GS = 7, and 50% GS >= 8 tumors (P = 0.013). Double rearrangements were associated with higher levels of ERG mRNA (P = 0.04). Double rearrangement plus PTEN loss was detected in 0% GS = 6; 14.7% GS = 7, and 29.4% GS >= 8 tumors (P = 0.032). Furthermore, this triple change was present in 19.2% stage T3-4 but not in any of stage T2 tumors (P = 0.05). No relationship was found with PSA progression-free survival. CONCLUSIONS: Single TMPRSS2-ERG translocation is associated with low grade PrCa. Subsequent development of SLC45A3-ERG results in higher ERG expression. The combination of double rearrangement plus PTEN loss, according to our series, is never found in low grade, low stage tumors. These findings could be potentially useful in therapeutic decision making in PrCa. Tumors with combined TMPRSS2-ERG/SLC45A3-ERG fusions plus PTEN loss should be excluded from watchful waiting and are candidates for intensive therapy. Prostate 76:854-865, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26959283 TI - A novel corneal explant model system to evaluate antiviral drugs against feline herpesvirus type 1 (FHV-1). AB - Feline herpesvirus type-1 (FHV-1) is the most common viral cause of ocular surface disease in cats. Many antiviral drugs are used to treat FHV-1, but require frequent topical application and most lack well-controlled in vivo studies to justify their clinical use. Therefore, better validation of current and novel treatment options are urgently needed. Here, we report on the development of a feline whole corneal explant model that supports FHV-1 replication and thus can be used as a novel model system to evaluate the efficacy of antiviral drugs. The anti-herpes nucleoside analogues cidofovir and acyclovir, which are used clinically to treat ocular herpesvirus infection in cats and have previously been evaluated in traditional two-dimensional feline cell cultures in vitro, were evaluated in this explant model. Both drugs suppressed FHV-1 replication when given every 12 h, with cidofovir showing greater efficacy. In addition, the potential efficacy of the retroviral integrase inhibitor raltegravir against FHV-1 was evaluated in cell culture as well as in the explant model. Raltegravir was not toxic to feline cells or corneas, and most significantly, inhibited FHV-1 replication at 500 uM in both systems. Importantly, this drug was effective when given only once every 24 h. Taken together, our data indicate that the feline whole corneal explant model is a useful tool for the evaluation of antiviral drugs and, furthermore, that raltegravir appears a promising novel antiviral drug to treat ocular herpesvirus infection in cats. PMID- 26959284 TI - Carbon Nanotube-Based Chemical Sensors. AB - The need to sense gases and vapors arises in numerous scenarios in industrial, environmental, security and medical applications. Traditionally, this activity has utilized bulky instruments to obtain both qualitative and quantitative information on the constituents of the gas mixture. It is ideal to use sensors for this purpose since they are smaller in size and less expensive; however, their performance in the field must match that of established analytical instruments in order to gain acceptance. In this regard, nanomaterials as sensing media offer advantages in sensitivity, preparation of chip-based sensors and construction of electronic nose for selective detection of analytes of interest. This article provides a review of the use of carbon nanotubes in gas and vapor sensing. PMID- 26959285 TI - Addictive Online Games: Examining the Relationship Between Game Genres and Internet Gaming Disorder. AB - Internet gaming disorder (IGD) is the most recent term used to describe problematic or pathological involvement with computer or video games. This study examined whether this disorder is more likely to involve pathological involvement with online (i.e., Internet) games as opposed to offline games. We also explored the addictive potential of nine video game genres by examining the relationship between IGD and 2,720 games played by a sample of 13- to 40-year olds (N = 2,442). Although time spent playing both online and offline games was related to IGD, online games showed much stronger correlations. This tendency is also reflected within various genres. Disordered gamers spent more than four times as much time playing online role-playing games than nondisordered gamers and more than thrice as much time playing online shooters, whereas no significant differences for offline games from these genres were found. Results are discussed within the frame of social interaction and competition provided by online games. PMID- 26959286 TI - Bandgap Engineering of Titanium-Oxo Clusters: Labile Surface Sites Used for Ligand Substitution and Metal Incorporation. AB - Through the labile coordination sites of a robust phosphonate-stabilized titanium oxo cluster, 14 O-donor ligands have been successfully introduced without changing the cluster core. The increasing electron-withdrawing effect of the organic species allows the gradual reduction of the bandgaps of the {Ti6 } complexes. Transition-metal ions are then incorporated by the use of bifunctional O/N-donor ligands, organizing these {Ti6 } clusters into polymeric structures. The coordination environments of the applied metal ions show significant influence on their visible-light adsorption. Both the above structural functionalizations also tune the photocatalytic H2 production activities of these clusters. This work provides a systematic bandgap engineering study of titanium oxo clusters, which is important not only for their future photocatalytic applications, also for the better understanding of the structure-property relationships. PMID- 26959287 TI - Association between cytokine gene polymorphisms and outcome of hepatitis B virus infection in southern Brazil. AB - A number of studies have demonstrated associations between cytokine gene polymorphisms and outcome of hepatitis B virus (HBV) infection. However, no general consensus has been reached, possibly due to differences between ethnic groups. In this study, 345 individuals living in southern Brazil, including 196 chronic HBV carriers and 149 subjects who had spontaneously recovered from acute infection, were enrolled to evaluate the influence of cytokine gene polymorphisms on the outcome of HBV infection. Most participants were of European descent. Genotyping of IL2-330 G/T, IL4-589C/T, IL6-174 G/C, IL10-592C/A, IL10-1082 A/G, IL17A-197 G/A, IL17A-692 T/C, TNF-alpha-238 G/A, and TNF-alpha-308 G/A single nucleotide polymorphisms was performed by using the minisequencing (single base extension) method. By multivariable analysis, a statistically significant association was found between genotypic profile AA + GA in TNF-alpha-308 and chronic HBV infection (OR, 1.82; 95%CI, 1.01-3.27; P = 0.046). In southern Brazil, the carriers of the -308A allele in the TNF-alpha gene promoter have a moderately higher risk of becoming chronic carriers in case of HBV infection. In addition, patients with chronic active hepatitis B (n = 60) exhibited a decreased frequency (3.3%) of the TNF-238A allele when compared to that (14.8%) found among asymptomatic HBV carriers (n = 136), suggesting that this could be a protective factor against liver injury (OR, 0.17; 95%CI, 0.04-0.076; P = 0.023). J. Med. Virol. 88:1759-1766, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26959288 TI - Both low circulating insulin-like growth factor-1 and high-density lipoprotein cholesterol are associated with hair loss in middle-aged women. AB - BACKGROUND: Multiple biomarkers have been associated with hair loss in women, but studies have shown inconsistent results. OBJECTIVES: We investigated the associations between markers of cardiovascular disease risk (e.g. serum lipid levels and hypertension) and ageing [e.g. 25-hydroxyvitamin D and insulin-like growth factor (IGF)] with hair loss in a population of middle-aged women. METHODS: In a random subgroup of 323 middle-aged women (mean age 61.5 years) from the Leiden Longevity Study, hair loss was graded by three assessors using the Sinclair scale; women with a mean score > 1.5 were classified as cases with hair loss. RESULTS: Every 1 SD increase in high-density lipoprotein (HDL) cholesterol was associated with a 0.65-times lower risk [95% confidence interval (CI) 0.46 0.91] of hair loss. For IGF-1 the risk was 0.68 times lower (95% CI 0.48-0.97) per 1 SD increase, independently of the other studied variables. Women with both IGF-1 and HDL cholesterol levels below the medians of the study population had a 3.47-times higher risk (95% CI 1.30-9.25) of having hair loss. CONCLUSIONS: Low HDL cholesterol and IGF-1 were associated with a higher risk of hair loss in women. However, further studies are required to infer causal relationships. PMID- 26959289 TI - The impact of FNAC in the management of salivary gland lesions: Institutional experiences leading to a risk-based classification scheme. AB - BACKGROUND: Fine-needle aspiration cytology (FNAC) has proven its value as an essential step in the diagnosis of salivary gland lesions. Although the majority of salivary gland lesions, especially those that are common and benign, can be diagnosed with ease on FNAC, limited cellularity and morphologic lesion heterogeneity can pose diagnostic challenges and lead to false-positive and false negative diagnoses. This study presents the institutional experience of FNAC of salivary gland lesions from 2 academic centers. METHODS: A retrospective analysis was conducted on 1729 salivary gland FNAC specimens that were diagnosed over an 8 year period from January 2008 to March 2015. All samples were processed either with liquid-based cytology alone or in combination with air-dried, Diff-Quik stained or alcohol-fixed, Papanicolaou-stained smears. RESULTS: Surgical excision was performed in 709 of 1749 FNACs (41%) that were diagnosed as nondiagnostic/inadequate (n = 29), benign (n = 111), neoplasm (n = 453), atypical (n = 15), suspicious for malignancy (n = 28), and malignant (n = 73). The overall concordance between cytologic and histologic diagnoses was 92.2%, with 91.8% concordance in the benign category and 89.5% concordance in cases diagnosed as suspicious for malignancy and malignant. The most frequent benign and malignant lesions were pleomorphic adenoma and squamous cell carcinoma, respectively. There were 46 false-negative and 13 false-positive results, leading to an overall specificity of 97.6% and diagnostic accuracy of 91.3%. CONCLUSIONS: FNAC is a reliable diagnostic modality for the diagnosis and management of salivary gland lesions based on its high specificity and diagnostic accuracy. Cancer Cytopathol 2016;124:388-96. (c) 2016 American Cancer Society. PMID- 26959290 TI - Comparison of Battery-Powered and Manual Bone Biopsy Systems for Core Needle Biopsy of Sclerotic Bone Lesions. AB - OBJECTIVE: The purpose of this study was to compare manual and battery-powered bone biopsy systems for diagnostic yield and procedural factors during core needle biopsy of sclerotic bone lesions. MATERIALS AND METHODS: A total of 155 consecutive CT-guided core needle biopsies of sclerotic bone lesions were performed at one institution from January 2006 to November 2014. Before March 2012, lesions were biopsied with manual bone drill systems. After March 2012, most biopsies were performed with a battery-powered system and either noncoaxial or coaxial biopsy needles. Diagnostic yield, crush artifact, CT procedure time, procedure radiation dose, conscious sedation dose, and complications were compared between the manual and battery-powered core needle biopsy systems by Fisher exact test and t test. One-way ANOVA was used for subgroup analysis of the two battery-powered systems for procedure time and radiation dose. RESULTS: The diagnostic yield for all sclerotic lesions was 60.0% (93/155) and was significantly higher with the battery-powered system (73.0% [27/37]) than with the manual systems (55.9% [66/118]) (p = 0.047). There was no significant difference between the two systems in terms of crush artifact, procedure time, radiation dose, conscious sedation administered, or complications. In subgroup analysis, the coaxial battery-powered biopsies had shorter procedure times (p = 0.01) and lower radiation doses (p = 0.002) than the coaxial manual systems, but the noncoaxial battery-powered biopsies had longer average procedure times and higher radiation doses than the coaxial manual systems. CONCLUSION: In biopsy of sclerotic bone lesions, use of a battery-powered bone drill system improves diagnostic yield over use of a manual system. PMID- 26959292 TI - Neuroanniversary 2016. PMID- 26959293 TI - Greater occipital nerve as target for refractory chronic headaches: from corticosteroid block to invasive neurostimulation and back. PMID- 26959294 TI - Live-in Care Workers in Sheltered Housing for Older Adults in Israel: The New Sheltered Housing Law. AB - Supportive housing schemes were historically aimed to provide group accommodation for older adults. With the aging of residents, facilities were required to enable them to receive care services in order to allow them to age in place. Thus, different countries and different facilities developed different models of housing with care, reflecting cultural and policy diversities. Despite all of the different models, there are many commonalities among the supportive housing schemes across countries. These include provision of dwelling units and care services provided by either the facility or by external agencies. The aims of this article are threefold: to describe the historical development of the ever evolving supportive care housing phenomena; to point at variations in models of housing and care within the international context; and to present a new Israeli model that enables residents to privately hire live-in care workers to meet their care needs. This is a unique model in the international context that has not been reported before. The article describes the main ideas of the new model and discusses the challenges that it raises and pinpoints the unresolved issues associated with the presence of live-in care workers employed by residents of sheltered housing that should be addressed. PMID- 26959295 TI - A Longitudinal Examination of Work-Life Balance in the Collegiate Setting. AB - CONTEXT: The literature regarding work-life balance (WLB) is plentiful, particularly in the National Collegiate Athletic Association Division I collegiate setting due to its demanding nature as defined by work hours and travel. Despite the comprehensive understanding of factors contributing to WLB for athletic trainers (ATs) in this setting, the effect of time of year has yet to be investigated. OBJECTIVE: To determine the influence sport season timing (ie, preseason, in-season, off-season) can have on perceptions and experiences of WLB for ATs. DESIGN: Qualitative, case-study design. SETTING: Division I collegiate practice setting. PATIENTS OR OTHER PARTICIPANTS: Six ATs employed in the Division I college setting (3 women, 3 men) volunteered and completed our study over 1 year. The average age of participants was 31.0 +/- 3 years, and they had 9.0 +/- 3 years of experience. DATA COLLECTION AND ANALYSIS: We conducted semistructured one-on-one phone interviews with each participant at 4 points during the year (August, November, February, June). All interviews were transcribed verbatim. Data were analyzed inductively, and we used peer review, multiple-analyst triangulation, and member checks for credibility. RESULTS: Time of year (eg, competitive in-season), organizational demands (eg, hours and travel), and life stage (eg, roles assumed) were factors that influenced WLB for ATs in the collegiate setting. Having a positive and adaptable mind-set; having coworker, supervisor, and personal support; and engaging in personal or family time were factors that counterbalanced the inhibitors. CONCLUSIONS: Our results indicate that a career as an AT in the collegiate setting can create WLB concerns; these concerns, however, seem to peak during the competitive in-season for the AT's primary coverage team. Additionally, conflict that arises for ATs seems to be stimulated by time, as work roles are often less accommodating due to the athletic atmosphere. PMID- 26959296 TI - Current Health-Related Quality of Life in Former National Collegiate Athletic Association Division I Collision Athletes Compared With Contact and Limited Contact Athletes. AB - CONTEXT: Previous researchers have shown that current health-related quality of life (HRQoL) is lower in former National Collegiate Athletic Association Division I athletes than in nonathletes. However, evidence supports the idea that individuals in collision sports (football) may suffer more serious injuries that may affect them later in life. OBJECTIVE: To measure HRQoL in former Division I collision, contact, and limited-contact athletes. DESIGN: Cross-sectional study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 374 former Division I athletes between the ages of 40 and 65 years were separated into collision, contact, and limited-contact groups. INTERVENTION(S): All individuals completed the Short Form 36 version 2 via a computer. MAIN OUTCOME MEASURES(S): The dependent variables were the physical component and mental component summary scores and the physical functioning, physical role functioning, bodily pain, general health, vitality, social role functioning, emotional role functioning, and mental health scales. An initial multivariate analysis of covariance included data from the 2 domains: physical component and mental component summary scores. The second multivariate analysis of covariance included data from the 8 dimensions: physical function, role physical, bodily pain scale, general health, mental health, role emotional, social function, and vitality scales. The alpha level was set at P < .05 with a covariate of sex. RESULTS: The responses were significantly lower (worse) for the former collision athletes compared with the contact and limited-contact athletes for the summary scores (F2,370 = 90.09, P < .01) and all 8 scales (F8,364 = 24.33, P < .01). The largest differences were between the collision and limited-contact athletes for the bodily pain and role physical scales, with mean differences of 12.91 and 11.80 points, respectively. CONCLUSIONS: Competing at the Division I level can be strenuous on an athlete's physical, mental, and social dimensions, which can affect the athlete later in life. Based on these data, collision athletes may sacrifice their future HRQoL compared with contact and limited-contact athletes. PMID- 26959297 TI - Fatigue and other adverse effects in men treated by pelvic radiation and long term androgen deprivation for locally advanced prostate cancer. AB - Background We compared the development of adverse effects and psychosocial measures from baseline to 36-month follow-up in patients with prostate cancer (T1 3 M0) referred to our department for definitive radiotherapy encompassing the prostate and pelvic lymph nodes (RAD + IMRT) or radiotherapy to the prostatic gland only (RAD), applied with standard adjuvant androgen deprivation (AD) in all patients. Few studies have explored the impact of fatigue on patients' reported quality of life (QoL) after combined therapy for prostate cancer. Material and methods The 206 consecutive eligible men (RAD + IMRT = 64 and RAD = 142) completed the UCLA-PCI questionnaire for adverse effects at baseline, 12, 24, and 36 months. QoL, anxiety and depression, and fatigue were rated at the same time points. Between-group and longitudinal within-group changes at different time points were reported. At 36 months variables associated with fatigue were analyzed with regression analyses. Results Our main novel finding is the long term high level of fatigue and high prevalence of chronic fatigue, affecting patients receiving radiotherapy combined with long-term AD. Except for urinary bother in the RAD + IMRT group all functions and the other bothers mean scores were significantly worse at 36 months compared to baseline. In multivariable analyses only physical QoL remained significantly associated with fatigue at 36 months follow-up. Conclusions Fatigue and impaired QoL in patients considered to curative irradiation with long-term AD should be addressed when counseling men to combined treatment. PMID- 26959298 TI - Implementation of Choice from Participants' Perspectives: A Study of Community Mental Healthcare Reform in Sweden. AB - The aim of this study was to explore participants' experiences and opinions about a free-choice system in relation to policy objectives articulated by the national government and local authorities. A case study was conducted. Thirty-five informants participated. Qualitative interviews were undertaken. Results are discussed on how to address different dimensions of choice, not only where, but also what, by whom, how much, and when. They also concern how to design systems that in some ways ensure predictability and continuity to avoid unwanted harm caused by the unpredictability embedded in competitive choice systems. Finally, different aspects of quality need to be addressed. PMID- 26959299 TI - Older Adults' Experience with a Novel Fall Detection Device. AB - BACKGROUND: Falls are a significant concern for the older adult (OA) population, many of whom are unable to get up following a fall. INTRODUCTION: While many devices exist designed to detect a fall, little work has been conducted to evaluate the usability of such devices. We present a longitudinal usability study of a fall detection (FD) device tested with OAs in real-world settings. MATERIALS AND METHODS: OAs were recruited and asked to use a wearable FD device for up to 4 months. Participants were interviewed at baseline and 2 and 4 months and encouraged to provide direct feedback on their experience. RESULTS: In total, 18 OAs participated in the study. Eight completed the 4-month trial. We conducted a total of 38 interviews (16 baseline, 7 midpoint, and 15 final) and logged a total of 78 comments. While participants enjoyed the GPS and automatic detection features of the device, they were unhappy with the volume of false alarms and obtrusiveness of the device. Many also did not see a great need for having the device or were embarrassed by the device. DISCUSSION: Engineers must work to better develop this technology so that it is accessible to people with hearing loss, limited dexterity, and low vision. Utilizing age-appropriate design techniques will help make such informatics tools more user friendly. CONCLUSION: We explored the usability of a particular FD device with OAs and provide design recommendations to help future device manufacturers create more age-appropriate devices. PMID- 26959308 TI - Zika Virus as a Cause of Neurologic Disorders. PMID- 26959309 TI - The Association of Alanine Aminotransferase in Early Pregnancy with Gestational Diabetes. AB - BACKGROUND: Elevated alanine amino transferase, attributed to nonalcoholic fatty liver, is associated with later development of type 2 diabetes mellitus. We sought to determine whether maternal ALT values are associated with subsequent development of gestational diabetes. METHODS: We performed a nested case-control study utilizing prospectively banked serum samples collected in early gestation. We excluded women with known diabetes, liver disease, or alcohol use. We included 83 cases of gestational diabetes mellitus (GDM) and 247 controls matched for prepregnancy body-mass index (BMI) and compared ALT values. We then performed a conditional logistic regression to model the adjusted odds of GDM in women with ALT >=19 U/L, stratified by prepregnancy BMI. RESULTS: The median (interquartile range) ALT in cases was 15 (12, 19) IU/L compared to 13 (11, 18) IU/L in controls (P = 0.07). Among women with a prepregnancy BMI <30 kg/m(2), ALT >=19 U/L was associated with a fourfold increased odds of GDM (adjusted odds ratio [aOR] 4.56 [1.45, 14.27]), while there was no such association among obese women (aOR 0.36 [0.11, 1.20]). Similarly, each unit increase in log-transformed ALT was associated with a threefold increased odds of GDM in nonobese (aOR 3.15 [1.04,9.54]), but not obese (aOR 3.15 [0.30,3.15]) women. CONCLUSION: The association of high normal ALT and later GDM in nonobese women may reflect the role of hepatic insulin resistance and visceral obesity. PMID- 26959310 TI - Addressing epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small cell lung cancer. AB - Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved the survival of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. However, nearly all EGFR mutant NSCLC tumors eventually acquire resistance to the currently used EGFR-TKIs and subsequently progress clinically. Acquired resistance to EGFR-TKIs is thus a huge issue in the treatment of EGFR-mutant NSCLC at present. On one hand, T790M second-site mutation has been recognized as a key mechanism of EGFR-TKI resistance, and third generation EGFR-TKIs such as osimertinib and rociletinib have been developed to overcome tumor cells harboring the T790M mutation. On the other hand, combination with cytotoxic chemotherapy is also expected as another strategy for preventing the acquired resistance to current EGFR-TKIs and prolonging the survival benefits by EGFR-TKIs. Here, we review updated strategies for preventing or overcoming acquired resistance to EGFR-TKIs. PMID- 26959311 TI - Phytochemical screening and chemical variability in volatile oils of aerial parts of Morinda morindoides. AB - Morinda morindoides is an important Liberian traditional medicine for the treatment of malaria, fever, worms etc. The plant was subjected to integrated approaches including phytochemical screening and gas chromatography mass spectrometry (GC-MS) analyses. Phytochemical investigation of the powdered plant revealed the presence of phenolics, tannins, flavonoids, saponins, terpenes, steroidal compounds and volatile oil. Steam distillation followed by GC-MS resulted in the identification of 47 volatiles in its aerial parts: 28 were in common including various bioactive volatiles. Major constituents of leaves were phytol (43.63%), palmitic acid (8.55%) and geranyl linalool (6.95%) and stem were palmitic acid (14.95%), eicosane (9.67%) and phytol (9.31%), and hence, a significant difference in the percentage composition of aerial parts was observed. To study seasonal changes, similarity analysis was carried out by calculating correlation coefficient (r) and vector angle cosine (z) that were more than 0.91 for stem-to-stem and leaf-to-leaf batches indicating considerable consistency. PMID- 26959312 TI - Feasibility Study of a Contrast-Enhanced Multi-Detector CT (64 Channels) Protocol for Papillary Thyroid Carcinoma: The Influence of Different Scan Delays on Tumor Conspicuity. AB - BACKGROUND: Recently, a number of studies have advocated the diagnostic benefit of contrast-enhanced computed tomography (CECT) in the current ultrasound (US) based preoperative evaluation of thyroid cancer. However, no study has been conducted to optimize a CECT protocol focusing on tumor conspicuity using a multi detector CT scanner. This study aimed at determining the optimal scan delay for increased CT attenuation differences between thyroid cancer and parenchymal background using a biphasic CECT examination. METHODS: This study retrospectively enrolled 84 patients (M:F = 7:77; Mage = 44.8 +/- 10.9 years) with 87 papillary thyroid carcinomas (Msize = 14.1 mm) who consecutively underwent US and CECT examination prior to surgery. In each patient, CT scanning was taken twice-once with a 40-second delay and once with a 70-second delay-using a 64-channel multi detector scanner. After obtaining the mean attenuation value (MAV) of the thyroid cancer and the ipsilateral parenchyma by drawing regions of interest on the CECT images based on their cytopathologic results and US findings, the parenchyma cancer differences (PCD) between the early and delayed scans were simply compared using a paired t-test. Then, the mean differences in the MAVs of the thyroid cancer and ipsilateral parenchyma (hereafter abbreviated as Group) between the early and delayed scans (abbreviated as Time) were compared after adjusting for the other factors that significantly affected MAVs, such as concentration of iodinated contrast medium (abbreviated as CCM) and size of thyroid cancer (abbreviated as Size) using a repeated-measures general linear model. RESULTS: Because the ipsilateral parenchyma exhibited significantly higher attenuation on the early scan and further decline on the delayed scan compared with thyroid cancer (p < 0.001), the PCD for thyroid cancer was significantly better with a 40 second scan delay than a 70-second delay (58.8 +/- 36.6 Hounsfield units [HU] vs. 40.4 +/- 25.6 HU; p < 0.001). Similar results were obtained from the repeated measures general linear model that considered the effects of CCM, Size, Group, and Time, and the interaction of Group and Time. CONCLUSION: Based on this CECT study that adjusted for the effects of CCM and size on MAV, early scans (e.g., 40 second scan delay) are helpful for improving the tumor conspicuity of thyroid cancer on CECT images. PMID- 26959313 TI - Paraconsistents artificial neural networks applied to the study of mutational patterns of the F subtype of the viral strains of HIV-1 to antiretroviral therapy. AB - The high variability of HIV-1 as well as the lack of efficient repair mechanisms during the stages of viral replication, contribute to the rapid emergence of HIV 1 strains resistant to antiretroviral drugs. The selective pressure exerted by the drug leads to fixation of mutations capable of imparting varying degrees of resistance. The presence of these mutations is one of the most important factors in the failure of therapeutic response to medications. Thus, it is of critical to understand the resistance patterns and mechanisms associated with them, allowing the choice of an appropriate therapeutic scheme, which considers the frequency, and other characteristics of mutations. Utilizing Paraconsistents Artificial Neural Networks, seated in Paraconsistent Annotated Logic Et which has the capability of measuring uncertainties and inconsistencies, we have achieved levels of agreement above 90% when compared to the methodology proposed with the current methodology used to classify HIV-1 subtypes. The results demonstrate that Paraconsistents Artificial Neural Networks can serve as a promising tool of analysis. PMID- 26959314 TI - Arsenic toxicity to cladocerans isolated and associated with iron: implications for aquatic environments. AB - Arsenic is an ametal ubiquitous in nature and known by its high toxicity. Many studies have tried to elucidate the arsenic metabolism in the cell and its impact to plants, animals and human health. In aqueous phase, inorganic arsenic is more common and its oxidation state (As III and As V) depends on physical and chemical environmental conditions. The aim of this study was to evaluate toxicity of arsenic to Daphnia similis and Ceriodaphnia silvestrii, isolated and associated with iron. The results showed differences in toxicity of As III and As V to both species. Effective concentration (EC50) mean values were 0.45 mg L-1 (As III) and 0.54 mg L-1 (As V) for D. similis, and 0.44 mg L-1 (As III) and 0.69 mg L-1 (As V) for C. silvestrii. However, As V IC25 mean value was 0.59 mg L-1, indicating that C. silvestrii has mechanisms to reduce arsenic toxicity. On the other hand, when associated with iron at 0.02 and 2.00 mg L-1, EC50 values decreased for D. similis (0.34 and 0.38 mg L-1) as well as C. silvestrii (0.37 and 0.37 mg L-1), showing synergistic effect of these substances. PMID- 26959315 TI - FISH-mapping of the 5S rDNA locus in chili peppers (Capsicum-Solanaceae). AB - We present here the physical mapping of the 5S rDNA locus in six wild and five cultivated taxa of Capsicum by means of a genus-specific FISH probe. In all taxa, a single 5S locus per haploid genome that persistently mapped onto the short arm of a unique metacentric chromosome pair at intercalar position, was found. 5S FISH signals of almost the same size and brightness intensity were observed in all the analyzed taxa. This is the first cytological characterization of the 5S in wild taxa of Capsicum by using a genus-derived probe, and the most exhaustive and comprehensive in the chili peppers up to now. The information provided here will aid the cytomolecular characterization of pepper germplasm to evaluate variability and can be instrumental to integrate physical, genetic and genomic maps already generated in the genus. PMID- 26959316 TI - Improvement on the concentrated grape juice physico-chemical characteristics by an enzymatic treatment and Membrane Separation Processes. AB - In this work, the improvement on the concentrated grape juice physico-chemical characteristics by using an enzymatic treatment followed by Membrane Separation Process (MSP) has been investigated. By using Novozym 33095(r) and Ultrazym AFP L(r) enzymes varying three operating parameters, the best result on the grape pulp characteristics was attained for the Novozym 33095(r) performed at 35oC, 15 min. and 50 mgL-1. In micro/ultra filtration processes after enzymatic pretreatment, the best performance of the MSP with high permeate flux value and suitable grape juice characteristics was attained using 0.05 mm membrane pore size, 1 bar pressure and 40 oC treatment temperature. When reverse osmosis process is operated at 40 bar and 40oC, high soluble solid and low turbidity values are attained. An enzymatic treatment along with MSP has shown an alternative and efficient grape juice processing system, being possible to extend to other foods. PMID- 26959317 TI - Analysis of results of biomass forest inventory in northeastern Amazon for development of REDD+ carbon project. AB - In Brazil, a significant reduction in deforestation rates occurred during the last decade. In spite of that fact, the average annual rates are still too high, approximately 400.000 ha/year (INPE/Prodes). The projects of emissions reduction through avoided deforestation (REED+) are an important tool to reduce deforestation rates in Brazil. Understanding the amazon forest structure, in terms of biomass stock is key to design avoided deforestation strategies. In this work, we analyze data results from aboveground biomass of 1,019.346,27 hectares in the state of Para. It was collected data from 16,722 trees in 83 random independent plots. It was tested 4 allometric equations, for DBH > 10cm: Brown et al. (1989), Brown and Lugo (1999), Chambers et al. (2000), Higuchi et al. (1998). It revealed that the biggest carbon stock of above ground biomass is stocked on the interval at DBH between 30cm and 80cm. This biomass compartment stocks 75.70% of total biomass in Higuchi et al. (1998) equation, 75.56% of total biomass in Brown et al. (1989) equation, 78.83% of total biomass in Chambers et al. (2000) equation, and 73.22% in Brown and Lugo (1999) equation. PMID- 26959318 TI - Post-embriononic development of Chrysomya putoria(Diptera: Calliphoridae) on a diet containing ampicillin in different concentrations. AB - Here we evaluate the effects of different concentrations of the antibiotic ampicillin on the growth and development of Chrysomya putoria. Third-generation, first instar larvae (L1) reared on 60 grams of homogenate+agar 65% were treated with ampicillin sodium. The experiment consisted of four replicates (40 larvae/replicate) of each antibiotic concentration tested (T1: 466ug/mL ; T2: 81.33 mg/mL and T3: 166.66mg/mL) and a T4: control. The body mass of the mature larvae, after they abandoned the diet, were recorded in batches of five. The variation between the mean body mass of larvae and the duration of larval and pupal stages, and overall duration of the development, viability and normal rates were analyzed by ANOVA. There were no significant differences between the four treatments in the following parameters: body mass of larvae that discontinued the diet as well as the duration of larval, pupal, and total development. The sex ratios found in the four treatments did not differ from those expected. Normality rates were 100% for all treatments. There were no significant differences between treatments for larval and overall viability, but pupal viability differed significantly between T1 and the control, T1 and T2, and between the control and T3. The antibiotic did not appear to significantly alter the development of C. putoria. PMID- 26959319 TI - Composition and structure of bird communities in vegetational gradients of Bodoquena Mountains, western Brazil. AB - The informations of bird species distribution in different habitats and the structure of their communities are crucial for bird conservation. We tested the differences in composition, richness and abundance of birds in different phytophysiognomies at Bodoquena Mountains, western Brazil, and we demonstrated the variations in richness and abundance of birds between different trophic groups. Sampling was conducted between July 2011 and June 2012 in 200 point counts arranged in the study area. A total of 3350 contacts were obtained belonging to 156 bird species. Woodland savannas, seasonal forests and arboreal savannas had higher bird abundance and richness, while riparian forests, clean pastures and dirty pastures had smaller values of these parameters. The bird community was organized according to local vegetational gradient, with communities of forests, open areas and savannas, although many species occurred in more than one vegetation type. The insectivorous, omnivorous, frugivorous and gramnivorous birds composed most of the community. These data showed how important environmental heterogeneity is to bird communities. Furthermore, the presence of extensive patches of natural habitats, the small distance between these patches and the permeability of pastures, with high arboreal and shrubby cover, are indicated as important factors to maintain the bird diversity. PMID- 26959320 TI - Interspecific variation in leaf pigments and nutrients of five tree species from a subtropical forest in southern Brazil. AB - The purpose of this study was to analyze the seasonal variation in the nutrient and pigment content of leaves from five tree species - of which three are perennial (Cupania vernalis, Matayba elaeagnoides and Nectandra lanceolata) and two are deciduous (Cedrela fissilis and Jacaranda micrantha) - in an ecotone between a Deciduous Seasonal Forest and a Mixed Ombrophilous Forest in the state of Santa Catarina, Brazil. Leaf samples were collected in the four seasons of the year to determine the content of macronutrients (N, K, P, Mg, Ca, S) and photosynthetic pigments (Chla, Chlb, Chltot, Cartot, Chla:Chlb and Cartot:Chltot). The principal component analysis showed that leaf pigments contributed to the formation of the first axis, which explains most of the data variance for all species, while leaf nutrient contribution showed strong interspecific variation. These results demonstrate that the studied species have different strategies for acquisition and use of mineral resources and acclimation to light, which are determinant for them to coexist in the forest environment. PMID- 26959321 TI - Green method by diffuse reflectance infrared spectroscopy and spectral region selection for the quantification of sulphamethoxazole and trimethoprim in pharmaceutical formulations. AB - An alternative method for the quantification of sulphametoxazole (SMZ) and trimethoprim (TMP) using diffuse reflectance infrared Fourier-transform spectroscopy (DRIFTS) and partial least square regression (PLS) was developed. Interval Partial Least Square (iPLS) and Synergy Partial Least Square (siPLS) were applied to select a spectral range that provided the lowest prediction error in comparison to the full-spectrum model. Fifteen commercial tablet formulations and forty-nine synthetic samples were used. The ranges of concentration considered were 400 to 900 mg g-1SMZ and 80 to 240 mg g-1 TMP. Spectral data were recorded between 600 and 4000 cm-1 with a 4 cm-1 resolution by Diffuse Reflectance Infrared Fourier Transform Spectroscopy (DRIFTS). The proposed procedure was compared to high performance liquid chromatography (HPLC). The results obtained from the root mean square error of prediction (RMSEP), during the validation of the models for samples of sulphamethoxazole (SMZ) and trimethoprim (TMP) using siPLS, demonstrate that this approach is a valid technique for use in quantitative analysis of pharmaceutical formulations. The selected interval algorithm allowed building regression models with minor errors when compared to the full spectrum PLS model. A RMSEP of 13.03 mg g-1for SMZ and 4.88 mg g-1 for TMP was obtained after the selection the best spectral regions by siPLS. PMID- 26959322 TI - Radiation dose determines the method for quantification of DNA double strand breaks. AB - Ionizing radiation induces DNA double strand breaks (DSBs) that trigger phosphorylation of the histone protein H2AX (gammaH2AX). Immunofluorescent staining visualizes formation of gammaH2AX foci, allowing their quantification. This method, as opposed to Western blot assay and Flow cytometry, provides more accurate analysis, by showing exact position and intensity of fluorescent signal in each single cell. In practice there are problems in quantification of gammaH2AX. This paper is based on two issues: the determination of which technique should be applied concerning the radiation dose, and how to analyze fluorescent microscopy images obtained by different microscopes. HTB140 melanoma cells were exposed to gamma-rays, in the dose range from 1 to 16 Gy. Radiation effects on the DNA level were analyzed at different time intervals after irradiation by Western blot analysis and immunofluorescence microscopy. Immunochemically stained cells were visualized with two types of microscopes: AxioVision (Zeiss, Germany) microscope, comprising an ApoTome software, and AxioImagerA1 microscope (Zeiss, Germany). Obtained results show that the level of gammaH2AX is time and dose dependent. Immunofluorescence microscopy provided better detection of DSBs for lower irradiation doses, while Western blot analysis was more reliable for higher irradiation doses. AxioVision microscope containing ApoTome software was more suitable for the detection of gammaH2AX foci. PMID- 26959324 TI - Sward structure and nutritive value of Alexandergrass fertilized with nitrogen. AB - This experiment evaluated forage production, sward structure, stocking rate, weight gain per area and nutritive value of forage as grazed by beef heifers on Alexandergrass (Urochloa plantaginea (Link) Hitch) pasture fertilized with nitrogen (N): 0; 100; 200 or 300 kg of N/ha. The experiment was a completely randomized design following a repeated measurement arrangement. The experimental animals were Angus heifers with initial age and weight of 15 months and 241.5+/-5 kg, respectively. The grazing method was continuous, with put-and-take stocking. N utilization, regardless of the level, increase by 25% the daily forage accumulation rate and the weight gain per area by 23%. The level of 97.2 kg N/ha leads to a higher leaf blade mass and increases by 20% the leaf:stem ratio. Alterations in sward structure changes the nutritive value of forage as grazed. The utilization of 112.7 kg of N/ha allows the highest stocking rate (2049.8 kg of BW/ha), equivalent to 7.5 heifers per hectare. PMID- 26959323 TI - The anti-inflammatory activity of standard aqueous stem bark extract of Mangifera indica L. as evident in inhibition of Group IA sPLA2. AB - The standard aqueous stem bark extract is consumed as herbal drink and used in the pharmaceutical formulations to treat patients suffering from various disease conditions in Cuba. This study was carried out to evaluate the modulatory effect of standard aqueous bark extract of M. indica on Group IA sPLA2. M. indica extract, dose dependently inhibited the GIA sPLA2 (NN-XIa-PLA2) activity with an IC50 value 8.1 ug/ml. M. indica extract effectively inhibited the indirect hemolytic activity up to 98% at ~40 ug/ml concentration and at various concentrations (0-50 ug/ml), it dose dependently inhibited the edema formation. When examined as a function of increased substrate and calcium concentration, there was no relieve of inhibitory effect on the GIA sPLA2. Furthermore, the inhibition was irreversible as evidenced from binding studies. It is observed that the aqueous extract ofM. indica effectively inhibits sPLA2 and it is associated inflammatory activities, which substantiate their anti-inflammatory properties. The mode of inhibition could be due to direct interaction of components present in the extract, with sPLA2 enzyme. Further studies on understanding the principal constituents, responsible for the anti-inflammatory activity would be interesting to develop this into potent anti-inflammatory agent. PMID- 26959325 TI - Evaluation of antioxidant activity of grapevine leaves extracts (Vitis labrusca) in liver of Wistar rats. AB - The aim of this study was to evaluate the hepatoprotection of organic and conventional grapevine leaves extract (Vitis labrusca). The total polyphenol content and the isolate polyphenols by HPLC were evaluate. The animals received intraperitoneal injections of saline or extracts (conventional or organic - 30 mg/kg) for 14 days. On day 15, the rats received carbon tetrachloride (CCl4) or mineral oil (i.p.). After 4h, the animals were euthanized. The analysis of the liver enzymes activity (AST, ALT, GGT) was performed using serum, obtained by blood and the levels of lipid peroxidation (TBARS), protein oxidation (carbonyl), and the activity of antioxidant enzymes superoxide dismutase and catalase were analyzed in the liver. The results showed that the organic extract is richer in polyphenol and resveratrol than the conventional one. Both extracts prevent lipid peroxidation and protein oxidation generated by CCl4. Moreover, the extracts demonstrated ability to modulate the activity of SOD and CAT, as well as to establish a balance in the ratio of SOD/CAT. We also found that the CCl4 increased the levels of AST and GGT, and that both extracts prevent this. These results indicate that grapevine leaves extracts, both, organic and conventional, can prevent liver disorders. PMID- 26959326 TI - Microbial, physical and chemical properties of irrigation water in rice fields of Southern Brazil. AB - This paper presents the results of the statistical analysis of microbiological, physical and chemical parameters related to the quality of the water used in rice fields in Southern Brazil. Data were collected during three consecutive crop years, within structure of a comprehensive monitoring program. The indicators used were: potential hydrogen, electrical conductivity, turbidity, nitrogen, phosphorus, potassium, calcium, total and fecal coliforms. Principal Component and Discriminant Analysis showed consistent differences between the water irrigation and drainage, as the temporal variation demonstrated a clear reduction in the concentration of most of the variables analyzed. The pattern of this reduction is not the same in the two regions - that is, the importance of each of the different variables in the observed differentiation is modified in two locations. These results suggested that the variations in the water quality utilized for rice irrigation was influenced by certain specific aspects of each rice region in South Brazilian - such as anthropic action or soil/climate conditions in each hydrographic basin. PMID- 26959327 TI - Sleep disturbances among Swedish soldiers after military service abroad. AB - Aims Since 1956, more than 100,000 Swedish soldiers have served abroad on various international missions. The aim of this paper was to determine whether there was a connection between military service abroad and sleep disorders among Swedish soldiers. Methods The prevalence of sleep disturbances among 1,080 veterans from Kosovo and Afghanistan was compared with almost 27,000 Swedes from a general population sample, using propensity score matching and logistic regression. The sleep disturbances studied were habitual snoring, difficulty inducing sleep (DIS), difficulty maintaining sleep (DMS), early morning awakenings (EMA), and excessive daytime sleepiness (EDS). Insomnia was defined as having at least one of DIS, DMS, or EMA. The covariates used in the matching and adjustments were age, gender, smoking habits, BMI, education, ever having had asthma, moist snuff, and exercise habits. Results The veterans had a significantly lower prevalence of insomnia (26.2% versus 30.4%) and EDS (22.7% versus 29.4%) compared with a matched group from the reference population, using propensity score matching. Analyses with logistic regression showed that belonging to the military population was related to a lower risk of having DMS (adjusted OR (95% CI) 0.77 (0.64-0.91)), insomnia (OR 0.82 (0.71-0.95)), and EDS (OR 0.74 (0.63-0.86)), whereas no significant difference was found for snoring, DIS, and EMA. Conclusion Swedish veterans have fewer problems with insomnia and daytime sleepiness than the general Swedish population. The explanation of our findings may be the selection processes involved in becoming a soldier and when sampling personnel for military assignments abroad. PMID- 26959328 TI - Competing health policies: insurance against universal public systems. AB - OBJECTIVES: This article analyzes the content and outcome of ongoing health reforms in Latin America: Universal Health Coverage with Health Insurance, and the Universal and Public Health Systems. It aims to compare and contrast the conceptual framework and practice of each and verify their concrete results regarding the guarantee of the right to health and access to required services. It identifies a direct relationship between the development model and the type of reform. The neoclassical-neoliberal model has succeeded in converting health into a field of privatized profits, but has failed to guarantee the right to health and access to services, which has discredited the governments. The reform of the progressive governments has succeeded in expanding access to services and ensuring the right to health, but faces difficulties and tensions related to the permanence of a powerful, private, industrial-insurance medical complex and persistence of the ideologies about medicalized 'good medicine'. Based on these findings, some strategies to strengthen unique and supportive public health systems are proposed. PMID- 26959329 TI - Coverage, universal access and equity in health: a characterization of scientific production in nursing. AB - OBJECTIVES: to characterize the scientific contribution nursing has made regarding coverage, universal access and equity in health, and to understand this production in terms of subjects and objects of study. MATERIAL AND METHODS: this was cross-sectional, documentary research; the units of analysis were 97 journals and 410 documents, retrieved from the Web of Science in the category, "nursing". Descriptors associated to coverage, access and equity in health, and the Mesh thesaurus, were applied. We used bibliometric laws and indicators, and analyzed the most important articles according to amount of citations and collaboration. RESULTS: the document retrieval allowed for 25 years of observation of production, an institutional and an international collaboration of 31% and 7%, respectively. The mean number of coauthors per article was 3.5, with a transience rate of 93%. The visibility index was 67.7%, and 24.6% of production was concentrated in four core journals. A review from the nursing category with 286 citations, and a Brazilian author who was the most productive, are issues worth highlighting. CONCLUSIONS: the nursing collective should strengthen future research on the subject, defining lines and sub-lines of research, increasing internationalization and building it with the joint participation of the academy and nursing community. PMID- 26959330 TI - Nurses' knowledge of universal health coverage for inclusive and sustainable elderly care services. AB - OBJECTIVES: to explore nurses' knowledge of universal health coverage (UHC) for inclusive and sustainable development of elderly care services. METHOD: this was a cross-sectional survey. A convenience sample of 326 currently practicing enrolled nurses (EN) or registered nurses (RN) was recruited. Respondents completed a questionnaire which was based on the implementation strategies advocated by the WHO Global Forum for Governmental Chief Nursing Officers and Midwives (GCNOMs). Questions covered the government initiative, healthcare financing policy, human resources policy, and the respondents' perception of importance and contribution of nurses in achieving UHC in elderly care services. RESULTS: the knowledge of nurses about UHC in elderly care services was fairly satisfactory. Nurses in both clinical practice and management perceived themselves as having more contribution and importance than those in education. They were relatively indifferent to healthcare policy and politics. CONCLUSION: the survey uncovered a considerable knowledge gap in nurses' knowledge of UHC in elderly care services, and shed light on the need for nurses to be more attuned to healthcare policy. The educational curriculum for nurses should be strengthened to include studies in public policy and advocacy. Nurses can make a difference through their participation in the development and implementation of UHC in healthcare services. PMID- 26959331 TI - The contribution of Portuguese nursing to universal health access and coverage. AB - OBJECTIVE: to analyze the contribution of Portuguese nursing to improving universal health access and coverage by means of the identification of nurses in the health system; evolution of health indicators; and access-promoting systems, in which nurses play a relevant role. METHOD: this was documentary research of publications from national and international organizations on planning and health outcomes. Statistical databases and legislation on health reforms were consulted. RESULTS: nurses represent 30.18% of human resources in the national health service; the systems of access promotion performed by nurses have good levels of efficacy (95.5%) and user satisfaction (99% completely satisfied); in the local care the creation of Community Care Units (185) occurred, and 85.80% of home consultations were performed by nurses. CONCLUSION: political strategies, the National Health Service and strengthening of human resources in healthcare are the main determinants. Nursing is the most numerous professional group in the National Health Service, however numbers remain deficient in primary health care. The improvement of academic qualification and self-regulation of this professional group has allowed for better answers in improving health for the Portuguese. PMID- 26959333 TI - Education, leadership and partnerships: nursing potential for Universal Health Coverage. AB - OBJECTIVE: to discuss possibilities of nursing contribution for universal health coverage. METHOD: a qualitative study, performed by means of document analysis of the World Health Organization publications highlighting Nursing and Midwifery within universal health coverage. RESULTS: documents published by nursing and midwifery leaders point to the need for coordinated and integrated actions in education, leadership and partnership development. FINAL CONSIDERATIONS: this article represents a call for nurses, in order to foster reflection and understanding of the relevance of their work on the consolidation of the principles of universal health coverage. PMID- 26959332 TI - Potential access to primary health care: what does the National Program for Access and Quality Improvement data show? AB - OBJECTIVE: to analyze the influence of contextual indicators on the performance of municipalities regarding potential access to primary health care in Brazil and to discuss the contribution from nurses working on this access. METHOD: a multicenter descriptive study based on secondary data from External Evaluation of the National Program for Access and Quality Improvement in Primary Care, with the participation of 17,202 primary care teams. The chi-square test of proportions was used to verify differences between the municipalities stratified based on size of the coverage area, supply, coordination, and integration; when necessary, the chi-square test with Yates correction or Fisher's exact test were employed. For the population variable, the Kruskal-Wallis test was used. RESULTS: the majority of participants were nurses (n=15.876; 92,3%). Statistically significant differences were observed between the municipalities in terms of territory (p=0.0000), availability (p=0.0000), coordination of care (p=0.0000), integration (p=0.0000) and supply (p=0.0000), verifying that the municipalities that make up area 6 tend to have better performance in these dimensions. CONCLUSION: areas 4,5 and 6 performed better in every analyzed dimension, and the nurse had a leading role in the potential to access primary health care in Brazil. PMID- 26959334 TI - Client satisfaction from the perspective of responsiveness: strategy for analysis of universal systems? AB - OBJECTIVE: to analyze patient satisfaction in a Family Health Unit (FHU) of a municipality in the interior of Sao Paulo, Brazil, from the perspective of responsiveness. METHOD: this was a qualitative study with 41 patients of families who used the FHU at least once in the last six months. A semi-structured interview was used for data collection, performed from November of 2010 to January of 2011, focusing on the dimensions of responsiveness: dignity, autonomy, facilities and physical environment, immediate attention, choice, confidentiality, and communication. A thematic analysis was conducted. RESULTS: four themes emerged from the analysis: the health unit environment; access and components of accessibility - favoring the responsiveness?; possibilities of developing a patient - health service staff relationship; and the FHU team - processing care and welcoming. CONCLUSION: responsiveness allows for the tracking and monitoring of non-medical aspects of care of the patients; it contributes to achieving universal coverage, emphasizing the quality of care. PMID- 26959335 TI - RNA G-Quadruplex Invasion and Translation Inhibition by Antisense gamma-Peptide Nucleic Acid Oligomers. AB - We have examined the abilities of three complementary gamma-peptide nucleic acid (gammaPNA) oligomers to invade an RNA G-quadruplex and potently inhibit translation of a luciferase reporter transcript containing the quadruplex-forming sequence (QFS) within its 5'-untranslated region. All three gammaPNA oligomers bind with low nanomolar affinities to an RNA oligonucleotide containing the QFS. However, while all probes inhibit translation with low to midnanomolar IC50 values, the gammaPNA designed to hybridize to the first two G-tracts of the QFS and adjacent 5'-overhanging nucleotides was 5-6 times more potent than probes directed to either the 3'-end or internal regions of the target at 37 degrees C. This position-dependent effect was eliminated after the probes and target were preincubated at an elevated temperature prior to translation, demonstrating that kinetic effects exert significant control over quadruplex invasion and translation inhibition. We also found that antisense gammaPNAs exhibited similarly potent effects against luciferase reporter transcripts bearing QFS motifs having G2, G3, or G4 tracts. Finally, our results indicate that gammaPNA oligomers exhibit selectivity and/or potency higher than those of other antisense molecules such as standard PNA and 2'-OMe RNA previously reported to target G quadruplexes in RNA. PMID- 26959337 TI - TMS-EEG: A window into the neurophysiological effects of transcranial electrical stimulation in non-motor brain regions. AB - Transcranial electrical stimulation (tES) techniques are able to induce changes in cortical excitability and plasticity through the administration of weak currents to the brain and are currently being used to manipulate a vast array of cognitive processes. Despite the widespread use of tES technologies within both research and remedial settings, their precise neurophysiological mechanisms of action are not well established outside of the motor cortex. The expanding use of tES within non-motor brain regions highlights the growing need for a more comprehensive understanding of the effects of stimulation across a diversity of cortical locations. The combination of transcranial magnetic stimulation with electroencephalography (TMS-EEG) provides a method of directly probing both local and widespread changes in brain neurophysiology, through the recording of TMS evoked potentials and cortical oscillations. In this review we explore TMS-EEG as a tool for examining the impact of tES on cortical function and argue that multimodal approaches which combine tES with TMS-EEG could lead to a deeper understanding of the mechanisms which underlie tES-induced cognitive modulation. PMID- 26959338 TI - FimH Antagonists: Phosphate Prodrugs Improve Oral Bioavailability. AB - The widespread occurrence of urinary tract infections has resulted in frequent antibiotic treatment, contributing to the emergence of antimicrobial resistance. Alternative approaches are therefore required. In the initial step of colonization, FimH, a lectin located at the tip of bacterial type 1 pili, interacts with mannosylated glycoproteins on the urothelial mucosa. This initial pathogen/host interaction is efficiently antagonized by biaryl alpha-d mannopyranosides. However, their poor physicochemical properties, primarily resulting from low aqueous solubility, limit their suitability as oral treatment option. Herein, we report the syntheses and pharmacokinetic evaluation of phosphate prodrugs, which show an improved aqueous solubility of up to 140-fold. In a Caco-2 cell model, supersaturated solutions of the active principle were generated through hydrolysis of the phosphate esters by brush border-associated enzymes, leading to a high concentration gradient across the cell monolayer. As a result, the in vivo application of phosphate prodrugs led to a substantially increased Cmax and prolonged availability of FimH antagonists in urine. PMID- 26959339 TI - In vitro digestion of Pickering emulsions stabilized by soft whey protein microgel particles: influence of thermal treatment. AB - Emulsions stabilized by soft whey protein microgel particles have gained research interest due to their combined advantages of biocompatibility and a high degree of resistance to coalescence. We designed Pickering oil-in-water emulsions using whey protein microgels by a facile route of heat-set gel formation followed by mechanical shear and studied the influence of heat treatment on emulsions stabilized by these particles. The aim of this study was to compare the barrier properties of the microgel particles and heat-treated fused microgel particles at the oil-water interface in delaying the digestion of the emulsified lipids using an in vitro digestion model. A combination of transmission electron microscopy and surface coverage measurements revealed an increased coverage of heat-treated microgel particles at the interface. The heat-induced microgel particle aggregation and, therefore, a fused network at the oil-water interface were more beneficial to delay the rate of digestion in the presence of pure lipase and bile salts compared to intact whey protein microgel particles, as shown by the measurements of zeta potential and free fatty acid release, plus theoretical calculations. However, simulated gastric digestion with pepsin impacted significantly on such barrier effects, due to the proteolysis of the particle network at the interface irrespective of the heat treatment, as visualized using sodium dodecyl sulfate polyacryl amide gel electrophoresis measurements. PMID- 26959340 TI - Pd@Cu(II)-MOF-Catalyzed Aerobic Oxidation of Benzylic Alcohols in Air with High Conversion and Selectivity. AB - A new 3D porous Cu(II)-MOF (1) was synthesized based on a ditopic pyridyl substituted diketonate ligand and Cu(OAc)2 in solution, and it features a 3D NbO motif which is determined by the X-ray crystallography. Furthermore, the Pd NPs loaded hybrid material Pd@Cu(II)-MOF (2) was prepared based on 1 via solution impregnation, and its structure was confirmed by HRTEM, SEM, XRPD, gas adsorption desorption, and ICP measurement. 2 exhibits excellent catalytic activity (conversion, 93% to >99%) and selectivity (>99% to benzaldehydes) for various benzyl alcohol substrates (benzyl alcohol and its derivatives with electron withdrawing and electron-donating groups) oxidation reactions in air. In addition, 2 is a typical heterogeneous catalyst, which was confirmed by hot solution leaching experiment, and it can be recycled at least six times without significant loss of its catalytic activity and selectivity. PMID- 26959336 TI - Assessing anhedonia in depression: Potentials and pitfalls. AB - The resurgence of interest in anhedonia within major depression has been fuelled by clinical trials demonstrating its utility in predicting antidepressant response as well as recent conceptualizations focused on the role and manifestation of anhedonia in depression. Historically, anhedonia has been understood as a "loss of pleasure", yet neuropsychological and neurobiological studies reveal a multifaceted reconceptualization that emphasizes different facets of hedonic function, including desire, effort/motivation, anticipation and consummatory pleasure. To ensure generalizability across studies, evaluation of the available subjective and objective methods to assess anhedonia is necessary. The majority of research regarding anhedonia and its neurobiological underpinnings comes from preclinical research, which uses primary reward (e.g. food) to probe hedonic responding. In contrast, behavioural studies in humans primarily use secondary reward (e.g. money) to measure many aspects of reward responding, including delay discounting, response bias, prediction error, probabilistic reversal learning, effort, anticipation and consummatory pleasure. The development of subjective scales to measure anhedonia has also increased in the last decade. This review will assess the current methodology to measure anhedonia, with a focus on scales and behavioural tasks in humans. Limitations of current work and recommendations for future studies are discussed. PMID- 26959342 TI - Stimulated Emission Enhancement Using Shaped Pulses. AB - Controlling stimulated emission is of importance because it competes with absorption and fluorescence under intense laser excitation. We performed resonant nonlinear optical spectroscopy measurements using femtosecond pulses shaped by pi or pi/2-step phase functions and carried out calculations based on density matrix representation to elucidate the experimental results. In addition, we compared enhancements obtained when using other pulse shaping functions (chirp, third-order dispersion, and a time-delayed probe). The light transmitted through the high optical density solution was dominated by an intense stimulated emission feature that was 14 times greater for shaped pulses than for transform limited pulses. Coherent enhancement depending on the frequency, temporal, and phase characteristics of the shaped pulse is responsible for the experimental observations. PMID- 26959343 TI - Transparent actuators and robots based on single-layer superaligned carbon nanotube sheet and polymer composites. AB - Transparent actuators have been attracting emerging interest recently, as they demonstrate potential applications in the fields of invisible robots, tactical displays, variable-focus lenses, and flexible cellular phones. However, previous technologies did not simultaneously realize macroscopic transparent actuators with advantages of large-shape deformation, low-voltage-driven actuation and fast fabrication. Here, we develop a fast approach to fabricate a high-performance transparent actuator based on single-layer superaligned carbon nanotube sheet and polymer composites. Various advantages of single-layer nanotube sheets including high transparency, considerable conductivity, and ultra-thin dimensions together with selected polymer materials completely realize all the above required advantages. Also, this is the first time that a single-layer nanotube sheet has been used to fabricate actuators with high transparency, avoiding the structural damage to the single-layer nanotube sheet. The transparent actuator shows a transmittance of 72% at the wavelength of 550 nm and bends remarkably with a curvature of 0.41 cm(-1) under a DC voltage for 5 s, demonstrating a significant advance in technological performances compared to previous conventional actuators. To illustrate their great potential usage, a transparent wiper and a humanoid robot "hand" were elaborately designed and fabricated, which initiate a new direction in the development of high-performance invisible robotics and other intelligent applications with transparency. PMID- 26959344 TI - Li(+) Local Structure in Hydrofluoroether Diluted Li-Glyme Solvate Ionic Liquid. AB - Hydrofluoroethers have recently been used as the diluent to a lithium battery electrolyte solution to increase and decrease the ionic conductivity and the solution viscosity, respectively. In order to clarify the Li(+) local structure in the 1,1,2,2-tetrafluoroethyl 2,2,3,3-tetrafluoropropyl ether (HFE) diluted [Li(G4)][TFSA] (G4, tetraglyme; TFSA, bis(trifluoromethanesulfonyl)amide) solvate ionic liquid, Raman spectroscopic study has been done with the DFT calculations. It has turned out that the HFE never coordinates to the Li(+) directly, and that the solvent (G4) shared ion pair of Li(+) with TFSA anion (SSIP) and the contact ion pair between Li(+) and TFSA anion (CIP) are found in the neat and HFE diluted [Li(G4)][TFSA] solvate ionic liquid. It is also revealed that the two kinds of the CIP in which TFSA anion coordinates to the Li(+) in monodentate and bidentate manners (hereafter, we call them the monodentate CIP and the bidentate CIP, respectively) exist with the SSIP of predominant [Li(G4)](+) ion-pair species in the neat [Li(G4)][TFSA] solvate ionic liquid, and that the monodentate CIP decreases as diluting with the HFE. To obtain further insight, X-ray total scattering experiments (HEXTS) were carried out with the aid of MD simulations, where the intermolecular force field parameters, mainly partial atomic charges, have been newly proposed for the HFE and glymes. A new peak appeared at around 0.6-0.7 A(-1) in X-ray structure factors, which was ascribed to the correlation between the [Li(G4)][TFSA] ion pairs. Furthermore, MD simulations were in good agreement with the experiments, from which it is suggested that the terminal oxygen atoms of the G4 in [Li(G4)](+) solvated cation frequently repeat coordinating/uncoordinating to the Li(+), although almost all of the G4 coordinates to the Li(+) to form [Li(G4)](+) solvated cation in the neat and HFE diluted [Li(G4)][TFSA] solvate ionic liquid. PMID- 26959345 TI - Interplay between Nanochannel and Microchannel Resistances. AB - Current nanochannel system paradigm commonly neglects the role of the interfacing microchannels and assumes that the ohmic electrical response of a microchannel nanochannel system is solely determined by the geometric properties of the nanochannel. In this work, we demonstrate that the overall response is determined by the interplay between the nanochannel resistance and various microchannel attributed resistances. Our experiments confirm a recent theoretical prediction that in contrast to what was previously assumed at very low concentrations the role of the interfacing microchannels on the overall resistance becomes increasingly important. We argue that the current nanochannel-dominated conductance paradigm can be replaced with a more correct and intuitive microchannel-nanochannel-resistance-model-based paradigm. PMID- 26959346 TI - The Influence of Minimalist and Maximalist Footwear on Patellofemoral Kinetics During Running. AB - The current study aimed to comparatively examine the effects of minimalist, maximalist, and conventional footwear on the loads experienced by the patellofemoral joint during running. Twenty male participants ran over a force platform at 4.0 m*s-1. Lower limb kinematics were collected using an 8-camera motion capture system allowing patellofemoral kinetics to be quantified using a musculoskeletal modeling approach. Differences in patellofemoral kinetic parameters were examined using one-way repeated-measures ANOVA. The results showed the peak patellofemoral force and pressure were significantly larger in conventional (4.70 +/- 0.91 BW, 13.34 +/- 2.43 MPa) and maximalist (4.74 +/- 0.88 BW, 13.59 +/- 2.63 MPa) compared with minimalist footwear (3.87 +/- 1.00 BW, 11.59 +/- 2.63 MPa). It was also revealed that patellofemoral force per mile was significantly larger in conventional (246.81 +/- 53.21 BW) and maximalist (251.94 +/- 59.17 BW) as compared with minimalist (227.77 +/- 58.60 BW) footwear. As excessive loading of the patellofemoral joint has been associated with the etiology of patellofemoral pain symptoms, the current investigation indicates that minimalist footwear may be able reduce runners' susceptibility to patellofemoral disorders. PMID- 26959347 TI - Transabdominal Cerclage. AB - The transabdominal cerclage procedure was first introduced 50 years ago as an approach in those patients who had failed transvaginal cerclage. We review the history, indications, surgical technique, complications, and reported outcomes of the procedure. The procedure has evolved over time in its application and risks appear to be less than previously perceived. Physicians have found additional patient situations in which the procedure may be beneficial outside the indications defined 50 years ago. This is a valuable surgical technique which is likely underused. PMID- 26959348 TI - PICU Volume and Outcome: A Severity-Adjusted Analysis. AB - OBJECTIVES: To determine the relationship between PICU volume and severity adjusted mortality in a large, national dataset. DESIGN: Retrospective cohort study. SETTING: The VPS database (VPS, LLC, Los Angeles, CA), a national multicenter clinical PICU database. PATIENTS: All patients with discharge dates between September 2009 and March 2012 and valid Pediatric Index of Mortality 2 and Pediatric Risk of Mortality III scores, who were not transferred to another ICU and were seen in an ICU that collected at least three quarters of data. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Anonymized data received included ICU mortality, hospital and patient demographics, and Pediatric Index of Mortality 2 and Pediatric Risk of Mortality III scores. PICU volume/quarter was determined (VPS sites submit data quarterly) per PICU and was divided by 100 to assess the impact per 100 discharges per quarter (volume). A mixed-effects logistic regression model accounting for repeated measures of patients within ICUs was performed to assess the association of volume on severity-adjusted mortality, adjusting for patient and unit characteristics. Multiplicative interactions between volume and severity of illness were also modeled. We analyzed 186,643 patients from 92 PICUs, with an overall ICU mortality rate of 2.6%. Volume ranged from 0.24 to 8.89 per ICU per quarter; the mean volume was 2.61. The mixed-effects logistic regression model found a small but nonlinear relationship between volume and mortality that varied based on the severity of illness. When severity of illness is low, there is no clear relationship between volume and mortality up to a Pediatric Index of Mortality 2 risk of mortality of 10%; for patients with a higher severity of illness, severity of illness-adjusted mortality is directly proportional to a unit's volume. CONCLUSIONS: For patients with low severity of illness, ICU volume is not associated with mortality. As patient severity of illness rises, higher volume units have higher severity of illness-adjusted mortality. This may be related to differences in quality of care, issues with unmeasured confounding, or calibration of existing severity of illness scores. PMID- 26959349 TI - Epidemiology of Polypharmacy and Potential Drug-Drug Interactions Among Pediatric Patients in ICUs of U.S. Children's Hospitals. AB - OBJECTIVES: Polypharmacy is common in hospitalized children in the United States and has been identified as a major risk factor for exposure to potential drug drug interactions. Little is known about the characteristics and prevalence of exposure of pediatric patients to polypharmacy and potential drug-drug interactions in PICUs. DESIGN: Retrospective cohort study using the Pediatric Health Information System database. SETTING: Forty-two freestanding children's hospitals throughout the United States. PATIENTS: A total of 54,549 patients less than 18 years old cared for in PICUs in 2011. Patients in neonatal ICUs were not included. MEASUREMENTS AND MAIN RESULTS: PICU patients were on average exposed to 10 distinct drugs each hospital day and to 20 drugs cumulatively during their hospitalization. Seventy-five percent of patients were exposed to greater than or equal to one potential drug-drug interaction regardless of severity level, 6% to greater than or equal to one contraindicated potential drug-drug interaction, 69% to greater than or equal to one major potential drug-drug interaction, 57% to greater than or equal to one moderate potential drug-drug interaction, 19% to greater than or equal to one minor potential drug-drug interaction. Potential drug-drug interaction exposures were significantly associated with specific diagnoses (p < 0.001), presence of complex chronic conditions (p < 0.001), increasing number of total distinct drugs used (p < 0.001), increasing length of stay in PICU (p < 0.001), and white race (p < 0.001). CONCLUSIONS: Many PICU patients are exposed to substantial polypharmacy and potential drug-drug interactions. Future research should identify the risk of adverse drug events following specific potential drug-drug interaction exposures, especially the risk of adverse drug events due to multiple potential drug-drug interaction exposures, and determine the probability and magnitude of the actual harm (if any) for each specific potential drug-drug interaction, especially for multiple potential drug drug interaction exposures. PMID- 26959350 TI - Increased Photoconductivity Lifetime in GaAs Nanowires by Controlled n-Type and p Type Doping. AB - Controlled doping of GaAs nanowires is crucial for the development of nanowire based electronic and optoelectronic devices. Here, we present a noncontact method based on time-resolved terahertz photoconductivity for assessing n- and p-type doping efficiency in nanowires. Using this technique, we measure extrinsic electron and hole concentrations in excess of 10(18) cm(-3) for GaAs nanowires with n-type and p-type doped shells. Furthermore, we show that controlled doping can significantly increase the photoconductivity lifetime of GaAs nanowires by over an order of magnitude: from 0.13 ns in undoped nanowires to 3.8 and 2.5 ns in n-doped and p-doped nanowires, respectively. Thus, controlled doping can be used to reduce the effects of parasitic surface recombination in optoelectronic nanowire devices, which is promising for nanowire devices, such as solar cells and nanowire lasers. PMID- 26959351 TI - Factors Associated with Nursing Activities in Humanitarian Aid and Disaster Relief. AB - BACKGROUND: Although nurses play an important role in humanitarian aid and disaster relief (HA/DR), little is known about the nursing activities that are performed in HA/DR. We aimed to clarify the nursing activities performed by Japanese nurses in HA/DR and to examine the factors associated with the frequency of nursing activities. METHODS: A self-administered questionnaire survey was completed by 147 nurses with HA/DR experience. The survey extracted information on demographic characteristics, past experience (e.g., disaster medical training experience, HA/DR experience), circumstances surrounding their dispatched to HA/DR (e.g., team size, disaster type, post-disaster phase, mission term), and the frequency of nursing activities performed under HA/DR. The frequency of nursing activities was rated on a 5-point Likert scale. Evaluation of nursing activities was conducted based on the "nursing activity score", which represents the frequency of each nursing activity. Factors related to the nursing activity score were evaluated by multiple logistic regression analysis. RESULTS: Nurses were involved in 27 nursing activities in HA/DR, 10 of which were performed frequently. On analysis, factors significantly associated with nursing activity score were nursing license as a registered nurse (OR 7.79, 95% CI 2.95-20.57), two or more experiences with disaster medical training (OR 2.90 95%, CI 1.12 7.49) and a post-disaster phase of three weeks or longer (OR 8.77, 95% CI 2.59 29.67). CONCLUSIONS: These results will contribute to the design of evidence based disaster medical training that improves the quality of nursing activities. PMID- 26959352 TI - Vulvar intraepithelial neoplasia: clinical presentation, management and outcomes in women infected with HIV. AB - OBJECTIVE: Immunocompromised patients are at increased risk of developing preinvasive lesions of the lower genital tract. There are a limited number of studies on vulvar intraepithelial neoplasia (VIN) in HIV-positive women. We aimed to review the clinical presentation of VIN, management and survival outcomes in this group of patients. DESIGN: Observational cohort study. METHODS: Data was collected from women diagnosed with VIN at the Hospital Vall d'Hebron between September 1994 and October 2011. The main outcome measures were recurrence-free survival (RFS) and progression-free survival (PFS). Risk factors for recurrence and progression were assessed using univariate and multivariate analyses. RESULTS: Thirty-seven out of 107 women were HIV positive (34.6%). The median follow-up time was 32 (range 12-179) months. Compared with the HIV-negative group, HIV-positive women were younger (median age 37 vs. 44 years, P = 0.003) and presented with multifocal and multicentric disease more frequently (63.6 vs. 22.2% and 84.8 vs. 43.3%, respectively, P < 0.0001). RFS and PFS were lower in the HIV-positive group (42.4 vs. 71.4% P = 0.043 and 69.7 vs. 95.2% P = 0.006, respectively). RFS was significantly associated to multicentric and multifocal disease on multivariate analysis. PFS was associated to HIV infection on univariate analysis. CONCLUSION: HIV-positive women are at increased risk of developing VIN and frequently present at a younger age with multifocal and multicentric disease. They have shorter RFS and PFS compared with HIV-negative women. Close surveillance of the lower genital tract is mandatory to enable early recognition and treatment of any suspicious lesions. Close follow-up after treatment of VIN is essential to exclude early recurrence or progression. PMID- 26959355 TI - Strengthening universal HIV 'test-and-treat' approaches with social science research. PMID- 26959356 TI - Raltegravir is safely used with long-term viral suppression for HIV-infected patients on hemodialysis: a pharmacokinetic study. PMID- 26959353 TI - Prevalence of and progression to abnormal noninvasive markers of liver disease (aspartate aminotransferase-to-platelet ratio index and Fibrosis-4) among US HIV infected youth. AB - OBJECTIVE: To longitudinally characterize noninvasive markers of liver disease in HIV-infected youth. DESIGN: HIV infection, without viral hepatitis coinfection, may contribute to liver disease. Noninvasive markers of liver disease [FIB-4 (Fibrosis-4) and APRI (aspartate aminotransferase-to-platelet ratio index)] have been evaluated in adults with concomitant HIV and hepatitis C, but are less studied in children. METHODS: In prospective cohorts of HIV-infected and HIV uninfected youth, we used linear regression models to compare log-transformed FIB 4 and APRI measures by HIV status based on a single visit at ages 15-20 years. We also longitudinally modeled trends in these measures in HIV-infected youth with two or more visits to compare those with behavioral vs. perinatal HIV infection (PHIV) using mixed effect linear regression, adjusting for age, sex, body mass index, and race/ethnicity. RESULTS: Of 1785 participants, 41% were men, 57% black non-Hispanic, and 27% Hispanic. More HIV-infected than uninfected youth had an APRI score more than 0.5 (13 vs. 3%, P < 0.001). Among 1307 HIV-infected participants with longitudinal measures, FIB-4 scores increased 6% per year (P < 0.001) among all HIV-infected youth, whereas APRI scores increased 2% per year (P = 0.007) only among PHIV youth. The incidence rates (95% confidence interval) of progression of APRI to more than 0.5 and more than 1.5 were 7.5 (6.5-8.7) and 1.4 (1.0-1.9) cases per 100 person-years of follow-up, respectively. The incidence of progression of FIB-4 to more than 1.5 and more than 3.25 were 1.6 (1.2-2.2) and 0.3 (0.2-0.6) cases per 100 person-years, respectively. CONCLUSION: APRI and FIB 4 scores were higher among HIV-infected youth. Progression to scores suggesting subclinical fibrosis or worse was common. PMID- 26959354 TI - CD4+/CD8+ ratio, age, and risk of serious noncommunicable diseases in HIV infected adults on antiretroviral therapy. AB - OBJECTIVE: In virologically suppressed HIV-infected adults, noncommunicable diseases (NCDs) have been associated with immune senescence and low CD4/CD8 lymphocyte ratio. Age differences in the relationship between CD4/CD8 ratio and NCDs have not been described. DESIGN: Observational cohort study. METHODS: We assessed CD4/CD8 ratio and incident NCDs (cardiovascular, cancer, liver, and renal diseases) in HIV-infected adults started on antiretroviral therapy between 1998 and 2012. Study inclusion began once patients maintained virologic suppression for 12 months (defined as baseline). We examined age and baseline CD4/CD8 ratio and used Cox proportional hazard models to assess baseline CD4/CD8 ratio and NCDs. RESULTS: This study included 2006 patients. Low baseline CD4/CD8 ratio was associated with older age, male sex, and low CD4 lymphocyte counts. In models adjusting for CD4 lymphocyte count, CD4/CD8 ratio was inversely associated with age (P < 0.01). Among all patients, 182 had incident NCDs, including 46 with coronary artery disease (CAD) events. CD4/CD8 ratio was inversely associated with risk of CAD events [adjusted HR per 0.1 increase in CD4/CD8 ratio = 0.87, 95% confidence interval (CI): 0.76-0.99, P = 0.03]. This association was driven by those under age 50 years (adjusted HR 0.83 [0.70-0.97], P = 0.02) vs. those over age 50 years (adjusted HR = 0.96 [0.79-1.18], P = 0.71). CD4/CD8 ratio was not significantly associated with incident noncardiac NCDs. CONCLUSIONS: Higher CD4/CD8 ratio after 1 year of HIV virologic suppression was independently predictive of decreased CAD risk, particularly among younger adults. Advanced immune senescence may contribute to CAD events in younger HIV patients on antiretroviral therapy. PMID- 26959357 TI - Subdominant Gag-specific anti-HIV efficacy in an HLA-B*57-positive elite controller. PMID- 26959358 TI - Water-in-Water Droplets by Passive Microfluidic Flow Focusing. AB - We present a simple microfluidic system that generates water-in-water, aqueous two phase system (ATPS) droplets, by passive flow focusing. ATPS droplet formation is achieved by applying weak hydrostatic pressures, with liquid-filled pipette tips as fluid columns at the inlets, to introduce low speed flows to the flow focusing junction. To control the size of the droplets, we systematically vary the interfacial tension and viscosity of the ATPS fluids and adjust the fluid column height at the fluid inlets. The size of the droplets scales with a power law of the ratio of viscous stresses in the two ATPS phases. Overall, we find a drop size coefficient of variation (CV; i.e., polydispersity) of about 10%. We also find that when drops form very close to the flow focusing junction, the drops have a CV of less than 1%. Our droplet generation method is easily scalable: we demonstrate a parallel system that generates droplets simultaneously and improves the droplet production rate by up to one order of magnitude. Finally, we show the potential application of our system for encapsulating cells in water-in-water emulsions by encapsulating microparticles and cells. To the best of our knowledge, our microfluidic technique is the first that forms low interfacial tension ATPS droplets without applying external perturbations. We anticipate that this simple approach will find utility in drug and cell delivery applications because of the all-biocompatible nature of the water-in-water ATPS environment. PMID- 26959359 TI - Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Cyclic ADP-Ribose (cADPR) Mediate Ca2+ Signaling in Cardiac Hypertrophy Induced by beta-Adrenergic Stimulation. AB - Ca2+ signaling plays a fundamental role in cardiac hypertrophic remodeling, but the underlying mechanisms remain poorly understood. We investigated the role of Ca2+-mobilizing second messengers, NAADP and cADPR, in the cardiac hypertrophy induced by beta-adrenergic stimulation by isoproterenol. Isoproterenol induced an initial Ca2+ transients followed by sustained Ca2+ rises. Inhibition of the cADPR pathway with 8-Br-cADPR abolished only the sustained Ca2+ increase, whereas inhibition of the NAADP pathway with bafilomycin-A1 abolished both rapid and sustained phases of the isoproterenol-mediated signal, indicating that the Ca2+ signal is mediated by a sequential action of NAADP and cADPR. The sequential production of NAADP and cADPR was confirmed biochemically. The isoproterenol mediated Ca2+ increase and cADPR production, but not NAADP production, were markedly reduced in cardiomyocytes obtained from CD38 knockout mice. CD38 knockout mice were rescued from chronic isoproterenol infusion-induced myocardial hypertrophy, interstitial fibrosis, and decrease in fractional shortening and ejection fraction. Thus, our findings indicate that beta-adrenergic stimulation contributes to the development of maladaptive cardiac hypertrophy via Ca2+ signaling mediated by NAADP-synthesizing enzyme and CD38 that produce NAADP and cADPR, respectively. PMID- 26959360 TI - Oral Administration of p-Hydroxycinnamic Acid Attenuates Atopic Dermatitis by Downregulating Th1 and Th2 Cytokine Production and Keratinocyte Activation. AB - Atopic dermatitis (AD) is a complex disease that is caused by various factors, including environmental change, genetic defects, and immune imbalance. We previously showed that p-hydroxycinnamic acid (HCA) isolated from the roots of Curcuma longa inhibits T-cell activation without inducing cell death. Here, we demonstrated that oral administration of HCA in a mouse model of ear AD attenuates the following local and systemic AD manifestations: ear thickening, immune-cell infiltration, production of AD-promoting immunoregulatory cytokines in ear tissues, increased spleen and draining lymph node size and weight, increased pro-inflammatory cytokine production by draining lymph nodes, and elevated serum immunoglobulin production. HCA treatment of CD4+ T cells in vitro suppressed their proliferation and differentiation into Th1 or Th2 and their Th1 and Th2 cytokine production. HCA treatment of keratinocytes lowered their production of the pro-inflammatory cytokines that drive either Th1 or Th2 responses in AD. Thus, HCA may be of therapeutic potential for AD as it acts by suppressing keratinocyte activation and downregulating T-cell differentiation and cytokine production. PMID- 26959361 TI - Anteroposterior Limb Skeletal Patterning Requires the Bifunctional Action of SWI/SNF Chromatin Remodeling Complex in Hedgehog Pathway. AB - Graded Sonic hedgehog (Shh) signaling governs vertebrate limb skeletal patterning along the anteroposterior (AP) axis by regulating the activity of bifunctional Gli transcriptional regulators. The genetic networks involved in this patterning are well defined, however, the epigenetic control of the process by chromatin remodelers remains unknown. Here, we report that the SWI/SNF chromatin remodeling complex is essential for Shh-driven limb AP patterning. Specific inactivation of Srg3/mBaf155, a core subunit of the remodeling complex, in developing limb buds hampered the transcriptional upregulation of Shh/Gli target genes, including the Shh receptor Ptch1 and its downstream effector Gli1 in the posterior limb bud. In addition, Srg3 deficiency induced ectopic activation of the Hedgehog (Hh) pathway in the anterior mesenchyme, resulting in loss of progressive asymmetry. These defects in the Hh pathway accompanied aberrant BMP activity and disruption of chondrogenic differentiation in zeugopod and autopod primordia. Notably, our data revealed that dual control of the Hh pathway by the SWI/SNF complex is essential for spatiotemporal transcriptional regulation of the BMP antagonist Gremlin1, which affects the onset of chondrogenesis. This study uncovers the bifunctional role of the SWI/SNF complex in the Hh pathway to determine the fate of AP skeletal progenitors. PMID- 26959362 TI - Functional Visual Acuity of Early Presbyopia. AB - PURPOSE: To evaluate visual function in patients with early presbyopia using the functional visual acuity (FVA) test. METHODS: This study included 27 eyes of 27 healthy older volunteers (mean age, 44.1 +/- 2.6 years) and 14 eyes of 14 healthy young volunteers (mean age, 28.4+/-4.8 years). The distance-corrected visual acuity (DCVA), distance-corrected near VA (DCNVA), subjective amplitude of accommodation (AA), and distance and near pupillary diameters were measured. The distance FVA and distance-corrected near FVA (DCNFVA) were measured using the FVA Measurement System. The standard Schirmer test and standard tear break-up time measurement also were performed. RESULTS: The logarithm of the minimum angle of resolution (logMAR) DCVA was better than 0 in all subjects. The percentages of subjects with logMAR DCNVA below 0 was significantly lower in the presbyopia group than in the young group. The DCNFVA in the presbyopia group was significantly (P < 0.001) poorer than the DCNVA in that group. Significant linear negative correlations were seen between the DCNVA and AA (r = -0.507, P < 0.001) and the DCNFVA and AA (r = -0.681, P < 0.001) in the older subjects. Stepwise regression analysis showed that only the AA was a significant factor predictive of the DCNFVA in the presbyopia group. Tear function parameters were not adopted in the regression model. CONCLUSIONS: Measurement of the DCNFVA can detect decreased AA in early presbyopia better than measurement of the conventional near VA. The DCNFVA is a good index for early presbyopia. PMID- 26959363 TI - A Holistic Landscape Description Reveals That Landscape Configuration Changes More over Time than Composition: Implications for Landscape Ecology Studies. AB - BACKGROUND: Space-for-time substitution-that is, the assumption that spatial variations of a system can explain and predict the effect of temporal variations is widely used in ecology. However, it is questionable whether it can validly be used to explain changes in biodiversity over time in response to land-cover changes. HYPOTHESIS: Here, we hypothesize that different temporal vs spatial trajectories of landscape composition and configuration may limit space-for-time substitution in landscape ecology. Land-cover conversion changes not just the surface areas given over to particular types of land cover, but also affects isolation, patch size and heterogeneity. This means that a small change in land cover over time may have only minor repercussions on landscape composition but potentially major consequences for landscape configuration. METHODS: Using land cover maps of the Paris region for 1982 and 2003, we made a holistic description of the landscape disentangling landscape composition from configuration. After controlling for spatial variations, we analyzed and compared the amplitudes of changes in landscape composition and configuration over time. RESULTS: For comparable spatial variations, landscape configuration varied more than twice as much as composition over time. Temporal changes in composition and configuration were not always spatially matched. SIGNIFICANCE: The fact that landscape composition and configuration do not vary equally in space and time calls into question the use of space-for-time substitution in landscape ecology studies. The instability of landscapes over time appears to be attributable to configurational changes in the main. This may go some way to explaining why the landscape variables that account for changes over time in biodiversity are not the same ones that account for the spatial distribution of biodiversity. PMID- 26959364 TI - Medical Students' Perceptions of Clinical Teachers as Role Model. AB - INTRODUCTION: Role models facilitate student learning and assists in the development of professional identity. However, social organization and cultural values influence the choice of role models. Considering that the social organization and cultural values in South East Asia are different from other countries, it is important to know whether this affects the characteristics medical students look for in their role models in these societies. METHODS: A 32 item questionnaire was developed and self-administered to undergraduate medical students. Participants rated the characteristics on a three point scale (0 = not important, 1 = mildly important, 2 = very important). One way ANOVA and student's t-test were used to compare the groups. RESULTS: A total of 349 (65.23%) distributed questionnaires were returned. The highest ranked themes were teaching and facilitating learning, patient care and continuing professional development followed by communication and professionalism. Safe environment and guiding personal and professional development was indicated least important. Differences were also observed between scores obtained by males and females. CONCLUSION: Globally there are attributes which are perceived as essential for role models, while others are considered desirable. An understanding of the attributes which are essential and desirable for role models can help medical educators devise strategies which can reinforce those attributes within their institutions. PMID- 26959365 TI - The Dose-Dependent Organ-Specific Effects of a Dipeptidyl Peptidase-4 Inhibitor on Cardiovascular Complications in a Model of Type 2 Diabetes. AB - OBJECTIVE: Although dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have a non-glucoregulatory protective effect in various tissues, the effects of long-term inhibition of DPP-4 on the micro- and macro-vascular complications of type 2 diabetes remain uncertain. The aim of the present study was to investigate the organ-specific protective effects of DPP-4 inhibitor in rodent model of type 2 diabetes. METHODS: Eight-week-old diabetic and obese db/db mice and controls (db/m mice) received vehicle or one of two doses of gemigliptin (0.04 and 0.4%) daily for 12 weeks. Urine albumin excretion and echocardiography measured at 20 weeks of age. Heart and kidney tissue were subjected to molecular analysis and immunohistochemical evaluation. RESULTS: Gemigliptin effectively suppressed plasma DPP-4 activation in db/db mice in a dose-dependent manner. The HbA1c level was normalized in the 0.4% gemigliptin, but not in the 0.04% gemigliptin group. Gemigliptin showed a dose-dependent protective effect on podocytes, anti-apoptotic and anti-oxidant effects in the diabetic kidney. However, the dose-dependent effect of gemigliptin on diabetic cardiomyopathy was ambivalent. The lower dose significantly attenuated left ventricular (LV) dysfunction, apoptosis, and cardiac fibrosis, but the higher dose could not protect the LV dysfunction and cardiac fibrosis. CONCLUSION: Gemigliptin exerted non-glucoregulatory protective effects on both diabetic nephropathy and cardiomyopathy. However, high-level inhibition of DPP-4 was associated with an organ-specific effect on cardiovascular complications in type 2 diabetes. PMID- 26959366 TI - "When Treatment Is More Challenging than the Disease": A Qualitative Study of MDR TB Patient Retention. AB - BACKGROUND: One-fifth of the patients on multidrug-resistant tuberculosis treatment at the Drug-Resistant-TB (DR-TB) Site in Gujarat are lost-to-follow up(LFU). OBJECTIVE: To understand patients' and providers' perspectives on reasons for LFU and their suggestions to improve retention-in-care. DESIGN: Qualitative study conducted between December 2013-March 2014, including in-depth interviews with LFU patients and DOT-providers, and a focus group discussion with DR-TB site supervisors. A thematic-network analysis approach was utilised. RESULTS: Three sub-themes emerged: (i) Struggle with prolonged treatment; (ii) Strive against stigma and toward support; (iii) Divergent perceptions and practices. Daily injections, pill burden, DOT, migratory work, social problems, prior TB treatment, and adverse drugs effects were reported as major barriers to treatment adherence and retention-in-care by patients and providers. Some providers felt that despite their best efforts, LFU patients remain. Patient movements between private practitioners and traditional healers further influenced LFU. CONCLUSION: The study points to a need for repeated patient counselling and education, improved co-ordination between various tiers of providers engaged in DR-TB care, collaboration between the public, private and traditional practitioners, and promotion of social and economic support to help patients adhere to MDR-TB treatment and avoid LFU. PMID- 26959367 TI - Comparative Transcriptomic Analysis of Rectal Tissue from Beef Steers Revealed Reduced Host Immunity in Escherichia coli O157:H7 Super-Shedders. AB - Super-shedder cattle are a major disseminator of E. coli O157:H7 into the environment, and the terminal rectum has been proposed as the primary E. coli O157:H7 colonization site. This study aimed to identify host factors that are associated with the super-shedding process by comparing transcriptomic profiles in rectal tissue collected from 5 super-shedder cattle and 4 non-shedder cattle using RNA-Seq. In total, 17,859 +/- 354 genes and 399 +/- 16 miRNAs were detected, and 11,773 genes were expressed in all animals. Fifty-eight differentially expressed (DE) genes (false discovery rate < 0.05) including 11 up regulated and 47 down-regulated (log 2 (fold change) ranged from -5.5 to 4.2), and 2 up-regulated DE miRNAs (log 2 (fold change) = 2.1 and 2.5, respectively) were identified in super-shedders compared to non-shedders. Functional analysis of DE genes revealed that 31 down-regulated genes were potentially associated with reduced innate and adaptive immune functions in super-shedders, including 13 lymphocytes membrane receptors, 3 transcription factors and 5 cytokines, suggesting the decreased key host immune functions in the rectal tissue of super shedders, including decreased quantity and migration of immune cells such as lymphocytes, neutrophils and dendritic cells. The up-regulation of bta-miR-29d-3p and the down regulation of its predicted target gene, regulator of G-protein signaling 13, suggested a potential regulatory role of this miRNA in decreased migration of lymphocytes in super-shedders. Based on these findings, the rectal tissue of super-shedders may inherently exhibit less effective innate and adaptive immune protection. Further study is required to confirm if such effect on host immunity is due to the nature of the host itself or due to actions mediated by E. coli O157:H7. PMID- 26959368 TI - Turning Up the Heat on a Hotspot: DNA Barcodes Reveal 80% More Species of Geometrid Moths along an Andean Elevational Gradient. AB - We sampled 14,603 geometrid moths along a forested elevational gradient from 1020 3021 m in the southern Ecuadorian Andes, and then employed DNA barcoding to refine decisions on species boundaries initially made by morphology. We compared the results with those from an earlier study on the same but slightly shorter gradient that relied solely on morphological criteria to discriminate species. The present analysis revealed 1857 putative species, an 80% increase in species richness from the earlier study that detected only 1010 species. Measures of species richness and diversity that are less dependent on sample size were more than twice as high as in the earlier study, even when analysis was restricted to an identical elevational range. The estimated total number of geometrid species (new dataset) in the sampled area is 2350. Species richness at single sites was 32-43% higher, and the beta diversity component rose by 43-51%. These impacts of DNA barcoding on measures of richness reflect its capacity to reveal cryptic species that were overlooked in the first study. The overall results confirmed unique diversity patterns reported in the first investigation. Species diversity was uniformly high along the gradient, declining only slightly above 2800 m. Species turnover also showed little variation along the gradient, reinforcing the lack of evidence for discrete faunal zones. By confirming these major biodiversity patterns, the present study establishes that incomplete species delineation does not necessarily conceal trends of biodiversity along ecological gradients, but it impedes determination of the true magnitude of diversity and species turnover. PMID- 26959369 TI - Benzene Uptake and Glutathione S-transferase T1 Status as Determinants of S Phenylmercapturic Acid in Cigarette Smokers in the Multiethnic Cohort. AB - Research from the Multiethnic Cohort (MEC) demonstrated that, for the same quantity of cigarette smoking, African Americans and Native Hawaiians have a higher lung cancer risk than Whites, while Latinos and Japanese Americans are less susceptible. We collected urine samples from 2,239 cigarette smokers from five different ethnic groups in the MEC and analyzed each sample for S phenylmercapturic acid (SPMA), a specific biomarker of benzene uptake. African Americans had significantly higher (geometric mean [SE] 3.69 [0.2], p<0.005) SPMA/ml urine than Whites (2.67 [0.13]) while Japanese Americans had significantly lower levels than Whites (1.65 [0.07], p<0.005). SPMA levels in Native Hawaiians and Latinos were not significantly different from those of Whites. We also conducted a genome-wide association study in search of genetic risk factors related to benzene exposure. The glutathione S-transferase T1 (GSTT1) deletion explained between 14.2-31.6% (p = 5.4x10-157) and the GSTM1 deletion explained between 0.2%-2.4% of the variance (p = 1.1x10-9) of SPMA levels in these populations. Ethnic differences in levels of SPMA remained strong even after controlling for the effects of these two deletions. These results demonstrate the powerful effect of GSTT1 status on SPMA levels in urine and show that uptake of benzene in African American, White, and Japanese American cigarette smokers is consistent with their lung cancer risk in the MEC. While benzene is not generally considered a cause of lung cancer, its metabolite SPMA could be a biomarker for other volatile lung carcinogens in cigarette smoke. PMID- 26959370 TI - A Novel Prior- and Motion-Based Compressed Sensing Method for Small-Animal Respiratory Gated CT. AB - Low-dose protocols for respiratory gating in cardiothoracic small-animal imaging lead to streak artifacts in the images reconstructed with a Feldkamp-Davis-Kress (FDK) method. We propose a novel prior- and motion-based reconstruction (PRIMOR) method, which improves prior-based reconstruction (PBR) by adding a penalty function that includes a model of motion. The prior image is generated as the average of all the respiratory gates, reconstructed with FDK. Motion between respiratory gates is estimated using a nonrigid registration method based on hierarchical B-splines. We compare PRIMOR with an equivalent PBR method without motion estimation using as reference the reconstruction of high dose data. From these data acquired with a micro-CT scanner, different scenarios were simulated by changing photon flux and number of projections. Methods were evaluated in terms of contrast-to-noise-ratio (CNR), mean square error (MSE), streak artefact indicator (SAI), solution error norm (SEN), and correction of respiratory motion. Also, to evaluate the effect of each method on lung studies quantification, we have computed the Jaccard similarity index of the mask obtained from segmenting each image as compared to those obtained from the high dose reconstruction. Both iterative methods greatly improved FDK reconstruction in all cases. PBR was prone to streak artifacts and presented blurring effects in bone and lung tissues when using both a low number of projections and low dose. Adopting PBR as a reference, PRIMOR increased CNR up to 33% and decreased MSE, SAI and SEN up to 20%, 4% and 13%, respectively. PRIMOR also presented better compensation for respiratory motion and higher Jaccard similarity index. In conclusion, the new method proposed for low-dose respiratory gating in small-animal scanners shows an improvement in image quality and allows a reduction of dose or a reduction of the number of projections between two and three times with respect to previous PBR approaches. PMID- 26959371 TI - Harvest Pressure on Coastal Atlantic Cod (Gadus morhua) from Recreational Fishing Relative to Commercial Fishing Assessed from Tag-Recovery Data. AB - Marine recreational fishing is a popular outdoor activity. However, knowledge about the magnitude of recreational catches relative to commercial catches in coastal fisheries is generally sparse. Coastal Atlantic cod (Gadus morhua) is a target species for recreational fishers in the North Atlantic. In Norway, recreational fishers are allowed to use a variety of traps and nets as well as long-line and rod and line when fishing for cod. From 2005 to 2013, 9729 cod (mean size: 40 cm, range: 15-93 cm) were tagged and released in coastal Skagerrak, southeast Norway. Both high-reward (NOK 500) and low-reward tags (NOK 50) were used in this study. Because some harvested fish (even those posting high reward tags) may go unreported by fishers, reporting rates were estimated from mark-recovery models that incorporate detection parameters in their structure, in addition to survival and mortality estimates. During 2005 to 2013, a total of 1707 tagged cod were recovered and reported by fishers. We estimate the overall annual survival to be 33% (SE 1.5). Recreational rod and line fishing were responsible for 33.7% (SE 2.4) of total mortality, followed by commercial fisheries (15.1% SE 0.8) and recreational fixed gear (6.8% SE 0.4). Natural mortality was 44.4% (SE 2.5) of total mortality. Our findings suggest that recreational fishing-rod and line fishing in particular-is responsible for a substantial part of fishing mortality exerted on coastal cod in southern Norway. PMID- 26959372 TI - 5-Methylcytosine-Rich Heterochromatin in the Indian Muntjac. AB - Two 5-methylcytosine (5-MeC)-rich heterochromatic regions were demonstrated in metaphase chromosomes of the Indian muntjac by indirect immunofluorescence using a monoclonal anti-5-MeC antibody. The metaphases were obtained from diploid and triploid cell lines. A major region is located in the 'neck' of the 3;X fusion chromosome and can be detected after denaturation of the chromosomal DNA with UV light irradiation for 1 h. It is located exactly at the border of the X chromosome and the translocated autosome 3. A minor region is found in the centromeric region of the free autosome 3 after denaturing the chromosomal DNA for 3 h or longer. The structure and possible function of the major hypermethylated region as barrier against spreading of the X-inactivation process into the autosome 3 is discussed. PMID- 26959373 TI - A Cross-Sectional Study on the Use of Urinalysis for Screening Early-Stage Renal Insufficiency. AB - BACKGROUND/AIMS: Proteinuria and hematuria detected by routine urinalysis can indicate impaired renal function. This study evaluated the effect of routine urinalysis in screening out patients with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 at an early stage and investigated its associated factors. METHODS: Healthy adults who underwent physical examination between September 2008 and September 2013 were enrolled in the study (n = 43,516). Urine was analyzed for protein, and red and white blood cells. Ten milliliter blood samples were collected for serum creatinine, urea, albumin and other parameters for the estimation of eGFR and renal function. RESULTS: Abnormal routine urinalysis was found in 7.1% and eGFR <60 ml/min/1.73 m2 was found in 0.9% of subjects. Age and gender were similar in the overall and abnormal urinalysis populations (43 vs. 43 years and 36.7 vs. 38.2% females, respectively), but the eGFR <60 ml/min/1.73 m2 group were older (64 years, p < 0.001) with increased females (46.4%, p = 0.002). Sensitivity for predicting eGFR <60 ml/min/1.73 m2 was 0.110 and specificity was 0.928. Univariate and multivariate analyses in 6,318 subjects with more detailed clinical data suggested significant associations of sex (OR 0.058, 95% CI 0.030-0.113), age (OR 1.045, 95% CI 1.027 1.064), and high density lipoprotein (HDL) (OR 0.158, 95% CI 0.043-0.587) with eGFR <60 ml/min/1.73 m2. CONCLUSION: Routine urinalysis showed a poor performance in the screening for early-stage renal insufficiency. In future, other screening methods should be considered. Age, gender and HDL were associated with eGFR <60 ml/min/1.73 m2. PMID- 26959374 TI - Structure and Function of the Unusual Tungsten Enzymes Acetylene Hydratase and Class II Benzoyl-Coenzyme A Reductase. AB - In biology, tungsten (W) is exclusively found in microbial enzymes bound to a bis pyranopterin cofactor (bis-WPT). Previously known W enzymes catalyze redox oxo/hydroxyl transfer reactions by directly coordinating their substrates or products to the metal. They comprise the W-containing formate/formylmethanofuran dehydrogenases belonging to the dimethyl sulfoxide reductase (DMSOR) family and the aldehyde:ferredoxin oxidoreductase (AOR) families, which form a separate enzyme family within the Mo/W enzymes. In the last decade, initial insights into the structure and function of two unprecedented W enzymes were obtained: the acetaldehyde forming acetylene hydratase (ACH) belongs to the DMSOR and the class II benzoyl-coenzyme A (CoA) reductase (BCR) to the AOR family. The latter catalyzes the reductive dearomatization of benzoyl-CoA to a cyclic diene. Both are key enzymes in the degradation of acetylene (ACH) or aromatic compounds (BCR) in strictly anaerobic bacteria. They are unusual in either catalyzing a nonredox reaction (ACH) or a redox reaction without coordinating the substrate or product to the metal (BCR). In organic chemical synthesis, analogous reactions require totally nonphysiological conditions depending on Hg2+ (acetylene hydration) or alkali metals (benzene ring reduction). The structural insights obtained pave the way for biological or biomimetic approaches to basic reactions in organic chemistry. PMID- 26959375 TI - Methanogenic Hydrocarbon Degradation: Evidence from Field and Laboratory Studies. AB - Microbial transformation of hydrocarbons to methane is an environmentally relevant process taking place in a wide variety of electron acceptor-depleted habitats, from oil reservoirs and coal deposits to contaminated groundwater and deep sediments. Methanogenic hydrocarbon degradation is considered to be a major process in reservoir degradation and one of the main processes responsible for the formation of heavy oil deposits and oil sands. In the absence of external electron acceptors such as oxygen, nitrate, sulfate or Fe(III), fermentation and methanogenesis become the dominant microbial metabolisms. The major end product under these conditions is methane, and the only electron acceptor necessary to sustain the intermediate steps in this process is CO2, which is itself a net product of the overall reaction. We are summarizing the state of the art and recent advances in methanogenic hydrocarbon degradation research. Both the key microbial groups involved as well as metabolic pathways are described, and we discuss the novel insights into methanogenic hydrocarbon-degrading populations studied in laboratory as well as environmental systems enabled by novel cultivation-based and molecular approaches. Their possible implications on energy resources, bioremediation of contaminated sites, deep-biosphere research, and consequences for atmospheric composition and ultimately climate change are also addressed. PMID- 26959376 TI - Neurotropism of Saffold virus in a mouse model. AB - Saffold virus (SAFV) is a highly seroprevalent human Cardiovirus discovered recently. No clear association between SAFV infection and human disease has been established. Rare infection cases, however, correlated with neurological symptoms. To gain insight into the pathogenesis potential of the virus, we performed experimental mouse infection with SAFV strains of genotypes 2 and 3 (SAFV-2 and SAFV-3). After intraperitoneal infection, both strains exhibited a typical Cardiovirus tropism. Viral load was most prominent in the pancreas. Heart, spleen, brain and spinal cord were also infected. In IFN-receptor 1 deficient (IFNAR-KO) mice, SAFV-3 caused a severe encephalitis. The virus was detected by immunohistochemistry in many parts of the brain and spinal cord, both in neurons and astrocytes, but astrocyte infection was more extensive. In vitro, SAFV-3 also infected astrocytes better than neurons in mixed primary cultures. Astrocytes were, however, very efficiently protected by IFN-alpha/beta treatment. PMID- 26959377 TI - Being "Good in Bed"-Body Concerns, Self-Perceptions, and Gender Expectations Among Swedish Heterosexual Female and Male Senior High-School Students. AB - We investigated gender differences regarding body perceptions, self-perceptions, values and expectations in sexual situations, and factors associated with expectations, among Swedish heterosexual female and male high-school students. A total of 2,765 students (aged 18 to 22) completed questionnaires. Women reported lower satisfaction with themselves and their body appearance (p < 0.001), and felt more inferior to their partner (p < 0.001). Men felt more superior to their partner, and felt higher expectations (p < 0.001). Male sex, difficulty saying no to sex, dissatisfaction with the body, feeling inferior or superior to partner, and considering partner's satisfaction as more important, were all associated with feeling expectations during sex. PMID- 26959378 TI - Highly efficient de novo mutant identification in a Sorghum bicolor TILLING population using the ComSeq approach. AB - Screening large populations for carriers of known or de novo rare single nucleotide polymorphisms (SNPs) is required both in Targeting induced local lesions in genomes (TILLING) experiments in plants and in screening of human populations. We previously suggested an approach that combines the mathematical field of compressed sensing with next-generation sequencing to allow such large scale screening. Based on pooled measurements, this method identifies multiple carriers of heterozygous or homozygous rare alleles while using only a small fraction of resources. Its rigorous mathematical foundations allow scalable and robust detection, and provide error correction and resilience to experimental noise. Here we present a large-scale experimental demonstration of our computational approach, in which we targeted a TILLING population of 1024 Sorghum bicolor lines to detect carriers of de novo SNPs whose frequency was less than 0.1%, using only 48 pools. Subsequent validation confirmed that all detected lines were indeed carriers of the predicted mutations. This novel approach provides a highly cost-effective and robust tool for biologists and breeders to allow identification of novel alleles and subsequent functional analysis. PMID- 26959379 TI - Cryo-sectioning of mice for whole-body imaging of drugs and metabolites with desorption electrospray ionization mass spectrometry imaging - a simplified approach. AB - A method is presented for whole-body imaging of drugs and metabolites in mice with desorption electrospray ionization mass spectrometry imaging (DESI-MSI). Unlike most previous approaches to whole-body imaging which are based on cryo sectioning using a cryo-macrotome, the presented approach is based on use of the cryo-microtome which is found in any histology lab. The tissue sections are collected on tape which is analyzed directly by DESI-MSI. The method is demonstrated on mice which have been dosed intraperitoneally with the antidepressive drug amitriptyline. By combining full-scan detection with the more selective and sensitive MS/MS detection, a number of endogenous compounds (lipids) were imaged simultaneously with the drug and one of its metabolites. The sensitivity of this approach allowed for imaging of drug and the metabolite in a mouse dosed with 2.7 mg amitriptyline per kg bodyweight which is comparable to the normal prescribed human dose. The simultaneous imaging of endogenous and exogenous compounds facilitates registration of the drug images to certain organs in the body by colored-overlay of the two types of images. The method represents a relatively low-cost approach to simple, sensitive and highly selective whole body imaging in drug distribution and metabolism studies. PMID- 26959380 TI - Is there any relationship between Toll-like receptor 3 c.1377C/T and -7C/A polymorphisms and susceptibility to Crimean Congo hemorrhagic fever? AB - Crimean-Congo hemorrhagic fever (CCHF) is an infectious disease that is caused by CCHF virus. A family of transmembrane receptors called as Toll-like receptors (TLRs) selectively acts in recognizing a wide range of microbial components and endogenous molecules released by damaged tissue and have been preserved throughout evolution. TLRs initiate some signaling cascades which activate the innate immune system. Mainly four TLRs act in protection against viral infections; TLR3 is one of them. TLR3 identifies dsRNA. By producing inflammatory cytokines and type I interferons, it generates an antiviral immune response. Proper response to TLR ligands may be impaired by single nucleotide polymorphisms (SNPs) within TLR genes in some indviduals, and this can cause varied susceptibility to infections. In the present work, polymerase chain reaction based restriction fragment length polymorphism is used to analyze the frequencies of TLR3 (c.1377C/T and -7C/A) polymorphisms in 149 CCHF patients and 171 healthy adults as controls, in Cumhuriyet University, Sivas/Turkey. We also investigated the relation between these polymorphisms and severity or mortality of CCHF disease. This is the first study investigating the TLR3 SNPs in patients with CCHF. In the present study, the frequency of the TLR3 (c.1377C/T and -7A/C) genotypes in fatal and non-fatal cases were comparable, however, the homozygous mutant (TT) genotype frequency of TLR3 c.1377C/T in CCHF patients was significantly higher than that of the healthy controls. In conclusion, presence of TLR3 c.1377 TT genotype may have a role in the susceptibility to CCHF. J. Med. Virol. 88:1690-1696, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26959381 TI - Association study between genome-wide significant variants of vitamin B12 metabolism and gastric cancer in a han Chinese population. AB - Gastric cancer is one of the leading causes of cancer mortality worldwide. Accumulating evidence suggests that vitamin B12 plays an important role in the development of gastric cancer. Genome-wide association studies on metabolites in the one-carbon metabolism pathway identified several vitamin B12-related polymorphisms. Therefore, we investigated the association between variants within vitamin B12-related genes and gastric cancer in a Han Chinese population. Eight variants within the genome were significant vitamin B12-related genes, and they were selected for analysis in this case-control study. This study used a total of 492 gastric cancer patients and 550 noncancer controls. The variant rs526934 from the TCN1 gene was associated with an increased risk of developing gastric cancer. Increased risks of gastric cancer occurrence were observed in the minor G allele (OR = 1.25, 95% CI = 1.03-1.52, P = 0.031) and GG genotype (OR = 2.06, 95% CI = 1.24-3.42, P = 0.0043) compared with the wild-type A allele and AA-GA genotype, respectively. In the haplotypic analysis, we found that the CUBN haplotypes were associated with an altered gastric cancer risk. The rs1801222T/rs11254363A (OR = 1.40, 95% CI = 1.05-1.86, P = 0.021) and rs1801222C/rs11254363G (OR = 4.39, 95% CI = 2.32-8.30, P < 0.0001) haplotypes exhibited an increased gastric cancer risk, while rs1801222T/rs11254363G showed protective effects against gastric cancer (OR = 0.43, 95% CI = 0.25-0.73, P = 0.002) compared with the wild-type rs1801222C/rs11254363A haplotype. The circulating vitamin B12 concentration related variants were associated with the occurrence of gastric cancer. This finding shed light on the unexpected role of vitamin B12 metabolism genes in gastric carcinogenesis and highlighted the interplay of diet, genetics, and human cancers. PMID- 26959382 TI - DWI at MR Enterography for Evaluating Bowel Inflammation in Crohn Disease. AB - OBJECTIVE: The purpose of this article is to provide a comprehensive review regarding DWI enterography used for evaluating Crohn disease and to summarize the relevant evidence. CONCLUSION: Active bowel inflammation in Crohn disease causes restricted diffusion on MR enterography with DWI. Enterographic DWI to evaluate Crohn disease is increasingly drawing attention for both academic research and clinical practice and has shown potential as a quantitative tool for assessing bowel inflammation. DWI enterography also has multiple unresolved issues and limitations. PMID- 26959383 TI - Correlates of health-promoting lifestyle behaviors among Vietnamese female immigrants in Taiwan. AB - Immigration is a demanding and challenging life event that may cause married immigrant women to be likely to adopt unhealthy lifestyle behaviors. The aim of the authors of this study was to assess the prevalence of health-promoting lifestyle behaviors and their correlates among Vietnamese female immigrants in Taiwan. A cross-sectional study was conducted with 140 Vietnamese female immigrants from November 2012 to October 2013. Measures included demographic information, the Chinese Health Questionnaire, the General Functioning Scale of the Family Assessment Device, and a short version of the Chinese Health-Promoting Lifestyle Profile. Data analyses included descriptive statistics, Pearson's product-moment correlation coefficients, t-tests, one-way analysis of variance, and a hierarchical multiple regression analysis. Vietnamese female immigrants with better individual health status, higher education from their original country, greater communication ability, better health status of the husband, and adaptive family functioning demonstrated greater participation in health promoting lifestyle behaviors. Particularly, better husband's health status and family functioning correlated with greater practices of health-promoting lifestyle behaviors after controlling for individual characteristics and experiences, with 38% of the total variance explained. Findings may serve to guide and design culturally specific, family-focused health promotion interventions to assist Vietnamese female immigrants and their families. PMID- 26959384 TI - Messages from the RICALOR Study. PMID- 26959386 TI - Trichomonas vaginalis induces IL-1beta production in a human prostate epithelial cell line by activating the NLRP3 inflammasome via reactive oxygen species and potassium ion efflux. AB - BACKGROUND: Trichomonas vaginalis is a sexually transmitted protozoan parasite that causes vaginitis in women, and urethritis and prostatitis in men. IL-1beta is synthesized as immature pro-IL-1beta, which is cleaved by activated caspase-1. Caspase-1 is, in turn, activated by a multi-protein complex known as an inflammasome. In this study, we investigated the inflammatory response of a prostate epithelial cell line (RWPE-1) to T. vaginalis and, specifically, the capacity of T. vaginalis to activate the NLRP3 inflammasome. METHODS: RWPE-1 cells were stimulated by live T. vaginalis, and subsequent expression of pro-IL 1beta, IL-1beta, NLRP3, ASC and caspase-1 was determined by real-time PCR and Western blotting. IL-1beta and caspase-1 production was also measured by ELISA. To evaluate the effects of NLRP3 and caspase-1 on IL-1beta production, the activated RWPE-1 cells were transfected with small interfering RNAs to silence the NLRP3 and caspase-1 genes. Activation of the NLRP3 inflammasome was observed by fluorescence microscopy. Intracellular reactive oxygen species (ROS) were evaluated by spectrofluorometry. RESULTS: When RWPE-1 cells were stimulated with live T. vaginalis, the mRNA and protein expression of IL-1beta, NLRP3, ASC, and caspase-1 increased. Moreover, silencing of NLRP3 and caspase-1 attenuated T. vaginalis-induced IL-1beta secretion. The NADPH oxidase inhibitor DPI and high extracellular potassium ion suppressed the production of IL-1beta, caspase-1, and the expression of NLRP3 and ASC proteins. The specific NF-kappaB inhibitor, Bay 11-7082, inhibited IL-1beta production, and also inhibited the production of caspase-1, ASC and NLRP3 proteins. CONCLUSIONS: T. vaginalis induces the formation of the NLRP3 inflammasome in human prostate epithelial cells via ROS and potassium ion efflux, and this results in IL-1beta production. This is the first evidence for activation of the NLRP3 inflammasome in the inflammatory response by prostate epithelial cells infected with T. vaginalis. Prostate 76:885 896, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26959385 TI - Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer. AB - BACKGROUND: Annual updates on cancer occurrence and trends in the United States are provided through an ongoing collaboration among the American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR). This annual report highlights the increasing burden of liver and intrahepatic bile duct (liver) cancers. METHODS: Cancer incidence data were obtained from the CDC, NCI, and NAACCR; data about cancer deaths were obtained from the CDC's National Center for Health Statistics (NCHS). Annual percent changes in incidence and death rates (age-adjusted to the 2000 US Standard Population) for all cancers combined and for the leading cancers among men and women were estimated by joinpoint analysis of long-term trends (incidence for 1992-2012 and mortality for 1975-2012) and short-term trends (2008-2012). In depth analysis of liver cancer incidence included an age-period-cohort analysis and an incidence-based estimation of person-years of life lost because of the disease. By using NCHS multiple causes of death data, hepatitis C virus (HCV) and liver cancer-associated death rates were examined from 1999 through 2013. RESULTS: Among men and women of all major racial and ethnic groups, death rates continued to decline for all cancers combined and for most cancer sites; the overall cancer death rate (for both sexes combined) decreased by 1.5% per year from 2003 to 2012. Overall, incidence rates decreased among men and remained stable among women from 2003 to 2012. Among both men and women, deaths from liver cancer increased at the highest rate of all cancer sites, and liver cancer incidence rates increased sharply, second only to thyroid cancer. Men had more than twice the incidence rate of liver cancer than women, and rates increased with age for both sexes. Among non-Hispanic (NH) white, NH black, and Hispanic men and women, liver cancer incidence rates were higher for persons born after the 1938 to 1947 birth cohort. In contrast, there was a minimal birth cohort effect for NH Asian and Pacific Islanders (APIs). NH black men and Hispanic men had the lowest median age at death (60 and 62 years, respectively) and the highest average person-years of life lost per death (21 and 20 years, respectively) from liver cancer. HCV and liver cancer-associated death rates were highest among decedents who were born during 1945 through 1965. CONCLUSIONS: Overall, cancer incidence and mortality declined among men; and, although cancer incidence was stable among women, mortality declined. The burden of liver cancer is growing and is not equally distributed throughout the population. Efforts to vaccinate populations that are vulnerable to hepatitis B virus (HBV) infection and to identify and treat those living with HCV or HBV infection, metabolic conditions, alcoholic liver disease, or other causes of cirrhosis can be effective in reducing the incidence and mortality of liver cancer. Cancer 2016;122:1312-1337. (c) 2016 American Cancer Society. PMID- 26959388 TI - Expression of amyloid-beta in mouse cochlear hair cells causes an early-onset auditory defect in high-frequency sound perception. AB - Increasing evidence indicates that defects in the sensory system are highly correlated with age-related neurodegenerative diseases, including Alzheimer's disease (AD). This raises the possibility that sensory cells possess some commonalities with neurons and may provide a tool for studying AD. The sensory system, especially the auditory system, has the advantage that depression in function over time can easily be measured with electrophysiological methods. To establish a new mouse AD model that takes advantage of this benefit, we produced transgenic mice expressing amyloid-beta (Abeta), a causative element for AD, in their auditory hair cells. Electrophysiological assessment indicated that these mice had hearing impairment, specifically in high-frequency sound perception (>32 kHz), at 4 months after birth. Furthermore, loss of hair cells in the basal region of the cochlea, which is known to be associated with age-related hearing loss, appeared to be involved in this hearing defect. Interestingly, overexpression of human microtubule-associated protein tau, another factor in AD development, synergistically enhanced the Abeta-induced hearing defects. These results suggest that our new system reflects some, if not all, aspects of AD progression and, therefore, could complement the traditional AD mouse model to monitor Abeta-induced neuronal dysfunction quantitatively over time. PMID- 26959387 TI - Syndecan-1 Attenuates Lung Injury during Influenza Infection by Potentiating c Met Signaling to Suppress Epithelial Apoptosis. AB - RATIONALE: Syndecan-1 is a cell surface heparan sulfate proteoglycan primarily expressed in the lung epithelium. Because the influenza virus is tropic to the airway epithelium, we investigated the role of syndecan-1 in influenza infection. OBJECTIVES: To determine the mechanism by which syndecan-1 regulates the lung mucosal response to influenza infection. METHODS: Wild-type (WT) and Sdc1(-/-) mice were infected with a H1N1 virus (PR8) as an experimental model of influenza infection. Human and murine airway epithelial cell cultures were also infected with PR8 to study the mechanism by which syndecan-1 regulates the inflammatory response. MEASUREMENT AND MAIN RESULTS: We found worsened outcomes and lung injury in Sdc1(-/-) mice compared with WT mice after influenza infection. Our data demonstrated that syndecan-1 suppresses bronchial epithelial apoptosis during influenza infection to limit widespread lung inflammation. Furthermore, we determined that syndecan-1 attenuated apoptosis by crosstalking with c-Met to potentiate its cytoprotective signals in airway epithelial cells during influenza infection. CONCLUSIONS: Our work shows that cell-associated syndecan-1 has an important role in regulating lung injury. Our findings demonstrate a novel mechanism in which cell membrane-associated syndecan-1 regulates the innate immune response to influenza infection by facilitating cytoprotective signals through c-Met signaling to limit bronchial epithelial apoptosis, thereby attenuating lung injury and inflammation. PMID- 26959389 TI - Motive Arousal Without Pictures? An Experimental Validation of a Hybrid Implicit Motive Test. AB - Pictures are widely used as stimuli in implicit motive tests. Hybrid forms of such tests present pictures and declarative statements underneath pictures. Some authors have argued that explicitly declaring agreement with motive-related statements presented underneath pictures might shift the validity of such tests from capturing less implicit motives to more explicit motives. If that is the case, pictures as elicitors of implicit motives might become less relevant. Adopting the views on validity presented by Borsboom, Mellenbergh, and van Heerden ( 2004 ) and Bornstein ( 2011 ), as well as item generation theory, we investigated whether the availability of pictures in hybrid motive tests causally affects test scores. To this end, we administered the Multi-Motive Grid (MMG; Sokolowski, Schmalt, Langens, & Puca, 2000 ), as an example of a hybrid motive test, either with or without pictures to 108 participants. Results revealed that the availability of pictures had no effect on 3 out of 6 test scores. Furthermore, eliminating pictures had only inconsistent effects on correlations with a test of explicit motives. We conclude that pictures might not unanimously elicit motives in implicit motive tests that use declarative statements as response options. PMID- 26959390 TI - Influence of Body Mass Index and Body Surface Area on the Behavior of Papillary Thyroid Carcinoma. AB - BACKGROUND: Previous studies have examined the relationship between body mass index (BMI) and the behavior of papillary thyroid carcinomas (PTC). However, the results are inconsistent. The purpose of this study was to clarify the association between PTC behavior and anthropometric parameters including BMI and body surface area (BSA). METHODS: This study retrospectively reviewed 5081 PTC patients who underwent total thyroidectomy with bilateral central neck dissection between January 2002 and June 2015. Because of sexual dimorphism in obesity, analyses were conducted separately for men and women. The World Health Organization BMI classification was used to classify patients as normal (18.5 <= BMI <25 kg/m(2)), overweight (25 <= BMI <30 kg/m(2)), or obese (BMI >=30 kg/m(2)). Since no consensus for BSA categorization exists, enrolled patients were grouped into BSA quartiles by sex: women BSA1 (BSA <1.52 m(2)), BSA2 (1.52 <= BSA <1.59 m(2)), BSA3 (1.59 <= BSA <1.67 m(2)), and BSA4 (BSA >=1.67 m(2)); and men BSA1 (BSA <1.77 m(2)), BSA2 (1.77 <= BSA <1.86 m(2)), BSA3 (1.86 <= BSA <1.96 m(2)), and BSA4 (BSA >=1.96 m(2)). RESULTS: In women, overweight (adjusted odds ratio [OR] = 1.187, p = 0.042) and obese (adjusted OR = 2.231, p < 0.001) were independent predictors for multiplicity. Furthermore, overweight (adjusted OR = 1.237, p = 0.012) and obese (adjusted OR = 1.789, p = 0.005) were independent predictors for extrathyroidal extension (ETE). However, higher BMI was not an independent predictor for bilaterality or central lymph node metastasis (CLNM). In addition, higher BSA-BSA3 (adjusted OR = 1.205, p = 0.049) and BSA4 (adjusted OR = 1.524, p < 0.001)-was an independent predictor for multiplicity. However, higher BSA was not a predictor for bilaterality, ETE, or CLNM. In men, higher BMI and BSA were not predictors for multiplicity, bilaterality, ETE, or CLNM. CONCLUSIONS: In women with PTC, higher BMI was an independent predictor for multiplicity and ETE. Furthermore, higher BSA was an independent predictor for multiplicity. However, BMI and BSA were not predictors for the PTC behavior in men. PMID- 26959395 TI - How Does Gameplaying Support Values and Psychological Well-Being Among Cancer Survivors? AB - OBJECTIVE: This qualitative study examined the extent to which playing recreational computer games and videogames is perceived by cancer survivors as supporting personal values. Values serve as behavioral guides and may thus impact health outcomes; therefore activities that have the potential to support values deserve further attention so their role in promoting health may be better understood. MATERIALS AND METHODS: We asked a sample of survivors who play recreational games (n = 73) open-ended questions about the types of recreational games they play, about something they really value in life, and the extent to which playing games supports the value. Data analysis used a grounded theory approach, supported by computer-assisted qualitative analysis software. RESULTS: Three major themes emerged linking gameplaying to survivors' values: the need to create and maintain social connections, the desire to help others, and the need to experience alternate realities (including escape and exploration). CONCLUSIONS: The present study offers a unique perspective by focusing on the intersection of values and gameplay among survivors. The findings suggest that playing recreational computer games and videogames may be congruent with survivors' personal values and may have potential to influence positive health outcomes among survivors. The findings have implications for developing effective values-based interventions for cancer survivors. PMID- 26959396 TI - In vivo imaging of microglial activation by positron emission tomography with [(11)C]PBR28 in the 5XFAD model of Alzheimer's disease. AB - Microglial activation has been linked with deficits in neuronal function and synaptic plasticity in Alzheimer's disease (AD). The mitochondrial translocator protein (TSPO) is known to be upregulated in reactive microglia. Accurate visualization and quantification of microglial density by PET imaging using the TSPO tracer [(11)C]-R-PK11195 has been challenging due to the limitations of the ligand. In this study, it was aimed to evaluate the new TSPO tracer [(11)C]PBR28 as a marker for microglial activation in the 5XFAD transgenic mouse model of AD. Dynamic PET scans were acquired following intravenous administration of [(11)C]PBR28 in 6-month-old 5XFAD mice and in wild-type controls. Autoradiography with [(3)H]PBR28 was carried out in the same brains to further confirm the distribution of the radioligand. In addition, immunohistochemistry was performed on adjacent brain sections of the same mice to evaluate the co-localization of TSPO with microglia. PET imaging revealed that brain uptake of [(11)C]PBR28 in 5XFAD mice was increased compared with control mice. Moreover, binding of [(3)H]PBR28, measured by autoradiography, was enriched in cortical and hippocampal brain regions, coinciding with the positive staining of the microglial marker Iba-1 and amyloid deposits in the same areas. Furthermore, double-staining using antibodies against TSPO demonstrated co-localization of TSPO with microglia and not with astrocytes in 5XFAD mice and human post-mortem AD brains. The data provided support of the suitability of [(11)C]PBR28 as a tool for in vivo monitoring of microglial activation and assessment of treatment response in future studies using animal models of AD. PMID- 26959397 TI - Pathological and clinical aspects of alpha/beta synuclein in Parkinson's disease and related disorders. AB - Parkinson's disease (PD) and related synucleinopathies are characterized by extensive neuronal cell loss, which is potentially triggered by alpha-synuclein misfolding and aggregation. Therefore it is reasonable to suggest that treatments targeting alpha-synuclein could reduce its levels and toxicity, rescue neuronal cells and halt the neurodegeneration process. Several approaches to decrease alpha-synuclein levels were employed thus far, mainly by using beta-synuclein, another protein from the same family, or immunotherapies. These treatments demonstrated some positive results in preclinical studies, which may pave the road to the development of new promising disease-modifying therapies (DMTs). This approach should be further examined in preclinical and clinical settings, together with a clear process in order to advance candidates, enable the ability to define when there are target engagements and to detect what is a meaningful pharmacological response, and how it will be translated in clinical efficacy. PMID- 26959398 TI - Cardiac Mortality in Children and Adolescents with Hodgkin's Lymphoma: A Surveillance, Epidemiology and End Results Analysis. AB - PURPOSE: The purpose of this study was to evaluate the risk of cardiac death in pediatric Hodgkin's lymphoma (HL) survivors and identify high-risk groups that may need additional surveillance. METHODS: The Surveillance, Epidemiology and End Results program database was queried to analyze the rates of radiation therapy (RT) use and cardiac-specific mortality (CSM) in HL patients, aged 0-21 years, treated from 1973 to 2007. Primary endpoint was cardiac mortality. RESULTS: A total of 6552 patients were included. Median follow-up was 12 years (range, 0 40). Median age at diagnosis was 17 years (range, 0-21). The majority were white (85.5%), from western states (41.2%), had nodular sclerosis HL (73.2%), presented with stage I or II disease (51.5%), and received RT (56.1%). Death from cardiac disease occurred in 114 patients (9.2% of all deaths). CSM for the entire cohort at 10-, 20-, and 30-year time points was 0.3%, 1.6%, and 5.0%, respectively. Median age at the time of cardiac death was 39 years (range, 18-58 years). Under multivariate analysis (MVA), adolescent patients (ages 13-21) had higher rates of CSM (hazard ratio [HR], 3.05; p = 0.005). Female gender (HR, 0.43; p < 0.001), patients treated from 1998 to 2007 (HR, 0.19; p = 0.018), and those with lymphocyte-rich histology (HR, 0.14; p = 0.047) had significantly lower rates of CSM. Use of RT was not associated with CSM under MVA (HR, 1.18, p = 0.452). CONCLUSION: The cumulative incidence of CSM in this population analysis of pediatric HL was 9.2%, with a steady decline over the past several decades. Adolescent patients at diagnosis and males were more likely to die of cardiac related causes. PMID- 26959399 TI - Breastmilk Is Unlikely to Be a Source of Mesenchymal Stem Cells. PMID- 26959400 TI - Calreticulin, a therapeutic target? AB - INTRODUCTION: Calreticulin is an endoplasmic reticulum (ER) resident protein critical for maintaining Ca(2+) homeostasis and glycoprotein folding in the ER. The protein has also been identified on the cell surface of apoptotic and necrotic cells and implicated to play a role in immunogenic cell death and other extracellular functions. The molecular events that promote cell surface association of calreticulin are not clear. Under cell stress conditions (environmental, drug induced, hypoxia), calreticulin may be upregulated as it attempts to regulate cell survival, death or repair. The initial signaling mechanisms involved in these processes may be regulated by the unfolded protein response (UPR) and genome damage response (GDR) pathways. AREA COVERED: Here, the phenomenon of cell surface calreticulin and its extracellular functions are discussed, with a major emphasis on the process of immunogenic cell death. The evidence of how cell surface calreticulin may act as a damage associated molecular pattern molecule is evaluated, in addition to how these properties of the protein can be exploited for therapeutic vaccine development, cancer treatment and mediating other inflammatory processes. In addition, clarification of calreticulin functions from its intracellular, cell surface, and extracellular locations are provided. EXPERT OPINION: While the protein folding and immune stimulatory properties of calreticulin can be exploited to develop therapies, the molecular pathways involved remain to be elucidated. Nevertheless, exploiting the multifaceted properties of calreticulin may in the future provide a means to treat a number of diseases. PMID- 26959401 TI - Assessment of Intima-Media Thickness in Healthy Children Aged 1 to 15 Years. AB - BACKGROUND: Carotid intima-media thickness (CIMT) has been shown to be increased in children and adolescents with traditional cardiovascular risk factors such as obesity, hypertension, and chronic kidney disease, compared with those of healthy children. OBJECTIVE: To assess the influence of sex, age and body mass index (BMI) on the CIMT in healthy children and adolescents aged 1 to 15 years. METHODS: A total of 280 healthy children and adolescents (males, n=175; mean age, 7.49+/-3.57 years; mean BMI, 17.94+/-4.1 kg/m2) were screened for CIMT assessment. They were divided into 3 groups according to age: GI, 1 to 5 years [n=93 (33.2%); males, 57; mean BMI, 16+/-3 kg/m2]; GII, 6 to 10 years [n=127 (45.4%); males, 78; mean BMI, 17.9+/-3.7 kg/m2], and GIII, 11 to 15 years [n=60 (21.4%); males, 40; mean BMI, 20.9+/-4.5 kg/m2]. RESULTS: There was no significant difference in CIMT values between male and female children and adolescents (0.43+/-0.06 mm vs. 0.42+/-0.05 mm, respectively; p=0.243). CIMT correlated with BMI neither in the total population nor in the 3 age groups according to Pearson correlation coefficient. Subjects aged 11 to 15 years had the highest CIMT values (GI vs. GII, p=0.615; GI vs. GIII, p=0.02; GII vs. GIII, p=0.004). CONCLUSIONS: CIMT is constant in healthy children younger than 10 years, regardless of sex or BMI. CIMT increases after the age of 10 years. PMID- 26959402 TI - Risk Prediction of Cardiovascular Complications in Pregnant Women With Heart Disease. AB - BACKGROUND: Heart disease in pregnancy is the leading cause of non- obstetric maternal death. Few Brazilian studies have assessed the impact of heart disease during pregnancy. OBJECTIVE: To determine the risk factors associated with cardiovascular and neonatal complications. METHODS: We evaluated 132 pregnant women with heart disease at a High-Risk Pregnancy outpatient clinic, from January 2005 to July 2010. Variables that could influence the maternal-fetal outcome were selected: age, parity, smoking, etiology and severity of the disease, previous cardiac complications, cyanosis, New York Heart Association (NYHA) functional class > II, left ventricular dysfunction/obstruction, arrhythmia, drug treatment change, time of prenatal care beginning and number of prenatal visits. The maternal-fetal risk index, Cardiac Disease in Pregnancy (CARPREG), was retrospectively calculated at the beginning of prenatal care, and patients were stratified in its three risk categories. RESULTS: Rheumatic heart disease was the most prevalent (62.12%). The most frequent complications were heart failure (11.36%) and arrhythmias (6.82%). Factors associated with cardiovascular complications on multivariate analysis were: drug treatment change (p = 0.009), previous cardiac complications (p = 0.013) and NYHA class III on the first prenatal visit (p = 0.041). The cardiovascular complication rates were 15.22% in CARPREG 0, 16.42% in CARPREG 1, and 42.11% in CARPREG > 1, differing from those estimated by the original index: 5%, 27% and 75%, respectively. This sample had 26.36% of prematurity. CONCLUSION: The cardiovascular complication risk factors in this population were drug treatment change, previous cardiac complications and NYHA class III at the beginning of prenatal care. The CARPREG index used in this sample composed mainly of patients with rheumatic heart disease overestimated the number of events in pregnant women classified as CARPREG 1 and > 1, and underestimated it in low-risk patients (CARPREG 0). PMID- 26959403 TI - Aerobic Training after Myocardial Infarction: Remodeling Evaluated by Cardiac Magnetic Resonance. AB - BACKGROUND: Numerous studies show the benefits of exercise training after myocardial infarction (MI). Nevertheless, the effects on function and remodeling are still controversial. OBJECTIVES: To evaluate, in patients after (MI), the effects of aerobic exercise of moderate intensity on ventricular remodeling by cardiac magnetic resonance imaging (CMR). METHODS: 26 male patients, 52.9 +/- 7.9 years, after a first MI, were assigned to groups: trained group (TG), 18; and control group (CG), 8. The TG performed supervised aerobic exercise on treadmill twice a week, and unsupervised sessions on 2 additional days per week, for at least 3 months. Laboratory tests, anthropometric measurements, resting heart rate (HR), exercise test, and CMR were conducted at baseline and follow-up. RESULTS: The TG showed a 10.8% reduction in fasting blood glucose (p = 0.01), and a 7.3 bpm reduction in resting HR in both sitting and supine positions (p < 0.0001). There was an increase in oxygen uptake only in the TG (35.4 +/- 8.1 to 49.1 +/- 9.6 mL/kg/min, p < 0.0001). There was a statistically significant decrease in the TG left ventricular mass (LVmass) (128.7 +/- 38.9 to 117.2 +/- 27.2 g, p = 0.0032). There were no statistically significant changes in the values of left ventricular end-diastolic volume (LVEDV) and ejection fraction in the groups. The LVmass/EDV ratio demonstrated a statistically significant positive remodeling in the TG (p = 0.015). CONCLUSIONS: Aerobic exercise of moderate intensity improved physical capacity and other cardiovascular variables. A positive remodeling was identified in the TG, where a left ventricular diastolic dimension increase was associated with LVmass reduction. PMID- 26959404 TI - Serial High-Sensitivity Troponin T in Post-Primary Angioplasty Exercise Test. AB - BACKGROUND: The kinetics of high-sensitivity troponin T (hscTnT) release should be studied in different situations, including functional tests with transient ischemic abnormalities. OBJECTIVE: To evaluate the release of hscTnT by serial measurements after exercise testing (ET), and to correlate hscTnT elevations with abnormalities suggestive of ischemia. METHODS: Patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary angioplasty were referred for ET 3 months after infarction. Blood samples were collected to measure basal hscTnT immediately before (TnT0h), 2 (TnT2h), 5 (TnT5h), and 8 hours (TnT8h) after ET. The outcomes were peak hscTnT, TnT5h/TnT0h ratio, and the area under the blood concentration-time curve (AUC) for hscTnT levels. Log transformation was performed on hscTnT values, and comparisons were assessed with the geometric mean ratio, along with their 95% confidence intervals. Statistical significance was assessed by analysis of covariance with no adjustment, and then, adjusted for TnT0h, age and sex, followed by additional variables (metabolic equivalents, maximum heart rate achieved, anterior wall STEMI, and creatinine clearance). RESULTS: This study included 95 patients. The highest geometric means were observed at 5 hours (TnT5h). After adjustments, peak hscTnT, TnT5h/TnT0h and AUC were 59% (p = 0.002), 59% (p = 0.003) and 45% (p = 0.003) higher, respectively, in patients with an abnormal ET as compared to those with normal tests. CONCLUSION: Higher elevations of hscTnT may occur after an abnormal ET as compared to a normal ET in patients with STEMI. PMID- 26959406 TI - High-Performance Carbon Nanotube/Polymer Composite Fiber from Layer-by-Layer Deposition. AB - So far, preparation of high-performance carbon nanotube (CNT)/polymer composites still faces big challenges mainly due to the limited control of CNT dispersion, fraction, and alignment in polymers. Here, a new "layer-by-layer deposition" method is put forward for preparing CNT/polymer composite fibers using poly(vinyl alcohol) (PVA) as an exemplary polymer. This is based on the continuous production of a hollow cylindrical CNT assembly from a high temperature reactor and its shrinking by a PVA-containing solution and deposition on a removable substrate wire. The in situ mixing of the two composite components at the molecular level allows CNTs to disperse and PVA to infiltrate into the fiber efficiently. As a result, remarkable effects of the CNT reinforcement on the PVA matrix are observed, including a strength improvement from ~50 to 1255 MPa and electrical conductivity from ~0 to 1948 S cm(-1). The new method offers good controllability of CNT dispersion and fraction in the polymer matrix, variability for making composite fibers using different polymers, and suitability for scaled up production. This study thus provides a new research direction for preparing CNT-reinforced composites and future performance maximization. PMID- 26959405 TI - Metformin Decouples Phospholipid Metabolism in Breast Cancer Cells. AB - INTRODUCTION: The antidiabetic drug metformin, currently undergoing trials for cancer treatment, modulates lipid and glucose metabolism both crucial in phospholipid synthesis. Here the effect of treatment of breast tumour cells with metformin on phosphatidylcholine (PtdCho) metabolism which plays a key role in membrane synthesis and intracellular signalling has been examined. METHODS: MDA MB-468, BT474 and SKBr3 breast cancer cell lines were treated with metformin and [3H-methyl]choline and [14C(U)]glucose incorporation and lipid accumulation determined in the presence and absence of lipase inhibitors. Activities of choline kinase (CK), CTP:phosphocholine cytidylyl transferase (CCT) and PtdCho phospholipase C (PLC) were also measured. [3H] Radiolabelled metabolites were determined using thin layer chromatography. RESULTS: Metformin-treated cells exhibited decreased formation of [3H]phosphocholine but increased accumulation of [3H]choline by PtdCho. CK and PLC activities were decreased and CCT activity increased by metformin-treatment. [14C] incorporation into fatty acids was decreased and into glycerol was increased in breast cancer cells treated with metformin incubated with [14C(U)]glucose. CONCLUSION: This is the first study to show that treatment of breast cancer cells with metformin induces profound changes in phospholipid metabolism. PMID- 26959407 TI - Age decreases mitochondrial motility and increases mitochondrial size in vascular smooth muscle. AB - KEY POINTS: Age is proposed to be associated with altered structure and function of mitochondria; however, in fully-differentiated cells, determining the structure of more than a few mitochondria at a time is challenging. In the present study, the structures of the entire mitochondrial complements of cells were resolved from a pixel-by-pixel covariance analysis of fluctuations in potentiometric fluorophore intensity during 'flickers' of mitochondrial membrane potential. Mitochondria are larger in vascular myocytes from aged rats compared to those in younger adult rats. A subpopulation of mitochondria in myocytes from aged, but not younger, animals is highly-elongated. Some mitochondria in myocytes from younger, but not aged, animals are highly-motile. Mitochondria that are motile are located more peripherally in the cell than non-motile mitochondria. ABSTRACT: Mitochondrial function, motility and architecture are each central to cell function. Age-associated mitochondrial dysfunction may contribute to vascular disease. However, mitochondrial changes in ageing remain ill-defined because of the challenges of imaging in native cells. We determined the structure of mitochondria in live native cells, demarcating boundaries of individual organelles by inducing stochastic 'flickers' of membrane potential, recorded as fluctuations in potentiometric fluorophore intensity (flicker-assisted localization microscopy; FaLM). In freshly-isolated myocytes from rat cerebral resistance arteries, FaLM showed a range of mitochondrial X-Y areas in both young adult (3 months; 0.05-6.58 MUm(2) ) and aged rats (18 months; 0.05-13.4 MUm(2) ). In cells from young animals, most mitochondria were small (mode area 0.051 MUm(2) ) compared to aged animals (0.710 MUm(2) ). Cells from older animals contained a subpopulation of highly-elongated mitochondria (5.3% were >2 MUm long, 4.2% had a length:width ratio >3) that was rare in younger animals (0.15% of mitochondria >2 MUm long, 0.4% had length:width ratio >3). The extent of mitochondrial motility also varied. 1/811 mitochondria observed moved slightly (~0.5 MUm) in myocytes from older animals, whereas, in the younger animals, directed and Brownian-like motility occurred regularly (215 of 1135 mitochondria moved within 10 min, up to distance of 12 MUm). Mitochondria positioned closer to the cell periphery showed a greater tendency to move. In conclusion, cerebral vascular myocytes from young rats contained small, motile mitochondria. In aged rats, mitochondria were larger, immobile and could be highly-elongated. These age-associated alterations in mitochondrial behaviour may contribute to alterations in cell signalling, energy supply or the onset of proliferation. PMID- 26959408 TI - ReAsH as a Quantitative Probe of In-Cell Protein Dynamics. AB - The tetracysteine (tc) tag/biarsenical dye system (FlAsH or ReAsH) promises to combine the flexibility of fluorescent protein tags with the small size of dye labels, allowing in-cell study of target proteins that are perturbed by large protein tags. Quantitative thermodynamic and kinetic studies in-cell using FlAsH and ReAsH have been hampered by methodological complexities presented by the fluorescence properties of the tag-dye complex probed by either Forster resonance energy transfer (FRET) or direct excitation. We label the model protein phosphoglycerate kinase (PGK) with AcGFP1 and ReAsH for direct comparison with AcGFP1/mCherry-labeled PGK. We find that fast relaxation imaging (FReI), combining millisecond temperature jump kinetics with fluorescence microscopy detection, circumvents many of the difficulties encountered working with the ReAsH system, allowing us to obtain quantitative FRET measurements of protein stability and kinetics both in vitro and in cells. We also demonstrate the to us surprising result that fluorescence from directly excited, unburied ReAsH at the C-terminus of the model protein also reports on folding in vitro and in cells. Comparing the ReAsH-labeled protein to a construct labeled with two fluorescent protein tags allows us to evaluate how a bulkier protein tag affects protein dynamics in cells and in vitro. We find that the average folding rate in the cell is closer to the in vitro rate with the smaller tag, highlighting the effect of tags on quantitative in-cell measurements. PMID- 26959409 TI - tert-Butyl Hydroperoxide Mediated Cascade Synthesis of 3-Arylsulfonylquinolines. AB - 3-Arylsulfonylquinoline derivatives play important roles as pharmaceutical drugs. A new method for the synthesis of 3-arylsulfonylquinoline derivatives has been achieved through tert-butyl hydroperoxide mediated cycloaddition between N propargyl aromatic amine derivatives and arylsulfonylhydrazides without the addition of any metals. This transformation offers a straightforward route to the formation of a C-S bond and quinoline ring in one step via a sulfonylation cyclization-aromatization process. PMID- 26959410 TI - Adherence to oral anticancer agents: Healthcare providers' perceptions, beliefs and shared decision making in Belgium and the Netherlands. AB - BACKGROUND: Little is known about healthcare providers' (HCPs) perceptions of adherence management of oral anticancer agents (OACA). The study aims to explore HCPs perceptions of OACA and adherence. METHODS: A cross-sectional, multi-center observational study among HCPs in hemato-oncology settings in Belgium and the Netherlands was conducted. Physicians, nurse practitioners, nurses and pharmacists were asked to complete questionnaires on their perception of patient adherence and its management (PAMQ) and their beliefs about OACA (BMQ-Specific). Physicians were also asked to complete a questionnaire on their perception of shared decision making (SDM-Q-Doc). RESULTS: The sample consisted of 254 HCPs. Variations were found between HCPs on the PAMQ: 56%, 50%, 28% and 23% of, respectively, physicians, nurse practitioners, nurses and pharmacists reported to know the level of adherence of their patients and 59%, 53%, 43% and 10% of, respectively, physicians, nurse practitioners, nurses and pharmacists think that patients discuss adherence with them. 70%, 82%, 63% and 62% of, respectively, physicians, nurse practitioners, nurses and pharmacists reported to have knowledge of causes of non-adherence, while 78%, 87%, 76% and 80% of them reported to have knowledge of consequences of non-adherence. 81%, 92%, 83% and 67% of, respectively, physicians, nurse practitioners, nurses and pharmacists felt able to influence adherence. Lower concerns beliefs were associated with a higher total score on the PAMQ [beta (SE)=-0.85 (0.24); CI -1.33--0.38]. Physicians scored a mean of 75 on the SDM-scale. CONCLUSIONS: A considerable part of the HCPs states they do not know the adherence of their patients, nor do they think patients discuss adherence with them. However, they feel to have knowledge of adherence and perceive to be able to influence adherence of their patients. PMID- 26959411 TI - Endoscopy in patients with diarrhea during treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors: Is the cause in the mucosa? AB - BACKGROUND: Diarrhea is a frequently occurring adverse event during treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) and is mostly accompanied by abdominal cramps, flatulence and pyrosis. These complaints impair quality of life and lead to dose reductions and treatment interruptions. It is hypothesized that the diarrhea might be due to ischemia in bowel mucosa or inflammation, but the exact underlying pathophysiological mechanism of the diarrhea is still unknown. We aimed at exploring the mechanism for diarrhea in these patients by thorough endoscopic and histological assessment. MATERIALS AND METHODS: Endoscopies of the upper and lower gastrointestinal (GI) tract in 10 patients with metastatic renal cell carcinoma (mRCC) who developed diarrhea during treatment with VEGFR TKIs were performed. RESULTS: Ten patients were included. The results showed endoscopically normal mucosa in the lower GI tract in seven patients without signs of ischemic colitis or inflammation. Gastroduodenoscopy revealed gastro-esophageal reflux disease, bulbitis and/or duodenitis with ulcers in eight patients. In three selected patients with bulbitis/duodenitis additional video capsule endoscopy was performed but revealed no additional intestinal abnormalities. CONCLUSION: We observed frequent mucosal abnormalities in the upper GI tract in VEGFR TKI treated mRCC patients with diarrhea. Although these abnormalities provide insufficient explanation for the occurrence of diarrhea, we suggest to perform routine upper GI endoscopy in VEGFR TKI-treated patients with GI complaints. PMID- 26959412 TI - Rhizoleucinoside, a Rhamnolipid-Amino Alcohol Hybrid from the Rhizobial Symbiont Bradyrhizobium sp. BTAi1. AB - Rhizoleucinoside (1), a unique rhamnolipid-amino alcohol hybrid, was isolated from the rhizobial symbiont bacterium Bradyrhizobium sp. BTAi1. Compound 1 features a rare rhamnolipid core attached to an unprecedented leucinol moiety. Its structure and absolute configuration were determined by spectroscopic analysis, tandem mass spectrometry, chemical degradation, and application of the Marfey's method. Compound 1 possesses moderate cytotoxicity to BV-2 murine microglia and highly aggressive proliferating immortalized (HAPI) rat microglia cells. PMID- 26959413 TI - Successful Control of Ebola Virus Disease: Analysis of Service Based Data from Rural Sierra Leone. AB - INTRODUCTION: The scale and geographical distribution of the current outbreak in West Africa raised doubts as to the effectiveness of established methods of control. Ebola Virus Disease (EVD) was first detected in Sierra Leone in May 2014 in Kailahun district. Despite high case numbers elsewhere in the country, transmission was eliminated in the district by December 2014. We describe interventions underpinning successful EVD control in Kailahun and implications for EVD control in other areas. METHODS: Internal service data and published reports from response agencies were analysed to describe the structure and type of response activities, EVD case numbers and epidemic characteristics. This included daily national situation reports and District-level data and reports of the Sierra Leone Ministry of Health and Sanitation, and Medecins Sans Frontieres (MSF) patient data and internal epidemiological reports. We used EVD case definitions provided by the World Health Organisation over the course of the outbreak. Characteristics assessed included level of response activities and epidemiological features such as reported exposure (funeral-related or not), time interval between onset of illness and admission to the EVD Management Centre (EMC), work-related exposures (health worker or not) and mortality. We compared these characteristics between two time periods--June to July (the early period of response), and August to December (when coverage and quality of response had improved). A stochastic model was used to predict case numbers per generation with different numbers of beds and a varying percentage of community cases detected. RESULTS: There were 652 probable/confirmed EVD cases from June-December 2014 in Kailahun. An EMC providing patient care opened in June. By August 2014 an integrated detection, treatment, and prevention strategy was in place across the district catchment zone. From June-July to August-December 2014 surveillance and contact tracing staff increased from 1.0 to 8.8 per confirmed EVD case, EMC capacity increased from 32 to 100 beds, the number of burial teams doubled, and health promotion activities increased in coverage. These improvements in response were associated with the following changes between the same periods: the proportion of confirmed/probable cases admitted to the EMC increased from 35% to 83% (chi(2) p-value<0.001), the proportion of confirmed patients admitted to the EMC <3 days of symptom onset increased from 19% to 37% (chi(2) p-value <0.001), and reported funeral contact in those admitted decreased from 33% to 16% (chi(2) p-value <0.001). Mathematical modelling confirmed the importance of both patient management capacity and surveillance and contact tracing for EVD control. DISCUSSION: Our findings demonstrate that control of EVD can be achieved using established interventions based on identification and appropriate management of those who are at risk of and develop EVD, including in the context of ongoing transmission in surrounding regions. Key attributes in achieving control were sufficient patient care capacity (including admission to specialist facilities of suspect and probable cases for assessment), integrated with adequate staffing and resourcing of community-based case detection and prevention activities. The response structure and coverage targets we present are of value in informing effective control in current and future EVD outbreaks. PMID- 26959414 TI - MiR-3162-3p Is a Novel MicroRNA That Exacerbates Asthma by Regulating beta Catenin. AB - Asthma is a common chronic respiratory disease. In a previous study, we found several circulating microRNA signatures associated with childhood asthma and selected miR-3162-3p for subsequent studies. Since the target proteins and underlying molecular mechanisms of miR-3162-3p in asthma etiopathogenesis are not well characterized, we designed this study to clarify its role. We employed bioinformatics and quantitative PCR methods as a first step to determine the target of miR-3162-3p, and we elucidated beta-catenin. Luciferase assays and western blot analysis confirmed beta-catenin as a direct target of miR-3162-3p as the 3'-untranslated region of beta-catenin mRNA possesses a specific miR-3162-3p pairing site. The correlation between the expression levels of miR-3162-3p and beta-catenin is confirmed by quantitative PCR and western blot studies in A549, Beas-2B and H1299 cell lines and OVA-induced asthma mouse model. Of note, upregulation of the endogenous miR-3162-3p level is concomitant with the reduction of beta-catenin mRNA and protein expression levels. MiR-3162-3p antagomir treatment antagonizes the endogenous miR-3162-3p and effectively rescues the attenuation of endogenous beta-catenin in OVA-induced asthmatic mice, which alleviates airway hyperresponsiveness and ameliorates airway inflammation. Collectively, our findings suggest a novel relationship between miR-3162-3p and beta-catenin and clarify their mechanistic role in asthma etiopathogenesis. PMID- 26959416 TI - Crossed and Locked Quotes in a Multi-Market Simulation. AB - Financial markets are often fragmented, introducing the possibility that quotes in identical securities may become crossed or locked. There are a number of theoretical explanations for the existence of crossed and locked quotes, including competition, simultaneous actions, inattentiveness, fee structure and market access. In this paper, we perform a simulation experiment designed to examine the effect of simple order routing procedures on the properties of a fragmented market consisting of a single security trading in two independent limit order books. The quotes in the two markets are connected solely by the routing decision of the market participants. We report on the health of the consolidated market as measured by the duration of crossed and locked states, as well as the spread and the volatility of transaction prices in the consolidated market. We aim to quantify exactly how the prevalence of order routing among a population of market participants affects properties of the consolidated market. Our model contributes to the zero-intelligence literature by treating order routing as an experimental variable. Additionally, we introduce a parsimonious heuristic for limit order routing, allowing us to study the effects of both market order routing and limit order routing. Our model refines intuition for the sometimes subtle relationships between the prevalence of order routing and various market measures. Our model also provides a benchmark for more complex agent-based models. PMID- 26959415 TI - Prior Adjuvant Tamoxifen Treatment in Breast Cancer Is Linked to Increased AIB1 and HER2 Expression in Metachronous Contralateral Breast Cancer. AB - AIM: The estrogen receptor coactivator Amplified in Breast Cancer 1 (AIB1) has been associated with an improved response to adjuvant tamoxifen in breast cancer, but also with endocrine treatment resistance. We hereby use metachronous contralateral breast cancer (CBC) developed despite prior adjuvant tamoxifen for the first tumor as an "in vivo"-model for tamoxifen resistance. AIB1-expression in the presumable resistant (CBC after prior tamoxifen) and naive setting (CBC without prior tamoxifen) is compared and correlated to prognosis after CBC. METHODS: From a well-defined population-based cohort of CBC-patients we have constructed a unique tissue-microarray including >700 patients. RESULTS: CBC developed after adjuvant tamoxifen more often had a HER2-positive/triple negative subtype and a high AIB1-expression (37% vs. 23%, p = 0.009), than if no prior endocrine treatment had been administered. In patients with an estrogen receptor (ER) positive CBC, a high AIB1-expression correlated to an inferior prognosis. However, these patients seemed to respond to tamoxifen, but only if endocrine therapy had not been administered for BC1. CONCLUSIONS: Metachronous CBC developed after prior endocrine treatment has a decreased ER-expression and an increased HER2-expression. This is consistent with endocrine treatment escape mechanisms previously suggested, and indicates metachronous CBC to be a putative model for studies of treatment resistance "in vivo". The increased AIB1 expression in CBC developed after prior tamoxifen suggests a role of AIB1 in endocrine treatment resistance. In addition, we found indications that the response to tamoxifen in CBC with a high AIB1-expression seem to differ depending on previous exposure to this drug. A different function for AIB1 in the tamoxifen treatment naive vs. resistant setting is suggested, and may explain previously conflicting results where a high AIB1-expression has been correlated to both a good response to adjuvant tamoxifen and tamoxifen resistance. PMID- 26959417 TI - Serum Removal from Culture Induces Growth Arrest, Ploidy Alteration, Decrease in Infectivity and Differential Expression of Crucial Genes in Leishmania infantum Promastigotes. AB - Leishmania infantum is one of the species responsible for visceral leishmaniasis. This species is distributed basically in the Mediterranean basin. A recent outbreak in humans has been reported in Spain. Axenic cultures are performed for most procedures with Leishmania spp. promastigotes. This model is stable and reproducible and mimics the conditions of the gut of the sand fly host, which is the natural environment of promastigote development. Culture media are undefined because they contain mammalian serum, which is a rich source of complex lipids and proteins. Serum deprivation slows down the growth kinetics and therefore, yield in biomass. In fact, we have confirmed that the growth rate decreases, as well as infectivity. Ploidy is also affected. Regarding the transcriptome, a high throughput approach has revealed a low differential expression rate but important differentially regulated genes. The most remarkable profiles are: up-regulation of the GINS Psf3, the fatty acyl-CoA synthase (FAS1), the glyoxylase I (GLO1), the hydrophilic surface protein B (HASPB), the methylmalonyl-CoA epimerase (MMCE) and an amastin gene; and down-regulation of the gPEPCK and the arginase. Implications for metabolic adaptations, differentiation and infectivity are discussed herein. PMID- 26959422 TI - Knowledge of A1c Predicts Diabetes Self-Management and A1c Level among Chinese Patients with Type 2 Diabetes. AB - This study was to identify current A1c understanding status among Chinese patients with type 2 diabetes, assess if knowledge of A1c affects their diabetes self-management and their glycemic control and recognize the factors influencing knowledge of A1c among patients with type 2 diabetes. A multi-center, cross sectional survey was conducted between April and July 2010 in 50 medical centers in the Mainland China. Participants were recruited from inpatients and outpatients who were admitted to or visited those medical centers. The survey included core questions about their demographic characteristics, diabetes self management behavior, and A1c knowledge. Overall, of 5957 patients, the percentage of patients with good understanding was 25.3%. In the multivariable logistic regression model, the variables related to the knowledge of A1c status are presented. We discovered that patients with longer diabetes duration (OR = 1.05; 95%CI = 1.04-1.06) and having received diabetes education (OR = 1.80; 95%CI = 1.49-2.17) were overrepresented in the good understanding of A1c group. In addition, compared to no education level, higher education level was statistically associated with good understanding of A1c (P<0.001). The percentage of patients with good understanding varied from region to region (P<0.001), with Eastern being highest (OR = 1.54; 95%CI = 1.32-1.80), followed by Central (OR = 1.25; 95%CI = 1.02-1.53), when referring to Western. Only a minority of patients with type 2 diabetes in China understood their A1c value. The patients who had a good understanding of their A1c demonstrated significantly better diabetes self management behavior and had lower A1c levels than those who did not. PMID- 26959423 TI - Uric Acid, Parathyroid Hormone, and Vitamin D: New Players in an Old Game. PMID- 26959424 TI - Climate Change Influences on the Global Potential Distribution of Bluetongue Virus. AB - The geographic distribution of arboviruses has received considerable attention after several dramatic emergence events around the world. Bluetongue virus (BTV) is classified among category "A" diseases notifiable to the World Organization of Animal Health (OIE), and is transmitted among ruminants by biting midges of the genus Culicoides. Here, we developed a comprehensive occurrence data set to map the current distribution, estimate the ecological niche, and explore the future potential distribution of BTV globally using ecological niche modeling and based on diverse future climate scenarios from general circulation models (GCMs) for four representative concentration pathways (RCPs). The broad ecological niche and potential geographic distribution of BTV under present-day conditions reflected the disease's current distribution across the world in tropical, subtropical, and temperate regions. All model predictions were significantly better than random expectations. As a further evaluation of model robustness, we compared our model predictions to 331 independent records from most recent outbreaks from the Food and Agriculture Organization Emergency Prevention System for Transboundary Animal and Plant Pests and Diseases Information System (EMPRES-i); all were successfully anticipated by the BTV model. Finally, we tested ecological niche similarity among possible vectors and BTV, and could not reject hypotheses of niche similarity. Under future-climate conditions, the potential distribution of BTV was predicted to broaden, especially in central Africa, United States, and western Russia. PMID- 26959425 TI - Get your share of the NHS healthy staff fund. PMID- 26959426 TI - Trust appoints clinical matrons to improve care quality on wards. PMID- 26959427 TI - RCNi's online learning resource will help you with revalidation. PMID- 26959429 TI - Bieber meets his NHS chart rivals. PMID- 26959428 TI - Public health commissioners not making the most of nurses' skills. PMID- 26959430 TI - Put care before immigration targets, warns RCN. PMID- 26959432 TI - The 'speaking up guardian' quits after two months. PMID- 26959431 TI - NHS England will help fund staff health drive for trusts that ditch junk food. PMID- 26959433 TI - CNS role reduces miscommunication. PMID- 26959435 TI - Nurses to test phone app to help women at risk of FGM. PMID- 26959436 TI - Patient group calls for league tables to fight hospital-acquired infections. PMID- 26959437 TI - Nurses lead endoscopy pilot. PMID- 26959438 TI - Stereotypes and cultural cringe still keeping men out of nursing. PMID- 26959444 TI - Myeloma. PMID- 26959445 TI - With responsibility comes vulnerability. AB - The Medical Defence Union warns that as nurses take on more responsibilities, they are more vulnerable to complaints and clinical negligence cases. Advanced nurse practitioners are advised to work within their competence, communicate clearly and apologise when things go wrong. PMID- 26959447 TI - More inspections for poor performers. AB - The CQC is consulting on changes to its inspection model. The proposals would mean better use of data, more inspections for the worse performing services and greater patient involvement in inspections. PMID- 26959446 TI - Spotting signs of dementia. AB - Care home staff are well placed to notice if an older person living in the home may be developing dementia. A tool developed for their use--DeAR GP (Dementia Assessment Referral to GP)--empowers care home staff, makes more efficient use of GPs' and specialist memory nurses' time, and improves diagnosis of dementia. PMID- 26959460 TI - GoodSAM Responder app. PMID- 26959448 TI - Scholarship can help ideas flourish. AB - Scholarships from the Florence Nightingale Foundation are providing nurses with the financial means to put innovative ideas into practice. Nurses from all four countries of the UK can apply for leadership, travel and research scholarships to support their career development and help improve patient care. PMID- 26959461 TI - Constructive criticism is essential, but so is praise. AB - In a fast paced, stressful and ever-changing NHS, it is essential that staff receive constructive criticism. This is a vital element of ongoing professional development and reflective practice, and benefits patient care and working relationships. Nurses must also learn how to act on constructive criticism, and use it to learn and develop their practice. PMID- 26959462 TI - Seven-day-a-week, non-emergency care will spread staff too thinly. PMID- 26959463 TI - Outstanding nurse-led practice is a model for the way forward. PMID- 26959464 TI - Even most caring nurses can end up feeling desensitised. PMID- 26959465 TI - Pension deal is nothing other than a stunt to save trust money. PMID- 26959466 TI - Equality of opportunity is of vital importance at all levels. PMID- 26959470 TI - How to suction via a tracheostomy. PMID- 26959471 TI - Using risk management to promote person-centred dementia care. AB - Risk management for people with dementia has traditionally focused on preventing physical harm. However, research has demonstrated that focusing on the physical safety of people with dementia may result in their social and psychological wellbeing being overlooked - the very aspects that are necessary to achieve person-centred care. This article discusses the main challenges for practitioners caring for people with dementia in various settings, and encourages a care approach which enables appropriate risk taking as a way of promoting person centred care. PMID- 26959472 TI - Promoting healthy sleep. AB - Nurses are accustomed to helping others with their sleep problems and dealing with issues such as pain that may delay or interrupt sleep. However, they may be less familiar with what constitutes a healthy night's sleep. This article examines what is known about the process and purpose of sleep, and examines the ways in which factors that promote wakefulness and sleep combine to help establish a normal circadian rhythm. Theories relating to the function of sleep are discussed and research is considered that suggests that sleep deficit may lead to metabolic risks, including heart disease, obesity, type 2 diabetes mellitus and several types of cancer. PMID- 26959473 TI - NMC revalidation. PMID- 26959474 TI - Prepare for interview. PMID- 26959475 TI - Take a walk on the wild side. PMID- 26959477 TI - An eye-opening placement. PMID- 26959478 TI - Interaction Between CYP4F2 rs2108622 and CPY4A11 rs9333025 Variants Is Significantly Correlated with Susceptibility to Ischemic Stroke and 20 Hydroxyeicosatetraenoic Acid Level. AB - AIMS: To investigate the association of four variants of two CYP omega hydroxylase genes and 20-hydroxyeicosatetraenoic acid (HETE) levels with ischemic stroke (IS) and whether gene-gene interactions between these genes increase the risk of IS. METHODS: Three hundred ninety-six patients with IS and 378 controls were genotyped for rs2269231, rs9333025, rs2108622, and rs3093135. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods. The 20-HETE levels was measured in 218 IS patients and 126 controls. RESULTS: The frequency of the GG genotype of rs9333025 was significantly higher in IS patients than in controls (p < 0.001). The GMDR analysis showed a significant gene-gene interaction between rs9333025 and rs2108622 (p = 0.0116). This gene-gene interaction predicted a significantly higher risk of IS in individuals carrying the genotypes of rs9333025 GG and rs2108622 GG (odds ratio = 1.92, 95% confidence interval = 1.12-4.26, p = 0.007). The plasma levels of 20-HETE were significantly higher in IS patients than in controls, and IS patients carrying the genotype combination of rs9333025 GG and rs2108622 GG had higher 20-HETE levels than IS patients with other combinations of the two variants. CONCLUSION: CYP4A1l rs9333025 GG and CYP4F2 rs2108622 GG two loci interaction significantly increases the risk for IS and an elevated 20-HETE level. PMID- 26959479 TI - Activity improvement of a Kluyveromyces lactis aldo-keto reductase KlAKR via rational design. AB - Optically pure t-butyl 6-cyano-(3R, 5R)-dihydroxyhexanoate ((R)-1b) is the key chiral precursor for atorvastatin calcium, the most widely used cholesterol lowering drug. Wild-type aldo-keto reductase KlAKR from Kluyveromyces lactis has ideal diastereoselectivity toward t-butyl 6-cyano-(5R)-hydroxy-3-oxohexanoate (1a, dep>99.5%) but poor activity. A rational engineering was used to improve the KlAKR activity. Based on homology modeling and molecular docking, two amino acid residues (295 and 296) were selected as mutation sites, and two rounds of site saturation mutagenesis were performed. Among the mutants, KlAKR-Y295W/W296L exhibited the highest catalytic efficiency (kcat/Km) toward 1a up to 12.37s( 1)mM(-1), which was 11.25-fold higher than that of wild-type KlAKR. Moreover, the majority of mutations have no negative impact on stereoselectivity. Using KlAKR Y295W/W296L coupled with Exiguobacterium sibiricum glucose dehydrogenase (EsGDH) for cofactor regeneration, (R)-1b was accumulated up to 162.7mM with dep value above 99.5%. KlAKR-Y295W/W296L represents a robust tool for (R)-1b synthesis. PMID- 26959480 TI - Epidemiology and Clinical Characteristics of Pediatric Drug-Resistant Tuberculosis in Chongqing, China. AB - To gain insight into the epidemiology of childhood drug resistant tuberculosis (DR-TB) in China that has the second largest burden of TB and the largest number of multidrug resistant (MDR) TB cases in the world, we performed the cross sectional study to investigate drug resistance of four first-line anti-TB drugs (isoniazid, rifampicin, streptomycin and ethambutol) using Mycobacterium tuberculosis isolates from 196 culture-confirmed pediatric TB cases diagnosed in the Children's Hospital of Chongqing Medical University, China during 2008-2013. Univariate and multivariate logistic regression analyses were performed to assess the associations between patient demographic and clinical characteristics and DR and MDR-TB, respectively. Twenty-eight percent (56/196) of the study patients exhibited resistance to at least one of the four first-line anti-TB drugs tested. MDR was found in 4.6% (9/196) of the study patients. More than half (5/9, 55.6%) of the MDR cases were from a single county of Chongqing. A significant association was found between being acid-fast bacilli-smear negative and DR-TB (adjusted OR, 2.33; 95% CI, 1.13-4.80) and between having concurrent thoracic extrathoracic involvement and MDR-TB (adjusted OR, 9.49; 95% CI, 1.05-85.92), respectively. The findings of this study indicate that the rate of DR is high among pediatric TB patients in Chongqing and suggest an urgent need for studies to identify MDR transmission hotspots in Chongqing, thereby contributing to the control DR- and MDR-TB epidemics in China. The study also generates new insight into the pathogenesis of DR and MDR M. tuberculosis strains and highlights the importance of studying childhood TB to the goal of global TB control. PMID- 26959481 TI - Influence of common genetic variants on childhood kidney outcomes. AB - BACKGROUND: Kidney measures in early life are associated with kidney disease in later life. We hypothesized that these associations are partly explained by common genetic variants that lead to both smaller kidneys with lower kidney function in early childhood and kidney disease in adulthood. METHODS: We examined in a population-based prospective cohort study among 4,119 children the associations of a weighted genetic risk score combining 20 previously identified common genetic variants related to adult eGFRcreat with kidney outcomes in children aged 6.0 years (95% range 5.7-7.8). Childhood kidney outcomes included combined kidney volume, glomerular filtration rate (eGFR) based on creatinine levels, and microalbuminuria based on albumin and creatinine urine levels. RESULTS: We observed that the genetic risk score based on variants related to impaired kidney function in adults was associated with a smaller combined kidney volume (P value 3.0 * 10(-3)) and with a lower eGFR (P value 4.0 * 10(-4)) in children. The genetic risk score was not associated with microalbuminuria. CONCLUSION: Common genetic variants related to impaired kidney function in adults already lead to subclinical changes in childhood kidney outcomes. The well-known associations of kidney measures in early life with kidney disease in later life may at least be partly explained by common genetic variants. PMID- 26959482 TI - Estimations of dietary vitamin D requirements in black and white children. AB - BACKGROUND: The Institute of Medicine (IOM) dietary guidelines for vitamin D are based on limited pediatric data. Our objective was to estimate the dietary vitamin D requirements for maintaining serum 25-hydroxyvitamin D [25(OH)D] concentrations at the various IOM-considered thresholds of vitamin D status (12, 16, and 20 ng/ml) during fall and winter in children. METHODS: Ninety-six healthy 8- to 14-y-old Pittsburgh-area black and white children enrolled in a randomized, placebo-controlled trial of vitamin D3 1,000 IU daily for 6 mo with baseline and 2-mo follow-up assessments completed during October through April were studied. Vitamin D intake from diet and study supplement adjusted for adherence and serum 25(OH)D were measured. RESULTS: The vitamin D intakes needed to maintain serum 25(OH)D concentrations at 12, 16, and 20 ng/ml in 90% of the children were 581, 1,062, and 1543 IU/day, respectively. The estimated vitamin D intakes needed to maintain serum 25(OH)D concentrations at 20 ng/ml in 97.5% of the children was 2,098 IU/day. CONCLUSION: Our data suggest that the current vitamin D recommended dietary allowance (RDA) (600 IU/day) is insufficient to cover the skeletal health needs of at least 50% of black and white children. PMID- 26959483 TI - Altered gene expression and possible immunodeficiency in cases of sudden infant death syndrome. AB - BACKGROUND: A large number of studies have tried to uncover a genetic predisposition for sudden infant death syndrome (SIDS), but there is still uncertainty concerning the pathogenesis of these deaths. The purpose of this study was to investigate mRNA gene expression in SIDS cases and controls, in order to uncover genes that are differentially expressed in the two groups. METHODS: Tissue from brain, heart, and liver from 15 SIDS cases and 15 controls were included in the study, and mRNA expression was determined using the Illumina whole genome gene expression DASL HT assay. RESULTS: Seventeen genes showed significantly altered expression compared to controls, after correction for multiple testing. Three genes involved in the immune system were of particular interest, including the downregulation of MyD88 in tissue from SIDS brains, as well as the downregulation of the genes encoding CCL3 and UNC13 in the liver. CONCLUSION: These findings indicate that there is an altered expression of genes involved in the inflammatory process in a proportion of SIDS cases, which further strengthen the hypothesis that impaired immune response play a role in this syndrome. PMID- 26959484 TI - Modafinil improves monocrotaline-induced pulmonary hypertension rat model. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) progressively leads to increases in pulmonary vasoconstriction. Modafinil plays a role in vasorelaxation and blocking KCa3.1 channel with a result of elevating intracellular cyclic adenosine monophosphate (cAMP) levels. The purpose of this study is to evaluate the effects on modafinil in monocrotaline (MCT)-induced PAH rat. METHODS: The rats were separated into three groups: the control group, the monocrotaline (M) group (MCT 60 mg/kg), and the modafinil (MD) group (MCT 60 mg/kg + modafinil). RESULTS: Reduced right ventricular pressure (RVP) was observed in the MD group. Right ventricular hypertrophy was improved in the MD group. Reduced number of intra-acinar pulmonary arteries and medial wall thickness were noted in the MD group. After the administration of modafinil, protein expressions of endothelin-1 (ET-1), endothelin receptor A (ERA) and KCa3.1 channel were significantly reduced. Modafinil suppressed pulmonary artery smooth muscle cell (PASMC) proliferation via cAMP and KCa3.1 channel. Additionally, we confirmed protein expressions such as Bcl-2-associated X, vascular endothelial growth factor, tumor necrosis factor-alpha, and interleukin-6 were reduced in the MD group. CONCLUSION: Modafinil improved PAH by vasorelaxation and a decrease in medial thickening via ET-1, ERA, and KCa3.1 down regulation. This is a meaningful study of a modafinil in PAH model. PMID- 26959485 TI - Clinical associations of immature breathing in preterm infants: part 1-central apnea. AB - BACKGROUND: Apnea of prematurity (AOP) is nearly universal among very preterm infants, but neither the apnea burden nor its clinical associations have been systematically studied in a large consecutive cohort. METHODS: We analyzed continuous bedside monitor chest impedance and electrocardiographic waveforms and oxygen saturation data collected on all neonatal intensive care unit (NICU) patients <35 wk gestation from 2009 to 2014 (n = 1,211; >50 infant-years of data). Apneas, with bradycardia and desaturation (ABDs), defined as central apnea >=10 s associated with both bradycardia <100 bpm and oxygen desaturation <80%, were identified using a validated automated algorithm. RESULTS: Number and duration of apnea events decreased with increasing gestational age (GA) and postmenstrual age (PMA). ABDs were more frequent in infants <31 wk GA at birth but were not more frequent in those with severe retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), or severe intraventricular hemorrhage (IVH) after accounting for GA. In the day before diagnosis of late-onset septicemia and necrotizing enterocolitis, ABD events were increased in some infants. Many infants continued to experience short ABD events in the week prior to discharge home. CONCLUSION: Frequency of apnea events is a function of GA and PMA in infants born preterm, and increased apnea is associated with acute but not with chronic pathologic conditions. PMID- 26959486 TI - CpG island shore methylation of ZFPM2 is identified in tetralogy of fallot samples. AB - BACKGROUND: ZFPM2 gene plays an important role in heart morphogenesis and development of coronary vessels from epicardium, however, little is known regarding its epigenetic regulation in the pathogenesis of tetralogy of fallot (TOF). METHODS: The methylation levels of ZFPM2 gene were measured by MassArray (Sequenom, San Diego, CA) and bisulfite sequencing polymerase chain reaction (PCR) (BSP). Real-time PCR was performed to analyze the mRNA levels for ZFPM2 gene in the myocardium of TOF. RESULTS: The methylation levels in the CpG island shore of ZFPM2 promoter were significantly higher in patients with TOF, with a median of 80.32% (interquartile range (IQR): 73.54-85.75%, N = 42), as compared to 59.63% in controls (IQR: 44.79-73.83%; P = 0.0186, N = 6). No significant difference was observed in the methylation status at the CpG island of ZFPM2 promoter. The ZFPM2 mRNA levels were significantly lower in patients with TOF compared to that in the controls (P < 0.05). The aberrant methylation values of ZFPM2 were negatively associated with significant changes in its mRNA level (r = 0.40, P = 0.008, N = 42). CONCLUSION: Aberrant methylation status at the promoter CpG island shore of ZFPM2 gene may be associated with its gene transcription regulation in the TOF patients. PMID- 26959488 TI - Differential Health and Social Needs of Older Adults Waitlisted for Public Housing or Housing Choice Vouchers. AB - Affordable housing is an important form of income security for low-income older persons. This article describes characteristics of older persons waitlisted for either public housing or a housing choice voucher (HCV; previously Section 8) in Portland, Oregon. 358 persons (32% response rate) completed a mailed survey with questions about demographics, health and housing status, food insecurity, and preference for housing with services. Findings indicate that many waitlisted older persons experienced homelessness or housing instability, poor health, high hospital use, and food insecurity. Public housing applicants were significantly more likely to report lower incomes, homelessness, and food insecurity than HCV applicants. We conclude with policy implications for housing and health agencies that serve low-income older persons. PMID- 26959487 TI - Endoplasmic Reticulum Stress and Autophagy in Homocystinuria Patients with Remethylation Defects. AB - Proper function of endoplasmic reticulum (ER) and mitochondria is crucial for cellular homeostasis, and dysfunction at either site as well as perturbation of mitochondria-associated ER membranes (MAMs) have been linked to neurodegenerative and metabolic diseases. Previously, we have observed an increase in ROS and apoptosis levels in patient-derived fibroblasts with remethylation disorders causing homocystinuria. Here we show increased mRNA and protein levels of Herp, Grp78, IP3R1, pPERK, ATF4, CHOP, asparagine synthase and GADD45 in patient derived fibroblasts suggesting ER stress and calcium perturbations in homocystinuria. In addition, overexpressed MAM-associated proteins (Grp75, sigma 1R and Mfn2) were found in these cells that could result in mitochondrial calcium overload and oxidative stress increase. Our results also show an activation of autophagy process and a substantial degradation of altered mitochondria by mitophagy in patient-derived fibroblasts. Moreover, we have observed that autophagy was partially abolished by antioxidants suggesting that ROS participate in this process that may have a protective role. Our findings argue that alterations in Ca2+ homeostasis and autophagy may contribute to the development of this metabolic disorder and suggest a therapeutic potential in homocystinuria for agents that stabilize calcium homeostasis and/or restore the proper function of ER-mitochondria communications. PMID- 26959489 TI - How Different Medical School Selection Processes Call upon Different Personality Characteristics. AB - BACKGROUND: Research indicates that certain personality traits relate to performance in the medical profession. Yet, personality testing during selection seems ineffective. In this study, we examine the extent to which different medical school selection processes call upon desirable personality characteristics in applicants. METHODS: 1019 of all 1055 students who entered the Dutch Bachelor of Medicine at University of Groningen, the Netherlands in 2009, 2010 and 2011 were included in this study. Students were admitted based on either top pre-university grades (n = 139), acceptance in a voluntary multifaceted selection process (n = 286), or lottery weighted for pre-university GPA. Within the lottery group, we distinguished between students who had not participated (n = 284) and students who were initially rejected (n = 310) in the voluntary selection process. Two months after admission, personality was assessed with the NEO-FFI, a measure of the five factor model of personality. We performed ANCOVA modelling with gender as a covariate to examine personality differences between the four groups. RESULTS: The multifaceted selection group scored higher on extraversion than all other groups(p<0.01), higher on conscientiousness than both lottery-admitted groups(p<0.01), and lower on neuroticism than the lottery admitted group that had not participated in the voluntary selection process. The latter group scored lower on conscientiousness than all other groups(p<0.05) and lower on agreeableness than the multifaceted selection group and the top pre university group(p<0.01). CONCLUSIONS: Differences between the four admission groups, though statistically significant, were relatively small. Personality scores in the group admitted through the voluntary multifaceted selection process seemed most fit for the medical profession. Personality scores in the lottery admitted group that had not participated in this process seemed least fit for the medical profession. It seems that in order to select applicants with suitable personalities, an admission process that calls upon desirable personality characteristics is beneficial. PMID- 26959492 TI - Pregnancy Requires Major Changes in the Quality of the Diet for Nutritional Adequacy: Simulations in the French and the United States Populations. AB - BACKGROUND: Maternal nutrition is critical to the health of both mother and offspring, but there is a paucity of data on the nutritional adequacy of diets during pregnancy. OBJECTIVE: Our objective was to identify to what extent pregnancy reduces the nutritional adequacy of the expecting mother's diet and if this nutritional gap can be resolved by simple quantitative or qualitative changes in the diet. MATERIALS AND METHODS: We evaluated the observed overall nutritional adequacy of diets of French and American women of childbearing age participating in ENNS (n = 344) and NHANES (n = 563) using the probabilistic approach of the PANDiet system, resulting in a 100-point score. Then, we simulated the changes in the PANDiet scores of women of childbearing age who would remain on their diet during pregnancy. Finally, by either increasing the quantity of consumed foods or using eleven snacks recommended during pregnancy, we simulated the effect of a 150-kcal increase in the energy intake of French women. RESULTS: Observed PANDiet scores were equal to 59.3 +/- 7.0 and 58.8 +/- 9.3 points respectively in France and in the US. Simulation of pregnancy for women of childbearing age led to a decrease in nutritional adequacy for key nutrients during pregnancy and resulted in reducing PANDiet scores by 3.3 +/- 0.1 and 3.7 +/- 0.1 points in France and in the US. Simulated 150-kcal increases in energy intake proved to be only partially effective in filling the gap both when the quantity of food consumed was increased and when recommended snacks were used. CONCLUSIONS: The decrease in nutritional adequacy induced by pregnancy cannot be addressed by simply following generic dietary guidelines. PMID- 26959493 TI - Generalized Scaling and the Master Variable for Brownian Magnetic Nanoparticle Dynamics. AB - Understanding the dynamics of magnetic particles can help to advance several biomedical nanotechnologies. Previously, scaling relationships have been used in magnetic spectroscopy of nanoparticle Brownian motion (MSB) to measure biologically relevant properties (e.g., temperature, viscosity, bound state) surrounding nanoparticles in vivo. Those scaling relationships can be generalized with the introduction of a master variable found from non-dimensionalizing the dynamical Langevin equation. The variable encapsulates the dynamical variables of the surroundings and additionally includes the particles' size distribution and moment and the applied field's amplitude and frequency. From an applied perspective, the master variable allows tuning to an optimal MSB biosensing sensitivity range by manipulating both frequency and field amplitude. Calculation of magnetization harmonics in an oscillating applied field is also possible with an approximate closed-form solution in terms of the master variable and a single free parameter. PMID- 26959494 TI - Cardiac Rehabilitation Prevents Recurrent Revascularization in Patients With Coronary Heart Disease: A POPULATION-BASED COHORT STUDY IN TAIWAN. AB - PURPOSE: To evaluate the effects of cardiac rehabilitation (CR) provided within the first 3 months of revascularization on reducing recurrent revascularization in patients with coronary heart disease in Taiwan. METHODS: In this population based cohort study, we used the claims data of 1 million beneficiaries who were randomly selected from all beneficiaries enrolled in Taiwan's National Health Insurance program from 1996 to 2000. Between 2000 and 2007, 2838 patients underwent a first-event revascularization. Of these patients, 442 (15.6%) underwent CR within the first 3 months of admission for revascularization. The remaining 84.4% (n = 2396) served as the non-CR group. All the study patients were followed-up until the end of 2008 for any recurrent revascularization. A propensity score-adjusted Cox proportional hazard model was used to estimate the relative risk of recurrent revascularization associated with CR. RESULTS: During the 1- to 9-year follow-up, 69 patients (15.6%) in the CR group and 840 (35.1%) patients in the non-CR group experienced recurrent revascularization. The results of the propensity score-adjusted Cox proportional hazard regression analysis showed that CR was significantly associated with a reduced risk of recurrent revascularization with a hazard ratio of 0.48 (95% CI, 0.37 to -0.62). CONCLUSIONS: Cardiac rehabilitation within the first 3 months of revascularization is significantly associated with a reduced risk of recurrent revascularization. This preventive effect was more pronounced in men compared with other subgroups of patients. PMID- 26959496 TI - Predicting Peak Oxygen Uptake From the 6-Minute Walk Test in Patients With Pulmonary Hypertension. AB - PURPOSE: To determine whether the 6-minute walk test (6MWT) is a predictor of peak oxygen uptake ((Equation is included in full-text article.)O2) in patients with idiopathic pulmonary arterial hypertension (IPAH). METHODS: A total of 157 patients treated for IPAH completed a 6MWT in accordance with American Thoracic Society standards. Heart rate, pulse oximetry, and Borg rating of perceived exertion were determined at baseline and posttest. A cardiopulmonary exercise test (CPET) was performed on a cycle ergometer using a ramp protocol. Participants were stratified post hoc by age into 3 groups: children (n = 26), adolescents (n = 49), and adults (n = 82). Multiple linear regression analysis was performed to predict peak (Equation is included in full-text article.)O2 from the 6MWT. RESULTS: The regression equation generated for the children was the only model to strongly predict peak (Equation is included in full-text article.)O2 (r = 0.87; P < .001). Similar models for adolescent (r = 0.59; P < .001) and adult groups (r = 0.68; P < .001) did not achieve the same level of correlation. CONCLUSION: Six-Minute Walk Test was able to accurately predict peak (Equation is included in full-text article.)O2 in children (6-12 years) with IPAH; however, the model was weaker for predicting peak (Equation is included in full-text article.)O2 in older populations. These findings suggest that 6MWT may be as valid a test for predicting peak (Equation is included in full-text article.)O2 in children with IPAH as CPET measured peak (Equation is included in full-text article.)O2. In older IPAH populations, CPET is the only reliable method for the evaluation of peak (Equation is included in full-text article.)O2. PMID- 26959495 TI - Strategic Moments: IDENTIFYING OPPORTUNITIES TO ENGAGE CLIENTS IN ATTENDING CARDIAC REHABILITATION AND MAINTAINING LIFESTYLE CHANGES. AB - PURPOSE: There has been extensive investigation of attendance rates at cardiac rehabilitation (CR) but little attention to client reasoning around attendance. This study explored decision-making drivers for attendance or nonattendance at CR programs in rural Victoria, Australia. METHODS: All new patients referred to the CR programs at either the local hospital or community health service over a 6 month period were invited to participate and were interviewed before, after, and at 6 months post-CR. Content analysis was used to identify and group common themes that emerged from the semistructured interviews. RESULTS: Eighty-four of the 114 patients referred agreed to participate in the study. Multiple barriers or facilitators affected the decisions of all clients. Three themes were identified that reflected the participant decision-making experience: (1) invitation and information about participation in CR; (2) person-centered approach to CR provision; and (3) ongoing support needs. Significant decision making points identified were after the cardiac event; before and after hospital based CR; before and after community-based CR; and at 6 months after the cardiac event. At any time there is a risk that the client can become lost or disengaged in the service system, but providing contact at these points can allow them to reengage. CONCLUSIONS: This study provided the opportunity to hear participant voices, describing their decisions around CR attendance after a cardiac event. They highlighted the complexity of issues confronting them and suggested improvements to optimize their attendance and to maintain lifestyle changes. PMID- 26959497 TI - Reproducibility of Anaerobic and Pain Thresholds in Male Patients With Intermittent Claudication. AB - PURPOSE: Maximal and submaximal parameters assessed during treadmill tests are used to prescribe exercise training and assess exercise-induced adaptations in patients with intermittent claudication (IC). Although reproducibility of maximal parameters is well documented, the reproducibility of submaximal is not clear. The aim of this study was to identify the reproducibility (reliability and agreement) of heart rate (HR) and oxygen uptake ((Equation is included in full text article.)O2) measured at the anaerobic (AT) and the pain (PT) thresholds assessed during a maximal test in patients with IC. METHODS: Twenty male patients with IC underwent 2 cardiopulmonary treadmill tests to maximal pain. The HR and (Equation is included in full-text article.)O2 at the AT and PT were identified, and differences between repeat tests were compared. Reliability was determined by intraclass coefficient correlation (ICC). Agreement was assessed by coefficient of variation (CV), standard error of measurement (SEM), smallest detectable difference (SDD), and limits of agreement (LOA). RESULTS: The (Equation is included in full-text article.)O2 at AT and PT exhibited moderate reliability and moderate/good agreement (ICC = 0.73 and 0.70; CV = 9.6% and 11.1%, respectively). The HR at the AT and PT exhibited high reliability and good agreement (ICC = 0.87 and 0.92; SEM = 3.9 and 3.2 bpm; SDD = 10.8 and 8.8 bpm, respectively). The LOA for (Equation is included in full-text article.)O2 at AT and PT were <=20% and for HR <=11 bpm. CONCLUSIONS: The (Equation is included in full-text article.)O2 and HR measured at the AT and PT were moderately to highly reproducible in male patients with IC. The HR and (Equation is included in full-text article.)O2 at AT and PT may be used to establish training intensity and evaluate training effectiveness for these patients in clinical practice and research. PMID- 26959500 TI - Use of Smartphones in Telemedicine: Comparative Study Between Standard and Teledermatological Evaluation of High-Complex Care Hospital Inpatients. AB - BACKGROUND: It is estimated that there are around 7 billion mobile phone subscriptions worldwide. Considering the availability and convenience, it appears to be a suitable device for store-and-forward (SF) consultations. INTRODUCTION: Although teledermatology has been suggested as an effective way of reducing costs and providing otherwise inaccessible expert evaluation, most studies have relied on high cost and high technological means. MATERIALS AND METHODS: We conducted a study with inpatients that required dermatological evaluation in a high complexity university hospital, accessing the correlation between traditional face-to-face evaluation and SF teledermatology, with data and pictures collected by medical students using smartphone cameras and then sent to consultants by e mail. RESULTS: For 2 months, we evaluated 100 patients and, as a result, the total agreement between both consultation modalities was 54%, the partial agreement was 27%, and the disagreement was 19%. DISCUSSION: This study points out that SF teledermatology with the use of mobile phone is comparable to traditional face-to-face evaluation. Furthermore, most of the disagreements were probably related to the inexperience of the medical residents. CONCLUSION: Our study suggests that a smartphone-based teledermatology inpatient consultation model could be a reasonable option for hospitals lacking dermatological services. Also, it may be as or more effective than face-to-face consultations, if performed by a more experienced dermatologist. When feasible, photographing training should be performed. PMID- 26959499 TI - Effects of High Dissolved Inorganic and Organic Carbon Availability on the Physiology of the Hard Coral Acropora millepora from the Great Barrier Reef. AB - Coral reefs are facing major global and local threats due to climate change induced increases in dissolved inorganic carbon (DIC) and because of land-derived increases in organic and inorganic nutrients. Recent research revealed that high availability of labile dissolved organic carbon (DOC) negatively affects scleractinian corals. Studies on the interplay of these factors, however, are lacking, but urgently needed to understand coral reef functioning under present and near future conditions. This experimental study investigated the individual and combined effects of ambient and high DIC (pCO2 403 MUatm/ pHTotal 8.2 and 996 MUatm/pHTotal 7.8) and DOC (added as Glucose 0 and 294 MUmol L-1, background DOC concentration of 83 MUmol L-1) availability on the physiology (net and gross photosynthesis, respiration, dark and light calcification, and growth) of the scleractinian coral Acropora millepora (Ehrenberg, 1834) from the Great Barrier Reef over a 16 day interval. High DIC availability did not affect photosynthesis, respiration and light calcification, but significantly reduced dark calcification and growth by 50 and 23%, respectively. High DOC availability reduced net and gross photosynthesis by 51% and 39%, respectively, but did not affect respiration. DOC addition did not influence calcification, but significantly increased growth by 42%. Combination of high DIC and high DOC availability did not affect photosynthesis, light calcification, respiration or growth, but significantly decreased dark calcification when compared to both controls and DIC treatments. On the ecosystem level, high DIC concentrations may lead to reduced accretion and growth of reefs dominated by Acropora that under elevated DOC concentrations will likely exhibit reduced primary production rates, ultimately leading to loss of hard substrate and reef erosion. It is therefore important to consider the potential impacts of elevated DOC and DIC simultaneously to assess real world scenarios, as multiple rather than single factors influence key physiological processes in coral reefs. PMID- 26959501 TI - Digoxin in Heart Failure with a Reduced Ejection Fraction: A Risk Factor or a Risk Marker. AB - Digoxin is one of the oldest compounds used in cardiovascular medicine. Nevertheless, its mechanism of action and most importantly its clinical utility have been the subject of an endless dispute. Positive inotropic and neurohormonal modulation properties are attributed to digoxin, and it was the mainstay of heart failure therapeutics for decades. However, since the institution of beta-blockers and aldosterone antagonists as part of modern heart failure medical therapy, digoxin prescription rates have been in free fall. The fact that digoxin is still listed as a valid therapeutic option in both American and European heart failure guidelines has not altered clinicians' attitude towards the drug. Since the publication of original Digitalis Investigation Group trial data, a series of reports based predominately on observational studies and post hoc analyses have raised concerns about the clinical efficacy and long-term safety of digoxin. In the present review, we will attempt a critical appraisal of the available clinical evidence regarding the efficacy and safety of digoxin in heart failure patients with a reduced ejection fraction. The methodological issues, strengths, and limitations of individual studies will be highlighted. PMID- 26959498 TI - Correlates of Exercise Self-efficacy in a Randomized Trial of Mind-Body Exercise in Patients With Chronic Heart Failure. AB - PURPOSE: Exercise self-efficacy is one of the strongest predictors of physical activity behavior. Prior literature suggests that tai chi, a mind-body exercise, may increase self-efficacy; however, this is not extensively studied. Little is known about the factors associated with development of exercise self-efficacy in a population with heart failure. METHODS: We utilized data from a randomized controlled trial of 12 weeks of group tai chi classes versus education in patients with chronic heart failure (n = 100). Multivariable linear regression was used to explore possible correlates of change in exercise self-efficacy in the entire sample and in the subgroup who received tai chi (n = 50). Covariates included baseline quality of life, social support, functional parameters, physical activity, serum biomarkers, sociodemographics, and clinical heart failure parameters. RESULTS: Baseline 6-minute walk (beta=-0.0003, SE = 0.0001, P = .02) and fatigue score (beta= 0.03, SE = 0.01, P = .004) were significantly associated with change in self-efficacy, with those in the lowest tertile for 6 minute walk and higher tertiles for fatigue score experiencing the greatest change. Intervention group assignment was highly significant, with self-efficacy significantly improved in the tai chi group compared to the education control over 12 weeks (beta= 0.39, SE = 0.11, P < .001). In the tai chi group alone, lower baseline oxygen uptake (beta=-0.05, SE = 0.01, P = .001), decreased mood (beta=-0.01, SE = 0.003, P = .004), and higher catecholamine level (epinephrine beta= 0.003, SE = 0.001, P = .005) were significantly associated with improvements in self-efficacy. CONCLUSIONS: In this exploratory analysis, our initial findings support the concept that interventions like tai chi may be beneficial in improving exercise self-efficacy, especially in patients with heart failure who are deconditioned, with lower functional status and mood. PMID- 26959502 TI - Screening in Primary Care for Diabetic Retinopathy, Maculopathy and Visual Loss in South Africa. AB - OBJECTIVE: The aim of the study was to determine the prevalence of diabetic retinopathy, maculopathy and visual loss in primary care patients and to identify associated risk factors. RESEARCH DESIGN AND METHODS: We conducted a cluster randomised trial at primary care clinics in the Tshwane district in South Africa. Grades of retinopathy and maculopathy (with fundus camera) and visual acuity (Snellen chart) were assessed and, using mobile screening and teleophthalmology, clinical and biochemical testing was conducted to obtain information about glycaemic control and microvascular complications. RESULTS: The prevalence rates for any retinopathy, preproliferative retinopathy and proliferative retinopathy were 24.9, 19.5 and 5.5%, respectively. The prevalence rates of diabetic maculopathy, observable maculopathy and referable maculopathy were 20.8, 11.8 and 9.0%, respectively. The presence of retinopathy was associated with high body mass index, systolic blood pressure, being on insulin treatment, high HbA1c and the presence of neuropathy. High systolic blood pressure, being on insulin treatment, high HbA1c level and high low-density lipoprotein cholesterol level as well as the presence of albuminuria were significant in predicting any diabetic maculopathy. Laser photocoagulation was given to 8.3% of patients from the mobile unit and 12% of patients were referred to the nearest hospital with an outpatient eye clinic for follow-up treatment of various other eye conditions. Using the WHO categories, the study found that 78.1% of diabetes patients had normal vision, 19.3% were visually impaired and 2.2% were severely impaired or blind. CONCLUSION: High prevalence rates for diabetic retinopathy, maculopathy and visual loss were found and associations were identified. PMID- 26959504 TI - Temperature and Pressure Dependent Phase Transitions of beta'-LiZr2(PO4)3 Studied by Raman Spectroscopy. AB - LiZr2(PO4)3 (LZP) belongs to the NASICON family of compounds whose ionic conductivity can be tuned by substitution of different cations or by increasing the temperature or pressure. Besides its conductivity, thermal and electrochemical stability makes it useful as a cathode material for lithium-ion energy storage devices. Temperature dependent Raman spectroscopic studies were carried out on the monoclinic (beta') phase of LZP in the temperature range 298 853 K. A reversible structural phase transition driven by disorder in lithium sites is observed at 603 K. The spectral data enable an understanding of dynamics of the mobile Li ion and PO4 internal modes across the orthorhombic structural phase transition. On the basis of these studies, a reported change in the conductivity around 600 K is explained. High pressure Raman spectroscopic measurements on beta'-LiZr2(PO4)3 reveal the onset of a structural phase transformation at 3.8 GPa and amorphization above 10 GPa. On decompression from 26 GPa, the amorphous phase remains unchanged, indicating irreversible nature of pressure-induced amorphization. Three low frequency Raman modes at 100, 124, and 144 cm(-1), which soften with an increase in pressure could be the driving force for the phase transition at 3.8 GPa. Pressure-induced phase transition prior to amorphization in beta'-LiZr2(PO4)3 could be due to collapse of Zr-O-P bond angles. Pressure-induced amorphization in this compound might be due to kinetic hindrance of equilibrium decomposition. PMID- 26959505 TI - Intraparticle Molecular Orbital Engineering of Semiconducting Polymer Nanoparticles as Amplified Theranostics for in Vivo Photoacoustic Imaging and Photothermal Therapy. AB - Optical theranostic nanoagents that seamlessly and synergistically integrate light-generated signals with photothermal or photodynamic therapy can provide opportunities for cost-effective precision medicine, while the potential for clinical translation requires them to have good biocompatibility and high imaging/therapy performance. We herein report an intraparticle molecular orbital engineering approach to simultaneously enhance photoacoustic brightness and photothermal therapy efficacy of semiconducting polymer nanoparticles (SPNs) for in vivo imaging and treatment of cancer. The theranostic SPNs have a binary optical component nanostructure, wherein a near-infrared absorbing semiconducting polymer and an ultrasmall carbon dot (fullerene) interact with each other to induce photoinduced electron transfer upon light irradiation. Such an intraparticle optoelectronic interaction augments heat generation and consequently enhances the photoacoustic signal and maximum photothermal temperature of SPNs by 2.6- and 1.3-fold, respectively. With the use of the amplified SPN as the theranostic nanoagent, it permits enhanced photoacoustic imaging and photothermal ablation of tumor in living mice. Our study thus not only introduces a category of purely organic optical theranostics but also highlights a molecular guideline to amplify the effectiveness of light-intensive imaging and therapeutic nanosystems. PMID- 26959506 TI - Characterization of Conformation and Locations of C-F Bonds in Graphene Derivative by Polarized ATR-FTIR. AB - It is still a challenge to explore the orientation and location of chemical groups in the two-dimensional derivative of graphene. In this study, polarized attenuated total reflectance Fourier transform infrared spectroscopy (polarized ATR-FTIR) was employed to investigate the orientation and location of C-F groups in the corresponding graphene derivative sheets, which facilitates building a relationship between the bonding nature and fine structure. There were two types of C-F bonding, (C-F)I and (C-F)II, in fluorinated graphene sheets. It was found that (C-F)II bonds were linked at the coplanar carbon atoms in the weakly fluorinated region (CxF, x >= 2), whereas the (C-F)I bonds cluster at the strongly deformed carbon framework with a F/C ratio of about 1. The thermostability of (C-F)II is lower than that of (C-F)I bonds. This is because the coplanar structure of the weakly fluorinated region tends to transform to the planar aromatic ring with the breaking of the C-F bond as compared with the strong fluorinated nonplanar region. PMID- 26959507 TI - Designing an Antibody-Based Chaperoning System through Programming the Binding and Release of the Folding Intermediate. AB - The protein folding pathway consists of sequential intramolecular interactions, while chaperones exert their functions either by stabilizing folding intermediates or by preventing nonspecific intermolecular interactions, which are often associated with aggregation involving exposed hydrophobic residues in folding intermediates. As chaperones do not possess specificity for individual client proteins, we designed an antibody-based chaperoning system to mimic the sequential binding and release of client proteins undergoing folding. The single chain variable fragment of antibody (scFv) A4 binds to human muscle creatine kinase (HCK) and prevents it from aggregating. The slow dissociation of HCK from A4 resulted in delayed but eventually high-quality refolding, as reflected by the higher recovery of enzymatic activity as well as abolished aggregation. Peptide P6, a sequence in HCK involved in A4 binding, competes with HCK, promotes its dissociation from A4, and accelerates the rate of high-quality refolding. The sequential addition of A4 and P6 is essential for the chaperoning effect. The programmed binding/release method can also be applied to refold HCK from inclusion bodies. Because the association/dissociation of the folding intermediate with the antibody is highly specific, the method can be used to design tailored refolding systems and to investigate chaperoning effects on protein folding/aggregation in a sequence-specific manner. PMID- 26959508 TI - Expansion of myeloid-derived suppressor cells promotes differentiation of regulatory T cells in HIV-1+ individuals. AB - OBJECTIVE: Regulatory T cells (Tregs) contribute to HIV-1 disease progression by impairing antiviral immunity; however, the precise mechanisms responsible for the development of Tregs in the setting of HIV-1 infection are incompletely understood. DESIGN: In this study, we provide evidence that HIV-induced expansion of monocytic myeloid-derived suppressor cells (M-MDSCs) promote the differentiation of Foxp3 Tregs. METHODS: We measured MDSC induction and cytokine expression by flow cytometry and analyzed their functions by coculturing experiments. RESULTS: We observed a dramatic increase in M-MDSC frequencies in the peripheral blood of HIV-1 seropositive (HIV-1) individuals, even in those on antiretroviral therapy with undetectable viremia, when compared with healthy participants. We also observed increases in M-MDSCs after incubating healthy peripheral mononuclear cells (PBMCs) with HIV-1 proteins (gp120 or Tat) or Toll like receptor 4 ligand lipopolysaccharides in vitro, an effect that could be abrogated in the presence of the phosphorylated signal transducer and activator of transcription 3 inhibitor, STA-21. Functional analyses indicated that M-MDSCs from HIV-1 individuals express higher levels of IL-10, tumor growth factor-beta, IL-4 receptor alpha, p47, programmed death-ligand 1, and phosphorylated signal transducer and activator of transcription 3 - all of which are known mediators of myelopoiesis and immunosuppression. Importantly, incubation of healthy CD4 T cells with MDSCs derived from HIV-1 individuals significantly increased differentiation of Foxp3 Tregs. In addition, depletion of MDSCs from PBMCs of HIV 1 individuals led to a significant reduction of Foxp3 Tregs and increase of IFNgamma production by CD4 T effector cells. CONCLUSIONS: These results suggest that HIV-induced MDSCs promote Treg cell development and inhibit T cell function a hallmark of many chronic infectious diseases. PMID- 26959509 TI - HIV-associated CD4+/CD8+ depletion in infancy is associated with neurometabolic reductions in the basal ganglia at age 5 years despite early antiretroviral therapy. AB - OBJECTIVE: Investigating consequences of early or late antiretroviral therapy (ART) initiation in infancy on young brain development using magnetic resonance spectroscopy. DESIGN: Most pediatric HIV/ART-related neurological studies are from neuropsychological/clinical perspectives. Magnetic resonance spectroscopy can elucidate the mechanisms underpinning neurocognitive outcomes by quantifying the brain's chemical condition through localized metabolism to provide insights into health and development. METHODS: Basal ganglia metabolite concentrations were assessed in thirty-eight 5-year-old HIV-infected children previously participating in a randomized trial comparing early limited ART to deferred continuous ART, as well as 15 uninfected controls (12 HIV exposed). Metabolite levels were compared between 26 infected children who initiated ART at/before 12 weeks and 12 who initiated afterward, and were correlated with clinical HIV and treatment-related measures. RESULTS: HIV-infected children initiating ART after 12 weeks had lower creatine, choline and glutamate (P < 0.05) than those initiating ART at/before 12 weeks. The CD4/CD8 ratio at baseline correlated with N-acetyl-aspartate (r = 0.56, P = 0.003) and choline (r = 0.36, P = 0.03) at 5 years, irrespective of treatment regimen and ART interruption. In comparison with uninfected controls, 80% of whom were HIV-exposed in utero, children on early treatment had higher N-acetyl-aspartate (P = 0.006) and choline (P = 0.03). CONCLUSIONS: Despite early ART (<12 weeks), low baseline CD4/CD8 predicts brain metabolite levels in later childhood. Also, HIV exposure and antiretroviral exposure for preventing vertical HIV transmission may hinder metabolite health, but needs further investigation. PMID- 26959511 TI - Identification of a novel and severe pattern of efavirenz drug-induced liver injury in South Africa. AB - Efavirenz now forms part of many antiretroviral regimens in low and middle-income countries. Efavirenz-related drug-induced liver injury is not well characterized but is thought to occur less frequently than with nevirapine. We describe our observation of three defined clinicopathological patterns of injury, one of which, submassive necrosis, is associated with significant morbidity and mortality. A high baseline CD4, younger age and possibly female gender, predicts for the injury. PMID- 26959512 TI - Correction to Bioactive Polyprenylated Acylphloroglucinol Derivatives from Hypericum cohaerens. PMID- 26959510 TI - Frequency and impact of suboptimal immune recovery on first-line antiretroviral therapy within the International Epidemiologic Databases to Evaluate AIDS in East Africa. AB - OBJECTIVE: To describe patterns of suboptimal immune recovery (SO-IR) and associated HIV-related-illnesses during the first 5 years following first-line antiretroviral therapy (ART) initiation across seven ART sites in East Africa. DESIGN: Retrospective analysis of data from seven ART clinical sites (three Uganda, two Kenya and two Tanzania). METHODS: SO-IR was described by proportions of ART-treated adults with CD4 cell counts less than 200, less than 350 and less than 500 cells/MUl. Kaplan-Meier survival analysis techniques were used to assess predictors of SO-IR, and incident rates of HIV-related illnesses at CD4 cell counts less than 200, 200-350, 351-499, and >500 cells/MUl, respectively. RESULTS: Overall 80 843 adults initiated non-nucleoside reverse transcriptase inhibitor-based first-line ART; 65% were women and median CD4 cell count was 126 [interquartile range (IQR), 52-202] cells/MUl. Cumulative probability of SO-IR <200 cells/MUl, <350 cells/MUl and <500 cells/MUl, after 5 years, was 11, 38 and 63%, respectively. Incidence of HIV-related illnesses was higher among those with CD4 cell counts less than 200 and 200-350 cells/MUl, than those who achieved CD4 counts above these thresholds. The most common events, at CD4 < 200 cells/MUl, were pulmonary tuberculosis [incident rate 15.98 (15.47-16.51)/100 person-years at risk (PYAR), oral candidiasis [incident rate 12.5 (12.03-12.94)] and herpes zoster [incident rate 6.30 (5.99-6.64)] events/100 PYAR. With attainment of a CD4 cell count level 200-350 cells/MUl, there was a substantial reduction in events/100 PYAR - by 91% to 1.45 (1.29-1.63) for TB, by 94% to 0.75 (0.64-0.89) for oral candidiasis, by 84% to 0.99 (0.86-1.14) for Herpes Zoster, and by 78% to 1.22 (1.07-1.39) for chronic diarrhea. The incidence of all events decreased further with CD4 counts above these thresholds. CONCLUSION: Around 40% of adults initiated on ART have suboptimal immune recovery with CD4 counts <350 cells/MUl after five years. Such patients will require closer monitoring for both HIV related and non-HIV-related clinical events. PMID- 26959513 TI - Toward the design of high voltage magnesium-lithium hybrid batteries using dual salt electrolytes. AB - We report a design of high voltage magnesium-lithium (Mg-Li) hybrid batteries through rational control of the electrolyte chemistry, electrode materials and cell architecture. Prototype devices with a structure of Mg-Li/LiFePO4 (LFP) and Mg-Li/LiMn2O4 (LMO) have been investigated. A Mg-Li/LFP cell using a dual-salt electrolyte 0.2 M [Mg2Cl2(DME)4][AlCl4]2 and 1.0 M LiTFSI exhibits voltages higher than 2.5 V (vs. Mg) and a high specific energy density of 246 W h kg(-1) under conditions that are amenable for practical applications. The successful demonstrations reported here could be a significant step forward for practical hybrid batteries. PMID- 26959514 TI - Endoscopic ultrasound-guided biliary interventions: an update on recent developments. AB - PURPOSE OF REVIEW: Endoscopic ultrasound (EUS)-guided biliary drainage procedures can be utilized in patients with biliary obstruction and incomplete drainage with prior interventions, in those whose ampulla is inaccessible (i.e. from surgically altered anatomy and malignant luminal obstruction), or in those who failed bile duct cannulation during endoscopic retrograde cholangiopancreatography. Improved techniques and accessories have streamlined these procedures; however, further investigation is required. The purpose of this review is to provide the highlights of the most recent literature on EUS-guided biliary drainage. RECENT FINDINGS: Recent literature has demonstrated the effectiveness and safety of EUS guided gallbladder drainage, both as a primary intervention in patients with cholecystitis who are unfit for urgent surgical intervention and as a secondary intervention to internalize biliary drainage after initial placement of a cholecystostomy catheter. EUS-guided bile duct drainage can be performed using various techniques. The optimal technique requires further study and may vary by clinical scenario. SUMMARY: The role of EUS-guided biliary drainage continues to evolve. The most recent literature has attempted to clarify the optimal strategies and indications for employing the various EUS-guided biliary drainage techniques. PMID- 26959515 TI - La2SrCr2O7F2: A Ruddlesden-Popper Oxyfluoride Containing Octahedrally Coordinated Cr(4+) Centers. AB - The low-temperature fluorination of the n = 2 Ruddlesden-Popper phase La2SrCr2O7 yields La2SrCr2O7F2 via a topochemical fluorine insertion reaction. The structure conserving nature of the fluorination reaction means that the chromium centers of the initial oxide phase retain an octahedral coordination environment in the fluorinated product, resulting in a material containing an extended array of apex linked Cr(4+)O6 units. Typically materials containing networks of octahedrally coordinated Cr(4+) centers can only be prepared at high pressure; thus, the preparation of La2SrCr2O7F2 demonstrates that low-temperature topochemical reactions offer an alternative synthesis route to materials of this type. Neutron diffraction, magnetization, and MU(+)SR data indicate that La2SrCr2O7F2 undergoes a transition to an antiferromagnetic state below TN ~ 140 K. The structure property relations of this phase and other Cr(4+) oxide phases are discussed. PMID- 26959516 TI - How the Structure of Pyrrolidinium Ionic Liquids Is Susceptible to High Pressure. AB - The structural landscape of room-temperature ionic liquids (RTILs) with longer cationic alkyl tail(s) exhibits polarity ordering (PO) along with charge ordering (CO). In polarity ordering, which is also referred to as intermediate-range ordering, polar groups are separated by segregated domains of apolar groups and vice versa. Charge ordering resembles alternation of positive-negative charge groups. In this work, how these two characteristic orderings respond to applied external pressure has been investigated via molecular dynamics simulations. The present study complements the recent experimental studies of Yoshimura et al. (J. Phys. Chem. B 2015, 119, 8146-8153) and computational studies of Russina et al. (Phys. Chem. Chem. Phys. 2015, 17, 29496-29500) wherein the authors described in detail the effects of pressure on the structural and conformational changes in imidazolium based ionic liquids. Our simulations predict that for 1-alkyl-1 methylpyrrolidinium bis(trifluoromethylsulfonyl)amide, Pyrr1,n(+)/NTf2(-) with n = 8 and 10, the PO and CO fade when the external pressure increases from ambient pressure to 10000 bar. We observe that the apolar tail group as well as the polar group correlations are susceptible to the applied pressure. The decrease of polar polar and apolar-apolar correlations at higher pressure is accompanied by the enhancement in the polar-apolar correlations and increased stability/probability of gauche conformations along the cationic tails. PMID- 26959517 TI - Predictors of Emergency Department Utilization Among Children in Vulnerable Families. AB - : Preventable visits to the emergency department (ED) are estimated to represent as much as 56% of overall annual ED utilization and contribute to the high cost of health care in the United States. There are more than 25 million annual pediatric ED visits. OBJECTIVE: The aim of this study was to identify factors associated with high ED utilization among children in vulnerable families. METHODS: The Fragile Families and Child Wellbeing Study is a longitudinal cohort of approximately 5000 vulnerable children. Data from the 9-year follow-up survey were used in this analysis. Bivariate and multivariate logistic regression analyses were performed to identify correlates with high ED utilization (>=4 visits per year). RESULTS: 2631 children were included in the analysis. In a multivariate model controlling for the child's sex, race, household income, and insurance status, 4 variables were significant predictors of ED utilization: history of hospitalization within the last year (odds ratio [OR], 15.97; 95% confidence interval [CI], 6.64-38.41; P < 0.001), diagnosis of asthma (OR, 2.53; 95% CI, 1.17-5.44; P = 0.02), number of child's office/clinic visits within the last year (OR, 1.22; 95% CI, 1.12-1.33; P < 0.001), and number of primary caregiver ED visits within last year (OR, 1.15; 95% CI, 1.03-1.28; P = 0.01). CONCLUSIONS: History of hospitalization, outpatient visits, primary caregiver ED utilization, and diagnosis of asthma independently predict high ED utilization by 9-year-old children in fragile families. Augmented continuity of care, disease management, and caregiver education may reduce high ED utilization in this population. PMID- 26959518 TI - Hot Water Epilepsy Successfully Treated With Daily Clobazam. AB - Hot water epilepsy (HWE) is a rare form of reflex epilepsy precipitated by a bath or shower in hot water. Although the condition is benign and a decreased bath temperature will help, antiepileptic drugs may be needed in some cases. Prophylactic clobazam is currently the first choice treatment option. Here we report the case of a 10-year-old boy with HWE successfully treated with daily doses of clobazam. Daily clobazam was preferred over prophylactic clobazam because of the patient's frequent bathing and parental concern. Daily clobazam is a novel treatment option for HWE and seems to be a good choice where antiepileptic drugs are necessary. PMID- 26959519 TI - Safety of Terbutaline for Treatment of Acute Severe Pediatric Asthma. AB - OBJECTIVES: The use of continuous intravenous terbutaline treatment in severe asthma attacks has been hampered by the lack of well-powered clinical trials where effects of such treatment are described in detail. Here, we aimed to provide a descriptive report on the largest cohort of severe pediatric asthma patients treated with terbutaline. METHODS: The study was conducted in a pediatric intensive care unit in a large metropolitan tertiary care university hospital on 124 patients receiving terbutaline infusion. To stratify the effect of, and determine any age-related differences of, terbutaline, the patients were divided into 3 age groups (0-6 years, 7-12 years, and 13-18 years). Clinical response and the potential harmful effects of terbutaline infusion were determined. RESULTS: There were significant reductions in systolic (varying between 86% and 93% of the baseline) and diastolic blood pressures (varying between 74% and 86% of the baseline level). However, the values returned to baseline level shortly after discontinuation of infusion. Terbutaline increased heart rates in all groups shortly after initiation (9%-13% above baseline), which returned to below baseline levels 1 hour after discontinuation. Serum potassium levels were also reduced in all patients compared to their baseline values after initiation of terbutaline infusion. However, none of the subjects required potassium replacement. CONCLUSIONS: The results indicate that overall, terbutaline infusion was well tolerated without irreversible adverse effects of the treatment. Although hemodynamic and metabolic disturbances occurred, these were clinically easily managed and posed little risk in emergency department or pediatric intensive care unit. PMID- 26959520 TI - A Knotted Urethral Catheter in the Emergency Department. AB - Inadvertent knotting of urethral catheters and enteric feeding tubes is a rare complication in pediatric patients. If a small flexible tube is used and advanced too far, upon withdrawal, the catheter may knot in the bladder. Surgical intervention for retrieval is required in most cases. We present a case of a 26 day-old female neonate who was catheterized with a 5 French enteric feeding tube, which was later removed in the emergency department with gentle traction alone. After removal, a knot was noted at the tip. It is important for emergency physicians to be aware of this complication, because this particular size feeding tube is most susceptible to kinking inside of the urinary tract. PMID- 26959521 TI - Intermolecular Homopropargyl Alcohol Addition to Alkyne and a Sequential 1,6 Enyne Cycloisomerization with Triazole-Gold Catalyst. AB - While gold-catalyzed homopropargyl alcohol cyclization is a known process, a triazole-gold catalyst prevented the intramolecular cyclization in the presence of terminal alkynes. As a result, an intermolecular addition to an alkyne was achieved. A sequential 1,6-enyne cycloisomerization gave the unusual 2,3 dihydrooxepine, which revealed another new reaction path. Diels-Alder reaction of oxepine followed by a 1,3-alkoxyl shift gave hydrobezofuran derivatives in high yields. Diasterioselective reaction of homopropargyl alcohol to final product enabled one-step formation of five stereogenic centers with excellent enantiomeric selectivity. PMID- 26959522 TI - Copper-Catalyzed Multicomponent Domino Reaction of 2-Bromoaldehydes, Benzylamines, and Sodium Azide for the Assembly of Quinazoline Derivatives. AB - An efficient three-component domino reaction of 2-bromoaldehydes, benzylamines, and sodium azide has been developed for the synthesis of quinazoline derivatives. This domino process involves copper-catalyzed SNAr, oxidation/cyclization, and denitrogenation sequences. The mild catalytic system enabled the effective construction of three C-N bonds in one operation. PMID- 26959523 TI - Functional Gene Markers for Fumarate-Adding and Dearomatizing Key Enzymes in Anaerobic Aromatic Hydrocarbon Degradation in Terrestrial Environments. AB - Anaerobic degradation is a key process in many environments either naturally or anthropogenically exposed to petroleum hydrocarbons. Considerable advances into the biochemistry and physiology of selected anaerobic degraders have been achieved over the last decades, especially for the degradation of aromatic hydrocarbons. However, researchers have only recently begun to explore the ecology of complex anaerobic hydrocarbon degrader communities directly in their natural habitats, as well as in complex laboratory systems using tools of molecular biology. These approaches have mainly been facilitated by the establishment of a suite of targeted marker gene assays, allowing for rapid and directed insights into the diversity as well as the identity of intrinsic degrader populations and degradation potentials established at hydrocarbon impacted sites. These are based on genes encoding either peripheral or central key enzymes in aromatic compound breakdown, such as fumarate-adding benzylsuccinate synthases or dearomatizing aryl-coenzyme A reductases, or on aromatic ring-cleaving hydrolases. Here, we review recent advances in this field, explain the different detection methodologies applied, and discuss how the detection of site-specific catabolic gene markers has improved the understanding of processes at contaminated sites. Functional marker gene-based strategies may be vital for the development of a more elaborate population-based assessment and prediction of aromatic degradation potentials in hydrocarbon-impacted environments. PMID- 26959524 TI - The involvement of clathrin-mediated endocytosis and two Sid-1-like transmembrane proteins in double-stranded RNA uptake in the Colorado potato beetle midgut. AB - RNA interference (RNAi) is a powerful tool in entomology and shows promise as a crop protection strategy, but variability in its efficiency across different insect species limits its applicability. For oral uptake of the double-stranded RNA (dsRNA), the RNAi trigger, two different mechanisms are known: systemic RNA interference deficient-1 (Sid-1) transmembrane channel-mediated uptake and clathrin-mediated endocytosis. So far, a wide range of experiments has been conducted, confirming the involvement of one of the pathways in dsRNA uptake, but never both pathways in the same species. We investigated the role of both pathways in dsRNA uptake in the Colorado potato beetle, Leptinotarsa decemlineata, known to have an efficient RNAi response. Through RNAi-of-RNAi experiments, we demonstrated the contribution of two different sid-1-like (sil) genes, silA and silC, and clathrin heavy chain and the 16kDa subunit of the vacuolar H(+) ATPase (vha16), elements of the endocytic pathway, to the RNAi response. Furthermore, the sid-1-like genes were examined through phylogenetic and hydrophobicity analysis. This article reports for the first time on the involvement of two pathways in dsRNA uptake in an insect species and stresses the importance of evaluating both pathways through a well-devised reporter system in any future experiments on cellular dsRNA uptake. PMID- 26959525 TI - Stable Isotope Probing Approaches to Study Anaerobic Hydrocarbon Degradation and Degraders. AB - Stable isotope probing (SIP) techniques have become state-of-the-art in microbial ecology over the last 10 years, allowing for the targeted detection and identification of organisms, metabolic pathways and elemental fluxes active in specific processes within complex microbial communities. For studying anaerobic hydrocarbon-degrading microbial communities, four stable isotope techniques have been used so far: DNA/RNA-SIP, PLFA (phospholipid-derived fatty acids)-SIP, protein-SIP, and single-cell-SIP by nanoSIMS (nanoscale secondary ion mass spectrometry) or confocal Raman microscopy. DNA/RNA-SIP techniques are most frequently applied due to their most meaningful phylogenetic resolution. Especially using 13C-labeled benzene and toluene as model substrates, many new hydrocarbon degraders have been identified by SIP under various electron acceptor conditions. This has extended the current perspective of the true diversity of anaerobic hydrocarbon degraders relevant in the environment. Syntrophic hydrocarbon degradation was found to be a common mechanism for various electron acceptors. Fundamental concepts and recent advances in SIP are reflected here. A discussion is presented concerning how these techniques generate direct insights into intrinsic hydrocarbon degrader populations in environmental systems and how useful they are for more integrated approaches in the monitoring of contaminated sites and for bioremediation. PMID- 26959527 TI - Lack of Clarity in the DSM-5 Criteria of Voyeuristic Disorder. PMID- 26959526 TI - Differential proteome and cellular adhesion analyses of the probiotic bacterium Lactobacillus acidophilus NCFM grown on raffinose - an emerging prebiotic. AB - Whole cell and surface proteomes were analyzed together with adhesive properties of the probiotic bacterium Lactobacillus acidophilus NCFM (NCFM) grown on the emerging prebiotic raffinose, exemplifying a synbiotic. Adhesion of NCFM to mucin and intestinal HT-29 cells increased three-fold after culture with raffinose versus glucose, as also visualized by scanning electron microscopy. Comparative proteomics using 2D-DIGE showed 43 unique proteins to change in relative abundance in whole cell lysates from NCFM grown on raffinose compared to glucose. Furthermore, 14 unique proteins in 18 spots of the surface subproteome underwent changes identified by differential 2DE, including elongation factor G, thermostable pullulanase, and phosphate starvation inducible stress-related protein increasing in a range of +2.1 - +4.7 fold. By contrast five known moonlighting proteins decreased in relative abundance by up to -2.4 fold. Enzymes involved in raffinose catabolism were elevated in the whole cell proteome; alpha galactosidase (+13.9 fold); sucrose phosphorylase (+5.4 fold) together with metabolic enzymes from the Leloir pathway for galactose utilization and the glycolysis; beta-galactosidase (+5.7 fold); galactose (+2.9/+3.1 fold) and fructose (+2.8 fold) kinases. The insights at the molecular and cellular levels contributed to the understanding of the interplay of a synbiotic composed of NCFM and raffinose with the host. PMID- 26959528 TI - Immunochemical characterization of the O antigens of two Proteus strains, O8 related antigen of Proteus mirabilis 12 B-r and O2-related antigen of Proteus genomospecies 5/6 12 B-k, infecting a hospitalized patient in Poland. AB - A hospitalized 73-year-old woman was infected with a Proteus mirabilis strain, 12 B-r, isolated from the place of injection of a blood catheter. Another strain, 12 B-k, recognized as Proteus genomospecies 5 or 6, was isolated from the patient's faeces, which was an example of a nosocomial infection rather than an auto infection. Serological investigation using ELISA and Western blotting showed that strain 12 B-k from faeces belonged to the Proteus O2 serogroup. Strain 12 B-r from the wound displayed cross-reactions with several Proteus O serogroups due to common epitopes on the core or O-specific parts of the lipopolysaccharide. Studies of the isolated 12 B-r O-specific polysaccharide by NMR spectroscopy revealed its close structural similarity to that of Proteus O8. The only difference in 12 B-r was the presence of an additional GlcNAc-linked phosphoethanolamine residue, which creates a putative epitope responsible for the cross-reactivity with Pt. mirabilis O16. The new O-antigen form could appear as a result of adaptation of the bacterium to a changing environment. On the basis of the data obtained, we suggest division of the O8 serogroup into two subgroups: O8a for strains of various Proteus species that have been previously classified into the O8 serogroup, and O8a,b for Pt. mirabilis 12 B-r, where 'a' is a common epitope and 'b' is a phosphoethanolamine-associated epitope. These findings further confirm serological and structural heterogeneity of O antigens of Proteus strains isolated lately from patients in Poland. PMID- 26959530 TI - Evaluation of Surefire's precision direct-to-tumor embolization device to augment therapeutic response to intra-arterial, liver-directed therapies for patients with primary and secondary liver cancers. AB - Patients with primary and secondary liver cancers generally have a poor prognosis with limited potentially curative options. Liver-directed, intra-arterial therapies such as selective internal radiotherapy (SIRT) and trans-arterial chemoembolization (TACE) are taking a larger role in the management of these patients. The current standard of therapy is for delivery of SIRT or TACE particles through an end-hole microcatheter. Antireflux microcatheters (ARM) are a novel class of microcatheters designed to enhance intra-arterial therapies. These catheters are designed with a flexible tip at the end of the microcatheter, which partially collapses during systole and expands during diastole, reducing antegrade and retrograde particle reflux while allowing for forward flow. Initially designed to reduce the risk of particle reflux during SIRT, there is evidence that ARMs may lead to improved particle distribution to tumors during SIRT. Furthermore, ARMs improve embolization efficiency which may lead to improved disease response from TACE for patients with hepatocellular carcinoma. PMID- 26959529 TI - LC-MS/MS analysis of permethylated free oligosaccharides and N-glycans derived from human, bovine, and goat milk samples. AB - Oligosaccharides in milk not only provide nutrition to the infants but also have significant immune biofunctions such as inhibition of pathogen binding to the host cell. The main component in milk oligosaccharides is free oligosaccharides. Since the proteins in milk are highly glycosylated, N-glycans in milk also play an import role. In this study, we investigated the permethylated free oligosaccharides and N-glycans extracted from bovine, goat, and human milks using LC-MS/MS. Quantitation profiles of free oligosaccharides and N-glycans were reported. The number of free oligosaccharides observed in bovine, goat, and human milk samples (without isomeric consideration) were 11, 8, and 11, respectively. Human milk had more complex free oligosaccharides structures than the other two milk samples. Totally 58, 21, and 43 N-glycan structures (without isomeric consideration) were associated with whey proteins extracted from bovine, goat, and human milk samples, respectively. Bovine milk free oligosaccharides and N glycans from whey proteins were highly sialylated and to a lesser extend fucosylated. Goat and human milk free oligosaccharides and N-glycans from whey proteins were both highly fucosylated. Also, the isomeric glycans in milk samples were determined by porous graphitic carbon LC at elevated temperatures. For example, separation of human milk free oligosaccharide Gal-GlcNAc-(Fuc)-Gal-Glc and Gal-GlcNAc-Gal-Glc-Fuc isomers was achieved using porous graphitic carbon column. Permethylation of the glycan structures facilitated the interpretation of MS/MS. For example, internal cleavage and glycosidic bond cleavage are readily distinguished in the tandem mass spectra of permethylated glycans. This feature resulted in the identification of several isomers. PMID- 26959531 TI - S1P prophylaxis mitigates acute hypobaric hypoxia-induced molecular, biochemical, and metabolic disturbances: A preclinical report. AB - Sphingosine-1-phosphate (S1P) is emerging to have hypoxic preconditioning potential in various preclinical studies. The study aims to evaluate the preclinical preconditioning efficacy of exogenously administered S1P against acute hypobaric hypoxia (HH)-induced pathological disturbances. Male Sprague Dawley rats (200 +/- 20 g) were preconditioned with 1, 10, and 100 MUg/kg body weight (b.w.) S1P (i.v.) for three consecutive days. On the third day, S1P preconditioned animals, along with hypoxia control animals, were exposed to HH equivalent to 7,620 m (280 mm Hg) for 6 h. Postexposure status of cardiac energy production, circulatory vasoactive mediators, pulmonary and cerebral oxidative damage, and inflammation were assessed. HH exposure led to cardiac energy deficit indicated by low ATP levels and pronounced AMPK activation levels, raised circulatory levels of brain natriuretic peptide and endothelin-1 with respect to total nitrate (NOx), redox imbalance, inflammation, and alterations in NOx levels in the pulmonary and cerebral tissues. These pathological precursors have been routinely reported to be coincident with high-altitude diseases. Preconditioning with S1P, especially 1 ug/kg b.w. dose, was seen to reverse the manifestation of these pathological disturbances. The protective efficacy could be attributed, at least in part, to enhanced activity of cardioprotective protein kinase C and activation of small GTPase Rac1, which led to further induction of hypoxia adaptive molecular mediators: hypoxia-inducible factor (HIF)-1alpha and Hsp70. This is a first such report, to the best of our knowledge, elucidating the mechanism of exogenous S1P-mediated HIF-1alpha/Hsp70 induction. Conclusively, systemic preconditioning with 1 MUg/kg b.w. S1P in rats protects against acute HH induced pathological disturbances. (c) 2016 IUBMB Life 68(5):365-375, 2016. PMID- 26959533 TI - Toward an Integrated Zebrafish Health Management Program Supporting Cancer and Neuroscience Research. AB - Zebrafish is already one of the most used model organisms in biomedical sciences and other research fields. It is therefore becoming increasingly important to assure that zebrafish maintained in laboratory aquaculture conditions are raised and housed under rigorous standards that promote health and welfare to guarantee the required quality and reproducibility of research data. Specifying the programs each facility is adopting would be the first step to achieve this by allowing other facilities to compare, improve, and discuss their protocols and fish performance. We provide in this article a detailed description of an integrated facility health management program, with protocols and readouts, fully designed and aimed at maximizing fish health, welfare, and performance for research. PMID- 26959532 TI - Oxidative Stress by Monoamine Oxidase-A Impairs Transcription Factor EB Activation and Autophagosome Clearance, Leading to Cardiomyocyte Necrosis and Heart Failure. AB - AIMS: In heart failure (HF), mitochondrial quality control and autophagy are progressively impaired, but the role of oxidative stress in this process and its underlying mechanism remain to be defined. By degrading norepinephrine and serotonin, the mitochondrial enzyme, monoamine oxidase-A (MAO-A), is a potent source of reactive oxygen species (ROS) in the heart and its activation leads to the persistence of mitochondrial damage. In this study, we analyzed the consequences of ROS generation by MAO-A on the autophagy-lysosome pathway in the heart. RESULTS: Cardiomyocyte-driven expression of MAO-A in mice led to mitochondrial fission and translocation of Drp1 and Parkin in the mitochondrial compartment. Ventricles from MAO-A transgenic mice displayed accumulation of LC3 positive autophagosomes, together with p62 and ubiquitylated proteins, indicating impairment of autophagy. In vitro adenoviral delivery of MAO-A in cardiomyocytes and the consequent generation of ROS blocked autophagic flux with accumulation of LC3II, p62, and ubiquitylated proteins, leading to mitochondrial fission and cell necrosis. In addition, MAO-A activation induced accumulation of lysosomal proteins, cathepsin D and Lamp1, reduced lysosomal acidification, and blocked the nuclear translocation of transcription factor-EB (TFEB), a master regulator of autophagy and lysosome biogenesis. Most interestingly, overexpression of TFEB attenuated autophagosome buildup, mitochondrial fission, cardiomyocyte death, and HF associated with MAO-A activation. INNOVATION AND CONCLUSION: This study unravels a new link between MAO-dependent H2O2 production and lysosomal dysfunction. Altogether, our findings demonstrate that the MAO-A/H2O2 axis has a negative impact on the elimination and recycling of mitochondria through the autophagy-lysosome pathway, which participates in cardiomyocyte death and HF. Antioxid. Redox Signal. 25, 10-27. PMID- 26959534 TI - Current topics on ultrasound in perinatology. PMID- 26959535 TI - Serum vascular endothelial cadherin and thrombomodulin are markers of non alcoholic fatty liver disease in children. AB - BACKGROUND: The diagnosis of non-alcoholic fatty liver disease (NAFLD) is usually based on liver ultrasonography and serum alanine aminotransferase (ALT) levels. However, the serum ALT level is not sensitive for detecting NAFLD. If more serum markers are available, serum analysis may play a more important role in the diagnosis of NAFLD. METHODS: Here, we have investigated whether vascular endothelial cadherin (VE-cad) and thrombomodulin (TM) are markers of NAFLD in children. After an examination of liver ultrasonography, 90 children were divided into a lean control group (n=32), an overweight/obese NAFLD group (group-NAFLD, n=34) and an overweight/obese non-NAFLD group (group-SOO, n=24). RESULTS: Two overweight/obese groups had similar obesity. However, serum VE-cad and TM levels were increased in group-NAFLD but not group-SOO. When data from all children were pooled, serum VE-cad and TM levels were positively correlated to body-mass index (BMI) and serum ALT levels. CONCLUSIONS: In conclusion, VE-cad and TM are markers of pediatric NAFLD. PMID- 26959536 TI - More than one way to skin a thyroid. Managing pediatric hypothyroidism with weekly intramuscular levothyroxine. AB - BACKGROUND: Oral levothyroxine (L-T4) supplementation is usually an effective therapy in pediatric hypothyroidism, except in patients with malabsorption or pseudomalabsorption. In these cases, parenteral L-T4 may be required, but there is a paucity of information about this delivery method in the pediatric population. CASE PRESENTATION: We present three cases of pediatric patients with primary hypothryoidism unresponsive to oral L-T4 that were successfully treated with intramuscular (IM) L-T4. CONCLUSIONS: This is the first pediatric case series of successful IM L-T4 therapy in refractory primary hypothyroidism. Our case series demonstrates that once weekly IM L-T4 dosing may be a safe and well tolerated treatment regimen for pediatric patients. PMID- 26959537 TI - Leigh syndrome associated with a novel mutation in the COX15 gene. AB - Leigh syndrome (LS) is a subacute necrotizing encephalomyelopathy with a diverse range of symptoms, such as psychomotor delay or regression, weakness, hypotonia, truncal ataxia, intention tremor as well as lactic acidosis in the blood, cerebrospinal fluid or urine. Both nuclear gene defects and mutations of the mitochondrial genome have been detected in these patients. Here we report a 7 year-old girl with hypotonia, tremor, developmental delay and psychomotor regression. However, serum lactate level as well as brain magnetic resonance imaging were normal. Mutational analysis has revealed a novel mutation in exon 4 of COX15 gene (c.415C>G) which results in p.Leu139Val. Previous studies have demonstrated that COX15 mutations are associated with typical LS as well as fatal infantile hypertrophic cardiomyopathy. Consequently, clinical manifestations of COX15 mutations may be significantly different in patients. Such information is of practical importance in genetic counseling. PMID- 26959538 TI - Corrigendum to: The functional role of all postsynaptic potentials examined from a first-person frame of reference. PMID- 26959539 TI - Fatty acid composition of achenes of Cirsium taxa (Asteraceae, Carduoideae) from Turkey. AB - The fatty acid compositions and total oil contents in achenes of 22 Cirsium taxa collected from different natural habitats in Turkey were investigated. The range of total fat in the taxa varied from 1.7% to 13.3%. The taxa contained palmitic (C16:0), stearic (C18:0), oleic (C18:1n-9), linoleic (C18:2n-6), and alpha linolenic (C18:3n-3) acid. Polyunsaturated fatty acids had the highest level, ranging from 52.1% to 75.2% (C18:2n-6) and 0.5%-17.3% (C18:3n-3). Total saturated (6.9%-17.4%), monounsaturated (11.7%-28.9%), and polyunsaturated (57.4%-79.9%) fatty acids varied substantially, whereas total unsaturated fatty acids ranged from 70.6% to 91.3%. Considerable variation was observed (P<0.05) within each taxon for these fatty acids, especially alpha-linolenic acid (C18:3n-3). Fatty acid compositions of the 22 taxa were compared by cluster analysis (UPGMA) and principle component analysis (PCA) based on six major fatty acids. This is the first report on the lipid content and fatty acid composition of achenes of Cirsium taxa growing in different areas of Turkey. Fatty acid profiles, relative proportions and levels of fatty acids can be used as additional biochemical markers in the taxonomy of Cirsium. PMID- 26959541 TI - Microscopic methods in analysis of submicron phospholipid dispersions. AB - Microscopy belongs to the group of tests, used in pharmaceutical technology, that despite the lapse of time and the development of new analytical methods, still remain irreplaceable for the characterization of dispersed drug dosage forms (e.g., suspensions and emulsions). To obtain complete description of a specific drug formulation, such as parenteral colloidal products, a combination of different microscopic techniques is sometimes required. Electron microscopy methods are the most useful ones; however, even such basic methods as optical microscopy may be helpful for determination of some properties of a sample. The publication explicates the most popular microscopical techniques used nowadays for characterization of the morphology of nanoparticles suspended in pharmaceutical formulations; advantages and disadvantages of these methods are also discussed. Parenteral submicron formulations containing lecithin or a particular phospholipid were chosen as examples. PMID- 26959540 TI - Thonningiiflavanonol A and thonningiiflavanonol B, two novel flavonoids, and other constituents of Ficus thonningii Blume (Moraceae). AB - A phytochemical study of Ficus thonningii has led to the isolation of two previously unreported compounds, thonningiiflavanonol A and thonningiiflavanonol B together with 16 known compounds: shuterin, naringenin, syringic acid, p hydroxybenzoic acid, genistein, 5,7,3',4',5'-pentahydroxyflavanone, luteolin, methylparaben, aromadendrin, garbanzol, dihydroquercetin, 5,7,3' trihydroxyflavanone, beta-sitosterol, sitosterolglucoside, lupeol acetate, and taraxerol. Their structures were elucidated on the basis of spectroscopic data. The new compounds and extracts displayed potent antioxidant activity. PMID- 26959542 TI - Design and statistical optimization of an effervescent floating drug delivery system of theophylline using response surface methodology. AB - The aim of this research was to formulate effervescent floating drug delivery systems of theophylline using different release retarding polymers such as ethyl cellulose, Eudragit(r) L100, xanthan gum and polyethylene oxide (PEO) N12K. Sodium bicarbonate was used as a gas generating agent. Direct compression was used to formulate floating tablets and the tablets were evaluated for their physicochemical and dissolution characteristics. PEO based formulations produced better drug release properties than other formulations. Hence, it was further optimized by central composite design. Further subjects of research were the effect of formulation variables on floating lag time and the percentage of drug released at the seventh hour (D7h). The optimum quantities of PEO and sodium bicarbonate, which had the highest desirability close to 1.0, were chosen as the statistically optimized formulation. No interaction was found between theophylline and PEO by Fourier Transformation Infrared spectroscopy (FTIR) and Differential Scanning Calorimetry (DSC) studies. PMID- 26959543 TI - Synthesis and structure elucidation of some novel thiophene and benzothiophene derivatives as cytotoxic agents. AB - Attempting to produce cyclized systems with potential anti-proliferative activity, a series of novel thiophene and benzothiophene derivatives were designed and synthesized. The reactivity of the latter derivatives towards different chemical reagents was studied. Twenty-one compounds were synthesized and evaluated as anti-cancer agents. The results showed that ethyl 5-amino-3-(4 chlorostyryl)-4-cyanothiophene-2-carboxylate (5b), ethyl 5-amino-4-((4 methoxyphenyl)carbonyl)-3-methylhiophene-2-carboxylate (8c) and 5-3-(ethoxy-3 oxopropanamido)-3-methyl-4-(phenylcarbamoyl)thiophene-2-carboxylate (9) were the most active compounds towards three tumor cell lines - MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and SF-268 (CNS cancer) and a normal fibro-blast human cell line (WI-38) compared to the anti proliferative effects of the reference control doxorubicin. PMID- 26959544 TI - Optimization of amino acid-stabilized erythropoietin parenteral formulation: In vitro and in vivo assessment. AB - The aim of this study was to optimize the formulation of erythropoietin (EPO) using amino acids instead of human serum albumin (HSA) and to evaluate its in vivo stability in order to avoid the risk of viral contamination and antigenicity. Different EPO formulations were developed in such a way as to allow studying the effects of amino acids and surfactants on the EPO stability profile. The main techniques applied for EPO analysis were ELISA, Bradford method, and SDS gel electrophoresis. The in vivo stability was evaluated in a Balb-c mouse animal model. The results showed that the presence of surfactant was very useful in preventing the initial adsorption of EPO on the walls of vials and in minimizing protein aggregation. Amino acid combinations, glycine with glutamic acid, provided maximum stability. Formulation F4 (containing glycine, glutamic acid and Tween 20) showed minimum aggregation and degradation and in vivo activity equivalent to commercially available HSA-stabilized EPO (Eprex(r)). PMID- 26959545 TI - Simultaneous quantitative analysis of olmesartan, amlodipine and hydrochlorothiazide in their combined dosage form utilizing classical and alternating least squares based chemometric methods. AB - Simultaneous spectrophotometric analysis of a multi-component dosage form of olmesartan, amlodipine and hydrochlorothiazide used for the treatment of hypertension has been carried out using various chemometric methods. Multivariate calibration methods include classical least squares (CLS) executed by net analyte processing (NAP-CLS), orthogonal signal correction (OSC-CLS) and direct orthogonal signal correction (DOSC-CLS) in addition to multivariate curve resolution-alternating least squares (MCR-ALS). Results demonstrated the efficiency of the proposed methods as quantitative tools of analysis as well as their qualitative capability. The three analytes were determined precisely using the aforementioned methods in an external data set and in a dosage form after optimization of experimental conditions. Finally, the efficiency of the models was validated via comparison with the partial least squares (PLS) method in terms of accuracy and precision. PMID- 26959546 TI - Effect of quercetin on the transport of ritonavir to the central nervous system in vitro and in vivo. AB - The aim of this study was to identify an effective flavonoid that could improve the intracellular accumulation of ritonavir in human brain-microvascular endothelial cells (HBMECs). An in vivo experiment on Sprague-Dawley rats was then designed to further determine the flavonoid's impact on the pharmacokinetics and tissue distribution of ritonavir. In the accumulation assay, the intracellular level of ritonavir was increased in the presence of 25 mmol L(-1) of flavonoids in HBMECs. Quercetin showed the strongest effect by improving the intracellular accumulation of ritonavir by 76.9 %. In the pharmacokinetic study, the presence of quercetin in the co-administration group and in the pretreatment group significantly decreased the area under the plasma concentration-time curve (AUC0 t) of ritonavir by 42.2 % (p < 0.05) and 53.5 % (p < 0.01), and decreased the peak plasma concentration (cmax) of ritonavir by 23.1 % (p < 0.05) and 45.8 % (p < 0.01), respectively, compared to the control group (ritonavir alone). In the tissue distribution study, the ritonavir concentration in the brain was significantly increased 2-fold (p < 0.01), during the absorption phase (1 h) and was still significantly higher (p < 0.05) during the distribution phase (6 h) in the presence of quercetin. PMID- 26959547 TI - High performance liquid chromatography for simultaneous determination of xipamide, triamterene and hydrochlorothiazide in bulk drug samples and dosage forms. AB - A novel, simple and robust high-performance liquid chromatography (HPLC) method was developed and validated for simultaneous determination of xipamide (XIP), triamterene (TRI) and hydrochlorothiazide (HCT) in their bulk powders and dosage forms. Chromatographic separation was carried out in less than two minutes. The separation was performed on a RP C-18 stationary phase with an isocratic elution system consisting of 0.03 mol L(-1) orthophosphoric acid (pH 2.3) and acetonitrile (ACN) as the mobile phase in the ratio of 50:50, at 2.0 mL min(-1) flow rate at room temperature. Detection was performed at 220 nm. Validation was performed concerning system suitability, limits of detection and quantitation, accuracy, precision, linearity and robustness. Calibration curves were rectilinear over the range of 0.195-100 MUg mL(-1) for all the drugs studied. Recovery values were 99.9, 99.6 and 99.0 % for XIP, TRI and HCT, respectively. The method was applied to simultaneous determination of the studied analytes in their pharmaceutical dosage forms. PMID- 26959548 TI - Physicochemical characterization and dissolution studies of acyclovir solid dispersions with Pluronic F127 prepared by the kneading method. AB - The dissolution rate of anhydrous acyclovir was improved by the preparation of physical mixtures and solid dispersions with the non-ionic polymer Pluronic F127 using the kneading method at different drug-to-polymer ratios. The obtained physical mixtures and solid dispersions were examined in terms of drug content and possible physical and chemical interactions between the drug and polymer using FTIR spectral studies, differential scanning calorimetry and powder X-ray diffraction analysis. The dissolution rate of acyclovir was determined using the rotating disk method. It was found that the minimal content of the polymer within the mixtures needed to increase the dissolution rate of the drug was 50 %. PMID- 26959549 TI - Preliminary in vitro evaluation of the anti-proliferative activity of guanylhydrazone derivatives. AB - Guanylhydrazones have shown promising antitumor activity in preclinical tumor models in several studies. In this study, we aimed at evaluating the cytotoxic effect of a series of synthetic guanylhydrazones. Different human tumor cell lines, by including HCT-8 (colon carcinoma), MDA-MB-435 (melanoma) and SF-295 (glioblastoma) were continuous exposed to guanylhydrazone derivatives for 72 hours and growth inhibition of tumor cell lines and macrophages J774 was measured using tetrazolium salt (MTT) assay. Compounds 7, 11, 16 and 17 showed strong cytotoxic activity with IC50 values lower than 10 MUmol L(-1) against four tumor cell lines. Among them, 7 was less toxic to non-tumor cells. Finally, obtained data suggest that guanylhydrazones may be regarded as potential lead compounds for the design of novel anticancer agents. PMID- 26959550 TI - Biphasic dissolution method for quality control and assurance of drugs containing active substances in the form of weak acid salts. AB - Substances in the form of weak acid salts have been found to be problematic for dissolution testing. Their absorption can start only after they are turned into the form of an acid following the gastric passage although they were administered in the form of a salt. Due to poor solubility, they cannot be tested in acidic gastric environment for a biased dissolution profile. The biphasic dissolution method is promising for overcoming this obstacle. Tablets with warfarin clathrate sodium salt in two concentrations and two different particle size distributions were tested as a suitable model for finding the medium and process conditions of dissolution. The dissolution method based on the use of the upper organic layer (1-octanol) and the lower aqueous layer 0.1 mol L(-1) HCl) was found suitable and discriminatory for tablets containing active substances in the form of salts of weak acids. The method also reflects physical differences in the quality of used substances. PMID- 26959551 TI - Methods for preliminary determination of pemetrexed in macromolecular drug carrier systems. AB - Pemetrexed (PMX) is an antifolate drug utilized in the treatment of non-small cell lung cancer. For studies of potential macromolecular carriers for PMX, fast and precise methods were developed to determine the bound and free drug contained in investigated conjugate preparations. The analysis of the total amount of PMX in conjugates was based on absorption spectrophotometry. The linearity was found in the range of 4.697-46.97 MUmol L(-1) PMX. The limit of quantitation was 1.070 MUmol L(-1). The method for the analysis of unbound PMX was based on size exclusion chromatography and detection at 225 nm. This method shows linear range of 2.230-223.0 MUmol L(-1). LOQ was 0.539 MUmol L(-1). The proposed methods can be used both for the characterization of the polysaccharide based conjugates of PMX and for the determination of conjugate drug release profiles. PMID- 26959552 TI - Assessment of cytochrome P450 inhibition and induction potential of lupeol and betulin in rat liver microsomes. AB - BACKGROUND: Lupeol and betulin are triterpenoids that are majorly found in dietary substances. The aim of present study was to investigate the inhibition and induction potential of lupeol and betulin on cytochrome P450 (CYP)1A2, CYP2C11, CYP2D6 and CYP3A2 activities in rat liver microsomes. METHODS: The inhibition and induction studies were conducted using ethoxy resorufin-O deethylase (CYP1A2), tolbutamide hydroxylase (CYP2C9), and midazolam hydroxylase (CYP3A4) activity assays. In vitro inhibition study was evaluated by incubating lupeol and betulin (1, 3, 10, 30 and 100 MUM) with rat liver microsomes, and the metabolite formation was analyzed by high-performance liquid chromatography. The induction study was conducted by administering lupeol (20 mg/kg) and betulin (50 mg/kg) intraperitoneally for 14 days to rats followed by liver isolation and microsome preparation. RESULTS: The IC50 values in inhibition studies were found to be 59.42 MUM (CYP1A2), >100 MUM (CYP2C11, CYP2D6, CYP3A2) for lupeol, 52.24 MUM (CYP1A2), and >100 MUM (CYP2C9, CYP2D6, CYP3A2) for betulin. There was no significant modification observed in the CYP450 isoforms, indicating neither inhibition nor induction potential of lupeol and betulin. CONCLUSIONS: Lupeol and betulin have very low propensity to interact with CYP enzyme, suggesting no CYP inhibitory and inducing potential in rat liver microsomes. PMID- 26959553 TI - Exploring mechanisms of IgE-mediated autoimmunity through the lens of bullous pemphigoid. AB - Bullous pemphigoid (BP) is the most common autoimmune blistering disease characterized by pathogenic autoantibodies targeting collagen XVII (col XVII), a hemidesmosomal adhesion molecule. Early studies utilizing IgG were critical for establishing col XVII-specific antibodies as primary mediators of blister formation; however, these studies lacked key features of the disease, including urticarial erythema and eosinophilic infiltration, which are often associated with IgE. Although it was recognized that BP patients often had elevated circulating IgE, investigations into the pathogenicity of these antibodies was delayed until discovery of col XVII-specific IgE in BP sera. Since then, a variety of in-vivo and in-vitro studies have provided clear evidence that IgE autoantibodies are a key component of BP. Furthermore, studies utilizing IgE receptor blockade in BP patients were the first to confirm a pathogenic role of IgE autoantibodies in human autoimmunity. In this review we will utilize BP as a prototypical autoimmune disease to better understand how IgE autoantibodies participate in human autoimmunity. PMID- 26959554 TI - The cancer registry as a cancer-control tool. PMID- 26959557 TI - Shame as a Cultural Artifact: A Call for Self-Awareness and Reflexivity in Personality Assessment. AB - It has become common for assessors to face therapeutic impasses and dilemmas when practicing within the Therapeutic Assessment (TA) model. This is due to the explicit goal of producing therapeutic changes in clients. In this article the author discusses the importance of assessors being aware of how their clinical practices relate to their assessment outcomes. To enhance such awareness, the author reviews the characteristics of psychological assessment practices as derived from 3 paradigms developed almost 1.5 centuries ago in Europe by the forefathers of psychology as a scientific discipline. Current assessment practices are deeply ingrained in specific cultural, social, and political frameworks originating in these paradigms. Being aware of such a historical and cultural background might help the assessor avoid blindly reenacting the values, norms, and latent relational schemas implied by different assessment methods, and instead use assessment tools as potent aids in the service of clients' change. Finally, the author illustrates how the experience of clients' shame in psychological assessment might also be understood as a by-product of the specific cultural and historical background of certain common assessment practices. PMID- 26959555 TI - Asymmetric Dimethylarginine Stimulates Akt1 Phosphorylation via Heat Shock Protein 70-Facilitated Carboxyl-Terminal Modulator Protein Degradation in Pulmonary Arterial Endothelial Cells. AB - Asymmetric dimethylarginine (ADMA) induces the mitochondrial translocation of endothelial nitric oxide synthase (eNOS) through the nitration-mediated activation of Akt1. However, it is recognized that the activation of Akt1 requires phosphorylation events at threonine (T) 308 and serine (S) 473. Thus, the current study was performed to elucidate the potential effect of ADMA on Akt1 phosphorylation and the mechanisms that are involved. Exposure of pulmonary arterial endothelial cells to ADMA enhanced Akt1 phosphorylation at both threonine 308 and Ser473 without altering Akt1 protein levels, phosphatase and tensin homolog activity, or membrane Akt1 levels. Heat shock protein (Hsp) 90 plays a pivotal role in maintaining Akt1 activity, and our results demonstrate that ADMA decreased Hsp90-Akt1 interactions, but, surprisingly, overexpression of a dominant-negative Hsp90 mutant increased Akt1 phosphorylation. ADMA exposure or overexpression of dominant-negative Hsp90 increased Hsp70 levels, and depletion of Hsp70 abolished ADMA-induced Akt1 phosphorylation. ADMA decreased the interaction of Akt1 with its endogenous inhibitor, carboxyl-terminal modulator protein (CTMP). This was mediated by the proteasomal-dependent degradation of CTMP. The overexpression of CTMP attenuated ADMA-induced Akt1 phosphorylation at Ser473, eNOS phosphorylation at Ser617, and eNOS mitochondrial translocation. Finally, we found that the mitochondrial translocation of eNOS in our lamb model of pulmonary hypertension is associated with increased Akt1 and eNOS phosphorylation and reduced Akt1-CTMP protein interactions. In conclusion, our data suggest that CTMP is directly involved in ADMA-induced Akt1 phosphorylation in vitro and in vivo, and that increasing CTMP levels may be an avenue to treat pulmonary hypertension. PMID- 26959558 TI - Individualized conditioning regimes in cord blood transplantation: Towards improved and predictable safety and efficacy. AB - INTRODUCTION: The conditioning regimen used in cord blood transplantation (CBT) may significantly impact the outcomes. Variable pharmacokinetics (PK) of drugs used may further influence outcome. Individualized dosing takes inter-patient differences in PK into account, tailoring drug dose for each individual patient in order to reach optimal exposure. Dose individualization may result in a better predictable regimen in terms of safety and efficacy, including timely T cell reconstitution, which may result in improved survival chances. AREAS COVERED: Conditioning regimens used in CBT varies significantly between and within centres. For busulfan, individualized dosing with therapeutic drug monitoring has resulted in better outcomes. Anti-thymocyte globulin (ATG), used to prevent rejection and GvHD, significantly hampers early T-cell reconstitution (IR). Timely IR is crucial in preventing viral reactivations and relapse. By individudalizing ATG, IR is better predicted and may prevent morbidity and mortality. EXPERT OPINION: Individualization of agents used in the conditioning regimen in CBT has proven its added value. Further fine-tuning, including new drugs and/or comprehensive models for all drugs, may result in better predictable conditioning regimens. A predictable conditioning regimen is also of interest/importance when studying adjuvant therapies, including immunotherapies (e.g. cellular vaccines or engineered T-cell) in a harmonized clinical trial design setting. PMID- 26959606 TI - Investigating the Relative Exercise Intensity of Exergames in Prepubertal Children. AB - OBJECTIVE: The literature remains equivocal as to whether exergames elicit energy expenditure (EE) commensurate with physical activity guidelines. Such discrepancies may be attributable to a reliance on absolute exercise intensities, which fail to account for differences in cardiorespiratory fitness levels. MATERIALS AND METHODS: Thirty-four prepubertal children (20 boys, 14 girls; 10.8 +/- 1.0 years old) completed a 30-minute exergame (two 15-minute games from "Kinect Adventures! Xbox 360" [Microsoft, Redmond, WA]) and an incremental treadmill test to determine peak oxygen uptake ( [Formula: see text]) throughout which breath-by-breath gas exchange was measured. RESULTS: Both games elicited moderate-intensity physical activity (5.7 +/- 1.5 and 5.5 +/- 1.4 metabolic equivalents [METs]), with 36 percent demonstrating a mean EE in excess of 6.0 METs, commensurate with vigorous intensity. Furthermore, boys demonstrated higher EE during both games (boys versus girls: Game 1, 6.0 +/- 1.7 versus 5.2 +/- 1.0 METs; Game 2, 6.0 +/- 1.4 versus girls, 4.9 +/- 1.2 METs; P < 0.05). Hierarchical linear regression revealed sex, maturity, and fitness to be significant predictors of EE, accounting for 24 percent of the variance: relative exergame [Formula: see text] = 24.53 + (2.12 * Sex) - (0.42 * Maturity offset) - (0.16 * Relative peak [Formula: see text]). There was no correlation between absolute [Formula: see text] during the exergames and peak [Formula: see text], but [Formula: see text] expressed as a percentage of peak [Formula: see text] was correlated with peak [Formula: see text] during both Game 1 (r = -0.62, P < 0.01) and Game 2 (r = -0.59, P < 0.01). CONCLUSIONS: The present findings provide further evidence that exergames can elicit EE values commensurate with national physical activity guidelines and extend our understanding of the mediators of EE. Specifically, cardiorespiratory fitness and sex must both be considered in the design and implementation of future interventions seeking to use exergames to enhance physical activity levels and/or cardiorespiratory fitness. PMID- 26959556 TI - MicroRNA-15b regulates mitochondrial ROS production and the senescence-associated secretory phenotype through sirtuin 4/SIRT4. AB - Mammalian sirtuins are involved in the control of metabolism and life-span regulation. Here, we link the mitochondrial sirtuin SIRT4 with cellular senescence, skin aging, and mitochondrial dysfunction. SIRT4 expression significantly increased in human dermal fibroblasts undergoing replicative or stress-induced senescence triggered by UVB or gamma-irradiation. In-vivo, SIRT4 mRNA levels were upregulated in photoaged vs. non-photoaged human skin. Interestingly, in all models of cellular senescence and in photoaged skin, upregulation of SIRT4 expression was associated with decreased levels of miR-15b. The latter was causally linked to increased SIRT4 expression because miR-15b targets a functional binding site in the SIRT4 gene and transfection of oligonucleotides mimicking miR-15b function prevented SIRT4 upregulation in senescent cells. Importantly, increased SIRT4 negatively impacted on mitochondrial functions and contributed to the development of a senescent phenotype. Accordingly, we observed that inhibition of miR-15b, in a SIRT4 dependent manner, increased generation of mitochondrial reactive oxygen species, decreased mitochondrial membrane potential, and modulated mRNA levels of nuclear encoded mitochondrial genes and components of the senescence-associated secretory phenotype (SASP). Thus, miR-15b is a negative regulator of stress-induced SIRT4 expression thereby counteracting senescence associated mitochondrial dysfunction and regulating the SASP and possibly organ aging, such as photoaging of human skin. PMID- 26959607 TI - Characterization of inflammatory markers and transcriptome profiles of differentially activated embryonic stem cell-derived microglia. AB - Microglia, the immune cells of the CNS, are highly adaptive cells that can acquire different pro- and anti-inflammatory activation states with distinct functions in CNS homeostasis and pathologies. To study microglial function in vitro, primary microglia or immortalized cell lines are commonly used. An alternative to these cells are embryonic stem cell-derived microglia (ESdM). ESdM have previously been shown to be very similar to primary microglia in terms of expression profiles and surface molecules. In this study, ESdM and primary microglia were treated with different inflammatory stimulants to analyze their ability to adopt different activation states. Using quantitative real-time PCR, comparative transcriptomics, ELISA, and flow cytometry, we found that different activation states can be induced in ESdM, which are similar to those found in primary microglia. These states are characterized by specific sets of inflammatory marker molecules and differential transcriptome signatures. Our results show that ESdM are a valuable alternative cell model to study microglial functions and neuroinflammatory mechanisms. PMID- 26959609 TI - Paediatric sedation for imaging is safe and effective in a district general hospital. AB - OBJECTIVE: To devise a safe and effective sedation protocol for imaging paediatric patients in a small district general hospital (DGH). METHODS: Chloral hydrate, alimemazine and learned best practice were used for imaging 105 children between January 2013 and May 2015. We retrospectively reviewed case notes for this time period to establish rates of successful sedation and adverse events. RESULTS: Scanning was successful in 100/105 (95%) children. No serious adverse events were reported. Non-serious adverse events occurred in eight cases. 12 patients were discharged more than 4 h after scanning owing to prolonged sedation. CONCLUSION: This is a safe and effective protocol for delivering sedation for imaging in paediatric patients. We would encourage similar centres to adopt this protocol where resources for i.v. sedation and general anaesthesia are limited. ADVANCES IN KNOWLEDGE: There are many different sedation protocols in the literature for imaging in paediatric patients, with varying levels of success and adverse event rates. We present here a protocol that offers a high efficacy and safe sedation for imaging in a DGH. PMID- 26959608 TI - Tumor cells with KRAS or BRAF mutations or ERK5/MAPK7 amplification are not addicted to ERK5 activity for cell proliferation. AB - ERK5, encoded by MAPK7, has been proposed to play a role in cell proliferation, thus attracting interest as a cancer therapeutic target. While oncogenic RAS or BRAF cause sustained activation of the MEK1/2-ERK1/2 pathway, ERK5 is directly activated by MEK5. It has been proposed that RAS and RAF proteins can also promote ERK5 activation. Here we investigated the interplay between RAS-RAF-MEK ERK and ERK5 signaling and studied the role of ERK5 in tumor cell proliferation in 2 disease-relevant cell models. We demonstrate that although an inducible form of CRAF (CRAF:ER*) can activate ERK5 in fibroblasts, the response is delayed and reflects feed-forward signaling. Additionally, oncogenic KRAS and BRAF do not activate ERK5 in epithelial cells. Although KRAS and BRAF do not couple directly to MEK5-ERK5, ERK5 signaling might still be permissive for proliferation. However, neither the selective MEK5 inhibitor BIX02189 or ERK5 siRNA inhibited proliferation of colorectal cancer cells harbouring KRAS(G12C/G13D) or BRAF(V600E). Furthermore, there was no additive or synergistic effect observed when BIX02189 was combined with the MEK1/2 inhibitor Selumetinib (AZD6244), suggesting that ERK5 was neither required for proliferation nor a driver of innate resistance to MEK1/2 inhibitors. Finally, even cancer cells with MAPK7 amplification were resistant to BIX02189 and ERK5 siRNA, showing that ERK5 amplification does not confer addiction to ERK5 for cell proliferation. Thus ERK5 signaling is unlikely to play a role in tumor cell proliferation downstream of KRAS or BRAF or in tumor cells with ERK5 amplification. These results have important implications for the role of ERK5 as an anti-cancer drug target. PMID- 26959610 TI - Reducing the within-patient variability of breathing for radiotherapy delivery in conscious, unsedated cancer patients using a mechanical ventilator. AB - OBJECTIVE: Variability in the breathing pattern of patients with cancer during radiotherapy requires mitigation, including enlargement of the planned treatment field, treatment gating and breathing guidance interventions. Here, we provide the first demonstration of how easy it is to mechanically ventilate patients with breast cancer while fully conscious and without sedation, and we quantify the resulting reduction in the variability of breathing. METHODS: 15 patients were trained for mechanical ventilation. Breathing was measured and the left breast anteroposterior displacement was measured using an Osiris surface-image mapping system (Qados Ltd, Sandhurst, UK). RESULTS: Mechanical ventilation significantly reduced the within-breath variability of breathing frequency by 85% (p < 0.0001) and that of inflation volume by 29% (p < 0.006) when compared with their spontaneous breathing pattern. During mechanical ventilation, the mean amplitude of the left breast marker displacement was 5 +/- 1 mm, the mean variability in its peak inflation position was 0.5 +/- 0.1 mm and that in its trough inflation position was 0.4 +/- 0.0 mm. Their mean drifts were not significantly different from 0 mm min(-1) (peak drift was -0.1 +/- 0.2 mm min(-1) and trough drift was 0.3 +/- 0.2 mm min(-1)). Patients had a normal resting mean systolic blood pressure (131 +/- 5 mmHg) and mean heart rate [75 +/- 2 beats per minute (bpm)] before mechanical ventilation. During mechanical ventilation, the mean blood pressure did not change significantly, mean heart rate fell by 2 bpm (p < 0.05) with pre-oxygenation and rose by only 4 bpm (p < 0.05) during pre-oxygenation with hypocapnia. No patients reported discomfort and all 15 patients were always willing to return to the laboratory on multiple occasions to continue the study. CONCLUSION: This simple technique for regularizing breathing may have important applications in radiotherapy. ADVANCES IN KNOWLEDGE: Variations in the breathing pattern introduce major problems in imaging and radiotherapy planning and delivery and are currently addressed to only a limited extent by asking patients to breathe to auditory or visual guidelines. We provide the first demonstration that a completely different technique, of using a mechanical ventilator to take over the patients' breathing for them, is easy for patients who are conscious and unsedated and reduces the within-patient variability of breathing. This technique has potential advantages in radiotherapy over currently used breathing guidance interventions because it does not require any active participation from or feedback to the patient and is therefore worthy of further clinical evaluation. PMID- 26959611 TI - Intraductal papillary mucinous neoplasms of the pancreas: radiological predictors of malignant transformation and the introduction of bile duct dilation to current guidelines. AB - OBJECTIVE: To evaluate the current guidelines as a model to predict malignancy and to determine further radiological predictors of malignancy in intraductal papillary mucinous neoplasms (IPMNs). METHODS: 384 patients who had undergone a pancreatic operation with the pathological diagnosis of IPMN as well as applicable pre-operative imaging (CT/MRI) were included in the study. Images were evaluated retrospectively in consensus by two radiologists, using a standardized checklist. Descriptive statistics, binary logistic regression and receiver operator curve analysis were performed to assess the International Consensus Guidelines and other radiological predictors of clinical malignancy (defined as carcinoma in situ and invasive carcinoma). RESULTS: The best independent predictors of malignancy (n = 191) were solid components [odds ratio (OR) 3.98], parenchymal atrophy with main pancreatic duct dilation 5-9 mm (OR: 5.1) and common bile duct (CBD) dilation (OR: 31.26). >96% of all cases with CBD dilation were malignant IPMNs (positive-predictive value 96.4%; negative-predictive value 63.1%). Analysis of the current guidelines showed a diagnostic improvement with the addition of CBD dilation on determining the malignancy of IPMNs (sensitivity 82.2%/86.9%; specificity 72.7%/74.6%). Subanalysis of branch duct intraductal papillary mucinous neoplasms (BD-IPMNs; n = 168) also resulted in a diagnostic improvement with the addition of CBD dilation (sensitivity 28.6%/45.2%; specificity 92.9%/92.1%). The best independent predictors of malignancy for BD IPMNs were parenchymal atrophy (OR: 4.00) and CBD dilation (OR: 29.3). Frequency analysis revealed that even small BD-IPMNs had already undergone malignant transformation (<=1 cm: 15%; 1-2 cm: 26%; 2-3 cm: 20%) with about 10% of those having a dilated bile duct. CONCLUSION: CBD dilation was a significant positive predictor of malignancy in IPMNs regardless of their size. ADVANCES IN KNOWLEDGE: Introduction of CBD dilation as a radiological predictor for malignancy might increase the diagnostic accuracy of current imaging-based guidelines. PMID- 26959612 TI - Comparison of dosimetric parameters and acute toxicity after whole-pelvic vs prostate-only volumetric-modulated arc therapy with daily image guidance for prostate cancer. AB - OBJECTIVE: To compare dosimetric parameters and acute toxicity rates between whole-pelvic (WP) and prostate-only (PO) volumetric-modulated arc therapy (VMAT) in patients with localized prostate cancer. METHODS: A total of 224 consecutive patients treated with definitive VMAT to 78 Gy in 39 fractions were enrolled. Of these, 119 patients received initial WP VMAT at 46.8 Gy in 26 fractions using a simultaneous integrated boost technique, and 105 patients received PO VMAT. Image guided radiotherapy was practised with daily cone beam CT. RESULTS: The mean rectal dose, the rectal volume receiving >=30 Gy (V30Gy), rectal V50Gy, the mean bladder dose, bladder V30Gy and bladder V50Gy were significantly increased in the WP group (p < 0.05 each); however, the rectal V70Gy did not differ between groups (p = 0.101), and the bladder V70Gy was significantly lower in the WP group (p = 0.029). The WP group experienced a significantly increased frequency of acute grade 2 diarrhoea relative to the PO group (5.9% vs 0%; p = 0.015). No differences were seen between the WP and PO groups in terms of acute grade 2 proctitis (10.1% vs 6.7%; p = 0.360) and genitourinary (GU) toxicity (12.6% vs 10.5%; p = 0.620). CONCLUSION: Despite larger rectum and bladder volumes at low- and medium-dose levels, WP VMAT resulted in no significant increase in acute proctitis or GU toxicity when compared with PO VMAT. ADVANCES IN KNOWLEDGE: This study demonstrates that whole-pelvic radiotherapy has comparable acute toxicity to those observed with prostate-only radiotherapy when VMAT with daily image guidance is used. PMID- 26959613 TI - Imaging features of blast injuries: experience from 2015 Ankara bombing in Turkey. AB - OBJECTIVE: To present the radiological features of blast-related injuries in the victims of the 10 October 2015 Ankara bombing and emphasize the importance of imaging. METHODS: This retrospective descriptive study included a total of 28 patients who underwent CT scan or radiographic imaging within 6 h after the bombing on 10 October 2015. CT scans and plain radiographs were evaluated regarding mechanisms of injuries. Injuries were categorized as primary, secondary, tertiary and quaternary. The number of shrapnel and distribution of injuries were noted. Injury Severity Score (ISS) was used to rank the severity of the injury. RESULTS: Primary blast injuries consisted of only tympanic membrane rupture. A high rate of patients (21/28 patients) in the study group suffered from secondary blast injuries. Tertiary injuries were detected in only three patients. Of the severely injured patients, five had abdominal injuries, three had thoracic injuries and six had extremity injuries. ISS was significantly higher in patients with thoracic and abdominal injuries. CONCLUSION: Our results after the suicide bomb attacks showed that the most common injury pattern was secondary blast injury. The torso was the most commonly injured body region, followed by the extremities. This specific injury pattern requires the use of immense radiological imaging. Hence, radiologists should be aware of the mechanisms and spectrums of blast-related injuries. ADVANCES IN KNOWLEDGE: Both the unique injury pattern and the following chaos make blast-related injuries a challenge in terms of triage, diagnosis and management. Radiologists should be familiar with the wide spectrum of these unique injuries. PMID- 26959614 TI - NMR-based metabolomics of prostate cancer: a protagonist in clinical diagnostics. AB - Advances in the application of NMR spectroscopy-based metabolomic profiling of prostate cancer comprises a potential tactic for understanding the impaired biochemical pathways arising due to a disease evolvement and progression. This technique involves qualitative and quantitative estimation of plethora of small molecular weight metabolites of body fluids or tissues using state-of-the-art chemometric methods delivering an important platform for translational research from basic to clinical, to reveal the pathophysiological snapshot in a single step. This review summarizes the present arrays and recent advancements in NMR based metabolomics and a glimpse of currently used medical imaging tactics, with their role in clinical diagnosis of prostate cancer. PMID- 26959615 TI - Mir-221/222 are promising targets for innovative anticancer therapy. AB - INTRODUCTION: MicroRNAs (miRNAs) are key non-coding RNA post-transcriptional regulators of messenger RNAs (mRNAs), and are deeply dysregulated in human cancer. A rising body of evidence indicates that miRNAs represent valuable therapeutic targets. In this light, the cluster miR-221/222 are of particular relevance, given that they are strongly upregulated in a variety of solid and hematologic malignancies. AREA COVERED: This review summarizes recent findings on the roles played by miR-221/222 in human cancer and their potential clinical value as promising targets for therapeutic studies. EXPERT OPINION: The rising body of advanced preclinical evidence on the biological significance of miR 221/222 in a variety of malignancies indicates that they will play a crucial role in the future of innovative therapeutic strategies, both as validated biomarkers and targets. PMID- 26959616 TI - The effect of prenatal exposure to 1800 MHz electromagnetic field on calcineurin and bone development in rats. AB - PURPOSE: To investigated the effects of exposure to an 1800 MHz electromagnetic field (EMF) on bone development during the prenatal period in rats. METHODS: Pregnant rats in the experimental group were exposed to radiation for six, 12, and 24 hours daily for 20 days. No radiation was given to the pregnant rats in the control group. We distributed the newborn rats into four groups according to prenatal EMF exposure as follows: Group 1 was not exposed to EMF; groups 2, 3, and 4 were exposed to EMF for six, 12, and 24 hours a day, respectively. The rats were evaluated at the end of the 60th day following birth. RESULTS: Increasing the duration of EMF exposure during the prenatal period resulted in a significant reduction of resting cartilage levels and a significant increase in the number of apoptotic chondrocytes and myocytes. There was also a reduction in calcineurin activities in both bone and muscle tissues. We observed that the development of the femur, tibia, and ulna were negatively affected, especially with a daily EMF exposure of 24 hours. CONCLUSION: Bone and muscle tissue development was negatively affected due to prenatal exposure to 1800 MHz radiofrequency electromagnetic field. PMID- 26959617 TI - Video-assisted ovariohysterectomy in domestic cats (Felis catus, Linnaeus, 1758) using two access portals. AB - PURPOSE: To describe video-assisted ovariohysterectomy (OHE) with two portals access in adult intact queens. METHODS Fifty-two females cats were used. A 4 mm cannula was positioned in the abdomen through an incision close to the umbilicus (first portal), and a pneumoperitoneum was established. A second portal was positioned in the midline of the pre-pubic region. Females were positioned in right lateral recumbency to locate the left ovarian pedicle, and the uterine horn was held by a transcutaneous suture. The pedicle was cauterized and incised. The procedure was then performed on the contralateral ovary. The ovaries were exteriorized from the abdomen, along with the uterus, through the second access point. The uterine body was exposed, fixed and sectioned, and the abdominal incisions were sutured. RESULTS Surgeries were performed in an average of 41.4+/ 14.2 minutes. The main complications included hypotension (7.7%) and subcutaneous emphysema (7.7%), and 13.5% of the surgeries were converted to laparotomy. CONCLUSION Ovariohysterectomy using a video-assisted technique and two access portals is safe, has minimal risks and is effective for the spaying of queens. PMID- 26959618 TI - Facial nerve identification with fluorescent dye in rats. AB - PURPOSE The parotidectomy technique still has an elevated paresis and paralysis index, lowering patient life's quality. The correct identification of the facial nerve can prevent nerve damage. Fluorescent dye identifies nerves in experimental studies but only few articles focused its use on facial nerve study in parotidectomies. We aimed to stain the rat facial nerve with fluorescent dye to facilitate visualization and dissection in order to prevent injuries. METHODS Forty adult male Wistar rats were submitted to facial injection of saline solution (Gsf-control group, 10) or fluorescent dye solution (Gdye group, 30) followed by parotidectomy preserving the facial nerve, measuring the time for localization and facility of localization (LocTime and LFN). Nerve function was assessed using the Vibrissae Movements (PMV) and Eyelid Closure Motion (PFP) scores. RESULTS Nerve localization was faster in Gdye group, with 83% Easy LFN rate. The Gdye group presented with low nerve injury degree and better PMV and PFP scores, with high sensitivity and accuracy. CONCLUSIONS This experimental method of facial nerve fluorescence was effective for intraoperative nerve visualization, identification and preservation. The technique may be used in future facial nerve studies, translated to humans, contributing to the optimization of parotid surgery in the near future. PMID- 26959619 TI - Ultrasound biomicroscopy and claudication test for in vivo follow-up of muscle repair enhancement based on platelet-rich plasma therapy in a rat model of gastrocnemius laceration. AB - PURPOSE: To track the regeneration process of lateral gastrocnemius due to a muscle laceration in rats, and to treatment with plateletrich plasma (PRP). METHODS: Ultrasound (40 MHz) images were used for measuring pennation angle (PA), muscle thickness (MT) and mean pixel intensity, along with claudication scores, of treated (PRPG) and non-treated (NTG) groups of rats. RESULTS: NTG showed a PA increase for the non-injured leg (p<0.05) and a tendency of MT to increase, whereas for PRPG there were no differences. There was a progressive reduction of the claudication score for the PRPG group throughout the entire period, with an immediate difference after seven days (p<0.05), whereas the NTG had a significant reduction only at day 28 (p<0.05). CONCLUSION: It was observed a compensatory hypertrophic response due to the overload condition imposed to healthy leg for NTG that did not occur in PRPG, suggesting an accelerated repair process of the injured leg due to treatment, anticipating its use. PMID- 26959620 TI - Effect of ozone on colon anastomoses in rat peritonitis model. AB - PURPOSE: To investigate the effects of medical ozone theraphy on the colon anastomosis of peritonitis model in rats. METHODS: Eighteen rats were randomly assigned into three equal groups; control, cecal punctuation and colon anastomosis and ozone theraphy. Sepsis was performed with a cecal punctuation in groups 2 and 3. The medical ozone theraphy was administered intraperitonealy for three weeks in group 3 while the other rats received saline injection. At the twenty second day serum were obtained for TNF-alpha and IL-1beta, the colonic burst pressures were measured and colonic tissue samples were obtained for MDA and MPO levels. Histolopatological examination was evaluated with H&E stain, and Ki-67, IL-1beta and the VEGF immunostaining densities were also compared. RESULTS: Intraperitoneal ozone administration reversed TNF-alpha, IL-1beta, MDA and MPO levels and the colonic burst pressures. There was also a significant difference at immunostaining densities of histopathological examination. CONCLUSION: Medical ozone therapy may contribute to tissue healing by affecting the proliferation and the vascularization thus has benefits on colonic anastomosis at peritonitis in rats. PMID- 26959621 TI - Effects of chitin and sepia ink hybrid sponge on the healing of burning wound rats and its impact on macrophages in vitro. AB - PURPOSE: To detect whether chitin and sepia ink sponge (CS) can promote wound healing and elevate impact of CS on phagocytosis ability of macrophages. METHODS: Forty-eight rats were assigned to four groups: Normal group (Normal), negative control group (Con), chitin and sepia ink sponge group (CS) and positive control Surgicel Gauze(r) group (SG). Deep second-degree burn model was created in rats. Wound area was recorded by digital imaging and determined using Image J software. Samples were collected and kept at -80oC on 3d, 7d, 14d and 21d for cytokines detecting. Transforming growth factor (TGF)-beta1, interleukin (IL)-6, matrix metalloproteinase (MMP)-1, hydroxyproline (Hyp) and macrophage activity reflected by tumor necrosis factor (TNF)-alpha were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Comparing to Con and SG, scabs in CS group fell off and basically healed on 21 day. TGF-beta1, IL-6, MMP-1 and Hyp were significantly increased by CS and SG comparing to Con (p < 0.05), CS had more apparently adjustment on TGF-beta1 and MMP-1 compared to SG; results in vitro indicated CS significantly promoted phagocytosis ability of macrophages reflected in TNF-alpha (p < 0.05). CONCLUSION: CS improved wound healing through exerting significant influences on secretion of kinds of cytokines and activating macrophages. PMID- 26959622 TI - Evaluation of the effect of allopurinol as a protective factor in post ischemia and reperfusion inflammation in Wistar rats. AB - PURPOSE: To investigate the potential protective effect of allopurinol on reperfusion injury by determining the inflammatory response through the measurement of tumor necrosis factor-alpha (TNF-alpha). METHODS: Sixty rats were distributed into two groups: control and allopurinol and each group was divided into three subgroups, ischemia for two hours, ischemia for three hours and ischemia simulation. Allopurinol group rats received 100mg/kg dose of allopurinol, whereas control group rats received an equivalent dose of saline. Clamping of the infrarenal aorta was performed for two or three hours depending on the subgroup. Ischemia simulation subgroups did not suffer ischemia, just aortic dissection, and maintenance for three hours. After 72 hours of reperfusion, blood was collected by cardiac puncture for TNF-alpha measurement. RESULTS: Allopurinol reduced TNF-alpha significantly (p <0.001) when compared to the matching control subgroups (control X allopurinol in ischemia for two hours and for three hours). CONCLUSION: Allopurinol reduced the concentrations of serum TNF-alpha when used at different times of ischemia followed by reperfusion, which might indicate reduction of the inflammation provoked by the reperfusion injury. PMID- 26959623 TI - Effect of adenosine A2A receptor antagonists on motor disorders induced by 6 hydroxydopamine in rat. AB - PURPOSE: To investigate the role of adenosine A2A receptors on 6-OHDA-induced motor disorder in rat. METHODS: In order to induce experimental model of Parkinson's disease, 6-hydoxydopamine (8 MUg/rat) was injected unilaterally into the SNc. After three weeks as a recovery period, 6-OHDA-induced bradykinesia and balance disturbances were assessed by using beam traversal test 10, 30 and 60 minutes after intraperitoneal injections of the drugs (caffeine, SCH58261). RESULTS: The results showed that 6-OHDA (8 MUg/rat, Intra-SNc) induced motor disorders of Parkinson's disease and increased elapsed time in the beam test (p<0.001). Injection of caffeine (30 mg/kg, i.p.) and SCH58261 (2 mg/kg, i.p.) attenuated elapsed time on beam (p<0.01 and p<0.001). We showed that acute administration of caffeine and SCH 58261 can improve the 6-OHDA-induced bradykinesia and motor disturbance. CONCLUSION: Adenosine A2AR antagonists improve 6-OHDA-motor deficit and this effect seems to be mediated by the inhibition of A2A presynaptic receptors in substantia nigra pars compacta. PMID- 26959624 TI - Technique for implanting intramuscular electrodes in the diaphragm by videolaparoscopy in pigs. AB - PURPOSE: To describe a novel approach for implanting intramuscular electrodes in the diaphragm through videolaparoscopy. METHODS: We used twelve pigs for this videolaparoscopic technique, which permits at the same time to explore the diaphragm, to locate its motor points and to fix the electrodes in the diaphragm bilaterally. In this technique we used three trocars: one portal for a 10-mm 0 degrees viewing angle laparoscope, one portal for the manipulation of structures and another for electrode implantation. RESULTS: All animals survived the procedure without pneumothorax/capnothorax or other complication. Implanted electrodes provided an appropriate interface between the muscle and the electrical current generator, and electroventilation was satisfactorily generated in all animals. CONCLUSION: This videolaparoscopic technique with three trocars enables the exploration and identification of motor points and an efficient fixation of one or two electrodes in each hemidiaphragm. PMID- 26959625 TI - Ellagic acid inhibits proliferation and induces apoptosis in human glioblastoma cells. AB - PURPOSE: To investigate the anticancer activity of ellagic acid (EA) in U251 human glioblastoma cells and its possible molecular mechanism. METHODS: The cells were treated with EA at various concentrations for different time periods. Cell viability and cell proliferation were detected by cell counting kit-8(CCK-8) assay and live/dead assay respectively. Cell apoptosis were measured with Annexin V-FITC/PI double staining method by flow cytometry and Mitochondrial membrane potential assay separately. Cell cycle was measured with PI staining method by flow cytometry. The expressions of Bcl-2, Survivin, XIAP, Caspase-3, Bax, JNK, p JNK, ERK1/2, p-ERK1/2, p38, p-p38, DR4, DR5, CHOP and GRP78-related proteins were detected by western blot after EA treatment. RESULTS: Cell viability and proliferation of glioblastoma cells treated with EA were significantly lower than the control group. EA caused robust apoptosis of the glioblastoma cells compared to the control group. EA significantly decreased the proportion at G0/G1 phases of cell cycling accompanied by increased populations at S phase in U251 cell lines. And the expressions of anti-apoptotic proteins were dramatically down regulated. CONCLUSION: Ellagic acid potentially up-regulated DR4, DR5 and MAP kinases (JNK, ERK1/2 and p38). EA also caused significant increase in the expressions of CHOP and GRP78. Our findings suggest that EA would be beneficial for the treatment of glioblastoma. PMID- 26959626 TI - Enhanced Lateral Ordering in Cylinder Forming PS-b-PMMA Block Copolymers Exploiting the Entrapped Solvent. AB - The self-assembly of block copolymer (BCP) thin films produces dense and ordered nanostructures. Their exploitation as templates for nanolithography requires the capability to control the lateral order of the nanodomains. Among a multiplicity of polymers, the widely studied all-organic polystyrene-block-poly(methyl methacrylate) (PS-b-PMMA) BCP can easily form nanodomains perpendicularly oriented with respect to the substrate, since the weakly unbalanced surface interactions are effectively neutralized by grafting to the substrate an appropriate poly(styrene-random-methyl methacrylate) P(S-r-MMA) random copolymer (RCP). This benefit along with the selective etching of the PMMA component and the chemical similarity with the standard photoresist materials deserved for PS-b PMMA the role of BCP of choice for the technological implementation in nanolithography. This work demonstrates that the synergic effect of thermal annealing with the initial solvent naturally trapped in the basic RCP + BCP system after the deposition process can be exploited to enhance the lateral order. The solvent content embedded in the total RCP + BCP system can be tuned by changing the molecular weight and thus the thickness of the grafted RCP brush layer, without introducing external reservoirs or dedicated setup and/or systems. The appropriate supply of solvent supports a grain coarsening kinetics following a power law with a 1/3 growth exponent for standing hexagonally ordered cylinders. PMID- 26959628 TI - BORZOUYEH, AN ANCIENT PERSIAN PHYSICIAN WHO FIRST REPORTED UTERINE CONTRACTIONS IN NORMAL VAGINAL DELIVERY. AB - During the final hours of pregnancy, uterine contractions cause the foetus to move through the birth canal and leave the mother's body. Haly Abbas (died 982 994 CE), is believed to be the first writer to explain the role of these contractions. However, this concept had in fact been described in the text titled Bab-e-Borzouyeh, written four centuries earlier by the physician Borzouyeh (Perzoes in Latin) as a prologue to his translation of the Indian collection of fables known as the Panchatantra. Because Haly Abbas probably had access to ancient Persian medical texts, the earliest report of uterine contractions may need to be re-attributed to this earlier author. PMID- 26959629 TI - INSIGHTS INTO AVICENNA'S KNOWLEDGE OF GASTROINTESTINAL MEDICINE AND HIS ACCOUNT OF AN ENEMA DEVICE. AB - Avicenna (980-1037 AD), also known as Sheikh or-Raeis, was an Muslim philosopher, physician, surgeon, astronomer, politician, encyclopedist, and mathematician. Avicenna's writings comprise of five books, know as the Al-Qanun fi al-Tibb (The Canon of Medicine) and the canon covers a wide variety of medical issues. This canon of medicine was the main reference for medical education in Western countries up until the 16th century and in the Middle East until the 19th century. Several chapters of the 3rd book of the Canon are devoted to a detailed description of gastrointestinal diseases including bowel obstruction, hemorrhoids anal fissures, perianal fistulas and perianal itching. Additionally, that same volume contains an illustration of an enema device. The aim of this paper was to present a brief review of Avicenna's 11th century views on bowel obstruction and to present his description of an enema device that has remained relatively unnoticed until now. Finally, this article illustrates similarities between Avicenna's explanation and modern medical science that celebrate Avicenna as an important contributor to medieval knowledge on gastrointestinal diseases, the science of which has been passed on to later generations. PMID- 26959627 TI - The intestinal cholinergic anti-inflammatory pathway. AB - The main task of the immune system is to distinguish and respond accordingly to 'danger' or 'non-danger' signals. This is of critical importance in the gastrointestinal tract in which immune cells are constantly in contact with food antigens, symbiotic microflora and potential pathogens. This complex mixture of food antigens and symbionts are essential for providing vital nutrients, so they must be tolerated by the intestinal immune system to prevent aberrant inflammation. Therefore, in the gut the balance between immune activation and tolerance should be tightly regulated to maintain intestinal homeostasis and to prevent hypersensitivity to harmless luminal antigens. Loss of this delicate equilibrium can lead to abnormal activation of the intestinal immune system resulting in devastating gastrointestinal disorders such as inflammatory bowel disease (IBD). Recent evidence supports the idea that the central nervous system interacts dynamically via the vagus nerve with the intestinal immune system to modulate inflammation through humoral and neural pathways, using a mechanism also referred to as the intestinal cholinergic anti-inflammatory pathway. In this review, we will focus on the current understanding of the mechanisms and neuronal circuits involved in the intestinal cholinergic anti-inflammatory pathway. Further investigation on the crosstalk between the nervous and intestinal immune system will hopefully provide new insights leading to the identification of innovative therapeutic approaches to treat intestinal inflammatory diseases. PMID- 26959630 TI - DR. SAKINEH PARI, THE FIRST IRANIAN FEMALE SURGEON. AB - Modern surgery has been evolved in Iran by the establishment of Dar al-Funun and Tehran University in 1851 and 1934 respectively. Professor Yahya Adl established the first academic department of surgery at Tehran University in 1930s and he is known as the father of modern surgery in Iran. Until recent times, women's options for obtaining advanced surgical training programs were severely restricted all over the world. Dr. Sakineh Pari, born in 1902, was the first Iranian female surgeon. The aim of this article is to introduce Dr. Sakineh Pari as the first woman surgeon in Iran. PMID- 26959631 TI - AVICENNA'S MEDICAL DIDACTIC POEM: URJUZEHTEBBI. AB - Historical research shows that many physicians experienced in medical sciences are also talented in art, literature and poetry. Avicenna was a sage who was skilled in poetry in addition to philosophy and medicine. He wrote two different types of poetry: those meant to be enjoyed for their literary qualities of novelty and imagination, and his didactic Urjuzeh. Didactic poems are different from poetry evoked by imagination and feeling. In didactic poetry, the poets want to learn science and philosophy, whether spiritual, ethical or practical to the readers. Rhyme and poetry were often used for scientific writing in Avicenna's era, and were considered a method for memorizing scientific information and raising students' interest in difficult scientific concepts. Verse was used to simplify the didactic content, ease memorization and make difficult scientific issues more attractive. In medieval Persia, students of medicine had learned the basics of philosophy before starting medical courses. Poetry could help the students memorize the poem itself in combination with its meaning, in a way that was better and easier than prose. Avicenna's masterpiece, UrjuzehTebbi, comprises a perfect course in traditional Persian medicine in rhyming text written in Arabic. This great work was translated into Persian at the research centre for traditional medicine and history of medicine. We hope that the Persian translation of Urjuzeh Tebbi will allow students and experts to better appreciate the role of didactic poems in compiling and transmitting the concepts of Iranian medicine. PMID- 26959632 TI - URINARY INCONTINENCE (SALASAL BAWL) IN GRECO-ARABIC MEDICINE: A REVIEW. AB - INTRODUCTION: Greco-Arabic Medicine imparts vast knowledge regarding diseases afflicting different systems. Urinary incontinence (UI) is involuntary leakage of urine. It is an undiagnosed, under-reported, and frequently untreated medical condition that greatlyaffects the quality of life of women in any age. Therefore, a literary search in classical literature of Greco-Arabic medicine for UI was explored to implement in current era. Material and METHODS: Meticulous literature search was carried out to comprehend the concept of urinary incontinence described in ancient Unani literature. The classical Greco-Arabic medicine texts were searched. Further, browsing of PubMed/Google Scholar and other websites was carried by searching complementary and alternative treatment for urinary incontinence and herbal remedies useful in urinary incontinence. RESULTS: The causes of urinary incontinence described in Greco-Arabic texts are abnormal temperament of body or bladder, dislocation of vertebrae, pregnancy, diuretic, laxity of musculature of bladder, diseases of surrounding structure such as uterine inflammation, omphalitis, constipation, etc. The principle treatment is treating the cause viz., the temperament is corrected by diet and herbs in abnormal temperament, and elimination of morbid humour is required in dominance of humour. Further, web search showed that herbs are useful in Urinary diseases. However, evidences are weak. CONCLUSION: The classical Greco-Arabic texts are enriched with important information. Thus documentation and preservation of the traditional knowledge is required so that it can still be conserved for future research in pharmaceuticals and drug discovery. PMID- 26959633 TI - Clinical stories and medical histories recorded by Rhazes (865-925), the Iranian Islamic physician in the medieval period. AB - Recording medical histories of patients is not a new issue in clinical medicine. However, the method practiced by the Iranian chemist physician, Rhazes, in the ninth century A.D is incredible. Rhazes has written several textbooks in clinical medicine, but a particular one, "Clinical Stories and Medical Histories" (Qesas va hekayat al-marazi), is a classical case book describing precise clinical courses of thirty three patients. Each chapter includes a title, the name and demographic data about a patient, his/her history of present illness, past medical and family history, findings of physical exam, impression and interventions by the physician, including pharmacological or surgical management. The reasons for each decision made by Rhazes as well as the outcomes are clearly discussed. This book review will shed light on the unknown medical practice methods in Islamic-Iranian golden era. PMID- 26959634 TI - IBN SINA AND THE ROOTS OF THE SEVEN DOCTRINES OF PRESERVATION OF HEALTH. AB - Ibn Sina, the most eminent Muslim physician, illuminative philosopher, great thinker and a versatile genius is regarded as the "Father of Early Modern Medicine" and as the "Father of Clinical Pharmacology". The "Kitab al-Qanun fi-al Tibb", commonly known as the "Canon Medicinae" is the most important of his medical works and, at the same time, the most carefully preserved treasury both in original Arabic and in the initial Latin version. It is the final codification of all Greco-Arabic medical thoughts up to his time, enriched and modified with his own scientific experimentations and independent observations. It is considered "The First Textbook of Medicine on the Earth". The "Canon" surpassed the books of Hippocrates and Galen and remained supreme for more than six centuries, in the West. Ibn Sina described "Seven Doctrines" for Preservation of Health, based on the Mudawa Salookia, in his magnum opus. The roots of these principles can be traced, to a significant extent, to Egyptian Medicine, Hebrew Medicine, Greek Medicine, Roman Medicine, Traditional Chinese Medicine, Ancient Persian Medicine, Ayurvedic Medicine (Hindu Medicine) and Islamic Medicine. PMID- 26959635 TI - ANORECTAL DISEASES IN AVICENNA'S "CANON OF MEDICINE". AB - Although the development of modern medicine has helped us detect and treat diseases better than in the past, especially in the field of surgery; the history of medicine may be a trigger that can help us use neglected aspects of prior knowledge for the advancement of modern-day science. Since historical papers that have specifically focused on anorectal diseases are rare, but those that exist contain brief discussions in this field, the current study aims to present a detailed review of Avicenna's approach to anorectal diseases. Therefore, we reviewed On the Diseases of the Anus, the 17th chapter of the third volume of the Canon of Medicine written by Avicenna, and compared his views on the classification and diagnosis of, and the approach to anorectal diseases with that of modern proctology. Avicenna discussed in detail about anorectal diseases such as hemorrhoid, fissure, perianal abscess and fistula, rectal prolapse, fecal incontinence, and pruritus ani. In addition, we introduce herbs which Avicenna used to treat these diseases. Our findings show that Avicenna's views on the classification and diagnosis of, and the approach to anorectal diseases have few fundamental differences with modern medicine. In addition, the pharmacological effects of some of the herbs that were recommended by Avicenna, and are used in current medicine are proven. Thus the Medieval knowledge can be further scientifically investigated to develop new therapeutic options for anorectal diseases. PMID- 26959636 TI - MANAGEMENT OF ANOREXIA IN ELDERLY AS REMARKED BY MEDIEVAL PERSIAN PHYSICIANS. AB - Normal ageing is often accompanied by loss of appetite and decrease in food intake. Weight loss of senescence is called anorexia of ageing. As an outstanding scientist and physician of Traditional Persian Medicine, Avicenna has introduced an unconventional approach to seniors. He also believed that the elderly should consider special schemes in order to maintain their health. These schemes include consideration of nutrition, mental states, sleep, bathing, and physical activities, and even choosing some appropriate hobbies. The elderly should consume foods and fruits with laxative and stool-softening properties to prevent constipation. They would also do better to decrease the amount of food eaten at meals, but at the same time increasing the number of meals to compensate for low food intake. Moreover, they should maintain their vital force and avoid any activities that tax the body. Furthermore, considering the principles of hifz-al sehah can help secure long and healthy lives for the elderly. PMID- 26959639 TI - Parasitism of Ground Beetles (Coleoptera: Carabidae) by a New Species of Hairworm (Nematomorpha: Gordiida) in Arctic Canada. AB - The host-parasite associations between ground beetles (Coleoptera: Carabidae) and hairworms (Nematomorpha: Gordiida) collected from the Arctic (an understudied and ecologically important region) is described. Carabids and their parasites were collected from 12 sites spanning the 3 northernmost ecoclimatic zones of Canada (north boreal, subarctic, and high Arctic) using standardized methods. The beetles and hairworms were identified using traditional morphological approaches. Seven beetle species are recorded as hosts: Amara alpina, Pterostichus caribou, Pterostichus brevicornis, Pterostichus tareumiut, Pterostichus haematopus, Patrobus septentrionis, and Notiophilus borealis. All represent new host records (increasing the known North American host list from 14 to 21), and this is the first record of hairworm infection in the genus Notiophilus. Beetles from Banks Island, Northwest Territory, were infected in high numbers (11-19% per sampling period) and were used as an ecological case study. There was no significant relationship between infection status and host species, body size, or sex. Beetles collected in yellow pan traps and in wet habitats were more likely to be infected, likely due to water-seeking behavior induced by the parasites. Morphological examinations indicate that the hairworms collected from all locations represent a single, new species of Gordionus, making it only the sixth hairworm species and the third species of that genus found in Canada. Hosts are unknown for all other Canadian (and 1 Alaskan) Gordionus species. PMID- 26959638 TI - Long Term Recordings with Immobile Silicon Probes in the Mouse Cortex. AB - A key experimental approach in neuroscience involves measuring neuronal activity in behaving animals with extracellular chronic recordings. Such chronic recordings were initially made with single electrodes and tetrodes, and are now increasingly performed with high-density, high-count silicon probes. A common way to achieve long-term chronic recording is to attach the probes to microdrives that progressively advance them into the brain. Here we report, however, that such microdrives are not strictly necessary. Indeed, we obtained high-quality recordings in both head-fixed and freely moving mice for several months following the implantation of immobile chronic probes. Probes implanted into the primary visual cortex yielded well-isolated single units whose spike waveform and orientation tuning were highly reproducible over time. Although electrode drift was not completely absent, stable waveforms occurred in at least 70% of the neurons tested across consecutive days. Thus, immobile silicon probes represent a straightforward and reliable technique to obtain stable, long-term population recordings in mice, and to follow the activity of populations of well-isolated neurons over multiple days. PMID- 26959640 TI - Rhodium-Catalyzed Selective Mono- and Diamination of Arenes with Single Directing Site "On Water". AB - A Rh(III)-catalyzed selective C-H amination of 2-phenylpyridine derivatives is reported. With pyridine as a directing group, the reaction has high mono- or diamination selectivity, and a wide range of effective substrates, including electron-deficient and -rich aryl azides. Water helps to promote C-H activation, and the concept of a water promoted rollover mechanism is postulated for the diamination step. The reactions were conducted using a Schlenk flask and proceeded smoothly "on water" under atmospheric conditions with nitrogen gas as the only byproduct. PMID- 26959641 TI - The Synergistic Effects of Matrix Stiffness and Composition on the Response of Chondroprogenitor Cells in a 3D Precondensation Microenvironment. AB - Improve functional quality of cartilage tissue engineered from stem cells requires a better understanding of the functional evolution of native cartilage tissue. Therefore, a biosynthetic hydrogel was developed containing RGD, hyaluronic acid and/or type-I collagen conjugated to poly(ethylene glycol) acrylate to recapitulate the precondensation microenvironment of the developing limb. Conjugation of any combination of the three ligands did not alter the shear moduli or diffusion properties of the PEG hydrogels; thus, the influence of ligand composition on chondrogenesis could be investigated in the context of varying matrix stiffness. Gene expression of ligand receptors (CD44 and the b1 integrin) as well as markers of condensation (cell clustering and N-cadherin gene expression) and chondrogenesis (Col2a1 gene expression and sGAG production) by chondroprogenitor cells in this system were modulated by both matrix stiffness and ligand composition, with the highest gene expression occurring in softer hydrogels containing all three ligands. Cell proliferation in these 3D matrices for 7 d prior to chondrogenic induction increased the rate of sGAG production in a stiffness-dependent manner. This biosynthetic hydrogel supports the features of early limb-bud condensation and chondrogenesis and is a novel platform in which the influence of the matrix physicochemical properties on these processes can be elucidated. PMID- 26959642 TI - Evaluation of PCR Approaches for Detection of Bartonella bacilliformis in Blood Samples. AB - BACKGROUND: The lack of an effective diagnostic tool for Carrion's disease leads to misdiagnosis, wrong treatments and perpetuation of asymptomatic carriers living in endemic areas. Conventional PCR approaches have been reported as a diagnostic technique. However, the detection limit of these techniques is not clear as well as if its usefulness in low bacteriemia cases. The aim of this study was to evaluate the detection limit of 3 PCR approaches. METHODOLOGY/PRINCIPAL FINDINGS: We determined the detection limit of 3 different PCR approaches: Bartonella-specific 16S rRNA, fla and its genes. We also evaluated the viability of dry blood spots to be used as a sample transport system. Our results show that 16S rRNA PCR is the approach with a lowest detection limit, 5 CFU/MUL, and thus, the best diagnostic PCR tool studied. Dry blood spots diminish the sensitivity of the assay. CONCLUSIONS/SIGNIFICANCE: From the tested PCRs, the 16S rRNA PCR-approach is the best to be used in the direct blood detection of acute cases of Carrion's disease. However its use in samples from dry blood spots results in easier management of transport samples in rural areas, a slight decrease in the sensitivity was observed. The usefulness to detect by PCR the presence of low-bacteriemic or asymptomatic carriers is doubtful, showing the need to search for new more sensible techniques. PMID- 26959644 TI - Obstacles in spatial evaluation of CBCT-reformatted panoramic imaging. AB - OBJECTIVES: Conventional panoramic radiography (cPR) underlines procedure-related limitations in the display of objects. CBCT is presumed to overcome these constraints. To virtualize a cPR view, reformatted panoramic images (rPIs) can be generated. This study evaluated the rPI with regard to its susceptibility to sterical object deposition in comparison with cPR. METHODS: A specially developed implant model with dental implants each of 4.0-mm diameter and 11.0-mm length was depositioned by shift, rotation and tilt of 5.00 mm (+/-0.01 mm) of horizontal shift and 5.0 degrees (+/-0.167 degrees ), respectively, on a highly precise goniometer rotation table, and cPRs and rPIs were generated. Automated evaluation of the cPRs was carried out using a specially developed software. rPIs were processed and analyzed by a semi-automated image analysis. RESULTS: Object deposition lead to distortive effects in the rPI analogue to cPR, but they appear in display only. Objects illustrated in the rPI were dimensionally correct, but sterical relations are elusive. Results are obtained for the horizontal shift, declination and reclination, lateral tilt and rotation. CONCLUSIONS: Distortions within the rPI represent the illustration of the hyperbolic-shaped layer out of the three-dimensional data set. With this study, we demonstrated these procedure related inherent but practically underestimated consequences. Effects of sterical object malpositioning must be compensated by the observer by adequate virtual adjustment of the processed layer. Accurate virtual adjustment leads to vertical dimensions. Sterical relations, e.g. angulation of two objects, are irretraceable unless precisely referenced. PMID- 26959643 TI - Alterations in the mir-15a/16-1 Loci Impairs Its Processing and Augments B-1 Expansion in De Novo Mouse Model of Chronic Lymphocytic Leukemia (CLL). AB - New Zealand Black (NZB) mice, a de novo model of CLL, share multiple characteristics with CLL patients, including decreased expression of miR-15a/16 1. We previously discovered a point mutation and deletion in the 3' flanking region of mir-16-1 of NZB and a similar mutation has been found in a small number of CLL patients. However, it was unknown whether the mutation is the cause for the reduced miR-15a/16-1 expression and CLL development. Using PCR and in vitro microRNA processing assays, we found that the NZB sequence alterations in the mir 15a/16-1 loci result in deficient processing of the precursor forms of miR-15a/16 1, in particular, we observe impaired conversion of pri-miR-15a/16-1 to pre-miR 15a/16-1. The in vitro data was further supported by derivation of congenic strains with replaced mir-15a/16-1 loci at one or both alleles: NZB congenic mice (NmiR+/-) and DBA congenic mice (DmiR-/-). The level of miR-15a/16-1 reflected the configuration of the mir-15a/16-1 loci with DBA congenic mice (DmiR-/-) showing reduced miR-15a levels compared to homozygous wild-type allele, while the NZB congenic mice (NmiR+/-) showed an increase in miR-15a levels relative to homozygous mutant allele. Similar to Monoclonal B-cell Lymphocytosis (MBL), the precursor stage of the human disease, an overall expansion of the B-1 population was observed in DBA congenic mice (DmiR-/-) relative to wild-type (DmiR+/+). These studies support our hypothesis that the mutations in the mir-15a/16-1 loci are responsible for decreased expression of this regulatory microRNA leading to B 1 expansion and CLL development. PMID- 26959645 TI - Carbon Sequestration Potential in Stands under the Grain for Green Program in Southwest China. AB - The Grain for Green Program (GGP) is the largest afforestation and reforestation project in China in the early part of this century. To assess carbon sequestration in stands under the GGP in Southwest China, the carbon stocks and their annual changes in the GGP stands in the region were estimated based on the following information: (1) collected data on the annually planted area of each tree species under the GGP in Southwest China from 1999 to 2010; (2) development of empirical growth curves and corresponding carbon estimation models for each species growing in the GPP stands; and (3) parameters associated with the stands such as wood density, biomass expansion factor, carbon fraction and the change rate of soil organic carbon content. Two forest management scenarios were examined: scenario A, with no harvesting, and scenario B, with logging at the customary rotation followed by replanting. The results showed that by the years 2020, 2030, 2040, 2050 and 2060, the expected carbon storage of the GGP stands in Southwest China is 139.58 TgC, 177.50-207.55 TgC, 196.86-259.65 TgC, 240.45 290.62 TgC and 203.22-310.03 TgC (T = 1012), respectively. For the same years, the expected annual change in carbon stocks is 7.96 TgCyr-1, -7.95-5.95 TgCyr-1, 0.10-4.67 TgCyr-1, 4.31-2.24 TgCyr-1 and -0.02-1.75 TgCyr-1, respectively. This indicates that the stands significantly contribute to forest carbon sinks in this region. In 2060, the estimated carbon stocks in the seven major species of GGP stands in Southwest China are 4.16-13.01 TgC for Pinus armandii, 6.30-15.01 TgC for Pinus massoniana, 11.51-13.44 TgC for Cryptomeria fortunei, 15.94-24.13 TgC for Cunninghamia lanceolata, 28.05 TgC for Cupressus spp., 5.32-15.63 TgC for Populus deltoides and 5.87-14.09 TgC for Eucalyptus spp. The carbon stocks in these seven species account for 36.8%-41.4% of the total carbon stocks in all GGP stands over the next 50 years. PMID- 26959647 TI - An Integrated and Interdisciplinary Model for Predicting the Risk of Injury and Death in Future Earthquakes. AB - BACKGROUND: A comprehensive technique for earthquake-related casualty estimation remains an unmet challenge. This study aims to integrate risk factors related to characteristics of the exposed population and to the built environment in order to improve communities' preparedness and response capabilities and to mitigate future consequences. METHODS: An innovative model was formulated based on a widely used loss estimation model (HAZUS) by integrating four human-related risk factors (age, gender, physical disability and socioeconomic status) that were identified through a systematic review and meta-analysis of epidemiological data. The common effect measures of these factors were calculated and entered to the existing model's algorithm using logistic regression equations. Sensitivity analysis was performed by conducting a casualty estimation simulation in a high vulnerability risk area in Israel. RESULTS: the integrated model outcomes indicated an increase in the total number of casualties compared with the prediction of the traditional model; with regard to specific injury levels an increase was demonstrated in the number of expected fatalities and in the severely and moderately injured, and a decrease was noted in the lightly injured. Urban areas with higher populations at risk rates were found more vulnerable in this regard. CONCLUSION: The proposed model offers a novel approach that allows quantification of the combined impact of human-related and structural factors on the results of earthquake casualty modelling. Investing efforts in reducing human vulnerability and increasing resilience prior to an occurrence of an earthquake could lead to a possible decrease in the expected number of casualties. PMID- 26959648 TI - 3-D graphene-supported mesoporous SiO2 @Fe3 O4 composites for the analysis of pesticides in aqueous samples by magnetic solid-phase extraction with high performance liquid chromatography. AB - Three-dimensional graphene-supported mesoporous silica@Fe3 O4 composites (mSiO2 @Fe3 O4 -G) were prepared by modifying mesoporous SiO2 -coated Fe3 O4 onto hydrophobic graphene nanosheets through a simple adsorption co-condensation method. The obtained composites possess unique properties of large surface area (332.9 m(2) /g), pore volume (0.68 cm(3) /g), highly open pore structure with uniform pore size (31.1 nm), as well as good magnetic separation properties. The adsorbent (mSiO2 @Fe3 O4 -G) was used for the magnetic solid-phase extraction of seven pesticides with benzene rings in different aqueous samples before high performance liquid chromatography. The main parameters affecting the extraction such as adsorbent amount, volume of elution solvent, time of extraction and desorption, salt effect, oscillation rate were investigated. Under the optimal conditions, this method provided low limits of detection (S/N = 3, 0.525-3.30 MUg/L) and good linearity (5.0-1000 MUg/L, R(2) > 0.9954). Method validation proved the feasibility of the developed adsorbent, which has a high extraction efficiency and excellent enhancement performance for pesticides in this study. The proposed method was successfully applied to real aqueous samples, and satisfactory recoveries ranging from 77.5 to 113.6% with relative standard deviations within 9.7% were obtained. PMID- 26959646 TI - DNA Sequence Determinants Controlling Affinity, Stability and Shape of DNA Complexes Bound by the Nucleoid Protein Fis. AB - The abundant Fis nucleoid protein selectively binds poorly related DNA sequences with high affinities to regulate diverse DNA reactions. Fis binds DNA primarily through DNA backbone contacts and selects target sites by reading conformational properties of DNA sequences, most prominently intrinsic minor groove widths. High affinity binding requires Fis-stabilized DNA conformational changes that vary depending on DNA sequence. In order to better understand the molecular basis for high affinity site recognition, we analyzed the effects of DNA sequence within and flanking the core Fis binding site on binding affinity and DNA structure. X ray crystal structures of Fis-DNA complexes containing variable sequences in the noncontacted center of the binding site or variations within the major groove interfaces show that the DNA can adapt to the Fis dimer surface asymmetrically. We show that the presence and position of pyrimidine-purine base steps within the major groove interfaces affect both local DNA bending and minor groove compression to modulate affinities and lifetimes of Fis-DNA complexes. Sequences flanking the core binding site also modulate complex affinities, lifetimes, and the degree of local and global Fis-induced DNA bending. In particular, a G immediately upstream of the 15 bp core sequence inhibits binding and bending, and A-tracts within the flanking base pairs increase both complex lifetimes and global DNA curvatures. Taken together, our observations support a revised DNA motif specifying high-affinity Fis binding and highlight the range of conformations that Fis-bound DNA can adopt. The affinities and DNA conformations of individual Fis-DNA complexes are likely to be tailored to their context specific biological functions. PMID- 26959649 TI - Planning Abilities in Patients with Anorexia Nervosa Compared with Healthy Controls. AB - OBJECTIVE: Altered cognitive functioning could have an important role in the development and maintenance of Anorexia Nervosa (AN). The majority of previous research has focused on flexibility and global-detail processing. The aim of this study was to explore planning abilities in women with AN. METHOD: Women with AN (n = 32) were compared to healthy controls (n = 42) using two different types of neuropsychological tasks for the assessment of planning abilities: Tower of London (ToL), a classic measure of planning abilities, and Zoo Map test, a more ecologically valid planning measure. Measures of AN psychopathology, anxiety, depression, and obsessive compulsivity were also collected. RESULTS: The AN group did not differ from controls in the ToL (all p-values p > .05), although they performed significantly worse than controls in the main score of the Zoo Map (p = .02). A worse performance in the Zoo Map test More was associated with more eating disorders (rho = -.44, p = .018) and depressive (rho = -.42, p = .026) symptoms in the AN group. CONCLUSIONS: Our study suggests the presence of subtle planning difficulties in women with AN which might be better detected using tasks with increased ecological validity. PMID- 26959650 TI - An Association Study of the SLC19A1 Gene Polymorphisms/Haplotypes with Idiopathic Recurrent Pregnancy Loss in an Iranian Population. AB - AIMS: The genetics of folate metabolism is one of the most significant mechanisms influencing fetal growth and may underlie some cases of unexplained recurrent miscarriage. Reduced folate carrier 1, encoded by the SLC19A1 gene, is a transporter of folate. Folate deficiency and elevated levels of homocysteine could be disadvantageous for the female reproductive system health. Thus, the balance between homocysteine and folate status can be used to measure the risk of recurrent pregnancy loss. METHODS: The purpose of this study was to determine the association between -43T>C, 80G>A, and 696C>T polymorphisms of the SLC19A1 gene in 147 women who had unexplained recurrent miscarriage in comparison with 150 healthy women. Amplification refractory mutation system-polymerase chain reaction was used to genotype the molecular polymorphisms of this gene. RESULTS: The results indicated that the -43T>C single nucleotide of the SLC19A1 gene was significantly associated with a risk of recurrent miscarriage in Iranian women (p < 0.05). No significant association was observed for the other two polymorphisms. The haplotype frequency distribution of -43C/80G/696C, -;43C/80G/696T, -43C/80G, and 80G/696T was significantly different in patients than controls, which may represent a novel risk factor for idiopathic recurrent pregnancy loss. CONCLUSIONS: Polymorphisms and haplotypes of the SLC19A1 gene can be considered risk factors for idiopathic recurrent pregnancy loss. PMID- 26959652 TI - The Effects of Hyperbaric Oxygen Therapy on Post-Training Recovery in Jiu-Jitsu Athletes. AB - OBJECTIVES: The present study aimed to evaluate the effects of using hyperbaric oxygen therapy during post-training recovery in jiu-jitsu athletes. METHODS: Eleven experienced Brazilian jiu-jitsu athletes were investigated during and following two training sessions of 1h30min. Using a cross-over design, the athletes were randomly assigned to passive recovery for 2 hours or to hyperbaric oxygen therapy (OHB) for the same duration. After a 7-day period, the interventions were reversed. Before, immediately after, post 2 hours and post 24 hours, blood samples were collected to examine hormone concentrations (cortisol and total testosterone) and cellular damage markers [creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH)]. Moreover, the rating of perceived exertion (RPE) and recovery (RPR) scales were applied. RESULTS: Final lactate [La] values (control: 11.9 +/- 1.4 mmol/L, OHB: 10.2 +/- 1.4 mmol/L) and RPE [control: 14 (13-17 a.u.), OHB: 18 (17-20 a.u.)] were not significantly different following the training sessions. Furthermore, there was no difference between any time points for blood lactate and RPE in the two experimental conditions (P>0.05). There was no effect of experimental conditions on cortisol (F1,20 = 0.1, P = 0.793, eta2 = 0.00, small), total testosterone (F1,20 = 0.03, P = 0.877, eta2 = 0.00, small), CK (F1,20 = 0.1, P = 0.759, eta2 = 0.01, small), AST (F1,20 = 0.1, P = 0.761, eta2 = 0.01, small), ALT (F1,20 = 0.0, P = 0.845, eta2 = 0.00, small) or LDH (F1,20 = 0.7, P = 0.413, eta2 = 0.03, small). However, there was a difference between the two experimental conditions in RPR with higher values at post 2 h and 24 h in OHB when compared to the control condition (P<0.05). CONCLUSIONS: Thus, it can be concluded that OHB exerts no influence on the recovery of hormonal status or cellular damage markers. Nonetheless, greater perceived recovery, potentially due to the placebo effect, was evident following the OHB condition. PMID- 26959651 TI - Enhanced Gene Expression Rather than Natural Polymorphism in Coding Sequence of the OsbZIP23 Determines Drought Tolerance and Yield Improvement in Rice Genotypes. AB - Drought is one of the major limiting factors for productivity of crops including rice (Oryza sativa L.). Understanding the role of allelic variations of key regulatory genes involved in stress-tolerance is essential for developing an effective strategy to combat drought. The bZIP transcription factors play a crucial role in abiotic-stress adaptation in plants via abscisic acid (ABA) signaling pathway. The present study aimed to search for allelic polymorphism in the OsbZIP23 gene across selected drought-tolerant and drought-sensitive rice genotypes, and to characterize the new allele through overexpression (OE) and gene-silencing (RNAi). Analyses of the coding DNA sequence (CDS) of the cloned OsbZIP23 gene revealed single nucleotide polymorphism at four places and a 15 nucleotide deletion at one place. The single-copy OsbZIP23 gene is expressed at relatively higher level in leaf tissues of drought-tolerant genotypes, and its abundance is more in reproductive stage. Cloning and sequence analyses of the OsbZIP23-promoter from drought-tolerant O. rufipogon and drought-sensitive IR20 cultivar showed variation in the number of stress-responsive cis-elements and a 35-nucleotide deletion at 5'-UTR in IR20. Analysis of the GFP reporter gene function revealed that the promoter activity of O. rufipogon is comparatively higher than that of IR20. The overexpression of any of the two polymorphic forms (1083 bp and 1068 bp CDS) of OsbZIP23 improved drought tolerance and yield related traits significantly by retaining higher content of cellular water, soluble sugar and proline; and exhibited decrease in membrane lipid peroxidation in comparison to RNAi lines and non-transgenic plants. The OE lines showed higher expression of target genes-OsRab16B, OsRab21 and OsLEA3-1 and increased ABA sensitivity; indicating that OsbZIP23 is a positive transcriptional-regulator of the ABA-signaling pathway. Taken together, the present study concludes that the enhanced gene expression rather than natural polymorphism in coding sequence of OsbZIP23 is accountable for improved drought tolerance and yield performance in rice genotypes. PMID- 26959653 TI - Investigation on torquetenovirus (TTV) microRNA transcriptome in vivo. AB - Torquetenovirus (TTV) is a widespread anellovirus that establishes persistent infections in human showing an increased viremia in immunosuppressed patients. TTV possesses microRNA (miRNA)-coding sequences that might be involved in viral immune evasion. Here, the presence of TTV DNA and miRNAs expression was investigated in plasma samples of 77 diseased (20 infected with human immunodeficiency virus (HIV), 18 infected with hepatitis B (HBV) virus, 18 infected with hepatitis C (HCV) virus, 21 solid organ transplanted) patients, and 25 healthy controls. TTV prevalence was significantly different in healthy controls (60%, 15/25) versus diseased patients (80%, 62/77), showing the highest TTV loads in transplant recipients. Genetic TTV analysis showed the highest prevalence of group 1, followed by groups 3, 4 and 5, and a lack of isolates of group 2. The expression of at least one TTV miRNAs of group 1, 3 and 5 was found in exosomes of plasma of the great majority of individuals (96%, 98/102 subjects) showing the higher prevalence of miRNAs of TTV group 3 (90%, 92/102), followed by miRNAs of group 1 (66%, 67/102), and miRNA of group 5 (49%, 50/102). TTV miRNAs expression and TTV viremia were not always directly correlated, and significant differences appeared in production of some TTV miRNAs between healthy controls and diseased patients. The reported TTV miRNAs status in exosomes encourages further investigation to understand their potential role in the expansion of anelloviruses upon immunosuppression. PMID- 26959654 TI - Virus-like particles of porcine bocavirus generated by recombinant baculoviruses can be applied to sero-epidemic studies. AB - Porcine bocaviruses (PBoVs), new members of the Bocavirus genus, have been identified in swine worldwide. However, the antigenicity and epidemiology of PBoVs are still unclear. Here we used a recombinant baculovirus expression system to express the main capsid protein VP2 of Japan strain JY31b in insect Tn5 cells, and successfully produced the virus-like particles of PBoV (PBoV-LPs). The diameter and densities of the PBoV-LPs were estimated to be 30nm and 1.300g/cm(3), respectively, which were similar to the values for the native virion of PBoV. Antigenic analysis demonstrated that the PBoV-LPs were not cross reactive with porcine circovirus 2, but were cross-reactive with human bocavirus 1, 2, 3 and 4. An ELISA for detection of anti-PBoV IgG antibodies was established using PBoV-LPs as antigen, which proved to be useful for monitoring PBoV infection in both swine and wild boars. The preliminary epidemiology research showed that 90.7% of pigs and 59.5% of wild boars were positive for the anti-PBoV IgG, suggesting that both species were also widely infected with PBoV. The seven PBoV strains detected in wild boars separated into four subgroups, demonstrating the genetic diversity of PBoV. PMID- 26959655 TI - Desilylation-Activated Propargylic Transformation: Enantioselective Copper Catalyzed [3+2] Cycloaddition of Propargylic Esters with beta-Naphthol or Phenol Derivatives. AB - A copper-catalyzed asymmetric [3+2] cycloaddition of 3-trimethylsilylpropargylic esters with either beta-naphthols or electron-rich phenols has been realized and proceeds by a desilylation-activated process. Under the catalysis of Cu(OAc)2?H2O in combination with a structurally optimized ketimine P,N,N-ligand, a wide range of optically active 1,2-dihydronaphtho[2,1-b]furans or 2,3-dihydrobenzofurans were obtained in good yields and with high enantioselectivities (up to 96 % ee). This represents the first desilylation-activated catalytic asymmetric propargylic transformation. PMID- 26959656 TI - Experiments testing macroscopic quantum superpositions must be slow. AB - We consider a thought experiment where the preparation of a macroscopically massive or charged particle in a quantum superposition and the associated dynamics of a distant test particle apparently allow for superluminal communication. We give a solution to the paradox which is based on the following fundamental principle: any local experiment, discriminating a coherent superposition from an incoherent statistical mixture, necessarily requires a minimum time proportional to the mass (or charge) of the system. For a charged particle, we consider two examples of such experiments, and show that they are both consistent with the previous limitation. In the first, the measurement requires to accelerate the charge, that can entangle with the emitted photons. In the second, the limitation can be ascribed to the quantum vacuum fluctuations of the electromagnetic field. On the other hand, when applied to massive particles our result provides an indirect evidence for the existence of gravitational vacuum fluctuations and for the possibility of entangling a particle with quantum gravitational radiation. PMID- 26959657 TI - Whom Do Centenarians Rely on for Support? Findings From the Second Heidelberg Centenarian Study. AB - This paper provides a detailed picture of the sources and types of informal support available to centenarians, depending on their housing and care arrangements. Participants were 112 centenarians and 96 primary contacts of centenarians enrolled in the population-based Second Heidelberg Centenarian Study. Findings indicate that children of centenarians were their primary source of support in daily life. Those without living children had overall less help. Most frequently reported was help with administrative tasks, regardless of centenarians' residence or living arrangement. All other types of help (e.g., with activities of daily living and housework) were reported by about one-third and were mostly provided by children; centenarians without children were more likely to have friends/neighbors involved in some of these tasks. The one category reported by a third of the centenarians regardless of residence, living arrangements, or presence of a child was help with socializing/companionship. Findings constitute an important step toward identifying and meeting the support needs of centenarians and their families. Policy implications are discussed. PMID- 26959658 TI - Topotecan Delivery to the Optic Nerve after Ophthalmic Artery Chemosurgery. AB - Extraocular retinoblastoma is a major challenge worldwide, especially in developing countries. Current treatment involves the administration of systemic chemotherapy combined with radiation, but there is a clear need for improvement of chemotherapy bioavailability in the optic nerve. Our aim was to study the ophthalmic artery chemosurgery (OAC) local route for drug delivery assessing ocular and optic nerve exposure to chemotherapy and to compare it to exposure after intravenous infusion (IV) of the same dose in an animal model. Topotecan was used as a prototype drug that is active in retinoblastoma and based on the extensive knowledge of its pharmacokinetics in preclinical and clinical settings. Five Landrace pigs received 4mg of topotecan via OAC as performed in retinoblastoma patients. At the end of the infusion, the eyes were enucleated, the optic nerve and retina were dissected, and the vitreous and plasma were separated. After recovery and a wash-out period, the animals received a 30-min IV infusion of topotecan (4 mg). The remaining eye was enucleated and tissues and fluids were separated. All samples were stored until quantitation using HPLC. A significantly higher concentration of topotecan in the optic nerve, vitreous, and retina was obtained in eyes after OAC compared to IV infusion (p<0.05). The median (range) ratio between topotecan concentration attained after OAC to IV infusion in the optic nerve, retina and vitreous was 84(54-668), 143(49-200) and 246(56-687), respectively. However, topotecan systemic exposure after OAC and IV infusion remained comparable (p>0.05). The median optic nerve-to-plasma ratio after OAC and IV was 44 and 0.35, respectively. Topotecan OAC delivery attained an 80-fold higher concentration in the optic nerve compared to the systemic infusion of the same dose with similar plasma concentrations in a swine model. Patients with retinoblastoma extension into the optic nerve may benefit from OAC for tumor burden by increased chemotherapy bioavailability in the optic nerve without increasing systemic exposure or toxicity. PMID- 26959662 TI - Improving the Significance and Direction of Sleep Management in Traumatic Brain Injury. PMID- 26959661 TI - The Efficacy of Acupuncture in Post-Operative Pain Management: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Postoperative pain resulting from surgical trauma is a significant challenge for healthcare providers. Opioid analgesics are commonly used to treat postoperative pain; however, these drugs are associated with a number of undesirable side effects. OBJECTIVE: This systematic review and meta-analysis evaluated the effectiveness of acupuncture and acupuncture-related techniques in treating postoperative pain. DATA SOURCE: MEDLINE, Cochrane Library, and EMBASE databases were searched until Sep 30, 2014. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials of adult subjects (>= 18 years) who had undergone surgery and who had received acupuncture, electroacupuncture, or acupoint electrical stimulation for managing acute post-operative pain were included. RESULTS: We found that patients treated with acupuncture or related techniques had less pain and used less opioid analgesics on Day 1 after surgery compared with those treated with control (P < 0.001). Sensitivity analysis using the leave one-out approach indicated the findings are reliable and are not dependent on any one study. In addition, no publication bias was detected. Subgroup analysis indicated that conventional acupuncture and transcutaneous electric acupoint stimulation (TEAS) were associated with less postoperative pain one day following surgery than control treatment, while electroacupuncture was similar to control (P = 0.116). TEAS was associated with significantly greater reduction in opioid analgesic use on Day 1 post surgery than control (P < 0.001); however conventional acupuncture and electroacupuncture showed no benefit in reducing opioid analgesic use compared with control (P >= 0.142). CONCLUSION: Our findings indicate that certain modes of acupuncture improved postoperative pain on the first day after surgery and reduced opioid use. Our findings support the use of acupuncture as adjuvant therapy in treating postoperative pain. PMID- 26959663 TI - Incidence, Characterization, and Predictors of Sleep Apnea in Consecutive Brain Injury Rehabilitation Admissions. AB - OBJECTIVE: To prospectively examine the incidence and risk factors for sleep apnea in consecutive brain injury rehabilitation admissions. SETTING: Inpatient neurorehabilitation hospital. PARTICIPANTS: Participants (n = 86) were consecutive neurorehabilitation admissions. DESIGN: Retrospective analysis of prospectively collected data. MAIN MEASURES: Polysomnography. RESULTS: Half (49%) of the sample was diagnosed with sleep apnea. For the full sample, univariate logistic regression revealed age (odds ratio: 1.08; 95% confidence interval: 1.04 1.11) and hypertension (odds ratio: 7.77; 95% confidence interval: 2.81-21.47) as significant predictors of sleep apnea diagnosis. Results of logistic regression conducted within the traumatic brain injury group revealed age (odds ratio: 1.07; 95% confidence interval: 1.02-1.13) as the only significant predictor of apnea diagnosis after adjustment for other variables. Hierarchical generalized linear regression models for the prediction of apnea severity (ie, apnea-hypopnea index found that Functional Independence Measure Cognition Score (P = .01) and age (P < .01) were significant predictors. Following adjustment for all other terms, only age (P < .01) remained significant. CONCLUSION: Sleep apnea is prevalent in acute neurorehabilitation admissions and traditional risk profiles for sleep apnea may not effectively screen for the disorder. Given the progressive nature of obstructive sleep apnea and morbidity associated with even mild obstructive sleep apnea, early identification and intervention may address comorbidities influencing acute and long-term outcome. PMID- 26959664 TI - Sleep Features on Continuous Electroencephalography Predict Rehabilitation Outcomes After Severe Traumatic Brain Injury. AB - OBJECTIVE: Sleep characteristics detected by electroencephalography (EEG) may be predictive of neurological recovery and rehabilitation outcomes after traumatic brain injury (TBI). We sought to determine whether sleep features were associated with greater access to rehabilitation therapies and better functional outcomes after severe TBI. METHODS: We retrospectively reviewed records of patients admitted with severe TBI who underwent 24 or more hours of continuous EEG (cEEG) monitoring within 14 days of injury for sleep elements and ictal activity. Patient outcomes included discharge disposition and modified Rankin Scale (mRS). RESULTS: A total of 64 patients underwent cEEG monitoring for a mean of 50.6 hours. Status epilepticus or electrographic seizures detected by cEEG were associated with poor outcomes (death or discharge to skilled nursing facility). Sleep characteristics were present in 19 (30%) and associated with better outcome (89% discharged to home/acute rehabilitation; P = .0002). Lack of sleep elements on cEEG correlated with a poor outcome or mRS > 4 at hospital discharge (P = .012). Of those patients who were transferred to skilled nursing/acute rehabilitation, sleep architecture on cEEG associated with a shorter inpatient hospital stay (20 days vs 27 days) and earlier participation in therapy (9.8 days vs 13.2 days postinjury). Multivariable analyses indicated that sleep features on cEEG predicted functional outcomes independent of admission Glasgow Coma Scale and ictal-interictal activity. CONCLUSION: The presence of sleep features in the acute period after TBI indicates earlier participation in rehabilitative therapies and a better functional recovery. By contrast, status epilepticus, other ictal activity, or absent sleep architecture may portend a worse prognosis. Whether sleep elements detected by EEG predict long-term prognosis remains to be determined. PMID- 26959665 TI - Concordance of Actigraphy With Polysomnography in Traumatic Brain Injury Neurorehabilitation Admissions. AB - OBJECTIVE: To examine concordance of accelerometer-based actigraphy (ACG) with polysomnography (PSG) in the determination of sleep states in inpatients with traumatic brain injury (TBI), and examine the impact of injury severity and comorbid conditions (spasticity, apnea) on concordance. PARTICIPANTS: This was a convenience sample of 50 participants with primarily severe TBI. DESIGN: This was a retrospective chart review of concurrent administration of PSG with ACG in nonconsecutive rehabilitation admissions with TBI. MAIN MEASURES: Total sleep time and sleep efficiency were measured by PSG and ACG. RESULTS: Moderate to strong correlations between ACG and PSG were observed for total sleep time (r = 0.78, P < .01) and sleep efficiency (r = 0.66, P < .01). PSG and ACG estimates of total sleep time (316 minutes vs 325 minutes, respectively) and sleep efficiency (78% vs 77%, respectively) were statistically indistinguishable. CONCLUSIONS: Actigraphy is a valid proxy for monitoring of sleep in this population across injury severity and common comorbidity groups. However, further research with larger sample sizes to examine concordance in patients with TBI with disorder of consciousness and spasticity is recommended. PMID- 26959666 TI - A Qualitative Study of Sleep-Wake Disturbance Among Veterans With Post-Acute Moderate to Severe Traumatic Brain Injury. AB - OBJECTIVE: Examine sleep-wake disturbance (SWD) characteristics, factors, consequences, and management strategies from the perspective of veterans with chronic stage, moderate/severe traumatic brain injury (TBI). SETTING: VA Medical Center, Rocky Mountain. US PARTICIPANTS: Nineteen male veterans with post-acute TBI and SWD in the VA Health Administration. DESIGN: Qualitative descriptive. MEASURES: Semistructured interviews, Ohio State University TBI-Identification Method, Insomnia Severity Index. RESULTS: Two main dimensions emerged: "Messed up sleep" and Surviving and Managing SWD. Sleep-wake disturbance has long-term multidimensional features, etiology, consequences, and practice implications. Although SWD may not be consistently discussed with providers, the problem appears to be pervasive in many aspects of the lives of the informants. Difficulty falling asleep, frequent awakenings, and poor sleep quality were common symptoms that were described as intrusive, isolating, and difficult to self-manage. Veterans discussed a host of physical symptoms, mental health issues, environmental, and behavioral factors that contributed to SWD. Medications, sleep apnea treatment, and self-imposed isolation were frequent management strategies. Veterans expressed a willingness to try new approaches and work with providers. CONCLUSION: Sleep-wake disturbance among veterans with chronic stage TBI is a multidimensional phenomenon with interplay between comorbidities, contributing factors, effects on functioning, and sleep management strategies. Implications for practice include early and routine evaluation, monitoring, and treatment of SWD. Research is needed to test interventions that address SWD and common TBI comorbidities. PMID- 26959667 TI - Actigraphic and Sleep Diary Measures in Veterans With Traumatic Brain Injury: Discrepancy in Selected Sleep Parameters. AB - OBJECTIVE: To examine the discrepancy between sleep diary and actigraphic measures of sleep in Veterans with moderate-severe post-acute traumatic brain injury (TBI) and to explore whether these discrepancies vary according to participant characteristics. SETTING: VA Medical Center in the Rocky Mountain United States. PARTICIPANTS: Nineteen males with moderate-severe post-acute TBI and insomnia symptoms as measured by the Insomnia Severity Index. DESIGN: Descriptive, cross-sectional. MAIN MEASURES: Sleep diary, wrist actigraphy, Ohio State University TBI-Identification Method, Insomnia Severity Index, and Hospital Anxiety and Depression Scale. RESULTS: There was poor agreement between actigraphic and sleep diary measurements of (1) total sleep time, (2) wake after sleep onset, and (3) sleep onset latency. On average, actigraphy measured greater duration of all 3 sleep parameters. Discrepancies were not found to be associated with specific TBI characteristics or mood-related symptoms. CONCLUSION: When measuring sleep-related outcomes among Veterans with moderate-severe post-acute TBI, notable mismatches were found between actigraphic and self-reported sleep diary data. Knowledge regarding measure-related limitations is important for both clinical and research practices among those with moderate-severe post-acute TBI. PMID- 26959669 TI - Adopting Abstract Images for Semantic Scene Understanding. AB - Relating visual information to its linguistic semantic meaning remains an open and challenging area of research. The semantic meaning of images depends on the presence of objects, their attributes and their relations to other objects. But precisely characterizing this dependence requires extracting complex visual information from an image, which is in general a difficult and yet unsolved problem. In this paper, we propose studying semantic information in abstract images created from collections of clip art. Abstract images provide several advantages over real images. They allow for the direct study of how to infer high level semantic information, since they remove the reliance on noisy low-level object, attribute and relation detectors, or the tedious hand-labeling of real images. Importantly, abstract images also allow the ability to generate sets of semantically similar scenes. Finding analogous sets of real images that are semantically similar would be nearly impossible. We create 1,002 sets of 10 semantically similar abstract images with corresponding written descriptions. We thoroughly analyze this dataset to discover semantically important features, the relations of words to visual features and methods for measuring semantic similarity. Finally, we study the relation between the saliency and memorability of objects and their semantic importance. PMID- 26959668 TI - Telephone Problem-Solving Treatment Improves Sleep Quality in Service Members With Combat-Related Mild Traumatic Brain Injury: Results From a Randomized Clinical Trial. AB - OBJECTIVE: Evaluate sleep quality, its correlates, and the effect of telephone based problem-solving treatment (PST) in active duty postdeployment service members with mild traumatic brain injury (mTBI) SETTING:: Randomized clinical trial. PARTICIPANTS: Active duty service members with combat-related mTBI. STUDY DESIGN: Education-only (EO) and PST groups (N = 178 each) received printed study materials and 12 educational brochures. The PST group additionally received up to 12 PST telephone calls addressing participant-selected issues. Outcomes were evaluated postintervention (6 months) and at 12 months. MAIN MEASURE: Pittsburgh Sleep Quality Index. RESULTS: Sleep quality was manifestly poor in both groups at baseline (Pittsburgh Sleep Quality Index = 12.5 +/- 4). Overall sleep quality was significantly different between the PST and EO groups at 6 months (P = .003) but not at 12 months. Longitudinally, PST significantly improved sleep quality at 6 months (P = .001) but not over the follow-up. Low sleep quality was associated with concussion symptoms, pain, depression, and posttraumatic stress disorder at all time points (P < .0001). CONCLUSIONS: Sleep disorders, common in postdeployment service members with mTBI, are strongly associated with the presence of pain, posttraumatic stress disorder, and depression. Telephone-based PST may be an effective therapeutic approach for reducing sleep disorders in this population. Research should focus on maintenance of treatment gains. PMID- 26959670 TI - Photometric Ambient Occlusion for Intrinsic Image Decomposition. AB - We present a method for computing ambient occlusion (AO) for a stack of images of a Lambertian scene from a fixed viewpoint. Ambient occlusion, a concept common in computer graphics, characterizes the local visibility at a point: it approximates how much light can reach that point from different directions without getting blocked by other geometry. While AO has received surprisingly little attention in vision, we show that it can be approximated using simple, per-pixel statistics over image stacks, based on a simplified image formation model. We use our derived AO measure to compute reflectance and illumination for objects without relying on additional smoothness priors, and demonstrate state-of-the art performance on the MIT Intrinsic Images benchmark. We also demonstrate our method on several synthetic and real scenes, including 3D printed objects with known ground truth geometry. PMID- 26959671 TI - Map-Based Probabilistic Visual Self-Localization. AB - Accurate and efficient self-localization is a critical problem for autonomous systems. This paper describes an affordable solution to vehicle self-localization which uses odometry computed from two video cameras and road maps as the sole inputs. The core of the method is a probabilistic model for which an efficient approximate inference algorithm is derived. The inference algorithm is able to utilize distributed computation in order to meet the real-time requirements of autonomous systems in some instances. Because of the probabilistic nature of the model the method is capable of coping with various sources of uncertainty including noise in the visual odometry and inherent ambiguities in the map (e.g., in a Manhattan world). By exploiting freely available, community developed maps and visual odometry measurements, the proposed method is able to localize a vehicle to 4 m on average after 52 seconds of driving on maps which contain more than 2,150 km of drivable roads. PMID- 26959672 TI - Leveraging the Wisdom of the Crowd for Fine-Grained Recognition. AB - Fine-grained recognition concerns categorization at sub-ordinate levels, where the distinction between object classes is highly local. Compared to basic level recognition, fine-grained categorization can be more challenging as there are in general less data and fewer discriminative features. This necessitates the use of a stronger prior for feature selection. In this work, we include humans in the loop to help computers select discriminative features. We introduce a novel online game called "Bubbles" that reveals discriminative features humans use. The player's goal is to identify the category of a heavily blurred image. During the game, the player can choose to reveal full details of circular regions ("bubbles"), with a certain penalty. With proper setup the game generates discriminative bubbles with assured quality. We next propose the "BubbleBank" representation that uses the human selected bubbles to improve machine recognition performance. Finally, we demonstrate how to extend BubbleBank to a view-invariant 3D representation. Experiments demonstrate that our approach yields large improvements over the previous state of the art on challenging benchmarks. PMID- 26959673 TI - Cascades of Regression Tree Fields for Image Restoration. AB - Conditional random fields (CRFs) are popular discriminative models for computer vision and have been successfully applied in the domain of image restoration, especially to image denoising. For image deblurring, however, discriminative approaches have been mostly lacking. We posit two reasons for this: First, the blur kernel is often only known at test time, requiring any discriminative approach to cope with considerable variability. Second, given this variability it is quite difficult to construct suitable features for discriminative prediction. To address these challenges we first show a connection between common half quadratic inference for generative image priors and Gaussian CRFs. Based on this analysis, we then propose a cascade model for image restoration that consists of a Gaussian CRF at each stage. Each stage of our cascade is semi-parametric, i.e., it depends on the instance-specific parameters of the restoration problem, such as the blur kernel. We train our model by loss minimization with synthetically generated training data. Our experiments show that when applied to non-blind image deblurring, the proposed approach is efficient and yields state-of-the-art restoration quality on images corrupted with synthetic and real blur. Moreover, we demonstrate its suitability for image denoising, where we achieve competitive results for grayscale and color images. PMID- 26959674 TI - Intrinsic Scene Properties from a Single RGB-D Image. AB - In this paper, we present a technique for recovering a model of shape, illumination, reflectance, and shading from a single image taken from an RGB-D sensor. To do this, we extend the SIRFS ("shape, illumination and reflectance from shading") model, which recovers intrinsic scene properties from a single image. Though SIRFS works well on neatly segmented images of objects, it performs poorly on images of natural scenes which often contain occlusion and spatially varying illumination. We therefore present Scene-SIRFS, a generalization of SIRFS in which we model a scene using a mixture of shapes and a mixture of illuminations, where those mixture components are embedded in a "soft" segmentation-like representation of the input image. We use the noisy depth maps provided by RGB-D sensors (such as the Microsoft Kinect) to guide and improve shape estimation. Our model takes as input a single RGB-D image and produces as output an improved depth map, a set of surface normals, a reflectance image, a shading image, and a spatially varying model of illumination. The output of our model can be used for graphics applications such as relighting and retargeting, or for more broad applications (recognition, segmentation) involving RGB-D images. PMID- 26959675 TI - Bayesian Constrained Local Models Revisited. AB - This paper presents a novel Bayesian formulation for aligning faces in unseen images. Our approach revisits the Constrained Local Models (CLM) formulation where an ensemble of local feature detectors are constrained to lie within the subspace spanned by a Point Distribution Model (PDM). Fitting such a model to an image typically involves two main steps: a local search using a detector, obtaining response maps for each landmark (likelihood term) and a global optimization that finds the PDM parameters that jointly maximize all the detections at once. The so-called global optimization can be posed as a Bayesian inference problem, where the posterior distribution of the shape (and pose) parameters can be inferred in a maximum a posteriori (MAP) sense. This work introduces an extended Bayesian global optimization strategy that includes two novel additions: (1) to perform second order updates of the PDM parameters (accounting for their covariance) and (2) to model the underlying dynamics of the shape variations, encoded in the prior term, by using recursive Bayesian estimation. Extensive evaluations were performed against state-of-the-art methods on several standard datasets (IMM, BioID, XM2VTS, LFW and FGNET Talking Face). Results show that the proposed approach significantly increases the fitting performance. PMID- 26959676 TI - Hierarchical Image Saliency Detection on Extended CSSD. AB - Complex structures commonly exist in natural images. When an image contains small scale high-contrast patterns either in the background or foreground, saliency detection could be adversely affected, resulting erroneous and non-uniform saliency assignment. The issue forms a fundamental challenge for prior methods. We tackle it from a scale point of view and propose a multi-layer approach to analyze saliency cues. Different from varying patch sizes or downsizing images, we measure region-based scales. The final saliency values are inferred optimally combining all the saliency cues in different scales using hierarchical inference. Through our inference model, single-scale information is selected to obtain a saliency map. Our method improves detection quality on many images that cannot be handled well traditionally. We also construct an extended Complex Scene Saliency Dataset (ECSSD) to include complex but general natural images. PMID- 26959677 TI - Recognition Using Hybrid Classifiers. AB - A canonical problem in computer vision is category recognition (e.g., find all instances of human faces, cars etc., in an image). Typically, the input for training a binary classifier is a relatively small sample of positive examples, and a huge sample of negative examples, which can be very diverse, consisting of images from a large number of categories. The difficulty of the problem sharply increases with the dimension and size of the negative example set. We propose to alleviate this problem by applying a "hybrid" classifier, which replaces the negative samples by a prior, and then finds a hyperplane which separates the positive samples from this prior. The method is extended to kernel space and to an ensemble-based approach. The resulting binary classifiers achieve an identical or better classification rate than SVM, while requiring far smaller memory and lower computational complexity to train and apply. PMID- 26959678 TI - Semantic Concept Co-Occurrence Patterns for Image Annotation and Retrieval. AB - Describing visual image contents by semantic concepts is an effective and straightforward way to facilitate various high level applications. Inferring semantic concepts from low-level pictorial feature analysis is challenging due to the semantic gap problem, while manually labeling concepts is unwise because of a large number of images in both online and offline collections. In this paper, we present a novel approach to automatically generate intermediate image descriptors by exploiting concept co-occurrence patterns in the pre-labeled training set that renders it possible to depict complex scene images semantically. Our work is motivated by the fact that multiple concepts that frequently co-occur across images form patterns which could provide contextual cues for individual concept inference. We discover the co-occurrence patterns as hierarchical communities by graph modularity maximization in a network with nodes and edges representing concepts and co-occurrence relationships separately. A random walk process working on the inferred concept probabilities with the discovered co-occurrence patterns is applied to acquire the refined concept signature representation. Through experiments in automatic image annotation and semantic image retrieval on several challenging datasets, we demonstrate the effectiveness of the proposed concept co-occurrence patterns as well as the concept signature representation in comparison with state-of-the-art approaches. PMID- 26959679 TI - What Makes for Effective Detection Proposals? AB - Current top performing object detectors employ detection proposals to guide the search for objects, thereby avoiding exhaustive sliding window search across images. Despite the popularity and widespread use of detection proposals, it is unclear which trade-offs are made when using them during object detection. We provide an in-depth analysis of twelve proposal methods along with four baselines regarding proposal repeatability, ground truth annotation recall on PASCAL, ImageNet, and MS COCO, and their impact on DPM, R-CNN, and Fast R-CNN detection performance. Our analysis shows that for object detection improving proposal localisation accuracy is as important as improving recall. We introduce a novel metric, the average recall (AR), which rewards both high recall and good localisation and correlates surprisingly well with detection performance. Our findings show common strengths and weaknesses of existing methods, and provide insights and metrics for selecting and tuning proposal methods. PMID- 26959680 TI - Arterial Spin Labeling Imaging for the Parotid Glands of Patients with Sjogren's Syndrome. AB - Sjogren's syndrome (SS) is characterized by hypofunction of the salivary and lacrimal glands. The salivary function is largely dependent upon the blood supply in the glands. However, the diseased states of the gland perfusion are not well understood. The arterial spin labeling (ASL) technique allows noninvasive quantitative assessment of tissue perfusion without the need for contrast agent. Here, we prospectively compared the perfusion properties of the parotid glands between patients with SS and those with healthy glands using ASL MR imaging. We analyzed salivary blood flow (SBF) kinetics of 22 healthy parotid glands from 11 volunteers and 28 parotid glands from 14 SS patients using 3T pseudo-continuous ASL imaging. SBF was determined in resting state (base SBF) and at 3 sequential segments after gustatory stimulation. SBF kinetic profiles were characterized by base SBF level, increment ratio at the SBF peak, and the differences in segments where the peak appeared (SBF types). Base SBFs of the SS glands were significantly higher than those of healthy glands (59.2 +/- 22.8 vs. 46.3 +/- 9.0 mL/min/100 g, p = 0.01). SBF kinetic profiles of the SS glands also exhibited significantly later SBF peaks (p < 0.001) and higher SBF increment ratios (74 +/- 49% vs. 47 +/- 39%, p = 0.04) than the healthy glands. The best SBF criterion (= 51.2 mL/min/100 mg) differentiated between control subjects and SS patients with 71% sensitivity and 82% specificity. Taken together, these results showed that the SS parotid glands were mostly hyperemic and the SS gland responses to gustatory stimulation were stronger and more prolonged than those of the healthy glands. The ASL may be a promising technique for assessing the diseased salivary gland vascularization of SS patients. PMID- 26959681 TI - Introgressive Hybridization and the Evolution of Lake-Adapted Catostomid Fishes. AB - Hybridization has been identified as a significant factor in the evolution of plants as groups of interbreeding species retain their phenotypic integrity despite gene exchange among forms. Recent studies have identified similar interactions in animals; however, the role of hybridization in the evolution of animals has been contested. Here we examine patterns of gene flow among four species of catostomid fishes from the Klamath and Rogue rivers using molecular and morphological traits. Catostomus rimiculus from the Rogue and Klamath basins represent a monophyletic group for nuclear and morphological traits; however, the Klamath form shares mtDNA lineages with other Klamath Basin species (C. snyderi, Chasmistes brevirostris, Deltistes luxatus). Within other Klamath Basin taxa, D. luxatus was largely fixed for alternate nuclear alleles relative to C. rimiculus, while Ch. brevirostris and C. snyderi exhibited a mixture of these alleles. Deltistes luxatus was the only Klamath Basin species that exhibited consistent covariation of nuclear and mitochondrial traits and was the primary source of mismatched mtDNA in Ch. brevirostris and C. snyderi, suggesting asymmetrical introgression into the latter species. In Upper Klamath Lake, D. luxatus spawning was more likely to overlap spatially and temporally with C. snyderi and Ch. brevirostris than either of those two with each other. The latter two species could not be distinguished with any molecular markers but were morphologically diagnosable in Upper Klamath Lake, where they were largely spatially and temporally segregated during spawning. We examine parallel evolution and syngameon hypotheses and conclude that observed patterns are most easily explained by introgressive hybridization among Klamath Basin catostomids. PMID- 26959684 TI - Thermodynamic Properties of Molecular Crystals Calculated within the Quasi Harmonic Approximation. AB - A computational study of the possibilities of contemporary theoretical chemistry as regards calculated thermodynamic properties for molecular crystals from first principles is presented. The study is performed for a testing set of 22 low temperature crystalline phases whose properties such as densities of phonon states, isobaric heat capacities, and densities are computed as functions of temperature within the quasi-harmonic approximation. Electronic structure and lattice dynamics are treated by plane-wave based calculations with optPBE-vdW functional. Comparison of calculated results with reliable critically assessed experimental data is especially emphasized. PMID- 26959685 TI - Labeling the Structural Integrity of Nanoparticles for Advanced In Situ Tracking in Bionanotechnology. AB - Observing structural integrity of nanoparticles is essential in bionanotechnology but not always straightforward to measure in situ and in real-time. Fluorescent labels used for tracking intrinsically nonfluorescent nanomaterials generally do not allow simultaneous observation of integrity. Consequently, structural changes like degradation and disassembly cannot easily be followed in situ using fluorescence signals. We show that thioflavin T (ThT), a fluorophore and molecular rotor known to tag specific fibril structures in amyloids, can "label" the structural integrity of widely used and intrinsically nonfluorescent, silica nanoparticles (SiNPs). Entrapment of ThT in SiNPs controls the fluorohphore's relaxation pathway and leads to a red-shifted fluorescence spectrum providing real time information on SiNP integrity. The dynamic change of ThT fluorescence during degradation of doped SiNPs is found much higher than that of common labels fluorescein and rhodamine. Degradation kinetics of core-shell structures recorded by ThT fluorescence and light scattering prove the capability to clearly distinguish structural features during SiNPs degradation and allow obtaining degradation kinetics in vitro, in biological media, in serum, and in cells. The effect is transferable to different types of materials, here shown for ThT incorporated SiNPs with tightly tailorable sizes (9-100 nm), poly(lactic-co glycolic acid) (PLGA) nanoparticles, poly(9-vinylcarbazole) (PVK) nanoparticles, and iron-doped-SiNPs (FeSiNPs). We thus suggest molecular rotors such as ThT as additional labels to effectively and easily sense nanoparticle structural status in situ and to enhance understanding and development of programmed nanoparticle disassembly in bionanotechnology. PMID- 26959686 TI - Hydrogen Isotopes as a Sentinel of Biological Invasion by the Japanese Beetle, Popillia japonica (Newman). AB - Invasive species alter ecosystems, threaten native and endangered species, and have negative economic impacts. Knowing where invading individuals are from and when they arrive to a new site can guide management. Here, we evaluated how well the stable hydrogen isotope composition (delta2H) records the recent origin and time since arrival of specimens of the invasive Japanese beetle (Popillia japonica Newman) captured near the Portland International Airport (Oregon, U.S.A.). The delta2H of Japanese beetle specimens collected from sites across the contiguous U.S.A. reflected the delta2H of local precipitation, a relationship similar to that documented for other organisms, and one confirming the utility of delta2H as a geographic fingerprint. Within weeks after experimental relocation to a new isotopic environment, the delta2H of beetles changed linearly with time, demonstrating the potential for delta2H to also mark the timing of arrival to a new location. We used a hierarchical Bayesian model to estimate the recent geographical origin and timing of arrival of each specimen based on its delta2H value. The geographic resolution was broad, with values consistent with multiple regions of origin in the eastern U.S.A., slightly favoring the southeastern U.S.A. as the more likely source. Beetles trapped from 2007-2010 had arrived 30 or more days prior to trapping, whereas the median time since arrival declined to 3-7 days for beetles trapped from 2012-2014. This reduction in the time between arrival and trapping at the Portland International Airport supports the efficacy of trapping and spraying to prevent establishment. More generally, our analysis shows how stable isotopes can serve as sentinels of biological invasions, verifying the efficacy of control measures, or, alternatively, indicating when those measures show signs of failure. PMID- 26959683 TI - Microglia Transcriptome Changes in a Model of Depressive Behavior after Immune Challenge. AB - Depression symptoms following immune response to a challenge have been reported after the recovery from sickness. A RNA-Seq study of the dysregulation of the microglia transcriptome in a model of inflammation-associated depressive behavior was undertaken. The transcriptome of microglia from mice at day 7 after Bacille Calmette Guerin (BCG) challenge was compared to that from unchallenged Control mice and to the transcriptome from peripheral macrophages from the same mice. Among the 562 and 3,851 genes differentially expressed between BCG-challenged and Control mice in microglia and macrophages respectively, 353 genes overlapped between these cells types. Among the most differentially expressed genes in the microglia, serum amyloid A3 (Saa3) and cell adhesion molecule 3 (Cadm3) were over expressed and coiled-coil domain containing 162 (Ccdc162) and titin-cap (Tcap) were under-expressed in BCG-challenged relative to Control. Many of the differentially expressed genes between BCG-challenged and Control mice were associated with neurological disorders encompassing depression symptoms. Across cell types, S100 calcium binding protein A9 (S100A9), interleukin 1 beta (Il1b) and kynurenine 3-monooxygenase (Kmo) were differentially expressed between challenged and control mice. Immune response, chemotaxis, and chemokine activity were among the functional categories enriched by the differentially expressed genes. Functional categories enriched among the 9,117 genes differentially expressed between cell types included leukocyte regulation and activation, chemokine and cytokine activities, MAP kinase activity, and apoptosis. More than 200 genes exhibited alternative splicing events between cell types including WNK lysine deficient protein kinase 1 (Wnk1) and microtubule-actin crosslinking factor 1(Macf1). Network visualization revealed the capability of microglia to exhibit transcriptome dysregulation in response to immune challenge still after resolution of sickness symptoms, albeit lower than that observed in macrophages. The persistent transcriptome dysregulation in the microglia shared patterns with neurological disorders indicating that the associated persistent depressive symptoms share a common transcriptome basis. PMID- 26959687 TI - Full-Field Calcium K-Edge X-ray Absorption Near-Edge Structure Spectroscopy on Cortical Bone at the Micron-Scale: Polarization Effects Reveal Mineral Orientation. AB - Here, we show results on X-ray absorption near edge structure spectroscopy in both transmission and X-ray fluorescence full-field mode (FF-XANES) at the calcium K-edge on human bone tissue in healthy and diseased conditions and for different tissue maturation stages. We observe that the dominating spectral differences originating from different tissue regions, which are well pronounced in the white line and postedge structures are associated with polarization effects. These polarization effects dominate the spectral variance and must be well understood and modeled before analyzing the very subtle spectral variations related to the bone tissue variations itself. However, these modulations in the fine structure of the spectra can potentially be of high interest to quantify orientations of the apatite crystals in highly structured tissue matrices such as bone. Due to the extremely short wavelengths of X-rays, FF-XANES overcomes the limited spatial resolution of other optical and spectroscopic techniques exploiting visible light. Since the field of view in FF-XANES is rather large the acquisition times for analyzing the same region are short compared to, for example, X-ray diffraction techniques. Our results on the angular absorption dependence were verified by both site-matched polarized Raman spectroscopy, which has been shown to be sensitive to the orientation of bone building blocks and by mathematical simulations of the angular absorbance dependence. As an outlook we further demonstrate the polarization based assessment of calcium-containing crystal orientation and specification of calcium in a beta-tricalcium phosphate (beta-Ca3(PO4)2 scaffold implanted into ovine bone. Regarding the use of XANES to assess chemical properties of Ca in human bone tissue our data suggest that neither the anatomical site (tibia vs jaw) nor pathology (healthy vs necrotic jaw bone tissue) affected the averaged spectral shape of the XANES spectra. PMID- 26959689 TI - Catalysis by Design: Well-Defined Single-Site Heterogeneous Catalysts. AB - Heterogeneous catalysis, a field important industrially and scientifically, is increasingly seeking and refining strategies to render itself more predictable. The main issue is due to the nature and the population of catalytically active sites. Their number is generally low to very low, their "acid strengths" or " redox properties" are not homogeneous, and the material may display related yet inactive sites on the same material. In many heterogeneous catalysts, the discovery of a structure-activity reationship is at best challenging. One possible solution is to generate single-site catalysts in which most, if not all, of the sites are structurally identical. Within this context and using the right tools, the catalyst structure can be designed and well-defined, to reach a molecular understanding. It is then feasible to understand the structure-activity relationship and to develop predictable heterogeneous catalysis. Single-site well defined heterogeneous catalysts can be prepared using concepts and tools of surface organometallic chemistry (SOMC). This approach operates by reacting organometallic compounds with surfaces of highly divided oxides (or of metal nanoparticles). This strategy has a solid track record to reveal structure activity relationship to the extent that it is becoming now quite predictable. Almost all elements of the periodical table have been grafted on surfaces of oxides (from simple oxides such as silica or alumina to more sophisticated materials regarding composition or porosity). Considering catalytic hydrocarbon transformations, heterogeneous catalysis outcome may now be predicted based on existing mechanistic proposals and the rules of molecular chemistry (organometallic, organic) associated with some concepts of surface sciences. A thorough characterization of the grafted metal centers must be carried out using tools spanning from molecular organometallic or surface chemistry. By selection of the metal, its ligand set, and the support taken as a X, L ligands in the Green formalism, the catalyst can be designed and generated by grafting the organometallic precursor containing the functional group(s) suitable to target a given transformation (surface organometallic fragments (SOMF)). The choice of these SOMF is based on the elementary steps known in molecular chemistry applied to the desired reaction. The coordination sphere necessary for any catalytic reaction involving paraffins, olefins, and alkynes also can thus be predicted. Only their most complete understanding can allow development of catalytic reactions with the highest possible selectivity, activity, and lifetime. This Account will examine the results of SOMC for hydrocarbon transformations on oxide surfaces bearing metals of group 4-6. The silica-supported catalysts are exhibiting remarkable performances for Ziegler-Natta polymerization and depolymerization, low temperature hydrogenolysis of alkanes and waxes, metathesis of alkanes and cycloalkanes, olefins metathesis, and related reactions. In the case of reactions involving molecules that do not contain carbon (water-gas shift, NH3 synthesis, etc.) this single site approach is also valid but will be considered in a later review. PMID- 26959688 TI - Clinical Efficacy and Safety of Oral Qing-Dai in Patients with Ulcerative Colitis: A Single-Center Open-Label Prospective Study. AB - BACKGROUND/AIMS: Chinese herbal medicine Qing-Dai (also known as indigo naturalis) has been used to treat various inflammatory conditions. However, not much has been studied about the use of oral Qing-Dai in the treatment for ulcerative colitis (UC) patients. Studies exploring alternative treatments for UC are of considerable interest. In this study, we aimed at prospectively evaluating the safety and efficacy of Qing-Dai for UC patients. METHODS: The open-label, prospective pilot study was conducted at Keio University Hospital. A total of 20 patients with moderate UC activity were enrolled. Oral Qing-Dai in capsule form was taken twice a day (daily dose, 2 g) for 8 weeks. RESULTS: At week 8, the rates of clinical response, clinical remission, and mucosal healing were 72, 33, and 61%, respectively. The clinical and endoscopic scores, CRP levels, and fecal occult blood results were also significantly improved. We observed 2 patients with mild liver dysfunction; 1 patient discontinued due to infectious colitis and 1 patient discontinued due to mild nausea. CONCLUSION: This is the first prospective study indicating that oral Qing-Dai is effective for inducing remission in patients with moderate UC activity and can be tolerated. Thus, Qing Dai may be considered an alternative treatment for patients, although further investigation is warranted. PMID- 26959690 TI - The Effect of Laser Panretinal Photocoagulation on Diabetic Macular Edema Using the Pascal(r) Photocoagulator versus the Conventional Argon Laser Photocoagulator. AB - PURPOSE: The aim of this study was to compare the effect of panretinal photocoagulation for proliferative diabetic retinopathy (PDR) on diabetic macular edema (DME) using a Pascal(r) Photocoagulator (PP) or a conventional argon laser photocoagulator (CALP). METHODS: Eighty eyes with PDR and center-involving DME were randomized to PP or CALP. Both groups had baseline assessment of best corrected visual acuity (BCVA) and were examined with optical coherence tomography and fluorescein angiography. RESULTS: The mean number of laser shots for the PP and CALP groups was 1,726.10 and 752.00 at session 1 and 1,589.00 and 830.00 (p < 0.001) at session 2, respectively. The mean central foveal thickness (CFT) at baseline was 306 +/- 100 and 314 +/- 98 for the PP and CALP groups, respectively. At 8 weeks, the mean CFT was 332 +/- 116 and 347 +/- 111 for the PP and CALP groups, respectively (p > 0.05). The mean BCVA was similar during the study period with no significant difference between the groups (p > 0.05). CONCLUSION: PP and CALP had similar effects on DME in PDR eyes and were equally safe with no significant increase in CFT. PMID- 26959691 TI - Cutaneous Manifestations of Familial Transthyretin Amyloid Polyneuropathy. AB - Familial amyloid polyneuropathy (FAP) is a rare inherited autosomal dominant form of systemic amyloidosis, which classically presents with severe motor, sensory, and autonomic dysfunction. Cutaneous involvement does not become clinically apparent until late stage symptomatic disease and is rarely reported in modern literature. Here, the authors review the clinical and histologic cutaneous findings of FAP previously described in the literature and report on 3 patients with unique genetic mutations (Thr60Ala and Gly6Ser; Trp41Leu; Glu89Gln) for which cutaneous involvement has not previously been described. Histologically, our patients showed variable amyloid deposition in the subcutaneous adipose tissue, papillary dermis, and dermal blood vessel walls. A review of the literature suggests cutaneous transthyretin deposition is an underrecognized feature of FAP that occurs early on in disease, even before neural involvement and related symptoms as seen in one of our patients. As such, a cutaneous punch biopsy can serve as quick, easy, and relatively noninvasive diagnostic tool in suspected cases. PMID- 26959692 TI - Polarized Microscopy in Lesions With Altered Dermal Collagen. AB - Alterations in dermal collagen are noted in dermatofibroma, dermatofibrosarcoma protuberans, morphea, lichen sclerosus et atrophicus, hypertrophic scars, and keloids. The authors sought to determine whether variations in birefringence of collagen by polarized microscopy could be of help in diagnosing such conditions. Representative hematoxylin and eosin sections of 400 cases, including dermatofibroma, dermatofibrosarcoma protuberans, hypertrophic scars, keloid, morphea, and lichen sclerosus, were examined under polarized microscopy. Distinct patterns of birefringence of collagen for each disease were noted under polarized microscopy. This study highlights the use of polarized microscopy as adjunctive tool in differentiating different diseases with collagen alteration. PMID- 26959693 TI - Demodex Folliculitis of the Scalp: Clinicopathological Study of an Uncommon Entity. AB - Demodex is a saprophytic mite in humans commonly present in the pilosebaceous units, which has been implicated as a pathogen in several skin conditions. The clinical presentation and histopathology of Demodex folliculitis of the scalp have been described in only a few case reports. This study was performed to further elucidate the clinicopathological features of this entity. We have studied 333 consecutively submitted scalp biopsies performed for hair loss and alopecia. All specimens were completely step-sectioned. Biopsies with Demodex mites were further studied histopathologically, and the patients' clinical files were reviewed. There were 17 biopsies (5.1%) with Demodex in at least 1 pilosebaceous unit. Based on the clinical presentation, histopathology, and response to therapy, Demodex was considered to be nonpathogenic in 13 cases. The remaining 4 cases were characterized by hair loss, scalp erythema, scales, and pustules. There were 2 or more pilosebaceous units with Demodex along mononuclear and/or neutrophilic infiltrates around and in the involved follicles and occasionally granulomas. All 4 cases responded completely to metronidazole therapy. In conclusion, Demodex is infrequently found in scalp biopsies for hair loss and alopecia, and, in most cases, it does not seem to be pathogenic. Occasionally, however, it is associated with folliculitis characterized by hair loss, erythema, scales, and pustules clinically; neutrophilic and/or mononuclear cell folliculitis with occasional granulomas histopathologically; and a prompt response to anti-Demodex therapy. PMID- 26959694 TI - Perianal Tumor With Overlap Features of Fibroadenoma and Phyllodes Tumor Arising From Anogenital Mammary-like Glands. PMID- 26959695 TI - Vemurafenib-Induced Neutrophilic Panniculitis: A New Case and Review of the Literature. AB - Vemurafenib has proved to be useful in the treatment of patients with unresectable or metastatic melanoma harboring the BRAF-V600E mutation, with better rates of overall and progression-free survival than previous treatments. Adverse cutaneous effects, such as alopecia, pruritus, photosensitivity reactions, verrucous keratosis, keratoacanthomas, or squamous cell carcinomas, have been described. Thirty cases of vemurafenib-associated panniculitis are available in the literature with variable clinical relevance. Only 9 of them exhibited definitive evidence of neutrophilic panniculitis. They all consist of multiple lesions, usually located in the lower limbs. Histopathologically, they have been described as predominantly neutrophilic, lymphocytic, or mixed, more commonly with lobular location. We report an additional case of neutrophilic panniculitis in a 45-year-old woman treated with vemurafenib for metastatic melanoma, presenting as a single lesion on his right leg. The lesion resolved spontaneously and did not need treatment reduction. The presentation of this condition with a single lesion is particularly challenging. Recognition of this association is important given the increasing use of vemurafenib and the potential implications of treatment withdrawal. PMID- 26959696 TI - Myoepithelioma-like Tumor of the Vulvar Region Presenting as a Nonmyxoid Spindle Cell Neoplasm: A Potential Histologic Mimicker of Solitary Fibrous Tumor. AB - A new entity termed "myoepithelioma-like tumor of the vulvar region (MELTVR)" has been proposed as a rare mesenchymal neoplasm of the vulvar area. Histologically, MELTVRs are usually similar to soft tissue myoepitheliomas; however, they have a characteristic immunoprofile, including positivity for estrogen receptor and negativity for S100 protein, and loss of SMARCB1 expression. In this first known case report of MELTVR, the authors present a case of MELTVR that was histologically categorized in a nonmyxoid spindle-cell tumor group and resembled solitary fibrous tumor rather than soft tissue myoepithelioma. PMID- 26959697 TI - Intravascular Myopericytoma of the Plantar Region: Case Report and Discussion of the Probable Origin From a Cutaneous Vascular Malformation. AB - Myopericytoma is a perivascular myoid neoplasm of skin and soft tissues characterized by numerous thin-walled blood vessels surrounded concentrically by round to spindle myoid tumor cells, which shows alpha-smooth muscle actin and h caldesmon coexpression and commonly negativity for desmin. These tumors arise predominantly in extremities of adult patients with benign clinical course. Based on the architectural pattern, there are various histologic variants as classical solid myopericytoma, hemangiopericytoma-like myopericytoma, angioleiomyoma-like myopericytoma, myofibroma-like myopericytoma, hipocelular fibroma-like myopericytoma, intravascular myopericytoma, cellular immature myopericytoma, and malignant myopericytoma. The authors report a case that fully satisfies the morphological and immunohistochemical criteria for intravascular myopericytoma, which plantar location is not previously described in the literature. In addition, the authors discuss about its possible development from a preexistent cutaneous vascular malformation. PMID- 26959698 TI - An Index Case of Cutaneous Hodgkin Lymphoma and Review of the Literature. AB - Hodgkin lymphoma (HL), although a common hematopoietic malignancy, presents as a primary cutaneous form in extraordinarily rare instances. In this study, we present a remarkable case of a 76-year-old woman with a history of bony metastatic breast cancer who developed multiple subcutaneous nodules on the left neck and scalp. A biopsy revealed the histological and immunohistochemical findings of classic HL. She was treated with systemic chemotherapy and quickly achieved disease remission. Five months later, she was alive and without evidence of lymphoma, consistent with our understanding of primary cutaneous HL as an indolent variant of HL. PMID- 26959699 TI - Clear-Cell Atypical Fibroxanthoma: A Combined Immunohistochemistry Analysis. AB - Atypical fibroxanthoma is considered to be a low-grade sarcoma, characterized by a proliferation of bizarre spindled cells. A case of a rare variant of this tumor, a clear-cell atypical fibroxanthoma, presenting with rapid growth on a 63 year-old female, is reported. The differential diagnosis of a clear cell proliferation and a review of the immunohistochemistry markers used in the diagnosis of atypical fibroxanthoma are discussed. In particular, the usefulness of markers such as CD10, procollagen 1, CD68, CD163, CD99, and S100A6, and the importance of negative markers such as S100, cytokeratin, and desmin are emphasized. Furthermore, the development of a keratoacanthoma at the site of previous Mohs surgery is recounted. PMID- 26959701 TI - Multinuclear silver(I) XPhos complexes with cyclooctatetraene: photochemical C-C bond cleavage of acetonitrile and cyanide bridged Ag cluster formation. AB - Cationic mono-, di-, tri- and tetra-nuclear silver complexes with Buchwald-type phosphane (XPhos) and cyclooctatetraene (COT) have been synthesized and characterized. Formation of [(XPhos-Ag)n(COT)][SbF6]n (n = 1 and 2) complexes was confirmed by single-crystal X-ray crystallography and multinuclear NMR spectroscopy. Variable-temperature NMR spectroscopy in CD2Cl2 solution shows the fluxionality of the COT ring in the mono-Ag(i) XPhos complex. Fluxionality of COT was also confirmed in the case of the di-Ag(i) XPhos complex by solid-state and solution (31)P NMR spectroscopy. The C-C bond cleavage of coordinated acetonitrile [XPhos-Ag(i)-NCCH3] resulting in cyanide bridged Ag cluster formation [(XPhos-Ag)2(MU-CN)n(MU-Ag)n-1] (n = 1, 2, 3 and 4) upon light excitation of [(XPhos-Ag)n(COT)] was confirmed by HRESI-MS, UV-Absorption and HR TEM. PMID- 26959700 TI - General and Stereocontrolled Approach to the Chemical Synthesis of Naturally Occurring Cyanogenic Glucosides. AB - An effective method for the chemical synthesis of cyanogenic glucosides has been developed as demonstrated by the synthesis of dhurrin, taxiphyllin, prunasin, sambunigrin, heterodendrin, and epiheterodendrin. O-Trimethylsilylated cyanohydrins were prepared and subjected directly to glucosylation using a fully acetylated glucopyranosyl fluoride donor with boron trifluoride-diethyl etherate as promoter to afford a chromatographically separable epimeric mixture of the corresponding acetylated cyanogenic glucosides. The isolated epimers were deprotected using a triflic acid/MeOH/ion-exchange resin system without any epimerization of the cyanohydrin function. The method is stereocontrolled and provides an efficient approach to chemical synthesis of other naturally occurring cyanogenic glucosides including those with a more complex aglycone structure. PMID- 26959702 TI - Terpyridine Molybdenum Dinitrogen Chemistry: Synthesis of Dinitrogen Complexes That Vary by Five Oxidation States. AB - A bimetallic molybdenum complex bridged by an activated dinitrogen ligand and supported by phosphine and terpyridine ligands, [{((Ph)Tpy)(PPh2Me)2Mo}2(MU2 N2)][BArF(24)]2 [(Ph)Tpy = 4'-Ph-2,2',6',2"-terpyridine; ArF(24) = (C6H3-3,5 (CF3)2)4], was synthesized and structurally characterized, and its electronic structure was determined using a combination of experimental and density functional theory computational methods. Each molybdenum atom is best described as molybdenum(II) bridged by a modestly activated [N2](2-) ligand. The cyclic voltammogram of [{((Ph)Tpy)(PPh2Me)2Mo}2(MU2-N2)](2+) displays two reversible reductive and two reversible oxidative features, prompting the preparation and characterization of a series of molybdenum dinitrogen compounds spanning five oxidation states ([{((Ph)Tpy)(PPh2Me)2Mo}2(MU2-N2)][BArF(24)]n, where n = 4, 3, 2, 1, 0). Raman and (15)N NMR spectroscopic data establish that the bridging nitrogen ligand remains intact across the redox series. Electron paramagnetic resonance spectroscopy was used to probe the nature of the unpaired electron in the mixed-valent electronic oxidized and reduced products. The singly occupied molecular orbital is principally metal-based in [{((Ph)Tpy)(PPh2Me)2Mo}2(MU2 N2)](3+) and ligand-localized in [{((Ph)Tpy)(PPh2Me)2Mo}2(MU2-N2)](+). PMID- 26959703 TI - Genetic insights into statin-associated diabetes risk. AB - PURPOSE OF REVIEW: Meta-analyses of major statin trials have suggested that statin therapy modestly increases the risk of developing diabetes. However, the quality of the data on which these findings are based is not without weaknesses and it has also been unclear whether this effect, if true, is an on-target or off target effect of statins. RECENT FINDINGS: In a major Mendelian randomization study of variants in the HMGCR gene, which encodes the protein through which statins exert their effect, two polymorphisms associated with lower LDL cholesterol were also associated with higher weight, higher waist circumference, higher glucose and higher diabetes risk. These findings correspond with findings from the statin trials. In addition, new observational studies using a genetic risk score for LDL-cholesterol suggest that other pathways linked to LDL cholesterol metabolism may also affect diabetes risk. SUMMARY: Genetic studies indicate that the observed effect of statins on diabetes risk in trials is highly likely to be a true on-target effect. Although other recent studies have suggested that genetically determined lower LDL-cholesterol may be linked to diabetes risk, further data from both genetic studies and clinical trials of other LDL-cholesterol lowering agents are needed to confirm or refute this. PMID- 26959705 TI - Role of sulfatase 2 in lipoprotein metabolism and angiogenesis. AB - PURPOSE OF REVIEW: This article summarizes the current evidence to support a role of sulfatase 2 (SULF2) in triglyceride-rich lipoprotein (TRL) metabolism and angiogenesis. RECENT FINDINGS: Heparan sulfate proteoglycans (HSPG) are involved in the hepatic clearance of TRLs in mice and in humans. Different genetically modified mouse models have been instrumental to provide evidence that syndecan1, the core protein of HSPG, but also the degree of sulfation of the heparin sulfate chain, attached to syndecan 1, is important for hepatic TRL metabolism. Studies in humans demonstrate the regulating role of SULF2 in the hepatic uptake of TRL by HSPG and demonstrate the importance of 6-O-sulfation, modulated by SULF2, for HSPG function. The role of SULF2 in angiogenesis is illustrated by increased SULF2 mRNA expression in the stalk cells of angiogenic vascular sprouts that use fatty acids derived from TRL as a source for biomass production. Interestingly, SULF2 also interferes with HSPG-vascular endothelial growth factor binding, which impacts upon the angiogenic properties of stalk cells. SUMMARY: SULF2 is a multifaceted protein involved in TRL homeostasis and angiogenesis. Future investigations should focus on the potential benefits of targeting SULF2 in atherosclerosis and angiogenesis. PMID- 26959704 TI - Trimethylamine-N-oxide: a link between the gut microbiome, bile acid metabolism, and atherosclerosis. AB - PURPOSE OF REVIEW: This article evaluates the link between trimethylamine-N-oxide (TMAO) and bile acids and the consequent impact on the development of atherosclerosis. RECENT FINDINGS: Elevation in plasma TMAO concentrations is associated with an increased risk of cardiovascular disease in many different patient cohorts. In addition to the recently identified direct effects of TMAO on the development of atherosclerosis, other components involved in TMAO metabolism may also have an impact. Furthermore, the relationship between TMAO and bile acid regulation is emerging as a possible mediator of atherosclerosis. SUMMARY: Studies that are emerging highlight the mechanistic relationship of TMAO to the development atherosclerosis in addition to its role as disease biomarker. The interplay between TMAO and bile acid metabolism mediated through multiple factors, such as the gut microbiome, farnesoid X receptor signaling, and flavin monooxygenase 3 activity may help identify another pathway by which atherosclerosis occurs. In this review, we discuss the most recent data regarding atherosclerosis, TMAO, and bile acid metabolism. PMID- 26959707 TI - Developing role of microRNA-33 in lipid metabolism and atherosclerosis. PMID- 26959708 TI - Cholesterol metabolism and breast cancer. PMID- 26959706 TI - Genetic susceptibility to cerebrovascular disease. AB - PURPOSE OF REVIEW: Cerebrovascular disease (CeVD) remains a major cause of death and a leading cause of disability worldwide. CeVD is a complex and multifactorial disease caused by the interaction of vascular risk factors, environment, and genetic factors. In the present article, we discussed genetic susceptibility to CeVD, with particular emphasis on genetic studies of the associations between lipid traits and CeVD. RECENT FINDINGS: Several animal and clinical studies clearly defined genetic predisposition to atherosclerosis and CeVD, and particularly to ischemic stroke. Recent evidence has shown that traditional vascular risk factors explain only a small proportion of variance in atherosclerosis, suggesting that additional nontraditional factors and novel genetic determinants impact CeVD. With the help of genome-wide technology, novel genetic variants have been implicated in CeVD and lipid metabolism such as those in protein convertase subtilisin/kexin type 9 (PCSK9) gene in stroke and familial hypercholesterolemia. These studies are important as they contribute to our understanding of the genetic mechanisms underlying CeVD and to developing more effective CeVD prevention strategies. SUMMARY: CeVD is a complex and multifactorial disease and genetics likely plays an important role in its pathogenesis. The gene-gene and gene-environment interactions of genes involved in biology of vascular disease, including the lipid metabolism are important factors for individual susceptibility to CeVD. Accounting for individual variation in genes, environment and lifestyle will bring us closer to precision medicine, which is an emerging and recently introduced new approach for disease treatment and prevention in clinical practice. PMID- 26959709 TI - Cholesterol-absorbed in thought. PMID- 26959710 TI - Endogenous or exogenous antioxidants vs. pro-oxidants in macrophage atherogenicity. PMID- 26959711 TI - Do the mechanisms by which LDL-c levels are reduced influence the extent of clinical benefit which subsequently accrues? PMID- 26959713 TI - Copy number variation in ALOX5 and PTGER1 is associated with NSAIDs-induced urticaria and/or angioedema. AB - OBJECTIVE: Cross-intolerance to NSAIDs is a class of drug hypersensitivity reaction, of which NSAIDs-induced urticaria and/or angioedema (NIUA) are the most frequent clinical entities. They are considered to involve dysregulation of the arachidonic acid pathway; however, this mechanism has not been confirmed for NIUA. In this work, we assessed copy number variations (CNVs) in eight of the main genes involved in the arachidonic acid pathway and their possible genetic association with NIUA. MATERIALS AND METHODS: CNVs in ALOX5, LTC4S, PTGS1, PTGS2, PTGER1, PTGER2, PTGER3, and PTGER4 were analyzed using TaqMan copy number assays. Genotyping was carried out by real-time quantitative PCR. Individual genotypes were assigned using the CopyCaller Software. Statistical analysis was carried out using GraphPad prism 5, PLINK, EPIDAT, and R version 3.1.2. RESULTS AND CONCLUSION: A total of 151 cases and 139 controls were analyzed during the discovery phase and 148 cases and 140 controls were used for replication. CNVs in open reading frames were found for ALOX5, PTGER1, PTGER3, and PTGER4. Statistically significant differences in the CNV frequency between NIUA and controls were found for ALOX5 (Pc=0.017) and PTGER1 (Pc=1.22E-04). This study represents the first analysis showing an association between CNVs in exonic regions of ALOX5 and PTGER1 and NIUA. This suggests a role of CNVs in this pathology that should be explored further. PMID- 26959714 TI - Deep sequencing identifies novel regulatory variants in the distal promoter region of the dopamine-beta-hydroxylase gene. AB - OBJECTIVE: Dopamine-beta-hydroxylase (DBH), an enzyme that converts dopamine into norepinephrine, is a drug target in cardiovascular and neuropsychiatric disorders. We aimed to identify functional variants in this gene by deep sequencing and enzyme phenotyping in an Indian cohort. MATERIALS AND METHODS: Targeted resequencing of 12 exons and 10 kb upstream sequences of DBH in healthy volunteers (n=50) was performed using the Ion Personal Genome Machine System. Enzyme quantity and activity in their sera samples were determined by ELISA and ultra performance liquid chromatography, respectively. The association of markers with phenotypes was determined using Matrix eQTL. Global P-values for haplotypes generated using UNPHASED 3.1.5 were graphed using GrASP v.082 beta. RESULTS: Of the 49 variants identified, nine were novel (minor allele frequency>=0.01). Though individual markers associated with enzyme quantity did not withstand multiple corrections, a novel distal promoter block driven by rs113249250 (global P=1.5*10) was associated. Of the nine single nucleotide polymorphisms (SNPs) associated with enzyme activity, rs3025369, rs1076151 and rs1611115, all from the upstream region, withstood false discovery rate correction (false discovery rate=0.03, 0.03 and 2.9*10, respectively). Conditioning for rs1611115 identified rs1989787 also to affect activity. Importantly, we report an association of a novel haplotype block distal to rs1076151 driven by rs3025369 (global P=8.9*10) with enzyme activity. This regulatory SNP explained 4.9% of the total 46.1% of variance in DBH activity caused by associated SNPs. CONCLUSION: This first study combining deep sequencing and enzyme phenotyping identified yet another regulatory SNP suggesting that regulatory variants may be central in the physiological or metabolic role of this gene of therapeutic and pharmacological relevance. PMID- 26959715 TI - Clinical efficacy of recombinant versus highly purified follicle-stimulating hormone according to follicle-stimulating hormone receptor genotype. AB - OBJECTIVE: Conflicting data have been reported on the comparative doses of recombinant follicle-stimulating hormone (rFSH) and urinary highly purified follicle-stimulating hormone (HP-FSH) required for ovarian stimulation. Nothing is known about the clinical efficacy of rFSH or HP-FSH depending on the N680S follicle-stimulating hormone receptor (FSHR) polymorphism. Our aim was to investigate whether the N680S polymorphism of the FSHR gene affects ovarian response with different forms of FSH. MATERIALS AND METHODS: This retrospective cohort study includes 382 cycles performed at Instituto Bernabeu from 191 oocyte donors. All donors carried out two cycles: one with rFSH and the other one with HP-FSH (group 1, n=63), both with HP-FSH (group 2, n=100) or both with rFSH (group 3, n=28). The results were compared by pairs from each patient. The main outcomes were oocyte yield, metaphase II matured oocytes (MII), days of stimulation, and gonadotropin dosage. RESULTS: No significant differences were found when we compared the cycles for donors in group 1. However, according to the FSHR polymorphism, statistical differences were shown. For the SS genotype, more oocytes (16.9 vs. 18.4) and MII (12.8 vs. 15.5) were yielded in the HP-FSH cycle. For the NS genotype, more oocyte (20.1 vs. 16.9) and MII (17.4 vs. 14.2) were yielded in the rFSH cycle. For the NN genotype, no differences were found. No differences were found when we compared the cycles in groups 2 and 3 irrespective of the FSHR polymorphism. CONCLUSION: For the first time, we have shown in a population of egg donors that the N680S FSHR gene polymorphism affects the efficacy of HP-FSH or rFSH. The FSHR genotype is an important factor to determine the dosage and the nature of the gonadotropin selected for ovarian stimulation. PMID- 26959718 TI - Rectified Proton Grotthuss Conduction Across a Long Water-Wire in the Test Nanotube of the Polytheonamide B Channel. AB - A hydrogen-bonded water-chain in a nanotube is highly proton conductive, and examining the proton flux under electric fields is crucial to understanding the one-dimensional Grotthuss conduction. Here, we exploited a nanotube-forming natural product, the peptide polytheonamide B (pTB), to examine proton conduction mechanisms at a single-molecule level. The pTB nanotube has a length of ~40 A that spans the membrane and a uniform inner diameter of 4 A that holds a single file water-chain. Single-channel proton currents were measured using planar lipid bilayers in various proton concentrations and membrane potentials (+/-400 mV). We found, surprisingly, that the current-voltage curves were asymmetric with symmetric proton concentrations in both solutions across the membrane (rectification). The proton flux from the C-terminal to the N-terminal end was 1.6 times higher than that from the opposite. At lower proton concentrations, the degree of rectification was attenuated, but with the addition of a pH-buffer (dichloroacetate) that supplies protons near the entrance, the rectification emerged. These results indicate that the permeation processes inside the pore generate the rectification, which is masked at low concentrations by the diffusion-limited access of protons to the pore entrance. The permeation processes were characterized by a discrete-state Markov model, in which hops of a proton followed by water-chain turnovers were implemented. The optimized model revealed that the water-chain turnover exhibited unusual voltage dependence, and the distinct voltage-dependencies of the forward and backward transition rates yielded the rectification. The pTB nanotube serves as a rectified proton conductor, and the design principles can be exploited for proton-conducting materials. PMID- 26959717 TI - HLA-DRB1*16: 01-DQB1*05: 02 is a novel genetic risk factor for flupirtine-induced liver injury. AB - OBJECTIVE: Flupirtine is a nonopioid analgesic with regulatory approval in a number of European countries. Because of the risk of serious liver injury, its use is now limited to short-term pain management. We aimed to identify genetic risk factors for flupirtine-related drug-induced liver injury (DILI) as these are unknown. MATERIALS AND METHODS: Six flupirtine-related DILI patients from Germany were included in a genome-wide association study (GWAS) involving a further 614 European cases of DILI because of other drugs and 10,588 population controls. DILI was diagnosed by causality assessment and expert review. Human leucocyte antigen (HLA) and single nucleotide polymorphism genotypes were imputed from the GWAS data, with direct HLA typing performed on selected cases to validate HLA predictions. Four replication cases that were unavailable for the GWAS were genotyped by direct HLA typing, yielding an overall total of 10 flupirtine DILI cases. RESULTS: In the six flupirtine DILI cases included in the GWAS, we found a significant enrichment of the DRB1*16:01-DQB1*05:02 haplotype compared with the controls (minor allele frequency cases 0.25 and minor allele frequency controls 0.013; P=1.4 * 10(-5)). We estimated an odds ratio for haplotype carriers of 18.7 (95% confidence interval 2.5-140.5, P=0.002) using population-specific HLA control data. The result was replicated in four additional cases, also with a haplotype frequency of 0.25. In the combined cohort (six GWAS plus four replication cases), the haplotype was also significant (odds ratio 18.7, 95% confidence interval 4.31-81.42, P=6.7 * 10(-5)). CONCLUSION: We identified a novel HLA class II association for DILI, confirming the important contribution of HLA genotype towards the risk of DILI generally. PMID- 26959719 TI - Ethyl Nitroacetate in Aza-Henry Addition on Trifluoromethyl Aldimines: A Solvent Free Procedure To Obtain Chiral Trifluoromethyl alpha,beta-Diamino Esters. AB - A self-catalyzed aza-Henry addition of ethyl nitroacetate on N-alkyl trifluoromethyl aldimines was reported to synthesize beta-amino alpha-nitro trifluoromethyl esters, precursors of alpha,beta-diamino acid derivatives. In the presence of a resident chiral center on the imine nitrogen, the use of a suitable Lewis acid leads to a good stereofacial control, always resulting from a nucleophilic unlike attack. By starting from optically pure N-protected trifluoromethyl aldimines or directly from N-alpha-amino ester trifluoromethyl aldimines, small psi[CH(CF3)NH]-peptidomimetic backbones can be achieved in which a new primary amine function represents a possible center for synthetic extension. Finally, a very interesting, and never observed before, palladium catalyzed syn beta-elimination occurred, leading to the selective nitro group reduction reaction on the syn-alpha-amino ester functionalized aza-Henry adducts and obtaining more stable optically pure trifluoromethyl conjugated imines. PMID- 26959716 TI - Dietary intake alters gene expression in colon tissue: possible underlying mechanism for the influence of diet on disease. AB - BACKGROUND: Although the association between diet and disease is well documented, the biologic mechanisms involved have not been entirely elucidated. In this study, we evaluate how dietary intake influences gene expression to better understand the underlying mechanisms through which diet operates. METHODS: We used data from 144 individuals who had comprehensive dietary intake and gene expression data from RNAseq using normal colonic mucosa. Using the DESeq2 statistical package, we identified genes that showed statistically significant differences in expression between individuals in high-intake and low-intake categories for several dietary variables of interest adjusting for age and sex. We examined total calories, total fats, vegetable protein, animal protein, carbohydrates, trans-fatty acids, mutagen index, red meat, processed meat, whole grains, vegetables, fruits, fiber, folate, dairy products, calcium, and prudent and western dietary patterns. RESULTS: Using a false discovery rate of less than 0.1, meat-related foods were statistically associated with 68 dysregulated genes, calcium with three dysregulated genes, folate with four dysregulated genes, and nonmeat-related foods with 65 dysregulated genes. With a more stringent false discovery rate of less than 0.05, there were nine meat-related dysregulated genes and 23 nonmeat-related genes. Ingenuity pathway analysis identified three major networks among genes identified as dysregulated with respect to meat-related dietary variables and three networks among genes identified as dysregulated with respect to nonmeat-related variables. The top networks (Ingenuity Pathway Analysis network score >30) associated with meat-related genes were (i) cancer, organismal injury, and abnormalities, tumor morphology, and (ii) cellular function and maintenance, cellular movement, cell death, and survival. Among genes related to nonmeat consumption variables, the top networks were (i) hematological system development and function, nervous system development and function, tissue morphology and (ii) connective tissue disorders, organismal injury, and abnormalities. CONCLUSION: Several dietary factors were associated with gene expression in our data. These findings provide insight into the possible mechanisms by which diet may influence disease processes. PMID- 26959720 TI - Evidence for horizontal transfer of a recently active Academ transposon. AB - Horizontal transfer (HT), the exchange of genetic material between species, plays important roles in transposon biology and genome evolution. In this study, we provide the first documented example of a new Academ transposon involved in recent and distant HTs into the genomes of species belonging to seven different orders of insects: Lepidoptera, Hymenoptera, Neuroptera, Embioptera, Dermaptera, Trichoptera and Zoraptera. These results suggest that HT of DNA transposons amongst insects has occurred on a broader scale than previously appreciated. The Academ transposon discovered in the Lepidoptera and parasitic wasps is of particular interest because the intimate association between wasps and their lepidopteran hosts might provide an opportunity for HT of transposons. PMID- 26959721 TI - Funnel-freezing versus heat-stabilization for the visualization of metabolites by mass spectrometry imaging in a mouse stroke model. AB - Tissue preparation is the key to a successful matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) experiment. Rapid post-mortem changes contribute a significant challenge to the use of MSI approaches for the analysis of peptides and metabolites. In this technical note we aimed to compare the tissue fixation method ex-vivo heat-stabilization with in situ funnel-freezing in a middle cerebral artery occlusion (MCAo) mouse model of stroke, which causes profound alterations in metabolite concentrations. The influence of the duration of the thaw-mounting of the tissue sections on metabolite stability was also determined. We demonstrate improved stability and biomolecule visualization when funnel-freezing was used to sacrifice the mouse compared with heat-stabilization. Results were further improved when funnel freezing was combined with fast thaw-mounting of the brain sections. PMID- 26959722 TI - Reciprocal Influences of Drinking Motives on Alcohol Use and Related Consequences: A Full Cross-Lagged Panel Study Among Young Adult Men. AB - Using a full cross-lagged model, this study investigates the extent to which drinking motives predict alcohol use and related consequences, and vice versa. At baseline and 15 months later, 4575 men (mean age = 19.4 years) in Switzerland completed a questionnaire assessing drinking motives, average weekly consumption, risky single-occasion drinking, and alcohol-related consequences. Results indicated that social and enhancement motives more strongly influenced alcohol use over time than the other way round. Coping motives predicted an increase in alcohol-related consequences, and vice versa. Higher social motives predicted an increase in coping motives while higher coping motives predicted a decrease in enhancement motives. These results suggest that social and enhancement motives amplify each other in early adulthood and predict increases in risky drinking. Structural measures aimed at reducing opportunities to engage in heavy drinking are recommended. Additionally, the detection of young adult men vulnerable to maladaptive coping behaviors appears important for alcohol prevention strategies. PMID- 26959723 TI - Correlates of partner and family violence among older Canadians: a life-course approach. AB - INTRODUCTION: Knowledge about individual and interpersonal correlates of violence in Canadian seniors is limited. This study identifies correlates of current and past violence by intimate partner and family member(s) in community-dwelling Canadian seniors, while accounting for childhood adverse circumstances. METHODS: We performed logistic regression analysis of baseline data from a longitudinal study of community-dwelling individuals aged 65 to 74 years and living in Kingston (Ontario) and Saint-Hyacinthe (Quebec). Domestic violence was assessed using the Hurt- Insult-Threaten-Scream (HITS) screening tool. Odds ratios (ORs) are reported with 95% confidence intervals (CIs). RESULTS: Current violence of a psychological nature was reported by 18% of the sample. Women were at greater risk of current and lifetime violence perpetrated by a family member (current violence: adjusted OR = 1.83; 95% CI: 1.02-3.30) as well as experiencing violence from their intimate partner in their lifetime than were men (adjusted OR = 2.48; 95% CI: 1.40-4.37). Risk factors have accumulated over the life course that were found to be consistently associated with both current and lifetime violence included having witnessed violence at home in childhood (lifetime violence by family member: adjusted OR = 9.46; 95% CI: 5.11-17.52), as well as poor quality of relationships with intimate partners, family and friends. CONCLUSION: Our research documents the ongoing impact of early adversity on subsequent partner and family violence in Canada. Findings identify some preventable factors associated with current psychological violence and past violence among community dwelling Canadian seniors. PMID- 26959725 TI - Metabolism of Hydrocarbons in n-Alkane-Utilizing Anaerobic Bacteria. AB - The glycyl radical enzyme-catalyzed addition of n-alkanes to fumarate creates a C C-bond between two concomitantly formed stereogenic carbon centers. The configurations of the two diastereoisomers of the product resulting from n-hexane activation by the n-alkane-utilizing denitrifying bacterium strain HxN1, i.e. (1 methylpentyl)succinate, were assigned as (2S,1'R) and (2R,1'R). Experiments with stereospecifically deuterated n-(2,5-2H2)hexanes revealed that exclusively the pro-S hydrogen atom is abstracted from C2 of the n-alkane by the enzyme and later transferred back to C3 of the alkylsuccinate formed. These results indicate that the alkylsuccinate-forming reaction proceeds with an inversion of configuration at the carbon atom (C2) of the n-alkane forming the new C-C-bond, and thus stereochemically resembles a SN2-type reaction. Therefore, the reaction may occur in a concerted manner, which may avoid the highly energetic hex-2-yl radical as an intermediate. The reaction is associated with a significant primary kinetic isotope effect (kH/kD >=3) for hydrogen, indicating that the homolytic C-H-bond cleavage is involved in the first irreversible step of the reaction mechanism. The (1-methylalkyl)succinate synthases of n-alkane-utilizing anaerobic bacteria apparently have very broad substrate ranges enabling them to activate not only aliphatic but also alkyl-aromatic hydrocarbons. Thus, two denitrifiers and one sulfate reducer were shown to convert the nongrowth substrate toluene to benzylsuccinate and further to the dead-end product benzoyl-CoA. For this purpose, however, the modified beta-oxidation pathway known from alkylbenzene utilizing bacteria was not employed, but rather the pathway used for n-alkane degradation involving CoA ligation, carbon skeleton rearrangement and decarboxylation. Furthermore, various n-alkane- and alkylbenzene-utilizing denitrifiers and sulfate reducers were found to be capable of forming benzyl alcohols from diverse alkylbenzenes, putatively via dehydrogenases. The thermophilic sulfate reducer strain TD3 forms n-alkylsuccinates during growth with n-alkanes or crude oil, which, based on the observed patterns of homologs, do not derive from a terminal activation of n-alkanes. PMID- 26959724 TI - Estimating the completeness of physician billing claims for diabetes case ascertainment using population-based prescription drug data. AB - INTRODUCTION: Changes in physician reimbursement policies may hinder the collection of billing claims in administrative data; this can result in biased estimates of disease prevalence and incidence. However, the magnitude of data loss is largely unknown. The purpose of this study was to estimate completeness of capture of disease cases for Manitoba physicians paid by fee-for-service (FFS) and non-fee-for-service (NFFS) methods. METHODS: Manitoba's administrative data were used to identify a cohort (>= 20 years) with a new diabetes medication between 1 April, 2007, and 31 March, 2009. Cohort members were classified by payment method of the prescribing physician (i.e. FFS vs. NFFS). The cohort was then classified as missing or not missing a diabetes diagnosis using physician claims and hospital records. Then, chi2 statistics were used to test for differences in the characteristics of the two groups. RESULTS: The cohort consisted of 12 394 individuals; 86.4% had a prescription for a diabetes medication from an FFS physician. A total of 1172 physicians (81.8% FFS) prescribed these medications for the cohort. Cohort members with a prescription from an FFS physician were older and more likely to reside in the urban Winnipeg health region than those with a prescription from a NFFS physician. A greater percentage of NFFS physicians' cases were missing a diabetes diagnosis (18.7%vs. 14.9% for FFS physicians). CONCLUSION: The results suggest minimal loss of physician claims associated with remuneration policies in Manitoba. This method of assessing data completeness could be applied to other chronic diseases and jurisdictions to estimate completeness. PMID- 26959727 TI - Current aortic endografts for the treatment of abdominal aortic aneurysms. AB - Endovascular Aneurysm Repair is a widely adopted method of treatment for patients with abdominal aortic aneurysms. The minimally invasive approach offered with EVAR has become popular not only among physicians and patients, but in the medical device industry as well. Over the past 25 years the global market for aortic endografts has increased rapidly, resulting in a wide range of devices from various companies. Currently, there are seven endografts approved by the FDA for the treatment of abdominal aortic aneurysms. These devices offer a wide range of designs intended to increase inclusion criteria while decreasing technical complications such as endoleak and migration. Despite advances in device design, secondary interventions and follow-up requirements remain a significant issue. New devices are currently being studied in the U.S. and abroad and may significantly reduce complications and secondary interventions. PMID- 26959726 TI - LC-MS/MS of permethylated N-glycans derived from model and human blood serum glycoproteins. AB - LC-MS/MS is one of the most powerful tools for N-glycan structure elucidation; however, it is still challenging to identify some glycan structures with low abundance. In this study, we investigated the chromatographic behavior of permethylated N-glycans. The relationship between retention times versus molecular weight of dextran, dextrin, and model glycans was investigated. Also, the nonpolar surface area of glycans was calculated and compared to their experimental retention times. Both retention time and nonpolar surface area trends are similar when the intermolecular interaction is included in the calculation. Moreover, retention time corresponds to glycan types and branch types. The N-glycans analysis model, which combines high mass accuracy and retention time, was applied to confirm serum N-glycans. In total, there were 78 N glycan compositions identified. A linear relationship between retention times and molecular weights were observed for each subgroup of glycan structures, for example, R(2) value for complex N-glycans was determined to be > 0.98. Moreover, the retention time could be further applied to distinguish between structural isomers as well as linkage isomers. MS/MS data were used to confirm the structural isomers. PMID- 26959728 TI - Pigtail catheter "propping" for MitraClip percutaneous transcatheter mitral valve repair. AB - In recent years percutaneous therapy has emerged as a feasible and effective option for the treatment of mitral regurgitation, particularly in cases where the risks of conventional cardiac surgery are prohibitively high. To date the most widely used percutaneous approach is beating heart, edge-to-edge repair with the MitraClip device (Abbott Vascular-Structural Heart, Menlo Park, CA). The technique requires simultaneous grasping and approximation of both mitral valve leaflets prior to securing and releasing the clip. However, this may be technically challenging or indeed impossible in patients with failure of coaptation, particularly when there is a large coaptation gap. We present an approach for overcoming this relatively common obstacle based on "propping" the anterior mitral valve leaflet toward its posterior counterpart with a diagnostic pigtail catheter to reduce the coaptation gap and to allow grasping of both leaflets without difficulty. (c) 2016 Wiley Periodicals, Inc. PMID- 26959729 TI - Fermentative Cyclohexane Carboxylate Formation in Syntrophus aciditrophicus. AB - Short-chain fatty acids such as acetic, propionic, butyric or lactic acids are typical primary fermentation products in the anaerobic feeding chain. Fifteen years ago, a novel fermentation type was discovered in the obligately anaerobic Deltaproteobacterium Syntrophus aciditrophicus. During fermentative growth with crotonate and/or benzoate, acetate is formed in the oxidative branch and cyclohexane carboxylate in the reductive branch. In both cases cyclohexa-1,5 diene-1-carboxyl-CoA (Ch1,5CoA) is a central intermediate that is either formed by a class II benzoyl-CoA reductase (fermentation of benzoate) or by reverse reactions of the benzoyl-CoA degradation pathway (fermentation of crotonate). Here, we summarize the current knowledge of the enzymology involved in fermentations yielding cyclohexane carboxylate as an excreted product. The characteristic enzymes involved are two acyl-CoA dehydrogenases specifically acting on Ch1,5CoA and cyclohex-1-ene-1-carboxyl-CoA. Both enzymes are also employed during the syntrophic growth of S. aciditrophicus with cyclohexane carboxylate as the carbon source in coculture with a methanogen. An investigation of anabolic pathways in S. aciditrophicus revealed a rather unusual pathway for glutamate synthesis involving a Re-citrate synthase. Future work has to address the unresolved question concerning which components are involved in reoxidation of the NADH formed in the oxidative branch of the unique cyclohexane carboxylate fermentation pathway in S. aciditrophicus. PMID- 26959730 TI - [Rules and regulations threaten non-pharmacological studies in children]. AB - Many non-pharmacological interventions have only been tested in adults, and evidence on using these in children is lacking. To enhance child healthcare, research is required into these interventions in children. However, current rules and regulations make it difficult to conduct research into these low-risk, minimal-burden interventions. We describe the current rules and regulations on conducting research in children in the Netherlands and discuss the possibilities for adapting certain rules in accordance with the type of research that is performed. PMID- 26959731 TI - [Anorectal symptoms after prostate radiotherapy]. AB - Prostate cancer is the most common cancer in Dutch men and has a relatively good survival rate. Anorectal symptoms after irradiation of the prostate, including rectal blood loss and faecal incontinence, can have a serious impact on quality of life. On endoscopy, the Vienna Rectoscopy Score may reveal telangiectasia or other mucosal changes, but there may also be other causes of blood loss. Endoscopy or watchful waiting can be considered in patients with rectal bleeding. Sucralfate enemas, argon plasma coagulation and hyperbaric oxygen therapy are effective treatments. Increase in frequency of defaecation, faecal urgency or incontinence are related to decreased rectal compliance or to lowered anal resting pressure. Dietary measures can be considered in patients with faecal urgency or incontinence, but scientific evidence for the effectiveness of this is marginal. More accurate radiation techniques and the use of a spacer or endorectal balloon will probably contribute to maintaining rectal and anal function. PMID- 26959732 TI - [Cognitive deterioration following intracranial haemorrhage: predominantly dependent on cognitive health before the event]. AB - Strokes are associated with an increased risk of cognitive dysfunction and dementia, but little is known about the effect of intracranial haemorrhage on cognitive deterioration. The paper discussed here evaluated 167 patients with an intracranial haemorrhage and with several mini-mental state examination (MMSE) measurements over time, starting 6 months after the index event. Only those risk factors already present before the haemorrhage, such as pre-existing cognitive dysfunction and cortical atrophy on MRI, were associated with more severe cognitive deterioration. This suggests that cognitive deterioration is independent of intracranial haemorrhage; however, there are several caveats. The lack of a control group and lack of cognitive data before the haemorrhage limit the number of conclusions that can be drawn. Whether it has an isolated or a neurodegenerative effect on cognition or not, a stroke is always best prevented. As strokes and dementia have considerable overlap in risk factors, prevention is the key. PMID- 26959733 TI - [Dieffenbachia poisoning in an infant]. AB - BACKGROUND: Plant poisoning is becoming an increasingly common reason to consult a doctor. CASE DESCRIPTION: A 7-month-old infant was sent to the emergency room by her general practitioner with a suspected apparent life-threatening event (ALTE). Her parents reported the sudden development of fluctuating restlessness and listlessness, superficial breathing, vomiting, drowsiness and episodes of loss of consciousness. On physical examination we saw a pale, listless and variably responsive girl. During admission for observation, she improved within a few hours, although she had one episode of blood admixture with the stool. After discharge from hospital, the infant's grandmother suggested that the symptoms could be due to poisoning from a Dieffenbachia plant. The literature supports this explanation. CONCLUSION: Young parents and doctors appear to know little about plant toxicity in general and Dieffenbachia in particular. In small children with poorly-understood symptoms, the possibility plant poisoning should be considered. PMID- 26959734 TI - [A woman with a locked knee]. AB - A 25-year-old female presented with locking of the left knee after an assertiveness training. The MRI scan showed a bucket-handle tear of the medial meniscus. The medial meniscus was dislocated into the intercondylar fossa, in which the image of a second posterior cruciate ligament (PCL) was simulated. This is also called a 'double PCL sign'. PMID- 26959735 TI - [Active career management needed for female doctors]. AB - For more than 15 years two-thirds of medical students have been women. Despite this, they represent a minority (16-25 %) of professors in academic medicine. There is still a major gender gap to the disadvantage of women in leading positions in academia, with women earning only 80% of the salary of their male counterparts and fewer opportunities for scientific grants. Recent studies have shown that career ambition among men and women in medicine is comparable. However, successful women more often doubt their own achievements than men do. This is known as the 'imposter phenomenon' and acts as a barrier to career progression. Female leadership should be more actively promoted and encouraged to establish the diversity and creativity that we need in our current healthcare system. PMID- 26959736 TI - [Primary care patients hastening death by voluntarily stopping eating and drinking]. AB - PURPOSE: Little is known about the role family physicians play when a patient deliberately hastens death by voluntarily stopping eating and drinking (VSED). The purpose of this study was to gain more insight for family physicians when confronted with patients who wish to hasten death by VSED. We aimed to describe physicians' involvement in VSED, to describe characteristics and motives of their patients, and to describe the process of VSED in terms of duration, as well as common symptoms in the last 3 days of life. METHOD: We undertook a survey of a random national sample of 1,100 family physicians (response rate 72%), and 500 of these physicians received questions about their last patient who hastened death by VSED. RESULTS: Of the 978 eligible physicians, 708 responded (72.4%); 46% had cared for a patient who hastened death by VSED. Of the 500 physicians who received the additional questions, 440 were eligible and 285 (64.8%) responded; they described 99 cases of VSED. Seventy percent of these patients were aged older than 80 years, 76% had severe disease (27% with cancer), and 77% were dependent on others for everyday care. Frequent reasons for the patients' death wish were somatic (79%), existential (77%), and dependence (58%). Median time until death was 7 days, and the most common symptoms before death were pain, fatigue, impaired cognitive functioning, and thirst or dry throat. Family physicians were involved in 62% of cases. CONCLUSION: Patients who hasten death by VSED are mostly in poor health. It is not unlikely for family physicians to be confronted with VSED. They can play an important role in caring for these patients and their proxies by informing them of VSED and by providing support and symptom management during VSED. PMID- 26959737 TI - MiR-26a and miR-144 inhibit proliferation and metastasis of esophageal squamous cell cancer by inhibiting cyclooxygenase-2. AB - The altered expression of miRNAs is involved in carcinogenesis of esophageal squamous cell carcinoma (ESCC), but whether miRNAs regulate COX-2 expression in ESCC is not clear. To this end, the expression levels of miR-26a and miR-144 in ESCC clinical tissues and cell lines were investigated by qRT-PCR. COX-2 and PEG2 were quantified by western blot and ELISA. Decrease in miR-26a and miR-144 expression in ESCC was found by a comparison between 30 pairs of ESCC tumor and adjacent normal tissues as well as in 11 ESCC cell lines (P < 0.001). Co transfection of miR-26a and miR-144 in ESCC cell lines more significantly suppressed cell proliferation, migration, and invasion than did either miR-26a or miR-144 alone (all P < 0.001), as shown by assays of CCK8, migration and invasion and flow cytometry. The inhibitory effect of these two miRNAs in vivo was also verified in nude mice xenograft models. COX-2 was confirmed as a target of miR 26a and miR-144. In conclusion, miR-26a and miR-144 expression is downregulated in ESCC. Co-expression of miR-26a and miR-144 in ESCC cells resulted in inhibition of proliferation and metastasis in vitro and in vivo, suggesting that targeting COX-2 may be the mechanism of these two miRNAs. PMID- 26959738 TI - Cholesterol consumption and risk of endometrial cancer: a systematic review and dose-response meta-analysis of observational studies. AB - In vivo and in vitro studies have indicated the link of cholesterol consumption and endometrial cancer risk, however, previous observational studies have yielded inconsistent results. Additionally, a previous meta-analysis published in 2007 found limited evidence of aforementioned association. Therefore, we performed the dose-response meta-analysis to address this concern. Studies were identified using the PubMed, EMBASE and Web of Science databases from the database inception to the end of June 2015 as well as by examining the references of retrieved articles. Two authors independently performed the eligibility evaluation and data extraction. The summary risk estimates and 95% confidence intervals (CIs) were summarized by the random-effects models. One cohort and nine case-control studies were included in the dose-response analyses. Risk of endometrial cancer increased by 6% for 100 mg/day increment in the dietary consumption of cholesterol (Odds ratio (OR) = 1.06; 95% CI = 1.00-1.12), with significant heterogeneity (I2 = 64.2, P = 0.003). When stratified by study design, the result was significant in case-control studies (OR = 1.07; 95% CI = 1.01-1.13). Additionally, although the direction of the associations were consistent in the subgroup analyses stratified by study characteristics and adjustment for potential confounders, not all of them showed statistical significance. In summary, findings of the present dose response meta-analysis partly support the positive association between dietary cholesterol consumption and risk of endometrial cancer. Since only one cohort study was included, more prospective studies and pooled analysis of observational studies are warranted to confirm our findings in the future. PMID- 26959739 TI - Androgen receptor in Sertoli cells regulates DNA double-strand break repair and chromosomal synapsis of spermatocytes partially through intercellular EGF-EGFR signaling. AB - Spermatogenesis does not progress beyond the pachytene stages of meiosis in Sertoli cell-specific AR knockout (SCARKO) mice. However, further evidence of meiotic arrest and underlying paracrine signals in SCARKO testes is still lacking. We utilized co-immunostaining of meiotic surface spreads to examine the key events during meiotic prophase I. SCARKO spermatocytes exhibited a failure in chromosomal synapsis observed by SCP1/SCP3 double-staining and CREST foci quantification. In addition, DNA double-strand breaks (DSBs) were formed but were not repaired in the mutant spermatocytes, as revealed by gamma-H2AX staining and DNA-dependent protein kinase (DNA-PK) activity examination. The later stages of DSB repair, such as the accumulation of the RAD51 strand exchange protein and the localization of mismatch repair protein MLH1, were correspondingly altered in SCARKO spermatocytes. Notably, the expression of factors that guide RAD51 loading onto sites of DSBs, including TEX15, BRCA1/2 and PALB2, was severely impaired when either AR was down-regulated or EGF was up-regulated. We observed that some ligands in the epidermal growth factor (EGF) family were over-expressed in SCARKO Sertoli cells and that some receptors in the EGF receptor (EGFR) family were ectopically activated in the mutant spermatocytes. When EGF-EGFR signaling was repressed to approximately normal by the specific inhibitor AG1478 in the cultured SCARKO testis tissues, the arrested meiosis was partially rescued, and functional haploid cells were generated. Based on these data, we propose that AR in Sertoli cells regulates DSB repair and chromosomal synapsis of spermatocytes partially through proper intercellular EGF-EGFR signaling. PMID- 26959740 TI - A single-nucleotide polymorphism in the 3'-UTR region of the adipocyte fatty acid binding protein 4 gene is associated with prognosis of triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor prognosis and high heterogeneity. The aim of this study was to screen patients for single-nucleotide polymorphisms (SNPs) associated with the prognosis of TNBC. Database-derived SNPs (NextBio, Ensembl, NCBI and MirSNP) located in the 3' untranslated regions (3'-UTRs) of genes that are differentially expressed in breast cancer were selected. The possible associations between 111 SNPs and progression risk among 323 TNBC patients were investigated using a two-step case control study with a discovery cohort (n=162) and a validation cohort (n=161). We identified the rs1054135 SNP in the adipocyte fatty acid binding protein 4 (FABP4) gene as a predictor of TNBC recurrence. The G allele of rs1054135 was associated with a reduced risk of disease progression as well as a prolonged disease-free survival time (DFS), with a hazard ratio (HR) for recurrence in the combined sample of 0.269 [95%CI: 0.098-0.735;P=0.001]. Notably, for individuals having the rs1054135 SNP with the AA/AG genotype, the magnitude of increased tumour recurrence risk for overweight patients (BMI>=25kg/m2) was significantly elevated (HR2.53; 95%CI: 1.06-6.03). Immunohistochemical staining of adipocytes adjacent to TNBC tissues showed that the expression level of FABP4 was statistically significantly lower in patients with the rs1054135-GG genotype and those in the disease-free group (P=0.0004 and P=0.0091, respectively). These results suggested that the expression of a lipid metabolism-related gene and an important SNP in the 3'-UTR of FABP4 are associated with TNBC prognosis, which may aid in the screening of high-risk patients with TNBC recurrence and the development of novel chemotherapeutic agents. PMID- 26959741 TI - SH2 domain-containing phosphatase 1 regulates pyruvate kinase M2 in hepatocellular carcinoma. AB - Pyruvate kinase M2 (PKM2) is known to promote tumourigenesis through dimer formation of p-PKM2Y105. Here, we investigated whether SH2-containing protein tyrosine phosphatase 1 (SHP-1) decreases p-PKM2Y105 expression and, thus, determines the sensitivity of sorafenib through inhibiting the nuclear-related function of PKM2. Immunoprecipitation and immunoblot confirmed the effect of SHP 1 on PKM2Y105 dephosphorylation. Lactate production was assayed in cells and tumor samples to determine whether sorafenib reversed the Warburg effect. Clinical hepatocellular carcinoma (HCC) tumor samples were assessed for PKM2 expression. SHP-1 directly dephosphorylated PKM2 at Y105 and further decreased the proliferative activity of PKM2; similar effects were found in sorafenib treated HCC cells. PKM2 was also found to determine the sensitivity of targeted drugs, such as sorafenib, brivanib, and sunitinib, by SHP-1 activation. Significant sphere-forming activity was found in HCC cells stably expressing PKM2. Clinical findings suggest that PKM2 acts as a predicting factor of early recurrence in patients with HCC, particularly those without known risk factors (63.6%). SHP-1 dephosphorylates PKM2 at Y105 to inhibit nuclear function of PKM2 and determines the efficacy of targeted drugs. Targeting PKM2 by SHP-1 might provide new therapeutic insights for patients with HCC. PMID- 26959743 TI - Intravenous administration of the selective toll-like receptor 7 agonist DSR 29133 leads to anti-tumor efficacy in murine solid tumor models which can be potentiated by combination with fractionated radiotherapy. AB - Strategies to augment anti-cancer immune responses have recently demonstrated therapeutic utility. To date clinical success has been achieved through targeting co-inhibitory checkpoints such as CTLA-4, PD-1, and PD-L1. However, approaches that target co-activatory pathways are also being actively being developed. Here we report that the novel TLR7-selective agonist DSR-29133 is well tolerated in mice and leads to acute immune activation. Administration of DSR-29133 leads to the induction of IFNalpha/gamma, IP-10, TNFalpha, IL-1Ra and IL-12p70, and to a reduction in tumor burden in syngeneic models of renal cancer (Renca), metastatic osteosarcoma (LM8) and colorectal cancer (CT26). Moreover, we show that the efficacy of DSR-29133 was significantly improved when administered in combination with low-dose fractionated radiotherapy (RT). Effective combination therapy required weekly administration of DSR-29133 commencing on day 1 of a fractionated RT treatment cycle, whereas no enhancement of radiation response was observed when DSR-29133 was administered at the end of the fractionated RT cycle. Combined therapy resulted in curative responses in a high proportion of mice bearing established CT26 tumors which was dependent on the activity of CD8+ T-cells but independent of CD4+ T-cells and NK/NKT cells. Moreover, long-term surviving mice originally treated with DSR-29133 and RT were protected by a tumor-specific memory immune response which could prevent tumor growth upon rechallenge. These results demonstrate that DSR-29133 is a potent selective TLR7 agonist that when administered intravenously can induce anti-tumor immune responses that can be further enhanced through combination with low-dose fractionated RT. PMID- 26959742 TI - Key roles of necroptotic factors in promoting tumor growth. AB - Necroptotic factors are generally assumed to play a positive role in tumor therapy by eliminating damaged tumor cells. Here we show that, contrary to expectation, necroptotic factors RIPK1, RIPK3, and MLKL promote tumor growth. We demonstrate that genetic knockout of necroptotic genes RIPK1, RIPK3, or MLKL in cancer cells significantly attenuated their abilities to grow in an anchorage independent manner. In addition, they exhibited significantly enhanced radiosensitivity. The knockout cells also showed greatly reduced ability to form tumors in mice. Moreover, necrosulfonamide (NSA), a previously identified chemical inhibitor of necroptosis, could significantly delay tumor growth in a xenograft model. Mechanistically, we show that necroptoic factors play a significant role in maintaining the activity of NF-kappaB. Finally, we found that high levels of phosphorylated MLKL in human esophageal and colon cancers are associated with poor overall survival. Taken together, we conclude that pro necroptic factors such as RIPK1, RIPK3, and MLKL may play a role in supporting tumor growth, and MLKL may be a promising target for cancer treatment. PMID- 26959744 TI - Combination of metronomic cyclophosphamide and dietary intervention inhibits neuroblastoma growth in a CD1-nu mouse model. AB - BACKGROUND: MYCN-amplification in high-grade Neuroblastoma (NB) tumors correlates with increased vascularization and therapy resistance. This study combines an anti-angiogenic approach with targeting NB metabolism for treatment. METHODS AND RESULTS: Metronomic cyclophosphamide (MCP) monotherapy significantly inhibited NB growth and prolonged host survival. Growth inhibition was more pronounced in MYCN amplified xenografts. Immunohistochemical evaluation of this subtype showed significant decrease in blood vessel density and intratumoral hemorrhage accompanied by blood vessel maturation and perivascular fibrosis. Up-regulation of VEGFA was not sufficient to compensate for the effects of the MCP regimen. Reduced Bcl-2 expression and increased caspase-3 cleavage were evident. In contrast non MYCN-amplified tumors developed resistance, which was accompanied by Bcl-2-up-regulation. Combining MCP with a ketogenic diet and/or calorie restriction significantly enhanced the anti-tumor effect. Calorie-restricted ketogenic diet in combination with MCP resulted in tumor regression in all cases. CONCLUSIONS: Our data show efficacy of combining an anti-angiogenic cyclophosphamide dosing regimen with dietary intervention in a preclinical NB model. These findings might open a new front in NB treatment. PMID- 26959745 TI - The survival benefit and safety of No. 12a lymphadenectomy for gastric cancer patients with distal or total gastrectomy. AB - There has still not been a consensus in aspects of survival benefit and safety on No.12a lymph nodes (LNs) dissection for gastric cancer patients. This study was aimed to evaluate this issue for patients with distal or total gastrectomy. Patients were retrospectively divided into 12aD+ group (with No.12a dissection) and 12aD-group (without No.12a dissection). Clinicopathologic characteristics, survival rate, morbidity and mortality were compared. There were 670 patients in 12aD+ group, while 567 in 12aD-group. The baselines between the two groups were comparable. The No.12a LNs metastasis ratio was 11.6% and higher in lower third tumor. The metastasis of No.5 LNs, N stage and M stage were correlated to metastasis of No.12a LNs. There was no difference in morbidity nor mortality between the two groups. The 5-year overall survival rates (5-y OS) were 59.6% and 55.1% in 12aD+ group and 12aD-group respectively (P = 0.075). The 5-y OS of patients with negative and positive No.12a LNs were 62.3% and 24.1%. The survival of stage III patients with No.12a positive was better than that of stage IV patients. The 5-y OS were better in 12aD+ group for patients with ages more than 60, lower third tumor, distal gastrectomy, N3 status, or III stages compared with 12aD-group. No.12a lymphadenectomy was independently better prognostic factors for stage III patients. No.12a LNs metastasis should not be considered as distant metastasis. No.12a lymphadenectomy can be performed safely and should be indicated for potentially curable progressive stage tumors requiring distal gastrectomy and might be reserved in patients with stage I or II, or upper third tumor. PMID- 26959746 TI - Therapy of pancreatic cancer via an EphA2 receptor-targeted delivery of gemcitabine. AB - First line treatment for pancreatic cancer consists of surgical resection, if possible, and a subsequent course of chemotherapy using the nucleoside analogue gemcitabine. In some patients, an active transport mechanism allows gemcitabine to enter efficiently into the tumor cells, resulting in a significant clinical benefit. However, in most patients, low expression of gemcitabine transporters limits the efficacy of the drug to marginal levels, and patients need frequent administration of the drug at high doses, significantly increasing systemic drug toxicity. In this article we focus on a novel targeted delivery approach for gemcitabine consisting of conjugating the drug with an EphA2 targeting agent. We show that the EphA2 receptor is highly expressed in pancreatic cancers, and accordingly, the drug-conjugate is more effective than gemcitabine alone in targeting pancreatic tumors. Our preliminary observations suggest that this approach may provide a general benefit to pancreatic cancer patients and offers a comprehensive strategy for enhancing delivery of diverse therapeutic agents to a wide range of cancers overexpressing EphA2, thereby potentially reducing toxicity while enhancing therapeutic efficacy. PMID- 26959747 TI - The paradigm-shifting idea and its practice: from traditional abortion Chinese medicine Murraya paniculata to safe and effective cancer metastatic chemopreventives. AB - Recent large epidemiological studies demonstrated benefit of oral contraceptives in reducing cancer risk, and our analysis also showed molecular and cellular similarities between embryo implantation and CTCs adhesion-invasion to endothelium. We here hypothesize that abortion traditional Chinese medicine (TCM) may serve well for pre-metastatic chemoprevention. To test the hypothesis, we selected the safe and well-known abortifacient TCM Murraya paniculata and identified a most-promising extracted fraction G (containing flavonoids and coumarins) from its many raw ethanol/dichloromethane extracts by using the bioactivity-guided fast screen assay. G showed free radical scavenging effect, and specifically inhibited both embryo implantation to human endometrial bed and cancer HT29 cells to human endothelium in a concentration-dependent manner (1-30 MUg/mL) without significant cytotoxicity demonstrated by its high adhesion inhibition ratio. The inhibition may result from its down-regulation on expression of integrin beta1 and alpha6, and CD44 on HT29 cells, as well as E selectin on endothelial cells. Furthermore, G inhibited invasion and migration of HT29 cells. Pretreatment followed by one-month oral administration of G to the immunocompetent mice inoculated with mouse melanoma cells produced significant inhibition on lung metastasis without marked side effects. Collectively, this paradigm-shifting study provides, for the first time, a new strategy to discover safe and effective pre-metastatic chemopreventives from abortion TCM. PMID- 26959751 TI - Introducing QMC/MMpol: Quantum Monte Carlo in Polarizable Force Fields for Excited States. AB - We present for the first time a quantum mechanics/molecular mechanics scheme which combines quantum Monte Carlo with the reaction field of classical polarizable dipoles (QMC/MMpol). In our approach, the optimal dipoles are self consistently generated at the variational Monte Carlo level and then used to include environmental effects in diffusion Monte Carlo. We investigate the performance of this hybrid model in describing the vertical excitation energies of prototypical small molecules solvated in water, namely, methylenecyclopropene and s-trans acrolein. Two polarization regimes are explored where either the dipoles are optimized with respect to the ground-state solute density (polGS) or different sets of dipoles are separately brought to equilibrium with the states involved in the electronic transition (polSS). By comparing with reference supermolecular calculations where both solute and solvent are treated quantum mechanically, we find that the inclusion of the response of the environment to the excitation of the solute leads to superior results than the use of a frozen environment (point charges or polGS), in particular, when the solute-solvent coupling is dominated by electrostatic effects which are well recovered in the polSS condition. QMC/MMpol represents therefore a robust scheme to treat important environmental effects beyond static point charges, combining the accuracy of QMC with the simplicity of a classical approach. PMID- 26959753 TI - Therapeutic Optimization as Part of the Precision Medicine Paradigm. PMID- 26959748 TI - Diagnostic FDG and FDOPA positron emission tomography scans distinguish the genomic type and treatment outcome of neuroblastoma. AB - Neuroblastoma (NB) is a heterogeneous childhood cancer that requires multiple imaging modalities for accurate staging and surveillances. This study aims to investigate the utility of positron emission tomography (PET) with 18F fluorodeoxyglucose (FDG) and 18F-fluoro-dihydroxyphenylalanine (FDOPA) in determining the prognosis of NB. During 2007-2014, forty-two NB patients (male:female, 28:14; median age, 2.0 years) undergoing paired FDG and FDOPA PET scans at diagnosis were evaluated for the maximum standardized uptake value (SUV(max)) of FDG or FDOPA by the primary tumor. Patients with older age, advanced stages, or MYCN amplification showed higher FDG and lower FDOPA SUV(max) (all P < 0.02). Receiver operating characteristics analysis identified FDG SUV(max) >= 3.31 and FDOPA SUV(max) < 4.12 as an ultra-high-risk feature (PET UHR) that distinguished the most unfavorable genomic types, i.e. segmental chromosomal alterations and/or MYCN amplification, at a sensitivity of 81.3% (54.4%-96.0%) and a specificity of 93.3% (68.1%-99.8%). Considering with age, stage, MYCN status, and anatomical image-defined risk factor, PET-UHR was an independent predictor of inferior event-free survival (multivariate hazard ratio, 4.9 [1.9-30.1]; P = 0.012). Meanwhile, the ratio between FDG and FDOPA SUV(max) (G:D) correlated positively with HK2 (Spearman's rho = 0.86, P < 0.0001) and negatively with DDC (rho = -0.58, P = 0.02) gene expression levels, which might suggest higher glycolytic activity and less catecholaminergic differentiation in NB tumors taking up higher FDG and lower FDOPA. In conclusion, the intensity of FDG and FDOPA uptake on diagnostic PET scans may predict the tumor behavior and complement the current risk stratification systems of NB. PMID- 26959755 TI - Career Profile. PMID- 26959756 TI - A framework for quantifying the influence of adherence and dose individualization. AB - A failure to accommodate for a patient's imperfect adherence may result in therapeutic failure. Similarly, failure to accommodate a patient's individual needs via dose individualization may also result in poor patient outcomes. The property of a drug that signifies the likelihood of therapeutic success to imperfect adherence is termed "forgiveness." We introduce an extension to this concept as: (1) a priori forgiveness (forgiveness when dose individualization is not considered) and (2) a posteriori forgiveness (forgiveness when considering dose individualization). We illustrate cases when adherence is of primary importance and in which dose individualization is of primary importance. The concept of a priori forgiveness and a posteriori forgiveness provides a quantitative measure that allows the influence of adherence to be disentangled from dose individualization and could be used to provide clear guidelines about the relative importance of each in clinical practice. PMID- 26959757 TI - Long working hours and the risk of coronary heart disease. PMID- 26959758 TI - Inter-correlation between working hours, sleep duration, obesity, and 10-year risk for CHD. PMID- 26959759 TI - Authors' response to letter to editor. PMID- 26959760 TI - Repeat Ultrasound-Guided Fine-Needle Aspiration for Thyroid Nodules 10 mm or Larger Can Be Performed 10.7 Months After Initial Nondiagnostic Results. AB - OBJECTIVE: The purpose of this study is to investigate when repeat ultrasound (US)-guided fine-needle aspiration (FNA) for thyroid nodules 10 mm or larger with initial nondiagnostic results due to inadequate or unsatisfactory specimen could be performed. MATERIALS AND METHODS: A total of 228 nodules 10 mm or larger with initial nondiagnostic results in 223 patients were classified into three groups according to the first follow-up US or US-guided FNA intervals after the initial US-guided FNA: within 3 months (group 1), 3-9 months (group 2), and more than 9 months (group 3). Nodules were classified according to size change. The malignancy detection rate and clinicopathologic characteristics were compared among the three groups. RESULTS: Seven nodules (3.1%) were malignant, and their cancer stages were the same as that determined at the initial US-guided FNA. Malignancy detection rates, as well as tumor size, extrathyroidal extension, and lymph node metastasis at pathologic analysis, were not significantly different among the three groups. Thirteen of 228 nodules (5.7%) showed increased size at a mean (+/- SD) of 34.5 +/- 25.1 months (range, 10.7-84.7 months) after initial US guided FNA, and one of the 13 nodules (7.7%) was malignant, a minimally invasive follicular carcinoma without lymph node metastasis found at 63.2 months. Of 177 nodules without change, six papillary thyroid carcinomas (3.4%) were found at a mean of 10.4 months. None of the 38 nodules with decreased size during a mean follow-up interval of 26.1 +/- 19.8 months (range, 2.8-79.5 months) was malignant. CONCLUSION: Repeat US-guided FNA for initial nondiagnostic thyroid nodules after 10.7 months can reduce unnecessary repeat US-guided FNAs without progression of malignancy. PMID- 26959761 TI - Measuring aging rates of mice subjected to caloric restriction and genetic disruption of growth hormone signaling. AB - Caloric restriction and genetic disruption of growth hormone signaling have been shown to counteract aging in mice. The effects of these interventions on aging are examined through age-dependent survival or through the increase in age dependent mortality rates on a logarithmic scale fitted to the Gompertz model. However, these methods have limitations that impede a fully comprehensive disclosure of these effects. Here we examine the effects of these interventions on murine aging through the increase in age-dependent mortality rates on a linear scale without fitting them to a model like the Gompertz model. Whereas these interventions negligibly and non-consistently affected the aging rates when examined through the age-dependent mortality rates on a logarithmic scale, they caused the aging rates to increase at higher ages and to higher levels when examined through the age-dependent mortality rates on a linear scale. These results add to the debate whether these interventions postpone or slow aging and to the understanding of the mechanisms by which they affect aging. Since different methods yield different results, it is worthwhile to compare their results in future research to obtain further insights into the effects of dietary, genetic, and other interventions on the aging of mice and other species. PMID- 26959763 TI - Evidence for Context Switching in the Effects of Average Item Length and Item Length Variability on Internal Consistency. AB - This investigation examined the effects of 3 item characteristics-the average number of words per item, within-scale variability in item length, and item "direction"-on internal consistency reliability and interitem correlation. In Study 1, we examined the effects of these variables on overall scale-level reliability using 444 subscales from 9 personality scales. In Study 2, we examined interitem correlation at the paired-item level using 477 nonredundant item pairs from 14 personality scales. Lower scale reliability was associated with more average words per item, greater within-scale variability in item length, and a greater percentage of reverse-keyed items. Similarly, smaller interitem correlations were associated with a greater degree of mismatch in item length between the paired items and with a mismatch (vs. match) in the items' respective "directions." The pattern of results across both studies supports our notion that lower internal consistency results from increased context switching; that is, from the confusion that occurs when respondents must switch back and forth between the interpretive frames pertaining to short versus long items, or between items pertaining to one pole of a personality dimension and its "opposite" pole. Suggestions for maximizing the internal consistency of personality scales are proposed. PMID- 26959762 TI - Immortalized Mouse Achilles Tenocytes Demonstrate Long-Term Proliferative Capacity While Retaining Tenogenic Properties. AB - Investigating the cellular processes underlying tendon healing can allow researchers to improve long-term outcomes after injury. However, conducting meaningful studies to uncover the injury healing mechanism at cellular and molecular levels remains challenging. This is due to the inherent difficulty in isolating, culturing, and expanding sufficient primary tenocytes, due to their limited proliferative capacity and short lifespan. In this study, we sought to establish a novel line of immortalized mouse Achilles tenocytes (iMATs) with primary tenocyte properties, but increased proliferative capacity suitable for extensive in vitro experimentation. We show that isolated primary mouse Achilles tenocytes (pMATs) can be effectively immortalized using a piggyBac transposon expressing SV40 large T antigen flanked by FLP recombination target site (FRT). The resulting iMATs exhibit markedly greater proliferation and survival, which can be reversed with FLP recombinase. Furthermore, iMATs express the same set of tendon-specific markers as that of primary cells, although in lower levels, and respond similarly to exogenous stimulation with bone morphogenetic protein 13 (BMP13) as has been previously reported with pMATs. Taken together, our results suggest that iMATs acquire long-term proliferative capacity while maintaining tenogenic properties. We believe that iMATs are a suitable model for studying not only the native cellular processes involved in injury and healing, but also potential therapeutic agents that may augment the stability of tendon repair. PMID- 26959764 TI - One new linear C14 polyacetylene glucoside with antiadipogenic activities on 3T3 L1 cells from the capitula of Coreopsis tinctoria. AB - Based on characteristic UV spectrum of the ene-diyne chromophore, one new polyacetylene glucoside and three known polyacetylene glucosides have been isolated from the EtOH extract of Coreopsis tinctoria. Their chemical structures were determined by detailed spectroscopic analysis and by comparison with literature data. Compounds 1-2 were tested for their antiadipogenic effects on 3T3-L1 adipocytes, and both of them reduced lipid accumulation dose-dependently in 3T3-L1 adipocytes. PMID- 26959798 TI - Metabolic load in dairy cows kept in herbage-based feeding systems and suitability of potential markers for compromised well-being. AB - Herbage feeding with only little input of concentrates plays an important role in milk production in grassland dominated countries like Switzerland. The objective was to investigate the effects of a solely herbage-based diet and level of milk production on performance, and variables related to the metabolic, endocrine and inflammatory status to estimate the stress imposed on dairy cows. Twenty-five multiparous Holstein cows were divided into a control (C+, n = 13) and a treatment group (C-, n = 12), according to their previous lactation yield (4679 10 808 kg) from week 3 ante partum until week 8 post-partum (p.p.). While C+ received fresh herbage plus additional concentrate, no concentrate was fed to C- throughout the experiment. Within C+ and C-, the median of the preceding lactation yields (7752 kg) was used to split cows into a high (HYC+, HYC-)- and low-yielding (LYC+, LYC-) groups. Throughout the study, HYC+ had a higher milk yield (35.9 kg/d) compared to the other subgroups (27.2-31.7 kg/d, p < 0.05). Plasma glucose (3.51 vs. 3.72 mmol/l) and IGF-1 (66.0 vs. 78.9ng/mL) concentrations were lower in HYC-/LYC- compared to HYC+/LYC+ cows (p < 0.05). Plasma FFA and BHBA concentrations were dramatically elevated in HYC- (1.1 and 1.6 mmol/l) compared to all other subgroups (mean values: 0.5 and 0.6 mmol/l, p < 0.05). Saliva cortisol, plasma concentrations of serum amyloid A (SAA), haptoglobin (Hp), beta-endorphin (BE) and activity of alkaline phosphatase (AP) were not different between C+ and C-. In conclusion, herbage-fed high-yielding cows without supplementary concentrate experienced a high metabolic load resulting in a reduced performance compared to cows of similar potential fed accordingly. Low-yielding cows performed well without concentrate supplementation. Interestingly, the selected markers for inflammation and stress such as cortisol, Hp, SAA, BE and AP gave no indication for the metabolic load being translated into compromised well-being. PMID- 26959799 TI - Omics for personalized medicine: defining the current we swim in. PMID- 26959800 TI - Constantin A. Bona, M.D., Ph.D. PMID- 26959801 TI - In This Issue: Molecular, Genetic and Cellular Aspects Related to Primary and Acquired Immunodeficiencies. PMID- 26959802 TI - Evaluation of Known Defective Signaling-Associated Molecules in Patients Who Primarily Diagnosed as Common Variable Immunodeficiency. AB - Common variable immunodeficiency (CVID) is a primary immunodeficiency disease, associated with defective antibody production and recurrent infections. Several defective signaling-associated molecules related to B-cell receptor, T-cell receptor, toll-like receptor, and other immune cell-associated receptors have been identified so far. In this review, defects of cell signaling associated molecules at three levels of surface cytoplasmic, and nuclear molecules are highlighted in patients who primarily diagnosed as CVID. It could be suggested that impaired cell signaling may be involved in the pathogenesis of CVID. PMID- 26959803 TI - Brazilian society of hepatology recommendations for the diagnosis and treatment of hepatocellular carcinoma. AB - Hepatocellular carcinoma is a malignancy of global importance and is associated with a high rate of mortality. Recent advances in the diagnosis and treatment of this disease make it imperative to update the recommendations on the management of the disease. In order to draw evidence-based recommendations concering the diagnosis and management of hepatocellular carcinoma, the Brazilian Society of Hepatology has sponsored a single-topic meeting in Joao Pessoa (PB). All the invited pannelists were asked to make a systematic review of the literature and to present topics related to the risk factors for its development, methods of screening, radiological diagnosis, staging systems, curative and palliative treatments and hepatocellular carcinoma in noncirrhotic liver. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of those recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present paper is the final version of the reviewed manuscript containing the recommendations of the Brazilian Society of Hepatology. PMID- 26959804 TI - Brazilian society of hepatology recommendations for the diagnosis and management of autoimmune diseases of the liver. AB - In order to draw evidence-based recommendations concerning the management of autoimmune diseases of the liver, the Brazilian Society of Hepatology has sponsored a single-topic meeting in October 18th, 2014 at Sao Paulo. An organizing committee comprised of seven investigators was previously elected by the Governing Board to organize the scientific agenda as well as to select twenty panelists to make a systematic review of the literature and to present topics related to the diagnosis and treatment of autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis and their overlap syndromes. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of those recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present paper is the final version of the reviewed manuscript organized in topics, followed by the recommendations of the Brazilian Society of Hepatology. PMID- 26959805 TI - Diagnosis and treatment of benign liver nodules: Brazilian Society of Hepatology (SBH) recommendations. AB - Space-occupying lesions of the liver may be cystic or solid. Ultrasonography is an extremely useful method for initial screening, and suffices for diagnosis of simple hepatic cysts. Complex cysts and solid masses require computed tomography or magnetic resonance imaging for confirmation. Wide surgical excision is indicated in cystadenoma or cystadenocarcinoma. Clinical and epidemiological data are important, as nodules in noncirrhotic livers are more likely to be benign. Hemangiomas, the most common benign tumors, require no follow-up after diagnostic confirmation if they are small and asymptomatic. Patients with giant, symptomatic hemangiomas or compression of adjacent structures should be referred to hepatobiliary centers for potential surgery. The genetic heterogeneity of hepatocellular adenomas and their epidemiology and prognosis prompted classification of these tumors into four subtypes based on histology and immunohistochemistry. The major complications of hepatocellular adenomas are rupture with bleeding and malignant transformation. Rupture occurs in approximately 30% of cases. The main risk factors are tumors size >5 cm and inflammatory subtype. Hepatocellular adenomas may enlarge during pregnancy due to marked hormonal stimulation. As oral contraceptive pills and anabolic steroids have associated with hepatocellular adenomas growth, particularly of the hepatocyte nuclear factor-1alfa subtype, these drugs should be discontinued. Focal nodular hyperplasia is the second most common benign tumor of the liver. It is most frequent in women aged 20 to 60, and 70% to 90% of cases are asymptomatic. In the absence of a central scar and/or other hallmarks of Focal nodular hyperplasia, with uncertainty between this diagnosis and hepatocellular adenoma, liver-specific contrast agents are indicated. PMID- 26959806 TI - Intensive care management of patients with liver disease: proceedings of a single topic conference sponsored by the Brazilian Society of Hepatology. AB - Survival rates of critically ill patients with liver disease has sharply increased in recent years due to several improvements in the management of decompensated cirrhosis and acute liver failure. This is ascribed to the incorporation of evidence-based strategies from clinical trials aiming to reduce mortality. In order to discuss the cutting-edge evidence regarding critical care of patients with liver disease, a joint single topic conference was recently sponsored by the Brazilian Society of Hepatology in cooperation with the Brazilian Society of Intensive Care Medicine and the Brazilian Association for Organ Transplantation. This paper summarizes the proceedings of the aforementioned meeting and it is intended to guide intensive care physicians, gastroenterologists and hepatologists in the care management of patients with liver disease. PMID- 26959807 TI - Some Aspects of Thermal Transport across the Interface between Graphene and Epoxy in Nanocomposites. AB - Owing to the superior thermal properties of graphene, graphene-reinforced polymer nanocomposites hold great potential as the thermal interface materials (TIMs) dissipating heat for electronic packages. However, this application is greatly hindered by the high thermal resistance at the interface between graphene and polymer. In this paper, some important aspects of the improvement of the thermal transport across the interface between graphene and epoxy in graphene-epoxy nanocomposites, including the effectiveness of covalent and noncovalent functionalization, isotope doping, and acetylenic linkage in graphene are systematically investigated using molecular dynamics (MD) simulations. The simulation results show that the covalent and noncovalent functionalization techniques could considerably reduce the graphene-epoxy interfacial thermal resistance in the nanocomposites. Among different covalent functional groups, butyl is more effective than carboxyl and hydroxyl in reducing the interfacial thermal resistance. Different noncovalent functional molecules, including 1 pyrenebutyl, 1-pyrenebutyric acid, and 1-pyrenebutylamine, yield a similar amount of reductions. Moreover, it is found that the graphene-epoxy interfacial thermal resistance is insensitive to the carbon isotope doping in graphene, while it can be reduced moderately by replacing the sp(2) bonds in graphene with acetylenic linkages. PMID- 26959808 TI - Effect of aerobic fitness on capillary blood volume and diffusing membrane capacity responses to exercise. AB - KEY POINTS: Endurance trained athletes exhibit enhanced cardiovascular function compared to non-athletes, although it is considered that exercise training does not enhance lung structure and function. An increased pulmonary capillary blood volume at rest is associated with a higher VO2 max . In the present study, we compared the diffusion capacity, pulmonary capillary blood volume and diffusing membrane capacity responses to exercise in endurance-trained males compared to non-trained males. Exercise diffusion capacity was greater in athletes, secondary to an increased membrane diffusing capacity, and not pulmonary capillary blood volume. Endurance-trained athletes appear to have differences within the pulmonary membrane that facilitate the increased O2 demand needed for high-level exercise. ABSTRACT: Endurance-trained athletes exhibit enhanced cardiovascular function compared to non-athletes, allthough it is generally accepted that exercise training does not enhance lung structure and function. Recent work has shown that an increased resting pulmonary capillary blood volume (VC ) is associated with a higher maximum oxygen consumption (VO2 max ), although there have been no studies to date examining how aerobic fitness affects the VC response to exercise. Based on previous work, we hypothesized that endurance trained athletes will have greater VC compared to non-athletes during cycling exercise. Fifteen endurance-trained athletes (HI: VO2 max 64.6 +/- 1.8 ml kg(-1) min(-1) ) and 14 non-endurance trained males (LO: VO2 max 45.0 +/- 1.2 ml kg(-1) min(-1) ) were matched for age and height. Haemoglobin-corrected diffusion capacity (DLCO), VC and diffusing membrane capacity (DM ) were determined using the Roughton and Forster () multiple fraction of inspired O2 (FI O2 )-DLCO method at baseline and during incremental cycle exercise up to 90% of peak O2 consumption. During exercise, both groups exhibited increases in DLCO, DM and VC with exercise intensity. Athletes had a greater DLCO and greater DM at 80 and 90% of VO2 max compared to non-athletes. However, VC was not different between groups during exercise. In contrast to our hypothesis, exercise VC was not greater in endurance-trained subjects compared to controls; rather, the increased DLCO in athletes at peak exercise was secondary to an enhanced DM . These findings suggest that endurance-trained athletes appear to have differences within the pulmonary membrane that facilitate the increased O2 demand needed for high-level exercise. PMID- 26959809 TI - Concentration-Dependent hMSC Differentiation on Orthogonal Concentration Gradients of GRGDS and BMP-2 Peptides. AB - Self-assembled monolayer substrates containing tethered orthogonal concentration profiles of GRGDS (glycine/arginine/glycine/aspartic acid/serine) and BMP-2 (bone morphogenetic protein) peptides are shown to accelerate or decelerate, depending on the concentrations, the proliferation and osteoblastic differentiation of human mesenchymal stem cell (hMSC) populations in vitro without the use of osteogenic additives in culture medium. Concurrently, the single peptide gradient controls (GRGDS or BMP-2 only) induce significantly different proliferation and differentiation behavior from the orthogonal substrates. Bone sialoprotein (BSP) and Runt-related transcription factor 2 (Runx2) PCR data acquired from hMSC populations isolated by laser capture microdissection correspond spatially and temporally to protein marker data obtained from immunofluorescent imaging tracking of the differentiation process. Although genomic and protein data at high concentrations area GRGDS (71-83 pmol/cm(2)):BMP-2 (25 pmol/cm(2)) reveal an implicit acceleration on the hMSC differentiation timeline relative to the individual peptide concentrations, most of the GRGDS and BMP-2 combinations displayed significant antagonistic behavior during the hMSC differentiation. These data highlight the utility of the orthogonal gradient approach to aid in identifying optimal concentration ranges of translationally relevant peptides and growth factors for targeting cell lineage commitment. PMID- 26959810 TI - Cortical Thickness in Mild Traumatic Brain Injury. AB - Magnetic resonance imaging data were acquired at ~24 h and ~3 months post-injury on mild traumatic brain injury (mTBI; n = 75) and orthopedic injury (n = 60) cohorts. The mTBI subjects were randomly assigned to a treatment group with atorvastatin or a non-treatment mTBI group. The treatment group was further divided into drug and placebo subgroups. FreeSurfer software package was used to compute cortical thickness based on the three dimensional T1-weighted images at both time-points. Cross-sectional analysis was carried out to compare cortical thickness between the mTBI and control groups. Longitudinal unbiased templates were generated for all subjects and cortical thickness measurements were compared between baseline and follow-up scans in the mTBI group. At baseline, significant reduction in cortical thickness was observed in the left middle temporal and the right superior parietal regions in the mTBI group, relative to the control group (p = 0.01). At follow-up, significant cortical thinning was again observed in the left middle temporal cortex in the mTBI group. Further analysis revealed significant cortical thinning only in the non-treatment group relative to the control group. In the follow-up, small regions with significant but subtle cortical thinning and thickening were seen in the frontal, temporal, and parietal lobes in the left hemisphere in the non-treatment group only. Our results indicate that cortical thickness could serve as a useful measure in identifying subtle changes in mTBI patients. PMID- 26959811 TI - Optimization of ultrasound-assisted hydroalcoholic extraction of phenolic compounds from walnut leaves using response surface methodology. AB - Context Walnut leaves are highly appreciated for their pharmacological effects and therapeutic properties which are mainly attributed to their high content of phenolic compounds. Objective This study optimizes ultrasound assisted hydroalcoholic extraction (UAE) of phenolic compounds from dried walnut leaves by the maximization of total phenolics content (TPC) and total flavanoids content (TFC) of the extracts. Materials and methods Optimal conditions with regard to ethanol concentration (X1: 12.17-95.83% v/v), extraction time (X2: 8.17-91.83 min) and liquid-to-solid ratio (X3: 4.96-25.04 v/w) were identified using central composite design combined with response surface methodology. A high-performance liquid chromatography method with diode-array detection was used to quantify phenolic acids (gallic, vanillic, chlorogenic, caffeic, syringic, p-coumaric, ferulic, sinapic, salicylic, ellagic and trans-cinnamic), flavonoids (catechin, epicatechin, rutin, myricetin and quercetin) and juglone in the extracts. Results Liquid-to-solid ratio and ethanol concentration proved to be the primary factors affecting the extraction efficiency. The maximum predicted TPC, under the optimized conditions (61% ethanol concentration, 51.28 min extraction time and 4.96 v/w liquid-to-solid ratio) was 10125.4 mg gallic acid equivalents per liter while maximum TFC (2925 mg quercetin equivalents per liter) occurred at 67.83% ethanol concentration, 4.96 v/w liquid-to-solid ratio and 49.37 min extraction time. High significant correlations were found between antioxidant activity and both TPC (R(2 )=( )0.81) and TFC (R(2 )=( )0.78). Discussion and conclusion Extracts very rich in polyphenols could be obtained from walnut leaves by using UAE, aimed at preparing dietary supplements, nutraceuticals or functional food ingredients. PMID- 26959812 TI - Predictive Coding: A Possible Explanation of Filling-In at the Blind Spot. AB - Filling-in at the blind spot is a perceptual phenomenon in which the visual system fills the informational void, which arises due to the absence of retinal input corresponding to the optic disc, with surrounding visual attributes. It is known that during filling-in, nonlinear neural responses are observed in the early visual area that correlates with the perception, but the knowledge of underlying neural mechanism for filling-in at the blind spot is far from complete. In this work, we attempted to present a fresh perspective on the computational mechanism of filling-in process in the framework of hierarchical predictive coding, which provides a functional explanation for a range of neural responses in the cortex. We simulated a three-level hierarchical network and observe its response while stimulating the network with different bar stimulus across the blind spot. We find that the predictive-estimator neurons that represent blind spot in primary visual cortex exhibit elevated non-linear response when the bar stimulated both sides of the blind spot. Using generative model, we also show that these responses represent the filling-in completion. All these results are consistent with the finding of psychophysical and physiological studies. In this study, we also demonstrate that the tolerance in filling-in qualitatively matches with the experimental findings related to non-aligned bars. We discuss this phenomenon in the predictive coding paradigm and show that all our results could be explained by taking into account the efficient coding of natural images along with feedback and feed-forward connections that allow priors and predictions to co-evolve to arrive at the best prediction. These results suggest that the filling-in process could be a manifestation of the general computational principle of hierarchical predictive coding of natural images. PMID- 26959813 TI - Rhinella marina (Amphibia: Bufonidae) Versus Rhabdias paraensis (Nematoda: Rhabdiasidae): Expanding the View on a Natural Infection. AB - Amphibian and reptile lungs are frequently infected with Rhabdias parasites, and this condition ultimately leads to reduced survival, performance, and growth because of granulomatous inflammation, nodule formation, and nematodal pneumonia onset. Here we investigate the histopathological features of naturally infected Rhinella marina by the lung nematode Rhabdias paraensis. A total of 10 host animals were captured in peridomiciliar areas in the eastern Brazilian Amazon, and anatomic-histological analyses were performed on both the infected and non infected lungs of these amphibians. Helminths were usually found within the secondary and primary septa of infected lungs whereas parasites were not detected within vessels or adhering to tissues. In addition, we observed discrete erythrocytes, diapedesis foci, few granulocytes and erythrocytes in the interseptal spaces, discrete cell infiltration, and a small number of melanomacrophages, and no granulomas or cysts were observed. New aspects related to changes in tissue and helminth-host interactions are discussed for the relationship of R. paraensis * Rhi. marina from the Amazon region. PMID- 26959815 TI - Facing the Heat: Does Desiccation and Thermal Stress Explain Patterns of Orientation in an Intertidal Invertebrate? AB - A key challenge for ecologists is to quantify, explain and predict the ecology and behaviour of animals from knowledge of their basic physiology. Compared to our knowledge of many other types of distribution and behaviour, and how these are linked to individual function, we have a poor level of understanding of the causal basis for orientation behaviours. Most explanations for patterns of animal orientation assume that animals will modify their exposure to environmental factors by altering their orientation. We used a keystone grazer on rocky shores, the limpet Cellana tramoserica, to test this idea. Manipulative experiments were done to evaluate whether orientation during emersion affected limpet desiccation or body temperature. Body temperature was determined from infrared thermography, a technique that minimises disturbance to the test organism. No causal relationships were found between orientation and (i) level of desiccation and (ii) their body temperature. These results add to the growing knowledge that responses to desiccation and thermal stress may be less important in modifying the behaviour of intertidal organisms than previously supposed and that thermoregulation does not always reflect patterns of animal orientation. Much of what we understand about orientation comes from studies of animals able to modify orientation over very short time scales. Our data suggests that for animals whose location is less flexible, orientation decisions may have less to do with responses to environmental factors and more to do with structural habitat properties or intrinsic individual attributes. Therefore we suggest future studies into processes affecting orientation must include organisms with differing levels of behavioural plasticity. PMID- 26959814 TI - Mevalonate-Farnesal Biosynthesis in Ticks: Comparative Synganglion Transcriptomics and a New Perspective. AB - Juvenile hormone (JH) controls the growth, development, metamorphosis, and reproduction of insects. For many years, the general assumption has been that JH regulates tick and other acarine development and reproduction the same as in insects. Although researchers have not been able to find the common insect JHs in hard and soft tick species and JH applications appear to have no effect on tick development, it is difficult to prove the negative or to determine whether precursors to JH are made in ticks. The tick synganglion contains regions which are homologous to the corpora allata, the biosynthetic source for JH in insects. Next-gen sequencing of the tick synganglion transcriptome was conducted separately in adults of the American dog tick, Dermacentor variabilis, the deer tick, Ixodes scapularis, and the relapsing fever tick, Ornithodoros turicata as a new approach to determine whether ticks can make JH or a JH precursor. All of the enzymes that make up the mevalonate pathway from acetyl-CoA to farnesyl diphosphate (acetoacetyl-CoA thiolase, HMG-S, HMG-R, mevalonate kinase, phosphomevalonate kinase, diphosphomevalonate decarboxylase, and farnesyl diphosphate synthase) were found in at least one of the ticks studied but most were found in all three species. Sequence analysis of the last enzyme in the mevalonate pathway, farnesyl diphosphate synthase, demonstrated conservation of the seven prenyltransferase regions and the aspartate rich motifs within those regions typical of this enzyme. In the JH branch from farnesyl diphosphate to JH III, we found a putative farnesol oxidase used for the conversion of farnesol to farnesal in the synganglion transcriptome of I. scapularis and D. variabilis. Methyltransferases (MTs) that add a methyl group to farnesoic acid to make methyl farnesoate were present in all of the ticks studied with similarities as high as 36% at the amino acid level to insect JH acid methyltransferase (JHAMT). However, when the tick MTs were compared to the known insect JHAMTs from several insect species at the amino acid level, the former lacked the farnesoic acid binding motif typical in insects. The P450s shown in insects to add the C10,11 epoxide to methyl farnesoate, are in the CYP15 family; this family was absent in our tick transcriptomes and in the I. scapularis genome, the only tick genome available. These data suggest that ticks do not synthesize JH III but have the mevalonate pathway and may produce a JH III precursor. PMID- 26959816 TI - Community Health Seeking Behavior for Suspected Human and Animal Rabies Cases, Gomma District, Southwest Ethiopia. AB - BACKGROUND: Timely presentation to appropriate health service provider of sick animals/humans from zoonotic diseases like rabies is important for early case/outbreak detection and management. However, data on community's health seeking practice for rabies in Ethiopia is limited. Therefore the objective of this study was to determine community's health seeking behavior on rabies, Southwest Ethiopia. METHODS: A cross-sectional survey was conducted from January 16-February 14, 2015 to collect data from 808 respondents where the respondents were selected using multistage sampling technique. Data were collected using interviewer administered structured questionnaire by trained epidemiology graduate level students. Data were entered to Epidata version 3.1 and analyzed using SPSS version 20 for windows. RESULT: Eight hundred three (99.4%) respondents participated in the study. Out of 28 respondents who reported their family members' exposure to rabies, 8 of them replied that the exposed family members sought treatment from traditional healers. More than nine in ten respondents perceived that humans and domestic animals with rabies exposure should seek help of which 85% of them suggested modern health care facilities as the preferred management option for the sick humans and domestic animals. However, among those who reported sick domestic animals, near to 72% of them had either slaughtered for human consumption, sold immediately, visited traditional healer, given home care or did nothing for the sick domestic animals. CONCLUSION: Majority of the respondents had favorable perception of seeking treatment from modern health care facilities for rabies. However, significant number of them had managed inappropriately for the sick domestic animals from rabies. Hence, raising awareness of the community about management of sick domestic animals from rabies and the need for reporting to both human and animal health service providers is needed. PMID- 26959818 TI - Preparation of Heteroaryl Ethers from Azine N-Oxides and Alcohols. AB - The heteroaryl ether is an important structural feature in molecules of biological interest, yet it remains a challenge to synthesize. A new and practical method for the synthesis of heteroaryl ethers is reported. In the presence of PyBroP, a variety of nonaromatic alcohols readily add to azine N oxides to afford the corresponding heteroaryl ethers. The reaction conditions are mild, economical, chemoselective, and compatible with a broad range of substrates. Thirty-eight examples are provided, as is a discussion of reaction optimization and mechanism. PMID- 26959817 TI - Comparative Transcriptome Analysis of Fetal Skin Reveals Key Genes Related to Hair Follicle Morphogenesis in Cashmere Goats. AB - Cashmere goat skin contains two types of hair follicles (HF): primary hair follicles (PHF) and secondary hair follicles (SHF). Although multiple genetic determinants associated with HF formation have been identified, the molecules that determine the independent morphogenesis of HF in cashmere goats remain elusive. The growth and development of SHF directly influence the quantity and quality of cashmere production. Here, we report the transcriptome profiling analysis of nine skin samples from cashmere goats using 60- and 120-day-old embryos (E60 and E120, respectively), as well as newborns (NB), through RNA sequencing (RNA-seq). HF morphological changes indicated that PHF were initiated at E60, with maturation from E120, while differentiation of SHF was identified at E120 until formation of cashmere occurred after birth (NB). The RNA-sequencing analysis generated over 20.6 million clean reads from each mRNA library. The number of differentially expressed genes (DEGs) in E60 vs. E120, E120 vs. NB, and E60 vs. NB were 1,024, 0 and 1,801, respectively, indicating that no significant differences were found at transcriptomic levels between E120 and NB. Key genes including B4GALT4, TNC, a-integrin, and FGFR1, were up-regulated and expressed in HF initiation from E60 to E120, while regulatory genes such as GPRC5D, PAD3, HOXC13, PRR9, VSIG8, LRRC15, LHX2, MSX-2, and FOXN1 were up-regulated and expressed in HF keratinisation and hair shaft differentiation from E120 and NB to E60. Several genes belonging to the KRT and KRTAP gene families were detected throughout the three HF developmental stages. The transcriptional trajectory analyses of all DEGs indicated that immune privilege, glycosaminoglycan biosynthesis, extracellular matrix receptor interaction, and growth factor receptors all played dominant roles in the epithelial-mesenchymal interface and HF formation. We found that the Wnt, transforming growth factor-beta/bone morphogenetic protein, and Notch family members played vital roles in HF differentiation and maturation. The DEGs we found could be attributed to the generation and development of HF, and thus will be critically important for improving the quantity and quality of fleece production in animals for fibres. PMID- 26959820 TI - Validation of the Recording of Acute Exacerbations of COPD in UK Primary Care Electronic Healthcare Records. AB - BACKGROUND: Acute Exacerbations of COPD (AECOPD) identified from electronic healthcare records (EHR) are important for research, public health and to inform healthcare utilisation and service provision. However, there is no standardised method of identifying AECOPD in UK EHR. We aimed to validate the recording of AECOPD in UK EHR. METHODS: We randomly selected 1385 patients with COPD from the Clinical Practice Research Datalink. We selected dates of possible AECOPD based on 15 different algorithms between January 2004 and August 2013. Questionnaires were sent to GPs asking for confirmation of their patients' AECOPD on the dates identified and for any additional relevant information. Responses were reviewed independently by two respiratory physicians. Positive predictive value (PPV) and sensitivity were calculated. RESULTS: The response rate was 71.3%. AECOPD diagnostic codes, lower respiratory tract infection (LRTI) codes, and prescriptions of antibiotics and oral corticosteroids (OCS) together for 5-14 days had a high PPV (>75%) for identifying AECOPD. Symptom-based algorithms and prescription of antibiotics or OCS alone had lower PPVs (60-75%). A combined strategy of antibiotic and OCS prescriptions for 5-14 days, or LRTI or AECOPD code resulted in a PPV of 85.5% (95% CI, 82.7-88.3%) and a sensitivity of 62.9% (55.4-70.4%). CONCLUSION: Using a combination of diagnostic and therapy codes, the validity of AECOPD identified from EHR can be high. These strategies are useful for understanding health-care utilisation for AECOPD, informing service provision and for researchers. These results highlight the need for common coding strategies to be adopted in primary care to allow easy and accurate identification of events. PMID- 26959819 TI - Plasmalogen Augmentation Reverses Striatal Dopamine Loss in MPTP Mice. AB - Plasmalogens are a class of glycerophospholipids shown to play critical roles in membrane structure and function. Decreased plasmalogens are reported in the brain and blood of Parkinson's disease (PD) patients. The present study investigated the hypothesis that augmenting plasmalogens could protect striatal dopamine neurons that degenerate in response to 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) treatment in mice, a PD model. First, in a pre treatment experiment male mice were treated for 10 days with the docosahexaenoic acid (DHA)-plasmalogen precursor PPI-1011 (10, 50 and 200 mg/kg). On day 5 mice received MPTP and were killed on day 11. Next, in a post-treatment study, male mice were treated with MPTP and then received daily for 5 days PPI-1011 (5, 10 and 50 mg/kg). MPTP treatment reduced serum plasmalogen levels, striatal contents of dopamine (DA) and its metabolites, serotonin, DA transporter (DAT) and vesicular monoamine transporter 2 (VMAT2). Pre-treatment with PPI-1011 (10 and 50 mg/kg) prevented all MPTP-induced effects. Positive correlations were measured between striatal DA contents and serum plasmalogen levels as well as striatal DAT and VMAT2 specific binding. Post-treatment with PPI-1011 prevented all MPTP induced effects at 50 mg/kg but not at lower doses. Positive correlations were measured between striatal DA contents and serum plasmalogen levels as well as striatal DAT and VMAT2 specific binding in the post-treatment experiment. PPI 1011 treatment (10 days at 5, 10 and 50 mg/kg) of intact mice left unchanged striatal biogenic amine contents. These data demonstrate that treatment with a plasmalogen precursor is capable of protecting striatal dopamine markers in an animal model of PD. PMID- 26959821 TI - Conscious Augmentation of Creative State Enhances "Real" Creativity in Open-Ended Analogical Reasoning. AB - Humans have an impressive ability to augment their creative state (i.e., to consciously try and succeed at thinking more creatively). Though this "thinking cap" phenomenon is commonly experienced, the range of its potential has not been fully explored by creativity research, which has often focused instead on creativity as a trait. A key question concerns the extent to which conscious augmentation of state creativity can improve creative reasoning. Although artistic creativity is also of great interest, it is creative reasoning that frequently leads to innovative advances in science and industry. Here, we studied state creativity in analogical reasoning, a form of relational reasoning that spans the conceptual divide between intelligence and creativity and is a core mechanism for creative innovation. Participants performed a novel Analogy Finding Task paradigm in which they sought valid analogical connections in a matrix of word-pairs. An explicit creativity cue elicited formation of substantially more creative analogical connections (measured via latent semantic analysis). Critically, the increase in creative analogy formation was not due to a generally more liberal criterion for analogy formation (that is, it appeared to reflect "real" creativity rather than divergence at the expense of appropriateness). The use of an online sample provided evidence that state creativity augmentation can be successfully elicited by remote cuing in an online environment. Analysis of an intelligence measure provided preliminary indication that the influential "threshold hypothesis," which has been proposed to characterize the relationship between intelligence and trait creativity, may be extensible to the new domain of state creativity. PMID- 26959822 TI - The Vascular Endothelial Growth Factor Inhibitors Ranibizumab and Aflibercept Markedly Increase Expression of Atherosclerosis-Associated Inflammatory Mediators on Vascular Endothelial Cells. AB - INTRODUCTION: Recent studies have suggested that the VEGF inhibitors, Ranibizumab and Aflibercept may be associated with an excess of cardiovascular events, potentially driven by increasing atheroma instability, leading to plaque rupture and clinical events. Inflammation plays a key role in the progression of atherosclerotic plaque and particularly conversion to an unstable phenotype. Here, we sought to assess the in vitro effects of these drugs on the expression of key inflammatory mediators on endothelial cells. METHODS: Human coronary artery endothelial cells were co-incubated for 16h with Ranibizumab (0.11nM) or Aflibercept (0.45nM), as determined by each drug's peak serum concentration (Cmax). Expression at protein (ELISA) and gene (RT-PCR) level of inflammatory chemokines CCL2, CCL5 and CXC3L1 as well as gene expression for the cell adhesion molecules VCAM-1, ICAM-1 and the key NF-kappab protein p65 was assessed. VEGF-A protein levels were also determined. RESULTS: Both drugs significantly increased chemokine, cell adhesion molecule (CAM) and p65 expression, while decreasing VEGF A protein secretion. At equivalent Cmax concentrations, Aflibercept was significantly more pro-inflammatory than Ranibizumab. Reduction of secreted VEGF A levels significantly attenuated inflammatory effects of both drugs, whereas blockade of the VEGF-A receptor or silencing of VEGF-A gene synthesis alone had no effect, suggesting that binding of drug to secreted VEGF-A is crucial in promoting inflammation. Finally, blockade of Toll-like receptor 4 significantly reduced inflammatory effects of both drugs. CONCLUSION: We demonstrated here, for the first time, that both drugs have potent pro-inflammatory effects, mediated via activation of Toll-like receptor 4 on the endothelial cell surface by drug bound to VEGF-A. Further studies are required to investigate whether these effects are also seen in vivo. PMID- 26959823 TI - If You're House Is Still Available, Send Me an Email: Personality Influences Reactions to Written Errors in Email Messages. AB - The increasing prevalence of social media means that we often encounter written language characterized by both stylistic variation and outright errors. How does the personality of the reader modulate reactions to non-standard text? Experimental participants read 'email responses' to an ad for a housemate that either contained no errors or had been altered to include either typos (e.g., teh) or homophonous grammar errors (grammos, e.g., to/too, it's/its). Participants completed a 10-item evaluation scale for each message, which measured their impressions of the writer. In addition participants completed a Big Five personality assessment and answered demographic and language attitude questions. Both typos and grammos had a negative impact on the evaluation scale. This negative impact was not modulated by age, education, electronic communication frequency, or pleasure reading time. In contrast, personality traits did modulate assessments, and did so in distinct ways for grammos and typos. PMID- 26959824 TI - What Evidence Underlies Clinical Practice in Paediatric Surgery? A Systematic Review Assessing Choice of Study Design. AB - OBJECTIVE: Identify every paediatric surgical article published in 1998 and every paediatric surgical article published in 2013, and determine which study designs were used and whether they were appropriate for robustly assessing interventions in surgical conditions. METHODS: A systematic review was conducted according to a pre-specified protocol (CRD42014007629), using EMBASE and Medline. Non-English language studies were excluded. Studies were included if meeting population criteria and either condition or intervention criteria. POPULATION: Children under the age of 18, or adults who underwent intervention for a condition managed by paediatric surgeons when they were under 18 years of age. CONDITION: One managed by general paediatric surgeons. INTERVENTION: Used for treatment of a condition managed by general paediatric surgeons. MAIN OUTCOME MEASURE: Studies were classified according to whether the IDEAL collaboration recommended their design for assessing surgical interventions or not. Change in proportions between 1998 and 2013 was calculated. RESULTS: 1581 paediatric surgical articles were published in 1998, and 3453 in 2013. The most commonly used design, accounting for 45% of studies in 1998 and 46.8% in 2013, was the retrospective case series. Only 1.8% of studies were RCTs in 1998, and 1.9% in 2013. Overall, in 1998, 9.8% of studies used a recommended design. In 2013, 11.9% used a recommended design (proportion increase 2.3%, 95% confidence interval 0.5% increase to 4% increase, p = 0.017). CONCLUSIONS AND RELEVANCE: A low proportion of published paediatric surgical manuscripts utilise a design that is recommended for assessing surgical interventions. RCTs represent fewer than 1 in 50 studies. In 2013, 88.1% of studies used a less robust design, suggesting the need for a new way of approaching paediatric surgical research. PMID- 26959826 TI - Peer-Led Team Learning Helps Minority Students Succeed. AB - Active learning methods have been shown to be superior to traditional lecture in terms of student achievement, and our findings on the use of Peer-Led Team Learning (PLTL) concur. Students in our introductory biology course performed significantly better if they engaged in PLTL. There was also a drastic reduction in the failure rate for underrepresented minority (URM) students with PLTL, which further resulted in closing the achievement gap between URM and non-URM students. With such compelling findings, we strongly encourage the adoption of Peer-Led Team Learning in undergraduate Science, Technology, Engineering, and Mathematics (STEM) courses. PMID- 26959825 TI - The Role of Aquaporins in pH-Dependent Germination of Rhizopus delemar Spores. AB - Rhizopus delemar and associated species attack a wide range of fruit and vegetables after harvest. Host nutrients and acidic pH are required for optimal germination of R. delemar, and we studied how this process is triggered. Glucose induced spore swelling in an acidic environment, expressed by an up to 3-fold increase in spore diameter, whereas spore diameter was smaller in a neutral environment. When suspended in an acidic environment, the spores started to float, indicating a change in their density. Treatment of the spores with HgCl2, an aquaporin blocker, prevented floating and inhibited spore swelling and germ tube emergence, indicating the importance of water uptake at the early stages of germination. Two putative candidate aquaporin-encoding genes-RdAQP1 and RdAQP2 were identified in the R. delemar genome. Both presented the conserved NPA motif and six-transmembrane domain topology. Expressing RdAQP1 and RdAQP2 in Arabidopsis protoplasts increased the cells' osmotic water permeability coefficient (Pf) compared to controls, indicating their role as water channels. A decrease in R. delemar aquaporin activity with increasing external pH suggested pH regulation of these proteins. Substitution of two histidine (His) residues, positioned on two loops facing the outer side of the cell, with alanine eliminated the pH sensing resulting in similar Pf values under acidic and basic conditions. Since hydration is critical for spore switching from the resting to activate state, we suggest that pH regulation of the aquaporins can regulate the initial phase of R. delemar spore germination, followed by germ-tube elongation and host-tissue infection. PMID- 26959827 TI - Estrogen Receptor Alpha Distribution and Expression in the Social Neural Network of Monogamous and Polygynous Peromyscus. AB - In microtine and dwarf hamsters low levels of estrogen receptor alpha (ERalpha) in the bed nucleus of the stria terminalis (BST) and medial amygdala (MeA) play a critical role in the expression of social monogamy in males, which is characterized by high levels of affiliation and low levels of aggression. In contrast, monogamous Peromyscus males display high levels of aggression and affiliative behavior with high levels of testosterone and aromatase activity. Suggesting the hypothesis that in Peromyscus ERalpha expression will be positively correlated with high levels of male prosocial behavior and aggression. ERalpha expression was compared within the social neural network, including the posterior medial BST, MeA posterodorsal, medial preoptic area (MPOA), ventromedial hypothalamus (VMH), and arcuate nucleus in two monogamous species, P. californicus and P. polionotus, and two polygynous species, P. leucopus and P. maniculatus. The results supported the prediction, with male P. polionotus and P. californicus expressing higher levels of ERalpha in the BST than their polygynous counter parts, and ERalpha expression was sexually dimorphic in the polygynous species, with females expressing significantly more than males in the BST in both polygynous species and in the MeA in P. leucopus. Peromyscus ERalpha expression also differed from rats, mice and microtines as in neither the MPOA nor the VMH was ERalpha sexually dimorphic. The results supported the hypothesis that higher levels of ERalpha are associated with monogamy in Peromyscus and that differential expression of ERalpha occurs in the same regions of the brains regardless of whether high or low expression is associated with social monogamy. Also discussed are possible mechanisms regulating this differential relationship. PMID- 26959828 TI - Surgical Management of a Case of a 360-Degree Giant Retinal Break. AB - PURPOSE: The aim is to describe tools and techniques that can be used to deal with total retinal detachment (open funnel) and associated proliferative vitreoretinopathy due to a 360-degree giant retinal break following ocular trauma. Setting/Venue: The video (available at www. karger.com/doi/10.1159/000444811) was created at the Ophthalmology Department, Faculty of Medicine Kasr Al Ainy, Cairo University Hospital, Cairo, Egypt. METHODS: A 16-year-old female patient presented to the Cairo University Hospital after blunt ocular trauma. She had traumatic cataract, and ultrasound examination showed total retinal detachment. She was scheduled for surgery at the Cairo University Hospital. Phacoemulsification of traumatic cataract was done after insertion of the 3-port 23-gauge trocar system. The 25-gauge chandelier illumination system was used to assist the peeling of adherent posterior hyaloid and epiretinal membranes, allowing bimanual work using an end-gripping forceps and a diamond-dusted retinal scrapper. Removal of the vitreous surrounding the retinal funnel was performed, and a small perfluorocarbon (PFC) bubble was used to support the posterior pole. This was followed by refreshing the rolled edges of the retinal break and shaving the vitreous base and anterior leaflet of the giant break by surgeon-assisted scleral indentation. The eye was completely filled with PFC, and Argon laser retinopexy was performed. Direct PFC-silicone oil exchange was done to avoid retinal slippage (silicone oil 5,000 cSt was used). RESULTS: Retinal attachment was successfully achieved at the end of the surgery. The silicone oil was removed 5 months after the initial surgery. The patient's uncorrected visual acuity 1 month after removal of the silicone was 0.4. CONCLUSIONS: The chandelier-assisted bimanual technique is an effective method for dealing with adherent posterior hyaloid and epiretinal membranes in a detached retina, particularly in cases of complex open-funnel retinal detachment. Proper shaving of the anterior leaflet and refreshing the edges of the retinal break helps decrease postoperative PVR formation. Direct PFC-silicone oil exchange in giant retinal breaks helps minimize the risk of retinal slippage occurrence. PMID- 26959830 TI - High Amounts of Total and Extracellular Vesicle-Derived Soluble HLA-G are Associated with HLA-G 14-bp Deletion Variant in Women with Embryo Implantation Failure. AB - PROBLEM: Human leukocyte antigen-G (HLA-G) expression is related to 14-bp insertion/deletion polymorphism at the 3'UTR of the HLA-G gene. Soluble forms of HLA-G are released as free molecules or via extracellular vesicles (EVs). Due to the crucial role of HLA-G during pregnancy, we analyzed the 14-bp polymorphism and the two secreted forms in implantation failure women (IF) and in fertile women (FW). METHOD OF STUDY: For the genetic analysis, 49 IF and 34 FW were genotyped. For sHLA-G quantification, serum samples from 35 IF and 23 FW were available. ExoQuick(TM) kit was used for EVs precipitation. The total soluble HLA G (sHLA-Gtot ) and vesicular sHLA-GEV were quantified by ELISA. The EVs size and concentration were determined by nanoparticle tracking analysis (NTA). RESULTS: An increased proportion of IF presented high levels of sHLA-Gtot (P = 0.02) and vesicular sHLA-GEV (P = 0.0003) compared to FW. The 14-bp deletion allele is more frequent in IF (P = 0.0002) and associated with high levels of sHLA-Gtot and vesicular sHLA-GEV . CONCLUSION: The high expression of sHLA-Gtot and sHLA-GEV , together with the presence of the 14-bp deletion allele, might be involved in implantation failure. PMID- 26959829 TI - Considering the Influence of Nonadaptive Evolution on Primate Color Vision. AB - Color vision in primates is variable across species, and it represents a rare trait in which the genetic mechanisms underlying phenotypic variation are fairly well-understood. Research on primate color vision has largely focused on adaptive explanations for observed variation, but it remains unclear why some species have trichromatic or polymorphic color vision while others are red-green color blind. Lemurs, in particular, are highly variable. While some species are polymorphic, many closely-related species are strictly dichromatic. We provide the first characterization of color vision in a wild population of red-bellied lemurs (Eulemur rubriventer, Ranomafana National Park, Madagascar) with a sample size (87 individuals; NX chromosomes = 134) large enough to detect even rare variants (0.95 probability of detection at >= 3% frequency). By sequencing exon 5 of the X linked opsin gene we identified opsin spectral sensitivity based on known diagnostic sites and found this population to be dichromatic and monomorphic for a long wavelength allele. Apparent fixation of this long allele is in contrast to previously published accounts of Eulemur species, which exhibit either polymorphic color vision or only the medium wavelength opsin. This unexpected result may represent loss of color vision variation, which could occur through selective processes and/or genetic drift (e.g., genetic bottleneck). To indirectly assess the latter scenario, we genotyped 55 adult red-bellied lemurs at seven variable microsatellite loci and used heterozygosity excess and M-ratio tests to assess if this population may have experienced a recent genetic bottleneck. Results of heterozygosity excess but not M-ratio tests suggest a bottleneck might have occurred in this red-bellied lemur population. Therefore, while selection may also play a role, the unique color vision observed in this population might have been influenced by a recent genetic bottleneck. These results emphasize the need to consider adaptive and nonadaptive mechanisms of color vision evolution in primates. PMID- 26959833 TI - Physical and Structural Characterization of Imidazolium-Based Organic-Inorganic Hybrid: (C3N2H5)2[CoCl4]. AB - (C3N2H5)2[CoCl4] (ICC) was characterized in a wide temperature range by the single-crystal X-ray diffraction method. Differential scanning calorimetry revealed two structural phase transitions: continuous at 245.5 K (from phase I to II) and a discontinuous one at 234/237 K (cooling/heating) (II -> III). ICC adopts monoclinic space groups C2/c and P21/c in phase (I) and (III), respectively. The intermediate phase (II) appears to be incommensurately modulated. Dynamic properties of polycrystalline ICC were studied by means of dielectric spectroscopy and proton magnetic resonance ((1)H NMR). The presence of a low frequency dielectric relaxation process in phase III reflects libration motion of the imidazolium cations. The temperature dependence of the (1)H spin lattice relaxation time indicated two motional processes with similar activation energies that are by about an order of magnitude smaller than the activation energy obtained from dielectric studies. There are no abrupt changes in the (1)H relaxation time at the phase transitions indicating that the dynamics of the imidazolium rings gradually varies with temperature; that is, it does not change suddenly at the phase transition. Negative values of the Weiss constant and the intermolecular exchange parameter were obtained, confirming the presence of a weak antiferromagnetic interaction between the nearest cobalt centers. Moreover, the magnitude of zero field splitting was determined. The AC susceptibility measurements show that a slow magnetic relaxation is induced by small external magnetic field. PMID- 26959834 TI - Increased PR Interval in Fetuses of Patients with Intrahepatic Cholestasis of Pregnancy. AB - OBJECTIVE: To evaluate the fetal mechanical PR interval in fetuses from pregnancies with intrahepatic cholestasis of pregnancy (ICP). METHODS: A case control study was conducted in the Maternal-Fetal Medicine Unit at Hospital Carlos Van Buren between 2011 and 2013. Fetal echocardiography was performed in patients with ICP and normal pregnancies. Demographic and clinical characteristics were compared using the Mann-Whitney U test for continuous variables. A p value <0.05 was considered significant. RESULTS: 51 patients with ICP were compared with 51 unaffected pregnancies. There were no significant differences in neither demographic nor clinical characteristics between the two groups. The fetal PR interval was significantly longer in the ICP group when compared to the control group (134.6 +/- 12 vs. 121.4 +/- 10 ms, p < 0.001). Moreover, four fetuses from the ICP group had a mechanical PR interval >150 ms, which is compatible with a first-degree atrioventricular block. Two fetuses were identified in the neonatal period and were transferred to pediatric cardiology for follow-up, with a normal mechanical PR after the first month of life. CONCLUSIONS: We demonstrated that the fetal cardiac conduction system is altered in fetuses of patients with ICP. Further research is necessary to determine whether this alteration is related to stillbirths seen in ICP. PMID- 26959835 TI - Choline and Geranate Deep Eutectic Solvent as a Broad-Spectrum Antiseptic Agent for Preventive and Therapeutic Applications. AB - Antiseptic agents are the primary arsenal to disinfect skin and prevent pathogens spreading within the host as well as into the surroundings; however the Food and Drug Administration published a report in 2015 requiring additional validation of nearly all current antiseptic agents before their continued use can be allowed. This vulnerable position calls for urgent identification of novel antiseptic agents. Recently, the ability of a deep eutectic, Choline And Geranate (CAGE), to treat biofilms of Pseudomonas aeruginosa and Salmonella enterica was demonstrated. Here it is reported that CAGE exhibits broad-spectrum antimicrobial activity against a number of drug-resistant bacteria, fungi, and viruses including clinical isolates of Mycobacterium tuberculosis, Staphylococcus aureus, and Candida albicans as well as laboratory strains of Herpes Simplex Virus. Studies in human keratinocytes and mice show that CAGE affords negligible local or systemic toxicity, and an ~180-14 000-fold improved efficacy/toxicity ratio over currently used antiseptic agents. Further, CAGE penetrates deep into the dermis and treats pathogens located in deep skin layers as confirmed by the ability of CAGE in vivo to treat Propionibacterium acnes infection. In combination, the results clearly demonstrate CAGE holds promise as a transformative platform antiseptic agent for preventive as well as therapeutic applications. PMID- 26959836 TI - A Peptidoglycan-Remodeling Enzyme Is Critical for Bacteroid Differentiation in Bradyrhizobium spp. During Legume Symbiosis. AB - In response to the presence of compatible rhizobium bacteria, legumes form symbiotic organs called nodules on their roots. These nodules house nitrogen fixing bacteroids that are a differentiated form of the rhizobium bacteria. In some legumes, the bacteroid differentiation comprises a dramatic cell enlargement, polyploidization, and other morphological changes. Here, we demonstrate that a peptidoglycan-modifying enzyme in Bradyrhizobium strains, a DD carboxypeptidase that contains a peptidoglycan-binding SPOR domain, is essential for normal bacteroid differentiation in Aeschynomene species. The corresponding mutants formed bacteroids that are malformed and hypertrophied. However, in soybean, a plant that does not induce morphological differentiation of its symbiont, the mutation does not affect the bacteroids. Remarkably, the mutation also leads to necrosis in a large fraction of the Aeschynomene nodules, indicating that a normally formed peptidoglycan layer is essential for avoiding the induction of plant immune responses by the invading bacteria. In addition to exopolysaccharides, capsular polysaccharides, and lipopolysaccharides, whose role during symbiosis is well defined, our work demonstrates an essential role in symbiosis for yet another rhizobial envelope component, the peptidoglycan layer. PMID- 26959837 TI - Genome-Wide Association Study Identifies Novel Candidate Genes for Aggressiveness, Deoxynivalenol Production, and Azole Sensitivity in Natural Field Populations of Fusarium graminearum. AB - Genome-wide association studies can identify novel genomic regions and genes that affect quantitative traits. Fusarium head blight is a destructive disease caused by Fusarium graminearum that exhibits several quantitative traits, including aggressiveness, mycotoxin production, and fungicide resistance. Restriction site associated DNA sequencing was performed for 220 isolates of F. graminearum. A total of 119 isolates were phenotyped for aggressiveness and deoxynivalenol (DON) production under natural field conditions across four environments. The effective concentration of propiconazole that inhibits isolate growth in vitro by 50% was calculated for 220 strains. Approximately 29,000 single nucleotide polymorphism markers were associated to each trait, resulting in 50, 29, and 74 quantitative trait nucleotides (QTNs) that were significantly associated to aggressiveness, DON production, and propiconazole sensitivity, respectively. Approximately 41% of these QTNs caused nonsynonymous substitutions in predicted exons, while the remainder were synonymous substitutions or located in intergenic regions. Three QTNs associated with propiconazole sensitivity were significant after Bonferroni correction. These QTNs were located in genes not previously associated with azole sensitivity. The majority of the detected QTNs were located in genes with predicted regulatory functions, suggesting that nucleotide variation in regulatory genes plays a major role in the corresponding quantitative trait variation. PMID- 26959839 TI - Electrically-tunable surface deformation of a soft elastomer. AB - The flat surface of a thin elastomer on a conducting substrate can be deformed by applying an electric field to a percolating network of metallic nanowires randomly dispersed over the surface. The magnitude of the field-induced surface undulations increases with the applied field and can locally be several times the diameter of the nanowires. Optical imaging indicates that the effect is reversible and the surface flatness is recovered when the electric field is removed. It is found that it is the field-induced changes in the surface morphology rather than the nanowires themselves that strongly scatter light. The optical effects could be exploited in functional devices including tunable privacy windows, displays, and camouflage. There is also the potential for tuning the adhesion of elastomers to other materials. PMID- 26959838 TI - Genome Sequencing and Transposon Mutagenesis of Burkholderia seminalis TC3.4.2R3 Identify Genes Contributing to Suppression of Orchid Necrosis Caused by B. gladioli. AB - From a screen of 36 plant-associated strains of Burkholderia spp., we identified 24 strains that suppressed leaf and pseudobulb necrosis of orchid caused by B. gladioli. To gain insights into the mechanisms of disease suppression, we generated a draft genome sequence from one suppressive strain, TC3.4.2R3. The genome is an estimated 7.67 megabases in size, with three replicons, two chromosomes, and the plasmid pC3. Using a combination of multilocus sequence analysis and phylogenomics, we identified TC3.4.2R3 as B. seminalis, a species within the Burkholderia cepacia complex that includes opportunistic human pathogens and environmental strains. We generated and screened a library of 3,840 transposon mutants of strain TC3.4.2R3 on orchid leaves to identify genes contributing to plant disease suppression. Twelve mutants deficient in suppression of leaf necrosis were selected and the transposon insertions were mapped to eight loci. One gene is in a wcb cluster that is related to synthesis of extracellular polysaccharide, a key determinant in bacterial-host interactions in other systems, and the other seven are highly conserved among Burkholderia spp. The fundamental information developed in this study will serve as a resource for future research aiming to identify mechanisms contributing to biological control. PMID- 26959840 TI - Automated screening of reversed-phase stationary phases for small-molecule separations using liquid chromatography with mass spectrometry. AB - There are various reversed-phase stationary phases that offer significant differences in selectivity and retention. To investigate different reversed-phase stationary phases (aqueous stable C18 , biphenyl, pentafluorophenyl propyl, and polar-embedded alkyl) in an automated fashion, commercial software and associated hardware for mobile phase and column selection were used in conjunction with liquid chromatography and a triple quadrupole mass spectrometer detector. A model analyte mixture was prepared using a combination of standards from varying classes of analytes (including drugs, drugs of abuse, amino acids, nicotine, and nicotine-like compounds). Chromatographic results revealed diverse variations in selectivity and peak shape. Differences in the elution order of analytes on the polar-embedded alkyl phase for several analytes showed distinct selectivity differences compared to the aqueous C18 phase. The electron-rich pentafluorophenyl propyl phase showed unique selectivity toward protonated amines. The biphenyl phase provided further changes in selectivity relative to C18 with a methanolic phase, but it behaved very similarly to a C18 when an acetonitrile-based mobile phase was evaluated. This study shows the value of rapid column screening as an alternative to excessive mobile phase variation to obtain suitable chromatographic settings for analyte separation. PMID- 26959842 TI - Molecular Interaction between Stress and Pain. PMID- 26959843 TI - How to minimize morbidity in radiotherapy of pharyngolaryngeal tumors? AB - PURPOSE OF REVIEW: Radiotherapy is one of the most effective treatment modalities for head and neck cancer. However, because of the intricacy between tumors and normal tissues, it can induce morbidity, such as mucositis, dermatitis, xerostomia, dysphagia, hearing loss, vision impairment, skin fibrosis, and osteoradionecrosis of the jaw, and it can dramatically impact on patient quality of life. RECENT FINDINGS: Throughout the last decade, significant improvements have been made in head and neck cancer radiotherapy, especially with the introduction on a routine basis of intensity-modulated radiotherapy. SUMMARY: In this context, this review manuscript will focus on how the implementation of intensity-modulated radiotherapy influences treatment morbidity. Specifically, the issues of target volume and organ-at-risk delineation, sparing of organs at risk, tailored treatment intensity, adaptive treatment, and the use of proton therapy will be discussed. PMID- 26959841 TI - Fenofibrate attenuates diabetic nephropathy in experimental diabetic rat's model via suppression of augmented TGF-beta1/Smad3 signaling pathway. AB - CONTEXT: Fibrates, the ligands of peroxisome profileferator-activated receptor alpha have been shown to have a renal protective action in diabetic nephropathy (DN). OBJECTIVE: This study aimed to elucidate the effect of fenofibrate on renal transforming growth factor-beta1 (TGF-beta1) and Smad3 in Streptozotocin (STZ) induced DN. METHODS: Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (55 mg/kg). Diabetic rats were given fenofibrate (100 mg/kg, p.o.). After 12 weeks, diabetic nephropathy biomarkers were assessed. The mRNA expression of collage I and III, TGF-beta1 and Smad3 and were detected by RT PCR. RESULTS: Fenofibrate reduced significantly serum creatinine, kidney/body weight ratio, serum albumin excretion Collage I & III, TGF-beta1 and Smad3 mRNA expression. CONCLUSIONS: Our results give further insights into the mechanisms underlying the protective role of fenofibrate in DN, suggesting that interference with TGF-beta1/Smad3 signaling pathway may be a useful therapeutic approach to prevent DN. PMID- 26959844 TI - Management of arterial injury during endoscopic sinus and skull base surgery. AB - PURPOSE OF REVIEW: The most feared complication during endonasal surgery is a carotid artery injury. The sheep model of carotid injury provides training for this event by giving a realistic endoscopic experience of major vascular injuries and tissue hemostasis. RECENT FINDINGS: The sheep model of carotid artery injury recreates the narrow nasal confines and high-flow/high-pressure vascular injury accurately reproducing the endoscopic challenges seen in such vascular emergencies. This has led to the development of surgical techniques that quickly and effectively control the field of bleeding and achieve reliable hemostasis including the crushed muscle patch new direct vascular closure technologies. Vascular emergency simulation training is achieving better outcomes for our patients. SUMMARY: All skull base surgeons are at risk of the unexpected carotid artery injury and recently, the sheep model not only effectively recreates this situation but has identified clinically tried and tested techniques at managing this situation and is improving patient outcomes. PMID- 26959854 TI - Proteome and carbon flux analysis of Pseudomonas aeruginosa clinical isolates from different infection sites. AB - Pseudomonas aeruginosa is known as opportunistic pathogen frequently isolated from different infection sites. To investigate the expression rates of P. aeruginosa proteins commonly expressed by different clinical isolates, absolute protein quantities were determined employing a gel-free and data-independent LC IMS(E) approach. Moreover, the metabolic diversity of these isolates was investigated by (13) C-metabolic flux analyses. 812 proteins were reproducibly identified and absolutely quantified for the reference strain P. aeruginosa PAO1, 363 of which were also identified and relatively quantified in all isolates. Whilst the majority of these proteins were expressed in constant amounts, expression rates of 42 proteins were highly variable between the isolates. Notably, the outer membrane protein OprH and the response regulator PhoP were strongly expressed in burned wounds isolates compared to lung/urinary tract isolates. Moreover, proteins involved in iron/amino acids uptake were found to be highly abundant in urinary tract isolates. The fluxome data revealed a conserved glycolysis, and a niche-specific divergence in fluxes through the glyoxylate shunt and the TCA cycle among the isolates. The integrated proteome/fluxome analysis did not indicate straightforward correlation between the protein amount and flux, but rather points to additional layers of regulation that mediate metabolic adaption of P. aeruginosa to different host environments. All MS data have been deposited in the ProteomeXchange with identifier PXD002373 (http://proteomecentral.proteomexchange.org/dataset/PXD002373). PMID- 26959855 TI - Evaluation of O-alkyl and aryl sulfonyl aromatic and heteroaromatic amidoximes as novel potent DNA photo-cleavers. AB - Several stable O-alkyl and aryl sulfonyl conjugated p-nitro-Ph and o-, m-, p pyridine N'-hydroxy imidamides, were subjected to UV irradiation at 312 nm with supercoiled circular plasmid DNA pBluescript KS II. The generated amidinyl and sulfonyloxyl radicals led to effective DNA photo-cleavage. Both alkyl and aryl sulfonyl derivatives were active and the order p-pyridine > p-nitro-Ph > o pyridine > m-pyridine was schematized for the N'-hydroxy imidamides moiety. Calf thymus-DNA affinity studies which comprised UV interactions, viscosity experiments and competitive studies with ethidium bromide showed good to excellent affinity of the compounds. These properties revealed sulfonyl amidoximes as novel effective DNA-photo-cleavers and may serve in the discovery of new leads for "on demand" biotechnological and medical applications. PMID- 26959846 TI - Polymer-coated pH-responsive high-density lipoproteins. AB - Intracellular drug delivery by nanoparticles is often hampered by their endosomal entrapment followed by their degradation in the lysosomal compartment and/or exocytosis. Here, we show that internalization and endosomal escape of cargoes in a cationized natural nanocarrier, high-density lipoprotein (HDL), can be controlled in a pH-dependent manner through stable complexation with a membranolytic anionic block polymer. A genetically and chemically cationized form of HDL (catHDL) is prepared for the first time by both genetic fusion with YGRKKRRQRRR peptide and incorporation of 1,2-dioleoyloxy-3 (trimethylammonium)propane. Upon addition of poly(ethylene glycol)-block poly(propyl methacrylate-co-methacrylic acid) (PA), catHDL yields inhibition of internalization at neutral pH and its subsequent recovery at mildly acidic pH. catHDL forms a stable discoidal-shape complex with PA (catHDL/PA) (ca. 50 nm in diameter), even in the presence of serum. Significant enhancement of endosomal escape of a catHDL component is observed after a 1-h treatment of human cancer cells with catHDL/PA. Doxorubicin and curcumin, fluorescent anti-cancer drugs, encapsulated into catHDL/PA are also translocated outside of endosomes, compared with that into catHDL, and their cytotoxicities are enhanced inside the cells. These data suggest that catHDL/PA may have a potential benefit to improve the cellular delivery and endosomal escape of therapeutics under mildly acidic conditions such as in tumor tissues. PMID- 26959857 TI - Controlling the Reactivity of Bifunctional Ligands: Carboxylate-Bridged Nonheme Diiron(II) Complexes Bearing Free Thiol Groups. AB - Carboxylate-bridged nonheme diiron(II) complexes, bearing free functional groups in general, and free thiol groups in particular, were sought. While the addition of sodium gamma-hydroxybutyrate into a mixture of Fe(BF4)2.6H2O, HN-Et-HPTB, and Et3N afforded the complex [Fe2(N-Et-HPTB)(MU-O2C-(CH2)3-OH)](BF4)2 (2) (where N Et-HPTB is the anion of N,N,N',N'-tetrakis(2-(1-ethylbenzimidazolyl))-2-hydroxy 1,3-diaminopropane), a similar, straightforward process could not be used for the synthesis of diiron(II) complexes with free thiol groups. In order to circumvent this problem, a new class of thiolate bridged diiron(II) complexes, [Fe2(N-Et HPTB)(MU-SR(1))](BF4)2 (R(1) = Me (1a), Et (1b), (t)Bu (1c), Ph (1d)) was synthesized. Selective proton exchange reactions of one representative compound, 1b, with reagents of the type HS-R(2)-COOH yielded the target compounds, [Fe2(N Et-HPTB)(MU-O2C-R(2)-SH)](BF4)2 (R(2) = C6H4 (3a), CH2CH2 (3b), CH2(CH2)5CH2 (3c)). Redox properties of the complexes 3a-3c were studied in comparison with the complex, [Fe2(N-Et-HPTB)(MU-O2CMe)](BF4)2 (5). Reaction of (Cp2Fe)(BF4) with 1b yielded [Fe(II)2(N-Et-HPTB)(DMF)3](BF4)3.DMF (4) (when crystallized from DMF/diethyl ether), which might indicate the formation of a transient ethanethiolate bridged {Fe(II)Fe(III)} species, followed by a rapid internal redox reaction to generate diethyldisulfide and the solvent coordinated diiron(II) complex, 4. This possibility was supported by a comparative cyclic voltammetric study of 1a-1c and 4. Prospects of the complexes of the type 3a-3c as potential building blocks for the synthesis of nonheme diiron(II) complexes covalently attached with other redox active metals has been substantiated by the synthesis of the complexes, [Fe2(N-EtHPTB)(MU-O2C-R(2)-S)Cu(Me3TACN)](BF4)2 (R = p-C6H4 (7a), CH2CH2 (7b)). All the compounds were characterized by a combination of single-crystal X-ray structure determinations and/or elemental analysis. PMID- 26959856 TI - Bioengineered Magnetoferritin Nanoprobes for Single-Dose Nuclear-Magnetic Resonance Tumor Imaging. AB - Despite all the advances in multimodal imaging, it remains a significant challenge to acquire both magnetic resonance and nuclear imaging in a single dose because of the enormous difference in sensitivity. Indeed, nuclear imaging is almost 10(6)-fold more sensitive than magnetic resonance imaging (MRI); thus, repeated injections are generally required to obtain sufficient MR signals after nuclear imaging. Here, we show that strategically engineered magnetoferritin nanoprobes can image tumors with high sensitivity and specificity using SPECT and MRI in living mice after a single intravenous injection. The magnetoferritin nanoprobes composed of (125)I radionuclide-conjugated human H-ferritin iron nanocages ((125)I-M-HFn) internalize robustly into cancer cells via a novel tumor specific HFn-TfR1 pathway. In particular, the endocytic recycling characteristic of TfR1 transporters solves the nuclear signal blocking issue caused by the high dose nanoprobes injected for MRI, thus enabling simultaneous functional and morphological tumor imaging without reliance on multi-injections. PMID- 26959858 TI - Successful Treatment of Refractory Dyskinesia Secondary to Anti-N-Methyl-D Aspartate Receptor Encephalitis With Electroconvulsive Therapy. PMID- 26959859 TI - Demographic and Clinical Profile of Patients With Dementia Receiving Electroconvulsive Therapy: A Case-Control Study. AB - PURPOSE: Little is known about the clinical characteristics of patients with dementia receiving electroconvulsive therapy (ECT) for the treatment of behavioral symptoms. This study examined the demographic and clinical profile of patients with dementia receiving ECT in China. METHODS: This was a retrospective, case-control study. The sample was composed of 23 patients with dementia treated with ECT and 71 sex- and age-matched controls treated for a period of 8 years (2007-2014) at the National Clinical Research Centre of Mental Disorders, China. Sociodemographic and clinical data were collected from the electronic chart management system. RESULTS: Multiple logistic regression analysis revealed that ECT was independently associated with high risk for suicide at admission. The recorded indications for ECT included both high risk for suicide and aggressive behavior. Most patients responded to ECT satisfactorily (56.5%) or partially (34.8%) with only mild-moderate transient memory impairment (30.4%). CONCLUSIONS: Although this is a preliminary study limited by the retrospective design and small sample size, findings suggest that ECT is an effective and safe therapeutic intervention to reduce the risk for suicide and aggressive behavior in dementia. PMID- 26959860 TI - Targeting Type 2: Linguistic Agency Assignment in Diabetes Prevention Policy Messaging. AB - We explored the effects of linguistic agency assignment on the persuasive impact of a fictitious medical journal editorial about Type 2 diabetes. Participants (N = 422) read 1 of 4 versions of an editorial that differed in the language used to describe the health threat posed by the disease (threat agency) and to outline a program for preventing it (prevention agency). Threat agency was assigned either to the disease (e.g., diabetes puts individuals' lives at risk) or to humans (e.g., individuals who acquire diabetes put their lives at risk). Prevention agency was assigned either to the recommended prevention behaviors (e.g., a healthy diet and regular exercise protect children from Type 2) or to humans (e.g., children who eat a healthy diet and exercise regularly protect themselves from Type 2). Respondents' perceptions of disease severity were higher when threat agency was assigned to diabetes rather than humans. However, attitudes toward the proposed prevention program were higher when prevention agency was assigned to humans rather than to the recommended behaviors. The latter finding contrasts with agency effects observed in previous research on a viral threat, suggesting that the optimal pattern of agency assignment in prevention messaging may be different for acute and chronic lifestyle diseases. PMID- 26959861 TI - The Driving of Immune Response by Th1 Adjuvants in Immunization of Mice with Trypanosoma cruzi marinkellei Elicits a Controversial Infection Control. AB - In previous studies, we have demonstrated that inoculation with a Trypanosoma cruzi marinkellei (avirulent RM1 strain) was able to reduce parasitemia in mice challenged with T. cruzi, although it was not able to prevent histopathological lesions. Th1 response stimulation by immunization is necessary for T. cruzi infection control, but the resistance is also dependent on immunoregulatory mechanisms, which can be induced by adjuvants. Thus, we evaluated whether inoculation of T. cruzi marinkellei associated with administration of different adjuvants would be capable of inducing different patterns of immune response to maximize the immune response against T. cruzi (virulent Romildo strain) infection. Two hundred eighty nonisogenic mice were divided into 14 groups according to the immunization scheme and the subsequent challenge with virulent Romildo T. cruzi strain. Nonimmunized groups and animals inoculated without adjuvants were also included. Immune protection was not observed with Th2 adjuvants (incomplete Freund's adjuvant [IFA] and Alum) due to high parasitemia. Th1/Th2-polarizing adjuvants also did not induce immune protection because inulin was unable to maintain survival, and immune-stimulating complexes induced intense inflammatory processes. Animals sensitized with RM1 strain without adjuvants were able to reduce parasitemia, increase survival, and protect against severe histological lesions, followed by adequate cytokine stimulation. Finally, our results demonstrate that the early and balanced IFN-gamma production becomes critical to promote protection and that Th1 adjuvant elicited a controversial infection control due to increased histopathological damage. Therefore, the host's immunomodulation remains one of the most important challenges in the research for effective protection against T. cruzi infection. Similarly, the identification of protective antigens in the RM1 strain of T. cruzi marinkellei may contribute to further studies on vaccine development against human Chagas disease. PMID- 26959862 TI - Neutral copper(I) complexes featuring phosphinesulfonate chelates. AB - The reaction of diphenylphosphinobenzenesulfonic acid with copper(i) oxide resulted in the formation of the new neutral dimeric copper(i) complex {Cu2(DPPBS)2.(MeOH)2}. X-ray diffraction studies revealed that the complex has a dimeric structure and a pyramidal trigonal geometry around the copper atom which contains coordinated methanol molecules at the copper centers. Cleavage of the dimer by reaction with various bipyrimidines enabled the preparation of the corresponding well-defined heterotopic mononuclear [Cu(P^O)(N^N)] and dinuclear {(P^O)Cu(N^N)Cu(P^O)} complexes. X-ray crystal structure determination shows these to have distorted tetrahedral geometries. Their absorption and emission properties were investigated experimentally and photophysical data were also confirmed by DFT and TD-DFT calculations. Owing to the methanol molecules, the neutral crystalline dimer {Cu2(DPPBS)2.(MeOH)2} displays green reversible photoluminescence upon UV irradiation in the solid state with an absolute luminescence quantum yield of 0.51. PMID- 26959863 TI - Boron-Catalyzed Aromatic C-H Bond Silylation with Hydrosilanes. AB - Metal-free catalytic C-H silylation of a series of aromatic compounds such as N,N disubstituted anilines with various hydrosilanes has been achieved for the first time using commercially available B(C6F5)3 as a catalyst. This protocol features simple and neutral reaction conditions, high regioselectivity, wide substrate scope (up to 40 examples), Si-Cl bond compatibility, and no requirement for a hydrogen acceptor. PMID- 26959864 TI - An Examination of the Biomedical Paradigm: A View of Social Work. AB - The biomedical paradigm provides foundational assumptions that shape the context within which social workers in health care settings practice. By providing social workers with a greater understanding of the history, epistemology, and key assumptions, this article aims to promote critical awareness and critical reflection on how the biomedical paradigm may be influencing health care environments. The analysis of this article raises important questions for social workers within health care environments, questions about how social workers are able to retain their disciplinary identity as agents of change in the pursuit of social justice. PMID- 26959865 TI - Femtosecond Time-Resolved Dynamics of trans-Azobenzene on Gold Nanoparticles. AB - We report a first femtosecond time-resolved transient absorption study of the photoinduced ultrafast dynamics of trans-azobenzene (AB) on gold nanoparticles (AuNPs). The observed changes in optical density following excitation at lambda = 357 nm were analyzed by using temperature-dependent Mie theory and by Lorentzian band fitting to disentangle the ultrafast relaxation of the local surface plasmon resonance (LSPR) excitation of the Au core and the electronic deactivation of the attached AB ligands. The analysis of the dynamics associated with the AB photochrome yielded lifetime constants of tau1 = 1.2 +/- 0.2 ps and tau2 = 4.7 +/ 1.1 ps. Both values together indicate surprisingly little difference in the dynamics of the AB ligand on the AuNPs vs in solution. Our results thus highlight the extraordinarily efficient electronic decoupling of the azo chromophore and the Au core by the alkyl linker chain. PMID- 26959866 TI - Contribution of Nicotine and Nornicotine toward the Production of N' Nitrosonornicotine in Air-Cured Tobacco (Nicotiana tabacum). AB - N'-Nitrosonornicotine (6) is a potent and organ-specific carcinogen found in tobacco and tobacco smoke in substantial amounts. Nicotine (1) and nornicotine (2) are proposed to be the precursors of 6 in tobacco. Since 1 can be rapidly demethylated to 2 in tobacco, to distinguish between the direct formation of 6 from these potential precursors is difficult. A gas chromatography/thermal energy analyzer method using two columns in series was developed to separate the enantiomers of 6, N'-nitrosoanabasine (7), and N'-nitrosoanatabine (8). Tobacco lines with different combinations of three nicotine demethylases inhibited were grown in the field. Air-cured leaves were analyzed for the enantiomeric composition of four main alkaloids and their corresponding tobacco-specific nitrosamines. The percentage of (R)-6 of total 6 varied from 7% to 69% in mutant lines. The measured 6 had the same enantiomeric composition as 2, rather than 1, even when the level of 2 was reduced to 0.6% of 1 in a triple mutant line. The pattern of the enantiomeric composition of 1, 2, and 6 demonstrated that the direct formation of 6 from 1, if it occurs, is negligible in air-cured tobacco. Since (S)-6 is more highly carcinogenic than its R form, the reduction of (S)-2 should be a priority for the reduction of 6. PMID- 26959867 TI - Enantioselective Friedel-Crafts Alkylation Reactions of 3-Substituted Indoles with Electron-Deficient Alkenes. AB - Highly enantioselective Friedel-Crafts C2-alkylation reactions of 3-substituted indoles with alpha,beta-unsaturated esters and nitroalkenes were developed using chiral Lewis acids as catalysts, which afforded chiral indole derivatives bearing C2-benzylic stereogenic centers in good to excellent yields (up to 99%) and enantioselectivities (up to 96% ee). PMID- 26959868 TI - Separation and Identification of Isomeric Glycans by Selected Accumulation Trapped Ion Mobility Spectrometry-Electron Activated Dissociation Tandem Mass Spectrometry. AB - One of the major challenges in structural characterization of oligosaccharides is the presence of many structural isomers in most naturally occurring glycan mixtures. Although ion mobility spectrometry (IMS) has shown great promise in glycan isomer separation, conventional IMS separation occurs on the millisecond time scale, largely restricting its implementation to fast time-of-flight (TOF) analyzers which often lack the capability to perform electron activated dissociation (ExD) tandem MS analysis and the resolving power needed to resolve isobaric fragments. The recent development of trapped ion mobility spectrometry (TIMS) provides a promising new tool that offers high mobility resolution and compatibility with high-performance Fourier transform ion cyclotron resonance (FTICR) mass spectrometers when operated under the selected accumulation-TIMS (SA TIMS) mode. Here, we present our initial results on the application of SA-TIMS ExD-FTICR MS to the separation and identification of glycan linkage isomers. PMID- 26959869 TI - Patient reported outcomes in randomized controlled cancer trials in advanced disease: a structured literature review. AB - INTRODUCTION: In advanced cancer quality of life (QoL) is the most important goal of care. It is measured by patient-reported-outcomes (PRO). This structured review evaluated how randomized controlled trials (RCTs) on anti-cancer therapy in advanced cancer reported PRO. METHODS: Search was performed in MEDLINE via PubMed for RCTs with median patient survival of <=2 years. Reporting was rated with the Consolidated Standards of Reporting Trials (CONSORT) PRO extension. RESULTS: Of 370 retrieved publications, 117 were eligible, but only 30/117 (26%) reported PRO. QoL was most frequently measured (29/30). On average, 4.4 (SD 2.5) of the 14 CONSORT items were met. CONCLUSION: PRO are insufficiently reported in advanced cancer trials. Yet, this is paramount to enable an informed and patient oriented decision making process. PMID- 26959871 TI - Differences in physical characteristics between Brazilian World Championship and South American Championship National basketball teams. PMID- 26959870 TI - Annotation of porcine milk oligosaccharides throughout lactation by hydrophilic interaction chromatography coupled with quadruple time of flight tandem mass spectrometry. AB - Swine plays a significant role in livestock agriculture. As a linkage between sows and piglets, porcine milk is crucial for the health of newborn piglets. Free milk oligosaccharides (MOs) are kinds of important bioactive substance in mammalian milk. However, little is known about the component and function of the porcine MOs (PMOs). In this study, a hydrophilic interaction chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (HILIC-Q-TOF MS) system was utilized to profile the PMOs. Forty-one distinct PMOs were identified totally in three breeds of sows. The PMOs were highly sialylated (~30%) and fucosylated PMOs (1-3%) were monitored at low levels. The most abundant oligosaccharide was a trisaccharide (Hex3 ) which contributed over 50% of the total PMOs abundance. Comparison of free MOs profiles revealed heterogeneity and variations among individuals and different breeds of sows, however, the MOs variation among breeds was limited even minor than that among individuals. Furthermore, most PMOs contents were higher in colostrum and decreased in the early lactation, but a few kinds increased at last. Different oligosaccharides had different patterns during lactation. Overall, these observations showed a more detailed PMOs library and would contribute to the exploration of influence of PMOs on piglets' health. PMID- 26959872 TI - Hand grip strength and anthropometric characteristics in Italian female national basketball teams. AB - BACKGROUND: The aim of this study was to investigate the influence of hand and body dimensions on hand grip strength and to define a reference scale for talent identification in basketball players. METHODS: Body and hand anthropometric data and the maximal handgrip strength of 109 female Italian basketball National players (Under14-Seniores) were measured. RESULTS: Handgrip strength and arm length trend increased, raising the statistical significant differences only for players from the age of 19 (U20, Seniores) with respect to sub-elite groups (U14, U15) (P<0.05). Handgrip strength showed low positive correlations with height and Body Mass Index but a positive relationships with arm length (r=0.5; P<0.001). Findings underline training and years of practice have effects on increasing handgrip strength. CONCLUSIONS: Data show that to select female basketball players by arm length means selecting by handgrip strength. Thus it is possible to suggest that in addition to height, arm length could also be considered a useful parameter in young female talent identification. PMID- 26959873 TI - Factors that influence ground reaction force profiles during counter movement jumping. AB - BAKGROUND: The purpose of this study was to examine how hip, knee and ankle kinetics and kinematics influence effective impulse production during countermovement jumps. METHODS: Eighteen semi-professional soccer players (22.8+/ 2.2 years) volunteered to participate in the study. Participants completed three maximal countermovement jumps on two force platforms (1000 Hz) that were linked to a nine camera infrared motion capture system (500 Hz). RESULTS: Kinetic and kinematic data revealed jumpers who fail to achieve uniform ground reaction force curves that result in optimal impulse production during their jump always display hip adduction and or hip internal rotation during the concentric phase of the countermovement jump. The variation of hip adduction and or internal rotation likely represents failed joint transition during the concentric phase of the countermovement jump and appears to account for a non-uniform force trace seen in these jumpers. CONCLUSIONS: The findings suggest rehabilitation and conditioning exercises for injury prevention and performance may benefit from targeting frontal and transverse plane movement. PMID- 26959874 TI - Dietary macronutrient distribution influences postexercise substrate utilization in women: a cross-sectional evaluation of metabolic flexibility. AB - BACKGROUND: Metabolic flexibility is the ability to alter substrate utilization in response to substrate availability, which may influence health and performance. The current study evaluated the effects of habitual macronutrient distribution on energy expenditure (EE) and metabolic flexibility in physically active women. METHODS: Participants (N.=20) completed a 3-day food log and a standardized bout of high-intensity interval training to determine EE and respiratory exchange ratio (RER). EE and RER were measured via indirect calorimetry at rest (PRE) and immediately (IP), 30 minutes (30 min), and 60 minutes postexercise (60 min). To evaluate metabolic flexibility, RER changes were calculated from PRE to IP, IP to 30 min, and IP to 60 min. For each macronutrient, participants were categorized into high- and low-intake groups using a median split. RESULTS: No significant correlations were observed between macronutrient distribution and EE when covaried for lean mass (all P>=0.232), and ANCOVAs revealed no significant group * time interactions (all P>=0.241). Fat intake was not associated with ?RER (all P>=0.477). Correlations between PRO intake and ?RER approached significance (r=0.373-0.411; P=0.079-0.115), as did inverse associations between CHO and ?RER (r=-0.404 - -0.409; P=0.084-0.087). Lower RER values were observed in the low-CHO group at 30 min and 60 min (P=0.030) compared to high-CHO. Higher RER values were observed in the high-PRO group at IP (P=0.042) compared to low-PRO. Estradiol was not correlated with RER at any time point, or different between diet groups (all P>=0.401). CONCLUSIONS: Results suggest that high PRO and low CHO intakes are associated with greater metabolic flexibility in women. PMID- 26959875 TI - Cross-sectional relationships between sedentary behavior and frailty in older adults. AB - BACKGROUND: The aim of this study was to analyze the association between frailty and sedentary behavior and to examine the discriminative ability of sedentary behavior in screening frailty in older adults. METHODS: This was a cross sectional study based on data from an epidemiologic population-based household survey involving 316 community-dwelling older adults (>=60 years) of both sexes (173 women and 143 men). The frailty was measured from an adapted version of the criteria proposed by Fried et al. in 2001, which is based on the presence of three or more of the following components: shrinking, weakness, poor endurance/exhaustion, slowness and low activity. Sedentary behavior was determined by the International Physical Activity Questionnaire (long version). RESULTS: The prevalence of frailty was 23.8%, and the average time in sedentary behavior was 6.1+/-3.2 h/day. Sedentary behavior was independently and positively associated with frailty (PR=1.10; 95% CI: 1.02-1.19; P=0.013). The ROC curve showed that the sedentary behavior could discriminate frail older adults (AUC=0.66; 95% CI: 0.61-0.72), and the best cutoff point was 7 h/day (sensitivity =54% and specificity =75%). CONCLUSIONS: Frailty is strongly associated with sedentary behavior. Sedentary behavior can be a potential marker in screening of frailty in community-dwelling older adults. Our findings suggest that reducing the time with sedentary behavior and increasing the time with physical activity may prevent frailty syndrome. PMID- 26959876 TI - Structure and Function of 4-Hydroxyphenylacetate Decarboxylase and Its Cognate Activating Enzyme. AB - 4-Hydroxyphenylacetate decarboxylase (4Hpad) is the prototype of a new class of Fe-S cluster-dependent glycyl radical enzymes (Fe-S GREs) acting on aromatic compounds. The two-enzyme component system comprises a decarboxylase responsible for substrate conversion and a dedicated activating enzyme (4Hpad-AE). The decarboxylase uses a glycyl/thiyl radical dyad to convert 4-hydroxyphenylacetate into p-cresol (4-methylphenol) by a biologically unprecedented Kolbe-type decarboxylation. In addition to the radical dyad prosthetic group, the decarboxylase unit contains two [4Fe-4S] clusters coordinated by an extra small subunit of unknown function. 4Hpad-AE reductively cleaves S-adenosylmethionine (SAM or AdoMet) at a site-differentiated [4Fe-4S]2+/+ cluster (RS cluster) generating a transient 5'-deoxyadenosyl radical that produces a stable glycyl radical in the decarboxylase by the abstraction of a hydrogen atom. 4Hpad-AE binds up to two auxiliary [4Fe-4S] clusters coordinated by a ferredoxin-like insert that is C-terminal to the RS cluster-binding motif. The ferredoxin-like domain with its two auxiliary clusters is not vital for SAM-dependent glycyl radical formation in the decarboxylase, but facilitates a longer lifetime for the radical. This review describes the 4Hpad and cognate AE families and focuses on the recent advances and open questions concerning the structure, function and mechanism of this novel Fe-S-dependent class of GREs. PMID- 26959877 TI - The CHRM3 gene is implicated in abnormal thalamo-orbital frontal cortex functional connectivity in first-episode treatment-naive patients with schizophrenia. AB - BACKGROUND: The genetic influences in human brain structure and function and impaired functional connectivities are the hallmarks of the schizophrenic brain. To explore how common genetic variants affect the connectivities in schizophrenia, we applied genome-wide association studies assaying the abnormal neural connectivities in schizophrenia as quantitative traits. METHOD: We recruited 161 first-onset and treatment-naive patients with schizophrenia and 150 healthy controls. All the participants underwent scanning with a 3 T-magnetic resonance imaging scanner to acquire structural and functional imaging data and genotyping using the HumanOmniZhongHua-8 BeadChip. The brain-wide association study approach was employed to account for the inherent modular nature of brain connectivities. RESULTS: We found differences in four abnormal functional connectivities [left rectus to left thalamus (REC.L-THA.L), left rectus to right thalamus (REC.L-THA.R), left superior orbital cortex to left thalamus (ORBsup.L THA.L) and left superior orbital cortex to right thalamus (ORBsup.L-THA.R)] between the two groups. Univariate single nucleotide polymorphism (SNP)-based association revealed that the SNP rs6800381, located nearest to the CHRM3 (cholinergic receptor, muscarinic 3) gene, reached genomic significance (p = 1.768 * 10-8) using REC.L-THA.R as the phenotype. Multivariate gene-based association revealed that the FAM12A (family with sequence similarity 12, member A) gene nearly reached genomic significance (nominal p = 2.22 * 10-6, corrected p = 0.05). CONCLUSIONS: Overall, we identified the first evidence that the CHRM3 gene plays a role in abnormal thalamo-orbital frontal cortex functional connectivity in first-episode treatment-naive patients with schizophrenia. Identification of these genetic variants using neuroimaging genetics provides insights into the causes of variability in human brain development, and may help us determine the mechanisms of dysfunction in schizophrenia. PMID- 26959878 TI - Carbon and Hydrogen Stable Isotope Fractionation Associated with the Aerobic and Anaerobic Degradation of Saturated and Alkylated Aromatic Hydrocarbons. AB - Saturated hydrocarbons (alkanes) and alkylated aromatic hydrocarbons are abundant environmental compounds. Hydrocarbons are primarily removed from the environment by biodegradation, a process usually associated with moderate carbon and significant hydrogen isotope fractionation allowing monitoring of biodegradation processes in the environment. Here, we review the carbon and hydrogen stable isotope fractionation associated with the cleavage of C-H bonds at alkyl chains of hydrocarbons. Propane, n-butane and ethylbenzene were used as model components for alkyl moieties of aliphatic and aromatic hydrocarbons with emphasis on the cleavage of the C-H bond without the involvement of molecular oxygen. The carbon and hydrogen isotope fractionation factors were further used to explore the diagnostic potential for characterizing the mode of bond cleavage under oxic and anoxic conditions. x039B; factors, calculated to correlate carbon and hydrogen fractionation, allowed to distinguish between aerobic and anaerobic biodegradation processes in the environment. PMID- 26959879 TI - A short-term increase of the postoperative naturally circulating dendritic cells subsets in flurbiprofen-treated patients with esophageal carcinoma undergoing thoracic surgery. AB - The present study evaluated whether flurbiprofen increased the naturally circulating dendritic cells (DCs) subsets in patients with esophageal squamous cell carcinoma (ESCC) undergoing esophageal resection. Compared to healthy donors (n=20), the significantly depressed percentages of plasmacytoid DCs (pDCs), CD1c+ myeloid DCs (mDCs), and CD141+ mDCs among ESCC patients (n=60) were confirmed. Flurbiprofen was administered before skin incision and at the end of operation in group F (n=30), as well as placebo in group C (n=30). The postoperative suppressed percentages of pDCs, CD1c+ mDCs, and CD141+ mDCs increased significantly following the perioperative treatment with flurbiprofen. Flurbiprofen also significantly stimulated the postoperative IFN-f and IL-17 production, but inhibited the immunosuppressive IL-10 and TGF-beta levels. Furthermore, flurbiprofen exerted a similar analgesic effect and brought a significantly less sufentanil consumption compared to group C. Taken together, flurbiprofen provided a short-term increase of postoperative naturally circulating DCs in ESCC patients. PMID- 26959880 TI - Prp19 facilitates invasion of hepatocellular carcinoma via p38 mitogen-activated protein kinase/twist1 pathway. AB - Pre-mRNA processing factor 19 (Prp19) is involved in many cellular events including pre-mRNA processing and DNA damage response. However, the pathological role of Prp19 in hepatocellular carcinoma (HCC) is still elusive. Here, we reported that Prp19 was increased in most HCC tissues and HCC cell lines, and its overexpression in HCC tissues was positively correlated with vascular invasion, tumor capsule breakthrough and poor prognosis. Prp19 potentiated migratory and invasive abilities of HCC cells in vitro and in vivo. Furthermore Prp19 facilitated Twist1-induced epithelial-mesenchymal transition. Mechanistic insights revealed that Prp19 directly binded with TGF-beta-activated kinase1 (TAK1) and promoted the activation of p38 mitogen-activated protein kinase (MAPK), preventing Twist1 from degradation. Finally Prp19/p38 MAPK/Twist1 axis was attested in nude mice xenografts and HCC patient specimens. This work implies that the gain of Prp19 is a critical event during the progression of HCC, making it a promising target for malignancies with aberrant Prp19 expression. PMID- 26959881 TI - Metformin combined with sodium dichloroacetate promotes B leukemic cell death by suppressing anti-apoptotic protein Mcl-1. AB - Metformin and the mitochondrial targeting dichloroacetate (DCA) have recently received attention due to their ability to inhibit anaerobic glycolysis, which renders most cancer cells resistant to apoptosis induction. We observed that Metformin alone exhibited a dose-dependent anti-leukemic activity in both B leukemic cell lines and primary B-chronic lymphocytic leukemia (B-CLL) patients' cells and its anti-leukemic activity was enhanced when used in combination with DCA. In order to overcome the problems of poor bioavailability and cellular uptake, which limit DCA efficacy, we have designed and synthetized cocrystals consisting of Metformin and DCA (Met-DCA) at different stoichiometric ratios. Of note, the MetH(2)(++)*2DCA(-) cocrystal exhibited enhanced in vitro anti-leukemic activity, with respect to the treatment with the mix consisting of Metformin plus DCA. In particular, the treatment with the cocrystal MetH(2)(++)*2DCA(-) induced a synergistic apoptotic cell death coupled to a marked down-modulation of the anti-apoptotic Mcl-1 protein. Taken together, our data emphasize that innovative compounds based on Metformin-DCA combination merit to be further evaluated as chemotherapeutic agents for the treatment of B-CLL. PMID- 26959882 TI - P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis. AB - TP53 also known as p53 is a tumor suppressor gene mutated in a variety of cancers. P53 is involved in cell cycle, apoptosis and DNA repair mechanisms and is thus tightly controlled by many regulators. Recently, strategies to treat cancer have focused on the development of MDM2 antagonists to induce p53 stabilization and restore cell death in p53 non-mutated cancers. However, some of these molecules display adverse effects in patients including induction of thrombocytopenia. In the present study, we have explored the effect of SAR405838 not only on human megakaryopoiesis but also more generally on hematopoiesis. We compared its effect to MI-219 and Nutlin, which are less potent MDM2 antagonists than SAR405838. We found that all these compounds induce a deleterious effect on all types of hematopoietic progenitors, as well as on erythroid and megakaryocytic differentiation. Moreover, they inhibit both early and late stages of megakaryopoiesis including ploidization and proplatelet formation. In conclusion, MDM2 antagonists induced a major hematopoietic defect in vitro as well as an inhibition of all stages of megakaryopoiesis that may account for in vivo thrombocytopenia observed in treated patients. PMID- 26959883 TI - Overexpression of USP39 predicts poor prognosis and promotes tumorigenesis of prostate cancer via promoting EGFR mRNA maturation and transcription elongation. AB - Castration resistance is a serious problem facing clinical treatment of prostate cancer (PCa). The underlying molecular mechanisms of acquired proliferation ability of tumor cells upon androgen deprivation are largely undetermined. In the present study, we identified that ubiquitin specific peptidase 39 (USP39) was significantly upregulated in PCa samples and cell lines. Elevated USP39 expression was positively correlated with Gleason score, predicted a poor outcome, and functioned as an independent risk factor for biochemical recurrence (BCR) especially in patients with a Gleason score <=7. Our cell-based study showed that the expression level of USP39 was the highest in AR-negative PCa cell lines. Knockdown of USP39 in PCa cells inhibited cancer colony formation and tumor cell growth, and induced G2/M arrest and cell apoptosis. Microarray analysis suggested that knockdown of USP39 caused a reduced expression of EGFR. Silencing of USP39 inhibited the expression of EGFR 3'-end, and presented a remarkable block to the maturation of EGFR mRNA, suggesting that silencing of USP39 decreased the transcriptional elongation and maturation of EGFR mRNA. Oncomine datasets analysis showed that USP39 expression was positively correlated with EGFR level. The above findings suggest that USP39 plays a vital oncogenic role in the tumorigenesis of PCa and may prove to be a potential biomarker for predicting the prognosis of PCa patients. PMID- 26959884 TI - Prognostic role of STAT3 in solid tumors: a systematic review and meta-analysis. AB - Accumulated studies have provided controversial evidences of the association between signal transducer and activator of transcription proteins 3 (STAT3) expression and survival of human solid tumors. To address this inconsistency, we performed a meta-analysis with 63 studies identified from PubMed, Medline and EBSCO. We found STAT3 overexpression was significantly associated with worse 3 year overall survival (OS) (OR = 2.06, 95% CI = 1.57 to 2.71, P < 0.00001) and 5 year OS (OR = 2.00, 95% CI = 1.53 to 2.63, P < 0.00001) of human solid tumors. Similar results were observed when disease free survival (DFS) were analyzed. Subgroup analysis showed that elevated STAT3 expression was associated with poor prognosis of gastric cancer, lung cancer, gliomas, hepatic cancer, osteosarcoma, prostate cancer, pancreatic cancer but better prognosis of breast cancer. The correlation between STAT3 and survival of solid tumors was related to its phosphorylated state. High expression level of STAT3 was also associated with advanced tumor stage. In conclusion, elevated STAT3 expression is associated with poor survival in most solid tumors. STAT3 is a valuable biomarker for prognosis prediction and a promising therapeutic target in human solid tumors. PMID- 26959885 TI - Mutations in histone modulators are associated with prolonged survival during azacitidine therapy. AB - Early therapeutic decision-making is crucial in patients with higher-risk MDS. We evaluated the impact of clinical parameters and mutational profiles in 134 consecutive patients treated with azacitidine using a combined cohort from Karolinska University Hospital (n=89) and from King's College Hospital, London (n=45). While neither clinical parameters nor mutations had a significant impact on response rate, both karyotype and mutational profile were strongly associated with survival from the start of treatment. IPSS high-risk cytogenetics negatively impacted overall survival (median 20 vs 10 months; p<0.001), whereas mutations in histone modulators (ASXL1, EZH2) were associated with prolonged survival (22 vs 12 months, p=0.01). This positive association was present in both cohorts and remained highly significant in the multivariate cox model. Importantly, patients with mutations in histone modulators lacking high-risk cytogenetics showed a survival of 29 months compared to only 10 months in patients with the opposite pattern. While TP53 was negatively associated with survival, neither RUNX1 mutations nor the number of mutations appeared to influence survival in this cohort. We propose a model combining histone modulator mutational screening with cytogenetics in the clinical decision-making process for higher-risk MDS patients eligible for treatment with azacitidine. PMID- 26959886 TI - Response of brain metastasis from lung cancer patients to an oral nutraceutical product containing silibinin. AB - Despite multimodal treatment approaches, the prognosis of brain metastases (BM) from non-small cell lung cancer (NSCLC) remains poor. Untreated patients with BM have a median survival of about 1 month, with almost all patients dying from neurological causes. We herein present the first report describing the response of BM from NSCLC patients to an oral nutraceutical product containing silibinin, a flavonoid extracted from the seeds of the milk thistle. We present evidence of how the use of the silibinin-based nutraceutical Legasil(r) resulted in significant clinical and radiological improvement of BM from NSCLC patients with poor performance status that progressed after whole brain radiotherapy and chemotherapy. The suppressive effects of silibinin on progressive BM, which involved a marked reduction of the peritumoral brain edema, occurred without affecting the primary lung tumor outgrowth in NSCLC patients. Because BM patients have an impaired survival prognosis and are in need for an immediate tumor control, the combination of brain radiotherapy with silibinin-based nutraceuticals might not only alleviate BM edema but also prove local control and time for either classical chemotherapeutics with immunostimulatory effects or new immunotherapeutic agents such as checkpoint blockers to reveal their full therapeutic potential in NSCLC BM patients. New studies aimed to illuminate the mechanistic aspects underlying the regulatory effects of silibinin on the cellular and molecular pathobiology of BM might expedite the entry of new formulations of silibinin into clinical testing for progressive BM from lung cancer patients. PMID- 26959887 TI - A wait-and-watch approach to small pancreatic neuroendocrine tumors: prognosis and survival. AB - BACKGROUND: Whether all the small (o<=20mm) non-functional pancreatic neuroendocrine neoplasms (pNENs) should be routinely resected is unclear. AIM: To assess the overall survival (OS) and progression-free survival (PFS) of patients with small pNENs, followed-up with different management options. MATERIAL AND METHODS: Between 2007-2014, 51 patients were newly diagnosed with pNEN. 15 patients with pNENs o <=20 mm underwent an intensive follow-up at 3-month intervals during the first year and then every 6 months (FU pNEN group). They were all at TNM stage I, except for one patient at stage IIA. 21 patients underwent surgical resection (SR pNEN group): 2 patients were at TNM stage I, 9 IIA, one IIIB, 9 IV. 15 patients received systemic therapy (ST pNEN group) due to advanced disease or contraindications to surgery: 5 were at stage IIA, 2 IIB, 8 IV. RESULTS: The median follow-up for the entire cohort was 50 months. Survival was similar in the FU and SR pNEN groups, but significantly worst in the ST pNEN patients (log-rank test P <0.05). The 4-year survival rate was 100% in the FU pNEN group, 90.5% among the SR pNEN patients, 61% for the ST pNEN ones (p <0.0001). The disease remained stable in all but one patient in the FU pNEN group, whereas six patients in the SR group and five in the ST group showed disease progression. CONCLUSIONS: The "wait-and-watch" approach to early-stage small pNENs appears to be safe although further studies are needed to confirm these results in larger cohorts of patients. PMID- 26959888 TI - Germline genetics of cancer of unknown primary (CUP) and its specific subtypes. AB - Cancer of unknown primary site (CUP) is a fatal cancer diagnosed through metastases at various organs. Little is known about germline genetics of CUP which appears worth of a search in view of reported familial associations in CUP. In the present study, samples from CUP patients were identified from 2 Swedish biobanks and a German clinical trial, totaling 578 CUP patients and 7628 regionally matched controls. Diagnostic data specified the organ where metastases were diagnosed. We carried out a genome-wide association study on CUP cases and controls. In the whole sample set, 6 loci reached an allelic p-value in the range of 10-7 and were supported by data from the three centers. Three associations were located next to non-coding RNA genes. rs2660852 flanked 5'UTR of LTA4H (leukotriene A4 hydrolase), rs477145 was intronic to TIAM1 (T-cell lymphoma invasion and metastases) and rs2835931 was intronic to KCNJ6 (potassium channel, inwardly rectifying subfamily J, member 6). In analysis of subgroups of CUP patients (smokers, non-smokers and CUP with liver metastases) genome-wide significant associations were noted. For patients with liver metastases associations on chromosome 6 and 11, the latter including a cluster of genes DHCR7 and NADSYN1, encoding key enzymes in cholesterol and NAD synthesis, and KRTAP5-7, encoding a keratin associated protein. This first GWAS on CUP provide preliminary evidence that germline genes relating to inflammation (LTA4H), metastatic promotion (TIAM1) in association with lipid metabolic disturbance (chromosome 11 cluster) may contribute to the risk of CUP. PMID- 26959891 TI - Automated Selection of Active Orbital Spaces. AB - One of the key challenges of quantum-chemical multi-configuration methods is the necessity to manually select orbitals for the active space. This selection requires both expertise and experience and can therefore impose severe limitations on the applicability of this most general class of ab initio methods. A poor choice of the active orbital space may yield even qualitatively wrong results. This is obviously a severe problem, especially for wave function methods that are designed to be systematically improvable. Here, we show how the iterative nature of the density matrix renormalization group combined with its capability to include up to about 100 orbitals in the active space can be exploited for a systematic assessment and selection of active orbitals. These benefits allow us to implement an automated approach for active orbital space selection, which can turn multi-configuration models into black box approaches. PMID- 26959889 TI - Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer. AB - Werner syndrome protein (WRN) is a RecQ helicase that participates in DNA repair, genome stability and cellular senescence. The five human RecQ helicases, RECQL1, Bloom, WRN, RECQL4 and RECQL5 play critical roles in DNA repair and cell survival after treatment with the anticancer drug camptothecin (CPT). CPT derivatives are widely used in cancer chemotherapy to inhibit topoisomerase I and generate DNA double-strand breaks during replication. Here we studied the effects of CPT on the stability and expression dynamics of human RecQ helicases. In the cells treated with CPT, we observed distinct effects on WRN compared to other human RecQ helicases. CPT altered the cellular localization of WRN and induced its degradation by a ubiquitin-mediated proteasome pathway. WRN knockdown cells as well as CPT treated cells became senescent and stained positive for senescence associated beta-galactosidase at a higher frequency compared to control cells. However, the senescent phenotype was attenuated by ectopic expression of WRN suggesting functional implication of WRN degradation in CPT treated cells. Approximately 5-23% of breast cancer tumors are known to respond to CPT-based chemotherapy. Interestingly, we found that the extent of CPT-induced WRN degradation correlates with increasing sensitivity of breast cancer cells to CPT. The abundance of WRN decreased in CPT-treated sensitive cells; however, WRN remained relatively stable in CPT-resistant breast cancer cells. In a large clinical cohort of breast cancer patients, we find that WRN and topoisomerase I expression correlate with an aggressive tumor phenotype and poor prognosis. Our novel observations suggest that WRN abundance along with CPT-induced degradation could be a promising strategy for personalizing CPT-based cancer chemotherapeutic regimens. PMID- 26959890 TI - Suppression of B-Raf(V600E) cancers by MAPK hyper-activation. AB - B-Raf(V600E) activates MEK/MAPK signalling and acts as oncogenic driver of a variety of cancers, including melanoma, colorectal and papillary thyroid carcinoma. Specific B-Raf(V600E) kinase inhibitors (e.g., Vemurafenib) prove initial efficacy in melanoma followed shortly by acquired resistance, while failing in most other B-Raf(V600E) cancers due to primary resistance. Resistance is due to acquired mutations in the Ras/Raf/MEK/MAPK pathway and/or other oncogenic drivers that bypass B-Raf(V600E). Surprisingly, hyper-activation of MAPK by inhibiting its protein phosphatase 2A by a synthetic long-chain fatty acid analogue (MEDICA), results in oncogene-induced growth arrest and apoptosis of B-Raf(V600E) cancer cells. Growth arrest is accompanied by MAPK-mediated serine/threonine phosphorylation and suppression of a variety of oncogenic drivers that resist treatment by B-Raf(V600E) kinase inhibitors, including ErbB members, c-Met, IGFR, IRS, STAT3 and Akt. The combined activities of mutated B Raf and MEDICA are required for generating hyper-activated MAPK, growth arrest and apoptosis, implying strict specificity for mutated B-Raf cancer cells. PMID- 26959892 TI - Antioxidant, antimutagenic and antiproliferative activities in selected seaweed species from Sinaloa, Mexico. AB - Context Seaweeds from the Mexican Pacific Ocean have not been evaluated as a source of chemoprotectants. Objective The objective of this study is to evaluate chemopreventive activities of the seaweeds Phaephyceae - Padina durvillaei (Dictyotaceae) - Rodhophyceae - Spyridia filamentosa (Spyridiaceae), Gracilaria vermiculophylla (Gracilariaceae) - and Chlorophyceae - Ulva expansa (Ulvaceae), Codium isabelae (Codiaceae), Rhizoclonium riparium (Cladophoraceae) and Caulerpa sertularioides (Caulerpaceae). Materials and methods Methanol, acetone and hexane seaweed extracts were assessed at 30 and 3 mg/mL on antioxidant capacity (DPPH and ABTS assays), 0.003-3.0 mg/plate on antimutagenic activity against AFB1 using Salmonella typhimurium TA98 and TA100 tester strains in Ames test, and 12.5 to 100 MUg/mL on antiproliferative activity on Murine B-cell lymphoma. Phenols, flavonoids and pigments content were also assessed as antioxidant compounds. Results Extraction yield was higher in methanol than in acetone and hexane extracts (6.4, 2.7 and 1.4% dw). Antioxidant capacity was higher in brown and green than in red seaweed species, particularly in P. durvillaei extracted in acetone (EC50 value= 16.9 and 1.56 mg/mL for DPPH and ABTS). Flavonoids and chlorophylls were identified as mainly antioxidant components; particularly in hexane extracts, which were correlated with the antioxidant capacity. Highest mutagenesis inhibition (> 40%) occurred in R. riparium at the lowest concentration assayed (0.003 mg/plate), while highest antiproliferative inhibition (37 and 72% for 12.5 and 25 MUg/mL) occurred in C. sertularioides. Discussion and conclusion Flavonoids and chlorophylls explained the chemopreventive activities assessed in S. filamentosa, R. riparium and C. sertularioides. These seaweeds have a high potential as a source of novel chemoprotectants. PMID- 26959893 TI - The impact of person-organization fit on innovative work behavior: the mediating effect of knowledge sharing behavior. AB - PURPOSE: The direct relationship between person-organization (P-O) fit and employee's positive work attitudes and behaviours have been well researched. However, there has been no study on the impact of P-O fit on innovative work behaviour (IWB) of the nurses. The purpose of this paper is to fill this gap in the literature. In order to give a complete understanding of the psychology surrounding P-O fit, this study has longitudinally analysed the relationship between P-O fit and IWB along with the impact of a potential mediator, i.e. knowledge sharing behaviour (KSB) on this relationship. DESIGN/METHODOLOGY/APPROACH: A total of 357 nurses and 71 doctors from three government hospitals of Thailand filled out the questionnaires. Structural equation modelling was used to analyse the relationships. FINDINGS: Results of the study indicate that a nurse's P-O fit is positively associated with both self and doctor ratings of innovative behaviours; and KSB acts as a partial mediator between P-O fit and IWB at both Times 1 and 2. These results imply that a nurse's perceived fit in the hospital impacts his/her engagement into IWB. As nurses share knowledge with their co-workers frequently, it tends to strengthen the relationship between P-O fit and IWB. ORIGINALITY/VALUE: Study findings begin to explain how P-O fit impacts IWB of nurses. Specifically, the author find that KSB explains the relationship between P-O fit and IWB. PMID- 26959894 TI - Combined quality function deployment and logical framework analysis to improve quality of emergency care in Malta. AB - PURPOSE: The purpose of this paper is to develop an integrated patient-focused analytical framework to improve quality of care in accident and emergency (A & E) unit of a Maltese hospital. DESIGN/METHODOLOGY/APPROACH: The study adopts a case study approach. First, a thorough literature review has been undertaken to study the various methods of healthcare quality management. Second, a healthcare quality management framework is developed using combined quality function deployment (QFD) and logical framework approach (LFA). Third, the proposed framework is applied to a Maltese hospital to demonstrate its effectiveness. The proposed framework has six steps, commencing with identifying patients' requirements and concluding with implementing improvement projects. All the steps have been undertaken with the involvement of the concerned stakeholders in the A & E unit of the hospital. FINDINGS: The major and related problems being faced by the hospital under study were overcrowding at A & E and shortage of beds, respectively. The combined framework ensures better A & E services and patient flow. QFD identifies and analyses the issues and challenges of A & E and LFA helps develop project plans for healthcare quality improvement. The important outcomes of implementing the proposed quality improvement programme are fewer hospital admissions, faster patient flow, expert triage and shorter waiting times at the A & E unit. Increased emergency consultant cover and faster first significant medical encounter were required to start addressing the problems effectively. Overall, the combined QFD and LFA method is effective to address quality of care in A & E unit. PRACTICAL/IMPLICATIONS: The proposed framework can be easily integrated within any healthcare unit, as well as within entire healthcare systems, due to its flexible and user-friendly approach. It could be part of Six Sigma and other quality initiatives. ORIGINALITY/VALUE: Although QFD has been extensively deployed in healthcare setup to improve quality of care, very little has been researched on combining QFD and LFA in order to identify issues, prioritise them, derive improvement measures and implement improvement projects. Additionally, there is no research on QFD application in A & E. This paper bridges these gaps. Moreover, very little has been written on the Maltese health care system. Therefore, this study contributes demonstration of quality of emergency care in Malta. PMID- 26959895 TI - Improving healthcare practice behaviors: an exploratory study identifying effective and ineffective behaviors in healthcare. AB - PURPOSE: The purpose of this paper is to present the results of exploratory research designed to develop an awareness of healthcare behaviors, with a view toward improving the customer satisfaction with healthcare services. It examines the relationship between healthcare providers and their consumers/patients/clients. DESIGN/METHODOLOGY/APPROACH: The study uses a critical incident methodology, with both effective and ineffective behavioral specimens examined across different provider groups. FINDINGS: The effects of these different behaviors on what Berry (1999) identified as the common core values of service organizations are examined, as those values are required to build a lasting service relationship. Also examined are categories of healthcare practice based on the National Quality Strategy priorities. RESEARCH LIMITATIONS/IMPLICATIONS: The most obvious is the retrospective nature of the method used. How accurate are patient or consumer memories? Are they capable of making valid judgments of healthcare experiences (Berry and Bendapudi, 2003)? While an obvious limitation, such recollections are clearly important as they may be paramount in following the healthcare practitioners' instructions, loyalty for repeat business, making recommendations to others and the like. Further, studies have shown retrospective reports to be accurate and useful (Miller et al., 1997). PRACTICAL IMPLICATIONS: With this information, healthcare educators should be in a better position to improve the training offered in their programs and practitioners to better serve their customers. SOCIAL IMPLICATIONS: The findings would indicate that the human values of excellence, innovation, joy, respect and integrity play a significant role in building a strong service relationship between consumer and healthcare provider. ORIGINALITY/VALUE: Berry (1999) has argued that the overriding importance in building a lasting service business is human values. This exploratory study has shown how critical incident analysis can be used to determine both effective and ineffective practices of different medical providers. It also provides guidelines as to what are effective and ineffective behaviors in healthcare. PMID- 26959896 TI - Advancing the Big Five of user-oriented care and accounting for its variations. AB - PURPOSE: Care process quality (i.e. how care is enacted by a care worker toward a client at the interpersonal level) is a strong predictor of satisfaction in a wide range of health care services. The purpose of this paper is to describe the basic elements of care process quality as user-oriented care. Specifically, the questions of how and why quality in user-oriented care varies were investigated in the context of elderly care. DESIGN/METHODOLOGY/APPROACH: Two municipalities were selected for in-depth field studies. First, in each municipality, the authors interviewed and observed care workers' interactions with the older persons in both home care and nursing homes during two weeks (Study 1). Second, in an attempt to gain a deeper understanding of why process quality in terms of user-oriented care varies, the authors conducted interviews with care workers and care unit managers (Study 2). FINDINGS: A new taxonomy for categorizing process quality variation, the Big Five of user-oriented care (task-focus, person-focus, affect, cooperation, and time-use), is proposed. In addition, the perceived reasons for process quality variation are reported in our own developed Quality Agents Model, suggesting that variations in care process evaluations may be explained from different perspectives at multiple levels (i.e., older person, care worker-, unit-, department-, and municipality level). ORIGINALITY/VALUE: The proposed taxonomy and model are useful for describing user-oriented care quality and the reasons for its variations. These findings are of relevance for future quality developments of elderly care services, but also may be adapted to applications in any other enterprise employing a user-oriented approach. PMID- 26959897 TI - Five focus strategies to organize health care delivery. AB - PURPOSE: The focused factory is one of the concepts that decision-makers have adopted for improving health care delivery. However, disorganized definitions of focus have led to findings that cannot be utilized systematically. The purpose of this paper is to discuss strategic options to focus health care operations. DESIGN/METHODOLOGY/APPROACH: First the literature on focus in health care is reviewed revealing conceptual challenges. Second, a definition of focus in terms of demand and requisite variety is defined, and the mechanisms of focus are explicated. A classification of five focus strategies that follow the original idea to reduce variety in products and markets is presented. Finally, the paper examines managerial possibilities linked to the focus strategies. FINDINGS: The paper proposes a framework of five customer-oriented focus strategies which aim at reducing variety in different characteristics of care pathways: population; urgency and severity; illnesses and symptoms; care practices and processes; and care outcomes. RESEARCH LIMITATIONS/IMPLICATIONS: Empirical research is needed to evaluate the costs and benefits of the five strategies and about system-level effects of focused units on competition and coordination. PRACTICAL IMPLICATIONS: Focus is an enabling condition that needs to be exploited using specific demand and supply management practices. It is essential to understand how focus mechanisms differ between strategies, and to select focus that fits with organization's strategy and key performance indicators. ORIGINALITY/VALUE: Compared to previous more resource-oriented approaches, this study provides theoretically solid and practically relevant customer-oriented framework for focusing in health care. PMID- 26959898 TI - Lean and Six Sigma in acute care: a systematic review of reviews. AB - PURPOSE: The purpose of this paper is to present a systematic review of literature reviews, summarizing how Lean and Six Sigma management techniques have been implemented in acute care settings to date, and assessing their impact. To aid decision makers who wish to use these techniques by identifying the sectors of activity most often targeted, the main results of the interventions, as well as barriers and facilitators involved. To identify areas of future research. DESIGN/METHODOLOGY/APPROACH: A literature search was conducted, using eight databases. The methodological quality of the selected reviews was appraised with AMSTAR. A narrative synthesis was performed according to the guidelines proposed by Popay et al. (2006). Data were reported according to PRISMA. FINDINGS: The literature search identified 149 publications published from 1999 to January 2015. Seven literature reviews were included into the systematic review, upon appraisal. The overall quality of the evidence was poor to fair. The clinical settings most described were specialized health care services, including operating suites, intensive care units and emergency departments. The outcomes most often appraised related to processes and quality. The evidence suggests that Lean and Six Sigma are better adapted to settings where processes involve a linear sequence of events. RESEARCH LIMITATIONS/IMPLICATIONS: There is a need for more studies of high methodological quality to better understand the effects of these approaches as well as the factors of success and barriers to their implementation. Field studies comparing the effects of Lean and Six Sigma to those of other process redesign or quality improvement efforts would bring a significant contribution to the body of knowledge. PRACTICAL IMPLICATIONS: Lean and Six Sigma can be considered valuable process optimization approaches in acute health care settings. The success of their implementation requires significant participation of clinical personnel from the frontline as well as clinical leaders and managers. More research is needed to better understand the factors of success and the barriers to their implementation, as well as their long-term impact. ORIGINALITY/VALUE: This is the first broad systematic review of reviews, synthesizing data pertaining to implementation issues and results in acute care settings, to be published. It will benefit health care managers assessing the potential of these approaches and the potential drawbacks associated with their implementation. Moreover, it identifies directions for future research. PMID- 26959899 TI - Performance management of the public healthcare services in Ireland: a review. AB - PURPOSE: Performance Management (PM) processes have become a potent part of strategic and service quality decisions in healthcare organisations. In 2005, the management of public healthcare in Ireland was amalgamated into a single integrated management body, named the Health Service Executive (HSE). Since then, the HSE has come up with a range of strategies for healthcare developments and reforms, and has developed a PM system as part of its strategic planning. The purpose of this paper is to review the application of PM in the Irish Healthcare system, with a particular focus on Irish Hospitals and Emergency Services. DESIGN/METHODOLOGY/APPROACH: An extensive review of relevant HSE's publications from 2005 to 2013 is conducted. Studies of the relevant literature related to the application of PM and of international best practices in healthcare performance systems are also presented. FINDINGS: PM and performance measurement systems used by the HSE include many performance reports designed to monitor performance trends and strategic goals. Issues in the current PM system include inconsistency of measures and performance reporting, unclear strategy alignment, and deficiencies in reporting (e.g. feedback and corrective actions). Furthermore, PM processes have not been linked adequately into Irish public hospitals' management systems. RESEARCH LIMITATIONS/IMPLICATIONS: The HSE delivers several services such as mental health, social inclusion, etc. This study focuses on the HSE's PM framework, with a particular interest in acute hospitals and emergency services. ORIGINALITY/VALUE: This is the first comprehensive review of Irish healthcare PM since the introduction of the HSE. A critical analysis of the HSE reports identifies the shortcomings in its current PM system. PMID- 26959900 TI - Management of surgical instruments with radio frequency identification tags. AB - PURPOSE: To prevent malpractices, medical staff has adopted inventory time-outs and/or checklists. Accurate inventory and maintenance of surgical instruments decreases the risk of operating room miscounting and malfunction. In our previous study, an individual management of surgical instruments was accomplished using Radio Frequency Identification (RFID) tags. The purpose of this paper is to evaluate a new management method of RFID-tagged instruments. DESIGN/METHODOLOGY/APPROACH: The management system of RFID-tagged surgical instruments was used for 27 months in clinical areas. In total, 13 study participants assembled surgical trays in the central sterile supply department. FINDINGS: While using the management system, trays were assembled 94 times. During this period, no assembly errors occurred. An instrument malfunction had occurred after the 19th, 56th, and 73 th uses, no malfunction caused by the RFID tags, and usage history had been recorded. Additionally, the time it took to assemble surgical trays was recorded, and the long-term usability of the management system was evaluated. ORIGINALITY/VALUE: The system could record the number of uses and the defective history of each surgical instrument. In addition, the history of the frequency of instruments being transferred from one tray to another was recorded. The results suggest that our system can be used to manage instruments safely. Additionally, the management system was acquired of the learning effect and the usability on daily maintenance. This finding suggests that the management system examined here ensures surgical instrument and tray assembly quality. PMID- 26959901 TI - Unlinked Mendelian inheritance of red and black pigmentation in snakes: Implications for Batesian mimicry. AB - Identifying the genetic basis of mimetic signals is critical to understanding both the origin and dynamics of mimicry over time. For species not amenable to large laboratory breeding studies, widespread color polymorphism across natural populations offers a powerful way to assess the relative likelihood of different genetic systems given observed phenotypic frequencies. We classified color phenotype for 2175 ground snakes (Sonora semiannulata) across the continental United States to analyze morph ratios and test among competing hypotheses about the genetic architecture underlying red and black coloration in coral snake mimics. We found strong support for a two-locus model under simple Mendelian inheritance, with red and black pigmentation being controlled by separate loci. We found no evidence of either linkage disequilibrium between loci or sex linkage. In contrast to Batesian mimicry systems such as butterflies in which all color signal components are linked into a single "supergene," our results suggest that the mimetic signal in colubrid snakes can be disrupted through simple recombination and that color evolution is likely to involve discrete gains and losses of each signal component. Both outcomes are likely to contribute to the exponential increase in rates of color evolution seen in snake mimicry systems over insect systems. PMID- 26959939 TI - The role of conserved Cys residues in Brassica rapa auxin amidohydrolase: Cys139 is crucial for the enzyme activity and Cys320 regulates enzyme stability. AB - Brassica rapa auxin amidohydrolase (BrILL2) participates in the homeostasis of the plant hormones auxins by hydrolyzing the amino acid conjugates of auxins, thereby releasing the free active form of hormones. Herein, the potential role of the two conserved Cys residues of BrILL2 (at sequence positions 139 and 320) has been investigated by using interdisciplinary approaches and methods of molecular biology, biochemistry, biophysics and molecular modelling. The obtained results show that both Cys residues participate in the regulation of enzyme activity. Cys320 located in the satellite domain of the enzyme is mainly responsible for protein stability and regulation of enzyme activity through polymer formation, as has been revealed by enzyme kinetics and differential scanning calorimetry analysis of the BrILL2 wild type and mutants C320S and C139S. Cys139 positioned in the active site of the catalytic domain is involved in the coordination of one Mn(2+) ion of the bimetal center and is crucial for the enzymatic activity. Although the point mutation Cys139 to Ser causes the loss of enzyme activity, it does not affect the metal binding to the BrILL2 enzyme, as has been shown by isothermal titration calorimetry, circular dichroism spectropolarimetry and differential scanning calorimetry data. MD simulations (200 ns) revealed a different active site architecture of the BrILL2C139S mutant in comparison to the wild type enzyme. Additional possible reasons for the inactivity of the BrILL2C139S mutant have been discussed based on MD simulations and MM-PBSA free energy calculations of BrILL2 enzyme complexes (wt and C139S mutant) with IPA-Ala as a substrate. PMID- 26959940 TI - Chromic oxide and acid-insoluble ash as markers in digestibility studies with growing pigs and sows. AB - The results of three experiments, focused on the determination of endogenous ileal flow (EIF) of amino acids (AA) and nitrogen (N) (Exp. 1), apparent ileal digestibility (AID) of AA and N (Exp. 2), and apparent total tract digestibility (ATTD) of dry matter (DM), organic matter (OM), N, calcium (Ca) and phosphorus (P) (Exps. 2 and 3), were used to compare chromic oxide (Cr2 O3 ) and acid insoluble ash (AIA) as digestibility markers. In Exps. 1 and 2, a total of six gilts fitted with T-cannula in terminal ileum, and in Exp. 3, a total of 24 pregnant sows were used. In Exps. 1 and 2, the pigs were assigned into four dietary treatments according to 4 * 6 crossover design (Exp. 1; diets with 0%, 4%, 8% and 12% of casein; Exp. 2 basal diet with different levels of phytase). In Exp. 3, the sows were assigned to four dietary treatments (basal diet with different levels of phytase) of six sows. In Exps. 1 and 2 ileal digesta and in Exps. 2 and 3 faeces were collected for the determination of EIF, AID and ATTD. Differences in EIF of AA determined by Cr2 O3 and AIA ranged (p ? 0.05) from 4.62 to 4.54%. The lowest EIF was for methionine and the greatest one for proline, determined by both markers. Apparent ileal digestibility determined by Cr2 O3 was slightly greater (p ? 0.05) in comparison with AIA. Differences ranged from 1.88% (Arg) to 7.08% (Gly). The greatest AID was for arginine and the lowest one for glycine, determined by both Cr2 O3 and AIA. Similarly for ATTD of DM, OM, N, Ca and P, there were no differences in digestibility determined by Cr2 O3 and AIA. Both, Cr2 O3 and AIA, are suitable and comparable markers for digestibility studies in pigs. PMID- 26959941 TI - Single-Incision Laparoscopy Could Be Better than Standard Laparoscopy in Right Colectomy for Cancer. AB - BACKGROUND: Human natural orifice transluminal endoscopic surgery (NOTES) is slowed down by technical hurdles. Concomitantly, single-incision laparoscopy has been increasingly reported as an alternative. By reducing the invasiveness of standard laparoscopy, we may further reduce postoperative pain, decrease morbidity, preserve abdominal wall, and enhance cosmesis. Such techniques have been widely applied, including in colorectal surgery. The aim of this multicenter study is to compare the results of single-incision right colectomy (SIRC) with the results of the standard laparoscopic right colectomy (SLRC) in patients with colon cancer. METHODS: The files of patients who underwent right colectomy for cancer in five hospitals between January 2010 and December 2013 have been reviewed. Exclusion criteria were open surgery, emergency setting, and American Society of Anesthesiologists (ASA) score >3. Patients were distributed in Groups A (SIRC) or B (SLRC). RESULTS: Five hundred ninety-two patients were included in this study, 336 in Group A and 256 in Group B. Mean operative time was 129.0 minutes (range 65-245) in Group A and 168.1 minutes in the Group B (range 70 290), respectively (P < .001). No mortality occurred in either group. The overall 30-day morbidity rates were 21.4% in Group A and 25% in Group B, respectively (P = .64). The median length of hospital stay was 4.95 days (range 3-14) in Group A and 5.5 days in Group B (range 3-12), respectively (P = .28). Conversion to laparotomy occurred in four patients in each group (P = 1). Length of skin incision was significantly shorter in Group A than in Group B (2.99 +/- 0.63 cm versus 4.94 +/- 0.65 cm, P < .001). Histological analysis of the operative specimens showed no significant differences. CONCLUSION: SIRC is feasible and sure for patients with colon cancer. As compared with SLRC, SIRC may offer some advantages, including lower operative morbidity, shorter hospital stay, and better cosmoses, without compromising the oncological quality of the resected specimen. PMID- 26959942 TI - Estimating spatially specific demand and supply of dental services: a longitudinal comparison in Northern Germany. AB - OBJECTIVES: Assessing the spatial distribution of oral morbidity-related demand and the workforce-related supply is relevant for planning dental services. We aimed to establish and validate a model for estimating the spatially specific demand and supply. This model was then applied to compare demand-supply ratios in 2001 and 2011 in the federal state of Mecklenburg-Vorpommern (Northern Germany). METHODS: The spatial units were zip code areas. Demand per area was estimated by linking population-specific oral morbidities to working times via insurance claim data. Estimated demand was validated against the provided demand in 2001 and 2011. Supply was calculated for both years using cohort data from the dentist register. The ratio of demand and supply was geographically mapped and its distribution between areas assessed using the Gini coefficient. RESULTS: Between 2001 and 2011, a significant decrease of the general population (-7.0 percent), the annual demand (-13.1 percent), and the annual supply (-12.9 percent) was recorded. The estimated demands were nearly (2001: -4 percent) and completely (2011: +/-0 percent) congruent with provided demands. The average demand-supply ratio did not change significantly between 2001 and 2011 (P > 0.05), but was increasingly unequally distributed. In both years, few areas were over-serviced, while many were under-serviced. CONCLUSIONS: The established model can be used to estimate spatially specific demand and supply. PMID- 26959943 TI - Stabilizing and Modulating Color by Copigmentation: Insights from Theory and Experiment. AB - Natural anthocyanin pigments/dyes and phenolic copigments/co-dyes form noncovalent complexes, which stabilize and modulate (in particular blue, violet, and red) colors in flowers, berries, and food products derived from them (including wines, jams, purees, and syrups). This noncovalent association and their electronic and optical implications constitute the copigmentation phenomenon. Over the past decade, experimental and theoretical studies have enabled a molecular understanding of copigmentation. This review revisits this phenomenon to provide a comprehensive description of the nature of binding (the dispersion and electrostatic components of pi-pi stacking, the hydrophobic effect, and possible hydrogen-bonding between pigment and copigment) and of spectral modifications occurring in copigmentation complexes, in which charge transfer plays an important role. Particular attention is paid to applications of copigmentation in food chemistry. PMID- 26959944 TI - Transfusion practices and infectious risks. AB - Transfusion-transmitted infections remain among the most-feared complications of allogeneic blood transfusion. Thanks to several strategies including donor screening and deferral, blood testing and pathogen inactivation, their risks have reached all-time low levels, particularly in developed nations. Nonetheless, new and emerging infections remain a threat that is likely to exacerbate in the coming years with continued globalization and climate change. More effective strategies of pathogen inactivation and more vigilant horizon screening are hoped to abate the risk. Additionally, allogeneic transfusion has repeatedly been shown to be associated with worsening of outcomes in patients, including the documented increased risk of infections (often nosocomial) in recipients of transfusions. The underlying mechanism is likely to be related to immunosuppressive effects of allogeneic blood, iron content, and bacterial contamination. This issue is best addressed by more judicious and evidence-based use of allogeneic blood components to ensure the potential benefits outweigh the risks. PMID- 26959945 TI - Microturbellarians (Platyhelminthes and Acoelomorpha) in Brazil: invisible organisms? AB - Microturbellarians typically belong to the benthos and may occur in a wide variety of environments. They are abundant in freshwater and marine ecosystems and may occur in moist terrestrial habitats. However, turbellarians are seldom taken into account in studies of biodiversity. Most studies on Brazilian microturbellarians had taxonomical purposes and were done in the years 1940-1950. Thus, information on their occurrence and ecological aspects are dispersed throughout several papers. We intend here to summarize the biogeographical distribution and ecological aspects of microturbellarians recorded for Brazil, indicating the main gaps in their knowledge and possible actions to enhance studies on this group. There are 239 species of microturbellarians registered for Brazil, with records distributed in 12 states. However, just three states located in southern Brazil have records of 94% of microturbellarian species. Thus, knowledge on the systematics and geographical distribution of Brazilian microturbellarians clearly reflect the scientific activity over many years or decades in two states of southeastern and southern Brazil. Considering the scant information on this group in Brazil, which is also the situation of the Neotropical microturbellarians in general, some actions should be proposed. First, it would be necessary to sample in the diverse biomes, as well as in the various river and sea basins, based on standardized sampling protocols. Second, it would be necessary to encourage diverse research groups to include microturbellarians and/or turbellarians in general into biodiversity inventories and studies on community structure of invertebrates. Third, it is necessary to increase the number of research groups on microturbellarians, in order to augment the studies on their morphology, systematics, and ecology. Considering their abundance, species richness and ecological importance in aquatic environments, despite some peculiarities regarding their sampling, sorting and identification procedures, the challenge to study microturbellarians and enhance knowledge about them in Brazilian ecosystems should be faced. PMID- 26959946 TI - Biomass allocation and nutrients balance related to the concentration of Nitrogen and Phosphorus in Salvinia auriculata (Salviniaceae). AB - Aquatic plants can use differential allocation (trade-off) of carbon among their structures depending on the nutrition concentration. Given that N and P are limiting in the growth of plants, our questions were: Are the N and P concentrations in S. auriculata related to the biomass allocation to its structures? Is a differential allocation of N and P between floating and submerged leaves? We evaluated the relation between the nutrients and the biomass allocation, and the trade-off among the leaves using the Spearman correlation. Our results showed that N and P concentrations in S. auriculata are related to the biomass allocation to its structures, and that there is no trade-off of these nutrients between "shoot and root". Thus, we can see the importance of N and P concentration in the biomass of S. auriculata, and why this plant is capable to development in different environments as a weedy. PMID- 26959947 TI - Phytotoxic potential of young leaves from Blepharocalyx salicifolius (Kunth) O. Berg (Myrtaceae). AB - The loss of leaves by plant species found in the Cerrado (Brazilian savanna) is an energetically expensive process due to adverse environmental conditions and predation by herbivory. The mature leaves have adaptations which minimize these events. However, the young individuals lack these structures and produce high leaf concentrations of secondary metabolites as a form of protection. These compounds can be used in bioprospection of natural herbicides. Thus, this study aimed to evaluate the phytotoxicity of hexane, ethyl acetate and aqueous extracts of young leaves from Blepharocalyx salicifolius (Kunth) O. Berg on the elongation of wheat coleoptiles (Triticum aestivum L.) and evaluate the potential phytotoxic of ethyl acetate extract on germination, growth and cell size of metaxylem of sesame (Sesamum indicum L.) seedlings. The hexane and ethyl acetate extracts inhibited the elongation of wheat coleoptiles at all concentrations; however, the most promising results were observed in coleoptile fragments treated with the ethyl acetate extract. This treatment changed the mean germination time and the synchrony of sesame seeds, inhibited the growth of shoots and roots, reduced the dry weight of seedlings, led to abnormalities in the seedlings and reduced the length of the metaxylem cells in the sesame seedlings. These results demonstrated the phytotoxic potential of young leaf extracts of B. salicifolius and the high phytotoxicity of the ethyl acetate extract in the initial development of S. indicum. PMID- 26959948 TI - An uncommon feeding habit: mutillid wasps (Hymenoptera, Mutillidae) visiting extrafloral nectaries in Malpighiaceae. PMID- 26959949 TI - Cytotoxicity of Cheese and Cheddar Cheese food flavorings on Allim cepa L root meristems. AB - Despite their great importance for the food industry, flavorings, in general, raise a number of questions regarding their cytotoxicity, mutagenicity and carcinogenicity, since, in the literature, there are few studies found evaluating the toxicity on the systemic and cellular level, of these chemical compounds. The root meristems of Allium cepa (onion) are widely used for the assessment of toxicity of chemical compounds of interest. Thus, this study aimed to evaluate, in A. cepa meristematic cells, individually and in combination at the cellular level, the toxicity of synthetic Cheese and Cheddar Cheese food flavorings, identical to the natural, at doses of 1.0 and 2.0 mL, at exposure times of 24 and 48 hours. In combination we used 0.5 mL of Cheese flavor associated with 0.5 mL of Cheddar flavor; and 1.0 mL of Cheese flavor associated with 1.0 mL of Cheddar flavor, at exposure times of 24 and 48 hours. For these evaluations, we used groups of five onion bulbs, which were first embedded in distilled water and then transferred to their respective doses. The root tips were collected and fixed in acetic acid (3:1) for 24 hours. The slides were prepared by crushing and were stained with 2% acetic orcein. Cells were analyzed throughout the cell cycle, totaling 5,000 for each control and exposure time. The mitotic indices calculated and cellular aberrations observed were subjected to statistical analysis using the chi-square test (p <0.05). No chromosomal abnormalities nor those of mitotic spindle were observed for the treatments performed. The results, both individually and in combination, showed that the flavorings under study significantly reduced the cell division rate of the test system cells used. Therefore, under the conditions studied, the two flavorings were cytotoxic. PMID- 26959950 TI - Calibration of the maximum carboxylation velocity (Vcmax) using data mining techniques and ecophysiological data from the Brazilian semiarid region, for use in Dynamic Global Vegetation Models. AB - The semiarid region of northeastern Brazil, the Caatinga, is extremely important due to its biodiversity and endemism. Measurements of plant physiology are crucial to the calibration of Dynamic Global Vegetation Models (DGVMs) that are currently used to simulate the responses of vegetation in face of global changes. In a field work realized in an area of preserved Caatinga forest located in Petrolina, Pernambuco, measurements of carbon assimilation (in response to light and CO2) were performed on 11 individuals of Poincianella microphylla, a native species that is abundant in this region. These data were used to calibrate the maximum carboxylation velocity (Vcmax) used in the INLAND model. The calibration techniques used were Multiple Linear Regression (MLR), and data mining techniques as the Classification And Regression Tree (CART) and K-MEANS. The results were compared to the UNCALIBRATED model. It was found that simulated Gross Primary Productivity (GPP) reached 72% of observed GPP when using the calibrated Vcmax values, whereas the UNCALIBRATED approach accounted for 42% of observed GPP. Thus, this work shows the benefits of calibrating DGVMs using field ecophysiological measurements, especially in areas where field data is scarce or non-existent, such as in the Caatinga. PMID- 26959951 TI - Analysis of food habits of skate Rioraja agassizii (Elasmobranchii, Rajidae) from southern Brazil. AB - Catches and exports of skate Rioraja agassizii place this species as "vulnerable to extinction" on the IUCN Red List; therefore, biological and ecological knowledge becomes an important instrument for its conservation control. This study described and quantified the diet composition of R. agassizii by means of stomach analysis contents in the periods 2005-2006 and 2012-2013. We analyzed and quantified stomach contents in terms of abundance (%N), weight (%M), frequency of occurrence (% FO), and index of relative importance (IRI). The results showed differences in the food rates between the periods. However, the groups of food items were the same: Teleostei fish, decapods, and mollusks. In 2005-2006, the diet consisted mainly of shrimp, however, in 2012-2013 it consisted of fish, followed by decapods, especially shrimps. The differences in diets may be attributed to shrimp abundance, which do not characterize a change in the eating habits in 2012-2013, because, in addition to fish, shrimps were also important food sources. The presence of a certain prey is more related to its availability rather than the feeding preference of skate. The amount of ingested items is associated to biological and environmental factors, so that further studies relating diet with capture area, seasonality, depth, and other factors should be conducted. PMID- 26959952 TI - Reproductive potential of Spodoptera eridania (Stoll) (Lepidoptera: Noctuidae) in the laboratory: effect of multiple couples and the size. AB - This study aimed to evaluate the effect of keeping three couples in the same cage, and the size of adults emerged from small, medium-sized and large pupae (278.67 mg; 333.20 mg and 381.58 mg, respectively), on the reproductive potential of S. eridania (Stoll, 1782) adults, under controlled conditions (25 +/- 1 degrees C, 70% RH and 14 hour photophase). We evaluated the survival, number of copulations, fecundity and fertility of the adult females. The survival of females from these different pupal sizes did not differ statistically, but the survival of males from large pupae was statistically shorter than from small pupae. Fecundity differed significantly and correlated positively with size. The number of effective copulations (espematophores) and fertility did not vary significantly with pupal size. Our results emphasize the importance of indicating the number of copulations and the size of the insects when reproductive parameters are compared. PMID- 26959953 TI - First record of Aglae caerulea (Hymenoptera, Apidae, Euglossini) in Brazilian Cerrado east of the Amazon Region, Maranhao State, Brazil. PMID- 26959954 TI - Can microcystins affect zooplankton structure community in tropical eutrophic reservoirs? AB - The aim of our study was to assess whether cyanotoxins (microcystins) can affect the composition of the zooplankton community, leading to domination of microzooplankton forms (protozoans and rotifers). Temporal variations in concentrations of microcystins and zooplankton biomass were analyzed in three eutrophic reservoirs in the semi-arid northeast region of Brazil. The concentration of microcystins in water proved to be correlated with the cyanobacterial biovolume, indicating the contributions from colonial forms such as Microcystis in the production of cyanotoxins. At the community level, the total biomass of zooplankton was not correlated with the concentration of microcystin (r2 = 0.00; P > 0.001), but in a population-level analysis, the biomass of rotifers and cladocerans showed a weak positive correlation. Cyclopoid copepods, which are considered to be relatively inefficient in ingesting cyanobacteria, were negatively correlated (r2 = - 0.01; P > 0.01) with the concentration of cyanotoxins. Surprisingly, the biomass of calanoid copepods was positively correlated with the microcystin concentration (r2 = 0.44; P > 0.001). The results indicate that allelopathic control mechanisms (negative effects of microcystin on zooplankton biomass) do not seem to substantially affect the composition of mesozooplankton, which showed a constant and high biomass compared to the microzooplankton (rotifers). These results may be important to better understand the trophic interactions between zooplankton and cyanobacteria and the potential effects of allelopathic compounds on zooplankton. PMID- 26959955 TI - First record of sea lice Lepeophtheirus curtus (Copepoda, Caligidae) in sea farmed Epinephelus marginatus (Serranidae) in Brazil. PMID- 26959956 TI - Geographic distribution of Pristimantis vinhai (Bokermann, 1975) (Anura, Craugastoridae: Ceuthomantinae) in the Brazilian Atlantic Forest. PMID- 26959957 TI - The effect of visitor number and spice provisioning in pacing expression by jaguars evaluated through a case study. AB - Captive animals exhibit stereotypic pacing in response to multiple causes, including the inability to escape from human contact. Environmental enrichment techniques can minimize pacing expression. By using an individual-based approach, we addressed whether the amount of time two males and a female jaguar (Panthera onca) devote to pacing varied with the number of visitors and tested the effectiveness of cinnamon and black pepper in reducing pacing. The amount of time that all jaguars engaged in pacing increased significantly with the number of visitors. Despite the difference between the males regarding age and housing conditions, both devoted significantly less time to pacing following the addition of both spices, which indicates their suitability as enrichment techniques. Mean time devoted to pacing among the treatments did not differ for the female. Our findings pointed out to the validity of individual-based approaches, as they can reveal how suitable olfactory stimuli are to minimizing stereotypies irrespective of particular traits. PMID- 26959958 TI - Comparison of rates of fecal colonization with extended-spectrum beta-lactamase producing enterobacteria among patients in different wards, outpatients and medical students. AB - Because asymptomatic carriage of extended-spectrum beta-lactamase (ESBL) producers is a risk factor for infection, data on colonization dynamics are important when planning infection control. This study investigated fecal colonization with ESBL producers among inpatients, outpatients and medical students and compares the characteristics of ESBL producers among these groups. Carriage rates were investigated in 5581 fecal samples; 4343 from inpatients (330, 1397, 619 and 1864 from adult ICUs [intensive care units], adult non-ICUs, pediatric ICUs and pediatric non-ICUs, respectively), 814 from outpatients and 424 from screening of medical students. ESBL producers were characterized by co resistance, integrons carried, and aminoglycoside resistance and ESBL genes. Dynamic regression models were built to identify relationships between combinations of time series of monthly antibiotic consumption, prevalence of carriers and infected subjects. Inpatients, ICU patients and adults showed higher prevalence than outpatients, non-ICU patients or children (7.4%, 9.3% and 12.0% vs. 3.1%, 6.1% and 4.1%, respectively). Klebsiella pneumoniae was more frequent in ICU patients; dominance of CTX-M-15 producers was more marked in adult than in pediatric inpatients. ESBL carriage was shown to be a consequence of infection in adults in the time-series analysis; antibiotic consumption had little effect. The epidemiology of colonization with ESBL producers differed between pediatric ICU, adult ICU and adult non-ICU patients. In adults, carriage of ESBL producers seems to be the consequence of infection, especially in ICU patients; the main source of colonization is nosocomial acquisition. In contrast, children are less likely to acquire colonizer strains in hospitals; importation of ESBL producers by colonized children seems to be significant. PMID- 26959959 TI - Timely Antecedent CT or MRI Can Help Predict Hemorrhage Site of Posttreatment Head and Neck Cancer, With Digital Subtraction Angiography Used as the Reference Standard. AB - OBJECTIVE: We investigated the timing of CT and MRI performed before digital subtraction angiography (DSA) in the prediction of hemorrhage sites in patients with head and neck cancers who present with acute oral or neck bleeding after receiving treatment. MATERIALS AND METHODS: A total of 123 DSA examinations that evaluated 123 oral or neck bleeding events in 85 patients were analyzed. The last CT or MRI examinations performed within a time frame of 0-337 days before transarterial embolization were reviewed retrospectively, with three findings (pseudoaneurysm, air-containing necrotic tissue, and residual tumor) used to predict hemorrhage sites. DSA findings of pseudoaneurysm or active contrast extravasation were used as a reference standard. The sensitivity of CT and MRI for correctly predicting hemorrhage sites was used to determine the optimal timing of CT or MRI examinations performed before DSA. RESULTS: A total of 8.9% of the DSA examinations (11/123) had equivocal findings but were followed by another bleeding event for which DSA findings were positive. CT or MRI was statistically significantly better at predicting hemorrhage sites in patients with bleeding events associated with nonhypopharyngeal cancers (p = 0.019) than in those with bleeding events associated with hypopharyngeal cancers. The sensitivity of CT or MRI in the prediction of hemorrhage sites was statistically significantly higher for the common carotid artery and the internal carotid artery when CT or MRI was performed less than 30 days before bleeding events occurred. Prediction of hemorrhagic sites was better with the use of CT angiography than with the use of enhanced CT or MRI, although it was not statistically significant. CONCLUSION: DSA findings can temporarily be equivocal. CT or MRI examinations performed within 30 days of bleeding events can predict the site of hemorrhage. If no CT or MRI findings from the past 30 days are available, we suggest performing emergent CT angiography for the sake of obtaining better arterial detail. PMID- 26959960 TI - Chemical constituents from the tubers of Scirpus yagara and their anti inflammatory activities. AB - A new natural compound, dehydrophyllodulcin (1) was isolated from the tubers of Scirpus yagara, together with 11 known compounds. Among them, compounds 2, 5-8, and 10-12 were isolated from this plant for the first time. (1)H NMR, (13)C NMR, and 2D NMR data of compound 1 are first reported in this article, though it was synthesized in 1996. The structures of all compounds were determined by comprehensive analyses of their spectroscopic data and compared with literature information. Moreover, the anti-inflammatory effects of compounds 1, 3, 4, 6, and 9 against inflammatory cytokines production in Lipopolysaccharide - or Pam3csk4 stimulated macrophage RAW264.7 cells were evaluated by Enzyme-linked immunosorbent assay. And these compounds significantly inhibited the tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 productions in RAW264.7 cells, with IC50 values less than 20 MUM. PMID- 26959961 TI - "A Psychopath by Any Other Name?": Juror Perceptions of the DSM-5 "Limited Prosocial Emotions" Specifier. AB - DSM-5 recently added the specifier "Limited Prosocial Emotions" (LPE) to the Conduct Disorder (CD) diagnosis, yet little is known about how these traits will affect attitudes toward CD youth. Laypersons attending jury duty (N = 326) were randomly assigned to one of four case vignette conditions in which a male juvenile offender was identified as having (a) CD symptoms only, (b) CD symptoms plus a diagnostic label, (c) CD symptoms plus a diagnostic label and description of LPE traits, or (d) CD symptoms plus a description of LPE traits and a "psychopath" label. LPE traits led to more negative perceptions of the youth (e.g., more dangerous, evil, and psychopathic) and adding the psychopath label to the LPE specifier resulted in somewhat stronger support for punishment and mandated treatment. The LPE specifier may provide useful diagnostic information, but these findings raise serious concerns that it will stigmatize youth in the legal system. PMID- 26959962 TI - Personality Disorder Symptoms and Suicidality: Low Desire and High Plans for Suicide in Military Inpatients and Outpatients. AB - This study characterizes the personality disorder (PD) symptoms of patients who endorse a perplexing combination of low desire and high plans for suicide. Five PD (antisocial, narcissistic, borderline, dependent, avoidant) symptoms were examined at the junction of two suicide risk factors: (a) suicidal desire/ideation and (b) resolved plans/preparations. Participants (N = 250) were recruited from U.S. Army Medical Center affiliated sites, including two outpatient clinics, an inpatient facility, and an emergency room. Self-report measures of PD and suicide symptoms were administered. The interaction of desire and plans was entered into multiple regression equations predicting PD symptoms. Patients endorsing low desire and high plans for suicide reported significantly more antisocial and narcissistic symptoms and fewer borderline, avoidant, and dependent PD symptoms. These findings support the existence of patients who endorse suicide plans in the absence of strong suicidal desire and suggest that they display antisocial and narcissistic personality characteristics. Future directions and clinical implications are discussed. PMID- 26959963 TI - Integrating Alternative Conceptions of Psychopathic Personality: A Latent Variable Model of Triarchic Psychopathy Constructs. AB - This study undertook confirmatory factor analyses (CFAs) of data from 567 participants to quantify constructs specified by the triarchic model of psychopathy (Patrick, Fowles, & Krueger, 2009)-boldness, meanness, and disinhibition-as latent variables. Indicators for the CFAs consisted of subscales of the Triarchic Psychopathy Measure along with triarchic scales derived from items of the Psychopathic Personality Inventory, Youth Psychopathic Traits Inventory, and Multidimensional Personality Questionnaire. A modified three factor model provided good fit to the data and outperformed alternative two- and one-factor models. Multiple-group CFAs demonstrated gender differences (male > female) in factor means and covariances, but not in factor loadings or intercepts. These findings support the idea that the triarchic model dimensions are embedded in differing models and measures of psychopathy and comprise essential building blocks for this clinical condition. Implications for understanding the structure of psychopathy, gender differences in psychopathic traits, and applications of latent variable modeling in future research are discussed. PMID- 26959964 TI - Other radiological lesions of the Lower Urinary Tract in patients after isolated pelvic radiotherapy and combined with surgery. AB - INTRODUCTION: The cystographic study of patients who have undergone radiotherapy (RT) and pelvic surgeries is uncommon in the literature, not described in patients without complications, and mostly related to urinary fistulae. OBJECTIVE: The study of the lower urinary tract (LUT) by cystography in these patients, with a description of some other types of radiation lesions. METHODS: 127 cystographies have been performed (88 men and 39 women) in consecutive patients undergoing radiotherapy (RT) (48 monotherapy and 79 cases combined with surgery), with a mean age of 69.6 years, and a mean time from radiation of 215 months (17 years). A General Electric X ray equipment has been used. We studied: behavior of the bladder neck at rest and during micturition, assessment of vesicoureteral reflux (VUR), bladder morphology (BM), urethral strictures (UE) and fistulas (F). RESULTS: We observed: Filling phase bladder neck incompetence (BNI) (37.8%), bladder smooth morphology (60.6%), coughing urinary incontinence (UI) (26.4%), basal cystocele (64.7%) and Valsalva cystocele (96.6%), a normal opening bladder neck (96,1%), reduction of the urethral diameter during voiding (41.3%), and vesicoureteral reflux (VUR) (13.2%). Five cases of filling BNI, were all related to prostate cancer (PC) (one of them with colon cancer as well). There were six cases of fistulae (4.14%), five of them women. Forty two patients (28.96%) had reduced urethral lumen, thirty five of them affecting the posterior urethra (83%), five (11.9%) the anterior and, finally, two cases of mixed lesion (5%). 95% were patients with PC without concurrent interventions (67%). Significant differences were found regarding the gender and the background of pelvic surgery. The filling BNI (p=0.007), the irregular bladder morphology (p=0.004) and the reduction of the urethral lumen (p<0.001) have been found to be more common in male patients, while the coughing UI was more common in women (p=0.007). The study shows that BNI (p=0.046), VUR (p=0.02) and the IU due to cough (p=0.03) were more frequent in operated patients, while reduced urethral lumen was less common (p<0.01). Patients with VUR present more time from radiotherapy, but not in other cystography variables. There was a relationship between RT and the BNI, stress urinary incontinence, anterior urethral stricture and VUR. The risk factor was increased by surgery. CONCLUSIONS: Bladder neck incompetence, stress UI, anterior urethral stricture and VUR have been related to radiotherapy. Surgery increased the risk factor in operated patients. PMID- 26959965 TI - Comparative study for the efficacy and safety of percutaneous nefhrolithotomy (PCNL) and retrograde intrarenal surgery (RIRS) for the treatment of 2-3,5 cm kidney stones. AB - OBJECTIVES: Retrograde intrarenal surgery (RIRS) has become an important alternative for the treatment of kidney stones due to its increased safety and efficiency. The purpose of this study is to compare efficacy and safety features of RIRS against percutaneous nephrolithotomy (PCNL) for the treatment of 2 - 3.5 cm kidney stones. METHODS: 142 cases (106 RIRS and 36 PCNL) encompassing 2 - 3.5 cm kidney stones that have been treated in our center between December 2009 and December 2011 have been considered. Demographic variables, stone characteristics, surgical stay and surgical time have been evaluated. Additionally, the complication prerate and success rate after one and two procedures (retreatment) have also been assessed. Student's T, Mann-Whitney U y Chi2 - V Cramer (p=0.05) tests were used for statistical analysis. RESULTS: There are not statistically significant differences in demographic or stone variables. The calculated mean surgical time was lower for PCNL (85 min) than for RIRS (112 min). Mean hospital stay was statistically significantly shorter in RIRS (16 h vs. 98 h in RIRS, p=0.001). PCNL exhibited a higher global complication rate of 19.4% vs. 6.6% for RIRS (p=0.001). PCNL also showed a higher successful rate (80.6% vs. 73.6% for RIRS), although this difference was not statistically significant (p=0.40). When comparing the success rate after a second procedure, PCNL results in 94.3% vs. 93.5% for RIRS (p=0.88). CONCLUSION: RIRS was found to be a safe and efficient procedure with a short hospital stay. Overall, RIRS can be considered as an alternative to PCNL for the treatment of renal stones smaller than 3.5 cm. PMID- 26959966 TI - [Folic acid: Primary prevention of neural tube defects. Literature Review]. AB - Neural tube defects (NTD) are the most common congenital malformations of the nervous system, they have a multifactorial etiology, are caused by exposure to chemical, physical or biological toxic agents, factors deficiency, diabetes, obesity, hyperthermia, genetic alterations and unknown causes. Some of these factors are associated with malnutrition by interfering with the folic acid metabolic pathway, the vitamin responsible for neural tube closure. Its deficit produce anomalies that can cause abortions, stillbirths or newborn serious injuries that cause disability, impaired quality of life and require expensive treatments to try to alleviate in some way the alterations produced in the embryo. Folic acid deficiency is considered the ultimate cause of the production of neural tube defects, it is clear the reduction in the incidence of Espina Bifida after administration of folic acid before conception, this leads us to want to further study the action of folic acid and its application in the primary prevention of neural tube defects. More than 40 countries have made the fortification of flour with folate, achieving encouraging data of decrease in the prevalence of neural tube defects. This paper attempts to make a literature review, which clarify the current situation and future of the prevention of neural tube defects. PMID- 26959967 TI - Scrotal tumors. AB - OBJECTIVE: Basal cell carcinoma and leiomyoma of the scrotum are rare. We describe three cases of scrotal tumors and provide information regarding this disease. METHODS: Between 2000 and 2014, 3 patients with scrotal tumors were diagnosed and treated at our institution. A review was performed using the clinical records of these patients. RESULTS: We describe two cases of basal cell carcinoma of the scrotum in men 72 and 71 year old, who presented with a left scrotal lesion that was excised and the pathological diagnosis was basal cell carcinoma. In one patient, surgical margin was affected and a recurrent basal cell carcinoma appeared. It was excised with enlargement of surgical margin. We also describe a case of scrotal leiomyoma in a 48 year old man with an elastic, firm and nontender lesion in the right scrotum. During follow-up the patients remain clinically asymptomatic. CONCLUSIONS: Scrotal lesions in the elderly should be excised and submitted for pathological examination. The basal cell carcinoma of the scrotum appears as a plaque, nodule or ulcer. Long-term surveillance is recommended for these patients. Leiomyoma of the scrotum is presented as a non-ulcerative nodule and his treatment is complete surgical excision. PMID- 26959968 TI - Dermatological side effects of intravesical Mitomycin C: Delayed hypersensitivity. AB - OBJECTIVE: To know the dermatologic side effects of intravesical treatment with Mitomycin C in non muscle invasive bladder cancer. METHODS: We describe two cases of palm and plantar dermatitis after such treatment. RESULT: We describe two types of dermatitis pathogenesis during treatment with intravesical Mitomycin C: contact dermatitis and delayed hypersensitivity dermatitis. CONCLUSIONS: Contact dermatitis of non-allergic origin is a common side effect described in many instances in the literature, on the other hand exists dermatitis secondary to delayed hypersensitivity type IV much less common, requiring treatment with corticosteroids. PMID- 26959969 TI - Use of urinary concentrations in mg/dl in relation to absolute values in 24-hour samples for the evaluation of lithogenic factors in stone forming patients. AB - OBJECTIVE: The aim of this study is to analyze urine concentrations (mg/dl) of different lithogenic factors in a sample of 24 h as a predictor of these changes rather than absolute values depend on the volume of diuresis. METHODS: A total of 131 patients from the North Almeria Health Management Area (Spain) with urinary calstone disease in whom a metabolic study was indicated were included from June 2014 to May 2015. The concentrations of calcium, oxalate, uric acid, citrate and magnesium were measured in the urine, and the calcium/citrate ratio was calculated. The classifications used were: hypercalciuria (>260mg/24h), hyperuricosuria (>750mg/24h), hyperoxaluria (>40mg/24h), hypocitraturia (<320mg/24h) and hypomagnesuria (<35mg/24h). The statistical analysis was performed using SPSS 17.0. RESULTS: A cut-off point of 12.55mg/dl, with a sensitivity of 90% and a specificity of 85% and a relative risk (RR) of 51.2 (13.9-188.4), was estimated for urinary calcium. For oxalate the cut-off point was 1.86mg/dl, with a sensitivity of 91% and a specificity of 84% with an estimated RR of 67.2 (8.3-540.6). As regards the uric acid concentration in urine, a cut-off point of 31.2mg/dl was estimated, with a sensitivity of 85% and a specificity of 70% and a RR of 12 (3.8-37.6). For citrate the cut-off point was 18.8mg/dl, with a sensitivity and specificity of 82% and 74%, respectively, with a RR of 13.7 (4.4- 42.6). The cut-off point for magnesium was 2.26mg/dl with a sensitivity of 95% and specificity of 78%, with a RR of 67.6 (11.4-398.3). CONCLUSION: The determination of urine concentrations, instead of absolute values, depends to a large extent on urine output, appears to be useful when estimating classic metabolic alterations and should be taken into account in the evaluation of patients with urinary stone disease. PMID- 26959970 TI - Plasmonic Color-Graded Nanosystems with Achromatic Subwavelength Architectures for Light Filtering and Advanced SERS Detection. AB - Plasmonic color-graded systems are devices featuring a spatially variable plasmonic response over their surface. They are widely used as nanoscale color filters; their typical size is small enough to allow integration with miniaturized electronic circuits, paving the way to realize novel nanophotonic devices. Currently, most plasmonic color-graded systems are intrinsically discrete because their chromatic response exploits the tailored plasmon resonance of microarchitectures characterized by different size or geometry for each target color. Here, we report the realization of multifunctional plasmon-graded devices where continuously graded chromatic response is achieved by smoothly tuning the composition of the resonator material while simultaneously maintaining an achromatic nanoscale geometry. The result is a new class of versatile materials: we show their application as plasmonic filters with a potential pixel size smaller than half of the exciting wavelength but also as multiplexed surface enhanced Raman spectroscopy (SERS) substrates. Many more implementations, such as photovoltaic efficiency boosters or color routers, await and will benefit from the low fabrication cost and intrinsic plasmonic flexibility of the presented systems. PMID- 26959971 TI - Teaching Strategies for Personality Assessment at the Undergraduate Level. AB - Personality assessment is a crucial component of clinical practice, and the training and proficiency criteria to develop competence are complex and multifaceted. Like many advanced topics, the field of personality assessment would benefit from early exposure in undergraduate classroom settings. This research evaluates how an undergraduate personality course can be enhanced through 2 enrichment activities (self-assessments and a personality project). Students completed several self-assessments of their personality and wrote a comprehensive and integrative personality assessment about themselves. Results demonstrated that these activities increased interest in personality assessment, deepened understanding of course material, and promoted student growth and self exploration. We discuss the benefits of these enrichment activities for the student, instructor, and field of personality science. PMID- 26959972 TI - Increased lead and cadmium tolerance of Typha angustifolia from Huaihe River is associated with enhanced phytochelatin synthesis and improved antioxidative capacity. AB - Heavy metal contamination of water is an increasing environmental problem worldwide, and the use of aquatic plants for phytoremediation of heavy metal pollution has become an important subject of research. One key to successful phytoremediation is the identification of plants that are efficient at sequestering heavy metals. In this study, we examined the growth and heavy metal accumulation of Typha angustifolia and compared growth characteristics and tolerance mechanisms in plants from the Huaihe and Chaohu Rivers irrigated with different concentrations of lead (Pb) and cadmium (Cd). T. angustifolia from Huaihe River showed enhanced tolerance and accumulation of Pb and Cd and had greater biomass and more vigorous growth than the ecotype from Chaohu River. In addition, higher phytochelatin (PC) content and significantly higher superoxide dismutase and catalase activities were detected in T. angustifolia from Huaihe River than in T. angustifolia from Chaohu River. These findings suggest that high Pb and Cd accumulation and tolerance in T. angustifolia from Chaohu River is associated with its higher PC synthesis and better antioxidative capacity, and that the Huaihe ecotype of T. angustifolia might also be an efficient species for phytoremediation of Pb and Cd in water contaminated by heavy metals. PMID- 26959973 TI - Copper-Catalyzed Hydroamination of Terminal Allenes. AB - The ligand-free copper-catalyzed hydroamination of allenes has been accomplished in the presence of cyclic secondary amines or anilines derivatives. This novel methodology undergoes the selective generation of (E)-allylamines under smooth conditions with total regio- and stereoselectivity. PMID- 26959974 TI - Assessment of Haemostasis in Disseminated Intravascular Coagulation by Use of Point-of-Care Assays and Routine Coagulation Tests, in Critically Ill Patients; A Prospective Observational Study. AB - BACKGROUND: Disseminated intravascular coagulopathy (DIC) relates to the consumption of coagulation factors and platelets with bleeding and micro thrombosis events. AIM: The aim of this study was to compare haemostasis parameters in critically ill patients with DIC versus patients without DIC, and in survivors versus non-survivors over time. Correlations between the DIC-score, the degree of organ failure and the haemostasis were assessed. METHOD: Patients admitted to the intensive care unit with a condition known to be associated with DIC and with an expected length of stay of >3 days were included. Routine laboratory tests, prothrombin time, activated partial thromboplastin time, platelet count, fibrinogen concentration and D-dimer were measured. Coagulation and platelet function were assessed with two point-of-care devices; Multiplate and ROTEM. DIC scores were calculated according to the International Society on Thrombosis and Haemostasis and Japanese Association for Acute Medicine. RESULTS: Blood was sampled on days 0-1, 2-3 and 4-10 from 136 patients with mixed diagnoses during 290 sampling events. The point-of-care assays indicated a hypocoagulative response (decreased platelet aggregation and reduced clot strength) in patients with DIC and, over time, in non-survivors compared to survivors. Patients with DIC as well as non-survivors had decreased fibrinolysis as shown by ROTEM. DIC scores were higher in non-survivors than in survivors. CONCLUSIONS: Patients with DIC displayed signs of a hypocoagulative response and impaired fibrinolysis, which was also evident over time in non-survivors. Patients with DIC had a higher mortality rate than non-DIC patients, and DIC scores were higher in non-survivors than in survivors. PMID- 26959976 TI - Religion and the Unmaking of Prejudice toward Muslims: Evidence from a Large National Sample. AB - In the West, anti-Muslim sentiments are widespread. It has been theorized that inter-religious tensions fuel anti-Muslim prejudice, yet previous attempts to isolate sectarian motives have been inconclusive. Factors contributing to ambiguous results are: (1) failures to assess and adjust for multi-level denomination effects; (2) inattention to demographic covariates; (3) inadequate methods for comparing anti-Muslim prejudice relative to other minority group prejudices; and (4) ad hoc theories for the mechanisms that underpin prejudice and tolerance. Here we investigate anti-Muslim prejudice using a large national sample of non-Muslim New Zealanders (N = 13,955) who responded to the 2013 New Zealand Attitudes and Values Study. We address previous shortcomings by: (1) building Bayesian multivariate, multi-level regression models with denominations modeled as random effects; (2) including high-resolution demographic information that adjusts for factors known to influence prejudice; (3) simultaneously evaluating the relative strength of anti-Muslim prejudice by comparing it to anti Arab prejudice and anti-immigrant prejudice within the same statistical model; and (4) testing predictions derived from the Evolutionary Lag Theory of religious prejudice and tolerance. This theory predicts that in countries such as New Zealand, with historically low levels of conflict, religion will tend to increase tolerance generally, and extend to minority religious groups. Results show that anti-Muslim and anti-Arab sentiments are confounded, widespread, and substantially higher than anti-immigrant sentiments. In support of the theory, the intensity of religious commitments was associated with a general increase in tolerance toward minority groups, including a poorly tolerated religious minority group: Muslims. Results clarify religion's power to enhance tolerance in peaceful societies that are nevertheless afflicted by prejudice. PMID- 26959975 TI - Disruption of STAT5b-Regulated Sexual Dimorphism of the Liver Transcriptome by Diverse Factors Is a Common Event. AB - Signal transducer and activator of transcription 5b (STAT5b) is a growth hormone (GH)-activated transcription factor and a master regulator of sexually dimorphic gene expression in the liver. Disruption of the GH hypothalamo-pituitary-liver axis controlling STAT5b activation can lead to metabolic dysregulation, steatosis, and liver cancer. Computational approaches were developed to identify factors that disrupt STAT5b function in a mouse liver gene expression compendium. A biomarker comprised of 144 STAT5b-dependent genes was derived using comparisons between wild-type male and wild-type female mice and between STAT5b-null and wild type mice. Correlations between the STAT5b biomarker gene set and a test set comprised of expression datasets (biosets) with known effects on STAT5b function were evaluated using a rank-based test (the Running Fisher algorithm). Using a similarity p-value <= 10(-4), the test achieved a balanced accuracy of 99% and 97% for detection of STAT5b activation or STAT5b suppression, respectively. The STAT5b biomarker gene set was then used to identify factors that activate (masculinize) or suppress (feminize) STAT5b function in an annotated mouse liver and primary hepatocyte gene expression compendium of ~1,850 datasets. Disruption of GH-regulated STAT5b is a common phenomenon in liver in vivo, with 5% and 29% of the male datasets, and 11% and 13% of the female datasets, associated with masculinization or feminization, respectively. As expected, liver STAT5b activation/masculinization occurred at puberty and suppression/feminization occurred during aging and in mutant mice with defects in GH signaling. A total of 70 genes were identified that have effects on STAT5b activation in genetic models in which the gene was inactivated or overexpressed. Other factors that affected liver STAT5b function were shown to include fasting, caloric restriction and infections. Together, these findings identify diverse factors that perturb the hypothalamo-pituitary-liver GH axis and disrupt GH-dependent STAT5b activation in mouse liver. PMID- 26959977 TI - Trading Off Global Fuel Supply, CO2 Emissions and Sustainable Development. AB - The United Nations Conference on Climate Change (Paris 2015) reached an international agreement to keep the rise in global average temperature 'well below 2 degrees C' and to 'aim to limit the increase to 1.5 degrees C'. These reductions will have to be made in the face of rising global energy demand. Here a thoroughly validated dynamic econometric model (Eq 1) is used to forecast global energy demand growth (International Energy Agency and BP), which is driven by an increase of the global population (UN), energy use per person and real GDP (World Bank and Maddison). Even relatively conservative assumptions put a severe upward pressure on forecast global energy demand and highlight three areas of concern. First, is the potential for an exponential increase of fossil fuel consumption, if renewable energy systems are not rapidly scaled up. Second, implementation of internationally mandated CO2 emission controls are forecast to place serious constraints on fossil fuel use from ~2030 onward, raising energy security implications. Third is the challenge of maintaining the international 'pro-growth' strategy being used to meet poverty alleviation targets, while reducing CO2 emissions. Our findings place global economists and environmentalists on the same side as they indicate that the scale up of CO2 neutral renewable energy systems is not only important to protect against climate change, but to enhance global energy security by reducing our dependence of fossil fuels and to provide a sustainable basis for economic development and poverty alleviation. Very hard choices will have to be made to achieve 'sustainable development' goals. PMID- 26959978 TI - Correction: Network Topology Analysis of Post-Mortem Brain Microarrays Identifies More Alzheimer's Related Genes and MicroRNAs and Points to Novel Routes for Fighting with the Disease. PMID- 26959979 TI - Life History Traits and Niche Instability Impact Accuracy and Temporal Transferability for Historically Calibrated Distribution Models of North American Birds. AB - A primary assumption of environmental niche models (ENMs) is that models are both accurate and transferable across geography or time; however, recent work has shown that models may be accurate but not highly transferable. While some of this is due to modeling technique, individual species ecologies may also underlie this phenomenon. Life history traits certainly influence the accuracy of predictive ENMs, but their impact on model transferability is less understood. This study investigated how life history traits influence the predictive accuracy and transferability of ENMs using historically calibrated models for birds. In this study I used historical occurrence and climate data (1950-1990s) to build models for a sample of birds, and then projected them forward to the 'future' (1960 1990s). The models were then validated against models generated from occurrence data at that 'future' time. Internal and external validation metrics, as well as metrics assessing transferability, and Generalized Linear Models were used to identify life history traits that were significant predictors of accuracy and transferability. This study found that the predictive ability of ENMs differs with regard to life history characteristics such as range, migration, and habitat, and that the rarity versus commonness of a species affects the predicted stability and overlap and hence the transferability of projected models. Projected ENMs with both high accuracy and transferability scores, still sometimes suffered from over- or under- predicted species ranges. Life history traits certainly influenced the accuracy of predictive ENMs for birds, but while aspects of geographic range impact model transferability, the mechanisms underlying this are less understood. PMID- 26959980 TI - From Community Laywomen to Breast Health Workers: A Pilot Training Model to Implement Clinical Breast Exam Screening in Malawi. AB - BACKGROUND: Breast cancer burden is high in low-income countries. Inadequate early detection contributes to late diagnosis and increased mortality. We describe the training program for Malawi's first clinical breast exam (CBE) screening effort. METHODS: Laywomen were recruited as Breast Health Workers (BHWs) with the help of local staff and breast cancer advocates. The four-week training consisted of lectures, online modules, role-playing, case discussions, CBE using simulators and patients, and practice presentations. Ministry of Health trainers taught health communication, promotion, and education skills. Breast cancer survivors shared their experiences. Clinicians taught breast cancer epidemiology, prevention, detection, and clinical care. Clinicians and research staff taught research ethics, informed consent, data collection, and professionalism. Breast cancer knowledge was measured using pre- and post training surveys. Concordance between BHW and clinician CBE was assessed. Breast cancer talks by BHW were evaluated on a 5-point scale in 22 areas by 3 judges. RESULTS: We interviewed 12 women, and 4 were selected as BHWs including 1 breast cancer survivor. Training was dynamic with modification based on trainee response and progress. A higher-than-anticipated level of comprehension and interest led to inclusion of additional topics like breast reconstruction. Pre-training knowledge increased from 49% to 91% correct (p<0.0001). Clinician and BHW CBE had 88% concordance (kappa 0.43). The mean rating of BHW educational talks was 4.4 (standard deviation 0.7). CONCLUSIONS: Malawian laywomen successfully completed training and demonstrated competency to conduct CBE and deliver breast cancer educational talks. Knowledge increased after training, and concordance was high between BHW and clinician CBE. PMID- 26959982 TI - Evidence for divergence of response in Indica, Japonica, and wild rice to high CO2 * temperature interaction. AB - High CO2 and high temperature have an antagonistic interaction effect on rice yield potential and present a unique challenge to adapting rice to projected future climates. Understanding how the differences in response to these two abiotic variables are partitioned across rice germplasm accessions may be key to identifying potentially useful sources of resilient alleles for adapting rice to climate change. In this study, we evaluated eleven globally diverse rice accessions under controlled conditions at two carbon dioxide concentrations (400 and 600 ppm) and four temperature environments (29 degrees C day/21 degrees C night; 29 degrees C day/21 degrees C night with additional heat stress at anthesis; 34 degrees C day/26 degrees C night; and 34 degrees C day/26 degrees C night with additional heat stress at anthesis) for a suite of traits including five yield components, five growth characteristics, one phenological trait, and four photosynthesis-related measurements. Multivariate analyses of mean trait data from these eight treatments divide our rice panel into two primary groups consistent with the genetic classification of INDICA/INDICA-like and JAPONICA populations. Overall, we find that the productivity of plants grown under elevated [CO2 ] was more sensitive (negative response) to high temperature stress compared with that of plants grown under ambient [CO2 ] across this diversity panel. We report differential response to CO2 * temperature interaction for INDICA/INDICA-like and JAPONICA rice accessions and find preliminary evidence for the beneficial introduction of exotic alleles into cultivated rice genomic background. Overall, these results support the idea of using wild or currently unadapted gene pools in rice to enhance breeding efforts to secure future climate change adaptation. PMID- 26959981 TI - UCP1 and UCP3 Expression Is Associated with Lipid and Carbohydrate Oxidation and Body Composition. AB - BACKGROUND/OBJECTIVE: Uncoupling proteins (UCPs) are located in the inner membrane of mitochondria. These proteins participate in thermogenesis and energy expenditure. This study aimed to evaluate how UCP1 and UCP3 expression influences substrate oxidation and elicits possible changes in body composition in patients submitted to bariatric surgery. SUBJECTS/METHODS: This is a longitudinal study comprising 13 women with obesity grade III that underwent bariatric surgery and 10 healthy weight individuals (control group). Body composition was assessed by bioelectrical impedance. Carbohydrate and fat oxidation was determined by indirect calorimetry. Subcutaneous adipose tissue was collected for gene expression analysis. QPCR was used to evaluate UCP1 and UCP3 expression. RESULTS: Obese patients and the control group differed significantly in terms of lipid and carbohydrate oxidation. Six months after bariatric surgery, the differences disappeared. Lipid oxidation correlated with the percentage of fat mass in the postoperative period. Multiple linear regression analysis showed that the UCP1 and UCP3 genes contributed to lipid and carbohydrate oxidation. Additionally, UCP3 expression was associated with BMI, percentage of lean body mass, and percentage of mass in the postoperative period. CONCLUSIONS: UCP1 and UCP3 expression is associated with lipid and carbohydrate oxidation in patients submitted to bariatric surgery. In addition, UCP3 participates in body composition modulation six months postoperatively. PMID- 26959983 TI - Influenza Vaccine Manufacturing: Effect of Inactivation, Splitting and Site of Manufacturing. Comparison of Influenza Vaccine Production Processes. AB - The aim of this study was to evaluate the impact of different inactivation and splitting procedures on influenza vaccine product composition, stability and recovery to support transfer of process technology. Four split and two whole inactivated virus (WIV) influenza vaccine bulks were produced and compared with respect to release criteria, stability of the bulk and haemagglutinin recovery. One clarified harvest of influenza H3N2 A/Uruguay virus prepared on 25.000 fertilized eggs was divided equally over six downstream processes. The main unit operation for purification was sucrose gradient zonal ultracentrifugation. The inactivation of the virus was performed with either formaldehyde in phosphate buffer or with beta-propiolactone in citrate buffer. For splitting of the viral products in presence of Tween(r), either TritonTM X-100 or di-ethyl-ether was used. Removal of ether was established by centrifugation and evaporation, whereas removal of Triton-X100 was performed by hydrophobic interaction chromatography. All products were sterile filtered and subjected to a 5 months real time stability study. In all processes, major product losses were measured after sterile filtration; with larger losses for split virus than for WIV. The beta propiolactone inactivation on average resulted in higher recoveries compared to processes using formaldehyde inactivation. Especially ether split formaldehyde product showed low recovery and least stability over a period of five months. PMID- 26959984 TI - STEMI Outcomes in Guangzhou and Hong Kong: Two-Centre Retrospective Interregional Study. AB - BACKGROUND AND OBJECTIVES: Healthcare systems are organized very differently in Hong Kong (HK) and Guangzhou (GZ). This study compared managements of the emergency departments (ED) and one-year mortalities of ST-segment elevation myocardial infarction (STEMI) patients in two teaching hospitals in Guangzhou and Hong Kong. METHODS: Retrospective observational study of STEMI mortalities and treatments in the Prince of Wales Hospital (PWH) and the Second Affiliated Hospital of Guangzhou Medical University (AHGZMU), was conducted between January and December 2010. The primary outcome was one-year all cause mortality. RESULTS: Univariate analysis of 76 cases from PWH and 111 cases from AHGZMU showed similar clinical characteristics, except for lower proportions of males (74% vs 92%, P = 0.002), hyperlipidemia (5% vs 25%, P<0.001), and Killip class I (56% vs 91%; P<0.001) in AHGZMU. The onset-to-door time of STEMI patients in AHGZMU was longer than in PWH (median 205 min [(IQR: 95-432) vs 120 min (IQR: 55-225), P = 0.001]. In AHGZMU, 85 (77%) patients received primary percutaneous coronary intervention (PPCI) as the main reperfusion treatment, whereas 18 (24%) received PPCI and 51 (67%) patients received thrombolytic therapy in PWH. Overall the one-year mortality in AHGZMU was 20%, whilst in PWH it was 14% (P = 0.436). The standardized one-year all-cause mortality ratios for AHGZMU and PWH were comparable (18.7 vs. 18.2%, P = 0894). Independent predictors of one-year mortality included older age (>67 years) and hyperglycemia (>10 mmol/L). Aged over 65 years, presence of anterior wall infarct, body weight <=65 kg, SBP <100 mmHg at ED and glucose level >10 mmol/L were the independent predictors of in hospital MACE. CONCLUSION: There was no statistically significant difference between the standardized one-year all-cause mortalities of STEMI patients in the setting mainly using thrombolysis with shorter door-to-treatment time and the setting mainly using PCI with longer door-to-treatment time. Aged over 67 years and glucose level over 10 mmol/L were the independent predictors of one-year mortality. Older age, presence of anterior wall infarct, lower body weight, lower SBP at ED and hyperglycemia were the independent predictors of in-hospital MACE. PMID- 26959992 TI - Children's Quality of Life Based on the KIDSCREEN-27: Child Self-Report, Parent Ratings and Child-Parent Agreement in a Swedish Random Population Sample. AB - BACKGROUND: The KIDSCREEN-27 is a measure of child and adolescent quality of life (QoL), with excellent psychometric properties, available in child-report and parent-rating versions in 38 languages. This study provides child-reported and parent-rated norms for the KIDSCREEN-27 among Swedish 11-16 year-olds, as well as child-parent agreement. Sociodemographic correlates of self-reported wellbeing and parent-rated wellbeing were also measured. METHODS: A random population sample consisting of 600 children aged 11-16, 100 per age group and one of their parents (N = 1200), were approached for response to self-reported and parent rated versions of the KIDSCREEN-27. Parents were also asked about their education, employment status and their own QoL based on the 26-item WHOQOL-Bref. Based on the final sampling pool of 1158 persons, a 34.8% response rate of 403 individuals was obtained, including 175 child-parent pairs, 27 child singleton responders and 26 parent singletons. Gender and age differences for parent ratings and child-reported data were analyzed using t-tests and the Mann-Whitney U-test. Post-hoc Dunn tests were conducted for pairwise comparisons when the p value for specific subscales was 0.05 or lower. Child-parent agreement was tested item-by-item, using the Prevalence- and Bias-Adjusted Kappa (PABAK) coefficient for ordinal data (PABAK-OS); dimensional and total score agreement was evaluated based on dichotomous cut-offs for lower well-being, using the PABAK and total, continuous scores were evaluated using Bland-Altman plots. RESULTS: Compared to European norms, Swedish children in this sample scored lower on Physical wellbeing (48.8 SE/49.94 EU) but higher on the other KIDSCREEN-27 dimensions: Psychological wellbeing (53.4/49.77), Parent relations and autonomy (55.1/49.99), Social Support and peers (54.1/49.94) and School (55.8/50.01). Older children self-reported lower wellbeing than younger children. No significant self-reported gender differences occurred and parent ratings showed no gender or age differences. Item-by-item child-parent agreement was slight for 14 items (51.9%), fair for 12 items (44.4%), and less than chance for one item (3.7%), but agreement on all dimensions as well as the total score was substantial according to the PABAK-OS. Visual interpretation of the Bland-Altman plot suggested that when children's average wellbeing score was lower parents seemed to rate their children as having relatively higher total wellbeing, but as children's average wellbeing score increased, parents tended to rate their children as having relatively lower total wellbeing. Children living with both parents had higher wellbeing than those who lived with only one parent. CONCLUSIONS: Results agreed with European findings that adolescent wellbeing decreases with age but contrasted with some prior Swedish research identifying better wellbeing for boys on all dimensions but Social support and peers. The study suggests the importance of considering children's own reports and not only parental or other informant ratings. Future research should be conducted at regular intervals and encompass larger samples. PMID- 26959991 TI - A Variant of GJD2, Encoding for Connexin 36, Alters the Function of Insulin Producing beta-Cells. AB - Signalling through gap junctions contributes to control insulin secretion and, thus, blood glucose levels. Gap junctions of the insulin-producing beta-cells are made of connexin 36 (Cx36), which is encoded by the GJD2 gene. Cx36-null mice feature alterations mimicking those observed in type 2 diabetes (T2D). GJD2 is also expressed in neurons, which share a number of common features with pancreatic beta-cells. Given that a synonymous exonic single nucleotide polymorphism of human Cx36 (SNP rs3743123) associates with altered function of central neurons in a subset of epileptic patients, we investigated whether this SNP also caused alterations of beta-cell function. Transfection of rs3743123 cDNA in connexin-lacking HeLa cells resulted in altered formation of gap junction plaques and cell coupling, as compared to those induced by wild type (WT) GJD2 cDNA. Transgenic mice expressing the very same cDNAs under an insulin promoter revealed that SNP rs3743123 expression consistently lead to a post-natal reduction of islet Cx36 levels and beta-cell survival, resulting in hyperglycemia in selected lines. These changes were not observed in sex- and age-matched controls expressing WT hCx36. The variant GJD2 only marginally associated to heterogeneous populations of diabetic patients. The data document that a silent polymorphism of GJD2 is associated with altered beta-cell function, presumably contributing to T2D pathogenesis. PMID- 26959993 TI - The Structural Basis of Coenzyme A Recycling in a Bacterial Organelle. AB - Bacterial Microcompartments (BMCs) are proteinaceous organelles that encapsulate critical segments of autotrophic and heterotrophic metabolic pathways; they are functionally diverse and are found across 23 different phyla. The majority of catabolic BMCs (metabolosomes) compartmentalize a common core of enzymes to metabolize compounds via a toxic and/or volatile aldehyde intermediate. The core enzyme phosphotransacylase (PTAC) recycles Coenzyme A and generates an acyl phosphate that can serve as an energy source. The PTAC predominantly associated with metabolosomes (PduL) has no sequence homology to the PTAC ubiquitous among fermentative bacteria (Pta). Here, we report two high-resolution PduL crystal structures with bound substrates. The PduL fold is unrelated to that of Pta; it contains a dimetal active site involved in a catalytic mechanism distinct from that of the housekeeping PTAC. Accordingly, PduL and Pta exemplify functional, but not structural, convergent evolution. The PduL structure, in the context of the catalytic core, completes our understanding of the structural basis of cofactor recycling in the metabolosome lumen. PMID- 26959995 TI - Therapeutic Opportunities for Caffeine and A2A Receptor Antagonists in Retinal Diseases. AB - Caffeine, the major component of coffee, is the most consumed psychostimulant in the world. Caffeine is an adenosine analog and acts as a nonselective adenosine receptor antagonist. The majority of the effects of caffeine are mainly mediated by the blockade of adenosine receptors, and the proved neuroprotective effects of caffeine in brain disorders have been mimicked by the blockade of adenosine A2A receptor (A2AR). A growing body of evidence demonstrates that microglia-mediated neuroinflammation plays a key role in the pathophysiology of brain and retinal diseases. Moreover, the control of microglia reactivity by blocking A2AR has been proposed to be the mechanism underlying the observed protective effects of caffeine. Hence, it is conceivable that caffeine and A2AR antagonists offer therapeutic value for the treatment of retinal diseases, mainly those involving microglia-mediated neuroinflammation. PMID- 26959996 TI - The Effect of Trail Pheromone and Path Confinement on Learning of Complex Routes in the Ant Lasius niger. AB - Route learning is key to the survival of many central place foragers, such as bees and many ants. For ants which lay pheromone trails, the presence of a trail may act as an important source of information about whether an error has been made. The presence of trail pheromone has been demonstrated to support route learning, and the effect of pheromones on route choice have been reported to persist even after the pheromones have been removed. This could be explained in two ways: the pheromone may constrain the ants onto the correct route, thus preventing errors and aiding learning. Alternatively, the pheromones may act as a 'reassurance', signalling that the learner is on the right path and that learning the path is worthwhile. Here, we disentangle pheromone presence from route confinement in order to test these hypotheses, using the ant Lasius niger as a model. Unexpectedly, we did not find any evidence that pheromones support route learning. Indeed, there was no evidence that ants confined to the correct route learned at all. Thus, while we cannot support the 'reassurance' hypothesis, we can rule out the 'confinement' hypothesis. Other findings, such as a reduction in pheromone deposition in the presence of trail pheromones, are remarkably consistent with previous experiments. As previously reported, ants which make errors on their outward journey upregulate pheromone deposition on their return. Surprisingly, ants which would go on to make an error down-regulate pheromone deposition on their outward journey, hinting at a capacity for ants to gauge the quality of their own memories. PMID- 26959994 TI - Still Searching for a Suitable Molecular Test to Detect Hidden Plasmodium Infection: A Proposal for Blood Donor Screening in Brazil. AB - BACKGROUND: Efforts have been made to establish sensitive diagnostic tools for malaria screening in blood banks in order to detect malaria asymptomatic carriers. Microscopy, the malaria reference test in Brazil, is time consuming and its sensitivity depends on microscopist experience. Although molecular tools are available, some aspects need to be considered for large-scale screening: accuracy and robustness for detecting low parasitemia, affordability for application to large number of samples and flexibility to perform on individual or pooled samples. METHODOLOGY: In this retrospective study, we evaluated four molecular assays for detection of malaria parasites in a set of 56 samples previously evaluated by expert microscopy. In addition, we evaluated the effect of pooling samples on the sensitivity and specificity of the molecular assays. A well characterized cultured sample with 1 parasite/MUL was included in all the tests evaluated. DNA was extracted with QIAamp DNA Blood Mini Kit and eluted in 50 MUL to concentrate the DNA. Pools were assembled with 10 samples each. Molecular protocols targeting 18S rRNA, included one qPCR genus specific (Lima-genus), one duplex qPCR genus/Pf (PET-genus, PET-Pf) and one duplex qPCR specie-specific (Rougemont: Roug-Pf/Pv and Roug-Pm/Po). Additionally a nested PCR protocol specie specific was used (Snou-Pf, Snou-Pv, Snou-Pm and Snou-Po). RESULTS: The limit of detection was 3.5 p/MUL and 0.35p/MUl for the PET-genus and Lima-genus assays, respectively. Considering the positive (n = 13) and negative (n = 39) unpooled individual samples according to microscopy, the sensitivity of the two genus qPCR assays was 76.9% (Lima-genus) and 72.7% (PET-genus). The Lima-genus and PET-genus showed both sensitivity of 86.7% in the pooled samples. The genus protocols yielded similar results (Kappa value of 1.000) in both individual and pooled samples. CONCLUSIONS: Efforts should be made to improve performance of molecular tests to enable the detection of low-density parasitemia if these tests are to be utilized for blood transfusion screening. PMID- 26959997 TI - Effects of Fluorine Substitution on the Microsolvation of Aromatic Azines: The Microwave Spectrum of 3-Fluoropyridine-Water. AB - The rotational spectra of the parent species and of four water isotopologues ( DOH, -HOD, -DOD, and -H(18)OH) of the adduct 3-fluoropyridine-water have been investigated using pulsed supersonic-jet Fourier-transform microwave spectroscopy. From the rotational constants, the structure of the adduct was deduced where the water is linked to the aromatic ring through an intermolecular O-H...N hydrogen bond with a bond distance of 1.9961(5) A and an O-H...N angle of 156.8(1) degrees . The shape of the complex is such that the water oxygen is in the plane of the aromatic ring, on the opposite side of fluorine, and forming a C H...N weak hydrogen bond with the adjacent aromatic hydrogen. PMID- 26959998 TI - A Textile-Based Stretchable Multi-Ion Potentiometric Sensor. AB - A textile-based wearable multi-ion potentiometric sensor array is described. The printed flexible sensors operate favorably under extreme mechanical strains (that reflect daily activity) while offering attractive real-time noninvasive monitoring of electrolytes such as sodium and potassium. PMID- 26959999 TI - Lack of Interactions Between an Antisense Oligonucleotide with 2'-O-(2 Methoxyethyl) Modifications and Major Drug Transporters. AB - ISIS 141923 is a model compound of 2'-O-(2-methoxyethyl) (2'-MOE) modified antisense oligonucleotides (ASOs). The purpose of this study is to determine whether ISIS 141923 is a substrate or an inhibitor against a panel of nine major uptake or efflux drug transporters, namely breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, OCT2, organic anion transporting polypeptide 1B (OATP1B)1, OATP1B3, and bile salt export pump (BSEP), in vitro. The uptake test system for transporters in the solute carrier (SLC) family (OAT1, OAT3, OCT1, OCT2, OATP1B1, and OATP1B3) was studied in Madin-Darby canine kidney (MDCK)-II cells transfected to express the transporters of interest. BCRP was studied using carcinoma colon-2 (Caco-2) cells with endogenously expressed BCRP. P-gp transporter was studied in MDCK-multi-drug resistance 1 (MDR1) cells, while BSEP was studied using Spodoptera frugiperda 9 (Sf9) membrane vesicles containing human BSEP. The ISIS 141293 concentrations evaluated were 10 and 100 MUM for the substrate and inhibition study, respectively. Cellular uptake of ISIS 141923 was analyzed using a high performance liquid chromatography-mass spectrometry method, while concentrations of known substrates (used as positive controls) of each transporters evaluated were determined by radiometric detection. At 10 MUM ISIS 141923, there was no significant transporter-mediated uptake of ISIS 141923 (P > 0.05) in the SLC family, and the efflux ratios were not above 2.0 for either BCRP or P-gp. Therefore, no transporter-mediated uptake of ISIS 141923 was observed by any of the nine transporters studied. At 100 MUM ISIS 141923, the % inhibition was in the range of -16.0% to 19.0% for the nine transporters evaluated. Therefore, ISIS 141923 is not considered as an inhibitor of the nine transporters studied. Overall, the results from this study suggest that it is unlikely that ISIS 141923 or similar 2'-MOE ASOs would interact with small molecule drugs either as a victim (substrate) or perpetrator (inhibitor) of major transporters in humans. The results from available clinical drug-drug interaction studies conducted with this class of compounds to date are also supportive of this conclusion. PMID- 26960000 TI - First Multitarget Chemo-Bioinformatic Model To Enable the Discovery of Antibacterial Peptides against Multiple Gram-Positive Pathogens. AB - Antimicrobial peptides (AMPs) have emerged as promising therapeutic alternatives to fight against the diverse infections caused by different pathogenic microorganisms. In this context, theoretical approaches in bioinformatics have paved the way toward the creation of several in silico models capable of predicting antimicrobial activities of peptides. All current models have several significant handicaps, which prevent the efficient search for highly active AMPs. Here, we introduce the first multitarget (mt) chemo-bioinformatic model devoted to performing alignment-free prediction of antibacterial activity of peptides against multiple Gram-positive bacterial strains. The model was constructed from a data set containing 2488 cases of AMPs sequences assayed against at least 1 out of 50 Gram-positive bacterial strains. This mt-chemo-bioinformatic model displayed percentages of correct classification higher than 90.00% in both training and prediction (test) sets. For the first time, two computational approaches derived from basic concepts in genetics and molecular biology were applied, allowing the calculations of the relative contributions of any amino acid (in a defined position) to the antibacterial activity of an AMP and depending on the bacterial strain used in the biological assay. The present mt chemo-bioinformatic model constitutes a powerful tool to enable the discovery of potent and versatile AMPs. PMID- 26960001 TI - Semi-micro reversed-phase liquid chromatography for the separation of alkyl benzenes and proteins exploiting methacrylate- and polystyrene-based monolithic columns. AB - Monolithic columns were synthesized inside 1.02 mm internal diameter fused-silica lined stainless-steel tubing. Styrene and butyl, hexyl, lauryl, and glycidyl methacrylates were the functional monomers. Ethylene glycol dimethacrylate and divinylbenzene were the crosslinkers. The glycidyl methacrylate polymer was modified with gold nanoparticles and dodecanethiol (C12 ). The separation of alkylbenzenes was investigated by isocratic elution in 60:40 v/v acetonitrile/water. The columns based on polystyrene-co-divinylbenzene and poly(glycidyl methacrylate)-co-ethylene glycol dimethacrylate modified with dodecanethiol did not provide any separation of alkyl benzenes. The poly(hexyl methacrylate)-co-ethylene glycol dimethacrylate and poly(lauryl methacrylate)-co ethylene glycol dimethacrylate columns separated the alkyl benzenes with plate heights between 30 and 60 MUm (50 MUL min(-1) and 60 degrees C). Similar efficiency was achieved in the poly(butyl methacrylate)-co-ethylene glycol dimethacrylate column, but only at 10 MUL min(-1) (0.22 mm s(-1) ). Backpressures varied from 0.38 MPa in the hexyl methacrylate to 13.4 MPa in lauryl methacrylate columns (50 MUL min(-1) and 60 degrees C). Separation of proteins was achieved in all columns with different efficiencies. At 100 MUL min(-1) and 60 degrees C, the lauryl methacrylate columns provided the best separation, but their low permeability prevented high flow rates. Flow rates up to 500 MUL min(-1) were possible in the styrene, butyl and hexyl methacrylate columns. PMID- 26960002 TI - Evaluation of the Fas/FasL signaling pathway in diabetic rat testis. AB - We investigated the role of the Fas/Fas ligand (FasL) signaling pathway in diabetic male infertility. Male rats were divided into two groups: a control group and a streptozotocin induced diabetic group. Thirty days after induction of diabetes, samples of testes were harvested and fixed in 10% formalin for light microscopy. Germ cell apoptosis was determined using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling (TUNEL) and immunostaining of caspase 8 and active caspase 3. We also investigated the expressions of Fas and FasL using immunohistochemistry. Streptozotocin-induced diabetes caused severe histopathological damage and increased apoptotic tubule and apoptotic cell indices, caspase 8 and caspase 3 expressions, and Fas and FasL-immunopositive cells in the rat testes. We suggest that the Fas/FasL signaling pathway may play a role in male infertility caused by diabetes. PMID- 26960004 TI - . . . Nothing Is So Credulous as Misery. PMID- 26960003 TI - The Use of a Novel Optical Algorithm in the Diagnosis of Cervical Pre-Invasive Pathology - A Preliminary Proof of Principal Study. AB - OBJECTIVE: To develop a novel optical probe monitoring cervical tissues in real time and to compare the new imaging technique to actual cervical pathologic findings on resected cone biopsy specimens. METHODS: A loop electro-excisional procedure was performed on 15 women with a biopsy diagnosis of dysplasia. The conization specimen was then assessed with the novel optical system and results recorded. The 'normal' and 'abnormal' areas were tested by the optical setup at several points. Extracted parameters were used as the input of the classifier function of a logistic regression algorithm model to assess for system accuracy vs. clinical examination. RESULTS: Ninety-seven samples were taken - forty-five samples from 'abnormal zones' and 42 samples from 'normal zones', as defined by the surgeon. The pathologist diagnosed 58 samples as dysplastic and 39 samples as normal. The novel optical method predicted 58 sample points as abnormal and 39 points as normal. The sensitivity of the system was 90% with a specificity of 77%. The probability of correct differentiation of dysplastic cervical tissue from normal cervical tissue was 85%. CONCLUSIONS: The optical probe and the algorithms of image processing in combination with the logistic regression algorithm correlated well with pathology results for cervical dysplasia ex-vivo. PMID- 26960005 TI - Origin, Reality, and Clinical Importance of the Arcade of Struthers, an Anatomic Study: Retraction. PMID- 26960006 TI - Use of Implant-Derived Minimally Invasive Sinus Floor Elevation: A Multicenter Clinical Observational Study With 12- to 65-Month Follow-Up. AB - The aim of this study is to evaluate the performance of implant-derived minimally invasive sinus floor elevation. A multicenter retrospective study was performed in 5 dental clinics. Patients requiring sinus augmentation for single implant placement were recorded and followed up. The dental implant used in this trial was a self-tapping endosseous dental implant that contains an internal channel to allow the introduction of liquids through the implant body into the maxillary sinus; those liquids include saline and a flowable bone grafting material. Overall, 37 implants were installed in 37 patients. The age range of the patients was 37-75 years (mean: 51.2 years). The average residual bone height prior to the procedure was 5.24 +/- 1 mm. Of all cases, 25 implants replaced the maxillary first molar and 12 replaced the maxillary second premolar. All surgeries were uneventful with no apparent perforation of the sinus membrane. The mean follow-up time was 24.81 +/- 13 months ranging from 12 to 65 months. All implants integrated and showed stable marginal bone level. No adverse events were recorded during the follow-up period. The presented method for transcrestal sinus floor elevation procedure can be accomplished using a specially designed dental implant. Further long-term studies are warranted to reaffirm the results of this study. PMID- 26960007 TI - Multidrug-resistant pathogens in patients with pneumonia coming from the community. AB - PURPOSE OF REVIEW: Identification of patients with multidrug-resistant (MDR) pathogens at initial diagnosis is essential for the appropriate selection of empiric treatment of patients with pneumonia coming from the community. The term Healthcare-Associated Pneumonia (HCAP) is controversial for this purpose. Our goal is to summarize and interpret the data addressing the association of MDR pathogens and community-onset pneumonia. RECENT FINDINGS: Most recent clinical studies conclude that HCAP risk factor does not accurately identify resistant pathogens. Several risk factors related to MDR pathogens, including new ones that were not included in the original HCAP definition, have been described and different risk scores have been proposed. The present review focuses on the most recent literature assessing the importance of different risk factors for MDR pathogens in patients with pneumonia coming from the community. These included generally MDR risk factors, specific risk factors related to methicillin resistant Staphylococcus aureus or Pseudomonas aeruginosa and clinical scoring systems develop to assess the MDR risk factors and its application in clinical practice. SUMMARY: Different MDR risk factors and prediction scores have been recently developed. However, further research is needed in order to help clinicians in distinguishing between different MDR pathogens causing pneumonia. PMID- 26960008 TI - Direct affinity of dopamine to lipid membranes investigated by Nuclear Magnetic Resonance spectroscopy. AB - Dopamine, a naturally occurring neurotransmitter, plays an important role in the brain's reward system and acts on sensory receptors in the brain. Neurotransmitters are contained in lipid membraned vesicles and are released by exocytosis. All neurotransmitters interact with transport and receptor proteins in glial cells, on neuronal dendrites, and at the axonal button, and also must interact with membrane lipids. However, the extent of direct interaction between lipid membranes in the absence of receptors and transport proteins has not been extensively investigated. In this report, we use UV and NMR spectroscopy to determine the affinity and the orientation of dopamine interacting with lipid vesicles made of either phosphatidylcholine (PC) or phosphatidylserine (PS) lipids which are primary lipid components of synaptic vesicles. We quantify the interaction of dopamine's aromatic ring with lipid membranes using our newly developed method that involves reference spectra in hydrophobic environments. Our measurements show that dopamine interacts with lipid membranes primarily through the aromatic side opposite to the hydroxyl groups, with this aromatic side penetrating deeper into the hydrophobic region of the membrane. Since dopamine's activity involves its release into extracellular space, we have used our method to also investigate dopamine's release from lipid vesicles. We find that dopamine trapped inside PC and PS vesicles is released into the external solution despite its affinity to membranes. This result suggests that dopamine's interaction with lipid membranes is complex and involves both binding as well as permeation through lipid bilayers, a combination that could be an effective trigger for apoptosis of dopamine-generating cells. PMID- 26960009 TI - Oxytocin mediates copulation-induced hypoalgesia of male rats. AB - Copulatory behavior has been reported to raise the pain threshold in male rats. In this study, we examined the effect of copulatory behavior with or without ejaculation on pain threshold measured by electrical shock via an electrode attached to the tail. It was demonstrated that ejaculation is not necessary to raise the pain threshold in male rats. In addition, we examined whether oxytocin, a hypothalamic neuropeptide, was involved in copulation-induced hypoalgesia. Sexually experienced males were subjected to stereotaxic implantation of a guide cannula targeting the lateral ventricle. After the recovery period, half of the males were intracerebroventricularly treated with an oxytocin antagonist (OTA, 100ng d(CH2)51,Tyr(Me)2,Thr4, Orn8,Tyr-NH29]-vasotocin/1MUL saline) and the remaining half were administered saline without anesthesia. Fifteen minutes later, half of each group were given sexual behavior with receptive females. We found no effect of OTA on sexual activity. Immediately after ejaculation, pain threshold was measured. While raised pain threshold was observed after sexual behavior in saline-treated males, no change in pain threshold was found in OTA treated males even after copulation. The results suggest that central oxytocin mediates copulation-induced hypoalgesia in male rats. PMID- 26960011 TI - Ultrafast Multidimensional Laplace NMR Using a Single-Sided Magnet. AB - Laplace NMR (LNMR) consists of relaxation and diffusion measurements providing detailed information about molecular motion and interaction. Here we demonstrate that ultrafast single- and multidimensional LNMR experiments, based on spatial encoding, are viable with low-field, single-sided magnets with an inhomogeneous magnetic field. This approach shortens the experiment time by one to two orders of magnitude relative to traditional experiments, and increases the sensitivity per unit time by a factor of three. The reduction of time required to collect multidimensional data opens significant prospects for mobile chemical analysis using NMR. Particularly tantalizing is future use of hyperpolarization to increase sensitivity by orders of magnitude, allowed by single-scan approach. PMID- 26960010 TI - Water column depth and light intensity modulate the zebrafish preference response in the black/white test. AB - Currently, the black/white preference test has been used to evaluate anxiety-like behaviors in zebrafish. However, several inconsistent results have been reported across literature. Since animal behavior can be influenced by several environmental factors, the main goal of the present study was to investigate the influence of different water column depths and light intensities on zebrafish behavioral responses in the black/white test. On a 4cm water column depth, animals spent more time in the black than in the white compartment. However, when animals were tested in an 8cm water column, no significant difference was found. Using an inclined acrylic floor inside the aquarium, animals spent more time in the deep compartment when this was black. However, there is no difference in time spent in each compartment when the deeper compartment was white. For light intensity test, animals showed preference for the white compartment only when both compartments were illuminated with 100lx. For the others illumination settings, there was no difference in the compartment preference. In conclusion, our results suggest that variations in water column depth and light intensity can modulate zebrafish preference in the black/white test. These variations may be implicated in the discrepancies observed in literature. PMID- 26960012 TI - Comparative proteomics analysis of silkworm hemolymph during the stages of metamorphosis via liquid chromatography and mass spectrometry. AB - The silkworm is a lepidopteran insect that has an open circulatory system with hemolymph consisting of blood and lymph fluid. Hemolymph is not only considered as a depository of nutrients and energy, but it also plays a key role in substance transportation, immunity response, and proteolysis. In this study, we used LC-MS/MS to analyze the hemolymph proteins of four developmental stages during metamorphosis. A total of 728 proteins were identified from the hemolymph of the second day of wandering stage, first day of pupation, ninth day of pupation, and first day as an adult moth. GO annotations and categories showed that silkworm hemolymph proteins were enriched in carbohydrate metabolism, proteolysis, protein binding, and antibacterial humoral response. The levels of nutrient, immunity-related, and structural proteins changed significantly during development and metamorphosis. Some, such as cuticle, odorant-binding, and chemosensory proteins, showed stage-specific expression in the hemolymph. In addition, the expression of several antimicrobial peptides exhibited their highest level of abundance in the hemolymph of the early pupal stage. These findings provide a comprehensive proteomic insight of the silkworm hemolymph and suggest additional molecular targets for studying insect metamorphosis. PMID- 26960013 TI - Electro-optical Neural Platform Integrated with Nanoplasmonic Inhibition Interface. AB - Engineering of neural interfaces with nanomaterials for remote manipulation facilitates the development of platforms for the study and treatment of brain disorders, yet extending their capability to inhibiting the electrical activities of unmodified neurons has been difficult. Here we report the development of an electro-optical neural platform integrated with gold nanorods for simultaneous electrical excitation and readout, and photothermal inhibition of neural activities. A monolayer of gold nanorods was placed at the electrode-neuron interfaces of a microelectrode array for photothermal stimulation of neural activities. This nanoplasmonic interface interacted well with neurons and metal electrodes without affecting the biological and electrical properties. We demonstrated that spontaneous firing of neurons and their signal propagation along the neurites evoked by electrical stimulation were optically inhibited on this neural platform. We believe that our platform could be an alternative to the optogenetic approach and may ultimately be applied to prosthetic devices based on optical neuromodulation. PMID- 26960014 TI - HYPERREFLECTIVE INTRARETINAL SPOTS IN RADIATION MACULAR EDEMA ON SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY. AB - PURPOSE: To better pathophysiologically characterize macular edema secondary to eye irradiation, analyzing the presence of optical coherence tomography (OCT) hyperreflective spots. METHODS: Twenty-five consecutive eyes affected by radiation maculopathy, secondary to irradiation for a primary uveal melanoma, without macular involvement in the irradiation field, were consecutively enrolled. All subjects underwent full ophthalmologic examination, including fluorescein angiography, color fundus photography, and spectral domain OCT, even in en face modality. Optical coherence tomography central subfield thickness was stratified into the following 3 categories: <400 MUm, 400 to 600 MUm, and >600 MUm. Spectral domain OCT images were analyzed to measure and localize hyperreflective spots by two independent masked graders. RESULTS: Hyperreflective spots were documented in all eyes (100%). Hyperreflective spots significantly increased in number according to OCT central subfield thickness (<400 MUm, 400 600 MUm, >600 MUm, P < 0.05). The intergrader agreement was at least substantial for all measurements (intraclass correlation coefficient: 0.80). CONCLUSION: Spectral domain OCT documents discrete intraretinal reflectivity changes (hyperreflective spots) in all (studied) eyes affected by radiation maculopathy. Hyperreflective spots increase in number with increasing central subfield thickness and could be considered as a new clinical biomarker of intraretinal inflammation in patients affected by macular edema secondary to irradiation for uveal melanoma. PMID- 26960015 TI - OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF THE MACULA AFTER PLAQUE RADIOTHERAPY OF CHOROIDAL MELANOMA: Comparison of Irradiated Versus Nonirradiated Eyes in 65 Patients. AB - PURPOSE: To study radiation retinopathy after plaque radiotherapy of choroidal melanoma using optical coherence tomography angiography. METHODS: Retrospective comparative analysis of 65 consecutive patients with choroidal melanoma, treated with standard dose I-125 plaque radiotherapy and imaged with optical coherence tomography angiography. A comparison of irradiated versus contralateral, nonirradiated (control) eyes was performed. RESULTS: The mean patient age was 55 years. Underlying medical diseases included diabetes mellitus (4/65, 4%) or hypertension (25/65, 38%), but no patient demonstrated disease-related retinopathy. The mean pretreatment melanoma diameter was 11 mm and mean thickness was 5 mm. The mean radiation dose to the foveola was 5663 centiGray. At mean follow-up of 46 months after plaque radiotherapy, the most frequent qualitative finding on optical coherence tomography angiography (irradiated eye) was nonperfusion in the superficial capillary plexus (19/65, 29%) and deep capillary plexus (20/65, 31%), followed by loss of choriocapillaris within tumor margins (11/65, 17%). The quantitative findings revealed foveal avascular zone with significantly larger mean area (irradiated vs. nonirradiated eye) in the superficial plexus (0.961 vs. 0.280 mm, P < 0.0001) and deep plexus (1.396 vs. 0.458 mm, P < 0.0001), even in eyes without clinical evidence of radiation maculopathy (superficial 0.278 mm, P = 0.03; deep 0.454 mm, P = 0.02). Parafoveal capillary density (superficial and deep) was decreased in all irradiated eyes (P < 0.001). This difference was maintained after subgroup analysis of eyes with (P < 0.001) or without (P < 0.001) clinical evidence of radiation maculopathy. Mean logMAR visual acuity was significantly reduced in irradiated eyes (0.7 vs. 0.1 [Snellen equivalent 20/100 vs. 20/25], P < 0.001) and the reduced vision was significant even in eyes without clinical evidence of radiation maculopathy (0.4 vs. 0.1 [Snellen equivalent 20/50 vs. 20/25], P < 0.001). CONCLUSION: Optical coherence tomography angiography demonstrated significant enlargement of the foveal avascular zone and decreased parafoveal capillary density of both superficial and deep capillary plexuses in eyes after plaque radiotherapy of choroidal melanoma, even in eyes with no clinical evidence of radiation maculopathy. PMID- 26960016 TI - Dissolution of Sn, SnO, and SnS in a Thiol-Amine Solvent Mixture: Insights into the Identity of the Molecular Solutes for Solution-Processed SnS. AB - Binary solvent mixtures of alkanethiols and 1,2-ethylenediamine have the ability to readily dissolve metals, metal chalcogenides, and metal oxides under ambient conditions to enable the facile solution processing of semiconductor inks; however, there is little information regarding the chemical identity of the resulting solutes. Herein, we examine the molecular solute formed after dissolution of Sn, SnO, and SnS in a binary solvent mixture comprised of 1,2 ethanedithiol (EDT) and 1,2-ethylenediamine (en). Using a combination of solution (119)Sn NMR and Raman spectroscopies, bis(1,2-ethanedithiolate)tin(II) was identified as the likely molecular solute present after the dissolution of Sn, SnO, and SnS in EDT-en, despite the different bulk material compositions and oxidation states (Sn(0) and Sn(2+)). All three semiconductor inks can be converted to phase-pure, orthorhombic SnS after a mild annealing step (~350 degrees C). This highlights the ability of the EDT-en solvent mixture to dissolve and convert a variety of low-cost precursors to SnS semiconductor material. PMID- 26960018 TI - Immune Responses to HIV. PMID- 26960019 TI - Understanding of human metabolic pathways of different sub-classes of phenols from Arbutus unedo fruit after an acute intake. AB - Arbutus unedo is a small Mediterranean fruit, commonly named strawberry tree, which is a rich source of different sub-classes of phenolic compounds, the more representative being the gallic acid derivatives, including its mono and oligomeric forms esterified with quinic and shikimic acids. In addition, galloyl derivatives, particularly gallotannins, described in A. unedo, are part of a very selective phenolic group, present in a reduced number of plant-products. The aim of the present study is to provide a better understanding of human metabolic pathways of different sub-classes of phenols from the A. unedo fruit after an acute intake by healthy adults. Therefore, the A. unedo phenolic metabolites were studied in whole blood samples (0 to 24 h), urine (24 h) and feces (12 and 24 h). Special focus was placed on the application of dried blood spot (DBS) cards for the sample collection and for the analysis of phenolic metabolites in whole blood samples. The results of the blood analysis revealed two peaks for the maximum concentrations of the main phenolic metabolites. Furthermore, it is appropriate to highlight the application of DBS cards as an efficient and accurate way to collect blood samples in post-prandial bioavailability studies. The analysis of urine (24 h) gave a wide range of phenolic metabolites showing the extensive metabolism that A. unedo phenolic compounds underwent in the human body. The results of the study provide a relevant contribution to the understanding of the in vivo human bioavailability of phenolic compounds, especially galloyl derivatives, a singular phenolic sub-group present in the A. unedo fruit. PMID- 26960017 TI - Relationship between Housing Status and Retention Rates among HIV-Positive African Americans Enrolled in a Comprehensive Care Program. AB - Service provision using "one-stop shopping" of medical, psychiatric, and case management services at the same location has been associated with superior client retention. The Yadumu project tested this premise, with attention to HIV-infected African Americans. Each client was assigned a case manager, who arranged meetings with mental health, substance abuse, and medical care professionals. The Center for Mental Health Services, National Outcome Measures (CMHS NOMs) questionnaire was used to evaluate client progress. Data were collected longitudinally and the program evaluation was performed by an outside center. Among 129 clients, 47% were male, 30% were female, and 22% were transgender. The majority (72%) were African American. Clients who lived in detox/drug treatment programs had higher completion rates (48%) than those who were homeless or otherwise housed (28%) (p = 0.04). Logistic regression was used to assess associations between independent factors and retention. Clients satisfied with their housing situation were less likely to retain in the program than those who were not satisfied with their housing situation (OR = 0.15, 95% CI: 0.03-0.78). High discharge rates among HIV infected people were observed and may reflect the unstable circumstances of the population studied, but structured residential programs could be advantageous for improving retention. PMID- 26960020 TI - Fabrication of Efficient Formamidinium Tin Iodide Perovskite Solar Cells through SnF2-Pyrazine Complex. AB - To fabricate efficient formamidinium tin iodide (FASnI3) perovskite solar cells (PSCs), it is essential to deposit uniform and dense perovskite layers and reduce Sn(4+) content. Here we used solvent-engineering and nonsolvent dripping process with SnF2 as an inhibitor of Sn(4+). However, excess SnF2 induces phase separation on the surface of the perovskite film. In this work, we report the homogeneous dispersion of SnF2 via the formation of the SnF2-pyrazine complex. Consequently, we fabricated FASnI3 PSCs with high reproducibility, achieving a high power conversion efficiency of 4.8%. Furthermore, the encapsulated device showed a stable performance for over 100 days, maintaining 98% of its initial efficiency. PMID- 26960021 TI - Negotiating Religiosity and Sexual Identity Among Hispanic Lesbian Mothers. AB - Hispanic lesbian mothers face bicultural tensions that stigmatize their roles as mothers. Religion could produce heightened conflict given their potential incompatibility with the role of a "good mother." In particular, there is a potential for conflict between the definition of a "good mother" set forth in Catholicism and the sexual orientation of Hispanic lesbians. I conducted semistructured in-depth interviews to examine how Hispanic lesbian mothers negotiate their Catholic religious identity with aspects of their sexual identity. More specifically, I examined the strategies that Hispanic lesbian mothers use to reconcile or navigate perceived conflict between their roles as a Catholic and as a lesbian. The research questions to be answered were: How do Hispanic lesbian mothers negotiate a Catholic religious and a sexual identity? How do Hispanic lesbian mothers create and maintain a religious narrative? How do Hispanic lesbian mothers redefine religion and spirituality? PMID- 26960022 TI - A Comparison of Zoo Animal Behavior in the Presence of Familiar and Unfamiliar People. AB - As recorded in domestic nonhuman animals, regular interactions between animals in zoos and keepers and the resulting relationship formed (human-animal relationship [HAR]) are likely to influence the animals' behaviors with associated welfare consequences. HAR formation requires that zoo animals distinguish between familiar and unfamiliar people. This ability was tested by comparing zoo animal behavioral responses to familiar (routine) keepers and unfamiliar keepers (participants in the "Keeper for the Day" program). Study subjects included 1 African elephant (Loxodonta Africana), 3 Rothschild's giraffes (Giraffa camelopardalis rothschildi), 2 Brazilian tapir (Tapirus terrestris), and 2 slender-tailed meerkats (Suricata suricatta). Different behavior was evident and observed as decreased avoidance behavior toward familiar keepers (t7 = 6.00, p < .001). This finding suggests the zoo animals have a lower level of fear toward familiar keepers. Keeper familiarity did not significantly affect any other behavioral measure. This finding suggests that in the current study, unfamiliar keeper presence did not appear to have detrimental effects. Furthermore, unfamiliar keeper-animal interactions could provide an increased number of positive human-animal interactions and potentially enhance animal welfare. PMID- 26960024 TI - Underwater Visual Computing: The Grand Challenge Just around the Corner. AB - Visual computing technologies have traditionally been developed for conventional setups where air is the surrounding medium for the user, the display, and/or the camera. However, given mankind's increasingly need to rely on the oceans to solve the problems of future generations (such as offshore oil and gas, renewable energies, and marine mineral resources), there is a growing need for mixed reality applications for use in water. This article highlights the various research challenges when changing the medium from air to water, introduces the concept of underwater mixed environments, and presents recent developments in underwater visual computing applications. PMID- 26960023 TI - The Tensions of In Situ Visualization. AB - In situ visualization is the coupling of visualization software with a simulation or other data producer to process the data "in memory" before the data are offloaded to a storage system. Although in situ visualization provides superior analysis, it has implementation tradeoffs resulting from conflicts with some traditional expected requirements. Numerous conflicting requirements create tensions that lead to difficult implementation tradeoffs. This article takes a look at the most prevailing tensions of in situ visualization. PMID- 26960025 TI - Pulsing Blood Vessels: A Figurative Approach to Traffic Visualization. AB - By using semantic figurative metaphors, a visualization designer invests in a more figurative graphic representation, seeking provocative perspectives on common topics and trying to invoke emotional responses while clearly communicating meaningful data stories. The use of figurative metaphors in visualization, however, involves adding nondata aspects to a visualization. The authors survey this exploratory side of visualization, using a visualization of Lisbon traffic data as a system of pulsing blood vessels as an example, and discuss the strengths and limitations of such as approach. PMID- 26960026 TI - Underwater Depth Estimation and Image Restoration Based on Single Images. AB - In underwater environments, the scattering and absorption phenomena affect the propagation of light, degrading the quality of captured images. In this work, the authors present a method based on a physical model of light propagation that takes into account the most significant effects to image degradation: absorption, scattering, and backscattering. The proposed method uses statistical priors to restore the visual quality of the images acquired in typical underwater scenarios. PMID- 26960027 TI - Evaluating Existing Strategies to Limit Video Game Playing Time. AB - Public concern surrounding the effects video games have on players has inspired a large body of research, and policy makers in China and South Korea have even mandated systems that limit the amount of time players spend in game. The authors present an experiment that evaluates the effectiveness of such policies. They show that forcibly removing players from the game environment causes distress, potentially removing some of the benefits that games provide and producing a desire for more game time. They also show that, with an understanding of player psychology, playtime can be manipulated without significantly changing the user experience or negating the positive effects of video games. PMID- 26960029 TI - Unfolding Dynamic Networks for Visual Exploration. AB - Visualization builds on the human capacity to quickly process parallel visual inputs and to offload cognitive processes. Interactive visualizations can become interfaces between humans, their data, and the phenomena represented by the data. Such interfaces can allow for exploration, enable serendipitous discoveries, and serve as a mental metaphor to help us remember and reason about the data. This article gives a brief overview of the author's dissertation research, which is concerned with creating and evaluating novel interfaces to explore dynamic networks, supporting analysts in formulating hypotheses, and discussing proper analysis methods. PMID- 26960028 TI - 3D Image Display Courses for Information Media Students. AB - Three-dimensional displays are used extensively in movies and games. These displays are also essential in mixed reality, where virtual and real spaces overlap. Therefore, engineers and creators should be trained to master 3D display technologies. For this reason, the Department of Information Media at the Kanagawa Institute of Technology has launched two 3D image display courses specifically designed for students who aim to become information media engineers and creators. PMID- 26960030 TI - Lessons Learned from Designing Visualization Dashboards. AB - A variety of visualization guidelines, principles, and techniques are available to help create a visualization-based dashboard, but few publications discuss the experience of designing dashboards in the real world. This article discuss the lessons learned from designing applications for small start-up companies and institutions. From their experience as visualization practitioners, the authors confirm the need for tailored and customizable approaches, emphasize the need for a quicker way to create functional prototypes, point out frequent misconceptions on the scope of a functional prototype, discuss how performance can affect prototyping, and discuss the resistance of industrial partners to involve their customers in requirements gathering. PMID- 26960031 TI - GyroWand: An Approach to IMU-Based Raycasting for Augmented Reality. AB - Optical see-through head-mounted displays enable augmented reality (AR) applications that display virtual objects overlaid on the real world. At the core of this new generation of devices are low-cost tracking technologies that allow us to interpret users' motion in the real world in relation to the virtual content for the purposes of navigation and interaction. The advantages of pervasive tracking come at the cost of limiting interaction possibilities, however. To address these challenges the authors introduce GyroWand, a raycasting technique for AR HMDs using inertial measurement unit (IMU) rotational data from a handheld controller. PMID- 26960033 TI - Conformational Study of N,N'-Diacyl Bispidines and Dioxo Bis-bispidines: Planar Chirality and Molecular Switching. AB - N,N'-Diacyl bispidines exhibit chirality in the absence of a chiral center and axis. Conformational analysis indicates planar chirality in the molecular structure as a result of open-ended chiral planes, which has been confirmed by X ray diffraction studies. Substantial chiral-achiral molecular switching is observed in di(haloacetyl) bispidines upon changing the solvent polarity. Tethering the chiral planes with a bispidine linker alters the planar chirality significantly and renders the resulting bis-bispidine macrocycles achiral. PMID- 26960032 TI - Identification of PTP1B and alpha-Glucosidase Inhibitory Serrulatanes from Eremophila spp. by Combined use of Dual High-Resolution PTP1B and alpha Glucosidase Inhibition Profiling and HPLC-HRMS-SPE-NMR. AB - According to the International Diabetes Federation, type 2 diabetes (T2D) has reached epidemic proportions, affecting more than 382 million people worldwide. Inhibition of protein tyrosine phosphatase-1B (PTP1B) and alpha-glucosidase is a recognized therapeutic approach for management of T2D and its associated complications. The lack of clinical drugs targeting PTP1B and side effects of the existing alpha-glucosidase drugs, emphasize the need for new drug leads for these T2D targets. In the present work, dual high-resolution PTP1B and alpha glucosidase inhibition profiles of Eremophila gibbosa, E. glabra, and E. aff. drummondii "Kalgoorlie" were used for pinpointing alpha-glucosidase and/or PTP1B inhibitory constituents directly from the crude extracts. A subsequent targeted high-performance liquid chromatography-high-resolution mass spectrometry-solid phase extraction-nuclear magnetic resonance spectroscopy (HPLC-HRMS-SPE-NMR) analysis and preparative-scale HPLC isolation led to identification of 21 metabolites from the three species, of which 16 were serrulatane-type diterpenoids (12 new) associated with either alpha-glucosidase and/or PTP1B inhibition. This is the first report of serrulatane-type diterpenoids as potential alpha-glucosidase and/or PTP1B inhibitors. PMID- 26960035 TI - Metal cation control of electroosmotic flow magnitude in phospholipid-coated capillaries. AB - CZE has become widespread for the separation and analysis of biomolecules such as proteins and peptides, due to factors such as, the speed of the separations, low sample volume, and high resolution associated with the technique. However, the separation of biomolecules by CZE does present a significant challenge due to the electrostatic attraction and adsorption of cationic, or cation containing, biomolecules to the capillary surface. To that end numerous methods have been developed to passivate, or protect the surface, in order to prevent the adsorption of analytes. Yet, in the process of protecting the capillary surface, the potential for further modification of the EOF, a factor crucial to effective analyte resolution, is greatly diminished. In seeking to overcome this limitation we have explored the potential of incorporating a range of metal cations into a phospholipid bilayer capillary coating. It has previously been established that the inclusion of calcium into the separation buffer with a phospholipid coating will reverse the EOF in the capillary. Here, we present our investigation of a broader range of metal cations included in the separation buffer (Ca(2+) , Mg(2+) , Co(2+) , Ni(2+) , Sr(2+) , Ba(2+) , and Ce(3+) ) revealing that the choice of metal cation can drastically influence the EOF, with observed values between 3.80 * 10(-4) and -5.74 * 10(-5) cm(2) /V.s. PMID- 26960034 TI - Atrial fibrillation management: evaluating rate vs rhythm control. AB - Atrial fibrillation (AF) is an increasing global issue leading to increased hospitalizations, adverse health related events and mortality. This review focuses on the management of atrial fibrillation, in particular in the past decade, comparing two major strategies, rate or rhythm control. We evaluate the evidence for each strategy, pharmacological options and the increasing utilization of invasive techniques, in particular catheter ablation and use of implantable cardiac pacing devices. Pharmacological comparative trials evaluating both strategies have shown rate control being non-inferior to rhythm control for clinical outcomes of mortality and other cardiovascular events (including stroke). Catheter ablation techniques, involving radiofrequency ablation and recently cryoablation, have shown promising results in particular with paroxysmal AF. However, persistent AF provides ongoing challenges and will be a particular focus of continued research. PMID- 26960036 TI - Guideline for the Treatment of Breakthrough and the Prevention of Refractory Chemotherapy-Induced Nausea and Vomiting in Children With Cancer. AB - This clinical practice guideline provides an approach to the treatment of breakthrough chemotherapy-induced nausea and vomiting (CINV) and the prevention of refractory CINV in children. It was developed by an international, interprofessional panel and is based on systematic literature reviews. Evidence based interventions for the treatment of breakthrough and prophylaxis of refractory CINV are recommended. Gaps in the evidence used to support the recommendations made in this clinical practice guideline were identified. The contribution of these recommendations to breakthrough and refractory CINV control in children requires prospective evaluation. PMID- 26960038 TI - [The diagnosis artifice]. AB - The clinical diagnosis is considered the cornerstone in the decisions making process, since it has various functions, including the executive. However, the diagnosis is not only a goal by itself, but a mean to help patients. It is not enough to identify how the disease which ails the patient is called; the diagnosis must be individualized as much as possible in each case, for the mere mention of the diagnosis can mean a wide variety of problems. PMID- 26960037 TI - Ultrasound-targeted hepatic delivery of factor IX in hemophiliac mice. AB - Ultrasound-targeted microbubble destruction (UTMD) was used to direct the delivery of plasmid and transposase-based vectors encoding human factor IX (hFIX) to the livers of hemophilia B (FIX-/-) mice. The DNA vectors were incorporated into cationic lipid microbubbles, injected intravenously, and transfected into hepatocytes by acoustic cavitation of the bubbles as they transited the liver. Ultrasound parameters were identified that produced transfection of hepatocytes in vivo without substantial damage or bleeding in the livers of the FIX-deficient mice. These mice were treated with a conventional expression plasmid, or one containing a piggyBac transposon construct, and hFIX levels in the plasma and liver were evaluated at multiple time points after UTMD. We detected hFIX in the plasma by western blotting from mice treated with either plasmid during the 12 days after UTMD, and in the hepatocytes of treated livers by immunofluorescence. Reductions in clotting time and improvements in the percentage of FIX activity were observed for both plasmids, conventional (4.15+/-1.98%), and transposon based (2.70+/-.75%), 4 to 5 days after UTMD compared with untreated FIX (-/-) control mice (0.92+/-0.78%) (P=0.001 and P=0.012, respectively). Reduced clotting times persisted for both plasmids 12 days after treatment (reflecting percentage FIX activity of 3.12+/-1.56%, P=0.02 and 3.08+/-0.10%, P=0.001, respectively). Clotting times from an additional set of mice treated with pmGENIE3-hFIX were evaluated for long-term effects and demonstrated a persistent reduction in average clotting time 160 days after a single treatment. These data suggest that UTMD could be a minimally invasive, nonviral approach to enhance hepatic FIX expression in patients with hemophilia. PMID- 26960039 TI - [Lymphocele surgical treatment in pediatric kidney transplantation]. AB - BACKGROUND: In a retrospective study, we evaluated; frequency, clinical presentation and treatment of lymphocele in pediatric patients with kidney transplant. METHODS: Between January 2004 and January 2009, we had 242 kidney transplantations, 197 from living donors and 45 from cadaveric donors. The technique was the usual, and the implants of the ureteres were by the technique Ricard modified. The treatment of lymphocele was by percutaneous punction and laparoscopic intraperitoneal drainage. RESULTS: We diagnosed lymphocele in seven patients (2.9 % with an IC95 %: 0.6- 5.2 %) one female and six males. All patients went trough percutaneous drainage. Six patients presented lymphocele recurrence at 48 to 72 hours after the drainage. Surgical laparoscopic intraperitoneal drainage was performed with success. CONCLUSIONS: Our frequency of lymphocele is the same reported in other studies (6-18 %). The treatment by laparoscopic intraperitoneal window seems to be the most appropriate in pediatric patients. PMID- 26960040 TI - [Dermatoglyphics differences among children with nephrotic syndrome according to steroid response]. AB - BACKGROUND: Although the association between the type of idiopathic nephrotic syndrome (INS) and a peculiar pattern of fingerprints digital would suggest the presence of genetic factors related to both, this has not been previously studied. This study aimed to evaluate if there are fingerprints patterns differences between children with steroid-resistant INS (SRNS) and those with steroid-sensitive INS (SSNS). METHODS: The frequencies distribution of arches, ulnar loops, radial loops, and whorls was studied in 60 children with SRNS, and 60 children with SSNS. Bivariate analysis to detect the relationship between each fingerprint pattern with the study groups was performed by chi-square test and to evaluate its possible association, the odds ratios (OR) were calculated with 95% confidence's intervals (95%CI). RESULTS: The patients with SRNS had a higher frequency of digital whorls compared with that of patients with SSNS (46.7% vs. 30.7%, p = 0.005). Additional comparisons using a "whorls excesses" definition obtained from normative data in our population (>= 7 whorls in females or >= 8 in males) were associated with increased odds for SRNS (OR 2.96, 95% CI 1.15-7.61). CONCLUSIONS: Our findings indicate that there are differences between children with SRNS and SSNS at the level of digital dermatoglyphics, but further studies are needed to confirm this association and its possible implications. PMID- 26960041 TI - [Predictive psychophysiological stress symptoms in dentists]. AB - BACKGROUND: Dentistry has been identified as one of the most stressful occupations in which a dentist's mental and/or physical health may be affected. The objective of this study was to identify chronic psychophysiological stress symptoms in relation with the presence of high stress levels perceived in dentists at a Social Security institution in Guadalajara, Mexico. METHODS: The design was cross-sectional and analytical by means of a 2011 census consisting of 87 dentists. The Stress Profile and the Stress Symptom Inventory were applied and the analysis was performed with multiple regression. RESULTS: The perceived stress levels were: high (67.8 %), medium (29.9 %) and low (2.3 %). The most frequent psychophysiological symptom of perceived high level of stress was fatigue with 51 %, and the female gender was the most affected. The existence of a meaningful association was shown between the chronic psychophysiological stress symptoms of insomnia, fatigue and the female gender, and perceived high level stress. CONCLUSIONS: Early identification of the symptoms of chronic stress in dentists would favor the implementation of appropriate preventive programs to care for their health and work place security. PMID- 26960042 TI - [Return to work in patients with heart disease after cardiac rehabilitation]. AB - BACKGROUND: Cardiac rehabilitation is a secondary prevention strategy which it includes a set of activities that would assure cardiac patients a place as normal as it could be into the society, being also essential for going back to work, by improving their quality of life and reducing costs for institutions. METHODS: A non-randomized clinical study was conducted at the "Siglo XXI" Cardiology Hospital; We included patients with the diagnosis of ischemic heart disease and/or valve disease, the response variables were: percentage of patients going back to work and disability time upon return to duty. Cardiac rehabilitation program was applied for 1 month and followed up at 2 months and 1 year. RESULTS: Two groups were formed, the ones who received cardiac rehabilitation, N = 40 (experimental group) against a control group, N = 25. The percentage of patients going back to work with a cardiac rehabilitation was 75 % versus 60 % of the group did not receive cardiac rehabilitation, p = 0.2, with a mean of 68 days of disability in the experimental group against 128 in the control group, p = 0.001. CONCLUSIONS: The experimental group showed a higher percentage of patients who returned to work, working time reentry (in days) was lower compared to the control group. PMID- 26960044 TI - [Identification of Mycobacterium avium-intracellulare complex by PCR of AIDS and disseminated mycobacteriosis]. AB - OBJECTIVE: The aim of this study is to differentially identify MAC by PCR in patients with AIDS and disseminated mycobacteriosis. METHODS: A cross sectional study was conducted in Mexico to identify MAC by Molecular Biology. Two sets of primers were synthesized: MAV and MIN, for M. avium and M. intracellulare, respectively. Whole-cell DNAs obtained from 29 clinical isolates and clinical serum specimens from other 24 patients with AIDS and disseminated mycobacterial infection were extracted and amplified by PCR with the MAV and MIN primers. The MAV and MIN primers each amplified one highly specific 1.3-kb segment of the homologous DNA, respectively. RESULTS: Twenty-nine DNAs from MAC clinical isolates identified by Gen-Probe AccuProbes were amplified with the MAV primers. Of the 24 clinical samples, 3 were positive for M. avium and 6 for M. tuberculosis. CONCLUSIONS: Our results demonstrated that PCR technique could be applied for the differentiation of M. avium and M. intracellulare by specific 16S rRNA primers. In patients with advanced stage AIDS and in whom disseminated mycobacteriosis is suspected, the presence of anemia (even with negative cultures), elevated alkaline phosphatase and a median CD4 count of 15.9/mL, the diagnosis of infection by MAC should be strongly considered; we suggest that in accordance with our findings, a more precise stratification of patients in terms of their CD4 T cell counts is warranted. PMID- 26960043 TI - [Neovascularization corneal regression in patients treated with photodynamic therapy with verteporfin]. AB - BACKGROUND: Corneal neovascularization is a vision-threatening condition usually associated with inflammatory or infectious disorders of the ocular surface. One current treatment is photodynamic therapy, which uses a photosensitizer to occlude the vessel, is successfully produced microvascular thrombosis with minimal damage to surrounding normal tissue. The aim of this article is to quantitatively determine the percentage of regression of corneal neovascularization experienced by patients treated with photodynamic therapy with verteporfin. METHODS: A before and after treatment; experimental, analytical, prospective and longitudinal. RESULTS: Of the 25 new vessels analyzed, 8 glasses (32 %) had total occlusion one month after, 15 vessels (60 %) had a partial occlusion in the range of 15.3 to 85.1 %, and 2 vessels (8 %) worsening in corneal vascularization. The mean area of corneal neovascularization decreased significantly a 70 % from 0.147 +/- 0.118 mm2 to 0.045 +/- 0.046 mm2 (p < 0.0005) after photodynamic therapy. No side efects were reported. CONCLUSIONS: Photodynamic therapy with verteporfin is a safe and effective method of reducing corneal neovascularization and can be used to inhibit angiogenesis in the cornea. PMID- 26960045 TI - [Evaluation of quality of life in patients with liver transplant]. AB - BACKGROUND: Complications in patients with liver transplant may occur in less than 10 % of cases. These appear in short and/or long term and are due to a vascular or biliary cause, rejection, recurrence of the disease or adverse effects of immunosuppression, among others, which may affect the quality of life. The aim of this article is to evaluate the quality of life in patients with deceased donor liver transplantation through the questionnaire SF-36. METHODS: A descriptive cross-sectional study. The quality of life of patients with deceased donor liver transplantation was assessed during the period from January 1, 2005 to December 31, 2012. The variables evaluated were: age, sex, time and main reason for transplantation and quality of life using the short form SF-36 version 1.1 for Mexican population. RESULTS: 37 patients were included. The mean age was 48.7 years. The most frequent cause was cirrhosis (n = 35). The highest average score corresponded to the mental health component, and the lowest score to the physical component. The average time of liver transplantation was 6.73 +/- 3.53 years. CONCLUSIONS: Liver transplantation is still the most effective treatment for end-stage liver disease. It can increase the patient's life expectancy and their quality of life, assessed with the SF-36 questionnaire. The results were similar to those in other studies in both the physical and mental component. PMID- 26960046 TI - [Incidence and risk factors associated with nosocomial infection in pediatric heart surgery]. AB - BACKGROUND: Nosocomial infections are responsible for a high rate of morbidity and mortality in pediatric patients undergoing heart surgery. Our objective was to determine the incidence and associated risk factors to nosocomial infections in this group of patients. METHODS: A descriptive, prospective, clinical study was conducted in a tertiary hospital for a year. We calculated the rate of incidence, accumulated incidence and devices used. Was Applied the EPIDAT 2004 version 3.1 program OPS for obtaining of Chi-square with Yates correction for p with a confidence of 95 %, alpha of 0.05 with a degree of freedom, we calculated odds ratio, besides of the identification of microorganisms, their sensitivity and resistance to antibiotics. RESULTS: We calculated rates of: 45 % the incidence, 80.6 % cumulative incidence, 7.4 % of mortality, 13.3 % of case fatality rate of infected and 2.7 % non-infected. The 44.4 % with pneumonia, 74 % associated with mechanical ventilation, 100 % nasogastric tube. The most frequently isolated microorganisms are: Acinetobacter baumanni, Staphylococcus aureus, Staphylococcus epidermidis and Pseudomonas aeruginosa with high resistance to antibiotics. CONCLUSIONS: Pediatric patients undergoing heart surgery have high risk of infection heart disease, cyanogen's have 5 times more risk. We observed a statistically significant association with infection using nasogastric probe and endotracheal tube, the risk increases to increased hospital stay. Infected patients have 4 times the risk of death. PMID- 26960048 TI - [Maternal morbidity and mortality in a unit of tertiary care without obstetrics]. AB - BACKGROUND: Maternal morbidity is a health problem for developing countries, the causes of death among obstetric patients varies according to geographic region and other factors, which include health services. The aim of this study was to identify the causes of maternal mortality and morbidity, as well as factors associated with mortality in patients attending on 2011-2012. METHODS: Clinical data of the patients on admission, severity of illness, presence of comorbidity, complications that occurred during treatment and causes of death in pregnant or postpartum patients were analyzed. RESULTS: 137 patients were analyzed, 87 (63.5 %) patients were hospitalized, 36 (41.3 %) cases with severe maternal complication (SMC); most patients with SMC were in the postpartum postcesarean. Eleven patients died, five maternal deaths and 6 late deaths. CONCLUSIONS: SMC and death were more frequent in the postpartum period. The indirect causes of death were more frequent. PMID- 26960047 TI - [Risk factors and rejection frequency in patients undergoing penetrating keratoplasty]. AB - BACKGROUND: Corneal transplantation is one of the surgical procedures most frequently performed worldwide and with better prognosis. Among its main indications include: keratoconus, bullous keratopathy, previous graft rejection, corneal dystrophy, and infection. The known risk factors for graft rejection are: recipient's age, presence of vessels in the recipient cornea, intraocular pressure, and retransplantation. The objective of this article is to determine the risk factors and frequency of corneal rejection in patients undergoing penetrant keratoplasty. METHODS: The study's design was descriptive, observational, transversal, analytical and retrospective. Patients operated of penetrating keratoplasty in cornea clinic with follow up during at least 6 months were studied. A review of the medical records of patients undergoing penetrating keratoplasty at the Hospital de Especialidades del Centro Medico Nacional Siglo XXI was performed. RESULTS: The 35.3 % of the transplanted patients had corneal transplant rejection. Corneal neovascularization of the recipient cornea previous to transplant was present in 21.3 %. CONCLUSIONS: In our study we found similar results to the reported in the literature, the most important risk factors for rejection was the use of threphine 7.50 mm, older patient with a history with previous corneal neovascularization, keratopathy and herpetic keratitis. PMID- 26960049 TI - [Brainstem auditory evoked potentials latencies, by age and sex, among Mexican adult population]. AB - BACKGROUND: Brainstem auditory evoked potentials (BAEP) evaluate the auditory pathway, and are a complementary test for tone audiometry in evaluating auditory diseases. The aim of the study was to determine BAEP mean latencies of waves and intervals, among healthy adults. METHODS: Cross-sectional study, comprising 196 subjects, aged 16 to 65 years, without auditory diseases, to whom family and personal history were asked, physical examination and laboratory studies were made, as well as tonal audiometry, impedanciometry and BAEP. RESULTS: A total of 107 men and 89 women were studied. The mean latency periods of waves I, III and V, and intervals I-III, III-V and I-V from both ears were similar. An increase in the latency periods for each age category was observed. Latency periods were significantly shorter in women compared to men. The predictors that increased the latency periods in the multiple linear regression models for waves and intervals were male gender and age >=45 years. CONCLUSIONS: Age and sex were the variables that showed more statistical power to explain the latencies' differences. PMID- 26960050 TI - [Technical guidelines for the prevention, diagnosis and treatment of Zika virus infection]. AB - Infection Zika virus is an emerging disease in the Americas region, which is caused by Zika virus (ZIKV), an arbovirus of the flavivirus genus. The ZIKV is transmitted by the bite of Aedes mosquitoes, both in urban and jungle area. After the mosquito bite, the disease symptoms usually appear after an incubation period of three to twelve days. The infection may be asymptomatic or presented with fever and not purulent conjunctivitis, headache, myalgia, arthralgia, asthenia, maculopapular rash, edema in lower limbs and, less frequently, retro-orbital pain, anorexia, vomiting, diarrhea or pain abdominal. Symptoms last for 4-7 days and are self-limiting. Neurological and autoimmune complications are rare. Since 2014 it has been detected native circulation of Zika virus in the Americas. So far, there is no specific antiviral treatment or effective vaccine, so it's giving priority symptomatic and supportive treatment for the acute phase and make an early diagnosis of atypical and severe forms. PMID- 26960051 TI - [Clinical features of Zika virus]. AB - BACKGROUND: Zika virus was introduced to the country and threatens to spread, so the health personnel must be able to identify the disease and face an operational definition given case; in this review the clinical manifestations of probable cases of Zika of the last five years were described. METHODS: A search was performed in Google Scholar and PubMed with "Zika". He settled for a database and obtained simple frequencies and calculated the limits for proportions with an alpha of 0.05 through test Wilson. RESULTS: 109 probable cases of fever came together by Zika, the clinical manifestations was heterogeneous, with predominant involvement to musculoskeletal, dermatological and systemic level. CONCLUSIONS: It is necessary to continue the documentation of the clinical manifestations of Zika virus, which will be achieved by strengthening epidemiological surveillance. PMID- 26960053 TI - [Burnout syndrome in medical residents at the General Hospital of Durango, Mexico]. AB - BACKGROUND: The burnout syndrome is commonly spread among health workers and students, due to the excessive demands they feel on their workspaces. Depersonalization, emotional exhaustion and personal accomplishment are the areas assessed. METHODS: To determine the prevalence of burnout syndrome in medical residents at the General Hospital of Durango; a descriptive, prolective, cross sectional study was designed and applied to residents of different specialties of the General Hospital of Durango who agreed to participate, the "Maslach Burnout Inventory" was applied. RESULTS: We surveyed 116 residents, 43.1 % (50) women and 56.89 % (66) men. The overall prevalence was 89.66 % (95 % CI: 82.63- 94.54). Affected in a single area the 48.28 % (95 % CI: 38.90-57.74), in two areas the 35.34 % (95 % CI: 26.69-44.76) and in the three areas 6.03 % (95 % CI: 2.46 12.04). Stratified by areas, high emotional exhaustion was 41.38 % (95 % CI: 32.31-50.90), high depersonalization in 54.31 % (95 % CI: 44.81-63.59), and low personal accomplishment 41.38 % (95 % CI: 32.31-50.90). CONCLUSIONS: The prevalence is higher than the reported. The most frequently affected is depersonalization, followed by emotional exhaustion and finally the personal accomplishment. In the areas of Gynecology and obstetrics, Internal medicine, Pediatrics and Orthopedics, the 100 % of the residents are affected. PMID- 26960052 TI - [The perception of ethics from the point of view of medical students]. AB - BACKGROUND: The present study was conducted to characterize the ethical environment in which medical students and internal are trained. The aim of this article is to identify the perception of ethics in medical students. METHODS: The instrument was constructed by pairs: the socially desirable and socially undesirable exploring 10 principles and 24 ethical values. Through rounds of experts the instrument was validated with 35 pairs with 70 statements. The internal consistency of the instrument with the coefficient of determination "r2" reached a "p" value of < 0.025. RESULTS: In the overall analysis to compare means, students gave higher scores than interns with "p" value of < 0.002. A comparison of the principal differences was found in seven of the ten principles explored and in three (freedom, honesty and solidarity) no differences were noted in the rate of perception of the ethics (RPE). The were statistically significant differences between groups with a "p" value of < 0.04 in which students perceive higher scores with interns. CONCLUSIONS: We conclude that learning environments are not prone to ethical reflection and changes depending on the degree in training in medical school, with a worse perception in greater degrees. PMID- 26960054 TI - [Key recommendations of the clinical guidelines of arterial hypertension in primary care]. AB - BACKGROUND: Hypertension ranks first medical care in first level units. It is estimated that half of the patients with hypertension are uncontrolled. The purpose of this document is to provide recommendations to guide diagnosis and treatment of arterial hypertension in primary care, which have been considered key to the process of care, in order to help health professionals in the clinical decision-making. METHODS: The guide is integrated with recommendations of international guidelines and evidence of published studies indicated the changes regarding the management and treatment of hypertension, as well as differences between the target populations of the guide. Searching for information it is performed by means of a standardized sequence in PubMed and Cochrane Library Plus, from the questions asked. The key recommendations were chosen by a consensus of a group of professionals and health managers. CONCLUSIONS: The key recommendations evidence-based standardized help you make decisions about prevention, diagnosis and treatment in patients with hypertension, and will contribute to reducing cardiovascular risk, promote changes in lifestyle, control the disease and reduce complications. PMID- 26960055 TI - [Allopurinol hypersensitivity syndrome. A report of two cases]. AB - Patients in treatment with allopurinol are in risk of having life threatening adverse reactions particularly at the beginning of the treatment. Two percent of the patients prescribed with this drug have associated severe cutaneous adverse reactions. We present two cases of allopurinol hypersensitivity syndrome in mexican patients in which asymptomatic hyperuricemia was the indication to its use. The general physician and the specialist must be alert of this syndrome that causes elevate morbidity and mortality. PMID- 26960056 TI - [Scorpionism causing severe acute flaccid paralysis. Case report]. AB - BACKGROUND: Scorpionism is a public health problem in various regions of the world, being Mexico the country with the highest number of cases. Clinical manifestations range from local symptoms to severe disease with an impact on cardiovascular, respiratory and neurological level, and even death. There are no reports of acute flaccid paralysis as a manifestation of the clinical picture of the scorpion sting of the Centruroides gender, Family Buthidae, highly toxic, causes high rates of morbidity and mortality in our region. CLINICAL CASE: We documented a case of scorpionism, caused by a scorpion gender Buthidae, Centruroides family, which caused acute flaccid paralysis, after resolution of other severe manifestations. There is only one case report of scorpionism that produces acute flaccid paralysis in the literature, but it is related to the Parabuthus scorpion, endemic of South Africa. CONCLUSIONS: The knowledge of this complication, new for our region, will maximize efforts to diagnose and appropriately manage this symptoms, with the adequate application of the specific fabotherapy and advanced life support for proper survival in the patients with compromise of vital functions and imminent risk of death mainly by respiratory failure. PMID- 26960057 TI - How Bond Length Alternation and Thermal Disorder Affect the Optical Excitation Energies of pi-Conjugated Chains: A Combined Density Functional Theory and Molecular Dynamics Study. AB - We dissect the sources of error leading to inaccuracies in the description of the geometry and optical excitation energies of pi-conjugated polymers. While the ground-state bond length alternation is shown to be badly reproduced by standard functionals, the recently adapted functionals PBEh* and omegaPBE* as well as the double hybrid functional XYGJ-OS manage to replicate results obtained at the CCSD(T) level. By analysis of the bond length alternation in the excited state, a sensitive dependence of the exciton localization on the long-range behavior of the functional and the amount of Hartree-Fock exchange present is shown. Introducing thermal disorder through molecular dynamics simulations allows the consideration of a range of thermally accessible configurations of each oligomer, including trans to cis rotations, which break the conjugation of the backbone. Thermal disorder has a considerable effect when combined with functionals that overestimate the delocalization of the excitation, such as B3LYP. For functionals with a larger amount of exact exchange such as our PBEh* and omegaPBE*, however, the effect is small, as excitations are often localized enough to fit between twists in the chain. PMID- 26960058 TI - Metformin pretreatment enhanced learning and memory in cerebral forebrain ischaemia: the role of the AMPK/BDNF/P70SK signalling pathway. AB - Context Metformin induced AMP-activated protein kinase (AMPK) and protected neurons in cerebral ischaemia. Objective This study examined pretreatment with metformin and activation of AMPK in molecular and behavioral levels associated with memory. Materials and methods Rats were pretreated with metformin (200 mg/kg) for 2 weeks and 4-vessels occlusion global cerebral ischaemia was induced. Three days after ischaemia, memory improvement was done by passive avoidance task and neurological scores were evaluated. The amount of Brain-Derived Neurotropic Factor (BDNF) and phosphorylated and total P70S6 kinase (P70S6K) were measured. Results Pretreatment with metformin (met) in the met + ischaemia/reperfusion (I/R) group reduced latency time for enter to dark chamber compared with the sham group (p < 0.001) and increased latency time compared with the I/R group (p < 0.001). Injection of Compound C (CC) (as an AMPK inhibitor) concomitant with metformin reduced latency time in I/R rats compared with the I/R + met group (p < 0.05). Neurological scores were reduced in met treated rats compared with the sham group. Pretreatment with metformin in I/R animals reduced levels of pro-BDNF compared with the I/R group (p < 0.001) but increased that compared with the sham group (p < 0.001). The level of pro-BDNF decreased in the met + CC + I/R group compared with the met + I/R group (p < 0.01). Pretreatment with metformin in I/R animals significantly increased P70S6K compared with the I/R group (p < 0.001). Conclusion Short-term memory in ischaemic rats treated with metformin increased step-through latency; sensory-motor evaluation was applied and a group of ischaemia rats that were pretreated with metformin showed high levels of BDNF, P70S6K that seemed to be due to increasing AMPK. PMID- 26960059 TI - Anaerobic Degradation of p-Alkylated Benzoates and Toluenes. AB - The anaerobic degradation of 4-alkylbenzoates and 4-alkyltoluenes is to date a rarely reported microbial capacity. The newly isolated Alphaproteobacterium Magnetospirillum sp. strain pMbN1 represents the first pure culture demonstrated to degrade 4-methylbenzoate completely to CO2 in a process coupled to denitrification. Differential proteogenomic studies in conjunction with targeted metabolite analyses and enzyme activity measurements elucidated a specific 4 methylbenzoyl-coenzyme A (CoA) pathway in this bacterium alongside the classical central benzoyl-CoA pathway. Whilst these two pathways are analogous, in the former the p-methyl group is retained and its 4-methylbenzoyl-CoA reductase (MbrCBAD) is phylogenetically distinct from the archetypical class I benzoyl-CoA reductase (BcrCBAD). Subsequent global regulatory studies on strain pMbN1 grown with binary or ternary substrate mixtures revealed benzoate to repress the anaerobic utilization of 4-methylbenzoate and succinate. The shared nutritional property of betaproteobacterial 'Aromatoleum aromaticum' pCyN1 and Thauera sp. strain pCyN2 is the anaerobic degradation of the plant-derived hydrocarbon p cymene (4-isopropyltoluene) coupled to denitrification. Notably, the two strains employ two different peripheral pathways for the conversion of p-cymene to 4 isopropylbenzoyl-CoA as the possible first common intermediate. In 'A. aromaticum' pCyN1 a putative p-cymene dehydrogenase (CmdABC) is proposed to hydroxylate the benzylic methyl group, which is subsequently further oxidized to the CoA-thioester. In contrast, Thauera sp. strain pCyN2 employs a reaction sequence analogous to the known anaerobic toluene pathway, involving a distinct branching (4-isopropylbenzyl)succinate synthase (IbsABCDEF). PMID- 26960060 TI - Hospital resource use of patients receiving isavuconazole vs voriconazole for invasive mold infections in the phase III SECURE trial. AB - OBJECTIVE: In the phase III SECURE trial, isavuconazole was non-inferior to voriconazole for all-cause mortality for the primary treatment of invasive mold disease (IMD) caused by Aspergillus spp. and other filamentous fungi. This analysis assessed whether hospital resource utilization was different between patients treated with isavuconazole vs voriconazole in SECURE. METHODS: The analysis population comprised adults with proven/probable/possible IMD enrolled in SECURE. The primary endpoint was hospital length of stay (LOS) in the overall trial population. Patients were also stratified by estimated glomerular filtration rate-modification of diet in renal disease category (< 60 mL/min/1.73 m(2) [moderate-to-severe impairment] and >=60 mL/min/1.73 m(2) [mild or no impairment]), body mass index (BMI; <25, >=25-<30, and >=30 kg/m(2)), and age (<=45, >45-<=65, and >65 years). RESULTS: Data from 516 patients (258 per arm) were evaluated. Overall, median LOS was not statistically significantly different between the isavuconazole (15.0 days) and voriconazole (16.0 days; p = 0.607) arms. Median LOS was statistically significantly shorter in patients with moderate-to-severe renal impairment treated with isavuconazole (9.0 days) vs voriconazole (19.0 days; hazard ratio [HR]: 3.44; 95% confidence interval [CI] = 1.51-7.83). Median LOS was shorter, but not significantly, in patients with a BMI >=30 kg/m(2) (isavuconazole 13.5 days vs voriconazole 22 days; HR = 1.57; 95% CI = 0.70-3.52) or aged >65 years (isavuconazole 15.0 days vs voriconazole 20.0 days; HR = 1.37; 95% CI = 0.87-2.16). LIMITATIONS: As the patient subgroups analyzed were small, sub-group findings should be interpreted with caution in light of the lack of statistical significance for each sub-group-by-treatment interaction. CONCLUSIONS: Isavuconazole may reduce hospital LOS in certain subgroups of patients with IMD, especially those with moderate-to-severe renal impairment. PMID- 26960061 TI - Anaerobic Microbial Degradation of Hydrocarbons: From Enzymatic Reactions to the Environment. AB - Hydrocarbons are abundant in anoxic environments and pose biochemical challenges to their anaerobic degradation by microorganisms. Within the framework of the Priority Program 1319, investigations funded by the Deutsche Forschungsgemeinschaft on the anaerobic microbial degradation of hydrocarbons ranged from isolation and enrichment of hitherto unknown hydrocarbon-degrading anaerobic microorganisms, discovery of novel reactions, detailed studies of enzyme mechanisms and structures to process-oriented in situ studies. Selected highlights from this program are collected in this synopsis, with more detailed information provided by theme-focused reviews of the special topic issue on 'Anaerobic biodegradation of hydrocarbons' [this issue, pp. 1-244]. The interdisciplinary character of the program, involving microbiologists, biochemists, organic chemists and environmental scientists, is best exemplified by the studies on alkyl-/arylalkylsuccinate synthases. Here, research topics ranged from in-depth mechanistic studies of archetypical toluene-activating benzylsuccinate synthase, substrate-specific phylogenetic clustering of alkyl /arylalkylsuccinate synthases (toluene plus xylenes, p-cymene, p-cresol, 2 methylnaphthalene, n-alkanes), stereochemical and co-metabolic insights into n alkane-activating (methylalkyl)succinate synthases to the discovery of bacterial groups previously unknown to possess alkyl-/arylalkylsuccinate synthases by means of functional gene markers and in situ field studies enabled by state-of-the-art stable isotope probing and fractionation approaches. Other topics are Mo-cofactor dependent dehydrogenases performing O2-independent hydroxylation of hydrocarbons and alkyl side chains (ethylbenzene, p-cymene, cholesterol, n-hexadecane), degradation of p-alkylated benzoates and toluenes, glycyl radical-bearing 4 hydroxyphenylacetate decarboxylase, novel types of carboxylation reactions (for acetophenone, acetone, and potentially also benzene and naphthalene), W-cofactor containing enzymes for reductive dearomatization of benzoyl-CoA (class II benzoyl CoA reductase) in obligate anaerobes and addition of water to acetylene, fermentative formation of cyclohexanecarboxylate from benzoate, and methanogenic degradation of hydrocarbons. PMID- 26960074 TI - Environmental constraints and call evolution in torrent-dwelling frogs. AB - Although acoustic signals are important for communication in many taxa, signal propagation is affected by environmental properties. Strong environmental constraints should drive call evolution, favoring signals with greater transmission distance and content integrity in a given calling habitat. Yet, few empirical studies have verified this prediction, possibly due to a shortcoming in habitat characterization, which is often too broad. Here we assess the potential impact of environmental constraints on the evolution of advertisement call in four groups of torrent-dwelling frogs in the family Ranidae. We reconstruct the evolution of calling site preferences, both broadly categorized and at a finer scale, onto a phylogenetic tree for 148 species with five markers (~3600 bp). We test models of evolution for six call traits for 79 species with regard to the reconstructed history of calling site preferences and estimate their ancestral states. We find that in spite of existing morphological constraints, vocalizations of torrent-dwelling species are most probably constrained by the acoustic specificities of torrent habitats and particularly their high level of ambient noise. We also show that a fine-scale characterization of calling sites allows a better perception of the impact of environmental constraints on call evolution. PMID- 26960076 TI - The importance of margins in head and neck cancer. AB - An estimated 200,000 deaths each year worldwide are due to cancer of the head and neck, mostly mucosal squamous cell carcinoma and nonmelanoma skin cancer. The status of surgical margins is important for prognosis and need for adjuvant therapy. We will discuss how margin status impacts outcomes and therapy, and the conundrum of determining margin status. PMID- 26960077 TI - Radiology Resident' Satisfaction With Their Training and Education in the United States: Effect of Program Directors, Teaching Faculty, and Other Factors on Program Success. AB - OBJECTIVE: Radiology residency education must evolve to meet the growing demands of radiology training. Resident opinions are a major resource to identify needs. However, few published data are available on a national level investigating the radiology resident perspective on factors that influence the resident experience. Our study investigates factors that affect residents' satisfaction with their residency experience and education. MATERIALS AND METHODS: A 67-item survey was sent to all radiology residency program directors and coordinators in the United States to be distributed at their discretion. Questions were multiple choice, free-text answer, or 5-point Likert scale. Statistical significance (p < 0.05) was determined using chi-square test, t test, and logistic regression analysis, respectively. RESULTS: Two hundred seventeen radiology residents responded to the survey (range, 212-217 responses per question). Overall, 77.8% (168/216) of residents were satisfied with their residency programs. Subcategories that showed a statistically significant correlation with overall satisfaction, in decreasing strength according to the odds ratio (OR), include the program director or administrative office (OR, 72.2; 95% CI, 27.4-221.9), the daily workstation experience (OR, 30.5; 95% CI, 12.8-80.9), the faculty (OR, 19.5; 95% CI, 8.9 45.4), educational conferences (OR, 7.9; 95% CI, 3.9-16.4), work hours (OR, 6.4; 95% CI, 3.2-13.2), teaching opportunities (OR, 6.5; 95% CI, 3.1-13.8), research opportunities (OR, 5.1; 95% CI, 2.6-10.6), personal study (OR, 2.1; 95% CI, 1.1 4.1), and compensation (OR, 1.9; 95% CI, 1.0-3.7). CONCLUSION: Our study provides incremental data to the existing literature that offers insight into factors that contribute to a successful radiology residency program. PMID- 26960078 TI - Benthic assemblages, biodiversity and invasiveness in marinas and commercial harbours: an investigation using a bioindicator group. AB - Fouling communities on artificial marine structures are generally different from benthic communities in natural rocky habitats. However, they may also differ among different types of artificial structures. Two artificial structures in direct contact with arriving vessels were compared: floating pontoons within recreational marinas, and sea-walls within commercial harbours. Natural rocky habitats were used as a reference, and the genus Eudendrium (Cnidaria, Hydrozoa) was chosen as a bioindicator. The assemblages were different among the three types of habitat studied, with different species characterising each habitat. The probability of finding an invasive Eudendrium species was significantly higher on pontoons. Diversity was the lowest on pontoons, but it was not significantly different between sea-walls and natural rocks. In general, a barrier to the spread of exotic species exists between harbours and natural rocky habitats. Floating pontoons seem to be a less suitable habitat for native fauna and a key element in marine biological invasions. PMID- 26960079 TI - Water and public health: updating the agenda. PMID- 26960075 TI - The current state of the art of quantitative phosphoproteomics and its applications to diabetes research. AB - Protein phosphorylation is a fundamental regulatory mechanism in many cellular processes and aberrant perturbation of phosphorylation has been implicated in various human diseases. Kinases and their cognate inhibitors have been considered as hotspots for drug development. Therefore, the emerging tools, which enable a system-wide quantitative profiling of phosphoproteome, would offer a powerful impetus in unveiling novel signaling pathways, drug targets and/or biomarkers for diseases of interest. This review highlights recent advances in phosphoproteomics, the current state of the art of the technologies and the challenges and future perspectives of this research area. Finally, some exemplary applications of phosphoproteomics in diabetes research are underscored. PMID- 26960080 TI - The human right to water and sanitation: a new perspective for public policies. AB - The recognition of the human right to water and sanitation (HRtWS) by the United Nations General Assembly and Human Rights Council in 2010 constituted a significant political measure whose direct consequences are still being assessed. Previous to this date, the HRtWS and its link to a healthy life and adequate standard of living had been recognised in diverse legal and judicial spheres worldwide, in some cases under the pressure of the initiatives of strong social movements. However, while the HRtWS is recognised by the UN State Members, it constitutes a concept in construction that has not been approached and interpreted in consensual ways by all concerned stakeholders. The present article presents a formal definition of this right with a base in human rights regulation. It attempts to dialogue with the different existing perspectives regarding the impact of its international recognition as a human right. It then elucidates the progressive development of the HRtWS in law and jurisprudence. Finally, it considers the urgency and challenge of monitoring the HRtWS and discusses important implications for public policies. PMID- 26960081 TI - Measuring the invisible: Analysis of the Sustainable Development Goals in relation to populations exposed to drought. AB - Brazil, together with all the member countries of the United Nations, is in a process of adoption of a group of Sustainable Development Goals, including targets and indicators. This article considers the implications of these goals and their proposed targets, for the Semi-Arid region of Brazil. This region has recurring droughts which may worsen with climate change, further weakening the situation of access of water for human consumption in sufficient quantity and quality, and as a result, the health conditions of the exposed populations. This study identifies the relationship between drought and health, in an effort to measure progress in this region (1,135 municipalities), comparing relevant indicators with the other 4,430 municipalities in Brazil, based on census data from 1991, 2000 and 2010. Important inequalities between the municipalities of this region and the municipalities of the rest of Brazil are identified, and discussed in the context of what is necessary for achieving the Sustainable Development Goals in the Semi-arid Region, principally in relation to the measures for adaptation to achieve universal and equitable access to drinking water. PMID- 26960082 TI - Loss and damage affecting the public health sector and society resulting from flooding and flash floods in Brazil between 2010 and 2014 - based on data from national and global information systems. AB - This article outlines the results of a descriptive study that analyses loss and damage caused by hydrometeorological disasters in Brazil between 2010 and 2014 using the EM DAT (global) and S2iD (national) databases. The analysis shows major differences in the total number of disaster events included in the databases (EM DAT = 36; S2iD = 4,070) and estimated costs of loss and damage (EM-DAT - R$ 9.2 billion; S2iD - R$331.4 billion). The analysis also shows that the five states most affected by these events are Santa Catarina, Rio Grande do Sul, Minas Gerais, Sao Paulo and Parana in Brazil's South and Southeast regions and that these results are consistent with the findings of other studies. The costs of disasters were highest for housing, public infrastructure works, collectively used public facilities, other public service facilities, and state health and education facilities. The costs associated with public health facilities were also high. Despite their limitations, both databases demonstrated their usefulness for determining seasonal and long-term trends and patterns, and risk areas, and thus assist decision makers in identifying areas that are most affected by and vulnerable to natural disasters. PMID- 26960083 TI - Assessment of the quality of water for consumption by river-bank communities in areas exposed to urban and industrial pollutants in the municipalities of Abaetetuba and Barcarena in the state of Para, Brazil. AB - In spite of the great technological advances in processes for treatment of water for human consumption, water actually used for supply has become a major public health challenge. This study assesses the quality of the water consumed in two riverside communities in the Brazilian state of Para, in an area exposed to domestic and industrial pollutants. Four campaigns of sampling were carried out in the two communities. The variables used for the calculation of the water quality index - Indice de Qualidade da Agua, or IQA - were: pH, total solids, chloride, fluoride, hardness and N-Nitrate. The waters used for human consumption in the Maranhao Community, where there is no contamination by industrial pollutants, presented adequate samples, with improvement in the dry season; on the other hand the waters of the Vila do Conde, a location close to the industrial activity, had quality that was unacceptable for human consumption in both the seasonal periods. The principal parameters affected were pH and N Nitrate, with values up to 25 times the reference level of the Brazilian legislation for water for human consumption. These results indicated greater anthropic interference in the vicinity of Vila do Conde, in Barcarena. It is concluded that this population is in need of clinical assessments by specialized professionals on the state of its health. PMID- 26960085 TI - Determinants in implementing a public policy for an essential volume of free water in Bogota and Medellin, Colombia. AB - Within the framework for the realization of the human right to water and sanitation, States have the obligation to implement programs and public policies that satisfy the basic needs of their population, especially its most vulnerable demographics. In Colombia, this challenge has been addressed through policies that provide a determined essential amount of free water to people whose access to water and sanitation services are limited due to low income. Through a review of legal and technical documents as well as relevant literature, this article presents an analysis of the particular determinants involved in implementing this program in Bogota and Medellin, as well as some related concerns. Among such factors, we discuss the evolution and changes of the tariff model used in service provision, estimates of basic consumption, the role of social movements and collective action, and user disconnection due to non-payment. The main particularities and differences of each case highlighted the inconveniences related to the method of identifying eligible users and applying assistance to beneficiary user groups, and the need for national guidelines in implementing this policy. PMID- 26960084 TI - Management of health sector actions in drought situations. AB - Water is essential for the socio-economic development of a region and also for the survival of human beings. Water scarcity has direct and indirect impacts on the environment, the economy and human health. It can change the profile of morbidity and mortality of diseases, as well as having an impact on the supply of services that are essential public to the quality of life. This study aims to contextualize the occurrence of drought in Brazil, its effects on human health, as well as actions to be developed by the health sector to reduce the risk to those living in affected areas, with an emphasis on the monitoring of the quality of drinking water. This is a descriptive, qualitative study with a documental basis. The documents that were researched were related to initiatives by the Health Surveillance Secretariat of the Ministry of Health up until 2014. It is necessary to strengthen the performance capacity of the Unified Health System (SUS) in order to develop timely responses to reduce the risk to public health. PMID- 26960086 TI - Using satellite data to study the relationship between rainfall and diarrheal diseases in a Southwestern Amazon basin. AB - The North region is the second region in Brazil with the highest incidence rate of diarrheal diseases in children under 5 years old. The aim of this study was to investigate the relationship between rainfall and water level during the rainy season principally with the incidence rate of this disease in a southwestern Amazon basin. Rainfall estimates and the water level were correlated and both of them were correlated with the diarrheal incidence rate. For the Alto Acre region, 2 to 3 days' time-lag is the best interval to observe the impact of the rainfall in the water level (R = 0.35). In the Lower Acre region this time-lag increased (4 days) with a reduction in the correlation value was found. The correlation between rainfall and diarrheal disease was better in the Lower Acre region (Acrelandia, R = 0.7) and rainfall upstream of the city. Between water level and diarrheal disease, the best results were found for the Brasileia gauging station (Brasileia, R = 0.3; Epitaciolandia, R = 0.5). This study's results may support planning and financial resources allocation to prioritize actions for local Civil Defense and health care services before, during and after the rainy season. PMID- 26960087 TI - Management and use of water resources and the expansion of agribusiness: water for what and for whom? AB - This article aims to conduct an analysis of the correlation between the management and use of water resources with the expansion of agribusiness and its reflections in environmental and human contamination, pointing toward challenges for SUS in the area of monitoring pesticides in water for human consumption. It is qualitative study with an adopted methodological framework of the case study, applied in an area of agribusiness expansion in the semi-arid region of the state of Ceara. The results demonstrate that there exists an unequal relationship in the management and use of water, in which agribusiness in Ceara is prioritized for access to water at the expense of the great majority of the rural population. As a result, pesticide contamination of surface and ground water brings challenges to surveillance of the control of pesticides in water for human consumption. In this sense, we present alternatives to develop health services with more effective actions in surveillance of health in general, and of Vigiagua in particular, such as: overcoming the fragmentation of vision and intervention regarding health problems; human exposure to multiple pesticides; the lack of laboratories and trained professionals; and enlarging the dissemination of information to the users of water. PMID- 26960088 TI - [Impact on human health of endocrine disruptors present in environmental water bodies: is there an association with obesity?]. AB - There is growing evidence that endocrine disruptors (ED) may adversely affect humans. Surface and underground water are the main sources for obtaining potable water, however they can be contaminated with ED, which are not completely removed by conventional water and sewage treatment processes. Some health problems are related to the exposure of humans to ED, obesity being one of them. There is currently an increase in the prevalence of obesity worldwide, a fact that is considered a concern in view of its potential impact on the health care system, since obesity is the major risk factor of the leading chronic diseases including diabetes and cardiovascular disease. By means of a review of the literature, this paper sought to gather scientific publications linking exposure to ED with obesity, in order to verify the importance of removal of ED from water bodies, thereby preserving the population's health and aquatic biota. Most of the selected studies suggest an association between ED and obesity in humans. PMID- 26960089 TI - Evaluation of simple diffusion chlorinators for decontamination of wells in a rural settlement in Amazonia, Brazil. AB - While the Amazon region has the world's largest reserve of fresh water, the lack of water services and water treatment, especially in non-urban regions, causes environmental and health problems. In isolated rural settlements supply is usually by shallow wells, and the quality of water is a concern for residents. These are situations where there are restricted options for water treatment. This study aimed to assess the use of simplified diffusion chlorinators as an alternative water treatment method. Bacteriological analyses were made of 100 samples of water from the wells, before and after application of the chlorinators, in the Rural Settlement of Rio Pardo, Presidente Figueiredo in the Brazilian State of Amazonas. The sources that were analyzed were considered inappropriate for consumption without prior treatment, and the use of the chlorinators eliminated all contamination by thermotolerant coliforms in the great majority of cases. Also, the method was well received by residents, because it does not leave a taste in the water, is relatively low-cost and handling is easy. We discuss the advantages and limitations of the use of this method of treatment for this social-environmental context and present suggestions for improvement and adaptation, for application of this methodology in other settlements. PMID- 26960090 TI - Diarrhea outbreaks in northeastern Brazil in 2013, according to media and health information systems - Surveillance of climate risk and health emergencies. AB - This study has the objective of analyzing information about diarrhea outbreaks in Brazil's northeast in the year 2013. Information came from electronic media and from health information systems. A total of 33 news events related to diarrhea outbreaks were identified, some of them mentioning causes and aggravating factors. The analysis of spatial and temporal distribution of the news, admissions and deaths showed that more than 100,000 persons were affected and, according to the news analyzed, the most affected states were Alagoas and Pernambuco, with a greater extent in the months from May to July. The use of alternative sources of water such as ponds, wells, water trucks and household water reservoirs were identified as the most immediate causes of these outbreaks. However, other underlying factors such as precarious water supply systems in the semi-arid region, the exceptional conditions of drought, considered the worst in the last 60 years, as well as the capacity of the health sector to respond to a large number of cases, should be considered to recover the context in which these outbreaks are produced. PMID- 26960092 TI - Environmental Education as a social mobilization strategy to face water scarcity. AB - Article 225 of the Brazilian Constitution establishes that all citizens have the right to an ecologically balanced environment, as a common good that is essential for a healthy life, and that the government and society have the duty to protect and preserve the environment for present and future generations. This article outlines a methodology for promoting social mobilization to address water scarcity developed under the National Environmental Education and Social Mobilization for Sanitation Program (PEAMSS, acronym in Portuguese). The main aim of this article is to show the importance of education as a driving force for empowerment for water resources management. It outlines the main concepts of emancipatory environmental education and then goes on to describe the elaboration of a PEAMMS action plan. It concludes that the universalization of the right to safe and clean drinking water and access to sanitation is only possible through democratic and participatory water resources management. Actions are necessary to evaluate the reach of the PEAMSS and define the way ahead for the program. PMID- 26960091 TI - The involvement of community leaders in healthcare, the environment and sanitation in areas of social vulnerability. AB - The main purpose of this article is to identify access to: social assistance inclusion programs; assistance from health agents; public water supply services; and water saving practices, in areas of irregular occupation in Brazil. A stratified random sampling technique by clusters was adopted with a simple sampling strategy. In the universe of 14,079 households, 68 community leaders were identified, representing 6,800 households on average, in a normalized distribution (mean zero, standard deviation 1), deemed to include situations covering 96% of the cases with a margin of error of + or - 1% of the average. The theoretical approach proposes a reflection and verification through questionnaires on the mechanisms of exclusion. Poverty perpetuates the vicious circle of inequality, risks to health and the environment, and it is necessary that these should be considered in the policies and procedures for urban expansion. As a conclusion, various challenges were identified for serving areas of social-environmental vulnerability - the needs to: improve the low quality of health and water services in subnormal agglomerations; modify the behavior of the population accessing the networks in a clandestine manner; and to put inclusive governance mechanisms in place. PMID- 26960093 TI - Disasters related to droughts and public health - a review of the scientific literature. AB - In Brazil, the history of droughts has been marked by constant social and health tragedies, with estimates of up to 3 million deaths from the early 19th century until the late 20th century. There is a record of nearly 32,000 events related to the above and more than 96 million people were affected between 1991 and 2010. Although droughts have historically brought disasters to Brazil, which was noted in the scientific expeditions of Arthur Neiva and Belisario Penna that documented these droughts, there have not been many studies on them. The objective of this paper is to present a revision of the scientific articles related to droughts and public health. The following databases were used: PubMed, the Preparation and Response to Disasters Portal from BVS and the Capes Periodical Portal. The descriptors drought and health were used to search titles and summaries of articles in English, Portuguese and Spanish. Among the repercussions related to health that were discovered: malnutrition and nutritional deficiencies, mental health problems, issues relating to water and air quality and commitments made concerning access to health services. As there is a trend for more intense droughts and a scarcity of water until 2030, there is an urgent need for more research and studies in these areas. PMID- 26960094 TI - Sociology of health textbooks and narratives: historical significance. AB - This article has as its starting point two central ideas: textbooks as a means of production and dissemination of knowledge and narrative as an approach. After a brief review of studies on health/medical sociology textbooks, I analyze a few of these textbooks from the 1900-2012 period, produced in the United States and England. I have selected eleven textbooks which I thought were representative. In addition to a content analysis, the textbooks are located within the process of constitution of the health/medical sociology with brief references to the biographies of the authors. The textbooks analyzed were classified according to the main narrative features: doctor-centered; interdisciplinary; pedagogical; analytical; almost autobiographical; critical; and synthetic-reflective. In the final remarks, some points about the textbooks, limits and possibilities are presented. PMID- 26960095 TI - The emergence of medical professions of [re]habilitation and childhood: a history intertwined with theoretical tensions. AB - This article is the product of a review of historical-critical literature that analyzes the global historical events during the 20th century that made the emergence and consolidation of the medical rehabilitation professions possible and an examination of the ways in which these professions approach childhood. The analysis of and reflections upon the reviewed documents are outlined below according to three theoretical tensions: 1) the child of today and the adult of tomorrow, 2) the meaning of habilitation-rehabilitation, and 3) the positioning of the subject in society. To account for the breadth of these topics, the text is divided into two sections: the first covers the first half of the 20th century, the period between the wars and the emergence of [re]habilitation, and the second covers the second half of the 20th century through the present, a period of political organization and technological advances. In the contemporary era, these views of [re]habilitation are confronted by the overwhelming reality of historical conceptions of childhood. The realities that children face today are diverse and complex; therefore, it is necessary to rethink the normalizing view of childhood that was instituted in the 20th century. PMID- 26960096 TI - Between flows and therapeutic projects: revisiting the notions of lines of care in health and therapeutic itineraries. AB - This essay discusses the possibilities of conceptual and practical connections between the ideas of line of care and therapeutic itineraries, beginning with the theoretical contributions that lay the foundations for the Line of Integrated Healthcare and the hermeneutic approaches to Care. The implementation of lines of care tuned to individual and collective health needs can be glimpsed in the construction of therapeutic projects, inasmuch as they privilege the particularities of each situation in the agreement of flows of appointments, exams, and other procedures. The therapeutic project - taken as an arrangement, strategy, device, or basic dimension of Care in the work process in health - can be seen as an image that lays out a possibility of the future, which in turn is a projection conditioned by past experiences of health, illness, and life. From the criticism of explanatory models, preponderant in the studies of therapeutic itineraries, we defend the investment in approaches that privilege interpretation and understanding, capable of recuperating, contextualizing, and reconstructing trajectories, beginning with the subjects involved in the care process. PMID- 26960097 TI - Sexual violence, mood disorders and suicide risk: a population-based study. AB - This article seeks to analyze the association between sexual violence, manic and depressive episodes, and suicide risk among young adults. This is a cross sectional population-based study carried out with young people between 18 and 24 years of age in a town in southern Brazil. The sample was selected through clusters. The prevalence of sexual violence, manic, depressive and mixed episodes and suicide risk were evaluated, as well as the association between them. The chi square test and Poisson regression were used for statistical analysis. The study sample comprised 1,560 subjects. Among these, 3.1% had suffered sexual violence at some point in their life. The prevalence of depressive, mixed episodes, and (hypo)manic episodes were 10%, 2.4% and 2.3%, respectively. Suicide risk had a prevalence of 8.6% in the total sample. Young people who have suffered sexual violence are more likely to be subject to mood changes or suicide risk than those who have not (p < 0.05), except for the occurrence of (hypo)manic episodes. These results revealed a strong association between sexual violence and depressive and mixed episodes and suicide risk. PMID- 26960098 TI - Patterns of cancer-related internet searches: reactiveness; risks; the role of affect. AB - The popularization of ICTs and the availability of information have not influenced the habits of prevention - cancers are lately diagnosed, as before in the scarcity of information era. This paper analyzes patterns of accesses to the National Cancer Institute website (already described in previous articles) as well as contradictions between the purposes and results of cancer prevention campaigns. We identified a reactive pattern of queries which was indifferent to information on prevention, but interested in treatment technologies and news about celebrity's diseases. These findings contrast with the paradigm of the best data for decision making, based in the heteronomy of "banking education", its means and efficacy. We discussthe symbolic power of campaigns under the theoretical framework of emotional heuristic models - analytical tools rarely employed in studies of risks, but here considered essential elements to the comprehention of public perception of health. Ambiguities are portrayed and as well as its pendulum between certainties and uncertainties in the midst on which they are formed. It is discussed the risk tripartition - as perception, analysis and policy, the latest posed as a public clash between the first concerning the major risks aligned to their historical circumstances. PMID- 26960099 TI - Violence against children in Brazilian scenery. AB - Violence is a social and public health phenomenon, with greater exacerbation when it affects children, causing an impact on child development and a catastrophic impact on the behavior of an adult life. The purpose of this article is to characterizing by the scientific evidence child abuse on the brasilian scene. There was used the integrative literature review and, as a source of research, the databases Lilacs and Scielo from August 2013. Among the six identified publications showed negligence as the main type of violence, five discoursed that Male gender is the most affected gender and ten stated that the perpetrator is always a family member. Also in this heart, it becomes clear that the parents are the greatest perpetrators of violence against children, especially the mother as the most frequent aggressors. The results demonstrate the need to identify early all types of violence, especially the neglect, recognizing that there is no significant distinction of violence between the genders and sharing the family environment as the most conducive environment for the growth of violent events. PMID- 26960101 TI - Incorporation of information technology in Primary Care of SUS in North-eastern Brazil: expectations and experiences. AB - The incorporation of information technology (IT) via an electronic record of health data in primary care is transforming the organization of labor and professional practices in Brazil. The scope of this study is to establish the expectations and experiences of incorporating IT in the primary health care of the Unified Health System (SUS) with the implementation of the National Health Card System (SCNS). It involved qualitative research with 50 interviews and 96 questionnaires comparing the opinion of health professionals about technological innovation in locations with the SCNS and where it has not yet been incorporated in the cities of Joao Pessoa and Aracaju, respectively. The expectation was that IT would speed up the work schedule, which was not confirmed at the location where the SCNS had been incorporated. IT can improve labor organization, the flow of data and information and enable the digital insertion of the professional. The "light" technology of health care cannot be expedited by IT, as it is necessary to impart knowledge to the professionals. However, it can improve working conditions by data gathering and organization, giving immediate feedback to the professional recording the data and enhance the ability to manage health policies. PMID- 26960100 TI - Coming to terms with the other's perspective: empathy in the relation between psychiatrists and persons diagnosed with schizophrenia. AB - This article presents qualitative research into the empathic dimension in the physician-patient relationship. The ways to gain access to the other's perspective and collaborate in clinical management are investigated. The material was researched in Community Mental Health Centers in Rio de Janeiro and Campinas. Focus groups were conducted with psychiatrists and persons diagnosed with schizophrenia and the transcribed material was analyzed using phenomenology and medical anthropology as theoretical frameworks. The narratives studied were organized into five main categories: clinical management; negotiation of medication; diagnosis communication; understanding the user's perspective; and limits of empathy. In these thematic categories the participants developed the following subjects: shared construction of care; the desire to know the diagnosis juxtaposed with hesitation to divulge it; managing the control of symptoms and side effects for the negotiation of medication; the effort to understand the user's experience; and crisis as the limit of empathy. PMID- 26960102 TI - [Supply and demand in home health care]. AB - The changes in the demographic and epidemiologic profiles of the Brazilian population and the need to rethink the health care model have led many countries like Brazil to consider Home Care (HC) as a care strategy. However, there is a gap between the supply of HC services, the demand for care and the health needs manifested by the population. Thus, this article analyzes scientific output regarding the status of the relation between supply, demand and the needs related to home health care. This work is based on an integrative review of the literature in the following databases: Cumulative Index to Nursing and Allied Health Literature (CINAHL), Latin America and the Caribbean Literature on Health and Science (Lilacs), Medical Literature Analysis and Retrieval System Online (Medline) and Web of Science. Despite the fact that few articles refer to the issue in question, there is evidence indicating that health demands and needs are seldom taken into account either in a quantitative or qualitative approach when developing the organization of HC services. The analysis would indicate that there is a national and international deficit in the supply of HC services considering the demand for health care and needs currently prevailing. PMID- 26960103 TI - [Ongoing Health Education in Brazil:education or ongoing management?]. AB - The scope of this study was to analyze the concept and principles of Ongoing Health Education (OHE) - the Brazilian acronym is PNEPS. The methodology was based on the analysis of documents from the Ministry of Health and related scientific articles. It was revealed that the concept of OHE transcends its pedagogical significance and is undergoing a service restructuring process in the face of the new demands of the model. Precisely at the time in which jobs are increasingly unstable and precarious, the Ministry of Health engages in discourse regarding innovative management, focusing on the issue of OHE. The idea is not one of ongoing education, but of ongoing management. Rather than being an instrument for radical transformation, OHE becomes an attractive ideology due to its appearance as a pedagogical novelty. PMID- 26960104 TI - [Homicides and social vulnerability]. AB - The goal of this study was to analyze the spatial distribution of homicide rates (H) according to the social vulnerability index (SVI) and the quality of urban life index (QUL) in Betim, State of Minas Gerais, from 2006 to 2011. Descriptive analysis was performed using Moran's spatial correlation analysis, and the H, SVI and QUL spatial analyses. During this period there were 1,383 deaths, mostly of males (91.9%), aged 15-24 years (46.9%), brown/black (76.9%), with secondary education (51.1%), and single (83.9%). No spatial autocorrelation was revealed, indicating that the distribution of homicide rates is random; the same occurred with the SVI and the QUL index. Taken together, however, the H, SVI and QUL index overlapped, which was analyzed using different theories of crime, such as those addressing socioeconomic issues, arms of drugs dealing and Durkheim's and Habermas' theories, namely anomie and colonization of the lifeworld. CONCLUSION: social vulnerability and homicide are associated from both empirical and theoretical perspectives. PMID- 26960105 TI - [Factors associated with linear growth of socially vulnerable children of the State of Paraiba, Brazil]. AB - This study set out to examine the associated factors, including zinc deficiency, of stunting in children attended in daycare centers in the State of Paraiba. It is a cross-sectional study, involving 353 children aged 6-72 months old. Data on biological characteristics, health situation and socioeconomic conditions of children were obtained by a questionnaire. Children with height for age indices two z scores below the median value of the reference population were considered to be stunted. The level of zinc in hair was determined by atomic absorption spectrophotometry. The prevalence of stunting was 7.36%. Low birth weight, age range 6-36 months, incomplete immunization, low maternal weight, per capita income of less than 0.5 minimum wages and living in a given/donated or invaded house were significantly associated with height for age index deficit. Stunted children were more prone to zinc deficiency, however, without statistical difference with normal growth children. Thus, there is a clear differential in linear growth that favors the children of higher socioeconomic status and favorable maternal history and health. PMID- 26960106 TI - [Impact on reading scientific articles:an attempt to dialogue with "my reader"]. AB - This article discusses the concept of "impact" and is based on the scientific output of the author that is examined for the analysis of impacts from the qualitative standpoint. It is done not as an end in itself, but under the aegis of the author/text/reader relationship. Seeking to establish this relationship, the way in which the author is quoted in a selected article, entering each of the quotes and identifying what aspects were emphasized by the readers who referenced the quote is explored in detail. This qualitative observation of each of the quotes provided an indication of how each author/reader perceived the original text. This personal experience of this finite and delicate dialogue with "my reader" is presented here as a recommendation, to anyone who may be interested, of a viable device that can be repeated by authors in order to re-visit their writings based on the acknowledgement of the impact that it has on others. PMID- 26960107 TI - [Unemployment and mental health among Hispanics in the US: an epidemiological analysis]. AB - The high unemployment rates observed in the United States during the recent economic crisis, that moreover vary between ethnic groups, make it relevant to inquire into how this problem is linked to the mental health of employed and unemployed persons. Therefore, in this paper the relationship between unemployment and mental health among Mexican immigrants, Mexicans born in the US, and other Hispanics in comparison with non-Hispanic native whites and Afro Americans in the US is analyzed. To achieve this objective prevalence, prevalence ratios and odds ratios for the population between 18 and 65 years of age in the labor force was calculated using data from the 1999 and 2009 National Health Interview Surveys. It was seen that in times of crisis the prevalence of Non Specific Psychological Disorders (NSPD) in the labor force increased in all ethnic groups. The prevalence ratios indicate that the unemployed face a higher risk of suffering from NSPD than the employed, especially for the non-Mexican Hispanics. Mexican immigrants, in contrast, show the lowest risks. PMID- 26960108 TI - Is there an association between the presence of dental fluorosis and dental trauma amongst school children? AB - Our objective was to evaluate whether there is an association with the different levels of dental fluorosis and the presence of dental trauma amongst school children. A transversal study was conducted amongst school children from the age of 12. Dental examinations were conducted by 24 well trained and fully qualified dental surgeons. Data was collected from 36 randomly selected public schools amongst 89 schools in a municipality. The criteria used to diagnose dental fluorosis was based on the Dean's fluorosis Index and for diagnosing dental trauma we looked for clinical signs of crown fractures and dental avulsions. Multiple descriptive analysis, which was bivariate, was carried out. Amongst the 2,755 school children that took part in the study 1,089 (39.6%) were diagnosed with dental fluorosis and 106 (3.8%) had one tooth or more with dental trauma. We noted a high prevalence of dental fluorosis, independent of the level of severity, amongst individuals with one tooth or more who had dental trauma. This association was even more evident where there were severely high levels of fluorosis. We also noted that the presence of fluorosis was greater amongst those that actively paid more attention to discoloration on their teeth and who received treatment from a dental professional at their schools. Nevertheless dental fluorosis was associated with the presence of dental trauma, independent of its severity. PMID- 26960109 TI - Situation of the supplementary diet of children between 6 and 24 months attended in the Primary Care Network of Macae, RJ, Brazil. AB - This study aimed to analyze the supplementary nutritional situation of children aged 6-24 months attended by the Primary Care unit of Macae/RJ. It was conducted as a cross-sectional study, and data was obtained from the SISVAN Web website, including and analyzing all of the records (n=218) of children between 6-24 months in the year 2013. In infants between 6-12 months, the consumption of 72.3% of vegetables, 75.3% of fruits, and 63.4% of meats was detected, considered indicators of healthy supplementary nutrition. In contrast, 23.8% were already consuming sugar-based food sources (honey, molasses, simple sugar, and unrefined cane sugar), 34.7% industrialized juice, and 17.8% soft drinks. The consumption of industrialized juice was significantly greater in boys (p-value <0.001). In children between 12-18 months, 77.6% consumed vegetables, 77.4% fruits, and 86.3% meats. The consumption of sugar-based foods was 31%, 58.6% for industrialized juices, and 50% for soft drinks. Between 18-24 months, it was recorded that 89.9% of children consumed vegetables, 83.1% fruits, and 96.7% meat. The consumption of sugar-based foods was 33.9%, 69.5% for industrialized juices, and 55.5% for soft drinks. We conclude that the indicators of healthy complementary nutrition come close to the target set by the Ministry of Health (80%). PMID- 26960111 TI - [Risks and benefits of breast cancer screening in Brazil]. PMID- 26960112 TI - Grapevine red blotch-associated virus is Present in Free-Living Vitis spp. Proximal to Cultivated Grapevines. AB - Red blotch is an emerging disease of grapevine associated with grapevine red blotch-associated virus (GRBaV). The virus spreads with infected planting stocks but no vector of epidemiological significance has been conclusively identified. A vineyard block of red-blotch-affected Vitis vinifera 'Cabernet franc' clone 214 was observed in California, with a clustering of infected, symptomatic vines focused along one edge of the field proximal to a riparian habitat with free living Vitis spp. No genetic heterogeneity was observed in a 587-nucleotide region of the GRBaV genome in a population of 44 Cabernet franc clone 214 isolates. By contrast, genetic differences were observed in isolates from other cultivars and clones growing in adjacent blocks. GRBaV was confirmed infecting four free-living vines, two of which were shown to be V. californica * V. vinifera hybrids. The genomes of three free-living GRBaV vine isolates and seven from V. vinifera cultivars were compared; free-living vine isolates were shown to be more similar to each other and a 'Merlot' isolate than to the other cultivated vine isolates. The finding that GRBaV is present in free-living Vitis spp. indicates the virus can be spread by natural (nonhuman-mediated) means, and we hypothesize that in-field spread of GRBaV is occurring. PMID- 26960113 TI - Direct to Consumer Mobile Teledermatology Apps: An Exploratory Study. AB - BACKGROUND: Since 2012, "Direct to Consumer" mobile teledermatology apps have become more available, relinquishing many data collection tasks normally done by healthcare professionals directly to patients. INTRODUCTION: To determine user friendliness, diagnostic quality, and service of commercially available mobile teledermatology apps. MATERIALS AND METHODS: All mobile teledermatology apps available at the Apple App Store were reviewed. The two most popular mobile teledermatology apps were identified and tested together with three apps having similar functionality using a single case of a patient who was also examined by a dermatologist in-person. RESULTS: Apps varied in diagnostic scope, data gathering methods, services, rendered results, and in geographic coverage and cost. DISCUSSION: None of the apps take a history as thoroughly as recommended by textbooks. Key medical questions like current medications and allergies are not asked often. Most apps rendered concordant results, except for the one having the least thorough history taking. CONCLUSIONS: Mobile teledermatology application interfaces, services, and cost vary, with some risking medical errors and possible distribution of continuity of care. The American Telemedicine Association's guidelines for teledermatology need to address the use of direct to consumer apps. To protect consumers, app regulation, certification, or guidelines suggesting appropriate development and use might be considered. PMID- 26960114 TI - Mapping the MMPI-2/MMPI-2-RF Restructured Clinical Scales Onto Mood Markers in an Israeli Sample. AB - This study cross-culturally evaluated the Minnesota Multiphasic Personality Inventory-2/MMPI-2 Restructured Form (MMPI-2/MMPI-2-RF) emotion-focused Restructured Clinical (RC) Scales to examine whether their patterns of associations with positive affect (PA) and negative affect (NA) are as expected based on Tellegen, Watson, and Clark's ( 1999a , 1999b ) mood model. The sample was composed of 100 men and 133 women from psychiatric settings in Israel who completed the MMPI-2 and the Mood Check List (MCL; Zevon & Tellegen, 1982 ). Results indicated that RCd was substantially correlated with both PA and NA in opposite directions, and that RC2 and RC7 were more highly correlated with PA and NA, respectively. Further, when compared with their Clinical Scale counterparts, RC2 and RC7 exhibited comparable convergent validities and improved discriminant properties. Findings provide support for Tellegen et al.'s ( 2003 ) goal to link the RC scales to contemporary conceptualizations of mood. PMID- 26960115 TI - Advances in experimental phasing. PMID- 26960116 TI - A history of experimental phasing in macromolecular crystallography. AB - It was just over a century ago that W. L. Bragg published a paper describing the first crystal structures to be determined using X-ray diffraction data. These structures were obtained from considerations of X-ray diffraction (Bragg equation), crystallography (crystal lattices and symmetry) and the scattering power of different atoms. Although W. H. Bragg proposed soon afterwards, in 1915, that the periodic electron density in crystals could be analysed using Fourier transforms, it took some decades before experimental phasing methods were developed. Many scientists contributed to this development and this paper presents the author's own perspective on this history. There will be other perspectives, so what follows is a history, rather than the history, of experimental phasing. PMID- 26960117 TI - Efficient merging of data from multiple samples for determination of anomalous substructure. AB - Merging of data from multiple crystals has proven to be useful for determination of the anomalously scattering atomic substructure for crystals with weak anomalous scatterers (e.g. S and P) and/or poor diffraction. Strategies for merging data from many samples, which require assessment of sample isomorphism, rely on metrics of variability in unit-cell parameters, anomalous signal correlation and overall data similarity. Local scaling, anomalous signal optimization and data-set weighting, implemented in phenix.scale_and_merge, provide an efficient protocol for merging data from many samples. The protein NS1 was used in a series of trials with data collected from 28 samples for phasing by single-wavelength anomalous diffraction of the native S atoms. The local-scaling, anomalous-optimization protocol produced merged data sets with higher anomalous signal quality indicators than did standard global-scaling protocols. The local scaled data were also more successful in substructure determination. Merged data quality was assessed for data sets where the multiplicity was reduced in either of two ways: by excluding data from individual crystals (to reduce errors owing to non-isomorphism) or by excluding the last-recorded segments of data from each crystal (to minimize the effects of radiation damage). The anomalous signal was equivalent at equivalent multiplicity for the two procedures, and structure determination success correlated with anomalous signal metrics. The quality of the anomalous signal was strongly correlated with data multiplicity over a range of 12-fold to 150-fold multiplicity. For the NS1 data, the local-scaling and anomalous-optimization protocol handled sample non-isomorphism and radiation induced decay equally well. PMID- 26960118 TI - An overview of heavy-atom derivatization of protein crystals. AB - Heavy-atom derivatization is one of the oldest techniques for obtaining phase information for protein crystals and, although it is no longer the first choice, it remains a useful technique for obtaining phases for unknown structures and for low-resolution data sets. It is also valuable for confirming the chain trace in low-resolution electron-density maps. This overview provides a summary of the technique and is aimed at first-time users of the method. It includes guidelines on when to use it, which heavy atoms are most likely to work, how to prepare heavy-atom solutions, how to derivatize crystals and how to determine whether a crystal is in fact a derivative. PMID- 26960119 TI - Phasing and structure of bestrophin-1: a case study in the use of heavy-atom cluster compounds with multi-subunit transmembrane proteins. AB - The purification and three-dimensional crystallization of membrane proteins are commonly affected by a cumulation of pathologies that are less prevalent in their soluble counterparts. This may include severe anisotropy, poor spot shape, poor to moderate-resolution diffraction, crystal twinning, translational pseudo symmetry and poor uptake of heavy atoms for derivatization. Such challenges must be circumvented by adaptations in the approach to crystallization and/or phasing. Here, an example of a protein that exhibited all of the above-mentioned complications is presented. Bestrophin-1 is a eukaryotic calcium-activated chloride channel, the structure of which was recently determined in complex with monoclonal antibody fragments using SAD phasing with tantalum bromide clusters (Ta6Br12.Br2). Some of the obstacles to obtaining improved diffraction and phasing for this particular channel are discussed, as well as the approach and adaptations that were key to determining the structure. PMID- 26960120 TI - Tackling the crystallographic structure determination of the COP9 signalosome. AB - The COP9 signalosome (CSN) is an essential multi-protein complex in eukaryotes. CSN is a master regulator of intracellular protein degradation, controlling the vast family of cullin-RING ubiquitin (E3) ligases (CRLs). Important in many cellular processes, CSN has prominent roles in DNA repair, cell-cycle control and differentiation. The recent crystal structure of human CSN provides insight into its exquisite regulation and functionality [Lingaraju et al. (2014), Nature (London), 512, 161-165]. Structure determination was complicated by low resolution diffraction from crystals affected by twinning and rotational pseudo symmetry. Crystal instability and non-isomorphism strongly influenced by flash cooling, radiation damage and difficulty in obtaining heavy-atom derivatives, were overcome. Many different subunits of the same fold class were distinguished at low resolution aided by combinatorial selenomethionine labelling. As an example of how challenging projects can be approached, the structure determination of CSN is described as it unfolded using cluster-compound MIRAS phasing, MR-SAD with electron-density models and cross-crystal averaging exploiting non-isomorphism among unit-cell variants of the same crystal form. PMID- 26960121 TI - Using selenomethionyl derivatives to assign sequence in low-resolution structures of the AP2 clathrin adaptor. AB - Selenomethionine incorporation is a powerful technique for assigning sequence to regions of electron density at low resolution. Genetic introduction of methionine point mutations and the subsequent preparation and crystallization of selenomethionyl derivatives permits unambiguous sequence assignment by enabling the placement of the anomalous scatterers (Se atoms) thus introduced. Here, the use of this approach in the assignment of sequence in a part of the AP2 clathrin adaptor complex that is responsible for clathrin binding is described. AP2 plays a pivotal role in clathrin-mediated endocytosis, a tightly regulated process in which cell-surface transmembrane proteins are internalized from the plasma membrane by incorporation into lipid-enclosed transport vesicles. AP2 binds cargo destined for internalization and recruits clathrin, a large trimeric protein that helps to deform the membrane to produce the transport vesicle. By selenomethionine labelling of point mutants, it was shown that the clathrin binding site is buried within a deep cleft of the AP2 complex. A membrane stimulated conformational change in AP2 releases the clathrin-binding site from autoinhibition, thereby linking clathrin recruitment to membrane localization. PMID- 26960122 TI - Can I solve my structure by SAD phasing? Anomalous signal in SAD phasing. AB - A key challenge in the SAD phasing method is solving a structure when the anomalous signal-to-noise ratio is low. A simple theoretical framework for describing measurements of anomalous differences and the resulting useful anomalous correlation and anomalous signal in a SAD experiment is presented. Here, the useful anomalous correlation is defined as the correlation of anomalous differences with ideal anomalous differences from the anomalous substructure. The useful anomalous correlation reflects the accuracy of the data and the absence of minor sites. The useful anomalous correlation also reflects the information available for estimating crystallographic phases once the substructure has been determined. In contrast, the anomalous signal (the peak height in a model-phased anomalous difference Fourier at the coordinates of atoms in the anomalous substructure) reflects the information available about each site in the substructure and is related to the ability to find the substructure. A theoretical analysis shows that the expected value of the anomalous signal is the product of the useful anomalous correlation, the square root of the ratio of the number of unique reflections in the data set to the number of sites in the substructure, and a function that decreases with increasing values of the atomic displacement factor for the atoms in the substructure. This means that the ability to find the substructure in a SAD experiment is increased by high data quality and by a high ratio of reflections to sites in the substructure, and is decreased by high atomic displacement factors for the substructure. PMID- 26960124 TI - A log-likelihood-gain intensity target for crystallographic phasing that accounts for experimental error. AB - The crystallographic diffraction experiment measures Bragg intensities; crystallographic electron-density maps and other crystallographic calculations in phasing require structure-factor amplitudes. If data were measured with no errors, the structure-factor amplitudes would be trivially proportional to the square roots of the intensities. When the experimental errors are large, and especially when random errors yield negative net intensities, the conversion of intensities and their error estimates into amplitudes and associated error estimates becomes nontrivial. Although this problem has been addressed intermittently in the history of crystallographic phasing, current approaches to accounting for experimental errors in macromolecular crystallography have numerous significant defects. These have been addressed with the formulation of LLGI, a log-likelihood-gain function in terms of the Bragg intensities and their associated experimental error estimates. LLGI has the correct asymptotic behaviour for data with large experimental error, appropriately downweighting these reflections without introducing bias. LLGI abrogates the need for the conversion of intensity data to amplitudes, which is usually performed with the French and Wilson method [French & Wilson (1978), Acta Cryst. A35, 517-525], wherever likelihood target functions are required. It has general applicability for a wide variety of algorithms in macromolecular crystallography, including scaling, characterizing anisotropy and translational noncrystallographic symmetry, detecting outliers, experimental phasing, molecular replacement and refinement. Because it is impossible to reliably recover the original intensity data from amplitudes, it is suggested that crystallographers should always deposit the intensity data in the Protein Data Bank. PMID- 26960123 TI - Can I solve my structure by SAD phasing? Planning an experiment, scaling data and evaluating the useful anomalous correlation and anomalous signal. AB - A key challenge in the SAD phasing method is solving a structure when the anomalous signal-to-noise ratio is low. Here, algorithms and tools for evaluating and optimizing the useful anomalous correlation and the anomalous signal in a SAD experiment are described. A simple theoretical framework [Terwilliger et al. (2016), Acta Cryst. D72, 346-358] is used to develop methods for planning a SAD experiment, scaling SAD data sets and estimating the useful anomalous correlation and anomalous signal in a SAD data set. The phenix.plan_sad_experiment tool uses a database of solved and unsolved SAD data sets and the expected characteristics of a SAD data set to estimate the probability that the anomalous substructure will be found in the SAD experiment and the expected map quality that would be obtained if the substructure were found. The phenix.scale_and_merge tool scales unmerged SAD data from one or more crystals using local scaling and optimizes the anomalous signal by identifying the systematic differences among data sets, and the phenix.anomalous_signal tool estimates the useful anomalous correlation and anomalous signal after collecting SAD data and estimates the probability that the data set can be solved and the likely figure of merit of phasing. PMID- 26960125 TI - Radiation damage and derivatization in macromolecular crystallography: a structure factor's perspective. AB - During, or even after, data collection the presence and effects of radiation damage in macromolecular crystallography may not always be immediately obvious. Despite this, radiation damage is almost always present, with site-specific damage occurring on very short time (dose) scales well before global damage becomes apparent. A result of both site-specific radiation damage and derivatization is a change in the relative intensity of reflections. The size and approximate rate of onset of X-ray-induced transformations is compared with the changes expected from derivatization, and strategies for minimizing radiation damage are discussed. PMID- 26960126 TI - Radiation-damage-induced phasing: a case study using UV irradiation with light emitting diodes. AB - Exposure to X-rays, high-intensity visible light or ultraviolet radiation results in alterations to protein structure such as the breakage of disulfide bonds, the loss of electron density at electron-rich centres and the movement of side chains. These specific changes can be exploited in order to obtain phase information. Here, a case study using insulin to illustrate each step of the radiation-damage-induced phasing (RIP) method is presented. Unlike a traditional X-ray-induced damage step, specific damage is introduced via ultraviolet light emitting diodes (UV-LEDs). In contrast to UV lasers, UV-LEDs have the advantages of small size, low cost and relative ease of use. PMID- 26960127 TI - Data collection with a tailored X-ray beam size at 2.69 A wavelength (4.6 keV): sulfur SAD phasing of Cdc23(Nterm). AB - The capability to reach wavelengths of up to 3.1 A at the newly established EMBL P13 beamline at PETRA III, the new third-generation synchrotron at DESY in Hamburg, provides the opportunity to explore very long wavelengths to harness the sulfur anomalous signal for phase determination. Data collection at lambda = 2.69 A (4.6 keV) allowed the crystal structure determination by sulfur SAD phasing of Cdc23(Nterm), a subunit of the multimeric anaphase-promoting complex (APC/C). At this energy, Cdc23(Nterm) has an expected Bijvoet ratio<|Fanom|>/of 2.2%, with 282 residues, including six cysteines and five methionine residues, and two molecules in the asymmetric unit (65.4 kDa; 12 Cys and ten Met residues). Selectively illuminating two separate portions of the same crystal with an X-ray beam of 50 um in diameter allowed crystal twinning to be overcome. The crystals diffracted to 3.1 A resolution, with unit-cell parameters a = b = 61.2, c = 151.5 A, and belonged to space group P43. The refined structure to 3.1 A resolution has an R factor of 18.7% and an Rfree of 25.9%. This paper reports the structure solution, related methods and a discussion of the instrumentation. PMID- 26960128 TI - Facilitating best practices in collecting anomalous scattering data for de novo structure solution at the ESRF Structural Biology Beamlines. AB - The constant evolution of synchrotron structural biology beamlines, the viability of screening protein crystals for a wide range of heavy-atom derivatives, the advent of efficient protein labelling and the availability of automatic data processing and structure-solution pipelines have combined to make de novo structure solution in macromolecular crystallography a less arduous task. Nevertheless, the collection of diffraction data of sufficient quality for experimental phasing is still a difficult and crucial step. Here, some examples of good data-collection practice for projects requiring experimental phasing are presented and recent developments at the ESRF Structural Biology beamlines that have facilitated these are illustrated. PMID- 26960129 TI - Data-collection strategy for challenging native SAD phasing. AB - Recent improvements in data-collection strategies have pushed the limits of native SAD (single-wavelength anomalous diffraction) phasing, a method that uses the weak anomalous signal of light elements naturally present in macromolecules. These involve the merging of multiple data sets from either multiple crystals or from a single crystal collected in multiple orientations at a low X-ray dose. Both approaches yield data of high multiplicity while minimizing radiation damage and systematic error, thus ensuring accurate measurements of the anomalous differences. Here, the combined use of these two strategies is described to solve cases of native SAD phasing that were particular challenges: the integral membrane diacylglycerol kinase (DgkA) with a low Bijvoet ratio of 1% and the large 200 kDa complex of the CRISPR-associated endonuclease (Cas9) bound to guide RNA and target DNA crystallized in the low-symmetry space group C2. The optimal native SAD data-collection strategy based on systematic measurements performed on the 266 kDa multiprotein/multiligand tubulin complex is discussed. PMID- 26960130 TI - In-vacuum long-wavelength macromolecular crystallography. AB - Structure solution based on the weak anomalous signal from native (protein and DNA) crystals is increasingly being attempted as part of synchrotron experiments. Maximizing the measurable anomalous signal by collecting diffraction data at longer wavelengths presents a series of technical challenges caused by the increased absorption of X-rays and larger diffraction angles. A new beamline at Diamond Light Source has been built specifically for collecting data at wavelengths beyond the capability of other synchrotron macromolecular crystallography beamlines. Here, the theoretical considerations in support of the long-wavelength beamline are outlined and the in-vacuum design of the endstation is discussed, as well as other hardware features aimed at enhancing the accuracy of the diffraction data. The first commissioning results, representing the first in-vacuum protein structure solution, demonstrate the promising potential of the beamline. PMID- 26960131 TI - Initiating heavy-atom-based phasing by multi-dimensional molecular replacement. AB - To obtain an electron-density map from a macromolecular crystal the phase problem needs to be solved, which often involves the use of heavy-atom derivative crystals and concomitant heavy-atom substructure determination. This is typically performed by dual-space methods, direct methods or Patterson-based approaches, which however may fail when only poorly diffracting derivative crystals are available. This is often the case for, for example, membrane proteins. Here, an approach for heavy-atom site identification based on a molecular-replacement parameter matrix (MRPM) is presented. It involves an n-dimensional search to test a wide spectrum of molecular-replacement parameters, such as different data sets and search models with different conformations. Results are scored by the ability to identify heavy-atom positions from anomalous difference Fourier maps. The strategy was successfully applied in the determination of a membrane-protein structure, the copper-transporting P-type ATPase CopA, when other methods had failed to determine the heavy-atom substructure. MRPM is well suited to proteins undergoing large conformational changes where multiple search models should be considered, and it enables the identification of weak but correct molecular replacement solutions with maximum contrast to prime experimental phasing efforts. PMID- 26960132 TI - Progress in low-resolution ab initio phasing with CrowdPhase. AB - Ab initio phasing by direct computational methods in low-resolution X-ray crystallography is a long-standing challenge. A common approach is to consider it as two subproblems: sampling of phase space and identification of the correct solution. While the former is amenable to a myriad of search algorithms, devising a reliable target function for the latter problem remains an open question. Here, recent developments in CrowdPhase, a collaborative online game powered by a genetic algorithm that evolves an initial population of individuals with random genetic make-up (i.e. random phases) each expressing a phenotype in the form of an electron-density map, are presented. Success relies on the ability of human players to visually evaluate the quality of these maps and, following a Darwinian survival-of-the-fittest concept, direct the search towards optimal solutions. While an initial study demonstrated the feasibility of the approach, some important crystallographic issues were overlooked for the sake of simplicity. To address these, the new CrowdPhase includes consideration of space-group symmetry, a method for handling missing amplitudes, the use of a map correlation coefficient as a quality metric and a solvent-flattening step. Performances of this installment are discussed for two low-resolution test cases based on bona fide diffraction data. PMID- 26960133 TI - Viral protein requirements for assembly and release of human parainfluenza virus type 3 virus-like particles. AB - To understand the roles of human parainfluenza virus 3 (HPIV3) proteins in assembly and release, viral proteins were expressed individually and in combination in 293T cells. Expression of the matrix (M) protein triggered release of enveloped, matrix-containing virus-like particles (VLPs) from cells. When M was co-expressed with the nucleocapsid (N), fusion (F) or haemagglutinin neuraminidase (HN) proteins, VLPs that contained M+N, M+F and M+HN, respectively, were generated, suggesting that M can independently interact with each protein to facilitate assembly and release. Additionally, expression of N protein enabled incorporation of the phosphoprotein (P) into VLPs, likely due to known N-P interactions. Finally, the HPIV3 C protein did not enhance VLP release, in contrast to observations with the related Sendai virus. These findings reinforce the central importance of the M protein in virus assembly and release, but also illustrate the variable roles of other paramyxovirus proteins during these processes. PMID- 26960135 TI - Strategic Sexual Signals: Women's Display versus Avoidance of the Color Red Depends on the Attractiveness of an Anticipated Interaction Partner. AB - The color red has special meaning in mating-relevant contexts. Wearing red can enhance perceptions of women's attractiveness and desirability as a potential romantic partner. Building on recent findings, the present study examined whether women's (N = 74) choice to display the color red is influenced by the attractiveness of an expected opposite-sex interaction partner. Results indicated that female participants who expected to interact with an attractive man displayed red (on clothing, accessories, and/or makeup) more often than a baseline consisting of women in a natural environment with no induced expectation. In contrast, when women expected to interact with an unattractive man, they eschewed red, displaying it less often than in the baseline condition. Findings are discussed with respect to evolutionary and cultural perspectives on mate evaluation and selection. PMID- 26960136 TI - Unpacking the mechanisms captured by a correlative species distribution model to improve predictions of climate refugia. AB - Climate refugia are regions that animals can retreat to, persist in and potentially then expand from under changing environmental conditions. Most forecasts of climate change refugia for species are based on correlative species distribution models (SDMs) using long-term climate averages, projected to future climate scenarios. Limitations of such methods include the need to extrapolate into novel environments and uncertainty regarding the extent to which proximate variables included in the model capture processes driving distribution limits (and thus can be assumed to provide reliable predictions under new conditions). These limitations are well documented; however, their impact on the quality of climate refugia predictions is difficult to quantify. Here, we develop a detailed bioenergetics model for the koala. It indicates that range limits are driven by heat-induced water stress, with the timing of rainfall and heat waves limiting the koala in the warmer parts of its range. We compare refugia predictions from the bioenergetics model with predictions from a suite of competing correlative SDMs under a range of future climate scenarios. SDMs were fitted using combinations of long-term climate and weather extremes variables, to test how well each set of predictions captures the knowledge embedded in the bioenergetics model. Correlative models produced broadly similar predictions to the bioenergetics model across much of the species' current range - with SDMs that included weather extremes showing highest congruence. However, predictions in some regions diverged significantly when projecting to future climates due to the breakdown in correlation between climate variables. We provide unique insight into the mechanisms driving koala distribution and illustrate the importance of subtle relationships between the timing of weather events, particularly rain relative to hot-spells, in driving species-climate relationships and distributions. By unpacking the mechanisms captured by correlative SDMs, we can increase our certainty in forecasts of climate change impacts on species. PMID- 26960137 TI - Correction: Regulation of Tyrosine Phosphatase STEP61 by Protein Kinase A during Motor Skill Learning in Mice. PMID- 26960134 TI - Acellularization-Induced Changes in Tensile Properties Are Organ Specific - An In Vitro Mechanical and Structural Analysis of Porcine Soft Tissues. AB - INTRODUCTION: Though xenogeneic acellular scaffolds are frequently used for surgical reconstruction, knowledge of their mechanical properties is lacking. This study compared the mechanical, histological and ultrastructural properties of various native and acellular specimens. MATERIALS AND METHODS: Porcine esophagi, ureters and skin were tested mechanically in a native or acellular condition, focusing on the elastic modulus, ultimate tensile stress and maximum strain. The testing protocol for soft tissues was standardized, including the adaption of the tissue's water content and partial plastination to minimize material slippage as well as templates for normed sample dimensions and precise cross-section measurements. The native and acellular tissues were compared at the microscopic and ultrastructural level with a focus on type I collagens. RESULTS: Increased elastic modulus and ultimate tensile stress values were quantified in acellular esophagi and ureters compared to the native condition. In contrast, these values were strongly decreased in the skin after acellularization. Acellularization-related decreases in maximum strain were found in all tissues. Type I collagens were well-preserved in these samples; however, clotting and a loss of cross-linking type I collagens was observed ultrastructurally. Elastins and fibronectins were preserved in the esophagi and ureters. A loss of the epidermal layer and decreased fibronectin content was present in the skin. DISCUSSION: Acellularization induces changes in the tensile properties of soft tissues. Some of these changes appear to be organ specific. Loss of cross-linking type I collagen may indicate increased mechanical strength due to decreasing transverse forces acting upon the scaffolds, whereas fibronectin loss may be related to decreased load-bearing capacity. Potentially, the alterations in tissue mechanics are linked to organ function and to the interplay of cells and the extracellular matrix, which is different in hollow organs when compared to skin. PMID- 26960140 TI - Hsp72 (HSPA1A) Prevents Human Islet Amyloid Polypeptide Aggregation and Toxicity: A New Approach for Type 2 Diabetes Treatment. AB - Type 2 diabetes is a growing public health concern and accounts for approximately 90% of all the cases of diabetes. Besides insulin resistance, type 2 diabetes is characterized by a deficit in beta-cell mass as a result of misfolded human islet amyloid polypeptide (h-IAPP) which forms toxic aggregates that destroy pancreatic beta-cells. Heat shock proteins (HSP) play an important role in combating the unwanted self-association of unfolded proteins. We hypothesized that Hsp72 (HSPA1A) prevents h-IAPP aggregation and toxicity. In this study, we demonstrated that thermal stress significantly up-regulates the intracellular expression of Hsp72, and prevents h-IAPP toxicity against pancreatic beta-cells. Moreover, Hsp72 (HSPA1A) overexpression in pancreatic beta-cells ameliorates h-IAPP toxicity. To test the hypothesis that Hsp72 (HSPA1A) prevents aggregation and fibril formation, we established a novel C. elegans model that expresses the highly amyloidogenic human pro-IAPP (h-proIAPP) that is implicated in amyloid formation and beta-cell toxicity. We demonstrated that h-proIAPP expression in body-wall muscles, pharynx and neurons adversely affects C. elegans development. In addition, we demonstrated that h-proIAPP forms insoluble aggregates and that the co-expression of h-Hsp72 in our h-proIAPP C. elegans model, increases h proIAPP solubility. Furthermore, treatment of transgenic h-proIAPP C. elegans with ADAPT-232, known to induce the expression and release of Hsp72 (HSPA1A), significantly improved the growth retardation phenotype of transgenic worms. Taken together, this study identifies Hsp72 (HSPA1A) as a potential treatment to prevent beta-cell mass decline in type 2 diabetic patients and establishes for the first time a novel in vivo model that can be used to select compounds that attenuate h-proIAPP aggregation and toxicity. PMID- 26960145 TI - Exposure Estimation for Risk Assessment of the Phthalate Incident in Taiwan. AB - BACKGROUND: In May 2011, di(2-ethylhexyl) phthalates (DEHP) and, to a lesser extent, di-iso-nonyl phthalate (DiNP) were found to have been illegally used for many years in Taiwan as clouding agents in foods including sports drinks, juice beverages, tea drinks, fruit jam/nectar/jelly, and health or nutrient supplements. OBJECTIVE: To estimate the DEHP exposure for the study participants for the follow-up epidemiological study and health risk assessment. METHODS: A total of 347 individuals possibly highly exposed to phthalate-tainted foods participated in the study. Exposure assessment was performed based on the participants' responses to a structured questionnaire, self-report of exposure history, urinary metabolite concentrations, and DEHP concentration information in 2449 food records. A Bayesian statistical approach using Markov chain Monte Carlo simulation was employed to deal with the uncertainties in the DEHP concentrations of the contaminated foods and the participants' likelihood of being exposed. RESULTS: An estimated 37% and 15% of children younger than 12 years old were exposed to DEHP at medium (20-50 MUg / kg_bw / day) and high AvDIs (50-100 MUg / kg_bw / day), respectively, prior to the episode (9% and 3% in adults, respectively). Moreover, 11% of children and 1% of adults were highly exposed (> 100 MUg / kg_bw / day), with a maximum of 414.1 MUg / kg_bw / day and 126.4 MUg / kg_bw / day, respectively. CONCLUSIONS: The phthalate exposure-associated adverse health effects for these participants warrant further investigation. The estimation procedure may be applied to other exposure assessment with various sources of uncertainties. PMID- 26960147 TI - Correction: Modular Coils with Low Hydrogen Content Especially for MRI of Dry Solids. PMID- 26960146 TI - Association among Dietary Flavonoids, Flavonoid Subclasses and Ovarian Cancer Risk: A Meta-Analysis. AB - BACKGROUND: Previous studies have indicated that intake of dietary flavonoids or flavonoid subclasses is associated with the ovarian cancer risk, but presented controversial results. Therefore, we conducted a meta-analysis to derive a more precise estimation of these associations. METHODS: We performed a search in PubMed, Google Scholar and ISI Web of Science from their inception to April 25, 2015 to select studies on the association among dietary flavonoids, flavonoid subclasses and ovarian cancer risk. The information was extracted by two independent authors. We assessed the heterogeneity, sensitivity, publication bias and quality of the articles. A random-effects model was used to calculate the pooled risk estimates. RESULTS: Five cohort studies and seven case-control studies were included in the final meta-analysis. We observed that intake of dietary flavonoids can decrease ovarian cancer risk, which was demonstrated by pooled RR (RR = 0.82, 95% CI = 0.68-0.98). In a subgroup analysis by flavonoid subtypes, the ovarian cancer risk was also decreased for isoflavones (RR = 0.67, 95% CI = 0.50-0.92) and flavonols (RR = 0.68, 95% CI = 0.58-0.80). While there was no compelling evidence that consumption of flavones (RR = 0.86, 95% CI = 0.71 1.03) could decrease ovarian cancer risk, which revealed part sources of heterogeneity. The sensitivity analysis indicated stable results, and no publication bias was observed based on the results of Funnel plot analysis and Egger's test (p = 0.26). CONCLUSIONS: This meta-analysis suggested that consumption of dietary flavonoids and subtypes (isoflavones, flavonols) has a protective effect against ovarian cancer with a reduced risk of ovarian cancer except for flavones consumption. Nevertheless, further investigations on a larger population covering more flavonoid subclasses are warranted. PMID- 26960148 TI - Exogenous Thyropin from p41 Invariant Chain Diminishes Cysteine Protease Activity and Affects IL-12 Secretion during Maturation of Human Dendritic Cells. AB - Dendritic cells (DC) play a pivotal role as antigen presenting cells (APC) and their maturation is crucial for effectively eliciting an antigen-specific immune response. The p41 splice variant of MHC class II-associated chaperone, called invariant chain p41 Ii, contains an amino acid sequence, the p41 fragment, which is a thyropin-type inhibitor of proteolytic enzymes. The effects of exogenous p41 fragment and related thyropin inhibitors acting on human immune cells have not been reported yet. In this study we demonstrate that exogenous p41 fragment can enter the endocytic pathway of targeted human immature DC. Internalized p41 fragment has contributed to the total amount of the immunogold labelled p41 Ii specific epitope, as quantified by transmission electron microscopy, in particular in late endocytic compartments with multivesicular morphology where antigen processing and binding to MHC II take place. In cell lysates of treated immature DC, diminished enzymatic activity of cysteine proteases has been confirmed. Internalized exogenous p41 fragment did not affect the perinuclear clustering of acidic cathepsin S-positive vesicles typical of mature DC. p41 fragment is shown to interfere with the nuclear translocation of NF-kappaB p65 subunit in LPS-stimulated DC. p41 fragment is also shown to reduce the secretion of interleukin-12 (IL-12/p70) during the subsequent maturation of treated DC. The inhibition of proteolytic activity of lysosomal cysteine proteases in immature DC and the diminished capability of DC to produce IL-12 upon their subsequent maturation support the immunomodulatory potential of the examined thyropin from p41 Ii. PMID- 26960150 TI - Difference in Restricted Mean Survival Time for Cost-Effectiveness Analysis Using Individual Patient Data Meta-Analysis: Evidence from a Case Study. AB - OBJECTIVE: In economic evaluation, a commonly used outcome measure for the treatment effect is the between-arm difference in restricted mean survival time (rmstD). This study illustrates how different survival analysis methods can be used to estimate the rmstD for economic evaluation using individual patient data (IPD) meta-analysis. Our aim was to study if/how the choice of a method impacts on cost-effectiveness results. METHODS: We used IPD from the Meta-Analysis of Radiotherapy in Lung Cancer concerning 2,000 patients with locally advanced non small cell lung cancer, included in ten trials. We considered methods either used in the field of meta-analysis or in economic evaluation but never applied to assess the rmstD for economic evaluation using IPD meta-analysis. Methods were classified into two approaches. With the first approach, the rmstD is estimated directly as the area between the two pooled survival curves. With the second approach, the rmstD is based on the aggregation of the rmstDs estimated in each trial. RESULTS: The average incremental cost-effectiveness ratio (ICER) and acceptability curves were sensitive to the method used to estimate the rmstD. The estimated rmstDs ranged from 1.7 month to 2.5 months, and mean ICERs ranged from ? 24,299 to ? 34,934 per life-year gained depending on the chosen method. At a ceiling ratio of ? 25,000 per life year-gained, the probability of the experimental treatment being cost-effective ranged from 31% to 68%. CONCLUSIONS: This case study suggests that the method chosen to estimate the rmstD from IPD meta-analysis is likely to influence the results of cost-effectiveness analyses. PMID- 26960151 TI - The GPlates Portal: Cloud-Based Interactive 3D Visualization of Global Geophysical and Geological Data in a Web Browser. AB - The pace of scientific discovery is being transformed by the availability of 'big data' and open access, open source software tools. These innovations open up new avenues for how scientists communicate and share data and ideas with each other and with the general public. Here, we describe our efforts to bring to life our studies of the Earth system, both at present day and through deep geological time. The GPlates Portal (portal.gplates.org) is a gateway to a series of virtual globes based on the Cesium Javascript library. The portal allows fast interactive visualization of global geophysical and geological data sets, draped over digital terrain models. The globes use WebGL for hardware-accelerated graphics and are cross-platform and cross-browser compatible with complete camera control. The globes include a visualization of a high-resolution global digital elevation model and the vertical gradient of the global gravity field, highlighting small scale seafloor fabric such as abyssal hills, fracture zones and seamounts in unprecedented detail. The portal also features globes portraying seafloor geology and a global data set of marine magnetic anomaly identifications. The portal is specifically designed to visualize models of the Earth through geological time. These space-time globes include tectonic reconstructions of the Earth's gravity and magnetic fields, and several models of long-wavelength surface dynamic topography through time, including the interactive plotting of vertical motion histories at selected locations. The globes put the on-the-fly visualization of massive data sets at the fingertips of end-users to stimulate teaching and learning and novel avenues of inquiry. PMID- 26960149 TI - HapX Mediates Iron Homeostasis in the Pathogenic Dermatophyte Arthroderma benhamiae but Is Dispensable for Virulence. AB - For many pathogenic fungi, siderophore-mediated iron acquisition is essential for virulence. The process of siderophore production and further mechanisms to adapt to iron limitation are strictly controlled in fungi to maintain iron homeostasis. Here we demonstrate that the human pathogenic dermatophyte Arthroderma benhamiae produces the hydroxamate siderophores ferricrocin and ferrichrome C. Additionally, we show that the iron regulator HapX is crucial for the adaptation to iron starvation and iron excess, but is dispensable for virulence of A. benhamiae. Deletion of hapX caused downregulation of siderophore biosynthesis genes leading to a decreased production of siderophores during iron starvation. Furthermore, HapX was required for transcriptional repression of genes involved in iron-dependent pathways during iron-depleted conditions. Additionally, the DeltahapX mutant of A. benhamiae was sensitive to high-iron concentrations indicating that HapX also contributes to iron detoxification. In contrast to other pathogenic fungi, HapX of A. benhamiae was redundant for virulence and a DeltahapX mutant was still able to infect keratinized host tissues in vitro. Our findings underline the highly conserved role of the transcription factor HapX for maintaining iron homeostasis in ascomycetous fungi but, unlike in many other human and plant pathogenic fungi, HapX of A. benhamiae is not a virulence determinant. PMID- 26960152 TI - Health and academic success: A look at the challenges of first-generation community college students. AB - BACKGROUND: Community colleges in the United States serve more than six million students and are the gateway to postsecondary education for individuals from typically underserved populations such as low-income, ethnic minorities, and first-generation college students. First-generation college students are defined as students whose adoptive or natural parents' highest level of education was a high school diploma or less. Postsecondary education has the potential to reduce both health and socioeconomic disparities. First-generation community college students face significant economic, social, and cultural barriers to academic success and are the most at risk for "dropping-out." PURPOSE: The purpose of this brief report was to explore what is known about social, psychological, and physical factors that impede first-generation community college students' academic success. CONCLUSION: Little is known about potential health and psychological barriers experienced by first-generation community college students that impact academic achievement. Advanced practice nurses (APNs) on community college campuses are in the ideal position to identify and treat health issues, and conduct much-needed research into these areas. College health centers are an important practice setting for APNs to provide direct care to students as well as influence college policies that improve student health, well-being, and promote academic success. PMID- 26960153 TI - Characterization of the Kenaf (Hibiscus cannabinus) Global Transcriptome Using Illumina Paired-End Sequencing and Development of EST-SSR Markers. AB - Kenaf (Hibiscus cannabinus L.) is an economically important natural fiber crop grown worldwide. However, only 20 expressed tag sequences (ESTs) for kenaf are available in public databases. The aim of this study was to develop large-scale simple sequence repeat (SSR) markers to lay a solid foundation for the construction of genetic linkage maps and marker-assisted breeding in kenaf. We used Illumina paired-end sequencing technology to generate new EST-simple sequences and MISA software to mine SSR markers. We identified 71,318 unigenes with an average length of 1143 nt and annotated these unigenes using four different protein databases. Overall, 9324 complementary pairs were designated as EST-SSR markers, and their quality was validated using 100 randomly selected SSR markers. In total, 72 primer pairs reproducibly amplified target amplicons, and 61 of these primer pairs detected significant polymorphism among 28 kenaf accessions. Thus, in this study, we have developed large-scale SSR markers for kenaf, and this new resource will facilitate construction of genetic linkage maps, investigation of fiber growth and development in kenaf, and also be of value to novel gene discovery and functional genomic studies. PMID- 26960154 TI - Determination of chlorinated polycyclic aromatic hydrocarbons in water by solid phase extraction coupled with gas chromatography and mass spectrometry. AB - Given the potential risks of chlorinated polycyclic aromatic hydrocarbons, the analysis of their presence in water is very urgent. We have developed a novel procedure for determining chlorinated polycyclic aromatic hydrocarbons in water based on solid-phase extraction coupled with gas chromatography and mass spectrometry. The extraction parameters of solid-phase extraction were optimized in detail. Under the optimal conditions, the proposed method showed wide linear ranges (1.0-1000 ng/L) with correlation coefficients ranging from 0.9952 to 0.9998. The limits of detection and the limits of quantification were in the range of 0.015-0.591 and 0.045-1.502 ng/L, respectively. Recoveries ranged from 82.5 to 102.6% with relative standard deviations below 9.2%. The obtained method was applied successfully to the determination of chlorinated polycyclic aromatic hydrocarbons in real water samples. Most of the chlorinated polycyclic aromatic hydrocarbons were detected and 1-monochloropyrene was predominant in the studied water samples. This is the first report of chlorinated polycyclic aromatic hydrocarbons in water samples in China. The toxic equivalency quotients of chlorinated polycyclic aromatic hydrocarbons in the studied tap water were 9.95 ng the toxic equivalency quotient m(-3) . 9,10-Dichloroanthracene and 1 monochloropyrene accounted for the majority of the total toxic equivalency quotients of chlorinated polycyclic aromatic hydrocarbons in tap water. PMID- 26960156 TI - Landscape Alteration by Pre-Pottery Neolithic Communities in the Southern Levant The Kaizer Hilltop Quarry, Israel. AB - This study focuses on Kaizer Hill, a quarry site located in the vicinity of the city of Modiin where remains of a single prehistoric cultural entity assigned to the Pre-Pottery Neolithic A were discovered. A systematic survey revealed that large-scale quarrying activities have left damage markings on the bedrock of the Hilltop and its slopes. We aim to present here our findings from the Hilltop, which are concerned with the human impact on rock surfaces and the lithic artifacts retrieved during the survey. It is evident that the Pre-Pottery Neolithic A inhabitants of the area changed their landscape forever, "stripping" the caliche surface and penetrating it in search of flint bedded in the bedrock. PMID- 26960155 TI - Invagination of Ectodermal Placodes Is Driven by Cell Intercalation-Mediated Contraction of the Suprabasal Tissue Canopy. AB - Ectodermal organs such as teeth, hair follicles, and mammary glands begin their development as placodes. These are local epithelial thickenings that invaginate into mesenchymal space. There is currently little mechanistic understanding of the cellular processes driving the early morphogenesis of these organs and of why they lead to invagination rather than simple tissue thickening. Here, we show that placode invagination depends on horizontal contraction of superficial layers of cells that form a shrinking and thickening canopy over underlying epithelial cells. This contraction occurs by cell intercalation and is mechanically coupled to the basal layer by peripheral basal cells that extend apically and centripetally while remaining attached to the basal lamina. This process is topologically analogous to well-studied apical constriction mechanisms, but very different from them both in scale and molecular mechanism. Mechanical cell-cell coupling is propagated through the tissue via E-cadherin junctions, which in turn depend on tissue-wide tension. We further present evidence that this mechanism is conserved among different ectodermal organs and is, therefore, a novel and fundamental morphogenetic motif widespread in embryonic development. PMID- 26960157 TI - Antipsychotic Drugs Differentially Affect mRNA Expression of Genes Encoding the Neuregulin 1-Downstream ErbB4-PI3K Pathway. AB - BACKGROUND/AIMS: The PIK3CD gene encodes the delta catalytic subunit of phosphoinositide 3-kinase (PI3K), an element of the neuregulin 1-downstream ErbB4 PI3K signaling pathway, which was recently identified as a molecular target for the treatment of schizophrenia. The aim of the study was to examine the effect of haloperidol (HALO), clozapine (CLO), olanzapine (OLA), quetiapine (QUE) and amisulpride (AMI) on the mRNA and protein expression of genes encoding the elements of ErbB4-PI3K pathway, in a human central nervous system cell line. METHODS: The U-87MG human glioblastoma cell line was used as an experimental model. Quantitative polymerase chain reaction was used to examine the expression of mRNA and enzyme-linked immunosorbent assay for protein expression. RESULTS: At concentrations reached in clinical settings in the brain, CLO, as well as OLA and QUE to a lesser extent, but not AMI and probably not HALO, decreased the mRNA expression of PIK3CD. Protein expression of the gene did not confirm the mRNA expression profile. CONCLUSIONS: The tested antipsychotic drugs (APDs) in the U 87MG glioblastoma cell line differentially regulates the mRNA expression of PIK3CD; however, the protein expression does not confirm these findings. The results of the study may help deepen the understanding of the mechanism of action of APDs. PMID- 26960158 TI - Ultrastructural investigation of the protective effects of propolis on bleomycin induced pulmonary fibrosis. AB - We investigated the antioxidant and anti-inflammatory effects of propolis on bleomycin induced lung fibrosis and compared these effects to prednisolone treatment. Forty rats were divided into four groups of ten: group 1 was treated with intratracheal infusion of 0.2 ml physiological saline followed by daily treatment with 0.5 ml physiological saline for 20 days. In the remaining groups (groups 2 - 4), 5 mg/kg bleomycin was given via the trachea. Rats in group 2 were given 0.5 ml physiological saline. Rats in group 3 were treated with 100 mg/kg propolis, and 10 mg/kg prednisolone was given to rats in group 4. The treatments for all groups were continued for 20 days. On postoperative day 21, blood and lung samples were taken for biochemistry, histopathology and electron microscopy evaluation. We compared oxidative stress parameters and found lower malondialdehyde and myeloperoxidase levels, and higher total sulfhydryl levels and catalase activities for the bleomycin + propolis group than for the bleomycin and bleomycin + prednisolone groups. The highest mean fibrosis score was detected in the bleomycin group. Although the mean fibrosis scores of the bleomycin + propolis and bleomycin + prednisolone groups were not significantly different, electron microscopy revealed that propolis diminished bleomycin induced lung fibrosis more effectively than prednisolone. The effects of propolis might be due to its potent antioxidant and anti-inflammatory properties. PMID- 26960159 TI - Molecular Phylogeny and Morphological Analysis Support a New Species and New Synonymy in Iranian Astragalus (Leguminosae). AB - As a result of a taxonomic and phylogenetic revision of Astragalus section Hymenostegis we identified a new species of Astragalus from northwestern Iran, namely A. remotispicatus spec. nov., which is described and illustrated here. It is morphologically similar to A. karl-heinzii in possessing a lax inflorescence. Phylogenetic inference of the nuclear ribosomal DNA internal transcribed spacer (ITS) region support A. remotispicatus as a clearly distinct species within the lax-inflorescence group of this section. Also the placement of A. sciureus var. subsessilis was found to be wrong and this taxon should be treated as a synonym within A. kohrudicus. PMID- 26960161 TI - Effects of nucleus accumbens oxytocin and its antagonist on social approach behavior. AB - Severe impairment of social interaction is a core symptom of numerous psychiatric disorders. Oxytocin (OT) has been shown to be involved in various aspects of social behavior related to reproduction, but little is known about its effects on nonreproductive social interaction between adults or the neuroanatomical location where OT exerts its action. Here, we examined the nucleus accumbens, a region of the brain containing high levels of the oxytocin receptor (OTR) and comprising an important node in the neural circuitry possibly related to social interaction. Behavioral effects of a local microinfusion of OT (0.1, 1, and 10 ng/side) and an oxytocin receptor antagonist (OTR-A) (1, 10, and 100 ng/side) were evaluated in naturally high social and low social female and male monogamous mandarin voles (Microtus mandarinus) using the social preference paradigm and open-field tests. The results showed that administration of 1 ng/side OT increased social preference; however, this effect was not apparent at lower or higher doses. OT did not alter anxiety-like behavior or total locomotion. Microinfusions of a selective OTR-A at 10 and 100 ng doses reduced social approach behavior; a dose of 1 ng had no effect. In conclusion, our results suggest that accumbal OT and OTR-A regulate social preferences in voles in a dose-dependent manner. PMID- 26960162 TI - GM1 ganglioside reverses the cognitive deficits induced by MK801 in mice. AB - Cognitive deficits are core symptoms of schizophrenia, but effective treatments are still lacking. Previous studies have reported that the brain-derived neurotrophic factor (BDNF) signaling is closely involved in learning and memory. Monosialotetrahexosylganglioside (GM1) is a ganglioside with wide-ranging pharmacologic effects that enhances the BDNF signaling cascade. This study aimed to assess the effects of GM1 on schizophrenia-related cognitive impairments. A brief disruption of N-methyl-D-aspartate receptors with MK801 was used to generate the animal model for cognitive deficits in schizophrenia. It was found that MK801-treated mice showed significant deficits in memory ability compared with control mice in different behavior tests, and this was accompanied by decreased hippocampal BDNF signaling pathway. Consecutive administration of GM1 fully restored the MK801-induced cognitive deficits and the impaired BDNF signaling in the hippocampus. Furthermore, a BDNF system inhibitor abolished the effects of GM1 in the MK801 model. Taken together, our results show that GM1 could reverse the MK801-induced cognitive deficits, suggesting a potential usefulness of GM1 in treating the schizophrenia-related cognitive impairments. PMID- 26960160 TI - Delayed yet persistent effects of daily risperidone on activity in developing rats. AB - Early-life administration of risperidone, the most widely used antipsychotic drug in children, leads to persistently elevated locomotor activity in adult rats. This study determined whether and when elevated locomotor activity emerges during developmental risperidone administration. Developing and adult rats were administered daily injections of risperidone (1.0 and 3.0 mg/kg) or vehicle for 4 weeks beginning at postnatal days 14 and 74, respectively. Starting with the first injection and every 7 days thereafter, locomotor activity was measured immediately after the injection and 20 min before the next day's injection. Activity was also recorded 1 week after the final injection. Risperidone markedly decreased locomotor activity in developing and adult rats immediately after injection. Within 24 h after their first injection, adult rats administered risperidone showed greater activity levels. In contrast, developing rats did not show compensatory hyperactivity until the beginning of the fourth week of risperidone administration. One week after the final risperidone injection, there was no evidence of hyperactivity in the adult rats maintained on risperidone, but developing rats administered risperidone, especially females, showed greater activity levels relative to vehicle-administered controls. In comparison with adult rats, the emergence of compensatory hyperactivity during long-term antipsychotic drug administration is delayed in developing rats, but persists after treatment cessation. PMID- 26960163 TI - Carotenoid intake from natural sources and colorectal cancer: a systematic review and meta-analysis of epidemiological studies. AB - Carotenoid intake from natural sources has been hypothesized to reduce the risk of colorectal cancer (CRC). The aim of this study was to systematically review the epidemiological evidence for the association between carotenoid intake from natural sources and CRC development. We carried out a systematic review and meta analysis of epidemiological studies to investigate whether the intake of specific carotenoids from natural sources, as well as combined carotenoids, is associated with the risk of CRC overall and by anatomic subsite. A comprehensive literature search of MEDLINE and Scopus databases was performed. Twenty-two articles were identified from the literature search, of which 16 were case-control studies and 6 were cohort studies. In the random-effects meta-analysis of case-control and cohort studies, we found no association between the intake of individual and total carotenoids and the risk of CRC overall and by anatomic subsite. Overall, our findings do not support a significant association between intake of specific carotenoids from dietary sources, as well as combined carotenoids, and the risk of CRC overall and by anatomic subsite. PMID- 26960164 TI - PRECIS-2 in perspective: what is next for pragmatic trials? PMID- 26960167 TI - Evolved Colloidosomes Undergoing Cell-like Autonomous Shape Oscillations with Buckling. AB - In living systems, there are many autonomous and oscillatory phenomena to sustain life, such as heart contractions and breathing. At the microscopic level, oscillatory shape deformations of cells are often observed in dynamic behaviors during cell migration and morphogenesis. In many cases, oscillatory behaviors of cells are not simplistic but complex with diverse deformations. So far, we have succeeded in developing self-oscillating polymers and gels, but complex oscillatory behaviors mimicking those of living cells have yet to be reproduced. Herein, we report a cell-like hollow sphere composed of self-oscillating microgels, that is, a colloidosome, that exhibits drastic shape oscillation in addition to swelling/deswelling oscillations driven by an oscillatory reaction. The resulting oscillatory profile waveform becomes markedly more complex than a conventional one. Especially for larger colloidosomes, multiple buckling and moving buckling points are observed to be analogous to cells. PMID- 26960166 TI - Dermal lymphatic dilation in a mouse model of alopecia areata. AB - Mouse models of various types of inflammatory skin disease are often accompanied by increased dermal angiogenesis. The C3H/HeJ inbred strain spontaneously develops alopecia areata (AA), a cell mediated autoimmune disorder that can be controllably expanded using full thickness skin grafts to young unaffected mice. This provides a reproducible and progressive model for AA in which the vascularization of the skin can be examined. Mice receiving skin grafts from AA or normal mice were evaluated at 5, 10, 15, and 20 weeks after engraftment. Lymphatics are often overlooked as they are small slit-like structures above the hair follicle that resemble artifact-like separation of collagen bundles with some fixatives. Lymphatics are easily detected using lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) by immunohistochemistry to label their endothelial cells. Using LYVE1, there were no changes in distribution or numbers of lymphatics although they were more prominent (dilated) in the mice with AA. Lyve1 transcripts were not significantly upregulated except at 10 weeks after skin grafting when clinical signs of AA first become apparent. Other genes involved with vascular growth and dilation or movement of immune cells were dysregulated, mostly upregulated. These findings emphasize aspects of AA not commonly considered and provide potential targets for therapeutic intervention. PMID- 26960168 TI - Isotype-specific glycosylation analysis of mouse IgG by LC-MS. AB - With mice being the top model organism in immunology and with Fc glycosylation being increasingly recognized as important modulator of antibody function, the time has come to take a look at the glycosylation of mouse IgG isotypes. Tryptic glycopeptides of mouse IgG1, IgG2, and IgG3 differ in mass and so these three isoforms can be easily discriminated by MS. Commercial IgG contained a rare IgG1 variant but no IgG3, which, however, was found in sera of C57BL/6 and BALB/c mice. These strains deviated with regard to IgG2a and IgG2b alleles. The Ig2a B allele was not observed in any of the four samples investigated. All a/c isotypes contain the same glycopeptide sequence, which deviates from that of IgG2b by containing Leu instead of Ile. The Leu/Ile glycopeptide variants were separated by RP chromatography and the order of elution was determined. The major glycoforms on all isotypes were fucosylated with no and one galactose (GnGnF and GnAF) followed by fully galactosylated AAF and smaller amounts of mono- and disialylated N-glycans. In the commercial serum pool, the relative ratios of glycans differed between isotypes. Sialic acid exclusively occurred as N glycolylneuraminic acid. Fucosylation was essentially complete. No bisected and no alpha1,3-galactosylated glycans were found. PMID- 26960169 TI - Growth Hormone Deficiency in Prepubertal Children: Predictive Markers of Cardiovascular Disease. AB - BACKGROUND: Cardiovascular (CV) risk factors have been identified in adults with untreated growth hormone deficiency (GHD). Existing evidence suggests that the development of the atheromatous plaque begins early in childhood. Previous reports have shown that GHD children are prone to increased CV risks including impaired cardiac function, dyslipidemia and abnormalities in body composition. Recent studies in epigenetics and metabolomics have defined specific fingerprints that might be associated with an increased risk of CV disease. AIM: The aim of this review is to point out the most significant biochemical and clinical predictive markers of CV disease in prepubertal children and to evaluate the effect of recombinant human growth hormone therapy on most of these alterations. The novel findings in epigenetics and metabolomics are also reviewed, with a particular focus on translating them into clinical practice. PMID- 26960170 TI - Clinical Practice Recommendations for the Management and Prevention of Cisplatin Induced Hearing Loss Using Pharmacogenetic Markers. AB - Currently no pharmacogenomics-based criteria exist to guide clinicians in identifying individuals who are at risk of hearing loss from cisplatin-based chemotherapy. This review summarizes findings from pharmacogenomic studies that report genetic polymorphisms associated with cisplatin-induced hearing loss and aims to (1) provide up-to-date information on new developments in the field, (2) provide recommendations for the use of pharmacogenetic testing in the prevention, assessment, and management of cisplatin-induced hearing loss in children and adults, and (3) identify knowledge gaps to direct and prioritize future research. These practice recommendations for pharmacogenetic testing in the context of cisplatin-induced hearing loss reflect a review and evaluation of recent literature, and are designed to assist clinicians in providing optimal clinical care for patients receiving cisplatin-based chemotherapy. PMID- 26960171 TI - Severe Colonic Stricture in Immunosuppressed Patient With Chronic CMV Colitis. PMID- 26960172 TI - Noninvasive Assessment of Nonalcoholic Steatohepatitis and Nonalcoholic Steatohepatitis-Related Fibrosis: Is There a Role for Cytokeratin 18? PMID- 26960173 TI - Are We Overdoing Pediatric Lower Gastrointestinal Endoscopy? AB - INTRODUCTION: Lower gastrointestinal endoscopy (LGIE)/colonoscopy is frequently performed for rectal bleeding, recurrent abdominal pain, and the diagnosis of inflammatory bowel disease (IBD). Although these are common indications, the causes of isolated rectal bleeding and recurrent abdominal pain in the otherwise well child have not been described. METHODS: A retrospective analysis of patients who had had an LGIE/colonoscopy from January 2001 to December 2010 was performed. The following data were collected: demographic data, indication, distance reached, macroscopic findings, microscopic findings, diagnosis, additional procedures, and complications. RESULTS: There were a total of 999 colonoscopies. The colonoscopy was normal in 390 of 999 (39%). The commonest indication for colonoscopy was a diagnosis of suspected IBD, 449 of 999 (45%). IBD was confirmed in 282 of 449 (63%), but colonoscopy was normal in 143 of 449 (32%) of suspected IBD. Colonoscopy was performed for rectal bleeding in 197 of 999 (20%) of whom 141 of 197 (72%) were normal. There were 46 (5%) colonoscopies performed for recurrent abdominal pain, which were all normal. Our completion rate to the cecum and beyond was 521 of 999 (52%). Our perforation rate during the 10 years was 0.2%. CONCLUSIONS: Colonoscopy is a safe procedure in pediatrics; however, 39% of colonoscopies in this series were normal. Many of these could have been avoided by eliminating colonoscopy in patients with recurrent abdominal pain in the absence of other clinical features, conservative management with laxatives for those with fresh blood per rectum typical of anal fissures, and fecal calprotectin screening before endoscopy in patients with suspected IBD. PMID- 26960174 TI - Identification of Circulating MicroRNAs in Biliary Atresia by Next-Generation Sequencing. AB - OBJECTIVES: Biliary atresia (BA) is an idiopathic neonatal liver disease, characterized by inflammatory and fibrotic obliteration of extrahepatic bile ducts. Therefore, reliable methods for noninvasive diagnosis are needed. The present study aimed to analyze circulating microRNAs (miRNAs) in patients with BA using next-generation sequencing for identifying novel diagnostic biomarkers. METHODS: An initial screening of miRNAs in plasma from patients with BA and healthy controls (HCs) was performed on an Illumina next-generation sequencing platform. Differential miRNAs were validated by quantitative real-time polymerase chain reaction (qPCR). Target genes and related signal transduction pathways of differential miRNAs were predicted by online software. RESULTS: In total, 146 differential miRNAs were identified by deep sequencing. Fifteen miRNAs with read counts >1000, that included 7 upregulated and 8 downregulated miRNAs, were predicted to be associated with liver fibrosis, biliary differentiation, and bile duct development. Of these, 6 miRNAs with read counts >5000 were analyzed by qPCR on an independent sample set comprising 44 patients with BA, 20 cholestatic disease controls, and 20 HCs. Two upregulated miRNAs (miR-122-5p, miR-100-5p) and 2 downregulated miRNAs (miR-140-3p, miR-126-3p) were confirmed by individual qPCR. Only miR-140-3p was significantly different from controls (P < 0.05), yielding an area under receiver operating characteristic curve of 0.75 with sensitivity of 66.7% and specificity of 79.1% at optimal threshold. CONCLUSIONS: Our findings indicate that patients with BA exhibit a distinct profile of circulating miRNAs and that plasma miR-140-3p may be a promising diagnostic biomarker for this disease. PMID- 26960176 TI - Complementary and Alternative Medicine Use in Children With Inflammatory Bowel Diseases: A Single-Center Survey. AB - OBJECTIVES: The prevalence of inflammatory bowel diseases (IBD) and use of complementary and alternative medicine (CAM) are both common and increasing. The definition of CAM therapy among both practitioners and patients is variable. The aim of our study was to update our understanding of how pediatric IBD patients use, perceive, and define CAM therapies. METHODS: We surveyed families of patients with IBD followed in the Gastroenterology Division at Nationwide Children's Hospital in summer 2014 during a routine clinic visit. The survey included questions about the following demographic and disease information; use and side effects associated with prior conventional therapies (CT); and attitudes toward, and use of CAM. RESULTS: The questionnaire was completed by 104 of 118 patients approached (14 +/- 3 years; 43% women). Patients had previously used an average of 3 CT. CAM therapy was used by 84% of patients surveyed, although only 24% of patients/families considered themselves to be using CAM. Common CAM therapies included vitamins/supplements, stress management techniques, and/or dietary changes. Factors associated with using specific CAM therapies included self-reported prior CT-related side effects (P < 0.01) and moderate/severe disease activity (P < 0.01). Most families (77%) desired to learn more about CAM. CONCLUSIONS: Patients seen in a tertiary care center for pediatric IBD frequently integrated CAM therapies into their treatment regimen. Patients with prior side effects from CT or more severe disease were more likely to use CAM. Given the high prevalence of CAM use, pediatric gastrointestinal physicians should be knowledgeable and open to discussions about CAM therapies with their patients. PMID- 26960178 TI - Creating Public Awareness of How Goats Are Reared and Milk Produced May Affect Consumer Acceptability. AB - This study evaluated whether showing a video of the different ways of raising goats for milk affected consumer acceptability. Four combinations, 2 Videos (intensive [INT] and semiextensive [SEM] system) * 2 Milk Types (semiskimmed [S] and whole [W] milk), were evaluated by 70 habitual consumers of goat milk, who scored their liking and purchase intention during blind (B), expected (E), and informed (I) acceptability sessions. In the B session, consumers tasted both milk types without information. S samples were preferred over W samples. In the E session, SEM video created high expectations in terms of milk liking and purchase intent, whereas the opposite happened when showing INT video. In the I session, consumers showed a clear preference for combinations created using SEM video, regardless of milk type. W-SEM and S-INT were worse (negative disconfirmation) and better (positive disconfirmation) than expected, respectively. A complete assimilation toward expectations occurred only for S-INT. INT video adversely affected the acceptability of S samples. Concerning purchase intent, W-SEM and S SEM were worse than expected, but the assimilation was complete only for S-SEM: SEM video increased purchase intent for S samples. PMID- 26960177 TI - Evaluation of the Physical Activity and Public Health Course for Practitioners. AB - PURPOSE: From 1996 to 2013, a 6-day Physical Activity and Public Health Course for Practitioners has been offered yearly in the United States. An evaluation was conducted to assess the impact of the course on building public health capacity for physical activity and on shaping the physical activity and public health careers of fellows since taking the courses. METHOD: An evaluation quantified time that fellows spent in different course offerings and surveyed fellows. RESULTS: From 1996 to 2012, 410 fellows attended the course, and in 2013, 186 participated in the Web-based survey (56% response rate). The number of fellows attending the course ranged from 15 to 33 yearly. From 1996 to 2012, the course averaged 38 hr of instructional time that included topics on interventions and environment/policy work to increase physical activity, program evaluation, public health research, and health disparities. The course included consultations, collaborative work, and field-based experiences. Fellows who participated in the survey agreed that the course had a positive impact on the physical activity research or practice work they did (98%), met their expectations (96%), helped them with research/practice collaborations with other physical activity professionals (96%), assisted them in conducting higher-quality interventions/programs (95%), helped increase their professional networking in the field (93%), and had a positive impact on other work they did (91%). Following the course, 66% and 56% had further contact with faculty and other fellows, respectively. CONCLUSION: The Physical Activity and Public Health Course for Practitioners made important contributions toward building the capacity of physical activity and public health practitioners. PMID- 26960179 TI - Methodological and conceptual issues regarding occupational psychosocial coronary heart disease epidemiology. AB - Overview Psychosocial occupational epidemiology has mainly focused on the demand control and, to a much lesser extent, the effort-reward-imbalance (ERI) models. These models and the strong focus on them raise some conceptual and methodological issues we will address in the following letter. The conceptual issues include the empirical confirmation of the assumptions of these models, the extent to which the focus on the demand-control and ERI models is warranted, and whether the sub-dimensions of the scales in these models have common health effects. We argue that there is a lack of empirical approval of (i) the assumptions behind both models and (ii) the focus on these models. The methodological issues include how exposure to job strain is categorized, how ERI previously has been measured, and the validity of self-reports of job strain. We argue that (i) a population independent definition of job strain is lacking, (ii) the older measurements of ERI mix exposure and effect, and (iii) we know little regarding the validity of the measurement of the psychosocial working environment. Finally, we suggest that analyses of monitoring data with a broader focus on the psychosocial working environment can be used to shed light to some of the issues raised above. Introduction In the last three decades (1, 2), psychosocial occupational epidemiology related to coronary heart disease (CHD) has mainly focused on the job-strain model, also referred to as the demand control model (3, 4). In this model, two aspects of work are deemed relevant: demands and control. Negative consequences to health are to be expected when high demands are simultaneously present with low control. This combination has been termed job strain (3, 4). Recently, there has also been increased interest in the ERI model (5, 6) which considers the level of effort relative to rewards at work: an imbalance is present when the efforts outweigh the rewards (5, 6). In longitudinal studies of CHD, there has been only a limited focus on investigating occupational psychosocial factors outside of these two models (1, 2). In this letter, we would like to raise some conceptual and methodological issues which are inherent to these two stress models but also which arise from the heavy emphasis placed on them. Conceptual issues The conceptual issues we discuss below are empirical confirmation of the assumptions of these models and to what extent the focus on the demand-control and ERI models is warranted. Investigating the assumptions of the models Both the demand-control and the ERI models are based on assumptions which have only been tested empirically to a limited extent (1, 2). We pose three specific questions: (i) Does the interaction of demands and control constitute a risk factor for CHD? (ii) Does the imbalance between effort and reward explain more variance in CHD risk than high effort and low reward alone? (iii) Do the sub-dimensions of the scales in these models have common health effects? Regarding the interaction of demands and control. The concept of the demand-control model is useful when the health risk of being exposed to job strain (simultaneous high demands and low control) differs greatly from the sum of individual health risks of being exposed solely to high demands and low control. If this interaction were not present, it would be warranted to look separately at high demands and low control. This would for instance counteract overlooking those persons exposed to low control but not high demands (known as "passive work"; 3, 4). It should be emphasized that the interaction of demands and control has only been tested in very few - underpowered - cases (1, 2). Initial support for an interaction within the demand-control model can be tentatively derived from the work of the IPD-Work Consortium (7): In a reanalysis of an earlier study (8), it was shown that while neither demands nor job control alone (appendix to 8) predicted CHD, job strain did when controlling for sex, age and socioeconomic status (SES) (9). This indicates that an interaction takes place. Controlling for SES is of high relevance - otherwise, the results point in a different direction (10). However, a formal test of interaction was not performed on the IPD-Work Consortium data. Even the IPD study itself might not have sufficient statistical power to analyze a possible interaction directly: this requires many more observations than simply looking at the main effects (2). If one is interested in investigating an interaction, more incident outcomes are often required (11). Regarding effort-reward imbalance. Similarly to the combined effect of demands and control described above, focusing on the ERI model makes sense only if the imbalance of effort and reward explains the risk of CHD over and above the effect of high efforts and low rewards. To our knowledge, this has not been verified in any longitudinal study of CHD (1, 2). Regarding the effect of sub-dimensions. Finally, using the scales of the two models (demands and control or efforts and rewards) is meaningful only if the sub-dimensions of the scales all have about equal effect sizes and signs. For example, the scale psychological demands covers the sub-dimensions work pace, role conflict and work amount while control covers both influence (decision authority) and opportunities for development (skill discretion). Do these dimensions predict the risk of CHD to equal amounts within their respective scales? For now, this has not been tested elaborately to our knowledge (1, 2, 12). Consequently, it is possible that certain risk factors in the psychosocial work environment may be overlooked due to different risk factors being merged into one scale. Is the focus on the demand control and ERI models warranted? In the past, longitudinal epidemiological research on psychosocial work characteristics and their association with the risk of CHD has mainly focused on the demand-control and - to a much lesser extent - ERI models (1). For example, in a recent review (2) covering 44 papers and including 170 analyses, 70% percent of those dealt with these models or sub dimensions thereof. Interestingly, the demand-control model alone accounted for 66% of the analyses and ERI only 4%. A further 11% of the analyses dealt with working hours, 9% with social support, 5% with job insecurity, 3% with leadership and the remaining 3% covered conflicts, justice or predictability. Maintaining the currently high degree of focus on the DC and ERI models requires evidence that job strain and ERI are by far the most important risk factors for CHD. The review by Pejtersen et al (2) has additionally pointed out that of the 44 studies mentioned above, only two - an IPD-Work Consortium study (8) and a Swedish case control study (13) - contained analyses with sufficient statistical power to detect an elevated CHD risk of 20%. These two sufficiently powered studies available as of April 2013 have led to the following conclusions: (i) job strain was found to be predictive of CHD in the IPD-Work Consortium study (8); and (ii) both low control and low social support predicted CHD in the Swedish study (13). Recently, a well-powered study on working hours (14) indicated that long working hours constitute a risk factor for CHD. Additionally, a recently published large study on job insecurity (15) is worth mentioning. While there was not sufficient power to detect a 20% increased risk due the relatively low prevalence of job insecurity, the study did have sufficient power to find a risk of 1.32 - which is the value actually found empirically (15). Summarizing the small number of well powered studies available at this time indicates that both model dimensions (job strain) as well as non-model dimensions (social support and working hours) predict CHD (8, 13-15). In this context, one should bear in mind that the variety of possible dimensions that can be considered as constituting "psychosocial work environment" is large. The latter is exemplified by a recent analysis of the psychosocial content of seven European work environment monitoring questionnaires which showed that there are 34 distinct dimensions of the psychosocial work environment (16). Around half of these dimensions are not found in either the demand-control or ERI models (16). These include for instance emotional demands, demands on hiding emotions, sensorial demands, meaning of work, commitment to the workplace, organizational influence, trust, social community at work, quality of leadership, predictability, role clarity, restructuring, safety culture, work life balance, and negative acts (eg, violence, bullying). Little is currently known on the health effects of these "non-model" dimensions. Research on their possible effects might show that they are small - and that the DC and ERI dimensions are indeed the main psychosocial risk factors for CHD. However, results may also point to the importance of the non-model dimensions. To date, this remains to be investigated. Methodological issues In addition to the conceptual issues discussed above, we would like to highlight some methodological issues related to one or both of these models. The three main points address: (i) how exposure to job strain is categorized; (ii) how ERI has been measured up to now; and (iii) the validity of self-reports of job strain. Practical definition of job strain Job strain is usually operationalized as a median split of the two dimensions demands and control in the population investigated (3, 17). Hence, whether a certain worker experiences job strain or not depends on which other workers are part of the sample (18). This poses a problem when the distributions of demands and control differ between populations. Comparisons between Denmark and Spain and across Europe suggest that such differences exist (19, 20), rendering it at the least a challenge to combine populations in meta-analyses. (ABSTRACT TRUNCATED) PMID- 26960181 TI - Detection of pathogenic Escherichia coli and microbiological quality of chilled shrimp sold in street markets. AB - Foodborne illnesses caused by Escherichia coli are one of the most important gastrointestinal diseases and therefore represent a public health risk. The presence of E. coli in water or in products such as shrimp indicates faecal contamination. However, indicator micro-organisms can be used to evaluate the microbiological quality of food sold in markets. This study focused on detecting isolates of E. coli containing the genes stx1A, stx2A, eae, LTI, STa, STb, aggR and pCVD432 in chilled shrimp sold in street markets in the municipality of Sao Paulo, Brazil, and to assess the microbiological quality of this product. Enteropathogenic and enterotoxigenic E. coli pathotypes were detected on the surface of two chilled shrimp samples. Salmonella spp. was not isolated. In addition, contamination of surface and muscle of the shrimp samples was found to be correlated. The detection of EPEC and ETEC pathotypes in chilled shrimp sold in street markets in Brazil provides useful epidemiological information for public health authorities to improve food safety and public health. SIGNIFICANCE AND IMPACT OF THE STUDY: Shrimps are crustaceans commonly produced and consumed in Brazil. Specimens of Farfantepenaeus brasiliensis and Litopenaeus schmitti sold in street markets were examined by PCR to detect the presence of Escherichia coli pathotypes (enteropathogenic, enterotoxigenic, enterohemorrhagic and enteroinvasive). EPEC and ETEC strains were detected in whole shrimp. These findings provide useful information for public health authorities to improve the food safety and health of the Brazilian population. PMID- 26960180 TI - Gastrostomy Complications in Pediatric Cancer Patients: A Retrospective Single Institution Review. AB - BACKGROUND: Complications in pediatric cancer patients after a gastrostomy (GT) placement have not been widely investigated. We aimed to evaluate the complication rate and nature of complications in this specific population. PROCEDURE: Medical records of pediatric cancer patients having a GT placed at our institution from 1998 to 2013 were retrospectively reviewed. Variables analyzed included gender, age, diagnosis, surgical procedure, GT device, duration of GT usage, absolute neutrophil count (ANC) level at surgery, and complications. RESULTS: One hundred seventy-one patients (92 males, 79 females), median age of 6 years (range, 0.2-21), who underwent 181 procedures (110 open, 59 endoscopic, and 12 laparoscopic) were identified. Diagnosis included central nervous system tumor (n = 101), solid tumor (n = 45), and leukemia/lymphoma (n = 25). A GT tube was used in 139 procedures and a GT button in 42. Median ANC level at procedure was 3,300/mm(3) (range, 0-38,988). Median duration of GT usage was 8 months (range, 0.2-142). One hundred seventy-seven complications occurred in 106 patients (61.9%) and were categorized as perioperative (<1 month after surgery, 20.3%) and late (>1 month after surgery, 79.7%). Major complications included 42 (23.7%) GT site infections and four (2.2%) intrabdominal complications. The most common minor complication was granulation tissue (28.8%). Younger age at procedure was associated with complications (P = 0.048) and an open technique was associated with GT site infection (P = 0.003). No statistical significance was observed between complications and gender, diagnosis, GT device, duration of GT usage, and ANC at procedure. CONCLUSIONS: Younger patients were more likely to have complications, and GT site infections were more common after open GT procedures. PMID- 26960183 TI - The Impact of Epigenetics on Mesenchymal Stem Cell Biology. AB - Changes in epigenetic marks are known to be important regulatory factors in stem cell fate determination and differentiation. In the past years, the investigation of the epigenetic regulation of stem cell biology has largely focused on embryonic stem cells (ESCs). Contrarily, less is known about the epigenetic control of gene expression during differentiation of adult stem cells (AdSCs). Among AdSCs, mesenchymal stem cells (MSCs) are the most investigated stem cell population because of their enormous potential for therapeutic applications in regenerative medicine and tissue engineering. In this review, we analyze the main studies addressing the epigenetic changes in MSC landscape during in vitro cultivation and replicative senescence, as well as follow osteocyte, chondrocyte, and adipocyte differentiation. In these studies, histone acetylation, DNA methylation, and miRNA expression are among the most investigated phenomena. We describe also epigenetic changes that are associated with in vitro MSC trans differentiation. Although at the at initial stage, the epigenetics of MSCs promise to have profound implications for stem cell basic and applied research. J. Cell. Physiol. 231: 2393-2401, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26960184 TI - Ethylbenzene Dehydrogenase and Related Molybdenum Enzymes Involved in Oxygen Independent Alkyl Chain Hydroxylation. AB - Ethylbenzene dehydrogenase initiates the anaerobic bacterial degradation of ethylbenzene and propylbenzene. Although the enzyme is currently only known from a few closely related denitrifying bacterial strains affiliated to the Rhodocyclaceae, it clearly marks a universally occurring mechanism used for attacking recalcitrant substrates in the absence of oxygen. Ethylbenzene dehydrogenase belongs to subfamily 2 of the DMSO reductase-type molybdenum enzymes together with paralogous enzymes involved in the oxygen-independent hydroxylation of p-cymene, the isoprenoid side chains of sterols and even possibly n-alkanes; the subfamily also extends to dimethylsulfide dehydrogenases, selenite, chlorate and perchlorate reductases and, most significantly, dissimilatory nitrate reductases. The biochemical, spectroscopic and structural properties of the oxygen-independent hydroxylases among these enzymes are summarized and compared. All of them consist of three subunits, contain a molybdenum-bis-molybdopterin guanine dinucleotide cofactor, five Fe-S clusters and a heme b cofactor of unusual ligation, and are localized in the periplasmic space as soluble enzymes. In the case of ethylbenzene dehydrogenase, it has been determined that the heme b cofactor has a rather high redox potential, which may also be inferred for the paralogous hydroxylases. The known structure of ethylbenzene dehydrogenase allowed the calculation of detailed models of the reaction mechanism based on the density function theory as well as QM-MM (quantum mechanics - molecular mechanics) methods, which yield predictions of mechanistic properties such as kinetic isotope effects that appeared consistent with experimental data. PMID- 26960182 TI - Enhanced binding of antibodies generated during chronic HIV infection to mucus component MUC16. AB - Transmission of HIV across mucosal barriers accounts for the majority of HIV infections worldwide. Thus, efforts aimed at enhancing protective immunity at these sites are a top priority, including increasing virus-specific antibodies (Abs) and antiviral activity at mucosal sites. Mucin proteins, including the largest cell-associated mucin, mucin 16 (MUC16), help form mucus to provide a physical barrier to incoming pathogens. Here, we describe a natural interaction between Abs and MUC16 that is enhanced in specific disease settings such as chronic HIV infection. Binding to MUC16 was independent of IgG subclass, but strongly associated with shorter Ab glycan profiles, with agalactosylated (G0) Abs demonstrating the highest binding to MUC16. Binding of Abs to epithelial cells was diminished following MUC16 knockdown, and the MUC16 N-linked glycans were critical for binding. Further, agalactosylated VRC01 captured HIV more efficiently in MUC16. These data point to a novel opportunity to enrich Abs at mucosal sites by targeting Abs to MUC16 through changes in Fc glycosylation, potentially blocking viral movement and sequestering the virus far from the epithelial border. Thus, next-generation vaccines or monoclonal therapeutics may enhance protective immunity by tuning Ab glycosylation to promote the enrichment of Abs at mucosal barriers. PMID- 26960186 TI - Nanoscale Mechanics of Graphene and Graphene Oxide in Composites: A Scientific and Technological Perspective. AB - Graphene shows considerable promise in structural composite applications thanks to its unique combination of high tensile strength, Young's modulus and structural flexibility which arise due to its maximal chemical bond strength and minimal atomic thickness. However, the ultimate performance of graphene composites will depend, in addition to the properties of the matrix and interface, on the morphology of the graphene used, including the size and shape of the sheets and the number of chemical defects present. For example, whilst oxidized sp(3) carbon atoms and vacancies in a graphene sheet can degrade its mechanical strength, they can also increase its interaction with other materials such as the polymer matrix of a composite, thus maximizing stress transfer and leading to more efficient mechanical reinforcement. Herein, we present an overview of some recently published work on graphene mechanical properties and discuss a list of challenges that need to be overcome (notwithstanding the strong hype existing on this material) for the development of graphene-based materials into a successful technology. PMID- 26960187 TI - Mercury concentrations in Pacific lamprey (Entosphenus tridentatus) and sediments in the Columbia River basin. AB - The accumulation of mercury was investigated in Pacific lamprey and stream sediments in the Columbia River basin. Mercury concentrations in larval lamprey differed significantly among sample locations (p < 0.001) and were correlated with concentrations in sediments (r2 = 0.83). Adult concentrations were highly variable (range, 0.1-9.5 MUg/g) and unrelated to holding time after collection. The results suggest that Pacific lamprey in the Columbia River basin may be exposed to mercury levels that have adverse ecological effects. Environ Toxicol Chem 2016;35:2571-2576. (c) 2016 SETAC. PMID- 26960188 TI - Analysis of Bipolar Radiofrequency Ablation in Treatment of Atrial Fibrillation Associated with Rheumatic Heart Disease. AB - BACKGROUND: Among patients with rheumatic heart disease (RHD), 45% to 60% present with atrial fibrillation (AF), which is associated with increased rates of thromboembolism, heart failure, and even death. The bipolar radiofrequency ablation (BRFA) combining with mitral valve procedure has been adopted in patients of AF associated with RHD, but evaluations about its effectiveness are still limited. METHODS: A total of 87 patients with RHD and long persistent AF who had accepted mitral valve replacement concomitant with BRFA were studied. Clinical data were collected to analyze the midterm results of BRFA and evaluate its efficiency. Univariate and multivariate analyses were used to identify the independent factors associated with late AF recurrence. RESULTS: Sixty-six (75.9%) patients maintained sinus rhythm after a mean follow-up of 13.4 +/- 5.2 months. Late AF recurrence had been detected in 21 (24.1%) patients, 11 (12.6%) patients were confirmed to be AF, 8 (9.2%) patients were atrial flutter and 2 (2.3%) patients were junctional rhythm. In Multivariate logistic regression analysis, body mass index (BMI) (OR = 1.756, 95% CI = 1.289-2.391, p = 0.000) and early AF recurrence (OR = 5.479, 95% CI = 1.189-25.254, p = 0.029) were independent predictors of late AF recurrence. In addition, left ventricular ejection fraction (LVEF) and New York Heart Association class showed a greater improvement in patients who maintained sinus rhythm than those who experienced late AF recurrence. CONCLUSION: BRFA is an effective technique for the treatment of long persistent AF associated with RHD during mitral valve replacement. The BMI and early AF recurrence are independent predictors for late AF recurrence. Patients with long-term restoration of sinus rhythm experienced a greater improvement of left ventricular function after BRFA. PMID- 26960189 TI - Effect of Exposure to Smoking in Movies on Young Adult Smoking in New Zealand. AB - ONSCREEN SMOKING IS A FORM OF TOBACCO MARKETING: Tobacco advertising has been prohibited in New Zealand since 1990, and the government has set a goal of becoming a smokefree nation by 2025. However, tobacco marketing persists indirectly through smoking in motion pictures, and there is strong evidence that exposure to onscreen smoking causes young people to start smoking. We investigated the relationship between exposure to smoking in movies and youth smoking initiation among New Zealand young adults. Data from an online survey of 419 smokers and non-smokers aged 18 to 25 were used to estimate respondents' exposure to smoking occurrences in 50 randomly-selected movies from the 423 US top box office movies released between 2008 and 2012. Analyses involved calculating movie smoking exposure (MSE) for each respondent, using logistic regression to analyse the relationship between MSE and current smoking behaviour, and estimating the attributable fraction due to smoking in movies. EFFECT OF SMOKING IN MOVIES ON NEW ZEALAND YOUTH: Exposure to smoking occurrences in movies was associated with current smoking status. After allowing for the influence of family, friends and co-workers, age and rebelliousness, respondents' likelihood of smoking increased by 11% for every 100-incident increase in exposure to smoking incidents, (aOR1.11; p< .05). The estimated attributable fraction due to smoking in movies was 54%; this risk could be substantially reduced by eliminating smoking from movies currently rated as appropriate for youth. We conclude that exposure to smoking in movies remains a potent risk factor associated with smoking among young adults, even in a progressive tobacco control setting such as New Zealand. Harmonising the age of legal tobacco purchase (18) with the age at which it is legal to view smoking in movies would support New Zealand's smokefree 2025 goal. PMID- 26960191 TI - Researchers' Individual Publication Rate Has Not Increased in a Century. AB - Debates over the pros and cons of a "publish or perish" philosophy have inflamed academia for at least half a century. Growing concerns, in particular, are expressed for policies that reward "quantity" at the expense of "quality," because these might prompt scientists to unduly multiply their publications by fractioning ("salami slicing"), duplicating, rushing, simplifying, or even fabricating their results. To assess the reasonableness of these concerns, we analyzed publication patterns of over 40,000 researchers that, between the years 1900 and 2013, have published two or more papers within 15 years, in any of the disciplines covered by the Web of Science. The total number of papers published by researchers during their early career period (first fifteen years) has increased in recent decades, but so has their average number of co-authors. If we take the latter factor into account, by measuring productivity fractionally or by only counting papers published as first author, we observe no increase in productivity throughout the century. Even after the 1980s, adjusted productivity has not increased for most disciplines and countries. These results are robust to methodological choices and are actually conservative with respect to the hypothesis that publication rates are growing. Therefore, the widespread belief that pressures to publish are causing the scientific literature to be flooded with salami-sliced, trivial, incomplete, duplicated, plagiarized and false results is likely to be incorrect or at least exaggerated. PMID- 26960190 TI - Cudrania tricuspidata Stem Extract Induces Apoptosis via the Extrinsic Pathway in SiHa Cervical Cancer Cells. AB - The focus of this study is the anti-cancer effects of Cudrania tricuspidata stem (CTS) extract on cervical cancer cells. The effect of CTS on cell viability was investigated in HPV-positive cervical cancer cells and HaCaT human normal keratinocytes. CTS showed significant dose-dependent cytotoxic effects in cervical cancer cells. However, there was no cytotoxic effect of CTS on HaCaT keratinocytes at concentrations of 0.125-0.5 mg/mL. Based on this cytotoxic effect, we demonstrated that CTS induced apoptosis by down-regulating the E6 and E7 viral oncogenes. Apoptosis was detected by DAPI staining, annexin V-FITC/PI staining, cell cycle analysis, western blotting, RT-PCR, and JC-1 staining in SiHa cervical cancer cells. The mRNA expression levels of extrinsic pathway molecules such as Fas, death receptor 5 (DR5), and TNF-related apoptosis-inducing ligand (TRAIL) were increased by CTS. Furthermore, CTS treatment activated caspase-3/caspase-8 and cleavage of poly (ADP-ribose) polymerase (PARP). However, the mitochondrial membrane potential and expression levels of intrinsic pathway molecules such as Bcl-2, Bcl-xL, Bax, and cytochrome C were not modulated by CTS. Taken together, these results indicate that CTS induced apoptosis by activating the extrinsic pathway, but not the intrinsic pathway, in SiHa cervical cancer cells. These results suggest that CTS can be used as a modulating agent in cervical cancer. PMID- 26960192 TI - Simultaneous monitoring of quantum dots and their assembly and disassembly with PreScission protease using capillary electrophoresis with fluorescence detection. AB - A novel assay was developed for the simultaneous monitoring of quantum dots and their assembly and disassembly with PreScission protease using capillary electrophoresis with fluorescence detection. Quantum dots and PreScission protease were injected into a capillary sequentially, then mixed and assembled via a thioether bond upon coupling to glutathione S-transferase tag inside the capillary. The in-capillary assembly was influenced by the molar ratio and the time interval of injection. Furthermore, the simultaneous monitoring of quantum dots and their assembly with PreScission protease and glutathione induced disassembly was achieved by adjusting the sampling sequence and the time interval of injection. More importantly, the in-capillary assay could be also applied to the online detection of glutathione. PMID- 26960193 TI - Glucose Augments Killing Efficiency of Daptomycin Challenged Staphylococcus aureus Persisters. AB - Treatment of Staphylococcus aureus in stationary growth phase with high doses of the antibiotic daptomycin (DAP) eradicates the vast majority of the culture and leaves persister cells behind. Despite resting in a drug-tolerant and dormant state, persister cells exhibit metabolic activity which might be exploited for their elimination. We here report that the addition of glucose to S. aureus persisters treated with DAP increased killing by up to five-fold within one hour. This glucose-DAP effect also occurred with strains less sensitive to the drug. The underlying mechanism is independent of the proton motive force and was not observed with non-metabolizable 2-deoxy-glucose. Our results are consistent with two hypotheses on the glucose-DAP interplay. The first is based upon glucose induced carbohydrate transport proteins that may influence DAP and the second suggests that glucose may trigger the release or activity of cell-lytic proteins to augment DAP's mode of action. PMID- 26960195 TI - A Pilot Randomized Placebo Controlled Trial of Electroacupuncture for Women with Pure Stress Urinary Incontinence. AB - BACKGROUND: Acupuncture is a potential conservative therapy for women with stress urinary incontinence (SUI). There is limited evidence to support its effectiveness due to the poor quality of existing studies. METHODS: We performed a pilot randomized, controlled trial to preliminarily assess the efficacy of electroacupuncture (EA) in women with pure SUI. A total of 80 women with pure SUI were randomly assigned to receive EA with deep needling at BL33 and BL35 (n = 40) or sham EA with non-penetrating needling at sham acupoints (n = 40) three sessions per week for 6 weeks. The women were followed for 24 weeks. The primary outcome was the change from baseline in the amount of urine leakage measured by a 1-hour pad test after 6 weeks. The secondary outcomes included the 72-hour incontinence episode frequency (IEF), International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) score, and patient self-evaluation of therapeutic effect. Adverse events (AEs) were monitored throughout the trial. RESULTS: The median decrease from baseline of urine leakage measured by the 1 hour pad test was 2.5 g [interquartile range (IQR): 1.80-14.6 in the EA group, which was greater than the median decrease of 0.05 g (IQR: -2.80-+0.50) in the sham EA group after 6 weeks (p<0.01). The differences between groups in the decrease from baseline of 72-hour IEF became statistically significant at week 30 with a median decrease of 3.25 g (IQR: 1.25-5.69) in the EA group, and a median decrease of 1.00 g (IQR: -0.69-+2.88) in the sham EA group (p = 0.01). The participants in the EA group showed greater decreases in ICIQ-SF score and higher ratings in the help they received from the treatment than those in the sham EA group at weeks 6,18 and 30 (all p<0.05). No obvious AEs were observed in either group. CONCLUSION: EA may effectively and safely relieve urinary incontinence symptoms and improve quality of life in women with pure SUI. EA demonstrated more than a placebo effect. Since this is a pilot study, results should be interpreted with caution. TRIAL REGISTRATION: ClinicalTrials.gov NCT02445573. PMID- 26960194 TI - Relationship between G1287A of the NET Gene Polymorphisms and Brain Volume in Major Depressive Disorder: A Voxel-Based MRI Study. AB - BACKGROUND: Earlier studies implicated norepinephrine transporter (NET) gene (SLC6A2) polymorphisms in the etiology of major depressive disorder (MDD). Recently, two single nucleotide SLC6A2 polymorphisms, G1287A in exon 9 and T-182C in the promoter region, were found to be associated with MDD in different populations. We investigated the relationship between the brain volume and these two polymorphisms of the SLC6A2 in MDD patients. METHODS: We obtained 3D high resolution T1-weighted images of 30 first-episode MDD patients and 48 age- and sex-matched healthy subjects (HS). All were divided into 4 groups based on polymorphism of either the G1287A or the T-182C genotype. VBM analysis examined the effects of diagnosis, genotype, and genotype-diagnosis interactions. RESULTS: Diagnosis effects on the brain morphology were found in the left superior temporal cortex. No significant genotype effects were found in the T-182C and the G1287A. A significant genotype (G1287A)-diagnosis interaction was found in the left dorsolateral prefrontal cortex. No significant genotype (T-182C)-diagnosis interaction effects were observed in any brain region. CONCLUSIONS: In MDD patients there seems to be a relationship between the volume of the dorsolateral prefrontal cortex and polymorphism of the SLC6A2 G1287A gene. PMID- 26960198 TI - Correction: Fine Tuning Inflammation at the Front Door: Macrophage Complement Receptor 3-mediates Phagocytosis and Immune Suppression for Francisella tularensis. PMID- 26960196 TI - Activity Based High-Throughput Screening for Novel O-GlcNAc Transferase Substrates Using a Dynamic Peptide Microarray. AB - O-GlcNAcylation is a reversible and dynamic protein post-translational modification in mammalian cells. The O-GlcNAc cycle is catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). O-GlcNAcylation plays important role in many vital cellular events including transcription, cell cycle regulation, stress response and protein degradation, and altered O-GlcNAcylation has long been implicated in cancer, diabetes and neurodegenerative diseases. Recently, numerous approaches have been developed to identify OGT substrates and study their function, but there is still a strong demand for highly efficient techniques. Here we demonstrated the utility of the peptide microarray approach to discover novel OGT substrates and study its specificity. Interestingly, the protein RBL-2, which is a key regulator of entry into cell division and may function as a tumor suppressor, was identified as a substrate for three isoforms of OGT. Using peptide Ala scanning, we found Ser 420 is one possible O-GlcNAc site in RBL-2. Moreover, substitution of Ser 420, on its own, inhibited OGT activity, raising the possibility of mechanism-based development for selective OGT inhibitors. This approach will prove useful for both discovery of novel OGT substrates and studying OGT specificity. PMID- 26960197 TI - Diagnostic Pathways as Social and Participatory Practices: The Case of Herpes Simplex Encephalitis. AB - Herpes simplex virus (HSV) encephalitis is a potentially devastating disease, with significant rates of mortality and co-morbidities. Although the prognosis for people with HSV encephalitis can be improved by prompt treatment with aciclovir, there are often delays involved in the diagnosis and treatment of the disease. In response, National Clinical Guidelines have been produced for the UK which make recommendations for improving the management of suspected viral encephalitis. However, little is currently known about the everyday experiences and processes involved in the diagnosis and care of HSV encephalitis. The reported study aimed to provide an account of the diagnosis and treatment of HSV encephalitis from the perspective of people who had been affected by the condition. Thirty narrative interviews were conducted with people who had been diagnosed with HSV encephalitis and their significant others. The narrative accounts reveal problems with gaining access to a diagnosis of encephalitis and shortfalls in care for the condition once in hospital. In response, individuals and their families work hard to obtain medical recognition for the problem and shape the processes of acute care. As a consequence, we argue that the diagnosis and management of HSV encephalitis needs to be considered as a participatory process, which is co-produced by health professionals, patients, and their families. The paper concludes by making recommendations for developing the current management guidelines by formalising the critical role of patients and their significant others in the identification, and treatment of, HSV encephalitis. PMID- 26960199 TI - Why Are Girls Less Physically Active than Boys? Findings from the LOOK Longitudinal Study. AB - BACKGROUND: A gender-based disparity in physical activity (PA) among youth, whereby girls are less active than boys is a persistent finding in the literature. A greater understanding of the mechanisms underlying this difference has potential to guide PA intervention strategies. METHODS: Data were collected at age 8 and 12 years (276 boys, 279 girls) from 29 schools as part of the LOOK study. Multilevel linear models were fitted separately for boys and girls to examine effects of individual, family and environmental level correlates on pedometer measured PA. Cardio-respiratory fitness (multi-stage run), percent fat (DEXA), eye-hand coordination (throw and catch test) and perceived competence in physical education (questionnaire) were used as individual level correlates. At the family level, parent's support and education (questionnaire) were used. School attended and extracurricular sport participation were included as environmental level correlates. RESULTS: Girls were 19% less active than boys (9420 vs 11360 steps/day, p<0.001, 95%CI [1844, 2626]). Lower PA among girls was associated with weaker influences at the school and family levels and through lower participation in extracurricular sport. School attended explained some of the variation in boys PA (8.4%) but not girls. Girls compared to boys had less favourable individual attributes associated with PA at age 8 years, including 18% lower cardio-respiratory fitness (3.5 vs 4.2, p<0.001, CI [0.5,0.9]), 44% lower eye-hand coordination (11.0 vs 17.3, p<0.001, CI [5.1,9.0]), higher percent body fat (28% vs 23%, p<0.001, CI [3.5,5.7]) and 9% lower perceived competence in physical education (7.7 vs 8.4, p<0.001, CI [0.2,0.9]). Participation in extracurricular sport at either age 8 or 12 years was protective against declines in PA over time among boys but not girls. CONCLUSION: Girls PA was less favourably influenced by socio-ecological factors at the individual, family, school and environmental levels. These factors are potentially modifiable suggesting the gap in PA between boys and girls can be reduced. Strategies aiming to increase PA should be multicomponent and take into consideration that pathways to increasing PA are likely to differ among boys and girls. PMID- 26960200 TI - Structural and Psycho-Social Limits to Climate Change Adaptation in the Great Barrier Reef Region. AB - Adaptation, as a strategy to respond to climate change, has limits: there are conditions under which adaptation strategies fail to alleviate impacts from climate change. Research has primarily focused on identifying absolute bio physical limits. This paper contributes empirical insight to an emerging literature on the social limits to adaptation. Such limits arise from the ways in which societies perceive, experience and respond to climate change. Using qualitative data from multi-stakeholder workshops and key-informant interviews with representatives of the fisheries and tourism sectors of the Great Barrier Reef region, we identify psycho-social and structural limits associated with key adaptation strategies, and examine how these are perceived as more or less absolute across levels of organisation. We find that actors experience social limits to adaptation when: i) the effort of pursuing a strategy exceeds the benefits of desired adaptation outcomes; ii) the particular strategy does not address the actual source of vulnerability, and; iii) the benefits derived from adaptation are undermined by external factors. We also find that social limits are not necessarily more absolute at higher levels of organisation: respondents perceived considerable opportunities to address some psycho-social limits at the national-international interface, while they considered some social limits at the local and regional levels to be effectively absolute. PMID- 26960201 TI - Left ventricular systolic dysfunction is associated with adverse outcomes in acute right ventricular infarction. AB - BACKGROUND: In patients with acute right ventricular infarction (RVI), global right ventricular (RV) performance is dependent on compensatory left ventricular (LV)-septal contractile contributions. This study was designed to assess the influence of depressed left ventricular ejection fraction (LVEF) on hemodynamics and clinical outcomes in patients with RVI. METHODS AND RESULTS: We retrospectively identified 338 patients with acute inferior ST elevation myocardial infarction (STEMI) undergoing a primary percutaneous coronary intervention. RVI was determined echocardiographically by right ventricular free wall motion abnormalities and depressed global RV performance (fractional area change); LV function was similarly calculated. RVI was documented in 185 (55%) cases. Compared with those with inferior myocardial infarction alone, patients with RVI suffered more hemodynamic compromise (need for inotropes or vasopressors 39 vs. 15%, P<0.0001, and intra-aortic balloon pump 32 vs. 13%, P<0.0001) and higher in-hospital mortality (14 vs. 3%, P=0.0006). In cases without RVI, the status of LV function did not influence in-hospital mortality (ejection fraction<=40%=7.3% vs. ejection fraction>40%=1.8, P=0.12). In contrast, in patients with RVI, LVEF was an important determinant of outcome: those with LVEF <= 40% suffered more hemodynamic compromise (need for inotropes or vasopressors 63 vs. 30%, P<0.0001, and intra-aortic balloon pump 59 vs. 22%, P<0.0001) and had markedly higher in-hospital mortality (33 vs. 7%, P<0.0001). CONCLUSION: In patients with acute inferior myocardial infarction complicated by RVI, depressed LVEF is associated with greater hemodynamic compromise and higher in-hospital mortality. These findings may have clinical implications for supportive efforts in such cases. PMID- 26960202 TI - Adrenocortical carcinoma in a 17th-century girl. AB - Adrenocortical carcinoma (ACC) is a rare, often fatal disease, that may be seen sporadically or with hereditary predisposition syndromes. Patients with ACC are usually girls under the age of seven who present signs of excess production of adrenal glucocorticoids and androgens, with the diagnosis being confirmed by imaging. Here we reproduce and examine what we believe to be the first autopsy case report of a child with ACC, reported by Dr. Henry Sampson in Philosophical Transactions, published by The Royal Society of London in 1697. The paper describes the autopsy of a girl with severe virilization and profound signs of Cushing syndrome who died at age six, strongly suggesting ACC. She apparently had extensive pulmonary metastases, and may have had liver involvement. The report indicates her disease arose from her left kidney and there is no indication of an adrenal origin, perhaps because the adrenal gland was not generally known as a separate organ at that time. This classic example of an early case report is particularly instructive in the context of medical knowledge and understanding in the 17th century compared to current knowledge. PMID- 26960203 TI - Disorders in the initial steps of steroid hormone synthesis. AB - Steroidogenesis begins with cellular internalization of low-density lipoprotein particles and subsequent intracellular processing of cholesterol. Disorders in these steps include Adrenoleukodystrophy, Wolman Disease and its milder variant Cholesterol Ester Storage Disease, and Niemann-Pick Type C Disease, all of which may present with adrenal insufficiency. The means by which cholesterol is directed to steroidogenic mitochondria remains incompletely understood. Once cholesterol reaches the outer mitochondrial membrane, its delivery to the inner mitochondrial membrane is regulated by the steroidogenic acute regulatory protein (StAR). Severe StAR mutations cause classic congenital lipoid adrenal hyperplasia, characterized by lipid accumulation in the adrenal, adrenal insufficiency, and disordered sexual development in 46,XY individuals. The lipoid CAH phenotype, including spontaneous puberty in 46,XX females, is explained by a two-hit model. StAR mutations that retain partial function cause a milder, non classic disease characterized by glucocorticoid deficiency, with lesser disorders of mineralocorticoid and sex steroid synthesis. Once inside the mitochondria, cholesterol is converted to pregnenolone by the cholesterol side-chain cleavage enzyme, P450scc, encoded by the CYP11A1 gene. Rare patients with mutations of P450scc are clinically and hormonally indistinguishable from those with lipoid CAH, and may also present as milder non-classic disease. Patients with P450scc defects do not have the massive adrenal hyperplasia that characterizes lipoid CAH, but adrenal imaging may occasionally fail to distinguish these, necessitating DNA sequencing. PMID- 26960204 TI - Pathway-Based Genomics Prediction using Generalized Elastic Net. AB - We present a novel regularization scheme called The Generalized Elastic Net (GELnet) that incorporates gene pathway information into feature selection. The proposed formulation is applicable to a wide variety of problems in which the interpretation of predictive features using known molecular interactions is desired. The method naturally steers solutions toward sets of mechanistically interlinked genes. Using experiments on synthetic data, we demonstrate that pathway-guided results maintain, and often improve, the accuracy of predictors even in cases where the full gene network is unknown. We apply the method to predict the drug response of breast cancer cell lines. GELnet is able to reveal genetic determinants of sensitivity and resistance for several compounds. In particular, for an EGFR/HER2 inhibitor, it finds a possible trans-differentiation resistance mechanism missed by the corresponding pathway agnostic approach. PMID- 26960205 TI - Antioxidant Activity and alpha-Glucosidase Inhibitory Activities of the Polycondensate of Catechin with Glyoxylic Acid. AB - In order to investigate polymeric flavonoids, the polycondensate of catechin with glyoxylic acid (PCG) was prepared and its chemically antioxidant, cellular antioxidant (CAA) and alpha-glucosidase inhibitory activities were evaluated. The DPPH and ABTS radical scavenging activities and antiproliferative effect of PCG were lower than those of catechin, while PCG had higher CAA activity than catechin. In addition, PCG had very high alpha-glucosidase inhibitory activities (IC50 value, 2.59 MUg/mL) in comparison to catechin (IC50 value, 239.27 MUg/mL). Inhibition kinetics suggested that both PCG and catechin demonstrated a mixture of noncompetitive and anticompetitive inhibition. The enhanced CAA and alpha glucosidase inhibitor activities of PCG could be due to catechin polymerization enhancing the binding capacity to the cellular membrane and enzymes. PMID- 26960206 TI - Plagiocephaly due to Frontosphenoidal Suture Synostosis: Report of 2 Cases and Literature Review. AB - BACKGROUND/AIMS: The most common cause of anterior plagiocephaly is the fusion of the unilateral coronal suture. In some rare cases, however, the fusion of the frontosphenoidal suture may lead to a resembling pattern with specific clinical and radiological features. The aim of the present study is to further enlighten this entity as it is misdiagnosed most of the time. METHODS: A report of 2 cases of plagiocephaly due to frontosphenoidal synostosis with a review of the literature. RESULTS: One female and one male baby were identified. The mean age at presentation was 11.5 months (range: 1-22). Head circumference was normal in each patient. The two fusions were on the left side. Unilateral frontal flattening and recession of the supraorbital rim were the most important physical findings. Computed tomography confirmed the patency of the frontoparietal suture and the closure of the frontosphenoidal suture. Fronto-orbital advancement was performed in both cases with good cosmetic outcome. CONCLUSION: Frontosphenoidal synostosis should be suspected and carefully searched when dealing with plagiocephaly with patent coronal suture. Good outcome requires a prompt diagnosis and early correction. PMID- 26960208 TI - Microhyla laterite sp. nov., A New Species of Microhyla Tschudi, 1838 (Amphibia: Anura: Microhylidae) from a Laterite Rock Formation in South West India. AB - In recent times, several new species of amphibians have been described from India. Many of these discoveries are from biodiversity hotspots or from within protected areas. We undertook amphibian surveys in human dominated landscapes outside of protected areas in south western region of India between years 2013 2015. We encountered a new species of Microhyla which is described here as Microhyla laterite sp. nov. It was delimited using molecular, morphometric and bioacoustics comparisons. Microhyla laterite sp. nov. appears to be restricted to areas of the West coast of India dominated by laterite rock formations. The laterite rock formations date as far back as the Cretaceous-Tertiary boundary and are considered to be wastelands in-spite of their intriguing geological history. We identify knowledge gaps in our understanding of the genus Microhyla from the Indian subcontinent and suggest ways to bridge them. PMID- 26960207 TI - Chemical Synthesis of Phosphorylated Histone H2A at Tyr57 Reveals Insight into the Inhibition Mode of the SAGA Deubiquitinating Module. AB - Monoubiquitination of histone H2B plays a central role in transcription activation and is required for downstream histone-methylation events. Deubiquitination of H2B by the Spt-Ada-Gcn5 acetyltransferase (SAGA) coactivator complex is regulated by a recently discovered histone mark, phosphorylated H2AY57 (H2AY57p), which inhibits deubiquitination of H2B by the SAGA complex as well as restricting demethylation of H3 and increasing its acetylation. Evidence for the effect of H2AY57p, however, was indirect and was investigated in vivo by monitoring the effects of chemical inhibition of Tyr kinase CK2 or by mutating the phosphorylation site. We applied the total chemical synthesis of proteins to prepare H2AY57p efficiently and study the molecular details of this regulation. This analogue, together with semisynthetically prepared ubiquitinated H2B, enabled us to provide direct evidence for the cross-talk between those two marks and the inhibition of SAGA activity by H2AY57p. PMID- 26960209 TI - New Options of Apheresis in Renal Diseases: How and When? AB - The 100-year anniversary of the first experimental apheresis performed by John Abel on uremic dogs in 1914 provides the opportunity for discussion on the current state of classic apheresis as well as technological progress and clinical experiences with its new options presented in the world literature in the last 15 years, such as the following: double filtration, plasma adsorption and immunoadsorption, leuko- and cytapheresis and low-density lipoprotein apheresis. In our review, we highlight the potential limitations for further development of those highly promising techniques, such as the following: the lack of multicenter, controlled clinical studies; insufficient knowledge of the mechanisms of those techniques and last but not least, the restricted access to apheresis, caused both by high expenditure and organizational negligence, even in highly developed countries. Special attention was paid to the most recent recommendations by the American Society of Apheresis in primary and secondary renal diseases, which are the subject of our professional interest. PMID- 26960210 TI - Use of Continuous Glucose Monitoring in Patients with Diabetes Mellitus on Peritoneal Dialysis: Correlation with Glycated Hemoglobin and Detection of High Incidence of Unaware Hypoglycemia. AB - INTRODUCTION: Glycated hemoglobin is used to assess diabetic control although its accuracy in dialysis has been questioned. How does it compare to the Continuous Glucose Monitoring System (CGMS) in peritoneal dialysis (PD) patients? METHODS: We conducted a retrospective analysis of 60 insulin-treated diabetic patients on PD. We determined the mean interstitial glucose concentration and the proportion of patients with hypoglycemia (<4 mmol/l) or hyperglycemia (>11 mmol/l). RESULTS: The correlation between HbA1c and glucose was 0.48, p < 0.0001. Three of 15 patients with HbA1c >75 mmol/mol experienced significant hypoglycemia (14-144 min per day). The patients with frequent episodes of hypoglycemia could not be differentiated from those with frequent hyperglycemia by demographics or PD prescription. CONCLUSION: HbA1c and average glucose levels measured by the CGMS are only weakly correlated. On its own, HbA1c as an indicator of glycemic control in patients with diabetes on PD appears inadequate. We suggest that the CGMS technology should be more widely adopted. PMID- 26960212 TI - The Role of Cell-Free Plasma DNA in Critically Ill Patients with Sepsis. AB - BACKGROUND: The identification of highly reliable outcome predictors in severe sepsis is important to define disease severity, predict bedside prognosis and monitor response to treatment. Cell-free plasma DNA (cfDNA) has been recently proposed as a possible prognostic marker of clinical outcome in septic patients. In this study, we investigated the prognostic value of cfDNA in patients with sepsis and its possible correlation with caspase-3, IL-6 and IL-18 levels. METHODS: We enrolled 34 patients admitted to the intensive care unit (ICU). Out of these 34, 27 patients were septic and 7 were non-septic. cfDNA was extracted from plasma and quantified by real time PCR. Plasma levels of caspase-3, IL-6 and IL-18 were measured by ELISA. RESULTS: We observed significantly higher levels of cfDNA in septic patients. No significant differences were found between cfDNA levels in patients with Gram+, Gram- and fungal infections. Out of the 27 septic patients, 12 developed acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT), and cfDNA levels resulted to be higher in this group. Out of the 27 septic patients, 11 had a negative outcome during the ICU stay. The cfDNA concentrations at admission were higher in non-survivors than in survivors. Caspase-3, IL-6 and IL-18 levels were significantly higher in septic patients when compared to these levels in non-septic patients and correlated with cfDNA levels. CONCLUSION: cfDNA can be considered a good prognostic marker of clinical outcome in septic patients. Its levels increase in case of AKI complicating sepsis, in particular if CRRT is needed, and are associated with poor outcome. Caspase-3, IL-6 and IL-18 levels are higher in septic patients and correlate to cfDNA concentrations. PMID- 26960211 TI - Telomere Attrition and Elongation after Chronic Dialysis Initiation in Patients with End-Stage Renal Disease. AB - AIMS: To analyze changes in telomere length (TL) after dialysis initiation. METHODS: In 59 Japanese incident dialysis patients, associations between TL in peripheral blood leukocytes, inflammatory biomarkers and nutritional status at baseline and changes in TL during 1 year of dialysis, were investigated. RESULTS: Whereas relative TL decreased by 8.6% (median 14.4%), TL elongation occurred in 16 patients (27%). Change in TL (x0394;TL), defined as TL at 1 year minus TL at baseline, was associated with baseline TL (x03C1; = -0.70, p < 0.0001) and leukocyte count (x03C1; = 0.26, p = 0.044). In a logistic regression model, baseline TL (p < 0.0001) and leukocyte count (p = 0.047) were associated with x0394;TL. CONCLUSIONS: TL shortening was observed in most incident dialysis patients. In 16 of the 59 patients, TL elongation occurred, possibly reflecting a more robust biological aging in patients whose naive leukocytes may have undergone less proliferation to replace lost leukocytes. PMID- 26960213 TI - Ionized Magnesium and Regional Citrate Anticoagulation for Continuous Renal Replacement Therapy. AB - BACKGROUND: The regional citrate anticoagulation (RCA) induces changes in total (Catot) and ionized (Ca2+) calcium. As of now, we do not have much information about parallel changes of total (Mgtot) and ionized (Mg2+) magnesium. METHODS: The authors compared changes of Mg2+ and Mgtot with changes of Ca2+ and Catot in 32 critically ill patients on 4% trisodium citrate (4% TSC) with calcium-free fluids. RESULTS: The median continuous venovenous hemodiafiltration balance of Mgtot was -0.91 (-1.18 to -0.53) mmol/h compared to the median balance of Catot 0.86 (0.08-1.55) mmol/h. Postfilter Mg2+ decreased by 68.3% (70.8-65.6) in parallel (r = 0.41, p = 0.03) to decrease of postfilter Ca2+ (by 70.2% (73.0 66.1)) and was significantly related to the postfilter Ca2+ (r = 0.50, p < 0.001). The decrease of prefilter to postfilter Ca2+ correlated to a dosage of 4% TSC per blood flow (r = 0.37, p = 0.04). CONCLUSIONS: The loss of Mgtot during RCA is not covered by magnesium concentration in ordinary dialysis/substitution fluid and may lead to the depletion of total body magnesium. The postfilter Mg2+ is significantly related to the postfilter Ca2+. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi = 440972. PMID- 26960214 TI - Anaerobic Degradation of Benzene and Polycyclic Aromatic Hydrocarbons. AB - Aromatic hydrocarbons such as benzene and polycyclic aromatic hydrocarbons (PAHs) are very slowly degraded without molecular oxygen. Here, we review the recent advances in the elucidation of the first known degradation pathways of these environmental hazards. Anaerobic degradation of benzene and PAHs has been successfully documented in the environment by metabolite analysis, compound specific isotope analysis and microcosm studies. Subsequently, also enrichments and pure cultures were obtained that anaerobically degrade benzene, naphthalene or methylnaphthalene, and even phenanthrene, the largest PAH currently known to be degradable under anoxic conditions. Although such cultures grow very slowly, with doubling times of around 2 weeks, and produce only very little biomass in batch cultures, successful proteogenomic, transcriptomic and biochemical studies revealed novel degradation pathways with exciting biochemical reactions such as for example the carboxylation of naphthalene or the ATP-independent reduction of naphthoyl-coenzyme A. The elucidation of the first anaerobic degradation pathways of naphthalene and methylnaphthalene at the genetic and biochemical level now opens the door to studying the anaerobic metabolism and ecology of anaerobic PAH degraders. This will contribute to assessing the fate of one of the most important contaminant classes in anoxic sediments and aquifers. PMID- 26960216 TI - Privacy-Preserving Patient-Centric Clinical Decision Support System on Naive Bayesian Classification. AB - Clinical decision support system, which uses advanced data mining techniques to help clinician make proper decisions, has received considerable attention recently. The advantages of clinical decision support system include not only improving diagnosis accuracy but also reducing diagnosis time. Specifically, with large amounts of clinical data generated everyday, naive Bayesian classification can be utilized to excavate valuable information to improve a clinical decision support system. Although the clinical decision support system is quite promising, the flourish of the system still faces many challenges including information security and privacy concerns. In this paper, we propose a new privacy-preserving patient-centric clinical decision support system, which helps clinician complementary to diagnose the risk of patients' disease in a privacy-preserving way. In the proposed system, the past patients' historical data are stored in cloud and can be used to train the naive Bayesian classifier without leaking any individual patient medical data, and then the trained classifier can be applied to compute the disease risk for new coming patients and also allow these patients to retrieve the top- k disease names according to their own preferences. Specifically, to protect the privacy of past patients' historical data, a new cryptographic tool called additive homomorphic proxy aggregation scheme is designed. Moreover, to leverage the leakage of naive Bayesian classifier, we introduce a privacy-preserving top- k disease names retrieval protocol in our system. Detailed privacy analysis ensures that patient's information is private and will not be leaked out during the disease diagnosis phase. In addition, performance evaluation via extensive simulations also demonstrates that our system can efficiently calculate patient's disease risk with high accuracy in a privacy-preserving way. PMID- 26960217 TI - A Novel Congestion Avoidance Technique for Simultaneous Real-Time Medical Data Transmission. AB - The use of wireless body sensor networks (WBSN) in medical services aims at providing continuous monitoring of patients' physiological data. However, the scarce resources in WBSN nodes limit their capabilities to cope with massive traffic during multiple, simultaneous data transmissions. This will create a high tendency for congestion, causing severe performance degradation. Congestion may lead to high number of packet loss and unbounded delay which are critical and may lead to wrong diagnosis. This paper, therefore, aims at improving this limitation using a novel congestion avoidance technique to avoid losing real-time and life critical medical data (e.g., electrocardiogram and electroencephalography) which are vital for diagnosis. The main idea is to integrate the existing rate control scheme of relaxation theory (RT) with a method known as max-min fairness (MMF) to achieve better performance. The MMF can be accomplished using a progressive filling algorithm, which cuts-down excessive sending rates that may overwhelme the limited buffer in WBSN. This paper builds upon our prior study, which provides a preliminary analysis of RT technique in single node. Our current technique integrates the MMF phase to enhance RT performance when the transmission rates exceed certain threshold. Performance evaluation on RT-MMF technique shows remarkable performance improvements, while maintaining the desired quality of service. PMID- 26960219 TI - Empirical Minimum Bayes Risk Prediction. AB - When building vision systems that predict structured objects such as image segmentations or human poses, a crucial concern is performance under task specific evaluation measures (e.g., Jaccard Index or Average Precision). An ongoing research challenge is to optimize predictions so as to maximize performance on such complex measures. In this work, we present a simple meta algorithm that is surprisingly effective - Empirical Min Bayes Risk. EMBR takes as input a pre-trained model that would normally be the final product and learns three additional parameters so as to optimize performance on the complex instance level high-order task-specific measure. We demonstrate EMBR in several domains, taking existing state-of-the-art algorithms and improving performance up to 8 percent, simply by learning three extra parameters. Our code is publicly available and the results presented in this paper can be replicated from our code release. PMID- 26960218 TI - Modeling Endovascular MRI Coil Coupling With Transmit RF Excitation. AB - OBJECTIVE: To model inductive coupling of endovascular coils with transmit RF excitation for selecting coils for MRI-guided interventions. METHODS: Independent and computationally efficient FEM models are developed for the endovascular coil, cable, transmit excitation, and imaging domain. Electromagnetic and circuit solvers are coupled to simulate net B1 + fields and induced currents and voltages. Our models are validated using the Bloch-Siegert B1 + mapping sequence for a series-tuned multimode coil, capable of tracking, wireless visualization, and high-resolution endovascular imaging. RESULTS: Validation shows good agreement at 24-, 28-, and 34-MUT background RF excitation within experimental limitations. Quantitative coil performance metrics agree with simulation. A parametric study demonstrates tradeoff in coil performance metrics when varying number of coil turns. Tracking, imaging, and wireless marker multimode coil features and their integration is demonstrated in a pig study. CONCLUSION: Developed models for the multimode coil were successfully validated. Modeling for geometric optimization and coil selection serves as a precursor to time consuming and expensive experiments. Specific applications demonstrated include parametric optimization, coil selection for a cardiac intervention, and an animal imaging experiment. SIGNIFICANCE: Our modular, adaptable, and computationally efficient modeling approach enables rapid comparison, selection, and optimization of inductively coupled coils for MRI-guided interventions. PMID- 26960220 TI - Detailed Evaluation of Five 3D Speckle Tracking Algorithms Using Synthetic Echocardiographic Recordings. AB - A plethora of techniques for cardiac deformation imaging with 3D ultrasound, typically referred to as 3D speckle tracking techniques, are available from academia and industry. Although the benefits of single methods over alternative ones have been reported in separate publications, the intrinsic differences in the data and definitions used makes it hard to compare the relative performance of different solutions. To address this issue, we have recently proposed a framework to simulate realistic 3D echocardiographic recordings and used it to generate a common set of ground-truth data for 3D speckle tracking algorithms, which was made available online. The aim of this study was therefore to use the newly developed database to contrast non-commercial speckle tracking solutions from research groups with leading expertise in the field. The five techniques involved cover the most representative families of existing approaches, namely block-matching, radio-frequency tracking, optical flow and elastic image registration. The techniques were contrasted in terms of tracking and strain accuracy. The feasibility of the obtained strain measurements to diagnose pathology was also tested for ischemia and dyssynchrony. PMID- 26960222 TI - Brain Tumor Segmentation Using Convolutional Neural Networks in MRI Images. AB - Among brain tumors, gliomas are the most common and aggressive, leading to a very short life expectancy in their highest grade. Thus, treatment planning is a key stage to improve the quality of life of oncological patients. Magnetic resonance imaging (MRI) is a widely used imaging technique to assess these tumors, but the large amount of data produced by MRI prevents manual segmentation in a reasonable time, limiting the use of precise quantitative measurements in the clinical practice. So, automatic and reliable segmentation methods are required; however, the large spatial and structural variability among brain tumors make automatic segmentation a challenging problem. In this paper, we propose an automatic segmentation method based on Convolutional Neural Networks (CNN), exploring small 3 *3 kernels. The use of small kernels allows designing a deeper architecture, besides having a positive effect against overfitting, given the fewer number of weights in the network. We also investigated the use of intensity normalization as a pre-processing step, which though not common in CNN-based segmentation methods, proved together with data augmentation to be very effective for brain tumor segmentation in MRI images. Our proposal was validated in the Brain Tumor Segmentation Challenge 2013 database (BRATS 2013), obtaining simultaneously the first position for the complete, core, and enhancing regions in Dice Similarity Coefficient metric (0.88, 0.83, 0.77) for the Challenge data set. Also, it obtained the overall first position by the online evaluation platform. We also participated in the on-site BRATS 2015 Challenge using the same model, obtaining the second place, with Dice Similarity Coefficient metric of 0.78, 0.65, and 0.75 for the complete, core, and enhancing regions, respectively. PMID- 26960221 TI - Sparse Multi-Response Tensor Regression for Alzheimer's Disease Study With Multivariate Clinical Assessments. AB - Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that has recently seen serious increase in the number of affected subjects. In the last decade, neuroimaging has been shown to be a useful tool to understand AD and its prodromal stage, amnestic mild cognitive impairment (MCI). The majority of AD/MCI studies have focused on disease diagnosis, by formulating the problem as classification with a binary outcome of AD/MCI or healthy controls. There have recently emerged studies that associate image scans with continuous clinical scores that are expected to contain richer information than a binary outcome. However, very few studies aim at modeling multiple clinical scores simultaneously, even though it is commonly conceived that multivariate outcomes provide correlated and complementary information about the disease pathology. In this article, we propose a sparse multi-response tensor regression method to model multiple outcomes jointly as well as to model multiple voxels of an image jointly. The proposed method is particularly useful to both infer clinical scores and thus disease diagnosis, and to identify brain subregions that are highly relevant to the disease outcomes. We conducted experiments on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, and showed that the proposed method enhances the performance and clearly outperforms the competing solutions. PMID- 26960223 TI - A generic hybrid model for the simulation of three-dimensional bulk elastodynamics for use in non-destructive evaluation. AB - A three-dimensional generic hybrid model is developed for the simulation of elastic waves in applications in Non- Destructive Evaluation that efficiently links different solution strategies but, crucially, is independent of the particular schemes employed. This is an important step forward in facilitating rapid and accurate large-scale simulations and this advances the twodimensional generic hybrid methodology recently developed by the authors. The hybrid model provides an efficient and effective tool for creating highly accurate simulations that model the wave propagation and scattering, enabling the interpretation of inspection data; the new methodology is verified against other numerical simulations. Furthermore, its deployment to simulate wave reflection from side drilled holes, comparing the results with experimental measurements, provides a realistic demonstration as well as further validation. PMID- 26960224 TI - Optimum Diffraction-Corrected Frequency-Shift Estimator of the Ultrasonic Attenuation Coefficient. AB - The ultrasonic attenuation coefficient is an important parameter that has been studied extensively in Quantitative Ultrasound and Tissue Characterization. There are various methods described in the literature that estimate this parameter by measuring either spectral difference (i.e., decay) or spectral shift of the backscattered echo signal. Under ideal conditions, i.e., in the absence of abrupt changes in tissue backscattering, Spectral Difference methods can produce estimates with high accuracy and precision. On the other hand, diffraction corrected Spectral Shift methods (e.g., the Hybrid method) are better suited for application in practical settings using clinical ultrasound scanners. However, current Spectral Shift methods use inefficient frequency shift estimators that ultimately degrade the quality of attenuation coefficient estimates. In this paper, a probabilistic model of the backscattered radiofrequency (RF) echo is used to derive the Cramer-Rao lower bound (CRLB) on estimation variance of the spectral centroid. Next, an efficient correlation-based shift estimator is presented that achieves the CRLB. Used in conjunction with a well-characterized reference phantom to correct for diffraction and other system-related effects, this estimator greatly improves the accuracy and precision of Spectral- Shift attenuation estimation. A theoretical analysis of this method is provided, and its performance is quantitatively compared with that of the Hybrid method using simulated and experimental phantom studies. A minimum of 3-fold reduction in the standard deviation of attenuation coefficient estimates is observed using the new method. PMID- 26960225 TI - Toward a Blind Deep Quality Evaluator for Stereoscopic Images Based on Monocular and Binocular Interactions. AB - During recent years, blind image quality assessment (BIQA) has been intensively studied with different machine learning tools. Existing BIQA metrics, however, do not design for stereoscopic images. We believe this problem can be resolved by separating 3D images and capturing the essential attributes of images via deep neural network. In this paper, we propose a blind deep quality evaluator (DQE) for stereoscopic images (denoted by 3D-DQE) based on monocular and binocular interactions. The key technical steps in the proposed 3D-DQE are to train two separate 2D deep neural networks (2D-DNNs) from 2D monocular images and cyclopean images to model the process of monocular and binocular quality predictions, and combine the measured 2D monocular and cyclopean quality scores using different weighting schemes. Experimental results on four public 3D image quality assessment databases demonstrate that in comparison with the existing methods, the devised algorithm achieves high consistent alignment with subjective assessment. PMID- 26960226 TI - Segmentation of Pollen Tube Growth Videos Using Dynamic Bi-Modal Fusion and Seam Carving. AB - The growth of pollen tubes is of significant interest in plant cell biology, as it provides an understanding of internal cell dynamics that affect observable structural characteristics such as cell diameter, length, and growth rate. However, these parameters can only be measured in experimental videos if the complete shape of the cell is known. The challenge is to accurately obtain the cell boundary in noisy video images. Usually, these measurements are performed by a scientist who manually draws regions-of-interest on the images displayed on a computer screen. In this paper, a new automated technique is presented for boundary detection by fusing fluorescence and brightfield images, and a new efficient method of obtaining the final cell boundary through the process of Seam Carving is proposed. This approach takes advantage of the nature of the fusion process and also the shape of the pollen tube to efficiently search for the optimal cell boundary. In video segmentation, the first two frames are used to initialize the segmentation process by creating a search space based on a parametric model of the cell shape. Updates to the search space are performed based on the location of past segmentations and a prediction of the next segmentation.Experimental results show comparable accuracy to a previous method, but significant decrease in processing time. This has the potential for real time applications in pollen tube microscopy. PMID- 26960227 TI - Low-Radiation Cellular Inductive Powering of Rodent Wireless Brain Interfaces: Methodology and Design Guide. AB - This paper presents a general methodology of inductive power delivery in wireless chronic rodent electrophysiology applications. The focus is on such systems design considerations under the following key constraints: maximum power delivery under the allowable specific absorption rate (SAR), low cost and spatial scalability. The methodology includes inductive coil design considerations within a low-frequency ferrite-core-free power transfer link which includes a scalable coil-array power transmitter floor and a single-coil implanted or worn power receiver. A specific design example is presented that includes the concept of low SAR cellular single-transmitter-coil powering through dynamic tracking of a magnet-less receiver spatial location. The transmitter coil instantaneous supply current is monitored using a small number of low-cost electronic components. A drop in its value indicates the proximity of the receiver due to the reflected impedance of the latter. Only the transmitter coil nearest to the receiver is activated. Operating at the low frequency of 1.5 MHz, the inductive powering floor delivers a maximum of 15.9 W below the IEEE C95 SAR limit, which is over three times greater than that in other recently reported designs. The power transfer efficiency of 39% and 13% at the nominal and maximum distances of 8 cm and 11 cm, respectively, is maintained. PMID- 26960228 TI - Haptics in Robot-Assisted Surgery: Challenges and Benefits. AB - Robotic surgery is transforming the current surgical practice, not only by improving the conventional surgical methods but also by introducing innovative robot-enhanced approaches that broaden the capabilities of clinicians. Being mainly of man-machine collaborative type, surgical robots are seen as media that transfer pre- and intraoperative information to the operator and reproduce his/her motion, with appropriate filtering, scaling, or limitation, to physically interact with the patient. The field, however, is far from maturity and, more critically, is still a subject of controversy in medical communities. Limited or absent haptic feedback is reputed to be among reasons that impede further spread of surgical robots. In this paper, objectives and challenges of deploying haptic technologies in surgical robotics are discussed, and a systematic review is performed on works that have studied the effects of providing haptic information to the users in major branches of robotic surgery. It attempts to encompass both classical works and the state-of-the-art approaches, aiming at delivering a comprehensive and balanced survey both for researchers starting their work in this field and for the experts. PMID- 26960229 TI - Quantized Iterative Learning Consensus Tracking of Digital Networks With Limited Information Communication. AB - This brief investigates the quantized iterative learning problem for digital networks with time-varying topologies. The information is first encoded as symbolic data and then transmitted. After the data are received, a decoder is used by the receiver to get an estimate of the sender's state. Iterative learning quantized communication is considered in the process of encoding and decoding. A sufficient condition is then presented to achieve the consensus tracking problem in a finite interval using the quantized iterative learning controllers. Finally, simulation results are given to illustrate the usefulness of the developed criterion. PMID- 26960230 TI - Maximizing Spectral Efficiency for Energy Harvesting-Aware WBAN. AB - In this paper, we investigate the spectral efficiency of a communication link in a wireless body area network (WBAN) capable of harvesting energy from the environment. We consider two scenarios for the transmission which are single- and dual-hop and achieve the power management policy for each scenario. In the first scenario, the aim is to maximize the link's spectral efficiency over N time slots subject to the battery capacity, energy harvesting constraint, and WBAN limitations including power and outage probability. In the second scenario, a decode-and-forward relay node is considered, and a spectral efficiency optimization problem with constraints similar to the first scenario is evaluated. In addition, since the channel distribution information is available at the transmitters, the lower and upper bounds of the average spectral efficiency are also derived in both scenarios. Finally, numerical results corroborate the analytical results. PMID- 26960232 TI - MIGS-GPU: Microarray Image Gridding and Segmentation on the GPU. AB - Complementary DNA (cDNA) microarray is a powerful tool for simultaneously studying the expression level of thousands of genes. Nevertheless, the analysis of microarray images remains an arduous and challenging task due to the poor quality of the images that often suffer from noise, artifacts, and uneven background. In this study, the MIGS-GPU [Microarray Image Gridding and Segmentation on Graphics Processing Unit (GPU)] software for gridding and segmenting microarray images is presented. MIGS-GPU's computations are performed on the GPU by means of the compute unified device architecture (CUDA) in order to achieve fast performance and increase the utilization of available system resources. Evaluation on both real and synthetic cDNA microarray images showed that MIGS-GPU provides better performance than state-of-the-art alternatives, while the proposed GPU implementation achieves significantly lower computational times compared to the respective CPU approaches. Consequently, MIGS-GPU can be an advantageous and useful tool for biomedical laboratories, offering a user friendly interface that requires minimum input in order to run. PMID- 26960231 TI - Prediction of Impaired Performance in Trail Making Test in MCI Patients With Small Vessel Disease Using DTI Data. AB - Mild cognitive impairment (MCI) is a common condition in patients with diffuse hyperintensities of cerebral white matter (WM) in T2-weighted magnetic resonance images and cerebral small vessel disease (SVD). In MCI due to SVD, the most prominent feature of cognitive impairment lies in degradation of executive functions, i.e., of processes that supervise the organization and execution of complex behavior. The trail making test is a widely employed test sensitive to cognitive processing speed and executive functioning. MCI due to SVD has been hypothesized to be the effect of WM damage, and diffusion tensor imaging (DTI) is a well-established technique for in vivo characterization of WM. We propose a machine learning scheme tailored to 1) predicting the impairment in executive functions in patients with MCI and SVD, and 2) examining the brain substrates of this impairment. We employed data from 40 MCI patients with SVD and created feature vectors by averaging mean diffusivity (MD) and fractional anisotropy maps within 50 WM regions of interest. We trained support vector machines (SVMs) with polynomial as well as radial basis function kernels using different DTI-derived features while simultaneously optimizing parameters in leave-one-out nested cross validation. The best performance was obtained using MD features only and linear kernel SVMs, which were able to distinguish an impaired performance with high sensitivity (72.7%-89.5%), specificity (71.4%-83.3%), and accuracy (77.5%-80.0%). While brain substrates of executive functions are still debated, feature ranking confirm that MD in several WM regions, not limited to the frontal lobes, are truly predictive of executive functions. PMID- 26960235 TI - Information Fusion of Passive Sensors for Detection of Moving Targets in Dynamic Environments. AB - This paper addresses the problem of target detection in dynamic environments in a semi-supervised data-driven setting with low-cost passive sensors. A key challenge here is to simultaneously achieve high probabilities of correct detection with low probabilities of false alarm under the constraints of limited computation and communication resources. In general, the changes in a dynamic environment may significantly affect the performance of target detection due to limited training scenarios and the assumptions made on signal behavior under a static environment. To this end, an algorithm of binary hypothesis testing is proposed based on clustering of features extracted from multiple sensors that may observe the target. First, the features are extracted individually from time series signals of different sensors by using a recently reported feature extraction tool, called symbolic dynamic filtering. Then, these features are grouped as clusters in the feature space to evaluate homogeneity of the sensor responses. Finally, a decision for target detection is made based on the distance measurements between pairs of sensor clusters. The proposed procedure has been experimentally validated in a laboratory setting for mobile target detection. In the experiments, multiple homogeneous infrared sensors have been used with different orientations in the presence of changing ambient illumination intensities. The experimental results show that the proposed target detection procedure with feature-level sensor fusion is robust and that it outperforms those with decision-level and data-level sensor fusion. PMID- 26960236 TI - Weighted Joint Sparse Representation for Removing Mixed Noise in Image. AB - Joint sparse representation (JSR) has shown great potential in various image processing and computer vision tasks. Nevertheless, the conventional JSR is fragile to outliers. In this paper, we propose a weighted JSR (WJSR) model to simultaneously encode a set of data samples that are drawn from the same subspace but corrupted with noise and outliers. Our model is desirable to exploit the common information shared by these data samples while reducing the influence of outliers. To solve the WJSR model, we further introduce a greedy algorithm called weighted simultaneous orthogonal matching pursuit to efficiently approximate the global optimal solution. Then, we apply the WJSR for mixed noise removal by jointly coding the grouped nonlocal similar image patches. The denoising performance is further improved by incorporating it with the global prior and the sparse errors into a unified framework. Experimental results show that our denoising method is superior to several state-of-the-art mixed noise removal methods. PMID- 26960237 TI - Cooperative Semi-Global Output Regulation of Nonlinear Strict-Feedback Multi Agent Systems With Nonidentical Relative Degrees. AB - In this paper, we study the cooperative semi-global output regulation problem for a class of nonlinear strict-feedback multi-agent systems, where the subsystems are assumed to have nonidentical relative degrees. We first introduce the so called distributed internal model that converts our problem into the cooperative semi-global stabilization problem of the corresponding augmented system composed of the original multi-agent system and the internal model. We then put this augmented system into the general block lower triangular form, and develop the block semi-global backstepping technique to stabilize it. Comparing with some existing literatures, our design has removed the identical relative degree assumption, and hence applies to a much larger group of nonlinear multi-agent systems. PMID- 26960238 TI - Distributed $k$ -Means Algorithm and Fuzzy $c$ -Means Algorithm for Sensor Networks Based on Multiagent Consensus Theory. AB - This paper is concerned with developing a distributed k-means algorithm and a distributed fuzzy c-means algorithm for wireless sensor networks (WSNs) where each node is equipped with sensors. The underlying topology of the WSN is supposed to be strongly connected. The consensus algorithm in multiagent consensus theory is utilized to exchange the measurement information of the sensors in WSN. To obtain a faster convergence speed as well as a higher possibility of having the global optimum, a distributed k-means++ algorithm is first proposed to find the initial centroids before executing the distributed k means algorithm and the distributed fuzzy c-means algorithm. The proposed distributed k-means algorithm is capable of partitioning the data observed by the nodes into measure-dependent groups which have small in-group and large out-group distances, while the proposed distributed fuzzy c-means algorithm is capable of partitioning the data observed by the nodes into different measure-dependent groups with degrees of membership values ranging from 0 to 1. Simulation results show that the proposed distributed algorithms can achieve almost the same results as that given by the centralized clustering algorithms. PMID- 26960239 TI - What's Hindering Dentistry From the Widespread Adoption of CT-Guided Surgery? AB - Although computed tomography (CT)-guided technology has been shown to increase implant placement accuracy, decrease surgical complications, and improve the predictability of implant case outcome, many in the dental implant community continue to resist using it for three main reasons: time, money, and fear. While it is true that there are additional preparatory steps necessary in patient case planning and the practitioner must invest in unfamiliar technologies and overcome a learning curve, increased efficiency, improved restorative outcomes, and clear benefits to both patients and practitioners make a strong case for adopting this approach. PMID- 26960240 TI - Today's Dental Imaging: Providing Clinicians Improved Control Over Treatment. PMID- 26960241 TI - New form of the journal Prilozi (Contributions) of the Macedonian Academy of Sciences and Arts, Section of Medical Sciences. PMID- 26960242 TI - Preface. PMID- 26960243 TI - Caring for Caregivers: Bridging the Care Gap. AB - While drawing on different perspectives, the insightful responses of our commentators all highlight the increasingly crucial role of informal, and mostly unpaid caregivers. They also raise key questions. The first question, "how should we refer to caregivers," pushes us to acknowledge the diversity of caregiver characteristics, contexts and roles. The second, "how should we understand the caregiver 'problem'," reminds us that although often thought of as an individual matter, caregiving is a public policy issue requiring broader systems thinking and approaches. The third, "what should we do about it," draws attention to the importance of building and strengthening social networks to support caregivers and bridge a "growing care gap." We offer the example of Japan which, as part of its national dementia care policy, is now encouraging the development of inter generational dementia-friendly communities. PMID- 26960244 TI - Letter from the editor. PMID- 26960246 TI - Three-Dimensional Metal-Fullerene Frameworks. AB - Hexakis-substituted [60]fullerene adducts with icosahedral symmetry provide an unprecedented scaffold for the spatial arrangement of twelve functional groups with high geometric precision. This unique molecular symmetry identifies such polyfunctional organic building blocks as potential highly connective linkers for coordination polymer and metal-organic framework synthesis. Hereby, the linker exhibits a higher connectivity than the metal ions and with the main connectivity based on the ligand, this can create a new type of inversely cross-linked framework. Two hexakis adducts bearing either twelve glycolic acid or 3 hydroxypropionic acid side chains attached to its malonate units were incorporated as organic connectivity centers in the first fullerene-containing three-dimensional frameworks by coordination with Zn(2+) . PMID- 26960245 TI - Tiotropium add-on therapy in adolescents with moderate asthma: A 1-year randomized controlled trial. AB - BACKGROUND: Results from phase III clinical trials in adults and phase II clinical trials in children and adolescents demonstrate that tiotropium is an effective treatment when added to inhaled corticosteroid (ICS) maintenance therapy. OBJECTIVE: We sought to assess the efficacy and safety of once-daily tiotropium Respimat added to ICSs with or without a leukotriene receptor antagonist in a phase III trial in adolescent patients with moderate symptomatic asthma. METHODS: In this 48-week, double-blind, placebo-controlled, parallel group study, 398 patients aged 12 to 17 years were randomized to receive 5 MUg (2 puffs of 2.5 MUg) or 2.5 MUg (2 puffs of 1.25 MUg) of once-daily tiotropium or placebo (2 puffs) administered through the Respimat device every evening, each as add-on treatment to ICS background therapy, with or without a leukotriene receptor antagonist; long-acting beta2-agonist therapy was not permitted during the study. RESULTS: Improvement in peak FEV1 within 3 hours after dosing at 24 weeks (primary end point) was statistically significant with both tiotropium doses compared with placebo: 5 MUg of tiotropium, 174 mL (95% CI, 76-272 mL); 2.5 MUg of tiotropium, 134 mL (95% CI, 34-234 mL). Significant improvements in trough FEV1 at week 24 (a secondary end point) were observed with the 5-MUg dose only. Trends for improvement in asthma control and health-related quality of life over the 48-week treatment period were observed. CONCLUSIONS: Once-daily tiotropium significantly improved lung function and was safe and well tolerated when added to at least ICS maintenance therapy in adolescent patients with moderate symptomatic asthma. Larger responses were observed with the 5-MUg tiotropium dose. PMID- 26960248 TI - Errata. PMID- 26960247 TI - Efficient network disintegration under incomplete information: the comic effect of link prediction. AB - The study of network disintegration has attracted much attention due to its wide applications, including suppressing the epidemic spreading, destabilizing terrorist network, preventing financial contagion, controlling the rumor diffusion and perturbing cancer networks. The crux of this matter is to find the critical nodes whose removal will lead to network collapse. This paper studies the disintegration of networks with incomplete link information. An effective method is proposed to find the critical nodes by the assistance of link prediction techniques. Extensive experiments in both synthetic and real networks suggest that, by using link prediction method to recover partial missing links in advance, the method can largely improve the network disintegration performance. Besides, to our surprise, we find that when the size of missing information is relatively small, our method even outperforms than the results based on complete information. We refer to this phenomenon as the "comic effect" of link prediction, which means that the network is reshaped through the addition of some links that identified by link prediction algorithms, and the reshaped network is like an exaggerated but characteristic comic of the original one, where the important parts are emphasized. PMID- 26960249 TI - Prescribers' behavior following below- versus above-range international normalized ratio values in warfarin-treated deep vein thrombosis patients. AB - Maintaining acceptable international normalized ratio (INR) control among deep vein thrombosis (DVT) patients taking warfarin is challenging. We evaluated prescribers' behavior to out-of-range INRs in DVT patients following initial INR stabilization. Following INR stabilization, a below-range INR was associated with fewer subsequent measurements and warfarin-dosing adjustments, and a longer time to re-achieve a therapeutic INR compared to an above-range INR. PMID- 26960251 TI - Corrigendum: X-Linked Retinoschisis: Phenotypic Variability in a Chinese Family. PMID- 26960250 TI - In vivo cross-sectional imaging of the phonating larynx using long-range Doppler optical coherence tomography. AB - Diagnosis and treatment of vocal fold lesions has been a long-evolving science for the otolaryngologist. Contemporary practice requires biopsy of a glottal lesion in the operating room under general anesthesia for diagnosis. Current in office technology is limited to visualizing the surface of the vocal folds with fiber-optic or rigid endoscopy and using stroboscopic or high-speed video to infer information about submucosal processes. Previous efforts using optical coherence tomography (OCT) have been limited by small working distances and imaging ranges. Here we report the first full field, high-speed, and long-range OCT images of awake patients' vocal folds as well as cross-sectional video and Doppler analysis of their vocal fold motions during phonation. These vertical cavity surface-emitting laser source (VCSEL) OCT images offer depth resolved, high-resolution, high-speed, and panoramic images of both the true and false vocal folds. This technology has the potential to revolutionize in-office imaging of the larynx. PMID- 26960252 TI - Late Sequel of Meningococcemia: Skeletal Dysplasia. PMID- 26960253 TI - [Toward a New Immunization Schedule in Spain, 2016 (Part 1)]. AB - The immunization Schedule is a dynamic public health tool that has incorporated different changes over the years influenced by the epidemiologic situation and the scientific evidence. The Immunization Advisory Committee [Ponencia de Programa y Registro de Vacunaciones], as the Interterritorial Council scientific and technical advisory body, carries out assessments of different programmes and vaccines and proposes changes that after approval will be introduced in the Regions schedule. This article is divided into two parts presenting the rationale followed to propose a new schedule for the immunization against diphtheria, tetanus, pertussis, hepatitis B and invasive disease by Haemophilus influenzae type b. This first part is focused in the reasoning to undertake the assessment, the review of the immunization policy and the impact of immunization in Spain, as well as a review of the immunization schedules in similar countries. PMID- 26960255 TI - Evaluating the capabilities model of dementia care: a non-randomized controlled trial exploring resident quality of life and care staff attitudes and experiences. AB - BACKGROUND: This 12 month, Australian study sought to compare the Capabilities Model of Dementia Care (CMDC) with usual long-term care (LTC), in terms of (1) the effectiveness of the CMDC in assisting care staff to improve Quality Of Life (QOL) for older people with dementia; and (2) whether implementation of the CMDC improved staff attitudes towards, and experiences of working and caring for the person with dementia. METHODS: A single blind, non-randomized controlled trial design, involving CMDC intervention group (three facilities) and a comparison usual LTC practice control group (one facility), was conducted from August 2010 to September 2011. Eighty-one staff members and 48 family members of a person with dementia were recruited from these four LTC facilities. At baseline, 6 and 12 months, staff completed a modified Staff Experiences of Working with Demented Residents questionnaire (SEWDR), and families completed the Quality of Life - Alzheimer's Disease questionnaire (QOL-AD). RESULTS: LTC staff in the usual care group reported significantly lower SEWDR scores (i.e. less work satisfaction) than those in the CMDC intervention group at 12 months (p = 0.005). Similarly, family members in the comparison group reported significantly lower levels of perceived QOL for their relative with dementia (QOL-AD scores) than their counterparts in the CMDC intervention group at 12 months (p = 0.012). CONCLUSIONS: Although the study has a number of limitations the CMDC appears to be an effective model of dementia care - more so than usual LTC practice. The CMDC requires further evaluation with participants from a diverse range of LTC facilities and stages of cognitive impairment. PMID- 26960256 TI - Correction: Self-monitored photothermal nanoparticles based on core-shell engineering. AB - Correction for 'Self-monitored photothermal nanoparticles based on core-shell engineering' by Erving C. Ximendes et al., Nanoscale, 2016, 8, 3057-3066. PMID- 26960254 TI - The unconventional myosin CRINKLED and its mammalian orthologue MYO7A regulate caspases in their signalling roles. AB - Caspases provide vital links in non-apoptotic regulatory networks controlling inflammation, compensatory proliferation, morphology and cell migration. How caspases are activated under non-apoptotic conditions and process a selective set of substrates without killing the cell remain enigmatic. Here we find that the Drosophila unconventional myosin CRINKLED (CK) selectively interacts with the initiator caspase DRONC and regulates some of its non-apoptotic functions. Loss of CK in the arista, border cells or proneural clusters of the wing imaginal discs affects DRONC-dependent patterning. Our data indicate that CK acts as substrate adaptor, recruiting SHAGGY46/GSK3-beta to DRONC, thereby facilitating caspase-mediated cleavage and localized modulation of kinase activity. Similarly, the mammalian CK counterpart, MYO7A, binds to and impinges on CASPASE-8, revealing a new regulatory axis affecting receptor interacting protein kinase-1 (RIPK1)>CASPASE-8 signalling. Together, our results expose a conserved role for unconventional myosins in transducing caspase-dependent regulation of kinases, allowing them to take part in specific signalling events. PMID- 26960257 TI - [Early detection or screening in the prevention of prostate cancer?] AB - Prostate cancer (PC) is the most common malignancy in men in the developed world and the second leading cause of cancer death in men in the USA, behind lung cancer. In Europe, it is the third leading cause of cancer death in men (after lung and colorectal cancers). The role of PC screening is currently being questioned. The following article summarises the most relevant epidemiological aspects of PC, as well as major clinical trials of PC screening, and recommendations of the various medical scientific associations on whether or not to screen for PC. PMID- 26960258 TI - Modifications in nitric oxide and superoxide anion metabolism induced by fructose overload in rat heart are prevented by (-)-epicatechin. AB - Fructose overload promotes functional and metabolic derangements in humans and in animal experimental models. Evidence suggests that dietary flavonoids have the ability to prevent/attenuate the development of metabolic diseases. In this work we investigated the effects of (-)-epicatechin on the modifications induced by fructose overload in the rat heart in terms of nitric oxide and superoxide metabolism. Male Sprague Dawley rats received 10% (w/v) fructose in the drinking water for 8 weeks, with or without (-)-epicatechin (20 mg per kg body weight per day) in the rat chow diet. These conditions of fructose overload did not lead to overt manifestations of heart hypertrophy or tissue remodeling. However, biochemical and molecular changes were observed and could represent the onset of functional alterations. (-)-Epicatechin prevented a compromised NO bioavailability and the development of oxidative stress produced by fructose overload essentially acting on superoxide anion metabolism. In this line, the increase in superoxide anion production, the overexpression of NOX2 subunit p47phox and of NOX4, the decrease in superoxide dismutase activity, and the higher oxidized/reduced glutathione ratio installed by fructose overload were absent in the rats receiving (-)-epicatechin. These results support the hypothesis that diets rich in (-)-epicatechin could prevent the onset and progression of heart dysfunctions associated with metabolic alterations. PMID- 26960260 TI - Response to: Sjogren's syndrome and halitosis: A case report. PMID- 26960259 TI - Brain mechanisms associated with internally directed attention and self-generated thought. AB - Internal cognition like imagination and prospection require sustained internally directed attention and involve self-generated thought. This fMRI study aimed to disentangle the brain mechanisms associated with attention-specific and task specific processes during internally directed cognition. The direction of attention was manipulated by either keeping a relevant stimulus visible throughout the task, or by masking it, so that the task had to be performed "in the mind's eye". The level of self-directed thought was additionally varied between a convergent and a divergent thinking task. Internally directed attention was associated with increased activation in the right anterior inferior parietal lobe (aIPL), bilateral lingual gyrus and the cuneus, as well as with extended deactivations of superior parietal and occipital regions representing parts of the dorsal attention network. The right aIPL further showed increased connectivity with occipital regions suggesting an active top-down mechanism for shielding ongoing internal processes from potentially distracting sensory stimulation in terms of perceptual decoupling. Activation of the default network was not related to internally directed attention per se, but rather to a higher level of self-generated thought. The findings hence shed further light on the roles of inferior and superior parietal cortex for internally directed cognition. PMID- 26960261 TI - The interlocking finger test in patients with Parkinson's disease and healthy subjects. AB - The interlocking finger test (ILFT) is a bedside screening test in which the subject must imitate four bimanual finger gestures without symbolic meaning. We assessed the utility of the test in the cognitive evaluation of patients with Parkinson's disease (PD). We evaluated 88 healthy subjects and 101 patients with PD using a simplified motor score of the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr and Schwab and England scales, Geriatric Depression Scale, Pfeffer Functional Activities Questionnaire, Clinical Dementia Rating, Mini-Mental State Examination, clock drawing test, digit span, word list battery of the Consortium to Establish a Registry for Alzheimer's Disease assessment, Frontal Assessment Battery, semantic verbal fluency test, and the ILFT. Diagnoses of mild cognitive impairment and dementia were made using the Movement Disorder Society diagnostic criteria. ILFT scores in healthy subjects correlated significantly with age (p=0.001) and only one healthy subject scored 2 in the test. ILFT scores were significantly lower in patients with PD and dementia (p=0.001) and significantly correlated with cognitive and functional tests, but not with depressive symptoms (p=0.607), Hoehn and Yahr scores (p=0.907), or Schwab and England scores (p=0.701). Twenty-five patients with dementia, three patients with mild cognitive impairment, and six patients with apparently normal cognition scored less than 3 in the ILFT. The area under the receiver operating characteristic curve for the ILFT to discriminate patients with dementia from those without it was 0.76 (cut-off score of 3/2: sensitivity of 61%, specificity of 0.85). In conclusion, the ILFT seems to be a useful bedside test to assess cognitive impairment in patients with PD. PMID- 26960262 TI - Chronic basilar artery dissection with an associated symptomatic aneurysm presenting with massive subarachnoid hemorrhage. AB - Basilar artery dissection (BAD) is a rare condition with a worse prognosis than a dissection limited to the vertebral artery. We report a rare case of chronic BAD with an associated symptomatic aneurysm presenting with massive subarachnoid hemorrhage (SAH) in a 54-year-old woman. The diagnosis of acute BAD could only be made retrospectively, based on clinical and neuroradiological studies from a hospital admission 10months earlier. Angiography performed after her SAH showed unequivocal signs of imperfect healing; she was either post-recanalization of a complete occlusion or post-dissection. Residual multi-channel intraluminal defects led to the development of a small aneurysm, which was responsible for the massive hemorrhage. The occurrence of an associated aneurysm, and wall disease, but not an intraluminal process, reinforces the diagnosis of dissection. The patient was fully recovered at 90day follow-up. This case reinforces the need for long-term neuroradiological surveillance after non-hemorrhagic intracranial dissections to detect the development of de novo aneurysms. PMID- 26960264 TI - Proteus mirabilis abscess involving the entire neural axis. AB - Intramedullary spinal cord abscesses are rare and potentially devastating lesions usually associated with other infective processes such as bacterial endocarditis, or pulmonary or urogenital infection. We describe a 2-year-old girl who presented with an infected dermal sinus leading to an intraspinal abscess. This abscess eventually spread and involved the entire neural axis leaving her quadriparetic. Drainage of the abscess resulted in recovery and the child regained normal function of her limbs. To our knowledge this is the first documented case of an intramedullary abscess involving the entire neural axis. PMID- 26960263 TI - Utility of positron emission tomography in schwannomatosis. AB - Schwannomatosis is characterized by multiple non-intradermal schwannomas with patients often presenting with a painful mass in their extremities. In this syndrome malignant transformation of schwannomas is rare in spite of their large size at presentation. Non-invasive measures of assessing the biological behavior of plexiform neurofibromas in neurofibromatosis type 1 such as positron emission tomography (PET), CT scanning and MRI are well characterized but little information has been published on the use of PET imaging in schwannomatosis. We report a unique clinical presentation portraying the use of PET imaging in schwannomatosis. A 27-year-old woman presented with multiple, rapidly growing, large and painful schwannomas confirmed to be related to a constitutional mutation in the SMARCB1 complex. Whole body PET/MRI revealed numerous PET-avid tumors suggestive of malignant peripheral nerve sheath tumors. Surgery was performed on multiple tumors and none of them had histologic evidence of malignant transformation. Overall, PET imaging may not be a reliable predictor of malignant transformation in schwannomatosis, tempering enthusiasm for surgical interventions for tumors not producing significant clinical signs or symptoms. PMID- 26960265 TI - Optimal duration of video-electroencephalographic monitoring to capture seizures. AB - We aimed to find the optimal duration of long-term video-electroencephalographic monitoring (VEM) to capture seizures in patients with epileptic seizures (ES) and psychogenic non-epileptic seizures (PNES) by evaluating the time to first clinical event and the diagnostic yield of clinical events and positive cases in each day of VEM. Patients aged ?18years who underwent VEM from May 2009 to June 2014 were studied retrospectively. Demographic, clinical and VEM data (including total monitoring length, type and time to first event, total number of ES/PNES) were collected. The difference in time to the first event between ES and PNES was analysed with Mann-Whitney U test. Of 207 VEM studies performed during the 5year period, 108 recordings captured seizures (ES and PNES) (52.2%). Median times to the first ES and PNES were 19.7 and 23.4hours, respectively (p=0.99). A small majority (53.7%) of event-positive patients had their first event on the first day of monitoring. By the end of the fifth day, 98% of all clinical events were captured and 99% of all positive cases were diagnosed. In conclusion, in a patient monitoring program where a diagnosis is reached by capturing seizures, 5days is probably sufficient to capture the greatest number of events and diagnose 99% of those patients. PMID- 26960266 TI - Geographical access to radiation therapy in North Queensland: a retrospective analysis of patient travel to radiation therapy before and after the opening of an additional radiotherapy facility. AB - INTRODUCTION: Access to radiation therapy (RT) underlies optimal care for prostate and breast cancer patients. This study investigates the impact of opening a new RT clinic on distance and road travel time to RT, and overall utilisation for prostate and breast cancer patients over a 3-year period in North Queensland (NQ), Australia. METHODS: The study used retrospective audit of two radiotherapy databases and a geographic information system to illustrate patient origins and distance to the RT clinic used over 3 years. Prostate and female breast cancer patients were selected from the radiation oncology databases of The Townsville Hospital (TTH) and Radiation Oncology Queensland (ROQ) Cairns between 1 July 2010 and 30 June 2013. Distance from a patient's home origin to the RT facility was mapped using a geographic information system (ArcGIS software), and travel time (minutes) and road distance (km) determined by Google Maps road directions. RESULTS: Overall number of prostate and breast cancer patients treated by RT in Cairns and Townsville clinics increased by 16% in 2011-2012 and by 29% in 2012-2013 from year 1 values. In 2010, 44% of the patients travelled 200-400 km to RT, which reduced to 21% in 2013. By 2013, with a second treatment facility, more than 70% of patients lived within 200 km of an RT facility (p<0.0001). Total median road travel time reduced annually from 201 minutes in 2010-2011 to 66 minutes in 2011-2012 and 56 minutes in 2012-2013 (p<0.0001), corresponding to a decrease in the median distance travelled to an RT facility. CONCLUSIONS: An additional RT facility in NQ has led to an increase in patients treated with RT for prostate and breast cancer and, on average, less travel distance and time to treatment, suggesting improvement in access to RT in NQ. PMID- 26960268 TI - Colorimetric method for rapid detection of Oxacillin resistance in Staphylococcus aureus and its comparison with PCR for mec A gene. AB - Rapid and accurate detection of Methicillin Resistant Staphylococcus aureus (MRSA) is an important role of clinical microbiology laboratories to avoid treatment failure. The detection of MRSA is based on phenotypic assays which require at least 24 h to perform. Detection of the mecA gene or of PBP 2a is the "gold standard", but not always available. The aim of this study was to evaluate a rapid method for detection of MRSA by using 3 (4, 5 dimethyl thiazole -2-yl) 2, 5 diphenyl tetrazolium bromide (MTT). Total 126 isolates of MRSA were collected from tertiary healthcare center and were confirmed by oxacillin screening agar test as per CLSI guidelines. Amplification of mecA gene was performed by using PCR. MTT assay was carried out for all the isolates in 96 well Microtitre plate and compared with standard methods of CLSI. Out of 126 isolates, 98 were found to be mecA positive. MTT method was found to be 98.98% sensitive and 96.43% specific. The MTT based colorimetric method is rapid and simple test for screening of oxacillin resistance in Staphylococcus aureus. It significantly shortens the time to just 7 h required to obtained a drug susceptibility test and could be useful to screen MRSA. PMID- 26960267 TI - Estrogen ameliorates microglial activation by inhibiting the Kir2.1 inward rectifier K(+) channel. AB - Microglial activation is implicated in the pathogenesis of Parkinson's disease (PD). Although the etiology of PD remains unclear, age and male gender are known PD risk factors. By comparing microglia and dopaminergic (DA) neurons in the substantia nigra (SN) of male and female mice of different ages, we found that the degrees of microglial activation and DA neuron loss increased with age in both genders, but were more pronounced in males, as were peripheral lipopolysaccharide (LPS)-induced microglial activation and DA neuron loss. A bilateral ovariectomy (OVX) eliminated the female-associated protection against age- and LPS-induced microglial activation, which suggests that ovary hormones are involved in gender-specific responses. Treating female mice with 17beta estradiol supplements reduced the age-associated microglial activation in OVX mice. Moreover, pretreating mouse BV2 microglial cells with 17beta-estradiol inhibited LPS-induced elevation of Toll-like receptor 4, phosphorylated p38, and TNF-alpha levels. We then examined the effect of 17beta-estradiol on inward rectifier K(+) channel Kir2.1, a known regulator of microglial activation. We found that 17beta-estradiol inhibited the Kir2.1 activity of BV2 cells by reducing the probability that the channel would be open. We conclude that age- and inflammation-associated microglial activation is attenuated by ovarian estrogen, because it inhibits Kir2.1. PMID- 26960269 TI - [A case of MELAS associated with histochemical findings of muscles characteristic of MERRF]. AB - We here report a 39-year-old woman of short stature with sensorineural deafness, who suddenly developed status epilepticus. T2-weighed image of brain magnetic resonance imaging (MRI) revealed a high signal lesion in the left temporal area, the distribution of which was not compatible with any particular arterial supply. Lactate and pyruvate were elevated in the serum and cerebrospinal fluid. As the mitochondrial gene analysis revealed the m.3243A>G mutation, diagnosis of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS) was made. In the histochemical study of a biopsied muscle, the intramuscular blood vessels reacted strongly with SDH (SSV), but the SSV was negative for cytochrome c oxidase (COX), the findings characteristic of myoclonic epilepsy with ragged-red fibers (MERRF). This is the first case of MELAS in which the muscle histochemistry showed positive SSV unassociated with increased COX. PMID- 26960270 TI - [A case of rhabdomyolysis after status epilepticus without stroke-like episodes in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes]. AB - A 24-year-old man was referred to our hospital emergency department due to a sudden onset of convulsions after drinking. On arrival he presented status epilepticus and was managed by artificial ventilation. He had no brainstem signs or meningeal irritation. Head MRI showed an old infarction-like lesion in the left occipital lobe, but no abnormal signals on diffusion-weighted images. The patient showed acute rhabdomyolysis (CK 18,000 IU/l) and renal failure, and hemodialysis was started. On 18 day after admission, he was transferred to our department with mild proximal limb muscle weakness and bilateral sensorineural hearing impairment. Electroencephalography demonstrated diffuse intermittent slow wave activities. We suspected a mitochondrial disease because of a significant increase in the lactate/pyruvate ratio (24.1) in the spinal fluid, and identified A3243G mutations in mitochondrial DNA (heteroplasmy 20%) in peripheral white blood cells. We diagnosed his illness as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). This is a rare case presenting an acute onset of rhabdomyolysis following alcohol intake related to A3243G mitochondrial mutation without preceding stroke-like episodes. PMID- 26960271 TI - [A case of primary central nervous system vasculitis diagnosed by second brain biopsy and treated successfully]. AB - We report a case of primary central nervous system vasculitis (PCNSV) diagnosed by second brain biopsy. A 53-year-old man initially presented with left lateral gaze diplopia. Brain MRI revealed multiple enhanced lesions in the bilateral frontal lobe, bilateral basal ganglia, left cerebellum and brainstem. An initial brain biopsy of the right frontal lobe suggested immune-related encephalitis with angiocentric accumulation of chronic inflammatory cells, while malignant lymphoma could not be completely ruled out. The patient deteriorated despite being treated with repeated methylprednisolone pulse therapy, cyclophosphamide, and plasmapheresis. A second brain biopsy of the right temporal lobe was then performed. The biopsied specimens showed vascular wall disruption and fibrinoid necrosis with perivascular inflammatory infiltrates, mainly composed of CD8 positive T cells, and PCNSV was diagnosed. He was treated with high dose corticosteroids, in combination with methotrexate (8 mg/week), which reduced the brain lesions. As brain biopsy is an essential investigation for the histological diagnosis of PCNSV; subsequent biopsies may be required when a histopathological diagnosis has not been obtained by the first biopsy, and further aggressive therapy is being considered. PMID- 26960272 TI - [Multiple cerebral artery occlusion due to non-bacterial thrombotic endocarditis: an autopsy case report]. AB - A 60-year-old man was admitted to our hospital because of vertigo and repeated vomiting, which suddenly occurred 25 hours before admission. Neurologic examination revealed Wallenberg syndrome on the left side, and brain MRI showed acute infarcts in the left lateral medulla as well as in the left internal carotid artery (ICA) territory. MR angiography did not depict the left vertebral artery (VA) and the left ICA. Despite antithrombotic treatment, he developed bulbar palsy, and then, brain herniation due to infarct growth in the left middle cerebral artery territory. He died on day 9. Histopathlogical examination found verruca involving the mitral leaflet, which was consistent with non-bacterial thrombotic endocarditis (NBTE). Atherosclerosis was also found in the systemic arteries, and there was sclerotic stenosis with calcification at the portion of piercing dulla matter in the left VA and at the cavernous segment of the left ICA. Because the cerebral emboli in the narrowed lumen presented a histologic appearance similar to that of the verruca, the diagnosis of brain embolism due to NBTE was confirmed. PMID- 26960273 TI - Correspondence: Reply to 'SEMA4A variation and risk of colorectal cancer'. PMID- 26960274 TI - Effect of students' determination of testing time on their test performance. AB - This article investigates whether giving students control over preparing for and the moment of taking a test affects their test results in comparison with when the school is in control of the amount of training followed by a predetermined test moment. The students participated in training for manual dexterity. After the training, the students performed a test. The results of the test were stored in a database. Students from the group with freedom to select the moment of the test performed much better than those in the other group who did not have the freedom to select the moment for the test, with significantly fewer students requiring three attempts to pass the test. The fact that students when given the responsibility to develop manual skills performed better than when guided by the policy of the school is hopeful in the sense that students can learn in an early stage of their study to take responsibility for learning. PMID- 26960276 TI - Endoscope-Assisted Microsurgical Removal of an Intraventricular Ependymal Cyst That Manifested with Tremor. AB - BACKGROUND: Intraventricular ependymal cysts (ECs) are rare, histologically benign neuroepithelial cysts. Most of these cysts are clinically silent and discovered incidentally. Rarely, they become symptomatic, leading to obstruction of the cerebrospinal fluid circulation. ECs located inside the ventricles may manifest with signs of increased intracranial pressure. CASE DESCRIPTION: A 32 year-old woman presented with a 6-year history of tremor affecting her left hand. In the last month, she had been experiencing headache as well, and the tremor of the left hand was affecting her quality of life. The patient demonstrated a fine resting and intention tremor of the left hand and a voice tremor. Magnetic resonance imaging revealed a large cystic, nonenhancing lesion within the right lateral ventricle. The fluid within the cyst was isointense to cerebrospinal fluid on all sequences. Because of the rapid progression of her symptoms and no response to medication, surgical decompression of the cyst was considered. The cyst was removed by an endoscope-assisted microsurgical technique. Her postoperative course was uneventful. A marked reduction in her tremor was noted in the immediate postoperative period. Histopathologic diagnosis was of an EC. During the follow-up period, the patient's tremor, although still present, had improved dramatically. At 6 months postoperatively, she could hold a drinking glass without spilling. CONCLUSIONS: This is a unique case of an intraventricular EC that manifested with tremor, which improved by endoscope-assisted microsurgical removal of the cyst. This case also supports the important role of endoscopic surgery in the treatment of intraventricular cystic lesions. PMID- 26960277 TI - Endoscopic Endonasal Anterior Skull Base Surgery: A Systematic Review of Complications During the Past 65 Years. AB - BACKGROUND: Endoscopic skull base surgery is becoming more popular as an approach to the anterior skull base for tumors and cerebrospinal fluid (CSF) fistulae. It offers the advantages of better cosmesis and improved quality of life after surgery. We reviewed the complication rates reported in the literature. METHODS: A literature search was performed in the electronic database Ovid MEDLINE (1950 to August 25, 2015) with the search item "([Anterior] AND Skull base surgery) AND endoscopic." RESULTS: We identified 82 relevant studies that included 7460 cases. An average overall complication rate of 17.1% (range 0%-68.0%) and a mortality rate of 0.4% (0%-10.0%) were demonstrated in a total of 82 studies that included 7460 cases. The average CSF leak rate for all studies was 8.9% (0%-40.0%) with meningiomas and clival lesions having the greatest CSF leak rates. The most frequent benign pathology encountered was pituitary adenomas (n = 3720, 49.8% of all cases) and the most frequent malignant tumor was esthesioneuroblastoma (n = 120, 1.6% of all cases). Studies that included only CSF fistula repairs had a lower average total complication rate (12.9%) but a greater rate of meningitis compared with studies that reported mixed pathology (2.4% vs. 1.3%). A trend towards a lower total complication rate with increasing study size was observed. CONCLUSIONS: The endoscopic approach is an increasingly accepted technique for anterior skull base tumor surgery and is associated with acceptable complication rates. Increasing experience with this technique can decrease rates of complications. PMID- 26960278 TI - Progesterone for Traumatic Brain Injury: A Meta-Analysis Review of Randomized Controlled Trials. AB - OBJECTIVE: To conduct a meta-analysis to determine whether progesterone, compared with placebo or no treatment, influences mortality and neurologic outcome in traumatic brain injury (TBI). METHODS: To identify eligible studies, systematic searches for randomized controlled trials of progesterone treatment in TBI were conducted in PubMed, Web of Science, EMBASE, Cochrane Library, and ClinicalTrials.gov databases. The search yielded 8 studies that were included in the meta-analysis. Included data were study characteristics, patient demographics, baseline characteristics, progesterone treatment protocol, main outcome of mortality, and secondary neurologic outcome evaluated using the Glasgow Outcome Scale. RESULTS: The 8 studies comprised 2585 patients. The meta analysis indicated that there was no evidence that progesterone treatment decreased the risk of mortality in patients with TBI; the overall risk ratio was 0.852 (95% confidence interval, 0.632-1.144; P = 0.284). In the secondary outcome analysis, progesterone had no neuroprotective role in improving neurologic outcome; the overall risk ratio was 1.151 (95% confidence interval, 0.0991-1.338; P = 0.06). Subgroup analysis according to the degree of injury assessed by the Glasgow Coma Scale demonstrated similar results. CONCLUSIONS: This study is the largest meta-analysis conducted to date to determine whether progesterone is effective in the treatment of TBI. The findings indicate that progesterone treatment does not decrease mortality or improve neurologic outcome in patients with TBI. PMID- 26960280 TI - Telemedicine Is Here. PMID- 26960281 TI - Operant Conditioning and the Practice of Defensive Medicine. PMID- 26960279 TI - Management Overview: Taking a Patient with Intracranial Hemorrhage Related to Direct Oral Anticoagulants to the Operating Room. AB - Options for anticoagulation have been expanding constantly during the past few years, providing a greater number of agents for prevention and management of thromboembolic disease. Although heparins and vitamin K antagonists (VKAs) has been used extensively for many decades, their narrow therapeutic range, interactions with other medications and food, and the need for routine monitoring of blood levels have led to the search for less problematic alternatives. Direct oral anticoagulants represent an important advance in anticoagulation therapy, directly inhibiting thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban) they represent an effective and safe alternatives to VKAs and heparins in the prevention and treatment of several thromboembolic disorders. DOCAs are associated with a low overall intracranial hemorrhage risk; however, life threatening bleeding can occur. Reversal agents are approved for some and under development for others, concerns over the lack of antidotes or difficulty in obtaining them has tempered enthusiasm for their use because of the perception of better safety with heparins and VKAs as a result of the availability of effective reversal strategies. Appropriate use of these agents requires knowledge of their individual characteristics, mechanisms of action, pharmacokinetics, ways of monitoring, and when needed, manage patients in need of urgent surgery especially in life-threatening bleeds. This article provides a suggested comprehensive approach to manage patients with intracranial hemorrhage while on direct oral anticoagulants who require an urgent surgical intervention and who cannot wait for plasma concentration to decline. PMID- 26960283 TI - The Philosophy of Kaizen and Telemedicine. PMID- 26960282 TI - High Carbonic Anhydrase-9 Expression Identifies a Subset of 1p/19q Co-Deletion and Favorable Prognosis in Oligodendroglioma. AB - OBJECTIVE: To investigate the relationship between 3 hypoxic markers, carbonic anhydrase-9 (CA-9), hypoxia-inducible factor (HIF)-1alpha, and HIF-2alpha and the traditional genetic markers, deletions of chromosomes 1p and 19q and Isocitrate dehydrogenase 1 (IDH1) R132H mutation in oligodendrogliomas. METHODS: Thirty-one oligodendrogliomas (27 World Health Organization Grade [WHO] II and 4 WHO Grade III) were processed into tissue microarray. Fluorescence in situ hybridization was exploited to detect chromosome deletion, whereas immunohistochemistry was performed to assess IDH1R132H mutation, CA-9, HIF-1alpha, and HIF-2alpha expression. RESULTS: The frequencies of 1p/19q co-deletion and IDH1 R132H mutation were 68% and 71%, respectively. High expression of CA-9 was observed in 42% and was associated with longer survival (P = 0.04) in WHO Grade II oligodendroglioma. High CA-9 expression also identified 62% of 1p/19q-codeleted oligodendroglioma (P = 0.001). In addition, all tumors with high CA-9 expression displayed 1p/19q-codeletion. HIF-1alpha and HIF-2alpha provided no additional prognostic value for survival. CONCLUSIONS: High expression of CA-9, a marker for hypoxia and acidosis, is associated with favorable prognosis in oligodendroglioma. In addition, it may serve as a simple screening test for 1p/19q co-deletion if validated in larger cohorts. PMID- 26960284 TI - Sacral Nerve Stimulation for Neurogenic Bladder. AB - BACKGROUND: Neurogenic bladder refers to dysfunction of the urinary bladder secondary to diseases of the nervous system that result in problems with urine storage, micturition, or both. The most common causes are multiple sclerosis and spinal cord injury. Patients commonly present with recurrent UTIs, obstructive uropathies, and urinary retention. Without proper treatment, neurogenic bladder may result in nephropathy and renal failure, both of which have a significant negative impact on the health and life expectancy of patients. Restoration of lost neural function using artificial stimulators is a feasible therapeutic strategy. This article reviews the pathophysiology of neurogenic bladder and the 2 most commonly employed sacral nerve stimulation methods-the Brindley procedure and sacral neuromodulation. PMID- 26960285 TI - Techniques and Outcomes of Gore-Tex Clip-Wrapping of Ruptured and Unruptured Cerebral Aneurysms. AB - OBJECTIVE: Some aneurysms without a definable neck and associated parent vessel pathology are particularly difficult to treat and may require clipping with circumferential wrapping. We report the largest available contemporary series examining the techniques of Gore-Tex clip-wrapping of ruptured and unruptured intracranial aneurysms and patient outcomes. METHODS: The presentation, location, and shape of the aneurysm; wrapping technique; outcome at discharge and last follow-up; and any change in the aneurysm at last angiographic follow-up were reviewed retrospectively in 30 patients with Gore-Tex clip-wrapped aneurysms. RESULTS: Gore-Tex clip-wrapping was used in 8 patients with ruptured aneurysms and 22 patients with unruptured aneurysms. Aneurysms included 23 fusiform, 3 blister, and 4 otherwise complex, multilobed, or giant aneurysms. Of the 30 aneurysms, 63% were in the anterior circulation. The overall mean patient age was 52.5 years (range, 17-80 years). Postoperatively, there were no deaths or worsening of neurologic status and no parent vessel stenoses or strokes. The mean Glasgow Outcome Scale score at last follow-up was 4.7. The mean follow-up time was 42.3 months (median, 37.0 months; range, 3-96 months). There were 105.8 patient follow-up years. Aneurysms recurred in 2 patients with Gore-Tex clip wrapping. No patients developed rehemorrhage. Overall risk of recurrence was 1.9% annually. CONCLUSIONS: Gore-Tex has excellent material properties for circumferential wrapping of aneurysms and parent arteries. It is inert and does not cause a tissue reaction or granuloma formation. Gore-Tex clip-wrapping can be used safely for microsurgical management of ruptured and unruptured cerebral aneurysms with acceptable recurrence and rehemorrhage rates. PMID- 26960286 TI - Patterns of Recurrence After Resection of Malignant Gliomas With BCNU Wafer Implants: Retrospective Review in a Single Institution. AB - BACKGROUND: Bis-chloroethylnitrosourea (BCNU) wafers have been demonstrated to be effective for prolonging survival for patients with malignant glioma and have been approved worldwide. BCNU wafers are implantable and have a unique feature of delivering chemotherapeutic drug at high concentration at tumor margin over time after resection. BCNU wafers presumably, by this mechanistic rationale, have a beneficial effect on local tumor control and thus could change the pattern of recurrence, which is most frequently local. However, no studies have demonstrated such phenomenon after BCNU wafer implants. METHODS: To investigate whether the surgeries with BCNU wafers alter the predominant tendency of local recurrence pattern, we retrospectively reviewed 8 malignant glioma patients treated with BCNU wafers (BCNU wafer group), together with 22 glioma patients who did not receive BCNU wafers (no-BCNU wafer group) for comparison. RESULTS: Out of 6 patients in BCNU wafer group who exhibited recurrence, 1 showed local, 2 showed diffuse, and 3 showed a distant recurrence pattern, which was away from resection cavity. On the other hand, out of 18 patients in the no-BCNU wafer group who exhibited recurrence, 10 showed a local pattern, 8 showed a diffuse pattern, and no cases showed distant pattern. Distant pattern was observed significantly more frequently in the BCNU wafer group than in the no-BCNU wafer group. CONCLUSIONS: These results suggest that BCNU wafers could have a beneficial effect on local tumor control and may provide BCNU wafers with a new profile that could be considered for establishing future chemotherapeutic strategy for glioma patients. PMID- 26960287 TI - Prognostic Factors in Patients with Primary Hemangiopericytomas of the Central Nervous System: A Series of 103 Cases at a Single Institution. AB - OBJECTIVE: Hemangiopericytoma (HPC) is a rare mesenchymal tumor that tends to affect the central nervous system and is associated with distant metastasis and a high recurrence rate. The purpose of this study was to analyze the prognostic factors in patients with primary HPC who received surgical treatment. METHODS: This retrospective study reviewed all adult patients with primary HPC of the central nervous system treated from 2001 to 2009 at our institution. Clinical information, adjuvant radiation, and expression levels of Ki-67 and p53 were correlated with patient outcomes. RESULTS: The final analysis included 103 patients. The mean follow-up period was 75.9 months +/- 36.5 (range, 1-165 months). There was a significant difference in progression-free survival (PFS) (P < 0.001) and overall survival (P = 0.014) between patients who underwent gross total resection versus subtotal resection. Expression of p53 was found in 48.5% of patients and showed utility as an independent unfavorable prognostic factor for PFS (P = 0.006). Multivariate analysis revealed that only extent of tumor resection (P = 0.004) and p53 expression (P = 0.024) were independent prognostic factors for PFS. Adjuvant radiation was found to extend PFS only in the p53 negative expression group (P = 0.044). CONCLUSIONS: Gross total resection significantly improves the outcome of patients with primary HPCs, whereas adjuvant radiation contributes significantly to PFS only in patients with negative p53 expression and in patients with incomplete resections. Extent of resection and p53 expression may serve as prognostic markers for the outcome of patients with primary HPC. PMID- 26960288 TI - Determination of Protein Content by NIR Spectroscopy in Protein Powder Mix Products. AB - Protein is a principal component in commonly used dietary supplements and health food products. The analysis of these products, within the consumer package form, is of critical importance for the purpose of ensuring quality and supporting label claims. A rapid test method was developed using near-infrared (NIR) spectroscopy as a compliment to current protein determination by the Dumas combustion method. The NIR method was found to be a rapid, low-cost, and green (no use of chemicals and reagents) complimentary technique. The protein powder samples analyzed in this study were in the range of 22-90% protein. The samples were prepared as mixtures of soy protein, whey protein, and silicon dioxide ingredients, which are common in commercially sold protein powder drink-mix products in the market. A NIR regression model was developed with 17 samples within the constituent range and was validated with 20 independent samples of known protein levels (85-88%). The results show that the NIR method is capable of predicting the protein content with a bias of +/-2% and a maximum bias of 3% between NIR and the external Dumas method. PMID- 26960289 TI - Associations between urban metrics and mortality rates in England. AB - BACKGROUND: Seventy-five percent of the population in Europe live in urban areas and analysing the effects of urban form on the health of the urban population is of great public health interest. Not much is known, however, on the effects of urban form on the health of city dwellers. This study uses a novel approach to investigate whether associations exist between different measures of urban form and mortality risks in cities in England. METHODS: We conducted an ecological, cross-sectional study for urban areas in England with more than 100,000 residents (n = 50) and included all registered premature deaths (<65 years) between 1(st) January 2002 and 31(st) December 2009. To describe and categorise urban form we quantified the distribution and density of population, land cover and transport networks and measures of geographical characteristics. We used Poisson regression models to examine associations between the measures of urban form and age standardised risks of deaths from all causes, cardiovascular disease, and traffic accidents after adjustment for socioeconomic status and smoking. Analysis was stratified by gender to explore differential associations between females and males. RESULTS: There were a total of 200,200 premature deaths during the study period (Females: 37 %; Males: 63 %). Transport network patterns were associated with overall and cardiovascular mortality rates in cities. We saw 12 % higher mortality risk after adjustment in cities with high junction density compared to cities with low density [Females: RR 1.12 (95 % CI 1.10 - 1.15); Males: RR 1.12 (95 % CI 1.10-1.14)]; the risk was slightly higher for cardiovascular mortality [Females: RR 1.16 (95 % CI 1.10 - 1.22); Males: RR 1.12 (95 % CI 1.09 - 1.16)]. Associations between mortality and population patterns were of similar magnitude [Females: RR 1.10 (95 % CI 1.09 - 1.13); Males: RR 1.09 (95 % CI 1.07-1.10)]; associations between mortality and land cover patterns were inconclusive. CONCLUSIONS: We found an association between transport patterns and risk of premature mortality. Associations between urban form and mortality observed in this study suggest that characteristics of city structure might have negative effects on the overall health of urban communities. Future urban planning and regeneration strategies can benefit from such knowledge to promote a healthy living environment for an increasing urban population. PMID- 26960290 TI - Analysis of Genetic Diversity and Development of SCAR Markers in a Mycogone perniciosa Population. AB - The fungus Mycogone perniciosa is a major pathogen of the common button mushroom Agaricus bisporus. Analysis of genetic diversity in M. Perniciosa may assist in developing methods for prophylaxis and treatment of M. Perniciosa infections. For this, it is necessary to classify M. Perniciosa into relevant class groups quickly and efficiently. Random amplified polymorphic DNA (RAPD), inter-simple sequence repeats (ISSR), and sequence-related amplified polymorphism (SRAP) markers were used to obtain genetic fingerprints and assess the genetic variation among 49 strains of M. perniciosa collected from different areas of Fujian Province in China. Analysis of DNA sequence polymorphism revealed two major distinct groups (Group I and Group II). Specific DNA fragments that were identified through RAPD, ISSR, and SRAP markers were sequenced and used for the designing of stable sequence-characterized amplified region (SCAR) markers. The resulting SCAR markers were then validated against the classified groups of M. perniciosa. PMID- 26960293 TI - Shakespeare in the Operating Theater: A Review of Steven Soderberg's The Knick, 2014. PMID- 26960291 TI - Spongiiferula fulva gen. nov., sp. nov., a Bacterium of the Family Flavobacteriaceae Isolated from a Marine Sponge. AB - A Gram stain-negative, strictly aerobic, brown-pigmented, non-motile, rod-shaped, chemoheterotrophic bacterial strain-designated A6F-119(T) was isolated from a marine sponge (Rhabdastrella sp.). Phylogenetic analyses based on the 16S rRNA gene sequence revealed that the new strain represented a member of the family Flavobacteriaceae of the phylum Bacteroidetes and that it showed highest sequence similarity (93 %) to Tenacibaculum maritimum NBRC 15946(T). The strain could be differentiated phenotypically from the recognized members of the family Flavobacteriaceae. The DNA G + C content of strain A6F-119(T) was determined to be 30.8 mol%; MK-6 was identified as the major menaquinone; and the presence of iso-C15:0, iso-C17:0 3-OH, and C16:1 omega7c and/or C16:1 omega6c as the major (>10 %) cellular fatty acids. A polar lipid profile was present consisting of phosphatidylethanolamine, an unidentified aminolipid, and three unidentified lipids. From the distinct phylogenetic position and combination of genotypic and phenotypic characteristics, the strain is considered to represent a novel genus for which the name Spongiiferula fulva gen. nov., sp. nov. is proposed. The type strain of S. fulva is A6F-119(T) (= KCTC 42752(T) = NBRC 111402(T)). PMID- 26960292 TI - Analysis of the Impact of Rosuvastatin on Bacterial Mevalonate Production Using a UPLC-Mass Spectrometry Approach. AB - Statins are widely prescribed cholesterol-lowering medications and act through inhibition of the human enzyme 3-methylglutaryl coenzyme A reductase (HMG-R) which produces mevalonate (MVAL), a key substrate for cholesterol biosynthesis. Some important microbial species also express an isoform of HMG-R; however, the nature of the interaction between statins and bacteria is currently unclear and studies would benefit from protocols to quantify MVAL in complex microbial environments. The objective of this study was to develop a protocol for the analytical quantification of MVAL in bacterial systems and to utilise this approach to analyse the effects of Rosuvastatin (RSV) on bacterial MVAL formation. To determine the effective concentration range of RSV, we examined the dose-dependent inhibition of growth in the HMG-R(+) bacterial pathogens Listeria monocytogenes, Staphylococcus aureus and Enterococcus faecium at various concentrations of pure RSV. Growth inhibition generally correlated with a reduction in bacterial MVAL levels, particularly in culture supernatants at high RSV concentrations, as determined using our ultra-performance liquid chromatography mass spectrometry protocol. This work therefore outlines a refined protocol for the analysis of MVAL in microbial cultures and provides evidence for statin-mediated inhibition of bacterial HMG-R. Furthermore, we show that MVAL is readily transported and secreted from bacterial cells into the growth media. PMID- 26960294 TI - Mindfulness, Mysticism, and Narrative Medicine. AB - Mindfulness based interventions (MBIs) are rapidly emerging in health care settings for their role in reducing stress and improving physical and mental health. In such settings, the religious roots and affiliations of MBIs are downplayed, and the possibilities for developing spiritual, even mystical, states of consciousness are minimized. This article helps rebalance this trend by using the tools of medical humanities and narrative medicine to explore MBI as a bridge between medical and spiritual approaches to health related suffering. My narrative medicine method draws insights from the arts and humanities that are rarely used in standard clinical research but are increasingly common among medical humanities and narrative medicine scholars. The specific path I take will be to work through historical, linguistic, and philosophic dimensions of mindfulness and mysticism as relevant to illness, suffering, death, and dying. I close with two case examples in which mindfulness is used as an intentionally spiritual practice for health concerns. PMID- 26960295 TI - Introduction - Beckett, Medicine and the Brain. PMID- 26960296 TI - Safety, Stability and Pharmacokinetic Properties of (super)Factor Va, a Novel Engineered Coagulation Factor V for Treatment of Severe Bleeding. AB - PURPOSE: Activated (super)Factor V ((super)FVa) is a novel engineered FV with excellent prohemostatic efficacy. (Super)FVa has three APC cleavage site mutations and an interdomain disulfide bond. Stability, pharmacokinetics, and immunogenic and thrombogenic potential are reported here. METHODS: Stability and circulating half-life were determined after incubation in buffer and human plasma, and after injection into FVIII-deficient mice. Immunogenicity potential was assessed by B- and T-cell specific epitope prediction and structural analysis using surface area and atomic depth computation. Thrombogenic potential was determined by quantification of lung fibrin deposition in wild-type mice after intravenous injection of (super)FVa (200 U/kg), recombinant human (rh) Tissue Factor (0.4-16 pmol/kg), rhFVIIa (3 mg/kg) or saline. RESULTS: FVa retained full activity over 30 h in buffer, the functional half-life in human plasma was 4.9 h, and circulating half-life in FVIII-deficient mice was ~30 min. Predicted immunogenicity was not increased compared to human FV. While rh Tissue Factor, the positive control, resulted in pronounced lung fibrin depositions (mean 121 MUg/mL), (super)FVa did not (6.7 MUg/mL), and results were comparable to fibrin depositions with rhFVIIa (7.6 MUg/mL) or saline (5.6 MUg/mL). CONCLUSION: FVa has an appropriate safety and stability profile for further preclinical development as a prohemostatic against severe bleeding. PMID- 26960299 TI - From four hands to two feet: human evolution in the context of primate evolution. PMID- 26960298 TI - Levonorgestrel-releasing intrauterine system placement for severe uterine cervical stenosis after conization: two case reports. AB - BACKGROUND: Several approaches for treating severe uterine cervical stenosis after conization for cervical intraepithelial neoplasia have been reported; yet, the condition can still be difficult to treat successfully. CASE PRESENTATION: We performed uterine cervical dilation surgery in two patients with severe stenosis, followed by insertion of the levonorgestrel-releasing intrauterine system, which is used for dysmenorrhea or endometriosis-related pain because of its strong progesterone activity. Patient 1 was a 34-year-old Japanese woman who was diagnosed with dysmenorrhea caused by recurrent uterine cervical stenosis and hematometra after laser conization. Patient 2 was a 44-year-old Japanese woman who developed dysmenorrhea and prolonged menstruation caused by uterine cervical stenosis without hematometra. After providing informed consent, they underwent cervical dilation surgery followed by insertion of the levonorgestrel-releasing intrauterine system. After treatment, their symptoms immediately improved, and after removal of their devices, they remained asymptomatic. CONCLUSIONS: To the best of our knowledge, this is the first report to confirm the usefulness and easy applicability of the levonorgestrel-releasing intrauterine system for uterine cervical stenosis. Although we had success with the method, this study of two patients is preliminary. Further study with larger numbers of patients is necessary to confirm the usefulness of our technique. PMID- 26960300 TI - "Identification Card": Sites on Histone Modification of Cancer Cell. AB - Formation of malignant tumor originating from normal healthy cell is a multistep process including genetic and epigenetic lesions. Previous studies of cell line model systems displayed that early important epigenetic events happened in stepwise fashion prior to cell immortalization. Once these epigenetic alterations are integrated into chromatin, they will perform vertical propagation through cell subculture. Hence, status of epigenetics is dramatically important in maintaining of cell identity. Histone modification is another factor of epigenetic alterations during human oncogenesis. Histones, one of main components of chromatin, can be modified post-translationally. Histone tail modifications are regulated by corresponding modification enzymes. This review focuses on the description of relationship between the main sites of histone modification and oncogenesis. PMID- 26960301 TI - Efficacy of Topical Tacrolimus for Erosive Oral Lichen Planus: A Meta-analysis. AB - OBJECTIVE: To assess the efficacy and safety of topical tacrolimus for erosive oral lichen planus (EOLP). METHODS: Literatures published up to December 2013 were searched from PubMed, Embase, CENTRAL, Chinese BioMedical Literature Database (CBM), and System for Information on Grey Literature in Europe (SIGLE). All randomized controlled trials (RCTs) of topical tacrolimus for EOLP which compared with other interventions or a placebo were considered in this Meta analysis. Two researchers collected data independently. The assessment of methodological quality was based on Cochrane Handbook and the materials were analyzed with the software Revman 5.2.5. The primary outcome measures were the symptoms (e.g. pain, discomfort) complained by patients. The secondary outcome measures included the improvement rate of clinical signs assessed by the investigators and the incidence of adverse effects (e.g. clinical candidiasis). RESULTS: A total of 9 RCTs involving 476 patients were finally included. The pooled odds ratio (OR) of clinical improvement for topical tacrolimus vs. topical corticosteroids was 1.19 [95% confidence interval (CI): 0.64-2.22, I2: 44%]. Regarding to 0.1% tacrolimus and 0.03% tacrolimus, the pooled OR were 1.87 (95% CI: 0.60-5.82) and 1.47 (95% CI: 0.14-16.04) respectively in subgroup analysis. No serious adverse events were reported in topical tacrolimus group. CONCLUSIONS: There was no evidence to support that topical tacrolimus for EOLP was more effective and safer than topical corticosteroids in this Meta-analysis. Clinical assessment criteria should be established and accepted by clinicians and researchers before further RCTs are undertaken. PMID- 26960297 TI - Rhinoviruses and Their Receptors: Implications for Allergic Disease. AB - Human rhinoviruses (RVs) are picornaviruses that can cause a variety of illnesses including the common cold, lower respiratory tract illnesses such as bronchitis and pneumonia, and exacerbations of asthma. RVs are classified into three species, RV-A, B, and C, which include over 160 types. They utilize three major types of cellular membrane glycoproteins to gain entry into the host cell: intercellular adhesion molecule 1 (ICAM-1) (the majority of RV-A and all RV-B), low-density lipoprotein receptor (LDLR) family members (12 RV-A types), and cadherin-related family member 3 (CDHR3) (RV-C). CDHR3 is a member of cadherin superfamily of transmembrane proteins with yet unknown biological function, and there is relatively little information available about the mechanisms of RV-C interaction with CDHR3. A coding single nucleotide polymorphism (rs6967330) in CDHR3 could promote RV-C infections and illnesses in infancy, which could in turn adversely affect the developing lung to increase the risk of asthma. Further studies are needed to determine how RV infections contribute to pathogenesis of asthma and to develop the optimal treatment approach to control asthma exacerbations. PMID- 26960302 TI - Effect of Ursolic Acid on Breast Cancer Resistance Protein-mediated Transport of Rosuvastatin In Vivo and Vitro. AB - OBJECTIVE: To evaluate whether ursolic acid can inhibit breast cancer resistance protein (BCRP)-mediated transport of rosuvastatin in vivo and in vitro. METHODS: Firstly, we explored the pharmacokinetics of 5-fluorouracil (5-FU, a substrate of BCRP) in rats in the presence or absence of ursolic acid. Secondly, we studied the pharmacokinetics of rosuvastatin in rats in the presence or absence of ursolic acid or Ko143 (inhibitor of BCRP). Finially, the concentration-dependent transport of rosuvastatin and the inhibitory effects of ursolic acid and Ko143 were examined in Madin-Darby Canine Kidney (MDCK) 2-BCRP421CC (wild type) cells and MDCK2-BCRP421AA (mutant type) cells. RESULTS: As a result, significant changes in pharmacokinetics parameters of 5-FU were observed in rats following pretreatment with ursolic acid. Both ursolic acid and Ko143 could significantly affect the pharmacokinetics of rosuvastatin. The rosuvastatin transport in the BCRP overexpressing system was increased in a concentration-dependent manner. However, there was no statistical difference in BCRP-mediated transport of rosuvastatin betweent the wild type cells and mutant cells. The same as Ko143, ursolic acid inhibited BCRP-mediated transport of rosuvastatin in vitro. CONCLUSION: Ursolic acid appears to be a potent modulator of BCRP that affects the pharmacokinetic of rosuvastatin in vivo and inhibits the transport of rosuvastatin in vitro. PMID- 26960303 TI - Management of Cesarean Scar Pregnancy: A Case Series. AB - OBJECTIVE: To survey effective treatment strategies for cesarean scar pregnancy (CSP). METHODS: The clinical data of 78 patients diagnosed with CSP from January 2010 to December 2013 were reviewed. RESULTS: Among these patients, 17 patients were first treated at our hospital; of them, 2 were misdiagnosed. The other 61 patients were referred from other hospitals; of them, 21 were initially misdiagnosed. There were 9 patients who were treated with laparotomy, 50 patients with curettage after uterine artery embolization (UAE) with or without local methotrexate (MTX) infusion, 10 patients with dilatation and curettage, 6 patients with transvaginal sonographic guided local intragestational MTX injection, and 3 patients with systemic MTX injection. All patients finally recovered. Patients with excessive vaginal hemorrhage underwent either emergency UAE treatment or laparotomy. These two treatments had similar success rates (81.82% vs. 100%, chi2 =0.289, P>0.05). CONCLUSIONS: The accurate diagnosis of CSP is important. Curettage after UAE with or without local MTX infusion is a safe and effective method. PMID- 26960304 TI - Gender Differences in Ventricular-vascular Coupling Following Exercise. AB - OBJECTIVE: To study the differences of cardiovascular system between men and women in response to exercise stress. METHODS: Forty healthy youth were tested according to Bruce protocol of exercise stress. They were detected by ultrasonography during the rest, peak exercise, and recovery stages, respectively. The left ventricular diastolic elastance (Ed), effective arterial elastance (Ea), left ventricular end-systolic elatance (Ees), ventricular vascular coupling index (VVI), and total stiffness index (TSI) were measured and calculated according to the formulas. The results of all stages were compared according to genders. RESULTS: All stages, the Ed, TSI, and VVI of women were higher than those of men, but the Ees was lower than that of men (all P<0.05); there was no significant difference in Ea between men and women. The Ed, Ees, Ea, and TSI were closely related with left ventricular oxygen consumption and heart function, and women showed more closely. Before and after exercise, the changes were different in Ed, Ees, Ea, TSI, and VVI (all P<0.05), and VVI changed least. CONCLUSIONS: Before and after exercise, the ventricular stiffness matched well with arterial stiffness and maintained within a narrow range. For women, the tolerance of exercise was lower than that of men. PMID- 26960305 TI - Retroperitoneal Versus Transperitoneal Laparoscopic Partial Nephrectomy: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To review published literatures comparing the safety and effectiveness of retroperitoneal laparoscopic partial nephrectomy (RLPN) with transperitoneal laparoscopic partial nephrectomy (TLPN) and provide reference for clinical work. METHODS: The search strategy was performed to identify relevant papers from the Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, Google Scholar, China Hospital Knowledge Database, Wangfang Chinese Periodical Database, and VIP Chinese Periodical Database. All papers comparing RLPN with TLPN were included from 2000 to 2015. Two to three reviewers independently screened, evaluated, and extracted the included papers. A Meta-analysis was executed by using Review Manager 5.3 software. The interesting outcomes were tumor size, operating time, estimated blood loss, warm ischaemia time, length of hospital stay, positive margin rate, open conversion rate, overall complication rate, and recurrence rate. RESULTS: The literature search obtained 378 papers, then 10 of them were ultimately met the inclusion criteria and included in the systematic review. Finally, 6 of the 10 papers were included in the Meta-analysis. RLPN had significantly less operating time [P = 0.01, mean difference (MD)=-33.68, 95% confidence interval (CI) within (-60.35, -7.01)] and shorter length of hospital stay [P < 0.0001, MD=-1.47, 95% CI within (-2.18, -0.76)] than TLPN. Significant differences were not found between RLPN and TLPN in other outcomes. CONCLUSIONS: RLPN may be equally safe and be faster than TLPN. Each center can choose a modality according to your own operating habits and experience. PMID- 26960306 TI - Effect of Atorvastatin on Expression of Peroxisome Proliferator-activated Receptor Beta/delta in Angiotensin II-induced Hypertrophic Myocardial Cells In Vitro. AB - OBJECTIVE: To explore the effect of atorvastatin on cardiac hypertrophy and to determine the potential mechanism involved. METHODS: An in vitro cardiomyocyte hypertrophy from neonatal rats was induced with angiotensin II (Ang II) stimulation. Before Ang II stimulation, the cultured rat cardiac myocytes were pretreated with atorvastatin at different concentrations (0.1, 1, and 10 MUmol/L). The following parameters were evaluated: the myocyte surface area, 3H leucine incorporation into myocytes, mRNA expressions of atrial natriuretic peptide, brain natriuretic peptide, matrix metalloproteinase 9, matrix metalloproteinase 2, and interleukin-1beta, mRNA and protein expressions of the delta/beta peroxisome proliferator-activated receptor (PPAR) subtypes. RESULTS: It was shown that atorvastatin could ameliorate Ang II-induced neonatal cardiomyocyte hypertrophy in the area of cardiomyocytes, 3H-leucine incorporation, and the expression of atrial natriuretic peptide and brain natriuretic peptide markedly. Meanwhile, atorvastatin also inhibited the augmented mRNA level of several cytokines in hypertrophic myocytes. Furthermore, the down-regulated expression of PPAR- delta/beta at both the mRNA and protein levels in hypertrophic myocytes could be significantly reversed by atorvastatin treatment. CONCLUSIONS: Atorvastatin could improve Ang II-induced cardiac hypertrophy and inhibit the expression of cytokines. Such effect might be partly achieved through activation of the PPAR-delta/beta pathway. PMID- 26960307 TI - Influence of Photodynamic Therapy on Apoptosis and Invasion of Human Cholangiocarcinoma QBC939 Cell Line. AB - OBJECTIVE: To investigate the effect of photodynamic therapy (PDT) mediated by hematoporphyrin derivative (HPD) on apoptosis and invasion of cholangiocarcinoma QBC939 cell lines. METHODS: In vitro cultured cholangiocarcinoma QBC939 cell line was exposed to 2, 4, 6, 8, 10, 12, and 14 MUg/ml HPD with 5, 10, and 15 J/cm2 light intensity, respectively. The optical density at 450 nm of the QBC939 cells was measured by CCK8 assay and its growth inhibition ratio was calculated. Flow cytometry and transwell migration assay were applied to detect cell apoptosis and invasion respectively. RT-PCR and immunocytochemistry analyses were used to detect expressions of vascular endothelial growth factor-C (VEGF-C), cyclooxygenase-2 (COX-2), and proliferating cell nuclear antigen (PCNA). Enzyme linked immunosorbent assay (ELISA) was carried out to examine the secretion of VEGF-C and COX-2 in QBC939 cells. RESULTS: Exposure to HPD-PDT can significantly suppress the growth of QBC939 cells (all P<0.05). HPD-PDT can promote apoptosis of QBC939 cells at the early stage. When the concentration of HPD was 2 MUg/ml and light irradiation was 5 J/cm2, HPD-PDT had no obvious inhibitory effect on QBC939 cell growth, but can obviously inhibit cell invasion, and significant difference was observed between the HPD-PDT and control groups (P<0.01). The HPD PDT can reduce the mRNA and protein expressions of VEGF-C, COX-2, and PCNA, and decrease the secretion of VEGF-C and COX-2 in QBC939 cells. CONCLUSION: PDT could promote apoptosis and inhibit growth and invasion of cholangiocarcinoma cells QBC939 in vitro. PMID- 26960308 TI - Inhibition Mechanism of Novel Pyrazolo[1,5-a]pyrazin-4(5H)-one Derivatives Against Proliferation of A549 and H322 Cancer Cells. AB - OBJECTIVE: To explore the inhibition mechanism and safety of pyrazolo[1,5 a]pyrazin-4(5H)-one derivatives against proliferation of human lung cancer A549 cells, H322 cells, and human umbilical vein endothelial cell (HUVEC). METHODS: Cells were treated with 40 MUmol/L of the ppo3a, ppo3b, ppo3i, and 0.1% DMSO (control) for 48 hours, respectively. Apoptosis was determined by Hoechst 33258 staining assay in H322 and A549 cells. Cell cycle distribution was determined by flow cytometry analysis in A549 cell. LC3-II, p53, and heat shock protein (HSP) 70 protein levels were detected by Western blotting in A549 cells treated with ppo3b for 48 hours. The morphology and viability of HUVEC were observed by inverted microscope and sulforhodamine B (SRB) assay. RESULTS: Ppo3a, ppo3b, and ppo3i significantly induced apoptosis in H322 and A549 cells. A strong G1-phase arrest was concomitant with the growth inhibitory effect on A549 cells. Ppo3b effectively elevated the p53 protein level, but significantly reduced the HSP70 protein level. There were no significantly inhibitory effect on the morphology and viability of HUVEC when treated with ppo3a, ppo3b, and ppo3i. CONCLUSIONS: ppo3a, ppo3b, and ppo3i could inhibit H322 proliferation through apoptosis and inhibit A549 through apoptosis and G1-phase arrest. The protein p53 and HSP70 might involve in the inhibition effects. These derivatives might be a clue to find effective and safe drug for lung cancers. PMID- 26960309 TI - Pseudophakic Malignant Glaucoma Treatment Assisted with Anterior Segment Optical Coherence Tomography: A Case Report. PMID- 26960310 TI - Extraskeletal Chondroma in the Popliteal Region: A Case Report. PMID- 26960311 TI - Adjusting to a Diagnosis of Cancer: Processes for Building Patient Capacity for Decision-Making. AB - This short report contributes to the expanding body of qualitative research literature about the cognitive processes of newly diagnosed cancer patients as they adjust to a diagnosis of cancer. The study is based on secondary qualitative analysis of audio records collected as part of a larger NIH study (RO1D: An Interdisciplinary Perspective: A Social Science Examination of Oncofertility RL1 HD058296). Core categories illustrate the processes of "naming it," "dealing with dealing with it," and finding the "new norm" and were based on nine patient experiences. We observe that our substantive conceptual categories have equivalents in bereavement and grief literature where researchers have posited the theory that processing the diagnosis of a terminal illness is the equivalent to adjusting to a bereavement. These findings emphasize the importance of understanding real-time patient thoughts and feelings as soon after diagnosis as was possible with full patient consent. PMID- 26960312 TI - Unilateral facial flushing precipitated by eating. PMID- 26960313 TI - Erratum to: DAPK plays an important role in panobinostat-induced autophagy and commits cells to apoptosis under autophagy deficient conditions. PMID- 26960314 TI - Novel SDHB and TMEM127 Mutations in Patients with Pheochromocytoma/Paraganglioma Syndrome. AB - Pheochromocytomas (Pheo) and paragangliomas (PGL) are rare tumors, with heterogeneous genetic background. In up to 30 % of all, apparently sporadic Pheo/PGL cases germline mutations can be identified in one of the 15 genes representing genetic susceptibility for Pheo/PGL. Malignancy is rare but it frequently associates with SDHB mutations. Our aim was to determine the prevalence of germline SDHx, SDHAF2, MAX and TMEM127 mutations in Hungarian patients with apparently sporadic Pheo/PGLs. Mutation screening of the SDHx, SDHAF2, MAX and TMEM127 genes was performed in 82 Hungarian patients with apparently sporadic Pheo/PGL using PCR and bidirectional Sanger sequencing. Disease-causing germline mutations were identified in 11 patients, of which 4 SDHB and 2 TMEM127 mutations were novel. Earlier development of Pheo/PGL, more malignant phenotype and multiple tumors were observed in genetically positive cases especially in those with SDHB mutations. The presence of bilateral or multiple tumors was the most predictive for identification of a pathogenic mutation. Together with cases harboring germline RET, VHL and NF1 mutations, Hungarian patients with Pheo/PGL exhibit a heterogeneous mutation spectrum, indicating that all of the Pheo/PGL susceptibility genes should be tested. Novel genotype-phenotype associations revealed by our study may contribute to improvement of diagnostic approaches and may help to achieve a better clinical follow up for patients with Pheo/PGL. PMID- 26960315 TI - The C2H2-type transcription factor, FlbC, is involved in the transcriptional regulation of Aspergillus oryzae glucoamylase and protease genes specifically expressed in solid-state culture. AB - Aspergillus oryzae produces a large amount of secreted proteins in solid-state culture, and some proteins such as glucoamylase (GlaB) and acid protease (PepA) are specifically produced in solid-state culture, but rarely in submerged culture. From the disruption mutant library of A. oryzae transcriptional regulators, we successfully identified a disruption mutant showing an extremely low production level of GlaB but a normal level of alpha-amylase production. This strain was a disruption mutant of the C2H2-type transcription factor, FlbC, which is reported to be involved in the regulation of conidiospore development. Disruption mutants of other upstream regulators comprising a conidiation regulatory network had no apparent effect on GlaB production in solid-state culture. In addition to GlaB, the production of acid protease in solid-state culture was also markedly decreased by flbC disruption. Northern blot analyses revealed that transcripts of glaB and pepA were significantly decreased in the flbC disruption strain. These results suggested that FlbC is involved in the transcriptional regulation of genes specifically expressed under solid-state cultivation conditions, possibly independent of the conidiation regulatory network. PMID- 26960317 TI - Erratum to: Impacts of ruminal microorganisms on the production of fuels: how can we intercede from the outside? PMID- 26960316 TI - Discovery of the cell-penetrating function of A2 domain derived from LTA subunit of Escherichia coli heat-labile enterotoxin. AB - Heat-labile enterotoxin (LT) is a protein toxin produced by enterotoxigenic Escherichia coli (ETEC). As a bacterial toxin, LT holotoxin can enter intestinal epithelial cells and cause diarrhea. In addition, LT is also a powerful mucosal adjuvant capable of enhancing the strong immune responses to co-administered antigens. However, the LT immunological mechanism is still not clear in some aspects, especially with the respect to how the LTA subunit functions alone. Here, we discovered that the A2 domain of LTA could carry a fluorescent protein into cells, whose function is similar to a cell-penetrating peptide. The transmembrane-transporting ability of the A2 domain is non-specific in its cell penetrating function, which was shown through testing with different cell types. Moreover, the LTA2 fusion protein penetrated a fluorescently labeled cell membrane that identified LTA2 internalization through membrane transport pathways, and showed it finally localized in the endoplasmic reticulum. Furthermore, low-temperature stress and pharmacological agent treatments showed that the LTA2 internalization route is a temperature-dependent process involving the clathrin-mediated endocytosis and the macropinocytosis pathways. These results could explain the internalization of the LTA subunit alone without the LTB pentamer, contributing to a better understanding of LTA working as a mucosal adjuvant; they also suggest that the A2 domain could be used as a novel transport vehicle for research and treatment of disease. PMID- 26960318 TI - Antibacterial activity of curcumin via apoptosis-like response in Escherichia coli. AB - Curcumin, a naturally occurring phenolic compound, has been shown to exhibit antimicrobial activity against Candida albicans, Escherichia coli, Pseudomonas aeruginosa, etc., but the mechanism remains unclear. The present study was designed to investigate the novel antibacterial mechanism of curcumin that shows an apoptosis-like response in E. coli. We found that curcumin induces membrane damage at relatively high concentrations, but there was no effect at the minimum inhibitory concentration (MIC). At the MIC, curcumin-treated cells displayed various apoptotic markers such as reactive oxygen species (ROS) accumulation, membrane depolarization, and Ca(2+) influx. Expression of RecA protein, which mediates a bacterial apoptosis-like response, was also increased by curcumin. In order to evaluate the influence of RecA on the appearance of other apoptotic markers, phosphatidylserine (PS) exposure and DNA fragmentation were examined and compared with a RecA deletion strain (DeltaRecA). These markers were detected in E. coli wild-type cells, but not in DeltaRecA cells. In conclusion, our data demonstrate that curcumin induces an apoptosis-like response in E. coli that involves RecA. PMID- 26960319 TI - Population and diversity of ammonia-oxidizing archaea and bacteria in a pollutants' receiving area in Hangzhou Bay. AB - The community structure of ammonia-oxidizing microorganisms is sensitive to various environmental factors, including pollutions. In this study, real-time PCR and 454 pyrosequencing were adopted to investigate the population and diversity of ammonia-oxidizing archaea (AOA) and bacteria (AOB) temporally and spatially in the sediments of an industrial effluent receiving area in the Qiantang River's estuary, Hangzhou Bay. The abundances of AOA and AOB amoA genes fluctuated in 10(5)-10(7) gene copies per gram of sediment; the ratio of AOA amoA/AOB amoA ranged in 0.39-5.52. The AOA amoA/archaeal 16S rRNA, AOB amoA/bacterial 16S rRNA, and AOA amoA/AOB amoA were found to positively correlate with NH4 (+)-N concentration of the seawater. Nitrosopumilus cluster and Nitrosomonas-like cluster were the dominant AOA and AOB, respectively. The community structures of both AOA and AOB in the sediments exhibited significant seasonal differences rather than spatial changes in the effluent receiving area. The phylogenetic distribution of AOB in this area was consistent with the wastewater treatment plants (WWTPs) discharging the effluent but differed from the Qiantang River and other estuaries, which might be an outcome of long-term effluent discharge. PMID- 26960320 TI - Biological denitrification using poly(butanediol succinate) as electron donor. AB - Poly(butanediol succinate) (PBS), a biodegradable polymer, was used as both solid carbon source and biofilm carrier for biological nitrate removal process, in which PBS was filled in a packed-bed bioreactor. The denitrification performance and the microbial diversity of biofilm attached on the surface of PBS were investigated. The experimental results showed that the volumetric denitrification rate was 0.60 kg m(-3) day(-1) when NO3-N loading rate was 0.63 kg m(-3) day(-1), and the average NO2-N concentration was below 0.20 mg L(-1). The effluent pH value decreased slightly from a range of 6.98-7.87 to 6.46-7.18. The analysis of microbial community structure of biofilm by pyrosequencing method showed that Proteobacteria was the most abundant phylum (89.87 %), and beta-Proteobacteria represented the most abundant class. Among the 76 identified genera, Dechloromonas (10.26 %), Alicycliphilus (9.15 %), Azospira (8.92 %), and Sinobacteraceae-uncultured (8.75 %) were the abundant genera. PBS, as a promising alternative carbon source, is a suitable solid carbon source and biofilm carrier for nitrate removal. PMID- 26960321 TI - Starmerella bacillaris and Saccharomyces cerevisiae mixed fermentations to reduce ethanol content in wine. AB - Decreasing the ethanol content in wine is a current challenge, mainly due to the global climate change and to the consumer preference for wines from grapes with increased maturity. In this study, a central composite design (CCD) and response surface methodology (RSM) approach was used to investigate the potential application of Starmerella bacillaris (synonym Candida zemplinina) in combination with Saccharomyces cerevisiae, in mixed (co-inoculated and sequential) cultures, to understand better the mechanism of co-habitation and achieve the objective of reducing the ethanol in wines. Laboratory scale fermentations demonstrated a decrease up to 0.7 % (v/v) of ethanol and an increase of about 4.2 g/L of glycerol when S. cerevisiae was inoculated with a delay of 48 h with respect to the inoculation of S. bacillaris. Pilot-scale fermentations, carried out in winemaking conditions, confirmed the laboratory results. This study demonstrates that the combination of strains and inoculation protocol could help to reduce the ethanol content in wines. PMID- 26960322 TI - Solid lipid nanoparticle loaded with paromomycin: in vivo efficacy against Leishmania tropica infection in BALB/c mice model. AB - Leishmaniasis is a parasitic disease transmitted through the bite of an infected phlebotomine sand fly and caused by protozoan parasites of the genus Leishmania. There is no available vaccine for leishmaniasis in human, and the current chemotherapy approaches are hampered by different clinical problems. Most of available drugs are confined to a limited number of toxic chemical compounds, which some parasite strains have evolved drug resistance against. Hence, drug discovery and production of a new anti leishmanial compound is essential. One promising strategy is using the nanoparticle delivery systems with the aim of accelerating the efficacy of the available treatments. In the present study, paromomycin sulfate (PM) was formulated in solid lipid nanoparticles (SLN) and the in vivo efficacy was investigated against Leishmania tropica in BALB/c mice model. To do so, the increase in footpad thickness was measured and real-time PCR was performed to quantify the parasite load after infectious challenge. The level of nitric oxide and cytokines including interleukin-4 (IL-4) and gamma interferon (IFN -gamma) were assessed. Altogether, the results show that PM loaded into SLN is significantly more effective than PM alone in inhibiting the parasite propagation and switching towards Th1 response. PMID- 26960323 TI - A breakthrough in enzyme technology to fight penicillin resistance-industrial application of penicillin amidase. AB - Enzymatic penicillin hydrolysis by penicillin amidase (also penicillin acylase, PA) represents a Landmark: the first industrially and economically highly important process using an immobilized biocatalyst. Resistance of infective bacteria to antibiotics had become a major topic of research and industrial activities. Solutions to this problem, the antibiotics resistance of infective microorganisms, required the search for new antibiotics, but also the development of derivatives, notably penicillin derivatives, that overcame resistance. An obvious route was to hydrolyse penicillin to 6-aminopenicillanic acid (6-APA), as a first step, for the introduction via chemical synthesis of various different side chains. Hydrolysis via chemical reaction sequences was tedious requiring large amounts of toxic chemicals, and they were cost intensive. Enzymatic hydrolysis using penicillin amidase represented a much more elegant route. The basis for such a solution was the development of techniques for enzyme immobilization, a highly difficult task with respect to industrial application. Two pioneer groups started to develop solutions to this problem in the late 1960s and 1970s: that of Gunter Schmidt-Kastner at Bayer AG (Germany) and that of Malcolm Lilly of Imperial College London. Here, one example of this development, that at Bayer, will be presented in more detail since it illustrates well the achievement of a solution to the problems of industrial application of enzymatic processes, notably development of an immobilization method for penicillin amidase suitable for scale up to application in industrial reactors under economic conditions. A range of bottlenecks and technical problems of large-scale application had to be overcome. Data giving an inside view of this pioneer achievement in the early phase of the new field of biocatalysis are presented. The development finally resulted in a highly innovative and commercially important enzymatic process to produce 6-APA that created a new antibiotics industry and that opened the way for the establishment of over 100 industrial processes with immobilized biocatalysts worldwide today. PMID- 26960324 TI - Extracted magnetic resonance texture features discriminate between phenotypes and are associated with overall survival in glioblastoma multiforme patients. AB - GBM is a markedly heterogeneous brain tumor consisting of three main volumetric phenotypes identifiable on magnetic resonance imaging: necrosis (vN), active tumor (vAT), and edema/invasion (vE). The goal of this study is to identify the three glioblastoma multiforme (GBM) phenotypes using a texture-based gray-level co-occurrence matrix (GLCM) approach and determine whether the texture features of phenotypes are related to patient survival. MR imaging data in 40 GBM patients were analyzed. Phenotypes vN, vAT, and vE were segmented in a preprocessing step using 3D Slicer for rigid registration by T1-weighted imaging and corresponding fluid attenuation inversion recovery images. The GBM phenotypes were segmented using 3D Slicer tools. Texture features were extracted from GLCM of GBM phenotypes. Thereafter, Kruskal-Wallis test was employed to select the significant features. Robust predictive GBM features were identified and underwent numerous classifier analyses to distinguish phenotypes. Kaplan-Meier analysis was also performed to determine the relationship, if any, between phenotype texture features and survival rate. The simulation results showed that the 22 texture features were significant with p value <0.05. GBM phenotype discrimination based on texture features showed the best accuracy, sensitivity, and specificity of 79.31, 91.67, and 98.75 %, respectively. Three texture features derived from active tumor parts: difference entropy, information measure of correlation, and inverse difference were statistically significant in the prediction of survival, with log-rank p values of 0.001, 0.001, and 0.008, respectively. Among 22 features examined, three texture features have the ability to predict overall survival for GBM patients demonstrating the utility of GLCM analyses in both the diagnosis and prognosis of this patient population. PMID- 26960325 TI - Automated Bone Scan Index as a quantitative imaging biomarker in metastatic castration-resistant prostate cancer patients being treated with enzalutamide. AB - BACKGROUND: Having performed analytical validation studies, we are now assessing the clinical utility of the upgraded automated Bone Scan Index (BSI) in metastatic castration-resistant prostate cancer (mCRPC). In the present study, we retrospectively evaluated the discriminatory strength of the automated BSI in predicting overall survival (OS) in mCRPC patients being treated with enzalutamide. METHODS: Retrospectively, we included patients who received enzalutamide as a clinically approved therapy for mCRPC and had undergone bone scan prior to starting therapy. Automated BSI, prostate-specific antigen (PSA), hemoglobin (HgB), and alkaline phosphatase (ALP) were obtained at baseline. Change in automated BSI and PSA were obtained from patients who have had bone scan at week 12 of treatment follow-up. Automated BSI was obtained using the analytically validated EXINI Bone(BSI) version 2. Kendall's tau (tau) was used to assess the correlation of BSI with other blood-based biomarkers. Concordance index (C-index) was used to evaluate the discriminating strength of automated BSI in predicting OS. RESULTS: Eighty mCRPC patients with baseline bone scans were included in the study. There was a weak correlation of automated BSI with PSA (tau = 0.30), with HgB (tau = -0.17), and with ALP (tau = 0.56). At baseline, the automated BSI was observed to be predictive of OS (C-index 0.72, standard error (SE) 0.03). Adding automated BSI to the blood-based model significantly improved the C-index from 0.67 to 0.72, p = 0.017. Treatment follow-up bone scans were available from 62 patients. Both change in BSI and percent change in PSA were predictive of OS. However, the combined predictive model of percent PSA change and change in automated BSI (C-index 0.77) was significantly higher than that of percent PSA change alone (C-index 0.73), p = 0.041. CONCLUSIONS: The upgraded and analytically validated automated BSI was found to be a strong predictor of OS in mCRPC patients. Additionally, the change in automated BSI demonstrated an additive clinical value to the change in PSA in mCRPC patients being treated with enzalutamide. PMID- 26960326 TI - Neurolymphomatosis in a cat. AB - A 9-year-old male mixed breed cat showed chronic progressive neurological symptoms, which are represented by ataxia and seizures. At necropsy, spinal roots and spinal ganglions at the level of sixth cervical nerve to second thoracic nerve were bilaterally swollen and replaced by white mass lesions. Right brachial plexus and cranial nerves (III, V and VII) were also swollen. A mass lesion was found in the right frontal lobe of the cerebrum. Histologically, neoplastic lymphocytes extensively involved the peripheral nerves, and they infiltrated into the cerebral and spinal parenchyma according to the peripheral nerve tract. Immunohistochemically, most neoplastic lymphocytes were positive for CD20. The clinical and histological features in this case resemble those of neurolymphomatosis in humans. PMID- 26960327 TI - Anopheles farauti is a homogeneous population that blood feeds early and outdoors in the Solomon Islands. AB - BACKGROUND: In the 1970s, Anopheles farauti in the Solomon Island responded to indoor residual spraying with DDT by increasingly feeding more outdoors and earlier in the evening. Although long-lasting insecticidal nets (LLINs) are now the primary malaria vector control intervention in the Solomon Islands, only a small proportion of An. farauti still seek blood meals indoors and late at night where they are vulnerable to being killed by contract with the insecticides in LLINs. The effectiveness of LLINs and indoor residual spraying (IRS) in controlling malaria transmission where the vectors are exophagic and early biting will depend on whether the predominant outdoor or early biting phenotypes are associated with a subpopulation of the vectors present. METHODS: Mark-release recapture experiments were conducted in the Solomon Islands to determine if individual An. farauti repeat the same behaviours over successive feeding cycles. The two behavioural phenotypes examined were those on which the WHO recommended malaria vector control strategies, LLINs and IRS, depend: indoor and late night biting. RESULTS: Evidence was found for An. farauti being a single population regarding time (early evening or late night) and location (indoor or outdoor) of blood feeding. Individual An. farauti did not consistently repeat behavioural phenotypes expressed for blood feeding (e.g., while most mosquitoes that fed early and outdoors, and would repeat those behaviours, some fed late at night or indoors in the next feeding cycle). CONCLUSIONS: The finding that An. farauti is a homogeneous population is significant, because during the multiple feeding cycles required to complete the extrinsic incubation period, many individual female anophelines will enter houses late at night and be exposed to the insecticides used in LLINs or IRS. This explains, in part, the control that LLINs and IRS have exerted against a predominantly outdoor feeding vector, such as An. farauti. These findings may be relevant to many of the outdoor feeding vectors that dominate transmission in much of the malaria endemic world and justifies continued use of LLINs. However, the population-level tendency of mosquitoes to feed outdoors and early in the evening does require complementary interventions to accelerate malaria control towards elimination. PMID- 26960328 TI - IL-22 Impedes the Proliferation of Schwann cells: Transcriptome Sequencing and Bioinformatics Analysis. AB - Schwann cells (SCs) proliferation is crucial for nerve regeneration following nerve injury. This study aims to investigate effects of interleukin-22 (IL-22) on SCs proliferation in vitro, as well as the corresponding mechanism. Rat SCs were treated with 100 ng/ml rat IL-22 for 48 h, and cell proliferation and apoptosis were detected using fluorescent staining and flow cytometry. After transcriptome sequencing, raw reads were filtered and mapped to reference genome rn5. Then, differentially expressed genes (DEGs) and long non-coding RNAs (DElncRNAs) between IL-22 and control groups were identified (tool: Cuffdiff). Functional and pathway enrichment analyses were performed (tool: GOFunction), and protein protein interaction (PPI) network was constructed (tool: STRING and Cytoscape). Furthermore, Pearson's correlations between DEGs and DElncRNAs were analyzed, and regulatory network of DEGs, DElncRNAs, and transcription factors (TFs) was constructed. IL-22 significantly inhibited proliferation (p value < 0.05) and promoted apoptosis of Schwann cells. Totally, 932 DEGs and 118 DElncRNAs were identified, among which Ccl2 and Ccna2 were hub genes in PPI network. Up regulated DEGs were enriched in apoptosis related terms, whereas down-regulated DEGs were enriched in proliferation related terms. DElncRNAs like NONRATT023505, NONRATG020400, and NONRATT022748 were correlated with multiple DEGs enriched in cell cycle and division. Moreover, up-regulated TFs Egr1, Cebpd, and Atf4 play crucial roles in regulatory network, and NONRATG020400-Cebpd-Ccl2, NONRATT023505/NONRATT022748-Atf4-Ccna2, and NONRATT022748-Egr1 Id1/Aldoc/Eno2/F3/Serpine1 regulatory pathways were identified in SCs after IL-22 treatment. IL-22 might influence SCs proliferation and apoptosis via regulating lncRNA-TF-gene pathways in SCs. However, more studies are required to confirm these results. PMID- 26960331 TI - Erratum to: 'MicroRNA target prediction using thermodynamic and sequence curves'. PMID- 26960329 TI - Chloride Co-transporter NKCC1 Inhibitor Bumetanide Enhances Neurogenesis and Behavioral Recovery in Rats After Experimental Stroke. AB - Bumetanide, a selective Na+-K+-Cl--co-transporter inhibitor, is widely used in clinical practice as a loop diuretic. In addition, bumetanide has been reported to attenuate ischemia-induced cerebral edema and reduce neuronal injury. This study examined whether bumetanide could influence neurogenesis and behavioral recovery in rats after experimentally induced stroke. Adult male Wistar rats were randomly assigned to four groups: sham, sham treated with bumetanide, ischemia, and ischemia treated with bumetanide. Focal cerebral ischemia was induced by injection of endothelin-1. Bumetanide (0.2 mg/kg/day) was infused into the lateral ventricle with drug administration being initiated 1 week after ischemia and continued for 3 weeks. Behavioral impairment and recovery were evaluated by tapered/ledged beam-walking test on post-stroke days 28. Then, the rats were perfused for BrdU/DCX (neuroblast marker), BrdU/NeuN (neuronal marker), BrdU/GFAP (astrocyte marker), and BrdU/Iba-1 (microglia marker) immunohistochemistry. The numbers of neuroblasts in the subventricular zone (SVZ) were significantly increased after the experimentally induced stroke. Bumetanide treatment increased migration of neuroblasts in the SVZ towards the infarct area, enhanced long-term survival of newborn neurons, and improved sensorimotor recovery, but it did not exert any effects on inflammation. In conclusion, our results demonstrated that chronic bumetanide treatment enhances neurogenesis and behavioral recovery after experimentally induced stroke in rats. PMID- 26960332 TI - Why balls are not put inside the basket? A reflection on testicular cancer clinical trial design. AB - New concepts of trial design are being developed based on biomarkers, namely basket and umbrella trials. Basket trials appear optimally positioned to evaluate new molecular markers for testicular germ cell tumors, a rare heterogeneous disease with relatively few molecular alterations. However, not uncommonly, the "balls" fall outside the "basket". In this short communication, we discussed the different causes limiting the inclusion of TGCT in basket trials and we proposed a new design for trials suitable for this malignancy. PMID- 26960330 TI - KU0063794, a Dual mTORC1 and mTORC2 Inhibitor, Reduces Neural Tissue Damage and Locomotor Impairment After Spinal Cord Injury in Mice. AB - Autophagy is an intracellular catabolic mechanism for the degradation of cytoplasmic constituents in the autophagosomal-lysosomal pathway. This mechanism plays an important role in homeostasis and it is defective in certain diseases. Preceding studies have revealed that autophagy is developing as an important moderator of pathological responses associated to spinal cord injury (SCI) and plays a crucial role in secondary injury initiating a progressive degeneration of the spinal cord. Thus, based on this evidence in this study, we used two different selective inhibitors of mTOR activity to explore the functional role of autophagy in an in vivo model of SCI as well as to determine whether the autophagic process is involved in spinal cord tissue damage. We treated animals with a novel synthetic inhibitor temsirolimus and with a dual mTORC1 and mTORC2 inhibitor KU0063794 matched all with the well-known inhibitor of mTOR the rapamycin. Our results demonstrated that mTOR inhibitors could regulate the neuroinflammation associated to SCI and the results that we obtained evidently demonstrated that rapamycin and temsirolimus significantly diminished the expression of iNOS, COX2, GFAP, and re-established nNOS levels, but the administration of KU0063794 is able to blunt the neuroinflammation better than rapamycin and temsirolimus. In addition, neuronal loss and cell mortality in the spinal cord after injury were considerably reduced in the KU0063794-treated mice. Accordingly, taken together our results denote that the administration of KU0063794 produced a neuroprotective function at the lesion site following SCI, representing a novel therapeutic approach after SCI. PMID- 26960333 TI - Erratum to: Clinical trial and in-vitro study comparing the efficacy of treating bony lesions with allografts versus synthetic or highly-processed xenogeneic bone grafts. PMID- 26960334 TI - High incidence of TERT mutation in brain tumor cell lines. AB - TERT promoter gene mutations are highly recurrent in malignant glioma. However, little information exists regarding their presence in experimental brain tumor models. To better characterize systems in which TERT mutation studies could be appropriately modeled experimentally, the TERT promoter was examined by conventional sequencing in primary brain tumor initiating cells (BTIC), two matched recurrent BTIC lines, a panel of established malignant glioma cell lines, and two meningioma cell lines. Telomerase gene expression was examined by quantitative PCR. We found that all glioblastoma BTIC lines harbored a TERT mutation, which was retained in two patient-matched recurrent BTIC. The TERT C228T or C250T mutation was found in 33/35 (94 %) of established malignant glioma cell lines and both meningioma cell lines examined. Brain tumor cell lines expressed variably high telomerase levels. Thus, a high percentage of glioma cell lines, as well as two meningioma cell lines, harbors TERT mutations. These data characterize tractable, accessible models with which to further explore telomerase biology in these tumor types. PMID- 26960335 TI - [Retrorectal space-occupying lesion: a rare differential diagnosis]. PMID- 26960336 TI - [A rare pathology of the pelvis with a high potential for complications]. PMID- 26960337 TI - Sevoflurane anesthesia during acute right ventricular ischemia in pigs preserves cardiac function better than propofol anesthesia. AB - BACKGROUND: The intention of the present study was to evaluate possible cardioprotective properties of inhalation anesthesia with sevoflurane. METHODS AND MATERIALS: A porcine, open-chest model of right ventricular ischemia was used in 7 pigs receiving inhalation anesthesia with sevoflurane. The model was earlier developed and published by our group, using pigs receiving intravenous anesthesia with propofol. They served as controls. The animals were observed for three hours after the induction of right ventricular ischemia by ligation of the main branches supplying the right ventricular free wall. RESULTS: In the sevoflurane group, the cardiac output recovered 2 hours after the induction of ischemia and intact right ventricular stroke work was observed. In the propofol group, no such recovery occurred. The release of troponin T was significantly lower than in the sevoflurane group. CONCLUSIONS: Inhalation anesthesia with sevoflurane seems superior to intravenous anesthesia with propofol in acute right ventricular ischemic dysfunction. PMID- 26960338 TI - Foxo3b but not Foxo3a activates cyp19a1a in Epinephelus coioides. AB - FOXO3 has been shown to be a critical transcription factor for folliculogenesis in mammals, while the information on its roles in reproduction of nonmammalian vertebrates remains scarce. In this study, two foxo3 homologs, namely foxo3a and foxo3b, were identified in a teleost, the orange-spotted grouper Epinephelus coioides. foxo3a was mainly expressed in the central nervous system, ovary, and gut whereas foxo3b was expressed ubiquitously in tissues examined. In contrast to the dominant expression of mammalian FOXO3 in germ cells but barely detectable in ovarian follicular cells, immunoreactive Foxo3a and Foxo3b were identified both in the ovarian germ cells and follicular cells. The immunointensities of both Foxo3a and Foxo3b in ovarian follicular cells during vitellogenesis were significantly increased stage-dependently, and co-localized with Cyp19a1a. In the nucleus of ovarian follicular cells, both Foxo3a and Foxo3b immunostaining could be detected at the vitellogenic stages. Transient transfection and EMSA showed that Foxo3a and Foxo3b upregulated cyp19a1a promoter activities in vitro through a conserved Foxo-binding site, with the latter being a more potent activator. However, ChIP analysis showed that only Foxo3b binds to cyp19a1a proximal promoter region containing the conserved Foxo-binding site in the vitellogenic ovary. Taken together, these results suggested that Foxo3a and Foxo3b are involved in the ovarian development possibly through regulating the ovarian germ cells as well as follicular cells, and Foxo3b but not Foxo3a may activate cyp19a1a in the ovarian follicular cells during vitellogenesis in the orange spotted grouper. PMID- 26960339 TI - Reasoning on the Autism Spectrum: A Dual Process Theory Account. AB - Dual process theory proposes two distinct reasoning processes in humans, an intuitive style that is rapid and automatic and a deliberative style that is more effortful. However, no study to date has specifically examined these reasoning styles in relation to the autism spectrum. The present studies investigated deliberative and intuitive reasoning profiles in: (1) a non-clinical sample from the general population with varying degrees of autism traits (n = 95), and (2) males diagnosed with ASD (n = 17) versus comparisons (n = 18). Taken together, the results suggest reasoning on the autism spectrum is compatible with the processes proposed by Dual Process Theory and that higher autism traits and ASD are characterised by a consistent bias towards deliberative reasoning (and potentially away from intuition). PMID- 26960342 TI - Boosting the Potency of T-cell Therapies. AB - Researchers in the adoptive T-cell therapy field are continuing to refine the ways in which the specificity of these immune cells can be redirected toward tumors. They've found that selecting the most persistent, proliferative T cells and genetically manipulating only these defined subsets-ensures a potent therapeutic product that's effective even at minuscule doses. PMID- 26960344 TI - Cellular and System Biology of Memory: Timing, Molecules, and Beyond. AB - The storage of information in the mammalian nervous systems is dependent on a delicate balance between change and stability of neuronal networks. The induction and maintenance of processes that lead to changes in synaptic strength to a multistep process which can lead to long-lasting changes, which starts and ends with a highly choreographed and perfectly timed dance of molecules in different cell types of the central nervous system. This is accompanied by synchronization of specific networks, resulting in the generation of characteristic "macroscopic" rhythmic electrical fields, whose characteristic frequencies correspond to certain activity and information-processing states of the brain. Molecular events and macroscopic fields influence each other reciprocally. We review here cellular processes of synaptic plasticity, particularly functional and structural changes, and focus on timing events that are important for the initial memory acquisition, as well as mechanisms of short- and long-term memory storage. Then, we cover the importance of epigenetic events on the long-time range. Furthermore, we consider how brain rhythms at the network level participate in processes of information storage and by what means they participating in it. Finally, we examine memory consolidation at the system level during processes of sleep. PMID- 26960340 TI - Targeted Thromboelastographic (TEG) Blood Component and Pharmacologic Hemostatic Therapy in Traumatic and Acquired Coagulopathy. AB - Trauma-induced coagulopathy (TIC) is a recently described condition which traditionally has been diagnosed by the common coagulation tests (CCTs) such as prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), platelet count, and fibrinogen levels. The varying sensitivity and specificity of these CCTs have led trauma coagulation researchers and clinicians to use Viscoelastic Tests (VET) such as Thromboelastography (TEG) to provide Targeted Thromboelastographic Hemostatic and Adjunctive Therapy (TTHAT) in a goal directed fashion to those trauma patients in need of hemostatic resuscitation. This review describes the utility of VETs, in particular, TEG, to provide TTHAT in trauma and acquired non-trauma-induced coagulopathy. PMID- 26960341 TI - Structural and Functional Aspects of Class A Carbapenemases. AB - The fight against infectious diseases is probably one of the greatest public health challenges faced by our society, especially with the emergence of carbapenem-resistant gram-negatives that are in some cases pan-drug resistant. Currently,beta-lactamase-mediated resistance does not spare even the newest and most powerful beta-lactams (carbapenems), whose activity is challenged by carbapenemases. The worldwide dissemination of carbapenemases in gram-negative organisms threatens to take medicine back into the pre-antibiotic era since the mortality associated with infections caused by these "superbugs" is very high, due to limited treatment options. Clinically-relevant carbapenemases belong either to metallo-beta- lactamases (MBLs) of Ambler class B or to serine-beta lactamases (SBLs) of Ambler class A and D enzymes. Class A carbapenemases may be chromosomally-encoded (SME, NmcA, SFC-1, BIC-1, PenA, FPH-1, SHV-38), plasmid encoded (KPC, GES, FRI-1) or both (IMI). The plasmid-encoded enzymes are often associated with mobile elements responsible for their mobilization. These enzymes, even though weakly related in terms of sequence identities, share structural features and a common mechanism of action. They variably hydrolyse penicillins, cephalosporins, monobactams, carbapenems, and are inhibited by clavulanate and tazobactam. Three-dimensional structures of class A carbapenemases, in the apo form or in complex with substrates/inhibitors, together with site-directed mutagenesis studies, provide essential input for identifying the structural factors and subtle conformational changes that influence the hydrolytic profile and inhibition of these enzymes. Overall, these data represent the building blocks for understanding the structure-function relationships that define the phenotypes of class A carbapenemases and can guide the design of new molecules of therapeutic interest. PMID- 26960345 TI - [Toward a New Immunization Schedule in Spain, 2016 (Part 2)]. AB - Immunization schedules are intrinsically dynamic in order to embed the immunologic and epidemiologic changes in any specific geographic Region. According to this, the current study addresses a proposal to modify the Childhood Immunization Schedule in Spain. In order to move from a three plus one schema to a two plus one, we undertake a review of the available literature to explore the immunological and clinical rationale behind this change, including an overview of the potential impact on this schedule of premature infants. Additionally, some recommendations are made regarding those Spanish regions which start hepatitis B vaccination at the newborn period. PMID- 26960347 TI - Managing pain by visually distorting the size of painful body parts: is there any therapeutic value? PMID- 26960346 TI - Repression of Biotin-Related Proteins by Benzo[a]Pyrene-Induced Epigenetic Modifications in Human Bronchial Epithelial Cells. AB - Benzo[a]pyrene (B[a]P) exposure has been associated with the alteration in epigenetic marks that are involved in cancer development. Biotinidase (BTD) and holocarboxylase synthetase (HCS) are 2 major enzymes involved in maintaining the homeostasis of biotinylation, and the deregulation of this pathway has been associated with a number of cancers. However, the link between B[a]P exposure and the dysregulation of BTD/HCS in B[a]P-associated tumorigenesis is unknown. Here we showed that the expression of both BTD and HCS was significantly decreased upon B[a]P treatment in human bronchial epithelial (16HBE) cells. Benzo[a]pyrene exposure led to the global loss of DNA methylation by immunofluorescence, which coincided with the reduction in acetylation levels on histones H3 and H4 in 16HBE cells. Consistent with decreased histone acetylation, histone deacetylases (HDACs) HDAC2 and HDAC3 were significantly upregulated in a dosage-dependent manner. When DNA methylation or HDAC activity was inhibited, we found that the reduction in BTD and HCS was separately regulated through distinct epigenetic mechanisms. Together, our results suggested the potential link between B[a]P toxicity and deregulation of biotin homeostasis pathway in B[a]P-associated cancer development. PMID- 26960348 TI - Aperture number influences pollen survival in Arabidopsis mutants. AB - PREMISE OF THE STUDY: Pollen grains are subject to intense dehydration before dispersal. They rehydrate after landing on a stigma or when placed in humid environment by absorbing water from the stigma or surroundings. Resulting fluctuations in water content cause pollen grains to undergo significant changes in volume. Thus, morphological or structural adaptations might exist to help pollen adjust to sudden volume changes, though little is known about the correlation between pollen morphology and its ability to accommodate volume changes. We studied the effect of one morphological feature of pollen grains, the aperture number, on pollen wall resistance to water inflow in Arabidopsis thaliana. METHODS: We used three Arabidopsis thaliana mutants that differ in the number of apertures in their pollen (zero, four, or a mix of four to eight, respectively) and the wild type with pollen with three apertures. We tested pollen survival in solutions with various mannitol concentrations. KEY RESULTS: The number of intact pollen grains increased with increasing mannitol concentration for all pollen morphs tested. At a given mannitol concentration, however, an increase in aperture number was associated with an increase in pollen breakage. CONCLUSIONS: Aperture patterns, i.e., number, shape, and position, influence the capacity to accommodate volume variations in pollen grains. When subjected to water inflow, pollen grains with few apertures survive better than pollen with many apertures. Trade-offs between survival and germination are likely to be involved in the evolution of pollen morphology. PMID- 26960349 TI - Hydrogel control of water uptake by pectins during in vitro pollen hydration of Eucalyptus globulus. AB - PREMISE OF THE STUDY: Upon pollination, dehydrated pollen grains take water out of the stigma surface, an event that constitutes the first functional checkpoint of sexual reproduction in higher plants. Little is known about possible functional connections between rehydration speed and further steps of fertilization. Here we addressed the mechanisms of water uptake control by dehydrated pollen grains. Because dehydrated cells have no energy-driven active mechanism such as membrane-based osmoregulation for controlling water movement, we tested the hypothesis that another mechanism might exist, namely, the use of hydrogel-behaving molecules. METHODS: We developed an imaging protocol to visualize and quantify the rate of water entry into pollen grains of Eucalyptus globulus and tested the influence of different treatments linked to hydrogel behaving molecules. We complemented these analyses by immunostaining pectins in the pollen grain with monoclonal antibodies JIM5 and JIM7. KEY RESULTS: Water entry seemed to proceed exclusively through the germination apertures of the pollen grain, and the changes observed in different hydration media are compatible with hydrogel behavior. When JIM5 and JIM7 were used to characterize pectins on the germination apertures during hydration, pectin localization and esterification changed during hydration and were affected by the hydration solutions. These results suggest that chemical modification of the pectins may change their hydrogel behavior, thus modifying the hydration speed. CONCLUSIONS: The hydrogel behavior of pectins and pectin localization on apertures strongly suggest that pectins act like "valves" for water entry, enabling a regulated process of water uptake into the dehydrated pollen grain. We propose that this regulation evolved in terms of achieving the correct self-organization of molecules and cellular components to resume metabolism and pollen tube growth, especially in species that are subject to demanding environmental water stress. PMID- 26960350 TI - Commentary on Nicola Williams and Stephen Wilkinson: 'Should Uterus Transplants Be Publicly Funded?'. PMID- 26960351 TI - Halliday's 'The ethics of a smoking licence'. PMID- 26960352 TI - Significant hypertriglyceridaemia and HDL cholesterol assays. PMID- 26960353 TI - Parallel inputs to memory in bee colour vision. AB - In the 19(th) century, it was found that attraction of bees to light was controlled by light intensity irrespective of colour, and a few critical entomologists inferred that vision of bees foraging on flowers was unlike human colour vision. Therefore, quite justly, Professor Carl von Hess concluded in his book on the Comparative Physiology of Vision (1912) that bees do not distinguish colours in the way that humans enjoy. Immediately, Karl von Frisch, an assistant in the Zoology Department of the same University of Munich, set to work to show that indeed bees have colour vision like humans, thereby initiating a new research tradition, and setting off a decade of controversy that ended only at the death of Hess in 1923. Until 1939, several researchers continued the tradition of trying to untangle the mechanism of bee vision by repeatedly testing trained bees, but made little progress, partly because von Frisch and his legacy dominated the scene. The theory of trichromatic colour vision further developed after three types of receptors sensitive to green, blue, and ultraviolet (UV), were demonstrated in 1964 in the bee. Then, until the end of the century, all data was interpreted in terms of trichromatic colour space. Anomalies were nothing new, but eventually after 1996 they led to the discovery that bees have a previously unknown type of colour vision based on a monochromatic measure and distribution of blue and measures of modulation in green and blue receptor pathways. Meanwhile, in the 20(th) century, search for a suitable rationalization, and explorations of sterile culs-de-sac had filled the literature of bee colour vision, but were based on the wrong theory. PMID- 26960354 TI - Histological, histochemical and ultrastructural studies on Harderian and lacrimal glands of the Capercaillie (Tetrao urogallus major L.). AB - This study describes the macroscopic anatomy and the microscopic and ultrastructural features of the Harderian gland and lacrimal gland of the Capercaillies. It was conducted both on adult male and female Capercaillies. Tissue sections were stained with hematoxylin and eosin, azan trichrome, modified Mallory's trichrome, methyl green-pyronin Y, periodic acid-Schiff, alcian blue pH 2.5, aldehyde fuchsin and Hale's dialysed iron. The morphometric study of the Harderian and lacrimal glands indicated that they are both larger in male than in female Capercaillies. The histological analysis showed that the HG has a multilobar tubulo-alveolar structure with numerous lymphocytes and plasma cells. The LG has a multilobar tubulo-acinar structure without lymphocytes and plasma cells. The periodic acid-Schiff staining and alcian blue pH 2.5 staining demonstrated a mild positive reaction in the epithelial cells of the Harderian gland and weak positive reaction in the lacrimal gland. The HDI staining detected the presence of carboxylated acid mucopolysaccharides in the Harderian and lacrimal glands. Transmission electron microscopy revealed the presence of two types of secretory vesicles in the cytoplasm of both studied glands. It also showed that lipid droplets and glycogen granules were more abundant in the Harderian gland than in the lacrimal gland of this species. PMID- 26960356 TI - Plant growth regulators induced urease activity in Cucurbita pepo L. cotyledons. AB - This study is aimed to investigate the activity of urease (EC 3.5.1.5, urea amidohydrolase) that catalyzes the hydrolysis of urea in 5-day-old Cucurbita pepo cotyledons subjected to various concentrations of different growth regulators. The treatment of C. pepo cotyledons with different concentrations (100-600 MUmol) of different auxins [indole-3-acetic acid (IAA), indole butyric acid (IBA), indole propionic acid (IPA) and naphthalene acetic acid (NAA)]; or with different concentrations (100-300 MUmol) of different cytokinins [kinetin, zeatin and benzyladenine (6-BA)] resulted in a significant increase of urease activity, compared to control. The optimal effects were recorded for each of 500 MUmol of IAA and 300 MUmol of zeatin treatments. A gradual increase in urease activity was detected in cotyledons treated with various concentrations (0.2-1.0 mM) of 28 homobrassinolide (HBL), in relative to control. A substantial increase in urease activity was observed in cotyledons subjected to different concentrations of triazole (10-60 mg L(-1)), containing either triadimefon (TDM) or hexaconazole (HEX), compared to control. The combination of 300 MUmol zeatin with any of protein inhibitors, namely 5-fluorouridine (FUrd), cordycepin and alpha-amanitin, resulted in the alleviation of their inhibitory effect on the urease activity. PMID- 26960355 TI - Tamarix arborea var. arborea and Tamarix parviflora: Two species valued for their adaptability to stress conditions. AB - The choice of stress resistant and highly adaptable species is a fundamental step for landscaping and ornamental purposes in arid and coastal environments such as those in the Mediterranean basin. The genus Tamarix L. includes about 90 species with a high endurance of adversity. We investigated the water relations and photosynthetic response of Tamarix arborea (Sieb. ex Ehrenb.) Bge. var. arborea and T. parviflora DC. growing in an urban environment. Both species showed no evidence of drought or salt stress in summer, and appeared to follow two strategies with T. arborea var. arborea investing in high carbon gain at the beginning of the summer, and then reducing photosynthetic activity at the end of the season, and T. parviflora showing lower but constant levels of photosynthetic activity throughout the vegetative season. For landscaping and ornamental purposes, we suggest T. arborea var. arborea when a fast-growing, high-cover species is necessary, and T. parviflora when less-invasive species are required. PMID- 26960358 TI - Synthesis and antimicrobial evaluation of some novel sulfonylamido-benzoxazoles. AB - A series of 2-(p-substituted phenyl)-5-[(4-substituted phenyl) sulfonylamido] benzoxazoles were synthesized and tested for their antimicrobial activities. The structures of the new derivatives were elucidated by spectral techniques. The minimum inhibitory concentrations (MIC) of the new benzoxazoles were determined against standard bacterial and fungal strains and drug-resistant isolates and compared to those of several reference drugs. PMID- 26960357 TI - Effect of water supply on growth and polyphenols of lemon balm (Melissa officinalis L.) and thyme (Thymus vulgaris L.). AB - A pot experiment was carried out with lemon balm (Melissa officinalis L.) and thyme (Thymus vulgaris L.). Different water supply was applied: 25%, 40% and 70% saturation of soil water capacity (SWC). Morphological traits, biomass and phenolic type active ingredients were investigated. Among the two species, main differences were registered in biomass and TPC. Lower SWC resulted in reduced biomass production of lemon balm, while the applied stress treatments did not effect the biomass of thyme. In lemon balm, highest TPC contents were measured in control plants both in shoots and roots but in thyme, the shoots showed a significantly increased TPC at the 25% SWC conditions. Neither the content of total flavonoids nor that of the rosmarinic acid was affected by the treatments. The antioxidant capacity proved to be in tight connection with the TPC in both species (r = 0.766-0.883). The rosmarinic acid content of lemon balm plants contributed to the antioxidant capacity, as well (r = 0.679-0.869). PMID- 26960359 TI - The role of oxidative stress genes and effect of pH on methylene blue sensitized photooxidation of Escherichia coli. AB - In this study, the survival time of wild type E. coli W3110 and 11 mutants was analysed with a plate count method in methylene blue added or control groups under daylight fluoroscence illumination (4950 lux) at different pH values (5.0, 6.0, 7.0, and 8.0) in phosphate buffer. As a result, while the number of bacteria did not decrease under photooxidative stress at pH 5.0 and 6.0 during a 6-hour incubation, the wild type and all mutants decreased more than 2 log. at pH 8.0, and approximately one log. at pH 7.0. It was determined that a 2 log decrease in wild type E. coli takes 3.7 h according to t99 value at pH 8, these values were 2.39 h in the katE mutant, 2.64 h in the soxR mutant, 2.67 h in the oxyR mutant, 2.71 h in the sodB mutant, 3 h in the btuE mutant, 3.38 h in the zwf mutant and 3.40 h in the soxS mutant, respectively (p < 0.05). The roles of these genes were proved with complement tests. Finally, it is found that the effectiveness of photooxidative stress is in direct relation with pH, and the katE, soxR, oxyR, sodB, btuE, zwf, and soxS genes are important for the protection against this stress. PMID- 26960360 TI - Modeling and predicting the biofilm formation of Salmonella Virchow with respect to temperature and pH. AB - Biofilm formation of Salmonella Virchow was monitored with respect to time at three different temperature (20, 25 and 27.5 degrees C) and pH (5.2, 5.9 and 6.6) values. As the temperature increased at a constant pH level, biofilm formation decreased while as the pH level increased at a constant temperature, biofilm formation increased. Modified Gompertz equation with high adjusted determination coefficient (Radj(2)) and low mean square error (MSE) values produced reasonable fits for the biofilm formation under all conditions. Parameters of the modified Gompertz equation could be described in terms of temperature and pH by use of a second order polynomial function. In general, as temperature increased maximum biofilm quantity, maximum biofilm formation rate and time of acceleration of biofilm formation decreased; whereas, as pH increased; maximum biofilm quantity, maximum biofilm formation rate and time of acceleration of biofilm formation increased. Two temperature (23 and 26 degrees C) and pH (5.3 and 6.3) values were used up to 24 h to predict the biofilm formation of S. Virchow. Although the predictions did not perfectly match with the data, reasonable estimates were obtained. In principle, modeling and predicting the biofilm formation of different microorganisms on different surfaces under various conditions could be possible. PMID- 26960361 TI - Characterisation of mitochondrial haplotypes occurred in a Candida albicans population. AB - The genetic background of mitochondrial DNA polymorphism in Candida albicans was studied by physical and functional mapping of four haplotypes identified recently in a hospital-population. The restriction patterns revealed considerable differences; however, the size of the mitochondrial DNA did not vary significantly. Sequence data demonstrated that size differences arose by short deletions, while restriction fragment length polymorphisms are caused by nucleotide substitutions in single sites. Gene rearrangement could not be detected; nevertheless, the coincidence of nucleotide substitution pattern in the inverted repeat region suggested the occurrence of homologue recombination. PMID- 26960362 TI - First report of Lividin and Spinulosain peptides from the skin secretion of an Indian frog. AB - Here, we report two novel peptides identified from the skin secretion, having homologies to Lividin and Spinulosain, of an endemic frog, Hydrophylax bahuvistara, of Western Ghats. This is the first report of these peptides from Indian frogs and first identification of Lividin from the Hydrophylax genus. Both peptides exhibited weak antimicrobial activity but very low haemolytic activity. The problems of naming amphibian host defense peptides (HDPs) are also discussed. PMID- 26960363 TI - Identification, localization, and functional analysis of the homologues of mouse CABS1 protein in porcine testis. AB - Previously, we have identified a calcium-binding protein that is specifically expressed in spermatids and localized to the flagella of the mature sperm in mouse, so-called mCABS1. However, the physiological roles of CABS1 in the male reproductive system have not been fully elucidated yet. In the current study, we aimed to localize and clarify the role of CABS1 in porcine (pCABS1). We determined for the first time the full nucleotides sequence of pCABS1 mRNA. pCABS1 protein was detected on SDS-PAGE gel as two bands at 75 kDa and 70 kDa in adult porcine testis, whereas one band at 70 kDa in epididymal sperm. pCABS1 immunoreactivity in seminiferous tubules was detected in the elongated spermatids, and that in the epididymal sperm was found in the acrosome as well as flagellum. The immunoreactivity of pCABS1 in the acrosomai region disappeared during acrosome reaction. We also identified that pCABS1 has a transmembrane domain using computational prediction of the amino acids sequence. The treatment of porcine capacitated sperm with anti-pCABS1 antiserum significantly decreased acrosome reactions. These results suggest that pCABS1 plays an important role in controlling calcium ion signaling during the acrosome reaction. PMID- 26960364 TI - Effects of Percutaneous Coronary Intervention on Serum Angiopoietin-2 in Patients with Coronary Heart Disease. AB - BACKGROUND: Angiopoietin-2 (Ang-2) plays a crucial role in hypoxia-induced angiogenesis and is expressed only in sites of vascular remodeling. Ang-2 expression can be regulated by hypoxia inducible factors and other regulators with exposure to hypoxia. The objective of this study was to investigate the influence of percutaneous coronary intervention (PCI) on serum Ang-2 concentrations, and analyze the correlation between serum Ang-2 and the severity of coronary artery stenosis in patients with coronary heart disease (CHD). METHODS: Sixty-four patients with CHD were selected as the study group, each undergone PCI. Thirty-two healthy subjects were selected as the control group. Pre-PCI and post-PCI serum Ang-2 were measured by enzyme-linked immunosorbent assay. The severity of coronary artery stenosis was evaluated using angiographic Gensini scores, and the coronary collateral vessels were scored according to Rentrop's classification. RESULTS: Concentrations of pre-PCI serum Ang-2 in the study group were significantly higher than those in the control group (4625.06 +/ 1838.06 vs. 1945.74 +/- 1588.17 pg/ml, P < 0.01); however, concentrations of post-PCI serum Ang-2 were significantly lower than those of pre-PCI (3042.63 +/- 1845.33 pg/ml vs. 4625.06 +/- 1838.06 pg/ml, P < 0.01). Concentrations of pre-PCI serum Ang-2 were significantly correlated with Gensini scores (r = 0.488, P < 0.01); however, the decrease in serum Ang-2 after PCI was not correlated with Gensini scores, coronary collateral vessel grading, or left ventricular ejection fraction. CONCLUSIONS: Serum Ang-2 concentrations significantly increased in patients with CHD, and PCI treatment significantly decreased these concentrations. Serum Ang-2 concentrations, but not the decrease in serum Ang-2 concentrations, were significantly correlated with the severity of coronary artery stenosis. These results suggested that Ang-2 may be a biomarker of myocardial ischemia and vessel remodeling. PMID- 26960365 TI - Cancer Incidence and Mortality Survey in Wuwei, Gansu Province, Northwestern China from 2003 to 2012: A Retrospective Population-based Study. AB - BACKGROUND: Population-based cancer registry collects the data on cancer incidence and mortality deaths from covered population to describe and survey the epidemics in certain areas. The aim of this study was to estimate the cancer incidence and mortality in Wuwei, Gansu province, Northwestern China from 2003 to 2012. The goal is to better understand cancer distribution and long-term development of cancer prevention and treatment in Wuwei. METHODS: Data were collected from the Wuwei Cancer Registry between 2003 and 2012. In this registry, data from 46 cancer report centers were included in this analysis. Incidence/mortality rates, age-specific incidence/mortality rates, age standardized incidence/mortality rates, and cumulative incidence/mortality rates were calculated. Totally, 9,836,740 person-years (5,110,342 for males and 4,726,398 for females) had been monitored over this time period. The gender ratio of male/female was 1.08:1. The number of new cancer cases and related deaths was 24,705 and 17,287 from 2003 to 2012, respectively. RESULTS: The proportion of morphological verification was 74.43%. The incidence of cases identified through death certification only was 1.21%, and the mortality to incidence ratio was 0.70. The average crude incidence was 251.15/100,000 persons (310.61 and 186.87 for males and females per 100,000 persons, respectively). The age-standardized rates by Chinese standard population (ASR-China) and by world standard population (ASR-world) were 207.76 and 245.42 per 100,000 persons, respectively. The crude cancer mortality was 175.74/100,000 persons (228.34 and 118.86 for males and females per 100,000 persons). ASR for China and the world was 149.57 and 175.13/100,000 persons, respectively. The most common cancers and leading causes of cancer-related deaths in Wuwei were as follows: cancers of stomach, esophagus, liver, lung, colorectum, breast, cervix, lymphoma, blood (leukemia), brain, and central nervous system. In Wuwei, during 2003 and 2012, cancer incidence and mortality rates increased by 1.32% and 1.31%/year, respectively. During this time, colorectum cancer incidence and mortality rates increased by 2.69% and 7.54%/year, respectively, in Wuwei. The incidence and mortality of other gastric, esophageal, liver, and lung cancers also all increased. CONCLUSIONS: The results of this study report a more accurate cancer burden among the population of Wuwei, China. Active research of cancers etiology and effective prevention should be established to reduce the incidence and mortality associated with cancers. PMID- 26960366 TI - Clinical Characteristics and Urodynamic Analysis of Urinary Dysfunction in Multiple Sclerosis. AB - BACKGROUND: Both lower urinary tract dysfunction and urinary symptoms are prevalent in patients with multiple sclerosis (MS). Although the significance of identifying and treating urinary symptoms in MS is currently well-known, there is no information about the real prevalence and therapeutic effect of urinary symptoms in patients with MS. The purpose of this study was to analyze the major symptoms and urodynamic abnormalities, and observe the therapeutic effect in different MS characteristics. METHODS: We enrolled 126 patients with urological dysfunction who were recruited between July 2008 and January 2015 in Beijing Tian Tan Hospital, Capital Medical University and conducted overactive bladder system score (OABSS), urodynamic investigation, and expanded disability status scale (EDSS). Changes of urinary symptoms and urodynamic parameters were investigated. RESULTS: Urgency was the predominant urinary symptom, and detrusor overactivity was the major bladder dysfunction. There was a positive correlation between EDSS and OABSS. Clinically isolated syndrome (CIS) had lowest EDSS and OABSS. CIS exhibited significant improvements in OABSS, maximum urinary flow rate (Qmax), and bladder volume at the first desire to voiding and maximum bladder volume after the treatment (P < 0.05). Relapsing-remitting MS showed significant improvements in the OABSS, Qmax, and bladder volume at the first desire to voiding, maximum bladder volume and bladder compliance after the treatment (P < 0.05). Progressive MS exhibited significant increase in the bladder volume at the first desire to voiding, the detrusor pressure at maximum flow rate (PdetQmax), and bladder compliance after the treatment (P < 0.05). CONCLUSIONS: Urodynamic parameters examined are important in providing an accurate diagnosis, guiding management decisions of MS. Early and effective treatment may improve the bladder function and the quality of life at the early stages of MS. PMID- 26960367 TI - Three-dimensional Evaluation of Nasal Surgery in Patients with Obstructive Sleep Apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a common sleep disorder and is characterized by airway collapse at multiple levels of upper airway. The effectiveness of nasal surgery has been discussed in several studies and shows a promising growing interest. In this study, we intended to evaluate the effects of nasal surgery on the upper airway dimensions in patients with OSA using three dimensional (3D) reconstruction of cone-beam computed tomography (CT). METHODS: Twelve patients with moderate to severe OSA who underwent nasal surgery were included in this study. All patients were diagnosed with OSA using polysomnography (PSG) in multi sleep health centers associated with Massachusetts General Hospital, Massachusetts Eye and Ear Infirmary and the Partners Health Care from May 31, 2011 to December 14, 2013. The effect of nasal surgery was evaluated by the examination of PSG, subjective complains, and 3D reconstructed CT scan. Cross-sectional area was measured in eleven coronal levels, and nasal cavity volume was evaluated from anterior nasal spine to posterior nasal spine. The thickness of soft tissue in oral pharynx region was also measured. RESULTS: Five out of the 12 patients were successfully treated by nasal surgery, with more than 50% drop of apnea-hypopnea index. All the 12 patients showed significant increase of cross-sectional area and volume postoperatively. The thickness of soft tissue in oral pharynx region revealed significant decrease postoperatively, which decreased from 19.14 +/- 2.40 cm 2 and 6.11 +/- 1.76 cm 2 to 17.13 +/- 1.91 cm 2 and 5.22 +/- 1.20 cm 2 . CONCLUSIONS: Nasal surgery improved OSA severity as measured by PSG, subjective complaints, and 3D reconstructed CT scan. 3D assessment of upper airway can play an important role in the evaluation of treatment outcome. PMID- 26960368 TI - Association Between Dentin Matrix Protein 1 (rs10019009) Polymorphism and Ankylosing Spondylitis in a Chinese Han Population from Shandong Province. AB - BACKGROUND: Ankylosing spondylitis (AS) is the most common rheumatic condition that is slowly progressive and predominantly affects adolescents. Pathological bone formation associated with AS is an important cause of disability. The aim of the study was to investigate the possible involvement of the genes related to endochondral ossification and ectopia ossification in genetic susceptibility to AS in a Chinese Han population. METHODS: Sixty-eight single nucleotide polymorphisms (SNPs) from 13 genes were genotyped in discovery cohorts including 300 AS patients and 180 healthy controls. The rs10019009 in dentin matrix protein 1 (DMP1) gene shown as association with AS after multiple testing corrections in discovery cohorts was replicated in a validation independent cohort of 620 AS patients and 683 healthy controls. The rs10019009 was assessed with bioinformatics including phylogenetic context, F-SNP and FastSNP functional predictions, secondary structure prediction, and molecular modeling. We performed a functional analysis of rs10019009 via reverse transcription-polymerase chain reaction, alkaline phosphatase (ALP) activity in human osteosarcoma U 2 OS cells. RESULTS: Interestingly, the SNP rs10019009 was associated with AS in both the discovery cohort (P = 0.0012) and validation cohort (P = 0.0349), as well as overall (P = 0.0004) in genetic case-control association analysis. After a multivariate logistic regression analysis, the effect of this genetic variant was observed to be independent of linkage disequilibrium. Via bioinformatics analysis, it was found that the amino acid change of the rs10019009 led to changes of SNP function, secondary structure, tertiary conformation, and splice mode. Finally, functional analysis of rs10019009 in U 2 OS cells demonstrated that the risk T allele of the rs10019009 increased enzymatic activity of ALP, compared to that of the nonrisk allele (P = 0.0080). CONCLUSIONS: These results suggested that the DMP1 gene seems to be involved in genetic predisposition to AS, which may contribute to the ectopic mineralization or ossification in AS. In addition, DMP1 gene may be a promising intervention target for AS in the future. PMID- 26960369 TI - Assessing the Early Response of Advanced Cervical Cancer to Neoadjuvant Chemotherapy Using Intravoxel Incoherent Motion Diffusion-weighted Magnetic Resonance Imaging: A Pilot Study. AB - BACKGROUND: Diffusion-weighted imaging (DWI) with the intravoxel incoherent motion (IVIM) model has shown promising results for providing both diffusion and perfusion information in cervical cancer; however, its use to predict and monitor the efficacy of neoadjuvant chemotherapy (NACT) in cervical cancer is relatively rare. The study aimed to evaluate the use of DWI with IVIM and monoexponential models to predict and monitor the efficacy of NACT in cervical cancer. METHODS: Forty-two patients with primary cervical cancer underwent magnetic resonance exams at 3 time points (pre-NACT, 3 weeks after the first NACT cycle, and 3 weeks after the second NACT cycle). The response to treatment was determined according to the response evaluation criteria in solid tumors 3 weeks after the second NACT treatment, and the subjects were classified as two groups: responders and nonresponders groups. The apparent diffusion coefficient (ADC), true diffusion coefficient (D), perfusion-related pseudo-diffusion coefficient (DFNx01), and perfusion fraction (f) values were determined. The differences in IVIM-derived variables and ADC between the different groups at the different time points were calculated using an independent samples t-test. RESULTS: The D and ADC values were all significantly higher for the responders than for the nonresponders at all 3 time points, but no significant differences were observed in the DFNx01 and f values. An analysis of the receiver operating characteristic (ROC) curves indicated that a D value threshold <0.93 * 10-3 mm 2 /s and an ADC threshold <1.11 * 10-3 mm 2 /s could differentiate responders from nonresponders at pre NACT time point, yielding area under the curve (AUC) of which were 0.771 and 0.806, respectively. The ROC indicated that the AUCs of D and ADC at the 3 weeks after the first NACT cycle and 3 weeks after the second NACT cycle were 0.823, 0.763, and 0.787, 0.794, respectively. The AUC values of D and ADC at these 3 time points were not significantly different (P = 0.641, 0.512, and 0.547, respectively). CONCLUSIONS: D and ADC values may be useful for predicting and monitoring the efficacy of NACT in cervical cancer. An IVIM model may be equal to monoexponential model in predicting and monitoring the efficacy of NACT in cervical cancer. PMID- 26960370 TI - Analyses of Genotypes and Phenotypes of Ten Chinese Patients with Wolf-Hirschhorn Syndrome by Multiplex Ligation-dependent Probe Amplification and Array Comparative Genomic Hybridization. AB - BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome that is typically caused by a deletion of the distal portion of the short arm of chromosome 4. However, there are few reports about the features of Chinese WHS patients. This study aimed to characterize the clinical and molecular cytogenetic features of Chinese WHS patients using the combination of multiplex ligation dependent probe amplification (MLPA) and array comparative genomic hybridization (array CGH). METHODS: Clinical information was collected from ten patients with WHS. Genomic DNA was extracted from the peripheral blood of the patients. The deletions were analyzed by MLPA and array CGH. RESULTS: All patients exhibited the core clinical symptoms of WHS, including severe growth delay, a Greek warrior helmet facial appearance, differing degrees of intellectual disability, and epilepsy or electroencephalogram anomalies. The 4p deletions ranged from 2.62 Mb to 17.25 Mb in size and included LETM1, WHSC1, and FGFR3. CONCLUSIONS: The combined use of MLPA and array CGH is an effective and specific means to diagnose WHS and allows for the precise identification of the breakpoints and sizes of deletions. The deletion of genes in the WHS candidate region is closely correlated with the core WHS phenotype. PMID- 26960371 TI - Aberrant Global and Regional Topological Organization of the Fractional Anisotropy-weighted Brain Structural Networks in Major Depressive Disorder. AB - BACKGROUND: Most previous neuroimaging studies have focused on the structural and functional abnormalities of local brain regions in major depressive disorder (MDD). Moreover, the exactly topological organization of networks underlying MDD remains unclear. This study examined the aberrant global and regional topological patterns of the brain white matter networks in MDD patients. METHODS: The diffusion tensor imaging data were obtained from 27 patients with MDD and 40 healthy controls. The brain fractional anisotropy-weighted structural networks were constructed, and the global network and regional nodal metrics of the networks were explored by the complex network theory. RESULTS: Compared with the healthy controls, the brain structural network of MDD patients showed an intact small-world topology, but significantly abnormal global network topological organization and regional nodal characteristic of the network in MDD were found. Our findings also indicated that the brain structural networks in MDD patients become a less strongly integrated network with a reduced central role of some key brain regions. CONCLUSIONS: All these resulted in a less optimal topological organization of networks underlying MDD patients, including an impaired capability of local information processing, reduced centrality of some brain regions and limited capacity to integrate information across different regions. Thus, these global network and regional node-level aberrations might contribute to understanding the pathogenesis of MDD from the view of the brain network. PMID- 26960372 TI - Failure to Identify Somatic Mutations in Monozygotic Twins Discordant for Schizophrenia by Whole Exome Sequencing. AB - BACKGROUND: Schizophrenia (SCZ) is a severe, debilitating, and complex psychiatric disorder with multiple causative factors. An increasing number of studies have determined that rare variations play an important role in its etiology. A somatic mutation is a rare form of genetic variation that occurs at an early stage of embryonic development and is thought to contribute substantially to the development of SCZ. The aim of the study was to explore the novel pathogenic somatic single nucleotide variations (SNVs) and somatic insertions and deletions (indels) of SCZ. METHODS: One Chinese family with a monozygotic (MZ) twin pair discordant for SCZ was included. Whole exome sequencing was performed in the co-twin and their parents. Rigorous filtering processes were conducted to prioritize pathogenic somatic variations, and all identified SNVs and indels were further confirmed by Sanger sequencing. RESULTS: One somatic SNV and two somatic indels were identified after rigorous selection processes. However, none was validated by Sanger sequencing. CONCLUSIONS: This study is not alone in the failure to identify pathogenic somatic variations in MZ twins, suggesting that exonic somatic variations are extremely rare. Further efforts are warranted to explore the potential genetic mechanism of SCZ. PMID- 26960373 TI - Expressions of Antimicrobial Peptides LL-37, Human Beta Defensin-2 and -3 in the Lesions of Cutaneous Tuberculosis and Tuberculids. AB - BACKGROUND: Antimicrobial peptides, including cathelicidin LL-37, human beta defensin (HBD)-2, and HBD-3, are important elements of the innate immune response and involved in modulation of the adaptive immunity, and they also play an important role in cutaneous defense against Mycobacterium tuberculosis. METHODS: The fresh skin tissues and paraffin-embedded biopsy samples from three cutaneous tuberculosis, two tuberculids, and ten healthy individuals were collected. The expressions of LL-37, HBD-2, and HBD-3 mRNA in the lesions of three cutaneous tuberculosis and two tuberculids were detected by quantitative real-time polymerase chain reaction; the protein expressions were detected by immunohistochemistry and Western blotting methods. RESULTS: The expressions of LL 37 mRNA and protein in the lesions of cutaneous tuberculosis and tuberculids were similar to that of normal skin. The expression of HBD-2 mRNA had an increasing trend in the lesions of cutaneous tuberculosis and tuberculids compared with that of normal skin; however, the expression of HBD-2 protein in the lesions of cutaneous tuberculosis had a decreasing trend compared with that of normal skin, and the expression of HBD-2 protein in the lesions of tuberculids was similar to that of normal skin. The expressions of HBD-3 mRNA and protein in lesions of cutaneous tuberculosis and tuberculids were similar to that of normal skin. CONCLUSIONS: Our study indicated that the expression of HBD-2 and HBD-3 mRNA and protein in lesions of cutaneous tuberculosis may be not consistent with that of tuberculids. However, an inherent limitation of the present study was that the sample size was small, and the roles and regulation mechanisms of LL-37, HBD-2, and HBD-3 in cutaneous tuberculosis and tuberculids need to be further investigated. PMID- 26960374 TI - Cerebral Metabolic Profiling of Hypothermic Circulatory Arrest with and Without Antegrade Selective Cerebral Perfusion: Evidence from Nontargeted Tissue Metabolomics in a Rabbit Model. AB - BACKGROUND: Antegrade selective cerebral perfusion (ASCP) is regarded to perform cerebral protection during the thoracic aorta surgery as an adjunctive technique to deep hypothermic circulatory arrest (DHCA). However, brain metabolism profile after ASCP has not been systematically investigated by metabolomics technology. METHODS: To clarify the metabolomics profiling of ASCP, 12 New Zealand white rabbits were randomly assigned into 60 min DHCA with (DHCA+ASCP [DA] group, n = 6) and without ( DHCA [D] group, n = 6) ASCP according to the random number table. ASCP was conducted by cannulation on the right subclavian artery and cross clamping of the innominate artery. Rabbits were sacrificed 60 min after weaning off cardiopulmonary bypass. The metabolic features of the cerebral cortex were analyzed by a nontargeted metabolic profiling strategy based on gas chromatography-mass spectrometry. Variable importance projection values exceeding 1.0 were selected as potentially changed metabolites, and then Student's t-test was applied to test for statistical significance between the two groups. RESULTS: Metabolic profiling of brain was distinctive significantly between the two groups (Q 2 Y = 0.88 for partial least squares-DA model). In comparing to group D, 62 definable metabolites were varied significantly after ASCP, which were mainly related to amino acid metabolism, carbohydrate metabolism, and lipid metabolism. Kyoto Encyclopedia of Genes and Genomes analysis revealed that metabolic pathways after DHCA with ASCP were mainly involved in the activated glycolytic pathway, subdued anaerobic metabolism, and oxidative stress. In addition, L-kynurenine (P = 0.0019), 5-methoxyindole-3-acetic acid (P = 0.0499), and 5-hydroxyindole-3 acetic acid (P = 0.0495) in tryptophan metabolism pathways were decreased, and citrulline (P = 0.0158) in urea cycle was increased in group DA comparing to group D. CONCLUSIONS: The present study applied metabolomics analysis to identify the cerebral metabolic profiling in rabbits with ASCP, and the results may shed new lights that cerebral metabolism is better preserved by ASCP compared with DHCA alone. PMID- 26960375 TI - microRNA-218 Inhibits Oxygen-induced Retinal Neovascularization via Reducing the Expression of Roundabout 1. AB - BACKGROUND: The mechanisms of pathological retinal neovascularization (RNV) remain unknown. Several microRNAs were reported to be involved in the process of RNV. Oxygen-induced retinopathy (OIR) is a useful model to investigate RNV. Our present work explored the expression and the role of microRNA-128 (miR-218) in oxygen-induced RNV. METHODS: OIR was used to establish RNV model. The expression level of miR-218 in the retina from OIR mice was assessed by quantitative real time reverse transcriptase polymerase chain reaction. Fluorescein angiography was performed in retinae of OIR mice, and RNV was quantified by hematoxylin and eosin staining to evaluate the effect of pCDH-CMV-miR-218 intravitreal injection on RNV in OIR mice. Roundabout 1 (Robo1) expression was detected by Western blotting in mouse retinal vascular endothelial cells expressing a high or low level of miR 218 and retinal tissues from OIR mice. Cell migration was evaluated by scratch wound assay. RESULTS: In OIR mice, the expression level of miR-218 was significantly down-regulated (P = 0.006). Retinal Robo1 expression was significantly increased at both mRNA and protein levels (P = 0.001, 0.008; respectively). miR-218 intravitreal injection inhibited retinal angiogenesis in OIR mice, and the restoration of miR-218 in retina led to down-regulation of Robo1. CONCLUSIONS: Our experiments showed that restoration of miR-218 inhibited retinal angiogenesis via targeting Robo1. MiR-218 contributed to the inhibition of retinal angiogenesis and miR-218 might be a new therapeutic target for preventing RNV. PMID- 26960376 TI - Estimated Financing Amount Needed for Essential Medicines in China, 2014. AB - BACKGROUND: At the present time, the government is considering to establish the independent financing system for essential medicines (EMs). However, it is still in the exploration phase. The objectives of this study were to calculate and estimate financing amount of EMs in China in 2014 and to provide data evidence for establishing financing mechanism of EMs. METHODS: Two approaches were adopted in this study. First, we used a retrospective research to estimate the cost of EMs in China in 2014. We identified all the 520 drugs listed in the latest national EMs list (2012) and calculated the total sales amount of these drugs in 2014. The other approach included the steps that first selecting the 109 most common diseases in China, then identifying the EMs used to treat them, and finally estimating the total cost of these drugs. RESULTS: The results of the two methods, which showed the estimated financing amounts of EMs in China in 2014, were 17,776.44 million USD and 19,094.09 million USD, respectively. CONCLUSIONS: Comparing these two results, we concluded that the annual budget needed to provide for the EMs in China would be about 20 billion USD. Our study also indicated that the irrational drug use continued to plague the health system with intravenous fluids and antibiotics being the typical examples, as observed in other studies. PMID- 26960377 TI - Assessment on the Efficacy and Safety of Aidi Injection Combined with Vinorelbine and Cisplatin for Treatment of Advanced Nonsmall Cell Lung Cancer. AB - BACKGROUND: The aim of this study was to assess the efficacy and safety of vinorelbine and cisplatin (NP chemotherapy) alone or in combination with Aidi injection for the treatment of advanced nonsmall cell lung cancer (NSCLC). METHODS: Pertinent publications were identified in PubMed, EMBASE, Cochrane Library, CNKI, CQVIP, and Wanfang databases, up to December 8, 2015. After quality assessment of all included randomized controlled trials evaluating Aidi injection combined with NP chemotherapy for the treatment of advanced NSCLC, a meta-analysis was performed by Review Manager 5.2 and STATA 12.0 for statistical analyses. RESULTS: Twelve studies including 509 and 503 cases in the experimental and control groups, respectively, were finally analyzed. The meta-analysis revealed that when cisplatin dose ranging from 20 to 40 mg/m 2 , combination of Aidi injection and NP chemotherapy was statistically different compared with NP chemotherapy alone in enhancing efficiency (relative risk [RR] = 1.24, 95% confidence interval [CI] [1.05-1.47], P = 0.010) and reducing the incidence of Grade II or above nausea and vomiting (RR = 0.49, 95% CI [0.30-0.80], P = 0.005). Meanwhile, with cisplatin ranging from 80 to 120 mg/m 2 , no significant differences in efficiency (RR = 1.11, 95% CI [0.87-1.42], P = 0.390) and Grade II or above nausea and vomiting (RR = 0.88, 95% CI [0.71-1.10], P = 0.260) were obtained. In addition, Aidi injection combined with NP chemotherapy was superior to NP chemotherapy alone in improving the quality of life, alleviating Grade II or above leukopenia and thrombocytopenia. CONCLUSIONS: Aidi injection combined with NP chemotherapy can enhance efficiency, improve the quality of life, and decrease adverse effects in patients with advanced NSCLC. PMID- 26960378 TI - Application and Exploration of Big Data Mining in Clinical Medicine. AB - OBJECTIVE: To review theories and technologies of big data mining and their application in clinical medicine. DATA SOURCES: Literatures published in English or Chinese regarding theories and technologies of big data mining and the concrete applications of data mining technology in clinical medicine were obtained from PubMed and Chinese Hospital Knowledge Database from 1975 to 2015. STUDY SELECTION: Original articles regarding big data mining theory/technology and big data mining's application in the medical field were selected. RESULTS: This review characterized the basic theories and technologies of big data mining including fuzzy theory, rough set theory, cloud theory, Dempster-Shafer theory, artificial neural network, genetic algorithm, inductive learning theory, Bayesian network, decision tree, pattern recognition, high-performance computing, and statistical analysis. The application of big data mining in clinical medicine was analyzed in the fields of disease risk assessment, clinical decision support, prediction of disease development, guidance of rational use of drugs, medical management, and evidence-based medicine. CONCLUSION: Big data mining has the potential to play an important role in clinical medicine. PMID- 26960380 TI - Acute Pulmonary Embolism Caused by Local Resection of Choroidal Melanoma. PMID- 26960379 TI - Lophomonas blattarum Infection or Just the Movement of Ciliated Epithelial Cells? PMID- 26960381 TI - A Case of Thromboembolism After Injection of Gonadotropin-releasing Hormone Agonist. PMID- 26960382 TI - Difficult Airway for Patients Undergoing Spine Surgeries. PMID- 26960383 TI - Serum Concentrations of Tumor Necrosis Factor-alpha and its Soluble Receptors in Soldiers with and Without Combat-related Posttraumatic Stress Disorder: Influence of Age and Body Mass Index. PMID- 26960384 TI - Venous Sinus Dysplasia Masking the Diagnosis of Cryptococcal Meningitis. PMID- 26960385 TI - Foreign Body Aspiration-induced Unusual Exacerbation of Chronic Obstructive Pulmonary Disease. PMID- 26960386 TI - In Situ Binding Sb Nanospheres on Graphene via Oxygen Bonds as Superior Anode for Ultrafast Sodium-Ion Batteries. AB - Graphene incorporation should be one effective strategy to develop advanced electrode materials for a sodium-ion battery (SIB). Herein, the micro/nanostructural Sb/graphene composite (Sb-O-G) is successfully prepared with the uniform Sb nanospheres (~100 nm) bound on the graphene via oxygen bonds. It is revealed that the in-situ-constructed oxygen bonds play a significant role on enhancing Na-storage properties, especially the ultrafast charge/discharge capability. The oxygen-bond-enhanced Sb-O-G composite can deliver a high capacity of 220 mAh/g at an ultrahigh current density of 12 A/g, which is obviously superior to the similar Sb/G composite (130 mAh/g at 10 A/g) just without Sb-O-C bonds. It also exhibits the highest Na-storage capacity compared to Sb/G and pure Sb nanoparticles as well as the best cycling performance. More importantly, this Sb-O-G anode achieves ultrafast (120 C) energy storage in SIB full cells, which have already been shown to power a 26-bulb array and calculator. All of these superior performances originate from the structural stability of Sb-O-C bonds during Na uptake/release, which has been verified by ex situ X-ray photoelectron spectroscopies and infrared spectroscopies. PMID- 26960387 TI - The concentration of ascorbic acid and glutathione in 13 provenances of Acacia melanoxylon. AB - Climate change can negatively affect sensitive tree species, affecting their acclimation and adaptation strategies. A common garden experiment provides an opportunity to test whether responses of trees from different provenances are genetically driven and if this response is related to factors at the site of origin. We hypothesized that antioxidative defence systems and leaf mass area ofAcacia melanoxylonR. Br. samples collected from different provenances will vary depending on local rainfall. Thirteen provenances ofA. melanoxylonoriginating from different rainfall habitats (500-2000 mm) were grown for 5 years in a common garden. For 2 years, phyllode samples were collected during winter and summer, for measurements of leaf mass area and concentrations of glutathione and ascorbic acid. Leaf mass area varied between seasons, years and provenances ofA. melanoxylon, and an increase was associated with decreasing rainfall at the site of origin. Ascorbic acid and glutathione concentrations varied between seasons, years (i.e., environmental factors) and among provenances ofA. melanoxylon In general, glutathione and ascorbic acid concentrations were higher in winter compared with summer. Ascorbic acid and glutathione were different among provenances, but this was not associated with rainfall at the site of origin. PMID- 26960388 TI - The importance of storage and redistribution in vascular plants. PMID- 26960390 TI - The bottlenose dolphin (Tursiops truncatus) faecal microbiota. AB - Cetaceans have evolved from herbivorous terrestrial artiodactyls closely related to ruminants and hippopotamuses. Delphinidae, a family included in this order, represent an extreme and successful re-adaptation of mammalian physiology to the marine habitat and piscivorous diet. The anatomical aspects of Delphinidae success are well understood, whereas some physiological aspects of their environmental fitness are less defined, such as the gut microbiota composition and its adaptation to their dietary niche. Here, we explored the faecal microbiota structure of nine adult bottlenose dolphins (Tursiops truncatus) and one breast-fed calf living in a controlled environment. According to our findings, dolphins possess a unique microbiota profile within the Mammalia class, highly resembling that of carnivorous marine fishes. The breast-fed calf showed a distinctive compositional structure of the gut microbial ecosystem, which partially overlaps with the mother's milk microbiota. Taken together, our data indicate that in dolphins the adaptation to the marine niche and piscivorous diet involved the convergence of their gut microbiota structure with that of marine fishes, overcoming the gut microbiota phylogenetic inertia previously described in terrestrial mammalians. PMID- 26960389 TI - Tree-ring delta13C and delta18O, leaf delta13C and wood and leaf N status demonstrate tree growth strategies and predict susceptibility to disturbance. AB - Understanding how tree growth strategies may influence tree susceptibility to disturbance is an important goal, especially given projected increases in diverse ecological disturbances this century. We use growth responses of tree rings to climate, relationships between tree-ring stable isotopic signatures of carbon (delta(13)C) and oxygen (delta(18)O), wood nitrogen concentration [N], and contemporary leaf [N] and delta(13)C values to assess potential historic drivers of tree photosynthesis in dying and apparently healthy co-occurring northern red oak (Quercus rubra L. (Fagaceae)) during a region-wide oak decline event in Arkansas, USA. Bole growth of both healthy and dying trees responded negatively to drought severity (Palmer Drought Severity Index) and temperature; healthy trees exhibited a positive, but small, response to growing season precipitation. Contrary to expectations, tree-ring delta(13)C did not increase with drought severity. A significantly positive relationship between tree-ring delta(13)C and delta(18)O was evident in dying trees (P < 0.05) but not in healthy trees. Healthy trees' wood exhibited lower [N] than that of dying trees throughout most of their lives (P < 0.05), and we observed a significant, positive relationship (P < 0.05) in healthy trees between contemporary leaf delta(13)C and leaf N (by mass), but not in dying trees. Our work provides evidence that for plants in which strong relationships between delta(13)C and delta(18)O are not evident, delta(13)C may be governed by plant N status. The data further imply that historic photosynthesis in healthy trees was linked to N status and, perhaps, C sink strength to a greater extent than in dying trees, in which tree-ring stable isotopes suggest that historic photosynthesis was governed primarily by stomatal regulation. This, in turn, suggests that assessing the relative dominance of photosynthetic capacity vs stomatal regulation as drivers of trees' C accrual may be a feasible means of predicting tree responses to some disturbance events. Our work demonstrates that a dual isotope, tree-ring approach can be integrated with tree N status to begin to unravel a fundamental question in forest ecology: why do some trees die during a disturbance, while other conspecifics with apparently similar access to resources remain healthy? PMID- 26960392 TI - Bacterial communities potentially involved in iron-cycling in Baltic Sea and North Sea sediments revealed by pyrosequencing. AB - To gain insight into the bacterial communities involved in iron-(Fe) cycling under marine conditions, we analysed sediments with Fe-contents (0.5-1.5 wt %) from the suboxic zone at a marine site in the Skagerrak (SK) and a brackish site in the Bothnian Bay (BB) using 16S rRNA gene pyrosequencing. Several bacterial families, including Desulfobulbaceae, Desulfuromonadaceae and Pelobacteraceae and genera, includingDesulfobacterandGeobacter, known to reduce Fe were detected and showed highest abundance near the Fe(III)/Fe(II) redox boundary. Additional genera with microorganisms capable of coupling fermentation to Fe-reduction, includingClostridiumandBacillus, were observed. Also, the Fe-oxidizing families Mariprofundaceae and Gallionellaceae occurred at the SK and BB sites, respectively, supporting Fe-cycling. In contrast, the sulphate (SO4 (2-)) reducing bacteriaDesulfococcusandDesulfobacteriumwere more abundant at greater depths concurring with a decrease in Fe-reducing activity. The communities revealed by pyrosequencing, thus, match the redox stratification indicated by the geochemistry, with the known Fe-reducers coinciding with the zone of Fe reduction. Not the intensely studied model organisms, such asGeobacterspp., but rather versatile microorganisms, including sulphate reducers and possibly unknown groups appear to be important for Fe-reduction in these marine suboxic sediments. PMID- 26960391 TI - Modulation of the eps-ome transcription of bifidobacteria through simulation of human intestinal environment. AB - Bacterial exopolysaccharides (EPSs) are mono- or oligo-saccharide units linked by glycosidic bonds, forming homo- or hetero-polymers. In gut commensals, these macromolecules are claimed to protect bacterial cells against gastrointestinal challenges and to be involved in modulating the cross talk between the producing bacterium and its gut environment. The predicted EPS arsenal of theBifidobacteriumgenus, which we designate here as theeps-ome, consists of 9epsgene clusters conserved among different bifidobacterial species and a further 44 uniqueepsloci, together representing a large proportion of the inter(sub)species variability identified among bifidobacterial genomes. Co cultivations of bifidobacterial species in media simulating adult and infant human gut environments resulted in an increased transcription of key genes for EPS biosynthesis, including glycosyltransferase-encoding genes, as well as genes specifying EPS transporter and polymerase functions, and saccharide biosynthesis and modification enzymes. PMID- 26960393 TI - Improving health in cities through systems approaches for urban water management. AB - BACKGROUND: As human populations become more and more urban, decision-makers at all levels face new challenges related to both the scale of service provision and the increasing complexity of cities and the networks that connect them. These challenges may take on unique aspects in cities with different cultures, political and institutional frameworks, and at different levels of development, but they frequently have in common an origin in the interaction of human and environmental systems and the feedback relationships that govern their dynamic evolution. Accordingly, systems approaches are becoming recognized as critical to understanding and addressing such complex problems, including those related to human health and wellbeing. Management of water resources in and for cities is one area where such approaches hold real promise. RESULTS: This paper seeks to summarize links between water and health in cities and outline four main elements of systems approaches: analytic methods to deal with complexity, interdisciplinarity, transdisciplinarity, and multi-scale thinking. Using case studies from a range of urban socioeconomic and regional contexts (Maputo, Mozambique; Surat and Kolkata, India; and Vienna, Austria). CONCLUSION: We show how the inclusion of these elements can lead to better research design, more effective policy and better outcomes. PMID- 26960394 TI - Left middle lobectomy for bronchiectasis in a patient with Kartagener syndrome: a case report. AB - BACKGROUND: Kartagener syndrome (KS) is a rare disorder characterized by the triad of chronic sinusitis, bronchiectasis, and situs inversus. CASE PRESENTATION: A 23-year-old man was admitted to our hospital because of recurrent cough with purulent expectoration, which had occurred intermittently for the past ten years. During the past 3 years, the episode frequency was 3-4 times per year. He was diagnosed with pulmonary infection and bronchiectasis of the left upper lobe, situs inversus, and KS. We concluded that the damaged left middle lobe was the source of repeat pulmonary infections. Thus the left middle lobe resection was performed to remove the source of the lung infection. CONCLUSIONS: The post operative course was successful and pneumonia was apparently resolved during the 6 months' follow-up period. We further describe this case in the following report. PMID- 26960397 TI - PD-L1 Negative Status is Associated with Lower Mutation Burden, Differential Expression of Immune-Related Genes, and Worse Survival in Stage III Melanoma. AB - PURPOSE: Understanding why some melanomas test negative for PD-L1 by IHC may have implications for the application of anti-PD-1 therapies in melanoma management. This study sought to determine somatic mutation and gene expression patterns associated with tumor cell PD-L1 expression, or lack thereof, in stage III metastatic melanoma to better define therapeutically relevant patient subgroups. EXPERIMENTAL DESIGN: IHC for PD-L1 was assessed in 52 American Joint Committee on Cancer stage III melanoma lymph node specimens and compared with specimen-matched comprehensive clinicopathologic, genomic, and transcriptomic data. RESULTS: PD-L1 negative status was associated with lower nonsynonymous mutation (NSM) burden (P = 0.017) and worse melanoma-specific survival [HR = 0.28 (0.12-0.66), P = 0.002] in stage III melanoma. Gene set enrichment analysis identified an immune-related gene expression signature in PD-L1-positive tumors. There was a marked increase in cytotoxic T-cell and macrophage-specific genes in PD-L1-positive melanomas. CD8A(high) gene expression was associated with better melanoma-specific survival [HR = 0.2 (0.05-0.87), P = 0.017] and restricted to PD-L1-positive stage III specimens. NF1 mutations were restricted to PD-L1-positive tumors (P = 0.041). CONCLUSIONS: Tumor negative PD-L1 status in stage III melanoma lymph node metastasis is a marker of worse patient survival and is associated with a poor immune response gene signature. Lower NSM levels were associated with PD-L1 negative status suggesting differences in somatic mutation profiles are a determinant of PD-L1-associated antitumor immunity in stage III melanoma. Clin Cancer Res; 22(15); 3915-23. (c)2016 AACR. PMID- 26960396 TI - The Genomic Landscape of Male Breast Cancers. AB - PURPOSE: Male breast cancer is rare, and its genomic landscape has yet to be fully characterized. Lacking studies in men, treatment of males with breast cancer is extrapolated from results in females with breast cancer. We sought to define whether male breast cancers harbor somatic genetic alterations in genes frequently altered in female breast cancers. EXPERIMENTAL DESIGN: All male breast cancers were estrogen receptor-positive, and all but two were HER2-negative. Fifty-nine male breast cancers were subtyped by immunohistochemistry, and tumor normal pairs were microdissected and subjected to massively parallel sequencing targeting all exons of 241 genes frequently mutated in female breast cancers or DNA-repair related. The repertoires of somatic mutations and copy number alterations of male breast cancers were compared with that of subtype-matched female breast cancers. RESULTS: Twenty-nine percent and 71% of male breast cancers were immunohistochemically classified as luminal A-like or luminal B like, respectively. Male breast cancers displayed a heterogeneous repertoire of somatic genetic alterations that to some extent recapitulated that of estrogen receptor (ER)-positive/HER2-negative female breast cancers, including recurrent mutations affecting PIK3CA (20%) and GATA3 (15%). ER-positive/HER2-negative male breast cancers, however, less frequently harbored 16q losses, and PIK3CA and TP53 mutations than ER-positive/HER2-negative female breast cancers. In addition, male breast cancers were found to be significantly enriched for mutations affecting DNA repair-related genes. CONCLUSIONS: Male breast cancers less frequently harbor somatic genetic alterations typical of ER-positive/HER2-negative female breast cancers, such as PIK3CA and TP53 mutations and losses of 16q, suggesting that at least a subset of male breast cancers are driven by a distinct repertoire of somatic changes. Given the genomic differences, caution may be needed in the application of biologic and therapeutic findings from studies of female breast cancers to male breast cancers. Clin Cancer Res; 22(16); 4045-56. (c)2016 AACR. PMID- 26960399 TI - Soluble B-Cell Maturation Antigen Mediates Tumor-Induced Immune Deficiency in Multiple Myeloma. AB - PURPOSE: Reduced uninvolved immunoglobulin (Ig) levels are a hallmark of multiple myeloma. We previously showed that B-cell maturation antigen (BCMA) is solubilized and at high levels in multiple myeloma patient serum. We hypothesize that soluble BCMA binds B-cell-activating factor (BAFF) preventing its function to stimulate late B cells, and would result in lower polyclonal antibody levels in these patients. EXPERIMENTAL DESIGN: Mice were dosed with recombinant human BCMA (rhBCMA) and BCMA-BAFF complexes were analyzed in plasma, and its effects on antibody and Ig heavy chain mRNA levels determined. Using flow cytometry, BAFF binding to B cells was examined in the presence of rhBCMA and sera from multiple myeloma patients. In multiple myeloma sera, BCMA-BAFF complex formation and BCMA, IgA, IgG levels, and heavy-light chain isoform pair levels were determined. RESULTS: rhBCMA-BAFF complexes formed in immune-competent and deficient mice. Mice with human multiple myeloma xenografts, which contain plasma hBCMA and hBCMA BAFF complexes, showed reduced plasma-free BAFF levels. rhBCMA administered to immune competent mice markedly reduced plasma IgA, IgG, and IgM levels and splenic Ig heavy chain mRNA levels. In serum from multiple myeloma patients, BCMA BAFF complexes were detected and BAFF levels were reduced. Multiple myeloma patient sera containing BCMA prevented binding of BAFF to B cells. There is an inverse correlation between serum BCMA and uninvolved polyclonal Ig level in multiple myeloma patients. CONCLUSIONS: Our results show that soluble BCMA sequesters circulating BAFF, thereby preventing it from performing its signaling to stimulate normal B-cell and plasma cell development, resulting in reduced polyclonal antibody levels in multiple myeloma patients. Clin Cancer Res; 22(13); 3383-97. (c)2016 AACR. PMID- 26960400 TI - Preparation and Evaluation of Stomatitis Film Using Xyloglucan Containing Loperamide. AB - Stomatitis induced by radiation therapy or cancer chemotherapy is a factor in sleep disorders and/or eating disorders, markedly decreasing patient quality of life. In recent years, disintegrating oral films that are easy to handle have been developed; therefore, we focused on the formulation of these films. We prepared an adhesive film for the oral cavity using xyloglucan (Xylo), which is a water-soluble macromolecule. We used loperamide, which has been reported to relieve pain caused by stomatitis effectively, as a model drug in this study. Films were prepared from Xylo solutions (3% (w/w)) and hypromellose (HPMC) solutions (1% (w/w)). Xylo and HPMC solutions were mixed at ratios of 1 : 1, 2 : 1, or 3 : 1 for each film, and films 2*2 cm weighing 3 g were prepared and dried at 37 degrees C for 24 h. Physicochemical properties such as strength, adhesiveness, disintegration behavior, and dissolution of loperamide from films were evaluated. Films prepared from Xylo solution alone had sufficient strength and mucosal adhesion. On the other hand, films prepared from a mixture of Xylo and HPMC were inferior to those made from Xylo, but showed sufficient strength and mucosal adhesion and were flexible and easy to handle. The films prepared in this study are useful as adhesion films in the oral cavity. PMID- 26960401 TI - Quality Aware Compression of Electrocardiogram Using Principal Component Analysis. AB - Electrocardiogram (ECG) compression finds wide application in various patient monitoring purposes. Quality control in ECG compression ensures reconstruction quality and its clinical acceptance for diagnostic decision making. In this paper, a quality aware compression method of single lead ECG is described using principal component analysis (PCA). After pre-processing, beat extraction and PCA decomposition, two independent quality criteria, namely, bit rate control (BRC) or error control (EC) criteria were set to select optimal principal components, eigenvectors and their quantization level to achieve desired bit rate or error measure. The selected principal components and eigenvectors were finally compressed using a modified delta and Huffman encoder. The algorithms were validated with 32 sets of MIT Arrhythmia data and 60 normal and 30 sets of diagnostic ECG data from PTB Diagnostic ECG data ptbdb, all at 1 kHz sampling. For BRC with a CR threshold of 40, an average Compression Ratio (CR), percentage root mean squared difference normalized (PRDN) and maximum absolute error (MAE) of 50.74, 16.22 and 0.243 mV respectively were obtained. For EC with an upper limit of 5 % PRDN and 0.1 mV MAE, the average CR, PRDN and MAE of 9.48, 4.13 and 0.049 mV respectively were obtained. For mitdb data 117, the reconstruction quality could be preserved up to CR of 68.96 by extending the BRC threshold. The proposed method yields better results than recently published works on quality controlled ECG compression. PMID- 26960398 TI - Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like Subsets. AB - PURPOSE: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm, whose biologic relationship to small cell lung carcinoma (SCLC) versus non-SCLC (NSCLC) remains unclear, contributing to uncertainty regarding optimal clinical management. To clarify these relationships, we analyzed genomic alterations in LCNEC compared with other major lung carcinoma types. EXPERIMENTAL DESIGN: LCNEC (n = 45) tumor/normal pairs underwent targeted next-generation sequencing of 241 cancer genes by Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform and comprehensive histologic, immunohistochemical, and clinical analysis. Genomic data were compared with MSK-IMPACT analysis of other lung carcinoma histologies (n = 242). RESULTS: Commonly altered genes in LCNEC included TP53 (78%), RB1 (38%), STK11 (33%), KEAP1 (31%), and KRAS (22%). Genomic profiles segregated LCNEC into 2 major and 1 minor subsets: SCLC-like (n = 18), characterized by TP53+RB1 co-mutation/loss and other SCLC-type alterations, including MYCL amplification; NSCLC-like (n = 25), characterized by the lack of coaltered TP53+RB1 and nearly universal occurrence of NSCLC-type mutations (STK11, KRAS, and KEAP1); and carcinoid-like (n = 2), characterized by MEN1 mutations and low mutation burden. SCLC-like and NSCLC-like subsets revealed several clinicopathologic differences, including higher proliferative activity in SCLC like tumors (P < 0.0001) and exclusive adenocarcinoma-type differentiation marker expression in NSCLC-like tumors (P = 0.005). While exhibiting predominant similarity with lung adenocarcinoma, NSCLC-like LCNEC harbored several distinctive genomic alterations, including more frequent mutations in NOTCH family genes (28%), implicated as key regulators of neuroendocrine differentiation. CONCLUSIONS: LCNEC is a biologically heterogeneous group of tumors, comprising distinct subsets with genomic signatures of SCLC, NSCLC (predominantly adenocarcinoma), and rarely, highly proliferative carcinoids. Recognition of these subsets may inform the classification and management of LCNEC patients. Clin Cancer Res; 22(14); 3618-29. (c)2016 AACR. PMID- 26960403 TI - Hip fractures in 2016, where do we stand and have we made any progress? PMID- 26960402 TI - Improvement of soybean transformation via Agrobacterium tumefaciens methods involving alpha-aminooxyacetic acid and sonication treatments enlightened by gene expression profile analysis. AB - KEY MESSAGE: Antagonists and sonication treatment relieved the structural barriers of Agrobacterium entering into cells; hindered signal perception and transmission; alleviated defense responses and increased cell susceptibility to Agrobacterium infection. Soybean gene expression analysis was performed to elucidate the general response of soybean plant to Agrobacterium at an early stage of infection. Agrobacterium infection stimulated the PAMPs-triggered immunity (BRI1, BAK1, BZR1, FLS2 and EFR) and effector-triggered immunity (RPM1, RPS2, RPS5, RIN4, and PBS1); up-regulated the transcript factors (WRKY25, WRKY29, MEKK1P, MKK4/5P and MYC2) in MAPK pathway; strengthened the biosynthesis of flavonoid and isoflavonoid in the second metabolism; finally led to a fierce defense response of soybean to Agrobacterium infection and thereby lower transformation efficiency. To overcome it, antagonist alpha-aminooxyacetic acid (AOA) and sonication treatment along with Agrobacterium infection were applied. This novel method dramatically decreased the expression of genes coding for F3'H, HCT, beta-glucosidase and IF7GT, etc., which are important for isoflavone biosynthesis or the interconversion of aglycones and glycon; genes coding for peroxidase, FLS2, PBS1 and transcription factor MYC2, etc., which are important components in plant-pathogen interaction; and genes coding for GPAT and alpha-L fucosidase, which are important in polyesters formation in cell membrane and the degradation of fucose-containing glycoproteins and glycolipids on the external surface of cell membrane, respectively. This analysis implied that AOA and sonication treatment not only relieved the structural membrane barriers of Agrobacterium entering into cells, but also hindered the perception of 'invasion' signal on cell membrane and intercellular signal transmission, thus effectively alleviated the defense responses and increased the cell susceptibility to Agrobacterium infection. All these factors benefit the transformation process; other measures should also be further explored to improve soybean transformation. PMID- 26960404 TI - Erratum to: Seeking to understand: using generic qualitative research to explore access to medicines and pharmacy services among resettled refugees. PMID- 26960405 TI - Harmful excipients in medicines for neonates in Spain. AB - BACKGROUND: Neonates may respond differently from adults to drug components. Hence, ingredients that seem safe in adults may not be safe in this age group. OBJECTIVE: To describe the content of harmful excipients in drugs used in our neonatal wards and compare the daily dose a neonate may receive with the accepted daily intake (ADI) in adults. METHODS: All drugs included in the hospital's neonatal treatment guide were reviewed, using information from the package inserts or the summary of product characteristics. Those containing at least one harmful excipient (e.g., metabisulfite, sorbitol) were analyzed. Minimum and maximum usual daily drug doses were determined, and excipient exposure was estimated by extrapolation of the minimum and maximum of excipient referred to the active ingredient. These amounts were compared with ADIs for each excipient in adults. RESULTS: In total, 32 % of intravenous and 62 % of oral formulations used in neonates contained at least one harmful excipient. On quantitative analysis, 25 % of intravenous and 19 % of oral drugs contained harmful excipients exceeding the ADI in adults. CONCLUSION: Several drugs commonly used to treat neonates contain harmful excipients in amounts that may exceed the ADI in adults. Clinicians should be aware of this to prescribe appropriate treatment in this population. PMID- 26960406 TI - Home medication management review in outpatients with chronic diseases in Jordan: a randomized control trial. AB - BACKGROUND: Medication Management Review (MMR) is a patient-focused, structured and collaborative health care service provided in the community setting to optimize patient understanding and quality use of medicines. OBJECTIVE: To conduct a randomized control trial of the MMR program in Jordan, by a pharmacist identifying treatment related problems (TRPs) through home visits, assessing type and frequency of TRPs, and eventual effect of resolving TRPs identified by the pharmacist and accepted by the physician on the health status of participating patients. SETTING: Outpatient clinic at the Jordan University Hospital, Amman, Jordan. METHOD: Consecutive patients from outpatient clinics who were eligible for the study were recruited and randomly distributed into two groups (control and intervention). All patients were visited at home by the pharmacist who delivered only for intervention group counseling regarding self-reported adherence, frequency of monitoring and education regarding pharmacological and non-pharmacological therapy. After identifying TRPs, the pharmacist sent a letter to the physician with certain recommendations for patients in the intervention group only. Physician ticked the approved recommendations and returned the report to the pharmacist, allowing the pharmacist to convey the approved changes to the patients. Patients were referred back to their physicians for confirmation of any changes in treatment. Both groups were reassessed after 2-3 months during their regular follow-up visits to their physicians. MAIN OUTCOME MEASURE: To assess the impact of home medication review on the number of TRPs and self-reported adherence in outpatients with chronic diseases via hospital-based clinics in Jordan. RESULTS: A total of 158 TRPs were identified in 112 patients; mean TRP number was 1.63 per patient. As a result of the pharmacist intervention, there was a significant decrease in number of TRPs in the intervention group, the change in the mean was (1.23 (+/-1.19), P < 0.001) versus the control group (0.29 (+/-1.24), P = 0.114). After 3 months, a reduction in non-adherence was observed in the intervention (-0.81 (+/-1.48), P < 0.001) in contrast to no change in self reported adherence in the control (0.22 (+/- 1.12), P = 0.168) group. CONCLUSION: Overall, home-based medication review for patients with chronic conditions decreased the total number of TRPs and improved patient self-reported adherence. PMID- 26960407 TI - Ultra-precise detection of mutations by droplet-based amplification of circularized DNA. AB - BACKGROUND: NGS (next generation sequencing) has been widely used in studies of biological processes, ranging from microbial evolution to cancer genomics. However, the error rate of NGS (0.1 % ~ 1 %) is still remaining a great challenge for comprehensively investigating the low frequency variations, and the current solution methods have suffered severe amplification bias or low efficiency. RESULTS: We creatively developed Droplet-CirSeq for relatively efficient, low bias and ultra-sensitive identification of variations by combining millions of picoliter uniform-sized droplets with Cir-seq. Droplet-CirSeq is entitled with an incredibly low error rate of 3 ~ 5 X 10(-6). To systematically evaluate the performances of amplification uniformity and capability of mutation identification for Droplet-CirSeq, we took the mixtures of two E. coli strains as specific instances to simulate the circumstances of mutations with different frequencies. Compared with Cir-seq, the coefficient of variance of read depth for Droplet-CirSeq was 10 times less (p = 2.6 X 10(-3)), and the identified allele frequency presented more concentrated to the authentic frequency of mixtures (p = 4.8 X 10(-3)), illustrating a significant improvement of amplification bias and accuracy in allele frequency determination. Additionally, Droplet-CirSeq detected 2.5 times genuine SNPs (p < 0.001), achieved a 2.8 times lower false positive rate (p < 0.05) and a 1.5 times lower false negative rate (p < 0.001), in the case of a 3 pg DNA input. Intriguingly, the false positive sites predominantly represented in two types of base substitutions (G- > A, C- > T). Our findings indicated that 30 pg DNA input accommodated in 5 ~ 10 million droplets resulted in maximal detection of authentic mutations compared to 3 pg (p = 1.2 X 10(-8)) and 300 pg input (p = 2.2 X 10(-3)). CONCLUSIONS: We developed a method namely Droplet-CirSeq to significantly improve the amplification bias, which presents obvious superiority over the currently prevalent methods in exploitation of ultra low frequency mutations. Droplet-CirSeq would be promisingly used in the identification of low frequency mutations initiated from extremely low input DNA, such as DNA of uncultured microorganisms, captured DNA of target region, circulation DNA of plasma et al, and its creative conception of rolling circle amplification in droplets would also be used in other low input DNA amplification fields. PMID- 26960408 TI - Establishment and characterization of a novel ovarian clear cell carcinoma cell line, TU-OC-2, with loss of ARID1A expression. AB - A new cell line of human ovarian clear cell carcinoma (CCC), TU-OC-2, was established and characterized. The cells were polygonal in shape, grew in monolayers without contact inhibition and were arranged in islands like pieces of a jigsaw puzzle. The chromosome numbers ranged from 41 to 96. A low rate of proliferation was observed and the doubling time was 37.5 h. The IC50 values of cisplatin, 7-ethyl-10-hydroxycamptothecin (SN38), which is an active metabolite of camptothecin, and paclitaxel were 7.7 MUM, 17.7 nM and 301 nM, respectively. The drug sensitivity assay indicated that TU-OC-2 was sensitive to SN38, but resistant to cisplatin and paclitaxel. Mutational analysis revealed that TU-OC-2 cells have no mutations of PIK3CA in exons 9 and 20 and of TP53 in exons 4-9. We observed the loss of ARID1A protein expression in TU-OC-2 cells by western blot analysis and in the original tumor tissue by immunohistochemistry. This cell line may be useful for studying the chemoresistant mechanisms of CCC and exploring novel therapeutic targets such as the ARID1A-related signaling pathway. PMID- 26960410 TI - Erratum to: Transportan 10 improves the anticancer activity of cisplatin. PMID- 26960411 TI - 2-Positional pyrene end-capped oligothiophenes for high performance organic field effect transistors. AB - Three new 2-positional pyrene end-capped oligothiophene co-oligomers, BPynT (n = 1, 2, 3), have been synthesized for application in organic field effect transistors (OFETs). BPy2T showed the highest hole mobility of 3.3 cm(2) V(-1) s( 1) in a single crystal OFET and a good photoluminescence efficiency of 32% in the crystalline state. A green light emission was observed for the OFET based on a BPy2T single crystal. PMID- 26960409 TI - In vitro assembly of the bacterial actin protein MamK from ' Candidatus Magnetobacterium casensis' in the phylum Nitrospirae. AB - Magnetotactic bacteria (MTB), a group of phylogenetically diverse organisms that use their unique intracellular magnetosome organelles to swim along the Earth's magnetic field, play important roles in the biogeochemical cycles of iron and sulfur. Previous studies have revealed that the bacterial actin protein MamK plays essential roles in the linear arrangement of magnetosomes in MTB cells belonging to the Proteobacteria phylum. However, the molecular mechanisms of multiple-magnetosome-chain arrangements in MTB remain largely unknown. Here, we report that the MamK filaments from the uncultivated 'Candidatus Magnetobacterium casensis' (Mcas) within the phylum Nitrospirae polymerized in the presence of ATP alone and were stable without obvious ATP hydrolysis-mediated disassembly. MamK in Mcas can convert NTP to NDP and NDP to NMP, showing the highest preference to ATP. Unlike its Magnetospirillum counterparts, which form a single magnetosome chain, or other bacterial actins such as MreB and ParM, the polymerized MamK from Mcas is independent of metal ions and nucleotides except for ATP, and is assembled into well-ordered filamentous bundles consisted of multiple filaments. Our results suggest a dynamically stable assembly of MamK from the uncultivated Nitrospirae MTB that synthesizes multiple magnetosome chains per cell. These findings further improve the current knowledge of biomineralization and organelle biogenesis in prokaryotic systems. PMID- 26960412 TI - Burden of hospitalization in relapsed acute lymphoblastic leukemia. AB - OBJECTIVE: This study sought to quantify the economic burden of adults with Philadelphia chromosome negative (Ph-) relapsed B-precursor acute lymphoblastic leukemia (ALL) by examining hospitalization events in the US. RESEARCH DESIGN AND METHODS: The Truven Health MarketScan Commercial Database was used to identify eligible patients hospitalized between April 2009 and July 2014. Eligible patients were continuously enrolled 6 months before (pre-index) their first claim with an eligible relapsed ALL diagnosis (index date) and followed up for a maximum of 18 weeks. RESULTS: A total of 583 hospitalizations involving 205 adults with Ph(-) relapsed B-precursor ALL were identified. Mean (SD) percentage of follow-up time spent in the hospital was 56.2% (40.0%). Mean (SD) length of stay per hospitalization was 13.1 (15.7) days; mean (SD) reimbursement per hospitalization stay was $89,663 ($195,725). The highest reimbursements were hospitalization for ALL in relapse ($132,137 [$178,742]) and ALL without remission ($120,932 [$134,254]). CONCLUSIONS: Adults with Ph(-) relapsed B precursor ALL had repeated and prolonged hospitalizations during chemotherapy treatment associated with extremely high costs. More effective, tolerable treatments are needed. LIMITATIONS: The key limitation was that the data source included only individuals from the health plans or the mid to large size employers in the MarketScan database. Patients who were not covered under these plans, or were only on Medicaid or only on Medicare, would not appear in our analysis. PMID- 26960413 TI - Graphene induces spontaneous cardiac differentiation in embryoid bodies. AB - Graphene was embedded into the structure of mouse embryoid bodies (EBs) using the hanging drop technique. The inclusion of 0.2 mg per mL graphene in the EBs did not affect the viability of the stem cells. However, the graphene decreased the stem cell proliferation, probably by accelerating cell differentiation. The graphene also enhanced the mechanical properties and electrical conductivity of the EBs. Interestingly, the cardiac differentiation of the EB-graphene was significantly greater than that of the EBs at day 5 of culture, as confirmed by high-throughput gene analysis. Electrical stimulation (voltage, 4 V; frequency, 1 Hz; and duration, 10 ms for 2 continuous days) further enhanced the cardiac differentiation of the EBs, as demonstrated by analyses of the cardiac protein and gene expression and the beating activity of the EBs. Taken together, the results demonstrated that graphene played a major role in directing the cardiac differentiation of EBs, which has potential cell therapy and tissue regeneration applications. PMID- 26960415 TI - Levansucrase from Leuconostoc mesenteroides NTM048 produces a levan exopolysaccharide with immunomodulating activity. AB - OBJECTIVES: A levansucrase from Leuconostoc mesenteroides NTM048 was cloned and expressed and its enzymatic product was characterized. RESULTS: The fructansucrase gene from Leuconostoc mesenteroides was cloned and expressed in Escherichia coli. The recombinant enzyme was purified as a single protein and its properties investigated. The polymer produced by the recombinant enzyme was identified as levan by various means including TLC and NMRs, and the enzyme was identified as a GH68 levansucrase. The enzyme was optimal at pH 5.5-6 and 30 degrees C, and its activity was stimulated by Ca(2+). The levan produced by this strain induced IgA production in mice. CONCLUSION: Leuconostoc mesenteroides, a probiotic strain, possessed levansucrase which catalyzed the produced levan that had immunomodulating activity. PMID- 26960417 TI - Low-molecular-weight polyphenols protect kidney damage through suppressing NF kappaB and modulating mitochondrial biogenesis in diabetic db/db mice. AB - Hyperglycemia, increased inflammatory responses, and dysregulation of mitochondrial function accompanied by type 2 diabetes may eventually lead to kidney damage. We examined the protective effects of oligonol, a low-molecular weight polyphenol derived from lychee fruit and green tea, on kidney damage in diabetic db/db mice. Dietary oligonol supplementation lowered glucose and insulin levels and improved oral glucose tolerance. Oligonol attenuated serum resistin and IL-6 levels and reduced glomerular hypertrophy and mesangial matrix expansion caused by diabetes. Oligonol reduced activation of nuclear factor-kappa B (NF kappaB) and p38 mitogen-activated protein kinase. Suppressed renal oxidative stress by oligonol was associated with stimulated sirtuin1 expression and restored AMP-activated kinase protein alpha activity, mitochondrial DNA copy number, and mitochondrial biogenesis associated genes including nuclear respiratory factor 1 and mitochondrial transcription factor A. In conclusion, oligonol reduced fasting glucose level, improved insulin sensitivity, suppressed inflammatory responses, and upregulated metabolic regulators involved in mitochondrial biogenesis, thereby leading to protection against diabetes-induced kidney damage. PMID- 26960416 TI - Matured hop extract reduces body fat in healthy overweight humans: a randomized, double-blind, placebo-controlled parallel group study. AB - BACKGROUND: Hops are the main components of beer that provide flavor and bitterness. Iso-alpha-acids, the bitter components of beer, have been reported to reduce body fat in humans, but the bitterness induced by effective doses of iso alpha-acids precludes their acceptance as a nutrient. The matured hop bitter acids (MHBA) of oxidized hops appear to have a more pleasant bitterness compared to the sharper bitterness of iso-alpha-acids. While there has been little information concerning the identity of the MHBA compounds and their physiological effects, MHBA was recently found to be primarily composed of oxides derived from alpha-acids, and structurally similar to iso-alpha-acids. Here, we investigated the effects of matured hop extract (MHE) containing MHBA on reducing abdominal body fat in healthy subjects with a body mass index (BMI) of 25 to below 30 kg/m(2), classified as "obese level 1" in Japan or as "overweight" by the WHO. TRIAL DESIGN: A randomized, double-blind, placebo-controlled parallel group study. METHODS: Two hundred subjects (male and female aged 20 to below 65 years with a BMI of 25 or more and less than 30 kg/m(2)) were randomly assigned to two groups. During a 12-week ingestion period, the subjects in each group ingested daily 350 mL of test-beverage, either containing MHE (with 35 mg MHBA), i.e. the namely active beverage, or a placebo beverage without MHE. The primary endpoint was reduction of the abdominal fat area as determined by CT scanning after continual ingestion of MHE for 12 weeks. RESULTS: Compared to the placebo group, a significant reduction was observed in the visceral fat area after 8 and 12 w, and in the total fat area after 12 w in the active group. There was also a concomitant decrease in body fat ratio in the active group compared to the placebo group. No adverse events related to the test beverages or clinically relevant abnormal changes in the circulatory, blood and urine parameters were observed in either group. CONCLUSIONS: The present study suggests that continual ingestion of MHE safely reduces body fat, particularly the abdominal visceral fat of healthy overweight subjects. TRIAL REGISTRATION: UMIN-CTR UMIN000014185. PMID- 26960418 TI - Cars kill chimpanzees: case report of a wild chimpanzee killed on a road at Bulindi, Uganda. AB - Roads have broadly adverse impacts on wildlife, including nonhuman primates. One direct effect is mortality from collisions with vehicles. While highly undesirable, roadkills provide valuable information on the health and condition of endangered species. We present a case report of a wild chimpanzee (Pan troglodytes schweinfurthii) killed crossing a road in Bulindi, Uganda, where chimpanzees inhabit forest fragments amid farmland. Details of the collision are constructed from eyewitness accounts of pedestrians. Physical examination of the cadaver indicated good overall body condition; at 40 kg, the deceased female was heavier than usual for an adult female East African chimpanzee. No external wounds or fractures were noted. Coprological assessment demonstrated infection by several gastrointestinal parasites commonly reported in living wild chimpanzees. Histopathology revealed eosinophilic enteritis and biliary hyperplasia potentially caused by parasite infection. However, eosinophilia was not widely spread into the submucosa, while egg/cyst counts suggested low-intensity parasite infections compared to healthy female chimpanzees of similar age in nearby Budongo Forest. No behavioral indicators of ill health were noted in the deceased female in the month prior to the accident. We conclude that cause of death was acute, i.e., shock from the collision, and was probably unrelated to parasite infection or any other underlying health condition. Notably, this female had asymmetrical polythelia, and, while nursing at the time of her death, had one functioning mammary gland only. In Uganda, where primates often inhabit human dominated landscapes, human population growth and economic development has given rise to increasing motor traffic, while road development is enabling motorists to travel at greater speeds. Thus, the danger of roads to apes and other wildlife is rising, necessitating urgent strategies to reduce risks. Installation of simple speed-bumps-common on Ugandan roads-would be effective in reducing risks to wildlife, and would also make roads safer for human pedestrians. PMID- 26960420 TI - Dramatic mechanistic switch in Sn/Au(I) group exchanges: transmetalation vs. oxidative addition. AB - The mechanism of Ph/X exchange in reactions involving SnPh(n)Bu3 and [AuXL] complexes switches dramatically from the usual concerted mechanism involving Ar/X mixed bridges when X = Cl, to an unexpected oxidative addition/reductive elimination pathway via an Au(III) intermediate when X = vinyl. PMID- 26960419 TI - Averting the legacy of kidney disease: focus on childhood. AB - World Kidney Day 2016 focuses on kidney disease in childhood and the antecedents of adult kidney disease that can begin in earliest childhood. Chronic kidney disease (CKD) in childhood differs from that in adults, as the largest diagnostic group among children includes congenital anomalies and inherited disorders, with glomerulopathies and kidney disease in the setting of diabetes being relatively uncommon. In addition, many children with acute kidney injury will ultimately develop sequelae that may lead to hypertension and CKD in later childhood or in adult life. Children born early or who are small-for date newborns have relatively increased risk for the development of CKD later in life. Persons with a high-risk birth and early childhood history should be watched closely in order to help detect early signs of kidney disease in time to provide effective prevention or treatment. Successful therapy is feasible for advanced CKD in childhood; there is evidence that children fare better than adults, if they receive kidney replacement therapy including dialysis and transplantation, while only a minority of children may require this ultimate intervention Because there are disparities in access to care, effort is needed so that those children with kidney disease, wherever they live, may be treated effectively, irrespective of their geographic or economic circumstances. Our hope is that World Kidney Day will inform the general public, policy makers and caregivers about the needs and possibilities surrounding kidney disease in childhood. PMID- 26960421 TI - Homeotropically-aligned main-chain and side-on liquid crystalline elastomer films with high anisotropic thermal conductivities. AB - Homeotropically-aligned main-chain and side-on liquid crystalline elastomer films are prepared by using LC thiol-ene and acrylate systems respectively. Evaluated by laser flash analysis, the room temperature thermal conductivities of these two LCP films in the film normal direction are both dramatically higher than those along the horizontal direction. PMID- 26960422 TI - Synovial haemangioma of the knee joint: an unusual cause of knee pain in a 14 month old girl. AB - We report a histologically proven case of synovial haemangioma of the knee in a 14-month old girl who presented to the emergency department with an acute 1-day history of refusing to weight-bear on the right leg and a preceding 3-week history of a right knee lump. Physical examination revealed a non-tender, soft lump over the lateral infrapatellar region. Radiographs revealed a poorly defined soft tissue density over the infrapatellar fat pad and a suprapatellar joint effusion. Ultrasound was used to confirm the presence of a vascular soft tissue mass compatible with a synovial haemangioma within the infrapatellar fat pad which showed both intra-articular and extra-articular extension. There was good correlation of the ultrasound findings with magnetic resonance imaging (MRI), highlighting the potential clinical utility of ultrasound as an alternative imaging modality in establishing the pre-operative diagnosis and extent of a synovial haemangioma about the knee joint. PMID- 26960424 TI - Percutaneous Coronary Intervention: Relationship Between Procedural Volume and Outcomes. AB - Percutaneous coronary intervention (PCI) is an integral treatment modality for acute coronary syndromes (ACS) as well as chronic stable coronary artery disease (CAD) not responsive to optimal medical therapy. This coupled with studies on the feasibility and safety of performing PCI in centers without on-site surgical backup led to widespread growth of PCI centers. However, this has been accompanied by a recent steep decline in the volume of PCIs at both the operator and hospital level, which raises concerns regarding minimal procedural volumes required to maintain necessary skills and favorable clinical outcomes. The 2011 ACC/AHA/SCAI competency statement required PCI be performed by operators with a minimal procedural volume of >75 PCIs annually at high-volume centers with >400 PCIs per year, a number which was relaxed in the 2013 ACC/AHA/SCAI update to >50 PCIs/operator/year in hospitals with >200 PCIs annually to coincide with reduction in national PCI volume. Recent data suggests that many hospitals do not meet these thresholds. We review data on the importance of volume as a vital quality metric at both an operator and hospital level in determining procedural outcomes following PCI. PMID- 26960423 TI - Role of Echocardiography Before Transcatheter Aortic Valve Implantation (TAVI). AB - Aortic stenosis (AS) is the most common primary valve disorder in the elderly with an increasing prevalence; transcatheter aortic valve implantation (TAVI) has become an accepted alternative to surgical aortic valve replacement (AVR) in the high risk or inoperable patient. Appropriate selection of patients for TAVI is crucial and requires a multidisciplinary approach including cardiothoracic surgeons, interventional cardiologists, anaesthetists, imaging experts and specialist nurses. Multimodality imaging including echocardiography, CT and MRI plays a pivotal role in the selection and planning process; however, echocardiography remains the primary imaging modality used for patient selection, intra-procedural guidance, post-procedural assessment and long-term follow-up. The contribution that contemporary transthoracic and transoesophageal echocardiography make to the selection and planning of TAVI is described in this article. PMID- 26960426 TI - Analysis of the Efficacy and Safety of Recombinant Tissue Plasminogen Activator for Chinese Patients over 80 Years of Age with Acute Ischemic Stroke: A Pilot Study. PMID- 26960427 TI - Corrigendum: Observation of strongly enhanced photoluminescence from inverted cone-shaped silicon nanostructures. PMID- 26960425 TI - Yeast Two-Hybrid Screening for Proteins that Interact with the Extracellular Domain of Amyloid Precursor Protein. AB - Alzheimer's disease (AD) is a neurodegenerative disorder in which amyloid beta plaques are a pathological characteristic. Little is known about the physiological functions of amyloid beta precursor protein (APP). Based on its structure as a type I transmembrane protein, it has been proposed that APP might be a receptor, but so far, no ligand has been reported. In the present study, 9 proteins binding to the extracellular domain of APP were identified using a yeast two-hybrid system. After confirming the interactions in the mammalian system, mutated PLP1, members of the FLRT protein family, and KCTD16 were shown to interact with APP. These proteins have been reported to be involved in Pelizaeus Merzbacher disease (PMD) and axon guidance. Therefore, our results shed light on the mechanisms of physiological function of APP in AD, PMD, and axon guidance. PMID- 26960429 TI - Intracellular acidification is required for full activation of the sweet taste receptor by miraculin. AB - Acidification of the glycoprotein, miraculin (MCL), induces sweet taste in humans, but not in mice. The sweet taste induced by MCL is more intense when acidification occurs with weak acids as opposed to strong acids. MCL interacts with the human sweet receptor subunit hTAS1R2, but the mechanisms by which the acidification of MCL activates the sweet taste receptor remain largely unexplored. The work reported here speaks directly to this activation by utilizing a sweet receptor TAS1R2 + TAS1R3 assay. In accordance with previous data, MCL-applied cells displayed a pH dependence with citric acid (weak acid) being right shifted to that with hydrochloric acid (strong acid). When histidine residues in both the intracellular and extracellular region of hTAS1R2 were exchanged for alanine, taste-modifying effect of MCL was reduced or abolished. Stronger intracellular acidification of HEK293 cells was induced by citric acid than by HCl and taste-modifying effect of MCL was proportional to intracellular pH regardless of types of acids. These results suggest that intracellular acidity is required for full activation of the sweet taste receptor by MCL. PMID- 26960430 TI - Tunable high-order sideband spectra generation using a photonic molecule optomechanical system. AB - A tunable high-order sideband spectra generation scheme is presented by using a photonic molecule optomechanical system coupled to a waveguide beyond the perturbation regime. The system is coherently driven by a two-tone laser consisting of a continuous-wave control field and a pulsed driving field which propagates through the waveguide. The frequency spectral feature of the output field is analyzed via numerical simulations, and we confirm that under the condition of intense and nanosecond pulse driving, the output spectrum exhibits the properties of high-order sideband frequency spectra. In the experimentally available parameter range, the output spectrum can be efficiently tuned by the system parameters, including the power of the driving pulse and the coupling rate between the cavities. In addition, analysis of the carrier-envelop phase dependent effect of high-order sideband generation indicates that the system may present dependence upon the phase of the pulse. This may provide a further insight of the properties of cavity optomechanics in the nonlinear and non perturbative regime, and may have potential applications in optical frequency comb and communication based on the optomechanical platform. PMID- 26960428 TI - Factors Associated with Productive Recruiting in a Respondent-Driven Sample of Men who Have Sex with Men in Vancouver, Canada. AB - Respondent-driven sampling (RDS) has become a preferred sampling strategy for HIV research and surveillance in many global settings. Methodological investigation into the validity of RDS-generated samples has helped improve theoretical components of design. However, the operational challenges of implementing RDS remain underreported. We sought to identify factors independently associated with productive recruiting in an urban RDS-generated sample of gay, bisexual, and other men who have sex with men (MSM). Data were collected from the Momentum Health Study, a cohort of MSM recruited by RDS in Vancouver, Canada. Eligible men were given up to six RDS coupons to recruit their peers. The primary outcome was a count variable of each participant's number of eligible recruits. Multivariable Poisson regression identified independent predictors of productive recruitment. In total, 719 individuals comprised this analysis, of which 119 were seeds. The distribution of eligible recruits was right skewed, with 391 (54.4 %) having never recruited another participant and only eight participants (1.1 %) having recruited five. Significant, independent predictors of recruiting one additional participant included network size per ten unit increase (adjusted risk ratio [aRR] 1.03), being of Aboriginal race/ethnicity compared with White (aRR 1.51), being HIV-positive (aRR 1.31), being sexually active with only males (aRR 2.48), being single compared with common law/married (aRR 1.37), having recently read gay newspapers (aRR 1.58), having recently sought sex partners online (aRR 1.33) and being out to a male parent (aRR 1.30). This analysis demonstrates the importance of social network size in RDS adjustment, but also identifies other socio-demographic and behavioral variables that increased RDS coupon return, which may help researchers better operationalize the implementation of RDS. PMID- 26960431 TI - Interphase APC/C-Cdc20 inhibition by cyclin A2-Cdk2 ensures efficient mitotic entry. AB - Proper cell-cycle progression requires tight temporal control of the Anaphase Promoting Complex/Cyclosome (APC/C), a large ubiquitin ligase that is activated by one of two co-activators, Cdh1 or Cdc20. APC/C and Cdc20 are already present during interphase but APC/C-Cdc20 regulation during this window of the cell cycle, if any, is unknown. Here we show that cyclin A2-Cdk2 binds and phosphorylates Cdc20 in interphase and this inhibits APC/C-Cdc20 activity. Preventing Cdc20 phosphorylation results in pre-mature activation of the APC/C Cdc20 and several substrates, including cyclin B1 and A2, are destabilized which lengthens G2 and slows mitotic entry. Expressing non-degradable cyclin A2 but not cyclin B1 restores mitotic entry in these cells. We have thus uncovered a novel positive feedback loop centred on cyclin A2-Cdk2 inhibition of interphase APC/C Cdc20 to allow further cyclin A2 accumulation and mitotic entry. PMID- 26960432 TI - Colour-Difference Measurement Method for Evaluation of Quality of Electrolessly Deposited Copper on Polymer after Laser-Induced Selective Activation. AB - In this work a novel colour-difference measurement method for the quality evaluation of copper deposited on a polymer is proposed. Laser-induced selective activation (LISA) was performed onto the surface of the polycarbonate/acrylonitrile butadiene styrene (PC/ABS) polymer by using nanosecond laser irradiation. The laser activated PC/ABS polymer was copper plated by using the electroless copper plating (ECP) procedure. The sheet resistance measured by using a four-point probe technique was found to decrease by the power law with the colour-difference of the sample images after LISA and ECP procedures. The percolation theory of the electrical conductivity of the insulator conductor mixture has been adopted in order to explain the experimental results. The new proposed method was used to determine an optimal set of the laser processing parameters for best plating conditions. PMID- 26960434 TI - Phylogenetic evidence for intratypic recombinant events in a novel human adenovirus C that causes severe acute respiratory infection in children. AB - Human adenoviruses (HAdVs) are prevalent in hospitalized children with severe acute respiratory infection (SARI). Here, we report a unique recombinant HAdV strain (CBJ113) isolated from a HAdV-positive child with SARI. The whole-genome sequence was determined using Sanger sequencing and high-throughput sequencing. A phylogenetic analysis of the complete genome indicated that the CBJ113 strain shares a common origin with HAdV-C2, HAdV-C6, HAdV-C1, HAdV-C5, and HAdV-C57 and formed a novel subclade on the same branch as other HAdV-C subtypes. BootScan and single nucleotide polymorphism analyses showed that the CBJ113 genome has an intra-subtype recombinant structure and comprises gene regions mainly originating from two circulating viral strains: HAdV-1 and HAdV-2. The parental penton base, pVI, and DBP genes of the recombinant strain clustered with the HAdV-1 prototype strain, and the E1B, hexon, fiber, and 100 K genes of the recombinant clustered within the HAdV-2 subtype, meanwhile the E4orf1 and DNA polymerase genes of the recombinant shared the greatest similarity with those of HAdV-5 and HAdV-6, respectively. All of these findings provide insight into our understanding of the dynamics of the complexity of the HAdV-C epidemic. More extensive studies should address the pathogenicity and clinical characteristics of the novel recombinant. PMID- 26960433 TI - NADPH oxidase promotes Parkinsonian phenotypes by impairing autophagic flux in an mTORC1-independent fashion in a cellular model of Parkinson's disease. AB - Oxidative stress and aberrant accumulation of misfolded proteins in the cytosol are key pathological features associated with Parkinson's disease (PD). NADPH oxidase (Nox2) is upregulated in the pathogenesis of PD; however, the underlying mechanism(s) of Nox2-mediated oxidative stress in PD pathogenesis are still unknown. Using a rotenone-inducible cellular model of PD, we observed that a short exposure to rotenone (0.5 MUM) resulted in impaired autophagic flux through activation of a Nox2 dependent Src/PI3K/Akt axis, with a consequent disruption of a Beclin1-VPS34 interaction that was independent of mTORC1 activity. Sustained exposure to rotenone at a higher dose (10 MUM) decreased mTORC1 activity; however, autophagic flux was still impaired due to dysregulation of lysosomal activity with subsequent induction of the apoptotic machinery. Cumulatively, our results highlight a complex pathogenic mechanism for PD where short- and long term oxidative stress alters different signaling pathways, ultimately resulting in anomalous autophagic activity and disease phenotype. Inhibition of Nox2 dependent oxidative stress attenuated the impaired autophagy and cell death, highlighting the importance and therapeutic potential of these pathways for treating patients with PD. PMID- 26960436 TI - Polish school nurses' knowledge of the first-aid in tooth avulsion of permanent teeth. AB - BACKGROUND: The frequency of dental trauma in schools is secondary only to accidents at home. The aim of this study was to evaluate the knowledge of first aid in the avulsion of permanent teeth presented by Polish school nurses from different areas. METHODS: A cross-sectional study with the use of a structured self-administrative questionnaire was conducted in 2014 on school nurses working in randomly selected Polish provinces. The instrument consisted of demographic questions, questions referring to nurses' experience and training in dental trauma and questions checking knowledge of first-aid in the avulsion of permanent teeth. The maximum number of points to be scored was eight. Data were analyzed with the Kruskal-Wallis, the Mann-Whitney U and Chi(2) tests with the level of statistical significance at p < 0.05. RESULTS: The final sample consisted of 164 nurses of which 70.1 % had experience with dental injuries and 45.7 % witnessed a tooth avulsion in pupils. 10.4 % nurses participated in training courses concerning tooth avulsion and 67.1 % of them independently broadened their knowledge. The knowledge of the first-aid management of an avulsed tooth was moderate (4.72 +/- 1.95 points). 78.1 % of nurses chose a correct definition of the term of 'tooth avulsion'. Only 7.3 % of them were aware that the replantation could be conducted by any witness of an accident. Saline was most often chosen as a proper transport medium for an avulsed tooth (57.9 %), whereas 16.1 % of nurses indicated milk. 13.4 % of evaluated nurses showed readiness to conduct an immediate replantation. Most respondents preferred calling child's parents and advising them to bring the child to a dentist (63.4 %). The main factor influencing nurses' level of knowledge was self-education (p < 0.001). Being a witness to dental trauma (p = 0.0032) and working in schools with sports classes (p = 0.0423) were positive determinants of improved knowledge. Nurses from large agglomerations had significantly lower knowledge (p = 0.005). The main source of information for self-education was the Internet. CONCLUSIONS: The evaluated nurses were in need of education with regard to the management of dental trauma cases. The Internet should be used to deliver evidence-based knowledge to medical staff working at schools. PMID- 26960435 TI - Macroscopic self-reorientation of interacting two-dimensional crystals. AB - Microelectromechanical systems, which can be moved or rotated with nanometre precision, already find applications in such fields as radio-frequency electronics, micro-attenuators, sensors and many others. Especially interesting are those which allow fine control over the motion on the atomic scale because of self-alignment mechanisms and forces acting on the atomic level. Such machines can produce well-controlled movements as a reaction to small changes of the external parameters. Here we demonstrate that, for the system of graphene on hexagonal boron nitride, the interplay between the van der Waals and elastic energies results in graphene mechanically self-rotating towards the hexagonal boron nitride crystallographic directions. Such rotation is macroscopic (for graphene flakes of tens of micrometres the tangential movement can be on hundreds of nanometres) and can be used for reproducible manufacturing of aligned van der Waals heterostructures. PMID- 26960437 TI - [Endoscopic therapy for gastroduodenal neuroendocrine neoplasms]. AB - Neuroendocrine neoplasms (NEN) represent a group of potentially malignant tumors, which can be located in every section of the gastrointestinal tract, the pancreas and the bronchopulmonary system. Gastroduodenal NENs have a relatively good prognosis in comparison to other subentities, e.g. pancreatic or ileojejunal NENs. In the stomach there are four different types of NENs, while in the duodenum there are five types and all vary in the malignant potential and the therapeutic approach. Due to the simple access endoscopic methods not only have diagnostic but also important therapeutic relevance in this subgroup. Lesions smaller than 1 cm can easily be resected with forceps or snare resection and for larger lesions up to 2 cm more invasive strategies, such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) are available. Important criteria in gastric NEN for the risk evaluation of endoscopic treatment alone are the size of the lesion, depth of invasion and the tumor biology, e.g. neuroendocrine tumor (NET) G1/G2 versus neuroendocrine carcinoma (NEC) G3. In duodenal NEN the aforementioned risk factors also apply and in addition only lesions outside the ampulla of Vater should be endoscopically resected whereas periampullary lesions need to be addressed surgically. As an individualized therapeutic approach the possibility of a combined endoscopic and laparoscopic resection technique exists. Follow-up endoscopic investigations are necessary, especially in gastric type 1 NENs, which have a tendency to relapse. PMID- 26960441 TI - Understanding underspecification: A comparison of two computational implementations. AB - Swets et al. (2008. Underspecification of syntactic ambiguities: Evidence from self-paced reading. Memory and Cognition, 36(1), 201-216) presented evidence that the so-called ambiguity advantage [Traxler et al. (1998). Adjunct attachment is not a form of lexical ambiguity resolution. Journal of Memory and Language, 39(4), 558-592], which has been explained in terms of the Unrestricted Race Model, can equally well be explained by assuming underspecification in ambiguous conditions driven by task-demands. Specifically, if comprehension questions require that ambiguities be resolved, the parser tends to make an attachment: when questions are about superficial aspects of the target sentence, readers tend to pursue an underspecification strategy. It is reasonable to assume that individual differences in strategy will play a significant role in the application of such strategies, so that studying average behaviour may not be informative. In order to study the predictions of the good-enough processing theory, we implemented two versions of underspecification: the partial specification model (PSM), which is an implementation of the Swets et al. proposal, and a more parsimonious version, the non-specification model (NSM). We evaluate the relative fit of these two kinds of underspecification to Swets et al.'s data; as a baseline, we also fitted three models that assume no underspecification. We find that a model without underspecification provides a somewhat better fit than both underspecification models, while the NSM model provides a better fit than the PSM. We interpret the results as lack of unambiguous evidence in favour of underspecification; however, given that there is considerable existing evidence for good-enough processing in the literature, it is reasonable to assume that some underspecification might occur. Under this assumption, the results can be interpreted as tentative evidence for NSM over PSM. More generally, our work provides a method for choosing between models of real-time processes in sentence comprehension that make qualitative predictions about the relationship between several dependent variables. We believe that sentence processing research will greatly benefit from a wider use of such methods. PMID- 26960438 TI - Proton pump inhibitors and gastroenteritis. AB - An association between proton pump inhibitor (PPI) therapy and bacterial gastroenteritis has been suggested as well as contradicted. The aim of this study was to examine the association between the use of PPIs and occurrence of bacterial gastroenteritis in the prospective Rotterdam Study. The Rotterdam Study is a population-based cohort study among 14,926 subjects aged 45 years and older with up to 24 years of follow-up. Analyses were performed with a generalized estimating equations method in participants who handed-in a diagnostic stool sample. Furthermore, a nested case-control analysis was performed using the total cohort as a reference group. A bacterial microorganism was isolated in 125 samples, whereas 1174 samples were culture negative. In the generalized estimating equations analysis, we found that participants with a bacterial gastroenteritis were more likely than controls to be current users of PPIs (adjusted OR 1.94; 95 % CI 1.15-3.25). Different sensitivity analyses did not change this result. A considerably higher effect was observed (adjusted OR 6.14; 95 % CI 3.81-9.91), using the total cohort as a reference in a nested case control analysis. Current PPI therapy is associated with an increased risk of bacterial gastroenteritis. However, by reducing the risk of selection and information bias in our study design, we demonstrated that the effect is lower than previously assumed. PMID- 26960442 TI - Trabeculectomy in patients with uveal melanoma after proton beam therapy. AB - BACKGROUND: Retrospective evaluation of intraocular pressure, use of topical and systemic anti-glaucoma medication, secondary complications, local tumor control and survival in patients treated with trabeculectomy for the regulation of the intraocular pressure (IOP) after proton beam therapy for uveal melanoma. METHODS: In this retrospective clinical case series we evaluated the follow-up of 15 patients receiving a trabeculectomy as surgical treatment if the IOP could not be lowered adequately by medications or laser surgery. All patients had received proton beam therapy for uveal melanoma at the Helmholtz-Zentrum Berlin between 1998 and 2010. RESULTS: The median IOP decreased significantly from 35 mmHg +/- 8.8 before TE to 16 mmHg +/- 8.2 (=52.3 %) six months after TE (Wilcoxon-Mann Whitney-U Test, p<0.01). None of the patients needed any glaucoma medication six months after trabeculectomy. Two patients developed local recurrence during follow-up, which were independent of the trabeculectomy. One patient had to be enucleated due to intractable pain and suspected remaining tumor activity. One patient died due to metastasis. CONCLUSIONS: Trabeculectomy is an option in intractable glaucoma in patients with uveal melanoma after proton beam therapy in single cases. Secondary interventions are common. Inoculation metastases are possible. Secure local tumor control must be a prerequisite for filtrating operations. PMID- 26960443 TI - Identification of training status differences using perceived exertion threshold. AB - We investigated if the rate of perceived exertion (RPE) threshold is as sensitive as the lactate threshold to detect training differences. Lactate and RPE thresholds were identified in well-trained cyclists and physically active males. Power output was higher in well-trained cyclists than in physically active individuals for both thresholds (p < 0.05). Our results suggest that RPE threshold is successful in discriminating differences between well-trained cyclists and physically active individuals. PMID- 26960444 TI - Day to day variability in fat oxidation and the effect after only 1 day of change in diet composition. AB - Indirect calorimetry is a common and noninvasive method to estimate rate of fat oxidation (FatOx) during exercise, and test-retest reliability should be considered when interpreting results. Diet also has an impact on FatOx. The aim of the present study was to investigate day to day variations in FatOx during moderate exercise given the same diet and 2 different isoenergetic diets. Nine healthy, moderately-trained females participated in the study. They performed 1 maximal oxygen uptake test and 4 FatOx tests. Habitual diets were recorded and repeated to assess day to day variability in FatOx. FatOx was also measured after 1 day of fat-rich (26.8% carbohydrates (CHO), 23.2% protein, 47.1% fat) and 1 day of CHO-rich diet (62.6% CHO, 20.1% protein, 12.4% fat). The reliability test revealed no differences in FatOx, respiratory exchange ratio (RER), oxygen uptake, carbon dioxide production, heart rate, blood lactate concentration, or blood glucose between the 2 habitual diet days. FatOx decreased after the CHO rich diet compared with the habitual day 2 (from 0.42 +/- 0.15 to 0.29 +/- 0.13 g.min(-1), p < 0.05). No difference was found in FatOx between fat-rich diet and the 2 habitual diet days. FatOx was 31% lower (from 0.42 +/- 0.14 to 0.29 +/- 0.13 g.min(-1), p < 0.01) after the CHO-rich diet compared with the fat-rich diet. Using RER data to measure FatOx is a reliable method as long as the diet is strictly controlled. However, even a 1-day change in macronutrient composition will likely affect the FatOx results. PMID- 26960445 TI - Protein "requirements" beyond the RDA: implications for optimizing health. AB - Substantial evidence supports the increased consumption of high-quality protein to achieve optimal health outcomes. A growing body of research indicates that protein intakes well above the current Recommended Dietary Allowance help to promote healthy aging, appetite regulation, weight management, and goals aligned with athletic performance. Higher protein intakes may help prevent age-related sarcopenia, the loss of muscle mass, and strength that predisposes older adults to frailty, disability, and loss of autonomy. Higher protein diets also improve satiety and lead to greater reductions in body weight and fat mass compared with standard protein diets, and may therefore serve as a successful strategy to help prevent and/or treat obesity. Athletes can also benefit from higher protein intakes to maximize athletic performance given the critical role protein plays in stimulating muscle protein remodelling after exercise. Protein quality, per meal dose, and timing of ingestion are also important considerations. Despite persistent beliefs to the contrary, we can find no evidence-based link between higher protein diets and renal disease or adverse bone health. This brief synopsis highlights recent learnings based on presentations at the 2015 Canadian Nutrition Society conference, Advances in Protein Nutrition across the Lifespan. Current evidence indicates intakes in the range of at least 1.2 to 1.6 g/(kg.day) of high-quality protein is a more ideal target for achieving optimal health outcomes in adults. PMID- 26960446 TI - Ebolavirus and evidence-based speculations. PMID- 26960447 TI - Association between insurance status and mortality in individuals with albuminuria: an observational cohort study. AB - BACKGROUND: In the general population, the association between uninsurance and mortality is well established. We sought to evaluate the association of health insurance status with mortality among working-age participants with albuminuria in the Third National Health and Nutrition Examination Survey, 1988-1994 (NHANES III). METHODS: We used data from non-elderly adult participants (18-64) of NHANES III (1988-1994), a nationally representative study of the US civilian, noninstitutionalized population, who provided information on insurance and who had albuminuria, defined as a urine albumin-to-creatinine ratio [UACR] >= 30 mg/g and their subsequent mortality to December 31, 2006. Cox proportional hazards models were used to determine associations between insurance status and all-cause mortality and cardiovascular mortality in patients with CKD while adjusting in a stepwise fashion for sociodemographic factors, co-morbidities, and co-morbidity severity/control covariates. RESULTS: In our sample of individuals with albuminuria (n = 903), mean estimated glomerular filtration rate (eGFR) was 101.6 ml/min/1.73 m(2) with 4.7 % with an eGFR <60. Approximately 15 % of the sample was uninsured, 18 % had public insurance and 67 % had private insurance. Compared to individuals with private insurance, those with public insurance or no insurance were significantly more likely to be a racial or ethnic minority, to have income <200 % below the federal poverty level, to have less than high school education; and they were less likely to be married and to report good or excellent health, all p < 0.05. Being uninsured or having public insurance was associated with increased all-cause mortality in the fully adjusted model (HR 2.97 and 3.65, respectively, p < 0.05). There was no significant relationship between insurance status and cardiovascular mortality. CONCLUSIONS: In a nationally representative sample of individuals with albuminuria, uninsurance and public insurance were associated with increased mortality compared to the private insurance even after controlling for sociodemographic, health status, and health care variables. Improving access to care and the quality of care received may potentially reduce mortality in individuals with evidence of early CKD. PMID- 26960449 TI - Biological Significance of Mutant Isocitrate Dehydrogenase 1 and 2 in Gliomagenesis. AB - Mutations of the isocitrate dehydrogenase (IDH) genes are considered an important event that occurs at an early stage during gliomagenesis. The mutations often occur in grade 2 or 3 gliomas and secondary glioblastomas. Most IDH mutations are associated with codon 132 and 172 in IDH1 and IDH2 in gliomas, respectively. While IDH1 and IDH2 catalyze the oxidative decarboxylation of isocitrate to form alpha-ketoglutarate (alpha-KG), IDH1 and IDH2 mutations convert alpha-KG to 2 hydroxyglutarate (2-HG). The accumulation of oncometabolite 2-HG is believed to lead progenitor cells into gliomas, inhibiting several alpha-KG-dependent enzymes, including ten-eleven translocation enzymes, histone demethylases, and prolyl hydroxylases, although the mechanisms have not been fully revealed. Herein, we review the contribution of IDH1 and IDH2 mutations to gliomagenesis. PMID- 26960448 TI - Acute Subdural Hematoma in Infants with Abusive Head Trauma: A Literature Review. AB - The number of cases with child abuse is increasing in Japan, and abusive head trauma (AHT) is a major cause of death in abused children. Child abuse has been recognized by the late 19th century, and widely accepted as battered child syndrome in the middle of the 20th century. As terms, there had been considerable mechanistic controversies between shaken-baby and -impact syndrome until the beginning of the 21st century. In recent years, AHT has been utilized as a less mechanistic term. Most of the characteristics of AHT in Japan have been similar to those in the United States as follows: infant is the most common victim, acute subdural hematoma (SDH) is the most common intracranial lesion, and retinal hemorrhage is often complicated. On the other hand, several characteristics have been different as follows: mother is the most common perpetrators, impact is a more common mechanism of trauma than shaking, and external trauma is more common reflecting the existence of impact. Since AHT as well as child abuse is a social pathological phenomenon influenced by victims, perpetrators, socioeconomic circumstances, and so on, various aspects of AHT as well as child abuse can be changed with times. Actually, a recent paper suggests such changes in infants with acute SDH due to AHT. In this review article, AHT, abusive infantile acute SDH in particular, are reviewed from the aspect of neurosurgical perspectives, including its mechanisms of trauma, biomechanics, clinical features, management, and prognosis, to update the trend in Japan. PMID- 26960451 TI - Aluminum-Doped Zinc Oxide as Highly Stable Electron Collection Layer for Perovskite Solar Cells. AB - Although low-temperature, solution-processed zinc oxide (ZnO) has been widely adopted as the electron collection layer (ECL) in perovskite solar cells (PSCs) because of its simple synthesis and excellent electrical properties such as high charge mobility, the thermal stability of the perovskite films deposited atop ZnO layer remains as a major issue. Herein, we addressed this problem by employing aluminum-doped zinc oxide (AZO) as the ECL and obtained extraordinarily thermally stable perovskite layers. The improvement of the thermal stability was ascribed to diminish of the Lewis acid-base chemical reaction between perovskite and ECL. Notably, the outstanding transmittance and conductivity also render AZO layer as an ideal candidate for transparent conductive electrodes, which enables a simplified cell structure featuring glass/AZO/perovskite/Spiro-OMeTAD/Au. Optimization of the perovskite layer leads to an excellent and repeatable photovoltaic performance, with the champion cell exhibiting an open-circuit voltage (Voc) of 0.94 V, a short-circuit current (Jsc) of 20.2 mA cm(-2), a fill factor (FF) of 0.67, and an overall power conversion efficiency (PCE) of 12.6% under standard 1 sun illumination. It was also revealed by steady-state and time resolved photoluminescence that the AZO/perovskite interface resulted in less quenching than that between perovskite and hole transport material. PMID- 26960452 TI - Cytochrome P450 1A1 genetic polymorphisms as cancer biomarkers. AB - Phase I metabolic enzyme CYP1A1 plays an important role in xenobiotics metabolism and has been extensively studied as a cancer risk biomarker. CYP1A1 is polymorphic and its four variants, e.g., CYP1A1* 2 A, CYP1A1* 2C, CYP1A1* 3 and CYP1A1* 4 with trivial names m1, m2, m3, and m4 respectively, are most commonly studied for cancer link. Gene- gene interaction studies combining polymorphisms of this enzyme with those of phase II detoxifying enzymes, especially glutathione S- transferases (GSTs) revealed greater risk for cancer susceptibility. Variants of CYP1A1 have also been found to be associated with chemotherapeutic adverse- effects. Results of these studies, however, remained largely contradictory mainly because of lack of statistical power due to involvement of small sample size. Strongly powered experimental designs involving gene- gene, gene- environment interactions are required in order to validate CYP1A1 as reliable cancer- biomarker. PMID- 26960450 TI - The investigation of killer cell immunoglobulin-like receptor genotyping in patients with systemic lupus erytematosus and systemic sclerosis. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by the production of autoantibodies and the involvement of multiple organ systems. Systemic sclerosis (SSc) is another autoimmune disease that causes fibrosis. We will aim to analyse the role of killer cell immunoglobulin-like receptor (KIR) genotypes and their existence with the respective HLA ligands in patients with SLE and SSc. Forty-five SLE, 25 SSc and 40 healthy controls were included. We examined the presence/absence of KIR2DL1, 2DL2, 2DL3, 2DL4, 2DL5A, 2DL5B, 2DS1, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DL1, 3DL2, 3DL3, 3DS1, 2DP1, 3DP1 and their known HLA ligands. In the SLE group, the KIR2DL5, KIR2DL5B and KIR2DS3 genes were significantly more frequent, and KIR2DL3 gene was significantly less than in controls (p values <0.05). In SSc patients, the KIR2DS3 gene was more frequent than in controls (p = 0.032). The KIR2DL3 gene was detected more frequently in controls while KIR2DS3 gene was more frequent in the patient group when SLE and SSc patients were combined (p values < 0.05). The KIR2DS2/HLA-C and KIR2DS2/HLA-C combinations were significantly more in both SLE and SSc groups than in controls. The KIR2DL2 and KIR2DL5B genes were protective from neurologic involvement in SLE patients (p values <0.05). The variations of some KIR genes such as KIR2DL5, KIR2DL5B, KIR2DS3 and KIR2DL3 may have a role in the pathogenesis of SLE and SSc. Also, the presence of KIR2DL2 and KIR2DL5B may cause major organ involvement, like neurologic involvement, in SLE. PMID- 26960453 TI - Arsenic contamination in Thai Ayurveda products and cancer risk estimation. PMID- 26960454 TI - Glutathione S transferase (GSTP 1, GSTM 1, and GSTT 1) gene polymorphisms in Egyptian patients with acute myeloid leukemia. AB - BACKGROUND: The super family of glutathione S-transferases (GSTs) is composed of multiple isoenzymes with significant evidence of functional polymorphic variation. GSTs detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Polymorphisms within the phase II metabolizer enzymes GST T1, GST M1, and GST P1 affect the body's ability to detoxify a range of potential leukemogens encountered in the environment. AIM OF WORK: To address how differences in the human GST isoenzyme expression patterns influence cancer susceptibility, prognosis, and treatment. PATIENTS AND METHODS: A total of 50 patients with acute myeloid leukemia (AML), as well as 50 age and sex matched apparently healthy volunteers were genotyped for GSTP 1, GSTM 1, and GSTT 1 gene polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and conventional polymerase chain reaction (PCR), respectively. RESULTS: For GSTP1 313 A -> G (GSTP1 Ile105Val) polymorphism, It was found that the wild genotype (AA) was significantly higher among control subjects (P value = 0.0277), while the frequency of heteromutant genotype (AG) and mutant G allele (AG + GG) was significantly higher among patients (P value = 0.0402, P value = 0.0277, respectively). For GSTM1 and GSTT1gene, we found statistically significantly higher frequency among patients regarding homozygous gene deletion (P value = 0.0005). CONCLUSION: We demonstrated that GSTM1 null or GSTT1 null genotypes may be considered independent risk factors for AML with no impact on prognosis and GSTP1 * 105 genotype is a prognostic factor, adding independent information to the routine laboratory parameters and cytogenetic and molecular alterations of the tumor cells. PMID- 26960455 TI - Bloodstream infections in children with febrile neutropenia: Isolates and their antimicrobial susceptibility profile. PMID- 26960456 TI - Invasive squamous cell carcinoma of cervix showing horizontal endometrial spread with extension and involvement of the myometrium: A case report. PMID- 26960457 TI - The role of Ki-67, p16, CD34, Bcl-2, cyclooxygenase-2 in the pathogenesis of proliferative verrucous leukoplakia. AB - CONTEXT: Proliferative verrucous leukoplakia (PVL) is a highly persistent and aggressive oral pre-malignant lesion with an obscure etiopathogenesis and a malignant transformation rate of 85-100%. AIMS: The aim of the present study is to assess the role of Ki-67, p16, CD34, Bcl-2, cyclooxygenase-2 (COX-2) in the spectrum of PVL to ascertain their role in its etiopathogenesis. SETTINGS AND DESIGN: A retrospective chart analysis was carried out on a series of seven confirmed cases of PVL, which were followed-up for 2 years. SUBJECTS AND METHODS: Immunohistochemical appraisal of these cases was carried out by a panel of markers, related to cell proliferation, cell cycle regulation, angiogenesis, apoptosis and inflammation. The expression of these markers was correlated with patients' clinicopathological profile. STATISTICAL ANALYSIS USED: The frequency distribution of the group data was analyzed. RESULTS: The latest labeling index of Ki-67 in our cases ranged from 8.18 to 12.6. p16 was positive in 3/7 cases. Bcl-2 expression was moderately positive in 2/7 cases. All cases were intensely positive for COX-2 staining. Microvascular density assessed by CD34 staining ranged from 11 to 20/high power fields. One case which transformed into squamous cell carcinoma demonstrated increased Ki-67, Bcl-2, COX-2, CD34 expression, but negative p16 and Bcl-2 expression. CONCLUSIONS: Application of these markers in understanding the behavior of PVL suggests that an imbalance between the proliferation apoptosis dynamics of the lesion accompanied by an increase in inflammation and angiogenesis underlie the molecular pathogenesis of the PVL spectrum. PMID- 26960458 TI - Microsatellite stable adenocarcinoma in a pediatric patient presenting as a dual mass in the colon and cecum: A rare presentation. PMID- 26960459 TI - Immunohistochemical expression of Bcl-2 in oral epithelial dysplasia and oral squamous cell carcinoma. AB - BACKGROUND: The B cell lymphoma-2 gene is a proto-oncogene whose protein product inhibits apoptosis. Its role is associated with keeping cells alive, but not by stimulating them to proliferation, as other proto-oncogenes do. Increased expression of protein product of Bcl-2 gene appears in the early phase of carcinogenesis leading to apoptosis impairment and in consequence to the progression of neoplastic changes. OBJECTIVE: To evaluate and compare the expression of Bcl-2 protein in oral epithelial dysplasia and oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Sixty cases of formalin-fixed paraffin embedded archival specimens comprising of 30 cases of leukoplakia with oral epithelial dysplasia and 30 cases of OSCC were taken for immunohistochemical analysis using monoclonal antibody against anti-human Bcl-2 oncoprotein. RESULTS: Immunostaining for Bcl-2 protein was identified in basal and parabasal layers as granular cytoplasmic staining in oral epithelial dysplasia. In OSCC, Bcl-2 immunoreactivity was most prominent in the peripheral cells of the infiltrating tumor islands which diminished toward the center in well-differentiated and moderately differentiated OSCC, whereas stronger and more diffuse expression of Bcl-2 oncoprotein was seen in poorly differentiated OSCC. Overall positivity of 26.7% (8/30) was observed in oral epithelial dysplasia and 30% (9/30) in OSCC in this study. INTERPRETATION AND CONCLUSION: Altered expression of Bcl-2 oncoprotein may be an early molecular event which leads to prolonged cell survival, increased chances of accumulation of genetic alterations, and subsequent increase in malignant transformation potential. PMID- 26960460 TI - "Gastro-Esophageal junction GIST". PMID- 26960461 TI - The accuracy of Breastlight in detection of breast lesions. AB - AIM: Breastlight is a new product to improve breast health awareness of women. However, its accuracy in detection of breast lesions (BLs) is unknown. The aim of this study was to determine the Breastlight accuracy in detection of BLs. MATERIALS AND METHODS: From July 2011 to September 2013, a total of 500 women referred to mammography unit in Yazd, Iran for screening were recruited to the study. The sensitivity and specificity of Breast light was measured with clinical breast examination (CBE), mammography and sonography. Sonographic and mammography examinations were performed according to breast density among women in two groups of younger (n = 105) and older (n = 395) than 30 years. RESULTS: The results have shown a statistically significant positive correlation between Breastlight, CBE, sonography, and mammography in detection of BLs. Breastlight significantly detected 60.3%, 35.8%, and 59% of lesions which were detected by mammography, CBE, and sonography, respectively. Its sensitivity varied significantly with breast density. Comparing the sensitivity of Breastlight among women younger and older than 30 years indicated that the Breastlight had a higher sensitivity for women older than 30 years. The greatest and lowest portion of positive predictive value occurred with CBE (94.7%) and mammography (91.1%). As well, its greatest and lowest portion of negative predictive value occurred with CBE (65.6%) and sonography (29.7%). CONCLUSION: The results of this study showed that the efficacy of Breastlight in detection of breast changes as domestic apparatus was appropriate. However, it is recommended further studies to evaluate the Breastlight efficacy and accuracy in detection of the BLs. PMID- 26960463 TI - Breast self-examination practices in Nigerian women attending a tertiary outpatient clinic. AB - BACKGROUND: The morbidity and mortality caused by breast cancer can be decreased by early detection with breast self-examination (BSE). The objective of this study was to determine the prevalence and the factors determining the practice of BSE. MATERIALS AND METHODS: The study was conducted on 140 women aged above 18 years who presented consecutively in a General Outpatient's clinic in a tertiary hospital in Nigeria. This was the baseline study from an intervention study which looked at the effect of demonstration of BSE on improving Clinical Breast Examination (CBE) among two groups of respondents. Structured questionnaires were validated and administered by an interviewer and the data were analyzed using Statistical Package for Social Sciences (SPSS) version 12. RESULTS: The overall self-reported prevalence of BSE practice was 62.1% among the respondents. Older women (16, 76.2%), married women (63, 65.6%) and women with tertiary education (51, 68.9%) had the highest prevalence of BSE practice. Prevalence rate was highest for civil servant (25, 78.1%), P = 0.04. The practice of BSE was higher among women with a previous history of breast disease (15, 68.2%) and in respondents with a family history of breast disease (7, 63.6%), Only 11 (12.6%) performed BSE as per guidelines, which was once in a month. CONCLUSION: The prevalence of BSE was found to be high, especially in those with tertiary education and in those with a past personal or family history of breast disease. In resource-constrained countries, BSE is a screening tool that can be employed to help reduce the breast cancer burden because routine mammography screening is not yet feasible. Women need to be informed about the when and how to perform BSE. PMID- 26960462 TI - Factors predicting lapatinib efficacy in HER-2+ metastatic breast carcinoma: Does it work better in different histologic subtypes? AB - CONTEXT: Introduction of trastuzumab, a recombinant monoclonal antibody against the extracellular domain of HER-2, is a cornerstone in the treatment of HER-2+ breast carcinoma. However, many cancers that have an initial response to trastuzumab will progress some time later. After progression on trastuzumab-based first-line treatment, there are several options. Although TDM-1 (Trastuzumab emtansine) has prolonged progression-free survival (PFS) and overall survival in patients previously treated with trastuzumab and taxane, it is still not available in Turkey. Patients may be switched to lapatinib (an oral tyrosine kinase inhibitor targeting both HER-1 and HER-2), or they may re-challenge with trastuzumab. There is no clear definition of the patients who should be switched to lapatinib. AIM: In this study, we investigated the factors predicting the efficacy of lapatinib. SUBJECTS AND METHODS: Totally, 94 patients treated with lapatinib for metastatic breast carcinoma was included in our study. Retrospective data including pathology, treatments and treatment results, metastatic sites, and laboratory tests were collected. RESULTS: Progression-free survival was 9.1 months. Histologic subtypes other than invasive ductal carcinoma and liver metastasis were inversely related with PFS. Overall survival was 22.1 months, and patients with histologic subtypes other than invasive ductal carcinoma and who progress with brain metastasis had a worse prognosis. CONCLUSION: Clinicians should give attention to histologic subtype and metastatic sites when choosing patients for lapatinib treatment. PMID- 26960464 TI - Unusual solitary splenic metastasis from pyriform fossa carcinoma detected by FDG PET. PMID- 26960466 TI - Leydig cell tumor of testis with indeterminate features. PMID- 26960465 TI - Male breast cancer: A single institute experience. AB - BACKGROUND: Male breast cancer (MBC) is a rare disease and accounts for 1% of all breast cancers. There is limited data on MBC from India. The aim of our study was to assess clinico-pathological parameters and outcome in MBC patients. MATERIALS AND METHODS: This analysis was carried out in 76 patients of MBC who were registered at Institute Rotary Cancer Hospital of All India Institute Of Medical Sciences between 1996 and 2012. Patients' records were retrospective reviewed and data obtained from the computer database using International Classification of Diseases code (C-50). RESULTS: The median age was 59 years (range: 28-80). The median duration of symptoms was 11 months (range: 0.5-40). Breast lump was the most common presenting symptom (left > right side). American Joint Committee on Cancer (7th edition) stage distribution was Stage I-2.6%, Stage II-13.1%, Stage III-59.3% and Stage IV-25%. Modified radical mastectomy was the commonest surgical procedure. Moreover, 30% of tumors were high-grade and 70% had pathological node positive disease. Estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER2)/neu positivity was 80% and 28%, respectively. Triple negative breast cancer constituted 19% of cases. With a median follow-up of 36 months, 3 years relapse free survival and overall survival was 60% and 80%. Advanced stage and visceral metastasis at baseline predicted poor outcome. CONCLUSION: MBC constituted 0.8% at our institute. Our study population had a longer time to presentation, advanced disease at presentation, more HER2/neu positivity and triple negativity higher than the available literature. PMID- 26960468 TI - Pathological examination after neoadjuvant chemotherapy (breast carcinoma): A diagnostic challenge in surgical pathology. PMID- 26960467 TI - Study on knowledge, experiences and barriers to mammography among working women from Delhi. AB - INTRODUCTION: Mammography is not a popular screening tool for deducting breast cancer in India although regular screening is associated with reduced mortality from breast cancer. OBJECTIVE: The objective of this study is to find out knowledge, experiences and barriers to mammography among working women of Delhi. MATERIALS AND METHODS: Cross-sectional descriptive study was conducted from October 2012 to March 2013 among working women from Delhi, India. The study was conducted as a part of ongoing training workshops organized for women on early detection of breast cancer. Total of eight such programs were organized and were attended by a total of 439 women. Each participant got a self-administered questionnaire to fill. Data was entered in Microsoft Excel and analysis was done using Statistical product and service solutions (SPSS) version 21 (IBM). RESULTS: A total of 439 participants were included in the study. 230 (52.4%) of the women were more than 40 years of age. Only four participants (1%) had not heard about the term mammography before. Less than half (45.1%) of the participants knew correctly the purpose of a mammogram. Only 11.8% of the women knew correctly about the age of getting the first baseline mammogram. Knowledge of frequency of getting the mammogram was also low only 95 (21.6%) correctly knew about it. Only 59 (11.9%) correctly responded that one needs to go to an imaging facility located either in a hospital or elsewhere to get mammogram done. Main experience shared by the women regarding mammography was that 42 (95.45%) did not know anything about the procedure when they went for this investigation. Out of a total of 230 women over 40 years of age only 38 (16.5%) had ever got a mammogram carried out. There is a statistically significant association between education status and practice of mammography (P < 0.05). There were 18 women with family history of breast cancer out, of which 10 (55.5%) had got mammography carried out. 192 out of 230 (83.5%) women over 40 years of age had never got a mammogram done. Main reason 74 (38.5%) cited for this was that they did not know/were not aware they were supposed to go for mammography. CONCLUSION: As knowledge and utilization of mammography is low among women, there is a need to have a multipronged strategy to inform women about mammography and bring about a behavioral change along with having a formal national level screening guidelines for breast cancer early detection. PMID- 26960469 TI - Bortezomib in newly diagnosed patients with multiple myeloma: A retrospective analysis from a tertiary care center in India. AB - INTRODUCTION: Bortezomib is a novel proteasome inhibitor in myeloma. There is a paucity of data from India regarding the efficacy and tolerance to bortezomib. MATERIALS AND METHODS: All patients with newly diagnosed multiple myeloma from January 2008 to December 2011 treated with bortezomib as the first-line therapy were studied in a retrospective analysis. The primary end point was the overall rate of response. Secondary end points were the progression free survival (PFS), reversibility of renal compromise and safety of bortezomib. RESULTS: Our study included 41 patients with newly diagnosed myeloma. The overall response to bortezomib was 88.5% (complete response [CR] 31.4%, very good partial response 34.2%, partial response [PR] 22.8%). A renal response (CR renal, PR renal or Minimal Response renal combined) was documented 96.2% patients with initial renal impairment. The median time to the first renal response was 21 days. 17 patients (41.4%) had severe toxicity (Grade 3 and 4). Bortezomib induced peripheral neuropathy (BIPN) was the most common toxicity seen (53.6%) and the most common cause for discontinuation of therapy. At a median follow-up of 9 months, median PFS was not reached. DISCUSSION: The results obtained in our study are comparable with those of established studies on bortezomib. Our patient population has similar responses and renal reversibility patterns. However, they are at an increased susceptibility to BIPN, leading to discontinuation of therapy. CONCLUSION: Bortezomib as first-line therapy has a good efficacy and safety. PMID- 26960470 TI - Retrospective audit of clinico-pathologic features and treatment outcomes in a cohort of elderly non-Hodgkin's lymphoma patients in a tertiary cancer center. AB - INTRODUCTION: There is limited data from India regarding elderly non-Hodgkin's lymphomas (NHL) patients. Hence, this audit was planned to study the clinic pathological features and treatment outcomes in elderly NHL patients. METHODS: Retrospective analysis of all NHL patients above age of 59 years treated at the author's institute, between December 2010 and December 2013 was done. Case records were reviewed for baseline details, staging details, prognostic factors, treatment delivered, response, toxicity and efficacy. SPSS version 16 (IBM, Newyork) was used for analysis. Descriptive statistics was performed. Kaplan-Meir survival analysis was done for estimation of progression-free survival (PFS) and overall survival (OS). Univariate analysis was done for identifying factors affecting PFS and OS. RESULTS: Out of 141 NHL patients, 67 patients were identified subjected to the inclusion criteria. The median age was 68 years (60 92). Majority were B-cell NHL (86.6%). The commonest subtype in B-cell was diffuse large B-cell lymphoma (55.2%). Fifty-four patients took treatment. The treatment intent was curative in 41 patients (61.2%). Among the patients receiving curative treatment, 16 patients couldn't receive treatment in accordance with NCCN guidelines due to financial issues. Two years PFS was 55%. Two years PFS for B-cell NHL and T-cell NHL were 55% and 50% respectively (P = 0.982). Two years PFS for standard Rx and nonstandard Rx were 62% and 50% respectively, but it didn't reach statistical significance (P = 0.537). Two years OS for the entire cohort was 84%. CONCLUSION: Standard treatment in accordance with guidelines can be delivered in elderly patients irrespective of age. There is a need for creating financial assistance for patients, so that potentially curative treatments are not denied. PMID- 26960471 TI - A new perspective in the treatment of radiodermatitis. PMID- 26960472 TI - Evaluation of primary thyroid lymphoma by ultrasonography combined with contrast enhanced ultrasonography: A pilot study. AB - OBJECTIVE: To evaluate the features of primary thyroid lymphoma (PTL) by ultrasonography (US) combined with contrast-enhanced ultrasonography (CEUS). MATERIALS AND METHODS: In this retrospective study, 20 patients (8 male and 12 female) with PTL were evaluated by conventional US and among them, 10 patients underwent CEUS examination. The appearance of US features was classified into three types: Diffusive mass type, multiple nodular type and mixed type. The CEUS patterns included diffusive homogeneous enhancement and diffusive heterogeneous enhancement pattern. Parameters of CEUS time-intensive curve were analyzed in primary tumor and involved lymph nodes compared to ipsilateral common carotid artery. RESULTS: Of 20 patients with PTL, 18 presented an enlarging neck mass that grew rapidly with an average duration of 3.2 months, and 17 were associated with Hashimoto's thyroiditis. In conventional US, all patients had marked hypoechoic masses. Among them, 12 patients were diffusive mass type, 6 were multiple nodular type and 2 were mixed type. For CEUS patterns, 8 were diffusive homogeneous enhancement and 2 were diffusive heterogeneous enhancement. Necrosis areas were showed in diffuse heterogeneous pattern which were hardly seen in conventional US. In the quantitative analysis of CEUS parameters, the time to peak of time-intensive curve in the primary tumors or involved lymph nodes was longer than that of the ipsilateral common carotid artery (P = 0.004). CONCLUSION: PTL mainly demonstrated as a diffusive mass type with marked hypoechogenecity on conventional US and diffusive homogeneous enhancement pattern on CEUS. And the heterogeneous enhancement pattern is also helpful for detecting necrosis areas of PTL. PMID- 26960473 TI - Estimation of cancer risk due to exposure to lead contamination in Thai Ayurveda products. PMID- 26960474 TI - Prevalence and clinical manifestation of lymphomas in North Eastern Nigeria. AB - BACKGROUND: Lymphomas are one of the commonest childhood malignancies. Due to varied clinical features many patients are misdiagnosed and treated for other diseases. It is imperative to keep health workers informed about the current trend of lymphomas in northeastern Nigeria to facilitate prompt diagnosis and treatment. OBJECTIVE: To evaluate the extent of lymphomas at presentation and to define the pattern of presentation in relation to gender and site. MATERIALS AND METHODS: Retrospective analysis of cases of lymphomas over a 15 year period was conducted. Structured questionnaires were used to document demographic characteristics and clinical features. The non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) cases were categorized using standard classification schemes. Data were analyzed using the Statistical Package for Social Sciences (SPSS) software version 16, Illinois, Chicago, USA. Spearman's correlation and Student's t-test were applied where appropriate. A P value < 0.05 was considered significant. RESULTS: Fifty cases of lymphoma, 10 (20%) belong to HL and 40 (80%) belong to NHL. Lymphoma is common in male, though the male to female preponderance was not significant in both the cases (P = 0.107 and 0.320, respectively). Maxilla was the commonest site of primary malignancy (36%) and late presentation of patients were observed. New trend was noticed, the NHL patients present commonly with severe symptoms than HL (P = 0.038). HL was dominated by lymphocytic predominant type, while NHL was dominated by the small non cleaved cells (Burkitt's) lymphoma (70%). CONCLUSION: Childhood lymphoma in northeastern Nigeria has a slight shift in varied clinical presentation in favor of NHL. Patients in this study had late presentation. PMID- 26960475 TI - "Low-grade adenocarcinoma of fetal lung type: In an elderly non-smoker female" with aberrant beta-catenin expression. PMID- 26960476 TI - Distribution of nodal lymphomas in a referral hospital of Mangalore city. AB - CONTEXT: The distribution of different types of lymphoma varies across geographic regions. AIMS: The present study was done to understand the occurrence of nodal lymphomas in a referral hospital of Mangalore city. SETTINGS AND DESIGN: Descriptive study. SETTING: The present study was conducted on 95 lymph node biopsy specimens, received in a referral hospital of Mangalore city. MATERIALS AND METHODS: All cases of nodal lymphoma diagnosed between January 2007 and June 2010 in a referral hospital of Mangalore were selected for the study. The patients age and clinical details were obtained. Immunophenotyping was done for all cases of NHL and selected cases of HL. IPI score for NHL was noted and correlated with the outcome. STATISTICAL ANALYSIS USED: Chi square test was used. RESULTS: Out of the total 95 cases of nodal lymphoma 37 (39%) were HL while 58 (61%) were NHL. Classical HL was diagnosed in 35 cases (37%) while 2 cases (2%) were diagnosed NLPHL. B cell lymphoma formed 72% of NHL. Follicular lymphoma accounted for 28% of all NHL. T cell lymphoma formed 28% of NHL. CONCLUSIONS: In conclusion the following points are significant about the distribution of lymphomas in a referral hospital of Mangalore city. The incidence of NSHL is higher while national data suggests MCHL as the most common subtype. The incidence of FL as well as T cell NHL is much higher when compared to national incidence. The epidemiological factors for this high frequency (either genetic or environmental) needs to be studied further. PMID- 26960477 TI - Bridging the gap between biostatisticians and oncologists: Need of the hour in comprehensive cancer research. PMID- 26960478 TI - Plasmablastic lymphoma in HIV patients: Experience at a tertiary care hospital in eastern India. AB - BACKGROUND: Plasmablastic lymphoma (PBL), a rare non-Hodgkin's lymphoma (NHL) variant specifically associated with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), expresses well-differentiated plasma cell markers like CD138, bright CD38, and MUM1; but not conventional B-cell markers. It occurs at unusual sites like oral cavity and orbit, and has poor survival rates. AIMS: This study serves as a review of a clinical experience with six HIV patients with PBL and observes the spectrum of clinical presentations, histopathologies, and 1-year outcomes in PBL patients. MATERIALS AND METHODS: This review of six PBL patients was conducted at a tertiary care hospital in eastern India using relevant radiological, histopathogical, and immunohistological studies. RESULTS: Incidence of PBL among HIV patients was 0.58% (6/1,028). Mean CD4 count at presentation was 125.5 +/- 71.1 cells/MUL. Sites of involvement included pleura, lung parenchyma, suprarenal gland, pelvic cavity, and retroorbital space (one each). Immunohistopathology of biopsied sample in each patient revealed PBL (positive plasma cell markers MUM-1/IRF4, CD38, and CD138/syndecan; and negative of B-cell markers CD3, CD20, and CD30). Three (60%) were positive for Epstein Barr virus (EBV) immunoglobulin G (IgG). Five surviving patients received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) regimen and attained partial remission (PR) after six cycles. Subsequently, three patients were started on EPOCH (etoposide, cyclophosphamide, doxorubicin, vincristine, prednisone) therapy; two attained near total regression after 6 months (four cycles). Overall, four patients remained alive with good quality of life at the end of 1 year of follow-up. CONCLUSION: PBL in HIV occurs at unusual sites with varying aggressivity. This study is too small to comment on the long-term outcomes of PBL in HIV; however, coadministration of antiretroviral therapy (ART) with standard chemotherapy may improve survival. PMID- 26960479 TI - Xeroderma pigmentosum with squamous cell carcinoma of face: A rare case report of two siblings. PMID- 26960480 TI - Therapy and progression--induced O6-methylguanine-DNA methyltransferase and mismatch repair alterations in recurrent glioblastoma multiforme. AB - Despite multimodality treatment protocol including surgical resection, radiotherapy, and chemotherapy in patients with glioblastoma multiforme (GBM), most suffer from treatment failure and tumor recurrence within a few months of initial surgery. The effectiveness of temozolomide (TMZ), the most commonly used chemotherapeutic agent, is largely dependent on the methylation status of the promoter of the gene O6-methylguanine-DNA methyltransferase (MGMT) and the integrity of the mismatch repair (MMR) system. Changes in these regulatory mechanisms at the time of recurrence may influence response to therapy. Deciphering the molecular mechanisms of resistance to these drugs may in future lead to improvised patient management. In this article, we provide an update of the spectrum of molecular changes that occur in recurrent GBMs, and thus may have an impact on patient survival and treatment response. For review, electronic search for the keywords "Recurrent GBM", "Recurrent GBM AND MGMT" "Recurrent glioma AND MGMT", "Recurrent GBM AND MMR" and "Recurrent glioma AND MMR", "Recurrent GBM AND MMR" and "Recurrent glioma AND MMR" was done on PubMed and relevant citations were screened including cross-references. PMID- 26960482 TI - An analysis of medulloblastoma: 10 year experience of a referral institution in South India. AB - BACKGROUND: Medulloblastoma is an embryonal tumor with aggressive behavior and is more commonly seen in children than adults. The aim of this study was to determine the epidemiological patterns of medulloblastoma in a tertiary care center in Southern India. MATERIALS AND METHODS: It is a retrospective study, in which the records of all the clinically diagnosed medulloblastoma cases in the last 10 years (2002-2012) were analyzed. RESULTS: A total of 58 cases were found, with the mean age at diagnosis being 10 years. There was a slight predilection for the male sex (58.62%). The first presenting symptom was mostly related to raise intracranial pressure and the mean duration of symptoms was 200 days. Nearly, 89.6% of patients were in Stage 0 and had a central tumor location. Multimodality treatment included surgery followed by craniospinal irradiation up to 36 gray followed by posterior fossa boost up to 54 gray. Median radiation therapy duration was 6.5 weeks and concurrent single agent vincristine was the most common chemotherapy used. Most of the patients showed only a partial response to treatment, mainly because of large tumors at presentation, which could be attributed to the lack of awareness, delayed medical attention and poor follow-up. CONCLUSION: Early diagnosis and treatment is the key to management of medulloblastoma, which still needs to be achieved. Bulky tumors have a poor outcome, efforts should be aimed at complete surgery and giving risk stratification based treatment. Resources need to be allocated to make more conformal methods of radiotherapy available, which will decrease the growth abnormalities and cognitive impairments. PMID- 26960481 TI - Leiomyosarcoma of urinary bladder-potential mimicker of carcinoma: Case report and short review of literature. PMID- 26960483 TI - Malignant peripheral nerve sheath tumor of fourth ventricle and 7-8(th) cranial nerve complex: Case report. PMID- 26960484 TI - Quality of life measures in glioma patients with different grades: A preliminary study. AB - BACKGROUND: Plethora of information exists in the literature on pathology of the glioma while prevailing research data on quality-of-life (QOL) of glioma patients marks dearth thus demanding more studies. AIMS: In this study, we examined the QOL of different grades of glioma patients among the Chennai population in India. MATERIALS AND METHODS: A total of 162 patients with different grades of glioma enrolled from August 2007 to February 2011, at their first contact to Department of Neurology and Neurosurgery, Government General Hospital, Chennai, India were included and their QOL was assessed by European Organization for Research and Treatment of Cancer Core QOL questionnaire (EORTC QLQc-30), EORTC brain cancer module (QLQ BN-20). RESULTS AND CONCLUSION: Both low and high grade glioma (LGG and HGG) patients had poor mean scores in social functioning (87.0), physical functioning (82.0) and emotional functioning (75.2) and role functioning (58.9). The mean scores on cognitive functioning (61.9) and global QOL (60.3) were better. Age, Karnofsky performance status, World Health Organization grades showed significant associations with all functional scales. The percentage values were higher for symptoms of fatigue (76.9%), pain (71.5%), financial difficulties (77.6%) and appetite loss (38.46%) in both LGG and HGG. Similarly, with respect to QLQ-BN20 domains, HGG patients showed more symptoms than low grade with a significant correlation in communication deficit problems (P = 0.02), headache (P = 0.04), seizures (P < 0.01), hair loss (P < 0.05) than the other symptoms. This initial assessment suggests that an increasing burden of symptoms exists, with poor QOL and survival, which has become a major concern in different grades of glioma patients. PMID- 26960485 TI - Lactating adenoma with infiltrating ductal carcinoma breast in a pregnant woman. PMID- 26960486 TI - Effect of dendritic cell vaccine therapy on lymphocyte subpopulation in refractory primary brain tumor. AB - BACKGROUND: Dendritic cell (DC)-based immunotherapy has the potential to induce an antitumor response within the immunologically privileged brain. AIMS: The aim of this study was to evaluate the short-term effect of DC vaccine therapy on lymphocyte subsets in patients with refractory primary brain tumor. MATERIALS AND METHODS: Eighteen cases with refractory primary brain tumor who refused any treatment against tumor within 6 months of the therapy, were referred to one medicine center, from January 2011 to October 2012. All patients received 1 * 10(7) tumor lysate-pulsed DC vaccinations both intradermal injection and intravenous infusion 3 times/week. RESULTS: There were increases of lymphocytes CD8+ (P = 0.002) and CD56+ (P = 4.207E-10), but no change of lymphocytes CD3+ (P = 0.651). Six patients were positive response of delayed-type hypersensitivity. There were improving of appetite in 14 cases and increasing of physical strength 17 cases. CONCLUSIONS: DC vaccine has the potential for inducing an immune cytotoxic effect directed toward tumor cells. PMID- 26960487 TI - Aggressive angiomyxoma perineum: A rare soft tissue neoplasm in males. PMID- 26960488 TI - Role of adjuvant radiation in the management of central neurocytoma: Experience from a tertiary cancer care center of India. AB - BACKGROUND AND OBJECTIVE: Neurocytoma (NC) is a rare benign neuronal tumor. A complete excision remains curative for most of these tumors, but atypical histology and extra-ventricular location often necessitates adjuvant therapy. We intended to explore the clinico-pathological features and treatment outcome in patients of NC in our institute. MATERIALS AND METHODS: Medical records were reviewed and data collected on NC over a 6-year period (2006-2012) from the departmental archives. Disease free survival (DFS) was analyzed by Kaplan-Meier method. RESULTS: A total of 18 patients met the study criteria. Fourteen patients had intra-ventricular neurocytoma (IVNC), right lateral ventricle being the most common site of origin. Gross total resection and near total resection were achieved in eight cases each whereas tumor decompression and biopsy could be done in two cases. On post-operative histopathological examination, eight patients were found to have atypical NC while 10 patients had typical NC. All patients underwent adjuvant radiation. The median dose of post-operative radiation was 56 Gy. All patients were alive at their final follow-up. One patient had both clinical and radiological evidence of local relapse. In the evaluable patients (n = 18), after a median follow-up of 35 months the DFS rate at 2 years and 3 years are 100% and 83% respectively. CONCLUSION: Use of adjuvant radiation to a total dose of 56 Gy enhances the local control and achieves superior survival in patients of NC. Use of 3D conformal planning techniques may help us to achieve better therapeutic ratio in patients with NC. PMID- 26960489 TI - Adrenal myelolipoma: A rare lesion of adrenal gland. PMID- 26960490 TI - Clinical outcome of patients with primary gliosarcoma treated with concomitant and adjuvant temozolomide: A single institutional analysis of 27 cases. AB - CONTEXT AND AIM: The prognosis of primary gliosarcoma (PGS) remains dismal with current treatment modalities. We analyzed the outcome of PGS patients treated with concurrent and adjuvant temozolomide (TMZ). SETTINGS AND DESIGN: Retrospective single institutional analysis. MATERIALS AND METHODS: We retrospectively evaluated 27 patients of PGS treated with radiotherapy (RT) and TMZ during 2007-2012. STATISTICAL ANALYSIS USED: Overall survival (OS) was estimated by the use of Kaplan Meier method and toxicities were evaluate using common terminology criteria for adverse events version 2.0 (National Cancer Institute, USA). RESULTS: Median age at presentation and Karnofsky performance status was 45 years and 90 respectively and male: female ratio was 20:7. Patients received adjuvant RT to a total dose of 60 Gy at 2 Gy/fraction. All patients except 5 received adjuvant TMZ to a median number of 6 cycles. Grade 2 and 3 hematological toxicity was seen in 8% and 4% of patients respectively during concurrent RT. During adjuvant chemotherapy, 13.6% had Grade 3 thrombocytopenia and 9.5% had Grade 3 neutropenia. Median OS was 16.7 months (1 year and 2 year actuarial OS was 70.8% and 32.6% respectively). Adjuvant TMZ was associated with a better survival (median survival 21.21 vs. 11.93 months; P = 0.0046) on univariate analysis and also on multivariate analysis (hazard ratio 1.82, 95% confidence interval: 1.503-25.58; P = 0.012). CONCLUSIONS: The results of our study, largest series of patients with PGS treated with concurrent and adjuvant TMZ shows an impressive survival with acceptable toxicity. We suggest TMZ be included in the "standard of care" for this tumor. PMID- 26960491 TI - Squamous cell and neuroendocrine carcinoma of esophagus: Collision versus composite tumor: A case report and review of literature. PMID- 26960492 TI - Carcinoma of buccal mucosa: A site specific clinical audit. AB - BACKGROUND: Carcinoma of buccal mucosa is the most common cancer of the oral cavity in India. Treatment of oral cancer poses unique reconstructive challenges, owing to the dynamic architecture of the oral cavity. Despite current progress in various treatment modalities, over the past 50 years survival rates have not improved drastically. Although, philosophy on treatment of buccal mucosa carcinoma remains well-established, due to the relative paucity of reported data, retrospective reviews of institutional experiences are of prime importance. This study provides a detailed insight on this site specific cancer of the oral cavity in the Indian population. AIM: The aim of this study is to analyze our experience with the management of carcinoma of buccal mucosa; associated clinical presentation, outcomes and prognostic factors. SETTINGS AND DESIGN: A retrospective chart review was performed of all cases of primary buccal mucosa carcinoma treated surgically between years 2008 and 2012 in SDM Craniofacial Unit, Karnataka, India. MATERIALS AND METHODS: All cases were analyzed based on patient characteristics, clinical presentation, surgical and adjuvant therapy rendered and treatment outcomes. A retrospective chart review was carried out using the hospital's data base for the same. STATISTICAL ANALYSIS USED: Kaplan Meier methods were used for analyzing disease free survival (DFS). Univariate analysis of prognostic factors was performed with log rank test. RESULTS: The significant variables in univariate analysis were: Overall stage, T-stage (T1/T2 vs. T3/T4) and nodal status (N0 vs. N+). We found that staging, tumor size and nodal status were significant prognostic factors for DFS. CONCLUSION: The strong influence of overall disease stage, tumor size, nodal status, final histopathological report and habits of tobacco/betel quid chewing, on prognosis; emphasizes the importance of early diagnosis and prevention of carcinoma of buccal mucosa in the Indian population. PMID- 26960493 TI - Pathology of advanced buccal mucosa cancer involving masticator space (T4b). AB - BACKGROUND: Buccal mucosa cancer involving masticator space is classified as very advanced local disease (T4b). The local recurrence rate is very high due to poor understanding of the extent of tumor spread in masticator space and technically difficult surgical clearance. The objective of this study is to understand the extent of tumor spread in masticator space to form basis for appropriate surgical resection. MATERIALS AND METHODS: All consecutive patients with T4b-buccal cancer underwent compartment resection, with complete anatomical removal of involved soft-tissue structures. Specimens were systematically studied to understand the extent of invasion of various structures. The findings of clinical history, imaging and pathologic evaluation were compared and the results were evaluated. RESULTS: A total of 45 patients with advanced buccal cancer (T4b) were included in this study. The skin, mandible and lymph nodes were involved in 30, 24 and 17 cases respectively. The pterygoid muscles were involved in 34 cases (medial pterygoid in 12 and both pterygoids in 22 cases) and masseter-muscle in 32 cases. Average distance for soft-tissue margins after compartment surgery was 2 cm and the margins were positive in 3 cases. The group with involvement of medial pterygoid muscle had safest margin with compartment surgery while it was also possible to achieve negative margins for group involving lateral pterygoid muscle and plates.The involvement of pterygomaxillary fissure was area of concern and margin was positive in 2 cases with one patient developing local recurrence with intracranial extension. At 21 months median follow-up (13-35 months), 38 patients were alive without disease while two developed local recurrence at the skull base. CONCLUSIONS: T4b buccal cancers have significant soft-tissue involvement in the masticator space. En bloc removal of all soft-tissues in masticator space is advocated to remove tumor contained within space. The compartment surgery provides an opportunity to achieve negative margins for cancers actually contained within masticator space.It is inappropriate to club all patients with masticator space involvement in one group. PMID- 26960494 TI - Dermatological lesions in acute lymphoblastic leukemia. PMID- 26960495 TI - Role of podoplanin in potentially malignant disorders and oral squamous cell carcinoma and its correlation with lymphangiogenesis. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) ranks as one of the most common types of cancer and oral potentially malignant lesions (OPMLs) provides with an overall increased risk for development of carcinoma. As podoplanin expression is attracting interest as a marker for cancer diagnosis and prognosis, this study assesses the role of podoplanin expression in such lesions. MATERIALS AND METHODS: Podoplanin expression and lymphatic vessel density (LVD) was determined using D2-40, a marker for podoplanin, in 70 diagnosed cases of potentially malignant lesions and OSCC. RESULTS: Normal epithelium showed negligible podoplanin expression, whereas the expression extended predominantly at the basal layer and the suprabasal layer or above at one or multiple areas in potentially malignant lesions. Podoplanin expression in OSCC showed two different patterns diffuse and focal. A statistically significant increase in mean LVD was seen from normal epithelium to potentially malignant lesions (P < 0.001) and to OSCC (P < 0.022) while a non-significant increase was seen (P < 0.594) between OPMLs and OSCC. Overall no significant correlation was found between D2-40 epithelial positivity and LVD (P = 0.122). CONCLUSION: This study suggests the utility of podoplanin as a biomarker for cancer risk assessment as it detects the early changes and thus provides an additional value beyond current clinical and histopathological evaluations. Hence, podoplanin is suggested to be a marker of tumor initiation and to a lesser extent of tumor progression. PMID- 26960496 TI - Co-occurrence of hepatocellular carcinoma and combined hepatocellular cholangiocarcinoma. PMID- 26960497 TI - External auditory canal carcinoma: Impact of chemotherapy. PMID- 26960498 TI - Oral squamous cell carcinoma in patients with and without predisposing habits in glossal and extra-glossal site: An institutional experience in South India. AB - INTRODUCTION: We report our cohort of oral squamous cell carcinoma (OSCC) patients with or without predisposing habits in glossal and extraglossal sites. MATERIALS AND METHODS: A retrospective analysis of OSCC cases over a period of 13.75 years from the archives of Ragas Dental College and Hospital, Chennai, India. Demographic details, site, details of habits, and grade of OSCC were retrieved. Social Package for Social Service version 17.0 was used to analyze the data. Descriptive statistics, Chi-square test, and comparison of mean were employed appropriately. RESULTS: There were 151 OSCC cases, of which 60.9% (92/151) were males, 21.2% (32/151) were aged <= 40 years and 27.82% (42/151) occurred in the tongue. The glossal to extraglossal site ratio was 1:2.6. Predisposing habits were present in 52.4% of glossal OSCC and 82.6% with extra glossal sites (P = 0.000). Besides tobacco, exclusive areca nut chewing was observed in 15.23% (23/151) patients. Thirty-nine (25.8%) belonged to non tobacco, non-areca nut, non-alcohol (NTND) group with male to female ratio was 1:3. DISCUSSION: In our cohort, 112 of 151 OSCC (74.8%) had at least one predisposing habit. Chewing of areca nut alone was a predisposing habit by itself. In addition, there was a small, subset of cases that were not associated with history of any habits. This study brings to focus the subsets of OSCC predisposed by areca nut and NTND, that needs to be studied further. PMID- 26960499 TI - Irreversible cerebellar toxicity after infusional 5-flurouracil therapy. PMID- 26960500 TI - Efficacy of second-line erlotinib in patients postprogression of first-line chemotherapy in head and neck cancers. AB - BACKGROUND: Oral tyrosine kinase inhibitor (gefitinib and erlotinib) have been used in the palliative treatment of head and neck cancers with limited success. In this report, we aim to quantify the symptomatic benefit, progression-free survival (PFS) and overall survival (OS) when erlotinib is given as second-line treatment in Head and neck cancers. METHODS: This was a post-hoc retrospective analysis of a randomized study comparing metronomic chemotherapy with cisplatin. A patient who progressed on chemotherapy and had a PS0-2 were offered second-line chemotherapy. Patients who had received erlotinib (150 mg PO OD) as second line treatment were selected for this analysis. Erlotinib was discontinued in case of either progression of disease or if the patient had intolerable side effects. Patient were monitored 1-week after the start of erlotinib and subsequently at monthly intervals. The toxicity was recorded in accordance with CTCAE version 4.02 (NCI,USA) and the response were graded in accordance with RECIST version 1.1. All of these patients were followed-up till death. RESULTS: Twenty-three patients were identified. The median age of these patients at the start of the second line was 47 years (interquartile range 40.5-51.75 years). The primary site of distribution was oral cavity primary in 17 patients (77.3%) and nonoral cavity primary in 05 (22.7%) patients. The immediate last chemotherapy regimen received was cisplatin in 9 patients (40.9%) and metronomic chemotherapy in 13 patients (59.1%). Symptomatic benefits post second-line erlotinib was seen in 18 patients (81.8%). The most common adverse events (any grade) seen were anemia in 20 patients (90.9%), rash in 10 patients (45.5%) and diarrhea in 7 patients (31.8%).The best radiological response documented were a partial response in 04 patients (19.2%). The median estimated PFS and OS were 110 days (95% confidence interval [CI]: 61-175 days) and 156 days (95% CI: 126-185 days) respectively. CONCLUSION: Erlotinib single agent has promising activity in the second line and needs to be explored in future studies. PMID- 26960501 TI - Does the use of induction chemotherapy in oral cavity cancer compromise subsequent loco-regional treatment delivery: Results from a matched pair analysis. AB - BACKGROUND: Neoadjuvant chemotherapy is being increasingly used in patients with unresectable oral cavity cancers to make them resectable. However, its impact on locoregional treatment delivery in such setting remains poorly studied. AIMS: To evaluate the impact of neoadjuvant chemotherapy on delivery of further locoregional treatment. SETTINGS AND DESIGN: Mono institutional retrospective audit of patients with oral cavity squamous cell cancers treated with neoadjuvant triplet chemotherapy in India. MATERIALS AND METHODS: Patients receiving neoadjuvant chemotherapy (n = 14) from May 2012 to April 2014 were matched 1:2 to patients undergoing upfront surgery (n = 28) based on age (>60 or 60 and less), gender (male or female) and subsite site (tongue and floor of mouth or buccoalveolar complex). Data regarding factors related to the delivery of locoregional treatment and toxicities were compiled. STATISTICAL ANALYSIS: Descriptive analysis in the form of median (range) for continuous variables and frequencies for categorical variables. RESULTS: Patients undergoing neoadjuvant chemotherapy required more extensive resections and had greater operative time (460 vs. 415 min, P < 0.001). A greater incidence of locoregional wound complications was seen as a consequence (57.1% vs. 14.3%, P, 0.01). However, toxicities during radiotherapy were not substantially different between the two groups and compliance to radiation was also similar. Total package time of 100 days or less, was maintained in 90% of patients in both groups. CONCLUSIONS: Delivery of neoadjuvant chemotherapy does not impair the ability to deliver locoregional treatment. PMID- 26960502 TI - Primary neuroendocrine carcinoma of the breast: A rare and distinct entity. PMID- 26960503 TI - Brachytherapy in modern oncology practice: A survey based assessment of knowledge levels among oncology professionals and need for comprehensive oncology education. PMID- 26960504 TI - The influence of the bowel and bladder preparation protocol for radiotherapy of prostate cancer using kilo-voltage cone beam CT: Our experience. AB - The purpose of this study is to determine the influence of bladder and bowel preparation protocols on the dose-volume histograms (DVHs) of these organs using the cone beam computed tomography (CBCT)-based intensity modulated radiotherapy (IMRT) treatment planning for prostate cancer patients. The pelvic DVHs of 12 prostate cancer patients were studied using CBCT images obtained immediately before each treatment. Six patients had bladder and bowel preparation protocol whilst the other six patients were the control group. Contoured bladder and rectal volumes on CBCT images were compared with planning computed tomography. All patients were treated with IMRT with 7800 cGy in 39 fractions over 8 weeks. Compared with the patient with bladder preparation protocol, patients without bladder preparation instruction had higher bladder volume and dose variation. The maximum variation in bladder volume was as high as 98% in the control group. Without bowel preparation protocol, the rectal volumes were more variability. Owing to changes in rectal filling on the day of treatment, the maximum variation in rectal volume was as high as + 96%. With bowel preparation protocol, the maximum rectum volume variations were less than 25%. The changes in prostate target dose compared with planning dose were minimal as would be expected from positioning with daily image guidance and gold seed implanted. PMID- 26960505 TI - Low-grade papillary adenocarcinoma of minor salivary glands in pregnancy. PMID- 26960506 TI - Outcome of radical prostatectomy as primary treatment for high-risk prostate cancer patients. AB - CONTEXT: Recently, there has been considerable interest in the role of radical prostatectomy (RP) in men with high-risk prostate cancer. AIMS: The objective of our study is to report the outcome of upfront RP in our patients with high-risk prostate cancer (Stage >= cT2c, a pre-operative serum prostate specific antigen >20 ng/ml or a biopsy Gleason score [GS] 8-10). SUBJECTS AND METHODS: From 1996 to 2010, 208 patients of prostate cancer (high risk category D'Amico's criteria) underwent open RP with bilateral pelvic lymphadenectomy. STATISTICAL ANALYSIS USED: The data was statistically analyzed using Kaplan Meier method and log rank test to calculate progression free, metastasis free survival (MFS) and cancer specific survival (CSS). Furthermore multivariate analysis (MVA) was carried out using SPSS 14 software. (IBM company). RESULTS: At 7 and 10 years, prostate cancer-specific survival (PCSS) was found to be 79.7% and 65%, respectively, biochemical recurrence free survival (BRFS) was 42.4% and 36.7%, respectively and the MFS was 71.1% and 64.4% respectively. High GS was highly predictable of PCSS, BRFS and MFS. Node positivity was the single poor risk factor on MVA whereas biopsy GS, pStage (P = 0.016) and seminal vesicle invasion (P = 0.045) had statistical significance in predicting the MFS. CONCLUSIONS: RP provides accurate pathologic staging of patients with high risk prostate cancer, allows better stratification of patients for further adjuvant therapy and either as an initial approach or part of a multimodal regimen, can provide durable local control and provides excellent CSS. PMID- 26960507 TI - Role of PET-CT versus MRI in carcinoma breast: Which one is indicated for detecting the primary? PMID- 26960508 TI - Hypofractionated radiotherapy for localized prostate cancer using three dimensional conformal radiotherapy technique: 3 years toxicity analysis. AB - BACKGROUND: Hypofractionated radiotherapy in the radical treatment of localized prostate cancer has potential biological advantages relative to conventional fractionation. We report prospectively collected toxicity data from a cohort of patients treated with a 3D conformal technique (3DCRT). MATERIALS AND METHODS: 90 patients receiving curative intent hypofractionated radiotherapy with 57Gy in 19 daily fractions over 3.8 weeks were evaluated prospectively for the development of radiation related toxicity over a 3 year period. RESULTS: All patients completed treatment. Maximal acute toxicity experienced was 58.6, 10 and 1.1% for grade 1, 2 and 3 genitourinary (GU) toxicity respectively and 75.6, 9 and 0% for gastrointestinal (GI) toxicity. For late toxicity the three year actuarial rates of grade 1, 2 and 3 GU and GI toxicity respectively were 47.3, 2.4 and 0%; and 40, 9.3 and 4.7%. There were no grade 4 or worse acute or late toxicities. 97.6% of evaluable patients remained free of biochemical failure 36 months post radiotherapy. CONCLUSIONS: A 57Gy in 19 daily fraction radiotherapy schedule using 3D conformal radiotherapy for the definitive treatment of localized prostate cancer has acceptable early and late toxicity. PMID- 26960509 TI - Line of abiraterone acetate in castration-resistant metastatic prostate cancer- Does it matter? report of a multi-institutional experience. AB - OBJECTIVE: We present our data comparing retrospectively the efficacy of abiraterone and cabazitaxel in patients who progress after docetaxel treatment. PATIENTS AND METHODS: The study included 56 patients diagnosed with hormone refractory metastatic prostate cancer who were previously treated with abiraterone therapy at four oncology centers in Turkey. RESULTS: With abiraterone, the patients had a median progression-free survival (PFS) of 5.9 months (95% confidence interval (CI) for hazard ratio (HR) (4.4-7.4)) and an overall survival of 13.4 months (95% CI for HR (5.5-21.3)). When we compared the disease-free survival (DFS) of reference patients treated with cabazitaxel as a second-line treatment with those receiving second-line abiraterone therapy, there was no significant difference. (PFS = 5.9 months with cabazitaxel vs. 6.7 months with abiraterone, P = 0.213). CONCLUSION: This study has shown that in our experience abiraterone acetate is an effective agent in metastatic castration resistant prostate cancer (mCRPC) regardless of the line of treatment. PMID- 26960510 TI - Aggressive spinal glioblastoma in a child with adrenocortical adenoma--Case report and review of literature. PMID- 26960511 TI - A review on harmful effects of pan masala. AB - Pan masala (PM) is a mixture of areca nut with slaked lime, catechu and other flavoring agents. It is widely available and used by all the sections of the Indian society. It is genotoxic as it increases sister chromatin exchange and chromatin aberrations. Among humans, it is a leading cause of oral submucous fibrosis that often progresses to oral cancer. Among experimental animals, it leads to neoplastic lesions in lung, liver and stomach. It is hepatotoxic leading to increased level of enzymes, deranged carbohydrate and lipid metabolism. It is harmful to kidneys and testes leading to increased creatinine and sperm deformities respectively. PM is a very harmful substance affecting almost all organ systems, and there is immediate need for a national policy on complete ban on the production, storage, sale and marketing of PM. PMID- 26960512 TI - Metachronous intradural and liver metastasis from adrenocortical carcinoma. PMID- 26960513 TI - Inflammatory pseudotumor of the pharynx: A rare entity. PMID- 26960515 TI - Subcutaneous panniculitis-like T-cell lymphoma: A report of five cases with review of literature. PMID- 26960514 TI - Dosimetric evaluation and clinical outcome in post-operative patients of carcinoma vulva treated with intensity-modulated radiotherapy. AB - BACKGROUND: To compare dosimetric parameters of intensity-modulated radiation therapy (IMRT) with 3D conformal radiotherapy (3DCRT) in post-operative patients of vulvar cancer and to assess clinical outcome and toxicity with IMRT. MATERIALS AND METHODS: A total of 8 post-operative patients of vulvar cancer were treated with IMRT. All patients were also planned by 3DCRT for comparison with IMRT. The two plans were compared in terms of conformity index, homogeneity index, tumor control probability (TCP) and normal tissue complication probability (NTCP) for the planning target volume and organs at risk (OAR). RESULTS: IMRT resulted in significantly lesser doses to rectum, bladder, bowel and femoral head as compared with 3DCRT plans. Mean conformity and homogeneity indices were better and within range with IMRT. The TCP was comparable between the two treatment plans and NTCP for rectum, bladder, bowel and femoral head was significantly less with IMRT as compared with 3DCRT. Treatment was well-tolerated and none of the patients developed Grade 3 or higher toxicity. CONCLUSION: IMRT yielded superior plans with respect to target coverage, homogeneity and conformality while lowering dose to adjacent OAR as compared with 3DCRT. Thus, IMRT offers a reduction in NTCP while maintaining TCP. PMID- 26960516 TI - Discrepancy between clinicoradiological and surgicopathological staging in stage 1 carcinoma endometrium: Identification of risk factors. AB - INTRODUCTION: Carcinoma endometrium carries an excellent prognosis when diagnosed early. But controversies exist in the management of Ca endometrium confined to the uterus as to whether a complete surgical staging including lymph node dissection is needed always. This may increase unnecessary surgical morbidity for some. On the other hand, if not done it fails to recognize a subset of patients who require adjuvant treatment, thus affecting the outcome. Hence it is very important to categorize the patients to assess the need of complete surgical staging. AIM: The aim of the following study is to identify the risk factors influencing the upstaging of disease in clinicoradiologically stage 1 carcinoma endometrium. MATERIALS AND METHODS: A retrospective database evaluation of all cases of clinicoradiologically stage 1 carcinoma endometrium from January 2009 to September 2012. STATISTICAL ANALYSIS: Done using the statistical software SPSS- version 16 for windows (SPSS Inc. 233 South Wacker Drive, 11th Floor Chicago, IL 60606-6412) Independent samples test (t-test for equality of means) were done and (two-tailed) P < 0.05--were significant. RESULTS: Carcinoma endometrium patients with grade 1, no or < 50% myometrial involvement, <2 cm size and no isthmus involvement had low risk of upstaging. CONCLUSION: Significant upstaging is seen in the present study with per-operative staging procedures. Until the standardization of magnetic resonance imaging (MRI) techniques and reporting, or until a more sensitive non-invasive technique is devised, staging lymphadenectomy appears to be invaluable in risk assessment and prognosis. PMID- 26960517 TI - Secondary plasmacytoma of the testis with hydrocele: A rare case report. PMID- 26960519 TI - Impact of modular training on tobacco control on the knowledge of health workers in two jurisdictions of northern India. AB - BACKGROUND: National Tobacco Control Programme was launched in India in year 2007 08. It was realized that community health workers can play an important role of agents for positive change to bring down the tobacco morbidity and mortality in the country. Keeping this in view, a health worker guide was developed by the Government of India, Ministry of Health and Family Welfare (GOI) in collaboration with The Union South-East Asia (The Union) in the year 2010. The guide provides the information needed by the most basic level of health workers to effectively address the problem of tobacco use in the community. A modular training was conducted in two jurisdictions in India (namely, Chandigarh and Hamirpur (Himachal Pradesh)) to assess the usefulness of the guide as training material for community health workers in undertaking tobacco control activities at community and village levels. MATERIALS AND METHODS: A total of 271 participants were trained, which included 133 from Chandigarh and 138 from Hamirpur. The pre and post-training assessment of knowledge of health worker was done. RESULTS: There was marked increase in post-test scores as compared to the pretest scores. The health workers scoring more than 60% increased from 40% in the pretest to over 80% in the post-test. Only three workers had a post-test score of less than 30% against 54 workers in the pretest. CONCLUSION: The understanding on tobacco control had increased significantly after the training in each group. It is strongly recommended that such training should be replicated to all community health workers across all the states in India. PMID- 26960518 TI - Tumor recurrence and tumor-related mortality in endometrial cancer: Analysis in 276 patients. AB - BACKGROUND: In this manuscript, we assessed tumor recurrence and tumor-related mortality in a clinical series of endometrial cancer patients. MATERIALS AND METHODS: A retrospective evaluation of 276 patients (mean age 64 years) with histologically confirmed endometrial cancer treated at a single hospital in Madrid (Spain) was conducted. The median follow-up was estimated using the inverse Kaplan-Meier method. RESULTS: Salient findings were endometrioid carcinoma (84.8% of cases), grade G1 (48.9%) and stages IB (35.1%) and IC (23.2%). Myometrial infiltration >50% was documented in 31.2% of cases and lymphovascular space invasion in 11.9%. After surgery, 52.5% of patients were classified into the low risk group, 21.4% into the intermediate risk group and 26.1% into the high risk group. Tumor recurrence occurred in 14.5% of patients, with an estimated median follow-up of 45 months (95% confidence interval (CI): 41.2-48.8), locoregional recurrence in 42.5% and distant recurrences in 57.5%. Furthermore, 40% of tumor recurrences developed during the first year after primary treatment and 90% over the first 3 years of follow-up. The tumor-related mortality rate was 15.9%. The estimated median follow-up was 46 months (95% CI: 43.0-49.0). Furthermore, 5.07% of death because of tumor developed during the first year after primary treatment and 13.77% over the first 3 years of follow up. CONCLUSION: The rates of tumor-related death and tumor recurrence in endometrial cancer patients are low, with the highest percentages occurring within 3 years of primary treatment. Most of the recurrences occur outside the pelvis. PMID- 26960520 TI - Intrascrotal paratesticular malignant fibrous histiocytoma-a rare case and its management. PMID- 26960521 TI - Tobacco use among high school children in Bangalore, India: A study of knowledge, attitude and practice. AB - INTRODUCTION: Tobacco use among school children is becoming a serious problem in developing countries. The early age of initiation underscores the urgent need to intervene and protect this vulnerable group from becoming victims of this addiction. AIM: To assess the knowledge, attitudes, and practices about tobacco use among 13-15 year old school children of Bangalore City. MATERIALS AND METHODS: A cross-sectional study was designed and data on tobacco usage was collected from 1288 students aged 13-15 years studying in six government and private schools of Bangalore using a self-administered closed ended questionnaire. Data was analyzed using SPSS 15.0 and descriptive statistics was applied. Chi-square tests were used to determine the significant differences in the variables of interest. RESULTS: Out of 1288 children, 1281 (99.5%) children had heard about tobacco and 1162 (90.2%) students knew the harmful effects of tobacco. Only 28 (2.2%) had used tobacco products. Peer pressure was the main reason for tobacco use among children and age was not a barrier in buying tobacco products. Television (58%) was the main source of information for tobacco products followed by newspapers (26%) and movies (16%). CONCLUSION: It is encouraging to find that majority of the 13-15 year old children surveyed in the present study did not use tobacco and were aware of the health risks associated with tobacco use. This calls for the school authorities to be included in stricter implementation and monitoring of the implementation of legislation. Regular and systematic education programs catering to teachers, children, and also their parents should be undertaken. PMID- 26960522 TI - Perception of young adults toward hookah use in Mumbai. AB - BACKGROUND: The use of tobacco has been on the rise globally including in India, posing a grave public health problem. Recently, tobacco use through hookah smoking has increased among young adults in India, Middle East, Southwest Asia, Africa, Europe and North America. Hookah prevalence of 0.4-15% has been reported in India. AIM: The aim of the study was to understand perception of hookah use among young adults in Mumbai. MATERIALS AND METHODS: A total of 500 college students, with/without hookah habit, were given a self-administered questionnaire to indicate their perception of hookah use, using yes/no responses. The responses were analyzed in the users/non-users and considered significantly different at P < 0.05. RESULTS: Responses were received from 122 hookah users and 325 non-users. The perception of hookah use between users and non-users and males and females, showed significant differences (P < 0.05), with respect to hookah being injurious to health, causes cancer, is addictive, influence of a close friend, flavors, curiosity toward hookah use and willingness to prepare hookah at home. Whereas, differences in the groups perception of hookah as safer than cigarettes, harmful air quality, ambience, cool look and means of socializing, was not observed. CONCLUSION: The perception of young adults in Mumbai, toward hookah use, indicates an increased trend to use hookah. We recommend deterrents for hookah use by display of health warnings on hookah assembly and the tobacco products, implementation of government policies on hookah and tobacco use and punitive measures for offenders. PMID- 26960523 TI - Bizarre leiomyoma of uterus/smooth muscle tumor of uncertain malignant potential: A diagnostic dilemma. PMID- 26960524 TI - Tobacco use among rural Nepalese women: Cross-sectional community based study. AB - INTRODUCTION: Tobacco use is responsible for a considerable number of morbidity and mortality in the world. Annually 14,000 deaths are attributed to tobacco use in Nepal. Despite having social acceptability of tobacco in Nepalese society, little has been known about tobacco use among rural women. The aim of this study was to report the prevalence of and examine the factors associated with tobacco consumption among women of reproductive age in a rural community of Dailekh district of Nepal. MATERIALS AND METHODS: It was descriptive, cross-sectional study carried out among women of reproductive age in the rural community of Dailekh district. A random sampling was used to obtain 110 women aged 15-49 years. RESULTS: More than two in five were tobacco user and among them 4 in 5 used smoked form of tobacco. This study showed early initiation of tobacco using habit (mean: 14.96 year) where 92% of participants initiated <19 years. Influencing factors for initiation of tobacco use was peer's pressure (95.8%), and respondents reported that they used tobacco to reduce stress (37.5%). CONCLUSION: Tobacco using pattern was high in reproductive age group women. Knowledge and perceptions on tobacco use were poor. Hence, an effective and appropriate community based awareness programs are required to discourage the use of tobacco. PMID- 26960525 TI - Giant cell glioblastoma with calcification and long-term survival. PMID- 26960526 TI - The unnoticed umbilical nodule of ovarian malignancy with seudomyxomaperitonei: A rare presentation. PMID- 26960527 TI - Indoor air quality due to secondhand smoke: Signals from selected hospitality locations in rural and urban areas of Bangalore and Dharwad districts in Karnataka, India. AB - BACKGROUND: Tobacco smoke has compounds that are known as human carcinogens. With every breath of secondhand smoke we inhale thousands of chemicals. The Government of India in the interest of public health has enacted the Cigarette and Other Tobacco Products Act (COTPA), 2003, which bans smoking in all the public places including hotels and restaurants. The purpose of this study was to observe and record air pollution in smoke free and smoke observed locations and thereby find out whether the owners/managers of hotels, restaurants, and bars comply with rules of COTPA. OBJECTIVES: The objectives of the study were to measure and compare the level of particulate air pollution from secondhand smoke (PM2.5) in smoking and nonsmoking venues. MATERIALS AND METHODS: The study was conducted from September 2009 to March 2010 in Karnataka, India following a nonrandom sample of 79 locations, which included restaurants, bars, cafes, hotels, and tea stalls in two districts. The concentration of PM2.5 was measured using a TSI SidePak AM510 Personal Aerosol Monitor. RESULTS: In Karnataka out of the 79 hospitality locations, smoking was observed in 58% places and only 28% had displayed the required "No Smoking" signage. Places where indoor smoking was observed had high levels of air pollution with average 135 PM2.5, which were 3.1 times higher than the average 43 PM2.5 in smoke-free locations and 14 times higher than the World Health Organization (WHO) target air quality guideline for PM2.5. The average PM2.5 levels in different locations ranged from 11 to 417 MUg/m(3) and was lower in the case of apparently compliant designated smoking area (DSR). CONCLUSIONS: The patrons and the workers in the hospitality sector continue to be exposed to secondhand smoke despite the enactment of COTPA, which bans smoking in public places. This situation demands stringent measures for effective implementation of the Smoke Free Act and negative response to smoking among civil society. PMID- 26960528 TI - Rash: An initial presentation of ovarian cancer. PMID- 26960530 TI - Prevention of Tetanus Outbreak Following Natural Disaster in Indonesia: Lessons Learned from Previous Disasters. AB - In Indonesia, the Aceh earthquake and tsunami in 2004 killed 127,000 people and caused half a million injuries, while the Yogyakarta earthquake in 2006 caused 5,700 deaths and 37,000 injuries. Because disaster-affected areas are vulnerable to epidemic-prone diseases and tetanus is one such disease that is preventable, we systematically reviewed the literature related to tetanus outbreaks following previous two natural disasters in Indonesia. Based on our findings, recommendations for proper vaccination and education can be made for future countermeasures. Using specified keywords related to tetanus and disasters, relevant documents were screened from PubMed, the WHO website, and books. Reports offering limited data and those released before 2004 were excluded. In all, 16 publications were reviewed systematically. Results show that 106 cases of tetanus occurred in Aceh, with a case fatality ratio (CFR) of 18.9%; 71 cases occurred in Yogyakarta, with CFR of 36.6%. For both outbreaks, most patients had been wounded during scavenging or evacuation after the disaster occurred. Poor access to health care because of limited transportation or hospital facilities, and low vaccination coverage and lack of awareness of tetanus risk contributed to delayed treatment and case severity. Tetanus outbreaks after disasters are preventable by increasing vaccination coverage, improving wound care treatment, and establishing a regular surveillance system, in addition to good practices of disaster management and supportive care following national guidelines. Furthermore, health education for communities should be provided to raise awareness of tetanus risk reduction. PMID- 26960531 TI - Relaxation Dynamics and Magnetic Anisotropy in a Low-Symmetry Dy(III) Complex. AB - The magnetic behaviour of a Dy(LH)3 complex (LH(-) is the anion of 2-hydroxy-N' [(E)-(2-hydroxy-3-methoxyphenyl)methylidene]benzhydrazide) was analysed in depth from both theoretical and experimental points of view. Cantilever torque magnetometry indicated that the complex has Ising-type anisotropy, and provided two possible directions for the easy axis of anisotropy due to the presence of two magnetically non-equivalent molecules in the crystal. Ab initio calculations confirmed the strong Ising-type anisotropy and disentangled the two possible orientations. The computed results obtained by using ab initio calculations were then used to rationalise the composite dynamic behaviour observed for both pure Dy(III) phase and Y(III) diluted phase, which showed two different relaxation channels in zero and non-zero static magnetic fields. In particular, we showed that the relaxation behaviour at the higher temperature range can be correctly reproduced by using a master matrix approach, which suggests that Orbach relaxation is occurring through a second excited doublet. PMID- 26960529 TI - Urban and transport planning, environmental exposures and health-new concepts, methods and tools to improve health in cities. AB - BACKGROUND: The majority of people live in cities and urbanization is continuing worldwide. Cities have long been known to be society's predominant engine of innovation and wealth creation, yet they are also a main source of pollution and disease. METHODS: We conducted a review around the topic urban and transport planning, environmental exposures and health and describe the findings. RESULTS: Within cities there is considerable variation in the levels of environmental exposures such as air pollution, noise, temperature and green space. Emerging evidence suggests that urban and transport planning indicators such as road network, distance to major roads, and traffic density, household density, industry and natural and green space explain a large proportion of the variability. Personal behavior including mobility adds further variability to personal exposures, determines variability in green space and UV exposure, and can provide increased levels of physical activity. Air pollution, noise and temperature have been associated with adverse health effects including increased morbidity and premature mortality, UV and green space with both positive and negative health effects and physical activity with many health benefits. In many cities there is still scope for further improvement in environmental quality through targeted policies. Making cities 'green and healthy' goes far beyond simply reducing CO2 emissions. Environmental factors are highly modifiable, and environmental interventions at the community level, such as urban and transport planning, have been shown to be promising and more cost effective than interventions at the individual level. However, the urban environment is a complex interlinked system. Decision-makers need not only better data on the complexity of factors in environmental and developmental processes affecting human health, but also enhanced understanding of the linkages to be able to know at which level to target their actions. New research tools, methods and paradigms such as geographical information systems, smartphones, and other GPS devices, small sensors to measure environmental exposures, remote sensing and the exposome paradigm together with citizens observatories and science and health impact assessment can now provide this information. CONCLUSION: While in cities there are often silos of urban planning, mobility and transport, parks and green space, environmental department, (public) health department that do not work together well enough, multi-sectorial approaches are needed to tackle the environmental problems. The city of the future needs to be a green city, a social city, an active city, a healthy city. PMID- 26960532 TI - Teaching and assessment of communication skills in undergraduate dental education - a survey in German-speaking countries. AB - INTRODUCTION: Teaching communication is perceived to be of importance in dental education. Several reports have been published worldwide in the educational literature describing modifications of the dental curriculum by implementing the teaching of communication skills. Surveys which evaluate the current state of training and assessment of communication skills in dental education in different countries exist already in some countries, but little information is available about German-speaking countries. MATERIAL AND METHODS: In a cross-sectional study with the aim of a census, all 36 dental schools in Germany (30), Austria (3), and Switzerland (3) were surveyed. RESULTS: The present survey revealed that at 26 of the 34 dental schools (76%), communication skills training has been implemented. Training of communication skills mainly takes place between the 6th and the 9th semester. Ten schools were able to implement a partly longitudinal curriculum, while the other sites only offer stand-alone courses. Of the 34 dental schools, six assess communication skills in a summative way. Three of those schools also use formative assessments for their students. Another seven sites only use formative assessment. From the various formats of assessment, OSCE is mentioned most frequently. CONCLUSION: The necessity to train and assess communication skills has reached German-speaking dental schools. The present survey allows an overview of the training and assessment of communication skills in undergraduate dental education in German-speaking Europe. PMID- 26960534 TI - Characteristics of neurocognitive functions in mild cognitive impairment with depression. AB - BACKGROUND: Previous studies suggest that there is a strong association between depression and cognitive decline, and that concurrent depressive symptoms in MCI patients could contribute to a difference in neurocognitive characteristics compared to MCI patients without depression. The authors tried to compare neurocognitive functions between MCI patients with and without depression by analyzing the results of neuropsychological tests. METHODS: Participants included 153 MCI patients. Based on the diagnosis of major depressive disorder, the participants were divided into two groups: depressed MCI (MCI/D+) versus non depressed MCI (MCI/D-). The general cognitive and functional statuses of participants were evaluated. And a subset of various neuropsychological tests was presented to participants. Demographic and clinical data were analyzed using Student t-test or chi 2 test. RESULTS: A total of 153 participants were divided into two groups: 94 MCI/D+ patients and 59 MCI/D- patients. Age, sex, and years of education were not significantly different between the two groups. There were no significant differences in general cognitive status between MCI/D+ and MCI/D- patients, but MCI/D+ participants showed significantly reduced performance in the six subtests (Contrasting Program, Go-no-go task, Fist-edge-palm task, Constructional Praxis, Memory Recall, TMT-A) compared with MCI/D- patients. CONCLUSIONS: There were significantly greater deficits in neurocognitive functions including verbal memory, executive function, attention/processing speed, and visual memory in MCI/D+ participants compared to MCI/D-. Once the biological mechanism is identified, distinct approaches in treatment or prevention will be determined. PMID- 26960533 TI - Atypical sensors for direct and rapid neuronal detection of bacterial pathogens. AB - Bacterial infection can threaten the normal biological functions of a host, often leading to a disease. Hosts have developed complex immune systems to cope with the danger. Preceding the elimination of pathogens, selective recognition of the non-self invaders is necessary. At the forefront of the body's defenses are the innate immune cells, which are equipped with particular sensor molecules that can detect common exterior patterns of invading pathogens and their secreting toxins as well as with phagocytic machinery. Inflammatory mediators and cytokines released from these innate immune cells and infected tissues can boost the inflammatory cascade and further recruit adaptive immune cells to maximize the elimination and resolution. The nervous system also seems to interact with this process, mostly known to be affected by the inflammatory mediators through the binding of neuronal receptors, consequently activating neural circuits that tune the local and systemic inflammatory states. Recent research has suggested new contact points: direct interactions of sensory neurons with pathogens. Latest findings demonstrated that the sensory neurons not only share pattern recognition mechanisms with innate immune cells, but also utilize endogenous and exogenous electrogenic components for bacterial pathogen detection, by which the electrical firing prompts faster information flow than what could be achieved when the immune system is solely involved. As a result, rapid pain generation and active accommodation of the immune status occur. Here we introduced the sensory neuron specific detector molecules for directly responding to bacterial pathogens and their signaling mechanisms. We also discussed extended issues that need to be explored in the future. PMID- 26960535 TI - Mesenchymal stem cells and cutaneous wound healing: novel methods to increase cell delivery and therapeutic efficacy. AB - Mesenchymal stem cells (MSCs) (also known as multipotent mesenchymal stromal cells) possess the capacity for self-renewal and multi-lineage differentiation, and their ability to enhance cutaneous wound healing has been well characterized. Acting via paracrine interactions, MSCs accelerate wound closure, increase angiogenesis, promote resolution of wound inflammation, favorably regulate extracellular matrix remodeling, and encourage regeneration of skin with normal architecture and function. A number of studies have employed novel methods to amplify the delivery and efficacy of MSCs. Non-traditional sources of MSCs, including Wharton's jelly and medical waste material, have shown efficacy comparable to that of traditional sources, such as bone marrow and adipose tissue. The potential of alternative methods to both introduce MSCs into wounds and increase migration of MSCs into wound areas has also been demonstrated. Taking advantage of the associations between MSCs with M2 macrophages and microRNA, methods to enhance the immunomodulatory capacity of MSCs have shown success. New measures to enhance angiogenic capabilities have also exhibited effectiveness, often demonstrated by increased levels of proangiogenic vascular endothelial growth factor. Finally, hypoxia has been shown to have strong wound healing potential in terms of increasing MSC efficacy. We have critically reviewed the results of the novel studies that show promise for the continued development of MSC-based wound-healing therapies and provide direction for continued research in this field. PMID- 26960536 TI - The performance of model-based versus rule-based phase I clinical trials in oncology : A quantitative comparison of the performance of model-based versus rule-based phase I trials with molecularly targeted anticancer drugs over the last 2 years. AB - Phase I studies with anticancer drugs are used to evaluate safety and tolerability and to choose a recommended phase II dose (RP2D). Traditionally, phase I trial designs are rule-based, but for several years there is a trend towards model-based designs. Simulations have shown that model-based designs perform better, faster and are safer to establish the RP2D than rule-based designs. However, the superiority of model-based designs has never been confirmed based on true trial performance in practice. To aid evidence-based decisions for designing phase I trials, we compared publications of model-based and rule-based phase I trials in oncology. We reviewed 172 trials that have been published in the last 2 years and assessed the following operating characteristics: efficiency (trial duration, population size, dose-levels), patient safety (dose-limiting toxicities (DLTs)) and treatment optimality (percentage of patients treated below and at or above the recommended phase 2 dose). Our results showed a non significant but clinically relevant difference in trial duration. Model-based trials needed 10 months less than rule-based trials (26 versus 36 months; p = 0.25). Additionally, fewer patients were treated at dose-levels below the RP2D (31 % versus 40 %; p = 0.73) while safety was preserved (13 % DLTs versus 14 % DLTs). In this review, we provide evidence to encourage the use of model-based designs for future phase I studies, based on a median of 10 months of time gain, acceptable toxicity rates and minimization of suboptimal treatment. PMID- 26960537 TI - Real-time SPARSE-SENSE cardiac cine MR imaging: optimization of image reconstruction and sequence validation. AB - OBJECTIVES: Improved real-time cardiac magnetic resonance (CMR) sequences have currently been introduced, but so far only limited practical experience exists. This study aimed at image reconstruction optimization and clinical validation of a new highly accelerated real-time cine SPARSE-SENSE sequence. METHODS: Left ventricular (LV) short-axis stacks of a real-time free-breathing SPARSE-SENSE sequence with high spatiotemporal resolution and of a standard segmented cine SSFP sequence were acquired at 1.5 T in 11 volunteers and 15 patients. To determine the optimal iterations, all volunteers' SPARSE-SENSE images were reconstructed using 10-200 iterations, and contrast ratios, image entropies, and reconstruction times were assessed. Subsequently, the patients' SPARSE-SENSE images were reconstructed with the clinically optimal iterations. LV volumetric values were evaluated and compared between both sequences. RESULTS: Sufficient image quality and acceptable reconstruction times were achieved when using 80 iterations. Bland-Altman plots and Passing-Bablok regression showed good agreement for all volumetric parameters. CONCLUSIONS: 80 iterations are recommended for iterative SPARSE-SENSE image reconstruction in clinical routine. Real-time cine SPARSE-SENSE yielded comparable volumetric results as the current standard SSFP sequence. Due to its intrinsic low image acquisition times, real time cine SPARSE-SENSE imaging with iterative image reconstruction seems to be an attractive alternative for LV function analysis. KEY POINTS: * A highly accelerated real-time CMR sequence using SPARSE-SENSE was evaluated. * SPARSE SENSE allows free breathing in real-time cardiac cine imaging. * For clinically optimal SPARSE-SENSE image reconstruction, 80 iterations are recommended. * Real time SPARSE-SENSE imaging yielded comparable volumetric results as the reference SSFP sequence. * The fast SPARSE-SENSE sequence is an attractive alternative to standard SSFP sequences. PMID- 26960538 TI - Safety of gadobutrol in over 23,000 patients: the GARDIAN study, a global multicentre, prospective, non-interventional study. AB - OBJECTIVES: To investigate the safety and tolerability of gadobutrol at the recommended dose in patients requiring contrast-enhanced magnetic resonance imaging/angiography (MRI/MRA) in the routine setting. METHODS: GARDIAN prospectively enrolled 23,708 patients undergoing routine gadobutrol-enhanced MRI/MRA for approved indications at 272 study centres in Europe, Asia, North America, and Africa and monitored for adverse events. RESULTS: Median gadobutrol dose was 0.11 mmol/kg body weight. The overall incidence of adverse drug reactions (ADRs) was 0.7 % (n = 170 patients), with similar incidences in patients with renal impairment or cardiac disease, from different geographic regions and in different gadobutrol dose groups. Patients at risk for contrast media reaction had an ADR incidence of 2.5 %. Five patients (0.02 %) experienced serious adverse events, four were drug-related. One patient experienced a fatal anaphylactoid shock, assessed to be related to injection of gadobutrol. The contrast quality of gadobutrol-enhanced images was rated by treating physicians as good or excellent in 97 % cases, with similar ratings in all patient subgroups and indications. CONCLUSIONS: The GARDIAN study shows that gadobutrol at the recommended dose is well tolerated across a large, diverse patient population. KEY POINTS: * Gadobutrol at recommended dose shows low rates of adverse drug reactions * Gadobutrol demonstrates a uniform safety profile across diverse patient groups * Gadobutrol provides excellent contrast quality in routine practice. PMID- 26960539 TI - Adipose tissue and muscle attenuation as novel biomarkers predicting mortality in patients with extremity sarcomas. AB - OBJECTIVES: To assess CT-attenuation of abdominal adipose tissue and psoas muscle as predictors of mortality in patients with sarcomas of the extremities. METHODS: Our study was IRB approved and HIPAA compliant. The study group comprised 135 patients with history of extremity sarcoma (mean age: 53 +/- 17 years) who underwent whole body PET/CT. Abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and psoas muscle attenuation (HU) was assessed on non-contrast, attenuation-correction CT. Clinical information including survival, tumour stage, sarcoma type, therapy and pre-existing comorbidities were recorded. Cox proportional hazard models were used to determine longitudinal associations between adipose tissue and muscle attenuation and mortality. RESULTS: There were 47 deaths over a mean follow-up period of 20 +/- 17 months. Higher SAT and lower psoas attenuation were associated with increased mortality (p = 0.03 and p = 0.005, respectively), which remained significant after adjustment for age, BMI, sex, tumor stage, therapy, and comorbidities (p = 0.002 and p = 0.02, respectively). VAT attenuation was not associated with mortality. CONCLUSION: Attenuation of SAT and psoas muscle, assessed on non-contrast CT, are predictors of mortality in patients with extremity sarcomas, independent of other established prognostic factors, suggesting that adipose tissue and muscle attenuation could serve as novel biomarkers for mortality in patients with sarcomas. KEY POINTS: * CT-attenuation of adipose tissue and muscle predict mortality in sarcoma patients * CT-attenuation predicts mortality independent of established prognostic factors * Patients with sarcomas often undergo CT for staging or surveillance * Adipose tissue and muscle attenuation could serve as biomarkers for mortality. PMID- 26960540 TI - Does size reliably predict malignancy in soft tissue tumours? AB - PURPOSE: In this retrospective study we examined whether size is a viable marker of tumour malignancy in soft tissue masses (STM) and if the ratio of width and length (RALD) of an STM reflects tumour biology more accurately. METHODS: Measurements of maximal lesion size and perpendicular diameter were performed in available MRI and ultrasonography studies of 212 patients (mean age 54.4 +/- 17.2 years, male:female 1:1.12) with a histologically verified diagnosis. RESULTS: Overall, 28.2 % of lesions were malignant, 11.1 % intermediate, and 58.8 % benign. Size alone was a weak predictor of malignancy in STMs (sensitivity 68.8 %, specificity 50.3 %, positive predictive value [PPV] 44.0 %, negative predictive value [NPV] 80.4 %). RALD showed better discriminatory power with greater separation between benign and malignant entities and higher values for sensitivity (83.6 %), specificity (53.6 %), and NPV (89.0 %). A weighted combination of size, age and RALD improved diagnostic power, demonstrating higher values for sensitivity (77.0 %), specificity (80.1 %), PPV (61.0 %), and NPV (89.6 %). CONCLUSIONS: Size should not be used alone to estimate an STM's malignancy. RALD better reflects a lesion's growth pattern and a combination of age, size, and RALD helps to discriminate more accurately between benign, intermediate, and malignant entities. These findings should help to estimate easily whether a newly found STM is benign or malignant prior to further workup. KEY POINTS: *Size does not reliably differentiate between benign, intermediate, and malignant tumours *The R ALD (ratio of lateral to axial diameter) improves diagnostic confidence *When combined with age and size, STM differentiation was further enhanced *These measurements can aid in earlier detection of sarcomas. PMID- 26960541 TI - A noise-optimized virtual monochromatic reconstruction algorithm improves stent visualization and diagnostic accuracy for detection of in-stent re-stenosis in lower extremity run-off CT angiography. AB - PURPOSE: To evaluate the impact of noise-optimized virtual monochromatic imaging (VMI+) on stent visualization and accuracy for in-stent re-stenosis at lower extremity dual-energy CT angiography (DE-CTA). MATERIAL AND METHODS: We evaluated third-generation dual-source DE-CTA studies in 31 patients with prior stent placement. Images were reconstructed with linear blending (F_0.5) and VMI+ at 40 150 keV. In-stent luminal diameter was measured and contrast-to-noise ratio (CNR) calculated. Diagnostic confidence was determined using a five-point scale. In 21 patients with invasive catheter angiography, accuracy for significant re-stenosis (>=50 %) was assessed at F_0.5 and 80 keV-VMI+ chosen as the optimal energy level based on image-quality analysis. RESULTS: At CTA, 45 stents were present. DSA was available for 28 stents whereas 12 stents showed significant re-stenosis. CNR was significantly higher with <=80 keV-VMI+ (17.9 +/- 6.4-33.7 +/- 12.3) compared to F_0.5 (16.9 +/- 4.8; all p < 0.0463); luminal stent diameters were increased at >=70 keV (5.41 +/- 1.8-5.92 +/- 1.7 vs. 5.27 +/- 1.8, all p < 0.001) and diagnostic confidence was highest at 70-80 keV-VMI+ (4.90 +/- 0.48-4.88 +/- 0.63 vs. 4.60 +/- 0.66, p = 0.001, 0.0042). Sensitivity, negative predictive value and accuracy for re-stenosis were higher with 80 keV-VMI+ (100, 100, 96.4 %) than F_0.5 (90.9, 94.1, 89.3 %). CONCLUSION: 80 keV-VMI+ improves image quality, diagnostic confidence and accuracy for stent evaluation at lower extremity DE CTA. KEY POINTS: * The impact of noise-optimized virtual monochromatic imaging on stent visualization was assessed. * Virtual monochromatic imaging significantly improves stent lumen visualization and diagnostic confidence. * At 80 keV diagnostic performance for detection of in-stent restenosis was increased. * 80 keV virtual monochromatic images are recommended for stent evaluation of lower extremity vasculature. PMID- 26960543 TI - Perspectives on the probiotic potential of lactic acid bacteria from African traditional fermented foods and beverages. AB - Diverse African traditional fermented foods and beverages, produced using different types of fermentation, have been used since antiquity because of their numerous nutritional values. Lactic acid bacteria (LAB) isolated from these products have emerged as a welcome source of antimicrobials and therapeutics, and are accepted as probiotics. Probiotics are defined as live microbial food supplements which beneficially affect the host by improving the intestinal microbial balance. Currently, popular probiotics are derived from fermented milk products. However, with the growing number of consumers with lactose intolerance that are affected by dietary cholesterol from milk products, there is a growing global interest in probiotics from other food sources. The focus of this review is to provide an overview of recent developments on the applications of probiotic LAB globally, and to specifically highlight the suitability of African fermented foods and beverages as a viable source of novel probiotics. PMID- 26960544 TI - Effects of quercetin on chronic constriction nerve injury in an experimental rat model. AB - BACKGROUND: Flavonoids are popular substances in the literature, with proven effects on cardiovascular, neoplastic and neurodegenerative diseases. Antioxidant effect is the most pronounced and studied one. Among thousands of flavonoids, quercetin (QUE) is a prototype with significant antioxidant effects. This study aims to demonstrate the effects of QUE in an experimental rat model of chronic constriction injury (CCI). METHOD: A two-level study was designed with 42 adult Wistar rats that were randomly assigned to different groups. In the first part, animals in sham, control, quercetin, morphine and gabapentine groups received chronic constriction injury to their sciatic nerves and received a single dose of QUE, morphine and gabapentine. In the second part, different dose regimens of QUE were administered to different groups of animals. Pre-injury and post-injury assessments for mechanical hypersensitivity, thermal sensitivity, locomotor activity and anxiety were recorded and statistical comparisons were performed between different groups. RESULTS: Comparison of QUE with morphine and gabapentine has revealed significant effects of this agent in the current chronic constriction injury model. QUE was significantly superior to Gabapentine and morphine in terms of alleviating mechanical and thermal hypersensitivity. Additionally, pre-injury administration of QUE for 4 days demonstrated long-term effectiveness on mechanical hypersensitivity. CONCLUSIONS: This preliminary report the on effects of QUE in a chronic constriction injury model proved significant effects of the agent, which should be supplemented with different studies using different dose regimens. PMID- 26960542 TI - MR molecular imaging of tumours using ferritin heavy chain reporter gene expression mediated by the hTERT promoter. AB - OBJECTIVES: Using the human telomerase reverse transcriptase (hTERT) promoter and the modified ferritin heavy chain (Fth) reporter gene, reporter gene expression for MRI was examined in telomerase positive and negative tumour cells and xenografts. METHODS: Activity of the reporter gene expression vector Lenti-hTERT Fth1-3FLAG-Puro was compared to constitutive CMV-driven expression and to the untransfected parental control in five tumour cell lines: A549, SKOV3, 293T, U2OS and HPDLF. In vitro, transfected cells were evaluated for FLAG-tagged protein expression, iron accumulation and transverse relaxation. In vivo, tumours transduced by lentiviral vector injection were imaged using T2*WI. Changes in tumour signal intensity were validated by histology. RESULTS: Only telomerase positive tumour cells expressed FLAG-tagged Fth and displayed an increase in R2* above the parental control, with a corresponding change in T2*WI. In addition, only telomerase positive tumours, transduced by injection of the reporter gene expression construct, exhibited a change in signal intensity on T2*WI. Tumour histology verified the expression of FLAG-tagged Fth and iron accumulation in telomerase positive tissue. CONCLUSION: Reporter gene expression for MRI, using the Fth reporter and the hTERT promoter, may be a useful strategy for the non invasive diagnosis of many types of cancer. KEY POINTS: * Modified heavy chain of ferritin can serve as an MR reporter gene * hTERT promoter can direct the expression of reporter gene in cancer cells * MR reporter imaging mediated by hTERT promoter can be used for cancer diagnosis. PMID- 26960546 TI - First Record of Drosophila buzzatii (Patterson & Wheeler) (Diptera: Drosophilidae) Emerging from a Non-Cactus Host. AB - Drosophila buzzatii (Patterson & Wheeler), a typical cactophilic species of the repleta group, is registered for the first time emerging from Melon (Cucumis melo) in western Argentina. The analysis of inversion polymorphism and genetic diversity of mitochondrial cytochrome oxidase subunit I gene (mtCOI) provided additional evidence that corroborated the presence of a high proportion of D. buzzatii among the flies emerged from melon. This finding set the scenario for a broader range of possible hosts and host-related distribution and dispersion for this widespread species. PMID- 26960545 TI - Effects of sodium bicarbonate concentration on growth, photosynthesis, and carbonic anhydrase activity of macroalgae Gracilariopsis lemaneiformis, Gracilaria vermiculophylla, and Gracilaria chouae (Gracilariales, Rhodophyta). AB - There is potential for bicarbonate to improve crop yields and economic efficiency of marine algae. However, few studies have focused on the effect of bicarbonate on the growth, photosynthesis, and enzyme activity associated with carbon utilization, especially in commercial macroalgae. Here, the addition of bicarbonate (up to 420 mg L(-1)) to macroalgal cultures has been evaluated for Gracilariopsis lemaneiformis, Gracilaria vermiculophylla, and Gracilaria chouae with respect to growth rate, photosynthetic activity, carbonic anhydrase activity, and biochemical composition. The results showed that the effects of NaHCO3 on growth, chlorophyll a, phycoerythrin, photosynthetic oxygen evolution, photochemical parameters of PSI and PSII, carbonic anhydrase activity, and nitrogen content were significant (P < 0.05) and followed the same pattern in the three species. The parameter values were promoted in lower NaHCO3 concentrations (up to 252 or 336 mg L(-1)) and inhibited in higher NaHCO3 concentrations (>336 mg L(-1) for Gp. lemaneiformis and >420 mg L(-1) for the other two species). Moreover, species-specific differences induced by supplementation with bicarbonate were discovered during culture. Optimal concentrations of NaHCO3 used in this study were 252 mg L(-1) for Gp. lemaneiformis and 336 mg L(-1) for G. vermiculophylla and G. chouae. These results suggest that an adequate supplementation of sodium bicarbonate is a viable strategy for promoting growth and photosynthetic activity in some macroalgae as well as for improving biochemical composition. The study will help to accelerate the growth rate of algae and improve the quality of thalli, and will also be useful for enhancing the understanding of carbon utilization in macroalgae. PMID- 26960547 TI - Transition of radiative recombination channels from delocalized states to localized states in a GaInP alloy with partial atomic ordering: a direct optical signature of Mott transition? AB - Anderson localization is a predominant phenomenon in condensed matter and materials physics. In fact, localized and delocalized states often co-exist in one material. They are separated by a boundary called the mobility edge. Mott transition may take place between these two regimes. However, it is widely recognized that an apparent demonstration of Anderson localization or Mott transition is a challenging task. In this article, we present a direct optical observation of a transition of radiative recombination dominant channels from delocalized (i.e., local extended) states to Anderson localized states in the GaInP base layer of a GaInP/GaAs single junction solar cell by the means of the variable-temperature electroluminescence (EL) technique. It is found that by increasing temperature, we can boost a remarkable transition of radiative recombination dominant channels from the delocalized states to the localized states. The delocalized states are induced by the local atomic ordering domains (InP/GaP monolayer superlattices) while the localized states are caused by random distribution of indium (gallium) content. The efficient transfer and thermal redistribution of carriers between the two kinds of electronic states was revealed to result in both a distinct EL mechanism transition and an electrical resistance evolution with temperature. Our study gives rise to a self-consistent precise picture for carrier localization and transfer in a GaInP alloy, which is an extremely technologically important energy material for fabricating high efficiency photovoltaic devices. PMID- 26960549 TI - Magnetic resonance imaging of breast augmentation: a pictorial review. AB - The increasing prevalence of breast augmentation presents new challenges in breast imaging interpretation. Magnetic resonance imaging (MRI) is recognized as the gold standard for the evaluation of augmented breasts. This article reviews the MRI features of different breast augmentation techniques, their associated complications, and the role of MRI in the assessment of concurrent breast abnormalities. TEACHING POINTS: * MRI has the highest sensitivity and specificity for implant rupture detection. * MRI is able to discriminate the nature of implanted prosthesis or injected materials. * Sensitivity of cancer detection by MRI is not reduced through implants. PMID- 26960548 TI - Comparative transcriptome analysis of Gastrodia elata (Orchidaceae) in response to fungus symbiosis to identify gastrodin biosynthesis-related genes. AB - BACKGROUND: Gastrodia elata Blume (Orchidaceae) is an important Chinese medicine with several functional components. In the life cycle of G. elata, the orchid develops a symbiotic relationship with two compatible mycorrhizal fungi Mycena spp. and Armillaria mellea during seed germination to form vegetative propagation corm and vegetative growth to develop tubers, respectively. Gastrodin (p hydroxymethylphenol-beta-D-glucoside) is the most important functional component in G. elata, and gastrodin significantly increases from vegetative propagation corms to tubers. To address the gene regulation mechanism in gastrodin biosynthesis in G. elata, a comparative analysis of de novo transcriptome sequencing among the vegetative propagation corms and tubers of G. elata and A. mellea was conducted using deep sequencing. RESULTS: Transcriptome comparison between the vegetative propagation corms and juvenile tubers of G. elata revealed 703 differentially expressed unigenes, of which 298 and 405 unigenes were, respectively up-regulated (fold-change >= 2, q-value < 0.05, the trimmed mean of M-values (TMM)-normalized fragments per kilobase of transcript per Million mapped reads (FPKM) > 10) and down-regulated (fold-change <= 0.5, q-value <0.05, TMM normalized FPKM > 10) in juvenile tubers. After Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, 112 up-regulated unigenes with KEGG Ortholog identifiers (KOids) or enzyme commission (EC) numbers were assigned to 159 isogroups involved in seventy-eight different pathways, and 132 down-regulated unigenes with KOids or EC numbers were assigned to 168 isogroups, involved in eighty different pathways. The analysis of the isogroup genes from all pathways revealed that the two unigenes TRINITY_DN54282_c0_g1 (putative monooxygenases) and TRINITY_DN50323_c0_g1 (putative glycosyltransferases) might participate in hydroxylation and glucosylation in the gastrodin biosynthetic pathway. CONCLUSIONS: The gene expression of the two unique unigenes encoding monooxygenase and glycosyltransferase significantly increases from vegetative propagation corms to tubers, and the molecular basis of gastrodin biosynthesis in the tubers of G. elata is proposed. PMID- 26960551 TI - High-flux ionic diodes, ionic transistors and ionic amplifiers based on external ion concentration polarization by an ion exchange membrane: a new scalable ionic circuit platform. AB - A microfluidic ion exchange membrane hybrid chip is fabricated using polymer based, lithography-free methods to achieve ionic diode, transistor and amplifier functionalities with the same four-terminal design. The high ionic flux (>100 MUA) feature of the chip can enable a scalable integrated ionic circuit platform for micro-total-analytical systems. PMID- 26960553 TI - On the phenotypic spectrum of serine biosynthesis defects. AB - L-serine is a non-essential amino acid that is de novo synthesized via the enzymes phosphoglycerate dehydrogenase (PGDH), phosphoserine aminotransferase (PSAT), and phosphoserine phosphatase (PSP). Besides its role in protein synthesis, L-serine is a precursor of a number of important compounds. Serine biosynthesis defects result from deficiencies in PGDH, PSAT, or PSP and have a broad phenotypic spectrum ranging from Neu-Laxova syndrome, a lethal multiple congenital anomaly disease at the severe end to a childhood disease with intellectual disability at the mild end, with infantile growth deficiency, and severe neurological manifestations as an intermediate phenotype. In this report, we present three subjects with serine biosynthesis effects. The first was a stillbirth with Neu-Laxova syndrome and a homozygous mutation in PHGDH. The second was a neonate with growth deficiency, microcephaly, ichthyotic skin lesions, seizures, contractures, hypertonia, distinctive facial features, and a homozygous mutation in PSAT1. The third subject was an infant with growth deficiency, microcephaly, ichthyotic skin lesions, anemia, hypertonia, distinctive facial features, low serine and glycine in plasma and CSF, and a novel homozygous mutation in PHGDH gene. Herein, we also review previous reports of serine biosynthesis defects and mutations in the PHGDH, PSAT1, and PSPH genes, discuss the variability in the phenotypes associated with serine biosynthesis defects, and elaborate on the vital roles of serine and the potential consequences of its deficiency. PMID- 26960552 TI - Molecular basis for globotriaosylceramide regulation and enzyme uptake in immortalized aortic endothelial cells from Fabry mice. AB - Fabry disease is caused by deficient activity of alpha-galactosidase A and subsequent intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3). Vascular endothelial cells may play important roles in disease pathogenesis, and are one of the main target cell types in therapeutic interventions. In this study, we generated immortalized aortic endothelial cell lines from a mouse model of Fabry disease. These cells retained endothelial cell specific markers and functions. Gb3 expression level in one of these clones (referred to as FMEC2) was highly susceptible to culture media, and appeared to be regulated by glucosylceramide synthase. Results also showed that Gb3 could be upregulated by hydrocortisone. FMEC2 express the mannose 6-phosphate receptor and sortilin but not the mannose receptor. Uptake studies suggested that sortilin plays a role in the binding and internalization of mammalian cell-produced alpha galactosidase A. Moss-aGal (a plant-made enzyme) was endocytosed by FMEC2 via a receptor other than the aforementioned receptors. In conclusion, this study suggests that glucosylceramide synthase and hydrocortisone may play important roles in modulating Gb3 levels in Fabry mouse aortic endothelial cells, and that endocytosis of recombinant alpha-galactosidase A involves a combination of multiple receptors depending on the properties of the enzyme. PMID- 26960554 TI - Monitoring of CRT-D devices during radiation therapy in vitro. AB - BACKGROUND: Using of active cardiac medical devices increases steadily. In Europe, there were 183 implants of ICD and 944 implants of PM, 119 of biventricular ICD and 41 of biventricular PM, all per million inhabitants in 2014. Healthcare environments, including radiotherapy treatment rooms, are considered challenging for these implantable devices. Exposure to radiation may cause the device to experience premature elective replacement indicator, decreased pacing amplitude or pacing inhibition, inappropriate shocks or inhibition of tachyarrhythmia therapy and loss of device function. These impacts may be temporary or permanent. The aim of this study was to evaluate the influence of linear accelerator ionizing radiation dose of 10 Gy on the activity of the biventricular cardioverter-defibrillator in different position in radiation beam. METHODS: Two identical wireless communication devices with all three leads were used for the measurement. Both systems were soused into solution saline and exposed in different position in the beam of linear accelerator per 10 Gy fractions. In comparison of usually used maximum recommended dose of 2 Gy, the radiation doses used in test were five times higher. Using the simultaneous monitoring wireless communication between device and its programmer allowed watching of the devices activities, noise occurrence or drop of biventricular pacing on the programmer screen, observed by local television loop camera. RESULTS: At any device position in radiation beam, there were no influences of the device activity at dose of 10 Gy neither a significant increase of a solution saline temperature in any of the measured positions of CRT-D systems in linear accelerator. CONCLUSIONS: The results of the study indicated, that the recommendation dose for treating the patients with implantable devices are too conservative and the risk of device failure is not so high. The systems can easily withstand the dose fractions of tens Gy, which would allow current single dose-procedure treatment in radiation therapy. Even though the process of the random alteration of device memory and electrical components by scatter particles not allowed to specify a safe dose during ionizing radiation, this study showed that the safe limit are above the today used dose fractions. PMID- 26960555 TI - Bacterial associations reveal spatial population dynamics in Anopheles gambiae mosquitoes. AB - The intolerable burden of malaria has for too long plagued humanity and the prospect of eradicating malaria is an optimistic, but reachable, target in the 21(st) century. However, extensive knowledge is needed about the spatial structure of mosquito populations in order to develop effective interventions against malaria transmission. We hypothesized that the microbiota associated with a mosquito reflects acquisition of bacteria in different environments. By analyzing the whole-body bacterial flora of An. gambiae mosquitoes from Burkina Faso by 16 S amplicon sequencing, we found that the different environments gave each mosquito a specific bacterial profile. In addition, the bacterial profiles provided precise and predicting information on the spatial dynamics of the mosquito population as a whole and showed that the mosquitoes formed clear local populations within a meta-population network. We believe that using microbiotas as proxies for population structures will greatly aid improving the performance of vector interventions around the world. PMID- 26960556 TI - Disease Heterogeneity in Na+/Citrate Cotransporter Deficiency. AB - We report a novel mutation found in two siblings, a male and a female aged 8 and 5 years, respectively. Both patients presented with developmental delay and intractable seizures consistent with previous reports of SLC13A5 transporter deficiency. Both had two mutations in the SLC13A5 gene, c.655G>A (G219R) and the novel mutation c.245A>G (Y82C). However, the phenotypes were not identical as the female had focal cortical dysplasia that led to brain surgery. This is another example of the heterogeneity in disease expression even when the genotype is identical in the affected individuals. PMID- 26960557 TI - A Founder Effect for the HGD G360R Mutation in Italy: Implications for a Regional Screening of Alkaptonuria. AB - We sought to establish rapid and specific genotyping methods for G360R mutation and for seven tightly linked markers in the homogentisate dioxygenase gene to address the question of whether G360R is a mutational hot spot or the result of a founder effect, as it has been repeatedly found in alkaptonuric patients from a geographic isolate in Italy.For G360R and single nucleotide polymorphism genotyping, high-resolution melting analysis was performed. Microsatellites were analysed by multiplex PCR and capillary electrophoresis. To investigate the natural history of the G360R mutation, we genotyped markers in 52 controls and in 8 unrelated patients from the UK and USA, who also segregated the G360R mutation, and calculated its age using DMLE+2.3 software.A distinct G360R-bearing haplotype was identified in all patients of Caucasian descent. Estimated mutation age was 545 generations (95% credible set, 402-854), suggesting that G360R arose in an ancestor who lived 8,000-10,000 years BC. Archaeological, historical and demographic data support that a G360R carrier has settled the remote valley where present-day population might have a heterozygote frequency of at least 6%.Given the late health-threatening complications of alkaptonuria and a cure within reach, inhabitants of this isolate would benefit from screening and genetic counselling. PMID- 26960558 TI - Comparison of clinical outcomes among 3 marking methods for toric intraocular lens implantation. AB - PURPOSE: To compare the clinical outcomes of 3 marking methods for toric intraocular lens (IOL) implantation in cataract patients. METHODS: This study included 48 eyes of 48 cataract patients who underwent cataract surgery with toric IOL implantation. The rotational errors of 3 marking methods-the iris pattern marking method (iris pattern group), the pendulum marking method (pendulum group), and the 3-point marking method (3-point group)-were assessed. RESULTS: The respective rotational errors were 4.0 degrees +/- 3.1 degrees (mean +/- SD), 5.3 degrees +/- 4.1 degrees , and 7.3 degrees +/- 6.0 degrees . The iris pattern group had significantly (P = 0.048) smaller rotational errors than did the 3-point group; no significant difference was found between the iris pattern and pendulum groups. However, the differences in postoperative uncorrected distance visual acuity and astigmatism did not reach significance among the 3 groups. CONCLUSION: The refractive and visual results of toric IOL implantation using the 3-point marking method were comparable to the other methods evaluated in this study, although the accuracy of the axis alignment of the toric IOLs was significantly lower than that obtained with the iris pattern method. PMID- 26960559 TI - Residual neck disease management in squamous-cell carcinoma of the head and neck treated with radiotherapy plus cetuximab. AB - PURPOSE: Management of residual neck disease (RND) is one of the unsolved points after bio-radiotherapy (BRT) in loco-regional advanced squamous-cell carcinoma of the head and neck (SCCHN). The aims of the study were to characterize the radiological pattern of response by computed tomography (CT) and to assess the role of positron-emission tomography (PET)/CT in this setting for a better decision-making in the indication of neck dissection (ND). METHODS: We retrospectively reviewed 202 patients consecutively diagnosed with node-positive SCCHN (N1: 24; N2: 152; N3: 26) who had been treated with concomitant radiotherapy and cetuximab with or without previous induction chemotherapy between 2006 and 2013. Radiological evaluation after treatment was assessed by standard criteria using CT and in addition by PET/CT when RND was suspected in cases from 2010. RESULTS: There were 42 (21 %) patients who achieved complete response of the primary tumor persisting RND by CT. From this group, 24 patients were managed without PET/CT, leading to the performance of ND in 22 (92 %). On the other hand, 18 patients underwent PET/CT and ND was performed in only 6 (33 %). The overall survival was not different between both groups (p = 0.32). After histological examination and follow-up, PET/CT obtained a positive predictive value of 56 % and a negative predictive value of 89 %. CONCLUSIONS: Radiological response after BRT is similar to that after treatment with chemo-radiotherapy, thereby validating in this scenario the accepted CT criteria to define complete response of the neck. However, when RND is suspected by CT, PET/CT is useful to prevent unnecessary ND. PMID- 26960560 TI - Extreme liver surgery as treatment of liver tumors involving the hepatocaval confluence. AB - OBJECTIVE: Analyze the characteristics, surgical technique, morbidity and survival of patients treated with extreme liver surgery. MATERIALS AND METHODS: We present a series of consecutive patients with malignant liver tumors in hepatocaval confluence treated in a single center with extreme liver surgery (April 2008-March 2015). Data were collected prospectively and analyzed with SPSS 21.0. RESULTS: 12 patients were included. 50 % were male and 50 % were female with a mean age of 59 +/- 10 years old. The median of comorbidities was 7 according to the Charlson Age Comorbidity Index. The 75 % of the tumors were metastases, most of them from colorectal cancer. Most of the patients received neoadjuvant chemotherapy and in 58 % preoperative portal embolization was performed. Major hepatectomies were performed (66.7 % extended right hepatectomy, 33.3 % left extended hepatectomy). The 83.3 % of the patients needed vascular reconstruction. Postoperative morbidity was more than grade II in 50 % of the patients according to Dindo-Clavien classification. There was no intraoperative mortality. The postoperative mortality rate at 90 days was 33 % due to hepatic failure and biliary fistula. In December 2015, 33 % of the patients are still alive with a mean survival of 19 months (13-23) with an ECOG Performance Status of 0. CONCLUSION: Extreme liver surgery carries a high rate of morbidity and mortality that seem to increase with age and with higher tumor volumes, according to the literature. It is a therapeutic option to consider in patients with low comorbidity suffering from malignant neoplasms that involve the hepatocaval confluence, when no other treatment with curative intention can be performed. PMID- 26960561 TI - Survival in glioblastoma: a review on the impact of treatment modalities. AB - Glioblastoma (GBM) is the most common and lethal tumor of the central nervous system. The natural history of treated GBM remains very poor with 5-year survival rates of 5 %. Survival has not significantly improved over the last decades. Currently, the best that can be offered is a modest 14-month overall median survival in patients undergoing maximum safe resection plus adjuvant chemoradiotherapy. Prognostic factors involved in survival include age, performance status, grade, specific markers (MGMT methylation, mutation of IDH1, IDH2 or TERT, 1p19q codeletion, overexpression of EGFR, etc.) and, likely, the extent of resection. Certain adjuncts to surgery, especially cortical mapping and 5-ALA fluorescence, favor higher rates of gross total resection with apparent positive impact on survival. Recurrent tumors can be offered re-intervention, participation in clinical trials, anti-angiogenic agent or local electric field therapy, without an evident impact on survival. Molecular-targeted therapies, immunotherapy and gene therapy are promising tools currently under research. PMID- 26960562 TI - (18)F-FACBC (anti1-amino-3-(18)F-fluorocyclobutane-1-carboxylic acid) versus (11)C-choline PET/CT in prostate cancer relapse: results of a prospective trial. AB - PURPOSE: To compare the accuracy of (18)F-FACBC and (11)C-choline PET/CT in patients radically treated for prostate cancer presenting with biochemical relapse. METHODS: This prospective study enrolled 100 consecutive patients radically treated for prostate cancer and presenting with rising PSA. Of these 100 patients, 89 were included in the analysis. All had biochemical relapse after radical prostatectomy (at least 3 months previously), had (11)C-choline and (18)F FACBC PET/CT performed within 1 week and were off hormonal therapy at the time of the scans. The two tracers were compared directly in terms of overall positivity/negativity on both a per-patient basis and a per-site basis. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were calculated for both the tracers; follow-up at 1 year (including correlative imaging, PSA trend and pathology when available) was considered as the standard of reference. RESULTS: In 51 patients the results were negative and in 25 patients positive with both the tracers, in eight patients the results were positive with (18)F-FACBC but negative with (11)C-choline, and in five patients the results were positive with (11)C-choline but negative with (18)F-FACBC. Overall in 49 patients the results were false-negative (FN), in two true-negative, in 24 true-positive (TP) and in none false-positive (FP) with both tracers. In terms of discordances between the tracers: (1) in one patient, the result was FN with (11)C-choline but FP with (18)F-FACBC (lymph node), (2) in seven, FN with (11)C-choline but TP with (18)F-FACBC (lymph node in five, bone in one, local relapse in one), (3) in one, FP with (11)C-choline (lymph node) but TP with (18)F-FACBC (local relapse), (4) in two, FP with (11)C-choline (lymph nodes in one, local relapse in one) but FN with (18)F-FACBC, and (5) in three, TP with (11)C-choline (lymph nodes in two, bone in one) but FN with (18)F-FACBC. With (11)C-choline and (18)F-FACBC, sensitivities were 32 % and 37 %, specificities 40 % and 67 %, accuracies 32 % and 38 %, PPVs 90 % and 97 %, and NPVs 3 % and 4 %, respectively. Categorizing patients by PSA level (<1 ng/ml 28 patients, 1 - <2 ng/ml 28 patients, 2 - <3 ng/ml 11 patients, >=3 ng/ml 22 patients), the number (percent) of patients with TP findings were generally higher with (18)F-FACBC than with (11)C-choline: six patients (21 %) and four patients (14 %), eight patients (29 %) and eight patients (29 %), five patients (45 %) and four patients (36 %), and 13 patients (59 %) and 11 patients (50 %), respectively. CONCLUSION: (18)F-FACBC can be considered an alternative tracer superior to (11)C-choline in the setting of patients with biochemical relapse after radical prostatectomy. PMID- 26960564 TI - Local control on precipitation in a fully coupled climate-hydrology model. AB - The ability to simulate regional precipitation realistically by climate models is essential to understand and adapt to climate change. Due to the complexity of associated processes, particularly at unresolved temporal and spatial scales this continues to be a major challenge. As a result, climate simulations of precipitation often exhibit substantial biases that affect the reliability of future projections. Here we demonstrate how a regional climate model (RCM) coupled to a distributed hydrological catchment model that fully integrates water and energy fluxes between the subsurface, land surface, plant cover and the atmosphere, enables a realistic representation of local precipitation. Substantial improvements in simulated precipitation dynamics on seasonal and longer time scales is seen for a simulation period of six years and can be attributed to a more complete treatment of hydrological sub-surface processes including groundwater and moisture feedback. A high degree of local influence on the atmosphere suggests that coupled climate-hydrology models have a potential for improving climate projections and the results further indicate a diminished need for bias correction in climate-hydrology impact studies. PMID- 26960563 TI - A systematic study on drug-response associated genes using baseline gene expressions of the Cancer Cell Line Encyclopedia. AB - We have studied drug-response associated (DRA) gene expressions by applying a systems biology framework to the Cancer Cell Line Encyclopedia data. More than 4,000 genes are inferred to be DRA for at least one drug, while the number of DRA genes for each drug varies dramatically from almost 0 to 1,226. Functional enrichment analysis shows that the DRA genes are significantly enriched in genes associated with cell cycle and plasma membrane. Moreover, there might be two patterns of DRA genes between genders. There are significantly shared DRA genes between male and female for most drugs, while very little DRA genes tend to be shared between the two genders for a few drugs targeting sex-specific cancers (e.g., PD-0332991 for breast cancer and ovarian cancer). Our analyses also show substantial difference for DRA genes between young and old samples, suggesting the necessity of considering the age effects for personalized medicine in cancers. Lastly, differential module and key driver analyses confirm cell cycle related modules as top differential ones for drug sensitivity. The analyses also reveal the role of TSPO, TP53, and many other immune or cell cycle related genes as important key drivers for DRA network modules. These key drivers provide new drug targets to improve the sensitivity of cancer therapy. PMID- 26960565 TI - Making the hydrogen evolution reaction in polymer electrolyte membrane electrolysers even faster. AB - Although the hydrogen evolution reaction (HER) is one of the fastest electrocatalytic reactions, modern polymer electrolyte membrane (PEM) electrolysers require larger platinum loadings (~0.5-1.0 mg cm(-2)) than those in PEM fuel cell anodes and cathodes altogether (~0.5 mg cm(-2)). Thus, catalyst optimization would help in substantially reducing the costs for hydrogen production using this technology. Here we show that the activity of platinum(111) electrodes towards HER is significantly enhanced with just monolayer amounts of copper. Positioning copper atoms into the subsurface layer of platinum weakens the surface binding of adsorbed H-intermediates and provides a twofold activity increase, surpassing the highest specific HER activities reported for acidic media under similar conditions, to the best of our knowledge. These improvements are rationalized using a simple model based on structure-sensitive hydrogen adsorption at platinum and copper-modified platinum surfaces. This model also solves a long-lasting puzzle in electrocatalysis, namely why polycrystalline platinum electrodes are more active than platinum(111) for the HER. PMID- 26960566 TI - Sex-specific local life-history adaptation in surface- and cave-dwelling Atlantic mollies (Poecilia mexicana). AB - Cavefishes have long been used as model organisms showcasing adaptive diversification, but does adaptation to caves also facilitate the evolution of reproductive isolation from surface ancestors? We raised offspring of wild-caught surface- and cave-dwelling ecotypes of the neotropical fish Poecilia mexicana to sexual maturity in a 12-month common garden experiment. Fish were raised under one of two food regimes (high vs. low), and this was crossed with differences in lighting conditions (permanent darkness vs. 12:12 h light:dark cycle) in a 2 * 2 factorial design, allowing us to elucidate potential patterns of local adaptation in life histories. Our results reveal a pattern of sex-specific local life history adaptation: Surface molly females had the highest fitness in the treatment best resembling their habitat of origin (high food and a light:dark cycle), and suffered from almost complete reproductive failure in darkness, while cave molly females were not similarly affected in any treatment. Males of both ecotypes, on the other hand, showed only weak evidence for local adaptation. Nonetheless, local life-history adaptation in females likely contributes to ecological diversification in this system and other cave animals, further supporting the role of local adaptation due to strong divergent selection as a major force in ecological speciation. PMID- 26960567 TI - A New NO-Releasing Nanoformulation for the Treatment of Pulmonary Arterial Hypertension. AB - Pulmonary arterial hypertension (PAH) is a chronic and progressive disease which continues to carry an unacceptably high mortality and morbidity. The nitric oxide (NO) pathway has been implicated in the pathophysiology and progression of the disease. Its extremely short half-life and systemic effects have hampered the clinical use of NO in PAH. In an attempt to circumvent these major limitations, we have developed a new NO-nanomedicine formulation. The formulation was based on hydrogel-like polymeric composite NO-releasing nanoparticles (NO-RP). The kinetics of NO release from the NO-RP showed a peak at about 120 min followed by a sustained release for over 8 h. The NO-RP did not affect the viability or inflammation responses of endothelial cells. The NO-RP produced concentration dependent relaxations of pulmonary arteries in mice with PAH induced by hypoxia. In conclusion, NO-RP drugs could considerably enhance the therapeutic potential of NO therapy for PAH. PMID- 26960568 TI - Improvement in Cardiovascular Risk Prediction with Electronic Health Records. AB - The aim of this study was to compare the QRISKII, an electronic health data-based risk score, to the Framingham Risk Score (FRS) and atherosclerotic cardiovascular disease (ASCVD) score. Risk estimates were calculated for a cohort of 8783 patients, and the patients were followed up from November 29, 2012, through June 1, 2015, for a cardiovascular disease (CVD) event. During follow-up, 246 men and 247 women had a CVD event. Cohen's kappa statistic for the comparison of the QRISKII and FRS was 0.22 for men and 0.23 for women, with the QRISKII classifying more patients in the higher-risk groups. The QRISKII and ASCVD were more similar with kappa statistics of 0.49 for men and 0.51 for women. The QRISKII shows increased discrimination with area under the curve (AUC) statistics of 0.65 and 0.71, respectively, compared to the FRS (0.59 and 0.66) and ASCVD (0.63 and 0.69). These results demonstrate that incorporating additional data from the electronic health record (EHR) may improve CVD risk stratification. PMID- 26960570 TI - I fed you milk as we condemned you to die. PMID- 26960569 TI - Structure of ThiM from Vitamin B1 biosynthetic pathway of Staphylococcus aureus - Insights into a novel pro-drug approach addressing MRSA infections. AB - Infections caused by the methicillin-resistant Staphylococcus aureus (MRSA) are today known to be a substantial threat for global health. Emerging multi-drug resistant bacteria have created a substantial need to identify and discover new drug targets and to develop novel strategies to treat bacterial infections. A promising and so far untapped antibiotic target is the biosynthesis of vitamin B1 (thiamin). Thiamin in its activated form, thiamin pyrophosphate, is an essential co-factor for all organisms. Therefore, thiamin analogous compounds, when introduced into the vitamin B1 biosynthetic pathway and further converted into non-functional co-factors by the bacterium can function as pro-drugs which thus block various co-factor dependent pathways. We characterized one of the key enzymes within the S. aureus vitamin B1 biosynthetic pathway, 5-(hydroxyethyl)-4 methylthiazole kinase (SaThiM; EC 2.7.1.50), a potential target for pro-drug compounds and analyzed the native structure of SaThiM and complexes with the natural substrate 5-(hydroxyethyl)-4-methylthiazole (THZ) and two selected substrate analogues. PMID- 26960571 TI - Promoting Health Literacy to Prevent Hospital Readmissions: Necessary but not Sufficient. PMID- 26960572 TI - Predictors of surgical outcome in thoracic ossification of the ligamentum flavum: focusing on the quantitative signal intensity. AB - The association between intramedullary increased signal intensity (ISI) on T2 weighted magnetic resonance imaging (MRI) and surgical outcome in thoracic ossification of the ligamentum flavum (OLF) remains controversial. We aimed to determine the impact of signal change ratio (SCR) on thoracic OLF surgical outcomes. We retrospectively reviewed 96 cases of thoracic OLF surgery and investigated myelopathy severity, symptom duration, MRI and computed tomographic findings, surgical technique and postoperative recoveries. Surgical outcomes were evaluated according to the modified Japanese Orthopaedic Association (JOA) score and recovery rate. JOA recovery rate <50% was defined as a poor surgical outcome. By multivariate logistic regression analysis, we identified risk factors associated with surgical outcomes. Forty patients (41.7%) had a recovery rate of <50%. In receiver operating characteristic (ROC) curves, the optimal preoperative SCR cutoff value as a predictor of poor surgical outcome was 1.54. Multivariate logistic regression analysis revealed that a preoperative SCR >=1.54 and symptom duration >12 months were significant risk factors for a poor surgical outcome. These findings suggest that preoperative SCR and duration of symptoms were significant risk factors of surgical outcome for patients with thoracic OLF. Patients with preoperative SCR >=1.54 can experience poor postoperative recovery. PMID- 26960574 TI - Treatment of clostridium difficile infections. PMID- 26960575 TI - Revisiting the Classics. PMID- 26960576 TI - Dentin Conditioning with Bioactive Molecule Releasing Nanoparticle System Enhances Adherence, Viability, and Differentiation of Stem Cells from Apical Papilla. AB - INTRODUCTION: Temporal-controlled bioactive molecule (BM) releasing systems allow the delivery of appropriate concentration of BM to enhance the interaction of stem cells to dentin matrix and subsequent odontogenic differentiation in regenerative endodontics. OBJECTIVES: The goal of this study was to evaluate the effect of dentin conditioning with 2 variants of dexamethasone (Dex) releasing chitosan nanoparticles (CSnp), (1) Dex-CSnpI (slow releasing) and (2) Dex-CSnpII (rapid releasing), on adherence, viability, and differentiation of stem cells from apical papilla (SCAP) on root dentin exposed to endodontic irrigants. METHODS: Slab-shaped dentin specimens were prepared parallel to the root canal and treated with 5.25% sodium hypochlorite (NaOCl) for 10 minutes and/or 17% EDTA for 2 minutes. Dentin was then conditioned accordingly by (1) no nanoparticle treatment, (2) CSnp, (3) Dex-CSnpI, and (4) Dex-CSnpII. The effect of nanoparticle conditioning on SCAP viability was determined by cell count and a circularity index. SCAP adherence and viability on dentin were assessed by fluorescence and scanning electron microscopy and odontogenic differentiation by immunofluorescence. RESULTS: SCAP on dentin treated with NaOCl alone or NaOCl as the last irrigant showed the least adherence, minimal cytoplasmic extensions, and higher circularity. SCAP adherence and viability on Dex-CSnpI and Dex-CSnpII conditioned dentin were increased and had a well-developed cytoplasmic matrix and significantly lower circularity (P < .05). SCAP cultured in Dex-CSnpII group expressed higher levels for DSPP and DMP-1 than in CSnp or Dex-CSnpI groups. CONCLUSIONS: Dex-CSnpI and Dex-CSnpII conditioning of dentin enhanced SCAP adherence and viability. Temporal-controlled release of Dex from Dex-CSnpII enhanced odontogenic differentiation of SCAP. This study highlighted the ability of dentin conditioning with temporal-controlled BM releasing nanoparticles to improve the local environment in regenerative endodontics. PMID- 26960573 TI - G9a-mediated methylation of ERalpha links the PHF20/MOF histone acetyltransferase complex to hormonal gene expression. AB - The euchromatin histone methyltransferase 2 (also known as G9a) methylates histone H3K9 to repress gene expression, but it also acts as a coactivator for some nuclear receptors. The molecular mechanisms underlying this activation remain elusive. Here we show that G9a functions as a coactivator of the endogenous oestrogen receptor alpha (ERalpha) in breast cancer cells in a histone methylation-independent manner. G9a dimethylates ERalpha at K235 both in vitro and in cells. Dimethylation of ERalphaK235 is recognized by the Tudor domain of PHF20, which recruits the MOF histone acetyltransferase (HAT) complex to ERalpha target gene promoters to deposit histone H4K16 acetylation promoting active transcription. Together, our data suggest the molecular mechanism by which G9a functions as an ERalpha coactivator. Along with the PHF20/MOF complex, G9a links the crosstalk between ERalpha methylation and histone acetylation that governs the epigenetic regulation of hormonal gene expression. PMID- 26960577 TI - Root Maturation in Teeth Treated by Unsuccessful Revitalization: 2 Case Reports. AB - This article deals with the unusual course of failed revascularization/revitalization cases. Up to this date the evidence of success and failure rates of revascularization/revitalization treatment is scarce. These case reports present "unsuccessful" revascularization/revitalization treatment of permanent immature teeth with apical periodontitis. Although the teeth were treated by protocol suggested by the American Association of Endodontists and the symptoms disappeared, maturation of teeth continued, and periapical lesion was reduced, the teeth went symptomatic during the follow-up. Subsequently, regular root canal treatment was performed. Despite chronic infection that was probably left inside the root canal after a disinfection protocol, the secondary aims of the treatment were achieved even when the primary ones were not. The possible causes of failures of revascularization/revitalization treatment and their prevention are discussed. PMID- 26960578 TI - Parathyroid hormone attenuates radiation-induced increases in collagen crosslink ratio at periosteal surfaces of mouse tibia. AB - As part of our ongoing efforts to understand underlying mechanisms contributing to radiation-associated bone fragility and to identify possible treatments, we evaluated the longitudinal effects of parathyroid hormone (PTH) treatment on bone quality in a murine model of limited field irradiation. We hypothesized PTH would mitigate radiation-induced changes in the chemical composition and structure of bone, as measured by microscope-based Raman spectroscopy. We further hypothesized that collagen crosslinking would be especially responsive to PTH treatment. Raman spectroscopy was performed on retrieved tibiae (6-7/group/time point) to quantify metrics associated with bone quality, including: mineral-to-matrix ratio, carbonate-to-phosphate ratio, mineral crystallinity, collagen crosslink (trivalent:divalent) ratio, and the mineral and matrix depolarization ratios. Irradiation disrupted the molecular structure and orientation of bone collagen, as evidenced by a higher collagen crosslink ratio and lower matrix depolarization ratio (vs. non-irradiated control bones), persisting until 12weeks post irradiation. Radiation transiently affected the mineral phase, as evidenced by increased mineral crystallinity and mineral-to-matrix ratio at 4weeks compared to controls. Radiation decreased bone mineral depolarization ratios through 12weeks, indicating increased mineral alignment. PTH treatment partially attenuated radiation-induced increases in collagen crosslink ratio, but did not restore collagen or mineral alignment. These post-radiation matrix changes are consistent with our previous studies of radiation damage to bone, and suggest that the initial radiation damage to bone matrix has extensive effects on the quality of tissue deposited thereafter. In addition to maintaining bone quality, preventing initial radiation damage to the bone matrix (i.e. crosslink ratio, matrix orientation) may be critical to preventing late-onset fragility fractures. PMID- 26960580 TI - Food allergy is associated with Staphylococcus aureus colonization in children with atopic dermatitis. PMID- 26960579 TI - Retrospective study of teicoplanin loading regimen that rapidly achieves target 15-30 MUg/mL serum trough concentration. AB - OBJECTIVES: There are several studies of assessment for teicoplanin loading dose regimen. However, the optimal loading dose achieving the target range 15-30 MUg/mL has been still unclear. We investigated the probability of target attachment as teicoplanin concentration 15-30 MUg/mL at the 3rd day after teicoplanin therapy started, clinical efficacy and safety in retrospective study. METHODS: In total, 42 patients treated with teicoplanin from January 2010 to July 2014 at Aichi Medical University Hospital were divided into three groups; group 1 (about 40 mg/kg for 2 days), group 2 (about 35 mg/kg for 2 days) and group 3 (about 30 mg/kg for 2 days; the previous regimen). The probability of target attachment as teicoplanin concentration, efficacy and toxicity were compared among three groups. RESULTS: The proportion of patients achieving the target range was 100% in group 1, 57.9% in group 2, and 38.9% in group 3 (p = 0.05). The percentage of patients that showed hepatotoxicity and nephrotoxicity was not different from three groups (hepatotoxicity: group 1, 20%; group 2, 21.1%; group 3, 16.7%: p = 0.48; nephrotoxicity: group 1, 0%; group 2, 5.3%; group 3, 16.7%: p = 0.38). Finally, there were not significant differences of clinical efficacy among three regimens, but CRP 4-7 day after teicoplanin therapy in group 1 and group 2 exhibited a significant lower value, compared with group 3. CONCLUSIONS: We suggested that 35-40 mg/kg for 2 days as a loading does would be needed for the early achieving target range (15-30 MUg/mL) and improvement of infection. PMID- 26960583 TI - Pregnancy-associated Deaths: 31-year Experience. AB - AIM: The aim of the present study was to elucidate the clinical characteristics of pregnancy-associated maternal deaths. METHODS: We performed a retrospective analysis with medical records and autopsy reports of cases of pregnancy associated deaths. We collected information on all maternal deaths related to pregnancy that occurred in 3 hospitals affiliated with Nippon Medical School in Japan from January 1, 1984, to December 31, 2014. Data analyzed were maternal age, past medical history, parity, gestational age, clinical signs and symptoms, cause of death, and maternal autopsy findings. RESULTS: A total of 26 maternal deaths occurred during the 31-year study period. Autopsies were performed for 16 patients (61.5%). The 26 deaths included 19 (73.1%) classified as direct maternal deaths and 7 (26.9%) classified as indirect maternal deaths. The mean maternal age at death was 33.1+/-4.3 years (range, 26-41 years). The highest percentage of women was aged 35 to 39 years (38.5%). Of the 26 maternal deaths, 69% occurred at 32 to 41 weeks of gestation. In cases of direct maternal death, the leading causes were amniotic fluid embolism (7 cases, 27.0% of all deaths) and hemorrhage (6 cases, 23.1% of all deaths). In cases of indirect obstetric deaths, the causes included cardiovascular disorders, cerebrovascular disorders, sepsis due to group A streptococcal infection, and hepatic failure of unknown etiology. CONCLUSIONS: Amniotic fluid embolism was the leading cause of maternal deaths and was followed by obstetric hemorrhage. To prevent and reduce the number of maternal deaths in Japan, further basic and clinical research on amniotic fluid embolism is required. PMID- 26960582 TI - Conservative Treatment for Fracture of the Proximal Femur with Complications. AB - We retrospectively compared two groups of patients with hip fractures and severe complications. One group had been treated surgically; the other group had been treated conservatively to prevent worsening of general status, with transfer to wheelchair as soon as possible. This study aimed to determine if early prognosis after conservative treatment would be worse than that following surgical treatment. MATERIALS AND METHODS: Subjects were patients (n=230) with hip fracture who had been admitted and treated at our hospital from 1993 through 2006. Patients' medical records were retroactively investigated to obtain information on age, sex, complications, type of fracture, and course of subsequent hospitalizations. Additional information for conservatively treated patients included reasons for avoiding surgery and time-to-transfer to wheelchair. In case of death, the cause and timing of death were investigated. RESULTS: Of the 230 patients, 22 (mean age, 83.5 years) were treated conservatively. Complications at admission included cardiac disease, respiratory disease, malignancy, renal disease, dementia, and other conditions. Multiple complications were commonly seen. The reasons for selecting conservative treatment were cardiac function disturbance in 13 cases and decision of patients' families in 9 cases. Almost all patients were able to transfer to wheelchair. A total of 9 patients died in the hospital: 8 were in the surgical treatment group and 1 was in the conservative treatment group. The patients who died in the surgical treatment group had a mean age of 80.3 years, and pneumonia was the main cause of death. The timing of death ranged from 12 to 129 days after surgery. The number of perioperative deaths was 3 (1.4%). DISCUSSION AND CONCLUSION: This study showed that in patients with hip fractures, severe complications, and poor general conditions, early prognosis after conservative treatment aiming for early transfer to wheelchair is no worse than that following surgical treatment. Thus, conservative treatment should be considered for patients with poor ability for activities of daily living. PMID- 26960581 TI - Perspectives of healthcare providers and HIV-affected individuals and couples during the development of a Safer Conception Counseling Toolkit in Kenya: stigma, fears, and recommendations for the delivery of services. AB - Reproduction is important to many HIV-affected individuals and couples and healthcare providers (HCPs) are responsible for providing resources to help them safely conceive while minimizing the risk of sexual and perinatal HIV transmission. In order to fulfill their reproductive goals, HIV-affected individuals and their partners need access to information regarding safer methods of conception. The objective of this qualitative study was to develop a Safer Conception Counseling Toolkit that can be used to train HCPs and counsel HIV affected individuals and couples in HIV care and treatment clinics in Kenya. We conducted a two-phased qualitative study among HCPs and HIV-affected individuals and couples from eight HIV care and treatment sites in Kisumu, Kenya. We conducted in-depth interviews (IDIs) and focus group discussions (FGDs) to assess the perspectives of HCPs and HIV-affected individuals and couples in order to develop and refine the content of the Toolkit. Subsequently, IDIs were conducted among HCPs who were trained using the Toolkit and FGDs among HIV-affected individuals and couples who were counseled with the Toolkit. HIV-related stigma, fears, and recommendations for delivery of safer conception counseling were assessed during the discussions. One hundred and six individuals participated in FGDs and IDIs; 29 HCPs, 49 HIV-affected women and men, and 14 HIV-serodiscordant couples. Participants indicated that a safer conception counseling and training program for HCPs is needed and that routine provision of safer conception counseling may promote maternal and child health by enhancing reproductive autonomy among HIV-affected couples. They also reported that the Toolkit may help dispel the stigma and fears associated with reproduction in HIV-affected couples, while supporting them in achieving their reproductive goals. Additional research is needed to evaluate the Safer Conception Toolkit in order to support its implementation and use in HIV care and treatment programs in Kenya and other HIV endemic regions of sub-Saharan Africa. PMID- 26960584 TI - Effect of Dual Therapy with Botulinum Toxin A Injection and Electromyography controlled Functional Electrical Stimulation on Active Function in the Spastic Paretic Hand. AB - BACKGROUND: Many previous studies have demonstrated that botulinum toxin A (BTX A) injections satisfactorily reduce spasticity. Nevertheless, BTX-A, with or without an adjuvant therapy, effectively improves the direct functional movement in few patients with spastic upper extremity paralysis. Therefore the present study aimed to determine the effectiveness of task-orientated therapy on spasticity and functional movement by using electromyography-triggered functional electrical stimulation (EMG-FES) after BTX-A injections. DESIGN: Open-label, prospective clinical trial Method: The subjects were 15 patients with spastic paresis (12 male, 3 female; age range, 17-74 years; 14 due to stroke, 1 due to spinal cord injury) who received BTX-A injections. Before the study was started, all subjects had undergone task-orientated therapy sessions with EMG-FES for 4 months. Despite all patients showing a various extent of improved upper extremity function, upper extremity function reached a plateau because of upper extremity spasticity. After BTX-A injection, all patients underwent task-orientated therapy sessions with EMG-FES for 4 months. The outcomes were assessed with the modified Ashworth scale, the simple test for evaluating hand function, box and block test, grip and release test, finger individual movement test, and grip strength. Assessments were performed at baseline and 10 days and 4 months after BTX-A injection. RESULTS: The median modified Ashworth scale score decreased from 2 at baseline to 1 at 10 days and 4 months after BTX-A injection. The finger individual movement test score increased slightly at 10 days (p=0.29) and further increased at 4 months (p<0.05). The simple test for evaluating hand function, grip and release test, box and block test, and grip strength decreased after 10 days (p<0.05, p=0.26, p<0.01, and p<0.01, respectively) but increased after 4 months (p<0.01, p<0.05, p<0.01, and p=0.18, respectively). CONCLUSION: Task orientated therapy with EMG-FES after BTX-A injection effectively reduced spasticity and improved upper limb motor function. Our results also suggest that spasticity occurs as a compensation for the force of the affected muscles and leads to misuse movements and ostensible dexterity in many patients. In addition, we hypothesize that BTX-A injection initializes the abnormal adapted movement pattern and that more active hand movements with facilitation of the paretic muscles when using EMG-FES induce an efficient muscle reeducation of the inherent physiological movement pattern that ultimately could prove useful in the activities of daily living. PMID- 26960585 TI - Superior Dislocation of the Patella in a Young Woman without Osteophytes: A Case Report. AB - Superior dislocation of the patella without patellar ligament injury is an extremely rare condition. A review of the English-language literature found only 23 reported cases. In addition, the primary factor for dislocation in most of these cases was considered to be osteophytes in the inferior pole of the patella and the anterior surface of the femoral condyle; only 1 case had no osteophytes. We treated a 19-year-old woman who sustained a painful locking of the left knee after colliding with a friend. Plain radiography and computed tomography showed superior-lateral dislocation of the patella and an interlocking between notches in the inferior pole of the patella and the anterior surface of the femoral condyle. Closed reduction without sedation was performed without difficulty, and the patient was able to walk home without pain. After 1 week, the knee was without problems. The patient had no osteophytes in the knee and had no other common risk factors, such as patella alta, ligamentous laxity, genu recurvatum, and paralytic disorders. After a comparison with previously reported cases of superior patella dislocation, we concluded that the primary factor in the present case might have been a different condition. PMID- 26960586 TI - Glue Embolization of a Blunt Traumatic Hepatic Arteriovenous Fistula under Inflow and Outflow Control. AB - We report on a rare case of blunt traumatic hepatic arteriovenous fistula arising from a pseudoaneurysm in a 35-year-old woman. Transarterial embolization was performed with n-butyl-2-cyanoacrylate, under inflow control with loose coil packing within the pseudoaneurysm and outflow control by balloon occlusion of the hepatic vein. A promising therapeutic outcome was achieved without any serious adverse events. Thus, the combination of these techniques to control inflow and outflow was successfully used to treat this rare hepatic vascular injury. PMID- 26960587 TI - Therapeutic Effect of 0.1% Topical Tacrolimus for Childhood Interstitial Keratitis Refractory to Cyclosporine. AB - PURPOSE: To report our findings in a case of childhood refractory interstitial keratitis successfully treated with 0.1% topical tacrolimus. METHODS: A 12-year old boy presented with a 3-year history of interstitial keratitis. For the recurrent interstitial keratitis he had been treated with topical and systemic acyclovir, steroids, and topical cyclosporine for 3 years. Our examinations revealed severe stromal infiltrates and neovascularization. Treatment was changed from topical 0.5% cyclosporine to topical 0.1% tacrolimus combined with topical acyclovir and betamethasone. RESULTS: After 2 weeks of treatment with topical tacrolimus, the degree of stromal infiltrates decreased. Although the improvements were slow, the stromal infiltrates resolved somewhat, and neovascularization and topical acyclovir and betamethasone were tapered and stopped in 18 months. Since then, the patient has not shown any recurrence for 9 months without medication. CONCLUSION: Our findings indicate that topical tacrolimus should be considered for treating refractory interstitial keratitis in children. PMID- 26960588 TI - Epstein-Barr Virus-positive T-cell Lymphoproliferative Disease Following Umbilical Cord Blood Transplantation for Acute Myeloid Leukemia. AB - We report a case of the extremely rare condition Epstein-Barr virus (EBV) positive T-cell lymphoproliferative disease (LPD) which occurred after umbilical cord blood transplantation. A 25-year-old Japanese man underwent cord blood transplantation from a male human leukocyte antigen 4/6-matched donor due to acute myeloid leukemia with trisomy 8. Bone marrow examination on day 30 showed chimerism with at least 90% donor cells and complete hematological response. Chronic symptoms of graft-versus-host disease appeared only on the skin and were successfully treated with cyclosporine alone. Three years later, however, the patient experienced repeated cold-like symptoms and was hospitalized with liver dysfunction. A high fever developed and was followed by significant edema of the right side of the face. The EBV DNA copy number in whole peripheral blood was 2*10(4)/mL. Liver biopsy showed invasion of EBV-infected CD8-positive T cells. Southern blotting analysis of the whole peripheral blood showed that the T-cell receptor Cbeta1 rearrangement was positive. On the basis of these results, EBV positive T-cell LPD was diagnosed and treated with prednisolone, cyclosporine, and etoposide, followed by cyclophosphamide, doxorubicin, vincristine, and prednisone. However, the patient died of cardiac function failure, pneumonia, and pulmonary hemorrhage, all of unidentified cause. Most cases of EBV-related LPD after hematopoietic stem cell transplantation consist of EBV-positive B-cell LPD, and, to our knowledge, de novo EBV-positive T-cell LPD subsequent to transplantation has not been previously reported. PMID- 26960590 TI - Self-perceived halitosis influences social interactions. AB - BACKGROUND: To determine the impact of self-perceived halitosis on social interactions, and the effect of using an oral rinse for management of halitosis. METHODS: A survey among a representative sample of the Dutch population (n = 1082), and a pre-post study among a sample of consecutive coming-by volunteers (n = 292). RESULTS: Participants of the representative sample rated their oral odor as 66.8 +/- 17.2 and the consecutive volunteers as 70.9 +/- 16.7 (range: 0-100). Sizable proportions (15.3 % and 38.1 %, respectively) indicated to always take into account their (bad) oral odor when meeting a person for the first time. The worse people perceived their oral odor, the more likely they were to take into account to keep a certain distance. Following the use of the oral rinse, a significant decline was found of the extent to which the participants reported to take into account their oral odor when meeting a person for the first time. Both studies identified a subgroup of individuals (9.1 % and 28.1 % respectively) who reported to keep a certain distance when meeting other people, despite a "fresh" self-perceived oral odor. CONCLUSION: The results suggest that self-perceived oral odor negatively affects social interactions, and that adequate management of halitosis has the potential to improve such interactions. PMID- 26960595 TI - Curriculum Vitae of James G. Anderson. PMID- 26960591 TI - Thoracoscopic side-to-side esophagogastrostomy by use of linear stapler-a simplified technique facilitating a minimally invasive Ivor-Lewis operation. AB - PURPOSE: Minimally invasive esophagectomy (MIE) has been met with increased interest for the surgical treatment of esophageal cancer. One critical obstacle for the implementation of MIE has been the intrathoracic anastomosis. In this study, we describe a technique of thoracoscopic intrathoracic anastomosis using a linear stapler in prone position and present the short-term outcomes of this procedure. METHODS: This prospective pilot study included 46 consecutive patients with a cancer either of the gastroesophageal junction (GEJ) or the distal esophagus who underwent either total MIE or thoracoscopic-assisted esophagectomy followed by intrathoracic stapled side-to-side anastomosis. The short-term outcomes including postoperative complications were recorded and analyzed. RESULTS: This pilot study included 41 males (89 %) and 5 females (11 %) with a mean age of 65.7 years. The majority had adenocarcinoma (93 %). Before surgery, 4 patients (8.7 %) had an incomplete endoscopic submucosal resection, 5 patients (11 %) received chemotherapy alone, and 33 patients (71 %) had chemoradiotherapy. Mean operation time was 408 minutes. Postoperative complications classified as Clavien-Dindo Grade IIIa or more severe occurred in 7 patients (15 %), of whom 4 patients (8.7 %) developed anastomotic leakages without any need for intensive care. Another 2 patients (4.3 %) required intensive care due to aspiration pneumonia and acute renal failure. No in-hospital mortality was registered. Only one patient (2.2 %) with anastomotic leakage developed postoperative anastomotic stenosis requiring balloon dilatation. CONCLUSIONS: The intrathoracic stapled side-to-side anastomosis technique seems to be feasible, safe, and easy to perform, associated with a limited postsurgical complication rate and a good functional outcome. PMID- 26960593 TI - James G. Anderson Tribute. PMID- 26960597 TI - MOOCers and shakers and chemistry course takers. PMID- 26960592 TI - Rescue management of early complications after liver transplantation-key for the long-term success. AB - PURPOSE: Postoperative complications may have not only immediate but also long term effects on the outcomes. Here, we analyzed the effect of postoperative complications requiring a reoperation (grade 3b) within the first 30 days on patients' and graft survival following liver transplantation. METHODS: Graft and patient survival in relation to donor and recipient variables and the need of reoperation for complications of 277 consecutive liver transplants performed from January 2007 to December 2012 were analyzed. RESULTS: Two hundred seventy-seven liver transplants were performed in 252 patients. Overall patient and graft survival at 1, 2, and 3 years were significantly reduced in patients requiring a reoperation. The labMELD score was significantly elevated (p = 0.04) and cold ischemia time was prolonged (p = 0.03) in recipients undergoing reoperations. Kaplan-Meier curves indicate that complications impact the outcome primarily within the first 3 months after transplantation. In multivariate analyses, the actual need of reoperation (p < 0.001), the labMELD score (p = 0.05), cold ischemia time (p = 0.02), and the need for hemodialysis pre-transplant (p = 0.05) were the only variables which correlated with the overall survival. CONCLUSION: Postoperative complications resulting in reoperations have a significant impact on the outcome primarily in the early phase after liver transplantation. Successful management of postoperative complications is key to every successful liver transplant program. PMID- 26960598 TI - Zika virus and microcephaly: is the correlation, causal or coincidental? PMID- 26960599 TI - Millennium development Goal 5: progress and challenges in reducing maternal deaths in Ghana. AB - BACKGROUND: High maternal deaths in developing countries are recognised as a public health issue. To address this concern, targets were set as part of the Millennium Development Goals, launched in 2000 by the United Nations General Assembly. However, despite focused efforts, the maternal health targets in developing regions may not be achieved by 2015. DISCUSSION: We highlight progress and challenges in reducing maternal deaths, with a particular focus on Ghana. We discuss key issues like the free maternal healthcare package, transportation and referral concerns, human resources challenges, as well as the introduction of direct-entry midwifery training and the Community-based Health and Planning Services rolled out to specifically help curb poor maternal health outcomes. A key contribution to the country's slow progress towards achieving Millennium Development Goal 5 is that policy choices have often been in response to emergency or advancing problems rather than the use of preventive measures. Ghana can benefit greatly from long-term preventive strategies, the development of human resources, infrastructure and community health education. PMID- 26960600 TI - Smart pH/Redox Dual-Responsive Nanogels for On-Demand Intracellular Anticancer Drug Release. AB - Efficient accumulation and intracellular drug release in cancer cells remain a crucial challenge in developing ideal anticancer drug delivery systems. Here, poly(N-isopropylacrylamide)-ss-acrylic acid (P(NIPAM-ss-AA)) nanogels based on NIPAM and AA cross-linked by N,N'-bis(acryloyl)cystamine (BAC) were constructed by precipitation polymerization. The nanogels exhibited pH/redox dual responsive doxorubicin (DOX) release behavior in vitro and in tumor cells, in which DOX release from nanogels was accelerated in lysosomal pH (pH 4.5) and cytosolic reduction (10 mM GSH) conditions. Moreover, intracellular tracking of DOX-loaded nanogels confirmed that after the nanogels and the loaded DOX entered the cells simultaneously mainly via lipid raft/caveolae-mediated endocytosis, DOX-loaded nanogels were transported to lysosomes and then the loaded DOX was released to nucleus triggered by lysosomal pH and cytoplasmic high GSH. MTT analysis showed that DOX-loaded nanogels could efficiently inhibit the proliferation of HepG2 cells. In vivo animal studies demonstrated that DOX-loaded nanogels were accumulated and penetrated in tumor tissues more efficiently than free DOX. Meanwhile, DOX-loaded nanogels exhibited stronger tumor inhibition activity and fewer side effects. This study indicated that pH/redox dual-responsive nanogels might present a prospective platform for intracellular drug controlled release in cancer therapy. PMID- 26960602 TI - "Frontiers of Vibrational Spectroscopy in Analytical Chemistry". PMID- 26960601 TI - "New Analytical Methodology and Materials for Mechanobiology". PMID- 26960603 TI - "Recent Advances in Nanoscale Particles and Structures for Analytical Applications". PMID- 26960604 TI - Backward-scattering-based Localized Surface Plasmon Resonance Sensors with Gold Nanospheres and Nanoshells. AB - Localized surface plasmon resonance (LSPR) sensors based on plasmonic nanoparticles are sensitive to changes in local refractive index, so that they are used for affinity-based chemical sensing and biosensing. Conventional LSPR sensors are generally based on transmission of light through the sensor and a sample solution, which could be colored or turbid. In this study, we develop backward-scattering-based LSPR sensors that can be applied to colored or turbid sample solutions. Au nanospheres (100 nm diameter) and Au nanoshells (25 nm thick) with SiO2 cores (80 nm diameter) are used as plasmonic nanoparticles and immobilized on a glass substrate. The refractive index sensitivities of the Au nanospheres and nanoshells are 128 and 278 nm RIU(-1), respectively, which are in good agreement with simulated values and the values for conventional transmission based LSPR sensors. The Au nanoshells require a lower amount of Au for the same scattering intensity in comparison with the Au nanospheres. The backward scattering-based LSPR sensing is possible with the Au nanospheres and nanoshells even in coffee as a colored and turbid sample. PMID- 26960605 TI - Thermal and Chemical Stabilization of Silver Nanoplates for Plasmonic Sensor Application. AB - Thermal and chemical stabilities of silver nanoplates (AgPLs), which are triangle plate-shaped silver nanoparticles, were improved by coating with titanium oxide. The titanium oxide layer prepared by a dip-coating method was certainly advantageous for the improvement of thermal stability. Furthermore, the overlayering of titanium oxide by a spray pyrolysis method was quite useful for improving the chemical stability against I(-) exposure. Such a coating exhibited satisfactory refractive index sensitivities. PMID- 26960606 TI - Optical Characterization of Gold Nanoparticle Layers Formed on Plastic Microbeads. AB - Generally, the characterization of a metal layer formed on a planar substrate has been achieved using scanning electron microscopy and transmission electron microscopy. These techniques provide details of the surface and/or the cross section of a planar structure with high resolution. However, the evaluation of sphere-like structures is troublesome owing to the necessity to observe a sample from various angles and/or to calculate the yield from many values obtained for many samples, since the conventional methods can observe a sample only from one direction. We have developed a simple evaluation method for a thin metal layer on plastic microbeads based on its light-scattering properties using dark-field microscopy coupled with a spectrometer. The light-scattering intensity of gold nanoparticle-coated microbeads depends significantly on the gold coverage. We believe that our study is significant because it describes the development and evaluation of the surface coverage of a thin metal layer on a sphere-like microstructure. PMID- 26960607 TI - Morphology Effects of Cap-shaped Silver Nanoparticle Films as a SERS Platform. AB - In this paper, we evaluate randomly adsorbed cap-shaped silver nanoparticles for applications to surface-enhanced Raman spectroscopy, SERS. They were prepared by depositing silver on top of surface-adsorbed monodisperse SiO2 nanospheres, in a manner similar to the method for preparing metal film on nanosphere, MFON, but one major difference lies in the fact that nanospheres are randomly adsorbed rather than as a close-packed MFON. With random MFON, it is possible to incorporate nanospheres with more than one size. Mixing has been found to increase SERS performance. More specifically, by using 50 and 100 nm nanospheres, we found that substrates containing both types outperform substrates prepared from 100% of either 50 or 100 nm nanospheres. As evaluated by spectrophotometry, this increase could not be attributed to an increase in the extinction coefficient of the substrate at the irradiation wavelength of SERS measurements. PMID- 26960608 TI - Biocatalytic Formation of Gold Nanoparticles Decorated with Functional Proteins inside Recombinant Escherichia coli Cells. AB - A novel strategy for the preparation of protein-decorated gold nanoparticles (Au NPs) was developed inside Escherichia coli cells, where an artificial oxidoreductase, composed of antibody-binding protein (pG), Bacillus stearothermophilus glycerol dehydrogenase (BsGLD) and a peptide tag with gold binding affinity (H6C), was overexpressed in the cytoplasm. In situ formation of Au NPs was promoted by a natural electron-donating cofactor, nicotinamide adenine dinucleotide (NAD), which was regenerated to the reduced form of NADH by the catalytic activity of the fusion protein (pG-BsGLD-H6C) overexpressed in the cytoplasm of E. coli, with the concomitant addition of exogenous glycerol to the reaction system. The fusion protein was self-immobilized on Au NPs inside the E. coli cells, which was confirmed by SDS-PAGE and western blotting analyses of the resultant Au NPs. Finally, the IgG binding ability of the pG moiety displayed on Au NPs was evaluated by an enzyme-linked immunosorbent assay. PMID- 26960609 TI - Light-scattering Characteristics of Metal Nanoparticles on a Single Bacterial Cell. AB - Metal nanoparticles express unique light-scattering characteristics based on the localized surface plasmon resonance, which depends on the metal species, particle size, and aggregation state of the nanoparticles. Therefore, we focused on the light-scattering characteristics of metal nanoparticles, such as silver, gold, and copper oxide, adsorbed on a bacterium. Monodisperse silver nanoparticles expressed the strongest scattered light among them, and showed various colors of scattered light. Although a monodisperse gold nanoparticle produced monochromatic light (green color), the color of the scattered light strongly depended on the aggregation state of the nanoparticles on a bacterium. On the other hand, copper oxide nanoparticles expressed monochromatic light (blue color), regardless of their aggregation states on a bacterium. We examined details concerning the light scattering characteristics of metal nanoparticles, and discussed the possibility of their applications to bacterial cell imaging. PMID- 26960610 TI - Dark Field Microscopic Sensitive Detection of Amyloid Fibrils Using Gold Nanoparticles Modified with Antibody. AB - Dark field microscopy (DFM) was employed to detect amyloid beta (Abeta) fibrils induced gold nanoparticle (AuNP) aggregation at the single-particle level, with a detection limit of 40 pM fibrils. The sensitivity of this method is higher than that of the current fibril-specific detection method using probe dye, such as thioflavin T, for which sub-MUM level of fibrils are necessary. This study further proved the potential application of DFM in the analytical methods based on AuNP aggregation. PMID- 26960611 TI - Spectrofluorimetric Method for Quantification of Triazine Herbicides in Agricultural Matrices. AB - A spectrofluorimetric method for determination of triazine herbicides was developed. The method involves reaction of ammonical 2-cyanoacetamide with the herbicide. The net fluorescent intensity (FI) of the product was measured at 376 nm using 330 nm as excitation wavelength. A linear relationship between concentration and FI was found in the range of 0.3 - 10 MUg mL(-1) for atrazine and 0.2 - 10 MUg mL(-1) for terbutryn. The LOD and LOQ were found to be 0.07 +/- 0.023 MUg mL(-1) and 0.23 +/- 0.023 MUg mL(-1), respectively, with %RSD <12.1% for atrazine and 0.027 +/- 0.009 MUg mL(-1) and 0.091 +/- 0.009 MUg mL(-1), respectively, with %RSD <5% for terbutryn. The %recoveries of the subject triazines from soil and wheat grains were found in the range of 90.0 +/- 0.14 to 96.0 +/- 0.15% for atrazine and 95.0 +/- 0.05 to 98 +/- 0.02% for terbutryn. PMID- 26960612 TI - Inhibition of Rhodamine B-Ferricyanide Chemiluminescence by Gold Nanoparticles and Sensitive Determination of Hazardous Cyanide. AB - We describe a new turn off-on chemiluminescence (CL) method for the sensitive and selective determination of cyanide based on the inhibiting effect of gold nanoparticles (AuNPs) on rhodamine B (RohB)-ferricyanide (Fe(CN)6(3-)) reaction. Free RohB can generate strong chemiluminescence emission when oxidized with Fe(CN)6(3-), but undergoes an intense extinction in the presence of AuNPs. Energy transfer and collisions between RohB molecules and AuNPs are probably the reason for this decreasing effect. Furthermore, it was found that CL intensity gradually recovered in the presence of cyanide due to its interaction with the AuNPs. The relation between the decreased CL intensity and cyanide concentration was exploited to develop a method for the determination of cyanide in the 16.7 - 1333 nmol L(-1) concentration range, with a detection limit of 13.6 nmol L(-1). In comparison with other nanoparticle-based methods, the presented assay shows good sensitivity and reliability for the determination of cyanide. The method was satisfactorily applied to the determination of cyanide in environmental and biological samples. PMID- 26960613 TI - A Sensitive and Disposable Graphene Oxide Electrochemical Immunosensor for Label free Detection of Human Immunoglobulin G. AB - In this work, a cost-effective and simple-to-prepare label-free electrochemical immunosensor was, for the first time, fabricated by modifying high-quality graphene oxide (GPO) onto a screen-printed carbon electrode (SPCE). The anti-IgG antibody was then covalently immobilized to the carboxylic group anchoring on the surface of GPO particles. Under the optimized condition, our newly developed immunosensor selectively bound to human immunoglobulin G (IgG), a model biomarker, with high sensitivity at a limit of detection of 1.99 ng mL(-1), potentially sensitive enough for IgG detection at the pathophysiological level, and had a linear range of 2.5 to 100 ng mL(-1). The proposed immunosensor also exhibited high reproducibility and regenerability, resulting in no significant change in electrochemical signals from different replicates of the electrode, and a robust electrochemical current after being subjected to alkaline base washing with several cycles. To this end, our immunosensor demonstrates ability as a promising diagnostic tool for clinical assessment. PMID- 26960614 TI - A Green Sequential Injection Spectrophotometric Approach Using Natural Reagent Extracts from Heartwood of Ceasalpinia sappan Linn. for Determination of Aluminium. AB - A cost-effective and environmentally friendly approach using a simple sequential injection spectrophotometric system with a non-synthetic reagent from plant extracts was proposed for a green analytical-chemistry methodology. The crude aqueous extracts from heartwood of Ceasalpinia sappan Linn. in acetate buffer pH 5.5 were utilized as an alternative natural reagent for the quantification of aluminium. The extracts contained homoisoflavonoid compounds, brazilin, and brazilein, which reacted with Al(3+) to form reddish complexes with the maximum absorption wavelength at 530 nm. The optimum conditions for the sequential injection parameters, such as sequential profile, sample and reagent volumes, and the pH effect, were investigated. Under the optimum conditions, a linear calibration graph in the range of 0.075 - 1.0 mg L(-1) Al(3+) was obtained with limits of detection and quantification of 0.021 and 0.072 mg L(-1) Al(3+), respectively. Relative standard deviations of 3.2 and 2.4% for 0.1 and 0.25 mg L( 1) Al(3+) (n = 11), respectively, and sampling rate of 128 injections h(-1) were achieved. The developed system was successfully applied to pharmaceutical preparations, water, and beverage samples. The results agreed well with those obtained from the ICP-AES method. Good recoveries between 87 and 104% were obtained. PMID- 26960615 TI - Flow-Injection Determination of Thiabendazole Fungicide in Water Samples Using a Diperiodatocuprate(III)-Sulfuric Acid-Chemiluminescence System. AB - Chemiluminescence (CL) with a flow-injection method is reported for the determination of thiabendazole (TBZ) fungicide based on its enhancement effect on diperiodatocuprate(III) (DPC)-sulfuric acid-CL system. The calibration graph was linear in the concentration range of 1 - 2000 MUg L(-1) (R(2) = 0.9999, n = 8) with a limit of detection (S/N = 3) of 0.3 MUg L(-1). The injection throughput was 160 h(-1) with relative standard deviations (RSD, n = 4) of 1.1 - 2.9% in the concentration range studied. The experimental variables e.g., reagents concentrations, flow rates, sample volume, and PMT voltage were optimized, and the potential interferences were investigated individually. The method was successfully applied to the determination of TBZ in water samples showing good agreement and recovery in the range of 92 +/- 2.2 - 108 +/- 3% (n = 3) using dispersive liquid-liquid micro-extraction (DLLME). The possible CL reaction mechanism for DPC-sulfuric acid-TBZ is also discussed. PMID- 26960616 TI - Enhanced Retention of Chelating Reagents in Octadecylsilyl Silica Phase by Interaction with Residual Silanol Groups in Solid Phase Extraction of Divalent Metal Ions. AB - Solid-phase extraction (SPE) of divalent metal ions with a lipophilic and potentially divalent hexadentate chelating reagent (H2L), with which octadecylsilyl silica (ODS), was impregnated with was studied to gain more insight into and develop the potential of this methodology. This is the first time to demonstrate that this reagent as well as other common nitrogen-containing reagents were retained both by adsorption due to hydrogen bonding between nitrogen atoms of the reagent and residual silanol groups in the ODS phase and by simple distribution into the hydrophobic space. An appreciably large amount of this reagent could be retained by the adsorption mechanism even with a relatively thin loading solution. The divalent metal ions of Mn(2+), Co(2+) and Zn(2+) were extracted as 1:1 neutral complexes ([ML]), while Ni(2+) and Cu(2+) as ion-pairs of 1:1 cationic complex ([MHL](+)) with anion in SPE with H2L. The extractability and selectivity were substantially the same as that in liquid-liquid extraction. PMID- 26960617 TI - An Easy-to-Use Polystyrene Microchip-based Cell Culture System. AB - In this study, we developed an integrated, low-cost microfluidic cell culture system that is easy to use. This system consists of a disposable polystyrene microchip, a polytetrafluoroethylene valve, an air bubble trap, and an indium tin oxide temperature controller. Valve pressure resistance was validated with a manometer to be 3 MPa. The trap protected against bubble contamination. The temperature controller enabled the culture of Macaca mulatta RF/6A 135 vascular endothelial cells, which are difficult to culture in glass microchips, without a CO2 incubator. We determined the optimal coating conditions for these cells and were able to achieve stable, confluent culture within 1 week. This practical system is suitable for low-cost screening and has potential applications as circulatory cell culture systems and research platforms in cell biology. PMID- 26960618 TI - Impedance Analysis of Colloidal Gold Nanoparticles in Chromatography Paper for Quantitation of an Immunochromatographic Assay. AB - A detection method of gold nanoparticles in chromatography paper has been developed for a simple, cost-effective and reliable quantitation of immunochromatographic strip test. The time courses of the solution resistance in chromatography paper with the gold nanoparticles solution are electrochemically measured by chrono-impedimetry. The dependence of the solution resistance on the concentration of gold nanoparticles has been successfully observed. The main factor to increase the solution resistance may be obstruction of the ion transport due to the presence of gold nanoparticles. The existence of gold nanoparticles with 1.92 * 10(9) particles/mL in an indistinctly-colored chromatography paper is also identified by a solution resistance measurement. This indicates that the solution resistance assay has the potential to lower the detection limit of the conventional qualitative assay. PMID- 26960619 TI - A Method for the Highly Selective, Colorimetric and Ratiometric Detection of Hg(2+) in a 100% Aqueous Solution. AB - Mercury (Hg) and its derivatives pose a serious threat to the environment and human health. Thus, the development of methods for the selective and sensitive determination of Hg(2+) is very important to understand its distribution, and to implement more detailed toxicological studies. Herein, we developed a new method for the detection of Hg(2+) based on the tricyanoethylene derivative and mercaptoethanol. This method could selectively detect Hg(2+) in a 100% aqueous solution by the naked-eye within the range of 1 - 60 MUM. Importantly, this method also could detect Hg(2+) quantitatively by ratiometic absorption spectroscopy in the range of 0.1 - 6 MUM with a detection limit of 55 nM. We anticipate that this proposed method will be used widely to monitor Hg(2+) in the environment. PMID- 26960620 TI - Improvement of the Mutation-Discrimination Threshold for Rare Point Mutations by a Separation-Free Ligase Detection Reaction Assay Based on Fluorescence Resonance Energy Transfer. AB - We previously developed a separation-free ligase detection reaction assay based on fluorescence resonance energy transfer from a donor quantum dot to an acceptor fluorescent dye. This assay could successfully detect one cancer mutation among 10 wild-type templates. In the current study, the mutation-discrimination threshold was improved by one order of magnitude by replacing the original acceptor dye (Alexa Fluor 647) with another fluorescent dye (Cyanine 5) that was spectrally similar but more fluorescent. PMID- 26960621 TI - A Rapid and Automated Device for Purifying Nucleic Acids. AB - We have developed a rapid, automated nucleic acid purification device in a single cartridge containing silica-coated magnetic beads. We succeeded in extracting the matrix protein gene of influenza A virus from pharyngeal swab samples within 3 min. The device will be widely applicable to detect a specific gene from the various samples for clinical diagnosis and genetic research. PMID- 26960623 TI - Highly Stable Mesoporous Zirconium Porphyrinic Frameworks with Distinct Flexibility. AB - The construction of highly stable metal-porphyrinic frameworks (MPFs) is appealing as these materials offer great opportunities for applications in artificial light-harvesting systems, gas storage, heterogeneous catalysis, etc. Herein, we report the synthesis of a novel mesoporous metal-porphyrinic framework (denoted as NUPF-1) and its catalytic properties. NUPF-1 is constructed from a new porphyrin linker and a Zr6 O8 structural building unit, possessing an unprecedented doubly interpenetrating scu net. The structure exhibits not only remarkable chemical and thermal stabilities, but also a distinct structural flexibility, which is seldom seen in metal-organic framework (MOF) materials. By the merit of high chemical stability, NUPF-1 could be easily post-metallized with [Ru3 (CO)12 ], and the resulting {NUPF-1-RuCO} is catalytically active as a heterogeneous catalyst for intermolecular C(sp(3) )-H amination. Excellent yields and good recyclability for amination of small substrates with various organic azides have been achieved. PMID- 26960624 TI - Pharmacokinetics, efficacy prediction indexes, and residue depletion of ribavirin in Atlantic salmon's (Salmo salar) muscle after oral administration in feed. AB - Ribavirin is an antiviral used in human medicine, but it has not been authorized for use in veterinary medicine although it is effective against infectious salmon anemia (ISA) virus, between others. In this study, we present a pharmacokinetic profile of ribavirin in Atlantic salmon (Salmo salar), efficacy prediction indexes, and the measure of its withdrawal time. To determine the pharmacokinetic profile, fishes were orally administered with a single ribavirin dose of 1.6 mg/kg bw, and then, plasma concentrations were measured at different times. From the time-vs.-concentration curve, Cmax = 413.57 ng/mL, Tmax = 6.96 h, AUC = 21394.01 MUg.h/mL, t1/2 = 81.61 h, and K10 = 0.0421/h were obtained. Ribavirin reached adequate concentrations during the pharmacokinetic study, with prediction indexes of Cmax /IC50 = 20.7, AUC/IC50 = 1069.7, and T>IC50 = 71 h, where IC is the inhibitory concentration 50%. For ribavirin depletion study, fishes were orally administered with a dairy dose of 1.6 mg/kg bw during 10 days. Concentrations were measured on edible tissue on different days post-treatment. A linear regression of the time vs. concentration was conducted, obtaining a withdrawal time of 1966 degrees C days. Results obtained reveal that the dose of 1.6 mg/kg bw orally administered is effective for ISA virus, originating a reasonable withdrawal period within the productive schedules of Atlantic salmon. PMID- 26960625 TI - From Editor's desk. PMID- 26960627 TI - Iatrogenic immunodeficiency-associated lymphoproliferative disorders in transplant and nontransplant settings. AB - Iatrogenic immunodeficiency-associated lymphoproliferative disorders comprise a group of lymphoid neoplasms that are associated with an immunosuppressed state, either in the posttransplant period, or during the treatment of various autoimmune and rheumatologic disorders by immunomodulatory medications. Their morphologies vary widely but are generally classified according to the lymphomas that they most closely resemble. This group is strongly associated with infections by the Epstein-Barr virus as a result of impaired immune function in the immunosuppressed state. Although further classification may become necessary in the coming years, they are distinguished from lymphomas in immunocompetent hosts because reduction or cessation of immunosuppressive or immunomodulatory therapy can result in complete clinical remission. PMID- 26960626 TI - The revised guidelines of the Medical Council of India for academic promotions: Need for a rethink. PMID- 26960628 TI - Panniculitis is a common unrecognized histopathological feature of cutaneous leishmaniasis. AB - BACKGROUND: Cutaneous leishmaniasis (CL) is a parasitic cutaneous infection caused by Leishmania parasite. The histopathology is usually granulomatous in nature. AIMS: The aim of the present study is to elucidate the histology of CL and evaluate the presence and the frequency of panniculitis among the affected patients. SETTINGS AND DESIGN: Case series interventional study. MATERIALS AND METHODS: Thirty-five patients with CL were diagnosed clinically between December 2012 and May-2013. Diagnostic confirmation established by smears, culture, and polymerase chain reaction (PCR). The histopathological assessment was carried out to study the general pathology and to look for the presence of panniculitis. STATISTICAL ANALYSIS USED: Simple statistics utilized via SPSS version 16.0 (SPSS, Inc., Chicago, USA). RESULTS: Eighteen women and 17 men with CL were enrolled in the present work with a mean duration of their disease was 3 months. The results of the diagnostic tests were as follow: The smear was positive in 21 (60%) of cases, Leishman-Donovan (LD) bodies were seen in 7 (20%) patients, culture was positive in 24 (68%), and PCR was positive in 32 (91.4%) patients. The epidermal changes included acanthosis, pseudoepitheliomatous hyperplasia, ulceration, focal spongiosis, and interface dermatitis while the dermal changes were dependent on the spectrum of the disease, so in the ulcerative lesions there was lymphohistiocytic infiltration with foci of plasma cells and sometimes aggregate of LD bodies, whereas in the dry lesions the pathology is mainly of epithelioid granuloma. Panniculitis was seen in 16 (46%) cases as a diffuse lymphohistiocytic infiltration of both the septum and lobules of the subcutaneous layer of the skin. CONCLUSION: Panniculitis is an important feature of CL that must be differentiated from other diseases that can simulate CL such as chronic skin infections, Discoid lupus erythematosus, and cutaneous lymphoma. PMID- 26960629 TI - A clinicopathological study of mediastinal masses operated in a tertiary care hospital in Eastern India in 3 years with special reference to thymoma. AB - INTRODUCTION: The mediastinum is the central portion of the thoracic cavity, limited by pleural cavities laterally, thoracic inlet superiorly, and the diaphragm inferiorly. Housing numerous organs, it is a veritable Pandora's box, within which various lesions may develop. This study was conducted to assess the epidemiologic profile, clinicoradiological features, cytological, and histopathological findings in patients presenting with mediastinal masses in a tertiary care hospital over a period of 3 years. MATERIALS AND METHODS: This is a retrospective study of cases presenting with mediastinal masses attending the Cardiothoracic Surgery Department of Medical College, Kolkata between May 2011 and April 2014. Detailed history, physical, and radiological findings were noted. Fine needle aspiration cytology (FNAC) was performed when feasible. Following surgery, histopathological, and immunohistochemical (IHC) examinations of the specimens were undertaken. RESULTS: Of the 22 cases included in our study, ten were anterior, seven middle, and five posterior mediastinal masses. Fifteen cases were male and seven were female. Thymic pathology was detected in seven cases, lymphoma in five, extragonadal germ cell tumor (GCT) in three, schwannoma and pericardial cyst in two cases each and neurofibroma, ganglioneuroma, and retrosternal thyroid in one case each. The age group of the patients for each diagnostic category was found to be of significance. FNAC was done in 15 cases. IHC was required for classification of lymphoma cases (CD45, CD15, CD30, CD20, CD3, Tdt, CD34, and Ki-67). CONCLUSION: This study reflects the incidence of different mediastinal masses in West Bengal with their clinicopathologic correlation. PMID- 26960630 TI - Clinico-histopathological study of varicose vein and role of matrix metalloproteinases-1, matrix metalloproteinases-9 and tissue inhibitor of matrix metalloproteinase-1 in varicose vein formation. AB - BACKGROUND AND AIMS: Varicose vein (VV) is an important cause of morbidity in the young and elderly population. Many studies of the Western country suggest that matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs have a crucial role in the pathogenesis of VV, but limited work has been done in Indian population. The aim of this study is to study detailed histology of VV and to see the expression of MMP-1, MMP-9 and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1). MATERIALS AND METHODS: A total of 63 cases of VV and 10 control leg veins were included in this prospective study. Paraffin sections of VV were prepared. Hematoxylin and eosin (H and E), Masson trichrome and Verhoeff's staining were performed. Immunohistochemistry of VV was done with MMP-1, MMP-9, and TIMP-1 antibodies. Cytoplasmic expression of MMP-1, MMP-9 and TIMP-1 were graded as intense positive (++), weak/slight positive (+), and absent (-). RESULTS: Focal intimal thickening (47.6%), increased medial thickening (73%) and fragmentation of elastin fibers (84.1%) were the major histological changes noted in H and E and special stained sections. MMP-1 expression increased in all layers of VV in 58 cases (92.1%) as compared to control veins. As compared to the control veins, intimal and adventitial expression of MMP-9 were increased in 31 (49.2%) and 40 (63.5%) cases, respectively. Expression of TIMP-1 was absent in both the varicose and the control veins. CONCLUSION: Increased expression of MMP 1 and MMP-9 suggests they have an important role in the pathogenesis of VV. PMID- 26960631 TI - Kaleidoscope of oral artifacts: A vivid picture through light and polarizing microscope. AB - BACKGROUND: This study is based on finding of an inexplicable artifact that was seen in the tissue received as periapical granuloma. AIM: To observe the histological appearance of different commonly implanted food particles and easily incorporated substances from a laboratory in the oral biopsy tissues. MATERIALS AND METHODS: Various food particles such as wheat chapatti, beans, peas, pulses, and coriander leaves and substances such as a suture, cotton, and paper that can easily gain entry during biopsy and histotechnical procedures were intentionally introduced in the tissue specimens of a uterus from outside. Both light and polarizing microscopes were utilized to view them. RESULTS: Different food particles and substances gave different appearances that could lead to misdiagnosis. Some of these also exhibited positive birefringence under the polarizing microscope. CONCLUSION: Knowledge and familiarity with probable foreign substances which can appear in tissues may help prevent misdiagnosis or erroneous diagnosis of biopsy specimens. PMID- 26960632 TI - Prognostic impact of epidermal growth factor receptor on clear cell renal cell carcinoma: Does it change with different expression patterns? AB - INTRODUCTION: The aim of this study was to assess whether epidermal growth factor receptor (EGFR) overexpression was a significant prognostic factor in clear cell renal cell carcinoma (CRCC) and whether its prognostic significance was affected by immunohistochemical expression patterns. MATERIALS AND METHODS: Immunohistochemistry was performed on 100 cases of CRCC using an antibody against EGFR. Tumors were grouped by nuclear grade (NG) as low-NG (NG1, 2) or high NG (NG3, 4), and by pathological stage as localized (pT1, 2), or locally invasive (pT3, 4). Clinical disease was grouped by clinical stage as early stage (stage I, II), or late stage (stage III, IV). Evaluation of the EGFR overexpression was based on cytoplasmic (EGFR Cyt), and membranous (EGFR Mem) staining. RESULTS: EGFR Cyt correlated with high NG (P = 0.001), lymphovascular invasion (P = 0.028), regional lymph node involvement (P = 0.027), metastasis (P = 0.001), late stage (P = 0.003), cancer-specific death (P = 0.036), and was a predictor for disease-specific survival (P = 0.012) whereas EGFR Mem correlated with only local invasion (P = 0.021) and perirenal invasion (P = 0.009) and did not show any correlation with cancer-specific death or disease specific survival. CONCLUSION: Our findings suggest that EGFR overexpression is an important prognostic factor in CRCC, and its prognostic value differs significantly with respect to the location of EGFR immunostaining. This prognostic difference may give direction on the management and treatment of CRCC patients. PMID- 26960633 TI - C-MYC and BCL2 translocation frequency in diffuse large B-cell lymphomas: A study of 97 patients. AB - PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with marked biologic heterogeneity. MYC and BCL2 rearrangements have been reported in a proportion of DLBCLs, where they may be associated with an adverse clinical outcome. The aim of this study was to determine the frequency of MYC and BCL2 translocations in DLBCL and assess the prognostic impact in DLBCL patients. MATERIALS AND METHODS: In the present study, we evaluated the expression patterns of CD 10, BCL6, and MUM 1 by immunohistochemistry in 121 cases with DLBCL in tissue microarray (TMA): 62 cases in germinal center B-cells (GCBs); and 59 cases in activated B-cells (ABCs) of which 60 were females and 61 were males. MYC and BCL2 rearrangements were investigated by interphase fluorescence in situ hybridization on TMAs in 97 DLBCLs. RESULT: MYC rearrangements were observed in 11 of 97 cases. There was no association with other clinical features, including age, sex, and nodal/extranodal disease. MYC rearrangement was associated with significantly worse overall survival (P < 0.01). BCL2 rearrangements were observed in 14 of 97 cases. There was no association with other clinical features including age and sex. BCL2 rearrangement had a worse outcome (P < 0.01). MYC and BCL2 rearrangements were observed in 3 of 97 cases with the age of 53 (female), 53, 63 years old, respectively, died in 24, 18, and 35 months after the diagnosis. Two cases had primary nodal and one case primary extranodal presentations. All these patients had stage IV disease. CONCLUSION: We concluded that C-MYC and BCL2 may contribute to aggressive transformation, and more mechanism-based therapy should be explored. Targeted therapies involving these rearrangements and its associated pathways may change the fate of DLBCLs. Analysis of MYC gene rearrangement along with BCL2 is critical in the identification of high-risk patients with poor prognosis. PMID- 26960634 TI - Rare and unusual isolates of viridans streptococci from the human oral cavity. AB - CONTEXT: The genus Streptococcus consists of more than 65 species. The taxonomic classification of these members is not well-defined. Among the viridans group streptococci (VGS), there are major taxonomic changes by the addition of many new species; whereas, most of the new strains are of animal origin and only a few have been reported to be isolated from humans. Rare and unusual species of VGS such as Streptococcus thoraltensis, S. pluranimalium and S. hyointestinalis are normally associated with different animals. Their isolation from human being is not yet reported. AIM: To find out the rare and unusual species of viridans group streptococci from human oral cavity. SETTINGS AND DESIGN: A case-controlled study carried out at hospital-based dental services in a tertiary care hospital. MATERIALS AND METHODS: Subgingival plaque samples of the tooth were collected from 80 patients (34 with periodontitis and 46 without periodontitis) undergoing tooth extraction. Cultures were subcultured onto special media such as Tryptone Soya blood Agar supplemented with strepto supplement and Mutans-Sanguis Agar. Identification of strains and antimicrobial susceptibilities were measured as minimum inhibitory concentration using Vitek 2 (BioMerieux, Paris, France) automated system. RESULTS: We have identified three strains of VGS - S. thoraltensis, S. pluranimalium and S. hyointestinalis from subgingival plaque samples from patients with periodontitis. S. thoraltensis and S. pluranimalium were found to be resistant to most of the antibiotics. CONCLUSIONS: To the best of our knowledge, this is the first report of isolation of these rare and unusual strains from the human oral cavity. PMID- 26960635 TI - Emergence of antimicrobial resistance and virulence factors among the unusual species of enterococci, from North India. AB - BACKGROUND: Several enterococcal species are increasingly being reported from clinical infections, besides the major species. AIM: This study was undertaken to determine the prevalence of unusual enterococcal species and their antimicrobial susceptibility patterns, virulence factors, and molecular characterization. STUDY DESIGN AND SETTINGS: The study was conducted in Department of Microbiology and associated Tertiary Care University Hospital in North India. MATERIALS AND METHODS: Enterococcal isolates were collected for a period of 2 years from clinical specimens. Identification and elaborate phenotypic characterization was done biochemically. All the isolates were tested by Kirby-Bauer disc diffusion method and breakpoint minimum inhibitory concentration for susceptibility against standard antibiotics. Screening for vancomycin-resistant enterococci (VRE), high level aminoglycoside resistance was done on brain heart infusion agar incorporated with 6 MUg/ml vancomycin, 500 MUg/ml gentamicin, and 2000 MUg/ml streptomycin, respectively. VRE isolates were tested for the presence of vanA, vanB, and vanC genes and high-level gentamicin resistant (HLGR) isolates for aac 6'- aph-2' gene by polymerase chain reaction (PCR). Hemolysin and gelatinase production, hemagglutination and biofilm formation were detected along with asa1, gelE, esp, hyl, and cylA genes by multiplex PCR. RESULTS: Of 403 enterococci, 93 (23.07%) isolates were identified as unusual species and atypical variants. Resistance of 52.68%, 46.23%, 44.08%, and 6.45% for ampicillin, ciprofloxacin, high strength gentamicin, and vancomycin, respectively were noted. Presence of vanC gene in Enterococcus gallinarum and Enterococcus casseliflavus isolates and vanA gene in Enterococcus durans and Enterococcus hirae and aac-6'- aph-2'' gene was found in 33.14% (14/41) of the HLGR isolates. The most frequent virulence factor was biofilm production. Only a few isolates harbored asa1 (2), gelE (9), and hyl (3) genes. CONCLUSION: Considerable prevalence of pathogenic unusual species of enterococci was seen along with their emerging drug resistance and virulence. Complete identification and routine speciation is essential to limit their emergence as major species in near future. PMID- 26960636 TI - Pleuropulmonary paragonimiasis with migrated lesions cured by multiple therapies. AB - Paragonimiasis is an infectious disease caused by Trematodes of the genus Paragonimus that is endemic in Asia, Africa, and South America. Most patients with paragonimiasis are cured by standard praziquantel treatment. However, several cases have been reported to have unsatisfactory responses to the standard praziquantel treatment. To probe the clinical characteristics, possible cause, and management of the paragonimiasis individuals improved by multiple therapies, we present a 12-year-old Chinese boy, who was infected with Paragonimus accompanied by arachnoid cyst involvement, as not having typical clinical symptoms, but repeatedly presenting with migrated lesions between the lung and pleura. He responded to treatment with 3 cycles of praziquantel and 1 cycle of albendazole. PMID- 26960638 TI - Influenza A(H1N1)pdm09 cases in sub-Himalayan region, 2014-2015 India. AB - Current influenza A(H1N1)pdm09 strain severely involved many parts of the country. The study was conducted to analyze the clinicoepidemiological trend of influenza A(H1N1)pdm09 cases from October 2014 to March 2015. Samples processing was done as per the Center for Disease Control guidelines. A total of 333 specimens were processed out of which influenza A(H1N1)pdm09 constituted 24% (81) of total, 5% (18) cases were seasonal influenza A virus strains. Mean age group involved was 49 years with case fatality rate of 20%. Patients died were 63% males and 44% had comorbidities, and among them, 38% patients died within 24 h of hospitalization. The mean age of comorbid patients who died was 59 years; whereas the mean age of patients died having no co-morbidities was 41 years (P < 0.005). Mortality was seen among 81% (13) of patients who were on ventilator support. Added mortality in specific human group demands continuous surveillance monitoring followed by the detection of mutation, even in susceptible animal population. PMID- 26960637 TI - Genetic diversity through human leukocyte antigen typing in end-stage renal disease patients and prospective donors of North India. AB - As the incidence of end-stage renal disease (ESRD) is rapidly increasing, the demand for dialysis and transplantation has dramatically increased, which has led to concerns about the availability and equitable allocation of kidneys for transplantation. The distribution of HLA-A, B and DR alleles in 148 renal transplant recipients and 191 live related prospective donors from 2009 to 2010 were analyzed. Allele frequencies and haplotype frequencies were calculated in recipients and donors. The prospective donors were further analyzed on the basis of their relationship to the patients and according to the sex ratio. A significant female preponderance was noted in the prospective donor population, most of whom were either siblings or parents of the recipients. On the contrary, the recipient population predominantly comprised of males. The most frequent HLA A, HLA-B, HLA-DRB1 alleles in renal transplant patients were HLA-AFNx0111, AFNx0102, AFNx0101, AFNx0124; HLA-BFNx0135, BFNx0140, BFNx0144, BFNx0115, BFNx0152, and HLA-DRB1FNx0115, DRB1FNx0107, DRB1FNx0113, DRB1FNx0111 respectively. The most frequent HLA-A, HLA-B, HLA-DRB1 alleles in prospective donors were HLA-AFNx0102, AFNx0111, AFNx0133, AFNx0124; HLA-BFNx0135, BFNx0144, BFNx0140, BFNx0115 and HLA-DRB1FNx0115, DRB1FNx0107, DRB1FNx0111, DRB1FNx0113 respectively. AFNx0111-BFNx0135, AFNx0102-DRB1FNx0115, BFNx0140-DRB1FNx0115 were the most common HLA A-B , HLA A-DR, HLA B-DR haplotypes respectively in renal transplant patients, whereas, AFNx0111-BFNx0135, AFNx0111-DRB1FNx0115, BFNx0144 DRB1FNx0107 were the most common haplotypes in renal donors. In three locus haplotype, HLA-AFNx0102-BFNx0140-DRB1FNx0115 was the most frequent haplotype in patients, whereas, in prospective renal donors HLA-AFNx0133-BFNx0144-DRB1FNx0107 was the most frequent haplotype. PMID- 26960639 TI - Application of a stool antigen test to evaluate the burden of Helicobacter pylori infection in dyspepsia patients. AB - Helicobacter pylori (HP) is causally associated with peptic ulcer disease and gastric carcinoma. Determination of the prevalence of HP infection in dyspepsia patients' in particular geographical area is imperative for the appropriate management of dyspepsia. HP antigen detection in stool is a noninvasive diagnostic test of HP infection. This prospective study was conducted to find out the prevalence of HP infection based on stool antigen testing in dyspeptic patients who had also undergone upper gastrointestinal (GI) endoscopy. This study highlights the high prevalence of HP infection in dyspeptic Indian patients, particularly males, and emphasizes the growing importance of the bacterium causing infection among children. We also found HP stool antigen testing to be superior to upper GI endoscopy for detecting HP infection. Hence, we recommend initial testing for HP stool antigen in dyspeptic patients before initiating treatment and before carrying out any invasive procedure such as endoscopy. PMID- 26960640 TI - Sclerosing liposarcoma of the anterior mediastinum: An unusual case. AB - Liposarcomas are extremely rare in the mediastinum. Patients usually present late due to the compressive effect of the tumor on the adjacent structures. Severity of the symptoms depend mainly on the size of the tumor and the structure it infiltrates. Well differentiated slow growing liposarcomas are the most common ones in the mediastinum followed by dedifferentiated and poorly differentiated ones. These tumors have bad prognosis because of incomplete surgical excision due to its inaccessible location. Hence these patients should be kept under close follow up because of high recurrent rates. Here we are presenting a rare case of anterior mediastinal sclerosing liposarcoma in a 77 year old male. PMID- 26960641 TI - Ambiguous genitalia: A rare case report. AB - Mixed gonadal dysgenesis (MGD) is a rare disorder of sexual development (DSD). A seven-year-old child with vagina and an elongated clitoris looking like a penile part of male external genitalia, presented in the Paediatric Surgery Department. Ultrasound of pelvis revealed a streak ovary on the right side and ovotestis on the left side. Uterus was not visualized. Karyotyping revealed 46, XY/45, XO genotype. Laparoscopic gonadectomy with vaginoplasty and the clitoral reduction was performed. A thorough histopathological examination of the specimen revealed structure of ovotestis-consisting of the ovary with Graafian follicles, fallopian tube, infantile testis with Leydig and Sertoli cells, epididymis, vas deference, and pampiniform plexus. Presence of Graafian follicle in the ovary, Leydig and Sertoli cells in the testis, at this age makes this case extremely interesting. The child was rehabilitated to lead her life as a girl. PMID- 26960642 TI - Type III collagen disorders: A case report and review of literature. AB - Collagen type III is a normal component of interstitium and blood vessels. Collagenofibrotic glomerulopathy (CG) and nail patella syndrome (NPS) are the diseases of abnormal type III collagen deposition. In spite of these curved frayed structures with a periodicity of 45-60 nm are deposited in subendothelium and mesangium in CG, they are found only in the basement membrane in NPS. The clinical features of CG are confined to the kidney, NPS has associated extra renal manifestations. Electron microscopy is essential to make the renal diagnosis in both these rare diseases. Both the entities considered to be systemic diseases evidence to suggest similar deposition in other organs, understanding etiopathogenesis and disease progression await research. PMID- 26960643 TI - Postradiation angiosarcoma of bladder with extensive osseous metaplasia. AB - Angiosarcomas are rare soft tissue neoplasms accounting for <2% of all sarcomas. Rare cases have been reported in other sites like breast, spleen, liver, bone and bladder. This is a case report of an angiosarcoma of the bladder in a 65 year old lady who came with complaints of haematuria. Ultrasonography and computerized tomography revealed a bladder tumour with calcification, which on cystoscopy also showed a calcified mass. The patient had a past history of carcinoma cervix for which she had undergone surgery and radiotherapy, 22 years ago. Biopsy of the bladder mass showed features of a high grade epithelioid sarcoma with extensive osseous metaplasia. On immune stains,the tumour was positive for CD31 and vimentin and negative for cytokeratin, desmin and CD34. Until now, only sixteen cases of angiosarcoma of the bladder have been reported in english literature, of which 6 occurred secondary to radiation. Our case is the first to occur after 22 years of radiotherapy and have extensive osseous metaplasia. PMID- 26960644 TI - Type D lymphomatoid papulosis simulating aggressive epidermotropic cytotoxic lymphoma. AB - Three histological subtypes of lymphomatoid papulosis (LyP), type A (histiocytic), type B (mycosis fungoides like) and type C (anaplastic large cell lymphoma like) are well recognized. Two new histological variants, type D (simulating an aggressive epidermotropic cytotoxic lymphoma) and type E (angioinvasive type) has been described recently. We describe a 27-year-old man presented with a history of asymptomatic erythematous papules on both upper and lower limbs noted since 10 years of age. There were no systemic symptoms. Biopsy revealed an atypical dermal lymphoid infiltrate with epidermotropism, and the immunohistochemical markers showed a diffuse positivity for CD3, CD8, CD56, T1A and granzyme B with the focal positivity of CD30. All other relevant tests were normal. In this case report of a recently described delineated variant of LyP we emphasize the indolent course of this entity although the histology would suggest a more aggressive disease. PMID- 26960646 TI - Primary endobronchial myxoid leiomyoma in a child: An unusual case report and review of literature. AB - Primary leiomyomas are rare benign tumors of the lung and only 25 cases have been documented in children, most of which are endobronchial. Leiomyomas are benign smooth muscle neoplasms, usually diagnosed on morphological characteristics. However, immunohistochemistry plays a crucial role in the lineage differentiation when these are encountered at unusual sites or with unexpected morphological features. We report a case of endobronchial tumor of a 13-year-old male child who presented with a dry cough and hemoptysis. A mass lesion in the right main bronchus was detected by bronchoscopy and contrast-enhanced computed tomography. On histopathological examination of the resected specimen, a diagnosis of myxoid leiomyoma was made. To the best of our knowledge, this is the first case of myxoid leiomyoma to be reported in the respiratory tract. This case also demonstrates the need for a high index of suspicion and the role of immunomarkers in the diagnosis of such challenging cases. PMID- 26960645 TI - Adult-onset Still's disease with myocarditis and hemophagocytic lymphohistiocytosis: Rare manifestation with fatal outcome. AB - Adult-onset Still's disease (AOSD) is a rare inflammatory disorder of unknown etiology characterized by fever, evanescent pink salmon rash, arthritis, and multiorgan involvement. Here, we report an unusual manifestation of AOSD in a 40 year-old male who presented to our hospital with pyrexia of unknown origin and rash of 3 weeks duration. All his serological investigations and imaging studies were unremarkable. He was fulfilling clinical and laboratory criteria as per Yamaguchi for AOSD and was managed for the same. Our patient did not respond well to the treatment, had a downhill course, and succumbed to his illness. Autopsy confirmed myocarditis and florid bone marrow reactive hemophagocytosis as the cause of his death. PMID- 26960647 TI - Synchronous existence of granular cell tumor and small cell carcinoma of lung: An unusual entity. AB - Granular cell tumor (GCT) is a rare benign mesenchymal tumor that uncommonly occurs in the lung and tracheobronchial tree. Small cell carcinoma of lung is a centrally located malignant neoplasm that commonly occurs in elderly smokers. Concomitant existence of both the neoplasm in lung is extremely rare with only one reported case in the literature. Few rare combinations of GCT with other primary bronchogenic carcinomas have also been reported. Clinical symptoms depend upon the site and size of the tumor. Definitive diagnosis is by histopathological and proper immunohistochemical analysis. Identification of this entity is important as treatment requires individual therapy protocols that depend on the presence of metastasis, location of the tumors, and type of bronchogenic carcinoma. PMID- 26960648 TI - Anaplastic lymphoma kinase positive inflammatory myofibroblastic tumor of the urachus: A rare neoplasm in an unusual location. AB - Inflammatory myofibroblastic tumors (IMTs) are uncommon benign neoplasms in the abdomen, and urachal involvement is very rare. IMT of the urachus is usually mistaken clinically and radiologically for a malignant tumor. The tumor has spindle cell proliferation with a prominent inflammatory infiltrate and myxoid degeneration favoring other designations such as inflammatory pseudotumor and fibromyxoid pseudotumor. Complete excision is the treatment of choice. The case documented here was in a 50-year-old male, with an abdominal mass diagnosed on computed tomography scan as adenocarcinoma of urachus infiltrating the bladder. Histopathology showed a benign spindle cell tumor invading bladder muscle. Immunohistochemistry aided in diagnosing an anaplastic lymphoma kinase (ALK)-1 positive IMT. Approximately, 50% of the IMTs show ALK positivity, and though when present, it indicates neoplastic nature of the spindle cells, the pathogenesis of IMT is still elusive. The urachal IMTs need documentation in literature for their rarity and diagnostic dilemma posed by them. PMID- 26960649 TI - Lipofibromatous hamartoma of the digital branches of the median nerve presenting as carpal tunnel syndrome: A rare case report with review of the literature. AB - Lipofibromatous hamartoma (LFH) is a rare, benign fibrofatty tumor composed of a proliferation of mature adipocytes within peripheral nerves, which form a palpable neurogenic mass. It affects the median nerve in 66-80% of cases, causing pain and sensory and motor deficits in the affected nerve distribution. Patients typically present with gradually enlarging nontender lesions in the distribution of the affected nerve. The lesion is also seen to be associated with macrodactyly. The pathophysiology of LFH is unknown. Treatment of LFH is based on symptoms of the condition. Histopathology is characteristic. We present a case of young male diagnosed as lipofibromatous hamartoma of the median nerve involving the right index finger. The case is presented due to its rarity. PMID- 26960650 TI - Hemoglobin Agenogi--A rare abnormal beta globin chain variant. AB - Haemoglobin (Hb) Agenogi is clinically asymptomatic, rare beta-globin chain variant characterized by a substitution of glutamic acid by lysine at position 90 of beta-chain. It elutes in the C-window on high-performance liquid chromatography (HPLC). We report a 10-year-old male with easy fatigability, lethargy, pallor, and mild splenomegaly. Hematological parameters revealed microcytic hypochromic anemia and mildly raised red blood cells count, suggestive of thalassemia trait. On HPLC, a predominant peak was observed in the C-window (82.6%) along with raised HbA 2 level (9.3%). Based on these findings, a possibility of HbC disease/beta-thalassemia trait doubly heterozygous was considered. Family studies were advised. HPLC findings in father were suggestive of beta-thalassemia trait, while both his mother and brother had an abnormal peak in the C-window of 42.7% and 40.8%, respectively, with elevated HbA 2 values of 5% and 4.9%, respectively. Direct DNA sequencing revealed intervening sequences 1 5 (G ; C) in father, confirming beta-thalassemia trait. His mother and brother had heterozygous gene mutation at codon 90 of beta-globin chain (G ; A) suggestive of Hb Agenogi. The child carried mutations for both beta-thalassemia trait as well as Hb Agenogi. PMID- 26960651 TI - The pursuit of rare hemoglobins. PMID- 26960652 TI - Acute monoblastic leukemia with abnormal eosinophils and inversion (16): A rare entity. AB - Acute myeloid leukemia (AML) is a malignant hematopoietic stem cell disorder which is sub-classified based on bone marrow morphology and the presence of specific genetic abnormalities. One such cytogenetic abnormality is the pericentric inversion (inv) of chromosome 16 which is typically seen in AML M4 with eosinophilia and is associated with a favorable prognosis. We report the inv (16) in a young woman with AML M5 and abnormal eosinophils. This is a rare entity with only about 20 cases being reported till date. PMID- 26960654 TI - Severe anemia due to parvovirus B19 in a silver haired boy. AB - Griscelli syndrome (GS) is a rare autosomal recessive immunodeficiency disorder in which the affected children present with characteristic silvery-white hairs. The hair microscopy of these children is characteristic and is helpful in differentiating GS from Chediak-Higashi syndrome which also presents with immunodeficiency and silver hairs. We report a 17-month-old boy with GS type 2 who presented with severe anemia. Bone marrow examination of the child suggested parvovirus B19 as the cause of severe anemia, which was later confirmed by DNA polymerase chain reaction. PMID- 26960653 TI - Bilineage T-lymphoblastic/myeloid extramedullary blast crisis in chronic myelogenous leukemia. AB - The blast crisis of chronic myelogenous leukemia (CML) can be hematological or extramedullary. About 25% of these cases fulfill the criteria for mixed phenotype acute leukemia. We here report a case of a second blast crisis of CML which was extramedullary and was immunophenotypically bilineage T/myeloid. PMID- 26960655 TI - Griscelli syndrome type 2: A rare and fatal syndrome in a South Indian boy. AB - Griscelli syndrome (GS) is a rare autosomal recessive disorder caused by mutation in the MYO5A (GS1), RAB27A (GS2), and MLPH (GS3) genes, characterized by a common feature, partial albinism. The common variant of three, GS type 2, in addition, shows primary immunodeficiency which leads to recurrent infections and hemophagocytic lymphohistiocytosis. We, herewith, describe a case of GS type 2, in a 4-year-old male child who presented with chronic and recurrent fever, lymphadenopathy, hepatosplenomegaly, and secondary neurological deterioration; highlighting the cytological and histopathological features of lymph nodes. Hair shaft examination of the child confirmed the diagnosis. PMID- 26960656 TI - Keratomycosis caused by Blastoschizomyces capitatus. AB - Keratomycosis or fungal infections of cornea are common causes of ocular morbidity particularly in developing countries and in tropical climate. Traumatic inoculation is the predominant predisposing factor for this condition. Most of the cases are caused by filamentous fungi. Blastoschizomyces capitatus is one of the emerging fungal agents causing infection in different organ systems particularly in immunocompromised individuals. Barring one case of keratitis and melting of corneal graft there is no report of keratomycosis by B. capitatus. Here we present a case of keratomycosis caused by B. capitatus, which is the first such case reported from India. PMID- 26960657 TI - Sphingomonas paucimobilis septicemia in a neonate: A rare case report. AB - Sphingomonas paucimobilis , a yellow-pigmented, aerobic, glucose nonfermenting, Gram-negative bacilli is a rare cause of human infection. It was first discovered as an infective agent in humans in 1977 and named Pseudomonas paucimobilis. It was renamed as S. paucimobilis in 1990 in accordance with phylogenetic data. S. paucimobilis is an aerobic bacterium found in soil and water; it is a rare cause of healthcare associated infections. S. paucimobilis can cause infections in healthy as well as immunocompromised individuals. At first, its colony looks like Gram-positive bacilli colony, so by mistake it is discarded as contaminants. S. paucimobilis is an emerging pathogen and it should not be discarded as contaminants. Here, we report a case of S. paucimobilis bacteremia in a neonate who presented with respiratory distress. PMID- 26960658 TI - Ovarian malignant mixed germ cell tumor: A rare combination with five germ cell components. PMID- 26960659 TI - Hepatic capillariasis: A rare parasitic infection. PMID- 26960660 TI - Pregnancy-like hyperplasia and cystic hypersecretory changes adjacent to metaplastic carcinoma of the breast. PMID- 26960661 TI - Cytokeratin-positive interstitial reticulum cells in the lymph node: A potential pitfall. PMID- 26960662 TI - Tracheobronchopathia osteochondroplastica: An unusual presentation with near total occlusion of airways. PMID- 26960663 TI - Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma: A case report and significance of timely ancillary testing. PMID- 26960664 TI - Myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable; rare cause of granulocytic sarcoma: A diagnostic dilemma. PMID- 26960665 TI - Immunoglobulin A gammopathy on serum electrophoresis: A diagnostic conundrum. PMID- 26960666 TI - Can Metabolic Profiles Be Used as a Phenotypic Readout of the Genome to Enhance Precision Medicine? PMID- 26960668 TI - Dental students' perception of their approaches to learning in a PBL programme. AB - AIM: To compare dental students' perceptions of their learning approaches between different years of a problem-based learning (PBL) programme. The hypothesis was that in a comparison between senior and junior students, the senior students would perceive themselves as having a higher level of deep learning approach and a lower level of surface learning approach than junior students would. This hypothesis was based on the fact that senior students have longer experience of a student-centred educational context, which is supposed to underpin student learning. PARTICIPANTS AND METHODS: Students of three cohorts (first year, third year and fifth year) of a PBL-based dental programme were asked to respond to a questionnaire (R-SPQ-2F) developed to analyse students' learning approaches, that is deep approach and surface approach, using four subscales including deep strategy, surface strategy, deep motive and surface motive. The results of the three cohorts were compared using a one-way analysis of variance (ANOVA). A P value was set at <0.05 for statistical significance. RESULTS: The fifth-year students demonstrated a lower surface approach than the first-year students (P = 0.020). There was a significant decrease in surface strategy from the first to the fifth year (P = 0.003). No differences were found concerning deep approach or its subscales (deep strategy and deep motive) between the mean scores of the three cohorts. CONCLUSIONS: The results did not show the expected increased depth in learning approaches over the programme years. PMID- 26960667 TI - Antianginal Efficacy of Ivabradine in Patients With History of Coronary Revascularization. AB - Although coronary revascularization procedures are widely performed in patients with coronary artery disease (CAD), angina is often reported, even after such procedures. This study evaluated the antianginal efficacy and effect of ivabradine treatment on quality of life (QOL) in patients with CAD and history of coronary revascularization. This is a post hoc analysis (926 post revascularization patients) of a prospective, noninterventional study, which included 2403 patients with CAD and stable angina. The data were recorded at baseline, at 1 month and 4 months after inclusion. After ivabradine administration, mean number of anginal events decreased from 2.2 +/- 2.3 (median: 2.0, minimum: 0.0, maximum: 21.0, range: 21.0) to 0.3 +/- 0.6 (median: 0.0, minimum: 0.0, maximum: 7.0, range: 7.0) times/week (P < .001), while nitroglycerin consumption decreased from 1.5 +/- 2.2 (median: 1.0, minimum: 0.0, maximum: 20.0, range: 20.0) to 0.1 +/- 0.4 times/week (median: 0.0, minimum: 0.0, maximum: 5.0, range: 5.0; P < .001). Quality of life improved at study completion compared to baseline (P < .001). Ivabradine addition on top of optimal individualized dose of beta-blockers is associated with decreased anginal events and improvement in QOL in patients with stable angina and history of coronary revascularization. PMID- 26960670 TI - Semi-in situ atomic force microscopy imaging of intracellular neurofilaments under physiological conditions through the 'sandwich' method. AB - Neurofilaments are intermediate filament proteins specific for neurons and characterized by formation of biochemically stable, obligate heteropolymers in vivo While purified or reassembled neurofilaments have been subjected to morphological analyses by electron microscopy and atomic force microscopy, there has been a need for direct imaging of cytoplasmic genuine intermediate filaments with minimal risk of artefactualization. In this study, we applied the modified 'cells on glass sandwich' method to exteriorize intracellular neurofilaments, reducing the risk of causing artefacts through sample preparation. SW13vim(-) cells were double transduced with neurofilament medium polypeptide (NF-M) and alpha-internexin (alpha-inx). Cultured cells were covered with a cationized coverslip after prestabilization with tannic acid to form a sandwich and then split into two. After confirming that neurofilaments could be deposited on ventral plasma membranes exposed via unroofing, we performed atomic force microscopy imaging semi-in situ in aqueous solution. The observed thin filaments, considered to retain native structures of the neurofilaments, exhibited an approximate periodicity of 50-60 nm along their length. Their structural property appeared to reflect the morphology formed by their constituents, i.e. NF-M and alpha-inx. The success of semi-in situ atomic force microscopy of exposed bona fide assembled neurofilaments through separating the sandwich suggests that it can be an effective and alternative method for investigating cytoplasmic intermediate filaments under physiological conditions by atomic force microscopy. PMID- 26960671 TI - AAP urges pediatricians to act against child poverty. PMID- 26960672 TI - Pretreatment Differences in Intraindividual Variability in Reaction Time between Women Diagnosed with Breast Cancer and Healthy Controls. AB - OBJECTIVES: Chemotherapy has adverse effects on cognitive performance in women treated for breast cancer, but less is known about the period before chemotherapy. Studies have focused on mean level of performance, yet there is increasing recognition that variability in performance within an individual is also an important behavioral indicator of cognitive functioning and underlying neural integrity. METHODS: We examined intraindividual variability (IIV) before chemotherapy and surgery in women diagnosed with breast cancer (n=31), and a healthy control group matched on age and education (n=25). IIV was calculated across trials of a computerized Stroop task, including an examination of the slowest and fastest trials of reaction time (RT) responses. RESULTS: The groups were equivalent on overall accuracy and speed, and participants in both groups were less accurate and slower on incongruent trials compared with congruent trials. However, women with breast cancer became more variable with increased task difficulty relative to healthy controls. Among the slowest RT responses, women with breast cancer were significantly more variable than healthy controls on incongruent trials. This suggests that a specific variability-producing process (e.g., attentional lapses) occurs in task conditions that require executive control (e.g., incongruent trials). CONCLUSIONS: Results are consistent with other evidence of executive dysfunction among women treated for breast cancer. These findings highlight the importance of pretreatment assessment and show that variability in performance provides information about cognition that measures of central tendency do not. PMID- 26960673 TI - Individual Differences in Loss Aversion: Conscientiousness Predicts How Life Satisfaction Responds to Losses Versus Gains in Income. AB - Loss aversion is considered a general pervasive bias occurring regardless of the context or the person making the decision. We hypothesized that conscientiousness would predict an aversion to losses in the financial domain. We index loss aversion by the relative impact of income losses and gains on life satisfaction. In a representative German sample (N = 105,558; replicated in a British sample, N = 33,848), with conscientiousness measured at baseline, those high on conscientiousness have the strongest reactions to income losses, suggesting a pronounced loss aversion effect, whereas for those moderately unconscientious, there is no loss aversion effect. Our research (a) provides the first evidence of personality moderation of any loss aversion phenomena, (b) supports contextual perspectives that both personality and situational factors need to be examined in combination, (c) shows that the small but robust relationship between income and life satisfaction is driven primarily by a subset of people experiencing highly impactful losses. PMID- 26960675 TI - Clinical Impact of Hypomethylating Agents in the Treatment of Myelodysplastic Syndromes. AB - Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic diseases, mainly affecting the elderly, characterized by unilinear or multilinear peripheral cytopenia, bone marrow ineffective haemopoiesis, and a varying risk of progression to acute myeloid leukemia (AML). On the basis of the prognostic score systems currently used, MDS patients are generally classified as having higher risk (HR) or lower risk (LR) MDS. Two drugs, azacitidine (AZA) and decitabine (DAC), defined, because of their proven mechanism of action, as DNA methyltransferase inhibitors (DNMTIs), or hypomethylating agents (HMAs), have proven effective in improving peripheral cytopenias and quality of life, reducing or eliminating transfusion need, delaying leukemic evolution, and (only for AZA) prolonging overall survival (OS). HMAs are currently the first therapeutic choice for MDS patients who are not candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT). HMAs have also been used before and after allo-HSCT, but their role in this setting needs to be confirmed by larger studies. Although data from several clinical and biological studies might help to identify patients with a higher probability to respond to HMAs, to date this treatment should not be denied to any HR MDS patient. Several attempts have been made to combine HMAs with other therapeutic agents, and these results await confirmation by further studies. PMID- 26960674 TI - Risk factors for erectile dysfunction in patients with cardiovascular disease. AB - OBJECTIVE: To examine the relationship between risk factors for cardiac disease and erectile dysfunction (ED) in men from Xi'an, China. METHODS: Participants were patients with cardiovascular disease who visited the Cardiovascular Medicine Department of Xi'an Jiaotong University First Affiliated Hospital between September 2011 and March 2012. Two hundred and fifty patients were issued with questionnaires and underwent a physical examination and blood test.Risk factors for ED were identified using univariate and multivariate analyses. RESULTS: In total, 222 participants returned valid questionnaires (89% response rate), underwent a physical examination and blood test, and were included in the study. The most common cardiovascular diseases were hypertension (n = 142; 64%), coronary heart disease (n = 90; 41%) and angina pectoris (n = 78; 35%). Most patients (n = 144; 65%) had two or more cardiovascular diseases. Age, smoking, body mass index, total cholesterol level, hypertension and the ratio of total cholesterol to high-density lipoprotein cholesterol were significantly associated with ED. Domestic location, level of education, participation in physical activity, diabetes and drinking alcohol were not associated with ED. CONCLUSIONS: Common risk factors for cardiovascular disease are associated with ED in patients with cardiovascular disease. This study furthers understanding of the risk factors for ED in Chinese patients with cardiovascular disease and paves the way for further research into the prevention of ED. PMID- 26960676 TI - Continuous glucose monitoring in preterm infants: evaluation by a modified Clarke error grid. AB - BACKGROUND: Continuous glucose monitoring using subcutaneous sensors has been validated in adults and children with diabetes, and was found to be useful in the management of glucose control. We aimed to assess feasibility and reliability of a new continuous glucose monitoring system (CGMS) in a population of preterm neonates using a Clarke error grid (CEG) specifically modified for preterm infants. METHODS: Preterm infants were recruited within 24 h from delivery. A subcutaneous sensor connected to a CGMS was inserted and maintained for 6 days. Data collected from CGMS were compared with data obtained using a glucometer. Management of the infants followed standard protocols and was not influenced by CGMS readings. RESULTS: Twenty patients (9 males) were included. Median (range) gestational age was 32 weeks (27-36) and median (range) birth weight was 1350 g (860-3360). Average CGMS recording time was 137 h, for a total of 449 paired glucose levels. CEG and modified CEG criteria for clinical significance were met. CONCLUSION: CGMS is a safe and clinically adequate method to estimate glucose levels in preterm infants. As the glucose level can be evaluated in real time, this CGMS could be useful to reduce the number of heel sticks, to observe glycaemic trends and to promptly detect episodes of both hypo- and hyper glycaemia. PMID- 26960677 TI - An evaluation of psychometric properties of caregiver burden outcome measures used in caregivers of children with cerebral palsy: a systematic review protocol. AB - BACKGROUND: Cerebral palsy (CP) is the most common, life-long paediatric disability. Taking care of a child with CP often results in caregiver burden/strain in the long run. As caregivers play an essential role in the rehabilitation of these children, it is therefore important to routinely screen for health outcomes in informal caregivers. Consequently, a plethora of caregiver burden outcome measures have been developed; however, there is a dearth of evidence of the most psychometrically sound tools. Therefore, the broad objective of this systematic review is to evaluate the psychometrical properties and clinical utility of tools used to measure caregiver burden in caregivers of children with CP. METHODS/DESIGN: This is a systematic review for the evaluation of the psychometric properties of caregiver burden outcome tools. Two independent and blinded reviewers will search articles on PubMed, Scopus, Web of Science, CINAHL, PsychINFO and Africa-Wide Google Scholar. Information will be analysed using predefined criteria. Thereafter, three independent reviewers will then screen the retrieved articles. The methodological quality of studies on the development and validation of the identified tools will be evaluated using the four point COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. Finally, the psychometric properties of the tools which were developed and validated from methodological sound studies will then be analysed using predefined criteria. DISCUSSION: The proposed systematic review will give an extensive review of the psychometrical properties of tools used to measure caregiver burden in caregivers of children with CP. We hope to identify tools that can be used to accurately screen for caregiver burden both in clinical setting and for research purposes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015028026. PMID- 26960678 TI - Unique Characteristics of Recombinant Hybrid Manganese Superoxide Dismutase from Staphylococcus equorum and S. saprophyticus. AB - A recombinant hybrid of manganese dependent-superoxide dismutase of Staphylococcus equorum and S. saprophyticus has successfully been overexpressed in Escherichia coli BL21(DE3), purified, and characterized. The recombinant enzyme suffered from degradation and aggregation upon storage at -20 degrees C, but not at room temperature nor in cold. Chromatographic analysis in a size exclusion column suggested the occurrence of dimeric form, which has been reported to contribute in maintaining the stability of the enzyme. Effect of monovalent (Na(+), K(+)), divalent (Ca(2+), Mg(2+)), multivalent (Mn(2+/4+), Zn(2+/4+)) cations and anions (Cl(-), SO4 (2-)) to the enzyme stability or dimeric state depended on type of cation or anion, its concentration, and pH. However, tremendous effect was observed with 50 mM ZnSO4, in which thermostability of both the dimer and monomer was increased. Similar situation was not observed with MnSO4, and its presence was detrimental at 200 mM. Finally, chelating agent appeared to destabilize the dimer around neutral pH and dissociate it at basic pH. The monomer remained stable upon addition of ethylene diamine tetraacetic acid. Here we reported unique characteristics and stability of manganese dependent-superoxide dismutase from S. equorum/saprophyticus. PMID- 26960679 TI - Preparation of Curcumin Loaded Egg Albumin Nanoparticles Using Acetone and Optimization of Desolvation Process. AB - In this study, acetone was used as a desolvating agent to prepare the curcumin loaded egg albumin nanoparticles. Response surface methodology was employed to analyze the influence of process parameters namely concentration (5-15%w/v) and pH (5-7) of egg albumin solution on solubility, curcumin loading and entrapment efficiency, nanoparticles yield and particle size. Optimum processing conditions obtained from response surface analysis were found to be the egg albumin solution concentration of 8.85%w/v and pH of 5. At this optimum condition, the solubility of 33.57%, curcumin loading of 4.125%, curcumin entrapment efficiency of 55.23%, yield of 72.85% and particles size of 232.6 nm were obtained and these values were related to the values which are predicted using polynomial model equations. Thus, the model equations generated for each response was validated and it can be used to predict the response values at any concentration and pH. PMID- 26960680 TI - In vitro/in vivo evaluation of an optimized fast dissolving oral film containing olanzapine co-amorphous dispersion with selected carboxylic acids. AB - Improvement of water solubility, dissolution rate, oral bioavailability, and reduction of first pass metabolism of OL (OL), were the aims of this research. Co amorphization of OL carboxylic acid dispersions at various molar ratios was carried out using rapid solvent evaporation. Characterization of the dispersions was performed using differential scanning calorimetry (DSC), Fourier transform infrared spectrometry (FTIR), X-ray diffractometry (XRD), and scanning electron microscopy (SEM). Dispersions with highest equilibrium solubility were formulated as fast dissolving oral films. Modeling and optimization of film formation were undertaken using artificial neural networks (ANNs). The results indicated co amorphization of OL-ascorbic acid through H-bonding. The co-amorphous dispersions at 1:2 molar ratio showed more than 600-fold increase in solubility of OL. The model optimized fast dissolving film prepared from the dispersion was physically and chemically stable, demonstrated short disintegration time (8.5 s), fast dissolution (97% in 10 min) and optimum tensile strength (4.9 N/cm2). The results of in vivo data indicated high bioavailability (144 ng h/mL) and maximum plasma concentration (14.2 ng/mL) compared with the marketed references. Therefore, the optimized co-amorphous OL-ascorbic acid fast dissolving film could be a valuable solution for enhancing the physicochemical and pharmacokinetic properties of OL. PMID- 26960681 TI - Relaxation behavior of shear-induced crystallization precursors in isotactic polypropylene containing sorbitol-based nucleating agents with different nucleating abilities. AB - The nature of shear-induced crystallization precursors, especially their relaxation behaviour, is an important issue in polymer chemical physics. In our work, relaxation behavior of shear-induced crystallization precursors in isotactic polypropylene containing various sorbitol-based nucleating agents (NAs) with different nucleating abilities was investigated by using both rheological and in situ small angle X-ray scattering (SAXS) methods. Rheological crystallization kinetics results showed that the amount of shear-induced precursors, calculated separately from the total nuclei, decayed exponentially with relaxation time in both pure and nucleated iPP. By fitting the decay of shear-induced precursors with relaxation time, the relaxation rate of precursors in nucleated iPP was found to be slower than that in pure iPP. Interestingly, it further decreased with the increase in the nucleating ability of sorbitol-based NAs. Meanwhile, the life-time of precursors was prolonged in nucleated iPP with increasing nucleating ability. Similar results were also testified by in situ SAXS measurements. By investigating the life-times at different temperatures, the activation energy for the relaxation of precursors was calculated and found to increase with stronger nucleating abilities. Our results demonstrated that sorbitol-based NAs could stabilize the iPP precursors and the effect of stabilization enhanced with the increase in nucleating ability. We believe that our work can not only help better reveal the relaxation behavior of shear-induced precursors but also provides a new perspective for understanding the role of NAs in real processing. PMID- 26960682 TI - Direct UV Spectrophotometry and HPLC Determination of Triton X-100 in Split Virus Influenza Vaccine. AB - One of the most commonly used surfactants in the production of split virus influenza vaccine is nonionic surfactant Triton X-100. After splitting of the virus is accomplished, Triton X-100 is removed from the vaccine by subsequent production steps. Because of toxicity of Triton X-100, which remains in the vaccine in residual amounts, a sufficiently sensitive method for its detection and quantification needs to be defined. Two methods for determination of Triton X 100 residuals were developed: the UV-spectrophotometry and HPLC methods. For both methods, preparation of vaccine samples and removal of proteins and virus particles were crucial: samples were treated with methanol (1:1) and then centrifuged at 25 000 * g for 30 min. After such treatment, the majority of vaccine components that interfered in the UV region were removed, and diluted samples could be directly measured. The chromatographic system included C18 column, step methanol gradient, and detection at 225 nm with a single peak of Triton X-100 at 12.6 min. Both methods were validated and gave satisfactory results for accuracy, precision, specificity, linearity, and robustness. LOQ was slightly lower for the HPLC method. Hence, it was shown that both methods are suitable for analysis of residual amounts of Triton X-100, with the advantages of the UV method being its simplicity and availability in most laboratories. PMID- 26960683 TI - Effect of the consumption of beta-lactoglobulin and epigallocatechin-3-gallate with or without calcium on glucose tolerance in C57BL/6 mice. AB - Interactions between beta-lactoglobulin (beta-lg) and epigallocatechin-3-gallate (EGCG) may modulate their health benefits. The objective of this study was therefore to investigate the synergistic effect of consuming beta-lg and EGCG complexes on glucose tolerance of C57BL/6 male mice given an oral glucose tolerance test (OGTT) and randomized to one of the following treatments administered prior to the OGTT: 1) simulated milk ultrafiltrate (SMUF(-)), 2) SMUF(-) + EGCG, 3) SMUF(-) + beta-lg, 4) SMUF(-) + EGCG + beta-lg, 5) SMUF + calcium (SMUF(+)) and 6) SMUF(+) + EGCG + beta-lg. We found no significant between-group difference in postprandial glucose response. However, when mice were separated in those who received beta-lg from those who did not, we found that the latter displayed significantly higher postprandial glucose concentrations. Our results support the beneficial impact of beta-lg on glycemic control and suggest that concomitant EGCG or calcium consumption does not improve this effect. PMID- 26960684 TI - Correction: Continuous inertial microparticle and blood cell separation in straight channels with local microstructures. AB - Correction for 'Continuous inertial microparticle and blood cell separation in straight channels with local microstructures' by Zhenlong Wu et al., Lab Chip, 2016, 16, 532-542. PMID- 26960685 TI - Therapeutic outcomes for patients with aneurysmal subarachnoid hemorrhage complicated by Takotsubo cardiomyopathy. AB - BACKGROUND: There are no guidelines regarding the optimal treatment of subarachnoid hemorrhage (SAH) patients complicated by Takotsubo cardiomyopathy (TCM). Although coiling has been favored as the first-line treatment, clipping may also be indicated in patients with ruptured middle cerebral artery aneurysms or in those with massive intracerebral hemorrhage. The study objective is (1) to report the feasibility/safety of clipping/coiling and (2) to identify possible prognosticators in that population. METHODS: Between January 2008 and December 2014, 371 consecutive patients with aneurysmal SAH underwent transthoracic echocardiography after admission, and 30 with TCM (7.7 %) were identified. We reviewed the incidence and type of perioperative complications among clipped (n = 11) and coiled (n = 19) patients. The 30 patients were dichotomized based on their 90-day modified Rankin scale (mRS) scores into favorable (mRS: 0-2) and unfavorable (mRS: 3-6) groups, and their demographic, laboratory and echocardiographic variables were compared. RESULTS: Neither clipped nor coiled patients developed serious perioperative cardiopulmonary complications, but coiled patients had a higher incidence of fatal procedure-related complications. Among the 30 patients, 13 (43 %) had favorable 90-day outcomes, and the favorable group was significantly younger. Age, but not the degree of cardiac dysfunction, correlated with outcomes by multivariate regression analysis. CONCLUSIONS: Clipping was shown to be a safe treatment modality in our cohort, and treatment selection may better be made on a case-by-case basis in most patients with SAH induced TCM. The lack of correlation between the degree of cardiac dysfunction and outcomes indicates that aggressive intervention is justified in patients with severely impaired cardiac function. PMID- 26960686 TI - Healthy ageing in Isan-Thai culture--A phenomenographic study based on older persons' lived experiences. AB - Healthy ageing is a concept that concerns older persons' quality of life and is a key factor in promoting well-being. The older population in Thailand is growing. Isan (a region of north-eastern Thailand) has been reported as having one of the most rapidly increasing older populations in the country. In order to care for and promote the health of older people, healthcare providers should understand how healthy ageing is perceived by this target group. Although healthy ageing has been studied in different contexts as well as perspectives, no studies have previously focused on older persons' experiences of healthy ageing from a lifeworld perspective in Isan-Thai. Therefore, the aim of this study is to describe older persons' qualitatively different conceptions of healthy ageing in Isan-Thai culture. A phenomenographic approach with an epistemological base in lifeworld theory was used to disclose the various ways to conceptualize healthy ageing. Individual, qualitative interviews were conducted with 17 people aged 60 and above who live in Isan-Thai. The findings of this study revealed three categories of descriptions: "being independent in dependence," "being at peace," and "being a valuable person." This study also found family members, friends, healthcare providers, and religion important to healthy ageing in the Isan-Thai culture. Understanding how older people conceptualize healthy ageing is valuable for healthcare providers. They can apply these findings regarding healthy ageing in their fieldwork when caring for older people. PMID- 26960687 TI - Analyzing Proportion Scores as Outcomes for Prevention Trials: a Statistical Primer. AB - In prevention trials, outcomes of interest frequently include data that are best quantified as proportion scores. In some cases, however, proportion scores may violate the statistical assumptions underlying common analytic methods. In this paper, we provide guidelines for analyzing frequency and proportion data as primary outcomes. We describe standard methods including generalized linear regression models to compare mean proportion scores and examine tools for testing normality and other assumptions for each model. Recommendations are made for instances when the assumptions are not met, including transformations for proportion scores that are non-normal. We also discuss more sophisticated analytical tools to model change in proportion scores over time. The guidelines provide ready-to-use analytical strategies for frequency and proportion data that are commonly encountered in prevention science. PMID- 26960688 TI - miR-522 contributes to cell proliferation of hepatocellular carcinoma by targeting DKK1 and SFRP2. AB - The morbidity and mortality of hepatocellular carcinoma (HCC) is very high, finding new therapeutic targets are critical for HCC treatment. miR-522 has been demonstrated to be upregulated in HCC tissues, but its role in HCC progression remains to be elucidated. In this report, we found miR-522 was upregulated in HCC cells and tissues, miR-522 overexpression promoted cell proliferation, colony formation, and cell cycle progression, whereas knockdown of miR-522 reduced these effects. We also analyzed the expression of several key cell cycle regulatory proteins and found overexpression of miR-522-inhibited cell cycle inhibitors p21 and p27 expression and enhanced cyclin D1 expression and the level of Rb phosphorylation, vice versa. These suggested miR-522-accelerated G1/S transition. DKK1 (dickkopf-1) and SFRP2 (secreted frizzled-related protein 2) were the targets of miR-522, their expression was inversely with miR-522 in HCC tissues. DKK1 and SFRP2 the antagonists of Wnt signaling, suggesting miR-522-promoted HCC progression through activating Wnt signaling. miR-522 might be a valuable target for HCC therapy. PMID- 26960689 TI - Low level of FOXL1 indicates a worse prognosis for gastric cancer patients. AB - The aim of this study was to detect forkhead box L1 (FOXL1) expression in gastric cancer (GC) and to analyze its association with the prognosis of GC patients. Immunohistochemical staining, Western blotting, and quantitative reverse transcriptase polymerase chain reaction were performed to detect FOXL1 tissue expression in 109 GC patients. Clinicopathological characteristics and survival data were retrospectively analyzed to discover the clinical importance of FOXL1 expression. The chi-square test was used to analyze the relationship between FOXL1 expression and the clinicopathological characteristics. Survival curves were plotted by using the Kaplan-Meier method and compared using the log-rank test. Survival data were evaluated using univariate and multivariate Cox regression analyses. The expression of FOXL1 messenger RNA (mRNA) was significantly higher in adjacent normal samples than in the tumor tissues (P = 0.043). Clinicopathological analysis showed that FOXL1 expression was significantly correlated with depth of invasion (P = 0.017), lymph node metastasis (P = 0.019), and distant metastasis (P = 0.047). FOXL1-negative as opposed to the FOXL1-positive patients had lower 5-year overall survival (14.06 vs. 37.78 %, P < 0.001). Multivariate analysis suggested that FOXL1 expression might be an independent prognostic indicator (hazard ratio = 0.307, 95 % confidence interval, 0.187-0.505; P < 0.001) for GC patients. In conclusion, our findings provide evidence that FOXL1 might serve as a candidate tumor suppressor and a potential prognostic biomarker for GC. PMID- 26960690 TI - PCA3 long noncoding RNA modulates the expression of key cancer-related genes in LNCaP prostate cancer cells. AB - Prostate cancer antigen 3 (PCA3) is a prostate-specific long noncoding RNA (lncRNA) involved in the control of prostate cancer (PCa) cell survival, through modulating androgen receptor (AR) signaling. To further comprehend the mechanisms by which PCA3 modulates LNCaP cell survival, we characterized the expression patterns of several cancer-related genes, including those involved in epithelial mesenchymal transition (EMT) and AR cofactors in response to PCA3 silencing. We also aimed to develop a strategy to stably silence PCA3. Small interfering RNA (siRNA) or short hairpin RNA (shRNA) was used to knock down PCA3 in LNCaP cells. The expression of 84 cancer-related genes, as well as those coding for AR cofactors and EMT markers, was analyzed by quantitative real-time PCR (qRT-PCR). LNCaP-PCA3 silenced cells differentially expressed 16 of the 84 cancer genes tested, mainly those involved in gene expression control and cell signaling. PCA3 knockdown also induced the upregulation of several transcripts coding for AR cofactors and modulated the expression of EMT markers. LNCaP cells transduced with lentivirus vectors carrying an shRNA sequence targeting PCA3 stably downregulated PCA3 expression, causing a significant drop (60 %) in the proportion of LNCaP cells expressing the transgene. In conclusion, our data provide evidence that PCA3 silencing modulates the expression of key cancer related genes, including those coding for AR cofactors and EMT markers. Transducing LNCaP cells with an shRNA sequence targeting PCA3 led to loss of viability of the cells, supporting the proposal of PCA3 knockdown as a putative therapeutic approach to inhibit PCa growth. PMID- 26960691 TI - Oligoesculin fraction induces anti-tumor effects and promotes immune responses on B16-F10 mice melanoma. AB - Laccase was used to enzymatically polymerize esculin. Oligoesculin fraction was obtained after ultrafiltration through a 5-kDa membrane. Several studies have been carried out to prove the effectiveness of natural substances such as immunomodulators to promote the anti-cancer activity in situ. The purpose of our report was to explore whether the anti-tumor potential of the oligoesculin fraction in vitro and in vivo is linked to its immunological mechanisms in melanoma-bearing mice. We revealed that oligoesculin fraction reduced B16-F10 proliferation and migration in vitro in a dose-related manner. Moreover, melanin synthesis and tyrosinase activity were inhibited in these melanoma cells in a concentration-dependent way. The anti-tumor potential of oligoesculin fraction was also assessed in vivo. Our results showed that intraperitoneal administration of oligoesculin fraction, at 50 mg/kg body weight (b.w.) for 21 days, reduced tumor size and weight with percentages of inhibition of 94 and 87 %, respectively. Oligoesculin fraction was effective in promoting lysosomal activity and nitric oxide (NO) production by peritoneal macrophages in tumor-implanted mice. In addition, the activities of natural killer (NK), cytotoxic T lymphocytes, and macrophages were significantly enhanced by oligoesculin fraction. These findings suggested that this polymer with its anti-tumor and immunomodulatory properties could be used for the treatment of melanoma. PMID- 26960692 TI - Body composition of the host influences dendritic cell phenotype in patients treated for colorectal cancer. AB - Dendritic cells (DCs) are antigen-presenting cells that can acquire tumour antigens and initiate cytotoxic T cell reactions. Obesity has been proposed as a cause for tumours escaping immune surveillance, but few studies investigate the impact of other body composition parameters. We examined the relationship of DC phenotype with computer tomography (CT)-defined parameters in patients with colorectal cancer (CRC). DCs were identified within peripheral blood mononuclear cells by flow cytometry as HLA-DR positive and negative for markers of other cell lineages in 21 patients. Analysis of CT scans was used to calculate lumbar skeletal muscle index (LSMI) and mean muscle attenuation (MA). Positive correlation between the LSMI and expression of CD40 in all DCs (r = 0.45; p = 0.04) was demonstrated. The MA was positively correlated with scavenger receptor CD36 [all DCs (r = 0.60; p = 0.01) and myeloid DCs (r = 0.63; p < 0.01)]. However, the MA was negatively correlated with CCR7 expression in all DCs (r = 0.46, p = 0.03.) and with CD83 [all DCs (r = -0.63; p = 0.01) and myeloid DCs (r = -0.75; p < 0.01)]. There were no relationships between the fat indexes and the DC phenotype. These results highlight a direct relationship between muscle depletion and changes in stimulatory, migratory and fatty acid-processing potential of DC in patients with CRC. PMID- 26960693 TI - Naringenin inhibits proliferation, migration, and invasion as well as induces apoptosis of gastric cancer SGC7901 cell line by downregulation of AKT pathway. AB - The preliminary anti-cancer activity of Naringenin (Nar) has been proven in several cancers. However, the therapeutic activity of Nar on gastric cancer SGC 7901 cell line is not yet well understood. The aim of the present study was to investigate the effect and mechanisms of Nar on proliferation, apoptosis, migration, and invasion of SGC-7901 cells. In this in vitro study, SGC-7901 cells were treated with Nar at serial concentrations. Our data showed that Nar efficiently inhibited SGC-7901 cell proliferation in a time- and concentration dependent manner, as well as downregulated proliferating cell nuclear antigen (PCNA) levels in a concentration-dependent manner. Meanwhile, the cell migration and invasion also dramatically decreased after Nar incubation, and the expressions of MMP2 and MMP9 were significantly downregulated. In addition, a strong proapoptotic effect was observed in the SGC-7901 cells after Nar treatment. Apoptosis-related proteins Bax and cleaved caspase-3 were up regulated, whereas Bcl-2 and Survivin were downregulated. After administration with Nar, we found that phosphorylation of AKT was inhibited, and this inhibitory action could be mildly enhanced by the combination treatment of Nar and AKT inhibitor LY294002. In conclusion, our study confirmed that Nar could inhibit SGC 7901cell proliferation, migration, and invasion as well as induces apoptosis, and Nar might provide a new potential therapeutic strategy for treating gastric cancer. PMID- 26960695 TI - Intracellular nanoparticles mass quantification by near-edge absorption soft X ray nanotomography. AB - We used soft X-ray three-dimensional imaging to quantify the mass of superparamagnetic iron oxide nanoparticles (SPION) within whole cells, by exploiting the iron oxide differential absorption contrast. Near-edge absorption soft X-ray nanotomography (NEASXT) combines whole-cell 3D structure determination at 50 nm resolution, with 3D elemental mapping and high throughput. We detected three-dimensional distribution of SPIONs within cells with 0.3 g/cm(3) sensitivity, sufficient for detecting the density corresponding to a single nanoparticle. PMID- 26960694 TI - Genome-wide association between single nucleotide polymorphisms with beef fatty acid profile in Nellore cattle using the single step procedure. AB - BACKGROUND: Saturated fatty acids can be detrimental to human health and have received considerable attention in recent years. Several studies using taurine breeds showed the existence of genetic variability and thus the possibility of genetic improvement of the fatty acid profile in beef. This study identified the regions of the genome associated with saturated, mono- and polyunsaturated fatty acids, and n-6 to n-3 ratios in the Longissimus thoracis of Nellore finished in feedlot, using the single-step method. RESULTS: The results showed that 115 windows explain more than 1 % of the additive genetic variance for the 22 studied fatty acids. Thirty-one genomic regions that explain more than 1 % of the additive genetic variance were observed for total saturated fatty acids, C12:0, C14:0, C16:0 and C18:0. Nineteen genomic regions, distributed in sixteen different chromosomes accounted for more than 1 % of the additive genetic variance for the monounsaturated fatty acids, such as the sum of monounsaturated fatty acids, C14:1 cis-9, C18:1 trans-11, C18:1 cis-9, and C18:1 trans-9. Forty genomic regions explained more than 1 % of the additive variance for the polyunsaturated fatty acids group, which are related to the total polyunsaturated fatty acids, C20:4 n-6, C18:2 cis-9 cis12 n-6, C18:3 n-3, C18:3 n-6, C22:6 n-3 and C20:3 n-6 cis-8 cis-11 cis-14. Twenty-one genomic regions accounted for more than 1 % of the genetic variance for the group of omega-3, omega-6 and the n-6:n 3 ratio. CONCLUSIONS: The identification of such regions and the respective candidate genes, such as ELOVL5, ESSRG, PCYT1A and genes of the ABC group (ABC5, ABC6 and ABC10), should contribute to form a genetic basis of the fatty acid profile of Nellore (Bos indicus) beef, contributing to better selection of the traits associated with improving human health. PMID- 26960696 TI - Ultrasonic vocalization in rats self-administering heroin and cocaine in different settings: evidence of substance-specific interactions between drug and setting. AB - RATIONALE: Clinical and preclinical evidence indicates that the setting of drug use affects drug reward in a substance-specific manner. Heroin and cocaine co abusers, for example, indicated distinct settings for the two drugs: heroin being used preferentially at home and cocaine preferentially outside the home. Similar results were obtained in rats that were given the opportunity to self-administer intravenously both heroin and cocaine. OBJECTIVES: The goal of the present study was to investigate the possibility that the positive affective state induced by cocaine is enhanced when the drug is taken at home relative to a non-home environment, and vice versa for heroin. METHODS: To test this hypothesis, we trained male rats to self-administer both heroin and cocaine on alternate days and simultaneously recorded the emission of ultrasonic vocalizations (USVs), as it has been reported that rats emit 50-kHz USVs when exposed to rewarding stimuli, suggesting that these USVs reflect positive affective states. RESULTS: We found that Non-Resident rats emitted more 50-kHz USVs when they self administered cocaine than when self-administered heroin whereas Resident rats emitted more 50-kHz USVs when self-administering heroin than when self administering cocaine. Differences in USVs in Non-Resident rats were more pronounced during the first self-administration (SA) session, when the SA chambers were completely novel to them. In contrast, the differences in USVs in Resident rats were more pronounced during the last SA sessions. CONCLUSION: These findings indicate that the setting of drug taking exerts a substance-specific influence on the ability of drugs to induce positive affective states. PMID- 26960697 TI - Women with premenstrual dysphoric disorder have altered sensitivity to allopregnanolone over the menstrual cycle compared to controls-a pilot study. AB - RATIONALE: In premenstrual dysphoric disorder (PMDD), a condition that afflicts 3 8 % of women in fertile ages, the cyclic recurrence of debilitating mood symptoms is restricted to the luteal phase of the menstrual cycle. The progesterone metabolite allopregnanolone is produced by the corpus luteum, and circulating levels are reflected in the brain. Allopregnanolone is a modulator of the GABAA receptor, enhancing the effect of gamma-aminobutyric acid (GABA). Previous studies have demonstrated different sensitivity to other GABAA receptor agonists, i.e., benzodiazepines, alcohol, and pregnanolone, in PMDD patients compared to controls. OBJECTIVES: This study aimed to investigate the sensitivity to intravenous allopregnanolone over the menstrual cycle in PMDD patients. METHODS: Allopregnanolone, 0.05 mg/kg, was administered intravenously once in the mid follicular and once in the luteal phase of the menstrual cycle to 10 PMDD patients and 10 control subjects. The saccadic eye velocity (SEV) was recorded by electrooculography as a measurement of functional GABAA receptor activity, at baseline and repeatedly after the injection. A mixed model was used to analyze data. RESULTS: There was a highly significant group * phase interaction in the SEV response to allopregnanolone (F(1,327.489) = 12.747, p < 0.001). In the PMDD group, the SEV response was decreased in the follicular phase compared to the luteal phase (F(1,168) = 7.776, p = 0.006), whereas in the control group, the difference was opposite during the menstrual cycle (F(1,158.45) = 5.70, p = 0.018). CONCLUSIONS: The effect of exogenous allopregnanolone is associated with menstrual cycle phase in PMDD patients and in controls. The results suggest an altered sensitivity to allopregnanolone in PMDD patients. PMID- 26960699 TI - Bedside Neonatal Intensive Care Unit Correction of Congenital Diaphragmatic Hernia: Is Repair without Compromise? AB - Objectives This study aims to evaluate the feasibility, safety, limitations, and outcomes of performing different surgical approaches and techniques for the bedside repair of congenital diaphragmatic hernia (CDH) in critically ill patients who cannot be transferred to the operating room. Study Design Between December 1997 and July 2013, medical charts of all neonates operated on at the bedside for CDH while on high-frequency oscillatory ventilation (HFOV) and nitric oxide were reviewed. Demographic data; contributing antenatal, perinatal, and postnatal factors; clinical presentation; associated anomalies; respiratory and hemodynamic status; operative details; complications, and outcome were analyzed. Results A total of 101 cases of CDH were operated on, of which 11 were in very critical condition and operated on at the bedside in the neonatal intensive care unit (NICU). The mean gestational age was 38.09 weeks, birth weight, 2.91 kg, and age at surgery, 10 days. All were on HFOV and inotropic support and had pulmonary hypertension. Nine of them were on nitric oxide. Mean preoperative parameters were as follows: O2, 52%; mean airway pressure, 15; pH, 7.40; Po 2, 88.5 mm Hg; and Pco 2, 47 mm Hg. Nine patients underwent laparotomy and two underwent thoracoscopy. All procedures were completed uneventfully. Conclusions Bedside repair of CDH in the NICU while on HFOV is feasible and safe. It is not associated with any compromise in the surgical approach or technique. PMID- 26960698 TI - Rottlerin impairs the formation and maintenance of psychostimulant-supported memory. AB - RATIONALE AND OBJECTIVE: Since brain proteins such as protein kinase C (PKC), brain-derived neurotrophic factor (BDNF), and mammalian target of rapamycin (mTOR) are involved in the establishment and maintenance of psychostimulant memory, we sought to determine if systemic treatment with rottlerin, a natural compound affecting all these proteins, may modulate stimulant-supported memory. MATERIALS AND METHODS: Stimulant-induced conditioned place preference (CPP) was used in modeling stimulant-supported memory. RESULTS: Three cocaine (10 mg/kg; COC) or three methamphetamine (1 mg/kg; MA) conditioning trials reliably established the drug-induced CPP in male C57BL/6 mice. An intra-peritoneal rottlerin injection (5 mg/kg) at least 24 h prior to the first COC or first MA conditioning trial prevented the establishment of CPP. Following the establishment of the COC- or MA-induced CPP, saline conditioning trial was used to extinguish the CPP. Rottlerin (5 mg/kg, intra-peritoneal (i.p.)) administered 20 h prior to the first saline conditioning trial diminished subsequent drug- and stressor-primed reinstatement of the extinguished CPP. Rottlerin (5 mg/kg, i.p.) produced a fast-onset and long-lasting increase in hippocampal BDNF levels. However, treatment with a BDNF tropomyosin receptor kinase B (TrkB) receptor antagonist, K252a (5 MUg/kg), did not affect rottlerin's suppressing effect on COC-induced CPP and treatment with 7,8-dihydroxyflavone (10 mg/kg x 6, 7,8-DHF), a selective TrkB agonist, prior to each conditioning trial did not affect COC induced CPP. CONCLUSION: These results suggest that systemic rottlerin treatment may impair the formation of COC- and MA-supported memory. Importantly, such a treatment may advance our understanding of the underlying mechanism through which extinction training resulted in the "forgetting" of the COC- and MA-supported memory. PMID- 26960700 TI - Clinical Indicators of Late-Onset Sepsis Workup in Very Low-Birth-Weight Infants in the Neonatal Intensive Care Unit. AB - Background Late-onset sepsis (LOS) in very low-birth-weight (VLBW) infants is associated with significant morbidity and mortality. Objectives To determine the incidence of LOS workup, association, and predictive value of clinical indicators leading to culture-positive versus culture-negative sepsis workup. Methods All sepsis workups performed after 7 days of life, in neonates with birth weight of < 1,500 g were included. Each case (culture-positive workup) was matched with a control (culture-negative workup) for gestational age (GA), birth weight, corrected gestational age, and chronological age, at the time of workup. The clinical indicators leading to the performance of sepsis workup were compared between cases and controls. Results The incidence of culture-positive workup was 87/345 (25.2%) and that of LOS was 84/279 (30.1%). Among various clinical indicators, hypothermia and apnea were significantly associated with culture positive sepsis workup (p = 0.015 and 0.004, respectively), with a positive predictive value of 81.2 and 71.4%, respectively. Conclusion In VLBW infants, one fourth of sepsis workups resulted in a positive culture. Apnea and hypothermia were the most significant predictors of culture-positive workup after matching for GA, birth weight, chronological age, and corrected GA at the time of the workup. PMID- 26960701 TI - Impact of Gestational Weight Gain on Perinatal Outcomes in Obese Women. AB - Objective This study aims to evaluate perinatal outcomes, according to gestational weight gain (GWG) in obese women. Study Design A retrospective cohort of perinatal outcomes in obese women who gained below, within, or above the 2009 Institute of Medicine guidelines and delivered >= 36 weeks. Additionally, outcomes, according to the rate of GWG (kg/week; minimal [< 0.16], moderate [0.16 0.49], or excessive [> 0.49]) were compared among women delivering preterm. Results Overall, 5,651 obese women delivered >= 36 weeks. GWG above guidelines was associated with increased cesarean section (adjusted odds ratio [aOR]: 1.44, 95% confidence interval [CI]: 1.21-1.72), gestational hypertension (aOR: 1.58, 95% CI: 1.21-2.06), and macrosomia (birth weight >= 4,000 g) (aOR: 2.08, 95% CI: 1.62-2.67). GWG below recommendations was associated with less large for gestational age infants (aOR: 0.60, 95% CI: 0.47-0.75). A total of 6,663 women delivered >= 20 weeks. Minimal weekly GWG was associated with increased spontaneous preterm birth (aOR: 1.56, 95% CI: 1.23-1.98) and more small for gestational age (SGA) infants (aOR: 1.55, 95% CI: 1.19-2.01). Excessive weekly GWG was associated with increased indicated preterm birth (aOR: 1.61, 95% CI: 1.29-2.01), cesarean section (aOR: 1.39, 95% CI: 1.20-1.61), preeclampsia (aOR: 1.83, 95% CI: 1.49-2.26), neonatal intensive care unit admission (aOR: 1.33, 95% CI: 1.08-1.63), and macrosomia (aOR: 2.40, 95% CI: 1.94-2.96). Conclusions Obese women with excessive GWG had worse outcomes than women with GWG within recommendations. Limited GWG was associated with increased spontaneous preterm birth and SGA infants. PMID- 26960702 TI - Perinatal Outcomes after Short versus Prolonged Indomethacin for Tocolysis in Women with Preterm Labor. AB - Objective Indomethacin tocolysis is generally limited to 48 hours. Indomethacin has been administered for longer durations to prolong gestation in extreme prematurity. Our aim is to compare perinatal outcomes after a prolonged course, > 48 hours versus <= 48 hours in preterm labor. Methods A retrospective chart review of women admitted with preterm labor < 32 weeks gestation who received indomethacin for tocolysis. The primary maternal outcome was latency from admission until delivery. The primary neonatal outcome was a composite of severe neonatal morbidities. Results A total of 73 women were included: 32 (43.8%) received indomethacin for > 48 hours (prolonged) and 41 (56.2%) for <= 48 hours (standard). Prolonged group started on indomethacin at an earlier gestational age compared with standard group (23.9 [23.1-27.3] vs. 25.7 [23.8-28.5] weeks, p = 0.03). Latency from admission until delivery was longer in the prolonged group versus the standard group (1.8 [1.1-3] vs. 0.4 [0.1-0.8] weeks, p < 0.001). Prolonged use was not associated with increased risk of the composite neonatal outcome; however, there was a trend for more necrotizing enterocolitis. Conclusion A prolonged course of indomethacin may be an option for women with preterm labor at risk of extreme prematurity; it may also be associated with higher risks of some adverse neonatal outcomes. PMID- 26960703 TI - Evaluating the Obstetrical Implications of Antenatal Testing for Women with Morbid Obesity: Maternal and Fetal Outcomes of Increased Surveillance. AB - Objectives Despite limited data, antenatal testing has been initiated in many institutions for women with morbid obesity given their increased risk of stillbirth. Therefore, our objective was to evaluate the obstetrical implications of antenatal testing in the morbidly obese population. Study Design We performed a retrospective cohort study of women undergoing antenatal testing from January 2011 through December 2012 who delivered at our institution. The exposed group was women undergoing antenatal testing with morbid obesity (body mass index [BMI] >= 40 kg/m(2)). This group was subdivided into two groups: group 1, which included women undergoing testing for morbid obesity alone, and group 2, which included women undergoing testing for morbid obesity with an additional medical comorbidity. The unexposed group (group 3) comprised nonmorbidly obese women (BMI < 35 kg/m(2)) undergoing antenatal testing for similar medical comorbidities. Our primary outcomes were induction of labor and gestational age at delivery. Results A total of 512 women met inclusion criteria. Group 1 had a lower induction rate as compared with groups 2 and 3 (22.2, 32.5, and 37.6%, respectively; p = 0.003). Additionally, women delivered at a later gestational age in group 1 (39.3 weeks [38.4-40.2]) compared with groups 2 (38.5 weeks [36.1-40.3]) or 3 (37.1 weeks [37.0-38.2]), p = 0.04. There were no significant differences in our secondary outcomes including rate of cesarean delivery (p = 0.11) or rate of nonreactive nonstress test (p = 0.4). Conclusions While it remains unknown whether antenatal testing decreases the stillbirth risk in morbidly obese women, this population does not appear to be at increased risk of induction of labor or delivery prior to 39 weeks secondary to testing. Future studies should evaluate neonatal implications and cost-effectiveness of antenatal testing in this group. PMID- 26960704 TI - Monitoring Uterine Activity during Labor: Clinician Interpretation of Electrohysterography versus Intrauterine Pressure Catheter and Tocodynamometry. AB - Objective The aim of this article was to compare clinical interpretation of uterine activity tracings acquired by tocodynamometry and electrohysterography with the gold standard, intrauterine pressure. Study Design Using data from a previous study, subjects who had simultaneous monitoring with all three uterine activity devices were included in this study. These were parturients who required intrauterine pressure catheter (IUPC) placement for obstetric indication. A Web based application displayed scrolling 30-minute segments of uterine activity. Two blinded obstetricians and two blinded obstetric nurses independently reviewed the segments, marking uninterpretable segments and the peak of each contraction. Interpretability was compared using positive percent agreement. False positives are contractions marked in the noninvasive strip that have no corresponding contraction in the IUPC strip. False negatives are the reverse. Results A total of 135 segments, acquired during either Stage 1 (active labor) or Stage 2 (pushing), from 105 women, were included in this analysis. For all four observers, both interpretability and sensitivity of electrohysterography exceeded that of tocodynamometry (p < 0.0001). This remained true for the obese population (96 segments). Conclusion Compared with the IUPC, electrohysterography is more sensitive and provides tracings that are more often interpretable than tocodynamometry for intrapartum monitoring; electrohysterography is also less affected by increasing maternal body mass index. PMID- 26960705 TI - Invited Commentary: Hypertension and Arterial Stiffness--Origins Remain a Dilemma. AB - In this issue of the Journal, Chen et al. (Am J Epidemiol. 2016;183(7):599-608) present repeated measures of aorto-femoral pulse wave velocity, capacitive compliance (C1), and oscillatory compliance (C2) in the Bogalusa Heart Study, with the purpose of addressing which comes first: blood pressure elevation or arterial stiffening. After an average follow-up period of 7 years (2000-2010), the authors found that blood pressure at a mean age of 36 years predicted change in arterial stiffening by a mean age of 43 years, but not the reverse. Essential hypertension results from a mosaic of pathological mechanisms. It has been theorized that biological pathways involving increased sympathetic tone, insulin resistance, renin-angiotensin-aldosterone activation, and inflammation lead to hyperkinetic circulation, volume overload, and vascular remodeling. The resultant accelerated vascular aging may be assessed by determining the degree of arterial stiffness. The findings of Chen et al. add important empirical information to the literature but do not solve the dilemma regarding the origins of essential hypertension, partly because there are many techniques for estimating the many aspects of arterial stiffness which are not fully understood. Mathematical features of estimates might not be uniform across the age range. There is a need for tracking blood pressure and different aspects of arterial stiffness from childhood onward, with an aim of preventing hypertension in adult life. PMID- 26960707 TI - In-situ preparation of functionalized molecular sieve material and a methodology to remove template. AB - A series of diaminosilane-functionalized silicoaluminophosphate molecular sieve (SAPO-37) was prepared by in-situ synthesis, and a novel method was developed for the selective removal of structure directing agent (SDA)/template from the functionalized SAPO-37.The complete removal of the SDA was evident according to FT-IR, TGA, (13)C MAS-NMR and elemental analysis. The developed method was found to be efficient for removal of template from microporous molecular sieve viz., SAPO-37 and can be applied for other microporous molecular sieves such as SAPO-5, SAPO-40, etc. The powder XRD pattern of the template-removed samples showed a highly crystalline SAPO-37 phase. Argentometric titration revealed that more than 90% of diamine functionality exposed on the surface was accessible for catalytic applications. The resultant materials showed promising activity for ring opening of epoxide with aniline to yield beta-amino-alcohol. PMID- 26960706 TI - Temporal Relationship Between Elevated Blood Pressure and Arterial Stiffening Among Middle-Aged Black and White Adults: The Bogalusa Heart Study. AB - This study assessed the temporal relationship between elevated blood pressure (BP) and arterial stiffness in a biracial (black-white) cohort of middle-aged adults aged 32-51 years from the semirural community of Bogalusa, Louisiana. Measurements of aortic-femoral pulse wave velocity (afPWV; n = 446) and large- and small-arterial compliance (n = 381) were obtained at 2 time points between 2000 and 2010, with an average follow-up period of 7 years. A cross-lagged path analysis model was used to examine the temporal relationship of elevated BP to arterial stiffness and elasticity. The cross-lagged path coefficients did not differ significantly between blacks and whites. The path coefficient (rho2) from baseline BP to follow-up afPWV was significantly greater than the path coefficient (rho1) from baseline afPWV to follow-up BP (rho2 = 0.20 vs. rho1 = 0.07 (P = 0.048) for systolic BP; rho2 = 0.19 vs. rho1 = 0.05 (P = 0.034) for diastolic BP). The results for this 1-directional path from baseline BP to follow up afPWV were confirmed, although marginally significant, by using large- and small-artery elasticity measurements. These findings provide strong evidence that elevated BP precedes large-artery stiffening in middle-aged adults. Unlike the case in older adults, the large-arterial wall is not stiff enough in youth to alter BP levels during young adulthood. PMID- 26960709 TI - Corrigendum: Elucidating the role of disorder and free-carrier recombination kinetics in CH3NH3PbI3 perovskite films. PMID- 26960708 TI - In vivo visualization and quantification of collecting lymphatic vessel contractility using near-infrared imaging. AB - Techniques to image lymphatic vessel function in either animal models or in the clinic are limited. In particular, imaging methods that can provide robust outcome measures for collecting lymphatic vessel function are sorely needed. In this study, we aimed to develop a method to visualize and quantify collecting lymphatic vessel function in mice, and to establish an in vivo system for evaluation of contractile agonists and antagonists using near-infrared fluorescence imaging. The flank collecting lymphatic vessel in mice was exposed using a surgical technique and a near-infrared tracer was infused into the inguinal lymph node. Collecting lymphatic vessel contractility and valve function could be easily visualized after the infusion. A diameter tracking method was established and the diameter of the vessel was found to closely correlate to near infrared fluorescence signal. Phasic contractility measures of frequency and amplitude were established using an automated algorithm. The methods were validated by tracking the vessel response to topical application of a contractile agonist, prostaglandin F2alpha, and by demonstrating the potential of the technique for non-invasive evaluation of modifiers of lymphatic function. These new methods will enable high-resolution imaging and quantification of collecting lymphatic vessel function in animal models and may have future clinical applications. PMID- 26960710 TI - Erratum to: Low expression of ULK1 is associated with operable breast cancer progression and is an adverse prognostic marker of survival for patients. AB - Erratum to: Breast Cancer Res Treat (2012),134:549-560,DOI 10.1007/s10549-012 2080-y. In the original publication of the article, Fig. 5c was published incorrectly. The authors apologize for this error and the correct Fig. 5c is given below. PMID- 26960711 TI - Increased CD4 and CD8-positive T cell infiltrate signifies good prognosis in a subset of triple-negative breast cancer. AB - Tumour-infiltrating lymphocytes (TILs) signify immune response to tumour in a variety of cancers including breast cancer. However, earlier studies examining the clinical significance of TILs in breast cancers have generated mixed results. There are only a few that address the relationship between TILs and clinical outcomes in triple-negative breast cancers (TNBC). The aim of this study is to evaluate the clinical significance of TILs that express CD4 + and CD8 + , in TNBC. Immunohistochemical staining of CD4 and CD8 was performed on tissue microarrays of 164 cases of TNBC. TILs were counted separately as intratumoral when within the cancer cell nests (iTILs) and as stromal when within cancer stroma (sTILs). High CD8 + iTILs and sTILs, and CD4 + iTILs correlated with histologic grade. On Kaplan-Meier analysis, a significantly better survival rate was observed in high CD8 + iTIL (disease-free survival, DFS: P = 0.004, overall survival, OS: P = 0.02) and both high CD4 + iTILs (DFS: P = 0.025, OS: P = 0.023) and sTILs (DFS: P = 0.01, OS: P = 0.002). In multivariate analysis, CD8 + iTILs (DFS: P = 0.0095), CD4 + sTILs (DFS: P = 0.0084; OS: P = 0.0118), and CD4 (high) CD8 (high) CD8 iTILs (DFS: P = 0.0121; OS: P = 0.0329) and sTILs (DFS: P = 0.0295) showed significantly better survival outcomes. These results suggest that high levels of both CD8 + iTILs and CD4 + sTILs as well as CD4 (high) CD8 (high) iTILs and sTILs are independent prognostic factors in TNBC. PMID- 26960712 TI - Adherence to the breast cancer surveillance program for women at risk for familial breast and ovarian cancer versus overscreening: a monocenter study in Germany. AB - Breast cancer (BC) is the leading cancer among women worldwide and in 5-10 % of cases is of hereditary origin, mainly due to BRCA1/2 mutations. Therefore, the German Consortium for Familial Breast and Ovarian Cancer (HBOC) with its 15 specialized academic centers offers families at high risk for familial/hereditary cancer a multimodal breast cancer surveillance program (MBCS) with regular breast MRI, mammography, ultrasound, and palpation. So far, we know a lot about the psychological effects of genetic testing, but we know little about risk correlated adherence to MBCS or prophylactic surgery over time. The aim of this study was to investigate counselees' adherence to recommendations for MBCS in order to adjust the care supply and define predictors for incompliance. All counselees, who attended HBOC consultation at the University Hospital Heidelberg between July 01, 2009 and July 01, 2011 were eligible to participate. A tripartite questionnaire containing sociodemographic information, psychological parameters, behavioral questions, and medical data collection from the German consortium were used. A high participation rate was achieved among the study population, with 72 % returning the questionnaire. This study showed a rate of 59 % of full-adherers to the MBCS. Significant predictors for partial or full adherence were having children (p = 0.0221), younger daughters (p = 0.01795), a higher awareness of the topic HBOC (p = 0.01795, p < 0.0001), a higher perceived breast cancer risk (p < 0.0001), and worries (p = 0.0008)/impairment (p = 0.0257) by it. Although the current data suggest a good adherence of MBCS, prospective studies are needed to understand counselees' needs to further improve surveillance programs and adherence to them. Adherence to the breast cancer surveillance program for women at risk for familial breast and ovarian cancer versus overscreening-a monocenter study in Germany. PMID- 26960714 TI - Challenges and Opportunities for Urban Environmental Health and Sustainability: the HEALTHY-POLIS initiative. AB - Cities around the world face many environmental health challenges including contamination of air, water and soil, traffic congestion and noise, and poor housing conditions exacerbated by unsustainable urban development and climate change. Integrated assessment of these risks offers opportunities for holistic, low carbon solutions in the urban environment that can bring multiple benefits for public health. The Healthy-Polis consortium aims to protect and promote urban health through multi-disciplinary, policy-relevant research on urban environmental health and sustainability. We are doing this by promoting improved methods of health risk assessment, facilitating international collaboration, contributing to the training of research scientists and students, and engaging with key stakeholders in government, local authorities, international organisations, industry and academia. A major focus of the consortium is to promote and support international research projects coordinated between two or more countries. The disciplinary areas represented in the consortium are many and varied, including environmental epidemiology, modelling and exposure assessment, system dynamics, health impact assessment, multi-criteria decision analysis, and other quantitative and qualitative approaches. This Healthy-Polis special issue presents a range of case studies and reviews that illustrate the need for a systems-based understanding of the urban environment. PMID- 26960713 TI - Synthesis and Larvicidal Activity of Novel Thenoylhydrazide Derivatives. AB - A pair of chemical isomeric structures of novel N-tert-butylphenyl thenoylhydrazide compounds I and II were designed and synthesized. Their structures were characterized by MS, IR, (1)H NMR, elemental analysis and X-ray single crystal diffraction. The regioselectivity of the Meerwein arylation reaction and the electrophilic substitution reaction of N-tert-butyl hydrazine were studied by density functional theory (DFT) quantum chemical method. The larvicidal tests revealed that some compounds I had excellent larvicidal activity against Culex pipiens pallens. As the candidates of insect growth regulators (IGRs), the larval growth inhibition and regulation against Culex pipiens pallens were examined for some compounds, especially I1 and I7. Compounds I1 and I7 were further indicated as an ecdysteroid agonist by reporter gene assay on the Spodoptera frugiperda cell line (Sf9 cells). Finally, a molecular docking study of compound I7 was conducted, which was not only beneficial to understand the structure-activity relationship, but also useful for development of new IGRs for the control of mosquitos. PMID- 26960715 TI - Contrast-enhanced ultrasound in diagnosis of epithelioid renal angiomyolipoma with renal vein and inferior vena cava extension. AB - Epithelioid angiomyolipoma is considered to be a rare variant of angiomyolipoma and potentially malignant. Reported cases of renal epithelioid angiomyolipoma with extension into the renal vein and inferior vena cava are even rarer. Once it occurs, it is difficult to differentiate from renal cell carcinoma on imaging. In addition, very few of the reported cases presented contrast-enhanced ultrasound images. Here, we report a case of a renal epithelioid angiomyolipoma extending into the renal vein and inferior vena cava along with its contrast-enhanced ultrasonic information. Contrast-enhanced ultrasound provided valuable information for diagnosis in this case. PMID- 26960716 TI - Gene Mutation in Neonatal Jaundice - Mutations in UGT1A1 and OATP2 Genes. AB - This study evaluated the correlation of UGT1A1, OATP2 gene mutations and hyperbilirubinemia in newborns in Northern China. Gene mutations were analyzed at the 211 locus of UGT1A1 (Gly71Arg) and 388 locus of OATP2 (Asn130Asp). The 226 enrolled infants were divided into high, moderate, and low risk subgroups according to American Academy of Pediatrics guideline. Blood samples of the enrolled infants were collected for the analysis of the PCR-restriction fragment length polymorphism. The genotypes and allele frequencies of the polymorphisms were compared in each group. Both UGT1A1 and OATP2 gene mutations occur more often in high risk group and moderate risk group than in low risk group. The results suggested that Gly71Arg and Asn130Asp mutations in UGT1A1 and OATP2 genes might be involved in the development of hyperbilirubinemia in neonates. PMID- 26960717 TI - Soluble Urokinase Plasminogen Activator Receptor: A New Biomarker in the Pediatric Intensive Care Unit. AB - OBJECTIVE: To evaluate the value of soluble urokinase plasminogen activator receptor (suPAR) in diagnosing sepsis and predicting mortality in critically ill children. METHODS: In a prospective cohort study, 69 critically ill children admitted into the pediatric intensive care unit (PICU) were randomly enrolled in addition to 15 healthy children as a control group. Clinical examination was performed, including calculation of the Pediatric Risk of Mortality (PRISM) and Pediatric Index of Mortality2 (PIM2). suPAR was measured in patients at admission as well as in the controls. Patients were followed up for 30 d. RESULTS: suPAR level was significantly higher among the total patient cohort compared to controls (p < 0.0001). suPAR was also significantly higher among patients with sepsis compared to both controls (p < 0.0001) and patients without sepsis (p < 0.0001). Furthermore, suPAR level was significantly elevated in non-survivors compared to survivors (p 0.008). Receiver operating characteristic curve (ROC curve) analysis revealed an area under the curve (AUC) of 0.80 for suPAR for diagnosis of sepsis while C-reactive protein (CRP) had an AUC of 0.82. Regarding the prognosis, suPAR had an AUC of 0.69 for prediction of mortality, whereas the AUC for PRISM, PIM2, and CRP were 0.82, 0.81, and 0.77 respectively. CONCLUSIONS: suPAR has both a diagnostic and a prognostic value for critically ill children. However, it does not seem to be superior to the classic laboratory markers and clinical scoring systems. PMID- 26960719 TI - Comment on: Mortality due to blaKPC Klebsiella pneumoniae bacteraemia. PMID- 26960720 TI - Mortality due to blaKPC Klebsiella pneumoniae bacteraemia-authors' response. PMID- 26960718 TI - Reduction Impairs the Antibacterial Activity but Benefits the LPS Neutralization Ability of Human Enteric Defensin 5. AB - Oxidized human defensin 5 (HD5OX), a Paneth cell-secreted antibacterial peptide with three characteristic disulfide bonds, protects the host from invasion by morbigenous microbes in the small intestine. HD5OX can be reduced by thioredoxin (Trx) in vitro, while the biochemical properties of the reduced linear peptide, HD5RED, remain unclear. Here, we first confirm that HD5RED does exist in vivo. Furthermore, we reveal that the recruitment of HD5RED to the outer membrane of Gram-negative bacteria and to the anionic lipid A is lower than that of HD5OX, and HD5RED is less efficient in penetrating bacterial outer and inner membranes and inducing membrane depolarization, which confers an attenuated antibacterial activity to HD5RED. However, due to its higher structural flexibility, the binding of HD5RED to bacterial lipopolysaccharide (LPS) is markedly stronger than that of HD5OX. Consequently, HD5RED is more effective in suppressing the production of the pro-inflammatory cytokine TNF-alpha in LPS-stimulated macrophages by blocking the interaction between LPS and LPS-binding protein, thus suggesting that HD5RED might act as a scavenger to neutralize LPS in the gut. This study provides insights into the antibacterial and immunoregulatory effects of HD5RED and expands the known repertoire of the enteric defensins. PMID- 26960721 TI - Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease. PMID- 26960722 TI - Anastomosing hemangiomas: locations of occurrence, imaging features, and diagnosis with percutaneous biopsy. AB - PURPOSE: To describe a series of anastomosing hemangiomas and report its locations, imaging features, and the use of image-guided percutaneous biopsy to establish the diagnosis. METHODS: In this institutional review board-approved, HIPAA compliant, retrospective study, an electronic pathology database was searched for all cases of anastomosing hemangioma from January 2009 to January 2015, yielding 32 cases (18 men, mean age 62 years). Tumor locations were recorded, and in a subgroup of patients with imaging, image characteristics (contour, attenuation, enhancement after intravenous contrast injection, the presence of hemorrhage or fat attenuation, and non-enhancing component) were evaluated. The number of cases diagnosed using percutaneous biopsy specimen was determined, and in a subgroup of these patients, biopsy technique and complications were assessed. RESULTS: Anastomosing hemangioma occurred in different locations, more commonly in the retroperitoneum (15/32, 47%), including the kidney (7/32, 22%), and more rarely in the ovary (4/32, 13%) and liver (2/32, 6%). Of the 5 cases with imaging available, four anastomosing hemangiomas were in the retroperitoneum (one in retroperitoneal fat, one para-aortic, one renal and one adrenal) and the fifth was mesenteric. Most tumors were well circumscribed (4/5, 80%), and on non-contrast CT, they appeared as mildly hyperdense (4/5, 80%) with avid contrast enhancement and heterogeneous attenuation (4/5, 80%) due to the presence of fat (2/5, 40%) or non-enhancing components (2/5, 40%). Diagnosis was rendered solely based on percutaneous biopsy in 7/32 (22%), all of which were core biopsy specimens. Fine-needle aspiration biopsy was performed in 1 case, which was non-diagnostic. CONCLUSIONS: Anastomosing hemangioma, a rare benign vascular tumor, is most commonly seen in the retroperitoneal fat and kidneys. On imaging, they are usually circumscribed, hyperdense, and heterogeneous due to fatty or non-enhancing hypodense areas and show avid post-contrast enhancement. Percutaneous biopsy can yield the diagnosis, potentially avoiding surgery. PMID- 26960723 TI - The role of the radiologist in new payment systems. AB - Many economists and policy makers believe that United States healthcare costs are rising at an unsustainable rate. In response, newer payment systems such as bundled payments, accountable care organizations, and population health management have been proposed. These new paradigms all aim to encourage collaboration between health care providers to conserve costs and increase quality. To succeed in this evolving environment, radiologists should consider embracing change by working to standardize radiology practice, participating in radiology utilization management, working with vendors to increase storage of radiology imaging data to improve access and interconnectivity, and exploring targeted screening in high risk populations. PMID- 26960724 TI - The actionable imaging report. AB - The goal of a diagnostic imaging examination is to provide the referring provider with an actionable imaging report that can be used to impart information to determine optimal clinical management for the patient. An actionable imaging report not only conveys the findings of the examination accurately, but does so in a timely and safe manner for an imaging examination that was performed appropriately and using the correct technique. The use of information technology tools has been paramount in improving the value of the imaging report and continues to play a prominent role in this process. The diversity of abdominal imaging, in both the variety of imaging modalities available and the organ systems evaluated, makes it well-suited to adopt these information technology solutions to improve report quality, including increased consistency in reports and in follow-up recommendations. This review discusses the components of the imaging chain involved in optimizing the imaging report with specific emphasis on the role of information technology applications to address the challenges that are frequently encountered. Specific abdominal imaging examples are presented to provide practical guidance and clinical context. PMID- 26960725 TI - A case of polypoid endometriosis with malignant transformation. AB - Polypoid endometriosis is a benign, rare variant of endometriosis which forms multiple polypoid nodules in the female pelvis mimicking malignant tumors; however, it may rarely cause malignant transformation. We report magnetic resonance imaging findings of a case of polypoid endometriosis with malignant transformation. Multiple high-signal intensity polypoid nodules in the cul-de-sac surrounded by low-signal intensity rim-like fibrous adhesion protruding to the posterior wall of the uterine body were demonstrated on T2-weighted images. The polypoid nodules showed weak contrast enhancement compared with that of uterine myometrium on post-contrast T1-weighted images, and slight high signal intensity on diffusion-weighted images with relatively high mean apparent diffusion coefficient. Reported cases of polypoid endometriosis showed intense contrast enhancement similar to that of uterine myometrium, and weak contrast enhancement similar to that of endometrial carcinoma may be suggestive for malignant transformation of polypoid endometriosis. PMID- 26960726 TI - Quantitative volumetric functional MR imaging: an imaging biomarker of early treatment response in hypo-vascular liver metastasis patients after yttrium-90 transarterial radioembolization. AB - PURPOSE: To evaluate the value of quantitative volumetric functional MR imaging in early assessment of response to yttrium-90-labeled ((90)Y) transarterial radioembolization (TARE) in patients with hypo-vascular liver metastases. MATERIALS AND METHODS: Seventy four metastatic lesions in 14 patients with hypo vascular liver metastases after TARE were included in this retrospective study. Diffusion and contrast-enhanced MR imaging was performed before and early after treatment. All MR images were analyzed by two experienced radiologists. Response by anatomic metrics (RECIST, mRECIST, EASL) and functional metrics (ADC and arterial and venous enhancement) were reported in targeted and non-targeted lesions. A two-sample paired t test was used to compare the changes after TARE. A p value of <0.05 was considered statistically significant. RESULTS: The anatomic metrics did not show any significant changes in both targeted and non-targeted groups. Targeted lesions demonstrated an increase in mean volumetric ADC (23.4%; p = 0.01), a decrease in arterial and venous enhancement (-22.9% and -6.7%, respectively; p < 0.001 and p = 0.002, respectively) 1 month after treatment. Twenty one responding lesions (42%) by RECIST at 6 months demonstrated a significant increase in volumetric ADC (37.2%; p = 0.01), decrease in arterial and venous enhancement (-58.5% and -23.9%, respectively; p < 0.001) at 1 month post-treatment. Responding lesions did not change significantly by anatomic metrics. CONCLUSIONS: RECIST, mRECIST, and EASL criteria failed to stratify lesions into responders and non-responders early after TARE in hypo-vascular liver metastasis. Quantitative volumetric functional MR imaging could be a promising tool as a biomarker for predicting early response and can potentially be utilized in clinical trials. PMID- 26960727 TI - Comparison of gadoxetic acid to gadobenate dimeglumine for assessment of biliary anatomy of potential liver donors. AB - PURPOSE: To compare MRI using gadobenate dimeglumine (Gd-BOPTA) vs. gadoxetic acid disodium (Gd-EOB-DTPA) for the assessment of biliary anatomy of potential liver donors. METHODS: 76 potential liver donors (39 M/37 F, mean 38 years) who underwent 1.5T MRI using Gd-BOPTA (n = 37) or Gd-EOB-DTPA (n = 39) were retrospectively evaluated. T2 cholangiogram (T2 MRC) and delayed hepatobiliary phase (HBP) T1 cholangiogram (T1 MRC) (performed during HBP 20 min after injection of Gd-EOB-DTPA and 1-2 h after Gd-BOPTA injection) were obtained in addition to MR angiogram/venogram. Two independent observers evaluated image quality (IQ) and conspicuity scores (CS) of the biliary system. Biliary anatomy was assessed in 3 reading sessions (T2 MRC, T1 MRC, and combined T2/T1 MRC). Reference standard consisted of consensus reading of two separate observers of all image sets, clinical/surgical information and intraoperative cholangiogram when available. Datasets were compared using the Mann-Whitney U test or Chi squared test. RESULTS: There was no difference in IQ for T1 MRC using either contrast agent or T2 MRC vs. T1 MRC for both observers (all p values >0.07). There was superior CS for T2 MRC vs. Gd-BOPTA T1 MRC for both observers and T2 MRC vs. Gd-EOB for one observer (p < 0.001). No difference was found for biliary variant detection for T1 MRC (with either contrast agent) vs. T2 MRC. Combined T2/T1 MRC demonstrated improved sensitivity for biliary variant detection using Gd-BOPTA for both observers (p < 0.004) and Gd-EOB-DTPA for one observer (p < 0.001). CONCLUSION: Equivalent image quality was found for T1 MRC obtained with Gd-BOPTA or Gd-EOB-DTPA and T2 MRC. T1 MRC is equivalent to T2 MRC for detection of variant biliary anatomy, and the combination of sequences may have added value. PMID- 26960728 TI - Percutaneous cryoablation of hepatic tumors: long-term experience of a large U.S. series. AB - PURPOSE: To report our long-term experience with percutaneous cryotherapy for primary and metastatic liver tumors, including historical perspectives on complications over time and local recurrence rates. MATERIALS AND METHODS: Following IRB approval under HIPAA compliance, 342 CT fluoroscopic-guided, percutaneous cryotherapy procedures were performed for 443 masses in 212 outpatients with hepatocellular carcinoma (HCC; N = 36), or metastatic disease (N = 176), grouped as colorectal carcinoma (CRC) and non-CRC metastases. Tumor and ablation sizes were noted in relation to adjacent vasculature. All complications were graded according to standardized criteria. Patients were followed by CT and/or MRI at 1, 3, 6, 12, 18, 24 months and yearly thereafter. Local recurrences were defined as either "procedural" within the ice ablation zone, or "satellite" within 1 cm of the ablation rim to evaluate recurrence patterns. RESULTS: Average tumor diameter of 2.8 cm was treated by average cryoprobe number of 4.5, which produced CT-visible ice ablation zone diameters averaging 5.2 cm. Grade >3 complications were primarily hematologic [N = 20/342; (5.8%)], and appeared related to pre-procedural anemia/thrombocytopenia, carcinoid tumor type, and large ablation volumes. No significant central biliary leak, strictures, or bilomas were noted. At a mean follow-up of 1.8 years, local tumor recurrences were 5.5%, 11.1%, and 9.4% for HCC, CRC, and non-CRC metastases, respectively, consisting mainly of satellite foci. No significant difference was noted for local recurrences near major blood vessels or tumors >3 cm diameter. CONCLUSIONS: Percutaneous hepatic cryotherapy is a well-visualized, safe procedure that produces very low local recurrence rates, even for tumors near vasculature and diameters over 3 cm. Cryoablation deserves to be in the armamentarium of percutaneous hepatic ablation, especially with careful patient selection for tumors <4 cm and patients with platelet counts >100,000. Percutaneous hepatic cryoablation represents a highly flexible technique with particular benefits near central biliary structures and/or adjacent crucial structures. PMID- 26960729 TI - Comparison of Doppler ultrasound and transient elastography in the diagnosis of significant fibrosis in patients with nonalcoholic steatohepatitis. AB - BACKGROUND: Liver fibrosis is an important prognostic determinant in patients with nonalcoholic steatohepatitis (NASH). Hepatic artery resistivity index (HARI) is a doppler ultrasonography (US) parameter that is used to follow up microcirculatory resistance in fatty liver. We aimed to asses whether it is possible to demonstrate significant fibrosis by means of doppler US in comparison with transient elastography (TE) and liver biopsy in NASH patients. PATIENTS AND METHODS: A total of 63 (mean age 47.1 +/- 8.4 years, 39 male, 24 female) biopsy proven NASH patients were enrolled in this prospective study. The study population was classified into two groups: significant and no-significant fibrosis patients. Doppler US and TE were performed in two groups. RESULTS: HARI and TE values were significantly higher in significant fibrosis group (0.81 +/- 0.05 vs. 0.63 +/- 0.14, p < 0.0005; 15.9 +/- 4.8 vs. 6.2 +/- 2.6 kilopascals, p < 0.0005; respectively). Based on the ROC curve, the optimal cut-off value of HARI for a significant fibrosis was >0.75, which yielded a sensitivity of 78% and a specificity of 75%, with the area under the curve at 0.90. The optimal cut-off value of TE for a significant fibrosis was >9.8 kilopascals, which yielded a sensitivity of 90% and a specificity of 91%, with the area under the curve at 0.95. HARI values were moderately correlated with TE values (r = 0.53, p < 0.001). CONCLUSION: Doppler US has moderate % sensitivity and % specificity, which is lower compared with TE for the diagnosis significant fibrosis. However, it may be used as an alternative method for the assessment of fibrosis in patients with NASH who are not good candidates for TE evaluation. PMID- 26960730 TI - Growth of high quality and uniformity AlGaN/GaN heterostructures on Si substrates using a single AlGaN layer with low Al composition. AB - By employing a single AlGaN layer with low Al composition, high quality and uniformity AlGaN/GaN heterostructures have been successfully grown on Si substrates by metal-organic chemical vapor deposition (MOCVD). The heterostructures exhibit a high electron mobility of 2150 cm(2)/Vs with an electron density of 9.3 * 10(12) cm(-2). The sheet resistance is 313 +/- 4 Omega/? with +/-1.3% variation. The high uniformity is attributed to the reduced wafer bow resulting from the balance of the compressive stress induced and consumed during the growth, and the thermal tensile stress induced during the cooling down process. By a combination of theoretical calculations and in situ wafer curvature measurements, we find that the compressive stress consumed by the dislocation relaxation (~1.2 GPa) is comparable to the value of the thermal tensile stress (~1.4 GPa) and we should pay more attention to it during growth of GaN on Si substrates. Our results demonstrate a promising approach to simplifying the growth processes of GaN-on-Si to reduce the wafer bow and lower the cost while maintaining high material quality. PMID- 26960731 TI - OsDMC1 Is Not Required for Homologous Pairing in Rice Meiosis. AB - Meiotic homologous recombination is pivotal to sexual reproduction. DMC1, a conserved recombinase, is involved in directing single-end invasion between interhomologs during meiotic recombination. In this study, we identified OsDMC1A and OsDMC1B, two closely related proteins in rice (Oryza sativa) with high sequence similarity to DMC1 proteins from other species. Analysis of Osdmc1a and Osdmc1b Tos17 insertion mutants indicated that these genes are functionally redundant. Immunolocalization analysis revealed OsDMC1 foci occurred at leptotene, which disappeared from late pachytene chromosomes in wild-type meiocytes. According to cytological analyses, homologous pairing is accomplished in the Osdmc1a Osdmc1b double mutant, but synapsis is seriously disrupted. The reduced number of bivalents and abnormal OsHEI10 foci in Osdmc1a Osdmc1b establishes an essential role for OsDMC1 in crossover formation. In the absence of OsDMC1, early recombination events probably occur normally, leading to normal localization of gammaH2AX, PAIR3, OsMRE11, OsCOM1, and OsRAD51C. Moreover, OsDMC1 was not detected in pairing-defective mutants, such as pair2, pair3, Oscom1, and Osrad51c, while it was loaded onto meiotic chromosomes in zep1, Osmer3, Oszip4, and Oshei10 Taken together, these results suggest that during meiosis, OsDMC1 is dispensable for homologous pairing in rice, which is quite different from the DMC1 homologs identified so far in other organisms. PMID- 26960732 TI - Gatekeeper Tyrosine Phosphorylation of SYMRK Is Essential for Synchronizing the Epidermal and Cortical Responses in Root Nodule Symbiosis. AB - Symbiosis receptor kinase (SYMRK) is indispensable for activation of root nodule symbiosis (RNS) at both epidermal and cortical levels and is functionally conserved in legumes. Previously, we reported SYMRK to be phosphorylated on "gatekeeper" Tyr both in vitro as well as in planta. Since gatekeeper phosphorylation was not necessary for activity, the significance remained elusive. Herein, we show that substituting gatekeeper with nonphosphorylatable residues like Phe or Ala significantly affected autophosphorylation on selected targets on activation segment/alphaEF and beta3-alphaC loop of SYMRK. In addition, the same gatekeeper mutants failed to restore proper symbiotic features in a symrk null mutant where rhizobial invasion of the epidermis and nodule organogenesis was unaffected but rhizobia remain restricted to the epidermis in infection threads migrating parallel to the longitudinal axis of the root, resulting in extensive infection patches at the nodule apex. Thus, gatekeeper phosphorylation is critical for synchronizing epidermal/cortical responses in RNS. PMID- 26960734 TI - Portal thrombosis and liver necrosis: Exceptional complication of acute pancreatitis. PMID- 26960736 TI - Lipoxygenase inhibitors from the latex of Calotropis Procera. AB - A radical-scavenging, guided phytochemical study of the latex of Calotropis Procera afforded five lignans (1-5), including a new one (4). The structural determination was accomplished using 1D- and 2D-NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and correlation with known compounds. Among the isolated compounds, acylated lignans (3-5) showed stronger antioxidant activity than non-acylated derivatives (1,2). Anti-inflammatory activity was evaluated by determining the inhibitory potential against 5- and 15-lipoxygenase enzymes. The highest anti-inflammatory activity was observed in compound 4, with IC50s values of 7.6 uM and 2.7 uM against 5-LOX and 15-LOX, respectively. PMID- 26960733 TI - Constructing 3D interaction maps from 1D epigenomes. AB - The human genome is tightly packaged into chromatin whose functional output depends on both one-dimensional (1D) local chromatin states and three-dimensional (3D) genome organization. Currently, chromatin modifications and 3D genome organization are measured by distinct assays. An emerging question is whether it is possible to deduce 3D interactions by integrative analysis of 1D epigenomic data and associate 3D contacts to functionality of the interacting loci. Here we present EpiTensor, an algorithm to identify 3D spatial associations within topologically associating domains (TADs) from 1D maps of histone modifications, chromatin accessibility and RNA-seq. We demonstrate that active promoter promoter, promoter-enhancer and enhancer-enhancer associations identified by EpiTensor are highly concordant with those detected by Hi-C, ChIA-PET and eQTL analyses at 200 bp resolution. Moreover, EpiTensor has identified a set of interaction hotspots, characterized by higher chromatin and transcriptional activity as well as enriched TF and ncRNA binding across diverse cell types, which may be critical for stabilizing the local 3D interactions. PMID- 26960735 TI - BRAF mutations in non-small cell lung cancer: has finally Janus opened the door? AB - B-Raf mutations occur in about 1-2% of non-small cell lung cancers (NSCLC). These mutations generate a permanent activation of the mitogen activated protein kinase (MAPK) pathway, which promotes tumor growth and proliferation. In the present review, we discuss B-Raf mutation epidemiology, diagnostic methods to detect B Raf mutations, the role of B-Raf as a driver mutation and a potential therapeutic target in NSCLC. The results of clinical trials involving B-Raf or MAPK pathway inhibitors for the treatment of NSCLC are also discussed. Clinical trials evaluating B-Raf inhibitors in BRAF mutated NSCLC patients have shown promising results, and larger prospective studies are warranted to validate these findings. Enrollment of these patients in clinical trials is an interesting strategy to offer a potentially more effective and less toxic targeted therapy. PMID- 26960737 TI - Effects of candesartan cilexetil and amlodipine orotate on receptor for advanced glycation end products expression in the aortic wall of Otsuka Long-Evans Tokushima Fatty (OETFF) type 2 diabetic rats. AB - The receptor for advanced glycation end products (RAGE) plays a key role in the development of vascular inflammation and acceleration of atherosclerosis in type 2 diabetes. We investigated the effect of candesartan cilexetil (CDRT) and amlodipine orotate (AMDP) on the expression of RAGE in the aortic walls of Otsuka Long-Evans Tokushima Fatty (OLETF) rats and AGE-treated endothelial cells. Twenty five-week-old OLETF rats were randomized to 8 week treatments consisting of CDRT (n = 8), AMDP (n = 8) or saline (control, n = 8). Immunohistochemical and dihydroethidine staining revealed reduced RAGE and reactive oxygen species (ROS) signals in rats treated with CDRT or AMDP compared with control rats. Both CDRT and AMDP suppressed the expression of p22phox and p47phox NADPH oxidase subunits. However, only CDRT significantly reduced expression of phosphorylated extracellular signal regulated kinase (pERK)1/2 in the aortic wall of OLETF rats. In addition, both drugs reduced RAGE expression and total and mitochondrial ROS production in the AGE-treated endothelial cells. Both ARBs and CCBs reduced RAGE expression in the aortic walls of OLETF rats, which was attributed to decreased ROS production through inhibition of NADPH oxidase. In addition, only CDRT reduced aortic expression of RAGE via suppression of the ERK1/2 pathway unlike AMDP. PMID- 26960738 TI - Early coagulopathy and metabolic acidosis predict transfusion of packed red blood cells in pediatric trauma patients. AB - BACKGROUND: Severely injured pediatric trauma patients often present to hospital with early coagulopathy and metabolic acidosis. These derangements are associated with poor outcomes, but it is unclear to what degree they predict transfusion of packed red blood cells (pRBC). METHODS: We retrospectively identified pediatric trauma patients from a level 1 trauma center from 2006 to 2013. Inclusion criteria were age less than 18years, Injury Severity Score greater than 12, and pRBC transfusion within 24h of admission. RESULTS: We identified 96 pediatric trauma patients who underwent pRBC transfusion within 24h of presentation to hospital. On admission, 43% of these patients had one or more signs of coagulopathy, and 81% had metabolic acidosis. Size of pRBC transfusion in the first 24h ranged from 3 to 177mL/kg (mean 29mL/kg), and nineteen patients (20%) underwent massive transfusion (>40ml/kg in 24h). Univariate analysis indicated that size of pRBC transfusion was associated with initial base excess (r=0.46), international normalized ratio (r=0.35), partial thromboplastin time (r=0.41), fibrinogen (r=0.46), and BIG score (Base deficit, INR, Glasgow Coma Scale (GCS), r=0.36). Platelet count, age, GCS, and direct versus referred presentation were not predictive. Multivariable linear regression confirmed that coagulopathy and metabolic acidosis remained predictive after adjusting for direct versus referred presentation (R(2)=0.30). CONCLUSIONS: Early coagulopathy and metabolic acidosis predict size of pRBC transfusion among pediatric trauma patients. Further research is needed to develop massive transfusion protocols and guidelines for activation. PMID- 26960741 TI - Aerobic and resistance exercise improve walking speed and endurance in people with multiple sclerosis. PMID- 26960740 TI - Bimanual coordination and the intermittency of visual information in isometric force tracking. AB - The effect of the intermittency of visual information in the bimanual coordination of an isometric force coordination task was investigated as a function of criterion force level. Eight levels of visual information intermittency (.2-25.6 Hz) were used in blocked fashion at each force level. Participants were required to produce a constant force output matching as accurately as possible the criterion force target. The results showed that performance improved as the intermittency of visual information was reduced-this effect being a function of force level. The distribution of the relative phase through the trial revealed a preference for the two hands to be coupled together (in-phase) at the slower rates of visual presentation (~.2 Hz). However, as the rate of visual feedback was increased (up to ~25.6 Hz), there was a transition to predominantly a negative correlation pattern (anti-phase). The pattern of bimanual coordination in this isometric tracking task is driven by the availability of information for error correction and the interactive influence of perceptual-motor constraints. PMID- 26960739 TI - Lateral occipitotemporal cortex (LOTC) activity is greatest while viewing dance compared to visualization and movement: learning and expertise effects. AB - The lateral occipitotemporal cortex (LOTC) is comprised of subregions selectively activated by images of human bodies (extrastriate body area, EBA), objects (lateral occipital complex, LO), and motion (MT+). However, their role in motor imagery and movement processing is unclear, as are the influences of learning and expertise on its recruitment. The purpose of our study was to examine putative changes in LOTC activation during action processing following motor learning of novel choreography in professional ballet dancers. Subjects were scanned with functional magnetic resonance imaging up to four times over 34 weeks and performed four tasks: viewing and visualizing a newly learned ballet dance, visualizing a dance that was not being learned, and movement of the foot. EBA, LO, and MT+ were activated most while viewing dance compared to visualization and movement. Significant increases in activation were observed over time in left LO only during visualization of the unlearned dance, and all subregions were activated bilaterally during the viewing task after 34 weeks of performance, suggesting learning-induced plasticity. Finally, we provide novel evidence for modulation of EBA with dance experience during the motor task, with significant activation elicited in a comparison group of novice dancers only. These results provide a composite of LOTC activation during action processing of newly learned ballet choreography and movement of the foot. The role of these areas is confirmed as primarily subserving observation of complex sequences of whole-body movement, with new evidence for modification by experience and over the course of real world ballet learning. PMID- 26960742 TI - A randomised trial of an intensive physiotherapy program for patients in intensive care [synopsis]. PMID- 26960743 TI - The Formation of Crystal Defects in a Fe-Mn-Si Alloy Under Cyclic Martensitic Transformations. AB - Formation of crystalline defects due to cyclic martensitic transformations (CMT) in the iron-manganese Fe-18 wt.% Mn-2 wt.% Si alloy was investigated using X-ray diffractometry. Conditions for accumulation of fragment sub-boundaries with low angle misorientations and chaotic stacking faults in crystal lattice of austenite and epsilon-martensite were analyzed. PMID- 26960744 TI - Cytotoxicity and anti-inflammatory effects of zinc ions and eugenol during setting of ZOE in immortalized human oral keratinocytes grown as three dimensional spheroids. AB - OBJECTIVES: The objective of this study is to assess the cytotoxic and anti inflammatory effects of ZOE cement during setting in two-dimensional (2D) or three-dimensional (3D) cultures of immortalized human oral keratinocytes (IHOKs) with determining the extract components responsible for these effects. METHODS: Extracts of mixed ZOE at different stages of setting were analyzed by a digital pH meter, ICP-MS, and GC-MS. Serial concentrations of extract and their mixture of ZnCl2, ZnSO4.H2O, and eugenol liquid were added to the 2D and 3D IHOK cultures to determine the half maximal effective concentration in investigating the cause of cytotoxicity by means of WST assay and to investigate mRNA expression levels of inflammatory cytokines by RT-PCR. RESULTS: Zn(2+) and eugenol (4-19 ppm) were detected in the extracts. In the early setting stage, significant cytotoxicity was observed in the 2D and 3D IHOK cultures (P<0.05). The EC50 of Zn(2+) from ZnCl2 was 5-44 ppm in both cultures, whereas the EC50 of eugenol was not detectable under 100 ppm. Along with the lower levels of inflammatory cytokine gene expressions in the extract, treatment of the 2D IHOKs with Zn(2+) alone and treatment of the 3D IHOKs with Zn(2+) plus eugenol resulted in significantly lower expression levels of IL-1beta, IL-6, and IL-8 (P<0.05). SIGNIFICANCE: The cytotoxic effect of ZOE on IHOKs was greater during the setting stage owing to the presence of Zn(2+). The anti-inflammatory response to ZOE was induced by a combination of Zn(2+) and eugenol. Cytotoxic and anti-inflammatory effects differed between the 2D and 3D IHOK cultures. PMID- 26960745 TI - Finding the Patient's Voice Using Big Data: Analysis of Users' Health-Related Concerns in the ChaCha Question-and-Answer Service (2009-2012). AB - BACKGROUND: The development of effective health care and public health interventions requires a comprehensive understanding of the perceptions, concerns, and stated needs of health care consumers and the public at large. Big datasets from social media and question-and-answer services provide insight into the public's health concerns and priorities without the financial, temporal, and spatial encumbrances of more traditional community-engagement methods and may prove a useful starting point for public-engagement health research (infodemiology). OBJECTIVE: The objective of our study was to describe user characteristics and health-related queries of the ChaCha question-and-answer platform, and discuss how these data may be used to better understand the perceptions, concerns, and stated needs of health care consumers and the public at large. METHODS: We conducted a retrospective automated textual analysis of anonymous user-generated queries submitted to ChaCha between January 2009 and November 2012. A total of 2.004 billion queries were read, of which 3.50% (70,083,796/2,004,243,249) were missing 1 or more data fields, leaving 1.934 billion complete lines of data for these analyses. RESULTS: Males and females submitted roughly equal numbers of health queries, but content differed by sex. Questions from females predominantly focused on pregnancy, menstruation, and vaginal health. Questions from males predominantly focused on body image, drug use, and sexuality. Adolescents aged 12-19 years submitted more queries than any other age group. Their queries were largely centered on sexual and reproductive health, and pregnancy in particular. CONCLUSIONS: The private nature of the ChaCha service provided a perfect environment for maximum frankness among users, especially among adolescents posing sensitive health questions. Adolescents' sexual health queries reveal knowledge gaps with serious, lifelong consequences. The nature of questions to the service provides opportunities for rapid understanding of health concerns and may lead to development of more effective tailored interventions. PMID- 26960746 TI - Post-laryngectomy voice rehabilitation with a voice prosthesis in a young girl with advanced thyroid cancer. AB - The aim of this report is to evaluate the effects of voice rehabilitation with a voice prosthesis in a young patient with thyroid cancer. A 17-year-old girl underwent voice restoration with a voice prosthesis after laryngectomy to treat thyroid cancer. She completed voice-related questionnaires (the Voice Handicap Index-10 and Voice-Related Quality Of Life Survey) at ages 17 and 21 and underwent phonetic functional evaluation. The sound spectrograms of her phonation using the voice prosthesis showed low frequency sounds without an obvious basic frequency. She was ashamed of her hoarse voice and did not use her voice prosthesis during high school. However, after beginning to work at age 20, she used her voice to communicate in the workplace. At age 21, her questionnaire scores, especially those related to the physical and functional domains, improved compared with those at age 17. Voice restoration with a voice prosthesis is recommended for young patients who undergo laryngectomy for advanced thyroid cancer. The advantages of voice restoration with a voice prosthesis may increase when the patient reaches working age, and it may improve post-laryngectomy quality of life considerably. PMID- 26960748 TI - Predictors of Trigeminal Neuropathy After Radiosurgery for Vestibular Schwannomas. AB - PURPOSE: To analyze the relationship between dosimetric characteristics and symptoms related to trigeminal neuropathy (TN) observed after radiosurgery (RS) for vestibular schwannomas (VS); to propose guidelines to optimize planification in VS RS regarding TN preservation; and to detail the mechanism of TN impairment after VS RS. METHODS AND MATERIALS: One hundred seventy-nine patients treated between 2011 and 2013 for VS RS and without trigeminal impairment before RS were included in a retrospective study. Univariate and multivariate analyses were performed to determine predictors of TN among characteristics of the patients, the dosimetry, and the VS. RESULTS: There were 20 Koos grade 1, 99 grade 2, 57 grade 3, and 3 grade 4. Fourteen patients (7.8%) presented a transitory or permanent TN. Between the patients with and without TN after VS RS, there was no significant difference regarding dosimetry or VS volume itself. Significant differences (univariate analysis P<.05, Mann-Whitney test) were found for parameters related to the cisternal portion of the trigeminal nerve: total integrated dose, maximum dose, mean dose, volume of the Vth nerve (Volv), and volume of the Vth nerve receiving at least 11 Gy (VolVcist>11Gy), but also for maximal dose to the Vth nerve nucleus and intra-axial portion (Dose maxVax). After multivariate analysis, the best model predicting TN included VolVcist>11Gy (P=.0045), Dose maxVax (P=.0006), and Volv (P=.0058). The negative predictive value of this model was 97%. CONCLUSIONS: The parameters VolVcist>11Gy, Dose maxVax, and Volv should be checked when designing dosimetry for VS RS. PMID- 26960747 TI - Carbon-Ion Pencil Beam Scanning Treatment With Gated Markerless Tumor Tracking: An Analysis of Positional Accuracy. AB - PURPOSE: Having implemented amplitude-based respiratory gating for scanned carbon ion beam therapy, we sought to evaluate its effect on positional accuracy and throughput. METHODS AND MATERIALS: A total of 10 patients with tumors of the lung and liver participated in the first clinical trials at our center. Treatment planning was conducted with 4-dimensional computed tomography (4DCT) under free breathing conditions. The planning target volume (PTV) was calculated by adding a 2- to 3-mm setup margin outside the clinical target volume (CTV) within the gating window. The treatment beam was on when the CTV was within the PTV. Tumor position was detected in real time with a markerless tumor tracking system using paired x-ray fluoroscopic imaging units. RESULTS: The patient setup error (mean +/- SD) was 1.1 +/- 1.2 mm/0.6 +/- 0.4 degrees . The mean internal gating accuracy (95% confidence interval [CI]) was 0.5 mm. If external gating had been applied to this treatment, the mean gating accuracy (95% CI) would have been 4.1 mm. The fluoroscopic radiation doses (mean +/- SD) were 23.7 +/- 21.8 mGy per beam and less than 487.5 mGy total throughout the treatment course. The setup, preparation, and irradiation times (mean +/- SD) were 8.9 +/- 8.2 min, 9.5 +/- 4.6 min, and 4.0 +/- 2.4 min, respectively. The treatment room occupation time was 36.7 +/- 67.5 min. CONCLUSIONS: Internal gating had a much higher accuracy than external gating. By the addition of a setup margin of 2 to 3 mm, internal gating positional error was less than 2.2 mm at 95% CI. PMID- 26960751 TI - Presumptive Gnathostoma binucleatum-infection in a Belgian traveler returning from South America. PMID- 26960750 TI - Diagnosis, management and follow-up of pregnant women with Zika virus infection: A preliminary report of the ZIKERNCOL cohort study on Sincelejo, Colombia. PMID- 26960749 TI - Dovitinib Acts As a Novel Radiosensitizer in Hepatocellular Carcinoma by Targeting SHP-1/STAT3 Signaling. AB - PURPOSE: Hepatocellular carcinoma (HCC) is among the most lethal human malignancies, and curative therapy is not an option for most patients. There is growing interest in the potential benefit of combining targeted therapies with radiation therapy (RT). This study aimed to characterize the efficacy and mechanism of an investigational drug, dovitinib, used in combination with RT. METHODS AND MATERIALS: HCC cell lines (PLC5, Hep3B, SK-Hep1, HA59T, and Huh-7) were treated with dovitinib, RT, or both, and apoptosis and signal transduction were analyzed. RESULTS: Dovitinib treatment resulted in Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1)-mediated downregulation of p-STAT3 and promoted potent apoptosis of HCC cells. Ectopic expression of STAT3, or inhibition of SHP-1, diminished the effects of dovitinib on HCC cells. By ectopic expression and purified recombinant proteins of various mutant forms of SHP-1, the N-SH2 domain of SHP-1 was found to be required for dovitinib treatment. Overexpression of STAT3 or catalytic-dead mutant SHP-1 restored RT-induced reduction of HCC cell survival. Conversely, ectopic expression of SHP-1 or activation of SHP-1 by dovitinib enhanced the effects of RT against HCC in vitro and in vivo. CONCLUSIONS: SHP-1/STAT3 signaling is critically associated with the radiosensitivity of HCC cells. Combination therapy with RT and the SHP-1 agonist, such as dovitinib, resulted in enhanced in vitro and in vivo anti-HCC effects. PMID- 26960754 TI - Balloon Atrial Septostomy in Congenital Heart Disease. PMID- 26960753 TI - Male professional tennis players maintain constant serve speed and accuracy over long matches on grass courts. AB - The potential effect of fatigue on stroke production in tennis players is still controversial. The aim of this study was to analyse the tennis serve speed and accuracy in prolonged male professional matches played on grass courts. We analysed tennis serve statistics from five-set Wimbledon matches (n = 15; 30 players). Results showed that match duration averaged 208.3 +/- 28.3 min. The overall serve speed was 177.0 +/- 10.2 km/h in the first set and 176.1 +/- 11.7 km/h in the fifth set (p = .34). The difference of all accuracy values of first set serves was not significantly different from those of the fifth set: percentage of valid first serves, 63.1 +/- 11.1% vs. 62.3 +/- 11.8%, respectively (p = .78); percentage of "aces", 11.2 +/- 9.1% vs. 10.0 +/- 8.9%, respectively (p = .39); percentage of "winners", 2.6 +/- 7.6% vs. 1.2 +/- 2.2%, respectively (p = .36); percentage of "double faults", 2.8 +/- 3.0% vs. 2.8 +/- 3.4% (p = .97). In conclusion, tennis players were able to maintain constant serve speed and accuracy over five-set matches played on grass courts. Professional tennis players are capable of overcoming fatigue and/or make movement adjustments to effectively perform complex technical strokes like the serve throughout matches played on grass courts lasting more than 3 h in average. PMID- 26960752 TI - Surveillance of mosquito-borne infectious diseases in febrile travelers entering China via Shenzhen ports, China, 2013. AB - BACKGROUND: About 100 million passengers enter China via Shenzhen ports every year and such huge populations increase the risk of various infectious diseases, particularly mosquito-borne diseases, entering China. This paper reports the testing and monitoring of mosquito-borne diseases in febrile travelers through Shenzhen ports in 2013. METHODS: The blood samples of 619 febrile cases were collected and the serum of each sample was used for the specific gene amplification and IgM antibody detection of five typical mosquito-borne pathogens: Dengue virus (DENV), Japanese encephalitis virus (JEV), Chikungunya virus (CHIKV), yellow fever virus (YFV), and West Nile Virus (WNV). Additionally, malaria was diagnosed by rapid diagnostic tests (RDTs). RESULTS: In total, 34 cases were detected of DENV infection (serotype I to IV), 17 cases of JEV infection, 2 cases of CHIKV infection, and 3 cases of malaria infection. No virus genes or IgM antibodies of YFV or WNV were detected in the samples. DENV, JEV and CHIKV cases were mainly from Southeast Asia, while malaria cases from Africa. CONCLUSIONS: DENV, JEV and CHIKV were the primary pathogens imported via Shenzhen ports. International travelers with mosquito-borne infections would accelerate the spread of these diseases, thus reinforcing the need for surveillance of mosquito-borne infections at ports should become a high priority. PMID- 26960755 TI - Balloon Atrial Septostomy in Congenital Heart Disease - Reply. PMID- 26960756 TI - Impact of Funneliformis mosseae on the growth, lead uptake, and localization of Sophora viciifolia. AB - On the basis of a pot experiment under lead (Pb) stress, we investigated the effects of an arbuscular mycorrhizal (AM) fungus (Funneliformis mosseae) on the growth and Pb uptake of Sophora viciifolia L., and explored the Pb localization in AM roots using transmission electron microscopy (TEM) and energy dispersive X ray spectroscopy (EDS). The results showed that high Pb levels (500 and 1000 MUg/g) inhibited the growth of S. viciifolia seedlings. Compared with the noninoculation treatment, F. mosseae inoculation decreased the Pb concentrations above- and belowground by 61.0% and 15.2%, when exposed to Pb at a concentration of 1000 MUg/g. The root length, fork number, tip number, surface area, and volume of mycorrhizal S. viciifolia were higher than those of the corresponding nonmycorrhizal plants. These parameters of mycorrhizal plants increased by 220%, 219%, 157%, 225%, and 278% when plants were exposed to Pb at 1000 MUg/g compared with nonmycorrhizal plants. The ratio of root length with diameters between 0-0.2 mm to the total root length significantly increased under Pb stress, and F. mosseae inoculation significantly reduced the ratio. Under Pb stress, F. mosseae increased the ratios of root length with 0.61-0.8 and 0.81-1.0 mm diameters to the total root length, indicating that F. mosseae tended to thicken the roots of S. viciifolia under Pb additions. The combined results of TEM and EDS indicated that Pb deposited in not only plant cells but also the cell walls and vacuoles of the AM fungal intracellular hyphae, thus revealing the subcellular-level mechanism of AM fungi in alleviating the Pb toxicity to the host plant. PMID- 26960757 TI - MicroRNAs let7 expression in thyroid cancer: correlation with their deputed targets HMGA2 and SLC5A5. AB - PURPOSE: Thyroid cancer (TC), the most common endocrine malignancy, increases its incidence worldwide. MicroRNAs have been shown to be abnormally expressed in tumors and could represent valid diagnostic markers for patients affected by TC. Our aim was to analyze the expression of tumorsuppressor hsa-let7b-5p and hsa let7f-5p, together with their predicted targets SLC5A5 (NIS) and HMGA2, in papillary (PTC), follicular (FTC) and anaplastic (ATC). METHODS: 8 FTC, 14 PTC, 12 ATC and three normal thyroid tissue samples were analyzed for the expression of pre-let7b, hsa-let7b-5p and hsa-let7f-5p as SLC5A5 and HMGA2 by RT-qPCR. Data were analyzed by REST 2008. RESULTS: FTC patients showed a significant down regulation of hsa-let7b-5p and its precursor. hsa-let7f-5p was overexpressed, and SLC5A5 was strongly suppressed. HMGA2 was overexpressed, reflecting no correlation with its regulatory let7 miRNAs. PTC samples were characterized by up regulation of hsa-let7b-5p, its precursor and hsa-let7f-5p. SLC5A5 was strongly suppressed in comparison with normal thyroid tissue. HMGA2 was overexpressed, as shown in FTC, also. ATC samples showed a similar miRNAs profile as PTC. In contrast with FTC and PTC, these patients showed a stable or up-regulated SLC5A5 and HMGA2. CONCLUSIONS: Expression of HMGA2 is not correlated with the regulatory let7 miRNAs. Interestingly, SLC5A5 was down-regulated in FTC and PTC. Its expression could be modulated by hsa-let-7f-5p. ATC showed a loss of SLC5A5/hsa let7f-5p correlation. SLC5A5, in ATC, needs further investigation to clarify the genetic/epigenetic mechanism altering its expression. PMID- 26960758 TI - SOX2 inhibits metastasis in gastric cancer. AB - PURPOSE: To investigate the potential role of SOX2 in gastric cancer (GC) metastasis. METHODS: The SOX2 expression was detected using immunohistochemistry on a GC tissue microarray. The correlations of SOX2 expression with clinicopathological factors and 5-year survival were evaluated. To test the role of SOX2 in inhibiting GC metastasis, the cell transwell assay was performed. Real time PCR and Western blot were used to explore the possible mechanism that SOX2 inhibits GC metastasis. RESULTS: In the present study, SOX2 expression was downregulated in GC tissues when compared to matching normal tissues. Moreover, patients with high SOX2 expression in cancerous tissues had less lymph node metastasis and better treatment outcome. At the subcellular level, SOX2 inhibited the GC cell migration and invasion by upregulating p21 expression. Moreover, SOX2 was determined to associate with the nuclear p21 expression. GC patients with high SOX2 and nuclear p21 expression had synergistically less lymph node metastasis and the better overall survival. CONCLUSION: Our results suggest that SOX2 is a promising and favorable metastatic biomarker for GC. PMID- 26960759 TI - Egr-1 deficiency protects from renal inflammation and fibrosis. AB - NF-kappaB and TGFbeta play critical roles in renal inflammation and fibrosis, and their regulation in the kidney is thus of great interest. Early growth response-1 (Egr-1), a transcription factor belonging to the immediate early gene family, has been found to regulate inflammation and fibrosis in non-kidney tissues, but its role in renal failure has not been clear. In this study, wild-type and Egr1 (-/-) mice were fed with an adenine-enriched diet to induce tubulointerstitial nephritis (TIN), and primary tubular epithelial cells (PTECs) were treated with pro-inflammatory and pro-fibrotic cytokines. Kidney tissues from patients with or without renal failure were stained for Egr-1. Our results showed that Egr-1 expression was upregulated in the kidney with TIN, and the tubular epithelial cell is the primary site for Egr-1 upregulation and nuclear translocation. Egr1 ( /-) mice were protected from renal failure, reflected by low levels of serum urea and creatinine. The protective effect was related to an attenuation of tubular injury, immune cell infiltration, NF-kappaB activity, and cytokine/chemokine expressions in the kidney. Renal fibrotic area and TGFbeta signaling were also reduced in Egr1 (-/-) mice. In vitro study showed that Egr-1 deficiency attenuated the ordinary responses of PTECs to TNFalpha and TGFbeta. Importantly, Egr-1 is of clinical significance since the activity of Egr-1 in renal tubular cells was upregulated in renal failure patients. Our study highlights the integrative role of Egr-1 in renal inflammation and fibrosis. Thus, Egr-1 may serve as a therapeutic target for human kidney diseases. KEY MESSAGES: Renal failure activates Egr-1 in human and mouse tubular cells. Egr-1 deficiency attenuates NF-kappaB and TGFbeta-mediated renal inflammation/fibrosis. Egr1 (-/-) PTECs respond weakly to pro-inflammatory or pro-fibrotic stimulation. PMID- 26960760 TI - K-Ras protein as a drug target. AB - K-Ras proteins are major drivers of human cancers, playing a direct causal role in about one million cancer cases/year. In cancers driven by mutant K-Ras, the protein is locked in the active, GTP-bound state constitutively, through a defect in the off-switch mechanism. As such, the mutant protein resembles the normal K Ras protein from a structural perspective, making therapeutic attack extremely challenging. K-Ras is a member of a large family of related proteins, which share very similar GDP/GTP-binding domains, making specific therapies more difficult. Furthermore, Ras proteins lack pockets to which small molecules can bind with high affinity, with a few interesting exceptions. However, new insights into the structure and function of K-Ras proteins reveal opportunities for intervention that were not appreciated many years ago, when efforts were launched to develop K Ras therapies. Furthermore, K-Ras undergoes post-translational modification and interactions with cellular signaling proteins that present additional therapeutic opportunities, such as specific binding to calmodulin and regulation of non canonical Wnt signaling. PMID- 26960762 TI - Perceived exercise barriers are reduced and benefits are improved with lifestyle modification in overweight and obese women with polycystic ovary syndrome: a randomised controlled trial. AB - BACKGROUND: This study assessed the perceived benefits and barriers to exercise participation in overweight and obese women with polycystic ovary syndrome (PCOS) and monitored changes in response to a lifestyle intervention. METHODS: Forty three overweight/obese PCOS women (Age, 30.3(6.2) yrs; BMI, 36.4(5.6) kg/m(2)) were randomised to one of three 20-week lifestyle programs: diet only (DO, n = 13), diet and aerobic exercise (DA, n = 11) and diet and combined aerobic resistance exercise (DC, n = 19). Exercise Benefits/Barriers Scale (EBBS), weight, aerobic fitness, depression and PCOS specific health-related quality of life were measured. RESULTS: Barriers score was related to depression (r = 0.45, P = 0.002) and aerobic fitness (r = -0.32, P = 0.04), while benefits score was related to aerobic fitness (r = 0.41, P = 0.007). EBBS, benefits and barriers scores improved overtime (P <= 0.001). Benefits subscales psychological outlook and social interaction increased (P <= 0.001) and life enhancement and preventative health did not change (P >= 0.3). Physical performance increased only in DA (P = 0.009). There were no differences between treatments for any of the other subscales (P >= 0.2). Barriers subscales exercise milieu, time expenditure and physical exertion reduced (P <= 0.003) and family discouragement did not change (P = 0.6). CONCLUSIONS: This study demonstrated that lifestyle modification consisting of an energy-restricted diet with or without exercise training improved the perceived benefits from and barriers to exercise. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Register ACTRN12606000198527, registered 26 May 2006. PMID- 26960761 TI - Regulation of Langerhans cell functions in a hypoxic environment. AB - Langerhans cells (LCs) are a specialized dendritic cell subset that resides in the epidermis and mucosal epithelia and is critical for the orchestration of skin immunity. Recent evidence suggest that LCs are involved in aberrant wound healing and in the development of hypertrophic scars and chronic wounds, which are characterized by a hypoxic environment. Understanding LCs biology under hypoxia may, thus, lead to the identification of novel pathogenetic mechanisms of wound repair disorders and open new therapeutic opportunities to improve wound healing. In this study, we characterize a previously unrecognized role for hypoxia in significantly affecting the phenotype and functional properties of human monocyte derived LCs, impairing their ability to stimulate naive T cell responses, and identify the triggering receptor expressed on myeloid (TREM)-1, a member of the Ig immunoregulatory receptor family, as a new hypoxia-inducible gene in LCs and an activator of their proinflammatory and Th1-polarizing functions in a hypoxic environment. Furthermore, we provide the first evidence of TREM-1 expression in vivo in LCs infiltrating hypoxic areas of active hypertrophic scars and decubitous ulcers, pointing to a potential pathogenic role of this molecule in wound repair disorders. KEY MESSAGES: Hypoxia modulates surface molecule expression and cytokine profile in Langerhans cells. Hypoxia impairs human Langerhans cell stimulatory activity on naive T cells. Hypoxia selectively induces TREM-1 expression in human Langerhans cells. TREM-1 engagement stimulates Langerhans cell inflammatory and Th1-polarizing activity. TREM-1 is expressed in vivo in Langerhans cells infiltrating hypoxic skin lesions. PMID- 26960763 TI - Regional-scale fluxes of zinc, copper, and nickel into and out of the agricultural soils of the Kermanshah province in western Iran. AB - It is important to study the status and trend of soil contamination with trace elements to make sustainable management strategies for agricultural soils. This study was conducted in order to model zinc (Zn), copper (Cu), and nickel (Ni) accumulation rates in agricultural soils of Kermanshah province using input and output fluxes mass balance and to evaluate the associated uncertainties. The input and output fluxes of Zn, Cu, and Ni into (from) the agricultural soils of Kermanshah province via livestock manure, mineral fertilizers, municipal waste compost, pesticides, atmospheric deposition, and crop removal were assessed for the period 2000-2014. The data were collected to compute the fluxes at both township and regional scales from available databases such as regional agricultural statistics. The basic units of the balance were 9 townships of Kermanshah province. Averaged over the entire study region, the estimated net fluxes of Zn, Cu, and Ni into agricultural soils were 341, 84, and131 g ha year( 1), with a range of 211 to 1621, 61 to 463, and 114 to 679 among the townships. The livestock manure was responsible for 55, 56, and 67 % of the total Zn, Cu, and Ni inputs at regional scale, while municipal waste compost and mineral fertilizers accounted for approximately 19, 38, and 15 % and 24, 4, and 14 % of the total Zn, Cu, and Ni inputs, respectively. Atmospheric deposition was a considerable source only for Ni and at township scale (7-29 % of total Ni input). For Zn, Cu, and Ni, the input-to-output ratio of the fluxes ranged from 1.8 to 48.9, 2 to 48.2, and 4 to 303 among townships and averaged 2.8, 3, and 9 for the entire study area, respectively. Considering that outputs other than with crop harvests are minor, this means that Zn, Cu, and Ni (in particular Ni) stocks are rapidly building up in soils of some parts of the study region. Uncertainties in the livestock manure and crop removal data were the main sources of estimation uncertainty in this study. This study provides the basic information to develop policies for controlling the trace elements inputs into agricultural soils of the study area. PMID- 26960764 TI - Spatial distribution and enteroparasite contamination in peridomiciliar soil and water in the Apucaraninha Indigenous Land, southern Brazil. AB - The prevalence and distribution of soil and water samples contaminated with enteroparasites of humans and animals with zoonotic potential (EHAZP) in Apucaraninha Indigenous Land (AIL), southern Brazil, was evaluated. An environmental survey was conducted to evaluate the presence of parasitic forms in peridomiciliary soil and associated variables. Soil samples were collected from 40/293 domiciles (10 domiciles per season), from November 2010 to June 2011, and evaluated by modified methods of Faust et al. and Lutz. Analyses of water from seven consumption sites were also performed. The overall prevalence of soil samples contaminated by EHAZP was 23.8 %. The most prevalent parasitic forms were cyst of Entamoeba spp. and eggs of Ascaris spp. The highest prevalence of contaminated soil samples was observed in winter (31 %). The probability map obtained with geostatistical analyses showed an average of 47 % soil contamination at a distance of approximately 140 m. The parasitological analysis of water did not detect Giardia spp. or Cryptosporidium spp. and showed that all collection points were within the standards of the Brazilian law. However, the microbiological analysis showed the presence of Escherichia coli in 6/7 sampled points. Despite the low level of contamination by EHAZP in peridomiciliar soil and the absence of pathogenic protozoa in water, the AIL soil and water (due to the presence of fecal coliforms) are potential sources of infection for the population, indicating the need for improvements in sanitation and water treatment, in addition periodic treatment of the population with antiparasitic. PMID- 26960766 TI - Land degradation due to erosion in public perception. Case study: Secasul Mare river basin settlements (Transylvanian Depression, Romania). AB - According to the International Decade for Natural Disaster Reduction (IDNDR 1990 1999), the risk indicates potential losses due to particular natural phenomenon, and these could be reduced by improving of prevention and education. People perceive these losses differently depending on phenomenon occurrence, severity, and impact in time. Starting from this idea, this research presents public perception on land degradation through erosion in a small area from the central part of Romania (south-west of Transylvanian Depression). The research was based on a questionnaire consisting of 16 questions. The items were structured by issues: awareness assessment regarding hazard and risk phenomena, assessment of type of property and land use, assessment of knowledge and information on the possible production of negative effects by natural phenomena, and evaluation of land owners' attitudes towards the occurrence of erosion on their land. Results reveal that the public perception on erosion is weak. This process is perceived as insignificant due to lack of phenomenon knowledge and especially because of scarcity preoccupation in land's quality monitoring. Even though the owned lands are affected by erosion forms, the owners are not aware of the phenomenon that generates them. Material damages caused by erosion, loss of soil quality, and land fertility decrease are less perceived because the economic losses fill only at long term. This perception leads to underestimating erosion risk compared to other natural phenomena and to a passive attitude towards this particular phenomenon. PMID- 26960767 TI - Erratum to: The dissolved organic matter as a potential soil quality indicator in arable soils of Hungary. PMID- 26960765 TI - Dental fluorosis and urinary fluoride concentration as a reflection of fluoride exposure and its impact on IQ level and BMI of children of Laxmisagar, Simlapal Block of Bankura District, W.B., India. AB - There has been growing public concern about intellectual performance of children at high levels of fluoride exposure. A cross-sectional study was conducted in Simlapal Block of Bankura District, West Bengal, to find out the relationship between fluoride (F) exposure as exposure dose (ED) with dental fluorosis (DF), urinary fluoride concentration (UF), intelligence quotient (IQ) and body mass index (BMI). Fifty groundwater samples were collected from the target area. One hundred forty-nine children belonging to age group 6 to 18 years were considered for this study. Experimental results reveal that mean F(-) concentration of that area is 2.11 mg/L (+/-SD 1.64). On the basis of F concentration in groundwater and water consumption pattern, ED was calculated to explore the impact of F(-) on DF, UF, IQ, and BMI. Paired t test results suggest that exposure rate of F does not show any significant differences (<0.05) among the children of 12 different places. As a result of F exposure, DF cases are mostly found in the order of moderate > severe > mild > very mild > questionable > normal conditions. The highest UF concentration was recorded as 17 mg/L, but the status of DF in the affected children was recorded as moderate. The results also reveal that ED has a positive correlation with DF (r = 0.299, P < 0.01) and UF (r = 0.513, P < 0.01) and a negative correlation with IQ (r = -0.343, P < 0.01) along with BMI (r = 0.083, non-significant). Therefore, from this study, it may be concluded that UF and DF concentration could act as a biomarker of fluoride toxicity. PMID- 26960770 TI - [Role of uridine adenosine tetraphosphate on vascular function in (patho) physiological states]. PMID- 26960769 TI - Graphene Biosensor Programming with Genetically Engineered Fusion Protein Monolayers. AB - We demonstrate a label-free biosensor concept based on specific receptor modules, which provide immobilization and selectivity to the desired analyte molecules, and on charge sensing with a graphene field effect transistor. The receptor modules are fusion proteins in which small hydrophobin proteins act as the anchor to immobilize the receptor moiety. The functionalization of the graphene sensor is a single-step process based on directed self-assembly of the receptor modules on a hydrophobic surface. The modules are produced separately in fungi or plants and purified before use. The modules form a dense and well-oriented monolayer on the graphene transistor channel and the receptor module monolayer can be removed, and a new module monolayer with a different selectivity can be assembled in situ. The receptor module monolayers survive drying, showing that the functionalized devices can be stored and have a reasonable shelf life. The sensor is tested with small charged peptides and large immunoglobulin molecules. The measured sensitivities are in the femtomolar range, and the response is relatively fast, of the order of one second. PMID- 26960771 TI - [Role/function of protease-activated receptor 2 on vascular endothelium in metabolic syndrome]. PMID- 26960772 TI - [Omentin and cardiovascular disease]. PMID- 26960768 TI - miRNA profiling, detection of BRAF V600E mutation and RET-PTC1 translocation in patients from Novosibirsk oblast (Russia) with different types of thyroid tumors. AB - BACKGROUND: The postoperative typing of thyroid lesions, which is instrumental in adequate patient treatment, is currently based on histologic examination. However, it depends on pathologist's qualification and can be difficult in some cases. Numerous studies have shown that molecular markers such as microRNAs and somatic mutations may be useful to assist in these cases, but no consensus exists on the set of markers that is optimal for that purpose. The aim of the study was to discriminate between different thyroid neoplasms by RT-PCR, using a limited set of microRNAs selected from literature. METHODS: By RT-PCR we evaluated the relative levels of 15 microRNAs (miR-221, -222, -146b, -181b, -21, -187, -199b, 144, -192, -200a, -200b, -205, -141, -31, -375) and the presence of BRAF(V600E) mutation and RET-PTC1 translocation in surgically resected lesions from 208 patients from Novosibirsk oblast (Russia) with different types of thyroid neoplasms. Expression of each microRNA was normalized to adjacent non-tumor tissue. Three pieces of lesion tissue from each patient (39 goiters, 41 follicular adenomas, 16 follicular thyroid cancers, 108 papillary thyroid cancers, 4 medullary thyroid cancers) were analyzed independently to take into account method variation. RESULTS: The diagnostic classifier based on profiling of 13 microRNAs was proposed, with total estimated accuracy varying from 82.7 to 99% for different nodule types. Relative expression of six microRNAs (miR-146b, 21, -221, -222, 375, -199b) appeared significantly different in BRAF(V600E) positive samples (all classified as papillary thyroid carcinomas) compared to BRAF(V600E)-negative papillary carcinoma samples. CONCLUSIONS: The results confirm practical feasibility of using molecular markers for typing of thyroid neoplasms and clarification of controversial cases. PMID- 26960773 TI - [Kampo pharmacology: modulation by Hojin formulations of age-dependent vasodilatation and the dependence of diseases]. PMID- 26960774 TI - [Molecular pharmacology of (-)maackiain, from Kujin, an anti-allergic Kampo medicine]. PMID- 26960775 TI - [Phytosterol saponin of ginseng (ginsenoside) provides cardiovascular protection as a specific non-genomic ligand of sex hormone receptors]. PMID- 26960776 TI - []Improving effects of chotosan on the brain malfunction in rodent's disease models]. PMID- 26960777 TI - [Small animal imaging studies and their prospects]. PMID- 26960778 TI - [Current status and new trends in therapeutic antibodies]. PMID- 26960779 TI - Copper-Catalyzed Reaction Cascade of Thiophenol Hydroxylation and S-Arylation through Disulfide-Directed C-H Activation. AB - Copper-catalyzed thiophenol C-H activation is described. Through an initial attempt to conduct C-arylation with arylboronic acid, a rather surprising sequential C-H activation and S-arylation was discovered. Mechanistic investigation revealed the disulfide intermediate as the key component in directing C-H oxidation. The overall reaction proceeded under mild conditions with molecular oxygen as the oxidant. Discovery of disulfide as the directing group provides a potential new direction for catalytic C-H functionalization under mild conditions. PMID- 26960780 TI - Genome characterization of a novel vibriophage VpKK5 (Siphoviridae) specific to fish pathogenic strain of Vibrio parahaemolyticus. AB - Vibrio parahaemolyticus has long been known pathogenic to shrimp but only recently it is also reported pathogenic to tropical cultured marine finfish. Traditionally, bacterial diseases in aquaculture are often treated using synthetic antibiotics but concern due to side effects of these chemicals is elevating hence, new control strategies which are both environmental and consumer friendly, are urgently needed. One promising control strategy is the bacteriophage therapy. In this study, we report the isolation and characterization of a novel vibriophage (VpKK5), belonging to the family Siphoviridae that was specific and capable of complete lysing the fish pathogenic strain of V. parahaemolyticus. The VpKK5 exhibited short eclipse and latent periods of 24 and 36 min, respectively, but with a large burst size of 180 pfu/cell. The genome analysis revealed that the VpKK5 is a novel bacteriophage with the estimated genome size of 56,637 bp and has 53.1% G + C content. The vibriophage has about 80 predicted open reading frames consisted of 37 complete coding sequences which did not match to any protein databases. The analysis also found no lysogeny and virulence genes in the genome of VpKK5. With such genome features, we suspected the vibriophage is novel and could be explored for phage therapy against fish pathogenic strains of V. parahaemolyticus in the near future. PMID- 26960781 TI - Dental students' self-perceived communication skills for patient motivation. AB - AIMS: The aim of this study was to evaluate dental students' self-perceived communication skills for patient motivation over the course of their training. MATERIALS AND METHODS: Pre-clinical and clinical dental students at the University of Bern School of Dental Medicine were surveyed annually from 2008 to 2011 utilising a written questionnaire. Self-reported data were pooled from all classes per time-point in the curriculum. RESULTS: A total of 157 students were surveyed from five classes with an overall response rate of 94.8%. A total of 393 questionnaires were available for analysis. The self-perceived skill-sets for general patient care and patient communication were rated at the end of the first clinical year with mean Visual Analog Scale values of 75.0 +/- 1.6 and 75.1 +/- 1.5, respectively. During the second clinical year, the self-perceived skills increased in both patient care (82.5 +/- 1.2, P = 0.0004) and patient communication (81.4 +/- 1.4, P = 0.0034). The students rated their competence higher when providing oral hygiene instructions as opposed to motivating patients to quit tobacco use, modify their diet or employ stress-reduction strategies (P < 0.005). At the end of the pre-clinical year, 74.5% of the students expressed interest in receiving more extensive communication training (P < 0.004). CONCLUSIONS: Though dental students in this study demonstrated a steady increase in their level of comfort motivating patients to utilise oral hygiene instructions, they also expressed the desire for more motivational training early in their curriculum. Therefore, these results may indicate the need to enhance communications training in patient motivation on all behavioural aspects early in the dental curriculum. PMID- 26960782 TI - Exposure-response relationship of wind turbine noise with self-reported symptoms of sleep and health problems: A nationwide socioacoustic survey in Japan. AB - The association of wind turbine noise (WTN) with sleep and physical/mental health has not been fully investigated. To investigate the relationship of WTN with the prevalence of self-reported symptoms of sleep and health problems, a socioacoustic survey of 1079 adult residents was conducted throughout Japan (2010 2012): 747 in 34 areas surrounding wind turbine plants and 332 in 16 control areas. During face-to-face interviews, the respondents were not informed of the purpose of the survey. Questions on symptoms such as sleeplessness and physical/mental complaints were asked without specifying reasons. Insomnia was defined as having one or any combination of the following that occurs three or more times a week and bothers a respondent: Difficulty initiating sleep, difficulty maintaining sleep, premature morning awakening, and feeling of light overnight sleep. Poor health was defined as having high scores for health complaints, as determined using the Total Health Index, exceeding the criteria proposed by the authors of the index. The noise descriptor for WTN was LAeq,n outdoor, estimated from the results of actual measurement at some locations in each site. Multiple logistic analysis was applied to the LAeq,n and insomnia or poor health. The odds ratio (OR) of insomnia was significantly higher when the noise exposure level exceeded 40 dB, whereas the self-reported sensitivity to noise and visual annoyance with wind turbines were also independently associated with insomnia. OR of poor health was not significant for noise exposure, but significant for noise sensitivity and visual annoyance. The above two moderators appear to indicate the features of respondents who are sensitive to stimuli or changes in their homeostasis. PMID- 26960783 TI - Comparison of direct measurement methods for headset noise exposure in the workplace. AB - The measurement of noise exposure from communication headsets poses a methodological challenge. Although several standards describe methods for general noise measurements in occupational settings, these are not directly applicable to noise assessments under communication headsets. For measurements under occluded ears, specialized methods have been specified by the International Standards Organization (ISO 11904) such as the microphone in a real ear and manikin techniques. Simpler methods have also been proposed in some national standards such as the use of general purpose artificial ears and simulators in conjunction with single number corrections to convert measurements to the equivalent diffuse field. However, little is known about the measurement agreement between these various methods and the acoustic manikin technique. Twelve experts positioned circum-aural, supra-aural and insert communication headsets on four different measurement setups (Type 1, Type 2, Type 3.3 artificial ears, and acoustic manikin). Fit-refit measurements of four audio communication signals were taken under quiet laboratory conditions. Data were transformed into equivalent diffuse field sound levels using third-octave procedures. Results indicate that the Type 1 artificial ear is not suited for the measurement of sound exposure under communication headsets, while Type 2 and Type 3.3 artificial ears are in good agreement with the acoustic manikin technique. Single number corrections were found to introduce a large measurement uncertainty, making the use of the third octave transformation preferable. PMID- 26960784 TI - Comparison of staff and family perceptions of causes of noise pollution in the Pediatric Intensive Care Unit and suggested intervention strategies. AB - Noise and excessive, unwanted sound in the Pediatric Intensive Care Unit (PICU) is common and has a major impact on patients' sleep and recovery. Previous research has focused mostly on absolute noise levels or included only staff as respondents to acknowledge the causes of noise and to plan for its reduction. Thus far, the suggested interventions have not ameliorated noise, and it continues to serve as a barrier to recovery. In addition to surveying PICU providers through internet-based software, patients' families were evaluated through in-person interviews utilizing a pretested instrument over 3 months. Families of patients admitted for more than 24 h were considered eligible for evaluation. Participants were asked to rank causes of noise from 1 to 8, with eight being highest, and identified potential interventions as effective or ineffective. In total, 50 families from 251 admissions and 65 staff completed the survey. Medical alarms were rated highest (mean +/- standard deviation [SD], 4.9 +/- 2.1 [2.8-7.0]), followed by noise from medical equipment (mean +/- SD, 4.7 +/ 2.1 [2.5-6.8]). This response was consistent among PICU providers and families. Suggested interventions to reduce noise included keeping a patient's room door closed, considered effective by 93% of respondents (98% of staff; 88% of families), and designated quiet times, considered effective by 82% (80% of staff; 84% of families). Keeping the patient's door closed was the most effective strategy among survey respondents. Most families and staff considered medical alarms an important contributor to noise level. Because decreasing the volume of alarms such that it cannot be heard is inappropriate, alternative strategies to alert staff of changes in vital signs should be explored. PMID- 26960785 TI - Noise and sleep on board vessels in the Royal Norwegian Navy. AB - Previous research indicates that exposure to noise during sleep can cause sleep disturbance. Seamen on board vessels are frequently exposed to noise also during sleep periods, and studies have reported sleep disturbance in this occupational group. However, studies of noise and sleep in maritime settings are few. This study's aim was to examine the associations between noise exposure during sleep, and sleep variables derived from actigraphy among seamen on board vessels in the Royal Norwegian Navy (RNoN). Data were collected on board 21 RNoN vessels, where navy seamen participated by wearing an actiwatch (actigraph), and by completing a questionnaire comprising information on gender, age, coffee drinking, nicotine use, use of medication, and workload. Noise dose meters were used to assess noise exposure inside the seamen's cabin during sleep. Eighty-three sleep periods from 68 seamen were included in the statistical analysis. Linear mixed-effects models were used to examine the association between noise exposure and the sleep variables percentage mobility during sleep and sleep efficiency, respectively. Noise exposure variables, coffee drinking status, nicotine use status, and sleeping hours explained 24.9% of the total variance in percentage mobility during sleep, and noise exposure variables explained 12.0% of the total variance in sleep efficiency. Equivalent noise level and number of noise events per hour were both associated with increased percentage mobility during sleep, and the number of noise events was associated with decreased sleep efficiency. PMID- 26960786 TI - Therapeutic role of Vitamin B12 in patients of chronic tinnitus: A pilot study. AB - True tinnitus is a phantom auditory perception arising from a source or trigger in the cochlea, brainstem, or at higher centers and has no detectable acoustic generator. The most accepted is the famous neurophysiologic model of Jastreboff, which stresses that tinnitus, is a subcortical perception and results from the processing of weak neural activity in the periphery. The aim of this study is to determine the role of Vitamin B12 in treatment of chronic tinnitus. In this randomized, double-blind pilot study, total 40 patients were enrolled, of which 20 in Group A (cases) received intramuscular therapy of 1 ml Vitamin B12 (2500 mcg) weekly for a period of 6 weeks and Group B (20) patients received placebo isotonic saline 01 ml intramuscular. The patients were subjected to Vitamin B12 assay and audiometry pre- and post-therapy. Of the total patients of tinnitus, 17 were Vitamin B12 deficient that is 42.5% showed deficiency when the normal levels were considered to be 250 pg/ml. A paired t-test showed that in Group A, patients with Vitamin B12 deficiency showed significant improvement in mean tinnitus severity index score and visual analog scale (VAS) after Vitamin B12 therapy. This pilot study highlights the significant prevalence of Vitamin B12 deficiency in North Indian population and improvement in tinnitus severity scores and VAS in cobalamin-deficient patients receiving intramuscular Vitamin B12 weekly for 6 weeks further provides a link between cobalamin deficiency and tinnitus thereby suggestive of a therapeutic role of B12 in cobalamin-deficient patients of tinnitus. PMID- 26960787 TI - Student's music exposure: Full-day personal dose measurements. AB - Previous studies have shown that collegiate level music students are exposed to potentially hazardous sound levels. Compared to professional musicians, collegiate level music students typically do not perform as frequently, but they are exposed to intense sounds during practice and rehearsal sessions. The purpose of the study was to determine the full-day exposure dose including individual practice and ensemble rehearsals for collegiate student musicians. Sixty-seven college students of classical music were recruited representing 17 primary instruments. Of these students, 57 completed 2 days of noise dose measurements using Cirrus doseBadge programed according to the National Institute for Occupational Safety and Health criterion. Sound exposure was measured for 2 days from morning to evening, ranging from 7 to 9 h. Twenty-eight out of 57 (49%) student musicians exceeded a 100% daily noise dose on at least 1 day of the two measurement days. Eleven student musicians (19%) exceeded 100% daily noise dose on both days. Fourteen students exceeded 100% dose during large ensemble rehearsals and eight students exceeded 100% dose during individual practice sessions. Approximately, half of the student musicians exceeded 100% noise dose on a typical college schedule. This finding indicates that a large proportion of collegiate student musicians are at risk of developing noise-induced hearing loss due to hazardous sound levels. Considering the current finding, there is a need to conduct hearing conservation programs in all music schools, and to educate student musicians about the use and importance of hearing protection devices for their hearing. PMID- 26960789 TI - Call centers and noise-induced hearing loss. AB - Noise is defined as unwelcome sound. It has been estimated that 16% of adult hearing loss in the world is due to noise exposure at the workplace. This report offers a case that diagnosed with hearing loss of whom working as a call center operator at home. Home agent operators should be explored. PMID- 26960788 TI - Effect of personal music system use on sacculocollic reflex assessed by cervical vestibular-evoked myogenic potential: A preliminary investigation. AB - Listening to music through a portable personal music system (PMS) is a growing trend, especially among the youth. The preferred listening level in such kinds of PMS has been reported to cross the safe levels and its impact on the auditory system was demonstrated in several previous investigations. Owing to the commonality in several aspects between the auditory and the vestibular systems, it appears likely that the deleterious effects of PMS use could also be impinging on the vestibular system, which has never been investigated. The present study therefore, aimed at evaluating the effects of PMS use on the sacculocollic reflex assessed by the cervical vestibular-evoked myogenic potential (cVEMP) technique. Thirty-two regular PMS users and 32 nonregular PMS users underwent cVEMP testing using alternating polarity 500 Hz tone bursts. The results revealed no significant group difference in latencies and interaural asymmetry ratio. However, the cVEMP was significantly reduced in the group of individuals in whom the diffused field equivalent sound pressure levels (SPLs) were above the damage risk criteria (DRC) compared to those with diffused field equivalent SPLs below it (P< 0.01). Therefore, the use of PMS at high levels of volume controls could be deleterious to the vestibular well-being of an individual. PMID- 26960790 TI - Fecal Microbiota Transplantation Inhibits Multidrug-Resistant Gut Pathogens: Preliminary Report Performed in an Immunocompromised Host. AB - Colonization of the gastrointestinal tract with multidrug-resistant (MDR) bacteria is a consequence of gut dysbiosis. We describe the successful utilization of fecal microbiota transplantation to inhibit Klebsiella pneumoniae MBL(+) and Escherichia coli ESBL(+) gut colonization in the immunocompromised host as a novel tool in the battle against MDR microorganisms. ClinicalTrials.gov identifier NCT02461199. PMID- 26960791 TI - An observational study assessing peripheral neuropathy related to multiple myeloma. AB - We aimed at assessing the prevalence of peripheral neuropathy in newly diagnosed, treatment-naive patients with multiple myeloma. We enrolled 153 patients with multiple myeloma at initial diagnosis. All patients underwent neurological examination and nerve conduction study. Patients with suspected pure small fiber neuropathy underwent skin biopsy. Of the 153 patients included in this study, 7.2 % had a multiple myeloma-related neuropathy. All patients suffered from a distal symmetric sensory peripheral neuropathy, associated with age (P = 0.04). Our study on prevalence rate of multiple myeloma-related peripheral neuropathy might provide a basis for improving the clinical management of this condition. PMID- 26960792 TI - Rga6 is a Fission Yeast Rho GAP Involved in Cdc42 Regulation of Polarized Growth. AB - Active Cdc42 is essential for the establishment of polarized growth. This GTPase is negatively regulated by the GTPase-activating proteins (GAPs), which are important for the spatial specificity of Cdc42 function. Rga4 is the only GAP described as negative regulator of fission yeast Cdc42. We report here that Rga6 is another fission yeast Cdc42 GAP which shares some functions with Rga4. Cells lacking Rga6 are viable but slightly shorter and broader than wild type, and cells lacking Rga6 and Rga4 simultaneously are rounded. In these cells, active Cdc42 is observed all around the membrane. These additive effects indicate that both GAPs collaborate in the spatial regulation of active Cdc42. Rga6 localizes to the plasma membrane forming clusters different from those formed by Rga4. A polybasic region at the Rga6 C-terminus is responsible for its membrane localization. Rga6-GFP fluorescence decreases considerably at the growing tips, and this decrease is dependent on the actin cables. Notably, in the absence of Rga6 the amplitude of active Cdc42 oscillations at the tips decreases, and less GTP-Cdc42 accumulates at the new end of the cells. We propose here that Rga6 collaborates with Rga4 to spatially restrict active Cdc42 at the cell tips and maintain cell dimensions. PMID- 26960793 TI - SNX9 promotes metastasis by enhancing cancer cell invasion via differential regulation of RhoGTPases. AB - Despite current advances in cancer research, metastasis remains the leading factor in cancer-related deaths. Here, we identify sorting nexin 9 (SNX9) as a new regulator of breast cancer metastasis. We detected an increase in SNX9 expression in human breast cancer metastases compared with primary tumors and demonstrated that SNX9 expression in MDA-MB-231 breast cancer cells is necessary to maintain their ability to metastasize in a chick embryo model. Reciprocally, SNX9 knockdown impairs the process. In vitro studies using several cancer cell lines derived from a variety of human tumors revealed a role for SNX9 in cell invasion and identified mechanisms responsible for this novel function. We showed that SNX9 controls the activation of RhoA and Cdc42 GTPases and also regulates cell motility via the modulation of well-known molecules involved in metastasis, namely RhoA-ROCK and N-WASP. In addition, we have discovered that SNX9 is required for RhoGTPase-dependent, clathrin-independent endocytosis, and in this capacity, can functionally substitute to the bona fide Rho GAP, GRAF1 (GTPase Regulator Associated with Focal Adhesion Kinase). Together, our data establish novel roles for SNX9 as a multifunctional protein scaffold that regulates, and potentially coordinates, several cellular processes that together can enhance cancer cell metastasis. PMID- 26960795 TI - SUMO-Targeted Ubiquitin Ligase (STUbL) Slx5 regulates proteolysis of centromeric histone H3 variant Cse4 and prevents its mislocalization to euchromatin. AB - Centromeric histone H3, CENP-ACse4, is essential for faithful chromosome segregation. Stringent regulation of cellular levels of CENP-ACse4 restricts its localization to centromeres. Mislocalization of CENP-ACse4 is associated with aneuploidy in yeast, flies and tumorigenesis in human cells; thus, defining pathways that regulate CENP-A levels is critical for understanding how mislocalization of CENP-A contributes to aneuploidy in human cancers. Previous work in budding yeast has shown that ubiquitination of overexpressed Cse4 by Psh1, an E3 ligase, partially contributes to proteolysis of Cse4. Here, we provide the first evidence that Cse4 is sumoylated by E3 ligases Siz1 and Siz2 in vivo and in vitro. Ubiquitination of Cse4 by Small Ubiquitin-related Modifier (SUMO)-Targeted Ubiquitin Ligase (STUbL) Slx5 plays a critical role in proteolysis of Cse4 and prevents mislocalization of Cse4 to euchromatin under normal physiological conditions. Accumulation of sumoylated Cse4 species and increased stability of Cse4 in slx5? strains suggest that sumoylation precedes ubiquitin-mediated proteolysis of Cse4. Slx5-mediated Cse4 proteolysis is independent of Psh1 since slx5? psh1? strains exhibit higher levels of Cse4 stability and mislocalization compared to either slx5? or psh1? strains. Our results demonstrate a role for Slx5 in ubiquitin-mediated proteolysis of Cse4 to prevent its mislocalization and maintain genome stability. PMID- 26960796 TI - Vinculin Regulates Directionality and Cell Polarity in 2D, 3D Matrix and 3D Microtrack Migration. AB - During metastasis, cells can use proteolytic activity to form tube-like "microtracks" within the extracellular matrix (ECM). Using these microtracks, cells can migrate unimpeded through the stroma. To investigate the molecular mechanisms of microtrack migration, we developed an in vitro 3D micromolded collagen platform. When in microtracks, cells tend to migrate unidirectionally. Since focal adhesions are the primary mechanism by which cells interact with the ECM, we examined the roles of several focal adhesion molecules in driving unidirectional motion. Vinculin knockdown results in the repeated reversal of migration direction compared with control cells. Tracking the position of the Golgi centroid relative to the position of the nucleus centroid reveals that vinculin knockdown disrupts cell polarity in microtracks. Vinculin also directs migration on 2D substrates and in 3D uniform collagen matrices, indicated by reduced speed, shorter net displacement and decreased directionality in vinculin deficient cells. In addition, vinculin is necessary for Focal Adhesion Kinase (FAK) activation in 3D as vinculin knockdown results in reduced FAK activation in both 3D uniform collagen matrices and microtracks, but not on 2D substrates, and accordingly, FAK inhibition halts cell migration in 3D microtracks. Together, these data indicate that vinculin plays a key role in polarization during migration. PMID- 26960794 TI - Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver. AB - Disturbances in protein folding and membrane compositions in the endoplasmic reticulum (ER) elicit the unfolded protein response (UPR). Each of three UPR sensory proteins-PERK (PEK/EIF2AK3), IRE1, and ATF6-is activated by ER stress. PERK phosphorylation of eIF2 represses global protein synthesis, lowering influx of nascent polypeptides into the stressed ER, coincident with preferential translation of ATF4 (CREB2). In cultured cells, ATF4 induces transcriptional expression of genes directed by the PERK arm of the UPR, including genes involved in amino acid metabolism, resistance to oxidative stress, and the proapoptotic transcription factor CHOP (GADD153/DDIT3). In this study, we characterize whole body and tissue-specific ATF4-knockout mice and show in liver exposed to ER stress that ATF4 is not required for CHOP expression, but instead ATF6 is a primary inducer. RNA-Seq analysis indicates that ATF4 is responsible for a small portion of the PERK-dependent UPR genes and reveals a requirement for expression of ATF4 for expression of genes involved in oxidative stress response basally and cholesterol metabolism both basally and under stress. Consistent with this pattern of gene expression, loss of ATF4 resulted in enhanced oxidative damage, and increased free cholesterol in liver under stress accompanied by lowered cholesterol in sera. PMID- 26960798 TI - Prediction of High-grade Vesicoureteral Reflux in Children Younger Than 2 Years Using Renal Sonography. AB - OBJECTIVES: To investigate the predictive value of renal sonography for vesicoureteral reflux (VUR) and the efficacy of renal sonography, technetium Tc 99m-labeled dimercaptosuccinic acid (DMSA) scanning, and a combination of the two for VUR screening in children younger than 2 years with a first episode of febrile urinary tract infection. METHODS: Thirty-eight patients younger than 2 years with a first febrile urinary tract infection were included in our study, which was conducted from April through October 2014. Each kidney was considered a separate renal unit. A retrospective review of clinical information and images (renal sonography, DMSA scanning, and voiding cystourethrography) was performed. RESULTS: Of the 14 renal units (18.4%) with VUR, 4 (28.5%) had high-grade VUR. Among single findings, dilatation of the renal collecting system, wall thickening of the renal collecting system, and DMSA scans significantly predicted VUR (P= .038, .027, and .01, respectively). Dilatation was the most common single finding (46 of 76 renal units). The sensitivity values for dilatation, wall thickening, and DMSA scans were 85.7%, 64.2%, and 50.0%, and the negative predictive values were 93.3%, 89.7%, and 87.9%. CONCLUSIONS: The negative predictive values indicate that normal renal sonographic and DMSA findings can predict the absence of high-grade VUR. We propose that renal sonographic findings of wall thickening as well as dilatation of the renal collecting system should be considered predictive of high-grade VUR. PMID- 26960797 TI - Expansion and concatenation of non-muscle myosin IIA filaments drive cellular contractile system formation during interphase and mitosis. AB - Cell movement and cytokinesis are facilitated by contractile forces generated by the molecular motor, non-muscle myosin II (NMII). NMII molecules form a filament (NMII-F) through interactions of their C-terminal rod domains, positioning groups of N-terminal motor domains on opposite sides. The NMII motors then bind and pull actin filaments toward the NMII-F, thus driving contraction. Inside of crawling cells, NMIIA-Fs form large macromolecular ensembles (i.e., NMIIA-F stacks) but how this occurs is unknown. Here we show NMIIA-F stacks are formed through two non-mutually exclusive mechanisms: expansion and concatenation. During expansion, NMIIA molecules within the NMIIA-F spread out concurrent with addition of new NMIIA molecules. Concatenation occurs when multiple NMIIA-F/NMIIA-F stacks move together and align. We found NMIIA-F stack formation was regulated by both motor activity and the availability of surrounding actin filaments. Furthermore, our data showed expansion and concatenation also formed the contractile ring in dividing cells. Thus, interphase and mitotic cells share similar mechanisms for creating large contractile units, and these are likely to underlie how other myosin II-based contractile systems are assembled. PMID- 26960800 TI - Ultrasound-Guided Fasciotomy for Anterior Chronic Exertional Compartment Syndrome of the Leg. AB - Chronic exertional compartment syndrome is characterized by exertional pain and elevated intracompartmental pressures affecting the leg in physically active young people. In patients who have failed conservative measures, fasciotomy is the treatment of choice. This study presents a new method for performing fasciotomy using high-resolution ultrasound (US) guidance and reports on the clinical outcomes in a group of these patients. Over a 3-year period, 7 consecutive patients with a total of 9 involved legs presented clinically with anterior compartment chronic exertional compartment syndrome, which was confirmed by intracompartmental pressure measurements before and after exercise. After a US examination, fasciotomy under US guidance was performed. Preoperative and postoperative pain and activity levels were assessed as well as number of days needed to "return to play." All patients had a decrease in pain, and all except 1 returned to presymptomatic exercise levels with a median return to play of 35 days. PMID- 26960801 TI - Nonobliteration of the Processus Vaginalis. Sonography of Related Abnormalities in Children. AB - The objective of this pictorial essay is to systematically classify processus vaginalis- related disorders in the light of embryology and present illustrative sonograms with corresponding diagrams. Failure of the processus vaginalis to obliterate during gestation results in a wide spectrum of anomalies, including communicating and noncommunicating hydroceles and inguinal and inguinoscrotal hernias, along with other related disorders of the genital system. There are varying classifications in the literature regarding the aforementioned entities. Proper and timely diagnosis of these entities is essential, given the differences in treatment. Although physical examination can narrow the differential diagnosis, sonography plays an essential role in establishing the diagnosis. PMID- 26960799 TI - Third- or Fourth-Degree Intrapartum Anal Sphincter Tears Are Associated With Levator Ani Avulsion in Primiparas. AB - OBJECTIVES: We evaluated primiparous women with clinically diagnosed third- and fourth-degree and anal sphincter tears, to evaluate the rate of levator ani muscle injury compared to primiparous women without sphincter tears. METHODS: Primiparous women delivering in our maternity ward with intrapartum diagnoses of third- or fourth-degree anal sphincter tears, repaired by the overlapping technique, were recruited to undergo 3-dimensional transperineal sonography of the pelvic floor anatomy, including the anterior and posterior compartments. Primiparas with uncomplicated vaginal deliveries were recruited as a comparison group. Patient files were examined, and maternal backgrounds and delivery and neonatal details were extracted for all patients. RESULTS: Ninety-four women with tears were recruited to the study group, and 464 women with normal vaginal deliveries constituted the comparison group. The groups differed significantly in the rates of levator ani defects: 38 of 94 women (40.4%) in the study group versus 75 of 464 (16.2%) in the comparison group (P < .001; odds ratio, 3.53; 95% confidence interval, 2.18-5.7). Neonatal head circumference differed significantly between the study and comparison groups: (mean ?} SD, 34.5 ?} 1.3 cm in the study group versus 33.9 ?} 1.3 cm in the comparison group; P= .005), as did birth weight (3322 ?} 430 g in the study group versus 3169 ?} 458 g in the comparison group; P= .007). The groups did not differ in maternal age, gestational age at delivery, length of second stage of labor, and rates of epidural anesthesia, episiotomy, and vacuum extraction. CONCLUSIONS: Third- and fourth-degree intrapartum sphincter tears are associated with levator ani avulsion. Knowledge of complex pelvic floor damage may allow for prompt referral to secondary preventive measures for pelvic floor disorders. PMID- 26960802 TI - Effects of Low-Intensity Pulsed Ultrasound on Implant Osseointegration in Ovariectomized Rats. AB - OBJECTIVES: To investigate the effect of low-intensity pulsed ultrasound (US) on periimplant bone healing and osseointegration under osteoporotic conditions. METHODS: Seventy-two 12-week-old female Sprague Dawley rats received bilateral ovariectomies. Twelve weeks later, titanium implants were bilaterally placed in the proximal tibial metaphysis. The right tibia was exposed to low-intensity pulsed US (40 mW/cm2, spatial and temporal average) for 20 min/d starting the 2nd day after implantation, and the left tibia served as a control without stimulation. The rats were randomly assigned to 6 groups of 12 each according to the US duration (group 1: weeks 0-2, 280 minutes; group 2: weeks 0-4, 560 minutes; group 3: weeks 0-6, 840 minutes; group 4: weeks 0-8, 1120 minutes; group 5: weeks 0-10, 1400 minutes; group 6: weeks 0-12, 1680 minutes). At the end of the 2nd, 4th, 6th, 8th, 10th, and 12th weeks, the rats were euthanized, and bilateral tibias were harvested. Peri-implant bone volume and bone-implant contact were assessed by micro-computed tomography; the implantbone interface was assessed histologically; and implant fixation strength was determined by a removal torque test. RESULTS: Low-intensity pulsed US increased bone-implant contact at the 4th, 6th, 8th, 10th, and 12th weeks (P = .019, .017, <.001, <.001, and <.001, respectively) and periimplant bone volume at all times (P = <.001, .002, .012, .007, .005, and .010). Removal torque on the US side was improved at the 6th, 8th, 10th, and 12th weeks (P= .012, <.001, .006, and .009). Ultrasound evoked a favorable bone response in the histologic study. CONCLUSIONS: Low intensity pulsed US might enhance new bone formation, especially at an early stage, and improve osseointegration in osteoporotic bone as an auxiliary method. However, further studies are needed to elucidate the mechanisms underlying its action. PMID- 26960803 TI - Portable A-Mode Ultrasound for Body Composition Assessment in Adolescents. AB - OBJECTIVES: Ultrasound (US) imaging is a low-cost, highly feasible alternative method for monitoring the nutritional status of a population; however, only a few studies have tested the body composition agreement between US and reference standard methods, especially in adolescents. The purposes of this study were to assess the agreement of portable US with a reference standard method, dual-energy x-ray absorptiometry (DXA), for body fat percentage (BF%) in adolescents and to verify whether the use of a new mathematical model, based on the anatomic thickness obtained by US, is capable of improving BF% prediction. METHODS: This research was a descriptive study. Measures of total body mass, BF% on DXA, and BF% on US were collected from 105 adolescents. RESULTS: The participants included 71 male adolescents (median age ?} interquartile range, 14.0 ?} 2.0 years) and 34 female adolescents (13.0 ?} 2.3 years). Ultrasound yielded significantly lower BF% values than DXA for male (mean ?} SD, US, 9.6% ?} 6.6%; DXA, 20.0% ?} 7.2%; R= 0.848; P< .05) and female (US, 22.5% ?} 5.7%; DXA, 30.3% ?} 4.9%; R = 0.495; P < .05) participants. In addition, Bland-Altman analysis showed low concordance. When a multivariate regression was tested, the results improved for both sexes (US, 20.3% ?} 4.6%; R= 0.848; P= .503) and female participants (US, 29.0% ?} 5.7%; R= 0.712; P = .993) with a standard estimate of error of 1.57%. CONCLUSIONS: This study has shown that US applied in a specific regression for BF% prediction in adolescents PMID- 26960805 TI - Ultra-processed food purchases in Norway: a quantitative study on a representative sample of food retailers - CORRIGENDUM. PMID- 26960804 TI - Serum retinol binding protein 4 is negatively related to estrogen in Chinese women with obesity: a cross-sectional study. AB - BACKGROUND: The association between serum Retinol Binding Protein 4 (RBP4) and obesity is still controversial. Serum RBP4 levels varies by gender, and estradiol may play a role in the difference. To investigate the participation of sex hormones in the association of RBP4 and obesity in humans, we measured serum RBP4, BMI, and sex hormones in 87 women from the outpatient. METHODS: Eighty seven subjects of Chinese women origin from the outpatient (aged 40.22 +/- 15.54 years) were enrolled. Subjects with diseases affecting the metabolic state or not suitable to participate in this study were excluded. Anthropometrics and laboratory tests, including lipid profile, luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), estradiol (E2),progesterone (PROG), testosterone (TESTO), and dehydroepiandrosterone (DHEA) were conducted. Serum RBP4 was detected by an enzyme immunoassay kit and validated by quantitative Western blotting. RESULTS: Circulating RBP4 levels were positively associated with BMI, waist circumference, waist-to-hip ratio (WHR), systolic and diastolic (SBP), diastolic blood pressure (DBP), triglycerides (TG), low high-density lipoprotein cholesterol(LDL-c), and testosterone (TESTO) in the total group. While only in obese individuals, serum RBP4 levels were negatively associated with E2. The highest value was in the subjects with both obesity and the low estrogen level. Multiple linear regression analysis revealed that RBP4 correlated independently with TG, TC and insulin in all subjects, TC in non- obese individuals. However, E2 were significantly associated with serum RBP4 only in obese individuals. CONCLUSIONS: RBP4 could be a marker of obesity-related factors; estrogen was negatively related to RBP4 and might be one of the influential factors. PMID- 26960807 TI - Crossing the line: NICE's value for money threshold. PMID- 26960806 TI - A genome-wide association study for genetic susceptibility to Mycobacterium bovis infection in dairy cattle identifies a susceptibility QTL on chromosome 23. AB - BACKGROUND: Bovine tuberculosis (bTB) infection in cattle is a significant economic concern in many countries, with annual costs to the UK and Irish governments of approximately ?190 million and ?63 million, respectively, for bTB control. The existence of host additive and non-additive genetic components to bTB susceptibility has been established. METHODS: Two approaches i.e. single-SNP (single nucleotide polymorphism) regression and a Bayesian method were applied to genome-wide association studies (GWAS) using high-density SNP genotypes (n = 597,144 SNPs) from 841 dairy artificial insemination (AI) sires. Deregressed estimated breeding values for bTB susceptibility were used as the quantitative dependent variable. Network analysis was performed using the quantitative trait loci (QTL) that were identified as significant in the single-SNP regression and Bayesian analyses separately. In addition, an identity-by-descent analysis was performed on a subset of the most prolific sires in the dataset that showed contrasting prevalences of bTB infection in daughters. RESULTS: A significant QTL region was identified on BTA23 (P value >1 * 10(-5), Bayes factor >10) across all analyses. Sires with the minor allele (minor allele frequency = 0.136) for this QTL on BTA23 had estimated breeding values that conferred a greater susceptibility to bTB infection than those that were homozygous for the major allele. Imputation of the regions that flank this QTL on BTA23 to full sequence indicated that the most significant associations were located within introns of the FKBP5 gene. CONCLUSIONS: A genomic region on BTA23 that is strongly associated with host susceptibility to bTB infection was identified. This region contained FKBP5, a gene involved in the TNFalpha/NFkappa-B signalling pathway, which is a major biological pathway associated with immune response. Although there is no study that validates this region in the literature, our approach represents one of the most powerful studies for the analysis of bTB susceptibility to date. PMID- 26960808 TI - Changes of serum aspergillus galactomannan during hematopoietic stem cell transplantation in children with prior invasive aspergillosis. AB - BACKGROUND: Invasive aspergillosis (IA) has recently increased and has a high mortality rate in immunocompromised patients. IA before hematopoietic stem cell transplantation (HSCT) is not uncommon, but how to cope with it is very tough. The serum aspergillus galactomannan antigen (GM) is a helpful marker for diagnosis of IA, and a serial follow-up of GM levels is important to evaluate the response of treatment. However, data on the changes of GM during HSCT are very limited. CASE PRESENTATION: Patient 1 was a 2-year-old female with severe aplastic anemia. A typical lung lesion in the computed tomography of the chest with elevated GM levels was noted, and probable IA was diagnosed. After a combination treatment of voriconazole and caspofungin, the GM levels decreased. Although of significant improvement, the pulmonary lesion in the chest X-ray did not disappear before HSCT. The GM levels increased when she received the conditioning regimen during HSCT. The GM levels remained high during the use of steroids for the graft-versus-host disease and declined gradually after tapering off steroids and cyclosporine. Patient 2 was a 12-year-old female with severe aplastic anemia. Voriconazole was administered after the diagnosis of a probable IA. The pulmonary lesions in the chest X-ray disappeared before HSCT. The GM levels flared up during the administration of conditioning regimen and declined after neutrophil engraftment. At present, the two patients were cured of the disease without requiring surgical resection of their pulmonary IA. CONCLUSION: To our knowledge, this is the first report about the changes of GM during HSCT in patients with prior IA. With appropriate antifungal therapy and restoration of patient's immunity, IA can be cured without surgical resection. Further studies are warranted. PMID- 26960812 TI - Recovery, non-profit organisations and mental health services: 'Hit and miss' or 'dump and run'? AB - BACKGROUND: The evolution of Recovery-oriented mental health services in Western nations across the globe has given rise to a growth in community-based psychosocial support services, to assist in meeting the diverse needs of consumers. This article reports findings of research that explored the perceptions of community workers who are employed by non-profit organisations and deliver psychosocial support services to support delivery of Recovery-oriented clinical mental health services. AIMS: The focus of the research reported in this article includes the benefits and challenges encountered by the community workers when working with clinicians. METHOD: The research was undertaken as part of a single-case embedded study, which evaluated the implementation of Recovery oriented approaches to the delivery of clinical mental health services in a major urban centre located in south-eastern Australia. RESULTS: Generally, community workers employed by the non-profit organisations perceived the implementation of Recovery-oriented clinical mental health services to be a positive step forward for consumers. Challenges to the delivery of Recovery-oriented services included issues arising from the many different understandings of what it means to experience mental health Recovery, the quality of communication between the community workers and clinicians and the clinicians' lack of understanding of the role of non-profit organisations and community workers. CONCLUSION: The article concludes with recommendations to address the challenges involved, with a view to improving the partnerships between community workers and clinicians, and the Recovery journey of people with serious mental illness. PMID- 26960809 TI - Drug-drug interactions and QT prolongation as a commonly assessed cardiac effect comprehensive overview of clinical trials. AB - BACKGROUND: Proarrhythmia assessment is one of the major concerns for regulatory bodies and pharmaceutical industry. ICH guidelines recommending preclinical tests have been established in attempt to eliminate the risk of drug-induced arrhythmias. However, in the clinic, arrhythmia occurrence is determined not only by the inherent property of a drug to block ion currents and disturb electrophysiological activity of cardiac myocytes, but also by many other factors modifying individual risk of QT prolongation and subsequent proarrhythmia propensity. One of those is drug-drug interactions. Since polypharmacy is a common practice in clinical settings, it can be anticipated that there is a relatively high risk that the patient will receive at least two drugs mutually modifying their proarrhythmic potential and resulting either in triggering the occurrence or mitigating the clinical symptoms. The mechanism can be observed either directly at the pharmacodynamic level by competing for the molecular targets, or indirectly by modifying the physiological parameters, or at the pharmacokinetic level by alteration of the active concentration of the victim drug. METHODS: This publication provides an overview of published clinical studies on pharmacokinetic and/or pharmacodynamic drug-drug interactions in humans and their electrophysiological consequences (QT interval modification). Databases of PubMed and Scopus were searched and combinations of the following keywords were used for Title, Abstract and Keywords fields: interaction, coadministration, combination, DDI and electrocardiographic, QTc interval, ECG. Only human studies were included. Over 4500 publications were retrieved and underwent preliminary assessment to identify papers accordant with the topic of this review. 76 papers reporting results for 96 drug combinations were found and analyzed. RESULTS: The results show the tremendous variability of drug-drug interaction effects, which makes one aware of complexity of the problem, and suggests the need for assessment of an additional risk factors and careful ECG monitoring before administration of drugs with anticipated QT prolongation. CONCLUSIONS: DDIs can play significant roles in drugs' cardiac safety, as evidenced by the provided examples. Assessment of the pharmacodynamic effects of the drug interactions is more challenging as compared to the pharmacokinetic due to the significant diversity in the endpoints which should be analyzed specifically for various clinical effects. Nevertheless, PD components of DDIs should be accounted for as PK changes alone do not allow to fully explain the electrophysiological effects in clinic situations. PMID- 26960813 TI - Self-assembled SnO2 micro- and nanosphere-based gas sensor thick films from an alkoxide-derived high purity aqueous colloid precursor. AB - Tin oxide is considered to be one of the most promising semiconductor oxide materials for use as a gas sensor. However, a simple route for the controllable build-up of nanostructured, sufficiently pure and hierarchical SnO2 structures for gas sensor applications is still a challenge. In the current work, an aqueous SnO2 nanoparticulate precursor sol, which is free of organic contaminants and sorbed ions and is fully stable over time, was prepared in a highly reproducible manner from an alkoxide Sn(OR)4 just by mixing it with a large excess of pure neutral water. The precursor is formed as a separate liquid phase. The structure and purity of the precursor is revealed using XRD, SAXS, EXAFS, HRTEM imaging, FTIR, and XRF analysis. An unconventional approach for the estimation of the particle size based on the quantification of the Sn-Sn contacts in the structure was developed using EXAFS spectroscopy and verified using HRTEM. To construct sensors with a hierarchical 3D structure, we employed an unusual emulsification technique not involving any additives or surfactants, using simply the extraction of the liquid phase, water, with the help of dry butanol under ambient conditions. The originally generated crystalline but yet highly reactive nanoparticles form relatively uniform spheres through self-assembly and solidify instantly. The spheres floating in butanol were left to deposit on the surface of quartz plates bearing sputtered gold electrodes, producing ready-for-use gas sensors in the form of ca. 50 MUm thick sphere-based-films. The films were dried for 24 h and calcined at 300 degrees C in air before use. The gas sensitivity of the structures was tested in the temperature range of 150-400 degrees C. The materials showed a very quickly emerging and reversible (20-30 times) increase in electrical conductivity as a response to exposure to air containing 100 ppm of H2 or CO and short (10 s) recovery times when the gas flow was stopped. PMID- 26960811 TI - Combined probes of X-ray scattering and optical spectroscopy reveal how global conformational change is temporally and spatially linked to local structural perturbation in photoactive yellow protein. AB - Real-time probing of structural transitions of a photoactive protein is challenging owing to the lack of a universal time-resolved technique that can probe the changes in both global conformation and light-absorbing chromophores of the protein. In this work, we combine time-resolved X-ray solution scattering (TRXSS) and transient absorption (TA) spectroscopy to investigate how the global conformational changes involved in the photoinduced signal transduction of photoactive yellow protein (PYP) is temporally and spatially related to the local structural change around the light-absorbing chromophore. In particular, we examine the role of internal proton transfer in developing a signaling state of PYP by employing its E46Q mutant (E46Q-PYP), where the internal proton transfer is inhibited by the replacement of a proton donor. The comparison of TRXSS and TA spectroscopy data directly reveals that the global conformational change of the protein, which is probed by TRXSS, is temporally delayed by tens of microseconds from the local structural change of the chromophore, which is probed by TA spectroscopy. The molecular shape of the signaling state reconstructed from the TRXSS curves directly visualizes the three-dimensional conformations of protein intermediates and reveals that the smaller structural change in E46Q-PYP than in wild-type PYP suggested by previous studies is manifested in terms of much smaller protrusion, confirming that the signaling state of E46Q-PYP is only partially developed compared with that of wild-type PYP. This finding provides direct evidence of how the environmental change in the vicinity of the chromophore alters the conformational change of the entire protein matrix. PMID- 26960810 TI - A Novel Strategy for the Preparation of Codon-Optimized Truncated Ulp1 and its Simplified Application to Cleavage the SUMO Fusion Protein. AB - Ubiquitin-like protease 1 (Ulp1) of Saccharomyces cerevisiae emerges as a fundamental tool to obtain the natural N-terminal target protein by cleavage of the small ubiquitin-related modifier (SUMO) fusion protein. However, the costly commercial Ulp1 and its complicated procedures limit its application in the preparation of the target protein with natural N-terminal sequence. Here, we describe the preparation of bioactive codon-optimized recombinant truncated Ulp1 (Leu403-Lys621) (rtUlp1) of S. cerevisiae in Escherichia coli using only one-step with Ni-NTA affinity chromatograph, and the application of rtUlp1 to cleave the SUMO fusion protein by simply mixing the purified rtUlp1, SUMO fusion protein and DL-Dithiothreitol in Tris-HCl buffer. The optimal expression level of non-fusion protein rtUlp1 accounts for approximately 50 % of the total cellular protein and 36% of the soluble form by addition of isopropyl beta-D-l-thiogalactopyranoside at a final concentration of 0.4 mM at 18 degrees C for 20 h. The purification of target protein rtUlp1 was conducted by Ni-NTA affinity chromatography. The final yield of rtUlp1 was 45 mg/l in flask fermentation with a purity up to 95%. Furthermore, the high purity of rtUlp1 could effectively cleave the SUMO tTbetaRII fusion protein (SUMO gene fused to truncated transforming growth factor beta receptor type II gene) with the above simplified approach, and the specific activity of the rtUlp1 reached up to 2.8 * 10(4) U/mg, which is comparable to the commercial Ulp1. The preparation and application strategy of the rtUlp1 with commonly available laboratory resources in this study will be convenient to the cleavage of the SUMO fusion protein to obtain the natural N-terminal target protein, which can be implemented in difficult-to-express protein functional analysis. PMID- 26960814 TI - A prospective study of sexual and urinary function before and after total mesorectal excision. AB - PURPOSE: Although rectal cancer is a very common malignancy and has an improved cure rate in response to oncological treatment, research on rectal cancer survivors' urogenital function remains limited. In this study, urogenital dysfunction after surgical rectal cancer treatment was measured and possible predisposing factors that may have an impact on the development of this disorder were discussed. METHODS: One hundred eight patients undergoing curative rectal cancer surgery from January 2008 to December 2014 were questioned using questionnaires: male urinary function was assessed using the International Prostatic Symptom Score (IPSS) questionnaire, for sexual function-International Index of Erectile Function (IIEF). The Bristol Female Lower Urinary Tract Symptoms (BFLUTS) questionnaire and the Female Sexual Function Index (FSFI) were used for female urogenital function assessment prior to the operation and 6 months postoperatively. RESULTS: A total of 67.0 % of male (36) and 33.0 % (18) of female patients who completed the questionnaire were included in the study. Preoperatively, male urinary dysfunction was 80.1 % and postoperatively-88.9 %. In female patients, preoperative urinary dysfunction was seen in 75.0 % patients, postoperatively-78.0 %. Erectile dysfunction was seen in 41.7 % males preoperatively and in 63.9 % postoperatively. A total of 83.3 % of female patients had sexual dysfunction preoperatively and 94 % postoperatively. CONCLUSION: Sexual and urinary problems after surgery for rectal cancer are common. Preoperative genitourinary dysfunction is not uncommon in patients older than 60 years as well. Female patients reported higher rates of sexual dysfunction than males. These results point out the importance of sexual and urinary (dys)function in survivors of rectal cancer. More attention should be drawn to this topic for clinical and research purposes. PMID- 26960815 TI - Novel elastic membrane vesicles (EMVs) and ethosomes-mediated effective topical delivery of aceclofenac: a new therapeutic approach for pain and inflammation. AB - CONTEXT: Aceclofenac (ACE) is a systematically designed drug, developed to circumvent the concerns associated with diclofenac. But ACE is also associated with non-steroidal anti-inflammatory drug (NSAIDs)-tagged side effects, although of decreased amplitude. OBJECTIVE: The present study aims to develop phospholipid based vesicles (elastic membrane vesicles; EMV and ethosomes) loaded with ACE and explore their potential in topical delivery. METHODS: Elastic membrane vesicles (EMVs) were prepared by thin-film hydration method and ethosomes by cold method. The composition of both the vesicular systems was selected on the basis of vesicle density and drug entrapment. The developed systems were characterized for micromeritics, surface charge, drug entrapment, and morphology. Ex vivo permeation and retention studies on Laca mice skin were performed. In vivo pharmacodynamic evaluation was performed by tail-flick method and carrageenan induced rat paw-edema model. During stability studies, percent drug leakage was studied. RESULTS: The selected ratios of phospholpid:drug:stearylamine for EMVs and ethosomes were 8:1:1 and 3:1:1, respectively. The ethosomes were found to offer more vesicle density, drug loading, and deformability index as compared with that of EMVs. The drug permeation and the retention offered by both the vesicular systems were superior to that of the conventional cream; however, performance of ethosomes superseded that of EMVs. The phospholipid-based vesicles were found to be well tolerated on mice skin. Although, the in vivo performance of ethosomes was found to be better than that of EMVs in both the studied models. CONCLUSION: The phospholipid-based vesicular systems, especially, ethosomes can be a promising tool to enhance the delivery and safety of ACE by topical route. PMID- 26960816 TI - Evaluation of the antioxidant capacity of a milk protein matrix in vitro and in vivo in women aged 50-70 years. AB - Bovine milk proteins have emerged as a novel, dairy-based source of dietary antioxidants and a component of a nutritional strategy to maintain muscle mass during ageing. The aim of this study was to characterise the in vitro antioxidant capacity (AOC) of a milk-based protein matrix (MPM) before and after simulated gastrointestinal digestion (SGID) and determine whether plasma AOC was similarly modified in vivo following acute ingestion of the MPM in healthy 50-70 years old women. To achieve this, the AOC of the MPM was measured by the oxygen radical absorbance capacity (ORAC) assay prior to and following SGID. In parallel, plasma obtained from women prior to and for 3 h following ingestion of the MPM was analysed ex vivo for change in AOC to evaluate the translation in vivo. SGID of the MPM increased AOC by ~ 35% (27,365 +/- 2152 versus 42,592 +/- 2299 MUmol TE/100 g dw; p < 0.05). Sampled ex vivo, ingestion of the MPM increased fasting plasma AOC by ~ 23% (10,952 +/- 751 to 13,519 +/- 800 MUmol TE/L; p < 0.05). These data provide preliminary evidence of an association between the change in the ORAC-based measurement of AOC of an MPM subjected to simulated digest in vitro and the change in plasma AOC following ingestion of the MPM sampled ex vivo from healthy elderly women. PMID- 26960818 TI - Hindered rotor tunneling splittings: an application of the two-dimensional non separable method to benzyl alcohol and two of its fluorine derivatives. AB - In this work we present a novel application of the two-dimensional non-separable (2D-NS) method to the calculation of torsional tunneling splittings in systems with two hindered internal rotors. This method could be considered an extension of one-dimensional methods for the case of compounds with two tops. The 2D-NS method includes coupling between torsions in the kinetic and potential energy. Specifically, it has been applied to benzyl alcohol (BA) and two of its fluorine derivatives: 3-fluorobenzyl alcohol (3FBA) and 4-fluorobenzyl alcohol (4FBA). These molecules present two torsions, i.e., about the -CH2OH (phi1) and -OH (phi2) groups. The electronic structure calculations to build the two-dimensional torsional potential energy surface were performed at the DF-LMP2-F12//DF-LMP2/cc pVQZ level of theory. For BA and 4FBA the calculated ground-state vibrational level splittings are 429 and 453 MHz, respectively, in good agreement with the experimental values of 337.10 and 492.82 MHz, respectively. In these two cases there are four equivalent wells and the tunneling splitting is the result of transitions between the two closer minima along phi1. The analysis of the wavefunctions, as well as the previous experimental work on the system, supports this conclusion. For 3FBA the observed ground-state splitting is 0.82 MHz, whereas in this case the calculated value amounts only to 0.02 MHz. The 2D-NS method, through the analysis of the wavefunctions, shows that this tiny tunneling splitting occurs between the two most stable minima of the potential energy surface. Additionally, we predict that the first vibrationally excited tunneling splitting will also be small and exclusively due to the interconversion between the second lowest minima. PMID- 26960817 TI - Exploring the gating mechanisms of aquaporin-3: new clues for the design of inhibitors? AB - The pH gating of human AQP3 and its effects on both water and glycerol permeabilities have been fully characterized for the first time using a human red blood cell model (hRBC). For comparison, the effects of pH on the gating of rat AQP3 have also been characterized in yeast. The obtained results highlight similarities as well as differences between the two isoforms. In addition, we investigated the molecular mechanism of hAQP3 pH gating in silico, which may disclose new pathways to AQP regulation by small molecule inhibitors, and therefore may be important for drug development. PMID- 26960819 TI - Dose-rate effects in radiation biology and radiation protection. AB - Quantification of biological effects (cancer, other diseases, and cell damage) associated with exposure to ionising radiation has been a major issue for the International Commission on Radiological Protection (ICRP) since its foundation in 1928. While there is a wealth of information on the effects on human health for whole-body doses above approximately 100 mGy, the effects associated with doses below 100 mGy are still being investigated and debated intensively. The current radiological protection approach, proposed by ICRP for workers and the public, is largely based on risks obtained from high-dose and high-dose-rate studies, such as the Japanese Life Span Study on atomic bomb survivors. The risk coefficients obtained from these studies can be reduced by the dose and dose-rate effectiveness factor (DDREF) to account for the assumed lower effectiveness of low-dose and low-dose-rate exposures. The 2007 ICRP Recommendations continue to propose a value of 2 for DDREF, while other international organisations suggest either application of different values or abandonment of the factor. This paper summarises the current status of discussions, and highlights issues that are relevant to reassessing the magnitude and application of DDREF. PMID- 26960820 TI - Current global and Korean issues in radiation safety of nuclear medicine procedures. AB - In recent years, the management of patient doses in medical imaging has evolved as concern about radiation exposure has increased. Efforts and techniques to reduce radiation doses are focussed not only on the basis of patient safety, but also on the fundamentals of justification and optimisation in cooperation with international organisations such as the International Commission on Radiological Protection, the International Atomic Energy Agency, and the World Health Organization. The Image Gently campaign in children and Image Wisely campaign in adults to lower radiation doses have been initiated in the USA. The European Association of Nuclear Medicine paediatric dosage card, North American consensus guidelines, and Nuclear Medicine Global Initiative have recommended the activities of radiopharmaceuticals that should be administered in children. Diagnostic reference levels (DRLs), developed predominantly in Europe, may be an important tool to manage patient doses. In Korea, overexposure to radiation, even from the use of medical imaging, has become a public issue, particularly since the accident at the Fukushima nuclear power plant. As a result, the Korean Nuclear Safety and Security Commission revised the technical standards for radiation safety management in medical fields. In parallel, DRLs for nuclear medicine procedures have been collected on a nationwide scale. Notice of total effective dose from positron emission tomography-computed tomography for cancer screening has been mandatory since mid-November 2014. PMID- 26960822 TI - Unroofing Technique as an Option for the Endoscopic Treatment of Giant Gastrointestinal Lipomas. AB - Gastrointestinal lipomas are usually asymptomatic, detected incidentally. However, they can cause severe symptoms such as obstruction, invagination, and bleeding. The transsection of an infarcted or large lipoma by needle sphincterotome (needle knife) and/or snare polypectomy of the upper part of the tumour is an option for the endoscopy treatment of giant infarcted lipomas. Cutting a top of lipoma (unroofing technique) allowed flow out of adipose tissue from the lipoma. PMID- 26960821 TI - Cell wall accumulation of fluorescent proteins derived from a trans-Golgi cisternal membrane marker and paramural bodies in interdigitated Arabidopsis leaf epidermal cells. AB - In most dicotyledonous plants, leaf epidermal pavement cells develop jigsaw puzzle-like shapes during cell expansion. The rapid growth and complicated cell shape of pavement cells is suggested to be achieved by targeted exocytosis that is coordinated with cytoskeletal rearrangement to provide plasma membrane and/or cell wall materials for lobe development during their morphogenesis. Therefore, visualization of membrane trafficking in leaf pavement cells should contribute an understanding of the mechanism of plant cell morphogenesis. To reveal membrane trafficking in pavement cells, we observed monomeric red fluorescent protein tagged rat sialyl transferases, which are markers of trans-Golgi cisternal membranes, in the leaf epidermis of Arabidopsis thaliana. Quantitative fluorescence imaging techniques and immunoelectron microscopic observations revealed that accumulation of the red fluorescent protein occurred mostly in the curved regions of pavement cell borders and guard cell ends during leaf expansion. Transmission electron microscopy observations revealed that apoplastic vesicular membrane structures called paramural bodies were more frequent beneath the curved cell wall regions of interdigitated pavement cells and guard cell ends in young leaf epidermis. In addition, pharmacological studies showed that perturbations in membrane trafficking resulted in simple cell shapes. These results suggested possible heterogeneity of the curved regions of plasma membranes, implying a relationship with pavement cell morphogenesis. PMID- 26960823 TI - Histological Changes of the Middle Ear Ossicles Harvested during Cholesteatoma Surgery. AB - BACKGROUND: In the cholesteatoma surgery ossicles can be replaced to reconstruct middle ear function. It is important that these ossicles are free of squamous epithelium, to prevent residual disease. This study focuses on the histological findings of the malleus and incus harvested during cholesteatoma surgery. MATERIALS AND METHODS: Eighty middle ears ossicles were examined in vivo and histologically to consider the relationship of cholesteatoma to ossicles, grade of bone destruction and invasion of cholesteatoma to deeper layers of bone. RESULTS: Serious ossicular destruction was observed more frequently in incus compared to malleus (p=0.0065). Difference of ossicles destruction between children and adults was not significant (p=0.3032). Deep invasion of cholesteatoma into the vascular spaces or inner core of the bone was not observed. CONCLUSIONS: Autograft ossicles from cholesteatomatous ears should not necessarily be rejected for reconstruction of the ossicular chain. Regarding the histological finding, the authors suggest mechanical cleaning of the ossicle surface to eliminate residual disease. PMID- 26960824 TI - Dental and Oral Lesions in HIV-Positive Individuals in East Bohemia--Czech Republic, Single Centre Experience. AB - BACKGROUND: Human immunodeficiency virus (HIV) continues to be a serious health issue and one of the world most devastating epidemics. An estimated 1.5 million people died from AIDS-related illnesses in 2013, and an estimated 37 million people with AIDS have died worldwide since the epidemic has begun. HIV infection is known for its oral manifestations which causes discomfort and pain for infected individuals. The objective of this study was to document oral conditions of HIV positive patients and the pattern and frequency of oral and dental lesions. METHODS: All patients with confirmed HIV infection who were treated at the Department of Dentistry, University Hospital in Hradec Kralove, were examined. RESULTS: During the study period, 29 HIV positive patients were examined and treated--19 men, 10 women, with mean age of 32.9 years (range 22-58 years). 72.41% patients received ART. In total, all patients underwent 186 visits. The most frequent treatments were associated with teeth and periodontal lesions (71.80%), oral mucosal lesions were diagnosed and treated only in 3.96% cases. CONCLUSION: Since the introduction of ART, the frequency of oral mucosal lesions is minimal in patients with HIV infection. PMID- 26960825 TI - Natural Detoxification Capacity to Inactivate Nerve Agents Sarin and VX in the Rat Blood. AB - BACKGROUND: The method of continual determination of the rat blood cholinesterase activity was developed to study the changes of the blood cholinesterases following different intervetions. AIMS: The aim of this study is registration of cholinesterase activity in the rat blood and its changes to demonstrate detoxification capacity of rats to inactivate sarin or VX in vivo. METHODS: The groups of female rats were premedicated (ketamine and xylazine) and cannulated to a. femoralis. Continual blood sampling (0.02 ml/min) and monitoring of the circulating blood cholinesterase activity were performed. Normal activity was monitored 1-2 min and then the nerve agent was administered i.m. (2*LD50). Using different time intervals of the leg compression and relaxation following the agent injection, cholinesterase activity was monitored and according to the inhibition obtained, detoxification capacity was assessed. RESULTS: Administration of sarin to the leg, then 1 and 5 min compression and 20 min later relaxation showed that further inhibition in the blood was not observed. On the other hand, VX was able to inhibit blood cholinesterases after this intervention. CONCLUSIONS: The results demonstrated that sarin can be naturally detoxified on the contrary to VX. Described method can be used as model for other studies dealing with changes of cholinesterases in the blood following different factors. PMID- 26960826 TI - Oesophageal Manometry in Experimental Pigs: Methods and Initial Experience. AB - The aim of this study project was to prepare our own method of porcine oesophageal manometry. Ten mature experimental pigs entered the study. Conventional water-perfused system was decided for manometry. Porcine resting and relaxed pressures of the lower oesophageal sphincter are fully comparable with healthy human subjects. Evocable swallowing is doable and oesophageal peristalsis is quantifiable. Basic manometric parameters were different in male and female animals. Oesophageal manometry in experimental pigs is feasible. Porcine oesophageal manometry will be usable for preclinical studies in future. PMID- 26960827 TI - The Evaluation of the Potency of Newly Developed Oximes (K727, K733) and Trimedoxime to Counteract Acute Neurotoxic Effects of Tabun in Rats. AB - AIM: The ability of two newly developed oximes (K727, K733) to reduce tabun induced acute neurotoxic signs and symptoms was evaluated and compared with currently available trimedoxime in rats. METHODS: The neuroprotective effects of the oximes studied combined with atropine on Wistar rats poisoned with tabun at a lethal dose (380 ug/kg i.m.; 90% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by the functional observational battery consisting of 38 measurements of sensory, motor and autonomic nervous functions at 2 hours following tabun challenge. RESULTS: All tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment. Both newly developed oximes (K727, K733) combined with atropine were able to decrease tabun induced neurotoxicity in the case of lethal poisoning although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. CONCLUSION: The ability of both novel bispyridinium oximes to decrease tabun-induced acute neurotoxicity was slightly lower than that of trimedoxime. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes such as trimedoxime in the treatment of acute tabun poisonings. PMID- 26960828 TI - Pneumoperitoneum in in-vitro Conceived Quadruplet Neonate: Rare Manifestation of Hirschsprung's Disease--Report of a Case. AB - INTRODUCTION: Hirschsprung's disease is a congenital colonic aganglionosis, usually presented as inability or difficulty in passing of meconium, chronic and persistent obstipation, maleficent feeding, vomiting, distension and lethargy. CASE PRESENTATION: We presented a case of an in-vitro conceived quadruplet premature neonate who presented with pneumoperitoneum caused by transverse colon spontaneous perforation and microcolon appearance of distal bowel, treated by resection and temporary colostomy turns to be a rare manifestation of Hirschsprung's disease. CONCLUSION: Assisted reproductive technologies increases chances for multiple pregnancies and may increase chance for major congenital anomalies. Rare manifestation of Hirschsprung's disease is spontaneous pneumoperitoneum which remains a surgical emergency. Delay in recognizing and treatment can significantly worsen prognosis. In neonate with intestinal perforation one should consider Hirschsprung's disease. PMID- 26960829 TI - Concha Bullosa Mucopyocele: a Case Report. AB - Concha bullosa (CB) is among the most common anatomic variations of sinonasal anatomy. Although usually asymptomatic, CB can occasionally cause nasal obstruction or headache. Obstructions within the mucociliary transport system can develop into a mucocele or mucopyocele. A 48-year-old female, with a history of progressive headache and nasal obstruction, was referred to our department. Paranasal sinus tomography revealed a nasal mass in the left nasal cavity resembling a mucopyocele in the middle turbinate. Under general anesthesia, the purulent material was aspirated, and the lateral part of the left turbinate was resected. Mucopyoceles are common within the paranasal sinuses, but uncommon with CB; thus, they should be considered in patients with a large hyperemic nasal mass. PMID- 26960830 TI - Dispersive Liquid-Liquid Microextraction for HPLC-UV Determination of PAHs in Milk. AB - A simple and rapid analytical method for the extraction and quantification of four polycyclic aromatic hydrocarbons in milk sample has been developed using dispersive liquid-liquid microextraction followed by the use of HPLC. Benzo(a)pyrene, benzo(a)anthracene, and benzo(b)fluoranthene were used as model compounds; the milk sample was spiked with these compounds to assess the extraction procedure. Experimental parameters that influence the extraction efficiency, including the nature and volume of the disperser and extraction solvents, pH, and the volume of milk sample, were optimized. Under the optimum extraction conditions (extraction solvent: chloroform, 200 MUL; dispersive solvent: acetonitrile, 700 MUL; and extraction time 5 s or less), the performance of the proposed method was evaluated. The chromatographic peak area was linear with concentrations in the range of 0.2-10 ng/mL(-1) and with correlation coefficients ranging from 0.9968 to 0.9985. The LODs, based on a S/N ratio of 3, ranged from 0.06 to 0.18 ng/mL(-1). The RSDs varied from 3.68 to 9.7% (n = 3). The recoveries of these compounds were from 88.38 to 100%. The performance of the present method was evaluated for the determination of polycyclic aromatic hydrocarbons in various types of milk samples. PMID- 26960834 TI - [A non-itching lesion on the stomach]. PMID- 26960836 TI - [Fever best measured rectally]. PMID- 26960835 TI - [Polypoid structures of the bulbus duodeni]]. PMID- 26960831 TI - A comprehensive characterization of cell cultures and xenografts derived from a human verrucous penile carcinoma. AB - This study aimed to establish and characterize primary cell cultures and xenografts derived from penile carcinoma (PeCa) in order to provide experimental models for cellular processes and efficacy of new treatments. A verrucous squamous cell carcinoma (VSCC) was macrodissected, dissociated, and cultivated in KSFM/DF12 medium. Cell cultures were evaluated at passage 5 (P5) using migration and invasion assays and were serially propagated, in vivo, in BALB/c nude mice until passage 3 (X1-X3). Immunophenotypic characterization of cultures and xenografts was performed. Genomic (CytoScan HD, Affymetrix) and transcriptomic profiles (HTA 2.0 platform, Affymetrix) for VSCC, cell cultures, and xenografts were assessed. P5 cells were able to migrate, invade the Matrigel, and produce tumors in immunodeficient mice, demonstrating their malignant potential. The xenografts unexpectedly presented a sarcomatoid-like carcinoma phenotype. Genomic analysis revealed a high similarity between the VSCC and tumor-derived xenograft, confirming its xenograft origin. Interestingly, a subpopulation of P5 cells presented stem cell-related markers (CD44(+)CD24(-) and ALDH1(high)) and sphere forming capacity, suggesting their potential xenograft origin. Cell cultures and xenografts retained the genomic alterations present in the parental tumor. Compared to VSCC, differentially expressed transcripts detected in all experimental conditions were associated with cellular morphology, movement, and metabolism and organization pathways. Malignant cell cultures and xenografts derived from a verrucous penile carcinoma were established and fully characterized. Nevertheless, xenograft PeCa models must be used with caution, taking into consideration the selection of specific cell populations and anatomical sites for cell/tumor implantation. PMID- 26960837 TI - [What happened to the diabetic stollen gone?]. PMID- 26960838 TI - [Sex and beauty]. PMID- 26960839 TI - [Beer belly worse than overweight]. PMID- 26960840 TI - [Currently your infectious diseases knowledge is required]. PMID- 26960841 TI - [Stricter blood pressure control improves the prognosis significantly]. PMID- 26960842 TI - ["A milestone study"]. PMID- 26960845 TI - [Home cooking protects against diabetes]. PMID- 26960846 TI - [Empagliflozin reduces heart failure risk by a third]. PMID- 26960847 TI - ["Enteritis" diagnosis seemed obvious, but was wrong]. PMID- 26960848 TI - [Phytotherapy for control of nausea and vomiting]. PMID- 26960850 TI - [Treatable traits" to replace exact diagnosis]. PMID- 26960849 TI - [Targeting inflammation]. PMID- 26960851 TI - [Opiate substitution records success stories]. PMID- 26960853 TI - [Gout: a systemic disease with many facets]. PMID- 26960852 TI - [Health care chain for lasting success]. PMID- 26960854 TI - [Observation first of all in acute hepatitis C]. PMID- 26960855 TI - [Arthroscopy referral in gonarthrosis will be eliminated]. PMID- 26960856 TI - [GOA reference: do not forget a numeral in venous treatment]. PMID- 26960857 TI - [A refreshing appropriate word at the right time]. PMID- 26960858 TI - [Iridescent danger from the aquarium]. PMID- 26960859 TI - [Family practice adventures in DDR and BDR]. PMID- 26960860 TI - [2015 Oskar Prize in Medicine awarded]. PMID- 26960861 TI - [Insurance fund must pay for breast reduction due to pain]. PMID- 26960862 TI - [Constitutional court finds no inappropriate aspect in G-BA]. PMID- 26960863 TI - [No obligation for overtime]. PMID- 26960864 TI - [Is your work - life balance appropriate? Take the test!]. PMID- 26960865 TI - [Family physician in the future]. PMID- 26960866 TI - [High calcium intake does not help old bones]. PMID- 26960867 TI - [Calcium mine in the extremities]. PMID- 26960868 TI - [Polyneuropathy begins in prediabetes]. PMID- 26960869 TI - [Children of mothers who smoke have increased asthma risk]. PMID- 26960870 TI - [Roentgen image shows a colon-simulating megaesophagus]. PMID- 26960871 TI - [Supplements for cognitive function unsuitable]. PMID- 26960872 TI - [Crohn's disease at the dentist]. PMID- 26960873 TI - [Label for colorectal cancer screening]. PMID- 26960874 TI - [Indispensable neurological key symptoms for the general practitioner]. PMID- 26960875 TI - [Medical attendance for refugees at Mc Graw barracks 2015. Medical report from Munich]. PMID- 26960876 TI - [Tendon injuries--a short overview?]. PMID- 26960877 TI - [Why is his heart stumbling?]. PMID- 26960878 TI - [Is city living detrimental to your health?]. PMID- 26960880 TI - [Multimodal non-pharmacological therapy of arterial hypertension]. PMID- 26960879 TI - [Clinical trials--benefit for the patient]. PMID- 26960881 TI - [Sacubitril/valsartan receives European approval]. PMID- 26960882 TI - [First NOAK with specific antidote]. PMID- 26960883 TI - [ICS not indicated in the early stage]. PMID- 26960884 TI - [Phytotherapy drug is convincing once again]. PMID- 26960885 TI - [New attempt in a benefit evaluation]. PMID- 26960887 TI - [Polypill for secondary coronary heart disease prevention]. PMID- 26960886 TI - [IQWiG confirms significant additional applications for edoxaban ]. PMID- 26960888 TI - [New NRTI with optimized long-term tolerance]. PMID- 26960889 TI - [How long should therapy last?]. PMID- 26960890 TI - [Fewer subcutaneous injections with the same effectiveness]. PMID- 26960891 TI - [From cancer prevention via precision medicine to patient involvement: 2016 German Oncology Congress offers a broad topic spectrum]. PMID- 26960892 TI - [PCSK9 inhibitor is convincing a large analysis]. PMID- 26960893 TI - [Physician routine encounter: therapy of thrombophlebitis]. PMID- 26960894 TI - [Rather phytotherapy than antibiotic]. PMID- 26960895 TI - [Dual effect prevents chronic course]. PMID- 26960896 TI - [Bandage system improves self management]. PMID- 26960897 TI - [Complication sequelae prevented, morbidity decreased]. PMID- 26960900 TI - Erratum to: 'DECKO: Single-oligo, dual-CRISPR deletion of genomic elements including long non-coding RNAs'. PMID- 26960902 TI - Detection of zinc oxide and cerium dioxide nanoparticles during drinking water treatment by rapid single particle ICP-MS methods. AB - Nanoparticles (NPs) entering water systems are an emerging concern as NPs are more frequently manufactured and used. Single particle inductively coupled plasma mass spectrometry (SP-ICP-MS) methods were validated to detect Zn- and Ce containing NPs in surface and drinking water using a short dwell time of 0.1 ms or lower, ensuring precision in single particle detection while eliminating the need for sample preparation. Using this technique, information regarding NP size, size distribution, particle concentration, and dissolved ion concentrations was obtained simultaneously. The fates of Zn- and Ce-NPs, including those found in river water and added engineered NPs, were evaluated by simulating a typical drinking water treatment process. Lime softening, alum coagulation, powdered activated carbon sorption, and disinfection by free chlorine were simulated sequentially using river water. Lime softening removed 38-53 % of Zn-containing and ZnO NPs and >99 % of Ce-containing and CeO2 NPs. Zn-containing and ZnO NP removal increased to 61-74 % and 77-79 % after alum coagulation and disinfection, respectively. Source and drinking water samples were collected from three large drinking water treatment facilities and analyzed for Zn- and Ce-containing NPs. Each facility had these types of NPs present. In all cases, particle concentrations were reduced by a minimum of 60 % and most were reduced by >95 % from source water to finished drinking water. This study concludes that uncoated ZnO and CeO2 NPs may be effectively removed by conventional drinking water treatments including lime softening and alum coagulation. PMID- 26960901 TI - Sex-dependent effects of microcystin-LR on hypothalamic-pituitary-gonad axis and gametogenesis of adult zebrafish. AB - While microcystins (MCs) have been reported to exert reproductive toxicity on fish with a sex-dependent effect, the underlying mechanism has been rarely investigated. In the present study, zebrafish were exposed to 1, 5 and 20 MUg/L MC-LR for 30 d. The gonad-somatic index declined in all treated males. 17beta estradiol (E2), testosterone (T), 11-keto testosterone (11-KT) and follicle stimulating hormone (FSH) levels increased in serum from all treated females, while T, FSH and luteinizing hormone (LH) levels changed in all treated males. Histomorphological observation showed that MC-LR exposure evidently retarded oogenesis and spermatogenesis. Transcriptional changes of 22 genes of the hypothalamic-pituitary-gonad (HPG) axis exhibited sex-specific responses, and the relationship between gene transcriptions and gametogenesis was evaluated by principle component analysis (PCA). Major contributors to PC1 (gnrh2, gnrhr3, ar, lhr, hmgra, hmgrb and cyp19a) were positively correlated with the number of post vitellogenic oocytes, while PC1 (gnrh2, lhbeta, erbeta, fshr, cyp11a and 17betahsd) were positively correlated with the number of spermatozoa. The protein levels of 17betaHSD and CYP19a were affected in both females and males. In conclusion, this study first investigated the sex-dependent effects of microcystins on fish reproduction and revealed some important molecular biomarkers related to gametogenesis in zebrafish suffered from MC-LR. PMID- 26960905 TI - Surface-directed modulation of supramolecular gel properties. AB - Supramolecular materials are widely studied and used for a variety of applications; in most applications, these materials are in contact with surfaces of other materials. Whilst much focus has been placed on elucidating factors that affect supramolecular material properties, the influence of the material surface on gel formation is poorly characterised. Here, we demonstrate that surface properties directly affect the fibre architecture and mechanical properties of self-assembled cytidine based gel films. PMID- 26960903 TI - Screening of the binding properties of molecularly imprinted nanoparticles via capillary electrophoresis. AB - In response to the need for straightforward analytical methods to assess the affinity of molecularly imprinted nanoparticles (MIP NPs) for ligands, capillary electrophoresis (CE) was exploited using MIP NPs targeting the iron-regulating hormone hepcidin. In this work, MIP NPs were challenged with their template peptide, i.e., the N-terminal 5-mer of hepcidin, in comparison to unrelated ligand peptides. A CE separation method was developed ex novo achieving, after optimization of the background electrolyte (150 mM sodium phosphate pH 7.4) and of the running temperature (35 degrees C), the full separation of the free ligand from the complexed MIP NPs. The CE binding isotherm allowed the estimation of a micromolar dissociation constant for the 5-mer template-MIP NPs complex, in agreement with independent measurements. The CE offered the advantages of a direct injection of the MIP NPs/ligand incubation mix, without preliminary fractionation steps, requiring only minimal sample volumes and short analysis times. In conclusion CE proved to be a valid technique for characterizing the interactions of MIP NP libraries for selected target compounds. PMID- 26960904 TI - Homogeneous electrochemical immunoassay of aflatoxin B1 in foodstuff using proximity-hybridization-induced omega-like DNA junctions and exonuclease III triggered isothermal cycling signal amplification. AB - A new homogeneous electrochemical immunosensing platform was designed for sensitive detection of aflatoxin B1 (AFB1) in foodstuff. The system consisted of anti-AFB1 antibody labeled DNA1 (Ab-DNA1), AFB1-bovine serum albumin (BSA) conjugated DNA2 (AFB1-DNA2), and methylene blue functionalized hairpin DNA. Owing to a specific antigen-antibody reaction between anti-AFB1 and AFB1-BSA, the immunocomplex formed assisted the proximity hybridization of DNA1 with DNA2, thus resulting in the formation of an omega-like DNA junction. Thereafter, the junction opened the hairpin DNA to construct a new double-stranded DNA, which could be readily cleaved by exonuclease III to release the omega-like DNA junction and methylene blue. The dissociated DNA junction could repeatedly hybridize with residual hairpin DNA molecules with exonuclease III-based isothermal cycling amplification, thereby releasing numerous free methylene blue molecules into the detection solution. The as-produced free methylene blue molecules could be captured by a negatively charged indium tin oxide electrode, each of which could produce an electronic signal within the applied potentials. On introduction of target AFB1, the analyte competed with AFB1-DNA2 for the conjugated anti-AFB1 on the Ab-DNA1, subsequently decreasing the amount of omega like DNA junctions formed, hence causing methylene blue labeled hairpin DNA to move far away from the electrode surface. Under optimal conditions the detectable electrochemical signal decreased with increasing amount of target AFB1 in a dynamic working range of 0.01-30 ng mL-1 with a detection limit of 4.8 pg mL-1. In addition, the precision and reproducibility of this system were acceptable. Finally, the method was further evaluated for analysis of naturally contaminated or AFB1-spiked peanut samples, giving results that matched well with those obtained with a commercial AFB1 ELISA kit. PMID- 26960906 TI - The Current Status of Oral Contraceptives: Progress and Recent Innovations. AB - Millions of women in the United States and abroad use oral contraceptive pills. These popular contraceptives are the most common reversible birth control method in the United States, and a wide variety of pills are available for prescription. Oral contraceptives provide safe and effective protection against pregnancy and offer several noncontraceptive benefits. Over the years, advances in the laboratory and knowledge gained through epidemiologic data promoted the development of new contraceptive preparations. Generations of oral contraceptives emerged over time, containing lower doses of estrogens and new and novel progestins. The current review discusses the clinical characteristics of oral contraceptives, with emphasis on basic pharmacology and the evolution of various contraceptive formulations and regimens. PMID- 26960907 TI - Permanent Contraception for Women. AB - Permanent contraception is a highly desired and commonly used contraceptive option for women around the world who desire never to become pregnant. Current methods of female permanent contraception require surgery. Postpartum tubal ligation and interval surgical tubal ligation are safe and effective, do not interfere with menstrual cycles, and require no ongoing cost or medical checkups. Hysteroscopic tubal occlusion offers a less invasive surgical approach, but requires an imaging study for verification of correct placement. However, not all women have access to a surgeon trained to provide permanent contraception, or they may face other prohibitive logistic or financial burdens. The development of novel permanent contraception methods that are immediately effective and/or nonsurgical could help improve access to and acceptability of permanent contraception. The expansion of permanent contraception options could help women achieve their family planning goals and reduce unintended pregnancies. PMID- 26960909 TI - The changing uses of accuracy in science communication. AB - Tracing its historical trajectories, this article explores the preoccupation with accuracy in science communication research and explores the resurgence in the present century of concerns about accuracy, balance and impartiality in public communication of science. It is argued that many of the original insights from news and journalism research are still relevant and important if re-formulated in constructionist terms about voice, access and claims-making, and asking, in whose interest? Key to this is also the recognition of a radically changing - technologically, economically and professionally - media and communications environment, with implications for science journalism and a very different dynamic regarding the range and type of actors involved in discursively constructing opinions and information about controversial science and expertise. The article concludes with proposals for future emphases and directions in research broadly concerned with accuracy in science communication. PMID- 26960908 TI - DBS-platform for biomonitoring and toxicokinetics of toxicants: proof of concept using LC-MS/MS analysis of fipronil and its metabolites in blood. AB - A simple, sensitive and high throughput LC-MS/MS method was developed and validated for quantification of fipronil, fipronil sulfone and fipronil desulfinyl in rat and human dried blood spots (DBS). DBS samples were prepared by spiking 10 MUl blood on DMPK-C cards followed by drying at room temperature. The whole blood spots were then punched from the card and extracted using acetonitrile. The total chromatographic run time of the method was only 2 min. The lower limit of quantification of the method was 0.1 ng/ml for all the analytes. The method was successfully applied to determine fipronil desulfinyl in DBS samples obtained from its toxicokinetic study in rats following intravenous dose (1 mg/kg). In conclusion, the proposed DBS methodology has significant potential in toxicokinetics and biomonitoring studies of environmental toxicants. This microvolume DBS technique will be an ideal tool for biomonitoring studies, particularly in paediatric population. Small volume requirements, minimally invasive blood sampling method, easier storage and shipping procedure make DBS a suitable technique for such studies. Further, DBS technique contributes towards the principles of 3Rs resulting in significant reduction in the number of rodents used and refinement in sample collection for toxicokinetic studies. PMID- 26960910 TI - Predictors of trust in the general science and climate science research of US federal agencies. AB - In this article, we focus on a key strategic objective of scientific organizations: maintaining the trust of the public. Using data from a nationally representative survey of American adults ( n = 1510), we assess the extent to which demographic factors and political ideology are associated with citizens' trust in general science and climate science research conducted by US federal agencies. Finally, we test whether priming individuals to first consider agencies' general science research influences trust in their climate science research, and vice versa. We found that federal agencies' general science research is more trusted than their climate science research-although a large minority of respondents did not have an opinion-and that political ideology has a strong influence on public trust in federal scientific research. We also found that priming participants to consider general scientific research does not increase trust in climate scientific research. Implications for theory and practice are discussed. PMID- 26960911 TI - Integrated mRNA and miRNA expression profiling in blood reveals candidate biomarkers associated with endurance exercise in the horse. AB - The adaptive response to extreme endurance exercise might involve transcriptional and translational regulation by microRNAs (miRNAs). Therefore, the objective of the present study was to perform an integrated analysis of the blood transcriptome and miRNome (using microarrays) in the horse before and after a 160 km endurance competition. A total of 2,453 differentially expressed genes and 167 differentially expressed microRNAs were identified when comparing pre- and post ride samples. We used a hypergeometric test and its generalization to gain a better understanding of the biological functions regulated by the differentially expressed microRNA. In particular, 44 differentially expressed microRNAs putatively regulated a total of 351 depleted differentially expressed genes involved variously in glucose metabolism, fatty acid oxidation, mitochondrion biogenesis, and immune response pathways. In an independent validation set of animals, graphical Gaussian models confirmed that miR-21-5p, miR-181b-5p and miR 505-5p are candidate regulatory molecules for the adaptation to endurance exercise in the horse. To the best of our knowledge, the present study is the first to provide a comprehensive, integrated overview of the microRNA-mRNA co regulation networks that may have a key role in controlling post-transcriptomic regulation during endurance exercise. PMID- 26960912 TI - Enhancing the use of Asthma and COPD Assessment Tools in Balearic Primary Care (ACATIB): a region-wide cluster-controlled implementation trial. AB - Asthma and chronic obstructive pulmonary disease (COPD) health status assessment tools have demonstrated their value in guiding clinical management. Their use in primary care is still suboptimal. The objective of this study was to assess the effect of an educational intervention programme on the use of the Asthma Control Test (ACT), modified Medical Research Council (mMRC) and COPD Assessment Test (CAT) among primary care settings of the Balearic Islands, Spain. In this region wide cluster-controlled implementation study, an educational intervention on the use of respiratory health status tools was provided to primary care practices in Mallorca (intervention group). Practices in Ibiza and Menorca functioned as control practices. Written and multimedia materials were provided to all participants to educate their colleagues. Primary outcome was the difference between intervention and control practices in the percentage of practices that increased the use-and recording-of ACT, CAT and mMRC tests between the 6-month period before intervention and the 6-month period after intervention. In the intervention group, 32 out of 45 (71%) centres enhanced the total number of tests, compared with 4 out of 12 (33%) in the non-intervention group (chi(2); P=0.02). Before intervention, 399 test scores were recorded in 88,194 patients (asthma: 57,339; COPD: 30,855). After intervention, 1,576 test scores were recorded in 92,714 patients (asthma: 61,841; COPD: 30,873). An educational intervention programme targeted on primary care physicians enhances the use of respiratory health status tools and promotes behavioural changes. However, the effect is very low and difficult to measure in clinical terms. PMID- 26960913 TI - Hemiarthroplasty Versus Total Shoulder Arthroplasty for Shoulder Osteoarthritis: A Matched Comparison of Return to Sports. AB - BACKGROUND: Return to activity is a commonly used indication for shoulder hemiarthroplasty (HA) compared with total shoulder arthroplasty (TSA). Despite clinical studies demonstrating better functional outcomes after TSA, the literature has failed to show a difference in return to sports. PURPOSE: To compare rates of return to sports in a matched cohort of TSA and HA patients with a preoperative diagnosis of glenohumeral osteoarthritis (OA). STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A prospectively collected registry was queried retrospectively for consecutive patients who underwent HA. Inclusion criteria were preoperative diagnosis of OA and more than 2 years of follow-up. After meeting the inclusion criteria, all HA patients were statistically matched to a TSA patient. All patients had end-stage OA with significant glenohumeral joint space narrowing. RESULTS: At final follow-up, 40 HA patients and 40 TSA patients were available. The average (+/-SD) age at surgery was 65.7 +/- 10.5 years and 66.2 +/- 9.6 years for the HA and TSA groups, respectively (P = .06). Average follow-up was 62.0 months and 61.1 months for the HA and TSA groups, respectively (P = .52). Average American Shoulder and Elbow Surgeons scores improved from 36.3 to 70.2 for HA patients and from 34.0 to 78.5 for TSA patients (P < .001 for both); final scores were not significantly different between groups (P = .21). Average visual analog scale pain scores improved from 6.3 to 2.2 for HA patients and from 6.1 to 0.6 for TSA patients (P < .001 for both). HA patients had significantly worse final visual analog scale scores compared with the TSA group (P = .002). Significantly more TSA patients were satisfied with their surgery compared with HA patients (100% vs 70%) (P = .01). Of both groups, 65.5% of HA patients (19 of 29) returned to at least 1 sport postoperatively compared with 97.3% of TSA patients (36 of 37) (P < .001). Average timing for return to full sports was 5.5 +/- 4.2 months and 5.4 +/- 3.1 months for the HA and TSA groups, respectively (P = .92). Significantly more TSA patients returned to higher upper extremity use sports (P = .01). CONCLUSION: In patients with OA, rate of return to sports was significantly better after TSA compared with HA. HA patients had significantly more pain, worse surgical satisfaction, and decreased ability to return to high upper extremity use sports. For patients with OA who wish to return to sporting activities, these results help manage expectations. PMID- 26960915 TI - Rhinoplasty for the Cleft Lip and Palate Patient. AB - Septorhinoplasties in cleft patients are challenging procedures to perform for even the most experienced surgeon. Unilateral cleft rhinoplasties present a unique challenge given that the tissue bed has had previous manipulation and scarring is found around the tissue matrix, making it typically necessary to place several sturdy cartilaginous grafts to provide structural support. Rib graft provides an abundance of cartilage that can be used for multiple areas. The ability to manipulate and adjust the thickness of the cartilage strut allows for improved integrity of the graft to resist deformation and warping from the formant scar tissue. PMID- 26960914 TI - Endoscopic ultrasound-guided fine needle core biopsy for the diagnosis of pancreatic malignant lesions: a systematic review and Meta-Analysis. AB - Endoscopic ultrasound-guided fine needle core biopsy (EUS-FNB) has been used as an effective method of diagnosing pancreatic malignant lesions. It has the advantage of providing well preserved tissue for histologic grading and subsequent molecular biological analysis. In order to estimate the diagnostic accuracy of EUS-FNB for pancreatic malignant lesions, studies assessing EUS-FNB to diagnose solid pancreatic masses were selected via Medline. Sixteen articles published between 2005 and 2015, covering 828 patients, met the inclusion criteria. The summary estimates for EUS-FNB differentiating malignant from benign solid pancreatic masses were: sensitivity 0.84 (95% confidence interval (CI), 0.82-0.87); specificity 0.98 (95% CI, 0.93-1.00); positive likelihood ratio 8.0 (95% CI 4.5-14.4); negative likelihood ratio 0.17 (95% CI 0.10-0.26); and DOR 64 (95% CI 30.4-134.8). The area under the sROC curve was 0.96. Subgroup analysis did not identify other factors that could substantially affect the diagnostic accuracy, such as the study design, location of study, number of centers, location of lesion, whether or not a cytopathologist was present, and so on. EUS FNB is a reliable diagnostic tool for solid pancreatic masses and should be especially considered for pathology where histologic morphology is preferred for diagnosis. PMID- 26960916 TI - Metal-Diazo Radicals of alpha-Carbonyl Diazomethanes. AB - Metal-diazo radicals of alpha-carbonyl diazomethanes are new members of the radical family and are precursors to metal-carbene radicals. Herein, using electron paramagnetic resonance spectroscopy with spin-trapping, we detect diazo radicals of alpha-carbonyl diazomethanes, induced by [Rh(I)Cl(cod)]2, [Co(II)(por)] and PdCl2, at room temperature. The unique quintet signal of the Rh diazo radical was observed in measurements of alpha-carbonyl diazomethane adducts of [Rh(I)Cl(cod)]2 in the presence of 5,5-dimethyl-pyrroline-1-N-oxide (DMPO). DFT calculations indicated that 97.2% of spin density is localized on the diazo moiety. Co- and Pd-diazo radicals are EPR silent but were captured by DMPO to form spin adducts of DMPO-N? (triplet-of-sextets signal). The spin-trapping also provides a powerful tool for detection of metal-carbene radicals, as evidenced by the DMPO-trapped carbene radicals (DMPO-C?, sextet signal) and 2-methyl-2 nitrosopropane-carbene adducts (MNP-C?, doublet-of-triplets signal). The transformation of alpha-carbonyl diazomethanes to metal-carbene radicals was confirmed to be a two-step process via metal-diazo radicals. PMID- 26960917 TI - Impact of hypertension on the lifetime risk of coronary heart disease. AB - The lifetime risk estimate conveys the probability of disease in the remaining lifetime for an index age. These estimates may be useful for general audience targeted knowledge translation activities against hypertension. There are only a few reports on the impact of hypertension on the lifetime risk of cardiovascular events. The Suita Study, a cohort study of urban residents, was established in 1989. We included all participants who were coronary heart disease (CHD) free at baseline. Age (in years) was used as the timescale. Age-specific incidence rates were calculated with the person-year method within 5-year bands. We estimated the sex- and index-age-specific lifetime risk of first-ever CHD, taking the competing risk of death into account. We followed 5834 participants from 1989 to 2007 for a total of 75 387.5 person-years. At age 45 years, the competing risk of death adjusted lifetime risk for all CHD for men was 14.12% for normotensive men and 26.95% for hypertensive men. The competing risk of death-adjusted lifetime risk for all CHD at 45 years of age for women was 6.21% for normotensive women and 14.85% for hypertensive women. This increased lifetime risk of CHD for hypertensive patients was observed among both men and women across all index ages. Although the overall lifetime risk of CHD was lower than in the Western population, hypertension showed a significant effect on the residual lifetime risk of CHD among Japanese middle-aged men and women. This easy-to-understand knowledge may be used as an important index to assist public health education and planning. PMID- 26960919 TI - Extubating Extremely Preterm Infants: Predictors of Success and Outcomes following Failure. AB - OBJECTIVES: To identify variables that predict extubation success in extremely preterm infants born <28 weeks gestational age (GA), and to compare outcomes between those who had successful or failed extubation. STUDY DESIGN: A secondary analysis of data from a randomized trial of postextubation respiratory support that included 174 extremely preterm infants. "Extubation success" was defined as not requiring reintubation within 7 days, and "extubation failure" the converse. Predictive variables that were different between groups were included in a multivariable logistic regression model. RESULTS: Sixty-eight percent of infants were successfully extubated. Compared with those infants who had extubation failure, they had a higher GA and birth weight, were extubated earlier, were more often exposed to prolonged ruptured membranes, more often avoided intubation in the delivery room, had a higher pre-extubation pH, and had lower mean pre extubation fraction of inspired oxygen and partial pressure of carbon dioxide (PCO2). Only GA and PCO2 remained significant in the multivariable analysis (area under a receiver operating characteristic curve = 0.81). Extubation failure was associated with death, bronchopulmonary dysplasia, severe retinopathy of prematurity, patent ductus arteriosus ligation, and longer durations of respiratory support, oxygen supplementation, and hospitalization. When adjusted for allocated treatment in the randomized trial, GA, and birth weight z-score, extubation failure remained associated with death before discharge and prolonged respiratory support and hospitalization. CONCLUSIONS: In extremely preterm infants, higher GA and lower pre-extubation PCO2 predicted extubation success. Infants in whom extubation failed were more likely to die and have prolonged respiratory support and hospitalization. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Network: ACTRN12610000166077. PMID- 26960918 TI - Areas with High Rates of Police-Reported Violent Crime Have Higher Rates of Childhood Asthma Morbidity. AB - OBJECTIVES: To assess whether population-level violent (and all) crime rates were associated with population-level child asthma utilization rates and predictive of patient-level risk of asthma reutilization after a hospitalization. STUDY DESIGN: A retrospective cohort study of 4638 pediatric asthma-related emergency department visits and hospitalizations between 2011 and 2013 was completed. For population-level analyses, census tract asthma utilization rates were calculated by dividing the number of utilization events within a tract by the child population. For patient-level analyses, hospitalized patients (n = 981) were followed until time of first asthma-related reutilization. The primary predictor was the census tract rate of violent crime as recorded by the police; the all crime (violent plus nonviolent) rate was also assessed. RESULTS: Census tract level violent and all crime rates were significantly correlated with asthma utilization rates (both P < .0001). The violent crime rate explained 35% of the population-level asthma utilization variance and remained associated with increased utilization after adjustment for census tract poverty, unemployment, substandard housing, and traffic exposure (P = .002). The all crime rate explained 28% of the variance and was similarly associated with increased utilization after adjustment (P = .02). Hospitalized children trended toward being more likely to reutilize if they lived in higher violent (P = .1) and all crime areas (P = .01). After adjustment, neither relationship was significant. CONCLUSIONS: Crime data could help facilitate early identification of potentially toxic stressors relevant to the control of asthma for populations and patients. PMID- 26960920 TI - Extremely Preterm-Born Infants Demonstrate Different Facial Recognition Processes at 6-10 Months of Corrected Age. AB - OBJECTIVES: To compare cortical hemodynamic responses to known and unknown facial stimuli between infants born extremely preterm and term-born infants, and to correlate the responses of the extremely preterm-born infants to regional cortical volumes at term-equivalent age. STUDY DESIGN: We compared 27 infants born extremely preterm (<28 gestational weeks) with 26 term-born infants. Corrected age and chronological age at testing were between 6 and 10 months, respectively. Both groups were exposed to a gray background, their mother's face, and an unknown face. Cerebral regional concentrations of oxygenated and deoxygenated hemoglobin were measured with near-infrared spectroscopy. In the preterm group, we also performed structural brain magnetic resonance imaging and correlated regional cortical volumes to hemodynamic responses. RESULTS: The preterm-born infants demonstrated different cortical face recognition processes than the term-born infants. They had a significantly smaller hemodynamic response in the right frontotemporal areas while watching their mother's face (0.13 MUmol/L vs 0.63 MUmol/L; P < .001). We also found a negative correlation between the magnitude of the oxygenated hemoglobin increase in the right frontotemporal cortex and regional gray matter volume in the left fusiform gyrus and amygdala (voxels, 25; r = 0.86; P < .005). CONCLUSION: At 6-10 months corrected age, the preterm-born infants demonstrated a different pattern in the maturation of their cortical face recognition process compared with term-born infants. PMID- 26960921 TI - Initial Presentation of Neonatal Herpes Simplex Virus Infection. AB - OBJECTIVE: To inform the decision to test and empirically treat for herpes simplex virus (HSV) by describing the initial clinical presentation and laboratory findings of infants with a confirmed diagnosis of neonatal HSV. STUDY DESIGN: This is a retrospective case series performed at 2 pediatric tertiary care centers. Infants who developed symptoms prior to 42 days of age with laboratory confirmed HSV from 2002 through 2012 were included. We excluded infants <34 weeks gestation, those who developed illness before discharge from their birth hospital, and those who developed symptoms after 42 days of age. RESULTS: We identified 49 infants with HSV meeting these criteria. Most infants (43/49, 88%) came to medical attention at <=28 days. Of 49 infants, 22 (45%) had disseminated, 16 (33%) central nervous system, and 10 (20%) skin, eye, mouth HSV disease. Eight infants (16%) had nonspecific presentations without the classic signs of seizure, vesicular rash, or critical illness (intensive care admission). All infants with nonspecific presentation were <=14 days, had cerebrospinal fluid pleocytosis, or both. CONCLUSIONS: The majority of infants with HSV (84%) presented with seizure, vesicular rash, or critical illness. A subset of patients (16%) lacked classic signs at hospitalization; most manifested signs suggestive of HSV within 24 hours. Further studies are needed to validate the risk factors identified in this study including age <14 days and cerebrospinal fluid pleocytosis at presentation. PMID- 26960922 TI - Stability of titania nanotube arrays in aqueous environment and the related factors. AB - Titania nanotube arrays (NTAs) on titanium (Ti) fabricated by electrochemical anodization have attracted tremendous interest for diverse applications, of which most perform in aqueous environment or related to interaction with water. The NTAs are widely studied however the related factor of stability of NTAs when applied in such environment has rarely been concerned. We report that the annealed anatase NTAs are stable but the non-annealed amorphous NTAs are unstable to undergo specific structural change accompanied with a process of amorphous TiO2 dissolution and anatase TiO2 recrystallization. Quite unexpectedly, the non annealed NTAs still show good stability without structural change in the cell culture media, possibly due to the presence of inorganics that may interfere with the TiO2 dissolution/redeposition process. The pH value of the aqueous environment is not a determinant factor for the structural change for non annealed NTAs or not, while the temperature and the existence of F(-) can accelerate the structural change process. F(-) may play a very important role in the change process. PMID- 26960924 TI - The normal-weight type 2 diabetes phenotype revisited. AB - BACKGROUND: Type 2 diabetes (T2DM) is associated with obesity, insulin resistance and the metabolic syndrome (MetS). In non-diabetic populations, features of metabolic obesity (MO) are observed in a minority of normal-weight (NW) subjects. The cardiometabolic status of metabolically obese but normal-weight (MONW) individuals has not yet been phenotyped in T2DM. PATIENTS AND METHODS: Prevalence and features of MONW were analyzed in 1244 T2DM patients, in whom MONW was identified as a BMI <25.0 and a MetS score >=3/5. Among NW (n=262; 21%), those without MetS (n=152; NW-MetS[-]) were compared to NW-MetS[+] (n=110; i.e. 42% of NW and 9% of all T2DM). RESULTS: There were no differences between groups in age; gender; diabetes duration; smoking; BP; and LDL-C. NW-MetS[+] had higher BMI; waist; fat mass; visceral fat; liver steatosis and HbA1c, and lower insulin sensitivity. Non-right-handedness was twice-higher (18%) in NW-MetS[-]. NW MetS[+] had higher apoB100 and triglycerides, and lower HDL-C and LDL size. Macroangiopathy was present in 39% of NW-MetS[+] vs. 22% of NW-MetS[-], as coronary (23% vs. 14%) or peripheral artery disease (14% vs. 5%) and TIA/stroke (15% vs. 7%). Microangiopathy was present in 54% of NW-MetS[+] vs. 32% of NW MetS[-], as retinopathy (25% vs. 13%); neuropathy (29% vs. 18%); and albuminuria (39% vs. 20%). CONCLUSIONS: MONW among T2DM represents a significant minority (about 1 in 10). Their cardiometabolic phenotype deserves attention due to multiple comorbidities, including a twice-higher prevalence of micro /macrovascular damage in patients wrongly perceived at lower risk due to normal BMI. Unexpectedly, non-right-handedness was over-represented among metabolically healthy patients. PMID- 26960923 TI - Three mechanisms control E-cadherin localization to the zonula adherens. AB - E-cadherin localization to the zonula adherens is fundamental for epithelial differentiation but the mechanisms controlling localization are unclear. Using the Drosophila follicular epithelium we genetically dissect E-cadherin transport in an in vivo model. We distinguish three mechanisms mediating E-cadherin accumulation at the zonula adherens. Two membrane trafficking pathways deliver newly synthesized E-cadherin to the plasma membrane. One is Rab11 dependent and targets E-cadherin directly to the zonula adherens, while the other transports E cadherin to the lateral membrane. Lateral E-cadherin reaches the zonula adherens by endocytosis and targeted recycling. We show that this pathway is dependent on RabX1, which provides a functional link between early and recycling endosomes. Moreover, we show that lateral E-cadherin is transported to the zonula adherens by an apically directed flow within the plasma membrane. Differential activation of these pathways could facilitate cell shape changes during morphogenesis, while their misregulation compromises cell adhesion and tissue architecture in differentiated epithelia. PMID- 26960926 TI - Glycemic index and glycemic load and risk of colorectal cancer: a population based cohort study (JPHC Study). AB - PURPOSE: The aim of this study was for the first time to assess the association between glycemic index (GI), glycemic load (GL), and colorectal cancer using a prospective Japanese population-based cohort. METHODS: In our study participants aged 40-69 at baseline of the Japan Public Health Center-based prospective Study (JPHC Study) in 10 prefectural public health centers (PHC) were included. Subjects responding to the five-year follow-up survey (1995-1999) without previous history of cancer and missing data were included in the current analysis n = 73,501 (men n = 34,560 and women n = 38,941). We reported results as hazard ratios (HR) and 95% confidence intervals (CI) by Cox proportional hazards modeling. RESULTS: The average follow-up time was 12.5 years (919,276 person years). A total of 1,468 colorectal cancer cases were detected. Overall, no significant results were observed; however, GL was inversely nonsignificantly associated with colon cancer in men HR = 0.74 (95% CI 0.51-1.09) and rectal cancer in women 0.52 (95% CI 0.24-1.14). The GL tended to be inversely associated with proximal colon cancer among men 0.62 (95% CI 0.36-1.08), while a positive association with the GI was observed among women 1.37 (95% CI 0.88-2.14). Sensitivity analyses excluding the first three years of observation showed similar results. Results stratified by diabetes status, BMI, smoking and red meat were nonsignificant. CONCLUSIONS: In conclusion, the prospective JPHC Study suggests that the GI and GL do not have a substantial impact on the risk of colorectal cancer in Japanese adults. PMID- 26960925 TI - Public health impacts of city policies to reduce climate change: findings from the URGENCHE EU-China project. AB - BACKGROUND: Climate change is a global threat to health and wellbeing. Here we provide findings of an international research project investigating the health and wellbeing impacts of policies to reduce greenhouse gas emissions in urban environments. METHODS: Five European and two Chinese city authorities and partner academic organisations formed the project consortium. The methodology involved modelling the impact of adopted urban climate-change mitigation transport, buildings and energy policy scenarios, usually for the year 2020 and comparing them with business as usual (BAU) scenarios (where policies had not been adopted). Carbon dioxide emissions, health impacting exposures (air pollution, noise and physical activity), health (cardiovascular, respiratory, cancer and leukaemia) and wellbeing (including noise related wellbeing, overall wellbeing, economic wellbeing and inequalities) were modelled. The scenarios were developed from corresponding known levels in 2010 and pre-existing exposure response functions. Additionally there were literature reviews, three longitudinal observational studies and two cross sectional surveys. RESULTS: There are four key findings. Firstly introduction of electric cars may confer some small health benefits but it would be unwise for a city to invest in electric vehicles unless their power generation fuel mix generates fewer emissions than petrol and diesel. Second, adopting policies to reduce private car use may have benefits for carbon dioxide reduction and positive health impacts through reduced noise and increased physical activity. Third, the benefits of carbon dioxide reduction from increasing housing efficiency are likely to be minor and co-benefits for health and wellbeing are dependent on good air exchange. Fourthly, although heating dwellings by in-home biomass burning may reduce carbon dioxide emissions, consequences for health and wellbeing were negative with the technology in use in the cities studied. CONCLUSIONS: The climate-change reduction policies reduced CO2 emissions (the most common greenhouse gas) from cities but impact on global emissions of CO2 would be more limited due to some displacement of emissions. The health and wellbeing impacts varied and were often limited reflecting existing relatively high quality of life and environmental standards in most of the participating cities; the greatest potential for future health benefit occurs in less developed or developing countries. PMID- 26960928 TI - Laparoscopic Insulinoma Enucleation from the Retro-Pancreatic Neck: A Stepwise Approach. AB - BACKGROUND: Enucleation is the preferred surgical management of small, likely benign, insulinomas. Sparing pancreatic parenchyma and minimizing morbidity are of greater importance in these patients due to their anticipated long survival time. Although a laparoscopic approach is ideal, it can be particularly challenging when the insulinoma is retropancreatic or adjacent to critical vascular structures [i.e., superior mesenteric vein-portal vein confluence (SMV PV)]. PATIENT: A 35-year-old woman with neuroglycopenic symptoms and hypoglycemia was diagnosed with hyperinsulinemia. Preoperative CT and EUS-FNA confirmed a 6- * 9-mm neuroendocrine tumor in the parenchyma of the posterior pancreatic neck along the left lateral aspect of the SMV-PV. TECHNIQUE: With the patient in stirrups and arms tucked (French Position), the lesser sac was opened to expose the pancreatic body. A retropancreatic tunnel was created anterior to the SMV-PV and the pancreatic neck encircled with umbilical tape to allow for retraction while minimizing pancreatic manipulation. The insulinoma was definitively identified using intraoperative ultrasound (IOUS). IOUS-guided clip placement facilitated direct identification and permitted safe image-guided enucleation. The enucleation was performed at the parenchymal interface, minimizing the risk of main pancreatic duct injury. CONCLUSIONS: Complete pancreatic neck mobilization and view through the laparoscope along the axis of the PV can facilitate exposure at the challenging location of the retropancreatic neck. Transpancreatic IOUS guidance is crucial to identify and safely enucleate small insulinomas in this location. This totally minimally invasive approach can reduce the morbidity of pancreatic surgery for these patients and permit organ-sparing despite the challenging anatomic location. PMID- 26960927 TI - Is Sentinel Lymph Node Biopsy Indicated at Completion Mastectomy for Ductal Carcinoma In Situ? AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) is recommended when mastectomy is performed for ductal carcinoma in situ (DCIS). The role of SLNB for women with DCIS who undergo mastectomy following one or more attempts at breast-conserving surgery (BCS) is uncertain. We examined the upgrade rate and SLNB yield in women who converted to mastectomy after one or more attempts at BCS for DCIS. METHODS: All patients who underwent one or more attempts at BCS prior to conversion to mastectomy with SLNB for DCIS were identified. Margin status as the indication for mastectomy was confirmed, and comparisons were made between patients with/without upgrade on final pathology. RESULTS: From February 2006 to November 2012, a total of 233 patients underwent completion mastectomy following one or more attempts at BCS for positive/close margins (median age 50 years; range 34 84). The median number of BCS attempts was 1 (range 1-4). Overall, 20 (9 %) patients were upgraded on final pathology; 15 (6 %) stage I, and 5 (3 %) stage II (three micrometastasis, two macrometastasis). In two of five cases with a positive SLN, invasive carcinoma was not identified in the mastectomy specimen. The only factor associated with any upgrade was the presence of micropapillary DCIS (80 vs. 55 %, with and without upgrade; p = 0.03). CONCLUSION: In this cohort of patients with DCIS who converted to mastectomy for positive/close margins after one or more attempts at BCS, 18 (8 %) would have required second stage axillary surgery had an SLNB not been performed, and in two (1 %) patients, the SLN provided the only evidence of invasion. These findings support the recommendation for SLNB at the time of completion mastectomy. PMID- 26960929 TI - Intraductal Papilloma with Benign Pathology on Breast Core Biopsy: To Excise or Not? AB - BACKGROUND: The management of intraductal papillomas on core biopsy continues to be controversial. Papillomas with atypia are typically excised. However, it is unclear whether surgical excision is warranted for benign lesions. METHODS: A retrospective review of our institution's pathology and radiology databases from January 2009 through May 2014 identified 119 patients with a diagnosis of benign papilloma without atypia on core biopsy. We determined the rate of carcinoma identification on surgical excision. RESULTS: The average patient age was 52.8 years (range 24-84 years). Indication for core biopsy included: abnormal imaging (n = 106), nipple discharge (n = 21), or palpable mass (n = 24). Seventy-five patients underwent surgical excision after core biopsy. Sixteen patients (21.3 %) had atypia in the excision specimen (combination atypical ductal hyperplasia, n = 11; atypical lobular hyperplasia, n = 8; lobular carcinoma-in situ, n = 3), 15 (93.8 %) of which were in the surrounding breast tissue. Two patients (2.7 %) had malignancy (ductal carcinoma-in situ and micropapillary carcinoma-in situ). As a result of surgical findings, 12 % of patients had a change in management. In comparing those with benign findings on surgical pathology and those whose disease was upstaged, there was no statistically significant difference in family history of breast cancer, indication for core biopsy, mammographic findings, or location of papilloma. CONCLUSIONS: Benign papillomas diagnosed on core biopsy are rarely upstaged to malignancy on surgical excision. However, at least 21 % of patients may have atypical findings in the surrounding tissue, which could change clinical management. Surgical excision should be considered in patients with benign papillomas. PMID- 26960930 TI - Biliary hemostasis using an endoscopic plastic stent placement for uncontrolled hemobilia caused by transpapillary forceps biopsy (with video). AB - A 78-year-old woman was referred to our hospital for the examination and treatment of jaundice. A transpapillary forceps biopsy for a long distal bile duct stricture was performed using endoscopic retrograde cholangiopancreatography. Immediately after the biopsy, massive bleeding was observed from the orifice of the papilla. Although hemobilia was pulsatile, an endoscopic biliary plastic stent placement was very effective in achieving hemostasis. However, a nasal biliary catheter was required because a blood clot clogged the stent on the following day. Although covered self-expandable metal stent (CSEMS) placement has been reported for achieving endoscopic hemostasis for bleeding, we chose to use a plastic stent to reduce the risk of post-procedure pancreatitis. The placement of both an endoscopic biliary plastic stent and a nasobiliary drainage catheter can be an alternative hemostatic tool to CSEMSs. PMID- 26960931 TI - Recent Developments in Pediatric Community-Acquired Pneumonia. AB - Community-acquired pneumonia (CAP) is the most common acute infectious cause of death in children worldwide. Consequently, research into the epidemiology, diagnosis, treatment, and prevention of pediatric CAP spans the translational research spectrum. Herein, we aim to review the most significant findings reported by investigators focused on pediatric CAP research that has been reported in 2014 and 2015. Our review focuses on several key areas relevant to the clinical management of CAP. First, we will review recent advances in the understanding of CAP epidemiology worldwide, including the role of vaccination in the prevention of pediatric CAP. We also report on the expanding role of existing and emerging diagnostic technologies in CAP classification and management, as well as advances in optimizing antimicrobial use. Finally, we will review CAP management from the policy and future endeavors standpoint, including the influence of clinical practice guidelines on clinician management and patient outcomes, and future potential research directions that are in the early stages of investigation. PMID- 26960933 TI - From Mind to Context, from Accuracy to Meaning. Exploring the Grammar of Remembering as a Socially Situated Act. AB - This paper begins by addressing the so-called memory crisis, a crisis which, since the 90s, has problematized the traditional manner in which memory is studied and understood. Special attention is paid to the changing role attributed to accuracy and meaning when remembering the past. In light of this crisis, I comment on Smorti and Fioretti's paper (2015), focusing on the point that they make regarding how autobiographical narratives affect and change autobiographical memories. Complementing that view, according to which memories are transformed when they are externalized through a communicative act by means of narratives, this paper focuses on a more narrative and situated approach to memory, shifting from mind to social settings, from accuracy to meaning. Building on that approach, I briefly discuss the notion of event as a narrative construction. Finally, drawing on Burke's pentad model (1969), I put forward a framework for studying remembering as a situated activity. The pentad of elements are addressed as follows: 1) Agency, or the mediational means for the construction of past events; 2) Act, or remembering as a reconstructive activity; 3) Scene, or the social dynamics of remembering; 4) Agent, or subjective positionings when reconstructing the past; and 5) Purpose, or uses of the past in relation to the future. PMID- 26960934 TI - Institutional Guidance of Affective Bonding: Moral Values Development in Brazilian Military Education. AB - In this article, our aim is to analyze institutional practices guided to promote the development of moral values within the context of military education of Brazilian Army combatant commissioned officers. From a cultural psychological approach, we discuss how social guidance within military culture operates at different levels of the affective-semiotic regulation of individuals, structuring complex experiences that give rise to hypergeneralized meaning fields regarding morality and military values. For this goal, we first introduce some theoretical topics related to values development, emphasizing their affective roots and role in the emergence, maintenance, amplification and attenuation of all relations between the person and the environment. Following a brief discussion on how social institutions try to promote changes in personal values, we provide an overview of values present in the military culture and socialization. Finally, the text focuses on the education of Brazilian Army combatant commissioned officers, describing how practices related to different levels of affective semiotic experience combine in order to promote the internalization and externalization of specific moral values. We conclude suggesting issues for future investigation. PMID- 26960932 TI - Systemic delivery of chTNT-3/CpG immunoconjugates for immunotherapy in murine solid tumor models. AB - CpG oligodeoxynucleotides (CpG) potently activate the immune system by mimicking microbial DNA. Conjugation of CpG to chTNT-3, an antibody targeting the necrotic centers of tumors, enabled CpG to accumulate in tumors after systemic delivery, where it can activate the immune system in the presence of tumor antigens. CpG chemically conjugated to chTNT-3 (chTNT-3/CpG) were compared to free CpG in their ability to stimulate the immune system in vitro and reduce tumor burden in vivo. In subcutaneous Colon 26 adenocarcinoma and B16-F10 melanoma models in BALB/c and C57BL/6 mice, respectively, chTNT-3/CpG, free CpG, or several different control constructs were administered systemically. Intraperitoneal injections of chTNT 3/CpG delayed tumor growth and improved survival and were comparable to intratumorally administered CpG. Compared to saline-treated mice, chTNT-3/CpG treated mice had smaller average tumor volumes by as much as 72% in Colon 26 bearing mice and 79% in B16-bearing mice. Systemically delivered free CpG and CpG conjugated to an isotype control antibody did not reduce tumor burden or improve survival. In this study, chTNT-3/CpG retained immunostimulatory activity of the CpG moiety and enabled delivery to tumors. Because systemically administered CpG rapidly clear the body and do not accumulate into tumors, chTNT-3/CpG provide a solution to the limitations observed in preclinical and clinical trials. PMID- 26960935 TI - Inhibition of store-operated calcium entry by sub-lethal levels of proteasome inhibition is associated with STIM1/STIM2 degradation. AB - Dysfunction of the ubiquitin-proteasome system (UPS) and calcium homeostasis has been implicated in the neurodegeneration of Alzheimer's and Parkinson's diseases. The cytosolic calcium concentration is maintained by store-operated calcium entry (SOCE), which is repressed by Alzheimer's disease-associated mutants, such as mutant presenilins. We hypothesized that inhibition of UPS impacts SOCE. This study showed that pretreatment with sub-lethal levels of proteasome inhibitors, including MG-132 and clasto-lactacystin-beta-lactone (LA), reduced SOCE after depletion of endoplasmic reticulum calcium in rat neurons. With the same treatment, MG-132 and LA reduced the protein levels of stromal interaction molecule 1and 2 (STIM1/2), but not the levels of Orai1 and canonical transient receptor potential channel 1 (TRPC1). STIM1 or STIM2 protein was mobilized to lysosome by MG-132/LA treatment as observed under an immunofluorescence confocal laser microscope. In the neurons, MG-132 and LA degraded p62/SQSTM1, promoted autophagy, converted LC3I to LC3II, and promoted co-localization of LC3 and lysosomes. Rapamycin, which enhances autophagy, reduced STIM1/2 protein levels, whereas bafilomycin, which inhibits autophagy, increased their protein levels. The protein levels of STIM1/2 and the amplitude of SOCE were decreased in SH-SY5Y with decreased protein level of proteasome subunit beta type-5 induced by shRNA. We conclude that sub-lethal levels of proteasome inhibition reduce SOCE and promote autophagy-mediated degradation of STIM1/2. UPS inhibition, a common finding in neurodegenerative diseases, interferes with calcium homeostasis via repression of SOCE. PMID- 26960937 TI - Calcium signalling in stem cells: Molecular physiology and multiple roles. PMID- 26960936 TI - Calcium signalling in pancreatic stellate cells: Mechanisms and potential roles. AB - Hepatic and pancreatic stellate cells may or may not be regarded as stem cells, but they are capable of remarkable transformations. There is less information about stellate cells in the pancreas than in the liver, where they were discovered much earlier and therefore have been studied longer and more intensively than in the pancreas. Most of the work on pancreatic stellate cells has been carried out in studies on cell cultures, but in this review we focus attention on Ca(2+) signalling in stellate cells in their real pancreatic environment. We review current knowledge on patho-physiologically relevant Ca(2+) signalling events and their underlying mechanisms. We focus on the effects of bradykinin in the initial stages of acute pancreatitis, an often fatal disease in which the pancreas digests itself and its surroundings. Ca(2+) signals, elicited in the stellate cells by the action of bradykinin, may have a negative effect on the outcome of the acute disease process and promote the development of chronic pancreatitis. The bradykinin-elicited Ca(2+) signals can be inhibited by blockade of type 2 receptors and also by blockade of Ca(2+)-release activated Ca(2+) channels. The potential benefits of such pharmacological inhibition for the treatment of pancreatitis are reviewed. PMID- 26960940 TI - Update on Baylisascariasis, a Highly Pathogenic Zoonotic Infection. AB - Baylisascaris procyonis, the raccoon roundworm, infects a wide range of vertebrate animals, including humans, in which it causes a particularly severe type of larva migrans. It is an important cause of severe neurologic disease (neural larva migrans [NLM]) but also causes ocular disease (OLM; diffuse unilateral subacute neuroretinitis [DUSN]), visceral larva migrans (VLM), and covert/asymptomatic infections. B. procyonis is common and widespread in raccoons, and there is increasing recognition of human disease, making a clinical consideration of baylisascariasis important. This review provides an update for this disease, especially its clinical relevance and diagnosis, and summarizes the clinical cases of human NLM and VLM known to date. Most diagnosed patients have been young children less than 2 years of age, although the number of older patients diagnosed in recent years has been increasing. The recent development of recombinant antigen-based serodiagnostic assays has aided greatly in the early diagnosis of this infection. Patients recovering with fewer severe sequelae have been reported in recent years, reinforcing the current recommendation that early treatment with albendazole and corticosteroids should be initiated at the earliest suspicion of baylisascariasis. Considering the seriousness of this zoonotic infection, greater public and medical awareness is critical for the prevention and early treatment of human cases. PMID- 26960942 TI - Quantitative structure-(chromatographic) retention relationship models for dissociating compounds. AB - The aim of this work was to develop mathematical models relating the hydrophobicity and dissociation constant of an analyte with its structure, which would be useful in predicting analyte retention times in reversed-phase liquid chromatography. For that purpose a large and diverse group of 115 drugs was used to build three QSRR models combining retention-related parameters (logkw chromatographic measure of hydrophobicity, S-slope factor from Snyder-Soczewinski equation, and pKa) with structural descriptors calculated by means of molecular modeling for both dissociated and nondissociated forms of analytes. Lasso, Stepwise and PLS regressions were used to build statistical models. Moreover a simple QSRR equations based on lipophilicity and dissociation constant parameters calculated in the ACD/Labs software were proposed and compared with quantum chemistry-based QSRR equations. The obtained relationships were further used to predict chromatographic retention times. The predictive performances of the obtained models were assessed using 10-fold cross-validation and external validation. The QSRR equations developed were simple and were characterized by satisfactory predictive performance. Application of quantum chemistry-based and ACD-based descriptors leads to similar accuracy of retention times' prediction. PMID- 26960944 TI - Towards new TB vaccines: What are the challenges? AB - New and effective tuberculosis (TB) vaccines are urgently needed to control pulmonary TB, and in particular to prevent the spread of drug-resistant strains of Mycobacterium tuberculosis. These drug-resistant strains can range from those resistant to first-line drugs to those that are almost impossible to treat. To develop new and effective vaccines for HIV and malaria has been difficult and it is proving to be just as challenging for TB. TB is a complicated disease with a spectrum from apparently controlled latent infection to active clinical disease and so different types of preventive or post-exposure vaccine may be needed. Identifying the most promising vaccine candidates to move into clinical trials is difficult, as we lack biomarker signatures that can predict protective efficacy. There is a risk that the failure of the MVA-85A vaccine to show efficacy when given to previously BCG-vaccinated South African infants will impact on the resources available for the development and trials of other candidate TB vaccines. Continued support for the development of new TB vaccines should remain a priority as an effective vaccine would bring huge public health benefits. PMID- 26960938 TI - Fosfomycin. AB - The treatment of bacterial infections suffers from two major problems: spread of multidrug-resistant (MDR) or extensively drug-resistant (XDR) pathogens and lack of development of new antibiotics active against such MDR and XDR bacteria. As a result, physicians have turned to older antibiotics, such as polymyxins, tetracyclines, and aminoglycosides. Lately, due to development of resistance to these agents, fosfomycin has gained attention, as it has remained active against both Gram-positive and Gram-negative MDR and XDR bacteria. New data of higher quality have become available, and several issues were clarified further. In this review, we summarize the available fosfomycin data regarding pharmacokinetic and pharmacodynamic properties, the in vitro activity against susceptible and antibiotic-resistant bacteria, mechanisms of resistance and development of resistance during treatment, synergy and antagonism with other antibiotics, clinical effectiveness, and adverse events. Issues that need to be studied further are also discussed. PMID- 26960939 TI - Plesiomonas shigelloides Revisited. AB - After many years in the family Vibrionaceae, the genus Plesiomonas, represented by a single species, P. shigelloides, currently resides in the family Enterobacteriaceae, although its most appropriate phylogenetic position may yet to be determined. Common environmental reservoirs for plesiomonads include freshwater ecosystems and estuaries and inhabitants of these aquatic environs. Long suspected as being an etiologic agent of bacterial gastroenteritis, convincing evidence supporting this conclusion has accumulated over the past 2 decades in the form of a series of foodborne outbreaks solely or partially attributable to P. shigelloides. The prevalence of P. shigelloides enteritis varies considerably, with higher rates reported from Southeast Asia and Africa and lower numbers from North America and Europe. Reasons for these differences may include hygiene conditions, dietary habits, regional occupations, or other unknown factors. Other human illnesses caused by P. shigelloides include septicemia and central nervous system disease, eye infections, and a variety of miscellaneous ailments. For years, recognizable virulence factors potentially associated with P. shigelloides pathogenicity were lacking; however, several good candidates now have been reported, including a cytotoxic hemolysin, iron acquisition systems, and lipopolysaccharide. While P. shigelloides is easy to identify biochemically, it is often overlooked in stool samples due to its smaller colony size or relatively low prevalence in gastrointestinal samples. However, one FDA-approved PCR-based culture-independent diagnostic test system to detect multiple enteropathogens (FilmArray) includes P. shigelloides on its panel. Plesiomonads produce beta-lactamases but are typically susceptible to many first-line antimicrobial agents, including quinolones and carbapenems. PMID- 26960945 TI - Altered spontaneous activity of posterior cingulate cortex and superior temporal gyrus are associated with a smoking cessation treatment outcome using varenicline revealed by regional homogeneity. AB - Compared to nonsmokers, smokers exhibit a number of potentially important differences in regional brain function. However, little is known about the associations between the local spontaneous brain activity and smoking cessation treatment outcomes. In the present analysis, we aimed to evaluate whether the local features of spontaneous brain activity prior to the target quit date was associated with the smoking cessation outcomes. All the participants underwent magnetic resonance imaging scans and smoking-related behavioral assessments. After a 12-week treatment with varenicline, 23 smokers succeeded in quitting smoking and 32 failed. Smokers underwent functional magnetic resonance imaging (fMRI) scanning prior to an open label smoking cessation treatment trial. Regional homogeneity (ReHo) was used to measure spontaneous brain activity, and whole-brain voxel-wise comparisons of ReHo were performed to detect brain regions with altered spontaneous brain activity between relapser and quitter groups. After controlling for potentially confounding factors including years of education, years smoked, cigarettes smoked per day and FTND score as covariates, compared to quitters, relapsers displayed significantly decreased ReHo in bilateral posterior cingulate cortex (PCC), as well as increased ReHo in left superior temporal gyrus (STG). These preliminary results suggest that regional brain function variables may be promising predictors of smoking relapse. This study provided novel insights into the neurobiological mechanisms underlying smoking relapse. A deeper understanding of the neurobiological mechanisms associated with relapse may result in novel pharmacological and behavioral interventions. PMID- 26960946 TI - "Small World" architecture in brain connectivity and hippocampal volume in Alzheimer's disease: a study via graph theory from EEG data. AB - Brain imaging plays an important role in the study of Alzheimer's disease (AD), where atrophy has been found to occur in the hippocampal formation during the very early disease stages and to progress in parallel with the disease's evolution. The aim of the present study was to evaluate a possible correlation between "Small World" characteristics of the brain connectivity architecture-as extracted from EEG recordings-and hippocampal volume in AD patients. A dataset of 144 subjects, including 110 AD (MMSE 21.3) and 34 healthy Nold (MMSE 29.8) individuals, was evaluated. Weighted and undirected networks were built by the eLORETA solutions of the cortical sources' activities moving from EEG recordings. The evaluation of the hippocampal volume was carried out on a subgroup of 60 AD patients who received a high-resolution T1-weighted sequence and underwent processing for surface-based cortex reconstruction and volumetric segmentation using the Freesurfer image analysis software. Results showed that, quantitatively, more correlation was observed in the right hemisphere, but the same trend was seen in both hemispheres. Alpha band connectivity was negatively correlated, while slow (delta) and fast-frequency (beta, gamma) bands positively correlated with hippocampal volume. Namely, the larger the hippocampal volume, the lower the alpha and the higher the delta, beta, and gamma Small World characteristics of connectivity. Accordingly, the Small World connectivity pattern could represent a functional counterpart of structural hippocampal atrophying and related-network disconnection. PMID- 26960947 TI - Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) is a deadly irreversible weakening and distension of the abdominal aortic wall. The pathogenesis of AAA remains poorly understood. Investigation into the physical and molecular characteristics of perivascular adipose tissue (PVAT) adjacent to AAA has not been done before and is the purpose of this study. METHODS AND RESULTS: Human aortae, periaortic PVAT, and fat surrounding peripheral arteries were collected from patients undergoing elective surgical repair of AAA. Control aortas were obtained from recently deceased healthy organ donors with no known arterial disease. Aorta and PVAT was found in AAA to larger extent compared with control aortas. Immunohistochemistry revealed neutrophils, macrophages, mast cells, and T-cells surrounding necrotic adipocytes. Gene expression analysis showed that neutrophils, mast cells, and T-cells were found to be increased in PVAT compared with AAA as well as cathepsin K and S. The concentration of ceramides in PVAT was determined using mass spectrometry and correlated with content of T-cells in the PVAT. CONCLUSIONS: Our results suggest a role for abnormal necrotic, inflamed, proteolytic adipose tissue to the adjacent aneurysmal aortic wall in ongoing vascular damage. PMID- 26960948 TI - Current developments and challenges in the assessment of negative symptoms. AB - Reliable and valid assessment of negative symptoms is crucial to further develop etiological models and improve treatments. Our understanding of the concept of negative symptoms has undergone significant advances since the introduction of quantitative assessments of negative symptoms in the 1980s. These include the conceptualization of cognitive dysfunction as separate from negative symptoms and the distinction of two main negative symptom factors (avolition and diminished expression). In this review we provide an overview of existing negative symptom scales, focusing on both observer-rated and self-rated measurement of negative symptoms. We also distinguish between measures that assess negative symptoms as part of a broader assessment of schizophrenia symptoms, those specifically developed for negative symptoms and those that assess specific domains of negative symptoms within and beyond the context of psychotic disorders. We critically discuss strengths and limitations of these measures in the light of some existing challenges, i.e. observed and subjective symptom experiences, the challenge of distinguishing between primary and secondary negative symptoms, and the overlap between negative symptoms and related factors (e.g. personality traits and premorbid functioning). This review is aimed to inform the ongoing development of negative symptom scales. PMID- 26960941 TI - Clinical Significance and Pathogenesis of Staphylococcal Small Colony Variants in Persistent Infections. AB - Small colony variants (SCVs) were first described more than 100 years ago for Staphylococcus aureus and various coagulase-negative staphylococci. Two decades ago, an association between chronic staphylococcal infections and the presence of SCVs was observed. Since then, many clinical studies and observations have been published which tie recurrent, persistent staphylococcal infections, including device-associated infections, bone and tissue infections, and airway infections of cystic fibrosis patients, to this special phenotype. By their intracellular lifestyle, SCVs exhibit so-called phenotypic (or functional) resistance beyond the classical resistance mechanisms, and they can often be retrieved from therapy refractory courses of infection. In this review, the various clinical infections where SCVs can be expected and isolated, diagnostic procedures for optimized species confirmation, and the pathogenesis of SCVs, including defined underlying molecular mechanisms and the phenotype switch phenomenon, are presented. Moreover, relevant animal models and suggested treatment regimens, as well as the requirements for future research areas, are highlighted. PMID- 26960949 TI - Atrial natriuretic peptide as a novel biomarker of hereditary angioedema. PMID- 26960943 TI - Pathogenesis of Candida albicans biofilm. AB - Candida albicans is the most common human fungal pathogen causing diseases ranging from mucosal to systemic infections. As a commensal, C. albicans asymptomatically colonizes mucosal surfaces; however, any disruption in the host environment or under conditions of immune dysfunction, C. albicans can proliferate and invade virtually any site in the host. The ability of this highly adaptable fungal species to transition from commensal to pathogen is due to a repertoire of virulence factors. Specifically, the ability to switch morphology and form biofilms are properties central to C. albicans pathogenesis. In fact, the majority of C. albicans infections are associated with biofilm formation on host or abiotic surfaces such as indwelling medical devices, which carry high morbidity and mortality. Significantly, biofilms formed by C. albicans are inherently tolerant to antimicrobial therapy and therefore, the susceptibility of Candida biofilms to the current therapeutic agents remains low. The aim of this review is to provide an overview of C. albicans highlighting some of the diverse biofilm-associated diseases caused by this opportunistic pathogen and the animal models available to study them. Further, the classes of antifungal agents used to combat these resilient infections are discussed along with mechanisms of drug resistance. PMID- 26960951 TI - Clinical and mutational features of X-linked agammaglobulinemia in Mexico. AB - X-linked agammaglobulinemia (XLA) is caused by BTK mutations, patients typically show <2% of peripheral B cells and reduced levels of all immunoglobulins; they suffer from recurrent infections of bacterial origin; however, viral infections, autoimmune-like diseases, and an increased risk of developing gastric cancer are also reported. In this work, we report the BTK mutations and clinical features of 12 patients diagnosed with XLA. Furthermore, a clinical revision is also presented for an additional cohort of previously reported patients with XLA. Four novel mutations were identified, one of these located in the previously reported mutation refractory SH3 domain. Clinical data support previous reports accounting for frequent respiratory, gastrointestinal tract infections and other symptoms such as the occurrence of reactive arthritis in 19.2% of the patients. An equal proportion of patients developed septic arthritis; missense mutations and mutations in SH1, SH2 and PH domains predominated in patients who developed arthritis. PMID- 26960950 TI - Soluble alpha-klotho is a potential biomarker associated with neuropsychiatric systemic lupus erythematosus. AB - A reduced level of the single-pass transmembrane protein alpha-Klotho is known to be associated with neuronal damage. We investigated whether alpha-Klotho in cerebrospinal fluid (CSF) could be a candidate marker for the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE). We analyzed the laboratory data, symptoms and radiological image findings of 34 NPSLE patients. Patients with SLE without neuropsychiatric manifestations (SLE) (n=25), and patients with viral meningitis (VM) (n=19), multiple sclerosis (MS) (n=20) or neuromyelitis optica (NMO) (n=20) were included as controls. The multivariable analyses revealed that lower CSF alpha-Klotho level, lower serum anti-Smith antibodies (U/mL) and higher serum C3 (mg/dL) were significant factors for predicting NPSLE. The CSF alpha-Klotho levels of the NPSLE patients were inversely correlated with the level of granulocyte/macrophage-colony stimulating factor. Our data suggested that the determination of CSF alpha-Klotho levels will contribute to the diagnosis of NPSLE and help elucidate the mechanisms underlying this disease. PMID- 26960952 TI - Histological improvement in salivary gland along with effector memory Th17-1 cell reduction in a primary Sjogren's syndrome patient with dermatomyositis and diffuse large B-cell lymphoma by R-CHOP therapy. AB - We treated a 45-year-old Japanese woman with primary Sjogren's syndrome (SS) complicated with dermatomyositis (DM) followed by diffuse large B-cell lymphoma. She was admitted to our hospital for further evaluation of fever, weight loss and peritoneal lymphadenopathy. The histological examination of her lymph node revealed diffuse large B-cell lymphoma. The patient was then treated with 8 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy, which resulted in histological and functional improvement of her salivary glands. Of note, the percentage of effector memory Th17-1 (CD3+CD4+CD45RA-CCR7-CXCR3+CCR6+) cells in the peripheral blood was decreased after the R-CHOP treatment. This case suggests that an altered Th17-1 cell subset by B-cell depletion therapy is critical for the improvement of tissue damage in patients with SS, and the case suggests that clinicians should consider measuring the effector memory Th-subsets to predict the disease activity in SS patients. PMID- 26960953 TI - Resveratrol protects PC12 cells against OGD/ R-induced apoptosis via the mitochondrial-mediated signaling pathway. AB - In this study, we investigated the neuroprotective potential of resveratrol against oxygen glucose deprivation/reoxygenation (OGD/R)-induced apoptotic damages in well-differentiated PC12 cells and the underlying mechanisms. Cells were incubated under normal condition or OGD/R in the presence or absence of 10 MUM resveratrol. Cell viability was determined with methyl-thiazolyl-tetrazolium (MTT) assay. Apoptotic ratio was determined with Hoechst 33342 staining and Annexin V-FITC/PI double staining. Oxidative stress was evaluated by measuring the intracellular reactive oxygen species (ROS), the mitochondrial superoxide, the malondialdehyde (MDA) content, and the activities of superoxide dismutase (SOD) and catalase (CAT). The intracellular calcium ([Ca2+]i) was estimated by Fluo-3/AM. The mitochondrial membrane potential (MMP) was evaluated by 5,5',6,6' tetrachloro-1,1,3,3'-tetraethyl-benzimidazolyl-carbocyanine iodide (JC-1) and rhodamine 123 (Rh123). The opening of mitochondrial permeability transition pore (MPTP) was determined by the Calcein/Co2+-quenching technique. The protein levels of cytochrome c, Bcl-2, Bax, cleaved caspase-9, and cleaved caspase-3 were detected by western blot analysis. The results showed that 10 MUM resveratrol attenuated OGD/R-induced cell viability loss and cell apoptosis, which was associated with the decreases in the MDA content and the increases in the SOD and CAT activities. Furthermore, the accumulation of intracellular ROS and mitochondrial superoxide, disturbance of [Ca2+]i homeostasis, reduction of MMP, opening of MPTP, and release of mitochondrial cytochrome c observed in OGD/R injured cells, which indicated a switch on the mitochondrial-mediated apoptotic pathway, were all reversed by resveratrol. These results suggest that resveratrol administration may play a neuroprotective role via modulating the mitochondrial mediated signaling pathway in OGD/R-induced PC12 cell injury. PMID- 26960954 TI - Next Generation Sequencing and Linkage Analysis for the Molecular Diagnosis of a Novel Overlapping Syndrome Characterized by Hypertrophic Cardiomyopathy and Typical Electrical Instability of Brugada Syndrome. AB - BACKGROUND: Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited disorder; mutations in at least 20 genes have been associated. Brugada syndrome (BrS) is an autosomal dominant inherited disorder caused by mutations mainly in theSCN5Agene. A new clinical entity that consists of HCM, typical electrical instability of BrS and sudden death (SD), is described. METHODS AND RESULTS: The family was constituted by 7 members, 4 of who presented clinical features of HCM and electrical instability of BrS. The clinical presentation of proband was ventricular fibrillation. All members were clinically evaluated by physical examination, 12-lead electrocardiography, 2-dimensional echocardiography, stress test, electrocardiogram Holter, flecainide test, and electrophysiological study. An integrated linkage analysis and next generation sequencing (NGS) approach was used to identify the causative mutation. Linkage with the alpha-tropomyosin (TPM1) gene on chromosome 15q22 was identified. The NGS study identified a missense mutation within theTPM1gene (c.574G>A; p.E192K), exactly located in a binding domain with polycystin-2 protein. No other pathogenic mutations were identified. CONCLUSIONS: This is the first report of an association between HCM and BrS, and the first to use a combined approach of linkage and NGS to identify a causative mutation in SD. The present study expands the clinical spectrum of disorders associated with theTPM1gene and may be useful to report novel mechanisms of electrical instability in HCM and BrS. PMID- 26960955 TI - Knowing the Risks of the Vessels From the Vessels. PMID- 26960956 TI - Innovative Edoxaban Overcomes Undesirable Characteristics of Warfarin in East Asian Patients. PMID- 26960957 TI - History of ABVD alters the number of oocytes vitrified after in vitro maturation in fertility preservation candidates. AB - AIM: This retrospective case-control study aimed at analyzing the results of in vitro maturation (IVM) of oocytes, used for fertility preservation (FP), in patients with history of ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) for classical Hodgkin lymphoma. PATIENTS & METHODS: A total of 22 candidates for FP, having received ABVD at least 2 years before IVM for FP were studied. IVM results were compared with those of 44 breast cancer patients, without history of chemotherapy, matched for ovarian reserve parameters. RESULTS: The number of cumulo-oocyte complexes recovered and the total number of matured oocytes vitrified was lower in patients having received AVBD (5.5 +/- 4.8 vs 8.5 +/- 4.4 oocytes; p = 0.03 and 3.5 +/- 3.7 vs 6 +/- 3.0 oocytes; p < 0.04, respectively). CONCLUSION: In light of these results, FP should be discussed before ABVD. PMID- 26960958 TI - Echinococcus multilocularis Leuckart, 1863 (Taeniidae): new data on sperm ultrastructure. AB - The present study establishes the ultrastructural organisation of the mature spermatozoon of Echinococcus multilocularis, which is essential for future research on the location of specific proteins involved in the sperm development in this species and also in Echinococcus granulosus. Thus, the ultrastructural characteristics of the sperm cell are described by means of transmission electron microscopy. The spermatozoon of E. multilocularis is a filiform cell, which is tapered at both extremities and lacks mitochondria. It exhibits all the characteristics of type VII spermatozoon of tapeworms, namely a single axoneme, crested bodies, spiralled cortical microtubules and nucleus, a periaxonemal sheath and intracytoplasmic walls. Other characteristics observed in the male gamete are the presence of a >900-nm long apical cone in its anterior extremity and only the axoneme in its posterior extremity. The ultrastructural characters of the spermatozoon of E. multilocularis are compared with those of other cestodes studied to date, with particular emphasis on representatives of the genus Taenia. The most interesting finding concerns the presence of two helical crested bodies in E. multilocularis while in the studied species of Taenia, there is only one crested body. Future ultrastructural studies of other species of the genus Echinococcus would be of particular interest in order to confirm whether or not the presence of two crested bodies is a characteristic of this genus. PMID- 26960959 TI - Molecular detection and characterization of Cryptosporidium spp. among breeding cattery cats in Japan. AB - Cryptosporidium spp. are pathogenic protozoan that can cause gastrointestinal illness in mammalian hosts. As a result of the close contact between humans and cats, there is concern regarding the potential zoonotic transmission of Cryptosporidium spp. from infected cats; however, few data have been reported regarding the prevalence of this pathogen among cats. Here, we report the prevalence of Cryptosporidium spp. among breeding cattery cats in Japan. A total of 286 fresh fecal samples were collected from breeding cattery cats at seven facilities located across Japan. A nested polymerase chain reaction (PCR) assay targeting the 18S rRNA gene was employed for the detection of Cryptosporidium spp. Four cats (1.4 %), from two catteries, were positive for Cryptosporidium spp. Age and fecal condition were not significantly associated with prevalence. The four positive samples displayed 99-100 % sequence similarity to Cryptosporidium felis sequences. Our findings indicated that the prevalence of Cryptosporidium spp. was low among breeding cattery cats in Japan, and therefore the risk of zoonotic transmission to humans was also likely to be low. PMID- 26960961 TI - Are Symbiotic Methanotrophs Key Microbes for N Acquisition in Paddy Rice Root? AB - The relationships between biogeochemical processes and microbial functions in rice (Oryza sativa) paddies have been the focus of a large number of studies. A mechanistic understanding of methane-nitrogen (CH4-N) cycle interactions is a key unresolved issue in research on rice paddies. This minireview is an opinion paper for highlighting the mechanisms underlying the interactions between biogeochemical processes and plant-associated microbes based on recent metagenomic, metaproteomic, and isotope analyses. A rice symbiotic gene, relevant to rhizobial nodulation and mycorrhization in plants, likely accommodates diazotrophic methanotrophs or the associated bacterial community in root tissues under low-N fertilizer management, which may permit rice plants to acquire N via N2 fixation. The amount of N fixed in rice roots was previously estimated to be approximately 12% of plant N based on measurements of (15)N natural abundance in a paddy field experiment. Community analyses also indicate that methanotroph populations in rice roots are susceptible to environmental conditions such as the microclimate of rice paddies. Therefore, CH4 oxidation by methanotrophs is a driving force in shaping bacterial communities in rice roots grown in CH4-rich environments. Based on these findings, we propose a hypothesis with unanswered questions to describe the interplay between rice plants, root microbiomes, and their biogeochemical functions (CH4 oxidation and N2 fixation). PMID- 26960960 TI - Spread and genotype of Toxoplasma gondii in naturally infected alpine chamois (Rupicapra r. rupicapra). AB - The complex life cycle of Toxoplasma gondii involves many animal species, raising zoonotic, economic, and conservation issues. This complexity is reflected in the molecular structure of T. gondii, whose different genotypes differ in pathogenicity. Among the intermediate hosts of T. gondii, wild ungulates may be a source of human infection. Despite intense hunting activity and the consumption of raw or undercooked meat, little information is available on the spread of T. gondii and the distribution of its genotypes in these species, including the alpine chamois (Rupicapra r. rupicapra). Ninety-three sera and 50 brain tissues from chamois were sampled (1) to investigate the spread of T. gondii with serological and molecular analyses, and (2) to genotype the strains with a restriction fragment length polymorphism analysis of the SAG2 locus. The prevalence of T. gondii was low on both serological (3.2 %) and molecular (2 %) analyses, and infections were concentrated in individuals >1 year old. These findings demonstrate the sporadic presence of the protozoan in this species on consistent diagnostic tests. Horizontal transmission seems to be the main route of infection, and cats are the only definitive host in the study area. This prevalence suggests that the environment of the chamois is less contaminated with oocysts than environments close to human settlements. The SAG2 type II genotype was detected in this species for the first time. Although this genotype is predominant in human toxoplasmosis, these results suggest that the chamois is a minor source of human infection. PMID- 26960962 TI - Determinants of intimate partner violence during pregnancy among married women in Abay Chomen district, Western Ethiopia: a community based cross sectional study. AB - BACKGROUND: Intimate partner violence during pregnancy is the most common form of violence that harms the health of women and the fetus but practiced commonly in developing countries. There is scarcity of information regarding intimate partner violence during pregnancy in Ethiopia. Thus, this study aimed to assess the prevalence and associated factors of intimate partner violence during recent pregnancy in Abay Chomen district, Western Ethiopia. METHODS: Community based cross sectional study was conducted among married pregnant women in Abay Chomen district in April, 2014 using a standard WHO multi-country study questionnaire. Two hundred eighty two randomly selected pregnant women aged 15-49 years participated in the study. Logistic regression and multivariate analysis were employed. RESULTS: The prevalence of intimate partner violence during recent pregnancy was 44.5% (95% CI, 32.6, 56.4). More than half 157 (55.5%) experienced all three forms of intimate partner violence during recent pregnancy. The joint occurrence of intimate partner physical and psychological violence during recent pregnancy as well as joint occurrence of intimate partner physical and sexual violence was 160 (56.5%). Pregnant women who were ever lived with their partner's family were 46% less likely to experience recent intimate partner violence. Dowry payment decreases intimate partner violence during recent pregnancy (AOR 0.09, 95% CI 0.04, 0.2) and pregnant women who didn't undergo marriage ceremony during their marriage were 79% are less likely to experience violence (AOR 0.21, 95% CI 0.1, 0.44). CONCLUSION: Nearly half of interviewed pregnant women experienced intimate partner violence during pregnancy implying the prevalence of such practice in the study site. To that end, increasing community awareness about the consequences of the practice could be important. Moreover, as health extension workers works closely with households, they could be crucial players to increase community awareness about intimate partner violence on pregnant mothers and halt it or its risk factors. PMID- 26960964 TI - Melting curve analysis in canine lymphoma by calculating maximum fluorescence decrease. AB - PARR is widely used in the diagnostics of canine lymphoma. In human and veterinary medicine, melting curve analysis (MCA) has successfully been introduced to facilitate the process. Since visual interpretation of melting curves can be rather subjective, the purpose of this study was to develop an objective interpretation of melting curves by calculating the maximum fluorescence decrease (dFmax ) within a defined rise of temperature. Lymph node aspirates and blood of 34 dogs with lymphoma and 28 control dogs were tested. 27/34 lymphoma cases were correctly detected to be monoclonal (sensitivity 79%). 2/28 control dogs showed a monoclonal rearrangement (specificity 93%). B- and T cell neoplasia were still detectable using DNA amount as low as 10 ng. In serial dilutions of tumor DNA with DNA of normal tonsils, the detection limit was 25% for B-cell lymphomas and 100% for T-cell lymphoma, suggesting that PCR conditions could still be optimized. PMID- 26960963 TI - Pd(0)-Catalyzed Direct C-H Functionalization of 2-H-4-Benzylidene Imidazolones: Friendly and Large-Scale Access to GFP and Kaede Protein Fluorophores. AB - The first one-pot synthesis of N-substituted 2-H-4-benzylidene imidazolones and their subsequent palladium-catalyzed and copper-assisted direct C2-H arylation and alkenylation with aryl- and alkenylhalides are described. This innovative synthesis is step-economical, azide-free, high yielding, highly flexible in the introduction of a variety of electronically different groups, and can be operated on large-scale. Moreover, the method allows direct access to C2-arylated or alkenylated imidazolone-based green fluorescent protein (GFP) and Kaede protein fluorophores, including ortho-hydroxylated models. PMID- 26960965 TI - Metformin prescription patterns among US adolescents aged 10-19 years: 2009-2013. AB - WHAT IS KNOWN AND OBJECTIVE: Metformin is the only oral antihyperglycemic agent approved for use in adolescents with type 2 diabetes mellitus (T2DM). There are reports of metformin used to treat conditions such as obesity, hyperinsulinemia, prediabetes, metabolic syndrome and polycystic ovarian syndrome (PCOS). It is important to understand metformin prescription patterns and underlying diagnoses in adolescents as it can provide estimates of the extent of on-label (i.e. treatment of T2DM) and off-label use of metformin in this population. Our study sought to assess metformin prescription patterns among US adolescents from 2009 to 2013. METHODS: Data from the National Disease and Therapeutic Index (NDTI) database, the MarketScan((r)) Commercial Claims and Encounters database and the Multi-State Medicaid database were analysed. The proportion of diagnoses associated with metformin that was recommended during a clinical visit was identified in the NDTI database. In the MarketScan((r)) Commercial and Medicaid databases, adolescents with at least one metformin prescription with +/-6 months continuous enrolment from the date of the index metformin prescription were included in the analyses. All diagnosis and procedure codes were extracted within +/-6 months of the index metformin prescription. The proportion of T2DM was calculated irrespective of any other medical conditions, whereas all other prespecified conditions were classified as positive only if no concurrent T2DM diagnosis codes were present. RESULTS AND DISCUSSION: In the NDTI database, the most common diagnoses associated with metformin use were diabetes (34.9%), followed by metabolic syndrome (20.9%), PCOS (17.2%) and obesity (6.5%). In the MarketScan((r)) Commercial database, T2DM was the most common diagnosis among girls aged 10-14 years (22.8-23.6%), boys aged 10-14 years (20.5-24.5%) and boys aged 15-19 years (37.1-43.1%), whereas PCOS (24.1-28.3%) was the most common diagnosis among girls aged 15-19 years. In the Medicaid database, T2DM was the most common diagnosis among all four groups and the proportions were higher than their counterparts in the Commercial database. WHAT IS NEW AND CONCLUSION: Analyses from three separate US data sources suggest that off-label prescribing of metformin is common among US adolescents aged 10-19 years. To avoid potential overestimation, caution should be exercised when utilizing metformin prescription as a proxy measure to estimate the burden of T2DM in adolescents. PMID- 26960966 TI - [Nerve injuries after elbow luxation fractures in childhood : Indication and timing for surgical revision]. AB - BACKGROUND: Supracondylar humerus fractures are very common in pediatric populations. In cases of dislocated fractures, closed reduction and percutaneous K-wire fixation is recommended. Initially, 10-16 % of the patients also present lesion of the ulnar nerve as well as median nerve palsy in 6.4% and radial nerve palsy in 2.6 % of cases, respectively. METHOD: We present the case of a 10-year old boy with a dislocation of the elbow and fracture of the medial epicondyle. After closed reduction and K-wire fixation from medial, he presents a median nerve palsy. That a lesion of the ulnar nerve is also present is only noticed 31/2 years posttraumatically. A surgical decompression and neurolysis of the ulnar and median nerve is performed and the postoperative grip and key strength presented. DISCUSSION: With the help of the presented case we discuss the indication and the point of surgical revision. Clinical assessment and neurosonography are essential for an exact diagnosis. PMID- 26960968 TI - Gene discovery for facioscapulohumeral muscular dystrophy by machine learning techniques. AB - Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder that shows a preference for the facial, shoulder and upper arm muscles. FSHD affects about one in 20-400,000 people, and no effective therapeutic strategies are known to halt disease progression or reverse muscle weakness or atrophy. Many genes may be incorrectly regulated in affected muscle tissue, but the mechanisms responsible for the progressive muscle weakness remain largely unknown. Although machine learning (ML) has made significant inroads in biomedical disciplines such as cancer research, no reports have yet addressed FSHD analysis using ML techniques. This study explores a specific FSHD data set from a ML perspective. We report results showing a very promising small group of genes that clearly separates FSHD samples from healthy samples. In addition to numerical prediction figures, we show data visualizations and biological evidence illustrating the potential usefulness of these results. PMID- 26960967 TI - Comparison of digital scanning and polyvinyl siloxane impression techniques by dental students: instructional efficiency and attitudes towards technology. AB - INTRODUCTION: With increasing use of digital scanning with restorative procedures in the dental office, it becomes necessary that educational institutions adopt instructional methodology for introducing this technology together with conventional impression techniques. OBJECTIVE: To compare the time differences between instructing dental students on digital scanning (DS) (LAVA C.O.S. digital impression system) and a conventional impression technique (CI) (polyvinyl siloxane), and to compare students' attitudes and beliefs towards both techniques. MATERIALS AND METHODS: Volunteer sophomore dental students (n = 25) with no prior experience in clinical impressions were recruited and IRB consent obtained. Participants responded to a pre-and post-exposure questionnaire. Participants were instructed on the use of both DS and CI for a single tooth full coverage crown restoration using a consecutive sequence of video lecture, investigator-led demonstration and independent impression exercise. The time necessary for each step (minutes) was recorded. Statistical significance was calculated using dependent t-tests (time measurements) and 2-sample Mann-Whitney (questionnaire responses). RESULTS: The time spent teaching students was greater for DS than CI for video lecture (15.95 and 10.07 min, P = 0.0000), demonstration time (9.06 and 4.70 min, P = 0.0000) and impression time (18.17 and 8.59 min, P = 0.0000). Prior to the instruction and practice, students considered themselves more familiar with CI (3.96) than DS (1.96) (P = 0.0000). After the instruction and practice, participants reported CI technique proved significantly easier than expected (pre-instruction: 3.52 and post-instruction: 4.08, P = 0.002). However, overall participants' perception of ease of use for DS was not influenced by this instruction and practice experience (pre-instruction: 3.84 and post-instruction: 3.56, P = 0.106). Despite the results, 96% of participants expressed an expectation that DS will become their predominant impression technique during their careers. CONCLUSIONS: Dental students with no clinical experience have high expectations for digital scanning, and despite their initial difficulty, expect it to become their primary impression technique during their professional futures. The instructional time necessary for introducing DS into the curriculum is significantly greater than CI in both classroom (lecture) and clinical simulation settings (investigator-led demonstration). PMID- 26960969 TI - Effects of postnatal alcohol exposure on hippocampal gene expression and learning in adult mice. AB - Fetal alcohol syndrome (FAS) is a condition resulting from excessive drinking by pregnant women. Symptoms of FAS include abnormal facial features, stunted growth, intellectual deficits and attentional dysfunction. Many studies have investigated FAS, but its underlying mechanisms remain unknown. This study evaluated the relationship between alcohol exposure during the synaptogenesis period in postnatal mice and subsequent cognitive function in adult mice. We delivered two injections, separated by 2 h, of ethanol (3 g/kg, ethanol/saline, 20% v/v) to ICR mice on postnatal day 7. After 10 weeks, we conducted a behavioral test, sacrificed the animals, harvested brain tissue and analyzed hippocampal gene expression using a microarray. In ethanol-treated mice, there was a reduction in brain size and decreased neuronal cell number in the cortex, and also cognitive impairment. cDNA microarray results indicated that 1,548 genes showed a > 2-fold decrease in expression relative to control, whereas 974 genes showed a > 2-fold increase in expression relative to control. Many of these genes were related to signal transduction, synaptogenesis and cell membrane formation, which are highlighted in our findings. PMID- 26960970 TI - CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome. AB - The implementation of regular colonoscopy programs has significantly decreased the mortality associated with colorectal cancer (CRC) in Lynch syndrome patients. However, interval CRCs in Lynch syndrome that remain undetected by colonoscopy still represent a substantial problem in the management of the syndrome. One possible reason of interval cancers could be a non-polypous pathway of cancer development. To examine the possibility of a non-polypous pathway of CRC development in Lynch syndrome, we analyzed the histological appearance of 46 Lynch syndrome-associated CRCs and compared them to 34 sporadic microsatellite unstable cancers. We observed that 25 (62.5 %) out of 40 assessable Lynch syndrome-associated carcinomas lacked evidence of polypous growth, compared to 17 (50 %) out of 34 sporadic MSI-H cancers. We detected CTNNB1 mutations in 8 (17.4 %) out of 46 Lynch syndrome-associated cancers compared to 0 out of 34 sporadic MSI-H cancers (p = 0.01). The majority of CTNNB1-mutant cancers presented with a histological appearance suggesting immediate invasive growth. Our results suggest that a distinct subgroup of CRCs in Lynch syndrome may in fact emerge from a non polypous precursor, thus potentially explaining the phenomenon of interval cancers. Such a non-polypous precursor may be the recently described mismatch repair-deficient crypt focus, which remains invisible for the examiner during colonoscopy. This calls for considering the implementation of active, primary preventive measures in the management of Lynch syndrome. Future studies on pathogenic pathways and precursor lesions in Lynch syndrome are strongly encouraged, and the clinical efficacy of new prevention approaches should be evaluated in prospective clinical trials. PMID- 26960971 TI - Estimating cumulative risks for breast cancer for carriers of variants in uncommon genes. AB - The rapid clinical embrace of next generation multigene cancer predisposition panels has resulted in discovery of DNA variants in genes for which very limited data on penetrance has been published. Evidence for increased risks associated with these genes is often expressed in odds ratios and studies often were conducted on a priori high risk cohorts, i.e. those with young onset disease and/or positive family histories. Despite these limitations, one can estimate cumulative risks, which may be useful for health care providers who are counselling individuals on their results. We present cumulative risks for several under-studied genes and provide generic information that can be extrapolated to data still emerging. PMID- 26960973 TI - Stress chaperone mortalin contributes to epithelial-mesenchymal transition and cancer metastasis. AB - Mortalin/mthsp70 (HSPA9) is a stress chaperone enriched in many cancers that has been implicated in carcinogenesis by promoting cell proliferation and survival. In the present study, we examined the clinical relevance of mortalin upregulation in carcinogenesis. Consistent with high mortalin expression in various human tumors and cell lines, we found that mortalin overexpression increased the migration and invasiveness of breast cancer cells. Expression analyses revealed that proteins involved in focal adhesion, PI3K-Akt and JAK-STAT signaling, all known to play key roles in cell migration and epithelial-to-mesenchymal transition (EMT), were upregulated in mortalin-expressing cancer cells. We further determined that expression levels of the mesenchymal markers vimentin (VIM), fibronectin (FN1), beta-catenin (CTNNB1), CK14 (KRT14) and hnRNP-K were also increased upon mortalin overexpression, whereas the epithelial markers E cadherin (CDH1), CK8 (KRT8), and CK18 (KRT18) were downregulated. Furthermore, shRNA-mediated and pharmacological inhibition of mortalin suppressed the migration and invasive capacity of cancer cells and was associated with a diminished EMT gene signature. Taken together, these findings support a role for mortalin in the induction of EMT, prompting further investigation of its therapeutic value in metastatic disease models. PMID- 26960974 TI - Quantitative phosphotyrosine profiling of patient-derived xenografts identifies therapeutic targets in pediatric leukemia. AB - Activating mutations in tyrosine kinases (TKs) drive pediatric high-risk acute lymphoblastic leukemia (ALL) and confer resistance to standard chemotherapy. Therefore, there is urgent need to characterize dysregulated TK signaling axes in patients with ALL and identify actionable kinase targets for the development of therapeutic strategies. Here, we present the first study to quantitatively profile TK activity in xenografted patient biopsies of high-risk pediatric ALL. We integrated a quantitative phosphotyrosine profiling method with 'spike-in' stable isotope labeling with amino acids in cell culture (SILAC) and quantified 1394 class I phosphorylation sites in 16 ALL xenografts. Moreover, hierarchical clustering of phosphotyrosine sites could accurately classify these leukemias into either B or T-cell lineages with the high-risk early T-cell precursor (ETP) and Ph-like ALL clustering as a distinct group. Furthermore, we validated this approach by using specific kinase pathway inhibitors to perturb ABL1, FLT3, and JAK TK signaling in four xenografted patient samples. By quantitatively assessing the tyrosine phosphorylation status of activated kinases in xenograft models of ALL, we were able to identify and validate clinically relevant targets. Therefore, this study highlights the application and potential of phosphotyrosine profiling for identifying clinically relevant kinase targets in leukemia. PMID- 26960972 TI - Testing the effects of narrative and play on physical activity among breast cancer survivors using mobile apps: study protocol for a randomized controlled trial. AB - BACKGROUND: Physical activity reduces risk for numerous negative health outcomes, but postmenopausal breast cancer survivors do not reach recommended levels. Many interventions encourage self-monitoring of steps, which can increase physical activity in the short term. However, these interventions appear insufficient to increase motivation for sustained change. There is a need for innovative strategies to increase physical activity motivation in this population. Narratives are uniquely persuasive, and video games show promise for increasing motivation. This study will determine the effectiveness of an intervention that combines narrative and gaming to encourage sustained physical activity. METHODS/DESIGN: SMARTGOAL (Self-Monitoring Activity: a Randomized Trial of Game Oriented AppLications) is a randomized controlled intervention trial. The intervention period is six months, followed by a six month maintenance period. Participants (overweight, sedentary postmenopausal breast cancer survivors aged 45-75) will be randomized to a self-monitoring group or an enhanced narrative game group. The self-monitoring group will be encouraged to use a mobile application for self-monitoring and feedback and will receive 15 counseling phone calls emphasizing self-regulation. The narrative game group will be encouraged to use a mobile application that includes self-monitoring and feedback as well as a narrative-based active video game. The 15 calls for this group will emphasize concepts related to the game storyline. Counseling calls in both groups will occur weekly in months 1 - 3 and monthly in months 4 - 6. No counseling calls will occur after month 6, but both groups will be encouraged to continue using their apps. The primary outcome of the study is minutes of moderate to vigorous physical activity at six months. Other objectively measured outcomes include fitness and physical function. Self-reported outcomes include quality of life, depression, and motivation. DISCUSSION: This protocol will result in implementation and evaluation of two technology-based physical activity interventions among breast cancer survivors. Both interventions hold promise for broad dissemination. Understanding the potential benefit of adding narrative and game elements to interventions will provide critical information to interventionists, researchers, clinicians, and policymakers. This study is uniquely suited to investigate not just whether but how and why game elements may improve breast cancer survivors' health. TRIAL REGISTRATION: clinicaltrials.gov NCT02341235 (January 9, 2015). PMID- 26960976 TI - Frequency and Dynamics of Leukemia-Initiating Cells during Short-term Ex Vivo Culture Informs Outcomes in Acute Myeloid Leukemia Patients. AB - Acute myeloid leukemia (AML) is sustained by a subpopulation of rare leukemia initiating cells (LIC) detected in the xenograft assay by their capacity to self renew and to generate non-LICs in vivo The xenotransplantation model captures functional properties of LICs that have clinical prognostic value. However, the long duration of this in vivo assay has hampered its use as a prognostic tool. Here, we show, using an ex vivo coculture system, that intermediate and poor risk AML patient samples at diagnosis have a 5 to 7 times higher frequency of leukemic long-term culture-initiating cells (L-LTC-IC) compared with the good risk group. We defined a fluorescence dilution factor (FDF) parameter that monitors sample proliferation over 1 week and established a strong correlation of this parameter with the L-LTC-IC frequency. A higher FDF was found for poor prognostic AMLs or for samples capable of engrafting NSG mice compared with good risk AMLs or nonengrafters. Importantly, FDF could classify normal karyotype intermediate risk patients into two groups with a significant difference in their overall survival, thus making this nongenetic and non-in vivo approach a new clinically relevant tool for better diagnosis of AML patients. Cancer Res; 76(8); 2082-6. (c)2016 AACR. PMID- 26960975 TI - The Error-Prone DNA Polymerase kappa Promotes Temozolomide Resistance in Glioblastoma through Rad17-Dependent Activation of ATR-Chk1 Signaling. AB - The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of human cancers, including glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that Pol kappa, an error-prone polymerase that participates in translesion DNA synthesis, was significantly upregulated in GBM cell lines and tumor tissues following temozolomide treatment. Overexpression of Pol kappa in temozolomide sensitive GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in orthotopic xenograft mouse models. Mechanistically, depletion of Pol kappa disrupted homologous recombination (HR)-mediated repair and restart of stalled replication forks, impaired the activation of ATR-Chk1 signaling, and delayed cell-cycle re entry and progression. Further investigation of the relationship between Pol kappa and temozolomide revealed that Pol kappa inactivation facilitated temozolomide-induced Rad17 ubiquitination and proteasomal degradation, subsequently silencing ATR-Chk1 signaling and leading to defective HR repair and the reversal of temozolomide resistance. Moreover, overexpression of Rad17 in Pol kappa-depleted GBM cells restored HR efficiency, promoted the clearance of temozolomide-induced DNA breaks, and desensitized cells to the cytotoxic effects of temozolomide observed in the absence of Pol kappa. Finally, we found that Pol kappa overexpression correlated with poor prognosis in GBM patients undergoing temozolomide therapy. Collectively, our findings identify a potential mechanism by which GBM cells develop resistance to temozolomide and suggest that targeting the DNA damage tolerance pathway may be beneficial for overcoming resistance. Cancer Res; 76(8); 2340-53. (c)2016 AACR. PMID- 26960978 TI - The role of a multidisciplinary student team in the community management of chronic obstructive pulmonary disease. AB - OBJECTIVE: To determine whether a community-based, multidisciplinary team consisting of home-based caregivers and supervised students could improve the functional status and quality of life of patients living with chronic obstructive pulmonary disease (COPD) in a low-income, peri-urban setting in South Africa. METHODS: This was a quasi-experimental study conducted over three months. Attention was paid to health literacy, inhaler technique, respiratory conditioning and nutrition. RESULTS: Health literacy was poor and most patients were not using their inhalers correctly. Five of 12 patients found exercising challenging and withdrew from the study early. In the remaining seven patients, statistically significant improvements in FEV1%, and quality of life scores were seen at three months. Improvements in exercise tolerance and BODE prognostic index did not reach statistical significance. CONCLUSION: A home-based multidisciplinary student team can improve the functional status and the quality of life in patients living with COPD in a low-income setting. This approach offers a suitable model for community-based service learning. PMID- 26960977 TI - Achievement of successful pulmonary vein isolation: methods of adenosine testing and incremental benefit of exit block. AB - PURPOSE: Several approaches were tried to achieve complete pulmonary vein isolation (PVI). The aims of this study were to (1) compare adenosine-induced PV conduction and exit conduction, (2) determine the adequate adenosine dose, and (3) investigate the correlation of dormant conduction and recurrence of atrial fibrillation (AF). METHODS: A total of 378 consecutive patients who underwent PVI from June 2012 to April 2015 were prospectively included (the de novo procedure in 318 (84.1 %) and a redo procedure in 60 (15.9 %)). After the exit block was assessed, 20 mg adenosine was injected into the left atrium. If dormant conduction was observed, 12 and 6 mg of adenosine were injected sequentially. RESULTS: Exit conduction during PV pacing was observed in 34 patients (9 %), and dormant conduction was observed in 92 patients (24.3 %). Among them, 74 (80.4 %, 74/92) demonstrated dormant conduction without exit conduction and 16 (47.1 %, 16/34) showed exit conduction without dormant conduction. The 20-mg dose of adenosine had an additive yield in patients with dormant conduction, compared to that of 12 mg (93 %, 86/92) or 6 mg (80 %, 74/92). There was no significant difference in the recurrence rate regarding dormant conduction. The pattern of prevalence of reconnected origin during the redo procedure was similar to that of dormant conduction during the index procedure. CONCLUSIONS: There was a discrepancy between adenosine-induced PVI and exit block. Therefore, exit block test has additional value to verify latent incomplete PVI in conjunction with adenosine test. Furthermore, high-dose adenosine had an additive yield. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov/ct2/show/NCT01932112. PMID- 26960980 TI - The challenge of basilar artery occlusion wake-up stroke: too late for intravenous thrombolysis? AB - We describe the case of a patient carried to our emergency department, with the wake-up finding of dysarthria, right hemiplegia and worsening consciousness impairment (NIHSS 12). After performing a CT angiography, which showed complete basilar occlusion, we determined the MR DWI-FLAIR mismatch to estimate the stroke onset time. Because of the favorable mismatch (DWI hyperintensity in the left pons, no FLAIR hyperintensity in the same region), the patient underwent thrombolysis with sudden neurological improvement. In addition, the DWI hyperintensity first observed in the left pons totally regressed after thrombolysis. Wake-up stroke constitutes about 14 % of all strokes, while the percentage of basilar artery occlusion wake-up strokes is still unknown. Although thrombolysis in patients with unknown-onset time is still an off-label therapy, basilar artery occlusion is a potentially fatal event. In our case we used RM DWI FLAIR mismatch to rapidly estimate the stroke onset time and to treat the patient with an off-label but potentially effective and safe therapy. PMID- 26960979 TI - The role of adenosine and adenosine receptors in the immunopathogenesis of multiple sclerosis. AB - INTRODUCTION: Multiple sclerosis (MS) is a heterogeneous neurological disorder with multifactorial etiologies characterized by demyelination, axonal degeneration, and oligodendroglial death. It is believed that both genetics and environmental risk factors such as infection are involved in disease etiology. Accumulating evidence indicates that alteration in purinergic system signaling is involved in immunity and inflammation. Adenosine, a key purine nucleoside, has been shown to be produced during metabolic stress, including ischemia, inflammatory condition, and tissue injury. METHODS: Extracellular adenosine directly affects various physiological and pathological processes of MS by stimulating G protein-coupled adenosine receptors A1, A2A, A2B, and A3 on the surface of immune cells. It has been suggested that promotion of adenosinergic system may be an important factor in MS pathophysiology and considered as promising therapeutic target for this disease. CONCLUSION: In this review, we will discuss about the immunopathologic effects of adenosine on MS and its animal model, experimental autoimmune encephalomyelitis. PMID- 26960981 TI - Medium-chain TAG improve energy metabolism and mitochondrial biogenesis in the liver of intra-uterine growth-retarded and normal-birth-weight weanling piglets. AB - We previously reported that medium-chain TAG (MCT) could alleviate hepatic oxidative damage in weanling piglets with intra-uterine growth retardation (IUGR). There is a relationship between oxidative status and energy metabolism, a process involved in substrate availability and glucose flux. Therefore, the aim of this study was to investigate the effects of IUGR and MCT on hepatic energy metabolism and mitochondrial function in weanling piglets. Twenty-four IUGR piglets and twenty-four normal-birth-weight (NBW) piglets were fed a diet of either soyabean oil (SO) or MCT from 21 d of postnatal age to 49 d of postnatal age. Then, the piglets' biochemical parameters and gene expressions related to energy metabolism and mitochondrial function were determined (n 4). Compared with NBW, IUGR decreased the ATP contents and succinate oxidation rates in the liver of piglets, and reduced hepatic mitochondrial citrate synthase (CS) activity (P<0.05). IUGR piglets exhibited reductions in hepatic mitochondrial DNA (mtDNA) contents and gene expressions related to mitochondrial biogenesis compared with NBW piglets (P<0.05). The MCT diet increased plasma ghrelin concentration and hepatic CS and succinate dehydrogenase activities, but decreased hepatic pyruvate kinase activity compared with the SO diet (P<0.05). The MCT-fed piglets showed improved mtDNA contents and PPARgamma coactivator-1alpha expression in the liver (P<0.05). The MCT diet alleviated decreased mRNA abundance of the hepatic PPARalpha induced by IUGR (P<0.05). It can therefore be postulated that MCT may have beneficial effects in improving energy metabolism and mitochondrial function in weanling piglets. PMID- 26960982 TI - Incidence of neoplasias and effectiveness of postoperative surveillance endoscopy for patients with ulcerative colitis: comparison of ileorectal anastomosis and ileal pouch-anal anastomosis. AB - BACKGROUND: The incidence of neoplasia after surgery has not been sufficiently evaluated in patients with ulcerative colitis (UC), particularly in the Japanese population, and it is not clear whether surveillance endoscopy is effective in detecting dysplasia/cancer in the remnant rectum or pouch. The aims of this study were to assess and compare postoperative development of dysplasia/cancer in patients with UC who underwent ileorectal anastomosis (IRA) or ileal pouch-anal anastomosis (IPAA) and to evaluate the effectiveness of postoperative surveillance endoscopy. METHODS: One hundred twenty patients who received postoperative surveillance endoscopy were retrospectively reviewed for development of dysplasia/cancer in the remnant rectal mucosa or pouch. RESULTS: Three hundred seventy-nine endoscopy sessions were conducted for 30 patients after IRA, while 548 pouch endoscopy sessions were conducted for 90 patients after IPAA. In the IRA group, 5 patients developed dysplasia/cancer during postoperative surveillance and in all cases, neoplasia was detected at an early stage. In the IRA group, no patient developed neoplasia within 10 years of diagnosis; the cumulative incidence of neoplasia after disease onset was 7.2, 12.0, and 23.9% at 15, 20, and 25 years, respectively. In one case after stapled IPAA, dysplasia was found at the ileal pouch; a subsequent 9 endoscopy sessions in 8 years did not detect any dysplasia. Neoplasia was found more frequently during postoperative surveillance in the IRA group than in the IPAA group (p = .0028). The cumulative incidence of neoplasia after IRA was 3.8, 8.7, and 21.7% at 10, 15, and 20 years, respectively, and that after IPAA was 1.6% at 20 years. CONCLUSIONS: The cumulative incidence of neoplasia after IPAA was minimal. Those who underwent IRA had a greater risk of developing neoplasia than those who underwent IPAA, although postoperative surveillance endoscopy was able to detect dysplasia/cancer at an early stage. IRA can be the surgical procedure of choice only in selected cases in which it would be of benefit to the patient, with more careful surveillance. PMID- 26960984 TI - Lipoprotein insertion into membranes of various complexity: lipid sorting, interfacial adsorption and protein clustering. AB - In a combined chemical-biological and biophysical approach we explored the membrane partitioning of the lipidated signaling proteins N-Ras and K-Ras4B into membrane systems of different complexity, ranging from one-component lipid bilayers and anionic binary and ternary heterogeneous membrane systems even up to partitioning studies on protein-free and protein-containing giant plasma membrane vesicles (GPMVs). To yield a pictorial view of the localization process, imaging using confocal laser scanning and atomic force microscopy was performed. The results reveal pronounced isoform-specific differences regarding the lateral distribution and formation of protein-rich membrane domains. Line tension is one of the key parameters controlling not only the size and dynamic properties of segregated lipid domains but also the partitioning process of N-Ras that acts as a lineactant. The formation of N-Ras protein clusters is even recorded for almost vanishing hydrophobic mismatch. Conversely, for K-Ras4B, selective localization and clustering are electrostatically mediated by its polybasic farnesylated C terminus. The formation of K-Ras4B clusters is also observed for the multi component GPMV membrane, i.e., it seems to be a general phenomenon, largely independent of the details of the membrane composition, including the anionic charge density of lipid headgroups. Our data indicate that unspecific and entropy driven membrane-mediated interactions play a major role in the partitioning behavior, thus relaxing the need for a multitude of fine-tuned interactions. Such a scenario seems also to be reasonable recalling the high dynamic nature of cellular membranes. Finally, we note that even relatively simple models of heterogeneous membranes are able to reproduce many of the properties of much more complex biological membranes. PMID- 26960983 TI - MK-4101, a Potent Inhibitor of the Hedgehog Pathway, Is Highly Active against Medulloblastoma and Basal Cell Carcinoma. AB - Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of many cancers, including medulloblastoma and basal cell carcinoma (BCC). In this study, using neonatally irradiated Ptch1(+/-) mice as a model of Hh-dependent tumors, we investigated the in vivo effects of MK-4101, a novel SMO antagonist, for the treatment of medulloblastoma and BCC. Results clearly demonstrated a robust antitumor activity of MK-4101, achieved through the inhibition of proliferation and induction of extensive apoptosis in tumor cells. Of note, beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1(+/-) mice. By identifying the changes induced by MK-4101 in gene expression profiles in tumors, we also elucidated the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in tumor cells, showing the maximum inhibitory effect on Gli1 MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. Members of the IGF and Wnt signaling pathways were among the most highly deregulated genes by MK 4101, suggesting that the interplay among Hh, IGF, and Wnt is crucial in Hh dependent tumorigenesis. Altogether, the results of this preclinical study support a therapeutic opportunity for MK-4101 in the treatment of Hh-driven cancers, also providing useful information for combination therapy with drugs targeting pathways cooperating with Hh oncogenic activity. Mol Cancer Ther; 15(6); 1177-89. (c)2016 AACR. PMID- 26960985 TI - NETTAB 2014: From high-throughput structural bioinformatics to integrative systems biology. AB - The fourteenth NETTAB workshop, NETTAB 2014, was devoted to a range of disciplines going from structural bioinformatics, to proteomics and to integrative systems biology. The topics of the workshop were centred around bioinformatics methods, tools, applications, and perspectives for models, standards and management of high-throughput biological data, structural bioinformatics, functional proteomics, mass spectrometry, drug discovery, and systems biology.43 scientific contributions were presented at NETTAB 2014, including keynote, special guest and tutorial talks, oral communications, and posters. Full papers from some of the best contributions presented at the workshop were later submitted to a special Call for this Supplement.Here, we provide an overview of the workshop and introduce manuscripts that have been accepted for publication in this Supplement. PMID- 26960987 TI - Editor's Note. PMID- 26960986 TI - Interleukin-6 gene polymorphisms in Egyptian children with febrile seizures: a case-control study. AB - BACKGROUND: Febrile seizures are the most common form of childhood seizures. Among pro-inflammatory cytokines, interleukin-6 is the key acute-phase cytokine. To date, only a few studies concerned the association of interleukin-6 gene polymorphisms with febrile seizures.In this study, we aimed to investigate 3 cytokine single-nucleotide polymorphisms situated at positions -174 (G/C), -572 (G/C), and -597 (G/A) in the promoter region of the interleukin-6 gene for the first time in Egyptian children with febrile seizures. METHODS: This was a case control study included 100 patients with febrile seizure, and matched with age, gender, ethnicity 100 healthy control subjects. Interleukin-6 -174 (G/C), -572 (G/C), and -597 (G/A) polymorphisms were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), while the serum IL6 levels were measured by ELISA method. RESULTS: Compared to the controls subjects, the frequency of the -174 GG and -597 GG IL6 genotypes were observed to be increased in children with febrile seizures (OR: 4.17; 95 % CI: 1.86-9.49; P <0.01 and OR: 1.96; 95 % CI: 1.06-3.63;P <0.05, respectively). We found a significant positive association between the -597 GG genotype and susceptibility to complex febrile seizures as did the G allele at the same position (OR: 4.2; 95 % CI: 1.4-13.3 for the GG genotype; P <0.01) and (OR: 2.89; 95 % CI: 1.1-7.7 for the G allele; P <0.05 respectively). Our data revealed no association between IL6- genotypes and serum IL6 levels in patients with febrile seizures (P > 0.05). CONCLUSION: In conclusion, our data brought a novel observation that the presence of a G allele or GG genotype at the -174 and the GG genotype at the -597 positions of the promoter region of the interleukin-6 gene constitute risk factors for developing febrile seizures in Egyptian children. Moreover, we observed a significant positive association between the IL6 -597 GG genotype and susceptibility to complex febrile seizures as did the G allele at the same position. However, we found no association between IL6- genotypes and serum IL6 levels in patients with febrile seizures. PMID- 26960988 TI - Canine parvovirus in vaccinated dogs: a field study. AB - The authors report a field study that investigated the canine parvovirus (CPV) strains present in dogs that developed the disease after being vaccinated. Faecal samples of 78 dogs that have been vaccinated against CPV and later presented with clinical signs suspected of parvovirus infection were used. Fifty (64.1 per cent) samples tested positive by PCR for CPV. No CPV vaccine type was detected. The disease by CPV-2b occurred in older and female dogs when compared with that by CPV-2c. The clinical signs presented by infected dogs were similar when any of both variants were involved. In most cases of disease, the resulting infection by field variants occurred shortly after CPV vaccination. Two dogs that had been subjected to a complete vaccination schedule and presented with clinical signs after 10 days of vaccination, had the CPV-2c variant associated. The phylogenetic studies showed a close relationship of the isolates in vaccinated dogs to European field strains. Despite the limited sample size in this study, the findings point to the significance of the continuous molecular typing of the virus as a tool to monitor the prevalent circulating CPV strains and access the efficacy of current vaccines. Adjustments on the vaccine types to be used may have to be evaluated again according to each epidemiological situation in order to achieve the dog's optimal immune protection against CPV. PMID- 26960989 TI - Mesoporous silica nanoparticles functionalized with fluorescent and MRI reporters for the visualization of murine tumors overexpressing alphavbeta3 receptors. AB - A novel fluorescein/Gd-DOTAGA containing nanoprobe for the visualization of tumors by optical and Magnetic Resonance Imaging (MRI) is reported herein. It is based on the functionalization of the surface of small mesoporous silica nanoparticles (MSNs) (~30 nm) with the arginine-glycine-aspartic (RGD) moieties, which are known to target alphavbeta3 integrin receptors overexpressed in several tumor cells. The obtained nanoprobe (Gd-MSNs-RGD) displays good stability, tolerability and high relaxivity (37.6 mM(-1) s(-1) at 21.5 MHz). After a preliminary evaluation of their cytotoxicity and targeting capability toward U87MG cells by in vitro fluorescence and MR imaging, the nanoprobes were tested in vivo by T1-weighted MR imaging of xenografted murine tumor models. The obtained results demonstrated that the Gd-MSNs-RGD nanoprobes are good reporters both in vitro and in vivo for the MR-visualization of tumor cells overexpressing alphavbeta3 integrin receptors. PMID- 26960990 TI - Asymptomatic bacteriuria among antenatal women in Lagos. AB - This cross-sectional study was undertaken to determine the prevalence of asymptomatic bacteriuria (ASB), the commonest bacterial isolates and the antibiotic sensitivity pattern among 556 pregnant women in Lagos University Teaching Hospital (LUTH), Nigeria. Women with a bacterial count over 100,000 colony-forming units per millilitre of the same organisms in paired urine samples were considered to have ASB. The prevalence of ASB was 14.6%. Klebsiella was the commonest micro-organism (39.2%) isolated. ASB was significantly associated with marital status, body mass index and parity. There was a significant relationship between urinary nitrites and ASB. The isolated organisms showed remarkable resistance to commonly prescribed antibiotics such as amoxicillin, cloxacillin and trimethoprim but good sensitivity to ofloxacin, gentamycin and ceftazidime. These facts have implications for the management of ASB in pregnancy. PMID- 26960991 TI - Peptide-tags for site-specific protein labelling in vitro and in vivo. AB - Peptide-tag based labelling can be achieved by (i) enzymes (ii) recognition of metal ions or small molecules and (iii) peptide-peptide interactions and enables site-specific protein visualization to investigate protein localization and trafficking. PMID- 26960993 TI - Culture of bullying at Birmingham hospital prevented staff from reporting high cardiac death rates. PMID- 26960992 TI - Poly(ester amine) constructed from polyethylenimine and pluronic for gene delivery in vitro and in vivo. AB - A series of poly (ester amines) (PEAs) constructed from low molecular weight polyethyleneimine (LPEI, Mw: 0.8k, 1.2k Da) and Pluronic (different molecular weight (Mw) and hydrophilic-lipophilic-balance (HLB)) components were synthesized, and evaluated in vitro and in vivo as gene delivery carriers. Most PEA polymers were able to bind and condense plasmid DNA effectively into particles of approximately 150 nm in solution at the polymer/DNA ratio of 5 and above. Transfection efficiency of the PEA polymers depends on particle size of the polymer/DNA complex, molecular weight and HLB of the Pluronics and the size of PEI within PEA composition, as well as the cell type. Significant improvement in gene delivery efficacy was achieved with PEA01/04/05 composed of Pluronic size (Mw: 3000-5000 Da), and HLB (12-18) in CHO, C2C12 and HSkM cell lines; and the effective transfection was reflected with PEA 01/04/07 composed of Pluronics with size (2000-5000 Da) and HLB (12-23) in mdx mice. The best formulation for pDNA delivery was obtained with PEA 01 producing transgene expression efficiency 5, 19 folds of that of PEI 25k in vitro and in vivo, respectively. These results potent some of these PEA polymers as attractive vehicles for gene or oligonucleotide delivery. PMID- 26960995 TI - Interlocked multi-armed carbon for stable oxygen reduction. AB - Structurally interlocked multi-armed carbon with a highly extended surface may be conveniently prepared by the deterministic growth of ZIF-8 on ZnO multiarms and the subsequent pyrolysis, which exhibits excellent stability and methanol corrosion resistance for oxygen reduction application. PMID- 26960994 TI - Resource Loss and Gain, Life Satisfaction, and Health Among Retirees in Spain. AB - OBJECTIVE: This article focuses on retirement transition from the Conservation of Resources (COR) perspective to better understand how aged participants' perceptions of retirement losses and gains significantly explain retirement well being. In this article, the mediation of social support in the losses-well-being relationship is explored. METHOD: The study was conducted with a two-wave longitudinal design. Participants at T1 were aged Spanish workers (>64 years) and at T2 were retirees, with a final sample of 275, who had retired during the previous 6 months. RESULTS: Findings supported the assertion that losses better explain well-being than gains. In addition, specific losses revealed a higher explaining power of life satisfaction and health complaints depending on their content. Social support mediated between perceived losses and well-being. DISCUSSION: This study suggests that both perceived losses and gains associated with retirement and social support during retirement should be taken into account when addressing postretirement well-being. PMID- 26960996 TI - Identification of different pathways of electron injection in dye-sensitised solar cells of electrodeposited ZnO using an indoline sensitiser. AB - Charge transfer dynamics in fully operational dye sensitised solar cells consisting of an electrolyte or organic spiroOMeTAD in contact with a highly porous electrodeposited ZnO film sensitised with a monolayer of the indoline dye DN216 were observed using ultrafast transient absorption spectroscopy. From the temporal evolution of spectral signatures assigned with the help of spectroelectrochemical experiments to the population and depopulation of initial, transient and final states, a model was completed for the multistep injection of photoexcited electrons from the molecular absorber to the ZnO acceptor. Injection was found to occur via three different paths with three characteristic rates: directly from the dye's lowest unoccupied molecular orbital into the ZnO conduction band (200 fs) and via intermediate molecular dominated and surface dominated hybrid states (2 ps and 10 ps, respectively). PMID- 26960997 TI - International consensus statement regarding the use of animal models for research on anastomoses in the lower gastrointestinal tract. AB - PURPOSE: This project aimed to reach consensus on the most appropriate animal models and outcome measures in research on anastomoses in the lower gastrointestinal tract (GIT). The physiology of anastomotic healing remains an important research topic in gastrointestinal surgery. Recent results from experimental studies are limited with regard to comparability and clinical translation. METHODS: PubMed and EMBASE were searched for experimental studies investigating anastomotic healing in the lower GIT published between January 1, 2000 and December 31, 2014 to assess currently used models. All corresponding authors were invited for a Delphi-based analysis that consisted of two online survey rounds followed by a final online recommendation survey to reach consensus on the discussed topics. RESULTS: Two hundred seventy-seven original articles were retrieved and 167 articles were included in the systematic review. Mice, rats, rabbits, pigs, and dogs are currently being used as animal models, with a large variety in surgical techniques and outcome measures. Forty-four corresponding authors participated in the Delphi analysis. In the first two rounds, 39/44 and 35/39 participants completed the survey. In the final meeting, 35 experts reached consensus on 76/122 items in six categories. Mouse, rat, and pig are considered appropriate animal models; rabbit and dog should be abandoned in research regarding bowel anastomoses. ARRIVE guidelines should be followed more strictly. CONCLUSIONS: Consensus was reached on several recommendations for the use of animal models and outcome measurements in research on anastomoses of the lower GIT. Future research should take these suggestions into account to facilitate comparison and clinical translation of results. PMID- 26960998 TI - Response of single bacterial cells to stress gives rise to complex history dependence at the population level. AB - Most bacteria live in ever-changing environments where periods of stress are common. One fundamental question is whether individual bacterial cells have an increased tolerance to stress if they recently have been exposed to lower levels of the same stressor. To address this question, we worked with the bacterium Caulobacter crescentus and asked whether exposure to a moderate concentration of sodium chloride would affect survival during later exposure to a higher concentration. We found that the effects measured at the population level depended in a surprising and complex way on the time interval between the two exposure events: The effect of the first exposure on survival of the second exposure was positive for some time intervals but negative for others. We hypothesized that the complex pattern of history dependence at the population level was a consequence of the responses of individual cells to sodium chloride that we observed: (i) exposure to moderate concentrations of sodium chloride caused delays in cell division and led to cell-cycle synchronization, and (ii) whether a bacterium would survive subsequent exposure to higher concentrations was dependent on the cell-cycle state. Using computational modeling, we demonstrated that indeed the combination of these two effects could explain the complex patterns of history dependence observed at the population level. Our insight into how the behavior of single cells scales up to processes at the population level provides a perspective on how organisms operate in dynamic environments with fluctuating stress exposure. PMID- 26961000 TI - Network synchronization in hippocampal neurons. AB - Oscillatory activity is widespread in dynamic neuronal networks. The main paradigm for the origin of periodicity consists of specialized pacemaking elements that synchronize and drive the rest of the network; however, other models exist. Here, we studied the spontaneous emergence of synchronized periodic bursting in a network of cultured dissociated neurons from rat hippocampus and cortex. Surprisingly, about 60% of all active neurons were self-sustained oscillators when disconnected, each with its own natural frequency. The individual neuron's tendency to oscillate and the corresponding oscillation frequency are controlled by its excitability. The single neuron intrinsic oscillations were blocked by riluzole, and are thus dependent on persistent sodium leak currents. Upon a gradual retrieval of connectivity, the synchrony evolves: Loose synchrony appears already at weak connectivity, with the oscillators converging to one common oscillation frequency, yet shifted in phase across the population. Further strengthening of the connectivity causes a reduction in the mean phase shifts until zero-lag is achieved, manifested by synchronous periodic network bursts. Interestingly, the frequency of network bursting matches the average of the intrinsic frequencies. Overall, the network behaves like other universal systems, where order emerges spontaneously by entrainment of independent rhythmic units. Although simplified with respect to circuitry in the brain, our results attribute a basic functional role for intrinsic single neuron excitability mechanisms in driving the network's activity and dynamics, contributing to our understanding of developing neural circuits. PMID- 26960999 TI - Origin and prediction of free-solution interaction studies performed label-free. AB - Interaction/reaction assays have led to significant scientific discoveries in the biochemical, medical, and chemical disciplines. Several fundamental driving forces form the basis of intermolecular and intramolecular interactions in chemical and biochemical systems (London dispersion, hydrogen bonding, hydrophobic, and electrostatic), and in the past three decades the sophistication and power of techniques to interrogate these processes has developed at an unprecedented rate. In particular, label-free methods have flourished, such as NMR, mass spectrometry (MS), surface plasmon resonance (SPR), biolayer interferometry (BLI), and backscattering interferometry (BSI), which can facilitate assays without altering the participating components. The shortcoming of most refractive index (RI)-based label-free methods such as BLI and SPR is the requirement to tether one of the interaction entities to a sensor surface. This is not the case for BSI. Here, our hypothesis is that the signal origin for free solution, label-free determinations can be attributed to conformation and hydration-induced changes in the solution RI. We propose a model for the free solution response function (FreeSRF) and show that, when quality bound and unbound structural data are available, FreeSRF correlates well with the experiment (R(2)> 0.99, Spearman rank correlation coefficients >0.9) and the model is predictive within ~15% of the experimental binding signal. It is also demonstrated that a simple mass-weighted deta/dC response function is the incorrect equation to determine that the change in RI is produced by binding or folding event in free solution. PMID- 26961002 TI - Allosteric switch regulates protein-protein binding through collective motion. AB - Many biological processes depend on allosteric communication between different parts of a protein, but the role of internal protein motion in propagating signals through the structure remains largely unknown. Through an experimental and computational analysis of the ground state dynamics in ubiquitin, we identify a collective global motion that is specifically linked to a conformational switch distant from the binding interface. This allosteric coupling is also present in crystal structures and is found to facilitate multispecificity, particularly binding to the ubiquitin-specific protease (USP) family of deubiquitinases. The collective motion that enables this allosteric communication does not affect binding through localized changes but, instead, depends on expansion and contraction of the entire protein domain. The characterization of these collective motions represents a promising avenue for finding and manipulating allosteric networks. PMID- 26961001 TI - Molecular hydrogen and catalytic combustion in the production of hyperpolarized 83Kr and 129Xe MRI contrast agents. AB - Hyperpolarized (hp) (83)Kr is a promising MRI contrast agent for the diagnosis of pulmonary diseases affecting the surface of the respiratory zone. However, the distinct physical properties of (83)Kr that enable unique MRI contrast also complicate the production of hp (83)Kr. This work presents a previously unexplored approach in the generation of hp (83)Kr that can likewise be used for the production of hp (129)Xe. Molecular nitrogen, typically used as buffer gas in spin-exchange optical pumping (SEOP), was replaced by molecular hydrogen without penalty for the achievable hyperpolarization. In this particular study, the highest obtained nuclear spin polarizations were P =29% for(83)Kr and P= 63% for (129)Xe. The results were reproduced over many SEOP cycles despite the laser induced on-resonance formation of rubidium hydride (RbH). Following SEOP, the H2 was reactively removed via catalytic combustion without measurable losses in hyperpolarized spin state of either (83)Kr or (129)Xe. Highly spin-polarized (83)Kr can now be purified for the first time, to our knowledge, to provide high signal intensity for the advancement of in vivo hp (83)Kr MRI. More generally, a chemical reaction appears as a viable alternative to the cryogenic separation process, the primary purification method of hp(129)Xe for the past 2 1/2 decades. The inherent simplicity of the combustion process will facilitate hp (129)Xe production and should allow for on-demand continuous flow of purified and highly spin-polarized (129)Xe. PMID- 26961004 TI - Correlates of postpartum common mental disorders: results from a population-based study in Amhara region, Ethiopia. AB - Postpartum common mental disorders are prevalent among women in Ethiopia. Data on associated factors are limited. This population-based study assessed mental health among 1294 nonpregnant, postpartum women in Amhara region. Poor health of the last delivered child and inequitable gender attitudes were associated with poor mental health among other factors. Social support from female friends was strongly protective. Community mental health services could strengthen social support between female friends with education and support group facilitation by health extension workers. PMID- 26961005 TI - Eating disorder symptoms pre- and postpartum. AB - The study aimed to investigate symptoms of disordered eating pre- and postpartum using a standardised and widely used measure of eating disorder (ED) psychopathology. A consecutive series of women attending either prenatal (N = 426) or postnatal (N = 345) clinics in metropolitan Stockholm were assessed using the Eating Disorder Examination Questionnaire (EDE-Q). Assessments were conducted at either the first visit to prenatal clinics (10-12 weeks of pregnancy) or 6 to 8 months postpartum. An optimised shortened version of the EDE-Q was best suited for studying eating disorders pre- and postpartum. Using the optimised version of the instrument with 14 items and a cut-off score of >=2.8, it was estimated that 5.3 % of prepartum and 12.8 % of postpartum mothers were suffering from clinical eating disorders. Seriously disordered eating behaviour during, and especially after, pregnancy may be more common than previously thought. It is imperative that health services focus increased attention on these problems by raising awareness, developing and extending specialist services, as well as through implementing educational programmes and training directed toward frontline healthcare services. PMID- 26961003 TI - Experiences of chronic stress and mental health concerns among urban Indigenous women. AB - We measured stress, depression and post-traumatic stress disorder (PTSD) levels of urban Indigenous women living with and without HIV in Ontario, Canada, and identified correlates of depression. We recruited 30 Indigenous women living with HIV and 60 without HIV aged 18 years or older who completed socio-demographic and health questionnaires and validated scales assessing stress, depression and PTSD. Descriptive statistics were conducted to summarize variables and linear regression to identify correlates of depression. 85.6 % of Indigenous women self identified as First Nation. Co-morbidities other than HIV were self-reported by 82.2 % (n = 74) of the sample. High levels of perceived stress were reported by 57.8 % (n = 52) of the sample and 84.2 % (n = 75) had moderate to high levels of urban stress. High median levels of race-related (51/88, IQR 42-68.5) and parental-related stress (40.5/90, IQR 35-49) scores were reported. 82.2 % (n = 74) reported severe depressive symptoms and 83.2 % (n = 74) severe PTSD. High levels of perceived stress was correlated with high depressive symptoms (estimate 1.28 (95 % CI 0.97-1.58), p < 0.001). Indigenous women living with and without HIV reported elevated levels of stress and physical and mental health concerns. Interventions cutting across diverse health care settings are required for improving and preventing adverse health outcomes. PMID- 26961007 TI - Refining a Web-based goal assessment interview: item reduction based on reliability and predictive validity. AB - BACKGROUND: Goals are an important basis for patients' cognitive appraisal processes underlying quality-of-life (QOL) assessment because they are the foundation to one's frame of reference. We sought to identify the best of six goal delineation items and relevant themes for two new versions of the QOL Appraisal Profile: an interview tool using a subset of the best open-ended goal delineation items, and a shorter close-ended version for use in survey research. METHODS: This is a secondary analysis of longitudinal data (n = 1126) of participants in the North American Research Committee on Multiple Sclerosis (MS) registry. The open-ended data were coded by at least two trained coders with moderately high inter-rater agreement. There were 31 themes reflecting goal content such as health, interpersonal, independence, mental health, and financial themes. Descriptive statistics identified most prevalent themes. Reliability analysis (alpha, item-total correlations) and hierarchical linear modeling identified the best goal items. RESULTS: Based on these qualitative and quantitative analyses, Solve (item 2) is the best single item because it is clear anchor for about a third of the goal themes, and explains the most variance in outcomes and demographic characteristics, suggesting that it taps into and reveals diversity in the sample. The next best items are Accomplish and Maintain (items 1 and 4), which are useful in tapping into and revealing diversity among people reporting cognitive deficits (Accomplish), and demographic factors (both Accomplish and Maintain items). CONCLUSIONS: The goal delineation items identified as best performers in this study will be used to develop a shorter open-ended version of the QOL Appraisal Profile, and an entirely close-ended version of the QOL Appraisal Profile for use in more standard survey research settings. These tools will enable coaching patients in medical decision making as well as investigations of appraisal and response shift in QOL research. PMID- 26961009 TI - Sialolithiasis in an Accessory Submandibular Gland Identified by Magnetic Resonance Sialography. AB - BACKGROUND: Accessory submandibular gland is a very rare anatomical variant. There have been only 6 reported cases of this entity in the English literature, only 1 of which was identified using magnetic resonance imaging. METHODS: We report the case of a 39-year-old female with symptoms of left submandibular sialoadenitis who was diagnosed of sialolithiasis within the left accessory submandibular gland by magnetic resonance sialography (MR-Si). RESULTS: The calculus was palpated near the submandibular papilla and was extracted by an intraoral approach. One-year follow-up revealed no evidence of recurrence. CONCLUSIONS: This is the first case reported to date in the English literature of a patient with sialolithiasis within an accessory submandibular gland diagnosed by MR-Si. PMID- 26961006 TI - Transcriptional induction of the heat shock protein B8 mediates the clearance of misfolded proteins responsible for motor neuron diseases. AB - Neurodegenerative diseases (NDs) are often associated with the presence of misfolded protein inclusions. The chaperone HSPB8 is upregulated in mice, the human brain and muscle structures affected during NDs progression. HSPB8 exerts a potent pro-degradative activity on several misfolded proteins responsible for familial NDs forms. Here, we demonstrated that HSPB8 also counteracts accumulation of aberrantly localized misfolded forms of TDP-43 and its 25 KDa fragment involved in most sporadic cases of Amyotrophic Lateral Sclerosis (sALS) and of Fronto Lateral Temporal Dementia (FLTD). HSPB8 acts with BAG3 and the HSP70/HSC70-CHIP complex enhancing the autophagic removal of misfolded proteins. We performed a high-through put screening (HTS) to find small molecules capable of inducing HSPB8 in neurons for therapeutic purposes. We identified two compounds, colchicine and doxorubicin, that robustly up-regulated HSPB8 expression. Both colchicine and doxorubicin increased the expression of the master regulator of autophagy TFEB, the autophagy linker p62/SQSTM1 and the autophagosome component LC3. In line, both drugs counteracted the accumulation of TDP-43 and TDP-25 misfolded species responsible for motoneuronal death in sALS. Thus, analogs of colchicine and doxorubicin able to induce HSPB8 and with better safety and tolerability may result beneficial in NDs models. PMID- 26961008 TI - The EQ-5D-5L valuation study in Korea. AB - PURPOSE: This study aimed to estimate Korean preference weights for EQ-5D-5L based on values elicited from Korean population by applying the EuroQol Valuation Technology (EQ-VT) program and the standard protocol by the EuroQol Group. METHODS: The multistage quota sampling method was used to recruit 1085 subjects from the general population in Korea. Each respondent valuated 10 health states using the composite time trade-off (cTTO) and 7 health states using discrete choice experiment. The EQ-VT program was developed by the EuroQol Group and translated into Korean with the Korean research team. Computer-assisted, face-to face interviews were conducted. A range of predictive models were explored using cTTO. The most appropriate model was determined after assessing goodness of fit, logical consistency, and parsimony. RESULTS: Of 3206 contacted, 1085 subjects completed interviews (33.8 %) and 1080 were used for modeling. A model with dummy variables for each level of severity and dimension and a term that picked up whether any dimension in the state was at level 4 or 5 was selected as the best predictive model. All coefficients of the final model were statistically significant and logically consistent. In addition, it was parsimonious. This model had mean absolute error of 0.027, and the absolute error for all 86 health states was below 0.1. CONCLUSIONS: The final model built in this study appears to predict the utilities of the states which were valuated directly. This model could be used to interpolate quality weights for all EQ-5D-5L health states. PMID- 26961010 TI - International trade causes large net economic losses in tropical countries via the destruction of ecosystem services. AB - Despite the large implications of the use of tropical land for exports ("land absorption") on ecosystem services (ES) and global biodiversity conservation, the magnitude of these externalities is not known. We quantify the net value of ES lost in tropical countries as a result of cropland, forestland and pastureland absorption for exports after deducting ES gains through imports ("land displacement"). We find that net ES gains occur only in 7 out of the 41 countries and regions considered. We estimate global annual net losses of over 1.7 x 10(12) international dollars (I$) (I$1.1 x 10(12) if carbon-related services are not considered). After deducting the benefits from agricultural, forest and livestock rents in land replacing tropical forests, the net annual losses are I$1.3 and I$0.7 x 10(12), respectively. The results highlight the large magnitude of tropical ES losses through international trade that are not compensated by the rents of land uses in absorbed land. PMID- 26961014 TI - [Facial skin like worm eaten wood]. PMID- 26961016 TI - [Losing weight more easily with vegetarian diet]. PMID- 26961011 TI - When is a forest a forest? Forest concepts and definitions in the era of forest and landscape restoration. AB - We present a historical overview of forest concepts and definitions, linking these changes with distinct perspectives and management objectives. Policies dealing with a broad range of forest issues are often based on definitions created for the purpose of assessing global forest stocks, which do not distinguish between natural and planted forests or reforests, and which have not proved useful in assessing national and global rates of forest regrowth and restoration. Implementing and monitoring forest and landscape restoration requires additional approaches to defining and assessing forests that reveal the qualities and trajectories of forest patches in a spatially and temporally dynamic landscape matrix. New technologies and participatory assessment of forest states and trajectories offer the potential to operationalize such definitions. Purpose-built and contextualized definitions are needed to support policies that successfully protect, sustain, and regrow forests at national and global scales. We provide a framework to illustrate how different management objectives drive the relative importance of different aspects of forest state, dynamics, and landscape context. PMID- 26961015 TI - [Travel warning due to Zika viruses]. PMID- 26961017 TI - [Commercially prepared milk changes baby's microbiome]. PMID- 26961018 TI - [Every second dosage is wrong]. PMID- 26961019 TI - [Skin symptoms only appear harmless]. PMID- 26961020 TI - [Purple coneflower as antiviral agent]. PMID- 26961022 TI - [How much exercise can a COPD patient tolerate?]. PMID- 26961021 TI - ["Better control of asthma with winter sports"]. PMID- 26961023 TI - [Ketogenic diet also for adult epileptics?]. PMID- 26961024 TI - [Discharge management in clinics: what is the general practitioner's role]. PMID- 26961025 TI - [This is how much debated appointment services must immediately function]. PMID- 26961026 TI - [Dramatic hours at the other end of the world]. PMID- 26961027 TI - [Visit to the refugee camp: diagnosis in the dark]. PMID- 26961028 TI - [Calculating all delegated services according to GOA]. PMID- 26961029 TI - [The paper calendar is far from dead!]. PMID- 26961030 TI - [Sick employee is not required to appear for a personal discussion]. PMID- 26961031 TI - [It won't get better than this unfortunately]. PMID- 26961032 TI - [Why Putin runs like a gunman]. PMID- 26961033 TI - [Rejection of the rejection of scientific articles]. PMID- 26961034 TI - [Let's at least make the world beautiful with our words!]. PMID- 26961035 TI - [Does the blood in veins really freeze in fear?]. PMID- 26961036 TI - [How Bob Dylan's citations pervade the medical literature]. PMID- 26961037 TI - [When eating becomes a problem]. PMID- 26961038 TI - [Anorexia nervosa--diagnostic criteria and state of the art therapy]. PMID- 26961039 TI - [Bulimia nervosa]. PMID- 26961041 TI - [Diverticular disease]. PMID- 26961040 TI - [Emergency checklist: Nosebleed again and again]. PMID- 26961042 TI - [Geriatric Assessment]. PMID- 26961043 TI - [Lymphangioma circumscriptum]. PMID- 26961044 TI - [Long-term consequences of physical and psychological trauma exposition]. PMID- 26961045 TI - [Phytotherapy usually better than "resistance by prescription"]. PMID- 26961046 TI - [New drug combination for initial therapy]. PMID- 26961047 TI - [Survey confirms high daily stress due to itchy hives]. PMID- 26961048 TI - [2nd PCSK9 inhibitor for effective LDL decrease]. PMID- 26961049 TI - [Retard morphine reduces craving for heroin]. PMID- 26961050 TI - [Compression therapy independent of etiology is useful]. PMID- 26961051 TI - [Networking with the diabetes team per smart phone app]. PMID- 26961052 TI - [LAMA/LABA supports physical activity in COPD patients]. PMID- 26961053 TI - [GLP-1 agonist supports weight loss]. PMID- 26961054 TI - [Topical psoriasis therapy becomes more tolerable]. PMID- 26961055 TI - [Not a cure, but a normal life]. PMID- 26961056 TI - [Drug therapy rarely fully utilized]. PMID- 26961057 TI - [Exacerbation alarm in eosinophilia]. PMID- 26961058 TI - [Grippe simulation on the internet]. PMID- 26961059 TI - The Matthew Effect. PMID- 26961061 TI - Asymmetrical Deterministic Lateral Displacement Gaps for Dual Functions of Enhanced Separation and Throughput of Red Blood Cells. AB - Deterministic lateral displacement (DLD) method for particle separation in microfluidic devices has been extensively used for particle separation in recent years due to its high resolution and robust separation. DLD has shown versatility for a wide spectrum of applications for sorting of micro particles such as parasites, blood cells to bacteria and DNA. DLD model is designed for spherical particles and efficient separation of blood cells is challenging due to non uniform shape and size. Moreover, separation in sub-micron regime requires the gap size of DLD systems to be reduced which exponentially increases the device resistance, resulting in greatly reduced throughput. This paper shows how simple application of asymmetrical DLD gap-size by changing the ratio of lateral-gap (GL) to downstream-gap (GD) enables efficient separation of RBCs without greatly restricting throughput. This method reduces the need for challenging fabrication of DLD pillars and provides new insight to the current DLD model. The separation shows an increase in DLD critical diameter resolution (separate smaller particles) and increase selectivity for non-spherical RBCs. The RBCs separate better as compared to standard DLD model with symmetrical gap sizes. This method can be applied to separate non-spherical bacteria or sub-micron particles to enhance throughput and DLD resolution. PMID- 26961062 TI - Effects of Nosema apis, N. ceranae, and coinfections on honey bee (Apis mellifera) learning and memory. AB - Western honey bees (Apis mellifera) face an increasing number of challenges that in recent years have led to significant economic effects on apiculture, with attendant consequences for agriculture. Nosemosis is a fungal infection of honey bees caused by either Nosema apis or N. ceranae. The putative greater virulence of N. ceranae has spurred interest in understanding how it differs from N. apis. Little is known of effects of N. apis or N. ceranae on honey bee learning and memory. Following a Pavlovian model that relies on the proboscis extension reflex, we compared acquisition learning and long-term memory recall of uninfected (control) honey bees versus those inoculated with N. apis, N. ceranae, or both. We also tested whether spore intensity was associated with variation in learning and memory. Neither learning nor memory differed among treatments. There was no evidence of a relationship between spore intensity and learning, and only limited evidence of a negative effect on memory; this occurred only in the co inoculation treatment. Our results suggest that if Nosema spp. are contributing to unusually high colony losses in recent years, the mechanism by which they may affect honey bees is probably not related to effects on learning or memory, at least as assessed by the proboscis extension reflex. PMID- 26961063 TI - Determination of Narasin in Chicken Fat: A Bridging Study Comparing the Bioautographic Method (FSIS CLG Method R22) to a Liquid Chromatography with Tandem Mass Spectrometry Method (AOAC Method 2011.24). AB - Lilly Method AM-AA-CA-R108-AB-755, which is substantially the same as U.S. Department of Agriculture, Food Safety and Inspection Service (FSIS) Chemistry Laboratory Guidebook (CLG) method R22, is the current regulatory method for determining narasin in cattle and chicken tissues and is based on bioautography, creating a zone of inhibition of bacterial growth, with the size of the zone correlating to the amount of narasin extracted from the tissue. AOAC Method 2011.24 is an LC-tandem mass spectrometry (MS/MS) method for determining narasin content from bovine, swine, or chicken tissues. It has many advantages over the regulatory method, including higher throughput, less solvent use, no use of carbon tetrachloride, a wider method range, inclusion of swine tissues, and it is less labor intensive. In this study, AOAC Method 2011.24 was compared to FSIS CLG method R22 for the determination of narasin in chicken abdominal fat. Fortified chicken-fat samples ranging from 20 to 960 ng/g and incurred chicken-fat samples ranging from 40 to 480 ng/g were assayed by both methods in triplicate. Mean accuracies for the two methods were similar, 77-110% for CLG R22 and 84-96% for AOAC Method 2011.24, and the method results showed a linear correlation. The methods differed in precision, however, with the CLG R22 method yielding 2.6-34% RSD and AOAC Method 2011.24 yielding 0.15-6.4% RSD. It is recommended that AOAC Method 2011.24-granted AOAC Official Method(SM) Final Action status-be adopted as the official U.S. regulatory method. PMID- 26961065 TI - Cardioprotection: Cardiotoxicity of anticancer therapy. PMID- 26961067 TI - Hypertension: Surgery remains treatment of choice for CTEPH. AB - The long-term outcomes of operated and nonoperated patients with chronic thromboembolic pulmonary hypertension were reported in a large, prospective, multicentre, European and Canadian registry. The long-term prognosis of operated patients was superior to that of nonoperated patients, indicating that surgery should be the first-choice treatment in this patient cohort. PMID- 26961066 TI - Heart failure: SGLT2 inhibitors and heart failure -- clinical implications. AB - The latest findings from the EMPA-REG OUTCOME trial show a 34% reduction in hospitalization for heart failure or cardiovascular death in patients receiving empagliflozin, a sodium/glucose cotransporter 2 (SGLT2) inhibitor, compared with placebo. These outstanding results call for discussion of the clinical implications, and in-depth studies of the mechanisms of action of SGLT2 inhibitors. PMID- 26961068 TI - Antiplatelet therapy: Safe to continue aspirin therapy before CABG surgery. PMID- 26961064 TI - Thrombus aspiration in acute myocardial infarction. AB - The success of primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) is often hampered by incomplete microvascular myocardial reperfusion owing to distal embolization of thrombus resulting in microvascular obstruction. To address this problem, thrombus aspiration devices have been developed that can be used to evacuate coronary thrombus either manually or mechanically. Thrombus aspiration has the potential to reduce the local thrombus load, minimize the need for balloon predilatation, facilitate direct stenting, prevent distal embolization, and ultimately improve myocardial reperfusion. Furthermore, thrombus aspiration has enabled us to study coronary thrombus in vivo, and has facilitated recognition of distinct mechanisms of coronary thrombosis. Clinical trials focusing on manual thrombus aspiration in primary PCI have generally shown improved myocardial reperfusion. However, in two large trials powered for clinical end points, no reduction in 1-year mortality or other adverse clinical events was observed with the use of this strategy. Moreover, one of these trials showed a marginally increased risk of stroke. Consequently, current guidelines do not recommend routine use of thrombus aspiration. Future studies should focus on the identification of subgroups of patients with STEMI who might derive benefit from manual thrombus aspiration, and establish the effect of operator performance on the efficacy and safety of the procedure. PMID- 26961070 TI - Silicon moderated the K deficiency by improving the plant-water status in sorghum. AB - Although silicon (Si) has been widely reported to alleviate plant nutrient deficiency, the underlying mechanism in potassium (K) deficiency is poorly understood. In this study, sorghum seedlings were treated with Si under a K deficiency condition for 15 days. Under control conditions, plant growth was not affected by Si application. The growth and water status were reduced by K deficient stress, but Si application significantly alleviated these decreases. The leaf gas exchanges, whole-plant hydraulic conductance (Kplant), and root hydraulic conductance (Lpr) were reduced by K deficiency, but Si application moderated the K-deficiency-induced reductions, suggesting that Si alleviated the plant hydraulic conductance. In addition, 29% of Si-alleviated transpiration was eliminated by HgCl2 treatment, suggesting that aquaporin was not the primary cause for the reversal of plant hydraulic conductance. Moreover, the K(+) concentration in xylem sap was significantly increased and the xylem sap osmotic potential was decreased by Si application, suggesting that the major cause of Si induced improvement in hydraulic conductance could be ascribed to the enhanced xylem sap K(+) concentration, which increases the osmotic gradient and xylem hydraulic conductance. The results of this study show that Si mediates K(+) accumulation in xylem, which ultimately alleviates the plant-water status under the K-deficient condition. PMID- 26961069 TI - Comprehensive molecular portrait using next generation sequencing of resected intestinal-type gastric cancer patients dichotomized according to prognosis. AB - In this study, we evaluated whether the presence of genetic alterations detected by next generation sequencing may define outcome in a prognostically-selected and histology-restricted population of resected gastric cancer (RGC). Intestinal type RGC samples from 34 patients, including 21 best and 13 worst prognostic performers, were studied. Mutations in 50 cancer-associated genes were evaluated. A significant difference between good and poor prognosis was found according to clinico-pathologic factors. The most commonly mutated genes in the whole population were PIK3CA (29.4%), KRAS (26.5%), TP53 (26.5%) MET (8.8%), SMAD4 (8.8%) and STK11 (8.8%). Multiple gene mutations were found in 14/21 (67%) patients with good prognosis, and 3/13 (23%) in the poor prognosis group. A single gene alteration was found in 5/21 (24%) good and 6/13 (46%) poor prognosis patients. No mutation was found in 2/21 (9.5%) and 4/13 (31%) of these groups, respectively. In the overall series, beta-catenin expression was the highest (82.4%), followed by E-Cadherin (76.5%) and FHIT (52.9%). The good prognosis group was characterized by a high mutation rate and microsatellite instability. Our proof-of-principle study demonstrates the feasibility of a molecular profiling approach with the aim to identify potentially druggable pathways and drive the development of customized therapies for RGC. PMID- 26961072 TI - Work Role Residuals Among Fully Retired Individuals: Results of a 10-Year Panel Study. AB - From a role theoretical perspective, it can be expected that individuals differ in the extent to which they experience aspects of the work role after they have fully retired from it. This study presents a measure of these "postretirement work role residuals" and examines them in relation to structural preretirement factors, psychological preretirement factors, and the nature of the retirement transition. Heckman selection models were estimated based on three-wave panel data collected among 848 older Dutch individuals who were employed at Wave 1 and fully retired thereafter. Although for the majority of retirees prior work plays only a minor role in their current lives, also for a considerable share prior work is still important. Higher levels of postretirement work role residuals were observed among those who expected to miss work-related social status in retirement, who were less disengaged from work in preretirement years, and among those who retired involuntarily. PMID- 26961071 TI - Inheritance of the Bantu/Benin haplotype causes less severe hemolytic and oxidative stress in sickle cell anemia patients treated with hydroxycarbamide. AB - Beta S-globin gene cluster haplotypes (beta(S)-haplotypes) can modulate the response to hydroxycarbamide (HC) treatment in sickle cell anemia (SCA) patients. In Brazil, the most common haplotypes are Bantu and Benin, and both confer a poor prognosis for patients when untreated with HC. We evaluated oxidative and hemolytic biomarkers in 48 SCA patients undergoing HC treatment separated in three subgroups: Bantu/Bantu, Bantu/Benin and Benin/Benin haplotype. On the basis of reduced haptoglobin (HP) levels, patients with Bantu/Bantu haplotypes had 3.0% higher hemolysis degree when compared with those with Bantu/Benin haplotypes (P=0.01). The Benin/Benin patients had 53.6% greater lipid peroxidation index than the Bantu/Bantu patients (P=0.01) because of evaluated thiobarbituric acid reactive species levels. The Bantu/Benin subgroup had intermediate levels of hemolytic and oxidative stress markers compared with the homozygous subgroups. Through strict inclusion criteria adopted, as well as consolidated and well described hemolytic and the oxidative parameters evaluated, we suggest a haplotype-interaction response to HC treatment mediated by a 'balance' between the genetic factors of each haplotype studied. PMID- 26961073 TI - Screen-printed flexible MRI receive coils. AB - Magnetic resonance imaging is an inherently signal-to-noise-starved technique that limits the spatial resolution, diagnostic image quality and results in typically long acquisition times that are prone to motion artefacts. This limitation is exacerbated when receive coils have poor fit due to lack of flexibility or need for padding for patient comfort. Here, we report a new approach that uses printing for fabricating receive coils. Our approach enables highly flexible, extremely lightweight conforming devices. We show that these devices exhibit similar to higher signal-to-noise ratio than conventional ones, in clinical scenarios when coils could be displaced more than 18 mm away from the body. In addition, we provide detailed material properties and components performance analysis. Prototype arrays are incorporated within infant blankets for in vivo studies. This work presents the first fully functional, printed coils for 1.5- and 3-T clinical scanners. PMID- 26961074 TI - FNDC5 is produced in the stomach and associated to body composition. AB - The fibronectin type III domain-containing protein 5 (FNDC5) discovered in 2002 has recently gained attention due to its potential role in protecting against obesity. In rat, no data exist regarding FNDC5 production and regulation in the stomach. The aim of the present work was to determine the expression of FNDC5 in the rat stomach and its potential regulation by body composition. The present data shows FNDC5 gene expression in the gastric mucosa. Immunohistochemical studies found FNDC5 immunopositivity in chief cells of gastric tissue. By the use of three different antibodies FNDC5 was found expressed in gastric mucosa and secreted by the stomach. The rate of gastric FNDC5 secretion parallels the circulating levels of FNDC5. The body fat mass increase after intervention with high fat diet coincided with a decrease in the secretion of FNDC5 from the stomach and a diminution in the FNDC5 circulating levels. In summary, the present data shows, for the first time, the expression of FNDC5 in the stomach of rats and its regulation by body composition, suggesting a potential role of gastric FNDC5 in energy homeostasis. PMID- 26961075 TI - Allele frequency distribution of 21 forensic autosomal STR loci of GoldeneyeTM DNA ID 22NC Kit in Chinese Tibetan group. PMID- 26961077 TI - Erratum to: ASNC imaging guidelines for SPECT nuclear cardiology procedures: Stress, protocols, and tracers. PMID- 26961076 TI - Enlightenment from a small but rapidly evolving penetrating aortic ulcer. AB - Penetrating aortic ulcer (PAU) is a pathologic type of acute aortic syndrome and usually locates in the descending aorta. The presentation, behavior and natural history of this disease process have not been clear. Here we report a case in which a rapidly evolving PAU in descending aorta needed aggressive percutaneous interventional treatment. The present case with its unique scenario might draw clinicians' attention on a "beyond the guidelines" issue. PMID- 26961078 TI - Awareness, knowledge and healthy lifestyle behaviors related to coronary heart disease among women: An integrative review. AB - The purpose of this review is to examine recent literature on the awareness, knowledge, and healthy lifestyle behaviors related to Coronary Heart Disease (CHD) among women. Literature published in the English language from 2004 to 2015 was reviewed. Of the 684 articles retrieved, 21 were deemed relevant. Being aware that CHD is the leading cause of death in women and knowledge of the risk factors of CHD were found to be generally suboptimal in the women studied. Awareness was seen to be positively associated with healthy lifestyle behaviors, though findings on the predictive relationship of knowledge of risk factors on healthy lifestyle behaviors in women seem to be divided. Diabetes was the prominent risk factor that most women did not associate with CHD. Translating these findings into clinical practice can help health care providers be more attuned when discussing CHD with their female patients so as to provide targeted education on CHD prevention. PMID- 26961079 TI - Sequence Data, Phylogenetic Inference, and Implications of Downward Causation. AB - Framing systematics as a field consistent with scientific inquiry entails that inferences of phylogenetic hypotheses have the goal of producing accounts of past causal events that explain differentially shared characters among organisms. Linking observations of characters to inferences occurs by way of why-questions implied by data matrices. Because of their form, why-questions require the use of common-cause theories. Such theories in phylogenetic inferences include natural selection and genetic drift. Selection or drift can explain 'morphological' characters but selection cannot be causally applied to sequences since fitness differences cannot be directly associated with individual nucleotides or amino acids. The relation of selection to sequence data is by way of downward or top down causation from those phenotypes upon which selection occurs. The application of phylogenetic inference to explain sequence data is thus restricted to instances where drift is the relevant theory; those nucleotides or amino acids that can be explained via downward causation are precluded from inclusion in the data matrix. The restrictions on the inclusion of sequence data in phylogenetic inferences equally apply to species hypotheses, precluding the more restrictive approach known as DNA barcoding. Not being able to discern drift and selection as relevant causal mechanisms can severely constrain the inclusion and explanations of sequence data. Implications of such exclusion are discussed in relation to the requirement of total evidence. PMID- 26961080 TI - Efficacy of simulation application SimMon for emergency response training. PMID- 26961081 TI - Integrated decision-making about housing, energy and wellbeing: a qualitative system dynamics model. AB - BACKGROUND: The UK government has an ambitious goal to reduce carbon emissions from the housing stock through energy efficiency improvements. This single policy goal is a strong driver for change in the housing system, but comes with positive and negative "unintended consequences" across a broad range of outcomes for health, equity and environmental sustainability. The resulting policies are also already experiencing under-performance through a failure to consider housing as a complex system. This research aimed to move from considering disparate objectives of housing policies in isolation to mapping the links between environmental, economic, social and health outcomes as a complex system. We aimed to support a broad range of housing policy stakeholders to improve their understanding of housing as a complex system through a collaborative learning process. METHODS: We used participatory system dynamics modelling to develop a qualitative causal theory linking housing, energy and wellbeing. Qualitative interviews were followed by two interactive workshops to develop the model, involving representatives from national and local government, housing industries, non government organisations, communities and academia. RESULTS: More than 50 stakeholders from 37 organisations participated. The process resulted in a shared understanding of wellbeing as it relates to housing; an agreed set of criteria against which to assess to future policy options; and a comprehensive set of causal loop diagrams describing the housing, energy and wellbeing system. The causal loop diagrams cover seven interconnected themes: community connection and quality of neighbourhoods; energy efficiency and climate change; fuel poverty and indoor temperature; household crowding; housing affordability; land ownership, value and development patterns; and ventilation and indoor air pollution. CONCLUSIONS: The collaborative learning process and the model have been useful for shifting the thinking of a wide range of housing stakeholders towards a more integrated approach to housing. The qualitative model has begun to improve the assessment of future policy options across a broad range of outcomes. Future work is needed to validate the model and increase its utility through computer simulation incorporating best quality data and evidence. Combining system dynamics modelling with other methods for weighing up policy options, as well as methods to support shifts in the conceptual frameworks underpinning policy, will be necessary to achieve shared housing goals across physical, mental, environmental, economic and social wellbeing. PMID- 26961082 TI - Expression and Characterization of a Novel 1,3-Propanediol Dehydrogenase from Lactobacillus brevis. AB - 1,3-Propanediol dehydrogenase (PDOR) is important in the biosynthesis of 1,3 propanediol. In the present study, the dhaT gene encoding PDOR was cloned from Lactobacillus brevis 6239 and expressed in Escherichia coli for the first time. Sequence analysis revealed that PDOR containing two Fe(2+)-binding motifs and a cofactor motif belongs to the type III alcohol dehydrogenase. The purified recombinant PDOR exhibited a single band of 42 kDa according to SDS-PAGE. Optimal temperatures and pH values of this dehydrogenase are 37 degrees C, 7.5 for reduction and 25 degrees C, 9.5 for oxidation, respectively. We found that PDOR was more stable in acid buffer than in alkaline condition, and 60 % of its relative activity still remained after a 2-h incubation at 37 degrees C. The activity of PDOR can be enhanced in the presence of Mn(2+) or Fe(2+) iron and inhibited by EDTA or PMSF by different degrees. The K m and V max of this dehydrogenase are 1.25 mM, 64.02 MUM min(-1) mg(-1) for propionaldehyde and 2.26 mM, 35.05 MUM min(-1) mg(-1) for 1,3-PD, respectively. Substrate specificity analysis showed that PDOR has a broad range of substrate specificities. The modeling superposition indicated that the structural differences may account for the diversity of PDORs' properties. Thus, our PDOR is a potential candidate for facilitating the 1,3-PD biosynthesis. PMID- 26961083 TI - Effect of Tetracycline Antibiotics on Performance and Microbial Community of Algal Photo-Bioreactor. AB - Tetracycline antibiotics have been increasingly used in medical applications and have been found in wastewater treatment plants as a result of human and industrial activities. This study investigates the combined effects of tetracycline antibiotics on the performance of an algal photo-bioreactor operated under different antibiotic concentrations in the ranges of 0.25 to 30 mg/L and considers the inhibition of algal growth, carbon and nutrient removal rates, and eukaryotic and cyanobacterial algal community changes. The results indicated that increases in the concentration of tetracycline mixtures have adverse effects on the algal community and the performance of a photo-bioreactor, and the eukaryotic algae species were more sensitive to tetracycline antibiotics than were the cyanobacterial species. Cultivation tests showed that approximately 94 % growth inhibition of mixed algae occurred at 30 mg/L. PMID- 26961084 TI - Immune checkpoint inhibitors enhance cytotoxicity of cytokine-induced killer cells against human myeloid leukaemic blasts. AB - We studied whether blockade of inhibitory receptors on cytokine-induced killer (CIK) cells by immune checkpoint inhibitors could increase its anti-tumour potency against haematological malignancies. CIK cultures were generated from seven normal donors and nine patients with acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) or multiple myeloma (MM). The inhibitory receptors B and T lymphocyte attenuator, CD200 receptor, lymphocyte activation gene-3 (LAG 3) and T cell immunoglobulin and mucin-domain-containing-3 (TIM-3) were present at variable percentages in most CIK cultures, while cytotoxic T lymphocyte associated protein 4 (CTLA-4), programmed death-1 (PD-1) and killer cell immunoglobulin-like receptors (KIR2DL1/2/3) were expressed at low level in most cultures. Without blockade, myeloid leukaemia cells were susceptible to autologous and allogeneic CIK-mediated cytotoxicity. Blockade of KIR, LAG-3, PD-1 and TIM-3 but not CTLA-4 resulted in remarkable increase in killing against these targets, even in those with poor baseline cytotoxicity. ALL and MM targets were resistant to CIK-mediated cytotoxicity, and blockade of receptors did not increase cytotoxicity to a meaningful extent. Combination of inhibitors against two receptors did not further increase cytotoxicity. Interestingly, potentiation of CIK killing by blocking antibodies was not predicted by expression of receptors on CIK and their respective ligands on the targets. Compared to un activated T and NK cells, blockade potentiated the cytotoxicity of CIK cells to a greater degree and at a lower E:T ratio, but without significant increase in cytotoxicity against normal white cell. Our findings provide the basis for clinical trial combining autologous CIK cells with checkpoint inhibitors for patients with AML. PMID- 26961085 TI - Poxvirus-based active immunotherapy synergizes with CTLA-4 blockade to increase survival in a murine tumor model by improving the magnitude and quality of cytotoxic T cells. AB - The dramatic clinical benefit of immune checkpoint blockade for a fraction of cancer patients suggests the potential for further clinical benefit in a broader cancer patient population by combining immune checkpoint inhibitors with active immunotherapies. The anti-tumor efficacy of MVA-BN-HER2 poxvirus-based active immunotherapy alone or in combination with CTLA-4 checkpoint blockade was investigated in a therapeutic CT26-HER-2 lung metastasis mouse model. MVA-BN-HER2 immunotherapy significantly improved the median overall survival compared to untreated controls or CTLA-4 blockade alone (p < 0.001). Robust synergistic efficacy was achieved with the combination therapy (p < 0.01). Improved survival following MVA-BN-HER2 administration was accompanied by increased tumor infiltration by HER-2-specific cytotoxic T lymphocytes (CTL). These tumor specific CTL had characteristics similar to antiviral CTL, including strong expression of activation markers and co-expression of IFNgamma and TNFalpha. Combination with CTLA-4 blockade significantly increased the magnitude of HER-2 specific T cell responses, with a higher proportion co-expressing TNFalpha and/or IL-2 with IFNgamma. Furthermore, in mice treated with MVA-BN-HER2 (alone or in combination with CTLA-4 blockade), the inducible T cell co-stimulator (ICOS) protein was expressed predominantly on CD4 and CD8 effector T cells but not on regulatory T cells (T(reg)). In contrast, mice left untreated or treated solely with CTLA-4 blockade harbored elevated ICOS(+) Treg, a phenotype associated with highly suppressive activity. In conclusion, poxvirus-based active immunotherapy induced robust tumor infiltration by highly efficient effector T cells. Combination with CTLA-4 immune checkpoint blockade amplified this response resulting in synergistically improved efficacy. These hypothesis-generating data may help elucidate evidence of enhanced clinical benefit from combining CTLA-4 blockade with poxvirus-based active immunotherapy. PMID- 26961086 TI - Long-term persistence to mono and combination therapies with angiotensin converting enzymes and angiotensin II receptor blockers in Australia. AB - PURPOSE: The purpose of this study was to compare the impact of initial antihypertensive therapy including angiotensin converting enzyme inhibitors (ACE) or angiotensin II receptor blockers (ARB) on long-term persistence to therapy. METHODS: A retrospective cohort study using prescription claims data from the Australian Pharmaceutical Benefit Scheme (PBS). Kaplan-Meier analysis of prescription refills and cox proportional hazard models were used to compare the time on therapy (persistence) in people newly initiated to monotherapy or combination therapy including ACE or ARB, between April 2007 and March 2008. Differences in persistence to initial drug class or any antihypertensive therapy were reported at 4-year follow-up. RESULTS: About 119,500 persons initiated ACE or ARB: 47 % initiated ACE monotherapy; 32 % ARB monotherapy; 13 % ACE combinations; and 8 % ARB combinations. Persistence (% on treatment at 4 years) to index therapy was lower in people starting ACE and ARB combinations compared to ACE or ARB monotherapies: ACE combination (12 %) versus ACE monotherapy (25 %) and ARB combinations (22 %) versus ARB monotherapy (35 %). Persistence was higher in those initiating fixed dose combinations (FDC) versus separate pill combinations of ACEs (19 vs. 10 %) and ARBs (25 vs. 14 %). Persistence at 4 years to any antihypertensive therapy was similar between initiators to ACE or ARB monotherapy (60 and 61 %, p = 0.08), ACE or ARB combinations (56 %, p = 0.99), and was slightly higher for separate pill combinations (57-59 %) versus FDC (55 %). CONCLUSION: Choice of initial antihypertensive may have little impact on long term persistence to therapy. PMID- 26961087 TI - Total Knee Arthroplasty for Posttraumatic Osteoarthritis: Is it Time for a New Classification? AB - BACKGROUND: Total knee arthroplasty (TKA) is often the best answer for end-stage, posttraumatic osteoarthritis after intra-articular and periarticular fractures about the knee. Although TKA in this setting is often considered more technically demanding, outcomes are typically worse for patients. This study examines the intraoperative differences and 30-day outcomes in posttraumatic vs primary TKA cohorts. METHODS: Patients undergoing TKA were selected from the National Surgical Quality Improvement Program database from 2010 to 2013. Patients were stratified on the basis of concurrent procedures and administrative codes indicating posttraumatic diagnoses. Thirty-day complications were recorded, and multivariate analyses were performed to determine whether posttraumatic arthritis was a risk factor for poor outcomes. RESULTS: A total of 67,675 primary and 674 posttraumatic TKAs were identified. Posttraumatic TKA patients were on average younger and healthier than the primary TKA population. The posttraumatic TKA group had higher rates of superficial surgical site infections and bleeding requiring transfusion. History of posttraumatic knee osteoarthritis was found to be an independent risk factor for prolonged operative time, increased length of hospital stay, and 30-day hospital readmission. CONCLUSION: We have demonstrated increased intraoperative times, heightened transfusion requirements and surgical site infections, and higher readmission rates after conversion TKA in the posttraumatic cohort. In contrast to total hip arthroplasty, current diagnosis and reimbursement schemes do not differentiate posttraumatic patients from primary osteoarthritis groups undergoing TKA. We believe that classification reform would improve medical documentation and improve patient care. PMID- 26961088 TI - Moderate Hypofractionation with Simultaneous Integrated Boost in Prostate Cancer: Long-term Results of a Phase I-II Study. AB - AIMS: To report 5 year outcome and late toxicity in prostate cancer patients treated with image-guided tomotherapy with a moderate hypofractionated simultaneous integrated boost approach. MATERIALS AND METHODS: In total, 211 prostate cancer patients, 78 low risk, 53 intermediate risk and 80 high risk were treated between 2005 and 2011. Intermediate- and high-risk patients received 51.8 Gy to pelvic lymph nodes and concomitant simultaneous integrated boost to prostate up to 74.2 Gy/28 fractions, whereas low-risk patients were treated to the prostate only with 71.4 Gy/28 fractions. Daily megavoltage computed tomography (MVCT) image guidance was applied. Androgen deprivation was prescribed for a median duration of 6 months for low-risk patients (for downsizing), 12 months for intermediate-risk and 36 months for high-risk patients. The 5 year biochemical relapse-free survival (bRFS), cancer-specific survival (CSS), overall survival and late gastrointestinal and genitourinary CTCAE.v3 toxicity were assessed. The effect of several clinical variables on both outcome and gastrointestinal/genitourinary toxicity was tested by uni- and multivariate Cox regression analyses. RESULTS: After a median follow-up of 5 years, the late toxicity actuarial incidence was: genitourinary >= grade 2: 20.2%; genitourinary >= grade 3: 5.9%; gastrointestinal >= grade 2: 17%; gastrointestinal >= grade 3: 6.3% with lower prevalence at the last follow-up visit (>= grade 3: genitourinary: 1.9%; gastrointestinal: 1.9%). Major predictors of >= grade 3 genitourinary and gastrointestinal late toxicity were genitourinary acute toxicity >= grade 2 (hazard ratio: 4.9) and previous surgery (hazard ratio: 3.4). The overall 5 year bRFS was 93.7% (low risk: 94.6%; intermediate risk: 96.2%; high risk: 91.1%), overall survival and CSS were 88.6% (low risk: 90.5%; intermediate risk: 87.4%; high risk: 87%) and 97.5% (low risk: 98.7%; intermediate risk: 95%; high risk: 94.3%), respectively. Risk classes and androgen deprivation were not significantly correlated with either bRFS, overall survival or CSS. Twelve patients experienced a biochemical relapse but none experienced clinically proven local and/or pelvic recurrence. CONCLUSION: A satisfactory 5 year outcome with an acceptable toxicity profile was observed. The combination of image-guided radiotherapy-intensity-modulated radiotherapy, high equivalent 2 Gy dose (EQD2) with a moderate hypofractionated approach and extensive prophylactic lymph node irradiation also leads to very good outcome in high-risk patients. PMID- 26961089 TI - Prognostic value of pre-operative glucose-corrected maximum standardized uptake value in patients with non-small cell lung cancer after complete surgical resection and 5-year follow-up. AB - INTRODUCTION: In this study we evaluated the value of pre-operative glucose corrected maximum standard uptake value (GC-SUVmax) as prognostic factor in patients with early stage non-small cell lung cancer (NSCLC) after complete surgical resection. METHODS: This study was designed as a retrospectively evaluated single center study with prospective data registry. Inclusion criteria were: histologically proven stage I NSCLC, 18F-FDG-PET/CT scan prior to surgery, complete resection (R0) and follow up in our outpatient department. Exclusion criteria were: history of malignancy other than NSCLC, diabetes and (neo) adjuvant therapy. Follow up period was 5 years. RESULTS: Between 2006 and 2008 a total of 33 patients (16 males, 17 females) met the inclusion criteria. SUVmax and GC-SUVmax were strongly correlated (Spearman's rho = 0.97). Five-year overall survival (OS) rate was 70 % (95 % CI = 56-87 %). Patients who died within 5 years of follow up had significantly higher pre-operative GC-SUVmax (median = 10.6, IQR = 8.3-14.4) than patients who were alive at 5-year follow up (median = 6.4, IQR = 3.0-9.8), p = 0.04. SUVmax showed similar differences: 10.4 (8-12.9) vs. 6.6 (3.0 8.8), p = 0.047. The area under the receiver-operating characteristic (ROC) curve at 5 years was 0.70 (95 % CI = 0.50-0.90) for GC-SUVmax and 0.71 (95 % CI = 0.51 0.91) for SUVmax (p = 0.75). CONCLUSION: Pre-operative FDG tumor uptake in patients with NSCLC is predictive for survival after complete surgical resection. GC-SUVmax, as an additional value to SUVmax, may better approach competitive inhibition of FDG and glucose in tumors, however, in this study this potential advantage, if any, was very small. PMID- 26961090 TI - Cannabis in Pain Treatment: Clinical and Research Considerations. AB - Cannabinoids show promise as therapeutic agents, particularly as analgesics, but their development and clinical use has been complicated by recognition of their botanical source, cannabis, as a substance of misuse. Although research into endogenous cannabinoid systems and potential cannabinoid pharmaceuticals is slowly increasing, there has been intense societal interest in making herbal (plant) cannabis available for medicinal use; 23 U.S. States and all Canadian provinces currently permit use in some clinical contexts. Whether or not individual professionals support the clinical use of herbal cannabis, all clinicians will encounter patients who elect to use it and therefore need to be prepared to advise them on cannabis-related clinical issues despite limited evidence to guide care. Expanded research on cannabis is needed to better determine the individual and public health effects of increasing use of herbal cannabis and to advance understanding of the pharmaceutical potential of cannabinoids as medications. This article reviews clinical, research, and policy issues related to herbal cannabis to support clinicians in thoughtfully advising and caring for patients who use cannabis, and it examines obstacles and opportunities to expand research on the health effects of herbal cannabis and cannabinoids. PERSPECTIVE: Herbal cannabis is increasingly available for clinical use in the United States despite continuing controversies over its efficacy and safety. This article explores important considerations in the use of plant Cannabis to better prepare clinicians to care for patients who use it, and identifies needed directions for research. PMID- 26961092 TI - Cognitive reserve moderates the relationship between neuropsychological performance and white matter fiber bundle length in healthy older adults. AB - Recent work using novel neuroimaging methods has revealed shorter white matter fiber bundle length (FBL) in older compared to younger adults. Shorter FBL also corresponds to poorer performance on cognitive measures sensitive to advanced age. However, it is unclear if individual factors such as cognitive reserve (CR) effectively moderate the relationship between FBL and cognitive performance. This study examined CR as a potential moderator of cognitive performance and brain integrity as defined by FBL. Sixty-three healthy adults underwent neuropsychological evaluation and 3T brain magnetic resonance imaging. Cognitive performance was measured using the Repeatable Battery of Assessment of Neuropsychological Status (RBANS). FBL was quantified from tractography tracings of white matter fiber bundles, derived from the diffusion tensor imaging. CR was determined by estimated premorbid IQ. Analyses revealed that lower scores on the RBANS were associated with shorter whole brain FBL (p = 0.04) and lower CR (p = 0.01) CR moderated the relationship between whole brain FBL and RBANS score (p < 0.01). Tract-specific analyses revealed that CR also moderated the association between FBL in the hippocampal segment of the cingulum and RBANS performance (p = 0.03). These results demonstrate that lower cognitive performance on the RBANS is more common with low CR and short FBL. On the contrary, when individuals have high CR, the relationship between FBL and cognitive performance is attenuated. Overall, CR protects older adults against lower cognitive performance despite age associated reductions in FBL. PMID- 26961093 TI - Relationships between workplace well-being, job demands and resources in a sample of veterinary nurses in New Zealand. AB - AIM: To use a job demands-resources model to examine the associations among perceived job demands, job resources, family-to-work enrichment, positive team relationships, work engagement, emotional exhaustion, cynicism and intention to leave, in a sample of New Zealand veterinary nurses. METHODS: Data were collected by means of a self-reported online survey, with the help of eight New Zealand tertiary education providers and the New Zealand Veterinary Nurses' Association. Nine measures or variables were assessed using questions or statements with responses categorised on a linear scale. Measurement models for each of the variables in the study were assessed to establish whether the variables represented the respective item-level data. Structural equation modelling was then used to test the hypothesised interrelationships among study variables. RESULTS: There were 253 respondents; 17.1% of individuals who classified themselves as veterinary nurses in the 2013 New Zealand census. In the final structural model job demands were associated with emotional exhaustion (standardised regression coefficient beta=0.57), which was related to cynicism (beta=0.52) and intention to leave (beta=0.56). Job resources were negatively related to emotional exhaustion (beta=-0.32). Higher work engagement was associated with lower emotional exhaustion (beta=-0.29) and lower intention to leave (beta=-0.30). Job resources were associated with work-to-family enrichment (beta=0.69), which was related to work engagement (beta=0.57); and job resources were associated with positive team relationships (beta=0.79). CONCLUSION: It is important that job resources are available to help deal with demanding work. Without resources, demanding work is associated with exhaustion, cynicism and increased intention to leave, while positive spill over between work and family life are related to higher work engagement. PMID- 26961095 TI - Trait anxiety and attenuated negative affect differentiation: a vulnerability factor to consider? AB - BACKGROUND AND OBJECTIVES: Describing emotional experiences using distinct terms, or affect differentiation, has been associated with emotion regulation and adaptive behavior under stress. There is little data, however, examining the association between differentiation and dispositional factors underlying psychopathology. The current study examines the association between differentiation and trait anxiety (TA) given prior evidence of cognitive biases in TA relevant to higher order processing of emotional experiences. DESIGN: We examined cross-sectionally, via lab-based repeated assessment, the association between differentiation of negative and positive experiences and TA. METHODS: Two hundred twenty-two adults completed an emotion reactivity task including repeated assessments of affect. We hypothesized that individuals higher in trait anxiety (HTA) would have greater difficulty differentiating their experiences. RESULTS: HTA individuals exhibited lower levels of negative affect (NA) differentiation even when controlling for depression. Although negative emotion intensity was consistently associated with lower differentiation, this did not account for the influence of HTA on differentiation. CONCLUSIONS: These data suggest that HTA individuals have greater difficulty differentiating negative emotions, regardless of negative emotion intensity and depression. As HTA is common to many emotional disorders; this evidence suggests that poor differentiation may also be an important transdiagnostic consideration in models of risk and of affective disease. PMID- 26961091 TI - Methylene blue modulates functional connectivity in the human brain. AB - Methylene blue USP (MB) is a FDA-grandfathered drug used in clinics to treat methemoglobinemia, carbon monoxide poisoning and cyanide poisoning that has been shown to increase fMRI evoked blood oxygenation level dependent (BOLD) response in rodents. Low dose MB also has memory enhancing effect in rodents and humans. However, the neural correlates of the effects of MB in the human brain are unknown. We tested the hypothesis that a single low oral dose of MB modulates the functional connectivity of neural networks in healthy adults. Task-based and task free fMRI were performed before and one hour after MB or placebo administration utilizing a randomized, double-blinded, placebo-controlled design. MB administration was associated with a reduction in cerebral blood flow in a task related network during a visuomotor task, and with stronger resting-state functional connectivity in multiple regions linking perception and memory functions. These findings demonstrate for the first time that low-dose MB can modulate task-related and resting-state neural networks in the human brain. These neuroimaging findings support further investigations in healthy and disease populations. PMID- 26961096 TI - Changes in Right Ventricular Volume and Function After Tricuspid Valve Surgery - Tricuspid Annuloplasty vs. Tricuspid Valve Replacement. AB - BACKGROUND: There is a concern that clinical outcome of tricuspid valve replacement (TVR) is inferior compared with tricuspid annuloplasty (TAP). The aim of this study was therefore to compare changes in right ventricular (RV) volume and function following TAP with that following TVR on cardiac magnetic resonance imaging (CMR) in patients with severe functional tricuspid regurgitation (TR). METHODS AND RESULTS: Forty patients who underwent surgery for severe functional TR and who underwent CMR preoperatively and on postoperative follow-up (24.8+/ 13.3 months after surgery) were enrolled. Thirteen patients underwent TAP (TAP group) and 27 patients underwent TVR (TVR group). Both RV end-diastolic and end systolic volume indices decreased significantly after surgery (from 178.9+/-53.9 to 116.3+/-26.7 ml/m(2), P<0.001, and from 95.7+/-36.1 to 67.3+/-28.0 ml/m(2), P<0.001, respectively), without intergroup differences. In the TAP group, RV ejection fraction (EF) was preserved following surgery (from 43.3+/-9.5 to 46.9+/ 10.9%, P=0.312). In the TVR group, however, it decreased significantly following surgery (from 51.8+/-9.2 to 42.4+/-12.3%, P<0.001). In addition, postoperative RVEF was lower in the TVR than TAP group, with a marginal significance (mean difference, -6.967; 95% confidence interval: -14.529 to 0.595; P=0.070). CONCLUSIONS: For patients with severe functional TR, both TAP and TVR are beneficial for reduction of RV volume indices. TAP, however, might be superior to TVR, because RVEF is well preserved following surgery. (Circ J 2016; 80: 1142 1147). PMID- 26961097 TI - Regenerated Endothelium and Its Senescent Response to Aggregating Platelets. AB - This essay summarizes 30 years of work attempting to understand why regenerated endothelium becomes dysfunctional. It focuses on the activation of endothelial nitric oxide synthase (eNOS) and the production of NO in response to platelet products and thrombin, which represents a first-line protection against vasospasm and atherosclerosis. Serotonin and adenosine diphosphate released by aggregating platelets are coupled to the activation of eNOS by different G-proteins. The endothelium-dependent relaxation that they cause is modulated non-selectively by the lipid content in the diet. When the endothelium regenerates after mechanical disruption, the newly formed endothelial cells selectively lose their Gi-mediated coupling and become less responsive to serotonin and thrombin. Accelerated senescence and the emergence of adipocyte-fatty acid binding protein leading to increased oxidative stress play a key role in the genesis of the dysfunction of regenerated endothelium. The consequent local NO deficiency not only favors the occurrence of vasospasm but sets the stage for the occurrence of atherosclerosis. PMID- 26961098 TI - Systemic Abnormalities Derived From Chronic Thromboembolic Pulmonary Hypertension and Their Improvement by Balloon Pulmonary Angioplasty. PMID- 26961100 TI - A dual-learning paradigm can simultaneously train multiple characteristics of walking. AB - Impairments in human motor patterns are complex: what is often observed as a single global deficit (e.g., limping when walking) is actually the sum of several distinct abnormalities. Motor adaptation can be useful to teach patients more normal motor patterns, yet conventional training paradigms focus on individual features of a movement, leaving others unaddressed. It is known that under certain conditions, distinct movement components can be simultaneously adapted without interference. These previous "dual-learning" studies focused solely on short, planar reaching movements, yet it is unknown whether these findings can generalize to a more complex behavior like walking. Here we asked whether a dual learning paradigm, incorporating two distinct motor adaptation tasks, can be used to simultaneously train multiple components of the walking pattern. We developed a joint-angle learning task that provided biased visual feedback of sagittal joint angles to increase peak knee or hip flexion during the swing phase of walking. Healthy, young participants performed this task independently or concurrently with another locomotor adaptation task, split-belt treadmill adaptation, where subjects adapted their step length symmetry. We found that participants were able to successfully adapt both components of the walking pattern simultaneously, without interference, and at the same rate as adapting either component independently. This leads us to the interesting possibility that combining rehabilitation modalities within a single training session could be used to help alleviate multiple deficits at once in patients with complex gait impairments. PMID- 26961099 TI - Serotonin modulates the excitatory synaptic transmission in the dentate granule cells. AB - Serotonergic fibers from the raphe nuclei project to the hippocampal formation, the activity of which is known to modulate the inhibitory interneurons in the dentate gyrus. On the other hand, serotonergic modulation of the excitatory synapses in the dentate gyrus is not well examined. In the present study, we examined the effects of 5-HT on the excitatory postsynaptic potentials (EPSPs) in the dentate granule cells evoked by the selective stimulation of the lateral perforant path (LPP), the medial perforant path (MPP), or the mossy cell fibers (MCF). 5-HT depressed the amplitude of unitary EPSPs (uEPSPs) evoked by the stimulation of LPP or MPP, whereas uEPSPs evoked by MCF stimulation were little affected. The effect was partly explained by the decrease of the resting membrane resistance following the activation of 5-HT1A receptors, which was confirmed by computer simulations. We also found that the probability of evoking uEPSP by LPP stimulation but not MPP or MCF stimulation was reduced by 5-HT and that the paired-pulse ratio of LPP-evoked EPSP but not that of MPP- or MCF-evoked ones was increased by 5-HT. These effects were blocked by 5-HT2 antagonist, suggesting that the transmitter release in the LPP-granule cell synapse is inhibited by the activation of 5-HT2 receptors. The present results suggest that 5-HT can modulate the EPSPs in the dentate granule cells by at least two distinct mechanisms. PMID- 26961101 TI - Unitary synaptic connections among substantia nigra pars reticulata neurons. AB - Neurons in substantia nigra pars reticulata (SNr) are synaptically coupled by local axon collaterals, providing a potential mechanism for local signal processing. Because SNr neurons fire spontaneously, these synapses are constantly active. To investigate their properties, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) from SNr neurons in brain slices, in which afferents from upstream nuclei are severed, and the cells fire rhythmically. The sIPSC trains contained a mixture of periodic and aperiodic events. Autocorrelation analysis of sIPSC trains showed that a majority of cells had one to four active unitary inputs. The properties of the unitary IPSCs (uIPSCs) were analyzed for cells with one unitary input, using a model of periodic presynaptic firing and stochastic synaptic transmission. The inferred presynaptic firing rates and coefficient of variation of interspike intervals (ISIs) corresponded well with direct measurements of spiking in SNr neurons. Methods were developed to estimate the success probability, amplitude distributions, and kinetics of the uIPSCs, while removing the contribution from aperiodic sIPSCs. The sIPSC amplitudes were not increased upon release from halorhodopsin silencing, suggesting that most synapses were not depressed at the spontaneous firing rate. Gramicidin perforated-patch recordings indicated that the average reversal potential of spontaneous inhibitory postsynaptic potentials was -64 mV. Because of the change in driving force across the ISI, the unitary inputs are predicted to have a larger postsynaptic impact when they arrive late in the ISI. Simulations of network activity suggest that this very sparse inhibitory coupling may act to desynchronize the activity of SNr neurons while having only a small effect on firing rate. PMID- 26961102 TI - GluA4 subunit of AMPA receptors mediates the early synaptic response to altered network activity in the developing hippocampus. AB - Development of the neuronal circuitry involves both Hebbian and homeostatic plasticity mechanisms that orchestrate activity-dependent refinement of the synaptic connectivity. AMPA receptor subunit GluA4 is expressed in hippocampal pyramidal neurons during early postnatal period and is critical for neonatal long term potentiation; however, its role in homeostatic plasticity is unknown. Here we show that GluA4-dependent plasticity mechanisms allow immature synapses to promptly respond to alterations in network activity. In the neonatal CA3, the threshold for homeostatic plasticity is low, and a 15-h activity blockage with tetrodotoxin triggers homeostatic upregulation of glutamatergic transmission. On the other hand, attenuation of the correlated high-frequency bursting in the CA3 CA1 circuitry leads to weakening of AMPA transmission in CA1, thus reflecting a critical role for Hebbian synapse induction in the developing CA3-CA1. Both of these developmentally restricted forms of plasticity were absent in GluA4(-/-) mice. These data suggest that GluA4 enables efficient homeostatic upscaling and responsiveness to temporal activity patterns during the critical period of activity-dependent refinement of the circuitry. PMID- 26961104 TI - Motor control differs for increasing and releasing force. AB - Control of the motor output depends on our ability to precisely increase and release force. However, the influence of aging on force increase and release remains unknown. The purpose of this study, therefore, was to determine whether force control differs while increasing and releasing force in young and older adults. Sixteen young adults (22.5 +/- 4 yr, 8 females) and 16 older adults (75.7 +/- 6.4 yr, 8 females) increased and released force at a constant rate (10% maximum voluntary contraction force/s) during an ankle dorsiflexion isometric task. We recorded the force output and multiple motor unit activity from the tibialis anterior (TA) muscle and quantified the following outcomes: 1) variability of force using the SD of force; 2) mean discharge rate and variability of discharge rate of multiple motor units; and 3) power spectrum of the multiple motor units from 0-4, 4-10, 10-35, and 35-60 Hz. Participants exhibited greater force variability while releasing force, independent of age (P < 0.001). Increased force variability during force release was associated with decreased modulation of multiple motor units from 35 to 60 Hz (R(2) = 0.38). Modulation of multiple motor units from 35 to 60 Hz was further correlated to the change in mean discharge rate of multiple motor units (r = 0.66) and modulation from 0 to 4 Hz (r = -0.64). In conclusion, these findings suggest that force control is altered while releasing due to an altered modulation of the motor units. PMID- 26961103 TI - A common neural element receiving rhythmic arm and leg activity as assessed by reflex modulation in arm muscles. AB - Neural interactions between regulatory systems for rhythmic arm and leg movements are an intriguing issue in locomotor neuroscience. Amplitudes of early latency cutaneous reflexes (ELCRs) in stationary arm muscles are modulated during rhythmic leg or arm cycling but not during limb positioning or voluntary contraction. This suggests that interneurons mediating ELCRs to arm muscles integrate outputs from neural systems controlling rhythmic limb movements. Alternatively, outputs could be integrated at the motoneuron and/or supraspinal levels. We examined whether a separate effect on the ELCR pathways and cortico motoneuronal excitability during arm and leg cycling is integrated by neural elements common to the lumbo-sacral and cervical spinal cord. The subjects performed bilateral leg cycling (LEG), contralateral arm cycling (ARM), and simultaneous contralateral arm and bilateral leg cycling (A&L), while ELCRs in the wrist flexor and shoulder flexor muscles were evoked by superficial radial (SR) nerve stimulation. ELCR amplitudes were facilitated by cycling tasks and were larger during A&L than during ARM and LEG. A low stimulus intensity during ARM or LEG generated a larger ELCR during A&L than the sum of ELCRs during ARM and LEG. We confirmed this nonlinear increase in single motor unit firing probability following SR nerve stimulation during A&L. Furthermore, motor-evoked potentials following transcranial magnetic and electrical stimulation did not show nonlinear potentiation during A&L. These findings suggest the existence of a common neural element of the ELCR reflex pathway that is active only during rhythmic arm and leg movement and receives convergent input from contralateral arms and legs. PMID- 26961105 TI - Failure to suppress low-frequency neuronal oscillatory activity underlies the reduced effectiveness of random patterns of deep brain stimulation. AB - Subthalamic nucleus (STN) deep brain stimulation (DBS) is an established treatment for the motor symptoms of Parkinson's disease (PD). However, the mechanisms of action of DBS are unknown. Random temporal patterns of DBS are less effective than regular DBS, but the neuronal basis for this dependence on temporal pattern of stimulation is unclear. Using a rat model of PD, we quantified the changes in behavior and single-unit activity in globus pallidus externa and substantia nigra pars reticulata during high-frequency STN DBS with different degrees of irregularity. Although all stimulus trains had the same average rate, 130-Hz regular DBS more effectively reversed motor symptoms, including circling and akinesia, than 130-Hz irregular DBS. A mixture of excitatory and inhibitory neuronal responses was present during all stimulation patterns, and mean firing rate did not change during DBS. Low-frequency (7-10 Hz) oscillations of single-unit firing times present in hemiparkinsonian rats were suppressed by regular DBS, and neuronal firing patterns were entrained to 130 Hz. Irregular patterns of DBS less effectively suppressed 7- to 10-Hz oscillations and did not regularize firing patterns. Random DBS resulted in a larger proportion of neuron pairs with increased coherence at 7-10 Hz compared with regular 130-Hz DBS, which suggested that long pauses (interpulse interval >50 ms) during random DBS facilitated abnormal low-frequency oscillations in the basal ganglia. These results suggest that the efficacy of high-frequency DBS stems from its ability to regularize patterns of neuronal firing and thereby suppress abnormal oscillatory neural activity within the basal ganglia. PMID- 26961106 TI - Low- and high-gamma oscillations deviate in opposite directions from zero-phase synchrony in the limbic corticostriatal loop. AB - The loop structure of cortico-striatal anatomy in principle enables both descending (cortico-striatal) and ascending (striato-cortical) influences, but the factors that regulate the flow of information in these loops are not known. We report that low- and high-gamma oscillations (~50 and ~80 Hz, respectively) in the local field potential of freely moving rats are highly synchronous between the infralimbic region of the medial prefrontal cortex (mPFC) and the ventral striatum (vStr). Strikingly, high-gamma oscillations in mPFC preceded those in vStr, whereas low-gamma oscillations in mPFC lagged those in vStr, with short (~1 ms) time lags. These systematic deviations from zero-phase synchrony were consistent across measures based on amplitude cross-correlation and phase slopes and were robustly maintained between behavioral states and different individual subjects. Furthermore, low- and high-gamma oscillations were associated with distinct ensemble spiking patterns in vStr, even when controlling for overt behavioral differences and slow changes in neural activity. These results imply that neural activity in vStr and mPFC is tightly coupled at the gamma timescale and raise the intriguing possibility that frequency-specific deviations from this coupling may signal transient leader-follower switches. PMID- 26961110 TI - Yellow nail syndrome. PMID- 26961108 TI - Demand on skillfulness modulates interhemispheric inhibition of motor cortices. AB - The role of primary motor cortex (M1) in the control of hand movements is still unclear. Functional magnetic resonance imaging (fMRI) studies of unimanual performance reported a relationship between level of precision of a motor task and additional ipsilateral M1 (iM1) activation. In the present study, we determined whether the demand on accuracy of a movement influences the magnitude of the inhibitory effect between primary motor cortices (IHI). We used transcranial magnetic stimulation (TMS) to measure active IHI (aIHI) of the iM1 on the contralateral M1 (cM1) in the premovement period of a left-hand motor task. Ten healthy participants manipulated a joystick to point to targets of two different sizes. For aIHI, the conditioning stimulus (CS) was applied to iM1, and the test stimulus (TS) to cM1, with an interstimulus interval of 10 ms. The amount of the inhibitory effect of the CS on the motor-evoked potential (MEP) of the subsequent TS was expressed as percentage of the mean MEP amplitude evoked by the single TS. Across different time points of aIHI measurements in the premovement period, there was a significant effect for target size on aIHI. Preparing to point to small targets was associated with weaker aIHI compared with pointing to large targets. The present findings suggest that, during the premovement period, aIHI from iM1 on cM1 is modulated by the demand on accuracy of the motor task. This is consistent with task fMRI findings showing bilateral M1 activation during high-precision movements but only unilateral M1 activity during low-precision movements. PMID- 26961107 TI - Active sensing associated with spatial learning reveals memory-based attention in an electric fish. AB - Active sensing behaviors reveal what an animal is attending to and how it changes with learning. Gymnotus sp, a gymnotiform weakly electric fish, generates an electric organ discharge (EOD) as discrete pulses to actively sense its surroundings. We monitored freely behaving gymnotid fish in a large dark "maze" and extracted their trajectories and EOD pulse pattern and rate while they learned to find food with electrically detectable landmarks as cues. After training, they more rapidly found food using shorter, more stereotyped trajectories and spent more time near the food location. We observed three forms of active sensing: sustained high EOD rates per unit distance (sampling density), transient large increases in EOD rate (E-scans) and stereotyped scanning movements (B-scans) were initially strong at landmarks and food, but, after learning, intensified only at the food location. During probe (no food) trials, after learning, the fish's search area and intense active sampling was still centered on the missing food location, but now also increased near landmarks. We hypothesize that active sensing is a behavioral manifestation of attention and essential for spatial learning; the fish use spatial memory of landmarks and path integration to reach the expected food location and confine their attention to this region. PMID- 26961111 TI - Impact of Total Risk Management on Coronary Plaque Regression in Diabetic Patients with Acute Coronary Syndrome. AB - AIM: Diabetic patients with coronary artery disease have a high incidence of cardiovascular events, which was associated with increased coronary plaque volume. Low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) play pivotal roles in the progression of coronary plaque. Several trials have shown that intervention for a single risk factor reduced the development of coronary plaque progression. However, it remained uncertain whether total risk management for LDL-C, BP, and glycosylated Hb (HbA1c) has a beneficial effect on coronary plaque volume in diabetic patients. METHODS: This study was a sub-study of the JAPAN-ACS that was a prospective, randomized, open-label trial that evaluated the impact of intensive lipid-lowering therapy on coronary plaque volume in patients with acute coronary syndrome (ACS). Among a total of 252 patients, 73 diabetic patients were analyzed. We examined the impact of total risk management (LDL-C <80 mg/dL, systolic BP <130 mmHg, and HbA1c <6.5%) on changes in coronary plaque volume. The patients were divided into four groups according to the number of risk factors that achieved the target value. RESULTS: Baseline characteristics were similar among the groups. The degree of coronary plaque regression was greater in patients who achieved total risk management. The number of risk factors that achieved the target level was associated with the extent of the coronary plaque volume reduction in a dose-dependent manner. CONCLUSION: Total risk management that focused on LDL-C, BP, and HbA1c had a beneficial impact on the coronary plaque regression in diabetic patients with ACS. PMID- 26961109 TI - VIP+ interneurons control neocortical activity across brain states. AB - GABAergic interneurons are positioned to powerfully influence the dynamics of neural activity, yet the interneuron-mediated circuit mechanisms that control spontaneous and evoked neocortical activity remains elusive. Vasoactive intestinal peptide (VIP+) interneurons are a specialized cell class which synapse specifically on other interneurons, potentially serving to facilitate increases in cortical activity. In this study, using in vivo Ca(2+) imaging, we describe the interaction between local network activity and VIP+ cells and determine their role in modulating neocortical activity in mouse visual cortex. VIP+ cells were active across brain states including locomotion, nonlocomotion, visual stimulation, and under anesthesia. VIP+ activity correlated most clearly with the mean level of population activity of nearby excitatory neurons during all brain states, suggesting VIP+ cells enable high-excitability states in the cortex. The pharmacogenetic blockade of VIP+ cell output reduced network activity during locomotion, nonlocomotion, anesthesia, and visual stimulation, suggesting VIP+ cells exert a state-independent facilitation of neural activity in the cortex. Collectively, our findings demonstrate that VIP+ neurons have a causal role in the generation of high-activity regimes during spontaneous and stimulus evoked neocortical activity. PMID- 26961112 TI - Control Status of Atherosclerotic Cardiovascular Risk Factors Among Japanese High Risk Subjects:Analyses of a Japanese Health Check Database from 2008 to 2011. AB - AIMS: Several guidelines propose target levels (TLs) of atherosclerotic risk factors (ARFs) to reduce atherosclerotic cardiovascular diseases; however, few data are available regarding the attainment statuses of TLs in Japan. In this study, utilizing the data obtained from the annual "Specific Health Check and Guidance in Japan" conducted from 2008 to 2011 (approximately 280,000 subjects each year), we determined TL attainments of ARFs in cardiovascular high-risk subjects. METHODS: Those who had suffered from cerebrovascular disease (pCVD) or coronary heart disease (pCHD) or were receiving diabetes mellitus treatment (DM) were selected, and the rates of subjects that attained TLs of blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and glycated hemoglobin (HbA1c) were analyzed. RESULTS: Approximately 70% of pCVD or pCHD and 35% of subjects with DM attained TLs of BP. With regard to HbA1c, >90% of pCVD or pCHD and approximately 50% of subjects with DM attained TLs. With regard to LDL-C, <25% of pCHD females and approximately 35% of pCHD males and 50%-55% of subjects with pCVD or DM attained TLs. The TL-attainment rates of HDL-C and TGs were approximately 90% and 75%, respectively, for the three diseases. Analyses of time course changes in their attainment statuses revealed that the attainment rates of BP and LDL-C significantly improved in all the diseases. CONCLUSIONS: TL-attainment rates of BP and LDL-C were not as high as those for HDL-C, TGs, and HbA1c; however, they both showed highly significant improvements during the study period. PMID- 26961114 TI - Rationale and Design of the Standard Versus Intensive Statin Therapy for Hypercholesterolemic Patients with Diabetic Retinopathy (EMPATHY) Study: a Randomized Controlled Trial. AB - AIM: Hyperlipidemia and diabetic retinopathy increase the risk of cardiovascular disease (CVD). The standard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study examines whether intensive lipid-lowering therapy is superior to standard therapy in reducing the incidence of cardiovascular events in patients with hyperlipidemia and diabetic retinopathy, but without a history of coronary artery disease. METHODS: Patients who had elevated low-density lipoprotein cholesterol (LDL-C) and diabetic retinopathy without a history of coronary artery disease were eligible for the study. Patients were randomly assigned in a 1:1 ratio to receive intensive or standard therapy. Patients are being treated with monotherapy with 3 hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) for a maximum of 5.5 years to achieve the following LDL-C target: <70 mg/dL for the intensive therapy group or >=100 and <120 mg/dL for the standard therapy group. The primary endpoint is a composite of incidence of CVD and death from CVD. RESULTS: Between May 2010 and October 2013, 5,995 patients were assessed for eligibility, and 5,144 were assigned to the study treatment (2,571 and 2,573 in the intensive and standard therapy groups, respectively), and baseline data were analyzed from 5,107 (2,550 in the intensive therapy group and 2,557 in the standard therapy group). CONCLUSIONS: This is the first study assessing the benefits of intensive statin therapy in patients with hypercholesterolemia and diabetic retinopathy in a primary prevention setting. Furthermore, this study evaluates the appropriateness of the treat-to-target approach because all patients are treated to achieve specific LDL-C targets by titrating statin therapy. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000003486. PMID- 26961113 TI - Association of Cytochrome P450 Genetic Variants with Clopidogrel Resistance and Outcomes in Acute Ischemic Stroke. AB - AIMS: Clopidogrel is an antiplatelet drug primarily used to treat or prevent acute ischemic stroke (IS) or myocardial infarction (MI). This prodrug requires biotransformation to an active metabolite by cytochrome P450 (CYP) enzymes, and CYP single nucleotide polymorphisms (SNPs) could affect the efficiency of such biotransformation. METHODS: A total of 375 consecutive IS patients were genotyped for eight CYP SNPs using mass spectrometry. Platelet aggregation activity was measured before and after the 7-10 day treatment. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) analysis. All patients received clopidogrel therapy and were followed up for six months. Primary outcomes were evaluated as a composite of recurrent ischemic stroke (RIS), MI, and death. The secondary outcome was the modified Rankin Scale (mRS). RESULTS: Clopidogrel resistance occurred in 153 patients (40.8%). The frequency of CYP3A5 (rs776746) GG/AG and CYP2C19*2 (rs4244285) AA/AG genotypes was significantly higher in clopidogrel-resistant patients than in sensitive patients. There was a significant gene-gene interaction between CYP3A5 (rs776746) and CYP2C19*2 (rs4244285). CYP2C19*2 AA and its interaction with CYP3A5 GG were independent predictors of clopidogrel resistance and affected the activity of platelet aggregation. Diabetes mellitus, CYP2C19*2 (rs4244285), clopidogrel resistance, and the interaction of CYP2C19*2 with CYP3A5 were all independent risk factors for the primary outcomes of clopidogrel treatment. Clopidogrel resistant patients were more likely to have poor outcomes (mRS >2 points) compared with clopidogrel-sensitive patients. CONCLUSION: CYP SNPs and their interactions are associated with drug resistance and outcomes in acute IS patients. PMID- 26961116 TI - Antigen-encoding bone marrow terminates islet-directed memory CD8+ T-cell responses to alleviate islet transplant rejection. AB - Islet-specific memory T cells arise early in type 1 diabetes (T1D), persist for long periods, perpetuate disease and are rapidly reactivated by islet transplantation. As memory T cells are poorly controlled by 'conventional' therapies, memory T-cell mediated attack is a substantial challenge in islet transplantation and this will extend to application of personalized approaches using stem-cell derived replacement beta cells. New approaches are required to limit memory autoimmune attack of transplanted islets or replacement beta cells. Here we show that transfer of bone marrow encoding cognate antigen directed to dendritic cells, under mild, immune-preserving conditions inactivates established memory CD8+ T-cell populations and generates a long-lived, antigen-specific tolerogenic environment. Consequently, CD8+ memory T cell-mediated targeting of islet-expressed antigens is prevented and islet graft rejection alleviated. The immunological mechanisms of protection are mediated through deletion and induction of unresponsiveness in targeted memory T-cell populations. The data demonstrate that hematopoietic stem cell-mediated gene therapy effectively terminates antigen-specific memory T-cell responses and this can alleviate destruction of antigen-expressing islets. This addresses a key challenge facing islet transplantation and importantly, the clinical application of personalized beta-cell replacement therapies using patient-derived stem cells. PMID- 26961115 TI - B-lymphocytes expressing an Ig specificity recognizing the pancreatic beta-cell autoantigen peripherin are potent contributors to type 1 diabetes development in NOD mice. AB - While the autoimmune destruction of pancreatic beta-cells underlying type 1 diabetes (1D) development is ultimately mediated by T-cells in NOD mice and also likely humans, B-lymphocytes play an additional key pathogenic role. It appears expression of plasma membrane bound immunoglobulin (Ig) molecules that efficiently capture beta-cell antigens allows autoreactive B-lymphocytes bypassing normal tolerance induction processes to be the subset of antigen presenting cells most efficiently activating diabetogenic T-cells. NOD mice transgenically expressing Ig molecules recognizing antigens that are (insulin) or not (hen egg lysozyme; HEL) expressed by beta-cells have proven useful in dissecting the developmental basis of diabetogenic B-lymphocytes. However, these transgenic Ig specificities were originally selected for their ability to recognize insulin or HEL as foreign, rather than autoantigens. Thus, we generated and characterized NOD mice transgenically expressing an Ig molecule representative of a large proportion of naturally occurring islet-infiltrating B lymphocytes in NOD mice recognizing the neuronal antigen peripherin. Transgenic peripherin autoreactive B-lymphocytes infiltrate NOD pancreatic islets, acquire an activated proliferative phenotype, and potently support accelerated T1D development. These results support the concept of neuronal autoimmunity as a pathogenic feature of T1D, and targeting such responses could ultimately provide an effective disease intervention approach. PMID- 26961117 TI - Is there a difference between the STOP-BANG and the Berlin Obstructive Sleep Apnoea Syndrome questionnaires for determining respiratory complications during the perioperative period? AB - AIMS AND OBJECTIVES: This study aimed to compare the efficiency of the STOP-BANG and Berlin Obstructive Sleep Apnoea Syndrome questionnaires for evaluating potential respiratory complications during the perioperative period. BACKGROUND: Questionnaires that are used to determine obstructive sleep apnoea risk are not widely used for surgical patients. Among the questionnaires that are commonly used for obstructive sleep apnoea screening, it remains unclear whether the STOP BANG or Berlin Obstructive Sleep Apnoea Syndrome questionnaire is more effective in terms of ease of use, usage period and diagnosis of surgical patients with obstructive sleep apnoea risk. DESIGN: This study was designed as a descriptive and prospective study. METHODS: The study included 126 patients over 18 years of age who were American Society of Anesthesiologists classification class I-II and underwent laparoscopic cholecystectomy. To determine the potential obstructive sleep apnoea syndrome risk, the STOP-BANG and Berlin questionnaires were administered. Respiratory complications were then observed during the perioperative period. RESULTS: During intubation and extubation, we observed statistically significant differences in difficult intubation, difficult facemask ventilation and desaturation frequency between the high- and low-risk groups for obstructive sleep apnoea syndrome, as determined by the STOP-BANG questionnaire. During extubation, statistically significant differences in coughing, breath holding and desaturation frequency were observed between the high-risk and low risk groups, according to the Berlin questionnaire. In the post-anaesthesia care unit, both questionnaires found statistically significant differences between the low- and high-risk groups. CONCLUSION: Obstructive sleep apnoea syndrome screening questionnaires administered during the preoperative period are useful for predicting perioperative respiratory complications. It may be most useful to administer the STOP-BANG questionnaire as the initial evaluation. RELEVANCE TO CLINICAL PRACTICE: Questionnaires may be used to determine the risk of obstructive sleep apnoea syndrome, which could impact the anaesthetisation of surgical patients. Questionnaires for determining the risk of obstructive sleep apnoea syndrome should be used regularly for surgical patients, and these questionnaires should be used to improve clinical protocols for anaesthesia and postanaesthesia care. PMID- 26961119 TI - Immunological and angiogenic markers during metronomic temozolomide and cyclophosphamide in canine cancer patients. AB - Metronomic chemotherapy stimulates the immune response via depletion of regulatory T cells (Tregs) and suppresses angiogenesis by modulating the secretion of thrombospondin-1 (TSP-1) and vascular endothelial growth factor (VEGF). In this study, blood was collected from 10 healthy dogs and from 30 canine cancer patients before and 2 and 4 weeks after treatment with metronomic temozolomide (6.6 mg m-2 ), cyclophosphamide (12.5 mg m-2 ) or cyclophosphamide and temozolomide. The percentage of circulating CD25+ Foxp3+ CD4+ Tregs and the plasma levels of TSP-1 and VEGF were measured. There was a significant difference in the percentage of Tregs between cancer patients and healthy dogs. A significant decrease in Tregs was noted in patients treated with metronomic cyclophosphamide and the combination. Treatment with temozolomide had no effect on the percentage of Tregs. TSP-1 and VEGF levels were, respectively, significantly lower and higher in cancer patients than in healthy dogs, but they were not influenced by any of the studied metronomic treatment regimens. PMID- 26961120 TI - Validity of Self-Reported Pre-Pregnancy Weight and Body Mass Index Classification in an Integrated Health Care Delivery System. AB - BACKGROUND: Self-reported weight prior to pregnancy is prone to error. We utilised a measured pre-conceptional weight from the electronic health record (EHR) to investigate error in recalled pre-pregnancy body mass index (BMI) category and compared how associations between pre-pregnancy BMI and pregnancy outcomes varied by using the two measures. METHODS: We assessed differences in means, correlations, and categorisation of pre-pregnancy BMI for 5092 singleton pregnancies delivered between 2007 and 2013 in Kaiser Permanente Northern California. Associations between measured and self-reported BMI category and gestational diabetes, infant size for gestational age, and exceeding the Institute of Medicine gestational weight gain recommendations were assessed. RESULTS: Overall, the two measures assigned the same BMI category for 86.7% of women with higher risks of misclassification for overweight (Relative Risk (RR) 3.38, 95% Confidence Interval (CI) 2.79, 4.10), obese class I (RR 3.81, 95% CI 3.07, 4.75), and obese class II (RR 1.80, 95% CI 1.28, 2.55) women compared to normal weight women. However, associations between self-reported or measured BMI category and several pregnancy outcomes were similar. CONCLUSIONS: Despite misclassification, self-reported and measured pre-pregnancy weights were similarly associated with perinatal outcomes in this study population. Our results illustrate the value of the EHR for recording measured pre-pregnancy weight for use in research. PMID- 26961118 TI - Identification of putative candidate genes for red rot resistance in sugarcane (Saccharum species hybrid) using LD-based association mapping. AB - Red rot is a serious disease of sugarcane caused by the fungus Colletotrichum falcatum that has a colossal damage potential. The fungus, prevalent mainly in the Indian sub-continent, keeps on producing new pathogenic strains leading to breakdown of resistance in newly released varieties and hence the deployment of linked markers for marker-assisted selection for resistance to this disease can fine tune the breeding programme. This study based on a panel of 119 sugarcane genotypes fingerprinted for 944 SSR alleles was undertaken with an aim to identify marker-trait associations (MTAs) for resistance to red rot. Mixed linear model containing population structure and kinship as co-factor detected four MTAs that were able to explain 10-16 % of the trait variation, individually. Among the four MTAs, EST sequences diagnostic of three could be BLAST searched to the sorghum genome with significant sequence homology. Several genes encoding important plant defence related proteins, viz., cytochrome P450, Glycerol-3 phosphate transporter-1, MAP Kinase-4, Serine/threonine-protein kinase, Ring finger domain protein and others were localized to the vicinity of these MTAs. These positional candidate genes are worth of further investigation and possibly these could contribute directly to red rot resistance, and may find a potential application in marker-assisted sugarcane breeding. PMID- 26961121 TI - Five-year follow-up of cognitive impairment in older adults with bipolar disorder. AB - OBJECTIVE: To date, cognitive impairment has been thought to be an integral part of bipolar disorder. In clinical staging models, cognitive impairment is one of the hallmarks to define the clinical stage and it plays an important role in identifying the risk factors for progression to later stages of the illness. It is important to examine neurocognitive performance over longer periods to test the hypothesis of neuroprogression of bipolar disorder. METHODS: A comprehensive neuropsychological test battery was applied at baseline and five years later to 56 euthymic older outpatients with bipolar disorder (mean age = 68.35 years, range: 60-90 years) and to a demographically matched sample of 44 healthy subjects. A group-by-time repeated measures multivariate analysis of variance was performed to measure changes over time for the two groups. The impact of baseline illness characteristics on the intra-individual change in neurocognitive performance within the bipolar disorder group was studied by using logistic regression analysis. RESULTS: At baseline and at follow-up, patients with bipolar disorder performed worse on all neurocognitive measures compared to the matched healthy subjects. However, there was no significant group-by-time interaction between the patients with bipolar disorder and the comparison group. CONCLUSIONS: Although older patients with bipolar disorder had worse cognitive function than healthy subjects, they did not have greater cognitive decline over a five-year period. The change in acquired cognitive impairment of patients with bipolar disorder might parallel the cognitive development as seen in normal aging. PMID- 26961122 TI - Inverse agonism: the classic concept of GPCRs revisited [Review]. AB - In the classical two-state model, G protein-coupled receptors (GPCRs) are considered to exist in equilibrium between an active and an inactive conformation. Thus, even at the resting state, some subpopulation of GPCRs is in the active state, which underlies the basal activity of the GPCRs. In this review, we discuss inverse agonists, which are defined as GPCR ligands that shift the equilibrium toward the inactive state and thereby suppress the basal activity. Theoretically, if constitutive activation plays an essential role in the pathogenesis of a disease, only inverse agonists, and not neutral antagonists, can reverse this pathophysiological activation. Although many pharmacological examples of inverse agonism have been identified, its clinical importance is still unclear and debated. Thus, even though inverse agonism of angiotensin receptor blockers (ARBs) has been discussed for more than 10 years, its clinical relevance remains to be completely clarified. PMID- 26961123 TI - Use of reproductive health care services among urban migrant women in Bangladesh. AB - BACKGROUND: Recent internal migration flows from rural to urban areas pose challenges to women using reproductive health care services in their migratory destinations. No studies were found which examined the relationship between migration, migration-associated indicators and reproductive health care services in Bangladesh. METHODS: We analyzed the 2006 Bangladesh Urban Health Survey (data made publically available in June 2013) of 14,191 ever-married women aged 10-59 years. Cross tabulations and logistic regression were conducted. RESULTS: Migrants and non-migrants did not differ significantly in their use of modern contraceptives and treatment for STI but were less likely to receive ANC even after controlling for a range of variables. Compared to non-migrants, more migrants had home births, did not take vitamin A after delivery, and had no medical exam post-birth. Migrant women being village-born (rather than urban born) were associated with risk of diminished: use of ANC; treatment for STI; medical exam post-birth; vitamin A post-birth. Migrating for work or education (rather than other reasons) was associated with risk of diminished: use of ANC; use of modern facilities for birth; and medical exam post-birth. Each additional year lived in urban areas was associated with a greater likelihood of receiving ANC. CONCLUSIONS: Women who migrated to urban areas in Bangladesh were significantly less likely than non-migrants to use reproductive health care services related to pregnancy care. Pro-actively identifying migrant women, especially those who originated from villages or migrated for work or education may be warranted to ensure optimal use of pregnancy-related services. PMID- 26961124 TI - Influence of temperature on patch residence time in parasitoids: physiological and behavioural mechanisms. AB - Patch time allocation has received much attention in the context of optimal foraging theory, including the effect of environmental variables. We investigated the direct role of temperature on patch time allocation by parasitoids through physiological and behavioural mechanisms and its indirect role via changes in sex allocation and behavioural defences of the hosts. We compared the influence of foraging temperature on patch residence time between an egg parasitoid, Trichogramma euproctidis, and an aphid parasitoid, Aphidius ervi. The latter attacks hosts that are able to actively defend themselves, and may thus indirectly influence patch time allocation of the parasitoid. Patch residence time decreased with an increase in temperature in both species. The increased activity levels with warming, as evidenced by the increase in walking speed, partially explained these variations, but other mechanisms were involved. In T. euproctidis, the ability to externally discriminate parasitised hosts decreased at low temperature, resulting in a longer patch residence time. Changes in sex allocation with temperature did not explain changes in patch time allocation in this species. For A. ervi, we observed that aphids frequently escaped at intermediate temperature and defended themselves aggressively at high temperature, but displayed few defence mechanisms at low temperature. These defensive behaviours resulted in a decreased patch residence time for the parasitoid and partly explained the fact that A. ervi remained for a shorter time at the intermediate and high temperatures than at the lowest temperature. Our results suggest that global warming may affect host-parasitoid interactions through complex mechanisms including both direct and indirect effects on parasitoid patch time allocation. PMID- 26961125 TI - Sickness certification for common mental disorders and GP return-to-work advice. AB - Aim To report the types and duration of sickness certification for different common mental disorders (CMDs) and the prevalence of GP advice aimed at returning the patient to work. BACKGROUND: In the United Kingdom, common mental health problems, such and depression and stress, have become the main reasons for patients requesting a sickness certificate to abstain from usual employment. Increasing attention is being paid to mental health and its impact on employability and work capacity in all parts of the welfare system. However, relatively little is known about the extent to which different mental health diagnoses impact upon sickness certification outcomes, and how the GP has used the new fit note (introduced in 2010) to support a return to work for patients with mental health diagnoses. METHODS: Sickness certification data was collected from 68 UK-based general practices for a period of 12 months. Findings The study found a large part of all sickness absence certified by GPs was due to CMDs (29% of all sickness absence episodes). Females, younger patients and those living in deprived areas were more likely to receive a fit note for a CMD (compared with one for a physical health problem). The highest proportion of CMD fit notes were issued for 'stress'. However, sickness certification for depression contributed nearly half of all weeks certified for mental health problems. Only 7% of CMD fit notes included any 'may be fit' advice from the GP, with type of advice varying by mental health diagnostic category. Patients living in the most socially deprived neighbourhoods were less likely to receive 'may be fit' advice on their CMD fit notes. PMID- 26961126 TI - Functional characterization of the Japanese flounder (Paralichthys olivaceus) Sox2 gene promoter. AB - Sox2 has essential roles in early embryogenesis and the development of the central nervous system. Sox2 is also necessary in maintaining the identity of progenitor cells. In our study, a 1.8-kb fragment of the 5' flanking region of Paralichthys olivaceus Sox2 (Po-Sox2) gene was cloned and functionally characterized. The activity and specificity of Po-Sox2 promoter were analyzed by comparing various deletion mutants for their ability to direct luciferase and GFP expression in flounder brain cell line. Results indicated that the basal promoter is located between -978 and -442 bp, and the region from -1370 to -978 bp enhances the promoter activity. The regulatory elements in the -1370 to -442 bp fragment were further investigated. Many binding sites of transcription factors closely related to neurogenesis and stem cell properties were found in this region. Mutational analysis indicated that Nanog, Pax6, p53, and POU binding sites play functional roles in the transcription of Po-Sox2 gene, whereas NF-Y binding sites did not affect this gene. In vivo studies using transient transgenic zebrafish embryos showed that the Po-Sox2 promoter region can drive GFP expression in brain, yolk syncytial layer, and notochord. Our results provide valuable information in understanding the molecular regulatory mechanisms of Po Sox2 gene during neurogenesis and embryonic development. PMID- 26961127 TI - Seasonality of reproduction in male spotted murrel Channa punctatus: correlation of environmental variables and plasma sex steroids with histological changes in testis. AB - The present study was undertaken to develop a comprehensive understanding of how environmental cues and sex steroids relate with cyclic changes in spermatogenesis in freshwater spotted snakehead Channa punctatus that is nutritious and economically important. The seasonal histological changes in testis and annual profile of gonadosomatic index (GSI) of C. punctatus delineated the testicular cycle into four phases: regressed (December-March), preparatory (April-June), spawning (July and August) and postspawning (September-November). Among environmental variables, correlation and regression analyses exhibited an important relationship between photoperiod and testicular weight while role of rainfall was seen confined to spawning. The seasonal profile of plasma sex steroids when correlated with cyclic changes in spermatogenesis in spotted snakehead, testosterone (T) seems to be involved in controlling the major events of spermatogenesis from renewal of stem cells to spawning of spermatozoa. Another important androgen prevalent in teleosts, 11-ketotestosterone (11-KT), was high during preparatory phase, suggesting that 11-KT in addition to T plays an important role in progression of spermatogenesis and spermiation in C. punctatus. However, 11-KT was not seen to be associated with milt production and release of spermatozoa during spawning. Plasma profile of estradiol-17beta (E2) during different reproductive phases revealed the involvement of E2 in repopulation of stem cells during postspawning phase and in maintaining quiescence of testis during regressed phase. PMID- 26961128 TI - Effect of chronic undernutrition on body mass and mechanical bone quality under normoxic and altitude hypoxic conditions. AB - Both undernutrition and hypoxia exert a negative influence on both growth pattern and bone mechanical properties in developing rats. The present study explored the effects of chronic food restriction on both variables in growing rats exposed to simulated high-altitude hypoxia. Male rats (n 80) aged 28 d were divided into normoxic (Nx) and hypoxic (Hx) groups. Hx rats were exposed to hypobaric air (380 mmHg) in decompression chambers. At T0, Nx and Hx rats were subdivided into four equal subgroups: normoxic control and hypoxic controls, and normoxic growth restricted and hypoxic growth-restricted received 80 % of the amount of food consumed freely by their respective controls for a 4-week period. Half of these animals were studied at the end of this period (T4). The remaining rats in each group continued under the same environmental conditions, but food was offered ad libitum to explore the type of catch-up growth during 8 weeks. Structural bone properties (strength and stiffness) were evaluated in the right femur midshaft by the mechanical three-point bending test; geometric properties (length, cross sectional area, cortical mass, bending cross-sectional moment of inertia) and intrinsic properties of the bone tissue (elastic modulus) were measured or derived from appropriate equations. Bone mineralisation was assessed by ash measurement of the left femur. These data indicate that the growth-retarded effects of diminished food intake, induced either by food restriction or hypoxia related inhibition of appetite, generated the formation of corresponding smaller bones in which subnormal structural and geometric properties were observed. However, they seemed to be appropriate to the body mass of the animals and suggest, therefore, that the bones were not osteopenic. When food restriction was imposed in Hx rats, the combined effects of both variables were additive, inducing a further reduction of bone mass and bone load-carrying capacity. In all cases, the mechanical properties of the mineralised tissue were unaffected. This and the capacity of the treated bones to undergone complete catch-up growth with full restoration of the biomechanical properties suggest that undernutrition, under either Nx or Hx conditions, does not affect bone behaviour because it remains appropriate to its mechanical functions. PMID- 26961129 TI - Solid-state NMR chemical-shift perturbations indicate domain reorientation of the DnaG primase in the primosome of Helicobacter pylori. AB - We here investigate the interactions between the DnaB helicase and the C-terminal domain of the corresponding DnaG primase of Helicobacter pylori using solid-state NMR. The difficult crystallization of this 387 kDa complex, where the two proteins interact in a six to three ratio, is circumvented by simple co sedimentation of the two proteins directly into the MAS-NMR rotor. While the amount of information that can be extracted from such a large protein is still limited, we can assign a number of amino-acid residues experiencing significant chemical-shift perturbations upon helicase-primase complex formation. The location of these residues is used as a guide to model the interaction interface between the two proteins in the complex. Chemical-shift perturbations also reveal changes at the interaction interfaces of the hexameric HpDnaB assembly on HpDnaG binding. A structural model of the complex that explains the experimental findings is obtained. PMID- 26961131 TI - A blue 4',7-diaminoflavylium cation showing an extended pH range stability. AB - The introduction of two amine substituents in 4' and 7 positions, leads to the formation of a blue flavylium cation, 7-(N,N'-diethylamino)-2-(9-julolidine)-1 benzopyrilium, which is extremely stable across a wide acidic pH range. The kinetic and thermodynamic constants of the multistate system have been calculated by studying the relaxation kinetics after equilibrium perturbation by addition of base (direct pH jumps) or acid (reverse pH jumps). Except for the cis-chalcone, which is an elusive species, the relative energy levels of the other species could be calculated and a global energy level diagram constructed. The diagram explains that the stability of the diamino compound is due to the high energy level of the hemiketal species, which is difficult to access in acidic medium. PMID- 26961130 TI - The Linked CENTURY Study: linking three decades of clinical and public health data to examine disparities in childhood obesity. AB - BACKGROUND: Despite the need to identify the causes of disparities in childhood obesity, the existing epidemiologic studies of early life risk factors have several limitations. We report on the construction of the Linked CENTURY database, incorporating CENTURY (Collecting Electronic Nutrition Trajectory Data Using Records of Youth) Study data with birth certificates; and discuss the potential implications of combining clinical and public health data sources in examining the etiology of disparities in childhood obesity. METHODS: We linked the existing CENTURY Study, a database of 269,959 singleton children from birth to age 18 years with measured heights and weights, with each child's Massachusetts birth certificate, which captures information on their mothers' pregnancy history and detailed socio-demographic information of both mothers and fathers. RESULTS: Overall, 74.2 % were matched, resulting in 200,343 children in the Linked CENTURY Study with 1,580,597 well child visits. Among this cohort, 94.0 % (188,334) of children have some father information available on the birth certificate and 60.9 % (121,917) of children have at least one other sibling in the dataset. Using maternal race/ethnicity from the birth certificate as an indicator of children's race/ethnicity, 75.7 % of children were white, 11.6 % black, 4.6 % Hispanic, and 5.7 % Asian. Based on socio-demographic information from the birth certificate, 20.0 % of mothers were non-US born, 5.9 % smoked during pregnancy, 76.3 % initiated breastfeeding, and 11.0 % of mothers had their delivery paid for by public health insurance. Using clinical data from the CENTURY Study, 22.7 % of children had a weight-for-length >= 95(th) percentile between 1 and 24 months and 12.0 % of children had a body mass index >= 95(th) percentile at ages 5 and 17 years. CONCLUSIONS: By linking routinely-collected data sources, it is possible to address research questions that could not be answered with either source alone. Linkage between a clinical database and each child's birth certificate has created a unique dataset with nearly complete racial/ethnic and socio-demographic information from both parents, which has the potential to examine the etiology of racial/ethnic and socioeconomic disparities in childhood obesity. PMID- 26961134 TI - Genetic variation in one-carbon metabolism in relation to genome-wide DNA methylation in breast tissue from heathy women. AB - Single nucleotide polymorphisms (SNPs) in one-carbon metabolism genes and lifestyle factors (alcohol drinking and breast folate) may be determinants of whole-genome methylation in the breast. DNA methylation profiling was performed using the Illumina Infinium HumanMethylation450 BeadChip in 81 normal breast tissues from women undergoing reduction mammoplasty and no history of cancer. ANCOVA, adjusting for age, race and BMI, was used to identify differentially methylated (DM) CpGs. Gene expression, by the Affymetrix GeneChip Human Transcriptome Array 2.0, was correlated with DM. Biological networks of DM genes were assigned using Ingenuity Pathway Analysis. Fifty-seven CpG sites were DM in association with eight SNPs in FTHFD, MTHFD1, MTHFR, MTR, MTRR, and TYMS (P <5.0 x 10-5); 56% of the DM CpGs were associated with FTHFD SNPs, including DM within FTHFD. Gene expression was negatively correlated with FTHFD methylation (r=-0.25, P=0.017). Four DM CpGs identified by SNPs in MTRR, MTHFR, and FTHFD were significantly associated with alcohol consumption and/or breast folate. The top biological network of DM CpGs was associated with Energy Production, Molecular Transportation, and Nucleic Acid Metabolism. This is the first comprehensive study of the association between SNPs in one-carbon metabolism genes and genome wide DNA methylation in normal breast tissues. These SNPs, especially FTHFD, as well as alcohol intake and folate exposure, appear to affect DM in breast tissues of healthy women. The finding that SNPs in FTHFD and MTR are associated with their own methylation is novel and highlights a role for these SNPs as cis methylation quantitative trait loci. PMID- 26961133 TI - Minimally invasive surgery for gastric cancer: the American experience. AB - BACKGROUND: Minimally invasive surgical techniques are increasingly being implemented in oncologic care. This study assesses the impact of minimally invasive surgery on oncologic and perioperative outcomes in the management of gastric cancer in the USA. METHODS: From the American College of Surgeons and American Cancer Society National Cancer Data Base, we identified 6427 patients who underwent gastrectomy for cancer from 2010 to 2012. Treatment groups were categorized with an intention-to-treat paradigm as robotic, laparoscopic, and open surgery. Univariate and multivariate analyses were performed to estimate the impact of the surgical approach on oncologic and perioperative outcomes. RESULTS: Of patients undergoing definitive surgical intervention, 3.5 % (n = 223) underwent robotic gastrectomy, 23.1 % (n = 1487) underwent laparoscopic gastrectomy, and 73.4 % (n = 4717) underwent open surgery. Minimally invasive gastrectomy was more frequently performed on white (P = 0.018), privately insured patients (P = 0.049) treated at academic centers (P < 0.0001) in the eastern USA (P < 0.0001). After demographics, comorbidities, and tumor-related factors had been controlled for, patients who underwent laparoscopic gastrectomy had the postoperative length of stay decreased by 1.08 days (P < 0.0001) and greater odds of having at least 15 lymph nodes resected (odds ratio 1.16, P = 0.023). Use of robotic surgery did not have a statistically significant effect on the postoperative length of stay relative to open surgery (P = 0.222) but the patients so treated had greater odds of having at least 15 lymph nodes resected (odds ratio 1.51, P = 0.005). There were no differences in R0 resection rates or perioperative mortality on the basis of the surgical approach alone. CONCLUSIONS: These findings suggest that use of minimally invasive surgery for gastric cancer in the USA is impacting the adequacy of oncologic resection but is not yet having a clinically significant impact on perioperative outcomes relative to a conventional open approach. PMID- 26961136 TI - Nanoplasmonics tuned "click chemistry". AB - Nanoplasmonics is a growing field of optical condensed matter science dedicated to optical phenomena at the nanoscale level in metal systems. Extensive research on noble metallic nanoparticles (NPs) has emerged within the last two decades due to their ability to keep the optical energy concentrated in the vicinity of NPs, in particular, the ability to create optical near-field enhancement followed by heat generation. We have exploited these properties in order to induce a localised "click" reaction in the vicinity of gold nanostructures under unfavourable experimental conditions. We demonstrate that this reaction can be controlled by the plasmonic properties of the nanostructures and we propose two physical mechanisms to interpret the observed plasmonic tuning of the "click" chemistry. PMID- 26961137 TI - Tandem autologous versus autologous/allogeneic transplantation for multiple myeloma: propensity score analysis. AB - Autologous hematopoietic stem cell transplantation (auto-HCT) is considered a standard therapy for transplant-eligible patients with multiple myeloma, while allogeneic HCT (allo-HCT) is controversial. We retrospectively analyzed 765 patients with myeloma who underwent tandem transplantation between 1998 and 2012 using Japanese registry data. We evaluated the clinical outcomes of tandem auto HCT (n = 676) and auto/allo-HCT (n = 89). To adjust for a selection bias, we compared overall survival (OS) between the two groups by a propensity score analysis. The probability of OS at six years was 58.5% for the tandem auto-HCT group and 54.4% for the tandem auto/allo-HCT group (p = 0.47). In a matched-pair analysis based on the propensity score, the difference in survival between the two groups was not statistically significant, although the survival curve appeared to reach a plateau beyond five years in the auto/allo group. Further strategies to reduce treatment-related mortality and enhance a graft-versus myeloma effect are necessary to improve OS. PMID- 26961138 TI - Selectivity profile of afatinib for EGFR-mutated non-small-cell lung cancer. AB - EGFR-mutated non-small-cell lung cancer (NSCLC) has long been a research focus in lung cancer studies. Besides reversible tyrosine kinase inhibitors (TKIs), new generation irreversible inhibitors, such as afatinib, embark on playing an important role in NSCLC treatment. To achieve an optimal application of these inhibitors, the correlation between the EGFR mutation status and the potency of such an inhibitor should be decoded. In this study, the correlation was profiled for afatinib, based on a cohort of patients with the EGFR-mutated NSCLC. Relying on extracted DNAs from the paraffin-embedded tumor samples, EGFR mutations were detected by direct sequencing. Progression-free survival (PFS) and the response level were recorded as study endpoints. These PFS and response values were analyzed and correlated to different mutation types, implying a higher potency of afatinib to classic activation mutations (L858R and deletion 19) and a lower one to T790M-related mutations. To further bridge the mutation status with afatinib related response or PFS, we conducted a computational study to estimate the binding affinity in a mutant-afatinib system, based on molecular structural modeling and dynamics simulations. The derived binding affinities were well in accordance with the clinical response or PFS values. At last, these computational binding affinities were successfully mapped to the patient response or PFS according to linear models. Consequently, a detailed mutation-response or mutation-PFS profile was drafted for afatinib, implying the selective nature of afatinib to various EGFR mutants and further encouraging the design of specialized therapies or innovative drugs. PMID- 26961139 TI - Genome and network visualization facilitates the analyses of the effects of drugs and mutations on protein-protein and drug-protein networks. AB - BACKGROUND: Biologists generally interrogate genomics data using web-based genome browsers that have limited analytical potential. New generation genome browsers such as the Integrated Genome Browser (IGB) have largely overcome this limitation and permit customized analyses to be implemented using plugins. We illustrate the use of a plugin for IGB that exploits advanced visualization techniques to integrate the analysis of genomics data with network and structural approaches. RESULTS: We show how visualization technologies that combine both genomics and network biology can facilitate the selection of the key amino acid contacts from protein-protein and protein-drug interactions. Starting from the MDM2-P53 interaction, which is a high-value target for cancer therapy, and Nutlin, the parent small molecule of an MDM2 antagonist that is currently in clinical trials, we show that this method can be generalized to analyze how drugs and mutations can interfere with both protein-protein and drug-protein networks. We illustrate this point by two additional use-cases exploring the molecular basis of tamoxifen side effects and of drug resistance in chronic myeloid leukemia patients. CONCLUSIONS: Combined network and structure biology approaches provide key insights into both the genetic and the edgetic roles of variants in diseases. 3D interactomes facilitate the identification of disease-relevant interactions that can then be specifically targeted by drugs. Recent advances in molecular interaction and structure visualization tools have greatly simplified the mapping of mutated residues to molecular interaction interfaces. Such approaches can now also be integrated with genome visualization tools to enable comparative analyses of interaction contacts. PMID- 26961132 TI - Achilles' heel of pluripotent stem cells: genetic, genomic and epigenetic variations during prolonged culture. AB - Pluripotent stem cells differentiate into almost any specialized adult cell type of an organism. PSCs can be derived either from the inner cell mass of a blastocyst-giving rise to embryonic stem cells-or after reprogramming of somatic terminally differentiated cells to obtain ES-like cells, named induced pluripotent stem cells. The potential use of these cells in the clinic, for investigating in vitro early embryonic development or for screening the effects of new drugs or xenobiotics, depends on capability to maintain their genome integrity during prolonged culture and differentiation. Both human and mouse PSCs are prone to genomic and (epi)genetic instability during in vitro culture, a feature that seriously limits their real potential use. Culture-induced variations of specific chromosomes or genes, are almost all unpredictable and, as a whole, differ among independent cell lines. They may arise at different culture passages, suggesting the absence of a safe passage number maintaining genome integrity and rendering the control of genomic stability mandatory since the very early culture passages. The present review highlights the urgency for further studies on the mechanisms involved in determining (epi)genetic and chromosome instability, exploiting the knowledge acquired earlier on other cell types. PMID- 26961140 TI - In patients with metastatic breast cancer the identification of circulating tumor cells in epithelial-to-mesenchymal transition is associated with a poor prognosis. AB - BACKGROUND: Although recent models suggest that the detection of Circulating Tumor Cells (CTC) in epithelial-to-mesenchymal transition (EM CTC) might be related to disease progression in metastatic breast cancer (MBC) patients, current detection methods are not efficient in identifying this subpopulation of cells. Furthermore, the possible association of EM CTC with both clinicopathological features and prognosis of MBC patients has still to be demonstrated. Aims of this study were: first, to optimize a DEPArray-based protocol meant to identify, quantify and sort single, viable EM CTC and, subsequently, to test the association of EM CTC frequency with clinical data. METHODS: This prospective observational study enrolled 56 MBC patients regardless of the line of treatment. Blood samples, depleted of CD45(pos) leukocytes, were stained with an antibody cocktail recognizing both epithelial and mesenchymal markers. Four CD45(neg) cell subpopulations were identified: cells expressing only epithelial markers (E CTC), cells co-expressing epithelial and mesenchymal markers (EM CTC), cells expressing only mesenchymal markers (MES) and cells negative for every tested marker (NEG). CTC subpopulations were quantified as both absolute cell count and relative frequency. The association of CTC subpopulations with clinicopathological features, progression free survival (PFS), and overall survival (OS) was explored by Wilcoxon-Mann-Whitney test and Univariate Cox Regression Analysis, respectively. RESULTS: By employing the DEPArray-based strategy, we were able to assess the presence of cells pertaining to the above-described classes in every MBC patient. We observed a significant association between specific CD45(neg) subpopulations and tumor subtypes (e.g. NEG and triple negative), proliferation (NEG and Ki67 expression) and sites of metastatic spread (e.g. E CTC and bone; NEG and brain). Importantly, the fraction of CD45(neg) cells co-expressing epithelial and mesenchymal markers (EM CTC) was significantly associated with poorer PFS and OS, computed, this latter, both from the diagnosis of a stage IV disease and from the initial CTC assessment. CONCLUSION: This study suggests the importance of dissecting the heterogeneity of CTC in MBC. Precise characterization of CTC could help in estimating both metastatization pattern and outcome, driving clinical decision-making and surveillance strategies. PMID- 26961141 TI - Pregnant Women's Infant Oral Health Knowledge and Beliefs: Influence of Having Given Birth and of Having a Child in the Home. AB - Introduction Prenatal oral health interventions can positively impact maternal and child oral health, yet limited information exists concerning how to best educate pregnant women about infant oral health. Our objective was to examine the influence of having given birth on pregnant women's infant oral health knowledge and beliefs. Methods We conducted a secondary analysis of data collected from a cross-sectional survey of pregnant women >=18 years old attending UNC's Ultrasound Clinic. Four binomial items were categorized as infant knowledge (IK) and five rated on a Likert scale (1-5) as infant belief (IB). Overall IK and IB scores were calculated, averaging the items within each construct. Respondents were categorized into two groups: multiparous (N = 268), women having at least one previous live birth and a child between 2 and 6 years old, or nulliparous (N = 186), women with no previous live births or a child between 2 and 6 years old. Regression models for IK and IB were conducted using SAS 9.2 with maternal demographic characteristics, dental utilization, and birth history as explanatory variables (p <= 0.05). Results IK was affected by race (p = 0.04), mother's oral health self-rating (p = 0.0002), and birth history (p < 0.0001). On average, IK was 0.12 units higher in subjects with a history of giving birth, adjusting for explanatory variables. IB was influenced by maternal oral health beliefs (p = 0.002) and history of access to dental care (p = 0.0002). IB did not differ based on birth history (p = 0.17). Discussion The influence of birth history on pregnant women's infant oral health knowledge and beliefs can be considered in future intervention designs to maximize available resources. PMID- 26961142 TI - Implications of Comprehensive Mental Health Services Embedded in an Adolescent Obstetric Medical Home. AB - Purpose Mental health issues in perinatal adolescents are well documented and studies have shown high rates of depressive disorders among this population. Treatment is challenging because pregnant adolescents are poorly adherent with mental health services. We describe a novel integrated mental health care program for pregnant and parenting adolescent mothers and their children. Methods The Colorado Adolescent Maternity Program (CAMP) is a comprehensive, multidisciplinary teen pregnancy and parenting medical home program serving an ethnically diverse and low socioeconomic status population in the Denver metro area. We describe the Healthy Expectations Adolescent Response Team (HEART), an embedded mental health care program focused on improving identification of mental health symptoms and increasing rates mental health treatment in adolescent mothers. Results From January 1, 2011-January 16 2014, 894 pregnant adolescents were enrolled in CAMP and 885 patients were screened for mental health issues. Prior to HEART's inception, 20 % of patients were identified as having mood symptoms in the postpartum period. Successful referrals to community mental health facilities occurred in only 5 % of identified patients. Following the creation of HEART, 41 % of patients were identified as needing mental health services. Nearly half of the identified patients (47 %) engaged in mental health treatment with the psychologist. Demographic factors including age, parity, ethnicity, and parent and partner involvement did not have a significant impact on treatment engagement. Trauma history was associated with lower treatment engagement. Conclusion Our findings suggest that an embedded mental health program in an adolescent obstetric and pediatric medical home is successful in improving identification and engagement in mental health treatment. Key components of the program include universal screening, intensive social work and case management involvement, and ready access to onsite mental health care providers. Limitations of the program are discussed as well directions for future research. PMID- 26961143 TI - Risk Factors for Non-use of Skilled Birth Attendants: Analysis of South Sudan Household Survey, 2010. AB - Objectives South Sudan has the lowest percentage of births attended by skilled health personnel in the world. This paper aims to identify potential risk factors associated with non-use of skilled birth attendants at delivery in South Sudan. Methods Secondary data analyses of the 2010 South Sudan Household Health Survey second round were conducted with data for 3504 women aged 15-49 years who gave birth in the 2 years prior to the survey. The risk of non-use of skilled birth attendants was examined using simple and multiple logistic regression analyses. Results The prevalence rates for skilled, unskilled and no birth attendants at delivery were 41 [95 % confidence interval (CI) 38.2, 43.0], 36 [95 % CI 33.9, 38.8], and 23 % [95 % CI 20.6, 24.9] respectively. Multivariable analyses indicated that educated mothers [adjusted odds ratio (AOR) 0.70; 95 % CI 0.57, 0.86], mothers who had three and more complications during pregnancy [AOR 0.77; 95 % CI 0.65, 0.90], mothers who had at least 1-3 ANC visits [AOR 0.38; 95 % CI 0.30, 0.49] and mothers from rich households [AOR 0.52; 95 % CI 0.42, 0.65] were significantly more likely to use skilled birth attendants (SBAs) at delivery. Mothers who lived in rural areas [AOR 1.44; 95 % CI 1.06, 1.96] were less likely to deliver with SBAs. Conclusion Intensive investments to recruit and train more skilled birth attendants' on appropriate delivery care are needed, as well as building a community-based skilled birth attendants' program to reduce avoidable maternal mortality in South Sudan. PMID- 26961144 TI - Transferrin liposomes of docetaxel for brain-targeted cancer applications: formulation and brain theranostics. AB - Diagnosis and therapy of brain cancer was often limited due to low permeability of delivery materials across the blood-brain barrier (BBB) and their poor penetration into the brain tissue. This study explored the possibility of utilizing theranostic d-alpha-tocopheryl polyethylene glycol 1000 succinate mono ester (TPGS) liposomes as nanocarriers for minimally invasive brain-targeted imaging and therapy (brain theranostics). The aim of this work was to formulate transferrin conjugated TPGS coated theranostic liposomes, which contain both docetaxel and quantum dots (QDs) for imaging and therapy of brain cancer. The theranostic liposomes with and without transferrin decoration were prepared and characterized for their particle size, polydispersity, morphology, drug encapsulation efficiency, in-vitro release study and brain theranostics. The particle sizes of the non-targeted and targeted theranostic liposomes were found below 200 nm. Nearly, 71% of drug encapsulation efficiency was achieved with liposomes. The drug release from transferrin conjugated theranostic liposomes was sustained for more than 72 h with 70% of drug release. The in-vivo results indicated that transferrin receptor-targeted theranostic liposomes could be a promising carrier for brain theranostics due to nano-sized delivery and its permeability which provided an improved and prolonged brain targeting of docetaxel and QDs in comparison to the non-targeted preparations. PMID- 26961145 TI - Dietary and lifestyle determinants of malondialdehyde DNA adducts in a representative sample of the Florence City population. AB - Malondialdehyde (MDA), a biomarker of lipid peroxidation and oxidative stress, is a mutagenic and carcinogenic compound that can react with DNA to form several types of DNA adducts including the deoxyguanosine adduct (M1dG). The aim of this cross-sectional study was to evaluate the association between individual dietary and lifestyle habits and M1dG levels, measured in peripheral leukocytes in a large representative sample of the general population of Florence City (Italy). Selected anthropometric measurements, detailed information on dietary and lifestyle habits and blood samples were available for 313 adults of the Florence City Sample enrolled in the frame of European Prospective Investigation into Cancer and nutrition (EPIC) study. A multivariate regression analysis adjusted for selected individual characteristics possibly related to M1dG levels (sex, age, BMI, smoke, physical activity level, education level, total caloric intake and a Mediterranean dietary score) was performed to estimate the association between these parameters and M1dG levels. M1dG levels were significantly higher in women (P = 0.014) and lower in moderately active or active subjects (P = 0.037).We also found a significant inverse association with the Modified Mediterranean dietary score (P for trend = 0.049), particularly evident for the highest categories of adherence. Our results indicate that M1dG levels can be modulated by selected individual characteristics such as gender, physical activity and a Mediterranean dietary pattern. PMID- 26961146 TI - Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. AB - BACKGROUND: The PARP inhibitor olaparib (LynparzaTM) demonstrates antitumor activity in women with relapsed ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior chemotherapy. PATIENTS AND METHODS: This analysis evaluated pooled data from two phase I trials [NCT00516373 (study 2); NCT00777582 (study 24)] and four phase II trials [NCT00494442 (study 9); NCT00628251 (study 12); NCT00679783 (study 20); NCT01078662 (study 42)] that recruited women with relapsed ovarian, fallopian tube or peritoneal cancer. All patients had a documented gBRCAm and were receiving olaparib 400 mg monotherapy twice daily (capsule formulation) at the time of relapse. Objective response rate (ORR) and duration of response (DoR) were evaluated using original patient outcomes data for patients with measurable disease at baseline. RESULTS: Of the 300 patients in the pooled population, 273 had measurable disease at baseline, of whom 205 (75%) had received >=3 lines of prior chemotherapy. In the pooled population, the ORR was 36% [95% confidence interval (CI) 30-42] and the median DoR was 7.4 months (95% CI 5.7-9.1). The ORR among patients who had received >=3 lines of prior chemotherapy was 31% (95% CI 25-38), with a DoR of 7.8 months (95% CI 5.6-9.5). The safety profile of olaparib was similar in patients who had received >=3 lines of prior chemotherapy compared with the pooled population; grade >=3 adverse events were reported in 54% and 50% of patients, respectively. CONCLUSION: Durable responses to olaparib were observed in patients with relapsed gBRCAm ovarian cancer who had received >=3 lines of prior chemotherapy. CLINICALTRIALSGOV: NCT00516373; NCT00494442; NCT00628251; NCT00679783; NCT00777582; NCT01078662. PMID- 26961147 TI - Combination of the MEK inhibitor pimasertib with BTK or PI3K-delta inhibitors is active in preclinical models of aggressive lymphomas. AB - BACKGROUND: Lymphomas are among the most common human cancers and represent the cause of death for still too many patients. The B-cell receptor with its downstream signaling pathways represents an important therapeutic target for B cell lymphomas. Here, we evaluated the activity of the MEK1/2 inhibitor pimasertib as single agent and in combination with other targeted drugs in lymphoma preclinical models. MATERIALS AND METHODS: Cell lines derived mature B cell lymphomas were exposed to increasing doses of pimasertib alone. Immunoblotting and gene expression profiling were performed. Combination of pimasertib with idelalisib or ibrutinib was assessed. RESULTS: Pimasertib as single agent exerted a dose-dependent antitumor activity across a panel of 23 lymphoma cell lines, although at concentrations higher than reported for solid tumors. Strong synergism was observed with pimasertib combined with the PI3K inhibitor idelalisib and the BTK inhibitor ibrutinib in cell lines derived from diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma. The data were confirmed in an in vivo experiment treating DLBCL xenografts with pimasertib and ibrutinib. CONCLUSION: The data presented here provide the basis for further investigation of regimens including pimasertib in relapsed and refractory lymphomas. PMID- 26961148 TI - Osimertinib (AZD9291)-a science-driven, collaborative approach to rapid drug design and development. PMID- 26961149 TI - Reduced intensity allogeneic stem cell transplantation for follicular lymphoma relapsing after an autologous transplant achieves durable long term disease control. An analysis from the Lymphoma Working Party Of the EBMT. AB - BACKGROUND: Patients with follicular lymphoma (FL) relapsing after an autologous transplant (autoSCT) may be treated with a variety of therapies including a reduced intensity allogeneic transplant (RICalloSCT). We conducted a retrospective analysis of a large cohort of patients undergoing RICalloSCT for FL in this setting. PATIENTS AND METHODS: 183 patients, median age 45 years (range 21-69), had undergone an autoSCT at a median of 30 months prior to the RICalloSCT. Before the RICalloSCT they had received a median of 4 lines (range 3 10) of therapy and 81% of patients had chemosensitive disease and 16% had chemoresistant disease. Grafts were donated from sibling (47%) or unrelated donors (53%). RESULTS: With a median follow up of 59 months the non-relapse mortality (NRM) was 27% at 2 years. The median remission duration post autoSCT and RICalloSCT were 14 and 43 months respectively. The 5 year relapse/progression rate, progression free survival (PFS) and overall survival (OS) were 16%, 48% and 51% respectively and were associated with age and disease status at RICalloSCT. CONCLUSION: This data suggests that a RICalloSCT is an effective salvage strategy in patients with FL recurring after a prior autoSCT and might overcome the poor prognostic impact of early relapse after autoSCT. PMID- 26961150 TI - Targeted treatment and immunotherapy in leptomeningeal metastases from melanoma. AB - BACKGROUND: Historically leptomeningeal metastases (LM) from melanoma have a poor prognosis, with a median survival of only 2 months despite treatment. Targeted therapy and immune checkpoint inhibitors are promising new treatment options in advanced melanoma. We sought to determine the impact of targeted therapy and immunotherapy on the outcome of melanoma patients with LM and to evaluate the influence of prognostic factors. PATIENTS AND METHODS: We analyzed a series of 39 consecutive patients diagnosed with LM from melanoma between May 2010 and March 2015 treated at the Netherlands Cancer Institute. Thirty-four of these patients also had brain metastases (BM). Statistical analyses assessed the influence of clinical and biological characteristics on survival. RESULTS: Median overall survival of the entire cohort was 6.9 weeks (95% confidence interval 0.9-12.8). Due to a poor performance status or rapidly progressive disease, 14 patients received no treatment. Median overall survival of untreated patients after the diagnosis of LM was 2.9 versus 16.9 weeks for treated patients (P < 0.001). The median survival of 21 patients treated with systemic targeted therapy and/or immunotherapy, with or without RT was 21.7 weeks (range 2-235 weeks). Five patients had LM without BM. Three of these patients died within 3 weeks before any treatment was given, whereas 2 patients are in ongoing remission for 26 weeks (following dabrafenib) and 235 weeks (following WBRT and ipilimumab). Elevated serum lactate dehydrogenase and S100B at diagnosis of LM were associated with shorter survival. CONCLUSION: LM from melanoma still has an extremely poor prognosis. As observed in extracranial metastatic disease, new treatment modalities such as systemic targeted therapy and immune checkpoint inhibitors seem to increase overall survival in LM, and may result in long-term remission. These new treatment options should be considered in patients with LM. PMID- 26961151 TI - Progression-free survival as surrogate end point for overall survival in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer. AB - BACKGROUND: The gold standard end point in randomized clinical trials in metastatic breast cancer (MBC) is overall survival (OS). Although therapeutics have been approved based on progression-free survival (PFS), its use as a primary end point is controversial. We aimed to assess to what extent PFS may be used as a surrogate for OS in randomized trials of anti-HER2 agents in HER2+ MBC. METHODS: Eligible trials accrued HER2+ MBC patients in 1992-2008. A correlation approach was used: at the individual level, to estimate the association between investigator-assessed PFS and OS using a bivariate model and at the trial level, to estimate the association between treatment effects on PFS and OS. Correlation values close to 1.0 would indicate strong surrogacy. RESULTS: We identified 2545 eligible patients in 13 randomized trials testing trastuzumab or lapatinib. We collected individual patient data from 1963 patients and retained 1839 patients from 9 trials for analysis (7 first-line trials). During follow-up, 1072 deaths and 1462 progression or deaths occurred. The median survival time was 22 months [95% confidence interval (CI) 21-23 months] and the median PFS was 5.7 months (95% CI 5.5-6.1 months). At the individual level, the Spearman correlation was equal to rho = 0.67 (95% CI 0.66-0.67) corresponding to a squared correlation value of 0.45. At the trial level, the squared correlation between treatment effects (log hazard ratios) on PFS and OS was provided by R(2) = 0.51 (95% CI 0.22-0.81). CONCLUSIONS: In trials of HER2-targeted agents in HER2+ MBC, PFS moderately correlates with OS at the individual level and treatment effects on PFS correlate moderately with those on overall mortality, providing only modest support for considering PFS as a surrogate. PFS does not completely substitute for OS in this setting. PMID- 26961152 TI - The effects of n-type doping on lithium storage in TiO2. AB - In this report, we discuss the Li-storage performance of niobium-doped TiO2 nanostructures (Ti(1-y)Nb(y)O(2+delta)), with a special focus on the effects of ionic/electronic charge carrier concentration (defect chemistry) on Li storage and transport properties. By Nb-doping, Li storage kinetics of titania electrode material is significantly improved mainly due to the increased electronic charge carrier concentration (n-type doping). However, it was found that there is a maximum beyond which further doping is rather detrimental to Li diffusion kinetics. Defect chemical analysis indicates that this limited doping effect is due to the trapping of free lithium ions by the critical electron-ion association reactions at room temperature such as Li(i)(*) + e' ? Li(i)(*) and Nb(Ti)(*) + e' ? Nb(Ti)(*). PMID- 26961154 TI - [Advances in pediatric rheumatology. Experimental and clinical]. PMID- 26961155 TI - Trusts have been set "impossible task" to balance books, say NHS leaders. PMID- 26961153 TI - Insight into determinants of substrate binding and transport in a multidrug efflux protein. AB - Multidrug resistance arising from the activity of integral membrane transporter proteins presents a global public health threat. In bacteria such as Escherichia coli, transporter proteins belonging to the major facilitator superfamily make a considerable contribution to multidrug resistance by catalysing efflux of myriad structurally and chemically different antimicrobial compounds. Despite their clinical relevance, questions pertaining to mechanistic details of how these promiscuous proteins function remain outstanding, and the role(s) played by individual amino acid residues in recognition, binding and subsequent transport of different antimicrobial substrates by multidrug efflux members of the major facilitator superfamily requires illumination. Using in silico homology modelling, molecular docking and mutagenesis studies in combination with substrate binding and transport assays, we identified several amino acid residues that play important roles in antimicrobial substrate recognition, binding and transport by Escherichia coli MdtM, a representative multidrug efflux protein of the major facilitator superfamily. Furthermore, our studies suggested that 'aromatic clamps' formed by tyrosine and phenylalanine residues located within the substrate binding pocket of MdtM may be important for antimicrobial substrate recognition and transport by the protein. Such 'clamps' may be a structurally and functionally important feature of all major facilitator multidrug efflux proteins. PMID- 26961156 TI - Positive prenatal well-being: conceptualising and measuring mindfulness and gratitude in pregnancy. AB - Little research has examined the usefulness of positive well-being factors during pregnancy. Recent mindfulness research demonstrates that inconsistencies and the suitability of extant measures have yet to be examined in pregnancy. Effects of gratitude during pregnancy have yet to be examined despite consistently reported benefits in non-pregnant groups. The aims of this paper were to develop the Gratitude during Pregnancy (GDP) scale, validate the Mindfulness Awareness Attention Scale (MAAS) and examine the importance of gratitude and mindfulness during pregnancy. In study 1, 375 pregnant women completed gratitude and mindfulness measures. The one-factor structure of the MAAS was retained and demonstrated good reliability alpha = 0.88. Using exploratory factor analysis, an 18-item GDP scale was developed, demonstrating good reliability alpha = 0.89. The four GDP factors are as follows: general gratitude, physical changes, antenatal care and social support. In study 2, 87 pregnant women completed well-being questionnaires, including the GDP and MAAS. Gratitude correlated with positive affect, life satisfaction and pregnancy uplifts (p < .001); mindfulness correlated negatively with negative affect and pregnancy hassles (p < .001) and positively correlated with positive affect and pregnancy uplifts (p < .05). These findings highlight the importance of mindfulness and gratitude and provide a reliable means to measure both constructs during pregnancy. PMID- 26961157 TI - Atomic structures of a liquid-phase bonded metal/nitride heterointerface. AB - Liquid-phase bonding is a technologically important method to fabricate high performance metal/ceramic heterostructures used for power electronic devices. However, the atomic-scale mechanisms of how these two dissimilar crystals specifically bond at the interfaces are still not well understood. Here we analyse the atomically-resolved structure of a liquid-phase bonded heterointerface between Al alloy and AlN single crystal using aberration corrected scanning transmission electron microscopy (STEM). In addition, energy dispersive X-ray microanalysis, using dual silicon drift X-ray detectors in STEM, was performed to analyze the local chemistry of the interface. We find that a monolayer of MgO is spontaneously formed on the AlN substrate surface and that a polarity-inverted monolayer of AlN is grown on top of it. Thus, the Al alloy is bonded with the polarity-inverted AlN monolayer, creating a complex atomic-scale layered structure, facilitating the bonding between the two dissimilar crystals during liquid-phase bonding processes. Density-functional-theory calculations confirm that the bonding stability is strongly dependent on the polarity and stacking of AlN and MgO monolayers. Understanding the spontaneous formation of layered transition structures at the heterointerface will be key in fabricating very stable Al alloy/AlN heterointerface required for high reliability power electronic devices. PMID- 26961158 TI - The prevalence of hyperglycaemia and its relationship with mortality, readmissions and length of stay in an older acute surgical population: a multicentre study. AB - BACKGROUND: The purpose of the study is to examine the prevalence of hyperglycaemia in an older acute surgical population and its effect on clinically relevant outcomes in this setting. METHODS: Using Older Persons Surgical Outcomes Collaboration (OPSOC) multicentre audit data 2014, we examined the prevalence of admission hyperglycaemia, and its effect on 30-day and 90-day mortality, readmission within 30 days and length of acute hospital stay using logistic regression models in consecutive patients, >=65 years, admitted to five acute surgical units in the UK hospitals in England, Scotland and Wales. Patients were categorised in three groups based on their admission random blood glucose: <7.1, between 7.1 and 11.1 and >=11.1 mmol/L. RESULTS: A total of 411 patients (77.25+/ 8.14 years) admitted during May and June 2014 were studied. Only 293 patients (71.3%) had glucose levels recorded on admission. The number (%) of patients with a blood glucose <7.1, 7.1-11.1 and >=11.1 mmol/L were 171 (58.4), 99 (33.8) and 23 (7.8), respectively. On univariate analysis, admission hyperglycaemia was not predictive of any of the outcomes investigated. Although the characteristics of those with no glucose level were not different from the included sample, 30-day mortality was significantly higher in those who had not had their admission glucose level checked (10.2% vs 2.7%), suggesting a potential type II error. CONCLUSION: Despite current guidelines, nearly a third of older people with surgical diagnoses did not have their glucose checked on admission highlighting the challenges in prognostication and evaluation research to improve care of older frail surgical patients. PMID- 26961159 TI - Carnosic acid slows photoreceptor degeneration in the Pde6b(rd10) mouse model of retinitis pigmentosa. AB - The photoreceptor cell death associated with the various genetic forms of retinitis pigmentosa (RP) is currently untreatable and leads to partial or complete vision loss. Carnosic acid (CA) upregulates endogenous antioxidant enzymes and has proven neuroprotective in studies of neurodegenerative models affecting the brain. In this study, we examined the potential effect of CA on photoreceptor death in the Pde6b(rd10) mouse model of RP. Our data shows that CA provided morphological and functional preservation of photoreceptors. CA appears to exert its neuroprotective effects through inhibition of oxidative stress and endoplasmic reticulum stress. PMID- 26961161 TI - "The Buoy": Utilization of a low-threshold ambulatory setting for traumatized children and adolescents in Austria. AB - BACKGROUND: This investigation intended to assess the use of an outpatient clinic providing low-threshold, short-term trauma therapy for children and adolescents across the first 6 years of its existence. METHODS: A retrospective analysis of the records of all patients undergoing treatment in this institution between 2001 and 2007 (n = 2510) has been performed. We evaluated demographic data, reason for contacting the unit, the referring person or institution, the person or institution in charge of the care and custody of the child, the number of contacts with the clinic, presence of physical or psychiatric illness of a parent, and medications prescribed. RESULTS: Ages of patients ranged from 1 to 17. Gender distribution was even. Having experienced the death of a relative, experienced violence, or having witnessed traumatic death were the main reasons for presentation. The utilization rates of immigrants rose throughout the observation period. Children from foster care were seen less frequently than expected. Medication was hardly prescribed. CONCLUSIONS: Ample utilization of this institution clearly demonstrates the need for short-term acute outpatient trauma therapy for children and adolescents. Efforts to provide easily accessible institutions for youth who experience traumatic events should be stepped up. PMID- 26961162 TI - Neural repair: Networking for regeneration. PMID- 26961160 TI - Cardiometabolic crosstalk in obesity-associated arterial hypertension. AB - Abdominal obesity and elevated blood pressure commonly occur in the same patient and are key components of the metabolic syndrome. However, the association between obesity and increased blood pressure is variable. We review mechanisms linking cardiovascular and metabolic disease in such patients including altered systemic and regional hemodynamic control, neurohumoral activation, and relative natriuretic peptide deficiency. Moreover, we discuss recent results using omics techniques providing insight in molecular pathways linking adiposity, metabolic disease, and arterial hypertension. Recognition of the mechanisms orchestrating the crosstalk between cardiovascular and metabolic regulation in individual patients may lead to better and more precise treatments. It is reassuring that recently developed cardiovascular and metabolic medications may in fact ameliorate, both, cardiovascular and metabolic risks. PMID- 26961165 TI - Neural circuits: A circuit to sigh for. PMID- 26961168 TI - A clinicopathologic study of paragangliomas of the urinary bladder: can the clinical behavior of the tumor be predicted? AB - Lymphovascular invasion (LVI) is an independent predictor of metastatic lymph node disease in penile carcinoma and is one factor used to guide clinical management. The presence of LVI with and without the use of the endothelial immunohistochemical (IHC) markers, ERG and CD31, was retrospectively assessed in 46 penectomy cases containing invasive penile carcinoma (43 squamous cell carcinoma and 3 non-squamous cell carcinoma). Concordance for the detection of LVI between the original report, upon pathology review, and with the use of IHC was determined and histologic pitfalls were identified. For penile squamous cell carcinoma, LVI was diagnosed in 27.9% of tumors in the original reports, 16.3% upon pathology review, and in 16.3% with use of ERG and CD31. Concordance of LVI identification in the original report compared to IHC was 74.4% while concordance of review compared to IHC was 95.3%. Using IHC data as the reference, false positive LVI diagnoses were more common in the original report than false negatives. Histologic mimickers of LVI including involvement of the penile corpora cavernosum or spongiosum vasculature, seromucinous colonization, and a nested pattern of tumor invasion were identified. We demonstrated that it was not uncommon for LVI in penile carcinoma to be overdiagnosed or underdiagnosed. The use of endothelial IHC markers, such as ERG or CD31, or additional pathology consultation is recommended for penectomy cases in which LVI is difficult to histologically discern. PMID- 26961170 TI - Large Optical Gain AlInN-Delta-GaN Quantum Well for Deep Ultraviolet Emitters. AB - The optical gain and spontaneous emission characteristics of low In-content AlInN delta-GaN quantum wells (QWs) are analyzed for deep ultraviolet (UV) light emitting diodes (LEDs) and lasers. Our analysis shows a large increase in the dominant transverse electric (TE) polarized spontaneous emission rate and optical gain. The remarkable enhancements in TE-polarized optical gain and spontaneous emission characteristics are attributed to the dominant conduction (C)-heavy hole (HH) transitions achieved by the AlInN-delta-GaN QW structure, which could lead to its potential application as the active region material for high performance deep UV emitters. In addition, our findings show that further optimizations of the delta-GaN layer in the active region are required to realize the high performance AlInN-based LEDs and lasers with the desired emission wavelength. This work illuminates the high potential of the low In-content AlInN-delta-GaN QW structure to achieve large dominant TE-polarized spontaneous emission rates and optical gains for high performance AlN-based UV devices. PMID- 26961163 TI - Rhythms of the hippocampal network. AB - The hippocampal local field potential (LFP) shows three major types of rhythms: theta, sharp wave-ripples and gamma. These rhythms are defined by their frequencies, they have behavioural correlates in several species including rats and humans, and they have been proposed to carry out distinct functions in hippocampal memory processing. However, recent findings have challenged traditional views on these behavioural functions. In this Review, I discuss our current understanding of the origins and the mnemonic functions of hippocampal theta, sharp wave-ripples and gamma rhythms on the basis of findings from rodent studies. In addition, I present an updated synthesis of their roles and interactions within the hippocampal network. PMID- 26961169 TI - Indomethacin treatment prior to pentylenetetrazole-induced seizures downregulates the expression of il1b and cox2 and decreases seizure-like behavior in zebrafish larvae. AB - BACKGROUND: It has been demonstrated that the zebrafish model of pentylenetetrazole (PTZ)-evoked seizures and the well-established rodent models of epilepsy are similar pertaining to behavior, electrographic features, and c fos expression. Although this zebrafish model is suitable for studying seizures, to date, inflammatory response after seizures has not been investigated using this model. Because a relationship between epilepsy and inflammation has been established, in the present study we investigated the transcript levels of the proinflammatory cytokines interleukin-1 beta (il1b) and cyclooxygenase-2 (cox2a and cox2b) after PTZ-induced seizures in the brain of zebrafish 7 days post fertilization. Furthermore, we exposed the fish to the nonsteroidal anti inflammatory drug indomethacin prior to PTZ, and we measured its effect on seizure latency, number of seizure behaviors, and mRNA expression of il1b, cox2b, and c-fos. We used quantitative real-time PCR to assess the mRNA expression of il1b, cox2a, cox2b, and c-fos, and visual inspection was used to monitor seizure latency and the number of seizure-like behaviors. RESULTS: We found a short-term upregulation of il1b, and we revealed that cox2b, but not cox2a, was induced after seizures. Indomethacin treatment prior to PTZ-induced seizures downregulated the mRNA expression of il1b, cox2b, and c-fos. Moreover, we observed that in larvae exposed to indomethacin, seizure latency increased and the number of seizure-like behaviors decreased. CONCLUSIONS: This is the first study showing that il1b and cox-2 transcripts are upregulated following PTZ induced seizures in zebrafish. In addition, we demonstrated the anticonvulsant effect of indomethacin based on (1) the inhibition of PTZ-induced c-fos transcription, (2) increase in seizure latency, and (3) decrease in the number of seizure-like behaviors. Furthermore, anti-inflammatory effect of indomethacin is clearly demonstrated by the downregulation of the mRNA expression of il1b and cox2b. Our results are supported by previous evidences suggesting that zebrafish is a suitable alternative for studying inflammation, seizures, and the effect of anti-inflammatory compounds on seizure suppression. PMID- 26961172 TI - Positive effects of aggressive vasodilator treatment of well-treated essential hypertensive patients. AB - Increased systemic vascular resistance and coronary microvascular dysfunction are well-documented in essential hypertension (EH). We investigated the effect of additional vasodilating treatment on coronary and peripheral resistance circulation in EH patients with high systemic vascular resistance index (SVRI) despite well-treated blood pressure (BP). We enroled patients on stable antihypertensive treatment that were given intensified vasodilating therapy (ACE inhibitor, angiotensin II receptor blocker or calcium channel blocker). Before and following 6 months of intensified therapy, coronary resting and maximal artery flow were measured by transthoracic Doppler echocardiography to calculate coronary flow reserve (CFR) and minimum vascular resistance (C-Rmin). Cardiac output was estimated by inert gas rebreathing to calculate SVRI. Maximal forearm blood flow was determined by venous occlusion plethysmography to calculate minimum vascular resistance (F-Rmin). Patients were assigned into two groups: high-SVRI and low-SVRI subgroups, based on a median split at baseline. Following additional treatment SVRI decreased more in the high-SVRI group than in the low SVRI group (14.4 vs -2.2%: P=0.003), despite similar baseline ambulatory BP (132/81 mm Hg) and BP reduction (6.5 and 4.6%: P=0.19). F-Rmin remained unchanged (6.5 vs -2.0%: P=0.30), while C-Rmin decreased by 22 and 24% (P=0.80) and CFR increased by 23 and 17% (P=0.16). Thus, intensified vasodilating therapy improved SVRI more in patients with high SVRI than in those with low SVRI. Regardless of SVRI status, the treatment improved cardiac but not forearm dilatation capacity. The substantial improvement of the hypertensive cardiac microvascular dysfunction was not related to the reduction in SVRI. PMID- 26961171 TI - The three-dimensional structure of Clostridium absonum 7alpha-hydroxysteroid dehydrogenase: new insights into the conserved arginines for NADP(H) recognition. AB - 7alpha-hydroxysteroid dehydrogenase (7alpha-HSDH) can catalyse the oxidation of C7 alpha-OH of the steroid nucleus in the bile acid metabolism. In the paper we determined the crystal structure of 7alpha-HSDH from Clostridium absonum (CA 7alpha-HSDH) complexed with taurochenodeoxycholic acid (TCDCA) and NADP(+) by X ray diffraction, which, as a tetramer, possesses the typical alpha/beta folding pattern. The four subunits of an asymmetric unit lie in the fact that there are the stable hydrophobic interactions between Q-axis-related subunits. Significantly, we captured an active state of the NADP(+), confirming that nicotinamide moiety of NADP(+) act as electron carrier in the dehydrogenation. On the basis of crystal structure analysis, site-directed mutagenesis and MD simulation, furthermore, we find that the guanidinium of Arg38 can form the stable cation-pi interaction with the adenine ring of NADP(+), and the cation-pi interaction and hydrogen bonds between Arg38 and NADP(+) have a significant anchor effect on the cofactor binding to CA 7alpha-HSDH. PMID- 26961173 TI - The occurrence of PAHs and faecal sterols in Dublin Bay and their influence on sedimentary microbial communities. AB - The source, concentration, and potential impact of sewage discharge and incomplete organic matter (OM) combustion on sedimentary microbial populations were assessed in Dublin Bay, Ireland. Polycyclic aromatic hydrocarbons (PAHs) and faecal steroids were investigated in 30 surface sediment stations in the bay. Phospholipid fatty acid (PLFA) content at each station was used to identify and quantify the broad microbial groups present and the impact of particle size, total organic carbon (%TOC), total hydrogen (%H) and total nitrogen (%N) was also considered. Faecal sterols were found to be highest in areas with historical point sources of sewage discharge. PAH distribution was more strongly associated with areas of deposition containing high %silt and %clay content, suggesting that PAHs are from diffuse sources such as rainwater run-off and atmospheric deposition. The PAHs ranged from 12 to 3072ng/g, with 10 stations exceeding the suggested effect range low (ERL) for PAHs in marine sediments. PAH isomer pair ratios and sterol ratios were used to determine the source and extent of pollution. PLFAs were not impacted by sediment type or water depth but were strongly correlated to, and influenced by PAH and sewage levels. Certain biomarkers such as 10Me16:0, i17:0 and a17:0 were closely associated with PAH polluted sediments, while 16:1omega9, 16:1omega7c, Cy17:0, 18:1omega6, i16:0 and 15:0 all have strong positive correlations with faecal sterols. Overall, the results show that sedimentary microbial communities are impacted by anthropogenic pollution. PMID- 26961174 TI - G protein-coupled receptor 37 is a negative regulator of oligodendrocyte differentiation and myelination. AB - While the formation of myelin by oligodendrocytes is critical for the function of the central nervous system, the molecular mechanism controlling oligodendrocyte differentiation remains largely unknown. Here we identify G protein-coupled receptor 37 (GPR37) as an inhibitor of late-stage oligodendrocyte differentiation and myelination. GPR37 is enriched in oligodendrocytes and its expression increases during their differentiation into myelin forming cells. Genetic deletion of Gpr37 does not affect the number of oligodendrocyte precursor cells, but results in precocious oligodendrocyte differentiation and hypermyelination. The inhibition of oligodendrocyte differentiation by GPR37 is mediated by suppression of an exchange protein activated by cAMP (EPAC)-dependent activation of Raf-MAPK-ERK1/2 module and nuclear translocation of ERK1/2. Our data suggest that GPR37 regulates central nervous system myelination by controlling the transition from early-differentiated to mature oligodendrocytes. PMID- 26961175 TI - A transducible nuclear/nucleolar protein, mLLP, regulates neuronal morphogenesis and synaptic transmission. AB - Cell-permeable proteins are emerging as unconventional regulators of signal transduction and providing a potential for therapeutic applications. However, only a few of them are identified and studied in detail. We identify a novel cell permeable protein, mouse LLP homolog (mLLP), and uncover its roles in regulating neural development. We found that mLLP is strongly expressed in developing nervous system and that mLLP knockdown or overexpression during maturation of cultured neurons affected the neuronal growth and synaptic transmission. Interestingly, extracellular addition of mLLP protein enhanced dendritic arborization, demonstrating the non-cell-autonomous effect of mLLP. Moreover, mLLP interacts with CCCTC-binding factor (CTCF) as well as transcriptional machineries and modulates gene expression involved in neuronal growth. Together, these results illustrate the characteristics and roles of previously unknown cell permeable protein mLLP in modulating neural development. PMID- 26961177 TI - Modelling High-temperature EBPR by Incorporating Glycogen and GAOs: Challenges from a Preliminary Study. AB - Recently reported kinetic and stoichiometric parameters of the Activated Sludge Model no. 2d (ASM2d) for high-temperature EBPR processes suggested that the absence of glycogen in the model contributed to underestimation of PHA accumulation at 32 degrees C. Here, two modified ASM2d models were used to further explore the contribution of glycogen in the process. The ASM2d-1G model incorporated glycogen metabolism by PAOs (polyphosphate-accumulating organisms), while the ASM2d-2G model further included processes by GAOs (glycogen accumulating organisms). These models were calibrated and validated using experimental data at 32 degrees C. The ASM2d-1G model supported the hypothesis that the excess PHA was attributed to glycogen, but remained inadequate to capture the dynamics of glycogen without considering GAOs activities. The ASM2d 2G model performed better, but it was challenging to calibrate as it often led to wash-out of either PAOs or GAOs. Associated hurdles are highlighted and additional efforts in calibrating ASM2d-2G more effectively are proposed. PMID- 26961176 TI - Inhibition of adhesion, migration and of alpha5beta1 integrin in the HCT-116 colorectal cancer cells treated with the ruthenium drug NAMI-A. AB - NAMI-A, imidazolium trans-imidazoledimethylsulfoxidetetrachlororuthenate, is a ruthenium-based drug characterised by the selective activity against tumour metastases. Previously we have shown the influence of the hepatic microenvironment to direct the arrest of the metastatic cells of colorectal cancer. Here we used the experimental model of HCT-116 colorectal cancer cells in vitro to explore whether the interference with alpha5beta1 integrin may mechanistically explain the anti-metastatic effect of NAMI-A. NAMI-A inhibits two important steps of the tumour metastatic progression of colorectal cancer, i.e. the adhesion and migration of the tumour cells on the extracellular matrix proteins. The fibronectin receptor alpha5beta1 integrin is likely involved in the anti-adhesive effects of NAMI-A on the HCT-116 colorectal cancer cells during their interaction with the extracellular matrix. Mechanistically, NAMI-A decreases the alpha5beta1 integrin expression, and reduces FAK (Focal Adhesion Kinase) auto-phosphorylation on Tyr397, an important signalling event, involved in alpha5beta1 integrin activation. These effects were validated by siRNA-induced knock down of the alpha5 integrin subunit and/or by the use of specific blocking mAbs against the active site of the integrin. Our results demonstrate the relevance of alpha5beta1 integrin for colorectal cancer. We also show that the anti-metastatic effect of NAMI-A depends on the modulation of this integrin. Thus, our data on NAMI-A support the new concept that metal-based drugs can inhibit tumour metastases through targeting of integrins and of other proteins which mediate tumour progression-related cell functions such as adhesion and migration. PMID- 26961178 TI - A Cross-Sectional Study of Medical Student Knowledge of Evidence-Based Medicine as Measured by the Fresno Test of Evidence-Based Medicine. AB - BACKGROUND: Evidence-based medicine (EBM) has been included in the Accreditation Council for Graduate Medical Education (ACGME) and the American Board of Emergency Medicine (ABEM) milestones project as a required component during emergency medicine (EM) residency training. Milestone Level One states that graduating medical students must be able to "describe basic principles of EBM." OBJECTIVE: We sought to identify the EBM skills of third- and fourth-year medical students. METHODS: Our institution, a network with 17 different residencies, hosts U.S. osteopathic and allopathic medical students. As a part of orientation, students are required to complete an entry Fresno Test of EBM (FTEBM). Retrospectively, medical student FTEBM scores from 2011 were assessed using descriptive statistics. RESULTS: Four hundred seventeen FTEBM scores were analyzed. Participants represented 40 medical schools, including 17 allopathic (MD) and 23 osteopathic (DO) schools. Fifty percent of participants (n = 210) were female, and 51.6% (n = 215) were from a DO medical school. Overall mean performance for the FTEBM was 47.2%. Exploring the results by individual question were (individual EBM question topics are in parentheses): 1A (study question), 62.0%; 1B (study question), 64.4%: 2 (sources of evidence), 67.6%; 3 (study design), 57.1%; 4 (search strategies), 53.2%; 5 (relevance), 41.2%; 6 (internal validity), 43.6%; 7 (magnitude), 37.8%; 8 (two-by-two grids), 30.0%; 9 (number needed to treat), 16.9%; 10 (confidence intervals), 34.3%; 11 (diagnosis), 5.0%; and 12 (prognosis), 43.4%. CONCLUSIONS: As measured by the FTEBM, senior medical students demonstrate understanding of about half of EBM. EM residencies can anticipate the need to instruct their residents in EBM concepts in order to meet ACGME/ABEM milestone requirements. PMID- 26961179 TI - Appropriate use criteria in clinical routine practice: implications in a nuclear cardiology lab. AB - The efforts for a broad application of the appropriate use criteria to reduce inappropriate nuclear stress testing have frequently been unsuccessful and the reported rates of inappropriateness have varied widely between studies. We sought to analyze the criteria of clinical appropriateness of a cohort of consecutive patients referred to our nuclear cardiology laboratory to perform stress myocardial perfusion imaging (MPI) and to assess the relationships between test appropriateness and the evaluation of ischaemia. A cohort of 251 consecutive patients, admitted to our Institute from January to March 2015, who underwent stress/rest MPI on a dedicated cardiac camera equipped with cadmium-zinc telluride detectors, was selected. The level of clinical appropriateness of each MPI test was categorized in each patient according to the AUC criteria. According to the accepted criteria, the majority of the MPI stress-tests could be classified as clinically appropriate (218 of 251, 87 % of the tests), while only 16 (6 %) and 17 (7 %) resulted of uncertain appropriateness or clearly inappropriate, respectively. Of the 251 appropriate tests, 22 (10 %), 65 (30 %), and 131 (60 %) showed the presence of a mild (SDS < 4), moderate (4 >= SDS < 7), and severe (SDS >= 7) ischemic burden, respectively, while none of the inappropriate test showed moderate-to-severe ischaemia (P < 0.001 for comparisons). The rate of inappropriate MPI tests is considerably low in a high volume laboratory. Appropriate and inappropriate studies identify patients at high and low probability of significant ischemia, respectively, providing insights on the effects of the level of appropriateness on stress-test results. PMID- 26961180 TI - Histology Atlas of the Developing Mouse Hepatobiliary Hemolymphatic Vascular System with Emphasis on Embryonic Days 11.5-18.5 and Early Postnatal Development. AB - A critical event in embryo development is the proper formation of the vascular system, of which the hepatobiliary system plays a pivotal role. This has led researchers to use transgenic mice to identify the critical steps involved in developmental disorders associated with the hepatobiliary vascular system. Vascular development is dependent upon normal vasculogenesis, angiogenesis, and the transformation of vessels into their adult counterparts. Any alteration in vascular development has the potential to cause deformities or embryonic death. Numerous publications describe specific stages of vascular development relating to various organs, but a single resource detailing the stage-by-stage development of the vasculature pertaining to the hepatobiliary system has not been available. This comprehensive histology atlas provides hematoxylin & eosin and immunohistochemical-stained sections of the developing mouse blood and lymphatic vasculature with emphasis on the hepatobiliary system between embryonic days (E) 11.5-18.5 and the early postnatal period. Additionally, this atlas includes a 3 dimensional video representation of the E18.5 mouse venous vasculature. One of the most noteworthy findings of this atlas is the identification of the portal sinus within the mouse, which has been erroneously misinterpreted as the ductus venosus in previous publications. Although the primary purpose of this atlas is to identify normal hepatobiliary vascular development, potential embryonic abnormalities are also described. PMID- 26961183 TI - Mouse-Based Research on Quiescent Primate Malaria Parasites. AB - Mice engrafted with primate tissue make two important plasmodial dormancy-related questions researchable. The first is concerned with whether latent merozoites in the lymphatic system can give rise to relapse-like, recurrent malaria in primates. The second is that genetic evidence of hypnozoite activation as the source of relapsing primate malaria can be looked for. PMID- 26961185 TI - Virtual shopping: A viable alternative to direct assessment of real life function? AB - OBJECTIVE: Real-life function is markedly impaired in schizophrenia and is an important outcome for interventions, but direct assessment is time consuming and resource intensive. Virtual reality (VR) enables assessment using simulation, akin to real life (RL), but allowing greater experimental control, reliability, and a more timely assessment. This study explores whether VR simulation predicts RL performance in supermarket shopping and how both relate to underlying cognitive abilities. METHOD: Forty three people with DSM-IV schizophrenia were included in the study. Participants were required to shop for items using a self directed search in both RL and VR. In each task, accuracy (number of correct items) and efficiency (time taken and number of aisles entered) were measured. IQ, executive function, working memory, spatial memory and social cognition were also assessed. RESULTS: Specific correlations were found between RL accuracy and VR accuracy, and between RL and VR efficiency measures. Multiple regression analyses indicated that VR efficiency measures contributed significant unique variance to RL efficiency outcomes, in addition to that explained by background cognitive measures, with a final model predicting 58% of variance in RL efficiency. CONCLUSIONS: VR functional shopping measures may enhance predictions of real life performance, over and above existing cognitive test procedures, and provide a more time-efficient method for evaluating real life outcomes. PMID- 26961186 TI - Anterior commissure versus corpus callosum: A quantitative comparison across mammals. AB - Mammals rely on two major pathways to transfer information between the two hemispheres of the brain: the anterior commissure and the corpus callosum. Metatheria and monotremes rely exclusively on the anterior commissure for interhemispheric transfer between the isocortices and olfactory allocortices of each side, whereas Eutheria use a combination of the anterior commissure and an additional pathway exclusive to Eutheria, the corpus callosum. Midline cross sectional area of the anterior commissure and corpus callosum were measured in a range of mammals from all three infraclasses and plotted against brain volume to determine how midline anterior commissure area and its size relative to the corpus callosum vary with brain size and taxon. In Metatheria, the square root of anterior commissure area rises in almost direct proportion with the cube root of brain volume (i.e. the ratio of the two is relatively constant), whereas among Eutheria the ratio of the square root of anterior commissure area to the cube root of brain volume declines slightly with increasing brain size. The total of isocortical and olfactory allocortical commissure area rises more rapidly with increasing brain volume among Eutheria than among Metatheria. This means that the midline isocortical and olfactory allocortical commissural area of metatherians with large brains (about 70 ml) is only about 50% of that among eutherians with similarly sized brains. On the other hand, isocortical and olfactory allocortical commissural area is similar in Metatheria and Eutheria at brain volumes around 1 ml. Among the Eutheria, some groups make less use of the anterior commissure pathway than do others: soricomorphs, rodents and cetaceans have smaller anterior commissures for their brain size than do afrosoricids, erinaceomorphs and proboscideans. The findings suggest that use of the anterior commissural route for isocortical commissural connections may have placed limitations on interhemispheric transfer of information among the metatherians, but only when brain size reaches 50 ml or more. PMID- 26961182 TI - The differential effects of metronomic gemcitabine and antiangiogenic treatment in patient-derived xenografts of pancreatic cancer: treatment effects on metabolism, vascular function, cell proliferation, and tumor growth. AB - BACKGROUND: Metronomic chemotherapy has shown promising activity against solid tumors and is believed to act in an antiangiogenic manner. The current study describes and quantifies the therapeutic efficacy, and mode of activity, of metronomic gemcitabine and a dedicated antiangiogenic agent (DC101) in patient derived xenografts of pancreatic cancer. METHODS: Two primary human pancreatic cancer xenograft lines were dosed metronomically with gemcitabine or DC101 weekly. Changes in tumor growth, vascular function, and metabolism over time were measured with magnetic resonance imaging, positron emission tomography, and immunofluorescence microscopy to determine the anti-tumor effects of the respective treatments. RESULTS: Tumors treated with metronomic gemcitabine were 10-fold smaller than those in the control and DC101 groups. Metronomic gemcitabine, but not DC101, reduced the tumors' avidity for glucose, proliferation, and apoptosis. Metronomic gemcitabine-treated tumors had higher perfusion rates and uniformly distributed blood flow within the tumor, whereas perfusion rates in DC101-treated tumors were lower and confined to the periphery. DC101 treatment reduced the tumor's vascular density, but did not change their function. In contrast, metronomic gemcitabine increased vessel density, improved tumor perfusion transiently, and decreased hypoxia. CONCLUSION: The aggregate data suggest that metronomic gemcitabine treatment affects both tumor vasculature and tumor cells continuously, and the overall effect is to significantly slow tumor growth. The observed increase in tumor perfusion induced by metronomic gemcitabine may be used as a therapeutic window for the administration of a second drug or radiation therapy. Non-invasive imaging could be used to detect early changes in tumor physiology before reductions in tumor volume were evident. PMID- 26961184 TI - Decision support for risk prioritisation of environmental health hazards in a UK city. AB - BACKGROUND: There is increasing appreciation of the proportion of the health burden that is attributed to modifiable population exposure to environmental health hazards. To manage this avoidable burden in the United Kingdom (UK), government policies and interventions are implemented. In practice, this procedure is interdisciplinary in action and multi-dimensional in context. Here, we demonstrate how Multi Criteria Decision Analysis (MCDA) can be used as a decision support tool to facilitate priority setting for environmental public health interventions within local authorities. We combine modelling and expert elicitation to gather evidence on the impacts and ranking of interventions. METHODS: To present the methodology, we consider a hypothetical scenario in a UK city. We use MCDA to evaluate and compare the impact of interventions to reduce the health burden associated with four environmental health hazards and rank them in terms of their overall performance across several criteria. For illustrative purposes, we focus on heavy goods vehicle controls to reduce outdoor air pollution, remediation to control levels of indoor radon, carbon monoxide and fitting alarms, and encouraging cycling to target the obesogenic environment. Regional data was included as model evidence to construct a ratings matrix for the city. RESULTS: When MCDA is performed with uniform weights, the intervention of heavy goods vehicle controls to reduce outdoor air pollution is ranked the highest. Cycling and the obesogenic environment is ranked second. CONCLUSIONS: We argue that a MCDA based approach provides a framework to guide environmental public health decision makers. This is demonstrated through an online interactive MCDA tool. We conclude that MCDA is a transparent tool that can be used to compare the impact of alternative interventions on a set of pre-defined criteria. In our illustrative example, we ranked the best intervention across the equally weighted selected criteria out of the four alternatives. Further work is needed to test the tool with decision makers and stakeholders. PMID- 26961187 TI - Enhancing L-Lysine Production of Beet Molasses by Engineered Escherichia coli Using an In Situ Pretreatment Method. AB - Reducing the viscosity of molasses environmentally and selectively removing the harmful ingredients for microbes are the keys to promoting the bioavailability of molasses. A simple and environmental in situ pretreatment method integrating surfactants and alkali was developed to reduce the viscosity of molasses prior to L-lysine production using Escherichia coli ZY0217. Adding activated carbon and modified orange peel based on the in situ pretreatment process effectively removed pigments and excessive zinc in the molasses and also significantly increased the cell growth and L-lysine yield from E. coli ZY0217. The experimental results showed that a mixture of secondary alkane sulfonate, an anionic surfactant, and HodagCB-6, a non-ionic surfactant, effectively reduced the viscosity of the molasses more so than any single surfactant. When the surfactant mixture was added at a concentration of 0.04 g/L to the molasses, the omega value was 0.4, and when ammonia was added at 0.6 %, the lowest viscosity of 705 mPa . s was obtained. Further, 91.5 % of the color and 86.68 % of the original levels of zinc were removed using an activated carbon and modified orange peel treatment on the molasses with the lowest viscosity, which further promoted cell growth and L-lysine production. In the fed-batch cultivation process, the L-lysine concentration achieved using a constant-speed feeding strategy was 45.89 g/L, with an L-lysine yield of 27.18 %, whereas the L-lysine yield from untreated molasses was only 10.13 %. The increase in L-lysine yield was related to the reduced viscosity and the detoxification of the molasses. Lastly, the pretreatment was found to significantly enhance the conversion of sugars in the molasses to L-lysine. PMID- 26961188 TI - Comprehensive Profiling of Proteome Changes Provide Insights of Industrial Penicillium chrysogenum During Pilot and Industrial Penicillin G Fermentation. AB - The intracellular proteomes of the Penicillium chrysogenum throughout pilot and industrial processes were investigated by using 2-DE combined with MALDI-TOF-TOF MS, respectively. We detected a total of 223 spots corresponding to 154 proteins and 231 spots corresponding to 157 proteins throughout pilot and industrial processes, respectively. The levels of glyceraldehyde-3-phosphate dehydrogenase increased (5.1- and 2.5-fold) under the pilot process, while its levels were no significant changes under the industrial process at 140 and 170 h when compared with that at 2 h. The levels of isocitrate lyase and fumarate hydratase were increased significantly under the industrial process, while their levels had no obvious changes after 20 h of fermentation throughout the pilot process. These results indicate that there were remarkable differences in carbohydrate metabolism (including glycolysis, gluconeogenesis, pentose phosphate pathway, and tricarboxylic acid cycle) of P. chrysogenum during the pilot and industrial fermentations, which likely result in alterations of the primary metabolism and penicillin biosynthesis. Moreover, the differences in the levels of proteins involved in amino acid metabolisms (including valine, cysteine, and alpha aminoadipic acid biosynthesis) indicated that the pilot and industrial processes influenced the supplies of penicillin precursors. Compared with that at 2 h, the maximum levels of superoxide (6.9-fold, at 32 h) and catalase (9-fold, at 80 h) during the industrial process and the maximum levels of superoxide (1.2-fold, at 20 h) and catalase (7.7-fold at 128 h) during the pilot process revealed the significant difference in cell redox homeostasis and stress responses during scale-up fermentation. Particularly, 10 spots corresponding to isopenicillin N synthetase and 4 spots corresponding to isopenicillin N (IPN) acyltransferase in pilot and industrial processes were identified, respectively. The levels of IPN acyltransferase (spots 197 and 198) and CoA ligase at 80 h during the industrial process were around 2-fold of that during the pilot process, indicating that the industrial process with a higher penicillin production per cell might provide available environments to induce over-expression of IPN acyltransferase and accelerate penicillin formation. These results provide new insights into the globally potential responses of P. chrysogenum to variations of environments in different fermentation scales so as to consequently regulate the penicillin production. PMID- 26961189 TI - Characterization and Inhibitor Screening of Plateau Zokor Lactate Dehydrogenase C4. AB - Lactate dehydrogenase C4 (LDH-C4) is considered to be a target protein for the development of contraceptives. In this work, the characterization of plateau zokor LDH-C4 and the screening of a series of N-substituted oxamic acids as inhibitors against zokor LDH-C4 were reported. The cDNA of zokor LDH-C gene was cloned and expressed in Escherichia coli, from which the protein was purified and further characterized. The protein was a tetramer (LDH-C4) and thermally stable up to 62 degrees C with a K m of 63.9 MUM for pyruvate and with optimal pH values of 7.95 and 10.1 for the forward and backward reactions respectively. Virtual and in vitro screening against zokor LDH-C4 revealed eight N-substituted oxamic acids with IC50s ranging from 198 to 2513 MUM, higher than that of oxamic acid (150 MUM) and (ethylamino)(oxo)acetic acid (59 MUM). The inhibition potencies of N-substituted oxamic acids tested are in the micromolar range, and the increase in the length of substituting chain seems not to increase inhibition potency. PMID- 26961190 TI - Olive Recombinant Hydroperoxide Lyase, an Efficient Biocatalyst for Synthesis of Green Leaf Volatiles. AB - Volatile C6-aldehydes are the main contributors to the characteristic odor of plants known as "green note" and are widely used by the flavor industry. Biotechnological processes were developed to fulfill the high demand in C6 aldehydes in natural flavorants and odorants. Recombinant hydroperoxide lyases (HPLs) constitute an interesting alternative to overcome drawbacks arising from the use of HPL from plant extracts. Thus, olive recombinant 13-HPL was assayed as biocatalysts to produce C6-aldehydes. Firstly, a cDNA encoding for olive HPL of Leccino variety was isolated and cloned in pQE-30 expression vector. In order to improve the enzyme solubility, its chloroplast transit peptide was deleted. Both enzymes (HPL wild type and HPL deleted) were expressed into Escherichia coli strain M15, purified, characterized, and then used for bioconversion of 13 hydroperoxides of linoleic and linolenic acids. Aldehydes produced were extracted, then identified and quantified using gas chromatography and mass spectrometry. Recombinant HPL wild type (HPLwt) allowed producing 5.61 mM of hexanal and 4.39 mM of 3Z-hexenal, corresponding to high conversion yields of 93.5 and 73 %, respectively. Using HPL deleted (HPLdel) instead of HPLwt failed to obtain greater quantities of hexanal or 3Z-hexenal. No undesirable products were formed, and no isomerization of 3Z-hexenal in 2E-hexenal occurred. The olive recombinant HPLwt appears to be a promising efficient biocatalyst for the production of C6-aldehydes. PMID- 26961191 TI - The incidence and risk factors for post-operative ileus after spinal fusion surgery: a multivariate analysis. AB - PURPOSE: Post-operative ileus is a recognized complication of surgery. Little is known about the incidence and risk factors for post-operative ileus following spinal fusion surgery. To report the incidence and to assess for independent risk factors of post-operative ileus after spinal fusion surgery. METHODS: Retrospective single-centre cohort study. Patients with prolonged or recurrent post-operative ileus were identified by review of hospital stay documentation. Patients with post-operative ileus were matched 1:2 to a control cohort without post-operative ileus. Uni and multi variate analyses were performed on demographic, comorbidity, surgical indication, medication, and peri-operative details to identify risk factors for post-operative ileus. RESULTS: Two thousand six hundred and twenty five patients underwent spinal fusion surgery between January 2012 and December 2012. Forty nine patients with post-operative ileus were identified (1.9 %). Post-operative length of hospital stay was significantly longer for patients with post-operative ileus (9.3 +/- 5.2 days), than control patients (5.5 +/- 3.2 days) (p < 0.001). Independent risk factors were Lactated Ringers solution (aOR: 2.12, p < 0.001), 0.9 % NaCl solution (aOR: 2.82, p < 0.001), and intra-operative hydromorphone (aOR: 2.31, p < 0.01) and a history of gastro-oesophageal reflux (aOR: 4.86, p = 0.03). Albumin administration (aOR: 0.09, p < 0.01) was protective against post-operative ileus. CONCLUSIONS: Post operative ileus is multifactorial in origin, and this study identified intra operative hydromorphone and post-operative crystalloid fluid administration >=2 litres as independent risk factors for the development of ileus. PMID- 26961192 TI - Natural hydroxyapatite as a bone graft extender for posterolateral spine arthrodesis. AB - PURPOSE: The aim of this retrospective analysis of spinal fusion, was to document the clinical, functional, and radiological outcomes with a local bone graft plus the highly osteoconductive hydroxyapatite, bio-derived Orthoss(r), with or without bone marrow aspirate. METHODS: Forty seven patients submitted to spinal posterolateral fusion were operated for four major indications: scoliosis in young patients (11), degenerative spine (18), lumbosacral transitional anomalies in young adults (14), and spine trauma (four). Sixteen patients had more than four levels fused. In addition to spinal decompression and instrumented fusion, autologous bone grafts from the excised lamina were augmented with Orthoss(r) granules in a 1:1 ratio. In addition iliac crest bone marrow aspirate was used in 70 % of the patients. The results were assessed clinically in terms of pain, and return to school or professional activities were checked at three, six, and 12 months following surgery with a mean follow-up of 20 months. In scoliotic patients, correction of the major angle was evaluated from one to four years after surgery. RESULTS: Pain persistence was reported only in four cases, after three months after surgery. A functional recovery was noted in almost all patients groups within these three months. Progressive bone formation with evidence of bone fusion masses were already observed at six months. No fusion failure was observed. CONCLUSIONS: Local bone enhanced by an osteoconductive long term stable scaffold, used with and without bone marrow aspirate, led to successful fusion in all patients by six months while functional recovery was reported already within three to six months. PMID- 26961193 TI - Bone morphogenetic protein use in spine surgery-complications and outcomes: a systematic review. AB - PURPOSE: Because of significant complications related to the use of autologous bone grafts in spinal fusion surgery, bone substitutes and growth factors such as bone morphogenetic protein (BMP) have been developed. One of them, recombinant human (rh) BMP-2, has been approved by the Food and Drug Administration (FDA) for use under precise conditions. However, rhBMP-2-related side effects have been reported, used in FDA-approved procedures, but also in off-label use.A systematic review of clinical data was conducted to analyse the rhBMP-2-related adverse events (AEs), in order to assess their prevalence and the associated surgery practices. METHODS: Medline search with keywords "bone morphogenetic protein 2", "lumbar spine", "anterolateral interbody fusion" (ALIF) and the filter "clinical trial". FDA published reports were also included. Study assessment was made by authors (experienced spine surgeons), based on quality of study designs and level of evidence. RESULTS: Extensive review of randomised controlled trials (RCTs) and controlled series published up to the present point, reveal no evidence of a significant increase of AEs related to rhBMP-2 use during ALIF surgeries, provided that it is used following FDA guidelines. Two additional RCTs performed with rhBMP-2 in combination with allogenic bone dowels reported increased bone remodelling in BMP-treated patients. This AE was transient and had no consequence on the clinical outcome of the patients. No other BMP-related AEs were reported in these studies. CONCLUSIONS: This literature review confirms that the use of rhBMP-2 following FDA-approved recommendations (i.e. one-level ALIF surgery with an LT-cage) is safe. The rate of complications is low and the AEs had been identified by the FDA during the pre-marketing clinical trials. The clinical efficiency of rhBMP-2 is equal or superior to that of allogenic or autologous bone graft in respect to fusion rate, low back pain disability, patient satisfaction and rate of re-operations. For all other off-label use, the safety and effectiveness of rhBMP-2 have not been established, and further RCTs with high level of evidence are required. PMID- 26961196 TI - Sporadic intramedullary hemangioblastoma with holo-hydrosyringomyelia. PMID- 26961195 TI - Computed tomography perfusion as a diagnostic tool for seizures after ischemic stroke. AB - INTRODUCTION: Cerebral cortical ischemia is a risk factor for post-stroke seizures. However, the optimal imaging method is unclear. We investigated CT perfusion (CTP) in detecting cortical ischemia and its correlation with post stroke seizures compared with non-contrast CT (NCCT). METHODS: We included patients with acute ischemic stroke admitted to the Royal Melbourne Hospital between 2009 and 2014. Post-stroke seizure information was collected. Cortical involvement was determined on acute NCCT and CTP (T max, cerebral blood volume [CBV], and cerebral blood flow [CBF]). The association between cortical involvement detected by different imaging modalities and post-stroke seizures was examined. RESULTS: Three-hundred fifty-two patients were included for analysis. Fifty-nine percent were male, and median age was 73 years (inter-quartile range 61-82). Follow-up was available for 96 %; median follow-up duration was 377 days (inter-quartile range 91-1018 days). Thirteen patients had post-stroke seizures (3.9 %). Cortical involvement was significantly associated with post-stroke seizures across all modalities. CBV had the highest hazard ratio (11.3, 95 % confidence interval (CI) 1.1-41.2), followed by NCCT (5.3, 95 % CI 1.5-18.0) and CBF (4.2, 95 % CI 1.1-15.2). Sensitivity was highest for T max (100 %), followed by CBV and CBF (both 76.9 %) and NCCT (63.6 %). Specificity was highest for CBV (77.8 %), then NCCT (75.6 %), CBF (54.0 %), and T max (29.1 %). Receiver operating characteristic area under the curve was significantly different between imaging modalities (p < 0.001), CBV 0.77, NCCT 0.70, CBF 0.65, and T max 0.65. CONCLUSION: CTP may improve sensitivity and specificity of cortical involvement for post-stroke seizures compared to NCCT. PMID- 26961194 TI - Adolescent idiopathic scoliosis: evidence for intrinsic factors driving aetiology and progression. AB - Adolescent idiopathic scoliosis (AIS) is now considered to be a multifactorial heterogeneous disease, with recent genomic studies supporting the role of intrinsic factors in contributing to the onset of disease pathology and curve progression. Understanding the key molecular signalling pathways by which these intrinsic factors mediate AIS pathology may facilitate the development of pharmacological therapeutics and the identification of predictive markers of progression. The heterogenic nature of AIS has implicated multiple tissue types in the disease pathophysiology, including spinal bone, intervertebral disc and paraspinal muscles. In this review, we highlight some of the mechanisms and intrinsic molecular regulators within these different tissue types and review the evidence for their involvement in AIS pathology. PMID- 26961197 TI - A particular case of pyogenic spondylodiscitis misdiagnosed as a vertebral fragility fracture and erroneously treated with balloon kyphoplasty. PMID- 26961199 TI - Giant ganglion cell tumor associated with thoracolumbar scoliosis. PMID- 26961198 TI - Transoral vertebroplasty for a C2 aneurysmal bone cyst. AB - BACKGROUND CONTEXT: Aneurysmal bone cysts at the cervical spine represent a real challenge both diagnostically and therapeutically, especially in young patients. PURPOSE: We present an unusual case of a C2 aneurysmal bone cyst expanding in the entire vertebral body in a girl successfully treated with a transoral vertebroplasty. STUDY DESIGN: This is a case report study. METHODS: We report the case of a 17-year-old girl with a history of cervical pain and occipital headache after a car accident. Routine x-rays disclosed a C2 lesion. Her neurologic examination was normal. Computed tomography showed a lytic lesion occupying almost the entire body of the C2 vertebra. The cortical bone was intact but notably thinned. Magnetic resonance imaging revealed a cystic image with blood inside. Transoral vertebroplasty was selected among other surgical options for the following reasons: (1) to improve the clinical symptoms, and (2) to prevent future vertebral collapse with devastating neurologic consequences. Under general anesthesia and continuous neurophysiological monitoring, we conducted a fluoroscopic-guided transoral vertebroplasty through a Jamshidi needle. A cytology sample from the cystic lesion was taken through the needle. RESULTS: The blood smear showed no tumoral cellularity. There were no complications during surgery or postoperative infections. After 4 years of follow-up, the patient is pain-free and leads a normal life. CONCLUSIONS: Transoral vertebroplasty seems to be a direct, safe, and effective technique to stabilize cystic lesions that endanger the stability of C2 and to improve symptoms. Aneurysmal bone cysts should be included in the differential diagnosis of lytic lesions at the C2 vertebral body. PMID- 26961200 TI - The usefulness of a mobile device-based system for patient-reported outcomes in a spine outpatient clinic. AB - BACKGROUND CONTEXT: Patient-reported outcomes (PROs) are typically collected using a paper form, but this format is cumbersome to incorporate into outpatient clinic visits as well as in research. Therefore, we developed a mobile device based system (mobile system) for spinal PRO. We hypothesized that this system may improve the quality of care in an outpatient clinic. PURPOSE: This study aimed to analyze the patient-reported efficacy of a mobile system through a survey of patients' responses compared with a paper system. STUDY DESIGN/SETTING: A prospective observational study was carried out. PATIENT SAMPLE: Surveys were conducted for 103 patients who had experience using both the paper and electronic systems in the outpatient clinic. OUTCOME MEASURES: Patient-reported positive response score (PRS) was the outcome measure. METHODS: The survey included the characteristics of the patients (sex, age, use of smartphone, familiarity with smartphone applications, proficiency of typing with mobile device, site of pain, and education level) and eight questions in four domains: (1) efficacy in the waiting room, (2) efficacy during the clinic visit, (3) overall satisfaction, and (4) opinion about the use of this system. The response to each question was scored from 1 to 5 (1, negative; 5, positive response). The patient-reported PRS was calculated by adding the scores of the 8 questions and converting the total range to 0-100 (60, neutral). RESULTS: The mean PRS of the 8 questions was 79.8 (95% CI, 76.7-83.9). The mean PRS was 78.9 (75.6-82.2) at the waiting room and was 80.5 (77.1-83.9) during the clinic. The PRS for overall satisfaction and use of this system were 83.3 (79.6-87.0) and 77.1 (71.9-82.3), respectively. The use of smartphones and the proficiency of typing were independently significant predictors of PRS with an R(2) value of 0.325. CONCLUSIONS: The mobile device based system improved the patient-reported efficacy in spine outpatient clinics. However, various factors such as the use of smartphones need to be considered when developing and applying mobile systems. PMID- 26961201 TI - Congenital lumbar hemivertebra kyphosis with progressive cauda equina compression. PMID- 26961202 TI - A portrait of prefrontal lobotomy performed at the Royal Prince Alfred Hospital in Sydney by Dr Rex Money. AB - OBJECTIVE: The objective of this article is to provide a portrait of prefrontal lobotomy performed at the Royal Prince Alfred Hospital, Sydney by the Head of Neurosurgery Dr Rex Money and to describe Dr Money's role in the promotion of psychosurgery in Sydney. METHODS: We draw attention to an oral presentation by Dr Rex Money in 1951, a journal article written by Money, archival information held at the Royal Prince Alfred Hospital, including Dr Money's accounts of his travels and his reports regarding neurosurgery - both internationally and in Australia. RESULTS: Dr Rex Money performed a series of 13 prefrontal lobotomies between 1945 and 1951, and presented the theoretical basis for his series, his operative procedures and the outcomes at the annual meeting of its medical officers' association. CONCLUSION: Notwithstanding various deficiencies in his clinical research, Money's descriptions give a relatively comprehensive account of one of the first series of prefrontal lobotomies performed in Australia. The current article also describes Dr Money's contributions to the promotion of psychosurgery in Sydney, and illustrates the participation of a senior neurosurgeon and of a major Sydney teaching hospital during the psychosurgery saga. PMID- 26961203 TI - The advent of psychosurgery in Australia-with particular attention to its introduction into Sydney. AB - OBJECTIVE: The objective of this study was to describe the advent of prefrontal lobotomy in Sydney and, less comprehensively, its introduction into Australia. METHOD: Reference to journal articles, books, reports and archival data held at the Royal Prince Alfred Hospital and via internet searches, interviews and personal memory. RESULT: This paper describes the arrival of psychosurgery in Sydney in the mid-1940s, and less comprehensively, its arrival in other Australian cities. CONCLUSIONS: In New South Wales, from 1945 or 1946, prefrontal lobotomies were conducted in private clinics and in public hospitals but, because of legal and practical hurdles, it is unlikely that psychosurgery was performed in mental hospitals prior to December 1958. This paper gives some details regarding the participation of neurosurgeons and of the major public hospitals in psychosurgery, and touches on the attitudes within the Australian medical profession towards this dramatic new therapy. PMID- 26961204 TI - The client "experiencing" scale as a predictor of treatment outcomes: A meta analysis on psychotherapy process. AB - OBJECTIVE: The experiencing scale (EXP) is an often used measure of client's depth of processing and meaning-making in-session. While research suggests that "client experiencing" predicts psychotherapy outcomes, this relationship has never been summarized in a meta-analysis. We examine this specific client factor as an in-session process predictor of good treatment outcomes. METHOD: A meta analysis quantified the relationship between client experiencing and therapy outcomes using a total of 10 studies and 406 clients. RESULTS: Analysis indicated that client experiencing is a small to medium predictor of standardized symptom improvements at final treatment outcomes with an effect of r = -.19 (95% CI -.10 to -.29), which we consider a "best estimate" for robustly quantifying the association between EXP and self-reported clinical outcomes. However, effects were higher (i.e., r = -.25) when observational measures of outcome were also included: Subgroup analyses indicated that EXP effects were moderated by the modality of outcome measurement (i.e., symptom reports vs. observational measures). On the other hand, statistical index, treatment phase, or treatment approach did not have significant impacts, which addresses some perennial questions in the EXP literature. CONCLUSIONS: Client experiencing is a small to medium predictor of treatment outcomes and a probable common factor. PMID- 26961205 TI - B-type natriuretic peptide and acute heart failure: Fluid homeostasis, biomarker and therapeutics. AB - Natriuretic peptides are a family of peptides with similar structures, but are genetically distinct with diverse actions in cardiovascular, renal and fluid homeostasis. The family consists of an atrial natriuretic peptide (ANP) and a brain natriuretic peptide (BNP) of myocardial cell origin, a C-type natriuretic peptide (CNP) of endothelial origin, and a urodilatin (Uro) which is processed from a prohormone ANP in the kidney. Nesiritide, a human recombinant BNP, was approved by the Federal Drug Administration (FDA) for the management of acute heart failure (AHF) in 2001. Human recombinant ANP (Carperitide) was approved for the same clinical indication in Japan in 1995, and human recombinant Urodilatin (Ularitide) is currently undergoing phase III clinical trial (TRUE AHF). This review will provide an update on important issues regarding the role of BNP in fluid hemostasis as a biomarker and therapeutics in AHF. PMID- 26961206 TI - The Tripartite Model of Risk Perception (TRIRISK): Distinguishing Deliberative, Affective, and Experiential Components of Perceived Risk. AB - BACKGROUND: Although risk perception is a key predictor in health behavior theories, current conceptions of risk comprise only one (deliberative) or two (deliberative vs. affective/experiential) dimensions. PURPOSE: This research tested a tripartite model that distinguishes among deliberative, affective, and experiential components of risk perception. METHOD: In two studies, and in relation to three common diseases (cancer, heart disease, diabetes), we used confirmatory factor analyses to examine the factor structure of the tripartite risk perception (TRIRISK) model and compared the fit of the TRIRISK model to dual factor and single-factor models. In a third study, we assessed concurrent validity by examining the impact of cancer diagnosis on (a) levels of deliberative, affective, and experiential risk perception, and (b) the strength of relations among risk components, and tested predictive validity by assessing relations with behavioral intentions to prevent cancer. RESULTS: The tripartite factor structure was supported, producing better model fit across diseases (studies 1 and 2). Inter-correlations among the components were significantly smaller among participants who had been diagnosed with cancer, suggesting that affected populations make finer-grained distinctions among risk perceptions (study 3). Moreover, all three risk perception components predicted unique variance in intentions to engage in preventive behavior (study 3). CONCLUSIONS: The TRIRISK model offers both a novel conceptualization of health-related risk perceptions, and new measures that enhance predictive validity beyond that engendered by unidimensional and bidimensional models. The present findings have implications for the ways in which risk perceptions are targeted in health behavior change interventions, health communications, and decision aids. PMID- 26961207 TI - Do Anxiety Disorders Play a Role in Adolescent Obesity? AB - BACKGROUND: There have been few prospective studies on the association between anxiety disorders and adolescent obesity; none examine potential reciprocal effects. PURPOSE: The purpose of this paper is to examine the prospective association between anxiety disorders and obesity among adolescents. METHODS: Using data from a two-wave, prospective study of 3134 adolescents, we examined reciprocal effects between body weight and DSM-IV anxiety disorders. RESULTS: Weight status did not increase future risk of anxiety disorders nor did anxiety disorders at baseline increase risk of future obesity in the overall sample. Stratifying by gender revealed an increased risk of overweight and obesity in males with anxiety disorders, but not for females. Major depression did not mediate these associations. CONCLUSION: Similar to prospective studies of depression, it appears anxiety disorders may increase risk of obesity. However, more research is needed on the role of psychopathology in adolescent obesity, in particular anxiety disorders and possible moderators (such as gender) and mediators. PMID- 26961208 TI - Characterization of wheat - Psathyrostachys huashanica small segment translocation line with enhanced kernels per spike and stripe rust resistance. AB - Psathyrostachys huashanica Keng (2n = 2x = 14, NsNs), a distant wild relative of common wheat, possesses rich potentially valuable traits, such as disease resistance and more spikelets and kernels per spike, that could be useful for wheat genetic improvement. Development of wheat - P. huashanica translocation lines will facilitate its practical utilization in wheat breeding. In the present study, a wheat - P. huashanica small segmental translocation line, K-13-835-3, was isolated and characterized from the BC1F5 population of a cross between wheat - P. huashanica amphiploid PHW-SA and wheat cultivar CN16. Cytological studies showed that the mean chromosome configuration of K-13-835-3 at meiosis was 2n = 42 = 0.10 I + 19.43 II (ring) + 1.52 II (rod). GISH analyses indicated that chromosome composition of K-13-835-3 included 40 wheat chromosomes and a pair of wheat - P. huashanica translocation chromosomes. FISH results demonstrated that the small segment from an unidentified P. huashanica chromosome was translocated into wheat chromosome arm 5DS, proximal to the centromere region of 5DS. Compared with the cultivar wheat parent CN16, K-13-835-3 was highly resistant to stripe rust pathogens prevalent in China. Furthermore, spikelets and kernels per spike in K-13-835-3 were significantly higher than those of CN16 in two growing seasons. These results suggest that the desirable genes from P. huashanica were successfully transferred into CN16 background. This translocation line could be used as novel germplasm for high-yield and, eventually, resistant cultivar breeding. PMID- 26961209 TI - Cardiac ultrasound at the bedside: the power of videos in medical education. PMID- 26961210 TI - Control of antibiotic resistance in China must not be delayed: The current state of resistance and policy suggestions for the government, medical facilities, and patients. AB - Antibiotics are medicines used to prevent and treat bacterial infections. Antibiotic resistance occurs when bacteria change in response to the use of these medicines. Antibiotic resistance is rising to dangerously high levels in all parts of the world, leading to higher medical costs, prolonged hospital stays, and increased mortality. In the European Union alone, drug-resistant bacteria are estimated to cause 25,000 deaths and cost more than US$1.5 billion every year in healthcare expenses and productivity losses. The problems of antibiotic misuse and antibiotic resistance are quite serious in China. In 2015, results of a study by the State Key Laboratory of Organic Geochemistry, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences indicated that the total antibiotic usage in China in 2013 was approximately 162,000 tons, including human use (48%) and use in animals (52%). This amount accounted for about half of the antibiotic usage worldwide. The per-capita use of antibiotics in China is more than 5 times that in Europe and the United States. These data mean that China is one of the world's leading countries with serious problems in terms of antibiotic misuse and antibiotic resistance. The current article analyzes the current state and harms of antibiotic misuse and causes of antibiotic resistance in China. The Government needs to pay close attention to the issue of antibiotic resistance in China and formulate a strategy at the national level. Thus, the following suggestions are offered: i) The Chinese Government should implement policies that promote antibiotic research and development; ii) Medical facilities in China should create multidisciplinary teams (MDTs) and encourage early action by MDTs to control the spread of multi-drug-resistant bacteria (MDRB); iii) An intervention in the form of health education should target patients and accompanying family members (AFM) in China. In other words, antibiotic resistance is not a personal problem but an urgent public health problem. Without urgent action, China is heading for a post-antibiotic era in which common infections and minor injuries can once again kill. Therefore, the aforementioned proposals have been offered with the hope that policy suggestions help to limit the phenomenon of antibiotic misuse and antibiotic resistance in China. PMID- 26961211 TI - Atypical pathogen infection in community-acquired pneumonia. AB - Community-acquired pneumonia (CAP) is a world wide cause of morbidity and mortality. The etiology of CAP is different between countries and changes over time. With the increasing incidence, atypical pathogens are attracting more and more attention all over the world. In many countries, atypical pathogens are one of the main pathogens of CAP, and even could be the most prevalent etiology in China. Atypical pathogen infections can cause multi-system complications, which leads to a worse prognosis. Although still controversial, empirical antibiotic coverage of atypical pathogens in CAP may improve outcomes, shorten length of hospitalization, reduce mortality and lower total hospitalization costs. The macrolide resistance rate of atypical pathogens, especially Mycoplasma Pneumoniae (M. Pneumoniae) is high, so fluoroquinolones or tetracyclines should be considered as alternative therapy. PMID- 26961212 TI - Controversy and progress for treatment of acute cholangitis after Tokyo Guidelines (TG13). AB - Tokyo Guideline 2013 (TG13) is an international guideline for the diagnosis, classification and treatment of acute cholangitis. Progress and controversy for the two years after TG13 was summarized. Endoscopic ultrasound (EUS) and magnetic resonance cholangiopancreatography (MRCP) are both effective imaging tests for common bile duct (CBD) stones. More factors e.g. obesity may be involved in severity assessment. Initiation of broad-spectrum antibiotics addressing the typical Gram-negative enteric bacteria spectrum and early biliary drainage are the mainstay therapeutic options. Early laparoscopic exploration is also an option for stone-related nonsevere acute cholangitis besides endoscopic retrograde cholangial or percutaneous transhepatic cholangial drainage. Surgical biliary drainage should be avoided in severe cholangitis. PMID- 26961214 TI - RETRACTED: A systematic review and meta-analysis of feasibility, safety and efficacy of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) versus twostage hepatectomy (TSH). PMID- 26961213 TI - Workload, burnout, and medical mistakes among physicians in China: A cross sectional study. AB - The purpose of this study is to determine the prevalence of burnout among different grade hospitals and to examine if a relation exists between burnout and medical mistakes. A multi-center cross-sectional survey was conducted. Physicians were interviewed in hospitals from 10 provinces in China. Burnout was measured using the Chinese version of the Maslach Burnout Inventory-General Survey. Overall, 1,537 physicians were included in this study. Of these, 76.9% reported some burnout symptoms or serious burnout symptoms and 54.8% reported committing medical mistakes during the last year. 39.6%, 50.0%, and 59.5% of the respondents in primary, secondary, and tertiary hospitals respectively reported having made mistakes over the course of the previous year. Multivariate analysis demonstrated that being female was protective against medical mistakes (OR = 0.72, 95% CI: 0.58-0.89), whereas physician-reported 60 or more work hours per week (OR = 1.65, 95% CI: 1.22-2.22), and physicians who reported serious burnout (OR = 2.28, 95% CI: 1.63-3.17) were independently associated with higher incidence of medical mistakes. In conclusion, Chinese physicians reported high workloads, high rates of burnout and high medical mistakes. Physicians in tertiary hospitals were especially overworked and suffered the most serious burnout. Longer work hours per week, and burnout were the independent risk factors for medical mistakes. PMID- 26961215 TI - Sodium-Oxygen Battery: Steps Toward Reality. AB - Rechargeable metal-oxygen batteries are receiving significant interest as a possible alternative to current state of the art lithium ion batteries due to their potential to provide higher gravimetric energies, giving significantly lighter or longer-lasting batteries. Recent advances suggest that the Na-O2 battery, in many ways analogous to Li-O2 yet based on the reversible formation of sodium superoxide (NaO2), has many advantages such as a low charge overpotential (~100 mV) resulting in improved efficiency. In this Perspective, we discuss the current state of knowledge in Na-O2 battery technology, with an emphasis on the latest experimental studies, as well as theoretical models. We offer special focus on the principle outstanding challenges and issues and address the advantages/disadvantages of the technology when compared with Li-O2 batteries as well as other state-of-the-art battery technologies. We finish by detailing the direction required to make Na-O2 batteries both commercially and technologically viable. PMID- 26961216 TI - Fluxional sigma-Bonds of the 2,5,8-Trimethylphenalenyl Dimer: Direct Observation of the Sixfold sigma-Bond Shift via a pi-Dimer. AB - Direct evidence for sigma-bond fluxionality in a phenalenyl sigma-dimer was successfully obtained by a detailed investigation of the solution-state dynamics of 2,5,8-trimethylphenalenyl (TMPLY) using both experimental and theoretical approaches. TMPLY formed three diamagnetic dimers, namely, the sigma-dimer (RR/SS), sigma-dimer (RS), and pi-dimer, which were fully characterized by (1)H NMR spectroscopy and electronic absorption measurements. The experimental findings gave the first quantitative insights into the essential preference of these competitive and unusual dimerization modes. The spectroscopic analyses suggested that the sigma-dimer (RR/SS) is the most stable in terms of energy, whereas the others are metastable; the energy differences between these three isomers are less than 1 kcal mol(-1). Furthermore, the intriguing dynamics of the TMPLY dimers in the solution state were fully revealed by means of (1)H-(1)H exchange spectroscopy (EXSY) measurements and variable-temperature (1)H NMR studies. Surprisingly, the sigma-dimer (RR/SS) demonstrated a sixfold sigma-bond shift between the six sets of alpha-carbon pairs. This unusual sigma-bond fluxionality is ascribed to the presence of a direct interconversion pathway between the sigma-dimer (RR/SS) and the pi-dimer, which was unambiguously corroborated by the EXSY measurements. The proposed mechanism of the sixfold sigma-bond shift based on the experimental findings was well-supported by theoretical calculations. PMID- 26961218 TI - Relationship between Non-High-Density Lipoprotein Cholesterol and Low-Density Lipoprotein Cholesterol in the General Population. AB - AIM: The Japan Atherosclerosis Society (JAS) Guidelines for Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases for Japanese 2012 version have set a non-high-density lipoprotein cholesterol (non-HDL-C)-management target of low-density lipoprotein cholesterol (LDL-C) +30 mg/dL. However, the actual difference between non-HDL-C and LDL-C is not clear. Therefore, we evaluated its joint distribution and assessed the validity of this criterion in the general Japanese population. METHODS: We used baseline cross-sectional data of 4,110 participants from two studies; the KOBE Study (n=1,108) and the Tsuruoka Metabolomic Cohort Study (n=3,002). To evaluate whether the difference between LDL-C and non-HDL-C in the general population match that of the current guidelines, we classified LDL-C levels into four groups according to the JAS Guideline and evaluated its agreement with the corresponding non-HDL-C group. Analysis was also done using six groups (the previous four groups plus the upper and lower cut-off values). RESULTS: The mean difference (mg/dL) between the non HDL-C and LDL-C (for the KOBE Study and Tsuruoka Metabolomic Cohort Study, respectively) was 19.6 and 24.1 (p<0.001) for men and 15.9 and 18.3 (p<0.001) for women. In both the cohort studies, the difference was lower than 30 mg/dL. It was especially small among individuals with normal triglyceride levels. CONCLUSIONS: In the general Japanese population, the difference between non-HDL-C and LDL-C was lower than the expected difference of 30 mg/dL. Changes to the criteria for non-HDL-C target levels may be considered in the future. PMID- 26961217 TI - Association of Advanced Glycation End Products with coronary Artery Calcification in Japanese Subjects with Type 2 Diabetes as Assessed by Skin Autofluorescence. AB - AIM: Advanced glycation end products (AGE) are considered to be among the critical pathogenic factors involved in the progression of diabetic complications. Skin autofluorescence (AF), a noninvasive measurement of AGE accumulation, has been recognized as a useful and convenient marker for diabetic vascular diseases in Caucasians. This study aimed to evaluate the association of tissue AGE, assessed using skin AF, with coronary artery calcification in Japanese subjects with type 2 diabetes. METHODS: In total, 122 Japanese subjects with type 2 diabetes enrolled in this cross-sectional study underwent multi-slice computed tomography for total coronary artery calcium scores (CACS) estimation and examination with a skin AF reader. RESULTS: Skin AF positively correlated with age, sex, diabetes duration, pulse wave velocity, systolic blood pressure, serum creatinine, and CACS. In addition, skin AF results negatively correlated with BMI, eGFR, and serum C-peptide concentration. According to multivariate analysis, age and systolic blood pressure showed strong positive correlation and eGFR showed negative correlation with skin AF values. Multiple linear regression analyses revealed a significant positive correlation between skin AF values and logCACS, independent of age, sex, diabetes duration, HbA1c, BMI, IMT, and blood pressure. However, skin AF showed no association with serum levels of AGE, such as Nepsilon-(carboxymethyl) lysine and 3-deoxyglucosone. CONCLUSION: Skin AF results positively correlated with CACS in Japanese subjects with type 2 diabetes. This result indicates that AGE plays a role in the pathogenesis of diabetic macrovascular disease. Measurement of skin AF values may be useful for assessing the severity of diabetic complications in Japanese subjects. PMID- 26961219 TI - Delirium recall - an integrative review. AB - AIMS AND OBJECTIVES: The aim of this article is to review and synthesise the empirical literature on patient recall of delirium episodes and to provide a direction for future research. BACKGROUND: Delirium is a common and costly condition seen in hospitalised and institutionalised patients. Much of the existing literature focuses on delirium detection, risk factors, aetiologies and treatment. Few studies describe the patient experience of delirium recall. DESIGN: A literature search was conducted using the databases of the National Library of Medicine (PubMed/MEDLINE/OVID), the Cumulative Index of Nursing and Allied Health Literature and the American Psychological Association (PsycINFO). Articles were restricted to the English language and from the years 1980-2014. METHODS: An integrative review of 12 selected studies on delirium recall was performed. RESULTS: The majority of participants recalled their delirious episodes and during these episodes experienced both perceptual disturbances and psychological distress. Common themes from the qualitative data included incomprehensible experiences, strong emotional feelings and fear. CONCLUSION: Delirium recall is common, is distressing and warrants further investigation. Future studies should employ standardised delirium detection tools and a systematic examination of factors that may predict delirium recall. RELEVANCE TO CLINICAL PRACTICE: Understanding delirium recall may help nurses mitigate the psychological morbidity and distress associated with the phenomenon and generate new theories to improve care. PMID- 26961220 TI - Assessment and parameter identification of simplified models to describe the kinetics of semi-continuous biomethane production from anaerobic digestion of green and food waste. AB - Biochemical reactions occurring during anaerobic digestion have been modelled using reaction kinetic equations such as first-order, Contois and Monod which are then combined to form mechanistic models. This work considers models which include between one and three biochemical reactions to investigate if the choice of the reaction rate equation, complexity of the model structure as well as the inclusion of inhibition plays a key role in the ability of the model to describe the methane production from the semi-continuous anaerobic digestion of green waste (GW) and food waste (FW). A parameter estimation method was used to investigate the most important phenomena influencing the biogas production process. Experimental data were used to numerically estimate the model parameters and the quality of fit was quantified. Results obtained reveal that the model structure (i.e. number of reactions, inhibition) has a much stronger influence on the quality of fit compared with the choice of kinetic rate equations. In the case of GW there was only a marginal improvement when moving from a one to two reaction model, and none with inclusion of inhibition or three reactions. However, the behaviour of FW digestion was more complex and required either a two or three reaction model with inhibition functions for both ammonia and volatile fatty acids. Parameter values for the best fitting models are given for use by other authors. PMID- 26961221 TI - Septic peritonitis in a dog caused by Anaerobiospirillum succiniproducens. AB - This is the first reported case of septic peritonitis caused by Anaerobiospirillum succiniproducens in a dog. The infection was associated with marked exfoliation of reactive mesothelial cells into the abdominal fluid mimicking neoplasia. The source of the infection was not determined but was presumed to be of gastrointestinal origin as A succiniproducens is part of the normal gastrointestinal flora of dogs. Anaerobiospirillum spp. have been previously reported as causing diarrhea and bacteremia in people, particularly if immunocompromised; however, there were no indicators for a compromised immune system in this dog. PMID- 26961222 TI - Photoinduced Copper-Catalyzed C-H Arylation at Room Temperature. AB - Room-temperature azole C-H arylations were accomplished with inexpensive copper(I) compounds by means of photoinduced catalysis. The expedient copper catalysis set the stage for site-selective C-H arylations of non-aromatic oxazolines under mild reaction conditions, and provides step-economical access to the alkaloid natural products balsoxin and texamine. PMID- 26961223 TI - Changing trends in the management of well-differentiated thyroid carcinoma in Korea. AB - A questionnaire administered in 2009 found that members of the Korean Association of Thyroid-Endocrine Surgeons (KATES) favored more aggressive treatment of well differentiated thyroid carcinoma (WDTC) than physicians from other countries. This study assessed the changes in practical management of WDTC in Korea from the previous survey. Questionnaires were sent by e-mail to KATES members. A total of 101 members completed the questionnaire. Their responses were compared with response for the 2009 survey. Of the respondents, 53.5% and 80.2% indicated that they would perform fine-needle aspiration cytology on nodules that were <0.5 cm and 0.5-1.0 cm in diameter, respectively. If the cytology was positive, a large number of respondents favored surgical treatment, regardless of tumor size. Compared with the 2009 survey, a slightly higher percentage favored observation for patients with tumors that were <0.5 cm in diameter, and a larger percentage recommended less-than-total thyroidectomy for patients with T1 cancers. Respondents in 2014 favored aggressive lymph node dissection less, irrespective of tumor size, preferring short-term treatment with thyroid stimulating hormone suppressors. The percentage preferring postoperative high-dose radioactive iodine therapy slightly increased, whereas the percentage favoring external irradiation decreased, in 2014 compared with 2009. The management of Korean patients with WDTC changed from 2009 to 2014. In 2009, Korean respondents favored more aggressive treatment of WDTC compared with respondents from other countries. In 2014, however, Korean respondents favored a more conservative approach, especially in patients with microcarcinomas. PMID- 26961224 TI - Combination with Red ginseng and Polygoni Multiflori ameliorates highfructose diet induced metabolic syndrome. AB - BACKGROUND: Metabolic syndrome such as dyslipidemia, hypertension, obesity, impaired glucose tolerance and fatty liver, can be caused by modification of diet by means of overconsumption of high fructose diet. This study was designed to investigate whether combination with Red ginseng and Polygoni Multiflori Radix (RGPM), widely used traditional herbal medicine, ameliorates on highfructose (HF) diet-induced metabolic syndrome. METHODS: SD rats were fed the 60% HF diet with/without rosiglitazone, and RGPM 100, 300 mg/kg/day, respectively. All groups received regular diet or HF diet, respectively, for 8 weeks. The last three groups treatment of rosiglitazone and RPGM orally for a period of 6 weeks. RESULTS: Chronic treatment with RGPM significantly decreased body weight, fat weight and adipocyte size. RGPM significantly prevented the development of the metabolic disturbances such as hypertension, hyperlipidemia and impaired glucose tolerance. RGPM also led to increase in high density lipoprotein level in the HF group. RGPM suppressed high-fructose diet induced vascular inflammation marker expression such as adhesion molecules and ET-1 in aorta as well as increasing of C-reactive protein (CRP) levels in plasma. Similarly, RGPM attenuated hepatic lipid accumulation by inhibition of monocyte chemoattractant protein-1 (MCP-1) expression. CONCLUSION: An administration of RGPM may be a beneficial therapy for the treatment of metabolic syndrome through the improvement of hypertension, obesity, hyperlipidemia, vascular inflammation and insulin resistance. PMID- 26961226 TI - CAEP 2015 Academic Symposium: Current State and Recommendations to Achieve Adequate and Sustainable Funding for Emergency Medicine Academic Units. AB - OBJECTIVES: To describe the current state of academic emergency medicine (EM) funding in Canada and develop recommendations to grow and establish sustainable funding. METHODS: A panel of eight leaders from different EM academic units was assembled. Using mixed methods (including a literature review, sharing of professional experiences, a survey of current EM academic heads, and data previously collected from an environmental scan), 10 recommendations were drafted and presented at an academic symposium. Attendee feedback was incorporated, and the second set of draft recommendations was further distributed to the Canadian Association Emergency Physicians (CAEP) Academic Section for additional comments before being finalized. RESULTS: Recommendations were developed around the funding challenges identified and solutions developed by academic EM university based units across Canada. A strategic plan was seen as integral to achieving strong funding of an EM unit, especially when it aligned with departmental and institutional priorities. A business plan, although occasionally overlooked, was deemed an important component for planning and sustaining the academic mission. A number of recommendations surrounding philanthropy consisted of creating partnerships with existing foundations and engaging multiple stakeholders and communities. Synergy between academic and clinical EM departments was also viewed as an opportunity to ensure integration of common missions. Education and networking for current and future leaders were also viewed as invaluable to ensure that opportunities are optimized through strong leadership development and shared experiences to further the EM academic missions across the country. CONCLUSIONS: These recommendations were designed to improve the financial circumstances for many Canadian EM units. There is a considerable wealth of resources that can contribute to financial stability for an academic unit, and an annual networking meeting and continuing education on these issues will facilitate more rapid implementation of these recommendations. PMID- 26961227 TI - [Current situation of experimental radiology in Germany]. PMID- 26961225 TI - Iodine status and thyroid function among Spanish schoolchildren aged 6-7 years: the Tirokid study. AB - I deficiency is still a worldwide public health problem, with children being especially vulnerable. No nationwide study had been conducted to assess the I status of Spanish children, and thus an observational, multicentre and cross sectional study was conducted in Spain to assess the I status and thyroid function in schoolchildren aged 6-7 years. The median urinary I (UI) and thyroid stimulating hormone (TSH) levels in whole blood were used to assess the I status and thyroid function, respectively. A FFQ was used to determine the consumption of I-rich foods. A total of 1981 schoolchildren (52 % male) were included. The median UI was 173 MUg/l, and 17.9 % of children showed UI<100 MUg/l. The median UI was higher in males (180.8 v. 153.6 MUg/l; P<0.001). Iodised salt (IS) intake at home was 69.8 %. IS consumption and intakes of >=2 glasses of milk or 1 cup of yogurt/d were associated with significantly higher median UI. Median TSH was 0.90 mU/l and was higher in females (0.98 v. 0.83; P<0.001). In total, 0.5 % of children had known hypothyroidism (derived from the questionnaire) and 7.6 % had TSH levels above reference values. Median TSH was higher in schoolchildren with family history of hypothyroidism. I intake was adequate in Spanish schoolchildren. However, no correlation was found between TSH and median UI in any geographical area. The prevalence of TSH above reference values was high and its association with thyroid autoimmunity should be determined. Further assessment of thyroid autoimmunity in Spanish schoolchildren is desirable. PMID- 26961228 TI - [Modern imaging of renal tumors - application in diagnostics and therapy. Characterization, operation planning and therapy monitoring of renal lesions]. AB - This article elucidates the various tools used for the diagnostics and characterization of renal lesions. The advantages and limitations of ultrasound, contrast-enhanced ultrasound (CEUS), computed tomography (CT) and magnetic resonance imaging (MRI) are presented and discussed. In addition, modern imaging features of CT and MRI, such as iodine quantification in CT as well as diffusion weighted and perfusion imaging in MRI are presented. Lastly, recent developments in standardized reporting of renal tumors regarding the intraoperative surgical risk are presented. PMID- 26961230 TI - Crystallographic origin of cycle decay of the high-voltage LiNi0.5Mn1.5O4 spinel lithium-ion battery electrode. AB - High-voltage spinel LiNi0.5Mn1.5O4 (LNMO) is considered a potential high-power density positive electrode for lithium-ion batteries, however, it suffers from capacity decay after extended charge-discharge cycling, severely hindering commercial application. Capacity fade is thought to occur through the significant volume change of the LNMO electrode occurring on cycling, and in this work we use operando neutron powder diffraction to compare the structural evolution of the LNMO electrode in an as-assembled 18650-type battery containing a Li4Ti5O12 negative electrode with that in an identical battery following 1000 cycles at high-current. We reveal that the capacity reduction in the battery post cycling is directly proportional to the reduction in the maximum change of the LNMO lattice parameter during its evolution. This is correlated to a corresponding reduction in the MnO6 octahedral distortion in the spinel structure in the cycled battery. Further, we find that the rate of lattice evolution, which reflects the rate of lithium insertion and removal, is ~9 and ~10% slower in the cycled than in the as-assembled battery during the Ni(2+)/Ni(3+) and Ni(3+)/Ni(4+) transitions, respectively. PMID- 26961232 TI - Taxonomic status and origin of the Egyptian weasel (Mustela subpalmata) inferred from mitochondrial DNA. AB - The Egyptian weasel (Mustela subpalmata) is a small mustelid with a distribution restricted to the lower Nile Valley and the Nile Delta. Traditionally considered a subspecies of the least weasel (M. nivalis), it is currently recognized as a separate species based on morphology. Here we present the first genetic assessment of the taxonomic status of the Egyptian weasel by comparing mitochondrial DNA (Cytochrome b gene and control region) sequences to those of least weasels from the western Palearctic, with a focus on the Mediterranean region. Our results provide no evidence to support the view that the Egyptian weasel is genetically distinct from the least weasel, as we found that, for both Cytochrome b and control region, haplotypes were shared between the two taxa. Specifically, the Cytochrome b and control region haplotypes detected in the Egyptian weasel were also present in M. nivalis from Turkey and Malta, two populations genetically analysed here for the first time. Our results suggest that the Egyptian weasel is distinct from the least weasel populations currently living in the Maghreb, which were inferred to be the result of an earlier colonization of North Africa, but the genetic data alone do not allow us to determine whether the Egyptian weasel is native or introduced. Nevertheless, the observed genetic patterns, together with the weasel fossil record in Israel and the unique commensal lifestyle of the Egyptian weasel, are consistent with the hypothesis that the Egyptian population is a relict of past range expansion from the Levant into Egypt. We suggest that the large size and characteristic sexual dimorphism of the Egyptian weasel are likely to represent ecotypic variation, but genomic studies are required to clarify the extent of its functional genetic divergence. PMID- 26961231 TI - Common mechanisms involved in Alzheimer's disease and type 2 diabetes: a key role of chronic bacterial infection and inflammation. AB - Strong epidemiologic evidence and common molecular mechanisms support an association between Alzheimer's disease (AD) and type 2-diabetes. Local inflammation and amyloidosis occur in both diseases and are associated with periodontitis and various infectious agents. This article reviews the evidence for the presence of local inflammation and bacteria in type 2 diabetes and discusses host pathogen interactions in chronic inflammatory disorders. Chlamydophyla pneumoniae, Helicobacter pylori and spirochetes are demonstrated in association with dementia and brain lesions in AD and islet lesions in type 2 diabetes. The presence of pathogens in host tissues activates immune responses through Toll-like receptor signaling pathways. Evasion of pathogens from complement-mediated attack results in persistent infection, inflammation and amyloidosis. Amyloid beta and the pancreatic amyloid called amylin bind to lipid bilayers and produce Ca(2+) influx and bacteriolysis. Similarly to AD, accumulation of amylin deposits in type 2 diabetes may result from an innate immune response to chronic bacterial infections, which are known to be associated with amyloidosis. Further research based on an infectious origin of both AD and type 2 diabetes may lead to novel treatment strategies. PMID- 26961233 TI - Chronic and Invasive Fungal Infections in a Family with CARD9 Deficiency. AB - Chronic mucocutaneous or invasive fungal infections are generally the result of primary or secondary immune dysfunction. Patients with autosomal recessive CARD9 mutations are also predisposed to recurrent mucocutaneous and invasive fungal infections with Candida spp., dermatophytes (e.g., Trichophyton spp.) and phaeohyphomycetes (Exophiala spp., Phialophora verrucosa). We study a consanguineous family of Turkish origin in which three members present with distinct clinical phenotypes of chronic mucocutaneous and invasive fungal infections, ranging from chronic mucocutaneous candidiasis (CMC) in one patient, treatment-resistant cutaneous dermatophytosis and deep dermatophytosis in a second patient, to CMC with Candida encephalitis and endocrinopathy in a third patient. Two patients consented to genetic testing and were found to have a previously reported homozygous R70W CARD9 mutation. Circulating IL-17 and IL-22 producing T cells were decreased as was IL-6 and granulocyte/macrophage colony stimulating factor (GM-CSF) secretion upon stimulation with Candida albicans. Patients with recurrent fungal infections in the absence of known immunodeficiencies should be analyzed for CARD9 gene mutations as the cause of fungal infection predisposition. PMID- 26961234 TI - Prevention and care of paediatric HIV infection in Ouagadougou, Burkina Faso: knowledge, attitudes and practices of the caregivers. AB - BACKGROUND: The paediatric Human Immunodeficiency Virus (HIV) epidemic still progresses because of operational challenges in implementing prevention of mother to-child HIV transmission (PMCT) programs. We assessed the knowledge, attitudes and practices (KAP) of children's caregivers regarding mother-to-child transmission (MTCT) of HIV, paediatric HIV infection, early infant diagnosis (EID), and paediatric antiretroviral treatment in Ouagadougou, Burkina Faso. METHODS: We undertook a qualitative survey in the four public hospitals managing HIV exposed or infected children, in Ouagadougou in 2011. A sociologist used a semi-structured questionnaire to interview caregivers of children less than 5 years old attending the paediatrics wards on their KAP. Study participants were divided into four groups as follows: those who did not yet know their children's HIV infection status, those who were waiting for their children's HIV test results, those who were waiting for antiretroviral treatment, and those who were already on antiretroviral treatment. RESULTS: A total of 37 caregivers were interviewed. The mean age was 32.5 years, and 29 (78 %) were mothers. Twenty seven (73 %) caregivers had primary or higher level of education, and 15 (40 %) described their occupation as "housewife". Overall, 36 (97 %) of caregivers knew that the main route of HIV transmission for infants was through MTCT and 14 (38 %) specified that it occurred during pregnancy or delivery. Five percent thought that MTCT of HIV occurred during conception. PMTCT interventions could help prevent infant HIV infection according to 32 (87 %) caregivers. Thirty five percent of caregivers stated EID as a prevention strategy. Fifty-four percent of the participants believed that replacement feeding option would prevent MTCT of HIV; 24 (65 %) stated that they would prefer medical practitioners seek caregivers' consent before carrying out any HIV-test for their child, and that caregivers' consent was not compulsory before antiretroviral treatment. All caregivers thought that it was necessary to treat HIV-infected children, although they did not know what interventions could be done. CONCLUSIONS: This study highlighted the low level of caregivers' knowledge on paediatric HIV prevention and care in Ouagadougou. Awareness programs targeting caregivers need to be strengthened in order to improve the uptake of HIV early infant diagnosis and care. PMID- 26961236 TI - [PCSK9 inhibitors in hypercholesterolemia. New hope for patients with diabetes mellitus?]. AB - The interrelation between glucose and lipid metabolism is complex and comprises many aspects. In this context diabetic dyslipidemia is of utmost importance as it represents the crucial link between diabetes and cardiovascular disease. Although hypertriglyceridemia is usually the most prominent lipid abnormality in diabetic patients, reduction of low-density lipoprotein (LDL) cholesterol is the most important strategy to prevent cardiovascular disease. Statin trials and more recently the combination of statin with ezetimibe clearly showed that diabetic patients benefit from low LDL cholesterol levels. In this context the newly developed proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors are of great interest as they reduce LDL cholesterol by 50-70 % independent of co medication and largely independent of the underlying dyslipidemia. Subgroup analyses of phase 2 and phase 3 studies indicated that diabetic patients show a similar response to PCSK9 inhibitors as non-diabetic patients. Furthermore, the overall very low rate of side effects seems to be comparable between diabetic and non-diabetic patients. In contrast to statins PCSK9 inhibitors do not lead to an increased rate of new onset diabetes. Although data from safety studies (post hoc analyses) are very promising concerning the prevention of cardiovascular events, data from outcome studies will only become available in 2016. Until then PCSK9 inhibitors should be restricted to patients with very high risk and a significant distance from the LDL cholesterol target values (despite maximum possible lipid lowering therapy with statins and ezetimibe). This approach will most likely have to be adapted when outcome data are available. PMID- 26961235 TI - Prostate-specific membrane antigen targeted protein contrast agents for molecular imaging of prostate cancer by MRI. AB - Prostate-specific membrane antigen (PSMA) is one of the most specific cell surface markers for prostate cancer diagnosis and targeted treatment. However, achieving molecular imaging using non-invasive MRI with high resolution has yet to be achieved due to the lack of contrast agents with significantly improved relaxivity for sensitivity, targeting capabilities and metal selectivity. We have previously reported our creation of a novel class of protein Gd(3+) contrast agents, ProCA32, which displayed significantly improved relaxivity while exhibiting strong Gd(3+) binding selectivity over physiological metal ions. In this study, we report our effort in further developing biomarker-targeted protein MRI contrast agents for molecular imaging of PSMA. Among three PSMA targeted contrast agents engineered with addition of different molecular recognition sequences, ProCA32.PSMA exhibits a binding affinity of 1.1 +/- 0.1 MUM for PSMA while the metal binding affinity is maintained at 0.9 +/- 0.1 * 10(-22) M. In addition, ProCA32.PSMA exhibits r1 of 27.6 mM(-1) s(-1) and r2 of 37.9 mM(-1) s( 1) per Gd (55.2 and 75.8 mM(-1) s(-1) per molecule r1 and r2, respectively) at 1.4 T. At 7 T, ProCA32.PSMA also has r2 of 94.0 mM(-1) s(-1) per Gd (188.0 mM(-1) s(-1) per molecule) and r1 of 18.6 mM(-1) s(-1) per Gd (37.2 mM(-1) s(-1) per molecule). This contrast capability enables the first MRI enhancement dependent on PSMA expression levels in tumor bearing mice using both T1 and T2-weighted MRI at 7 T. Further development of these PSMA-targeted contrast agents are expected to be used for the precision imaging of prostate cancer at an early stage and to monitor disease progression and staging, as well as determine the effect of therapeutic treatment by non-invasive evaluation of the PSMA level using MRI. PMID- 26961237 TI - A recurring rollercoaster ride: a qualitative study of the emotional experiences of parents of children with juvenile idiopathic arthritis. AB - BACKGROUND: Despite the wealth of clinical research carried out in children with juvenile idiopathic arthritis (JIA), little is known about the emotional experiences of their parents. This article describes the predominant emotional experiences reported by parents of children with JIA in two Canadian cities. METHODS: Research participants included 15 experienced parents and 8 novice parents (<6 months since children's JIA diagnosis). Their children were 2 to 16 years old with various JIA categories. A qualitative dataset including audio recordings and verbatim transcripts of three focus groups, and written reports of 59 reciprocal interviews (parents interviewing each other) were examined by a multidisciplinary research team following a four-step qualitative analytical process. RESULTS: Parents of children with JIA experienced recurrent mixed negative and positive emotions that varied over time. Between disease onset and diagnosis, mounting anxiety, fear and confusion were the predominant emotions. Shortly after diagnosis there were shock, disbelief, and fear, with a sense of having being blindsided by the disease. At times of disease quiescence there was hope and gratitude, but also fatigue and frustration with ongoing treatment and fear of flares. During periods of increasing or ongoing symptoms there was admiration and sympathy for the courageous way children coped with JIA, as well as sorrow and frustration for ongoing pain and limitations. There were at times, frustration and indignation with peers and teachers unable to understand the child's fluctuations in physical activity and schoolwork. Throughout the disease, parents felt an underlying anxiety and powerlessness. CONCLUSIONS: Parents of children with JIA described complex emotional journeys akin to the recurring ups and downs of rollercoaster rides, instead of ordered emotional phases ending in resolution. This has implications for healthcare providers who need to be aware of the complexity of these emotional journeys to support parents more effectively, thereby helping improve patient outcomes. PMID- 26961238 TI - Potential Role of Regulator of G-Protein Signaling 5 in the Protection of Vagal Related Bradycardia and Atrial Tachyarrhythmia. AB - BACKGROUND: The regulator of G-protein signaling 5 (Rgs5), which functions as the regulator of G-protein-coupled receptor (GPCR) including muscarinic receptors, has a potential effect on atrial muscarinic receptor-activated IKA ch current. METHODS AND RESULTS: In the present study, hearts of Rgs5 knockout (KO) mice had decreased low-frequency/high-frequency ratio in spectral measures of heart rate variability. Loss of Rgs5 provoked dramatically exaggerated bradycardia and significantly (P<0.05) prolonged sinus nodal recovery time in response to carbachol (0.1 mg/kg, intraperitoneally). Compared to those from wild-type (WT) mice, Langendorff perfused hearts from Rgs5 KO mice had significantly (P<0.01) abbreviated atrial effective refractory periods and increased dominant frequency after administration of acetylcholine (ACh; 1 MUmol/L). In addition, whole patch clamp analyses of single atrial myocytes revealed that the ACh-regulated potassium current (IKA ch) was significant increased in the time course of activation and deactivation (P<0.01) in Rgs5 KO, compared to those in WT, mice. To further determine the effect of Rgs5, transgenic mice with cardiac-specific overexpression of human Rgs5 were found to be resistant to ACh-related effects in bradycardia, atrial electrophysiology, and atrial tachyarrhythmia (AT). CONCLUSION: The results of this study indicate that, as a critical regulator of parasympathetic activation in the heart, Rgs5 prevents vagal-related bradycardia and AT through negatively regulating the IKA ch current. PMID- 26961241 TI - Phosphocholine conjugation: an unexpected in vivo conjugation pathway associated with hepatitis c ns5b inhibitors featuring a bicyclo[1.1.1]pentane. AB - During a medicinal chemistry campaign to identify inhibitors of the hepatitis C virus nonstructural protein 5B (RNA-dependent RNA polymerase), a bicyclo[1.1.1]pentane was introduced into the chemical scaffold to improve metabolic stability. The inhibitors bearing this feature, 5-(3 (bicyclo[1.1.1]pentan-1-ylcarbamoyl)-4-fluorophenyl)-2-(4-fluorophenyl)-N-methyl 6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridine-3-carboxamide (1) and 5-(3 (bicyclo[1.1.1]pentan-1-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(3,3,3 trifluoropropyl)furo[2,3-b]pyridine-3-carboxamide (2), exhibited low turnover in incubations with liver S9 or hepatocytes (rat, human), with hydroxylation of the bicyclic moiety being the only metabolic pathway observed. In subsequent disposition studies using bile-duct-cannulated rats, the metabolite profiles of bile samples revealed, in addition to multiple products of bicyclopentane oxidation, unexpected metabolites characterized by molecular masses that were 181 Da greater than those of 1 or 2. Further LC/MSn and NMR analysis of the isolated metabolite of 1 demonstrated the presence of a phosphocholine (POPC) moiety bound to the methine carbon of the bicyclic moiety through an ester bond. The POPC conjugate of the NS5B inhibitors was assumed to result from two sequential reactions: hydroxylation of the bicyclic methine to a tertiary alcohol and addition of POPC by CDP-choline: 1,2-diacylglycerol cholinephosphotransferase, an enzyme responsible for the final step in the biosynthesis of phosphatidylcholine. However, this pathway could not be recapitulated using CDP-choline-supplemented liver S9 or hepatocytes due to inadequate formation of the hydroxylation product in vitro. The observation of this unexpected pathway prompted concerns about the possibility that 1 and 2 might interfere with routine phospholipid synthesis. These results demonstrate the participation in xenobiotic metabolism of a process whose function is ordinarily limited to the synthesis of endogenous compounds. PMID- 26961239 TI - Traditional Chinese Exercise for Cardiovascular Diseases: Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Traditional Chinese exercise (TCE) has widespread use for the prevention and treatment of cardiovascular disease; however, there appears to be no consensus about the benefits of TCE for patients with cardiovascular disease. The objective of this systematic review was to determine the effects of TCE for patients with cardiovascular disease. METHODS AND RESULTS: Relevant studies were searched by PubMed, Embase, Web of Science, the Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature, and the China National Knowledge Infrastructure. We covered only published articles with randomized controlled trials. The outcome measures included physiological outcomes, biochemical outcomes, physical function, quality of life, and depression. A total of 35 articles with 2249 cardiovascular disease patients satisfied the inclusion criteria. The pooling revealed that TCE could decrease systolic blood pressure by 9.12 mm Hg (95% CI -16.38 to -1.86, P=0.01) and diastolic blood pressure by 5.12 mm Hg (95% CI -7.71 to -2.52, P<0.001). Patients performing TCE also found benefits compared with those in the control group in terms of triglyceride (standardized mean difference -0.33, 95% CI -0.56 to -0.09, P=0.006), 6-minute walk test (mean difference 59.58 m, 95% CI -153.13 to 269.93, P=0.03), Minnesota Living With Heart Failure Questionnaire results (mean difference -17.08, 95% CI 23.74 to -10.41, P<0.001), 36-Item Short Form physical function scale (mean difference 0.82, 95% CI 0.32-1.33, P=0.001), and Profile of Mood States depression scale (mean difference -3.02, 95% CI -3.50 to -2.53, P<0.001). CONCLUSIONS: This study demonstrated that TCE can effectively improve physiological outcomes, biochemical outcomes, physical function, quality of life, and depression among patients with cardiovascular disease. More high-quality randomized controlled trials on this topic are warranted. PMID- 26961240 TI - Immobilized Cytochrome P450 for Monitoring of P450-P450 Interactions and Metabolism. AB - Cytochrome P450 (P450) protein-protein interactions have been shown to alter their catalytic activity. Furthermore, these interactions are isoform specific and can elicit activation, inhibition, or no effect on enzymatic activity. Studies show that these effects are also dependent on the protein partner cytochrome P450 reductase (CPR) and the order of protein addition to purified reconstituted enzyme systems. In this study, we use controlled immobilization of P450s to a gold surface to gain a better understanding of P450-P450 interactions between three key drug-metabolizing isoforms (CYP2C9, CYP3A4, and CYP2D6). Molecular modeling was used to assess the favorability of homomeric/heteromeric P450 complex formation. P450 complex formation in vitro was analyzed in real time utilizing surface plasmon resonance. Finally, the effects of P450 complex formation were investigated utilizing our immobilized platform and reconstituted enzyme systems. Molecular modeling shows favorable binding of CYP2C9-CPR, CYP2C9 CYP2D6, CYP2C9-CYP2C9, and CYP2C9-CYP3A4, in rank order.KDvalues obtained via surface plasmon resonance show strong binding, in the nanomolar range, for the above pairs, with CYP2C9-CYP2D6 yielding the lowestKD, followed by CYP2C9-CYP2C9, CYP2C9-CPR, and CYP2C9-CYP3A4. Metabolic incubations show that immobilized CYP2C9 metabolism was activated by homomeric complex formation. CYP2C9 metabolism was not affected by the presence of CYP3A4 with saturating CPR concentrations. CYP2C9 metabolism was activated by CYP2D6 at saturating CPR concentrations in solution but was inhibited when CYP2C9 was immobilized. The order of addition of proteins (CYP2C9, CYP2D6, CYP3A4, and CPR) influenced the magnitude of inhibition for CYP3A4 and CYP2D6. These results indicate isoform-specific P450 interactions and effects on P450-mediated metabolism. PMID- 26961243 TI - Metabolism of glycerophospholipid, bile acid and retinol is correlated with the early outcomes of autoimmune hepatitis. AB - Autoimmune hepatitis (AIH) is a complex liver disease with an increasing prevalence in recent years and can develop into the severe or fulminant form if the patients are not diagnosed accurately or treated in time. However, AIH accurate diagnosis, especially at the early stage, is still difficult to perform due to the absence of specific diagnostic markers and the large heterogeneity of its clinical, laboratory and histological features. To evaluate the biochemical process of AIH at the early stage, we investigated serum metabolic alterations in mice with liver injury induced by concanavalin A (Con A), which closely mimics the immune and inflammatory response of AIH in humans. Metabonomic profiling was performed by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC Q-TOF MS). As a result, fourteen metabolites were detected as potential biomarkers related to the early stage of the liver injury, including two bile acids (taurocholic acid (V1) and taurochenodeoxycholic acid (V2)), three long-chain acylcarnitines (tetradecanoylcarnitine (V4), linoleyl carnitine (V8) and l-palmitoylcarnitine (V9)), seven glycerophospholipids (lysoPE (18 : 0/0 : 0) (V3), lysoPC (16 : 0) (V5), lysoPC (18 : 1) (V7), lysoPC (18 : 0) (V10), lysoPC (20 : 1) (V11), lysoPE (22 : 0/0 : 0) (V12) and lysoPC (20 : 0) (V13)), a bilirubin (V14), and a retinyl ester (V6). Moreover, partial least square regression analysis (RLS-RA) showed that metabolism of glycerophospholipids (P2), bile acids (P4) and retinol (P5) was highly correlated with the clinical outcomes, suggesting they played key roles in the early stage of the liver injury. Our results also demonstrated that a metabonomic approach coupled with PLS-RA is a powerful tool with which changes can be characterized in the levels of endogenous metabolites associated with disease progression and to assist in further understanding the molecular mechanism of the disease. PMID- 26961242 TI - A five-gene reverse transcription-PCR assay for pre-operative classification of breast fibroepithelial lesions. AB - BACKGROUND: Breast fibroepithelial lesions are biphasic tumors and include fibroadenomas and phyllodes tumors. Preoperative distinction between fibroadenomas and phyllodes tumors is pivotal to clinical management. Fibroadenomas are clinically benign while phyllodes tumors are more unpredictable in biological behavior, with potential for recurrence. Differentiating the tumors may be challenging when they have overlapping clinical and histological features especially on core biopsies. Current molecular and immunohistochemical techniques have a limited role in the diagnosis of breast fibroepithelial lesions. We aimed to develop a practical molecular test to aid in distinguishing fibroadenomas from phyllodes tumors in the pre-operative setting. METHODS: We profiled the transcriptome of a training set of 48 formalin-fixed, paraffin-embedded fibroadenomas and phyllodes tumors and further designed 43 quantitative polymerase chain reaction (qPCR) assays to verify differentially expressed genes. Using machine learning to build predictive regression models, we selected a five gene transcript set (ABCA8, APOD, CCL19, FN1, and PRAME) to discriminate between fibroadenomas and phyllodes tumors. We validated our assay in an independent cohort of 230 core biopsies obtained pre-operatively. RESULTS: Overall, the assay accurately classified 92.6 % of the samples (AUC = 0.948, 95 % CI 0.913-0.983, p = 2.51E-19), with a sensitivity of 82.9 % and specificity of 94.7 %. CONCLUSIONS: We provide a robust assay for classifying breast fibroepithelial lesions into fibroadenomas and phyllodes tumors, which could be a valuable tool in assisting pathologists in differential diagnosis of breast fibroepithelial lesions. PMID- 26961244 TI - Emergency Peripartum Hysterectomy: A Multicenter Study of Incidence, Indications and Outcomes in Southwestern Nigeria. AB - Objective To determine the incidence, indications and outcomes of emergency peripartum hysterectomy (EPH) in three tertiary institutions in south-west Nigeria between January, 2010 and December , 2013. Methods A retrospective review of all cases of EPH over a 4 year period was done. EPH was defined as hysterectomy performed at the time of delivery or within 24 h of delivery for uncontrollable postpartum bleeding not responsive to conservative measures. Relevant information was extracted from the hospital records and operation notes. Statistical analysis was done using SPSS software version 17.0. Statistical significance was set at p < 0.05. Results There were 102 EPHs performed among 39,738 deliveries within the study period, giving a rate of 2.6 per thousand deliveries. Indications were uterine rupture (44.1 %), uterine atony (37.3 %), morbidly adherent placenta (17.6 %) and extension of caesarean section incision involving the uterine arteries (1 %). Subtotal hysterectomy was performed in most cases (67.6 %).Maternal case fatality rate was 11.8 % and perinatal mortality rate was 55.9 %. Blood transfusion, severe postoperative anaemia, wound sepsis, febrile morbidity and acute kidney injury were common morbidities associated with the procedure. Following multivariate logistic regression, the unbooked status [odds-ratio 95 % CI = 12.80 (1.22-133.97) p = 0.03] was the only variable that significantly predicted maternal death. Conclusion The incidence of EPH from our study is high. Much more needs to be done in maternal health services, particularly provision of quality obstetric care to reduce the rates of EPH and the associated high maternal and perinatal morbidity and mortality. PMID- 26961245 TI - Surfactant-free poly(lactide-co-glycolide) nanoparticles for improving in vitro anticancer efficacy of tetrandrine. AB - The objective of this study was to improve the efficacy of a natural compound tetrandrine against cancer by designing surfactant-free poly(lactic-co-glycolic acid) (PLGA) nanoparticles as drug carriers for tetrandrine. Nanoparticles were prepared from PLGA via the nano-precipitation method with or without the presence of surfactant poly(vinyl alcohol) (PVA) to encapsulate tetrandrine. Tetrandrine loaded surfactant-free PLGA nanoparticles had an average particle size of 169.3 nm and morphology similar to the PLGA nanoparticles prepared using PVA as the surfactant. Tetrandrine-loaded surfactant-free PLGA nanoparticles could retard drug release in phosphate buffered saline (PBS) at pH 7.4 and the cumulative release of tetrandrine reached up to 68.33% over a period of 120 h. A549 cell line was used as the model cancer cells to investigate anticancer capability of tetrandrine-loaded surfactant-free PLGA nanoparticles via apoptosis assay, cytotoxicity and lysosome injury studies. The results showed that tetrandrine loaded surfactant-free PLGA nanoparticles could effectively reduce cell viability and synergistically enhance tetrandrine-induced cell apoptosis. PMID- 26961246 TI - A novel molecular dynamics approach to evaluate the effect of phosphorylation on multimeric protein interface: the alphaB-Crystallin case study. AB - BACKGROUND: Phosphorylation is one of the most important post-translational modifications (PTM) employed by cells to regulate several cellular processes. Studying the effects of phosphorylations on protein structures allows to investigate the modulation mechanisms of several proteins including chaperones, like the small HSPs, which display different multimeric structures according to the phosphorylation of a few serine residues. In this context, the proposed study is aimed at finding a method to correlate different PTM patterns (in particular phosphorylations at the monomers interface of multimeric complexes) with the dynamic behaviour of the complex, using physicochemical parameters derived from molecular dynamics simulations in the timescale of nanoseconds. RESULTS: We have developed a methodology relying on computing nine physicochemical parameters, derived from the analysis of short MD simulations, and combined with N identifiers that characterize the PTMs of the analysed protein. The nine general parameters were validated on three proteins, with known post-translational modified conformation and unmodified conformation. Then, we applied this approach to the case study of alphaB-Crystallin, a chaperone which multimeric state (up to 40 units) is supposed to be controlled by phosphorylation of Ser45 and Ser59. Phosphorylation of serines at the dimer interface induces the release of hexamers, the active state of alphaB-Crystallin. 30 ns of MD simulation were obtained for each possible combination of dimer phosphorylation state and average values of structural, dynamic, energetic and functional features were calculated on the equilibrated portion of the trajectories. Principal Component Analysis was applied to the parameters and the first five Principal Components, which summed up to 84 % of the total variance, were finally considered. CONCLUSIONS: The validation of this approach on multimeric proteins, which structures were known both modified and unmodified, allowed us to propose a new approach that can be used to predict the impact of PTM patterns in multi-modified proteins using data collected from short molecular dynamics simulations. Analysis on the alphaB Crystallin case study clusters together all-P dimers with all-P hexamers and no-P dimer with no-P hexamer and results suggest a great influence of Ser59 phosphorylation on chain B. PMID- 26961248 TI - Synthesis, characterization, DNA binding, cleavage activity, cytotoxicity and molecular docking of new nano water-soluble [M(5-CH2PPh3-3,4-salpyr)](ClO4)2 (M = Ni, Zn) complexes. AB - Some new water soluble complexes [N,N'-bis{5-[(triphenyl phosphonium chloride) methyl]salicylidine}-3,4-diaminopyridine] M(ii), which are formulated as nano [Zn(5-CH2PPh3-3,4-salpyr)](ClO4)2 (), [Zn(5-CH2PPh3-3,4-salpyr)](ClO4)2 (), nano [Ni(5-CH2PPh3-3,4-salpyr)](ClO4)2 (), [Ni(5-CH2PPh3-3,4-salpyr)](ClO4)2 (), and [N,N'-bis{5-[(triphenyl phosphonium chloride)-methyl]salicylidine}-2,3 diaminopyridine]Ni(ii) [Ni(5-CH2PPh3-2,3-salpyr)](ClO4)2 () have been isolated and characterized by elemental analysis, FT-IR, (1)H NMR, (13)C NMR, (31)P NMR, and UV-vis spectroscopy. The morphology and size of the nano complexes were determined using FE-SEM and TEM. In vitro DNA binding studies were investigated by UV-vis absorption spectroscopy, viscosity measurements, CD spectroscopy, cyclic voltammetry, emission spectra and gel electrophoresis, which suggest that the metal complexes act as efficient DNA binders. The absorption spectroscopy of the compounds with DNA reveals that the DNA binding affinity (Kb) has this order: > > > > > Ligand. The metal complexes show DNA binding stronger than the ligand, which is expected due to the nature of the metal. The nano complexes display DNA binding stronger than the other complexes which is related to the effect of size on binding affinity and the Ni(ii) complexes reveal DNA binding stronger than the corresponding Zn(ii) analogues, which is expected due to their z* effect and geometry. The prominent double strand DNA cleavage abilities of compound are observed in the absence of H2O2 with efficiencies of more than 50% even at 70 MUM complex concentration. Surprisingly, Zn(ii) complexes (compounds & ) exhibit a higher cytotoxicity (IC50: 7.3 & 10.9 MUM at 24 h; IC50: 4.6 & 8.7 MUM at 48 h) against human hepatoma (HepG2) and HeLa cell lines than the Ni(ii) complexes (compounds , & ) and 5-fluorouracil as control in spite of their inability to cleave DNA. Finally, DNA binding interactions were performed by docking studies. Density functional theory (DFT) studies were performed using the GAUSSIAN 03 program. The DFT method with B3LYP functional, LANL2DZ basis set for metal centers and 6-311g* for other atoms was used. The synthesized compounds and DNA were simulated by molecular docking to explore more details of the ligands conformation and their orientations in the active site of the receptor. PMID- 26961247 TI - Dynamics of spinal microglia repopulation following an acute depletion. AB - Our understanding on the function of microglia has been revolutionized in the recent 20 years. However, the process of maintaining microglia homeostasis has not been fully understood. In this study, we dissected the features of spinal microglia repopulation following an acute partial depletion. By injecting intrathecally Mac-1-saporin, a microglia selective immunotoxin, we ablated 50% microglia in the spinal cord of naive mice. Spinal microglia repopulated rapidly and local homeostasis was re-established within 14 days post-depletion. Mac-1 saporin treatment resulted in microglia cell proliferation and circulating monocyte infiltration. The latter is indeed part of an acute, transient inflammatory reaction that follows cell depletion, and was characterized by an increase in the expression of inflammatory molecules and by the breakdown of the blood spinal cord barrier. During this period, microglia formed cell clusters and exhibited a M1-like phenotype. MCP-1/CCR2 signaling was essential in promoting this depletion associated spinal inflammatory reaction. Interestingly, ruling out MCP-1-mediated secondary inflammation, including blocking recruitment of monocyte derived microglia, did not affect depletion-triggered microglia repopulation. Our results also demonstrated that newly generated microglia kept their responsiveness to peripheral nerve injury and their contribution to injury associated neuropathic pain was not significantly altered. PMID- 26961249 TI - A novel method for correcting scanline-observational bias of discontinuity orientation. AB - Scanline observation is known to introduce an angular bias into the probability distribution of orientation in three-dimensional space. In this paper, numerical solutions expressing the functional relationship between the scanline observational distribution (in one-dimensional space) and the inherent distribution (in three-dimensional space) are derived using probability theory and calculus under the independence hypothesis of dip direction and dip angle. Based on these solutions, a novel method for obtaining the inherent distribution (also for correcting the bias) is proposed, an approach which includes two procedures: 1) Correcting the cumulative probabilities of orientation according to the solutions, and 2) Determining the distribution of the corrected orientations using approximation methods such as the one-sample Kolmogorov Smirnov test. The inherent distribution corrected by the proposed method can be used for discrete fracture network (DFN) modelling, which is applied to such areas as rockmass stability evaluation, rockmass permeability analysis, rockmass quality calculation and other related fields. To maximize the correction capacity of the proposed method, the observed sample size is suggested through effectiveness tests for different distribution types, dispersions and sample sizes. The performance of the proposed method and the comparison of its correction capacity with existing methods are illustrated with two case studies. PMID- 26961251 TI - The role of glial-specific Kir4.1 in normal and pathological states of the CNS. AB - Kir4.1 is an inwardly rectifying K(+) channel expressed exclusively in glial cells in the central nervous system. In glia, Kir4.1 is implicated in several functions including extracellular K(+) homeostasis, maintenance of astrocyte resting membrane potential, cell volume regulation, and facilitation of glutamate uptake. Knockout of Kir4.1 in rodent models leads to severe neurological deficits, including ataxia, seizures, sensorineural deafness, and early postnatal death. Accumulating evidence indicates that Kir4.1 plays an integral role in the central nervous system, prompting many laboratories to study the potential role that Kir4.1 plays in human disease. In this article, we review the growing evidence implicating Kir4.1 in a wide array of neurological disease. Recent literature suggests Kir4.1 dysfunction facilitates neuronal hyperexcitability and may contribute to epilepsy. Genetic screens demonstrate that mutations of KCNJ10, the gene encoding Kir4.1, causes SeSAME/EAST syndrome, which is characterized by early onset seizures, compromised verbal and motor skills, profound cognitive deficits, and salt-wasting. KCNJ10 has also been linked to developmental disorders including autism. Cerebral trauma, ischemia, and inflammation are all associated with decreased astrocytic Kir4.1 current amplitude and astrocytic dysfunction. Additionally, neurodegenerative diseases such as Alzheimer disease and amyotrophic lateral sclerosis demonstrate loss of Kir4.1. This is particularly exciting in the context of Huntington disease, another neurodegenerative disorder in which restoration of Kir4.1 ameliorated motor deficits, decreased medium spiny neuron hyperexcitability, and extended survival in mouse models. Understanding the expression and regulation of Kir4.1 will be critical in determining if this channel can be exploited for therapeutic benefit. PMID- 26961250 TI - Ancient Duplications Have Led to Functional Divergence of Vitellogenin-Like Genes Potentially Involved in Inflammation and Oxidative Stress in Honey Bees. AB - Protection against inflammation and oxidative stress is key in slowing down aging processes. The honey bee (Apis mellifera) shows flexible aging patterns linked to the social role of individual bees. One molecular factor associated with honey bee aging regulation is vitellogenin, a lipoglycophosphoprotein with anti inflammatory and antioxidant properties. Recently, we identified three genes in Hymenopteran genomes arisen from ancient insect vitellogenin duplications, named vg-like-A, -B, and -C. The function of these vitellogenin homologs is unclear. We hypothesize that some of them might share gene- and protein-level similarities and a longevity-supporting role with vitellogenin. Here, we show how the structure and modifications of the vg-like genes and proteins have diverged from vitellogenin. Furthermore, all three vg-like genes show signs of positive selection, but the spatial location of the selected protein sites differ from those found in vitellogenin. We show that all these genes are expressed in both long-lived winter worker bees and in summer nurse bees with intermediate life expectancy, yet only vg-like-A shows elevated expression in winter bees as found in vitellogenin. Finally, we show that vg-like-A responds more strongly than vitellogenin to inflammatory and oxidative conditions in summer nurse bees, and that also vg-like-B responds to oxidative stress. We associate vg-like-A and, to lesser extent, vg-like-B to the antiaging roles of vitellogenin, but that vg-like C probably is involved in some other function. Our analysis indicates that an ancient duplication event facilitated the adaptive and functional divergence of vitellogenin and its paralogs in the honey bee. PMID- 26961253 TI - Biological properties of novel ruthenium- and osmium-nitrosyl complexes with azole heterocycles. AB - Since the discovery that nitric oxide (NO) is a physiologically relevant molecule, there has been great interest in the use of metal nitrosyl compounds as antitumor pharmaceuticals. Particularly interesting are those complexes which can deliver NO to biological targets. Ruthenium- and osmium-based compounds offer lower toxicity compared to other metals and show different mechanisms of action as well as different spectra of activity compared to platinum-based drugs. Novel ruthenium- and osmium-nitrosyl complexes with azole heterocycles were studied to elucidate their cytotoxicity and possible interactions with DNA. Apoptosis induction, changes of mitochondrial transmembrane potential and possible formation of reactive oxygen species were investigated as indicators of NO mediated damage by flow cytometry. Results suggest that ruthenium- and osmium nitrosyl complexes with the general formula (indazolium)[cis/trans-MCl4(NO)(1H indazole)] have pronounced cytotoxic potency in cancer cell lines. Especially the more potent ruthenium complexes strongly induce apoptosis associated with depolarization of mitochondrial membranes, and elevated reactive oxygen species levels. Furthermore, a slight yet not unequivocal trend to accumulation of intracellular cyclic guanosine monophosphate attributable to NO-mediated effects was observed. PMID- 26961252 TI - Nitrogen acquisition by plants and microorganisms in a temperate grassland. AB - Nitrogen (N) limitation is common in most terrestrial ecosystems, often leading to strong competition between microorganisms and plants. The mechanisms of niche differentiation to reduce this competition remain unclear. Short-term (15)N experiments with NH4(+), NO3(-), and glycine were conducted in July, August and September in a temperate grassland to evaluate the chemical, spatial and temporal niche differentiation by competition between plants and microorganisms for N. Microorganisms preferred NH4(+) and NO3(-), while plants preferred NO3(-). Both plants and microorganisms acquired more N in August and September than in July. The soil depth had no significant effects on microbial uptake, but significantly affected plant N uptake. Plants acquired 67% of their N from the 0-5 cm soil layer and 33% from the 5-15 cm layer. The amount of N taken up by microorganisms was at least seven times than plants. Although microorganisms efficiently compete for N with plants, the competition is alleviated through chemical partitioning mainly in deeper soil layer. In the upper soil layer, neither chemical nor temporal niche separation is realized leading to strong competition between plants and microorganisms that modifies N dynamics in grasslands. PMID- 26961255 TI - The Sentinel Lymph Node Concept and Novel Approaches in Detecting Lymph Node Metastasis in Prostate Cancer. PMID- 26961254 TI - MPs criticise government for complacency over GP crisis. PMID- 26961256 TI - Pt-Free Counter Electrodes with Carbon Black and 3D Network Epoxy Polymer Composites. AB - Carbon black (CB) and a 3D network epoxy polymer composite, representing dual functions for conductive corrosion protective layer (CCPL) and catalytic layer (CL) by the control of CB weight ratio against polymer is developed. Our strategy provides a proper approach which applies high catalytic ability and chemical stability of CB in corrosive triiodide/iodide (I3(-)/I(-)) redox electrolyte system. The CB and a 3D network epoxy polymer composite coated on the stainless steel (SS) electrode to alternate counter electrodes in dye sensitized solar cells (DSSCs). A two-step spray pyrolysis process is used to apply a solution containing epoxy monomers and a polyfunctional amine hardener with 6 wt% CB to a SS substrate, which forms a CCPL. Subsequently, an 86 wt% CB is applied to form a CL. The excellent catalytic properties and corrosion protective properties of the CB and 3D network epoxy polymer composites produce efficient counter electrodes that can replace fluorine-doped tin oxide (FTO) with CCPL/SS and Pt/FTO with CL/CCPL/SS in DSSCs. This approach provides a promising approach to the development of efficient, stable, and cheap solar cells, paving the way for large scale commercialization. PMID- 26961259 TI - Sustainable development goals put violence prevention on the map. PMID- 26961257 TI - Complement factor H binding of monomeric C-reactive protein downregulates proinflammatory activity and is impaired with at risk polymorphic CFH variants. AB - Inflammation and immune-mediated processes are pivotal to the pathogenic progression of age-related macular degeneration (AMD). Although plasma levels of C-reactive protein (CRP) have been shown to be associated with an increased risk for AMD, the pathophysiological importance of the prototypical acute-phase reactant in the etiology of the disease is unknown, and data regarding the exact role of CRP in ocular inflammation are limited. In this study, we provide mechanistic insight into how CRP contributes to the development of AMD. In particular, we show that monomeric CRP (mCRP) but not the pentameric form (pCRP) upregulates IL-8 and CCL2 levels in retinal pigment epithelial cells. Further, we show that complement factor H (FH) binds mCRP to dampen its proinflammatory activity. FH from AMD patients carrying the "risk" His402 polymorphism displays impaired binding to mCRP, and therefore proinflammatory effects of mCRP remain unrestrained. PMID- 26961258 TI - Practice patterns and complication rates of thrombolysis for pulmonary embolism. AB - Practice patterns, bleeding complication rates, and outcomes of thrombolytic use for pulmonary embolism (PE) outside of clinical trials are not well characterized. Retrospective cohort study of patients with PE, using an enhanced administrative database of approximately 20 % of hospitalizations in the United States, 2008-2011. We used hierarchical logistic regression to identify patient- and hospital-level factors associated with thrombolytic use and quantified between-hospital variation in thrombolysis. We calculated rates of hemorrhagic complications and mortality in patients receiving thrombolytics stratified by vasopressor use. We identified 91,860 hospitalizations for PE; thrombolytics were utilized in 13.2 % (578/4363) who received vasopressors and 1.6 % (1320/82,997) who did not receive vasopressors. Patients who received thrombolytics were younger, more likely white, with private insurance, fewer comorbidities and more acute organ failures. Hospitals varied widely in thrombolysis rates for PE (0-100 % of patients on vasopressors, 0-12.5 % not on vasopressors) with 17 % of variation unexplained by patient or hospital characteristics. Bleeding complication rates for patients receiving thrombolytics versus no thrombolytics, respectively, were: ICH (0.8 vs. 0.08 %, p < 0.01), major bleeding (13 vs. 3 %, p < 0.01), and major bleeding with transfusion (2.5 vs. 0.05 %, p < 0.01). Among patients given vasopressors, thrombolytics were not associated with hospital mortality (thrombolysis 41 % vs. no thrombolysis 35 % mortality; adjusted OR 0.97, 95 % CI 0.93-1.01, p = 0.15). There is wide variation in thrombolytic use for PE in the US. Patient characteristics and complications associated with real world thrombolytic use were similar to published randomized trials. PMID- 26961261 TI - Accelerating access to new medicines: Current status of facilitated regulatory pathways used by emerging regulatory authorities. AB - OBJECTIVES: We assessed the characteristics of currently implemented expedited (facilitated) regulatory pathways (FRPs) used by national regulatory authorities (NRAs) in emerging economies to speed access to important new medicines. METHODS: We identified NRAs with FRPs through Thomson Reuters Cortellis Regulatory Intelligence and through agency Websites. We developed a list of 27 FRP characteristics. We categorised characteristics as procedural or substantive and based them on five sequential regulatory activities. FINDINGS: We assessed 29 countries with 33 FRPs. The regions with the characteristics described most extensively by their FRPs were the Middle East/North Africa and Eastern Europe. The Sub-Saharan African region included the FRPs that were least specific in describing characteristics. Overall, FRPs presented at least twice as many procedural as substantive characteristics. CONCLUSIONS: We observed diversity by region in FRP characteristics, suggesting a role for further engagement with emerging NRAs in their design and implementation. Common processes could advance regulatory alignment initiatives and help the WHO inform the development of novel, globally aligned accelerated development and regulatory pathways for products that fulfil serious unmet public health needs.Journal of Public Health Policy advance online publication, 10 March 2016; doi:10.1057/jphp.2016.8. PMID- 26961260 TI - Eviction and loss of income assistance among street-involved youth in Canada. AB - Loss of housing and income assistance among vulnerable youth has not been well described in the literature, yet it is a crucial issue for public health. This study examines the prevalence and correlates of loss of income assistance as well as eviction among street-involved youth. We collected data from a prospective cohort of street-involved youth aged 14-26. Among 770 participants, 64.3 per cent reported having housing and 77.1 per cent reported receiving income assistance at some point during the study period. Further, 28.6 and 20.0 per cent of youth reported having been evicted and losing income assistance, respectively. In multivariable generalized estimating equations analysis, heavy alcohol use, unprotected sex, being a victim of violence, and homelessness were all independently associated with eviction. Separately, homelessness, recent incarceration, and drug dealing were independently associated with loss of income assistance. Eviction and loss of income assistance are common experiences among street-involved youth with multiple vulnerabilities. Our findings highlight the importance of improving continued engagement with critical social services. PMID- 26961262 TI - Moyamoya Syndrome in South African Children With HIV-1 Infection. AB - A national multicenter study identified 17 South African children with vertically acquired HIV-1 infection and HIV-associated vasculopathy. Five of the children (all indigenous African ancestry) had progressive vascular disease, consistent with moyamoya syndrome. Median presentation age 5.8 years (range 2.2-11). The children with moyamoya syndrome presented with abnormal CD4 counts and raised viral loads. Clinical features included motor deficits, neuroregression, and intellectual disability. Neuroimaging supported progressive vascular disease with preceding clinically silent disease course. Neurologic recovery occurred in 1 patient with improved CD4 counts. Four of the 5 children presented during the era when access to antiretroviral therapy was limited, suggesting that with improved management of HIV-1, progressive vasculopathy is less prevalent. However the insidious disease course illustrated indicates that the syndrome can progress "silently," and manifest with misleading phenotypes such as cognitive delay or regression. Sub-Saharan Africa has limited access to neuroimaging and affected children may be underdiagnosed. PMID- 26961264 TI - Acute Cerebellitis in Children: A Many-Faceted Disease. AB - Acute cerebellitis is a rare inflammatory condition. It may have a benign, self limiting course or present as a fulminant disease resulting in severe cerebellar damage or even sudden death. We present the clinical, laboratory, and radiologic data in 9 children diagnosed with acute cerebellitis, who were identified by database search in our pediatric medical center from January 2000 to November 2014. The main presenting symptom was headache, and the main presenting sign was ataxia. Bilateral diffuse hemispheric involvement was the most common imaging finding at presentation. Mycoplasma pneumoniae was the most common infectious pathogen found. Treatment included steroids in all cases, antibiotics in 4, and intravenous immunoglobulins in 6. Six patients had a full recovery, and 3 had residual neurologic complications. Magnetic resonance imaging (MRI) is the modality of choice for diagnosis. The course of acute cerebellitis varies from a commonly benign and self-limiting disease to an occasionally fulminant disease, resulting in severe cerebellar damage or sudden death. PMID- 26961263 TI - The Genetics of Benign Paroxysmal Torticollis of Infancy: Is There an Association With Mutations in the CACNA1A Gene? AB - Benign paroxysmal torticollis of infancy is an unusual movement disorder, often accompanied by a family history of migraine. Some benign paroxysmal torticollis cases are associated with CACNA1A mutations. The authors sought to determine the frequency of CACNA1A mutations in benign paroxysmal torticollis by testing 8 children and their parents and by searching the literature for benign paroxysmal torticollis cases with accompanying CACNA1A mutations or other disorders linked to the same gene. In our 8 benign paroxysmal torticollis cases, the authors found 3 different polymorphisms, but no pathogenic mutations. By contrast, in the literature, the authors found 4 benign paroxysmal torticollis cases with CACNA1A mutations, 3 with accompanying family histories of 1 or more of familial hemiplegic migraine, episodic ataxia, and paroxysmal tonic upgaze. Thus, CACNA1A mutations are more likely to be found in children with benign paroxysmal torticollis if accompanied by family histories of familial hemiplegic migraine, episodic ataxia, or paroxysmal tonic upgaze. PMID- 26961265 TI - Quantitative Analysis of Lower Leg Adipose Tissue Distribution in Youth with Myelomeningocele. AB - Children with myelomeningocele have a high prevalence of obesity and excess fat accumulation in their lower extremities. However, it is not known if this is subcutaneous or intramuscular fat, the latter of which has been associated with insulin resistance and metabolic disorders. This study quantified lower leg bone, muscle, and adipose tissue volume in children with myelomeningocele, classifying adipose as subcutaneous or muscle-associated. Eighty-eight children with myelomeningocele and 113 children without myelomeningocele underwent lower leg computed tomographic scans. Subcutaneous and muscle-associated adipose were classified based on location relative to the crural fascia. No differences were seen in subcutaneous adipose. Higher level disease severity was associated with increased muscle-associated adipose volume and decreased muscle volume. Bone volume tended to decrease with higher levels of involvement. Increases in lower leg adiposity in children with myelomeningocele are primarily attributable to accumulation of muscle-associated adipose, which may signify increased risk for metabolic disorders. PMID- 26961266 TI - Behavioral Symptoms in Pediatric Multiple Sclerosis: Relation to Fatigue and Cognitive Impairment. AB - The emotional and behavioral problems associated with pediatric multiple sclerosis remain unclear. Participants with pediatric multiple sclerosis or clinically isolated syndrome (n = 140; ages 5-18 years) completed self- and parent ratings using the Behavioral Assessment System for Children, Second Edition, neurologic exam, the Fatigue Severity Scale, and neuropsychological assessment. Mean self- and parent-ratings on the Behavioral Assessment System for Children, Second Edition, were in the typical range across all scales. However, 33.1% indicated a clinically significant problem on a least 1 scale. Although the type of clinical problems varied across participants, attention problems, somatization, and anxiety were found to be most common. Disease features including duration, age of onset, neurologic disability, and fatigue did not distinguish those with and without clinical problems. However, cognitive functioning significantly predicted the presence of a clinical problem (P =02). Pediatric multiple sclerosis is associated with a range of nonspecific emotional and behavioral clinical problems, occurring more frequently in those patients with cognitive involvement. PMID- 26961267 TI - The Impact of a 35-Week Long-Term Exercise Therapy on Psychosocial Health of Children With Benign Epilepsy. AB - The purpose of this study was to evaluate the feasibility of a 35-week exercise program and its efficacy on neurocognitive and psychological variables in children with benign epilepsy with centrotemporal spikes. Ten children with benign epilepsy with centrotemporal spikes (aged 8 to 12 years) completed a 35 week exercise program consisting of supervised sport activities for 5 weeks and home-based exercise program for 30 weeks. The children and their parents participated in neurocognitive and psychological evaluations including measures of attention, executive function, behaviors, and quality of life at baseline and postexercise follow-up at the 35th week. At postintervention evaluation, significant improvements were seen relative to baseline in neurocognitive domains such as psychomotor speed, sustained attention, divided attention, and inhibition disinhibition ability, and in psychological domains including internalizing behavior problems, general health, and general quality of life. Long-term exercise intervention may have benefits for some aspects of neurocognitive and psychological function in children with benign epilepsy. PMID- 26961269 TI - Impaired Automatic Arm Movements in Obstetric Brachial Plexus Palsy Suggest a Central Disorder. AB - The authors aimed to find evidence for a central component of the impairment of movement of the affected arm in children with obstetric brachial plexus palsy. The authors performed a cross-sectional study in 19 children (median age 5 years) with obstetric brachial plexus palsy who were able to voluntarily abduct their affected arm beyond 90 degrees. They were asked to perform 4 tasks designed to provoke automatic arm movements to maintain balance. The authors assumed automatic motor programming to be impaired when 2 of 3 investigators agreed using video recordings that the affected arm did not abduct beyond 90 degrees while the unaffected arm did. Children abducted the affected arm less often than the healthy one (generalized binary logistic model of all 4 tasks, P = .001). The deficit during automatic arm abduction was not observed during voluntary movements and therefore cannot be explained by a peripheral deficit, suggesting a central component. PMID- 26961268 TI - Diet Redux: Outcomes from Reattempting Dietary Therapy for Epilepsy. AB - The outcome for patients attempting dietary therapy for epilepsy a second time is unknown. Twenty-six subjects treated with the ketogenic diet as children who then began either the ketogenic diet or a Modified Atkins Diet (MAD) at least 6 months later were evaluated. The mean age at the first diet trial was 5.6 years and at the second diet trial was 11.5 years. Most restarted dietary therapy because of persistent seizures (65%) or recurrence after seizure freedom (19%). Overall, 77% had a >=50% seizure reduction with the first diet, and 50% with the second diet, P = .04. Individual subject responses were largely similar, with 14 (54%) having identical seizure reduction both times, 9 worse (35%) with the second attempt, and 3 (16%) improved. The second diet trial was more likely to lead to >50% seizure reduction if the first trial was started at a later age (7.4 vs 3.9 years, P = .04). PMID- 26961270 TI - Validating the Diagnostic Accuracy of the Sleep Apnea Clinical Score for Use in Primary Care Populations. AB - OBJECTIVE: To provide external validation of the diagnostic accuracy of the Sleep Apnea Clinical Score (SACS) tool in a new setting and patient population. PATIENTS AND METHODS: We conducted a prospective cohort study. Potential participants were adult family medicine patients. We excluded patients with a SACS of 0, known obstructive sleep apnea (OSA), negative results of previous testing, or life-limiting conditions. After SACS determination, participants completed overnight oximetry, sleep medicine consultation, and polysomnography. Those interpreting tests were blind to the participant's SACS. We determined likelihood ratios (LRs) for OSA diagnosis and posttest probabilities (PTPs). We calculated OSA prevalence (pretest probability), sensitivity, specificity, and positive and negative predictive values. RESULTS: One hundred ninety-one of 312 participants (61%) completed all steps. The prevalence of OSA was similar to that found in the derivation cohort (40% vs 45%; P=.31). With OSA defined as Apnea Hypopnea Index greater than 10, a SACS greater than 15 was 40% sensitive and 90% specific, with a positive predictive value of 73% and a negative predictive value of 69%. A SACS greater than 15 in our cohort produced an LR of 4.03 (95% CI, 3.12 5.22) with 73% PTP for OSA as compared with an LR of 5.17 (95% CI, 2.54-10.51) with 78% PTP found in the derivation cohort. CONCLUSION: The present study provides external validation of the SACS tool. It reliably predicted OSA for patients in our family medicine practice. Broader implementation in primary care practice is recommended. Further study will examine SACS uptake by clinicians and the resulting impact on utilization and clinical efficiency in primary care practices. PMID- 26961271 TI - Mobility overestimation due to gated contacts in organic field-effect transistors. AB - Parameters used to describe the electrical properties of organic field-effect transistors, such as mobility and threshold voltage, are commonly extracted from measured current-voltage characteristics and interpreted by using the classical metal oxide-semiconductor field-effect transistor model. However, in recent reports of devices with ultra-high mobility (>40 cm(2) V(-1) s(-1)), the device characteristics deviate from this idealized model and show an abrupt turn-on in the drain current when measured as a function of gate voltage. In order to investigate this phenomenon, here we report on single crystal rubrene transistors intentionally fabricated to exhibit an abrupt turn-on. We disentangle the channel properties from the contact resistance by using impedance spectroscopy and show that the current in such devices is governed by a gate bias dependence of the contact resistance. As a result, extracted mobility values from d.c. current voltage characterization are overestimated by one order of magnitude or more. PMID- 26961272 TI - Timing of Delivery in Gestational Diabetes Mellitus: Need for Person-Centered, Shared Decision-Making. AB - Gestational diabetes mellitus (GDM) is a medical as well as obstetric challenge, which needs person-centered management. The timing of delivery of women with GDM is discussed by various obstetric professional bodies. We highlight pertinent medical, obstetric, and psychosocial factors which may influence the timing of delivery in women with GDM. This commentary proposes a person-centered approach to decide the delivery timing in GDM and supports shared decision-making based upon the individual's biopsychosocial characteristics and environmental factors. PMID- 26961273 TI - Twin Boundaries merely as Intrinsically Kinematic Barriers for Screw Dislocation Motion in FCC Metals. AB - Metals with nanoscale twins have shown ultrahigh strength and excellent ductility, attributed to the role of twin boundaries (TBs) as strong barriers for the motion of lattice dislocations. Though observed in both experiments and simulations, the barrier effect of TBs is rarely studied quantitatively. Here, with atomistic simulations and continuum based anisotropic bicrystal models, we find that the long-range interaction force between coherent TBs and screw dislocations is negligible. Further simulations of the pileup behavior of screw dislocations in front of TBs suggest that screw dislocations can be blocked kinematically by TBs due to the change of slip plane, leading to the pileup of subsequent dislocations with the elastic repulsion actually from the pinned dislocation in front of the TB. Our results well explain the experimental observations that the variation of yield strength with twin thickness for ultrafine-grained copper follows the Hall-Petch relationship. PMID- 26961274 TI - Serological and molecular investigation of Ehrlichia spp. and Anaplasma spp. in ticks and blood of dogs, in the Thrace Region of Turkey. AB - In recent years, tick-borne diseases like ehrlichiosis and anaplasmosis became widespread worldwide threatening the health of both human and companion animals. Therefore, the aim of this study was to determine the presence of Anaplasma spp., and Ehrlichia spp. in dogs and ticks in the Thrace Region of Turkey. A total of 400 blood samples and 912 ticks were collected from dogs living in shelters that are located in four cities (Istanbul, Edirne, Tekirdag and Kirklareli) of the Thrace Region. Blood and buffy coat smears were prepared for microscopic examination. Hematologic and serologic analyses were performed using cell counter and commercial Snap3Dx test kit, respectively. Eight hundred fifty of collected ticks were classified as Rhipicephalus sanguineus, 33 as Rhipicephalus turanicus and 29 as Ixodes ricinus. After DNA extraction from blood samples and pooled ticks (127 tick pools, in total), nested PCR was performed to detect the DNA of Anaplasma spp., and Ehrlichia spp. The seroprevalence of Ehrlichia canis was 27.25% (109) by Snap3Dx test and the total molecular positivity was 11.75% (47) in dog blood samples and 21.25% (27) in tick pools by nested PCR. The frequencies of the infected blood samples with E. canis, Anaplasma phagocytophilum and Anaplasma platys were detected as 6%, 4% and 6%, respectively. E. canis and A. platys were detected in R. sanguineus pools with a ratio of 15.75% and 0.7%, respectively. In addition, A. platys was also detected in R. turanicus pools (0.7%). A. phagocytophilum was found only in I. ricinus pools (3.93%). Morulae of three species were detected in buffy coat and blood smears. While anemia was observed in dogs infected with E. canis and co-infected (with one or more species), thrombocytopenia was observed only in co-infected dogs. This is the first study providing evidence for the presence of Anaplasma spp. and Ehrlichia spp. in dogs and ticks in the Thrace Region of Turkey. Based on the results of the tests used in this study, we recommend the combined use of serologic, molecular, cytologic, hematologic analyses and physical examination of tick exposure for an accurate diagnosis of ehrlichiosis and anaplasmosis. PMID- 26961275 TI - Geographical differences in seroprevalence of Borrelia burgdorferi antibodies in Norway, 2011-2013. AB - Detection of specific antibodies against Borrelia burgdorferi sensu lato is a useful aid for the diagnosis of Lyme borreliosis. However, antibodies are present in the general population. The seroprevalence increase with age, and varies according to the prevalence of infected ticks. We performed a seroprevalence study of IgM and IgG antibody reactivity against B. burgdorferi sensu lato in Norway by age-groups and geography, in order to provide a reference set of seroprevalence to inform the interpretation of positive test results. We used two commercially available enzyme immuno assays (EIA) and a multiplexed bead assay to detect Borrelia IgG antibodies in a convenience sample of 3057 sera collected from clinical chemistry laboratories in 10 of 19 counties in Norway between December 2011 and January 2013. We estimated seroprevalence by age and county by a logistic regression model. IgM antibodies were detected by two commercially available EIAs and a multiplexed bead assay. The overall seroprevalence of Borrelia IgG was 4.0% (95% CI: 2.4-6.6%) and 4.2% (2.6-6.8%) by the two EIAs, respectively. The seroprevalence increased by age, and by geography from north to south. The IgG assays showed a good agreement for positive test results. All sera positive for IgG in the multiplexed bead assay reacted with the VlsE antigen, and also had high antibody levels by EIA. The Borrelia seroprevalence varied by geography and increased by age. The results indicate regional differences in pre test probabilities for positive test results, and can inform the interpretation of laboratory results. PMID- 26961276 TI - Long-Term Cost-Effectiveness of Insulin Glargine Versus Neutral Protamine Hagedorn Insulin for Type 2 Diabetes in Thailand. AB - BACKGROUND: Even though Insulin glargine (IGlar) has been available and used in other countries for more than a decade, it has not been adopted into Thai national formulary. This study aimed to evaluate the long-term cost effectiveness of IGlar versus neutral protamine Hagedorn (NPH) insulin in type 2 diabetes from the perspective of Thai Health Care System. METHODS: A validated computer simulation model (the IMS CORE Diabetes Model) was used to estimate the long-term projection of costs and clinical outcomes. The model was populated with published characteristics of Thai patients with type 2 diabetes. Baseline risk factors were obtained from Thai cohort studies, while relative risk reduction was derived from a meta-analysis study conducted by the Canadian Agency for Drugs and Technology in Health. Only direct costs were taken into account. Costs of diabetes management and complications were obtained from hospital databases in Thailand. Both costs and outcomes were discounted at 3 % per annum and presented in US dollars in terms of 2014 dollar value. Incremental cost-effectiveness ratio (ICER) was calculated. One-way and probabilistic sensitivity analyses were also performed. RESULTS: IGlar is associated with a slight gain in quality-adjusted life years (0.488 QALYs), an additional life expectancy (0.677 life years), and an incremental cost of THB119,543 (US$3522.19) compared with NPH insulin. The ICERs were THB244,915/QALY (US$7216.12/QALY) and THB176,525/life-year gained (LYG) (US$5201.09/LYG). The ICER was sensitive to discount rates and IGlar cost. At the acceptable willingness to pay of THB160,000/QALY (US$4714.20/QALY), the probability that IGlar was cost effective was less than 20 %. CONCLUSIONS: Compared to treatment with NPH insulin, treatment with IGlar in type 2 diabetes patients who had uncontrolled blood glucose with oral anti-diabetic drugs did not represent good value for money at the acceptable threshold in Thailand. PMID- 26961277 TI - Human temperatures for syndromic surveillance in the emergency department: data from the autumn wave of the 2009 swine flu (H1N1) pandemic and a seasonal influenza outbreak. AB - BACKGROUND: The emergency department (ED) increasingly acts as a gateway to the evaluation and treatment of acute illnesses. Consequently, it has also become a key testing ground for systems that monitor and identify outbreaks of disease. Here, we describe a new technology that automatically collects body temperatures during triage. The technology was tested in an ED as an approach to monitoring diseases that cause fever, such as seasonal flu and some pandemics. METHODS: Temporal artery thermometers that log temperature measurements were placed in a Boston ED and used for initial triage vital signs. Time-stamped measurements were collected from the thermometers to investigate the performance a real-time system would offer. The data were summarized in terms of rates of fever (temperatures >=100.4 degrees F [>=38.0 degrees C]) and were qualitatively compared with regional disease surveillance programs in Massachusetts. RESULTS: From September 2009 through August 2011, 71,865 body temperatures were collected and included in our analysis, 2073 (2.6 %) of which were fevers. The period of study included the autumn-winter wave of the 2009-2010 H1N1 (swine flu) pandemic, during which the weekly incidence of fever reached a maximum of 5.6 %, as well as the 2010-2011 seasonal flu outbreak, during which the maximum weekly incidence of fever was 6.6 %. The periods of peak fever rates corresponded with the periods of regionally elevated flu activity. CONCLUSIONS: Temperature measurements were monitored at triage in the ED over a period of 2 years. The resulting data showed promise as a potential surveillance tool for febrile disease that could complement current disease surveillance systems. Because temperature can easily be measured by non experts, it might also be suitable for monitoring febrile disease activity in schools, workplaces, and transportation hubs, where many traditional syndromic indicators are impractical. However, the system's validity and generalizability should be evaluated in additional years and settings. PMID- 26961278 TI - Do patients want choice? An observational study of neurology consultations. AB - OBJECTIVES: To determine how often patients are given choice in neurology outpatient consultations and whether choice is associated with greater patient satisfaction. METHODS: Prospective study in outpatient clinics in two United Kingdom centres. Interactions between 14 neurologists and 223 patients were studied. Participating doctors and patients completed post-appointment questionnaires asking whether choice had been offered/perceived. Patients completed the Medical Interview Satisfaction Scale 21 (MISS-21). RESULTS: Choice was reported after most encounters (patients 71.8%, neurologists 67.9%). Patients and Neurologists failed to agree about whether choice was offered after 32% of consultations. Choice was not associated with increased patient satisfaction. In fact, satisfaction was greater when no choice had been offered (p=0.05). Satisfaction scores were also greater when doctors were more certain about the diagnosis and when symptoms were considered explained by a medical condition (p<=0.001). CONCLUSIONS: Choice featured in the majority of clinical interactions but clinicians and patients often disagreed whether this was the case. Choice was not associated with greater patient satisfaction. PRACTICE IMPLICATIONS: Clinicians need to be very explicit if they want patients to know that they are being given choices. Choice is not necessarily valued by patients in all clinical interactions. PMID- 26961281 TI - Editorial response to JPUROL-D-15-00312: Study of clitoral hood anatomy in the pediatric population. PMID- 26961280 TI - Hypospadias anatomy: Elastosonographic evaluation of the normal and hypospadic penis. AB - BACKGROUND: Hypospadias is one of the most common congenital anomalies in childhood. The aim of this study is to apply elastosonography on normal and hypospadic penis to verify the structural differences in tissues composition and stiffness. MATERIALS AND METHODS: We analyzed medical chart of patients treated at our Institution for hypospadias during the period December 2005 and December 2014 (group 1). Other two groups were enrolled for this study: group 2- patients with hypospadias waiting for surgery and group 3-patients without hypospadias. Inclusion and exclusion criteria were created; all patients underwent penile ultrasound and elastosonography. Elastographic index of elasticity was defined as soft, medium-hard or hard. We assigned the value 1 to soft tissue, 2 and 3 to medium-hard and hard respectively. RESULTS: During the study period 294 patients were treated for hypospadias. After reviewing medical chart 115 patients were considered for analysis (group 1). 22 patients were enrolled in group 2 and 38 patients were enrolled in group 3. Group 1: 7 proximal hypospadias, 29 penile hypospadias, 79 distal hypospadias. Patients with hypospadias had malformation also at corpus spongiosum and cavernosum respect to controls. Elastography showed a corpus spongiosum stiffness defined as medium-hard or hard in all cases of the pathologic group and soft in all the subjects of the control group (p < 0.05). CONCLUSIONS: Elastosonography showed how the hypospadia anatomy is deeply altered, even in an anatomical area far from meatal abnormality: corpus spongiosum in hypospadic penis seems to be globally stiffer and less elastic and cavernous corpora are less developed. PMID- 26961279 TI - Extension and grading of osteomyelitis are not related to limb salvage in Charcot neuropathic osteoarthropathy: A cohort prospective study. AB - AIMS: Charcot neuropathic osteoarthropathy (CN) represents a complication for diabetic patients which involves a progressive alteration of the osteoarticular apparatus with high risk of amputation. The aim of the study was to assess whether the localization of CN and the extent or grading of the osteomyelitis have an influence on the rate of limb salvage and the time to recovery. METHODS: We treated a diabetic population affected by CN complicated by ulceration and widespread osteomyelitic involvement. All patients were treated surgically to eliminate infected tissues, stabilize and correct the bone deformities. Histopathological and microbiological analyses were carried out on the bone specimens. RESULTS: Thirty-three patients affected by CN complicated by large osteomyelitic involvement of midfoot and/or ankle were treated between January 2010 and May 2014. The mean follow-up was 409,35 +/- 154,06 days. Thirty patients had complete recovery (90.91%) at the end of follow-up. No difference in limb salvage rate and time to recovery was observed when stratifying the population according to CN localization, extent and grading of osteomyelitis. CONCLUSIONS: In this cohort prospective study we observed a high percentage of limb salvage in patients affected by CN complicated by diffuse midfoot/hindfoot osteomyelitis. The localization of Charcot deformity and the extent/stage of osteomyelitis did not change the rate of limb salvage. PMID- 26961282 TI - Rainfall Threshold Assessment Corresponding to the Maximum Allowable Turbidity for Source Water. AB - This study aims to assess the upstream rainfall thresholds corresponding to the maximum allowable turbidity of source water, using monitoring data and artificial neural network computation. The Taipei Water Source Domain was selected as the study area, and the upstream rainfall records were collected for statistical analysis. Using analysis of variance (ANOVA), the cumulative rainfall records of one-day Ping-lin, two-day Ping-lin, two-day Tong-hou, one-day Guie-shan, and one day Tai-ping (rainfall in the previous 24 or 48 hours at the named weather stations) were found to be the five most significant parameters for downstream turbidity development. An artificial neural network model was constructed to predict the downstream turbidity in the area investigated. The observed and model calculated turbidity data were applied to assess the rainfall thresholds in the studied area. By setting preselected turbidity criteria, the upstream rainfall thresholds for these statistically determined rain gauge stations were calculated. PMID- 26961284 TI - Genetic evolution during tumor progression: from basic research to clinical practice. PMID- 26961283 TI - In vitro and in silico PTP-1B inhibition and in vivo antidiabetic activity of semisynthetic moronic acid derivatives. AB - Six derivatives (1-6) of moronic acid were semi-synthesized and their in vitro protein tyrosine phosphatase 1B (PTP-1B) inhibition activity assessed. Derivatives 2 (IC50=10.8 +/- 0.5 MUM) and 6 (IC50=7.5 +/- 0.1 MUM) displayed the most potent inhibitory activity. Therefore, they (50mg/Kg) were tested for their antidiabetic effect in vivo using a non-insulin dependent diabetes mellitus rat model. The results indicated that they decrease plasma glucose levels during all the experiment (p <0.05). Docking analysis of 2 and 6 with PTP-1B orthosteric site A and allosteric site B, showed that 2 had polar and Van der Waals interactions in both sites with Val49, Gln262, Met258, Phe182, Ala217, Ile219 and Gly259, displaying more affinity for site A. Compound 6 showed polar interaction with Gln262 and Van der Waals with Val49, Ile219, Gly259, Arg254, Ala27, Phe52, Met258, Asp48 and Phe182, suggesting that the potential binding site is localized in site B, close to the catalytic site A. Therefore, derivatives 2 and 6 have potential for the development of antidiabetic agents. PMID- 26961285 TI - How do clinicians become teachers? A communities of practice perspective. AB - There is widespread acceptance that clinical educators should be trained to teach, but faculty development for clinicians is undermined by poor attendance and inadequate learning transfer. As a result there has been growing interest in situating teacher development initiatives in clinical workplaces. The relationship between becoming a teacher and clinical workplace contexts is under theorised. In response, this qualitative research set out to explore how clinicians become teachers in relation to clinical communities and institutions. Using communities of practice (CoP) as a conceptual framework this research employed the sensitising concepts of regimes of competence and vertical (managerial) and horizontal (professional) planes of accountability to elucidate structural influences on teacher development. Fourteen hospital physicians completed developmental timelines and underwent semi-structured interviews, exploring their development as teachers. Despite having very different developmental pathways, participants' descriptions of their teacher identities and practice that were remarkably congruent. Two types of CoP occupied the horizontal plane of accountability i.e. clinical teams (Firms) and communities of junior doctors (Fraternities). Participants reproduced teacher identities and practice that were congruent with CoPs' regimes of competence in order to gain recognition and legitimacy. Participants also constructed their teacher identities in relation to institutions in the vertical plane of accountability (i.e. hospitals and medical schools). Institutions that valued teaching supported the development of teacher identities along institutionally defined lines. Where teaching was less valued, clinicians adapted their teacher identities and practices to suit institutional norms. Becoming a clinical educator entails continually negotiating one's identity and practice between two potentially conflicting planes of accountability. Clinical CoPs are largely conservative and reproductive of teaching practice whereas accountability to institutions is potentially disruptive of teacher identity and practice. PMID- 26961286 TI - Attribution of mortality to the urban heat island during heatwaves in the West Midlands, UK. AB - BACKGROUND: The Urban Heat Island (UHI) effect describes the phenomenon whereby cities are generally warmer than surrounding rural areas. Traditionally, temperature monitoring sites are placed outside of city centres, which means that point measurements do not always reflect the true air temperature of urban centres, and estimates of health impacts based on such data may under-estimate the impact of heat on public health. Climate change is likely to exacerbate heatwaves in future, but because climate projections do not usually include the UHI, health impacts may be further underestimated. These factors motivate a two dimensional analysis of population weighted temperature across an urban area, for heat related health impact assessments, since populations are typically densest in urban centres, where ambient temperatures are highest and the UHI is most pronounced. We investigate the sensitivity of health impact estimates to the use of population weighting and the inclusion of urban temperatures in exposure data. METHODS: We quantify the attribution of the UHI to heat related mortality in the West Midlands during the heatwave of August 2003 by comparing health impacts based on two modelled temperature simulations. The first simulation is based on detailed urban land use information and captures the extent of the UHI, whereas in the second simulation, urban land surfaces have been replaced by rural types. RESULTS AND CONCLUSIONS: The results suggest that the UHI contributed around 50 % of the total heat-related mortality during the 2003 heatwave in the West Midlands. We also find that taking a geographical, rather than population weighted, mean of temperature across the regions under-estimates the population exposure to temperatures by around 1 degrees C, roughly equivalent to a 20 % underestimation in mortality. We compare the mortality contribution of the UHI to impacts expected from a range of projected temperatures based on the UKCP09 Climate Projections. For a medium emissions scenario, a typical heatwave in 2080 could be responsible for an increase in mortality of around 3 times the rate in 2003 (278 vs. 90 deaths) when including changes in population, population weighting and the UHI effect in the West Midlands, and assuming no change in population adaptation to heat in future. PMID- 26961287 TI - Efficacy and safety of porous hydroxyapatite/type 1 collagen composite implantation for bone regeneration: A randomized controlled study. AB - BACKGROUND: Porous hydroxyapatite/collagen composite (HAp/Col) is a bioresorbable bone substitute composed of nano-scale HAp and porcine type 1 collagen. In this study, the efficacy and safety were assessed in comparison to commercially available porous beta-tricalcium phosphate (beta-TCP). METHODS: Patients with bone defects caused by benign bone tumors, fractures, or harvesting of autografts were randomly allocated for implantation of porous HAp/Col (n = 63) or porous beta-TCP (n = 63). X-ray images were scored and used to evaluate the efficacy of the implantation until 24 weeks after surgery. Blood tests and observation of the surgical site were also performed to evaluate the safety of the implants. In total, 59 and 60 cases were analyzed in the porous HAp/Col and beta-TCP groups, respectively. RESULTS: At 18 and 24 weeks after surgery, the highest grade of bone regeneration was more frequent in the porous HAp/Col group than in the porous beta-TCP group (p = 0.0004 and 0.0254 respectively). Wilcoxon's rank sum test confirmed the superiority of porous HAp/Col from early time points onward (p = 0.0084, 4 w; p = 0.0037, 8 w; p = 0.0030, 12 w; p < 0.0001, 18 w; and p = 0.0316, 24 w). The incidence of adverse effects was higher in the porous HAp/Col group than in the beta-TCP group. However, no serious adverse events were reported and no cases needed to drop out of the clinical trial. CONCLUSIONS: The superiority of porous HAp/Col for bone regeneration in comparison to an established porous beta-TCP was confirmed. Although the incidence of side effects associated with the porous HAp/Col implant was higher than that in the beta-TCP group, no serious adverse events occurred that resulted in rejection of the implants. PMID- 26961289 TI - An approximation technique for primary anastomosis (Gazi method) in selected cases of long gap esophageal atresia. PMID- 26961290 TI - Correspondence. PMID- 26961288 TI - The etiology of congenital nephrotic syndrome: current status and challenges. AB - BACKGROUND: Congenital nephrotic syndrome (CNS), defined as heavy proteinuria, hypoalbuminemia, hyperlipidemia and edema presenting in the first 0-3 months of life, may be caused by congenital syphilis, toxoplasmosis, or congenital viral infections (such as cytomegalovirus). However, the majority of CNS cases are caused by monogenic defects of structural proteins that form the glomerular filtration barrier in the kidneys. Since 1998, an increasing number of genetic defects have been identified for their involvements in the pathogenesis of CNS, including NPHS1, NPHS2, WT1, PLCE1, and LAMB2. DATA SOURCES: We searched databases such as PubMed, Elsevier and Wanfang with the following key words: congenital nephrotic syndrome, proteinuria, infants, neonate, congenital infection, mechanism and treatment; and we selected those publications written in English that we judged to be relevant to the topic of this review. RESULTS: Based on the data present in the literature, we reviewed the following topics: 1) Infection associated CNS including congenital syphilis, congenital toxoplasmosis, and congenital cytomegalovirus infection; 2) genetic CNS including mutation of NPHS1 (Nephrin), NPHS2 (Podocin), WT1, LAMB2 (Laminin-beta2), PLCE1 (NPHS3); 3) Other forms of CNS including maternal systemic lupus erythematosus, mercury poisoning, renal vein thrombosis, neonatal alloimmunization against neutral endopeptidase. CONCLUSION: At present, the main challenge in CNS is to identify the cause of disease for individual patients. To make a definitive diagnosis, with the exclusion of infection-related CNS and maternal-associated disorders, pathology, family history, inheritance mode, and other accompanying congenital malformations are sometimes, but not always, useful indicators for diagnosing genetic CNS. Next-generation sequencing would be a more effective method for diagnosing genetic CNS in some patients, however, there are still some challenges with next-generation sequencing that need to be resolved in the future. PMID- 26961291 TI - The Efficacy of Boric Acid Used to Treat Experimental Osteomyelitis Caused by Methicillin-Resistant Staphylococcus aureus: an In Vivo Study. AB - We explored the ability of local and systemic applications of boric acid (BA) to reduce the numbers of methicillin-resistant Staphylococcus aureus (MRSA) in a rat model of tibial osteomyelitis (OM), and compared boric acid with vancomycin (V). Implant-associated osteomyelitis was established in 35 rats. After 4 weeks, at which time OM was evident both radiologically and serologically in all animals, the rats were divided into five groups of equal number: group 1, control group (no local application of BA or other medication); group 2, V group; group 3, local BA + V group; group 4, local BA group; and group 5, local + systemic BA group. Serum total antioxidant status, and the levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, were measured. Pathological changes attributable to bone OM were evaluated using a grading system. Bacterial colony forming units (CFUs) per gram of bone were counted. The lowest bacterial numbers were evident in group 3, and the bacterial numbers were significantly lower than that of the control group in all four test groups (p < 0.001). Group 3 also had the least severe bone infection (OM score 1.7 +/- 1.1, p < 0.05). Upon histological and microbiological evaluation, no significant difference was evident between groups 2 and 3. Total antioxidant levels were significantly different in all treatment groups compared to the control group. Microbiological and histopathological evaluation showed that systemic or local application of BA was effective to treat OM, although supplementary V increased the effectiveness of BA. PMID- 26961292 TI - In Vitro Anticancer Activity of Au, Ag Nanoparticles Synthesized Using Commelina nudiflora L. Aqueous Extract Against HCT-116 Colon Cancer Cells. AB - Recently, metal nanoparticles have been getting great medical and social interests due to their potential physico-chemical properties such as higher affinity, low molecular weight, and larger surface area. The biosynthesized gold and silver nanoparticles are spherical, triangular in shape with an average size of 24-150 nm as reported in our earlier studies. The biological properties of synthesized gold and silver nanoparticles are demonstrated in this paper. The different in vitro assays such as MTT, flow cytometry, and reverse transcription polymerase chain reaction (RT-qPCR) techniques were used to evaluate the in vitro anticancer properties of synthesized metal nanoparticles. The biosynthesized gold and silver nanoparticles have shown reduced cell viability and increased cytotoxicity in HCT-116 colon cancer cells with IC50 concentration of 200 and 100 MUg/ml, respectively. The flow cytometry experiments revealed that the IC50 concentrations of gold and silver nanoparticle-treated cells that have significant changes were observed in the sub-G1 cell cycle phase compared with the positive control. Additionally, the relative messenger RNA (mRNA) gene expressions of HCT-116 cells were studied by RT-qPCR techniques. The pro apoptotic genes such as PUMA (++), Caspase-3 (+), Caspase-8 (++), and Caspase-9 (++) were upregulated in the treated HCT-116 cells compared with cisplatin. Overall, these findings have proved that the synthesized gold and silver nanoparticles could be potent anti-colon cancer drugs. PMID- 26961293 TI - Trace Elements and Chemotherapy Sensitivity. AB - Trace elements might be associated with the development of hepatocellular carcinoma (HCC) and the efficacy of chemotherapy against HCC. Therefore, this study aimed to explore the association between trace elements and efficacy of chemotherapy in patients with HCC. Cancer, cancer-adjacent, and cancer-free tissues were collected intraoperatively from 55 patients with HCC between January 2001 and April 2004 at the Affiliated Tumor Hospital of Guangxi Medical University in Guangxi (China), a high HCC incidence area in the world. Trace element levels were analyzed by atomic absorption spectrophotometry. In vitro sensitivity of cancer cells to five chemotherapeutic drugs (5-fluorouracil, doxorubicin, cisplatin, carboplatin, and mitomycin) was tested using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in cancer cells from 32 patients. Zinc, copper, manganese, and selenium levels had the same gradient distribution in different liver tissues: cancer < cancer-adjacent < cancer-free tissues. Copper levels of cancer tissues were negatively correlated with body weight (r = -0.278, P = 0.027), while manganese and selenium levels were negatively correlated with age (r = -0.297, P = 0.015; r = -0.285, P = 0.018, respectively). Simple correlation analyses revealed that the carboplatin sensitivity was negatively correlated with selenium levels of cancer tissues, while doxorubicin sensitivity was negatively correlated with manganese levels (r = -0.497, P = 0.004). Partial correlation analyses showed that doxorubicin sensitivity only was negatively correlated with manganese levels (r = -0.450, P = 0.014). These results suggest that the selenium and manganese content in primary HCC tissues could influence the response of the HCC cells to carboplatin and doxorubicin. These preliminary results provide a basis for future studies. PMID- 26961295 TI - In primary Sjogren's syndrome high absolute numbers and proportions of B cells in parotid glands predict responsiveness to rituximab as defined by ESSDAI, but not by SSRI. PMID- 26961294 TI - Pan PPAR agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis. AB - BACKGROUND: The pathogenesis of systemic sclerosis (SSc) involves a distinctive triad of autoimmune, vascular and inflammatory alterations resulting in fibrosis. Evidence suggests that peroxisome proliferator-activated receptors (PPARs) play an important role in SSc-related fibrosis and their agonists may become effective therapeutic targets. OBJECTIVE: To determine the expression of PPARs in human fibrotic skin and investigate the effects of IVA337, a pan PPAR agonist, in in vitro and in vivo models of fibrosis. METHODS: The antifibrotic effects of IVA337 were studied using a bleomycin-induced mouse model of dermal fibrosis. The in vivo effect of IVA337 on wound closure and inflammation were studied using an excisional model of wound healing. RESULTS: Low levels of PPARalpha and PPARgamma were detected in the skin of patients with SSc compared with controls. In mice, IVA337 was associated with decreased extracellular matrix (ECM) deposition and reduced expression of phosphorylated SMAD2/3-intracellular effector of transforming growth factor (TGF)-beta1. Although the antifibrotic effect of pan PPAR was similar to that of PPARgamma agonist alone, a significant downregulation of several markers of inflammation was associated with IVA337. Despite its anti inflammatory and antifibrotic properties, IVA337 did not interfere with wound closure. In vitro effects of IVA337 included attenuation of transcription of ECM genes and alteration of canonical and non-canonical TGF-beta signalling pathways. CONCLUSIONS: These findings indicate that simultaneous activation of all three PPAR isoforms exerts a dampening effect on inflammation and fibrosis, making IVA337 a potentially effective therapeutic candidate in the treatment of fibrotic diseases including SSc. PMID- 26961297 TI - Comparative effectiveness of antiarrhythmic drugs and catheter ablation for the prevention of recurrent ventricular tachycardia in patients with implantable cardioverter-defibrillators: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Treatment strategies to prevent ventricular tachycardia (VT) in patients with an implantable cardioverter-defibrillator (ICD) include antiarrhythmic drugs (AADs) and catheter ablation (CA). OBJECTIVE: The purpose of this study was to systematically compare the efficacy of AADs and CA for the prevention of VT in patients with ICDs. METHODS: Major databases were searched (October 2015) for randomized trials evaluating AADs or CA vs standard medical therapy to prevent VT in ICD patients. Primary outcome was the number of VT episodes leading to appropriate ICD interventions. RESULTS: Eight trials (n = 2268, follow-up 15 +/- 6 months) evaluated AADs, and 6 trials (n = 427, follow-up 14 +/- 8 months) evaluated CA. A significant reduction in appropriate ICD interventions was found with both CA (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.28-0.71, P = .001) and AADs (OR 0.66, 95% CI 0.44-0.97, P = .037), with no significant difference between the 2 treatment strategies. The benefit of AADs was driven by amiodarone and not confirmed with other AADs. A reduction of inappropriate ICD interventions was found with AADs (OR 0.30, P = .001) but not with CA. Both CA and AADs were not associated with decreased mortality over follow-up. Amiodarone appeared to increase the risk of death (OR 3.36, 95% CI 1.36-8.30, P = .009). CONCLUSION: In patients with an ICD, both AADs (amiodarone) and CA reduce the risk of recurrent VT compared to control medical therapy, with no significant difference between the 2 treatments. AADs are also associated with a reduction of inappropriate ICD therapies. The significant reduction of recurrent VT episodes does not appear to result in a mortality benefit, with a potential for increased mortality with amiodarone. PMID- 26961298 TI - Performance of a new atrial fibrillation detection algorithm in a miniaturized insertable cardiac monitor: Results from the Reveal LINQ Usability Study. AB - BACKGROUND: For clinicians, confidence in atrial fibrillation (AF) episode classification is an important consideration when electing to use insertable cardiac monitors (ICMs). OBJECTIVE: The purpose of this study was to report on the improved AF detection algorithm in the Reveal LINQ ICM. METHODS: The Reveal LINQ Usability Study is a nonrandomized, prospective, multicenter trial. The ICM has been miniaturized, uses wireless telemetry for remote patient monitoring, and its AF algorithm includes a new p-wave filter. At 1 month post-device insertion, Holter monitor data were collected and annotated for true AF episodes >=2 minutes, and performance metrics were evaluated by comparing Holter annotations with ICM detections. RESULTS: The study enrolled 151 patients (age 56.6 +/- 12.1, male 67%). Reasons for monitoring included AF ablation or AF management in 81.5% (n = 123), syncope in 12.6% (n = 19), and other indications in 5.9% (n = 9) of patients. Of the 138 patients with an analyzable Holter recording, a total of 112 true AF episodes were identified in 38 patients (27.5%). The overall accuracy of the ICM to detect durations of AF or non-AF episodes was 99.4%, and the AF burden measured by the ICM was highly correlated with the Holter (Pearson coefficient 0.995). CONCLUSION: The new AF detection algorithm in the Reveal LINQ ICM accurately detects the presence or absence of AF. Additionally, it showed high sensitivity in detecting AF duration in patients with a history of intermittent and symptomatic AF. PMID- 26961296 TI - Mechanism and outcomes of catheter ablation for ventricular tachycardia in adults with repaired congenital heart disease. AB - BACKGROUND: Repaired congenital heart disease (rCHD) is strongly associated with ventricular tachycardia (VT) as an important late cause of morbidity and mortality. Ventricular reentry most commonly includes anatomic isthmuses created during the repair procedures. OBJECTIVE: The purpose of this study was to analyze the long-term outcomes of catheter ablation, a commonly used standalone or adjunctive therapy, in a cohort of rCHD patients. METHODS: A retrospective analysis of 21 consecutive patients with rCHD (45.0 +/- 3.0 years, 71.4% male) undergoing ablation for VT was performed. The primary composite outcome was defined as in-hospital arrhythmic death, out-of-hospital sudden cardiac death, or appropriate implantable cardioverter-defibrillator therapy. RESULTS: At initial electrophysiologic study, 14 patients (66.7%) had reentrant VT through an electroanatomic isthmus; the remaining 7 patients (33.3%) demonstrated focal VT. Isthmus-dependent reentry was identified as the mechanism for VT in 14 patients (66.7%), and conduction block was confirmed in 8 of these patients (57.1%). No patients with confirmed block developed VT recurrence. During long-term follow-up (33 +/- 7 months), 20 of 21 patients (95.2%) had not reached the primary composite outcome. Three patients died of nonarrhythmic causes. CONCLUSION: Catheter-based VT ablation in patients with rCHD is associated with a low rate of VT recurrence. Focal VT was not uncommon in this cohort. If a reentrant mechanism is present, confirmation of conduction block across the isthmus is vital to prevent recurrence. PMID- 26961299 TI - Effects of stepwise denervation of the stellate ganglion: Novel insights from an acute canine study. AB - BACKGROUND: The stellate ganglion (SG) is important for cardiac autonomic control. SG modification is an option for treating refractory ventricular tachyarrhythmias. The optimal extent of left- and right-sided SG denervation necessary for antiarrhythmic effect, however, remains to be learned. OBJECTIVE: The purpose of this study was to evaluate the effects of stepwise SG denervation on hemodynamic and electrophysiological parameters in dogs. METHODS: After sequential left and right thoracotomy in 8 healthy dogs, the SG was exposed by dissection. Two pacing wires were placed in the upper SG to deliver high frequency stimulation. The lower SG, ansae subclaviae, and upper SG were removed in a stepwise manner. The same protocol was performed on the right side. Blood pressure (BP), heart rate, and electrophysiological parameters were recorded at baseline and after 5 minutes of stimulation. RESULTS: Systolic and diastolic BP significantly increased during stimulation of the upper left SG. The mean increase in systolic BP from baseline was 49.4 +/- 26.6 mm Hg (P = .007), 25.5 +/ 14.1 mm Hg after the lower SG was removed (P = .02), and 8.6 +/- 3.4 mm Hg after resection of the ipsilateral ansae subclaviae (P = .048). Heart rate and other electrophysiological parameters did not change significantly. After the complete removal of the left SG, systolic BP increased by 34.0 +/- 17.6 mm Hg (P = .005) after stimulation of the right SG. CONCLUSION: Sympathetic output remains after the lower SG is removed, and sympathetic output from the right SG remains after the complete resection of the left SG and ansae subclaviae. Thus, some patients who undergo left SG denervation can still have significant sympathetic response via right SG regulation. PMID- 26961300 TI - Typical, atypical, and asymptomatic presentations of new-onset atrial fibrillation in the community: Characteristics and prognostic implications. AB - BACKGROUND: The prognostic significance of the clinical presentation of atrial fibrillation (AF) is poorly defined. OBJECTIVE: The purpose of this study was to determine the frequency, associations, and prognostic impact of different clinical presentations of new-onset AF. METHODS: One thousand patients with incident AF in Olmsted County, Minnesota, were randomly selected (2000-2010). Patients with AF that was complicated at presentation (heart failure [n = 71], thromboembolism [n = 24]), provoked (n = 346), or unable to determine symptoms (n = 83) were excluded. In the remaining patients, characteristics and prognosis associated with different types of symptoms were examined. RESULTS: Among 476 patients, 193 had typical (palpitations), 122 had atypical (other non-palpitation symptoms), and 161 had asymptomatic AF presentation. Patients with typical presentation had lower CHA2DS2-VASc scores (mean 2.3 +/- 2) compared to atypical and asymptomatic presentation (mean 3.2 +/- 1.8 and 3.3 +/- 1.9, respectively; P <.001). Fifty-nine cerebrovascular events and 149 deaths (n = 49 cardiovascular) were documented over median 5.6 and 6.0 years, respectively. Atypical and asymptomatic AF conferred higher risks of cerebrovascular events compared to typical AF after adjustment for CHA2DS2-VASc score and age (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.65-7.48, and HR 2.70, 95% CI 1.29-5.66, respectively), and associations remained statistically significant after further adjustments including comorbidities and warfarin use. Asymptomatic AF was associated with an increased risk of cardiovascular (HR 3.12, 95% CI 1.50-6.45) and all-cause mortality (HR 2.96, 95% CI 1.89-4.64) compared to typical AF after adjustment for CHA2DS2-VASc score and age. CONCLUSION: The type of clinical presentation may have important implications for the prognosis of new-onset AF in the community. PMID- 26961302 TI - Long-term efficacy of catheter ablation for paroxysmal atrial fibrillation in patients with Brugada syndrome and an implantable cardioverter-defibrillator to prevent inappropriate shock therapy. AB - BACKGROUND: In patients with an implantable cardioverter-defibrillator (ICD) and Brugada syndrome (BrS), the long-term efficacy of catheter ablation for preventing inappropriate shock therapy due to paroxysmal atrial fibrillation (PAF) has not been elucidated. OBJECTIVE: To evaluate the efficacy of atrial fibrillation (AF) ablation for PAF for prevention of inappropriate ICD therapy over a longer follow-up period. METHODS: We enrolled 76 men with BrS and an ICD, with a mean age of 46.2 +/- 16.5 years. Twenty-one patients had AF (19 had PAF, 1 had persistent AF, and 1 had longstanding persistent AF). Fourteen patients with PAF underwent pulmonary vein isolation (PVI) and received follow-up electrophysiological study (EPS) 6 months after the first PVI. If necessary, ablation was performed. RESULTS: Over a mean follow-up period of 3.3 +/- 1.4 years after the repeat session, 13 of the 14 patients (92.9%) had no recurrence of AF. Six patients with PAF without inappropriate ICD therapy before PVI had no recurrence of AF and no inappropriate therapy during follow-up. Among the 8 patients who had inappropriate therapy because of PAF before PVI, 1 patient who had recurrent AF underwent another ablation session. After this final session, there were no recurrences of AF and no inappropriate therapy (mean follow-up period 3.1+/- 1.2 years). CONCLUSION: Catheter ablation is effective in patients with BrS and an ICD, and prevents inappropriate ICD therapy owing to PAF; thus, catheter ablation is an appropriate first-line therapy for PAF among such patients. PMID- 26961301 TI - Small conductance calcium-activated potassium current and the mechanism of atrial arrhythmia in mice with dysfunctional melanocyte-like cells. AB - BACKGROUND: The melanin synthesis enzyme dopachrome tautomerase (Dct) regulates intracellular Ca(2+) in melanocytes. Homozygous Dct knockout (Dct(-/-)) adult mice are vulnerable to atrial arrhythmias (AA). OBJECTIVE: The purpose of this study was to determine whether apamin-sensitive small conductance Ca(2+) activated K(+) (SK) currents are upregulated in Dct(-/-) mice and contribute to AA. METHODS: Optical mapping was used to study the membrane potential of the right atrium in Langendorff perfused Dct(-/-) (n = 9) and Dct(+/-) (n = 9) mice. RESULTS: Apamin prolonged action potential duration (APD) by 18.8 ms (95% confidence interval [CI] 13.4-24.1 ms) in Dct(-/-) mice and by 11.5 ms (95% CI 5.4-17.6 ms) in Dct(+/-) mice at a pacing cycle length of 150 ms (P = .047). The pacing cycle length threshold to induce APD alternans was 48 ms (95% CI 34-62 ms) for Dct(-/-) mice and 21 ms (95% CI 12-29 ms) for Dct(+/-) mice (P = .002) at baseline, and it was 35 ms (95% CI 21-49 ms) for Dct(-/-) mice and 22 ms (95% CI 11-32 ms) for Dct(+/-) mice (P = .025) after apamin administration. Apamin prolonged post-burst pacing APD by 8.9 ms (95% CI 3.9-14.0 ms) in Dct(-/-) mice and by 1.5 ms (95% CI 0.7-2.3 ms) in Dct(+/-) mice (P = .005). Immunoblot and quantitative polymerase chain reaction analyses showed that protein and transcripts levels of SK1 and SK3 were increased in the right atrium of Dct(-/-) mice. AA inducibility (89% vs 11%; P = .003) and duration (281 seconds vs 66 seconds; P = .008) were greater in Dct(-/-) mice than in Dct(+/-) mice at baseline, but not different (22% vs 11%; P = 1.00) after apamin administration. Five of 8 (63%) induced atrial fibrillation episodes in Dct(-/-) mice had focal drivers. CONCLUSION: Apamin-sensitive SK current upregulation in Dct(-/-) mice plays an important role in the mechanism of AA. PMID- 26961303 TI - Bipolar left ventricular pacing is associated with significant reduction in heart failure or death in CRT-D patients with LBBB. AB - BACKGROUND: There are limited data on the significance of left ventricular (LV) lead pacing polarity to predict clinical outcomes. OBJECTIVES: We aimed to determine the association between the LV lead pacing polarity for heart failure (HF) or death and ventricular tachyarrhythmias (VTA) in patients enrolled in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy), receiving a cardiac resynchronization therapy device with implanted cardioverter-defibrillator (CRT-D). METHODS: We retrospectively analyzed LV pacing polarity. Patients with LV bipolar leads paced between LV ring and LV tip were identified as True Bipolar, while those with LV bipolar leads paced between LV tip or LV ring and right ventricular coil or unipolar leads were identified as Unipolar/Extended Bipolar. Kaplan-Meier survival analyses and multivariate Cox proportional hazards regression models were used. RESULTS: Of the 969 patients, 421 had True Bipolar pacing while the remainder (n = 548) had Unipolar/Extended Bipolar pacing. Among patients with left bundle branch block (LBBB), True Bipolar pacing was associated with lower cumulative incidence of death (P = .022) and HF/death (P = .046) compared to those with Unipolar/Extended Bipolar LV pacing. After adjustment for clinical covariates, bipolar LV pacing in LBBB patients was associated with 54% lower risk for death (HR: 0.46; 95% CI: 0.24-0.88; P = .020) and 32% lower risk for HF/death (HR: 0.68; 95% CI: 0.46 1.00; P = .048) compared to Unipolar/Extended Bipolar LV pacing, but not in those with non-LBBB. No association was seen with risk of ventricular tachyarrhythmia. CONCLUSION: True Bipolar LV pacing configuration is associated with a significantly lower risk of HF/death and all-cause mortality in CRT-D patients with LBBB. PMID- 26961304 TI - A new electrophysiologic observation in patients with idiopathic left ventricular tachycardia. AB - BACKGROUND: In patients with idiopathic left ventricular tachycardia (ILVT), the arrhythmogenic substrate is poorly understood. OBJECTIVE: The purpose of this study was to elucidate the ILVT characteristics and outcome of radiofrequency catheter ablation in patients with ILVT. METHODS: Twenty-four patients with ILVT and 15 patients with left accessory pathways (control) underwent high-density mapping of the left His-Purkinje system during sinus rhythm (SR) using 3 dimensional electroanatomic mapping. RESULTS: Fragmented antegrade Purkinje potential (FAP) was represented at the left ventricular septum slightly inferoposterior to the left posterior fascicle (LPF) in 23 patients with ILVT. In control subjects, no FAPs could be recorded at the same region, FAPs were identified at the proximal portion of the LPF (4 patients) and at the distal LPF (1 patient). The finding of any FAPs in ILVT patients was significantly higher than that in control patients (23/24 vs 5/15, P < .01). Radiofrequency ablation at the area of FAP resulted in successful ablation in 23 patients with ILVT. No ILVT recurred during follow-up of 16.3 +/- 7.2 months. CONCLUSION: In patients with ILVT, FAP located at the left ventricular septum slightly inferoposterior to the LPF is a novel finding using 3-dimensional electroanatomic mapping. The FAP may represent an arrhythmogenic substrate in ILVT and may be used for guiding successful ablation. PMID- 26961305 TI - Ecological Status of a Patagonian Mountain River: Usefulness of Environmental and Biotic Metrics for Rehabilitation Assessment. AB - This work evaluates the consequences of anthropogenic pressures at different sections of a Patagonian mountain river using a set of environmental and biological measures. A map of risk of soil erosion at a basin scale was also produced. The study was conducted at 12 sites along the Percy River system, where physicochemical parameters, riparian ecosystem quality, habitat condition, plants, and macroinvertebrates were investigated. While livestock and wood collection, the dominant activities at upper and mean basin sites resulted in an important loss of the forest cover still the riparian ecosystem remains in a relatively good status of conservation, as do the in-stream habitat conditions and physicochemical features. Besides, most indicators based on macroinvertebrates revealed that both upper and middle basin sections supported similar assemblages, richness, density, and most functional feeding group attributes. Instead, the lower urbanized basin showed increases in conductivity and nutrient values, poor quality in the riparian ecosystem, and habitat condition. According to the multivariate analysis, ammonia level, elevation, current velocity, and habitat conditions had explanatory power on benthos assemblages. Discharge, naturalness of the river channel, flood plain morphology, conservation status, and percent of urban areas were important moderators of plant composition. Finally, although the present land use in the basin would not produce a significant risk of soil erosion, unsustainable practices that promotes the substitution of the forest for shrubs would lead to severe consequences. Mitigation efforts should be directed to protect headwater forest, restore altered riparian ecosystem, and to control the incipient eutrophication process. PMID- 26961306 TI - Enhanced gray-white matter differentiation on non-enhanced CT using a frequency selective non-linear blending. AB - INTRODUCTION: The aim if this study is to find out if contrast between gray (GM) and white matter (WM) on non-enhanced brain CT (NECT) can be enhanced by using a frequency selective non-linear blending. METHODS: Thirty consecutive patients (40 % female; mean age 67.73 +/- 12.71 years), who underwent NECT of the brain, were retrospectively included in this study. Brain scan readings were performed by two radiologists independently, for NECT and subsequently the images were read using a new frequency selective non-linear blending algorithm (best contrast, BC). Optimal settings of BC for enhanced delineation of anatomical structures were set at an averaged center of 30 HU, averaged delta of 5 HU, and a slope of 5. For contrast-to-noise ratio calculation (CNR), gray and white matter attenuation values were measured for both NECT and BC in different anatomical structures. RESULTS: CNR increase in the gray matter was 5.91 +/- 2.45 for the cortical gray matter and 4.41 +/- 1.82 for the basal ganglia. The contrast ratio between cortical gray and white matter was 1.87 and 1.7 (basal ganglia/WM) for BC quantification vs. 1.43 (cortex/WM) and 1.33 (basal ganglia/WM) for standard NECT (both p < 0.0001). Improved CNR did not depend on the anatomical structures measured. CONCLUSION: Frequency selective non-linear blending allows better discrimination between WM and GM and therefore may enhance diagnostic accuracy of NECT. PMID- 26961307 TI - Neural substrates of lower extremity motor, balance, and gait function after supratentorial stroke using voxel-based lesion symptom mapping. AB - INTRODUCTION: Stroke impairs motor, balance, and gait function and influences activities of daily living. Understanding the relationship between brain lesions and deficits can help clinicians set goals during rehabilitation. We sought to elucidate the neural substrates of lower extremity motor, balance, and ambulation function using voxel-based lesion symptom mapping (VLSM) in supratentorial stroke patients. METHODS: We retrospectively screened patients who met the following criteria: first-ever stroke, supratentorial lesion, and available brain magnetic resonance imaging (MRI) data. MRIs of 133 stroke patients were selected for VLSM analysis. We generated statistical maps of lesions related to lower extremity motor (lower extremity Fugl-Meyer assessment, LEFM), balance (Berg Balance Scale, BBS), and gait (Functional Ambulation Category, FAC) using VLSM. RESULTS: VLSM revealed that lower LEFM scores were associated with damage to the bilateral basal ganglia, insula, internal capsule, and subgyral white matter adjacent to the corona radiata. The lesions were more widely distributed in the left than in the right hemisphere, representing motor and praxis function necessary for performing tasks. However, no associations between lesion maps and balance and gait function were established. CONCLUSION: Motor impairment of the lower extremities was associated with lesions in the basal ganglia, insula, internal capsule, and white matter adjacent to the corona radiata. However, VLSM revealed no specific lesion locations with regard to balance and gait function. This might be because balance and gait are complex skills that require spatial and temporal integration of sensory input and execution of movement patterns. For more accurate prediction, factors other than lesion location need to be investigated. PMID- 26961308 TI - C-terminal region of bacterial Ku controls DNA bridging, DNA threading and recruitment of DNA ligase D for double strand breaks repair. AB - Non-homologous end joining is a ligation process repairing DNA double strand breaks in eukaryotes and many prokaryotes. The ring structured eukaryotic Ku binds DNA ends and recruits other factors which can access DNA ends through the threading of Ku inward the DNA, making this protein a key ingredient for the scaffolding of the NHEJ machinery. However, this threading ability seems unevenly conserved among bacterial Ku. As bacterial Ku differ mainly by their C-terminus, we evaluate the role of this region in the loading and the threading abilities of Bacillus subtilis Ku and the stimulation of the DNA ligase LigD. We identify two distinct sub-regions: a ubiquitous minimal C-terminal region and a frequent basic C-terminal extension. We show that truncation of one or both of these sub-regions in Bacillus subtilis Ku impairs the stimulation of the LigD end joining activity in vitro. We further demonstrate that the minimal C-terminus is required for the Ku-LigD interaction, whereas the basic extension controls the threading and DNA bridging abilities of Ku. We propose that the Ku basic C-terminal extension increases the concentration of Ku near DNA ends, favoring the recruitment of LigD at the break, thanks to the minimal C-terminal sub-region. PMID- 26961309 TI - Endonuclease domain of non-LTR retrotransposons: loss-of-function mutants and modeling of the R2Bm endonuclease. AB - Non-LTR retrotransposons are an important class of mobile elements that insert into host DNA by target-primed reverse transcription (TPRT). Non-LTR retrotransposons must bind to their mRNA, recognize and cleave their target DNA, and perform TPRT at the site of DNA cleavage. As DNA binding and cleavage are such central parts of the integration reaction, a better understanding of the endonuclease encoded by non-LTR retrotransposons is needed. This paper explores the R2 endonuclease domain from Bombyx mori using in vitro studies and in silico modeling. Mutations in conserved sequences located across the putative PD-(D/E)XK endonuclease domain reduced DNA cleavage, DNA binding and TPRT. A mutation at the beginning of the first alpha-helix of the modeled endonuclease obliterated DNA cleavage and greatly reduced DNA binding. It also reduced TPRT when tested on pre cleaved DNA substrates. The catalytic K was located to a non-canonical position within the second alpha-helix. A mutation located after the fourth beta-strand reduced DNA binding and cleavage. The motifs that showed impaired activity form an extensive basic region. The R2 biochemical and structural data are compared and contrasted with that of two other well characterized PD-(D/E)XK endonucleases, restriction endonucleases and archaeal Holliday junction resolvases. PMID- 26961310 TI - E2F7 regulates transcription and maturation of multiple microRNAs to restrain cell proliferation. AB - E2F transcription factors (E2F1-8) are known to coordinately regulate the expression of a plethora of target genes, including those coding for microRNAs (miRNAs), to control cell cycle progression. Recent work has described the atypical E2F factor E2F7 as a transcriptional repressor of cell cycle-related protein-coding genes. However, the contribution of E2F7 to miRNA gene expression during the cell cycle has not been defined. We have performed a genome-wide RNA sequencing analysis to identify E2F7-regulated miRNAs and show that E2F7 plays as a major role in the negative regulation of a set of miRNAs that promote cellular proliferation. We provide mechanistic evidence for an interplay between E2F7 and the canonical E2F factors E2F1-3 in the regulation of multiple miRNAs. We show that miR-25, -26a, -27b, -92a and -7 expression is controlled at the transcriptional level by the antagonistic activity of E2F7 and E2F1-3. By contrast, let-7 miRNA expression is controlled indirectly through a novel E2F/c MYC/LIN28B axis, whereby E2F7 and E2F1-3 modulate c-MYC and LIN28B levels to impact let-7 miRNA processing and maturation. Taken together, our data uncover a new regulatory network involving transcriptional and post-transcriptional mechanisms controlled by E2F7 to restrain cell cycle progression through repression of proliferation-promoting miRNAs. PMID- 26961311 TI - Evolutionarily conserved autoregulation of alternative pre-mRNA splicing by ribosomal protein L10a. AB - Alternative splicing of pre-mRNAs can regulate expression of protein-coding genes by generating unproductive mRNAs rapidly degraded by nonsense-mediated mRNA decay (NMD). Many of the genes directly regulated by alternative splicing coupled with NMD (AS-NMD) are related to RNA metabolism, but the repertoire of genes regulated by AS-NMD in vivo is to be determined. Here, we analyzed transcriptome data of wild-type and NMD-defective mutant strains of the nematode worm Caenorhabditis elegans and demonstrate that eight of the 82 cytoplasmic ribosomal protein (rp) genes generate unproductively spliced mRNAs. Knockdown of any of the eight rp genes exerted a dynamic and compensatory effect on alternative splicing of its own transcript and inverse effects on that of the other rp genes. A large subunit protein L10a, termed RPL-1 in nematodes, directly and specifically binds to an evolutionarily conserved 39-nt stretch termed L10ARE between the two alternative 5' splice sites in its own pre-mRNA to switch the splice site choice. Furthermore, L10ARE-mediated splicing autoregulation of the L10a-coding gene is conserved in vertebrates. These results indicate that L10a is an evolutionarily conserved splicing regulator and that homeostasis of a subset of the rp genes are regulated at the level of pre-mRNA splicing in vivo. PMID- 26961313 TI - Anticancer Vitamin K3 Analogs: A Review. AB - Menadione (Vitamin K3) comprises of 1,4-naphthoquinone (NQ) moiety that can form redox isomers such as napthosemiquinone (NSQ) and catechol by accepting one or two electrons, respectively. The quinone redox cycling ability leads to the generation of "reactive oxygen species" (ROS) as well as arylation reactions, which are of biological relevance. This ability can be modulated with the help of suitable derivatization. A pharmacophore can be appended at suitable position of Vitamin K3 to have a synergistic or additive effect. In the present review, an attempt has been made to accrue such derivatives modified at 1 or 2 position and evaluated for their cytotoxicity activity on different series of human cancer cell lines such as HeLa, HL-60 and MCF- 7 etc. Production of reactive oxygen species (ROS) and mitochondrial dysfunction caused by Vitamin K3 derivatives leads to apoptosis and tumor inhibition. Recently, the CR-108 compound has shown to exhibit oxidative path together with non-oxidative phosphorylation of p38 MAP kinase in human breast cancer cells. Thus the chemical-biological interactions have been discussed which can be further extrapolated for the development of a potent anticancer drug. PMID- 26961312 TI - Fab(nimotuzumab)-HYNIC-99mTc: Antibody Fragmentation for Molecular Imaging Agents. AB - Finally, fast blood clearance nimotuzumab is a humanized monoclonal antibody that recognise, with high specific affinity, the epidermal growth factor receptor (EGF R) which play an important role in the growth process associated with many solid tumors. In this work, the whole antibody was digested with papain in order to generate a Fab fragment, derivatized with NHS-HYNIC-Tfa and radiolabel with technetium-99m (99mTc) as a potential agent of molecular imaging of cancer. Both, whole and fragment radiolabels were in-vivo and in-vitro characterized. Radiolabeling conditions with Tricine as coligand and quality controls were assessed to confirm the integrity of the labeled fragment. Biodistribution and imaging studies in normal and spontaneous adenocarcinoma mice were performed at different times to determine the in-vivo characteristics of the radiolabel fragment. Tumor localization was visualized by conventional gamma camera imaging studies, and the results were compared with the whole antibody. Also, an immunoreactivity assay was carried out for both. The results showed clearly the integrity of the nimotuzumab fragment and the affinity by the receptor was verified. Fab(nimotuzumab)-HYNIC was obtained with high purity and a simple strategy of radiolabeling was performed. Finally, a fast blood clearance was observed in the biodistribution studies increasing the tumor uptake of Fab(nimotuzumab)- HYNIC-99mTc over time, with tumor/muscle ratios of 3.81 +/- 0.50, 5.16 +/- 1.97 and 6.32 +/- 1.98 at 1 h, 4 h and 24 h post injection. Urinary excretion resulted in 32.89 +/- 3.91 %ID eliminated at 24 h. Scintigraphy images showed uptake in the tumor and the activity in non-target organs was consistent with the biodistribution data at the same time points. Hence, these preliminary results showed important further characteristic of Fab(nimotuzumab) HYNIC-99mTc as a molecular imaging agent of cancer. PMID- 26961314 TI - Evolving Role of Radiopharmaceuticals in Hepatocellular Carcinoma Treatment. AB - The global incidence of primary liver cancer has been increased during recent decades. Among the primary liver malignancies, hepatocellular carcinoma (HCC) is recognized as the most prevalent and aggressive. Although HCC has come to be regarded as a radioresponsive tumor during the last decade, it has also been noted that the ability to deliver destructive radioactive doses exclusively to HCC is limited with conventional external irradiation techniques. This review examines a number of radiotherapeutic techniques used to treat HCC, and the radiopharmaceuticals associated with those techniques. Selective internal radiotherapy (SIRT) is a powerful therapeutic technique developed during recent decades that is increasingly used in HCC treatment due to its superior ability to target and destroy cancer cells while sparing normal tissue. The radiopharmaceuticals used in SIRT are usually comprised of a simple ion and a complex or a carrier. Transarterial radioembolization (TARE) is a technique that is increasingly used in adjuvant or neoadjuvant therapy following the surgical treatment of HCC, as well as the treatment of unresectable or untransplantable HCC. The primary radiopharmaceuticals used in TARE include Iodine- 131-labeled Lipiodol and Yttrium-90 microspheres. Radioimmunotherapy (RAIT) is currently used as targeted procedure for adjuvant therapy and combination therapy of HCC. The primary radiopharmaceutical used in RAIT is 131I-metuximab. Interstitial brachytherapy has also been the subject of recent HCC treatment investigations. The primary radiopharmaceuticals used in interstitial brachytherapy are implanted iodine-125 seed strands. This review surveys the important milestones in the development and clinical implementation of the radiopharmaceuticals used in HCC therapy and critically examines new and emerging trends for the delivery of radiopharmaceuticals to HCC tissues. PMID- 26961316 TI - Cytotoxicity and Anti-proliferative Properties of Heterocyclic Compounds Derived from Progesterone. AB - The following study explored the cytotoxic effect on human cancer cells of a series of novel progesterone derivatives through the synthesis of heterocyclic compounds incorporating progesterone moiety. The reaction of progesterone (1) with cyanoacetanilide derivatives gave the condensation products 3a,b. Either of compound 3a or 3b reacted with elemental sulfur affording the thiophene derivatives 4a and 4b, respectively. In addition, progesterone (1) underwent some multi-component reactions with aromatic aldehydes and cyanomethylene reagents in triethylamine to give the pyran derivatives 10a-f. Carrying the same reactions but using ammonium acetate afforded the pyridine derivatives 11a-f. The anti tumor evaluations of the newly synthesized products were tested against six human cancer and normal cell lines. The results showed that nine compounds (3b, 7c, 10b, 10d, 10f, 11d, 13a, 13b and 14b) revealed optimal cytotoxic effect against cancer cell lines with IC50 ? 550 nM and their cytotoxicity's were higher than that of progesterone. Moreover, the toxicity of the most active compounds was measured against shrimp larvae. In addition, the anti-proliferative evaluations of these potent compounds were measured. PMID- 26961318 TI - Sirtuin Inhibitors: An Overview from Medicinal Chemistry Perspective. AB - The role of sirtuins in age-related diseases is an area of rapidly expanding investigation. Sirtuins are NAD+ -dependent class III histone deacetylases (HDACs) that share extensive homologies with the yeast HDAC Sir2. Class I and class II HDACs inhibitors have been identified as potential anticancer agents and are in clinical studies, but much less is known about class III HDAC inhibitors. However, inhibitors of sirtuins are currently being targeted as potential therapeutic agents for disease such as cancer, neurodegenerative disease and other disorders as sirtuins are discovered to regulate numerous downstream enzymes. Given the link between sirtuins and cancer, understanding the functionality of these enzymes may ultimately have significant impact in cancer prevention or cancer treatment. This review gives an updated overview regarding the regulation of sirtuin enzymes, their implications in cancer, various sirtuin inhibitor scaffolds and their insights in drug design. PMID- 26961315 TI - New 2-Imino-2H-Chromene-3(N-aryl)carboxamides as Potential Cytotoxic Agents. AB - Synthesis and structure activity relationships of four series of novel 2-imino-2H chromene-3(N-aryl) carboxamides (V-VIII) have been described by bioisosteric replacement of usually present ketone at 2nd position of coumarin with imine. Various substitutents are introduced on aryl and chromene ring of iminocoumarin to investigate the effect of lipophilicity and electronic properties of substituents on cytotoxic activity against four human cancer cell lines. Novel 2 imino-2H-chromene-3(N-aryl)carboxamides (V-VIII) were synthesized by the reaction of substituted 2- cyanoacetamides with different salicyaldehydes in the presence of sodium acetate in glacial acetic acid. Compound VIa showed potent activity against MCF-7 (IC50 = 8.5 MUM), PC-3 (IC50 = 35.0 MUM), A-549 (IC50 = 0.9 MUM) and Caco-2 (IC50 = 9.9 MUM) cell lines. The anticancer results revealed that most of the synthesized compounds showed equipotent activity with the standard 5 fluorouracil and docetaxel on Caco-2 and MCF-7 cell lines, respectively. PMID- 26961317 TI - alpha(N)-Heterocyclic Thiosemicarbazones: Iron Chelators that are Promising for Revival of Gallium in Cancer Chemotherapy. AB - The metal-based drugs have gained increasing attention in the fight against cancer. Ga(III) in the form of inorganic salts has demonstrated efficacy in the treatment of a number of malignancies in experimental animals and humans, and has therefore attracted considerable pharmaceutical interest. However, the poor hydrolytic stability of Ga(III) in physiological medium owing to its property of hard Lewis acid prevents its widespread use in systemic cancer chemotherapy. Complexation of suitable chelators capable of stabilising Ga(III) against hydrolysis affords an opportunity for overcoming this drawback. Thiosemicarbazone (TSC) derivatives, a class of well-studied iron chelators featuring softer donor sulfur, also were evaluated to possess antineoplastic activities in an arrary of tumour cell lines. The structural modifications can affect the activities of TSCs, and related structure-activity relationships (SAR) have been studied over these years. Combination of Ga(III) and TSCs that are both pharmaceutically active has proved to exert synergistic effects of each component in one compound in most cases, and may produce more potent Ga(III) drugs. In this review, the SAR of alpha(N)-heterocyclic thiosemicarbazone (HCT) analogues, a family of TSCs, were scrupulously surveyed, and the effect of Ga(III) complexation on their anticancer activity sparsely reported in literature was comparatively examined, in order to stimulate further advances in the field of gallium-based anticancer drugs. PMID- 26961319 TI - Modeling, control, and simulation of grid connected intelligent hybrid battery/photovoltaic system using new hybrid fuzzy-neural method. AB - Nowadays, photovoltaic (PV) generation is growing increasingly fast as a renewable energy source. Nevertheless, the drawback of the PV system is its dependence on weather conditions. Therefore, battery energy storage (BES) can be considered to assist for a stable and reliable output from PV generation system for loads and improve the dynamic performance of the whole generation system in grid connected mode. In this paper, a novel topology of intelligent hybrid generation systems with PV and BES in a DC-coupled structure is presented. Each photovoltaic cell has a specific point named maximum power point on its operational curve (i.e. current-voltage or power-voltage curve) in which it can generate maximum power. Irradiance and temperature changes affect these operational curves. Therefore, the nonlinear characteristic of maximum power point to environment has caused to development of different maximum power point tracking techniques. In order to capture the maximum power point (MPP), a hybrid fuzzy-neural maximum power point tracking (MPPT) method is applied in the PV system. Obtained results represent the effectiveness and superiority of the proposed method, and the average tracking efficiency of the hybrid fuzzy-neural is incremented by approximately two percentage points in comparison to the conventional methods. It has the advantages of robustness, fast response and good performance. A detailed mathematical model and a control approach of a three phase grid-connected intelligent hybrid system have been proposed using Matlab/Simulink. PMID- 26961320 TI - Observation and sliding mode observer for nonlinear fractional-order system with unknown input. AB - The main purpose of this paper is twofold. First, the observability and the left invertibility properties and the observable canonical form for nonlinear fractional-order systems are introduced. By using a transformation, we show that these properties can be deduced from an equivalent nonlinear integer-order system. Second, a step by step sliding mode observer for fault detection and estimation in nonlinear fractional-order systems is proposed. Starting with a chained fractional-order integrators form, a step by step first-order sliding mode observer is designed. The finite time convergence of the observer is established by using Lyapunov stability theory. A numerical example is given to illustrate the performance of the proposed approach. PMID- 26961321 TI - When does chronic migraine strike? A clinical comparison of migraine according to the headache days suffered per month. AB - Introduction According to the IHCD-3beta classification, chronic migraine (CM) is headache occurring on 15 or more days/month. Episodic migraine (EM) can be divided into low frequency (LFEM) and high frequency (HFEM) depending on the headache days suffered per month. Methods We performed a clinical comparison of migraine characteristics according to monthly headache days suffered. Patients were divided into three groups: LFEM (1-9 headache days/month), HFEM (10-14 headache days/month) and CM (>=15 headache days/month). Results The analysis included 1109 patients. Previously reported differences between EM and CM were replicated. However, there were three times more clinical differences between LFEM and HFEM than between HFEM and CM (15 vs. 6). A new model that takes 10 headache days as a cut-off value for CM would have a minimally higher predictive capacity (72.8%) and no statistical differences (71.8%) when comparing it to the current classification. Conclusions HFEM patients have few clinical differences compared with CM patients. This includes the poor outcomes regarding headache related disability and impact on daily life. According to these findings, neurologists and headache specialists should consider that the emotional and functional impact in HFEM patients could be as disabling as in those with CM. PMID- 26961322 TI - Anti-melanoma and UV-B protective effect of microbial pigment produced by marine Pseudomonas aeruginosa GS-33. AB - Bioactivity of a microbial pigment, extracted from fermented broth of culture marine Pseudomonas aeruginosa was screened for anticancer activity against human skin melanoma cell line SK-MEL-2. Upon characterisation, the pigment was confirmed as Phenazine-1-carboxylic acid (PCA). The PCA was found effective against SK-MEL-2 cell line at low concentration (GI50 value <10 MUg/mL). Reduced cell density and cell shrinkage with typical morphological changes such as rounding of cells with loss/breaking of cell membrane were seen in SK-MEL-2 cells treated with PCA and Adriamycin. The pigment exhibited UV-B protecting activity as calculated by in vitro spectrophotometric assay and potentiated sun protection factor of commercial sunscreen lotion. Moreover, the pigment was non-toxic up to concentration of 100 ppm as assessed erythrocyte haemolysis assay. These results suggest that microbial pigment PCA could be effective and promising in the treatment as well as prevention of melanoma skin cancers. PMID- 26961323 TI - Pyrosequencing as a fast and reliable tool to determine clade affiliation for equine Influenza A virus. AB - The objective of our study was to determine the clade affiliation of 116 contemporary equine Influenza A virus (EIV) isolates using pyrosequencing. The EIV isolates originated from horses with clinical signs of equine influenza and laboratory confirmation of EIV by real-time quantitative PCR (qPCR) in nasal secretions. Clade affiliation was performed on the basis of a single nucleotide polymorphism at 2 positions of the hemagglutinin 1 gene. Pyrosequencing was able to clearly classify EIV Florida sublineage prototype A/equine/Ohio/1/2003 and prototype A/equine/Richmond/1/2007 as clade 1 and 2, respectively. Out of the 116 EIV qPCR-positive samples, 113 (97.4%) were classified as belonging to clade 1 Florida sublineage, whereas 3 (2.6%) were classified as clade 2. All clade 1 EIV strains were detected in domestic horses, whereas the 3 clade 2 EIV strains originated from horses recently imported to the United States. Although clade 1 EIV strains are endemic in the United States, international transportation of horses represents a real risk in introducing clade 2 EIV strains into North America. PMID- 26961324 TI - Validation of an enzyme-linked immunosorbent assay for measurement of feline haptoglobin. AB - Haptoglobin is a positive moderate acute phase protein (APP) in cats. Measurement of haptoglobin can be used in the diagnosis, prognosis, and monitoring of systemic inflammatory disease, especially by creating profiles with major APPs. The aim of our study was to validate a sandwich enzyme-linked immunosorbent assay (ELISA) for measurement of feline haptoglobin. The validation included an assessment of precision, accuracy, detection limit, method comparison with a spectrophotometric assay, and evaluation of the overlap performance. The concentration of haptoglobin was measured in serum from 27 healthy and 23 sick cats. The coefficients of variation were 2.5-4.7% for intra-assay variability and 7.1-11.6% for interassay variability. The ratio of observed to expected dilutional parallelism of 4 serum samples was 108.1-118.4%. The ratio of observed to expected spike recovery of 4 serum samples was 90.8-94.0%. The lower detection limit was 0.19 g/L. Method comparison revealed a positive correlation (rs = 0.949, P < 0.0001) and a proportional bias between the methods of -38.9%. Agreement between the methods was not clinically acceptable. Overlap performance of the ELISA was deemed satisfactory. The sandwich ELISA measures feline haptoglobin with an analytical and overlap performance acceptable for clinical purposes. Given the observed bias, the ELISA cannot be used interchangeably with the spectrophotometric assay. PMID- 26961325 TI - Megaloblastic anemia presenting with skin hyperpigmentation. PMID- 26961326 TI - The Priority and Challenge of High-Power Performance of Low-Platinum Proton Exchange Membrane Fuel Cells. AB - Substantial progress has been made in reducing proton-exchange membrane fuel cell (PEMFC) cathode platinum loadings from 0.4-0.8 mgPt/cm(2) to about 0.1 mgPt/cm(2). However, at this level of cathode Pt loading, large performance loss is observed at high-current density (>1 A/cm(2)), preventing a reduction in the overall stack cost. This next developmental step is being limited by the presence of a resistance term exhibited at these lower Pt loadings and apparently due to a phenomenon at or near the catalyst surface. This issue can be addressed through the design of catalysts with high and stable Pt dispersion as well as through development and implementation of ionomers designed to interact with Pt in a way that does not constrain oxygen reduction reaction rates. Extrapolating from progress made in past decades, we are optimistic that the concerted efforts of materials and electrode designers can resolve this issue, thus enabling a large step toward fuel cell vehicles that are affordable for the mass market. PMID- 26961327 TI - Tenascin C affects mineralization of SaOS2 osteoblast-like cells through matrix vesicles. AB - Tenascin C (TNC) is an extracellular matrix glycoprotein involved in osteogenesis and bone mineralization. In a previous study, we identified TNC protein located in the matrix vesicles (MVs) of osteoblasts. MVs are determinant in the mineralization formation. Therefore, we hypothesize whether TNC can modulate osteoblast mineralization via MVs. In this study, we demonstrated that the expression level of TNC was increased with osteoblast differentiation of osteoblast-like SaOS2 cells, and down-regulation of TNC expression by siRNA could significantly inhibit SaOS2 differentiation toward osteoblasts and mineralization as evidenced by decreases in ALP activity, mineralized nodule formation, calcium deposition, and down-regulation of osteogenic marker genes ALP, and COL1A1. Furthermore, we validated that TNC located in the MVs of mineralized SaOS2 cells, and that down-regulation of TNC could decrease MVs mineralization ability in vitro, and the decrease of MVs mineralization ability was not associated with annexins. In conclusion, in this study, we extended the role of TNC during osteogenesis previous progresses, and that supported TNC as an important functional MVs component in modulating osteoblast mineralization. PMID- 26961328 TI - Evaluation of anti-diabetic drugs by using silkworm, Bombyx mori. AB - Since diabetes patients are increasing in the world, establishment of a novel method for development of anti-diabetic drugs is desired. In this review, we describe recent results of our studies regarding diabetic model using silkworms for evaluation of anti-diabetic drugs for patients of both type I and type II diabetes. The use of the evaluation systems using silkworms is expected to contribute to reduction in cost and in the number of mammals sacrificed for screening of anti-diabetic drugs. PMID- 26961329 TI - Rhodium-Catalyzed Stitching Reaction: Convergent Synthesis of Quinoidal Fused Oligosiloles. AB - Quinoidal fused oligosiloles, a new family of silicon-bridged pi-conjugated compounds, have been synthesized for the first time based on a new synthetic strategy, a stitching reaction. Multiple carbon-carbon bonds can be formed consecutively between two oligo(silylene-ethynylene)s under rhodium catalysis in a stitching manner, and up to five siloles have been fused in a quinoidal form. Physical properties of these oligosiloles have also been investigated to find a unique trend in their LUMO levels, which become higher with longer pi conjugation. PMID- 26961330 TI - Comparison of Adhesive Resistance to Chewing Gum among Denture Base Acrylic Resin, Cobalt-Chromium Alloy, and Zirconia. AB - The purpose of this study was to compare the adhesiveness of chewing gum to acrylic resin, cobalt-chromium alloy, and zirconia. Test specimens were fabricated using acrylic resin (resin), cobalt-chromium alloy (Co-Cr), and Ceria stabilized tetragonal zirconia polycrystal-based nanostructured zirconia/alumina composite (zirconia). Specimens of each material were attached to the upper and lower terminals of a digital force gauge. The operator masticated chewing gum, wiped off any saliva, and placed the gum on the lower specimen. The gum was compressed to a thickness of 1 mm between the upper and lower specimens. Thereafter, traction was applied to the upper specimen at a cross-head speed of 100 mm/min under 3 different conditions (dry, wet with distilled water, and wet with artificial saliva) to determine the maximum adhesive strength of the chewing gum. The statistical analysis was performed using the Bonferroni test after a one way analysis of variance (alpha=0.05). Under dry conditions, adhesive force was 14.8+/-6.8 N for resin, 14.0+/-4.8 N for Co-Cr, and 4.3+/-2.3 N for zirconia. Significant differences were noted between resin and zirconia, and between Co-Cr and zirconia. When distilled water was applied to the specimen surface, the adhesive strength was 16.8+/-1.7 N for resin, 8.3+/-2.1 N for Co-Cr, and 2.7+/ 0.8 N for zirconia. Significant differences were noted between resin and Co-Cr, resin and zirconia, and Co-Cr and zirconia. When artificial saliva was applied to the specimen surface, the adhesive force was 18.5+/-2.8 N for resin, 5.3+/-0.8 N for Co-Cr, and 3.0+/-1.7 N for zirconia. Significant differences were noted between resin and Co-Cr, and resin and zirconia. Chewing gum adhered less strongly to zirconia than to acrylic resin or cobalt-chromium alloy. PMID- 26961331 TI - Effect of Cuff Pressure Elevation on Internal Diameter of Tracheal Tube in Simulated Trachea. AB - Application of nitrous oxide during anesthesia causes an increase in tracheal tube cuff pressure over time. The purpose of this study was to investigate the effect of an increase in cuff pressure on 3 types of tube (the Portex, Mallinckrodt, and Parker) commonly used for nasotracheal intubation. A cylindrical vessel was used to simulate a trachea. Cuff pressure was set at 0 cmH2O (R0) or 20 cmH2O (R20) at room temperature, or at 20 cmH2O (H20), 40 cmH2O (H40), 60 cmH2O (H60), or 80 cmH2O (H80) in 38 degrees C hot water and pressure applied for 30 min. The value obtained at R0 was used as a reference (100%) and the rate of change under each condition determined. No change was observed at R20 in any of the 3 groups. In 38 degrees C hot water, internal diameter in the Portex group decreased by 5.4% at H20 and 7.3% at H40, while that in the Mallinckrodt group decreased by 6% at H40. No significant change was observed in internal diameter in the Parker group, even when cuff pressure was increased. The internal diameter in the Portex group was the smallest at all cuff pressures in hot water. When the nasotracheal intubation tubes selected were placed in a simulated trachea and cuff pressure increased, internal diameter in the Portex and Mallinckrodt groups decreased. PMID- 26961332 TI - Tooth Loss in Problem-oriented, Irregular, and Regular Attenders at Dental Offices. AB - The aim of this retrospective study was to compare number of teeth lost among regular attenders (RAs), irregular attenders (IRAs), and problem-oriented attenders (POAs) at dental offices over a 10-yr observation period. Information on tooth loss was obtained from general practitioners. Patients were divided into 3 groups based on appointment adherence. A total of 1,886 teeth were lost in 1,400 patients. The mean number of teeth lost in men was 2.2+/-2.6 per patient over 10 yr in POAs, 1.2+/-1.7 in IRAs, and 1.5+/-1.5 in RAs. This number was significantly lower in IRAs (p = 0.011) or RAs (p=0.012) than in POAs. When the dependent variable was defined as "a patient with at least 2 or more extracted teeth", the independent variables showed the following correlations with tooth loss: IRAs (OR: 0.54; 95%CI: 0.35-0.84), RAs (OR: 0.65; 95%CI: 0.47-0.89), man (OR: 1.43; 95%CI: 1.11-1.83), hypertension (OR: 1.38; 95%CI: 1.04-1.85), 20-25 present teeth (OR: 2.41; 95%CI: 1.81-3.22), and 1-19 present teeth (OR: 3.75; 95%CI: 2.73-5.16). The risk of tooth loss showed a 0.65-fold increase in RAs undergoing maintenance compared with POAs. Motivating patients to visit the dentist more regularly and undergo maintenance is important. The present results may be of use to dental professionals in providing patients with detailed information on potential tooth loss and associated risk factors with the aim of achieving such a change in behavior. PMID- 26961333 TI - Application of 17% EDTA Enhances Diffusion of (45)Ca-labeled OH(-) and Ca(2+) in Primary Tooth Root Canal. AB - Proper cleaning of the root canal is key to the success of endodontic treatment as it allows more effective diffusion of medication throughout the dentinal tubules. The aim of this in vitro study was to investigate the efficacy of 17% ethylenediaminetetraacetic acid (EDTA) in enhancing diffusion of hydroxyl (OH(-)) and calcium ions (Ca(2+)) throughout the root canal in primary teeth. The canals of 25 primary tooth roots were cleaned with endodontic files and 1% sodium hypochlorite. Three groups (G) were then established: GI, in which final irrigation was performed with 1% sodium hypochlorite; GII, in which 17% EDTA was used; and GIII, in which no irrigation was performed. The roots canals in GI and GII were filled with a calcium hydroxide-based paste labeled with the radioisotope calcium-45. Diffusion of OH(-) was detected with pH strips and Ca(2+) analyzed by measuring radioactivity in counts per min. Group II differed statistically from the other groups in diffusion of OH(-) at 24 hr (p<0.05), but no significant difference among groups was found at the day 7 evaluation; GII also differed statistically from the other groups in diffusion of Ca(2+) at 24 hr (p<0.05). These results suggest that application of 17% EDTA in primary tooth enhances diffusion of OH(-) and Ca(2+). PMID- 26961334 TI - Post-treatment Stability in Angle Class III Cases. AB - The purpose of this study was to compare post-treatment stability in Angle Class III cases grouped by treatment modality into extraction, non-extraction, or surgical. Twenty-seven Angle Class III patients (9 men, 18 women) were selected from among the records of qualified retention cases treated at the Department of Orthodontics, Tokyo Dental College. The patients were divided into the following groups: Group 1, extraction (n=10); Group 2, non-extraction (n=9); and Group 3, surgery (n=8). Lateral cephalograms, panoramic X-rays, and study casts were obtained at baseline (T0), after active treatment (T1), and after retention (T2). The ABO Model Grading System (ABO) and Gottlieb's Grading Analysis (GGA) were used as indices of occlusion, and the scores at each stage and differences in scores at T1 and T2 (|T1-T2|), defined as post-retention stability, recorded. Little's Irregularity Index (IRI) from the study casts and the ANB from lateral cephalograms at T0, T1, and T2 were also recorded to assess post-treatment stability from a different perspective. The Kruskal-Wallis test was performed for statistical comparisons. Mean ranking according to the ABO and Kruskal-Wallis test at T1, T2, and |T1-T2| was lowest in Group 1 and highest in Group 3, and the mean amount of change in the ABO score after active treatment was also the same. This suggests that post-treatment stability is highest in non-extraction cases and lowest in surgical cases. This result correlated with change in the ANB from T0 to T1. This indicates that amount of change in the ANB affects post-treatment stability and that relapse will tend to be greater in surgical cases. However, the amount of change in IRI after active treatment was highest in Group 2 and lowest in Group 3, suggesting that relapse of the lower incisors is greatest in non-extraction cases. PMID- 26961335 TI - Endodontic Management of Maxillary First Molar with Five Root Canals, Including Two Distobuccal Root Canals: A Case Report. AB - Multiple canals in the root are part of the normal morphology of the tooth. A canal may sometimes be overlooked, however, and this may lead to failure of treatment. The first step in successful endodontic treatment, therefore, is gaining access to the pulp chamber and locating all the canals. In order to achieve this goal, practitioners need to be familiar with all possible variations in root canal morphology, and should thoroughly explore roots to ensure that all canals are identified, debrided, and obturated. Here, we report the diagnosis, treatment planning, and endodontic management of a maxillary first molar with five root canals, including two distobuccal root canals, in a 22-year-old woman. PMID- 26961336 TI - Prenatal Counseling on Prenatal Diagnosis of Cleft Lip and/or Cleft Palate at Tokyo Dental College Ichikawa General Hospital. AB - Remarkable technological advances have been made in the field of medicine in recent years, one result of which is that a prenatal diagnosis of cleft lip and/or cleft palate (CL/P) is now possible. In this situation, it is extremely important to provide the parents with mental care from the moment they are informed. Here, we describe cases of CL/P treated at our hospital and how such a diagnosis and prenatal counseling are handled. A survey was carried out on 4 cases seen at our department between April 2013 and March 2014. Patients are referred to our department from local or our own obstetrics clinics on a prenatal diagnosis of CL/P based on findings from ultrasonography. If the case is a referral from outside, the patient will first be seen at our own obstetrics department. Our department may then be subsequently requested to provide the parents with prenatal counseling. Effort is made to reassure the parents that postnatal support will be provided, right from the start. Next, the multidisciplinary nature of the treatment process is explained. However, only the essential outline is given at first so as to avoid inducing unnecessary anxiety. A response is also given to any questions the parents may have. Our experience of giving such care leads us to believe that improvements are required in the way that explanations and assistance are provided. The number of cases in which prenatal counseling is required is expected to increase in future. PMID- 26961338 TI - End-Group-Functionalized Poly(alpha-olefinates) as Non-Polar Building Blocks: Self-Assembly of Sugar-Polyolefin Hybrid Conjugates. AB - Living coordinative chain-transfer polymerization of alpha-olefins, followed by chemical functionalization of a Zn(polymeryl)2 intermediate, provides entry to end-group functionalized poly(alpha-olefinates) (x-PAOs) that can serve as a new class of non-polar building block with tailorable occupied volumes. Application of these x-PAOs for the synthesis and self-assembly of sugar-polyolefin hybrid conjugates demonstrate the ability to manipulate the morphology of the ultra-thin film nanostructure through variation in occupied volume of the x-PAO domain. PMID- 26961337 TI - It is important that they care - older persons' experiences of telephone advice nursing. AB - AIMS AND OBJECTIVES: The aim of the study was to explore older persons' experiences of telephone advice nursing at primary healthcare centres. BACKGROUND: Telephone advice nursing is expanding worldwide, and the older population is increasing. Little is known about older persons' experiences of telephone advice nursing provided by primary healthcare. DESIGN: This study has a descriptive design with a qualitative inductive approach. METHODS: Data were collected via interviews with a purposive sample of 10 older persons in 2014. The data were analysed using qualitative content analysis. RESULTS: The older persons' experiences were described in two themes: the patient-friendly aspects of telephone advice nursing and the patient-unfriendly aspects of telephone advice nursing. The themes can be understood as two sides of the same coin; the differences point to both the advantages and disadvantages of the service and are further illuminated through seven subthemes. CONCLUSIONS: This study contributes to increased awareness of the advantages and disadvantages of the telephone advice nursing system as experienced by older persons. To be the focus of attention during calls was highlighted as important; and clear communication was deemed crucial. When the communication between the nurse and the older persons was perceived as good and the perspective of the caller was the focus, an experience of safety and satisfaction was described. Older persons had great confidence in the telephone nurses' competence and perceived their ability to access the service as mostly good, even if it was sometimes difficult to use the service. RELEVANCE TO CLINICAL PRACTICE: The communicative competence of telephone nurses is essential when providing telephone advice nursing to older persons. In addition, a person-centred approach is important to provide optimal care in telephone advice nursing. PMID- 26961339 TI - Insulin degludec: The new standard long acting insulin analogue for people with type 1 diabetes? [Letter to the Editor]. PMID- 26961340 TI - A simple and effective method to apply TachoSil(r) Tissue Sealing sheet using Esmarch's bandage. AB - We report a novel hemostatic method for using hemostatic patches impregnated with human fibrinogen and thrombin (TachoSil(r)) together with Esmarch's bandage. The combined use of TachoSil(r) with Esmarch's bandage is easy and inexpensive. Further, it would ensure sustained and appropriate pressure on the bleeding site, while providing further adhesive strength to TachoSil(r) at the site. PMID- 26961341 TI - Surgical treatment for elderly patients with secondary spontaneous pneumothorax. AB - OBJECTIVES: Our objective was to evaluate the validity of surgery for secondary spontaneous pneumothorax (SSP) by comparison with other treatments or with perioperative results for primary spontaneous pneumothorax (PSP). METHODS: Between January 2009 and March 2015, 144 patients with SSP, aged 60 years or over, were treated in our institution. We reviewed the patients' characteristics, perioperative results, and relapse rate. Treatment to arrest air-leakage included surgery (n = 79), drainage only (n = 30), and pleurodesis (n = 35), and the pneumothorax relapse rate or mortality before discharge was compared for each. Additionally, we compared the perioperative results or relapse rate between SSP (n = 70) and PSP (n = 70) in patients who underwent 3-port thoracoscopic surgery. RESULTS: There was a significant difference in the relapse rate between the surgery and non-surgery groups (5.3 vs. 27.4 %, p = 0.0006). However, no significant difference in mortality before discharge was determined (p = 0.66). Significant differences were identified between the SSP and PSP groups for operation time, duration of chest drainage, and the length of postoperative hospitalization, and the postoperative morbidity were greater in the SSP group (p < 0.0001 for all). However, there was no significant difference in postoperative 30-day mortality or the relapse rate (p = 0.5, p = 0.68, respectively). CONCLUSIONS: Surgical treatment under general anesthesia for SSP is effective for arresting persistent air leaks or avoiding pneumothorax relapse, compared with drainage or pleurodesis, and is feasible if the appropriate perioperative management is performed. PMID- 26961342 TI - Continuity of cannabis use and violent offending over the life course. AB - BACKGROUND: Although the association between cannabis use and violence has been reported in the literature, the precise nature of this relationship, especially the directionality of the association, is unclear. METHOD: Young males from the Cambridge Study of Delinquent Development (n = 411) were followed up between the ages of 8 and 56 years to prospectively investigate the association between cannabis use and violence. A multi-wave (eight assessments, T1-T8) follow-up design was employed that allowed temporal sequencing of the variables of interest and the analysis of violent outcome measures obtained from two sources: (i) criminal records (violent conviction); and (ii) self-reports. A combination of analytic approaches allowing inferences as to the directionality of associations was employed, including multivariate logistic regression analysis, fixed-effects analysis and cross-lagged modelling. RESULTS: Multivariable logistic regression revealed that compared with never-users, continued exposure to cannabis (use at age 18, 32 and 48 years) was associated with a higher risk of subsequent violent behaviour, as indexed by convictions [odds ratio (OR) 7.1, 95% confidence interval (CI) 2.19-23.59] or self-reports (OR 8.9, 95% CI 2.37-46.21). This effect persisted after controlling for other putative risk factors for violence. In predicting violence, fixed-effects analysis and cross-lagged modelling further indicated that this effect could not be explained by other unobserved time invariant factors. Furthermore, these analyses uncovered a bi-directional relationship between cannabis use and violence. CONCLUSIONS: Together, these results provide strong indication that cannabis use predicts subsequent violent offending, suggesting a possible causal effect, and provide empirical evidence that may have implications for public policy. PMID- 26961343 TI - 'Restoring the person's life': a qualitative study to inform development of care for people with severe mental disorders in rural Ethiopia. AB - AIMS: In low-income countries, care for people with severe mental disorders (SMDs) who manage to access treatment is usually emergency-based, intermittent or narrowly biomedical. The aim of this study was to inform development of a scalable district-level mental health care plan to meet the long-term care needs of people with SMD in rural Ethiopia. METHODS: The present study was carried out as formative work for the Programme for Improving Mental health CarE which seeks to develop, implement and evaluate a district level model of integrating mental health care into primary care. Six focus group discussions and 25 in-depth interviews were conducted with service planners, primary care providers, traditional and religious healers, mental health service users, caregivers and community representatives. Framework analysis was used, with findings mapped onto the domains of the Innovative Care for Chronic Conditions (ICCC) framework. RESULTS: Three main themes were identified. (1) Focused on 'Restoring the person's life', including the need for interventions to address basic needs for food, shelter and livelihoods, as well as spiritual recovery and reintegration into society. All respondents considered this to be important, but service users gave particular emphasis to this aspect of care. (2) Engaging with families, addressed the essential role of families, their need for practical and emotional support, and the importance of equipping families to provide a therapeutic environment. (3) Delivering collaborative, long-term care, focused on enhancing accessibility to biomedical mental health care, utilising community-based health workers and volunteers as an untapped resource to support adherence and engagement with services, learning from experience of service models for chronic communicable diseases (HIV and tuberculosis) and integrating the role of traditional and religious healers alongside biomedical care. Biomedical approaches were more strongly endorsed by health workers, with traditional healers, religious leaders and service users more inclined to see medication as but one component of care. The salience of poverty to service planning was cross cutting. CONCLUSIONS: Stakeholders prioritised interventions to meet basic needs for survival and endorsed a multi-faceted approach to promoting recovery from SMD, including social recovery. However, sole reliance on this over-stretched community to mobilise the necessary resources may not be feasible. An adapted form of the ICCC framework appeared highly applicable to planning an acceptable, feasible and sustainable model of care. PMID- 26961344 TI - Perioperative spleen embolization as a useful tool in laparoscopic splenectomy for simple and massive splenomegaly in children: a prospective study. AB - OBJECTIVE: The purpose of this prospective study is to evaluate the efficiency of perioperative spleen embolization prior to laparoscopic splenectomy indicated for hypersplenism. METHODS: We conducted a prospective study exploring a technique combining ultra-selective perioperative embolization and splenectomy. Between January 2008 and March 2013, 16 splenectomies were performed in children suffering from hypersplenism due to varying hematologic diseases. Spleen embolization was performed by an interventional radiologist in the operating room (OR) just before splenectomy and during the same general anesthesia. Ages varied from 3 to 17 years. Spleen volume was measured by preoperative ultrasound. One patient underwent a laparotomy because of suspected adhesions due to previous surgery. All other operations were performed laparoscopically. RESULTS: One complication arose from embolization: a perforation of the splenic artery. After immediately placing a platinum coil proximal to the perforation, the splenectomy was carried out as usual. Fourteen children (87.5 %) had splenomegaly, of which eight (50 %) had massive splenomegaly. There were no deaths, no conversions to laparotomy, no reoperations and none of these patients had to be transfused. CONCLUSIONS: Perioperative spleen embolization performed in the OR by an interventional radiologist makes laparoscopic splenectomy a safer procedure. We propose a preoperative method for spleen measurement that is adapted to children: simple and massive splenomegaly is defined through patient body weight and a preoperative ultrasound. We conclude that spleen size is no more a limiting factor for laparoscopic splenectomy in children. PMID- 26961345 TI - Evaluation of the HystSimTM-virtual reality trainer: an essential additional tool to train hysteroscopic skills outside the operation theater. AB - BACKGROUND: Minimally invasive surgery is a major pillar of gynecological surgery. However, there are very few training opportunities outside the operation theater (OR) due to the cost and equipment requirements of organ simulators, virtual reality trainers (VRT) are promising tools to fill this gap. METHODS: Experienced and inexperienced participants of a minimally invasive surgery course followed the standardized HystSimTM-VRT training program. RESULTS: Performance of 39 Participants (15 inexperienced and 24 experienced) was evaluated in the standardized hysteroscopic program HystSimTM. Tasks included three rounds of both a polyp and a myoma resection. Primary measurements were improvement in resection time, cumulative resection path length, and distention media use. CONCLUSION: The HystSimTM-VRT is an effective tool to improve the psychomotor skills needed in hysteroscopic surgery for experienced and inexperienced surgeons prior to OR exposure. Additional organ models training is advisable for hysteroscopic haptic skills. PMID- 26961346 TI - The Nephrologist's Tumor: Basic Biology and Management of Renal Cell Carcinoma. AB - Kidney cancer, or renal cell carcinoma (RCC), is a disease of increasing incidence that is commonly seen in the general practice of nephrology. However, RCC is under-recognized by the nephrology community, such that its presence in curricula and research by this group is lacking. In the most common form of RCC, clear cell renal cell carcinoma (ccRCC), inactivation of the von Hippel-Lindau tumor suppressor is nearly universal; thus, the biology of ccRCC is characterized by activation of hypoxia-relevant pathways that lead to the associated paraneoplastic syndromes. Therefore, RCC is labeled the internist's tumor. In light of this characterization and multiple other metabolic abnormalities recently associated with ccRCC, it can now be viewed as a metabolic disease. In this review, we discuss the basic biology, pathology, and approaches for treatment of RCC. It is important to distinguish between kidney confinement and distant spread of RCC, because this difference affects diagnostic and therapeutic approaches and patient survival, and it is important to recognize the key interplay between RCC, RCC therapy, and CKD. Better understanding of all aspects of this disease will lead to optimal patient care and more recognition of an increasingly prevalent nephrologic disease, which we now appropriately label the nephrologist's tumor. PMID- 26961348 TI - Predicting Individual Renal Allograft Outcomes Using Risk Models with 1-Year Surveillance Biopsy and Alloantibody Data. AB - The ability to predict outcomes for individual patients would be a significant advance for not only counseling, but also identifying those for whom interventions may be needed. The goals of this study were to validate an existing risk prediction score that incorporates easily obtainable clinical factors and determine if histologic findings at 1-year surveillance biopsy and/or serum donor specific alloantibody status could improve predictability of graft loss by 5 years. We retrospectively studied 1465 adults who received a solitary kidney transplant between January of 1999 and December of 2008 and had sufficiently detailed 5-year follow-up data for modeling. In this cohort, the Birmingham risk model (incorporating recipient factors at 1 year, including age, sex, ethnicity, renal function, proteinuria, and prior acute rejection) predicted death-censored and overall graft survival (c statistics =0.84 and 0.78, respectively). The presence of glomerulitis or chronic interstitial fibrosis (g and ci scores by Banff, respectively) on 1-year biopsy specimens independently correlated with graft loss by 5 years. Adding these variables to the model for death-censored graft loss increased predictability (c statistic =0.90), improved calibration (ability to stratify risk from high to low), and reclassified risk of failure in 29% of patients. Adding the presence of donor-specific alloantibody at 1 year did not improve predictability or reclassification but did improve calibration marginally. We conclude that, at 1 year after kidney transplant, a risk model of graft survival that incorporates clinical factors and histologic findings at surveillance biopsy is highly predictive of individual risk and well calibrated. PMID- 26961352 TI - Coordination polymers of Fe(iii) and Al(iii) ions with TCA ligand: distinctive fluorescence, CO2 uptake, redox-activity and oxygen evolution reaction. AB - Fe and Al belong to different groups in the periodic table, one from the p-block and the other from the d-block. In spite of their different groups, they have the similarity of exhibiting a stable 3+ oxidation state. Here we have prepared Fe(iii) and Al(iii) based coordination polymers in the form of metal-organic gels with the 4,4',4''-tricarboxyltriphenylamine (TCA) ligand, namely Fe-TCA and Al TCA, and evaluated some important physicochemical properties. Specifically, the electrical conductivity, redox-activity, porosity, and electrocatalytic activity (oxygen evolution reaction) of the Fe-TCA system were noted to be remarkably higher than those of the Al-TCA system. As for the photophysical properties, almost complete quenching of the fluorescence originating from TCA was observed in case of the Fe-TCA system, whereas for the Al-TCA system a significant retention of fluorescence with red-shifted emission was observed. Quantum mechanical calculations based on density functional theory (DFT) were performed to unravel the origin of such discriminative behaviour of these coordination polymer systems. PMID- 26961347 TI - YAP/TAZ Are Mechanoregulators of TGF-beta-Smad Signaling and Renal Fibrogenesis. AB - Like many organs, the kidney stiffens after injury, a process that is increasingly recognized as an important driver of fibrogenesis. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are related mechanosensory proteins that bind to Smad transcription factors, the canonical mediators of profibrotic TGF-beta responses. Here, we investigated the role of YAP/TAZ in the matrix stiffness dependence of fibroblast responses to TGF beta In contrast to growth on a stiff surface, fibroblast growth on a soft matrix led to YAP/TAZ sequestration in the cytosol and impaired TGF-beta-induced Smad2/3 nuclear accumulation and transcriptional activity. YAP knockdown or treatment with verteporfin, a drug that was recently identified as a potent YAP inhibitor, elicited similar changes. Furthermore, verteporfin reduced YAP/TAZ levels and decreased the total cellular levels of Smad2/3 after TGF-beta stimulation. Verteporfin treatment of mice subjected to unilateral ureteral obstruction similarly reduced YAP/TAZ levels and nuclear Smad accumulation in the kidney, and attenuated renal fibrosis. Our data suggest that organ stiffening cooperates with TGF-beta to induce fibrosis in a YAP/TAZ- and Smad2/3-dependent manner. Interference with this YAP/TAZ and TGF-beta/Smad crosstalk likely underlies the antifibrotic activity of verteporfin. Finally, through repurposing of a clinically used drug, we illustrate the therapeutic potential of a novel mechanointerference strategy that blocks TGF-beta signaling and renal fibrogenesis. PMID- 26961353 TI - Examining the role of a decision aid in reducing decisional conflict amongst hospital healthcare workers towards receiving the influenza vaccine. AB - BACKGROUND: Currently the uptake of the influenza vaccine amongst Australian hospital staff remains low. While some staff members choose not to receive the vaccine, others may feel decisional conflict around whether to receive the vaccine or not. Having access to information that is personalized to the staff members' concerns may alleviate this conflict. Our study aimed to explore the attitudes of hospital staff towards an online decision aid (DA), which focuses on influenza and the vaccine. We were also interested to examine whether they accepted the new tool and whether they had any suggestions for improvements. METHODS: Forty-one semi-structured interviews were undertaken with a range of hospital staff from two major public hospitals in Sydney and Melbourne, Australia in 2013. Emails and posters were used to inform staff members about the study. Thematic analysis was performed to explore the attitudes of hospital staff towards the DA. RESULTS: Our participants were well aware of the time/location of the staff vaccination clinics, however very few reported attending or receiving any educational material about the disease or the vaccine. Amongst those who did receive material, they felt that the messages were "dumbed down". There was a mostly positive response to the DA from participants, however they felt that unless it was included as part of mandatory training or orientation, it would be difficult to get staff to use the tool. CONCLUSIONS: Previous studies have established that education is an important component of an influenza vaccination program. We believe that the decision aid offers an alternative approach to delivering balanced information to staff members, which may reduce workload burdens on administrators and drive up rates. PMID- 26961349 TI - Dichloroacetate Prevents Cisplatin-Induced Nephrotoxicity without Compromising Cisplatin Anticancer Properties. AB - Cisplatin is an effective anticancer drug; however, cisplatin use often leads to nephrotoxicity, which limits its clinical effectiveness. In this study, we determined the effect of dichloroacetate, a novel anticancer agent, in a mouse model of cisplatin-induced AKI. Pretreatment with dichloroacetate significantly attenuated the cisplatin-induced increase in BUN and serum creatinine levels, renal tubular apoptosis, and oxidative stress. Additionally, pretreatment with dichloroacetate accelerated tubular regeneration after cisplatin-induced renal damage. Whole transcriptome sequencing revealed that dichloroacetate prevented mitochondrial dysfunction and preserved the energy-generating capacity of the kidneys by preventing the cisplatin-induced downregulation of fatty acid and glucose oxidation, and of genes involved in the Krebs cycle and oxidative phosphorylation. Notably, dichloroacetate did not interfere with the anticancer activity of cisplatin in vivo. These data provide strong evidence that dichloroacetate preserves renal function when used in conjunction with cisplatin. PMID- 26961351 TI - Endothelial Sphingosine 1-Phosphate Receptor-1 Mediates Protection and Recovery from Acute Kidney Injury. AB - Epithelial and endothelial injury and a cascade of immune and interstitial cell activation in the kidney lead to AKI. After mild to moderate AKI, the epithelium can regenerate and restore kidney function, yet little is known about the endothelium during these repair processes. Sphingosine 1-phosphate receptor 1 (S1P1), a G protein-coupled receptor, is necessary for vascular homeostasis. Here, we used an inducible genetic approach in a mouse model of AKI, ischemia reperfusion injury (IRI), to determine the temporal effects of endothelial S1P1 during AKI. Deletion of endothelial S1P1 before IRI exacerbated kidney injury and inflammation, and the delayed deletion of S1P1 after IRI prevented kidney recovery, resulting in chronic inflammation and progressive fibrosis. Specifically, S1P1 directly suppressed endothelial activation of leukocyte adhesion molecule expression and inflammation. Altogether, the data indicate activation of endothelial S1P1 is necessary to protect from IRI and permit recovery from AKI. Endothelial S1P1 may be a therapeutic target for the prevention of early injury as well as prevention of progressive kidney fibrosis after AKI. PMID- 26961355 TI - Time-evolution of in vivo protein corona onto blood-circulating PEGylated liposomal doxorubicin (DOXIL) nanoparticles. AB - Nanoparticles (NPs) are instantly modified once injected in the bloodstream because of their interaction with the blood components. The spontaneous coating of NPs by proteins, once in contact with biological fluids, has been termed the 'protein corona' and it is considered to be a determinant factor for the pharmacological, toxicological and therapeutic profile of NPs. Protein exposure time is thought to greatly influence the composition of protein corona, however the dynamics of protein interactions under realistic, in vivo conditions remain unexplored. The aim of this study was to quantitatively and qualitatively investigate the time evolution of in vivo protein corona, formed onto blood circulating, clinically used, PEGylated liposomal doxorubicin. Protein adsorption profiles were determined 10 min, 1 h and 3 h post-injection of liposomes into CD 1 mice. The results demonstrated that a complex protein corona was formed as early as 10 min post-injection. Even though the total amount of protein adsorbed did not significantly change over time, the fluctuation of protein abundances observed indicated highly dynamic protein binding kinetics. PMID- 26961354 TI - Improved survival in HIV treatment programmes in Asia. AB - BACKGROUND: Antiretroviral treatment (ART) for HIV-positive patients has expanded rapidly in Asia over the last 10 years. Our study aimed to describe the time trends and risk factors for overall survival in patients receiving first-line ART in Asia. METHODS: We included HIV-positive adult patients who initiated ART between 2003-2013 (n=16,546), from seven sites across six Asia-Pacific countries. Patient follow-up was to May 2014. We compared survival for each country and overall by time period of ART initiation using Kaplan-Meier curves. Factors associated with mortality were assessed using Cox regression, stratified by site. We also summarized first-line ART regimens, CD4+ T-cell count at ART initiation, and CD4+ T-cell and HIV viral load testing frequencies. RESULTS: There were 880 deaths observed over 54,532 person-years of follow-up, a crude rate of 1.61 (95% CI 1.51, 1.72) per 100 person-years. Survival significantly improved in more recent years of ART initiation. The survival probability at 4 years follow-up for those initiating ART in 2003-2005 was 92.1%, 2006-2009 was 94.3% and 2010-2013 was 94.5% (P<0.001). Factors associated with higher mortality risk included initiating ART in earlier time periods, older age, male sex, injecting drug use as HIV exposure and lower pre-ART CD4+ T-cell count. Concurrent with improved survival was increased tenofovir use, ART initiation at higher CD4+ T-cell counts and greater monitoring of CD4+ T-cells and HIV viral load. CONCLUSIONS: Our results suggest that HIV-positive patients from Asia have improved survival in more recent years of ART initiation. This is likely a consequence of improvements in treatment, patient management and monitoring over time. PMID- 26961356 TI - [Late consequences of urethral injuries. Reconstruction options]. AB - BACKGROUND: Stricture excision and posterior urethroplasty is the most common procedure after posttraumatic urethral strictures. RESULTS: Re-strictures and fistulas are treated by repeat urethroplasty. Tension-free anastomosis is prerequisite for surgical success. Urinary incontinence after posttraumatic injuries is treated by an artificial urinary sphincter. PMID- 26961357 TI - Comparative analysis of genome-wide Mlo gene family in Cajanus cajan and Phaseolus vulgaris. AB - The Mlo gene was discovered in barley because the mutant 'mlo' allele conferred broad-spectrum, non-race-specific resistance to powdery mildew caused by Blumeria graminis f. sp. hordei. The Mlo genes also play important roles in growth and development of plants, and in responses to biotic and abiotic stresses. The Mlo gene family has been characterized in several crop species, but only a single legume species, soybean (Glycine max L.), has been investigated so far. The present report describes in silico identification of 18 CcMlo and 20 PvMlo genes in the important legume crops Cajanus cajan (L.) Millsp. and Phaseolus vulgaris L., respectively. In silico analysis of gene organization, protein properties and conserved domains revealed that the C. cajan and P. vulgaris Mlo gene paralogs are more divergent from each other than from their orthologous pairs. The comparative phylogenetic analysis classified CcMlo and PvMlo genes into three major clades. A comparative analysis of CcMlo and PvMlo proteins with the G. max Mlo proteins indicated close association of one CcMlo, one PvMlo with two GmMlo genes, indicating that there was no further expansion of the Mlo gene family after the separation of these species. Thus, most of the diploid species of eudicots might be expected to contain 15-20 Mlo genes. The genes CcMlo12 and 14, and PvMlo11 and 12 are predicted to participate in powdery mildew resistance. If this prediction were verified, these genes could be targeted by TILLING or CRISPR to isolate powdery mildew resistant mutants. PMID- 26961358 TI - Human T Follicular Helper Cells in Primary Immunodeficiency: Quality Just as Important as Quantity. AB - T follicular helper (Tfh) cells are a subset of effector CD4(+) T cells specialised to induce Ab production by B cells. This review highlights some of the recent advances in the field of human Tfh cells that have come from the study of primary immunodeficiencies. In particular it is increasingly evident that the quality of the Tfh cells that are generated, is just as important as the quantity. PMID- 26961359 TI - Immune Complex-Mediated Glomerulonephritis in a Patient with Wiskott-Aldrich Syndrome. PMID- 26961361 TI - A 'Too Negative' ANA Test Predicts Antibody Deficiency. PMID- 26961360 TI - The Elements Steering Pathogenesis in IgG-Mediated Alloimmune Diseases. AB - Alloimmune diseases can occur in pregnancy and after blood transfusions, where antibodies are formed, targeting foreign cells and tissues for destruction by myeloid cells through IgG Fc-receptors (FcgammaR). In pregnancy, antibodies against human blood group or platelet antigens (e.g. HPA1-a) cause life threatening anemia or thrombocytopenia in the developing fetus or newborn. Here we discuss how both the induction of those IgG antibodies as well as the proinflammatory status of the fetus affects the effector functions through FcgammaR. Recent studies have found IgG-glycosylation to be important with low IgG-Fc-core fucosylation resulting in increased affinity to FcgammaRIIIa and FcgammaRIIIb and enhanced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis. The importance of these and other features, including oxidative stress and acute phase responses (C-reactive protein, CRP), will be discussed and how these features may collectively synergize resulting in elevated disease pathology in these allo-, but also autoimmune mediated diseases. PMID- 26961362 TI - Spondylodiscitis in a Boy with X-linked Agammaglobulinemia: an Unusual Occurrence. PMID- 26961363 TI - Translation, Validation, and Reliability of the Dutch Late-Life Function and Disability Instrument Computer Adaptive Test. AB - BACKGROUND: Adequate and user-friendly instruments for assessing physical function and disability in older adults are vital for estimating and predicting health care needs in clinical practice. The Late-Life Function and Disability Instrument Computer Adaptive Test (LLFDI-CAT) is a promising instrument for assessing physical function and disability in gerontology research and clinical practice. OBJECTIVE: The aims of this study were: (1) to translate the LLFDI-CAT to the Dutch language and (2) to investigate its validity and reliability in a sample of older adults who spoke Dutch and dwelled in the community. DESIGN: For the assessment of validity of the LLFDI-CAT, a cross-sectional design was used. To assess reliability, measurement of the LLFDI-CAT was repeated in the same sample. METHODS: The item bank of the LLFDI-CAT was translated with a forward backward procedure. A sample of 54 older adults completed the LLFDI-CAT, World Health Organization Disability Assessment Schedule 2.0, RAND 36-Item Short-Form Health Survey physical functioning scale (10 items), and 10-Meter Walk Test. The LLFDI-CAT was repeated in 2 to 8 days (mean=4.5 days). Pearson's r and the intraclass correlation coefficient (ICC) (2,1) were calculated to assess validity, group-level reliability, and participant-level reliability. RESULTS: A correlation of .74 for the LLFDI-CAT function scale and the RAND 36-Item Short Form Health Survey physical functioning scale (10 items) was found. The correlations of the LLFDI-CAT disability scale with the World Health Organization Disability Assessment Schedule 2.0 and the 10-Meter Walk Test were -.57 and -.53, respectively. The ICC (2,1) of the LLFDI-CAT function scale was .84, with a group level reliability score of .85. The ICC (2,1) of the LLFDI-CAT disability scale was .76, with a group-level reliability score of .81. LIMITATIONS: The high percentage of women in the study and the exclusion of older adults with recent joint replacement or hospitalization limit the generalizability of the results. CONCLUSIONS: The Dutch LLFDI-CAT showed strong validity and high reliability when used to assess physical function and disability in older adults dwelling in the community. PMID- 26961364 TI - Multiple anti-epileptic drug use in children with epilepsy in Mulago hospital, Uganda: a cross sectional study. AB - BACKGROUND: Seizures in up to one third of children with epilepsy may not be controlled by the first anti-epileptic drug (AED). In this study, we describe multiple AED usage in children attending a referral clinic in Uganda, the factors associated with multiple AED use and seizure control in affected patients. METHODS: One hundred thirty nine patients attending Mulago hospital paediatric neurology clinic with epilepsy and who had been on AEDs for >=6 months were consecutively enrolled from July to December 2013 to reach the calculated sample size. With consent, the history and physical examination were repeated and the neurophysiologic and imaging features obtained from records. Venous blood was also drawn to determine AED drug levels. We determined the proportion of children on multiple AEDs and performed regression analyses to determine factors independently associated with multiple AED use. RESULTS: Forty five out of 139 (32.4 %) children; 46.7 % female, median age 6 (IQR = 3-9) years were on multiple AEDs. The most common combination was sodium valproate and carbamazepine. We found that 59.7 % of children had sub-therapeutic drug levels including 42.2 % of those on multi-therapy. Sub-optimal seizure control (adjusted odds ratio [OR(a)] 3.93, 95 % CI 1.66-9.31, p = 0.002) and presence of focal neurological deficits (OR(a) 3.86, 95 % CI 1.31-11.48, p = 0.014) were independently associated with multiple AED use but not age of seizure onset, duration of epilepsy symptoms, seizure type or history of status epilepticus. CONCLUSION: One third of children with epilepsy in Mulago receive multiple AEDs. Multiple AED use is most frequent in symptomatic focal epilepsies but doses are frequently sub-optimal. There is urgent need to improve clinical monitoring in our patients. PMID- 26961365 TI - Long-term cost effectiveness of cardiac secondary prevention in primary care in the Republic of Ireland and Northern Ireland. AB - While cardiac secondary prevention in primary care is established practice, little is known about its long-term cost effectiveness. This study examines the cost effectiveness of a secondary prevention intervention in primary care in the Republic of Ireland and Northern Ireland over 6 years. An economic evaluation, based on a cluster randomised controlled trial of 903 patients with heart disease, was conducted 4.5 years after the intervention ceased to be delivered. Patients originally randomised to the control received usual practice while those randomised to the intervention received a tailored care package over the 1.5-year delivery period. Data on healthcare costs and quality adjusted life expectancy were used to undertake incremental cost utility analysis. Multilevel regression was used to estimate mean cost effectiveness and uncertainty was examined using cost effectiveness acceptability curves. At 6 years, there was a divergence in the results across jurisdictions. While the probability of the intervention being cost effective in the Republic of Ireland was 0.434, 0.232, 0.180, 0.150, 0.115 and 0.098 at selected threshold values of ?5000, ?15,000, ?20,000, ?25,000, ?35,000 and ?45,000, respectively, all equivalent probabilities for Northern Ireland equalled 1.000. Our findings suggest that the intervention in its current format is likely to be more cost effective than usual general practice care in Northern Ireland, but this is not the case in the Republic of Ireland. PMID- 26961366 TI - Potential role of microRNA-7 in the anti-neuroinflammation effects of nicorandil in astrocytes induced by oxygen-glucose deprivation. AB - BACKGROUND: It is generally recognized that the inflammatory reaction in glia is one of the important pathological factors in brain ischemic injury. Our previous study has revealed that opening ATP-sensitive potassium (K-ATP) channels could attenuate glial inflammation induced by ischemic stroke. However, the detailed mechanisms are not well known. METHODS: Primary cultured astrocytes separated from C57BL/6 mice were subjected to oxygen-glucose deprivation (OGD); cellular injuries were determined via observing the changes of cellular morphology and cell viability. MicroRNA (miR) and messenger RNA (mRNA) level was validated by real-time PCR. The interaction between microRNA and the target was confirmed via dual luciferase reporter gene assay. Expressions of proteins and inflammatory cytokines were respectively assessed by western blotting and enzyme-linked immunosorbent assay. RESULTS: OGD resulted in astrocytic damage, which was prevented by K-ATP channel opener nicorandil. Notably, we found that OGD significantly downregulated miR-7 and upregulated Herpud2. Our further study proved that miR-7 targeted Herpud2 3'UTR, which encoded endoplasmic reticulum (ER) stress protein-HERP2. Correspondingly, our results showed that OGD increased the levels of ER stress proteins along with significant elevations of pro inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). Pretreatment with nicorandil could remarkably upregulate miR-7, depress the ER-related protein expressions including glucose regulated protein 78 (GRP78), C/EBP-homologous protein (CHOP), and Caspase-12, and thereby attenuate inflammatory responses and astrocytic damages. CONCLUSIONS: These findings demonstrate that opening K-ATP channels protects astrocytes against OGD-mediated neuroinflammation. Potentially, miR-7-targeted ER stress acts as a key molecular brake on neuroinflammation. PMID- 26961367 TI - Effectiveness and cost-effectiveness of a patient-initiated botulinum toxin treatment model for blepharospasm and hemifacial spasm compared to standard care: study protocol for a randomised controlled trial. AB - BACKGROUND: Blepharospasm and hemifacial spasm are debilitating conditions that significantly impact on patient quality of life. Cyclical treatment with botulinum toxin injections offers temporary relief, but the duration of treatment efficacy is variable. The standard model of patient care defines routine fixed time based scheduled treatment cycles which may lead to unnecessarily frequent treatment for some patients and experience of distressing symptoms in others, if symptoms return before the scheduled follow-up period. METHODS/DESIGN: A randomised controlled trial will compare a patient-initiated model of care, where patients determine botulinum toxin treatment timing, to the standard model of care in which care is scheduled by the clinical team. A sample of 266 patients with blepharospasm or hemifacial spasm will be recruited from Moorfields Eye Hospital (MEH), London. The trial will be accompanied by a mixed-methods evaluation of acceptability of the new service. Patients who meet eligibility criteria will be assessed at baseline and those in the intervention group will be provided with instructions on how to book their own treatment appointments. Patients in both groups will be followed up 3 and 9 months into the trial and all patients will be returned to usual care after 9 months to meet safety protocols. Primary outcome measures include disease severity (questionnaire), functional disability (questionnaire) and patient satisfaction with care (questionnaire). Secondary outcomes include disease-specific quality of life (questionnaire), mood (questionnaire), illness and treatment perceptions (questionnaire and semi structured interviews), economic impact (questionnaire) and acceptability (questionnaire and semi-structured interviews). DISCUSSION: This trial will assess the effectiveness and cost-effectiveness of a patient-led care model for botulinum toxin therapy. If the new model is shown to be effective in reducing distress and disability in these populations and is found to be acceptable to patients, whilst being cost-effective, this will have significant implications for service organisation across the NHS. TRIAL REGISTRATION: UK Clinical Research Network (UKCRN) Portfolio 18660. Clinicaltrials.gov ID NCT102577224 (registered 29 October 2015). PMID- 26961368 TI - Differential effect of Se on insulin resistance: regulation of adipogenesis and lipolysis. AB - Insulin resistance is the characteristic of type 2 diabetes mellitus and metabolic disorder. The biological effect of selenium (Se) on insulin sensitivity and metabolic function was contradictory. In this study, we designed two animal protocols to investigate the effect of physiological Se on high-fat (HF) diet induced insulin resistance in mice and examined the influence of Se on adipocyte differentiation and lipolysis in isolated bone marrow stromal stem cells. The results showed that pre-treatment with Se, mimicking thiazolidinediones, increased adipocyte differentiation and fat deposit in adipose tissue and reduced ectopic lipid content and consequent ROS generation and mitochondrial dysfunction in livers, protecting against HF diet-induced insulin resistance. Post-treatment with Se promoted lipolysis in adipose tissue and ectopic lipid accumulation in livers and aggravated subsequent ROS generation and mitochondrial dysfunction, exacerbating insulin resistance induced by HF diet. Activation of GPx1 and Sepp1 was responsible for Se-exhibited bi-directional significance, which was at the crossroad of the biological effect of Se, leading to differential directions: one way is to accelerate mitotic clonal expansion and increase key regulators of adipocyte differentiation, such as PPARgamma and C/EBPalpha/beta, leading to enhancement of adipogenic differentiation; the other way is to activate PKA/HSL pathway, reinforcing lipolysis. Further studies are needed to elucidate the mechanism underlying GPx1 and Sepp1-exerted differential effects under different conditions. Anyhow, these findings may partly explain the contradiction of the biological significance of Se and demonstrate a novel understanding of the mechanism of Se-exerted benefit or harmful effects in the context of high consumption of fat. PMID- 26961369 TI - Multi-Center, Community-Based Cardiac Implantable Electronic Devices Registry: Population, Device Utilization, and Outcomes. AB - BACKGROUND: The purpose of this study is to describe key elements, clinical outcomes, and potential uses of the Kaiser Permanente-Cardiac Device Registry. METHODS AND RESULTS: This is a cohort study of implantable cardioverter defibrillators (ICD), pacemakers (PM), and cardiac resynchronization therapy (CRT) devices implanted between January 1, 2007 and December 31, 2013 by ~400 physicians in 6 US geographical regions. Registry data variables, including patient characteristics, comorbidities, indication for procedures, complications, and revisions, were captured using the healthcare system's electronic medical record. Outcomes were identified using electronic screening algorithms and adjudicated via chart review. There were 11 924 ICDs, 33 519 PMs, 4472 CRTs, and 66 067 leads registered. A higher proportion of devices were implanted in males: 75.1% (ICD), 55.0% (PM), and 66.7% (CRT), with mean patient age 63.2 years (ICD), 75.2 (PM), and 67.2 (CRT). The 30-day postoperative incidence of tamponade, hematoma, and pneumothorax were <=0.3% (ICD), <=0.6% (PM), and <=0.4% (CRT). Device failures requiring revision occurred at a rate of 2.17% for ICDs, 0.85% for PMs, and 4.93% for CRTs, per 100 patient observation years. Superficial infection rates were <0.03% for all devices; deep infection rates were 0.6% (ICD), 0.5% (PM), and 1.0% (CRT). Results were used to monitor vendor-specific variations and were systematically shared with individual regions to address potential variations in outcomes, utilization, and to assist with the management of device recalls. CONCLUSIONS: The Kaiser Permanente-Cardiac Device Registry is a robust tool to monitor postprocedural patient outcomes and postmarket surveillance of implants and potentially change practice patterns. PMID- 26961371 TI - Fast, accurate, and lightweight analysis of BS-treated reads with ERNE 2. AB - BACKGROUND: Bisulfite treatment of DNA followed by sequencing (BS-seq) has become a standard technique in epigenetic studies, providing researchers with tools for generating single-base resolution maps of whole methylomes. Aligning bisulfite treated reads, however, is a computationally difficult task: bisulfite treatment decreases the (lexical) complexity of low-methylated genomic regions, and C-to-T mismatches may reflect cytosine unmethylation rather than SNPs or sequencing errors. Further challenges arise both during and after the alignment phase: data structures used by the aligner should be fast and should fit into main memory, and the methylation-caller output should be somehow compressed, due to its significant size. METHODS: As far as data structures employed to align bisulfite treated reads are concerned, solutions proposed in the literature can be roughly grouped into two main categories: those storing pointers at each text position (e.g. hash tables, suffix trees/arrays), and those using the information theoretic minimum number of bits (e.g. FM indexes and compressed suffix arrays). The former are fast and memory consuming. The latter are much slower and light. In this paper, we try to close this gap proposing a data structure for aligning bisulfite-treated reads which is at the same time fast, light, and very accurate. We reach this objective by combining a recent theoretical result on succinct hashing with a bisulfite-aware hash function. Furthermore, the new versions of the tools implementing our ideas|the aligner ERNE-BS5 2 and the caller ERNE-METH 2|have been extended with increased downstream compatibility (EPP/Bismark cov output formats), output compression, and support for target enrichment protocols. RESULTS: Experimental results on public and simulated WGBS libraries show that our algorithmic solution is a competitive tradeoff between hash-based and BWT based indexes, being as fast and accurate as the former, and as memory-efficient as the latter. CONCLUSIONS: The new functionalities of our bisulfite aligner and caller make it a fast and memory efficient tool, useful to analyze big datasets with little computational resources, to easily process target enrichment data, and produce statistics such as protocol efficiency and coverage as a function of the distance from target regions. PMID- 26961372 TI - Cost-effectiveness of systemic treatments for moderate-to-severe psoriasis in the German health care setting. AB - Systemic treatments of moderate-to-severe psoriasis differ substantially in terms of effectiveness and costs. Comprehensive economic-evaluations of all systemic treatments for psoriasis from a societal perspective are missing. The objective of our study was to compare the cost-effectiveness all systemic treatments approved for moderate-to-severe psoriasis from a societal perspective, by including all cost categories. An incremental cost-effectiveness-analysis was performed for all systemic treatments for psoriasis, currently recommended by the German S3-Guideline i.e. methotrexate, cyclosporine, fumaric acid esters, and retinoids, adalimumab, etanercept, infliximab and ustekinumab. We used a Markov model with time-dependent transition probabilities and a time horizon of 2 years to investigate incremental cost-effectiveness ratios. Both direct and indirect costs were considered to reflect the societal perspective. Effectiveness outcome was PASI-75 response. One-way and probabilistic sensitivity analyses explored the effect of treatment duration, discount rate, effectiveness, and the perspective (societal vs. healthcare system) on the findings. According to the base-case analysis a cost-effective treatment pathway for moderate-to-severe psoriasis starts with methotrexate, followed by ustekinumab 90 mg and infliximab, if methotrexate does not achieve or maintain PASI-75 response. Sensitivity analyses confirmed the general robustness of these findings with methotrexate being most cost-effective. However, from a third-party-payer perspective (without indirect cost) conventional therapies were generally more cost-effective than biologics. From a value-based healthcare perspective, methotrexate should be the systemic treatment of first choice, ustekinumab 90 mg second choice and infliximab third choice for patients with moderate-to-severe psoriasis. From a societal perspective, the other treatments are less efficient according to our model. From a third-party-payer perspective conventional therapies are more cost-effective than biologics. PMID- 26961373 TI - Metallopolymer precursors to L10-CoPt nanoparticles: synthesis, characterization, nanopatterning and potential application. AB - Ferromagnetic (L10 phase) CoPt alloy nanoparticles (NPs) with extremely high magnetocrystalline anisotropy are promising candidates for the next generation of ultrahigh-density data storage systems. It is a challenge to generate L10 CoPt NPs with high coercivity, controllable size, and a narrow size distribution. We report here the fabrication of L10 CoPt NPs by employing a heterobimetallic CoPt containing polymer as a single-source precursor. The average size of the resulting L10 CoPt NPs is 3.4 nm with a reasonably narrow size standard deviation of 0.58 nm. The coercivity of L10 CoPt NPs is 0.54 T which is suitable for practical application. We also fabricated the L10 CoPt NP-based nanoline and nanodot arrays through nanoimprinting the polymer blend of CoPt-containing metallopolymer and polystyrene followed by pyrolysis. The successful transfer of the pre-defined patterns of the stamps onto the surface of the polymer blend implies that this material holds great application potential as a data storage medium. PMID- 26961370 TI - Genome-wide survey of codons under diversifying selection in a highly recombining bacterial species, Helicobacter pylori. AB - Selection has been a central issue in biology in eukaryotes as well as prokaryotes. Inference of selection in recombining bacterial species, compared with clonal ones, has been a challenge. It is not known how codons under diversifying selection are distributed along the chromosome or among functional categories or how frequently such codons are subject to mutual homologous recombination. Here, we explored these questions by analysing genes present in >90% among 29 genomes of Helicobacter pylori, one of the bacterial species with the highest mutation and recombination rates. By a method for recombining sequences, we identified codons under diversifying selection (dN/dS> 1), which were widely distributed and accounted for ~0.2% of all the codons of the genome. The codons were enriched in genes of host interaction/cell surface and genome maintenance (DNA replication,recombination, repair, and restriction modification system). The encoded amino acid residues were sometimes found adjacent to critical catalytic/binding residues in protein structures.Furthermore, by estimating the intensity of homologous recombination at a single nucleotide level, we found that these codons appear to be more frequently subject to recombination.We expect that the present study provides a new approach to population genomics of selection in recombining prokaryotes. PMID- 26961374 TI - Leukocyte receptor expression in chronic periodontitis. AB - BACKGROUND AND OBJECTIVE: Microbial recognition in the periodontium through specific leukocyte receptors gives rise to the response which in susceptible individuals can lead to periodontal diseases. The aim of this study was to explore the expression of leukocyte receptors in the gingival tissues of chronic periodontitis patients and to analyse differences between diseased and control sites (sites with probing pocket depth <4 mm). MATERIAL AND METHODS: Thirty-seven chronic periodontitis patients were included in the study. Gingival biopsies were harvested from diseased and control sites and processed by flow cytometry for the determination of the expression of 16 leukocyte receptors (CD4, CD8, CD11b, CD14, CD16, CD19, CD25, CD28, CD49d, CD49e, CD62, CD71, CD80, CCR7, Ly6G and HLA-DR). RESULTS: Expression of all studied receptors was higher in test compared with control sites (p < 0.005). Sampled sites with less bleeding on probing exhibited higher expression of CD16 and CD14 receptors (p = 0.020 and 0.011, respectively). CONCLUSIONS: This study points towards considerable differences in the expression of leukocyte receptors between diseased and control sites in the same periodontal patients. PMID- 26961377 TI - Memorized chiral arrangement of gemini surfactant assemblies in nanometric hybrid organic-silica helices. AB - Hybrid nanohelices were obtained from silicification of self-assemblies of gemini surfactants with tartrate counterions. The chiral arrangement of these non-chiral gemini surfactants was preserved in the silica matrix even after the counterion exchange for a non-chiral bromide, and was capable of inducing the chiral organisation of a non-chiral dye, methyl orange. PMID- 26961375 TI - Dabigatran and rivaroxaban do not affect AA- and ADP-induced platelet aggregation in patients receiving concomitant platelet inhibitors. AB - Dabigatran and rivaroxaban are novel, vitamin K-independent oral anticoagulants (NOACs) and act via antagonism of the coagulation factor (F) IIa (dabigatran) or FXa (rivaroxaban), respectively. Compared to vitamin-K-antagonists, NOACs have shown non-inferiority of risk and benefit in patients with non valvular atrial fibrillation (AF). In clinical practice there is increasing use of NOACs combined with platelet inhibitors in patients with AF and coronary artery disease. However, whether NOACs affect the function of platelet inhibitors remains incompletely known. This observational study aimed to assess the platelet function in patients receiving dabigatran or rivaroxaban and concomitant platelet inhibitors. A single centre observational study was performed analysing the platelet aggregation of patients treated with dabigatran or rivaroxaban with or without concomitant platelet inhibitors. Measurements before the initiation of NOAC therapy served as the respective control group. Platelet aggregation was measured by multiple electrode aggregometry and was induced with adenosine diphosphate (ADP, 6.5 uM) and arachidonic acid (AA, 0.5 mM), respectively. In order to evaluate whether NOACs interact with platelet inhibition by ASA or the P2Y12-antagonist clopidogrel, 87 patients were grouped according to their concomitant antiplatelet medication. Comparing the ADP- and AA-induced platelet aggregation in patients without concomitant platelet inhibitors (n = 45) no significant differences under therapy with dabigatran (d) or rivaroxaban (r) compared to the control group (c) were observed. In patients taking clopidogrel as a concomitant platelet inhibitor (n = 21), neither dabigatran nor rivaroxaban affected the ADP-induced platelet aggregation (c 20 +/- 11, d 21 +/- 14, r 18 +/- 8 AU*min, p = 0.200). Patients receiving dabigatran or rivaroxaban in combination with ASA (n = 42; 21 ASA only, 21 ASA + clopidogrel) showed no significant differences of the AA-induced aggregation compared to the control group (c 10 +/- 8, d 9 +/- 7, r 10 +/- 8 AU*min, p = 0.810). The antiplatelet effects of ASA and clopidogrel monitored by AA- or ADP-induced platelet aggregation were not affected by NOAC therapy. PMID- 26961378 TI - Erratum to: The use of the Godin-Shephard Leisure-Time Physical Activity Questionnaire in oncology research: a systematic review. PMID- 26961379 TI - Treatment of the iatrogenic lesion of the biliary tree secondary to laparoscopic cholecystectomy: a single center experience. AB - Surgical bile duct injury (SBDI), during laparoscopic cholecystectomy, is a worldwide ongoing problem. The purpose of this study is to analyze a single center retrospective experience with this topic. From 1999 to 2012, 30 patients with diagnosis of SBDI after laparoscopic cholecystectomy performed in other institute for gallbladder lithiasis and then transferred to our facility were enrolled in this analysis. We considered in the study the following parameters: classification and site of the bile duct injury, infective complications and therapeutic management according to early or late referral. Twenty four patients (80 %) had a SBDI type E1; a concomitant vascular injury was described in 3/30 (10 %) in right hepatic artery. 11 patients had HJJ as primary surgical treatment in our hospital. Surgical site infection was documented in 9/30 (30 %). The most common micro-organisms documented in SSI were E. coli with an incidence of 55.5 % of SSI. Worse infective complications were detected in the late referral group. Complex SBDI occurred during laparoscopic cholecystectomy should be early referred to advanced hepatobiliary program, for appropriate multidisciplinary management. PMID- 26961380 TI - Barriers to Linkage to HIV Care in Ugandan Fisherfolk Communities: A Qualitative Analysis. AB - Among Ugandan fisherfolk, HIV prevalence (with estimates ranging from 15 to 40 %) is higher than in the general population (about 7 %), potentially due to high risk behaviors and low access to HIV testing and healthcare. We conducted semi structured interviews on barriers to linkage to care with 10 key stakeholders and 25 fisherfolk within 1-2 months of their testing HIV-positive at clinic outreach events in Ugandan Lake Victoria communities. Interviews were recorded, transcribed, translated, and coded using grounded theory methods. Participants cited low healthcare access and quality of care, mobility, competing needs for work during clinic hours, stigma, and low social support as barriers. Over 10 % of clients screened positive for HIV at outreach events, and only half accessed care. Linkage to care issues may begin with the failure to attract high-risk fisherfolk to testing. New models of HIV testing and treatment delivery are needed to reach fisherfolk. PMID- 26961382 TI - Saikosaponin-D Reduces H2O2-Induced PC12 Cell Apoptosis by Removing ROS and Blocking MAPK-Dependent Oxidative Damage. AB - Neuronal oxidative stress (OS) injury has been proven to be associated with many neurodegenerative diseases, and thus, antioxidation treatment is an effective method for treating these diseases. Saikosaponin-D (SSD) is a sapogenin extracted from Bupleurum falcatum and has been shown to have many pharmacological activities. The main purpose of this study was to investigate whether and how SSD protects PC12 cells from H2O2-induced apoptosis. The non-toxic level of SSD significantly mitigated the H2O2-induced decrease in cell viability, reduced the apoptosis rate, improved the nuclear morphology, and reduced caspase-3 activation and poly ADP-ribose polymerase (PARP) cleavage. Additionally, exogenous H2O2 induced apoptosis by damaging the intracellular antioxidation system. SSD significantly slowed the H2O2-induced release of malonic dialdehyde (MDA) and lactate dehydrogenase and increased the activity of superoxide dismutase (SOD) and the total antioxidant capacity, thereby reducing apoptosis. More importantly, SSD effectively blocked H2O2-induced phosphorylation of extracellular-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38MAPK), and specific inhibitors of ERK, JNK, and p38-reduced OS injury and apoptosis, suggesting that SSD reduces OS injury and apoptosis via MAPK signalling pathways. Finally, we confirmed that SSD significantly reduced H2O2 induced reactive oxygen species (ROS) accumulation, and the ROS inhibitor blocked the apoptosis caused by MAPK activation and cellular oxidative damage. In short, our study confirmed that SSD reduces H2O2-induced PC12 cell apoptosis by removing ROS and blocking MAPK-dependent oxidative damage. PMID- 26961383 TI - Reducing burden of disease from residential indoor air exposures in Europe (HEALTHVENT project). AB - BACKGROUND: The annual burden of disease caused indoor air pollution, including polluted outdoor air used to ventilate indoor spaces, is estimated to correspond to a loss of over 2 million healthy life years in the European Union (EU). Based on measurements of the European Environment Agency (EEA), approximately 90 % of EU citizens live in areas where the World Health Organization (WHO) guidelines for air quality of particulate matter sized < 2.5 mm (PM2.5) are not met. Since sources of pollution reside in both indoor and outdoor air, selecting the most appropriate ventilation strategy is not a simple and straightforward task. METHODS: A framework for developing European health-based ventilation guidelines was created in 2010-2013 in the EU-funded HEALTHVENT project. As a part of the project, the potential efficiency of control policies to health effects caused by residential indoor exposures of fine particulate matter (PM2.5), outdoor bioaerosols, volatile organic compounds (VOC), carbon oxide (CO) radon and dampness was estimated. The analysis was based on scenario comparison, using an outdoor-indoor mass-balance model and varying the ventilation rates. Health effects were estimated with burden of diseases (BoD) calculations taking into account asthma, cardiovascular (CV) diseases, acute toxication, respiratory infections, lung cancer and chronic obstructive pulmonary disease (COPD). RESULTS: The quantitative comparison of three main policy approaches, (i) optimising ventilation rates only; (ii) filtration of outdoor air; and (iii) indoor source control, showed that all three approaches are able to provide substantial reductions in the health risks, varying from approximately 20 % to 44 %, corresponding to 400 000 and 900 000 saved healthy life years in EU-26. PM2.5 caused majority of the health effects in all included countries, but the importance of the other pollutants varied by country. CONCLUSIONS: The present modelling shows, that combination of controlling the indoor air sources and selecting appropriate ventilation rate was the most effective to reduce health risks. If indoor sources cannot be removed or their emissions cannot be limited to an accepted level, ventilation needs to be increased to remove remaining pollutants. In these cases filtration of outdoor air may be needed to prevent increase of health risks. PMID- 26961381 TI - Beyond Condoms: Risk Reduction Strategies Among Gay, Bisexual, and Other Men Who Have Sex With Men Receiving Rapid HIV Testing in Montreal, Canada. AB - Gay, bisexual, and other men who have sex with men (MSM) have adapted their sexual practices over the course of the HIV/AIDS epidemic based on available data and knowledge about HIV. This study sought to identify and compare patterns in condom use among gay, bisexual, and other MSM who were tested for HIV at a community-based testing site in Montreal, Canada. Results showed that while study participants use condoms to a certain extent with HIV-positive partners and partners of unknown HIV status, they also make use of various other strategies such as adjusting to a partner's presumed or known HIV status and viral load, avoiding certain types of partners, taking PEP, and getting tested for HIV. These findings suggest that MSM who use condoms less systematically are not necessarily taking fewer precautions but may instead be combining or replacing condom use with other approaches to risk reduction. PMID- 26961384 TI - Insight into the Conformational Variations in SoxYZ Protein Complex from Two Different Members of the beta-Proteobacterial Family Involved in Sulfur Oxidation. AB - Sulfur anions serve as the important environmental pollutants. Microbes use hydrogen sulfide in different redox reactions and thus make the environment pollution-free. The sulfur redox processes are performed by a gene cluster called the sox operon, possessed by a diverse set of microorganisms. However, most of the previous studies were confined to alpha-proteobacteria. In this work, we tried to elucidate the mechanistic details of sulfur oxidation in beta proteobacteria. We compared the molecular mechanism of sulfur oxidation process using Dechloromonas aromatica and Thiobacillus denitrificans. Dechloromonas aromatica possesses the entire sox operon, whereas T. denitrificans lacks SoxCD. In both the organisms, SoxYZ complex formation is essential for thiosulfate oxidation. This SoxYZ protein complex interacts with SoxCD and SoxAX, respectively, for recycling the thiosulfate-bound SoxY protein. For this purpose, individual proteins were modeled via manifold modeling techniques. Protein protein docking studies were executed to generate duo- and quadro-protein complexes. Different stability parameters such as free energy of folding, solvent accessibility area (for final complexes), and electrostatic surface potential (for SoxYZ complexes) were calculated and analyzed. Fifteen strengthening ionic interactions were accomplished in the SoxYZAX complex, whereas eight such interactions were observed in SoxYZCD complex. From the result, SoxYZAX complex was found to be more stable and interactive one. This study is the first of its kind that analyzes the comparative aspects of the binding interactions of the proteins involved in redox reactions of sulfur anions. This study may, therefore, be helpful in tailoring the microorganisms to function in a better way to remove the environmental sulfur pollutants. PMID- 26961385 TI - Rising Strengths Hong Kong SAR in Bioinformatics. AB - Hong Kong's bioinformatics sector is attaining new heights in combination with its economic boom and the predominance of the working-age group in its population. Factors such as a knowledge-based and free-market economy have contributed towards a prominent position on the world map of bioinformatics. In this review, we have considered the educational measures, landmark research activities and the achievements of bioinformatics companies and the role of the Hong Kong government in the establishment of bioinformatics as strength. However, several hurdles remain. New government policies will assist computational biologists to overcome these hurdles and further raise the profile of the field. There is a high expectation that bioinformatics in Hong Kong will be a promising area for the next generation. PMID- 26961387 TI - A 3D MOF constructed from dysprosium(III) oxalate and capping ligands: ferromagnetic coupling and field-induced two-step magnetic relaxation. AB - A novel 3D MOF based on dysprosium(iii) oxalate and 1,10-phenanthroline (phen), {[Dy(C2O4)1.5phen].0.5H2O}n (1), has been hydrothermally synthesized. The Dy(3+) ion acts as a typical Y-shaped node, linking to each other to generate an interesting 3D topology structure. Complex 1 is the first 3D DyMOF displaying both ferromagnetic coupling and field-induced two-step magnetic relaxation. PMID- 26961388 TI - Radiological indeterminate vestibular schwannoma and meningioma in cerebellopontine angle area: differentiating using whole-tumor histogram analysis of apparent diffusion coefficient. AB - PURPOSE: To assess the role of whole-tumor histogram analysis of apparent diffusion coefficient (ADC) maps in differentiating radiological indeterminate vestibular schwannoma (VS) from meningioma in cerebellopontine angle (CPA). MATERIALS AND METHODS: Diffusion-weighted (DW) images (b = 0 and 1000 s/mm2) of pathologically confirmed and radiological indeterminate CPA meningioma (CPAM) (n = 27) and VS (n = 12) were retrospectively collected and processed with mono exponential model. Whole-tumor regions of interest were drawn on all slices of the ADC maps to obtain histogram parameters, including the mean ADC (ADCmean), median ADC (ADCmedian), 10th/25th/75th/90th percentile ADC (ADC10, ADC25, ADC75 and ADC90), skewness and kurtosis. The differences of ADC histogram parameters between CPAM and VS were compared using unpaired t-test. Multiple receiver operating characteristic (ROC) curves analysis was used to determine and compare the diagnostic value of each significant parameter. RESULTS: Significant differences were found on the ADCmean, ADCmedian, ADC10, ADC25, ADC75 and ADC90 between CPAM and VS (all p values < 0.001), while no significant difference was found on kurtosis (p = 0.562) and skewness (p = 0.047). ROC curves analysis revealed, a cut-off value of 1.126 * 10-3 mm2/s for the ADC90 value generated highest area under curves (AUC) for differentiating CPAM from VS (AUC, 0.975; sensitivity, 100%; specificity, 88.9%). CONCLUSIONS: Histogram analysis of ADC maps based on whole tumor can be a useful tool for differentiating radiological indeterminate CPAM from VS. The ADC90 value was the most promising parameter for differentiating these two entities. PMID- 26961386 TI - Molecular and Immunological Basis of Tubulo-Interstitial Injury in Lupus Nephritis: a Comprehensive Review. AB - Lupus nephritis is an important cause of kidney failure in patients of Asian, African, or Hispanic descent. Its etiology and pathogenesis are multifactorial and remain to be elucidated. Accumulating evidence suggests that anti-double stranded DNA (dsDNA) antibodies play a critical role in the pathogenesis, through its direct binding to cross-reactive antigens on resident renal cells or indirect binding through chromatin material to extracellular matrix components, resulting in complement activation, cell activation and proliferation, and induction of inflammatory and fibrotic processes. While tubulo-interstitial damage portends poor long-term renal prognosis, the mechanisms leading to tubulo-interstitial injury in lupus nephritis has received relatively less attention to date. Immune deposition along the tubular basement membrane is often observed in lupus nephritis and correlates with tubulo-interstitial infiltration of immune cells and interstitial fibrosis. Anti-dsDNA antibodies bind to resident renal cells, including proximal renal tubular epithelial cells, and contribute to renal inflammation and fibrosis. There is emerging evidence that epigenetic influence such as DNA methylation, histone modification, and microRNAs (miRs) also contribute to kidney fibrosis. Overexpression of miR-150 is observed in renal biopsies from patients with lupus nephritis and correlates with kidney fibrosis and chronicity score. Mycophenolate mofetil (MMF) is an established and effective standard-of-care therapy for patients with lupus nephritis. Accumulating data suggest that in addition to its immunosuppressive actions on lymphocyte proliferation, mycophenolic acid (MPA), the active metabolite of MMF, can exert a direct effect on nonimmune cells. Mediators of inflammation and fibrosis induced by anti-dsDNA antibodies in cultured proximal renal tubular epithelial cells are ameliorated by the addition of MPA, suggesting that in addition to its immunosuppressive actions, MPA may also have a beneficial effect in improving tubulo-interstitial inflammation and fibrosis through its direct action on proximal renal tubular epithelial cells. PMID- 26961391 TI - [When the information provided to participants of a comparative effectiveness trial ends up in the court: The opening of Pandora's box?]. PMID- 26961389 TI - Preliminary analysis of salivary microbiome and their potential roles in oral lichen planus. AB - Several studies have explored the origin and development mechanism of oral lichen planus (OLP) with limited attention to the role of bacteria in the progression of this common oral disease. Here we utilized MiSeq sequencing of 16S rRNA gene amplicons to identify complex oral microbiota associated with OLP from saliva samples of two subtypes (reticular and erosive) of OLP patients and healthy controls. Our analyses indicated that the overall structure of the salivary microbiome was not significantly affected by disease status. However, we did observe evident variations in abundance for several taxonomic groups in OLP. Porphyromonas and Solobacterium showed significantly higher relative abundances, whereas Haemophilus, Corynebacterium, Cellulosimicrobium and Campylobacter showed lower abundances in OLP patients, as compared with healthy controls. In addition, we explored specific microbial co-occurrence patterns in OLP, and revealed significantly fewer linkers of Streptococcus comprising species in erosive OLP. Furthermore, the disease severity and immune dysregulation were also genus associated, including with Porphyromonas that correlated to disease scores and salivary levels of interleukin (IL)-17 and IL-23. Overall, this study provides a general description of oral microbiome in OLP, and it will be useful for further investigation of their potential roles in the initiation and immune modulation of OLP. PMID- 26961390 TI - Patients' Knowledge, Beliefs, and Distress Associated with Detection and Evaluation of Incidental Pulmonary Nodules for Cancer: Results from a Multicenter Survey. AB - INTRODUCTION: Pulmonary nodules are detected in more than 1 million Americans each year. Prior qualitative work suggests that the detection of incidental pulmonary nodules can be burdensome for patients, but whether these findings generalize to a broader sample of patients is unknown. We categorized patients' knowledge, beliefs, and distress associated with detection and evaluation of a pulmonary nodule, as well as their impressions of clinician communication. METHODS: We administered a cross-sectional survey to adults with an incidental pulmonary nodule who were recruited from a rural medical center, an urban safety net hospital, and a Veterans Affairs hospital. RESULTS: Of the 490 individuals mailed surveys, 244 (50%) responded. Median nodule size was 7 mm, mean patient age was 67 years, 29% of respondents were female, and 86% were white. A quarter of the respondents (26%) reported clinically significant distress related to their nodule, our primary outcome, as measured by the Impact of Event Scale. Patients reported multiple concerns, including uncertainty about the nodule's cause (78%), the possibility of cancer (73%), and the possible need for surgery (64%). Only 25% of patients accurately estimated their lung cancer risk (within 15% of their actual risk); overall, there was no correlation between perceived and actual risk (r = -0.007, p = 0.93). The 23% of patients who did receive information on cancer risk from their provider were more likely to find this information reassuring (16%) than scary (7%). CONCLUSION: A quarter of patients with incidental pulmonary nodules experienced clinically significant distress. Knowledge about cancer risk and evaluation was poor. Clinician communication may help bridge knowledge gaps and alleviate distress in some patients. PMID- 26961392 TI - [Leptomeningeal gliomatosis]. PMID- 26961393 TI - [Hospital complications in the elderly]. PMID- 26961394 TI - [Diagnosis of antiphospholipid syndrome: From an historical perspective to the emergence of new autoantibodies]. PMID- 26961395 TI - [Non-Hodgkin's lymphoma presenting as Sneddon syndrome]. PMID- 26961396 TI - [Current treatment of chronic obstructive pulmonary disease]. PMID- 26961397 TI - [Levels of vitamin D in relation to injury profiles of professional football players]. PMID- 26961398 TI - [Schnitzler syndrome: Report of 3 cases]. PMID- 26961399 TI - [Current aspects of sarcoidosis]. PMID- 26961400 TI - [Pulmonary alveolar proteinosis: Analysis of 7 cases]. PMID- 26961401 TI - [Rituximab action on the antiphospholipid antibodies in patients with thrombotic antiphospholipid syndrome]. PMID- 26961402 TI - [Primary anetoderma: A cutaneous marker of prothrombotic states]. PMID- 26961403 TI - [Digital clubbing in pulmonary veno-occlusive disease]. PMID- 26961404 TI - [IgG4-related Riedel's thyroiditis]. PMID- 26961405 TI - Environmental dynamics of metal oxide nanoparticles in heterogeneous systems: A review. AB - Metal oxide nanoparticles (MNPs) have been used for many purposes including water treatment, health, cosmetics, electronics, food packaging, and even food products. As their applications continue to expand, concerns have been mounting about the environmental fate and potential health risks of the nanoparticles in the environment. Based on the latest information, this review provides an overview of the factors that affect the fate, transformation and toxicity of MNPs. Emphasis is placed on the effects of various aquatic contaminants under various environmental conditions on the transformation of metal oxides and their transport kinetics - both in homogeneous and heterogeneous systems - and the effects of contaminants on the toxicity of MNPs. The presence of existing contaminants decreases bioavailability through hetero-aggregation, sorption, and/or complexation upon an interaction with MNPs. Contaminants also influence the fate and transport of MNPs and exhibit their synergistic toxic effects that contribute to the extent of the toxicity. This review will help regulators, engineers, and scientists in this field to understand the latest development on MNPs, their interactions with aquatic contaminants as well as the environmental dynamics of their fate and transformation. The knowledge gap and future research needs are also identified, and the challenges in assessing the environmental fate and transport of nanoparticles in heterogeneous systems are discussed. PMID- 26961406 TI - Immunomodulation of Lactobacillus rhamnosus GG (LGG)-derived soluble factors on antigen-presenting cells of healthy blood donors. AB - Lactobacillus rhamnosus GG (LGG) cells have been shown to promote type-1 immune responsiveness; however knowledge of immunomodulation of soluble factors secreted by LGG is limited. This is the first study to investigate whether LGG soluble factors promote a comparable immune responsiveness as the bacterial cells. Both treatments - LGG conditioned medium with (CM + LGG) or without (CM) LGG cells, in this study increased expression of several toll-like receptors (TLRs) in all studied cell types and antigen presentation-associated receptor HLA-DR in macrophages and "intermediate" monocytes; but decreased that of activation markers on monocytes and macrophages and production of IL-10, IL-12 and TNFalpha in macrophages. In co-culture with mononuclear cells, CM increased Th1-type cytokine profile but not as pronounced as CM + LGG. This study suggests that LGG soluble factors exert similar immunomodulatory effects as the intact cells, but cells may be required for optimal type-1 immune responsiveness polarizing capacity of this probiotic strain. PMID- 26961407 TI - Protein Kinase C-alpha is a Critical Protein for Antisense Oligonucleotide mediated Silencing in Mammalian Cells. AB - We have identified the existence of a productive, PKC-alpha-dependent endocytotic silencing pathway that leads gymnotically-delivered locked nucleic acid (LNA) gapmer phosphorothioate antisense oligonucleotides (ASOs) into late endosomes. By blocking the maturation of early endosomes to late endosomes, silencing the expression of PKC-alpha results in the potent reduction of ASO silencing ability in the cell. We have also demonstrated that silencing of gene expression in the cytoplasm is vitiated when PKC-alpha expression is reduced. Restoring PKC-alpha expression via a reconstitution experiment reinstates the ability of ASOs to silence. These results advance our understanding of intracellular ASO trafficking and activity following gymnotic delivery, and further demonstrate the existence of two distinct silencing pathways in mammalian cells, one in the cytoplasmic and the other in the nuclear compartment. PMID- 26961410 TI - Temperature and pressure variations of d-d luminescence band maxima of bis(pyridylalkenolato)palladium(II) complexes with different ligand substituents: opposite-signed trends. AB - Luminescence spectra of two d(8)-configured bis(pyridylalkenolato)palladium(ii) complexes, [Pd{PyCHC(C3F7)O}2] and [Pd{PyCHC(CH3)O}2], are presented at variable temperature and pressure. Bands are assigned as d-d transitions. The heptafluoropropyl and methyl substituents on the ligands have different steric demands, influencing luminescence spectra. Broad bands with maxima at approximately 12 700 cm(-1) (790 nm) for ligands with heptafluoropropyl substituents and 12,100 cm(-1) (830 nm) for ligands with methyl substituents and widths of approximately 2100 cm(-1) for both complexes are observed at 80 K. Quenching of the luminescence is observed as temperature increases. The maxima of [Pd{PyCHC(C3F7)O}2] show a shift of -0.9 +/- 0.1 cm(-1) K(-1) due to broadening of the spectra to lower energy. The luminescence maxima of [Pd{PyCHC(CH3)O}2] shift in the opposite direction by +7.2 +/- 0.7 cm(-1) K(-1). Shifts with different signs are also obtained from variable-pressure luminescence spectra, with values of +13 +/- 2 cm(-1) kbar(-1) and -15 +/- 7 cm(-1) kbar(-1) for [Pd{PyCHC(C3F7)O}2] and [Pd{PyCHC(CH3)O}2], respectively. The pressure-induced decrease is unusual and likely caused by intermolecular interactions involving the palladium(ii) center and a vinylic proton of a neighboring complex. PMID- 26961409 TI - Graphene growth from reduced graphene oxide by chemical vapour deposition: seeded growth accompanied by restoration. AB - Understanding the underlying mechanisms involved in graphene growth via chemical vapour deposition (CVD) is critical for precise control of the characteristics of graphene. Despite much effort, the actual processes behind graphene synthesis still remain to be elucidated in a large number of aspects. Herein, we report the evolution of graphene properties during in-plane growth of graphene from reduced graphene oxide (RGO) on copper (Cu) via methane CVD. While graphene is laterally grown from RGO flakes on Cu foils up to a few hundred nanometres during CVD process, it shows appreciable improvement in structural quality. The monotonous enhancement of the structural quality of the graphene with increasing length of the graphene growth from RGO suggests that seeded CVD growth of graphene from RGO on Cu surface is accompanied by the restoration of graphitic structure. The finding provides insight into graphene growth and defect reconstruction useful for the production of tailored carbon nanostructures with required properties. PMID- 26961408 TI - Vastatin, an Endogenous Antiangiogenesis Polypeptide That Is Lost in Hepatocellular Carcinoma, Effectively Inhibits Tumor Metastasis. AB - Hepatocellular carcinoma (HCC) is a hypervascular cancer without effective treatment. Here we report that polypeptide of NC1 domain of type VIII collagen (Vastatin) is an endogenous polypeptide expressed in normal liver tissue but lost in the liver of most HCC patients (73.1%). Its expression level is negatively associated with tumor size (P = 0.035) and metastasis (P = 0.016) in HCC patients. To evaluate its potential use as a therapeutic, we constructed a recombinant adeno-associated virus carrying Vastatin (rAAV-Vastatin) to treat HCC in an orthotopic Buffalo rat model. rAAV-Vastatin treatment significantly prolonged the median survival, inhibited tumor growth, and completely prevented metastasis in HCC-bearing rats by decreasing microvessel density and increasing tumor necrosis. No detectable toxicity in nontumor-bearing mice was observed. To investigate its molecular mechanisms, we performed DNA microarray, western blotting assays, and bioinformatic analysis to determine its effect on global gene expression patterns and signal transduction pathways. Our results indicated that rAAV-Vastatin significantly reduced the expressions of Pck1, JAG2, and c Fos, thus inhibiting the cellular metabolism, Notch and AP-1 signaling pathways, respectively. Hence, we demonstrated for the first time that Vastatin is a novel, safe, and effective antiangiogenic therapeutic and a potential biomarker for HCC. PMID- 26961411 TI - Experimental Investigation of Temperature-Dependent Gilbert Damping in Permalloy Thin Films. AB - The Gilbert damping of ferromagnetic materials is arguably the most important but least understood phenomenological parameter that dictates real-time magnetization dynamics. Understanding the physical origin of the Gilbert damping is highly relevant to developing future fast switching spintronics devices such as magnetic sensors and magnetic random access memory. Here, we report an experimental study of temperature-dependent Gilbert damping in permalloy (Py) thin films of varying thicknesses by ferromagnetic resonance. From the thickness dependence, two independent contributions to the Gilbert damping are identified, namely bulk damping and surface damping. Of particular interest, bulk damping decreases monotonically as the temperature decreases, while surface damping shows an enhancement peak at the temperature of ~50 K. These results provide an important insight to the physical origin of the Gilbert damping in ultrathin magnetic films. PMID- 26961413 TI - Three-Dimensional Printing and Surgical Simulation for Preoperative Planning of Deformity Correction in Foot and Ankle Surgery. AB - A paucity of published data is available describing the methods for the integration of 3-dimensional (3D) printing technology and surgical simulation into orthopedic surgery. The cost of this technology has decreased and the ease of use has increased, making routine use of 3D printed models and surgical simulation for difficult orthopedic problems a realistic option. We report the use of 3D printed models and surgical simulation for preoperative planning and patient education in the case of deformity correction in foot and ankle surgery using open source, free software. PMID- 26961412 TI - Hyperactive mTOR signals in the proopiomelanocortin-expressing hippocampal neurons cause age-dependent epilepsy and premature death in mice. AB - Epilepsy is a frequent comorbidity in patients with focal cortical dysplasia (FCD). Recent studies utilizing massive sequencing data identified subsets of genes that are associated with epilepsy and FCD. AKT and mTOR-related signals have been recently implicated in the pathogenic processes of epilepsy and FCD. To clarify the functional roles of the AKT-mTOR pathway in the hippocampal neurons, we generated conditional knockout mice harboring the deletion of Pten (Pten-cKO) in Proopiomelanocortin-expressing neurons. The Pten-cKO mice developed normally until 8 weeks of age, then presented generalized seizures at 8-10 weeks of age. Video-monitored electroencephalograms detected paroxysmal discharges emerging from the cerebral cortex and hippocampus. These mice showed progressive hypertrophy of the dentate gyrus (DG) with increased expressions of excitatory synaptic markers (Psd95, Shank3 and Homer). In contrast, the expression of inhibitory neurons (Gad67) was decreased at 6-8 weeks of age. Immunofluorescence studies revealed the abnormal sprouting of mossy fibers in the DG of the Pten-cKO mice prior to the onset of seizures. The treatment of these mice with an mTOR inhibitor rapamycin successfully prevented the development of seizures and reversed these molecular phenotypes. These data indicate that the mTOR pathway regulates hippocampal excitability in the postnatal brain. PMID- 26961415 TI - Do Broken Toes Need Follow-Up in the Fracture Clinic? AB - Most toe phalangeal fractures can be successfully treated nonoperatively without any residual deformity and are usually clinically asymptomatic. Toe phalangeal fractures are nevertheless common fracture clinic referrals. Our aim was to evaluate the injury characteristics of patients with toe fractures attending a fracture clinic and to understand how current management affects the fracture clinic workload. We retrospectively evaluated all new referrals to a subspecialized foot and ankle fracture clinic during a 12-month period at our institution under the care of 1 consultant. Data were collected regarding patient demographics, fracture type, patient outcome, and the number of clinic appointments attended, cancelled, or not attended. A total of 707 new patients (mean age 39 +/- 19 years; 345 males, 362 females) were seen in 47 foot and ankle fracture clinics within the study period. Seventy-four phalangeal fractures were identified in 65 patients. A total of 135 outpatient appointments were scheduled for these patients (initial and follow-up), with 93 (69%) attended, 25 (19%) not attended, and 15 (11%) cancelled and rescheduled at the patient's request. Seventeen patients (13%) failed to attend their first clinic appointment. The results of the present study highlight that 9% of all new patient referrals to a fracture clinic were for toe phalangeal fractures. Only 2 patients required surgery for significant loss of articular congruency or deformity. No patient subsequently developed a symptomatic malunion or required toe surgery during the following 2 years. We believe that undisplaced and stable toe phalangeal fractures do not need to be referred to the fracture clinic. This would result in a reduction of outpatient appointments for toe fractures by 52%. PMID- 26961414 TI - An Alternative Surgical Approach to Pseudoainhum: A Case Report. AB - Pseudoainhum is a disorder of unknown etiology that is usually congenital and nonprogressive. One theory states it is caused by amnion band constriction in utero. These constriction bands lead, not only to a less cosmetically appealing foot, but also to long-term neurovascular compromise, resulting in amputation of the digit. The described surgical approaches have been limited within published data. The 2 procedures that have been described are either a Z-plasty or amputation, depending on the degree of the deformity. The present case report provides an alternative surgical approach to a pseudoainhum deformity of a third digit. PMID- 26961416 TI - Fatigue Stress Fracture of the Talar Body: An Uncommon Cause of Ankle Pain. AB - Fatigue stress fractures of the talus are rare and usually involve the head of the talus in military recruits. We report an uncommon cause of ankle pain due to a fatigue stress fracture of the body of the talus in a 32-year-old male social soccer player. Healing was achieved after weightbearing suppression for 6 weeks. Although rare, a stress fracture of the body of the talus should be considered in an athlete with a gradual onset of chronic ankle pain. Magnetic resonance imaging and bone scan are useful tools for early diagnosis. PMID- 26961418 TI - Corrigendum: Soot superaggregates from flaming wildfires and their direct radiative forcing. PMID- 26961417 TI - Talar Neck Fractures Treated Using a Highly Selective Incision: A Case-Control Study and Review of the Literature. AB - We describe a highly selective incision combined with percutaneous manipulation for reduction and internal fixation of talar neck fractures. We retrospectively investigated the clinical data from 29 cases of talar neck fractures treated from January 2009 to June 2013. Fifteen patients (study group) were treated using a 1- to 2-cm limited incision placed on the anteromedial or anterolateral side of the talus, followed by percutaneous reduction and fixation. Another 14 patients (control group) underwent open reduction and internal fixation through a conventional anteromedial or anterolateral approach. All cases were fixed with Herbert screws or cannulated titanium screws. All the patients were followed up for a minimum of 18 (median 24) months. All the fractures displayed bony union at or before the final follow-up visit. The mean American Orthopaedic Foot and Ankle Society ankle scale score in the study group was 75.3 +/- 17.7, 9 patients (60%) had good or excellent results, and 3 (20%) developed talar avascular necrosis. The mean ankle scale score in the control group was 78.9 +/- 15.2, 9 patients (64.3%) had good to excellent results, and 6 (42.9%) developed avascular necrosis. No statistically significant differences were found in the American Orthopaedic Foot and Ankle Society score, the number of good to excellent outcomes, or the incidence of complications between the incision groups. A highly selective incision combined with percutaneous reduction and internal fixation can be used to treat fractures of the neck of the talus satisfactorily. PMID- 26961419 TI - Application of Effective Discharge Analysis to Environmental Flow Decision Making. AB - Well-informed river management decisions rely on an explicit statement of objectives, repeatable analyses, and a transparent system for assessing trade offs. These components may then be applied to compare alternative operational regimes for water resource infrastructure (e.g., diversions, locks, and dams). Intra- and inter-annual hydrologic variability further complicates these already complex environmental flow decisions. Effective discharge analysis (developed in studies of geomorphology) is a powerful tool for integrating temporal variability of flow magnitude and associated ecological consequences. Here, we adapt the effectiveness framework to include multiple elements of the natural flow regime (i.e., timing, duration, and rate-of-change) as well as two flow variables. We demonstrate this analytical approach using a case study of environmental flow management based on long-term (60 years) daily discharge records in the Middle Oconee River near Athens, GA, USA. Specifically, we apply an existing model for estimating young-of-year fish recruitment based on flow-dependent metrics to an effective discharge analysis that incorporates hydrologic variability and multiple focal taxa. We then compare three alternative methods of environmental flow provision. Percentage-based withdrawal schemes outcompete other environmental flow methods across all levels of water withdrawal and ecological outcomes. PMID- 26961421 TI - A critical role of mevalonate for peptidoglycan synthesis in Staphylococcus aureus. AB - 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, a mevalonate synthetase, is required for the growth of Staphylococcus aureus. However, the essential role of the enzyme in cell growth has remained unclear. Here we show that three mutants possessed single-base substitutions in the mvaA gene, which encodes HMG-CoA reductase, show a temperature-sensitive phenotype. The phenotype was suppressed by the addition of mevalonate or farnesyl diphosphate, which is a product synthesized from mevalonate. Farnesyl diphosphate is a precursor of undecaprenyl phosphate that is required for peptidoglycan synthesis. The rate of peptidoglycan synthesis was decreased in the mvaA mutants under the non-permissive conditions and the phenotype was suppressed by the addition of mevalonate. HMG-CoA reductase activities of mutant MvaA proteins in the temperature sensitive mutants were lower than that of wild-type MvaA protein. Our findings from genetic and biochemical analyses suggest that mevalonate produced by HMG-CoA reductase is required for peptidoglycan synthesis for S. aureus cell growth. PMID- 26961422 TI - [Prognosis of symptomatic epilepsies in relation to their age of onset, monitored at a neuropediatric section of regional reference over a period of three years]. AB - AIM: To analyze the factors involved in the prognosis of symptomatic epilepsies in relation to their age at onset, monitored at a neuropediatric section of regional reference over a period of three years. PATIENTS AND METHODS: Children diagnosed with symptomatic epilepsy, supervised from January 1, 2008 to December 31, 2010, collecting epidemiological, clinical and developmental data. RESULTS: Of the 4595 children attended during the period, the diagnosis of epilepsy was established at 605 (13.17%): 277 (45.79%) symptomatic epilepsies. Symptomatic etiology predomininates in epileptic patients that started below one year of age, 67.72%, and between 1-3 years, 61.39%. 37.54% of symptomatic epilepsy is refractory, 72.92% have cognitive impairment, 55.23% have motor impairment and 17.32% have autism spectrum disorder. The younger the patient, the higher the percentage of refractoriness and display of any neurological or associated development impact. Some etiologies have higher rates of refractoriness. CONCLUSIONS: A useful classification would be etiological, with two groups: a large group with established etiology or very likely genetic syndromes and another with no established cause. The age of onset of epilepsy in each etiological group adds prognostic orientation. Prognosis of epilepsy is overshadowed by refractoriness and associated neurodevelopmental disorders, which are generally worse at an earlier onset and in certain etiologies. PMID- 26961420 TI - Utilization of Alcohol Treatment Among HIV-Positive Women with Hazardous Drinking. AB - Hazardous alcohol consumption has been frequently reported among women with HIV infection and is associated with a variety of negative health consequences. Treatments to reduce alcohol use may bring in health benefits. However, little is known regarding the utilization of alcohol treatment services among HIV+ women with hazardous drinking. Using data from the Women's Interagency HIV Study (WIHS), this study assessed utilization of any alcohol treatment in the past 6 months and performed multivariable logistic regression to determine correlates of receipt of any alcohol treatment. Among 474 HIV+ women reporting recent hazardous drinking, less than one in five (19%) reported recent utilization of any alcohol treatment. Alcoholics Anonymous (AA) was the most commonly reported (12.9%), followed by inpatient detoxification (9.9%) and outpatient alcohol treatment program (7.0%). Half (51%) receiving any alcohol treatment reported utilization of multiple treatments. Multivariable analyses found alcohol treatment was more often utilized by those who had social support (odds ratio [OR]=1.68, 95% confidence interval [CI]=1.00 to 2.83), fewer economic resources (income <=$12,000 vs. >$12,000, OR=3.10, 95% CI=1.53 to 6.27), higher levels of drinking (16-35 drinks/week vs. 12-15 drinks/week, OR=3.02, 95% CI=1.47 to 6.21; 36+ drinks/week vs. 12-15 drinks/week, OR=4.41, 95% CI=2.03 to 9.59), and those who reported any illicit drug use (OR=2.77, 95% CI=1.44 to 5.34). More efforts are needed to enhance the utilization of alcohol treatment. Our findings highlight the unique profile of those who utilized alcohol treatment. Such information is vital to improve treatment delivery to address unmet need in this particular population. PMID- 26961423 TI - [Neuropsychological profile in opsoclonus-myoclonus-ataxia syndrome presenting as neuroblastic tumours]. AB - INTRODUCTION: Sociosanitary improvements experienced in western society have significantly increased the survival of patients with opsoclonus-myoclonus-ataxia syndrome (OMAS). However, several studies have reported neurological, cognitive behavioral and development persistent deficits in 70-80% of these patients. PATIENTS AND METHODS: We reviewed cases of neuroblastic tumors diagnosed in a total period of 13 years and six months (from January 2000 to May 2013) and its association with OMAS in the pediatric service of a general hospital of a third level. Furthermore, it conducts a full neuropsychological study in three children diagnosed with OMAS. RESULTS: We objectified deficits in intelligence, attention, processing speed, memory, language, visuospatial and visuoconstructive skills, fine motor skills and executive functions. In addition, we found alterations in the psychological profile. CONCLUSIONS: Data emphasize the role of the cerebellum in complex cognitive processing in child population probably linked to neurodevelopmental deficits in this structure caused by deficiencies of the immune system. The results are interpreted in the framework of child neuropsychology and their interest in studying the brain-behavior relationships in the dynamic context of brain development. PMID- 26961424 TI - [Postmastectomy pain syndrome in our region: characteristics, treatment, and experience with gabapentin]. AB - INTRODUCTION: Postmastectomy pain syndrome affects up to a half of the patients treated for breast cancer. AIMS: Characterization of this syndrome and its evolution. Measure pharmaceutical treatment (specifically with gabapentin). PATIENTS AND METHODS: A retrospective study of 89 patients with more than five years monitoring was carried out. RESULTS: Of the patients included in the study 88% had not been previously diagnosed. The mean age of the patients was 56.49 years old. The pain lasted on average 29.15 months. In 71% the neurological symptoms corresponded to the second intercostobrachial nerve. The average pain value for patients before treatment on the Visual Analog Scale was 66.5 and 13.14 on the Lattinen Index. The treatment with gabapentin at an average dose of 1,135 mg for 14 weeks reduced pain in 80% of the patients (p < 0.0001). In the majority of the patients the reduction was maintained in the long term. Ten percent continued the treatment whereas another 10% suspended treatment due to side effects. The average necessary number of patients to be treated was 2.13. Of those treated with gabapentin 35% relapsed while 15.68% changed medication compared to 50% of those treated with other indicated neuropathic drugs (p = 0.046). No difference in the effectiveness between both groups was found. CONCLUSIONS: Postmastectomy pain is an under-diagnosed pathology. Treatment (in particular with gabapentin) can be significantly effective and well tolerated in up to 90% of postmastectomy pain syndrome patients. PMID- 26961425 TI - [Effects of a 'theory of mind' cognitive development pilot programme in three children with autism: emotional component]. AB - INTRODUCTION: Theory of mind is defined as the capacity to predict, understand and act when faced with other people's behaviour, their knowledge, their intentions, their emotions and their beliefs. It is proposed as a feasible alternative for establishing a programme adapted to the characteristics of children diagnosed with autism spectrum disorder. CASE REPORTS: The effect of a 'theory of mind' cognitive development pilot programme on the emotional skills of three children with autism spectrum disorder is reported. Case 1: 9-year-old boy, with scarce emotional identification and expression, as well as difficulties to hold fluent and coherent conversations. Case 2: 10-year-old boy, with mechanical, not very fluent language, and difficulties to start and maintain a conversation. Case 3: 8-year-old girl who presents deficits in the non-verbal communicative behaviours used in social interaction and difficulties to adapt to situations other than everyday ones. In the three cases there is an improvement in the emotional capacities following implementation of the programme; moreover, their parents, teachers or therapists perceived positive changes in the children's adaptive skills. CONCLUSIONS: The methodological and structural aspects of the cognitive development programme were well-suited to the children with autism who took part in the research study. Due to the preliminary nature of this study, it is suggested that future research should utilise a larger sample and a double blind design with randomised case-controls that allow the findings to be generalised. PMID- 26961426 TI - [Enhancement of motor relearning and functional recovery in stroke patients: non invasive strategies for modulating the central nervous system]. AB - INTRODUCTION: Most of the stroke survivors do not recover the basal state of the affected upper limb, suffering from a severe disability which remains during the chronic phase of the illness. This has an extremely negative impact in the quality of life of these patients. Hence, neurorehabilitation strategies aim at the minimization of the sensorimotor dysfunctions associated to stroke, by promoting neuroplasticity in the central nervous system. DEVELOPMENT: Brain reorganization can facilitate motor and functional recovery in stroke subjects. None-theless, after the insult, maladaptive neuroplastic changes can also happen, which may lead to the appearance of certain sensori-motor disorders such as spasticity. Noninvasive brain stimulation strategies, like transcranial direct current stimulation or transcranial magnetic stimulation, are widely used techniques that, when applied over the primary motor cortex, can modify neural networks excitability, as well as cognitive functions, both in healthy subjects and individuals with neurological disorders. Similarly, brain-machine-interface systems also have the potential to induce a brain reorganization by the contingent and simultaneous association between the brain activation and the peripheral stimulation. CONCLUSION: This review describes the positive effects of the previously mentioned neurorehabilitation strategies for the enhancement of cortical reorganization after stroke, and how they can be used to alleviate the symptoms of the spasticity syndrome. PMID- 26961427 TI - [Management of a traumatic bilateral carotid-cavernous fistula: a schematic representation of the different types of carotid-cavernous communication]. PMID- 26961428 TI - [Alice in Wonderland syndrome as a prodrome of streptococcal tonsillopharyngitis]. PMID- 26961429 TI - [Thalamic stroke secondary to vertebral dissection after doing yoga]. PMID- 26961430 TI - [In Memoriam. Jaime Campos Castello (1940-2015)]. PMID- 26961431 TI - Evolution of the alpha-Subunit of Na/K-ATPase from Paramecium to Homo sapiens: Invariance of Transmembrane Helix Topology. AB - Na/K-ATPase is a key plasma membrane enzyme involved in cell signaling, volume regulation, and maintenance of electrochemical gradients. The alpha-subunit, central to these functions, belongs to a large family of P-type ATPases. Differences in transmembrane (TM) helix topology, sequence homology, helix-helix contacts, cell signaling, and protein domains of Na/K-ATPase alpha-subunit were compared in fungi (Beauveria), unicellular organisms (Paramecia), primitive multicellular organisms (Hydra), and vertebrates (Xenopus, Homo sapiens), and correlated with evolution of physiological functions in the alpha-subunit. All alpha-subunits are of similar length, with groupings of four and six helices in the N- and C-terminal regions, respectively. Minimal homology was seen for protein domain patterns in Paramecium and Hydra, with high correlation between Hydra and vertebrates. Paramecium alpha-subunits display extensive disorder, with minimal helix contacts. Increases in helix contacts in Hydra approached vertebrates. Protein motifs known to be associated with membrane lipid rafts and cell signaling reveal significant positional shifts between Paramecium and Hydra vulgaris, indicating that regional membrane fluidity changes occur during evolution. Putative steroid binding sites overlapping TM-3 occurred in all species. Sites associated with G-protein-receptor stimulation occur both in vertebrates and amphibia but not in Hydra or Paramecia. The C-terminus moiety "KETYY," necessary for the Na(+) activation of pump phosphorylation, is not present in unicellular species indicating the absence of classical Na(+)/K(+) pumps. The basic protein topology evolved earliest, followed by increases in protein domains and ordered helical arrays, correlated with appearance of alpha subunit regions known to involve cell signaling, membrane recycling, and ion channel formation. PMID- 26961433 TI - Detection of Epidermal Growth Factor Receptor Mutations in Lung Adenocarcinoma: Comparing Cobas 4800 EGFR Assay With Sanger Bidirectional Sequencing. AB - INTRODUCTION: Accurate detection of epidermal growth factor receptor (EGFR) mutations has a crucial role in the current treatment of patients with lung adenocarcinoma, and identification of clinically relevant mutations would qualify patients for treatment with tyrosine kinase inhibitors. Historically, Sanger sequencing has been used as the reference standard assay for EGFR mutational analysis; however, Cobas 4800 is a relatively new method. In the present study, we compared the performance of the Cobas assay against that of Sanger sequencing. MATERIALS AND METHODS: A total of 493 consecutive formalin-fixed paraffin embedded samples of lung adenocarcinoma were simultaneously tested for EGFR mutations using both methods. RESULTS: After exclusion of the invalid results (n = 19), 474 samples from 455 patients were analyzed. The Cobas assay showed a mutation detection rate comparable to that of Sanger sequencing (18.1% vs. 17.9%, respectively; P < .05). Excellent agreement of 98.9% (kappa, 0.964) was observed between the 2 methods. CONCLUSION: The Cobas assay is a fast and diagnostically robust platform with high analytical sensitivity; however, it is limited by its detection range and low tolerance to low DNA quality. Sanger sequencing is mostly affected by its lower analytic sensitivity. Ultimately, a dual testing strategy will be justified to increase the detection of novel mutations and reduce the false-negative results within an acceptable turnaround time. PMID- 26961432 TI - Unmasking the ancestral activity of integron integrases reveals a smooth evolutionary transition during functional innovation. AB - Tyrosine (Y)-recombinases have evolved to deliver mechanistically different reactions on a variety of substrates, but these evolutionary transitions are poorly understood. Among them, integron integrases are hybrid systems recombining single- and double-stranded DNA partners. These reactions are asymmetric and need a replicative resolution pathway, an exception to the canonical second strand exchange model of Y-recombinases. Integron integrases possess a specific domain for this specialized pathway. Here we show that despite this, integrases are still capable of efficiently operating the ancestral second strand exchange in symmetrical reactions between double-stranded substrates. During these reactions, both strands are reactive and Holliday junction resolution can follow either pathway. A novel deep-sequencing approach allows mapping of the crossover point for the second strand exchange. The persistence of the ancestral activity in integrases illustrates their robustness and shows that innovation towards new recombination substrates and resolution pathways was a smooth evolutionary process. PMID- 26961434 TI - Distal locking in short hip nails: Cause or prevention of peri-implant fractures? AB - OBJECTIVES: The most common cause of femoral fractures after osteosynthesis of trochanteric fractures with short nails is weakening of the femoral cortex via distal locking and stress concentrations at the tip of the nail. The aim of the study was to verify whether the incidence of peri-implant fractures is dependent upon the distal locking technique. METHODS: We prospectively analysed a group of 849 pertrochanteric fractures (AO/ASIF 31-A1+2) managed with short nails from 2009 to 2013. Unlocked nailing was performed in 70.1% and distal dynamic locking was performed in 29.9%. The mean age was 82.0 years. Peri-implant fractures were divided into 3 groups according to the height of the fracture in relation to the tip of the nail. RESULTS: In total 17 fractures (2.0%) were detected. One peri implant fracture occurred after locked nailing, whereas 16 cases occurred after unlocked nailing (p=0.037). Patients without distal locking had an 85.7% greater risk of peri-implant fracture. Fractures of the proximal femur (Type I) occurred significantly earlier than fractures at the tip of the nail (Type II) (p=0.028). CONCLUSION: Unlocked nails do not guarantee sufficient stability. Distal locking serves to prevent postoperative femoral fractures. We recommend the routine use of distal locking when utilizing short nails. PMID- 26961435 TI - A forensic inquiry into compliance to guidelines for emergency resuscitative thoracotomy in trauma: If the dead can't talk and the living won't tell, it is a story half told. PMID- 26961437 TI - What we need to know about Zika virus. PMID- 26961438 TI - Understanding safe discharge of patients with dementia from the acute hospital. PMID- 26961440 TI - Transcatheter aortic valve implantation: past, present and future. AB - Transcatheter aortic valve implantation is one of the most significant technological advances in cardiovascular medicine. It offers a safe alternative in high risk cardiac patients with proven durability, economical viability and survival advantage. Current trials may expand its application in intermediate or low risk groups. PMID- 26961436 TI - Cross-cultural variation in preference for replantation or revision amputation: Societal and surgeon views. AB - Treatment decisions after an injury like finger amputation are made based on injury and patient factors. However, decisions can also be influenced by provider and patient preferences. We compared hand surgeon and societal preferences and attitudes regarding finger amputation treatment in Japan and the US. We performed a cross-sectional survey with subjects derived from large tertiary care academic institutions in the US and Japan. We secured 100% participation of American hand surgeon members of the Finger Replantation and Amputation Multicenter Study and presenting hand surgeons at the 32nd Annual meeting of the Central Japanese Society for Surgery of the Hand. Societal preferences were gathered from volunteers at the 2 universities in the US and Japan. There were no significant differences in estimations of function, sensation, or appearance after replantation; American and Japanese societal participants preferred replantation compared to surgeons, although this was more pronounced in Japan. The Japanese society displayed more negative attitudes toward finger amputees than did Japanese surgeons. American respondents anticipated more public stigmatisation of amputees than did American surgeons. Societal preference for replantation was not caused by inflated expectations of outcomes after replantation. Japanese societal preference was likely driven by negative views of finger amputees. American society noted no decrease in physical health after amputation, but did note a quality of life decrease attributed to public stigmatisation. Japanese society and surgeons had a stronger preference for replantation than American society and surgeons, possibly attributed to cultural differences. PMID- 26961441 TI - The assessment of aortic stenosis: echocardiography and beyond. AB - Aortic stenosis is the most common primary valve problem. This article describes its assessment and clinical interpretation using echocardiography and also shows how magnetic resonance, cardiac computed tomography and stress testing may be useful. PMID- 26961442 TI - Sound mind vs sound heart. AB - Depressive and anxiety disorders have both have been associated with an increased risk of cardiovascular disease. This article highlights the multifactorial and bidirectional interaction between cardiovascular diseases, depression and anxiety, and the need for early assessment, diagnosis and intervention. PMID- 26961443 TI - Abdominal wall reconstruction: an emerging and rewarding specialty. PMID- 26961444 TI - Abdominal wall reconstruction. AB - Abdominal wall hernias can be challenging and complicated to manage. The techniques to deal with them are evolving rapidly with increasing adaptation and utilization in general surgery. PMID- 26961445 TI - Which mesh or graft? Prosthetic devices for abdominal wall reconstruction. AB - This article reviews the ever-increasing number of prosthetic devices--both synthetic mesh and biologic grafts--now in use for abdominal wall reconstruction. It also introduces a novel hybrid synthetic/biologic graft (Zenapro) and suture passer device (Novapass). PMID- 26961446 TI - Transforming surgery through biomaterial template technology. AB - Templates inserted into surgical wounds strongly influence the healing responses in humans. The science of these templates, in the form of extracellular matrix biomaterials, is rapidly evolving and improving as the natural interactions with the body become better understood. PMID- 26961447 TI - The Liverpool Care Pathway: what went right and what went wrong. AB - The history of the Liverpool Care Pathway shows how the best of intentions, and good guidelines, can be perverted by poor practice, lack of thought, poor training and inadequate communication. Good clinical leadership can encourage high quality care of dying people, whatever guidelines are being used, or not. PMID- 26961448 TI - The management of bipolar disorder. AB - Bipolar disorder is a common mental disorder which is relapsing and remitting in nature. Subsyndromal symptoms are common and associated with poorer outcomes. Management of the disorder can be challenging and depends on the polarity and severity of the mood episode. PMID- 26961450 TI - Safe and sustainable increases in day case emergency surgery. AB - Selected patients referred to emergency general surgery departments are suitable for day case emergency surgery with no overnight hospital stay. There are no well described sustainable pathways for these expedited operations and in many hospitals patients undergo unnecessary admissions and experience long waiting times. METHODS: The authors proposed a new, sustainable, day case emergency surgery pathway which was implemented to streamline the assessment, treatment and discharge of acute surgical referrals. It requires rapid assessment of the patient by a senior clinician, and ready availability of diagnostic services and operating facilities. To assess this pathway, the authors conducted a prospective audit of general surgical referrals to a district general hospital in the UK. RESULTS: During the inclusion period 746 emergency referrals were assessed, 281 (37%) of these underwent an operation. Over a 5-month investigation period, the audit found that approximately 27% of all emergency general surgery patients requiring an operation could be managed with day case emergency surgery. This figure was maintained throughout the duration of the study. Operations included incision and drainage of abscesses, incarcerated hernia repairs and appendicectomies. The average length of stay of all surgical admissions decreased from 5 days to less than 3 days and the median time to senior review was 30 minutes. DISCUSSION: The authors have developed a pathway involving permanent members of the surgical assessment team that is sustainable over a 5-month period. The pathway has allowed rapid assessment of patients and reduced unnecessary inpatient stay in a sustainable and reproducible manner. PMID- 26961451 TI - The importance and practice of debrief in medical simulation. PMID- 26961452 TI - Non-Hodgkin's lymphoma causing light-chain (AL) amyloidosis. PMID- 26961453 TI - Recognizing and managing food-dependent exercise-induced anaphylaxis. PMID- 26961454 TI - Hamman syndrome. PMID- 26961455 TI - Elie Metchnikoff, father of phagocytosis. PMID- 26961457 TI - Regional anaesthesia: asleep vs awake? PMID- 26961458 TI - Hand anatomy. PMID- 26961459 TI - Assessment of hand injuries. PMID- 26961460 TI - Examination of the adult knee. PMID- 26961461 TI - Cardiorenal syndrome type 4: From chronic kidney disease to cardiovascular impairment. AB - Cardiorenal syndrome type 4 (CRS type 4), or chronic renocardiac syndrome, has been defined as "chronic abnormalities in renal function leading to cardiac disease" and recognizes the extreme burden of cardiovascular disease (CVD) risk in patients with chronic kidney disease (CKD). CKD is common and increasingly recognized as a risk factor for CVD. Even though the treatment for CVD has dramatically improved over the past decades, it still takes responsibility for up to 50% of deaths in CKD patients. For this reason, patients with CKD should be thoroughly evaluated for cardiovascular risk factors that require careful management, given the significant burden of CRS type 4 on the healthcare system. This review focuses on the most significant conventional and non-conventional CVD risk factors related to CKD. PMID- 26961462 TI - A smart fluorescence nanoprobe for the detection of cellular alkaline phosphatase activity and early osteogenic differentiation. AB - In the past decades, biomaterials were designed to induce stem cell toward osteogenic differentiation. However, conventional methods for evaluation osteogenic differentiation all required a process of cell fixation or lysis, which induce waste of a large number of cells. In this study, a fluorescence nanoprobe was synthesized by combining phosphorylated fluoresceinamine isomer I (FLA) on the surface of mesoporous silica-coated superparamagnetic iron oxide (Fe3O4@mSiO2) nanoparticles. In the presence of alkaline phosphatase (ALP), the phosphorylated FLA on the nanoprobe would be hydrolyzed, resulting in a fluorescence recovery of FLA. During early osteogenic differentiation, a high level expression of cellular ALP was induced, which accelerated the hydrolysis of phosphorylated FLA, resulting in an enhancement of cellular fluorescence intensity. This fluorescence nanoprobe provides us a rapid and non-toxic method for the detection of cellular ALP activity and early osteogenic differentiation. PMID- 26961464 TI - Enhanced efficacy and anti-biofilm activity of novel nanoemulsions against skin burn wound multi-drug resistant MRSA infections. AB - Multi-drug resistant MRSA (methicillin-resistant Staphylococcus aureus) is a global problem for human health, especially skin burn wound patients. Therefore, we estimated the antibacterial and anti-biofilm activity of a chlorhexidine acetate nanoemulsion (CNE) by previously ourselves designed against skin burn wound MRSA infections. Compared with its water solution (CHX), CNE showed a better and faster action against MRSA both in vitro and in vivo. Importantly, CNE was more effective at inhibiting biofilm formation and clearing the biofilm. We also found that the cell walls and membranes of MRSA were severely disrupted after treatment with CNE. Moreover, the relative electrical conductivity and the leakage of alkaline phosphates, K(+), Mg(2+), DNA and protein obviously increased because the cell wall and membrane were damaged. These data show that novel CNE is a promising potential antimicrobial candidate, especially for skin burn wound MRSA infections. PMID- 26961463 TI - Cellular distribution of injected PLGA-nanoparticles in the liver. AB - The cellular fate of nanoparticles in the liver is not fully understood. Because the effectiveness and safety of nanoparticles in liver therapy depends on targeting nanoparticles to the right cell populations, this study aimed to determine a relative distribution of PLGA-nanoparticles (sizes 271+/-1.4 nm) among liver cells in vivo. We found that Kupffer cells were the major cells that took up nanoparticles, followed by liver sinusoidal endothelial cells and hepatic stellate cells. Nanoparticles were found in only 7% of hepatocytes. Depletion of Kupffer cells by clodronate liposomes increased nanoparticle retention in liver sinusoidal endothelial cells and hepatic stellate cells, but not in hepatocytes. It is importantly suggested that studies of drug-loaded nanoparticle delivery to the liver have to demonstrate not only uptake of nanoparticles by the target cell type but also non-uptake by other cell types to assess their effect as well as ensure their safety. PMID- 26961465 TI - The osteogenic capacity of biomimetic hierarchical micropore/nanorod-patterned Sr HA coatings with different interrod spacings. AB - Advanced titanium based bone implant with fast established, rigid and stable osseointegration is stringently needed in clinic. Here the hierarchical micropore/nanorod-patterned strontium doped hydroxyapatite (Ca9Sr1(PO4)6(OH)2, Sr1-HA) coatings (MNRs) with different interrod spacings varying from about 300 to 33nm were developed. MNRs showed dramatically differential biological performance closely related to the interrod spacing. Compared to micropore/nanogranule-patterned Sr1-HA coating (MNG), MNRs with an interrod spacing of larger than 137nm resulted in inhibited in vitro mesenchymal stem cell functions and in vivo osseointegration, while those of smaller than 96nm gave rise to dramatically enhanced the biological effect, especially those of mean 67nm displayed the best effect. The differential biological effect of MNRs was related to their modulation on the focal adhesion mediated mechanotransduction. These results suggest that MNRs with a mean interrod spacing of 67nm may give rise to an advanced implant of improved clinical performance. PMID- 26961466 TI - Investigating the role of mucin in the delivery of nanoparticles to cellular models of human cancer disease: an in vitro study. AB - Mucin, a glycosylated protein, is aberrantly overexpressed in a variety of tumor cells. The glycoprotein mesh decreases the rate of intracellular drug uptake and effectiveness. We investigated the influence of the mucin mesh on the cellular uptake of anti-MUC1 antibody and nanoparticles by fluorescence spectroscopy and microscopy. A glycosylation inhibitor (benzyl-alpha-GalNAc) was employed to regulate mucin glycosylation events. In our panel of pancreatic cell lines, only PANC-1 cells exhibited a significant increase in the uptake of liposomes following glycosylation inhibition, resulting in improved cytotoxicity of gemcitabine-loaded liposomes. Interestingly, areas devoid of liposome uptake were observed for pancreatic cancer cell lines PANC-1, Capan-1, and Capan-2; however, these restricted regions could be diminished for PANC1 cells only. In conclusion, investigating the reason(s) for differential cellular uptake of nanoparticles, in association with the production of mucin glycosylation mesh, should provide valuable leads to the future development of nanomedicine for cancer treatment. PMID- 26961467 TI - Coassembled nanostructured bioscaffold reduces the expression of proinflammatory cytokines to induce apoptosis in epithelial cancer cells. AB - The local inflammatory environment of the cell promotes the growth of epithelial cancers. Therefore, controlling inflammation locally using a material in a sustained, non-steroidal fashion can effectively kill malignant cells without significant damage to surrounding healthy cells. A promising class of materials for such applications is the nanostructured scaffolds formed by epitope presenting minimalist self-assembled peptides; these are bioactive on a cellular length scale, while presenting as an easily handled hydrogel. Here, we show that the assembly process can distribute an anti-inflammatory polysaccharide, fucoidan, localized to the nanofibers within the scaffold to create a biomaterial for cancer therapy. We show that it supports healthy cells, while inducing apoptosis in cancerous epithelial cells, as demonstrated by the significant down regulation of gene and protein expression pathways associated with epithelial cancer progression. Our findings highlight an innovative material approach with potential applications in local epithelial cancer immunotherapy and drug delivery. PMID- 26961468 TI - RGD peptide-conjugated selenium nanoparticles: antiangiogenesis by suppressing VEGF-VEGFR2-ERK/AKT pathway. AB - Angiogenesis is essential for tumorigenesis, progression and metastasis. Herein we described the synthesis of RGD peptide-decorated and doxorubicin-loaded selenium nanoparticles (RGD-NPs) targeting tumor vasculature to enhance the cellular uptake and antiangiogenic activities in vitro and in vivo. After internalization by receptor-mediated endocytosis, this nanosystem disassembled under acidic condition with the presence of lysozymes and cell lysate, leading to bioresponsive triggered drug release. Mechanistic investigation revealed that RGD NPs inhibited angiogenesis through induction of apoptosis and cell cycle arrest in human umbilical vein endothelial cells (HUVECs) via suppression of VEGF-VEGFR2 ERK/AKT signaling axis by triggering ROS-mediated DNA damage. Additionally, RGD NPs can inhibit MCF-7 tumor growth and angiogenesis in nude mice via down regulation of VEGF-VEGFR2, effectively reduce the toxicity and prolong the blood circulation in vivo. Our results suggest that the strategy to use RGD-peptide functionalized SeNPs as carriers of anticancer drugs is an efficient way to achieve cancer-targeted antiangiogenesis synergism. PMID- 26961469 TI - Asymmetric Total Syntheses of Aspidodasycarpine, Lonicerine, and the Proposed Structure of Lanciferine. AB - Aspidodasycarpine and lonicerine are a pair of epimeric aspidophylline-type alkaloids bearing vicinal quaternary C7 and C16. The first and enantioselective total syntheses of these molecules are described here. A Ru-catalyzed asymmetric transfer hydrogenation established the first stereocenter. An Au-promoted Toste cyclization was exploited to assemble the bridged tetracyclic core and define the geometry of the exocyclic olefin; electron deficient (p-CF3C6H4)3P was a suitable ligand for this transformation. An aldol condensation followed by an intramolecular indole C3 alkylation constructed the adjacent quaternary C7 and C16 diastereoselectively, leading to a pentacyclic lactol as an advanced common intermediate for synthesizing both alkaloids. The proposed structure of lanciferine, a highly oxidized congener of aspidodasycarpine, was synthesized from the lactol by tuning the oxidation states of various carbons. PMID- 26961470 TI - An Introduction to a Special Issue on Stormwater. PMID- 26961471 TI - Impact of Stormwater Discharges on Water Quality in Coastal Marine Protected Areas. AB - Marine protected areas worldwide limit harvest to protect sensitive fisheries, but rarely do they address water quality goals that may have equally demonstrable impacts. California has over 500 coastal shoreline miles of marine protected areas designated as Areas of Special Biological Significance (ASBS), but receives untreated wet weather runoff discharges from over 1600 storm drain outfalls. The goal of this study was to assess the extent and magnitude of water quality impacts in ASBS following storm events. A stratified probabilistic design was used for sampling receiving water shorelines near (discharge) and far (non discharge) from storm drain outfalls. In general, reasonably good water quality exists in California's ASBS following storm events. Many of the target analytes measured did not exceed water quality standards. The post-storm concentrations of most constituents in discharge and non-discharge strata of ASBS were similar. The three potentially problematic parameters identified were total PAH, chromium, and copper. PMID- 26961473 TI - Laboratory Evaluation of Sorptive Filtration Media Mixtures for Targeted Pollutant Removals from Simulated Stormwater. AB - Urban stormwater pollutants including nutrients, trace metals, polycyclic aromatic hydrocarbons (PAHs), total suspended solids (TSS) and indicator microorganisms (E. coli) were the target pollutants in this study. Their simultaneous removal from synthetic stormwater using different sorptive media was investigated through laboratory-scale column experiments. The media considered for testing were calcite (C), sand (S), zeolite (Z) and iron filings (Fe(0)). These media are easily/commercially available, environmentally benign, long lasting (non-biodegradable), highly permeable and effective in removing multiple target pollutants. Based on individual media testing, three different mixed media compositions were selected (1) C-Z-S, (2) C-S-Fe(0) and (3) C-Z-S-Fe(0), for simultaneous removal of target pollutants using column experiments. The mixed media composition, C-Z-S-Fe(0) showed significantly better simultaneous removal of all the target pollutants as compared to the other two compositions. These compositions can be tailored to meet site-specific stormwater pollutant removal in a passive in-ground sorptive media filter. PMID- 26961472 TI - Settling Efficiency of Urban Particulate Matter Transported by Stormwater Runoff. AB - The main purpose of control measures in urban areas is to retain particulate matter washed out by stormwater over impermeable surfaces. In stormwater control measures, particulate matter removal typically occurs via sedimentation. Settling column tests were performed to examine the settling efficiency of such units using monodisperse and heterodisperse particulate matter (for which the particle size distributions were measured and modelled by the cumulative gamma distribution). To investigate the dependence of settling efficiency from the particulate matter, a variant of the evolutionary polynomial regression (EPR), a Microsoft Excel function based on multi-objective EPR technique (EPR-MOGA), called EPR MOGA XL, was used as a data-mining strategy. The results from this study have shown that settling efficiency is a function of the initial total suspended solids (TSS) concentration and of the median diameter (d50 index), obtained from the particle size distributions (PSDs) of the samples. PMID- 26961474 TI - Effects of Stormwater Pipe Size and Rainfall on Sediment and Nutrients Delivered to a Coastal Bayou. AB - Pollutants discharged from stormwater pipes can cause water quality and ecosystem problems in coastal bayous. A study was conducted to characterize sediment and nutrients discharged by small and large (< 20 cm and >20 cm in internal diameters, respectively) pipes under different rainfall intensities (< 2.54 cm and > 2.54 cm, respectively). Results showed that large pipes had greater discharge than small pipes. Pollutants concentrations did not vary by pipe size. Large pipes had greater loads of TSS (138.2 vs. 24.0 mg/s), NO3(-) (5.54 vs. 2.74 mg/s), and NH4(+) (0.39 vs. 0.19 mg/s) than small pipes. Neither discharge nor constituents varied by rainfall events. Pipe size may be a useful metric for estimating loads to a system. Nutrient reduction efforts should be directed to reducing the dissolved nutrient pools, while stormwater management efforts should be directed to reducing pipe freshwater discharge volumes that drive constituent loads. PMID- 26961475 TI - Emission of Carbon Dioxide and Methane from Duckweed Ponds for Stormwater Treatment. AB - This study determined the greenhouse gas emission from two laboratory-scale duckweed ponds for stormwater treatment. The rate of carbon dioxide (CO2) emission from the two duckweed systems was 1472 +/- 721 mg/m(2).d and 626 +/- 234 mg/m(2).d, respectively. After the removal of duckweeds, CO2 emissions decreased to 492 +/- 281 mg/m(2).d and 395 +/- 53 mg/m(2).d, respectively. The higher CO2 emissions in the duckweed systems were attributed to duckweed biomass decay on the pond soil surface. A thin-film model was able to predict the increasing CO2 concentrations in the closed static chamber during 2 weeks of sampling. The initial methane fluxes from the duckweed systems were 299 +/- 74 mg/m(2).d and 180 +/- 91 mg/m(2).d, respectively. After the removal of duckweeds, the flux increased to 559 +/- 215 mg/m(2).d and 328 +/- 114 mg/m(2).d, respectively. PMID- 26961476 TI - Characterization of Stormwater Runoff from a Light Rail Transit Area. AB - The monitoring of stormwater runoff from Light Rail Transit (LRT) facilities is insufficient in many regions around the world. In this study, runoff quality and quantity were monitored during operational and non-operational LRT phases during 2010-2013. The event mean concentration (EMC) of pollutants showed little statistical variability during both phases. The antecedent dry day (ADD) showed a strong to moderate positive correlation with most pollutant EMCs during the non operational phase. The existence and magnitude of the first flush from LRT runoff was found to be similar to those from other transportation land uses. The comparison of LRT runoff data with an adjacent road bridge site showed that the pollutant EMC and unit load were 2 to 9 times higher from the road bridge. It was suggested that LRT automated operation and the elevated track makes this transportation mode a viable option for the management of non-point source pollution. PMID- 26961477 TI - Roofing Materials Assessment: Investigation of Five Metals in Runoff from Roofing Materials. AB - To assess the contribution of five toxic metals from new roofing materials to stormwater, runoff was collected from 14 types of roofing materials and controls during 20 rain events and analyzed for metals. Many of the new roofing materials evaluated did not show elevated metals concentrations in the runoff. Runoff from several other roofing materials was significantly higher than the controls for arsenic, copper, and zinc. Notably, treated wood shakes released arsenic and copper, copper roofing released copper, PVC roofing released arsenic, and Zincalume(r) and EPDM roofing released zinc. For the runoff from some of the roofing materials, metals concentrations decreased significantly over an approximately one-year period of aging. Metals concentrations in runoff were demonstrated to depend on a number of factors, such as roofing materials, age of the materials, and climatic conditions. Thus, application of runoff concentrations from roofing materials to estimate basin-wide releases should be undertaken cautiously. PMID- 26961478 TI - Critical Review of Technical Questions Facing Low Impact Development and Green Infrastructure: A Perspective from the Great Plains. AB - Since its inception, Low Impact Development (LID) has become part of urban stormwater management across the United States, marking progress in the gradual transition from centralized to distributed runoff management infrastructure. The ultimate goal of LID is full, cost-effective implementation to maximize watershed scale ecosystem services and enhance resilience. To reach that goal in the Great Plains, the multi-disciplinary author team presents this critical review based on thirteen technical questions within the context of regional climate and socioeconomics across increasing complexities in scale and function. Although some progress has been made, much remains to be done including continued basic and applied research, development of local LID design specifications, local demonstrations, and identifying funding mechanisms for these solutions. Within the Great Plains and beyond, by addressing these technical questions within a local context, the goal of widespread acceptance of LID can be achieved, resulting in more effective and resilient stormwater management. PMID- 26961479 TI - Biosecurity Measures Applied in the United Arab Emirates - a Comparative Study Between Livestock and Wildlife Sectors. AB - In 2013, the livestock population in the UAE exceeded 4.3 million heads with sheep and goats accounting for 90% of this. The overall number of captive wild ungulates (gazelle types) is difficult to assess as there is no registration system in place or enforced in the UAE with regard to the possession of wildlife. Those animal collections, mainly owned by high-ranking families, are therefore not registered and kept far from public viewing. Nonetheless, some collections are housing more than 30 000 ungulates in one location. The primary objective of this study was to describe the biosecurity measures currently applied in UAE ungulate facilities for different wildlife and livestock sectors. A secondary objective was to use the output from this biosecurity survey to investigate which sector could be categorized into risk groups for disease introduction and spread. Between October 2014 and May 2015, biosecurity questionnaire data were collected in the Emirates of Abu Dhabi, Dubai, Ras Al Khaimah, Fujeirah, Ajman, Umm al Quwain and Sharjah from 14 wildlife collections, 30 livestock farms and 15 mixed (wildlife and livestock farms). These investigations through questionnaires allowed us to quantify and assess statistically biosecurity practices and levels for both livestock and wildlife sectors. In both sectors, biosecurity measures could be improved and only a few facilities had high biosecurity scores. The group of small unregistered farms (Ezba) represented the highest risk of disease transmission to other animals due to their lack of biosecurity awareness. PMID- 26961480 TI - An Analysis of the Effects and the Molecular Mechanism of Deep Hypothermic Low Flow on Brain Tissue in Mice. AB - OBJECTIVES: This study examined the effects and molecular mechanisms of deep hypothermic low flow (DHLF) on brain tissue in three genotypes of 3-week-old C57BL/6 mice (N = 180). METHODS: Mice in the model condition were subjected to cerebral ischemia-reperfusion (I-R) while undergoing DHLF, then reperfused and rewarmed. Brain tissue damage was measured with 2,3,5-triphenyltetrazolium chloride (TTC) staining, and protein expression was measured by Western blot at 2 h, 24 h, and 72 h after treatment; messenger ribonucleic acid (mRNA) expressions were measured by real-time polymerase chain reaction (PCR) at 2 h, 24 h, and 72 h. RESULTS: The expressions of p-Akt1 and p-GSK-3beta were significantly higher in the model condition than the condition across genotypes, but both were significantly lower in the Akt1 mice. The expressions of Akt1 mRNA and Akt3 mRNA, but not Akt2 mRNA, were significantly higher in the model condition across genotypes. Brain damage was significantly greater in the Akt1 knockout gene mice compared with Akt2 gene knockout and wild type mice at 24 h and 72 h. CONCLUSION: These results suggest that the neuroprotective effects of DHLF reflect increased expression of p-GSK-3beta induced through the PI3K/Akt signal pathway. Findings of real-time PCR imply that Akt1 mRNA and Akt3 mRNA may influence the expression of p-Akt1 and p-GSK-3beta in mice undergoing DHLF. PMID- 26961481 TI - The Outcomes of Endovascular Aneurysm Repair with the Chimney Technique for Juxtarenal Aortic Aneurysms. AB - PURPOSE: We collected our experience in the use of chimney technique with endovascular aneurysm repair (Ch-EVAR) for juxtarenal aortic aneurysms (JAAs), and reviewed the outcomes. METHODS: The patients who were treated with Ch-EVAR between January 2012 and December 2015 were retrospectively reviewed. All of the patients underwent endovascular aneurysm repair (EVAR) under general anesthesia. Femoral arterial access was obtained to place the main body of the endograft; brachial or axillary access was obtained to perform the placement of the chimney stent. RESULTS: We treated 12 patients with 15 renal arteries using the Ch-EVAR procedure. Technical success was achieved in 11 of the 12 (91.6%) cases. Within the first 30 days of postoperative period, the target vessel patency rate was 93.3% (14 of 15 renal arteries). After a median follow-up period of 28 months, one patient required Ch-EVAR-related re-intervention due to a type Ia endoleak, and 13 of the 15 renal arteries were patent at the end of the follow-up period. CONCLUSION: Our findings demonstrate that Ch-EVAR can be completed with a high rate of success. Although early target vessel occlusion or early postoperative mortality might occur, Ch-EVAR could be an alternative treatment for JAA, especially in high risk patients. PMID- 26961482 TI - Editorial: Special Thematic Issuue: Development of Biomarkers in Tumors of Digestive System Part I. PMID- 26961483 TI - MicroRNA-183 Functions As an Oncogene by Regulating PDCD4 in Gastric Cancer. AB - MicroRNA-183 (miR-183) has recently been identified to be implicated in a variety of critical processes in multiple human malignancies, and its fuction has been poorly characterized in gastric cancer (GC). Here we reported that miR-183 was markedly over-expressed in GC and its up-regulation was markedly associated with GC clinicopathologicalcharacters. Endogenous miR-183 was inhibited in GC cells, which dramatically attenuated cell proliferation, colony formation, migration, invasion and adhesion and enhancedGC cells apoptosis in vitro. Furthermore, in this study we demonstrated that the tumor suppressor gene PDCD4 was a target of miR-183 in GC. Collectively, these observations showed that miR-183 maybe function as an oncogene by regulating GC cell proliferation, apoptosis and metastasis and the oncogenic effect of miR-183 may relate the direct targeting PDCD4. PMID- 26961484 TI - Dasatinib induces severe hemorrhagic colitis in a patient with accelerated phase of chronic myelogenous leukemia. PMID- 26961486 TI - Phenolic Composition and Evaluation of Methanol and Aqueous Extracts of Bitter Gourd (Momordica charantia L) Leaves on Angiotensin-I-Converting Enzyme and Some Pro-oxidant-Induced Lipid Peroxidation In Vitro. AB - This study sought to assess the effects of bitter gourd leaf extracts (methanol and aqueous) on enzyme linked with hypertension (angiotensin-I-converting enzyme and some pro-oxidants (iron sulfate, sodium nitroprusside, and cisplatin]-induced lipid peroxidation in rat kidney homogenates. Chromatographic analysis of the extract was done using high-performance liquid chromatography-diode array detection. The results revealed that methanol extract (IC50 = 109.63 ug/mL) had significantly (P < .05) higher angiotensin-I converting enzyme inhibitory activity than aqueous extract (IC50 = 182.95 ug/mL). Similarly, methanol extract had significantly (P < .05) higher inhibitory effect on Fe2+- and cisplatin induced lipid peroxidation than aqueous extract. However, there was no significant (P > .05) difference in the inhibition of sodium nitroprusside induced lipid peroxidation of both extracts. High-performance liquid chromatography-diode array detection analysis revealed the presence of quercetin, caffeic, gallic, and chlorogenic acids in the leaf. Thus, inhibition of angiotensin-I converting enzyme activity and the antioxidant properties of the extracts could be linked to the presence of phenolic phytochemicals. PMID- 26961487 TI - Does Rapid Diffusion of HbA1c Testing Affect Amputation Rates? AB - BACKGROUND: The association of speed of diffusion of Hemoglobin A1C (hbA1c) testing with temporal changes in outcomes of primary importance to patients with diabetes, such as amputation, remains an issue of debate. We investigated these correlations. METHODS: We performed a retrospective cohort study of diabetics, based on Medicare fee-for-service claims data from 2002 to 2012. We examined the association of the rate of diffusion of HbA1c testing with changes in amputation rates. Our unit of analysis was the hospital referral region (HRR), a definition of tertiary care markets defined in the Dartmouth Atlas of Health Care. RESULTS: From the 11 096 270 diabetics followed in our study for a mean follow-up of 4.1 years, 106 340 (0.96%) underwent lower extremity amputations. The speed of diffusion of HbA1c testing had a moderate association with the speed of diffusion of lower extremity amputations, after adjusting for multiple factors including baseline regional amputation and testing rates (adjusted difference, -0.7%; 95% confidence interval, -1.0% to -0.3%). The risk-adjusted HRR-level speed of diffusion of testing demonstrated significant correlation with the risk-adjusted HRR-level diffusion of amputations (r = .250, P < .001). CONCLUSIONS: We observed a moderate association of the speed of diffusion of HbA1c testing with the speed of diffusion of lower extremity amputations among Medicare patients with diabetes. Improvements in performance on quality metrics such as HbA1c testing may not immediately translate into tangible patient outcomes. PMID- 26961488 TI - Erratum to: A comparison of heterosexual and LGBTQ cancer survivors' outlooks on relationships, family building, possible infertility, and patient-doctor fertility risk communication. PMID- 26961485 TI - Efficacy and safety of low-dose tacrolimus for active rheumatoid arthritis with an inadequate response to methotrexate. AB - BACKGROUND/AIMS: To determine the efficacy and safety of low-dose tacrolimus in Korean rheumatoid arthritis (RA) subjects with an inadequate response to methotrexate (MTX). METHODS: This was a multicenter, open-label study conducted at five Korean sites. Fifty-six patients with active RA, despite treatment for >= 1 month with a stable, maximally tolerated dosage of oral MTX (median dosage, 15 mg/wk), were enrolled and received 1.5 mg/day of tacrolimus as a single oral dose once per day for 16 weeks while continuing to receive MTX. All other disease modifying anti-rheumatic drugs were discontinued, whereas stable dosages of nonsteroidal anti-inflammatory drugs and oral corticosteroids (<= 10 mg/day of prednisone or an equivalent corticosteroid) were allowed. The primary clinical response criterion was the American College of Rheumatology's definition of 20% improvement (ACR20) at the end of treatment. RESULTS: The ACR20 response rate was 42.9% (24 of 56 patients) in patients who had received tacrolimus at least once. The overall ACR50 and ACR70 responses at the end of treatment for all patients were 30.4% and 10.7%, respectively. Throughout the treatment period, 37 patients experienced 71 adverse events (AEs) in total, and four patients left the study because of AEs. In addition, 15 patients in total experienced treatment-related AEs. Throughout the treatment period, two patients were reported to experience two serious AEs, and one patient left the study because of a serious AE. CONCLUSIONS: In patients whose active RA persists despite treatment with MTX, low dose tacrolimus in combination with MTX appears to be safe and well tolerated, and provides clinical benefit. PMID- 26961489 TI - Adiponectin Promotes Human Jaw Bone Marrow Stem Cell Osteogenesis. AB - Human jaw bone marrow mesenchymal stem cells (h-JBMMSCs) are multipotent progenitor cells with osteogenic differentiation potential. The relationship between adiponectin (APN) and the metabolism of h-JBMMSCs has not been fully elucidated, and the underlying mechanism remains unclear. The aim of the study was to investigate the effect and mechanism of APN on h-JBMMSC metabolism. h JBMMSCs were obtained from the primary culture of human jaw bones and treated with or without APN (1 ug/mL). Osteogenesis-related gene expression was evaluated by real-time polymerase chain reaction (PCR), alkaline phosphatase (ALP) activity assay, and enzyme-linked immunosorbent assay (ELISA). To further investigate the signaling pathway, mechanistic studies were performed using Western blotting, immunofluorescence, lentiviral transduction, and SB202190 (a specific p38 inhibitor). Alizarin Red staining showed that APN promoted h-JBMMSC osteogenesis. Real-time PCR, ALP assay, and ELISA showed that ALP, osteocalcin (OCN), osteopontin, and integrin-binding sialoprotein were up-regulated in APN-treated cells compared to untreated controls. Immunofluorescence revealed that adaptor protein containing a pleckstrin homology domain, phosphotyrosine domain, and leucine zipper motif (APPL1) translocated from the nucleus to the cytoplasm with APN treatment. Additionally, the phosphorylation of p38 mitogen-activated protein kinase (MAPK) increased over time with APN treatment. Moreover, knockdown of APPL1 or p38 MAPK inhibition blocked the expression of APN-induced calcification related genes including ALP, Runt-related transcription factor 2 (RUNX2), and OCN. Furthermore, Alizarin Red staining of calcium nodes was not increased by the knockdown of APPL1 or p38 inhibition. Our data suggest that this regulation is mediated through the APPL1-p38 MAPK signaling pathway. These findings collectively provide evidence that APN induces the osteogenesis of h-JBMMSCs through APPL1-mediated p38 MAPK activation. PMID- 26961490 TI - Autophagy Modulates Cell Mineralization on Fluorapatite-Modified Scaffolds. AB - As a major intracellular degradation and recycling machinery, autophagy plays an important role in maintaining cellular homeostasis and remodeling during normal development. Our previous study showed that fluorapatite (FA) crystal-coated electrospun polycaprolactone (PCL) was capable of inducing differentiation and mineralization of human dental pulp stem cells. However, how autophagy changes and whether autophagy plays a vital role during these processes is still unknown. In this study, we seeded STEMPRO human adipose-derived stem cells (ASCs) on both PCL+FA and PCL scaffolds to investigate the osteogenic inductive ability of FA crystals and we observed the autophagy changes of these cells. Scanning electron microscopy and fluorescence microscopy images, along with DNA quantitation, showed that both PCL+FA and PCL scaffolds could sustain ASC growth but only the PCL+FA scaffold could sustain cell mineralization. This was confirmed by alkaline phosphatase activity and Alizarin red and Von Kossa staining results. The autophagy RT2 Profiler polymerase chain reaction array analysis showed many autophagy-related genes changes during ASC differentiation. Western blot analysis indicated that several autophagy-related proteins fluctuated during the procedure. Among them, the microtubule-associated protein 1 light chain 3 (LC3) II protein changes of the ASCs grown on the 2- or 3-dimensional environments at 6 h, 12 h, 1 d, 3 d, 7 d, 14 d, and 21 d reached a peak value at day 7 during osteogenesis. At earlier stages (from day 0 to day 3), the addition of autophagy inhibitors (3-mathyladenine, bafilomycin A1, and NH4Cl) attenuated the expression of osteogenic related markers (osteopontin, alkaline phosphatase activity, Alizarin red, and Von Kossa) compared with the control group. All data indicated that autophagy played an important role in ASC differentiation on the PCL+FA scaffold. Inhibition of autophagy before day 3 strongly inhibited osteogenic differentiation and mineralization of ASCs in the 3-dimensional model. This observation further elucidates the mechanism of autophagy in mesenchymal stem cell osteogenic differentiation. PMID- 26961491 TI - Surface Engineering of Nanostructured Titanium Implants with Bioactive Ions. AB - Surface nanofeatures and bioactive ion chemical modification are centrally important in current titanium (Ti) oral implants for enhancing osseointegration. However, it is unclear whether the addition of bioactive ions definitively enhances the osteogenic capacity of a nanostructured Ti implant. We systematically investigated the osteogenesis process of human multipotent adipose stem cells triggered by bioactive ions in the nanostructured Ti implant surface. Here, we report that bioactive ion surface modification (calcium [Ca] or strontium [Sr]) and resultant ion release significantly increase osteogenic activity of the nanofeatured Ti surface. We for the first time demonstrate that ion modification actively induces focal adhesion development and expression of critical adhesion-related genes (vinculin, talin, and RHOA) of human multipotent adipose stem cells, resulting in enhanced osteogenic differentiation on the nanofeatured Ti surface. It is also suggested that fibronectin adsorption may have only a weak effect on early cellular events of mesenchymal stem cells (MSCs) at least in the case of the nanostructured Ti implant surface incorporating Sr. Moreover, results indicate that Sr overrides the effect of Ca and other important surface factors (i.e., surface area and wettability) in the osteogenesis function of various MSCs (derived from human adipose, bone marrow, and murine bone marrow). In addition, surface engineering of nanostructured Ti implants using Sr ions is expected to exert additional beneficial effects on implant bone healing through the proper balancing of the allocation of MSCs between adipogenesis and osteogenesis. This work provides insight into the future surface design of Ti dental implants using surface bioactive ion chemistry and nanotopography. PMID- 26961493 TI - A message to the next generation of biomedical informatics professionals. PMID- 26961494 TI - The Chief Clinical Informatics Officer (CCIO). PMID- 26961492 TI - The nephrologist of tomorrow: towards a kidney-omic future. AB - Omics refers to the collective technologies used to explore the roles and relationships of the various types of molecules that make up the phenotype of an organism. Systems biology is a scientific discipline that endeavours to quantify all of the molecular elements of a biological system. Therefore, it reflects the knowledge acquired by omics in a meaningful manner by providing insights into functional pathways and regulatory networks underlying different diseases. The recent advances in biotechnological platforms and statistical tools to analyse such complex data have enabled scientists to connect the experimentally observed correlations to the underlying biochemical and pathological processes. We discuss in this review the current knowledge of different omics technologies in kidney diseases, specifically in the field of pediatric nephrology, including biomarker discovery, defining as yet unrecognized biologic therapeutic targets and linking omics to relevant standard indices and clinical outcomes. We also provide here a unique perspective on the field, taking advantage of the experience gained by the large-scale European research initiative called "Systems Biology towards Novel Chronic Kidney Disease Diagnosis and Treatment" (SysKid). Based on the integrative framework of Systems biology, SysKid demonstrated how omics are powerful yet complex tools to unravel the consequences of diabetes and hypertension on kidney function. PMID- 26961496 TI - No mental health without physical health - a call to arms. PMID- 26961495 TI - Influence of Corynebacterium pseudotuberculosis infection on level of acute phase proteins in goats. AB - BACKGROUND: Goat caseous lymphadenitis (CLA) is a chronic disease caused by Corynebacterium pseudotuberculosis. However, there is paucity of data about goat's acute phase response during the course of CLA. This study was conducted to investigate the response of acute phase proteins, mainly haptoglobin (Hp), serum amyloid A (SAA) and the negative acute phase response, especially albumin after an experimental challenge of C. pseudotuberculosis and phospholipase D (PLD) in Cross bred Boer goats. RESULTS: Serum Hp concentration in goats challenged with C. pseudotuberculosis (inoculated with 1x10(9) cfu subcutaneously) showed a significant increase, 5 fold in males (0.98 +/- 0.12 mg/ml) and 3 fold in females (0.66 +/- 0.12 mg/ml) compared to the control (0.2 +/- 0.02 mg/ml). Challenge with PLD (1 ml/20 kg body weight intravenously) also showed significant increase, 4 fold in males and females (0.89 +/- 0.11 mg/ml; 0.82 +/- 0.12 mg/ml) respectively compared to the control (0.2 +/- 0.02 mg/ml). Albumin concentration showed a significant decrease in both treated groups compared to the control. There were no significant changes in SAA concentration between challenged and control goats. CONCLUSIONS: There was a significant response by Hp to C. pseudotuberculosis infection and PLD challenge. This was supported by the early acute response in which Hp was detected before CLA lesions were developed. Therefore, it concluded that C. pseudotuberculosis and PLD can influence the level of acute phase proteins in goats. PMID- 26961497 TI - Lewis Acid Catalyzed Borotropic Shifts in the Design of Diastereo- and Enantioselective gamma-Additions of Allylboron Moieties to Aldimines. AB - Catalytic allylboron additions to aldimines are presented for which small amounts of Zn(OMe)2 serve as the co-catalyst to accelerate allyl exchange and 1,3 borotropic shift processes. Low-yielding and moderately alpha- and diastereoselective reactions are thus turned into highly efficient gamma-, diastereo-, and enantioselective transformations that exhibit considerable scope. PMID- 26961498 TI - Evaluation of bishexadecyltrimethyl ammonium palladium tetrachloride based dual functional colloidal carrier as an antimicrobial and anticancer agent. AB - We have developed a dual function carrier using bishexadecyltrimethyl ammonium palladium tetrachloride, which has anticancer as well as antibacterial activity, using a ligand insertion method with a simple and easy work procedure. The complex is prepared by a simple and cost effective method using hexadecyltrimethyl ammonium chloride and palladium chloride under controlled stoichiometry. Herein, we report the aggregation (self assembly) of the metallosurfactant having palladium as a counter ion, in aqueous medium along with its binding affinity with bovine serum albumin. The palladium surfactant has exhibited excellent antimicrobial efficacy against fungus and bacteria (both Gram positive and Gram-negative bacteria). Cytotoxicity of palladium surfactant against cancerous (Human leukemia HL-60, pancreatic MIA-Pa-Ca-2 and prostate cancer PC-3) and healthy cells (fR2 human breast epithelial cells) was also evaluated using MTT assay. The present dual functional moiety shows a low IC50 value and has potential to be used as an anticancer agent. Our dual function carrier which itself possesses antimicrobial and anticancer activity represents a simple and effective system and can also be utilized as a drug carrier in the future. PMID- 26961499 TI - Five year follow-up of non-psychotic adults with frequent auditory verbal hallucinations: are they still healthy? AB - BACKGROUND: Previously, we described 103 adults (mean age 41 years) who experienced frequent, auditory verbal hallucinations (AVH), in the absence of a need for mental healthcare. Importantly, these adults were largely past the peak incidence age for psychosis (15-35 years). It is unclear if these older individuals with AVH are still at increased risk for psychosis or other psychopathology. To address this question, we conducted a 5-year follow-up of previously included individuals (103 with AVH, 60 controls). METHOD: Eighty-one adults with AVH (78.6%) and forty-nine controls (81.7%) could be contacted and were willing to participate. Participants were screened for psychosis and a need for mental healthcare at follow-up using the Comprehensive Assessment of Symptoms and History interview (CASH). Need for mental healthcare was defined as a clinical diagnosis as identified using the CASH and/or treatment by a mental healthcare specialist. Phenomenology of AVH was assessed with the PSYRATS Auditory Hallucinations Rating Scale. RESULTS: Five individuals with AVH (6.2%) had developed psychosis and 32 (39.5%) had developed a need for mental healthcare. Voice-related distress at baseline significantly predicted need for mental healthcare. AVH persisted in most individuals (86.4%), without significant changes in phenomenology. None of the controls had developed psychotic symptoms, and need for mental healthcare (n = 6, 12.2%) was significantly lower in this group. CONCLUSIONS: These findings suggest that frequent AVH in non-psychotic adults past the peak incidence age for psychosis constitute a rather static symptom and that individuals with AVH may be best viewed as situated on a need for care continuum. PMID- 26961500 TI - Eye lens dosimetry in anesthesiology: a prospective study. AB - The eye lens is one of the most sensitive organs for radiation injury and exposure might lead to radiation induced cataract. Eye lens dosimetry in anesthesiology has been published in few clinical trials and an active debate about the causality of radiation induced cataract is still ongoing. Recently, the International Commission on Radiological Protection (ICRP) recommended a reduction in the annual dose limit for occupational exposure for the lens of the eye from 150 to 20 mSv, averaged over a period of 5 years, with the dose in a single year not exceeding 50 mSv. This prospective study investigated eye lens dosimetry in anesthesiology practice during a routine year of professional activity. The radiation exposure measured represented the exposure in a normal working schedule of a random anesthesiologist during 1 month and this cumulative eye lens dose was extrapolated to 1 year. Next, eye lens doses were measured in anesthesiology during neuro-embolisation procedures, radiofrequency ablations or vertebroplasty/kyphoplasty procedures. The eye lens doses are measured in terms of the dose equivalent H p(3) with the Eye-D dosimeter (Radcard, Poland) close to the right eye (on the temple). In 16 anesthesiologists, the estimated annual eye lens doses range from a minimum of 0.4 mSv to a maximum of 3.5 mSv with an average dose of 1.33 mSv. Next, eye lens doses were measured for nine neuro embolisation procedures, ten radiofrequency ablations and six vertebroplasty/kyphoplasty procedures. Average eye lens doses of 77 +/- 76 uSv for neuro-embolisations, 38 +/- 34 uSv for cardiac ablations and 40 +/- 44 uSv for vertebro-/kyphoplasty procedures were recorded. The maximum doses were respectively 264, 97 and 122 uSv. This study demonstrated that the estimated annual eye lens dose is well below the revised ICRP's limit of 20 mSv/year. However, we demonstrated high maximum and average doses during neuro embolisation, cardiac ablation and vertebro-/kyphoplasty procedures. With radiation induced cataract being explained as a possible stochastic effect, without a threshold dose, anesthesiologists who regularly work in a radiological environment should remain vigilant and maintain radiation safety standards at all times. This includes adequately protective equipment (protection shields, apron, thyroid shield and leaded eye wear), keeping distance, routine monitoring and appropriate education. PMID- 26961501 TI - Smart respiratory monitoring: clinical development and validation of the IPITM (Integrated Pulmonary Index) algorithm. AB - Continuous electronic monitoring of patient respiratory status frequently includes PetCO2 (end tidal CO2), RR (respiration rate), SpO2 (arterial oxygen saturation), and PR (pulse rate). Interpreting and integrating these vital signs as numbers or waveforms is routinely done by anesthesiologists and intensivists but is challenging for clinicians in low acuity areas such as medical wards, where continuous electronic respiratory monitoring is becoming more common place. We describe a heuristic algorithm that simplifies the interpretation of these four parameters in assessing a patient's respiratory status, the Integrated Pulmonary Index (IPI). The IPI algorithm is a mathematical model combining SpO2, RR, PR, and PetCO2 into a single value between 1 and 10 that summarizes the adequacy of ventilation and oxygenation at that point in time. The algorithm was designed using a fuzzy logic inference model to incorporate expert clinical opinions. The algorithm was verified by comparison to experts' scoring of clinical scenarios. The validity of the index was tested in a retrospective analysis of continuous SpO2, RR, PR, and PetCO2 readings obtained from 523 patients in a variety of clinical settings. IPI correlated well with expert interpretation of the continuous respiratory data (R = 0.83, p <<< 0.001), with agreement of -0.5 +/- 1.4. Receiver operating curves analysis resulted in high levels of sensitivity (ranging from 0.83 to 1.00), and corresponding specificity (ranging from 0.96 to 0.74), based on IPI thresholds 3-6. The IPI reliably interpreted the respiratory status of patients in multiple areas of care using off-line continuous respiratory data. Further prospective studies are required to evaluate IPI in real time in clinical settings. PMID- 26961502 TI - Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes, respectively. AB - AIMS/HYPOTHESIS: Genome-wide association (GWA) studies have identified hundreds of common genetic variants associated with obesity and type 2 diabetes. These studies have usually focused on additive association tests. Identifying deviations from additivity may provide new biological insights and explain some of the missing heritability for these diseases. METHODS: We performed a GWA study using a dominance deviation model for BMI, obesity (29,925 cases) and type 2 diabetes (4,040 cases) in 120,286 individuals of British ancestry from the UK Biobank study. We also investigated whether single nucleotide polymorphisms previously shown to be associated with these traits showed any enrichment for departures from additivity. RESULTS: Known obesity-associated variants in FTO showed strong evidence of deviation from additivity (p DOMDEV = 3 * 10(-5)) through a recessive effect of the allele associated with higher BMI. The average BMI of individuals carrying zero, one or two BMI-raising alleles was 27.27 (95% CI 27.22, 27.31) kg/m(2), 27.54 (95% CI 27.50, 27.58) kg/m(2) and 28.07 (95% CI 28.00, 28.14) kg/m(2), respectively. A similar effect was observed in 105,643 individuals from the GIANT Consortium (p DOMDEV = 0.003; meta-analysis p DOMDEV = 1 * 10(-7)). For type 2 diabetes, we detected a recessive effect (p DOMDEV = 5 * 10(-4)) at CDKAL1. Relative to homozygous non-risk allele carriers, homozygous risk allele carriers had an OR of 1.48 (95% CI 1.32, 1.65), while the heterozygous group had an OR of 1.06 (95% CI 0.99, 1.14), a result consistent with that of a previous study. We did not identify any novel associations at genome-wide significance. CONCLUSIONS/INTERPRETATION: Although we found no evidence of widespread non-additive genetic effects contributing to obesity and type 2 diabetes risk, we did find robust examples of recessive effects at the FTO and CDKAL1 loci. ACCESS TO RESEARCH MATERIALS: Summary statistics are available at www.t2diabetesgenes.org and by request (a.r.wood@exeter.ac.uk). All underlying data are available on application from the UK Biobank. PMID- 26961503 TI - Pleotropic effects of leptin to reverse insulin resistance and diabetic ketoacidosis. AB - In this review we discuss the mechanisms for the pleotropic effects of leptin replacement therapy to reverse liver and muscle insulin resistance in lipodystrophic individuals, as well as insulin-independent effects of leptin replacement therapy to suppress white adipose tissue lipolysis, hepatic gluconeogenesis and fasting hyperglycaemia in rodent models of poorly controlled diabetes. On the basis of these studies we conclude with a view of the potential therapeutic applications of leptin replacement therapy in humans. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Thomas Meek and Gregory Morton, DOI: 10.1007/s00125-016 3898-3 , and by Christoffer Clemmensen and colleagues, DOI: 10.1007/s00125-016 3906-7 ) and an overview by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016 3894-7 ). PMID- 26961505 TI - Erratum to: 'Tocolysis for inhibiting preterm birth in extremely preterm birth, multiple gestations and in growth-restricted fetuses: a systematic review and meta-analysis'. PMID- 26961504 TI - Erratum to: Low-energy diets differing in fibre, red meat and coffee intake equally improve insulin sensitivity in type 2 diabetes: a randomised feasibility trial. PMID- 26961506 TI - Efficient phosphate sequestration for water purification by unique sandwich-like MXene/magnetic iron oxide nanocomposites. AB - Rationally tailored intercalation for two-dimensional (2D) layered MXene materials has aroused extraordinary enthusiasm for broadening their applications. Herein, a novel sandwiched structural 2D MXene-iron oxide (MXI) material, prepared by selectively exfoliating an Al layer followed by magnetic ferric oxide intercalation, exhibits remarkable applicability to trace phosphate sequestration in the environmental remediation realm. Compared with commercial adsorbents, the resultant MXI nanocomposite exhibits a fast separation in 120 s together with the superior treatment capacities of 2100 kg and 2400 kg per kg in simulated and real phosphate wastewater applications, respectively. Such efficient sequestration is ascribed to the formation of a unique nano-ferric oxide morphology. The ultrafine nano-Fe2O3 particles can intercalate into the interior layers of MXene, widening the layer distance, and stimulating the available overlapping activated layers; while the efficient phosphate removal can be achieved by the strong complexation onto the embedded magnetic nano-Fe3O4 with a unique sandwich-structure as well as the stimulated Ti-O terminal within MXene. Apart from the fact that this approach suggests a complementary means for environmental remediation, it opens a new trajectory to achieve the functionalization of MXene. PMID- 26961507 TI - Measurement of breast-tissue x-ray attenuation by spectral mammography: solid lesions. AB - Knowledge of x-ray attenuation is essential for developing and evaluating x-ray imaging technologies. For instance, techniques to distinguish between cysts and solid tumours at mammography screening would be highly desirable to reduce recalls, but the development requires knowledge of the x-ray attenuation for cysts and tumours. We have previously measured the attenuation of cyst fluid using photon-counting spectral mammography. Data on x-ray attenuation for solid breast lesions are available in the literature, but cover a relatively wide range, likely caused by natural spread between samples, random measurement errors, and different experimental conditions. In this study, we have adapted a previously developed spectral method to measure the linear attenuation of solid breast lesions. A total of 56 malignant and 5 benign lesions were included in the study. The samples were placed in a holder that allowed for thickness measurement. Spectral (energy-resolved) images of the samples were acquired and the image signal was mapped to equivalent thicknesses of two known reference materials, which can be used to derive the x-ray attenuation as a function of energy. The spread in equivalent material thicknesses was relatively large between samples, which is likely to be caused mainly by natural variation and only to a minor extent by random measurement errors and sample inhomogeneity. No significant difference in attenuation was found between benign and malignant solid lesions. The separation between cyst-fluid and tumour attenuation was, however, significant, which suggests it may be possible to distinguish cystic from solid breast lesions, and the results lay the groundwork for a clinical trial. In addition, the study adds a relatively large sample set to the published data and may contribute to a reduction in the overall uncertainty in the literature. PMID- 26961509 TI - Erratum to: 'Updated prevalence rates of overweight and obesity in 11- to 17-year old adolescents in Germany. Results from the telephone-based KiGGS Wave 1 after correction for bias in self-reports'. PMID- 26961508 TI - Dimorphic male scutal patterns and upper-eye facets of Simulium mirum n. sp. (Diptera: Simuliidae) from Malaysia. AB - BACKGROUND: A species of Simulium in the Simulium melanopus species-group of the subgenus Simulium (formerly misidentified as S. laterale Edwards from Sabah and Sarawak, Malaysia) is suspected to have dimorphic male scutal color patterns linked with different numbers of upper-eye facets. This study aimed to confirm whether or not these two forms of adult males represent a single species. METHODS: DNA sequences generated from four genetic loci, the mitochondrial encoded COI, COII, 12S rRNA and 16S rRNA genes, of both forms of Simulium sp. males were compared with each other and also with those of the females and larvae of the same species. Four other related Simulium spp. were also used for comparison. RESULTS: Both the concatenated dataset and single-locus phylogenetic analyses indicate that the two distinct morphological males of Simulium sp. are indeed conspecific, and represent, together with their associated females and larvae, a distinct species. CONCLUSIONS: Based on DNA analyses, Simulium sp. is proven to show dimorphism in males and is herein described as a new species, Simulium mirum Takaoka, Sofian-Azirun & Low. This is the first report of such a novel species among the family Simuliidae. PMID- 26961510 TI - [Not Available]. PMID- 26961512 TI - Computational modeling of the arterial wall based on layer-specific histological data. AB - Arterial walls typically have a heterogeneous structure with three different layers (intima, media, and adventitia). Each layer can be modeled as a fiber reinforced material with two families of relatively stiff collagenous fibers symmetrically arranged within an isotropic soft ground matrix. In this paper, we present two different modeling approaches, the embedded fiber (EF) approach and the angular integration (AI) approach, to simulate the anisotropic behavior of individual arterial wall layers involving layer-specific data. The EF approach directly incorporates the microscopic arrangement of fibers that are synthetically generated from a random walk algorithm and captures material anisotropy at the element level of the finite element formulation. The AI approach smears fibers in the ground matrix and treats the material as homogeneous, with material anisotropy introduced at the constitutive level by enhancing the isotropic strain energy with two anisotropic terms. Both approaches include the influence of fiber dispersion introduced by fiber angular distribution (departure of individual fibers from the mean orientation) and take into consideration the dispersion caused by fiber waviness, which has not been previously considered. By comparing the numerical results with the published experimental data of different layers of a human aorta, we show that by using histological data both approaches can successfully capture the anisotropic behavior of individual arterial wall layers. Furthermore, through a comprehensive parametric study, we establish the connections between the AI phenomenological material parameters and the EF parameters having straightforward physical or geometrical interpretations. This study provides valuable insight for the calibration of phenomenological parameters used in the homogenized modeling based on the fiber microscopic arrangement. Moreover, it facilitates a better understanding of individual arterial wall layers, which will eventually advance the study of the structure-function relationship of arterial walls as a whole. PMID- 26961513 TI - From the image towards a new concept. PMID- 26961514 TI - Recent advances in 2D materials for photocatalysis. AB - Two-dimensional (2D) materials have attracted increasing attention for photocatalytic applications because of their unique thickness dependent physical and chemical properties. This review gives a brief overview of the recent developments concerning the chemical synthesis and structural design of 2D materials at the nanoscale and their applications in photocatalytic areas. In particular, recent progress on the emerging strategies for tailoring 2D material based photocatalysts to improve their photo-activity including elemental doping, heterostructure design and functional architecture assembly is discussed. PMID- 26961515 TI - Promising therapeutic agents for the treatment of Parkinson's disease. AB - INTRODUCTION: The therapeutic management of Parkinson's disease has not yet been fully resolved, with motor fluctuations and levodopa-induced dyskinesia representing special therapeutic challenges. Furthermore, no disease-modifying therapies are currently available. AREAS COVERED: This review focuses on promising novel therapies that are at present under investigation in Phase I or Phase II trials. Special emphasis is placed on gene therapies: vectors, the utilized gene constructs and the side-effects. Moreover, the main risk factors of the gene therapy (the insertional mutagenesis, the uncontrolled overproduction of the expressed protein and the autoimmune and inflammatory responses) are described. EXPERT OPINION: Gene therapies represent a promising field in the therapeutic palette. In order to mitigate the side-effects of this therapy, the developments focus on the vectors applied. Gene therapy appears to be promising candidate for the management of motor complications in advanced stages of Parkinson's disease. In addition to dopamine replacement therapy, this field may also offer a solution for neurogenesis and neuroprotection. PMID- 26961516 TI - Geena 2, improved automated analysis of MALDI/TOF mass spectra. AB - BACKGROUND: Mass spectrometry (MS) is producing high volumes of data supporting oncological sciences, especially for translational research. Most of related elaborations can be carried out by combining existing tools at different levels, but little is currently available for the automation of the fundamental steps. For the analysis of MALDI/TOF spectra, a number of pre-processing steps are required, including joining of isotopic abundances for a given molecular species, normalization of signals against an internal standard, background noise removal, averaging multiple spectra from the same sample, and aligning spectra from different samples. In this paper, we present Geena 2, a public software tool for the automated execution of these pre-processing steps for MALDI/TOF spectra. RESULTS: Geena 2 has been developed in a Linux-Apache-MySQL-PHP web development environment, with scripts in PHP and Perl. Input and output are managed as simple formats that can be consumed by any database system and spreadsheet software. Input data may also be stored in a MySQL database. Processing methods are based on original heuristic algorithms which are introduced in the paper. Three simple and intuitive web interfaces are available: the Standard Search Interface, which allows a complete control over all parameters, the Bright Search Interface, which leaves to the user the possibility to tune parameters for alignment of spectra, and the Quick Search Interface, which limits the number of parameters to a minimum by using default values for the majority of parameters. Geena 2 has been utilized, in conjunction with a statistical analysis tool, in three published experimental works: a proteomic study on the effects of long-term cryopreservation on the low molecular weight fraction of serum proteome, and two retrospective serum proteomic studies, one on the risk of developing breat cancer in patients affected by gross cystic disease of the breast (GCDB) and the other for the identification of a predictor of breast cancer mortality following breast cancer surgery, whose results were validated by ELISA, a completely alternative method. CONCLUSIONS: Geena 2 is a public tool for the automated pre-processing of MS data originated by MALDI/TOF instruments, with a simple and intuitive web interface. It is now under active development for the inclusion of further filtering options and for the adoption of standard formats for MS spectra. PMID- 26961517 TI - 10 years of Vertigo Clinic at National Hospital Abuja, Nigeria: what have we learned? AB - The clinician's major role in management of the dizzy patient involves determining what dizziness is vertigo, and what vertigo is of central or peripheral origin. These demand attention to details of history, otolaryngological workup including vestibular assessment, and often use of diagnostic and management algorithms. There is paucity of published reports of the management outcomes of peripheral vestibular diseases from Africa. Two tertiary care otologist-led dedicated vertigo clinics are located in Abuja, Nigeria. A prospective, non-randomized study of patients presenting with features of peripheral vestibular diseases attending the National Hospital Abuja Nigeria (between May 2005 and April 2014) and CSR Otologics Specialist Clinics (May 2010 to April 2014) was carried out. Both institutions adopted the same diagnostic and management protocols. Data extracted from anonymized databases created for this study include age, sex, vertigo duration (acute <12 weeks, chronic >12 weeks), dizziness handicap inventory score at presentation and at subsequent visits, otological and vestibular findings, ice-water caloric testing results, other investigation outcomes, treatments offered and outcomes. 561/575 (97.5 %) of the cases recorded had peripheral vestibular disease. The male-to-female ratio was 290:271. The mean age of the subjects was 44.7 years. Duration of vertigo at presentation was acute in 278 subjects and chronic in 283 subjects. Identifiable clinical diagnostic groups include BPPV (n = 200), Meniere's disease (n = 189), cervicogenic vertigo (n = 35), labyrinthitis (n = 32), Migraine-associated vertigo (MAV) (n = 32), cholesteatoma/perilymph Fistula (n = 10), climacteric vertigo (n = 8) and unclassified vertigo (n = 55). Migraine-associated vertigo recorded the highest DHI score (95 % CI 75 +/- 4.3), followed by cholesteatoma/perilymph fistula (95 % CI 72 +/- 6.1) and labyrinthitis (95 % CI 62 +/- 1.9). Pure tone audiometry (95 % CI 67.3 +/- 3.43), followed by thyroid function tests (95 % CI 66.7 +/- 23.55) and ice-water caloric testing (95 % CI 59.7 +/- 2.69) were investigations with the highest yields. 86.5 % of cases were treated by either vestibular suppressant medications alone (n = 285) and/or particle repositioning maneuver (n = 200) with improvement in vertigo control (95 % CI 63.63 to 74.37 % and 62.59 to 75.41 %, respectively). Peripheral vestibular diseases constitute majority of cases of self-reported vertigo seen in our setting. Migraine-associated vertigo seen in our setting all have peripheral vestibular signs. Dedicated vertigo clinics could significantly improve the diagnostic and treatment yield in a resource-constrained setting like ours. Most cases can be managed using non-operative measures. PMID- 26961518 TI - Oral HPV prevalence in women positive for cervical HPV infection and their sexual partners: a German screening study. AB - The incidence of human papillomavirus (HPV) associated oropharyngeal squamous cell cancer (OSCC) is on the rise. With the HPV-positive uterine cervix as a reservoir, HPV-positive OSCC is discussed as a sexually transmitted disease. Mechanisms of HPV transmission to the oral cavity are poorly understood. To gain more insight into HPV-transmission routes, cervically HPV-positive women and their sexual partners are screened for oral HPV infection. Women with cervical dysplasia underwent HPV testing of the uterine cervix and tonsillar region via brush test. In addition, sexual partners received oral HPV testing. Tonsillar brush tests of patients admitted for routine surgery served as the control group. The HPV-PCR (Roche Linear Array Kit) was used to differentiate 37 HPV types. All participants completed a risk-factor questionnaire focusing on sexual habits. 101 women were tested HPV-positive at the cervix. Only 3/101 (3 %) were tested HPV positive in the oropharynx. In 60/101 (60 %) women the sexual partner could be tested for oral HPV infection: testing was positive in 3/60 (5 %). No oral HPV was detected in the control group. The risk-factor questionnaire revealed significant differences between the female study- and control group in terms of age at first sexual intercourse and smoking habits. The limited data suggest that among sexual partners in Germany, HPV transmission to the oropharynx by oral genital sex or by autoinoculation is a rare and unlikely event with low HPV concordance. Another explanation for the low oral prevalence could be an independent clearance of HPV from the oropharyngeal site compared to cervix uteri or at different time intervals. PMID- 26961519 TI - Insertion trauma of a cochlear implant electrode array with Nitinol inlay. AB - The integration of a shape memory actuator is a potential mechanism to achieve a consistent perimodiolar position after electrode insertion during cochlear implant surgery. After warming up, and therefore activation of the shape memory effect, the electrode array will change from a straight configuration into a spiral shaped one leading to a final position close to the modiolus. The aim of this study was to investigate whether the integration of an additional thin wire (referred to as an "inlay") made of Nitinol, a well-established shape memory alloy, in a conventional hearing preservation electrode array will affect the insertion behaviour in terms of increased risk of insertion trauma. Six conventional Hybrid-L electrode arrays (Cochlear Ltd., Sydney, Australia) were modified to incorporate a wire inlay made of Nitinol. The diameter of the wires was 100 um with a tapered tip region. Electrodes were inserted into human temporal bone specimens using a standard surgical approach. After insertion and embedding in epoxy resin, histological sections were prepared to evaluate insertion trauma. Insertion was straightforward and no difficulties were observed. The addition of a shape memory wire, thin but also strong enough to curl the electrode array, does not result in histologically detectable insertion trauma. Atraumatic insertion seems possible. PMID- 26961521 TI - Personalised discharge care planning for postmyocardial infarction patients through the use of the Personalised Patient Education Protocol - implementing theory into practice. AB - AIMS AND OBJECTIVES: This study aims to evaluate the service impact of the integration of an evidence-based instrument - the Personalised Patient Education Protocol - into an existing postmyocardial infarction care pathway. BACKGROUND: Recent research indicates that while better patient health outcomes can be achieved when care planning is personalised, delivery staff feel less satisfied and less confident in its provision. To achieve a shift to personalised care, innovations are needed to enable an effective transition for staff. DESIGN: A service evaluation using a patient survey and nurse interviews. METHOD: A longitudinal patient survey measured changes in patient illness beliefs, cardiac diet and exercise self-efficacy, anxiety, depression and quality of life study of a patient cohort of 74. Paired t-tests analysed the effects before and after the implementation of the Personalised Patient Education Protocol. Cardiac rehabilitation nurses who implemented the Personalised Patient Education Protocol were interviewed and a patient survey identified perceptions of the usefulness of the service innovation. RESULTS: Analysis of change from baseline to three months results showed statistically significant changes in Illness Belief component 'Understanding' and the Dartmouth Quality of Life 'General Health'. The integration of the Personalised Patient Education Protocol into the existing discharge process identified service improvements for cardiac nurse training and care pathway delivery, while patients identified the level and frequency of their use of the protocol following discharge. CONCLUSION: The introduction of the Personalised Patient Education Protocol succeeded in increasing patient engagement, facilitated a more patient-centred service by enabling practitioners to systematically provide personalised patient education, and gave patients a postdischarge structure to better follow-up their illness concerns with health professionals in the community. RELEVANCE TO CLINICAL PRACTICE: Integration of the Personalised Patient Education Protocol into an existing postmyocardial infarction care pathway enabled nurses to systematically respond to individual patients' illness beliefs and expectations. PMID- 26961520 TI - Sample Size in Clinical Cardioprotection Trials Using Myocardial Salvage Index, Infarct Size, or Biochemical Markers as Endpoint. AB - BACKGROUND: Cardiac magnetic resonance (CMR) can quantify myocardial infarct (MI) size and myocardium at risk (MaR), enabling assessment of myocardial salvage index (MSI). We assessed how MSI impacts the number of patients needed to reach statistical power in relation to MI size alone and levels of biochemical markers in clinical cardioprotection trials and how scan day affect sample size. METHODS AND RESULTS: Controls (n=90) from the recent CHILL-MI and MITOCARE trials were included. MI size, MaR, and MSI were assessed from CMR. High-sensitivity troponin T (hsTnT) and creatine kinase isoenzyme MB (CKMB) levels were assessed in CHILL MI patients (n=50). Utilizing distribution of these variables, 100 000 clinical trials were simulated for calculation of sample size required to reach sufficient power. For a treatment effect of 25% decrease in outcome variables, 50 patients were required in each arm using MSI compared to 93, 98, 120, 141, and 143 for MI size alone, hsTnT (area under the curve [AUC] and peak), and CKMB (AUC and peak) in order to reach a power of 90%. If average CMR scan day between treatment and control arms differed by 1 day, sample size needs to be increased by 54% (77 vs 50) to avoid scan day bias masking a treatment effect of 25%. CONCLUSION: Sample size in cardioprotection trials can be reduced 46% to 65% without compromising statistical power when using MSI by CMR as an outcome variable instead of MI size alone or biochemical markers. It is essential to ensure lack of bias in scan day between treatment and control arms to avoid compromising statistical power. PMID- 26961522 TI - Frequency of remnants of sealants left behind in pits and fissures of occlusal surfaces after 2 and 3 years. AB - OBJECTIVES: The null-hypothesis tested was that there was no difference in the frequency of remnants of high-viscosity glass-ionomer sealants left behind in pits and fissures of occlusal surfaces of first permanent molars and that of resin composite and glass-carbomer sealants. MATERIALS AND METHODS: Based on the results of a sealant trial, a sample of sealed teeth from which the material had apparently completely disappeared from at least one of the three sections into which the occlusal surface was divided, assessed through visible clinical examination, was also assessed from images of colour photographs and Scanning Electron Microscopy (SEM) as the reference image. The sample size consisted of 112 and 120 teeth from 59 and 98 children at evaluation years 2 and 3 respectively. Two examiners performed the assessments. Fisher's Exact Test was applied to test for the differences between the dependent variable and the sealant groups. RESULTS: The remnants of sealant material left in the deeper parts of pits and fissures were assessed from colour photograph and SEM images in five sections at year 2 and in eight sections at year 3. The assessment found no sealant group effect. CONCLUSION: The frequency of remnants of glass-ionomer sealant in pits and fissures of occlusal surfaces in first permanent molars is not higher than the frequency of glass-carbomer and resin sealants after 2 and 3 years. CLINICAL RELEVANCE: Contrary to the current assumption, there appears to be no significant difference in the frequency of remnants left behind in pits and fissures between glass-ionomer and resin sealants. PMID- 26961523 TI - Treatment of real coal gasification wastewater using a novel integrated system of anoxic hybrid two stage aerobic processes: performance and the role of pure oxygen microbubble. AB - A novel integrated system of anoxic-pure oxygen microbubble-activated sludge reactor-moving bed biofilm reactor was employed in treatment of real coal gasification wastewater. The results showed the integrated system had efficient performance of pollutants removal in short hydraulic retention time. While pure oxygen microbubble with the flow rate of 1.5 L/h and NaHCO3 dosage ratio of 2:1 (amount NaHCO3 to NH4 (+)-N ratio, mol: mol) were used, the removal efficiencies of COD, total phenols (TPh) and NH4 (+)-N reached 90, 95, and 95 %, respectively, with the influent loading rates of 3.4 kg COD/(m(3) d), 0.81 kg TPh/(m(3) d), and 0.28 kg NH4 (+)-N/(m(3) d). With the recycle ratio of 300 %, the concentrations of NO2 (-)-N and NO3 (-)-N in effluent decreased to 12 and 59 mg/L, respectively. Meanwhile, pure oxygen microbubble significantly improved the enzymatic activities and affected the effluent organic compositions and reduced the foam expansion. Thus, the novel integrated system with efficient, stable, and economical advantages was suitable for engineering application. PMID- 26961524 TI - Degradation and acute toxicity removal of the antidepressant Fluoxetine (Prozac((r))) in aqueous systems by electron beam irradiation. AB - Electron beam irradiation (EBI) has been considered an advanced technology for the treatment of water and wastewater, whereas very few previous investigations reported its use for removing pharmaceutical pollutants. In this study, the degradation of fluoxetine (FLX), an antidepressant marketed as Prozac((r)), was investigated by using EBI at FLX initial concentration of 19.4 +/- 0.2 mg L(-1). More than 90 % FLX degradation was achieved at 0.5 kGy, with FLX below the detection limit (0.012 mg L(-1)) at doses higher than 2.5 kGy. The elucidation of organic byproducts performed using direct injection mass spectrometry, along with the results of ion chromatography, indicated hydroxylation of FLX molecules with release of fluoride and nitrate anions. Nevertheless, about 80 % of the total organic carbon concentration remained even for 7.5 kGy or higher doses. The decreases in acute toxicity achieved 86.8 and 9.6 % for Daphnia similis and Vibrio fischeri after EBI exposure at 5 kGy, respectively. These results suggest that EBI could be an alternative to eliminate FLX and to decrease residual toxicity from wastewater generated in pharmaceutical formulation facilities, although further investigation is needed for correlating the FLX degradation mechanism with the toxicity results. PMID- 26961525 TI - Potentially toxic element contamination in soil and accumulation in maize plants in a smelter area in Kosovo. AB - A biogeochemical field study was carried out in the industrial area of Kosovska Mitrovica in northern Kosovo, where agricultural soils were contaminated by potentially toxic elements due to smelting activity. Total and bioavailable contents of As, Cd, Co, Cu, Pb, Sb, U and Zn in soil and their concentrations in maize roots and grains were determined. Soil contamination by As, Cd, Cu, Pb, Sb and Zn was variable from slightly to highly contaminated soils and influenced both the bioavailable fraction and accumulation of these potentially toxic elements in maize tissues. The comparison between potentially toxic element concentrations in roots and grains indicated that maize is able to limit the transfer of non-essential elements to edible parts. The plant-to-soil bioconcentration indices suggested that the transfer of potentially toxic elements from soil to plant was predicted better by bioavailable concentrations than by the total contents. These indices further identified some competitions and interactions among these elements in root uptake and root-to-grain translocation. PMID- 26961526 TI - Polycyclic aromatic hydrocarbons in urban tunnels of Guanajuato city (Mexico) measured in deposited dust particles and in transplanted lichen Xanthoparmelia mexicana (Gyeln.) Hale. AB - Sixteen priority PAHs were determined in five urban tunnels of Guanajuato city, through which about 4 % of population walks and about 25,000 vehicles pass daily. Xanthoparmelia mexicana (Gyeln.) Hale, highly abundant lichen in this region, was exposed during 6 months and then the samples were collected together with the wall dust; both materials were analyzed by gas chromatography-mass spectrometry. Total PAH concentrations in dust and in lichen samples were in the range 1392 7961 ng g(-1) (average per tunnel 4637 ng g(-1)) and 522-3571 ng g(-1) (average 2587 ng g(-1)), respectively. In dust, the highest concentrations corresponded to PYR, FLA, BaA, CHR, BaP, and PHE, whereas in lichens the most abundant were DahA, IcdP, BghiP, and PYR. The obtained results suggested passive deposition of PAHs on lipophilic lichen surface rather than phenomena associated with metabolic activity of the exposed organisms. Application of seven different molecular diagnostic ratios pointed to gasoline-operated cars as the principal source of PAHs. Based on the obtained results and their comparison with data reported for other geographical regions, Guanajuato tunnels were considered moderately contaminated with PAHs; however toxic BaP equivalent concentrations integrated for seven carcinogenic compounds presented relatively high values in four tunnels: 567-1051 ngBaPeq g(-1) as evaluated for dust samples. Since up to 7000 persons walk daily through tunnels, the obtained data call for more detailed study evaluating PAHs toxicity in Guanajuato population. PMID- 26961527 TI - Preliminary investigation on the effect of earthworm and vegetation for sludge treatment in sludge treatment reed beds system. AB - Sewage sludge treatment is becoming one of the most significant challenges for domestic wastewater management. Optimization of sludge management for reducing sludge handling cost in wastewater treatment plant is highly demanded. Sludge treatment reed bed system (STRB) is an eco-environmentally friendly technology which has a low investment input and reduced costs for operation and maintenance. The objective of this study is to evaluate the effect of earthworm assistant STRB in terms of sludge dewatering and stabilization of surplus sludge. The results show that draining and evapotranspiration (ET) take the main role for sludge dewatering; with maximum of 77 and 43 % water was removed through draining and ET, respectively. Plants improved ET rate up to 13.1 % in the planted STRB compare with the unplanted STRB. The combination of plants and earthworms increased ET rate of 20.9 % more than the control STRB (unplanted without earthworms). The planted STRB with earthworm reached the lowest water content in accumulated sludge of 46 %. There was a systematic increase of total solids (TS) concentration from 0.5 % in the influent to 25-54 % in the accumulated sludge. Earthworms enhanced the sludge stabilization dramatic with the ratio of volatile solids (VS)/TS decreased from 49 % in the influent to 18 % in the accumulated sludge in the earthworm assistant STRB. The results demonstrated a good efficiency for sludge dewatering and stabilization with the assistant of earthworms in STRBs, which can be an alternative technology for sludge treatment in wastewater treatment plants. PMID- 26961528 TI - Changing roles of ammonia-oxidizing bacteria and archaea in a continuously acidifying soil caused by over-fertilization with nitrogen. AB - Nitrification coupled with nitrate leaching contributes to soil acidification. However, little is known about the effect of soil acidification on nitrification, especially on ammonia oxidation that is the rate-limiting step of nitrification and performed by ammonia-oxidizing bacteria (AOB) and archaea (AOA). Serious soil acidification occurs in Chinese greenhouses due to the overuse of N-fertilizer. In the present study, greenhouse soils with 1, 3, 5, 7, and 9 years of vegetable cultivation showed a consistent pH decline (i.e., 7.0, 6.3, 5.6, 4.9, and 4.3). Across the pH gradient, we analyzed the community structure and abundance of AOB and AOA by pyrosequencing and real-time PCR techniques, respectively. The recovered nitrification potential (RNP) method was used to determine relative contributions of AOA and AOB to nitrification potential. The results revealed that soil acidification shaped the community structures of AOA and AOB. In acidifying soil, soil pH, NH3 concentration, and DOC content were critical factors shaping ammonia oxidizer community structure. AOB abundance, but not AOA, was strongly influenced by soil acidification. When soil pH was below 5.0, AOA rather than AOB were responsible for almost all of the RNP. However, when soil pH ranged from 5.6 to 7.0, AOB were the major contributors to RNP. The group I.1a associatied AOA had more relative abundance in low pH (pH<6.3), whereas group I.1b tended to prefer neutral pH. Clusters 2, 10, and 12 in AOB were more abundant in acidic soil (pH <5.6), while Nitrosomonas-like lineage and unclassified lineage 3 were prevailing in neutral soil and slightly acidic soil (pH, 6.0-6.5), respectively. These results suggested that soil acidification had a profound impact on ammonia oxidation and more specific lineages in AOB occupying different pH-associated niches required further investigation. PMID- 26961529 TI - Mercury concentrations in the coastal marine food web along the Senegalese coast. AB - This paper presents the results of seasonal (wet and dry seasons) and spatial (five sites) variation of mercury concentration in seven marine organisms representative for shallow Senegalese coastal waters and including species of commercial importance. Total mercury levels were recorded in the green algae (Ulva lactuca); the brown mussel (Perna perna); the Caramote prawn (Penaeus kerathurus); and in the liver and muscles of the following fish: Solea senegalensis, Mugil cephalus, Saratherondon melanotheron, and Sardinella aurita. The total selenium (Se) contents were determined only in the edible part of Perna perna, Penaeus kerathurus and in the muscles of Sardinella aurita and Solea senegalensis. Hg concentration in fish species was higher in liver compared to the muscle. Between species differences in Hg, concentrations were recorded with the highest concentration found in fish and the lowest in algae. The spatiotemporal study showed that there was no clear seasonal pattern in Hg concentrations in biota, but spatial differences existed with highest concentrations in sites located near important anthropogenic pressure. For shrimp, mussel, and the muscles of sardine and sole, Hg concentrations were below the health safety limits for human consumption as defined by the European Union. The Se/Hg molar ratio was always higher than one whatever the species or location suggesting a protection of Se against Hg potential adverse effect. PMID- 26961530 TI - Comparative study on metal biosorption by two macroalgae in saline waters: single and ternary systems. AB - The biosorption capability of two marine macroalgae (green Ulva lactuca and brown Fucus vesiculosus) was evaluated in the removal of toxic metals (Hg, Cd and Pb) from saline waters, under realistic conditions. Results showed that, independently of the contamination scenario tested, both macroalgae have a remarkable capacity to biosorb Hg and Pb. In single-contaminant systems, by using only c.a. 500 mg of non-pre-treated algae biomass (size <200 MUm) per litter, it was possible to achieve removal efficiencies between 96 and 99 % for Hg and up to 86 % for Pb. Despite the higher removal of Hg, equilibrium was reached more quickly for Pb (after 8 h). In multi-contaminant systems, macroalgae exhibited a similar selectivity toward the target metals: Hg > Pb> > Cd, although Pb removal by U. lactuca was more inhibited than that achieved by F. vesiculosus. Under the experimental conditions used, none of the macroalgae was effective to remove Cd (maximum removal of 20 %). In all cases, the kinetics of biosorption was mathematically described with success. Globally, it became clear that the studied macroalgae may be part of simple, efficient, and cost-effective water treatment technologies. Nevertheless, Fucus vesiculosus has greater potential, since it always presented higher initial sorption rates and higher removal efficiencies. PMID- 26961531 TI - Characteristic oxidation behavior of beta-cyclocitral from the cyanobacterium Microcystis. AB - The cyanobacterium Microcystis produces volatile organic compounds such as beta cyclocitral and 3-methyl-1-butanol. The lysis of cyanobacteria involving the blue color formation has been occasionally observed in a natural environment. In this study, we focused on the oxidation behavior of beta-cyclocitral that contributed to the blue color formation in a natural environment and compared beta cyclocitral with a structurally related compound concerning its oxidation, acidification, and lytic behavior. The oxidation products of beta-cyclocitral were identified by the addition of beta-cyclocitral in water, in which 2,2,6 trimethylcyclohex-1-ene-1-yl formate and 2,2,6-trimethylcyclohexanone were structurally characterized. That is, beta-cyclocitral was easily oxidized to produce the corresponding carboxylic acid and the enol ester in water without an oxidizing reagent, suggesting that this oxidation proceeded according to the Baeyer-Villiger oxidation. The oxidation behavior of beta-cyclocitral in a laboratory was different from that in the natural environment, in which 2,2,6- trimethylcyclohexanone was detected at the highest amount in the natural environment, whereas the highest amount in the laboratory was beta-cyclocitric acid. A comparison of beta-cyclocitral with structurally similar aldehydes concerning the lytic behavior of a Microcystis strain and the acidification process indicated that only beta-cyclocitral was easily oxidized. Furthermore, it was found that a blue color formation occurred between pH 5.5 and 6.5, suggesting that chlorophyll a and beta-carotene are unstable and decomposed, whereas phycocyanin was stable to some extent in this range. The obtained results of the characteristic oxidation behavior of beta-cyclocitral would contribute to a better understanding of the cyanobacterial life cycle. PMID- 26961533 TI - Isolation and characterization of Sphingomonas sp. Y2 capable of high-efficiency degradation of nonylphenol polyethoxylates in wastewater. AB - Nonylphenol polyethoxylates (NPEOs), although banned for decades, are still widely used in manufactories and thus affect human lives. In this study, a highly efficient NPEO-degrading bacterium, Sphingomonas sp. Y2, was isolated from sewage sludge by enrichment culture. Strain Y2 ensured the complete removal of NPEO in 48 h and degraded 99.2 % NPEO (1,000 mg L(-1)) within 30 h at a specific growth rate of 0.73 h(-1) in minimum salt medium. To date, this degradation efficiency is the highest reported for NPEO metabolism by a pure bacterium under this condition. Furthermore, the application of this bacterium to wastewater treatment demonstrated that it metabolized 98.5 % NPEO (1,000 mg L(-1)) within 5 days with a specific growth rate of 2.03 day(-1). The degradation intermediates, identified as nonylphenol, short-chain NPEOs and short-chain nonylphenol polyethoxycarboxylates by high-performance liquid chromatography and gas chromatography-mass spectrometry, indicated the sequential exo-cleavage of the EO chain. Additionally, the enzymes involved in the biodegradation were inducible rather than constitutive. Considering that strain Y2 exhibits prominent biodegradation advantages in industrial wastewater treatment, it might serve as a promising potential candidate for in situ bioremediation of contamination by NPEOs and other structurally similar compounds. PMID- 26961532 TI - Escherichia coli as a fatty acid and biodiesel factory: current challenges and future directions. AB - Biodiesel has received widespread attention as a sustainable, environment friendly, and alternative source of energy. It can be derived from plant, animal, and microbial organisms in the form of vegetable oil, fats, and lipids, respectively. However, biodiesel production from such sources is not economically feasible due to extensive downstream processes, such as trans-esterification and purification. To obtain cost-effective biodiesel, these bottlenecks need to be overcome. Escherichia coli, a model microorganism, has the potential to produce biodiesel directly from ligno-cellulosic sugars, bypassing trans-esterification. In this process, E. coli is engineered to produce biodiesel using metabolic engineering technology. The entire process of biodiesel production is carried out in a single microbial cell, bypassing the expensive downstream processing steps. This review focuses mainly on production of fatty acid and biodiesel in E. coli using metabolic engineering approaches. In the first part, we describe fatty acid biosynthesis in E. coli. In the second half, we discuss bottlenecks and strategies to enhance the production yield. A complete understanding of current developments in E. coli-based biodiesel production and pathway optimization strategies would reduce production costs for biofuels and plant-derived chemicals. PMID- 26961534 TI - Fate and removal of various antibiotic resistance genes in typical pharmaceutical wastewater treatment systems. AB - The high levels of antibiotic residues in pharmaceutical wastewater treatment plants (PWWTPs) make these plants the hotspots for the proliferation of antibiotic resistance genes (ARGs). This study investigated the fate and removal of 11 ARG subtypes for sulfonamide, tetracycline, beta-lactam, and macrolide resistance in each processing stage of two full-scale PWWTPs in northern China. The levels of typical ARG subtypes in the final effluents ranged from (2.56 +/- 0.13) * 10(1) to (2.36 +/- 0.11) * 10(7) copies/ml. The absolute abundance of ARGs in effluents accounted for only 0.03-78.1 % of influents of the two PWWTPs, while the majority of the ARGs were transported to the dewatered sludge with concentrations from (2.65 +/- 0.43) * 10(5) to (4.27 +/- 0.03) * 10(10) copies/g dry weight (dw). The total loads of ARGs discharged through dewatered sludge plus effluent was 1.01-14.09-fold higher than that in the raw influents, suggesting the proliferation of ARGs occurred in the wastewater treatment. The proliferation of ARGs mainly occurs in biological treatment process, such as aeration tank, anoxic tank, sequencing batch reactor (SBR), and bio-contact oxidation, facilitates the proliferation of various ARGs, implying significant replication of certain ARG subtypes may be attributable to microbial growth. Chemical oxidation seems promising to remove ARGs, with removal efficiency ranged from 29.3 to 85.7 %, while the partial correlation analysis showed significant correlations between antibiotic concentration and ARG removal. Thus, the high antibiotic residues within the PWWTPs may have an influence on the proliferation, fate, and removal of the associated ARG subtypes. PMID- 26961535 TI - Microbial composition and ecological features of phototrophic biofilms proliferating in the Moidons Caves (France): investigation at the single-cell level. AB - The authors investigated the microbial composition of phototrophic biofilms proliferating in a show cave using flow cytometry for the first time in such a context. Results are based on several biofilms sampled in the Moidons Caves (France) and concern both heterotrophic prokaryotes and autotrophic microorganisms. Heterotrophic microorganisms with low nucleic acid content were dominant in biofilms, as can be expected from the oligotrophic conditions prevailing within the cave. Analysis of the biofilm autotrophic components revealed the presence of several taxa, particularly the unicellular green algae Chlorella minutissima, specifically well adapted to this cave. Relationships between flow cytometry results and environmental variables determined in the cave were established and discussed so as to better understand biofilm proliferation processes in caves. PMID- 26961537 TI - Sixty seconds on . . . meldonium. PMID- 26961536 TI - Signal of Gastrointestinal Congenital Malformations with Antipsychotics After Minimising Competition Bias: A Disproportionality Analysis Using Data from Vigibase((r)). AB - INTRODUCTION: Investigations have highlighted the lack of evidence regarding the likelihood of congenital malformations following exposure to antipsychotic drugs during pregnancy. To gain further knowledge regarding their safety, we evaluated signals of congenital malformations with antipsychotics using VigiBase((r)), the World Health Organization (WHO) Global Individual Case Safety Report (ICSR) database. METHOD: A case/non-case study was conducted in VigiBase((r)) between 1967 and 2014. Signals of disproportionate reporting (SDRs) were detected using the proportional reporting ratio (PRR), which defines SDRs as drug-report associations with a PRR >=2, Chi square >=4, and number of cases >=3. SDR detection for antipsychotics was performed for congenital malformations after removing all reports related to drug competitors and reports of movement disorders from the database. RESULTS: After removing reports related to drug competitors (antiepileptics, antidepressants, antivirals) and movement disorders, three signals were revealed: 'palate disorders congenital' (PRR 2.1, 95 % CI 1.6 2.9, Chi square = 30; n = 41), 'oesophageal disorders congenital' (PRR 2.5, 95 % CI 1.3-4.7, Chi square = 11; n = 10) and 'anorectal disorders congenital' (PRR 3.0, 95 % CI 1.6-5.6, Chi square = 13; n = 11). Among antipsychotics, phenothiazines with a piperazine side-chain, risperidone and aripiprazole appeared to be more suspect. CONCLUSION: Confirming a first signal from spontaneous reporting data, three SDRs for antipsychotics and gastrointestinal congenital abnormalities were unmasked in VigiBase((r)). This signal should be further explored by ad hoc pharmacoepidemiologic studies in order to assess whether it is relevant for prescription and public health. PMID- 26961538 TI - Measuring Health Literacy Among Adults with HIV Infection in Mozambique: Development and Validation of the HIV Literacy Test. AB - The role of health literacy on HIV outcomes has not been evaluated widely in Africa, in part because few appropriate literacy measures exist. We developed a 16-item scale, the HIV Literacy Test (HIV-LT) to assess literacy-related tasks needed to participate in HIV care. Items were scored as correct or incorrect; higher scores indicated higher literacy skill (range 0-100 %). We tested internal reliability (Kuder-Richardson coefficient) of the HIV-LT in a convenience sample of 319 Portuguese-speaking, HIV infected adults on antiretroviral treatment in Maputo, Mozambique. Construct validity was assessed by a hypothetical model developed a priori. The HIV-LT was reliable and valid to measure participants' literacy skills. The mean HIV-LT score was 42 %; literacy skills applicable to HIV care were challenging for many participants. The HIV-LT could be used to assess the relationship of literacy and HIV-related outcomes in diverse settings, and evaluate interventions to improve health communication for those in HIV care. PMID- 26961539 TI - Pharmacokinetics, Safety and Tolerability of Sacubitril/Valsartan (LCZ696) After Single-Dose Administration in Healthy Chinese Subjects. AB - BACKGROUND AND OBJECTIVE: Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects. METHODS: In this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study. RESULTS: Following oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (T max) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T 1/2) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last), and maximum plasma concentration (C max) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects. CONCLUSION: The pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects. PMID- 26961540 TI - Identification of Transporters Involved in Beraprost Sodium Transport In Vitro. AB - BACKGROUND AND OBJECTIVE: Beraprost sodium (BPS) is a chemically stable and orally active prostacyclin analog that is used in the treatment of chronic arterial occlusive disease since 1992 and primary pulmonary hypertension since 1999 in Japan. Multiple-drug therapy is common in clinical practice, and BPS is co-administered with other drugs. Membrane transporters are known to markedly affect pharmacokinetics, safety and efficacy, and many transporter-based drug drug interactions have been recently reported. However, information on the transporters involved in the pharmacokinetics of BPS is limited. METHODS: First of all, we have examined 11 transporters, ABCB1 (P-glycoprotein: P-gp), ABCG2 (breast cancer resistance protein: BCRP), SLC22A6 (organic anion transporter 1: OAT1), SLC22A8 (organic anion transporter 3: OAT3), SLCO1B1 (organic anion transporting polypeptide 1B1: OATP1B1), SLCO1B3 (organic anion transporting polypeptide 1B3: OATP1B3), SLCO2B1 (organic anion transporting polypeptide 2B1: OATP2B1), SLC22A1 (organic cation transporter 1: OCT1), SLC22A2 (organic cation transporter 2: OCT2), ABCB11 (bile-salt export pump: BSEP), and ABCC2 (multidrug resistance associated protein 2: MRP2) to clarify which of them would be candidates that might recognize BPS as their substrate in transporter-expressing LLC-PK1, S2, and HEK293 cells as well as in membrane vesicles. Furthermore, we determined whether the transport of BPS was inhibited by the typical inhibitors of each transporter, i.e., verapamil for P-gp, Ko143 for BCRP, probenecid for OAT3, rifampicin for OATP1B1 and OATP1B3, cyclosporine for BSEP, and sulfobromophthalein (BSP) for MRP2. RESULTS: The results obtained showed that P gp, BCRP, OAT3, OATP1B1, OATP1B3, BSEP and MRP2 might be candidates for BPS transporters. From the further evaluation with the typical inhibitors of each transporter, it was confirmed that BPS is a substrate for P-gp, BCRP, OAT3, OATP1B1, OATP1B3 and MRP2, because the typical inhibitor, cyclosporine, had no effects on BPS transport by BSEP. CONCLUSIONS: BPS is a substrate of 6 transporters: P-gp, BCRP, OAT3, OATP1B1, OATP1B3, and MRP2, because their expressing cells and vesicles transported BPS more than in the controls, and BPS transport activities were reduced by the typical inhibitors of tested transporters. Although there are no reports regarding drug-drug interactions between BPS and possible combination drugs expected due to transporters, it may be necessary to notice that that substrates or inhibitors for the 6 mentioned transporters may have effects on pharmacokinetics of BPS when co-administered. PMID- 26961541 TI - Changes in population susceptibility to heat and cold over time: assessing adaptation to climate change. AB - BACKGROUND: In the context of a warming climate and increasing urbanisation (with the associated urban heat island effect), interest in understanding temperature related health effects is growing. Previous reviews have examined how the temperature-mortality relationship varies by geographical location. There have been no reviews examining the empirical evidence for changes in population susceptibility to the effects of heat and/or cold over time. The objective of this paper is to review studies which have specifically examined variations in temperature related mortality risks over the 20(th) and 21(st) centuries and determine whether population adaptation to heat and/or cold has occurred. METHODS: We searched five electronic databases combining search terms for three main concepts: temperature, health outcomes and changes in vulnerability or adaptation. Studies included were those which quantified the risk of heat related mortality with changing ambient temperature in a specific location over time, or those which compared mortality outcomes between two different extreme temperature events (heatwaves) in one location. RESULTS: The electronic searches returned 9183 titles and abstracts, of which eleven studies examining the effects of ambient temperature over time were included and six studies comparing the effect of different heatwaves at discrete time points were included. Of the eleven papers that quantified the risk of, or absolute heat related mortality over time, ten found a decrease in susceptibility over time of which five found the decrease to be significant. The magnitude of the decrease varied by location. Only two studies attempted to quantitatively attribute changes in susceptibility to specific adaptive measures and found no significant association between the risk of heat related mortality and air conditioning prevalence within or between cities over time. Four of the six papers examining effects of heatwaves found a decrease in expected mortality in later years. Five studies examined the risk of cold. In contrast to the changes in heat related mortality observed, only one found a significant decrease in cold related mortality in later time periods. CONCLUSIONS: There is evidence that across a number of different settings, population susceptibility to heat and heatwaves has been decreasing. These changes in heat related susceptibility have important implications for health impact assessments of future heat related risk. A similar decrease in cold related mortality was not shown. Adaptation to heat has implications for future planning, particularly in urban areas, with anticipated increases in temperature due to climate change. PMID- 26961542 TI - Cellular Uptake of alpha-Synuclein Oligomer-Selective Antibodies is Enhanced by the Extracellular Presence of alpha-Synuclein and Mediated via Fcgamma Receptors. AB - Immunotherapy targeting aggregated alpha-synuclein has emerged as a potential treatment strategy against Parkinson's disease and other alpha-synucleinopathies. We have developed alpha-synuclein oligomer/protofibril selective antibodies that reduce toxic alpha-synuclein in a human cell line and, upon intraperitoneal administration, in spinal cord of transgenic mice. Here, we investigated under which conditions and by which mechanisms such antibodies can be internalized by cells. For this purpose, human neuroglioma H4 cells were treated with either monoclonal oligomer/protofibril selective alpha-synuclein antibodies, linear epitope monoclonal alpha-synuclein antibodies, or with a control antibody. The oligomer/protofibril selective antibody mAb47 displayed the highest cellular uptake and was therefore chosen for additional analyses. Next, alpha-synuclein overexpressing cells were incubated with mAb47, which resulted in increased antibody internalization as compared to non-transfected cells. Similarly, regular cells exposed to mAb47 together with media containing alpha-synuclein displayed a higher uptake as compared to cells incubated with regular media. Finally, different Fcgamma receptors were targeted and we then found that blockage of FcgammaRI and FcgammaRIIB/C resulted in reduced antibody internalization. Our data thus indicate that the robust uptake of the oligomer/protofibril selective antibody mAb47 by human CNS-derived cells is enhanced by extracellular alpha synuclein and mediated via Fcgamma receptors. Altogether, our finding lend further support to the belief that alpha-synuclein pathology can be modified by monoclonal antibodies and that these can target toxic alpha-synuclein species in the extracellular milieu. In the context of immunotherapy, antibody binding of alpha-synuclein would then not only block further aggregation but also mediate internalization and subsequent degradation of antigen-antibody complexes. PMID- 26961543 TI - Pretreatment of Mouse Neural Stem Cells with Carbon Monoxide-Releasing Molecule-2 Interferes with NF-kappaB p65 Signaling and Suppresses Iron Overload-Induced Apoptosis. AB - Neural stem cell (NSC) transplantation is a promising approach to repair the damaged brain after hemorrhagic stroke; however, it is largely limited by the poor survival of donor cells. Breakdown products of the hematoma and subsequent iron overload contribute to the impairment of survival of neural cells. There is little information regarding the mechanism involved in the death of grafted cells. Furthermore, therapeutic research targeted to improving the survival of grafted neural stem cells (NSCs) is strikingly lacking. Here, we showed that iron overload induced apoptosis of C17.2 cells, a cell line originally cloned from mouse NSCs and immortalized by v-myc. Pretreatment with carbon monoxide-releasing molecule-2 (CORM-2) markedly protected C17.2 cells against iron overload in a dose-dependent manner. Moreover, CORM-2 interfered with NF-kappaB signaling, including inhibition of nuclear translocation and down-regulation of NF-kappaB p65. TUNEL staining showed that preconditioning C17.2 cells with CORM-2 enhanced their resistance to apoptosis induced by iron overload, which was concomitant with down-regulation of the pro-apoptotic proteins (Bax and cleaved caspase-3) and up-regulation of the anti-apoptotic protein Bcl2. The protective effect of CORM-2 could be simulated by BAY11-7082, a special inhibitor of NF-kappaB p65. These results provide a novel and effective strategy to enhance the survival of NSCs after transplantation and, therefore, their efficacy in repairing brain injury due to hemorrhagic stroke. PMID- 26961545 TI - CD40 Negatively Regulates ATP-TLR4-Activated Inflammasome in Microglia. AB - During acute brain injury and/or sterile inflammation, release of danger associated molecular patterns (DAMPs) activates pattern recognition receptors (PRRs). Microglial toll-like receptor (TLR)-4 activated by DAMPs potentiates neuroinflammation through inflammasome-induced IL-1beta and pathogenic Th17 polarization which critically influences brain injury. TLR4 activation accompanies increased CD40, a cognate costimulatory molecule, involved in microglia-mediated immune responses in the brain. During brain injury, excessive release of extracellular ATP (DAMPs) is involved in promoting the damage. However, the regulatory role of CD40 in microglia during ATP-TLR4-mediated inflammasome activation has never been explored. We report that CD40, in the absence of ATP, synergizes TLR4-induced proinflammatory cytokines but not IL 1beta, suggesting that the response is independent of inflammasome. The presence of ATP during TLR4 activation leads to NLRP3 inflammasome activation and caspase 1-mediated IL-1beta secretion which was inhibited during CD40 activation, accompanied with inhibition of ERK1/2 and reactive oxygen species (ROS), and elevation in p38 MAPK phosphorylation. Experiments using selective inhibitors prove indispensability of ERK 1/2 and ROS for inflammasome activation. The ATP TLR4-primed macrophages polarize the immune response toward pathogenic Th17 cells, whereas CD40 activation mediates Th1 response. Exogenous supplementation of IFN-gamma (a Th1 cytokine and CD40 inducer) results in decreased IL-1beta, suggesting possible feedback loop mechanism of inflammasome inhibition, whereby IFN-gamma-mediated increase in CD40 expression and activation suppress neurotoxic inflammasome activation required for Th17 response. Collectively, the findings indicate that CD40 is a novel negative regulator of ATP-TLR4-mediated inflammasome activation in microglia, thus providing a checkpoint to regulate excessive inflammasome activation and Th17 response during DAMP-mediated brain injury. PMID- 26961544 TI - Neuroprotective Effects of Resatorvid Against Traumatic Brain Injury in Rat: Involvement of Neuronal Autophagy and TLR4 Signaling Pathway. AB - Accumulating evidence indicates that autophagy and inflammatory responses contributes to secondary brain injury after traumatic brain injury (TBI), and toll-like receptor 4 (TLR4) is considered to involvement of this cascade and plays an important role. The present study was designed to determine the hypothesis that administration of resatorvid (TAK-242), a TLR4 antagonist, might provide a neuroprotective effect by inhibit TLR4-mediated pathway in a TBI rat model. Rat subjected to controlled cortical impact injury were injected with TAK 242 (0.5 mg/kg, i.v. injected) 10 min prior to injury. The results demonstrated that TAK-242 treatment significantly attenuated TBI-induced neurons loss, brain edema, and neurobehavioral impairment in rats. Immunoblotting analysis showed that TAK-242 treatment reduced TBI-induced TLR4, Beclin 1, and LC3-II levels, and maintained p62 levels at 24 h. Double immunolabeling demonstrated that LC3 dots co-localized with the hippocampus pyramidal neurons, and TLR4 was localized with the hippocampus neurons and astrocytes. In addition, the expression of TLR4 downstream signaling molecules, including MyD88, TRIF, NF-kappaB, TNF-alpha, and IL-1beta, was significantly downregulated in hippocampus tissue by Western blot analysis. In conclusion, our findings indicate that pre-injury treatment with TAK 242 could inhibit neuronal autophagy and neuroinflammation responses in the hippocampus in a rat model of TBI. The neuroprotective effects of TAK-242 may be related to modulation of the TLR4-MyD88/TRIF-NF-kappaB signaling pathway. Furthermore, the study also suggests that TAK-242, an attractive potential drug, may be a promising drug candidate for TBI. PMID- 26961546 TI - Safety of Adalimumab and Predictors of Adverse Events in 1693 Japanese Patients with Crohn's Disease. AB - BACKGROUND AND AIMS: Data from an all-cases post-marketing study were used to evaluate the safety and effectiveness of adalimumab in Japanese patients with Crohn's disease [CD]. METHODS: Patients received adalimumab for 24 weeks. Data from all patients [n = 1693] were used for the safety assessment. Data from patients with CD activity index [CDAI] >= 150 at baseline were used for the effectiveness assessment. RESULTS: The most frequent serious adverse drug reaction [ADR] was infection and infestations [6.6 events/100 patient-years]. The risk of serious infections increased in patients who had a history of malignancy and those with concomitant corticosteroid use. Of 415 patients who had switched from another anti-tumour necrosis factor alpha [TNFalpha] agent to adalimumab due to ADRs, 7.2% discontinued due to ADRs to adalimumab. Ten of 13 patients with a history of tuberculosis [TB] received prophylactic medication, and none developed TB. TB developed in one patient with no history of TB or anti-TB prophylaxis. Remission rates were 41.3% and 32.4% at 4 and 24 weeks, respectively. Remission rates did not differ between patients with and without concomitant use of immunomodulators. Predictive variables for increased effectiveness were CDAI <= 220 and disease duration of <= 2 years. Perianal lesions and loss of response to previous anti-TNFalpha agents affected effectiveness. CONCLUSIONS: The most frequent serious ADR was infection. Adalimumab significantly reduced disease activity, without any unexpected ADRs. Development of active TB during adalimumab therapy can be prevented through TB screening and prophylaxis. In patients who switched from another anti-TNFalpha agent to adalimumab due to ADRs, adalimumab was well tolerated. PMID- 26961547 TI - Guided online self-management interventions in primary care: a survey on use, facilitators, and barriers. AB - BACKGROUND: Guided online psychological self-management interventions offer broad prospects for the treatment of people with mild to moderate mental health problems, but implementation is challenging. The aims of this study are (1) to gain insight into use of and intention to use these interventions among primary care health professionals, (2) to determine the main barriers to use such interventions among non-users. METHODS: An online survey based on the Unified Theory of Acceptance and Use of Technology (UTAUT) was disseminated among mental health counsellors (MHCs; in Dutch POHs) in GP practices and primary care psychologists (PCP) in mental health care practices. The survey covered the current use of online interventions, the intention to use these in the future, and an operationalization of the UTAUT concepts: performance expectancy, effort expectancy, social influence, and facilitating conditions. RESULTS: In total, 481 MHCs and 290 PCPs responded (24%). Of them, 49% of MHCs and 21% of PCPs currently use online interventions in their treatments. A further 40% of MHCs and 27% of PCPs plan to introduce such interventions within the next year. Both groups were moderately positive about the presence of eHealth facilitators in their daily practice. Among current non-users, performance expectancy and facilitating conditions were significant predictors of usage intention in both groups of health professionals. CONCLUSIONS: Use of and intention to use online interventions is relatively high in Dutch primary care. Non-users, particularly, experience several barriers which need attention to enhance implementation. There is a need for further efforts regarding facilitation of and education on eHealth, as well as for research directed to its normalization in daily practice. PMID- 26961548 TI - Low-dose tolvaptan for the treatment of hyponatremia in the syndrome of inappropriate ADH secretion (SIADH). PMID- 26961549 TI - Transient severe tricuspid regurgitation during atrioventricular block. PMID- 26961551 TI - Carotid artery calcification. PMID- 26961550 TI - Hospitalized acute patients with fever and severe infection have lower mortality than patients with hypo- or normothermia: a follow-up study. AB - OBJECTIVES: Severe infection is a frequent cause of admission to an acute medical unit (AMU). However, not all infected patients present with fever. The aim was to assess differences in 30-day mortality among patients hospitalized with community acquired severe infection presenting with hypothermia, normothermia or fever. METHODS: A retrospective single-center follow-up at an AMU from August 1, 2009 to August 31, 2011. Patients were included the first time they presented with severe infection within the study period. Temperature was categorized into hypothermia (<36.0oC), normothermia (36.0oC-38.0oC) and fever (>38.0oC). Severe infection was defined as a discharge diagnosis indicating infection combined with organ failure within the first 24 h after arrival. Multivariable Cox regression analysis was computed to assess the association between temperature and 30-day mortality. RESULTS: A total of 2128 patients with severe infection were included. 3.0% (N = 64) were hypothermic, 57.1% (N = 1216) normothermic and 39.9% (N = 848) had fever at arrival. Crude 30-day mortality was 16.1% (N = 342, 95%CI 14.5-17.7%); 37.5% (N = 24, 95% CI 25.7-50.5%) for hypothermic patients, 18.3% (N = 223, 95%CI 16.2-20.6%) for normothermic patients and 11.2% (N = 95, 95%CI 9.2-13.5%) for patients with fever. Compared to normothermic patients, the adjusted hazard ratio of 30-day mortality among hypothermic patients was 1.62 (95%CI 1.06-2.49) and 0.74 (95%CI 0.58-0.94) among patients with fever. CONCLUSIONS: Over half of the patients admitted to an AMU with severe infection were normothermic at arrival. Hypothermia was associated with an increased risk of short-term mortality, whereas patients with fever were associated with a lower risk compared to those with normothermia. PMID- 26961552 TI - Swallow syncope unravelled by fizzy drink challenge. PMID- 26961553 TI - Rare case of accidental fire and burns caused by e-cigarette batteries. AB - E-cigarettes have become very popular among adult smokers, and many users carry e cigarette devices and their components on their person. We present a case of a 35 year-old man who was admitted to our regional burns unit after his clothing was set-alight following the self-combustion of an e-cigarette lithium battery that was in his pocket. The patient had sustained a 1.5% mixed depth burn to the lateral aspect of his right thigh. Ward debridement under local anaesthetic was performed to remove clothing residue and reduce the risk of tattooing. Following conservative management with outpatient dressings, the burn wound healed by day 56. PMID- 26961554 TI - Spontaneous tumour lysis syndrome secondary to the transformation of chronic myelomonocytic leukaemia into acute myeloid leukaemia. AB - A 78-year-old man, with a 6-year history of stable chronic myelomonocytic leukaemia (CMML), presented with general deterioration and worsening pancytopenia. Bone marrow biopsy showed that his disease had transformed into acute myeloid leukaemia (AML). He was started on a supportive transfusion regimen and did not receive any chemotherapy or corticosteroids. Several weeks later, he developed acute renal failure and was admitted to a medical admissions ward. Spontaneous tumour lysis syndrome (sTLS, grade 1) was diagnosed, as per the Cairo and Bishop criteria. He was treated with intravenous fluids, rasburicase and allopurinol. His renal function improved and he recovered from the sTLS. The authors believe that this is the first published case of sTLS occurring as a result of CMML transforming into AML; it highlights the importance of recognising sTLS as a cause of renal failure and electrolyte disturbance before cancer treatment begins. PMID- 26961555 TI - Ruptured intracranial dermoid cyst causing headache and meningism. PMID- 26961556 TI - Cardiac arrest in an 18-year-old man caused by anomalous right coronary artery origin. AB - An 18-year-old man presented to hospital following an out of hospital ventricular fibrillation cardiac arrest, with successful resuscitation at the scene. The incident happened during a competitive football match in which the man was playing. In the course of an extensive work up, a CT coronary angiogram demonstrated an anomalous right coronary artery (RCA) origin in the left coronary sinus. The RCA followed an initial intramural and subsequent interarterial course between the ascending aorta and pulmonary artery trunk. Cardiac MRI showed a small subendocardial area of delayed gadolinium enhancement in the inferoseptal wall, consistent with a small infarct. Treatment involved elective coronary artery bypass of the RCA with a right internal mammary artery graft. The patient made a full recovery. An implantable cardioverter-defibrillator was not inserted and he was advised not to return to competitive sports. PMID- 26961558 TI - Rare case of sacral mass due to chondromyxoid fibroma. PMID- 26961557 TI - Long-term survival in a patient with brain metastases of papillary thyroid carcinoma. AB - We present the case of a 43-year-old woman who underwent total thyroidectomy with bilateral lymphadenectomy for a papillary thyroid carcinoma (PTC), solid variant (T4bN1bMx), with V600E BRAF mutation. After ablative therapy, she presented undetectable thyroglobulin (Tg) but progressively increasing anti-Tg antibodies (TgAbs). During follow-up, nodal, lung and brain metastases were identified. She was submitted to surgical excision of lung lesions, radiosurgery of brain metastases and five radioiodine treatments. The latest brain MRI showed no lesions, pulmonary CT showed stable micronodules and there was progressive reduction in TgAbs. This is a peculiar case of a PTC with lung and brain metastatic lesions detected through TgAbs. Initial histological and molecular study suggested a more aggressive clinical behaviour, which was eventually confirmed. Although PTC brain metastases are extremely rare and present poor prognosis, our patient presented a good response to treatment and longer survival than usually reported for similar cases. PMID- 26961559 TI - Solitary plasmacytoma of the mandible: report of two cases. AB - Plasma cell neoplasms (plasmacytoma) are discrete, solitary masses of lymphoid neoplastic proliferations of B cells. Plasmacytomas comprise three groups: multiple myeloma, solitary plasmacytoma (SP) and extramedullary plasmacytoma. SP originates as a clone of transformed malignant plasma cells in the bone marrow. SP of the jaw is a rare condition; therefore diagnosis is quite difficult and often results in misdiagnosis. MM is a lymphoproliferative disease the prognosis of which is worse than SP. SP can progress to MM in a few months to years after diagnosis. In this regard, early diagnosis of the disease is of utmost importance. This article presents two cases of SP diagnosed in the mandible and documented with clinical, radiographic and histological findings. PMID- 26961560 TI - Meyer dysplasia: a diagnosis to consider. PMID- 26961561 TI - Bowel perforation after endoscopic submucosal dissection due to colon cancer and successful endoscopic treatment using an Ovesco clip. AB - An 83-year-old woman under intravenous anaesthesia underwent endoscopic submucosal dissection due to early well-differentiated colon cancer with no deep invasion (pT1). Wide perforation in the deep site of excision of the descending colon was identified and an Ovesco clip placed to close the defect. The patient was discharged from the hospital on day 4 after the procedure, with no abdominal pain and no peritoneal signs of inflammation. Follow-up CT and colonoscopy were performed after 6 months, and no recurrence was observed. PMID- 26961562 TI - Early and delayed presentation of traumatic small bowel injury. AB - Traumatic small bowel injury (TSBI) is rare and presents in only 1% of patients following blunt trauma. Delay in diagnosis can result in significant morbidity so a high index of suspicion is required in patients with abdominal injuries and a significant mechanism of injury. We discuss three cases of TSBI with varying presentations, and discuss their investigation and treatment. PMID- 26961563 TI - Adult jejunojejunal intussusception in the face of jejunal adenocarcinoma: two infrequently encountered entities. AB - Adult intussusception and small bowel adenocarcinoma are rarely encountered together. Intussusception should be considered in the differential diagnosis of adult patients presenting with abdominal pain, especially those with unremitting symptoms. Concomitant anaemia should lower the threshold for suspicion of underlying malignancy. Jejunal adenocarcinoma represents a rare, but possible aetiology. PMID- 26961564 TI - Carotid body tumour associated with cyanotic heart disease. PMID- 26961565 TI - A discrepancy between plasma glycated albumin and HbA1c levels in a patient with steroid-induced diabetes mellitus. AB - A 57-year-old man was admitted for the treatment of steroid-induced diabetes mellitus (DM). He also had interstitial pneumonia and, to treat it, 20 mg prednisolone had been started in April 2014. Although glycated haemoglobin (HbA1c) level was 7.8% (62 mmol/mol), his glycated albumin (GA) level was normal (13.9%) and the ratio of GA to HbA1c (GA:HbA1c) was lower than that of normal participants and patients with type 2 DM. Plasma GA and GA:HbA1c levels became persistently lower. In September 2015, HbA1c levels measured by HPLC and immunoprecipitation methods were almost the same (6.8% (51 mmol/mol) and 6.7% (50 mmol/mol), respectively), but GA (10.2%) and GA:HbA1c (1.6) were much lower. We report the case of a patient with DM where steroid administration may have caused a decrease in plasma GA and GA:HbA1c levels via increased albumin turnover. PMID- 26961566 TI - Progressive pseudorheumatoid dysplasia: a close mimicker of juvenile idiopathic arthritis. PMID- 26961567 TI - Spontaneous intraperitoneal rupture of a postpartum rectus sheath haematoma. AB - A 35-year-old woman presented to the emergency department (ED) with acute severe abdominal pain at 4 days postpartum. CT of the abdomen revealed a type II rectus sheath haematoma for which she was initially treated conservatively and discharged. A few hours later, she returned to the ED with a picture suggestive of peritonitis. Exploratory laparoscopy was performed and revealed haemoperitoneum and a ruptured area on the posterior rectus sheath. Approximately 2 L of blood was aspirated. Haemostatic control was achieved and closed suction drains secured in position. The patient was discharged in stable condition on postadmission day 6. She continued to follow-up on an outpatient basis and was doing well 3 months postoperatively. PMID- 26961569 TI - Pediatric Cardiology Boot Camp: Description and Evaluation of a Novel Intensive Training Program for Pediatric Cardiology Trainees. AB - The transition from residency to subspecialty fellowship in a procedurally driven field such as pediatric cardiology is challenging for trainees. We describe and assess the educational value of a pediatric cardiology "boot camp" educational tool designed to help prepare trainees for cardiology fellowship. A two-day intensive training program was provided for pediatric cardiology fellows in July 2015 at a large fellowship training program. Hands-on experiences and simulations were provided in: anatomy, auscultation, echocardiography, catheterization, cardiovascular intensive care (CVICU), electrophysiology (EP), heart failure, and cardiac surgery. Knowledge-based exams as well as surveys were completed by each participant pre-training and post-training. Pre- and post-exam results were compared via paired t tests, and survey results were compared via Wilcoxon rank sum. A total of eight participants were included. After boot camp, there was a significant improvement between pre- and post-exam scores (PRE 54 +/- 9 % vs. POST 85 +/- 8 %; p <= 0.001). On pre-training survey, the most common concerns about starting fellowship included: CVICU emergencies, technical aspects of the catheterization/EP labs, using temporary and permanent pacemakers/implantable cardiac defibrillators (ICDs), and ECG interpretation. Comparing pre- and post surveys, there was a statistically significant improvement in the participants comfort level in 33 of 36 (92 %) areas of assessment. All participants (8/8, 100 %) strongly agreed that the boot camp was a valuable learning experience and helped to alleviate anxieties about the start of fellowship. A pediatric cardiology boot camp experience at the start of cardiology fellowship can provide a strong foundation and serve as an educational springboard for pediatric cardiology fellows. PMID- 26961568 TI - Comparing the defence-related gene expression changes upon root-knot nematode attack in susceptible versus resistant cultivars of rice. AB - Rice is one of the major staple food crops in the world and an excellent model system for studying monocotyledonous plants. Diseases caused by nematodes in rice are well documented and among them, root-knot nematode (RKN), Meloidogyne graminicola, causes extensive yield decline. It is therefore necessary to identify novel sources of natural resistance to RKN in rice and to investigate the rice-RKN interaction in detail to understand the basal plant defence mechanisms and nematode manipulation of the host physiology. To this end, six different cultivars of rice were initially screened for RKN infection and development; Pusa 1121 and Vandana were found to be most susceptible and resistant to RKN infection, respectively. In order to investigate the role of major hormone-regulated plant defence pathways in compatible/incompatible rice RKN interaction, some well-identified marker genes involved in salicylate/jasmonate/ethylene pathway were evaluated for their differential expression through qRT-PCR. In general, our study shows a remarkable discrepancy in the expression pattern of those genes between compatible and incompatible rice RKN interaction. As most information on the molecular interplay between plants and nematodes were generated on dicotyledonous plants, the current study will strengthen our basic understanding of plant-nematode interaction in the monocot crops, which will aid in defining future strategies for best plant health measures. PMID- 26961570 TI - Radiofrequency Catheter Ablation of Accessory Atrioventricular Pathways in Infants and Toddlers <= 15 kg. AB - Accessory atrioventricular pathways (AP) are the most common substrate for paroxysmal supraventricular tachycardia in infants and small children. Up-to-date data on AP ablation in infants and small children are limited. The aim of the present study was to gain additional insight into radiofrequency (RF) catheter ablation of AP in infants and toddlers focusing on efficacy and safety in patients with a body weight of <= 15 kg. Since 10/2002, RF ablation of AP was performed in 281 children in our institution. Indications, procedural data as well as success and complication rates in children with a body weight <= 15 kg (n = 22) were compared with children > 15 kg (n = 259). Prevalence of structural heart anomalies was significantly higher among children <= 15 kg (27 vs. 5.7 %; p = 0.001). Procedure duration (median 262 vs. 177 min; p = 0.001) and fluoroscopy time (median 20.6 vs. 14.0 min; p = 0.007) were significantly longer among patients <= 15 kg. Procedural success rate did not differ significantly between the two groups (82 vs. 90 %). More RF lesions were required for AP ablation in the smaller patients (median 12 vs. 7; p = 0.019). Major complication rate was significantly higher in children <= 15 kg (9 vs. 1.1 %; p = 0.05) with femoral vessel occlusion being the only major adverse event in patients <= 15 kg. Catheter ablation of AP in children was effective irrespective of body weight. In children <= 15 kg, however, procedures were more challenging and time-consuming. Complication rate and number of RF lesions in smaller children were higher when compared to older children. PMID- 26961571 TI - Clinical Factors Associated with Dose of Loop Diuretics After Pediatric Cardiac Surgery: Post Hoc Analysis. AB - A post hoc analysis of a randomized controlled trial comparing the clinical effects of furosemide and ethacrynic acid was conducted. Infants undergoing cardiac surgery with cardiopulmonary bypass were included in order to explore which clinical factors are associated with diuretic dose in infants with congenital heart disease. Overall, 67 patients with median (interquartile range) age of 48 (13-139) days were enrolled. Median diuretic dose was 0.34 (0.25-0.4) mg/kg/h at the end of postoperative day (POD) 0 and it significantly decreased (p = 0.04) over the following PODs; during this period, the ratio between urine output and diuretic dose increased significantly (p = 0.04). Age (r -0.26, p = 0.02), weight (r -0.28, p = 0.01), cross-clamp time (r 0.27, p = 0.03), administration of ethacrynic acid (OR 0.01, p = 0.03), and, at the end of POD0, creatinine levels (r 0.3, p = 0.009), renal near-infrared spectroscopy saturation (-0.44, p = 0.008), whole-blood neutrophil gelatinase-associated lipocalin levels (r 0.30, p = 0.01), pH (r -0.26, p = 0.02), urinary volume (r -0.2755, p = 0.03), and fluid balance (r 0.2577, p = 0.0266) showed a significant association with diuretic dose. At multivariable logistic regression cross-clamp time (OR 1.007, p = 0.04), use of ethacrynic acid (OR 0.2, p = 0.01) and blood pH at the end of POD0 (OR 0.0001, p = 0.03) was independently associated with diuretic dose. Early resistance to loop diuretics continuous infusion is evident in post-cardiac surgery infants: Higher doses are administered to patients with lower urinary output. Independently associated variables with diuretic dose in our population appeared to be cross-clamping time, the administration of ethacrynic acid, and blood pH. PMID- 26961572 TI - Abnormal Mitral Valve Dimensions in Pediatric Patients with Hypertrophic Cardiomyopathy. AB - The hearts of patients with hypertrophic cardiomyopathy (HCM) show structural abnormalities other than isolated wall thickening. Recently, adult HCM patients have been found to have longer mitral valve leaflets than control subjects. The aim of the current study was to assess whether children and adolescents with HCM have similar measureable differences in mitral valve leaflet dimensions when compared to a healthy control group. Clinical and echocardiographic data from 46 children with myocardial hypertrophy and a phenotype and/or genotype consistent with sarcomeric HCM were reviewed. Cardiac magnetic resonance imaging studies were evaluated. The anterior and posterior mitral valve leaflet lengths and myocardial structure were compared to 20 healthy controls. The anterior mitral valve was longer in the HCM group than in the control group (28.4 +/- 4.9 vs. 25.2 +/- 3.6 mm in control patients, p = 0.013) as was the posterior mitral valve leaflet (16.3 +/- 3.0 vs. 13.1 +/- 2.3 mm for controls <0.0001). There was no correlation between the resting left ventricular outflow tract gradient and anterior mitral valve leaflet length, nor was the anterior mitral valve leaflet longer in those with systolic anterior motion of the mitral valve compared to those without (28.9 +/- 6.1 vs. 28.1 +/- 4.5 mm, p = 0.61). Children and adolescents with HCM have abnormally long mitral valve leaflets when compared with healthy control subjects. These abnormalities do not appear to result in, or be due to, obstruction to left ventricular outflow. The mechanism of this mitral valve elongation is not clear but appears to be independent of hemodynamic disturbances. PMID- 26961574 TI - Blood pressure lowering efficacy of beta-1 selective beta blockers for primary hypertension. AB - BACKGROUND: Beta blockers are commonly used to treat hypertension. The blood pressure reading is the primary tool for physicians and patients to assess the efficacy of the treatment. The blood pressure lowering effect of beta-1 selective blockers is not known. OBJECTIVES: To quantify the dose-related effects of various doses and types of beta-1 selective adrenergic receptor blockers on systolic and diastolic blood pressure versus placebo in people with primary hypertension. SEARCH METHODS: We searched the Database of Abstracts of Reviews of Effectiveness (DARE) for related reviews.We searched the following databases for primary studies: the Cochrane Hypertension Specialised Register (All years to 15 October 2015), CENTRAL via the Cochrane Register of Studies Online (2015, Issue 10), Ovid MEDLINE (1946 to 15 October 2015), Ovid EMBASE (1974 to 15 October 2015) and ClinicalTrials.gov (all years to 15 October 2015).The Hypertension Group Specialised Register includes controlled trials from searches of CAB Abstracts, CINAHL, Cochrane Central Register of Controlled Trials, EMBASE, Food Science and Technology Abstracts (FSTA), Global Health, LILACS, MEDLINE, ProQuest Dissertations & Theses, PsycINFO, Web of Science and the WHO International Clinical Trials Registry Platform (ICTRP).Electronic databases were searched using a strategy combining the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity-maximizing version (2008 revision) with selected MeSH terms and free text terms. No language restrictions were used. The MEDLINE search strategy was translated into CENTRAL, EMBASE, the Hypertension Group Specialised Register and ClinicalTrials.gov using the appropriate controlled vocabulary as applicable. Full strategies are in Appendix 1. SELECTION CRITERIA: Randomised, double-blind, placebo-controlled parallel or cross-over trials. Studies had to contain a beta blocker monotherapy arm with fixed dose. People enrolled into the studies had to have primary hypertension at baseline. Duration of studies had to be between 3 weeks to 12 weeks. Drugs in this class of beta blockers are atenolol, betaxolol, bevantolol, bisoprolol, esmolol, metoprolol, nebivolol, pafenolol, practolol. DATA COLLECTION AND ANALYSIS: Two authors confirmed the inclusion of studies and extracted the data independently. Review Manager (RevMan) 5.3.5 was used to synthesise data. MAIN RESULTS: We identified 56 RCTs (randomised controlled trials) that examined the blood pressure (BP) lowering efficacy of beta-1 selective blockers (beta-1 blocker) in 7812 primary hypertensive patients. Among the included trials, 26 RCTs were parallel studies and 30 RCTs were cross-over studies, examining eight beta-1 blockers. Overall, the majority of beta-1 blockers studied significantly lowered systolic blood pressure (SBP) and diastolic blood pressure (DBP). In people with mild to moderate hypertension, beta-1 selective blockers lowered BP by an average of -10/-8 mmHg and reduced heart rate by 11 beats per minute. The maximum BP reduction of beta-1 blockers occurred at twice the starting dose. Individual beta-1 blockers did not exhibit a graded dose-response effect on SBP and DBP over the recommended dose range.Most beta-1 blockers tested significantly lowered heart rate. A graded dose-response of beta-1 blockers on heart rate was evident. Higher dose beta-1 blockers lowered heart rate more than lower doses. Individually and overall beta-1 blockers did not affect pulse pressure, which distinguishes them from other classes of drugs. AUTHORS' CONCLUSIONS: This review provides low quality evidence that in people with mild to moderate hypertension, beta-1 selective blockers lowered BP by an average of -10/-8 mmHg and reduced heart rate by 11 beats per minute as compared to placebo. The effect of beta-1 blockers at peak hours, -12/-9 mmHg, was greater than the reduction at trough hours, -8/-7 mmHg. Beta-1 selective blockers lowered BP by a greater magnitude than dual receptor beta-blockers and partial agonist beta-blockers, lowered BP similarly to nonselective beta-blockers. Beta-1 selective blockers lowered SBP by a similar degree and lowered DBP by a greater degree than diuretics, angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Because DBP is lowered by a similar extent to SBP, beta-1 selective blockers do not reduce pulse pressure. PMID- 26961573 TI - Castration influences intestinal microflora and induces abdominal obesity in high fat diet-fed mice. AB - Late-onset hypogonadism (i.e. androgen deficiency) raises the risk for abdominal obesity in men. The mechanism for this obesity is unclear. Here, we demonstrated that hypogonadism after castration caused abdominal obesity in high-fat diet (HFD)-fed, but not in standard diet (SD)-fed, C57BL/6J mice. Furthermore, the phenotype was not induced in mice treated with antibiotics that disrupt the intestinal microflora. In HFD-fed mice, castration increased feed efficiency and decreased fecal weight per food intake. Castration also induced in an increase of visceral fat mass only in the absence of antibiotics in HFD-fed mice, whereas subcutaneous fat mass was increased by castration irrespective of antibiotics. Castration reduced the expression in the mesenteric fat of both adipose triglyceride lipase and hormone-sensitive lipase in HFD-fed mice, which was not observed in the presence of antibiotics. Castration decreased thigh muscle (i.e. quadriceps and hamstrings) mass, elevated fasting blood glucose levels, and increased liver triglyceride levels in a HFD-dependent manner, whereas these changes were not observed in castrated mice treated with antibiotics. The Firmicutes/Bacteroidetes ratio and Lactobacillus species increased in the feces of HFD-fed castrated mice. These results show that androgen (e.g. testosterone) deficiency can alter the intestinal microbiome and induce abdominal obesity in a diet-dependent manner. PMID- 26961575 TI - Antihypertensive pharmacotherapy for prevention of sudden cardiac death in hypertensive individuals. AB - BACKGROUND: High blood pressure is an important public health problem because of associated risks of stroke and cardiovascular events. Antihypertensive drugs are often used in the belief that lowering blood pressure will prevent cardiac events, including myocardial infarction and sudden death (death of unknown cause within one hour of the onset of acute symptoms or within 24 hours of observation of the patient as alive and symptom free). OBJECTIVES: To assess the effects of antihypertensive pharmacotherapy in preventing sudden death, non-fatal myocardial infarction and fatal myocardial infarction among hypertensive individuals. SEARCH METHODS: We searched the Cochrane Hypertension Specialised Register (all years to January 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (2016, Issue 1), Ovid MEDLINE (1946 to January 2016), Ovid EMBASE (1980 to January 2016) and ClinicalTrials.gov (all years to January 2016). SELECTION CRITERIA: All randomised trials evaluating any antihypertensive drug treatment for hypertension, defined, when possible, as baseline resting systolic blood pressure of at least 140 mmHg and/or resting diastolic blood pressure of at least 90 mmHg. Comparisons included one or more antihypertensive drugs versus placebo, or versus no treatment. DATA COLLECTION AND ANALYSIS: Review authors independently extracted data. Outcomes assessed were sudden death, fatal and non-fatal myocardial infarction and change in blood pressure. MAIN RESULTS: We included 15 trials (39,908 participants) that evaluated antihypertensive pharmacotherapy for a mean duration of follow-up of 4.2 years. This review provides moderate-quality evidence to show that antihypertensive drugs do not reduce sudden death (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.81 to 1.15) but do reduce both non-fatal myocardial infarction (RR 0.85, 95% CI 0.74, 0.98; absolute risk reduction (ARR) 0.3% over 4.2 years) and fatal myocardial infarction (RR 0.75, 95% CI 0.62 to 0.90; ARR 0.3% over 4.2 years). Withdrawals due to adverse effects were increased in the drug treatment group to 12.8%, as compared with 6.2% in the no treatment group. AUTHORS' CONCLUSIONS: Although antihypertensive drugs reduce the incidence of fatal and non-fatal myocardial infarction, they do not appear to reduce the incidence of sudden death. This suggests that sudden cardiac death may not be caused primarily by acute myocardial infarction. Continued research is needed to determine the causes of sudden cardiac death. PMID- 26961576 TI - Diet, physical activity, and behavioural interventions for the treatment of overweight or obesity in preschool children up to the age of 6 years. AB - BACKGROUND: Child overweight and obesity has increased globally, and can be associated with short- and long-term health consequences. OBJECTIVES: To assess the effects of diet, physical activity, and behavioural interventions for the treatment of overweight or obesity in preschool children up to the age of 6 years. SEARCH METHODS: We performed a systematic literature search in the databases Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, and LILACS, as well as in the trial registers ClinicalTrials.gov and ICTRP Search Portal. We also checked references of identified trials and systematic reviews. We applied no language restrictions. The date of the last search was March 2015 for all databases. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of diet, physical activity, and behavioural interventions for treating overweight or obesity in preschool children aged 0 to 6 years. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias, evaluated the overall quality of the evidence using the GRADE instrument, and extracted data following the Cochrane Handbook for Systematic Reviews of Interventions. We contacted trial authors for additional information. MAIN RESULTS: We included 7 RCTs with a total of 923 participants: 529 randomised to an intervention and 394 to a comparator. The number of participants per trial ranged from 18 to 475. Six trials were parallel RCTs, and one was a cluster RCT. Two trials were three-arm trials, each comparing two interventions with a control group. The interventions and comparators in the trials varied. We categorised the comparisons into two groups: multicomponent interventions and dietary interventions. The overall quality of the evidence was low or very low, and six trials had a high risk of bias on individual 'Risk of bias' criteria. The children in the included trials were followed up for between six months and three years.In trials comparing a multicomponent intervention with usual care, enhanced usual care, or information control, we found a greater reduction in body mass index (BMI) z score in the intervention groups at the end of the intervention (6 to 12 months): mean difference (MD) -0.3 units (95% confidence interval (CI) -0.4 to -0.2); P < 0.00001; 210 participants; 4 trials; low-quality evidence, at 12 to 18 months' follow-up: MD -0.4 units (95% CI -0.6 to -0.2); P = 0.0001; 202 participants; 4 trials; low-quality evidence, and at 2 years' follow-up: MD -0.3 units (95% CI 0.4 to -0.1); 96 participants; 1 trial; low-quality evidence.One trial stated that no adverse events were reported; the other trials did not report on adverse events. Three trials reported health-related quality of life and found improvements in some, but not all, aspects. Other outcomes, such as behaviour change and parent-child relationship, were inconsistently measured.One three-arm trial of very low-quality evidence comparing two types of diet with control found that both the dairy-rich diet (BMI z score change MD -0.1 units (95% CI -0.11 to 0.09); P < 0.0001; 59 participants) and energy-restricted diet (BMI z score change MD -0.1 units (95% CI -0.11 to -0.09); P < 0.0001; 57 participants) resulted in greater reduction in BMI than the comparator at the end of the intervention period, but only the dairy-rich diet maintained this at 36 months' follow-up (BMI z score change in MD -0.7 units (95% CI -0.71 to -0.69); P < 0.0001; 52 participants). The energy-restricted diet had a worse BMI outcome than control at this follow-up (BMI z score change MD 0.1 units (95% CI 0.09 to 0.11); P < 0.0001; 47 participants). There was no substantial difference in mean daily energy expenditure between groups. Health-related quality of life, adverse effects, participant views, and parenting were not measured.No trial reported on all-cause mortality, morbidity, or socioeconomic effects.All results should be interpreted cautiously due to their low quality and heterogeneous interventions and comparators. AUTHORS' CONCLUSIONS: Muticomponent interventions appear to be an effective treatment option for overweight or obese preschool children up to the age of 6 years. However, the current evidence is limited, and most trials had a high risk of bias. Most trials did not measure adverse events. We have identified four ongoing trials that we will include in future updates of this review.The role of dietary interventions is more equivocal, with one trial suggesting that dairy interventions may be effective in the longer term, but not energy-restricted diets. This trial also had a high risk of bias. PMID- 26961577 TI - Comparison of central adjudication of outcomes and onsite outcome assessment on treatment effect estimates. AB - BACKGROUND: Assessment of events by adjudication committees (ACs) is recommended in multicentre randomised controlled trials (RCTs). However, its usefulness has been questioned. OBJECTIVES: The aim of this systematic review was to compare 1) treatment effect estimates of subjective clinical events assessed by onsite assessors versus by AC, and 2) treatment effect estimates according to the blinding status of the onsite assessor as well as the process used to select events to adjudicate. SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, PsycINFO, CINAHL and Google Scholar (25 August 2015 as the last updated search date), using a combination of terms to retrieve RCTs with commonly used terms to describe ACs. SELECTION CRITERIA: We included all reports of RCTs and the published RCTs included in reviews and meta analyses that reported the same subjective outcome event assessed by both an onsite assessor and an AC. DATA COLLECTION AND ANALYSIS: We extracted the odds ratio (OR) from onsite assessment and the corresponding OR from AC assessment and calculated the ratio of the odds ratios (ROR). A ratio of odds ratios < 1 indicated that onsite assessors generated larger effect estimates in favour of the experimental treatment than ACs. MAIN RESULTS: Data from 47 RCTs (275,078 patients) were used in the meta-analysis. We excluded 11 RCTs because of incomplete outcome data to calculate the OR for onsite and AC assessments. On average, there was no difference in treatment effect estimates from onsite assessors and AC (combined ROR: 1.00, 95% confidence interval (CI) 0.97 to 1.04; I(2) = 0%, 47 RCTs). The combined ROR was 1.00 (95% CI 0.96 to 1.04; I(2) = 0%, 35 RCTs) when onsite assessors were blinded; 0.76 (95% CI 0.48 to 1.12, I(2) = 0%, two RCTs) when AC assessed events identified independently from unblinded onsite assessors; and 1.11 (95% CI 0.96 to 1.27, I(2) = 0%, 10 RCTs) when AC assessed events identified by unblinded onsite assessors. However, there was a statistically significant interaction between these subgroups (P = 0.03) AUTHORS' CONCLUSIONS: On average, treatment effect estimates for subjective outcome events assessed by onsite assessors did not differ from those assessed by ACs. Results of subgroup analysis showed an interaction according to the blinded status of onsite assessors and the process used to submit data to AC. These results suggest that the use of ACs might be most important when onsite assessors are not blinded and the risk of misclassification is high. Furthermore, research is needed to explore the impact of the different procedures used to select events to adjudicate. PMID- 26961578 TI - Damage-free vibrational spectroscopy of biological materials in the electron microscope. AB - Vibrational spectroscopy in the electron microscope would be transformative in the study of biological samples, provided that radiation damage could be prevented. However, electron beams typically create high-energy excitations that severely accelerate sample degradation. Here this major difficulty is overcome using an 'aloof' electron beam, positioned tens of nanometres away from the sample: high-energy excitations are suppressed, while vibrational modes of energies <1 eV can be 'safely' investigated. To demonstrate the potential of aloof spectroscopy, we record electron energy loss spectra from biogenic guanine crystals in their native state, resolving their characteristic C-H, N-H and C=O vibrational signatures with no observable radiation damage. The technique opens up the possibility of non-damaging compositional analyses of organic functional groups, including non-crystalline biological materials, at a spatial resolution of ~10 nm, simultaneously combined with imaging in the electron microscope. PMID- 26961579 TI - Serum anti-Mullerian hormone concentration in women with polycystic ovary syndrome and type 1 diabetes mellitus. AB - PURPOSE: A single prior study conducted in Chilean women has shown that women with type 1 diabetes mellitus (T1DM) and polycystic ovary syndrome (PCOS) have a normal serum anti-Mullerian hormone (AMH) concentrations despite polycystic ovarian morphology. As it is not clear why women with PCOS+T1DM would not have an elevated concentrations of AMH, we hypothesize that women with T1DM and PCOS have a similar hormonal profile and serum AMH levels as is observed in classic PCOS. METHODS: We studied 89 women: 37 with T1DM (16 with PCOS+T1DM, 21 with T1DM/no PCOS), 36 with PCOS (PCOS) and 16 healthy women (control group) matched for age and body mass index (BMI). A clinical examination, determination of serum AMH and sex hormones, and an ultrasonographic evaluation of the ovaries were performed for all study participants. RESULTS: Serum AMH concentrations were significantly higher in women with PCOS+T1DM than in those with T1DM/no-PCOS (p<0.001) and was not different between both PCOS groups (PCOS vs PCOS+T1DM). Ovarian volume and ovarian follicle count did not differ between women with PCOS+T1DM and PCOS. The number of ovarian follicles was higher in patients with PCOS+T1DM and PCOS versus the control (p=0.007, p<0.001) and versus cases of T1DM/no-PCOS (p<0.001, p<0.001, respectively). Cross-sectionally, AMH concentrations correlated positively with luteinizing hormone (LH) (r=0.4; p<0.001), testosterone (r=0.2, p=0.02), ovarian volume (r=0.4, p<0.001) and follicle count (r=0.7, p<0.001). In both groups, PCOS+T1DM and PCOS, AMH was related to LH (r=0.5; p=0.036; r=0.3; p=0.031) and to ovarian follicle number (r=0.7; p<0.001; r=0.4; p=0.006). In multivariate logistic regression analysis, serum AMH was the only predictor of PCOS in T1DM women (OR=1.73; 95% CI 1.07-2.79, p=0.023). CONCLUSIONS: Women with T1DM and PCOS have a similar hormonal profile and serum AMH concentrations as observed in classic PCOS. PMID- 26961580 TI - Similarities and differences between pediatric and adult nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is highly common and potentially serious in children and adolescents. The term NAFLD refers to a spectrum of diseases ranging from accumulation of fat in the liver (simple steatosis or nonalcoholic fatty liver "NAFL") to the potentially progressive form of nonalcoholic steatohepatitis (NASH) characterized by hepatocyte ballooning, inflammation, and often associated with fibrosis. While large prospective longitudinal studies in pediatric NAFLD are still lacking, growing evidence suggests that children with NAFL are at increased risk for cardiometabolic complications, while those with NASH and advance fibrosis are also at risk for significant liver-related morbidity including cirrhosis and its complications. Pediatric NAFLD shares features of adult NAFLD but also shows many different characteristics in terms of prevalence, histology, diagnosis and management. Translational studies suggest that NAFLD is a highly heritable disease in which genetic variations and environment closely interact to determine the disease phenotype and the progression to the more advanced forms of the disease. Changes in lifestyle, targeting gradual weight reduction, and physical exercise continue to be the mainstay of treatment for NAFLD in children. Recent advances in development of noninvasive diagnostic modalities and the potential for identifying effective pharmacological interventions may result in significant progress in the management of NAFLD in the pediatric population. PMID- 26961581 TI - Obesity and Structural Brain Integrity in Older Women: The Women's Health Initiative Magnetic Resonance Imaging Study. AB - BACKGROUND: Midlife obesity has been linked to age-related brain atrophy and risk of dementia, but the relationships are less clear for older individuals. These associations may be explained by changes in appetite or metabolism in the dementia prodrome; thus, prospective studies with adequate follow-up are needed. We examined the associations that obesity (body mass index, BMI) and change in BMI over an average of 6.6 (1.0-9.1) years have with global and regional brain and white matter lesion volumes in a sample of 1,366 women aged 65-80. METHODS: Least square means for regional brain volumes and white matter lesion loads for women grouped by BMI and changes in BMI were generated from multivariable linear models with and without adjustment for demographic and health covariates. RESULTS: Both global obesity and increase in BMI were associated with lower cerebrospinal fluid and higher specific brain volumes (ps < .05), after controlling for diabetes and other cerebrovascular disease risk factors. Obesity, but not change in BMI, predicted lower lesion loads for the total, parietal, and occipital white matter (ps < .05). CONCLUSIONS: Obesity in this cohort is associated with less brain atrophy and lower ischemic lesion loads. The findings are consistent with our previous report of worse cognitive performance in association with weight loss (probably not due to frailty) in this cohort and in line with the idea of the "obesity paradox" as differences in dementia risk vary across time, whereby midlife obesity seems to be a predictor of dementia, whereas weight loss seems to be a better predictor at older ages. PMID- 26961582 TI - Cystatin C and Objectively Measured Mobility 10 Years Later in Older Women. AB - BACKGROUND: Serum biomarkers predicting physical performance in late life are uncertain. We tested the hypotheses that lower serum cystatin C (cysC) in older women is associated with good mobility 10 years later. METHODS: We conducted a longitudinal analysis of a prospective cohort of 1,384 women attending Year 10 and Year 20 examinations of the Study of Osteoporotic Fractures. Serum cysC was measured using Year 10 frozen serum specimens. Year 20 mobility was ascertained by the Short Physical Performance Battery; scores of 10-12 indicated good mobility. RESULTS: At Year 20, mean age was 87.5 years and 364 women (26.3%) had good mobility. After adjustment for age, race, education, health status, diabetes, cardiovascular disease, and body mass index, lower cysC at Year 10 was associated with a higher likelihood of good mobility at Year 20. Compared with quartile (Q) 4 of cysC (referent group), odds ratios (95% confidence interval) were 1.52 (1.02-2.25) for Q3, 1.93 (1.32-2.84) for Q2 and 1.80 (1.21-2.67) for Q1 (p trend across Qs .003). The association was only modestly attenuated after further adjustment for mobility as assessed by a modified Short Physical Performance Battery at Year 10 (p trend .02) or consideration of potential biologic mediators including Year 10 levels of serum 25-hydroxyvitamin D, interleukin 6, and cytokine soluble receptors (p trend .04). CONCLUSIONS: Lower cysC in older women is independently associated with good mobility 10 years later and may be a biomarker for successful aging as manifested by preservation of lower extremity performance in late life. PMID- 26961583 TI - Effects of Mobility and Cognition on Hospitalization and Inpatient Days in Women in Late Life. AB - Background: This study examines effects of mobility and cognition on hospitalization and inpatient days among women late in life. Methods: Prospective study of 663 women (mean age 87.7 years) participating in the Study of Osteoporotic Fractures Year 20 examination (2006-2008) linked with their inpatient claims data. At Year 20, mobility ascertained by Short Physical Performance Battery categorized as poor, intermediate, or good. Cognitive status adjudicated based on neuropsychological tests and classified as normal, mild cognitive impairment, or dementia. Hospitalizations (n = 182) during 12 months following Year 20. Results: Reduced mobility and poorer cognition were each associated in a graded manner with higher inpatient health care utilization, even after accounting for each other and traditional prognostic indicators. For example, adjusted mean inpatient days per year were 0.94 (95% confidence interval [CI] 0.52-1.45) among women with good mobility increasing to 2.80 (95% CI 1.64 3.89) among women with poor mobility and 1.59 (95% CI 1.08-2.03) among women with normal cognition increasing to 2.53 (95% CI 1.55-3.40) among women with dementia. Women with poor mobility/dementia had a nearly sixfold increase in mean inpatient days per year (4.83, 95% CI 2.73-8.54) compared with women with good mobility/normal cognition (0.84, 95% CI 0.49-1.44). Conclusions: Among women late in life, mobility limitations and cognitive deficits were each independent predictors of higher inpatient health care utilization even after considering each other and conventional predictors. Additive effects of reduced mobility and poorer cognition may be important to consider in medical decision making and health care policy planning for the growing population of adults aged >=85 years. PMID- 26961585 TI - Geriatric assessment in daily oncology practice for nurses and allied health care professionals: Opinion paper of the Nursing and Allied Health Interest Group of the International Society of Geriatric Oncology (SIOG). AB - The management of older persons with cancer has become a major public health concern in developed countries because of the aging of the population and the steady increase in cancer incidence with advancing age. Nurses and allied health care professionals are challenged to address the needs of this growing population. The International Society of Geriatric Oncology (SIOG) Nursing and Allied Health (NAH) Interest Group described key issues that nurses and allied health care professionals face when caring for older persons with cancer. The domains of the Geriatric Assessment (GA) are used as a guiding framework. The following geriatric domains are described: demographic data and social support, functional status, cognition, mental health, nutritional status, fatigue, comorbidities, polypharmacy, and other geriatric syndromes (e.g. falls, delirium). In addition to these geriatric domains, quality of life (QoL) is described based on the overall importance in this particular population. Advice for integration of assessment of these geriatric domains into daily oncology practice is made. Research has mainly focused on the role of treating physicians but the involvement of nurses and allied health care professionals is crucial in the care of older persons with cancer through the GA process. The ability of nurses and allied health care professionals to perform this assessment requires specialized training and education beyond standard oncology knowledge. PMID- 26961584 TI - Thermosporothrix narukonensis sp. nov., belonging to the class Ktedonobacteria, isolated from fallen leaves on geothermal soil, and emended description of the genus Thermosporothrix. AB - A thermophilic, Gram-stain-positive, spore-forming bacterium that formed branched vegetative and aerial mycelia was isolated from fallen leaves on geothermal soil. This strain, designated F4T, grew at temperatures between 30 and 60 degrees C; optimum growth temperature was 50 degrees C, whereas no growth was observed below 28 degrees C or above 65 degrees C. The pH range for growth was 4.9-9.5; the pH for optimum growth was 7.0, but no growth was observed at pH below 4.4 or above 10.0. Strain F4T was able to hydrolyse polysaccharides such as cellulose, xylan, chitin and starch. The G+C content in the DNA of strain F4T was 52.5 mol%. The major fatty acid was iso-C17 : 0 and the major menaquinone was MK-9 (H2). The cell wall of strain F4T contained glutamic acid, serine, glycine, alanine and ornithine in a molar ratio of 1.0:1.5:1.4:1.8:0.7. The polar lipids of this strain consisted of phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, one unknown phospholipid, three unknown glycolipids and two unknown lipids. The cell-wall sugar was mannose. Detailed phylogenetic analysis based on 16S rRNA gene sequences indicated that strain F4T belongs to the genus Thermosporothrix, and that it was related most closely to Thermosporothrix hazakensis SK20-1T (98.7 % similarity). DNA-DNA hybridization showed relatedness values of less than 15 % with the type strain of Thermosporothrix hazakensis. On the basis of phenotypic features and phylogenetic position, strain F4T is considered to represent a novel species, Thermosporothrix narukonensis sp. nov. The type strain is F4T(=NBRC 111777T=BCCM/LMG 29329T). PMID- 26961586 TI - Percolation, sliding, localization and relaxation in topologically closed circuits. AB - Considering a random walk in a random environment in a topologically closed circuit, we explore the implications of the percolation and sliding transitions for its relaxation modes. A complementary question regarding the "delocalization" of eigenstates of non-hermitian Hamiltonians has been addressed by Hatano, Nelson, and followers. But we show that for a conservative stochastic process the implied spectral properties are dramatically different. In particular we determine the threshold for under-damped relaxation, and observe "complexity saturation" as the bias is increased. PMID- 26961587 TI - Ethical health care of sex workers. PMID- 26961588 TI - Fetal vascular adaptation before and after treatment of severe maternal anemia in pregnancy. AB - OBJECTIVES: To use color Doppler ultrasonography indices to study the effects on fetal circulation of treating severe maternal anemia. METHODS: A prospective cohort study enrolled patients who were at 30-34weeks of pregnancy and had hemoglobin levels below 70g/L between November 1, 2011 and March 31, 2013 at a hospital in New Delhi, India. A control group consisting of patients with the same duration of pregnancy and with hemoglobin levels above 110g/L was included. Umbilical artery and middle cerebral artery velocimetry were performed using color Doppler ultrasonography at admission and after 4weeks and 6weeks of treatment. RESULTS: The maternal anemia cohort demonstrated a significantly lower middle cerebral artery resistance index and middle cerebral/umbilical artery resistance ratio (P<0.001) at admission. Following 4weeks of treatment for maternal anemia, significant increases in these parameters were observed (P<0.001). CONCLUSION: Fetuses of individuals with severe maternal anemia demonstrated altered cerebral and umbilical artery flows. Normal flows were restored following treatment of maternal anemia. PMID- 26961589 TI - Evaluation of the speed of kill, effects on reproduction, and effectiveness in a simulated infested-home environment of sarolaner (SimparicaTM) against fleas on dogs. AB - Four studies were conducted to evaluate the speed of kill, effect on egg production, and efficacy in a simulated infested-home environment of a novel isoxazoline, sarolaner (SimparicaTM, Zoetis), against fleas on dogs. Individually identified and housed, purpose-bred Beagles were used in each study and were allocated randomly to groups based on pretreatment parasite counts. In two speed of kill studies, groups of dogs infested with 100 fleas prior to treatment were treated orally with placebo or sarolaner tablets providing the minimum dose of 2mg/kg and then re-infested with fleas weekly for five weeks post-treatment. Comb counts were conducted to determine the numbers of viable fleas at one to three, four, eight and 12h after treatment and each subsequent infestation. In the egg production study, sarolaner- and placebo-treated dogs were similarly challenged with fleas and at 48h after each infestation the dogs were housed for 20h in cages allowing the collection and counting of all flea eggs produced during this period. Collected eggs were incubated to evaluate hatch and development to adults. The last study used dogs housed in a flea-infested simulated-home environment. Dogs were allocated to treatment with either placebo or sarolaner tablets providing a dose of 2mg/kg once a month for three treatments. Flea infestations were assessed by comb counts (fleas were replaced on the dogs) on Days 14, 30, 44, 60, 74 and 90. The speed of kill studies demonstrated that a single 2mg/kg oral dose of sarolaner started killing fleas within three to four hours after treatment or subsequent re-infestations for up to a month, and achieved >=98% control of fleas by eight hours after treatment or re-infestation for 28 days. In the study to assess effects on flea reproduction, a single oral treatment of sarolaner resulted in the complete cessation of egg-laying for 35 days. This rapid kill of fleas and inhibition of reproduction were confirmed in a simulated-home environment where the existing infestations were reduced by >95% within two weeks of the first treatment and eliminated from the dogs after two monthly doses. PMID- 26961590 TI - Discovery of sarolaner: A novel, orally administered, broad-spectrum, isoxazoline ectoparasiticide for dogs. AB - The novel isoxazoline ectoparasiticide, sarolaner, was identified during a lead optimization program for an orally-active compound with efficacy against fleas and ticks on dogs. The aim of the discovery program was to identify a novel isoxazoline specifically for use in companion animals, beginning with de novo synthesis in the Zoetis research laboratories. The sarolaner molecule has unique structural features important for its potency and pharmacokinetic (PK) properties, including spiroazetidine and sulfone moieties. The flea and tick activity resides in the chirally pure S-enantiomer, which was purified to alleviate potential off-target effects from the inactive enantiomer. The mechanism of action was established in electrophysiology assays using CHO-K1 cell lines stably expressing cat flea (Ctenocephalides felis) RDL (resistance-to dieldrin) genes for assessment of GABA-gated chloride channel (GABACls) pharmacology. As expected, sarolaner inhibited GABA-elicited currents at both susceptible (CfRDL-A285) and resistant (CfRDL-S285) flea GABACls with similar potency. Initial whole organism screening was conducted in vitro using a blood feeding assay against C. felis. Compounds which demonstrated robust activity in the flea feed assay were subsequently tested in an in vitro ingestion assay against the soft tick, Ornithodoros turicata. Efficacious compounds which were confirmed safe in rodents at doses up to 30mg/kg were progressed to safety, PK and efficacy studies in dogs. In vitro sarolaner demonstrated an LC80 of 0.3MUg/mL against C. felis and an LC100 of 0.003MUg/mL against O. turicata. In a head-to-head comparative in vitro assay with both afoxolaner and fluralaner, sarolaner demonstrated superior flea and tick potency. In exploratory safety studies in dogs, sarolaner demonstrated safety in dogs>=8 weeks of age upon repeated monthly dosing at up to 20mg/kg. Sarolaner was rapidly and well absorbed following oral dosing. Time to maximum plasma concentration occurred within the first day post-dose. Bioavailability for sarolaner was calculated at >85% and the compound was highly protein bound (>99.9%). The half-life for sarolaner was calculated at 11-12 days. Sarolaner plasma concentrations indicated dose proportionality over the range 1.25-5mg/kg, and these same doses provided robust efficacy (>99%) for >=35days against both fleas (C. felis) and multiple species of ticks (Rhipicephalus sanguineus, Ixodes ricinus and Dermacentor reticulatus) after oral administration to dogs. As a result of these exploratory investigations, sarolaner was progressed for development as an oral monthly dose for treatment and control of fleas and ticks on dogs. PMID- 26961591 TI - Phylogenetic inference of the porcine Rotavirus A origin of the human G1 VP7 gene. AB - Rotavirus A (RVA) is an important cause of acute gastroenteritis in children worldwide. The most common VP7 genotype of human RVA is G1, but G1 is rarely detected in porcine strains. To understand the evolutionary relationships between human and porcine G1 VP7 genes, we sequenced the VP7 genes of three Japanese G1 porcine strains; the first two (PRV2, S80B) were isolated in 1980 and the third (Kyusyu-14) was isolated in 2001. Then, we performed phylogenetic and in-silico structural analyses. All three VP7 sequences clustered into lineage VI, and the mean nucleotide sequence identity between any pair of porcine G1 VP7 sequences belonging to lineage VI was 91.9%. In contrast, the mean nucleotide sequence identity between any pair of human G1 VP7 sequences belonging to lineages I-V was 95.5%. While the mean nucleotide sequence identity between any pair of porcine lineage VI strain and human lineage I-V strain was 85.4%, the VP7 genes of PRV2 and a rare porcine-like human G1P[6] strain (AU19) were 98% identical, strengthening the porcine RVA origin of AU19. The phylogenetic tree suggests that human G1 VP7 genes originated from porcine G1 VP7 genes. The time of their most recent common ancestor was estimated to be 1948, and human and porcine RVA strains evolved along independent pathways. In-silico structural analyses identified 7 amino acid residues within the known neutralisation epitopes that show differences in electric charges and shape between different porcine and human G1 strains. When compared with much divergent porcine G1 VP7 lineages, monophyletic, less divergent human G1 VP7 lineages support the hypothesis that all human G1 VP7 genes included in this study originated from a rare event of a porcine RVA transmitting to humans that was followed by successful adaptation to the human host. By contrast, AU19 represents interspecies transmission that terminated in dead-end infection. PMID- 26961592 TI - Phenotypic and genotypic characterization of Streptococcus pneumoniae resistant to macrolide in Casablanca, Morocco. AB - In Morocco, the 13-valent pneumococcal conjugate vaccine (PCV-13) was introduced in the national immunization program (NIP) in October 2010 and replaced by the PCV-10 in July 2012. The present study aimed to determine the prevalence of erythromycin-resistant Streptococcus pneumoniae (ERSP) and to analyze the phenotypic and genotypic characteristics of these isolates in Casablanca, Morocco from January 2007 to December 2014. Isolates were obtained from the Microbiology Laboratory of Ibn Rochd University Hospital Centre of Casablanca. Serogrouping was done using Pneumotest Kit and serotyping by the Quellung capsular swelling. Antibiotic susceptibility pattern was determined by disk diffusion and Etest methods. A total of 655S. pneumoniae isolates were collected from 2007 to 2014 from pediatric and adult patients. Fifty-five percent of these isolates were from invasive pneumococcal diseases. Of the 655 isolates, 92 (14%) were ERSP. Globally, the proportion of ERSP from 2007 to 2010 (before vaccination) and from 2011 to 2014 (after vaccination) were 11.6% and 17.2% (p=0.04), respectively. Of the 92 ERSP, 89%, 4% and 7% displayed constitutive MLSB (resistance to macrolide, lincosamide and streptogramin B), inducible MLSB, and M phenotype (resistance to macrolide only), respectively. ERSP genotypic analysis showed that 90.2% carried the ermB gene, 6.5% the mefE gene, and 3.3% both the genes (ermB+mefE). The most prevalent ERSP serotypes were 6B, 19F and 23F before vaccination and 19F, 6B, 6A and 23F after vaccination. Erythromycin resistance among S. pneumoniae is relatively high in Casablanca. The contribution of PCVs to the reduction in antibiotic use is encouraging but this should be accompanied by a rational use of antibiotic. PMID- 26961593 TI - ORF5 of porcine reproductive and respiratory syndrome virus (PRRSV) is a target of diversifying selection as infection progresses from acute infection to virus rebound. AB - Genetic variation in both structural and nonstructural genes is a key factor in the capacity of porcine reproductive and respiratory syndrome virus (PRRSV) to evade host defenses and maintain within animals, farms and metapopulations. However, the exact mechanisms by which genetic variation contribute to immune evasion remain unclear. In a study to understand the role of host genetics in disease resistance, a population of pigs were experimentally infected with a type 2 PRRSV isolate. Four pigs that showed virus rebound at 42days post-infection (dpi) were analyzed by 454 sequencing to characterize the rebound quasispecies. Deep sequencing of variable regions in nsp1, nsp2, ORF3 and ORF5 showed the largest number of nucleotide substitutions at day 28 compared to days 4 and 42 post-infection. Differences were also found in genetic variations when comparing tonsil versus serum. The results of dN/dS ratios showed that the same regions evolved under negative selection. However, eight amino acid sites were identified as possessing significant levels of positive selection, including A27V and N32S substitutions in the GP5 ectodomain region. These changes may alter GP5 peptide signal sequence processing and N-glycosylation, respectively. The results indicate that the greatest genetic diversity occurs during the transition between acute and rebound stages of infection, and the introduction of mutations that may result in a gain of fitness provides a potential mechanism for persistence. PMID- 26961595 TI - Potential use of sludge cake from paper mill wastewater treatment as degradable flower pot. AB - OBJECTIVES: Sludge cake produced in paper mill industries is disposed into a landfill and may cause the environmental and health problems. Now many researchers have tried to recycle rigid materials from it for the purpose of decreasing its volume. The aims of this study were to clarify three hypotheses: (1) whether a flower pot would be economically made from sludge cake, (2) whether it would be safe for environment, and (3) when vegetables would grow enough in it, whether they would be safe for human consumption. METHODS: Sludge cake was mixed with soil (soil texture: heavy clay). The circular plaster mold was used as a fixed mold. As the toxicological testing, leaching test and seed germination test were used. Heavy metal concentrations in vegetables grown in the flower pot were measured. RESULTS: The flower pot was sufficiently formed by drying in natural open air. The results of leaching test showed three heavy metals, lead, nickel and copper, were lower than the standard in Thailand. The seed germination test suggested no negative effects of the flower pot on the germination of Chinese kale. Lead concentrations in the Chinese kale were higher than the recommended maximum level in leafy vegetables. CONCLUSION: The new flower pot can be made from sludge cake with soil. It has the possibility to have no negative effect on the environment. Although the vegetables grown in this flower pot are not suitable to eat, this flower pot has the possibility to solve the environmental and health problems. PMID- 26961594 TI - Integrated analysis of mRNA-seq and miRNA-seq in the liver of Pelteobagrus vachelli in response to hypoxia. AB - Pelteobagrus vachelli is a well-known commercial species in Asia. However, a sudden lack of oxygen will result in mortality and eventually to pond turnover. Studying the molecular mechanisms of hypoxia adaptation in fishes will not only help us to understand fish speciation and the evolution of the hypoxia-signaling pathway, but will also guide us in the breeding of hypoxia-tolerant fish strains. Despite this, the genetic regulatory network for miRNA-mRNA and the signaling pathways involved in hypoxia responses in fish have remained unexamined. In the present study, we used next-generation sequencing technology to characterise mRNA seq and miRNA-seq of control- and hypoxia-treated P. vachelli livers to elucidate the molecular mechanisms of hypoxia adaptation. We were able to find miRNA-mRNA pairs using bioinformatics analysis and miRNA prediction algorithms. Furthermore, we compared several key pathways which were identified as involved in the hypoxia response of P. vachelli. Our study is the first report on integrated analysis of mRNA-seq and miRNA-seq in fishes and offers a deeper insight into the molecular mechanisms of hypoxia adaptation. qRT-PCR analysis further confirmed the results of mRNA-Seq and miRNA-Seq analysis. We provide a good case study for analyzing mRNA/miRNA expression and profiling a non-model fish species using next generation sequencing technology. PMID- 26961596 TI - Large-scale production of functional human lysozyme from marker-free transgenic cloned cows. AB - Human lysozyme is an important natural non-specific immune protein that is highly expressed in breast milk and participates in the immune response of infants against bacterial and viral infections. Considering the medicinal value and market demand for human lysozyme, an animal model for large-scale production of recombinant human lysozyme (rhLZ) is needed. In this study, we generated transgenic cloned cows with the marker-free vector pBAC-hLF-hLZ, which was shown to efficiently express rhLZ in cow milk. Seven transgenic cloned cows, identified by polymerase chain reaction, Southern blot, and western blot analyses, produced rhLZ in milk at concentrations of up to 3149.19 +/- 24.80 mg/L. The purified rhLZ had a similar molecular weight and enzymatic activity as wild-type human lysozyme possessed the same C-terminal and N-terminal amino acid sequences. The preliminary results from the milk yield and milk compositions from a naturally lactating transgenic cloned cow 0906 were also tested. These results provide a solid foundation for the large-scale production of rhLZ in the future. PMID- 26961598 TI - Intramolecular sensitization of americium luminescence in solution: shining light on short-lived forbidden 5f transitions. AB - The photophysical properties and solution thermodynamics of water soluble trivalent americium (Am(III)) complexes formed with multidentate chromophore bearing ligands, 3,4,3-LI(1,2-HOPO), Enterobactin, and 5-LIO(Me-3,2-HOPO), were investigated. The three chelators were shown to act as antenna chromophores for Am(III), generating sensitized luminescence emission from the metal upon complexation, with very short lifetimes ranging from 33 to 42 ns and low luminescence quantum yields (10(-3) to 10(-2)%), characteristic of Near Infra-Red emitters in similar systems. The specific emission peak of Am(III) assigned to the (5)D1 -> (7)F1 f-f transition was exploited to characterize the high proton independent stability of the complex formed with the most efficient sensitizer 3,4,3-LI(1,2-HOPO), with a log beta110 = 20.4 +/- 0.2 value. In addition, the optical and solution thermodynamic features of these Am(III) complexes, combined with density functional theory calculations, were used to probe the influence of electronic structure on coordination properties across the f-element series and to gain insight into ligand field effects. PMID- 26961597 TI - Tranexamic Acid Reduces Hidden Blood Loss in Patients Undergoing Total Knee Arthroplasty: A Comparative Study and Meta-Analysis. AB - BACKGROUND: To explore the efficacy of tranexamic acid (TXA) on reducing hidden blood loss (HBL) in total knee arthroplasty (TKA) by conducting a comparative study and meta-analysis. MATERIAL/METHODS: A total of 108 patients underwent TKA was equally distributed to experimental and control groups. The only difference between two groups was the administrations of 15 mg of TXA mixed in 100 mL normal saline for experimental group and 100 mL of normal saline for control group. The volumes of blood loss, red blood loss (RBL) were recorded, calculated and analyzed. Stata 12.0 software was applied for data analysis. RESULTS: The intraoperative and postoperative blood loss volume in experimental group were remarkably reduced compared with those in control group (intraoperative: 105.1+/ 12.1 mL vs. 185.5+/-20.3 mL, P<0.001; postoperative: 220.7+/-16.8 mL vs. 290.5+/ 22.4 mL, P<0.001). Accordingly, the control group had significantly higher transfusion rate than experimental group (3.7% vs.25.9%, P=0.001). Our results also found that both the measured and hidden RBL were obviously reduced in experimental group compared with control group (measured RBL: 96.9+/-11.8 mL vs. 135.2+/-13.5 mL, P<0.001; hidden RBL: 170.8+/-37.2 mL vs. 364.2+/-41.5 mL, P<0.001). Furthermore, meta-analysis confirmed that TXA can notably decrease HBL (SMD=2.68, 95%CI=1.55~3.80, P<0.001). CONCLUSIONS: TXA can significantly reduce the intraoperative and postoperative blood loss and HBL, therefore decreasing the transfusion need in TKA. PMID- 26961599 TI - The urinary metabolomic profile following the intake of meals supplemented with a cocoa extract in middle-aged obese subjects. AB - Metabolomics is used to assess the compliance and bioavailability of food components, as well as to evaluate the metabolic changes associated with food consumption. This study aimed to analyze the effect of consuming ready-to-eat meals containing a cocoa extract, within an energy restricted diet on urinary metabolomic changes. Fifty middle-aged volunteers [30.6 (2.3) kg m(-2)] participated in a 4-week randomised, parallel and double-blind study. Half consumed meals supplemented with 1.4 g of cocoa extract (645 mg polyphenols) while the remaining subjects received meals without cocoa supplementation. Ready to-eat meals were included within a 15% energy restricted diet. Urine samples (24 h) were collected at baseline and after 4 weeks and were analyzed by high performance-liquid chromatography-time-of-flight-mass-spectrometry (HPLC-TOF-MS) in negative and positive ionization modes followed by multivariate analysis. The relationship between urinary metabolites was evaluated by the Spearman correlation test. Interestingly, the principal component analysis discriminated among the baseline group, control group at the endpoint and cocoa group at the endpoint (p < 0.01), although in the positive ionization mode the baseline and control groups were not well distinguished. Metabolites were related to theobromine metabolism (3-methylxanthine and 3-methyluric acid), food processing (L-beta-aspartyl-L-phenylalanine), flavonoids (2,5,7,3',4'-pentahydroxyflavanone 5-O-glucoside and 7,4'-dimethoxy-6-C-methylflavanone), catecholamine (3-methoxy-4 hydroxyphenylglycol-sulphate) and endogenous metabolism (uridine monophosphate). These metabolites were present in higher (p < 0.001) amounts in the cocoa group. 3-Methylxanthine and l-beta-aspartyl-L-phenylalanine were confirmed with standards. Interestingly, 3-methoxy-4-hydroxyphenylglycol-sulphate was positively correlated with 3-methylxanthine (rho = 0.552; p < 0.001) and 7,4'-dimethoxy-6-C methylflavanone (rho = 447; p = 0.002). In conclusion, the metabolomic approach supported the compliance of the volunteers with the intervention and suggested the bioavailability of cocoa compounds within the meals. PMID- 26961600 TI - Triple Boron-Cored Chromophores Bearing Discotic 5,11,17-Triazatrinaphthylene Based Ligands. AB - A series of novel chromophores fused with multiple boron cores have been successfully synthesized by the complexation of three difluoroboryl or diphenylboryl at the periphery of 5,11,17-triazatrinaphthylene derivative ligands. Their sterically congested molecular scaffolds with expanded pi conjugated discotic backbones render them with unique electronic properties including large Stokes shifts, tunable electrochemical behaviors, and low-lying LUMO energy levels up to -3.18 eV. PMID- 26961602 TI - miR-23b targets Smad 3 and ameliorates the LPS-inhibited osteogenic differentiation in preosteoblast MC3T3-E1 cells. AB - Lipopolysaccharide (LPS) has been confirmed to be the main inhibitor in osteogenic differentiation, posing a clinical challenge to bone healing, particularly for trauma followed by endotoxinemia/sepsis. However, the molecular mechanism remains ambiguous. miR-23b, which regulates multiple signaling pathways in inflammation, has been shown to be deregulated by LPS. In this study, we examined the LPS-mediated regulation on the expression of miR-23b and Smad 3 in preosteoblast MC3T3-E1 cells. Then we determined the regulation of miR-23b overexpression on the Smad 3 expression and on the LPS-mediated inhibition of bone morphogenetic protein-2 (BMP-2)-induced osteogenic differentiation. Our results demonstrated that LPS significantly downregulated the expression of miR 23b, while upregulating Smad 3 in MC3T3-E1 cells. However, the transfection with miR-23b mimics markedly downregulated the Smad 3 in both mRNA and protein levels, via the specific binding to the 3'-untranslated region (UTR) of Smad 3. Moreover, though LPS markedly downregulated the BMP-2-induced osteogenic differentiation of MC3T3-E1 cells by inhibiting the expression of alkaline phosphatase (ALP), Osteocalcin (OCN), Osteopontin (OPN) and Runt-related transcription factor 2 (RUNX2). The upregulated miR-23b reversed such downregulation of ALP, OCN, OPN and RUNX2 in the MC3T3-E1 cells which were treated both with LPS and BMP-2. In conclusion, our data indicates that miR-23b ameliorates the LPS-mediated inhibition of BMP-2-induced osteogenic differentiation in MC3T3-E1 cells, implying the protective role of miR-23b in the LPS-mediated inhibition of osteogenic differentiation and bone formation. PMID- 26961601 TI - Evaluation of the potential toxicity of unmodified and modified cyclodextrins on murine blood-brain barrier endothelial cells. AB - In this study, we investigated the cytotoxic effects of unmodified alpha cyclodextrin (alpha-CD) and modified cyclodextrins, including trimethyl-beta cyclodextrin (TRIMEB) and hydroxypropyl-beta-cyclodextrin (HPbetaCD), on immortalized murine microvascular endothelial (cEND) cells of the blood-brain barrier (BBB). A CellTiter-Glo viability test, performed on the cEND cells showed significant differences among the different cyclodextrins. After 24 hr of incubation, TRIMEB was the most cytotoxic, and HPbetaCD was non-toxic. alpha-CD and TRIMEB exhibited greater cytotoxicity in the Dulbecco's modified Eagle's medium than in heat-inactivated human serum indicating protective properties of the human serum. The predicted dynamic toxicity profiles (Td) for alpha-CD and TRIMEB indicated higher cytotoxicity for these cyclodextrins compared to the reference compound (dimethylsulfoxide). Molecular dynamics simulation of cholesterol binding to the CDs suggested that not just cholesterol but phospholipids extraction might be involved in the cytotoxicity. Overall, the results demonstrate that HPbetaCD has the potential to be used as a candidate for drug delivery vector development and signify a correlation between the in vitro cytotoxic effect and cholesterol binding of cyclodextrins. PMID- 26961603 TI - In utero-exposed di(n-butyl) phthalate induce dose dependent, age-related changes of morphology and testosterone-biosynthesis enzymes/associated proteins of Leydig cell mitochondria in rats. AB - Female pregnant Sprague-Dawley rats were intragastrically (ig) administered di(n butyl) phthalate (DBP) at four doses (0, 10, 50 and 100 mg/kg) during gestation days (GD) 12-21 (n = 5 per group). The age-related morphological changes of Leydig cell mitochondrion (LC-Mt) and testosterone biosynthesis enzymes/associated genes/proteins expression levels were investigated. As compared to the control (no DBP), the 10 mg, and 50 mg DBP dose groups, the 100 mg DBP dose group at weeks 5 and 7 showed a significant amount of small LC-Mt. Thereafter, from weeks 9 to 17, the LC-Mt size and quantity in the 100 mg DBP dose group increased and became statistically similar to the other dose groups; hence, dose and time-dependent LC-Mt changes were observed. Throughout the study, the 100 mg DBP dose group had significantly lower testosterone levels. In addition, the 100 mg DBP dose group displayed lower StAR (StAR, steroidogenic acute regulatory protein) and P450scc (CYP11a1, cholesterol side-chain cleavage enzyme) levels at weeks 5 and 7, but they became statistically similar to all other dose groups at weeks 9 to 17; in contrast, the SR-B1 (Sarb1, scavenger receptor class B member 1) levels were similar for all DBP dose groups. The rats in utero 100 mg DBP /kg/day (GD 12-21) exposure results from this study indicate a dose-dependent, age-related morphological change in LC-Mt which are linked to reductions in testosterone biosynthesis genes / proteins expression, specifically StAR and P450scc. PMID- 26961604 TI - Tributyltin induces G2/M cell cycle arrest via NAD(+)-dependent isocitrate dehydrogenase in human embryonic carcinoma cells. AB - Organotin compounds, such as tributyltin (TBT), are well-known endocrine disrupting chemicals (EDCs). We have recently reported that TBT induces growth arrest in the human embryonic carcinoma cell line NT2/D1 at nanomolar levels by inhibiting NAD(+)-dependent isocitrate dehydrogenase (NAD-IDH), which catalyzes the irreversible conversion of isocitrate to alpha-ketoglutarate. However, the molecular mechanisms by which NAD-IDH mediates TBT toxicity remain unclear. In the present study, we examined whether TBT at nanomolar levels affects cell cycle progression in NT2/D1 cells. Propidium iodide staining revealed that TBT reduced the ratio of cells in the G1 phase and increased the ratio of cells in the G2/M phase. TBT also reduced cell division cycle 25C (cdc25C) and cyclin B1, which are key regulators of G2/M progression. Furthermore, apigenin, an inhibitor of NAD IDH, mimicked the effects of TBT. The G2/M arrest induced by TBT was abolished by NAD-IDHalpha knockdown. Treatment with a cell-permeable alpha-ketoglutarate analogue recovered the effect of TBT, suggesting the involvement of NAD-IDH. Taken together, our data suggest that TBT at nanomolar levels induced G2/M cell cycle arrest via NAD-IDH in NT2/D1 cells. Thus, cell cycle analysis in embryonic cells could be used to assess cytotoxicity associated with nanomolar level exposure of EDCs. PMID- 26961605 TI - Zinc diethyldithiocarbamate as an inducer of metallothionein in cultured vascular endothelial cells. AB - Vascular endothelial cells are in direct contact with blood. Inorganic zinc is thought to be incapable of inducing metallothionein, which protects cells from heavy metal toxicity and oxidative stress, in vascular endothelial cells. Here, we aimed to further characterize the induction of metallothionein in vascular endothelial cells. Our results confirmed that inorganic zinc could not induce metallothionein in vascular endothelial cells. Moreover, ZnSO4 could not activate both the metal response element (MRE) transcription factor 1 (MTF-1)/MRE and Nrf2/antioxidant response element (ARE) pathways and was incapable of inducing metallothionein. In addition, bis(L-cysteinato)zincate(II), a zinc complex that activates the MTF-1/MRE pathway, increased MRE promoter activity but failed to induce metallothionein, suggesting that vascular endothelial metallothionein was not induced only by activation of the MTF-1/MRE pathway. Further analysis of a library of zinc complexes showed that zinc(II) bis(diethyldithiocarbamate) activated the MTF-1/MRE pathway but not the Nrf2/ARE pathway, increased MT-1A, MT 1E, and MT-2A mRNA levels, and induced metallothionein proteins. These data indicated that zinc complexes may be excellent tools to analyze metallothionein induction in vascular endothelial cells. PMID- 26961607 TI - A simple method for oral mucosal irritation test by intraoral instillation in rats. AB - Evaluation of oral mucosal irritation is required by regulatory agencies when the intended clinical route of the drug candidate is intraoral administration. In this study, we investigated whether it was possible to evaluate oral mucosal irritation in rats by an intraoral instillation which was thought to mimic the clinical route of gargle products. Although no oral mucosal irritation was observed in the animals instilled with 0.5% and 4% sodium dodecyl sulfate (SDS, an anionic detergent) solutions for 10 days, instillation of 15% SDS solution for 4 days induced oral mucosal irritation macro- and microscopically, and this was evaluated as moderate irritant. It was suggested that the oral mucosal irritation test by intraoral instillation in rats could be a simple and useful method mimicking the clinical route of gargle products. PMID- 26961606 TI - Induction of metallothionein isoforms by copper diethyldithiocarbamate in cultured vascular endothelial cells. AB - Metallothionein (MT) plays a central role in cellular defense against heavy metals and oxidative stress. Since the induction of MT requires the activation of metal response element (MRE)-binding transcription factor-1 (MTF-1) by binding of zinc ions, inorganic zinc is regarded as a typical MT inducer. However, in a previous report, we showed that inorganic zinc could not induce MT in vascular endothelial cells. While it is suggested that endothelial MT presents mechanisms different from those of other cell types, these remain unclear. In this study, we investigated whether the induction of endothelial MT expression involves the Nrf2 ARE pathway using copper(II) bis(diethyldithiocarbamate), termed Cu10, using a culture system of bovine aortic endothelial cells. Cu10 induced MT-1/2 protein expression and increased the expression of mRNAs for MT-1A, MT-1E, and MT-2, MT isoforms expressed in the cells. Cu10 activated not only the MTF-1-MRE, but also the Nrf2-ARE pathway. MTF-1 knockdown resulted in the repression of Cu10-induced MT-1 and -2 expression. Cu10-induced MT-1 expression was down-regulated by Nrf2 knockdown. However, MT-2 expression was not affected by Nrf2 knockdown. These results suggest that the expression of endothelial MT is up-regulated by the Nrf2 ARE pathway as well as by the MTF-1-MRE pathway. Moreover, MT-1 regulation mechanisms differ from that of MT-2. Specifically, the present data support the hypothesis that MT-1 participates in the biological defense system, while MT-2 mainly regulates intracellular zinc metabolism. PMID- 26961608 TI - Metallomics approach to changes in element concentration during differentiation from fibroblasts into adipocytes by element array analysis. AB - We aimed to establish an element array analysis that involves the simultaneous detection of all elements in cells and the display of changes in element concentration before and after a cellular event. In this study, we demonstrated changes in element concentration during the differentiation of 3T3-L1 mouse fibroblasts into adipocytes. This metallomics approach yielded unique information of cellular response to physiological and toxicological events. PMID- 26961609 TI - Decreased hepatic phosphorylated p38 mitogen-activated protein kinase contributes to attenuation of thioacetamide-induced hepatic necrosis in diet-induced obese mice. AB - We previously reported that thioacetamide (TA)-induced hepatocellular necrosis was attenuated in mice fed a high-fat diet (HFD mice) compared with mice fed a normal rodent diet (ND mice). In this study, we investigated whether p38 mitogen activated protein kinase (p38 MAPK) was involved in this attenuation. Western blot analysis revealed that hepatic phosphorylated p38 MAPK protein decreased at 8 and 24 hours (hr) after TA dosing in the HFD mice, while it decreased only at 24 hr in the ND mice in comparison to the time- and diet-matched, vehicle-treated mice. p38 MAPK regulates various biological functions including inflammation, therefore, hepatic metabolomics analysis focusing on pro-inflammatory lipid mediators was performed. At 24 hr after TA dosing, only one pro-inflammatory mediator, 12-hydroxyeicosatetraenoic acid (HETE), was higher in the HFD mice. On the other hand, in addition to 12-HETE, 15-HETE and 12-hydroxyeicosapentaenoic acid (HEPE) were higher and omega-3/omega-6 polyunsaturated fatty acids ratios were lower in the ND mice at 24 hr. These results of metabolomics indicated that less pro-inflammatory state was seen in HFD mice than in ND mice at 24 hr. Finally, to confirm whether the observed decrease in phosphorylated p38 MAPK could attenuate TA-induced hepatocellular necrosis, we showed that SB203580 hydrochloride, an inhibitor of p38 MAPK, partially attenuated TA-induced hepatic necrosis in ND mice. Collectively, these results suggest that a prompt decrease in phosphorylation of p38 MAPK after TA administration is one of the factors that attenuate TA-induced hepatic necrosis in HFD mice. PMID- 26961610 TI - Methoxychlor and fenvalerate induce neuronal death by reducing GluR2 expression. AB - GluR2, an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit, plays important roles in neuronal survival. We previously showed that exposure of cultured rat cortical neurons to several chemicals decreases GluR2 protein expression, leading to neuronal toxicity. Methoxychlor, the bis-p-methoxy derivative of dichlorodiphenyltrichloroethane, and fenvalerate, a synthetic pyrethroid chemical, have been used commercially as agricultural pesticides in several countries. In this study, we investigated the effects of long-term methoxychlor and fenvalerate exposure on neuronal glutamate receptors. Treatment of cultured rat cortical neurons with 1 or 10 uM methoxychlor and fenvalerate for 9 days selectively decreased GluR2 protein expression; the expression of other AMPA receptor subunits GluR1, GluR3, and GluR4 did not change under the same conditions. Importantly, the decreases in GluR2 protein expression were also observed on the cell surface membrane where AMPA receptors typically function. In addition, both chemicals decreased neuronal viability, which was blocked by pretreatment with 1-naphtylacetylspermine, an antagonist of GluR2 lacking AMPA receptors, and MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. These results suggest that long-term exposure to methoxychlor and fenvalerate decreases GluR2 protein expression, leading to neuronal death via overactivation of GluR2-lacking AMPA and NMDA receptors. PMID- 26961611 TI - Maternal administration of nanomaterials elicits hemoglobin upregulation in the neonatal brain of non-human primates. AB - To investigate the influence of nanomaterial exposure during fetal development, diesel exhaust particles (DEPs), carbon black (CB), or titanium dioxide (TiO2) was injected intradermally to pregnant rhesus macaques. The hippocampus and cerebellum of newborn infants were then examined. DNA microarray and quantitative real-time RT-PCR, western blot, and immunohistochemical analyses were used to measure the expression of the hemoglobin genes, HBA, HBB, and HBG. Of the nanomaterials tested, DEP elicited the greatest increase in mRNA and protein levels of hemoglobin genes in the brain tissues. Strong signal of HbA protein was detected in the pyramidal cell layer, the polymorphic cell layer and in the alveus of the hippocampi of the DEP-treated animals. The altered gene expression was likely due to responses to oxidative or nitrosative stress and/or hypoxia in the fetal/neonatal brain. Since excessive hemoglobin is reportedly neurotoxic, the vulnerability of developing brains by long-term upregulation of hemoglobin should be considered. Maternal exposure to nanomaterials may increase the risk of brain dysfunction in offspring. PMID- 26961612 TI - NF-kappaB activation via MyD88-dependent Toll-like receptor signaling is inhibited by trichothecene mycotoxin deoxynivalenol. AB - Macrophages induce the innate immunity by recognizing pathogens through Toll-like receptors (TLRs), which sense pathogen-associated molecular patterns. Myeloid differentiation factor 88 (MyD88), which is an essential adaptor molecule for most TLRs, mediates the induction of inflammatory cytokines through nuclear factor kappaB (NF-kappaB). Trichothecene mycotoxin deoxynivalenol (DON) shows immunotoxic effects by interrupting inflammatory mediators produced by activated macrophages. The present study investigates the effect of DON on NF-kappaB in activated macrophages through MyD88-dependent pathways. DON inhibited NF-kappaB dependent reporter activity induced by MyD88-dependent TLR agonists. In addition, lipopolysaccharide-induced phosphorylation of interleukin-1 receptor-associated kinase 1 and inhibitor kappaBalpha were attenuated by DON. Furthermore, DON downregulated the expression level of MyD88. These results suggest that DON inhibits NF-kappaB activation in macrophages stimulated with TLR ligands via MyD88-dependent TLR signals. Therefore exposure to DON may lead to the inhibition of MyD88-dependent pathway of TLR signaling. PMID- 26961613 TI - Detection of non-genotoxic hepatocarcinogens and prediction of their mechanism of action in rats using gene marker sets. AB - Several studies have successfully detected hepatocarcinogenicity in rats based on gene expression data. However, prediction of hepatocarcinogens with certain mechanisms of action (MOAs), such as enzyme inducers and peroxisome proliferator activated receptor alpha (PPARalpha) agonists, can prove difficult using a single model and requires a highly toxic dose. Here, we constructed a model for detecting non-genotoxic (NGTX) hepatocarcinogens and predicted their MOAs in rats. Gene expression data deposited in the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) was used to investigate gene marker sets. Principal component analysis (PCA) was applied to discriminate different MOAs, and a support vector machine algorithm was applied to construct the prediction model. This approach identified 106 probe sets as gene marker sets for PCA and enabled the prediction model to be constructed. In PCA, NGTX hepatocarcinogens were classified as follows based on their MOAs: cytotoxicants, PPARalpha agonists, or enzyme inducers. The prediction model detected hepatocarcinogenicity with an accuracy of more than 90% in 14- and 28-day repeated-dose studies. In addition, the doses capable of predicting NGTX hepatocarcinogenicity were close to those required in rat carcinogenicity assays. In conclusion, our PCA and prediction model using gene marker sets will help assess the risk of hepatocarcinogenicity in humans based on MOAs and reduce the number of two-year rodent bioassays. PMID- 26961614 TI - Systematic identification of seven ribosomal protein genes in bighead carp and their expression in response to microcystin-LR. AB - Microcystin-LR (MCLR) is one of the most toxic cyanotoxins produced in algal blooms. The toxic effects of MCLR on the expression of some organelles genes (mitochondrion, endoplasmic reticulum, and cytoskeleton etc) have been widely investigated, but little is known how it impacts on the expression of ribosomal genes. In this study we identified seven ribosomal protein genes RPS6, RPS12, RPS24, RPS27a, RPL12, RPL27 and RPL29 in bighead carp (Aristichthys nobilis), whose expression was regulated by MCLR. The amino acid sequences of those 7 genes shared more than 90% identity with corresponding sequences from zebrafish, and were well conserved throughout evolution. The 3D structure prediction showed that the structures of these ribosomal proteins were conserved, but had species specificity. Q-PCR analysis revealed that expression of seven genes changed dramatically at 3 hr, then went back to a moderate change- level at 24 hr in almost all tested tissues (liver, kidney, intestine, heart, spleen and gill) post MCLR injection, but in brain expression of the seven genes stayed same as the normal level. This study will help us to know not only about the evolution and functions of ribosomal proteins in anti-MCLR response in bighead carp, but also about the MCLR toxicity and its impact on aquaculture and human health. PMID- 26961615 TI - Effects of prolonged antipsychotic administration on neuregulin-1/ErbB signaling in rat prefrontal cortex and myocardium: implications for the therapeutic action and cardiac adverse effect. AB - Patients with schizophrenia (SCZ) are at higher risk for developing cardiovascular disease (CVD) and neuregulin-1 (NRG1)/ErbB signaling has been identified as a common susceptibility pathway for the comorbidity. Antipsychotic treatment can change NRG1/ErbB signaling in the brain, which has been implicated in their therapeutic actions, whereas the drug-induced alterations of NRG1/ErbB pathway in cardiovascular system might be associated with the prominent cardiac side-effects of antipsychotic medication. To test this hypothesis, we examined NRG1/ErbB system in rat prefrontal cortex (PFC) and myocardium following 4-week intraperitoneal administration of haloperidol, risperidone or clozapine. Generally, the antipsychotics significantly enhanced NRG1/ErbB signaling with increased expression of NRG1 and phosphorylation of ErbB4 and ErbB2 in the brain and myocardium, except that clozapine partly blocked the cardiac NRG1/ErbB2 activation, which could be associated with its more severe cardiac adverse actions. Combined, our data firstly showed evidence of the effect of antipsychotic exposure on myocardial NRG1/ErbB signaling, along with the activated NRG1/ErbB system in brain, providing a potential link between the therapeutic actions and cardiotoxicity. PMID- 26961616 TI - Low doses of the mycotoxin citrinin protect cortical neurons against glutamate induced excitotoxicity. AB - Citrinin, a natural mycotoxin that is found in fermented foods, is known as a cytotoxin and nephrotoxin. Exposure to high doses of citrinin result in apoptosis; however, the effects of low doses are not fully understood. Glutamate excitotoxicity is responsible for neuronal death in acute neurological disorders including stroke, trauma and other neurodegenerative diseases. Here, we show the neuroprotective effect of low doses of citrinin against glutamate-induced excitotoxicity. We examined the effect of citrinin exposure on glutamate-induced cell death in cultured rat cortical neurons under two conditions: simultaneous treatment with citrinin 0.1 to 1,000 nM and glutamate (30 MUM) for 1, 3 hr; the same simultaneous treatment for 3 hr after pretreatment with citrinin for 21 hr. Both the MTT and immunocytochemical assay showed significant neuroprotective effects at several doses and exposure times tested. All concentrations of citrinin tested showed no remarkable cell death following 14-day exposure, and no marked alterations to synapses. These data suggest that low doses of citrinin can be used as a neuroprotective agent against glutamate-induced excitotoxicity without additional harmful cellular alterations. PMID- 26961618 TI - Who ordered that? PMID- 26961617 TI - Establishment of an in silico phospholipidosis prediction method using descriptors related to molecular interactions causing phospholipid-compound complex formation. AB - Although phospholipidosis (PLD) often affects drug development, there is no convenient in vitro or in vivo test system for PLD detection. In this study, we developed an in silico PLD prediction method based on the PLD-inducing mechanism. We focused on phospholipid (PL)-compound complex formation, which inhibits PL degradation by phospholipase. Thus, we used some molecular interactions, such as electrostatic interactions, hydrophobic interactions, and intermolecular forces, between PL and compounds as descriptors. First, we performed descriptor screening for intermolecular force and then developed a new in silico PLD prediction using descriptors related to molecular interactions. Based on the screening, we identified molecular refraction (MR) as a descriptor of intermolecular force. It is known that ClogP and most-basic pKa can be used for PLD prediction. Thereby, we developed an in silico prediction method using ClogP, most-basic pKa, and MR, which were related to hydrophobic interactions, electrostatic interactions, and intermolecular forces. In addition, a resampling method was used to determine the cut-off values for each descriptor. We obtained good results for 77 compounds as follows: sensitivity = 95.8%, specificity = 75.9%, and concordance = 88.3%. Although there is a concern regarding false-negative compounds for pKa calculations, this predictive ability will be adequate for PLD screening. In conclusion, the mechanism-based in silico PLD prediction method provided good prediction ability, and this method will be useful for evaluating the potential of drugs to cause PLD, particularly in the early stage of drug development, because this method only requires knowledge of the chemical structure. PMID- 26961619 TI - Food processing. PMID- 26961620 TI - Gene intelligence. PMID- 26961621 TI - Support communities involved in disease studies. PMID- 26961632 TI - 'Open-hardware' pioneers push for low-cost lab kit. PMID- 26961633 TI - How the US CRISPR patent probe will play out. PMID- 26961634 TI - Chinese gravitational-wave hunt hits crunch time. PMID- 26961635 TI - Statisticians issue warning over misuse of P values. PMID- 26961636 TI - Five million US seeds banked for resurrection experiment. PMID- 26961637 TI - First Zika-linked birth defects detected in Colombia. PMID- 26961638 TI - CRISPR everywhere. PMID- 26961639 TI - CRISPR: gene editing is just the beginning. PMID- 26961640 TI - Welcome to the CRISPR zoo. PMID- 26961646 TI - Zika virus: accurate terminology matters. PMID- 26961642 TI - Governance: Learn from DIY biologists. PMID- 26961641 TI - Policy: Reboot the debate on genetic engineering. PMID- 26961647 TI - Europe: Better management of alien species. PMID- 26961648 TI - Disciplinary balance: How to engage social scientists in IPBES. PMID- 26961649 TI - Scientific record: Class uncorrected errors as misconduct. PMID- 26961650 TI - Zika virus: designate standardized names. PMID- 26961651 TI - Superconductors: Exponential boost for quantum information. PMID- 26961652 TI - Plant biology: LURE is bait for multiple receptors. PMID- 26961653 TI - Sustainable chemistry: Putting carbon dioxide to work. PMID- 26961654 TI - Exponential protection of zero modes in Majorana islands. AB - Majorana zero modes are quasiparticle excitations in condensed matter systems that have been proposed as building blocks of fault-tolerant quantum computers. They are expected to exhibit non-Abelian particle statistics, in contrast to the usual statistics of fermions and bosons, enabling quantum operations to be performed by braiding isolated modes around one another. Quantum braiding operations are topologically protected insofar as these modes are pinned near zero energy, with the departure from zero expected to be exponentially small as the modes become spatially separated. Following theoretical proposals, several experiments have identified signatures of Majorana modes in nanowires with proximity-induced superconductivity and atomic chains, with small amounts of mode splitting potentially explained by hybridization of Majorana modes. Here, we use Coulomb-blockade spectroscopy in an InAs nanowire segment with epitaxial aluminium, which forms a proximity-induced superconducting Coulomb island (a 'Majorana island') that is isolated from normal-metal leads by tunnel barriers, to measure the splitting of near-zero-energy Majorana modes. We observe exponential suppression of energy splitting with increasing wire length. For short devices of a few hundred nanometres, sub-gap state energies oscillate as the magnetic field is varied, as is expected for hybridized Majorana modes. Splitting decreases by a factor of about ten for each half a micrometre of increased wire length. For devices longer than about one micrometre, transport in strong magnetic fields occurs through a zero-energy state that is energetically isolated from a continuum, yielding uniformly spaced Coulomb-blockade conductance peaks, consistent with teleportation via Majorana modes. Our results help to explain the trivial-to-topological transition in finite systems and to quantify the scaling of topological protection with end-mode separation. PMID- 26961655 TI - Carbon dioxide utilization via carbonate-promoted C-H carboxylation. AB - Using carbon dioxide (CO2) as a feedstock for commodity synthesis is an attractive means of reducing greenhouse gas emissions and a possible stepping stone towards renewable synthetic fuels. A major impediment to synthesizing compounds from CO2 is the difficulty of forming carbon-carbon (C-C) bonds efficiently: although CO2 reacts readily with carbon-centred nucleophiles, generating these intermediates requires high-energy reagents (such as highly reducing metals or strong organic bases), carbon-heteroatom bonds or relatively acidic carbon-hydrogen (C-H) bonds. These requirements negate the environmental benefit of using CO2 as a substrate and limit the chemistry to low-volume targets. Here we show that intermediate-temperature (200 to 350 degrees Celsius) molten salts containing caesium or potassium cations enable carbonate ions (CO3(2 )) to deprotonate very weakly acidic C-H bonds (pKa > 40), generating carbon centred nucleophiles that react with CO2 to form carboxylates. To illustrate a potential application, we use C-H carboxylation followed by protonation to convert 2-furoic acid into furan-2,5-dicarboxylic acid (FDCA)--a highly desirable bio-based feedstock with numerous applications, including the synthesis of polyethylene furandicarboxylate (PEF), which is a potential large-scale substitute for petroleum-derived polyethylene terephthalate (PET). Since 2-furoic acid can readily be made from lignocellulose, CO3(2-)-promoted C-H carboxylation thus reveals a way to transform inedible biomass and CO2 into a valuable feedstock chemical. Our results provide a new strategy for using CO2 in the synthesis of multi-carbon compounds. PMID- 26961656 TI - The terrestrial biosphere as a net source of greenhouse gases to the atmosphere. AB - The terrestrial biosphere can release or absorb the greenhouse gases, carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O), and therefore has an important role in regulating atmospheric composition and climate. Anthropogenic activities such as land-use change, agriculture and waste management have altered terrestrial biogenic greenhouse gas fluxes, and the resulting increases in methane and nitrous oxide emissions in particular can contribute to climate change. The terrestrial biogenic fluxes of individual greenhouse gases have been studied extensively, but the net biogenic greenhouse gas balance resulting from anthropogenic activities and its effect on the climate system remains uncertain. Here we use bottom-up (inventory, statistical extrapolation of local flux measurements, and process-based modelling) and top-down (atmospheric inversions) approaches to quantify the global net biogenic greenhouse gas balance between 1981 and 2010 resulting from anthropogenic activities and its effect on the climate system. We find that the cumulative warming capacity of concurrent biogenic methane and nitrous oxide emissions is a factor of about two larger than the cooling effect resulting from the global land carbon dioxide uptake from 2001 to 2010. This results in a net positive cumulative impact of the three greenhouse gases on the planetary energy budget, with a best estimate (in petagrams of CO2 equivalent per year) of 3.9 +/- 3.8 (top down) and 5.4 +/- 4.8 (bottom up) based on the GWP100 metric (global warming potential on a 100-year time horizon). Our findings suggest that a reduction in agricultural methane and nitrous oxide emissions, particularly in Southern Asia, may help mitigate climate change. PMID- 26961657 TI - Tip-localized receptors control pollen tube growth and LURE sensing in Arabidopsis. AB - Directional control of tip-growing cells is essential for proper tissue organization and cell-to-cell communication in animals and plants. In the sexual reproduction of flowering plants, the tip growth of the male gametophyte, the pollen tube, is precisely guided by female cues to achieve fertilization. Several female-secreted peptides have recently been identified as species-specific attractants that directly control the direction of pollen tube growth. However, the method by which pollen tubes precisely and promptly respond to the guidance signal from their own species is unknown. Here we show that tip-localized pollen specific receptor-like kinase 6 (PRK6) with an extracellular leucine-rich repeat domain is an essential receptor for sensing of the LURE1 attractant peptide in Arabidopsis thaliana under semi-in-vivo conditions, and is important for ovule targeting in the pistil. PRK6 interacted with pollen-expressed ROPGEFs (Rho of plant guanine nucleotide-exchange factors), which are important for pollen tube growth through activation of the signalling switch Rho GTPase ROP1 (refs 7, 8). PRK6 conferred responsiveness to AtLURE1 in pollen tubes of the related species Capsella rubella. Furthermore, our genetic and physiological data suggest that PRK6 signalling through ROPGEFs and sensing of AtLURE1 are achieved in cooperation with the other PRK family receptors, PRK1, PRK3 and PRK8. Notably, the tip-focused PRK6 accumulated asymmetrically towards an external AtLURE1 source before reorientation of pollen tube tip growth. These results demonstrate that PRK6 acts as a key membrane receptor for external AtLURE1 attractants, and recruits the core tip-growth machinery, including ROP signalling proteins. This work provides insights into the orchestration of efficient pollen tube growth and species-specific pollen tube attraction by multiple receptors during male-female communication. PMID- 26961660 TI - Metastability and no criticality. PMID- 26961658 TI - Structure, inhibition and regulation of two-pore channel TPC1 from Arabidopsis thaliana. AB - Two-pore channels (TPCs) comprise a subfamily (TPC1-3) of eukaryotic voltage- and ligand-gated cation channels with two non-equivalent tandem pore-forming subunits that dimerize to form quasi-tetramers. Found in vacuolar or endolysosomal membranes, they regulate the conductance of sodium and calcium ions, intravesicular pH, trafficking and excitability. TPCs are activated by a decrease in transmembrane potential and an increase in cytosolic calcium concentrations, are inhibited by low luminal pH and calcium, and are regulated by phosphorylation. Here we report the crystal structure of TPC1 from Arabidopsis thaliana at 2.87 A resolution as a basis for understanding ion permeation, channel activation, the location of voltage-sensing domains and regulatory ion binding sites. We determined sites of phosphorylation in the amino-terminal and carboxy-terminal domains that are positioned to allosterically modulate cytoplasmic Ca(2+) activation. One of the two voltage-sensing domains (VSD2) encodes voltage sensitivity and inhibition by luminal Ca(2+) and adopts a conformation distinct from the activated state observed in structures of other voltage-gated ion channels. The structure shows that potent pharmacophore trans Ned-19 (ref. 17) acts allosterically by clamping the pore domains to VSD2. In animals, Ned-19 prevents infection by Ebola virus and other filoviruses, presumably by altering their fusion with the endolysosome and delivery of their contents into the cytoplasm. PMID- 26961661 TI - Palmer et al. reply. PMID- 26961663 TI - Corrigendum: Can silicon carbide serve as a saturable absorber for passive mode locked fiber lasers? PMID- 26961662 TI - Total testosterone levels are correlated to metabolic syndrome components. AB - INTRODUCTION: Metabolic syndrome (MetS) is a constellation of interrelated risk factors of metabolic origin. Some studies suggest a possible link between low total testosterone (TT) levels and the presence of MetS. AIM: To analyze the strength and independence of associations between TT and MetS components in non diabetic men. METHODS: In this cross-sectional study, 143 non-diabetic men older than 40 were analyzed. MAIN OUTCOMES MEASURE: Blood samples were collected to evaluate metabolic profile and TT levels. MetS was defined as the presence of three or more of the following characteristics: fasting blood glucose levels >= 100 mg/dL, triglyceride >= 150 mg/dL, HDL-c < 40 mg/dL, hypertension or blood pressure >= 130/85 mmHg, and waist girth > 102 cm. RESULTS: Mean age of the study population was 61.5 +/- 8.61 years old. MetS was present in 47.9% of the individuals. Thirty-four men had low TT and MetS was observed in 23 (70%) against 50 (46%) in those with normal TT (>= 300 ng/dL) (OR 4.94, p < 0.01), adjusted to confounder's factors. In multiple linear regression analysis, only waist circumference (Beta: -0.395; p = 0.03) and HDL-c (Beta: 0.19; p = 0.04) remained significantly correlated with TT levels. CONCLUSIONS: Low TT levels were associated with MetS diagnosis. Abdominal obesity was the MetS component independently correlated to low TT levels. PMID- 26961664 TI - Lifelong Cyclic Mechanical Strain Promotes Large Elastic Artery Stiffening: Increased Pulse Pressure and Old Age-Related Organ Failure. AB - The arterial wall is under a huge mechanical constraint imposed by the cardiac cycle that is bound to generate damage with time. Each heartbeat indeed imposes a pulsatile pressure that generates a vascular stretch. Lifetime accumulation of pulsatile stretches will eventually induce fatigue of the elastic large arterial walls, such as aortic and carotid artery walls, promoting their stiffening that will gradually perturb the normal blood flow and local pressure within the organs, and lead to organ failure. The augmented pulse pressure induced by arterial stiffening favours left ventricular hypertrophy because of the repeated extra work against stiff high-pressure arteries, and tissue damage as a result of excessive pulsatile pressure transmitted into the microcirculation, especially in low resistance/high-flow organs such as the brain and kidneys. Vascular aging is therefore characterized by the stiffening of large elastic arteries leading to a gradual increase in pulse pressure with age. In this review we focus on the effect of age-related stiffening of large elastic arteries. We report the clinical evidence linking arterial stiffness and organ failure and discuss the molecular pathways that are activated by the increase of mechanical stress in the wall. We also discuss the possible interventions that could limit arterial stiffening with age, such as regular aerobic exercise training, and some pharmacological approaches. PMID- 26961665 TI - Dyspnea and Chest Pain in a Young Woman Caused by a Giant Pericardial Lymphohemangioma: Diagnosis and Treatment. AB - We describe a 21-year-old woman who presented with chest pain and dyspnea on exertion and who was found to have a large pericardial mass. Multimodality imaging was instrumental in narrowing the differential diagnosis and planning surgical treatment, which included coronary artery bypass and right-sided heart reconstruction. The final pathologic diagnosis was lymphohemangioma; to our knowledge, this was the largest cardiac/pericardial vascular tumor ever to be reported in the literature. PMID- 26961667 TI - Recent Patents in Oncolytic Virotherapy. AB - Recent innovative and advanced developments in the diagnosis and treatment of human diseases as well as enhanced in-depth understanding of virus molecular biology have opened novel avenues with respect to the patent landscape. Included are viruses utilized in the development of anticancer agents, agents that are employed against the spread of infectious viral diseases, RNA silencing agents and virus-derived expression vectors that can be used for over-expression of therapeutic proteins or as gene therapy vehicles. The current review describes several recent patents pertaining to virus sequences and their medical and biotechnological applications. PMID- 26961666 TI - Definition and estimation of osteonecrosis of jaw (ONJ), and optimal duration of antiresorptive treatment in bone metastatic cancer patients: supplementary data from the denosumab extension study? PMID- 26961668 TI - Recent Patents for Homologous Recombination Deficiency Assays Among Women with Ovarian Cancer. AB - Ovarian cancer continues to present a significant health challenge with little progress being made over the past two decades in reducing the incidence and mortality. More recently, novel therapeutics have emerged as a potential way of improving outcomes for women with advanced ovarian cancer who harbor mutations in genes involved in homologous recombination (HR), most notably BRCA1 and BRCA2. In the United States, Olaparib, a PARP inhibitor, has been recently approved for ovarian cancer patients treated with three or more lines of prior chemotherapy who harbor germline mutations in BRCA1 or BRCA2. As a caveat to Olaparib's FDA approval, BRACAnalysis CDx((r)) was approved as a companion diagnostic test for women with ovarian cancer to determine their BRCA1/2 mutation status and eligibility for treatment. This review article will provide essential background information on hereditary breast and ovarian cancer (HBOC), describe the therapeutic mechanism of PARP inhibitors, and will chronicle the current and emerging homologous recombination deficiency (HRD) assays and their associated patents. PMID- 26961669 TI - Hexavalent Chromium Reduction by Microbacterium oleivorans A1: A Possible Mechanism of Chromate -Detoxification and -Bioremediation. AB - BACKGROUND: Hexavalent chromium (Cr(6+)) contamination is one of the mejor problems of environmental protection for its carcinogenic effect on human health. Remediation of Cr(6+) contaminated environment thus becomes highest priority. METHODS: A Gram positive tiny rod shaped chromate (Cr(6+)) reducing bacterium strain A1 was isolated from uranium ore collected from Jaduguda, East Singhbhum, Jharkhand. The strain was identified and characterized in terms of its potential to reduce more toxic Cr(6+) to its less toxic form for its application in bioremediation of Cr(6+) contaminated environments. RESULTS: 16S rRNA gene based phylogentic analysis identified the strain as Microbacterium oleivorans. Along with Cr(6+), the strain showed resistance to other heavy metals including Ag, Cu, Co, Hg, Ni and Zn also. Complete reduction of Cr(6+) (750 uM) was achieved within 84 h with optimum reduction at pH 9 and 30 degrees C. Effect of different parameters including cell mass concentration, pH, induction with Cr(6+), SO4 = ion, heavy metals, etc. on Cr(6+) reduction were studied thoroughly at resting cell condition to study its potential towards Cr(6+) bioremediation. Chromate reductase gene (chrA) was detected within this strain. CONCLUSION: Along with presence of appropriate genetic determinant, efficient Cr(6+) reduction ability of the strain indicated its potential for developing redox based Cr(6+) remediation system for varied concentrations of Cr6+ under a wide range of environmental conditions. Patent data have suggested the efficient application of Cr(6+) reducing bacteria in cleaning up of Cr(6+) contaminated environments. PMID- 26961670 TI - Exploration of Recombinant Streptokinase Degradation Products Under Various pH Reduction Conditions in Downstream Processing. AB - BACKGROUND: Methods of producing streptokinase, which can be used in the treatment of myocardial infarction, by hemolytic streptococci and recombinant E. coli have been described in patents since 1955. Degradation products in active pharmaceutical ingredients (APIs) and finished pharmaceutical products are considered as impurities and it is required that these degradation impurities are minimized or rather avoided throughout manufacturing process. OBJECTIVE: The aim of this study was to explore the occurrence of rSK degradation during acidification step in downstream processing. METHODS: The polyclonal antibody was produced by immunization of New Zealand white (NZW) rabbit with pure rSK (purity>98%). The solubilized inclusion bodies with various pH values (4.2, 5.0 and 6.0) were analyzed by Western blotting using rSK polyclonal antibody. RESULTS: Western blot analysis demonstrated the generation of rSK degradation products (with the molecular weight of about 27, 20 and 17 kDa) when the pH value of the solubilized inclusion bodies was reduced to 5.0 and 4.2, while no degradation of rSK observed at pH 6.0. CONCLUSION: This study demonstrates that the level of pH reduction in the solubilized inclusion bodies during downstream processing plays an important role in generating rSK degradation products, and substantial post-solubilization degradation of rSK occurs at pH lower than 6.0. Development of these degradation impurities, which cannot be eliminated by subsequent chromatographic purifications, can be exclusively avoided during acidification procedure by appropriate pH adjustment approach in downstream processing. PMID- 26961671 TI - Phytochemistry, Antinociceptive and Anti-inflammatory Actvities of Methanolic Leaves Extract of Lannea schimperi (Hoschst. Ex Rich) ENG. AB - BACKGROUND: Pain whether acute or chronic, peripheral or central is believed to originate from inflammation and inflammatory response. The potential toxicity of antinociceptive and antiinflammatory agents such as non steroidal anti inflammatory drugs (NSAIDs) necessitates sourcing for less toxic alternative drugs. Many natural substances have been used for the management of pain and inflammation with success traditionally. METHODS: The present study sought to investigate phytochemistry, antinociceptive and anti-inflammatory potentials of the methanolic leaves extract of Lannea schimperi. Preliminary phytochemical test was conducted on the extract. Antinociceptive and anti-inflammatory potentials of the extract at doses of 12 and 24 mg/kg were evaluated using acetic acid induced writhing model in mice and egg albumin induced acute inflammation model in rats' respectively. Aspirin at dose of 80 mg/kg was used as the standard drug given to the positive control group, while the drug vehicle was given to the negative control group. RESULT: Phytochemical analysis revealed the presence of carbohydrate, glycoside, reducing sugars, triterpene, steroids, cardiac glycosides, flavonoids, phenolic glycosides, alkaloids, tannins, condensed tannins and saponins. The data obtained showed that at both doses the extract significantly (P< 0.05) decreased the acetic acid induced writhing reflex in mice when compared to the negative control group. The result also demonstrated significant (P< 0.05) anti-inflammatory activity of the extract at both doses. However, there was no significant difference (P> 0.05) between the extract treated groups and the group treated with the standard drug (positive control). CONCLUSION: The patent data revealed the antinociceptive and anti-inflammatory potentials of the methanolic leaves extract of Lannea schimperi which could be beneficial in alleviating painful inflammatory conditions. PMID- 26961673 TI - Diagnostic potential of YKL-40 in bladder cancer. AB - OBJECTIVES: YKL-40 is a glycoprotein, which is thought to play a role in inflammatory conditions and tissue remodeling. Although it has been investigated in numerous cancers, there is very limited knowledge about the role of YKL-40 in bladder cancer. In this study, our aim was to determine the levels of YKL-40 in the sera and urines of the patients with bladder cancer, and compare it to urinary bladder tumor antigen (BTA), a tumor marker that can be used in the diagnosis of bladder cancer. METHODS: The study was comprised of 2 major groups as 65 healthy controls and 67 patients with bladder cancer. The patient group was also divided into subgroups according to tumor stage and grade. Serum and urine YKL-40 levels and urine BTA levels in controls and patients were determined using commercially available enzyme-linked immunosorbent assay kits. RESULTS: Serum YKL 40 and urinary BTA levels were significantly elevated in patients and all patient subgroups compared to healthy controls. Urine YKL-40 levels, on the other hand, were significantly elevated in all subgroups except low stage (Ta) and low grade, compared to controls. Although serum YKL-40 levels could not differentiate any subgroup from one another, urinary BTA could only differentiate low stage (Ta) from all invasive (T1-T4) cancers. However, urine YKL-40 levels were significantly elevated in all invasive subgroups (T1, T2-T4, and T1-T4), compared to low stage (Ta). CONCLUSIONS: In summary, urine YKL-40 levels can be used to assist BTA in the diagnosis of bladder cancer as a marker for early invasiveness and thus help determine its treatment regimen. PMID- 26961672 TI - Differential macrophage function in Brown Swiss and Holstein Friesian cattle. AB - There is strong evidence that high yielding dairy cows are extremely susceptible to infectious diseases, and that this has severe economic consequences for the dairy industry and welfare implications. Here we present preliminary functional evidence showing that the innate immune response differs between cow breeds. The ability of macrophages (MO) to kill pathogens depends in part on oxygen-dependent and independent mechanisms. The oxygen-dependent mechanisms rely on the generation of reactive oxygen and nitrogen species (ROS/RNS, respectively). ROS production has been shown to activate the inflammasome complex in MO leading to increased production of the pro-inflammatory cytokine Interleukin-1beta (IL 1beta). Conversely RNS inhibits inflammasome mediated IL-1beta activation, indicating a division between inflammasome activation and RNS production. In the present study MO from Brown Swiss (BS) cattle produce significantly more RNS and less IL-1beta when compared to cells from Holstein Friesian (HF) cattle in response to bacterial or fungal stimuli. Furthermore, BS MO killed ingested Salmonella typhimurium more efficiently, supporting anecdotal evidence of increased disease resistance of the breed. Inhibition of autophagy by 3 methyladenine (3-MA) stimulated IL-1beta secretion in cells from both breeds, but was more pronounced in HF MO. Blocking RNS production by l-arginase completely abolished RNS production but increased IL-1beta secretion in BS MO. Collectively these preliminary data suggest that the dichotomy of inflammasome activation and RNS production exists in cattle and differs between these two breeds. As pattern recognition receptors and signaling pathways are involved in the assessed functional differences presented herein, our data potentially aid the identification of in vitro predictors of appropriate innate immune response. Finally, these predictors may assist in the discovery of candidate genes conferring increased disease resistance for future use in combination with known production traits. PMID- 26961674 TI - Isoorientin Prevents Hyperlipidemia and Liver Injury by Regulating Lipid Metabolism, Antioxidant Capability, and Inflammatory Cytokine Release in High Fructose-Fed Mice. AB - Isoorientin (ISO), a natural flavonoid, has been found to have multiple biological properties. In the present study, obese mice with high-fructose (HF) induced liver injury were used to investigate the hepatoprotective effects of ISO. The results showed that ISO significantly reduced the serum lipid parameters in mice fed 20% HF water. Meanwhile, ISO appeared to alleviate HF-induced lipid metabolic disorders by increasing the serum levels of apo-A1 and decreasing the serum apoB levels, apoB/apo-A1 ratio, and FAS activity in the liver. ISO also remarkably ameliorated HF-induced hepatic oxidative injury and inflammation by decreasing ALT, AST, and ALP levels; enhancing antioxidant enzyme activities; and inhibiting inflammatory cytokine (TNF-alpha, IL-1, IL-6) release. Histopathology of liver stained by H&E and Oil Red O showed the liver steatosis and oxidative injury after HF treatment and the protective effect of ISO. Furthermore, aortic pathology observation found that ISO had a protective effect on the vascular endothelium. This is the first report that ISO efficiently inhibited HF-induced hyperlipidemia and liver injury by ameliorating lipid metabolism, enhancing the antioxidant defensedefense system, and regulating the secretion of inflammatory cytokines. PMID- 26961675 TI - Population Attributable Risk Fractions of Maternal Overweight and Obesity for Adverse Perinatal Outcomes. AB - The objective of the current study was to determine the proportion of adverse perinatal outcomes that could be potentially prevented if maternal obesity were to be reduced or eliminated (population attributable risk fractions, PARF); and the number needed to treat (NNT) of overweight or obese women to prevent one case of adverse perinatal outcome. Data from the Atlee Perinatal Database on 66,689 singleton infants born in Nova Scotia, Canada, between 2004 and 2014, and their mothers were used. Multivariable-adjusted PARFs and NNTs of maternal pre pregnancy weight status were determined for various perinatal outcomes under three scenarios: If all overweight and obese women were to i) become normal weight before pregnancy; ii) shift down one weight class; or iii) lose 10% of their body weight, significant relative reductions would be seen for gestational diabetes mellitus (GDM, 57/33/15%), hypertensive disorders of pregnancy (HDP, 26/16/6%), caesarean section (CS, 18/10/3%), and large for gestational age births (LGA, 24/14/3%). The NNT were lowest for the outcomes GDM, induction of labour, CS, and LGA, where they ranged from 13 to 73. The study suggests that a substantial proportion of adverse perinatal outcomes may be preventable through reductions in maternal pre-pregnancy weight. PMID- 26961676 TI - A Simple Model to Rank Shellfish Farming Areas Based on the Risk of Disease Introduction and Spread. AB - The European Union Council Directive 2006/88/EC requires that risk-based surveillance (RBS) for listed aquatic animal diseases is applied to all aquaculture production businesses. The principle behind this is the efficient use of resources directed towards high-risk farm categories, animal types and geographic areas. To achieve this requirement, fish and shellfish farms must be ranked according to their risk of disease introduction and spread. We present a method to risk rank shellfish farming areas based on the risk of disease introduction and spread and demonstrate how the approach was applied in 45 shellfish farming areas in England and Wales. Ten parameters were used to inform the risk model, which were grouped into four risk themes based on related pathways for transmission of pathogens: (i) live animal movement, (ii) transmission via water, (iii) short distance mechanical spread (birds) and (iv) long distance mechanical spread (vessels). Weights (informed by expert knowledge) were applied both to individual parameters and to risk themes for introduction and spread to reflect their relative importance. A spreadsheet model was developed to determine quantitative scores for the risk of pathogen introduction and risk of pathogen spread for each shellfish farming area. These scores were used to independently rank areas for risk of introduction and for risk of spread. Thresholds were set to establish risk categories (low, medium and high) for introduction and spread based on risk scores. Risk categories for introduction and spread for each area were combined to provide overall risk categories to inform a risk-based surveillance programme directed at the area level. Applying the combined risk category designation framework for risk of introduction and spread suggested by European Commission guidance for risk-based surveillance, 4, 10 and 31 areas were classified as high, medium and low risk, respectively. PMID- 26961677 TI - Peripherally Inserted Central Venous Catheter Complications in Children Receiving Outpatient Parenteral Antibiotic Therapy (OPAT). AB - OBJECTIVE To identify the frequency of and risk factors associated with complications necessitating removal of the peripherally inserted central catheters (PICCs) in patients receiving outpatient parenteral antibiotic therapy (OPAT) and to determine the appropriateness of OPAT in children with OPAT-related complications. METHODS A retrospective cohort of children who had a PICC inserted at the Johns Hopkins Children's Center between January 1, 2003, and December 31, 2013, and were discharged from the hospital on OPAT was assembled. RESULTS A total of 1,465 PICCs were used to provide antibiotic therapy for 955 children after hospital discharge. Among these, 117 PICCs (8%) required removal due to a complication (4.6 of 1,000 catheter days). Children discharged to a long-term care facility were at increased risk of adverse PICC events (incidence risk ratio [IRR], 3.32; 95% confidence interval [CI], 1.79-6.17). For children receiving OPAT, age of the child (adjusted IRR [aIRR], 0.95; 95% CI, 0.92-0.98), noncentral PICC tip location (aIRR, 2.82; 95% CI, 1.66-4.82), and public insurance (aIRR, 1.63; 95% CI, 1.10-2.40) were associated with adverse PICC events. In addition, 34 patients (32%) with adverse events may not have required intravenous antibiotics at the time of hospital discharge. CONCLUSIONS Of children discharged with PICCs on OPAT during the study period, 8% developed a complication necessitating PICC removal. Children discharged to a long-term care facility had an increased rate of complication compared with children who were discharged home. With improved education regarding appropriate duration of antibiotic therapy and situations in which early conversion to enteral therapy should be considered, PICC-related complications may have been avoided in 32% of children. Infect. PMID- 26961678 TI - Computed tomography, radiology and echocardiography in cats naturally infected with Aelurostrongylus abstrusus. AB - Objectives The aims of the study were to describe the radiographic and computed tomographic features in cats naturally infected with Aelurostrongylus abstrusus, and to identify signs of pulmonary hypertension with echocardiography. Methods Fourteen cats positive on Baermann test for A abstrusus were included in the study. All cats underwent thoracic radiography, CT and echocardiography. Results The most common clinical signs were coughing (10/14) and dyspnoea (5/14). Radiographic findings included a generalised unstructured interstitial pulmonary pattern (8/14), mixed bronchointerstitioalveolar pattern (3/14) and bronchointerstitial pattern with bronchial wall thickening (3/14). Sternal lymphadenopathy was detected on thoracic radiographs in six cats. On CT, features were mixed bronchointerstitioalveolar pattern with ground-glass appearance in six cats, interstitioalveolar with multiple pulmonary nodules in five, interstitial ground-glass infiltrates in three, regional lymph node enlargement in 11 (10 sternal, three cranial mediastinal and three tracheobronchial lymph nodes) and subpleural thickening in four. None of the thoracic radiographs revealed subpleural thickening. In all cases, pulmonary vessels were normal in terms of size, shape and attenuation on both radiography and CT. Pulmonary hypertension and cardiac abnormalities were not observed in any cat during echocardiography. Conclusions and relevance CT provided a more thorough characterisation of pulmonary and mediastinal lesions compared with thoracic radiographs in cats naturally infected with A abstrusus. Although feline aelurostrongylosis has been previously associated with histopathological lesions in lung arteries, in this cohort clinical evidence of pulmonary hypertension was not documented. PMID- 26961679 TI - Reconstruction of orbital exenteration defects with bilobed forehead flap. AB - To describe the use of bilobed forehead flap for reconstruction of orbital exenteration defect. The medical records of 2 patients in whom orbital exenteration defect repair was performed with bilobed forehead flap were reviewed. In both patients (male, ages 74 and 65 years), extended exenteration was performed because of basal cell carcinoma infiltrating the upper and lower eyelids and orbit. One patient had a history of multiple eyelid surgeries and periorbital radiotherapy. In the other, the tumor also involved the maxillary and ethmoid sinuses and nasal dorsum. The bilobed flap was combined with a cheek advancement flap in 1 patient. The excisional defect could be primarily covered in both patients. In 1 patient, a skin graft was needed to cover the forehead donor area defect. In both patients, transient, distal flap ischemia developed after surgery and, in 1 patient, eyebrow malposition required surgical correction at the late period. No other complication developed during follow-up (18 and 26 months). The bilobed forehead flap can be effectively used to reconstruct total or extended orbital exenteration defects. PMID- 26961680 TI - Identification of two novel mutations in the cornea-specific TGFBI gene causing unique phenotypes in patients with corneal dystrophies. AB - The purpose of this study was to report on two novel missense mutations of the cornea-specific TGFBI gene in one single patient and in two generations of a family diagnosed with unique corneal dystrophy (CD) phenotypes. Ophthalmologic examination, in several cases ocular coherence tomography of the anterior segment (AS-OCT), was performed in 21 affected patients and in two unaffected members of one affected family. Coding regions of the TGFBI gene were direct sequenced in all 23 individuals. The two novel mutations were verified by RFLP analysis. A novel mutation c.1640T > G (p.Phe574Cys) in exon 12 of the TGFBI gene was detected in one single patient with recurrent granular intrastromal deposits comparable to a type of granular dystrophy. In AS-OCT, the deposit pattern reached up to the Descemet's layer. A further novel mutation c.393G > T(p.Glu131Asp) in exon 4 of the TGFBI gene was detected in all three affected members of one family with superficial cloud- and honeycomb-like opacifications, comparable to a Schnyder corneal dystrophy. Two unaffected members did not carry this alteration. The two identified novel mutations add other two phenotypes in patients suffering from TGFBI-linked CD to those reported so far. In one case, clinical finding indicates a Schnyder corneal dystrophy-like phenotype due to its superficial crystalline shape, and in the second one, granular deposits who reach Descemet's layer indicate a granular CD subtype. Molecular genetic analysis may help to distinguish those subtypes and to decide for specific treatment in time of a wide variation of corneal surgical techniques. PMID- 26961681 TI - Seasonal Changes Affect Root Prunasin Concentration in Prunus serotina and Override Species Interactions between P. serotina and Quercus petraea. AB - The allocation of resources to chemical defense can decrease plant growth and photosynthesis. Prunasin is a cyanogenic glycoside known for its role in defense against herbivores and other plants. In the present study, fluctuations of prunasin concentrations in roots of Prunus serotina seedlings were hypothesized to be: (1) dependent on light, air temperature, and humidity; (2) affected by competition between Prunus serotina and Quercus petraea seedlings, with mulching with Prunus serotina leaves; (3) connected with optimal allocation of resources. For the first time, we determined prunasin concentration in roots on several occasions during the vegetative season. The results indicate that seasonal changes have more pronounced effects on prunasin concentration than light regime and interspecific competition. Prunus serotina invested more nitrogen in the synthesis of prunasin under highly restricted light conditions than in higher light environments. In full sun, prunasin in roots of Prunus serotina growing in a monoculture was correlated with growth and photosynthesis, whereas these relationships were not found when interspecific competition with mulching was a factor. The study demonstrates that prunasin concentration in Prunus serotina roots is the result of species-specific adaptation, light and temperature conditions, ontogenetic shift, and, to a lesser extent, interspecific plant-plant interactions. PMID- 26961682 TI - Movement distributions of stroke survivors exhibit distinct patterns that evolve with training. AB - BACKGROUND: While clinical assessments provide tools for characterizing abilities in motor-impaired individuals, concerns remain over their repeatability and reliability. Typical robot-assisted training studies focus on repetition of prescribed actions, yet such movement data provides an incomplete account of abnormal patterns of coordination. Recent studies have shown positive effects from self-directed movement, yet such a training paradigm leads to challenges in how to quantify and interpret performance. METHODS: With data from chronic stroke survivors (n = 10, practicing for 3 days), we tabulated histograms of the displacement, velocity, and acceleration for planar motion, and examined whether modeling of distributions could reveal changes in available movement patterns. We contrasted these results with scalar measures of the range of motion. We performed linear discriminant analysis (LDA) classification with selected histogram features to compare predictions versus actual subject identifiers. As a basis of comparison, we also present an age-matched control group of healthy individuals (n = 10, practicing for 1 day). RESULTS: Analysis of range of motion did not show improvement from self-directed movement training for the stroke survivors in this study. However, examination of distributions indicated that increased multivariate normal components were needed to accurately model the patterns of movement after training. Stroke survivors generally exhibited more complex distributions of motor exploration compared to the age-matched control group. Classification using linear discriminant analysis revealed that movement patterns were identifiable by individual. Individuals in the control group were more difficult to identify using classification methods, consistent with the idea that motor deficits contribute significantly to unique movement signatures. CONCLUSIONS: Distribution analysis revealed individual patterns of abnormal coordination in stroke survivors and changes in these patterns with training. These findings were not apparent from scalar metrics that simply summarized properties of motor exploration. Our results suggest new methods for characterizing motor capabilities, and could provide the basis for powerful tools for designing customized therapy. PMID- 26961683 TI - CoINcIDE: A framework for discovery of patient subtypes across multiple datasets. AB - Patient disease subtypes have the potential to transform personalized medicine. However, many patient subtypes derived from unsupervised clustering analyses on high-dimensional datasets are not replicable across multiple datasets, limiting their clinical utility. We present CoINcIDE, a novel methodological framework for the discovery of patient subtypes across multiple datasets that requires no between-dataset transformations. We also present a high-quality database collection, curatedBreastData, with over 2,500 breast cancer gene expression samples. We use CoINcIDE to discover novel breast and ovarian cancer subtypes with prognostic significance and novel hypothesized ovarian therapeutic targets across multiple datasets. CoINcIDE and curatedBreastData are available as R packages. PMID- 26961684 TI - Hierarchical organization and molecular diffusion in gold nanorod/silica supercrystal nanocomposites. AB - Hierarchical organization of gold nanorods was previously obtained on a substrate, allowing precise control over the morphology of the assemblies and macroscale spatial arrangement. Herein, a thorough description of these gold nanorod assemblies and their orientation within supercrystals is presented together with a sol-gel technique to protect the supercrystals with mesoporous silica films. The internal organization of the nanorods in the supercrystals was characterized by combining focused ion beam ablation and scanning electron microscopy. A mesoporous silica layer is grown both over the supercrystals and between the individual lamellae of gold nanorods inside the structure. This not only prevented the detachment of the supercrystal from the substrate in water, but also allowed small molecule analytes to infiltrate the structure. These nanocomposite substrates show superior Raman enhancement in comparison with gold supercrystals without silica owing to improved accessibility of the plasmonic hot spots to analytes. The patterned supercrystal arrays with enhanced optical and mechanical properties obtained in this work show potential for the practical implementation of nanostructured devices in spatially resolved ultradetection of biomarkers and other analytes. PMID- 26961685 TI - 'Don't put the parent out': parents' perspectives of being present during an inter-hospital transfer. AB - AIMS AND OBJECTIVES: To understand Irish parents' experiences of the inter hospital transfer of their acutely ill child from a regional hospital to a tertiary children's hospital. BACKGROUND: Much of the literature on inter hospital transfer focuses on the medical outcome of children who have been transferred for specialist care. While parental presence during this journey is the focus of discussion papers, little is known about the experience of parents as service users. DESIGN: A qualitative design using a Husserlian phenomenological approach was adopted for this study. METHODS: Semi-structured interviews were conducted with ten parents between March and October 2014 to explore their experiences of parental presence during the transfer of an acutely ill child. Data were analysed using the modified Van Kaam method. RESULTS: Two key themes emerged 'don't put the parent out' and 'being a parent'. Given a choice, all parents interviewed would have wished to stay with their child during transfer and the findings portray the specific contribution of parents during the journey. CONCLUSIONS: Not being permitted to travel with their acutely ill child had a negative effect on parents' perceptions of their ability to continue to parent their child during transfer to specialist paediatric services. To address this there is a need for parents to have the choice, when at all possible, to stay with their child at this time. RELEVANCE TO CLINICAL PRACTICE: There is a need to maximise the facilitation of parental presence in an Irish context through the introduction of guidelines to support staff involved in the transfer of an acutely ill child. PMID- 26961687 TI - Self-calibration of cone-beam CT geometry using 3D-2D image registration. AB - Robotic C-arms are capable of complex orbits that can increase field of view, reduce artifacts, improve image quality, and/or reduce dose; however, it can be challenging to obtain accurate, reproducible geometric calibration required for image reconstruction for such complex orbits. This work presents a method for geometric calibration for an arbitrary source-detector orbit by registering 2D projection data to a previously acquired 3D image. It also yields a method by which calibration of simple circular orbits can be improved. The registration uses a normalized gradient information similarity metric and the covariance matrix adaptation-evolution strategy optimizer for robustness against local minima and changes in image content. The resulting transformation provides a 'self-calibration' of system geometry. The algorithm was tested in phantom studies using both a cone-beam CT (CBCT) test-bench and a robotic C-arm (Artis Zeego, Siemens Healthcare) for circular and non-circular orbits. Self-calibration performance was evaluated in terms of the full-width at half-maximum (FWHM) of the point spread function in CBCT reconstructions, the reprojection error (RPE) of steel ball bearings placed on each phantom, and the overall quality and presence of artifacts in CBCT images. In all cases, self-calibration improved the FWHM-e.g. on the CBCT bench, FWHM = 0.86 mm for conventional calibration compared to 0.65 mm for self-calibration (p < 0.001). Similar improvements were measured in RPE-e.g. on the robotic C-arm, RPE = 0.73 mm for conventional calibration compared to 0.55 mm for self-calibration (p < 0.001). Visible improvement was evident in CBCT reconstructions using self-calibration, particularly about high-contrast, high-frequency objects (e.g. temporal bone air cells and a surgical needle). The results indicate that self-calibration can improve even upon systems with presumably accurate geometric calibration and is applicable to situations where conventional calibration is not feasible, such as complex non-circular CBCT orbits and systems with irreproducible source-detector trajectory. PMID- 26961689 TI - Referrals to Pediatric Cardiology Outpatients: Continued Evidence of Increasing Workload. PMID- 26961688 TI - The Case of the Previously Shaky, Unimmunized, Itchy Infant With Rash and Pancytopenia. PMID- 26961686 TI - Adenosine can thwart antitumor immune responses elicited by radiotherapy : Therapeutic strategies alleviating protumor ADO activities. AB - BACKGROUND: By studying the bioenergetic status we could show that the development of tumor hypoxia is accompanied, apart from myriad other biologically relevant effects, by a substantial accumulation of adenosine (ADO). ADO has been shown to act as a strong immunosuppressive agent in tumors by modulating the innate and adaptive immune system. In contrast to ADO, standard radiotherapy (RT) can either stimulate or abrogate antitumor immune responses. Herein, we present ADO-mediated mechanisms that may thwart antitumor immune responses elicited by RT. MATERIALS AND METHODS: An overview of the generation, accumulation, and ADO related multifaceted inhibition of immune functions, contrasted with the antitumor immune effects of RT, is provided. RESULTS: Upon hypoxic stress, cancer cells release ATP into the extracellular space where nucleotides are converted into ADO by hypoxia-sensitive, membrane-bound ectoenzymes (CD39/CD73). ADO actions are mediated upon binding to surface receptors, mainly A2A receptors on tumor and immune cells. Receptor activation leads to a broad spectrum of strong immunosuppressive properties facilitating tumor escape from immune control. Mechanisms include (1) impaired activity of CD4 (+) T and CD8 (+) T, NK cells and dendritic cells (DC), decreased production of immuno-stimulatory lymphokines, and (2) activation of Treg cells, expansion of MDSCs, promotion of M2 macrophages, and increased activity of major immunosuppressive cytokines. In addition, ADO can directly stimulate tumor proliferation and angiogenesis. CONCLUSION: ADO mechanisms described can thwart antitumor immune responses elicited by RT. Therapeutic strategies alleviating tumor-promoting activities of ADO include respiratory hyperoxia or mild hyperthermia, inhibition of CD39/CD73 ectoenzymes or blockade of A2A receptors, and inhibition of ATP-release channels or ADO transporters. PMID- 26961691 TI - The use and risks of antibiotics in critically ill patients. AB - INTRODUCTION: The altered pathophysiology in critically ill patients presents a unique challenge in both the diagnosis of infection and the appropriate prescription of antibiotics. In this context, the importance of effective and timely treatment needs to be weighed against the individual and community harms associated with antibiotic collateral damage and antibiotic resistance. AREAS COVERED: We evaluate the principles of antibiotic use in critically ill patients, including dose optimisation, use of combination antibiotic therapy, therapeutic drug monitoring, appropriate antibiotic therapy duration, de-escalation, and utilisation of sepsis biomarkers. We also describe the potential risks associated with antibiotic therapy including antibiotic resistance, delayed treatment, treatment failure, and collateral damage. EXPERT OPINION: Prescribing teams must be aware of the impact of critical illness on their patients and tailor antibiotic therapy appropriately to prevent the significant harms associated with suboptimal antibiotic administration. PMID- 26961690 TI - Lenalidomide potentiates CD4+CD25+Treg-related suppression of lymphoma B-cell proliferation. AB - We have previously found that ex vivo expanded human CD4+CD25+Treg cells suppress proliferation of lymphoma B-cell lines. Here we demonstrate that the immunomodulatory drug lenalidomide potentiates suppression of lymphoma B-cell proliferation by freshly isolated CD4+CD25+Tregs, as well as suppression by Tregs expanded polyclonally in the presence of rapamycin from CD4+CD25+T cells or CD4+CD25+CD127loT cells. The regulation of lymphoma cell proliferation by Tregs pre-expanded with "third-party" allogeneic MoDCs in the presence of rapamycin was also potentiated by lenalidomide. Lenalidomide contributed to the suppression exerted by Tregs despite concomitant downregulation of Treg proliferation. Lenalidomide did not reduce the suppression of conventional T cells by expanded Tregs. The exposure of polyclonally expanded Tregs to lenalidomide did not significantly alter their phenotype. There was no uniform pattern of lenalidomide effect on Treg-mediated regulation of lymphoma B cells freshly isolated from patients. Freshly isolated lymphoma cells activated with multimeric CD40L and IL 4 to support their survival in vitro varied in their sensitivity to lenalidomide, and the regulatory effect of Tregs on such lymphoma cells ranged from suppression to help in individual patients. Lenalidomide potentiated or attenuated Treg effects on the survival of freshly isolated lymphoma cells. A combination of lenalidomide treatment with adoptive transfer of CD4+CD25+Tregs or CD4+CD25+CD127loTregs expanded ex vivo could be used to suppress proliferation of residual lymphoma in select patients with lymphoma responsive to the regulation by Tregs and sensitive to lenalidomide. PMID- 26961693 TI - Lessons learned from the past on mental health care of refugee children in Serbia. PMID- 26961692 TI - Multiplex methods provide effective integration of multi-omic data in genome scale models. AB - BACKGROUND: Genomic, transcriptomic, and metabolic variations shape the complex adaptation landscape of bacteria to varying environmental conditions. Elucidating the genotype-phenotype relation paves the way for the prediction of such effects, but methods for characterizing the relationship between multiple environmental factors are still lacking. Here, we tackle the problem of extracting network level information from collections of environmental conditions, by integrating the multiple omic levels at which the bacterial response is measured. RESULTS: To this end, we model a large compendium of growth conditions as a multiplex network consisting of transcriptomic and fluxomic layers, and we propose a multi-omic network approach to infer similarity of growth conditions by integrating layers of the multiplex network. Each node of the network represents a single condition, while edges are similarities between conditions, as measured by phenotypic and transcriptomic properties on different layers of the network. We then fuse these layers into one network, therefore capturing a global network of conditions and the associated similarities across two omic levels. We apply this multi-omic fusion to an updated genome-scale reconstruction of Escherichia coli that includes underground metabolism and new gene-protein-reaction associations. CONCLUSIONS: Our method can be readily used to evaluate and cross-compare different collections of conditions among different species. Acquiring multi-omic information on the topology of the space of experimental conditions makes it possible to infer the position and to build condition-specific models of untested or incomplete profiles for which experimental data is not available. Our weighted network fusion method for genome-scale models is freely available at https://github.com/maxconway/SNFtool . PMID- 26961694 TI - Age-related decline in muscle mass and muscle function in Flemish Caucasians: a 10-year follow-up. AB - Aging is a complex process that is accompanied with changes in both muscle mass and muscle function (strength and performance). Therefore, the current longitudinal study aimed to provide a better insight in 10-year aging-related changes in whole-body muscle mass and strength performance of the leg extensors during the adult life span. Data were gathered within the framework of the first- (2002-2004: baseline) and third-generation Flemish Policy Research Center Sport (2012-2014: follow-up). Results are based on muscle characteristics data of 591 Flemish Caucasian adults (19-73 years, 381 men). Skeletal muscle mass (SMM) was determined with bioelectrical impedance analysis. Biodex Medical System 3(r) dynamometer was used to measure isometric (PTstatic120 degrees ) and isokinetic (PTdynamic60 degrees and PTdynamic240 degrees ) strength, ballistic movement speed (S 20 %), and muscular endurance (work) of the knee extensors. Overall strength performance was higher at both evaluation moments in men compared to women (p < 0.01). But only S 20 % declined significantly faster in men compared to women (p < 0.01). Age and baseline strength performance were negatively related with the change in strength performance, even when corrected for SMM, protein intake, and energy expenditure during sports (E sport). In conclusion, strength performance was not associated with E sport in this study, but protein intake was associated with isometric strength in men, and with ballistic and isokinetic strength in women. Changes in S 20 % were significantly greater in men compared to women. Baseline values of strength performance and age were associated with changes in strength performance parameters, even after correction for SMM, protein intake, and E sport. PMID- 26961696 TI - Pharmacist-Led Home Medicines Review and Residential Medication Management Review: The Australian Model. AB - Older people are often prescribed multiple medicines and have a high prevalence of polypharmacy. Polypharmacy is associated with an increased risk of inappropriate use of medicines and drug-related problems. As experts in pharmacotherapy, pharmacists are well placed to review complex medication regimens and identify causes of drug-related problems and recommend solutions to prevent or resolve them. Involvement in medication review services represents a major philosophical shift and paradigm change in the way pharmacists practice, in that the focus is shifted away from the dispensing of prescription medicines to the provision of a professional service for a patient, in collaboration with their general practitioner (GP). In Australia, there are two established medication review programs: Home Medicines Review (HMR) and Residential Medication Management Review (RMMR). The objectives of this article were to describe the process of government-funded medication review services in Australia and to evaluate the contribution of pharmacists to HMR and RMMR, using evidence based measures, such as the Drug Burden Index (DBI) and the Medication Appropriateness Index (MAI). This review found that there is good evidence to support the role of pharmacists in delivering medication review services across different settings. Although the positive impact of such services has been demonstrated using a variety of validated measures (DBI, MAI), there remains a need to also evaluate actual clinical outcomes and/or patient-reported outcomes. PMID- 26961695 TI - Differences in EEG power in young and mature healthy adults during an incidental/spatial learning task are related to age and execution efficiency. AB - The differential characteristics of absolute power in the EEG theta (4-8 Hz) and gamma (30-45 Hz) frequency bands have been analysed in young (18-25 years old, n = 14) and mature adults (45-65 years old, n = 12) during the incidental or intentional behavioural conditions of learning and recalling in a visuospatial task. A printed drawing of a maze including eight figures of common objects in specific placements, solved by connecting its entrance and exit points, allowed the subject's performance efficiency to be measured based on the number, position accuracy and/or identity of incidentally or intentionally learned and remembered objects. Meanwhile, EEG recordings from frontal, parietal and temporal derivations were obtained to determine the power values of the theta (4-8 Hz) and gamma (30-45 Hz) bands for each behavioural condition and derivation. Relative to the young adults, the mature adults generally showed lower absolute theta power values, mainly due to their low theta powers under the basal and incidental learning conditions, and higher absolute gamma power values in the frontal and temporal regions. Furthermore, higher theta band power in the frontal regions was related to higher performance efficiency in both incidental and intentional learning, regardless of the subjects' age. A significant negative correlation between the parameters of individual incidental or intentional learning performance and age was also found. Indeed, a differential accuracy of remembered information seems to be associated with age and incidental or intentional learning/memory testing conditions. These data support an increasing vulnerability of visuospatial learning abilities at mature ages and as ageing progresses. PMID- 26961698 TI - Association Between Severe Hypoglycemia and Cardiovascular Disease Risk in Japanese Patients With Type 2 Diabetes. AB - BACKGROUND: It remains unclear whether severe hypoglycemia is associated with cardiovascular disease (CVD) in Asian populations with type 2 diabetes (T2D). Furthermore, no study in Japan, where the prescription patterns differ from those in other countries, has examined this association. METHODS AND RESULTS: We retrospectively included 58 223 patients (18-74 years old) with T2D. First, we examined the potential predictors of severe hypoglycemia. Then, we investigated the association between severe hypoglycemia and CVD risk. Finally, we performed an updated systematic review and meta-analysis to incorporate our findings and recently published studies into the previous systematic review and meta-analysis. During 134 597 person-years from cumulative observation periods, 128 persons experienced severe hypoglycemia and 550 developed CVD events. In a multivariate Cox proportional hazard model, severe hypoglycemia was strongly and positively associated with the risk of CVD (multivariate-adjusted adjusted hazard ratio, 3.39; 95% CI, 1.25-9.18). In a propensity score-matched cohort that had similar baseline characteristics for patients with severe hypoglycemia and those without, severe hypoglycemia was more strongly associated with the risk of CVD. An updated systematic review and meta-analysis that included 10 studies found that severe hypoglycemia was associated with an ~2-fold increased risk of CVD (pooled relative risk, 1.91; 95% CI, 1.69-2.15). CONCLUSIONS: Our results suggest that severe hypoglycemia is strongly associated with an increased risk of CVD in Japanese patients with T2D, further supporting the notion that avoiding severe hypoglycemia may be important in preventing CVD in this patient population. PMID- 26961699 TI - First report of the emerging zoonotic agent Wohlfahrtiimonas chitiniclastica isolated from a retail frozen chicken in Rio de Janeiro, Brazil. AB - Wohlfahrtiimonas chitiniclastica is an emerging zoonotic bacterium commensally living in larvae of particular flies. It has been associated with human and animal infections but never isolated from food. In the present study, a whole chicken carcass was rinsed in buffered peptone water which was then inoculated into BHI and the growth plated onto selective medium. Species identification was performed by MALDI-TOF MS. Those bacteria identified as W. chitiniclastica were subjected to 16S rRNA sequencing for confirmation and MEGA software was used to obtain their phylogenetic position. The findings of this study raise concerns regarding the abattoir, transport and stock practices of frozen meat carcasses and should be of interest with regard to microbiology, entomology and food production. PMID- 26961697 TI - Management of Elderly Patients with Newly Diagnosed Chronic Myeloid Leukemia in the Accelerated or Blastic Phase. AB - In the elderly population, the accelerated and blastic phases of chronic myeloid leukemia (CML) are difficult to treat, not just because of the higher chance of acquired mutations than in younger individuals, but because of additional associated co-morbidities. Tyrosine kinase inhibitors are well-established in the treatment of the chronic phase of CML, and their use in advanced phases is ever increasing. Elderly patients who are still eligible candidates for transplant can undergo reduced-intensity transplants from related or unrelated donors after reverting to chronic phase. Post-transplantation, these patients require adequate monitoring and therapy to prevent relapses. Newer modalities of treatment or interventions are urgently required in this complex group of patients. PMID- 26961700 TI - Health and climate related ecosystem services provided by street trees in the urban environment. AB - Urban tree planting initiatives are being actively promoted as a planning tool to enable urban areas to adapt to and mitigate against climate change, enhance urban sustainability and improve human health and well-being. However, opportunities for creating new areas of green space within cities are often limited and tree planting initiatives may be constrained to kerbside locations. At this scale, the net impact of trees on human health and the local environment is less clear, and generalised approaches for evaluating their impact are not well developed.In this review, we use an urban ecosystems services framework to evaluate the direct, and locally-generated, ecosystems services and disservices provided by street trees. We focus our review on the services of major importance to human health and well being which include 'climate regulation', 'air quality regulation' and 'aesthetics and cultural services'. These are themes that are commonly used to justify new street tree or street tree retention initiatives. We argue that current scientific understanding of the impact of street trees on human health and the urban environment has been limited by predominantly regional-scale reductionist approaches which consider vegetation generally and/or single out individual services or impacts without considering the wider synergistic impacts of street trees on urban ecosystems. This can lead planners and policymakers towards decision making based on single parameter optimisation strategies which may be problematic when a single intervention offers different outcomes and has multiple effects and potential trade-offs in different places.We suggest that a holistic approach is required to evaluate the services and disservices provided by street trees at different scales. We provide information to guide decision makers and planners in their attempts to evaluate the value of vegetation in their local setting. We show that by ensuring that the specific aim of the intervention, the scale of the desired biophysical effect and an awareness of a range of impacts guide the choice of i) tree species, ii) location and iii) density of tree placement, street trees can be an important tool for urban planners and designers in developing resilient and resourceful cities in an era of climatic change. PMID- 26961701 TI - Overcoming doxorubicin resistance of cancer cells by Cas9-mediated gene disruption. AB - In this study, Cas9 system was employed to down-regulate mdr1 gene for overcoming multidrug resistance of cancer cells. Disruption of the MDR1 gene was achieved by delivery of the Cas9-sgRNA plasmid or the Cas9-sgRNA ribonucleoprotein complex using a conventional gene transfection agent and protein transduction domain (PTD). Doxorubicin showed considerable cytotoxicity to the drug-resistant breast cancer cells pre-treated with the RNA-guided endonuclease (RGEN) systems, whereas virtually non-toxic to the untreated cells. The potency of drug was enhanced in the cells treated with the protein-RNA complex as well as in those treated with plasmids, suggesting that mutation of the mdr1 gene by intracellular delivery of Cas9-sgRNA complex using proper protein delivery platforms could recover the drug susceptibility. Therefore, Cas9-mediated disruption of the drug resistance related gene can be considered as a promising way to overcome multidrug resistance in cancer cells. PMID- 26961702 TI - I'm over 65, but I don't need a discounted bus fare. PMID- 26961703 TI - The Interactive Effects of Stressful Family Life Events and Cortisol Reactivity on Adolescent Externalizing and Internalizing Behaviors. AB - This study investigated the associations between stressful family life events and adolescent externalizing and internalizing behaviors, and the interactive effects of family life events and cortisol reactivity on problem behaviors. In a sample of 100 mothers and their adolescents (M age = 15.09; SD age = .98; 68 % girls), adolescent cortisol reactivity was measured in response to a mother-adolescent conflict interaction task designed to elicit a stress response. Mothers reported on measures of family life events and adolescent problem behaviors. Results indicated that a heightened adolescent cortisol response moderated the relations between stressful family life events and both externalizing and internalizing behaviors. Results support context-dependent theoretical models, suggesting that for adolescents with higher cortisol reactivity (compared to those with lower cortisol reactivity), higher levels of stressful family life events were associated with greater problem behaviors, whereas lower levels of stressful family life events were related to fewer problem behaviors. PMID- 26961705 TI - Human activity accelerating the rapid desertification of the Mu Us Sandy Lands, North China. AB - Over the past several thousand years, arid and semiarid China has experienced a series of asynchronous desertification events in its semiarid sandy and desert regions, but the precise identification of the driving forces of such events has remained elusive. In this paper we identify two rapid desertification events (RDEs) at ~4.6 +/- 0.2 ka BP and ~3.3 +/- 0.2 ka BP from the JJ Profile, located in the eastern Mu Us Sandy Lands. These RDEs appear to have occurred immediately following periods marked by persistently frequent and intense fires. We argue that such fire patterns, directly linked to an uncontrolled human use of vegetation as fuel, played a key role in accelerating RDEs by ensuring that the land surface was degraded beyond the threshold required for rapid desertification. This would suggest that the future use of a massive and sustained ecological program of vegetation rehabilitation should reduce the risk of destructive fire. PMID- 26961704 TI - A Case of Cushing's Syndrome with Multiple Adrenocortical Adenomas Composed of Compact Cells and Clear Cells. AB - A 58-year-old woman was referred to our hospital for Cushingoid features and diagnosed as adrenal Cushing's syndrome due to a right adrenocortical mass (60 * 55 mm). The mass was composed of three different tumors; the first one was homogeneously lipid-poor neoplasm measuring 20 * 13 mm located at the most dorsal region, the second one was heterogeneous and lipid-rich tumor containing multiple foci of calcification measuring 50 * 32 mm located at the central region, and the last one was heterogeneous harboring dilated and tortuous vessels and lipid-poor one measuring 35 * 18 mm at the most ventral region of the adrenal gland. A right adrenalectomy was subsequently performed by open surgery. Macroscopic and microscopic analyses revealed that all three tumors were adrenocortical adenomas; the first one represents a pigmented adrenocortical adenoma, the second one adrenocortical adenoma associated with degeneration, and the third one adrenocortical adenoma harboring extensive degeneration. Immunohistochemical analysis of the steroidogenic enzymes also revealed that all of the tumors had the capacity of synthesizing cortisol. This is a very rare case of Cushing's syndrome caused by multiple adrenocortical adenomas including a pigmented adenoma. Immunohistochemical analysis of steroidogenic enzymes contributed to understanding of steroidogenesis in each of these three different adrenocortical adenomas in this case. PMID- 26961706 TI - The Effect of Chronic Mild Stress and Imipramine on the Markers of Oxidative Stress and Antioxidant System in Rat Liver. AB - Liver abnormalities have been reported to occur in up to 20 % of patients on a long-term therapy with the tricyclic antidepressant drug imipramine (IMI). The mechanism involved in this IMI-induced process is unknown but a contribution of oxidative stress is highly likely. Chronic mild stress (CMS) is widely used for modeling depressive-like behavior in rats. In the present study, we examined the effects of CMS and chronic IMI treatment, applied alone or in combination, on the levels of oxidative stress markers, such as reactive oxygen species (ROS), malondialdehyde (MDA), non-protein sulfhydryl groups, and sulfane sulfur as well as on activities of key antioxidant enzymes: catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase in the rat liver. Administration of IMI for 5 weeks to rats subjected to CMS resulted in a gradual significant reduction of anhedonia measured by sucrose intake, in a majority of animals (CMS IMI-reactive, CMS IMI-R), although about 20 % of rats did not respond to the IMI treatment (CMS IMI non-reactive, CMS IMI-NR). CMS-induced hepatic oxidative stress, estimated by increased ROS and MDA concentrations, was not prevented by the IMI administration, moreover, in CMS IMI-NR animals, the level of the marker of lipid peroxidation, i.e., MDA was increased in comparison to CMS-subjected rats and activity of antioxidant enzymes (GPx and CAT) was decreased compared to IMI-treated rats. The clinical significance of this observation remains to be established. PMID- 26961707 TI - Self-perceived health in functionally independent older people: associated factors. AB - BACKGROUND: Self-perceived health (SPH) is a powerful indicator of the health status of elderly people. This issue has been widely studied in oldest populations considering altogether functionally independent and dependent individuals. The objective of this study was to describe SPH and to identify the main factors that have an impact on SPH in a sample of functionally independent community-dwelling older adults. METHODS: For this cross-sectional study, face-to face interviews were carried out with non-institutionalized functionally independent older individuals in a northern region of Spain. Participants were asked: "Overall, you would say that your health is excellent, very good, good, fair or poor?". SPH responses were grouped in two categories: good and poor. Binary logistic regression was used to identify factors associated with poor SPH. RESULTS: A sample of 634 individuals was studied, of whom 55 % were women. The mean age was 74.8 (SD 6.7) years. About 18 % of the respondents rated their health as poor. In the multivariate model adjusted for age and sex, reported poor health was significantly associated with polypharmacy (>=3 drugs per day) (OR: 5.76, 95 % CI: 3.60-9.18), the presence of sensory impairment (OR: 1.87, 95 % CI: 1.15-3.04), bad sleep quality (OR:1.82, 95 % CI: 1.02-3.28), a bad nutrition pattern (OR: 2.37, 95 % CI: 1.08-5.21), not engaging in cognitively stimulating activities (OR: 4.08, 95 % CI: 1.64-10.20), or group social activities (OR: 2.62, 95 % CI: 1.63-4.23). CONCLUSIONS: The study indicates that several health and social variables are strongly related to SPH in independent community-dwelling older adults. This finding highlights the need for thorough assessment of factors related to SPH in older independent adults, this being essential to develop health-related programmes for promoting active and healthy ageing and to delay the onset of dependence in this population. PMID- 26961708 TI - Spatial control of chemical processes on nanostructures through nano-localized water heating. AB - Optimal performance of nanophotonic devices, including sensors and solar cells, requires maximizing the interaction between light and matter. This efficiency is optimized when active moieties are localized in areas where electromagnetic (EM) fields are confined. Confinement of matter in these 'hotspots' has previously been accomplished through inefficient 'top-down' methods. Here we report a rapid 'bottom-up' approach to functionalize selective regions of plasmonic nanostructures that uses nano-localized heating of the surrounding water induced by pulsed laser irradiation. This localized heating is exploited in a chemical protection/deprotection strategy to allow selective regions of a nanostructure to be chemically modified. As an exemplar, we use the strategy to enhance the biosensing capabilities of a chiral plasmonic substrate. This novel spatially selective functionalization strategy provides new opportunities for efficient high-throughput control of chemistry on the nanoscale over macroscopic areas for device fabrication. PMID- 26961709 TI - Impact of early postoperative platelet count on volumetric liver gain and perioperative outcomes after major liver resection. AB - BACKGROUND: Although perioperative platelet count has been associated with postoperative morbidity and mortality, its impact on liver regeneration has not been examined directly. This study sought to determine the impact of platelet count on liver regeneration after major liver resection using cross-sectional imaging volumetric assessment. METHODS: Patients who underwent major liver resection between 2004 and 2015 and had available data on immediate postoperative platelet count, as well as preoperative and postoperative CT images, were identified retrospectively. Resected liver volume was subtracted from total liver volume (TLV) to define postoperative remnant liver volume (RLVp ). The liver regeneration index was defined as the relative increase in liver volume within 2 months ((RLV2m - RLVp )/RLVp , where RLV2m is the remnant liver volume around 2 months after surgery). The association between platelet count, liver regeneration and outcomes was assessed. RESULTS: A total of 99 patients met the inclusion criteria. Overall, 25 patients (25 per cent) had a low platelet count (less than 150 * 10(9) /l), whereas 74 had a normal-high platelet count (at least 150 * 10(9) /l). Despite having comparable clinicopathological characteristics and RLVp /TLV at surgery (P = 0.903), the relative increase in liver volume within 2 months was considerably lower in the low-platelet group (3.9 versus 16.5 per cent; P = 0.043). Patients with a low platelet count had an increased risk of postoperative complications (72 versus 38 per cent; P = 0.003), longer hospital stay (8 versus 6 days; P = 0.004) and worse median overall survival (24.5 versus 67.3 months; P = 0.005) than those with a normal or high platelet count. CONCLUSION: After major liver resection, a low postoperative platelet count was associated with inhibited liver regeneration, as well as worse short- and long term outcomes. Immediate postoperative platelet count may be an early indicator to identify patients at increased risk of worse outcomes. PMID- 26961710 TI - The diagnosis of death by neurological criteria in infants less than 2 months old: RCPCH guideline 2015. PMID- 26961711 TI - It Is Time for Carotid Artery Stenting to Rise from the Ashes. PMID- 26961713 TI - Enzymatic saccharification of brown seaweed for production of fermentable sugars. AB - This study shows that high drying temperatures negatively affect the enzymatic saccharification yield of the brown seaweed Saccharina latissima. The optimal drying temperature of the seaweed in terms of enzymatic sugar release was found to be 30 degrees C. The enzymatic saccharification process was optimized by investigating factors such as kinetics of sugar release, enzyme dose, solid loading and different blend ratios of cellulases and an alginate lyase. It was found that the seaweed biomass could be efficiently hydrolysed to fermentable sugars using a commercial cellulase cocktail. The inclusion of a mono-component alginate lyase was shown to improve the performance of the enzyme blend, in particular at high solid loadings. At 25% dry matter loading a combined glucose and mannitol concentration of 74g/L was achieved. PMID- 26961712 TI - Abundance and Diversity of Bacterial, Archaeal, and Fungal Communities Along an Altitudinal Gradient in Alpine Forest Soils: What Are the Driving Factors? AB - Shifts in soil microbial communities over altitudinal gradients and the driving factors are poorly studied. Their elucidation is indispensable to gain a comprehensive understanding of the response of ecosystems to global climate change. Here, we investigated soil archaeal, bacterial, and fungal communities at four Alpine forest sites representing a climosequence, over an altitudinal gradient from 545 to 2000 m above sea level (asl), regarding abundance and diversity by using qPCR and Illumina sequencing, respectively. Archaeal community was dominated by Thaumarchaeota, and no significant shifts were detected in abundance or community composition with altitude. The relative bacterial abundance increased at higher altitudes, which was related to increasing levels of soil organic matter and nutrients with altitude. Shifts in bacterial richness and diversity as well as community structure (comprised basically of Proteobacteria, Acidobacteria, Actinobacteria, and Bacteroidetes) significantly correlated with several environmental and soil chemical factors, especially soil pH. The site at the lowest altitude harbored the highest bacterial richness and diversity, although richness/diversity community properties did not show a monotonic decrease along the gradient. The relative size of fungal community also increased with altitude and its composition comprised Ascomycota, Basidiomycota, and Zygomycota. Changes in fungal richness/diversity and community structure were mainly governed by pH and C/N, respectively. The variation of the predominant bacterial and fungal classes over the altitudinal gradient was the result of the environmental and soil chemical factors prevailing at each site. PMID- 26961714 TI - Bioelectrochemical systems-driven directional ion transport enables low-energy water desalination, pollutant removal, and resource recovery. AB - Bioelectrochemical systems (BESs) are integrated water treatment technologies that generate electricity using organic matter in wastewater. In situ use of bioelectricity can direct the migration of ionic substances in a BES, thereby enabling water desalination, resource recovery, and valuable substance production. Recently, much attention has been placed on the microbial desalination cells in BESs to drive water desalination, and various configurations have optimized electricity generation and desalination performance and also coupled hydrogen production, heavy metal reduction, and other reactions. In addition, directional transport of other types of charged ions can remediate polluted groundwater, recover nutrient, and produce valuable substances. To better promote the practical application, the use of BESs as directional drivers of ionic substances requires further optimization to improve energy use efficiency and treatment efficacy. This article reviews existing researches on BES-driven directional ion transport to treat wastewater and identifies a few key factors involved in efficiency optimization. PMID- 26961715 TI - Fractionated stereotactic radiation therapy for vestibular schwannomas: Dosimetric factors predictive of hearing outcomes. AB - PURPOSE: To determine dosimetric factors predictive of hearing loss in vestibular schwannoma (VS) patients treated with definitive fractionated stereotactic radiation therapy (FSRT), and to report tumor control, serviceable hearing preservation, and cranial nerve toxicities. METHODS AND MATERIALS: We identified 45 patients (29 men and 16 women) with unilateral sporadic VS, who underwent definitive FSRT. All patients had serviceable hearing prior to treatment, defined as Gardner-Robertson Class 1 or 2. All patients underwent an audiogram before the start of treatment and serial audiometric assessments after treatment. The median audiometric follow-up time was 35.2 months (range, 5.0-89.7 months). Patients underwent a median of 4.5 (range, 1-9) posttreatment audiograms. The ipsilateral cochlea was contoured retrospectively, and dosimetric data were used to determine factors predictive of losing serviceable hearing. The median clinical follow-up time was 29.9 months (range, 1.5-83.6 months). RESULTS: At the time of the last audiometric follow-up, 62% of patients retained serviceable hearing. The actuarial 1-, 2-, and 3-year serviceable hearing preservation rates were 83%, 75%, and 51%, respectively. The estimated median time to loss of serviceable hearing was 42.2 months. On multivariate analysis, cochlear volume <0.15 mL (hazard ratio, 2.849; 95% confidence interval, 1.116-7.270; P = .029) and mean cochlear dose <4000 cGy (hazard ratio, 3.178; 95% confidence interval, 1.116 9.049; P = .030) were statistically significant variables associated with serviceable hearing preservation. The actuarial tumor control was 100%. Three of 39 patients (8%) developed hemifacial spasm after FSRT (House-Brackmann Grade 3), 2 of which completely resolved. No patients experienced deterioration in trigeminal nerve function after FSRT. CONCLUSIONS: Fractionated stereotactic radiation therapy can provide excellent tumor control with acceptable clinical outcomes. The mean dose to the cochlea is highly predictive of the probability of maintaining serviceable hearing after FSRT. PMID- 26961716 TI - Bladder dose-volume parameters are associated with urinary incontinence after postoperative intensity modulated radiation therapy for prostate cancer. AB - PURPOSE: Urinary incontinence is a potential side effect of prostatectomy and intensity modulated radiation therapy (IMRT) for prostate cancer. There are limited data on dosimetric parameters that may predict for poor continence recovery in men who receive postoperative IMRT. METHODS AND MATERIALS: Eighty seven men with nonmetastatic prostate cancer who underwent prostatectomy followed by adjuvant (13%) or salvage (87%) IMRT were identified. The Expanded Prostate Cancer Index composite questionnaire was prospectively collected at baseline, 6 weeks, and 6, 12, 18, 24, 36, and 48 months post-IMRT. Relevant critical structures were contoured and dose-volume metrics collected. The primary endpoint was urinary continence global score. Longitudinal analysis using a generalized estimating equation model was performed. RESULTS: There was no statistically significant change in Expanded Prostate Cancer Index composite urinary continence global scores over time as compared with baseline (all P > .05). In univariate analysis, bladder volume receiving 70 Gy (V70 Gy) and penile bulb V70 Gy were associated with urinary continence (odds ratio, 0.82; P < .05). In a multivariable model that included body mass index, distance between vesicourethral junction and genitourinary diaphragm, time from surgery, use of antihypertensive medications, age, diabetes, and bladder V70 Gy, only bladder V70 Gy (odds ratio, 0.82; P = .03) was associated with outcome. After 2 years, there was a significant difference in global score for those with V70 Gy < 42.27 versus >=42.27 mL (all P < .05 at 2 and 3 years post-IMRT). CONCLUSION: There was no significant change in patient-reported urinary continence scores after postprostatectomy IMRT. Bladder V70 Gy was independently associated with a decrease in urinary continence scores. Further evaluation is necessary to optimize quality of life in these men. PMID- 26961718 TI - Hymenobacter marinus sp. nov., isolated from coastal seawater. AB - A Gram-stain-negative and non-motile bacterial strain that formed straight rods and reddish colonies, designated KJ035T, was isolated from seawater from the East Sea, Republic of Korea. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain KJ035T belonged to the genus Hymenobacter. The most closely related species were Hymenobacter metalli A2-91T (96.8 % 16S rRNA gene sequence similarity), Hymenobacter flocculans A2-50AT (96.7 %) and Hymenobacter ginsengisoli DCY57T (96.0 %). The major fatty acids were iso-C15:0, anteiso C15:0, C16:1omega5c and summed feature 3 (comprising C16:1omega6c and/or C16:1omega7c). The major isoprenoid quinone and polyamine were menaquinone 7 (MK 7) and homospermidine, respectively. The major polar lipids were phosphatidylethanolamine, three unidentified aminophospholipids, three unidentified aminolipids, one unidentified phospholipid and five unidentified polar lipids. The DNA G+C content of the genomic DNA was 61.0 mol%. The results of physiological and biochemical tests allowed the discrimination of the new isolate from its phylogenetic relatives. Strain KJ035T is thus considered to be a representative of a novel species of the genus Hymenobacter, for which the name Hymenobacter marinus sp. nov. is proposed. The type strain is KJ035T (=KCTC 42854T=CECT 9069T). PMID- 26961719 TI - Memorial - Professor Samuel Sideman. PMID- 26961717 TI - TXNIP/TRX/NF-kappaB and MAPK/NF-kappaB pathways involved in the cardiotoxicity induced by Venenum Bufonis in rats. AB - Venenum Bufonis (VB) is a widely used traditional medicine with serious cardiotoxic effects. The inflammatory response has been studied to clarify the mechanism of the cardiotoxicity induced by VB for the first time. In the present study, Sprague Dawley (SD) rats, were administered VB (100, 200, and 400 mg/kg) intragastrically, experienced disturbed ECGs (lowered heart rate and elevated ST segment), increased levels of serum indicators (creatine kinase (CK), creatine kinase isoenzyme-MB (CK-MB), alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and serum interleukin (IL-6, IL-1beta, TNF-alpha) at 2 h, 4 h, 6 h, 8 h, 24 h, and 48 h, which reflected that an inflammatory response, together with cardiotoxicity, were involved in VB-treated rats. In addition, the elevated serum level of MDA and the down-regulated SOD, CAT, GSH, and GPx levels indicated the appearance of oxidative stress in the VB-treated group. Furthermore, based on the enhanced expression levels of TXNIP, p-NF-kappaBp65, p IkappaBalpha, p-IKKalpha, p-IKKbeta, p-ERK, p-JNK, and p-P38 and the obvious myocardial degeneration, it is proposed that VB-induced cardiotoxicity may promote an inflammatory response through the TXNIP/TRX/NF-kappaB and MAPK/NF kappaB pathways. The observed inflammatory mechanism induced by VB may provide a theoretical reference for the toxic effects and clinical application of VB. PMID- 26961721 TI - IMPORTANCE OF MULTIPLE CRITERIA FOR PRIORITY SETTING OF HIV/AIDS INTERVENTIONS. AB - OBJECTIVES: This study describes the views of various stakeholders on the importance of different criteria for priority setting of HIV/AIDS interventions in Indonesia. METHODS: Based on a general list of criteria and a focus group discussion with stakeholders (n = 6), a list was developed of thirty-two criteria that play a role in priority setting in HIV/AIDS control in West-Java province. Criteria were categorized according to the World Health Organization's health system goals and building block frameworks. People living with HIV/AIDS (n = 49), healthcare workers (HCW) (n = 41), the general population (n = 43), and policy makers (n = 22) rated the importance of thirty-two criteria on a 5-point Likert scale. Thereafter, respondents ranked the highest rated criteria to express more detailed preferences. RESULTS: Stakeholders valued the following criteria as most important for the priority setting of HIV/AIDS interventions: an intervention's impact on the HIV/AIDS epidemic, reduction of stigma, quality of care, effectiveness on individual level, and feasibility in terms of current capacity of the health system (i.e., HCW, product, information, and service requirements), financial sustainability, and acceptance by donors. Overall, stakeholders' preferences for the importance of criteria are similar. CONCLUSIONS: Our study design outlines an approach for other settings to identify which criteria are important for priority setting of health interventions. For Indonesia, these study results may be used in priority setting processes for HIV/AIDS control and may contribute to more transparent and systematic allocation of resources. PMID- 26961720 TI - A Dual-Function Transcription Factor, AtYY1, Is a Novel Negative Regulator of the Arabidopsis ABA Response Network. AB - Abscisic acid (ABA) plays crucial roles in plant growth and development, as well as in response to various environmental stresses. To date, many regulatory genes involved in the ABA response network have been identified; however, their roles have remained to be fully elucidated. In this study, we identified AtYY1, an Arabidopsis homolog of the mammalian C2H2 zinc-finger transcription factor Yin Yang 1 (YY1), as a novel negative regulator of the ABA response. AtYY1 is a dual function transcription factor with both repression and activation domains. The expression of AtYY1 was induced by ABA and stress conditions including high salt and dehydration. The yy1 mutant was more sensitive to ABA and NaCl than the wild type, while overexpressing AtYY1 plants were less sensitive. AtYY1 loss also enhanced ABA-induced stomatal closing and drought resistance. Moreover, AtYY1 can bind the ABA REPRESSOR1 (ABR1) promoter and directly upregulate ABR1 expression, as well as negatively regulate ABA- and salt-responsive gene expression. Additional analysis indicated that ABA INSENSITIVE4 (ABI4) might positively regulate AtYY1 expression and that ABR1 can antagonize this regulation. Our findings provide direct evidence that AtYY1 is a novel negative regulator of the ABA response network and that the ABI4-AtYY1-ABR1 regulatory pathway may fine tune ABA-responsive gene expression in Arabidopsis. PMID- 26961722 TI - REVIEWING TRANSFERABILITY IN ECONOMIC EVALUATIONS ORIGINATING FROM EASTERN EUROPE. AB - OBJECTIVES: The aim of this study is to analyze the quality and transferability issues reported in published peer-reviewed English-language economic evaluations based in healthcare settings of the Central and Eastern European (CEE) and former Soviet countries. METHODS: A systematic search of economic evaluations of healthcare interventions was performed for Armenia, Azerbaijan, Belarus, Bulgaria, Estonia, Georgia, Turkmenistan, Kazakhstan, Lithuania, the former Yugoslav Republic of Macedonia, Republic of Moldova, Romania, the Russian Federation, Serbia, Slovenia, and Ukraine. The included studies were assessed according to their characteristics, quality (using Drummond's checklist), use of local data, and the transferability of inputs and results, if addressed. RESULTS: Most of the thirty-four economic evaluations identified were conducted from a healthcare or payer perspective (74 percent), with 47 percent of studies focusing on infectious diseases. The least frequently and transparently addressed parameters were the items' stated perspectives, relevant costs included, accurately measured costs in appropriate units, outcomes and costs credibly valued, and uncertainties addressed. Local data were often used to assess unit costs, baseline risk, and resource usage, while jurisdiction-specific utilities were included in only one study. Only 32 percent of relevant studies discussed the limitations of using foreign data, and 36 percent of studies discussed the transferability of their own study results to other jurisdictions. CONCLUSIONS: Transferability of the results is not sufficiently discussed in published economic evaluations. To simplify the transferability of studies to other jurisdictions, the following should be comprehensively addressed: uncertainty, impact of influential parameters, and data transferability. The transparency of reporting should be improved. PMID- 26961723 TI - Conformal Invariance of Graphene Sheets. AB - Suspended graphene sheets exhibit correlated random deformations that can be studied under the framework of rough surfaces with a Hurst (roughness) exponent 0.72 +/- 0.01. Here, we show that, independent of the temperature, the iso-height lines at the percolation threshold have a well-defined fractal dimension and are conformally invariant, sharing the same statistical properties as Schramm-Loewner evolution (SLEkappa) curves with kappa = 2.24 +/- 0.07. Interestingly, iso-height lines of other rough surfaces are not necessarily conformally invariant even if they have the same Hurst exponent, e.g. random Gaussian surfaces. We have found that the distribution of the modulus of the Fourier coefficients plays an important role on this property. Our results not only introduce a new universality class and place the study of suspended graphene membranes within the theory of critical phenomena, but also provide hints on the long-standing question about the origin of conformal invariance in iso-height lines of rough surfaces. PMID- 26961725 TI - A novel photo-responsive europium(III) complex for advanced anti-counterfeiting and encryption. AB - A novel europium(iii) complex simultaneously exhibiting photocolorimetric and photofluorometric behavior was obtained. Multiple distinguishable identities can be obtained and reversibly modulated using light as external stimuli. With this novel photo-responsive complex, double encryption and advanced anti counterfeiting were realized. PMID- 26961724 TI - Antioxidant Lignans and Neolignans from Acorus tatarinowii. AB - Eleven new lignans and neolignans, named acortatarinowins G-N (1-8), including three pairs of enantiomers (1a/1b-3a/3b) and five optically pure lignans and neolignans (4-8), along with five known analogs (9-14), were isolated from the rhizomes of Acorus tatarinowii Schott. Compounds 1-3 were successfully separated by chiral HPLC to afford 1a/1b-3a/3b. The planar structures of 1-8 were elucidated by extensive spectroscopic analyses including HRESIMS and NMR. Their absolute configurations were determined by analyses of single-crystal X-ray diffraction and a modified Mosher's method, assisted by experimental and calculated electronic circular dichroism (ECD) data. Compounds 1a and 1b were rare 7,8'-epoxy-8,7'-oxyneolignane. Compounds 1-8 were evaluated for their antioxidant activities using 2,2-diphenyl-1-picrylhydrazyl (DPPH) reducing antioxidant power assay. Compound 6, exhibiting strong DPPH radical scavenging capacity with IC50 value of 16.4 +/- 0.22 MUg/mL, could interpret the herbal traditional usage. PMID- 26961726 TI - Investigations of in vitro bioaccessibility from interesterified stearic and oleic acid-rich blends. AB - Interesterification was previously found to impact stearic acid absorption in a randomized cross-over study, when human volunteers consumed a 70 : 30 wt% high oleic sunflower and canola stearin blend (NIE) compared to the same blend which had undergone either chemical (CIE) or enzymatic (EIE) interesterification. In this research, in vitro lipid digestion, bioaccessibility, and changes in undigested lipid composition and melting behavior of these same test fats were investigated using the dynamic, multi-compartmental TIM-1 digestion model and compared with the previous human study. Overall, TIM-1 bioaccessibility was higher with interesterification (p < 0.05). Oleic acid bioaccessibility was higher than stearic acid bioaccessibility for NIE, and vice versa for the interesterified blends (p < 0.05). Stearic acid was more concentrated in the undigested triacylglycerols (TAG) from NIE, corresponding to a relatively higher melting temperature of the undigested lipids. The results confirm the impact of TAG composition, fatty acid position and/or physical properties on lipid digestion. TIM-1 bioaccessibility was linearly correlated (R(2) = 0.8640) with postprandial serum TAG concentration in the human study. Therefore, the in vitro digestion model offered predictive insights related to the impacts of lipid interesterificaton on absorption. PMID- 26961727 TI - Acromegaly-induced cardiomyopathy with dobutamine-induced outflow tract obstruction. AB - A 50-year-old man with a history of acromegaly was referred for preoperative cardiac evaluation preceding trans-sphenoidal resection of a pituitary macroadenoma. Dobutamine stress echocardiography was negative for myocardial ischaemia. Resting left ventricular (LV) LV ejection fraction (LVEF) was 64% and there was hypertrophy of ventricular septum (18 mm) without resting LV outflow tract obstruction. With 40 ug/kg/min of dobutamine, the LVEF became hyperdynamic at 80%, and there was a maximal instantaneous LV outflow tract gradient of 77 mm Hg. There was no delayed myocardial enhancement on cardiac MRI and the pattern of hypertrophy was concentric. Acromegaly-induced cardiomyopathy can mimic hypertrophic cardiomyopathy in the setting of dobutamine provocation. Because cardiomyopathy is an important cause of mortality in acromegaly, diagnosis and appropriate management are critical to improve survival. PMID- 26961728 TI - Inferior wall STEMI presenting with a ruptured intraseptal pseudoaneurysm. PMID- 26961729 TI - "Floating shoulder" injuries. AB - "Floating shoulder" is a rare injury complex resulting from high-energy blunt force trauma to the shoulder, resulting in scapulothoracic dissociation. It is commonly associated with catastrophic neurovascular injury. Two cases of motorcyclists with floating shoulder injuries are described. PMID- 26961736 TI - Corrigendum: X-ray Scatter Imaging of Hepatocellular Carcinoma in a Mouse Model Using Nanoparticle Contrast Agents. PMID- 26961734 TI - Correspondence: SEMA4A variation and risk of colorectal cancer. PMID- 26961735 TI - The lady with the dragon tattoo. AB - BACKGROUND: Though the skin is affected in sarcoidosis in about one-third of cases, granulomatous tattoo reactions are an unusual manifestation of the disease. It is important phenomenon to recognize, as it frequently leads to the diagnosis of systemic sarcoidosis. CASE PRESENTATION: A 35-year-old Caucasian female with multiple tattoos presented with a 5-week history of tenderness of the black dye in a tattoo depicting a dragon. She also described a 15-month history of fatigue, polyarthralgia, and mild dyspnea. Skin biopsy demonstrated multiple dermal non-caseating granulomata with associated tattoo ink. Further investigation revealed the presence of systemic sarcoidosis. Her symptoms and skin changes improved with conservative management. CONCLUSION: Sarcoidal tattoo reactions in those without systemic sarcoidosis are a rare occurrence, and their presence should prompt a search for systemic involvement. The accurate identification of skin involvement in sarcoidosis is important, as it tends to occur early in the course of disease, and the skin is a readily accessible site for biopsy, allowing for prompt diagnosis. PMID- 26961737 TI - Hepatocellular Carcinoma Post Embolotherapy: Imaging Appearances and Pitfalls on Computed Tomography and Magnetic Resonance Imaging. AB - Embolotherapies used in the treatment of hepatocellular carcinoma (HCC) include bland embolization, conventional transarterial chemoembolization (cTACE) using ethiodol as a carrier, TACE with drug-eluting beads and super absorbent polymer microspheres (DEB-TACE), and selective internal radiation therapy (SIRT). Successfully treated HCC lesions undergo coagulation necrosis, and appear as nonenhancing hypoattenuating or hypointense lesions in the embolized region on computed tomography (CT) and magnetic resonance. Residual or recurrent tumours demonstrate arterial enhancement with portal venous phase wash-out of contrast, features characteristic of HCC, in and/or around the embolized area. Certain imaging features that result from the procedure itself may limit assessment of response. In conventional TACE, the high-attenuating retained ethiodized oil may obscure arterially-enhancing tumours and limit detection of residual tumours; thus a noncontrast CT on follow-up imaging is important post-cTACE. Hyperenhancement within or around the treated zone can be seen after cTACE, DEB TACE, or SIRT due to physiologic inflammatory response and may mimic residual tumour. Recognition of these pitfalls is important in the evaluation embolotherapy response. PMID- 26961738 TI - Current treatment approaches and trials in central sleep apnea. AB - Central sleep apnea (CSA) is one of the most common comorbidities in patients with heart failure with reduced ejection fraction and is associated with negative consequences. Despite several recent advances, there are currently no widely accepted therapies for CSA. In this review we will discuss available therapies for CSA and review the published trials addressing treatment of CSA in HFrEF patients. PMID- 26961739 TI - Relationship between central sleep apnea and Cheyne-Stokes Respiration. AB - Central sleep apnea (CSA) in patients with heart failure (HF) occurs frequently and shows a serious influence on prognosis in this population. The key elements in the pathophysiology of CSA are respiratory instability with chronic hyperventilation, changes of arterial carbon dioxide pressure (pCO2) and elongated circulation time. The main manifestation of CSA in patients with HF is Cheyne-Stokes Respiration (CSR). The initial treatment is the optimization of HF therapy. However, many other options of the therapeutic management have been studied, particularly those based on positive airway pressure methods. In patients with heart failure we often can observe the overlap of CSA and CSR; we will discuss the differences between these forms of breathing disorders during sleep. We will also discuss when CSA and CSR occur independently of each other and the importance of CSR occurring during the daytime in context of CSA during the nighttime. PMID- 26961740 TI - Left coronary cusp cryoablation guided by electroanatomic mapping for outflow ventricular arrhythmias. PMID- 26961741 TI - Exercise-based pre-habilitation is feasible and effective in radical cystectomy pathways-secondary results from a randomized controlled trial. AB - BACKGROUND: Physical exercises offer a variety of health benefits to cancer survivors during and post-treatment. However, exercise-based pre-habilitation is not well reported in major uro-oncology surgery. The aim of this study was to investigate the feasibility, the adherence, and the efficacy of a short-term physical pre-habilitation program to patients with invasive bladder cancer awaiting radical cystectomy (RC). METHODS: A parent prospective randomized controlled clinical trial investigated efficacy of a multidisciplinary rehabilitation program on length of stay following RC. A total of 107 patients were included in the intension-to-treat population revealing 50 patients in the intervention group and 57 patients in the standard group. Pre-operatively, the intervention group was instructed to a standardized exercise program consisting of both muscle strength exercises and endurance training. The number of training sessions and exercise repetitions was patient-reported. Feasibility was expressed as adherence to the program and efficacy as the differences in muscle power within and between treatment groups at time for surgery. RESULTS: A total of 66 % (95 % confidence interval (CI) 51; 78) adhered more than 75 % of the recommended progressive standardized exercise program. In the intervention group, a significant improvement in muscle power of 18 % (p < 0.002) was found at time for surgery. Moreover, muscle power was significantly improved compared to that in the standard group with 0.3 W/kg (95 % CI 0.08; 0.5 %) (p < 0.006). Adherence was not associated with pre-operative BMI, nutritional risk, comorbidity, pain, gender, or age. CONCLUSION: In patients awaiting RC, a short-term exercise-based pre-habilitation intervention is feasible and effective and should be considered in future survivorship strategies. PMID- 26961742 TI - Protein Structural Analysis of Calbindin D28k Function and Dysregulation: Potential Competition Between Ca(2+) and Zn(2.). AB - Calcium homeostasis is an essential physiological process requiring tight control in the normal cell. The dysregulation of calcium homeostasis may play a key role in the onset of Alzheimer's disease (AD) and other disorders, whether through the loss of calcium binding or calcium sensing capacity. Calbindin D28k (CB-D28k), a calcium binding protein composed of six EF-hands, four of which can bind Ca(2+), has been implicated in AD-related calcium dysregulation. In this study, docking and molecular dynamics calculations were employed to refine the protein data base model in order to understand the underlying structural variations between functional and non-functional EF-hands. Molecular modeling calculations improved the modelled protein structure: helix-loop-helix sequences were formed in all hands and most canonical interactions were formed in the four functional hands. The protein can also bind Zn(2+), potentially altering the Ca(2+) binding capability. Analysis of calculated structures of Zn(2+) bound protein showed that only half of the correct EF-hand canonical interactions of Ca(2+) were formed with loop residues. These results have important implications for the understanding of calcium dysregulation as well as for the development of novel therapeutic strategies in AD and other central nervous system disease processes, or in conditions of brain injury where calcium homeostasis is compromised. PMID- 26961743 TI - Distress, misperceptions, poor coping and suicidal ideation in psoriatic arthritis: a qualitative study. AB - OBJECTIVE: PsA is associated with significant distress and can be life-ruining. Reducing distress can improve quality of life and disease outcomes. Quality of life measures broadly identify the extent to which PsA impacts on people's lives but do not enable clinicians to address PsA-specific distress in the setting of the clinic. The aim of this study was to explore people's illness beliefs, emotions and behaviours that relate to living with PsA and account for the distress experienced by those living with this condition. METHODS: Semi structured individual interviews were conducted in the UK with adults with PsA. Interview questions were theoretically informed by the Common-Sense Self Regulation Model (CS-SRM). Two stages of data analysis, in line with thematic and framework analysis principles, involved coding pre-determined CS-SRM components and identifying any additional emergent themes. Constant comparison techniques allowed for patterns across CS-SRM components to emerge inductively from the data. RESULTS: Twenty-four people with PsA participated (54% male; aged 27-71; time since onset ranged between 4 months and 29 years). Four core themes comprising clusters of illness beliefs, emotions and related behaviours emerged accounting for patient distress: restrictions, role of others, resentment and resignation. Suicidal ideation in the sample was commonly expressed and patients feared exponential degeneration of their condition. Patients reported the condition being dismissed or belittled by others and therefore hiding their distress from people around them. CONCLUSION: People with PsA experience significant disease-related distress, including suicidal ideation. Misperceptions, ineffective coping styles (e.g. avoidance/blocking) and negative emotions should be actively identified and addressed with people with PsA. PMID- 26961745 TI - Using the common sense model of illness to examine interrelationships between symptom severity and health outcomes in end-stage osteoarthritis patients. AB - OBJECTIVE: The aim was to evaluate the utility of the common sense model (CSM) in characterizing contributors to psychological well-being and quality of life (QoL) in patients with end-stage OA. METHODS: One hundred and twenty patients [34 males, 86 females; mean (s.d.) age 65.52 (9.14) years] with end-stage OA (57.5% hip, 42.5% knee) were recruited. OA symptom severity was evaluated according to the WOMAC; coping styles were assessed with the Carver Brief COPE scale; illness perceptions were explored with the Brief Illness Perceptions Questionnaire; self efficacy was assessed with the Arthritis Self-efficacy scale; anxiety, depression and overall distress were measured using the Hospital Anxiety and Depression Scale; and QoL was assessed using the WHO Quality of Life-short version. The CSM was used to explore the interrelationships between OA symptom severity, illness perceptions and coping strategies in patients. RESULTS: Two structural equation models were developed, with both found to have good fit. Consistent with the CSM, the standard model indicated that self-reported OA symptom severity directly influenced illness perceptions, which in turn had direct impacts upon maladaptive coping, distress and QoL. The addition of self-efficacy to the CSM resulted in a complex interaction, with OA severity directly influencing self-efficacy and self efficacy influencing maladaptive coping, distress and QoL. CONCLUSION: We found interrelationships amongst OA activity, illness perceptions, coping strategies, self-efficacy, psychological distress and QoL broadly consistent with the CSM. The CSM may help inform the approach to the psychological support that patients with end-stage OA often require. PMID- 26961744 TI - Autoantibodies to human citrullinated fibrinogen and their subfamilies to the alpha36-50Cit and beta60-74Cit fibrin peptides similarly predict radiographic damages: a prospective study in the French ESPOIR cohort of very early arthritides. AB - OBJECTIVE: To investigate whether subfamilies of the RA-specific autoantibodies to human citrullinated fibrinogen (AhFibA) differentially associate with the RA risk factors, HLA-DRB1 shared epitope containing alleles (SE alleles) and cigarette smoking, and thus help to predict the disease outcome. METHODS: AhFibA and their anti-alpha36-50Cit and anti-beta60-74Cit subfamilies were assayed by ELISA, at baseline, in the French ESPOIR (Etude et Suivi des Polyarthrites Indifferenciees Recentes) cohort composed of undifferentiated arthritides and RA patients of < 6 months' duration. Cigarette smoking, SE alleles' presence, DAS28, HAQ and modified Sharp-van der Heijde Score data were obtained at baseline, and after follow-up. RESULTS: After 3 years, 701 patients were classified as having RA according to the ACR/EULAR 2010 criteria. Among them, 349 (50%), 203 (29%) and 257 (37%) were AhFibA-, anti-alpha36-50Cit- and anti-beta60-74Cit-positive, respectively. The presence and titres of AhFibA and their subfamilies similarly associated with SE alleles, irrespective of their fine specificity, without significant effect of smoking. Neither their presence nor their titre was associated with DAS28 or HAQ. The presence of at least one subfamily was associated with a faster Sharp/van der Heijde score progression, albeit without correlation with the titre. CONCLUSION: AhFibA and their main subfamilies are similarly associated with SE alleles without additional effect of smoking. Whatever their fine specificity was, their presence (but not their titre) similarly constituted a marker of faster joint destruction. PMID- 26961747 TI - Landfill site selection using combination of GIS and fuzzy AHP, a case study: Iranshahr, Iran. AB - One of the most important recent challenges in solid waste management throughout the world is site selection of sanitary landfill. Commonly, because of simultaneous effects of social, environmental, and technical parameters on suitability of a landfill site, landfill site selection is a complex process and depends on several criteria and regulations. This study develops a multi-criteria decision analysis (MCDA) process, which combines geographic information system (GIS) analysis with a fuzzy analytical hierarchy process (FAHP), to determine suitable sites for landfill construction in Iranshahr County, Iran. The GIS was used to calculate and classify selected criteria and FAHP was used to assess the criteria weights based on their effectiveness on selection of potential landfill sites. Finally, a suitability map was prepared by overlay analyses and suitable areas were identified. Four suitability classes within the study area were separated, including high, medium, low, and very low suitability areas, which represented 18%, 15%, 55%, and 12% of the study area, respectively. PMID- 26961746 TI - Have radiographic progression rates in early rheumatoid arthritis changed? A systematic review and meta-analysis of long-term cohorts. AB - OBJECTIVE: To evaluate, firstly, all published data on baseline and annual progression rates of radiographic damage from all longitudinal observational cohorts, and secondly, the association of standard clinical and laboratory parameters with long-term radiographic joint damage. METHODS: A comprehensive search of the literature from 1975 to 2014, using PubMed, SCOPUS and Cochrane databases, identified a total of 28 studies that investigated long-term radiographic progression, and 41 studies investigating predictors of long-term radiographic progression. This was submitted and approved by PROSPERO in February 2014 (Registration Number: CRD42014007589). RESULTS: Meta-analysis indicated an overall baseline rate of 2.02%, and a yearly increase of 1.08% of maximum damage. Stratified analysis found that baseline radiographic scores did not differ significantly between cohorts recruiting patients pre- and post-1990 (2.01% vs 2.03%; P > 0.01); however, the annual rate of progression was significantly reduced in the post-1990 cohorts (0.68% vs 1.50%; P < 0.05). High levels of acute phase markers, baseline radiographic damage, anti-CCP and RF positivity remain consistently predictive of long-term radiographic joint damage. CONCLUSION: Critical changes in treatment practices over the last three decades are likely to explain the reduction in the long-term progression of structural joint damage. Acute phase markers and presence of RF/anti-CCP are strongly associated with increased radiographic progression. PMID- 26961749 TI - Multistable internal resonance in electroelastic crystals with nonlinearly coupled modes. AB - Nonlinear modal interactions have recently become the focus of intense research in micro- and nanoscale resonators for their use to improve oscillator performance and probe the frontiers of fundamental physics. However, our understanding of modal coupling is largely restricted to clamped-clamped beams, and lacking in systems with both geometric and material nonlinearities. Here we report multistable energy transfer between internally resonant modes of an electroelastic crystal plate and use a mixed analytical-numerical approach to provide new insight into these complex interactions. Our results reveal a rich bifurcation structure marked by nested regions of multistability. Even the simple case of two coupled modes generates a host of topologically distinct dynamics over the parameter space, ranging from the usual Duffing bistability to complex multistable behaviour and quasiperiodic motion. PMID- 26961750 TI - Efficient Conversion of Inulin to Inulooligosaccharides through Endoinulinase from Aspergillus niger. AB - Inulooligosaccharides (IOS) represent an important class of oligosaccharides at industrial scale. An efficient conversion of inulin to IOS through endoinulinase from Aspergillus niger is presented. A 1482 bp codon optimized gene fragment encoding endoinulinase from A. niger DSM 2466 was cloned into pPIC9K vector and was transformed into Pichia pastoris KM71. Maximum activity of the recombinant endoinulinase, 858 U/mL, was obtained at 120 h of the high cell density fermentation process. The optimal conditions for inulin hydrolysis using the recombinant endoinulinase were investigated. IOS were harvested with a high concentration of 365.1 g/L and high yield up to 91.3%. IOS with different degrees of polymerization (DP, mainly DP 3-6) were distributed in the final reaction products. PMID- 26961751 TI - Construction of Quaternary Stereogenic Carbon Centers through Copper-Catalyzed Enantioselective Allylic Alkylation of Azoles. AB - Copper-catalyzed enantioselective allylic alkylation of azoles with gamma,gamma disubstituted primary allylic phosphates was achieved using a new chiral N heterocyclic carbene ligand bearing a naphtholic hydroxy group. This reaction occurred with excellent branch regioselectivity and high enantioselectivity, thus forming a controlled all-carbon quaternary stereogenic center at the position alpha to the heteroaromatic ring. PMID- 26961752 TI - The Pharmacokinetics of Pregabalin in Breast Milk, Plasma, and Urine of Healthy Postpartum Women. AB - BACKGROUND: Limited data exist on the presence of pregabalin in human breast milk of nursing mothers. OBJECTIVES: This study aimed to determine pregabalin concentrations in breast milk, estimate the infant daily pregabalin dose from nursing mothers, and evaluate pregabalin pharmacokinetic data in lactating women (>= 12 weeks postpartum). METHODS: In this multiple-dose, open-label, pharmacokinetic study, 4 doses of pregabalin 150 mg were administered orally at 12-hour intervals. Urine, blood, and breast milk samples were collected up to 12, 24, and 48 hours, respectively, following the fourth dose. Pharmacokinetic parameters were estimated using noncompartmental methods. Adverse events were monitored throughout. RESULTS: Ten healthy lactating women (age 24-37 years) received pregabalin. Geometric mean pregabalin Cmaxss and AUCtau values in breast milk were approximately 53% and 76%, respectively, of those for plasma. The mean amount of pregabalin in breast milk recovered in a 24-hour period after the last dose was 574 MUg (range, 270-1720 MUg), which is approximately 0.2% of the administered daily maternal dose of 300 mg. The estimated average daily infant dose of pregabalin from breast milk was 0.31 mg/kg/day, which would be approximately 7% (23% coefficient of variation) of the body weight normalized maternal dose. Approximately 89% of the dose administered was recovered in urine. Renal clearance averaged 68.2 mL/min. Adverse events were of mild or moderate severity. CONCLUSION: Lactation appears to have had little influence on pregabalin pharmacokinetics. Overall, the estimated dose of pregabalin in breastfed children of women receiving pregabalin is low. Pregabalin was well tolerated in lactating women. DECLARATION OF CONFLICTING INTERESTS: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Peter A. Lockwood, Lynne Pauer, Joseph M. Scavone, Maud Allard, Laure Mendes da Costa, Tanja Alebic Kolbah, Anna Plotka, Christine W. Alvey, and Marci L. Chew were all full-time employees of Pfizer at the time the study was completed and hold stock and/or stock options in Pfizer. FUNDING: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Pfizer, which was involved in the study design, the collection, analysis, and interpretation of the data, the writing of the report, and the decision to submit the paper for publication. Medical writing support was provided by Penny Gorringe, MSc, of Engage Scientific Solutions and funded by Pfizer. PMID- 26961753 TI - Vernal Keratoconjunctivitis in Kashmir: A temperate zone. AB - The objective of this study was to observe the clinical features of patients with vernal keratoconjunctivitis attending the Outpatient Department of a mobile eye unit, Directorate of Health Services, Jammu and Kashmir over a period of 1 year. The greater prevalence of VKC is seen in the regions with hot, humid climate, and higher load of airborne allergens. The clinical profile of this disease seems to have geographical variation. The study was conducted in the mobile eye unit, Directorate of Health Services, Kashmir, a comparatively cooler area. All the patients with vernal keratoconjunctivitis who presented to the OPD during this period were examined. The diagnosis of vernal keratoconjunctivitis was based on typical history, clinical features, and examination. All the patients with the complaints of itching, watering, and photophobia were examined. After proper history, clinical features, and ocular examination under slit lamp, the data were recorded for patients who were diagnosed with vernal keratoconjunctivitis. Of all the patients who had allergic ocular disorders, a total of 212 patients were diagnosed as cases with vernal keratoconjunctivitis. This is a non-interventional study, and the ethical clearance was obtained from the regulatory board of the hospital. The study abides by the tenets laid down in the declaration of Helsinki. During this 1-year period, 212 vernal keratoconjunctivitis patients were examined, of whom 155 (73 %) were males and 57 (27 %) were females. As per the age group, 40 % (85) of patients were in the age group of 11-15 years. 93 % (197) of patients had bilateral disease, and 7 % (15) had unilateral. It was seen that 75 % (159) had seasonal attack. Different types of disease were observed: 77 % (163) had bulbar disease, 7 % (15) had palpebral, and 16 % (34) had mixed disease. During this period, we noticed that VKC led to complications also. It was seen that 3 % (6) of patients had steroid induced glaucoma, 5 % (11) had developed cataract, 6 % (13) of patients had keratoconus, and 6 % (13) of patients had corneal scarring. Other complications were also seen. VKC is a bilateral disease. Males are affected more than females. Ocular complications were seen in around 30 % of patients. Visual impairment ranging from severe visual impairment to blindness was observed in 2 % of patients. VKC patients should be instructed to use medication under the supervision of an ophthalmologist. There is a need to assess disease severity in order to develop standardized guidelines based on the stage of vernal keratoconjunctivitis. PMID- 26961748 TI - Efficient and biologically relevant consensus strategy for Parkinson's disease gene prioritization. AB - BACKGROUND: The systemic information enclosed in microarray data encodes relevant clues to overcome the poorly understood combination of genetic and environmental factors in Parkinson's disease (PD), which represents the major obstacle to understand its pathogenesis and to develop disease-modifying therapeutics. While several gene prioritization approaches have been proposed, none dominate over the rest. Instead, hybrid approaches seem to outperform individual approaches. METHODS: A consensus strategy is proposed for PD related gene prioritization from mRNA microarray data based on the combination of three independent prioritization approaches: Limma, machine learning, and weighted gene co-expression networks. RESULTS: The consensus strategy outperformed the individual approaches in terms of statistical significance, overall enrichment and early recognition ability. In addition to a significant biological relevance, the set of 50 genes prioritized exhibited an excellent early recognition ability (6 of the top 10 genes are directly associated with PD). 40 % of the prioritized genes were previously associated with PD including well-known PD related genes such as SLC18A2, TH or DRD2. Eight genes (CCNH, DLK1, PCDH8, SLIT1, DLD, PBX1, INSM1, and BMI1) were found to be significantly associated to biological process affected in PD, representing potentially novel PD biomarkers or therapeutic targets. Additionally, several metrics of standard use in chemoinformatics are proposed to evaluate the early recognition ability of gene prioritization tools. CONCLUSIONS: The proposed consensus strategy represents an efficient and biologically relevant approach for gene prioritization tasks providing a valuable decision-making tool for the study of PD pathogenesis and the development of disease-modifying PD therapeutics. PMID- 26961754 TI - Stability of colloidal dispersions in the presence of protein fibrils. AB - We studied the stability of monodispersed polystyrene latex dispersions with protein fibrils at different concentrations at pH 2 using microscopy and diffusing wave spectroscopy. At low fibril concentrations, fibrils induced bridging flocculation due to the opposite charges between fibrils and the latex particles. At higher fibril concentration the dispersions were stabilized due to steric and/or electrostatic repulsion. Upon further increasing fibril concentration, we find that the dispersion is destabilized again by depletion interaction. At even higher fibril concentration, the dispersions are stabilized again. These dispersions have a higher stability compared to the dispersions without fibrils. Interestingly, these dispersions contain single particles and small clusters of particles that do not grow beyond a certain size. Although the stabilization mechanism is not clear yet, the results from microscopy and diffusing wave spectroscopy point in the direction of a kinetic barrier that depends on fibril concentration. PMID- 26961755 TI - Interactions between Bacteria And Aspen Defense Chemicals at the Phyllosphere - Herbivore Interface. AB - Plant- and insect-associated microorganisms encounter a diversity of allelochemicals, and require mechanisms for contending with these often deleterious and broadly-acting compounds. Trembling aspen, Populus tremuloides, contains two principal groups of defenses, phenolic glycosides (salicinoids) and condensed tannins, which differentially affect the folivorous gypsy moth, Lymantria dispar, and its gut symbionts. The bacteria genus Acinetobacter is frequently associated with both aspen foliage and gypsy moth consuming that tissue, and one isolate, Acinetobacter sp. R7-1, previously has been shown to metabolize phenolic glycosides. In this study, we aimed to characterize further interactions between this Acinetobacter isolate and aspen secondary metabolites. We assessed bacterial carbon utilization and growth in response to different concentrations of phenolic glycosides and condensed tannins. We also tested if enzyme inhibitors reduce bacterial growth and catabolism of phenolic glycosides. Acinetobacter sp. R7-1 utilized condensed tannins but not phenolic glycosides or glucose as carbon sources. Growth in nutrient-rich medium was increased by condensed tannins, but reduced by phenolic glycosides. Addition of the P450 enzyme inhibitor piperonyl butoxide increased the effects of phenolic glycosides on Acinetobacter sp. R7-1. In contrast, the esterase inhibitor S,S,S,-tributyl phosphorotrithioate did not affect phenolic glycoside inhibition of bacterial growth. Degradation of phenolic glycosides by Acinetobacter sp. R7-1 appears to alleviate the cytotoxicity of these compounds, rather than provide an energy source. Our results further suggest this bacterium utilizes additional, complementary mechanisms to degrade antimicrobial phytochemicals. Collectively, these results provide insight into mechanisms by which microorganisms contend with their environment within the context of plant-herbivore interactions. PMID- 26961756 TI - Glucosinolate Desulfation by the Phloem-Feeding Insect Bemisia tabaci. AB - Glucosinolates are plant secondary defense metabolites confined nearly exclusively to the order Brassicales. Upon tissue rupture, glucosinolates are hydrolyzed to various bioactive breakdown products by the endogenous plant enzyme myrosinase. As the feeding of chewing insect herbivores is associated with plant tissue damage, these insects have developed several independent strategies for coping with the glucosinolate-myrosinase defense system. On the other hand, our knowledge of how phloem-feeding insects interact with the glucosinolate myrosinase system is much more limited. In fact, phloem feeders might avoid contact with myrosinase altogether so their susceptibility to intoxication by glucosinolate hydrolysis products is unclear. Previous studies utilizing Arabidopsis thaliana plants accumulating high levels of aliphatic- or indolic glucosinolates indicated that both glucosinolate groups have moderate negative effects on the reproductive performance of Bemisia tabaci, a generalist phloem feeding insect. To get a deeper understanding of the interaction between B. tabaci and glucosinolate-defended plants, adults were allowed to feed on artificial diet containing intact glucosinolates or on Brussels sprout and A. thaliana plants, and their honeydew was analyzed for the presence of possible metabolites. We found that B. tabaci is capable of cleaving off the sulfate group of intact glucosinolates, producing desulfoglucosinolates that cannot be activated by myrosinases, a mechanism described to date only in several chewing insect herbivores. The presence of desulfated glucosinolates in the honeydew of a generalist phloem-feeder may indicate the necessity to detoxify glucosinolates, likely due to some level of cellular damage during feeding, which results in glucosinolate activation, or as a mechanism to circumvent the non-enzymatic breakdown of indolic glucosinolates. PMID- 26961757 TI - Management of Epidermal Growth Factor Receptor Inhibitor-Induced Hypomagnesemia: A Systematic Review. AB - BACKGROUND: Despite occurring in 30% of patients, there are no evidence-based guidelines on the management of epidermal growth factor receptor inhibitor (EGFRI)-induced hypomagnesemia. Based on expert opinion, severe hypomagnesemia should be treated by intravenous magnesium replacement. A systematic review of published data of intervention on EGFRI-induced hypomagnesemia was performed. METHODS: Articles from 1960 to March 2015 were identified from Medline, Embase, Cochrane Central Register of Controlled Trials, and PubMed using a peer-reviewed systematic search strategy. Eligible studies included randomized controlled trials or observational studies that evaluated management of hypomagnesemia in adult patients treated with EGFRIs. Risk factors for severe hypomagnesemia were also assessed. The quality of included studies was rated using Jadad scores. RESULTS: A total of 1327 references were identified, and 6 studies, involving 486 patients, met inclusion criteria for analysis. There were no randomized controlled trials, and all included studies were of poor quality. From the studies included in this review, severity of EGFRI-induced hypomagnesemia was associated with length of EGFRI treatment, concomitant platinum chemotherapy, increasing age, and baseline magnesium concentration. In most patients with grade 3 or 4 hypomagnesemia, high-dose intravenous magnesium replacement did not achieve sustainable magnesium repletion beyond 72 hours. Oral magnesium supplementation was not effective or tolerable. Severe hypomagnesemia has been associated with tachycardia and mental alteration. After discontinuation of EGFRI therapy, hypomagnesemia generally resolves within weeks to months. CONCLUSIONS: There is an absence of high-quality evidence for the management of EGFRI-induced hypomagnesemia. As hypomagnesemia is often refractory to frequent intravenous or oral replacement, there is a need for prospective trials of new interventions for this common toxicity. PMID- 26961759 TI - Perceived feasibility of a primary care intervention for Tobacco Cessation on Prescription targeting disadvantaged groups in Sweden: a qualitative study. AB - BACKGROUND: There is a lack of scientific evidence on how socioeconomically disadvantaged tobacco users can be reached with tobacco cessation interventions in Swedish primary healthcare (PHC). In this setting other lifestyle interventions are available by prescription, and there is the potential to develop a similar tool for tobacco cessation. The aim of this study was thus to explore the perceived feasibility and optimal design of Tobacco Cessation on Prescription (TCP) in PHC, targeting disadvantaged groups in Sweden. METHODS: This qualitative study is based on semi-structured interviews with 32 participants including (1) three experts in lifestyle interventions on prescription, (2) 14 healthcare providers and (3) 15 clients from three PHC centres in socioeconomically disadvantaged areas in Stockholm where tobacco use is high. The interviews were audio-recorded and transcribed verbatim. The manifest content of the transcripts was analysed according to a modified conventional approach to content analysis. RESULTS: The interviewees proposed that TCP should include a template comprising the client's information, evidence based tobacco cessation options and choices for follow-up. They also suggested including information about the benefits of tobacco cessation, as well as empowerment and planning support tools. The participants also commented that other measures for tobacco cessation could be included on the prescription. From the clients' point of view, the perceived advantages of TCP were often linked to an emotional meaning (e.g. increased motivation to quit tobacco use, sign of support from the healthcare system to seek care for tobacco cessation). For providers, advantages with TCP were frequently related to a practical meaning (e.g. improved documentation and facilitation of tobacco cessation treatment). The disadvantages identified were mainly connected with the future implementation of TCP (e.g. low self-efficacy among clients and providers). CONCLUSIONS: TCP was perceived to be a useful tool for both clients and providers, potentially facilitating a structured and effective approach to tobacco cessation in PHC, and targeting disadvantaged groups. More research is needed to develop the prescription and investigate its effectiveness and cost-effectiveness compared to current strategies for tobacco cessation in a PHC setting. PMID- 26961761 TI - Endostapling Can Constrain a Hyperangulated Neck and Successfully Treat a Proximal Type I Endoleak After EVAR. PMID- 26961760 TI - Globalization and Health: developing the journal to advance the field. AB - Founded in 2005, Globalization and Health was the first open access global health journal. The journal has since expanded the field, and its influence, with the number of downloaded papers rising 17-fold, to over 4 million. Its ground breaking papers, leading authors -including a Nobel Prize winner- and an impact factor of 2.25 place it among the top global health journals in the world. To mark the ten years since the journal's founding, we, members of the current editorial board, undertook a review of the journal's progress over the last decade. Through the application of an inductive thematic analysis, we systematically identified themes of research published in the journal from 2005 to 2014. We identify key areas the journal has promoted and consider these in the context of an existing framework, identify current gaps in global health research and highlight areas we, as a journal, would like to see strengthened. PMID- 26961762 TI - Mid- and Longer-term Follow up of Chimney and/or Periscope Grafts and Risk Factors for Failure. AB - OBJECTIVE: The aim was to report on chimney and periscope grafts (CPGs) and their mid- and longer-term outcomes when they are used to preserve reno-visceral artery (RVA) perfusion in endovascular repair of pararenal (PRAAs) or thoraco-abdominal aortic aneurysm (TAAAs). In addition, factors associated with CPG failure are presented. Limited data exist on the outcomes of CPGs, and mid- and long-term results are generally not reported. METHODS: This was a prospective study in a cohort of 100 patients with PRAA (69) or TAAA (31). A total of 224 (mean 2.24 per patient) RVAs were preserved with 136 (61%) chimney and 88 (39%) periscope grafts. CPGs were constructed mainly using self expandable stent grafts. Patients were followed by clinical examination, CTA (82%), and/or duplex (18%). Data were collected until February 2015. RESULTS: CPG immediate technical success was 99% (222/224 branches). Mean follow up was 29 months (range 0-65; SD 17); 59% patients were followed > 2 years, 30% > 3 years, and 16% > 4 years. Post operatively, CPG occlusion was observed early (<=30 days) in three (1.3%) branches and during follow up in 10 (4.5%). At 36 and 48 months, the estimated primary patency was 93% and 93%. After corrective percutaneous (10) or surgical (3) re-interventions, the estimated secondary patency was 96% and 96%. Thirty day mortality was 2%; at 36 and 48 months the estimated patient survival was 79%. Significant shrinkage (72 [SD 23] vs. 62 [SD 24] mm; p < .001) was observed, with a substantial reduction (>5 mm) in 55 patients, and sac enlargement in four. Incomplete aneurysm sac sealing was treated successfully by a secondary intervention in 15 patients. CONCLUSIONS: Self expandable CPGs have proved to be a highly successful and durable treatment for RVA preservation up to 5 years. Incomplete CPG expansion, inadequate length, and CPG use in small and diseased target arteries were risk factors for occlusion. These mid- and longer-term results support CPG use to treat PRAAs or TAAAs in patients unfit for open surgery or fenestrated/branched stent grafts. PMID- 26961763 TI - Audit and Feedback Processes Among Antimicrobial Stewardship Programs: A Survey of the Society for Healthcare Epidemiology of America Research Network. AB - Optimal implementation of audit-and-feedback is an important part of advancing antimicrobial stewardship programs. Our survey demonstrated variability in how 61 programs approach audit-and-feedback. The median (interquartile range) number of recommendations per week was 9 (5-19) per 100 hospital-beds. A major perceived barrier to more comprehensive stewardship was lack of resources. Infect Control Hosp Epidemiol 2016;37:704-706. PMID- 26961764 TI - Validation of a track repeating algorithm for intensity modulated proton therapy: clinical cases study. AB - Monte Carlo (MC) methods are acknowledged as the most accurate technique to calculate dose distributions. However, due its lengthy calculation times, they are difficult to utilize in the clinic or for large retrospective studies. Track repeating algorithms, based on MC-generated particle track data in water, accelerate dose calculations substantially, while essentially preserving the accuracy of MC. In this study, we present the validation of an efficient dose calculation algorithm for intensity modulated proton therapy, the fast dose calculator (FDC), based on a track-repeating technique. We validated the FDC algorithm for 23 patients, which included 7 brain, 6 head-and-neck, 5 lung, 1 spine, 1 pelvis and 3 prostate cases. For validation, we compared FDC-generated dose distributions with those from a full-fledged Monte Carlo based on GEANT4 (G4). We compared dose-volume-histograms, 3D-gamma-indices and analyzed a series of dosimetric indices. More than 99% of the voxels in the voxelized phantoms describing the patients have a gamma-index smaller than unity for the 2%/2 mm criteria. In addition the difference relative to the prescribed dose between the dosimetric indices calculated with FDC and G4 is less than 1%. FDC reduces the calculation times from 5 ms per proton to around 5 MUs. PMID- 26961766 TI - Becoming ex-obese: narrations about identity changes before and after the experience of the bariatric surgery. AB - AIMS AND OBJECTIVES: This exploratory research investigates obese patients' beliefs and expectations before and one year after bariatric surgery. Changes and resistance to change in the identity system, in the perception of the body, in relationships and in the quality of life were of particular interest. BACKGROUND: Although bariatric surgery represents a promising treatment for obesity, nevertheless, it is still under utilised. This may be because, either the intervention is not always easily accessible or because very little is known about its psychological implications. DESIGN: Open answers provided by participants were analysed through discourse analysis. METHODS: A semi-structured interview about the exchanges in self-representations through time was administered to 30 Italian women, 15 of whom were obese before surgery and 15 were ex-obese, one year after surgery. RESULTS: The research shows that those participants who have already been operated on are generally satisfied with the results obtained; however, they faced considerable difficulties in adapting their identity to their new body. Participants reported that even one year after surgery they still thought, behaved and related to others as though they were still obese, and only after a change in awareness did they become able to realise they are now ex-obese. CONCLUSIONS: This paper contributes to the understanding of the unrealistic expectations of patients before surgery compared with the real changes in their lives, as well the difficulties they still faced one year later. More studies in evaluating how bariatric patients live with this long-term condition are recommended to foster patient-centered care. RELEVANCE TO CLINICAL PRACTICE: Health professionals should also help people to face the difficulties of the postsurgery period, which are linked to the acceptance of the new body and of the new emerging self-image in relationships with others. PMID- 26961765 TI - Sleep duration and risk of obesity among a sample of Victorian school children. AB - BACKGROUND: Insufficient sleep is potentially an important modifiable risk factor for obesity and poor physical activity and sedentary behaviours among children. However, inconsistencies across studies highlight the need for more objective measures. This paper examines the relationship between sleep duration and objectively measured physical activity, sedentary time and weight status, among a sample of Victorian Primary School children. METHODS: A sub-sample of 298 grades four (n = 157) and six (n = 132) Victorian primary school children (aged 9.2-13.2 years) with complete accelerometry and anthropometry data, from 39 schools, were taken from a pilot study of a larger state based cluster randomized control trial in 2013. Data comprised: researcher measured height and weight; accelerometry derived physical activity and sedentary time; and self-reported sleep duration and hypothesised confounding factors (e.g. age, gender and environmental factors). RESULTS: Compared with sufficient sleepers (67 %), those with insufficient sleep (<10 hrs/day) were significantly more likely to be overweight (OR 1.97, 95 % CI:1.11-3.48) or obese (OR 2.43, 95 % CI:1.26-4.71). No association between sleep and objectively measured physical activity levels or sedentary time was found. CONCLUSION: The strong positive relationship between weight status and sleep deprivation merits further research though PA and sedentary time do not seem to be involved in the relationship. Strategies to improve sleep duration may help obesity prevention initiatives in the future. PMID- 26961767 TI - [Guidelines desirable for treatment of carbon monoxide poisoning]. PMID- 26961768 TI - [Structure follows Process follows Strategy]. PMID- 26961769 TI - Fluorescent boronate-based polymer nanoparticles with reactive oxygen species (ROS)-triggered cargo release for drug-delivery applications. AB - A new drug-delivery system of polymer nanoparticles (NPs) bearing pinacol-type boronic ester and alkyne moieties displaying triggered self-immolative polymer degradation in the presence of reactive oxygen species (ROS) with the capability of cellular imaging is presented. The NPs specifically release their drug cargo under concentrations of ROS that are commonly found in the intracellular environment of certain tumors and of inflamed tissues and exhibit significant cytotoxicity to cancer cells compared to their non-ROS-responsive counterparts. PMID- 26961770 TI - A study on calcium oxalate crystals in Tinantia anomala (Commelinaceae) with special reference to ultrastructural changes during anther development. AB - Calcium oxalate (CaOx) crystals in higher plants occur in five forms: raphides, styloids, prisms, druses, and crystal sand. CaOx crystals are formed in almost all tissues in intravacuolar crystal chambers. However, the mechanism of crystallization and the role of CaOx crystals have not been clearly explained. The aim of this study was to explore the occurrence and location of CaOx crystals in organs of Tinantia anomala (Torr.) C.B. Clarke (Commelinaceae) with special attention to ultrastructural changes in the quantity of tapetal raphides during microsporogenesis. We observed various parts of the plant, that is, stems, leaves, sepals, petals, anthers, staminal trichomes and stigmatic papillae and identified CaOx crystals in all parts except staminal trichomes and stigmatic papillae in Tinantia anomala. Three morphological forms: styloids, raphides and prisms were found in different amounts in different parts of the plant. Furthermore, in this species, we identified tapetal raphides in anthers. The number of tapetal raphides changed during microsporogenesis. At the beginning of meiosis, the biosynthesis of raphides proceeded intensively in the provacuoles. These organelles were formed from the endoplasmic reticulum system. In the tetrad stage, we observed vacuoles with needle-shaped raphides (type I) always localised in the centre of the organelle. When the amoeboid tapetum was degenerating, vacuoles also began to fade. We observed a small number of raphides in the stage of mature pollen grains. PMID- 26961771 TI - Long-term results of hypofractionated stereotactic radiotherapy with CyberKnife for growth hormone-secreting pituitary adenoma: evaluation by the Cortina consensus. AB - The aim of the present study was to evaluate the safety and feasibility of hypofractionated stereotactic radiotherapy (SRT) with CyberKnife for growth hormone-secreting pituitary adenoma (GH-PA). Fifty-two patients with GH-PA were treated with hypofractionated SRT between September 2001 and October 2012. Eight patients had clinically silent GH-PA and 44 were symptomatic. Only 1 patient was inoperable. The other patients had recurrent or postoperative residual tumors on MRI. All patients had received pharmacotherapy prior to SRT with a somatostatin analog, dopamine agonist, and/or GH receptor antagonist. The marginal doses were 17.4-26.8 Gy for the 3-fraction schedule and 20.0-32.0 Gy for the 5-fraction schedule. Endocrinological remission was assessed by the Cortina consensus criteria 2010 (random GH <1 ng/ml or nadir GH after an oral glucose tolerance test <0.4 ng/ml and normalization of age- and sex-adjusted insulin-like growth factor-1). The median follow-up period was 60 months (range 27-137). The 5-year overall survival, local control, and disease-free survival rates were 100, 100, and 96 %, respectively. Nine patients (5 clinically silent and 4 symptomatic patients) satisfied the Cortina criteria without receiving further pharmacotherapy, whereas the remaining 43 patients did not. No post-SRT grade 2 or higher visual disorder occurred. Symptomatic post-SRT hypopituitarism was observed in 1 patient. CyberKnife hypofractionated SRT is safe and effective when judged by imaging findings for GH-PA. However, it may be difficult to satisfy the Cortina consensus criteria in most symptomatic patients with SRT alone. Further investigations of optimal treatments are warranted. PMID- 26961774 TI - Consequential considerations when mapping tRNA fragments. AB - We examine several of the choices that went into the design of tDRmapper, a recently reported tool for identifying transfer RNA (tRNA) fragments in deep sequencing data, evaluate them in the context of currently available knowledge, and discuss their potential impact on the output that the tool generates. PMID- 26961772 TI - The brain tissue response to surgical injury and its possible contribution to glioma recurrence. AB - Surgery is the first line therapy for glioma. However, glioma recurs in 90 % of the patients in the resection margin. The impact of surgical brain injury (SBI) on glioma recurrence is largely overlooked. Herein, we review some of the mechanisms involved in tissue repair that may impact glioma recurrence at the resection margin. Many processes or molecules involved in tissue repair after brain injury are also critical for glioma growth. They include a wide array of secreted growth factors, cytokines and transcription factors including NFKB and STAT3 which in turn activate proliferative and anti-apoptotic genes and processes such as angiogenesis and inflammation. Because some residual glioma cells always remain in the tumor resection margin, there are now compelling arguments to suggest that some aspects of the brain tissue response to SBI can also participate to glioma recurrence at the resection margin. Brain tissue response to SBI recruits angiogenesis and inflammation that precede and then follow tumor recurrence at the resection margin. The healing response to SBI is double edged, as inflammation is involved in regeneration and healing, and has both pro- and anti-tumorigenic functions. A promising therapeutic approach is to normalize and re-educate the molecular and cellular responses at the resection margin to promote anti-tumorigenic processes involved in healing while inhibiting pro tumorigenic activities. Manipulation of the inflammatory response to SBI to prevent local recurrence could also enhance the efficacy of other therapies such as immunotherapy. However, our current knowledge is far from sufficient to achieve this goal. Acknowledging, understanding and manipulating the double-edged role played by SBI in glioma recurrence is surely challenging, but it cannot be longer delayed. PMID- 26961773 TI - Tumor DNA in cerebral spinal fluid reflects clinical course in a patient with melanoma leptomeningeal brain metastases. AB - Cerebral spinal fluid (CSF) from brain tumor patients contains tumor cellular and cell-free DNA (cfDNA), which provides a less-invasive and routinely accessible method to obtain tumor genomic information. In this report, we used droplet digital PCR to test mutant tumor DNA in CSF of a patient to monitor the treatment response of metastatic melanoma leptomeningeal disease (LMD). The primary melanoma was known to have a BRAF (V600E) mutation, and the patient was treated with whole brain radiotherapy and BRAF inhibitors. We collected 9 CSF samples over 6 months. The mutant cfDNA fraction gradually decreased from 53 % (time of diagnosis) to 0 (time of symptom alleviation) over the first 6 time points. Three months after clinical improvement, the patient returned with severe symptoms and the mutant cfDNA was again detected in CSF at high levels. The mutant DNA fraction corresponded well with the patient's clinical response. We used whole exome sequencing to examine the mutation profiles of the LMD tumor DNA in CSF before therapeutic response and after disease relapse, and discovered a canonical cancer mutation PTEN (R130*) at both time points. The cellular and cfDNA revealed similar mutation profiles, suggesting cfDNA is representative of LMD cells. This study demonstrates the potential of using cellular or cfDNA in CSF to monitor treatment response for LMD. PMID- 26961775 TI - Comparison of two- and six-minute walk tests in detecting oxygen desaturation in patients with severe chronic obstructive pulmonary disease - A randomized crossover trial. AB - The two-minute walk test (2MWT) is less well validated than the well-known six minute walk test (6MWT) as a field walking test in patients with chronic obstructive pulmonary disease (COPD). The primary objective of this study was to compare the accuracy of the 2MWT to the 6MWT in detecting exercise-induced oxygen desaturation in patients with severe COPD. Twenty-six patients with COPD (age: 61 +/- 10 years, forced expired volume in one second: 37 +/- 10%) that were normoxemic at rest performed a 2MWT and a 6MWT under normal ambient conditions on two consecutive days in random order. Oxygen saturation, total walking distance, heart rate, breathing frequency, dyspnea, and leg fatigue were evaluated. Average walking distances were 150 m (95% confidence interval (95% CI): 134-165 m) and 397 m (95% CI: 347-447 m) for the 2MWT and 6MWT, respectively (r = 0.80, p < 0.0001). The difference in minimum oxygen saturation during the 2MWT (83%, 95% CI: 81-86%) and 6MWT (mean 82%, 95% CI: 80-84%) was not statistically different and the data strongly correlated between the groups (r = 0.81, p < 0.0001). Other measurements from the 6MWT, including heart rate, breathing rate, and levels of perceived exertion were also comparable in 2MWT. The 2MWT showed comparable validity in detecting exercise-induced oxygen desaturation in patients with severe COPD compared to the 6MWT. PMID- 26961776 TI - A study on the effect of the internal exposure to (210)Po on the excretion of urinary proteins in rats. AB - This study was designed to assess the feasibility of a noninvasive urine specimen for the detection of proteins as indicators of internal exposure to ionizing radiation. Three groups of rats (five in each group) were intravenously injected with 1601 +/- 376, 10,846 +/- 591 and 48,467 +/- 2812 Bq of (210)Po in citrate form. A sham-exposed control group of five rats was intravenously injected with sterile physiological saline. Daily urine samples were collected over 4 days following injection. Purification and pre-concentration of urinary proteins were carried out by ultrafiltration using a 3000 Da molecular weight cutoff membrane filter. The concentration of common urinary proteins, namely albumin, alpha-1 acid glycoprotein, immunoglobulins IgA and IgG, was measured by an enzyme-linked immunosorbent assay. Urinary excretion of albumin decreased dose-dependently (p < 0.05) 96 h post-injection relative to the control group. In contrast, no statistically significant effects were observed for other proteins tested. The dose-dependent decrease in urinary excretion of albumin observed in this study underscores the need for further research, which may lead to the discovery of new biomarkers that would reflect the changes in the primary target organs for deposition of (210)Po. PMID- 26961777 TI - Diversity of gene cassettes and the abundance of the class 1 integron-integrase gene in sediment polluted by metals. AB - The integron-gene cassette system has typically been associated with antibiotic resistant pathogens. However, the diversity of gene cassettes and the abundance of class 1 integrons outside of the clinical context are not fully explored. Primers targeting the conserved segments of attC recombination sites were used to amplify gene cassettes from the sediment of the Mina stream, which exhibited a higher degree of stress to metal pollution in the dry season than the rainy season. Of the 143 total analyzed sequences, 101 had no matches to proteins in the database, where cassette open reading frames could be identified by homology with database entries. There was a predominance of sequences encoding essential cellular functions. Each season that was sampled yielded a specific pool of gene cassettes. Real-time PCR revealed that 8.5 and 41.6 % of bacterial cells potentially harbored a class 1 integron in the rainy and dry seasons, respectively. In summary, our findings demonstrate that most of the gene cassettes have no ascribable function and, apparently, historically metal contaminated sediment favors the maintenance of bacteria containing the intI1 gene. Thus, the diversity of gene cassettes is far from being fully explored deserving further attention. PMID- 26961778 TI - Examining the Path Taken and the Road Ahead. AB - Much has changed in the world of addictions and mental health in the last decade. As we reflect on the changes to legislation and public attitudes of recovery, we must focus on what matters to continue the momentum to improve outcomes for people with mental illness and addictions into the next 10 years. PMID- 26961779 TI - Discretely Integrated Condition Event (DICE) Simulation for Pharmacoeconomics. AB - Several decision-analytic modeling techniques are in use for pharmacoeconomic analyses. Discretely integrated condition event (DICE) simulation is proposed as a unifying approach that has been deliberately designed to meet the modeling requirements in a straightforward transparent way, without forcing assumptions (e.g., only one transition per cycle) or unnecessary complexity. At the core of DICE are conditions that represent aspects that persist over time. They have levels that can change and many may coexist. Events reflect instantaneous occurrences that may modify some conditions or the timing of other events. The conditions are discretely integrated with events by updating their levels at those times. Profiles of determinant values allow for differences among patients in the predictors of the disease course. Any number of valuations (e.g., utility, cost, willingness-to-pay) of conditions and events can be applied concurrently in a single run. A DICE model is conveniently specified in a series of tables that follow a consistent format and the simulation can be implemented fully in MS Excel, facilitating review and validation. DICE incorporates both state transition (Markov) models and non-resource-constrained discrete event simulation in a single formulation; it can be executed as a cohort or a microsimulation; and deterministically or stochastically. PMID- 26961781 TI - "Hospital was the Only Option": Experiences of Frequent Emergency Department Users in Mental Health. AB - The experiences of individuals with mental illness and addictions who frequently present to hospital emergency departments (EDs) have rarely been explored. This study reports findings from self-reported, quantitative surveys (n = 166) and in depth, qualitative interviews (n = 20) with frequent ED users with mental health and/or substance use challenges in a large urban centre. Participants presented to hospital for mental health (35 %), alcohol/drug use (21 %), and physical health (39 %) concerns and described their ED visits as unavoidable and appropriate, despite feeling stigmatized by hospital personnel and being discharged without expected treatment. Supporting this population may require alternative service models and attention to staff training in both acute and community settings. PMID- 26961780 TI - Urbanization and health in China, thinking at the national, local and individual levels. AB - BACKGROUND: China has the biggest population in the world, and has been experiencing the largest migration in history, and its rapid urbanization has profound and lasting impacts on local and national public health. Under these conditions, a systems understanding on the correlation among urbanization, environmental change and public health and to devise solutions at national, local and individual levels are in urgent need. METHODS: In this paper, we provide a comprehensive review of recent studies which have examined the relationship between urbanization, urban environmental changes and human health in China. Based on the review, coupled with a systems understanding, we summarize the challenges and opportunities for promoting the health and wellbeing of the whole nation at national, local, and individual levels. RESULTS: Urbanization and urban expansion result in urban environmental changes, as well as residents' lifestyle change, which can lead independently and synergistically to human health problems. China has undergone an epidemiological transition, shifting from infectious to chronic diseases in a much shorter time frame than many other countries. Environmental risk factors, particularly air and water pollution, are a major contributing source of morbidity and mortality in China. Furthermore, aging population, food support system, and disparity of public service between the migrant worker and local residents are important contributions to China's urban health. CONCLUSIONS: At the national level, the central government could improve current environmental policies, food safety laws, and make adjustments to the health care system and to demographic policy. At the local level, local government could incorporate healthy life considerations in urban planning procedures, make improvements to the local food supply, and enforce environmental monitoring and management. At the individual level, urban residents can be exposed to education regarding health behaviour choices while being encouraged to take responsibility for their health and to participate in environmental monitoring and management. PMID- 26961782 TI - Human malignant mesothelioma is recapitulated in immunocompetent BALB/c mice injected with murine AB cells. AB - Malignant Mesothelioma is a highly aggressive cancer, which is difficult to diagnose and treat. Here we describe the molecular, cellular and morphological characterization of a syngeneic system consisting of murine AB1, AB12 and AB22 mesothelioma cells injected in immunocompetent BALB/c mice, which allows the study of the interplay of tumor cells with the immune system. Murine mesothelioma cells, like human ones, respond to exogenous High Mobility Group Box 1 protein, a Damage-Associated Molecular Pattern that acts as a chemoattractant for leukocytes and as a proinflammatory mediator. The tumors derived from AB cells are morphologically and histologically similar to human MM tumors, and respond to treatments used for MM patients. Our system largely recapitulates human mesothelioma, and we advocate its use for the study of MM development and treatment. PMID- 26961783 TI - Conditioned context aversion learning in the laboratory mouse. AB - It is well known that pairing of large contextual changes with illness can cause conditioned context aversion in laboratory rats. The aim of present study was to develop a paradigm to study this phenomenon in laboratory mice, a species widely employed in neurobehavioral studies. Genetically heterogeneous mice, drinking from plastic bottles in the colony room, learned to avoid glass bottles after a single conditioning trial when drinking from these was paired with injections of lithium chloride. The aversion was independent of any difference in the taste of water in plastic vs. glass bottles. When the variation in the visual stimulus was less distinct, development of a strong aversion required two conditioning trials and was not retained as well. The results also showed that conditioned context aversion, just like conditioned taste aversion, could also be developed across a 30-minute CS-UCS delay. The fact that taste was not a factor in distinguishing drinking from glass and plastic water bottles raises the possibility that, contextual stimuli, not taste, may have been the CS when rats (in Garcia's original experiments) avoided drinking from plastic bottles that had been paired with radiation. The development of contextual aversion conditioning protocols for mice will enable the molecular resources available for this species to be exploited. Furthermore, representation of the CS by discrete rather than the multimodal CSs typically used in most studies on contextual conditioning offers more focus when considering its neuroanatomical basis. PMID- 26961786 TI - Tough to Swallow: Esophageal Food Impaction from Esophageal Amyloidosis. PMID- 26961785 TI - New fossil insect order Permopsocida elucidates major radiation and evolution of suction feeding in hemimetabolous insects (Hexapoda: Acercaria). AB - With nearly 100,000 species, the Acercaria (lice, plant lices, thrips, bugs) including number of economically important species is one of the most successful insect lineages. However, its phylogeny and evolution of mouthparts among other issues remain debatable. Here new methods of preparation permitted the comprehensive anatomical description of insect inclusions from mid-Cretaceous Burmese amber in astonishing detail. These "missing links" fossils, attributed to a new order Permopsocida, provide crucial evidence for reconstructing the phylogenetic relationships in the Acercaria, supporting its monophyly, and questioning the position of Psocodea as sister group of holometabolans in the most recent phylogenomic study. Permopsocida resolves as sister group of Thripida + Hemiptera and represents an evolutionary link documenting the transition from chewing to piercing mouthparts in relation to suction feeding. Identification of gut contents as angiosperm pollen documents an ecological role of Permopsocida as early pollen feeders with relatively unspecialized mouthparts. This group existed for 185 million years, but has never been diverse and was superseded by new pollenivorous pollinators during the Cretaceous co-evolution of insects and flowers. The key innovation of suction feeding with piercing mouthparts is identified as main event that triggered the huge post-Carboniferous radiation of hemipterans, and facilitated the spreading of pathogenic vectors. PMID- 26961787 TI - Radiographic Localization Study of a Novel Potassium-Competitive Acid Blocker, Vonoprazan, in the Rat Gastric Mucosa. AB - BACKGROUND: Vonoprazan fumarate (TAK-438) is a novel potassium-competitive acid blocker that appears to exert a longer/more potent antisecretory effect than lansoprazole due to high accumulation/slow clearance from the gastric glands. However, there is no direct evidence that vonoprazan selectively accumulates in gastric parietal cells of gastric glands. AIM: To investigate the distribution of radioactivity in the rat stomach after single intravenous administration of [(3)H]-labeled vonoprazan. METHODS/RESULTS: Autoradioluminography of the stomach revealed that at 5 h after administration, radioactivity levels in the corpus mucosal layer was higher than radioactivity levels in the muscular layer, pylorus, and forestomach. At 24 h, although overall radioactivity was significantly decreased, the highest radioactivity was still observed in the mucosal layer. Accumulation of radioactivity in gastric parietal cells was quantitatively analyzed using microautoradiography. The number of silver granules in parietal cells from vonoprazan-injected rats was higher than in cells from a saline-injected rat. At 24 h, the number of granules was approximately at 20 % of the number of granules at 5 h. There was no clear deposition of granules in other components. At 5 h, radioactivity was measured at 1.799 ug Eq/g in the stomach and 0.172 ug Eq/mL in plasma. After 24 h, radioactivity had decreased to 0.584 ug Eq/g in the stomach and 0.078 ug Eq/mL in plasma. CONCLUSIONS: Vonoprazan selectively accumulates in gastric parietal cells in the mucosal layer of the rat stomach after intravenous administration. PMID- 26961788 TI - A metallic mosaic phase and the origin of Mott-insulating state in 1T-TaS2. AB - Electron-electron and electron-phonon interactions are two major driving forces that stabilize various charge-ordered phases of matter. In layered compound 1T TaS2, the intricate interplay between the two generates a Mott-insulating ground state with a peculiar charge-density-wave (CDW) order. The delicate balance also makes it possible to use external perturbations to create and manipulate novel phases in this material. Here, we study a mosaic CDW phase induced by voltage pulses, and find that the new phase exhibits electronic structures entirely different from that of the original Mott ground state. The mosaic phase consists of nanometre-sized domains characterized by well-defined phase shifts of the CDW order parameter in the topmost layer, and by altered stacking relative to the layers underneath. We discover that the nature of the new phase is dictated by the stacking order, and our results shed fresh light on the origin of the Mott phase in 1T-TaS2. PMID- 26961790 TI - Adenocarcinoma of Gall Bladder Metastasis to Cervix: a Case Report with Review of Literature. PMID- 26961789 TI - A Patient with HIV-Associated Metastatic Anal Squamous Cell Carcinoma Receiving Multimodality Therapy with Curative Intent: Case Report and Review of the Literature. PMID- 26961792 TI - Stephen Bolsin: Whistleblower on the Bristol scandal. PMID- 26961791 TI - Racial and Ethnic Variability in the Prevalence and Incidence of Comorbidities Associated with Gastric Cancer in the United States. AB - PURPOSE: Comorbidities are known to impact quality of life, treatment choices, and survival. Our objectives were to characterize comorbid conditions in a cohort of elderly gastric cancer patients and to determine if there is variability in the prevalence or incidence of the comorbid conditions across racial/ethnic groups. METHODS: A total of 12,612 individuals, >=66 years of age, diagnosed with gastric cancer between 2000 and 2007, and an equal number of gender- and region matched cancer-free individuals, were identified using the National Cancer Institute's Surveillance, Epidemiology, and End Results registry linked to Medicare claims in the United States. The prevalence (%) in the year before diagnosis and the 12-month incidence rates after diagnosis were estimated for 32 chronic and ten acute comorbid conditions for the entire cohort and by race/ethnicity (Asian, Black, Hispanic, White, and other) and Asian subgroups (e.g., Chinese, Filipino, Japanese, Pacific Islander). RESULTS: White and Black cases exhibited the highest prevalence of most comorbid conditions. Asian and Pacific Islander cases exhibited the lowest. There was substantial variability in the 12-month incidence of the comorbidities across the racial/ethnic groups. Electrolyte disorder was the most common incident condition among Whites and Blacks. With the exception of Whites, anemia was the most common incident condition in all racial and ethnic groups 180 days following chemotherapy. CONCLUSIONS: There is variability in the prevalence and incidence in comorbidities across racial/ethnic groups. PMID- 26961794 TI - Methamphetamine Intoxication Encephalopathy Associated With Hyperammonemia. PMID- 26961793 TI - Salvage Treatment of Adrenocortical Carcinoma with Trofosfamide. AB - Adrenocortical carcinoma (ACC) has a dismal prognosis in advanced stages. Despite treatment with the adrenal toxicant mitotane and/or aggressive chemotherapy, tumor control is often short-lived. Here, we examine trofosfamide as a salvage treatment of ACC in an observational cohort study within the German ACC registry. Response defined as progression-free survival (PFS) at first tumor evaluation was assessed by RECIST 1.1 or clinically, and PFS and overall survival (OS) were estimated by the Kaplan-Meier method. Twenty-seven patients (11 males; median age 46.9 years) progressing after mitotane and three (median, range 0-5) other systemic treatments were evaluated for safety. Trofosfamide (150 mg/day) was administered as monotherapy (n = 13) or in combination with mitotane (n = 14). Overall tolerability was good with only mild adverse events. Six patients did not meet criteria for response assessment. Of the 21 patients, 8 patients had clinically progressive disease (3 deaths from ACC); among the 13 patients evaluable by RECIST 1.1, best response to treatment was stable disease (SD, n = 3) or progressive disease (n = 10). Hence, predefined response criteria were met in 3/21 patients (14 %). Median PFS was 84 days (95 % confidence interval 74-95) and median OS survival 198 days (95 % CI 89-307). One prolonged disease stabilization (best response by RECIST 1.1 -26 %) was observed for 479 days. In conclusion, trofosfamide is overall well tolerated but disease stabilization is rather rare. Accordingly, it may be used in selected cases of ACC not amenable to other treatment options such as clinical trials. PMID- 26961795 TI - Anti-inflammatory, analgesic and antioxidant activities of novel kyotorphin nitroxide hybrid molecules. AB - Mitochondrial oxidative damage contributes to a wide range of pathologies, including ischemia/reperfusion (I/R) injury, cardiovascular disorders and neurodegenerative diseases. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel kyotorphin-nitroxide hybrid molecules, and examined their free radical scavenging activities, in addition to their anti inflammatory and analgesic activities. We have further characterized these compounds in a simulated I/R cellular model. Our findings suggest that the protective effects of kyotorphin-nitroxides partially reside in maintaining optimal mitochondrial function. PMID- 26961796 TI - Interventional Cardiology 2015: A Selection of Topical Issues. PMID- 26961798 TI - Multiphysics simulation of the effect of leaflet thickness inhomogeneity and material anisotropy on the stress-strain distribution on the aortic valve. AB - This study developed a realistic 3D FSI computational model of the aortic valve using the fixed-grid method, which was eventually employed to investigate the effect of the leaflet thickness inhomogeneity and leaflet mechanical nonlinearity and anisotropy on the simulation results. The leaflet anisotropy and thickness inhomogeneity were found to significantly affect the valve stress-strain distribution. However, their effect on valve dynamics and fluid flow through the valve were minor. Comparison of the simulation results against in-vivo and in vitro data indicated good agreement between the computational models and experimental data. The study highlighted the importance of simulating multi physics phenomena (such as fluid flow and structural deformation), regional leaflet thickness inhomogeneity and anisotropic nonlinear mechanical properties, to accurately predict the stress-strain distribution on the natural aortic valve. PMID- 26961799 TI - Cell death induced by mechanical compression on engineered muscle results from a gradual physiological mechanism. AB - Deep tissue injury (DTI), a type of pressure ulcer, arises in the muscle layers adjacent to bony prominences due to sustained mechanical loading. DTI presents a serious problem in the clinic, as it is often not visible until reaching an advanced stage. One of the causes can be direct mechanical deformation of the muscle tissue and cell. The mechanism of cell death induced by mechanical compression was studied using bio-artificial skeletal muscle tissues. Compression was applied by placing weights on top of the constructs. The morphological changes of the cytoskeleton and the phosphorylation of mitogen-activated protein kinases (MAPK) under compression were investigated. Moreover, inhibitors for each of the three major MAPK groups, p38, ERK, and JNK, were applied separately to look at their roles in the compression caused apoptosis and necrosis. The present study for the first time showed that direct mechanical compression activates MAPK phosphorylation. Compression also leads to a gradual destruction of the cytoskeleton. The percentage apoptosis is strongly reduced by p38 and JNK inhibitors down to the level of the unloaded group. This phenomenon could be observed up to 24h after initiation of compression. Therefore, cell death in bio artificial muscle tissue caused by mechanical compression is primarily caused by a physiological mechanism, rather than through a physical mechanism which kills the cell directly. These findings reveal insight of muscle cell death under mechanical compression. Moreover, the result indicates a potential clinical solution to prevent DTI by pre-treating with p38 or/and JNK inhibitors. PMID- 26961801 TI - The Hypercoagulable state in Hyperthyroidism is mediated via the Thyroid Hormone beta Receptor pathway. AB - OBJECTIVE: Hyperthyroidism is associated with a hypercoagulable state, but the underlying mechanism is unknown. Patients with resistance to thyroid hormone (RTH) due to defective thyroid hormone receptor beta (TRbeta) exhibit elevated circulating thyroid hormones (TH) with refractoriness to TH action in TRbeta expressing tissues. We tested the hypothesis that the hypercoagulable state in hyperthyroidism is mediated via the TRbeta. DESIGN: We conducted a cross sectional study from November 2013 to January 2015 in 3 hospitals in the Netherlands and the United Kingdom. METHODS: Patients with RTH due to defective TRbeta (n=18), patients with hyperthyroidism (n=16) and euthyroid subjects (n=18) were included. TH concentrations and markers of coagulation and fibrinolysis were measured. Data are expressed as median [interquartile range]. RESULTS: Free thyroxine (FT4) levels were slightly higher in hyperthyroid patients than in RTH patients (53.9 [30.5-70.0] and 34.9 [28.4-42.2]pmol/l, respectively, P=0.042). Both groups had raised FT4 levels compared to euthyroid subjects (14.0 [13.0 15.8] pmol/l, P<=0.001). Levels of von Willebrand factor (VWF), factor (F) VIII, fibrinogen, and D-dimer were significantly higher in hyperthyroid patients than in RTH patients (VWF 231 [195-296] vs. 111 [82-140]%, FVIII 215 [192-228] vs. 145 [97-158]%, fibrinogen 3.6 [3.0-4.4] vs. 2.8 [2.5-3.2]g/L, D-dimer 0.41 [0.31 0.88] vs. 0.20 [0.17-0.26]mg/L, respectively, P<=0.001), while there were no differences between RTH patients and euthyroid controls. CONCLUSIONS: Parameters of coagulation and fibrinolysis were elevated in hyperthyroid patients compared to patients with RTH due to defective TRbeta, whereas these parameters were not different between euthyroid controls and RTH patients, despite elevated FT4 concentrations in RTH patients. This indicates that the procoagulant effects observed in hyperthyroidism are mediated via the TRbeta. PMID- 26961797 TI - Generation of a novel, multi-stage, progressive, and transplantable model of plasma cell neoplasms. AB - Multiple myeloma is a plasma cell neoplasm with an extremely variable clinical course. Animal models are needed to better understand its pathophysiology and for preclinical testing of potential therapeutic agents. Hematopoietic cells expressing the hypermorphic Rad50(s) allele show hematopoietic failure, which can be mitigated by the lack of a transcription factor, Mef/Elf4. However, we find that 70% of Mef(-/-)Rad50(s/s) mice die from multiple myeloma or other plasma cell neoplasms. These mice initially show an abnormal plasma cell proliferation and monoclonal protein production, and then develop anemia and a decreased bone mineral density. Tumor cells can be serially transplanted and according to array CGH and whole exome sequencing, the pathogenesis of plasma cell neoplasms in these mice is not linked to activation of a specific oncogene, or inactivation of a specific tumor suppressor. This model recapitulates the systemic manifestations of human plasma cell neoplasms, and implicates cooperativity between the Rad50(s) and Mef/Elf4 pathways in initiating myelomagenic mutations that promote plasma cell transformation. PMID- 26961800 TI - Posterior tympanotomy is a riskier procedure in chronic otitis media than in a normal mastoid: a high-resolution computed tomography study. AB - PURPOSE: The aim of our study was to compare the difficulty in performing a posterior tympanotomy in chronic otitis media (COM) versus the same procedure in a normal mastoid. MATERIALS AND METHODS: The study included 122 patients who underwent tympanomastoidectomy for unilateral chronic otitis media with contralateral normal mastoid pneumatization. We evaluated the anatomical relationships between the mastoid segment and neighboring structures by analyzing axial temporal bone computed tomography scans. A vertical line (line A) was drawn tangential to the most lateral end of the posterior semicircular canal (point A). Three distances were measured: the distance (D1) between the point A and the most lateral end of the mastoid segment of the facial nerve (point B), the distance (D2) between the line A and the point B, and the distance (D3) between the point B and the posterior end of the bony annulus of the external auditory canal. RESULTS: The average measurements of D1 and D3 were 3.79 +/- 0.55 and 2.63 +/- 0.51 mm, respectively, in the normal mastoid ears and 3.47 +/- 0.59 and 2.35 +/- 0.44 mm, respectively, in the COM ears. The measurements of D1 and D3 were statistically shorter in the COM ears than in the normal ears. CONCLUSIONS: These findings suggest that the facial recess in COM may be narrower than in a normal mastoid and that performing a posterior tympanotomy may be riskier in COM than in a normal mastoid due to the potential for injury to the neighboring structures and the facial nerve. PMID- 26961802 TI - Analysis of Dissolved Organic Nutrients in the Interstitial Water of Natural Biofilms. AB - In biofilms, the matrix of extracellular polymeric substances (EPSs) retains water in the interstitial region of the EPS. This interstitial water is the ambient environment for microorganisms in the biofilms. The nutrient condition in the interstitial water may affect microbial activity in the biofilms. In the present study, we measured the concentrations of dissolved organic nutrients, i.e., saccharides and proteins, contained in the interstitial water of biofilms formed on the stones. We also analyzed the molecular weight distribution, chemical species, and availability to bacteria of some saccharides in the interstitial water. Colorimetric assays showed that the concentrations of saccharides and proteins in the biofilm interstitial water were significantly higher (ca. 750 times) than those in the surrounding lake waters (p < 0.05). Chromatographic analyses demonstrated that the saccharides in the interstitial waters were mainly of low molecular-weight saccharides such as glucose and maltose, while proteins in the interstitial water were high molecular-weight proteins (over 7000 Da). Bacterial growth and production of EPS occurred simultaneously with the decrease in the low molecular-weight saccharide concentrations when a small portion of biofilm suspension was inoculated to the collected interstitial water, suggesting that the dissolved saccharides in the interstitial water support bacterial growth and formation of biofilms. PMID- 26961803 TI - PELA microspheres with encapsulated arginine-chitosan/pBMP-2 nanoparticles induce pBMP-2 controlled-release, transfected osteoblastic progenitor cells, and promoted osteogenic differentiation. AB - Repair of the bone injury remains a challenge in clinical practices. Recent progress in tissue engineering and therapeutic gene delivery systems have led to promising new strategies for successful acceleration of bone repair process. The aim of this study was to create a controlled-release system to slowly release the arginine-chitosan/plasmid DNA nanoparticles encoding BMP-2 gene (Arg-CS/pBMP-2 NPs), efficiently transfect osteoblastic progenitor cells, secrete functional BMP 2 protein, and promote osteogenic differentiation. In this study, chitosan was conjugated with arginine to generate arginine-chitosan polymer (Arg-CS) for gene delivery. Mix the Arg-CS with pBMP-2 to condense pBMP-2 into nano-sized particles. In vitro transfection assays demonstrated that the transfection efficiency of Arg-CS/pBMP-2 nanoparticles and the expression level of BMP-2 was obviously exceed control groups. Further, PELA microspheres as the controlled release carrier for the nanoparticles were used to encapsulate Arg-CS/pBMP-2 NPs. We demonstrated that the Arg-CS/pBMP-2 NPs could slowly release from the PELA microspheres at least for 42 d. During the co-culture with the PELA microspheres, the content of BMP-2 protein secreted by MC3T3-E1 reached the peak at 7 d. After 21d, the secretion of BMP-2 protein still maintain a higher level. The alkaline phosphatase activity, alizarin red staining, and osteogenesis-related gene expression by real-time quantitative PCR analysis all showed the PELA microspheres entrapping with Arg-CS/pBMP-2 NPs can obviously induce the osteogenic differentiation. The results indicated that the Arg-CS is a suitable gene vector which can promote the gene transfection. And the novel PELA microspheres-nanoparticle controlled-release system has potential clinical application in the future after further research. PMID- 26961804 TI - Material properties of mouse cervical tissue in normal gestation. AB - An appropriately timed cervical remodeling process is critical for a healthy delivery, yet little is known about the material property changes of the cervix in pregnancy because obtaining human tissue samples is difficult. Rodent models offer advantages including accurately timed pregnant tissues and genetically altered models. Determining the material properties of the mouse cervix, however, is challenging because of its small size and complex geometry. The aim of this study is to quantify cervical material property changes in a normal mouse pregnancy using a microstructurally-inspired porous fiber composite model. We mechanically test intact, whole, gestation-timed mouse cervix by pulling apart tensioned sutures through its inner canal. To interpret our mechanical testing results, we conduct an inverse finite element analysis, taking into account the combined loading state of the thick-walled cylindrical tissue. We fit the material model to previous osmotic swelling data and load-deformation data from this study using a nonlinear optimization scheme, and validate the model by predicting a separate set of deformation data. Overall, the proposed porous fiber composite model captures the mechanical behavior of the mouse cervix in large deformation. The evolution of cervical material parameters indicates that in a normal mouse pregnancy, the cervix begins to soften between day 6 and day 12 of a 19-day gestation period. The material parameter associated with the collagen fiber stiffness decreases from 3.4MPa at gestation day 6 to 9.7e-4MPa at gestation day 18, while the ground substance stiffness decreases from 2.6e-1MPa to 7.0e-4MPa. STATEMENT OF SIGNIFICANCE: Accelerated cervical remodeling can lead to extremely premature births. Little is known, however, about the material property changes of the cervix in pregnancy because pregnant human tissue samples are limited. Rodent models overcome this limitation and provide access to gestation-timed samples. Measuring the material property changes of the mouse cervix in pregnancy is challenging due to its small size and complex geometry. Here, we establish a combined experimental and modeling framework. We use this framework to determine the cervical material property changes throughout a normal mouse pregnancy. We present our experimental methods for mechanically testing whole, intact cervical tissue samples. We fit a porous fiber composite material model to the mechanical data and show that the mouse cervix begins to soften between day 6 and day 12 of a 19-day gestation period. PMID- 26961806 TI - Development of anti-biofouling interface on hydroxyapatite surface by coating zwitterionic MPC polymer containing calcium-binding moieties to prevent oral bacterial adhesion. AB - The purpose of the present study is to synthesize a 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer capable of being immobilized on the tooth surface to prevent oral bacterial adhesion. The strategy is to develop an MPC-based polymer with Ca(2+)-binding moieties, i.e., phosphomonoester groups, for stronger binding with hydroxyapatite (HA) of the tooth surface. To this end, a 2 methacryloyloxyethyl phosphate (MOEP) monomer was synthesized and copolymerized with MPC by free radical polymerization. The coating efficiency of the synthesized polymer, MPC-ran-MOEP (abbreviated as PMP) with varied composition, onto a HA surface was estimated by means of contact angle measurement and X-ray photoelectron spectroscopy. The anti-biofouling nature of PMP-coated HA surfaces was estimated by analyzing protein adsorption, cell adhesion, and Streptococcus mutans adhesion. As a result, HA surface coated with a copolymer containing around 50% MPC (PMP50) showed the best performance in preventing protein adsorption and the downstream cell and bacterial adhesion. STATEMENT OF SIGNIFICANCE: Preparation of anti-biofouling surface on the tooth enamel is the key technique to prevent dental and periodontal diseases, which are closely related with the biofilm formation that induced by the adsorption of salivary proteins and the adhesion of oral bacteria on the tooth surface. In this research, a PMP copolymer with an optimized ratio of zwitterionic and Ca(2+) binding moieties could form a highly effective and robust anti-biofouling surface on HA surfaces by a simple coating method. The PMP-coated surface with high stability can provide a new strategy for an anti-adsorptive and anti-bacterial platform in dentistry and related fields. PMID- 26961807 TI - Fibrin hydrogels functionalized with cartilage extracellular matrix and incorporating freshly isolated stromal cells as an injectable for cartilage regeneration. AB - Freshly isolated stromal cells can potentially be used as an alternative to in vitro expanded cells in regenerative medicine. Their use requires the development of bioactive hydrogels or scaffolds which provide an environment to enhance their proliferation and tissue-specific differentiation in vivo. The goal of the current study was to develop an injectable fibrin hydrogel functionalized with cartilage ECM microparticles and transforming growth factor (TGF)-beta3 as a putative therapeutic for articular cartilage regeneration. ECM microparticles were produced by cryomilling and freeze-drying porcine articular cartilage. Up to 2% (w/v) ECM could be incorporated into fibrin without detrimentally affecting its capacity to form stable hydrogels. To access the chondroinductivity of cartilage ECM, we compared chondrogenesis of infrapatellar fat pad-derived stem cells in fibrin hydrogels functionalized with either particulated ECM or control gelatin microspheres. Cartilage ECM particles could be used to control the delivery of TGF-beta3 to IFP-derived stem cells within fibrin hydrogels in vitro, and furthermore, led to higher levels of sulphated glycosaminoglycan (sGAG) and collagen accumulation compared to control constructs loaded with gelatin microspheres. In vivo, freshly isolated stromal cells generated a more cartilage like tissue within fibrin hydrogels functionalized with cartilage ECM particles compared to the control gelatin loaded constructs. These tissues stained strongly for type II collagen and contained higher levels of sGAGs. These results support the use of fibrin hydrogels functionalized with cartilage ECM components in single-stage, cell-based therapies for joint regeneration. STATEMENT OF SIGNIFICANCE: An alternative to the use of in vitro expanded cells in regenerative medicine is the use of freshly isolated stromal cells, where a bioactive scaffold or hydrogel is used to provide an environment that enhances their proliferation and tissue-specific differentiation in vivo. The objective of this study was to develop an injectable fibrin hydrogel functionalized with cartilage ECM micro-particles and the growth factor TGF-beta3 as a therapeutic for articular cartilage regeneration. This study demonstrates that freshly isolated stromal cells generate cartilage tissue in vivo when incorporated into such a fibrin hydrogels functionalized with cartilage ECM particles. These findings open up new possibilities for in-theatre, single-stage, cell-based therapies for joint regeneration. PMID- 26961805 TI - A novel platelet lysate hydrogel for endothelial cell and mesenchymal stem cell directed neovascularization. AB - Mesenchymal stem cells (MSC) hold promise in promoting vascular regeneration of ischemic tissue in conditions like critical limb ischemia of the leg. However, this approach has been limited in part by poor cell retention and survival after delivery. New biomaterials offer an opportunity to localize cells to the desired tissue after delivery, but also to improve cell survival after delivery. Here we characterize the mechanical and microstructural properties of a novel hydrogel composed of pooled human platelet lysate (PL) and test its ability to promote MSC angiogenic activity using clinically relevant in vitro and in vivo models. This PL hydrogel had comparable storage and loss modulus and behaved as a viscoelastic solid similar to fibrin hydrogels despite having 1/4-1/10th the fibrin content of standard fibrin gels. Additionally, PL hydrogels enabled sustained release of endogenous PDGF-BB for up to 20days and were resistant to protease degradation. PL hydrogel stimulated pro-angiogenic activity by promoting human MSC growth and invasion in a 3D environment, and enhancing endothelial cell sprouting alone and in co-culture with MSCs. When delivered in vivo, the combination of PL and human MSCs improved local tissue perfusion after 8days compared to controls when assessed with laser Doppler perfusion imaging in a murine model of hind limb ischemia. These results support the use of a PL hydrogel as a scaffold for MSC delivery to promote vascular regeneration. STATEMENT OF SIGNIFICANCE: Innovative strategies for improved retention and viability of mesenchymal stem cells (MSCs) are needed for cellular therapies. Human platelet lysate is a potent serum supplement that improves the expansion of MSCs. Here we characterize our novel PL hydrogel's desirable structural and biologic properties for human MSCs and endothelial cells. PL hydrogel can localize cells for retention in the desired tissue, improves cell viability, and augments MSCs' angiogenic activity. As a result of these unique traits, PL hydrogel is ideally suited to serve as a cell delivery vehicle for MSCs injected into ischemic tissues to promote vascular regeneration, as demonstrated here in a murine model of hindlimb ischemia. PMID- 26961808 TI - Aliifodinibius halophilus sp. nov., a moderately halophilic member of the genus Aliifodinibius, and proposal of Balneolaceae fam. nov. AB - A novel Gram-stain-negative, rod-shaped, facultatively anaerobic, oxidase negative and catalase-positive bacterium, designated 2W32T, was isolated from a marine solar saltern on the coast of Weihai, Shandong Province, China. Strain 2W32T was tolerant to moderate salt conditions. Optimal growth occurred at 33-37 degrees C (range 20-45 degrees C) and pH 7.5-8.0 (range pH 7.0-8.5) with 6-10 % (w/v) NaCl (range 2-18 %). Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain 2W32T shared highest similarity with Aliifodinibius sediminis YIM J21T (94.6 %), Aliifodinibius roseus YIM D15T (94.4 %), Fodinibius salinus YIM C003T (93.6 %), Gracilimonas tropica CL-CB462T (88.6 %) and Balneola vulgaris 13IX/A01/164T (86.4 %) and less than 83.0 % similarity with other species of the phylum Bacteroidetes. The isolate and closely related species formed a novel family-level clade in the phylum Bacteroidetes. The polar lipid profile of the novel isolate consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, an unidentified aminolipid, an unidentified glycolipid and an unidentified lipid. The dominant cellular fatty acids (>10 %) were iso-C15 : 0, iso-C17 : 1omega9c and summed feature 3 (C16:1omega7c and/or iso-C15 : 0 2-OH) and the sole respiratory quinone was menaquinone 7 (MK-7). The DNA G+C content of strain 2W32T was 47.5 mol %. Comparative analysis of 16S rRNA gene sequences and characterization indicated that strain 2W32T represents a novel species within the genus Aliifodinibius, for which the name Aliifodinibius halophilus sp. nov. is proposed. The type strain is 2W32T (=KCTC 42497T=CICC 23869T). In addition, a novel family, Balneolaceae fam. nov., is proposed to accommodate the genera Fodinibius, Aliifodinibius, Gracilimonas and Balneola. PMID- 26961810 TI - Contrast Medium Extravasation: The Importance of Radiographic Assessment. PMID- 26961809 TI - Novel GRN Mutations in Patients with Corticobasal Syndrome. AB - Loss-of-function GRN mutations lead to GRN haploinsufficiency and consequently neurodegeneration with significant heterogeneity in clinical presentation of various syndromes. The aim of this study was to investigate the genetics and clinical features of patients with GRN-related frontotemporal lobar degeneration (FTLD) syndromes. We performed mutation analysis of GRN in 45 unrelated Canadian patients with a broad spectrum of FTLD-like syndromes (mean age at onset of 64.0 +/- 11.2 years). In our cohort, two patients were carriers of two novel heterozygous alterations in GRN: 2 bp insertion (c.769-770insCC:p.Q257fs) and 12 bp deletion (c.1009-1020del:p.337-340del). Both patients presented with corticobasal syndrome supported by clinical and radiological findings. The absence of the mutant allele in the RT-PCR product was only observed for the sample with 2 bp insertion in GRN. In contrast, the allele with 12 bp deletion in GRN was not down-regulated at the RNA level and did not segregate with FTLD in the family. Our report extends the evidence for genetic and phenotypic variability in FTLD disorders, and detects a novel pathogenic GRN mutation, carriers of which could eventually help to evaluate the efficacy of different treatments at early stages of dementia. PMID- 26961811 TI - Intrinsic phenotypic stability of a bi-stable auto regulatory gene. AB - Even under homogenous conditions clonal cells can assume different distinct states for generations to follow, also known as epigenetic inheritance. Such long periods of different phenotypic states can be formed due to the existence of more than one stable state in the molecule concentration, where the different states are explored through molecular fluctuations. By formulating a single reaction variable representing the birth and death of molecules, including transcription, translation and decay, we calculate the escape time from the phenotypic states attained from autocatalytic synthesis through a Fokker- Planck formulation and integration of an effective pseudo-potential. We calculate the stability of the phenotypic states both for cooperative binding feedback and dimer binding feedback, resulting in non-linear decay. PMID- 26961812 TI - Inactivation of urease by 1,4-benzoquinone: chemistry at the protein surface. AB - The high activity of urease, a Ni(ii) enzyme, has several adverse effects on human health and agriculture, and its modulation needs the use of inhibitors. 1,4 Benzoquinone (BQ) irreversibly inactivates Sporosarcina pasteurii urease (SPU), with first order kinetics for both the inhibitor and the enzyme. This reaction is stoichiometrically quenched in the presence of sulphite. The 2.07 A crystal structure of SPU bound to BQ shows the presence of a 1,4-hydroquinone moiety covalently bound to the thiol group of alphaCys322, a key residue found on the mobile flap regulating the substrate access to the active site. The 1.75 A crystal structure obtained when sulphite is added to a solution of SPU previously incubated with BQ shows the presence of a 2,5-dihydroxy-benzenesulphonate moiety bound to the alphaCys322 thiol group. These data reveal how the active site cysteine reacts with a prototypical BQ moiety, found in a large number of natural substances potentially suitable to control the urease activity. PMID- 26961813 TI - Analytical Methods for Assessing Chondroitin Sulfate in Human Plasma. AB - Chondroitin sulfate (CS) is a linear heteropolysaccharide of repeating disaccharide units bearing sulfate groups in various positions, commonly at C4 and/or C6 of galactosamine. CS plays important roles in various (patho)physiological processes also performing intriguing biological and therapeutical activities. Plasmatic CS is mainly composed of nonsulfated and 4 sulfated disaccharides. To obtain samples for the determination of CS amount and composition in blood/plasma, dried blood spot (DBS) could be used. DBSs have many advantages over other laboratory methods, allowing for large-scale population screening. Many analytical techniques may be used for the determination of CS. In particular, CE has proved to be a very attractive alternative separation technique for complex polysaccharide characterization. In this work, we compared CS levels between plasma and DBS samples, using CE equipped with the highly sensitive laser-induced fluorescence detector. CS from DBS differs from plasma CS owing to the high content of disaccharides sulfated in C4 and C6. This is due to the presence of the more sulfated CS derived from blood cellular fraction, in particular leukocytes. The identification and quantification of CS in blood plasma could be a useful prognostic and diagnostic tool in pathological conditions and for pharmacological applications. PMID- 26961814 TI - Prebiotics as functional food ingredients preventing diet-related diseases. AB - This paper reviews the potential of prebiotic-containing foods in the prevention or postponement of certain diet-related diseases, such as cardiovascular diseases with hypercholesterolemia, osteoporosis, diabetes, gastrointestinal infections and gut inflammation. Also the data on prebiotics as food ingredients and their impact on food product quality are presented. Prebiotics are short chain carbohydrates that are resistant to the digestion process in the upper part of the digestive system, are not absorbed in any segment of the gastrointestinal system, and finally are selectively fermented by specific genera of colonic bacteria. The mechanisms of the beneficial impacts of prebiotics on human health are very difficult to specify directly, because their health-promoting functions are related to fermentation by intestinal microflora. The impact of prebiotics on diet-related diseases in many ways also depends on the products of their fermentation. Prebiotics as functional food ingredients also have an impact on the quality of food products, due to their textural and gelling properties. Prebiotics as food additives can be very valuable in the creation of functional food aimed at preventing or postponing many diet-related diseases. They additionally have beneficial technological properties which improve the quality of food products. PMID- 26961815 TI - Access to chlamydia testing in remote and rural Scotland. AB - INTRODUCTION: The aim of this study was to assess access to sexual health care in remote and rural settings using Chlamydia testing as a focus by measuring the extent of Chlamydia testing and positivity across the Scottish Highlands in relation to the Scottish Index of Multiple Deprivation Quintile (SIMD) and Urban Rural 8-fold index (UR8). METHODS: Tests processed through Raigmore Hospital in Inverness, the main testing laboratory for microbiology tests in North and West and South and Mid Highlands, were studied. Where people are tested in relation to where they live was assessed, as well as the type of test they opt for. Also assessed was the rate of positivity in male and female patients in rural compared with urban settings using the Scottish Government UR8 and in relation to the SIMD. RESULTS: 9644 results were analysed. 77.2% of the results were for females and 22.4% for males. 8.1% of the results were positive and 84.4% were negative. There were proportionately more positive tests from the sexual health sources than from general practice. The proportion of men who had positive tests was almost double that for women (12.7% vs 6.6%) although men made up only 27.9% of the total number of tests. There was no significant difference in positivity when compared with UR8 index or SIMD. 37.7% of people living in the most rural areas (UR8 7-8) had their test performed in a more urban setting (UR8 1-6), and 20.4% people had their test performed in a very urban setting (UR8 1-2). Of these tests, there was a tendency for UR8 7-8 patients to be more likely to have a positive test if tested in an urban setting. CONCLUSIONS: These results are similar to previous results in other countries that suggest that Chlamydia positivity is similar in rural and urban settings. A large proportion of people living in more rurally classified areas, and perhaps those with a higher risk, have their test in a central setting, suggesting that they may be bypassing local resources to get a test. The reason for this is not clear. The results also show that men are more likely to have their test in a genitourinary setting as well as have proportionately more positive results. These results support the case for customising sexual health services to the most rural areas and suggest that providing an anonymous testing service in these areas might be beneficial, especially for men. PMID- 26961816 TI - Acoustic trapping of active matter. AB - Confinement of living microorganisms and self-propelled particles by an external trap provides a means of analysing the motion and behaviour of active systems. Developing a tweezer with a trapping radius large compared with the swimmers' size and run length has been an experimental challenge, as standard optical traps are too weak. Here we report the novel use of an acoustic tweezer to confine self propelled particles in two dimensions over distances large compared with the swimmers' run length. We develop a near-harmonic trap to demonstrate the crossover from weak confinement, where the probability density is Boltzmann-like, to strong confinement, where the density is peaked along the perimeter. At high concentrations the swimmers crystallize into a close-packed structure, which subsequently 'explodes' as a travelling wave when the tweezer is turned off. The swimmers' confined motion provides a measurement of the swim pressure, a unique mechanical pressure exerted by self-propelled bodies. PMID- 26961817 TI - Associations between schizotypy and cerebral laterality. AB - Atypical lateralization for language has been found in schizophrenia, suggesting that language and thought disorders on the schizophrenia spectrum may be due to left hemispheric dysfunction. However, research with those with non-clinical schizotypy has been inconsistent, with some studies finding reduced or reversed language laterality (particularly with positive schizotypal traits), and others finding typical left hemispheric specialization. The aim of the current study was to use both a behavioural (dual reading-finger tapping) task and an functional magnetic resonance imaging lexical decision task to investigate language laterality in a university sample of high- and low-schizotypal adults. Findings revealed no evidence for atypical lateralization in our sample for both overall schizotypy (measured by the Oxford-Liverpool Inventory of Feelings and Experiences) and positive schizotypy (measured by the Unusual Experiences subscale) groups. Our findings provide further evidence that non-clinical schizotypy is not associated with atypical language laterality. PMID- 26961818 TI - Development of a Physiologically Based Pharmacokinetic Model to Predict Disease Mediated Therapeutic Protein-Drug Interactions: Modulation of Multiple Cytochrome P450 Enzymes by Interleukin-6. AB - Disease-mediated therapeutic protein-drug interactions have recently gained attention from regulatory agencies and pharmaceutical industries in the development of new biological products. In this study, we developed a physiologically based pharmacokinetic (PBPK) model using SimCYP to predict the impact of elevated interleukin-6 (IL-6) levels on cytochrome P450 (CYP) enzymes and the treatment effect of an anti-IL-6 monoclonal antibody, sirukumab, in patients with rheumatoid arthritis (RA). A virtual RA patient population was first constructed by incorporating the impact of systemic IL-6 level on hepatic and intestinal expression of multiple CYP enzymes with information from in vitro studies. Then, a PBPK model for CYP enzyme substrates was developed for healthy adult subjects. After incorporating the virtual RA patient population, the PBPK model was applied to quantitatively predict pharmacokinetics of multiple CYP substrates in RA patients before and after sirukumab treatment from a clinical cocktail drug interaction study. The results suggested that, compared with observed clinical data, changes in systemic exposure to multiple CYP substrates by anti-IL-6 treatment in virtual RA patients have been reasonably captured by the PBPK model, as manifested by modulations in area under plasma concentration versus time curves for midazolam, omeprazole, S-warfarin, and caffeine. This PBPK model reasonably captured the modulation effect of IL-6 and sirukumab on activity of CYP3A, CYP2C9, CYP2C19, and CYP1A2 and holds the potential to be utilized to assess the modulation effect of sirukumab on the metabolism and pharmacokinetics of concomitant small-molecule drugs in RA patients. PMID- 26961820 TI - Non-lactate strong ion difference: a clearer picture. AB - PURPOSE: The recommended method for elucidating the effects of strong ions other than lactate on acid-base balance is to calculate the non-lactate strong ion difference (SIDnl). A relationship between HCO3 (-) and SIDnl in hyperchloremic patients has already been demonstrated; in the present study, the relationships between SIDnl, the apparent strong ion difference (SIDa), and mortality at intensive care unit (ICU) admission were investigated. METHODS: In our two-center study, 2691 patients admitted to the ICU were retrospectively evaluated, including 1069 critically ill patients. These patients were divided into three subgroups according to their SIDnl levels at admission to the ICU: low (<38 mmol L(-1)), normal (38-40 mmol L(-1)), and high (>40 mmol L(-1)). Patient age, gender, diagnosis, blood gas values, length of ICU stay, and mortality were recorded. RESULTS: The low-SIDnl group included 768 patients (71.8 %), the normal SIDnl group consisted of 127 patients (11.9 %), and the high-SIDnl group contained 174 patients (16.3 %). There was no significant difference in lactate levels among the SIDnl groups (p = 0.635). In a multivariate logistic regression model, likelihood of mortality was increased 1.24-fold (1.20-1.28), 2.56-fold (1.61-4.08) and 2.55-fold (1.003-6.47) by APACHE II, lactate level >=2mmol L(-) and low SIDnl (p < 0.001, p < 0.001, and p = 0.049, respectively). CONCLUSIONS: SIDnl can be used to determine the effects of strong ions other than lactate on SIDa values and acid-base balance. Furthermore, a low SIDnl at ICU admission can be a prognostic indicator of mortality. PMID- 26961821 TI - Hemodynamic monitoring and management in high-risk surgery: a survey among Japanese anesthesiologists. AB - The aim of this study was to assess the current practices of hemodynamic management in high-risk surgical patients among Japanese anesthesiologists. An invitation letter to the survey, which included 35 questions related to hemodynamic monitoring in high-risk surgery, was mailed to every hospital approved by the Japanese Society of Anesthesiologists (JSA) (1260 hospitals). Of the 692 JSA respondents, 573 completed the survey. Despite reporting a high rate of cardiac output (CO) and stroke volume variation (SVV) monitoring in JSA members (70 and 74 %, respectively), fluid goal-directed therapy was poorly implemented in high-risk surgery (7.4 %). Also, 47 % of the JSA respondents did not consistently perform CO optimization. SVV was more commonly used (76 %) as an indicator of volume expansion among JSA respondents, while central venous pressure was less frequently used (48 %). Despite a broader use of advanced hemodynamic monitoring, optimization of CO is still poorly protocolized and applied in Japan. The development of guidelines and protocols for hemodynamic management, including the establishment of strong evidence aimed at improving clinical outcomes, is needed to assist anesthesiologists in more universal adoption of perioperative CO optimization. PMID- 26961819 TI - Minimally invasive or noninvasive cardiac output measurement: an update. AB - Although cardiac output (CO) by pulmonary artery catheterization (PAC) has been an important guideline in clinical management for more than four decades, some studies have questioned the clinical efficacy of CO in certain patient populations. Further, the use of CO by PAC has been linked to numerous complications including dysrhythmia, infection, rupture of pulmonary artery, injury to adjacent arteries, embolization, pulmonary infarction, cardiac valvular damage, pericardial effusion, and intracardiac catheter knotting. The use of PAC has been steadily declining over the past two decades. Minimally invasive and noninvasive CO monitoring have been studied in the past two decades with some evidence of efficacy. Several different devices based on pulse contour analysis are available currently, including the uncalibrated FloTrac/Vigileo system and the calibrated PiCCO and LiDCO systems. The pressure-recording analytical method (PRAM) system requires only an arterial line and is commercially available as the MostCare system. Transesophageal echocardiography (TEE) can measure CO by non Doppler- or Doppler-based methods. The partial CO2 rebreathing technique, another method to measure CO, is marketed by Novametrix Medical Systems as the NICO system. Thoracic electrical bioimpedance (TEB) and electric bioreactance (EB) are totally noninvasive CO monitoring. Nexfin HD and the newer ClearSight systems are examples of noninvasive CO monitoring devices currently being marketed by Edwards Lifesciences. The developing focus in CO monitoring devices appears to be shifting to tissue perfusion and microcirculatory flow and aimed more at markers that indicate the effectiveness of circulatory and microcirculatory resuscitations. PMID- 26961823 TI - Facial and Efficient Access to Dihydropyrano[3,2-c]Chromenes via Three-Component Reaction Using N,N-Dimethylbenzylamine As a New Organocatalyst. AB - The N,N-dimethylbenzylamine (DMBA), as an efficient and commercially available organocatalyst was employed for the one-pot synthesis of dihydropyrano[3,2 c]chromene derivatives in ethanol medium. In this work, the one-pot Knoevenagel Michael-Thorpe-Ziegler type cascade heterocyclization has been developed for the synthesis of dihydropyrano[3,2-c]chromene-containing heterocycles from the one pot multicomponent condensation reaction of 4-hydroxycoumarin, malononitrile/ethyl cyanoacetate, and various aldehydes at 60 degrees C. The salient features of this basecatalyzed reaction are mild reaction conditions, reusability of the reaction medium, shorter reaction times, and easy separation of the reaction mixture. PMID- 26961822 TI - Transcriptome analysis reveals a ribosome constituents disorder involved in the RPL5 downregulated zebrafish model of Diamond-Blackfan anemia. AB - BACKGROUND: Diamond-Blackfan anemia (DBA) was the first ribosomopathy associated with mutations in ribosome protein (RP) genes. The clinical phenotypes of DBA include failure of erythropoiesis, congenital anomalies and cancer predisposition. Mutations in RPL5 are reported in approximately 9 ~ 21 % of DBA patients, which represents the most common pathological condition related to a large-subunit ribosomal protein. However, it remains unclear how RPL5 downregulation results in severe phenotypes of this disease. RESULTS: In this study, we generated a zebrafish model of DBA with RPL5 morphants and implemented high-throughput RNA-seq and ncRNA-seq to identify key genes, lncRNAs, and miRNAs during zebrafish development and hematopoiesis. We demonstrated that RPL5 is required for both primitive and definitive hematopoiesis processes. By comparing with other DBA zebrafish models and processing functional coupling network, we identified some common regulated genes, lncRNAs and miRNAs, that might play important roles in development and hematopoiesis. CONCLUSIONS: Ribosome biogenesis and translation process were affected more in RPL5 MO than in other RP MOs. Both P53 dependent (for example, cell cycle pathway) and independent pathways (such as Aminoacyl-tRNA biosynthesis pathway) play important roles in DBA pathology. Our results therefore provide a comprehensive basis for the study of molecular pathogenesis of RPL5-mediated DBA and other ribosomopathies. PMID- 26961826 TI - Evaluation of a Team-Based, Transition-of-Care Management Service on 30-Day Readmission Rates. AB - BACKGROUND: Transitions of care from the hospital to the outpatient setting often fail to meet the Triple Aim of improving quality, improving the health of populations, and decreasing the cost of care. A major push to improve the quality of transitions and reduce hospital readmissions is under way. METHODS: We implemented a team-based, transition-of-care model and assessed the impact on 30 day readmission rates. The 3 components of the intervention were contact with a nurse care manager, medication reconciliation, and follow-up with a physician. We compared 30-day readmission rates for the period before versus after implementation of this intervention. RESULTS: The 30-day readmission rate decreased from 14.2% in the usual care group to 5.3% in the intervention group (P = .011). Almost 90% of patients in the intervention group received all 3 components of the intervention. LIMITATIONS: Generalizability is limited to practices with embedded team members. Not all patients received all 3 components of the intervention. CONCLUSIONS: Development of a team-based intervention was associated with a significant reduction in hospital readmissions. This method could be implemented in other primary care offices with team-based care. PMID- 26961825 TI - Intra-Arterial Therapy for Acute Stroke and the Effect of Technological Advances on Recanalization: Findings in a Community Hospital. AB - BACKGROUND: Recent randomized controlled studies have shown improvement in recanalization outcomes when physicians use the latest intra-arterial therapy devices in patients with acute, large-vessel, intracranial occlusions. The goal of this study was to explore how new procedures affected degree of and time to recanalization at a single center over the past 12 years as technology has improved. METHODS: Patients were included in the study if they had a large or medium intracranial vessel occlusion and had undergone intra-arterial therapy for acute stroke during the period 2002-2013. Therapies were categorized as intra arterial thrombolysis with tissue plasminogen activator (IA tPA), mechanical thrombectomy using 1st-generation devices (Merci and Penumbra), or mechanical thrombectomy using 2nd-generation devices (stent-trievers). Recanalization was defined using a modified Thrombolysis in Cerebral Infarction (TICI) scale. RESULTS: Primary treatment was IA tPA in 24 (12.4%) patients, 1st-generation devices in 128 (66.0%) patients, and 2nd-generation devices in 42 (21.6%) patients. TICI 2b was achieved in 7 (29.2%) patients treated with IA tPA, in 79 (61.7%) patients treated with 1st-generation devices, and in 38 (90.5%) patients treated with 2nd-generation devices. Compared to patients treated with IA tPA, patients treated with 2nd-generation devices were more likely to reach TICI 2b recanalization (odds ratio, 11.66; 95% CI, 1.56-87.01), and they did so in shorter times. CONCLUSION: Technological advances over 12 years in endovascular stroke treatments significantly improved the chance of and reduced time to achieving TICI 2b recanalization in our community hospital. This shows the importance of adopting new technologies in a rapidly evolving field in order to provide the best-practice standard of care for the people of our region. PMID- 26961824 TI - Pre- and Perinatal Risk for Attention-Deficit Hyperactivity Disorder: Does Neuropsychological Weakness Explain the Link? AB - Etiological investigations of attention-deficit hyperactivity disorder (ADHD) and disruptive behavior problems support multiple causal pathways, including involvement of pre- and perinatal risk factors. Because these risks occur early in life, well before observable ADHD and externalizing symptoms emerge, the relation between risk and symptoms may be mediated by neurodevelopmental effects that manifest later in neuropsychological functioning. However, potential dissociable effects of pre/perinatal risk elements on ADHD and familial confounds must also be considered to test alternative hypotheses. 498 youth aged 6-17 years (55.0 % male) completed a multi-stage, multi-informant assessment including parent and teacher symptom reports of symptoms and parent ratings of pre/perinatal health risk indicators. Youth completed a neuropsychological testing battery. Multiple mediation models examined direct effects of pre- and perinatal health risk on ADHD and other disruptive behavior disorder symptoms and indirect effects via neuropsychological functioning. Parental ADHD symptoms and externalizing status was covaried to control for potential familial effects. Effects of prenatal substance exposure on inattention were mediated by memory span and temporal processing deficits. Further, effects of perinatal health risk on inattention, hyperactivity-impulsivity, and ODD were mediated by deficits in response variability and temporal processing. Further, maternal health risks during pregnancy appeared to exert direct rather than indirect effects on outcomes. Results suggest that after controlling for familial relatedness of ADHD between parent and child, early developmental health risks may influence ADHD via effects on neuropsychological processes underpinning the disorder. PMID- 26961828 TI - Building a Value-Based Workforce in North Carolina. AB - Health care in the United States is likely to change more in the next 10 years than in any previous decade. However, changes in the workforce needed to support new care delivery and payment models will likely be slower and less dramatic. In this issue of the NCMJ, experts from education, practice, and policy reflect on the "state of the state" and what the future holds for multiple health professional groups. They write from a broad range of perspectives and disciplines, but all point toward the need for change-change in the way we educate, deploy, and recruit health professionals. The rapid pace of health system change in North Carolina means that the road map is being redrawn as we drive, but some general routes are evident. In this issue brief we suggest that, to make the workforce more effective, we need to broaden our definition of who is in the health workforce; focus on retooling and retraining the existing workforce; shift from training workers in acute settings to training them in community-based settings; and increase accountability in the system so that public funds spent on the health professions produce the workforce needed to meet the state's health care needs. North Carolina has arguably the best health workforce data system in the country; it has historically provided the data needed to inform policy change, but adequate and ongoing financial support for that system needs to be assured. PMID- 26961827 TI - Keeping the End in Mind. PMID- 26961829 TI - Challenges of Recruitment and Retention in Rural Areas. AB - There have long been rural health care workforce shortages; however, the urgency to find real solutions has increased with the changing health care landscape. The evidence makes a compelling case to be intentional in the candidates we support and to align educational resources across multiple systems. Programs need to continually evolve, utilizing workforce data, best practices, and new technological advances. This leads the Office of Rural Health (ORH) to secure funding for therapists practicing in integrated settings and to expand loan repayment to general surgeons and providers creating access through telehealth. While access is ORH's core mission, North Carolina's rural health plan reframed the discussion around creating healthy rural communities. This will require further refinement of the critical workforce definition, and it brings to the forefront the fact that a variety of new partnerships will be key to achieving the objective of healthy rural communities. PMID- 26961830 TI - Surviving the Silver Tsunami: Training a Health Care Workforce to Care for North Carolina's Aging Population. AB - North Carolina's aging population will require a health care workforce prepared to meet patients' complex care needs. The keys to training this workforce include continuing to mobilize the state's educational infrastructure to provide interprofessional, community-based experiences and maximizing exposure to new models of care. PMID- 26961831 TI - Access to Health Care of Your Choice. PMID- 26961832 TI - Educating North Carolina's Oral Health Workforce in an Evolving Environment. AB - In 2014, North Carolina had 4,681 actively practicing dentists and ranked 47th among US states in dentist-to-population ratio. The need for dentists is increasing as the population grows, and underserved areas persist. This commentary discusses the impact of the state's 2 dental schools and external factors on dental workforce trends. PMID- 26961833 TI - The Impacts of Electronic Health Record Implementation on the Health Care Workforce. AB - Health care organizations at various levels are transitioning into the new electronic era by implementing and adopting electronic health record systems. New job roles will be needed for this transition, and some current job roles will inevitably become obsolete due to the change. In addition to training new personnel to fill these new roles, the focus should also be on equipping the current health care workforce with knowledge and skills in health information technology and health informatics that will support their work and improve quality of care. PMID- 26961834 TI - Transforming Medical Education is the Key to Meeting North Carolina's Physician Workforce Needs. AB - To meet the needs of the population of North Carolina, an epic transformation is under way in health care. This transformation requires that we find new ways to educate and train physicians and other health care professionals. In this commentary, we propose that the success of the Brody School of Medicine in preparing a primary care physician workforce can serve as a model for meeting the state's future physician workforce needs. Other considerations include increasing graduate medical education positions through state funding and providing incentives for medical students who stay in North Carolina. PMID- 26961835 TI - Kenan Primary Care Medical Scholars Program: Preparing Physicians for Service in Rural North Carolina. PMID- 26961836 TI - Improving the Return on Investment of Graduate Medical Education in North Carolina. AB - The National Academy of Medicine has called for fundamental reform in the governance and accountability of graduate medical education, but how to implement this change is unclear. We describe the North Carolina graduate medical education system, and we propose tracking outcomes and aligning residency stipends with outcomes such as specialty choice, practice in North Carolina, and acceptance of new Medicaid and Medicare patients. PMID- 26961837 TI - New Psychiatry Residency Program at Carolinas HealthCare System. PMID- 26961838 TI - The Importance of Interprofessional Practice and Education in the Era of Accountable Care. AB - In order to succeed in today's health care environment, interprofessional teams are essential. The terms "multidisciplinary care" and "interdisciplinary care" have been replaced by the more contemporary term "interprofessional practice and education" (IPE), which occurs when individuals "from two or more professions learn about, from and with each other to enable effective collaboration and improve health outcomes." This commentary discusses new models of care, team members who contribute to IPE, and incentives and challenges. PMID- 26961839 TI - Community Health Workers: An Integral Part of an Integrated Health Care Team. PMID- 26961840 TI - Transition of New Graduate Nurses to the Workforce: Challenges and Solutions in the Changing Health Care Environment. AB - New graduate nurses face a host of challenges that impact successful transition to practice. Health care organizations thus need to understand how changes in the health care landscape impact new graduate nurses who are transitioning to the practice environment. This commentary discusses challenges and possible solutions to successful transition of new graduates into the work environment. PMID- 26961841 TI - Improving Diversity in the Health Professions. AB - The health professional workforce of North Carolina does not reflect the rich diversity of the state's population, and the underrepresentation of various demographic groups in health care may affect the health outcomes of the state's citizens. There are opportunities for educational institutions to partner with others, share successful strategies, and implement measures to promote diversity among health professionals. PMID- 26961842 TI - Does North Carolina's Health Care Workforce Reflect the Diversity of the State's Population? PMID- 26961843 TI - Beyond Climate Change: Why Medical Institutions Should Divest From Fossil Fuels. PMID- 26961844 TI - 2016 North Carolina Child Health Report Card. PMID- 26961846 TI - Expanding Wilderness Medicine Fellowship Eligibility Beyond Emergency Medicine. PMID- 26961845 TI - Synthesis, DNA/HSA Interaction Spectroscopic Studies and In Vitro Cytotoxicity of a New Mixed Ligand Cu(II) Complex. AB - A new mixed ligand copper(II)-dipeptide complex with 2-(2'-pyridyl)benzothiazole (pbt), [Cu(Gly-L-leu)(pbt)(H2O)].ClO4 (Gly-L-leu = Glycyl-L-leucine anion) was synthesized and characterized by various physico-chemical means. The DNA binding and cleavage properties of the complex investigated by viscosity, agarose gel electrophoresis and multi-spectroscopic techniques (UV, circular dichroism (CD) and fluorescence) showed that the complex was bound to CT-DNA through intercalation mode with moderate binding constant (K b = 3.132 * 10(4) M(-1)), and cleaved pBR322 DNA efficiently (~ 5 MUM) in the presence of Vc, probably via an oxidative mechanism induced by *OH. Additionally, the interaction of the complex with human serum albumin (HSA) was explored by UV-visible, CD, fluorescence, synchronous fluorescence and 3D fluorescence spectroscopy. The complex exhibits desired affinity to HSA through hydrophobic interaction. Moreover, the cytotoxicity of the complex against three human carcinoma cell lines (HeLa, HepG2 and A549) was evaluated by MTT assay, which showed that the complex had effective cytotoxicity and higher inhibition toward A549 cell lines with IC50 of 38.0 +/- 3.2 MUM. PMID- 26961847 TI - Twostriped Walkingstick Targets Human Eye With Chemical Defense Spray. AB - Stick insects are commonly known for their fascinating and functional shape, which allows them to blend with their surroundings. However, many may not be aware of another, more threatening protective feature, a toxic spray. Anisomorpha buprestoides, one of two stick insect types in the United States to use this defense, targets the eyes and can cause ocular injury, with cases ranging from conjunctivitis to corneal ulceration. We present the case of an older woman exposed to the walkingstick's painful venom while in her home. The patient presented to an Orlando emergency department with conjunctival injection and tearing that improved with water irrigation. PMID- 26961848 TI - Attenuation of Urinary Cadmium in Inhabitants of the Environmentally Exposed Jinzu River Basin Determined by Applying a Mixed Linear Model. AB - Half-life of urinary cadmium level (U-Cd) was estimated in inhabitants whose initial U-Cd was >=5 MUg/L (131 men and 177 women) or >=5 MUg/gcr (195 men and 246 women), using a linear mixed model adjusted for the baseline age. To clarify the effect of initial U-Cd, the target participants were divided into higher or lower initial U-Cd group. In the higher groups, the half-lives were 15.4 and 13.1 years for unadjusted U-Cd and 19.0 and 23.0 years for creatinine-adjusted U-Cd, in men and women, respectively. In the lower groups, the half-lives were 38.0 and 26.0 years for unadjusted U-Cd in men and women. For creatinine-adjusted U-Cd, it was 42.9 years in men. For attenuation of U-Cd, there were an early fast component shown in the higher group and late slow component shown in the lower group. The attenuation of U-Cd is slower in the longer time compared to that previously reported. PMID- 26961849 TI - Recovery of the Reproductive Capability Following Exposure to 4-tert-Octylphenol in the Neotropical Cichlid Fish Cichlasoma dimerus. AB - Here, we analyzed the recovery of the reproductive capability in male Cichlasoma dimerus after exposure to sublethal concentrations of 4-tert-octylphenol (OP), a demonstrated estrogenic chemical. Adult fish were exposed to 0, 30, 150 and 300 MUg/L OP during 60 days and subsequently transferred to OP-free water for another 60 days. At 150 and 300 MUg/L, absence of fertilized spawnings were recorded during the first 4 weeks following OP exposure, which could be explained by the impairment of testis architecture recorded at the highest OP concentrations. The restoration of the testicular organization began by day 14 in OP-free water, when the germinal epithelium re-started to proliferate. Testicular functionality was recovered by day 28, yielding fertilized eggs and viable F1 embryos. These results show that pathological features induced in the testes of C. dimerus by OP exposure are not permanent since fish recover their fertilization capacity after an adequate depuration period. PMID- 26961850 TI - Penile cancer metastasizing to the breast: a case report. AB - BACKGROUND: Penile cancer is a relatively uncommon cancer in developed nations. Metastatic disease is rare, but lymphatic or vascular spreading has been previously reported to the liver, lungs, bones, brain, heart and skin. CASE PRESENTATION: We report a case of a 49-year-old white man with a penile squamous cell carcinoma previously treated with partial penectomy and bilateral inguinal lymph node dissection, followed by adjuvant therapy. Three years after treatment, the primitive neoplasm metastasized to the breast, presenting as a painful lump. Differentials of a secondary versus a malignant primary tumor were considered and in view of a diagnostic dilemma the lesion was excised. CONCLUSIONS: This case is unusual in its site of metastatic progression as well as in its pattern of clinical presentation. Awareness of such a condition by physicians is mandatory in order to make an early diagnosis and start prompt and correct therapeutic planning. PMID- 26961852 TI - Recombinant Tyrosinase from Polyporus arcularius: Overproduction in Escherichia coli, Characterization, and Use in a Study of Aurones as Tyrosinase Effectors. AB - Tyrosinases act in the development of organoleptic properties of tea, raisins, etc., but also cause unwanted browning of fruits, vegetables, and mushrooms. The tyrosinase from Agaricus bisporus has been used as a model to study tyrosinase inhibitors, which are also indispensable in the treatment of skin pigmentation disorders. However, this model has disadvantages such as side enzyme activities and the presence of multiple isoenzymes. Therefore, we aimed to introduce a new tyrosinase model. The pro-tyrosinase from Polyporus arcularius was overproduced in Escherichia coli. Trypsin digestion led to a cleavage after R388 and hence enzyme activation. The tyrosinase was a homodimer and transformed L-DOPA and tert butylcatechol preferentially. Various aurons were examined as effectors of this enzyme. 2'- and 3'-hydroxyaurones acted as its activators and 2',4' dihydroxyaurone as an inhibitor, whereas 4'-hydroxyaurones were its substrates. The enzyme is a promising model for tyrosinase effector studies, being a single isoenzyme and void of side enzyme activities. PMID- 26961853 TI - Correction: Particle shape optimization by changing from an isotropic to an anisotropic nanostructure: preparation of highly active and stable supported Pt catalysts in microemulsions. AB - Correction for 'Particle shape optimization by changing from an isotropic to an anisotropic nanostructure: preparation of highly active and stable supported Pt catalysts in microemulsions' by Riny Y. Parapat et al., Nanoscale, 2013, 5, 796 805. PMID- 26961851 TI - Hepatocellular adenoma classification: a comparative evaluation of immunohistochemistry and targeted mutational analysis. AB - BACKGROUND: Four subtypes of hepatocellular adenomas (HCA) are recognized: hepatocyte-nuclear-factor-1alpha mutated (H-HCA), beta-catenin-mutated type with upregulation of glutamine synthetase (b-HCA), inflammatory type (IHCA) with serum amyloid-A overexpression, and unclassified type. Subtyping may be useful since b HCA appear to have higher risk of malignant transformation. We sought to apply subtype analysis and assess histological atypia, correlating these with next generation sequencing analysis. METHODS: Twenty-six HCA were stained with serum amyloid A (SAA), liver fatty acid-binding protein (LFABP), glutamine synthetase (GS), and beta-catenin IHC, followed by analysis with a targeted multiplex sequencing panel. RESULTS: By IHC, 4 HCA (15.4 %) were classified as b-HCA, 11 (42.3 %) as IHCA, 9 (34.6 %) as H-HCA, and two (7.7 %) unclassifiable. Eight HCA (30.8 %) showed atypia (3 b-HCA, 4 IHCA and 1 H-HCA). Targeted sequencing confirmed HNF1A mutations in all H-HCA, confirming reliability of LFABP IHC in identifying these lesions. CTNNB1 mutations were detected in 1 of 4 (25 %) of GS/beta-catenin-positive cases, suggesting that positive GS stain does not always correlate with CTNNB1 mutations. CONCLUSIONS: Immunohistochemistry does not consistently identify b-HCA. Mutational analysis improves the diagnostic accuracy of beta-catenin-mutated HCA and is an important tool to assess risk of malignancy in HCA. PMID- 26961854 TI - Corrigendum: Studying biological membranes with extended range high-speed atomic force microscopy. PMID- 26961855 TI - Direct and Highly Selective Conversion of Synthesis Gas into Lower Olefins: Design of a Bifunctional Catalyst Combining Methanol Synthesis and Carbon-Carbon Coupling. AB - The direct synthesis of lower (C2 to C4) olefins, key building-block chemicals, from syngas (H2/CO), which can be derived from various nonpetroleum carbon resources, is highly attractive, but the selectivity for lower olefins is low because of the limitation of the Anderson-Schulz-Flory distribution. We report that the coupling of methanol-synthesis and methanol-to-olefins reactions with a bifunctional catalyst can realize the direct conversion of syngas to lower olefins with exceptionally high selectivity. We demonstrate that the choice of two active components and the integration manner of the components are crucial to lower olefin selectivity. The combination of a Zr-Zn binary oxide, which alone shows higher selectivity for methanol and dimethyl ether even at 673 K, and SAPO 34 with decreased acidity offers around 70% selectivity for C2-C4 olefins at about 10% CO conversion. The micro- to nanoscale proximity of the components favors the lower olefin selectivity. PMID- 26961856 TI - Contribution of a Comparative Western Blot Method to Early Postnatal Diagnosis of Congenital Syphilis. AB - Serology has a pivotal role in the diagnosis of congenital syphilis (CS), but problems arise because of the passive transfer of IgG antibodies across the placenta. The aim of this study was to assess the diagnostic value of a comparative Western blot (WB) method finalized to match the IgG immunological profiles of mothers and their own babies at birth in order to differentiate between passively transmitted maternal antibodies and antibodies synthesized by the infants against Treponema pallidum Thirty infants born to mothers with unknown or inadequate treatment for syphilis were entered in a retrospective study, conducted at St. Orsola-Malpighi Hospital, Bologna, Italy. All of the infants underwent clinical, instrumental, and laboratory examinations, including IgM WB testing. For the retrospective study, an IgG WB assay was performed by blotting T. pallidum antigens onto nitrocellulose sheets and incubating the strips with serum specimens from mother-child pairs. CS was diagnosed in 11 out of the 30 enrolled infants; 9/11 cases received the definitive diagnosis within the first week of life, whereas the remaining two were diagnosed later because of increasing serological test titers. The use of the comparative IgG WB testing performed with serum samples from mother-child pairs allowed a correct CS diagnosis in 10/11 cases. The CS diagnosis was improved by a strategy combining comparative IgG WB results with IgM WB results, leading to a sensitivity of 100%. The comparative IgG WB test is thus a welcome addition to the conventional laboratory methods used for CS diagnosis, allowing identification and adequate treatment of infected infants and avoiding unnecessary therapy of uninfected newborns. PMID- 26961857 TI - Development of a Simple, Peripheral-Blood-Based Lateral-Flow Dipstick Assay for Accurate Detection of Patients with Enteric Fever. AB - Enteric fever is a systemic infection caused by typhoidal strains of Salmonella enterica and is a significant cause of mortality and morbidity in many parts of the world, especially in resource-limited areas. Unfortunately, currently available diagnostic tests for enteric fever lack sensitivity and/or specificity. No true clinically practical gold standard for diagnosing patients with enteric fever exists. Unfortunately, microbiologic culturing of blood is only 30 to 70% sensitive although 100% specific. Here, we report the development of a lateral flow immunochromatographic dipstick assay based on the detection of Salmonella enterica serovar Typhi (S Typhi) lipopolysaccharide (LPS)-specific IgG in lymphocyte culture secretion. We tested the assay using samples from 142 clinically suspected enteric fever patients, 28 healthy individuals residing in a zone where enteric fever is endemic, and 35 patients with other febrile illnesses. In our analysis, the dipstick detected all blood culture-confirmed S Typhi cases (48/48) and 5 of 6 Salmonella enterica serovar Paratyphi A blood cultured-confirmed cases. The test was negative in all 35 individuals febrile with other illnesses and all 28 healthy controls from the zone of endemicity. The test was positive in 19 of 88 individuals with suspected enteric fever but with negative blood cultures. Thus, the dipstick had a sensitivity of 98% compared to blood culture results and a specificity that ranged from 78 to 100% (95% confidence interval [CI], 70 to 100%), depending on the definition of a true negative. These results suggest that this dipstick assay can be very useful for the detection of enteric fever patients especially in regions of endemicity. PMID- 26961859 TI - Gradients in pore size enhance the osteogenic differentiation of human mesenchymal stromal cells in three-dimensional scaffolds. AB - Small fractures in bone tissue can heal by themselves, but in case of larger defects current therapies are not completely successful due to several drawbacks. A possible strategy relies on the combination of additive manufactured polymeric scaffolds and human mesenchymal stromal cells (hMSCs). The architecture of bone tissue is characterized by a structural gradient. Long bones display a structural gradient in the radial direction, while flat bones in the axial direction. Such gradient presents a variation in bone density from the cancellous bone to the cortical bone. Therefore, scaffolds presenting a gradient in porosity could be ideal candidates to improve bone tissue regeneration. In this study, we present a construct with a discrete gradient in pore size and characterize its ability to further support the osteogenic differentiation of hMSCs. Furthermore, we studied the behaviour of hMSCs within the different compartments of the gradient scaffolds, showing a correlation between osteogenic differentiation and ECM mineralization, and pore dimensions. Alkaline phosphatase activity and calcium content increased with increasing pore dimensions. Our results indicate that designing structural porosity gradients may be an appealing strategy to support gradual osteogenic differentiation of adult stem cells. PMID- 26961860 TI - Novel BODIPY-based Ru(II) and Ir(III) metalla-rectangles: cellular localization of compounds and their antiproliferative activities. AB - The first examples of Ru(ii) and Ir(iii) metalla-rectangles [1](4+)-[4](4+) containing a BODIPY-based linker are reported; some of these compounds exhibited highly selective anticancer activity and interact strongly with DNA as well as protein. The characteristic green fluorescence of a BODIPY ligand and associated aggregation-induced emission (AIE) permitted visualization of compounds inside the cells using confocal microscopy. PMID- 26961861 TI - Introducing Chirality into Nonionic Dendritic Amphiphiles and Studying Their Supramolecular Assembly. AB - Chiral head groups have been introduced into water-soluble hydroxyl-terminated nonionic amphiphiles and the impact of the head group stereochemistry on the supramolecular ultrastructures has been studied. Enantiomeric isomers were compared with the achiral meso form and the racemic mixture by means of cryogenic transmission electron microscopy and circular dichroism spectroscopy. Structurally, all amphiphiles are composed of the first-generation hydrophilic polyglycerol head group coupled to a single hydrophobic hexadecyl chain through an amide linkage and diaromatic spacer. The enantiomers aggregate to form twisted ribbons with uniform handedness, whereas the meso stereoisomer and racemic mixture produce elongated assemblies, namely, tubules and platelets, but without a chiral ultrastructure. Simulations on the molecular packing geometries of the stereoisomers indicate different preferential assembly routes that explain the individual supramolecular aggregation behavior. PMID- 26961858 TI - Viability and Functionality of Cryopreserved Peripheral Blood Mononuclear Cells in Pediatric Dengue. AB - Cryopreserved peripheral blood mononuclear cells (PBMCs) are widely used in studies of dengue. In this disease, elevated frequency of apoptotic PBMCs has been described, and molecules such as soluble tumor necrosis factor (TNF)-related apoptosis-inducing ligands (sTRAIL) are involved. This effect of dengue may affect the efficiency of PBMC cryopreservation. Here, we evaluate the viability (trypan blue dye exclusion and amine-reactive dye staining) and functionality (frequency of gamma interferon [IFN-gamma]-producing T cells after polyclonal stimulation) of fresh and cryopreserved PBMCs from children with dengue (in acute and convalescence phases), children with other febrile illnesses, and healthy children as controls. Plasma sTRAIL levels were also evaluated. The frequencies of nonviable PBMCs detected by the two viability assays were positively correlated (r = 0.74; P < 0.0001). Cryopreservation particularly affected the PBMCs of children with dengue, who had a higher frequency of nonviable cells than healthy children and children with other febrile illnesses (P <= 0.02), and PBMC viability levels were restored in the convalescent phase. In the acute phase, an increased frequency of CD3+ CD8+ amine-positive cells was found before cryopreservation (P = 0.01). Except for B cells in the acute phase, cryopreservation usually did not affect the relative frequencies of viable PBMC subpopulations. Dengue infection reduced the frequency of IFN-gamma-producing CD3+ cells after stimulation compared with healthy controls and convalescent phase patients (P <= 0.003), and plasma sTRAIL correlated with this decreased frequency in dengue (rho = -0.56; P = 0.01). Natural dengue infection in children can affect the viability and functionality of cryopreserved PBMCs. PMID- 26961862 TI - Long-term clinical outcomes after successful and failed recanalization to native chronic Total occlusion: Insights from the Busan chronic Total occlusion (B-CTO) Registry. AB - OBJECTIVE: To assess hard major adverse clinical events (HMACE) after successful versus failed percutaneous coronary intervention for chronic total occlusion (PCI CTO). BACKGROUND: There are limited data regarding long-term HMACE risks based on PCI-CTO success. METHODS: First-time PCI was performed in 438 consecutive patients with 473 target CTO lesions. Patients after procedural success (n=355; 378 CTO lesions) and failure (n=83; 95 CTO lesions) were followed for an average 40months (7-77months range). We compared HMACE (composite of cardiac death, non fatal myocardial infarction (MI), and stroke) dependent on the success of PCI. RESULTS: The incidence of HMACE was low, with a total of 16 events, and did not differ {6% vs.3.1%, HR=0.47; CI [0.16-1.35; p=0.162} dependent on the success of PCI-CTO. There were less cardiac deaths {0.3% vs. 1.2%, RR=0.22; CI [0.01 3.50];p=0.283}, non fatal MI {1.1% vs.3.6%, RR=0.27; CI [0.06-1.22], p=0.089}, but more strokes {1.7% vs.1.2%, RR=1.32; CI [0.16-10.99], p=0.795} after successful PCI-CTO. CONCLUSIONS: The risks of HMACE after PCI-CTO over long-term follow-up were minimal, and do not depend on the procedure success. This unexpected finding somewhat challenge the aggressive interventional approach, and should be confirmed in the adequately powered randomized trial. PMID- 26961863 TI - AGEs and HMGB1 Increase Inflammatory Cytokine Production from Human Placental Cells, Resulting in an Enhancement of Monocyte Migration. AB - PROBLEM: Advanced glycation end products (AGEs) and high-mobility group box-1 (HMGB1) are considered contributing to placental inflammation. We examined the effect of AGEs and HMGB1 on cytokines from Sw.71 human trophoblast cell lines and the interactions between Sw.71 cells and THP-1-monocytes. METHODS OF STUDY: Sw.71 cells were cultured with/without AGEs or HMGB1. We examined the role of AGEs or HMGB1 on THP1 migration and effect of AGEs on IL-6 from Sw.71 cells using co cultures or conditioned medium from THP-1 cells. RESULTS: AGEs and HMGB1 increased interleukin (IL)-6, IL-8, and chemokine C-C motif ligand 2 (CCL2) secretion from Sw.71 cells. The secretion of IL-6 was dependent on reactive oxygen species (ROS) and NF-kappaB. AGEs stimulated IL-6 secretion through receptor RAGE and TLR4, whereas HMGB1 stimulated it through TLR4. AGEs, but not HMGB1, increased monocyte migration via IL-8 and CCL2 from Sw.71 cells. THP-1 monocytes induced IL-6 secretion from Sw.71 cells, and AGEs further stimulated it. CONCLUSIONS: AGEs and HMGB1 may promote sterile placental inflammation cooperating with monocytes/macrophages. PMID- 26961864 TI - Revisiting photodynamic therapy dosimetry: reductionist & surrogate approaches to facilitate clinical success. AB - Photodynamic therapy (PDT) can be a highly complex treatment, with many parameters influencing treatment efficacy. The extent to which dosimetry is used to monitor and standardize treatment delivery varies widely, ranging from measurement of a single surrogate marker to comprehensive approaches that aim to measure or estimate as many relevant parameters as possible. Today, most clinical PDT treatments are still administered with little more than application of a prescribed drug dose and timed light delivery, and thus the role of patient specific dosimetry has not reached widespread clinical adoption. This disconnect is at least partly due to the inherent conflict between the need to measure and understand multiple parameters in vivo in order to optimize treatment, and the need for expedience in the clinic and in the regulatory and commercialization process. Thus, a methodical approach to selecting primary dosimetry metrics is required at each stage of translation of a treatment procedure, moving from complex measurements to understand PDT mechanisms in pre-clinical and early phase I trials, towards the identification and application of essential dose-limiting and/or surrogate measurements in phase II/III trials. If successful, identifying the essential and/or reliable surrogate dosimetry measurements should help facilitate increased adoption of clinical PDT. In this paper, examples of essential dosimetry points and surrogate dosimetry tools that may be implemented in phase II/III trials are discussed. For example, the treatment efficacy as limited by light penetration in interstitial PDT may be predicted by the amount of contrast uptake in CT, and so this could be utilized as a surrogate dosimetry measurement to prescribe light doses based upon pre-treatment contrast. Success of clinical ALA-based skin lesion treatment is predicted almost uniquely by the explicit or implicit measurements of photosensitizer and photobleaching, yet the individualization of treatment based upon each patients measured bleaching needs to be attempted. In the case of ALA, lack of PpIX is more likely an indicator that alternative PpIX production methods must be implemented. Parsimonious dosimetry, using surrogate measurements that are clinically acceptable, might strategically help to advance PDT in a medical world that is increasingly cost and time sensitive. Careful attention to methodologies that can identify and advance the most critical dosimetric measurements, either direct or surrogate, are needed to ensure successful incorporation of PDT into niche clinical procedures. PMID- 26961865 TI - The partner in late-life repartnering: caregiving expectations from an intergenerational perspective. AB - BACKGROUND: Late-life repartnering among functionally independent adults, resulting in complex stepfamilies, has emerged with increased life expectancy, and is likely to develop further. It is perceived as a chance for renewal and autonomy, enabling a release from dependency on offspring, whereas caregiving is associated with dependency and becoming a burden on family members. Thus, the experiences of late-life repartnering and caregiving are opposites. Using a life course perspective, we explore partner caregiving expectations in late-life repartnering from the viewpoints of three generations in complex stepfamilies in Israel, a society characterized by collectivist alongside individualist familial norms. METHODS: Using criterion sampling, we recruited 19 stepfamily units (38 families) of functionally independent persons who repartnered at the official retirement age or older and had offspring from a lifelong marriage that ended in widowhood or divorce. One-hundred-seven semi-structured qualitative interviews with older partners, their adult children, and grandchildren were audio-recorded and transcribed verbatim. Analysis was based on grounded theory principles and dyadic analysis adapted to families. RESULTS: Two themes emerged: caregiving commitment and decision making. Issues included: influences of partner-caregiving history; chronic versus temporary caregiving situations; caregiving strengthening partner relationships and influencing stepfamily relationships, and moral dilemmas, such as what happens when fun - a motive for repartnering - is no longer possible. Could abandonment become an option? CONCLUSIONS: From a life course perspective, caregiving, as "on-time," and late-life repartnering, as "off time," highlight the lack of norms and the need to establish normative behavior for caregiving in late-life repartnering in diverse cultural contexts along with its reservations. PMID- 26961866 TI - [Competence Network for Congenital Heart Defects: innovative research for a young patient group]. AB - BACKGROUND: Congenital heart disease is the most frequent congenital malformation in humans and affects almost 1 % of all newborns. Thanks to advances in diagnostics and treatment, over 90 % of those affected reach adulthood today. Patient numbers are therefore growing constantly. The majority of those affected, however, remain chronically ill throughout life and require continuous specialized care. The spectrum of different clinical pictures is vast. Since this is a relatively young patient group, both research and care are lacking relevant knowledge and experience. OBJECTIVE: The Competence Network for Congenital Heart Defects (CNCHD) was founded in 2003 to tackle the challenge of heterogeneity and accordingly small sample sizes by means of networked research. The following article offers an overview of the network and its mode of operation. MATERIAL AND METHODS: The Germany-wide research network involves all relevant levels of research, public health care, the patient community and the general public. On the basis of a complex and flexible database infrastructure, it facilitates multicenter and interdisciplinary research in the field of congenital heart disease. RESULTS AND DISCUSSION: The CNCHD succeeded in establishing research on congenital heart disease throughout Germany by providing a powerful research network and a suitable infrastructure. Scientists from across Germany and all over the world use this basis to jointly find answers to burning questions in the field of congenital heart disease. PMID- 26961867 TI - [From the Competence Network on Depression and Suicidality to the German Depression Foundation. National and international prevention of suicidal behaviour and optimizing health care through using of E-Mental-Health]. AB - Depression is a very common, severe, socio-economically highly relevant disorder and the main cause for approximately 10,000 suicides in Germany annually. There is capital room for improvement and optimization of the care for depressed patients, as effective and evidence-based treatment options are available. However, they are only used optimally by a minority of the people affected due to huge diagnostic and therapeutic deficits. The "Compentence Network on Depression and Suicidality" provided several evidence-based concepts to improve care for patients affected by depression and to prevent suicidal behaviour. Especially the four-level intervention approach of the Alliances Against Depression has been successfully adapted and implemented by more than 100 regions within Europe and globally as well. The infrastructure of the Competence Network could be efficiently sustained throughout the establishment of the German Depression Foundation and the European Alliance against Depression. Since 2014, all research activities have been extended nationally and internationally by the establishment of a Depression Research Centre with a special focus on various E-Mental-Health projects. PMID- 26961868 TI - [The Competence Network for HIV/AIDS. Data, Samples, Facts]. AB - BACKGROUND: With funding for the Competence Networks in Medicine from the Federal Ministry of Education and Research, the Competence Network for HIV/AIDS (KompNet HIV/AIDS) was established as an interdisciplinary research association. Essential working groups were incorporated all over Germany, which are active in clinical and basic HIV/AIDS research. OBJECTIVES: After successful establishment, providing research infrastructure for national and international cooperation in the field of HIV/AIDS was the focus of the network. By bringing together research activities, preconditions are created for improving HIV infection treatment and increasing life expectancy of HIV-infected patients. MATERIALS AND METHODS: The members of KompNet HIV/AIDS are HIV experts from university clinics, HIV physicians, patient representatives, as well as national reference centers. As a scientific research basis, the network established an HIV patient cohort. Clinical and sociodemographic data of HIV patients were documented biannually and complemented by serum and DNA-samples collected twice per year. Furthermore, a child cohort was set up. RESULTS AND CONCLUSION: Within the KompNet HIV/AIDS, a research infrastructure for HIV was established for internal, external as well international scientists. Within the HIV cohort a total of 16,500 patients are documented. The associated biobank comprises ~ 56,000 serum samples and ~ 16,000 DNA samples. The child cohort consists of 647 HIV-exposed and 230 infected children. The KompNet HIV/AIDS cohorts became an important partner in several international collaborations. Nevertheless, the maintenance of such infrastructures without public funding is a challenge. PMID- 26961869 TI - Transforming Growth Factor-beta Family Ligands Can Function as Antagonists by Competing for Type II Receptor Binding. AB - Transforming growth factor-beta (TGF-beta) family ligands are pleiotropic cytokines. Their physiological activities are not determined by a simple coupling of stimulus and response, but depend critically on context, i.e. the interplay of receptors, ligands, and regulators that form the TGF-beta signal transduction system of a cell or tissue. How these different components combine to regulate signaling activities remains poorly understood. Here, we describe a ligand mediated mechanism of signaling regulation. Based on the observation that the type II TGF-beta family receptors ActRIIA, ActRIIB, and BMPRII interact with a large group of overlapping ligands at overlapping epitopes, we hypothesized high affinity ligands compete with low affinity ligands for receptor binding and signaling. We show activin A and other high affinity ligands directly inhibited signaling by the low affinity ligands BMP-2, BMP-7, and BMP-9. We demonstrate activin A functions as a competitive inhibitor that blocks the ligand binding epitope on type II receptors. We propose binding competition and signaling antagonism are integral functions of the TGF-beta signal transduction system. These functions could help explain how activin A modulates physiological signaling during extraordinary cellular responses, such as injury and wound healing, and how activin A could elicit disease phenotypes such as cancer-related muscle wasting and fibrosis. PMID- 26961870 TI - Human and Murine Interleukin 23 Receptors Are Novel Substrates for A Disintegrin and Metalloproteases ADAM10 and ADAM17. AB - IL-23 (interleukin 23) regulates immune responses against pathogens and plays a major role in the differentiation and maintenance of TH17 cells and the development of autoimmune diseases and cancer. The IL-23 receptor (IL-23R) complex consists of the unique IL-23R and the common IL-12 receptor beta1 (IL 12Rbeta1). Differential splicing generates antagonistic soluble IL-23R (sIL-23R) variants, which might limit IL-23-mediated immune responses. Here, ectodomain shedding of human and murine IL-23R was identified as an alternative pathway for the generation of sIL-23R. Importantly, proteolytically released sIL-23R has IL 23 binding activity. Shedding of IL-23R was induced by stimulation with the phorbol ester phorbol 12-myristate 13-acetate (PMA), but not by ionomycin. PMA induced shedding was abrogated by an ADAM (A disintegrin and metalloprotease) 10 and 17 selective inhibitor, but not by an ADAM10 selective inhibitor. ADAM17 deficient but not ADAM10-deficient HEK293 cells failed to shed IL-23R after PMA stimulation, demonstrating that ADAM17 but not ADAM10 cleaves the IL-23R. Constitutive shedding was, however, inhibited by an ADAM10 selective inhibitor. Using deletions and specific amino acid residue exchanges, we identified critical determinants of ectodomain shedding within the stalk region of the IL-23R. Finally, interaction studies identified domains 1 and 3 of the IL-23R as the main ADAM17 binding sites. In summary, we describe human and murine IL-23R as novel targets for protein ectodomain shedding by ADAM10 and ADAM17. PMID- 26961871 TI - Englerin A Inhibits EWS-FLI1 DNA Binding in Ewing Sarcoma Cells. AB - High-throughput screening of extracts from plants, marine, and micro-organisms led to the identification of the extract from the plant Phyllanthus engleri as the most potent inhibitor of EWS-FLI1 induced luciferase reporter expression. Testing of compounds isolated from this extract in turn led to the identification of Englerin A (EA) as the active constituent of the extract. EA induced both necrosis and apoptosis in Ewing cells subsequent to a G2M accumulation of cells in the cell cycle. It also impacted clonogenic survival and anchorage-independent proliferation while also decreasing the proportion of chemotherapy-resistant cells identified by high ALDH activity. EA also caused a sustained increase in cytosolic calcium levels. EA appears to exert its effect on Ewing cells through a decrease in phosphorylation of EWS-FLI1 and its ability to bind DNA. This effect is mediated, at least in part, through a decrease in the levels of the calcium dependent protein kinase PKC-betaI after a transient up-regulation. PMID- 26961873 TI - Bithionol Potently Inhibits Human Soluble Adenylyl Cyclase through Binding to the Allosteric Activator Site. AB - The signaling molecule cAMP regulates functions ranging from bacterial transcription to mammalian memory. In mammals, cAMP is synthesized by nine transmembrane adenylyl cyclases (ACs) and one soluble AC (sAC). Despite similarities in their catalytic domains, these ACs differ in regulation. Transmembrane ACs respond to G proteins, whereas sAC is uniquely activated by bicarbonate. Via bicarbonate regulation, sAC acts as a physiological sensor for pH/bicarbonate/CO2, and it has been implicated as a therapeutic target, e.g. for diabetes, glaucoma, and a male contraceptive. Here we identify the bisphenols bithionol and hexachlorophene as potent, sAC-specific inhibitors. Inhibition appears mostly non-competitive with the substrate ATP, indicating that they act via an allosteric site. To analyze the interaction details, we solved a crystal structure of an sAC.bithionol complex. The structure reveals that the compounds are selective for sAC because they bind to the sAC-specific, allosteric binding site for the physiological activator bicarbonate. Structural comparison of the bithionol complex with apo-sAC and other sAC.ligand complexes along with mutagenesis experiments reveals an allosteric mechanism of inhibition; the compound induces rearrangements of substrate binding residues and of Arg(176), a trigger between the active site and allosteric site. Our results thus provide 1) novel insights into the communication between allosteric regulatory and active sites, 2) a novel mechanism for sAC inhibition, and 3) pharmacological compounds targeting this allosteric site and utilizing this mode of inhibition. These studies provide support for the future development of sAC-modulating drugs. PMID- 26961872 TI - Multidrug Resistance-associated Protein-1 (MRP-1)-dependent Glutathione Disulfide (GSSG) Efflux as a Critical Survival Factor for Oxidant-enriched Tumorigenic Endothelial Cells. AB - Endothelial cell tumors are the most common soft tissue tumors in infants. Tumor forming endothelial (EOMA) cells are able to escape cell death fate despite excessive nuclear oxidant burden. Our previous work recognized perinuclear Nox-4 as a key contributor to EOMA growth. The objective of this work was to characterize the mechanisms by which EOMA cells evade oxidant toxicity and thrive. In EOMA cells, compared with in the cytosol, the nuclear GSSG/GSH ratio was 5-fold higher. Compared to the ratio observed in healthy murine aortic endothelial (MAE) cells, GSSG/GSH was over twice as high in EOMA cells. Multidrug resistance-associated protein-1 (MRP-1), an active GSSG efflux mechanism, showed 2-fold increased activity in EOMA compared with MAE cells. Hyperactive YB-1 and Ape/Ref-1 were responsible for high MRP-1 expression in EOMA. Proximity ligand assay demonstrated MRP-1 and YB-1 binding. Such binding enabled the nuclear targeting of MRP-1 in EOMA in a leptomycin-B-sensitive manner. MRP-1 inhibition as well as knockdown trapped nuclear GSSG, causing cell death of EOMA. Disulfide loading of cells by inhibition of GSSG reductase (bischoloronitrosourea) or thioredoxin reductase (auranofin) was effective in causing EOMA death as well. In sum, EOMA cells survive a heavy oxidant burden by rapid efflux of GSSG, which is lethal if trapped within the cell. A hyperactive MRP-1 system for GSSG efflux acts as a critical survival factor for these cells, making it a potential target for EOMA therapeutics. PMID- 26961874 TI - alphaB-Crystallin Interacts with Nav1.5 and Regulates Ubiquitination and Internalization of Cell Surface Nav1.5. AB - Nav1.5, the pore-forming alpha subunit of the cardiac voltage-gated Na(+) channel complex, is required for the initiation and propagation of the cardiac action potential. Mutations in Nav1.5 cause cardiac arrhythmias and sudden death. The cardiac Na(+) channel functions as a protein complex; however, its complete components remain to be fully elucidated. A yeast two-hybrid screen identified a new candidate Nav1.5-interacting protein, alphaB-crystallin. GST pull-down, co immunoprecipitation, and immunostaining analyses validated the interaction between Nav1.5 and alphaB-crystallin. Whole-cell patch clamping showed that overexpression of alphaB-crystallin significantly increased peak sodium current (INa) density, and the underlying molecular mechanism is the increased cell surface expression level of Nav1.5 via reduced internalization of cell surface Nav1.5 and ubiquitination of Nav1.5. Knock-out of alphaB-crystallin expression significantly decreased the cell surface expression level of Nav1.5. Co immunoprecipitation analysis showed that alphaB-crystallin interacted with Nedd4 2; however, a catalytically inactive Nedd4-2-C801S mutant impaired the interaction and abolished the up-regulation of INa by alphaB-crystallin. Nav1.5 mutation V1980A at the interaction site for Nedd4-2 eliminated the effect of alphaB-crystallin on reduction of Nav1.5 ubiquitination and increases of INa density. Two disease-causing mutations in alphaB-crystallin, R109H and R151X (nonsense mutation), eliminated the effect of alphaB-crystallin on INa This study identifies alphaB-crystallin as a new binding partner for Nav1.5. alphaB Crystallin interacts with Nav1.5 and increases INa by modulating the expression level and internalization of cell surface Nav1.5 and ubiquitination of Nav1.5, which requires the protein-protein interactions between alphaB-crystallin and Nav1.5 and between alphaB-crystallin and functionally active Nedd4-2. PMID- 26961875 TI - Demonstration That the Radical S-Adenosylmethionine (SAM) Enzyme PqqE Catalyzes de Novo Carbon-Carbon Cross-linking within a Peptide Substrate PqqA in the Presence of the Peptide Chaperone PqqD. AB - The radical S-adenosylmethionine (SAM) protein PqqE is predicted to function in the pyrroloquinoline quinone (PQQ) biosynthetic pathway via catalysis of carbon carbon bond formation between a glutamate and tyrosine side chain within the small peptide substrate PqqA. We report here that PqqE activity is dependent on the accessory protein PqqD, which was recently shown to bind PqqA tightly. In addition, PqqE activity in vitro requires the presence of a flavodoxin- and flavodoxin reductase-based reduction system, with other reductants leading to an uncoupled cleavage of the co-substrate SAM. These results indicate that PqqE, in conjunction with PqqD, carries out the first step in PQQ biosynthesis: a radical mediated formation of a new carbon-carbon bond between two amino acid side chains on PqqA. PMID- 26961877 TI - O-Glycosylation of a Secretory Granule Membrane Enzyme Is Essential for Its Endocytic Trafficking. AB - Peptidylglycine alpha-amidating monooxygenase (PAM) (EC 1.14.17.3) catalyzes peptide amidation, a crucial post-translational modification, through the sequential actions of its monooxygenase (peptidylglycine alpha-hydroxylating monooxygenase) and lyase (peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL)) domains. Alternative splicing generates two different regions that connect the protease-resistant catalytic domains. Inclusion of exon 16 introduces a pair of Lys residues, providing a site for controlled endoproteolytic cleavage of PAM and the separation of soluble peptidylglycine alpha-hydroxylating monooxygenase from membrane-associated PAL. Exon 16 also includes two O-glycosylation sites. PAM-1 lacking both glycosylation sites (PAM-1/OSX; where OSX is O-glycan-depleted mutant of PAM-1) was stably expressed in AtT-20 corticotrope tumor cells. In PAM 1/OSX, a cleavage site for furin-like convertases was exposed, generating a shorter form of membrane-associated PAL. The endocytic trafficking of PAM-1/OSX differed dramatically from that of PAM-1. A soluble fragment of the cytosolic domain of PAM-1 was produced in the endocytic pathway and entered the nucleus; very little soluble fragment of the cytosolic domain was produced from PAM-1/OSX. Internalized PAM-1/OSX was rapidly degraded; unlike PAM-1, very little internalized PAM-1/OSX was detected in multivesicular bodies. Blue native PAGE analysis identified high molecular weight complexes containing PAM-1; the ability of PAM-1/OSX to form similar complexes was markedly diminished. By promoting the formation of high molecular weight complexes, O-glycans may facilitate the recycling of PAM-1 through the endocytic compartment. PMID- 26961876 TI - Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch. AB - TRPV4 ion channels function in epidermal keratinocytes and in innervating sensory neurons; however, the contribution of the channel in either cell to neurosensory function remains to be elucidated. We recently reported TRPV4 as a critical component of the keratinocyte machinery that responds to ultraviolet B (UVB) and functions critically to convert the keratinocyte into a pain-generator cell after excess UVB exposure. One key mechanism in keratinocytes was increased expression and secretion of endothelin-1, which is also a known pruritogen. Here we address the question of whether TRPV4 in skin keratinocytes functions in itch, as a particular form of "forefront" signaling in non-neural cells. Our results support this novel concept based on attenuated scratching behavior in response to histaminergic (histamine, compound 48/80, endothelin-1), not non-histaminergic (chloroquine) pruritogens in Trpv4 keratinocyte-specific and inducible knock-out mice. We demonstrate that keratinocytes rely on TRPV4 for calcium influx in response to histaminergic pruritogens. TRPV4 activation in keratinocytes evokes phosphorylation of mitogen-activated protein kinase, ERK, for histaminergic pruritogens. This finding is relevant because we observed robust anti-pruritic effects with topical applications of selective inhibitors for TRPV4 and also for MEK, the kinase upstream of ERK, suggesting that calcium influx via TRPV4 in keratinocytes leads to ERK-phosphorylation, which in turn rapidly converts the keratinocyte into an organismal itch-generator cell. In support of this concept we found that scratching behavior, evoked by direct intradermal activation of TRPV4, was critically dependent on TRPV4 expression in keratinocytes. Thus, TRPV4 functions as a pruriceptor-TRP in skin keratinocytes in histaminergic itch, a novel basic concept with translational-medical relevance. PMID- 26961878 TI - Acquisition of Chemoresistance and Other Malignancy-related Features of Colorectal Cancer Cells Are Incremented by Ribosome-inactivating Stress. AB - Colorectal cancer (CRC) as an environmental disease is largely influenced by accumulated epithelial stress from diverse environmental causes. We are exposed to ribosome-related insults, including ribosome-inactivating stress (RIS), from the environment, dietary factors, and medicines, but their physiological impacts on the chemotherapy of CRC are not yet understood. Here we revealed the effects of RIS on chemosensitivity and other malignancy-related properties of CRC cells. First, RIS led to bidirectional inhibition of p53-macrophage inhibitory cytokine 1 (MIC-1)-mediated death responses in response to anticancer drugs by either enhancing ATF3-linked antiapoptotic signaling or intrinsically inhibiting MIC-1 and p53 expression, regardless of ATF3. Second, RIS enhanced the epithelial mesenchymal transition and biogenesis of cancer stem-like cells in an ATF3 dependent manner. These findings indicate that gastrointestinal exposure to RIS interferes with the efficacy of chemotherapeutics, mechanistically implying that ATF3-linked malignancy and chemoresistance can be novel therapeutic targets for the treatment of environmentally aggravated cancers. PMID- 26961879 TI - Molecular Basis and Consequences of the Cytochrome c-tRNA Interaction. AB - The intrinsic apoptosis pathway occurs through the release of mitochondrial cytochrome c to the cytosol, where it promotes activation of the caspase family of proteases. The observation that tRNA binds to cytochrome c revealed a previously unexpected mode of apoptotic regulation. However, the molecular characteristics of this interaction, and its impact on each interaction partner, are not well understood. Using a novel fluorescence assay, we show here that cytochrome c binds to tRNA with an affinity comparable with other tRNA-protein binding interactions and with a molecular ratio of ~3:1. Cytochrome c recognizes the tertiary structural features of tRNA, particularly in the core region. This binding is independent of the charging state of tRNA but is regulated by the redox state of cytochrome c. Compared with reduced cytochrome c, oxidized cytochrome c binds to tRNA with a weaker affinity, which correlates with its stronger pro-apoptotic activity. tRNA binding both facilitates cytochrome c reduction and inhibits the peroxidase activity of cytochrome c, which is involved in its release from mitochondria. Together, these findings provide new insights into the cytochrome c-tRNA interaction and apoptotic regulation. PMID- 26961881 TI - Different Roles of Negative and Positive Components of the Circadian Clock in Oncogene-induced Neoplastic Transformation. AB - In mammals, circadian rhythms in physiological function are generated by a molecular oscillator driven by transcriptional-translational feedback loop consisting of negative and positive regulators. Disruption of this circadian clock machinery is thought to increase the risk of cancer development, but the potential contributions of each component of circadian clock to oncogenesis have been little explored. Here we reported that negative and positive transcriptional regulators of circadian feedback loop had different roles in oncogene-induced neoplastic transformation. Mouse embryonic fibroblasts prepared from animals deficient in negative circadian clock regulators, Period2 (Per2) or Cryptochrome1/2 (Cry1/2), were prone to transformation induced by co-expression of H-ras(V12) and SV40 large T antigen (SV40LT). In contrast, mouse embryonic fibroblasts prepared from mice deficient in positive circadian clock regulators, Bmal1 or Clock, showed resistance to oncogene-induced transformation. In Per2 mutant and Cry1/2-null cells, the introduction of oncogenes induced expression of ATF4, a potent repressor of cell senescence-associated proteins p16INK4a and p19ARF. Elevated levels of ATF4 were sufficient to suppress expression of these proteins and drive oncogenic transformation. Conversely, in Bmal1-null and Clock mutant cells, the expression of ATF4 was not induced by oncogene introduction, which allowed constitutive expression of p16INK4a and p19ARF triggering cellular senescence. Although genetic ablation of either negative or positive transcriptional regulators of the circadian clock leads to disrupted rhythms in physiological functions, our findings define their different contributions to neoplastic cellular transformation. PMID- 26961882 TI - Rapidly Translated Polypeptides Are Preferred Substrates for Cotranslational Protein Degradation. AB - Nascent polypeptides are degraded by the proteasome concurrently with their synthesis on the ribosome. This process, called cotranslational protein degradation (CTPD), has been observed for years, but the underlying mechanisms remain poorly understood. Equally unclear are the identities of cellular proteins genuinely subjected to CTPD. Here we report the identification of CTPD substrates in the yeast Saccharomyces cerevisiae via a quantitative proteomic analysis. We compared the abundance of individual ribosome-bound nascent chains between a wild type strain and a mutant defective in CTPD. Of 1,422 proteins acquired from the proteomic analysis, 289 species are efficient CTPD substrates, with >30% of their nascent chains degraded cotranslationally. We found that proteins involved in translation, ribosome biogenesis, nuclear transport, and amino acid metabolism are more likely to be targeted for CTPD. There is a strong correlation between CTPD and the translation efficiency. CTPD occurs preferentially to rapidly translated polypeptides. CTPD is also influenced by the protein sequence length; longer polypeptides are more susceptible to CTPD. In addition, proteins with N terminal disorder have a higher probability of being degraded cotranslationally. Interestingly, the CTPD efficiency is not related to the half-lives of mature proteins. These results for the first time indicate an inverse correlation between CTPD and cotranslational folding on a proteome scale. The implications of this study with respect to the physiological significance of CTPD are discussed. PMID- 26961883 TI - Influence of internal migration on reproductive health in Myanmar: results from a recent cross-sectional survey. AB - BACKGROUND: Maternal and reproductive health remains a significant public health issue in Myanmar. Little data exists on women's health issues, including social and demographic influences. While past studies have demonstrated rural/urban health disparities, an increasingly important population resulting from urban growth in Myanmar is the internal migrant population, individuals moving within the country for better job or educational opportunities. Past studies suggest that women make up more than half of internal migrants, yet there is a dearth of information on this new wave of migration, particularly on women's reproductive health issues. The objective of this study is to assess the influence of women's migration in Myanmar on reproductive health outcomes, including delivering in a facility, using a skilled birth attendant, and using a modern method of family planning. METHODS: Data from a cross-sectional household survey using multistage cluster sampling design conducted between September to October 2014 was used to assess the accessibility and the use of maternal and child health products and services. A total of 1800 currently married women of reproductive age, including 348 from urban and 1452 from rural areas, were recruited to complete surveys. A set of multivariable regressions was performed to assess reproductive health outcomes and predictors. RESULTS: Across health indicators, female migrants had better health outcomes compared to non-migrants. Controlling for demographic characteristics, migrants were 1.60 times more likely to use a modern form of family planning compared to non-migrants (p < 0.01) and use antenatal care during pregnancy (p < 0.05). While not statistically significant, migrants were 1.29 times more likely to deliver with a skilled attendant and 1.08 times more likely to deliver in a facility. CONCLUSIONS: This study found that female migrants in Myanmar reported better health outcomes compared to non-migrant women in regards to family planning and maternal health. Future research should focus on monitoring the outcomes of migrants and their children over time to assess long term impacts. PMID- 26961880 TI - Proteinase 3 Is a Phosphatidylserine-binding Protein That Affects the Production and Function of Microvesicles. AB - Proteinase 3 (PR3), the autoantigen in granulomatosis with polyangiitis, is expressed at the plasma membrane of resting neutrophils, and this membrane expression increases during both activation and apoptosis. Using surface plasmon resonance and protein-lipid overlay assays, this study demonstrates that PR3 is a phosphatidylserine-binding protein and this interaction is dependent on the hydrophobic patch responsible for membrane anchorage. Molecular simulations suggest that PR3 interacts with phosphatidylserine via a small number of amino acids, which engage in long lasting interactions with the lipid heads. As phosphatidylserine is a major component of microvesicles (MVs), this study also examined the consequences of this interaction on MV production and function. PR3 expressing cells produced significantly fewer MVs during both activation and apoptosis, and this reduction was dependent on the ability of PR3 to associate with the membrane as mutating the hydrophobic patch restored MV production. Functionally, activation-evoked MVs from PR3-expressing cells induced a significantly larger respiratory burst in human neutrophils compared with control MVs. Conversely, MVs generated during apoptosis inhibited the basal respiratory burst in human neutrophils, and those generated from PR3-expressing cells hampered this inhibition. Given that membrane expression of PR3 is increased in patients with granulomatosis with polyangiitis, MVs generated from neutrophils expressing membrane PR3 may potentiate oxidative damage of endothelial cells and promote the systemic inflammation observed in this disease. PMID- 26961885 TI - Erratum to: C3 Polymorphism Influences Circulating Levels of C3, ASP and Lipids in Schizophrenic Patients. PMID- 26961884 TI - Light environment within a leaf. II. Progress in the past one-third century. AB - Studies directly related to light environments within a leaf, conduced mainly in the past one-third century, are reviewed. In particular, studies that revealed the profiles of light absorption and photosynthetic capacity are highlighted. Progress in this research field has been accelerated by devising innovative techniques. Roles of the main photosynthetic tissues, the palisade and spongy tissues, as the light guide and diffuser, respectively, are discussed. When the leaf is illuminated with diffuse light, light is absorbed more by the chloroplasts located near the illuminated surface. The meanings of the occupation of the mesophyll surfaces facing the intercellular spaces by chloroplasts and chloroplast movement are also discussed. The discrepancy between the light absorption profile and that of photosynthetic capacity is examined most intensively. PMID- 26961886 TI - CX3CR1-Mediated Akt1 Activation Contributes to the Paclitaxel-Induced Painful Peripheral Neuropathy in Rats. AB - Painful peripheral neuropathy is a serious dose-limiting side effect of paclitaxel therapy, which unfortunately often happens during the optimal clinical management of chemotherapy in cancer patients. Currently the underlying mechanisms of the painful peripheral neuropathy remain largely unknown. Here, we found that paclitaxel treatment (3 * 8 mg/kg, cumulative dose 24 mg/kg) upregulated the expression of CX3CR1 and phosphorylated Akt1 in DRG and spinal dorsal horn. Blocking of Akt1 pathway activation with different inhibitor (MK 2206 or LY294002) significantly attenuated mechanical allodynia and thermal hyperalgesia induced by paclitaxel. Furthermore, inhibition of CX3CR1 by using neutralizing antibody not only prevented Akt1 activation in DRG and spinal dorsal horn but also alleviated pain-related behavior induced by paclitaxel treatment. This study suggested that CX3CR1/Akt1 signaling pathway may be a potential target for prevention and reversion of the painful peripheral neuropathy induced by paclitaxel. PMID- 26961887 TI - (7R,8S)-Dehydrodiconiferyl Alcohol Suppresses Lipopolysaccharide-Induced Inflammatory Responses in BV2 Microglia by Inhibiting MAPK Signaling. AB - (7R,8S)-Dehydrodiconiferyl alcohol (DDA), a lignan isolated from the dried stems of Clematis armandii, has been found to exert potential anti-inflammatory activity in vitro. In the present study, we investigated the effects and possible mechanisms of DDA on lipopolysaccharide (LPS)-mediated inflammatory response in murine BV2 microglia. Our results revealed that non-toxic concentrations (6.25-25 MUM) of DDA markedly suppressed LPS-induced production of nitric oxide, expression of inducible nitric oxide synthase and cyclooxygenase-2, and release of inflammatory factors, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 in a concentration dependent manner. In addition, DDA time- and concentration-dependently attenuated LPS-induced phosphorylation of c-Jun N terminal kinase 1/2 (JNK), but not protein kinase B, p38, or extracellular signal regulated kinase 1/2. Moreover, DDA significantly suppress LPS-mediated nuclear factor-kappaB (NF-kappaB) activation by inhibiting phosphorylation and nuclear translocation of NF-kappaB p65. Collectively, our results demonstrated that DDA inhibited LPS-stimulated inflammatory response in BV2 cell, at least in part, through inhibition of NF-kappaB activation and modulation of JNK signaling. PMID- 26961888 TI - Endogenous CBS-H2S Pathway Contributes to the Development of CCI-Induced Neuropathic Pain. AB - Studies showed a complex relationship between hydrogen sulfide (H2S) and neuropathic pain. In this study, the relationship between endogenous CBS-H2S pathway in L4-6 spinal cord and neuropathic pain was explored. A total of 163 adult Kunming mice were used in this study. CBS expression and H2S formation in L4-6 spinal cord were detected in the development of neuropathic pain firstly. Then, effect of AOAA, an CBS inhibitor, on treatment of neuropathic pain by chronic construction injury surgery (CCI) was detected. Pain thresholds and activation of NF-kappaB(p65), ERK1/2 and CREB were measured as biomarks of neuropathic pain. Results showed that CCI surgery significantly upregulated protein expression of CBS and H2S formation. Correlation analysis showed pain thresholds had negative relationships with protein expression of CBS and H2S formation. Treatment with AOAA, a CBS inhibitor, inhibited CCI-induced upregulation of CBS expression and H2S formation (P < 0.05). Further, AOAA significantly decreased activation of NF-kappaB(p65), ERK1/2 and CREB pathway, and reversed CCI-induced allodynia (P < 0.05). This indicated that CBS-H2S pathway promoted the development of neuropathic pain. CBS-H2S pathway could be a promising target for treatment of neuropathic pain. PMID- 26961890 TI - Role of the RVM in Descending Pain Regulation Originating from the Cerebrospinal Fluid-Contacting Nucleus. AB - Evidence has suggested that cerebrospinal fluid-contacting nucleus (CSF contacting nucleus) is correlated with the development and recurrence of pain. A recent research showed that the CSF-contacting nucleus acts as a component of the descending 5-hydroxytryptamine (5-HT) system and plays a role in descending pain inhibition. However, limited studies are conducted to investigate the relationship between the CSF-contacting nucleus and pain. In present study, we explored the effect of CSF-contacting nucleus on nociceptive behaviors in both normal and neuropathic rats via targeted ablation of the CSF-contacting nucleus in the brainstem, using cholera toxin subunit B-saporin (CB-SAP), a cytotoxin coupled to cholera toxin subunit B. The CB-SAP-treated rats showed aggravated thermal hyperalgesia and mechanical allodynia. Also, results from immunohistochemical experiments showed that rostral ventromedial medulla (RVM) received fiber projection from the CSF-contacting nucleus, which disappeared after ablation of the CSF-contacting nucleus, and the CB-SAP treated rats showed downregulation of c-Fos expression in the RVM as compared with the rats receiving i.c.v. injection of phosphate buffer saline (PBS). A significant downregulation of 5-HT-labeled neurons and tryptophan hydroxylase 2 (TPH2) as the marker of 5-HT cells in the RVM, and 5-HT expression in spinal dorsal horn in both normal and chronic constriction injury (CCI) rats after i.c.v. injection of CB-SAP was observed. These results suggested that RVM may be involved in descending pain modulation originating from the CSF-contacting nucleus. PMID- 26961889 TI - Apelin-13 Protects PC12 Cells from Corticosterone-Induced Apoptosis Through PI3K and ERKs Activation. AB - It is widely accepted that environmental stress is a risk factor for mental disorders. Glucocorticoid hormones play a vital role in the regulation of physiological response to stress. High concentrations of corticosterone can induce cellular damage in PC12 cells, which possess typical neuronal features. Apelin and its receptor APJ are widely distributed in the central nervous system including limbic structures involved in stress responses. Previous studies have suggested that apelin has a neuroprotective function. However, the effect of apelin on corticosterone-induced neuronal damage remains to be elucidated. In the present study, we explored the potential protective activity of apelin-13 in PC12 cells treated with corticosterone and its underling mechanisms. The viability of the cells, the apoptosis of the cells, the level of phosphorylation of Akt (p Akt) and extracellular signal-regulated kinases (p-ERKs) and cleaved caspase-3 expression were detected by MTT, Hoechst staining and flow cytometer assays and Western blotting. Results showed that corticosterone induced cells viability loss, cell apoptosis, down-regulation of p-Akt and p-ERKs and up-regulation of cleaved caspase-3. The effects induced by corticosterone were attenuated by apelin-13 pretreatment. Furthermore, apelin-13-mediated anti-viability loss, antiapoptosis and caspase-3 suppression activities were blocked by specific inhibitors of phosphatidylinositol 3-kinase (PI3K) (LY294002) and ERKs (PD98059). The data suggest that apelin-13 protects PC12 cells from corticosterone-induced apoptosis through activating PI3K/Akt and ERKs signaling pathways. PMID- 26961892 TI - FastPop: a rapid principal component derived method to infer intercontinental ancestry using genetic data. AB - BACKGROUND: Identifying subpopulations within a study and inferring intercontinental ancestry of the samples are important steps in genome wide association studies. Two software packages are widely used in analysis of substructure: Structure and Eigenstrat. Structure assigns each individual to a population by using a Bayesian method with multiple tuning parameters. It requires considerable computational time when dealing with thousands of samples and lacks the ability to create scores that could be used as covariates. Eigenstrat uses a principal component analysis method to model all sources of sampling variation. However, it does not readily provide information directly relevant to ancestral origin; the eigenvectors generated by Eigenstrat are sample specific and thus cannot be generalized to other individuals. RESULTS: We developed FastPop, an efficient R package that fills the gap between Structure and Eigenstrat. It can: 1, generate PCA scores that identify ancestral origins and can be used for multiple studies; 2, infer ancestry information for data arising from two or more intercontinental origins. We demonstrate the use of FastPop using 2318 SNP markers selected from the genome based on high variability among European, Asian and West African (African) populations. We conducted an analysis of 505 Hapmap samples with European, African or Asian ancestry along with 19661 additional samples of unknown ancestry. The results from FastPop are highly consistent with those obtained by Structure across the 19661 samples we studied. The correlations of the results between FastPop and Structure are 0.99, 0.97 and 0.99 for European, African and Asian ancestry scores, respectively. Compared with Structure, FastPop is more efficient as it finished ancestry inference for 19661 samples in 16 min compared with 21-24 h required by Structure. FastPop also provided scores based on SNP weights so the scores of reference population can be applied to other studies provided the same set of markers are used. We also present application of the method for studying four continental populations (European, Asian, African, and Native American). CONCLUSIONS: We developed an algorithm that can infer ancestries on data involving two or more intercontinental origins. It is efficient for analyzing large datasets. Additionally the PCA derived scores can be applied to multiple data sets to ensure the same ancestry analysis is applied to all studies. PMID- 26961891 TI - Protective Effect of Silibinin on Learning and Memory Impairment in LPS-Treated Rats via ROS-BDNF-TrkB Pathway. AB - Silibinin, a flavonoid derived from the herb milk thistle (Silybum marianum), has been used as a hepato-protectant in the clinical treatment of liver disease. In the present study, the effect of silibinin on lipopolysaccharide (LPS)-induced neuroinflammatory impairment in rats is investigated. Injection of LPS into lateral ventricle caused learning and memory impairment. Rats were treated with silibinin to see the effect in comparison with resveratrol as a positive control. Y-maze and Morris water maze tests showed that silibinin significantly attenuated memory damage caused by LPS treatment. At the molecular analysis, the levels of IL-1beta and of IL-4 in the hippocampus were decreased and enhanced, respectively, by the treatment with silibinin. NF-kappaB expression was attenuated by silibinin treatment. Furthermore, generation of total reactive oxygen species (ROS) in the hippocampus was elevated in silibinin-treated groups, and so were the expressions of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB). At the same time, LPS-induced reduction of neurons in hippocampus was reversed by silibinin. In conclusion, silibinin ameliorated the impairment of learning and memory of LPS-injection rats, possibly due to the activation of ROS-BDNF-TrkB pathway in the hippocampus as well as the suppression of inflammatory response. This study gives an insight on the beneficial consequences of ROS in central nervous system. Silibinin might be a potential candidate drug for neurodegenerative diseases. PMID- 26961893 TI - Testis-specific serine/threonine protein kinase 4 (Tssk4) phosphorylates Odf2 at Ser-76. AB - As a member of the testis-specific serine/threonine protein kinase (TSSK) family, Tssk4 is exclusively expressed in the testis and plays an essential role in male fertility. We previously reported that Tssk4 can associate with and phosphorylate Odf2, but the phosphorylation site is still unknown. Here we confirm that the C terminal region (amino acids 214-638) of Odf2 is required for association with Tssk4. Furthermore, to identify the site at which Tssk4 phosphorylates Odf2, we generated several Odf2 point mutants (Ser/Thr/Lys to Ala) and identified serine 76 of Odf2 as one of the phosphorylation sites. In vivo, phosphorylated Odf2 was evaluated in mouse sperm using a specific phospho-Ser-76 Odf2 antibody and LC MS/MS. These findings are the first to demonstrate the phosphorylation site in Odf2 by Tssk4, providing essential clues regarding the function of Tssk4 in regulating sperm motility and/or structure and thus male fertility. PMID- 26961894 TI - Uncertainty in identifying local extinctions: the distribution of missing data and its effects on biodiversity measures. AB - Identifying local extinctions is integral to estimating species richness and geographic range changes and informing extinction risk assessments. However, the species occurrence records underpinning these estimates are frequently compromised by a lack of recorded species absences making it impossible to distinguish between local extinction and lack of survey effort-for a rigorously compiled database of European and Asian Galliformes, approximately 40% of half degree cells contain records from before but not after 1980. We investigate the distribution of these cells, finding differences between the Palaearctic (forests, low mean human influence index (HII), outside protected areas (PAs)) and Indo-Malaya (grassland, high mean HII, outside PAs). Such cells also occur more in less peaceful countries. We show that different interpretations of these cells can lead to large over/under-estimations of species richness and extent of occurrences, potentially misleading prioritization and extinction risk assessment schemes. To avoid mistakes, local extinctions inferred from sightings records need to account for the history of survey effort in a locality. PMID- 26961895 TI - Reduced cellular immune response in social insect lineages. AB - Social living poses challenges for individual fitness because of the increased risk of disease transmission among conspecifics. Despite this challenge, sociality is an evolutionarily successful lifestyle, occurring in the most abundant and diverse group of organisms on earth--the social insects. Two contrasting hypotheses predict the evolutionary consequences of sociality on immune systems. The social group hypothesis posits that sociality leads to stronger individual immune systems because of the higher risk of disease transmission in social species. By contrast, the relaxed selection hypothesis proposes that social species have evolved behavioural immune defences that lower disease risk within the group, resulting in lower immunity at the individual level. We tested these hypotheses by measuring the encapsulation response in 11 eusocial and non-eusocial insect lineages. We built phylogenetic mixed linear models to investigate the effect of behaviour, colony size and body size on cellular immune response. We found a significantly negative effect of colony size on encapsulation response (Markov chain Monte Carlo generalized linear mixed model (mcmcGLMM) p < 0.05; phylogenetic generalized least squares (PGLS) p < 0.05). Our findings suggest that insects living in large societies may rely more on behavioural mechanisms, such as hygienic behaviours, than on immune function to reduce the risk of disease transmission among nest-mates. PMID- 26961896 TI - Genetic diversity confers colony-level benefits due to individual immunity. AB - Several costs and benefits arise as a consequence of eusociality and group living. With increasing group size, spread of disease among nest-mates poses selective pressure on both individual immunity and group-level mechanisms of disease resistance (social immunity). Another factor known to influence colony level expression of disease is intracolony genetic diversity, which in honeybees (Apis mellifera) is a direct function of the number of mates of the queen. Colonies headed by queens with higher mating numbers have less variable infections of decreased intensity, though the underlying mechanisms remain unclear. By pathogen-challenging larvae in vitro, we decoupled larval immune response from mechanisms of social immunity. Our results show that baseline immunity and degree of immune response do not vary with genetic diversity. However, intracolony variance in antimicrobial peptide production after pathogen challenge decreases with increasing genetic diversity. This reduction in variability of the larval immune response could drive the mitigation of disease observed in genetically diverse colonies. PMID- 26961897 TI - Chronic idiopathic axonal polyneuropathy: a systematic review. AB - Chronic idiopathic axonal polyneuropathy (CIAP) is a term describing neuropathies with both sensory and motor involvement in a length dependant distribution where neurophysiology reveals axonal damage, neuropathy onset is insidious and shows slow or no progression of the disease over at least 6 months with no aetiology being identified despite appropriate investigations. This entity merits further consideration given how common it is, the absence of clarity regarding aetiopathogenesis, natural history and therapies. A systematic computer-based literature search was conducted on PubMed database. We used two Medical Subject Headings terms in title. Term A was "axonal", "cryptogenic", "idiopathic" or "unknown" and Term B was "neuropathy" or "polyneuropathy". This search strategy resulted in the identification of 658 articles. After eligibility assessment, 48 papers were used for this review. CIAP is usually diagnosed in the sixth decade of life and it is more prevalent in males (ratio 3:2). It is usually slowly progressive. Some data support a potential role of autoimmunity in CIAP and further larger prospective studies are required to address such potential link and any treatment implications. CIAP is a common type of polyneuropathy but the least studied. Increasing awareness and research into this entity may result in better understanding and in the development of treatment strategies. PMID- 26961899 TI - Circulating human cytomegalovirus-encoded HCMV-miR-US4-1 as an indicator for predicting the efficacy of IFNalpha treatment in chronic hepatitis B patients. AB - The efficacy of interferon alpha (IFNalpha) therapy for chronic hepatitis B (CHB) patients is about 40% and often associates with adverse side-effects, thus identification of an easy accessible biomarker that can predict the outcome of IFNalpha treatment for individual CHB patients would be greatly helpful. Recent reports by us and others show that microRNAs encoded by human cytomegalovirus (HCMV) were readily detected in human serum and can interfere with lymphocyte responses required by IFNalpha therapeutic effect. We thus postulate that differential expression profile of serum HCMV miRNAs in CHB patients may serve as indicator to predict the efficacy of IFNalpha treatment for CHB patients. Blood was drawn from 56 individual CHB patients prior to IFNalpha treatment. By quantifying 13 HCMV miRNAs in serum samples, we found that the levels of HCMV-miR US4-1 and HCMV-miR-UL-148D were significantly higher in IFNalpha-responsive group than in IFNalpha-non-responsive group. In a prospective study of 96 new CHB patients, serum level of HCMV-miR-US4-1 alone classified those who were and were not responsive to IFN-alpha treatment with correct rate of 84.00% and 71.74%, respectively. In conclusion, our results demonstrate that serum HCMV-miR-US4-1 can serve as a novel biomarker for predicting the outcome of IFNalpha treatment in CHB patients. PMID- 26961901 TI - Stable topological insulators achieved using high energy electron beams. AB - Topological insulators are potentially transformative quantum solids with metallic surface states which have Dirac band structure and are immune to disorder. Ubiquitous charged bulk defects, however, pull the Fermi energy into the bulk bands, denying access to surface charge transport. Here we demonstrate that irradiation with swift (~2.5 MeV energy) electron beams allows to compensate these defects, bring the Fermi level back into the bulk gap and reach the charge neutrality point (CNP). Controlling the beam fluence, we tune bulk conductivity from p- (hole-like) to n-type (electron-like), crossing the Dirac point and back, while preserving the Dirac energy dispersion. The CNP conductance has a two dimensional character on the order of ten conductance quanta and reveals, both in Bi2Te3 and Bi2Se3, the presence of only two quantum channels corresponding to two topological surfaces. The intrinsic quantum transport of the topological states is accessible disregarding the bulk size. PMID- 26961900 TI - Phase 1 clinical trial demonstrated that MUC1 positive metastatic seminal vesicle cancer can be effectively eradicated by modified Anti-MUC1 chimeric antigen receptor transduced T cells. AB - Recent progress in chimeric antigen receptor-modified T-cell (CAR-T cell) technology in cancer therapy is extremely promising, especially in the treatment of patients with B-cell acute lymphoblastic leukemia. In contrast, due to the hostile immunosuppressive microenvironment of a solid tumor, CAR T-cell accessibility and survival continue to pose a considerable challenge, which leads to their limited therapeutic efficacy. In this study, we constructed two anti MUC1 CAR-T cell lines. One set of CAR-T cells contained SM3 single chain variable fragment (scFv) sequence specifically targeting the MUC1 antigen and co expressing interleukin (IL) 12 (named SM3-CAR). The other CAR-T cell line carried the SM3 scFv sequence modified to improve its binding to MUC1 antigen (named pSM3 CAR) but did not co-express IL-12. When those two types of CAR-T cells were injected intratumorally into two independent metastatic lesions of the same MUC1(+) seminal vesicle cancer patient as part of an interventional treatment strategy, the initial results indicated no side-effects of the MUC1 targeting CAR T cell approach, and patient serum cytokines responses were positive. Further evaluation showed that pSM3-CAR effectively caused tumor necrosis, providing new options for improved CAR-T therapy in solid tumors. PMID- 26961902 TI - Prevalence of malocclusion and assessment of treatment needs in beta-thalassemia major children. AB - BACKGROUND: The objective of this study is to evaluate the prevalence of malocclusion and treatment needs in transfusion dependent beta-thalassemia major children. METHODS: One hundred transfusion dependent beta-thalassemia major children visiting the Department of Pediatrics were selected randomly and evaluated for malocclusion with Angle's classification and Dewey's modification. The orthodontic treatment needs were also assessed using Grainger's treatment priority index (TPI). The orthodontic treatment needs were compared to normal children. RESULTS: The assessment of treatment needs revealed a higher prevalence of handicapping and severely handicapping malocclusion in thalassemic children compared to normal children. The thalassemic patients were found to show significantly more Angle's Class II malocclusion (55% vs. 15.7%) when compared to normal children. CONCLUSIONS: The higher prevalence of Angle's Class II malocclusion and definitive malocclusion in thalassemic children indicates the importance of preventive orthodontic procedures and efforts towards providing orthodontic treatment to these children. PMID- 26961904 TI - Imaging the spine. PMID- 26961905 TI - Reducing failures of working memory with performance feedback. AB - Fluctuations in attentional control can lead to failures of working memory (WM), in which the subject is no better than chance at reporting items from a recent display. In three experiments, we used a whole-report measure of visual WM to examine the impact of feedback on the rate of failures. In each experiment, subjects remembered an array of colored items across a blank delay, and then reported the identity of items using a whole-report procedure. In Experiment 1, we gave subjects simple feedback about the number of items they correctly identified at the end of each trial. In Experiment 2, we gave subjects additional information about the cumulative number of items correctly identified within each block. Finally, in Experiment 3, we gave subjects weighted feedback in which poor trials resulted in lost points and consistent successful performance received "streak" points. Surprisingly, simple feedback (Exp. 1) was ineffective at improving average performance or decreasing the rate of poor-performance trials. Simple cumulative feedback (Exp. 2) modestly decreased poor-performance trials (by 7 %). Weighted feedback produced the greatest benefits, decreasing the frequency of poor-performance trials by 28 % relative to baseline performance. This set of results demonstrates the usefulness of whole-report WM measures for investigating the effects of feedback on WM performance. Further, we showed that only a feedback structure that specifically discouraged lapses using negative feedback led to large reductions in WM failures. PMID- 26961903 TI - Climate change projections of West Nile virus infections in Europe: implications for blood safety practices. AB - BACKGROUND: West Nile virus (WNV) is transmitted by mosquitoes in both urban as well as in rural environments and can be pathogenic in birds, horses and humans. Extrinsic factors such as temperature and land use are determinants of WNV outbreaks in Europe, along with intrinsic factors of the vector and virus. METHODS: With a multivariate model for WNV transmission we computed the probability of WNV infection in 2014, with July 2014 temperature anomalies. We applied the July temperature anomalies under the balanced A1B climate change scenario (mix of all energy sources, fossil and non-fossil) for 2025 and 2050 to model and project the risk of WNV infection in the future. Since asymptomatic infections are common in humans (which can result in the contamination of the donated blood) we estimated the predictive prevalence of WNV infections in the blood donor population. RESULTS: External validation of the probability model with 2014 cases indicated good prediction, based on an Area Under Curve (AUC) of 0.871 (SD = 0.032), on the Receiver Operating Characteristic Curve (ROC). The climate change projections for 2025 reveal a higher probability of WNV infection particularly at the edges of the current transmission areas (for example in Eastern Croatia, Northeastern and Northwestern Turkey) and an even further expansion in 2050. The prevalence of infection in (blood donor) populations in the outbreak-affected districts is expected to expand in the future. CONCLUSIONS: Predictive modelling of environmental and climatic drivers of WNV can be a valuable tool for public health practice. It can help delineate districts at risk for future transmission. These areas can be subjected to integrated disease and vector surveillance, outreach to the public and health care providers, implementation of personal protective measures, screening of blood donors, and vector abatement activities. PMID- 26961906 TI - Convection-enhancement delivery of liposomal formulation of oxaliplatin shows less toxicity than oxaliplatin yet maintains a similar median survival time in F98 glioma-bearing rat model. AB - Results of clinical trials with oxaliplatin in treating glioblastoma are dismal. Previous works showed that intravenous (i.v.) delivery of oxaliplatin did not increase the survival of F98 glioma-bearing Fisher rats. Low accumulation of the drug in tumor cells is presumed to be responsible for the lack of antitumor effect. In the present study, convection-enhanced delivery (CED) was used to directly inject oxaliplatin in brain tumor implanted in rats. Since CED can led to severe toxicity, the liposomal formulation of oxaliplatin (LipoxalTM) was also assessed. The maximum tolerated dose (MTD) of oxaliplatin was 10 MUg, while that of LipoxalTM was increased by 3-times reaching 30 MUg. Median survival time (MeST) of F98 glioma-bearing rats injected with 10 MUg oxaliplatin by CED was 31 days, 7.5 days longer than untreated control (p = 0.0002); while CED of 30 MUg LipoxalTM reached the same result. Compared to previous study on i.v. delivery of these drugs, their injection by CED significantly increased their tumoral accumulations as well as MeSTs in the F98 glioma bearing rat model. The addition of radiotherapy (15 Gy) to CED of oxaliplatin or LipoxalTM increased the MeST by 4.0 and 3.0 days, respectively. The timing of radiotherapy (4 h or 24 h after CED) produced similar results. However, the treatment was better tolerated when radiotherapy was performed 24 h after CED. In conclusion, a better tumoral accumulation was achieved when oxaliplatin and LipoxalTM were injected by CED. The liposomal encapsulation of oxaliplatin reduced its toxic, while maintaining its antitumor potential. PMID- 26961907 TI - Phase I study of IMGN901, a CD56-targeting antibody-drug conjugate, in patients with CD56-positive solid tumors. AB - Background IMGN901 is a CD56-targeting antibody-drug conjugate designed for tumor selective delivery of the cytotoxic maytansinoid DM1. This phase 1 study investigated the safety, tolerability, pharmacokinetics, and preliminary activity of IMGN901 in patients with CD56-expressing solid tumors. Methods Patients were enrolled in cohorts of escalating IMGN901 doses, administered intravenously, on 3 consecutive days every 21 days. A dose-expansion phase accrued patients with small cell lung cancer (SCLC), Merkel cell carcinoma (MCC), or ovarian cancer. Results Fifty-two patients were treated at doses escalating from 4 to 94 mg/m(2)/day. The maximum tolerated dose (MTD) was determined to be 75 mg/m(2). Dose-limiting toxicities included fatigue, neuropathy, headache or meningitis like symptoms, chest pain, dyspnea, and myalgias. In the dose-expansion phase (n = 45), seven patients received 75 mg/m(2) and 38 received 60 mg/m(2) for up to 21 cycles. The recommended phase 2 dose (RP2D) was established at 60 mg/m(2) during dose expansion. Overall, treatment-emergent adverse events (TEAEs) were experienced by 96.9 % of all patients, the majority of which were Grade 1 or 2. The most commonly reported Grade 3 or 4 TEAEs were hyponatremia and dyspnea (each 8.2 %). Responses included 1 complete response (CR), 1 clinical CR, and 1 unconfirmed partial response (PR) in MCC; and 1 unconfirmed PR in SCLC. Stable disease was seen for 25 % of all evaluable patients who received doses >=60 mg/m(2). Conclusions The RP2D for IMGN901 of 60 mg/m(2) administered for 3 consecutive days every 3 weeks was associated with an acceptable tolerability profile. Objective responses were observed in patients with advanced CD56+ cancers. PMID- 26961908 TI - 3-Methyl-1-butanol Biosynthesis in an Engineered Corynebacterium glutamicum. AB - Biofuel offers a promising solution to the adverse environmental problems and depletion in reserves of fossil fuels. Higher alcohols including 3-methyl-1 butanol were paid much more attention as fuel substitute in recent years, due to its similar properties to gasoline. In the present work, 3-methyl-1-butanol production in engineered Corynebacterium glutamicum was studied. alpha Ketoisovalerate decarboxylase gene (kivd) from Lactococcus lactis combined with alcohol dehydrogenase gene (adh2, adhA, and adh3) from three organisms were overexpressed in C. glutamicum. Enzymatic assay and alcohol production results showed that adh3 from Zymomonas mobilis was the optimum candidate for 3-methyl-1 butanol production in C. glutamicum. The recombinant with kivd and adh3 could produce 0.182 g/L of 3-methyl-1-butanol and 0.144 g/L of isobutanol after 12 h of incubation. Further inactivation of the E1 subunit of pyruvate dehydrogenase complex gene (aceE) and lactic dehydrogenase gene (ldh) in the above C. glutamicum strain would improve the 3-Methyl-1-butanol titer to 0.497 g/L after 12 h of incubation. PMID- 26961909 TI - Lactococcus lactis is an Efficient Expression System for Mammalian Membrane Proteins Involved in Liver Detoxification, CYP3A4, and MGST1. AB - Despite the great importance of human membrane proteins involved in detoxification mechanisms, their wide use for biochemical approaches is still hampered by several technical difficulties considering eukaryotic protein expression in order to obtain the large amounts of protein required for functional and/or structural studies. Lactococcus lactis has emerged recently as an alternative heterologous expression system to Escherichia coli for proteins that are difficult to express. The aim of this work was to check its ability to express mammalian membrane proteins involved in liver detoxification, i.e., CYP3A4 and two isoforms of MGST1 (rat and human). Genes were cloned using two different strategies, i.e., classical or Gateway-compatible cloning, and we checked the possible influence of two affinity tags (6*-His-tag and Strep-tag II). Interestingly, all proteins could be successfully expressed in L. lactis at higher yields than those previously obtained for these proteins with classical expression systems (E. coli, Saccharomyces cerevisiae) or those of other eukaryotic membrane proteins expressed in L. lactis. In addition, rMGST1 was fairly active after expression in L. lactis. This study highlights L. lactis as an attractive system for efficient expression of mammalian detoxification membrane proteins at levels compatible with further functional and structural studies. PMID- 26961911 TI - Local fluid transfer regulation in heart extracellular matrix. AB - The interstitial myocardial matrix is a complex and dynamic structure that adapts to local fluctuations in pressure and actively contributes to the heart's fluid exchange and hydration. However, classical physiologic models tend to treat it as a passive conduit for water and solute, perhaps because local interstitial regulatory mechanisms are not easily accessible to experiment in vivo. Here, we examined the interstitial contribution to the fluid-driving pressure ex vivo. Interstitial hydration potentials were determined from influx/efflux rates measured in explants from healthy and ischemia-reperfusion-injured pigs during colloid osmotic pressure titrations. Adaptive responses were further explored by isolating myocardial fibroblasts and measuring their contractile responses to water activity changes in vitro. Results show hydration potentials between 5 and 60 mmHg in healthy myocardia and shifts in excess of 200 mmHg in edematous myocardia after ischemia-reperfusion injury. Further, rates of fluid transfer were temperature-dependent, and in collagen gel contraction assays, myocardial fibroblasts tended to preserve the micro-environment's hydration volume by slowing fluid efflux rates at pressures above 40 mmHg. Our studies quantify components of the fluid-driving forces in the heart interstitium that the classical Starling's equation does not explicitly consider. Measured hydration potentials in healthy myocardia and shifts with edema are larger than predicted from the known values of hydrostatic and colloid osmotic interstitial fluid pressures. Together with fibroblast responses in vitro, they are consistent with regulatory mechanisms that add local biological controls to classic fluid-balance models. PMID- 26961912 TI - Depersonalisation and schizophrenia: Comparative study of initial and multiple episodes of schizophrenia. AB - INTRODUCTION: The phenomena of depersonalisation/derealisation have classically been associated with the initial phases of psychosis, and it is assumed that they would precede (even by years) the onset of clinical psychosis, being much more common in the prodromal and acute phases of the illness. The aims of the present study are to analyse the differences in depersonalisation/derealisation between patients with initial and multiple episodes and the factors that could influence this. MATERIAL AND METHODS: A descriptive, controlled and cross-sectional study of 48 patients diagnosed with paranoid schizophrenia (20 with an initial episode and 28 with multiple episodes). These patients were assessed using scales such as the Cambridge Depersonalization Scale, the Positive and Negative Symptom Scale, and the Dissociative Experiences Scale. RESULTS: Participants with initial episodes score higher on both the Cambridge Depersonalisation Scale, and the subscale of the Dissociative Experiences Scale that evaluates such experiences. There were no associations between these types of experience and the positive symptoms subscale of the Positive and Negative Symptom Scale. CONCLUSIONS: Depersonalisation/derealisation experiences appear with greater frequency, duration and intensity in patients in the early stages of the illnesses, gradually decreasing as they become chronic. PMID- 26961910 TI - Cationic beta-Cyclodextrin-Chitosan Conjugates as Potential Carrier for pmCherry C1 Gene Delivery. AB - In this study cationic beta-cyclodextrin-chitosan-mediated nanoparticles were used to transfer pmCherry-C1 into glioblastoma cells and their transfection efficiency were compared to lipofectamine and electroporation. Physicochemical characteristics of nanoparticles were evaluated by photon correlation spectroscopy and scanning electron microscopy. Electrophoretic nuclease resistance and stability assays were used to check the protection of DNA from nucleases digestion. mCherry reporter construct was used for visualization, followed by quantitation of cell survival and gene expression by fluorescence activated cell sorting analysis and fluorescence microscopy. Particle size was approximately 200 nm and did not change at 4 degrees C even after 12 weeks. Importantly, the positively charged complexes interacted with DNA could serve as an efficient DNA delivery systems. Most of the gene was associated with the nanoparticles and was efficiently protected from DNAse I digestion. More than 80 % of transfected cells expressed mCherry efficiently. PMID- 26961914 TI - Separation of maleic anhydride grafted polypropylene using multidimensional high temperature liquid chromatography. AB - Functionalization addresses a property gap of polyolefins and opens new perspectives due to improved surface properties in applications like composites (e.g., glass fiber reinforced polypropylene) and anti-corrosive coatings for metals. Various techniques have been developed to characterize functionalized polyolefins, yet no analytical approach addressing their chemical heterogeneity exists. Using High Temperature Size Exclusion Chromatography (HT-SEC) coupled to infrared spectroscopy we could show for two model samples of polypropylene grafted maleic anhydride (PP-g-MA), differing in their nominal MA content, that the grafting density increases with decreasing molar mass. Crystallization Analysis Fractionation (CRYSTAF) does not enable to separate these samples according to their composition to the extent required. Yet, when using High Temperature High Performance Liquid Chromatography (HT-HPLC), with either silica gel or Mica as stationary phase and a gradient mobile phase, a deformulation into a grafted and a non-grafted fraction could be achieved. This was confirmed by analyzing the eluted fractions by infrared spectroscopy. Hyphenating the separation according to composition with a separation according to molar mass (HT HPLC x HT-SEC) enabled for the first time to reveal the bivariate distribution of PP-g-MA with regard to the molar mass and composition. Using on-line infrared detection quantitative information on the compositional and molar mass parameters of the individual fractions could be obtained. PMID- 26961913 TI - Characterization of the ultraviolet-visible photoproducts of thiophanate-methyl using high performance liquid chromatography coupled with high resolution tandem mass spectrometry-Detection in grapes and tomatoes. AB - UV-visible irradiation of thiophanate-methyl (TM) led to the formation of nine photoproducts that were characterized by high performance liquid chromatography coupled with high resolution Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). Although carbendazime has been reported in the literature to be the major metabolite and photoproduct of thiophanate-methyl, it was not detected in this study. However, an isomer of carbendazime referred as PP2, which was unambiguously characterized owing to CID experiments, was found in great abundance. Grape berries and cherry tomatoes treated with aqueous solutions of thiophanate-methyl were submitted to irradiation under laboratory conditions. TM and PP2 were detected in both peel and flesh of berries. The ability of TM and PP2 to pass through the fruit skin has been shown to be highly compound and matrix dependent. In vitro bioassays on Vibrio fischeri bacteria showed that the global ecotoxicity of the TM solution increases significantly with the irradiation time. PP2 should likely contribute to this ecotoxicity enhancement since in silico estimations for Daphnia magna provide a LC50 value seven times lower for PP2 than for the parent molecule. PMID- 26961915 TI - Polydimethylsiloxane/covalent triazine frameworks coated stir bar sorptive extraction coupled with high performance liquid chromatography-ultraviolet detection for the determination of phenols in environmental water samples. AB - In this work, covalent triazine frameworks (CTFs) were introduced in stir bar sorptive extraction (SBSE) and a novel polydimethylsiloxane(PDMS)/CTFs stir bar coating was prepared by sol-gel technique for the sorptive extraction of eight phenols (including phenol, 2-chlorophenol, 2-nitrophenol, 4-nitrophenol, 2,4 dimethylphenol, p-chloro-m-cresol and 2,4-dichlorophenol, 2,4,6-trichlorophenol) from environmental water samples followed by high performance liquid chromatography-ultraviolet (HPLC-UV) detection. The prepared PDMS/CTFs coated stir bar showed good preparation reproducibility with the relative standard deviations (RSDs) ranging from 3.5 to 5.7% (n=7) in one batch, and from 3.7 to 9.3% (n=7) among different batches. Several parameters affecting SBSE of eight target phenols including extraction time, stirring rate, sample pH, ionic strength, desorption solvent and desorption time were investigated. Under the optimal experimental conditions, the limits of detection (LODs, S/N=3) were found to be in the range of 0.08-0.30 MUg/L. The linear range was 0.25-500 MUg/L for 2 nitrophenol, 0.5-500 MUg/L for phenol, 2-chlorophenol, 4-nitrophenol as well as 2,4-dimethylphenol, and 1-500 MUg/L for p-chloro-m-cresol, 2,4-dichlorophenol as well as 2,4,6-trichlorophenol, respectively. The intra-day relative standard deviations (RSDs) were in the range of 4.3-9.4% (n=7, c=2 MUg/L) and the enrichment factors ranged from 64.9 to 145.6 fold (theoretical enrichment factor was 200-fold). Compared with commercial PDMS coated stir bar (Gerstel) and PEG coated stir bar (Gerstel), the prepared PDMS/CTFs stir bar showed better extraction efficiency for target phenol compounds. The proposed method was successfully applied to the analysis of phenols in environmental water samples and good relative recoveries were obtained with the spiking level at 2, 10, 50 MUg/L, respectively. PMID- 26961916 TI - Examination of the chemical changes in cured phenol-formaldehyde resins during storage. AB - Chemical changes occurring within cured phenol-formaldehyde resins (resite and novolak type) during their storage were investigated by FT-NIR, py-GCMS and inverse gas chromatography. It was shown that a mixture of resite with novolak was less stable than resite or novolak itself as regards bulk properties. This aging phenomenon is mainly due to reaction of ammonia (product of hexa decomposition) with CH2OH groups present in resite. FT-NIR technique seems to be the least sensitive method for assessment chemical changes occurring during cured resins storage. Applications of py-GCMS and IGC method made able to indicate that more significant changes were for bulk samples (py-GCMS results) than on their surface (IGC results). PMID- 26961917 TI - Simultaneous determination of 16 organophosphorus flame retardants and plasticizers in fish by liquid chromatography-tandem mass spectrometry. AB - In this work a method to analyze simultaneously sixteen organophosphorus flame retardants (OPFRs) by liquid chromatography-quadrupole-linear ion trap mass spectrometry (LC-QqLIT-MS) in fish samples was successfully developed. Sample preparation strategies, including different extraction techniques and clean-ups were tested. The chosen methodology is based on the extraction of 0.25 g of dried fish by ultrasound and clean-up by solid phase extraction (SPE) with a tandem of C18 and basic alumina cartridges. Recoveries were between 45 to 115%, with RSDs lower than 25%. mLODs and mLOQs were between 0.34-11.6 ng/g lw and 1.12-38.8 ng/g lw, respectively, with the exception of Tris(tribromoneopentyl)phosphate (TBNPP) (37.4 and 125 ng/g lw, respectively) and Tris(isopropyl-phenyl)phosphate (IPPP) (51.6 and 172 ng/g lw, respectively) which had higher limits. The developed method was applied to twelve river fish samples. Thirteen out of sixteen analyzed compounds were detected. At least, one of the sixteen studied OPFRs was detected in all the analyzed samples, with SigmaOPFR levels up to 2423 ng/g lw. This is the first study reporting IPPP and Isodecyldiphenyl phosphate (IDPP) levels in biota samples. Moreover, levels found for IPPP are quite high (up to 601 ng/g lw) and thus it is important to consider in the future development of analytical methodologies for OPFR analysis. PMID- 26961918 TI - Relationship between job burnout, psychosocial factors and health care-associated infections in critical care units. AB - PURPOSE: Burnout is a serious problem for critical care unit workers because they are exposed to chronic psychosocial stressors, including high responsibility, advanced technology and high patient acuity. Recent evidence showed that staff burnout was directly associated with hospital infections, thus affecting quality and safety of care provided. METHODS: The research aim was to investigate how burnout was associated with some psychosocial factors and with health care associated infections in hospitalised patients. A total of 130 healthcare professionals from critical care units completed a self-reported questionnaire. The infection data were collected prospectively over a six-month period. RESULTS: The results showed that emotional exhaustion was related to cynicism due to high work demands. Cynicism affected team communication, which in turn was positively related to team efficacy, thus acting as a mediator. Finally, team efficacy was negatively related to infections. CONCLUSIONS: The study showed that emotional exhaustion and cynicism were related to psychosocial aspects, which in turn had a significant impact on healthcare-associated infections. Our findings suggest how burnout can indirectly affect healthcare-related infections as a result of the quality of teamwork. Thus, reducing burnout can be a good strategy to decrease infections, thus increasing workers' well-being while improving patient care. PMID- 26961919 TI - Impact of mobilisation therapy on the haemodynamic and respiratory status of elderly intubated patients in an intensive care unit: A retrospective analysis. AB - OBJECTIVES: This study identified respiratory and haemodynamic parameters affected by limited mobilisation therapy in elderly, critically ill, intubated patients in an intensive care unit. METHODS: Over 18 months, we retrospectively assessed physiological changes during 43 mobilisation therapy sessions in 23 patients requiring mechanical ventilation for >48h. We compared heart rate, mean arterial blood pressure, respiratory rate, partial pressure of oxygen in arterial blood/inspired fraction of oxygen and lactate before and after mobilisation therapy, which entailed sitting on the edge of a hospital bed without back support. We analysed baseline characteristics and therapy duration. RESULTS: Patients' median age was 75 (interquartile range: 65-79) years, and the median Acute Physiology and Chronic Health Evaluation II score was 27 (26-31). Average therapy duration was 1h (0.5-2h). Therapy did not significantly modify heart rate or arterial blood pressure but increased the partial pressure of oxygen in arterial blood/inspired fraction of oxygen ratio significantly, from 218.8 (135.4 271.7) to 237.3 (167.2-284.9; p=0.007), indicating improved lung function. CONCLUSION: In this retrospective review, mobilisation therapy had no adverse effect on elderly, critically ill, intubated patients' haemodynamic status and appeared to improve the PaO2/FIO2 ratio; further research is required to confirm this finding. PMID- 26961920 TI - Erratum to: 'Identification and characterization of the bacterial etiology of clinically problematic acute otitis media after tympanocentesis or spontaneous otorrhea in German children'. PMID- 26961921 TI - General solution of 2D and 3D superconducting quasiclassical systems: coalescing vortices and nanoisland geometries. AB - An extension of quasiclassical Keldysh-Usadel theory to higher spatial dimensions than one is crucial in order to describe physical phenomena like charge/spin Hall effects and topological excitations like vortices and skyrmions, none of which are captured in one-dimensional models. We here present a numerical finite element method which solves the non-linearized 2D and 3D quasiclassical Usadel equation relevant for the diffusive regime. We show the application of this on three model systems with non-trivial geometries: (i) a bottlenecked Josephson junction with external flux, (ii) a nanodisk ferromagnet deposited on top of a superconductor and (iii) superconducting islands in contact with a ferromagnet. In case (i), we demonstrate that one may control externally not only the geometrical array in which superconducting vortices arrange themselves, but also to cause coalescence and tune the number of vortices. In case (iii), we show that the supercurrent path can be tailored by incorporating magnetic elements in planar Josephson junctions which also lead to a strong modulation of the density of states. The finite element method presented herein paves the way for gaining insight in physical phenomena which have remained largely unexplored due to the complexity of solving the full quasiclassical equations in higher dimensions. PMID- 26961922 TI - Smoking Cessation Support Among Oncology Practitioners in a Regional Cancer Center in the Middle East-Improving a Critical Service for Cancer Care. PMID- 26961925 TI - Smoking ban does not apply to prisons, Court of Appeal rules. PMID- 26961924 TI - Sentinel Lymph Node Mapping in Endometrial Cancer: An Update. AB - : Lymph node removal for staging, as part of the initial surgical management of patients with endometrial carcinoma, remains a controversial topic in gynecologic oncology. There is currently wide variability among clinical practices, with surgical approaches ranging from no nodal evaluation to comprehensive pelvic and aortic lymphadenectomy. Lymphatic mapping has emerged as an increasingly popular option over the past few years, with several attractive features in its concept, innovative surgical approach, and encouraging preliminary results. At this time, however, several different techniques have been described and used for lymphatic mapping in endometrial cancer, incorporating a variety of mapping agents and injection sites. Although recently published results are encouraging, they are limited to single-institution series or multi-institutional collaborations undertaken without the aegis of a prospective randomized controlled trial. However, the surgical staging of endometrial cancer with lymphadenectomy was historically established based not on randomized trial data but on prospective clinicopathologic studies. Another evolving field in endometrial cancer staging is the interpretation of pathologic ultrastaging of sentinel lymph nodes (SLNs), which can identify low-volume metastases for which the clinical significance and the ideal management remain uncertain. This is particularly an issue with extremely low-volume nodal metastasis and isolated tumor cells. Furthermore, it has become apparent that applying a predefined SLN algorithm can decrease false negative rates. The Memorial Sloan Kettering Cancer Center SLN algorithm can be used as a checklist to ensure standardization of care and to reduce the chance of missing nodal disease. Prospective trials are under way at many institutions to help establish the definitive role of SLN mapping for staging of endometrial cancer. The objective of this study was to provide an update on the latest clinical data related to lymphatic mapping for the staging and management of endometrial cancer and its role in clinical practice. IMPLICATIONS FOR PRACTICE: Lymphatic mapping is an increasingly popular option in the surgical treatment of endometrial cancer. The aim of using this tool is to target the lymph nodes that are the most likely to be involved with metastatic cancer cells (sentinel lymph nodes) and thereby limit the extent of surgery needed and decrease surgical complications and long-term side effects associated with extensive lymph node removal. By examining a limited number of sentinel lymph nodes, a more detailed examination of the node can be done (ultrastaging). This allows for the detection of a small number of cancer cells (low-volume metastasis) that can be missed with standard techniques. PMID- 26961923 TI - The Human Papillomavirus Vaccine: Current Perspective and Future Role in Prevention and Treatment of Anal Intraepithelial Neoplasia and Anal Cancer. AB - The incidences of human papillomavirus (HPV)-related anal cancer and its precursor lesion, anal intraepithelial neoplasia, are rising in the U.S. and globally. Five-year survival rates with current modalities of treatment for anal cancer are generally favorable for localized and regional disease. For metastatic disease, the relative survival rate is poor. Major contributing factors for the increase in anal cancer incidence include increasing receptive anal intercourse (hetero- and homosexual), increasing HPV infections, and longer life expectancy of treated people who are seropositive for human immunodeficiency virus. Because treatment outcomes with systemic therapy in patients with advanced disease are so poor, prevention may be the best approach for reducing disease burden. The association of a major causative agent with anal cancer provides an excellent opportunity for prevention and treatment. The advent of the HPV vaccine for anal cancer prevention and treatment is a significant milestone and has the potential to greatly impact these cancers. The data regarding potential use of the HPV vaccine in anal cancer prevention and treatment are reviewed. IMPLICATIONS FOR PRACTICE: The incidences of human papillomavirus (HPV)-related anal cancer and its precursor lesion, anal intraepithelial neoplasia, are on the rise in the U.S. and globally. Based on recent studies, the HPV vaccine is approved for prevention of the infection and development of HPV-related anal cancer. In addition, several small studies have shown that the vaccine may be useful as adjuvant therapy for anal cancer. There is a need for public health strategies aimed at education of both patients and practitioners to improve the use of the vaccine for prevention of HPV-related anal cancer. The development of a therapeutic vaccine is a work in progress. PMID- 26961926 TI - Sugar-sweetened beverage intake, chromosome 9p21 variants, and risk of myocardial infarction in Hispanics. AB - BACKGROUND: Chromosome 9p21 variants are among the most robust genetic markers for coronary artery disease (CAD), and previous studies have suggested that genetic effects of this locus might be modified by dietary factors. Intake of sugar-sweetened beverages (SSBs), which are the main dietary source of added sugar, has been shown to interact with genetic factors in affecting CAD risk factors such as obesity. OBJECTIVE: We aimed to test whether SSB intake modified the association between chromosome 9p21 variants and CAD risk in Hispanics living in Costa Rica. DESIGN: The current study included 1560 incident cases of nonfatal myocardial infarction (MI) and 1751 population-based controls. Three independent single nucleotide polymorphisms (SNPs) at the chromosome 9p21 locus were genotyped. SSB intake was assessed with the use of a food-frequency questionnaire and was defined as the frequency of intake of daily servings of sweetened beverages and fruit juice. RESULTS: We showed a significant interaction between SSB intake and one of the 3 variants (i.e., rs4977574) on MI risk. The per-risk allele OR (95% CI) of rs4977574 for MI was 1.44 (1.19, 1.74) in participants with higher SSB consumption (>2 servings/d), 1.21 (1.00, 1.47) in those with average consumption (1-2 servings/d), and 0.97 (0.81, 1.16) in subjects with lower consumption (<1 serving/d; P-interaction = 0.005). A genetic risk score derived from the sum of risk alleles of the 3 SNPs also showed a significant interaction with SSB intake on MI risk (P-interaction = 0.03). CONCLUSION: Our data suggest that unhealthy dietary habits such as higher intake of SSBs could exacerbate the effects of chromosome 9p21 variants on CAD. PMID- 26961927 TI - Best (but oft-forgotten) practices: the design, analysis, and interpretation of Mendelian randomization studies. AB - Mendelian randomization (MR) is an increasingly important tool for appraising causality in observational epidemiology. The technique exploits the principle that genotypes are not generally susceptible to reverse causation bias and confounding, reflecting their fixed nature and Mendel's first and second laws of inheritance. The approach is, however, subject to important limitations and assumptions that, if unaddressed or compounded by poor study design, can lead to erroneous conclusions. Nevertheless, the advent of 2-sample approaches (in which exposure and outcome are measured in separate samples) and the increasing availability of open-access data from large consortia of genome-wide association studies and population biobanks mean that the approach is likely to become routine practice in evidence synthesis and causal inference research. In this article we provide an overview of the design, analysis, and interpretation of MR studies, with a special emphasis on assumptions and limitations. We also consider different analytic strategies for strengthening causal inference. Although impossible to prove causality with any single approach, MR is a highly cost effective strategy for prioritizing intervention targets for disease prevention and for strengthening the evidence base for public health policy. PMID- 26961930 TI - Undernutrition screening survey in 564,063 patients: patients with a positive undernutrition screening score stay in hospital 1.4 d longer. AB - BACKGROUND: Undernutrition is a common complication of disease and a major determinant of hospital stay outcome. Dutch hospitals are required to screen for undernutrition on the first day of admission. OBJECTIVE: We sought to determine the prevalence of the screening score "undernourished" with the use of the Short Nutritional Assessment Questionnaire (SNAQ) or Malnutrition Universal Screening Tool (MUST) and its relation to length of hospital stay (LOS) in the general hospital population and per medical specialty. DESIGN: We conducted an observational cross-sectional study at 2 university, 3 teaching, and 8 general hospitals. All adult inpatients aged >=18 y with an LOS of at least 1 d were included. Between 2007 and 2014, the SNAQ/MUST score, admitting medical specialty, LOS, age, and sex of each patient were extracted from the digital hospital chart system. Linear regression analysis with ln(LOS) as an outcome measure and SNAQ >=3 points/MUST >=2 points, sex, and age as determinant variables was used to test the relation between SNAQ/MUST score and LOS. RESULTS: In total, 564,063 patients were included (48% males and 52% females aged 62 +/- 18 y). Of those, 74% (419,086) were screened with SNAQ and 26% (144,977) with MUST, and 13.7% (SNAQ) and 14.9% (MUST) of the patients were defined as being undernourished. Medical specialties with the highest percentage of the screening score of undernourished were geriatrics (38%), oncology (33%), gastroenterology (27%), and internal medicine (27%). Patients who had an undernourished screening score had a higher LOS than did patients who did not (median 6.8 compared with 4.0 d; P < 0.001). Regression analysis showed that a positive SNAQ/MUST score was significantly associated with LOS [SNAQ: +1.43 d (95% CI: 1.42, 1.44 d), P < 0.001; MUST: +1.47 d (95% CI: 1.45, 1.49 d), P < 0.001]. CONCLUSIONS: This study provides benchmark data on the prevalence of undernutrition, including more than half a million patients. One out of 7 patients was scored as undernourished. For geriatrics, oncology, gastroenterology, and internal medicine, this ratio was even greater (1 out of 3-4). Hospital stay was 1.4 d longer among undernourished patients than among those who were well nourished. PMID- 26961931 TI - Event-rate and delta inflation when evaluating mortality as a primary outcome from randomized controlled trials of nutritional interventions during critical illness: a systematic review. AB - BACKGROUND: There is a lack of high-quality evidence that proves that nutritional interventions during critical illness reduce mortality. OBJECTIVES: We evaluated whether power calculations for randomized controlled trials (RCTs) of nutritional interventions that used mortality as the primary outcome were realistic, and whether overestimation was systematic in the studies identified to determine whether this was due to overestimates of event rate or delta. DESIGN: A systematic review of the literature between 2005 and 2015 was performed to identify RCTs of nutritional interventions administered to critically ill adults that had mortality as the primary outcome. Predicted event rate (predicted mortality during the control), predicted mortality during intervention, predicted delta (predicted difference between mortality during the control and intervention), actual event rate (observed mortality during control), observed mortality during intervention, and actual delta (difference between observed mortality during the control and intervention) were recorded. The event-rate gap (predicted event rate minus observed event rate), the delta gap (predicted delta minus observed delta), and the predicted number needed to treat were calculated. Data are shown as median (range). RESULTS: Fourteen articles were extracted, with power calculations provided for 10 studies. The predicted event rate was 29.9% (20.0-52.4%), and the predicted delta was 7.9% (3.0-20.0%). If the study hypothesis was proven correct then, on the basis of the power calculations, the number needed to treat would have been 12.7 (5.0-33.3) patients. The actual event rate was 25.3% (6.1-50.0%), the observed mortality during the intervention was 24.4% (6.3-39.7%), and the actual delta was 0.5% (-10.2-10.3%), such that the event-rate gap was 2.6% (-3.9-23.7%) and delta gap was 7.5% (3.2-25.2%). CONCLUSIONS: Overestimates of delta occur frequently in RCTs of nutritional interventions in the critically ill that are powered to determine a mortality benefit. Delta inflation may explain the number of "negative" studies in this field of research. PMID- 26961928 TI - Dietary folate, B vitamins, genetic susceptibility and progression to advanced nonexudative age-related macular degeneration with geographic atrophy: a prospective cohort study. AB - BACKGROUND: There is growing evidence of the importance of nutrition in age related macular degeneration (AMD), but few studies have explored associations with folate and B vitamins. No effective therapeutic strategy for geographic atrophy (GA) is available, and prevention could be of great value. OBJECTIVE: We investigated associations between dietary folate, B vitamins, and progression to GA and whether these associations might be modified by genetic susceptibility. DESIGN: Among 2525 subjects (4663 eyes) in the Age-Related Eye Disease Study, 405 subjects (528 eyes) progressed to GA over 13 y. Folate and B vitamins were log transformed and calorie adjusted separately for men and women. Ten loci in 7 AMD genes [complement factor H, age-related maculopathy susceptibility 2/high temperature requirement A serine peptidase 1, complement component 2, complement component 3, complement factor B, collagen type VIII alpha 1, and RAD51 paralog B] were examined. Survival analysis was used to assess associations between incident GA and dietary intake of folate and B vitamins. Interaction effects between these nutrients and genetic variation on AMD risk were also evaluated. Subjects with at least one eye free of advanced AMD at baseline were included in these analyses. RESULTS: There was a reduced risk of progression to GA with increasing intake of thiamin, riboflavin, and folate after adjusting for age, sex, and total energy intake (P-trend = 0.01, 0.03, and 0.001, respectively). After adjustment for demographic, behavioral, ocular, and genetic covariates, trends remained statistically significant for folate (P-trend = 0.007) and were borderline for thiamin (P-trend = 0.05). Riboflavin did not retain statistical significance (P-trend = 0.20). Folate was significantly associated with lower risk of incident GA among subjects homozygous for the complement component 3 (C3) R102G rs2230199 nonrisk genotype (CC) (HR = 0.43; 95% CI: 0.27, 0.70; P = 0.0005) but not subjects carrying the risk allele (G) (P = 0.76). Neither folate nor any B vitamin was significantly associated with neovascular AMD. CONCLUSIONS: High folate intake was associated with a reduced risk of progression to GA. This relation could be modified by genetic susceptibility, particularly related to the C3 genotype. This trial was registered at clinicaltrials.gov as NCT00594672. PMID- 26961932 TI - Endocrine-disrupting polychlorinated biphenyls in metabolically healthy and unhealthy obese subjects before and after weight loss: difference at the start but not at the finish. AB - BACKGROUND: A subset of obese individuals does not exhibit metabolically unfavorable features; this group is referred to as metabolically healthy obese (MHO). Serum concentrations of polychlorinated biphenyls (PCBs), which are chemicals with endocrine-disrupting properties, have been shown to be lower in MHO than in metabolically unhealthy obese (MUO). OBJECTIVE: We studied PCB serum concentrations during and after weight loss and their relation with metabolic health. DESIGN: We determined metabolic health features (weight, blood pressure, lipids, inflammation, and glucose metabolism) and serum PCB concentrations of 27 PCBs in a cohort of 184 overweight and obese subjects. Metabolic health was evaluated with the use of the criteria of the metabolic syndrome (MetS) [metabolic syndrome according to Adult Treatment Panel III criteria present (MetS+) or metabolic syndrome according to Adult Treatment Panel III criteria absent (MetS-)] or with extended criteria with inflammation and insulin resistance taken into account (MUO compared with MHO). Participants were treated with lifestyle counseling or bariatric surgery. A metabolic and toxicological re evaluation was performed after 6 and 12 mo. RESULTS: At baseline, serum SigmaPCB concentrations were significantly higher in MUO than in MHO (SigmaPCBs: 138 +/ 105 compared with 365 +/- 481 ng/g lipid weight; P = 0.01) but not in MetS+ compared with MetS- subjects. No difference was detected in the percentage increase in PCB serum concentrations in MetS+ compared with MetS- subjects (median: 58% compared with 43% and 31% compared with 69% at 6 and 12 mo, respectively). The comparison of persistent with resolved MetS and MUO did not reveal any difference in SigmaPCB concentration increments (median: 49% compared with 58% at 12 mo for MUO; P > 0.05). In a regression model with age, smoking, and body mass index corrected for, PCB serum concentrations at baseline were not predictive of the persistence or resolution of a metabolically unfavorable state. CONCLUSION: Our study indicates that the increment in serum concentrations of PCBs does not differ according to metabolic health and does not seem to influence the beneficial metabolic health effects of weight loss. This study was registered at clinicaltrials.gov at NCT01778868. PMID- 26961929 TI - Effect of omega-3 supplementation on placental lipid metabolism in overweight and obese women. AB - BACKGROUND: The placentas of obese women accumulate lipids that may alter fetal lipid exposure. The long-chain omega-3 fatty acids (n-3 FAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) alter FA metabolism in hepatocytes, although their effect on the placenta is poorly understood. OBJECTIVE: We aimed to investigate whether n-3 supplementation during pregnancy affects lipid metabolism in the placentas of overweight and obese women at term. DESIGN: A secondary analysis of a double-blind randomized controlled trial was conducted in healthy overweight and obese pregnant women who were randomly assigned to DHA plus EPA (2 g/d) or placebo twice a day from early pregnancy to term. Placental FA uptake, esterification, and oxidation pathways were studied by measuring the expression of key genes in the placental tissue of women supplemented with placebo and n-3 and in vitro in isolated trophoblast cells in response to DHA and EPA treatment. RESULTS: Total lipid content was significantly lower in the placentas of overweight and obese women supplemented with n-3 FAs than in those supplemented with placebo (14.14 +/- 1.03 compared with 19.63 +/- 1.45 mg lipid/g tissue; P < 0.05). The messenger RNA expression of placental FA synthase (FAS) and diacylglycerol O-acyltransferase 1 (DGAT1) was negatively correlated with maternal plasma enrichment in DHA and EPA (P < 0.05). The expression of placental peroxisome proliferator-activated receptor gamma (r = -0.39, P = 0.04) and its target genes DGAT1 (r = -0.37, P = 0.02) and PLIN2 (r = -0.38, P = 0.04) significantly decreased, with an increasing maternal n-3:n-6 ratio (representing the n-3 status) near the end of pregnancy. The expression of genes that regulate FA oxidation or uptake was not changed. Birth weight and length were significantly higher in the offspring of n-3-supplemented women than in those in the placebo group (P < 0.05), but no differences in the ponderal index were observed. Supplementation of n-3 significantly decreased FA esterification in isolated trophoblasts without affecting FA oxidation. CONCLUSION: Supplementing overweight and obese women with n-3 FAs during pregnancy inhibited the ability of the placenta to esterify and store lipids. This trial was registered at clinicaltrials.gov as NCT00957476. PMID- 26961933 TI - Pegylated interferon for the treatment of early myelofibrosis: correlation of serial laboratory studies with response to therapy. AB - Pegylated interferon alpha-2a (Peg-IFN) has been shown to induce hematologic and molecular responses in patients with the Philadelphia-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV) and essential thrombocythemia (ET). We describe a series of patients with long-standing MPNs among whom Peg-IFN was initiated when they developed anemia and increased bone marrow reticulin fibrosis suggestive of early transformation to post-ET (PET) or post-PV (PPV) myelofibrosis (MF). Six patients were treated with Peg-IFN for a mean duration of 33.8 months (range 2-63 months). Five patients had long-standing ET (three were calreticulin (CALR)-positive, one janus kinase 2 (JAK2)-positive, and one JAK2 negative and CALR-negative), and one had long-standing JAK2-positive PV prior to starting Peg-IFN. This is the first study to report that, concurrent with the improvement in anemia, serial laboratory studies demonstrate an increase in serum LDH and left-shifted myeloid cells in the peripheral circulation over approximately 6 months, followed by a gradual normalization of these findings. Splenomegaly also increased and then resolved among responding patients. Serial bone marrow biopsies were available, which showed little change except for improvement in the grade of reticulin fibrosis in two patients. Among patients with early transformation to PET or PPV MF, our data support the efficacy of Peg IFN in improving hemoglobin levels and reducing splenomegaly. These peripheral blood findings should not, therefore, be considered evidence of treatment failure within the first year of Peg-IFN therapy. PMID- 26961934 TI - A comprehensive approach to the prevention of central venous catheter complications: results of 10-year prospective surveillance in pediatric hematology-oncology patients. AB - We report our decennial experience with 1161 newly-placed long-term central venous catheters inserted in 919 hematology-oncology patients for a total of 413,901 CVC-days of observation. Most of the CVCs were partially-implanted, open ended, Broviac-Hickman type of CVC (95 %). One thousand and twenty-four complications were recorded equal to 2.47 per 1000 CVC-days. The frequency of complications per CVC, the rate of episodes per 1000 CVC-days, and removal rate were malfunction/occlusion 42 %, 1.18/1000, and 2.3 %; mechanical (dislodgement/rupture/kinking) 18.3 %, 0.51/1000, and 77.4 %; bacteremia 14.8 %, 0.42/1000, and 18.6 %; exit-site/tunnel infection 11.5 %, 0.32/1000, and 9.7 %; thrombosis 0.86 %, 0.02/1000, and 30 %; pneumothorax 0.52 %, 0.01/1000, and 0. In multivariate analysis, the risk factors were for mechanical complications, a younger age <6.1 years at CVC insertion (HR 1.8, p = 0.0006); for bacteremia, a double lumen CVC (HR 3.1, p < 0.0001) and the surgical modality of CVC insertion (HR 1.5, p = 0.03); for exit-site/tunnel infection, a double lumen CVC (HR 2.1, p = 0.0003) and a diagnosis of leukemia or lymphoma (HR 1.8, p = 0.01); for malfunction/occlusion, an age <6.1 years (HR 1.6, p = 0.0003), the diagnosis of leukemia or lymphoma (HR 1.9, p < 0.0001) and double lumen CVC (HR 1.33, p = 0.023). The cumulative incidence of premature CVC removal was 29.2 % and the risk factors associated with this event were the surgical modality of CVC insertion (HR 1.4, p = 0.0153) and an age at CVC positioning less than 6.1 years (HR 1.6, p = 0.0025). We conclude that a best-practice set of rules resulted in reduced CVC complications. PMID- 26961935 TI - Missed Opportunities for Condom Counseling Among Adolescent Males. AB - The purpose of this study was to quantify the rate of condom counseling (CC) among adolescent males at preventive (PV) and non-PV (NPV) clinic visits in order to identify missed opportunities for contraception counseling. Adolescent males attending an outpatient clinic at a tertiary children's hospital from 2009 to 2013 were included. Patient demographics and provider responses to a postvisit electronic medical record questionnaire regarding CC were collected. Over 4 years, 2,439 males attended 6,123 visits; 33% were PVs. CC occurred at 92% PVs versus 43% NPVs ( p < .001). Those receiving CC were more likely to be older (16.1 vs. 15.9 years; p < .001) and minority (odds ratio = 1.43; 95% confidence interval = 1.28-1.61). In conclusion, in this single-center study among adolescent males, CC occurred routinely at PVs but infrequently at NPVs. CC was more likely among older, minority males. Providing CC at NPVs and ensuring younger, White males receive CC are two strategies to increase rates of CC among adolescent males. PMID- 26961937 TI - Male Gender Equality in Health Care. PMID- 26961936 TI - Factors Associated With HIV Testing Among Men in Haiti: Results From the 2012 Demographic and Health Survey. AB - HIV testing serves as the gateway to HIV prevention and treatment. However, research examining men's HIV testing behaviors in the Caribbean remains limited. The Andersen Behavioral Model of Health Services Utilization was used to examine factors associated with HIV testing among 7,354 men who participated in the 2012 Demographic and Health Survey conducted in Haiti. Few men (35%) reported having ever been tested for HIV. Logistic regression analyses revealed that HIV testing increased with education and wealth. Marital status was associated with HIV testing, with married men more likely to have been tested (adjusted odds ratio: 2.57, 95% CI [2.07, 3.19]) than unmarried men. Positive attitudes toward people living with HIV, indicated by willing to care for a relative who has HIV/AIDS, was also correlated with higher odds of having been tested (adjusted odds ratio: 1.28, 95% CI [1.08, 1.51]). Men who reported condom use during last sex were more likely to have been tested (odds ratio: 1.58, 95% CI [1.33, 1.88). The findings indicate that HIV testing rates remain low among men in Haiti and more efforts are needed to increase HIV testing among men who are not married, have low level of education, and engage in unprotected sex. PMID- 26961938 TI - Proteomic analysis of dystrophin deficiency and associated changes in the aged mdx-4cv heart model of dystrophinopathy-related cardiomyopathy. AB - Cardiomyopathy is a serious complication in Duchenne muscular dystrophy, an X linked neuromuscular disease of childhood that is triggered by primary abnormalities in the dystrophin gene. In order to directly correlate the deficiency in the membrane cytoskeletal protein dystrophin to secondary abnormalities in the dystrophic heart, this study has used label-free mass spectrometry to compare protein expression patterns in the aged mdx-4cv heart model of dystrophinopathy versus wild type heart. This report is the first successful identification of members of the cardiac dystrophin-glycoprotein complex by comparative whole tissue proteomics. The mass spectrometric analysis confirmed the loss of dystrophin and concomitant reduction of syntrophin and sarcoglycans in the dystrophin-deficient heart. Proteomic profiling of secondary changes identified distinct alterations in the basal lamina component laminin, the Ca(2+)-binding protein sarcalumenin, the matricellular protein periostin, the proteoglycans asporin and lumican, the cardiac-specific myosin light chain kinase, heat shock proteins and a large number of mitochondrial and glycolytic enzymes. The proteomic findings indicate that the molecular pathogenesis of muscular dystrophy-associated cardiomyopathy is highly complex and involves impairments, modulations and/or adaptations of mitochondrial metabolism, glycolysis, protein chaperoning and ion homeostasis, as well as the maintenance of the contractile apparatus, the intracellular cytoskeleton and the extracellular matrisome. SIGNIFICANCE: The X-linked inherited disorder Duchenne muscular dystrophy is the most frequently inherited neuromuscular disease of childhood. Primary abnormalities in the dystrophin gene trigger progressive skeletal muscle wasting and impaired cardiorespiratory functions. In order to improve our general understanding of the molecular pathogenesis of muscular dystrophy-associated cardiomyopathy and to identify new marker candidates of cardiac changes in dystrophinopathy, we have carried out a comparative proteomic study of the mdx-4cv mouse model of Duchenne muscular dystrophy. The mass spectrometric profiling of whole heart preparations has identified the reduction in the dystrophin-glycoprotein complex and a large variety of secondary changes in the dystrophic heart. Cardiac proteins with a changed abundance were shown to be involved in fibre contraction, energy metabolism, cellular signalling, the cytoskeletal network, the extracellular matrix and the stress response. In the future, the newly identified cardiac proteins may be useful to improve predictive, diagnostic, prognostic or therapy-monitoring approaches in the field of muscular dystrophy and cardiomyopathy. PMID- 26961939 TI - Identification of cypermethrin induced protein changes in green algae by iTRAQ quantitative proteomics. AB - Cypermethrin (CYP) is one of the most widely used pesticides in large scale for agricultural and domestic purpose and the residue often seriously affects aquatic system. Environmental pollutant-induced protein changes in organisms could be detected by proteomics, leading to discovery of potential biomarkers and understanding of mode of action. While proteomics investigations of CYP stress in some animal models have been well studied, few reports about the effects of exposure to CYP on algae proteome were published. To determine CYP effect in algae, the impact of various dosages (0.001MUg/L, 0.01MUg/L and 1MUg/L) of CYP on green algae Chlorella vulgaris for 24h and 96h was investigated by using iTRAQ quantitative proteomics technique. A total of 162 and 198 proteins were significantly altered after CYP exposure for 24h and 96h, respectively. Overview of iTRAQ results indicated that the influence of CYP on algae protein might be dosage-dependent. Functional analysis of differentially expressed proteins showed that CYP could induce protein alterations related to photosynthesis, stress responses and carbohydrate metabolism. This study provides a comprehensive view of complex mode of action of algae under CYP stress and highlights several potential biomarkers for further investigation of pesticide-exposed plant and algae. PMID- 26961940 TI - The variations in the nuclear proteome reveal new transcription factors and mechanisms involved in UV stress response in Pinus radiata. AB - The importance of UV stress and its side-effects over the loss of plant productivity in forest species demands a deeper understanding of how pine trees respond to UV irradiation. Although the response to UV stress has been characterized at system and cellular levels, the dynamics within the nuclear proteome triggered by UV is still unknown despite that they are essential for gene expression and regulation of plant physiology. To fill this gap this work aims to characterize the variations in the nuclear proteome as a response to UV irradiation by using state-of-the-art mass spectrometry-based methods combined with novel bioinformatics workflows. The combination of SEQUEST, de novo sequencing, and novel annotation pipelines allowed cover sensing and transduction pathways, endoplasmic reticulum-related mechanisms and the regulation of chromatin dynamism and gene expression by histones, histone-like NF-Ys, and other transcription factors previously unrelated to this stress source, as well as the role of alternative splicing and other mechanisms involved in RNA translation and protein synthesis. The determination of 33 transcription factors, including NF YB13, Pp005698_3 (NF-YB) and Pr009668_2 (WD-40), which are correlated to stress responsive mechanisms like an increased accumulation of photoprotective pigments and reduced photosynthesis, pointing them as strong candidate biomarkers for breeding programs aimed to improve UV resistance of pine trees. SIGNIFICANCE: The description of the nuclear proteome of Pinus radiata combining a classic approach based on the use of SEQUEST and the use of a mass accuracy precursor alignment (MAPA) allowed an unprecedented protein coverage. This workflow provided the methodological basis for characterizing the changes in the nuclear proteome triggered by UV irradiation, allowing the depiction of the nuclear events involved in stress response and adaption. The relevance of some of the discovered proteins will suppose a major advance in stress biology field, also providing a set of transcription factors that can be considered as strong biomarker candidates to select trees more tolerant to UV radiation in forest upgrade programs. PMID- 26961942 TI - Human Choice Strategy Varies with Anatomical Projections from Ventromedial Prefrontal Cortex to Medial Striatum. AB - Two distinct systems, goal-directed and habitual, support decision making. It has recently been hypothesized that this distinction may arise from two computational mechanisms, model-based and model-free reinforcement learning, neuronally implemented in frontostriatal circuits involved in learning and behavioral control. Here, we test whether the relative strength of anatomical connectivity within frontostriatal circuits accounts for variation in human individuals' reliance on model-based and model-free control. This hypothesis was tested by combining diffusion tensor imaging with a multistep decision task known to distinguish model-based and model-free control in humans. We found large interindividual differences in the degree of model-based control, and those differences are predicted by the structural integrity of white-matter tracts from the ventromedial prefrontal cortex to the medial striatum. Furthermore, an analysis based on masking out of bottom-up tracts suggests that this effect is driven by top-down influences from ventromedial prefrontal cortex to medial striatum. Our findings indicate that individuals with stronger afferences from the ventromedial prefrontal cortex to the medial striatum are more likely to rely on a model-based strategy to control their instrumental actions. These findings suggest a mechanism for instrumental action control through which medial striatum determines, at least partly, the relative contribution of model-based and model free systems during decision-making according to top-down model-based information from the ventromedial prefrontal cortex. These findings have important implications for understanding the neural circuitry that might be susceptible to pathological computational processes in impulsive/compulsive psychiatric disorders. PMID- 26961941 TI - Human Dorsolateral Prefrontal Cortex Is Not Necessary for Spatial Working Memory. AB - A dominant theory, based on electrophysiological and lesion evidence from nonhuman primate studies, posits that the dorsolateral prefrontal cortex (dlPFC) stores and maintains working memory (WM) representations. Yet, neuroimaging studies have consistently failed to translate these results to humans; these studies normally find that neural activity persists in the human precentral sulcus (PCS) during WM delays. Here, we attempt to resolve this discrepancy. To test the degree to which dlPFC is necessary for WM, we compared the performance of patients with dlPFC lesions and neurologically healthy controls on a memory guided saccade task that was used in the monkey studies to measure spatial WM. We found that dlPFC damage only impairs the accuracy of memory-guided saccades if the damage impacts the PCS; lesions to dorsolateral dlPFC that spare the PCS have no effect on WM. These results identify the necessary subregion of the frontal cortex for WM and specify how this influential animal model of human cognition must be revised. PMID- 26961943 TI - Reactivation of Reward-Related Patterns from Single Past Episodes Supports Memory Based Decision Making. AB - Rewarding experiences exert a strong influence on later decision making. While decades of neuroscience research have shown how reinforcement gradually shapes preferences, decisions are often influenced by single past experiences. Surprisingly, relatively little is known about the influence of single learning episodes. Although recent work has proposed a role for episodes in decision making, it is largely unknown whether and how episodic experiences contribute to value-based decision making and how the values of single episodes are represented in the brain. In multiple behavioral experiments and an fMRI experiment, we tested whether and how rewarding episodes could support later decision making. Participants experienced episodes of high reward or low reward in conjunction with incidental, trial-unique neutral pictures. In a surprise test phase, we found that participants could indeed remember the associated level of reward, as evidenced by accurate source memory for value and preferences to re-engage with rewarded objects. Further, in a separate experiment, we found that high-reward objects shown as primes before a gambling task increased financial risk taking. Neurally, re-exposure to objects in the test phase led to significant reactivation of reward-related patterns. Importantly, individual variability in the strength of reactivation predicted value memory performance. Our results provide a novel demonstration that affect-related neural patterns are reactivated during later experience. Reactivation of value information represents a mechanism by which memory can guide decision making. PMID- 26961945 TI - Different Roles of Direct and Indirect Frontoparietal Pathways for Individual Working Memory Capacity. AB - The ability to temporarily store and manipulate information in working memory is a hallmark of human intelligence and differs considerably across individuals, but the structural brain correlates underlying these differences in working memory capacity (WMC) are only poorly understood. In two separate studies, diffusion MRI data and WMC scores were collected for 70 and 109 healthy individuals. Using a combination of probabilistic tractography and network analysis of the white matter tracts, we examined whether structural brain network properties were predictive of individual WMC. Converging evidence from both studies showed that lateral prefrontal cortex and posterior parietal cortex of high-capacity individuals are more densely connected compared with low-capacity individuals. Importantly, our network approach was further able to dissociate putative functional roles associated with two different pathways connecting frontal and parietal regions: a corticocortical pathway and a subcortical pathway. In Study 1, where participants were required to maintain and update working memory items, the connectivity of the direct and indirect pathway was predictive of WMC. In contrast, in Study 2, where participants were required to maintain working memory items without updating, only the connectivity of the direct pathway was predictive of individual WMC. Our results suggest an important dissociation in the circuitry connecting frontal and parietal regions, where direct frontoparietal connections might support storage and maintenance, whereas subcortically mediated connections support the flexible updating of working memory content. PMID- 26961946 TI - Top-Down-Mediated Facilitation in the Visual Cortex Is Gated by Subcortical Neuromodulation. AB - Response properties in primary sensory cortices are highly dependent on behavioral state. For example, the nucleus basalis of the forebrain plays a critical role in enhancing response properties of excitatory neurons in primary visual cortex (V1) during active exploration and learning. Given the strong reciprocal connections between hierarchically arranged cortical regions, how are increases in sensory response gain constrained to prevent runaway excitation? To explore this, we used in vivo two-photon guided cell-attached recording in conjunction with spatially restricted optogenetic photo-inhibition of higher order visual cortex in mice. We found that the principle feedback projection to V1 originating from the lateral medial area (LM) facilitated visual responses in layer 2/3 excitatory neurons by ~20%. This facilitation was reduced by half during basal forebrain activation due to differential response properties between LM and V1. Our results demonstrate that basal-forebrain-mediated increases in response gain are localized to V1 and are not propagated to LM and establish that subcortical modulation of visual cortex is regionally distinct. PMID- 26961944 TI - Microglial Cells Prevent Hemorrhage in Neonatal Focal Arterial Stroke. AB - Perinatal stroke leads to significant morbidity and long-term neurological and cognitive deficits. The pathophysiological mechanisms of brain damage depend on brain maturation at the time of stroke. To understand whether microglial cells limit injury after neonatal stroke by preserving neurovascular integrity, we subjected postnatal day 7 (P7) rats depleted of microglial cells, rats with inhibited microglial TGFbr2/ALK5 signaling, and corresponding controls, to transient middle cerebral artery occlusion (tMCAO). Microglial depletion by intracerebral injection of liposome-encapsulated clodronate at P5 significantly reduced vessel coverage and triggered hemorrhages in injured regions 24 h after tMCAO. Lack of microglia did not alter expression or intracellular redistribution of several tight junction proteins, did not affect degradation of collagen IV induced by the tMCAO, but altered cell types producing TGFbeta1 and the phosphorylation and intracellular distribution of SMAD2/3. Selective inhibition of TGFbr2/ALK5 signaling in microglia via intracerebral liposome-encapsulated SB 431542 delivery triggered hemorrhages after tMCAO, demonstrating that TGFbeta1/TGFbr2/ALK5 signaling in microglia protects from hemorrhages. Consistent with observations in neonatal rats, depletion of microglia before tMCAO in P9 Cx3cr1(GFP/+)/Ccr2(RFP/+) mice exacerbated injury and induced hemorrhages at 24 h. The effects were independent of infiltration of Ccr2(RFP/+) monocytes into injured regions. Cumulatively, in two species, we show that microglial cells protect neonatal brain from hemorrhage after acute ischemic stroke. PMID- 26961947 TI - Intermolecular Interaction between Anchoring Subunits Specify Subcellular Targeting and Function of RGS Proteins in Retina ON-Bipolar Neurons. AB - In vertebrate retina, light responses generated by the rod photoreceptors are transmitted to the second-order neurons, the ON-bipolar cells (ON-BC), and this communication is indispensible for vision in dim light. In ON-BCs, synaptic transmission is initiated by the metabotropic glutamate receptor, mGluR6, that signals via the G-protein Go to control opening of the effector ion channel, TRPM1. A key role in this process belongs to the GTPase Activating Protein (GAP) complex that catalyzes Go inactivation upon light-induced suppression of glutamate release in rod photoreceptors, thereby driving ON-BC depolarization to changes in synaptic input. The GAP complex has a striking molecular complexity. It contains two Regulator of G-protein Signaling (RGS) proteins RGS7 and RGS11 that directly act on Go and two adaptor subunits: RGS Anchor Protein (R9AP) and the orphan receptor, GPR179. Here we examined the organizational principles of the GAP complex in ON-BCs. Biochemical experiments revealed that RGS7 binds to a conserved site in GPR179 and that RGS11 in vivo forms a complex only with R9AP. R9AP and GPR179 are further integrated via direct protein-protein interactions involving their cytoplasmic domains. Elimination of GPR179 prevents postsynaptic accumulation of R9AP. Furthermore, concurrent knock-out of both R9AP and RGS7 does not reconfigure the GAP complex and completely abolishes synaptic transmission, resulting in a novel mouse model of night blindness. Based on these results, we propose a model of hierarchical assembly and function of the GAP complex that supports ON-BCs visual signaling. PMID- 26961949 TI - Adaptation Independent Modulation of Auditory Hair Cell Mechanotransduction Channel Open Probability Implicates a Role for the Lipid Bilayer. AB - The auditory system is able to detect movement down to atomic dimensions. This sensitivity comes in part from mechanisms associated with gating of hair cell mechanoelectric transduction (MET) channels. MET channels, located at the tops of stereocilia, are poised to detect tension induced by hair bundle deflection. Hair bundle deflection generates a force by pulling on tip-link proteins connecting adjacent stereocilia. The resting open probability (P(open)) of MET channels determines the linearity and sensitivity to mechanical stimulation. Classically, P(open) is regulated by a calcium-sensitive adaptation mechanism in which lowering extracellular calcium or depolarization increases P(open). Recent data demonstrated that the fast component of adaptation is independent of both calcium and voltage, thus requiring an alternative explanation for the sensitivity of P(open) to calcium and voltage. Using rat auditory hair cells, we characterize a mechanism, separate from fast adaptation, whereby divalent ions interacting with the local lipid environment modulate resting P(open). The specificity of this effect for different divalent ions suggests binding sites that are not an EF-hand or calmodulin model. GsMTx4, a lipid-mediated modifier of cationic stretch activated channels, eliminated the voltage and divalent sensitivity with minimal effects on adaptation. We hypothesize that the dual mechanisms (lipid modulation and adaptation) extend the dynamic range of the system while maintaining adaptation kinetics at their maximal rates. PMID- 26961948 TI - Absence of Prenatal Forebrain Defects in the Dp(16)1Yey/+ Mouse Model of Down Syndrome. AB - Studies in humans with Down syndrome (DS) show that alterations in fetal brain development are followed by postnatal deficits in neuronal numbers, synaptic plasticity, and cognitive and motor function. This same progression is replicated in several mouse models of DS. Dp(16)1Yey/+ (hereafter called Dp16) is a recently developed mouse model of DS in which the entire region of mouse chromosome 16 that is homologous to human chromosome 21 has been triplicated. As such, Dp16 mice may more closely reproduce neurodevelopmental changes occurring in humans with DS. Here, we present the first comprehensive cellular and behavioral study of the Dp16 forebrain from embryonic to adult stages. Unexpectedly, our results demonstrate that Dp16 mice do not have prenatal brain defects previously reported in human fetal neocortex and in the developing forebrains of other mouse models, including microcephaly, reduced neurogenesis, and abnormal cell proliferation. Nevertheless, we found impairments in postnatal developmental milestones, fewer inhibitory forebrain neurons, and deficits in motor and cognitive performance in Dp16 mice. Therefore, although this new model does not express prenatal morphological phenotypes associated with DS, abnormalities in the postnatal period appear sufficient to produce significant cognitive deficits in Dp16. PMID- 26961951 TI - Feeding and Reward Are Differentially Induced by Activating GABAergic Lateral Hypothalamic Projections to VTA. AB - Electrical stimulation of the lateral hypothalamus (LH) has two motivational effects: long trains of stimulation induce drive-like effects such as eating, and short trains are rewarding. It has not been clear whether a single set of activated fibers subserves the two effects. Previous optogenetic stimulation studies have confirmed that reinforcement and induction of feeding can each be induced by selective stimulation of GABAergic fibers originating in the bed nucleus of the LH and projecting to the ventral tegmental area (VTA). In the present study we determined the optimal stimulation parameters for each of the two optogenetically induced effects in food-sated mice. Stimulation-induced eating was strongest with 5 Hz and progressively weaker with 10 and 20 Hz. Stimulation-induced reward was strongest with 40 Hz and progressively weaker with lower or higher frequencies. Mean preferred duration for continuous 40 Hz stimulation was 61.6 s in a "real-time" place preference task; mean preferred duration for 5 Hz stimulation was 45.6 s. The differential effects of high- and low-frequency stimulation of this pathway seem most likely to be due to differential effects on downstream targets. PMID- 26961952 TI - Pitch-Responsive Cortical Regions in Congenital Amusia. AB - Congenital amusia is a lifelong deficit in music perception thought to reflect an underlying impairment in the perception and memory of pitch. The neural basis of amusic impairments is actively debated. Some prior studies have suggested that amusia stems from impaired connectivity between auditory and frontal cortex. However, it remains possible that impairments in pitch coding within auditory cortex also contribute to the disorder, in part because prior studies have not measured responses from the cortical regions most implicated in pitch perception in normal individuals. We addressed this question by measuring fMRI responses in 11 subjects with amusia and 11 age- and education-matched controls to a stimulus contrast that reliably identifies pitch-responsive regions in normal individuals: harmonic tones versus frequency-matched noise. Our findings demonstrate that amusic individuals with a substantial pitch perception deficit exhibit clusters of pitch-responsive voxels that are comparable in extent, selectivity, and anatomical location to those of control participants. We discuss possible explanations for why amusics might be impaired at perceiving pitch relations despite exhibiting normal fMRI responses to pitch in their auditory cortex: (1) individual neurons within the pitch-responsive region might exhibit abnormal tuning or temporal coding not detectable with fMRI, (2) anatomical tracts that link pitch-responsive regions to other brain areas (e.g., frontal cortex) might be altered, and (3) cortical regions outside of pitch-responsive cortex might be abnormal. The ability to identify pitch-responsive regions in individual amusic subjects will make it possible to ask more precise questions about their role in amusia in future work. PMID- 26961950 TI - Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward. AB - Upregulation of beta2 subunit-containing (beta2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects of nicotine addiction, and menthol cigarette smokers tend to upregulate beta2* nAChRs more than nonmenthol cigarette smokers. We investigated the effect of long-term menthol alone on midbrain neurons containing nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of alpha4 and alpha6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of alpha4* nAChRs, complementing that of chronic nicotine alone, which upregulates alpha4 subunit-containing (alpha4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation. Furthermore, menthol exposure before nicotine abolished nicotine reward-related behavior in mice. In neuroblastoma cells transfected with fluorescent nAChR subunits, exposure to 500 nm menthol alone also increased nAChR number and favored the formation of (alpha4)3(beta2)2 nAChRs; this contrasts with the action of nicotine itself, which favors (alpha4)2(beta2)3 nAChRs. Menthol alone also increases the number of alpha6beta2 receptors that exclude the beta3 subunit. Thus, menthol stabilizes lower-sensitivity alpha4* and alpha6 subunit containing nAChRs, possibly by acting as a chemical chaperone. The abolition of nicotine reward-related behavior may be mediated through menthol's ability to stabilize lower-sensitivity nAChRs and alter DA neuron excitability. We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway. PMID- 26961954 TI - Independence of Movement Preparation and Movement Initiation. AB - Initiating a movement in response to a visual stimulus takes significantly longer than might be expected on the basis of neural transmission delays, but it is unclear why. In a visually guided reaching task, we forced human participants to move at lower-than-normal reaction times to test whether normal reaction times are strictly necessary for accurate movement. We found that participants were, in fact, capable of moving accurately ~80 ms earlier than their reaction times would suggest. Reaction times thus include a seemingly unnecessary delay that accounts for approximately one-third of their duration. Close examination of participants' behavior in conventional reaction-time conditions revealed that they generated occasional, spontaneous errors in trials in which their reaction time was unusually short. The pattern of these errors could be well accounted for by a simple model in which the timing of movement initiation is independent of the timing of movement preparation. This independence provides an explanation for why reaction times are usually so sluggish: delaying the mean time of movement initiation relative to preparation reduces the risk that a movement will be initiated before it has been appropriately prepared. Our results suggest that preparation and initiation of movement are mechanistically independent and may have a distinct neural basis. The results also demonstrate that, even in strongly stimulus-driven tasks, presentation of a stimulus does not directly trigger a movement. Rather, the stimulus appears to trigger an internal decision whether to make a movement, reflecting a volitional rather than reactive mode of control. PMID- 26961953 TI - The Odorant Receptor-Dependent Role of Olfactory Marker Protein in Olfactory Receptor Neurons. AB - Olfactory receptor neurons (ORNs) in the nasal cavity detect and transduce odorants into action potentials to be conveyed to the olfactory bulb. Odorants are delivered to ORNs via the inhaled air at breathing frequencies that can vary from 2 to 10 Hz in the mouse. Thus olfactory transduction should occur at sufficient speed such that it can accommodate repetitive and frequent stimulation. Activation of odorant receptors (ORs) leads to adenylyl cyclase III activation, cAMP increase, and opening of cyclic nucleotide-gated channels. This makes the kinetic regulation of cAMP one of the important determinants for the response time course. We addressed the dynamic regulation of cAMP during the odorant response and examined how basal levels of cAMP are controlled. The latter is particularly relevant as basal cAMP depends on the basal activity of the expressed OR and thus varies across ORNs. We found that olfactory marker protein (OMP), a protein expressed in mature ORNs, controls both basal and odorant induced cAMP levels in an OR-dependent manner. Lack of OMP increases basal cAMP, thus abolishing differences in basal cAMP levels between ORNs expressing different ORs. Moreover, OMP speeds up signal transduction for ORNs to better synchronize their output with high-frequency stimulation and to perceive brief stimuli. Last, OMP also steepens the dose-response relation to improve concentration coding although at the cost of losing responses to weak stimuli. We conclude that OMP plays a key regulatory role in ORN physiology by controlling multiple facets of the odorant response. PMID- 26961955 TI - Optogenetic Activation of Septal Glutamatergic Neurons Drive Hippocampal Theta Rhythms. AB - The medial septum and diagonal band of Broca (MS-DBB) has an essential role for theta rhythm generation in the hippocampus and is critical for learning and memory. The MS-DBB contains cholinergic, GABAergic, and recently described glutamatergic neurons, but their specific contribution to theta generation is poorly understood. Here, we examined the role of MS-DBB glutamatergic neurons in theta rhythm using optogenetic activation and electrophysiological recordings performed in in vitro preparations and in freely behaving mice. The experiments in slices suggest that MS-DBB glutamatergic neurons provide prominent excitatory inputs to a majority of local GABAergic and a minority of septal cholinergic neurons. In contrast, activation of MS-DBB glutamatergic fiber terminals in hippocampal slices elicited weak postsynaptic responses in hippocampal neurons. In the in vitro septo-hippocampal preparation, activation of MS-DBB glutamatergic neurons did increase the rhythmicity of hippocampal theta oscillations, whereas stimulation of septo-hippocampal glutamatergic fibers in the fornix did not have an effect. In freely behaving mice, activation of these neurons in the MS-DBB strongly synchronized hippocampal theta rhythms over a wide range of frequencies, whereas activation of their projections to the hippocampus through fornix stimulations had no effect on theta rhythms, suggesting that MS-DBB glutamatergic neurons played a role in theta generation through local modulation of septal neurons. Together, these results provide the first evidence that MS-DBB glutamatergic neurons modulate local septal circuits, which in turn contribute to theta rhythms in the hippocampus. PMID- 26961957 TI - Representation of Functional Category in the Monkey Prefrontal Cortex and Its Rule-Dependent Use for Behavioral Selection. AB - Humans, monkeys, and other animals are considered to have the cognitive ability to use functional categories--that is, stimulus groups based on functional equivalence independent of physical properties. To investigate the underlying neural mechanisms of the use of functional categories, we recorded single-unit activity in the prefrontal cortex of monkeys performing a behavioral task in which the rule-dependent usage of functional category was needed to select an appropriate response. We found a neural correlate of functional categories on the single-neuron level and found that category information is coded independently of other task-relevant information such as rule and contingency information. Analysis of the time course of the information activation suggested that contingency information used for action selection is derived by integrating incoming category information with rule information maintained throughout a session. Such neural computation can be considered as the neural background of flexible behavioral control based on category and rule. PMID- 26961956 TI - The Activators of Cyclin-Dependent Kinase 5 p35 and p39 Are Essential for Oligodendrocyte Maturation, Process Formation, and Myelination. AB - The regulation of oligodendrocyte development and myelin formation in the CNS is poorly defined. Multiple signals influence the rate and extent of CNS myelination, including the noncanonical cyclin-dependent kinase 5 (Cdk5) whose functions are regulated by its activators p35 and p39. Here we show that selective loss of either p35 or p39 perturbed specific aspects of oligodendrocyte development, whereas loss of both p35 and p39 completely inhibited the development of mature oligodendrocytes and myelination. In the absence of p35, oligodendrocyte differentiation was delayed, process outgrowth was truncated in vitro, and the patterning and extent of myelination were perturbed in the CNS of p35(-/-) mice. In the absence of p39, oligodendrocyte maturation was transiently affected both in vitro and in vivo. However, loss of both p35 and p39 in oligodendrocyte lineage cells completely inhibited oligodendrocyte progenitor cell differentiation and myelination both in vitro and after transplantation into shiverer slice cultures. Loss of p35 and p39 had a more profound effect on oligodendrocyte development than simply the loss of Cdk5 and could not be rescued by Cdk5 overexpression. These data suggest p35 and p39 have specific and overlapping roles in oligodendrocyte development, some of which may be independent of Cdk5 activation. PMID- 26961959 TI - Age-Related Changes in D-Aspartate Oxidase Promoter Methylation Control Extracellular D-Aspartate Levels and Prevent Precocious Cell Death during Brain Aging. AB - The endogenous NMDA receptor (NMDAR) agonist D-aspartate occurs transiently in the mammalian brain because it is abundant during embryonic and perinatal phases before drastically decreasing during adulthood. It is well established that postnatal reduction of cerebral D-aspartate levels is due to the concomitant onset of D-aspartate oxidase (DDO) activity, a flavoenzyme that selectively degrades bicarboxylic D-amino acids. In the present work, we show that d aspartate content in the mouse brain drastically decreases after birth, whereas Ddo mRNA levels concomitantly increase. Interestingly, postnatal Ddo gene expression is paralleled by progressive demethylation within its putative promoter region. Consistent with an epigenetic control on Ddo expression, treatment with the DNA-demethylating agent, azacitidine, causes increased mRNA levels in embryonic cortical neurons. To indirectly evaluate the effect of a putative persistent Ddo gene hypermethylation in the brain, we used Ddo knock-out mice (Ddo(-/-)), which show constitutively suppressed Ddo expression. In these mice, we found for the first time substantially increased extracellular content of d-aspartate in the brain. In line with detrimental effects produced by NMDAR overstimulation, persistent elevation of D-aspartate levels in Ddo(-/-) brains is associated with appearance of dystrophic microglia, precocious caspase-3 activation, and cell death in cortical pyramidal neurons and dopaminergic neurons of the substantia nigra pars compacta. This evidence, along with the early accumulation of lipufuscin granules in Ddo(-/-) brains, highlights an unexpected importance of Ddo demethylation in preventing neurodegenerative processes produced by nonphysiological extracellular levels of free D-aspartate. PMID- 26961958 TI - Ghrelin-AMPK Signaling Mediates the Neuroprotective Effects of Calorie Restriction in Parkinson's Disease. AB - Calorie restriction (CR) is neuroprotective in Parkinson's disease (PD) although the mechanisms are unknown. In this study we hypothesized that elevated ghrelin, a gut hormone with neuroprotective properties, during CR prevents neurodegeneration in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. CR attenuated the MPTP-induced loss of substantia nigra (SN) dopamine neurons and striatal dopamine turnover in ghrelin WT but not KO mice, demonstrating that ghrelin mediates CR's neuroprotective effect. CR elevated phosphorylated AMPK and ACC levels in the striatum of WT but not KO mice suggesting that AMPK is a target for ghrelin-induced neuroprotection. Indeed, exogenous ghrelin significantly increased pAMPK in the SN. Genetic deletion of AMPKbeta1 and 2 subunits only in dopamine neurons prevented ghrelin-induced AMPK phosphorylation and neuroprotection. Hence, ghrelin signaling through AMPK in SN dopamine neurons mediates CR's neuroprotective effects. We consider targeting AMPK in dopamine neurons may recapitulate neuroprotective effects of CR without requiring dietary intervention. PMID- 26961961 TI - Attention Strongly Modulates Reliability of Neural Responses to Naturalistic Narrative Stimuli. AB - Attentional engagement is a major determinant of how effectively we gather information through our senses. Alongside the sheer growth in the amount and variety of information content that we are presented with through modern media, there is increased variability in the degree to which we "absorb" that information. Traditional research on attention has illuminated the basic principles of sensory selection to isolated features or locations, but it provides little insight into the neural underpinnings of our attentional engagement with modern naturalistic content. Here, we show in human subjects that the reliability of an individual's neural responses with respect to a larger group provides a highly robust index of the level of attentional engagement with a naturalistic narrative stimulus. Specifically, fast electroencephalographic evoked responses were more strongly correlated across subjects when naturally attending to auditory or audiovisual narratives than when attention was directed inward to a mental arithmetic task during stimulus presentation. This effect was strongest for audiovisual stimuli with a cohesive narrative and greatly reduced for speech stimuli lacking meaning. For compelling audiovisual narratives, the effect is remarkably strong, allowing perfect discrimination between attentional state across individuals. Control experiments rule out possible confounds related to altered eye movement trajectories or order of presentation. We conclude that reliability of evoked activity reproduced across subjects viewing the same movie is highly sensitive to the attentional state of the viewer and listener, which is aided by a cohesive narrative. PMID- 26961962 TI - Continuous variable quantum optical simulation for time evolution of quantum harmonic oscillators. AB - Quantum simulation enables one to mimic the evolution of other quantum systems using a controllable quantum system. Quantum harmonic oscillator (QHO) is one of the most important model systems in quantum physics. To observe the transient dynamics of a QHO with high oscillation frequency directly is difficult. We experimentally simulate the transient behaviors of QHO in an open system during time evolution with an optical mode and a logical operation system of continuous variable quantum computation. The time evolution of an atomic ensemble in the collective spontaneous emission is analytically simulated by mapping the atomic ensemble onto a QHO. The measured fidelity, which is used for quantifying the quality of the simulation, is higher than its classical limit. The presented simulation scheme provides a new tool for studying the dynamic behaviors of QHO. PMID- 26961960 TI - Cyclic AMP and Polyamines Overcome Inhibition by Myelin-Associated Glycoprotein through eIF5A-Mediated Increases in p35 Expression and Activation of Cdk5. AB - Inhibitory molecules associated with CNS myelin, such as myelin-associated glycoprotein (MAG), represent major obstacles to axonal regeneration following CNS injury. Our laboratory has shown that elevating levels of intracellular cAMP, via application of the nonhydrolyzable analog dibutyryl cAMP (dbcAMP), can block the inhibitory effects of MAG and myelin. We have also shown that elevation of cAMP results in upregulation of arginase I and increased polyamine synthesis. Treatment with putrescine or spermidine blocks myelin-mediated inhibition of neurite outgrowth, but the mechanism underlying this effect has not yet been elucidated. Here we show that cyclin-dependent kinase 5 (Cdk5) is required for dbcAMP and putrescine to overcome MAG-mediated inhibition. The ability of dbcAMP and putrescine to overcome inhibition by MAG is abolished in the presence of roscovitine, a Cdk inhibitor that has greater selectivity for Cdk5, and expression of dominant negative Cdk5 abolishes the ability of dbcAMP or putrescine to enhance neurite outgrowth in the presence of MAG. Importantly, dbcAMP and putrescine increase expression of p35, the neuron-specific activator of Cdk5, and rat DRG neurons transduced with HSV overexpressing p35 can overcome inhibition by MAG. The upregulation of p35 by putrescine is also reflected in increased localization of p35 to neurites and growth cones. Last, we show that putrescine upregulates p35 expression by serving as a substrate for hypusine modification of eIF5A, and that this hypusination is necessary for putrescine's ability to overcome inhibition by MAG. Our findings reveal a previously unknown mechanism by which polyamines may encourage regeneration after CNS injury. PMID- 26961963 TI - Recovery benefits of the "therapeutic alliance" among 12-step mutual-help organization attendees and their sponsors. AB - BACKGROUND: The "therapeutic alliance" between clinicians and patients has been associated with treatment response and outcomes in professionally-delivered psychotherapies. Although 12-step mutual help organizations (MHOs), such as Alcoholics Anonymous, are the most commonly sought source of support for individuals with substance use disorder (SUD), little is known about whether a stronger alliance in comparable MHO relationships between 12-step sponsors and those they help ("sponsees") confers benefits similar to those observed in professional contexts. Greater knowledge could inform clinical recommendations and enhance models that explain how individuals benefit from 12-step MHOs. METHOD: Young adults (N=302) enrolled in a prospective, clinical effectiveness study of residential SUD treatment were assessed at treatment entry, and 3, 6, and 12 months after discharge on whether they had a sponsor, contact with a sponsor, and degree of sponsor alliance. Hierarchical linear models (HLM) tested their effects on 12-step MHO attendance, involvement, and percent days abstinent (PDA). RESULTS: Approximately two-thirds of the sample (n=208, 68.87%) reported having a sponsor at one or more follow-up time points. Both having sponsor contact and stronger sponsor alliance were significantly associated with greater 12-step participation and abstinence, on average, during follow-up. Interaction results revealed that more sponsor contact was associated with increasingly higher 12-step participation whereas stronger sponsor alliance was associated with increasingly greater abstinence. CONCLUSIONS: Similar to the professional clinical realm, the "therapeutic alliance" among sponsees and their sponsors predicts better substance use outcomes and may help augment explanatory models estimating effects of MHOs in SUD recovery. PMID- 26961965 TI - Predicting missing links and identifying spurious links via likelihood analysis. AB - Real network data is often incomplete and noisy, where link prediction algorithms and spurious link identification algorithms can be applied. Thus far, it lacks a general method to transform network organizing mechanisms to link prediction algorithms. Here we use an algorithmic framework where a network's probability is calculated according to a predefined structural Hamiltonian that takes into account the network organizing principles, and a non-observed link is scored by the conditional probability of adding the link to the observed network. Extensive numerical simulations show that the proposed algorithm has remarkably higher accuracy than the state-of-the-art methods in uncovering missing links and identifying spurious links in many complex biological and social networks. Such method also finds applications in exploring the underlying network evolutionary mechanisms. PMID- 26961964 TI - Effects of yohimbine and drug cues on impulsivity and attention in cocaine dependent men and women and sex-matched controls. AB - BACKGROUND: Deficits in executive function have been associated with risk for relapse. Data from previous studies suggest that relapse may be triggered by stress and drug-paired cues and that there are significant sex differences in the magnitude of these responses. The aim of this study was to examine the impact of the pharmacological stressor and alpha-2 adrenergic receptor antagonist yohimbine and cocaine cues on executive function in cocaine-dependent men and women. METHODS: In a double-blind placebo controlled cross-over study, cocaine-dependent men (n=12), cocaine-dependent women (n=27), control men (n=31) and control women (n=25) received either yohimbine or placebo prior to two cocaine cue exposure sessions. Participants performed the Connors' Continuous Performance Test II prior to medication/placebo administration and immediately after each cue exposure session RESULTS: Healthy controls had a significant increase in commission errors under the yohimbine condition [RR (95% CI)=1.1 (1.0-1.3), chi(2)1=2.0, p=0.050]. Cocaine-dependent individuals exhibited a significant decrease in omission errors under the yohimbine condition [RR (95% CI)=0.6 (0.4 0.8), chi(2)1=8.6, p=0.003]. Cocaine-dependent women had more omission errors as compared to cocaine-dependent men regardless of treatment [RR (95% CI)=7.2 (3.6 14.7), chi(2)1=30.1, p<0.001]. Cocaine-dependent women exhibited a slower hit reaction time as compared to cocaine-dependent men [Female 354 +/- 13 vs. Male 415 +/- 14; t89=2.6, p=0.012]. CONCLUSIONS: These data add to a growing literature demonstrating significant sex differences in behaviors associated with relapse in cocaine-dependent individuals. PMID- 26961966 TI - Pontibacter mucosus sp. nov., isolated from hexachlorocyclohexane-contaminated pond sediment. AB - A halotolerant, Gram-stain-negative, rod-shaped and light-pink-pigmented bacterial strain, PB3T, was isolated from a pond sediment near a hexachlorocyclohexane-producing factory, located at Chinhat, Lucknow, India. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain PB3T formed a distinct phyletic clade along with the members of the genus Pontibacter. The 16S rRNA gene sequence similarity with other members of the genus Pontibacter ranged from 94.5 to 98.9 %. The cells were motile, aerobic, and catalase- and oxidase-positive. The major fatty acids were iso-C15:0, iso-C15:0 3-OH, iso-C17:0 3-OH, C16:1omega5c, summed feature 3 (C16:1omega6c/C16:1omega7c) and summed feature 4 (iso-C17:1I/ anteiso-C17:1 B). The polar lipid profile of strain PB3T showed the presence of phosphatidylethanolamine, an unidentified aminophospholipid, unknown aminolipids and other unknown polar lipids. DNA-DNA hybridization based homology of strain PB3T with respect to its most closely related species, Pontibacter chinhatensis LP51T, was 44.7 %. The DNA G+C content was 53.5 mol%. On the basis of these data, it is proposed that the isolate belongs to the genus Pontibacter and represents a novel species, for which the name Pontibacter mucosus is proposed. The type strain is PB3T (=DSM 100162T=KCTC 42942T). PMID- 26961967 TI - Rationally rewiring the connectivity of the XylR/Pu regulatory node of the m xylene degradation pathway in Pseudomonas putida. AB - The XylR/Pu regulatory node of the m-xylene biodegradation pathway of Pseudomonas putida mt-2 is one of the most intricate cases of processing internal and external cues into a single controlling element. Despite this complexity, the performance of the regulatory system is determined in vivo only by the occupation of Pu by m-xylene-activated XylR and sigma(54)-RNAP. The stoichiometry between these three elements defines natural system boundaries that outline a specific functional space. This space can be expanded artificially following different strategies that involve either the increase of XylR or sigma(54) or both elements at the same time (each using a different inducer). In this work we have designed a new regulatory architecture that drives the system to reach a maximum performance in response to one single input. To this end, we first explored using a simple mathematical model whether the output of the XylR/Pu node could be amended by simultaneously increasing sigma(54) and XylR in response to only natural inducers. The exacerbation of Pu activity in vivo was tested in strains bearing synthetic transposons encoding xylR and rpoN (the sigma(54) coding gene) controlled also by Pu, thereby generating a P. putida strain with the XylR/Pu output controlled by two intertwined feed forward loops (FFLs). The lack of a negative feedback loop in the expression node enables Pu activity to reach its physiological maximum in response to a single input. Only competition for cell resources might ultimately check the upper activity limit of such a rewired m xylene sensing device. PMID- 26961968 TI - A Comparative Study on Dissolution Enhancement of Acetaminophen by Cooling, Anti solvent, and Solvent Evaporation Crystallization. AB - The aim of this study was to prepare APAP crystals by cooling, anti-solvent, and solvent evaporation crystallization to enhance its dissolution rate and to make comparisons of the three methods. Agitating speeds and types were regarded as factors affecting crystallization procedure. Samples were made with different ratios of PEG4000. They were characterized by X-ray diffraction and scanning electron microscopy. Dissolution tests were conducted to assess their dissolution property. The proportions of carriers existing in crystals by cooling and anti solvent crystallization ranged from 1.3 to 5.1%. Mean dissolution time (MDT) of samples by the two methods was about 3 min, which was 17.2 min for untreated APAP. Addition of too much PEG4000 in solvent evaporation crystallization could decrease dissolution rate of APAP. Samples agitated by a rotor with speed of 100, 500, and 1000 rpm dissolved faster than those by a high shear mixer with speed of 3400 and 5000 rpm or by a glass rod. Agitating speed and type could affect particle size and drug dissolution. Dissolution enhancement of APAP might be attributed to decrease of fine particles and increase of particle wettability. PMID- 26961969 TI - Chronotherapeutically Modulated Pulsatile System of Valsartan Nanocrystals-an In Vitro and In Vivo Evaluation. AB - The objective was to improve the dissolution of valsartan by developing valsartan nanocrystals and design a pulsed release system for the chronotherapy of hypertension. Valsartan nanocrystals were prepared by sonication-anti-solvent precipitation method and lyophilized to obtain dry powder. Nanocrystals were directly compressed to minitablets and coated to achieve pulsatile valsartan release. Pharmacokinetic profiles of optimized and commercial formulations were compared in rabbit model. The mean particle size and PDI of the optimized nanocrystal batch V4 was reported as 211 nm and 0.117, respectively. DSC and PXRD analysis confirmed the crystalline nature of valsartan in nanocrystals. The dissolution extent of valsartan was markedly enhanced with both nanocrystals and minitablets as compared to pure valsartan irrespective of pH of the medium. Core minitablet V4F containing 5% w/w polyplasdone XL showed quickest release of valsartan, over 90% within 15 min. Coated formulation CV4F showed two spikes in release profile after successive lag times of 235 and 390 min. The pharmacokinetic study revealed that the bioavailability of optimized formulation (72.90%) was significantly higher than the commercial Diovan tablet (30.18%). The accelerated stability studies showed no significant changes in physicochemical properties, release behavior, and bioavialability of CV4F formulation. The formulation was successfully designed to achieve enhanced bioavailability and dual pulsatile release. Bedtime dosing will more efficiently control the circadian spikes of hypertension in the morning. PMID- 26961970 TI - A nanofiber assembly directed by the non-classical antiparallel beta-structure from 4S-(OH) proline polypeptide. AB - The antiparallel arrangement of two strands of the non-classical beta-structure, formed exclusively via cis-4S-(OH) prolyl polypeptide as established by FRET, propagates into self-assembled nanofibers upon conjugation with C12/C14/C16 hydrocarbon chains. PMID- 26961971 TI - The Use of EGFR Tyrosine Kinase Inhibitors in EGFR Wild-Type Non-Small-Cell Lung Cancer. AB - The objective response rate and progression-free survival observed with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with metastatic epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) are modest. The adverse events associated with EGFR TKIs are manageable but they must be considered in the context of the limited efficacy. The development of anti-PD-1 immunotherapy as second-line therapy has reduced the role of EGFR TKIs in EGFR wild-type NSCLC. Recently, there has been increased recognition of the benefit of the earlier integration of palliative care and symptom management, and this is reasonable alternative to treatment with an EGFR TKI for many patients. My practice pattern for patients with EGFR wild-type NSCLC is platinum-based chemotherapy as first-line therapy, immunotherapy as second line therapy, and single-agent chemotherapy as third-line therapy for patients with preserved performance status who want to pursue further therapy. Only a small proportion of patients are eligible for fourth-line therapy, and I prefer to enroll them in clinical trials rather than use EGFR TKIs. I suspect that the use of EGFR TKIs in clinical use and as a comparator arm for clinical trials will continue to decline over the next several years. PMID- 26961972 TI - Development of the Italian version of the modified Japanese orthopaedic association score (mJOA-IT): cross-cultural adaptation, reliability, validity and responsiveness. AB - PURPOSE: The modified Japanese orthopaedic association scale (mJOA) is considered one of the most appropriate outcome measures for the assessment of cervical spondylotic myelopathy (CSM). Moreover, mJOA has been recognised among the key predictors of surgical outcome at a global level. To apply the mJOA successfully at an international level, it should be translated and culturally adapted in the native language of the investigators using this scale. A translated version of the mJOA or any other functional scale has never been studied within an Italian population affected by CSM. The aim of this study has been to describe translation, cultural adaptation and psychometric properties of the Italian version of the mJOA (mJOA-IT). METHODS: The mJOA-IT was developed following a forward-backward translation procedure. Psychometric properties were assessed on a cohort of patients with CSM undergone anterior or posterior decompression associated with stabilisation in lordosis. RESULTS: The mJOA-IT proved to be a reliable outcome measure for CSM (internal consistency 0.60, test-retest stability 0.910, P < 0.001, inter-observer reliability 0.80, P < 0.001). The mJOA IT was associated with the Nurick scale (r = -0.615) while it was not associated with NDI, SF-36 and SF-36 components. The mJOA-IT was also responsive (d = 0.867). CONCLUSIONS: The mJOA-IT proved to be a reliable and valid tool to assess patients affected by CSM. This form is recommended to be used for clinical and research purposes in Italy, to promote the global standardisation of assessment tools and to compare studies on CSM worldwide. PMID- 26961974 TI - Continuous Glucose Monitoring in Type 1 Diabetes. AB - BACKGROUND: Continuous glucose monitoring (CGM) patient systems have been shown to improve diabetes self-treatment when used consistently. The meaningful integration of this technology into everyday life, however, can vary greatly among CGM users and not all people with diabetes use CGM to its full potential. To address this issue, the study pursued 2 aims: first, to identify patient characteristics that underlie the acceptance of CGM in people with type 1 diabetes and, second, to examine the effects of different levels of experience with CGM use. METHODS: Guided by a model based on the technology acceptance model (TAM), structural equation modeling (SEM) was employed to model the patient characteristics as predictors of CGM acceptance. In all, 111 participants (60.4% female, mean = 37.6 years, SD = 11.2) participated in a web-based survey; 40 were current CGM users, 18 were former users and 53 had no experience with CGM systems. RESULTS: In general, participants evaluated CGM positively; however, the feeling of information overload represented a major barrier to the sustained use of CGM, while perceptions of usefulness and ease of use constituted incentives for using this technology. Moreover, patients without CGM experience imagined more information overload than current users reported. Current users showed more intention to use CGM than former users. CONCLUSION: This study highlights the importance of CGM user experience for the effective use of this technology. PMID- 26961973 TI - Expression of complement and toll-like receptor pathway genes is associated with malaria severity in Mali: a pilot case control study. AB - BACKGROUND: The host response to infection by Plasmodium falciparum, the parasite most often responsible for severe malaria, ranges from asymptomatic parasitaemia to death. The clinical trajectory of malaria is influenced by host genetics and parasite load, but the factors determining why some infections produce uncomplicated malaria and some proceed to severe disease remain incompletely understood. METHODS: To identify molecular markers of severe falciparum malaria, human gene expression patterns were compared between children aged 6 months to 5 years with severe and uncomplicated malaria who were enrolled in a case-control study in Bandiagara, Mali. Microarrays were used to obtain expression data on severe cases and uncomplicated controls at the time of acute disease presentation (five uncomplicated and five severe), 1 week after presentation (three uncomplicated and three severe) and treatment initiation, and in the subsequent dry season (late convalescence, four uncomplicated and four severe). This is a pilot study for the first use of microarray technology in Mali. RESULTS: Complement and toll-like receptor (TLR) pathways were differentially expressed, with severe cases showing higher expression of the C1q, TLR2, TLR4, TLR8, and CR1 genes. Other genes previously associated with malaria pathogenesis, GZMB, FOS and HSPA6, were also higher among severe cases. TLR2, TLR4, TLR8, CR1, GZMB, FOS, and HSPA6 genes were expressed at lower levels in severe cases at late convalescence. CONCLUSIONS: Overexpression of genes previously associated with uncomplicated malaria was associated with severe disease. Low baseline expression of these genes may represent candidate markers for severe malaria. Despite the small sample size, results of this pilot study offer promising targets for follow-up analyses. PMID- 26961975 TI - Recurrent Endocrine Cycles. AB - BACKGROUND: The chaotic nature of blood glucose creates a formidable clinical challenge for diabetes healthcare. The recent discovery of recurrent endocrine cycles offers the advantage of advanced-prediction (proactive) health care. METHODS: Historical studies covering 111 patients and 1 subject collected several months of glucose readings and their daily metrics. Phase portraits and phase analytics can detect recurrent metric cycles and test their ability to anticipate serious glycemic conditions. RESULTS: Recurrent patterns were detected having a rate of ~7 days per complete cycle. Plots and risk models based on these cycles produced advanced alerts for acute glycemia, capturing greater than 96% of true positive days with a 5% false-positive rate. CONCLUSIONS: This method can be implemented graphically and functionally within a BG monitoring system to warn doctors and patients of impending serious glycemic levels. PMID- 26961976 TI - Salivary Glucose as a Diagnostic Marker for Diabetes Mellitus. PMID- 26961977 TI - Monoamine Oxidase Inhibition in a Patient With Type 1 Diabetes and Depression. PMID- 26961979 TI - Corrigendum: Lovastatin blocks Kv1.3 channel in human T cells: a new mechanism to explain its immunomodulatory properties. PMID- 26961978 TI - Family Communication and Cascade Testing for Fragile X Syndrome. AB - A total of 679 families who had at least one child with fragile X syndrome (FXS) were recruited from a research registry to participate in a survey examining cascade testing and communication about FXS. Families had a total of 1117 children (804 males, 313 females). Most families (84 %) had tested all of their children. The main reason for not testing, which did not differ by gender or age of the child, was that the child did not show signs of FXS (68 %). Families talked with their children about FXS occasionally (47 %) although 16 % said they do not talk about it. Most families (66 %) had told their children their FXS status, with males and those with the premutation being less likely to be told test results. Of those that did not, 46 % said that they would tell their child when they were old enough to understand, whereas 34 % had either decided they would not tell or were not sure if or when they were going to tell. About a quarter of respondents (28 %) indicated that no extended family members had been tested, with income and communication about FXS being the strongest predictors. Results from this large scale survey provide important data on how families communicate about FXS and reasons testing is or is not sought. This information can be used by genetic counsellors in providing follow-up to families after a FXS diagnosis. PMID- 26961980 TI - Novel insights into renal D-amino acid oxidase accumulation: propiverine changes DAAO localization and peroxisomal size in vivo. AB - Chronic exposure to propiverine, a frequently prescribed pharmaceutical for treatment of overactive bladder and incontinence, provokes massive protein accumulation in the cytosol and nucleus of renal proximal tubule epithelial cells in rats. Previously, the accumulating protein was identified as D-amino acid oxidase (DAAO), a peroxisomal flavoenzyme expressed in kidney, liver and brain. The cellular mechanism of propiverine-induced DAAO accumulation, however, remains unexplained and poorly characterized. Therefore, to further increase the understanding of DAAO accumulation in rat kidney, this study aimed to characterize DAAO accumulations using differential immunofluorescent staining of rat kidney sections as well as in vitro binding analyses and proteasomal activity studies. We demonstrated that propiverine is neither a ligand of DAAO nor an inhibitor of the proteasome in vitro. However, propiverine treatment resulted in a significant decrease of peroxisomal size in rat proximal tubule epithelial cells. Moreover, peroxisomal catalase also accumulated in the cytosol and nuclei of propiverine-treated rats concurrently with DAAO. Taken together, our study indicates that propiverine treatment affects the trafficking and/or degradation of peroxisomal proteins such as DAAO and catalase by a so far unique and unknown mechanism. PMID- 26961981 TI - [The Competence Network Parkinson (CNP)]. AB - The Competence Network Parkinson (CNP) is a research infrastructure for disease oriented translational and clinical research in the field of Parkinson syndromes (PS). It was initiated in 1999 and funded until 2008 by the German Ministry for Education and Research (BMBF). The CNP created a highly frequented website with information on PS for the general public and for experts. The CNP designed and established one of the first electronic internet-based data entry systems (secuTrial(r)) - fulfilling the legal standards of data safety and security - a material bank for genetic research on Parkinson's disease (PD), implemented and investigated new methods for early diagnosis of PD and related atypical PS including in vivo dopamine transporter imaging (DAT SPECT), established the German Parkinson Study Group (GPS-Pharma) with 40 certified trial centres for pharmacotherapeutical trials and the German interdisciplinary Parkinson Study Group (neurology and neurosurgery) for deep brain stimulation (GPS-DBS), and carried out several pharmacoeconomic and health care studies on PD in Germany. Sustainability of the infrastructure CNP has in part been achieved in form of the GPS-Pharma and the GPS-DBS, as well as in the German Study Group on REM Sleep Behaviour Disorder (RBD), a prodromal phase of PD. Part of the CNP activities, such as genetic research and research on cohorts of PD patients, have been incorporated into the German Center for Neurodegenerative Disorders (DZNE). Furthermore, topics such as health care research are funded within projects of the EU research program. The article describes problems in setting up a competence network from scratch and contains recommendations how to avoid them in the future. PMID- 26961982 TI - Localization of Diagnostically Relevant Regions of Interest in Whole Slide Images: a Comparative Study. AB - Whole slide digital imaging technology enables researchers to study pathologists' interpretive behavior as they view digital slides and gain new understanding of the diagnostic medical decision-making process. In this study, we propose a simple yet important analysis to extract diagnostically relevant regions of interest (ROIs) from tracking records using only pathologists' actions as they viewed biopsy specimens in the whole slide digital imaging format (zooming, panning, and fixating). We use these extracted regions in a visual bag-of-words model based on color and texture features to predict diagnostically relevant ROIs on whole slide images. Using a logistic regression classifier in a cross validation setting on 240 digital breast biopsy slides and viewport tracking logs of three expert pathologists, we produce probability maps that show 74 % overlap with the actual regions at which pathologists looked. We compare different bag-of words models by changing dictionary size, visual word definition (patches vs. superpixels), and training data (automatically extracted ROIs vs. manually marked ROIs). This study is a first step in understanding the scanning behaviors of pathologists and the underlying reasons for diagnostic errors. PMID- 26961983 TI - Automated Lung Segmentation from HRCT Scans with Diffuse Parenchymal Lung Diseases. AB - Performing accurate and fully automated lung segmentation of high-resolution computed tomography (HRCT) images affected by dense abnormalities is a challenging problem. This paper presents a novel algorithm for automated segmentation of lungs based on modified convex hull algorithm and mathematical morphology techniques. Sixty randomly selected lung HRCT scans with different abnormalities are used to test the proposed algorithm, and experimental results show that the proposed approach can accurately segment the lungs even in the presence of disease patterns, with some limitations in the apices and bases of lungs. The algorithm demonstrates a high segmentation accuracy (dice similarity coefficient = 98.62 and shape differentiation metrics dmean = 1.39 mm, and drms = 2.76 mm). Therefore, the developed automated lung segmentation algorithm is a good candidate for the first stage of a computer-aided diagnosis system for diffuse lung diseases. PMID- 26961984 TI - Large-scale mutational analysis in the EXT1 and EXT2 genes for Japanese patients with multiple osteochondromas. AB - BACKGROUND: Multiple osteochondroma (MO) is an autosomal dominant skeletal disorder characterized by the formation of multiple osteochondromas, and exostosin-1 (EXT1) and exostosin-2 (EXT2) are major causative genes in MO. In this study, we evaluated the genetic backgrounds and mutational patterns in Japanese families with MO. RESULTS: We evaluated 112 patients in 71 families with MO. Genomic DNA was isolated from peripheral blood leucocytes. The exons and exon/intron junctions of EXT1 and EXT2 were directly sequenced after PCR amplification. Fifty-two mutations in 47 families with MO in either EXT1 or EXT2, and 42.3% (22/52) of mutations were novel mutations. Twenty-nine families (40.8%) had mutations in EXT1, and 15 families (21.1%) had mutations in EXT2. Interestingly, three families (4.2%) had mutations in both EXT1 and EXT2. Twenty four families (33.8%) did not exhibit mutations in either EXT1 or EXT2. With regard to the types of mutations identified, 59.6% of mutations were inactivating mutations, and 38.5% of mutations were missense mutations. CONCLUSIONS: We found that the prevalence of EXT1 mutations was greater than that of EXT2 mutations in Japanese MO families. Additionally, we identified 22 novel EXT1 and EXT2 mutations in this Japanese MO cohort. This study represents the variety of genotype in MO. PMID- 26961985 TI - Commentary on: Evaluation of Facial Volume Changes after Rejuvenation Surgery Using a 3-Dimensional Camera. PMID- 26961986 TI - Commentary on: Double-Blind Comparison of Ultrasonic and Conventional Osteotomy in Terms of Early Postoperative Edema and Ecchymosis. PMID- 26961987 TI - Nine-Year Core Study Data for Sientra's FDA-Approved Round and Shaped Implants with High-Strength Cohesive Silicone Gel. AB - BACKGROUND: Since approval in March 2012, data on Sientra's (Santa Barbara, CA) silicone gel implants have been updated and published regularly to provide immediate visibility to the continued safety and performance of these devices. The 9 year follow-up data support the previously published data confirming the ongoing safety and efficacy of Sientra silicone gel breast implants. OBJECTIVES: The authors provide updated 9 year study data for Sientra's round and shaped silicone gel breast implants. METHODS: The Core Study is an ongoing 10 year study that enrolled 1788 patients with 3506 Sientra implants across four indications (primary augmentation, revision-augmentation, primary reconstruction, and revision-reconstruction). For the safety analysis, Kaplan-Meier risk rates were calculated to evaluate postoperative complications, including all breast implant related adverse effects. For the effectiveness analyses, results were presented through 8 years as patient satisfaction scores were assessed at even years. RESULTS: Through 9 years, the overall risk of capsular contracture was 12.6%. Smooth devices (16.6%, 95% CI, 14.2%, 19.5%) had a statistically significantly higher rate of capsular contracture compared to textured devices (8.0%, 95% CI, 6.2%, 10.4%). Out of the 610 reoperations in 477 patients, over half of all reoperations were due to cosmetic reasons (n = 315; 51.6%). Patient satisfaction remains high through 8 years, with 90% of primary augmentation patients indicating their breast implants look natural and feel soft. CONCLUSIONS: The 9 year follow-up data from the ongoing Core Study of the Sientra portfolio of HSC and HSC+ silicone gel breast implants reaffirm the very strong safety profile as well as continued patient satisfaction. LEVEL OF EVIDENCE: 2 Therapeutic. PMID- 26961988 TI - Safety and Efficacy of Novel Oral Anticoagulants vs Low Molecular Weight Heparin for Thromboprophylaxis in Large-Volume Liposuction and Body Contouring Procedures. AB - BACKGROUND: Preventing venous thromboembolism (VTE) remains an important topic in the plastic surgery community. However, there is little consensus regarding appropriate VTE prophylaxis for patients undergoing common body contouring procedures. OBJECTIVES: This study compared the use of two novel oral anticoagulants (Rivaroxaban and Apixiban) vs low molecular weight heparin (LMWH) for postoperative chemical prophylaxis in body contouring plastic surgery procedures. METHODS: A single center retrospective chart review of 1572 patients who underwent body contouring plastic surgery procedures from January 2012 to February 2015 was performed. Major complications associated with chemical prophylaxis were reviewed including hematomas requiring surgical evacuation, acute blood loss anemia requiring transfusions, and thrombotic or hemorrhagic events. RESULTS: Drug-related adverse events occurred in 1.27% (n = 20) of patients. The complications encountered by the 454 patients on LMWH consisted of 0.88% (n = 4) with hematomas requiring surgical evacuation, 0.44% (n = 2) with decreased hemoglobin requiring transfusions, and 0.22% (n = 1) with a deep vein thrombosis (DVT). The complications encountered by 703 patients on with Rivaroxaban consisted of 1.3% (n = 9) with hematomas requiring surgical evacuation, 0.43% (n = 3) with decreased hemoglobin requiring transfusions, and 0.1% (n = 1) with a DVT and pulmonary embolism. The complications encountered by 415 patients on with Apixaban consisted of 0.48% (n = 2) with a DVT. CONCLUSIONS: Novel oral anticoagulants (Rivaroxaban and Apixiban) are comparable to LMWH for chemical prophylaxis after body contouring procedures with similar rates of drug related complications. Further investigation is warranted with more clinical cases in order to recommend the use of this medication for routine postoperative chemical prophylaxis after body contouring procedures. LEVEL OF EVIDENCE: 3 Therapeutic. PMID- 26961990 TI - Commentary on: Analysis of the American Society of Anesthesiologists Physical Status Classification System and Caprini Risk Assessment Model in Predicting Venous Thromboembolic Outcomes in Plastic Surgery Patients. PMID- 26961989 TI - Autologous Fat Grafting: The Science Behind the Surgery. AB - An invaluable part of the plastic surgeon's technical arsenal for soft tissue contouring, fat grafting continues to be plagued by unpredictable outcomes, resulting in either reoperation and/or patient dissatisfaction. Thus, extensive research has been conducted into the effects of adipose tissue procurement, processing, and placement on fat graft quality at both the cellular level and in terms of overall volume retention. Herein, we present an overview of the vast body of literature in these areas, with additional discussion of cell-assisted lipotransfer as a therapy to improve volume retention, and on the controversial use of autologous fat in the setting of prior irradiation. PMID- 26961991 TI - Platelet-Rich Fibrin Improves the Viability of Diced Cartilage Grafts in a Rabbit Model. AB - BACKGROUND: Diced cartilage may be wrapped with synthetic or biological materials before grafting to a recipient site. These materials have unique advantages and disadvantages, and a gold standard is not available. OBJECTIVES: The authors investigated the effects of platelet-rich fibrin (PRF) on the survival of cartilage grafts in a rabbit model. METHODS: In this experimental study, diced cartilage pieces from the ears of 9 male rabbits were left unwrapped or were wrapped with PRF, oxidized regenerated cellulose, or fascia. Specimens then were placed into subcutaneous pockets prepared on the backs of the rabbits. The animals were sacrificed 2 months after the procedure, and the grafts were excised for macroscopic and histopathologic examination. RESULTS: The cartilage graft wrapped with PRF showed superior viability compared with the cartilage graft wrapped with oxidized regenerated cellulose. No significant differences were found among the other groups. The groups were not significantly different in terms of rates of inflammation, fibrosis, or vascularization. CONCLUSIONS: PRF enhances the viability of diced cartilage grafts and should be considered an appropriate biological wrapping material for cartilage grafting. PMID- 26961992 TI - A Cutaneous Reaction to Microneedling for Postacne Scarring Caused by Nickel Hypersensitivity. PMID- 26961993 TI - Physical performance and muscle strength in older patients with and without diabetes from a public hospital in Lima, Peru. AB - OBJECTIVE: To assess the relationship between physical performance (PP) and muscle strength (MS) in elderly subjects with and without diabetes in a public hospital of Lima, Peru. SUBJECTS AND METHOD: A cross-sectional analysis of subjects aged 60 years or older with and without diabetes. MS was measured with a handheld dynamometer, and PP with the "timed get-up-and-go" test. Nutritional status was determined using body mass index, body fat percentage measured with a handheld fat loss monitor and protein intake based on the 24-hour recall. Age, sex, and history of hospitalization and supplementation were also recorded. The association was assessed using adjusted prevalence ratios. RESULTS: Overall, 139 patients with diabetes (26.6% with low PP and 13.7% with decreased MS) and 382 subjects without diabetes (36.6% with low PP and 23.0% with decreased MS) were evaluated. No association was found between T2DM and MS (aPR: 0.99; 95% CI: 0.67 1.57) or PP (aPR: 1.13; 95% CI: 0.84-1.52). Protein and supplement consumption was also unrelated (P>.05); however, history of hospitalization, age, sex, nutritional status, and body fat percentage were related (P>.05). CONCLUSIONS: No association was found between T2DM, MS, and PP. However, low PP was associated to female sex and overweight/obesity, and decreased MS was associated to high body fat percentage and underweight. Moreover, MS and PP were related to older age and history of hospitalization. PMID- 26961994 TI - Fecal Microbiome in Epidemiologic Studies-Response. PMID- 26961995 TI - Fecal Microbiome in Epidemiologic Studies-Letter. PMID- 26961996 TI - Plasma Anti-Mullerian Hormone Concentrations and Risk of Breast Cancer among Premenopausal Women in the Nurses' Health Studies. AB - BACKGROUND: Anti-Mullerian hormone (AMH) is a member of the TGFbeta family of growth and differentiation factors with a key role in regulating folliculogenesis. In experimental studies, using supraphysiologic concentrations, AMH inhibits breast cancer growth. However, high levels of AMH were associated with increased breast cancer risk in two prior prospective epidemiologic studies. METHODS: We conducted a nested case-control study of premenopausal plasma AMH and breast cancer risk within the Nurses' Health Study (NHS) and NHSII. In NHS, 32,826 women donated blood samples in 1989-1990; in NHSII, 29,611 women donated samples in 1996-1999. After blood collection and before February 2004 (NHS) or July 2010 (NHSII), 539 cases were diagnosed among women premenopausal at diagnosis, and were matched 1:1 to controls. ORs and 95% confidence intervals (CI) were calculated using unconditional logistic regression, adjusting for matching and breast cancer risk factors. RESULTS: Higher plasma levels of AMH were associated with increased breast cancer risk (top vs. bottom quintile multivariate OR, 2.20; 95% CI, 1.34-3.63; P trend = 0.001). The association did not vary by invasive versus in situ disease or by estrogen receptor status. Associations were not significantly different by age at blood or diagnosis. Further adjustment for plasma estradiol or testosterone yielded similar results. CONCLUSIONS: Higher circulating AMH levels are associated with increased breast cancer risk among premenopausal women. IMPACT: The significant positive association between premenopausal plasma AMH levels and subsequent breast cancer risk before menopause suggests AMH may be useful as a marker of breast cancer risk in younger women. Cancer Epidemiol Biomarkers Prev; 25(5); 854-60. (c)2016 AACR. PMID- 26961997 TI - Increased risk of hydrocephalus in long-term dialysis patients. AB - BACKGROUND: The risk of hydrocephalus in end-stage renal disease (ESRD) patients on dialysis has not been studied in depth. METHODS: Using Taiwan National Health Insurance claims data, we identified 29 684 incident ESRD patients from 2000 to 2010, including 10 030 peritoneal dialysis (PD) patients and 19 654 hemodialysis (HD) patients. The control cohort consisted of 118 736 people randomly selected from those without kidney disease, frequency matched with ESRD patients by age, sex and index year. We also established propensity score-matched cohorts with 10 014 PD and 10 014 HD patients. The incidence rates and hazard ratios (HRs) of hydrocephalus were calculated until the end of 2011. RESULTS: Incidence rates of hydrocephalus were greater in HD and PD patients than in controls (8.44 and 11.0 versus 4.11 per 10 000 person-years, respectively), with an adjusted HR of 1.86 [95% confidence interval (CI) 1.43-2.41] for all ESRD patients compared with controls. A higher proportion of hydrocephalus patients underwent surgical bypass to relieve hydrocephalus in ESRD patients than controls, 40.7% (46/113) versus 24.5% (67/273), with an adjusted odds ratio of 2.11 (95% CI 1.33-3.36). Compared with controls, the adjusted HRs of communicating hydrocephalus for HD and PD patients were 1.77 (95% CI 1.22-2.55) and 2.51 (95% CI 1.61-3.89), respectively. The propensity score-matched analysis showed an HR of 0.72 (95% CI 0.42-1.23) for hydrocephalus in HD patients compared with PD patients. CONCLUSIONS: Patients with ESRD are at an increased risk of hydrocephalus. The risk difference between HD and PD patients is not significant. PMID- 26961998 TI - The influence of renal transplantation on retained microbial-human co metabolites. AB - BACKGROUND: Colonic microbial metabolism contributes substantially to uraemic retention solutes accumulating in chronic kidney disease (CKD) and various microbial-human co-metabolites relate to adverse outcomes. The influence of renal transplantation on these solutes is largely unexplored. METHODS: We prospectively followed 51 renal transplant recipients at the time of transplantation, Day 7 and Months 3 and 12 post-transplantation. Serum levels of p-cresyl sulphate (PCS), p cresyl glucuronide (PCG), indoxyl sulphate (IS), trimethylamine N-oxide (TMAO) and phenylacetylglutamine (PAG) were determined with liquid chromatography-tandem mass spectrometry. At each time point, transplant recipients were compared with CKD control patients matched for age, gender, diabetes mellitus and renal function. Determinants of serum levels were also compared between an unrelated cohort of 65 transplant recipients at Month 3 post-transplantation and CKD patients with 24-h urinary collection. RESULTS: Serum levels of the tested microbial-human co-metabolites significantly decreased following renal transplantation (P < 0.001). At each time point post-transplantation, serum levels of PCS, PCG, PAG and, to a lesser extent, IS, but not TMAO, were significantly lower in transplant recipients when compared with CKD control patients. Further analysis demonstrated significantly lower 24-h urinary excretion of these solutes in transplant recipients (P < 0.001). Also, renal clearances of PCG, IS, TMAO and PAG were significantly lower in transplant recipients without differences in estimated glomerular filtration rate. CONCLUSIONS: Colonic microbiota-derived uraemic retention solutes substantially decrease following renal transplantation. The 24-h urinary excretion of these microbial-human co-metabolites is lower when compared with CKD patients, suggesting an independent influence of transplantation on intestinal uptake, a composite of colonic microbial metabolism and intestinal absorption. Renal solute handling may differ between transplant recipients and CKD patients. PMID- 26961999 TI - Selective screening for distal renal tubular acidosis in recurrent kidney stone formers: initial experience and comparison of the simultaneous furosemide and fludrocortisone test with the short ammonium chloride test. AB - BACKGROUND: Distal renal tubular acidosis (dRTA) is associated with renal stone disease, and it often needs to be considered and excluded in some recurrent calcium kidney stone formers (KSFs). However, a diagnosis of dRTA, especially when 'incomplete', can be missed and needs to be confirmed by a urinary acidification (UA) test. The gold standard reference test is still the short ammonium chloride (NH4Cl) test, but it is limited by gastrointestinal side effects and occasionally failure to ingest sufficient NH4Cl. For this reason, the furosemide plus fludrocortisone (F+F) test has been proposed as an easier and better-tolerated screening test. The aim of the present study was to assess the usefulness of the F+F test as a clinical screening tool for dRTA in a renal stone clinic. METHODS: We studied 124 patients retrospectively in whom incomplete dRTA was suspected: 71 had kidney stones only, 9 had nephrocalcinosis only and 44 had both. A total of 158 UA tests were performed: 124 F+F and 34 NH4Cl; both tests were completed in 34 patients. RESULTS: The mean age was 45.4 +/- 15 years, and 49% of patients were male. The prevalence of complete and incomplete dRTAs was 7 and 13.7%, respectively. Of the 34 patients tested using both tests, 17 (50%) were abnormal and 4 (12%) were normal. Thirteen (39%) patients were abnormal by F+F, but normal by NH4Cl [sensitivity 100% (95% CI 80-100), specificity 24% (95% CI 7-50), positive predictive value 57% (95% CI 37-75), negative predictive value 100% (95% CI 40-100)]. CONCLUSIONS: The F+F test is characterized by an excellent sensitivity and negative predictive value, and the diagnosis of incomplete dRTA can be excluded reliably in a patient who acidifies their urine normally with this test. However, its lack of specificity is a drawback, and if there is any doubt, an abnormal F+F test may need to be confirmed by a follow-up NH4Cl test. Ideally, a prospective blinded study in unselected KSFs is needed to accurately assess the reliability of the F+F test in diagnosing, rather than excluding, dRTA. PMID- 26962001 TI - HDAC2 regulates FoxO1 during RANKL-induced osteoclastogenesis. AB - The bone-resorbing osteoclast (OC) is essential for bone homeostasis, yet deregulation of OCs contributes to diseases such as osteoporosis, osteopetrosis, and rheumatoid arthritis. Here we show that histone deacetylase 2 (HDAC2) is a key positive regulator during receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis and bone resorption. Bone marrow macrophages (BMMs) showed increased HDAC2 expression during osteoclastogenesis. HDAC2 overexpression enhanced, whereas HDAC2 deletion suppressed osteoclastogenesis and bone resorption using lentivirus infection. Mechanistically, upon RANKL activation, HDAC2 activated Akt; Akt directly phosphorylates and abrogates Forkhead box protein O1 (FoxO1), which is a negative regulator during osteoclastogenesis through reducing reactive oxygen species. HDAC2 deletion in BMMs resulted in decreased Akt activation and increased FoxO1 activity during osteoclastogenesis. In conclusion, HDAC2 activates Akt thus suppresses FoxO1 transcription results in enhanced osteoclastogenesis. Our data imply the potential value of HDAC2 as a new target in regulating osteoclast differentiation and function. PMID- 26962003 TI - The "Cadillac Tax" on Health Benefits in the United States Will Hit the Middle Class Hardest: Refuting the Myth That Health Benefit Tax Subsidies Are Regressive. AB - U.S. employment-based health benefits are exempt from income and payroll taxes, an exemption that provided tax subsidies of $326.2 billion in 2015. Both liberal and conservative economists have denounced these subsidies as "regressive" and lauded a provision of the Affordable Care Act-the Cadillac Tax-that would curtail them. The claim that the subsidies are regressive rests on estimates showing that the affluent receive the largest subsidies in absolute dollars. But this claim ignores the standard definition of regressivity, which is based on the share of income paid by the wealthy versus the poor, rather than on dollar amounts. In this study, we calculate the value of tax subsidies in 2009 as a share of income for each income quintile and for the wealthiest Americans. In absolute dollars, tax subsidies were highest for families between the 80th and 95th percentiles of family income and lowest for the poorest 20%. However, as shares of income, subsidies were largest for the middle and fourth income quintiles and smallest for the wealthiest 0.5% of Americans. We conclude that the tax subsidy to employment-based insurance is neither markedly regressive, nor progressive. The Cadillac Tax will disproportionately harm families with (2009) incomes between $38,550 and $100,000, while sparing the wealthy. PMID- 26962002 TI - Screening for GPR101 defects in pediatric pituitary corticotropinomas. AB - Cushing disease (CD) in children is caused by adrenocorticotropic hormone (ACTH) secreting pituitary adenomas. Germline or somatic mutations in genes such as MEN1, CDKIs, AIP, and USP8 have been identified in pediatric CD, but the genetic defects in a significant percentage of cases are still unknown. We investigated the orphan G protein-coupled receptor GPR101, a gene known to be involved in somatotropinomas, for its possible involvement in corticotropinomas. We performed GPR101 sequencing, expression analyses by RT-qPCR and immunostaining, and functional studies (cell proliferation, pituitary hormones secretion, and cAMP measurement) in a series of patients with sporadic CD secondary to ACTH-secreting adenomas in whom we had peripheral and tumor DNA (N=36). No increased GPR101 expression was observed in tumors compared to normal pituitary (NP) tissues, nor did we find a correlation between GPR101 and ACTH expression levels. Sequence analysis revealed a very rare germline heterozygous GPR101 variant (p.G31S) in one patient with CD. Overexpression of the p.G31S variant did not lead to increased growth and proliferation, although modest effects on cAMP signaling were seen. GPR101 is not overexpressed in ACTH-secreting tumors compared to NPs. A rare germline GPR101 variant was found in one patient with CD but in vitro studies did not support a consistent pathogenic effect. GPR101 is unlikely to be involved in the pathogenesis of CD. PMID- 26962004 TI - The Perceived Barriers of Access to Health Care Among a Group of Non-camp Syrian Refugees in Jordan. AB - The aims of this study were to identify the most needed health care services, accessibility of various health care services, and barriers to access as perceived by a group of Syrian refugees living in non-camp settings in Jordan and to compare accessibility among different groups. The study was conducted in the Amman, Irbid, Karak, and Maan governorates of Jordan. This is a cross-sectional, analytical, observational study using convenience and snowball sampling for data collection. A structured questionnaire was included in an ongoing needs assessment of a Jordanian nongovernment organization in April 2014, with a total of 196 surveys conducted. In addition to the prevalent acute and communicable diseases, chronic diseases and dental problems were common. Preventive and primary health care were more accessible than advanced services. Structural and financial barriers hindered access. The specific survey location and governorate were associated with a difference in reported access. Registration status, health provider, duration, and out-of-pocket payment did not affect accessibility. The capacities of health facilities at different levels should be increased. Enhanced information sharing among health providers can improve identification of needs and gaps. PMID- 26962005 TI - Shewanella algicola sp. nov., a marine bacterium isolated from brown algae. AB - A Gram-stain-negative, aerobic, rod-shaped bacterium motile by means of a single polar flagella, strain ST-6T, was isolated from a brown alga (Sargassum thunbergii) collected in Jeju, Republic of Korea. Strain ST-6T was psychrotolerant, growing at 4-30 degrees C (optimum 20 degrees C). Phylogenetic analysis based on 16S rRNA and gyrB gene sequences revealed that strain ST-6T belonged to a distinct lineage in the genus Shewanella. Strain ST-6T was related most closely to Shewanella basaltis J83T, S. gaetbuli TF-27T, S. arctica IT12T, S. vesiculosa M7T and S. aestuarii SC18T, showing 96-97 % and 85-70 % 16S rRNA and gyrB gene sequences similarities, respectively. DNA-DNA relatedness values between strain ST-6T and the type strains of two species of the genus Shewanella were <22.6 %. The major cellular fatty acids (>5 %) were summed feature 3 (comprising C16:1omega7c and/ or iso-C15:0 2-OH), C16:0, iso-C13:0 and C17:1omega8c. The DNA G+C content of strain ST-6Twas 42.4 mol%, and the predominant isoprenoid quinones were menaquinone MK-7 and ubiquinones Q-7 and Q 8. On the basis of its phenotypic properties and phylogenetic distinctiveness, strain ST-6T is considered to represent a novel species of the genus Shewanella, for which the name Shewanella algicola sp. nov. is proposed. The type strain is ST-6T (= KCTC 23253T = JCM 31091T). PMID- 26962006 TI - ROC-ing along: Evaluation and interpretation of receiver operating characteristic curves. AB - BACKGROUND: It is vital for clinicians to understand and interpret correctly medical statistics as used in clinical studies. In this review, we address current issues and focus on delivering a simple, yet comprehensive, explanation of common research methodology involving receiver operating characteristic (ROC) curves. ROC curves are used most commonly in medicine as a means of evaluating diagnostic tests. METHODS: Sample data from a plasma test for the diagnosis of colorectal cancer were used to generate a prediction model. These are actual, unpublished data that have been used to describe the calculation of sensitivity, specificity, positive predictive and negative predictive values, and accuracy. The ROC curves were generated to determine the accuracy of this plasma test. These curves are generated by plotting the sensitivity (true-positive rate) on the y axis and 1 - specificity (false-positive rate) on the x axis. RESULTS: Curves that approach closest to the coordinate (x = 0, y = 1) are more highly predictive, whereas ROC curves that lie close to the line of equality indicate that the result is no better than that obtained by chance. The optimum sensitivity and specificity can be determined from the graph as the point where the minimum distance line crosses the ROC curve. This point corresponds to the Youden index (J), a function of sensitivity and specificity used commonly to rate diagnostic tests. The area under the curve is used to quantify the overall ability of a test to discriminate between 2 outcomes. CONCLUSION: By following these simple guidelines, interpretation of ROC curves will be less difficult and they can then be interpreted more reliably when writing, reviewing, or analyzing scientific papers. PMID- 26962007 TI - Hydrosilylation in Aryliminopyrrolide-Substituted Silanes. AB - A range of silanes was synthesized by the reaction of HSiCl3 with iminopyrrole derivatives in the presence of NEt3 . In certain cases, intramolecular hydrosilylation converts the imine ligand into an amino substituent. This reaction is inhibited by factors such as electron-donating substitution on Si and steric bulk. The monosubstituted ((Dipp) IMP)SiHMeCl ((Dipp) IMP=2-[N-(2,6 diisopropylphenyl)iminomethyl]pyrrolide), is stable towards hydrosilylation, but slow hydrosilylation is observed for ((Dipp) IMP)SiHCl2 . Reaction of two equivalents of (Dipp) IMPH with HSiCl3 results in the hydrosilylation product ((Dipp) AMP)((Dipp) IMP)SiCl ((Dipp) AMP=2-[N-(2,6 diisopropylphenyl)aminomethylene]pyrrolide), but the trisubsitituted ((Dipp) IMP)3 SiH is stable. Monitoring the hydrosilylation reaction of ((Dipp) IMP)SiHCl2 reveals a reactive pathway involving ligand redistribution reactions to form the disubstituted ((Dipp) AMP)((Dipp) IMP)SiCl as an intermediate. The reaction is strongly accelerated in the presence of chloride anions. PMID- 26962008 TI - Blood-Borne Pathogens: A Canadian Blood Services Centre for Innovation Symposium. AB - Testing donations for pathogens and deferring selected blood donors have reduced the risk of transmission of known pathogens by transfusion to extremely low levels in most developed countries. Protecting the blood supply from emerging infectious threats remains a serious concern in the transfusion medicine community. Transfusion services can employ indirect measures such as surveillance, hemovigilance, and donor questioning (defense), protein-, or nucleic acid based direct testing (detection), or pathogen inactivation of blood products (destruction) as strategies to mitigate the risk of transmission transmitted infection. In the North American context, emerging threats currently include dengue, chikungunya, and hepatitis E viruses, and Babesia protozoan parasites. The 2003 SARS and 2014 Ebola outbreaks illustrate the potential of epidemics unlikely to be transmitted by blood transfusion but disruptive to blood systems. Donor-free blood products such as ex vivo generated red blood cells offer a theoretical way to avoid transmission-transmitted infection risk, although biological, engineering, and manufacturing challenges must be overcome before this approach becomes practical. Similarly, next generation sequencing of all nucleic acid in a blood sample is currently possible but impractical for generalized screening. Pathogen inactivation systems are in use in different jurisdictions around the world, and are starting to gain regulatory approval in North America. Cost concerns make it likely that pathogen inactivation will be contemplated by blood operators through the lens of health economics and risk based decision making, rather than in zero-risk paradigms previously embraced for transfusable products. Defense of the blood supply from infectious disease risk will continue to require innovative combinations of surveillance, detection, and pathogen avoidance or inactivation. PMID- 26962009 TI - The GATA transcription factor gene gtaG is required for terminal differentiation in Dictyostelium. AB - The GATA transcription factor GtaG is conserved in Dictyostelids and essential for terminal differentiation in Dictyostelium discoideum, but its function is not well understood. Here we show that gtaG is expressed in prestalk cells at the anterior region of fingers and in the extending stalk during culmination. The gtaG- phenotype is cell-autonomous in prestalk cells and non-cell-autonomous in prespore cells. Transcriptome analyses reveal that GtaG regulates prestalk gene expression during cell differentiation before culmination and is required for progression into culmination. GtaG-dependent genes include genetic suppressors of the Dd-STATa-defective phenotype as well as Dd-STATa target-genes, including extra cellular matrix genes. We show that GtaG may be involved in the production of two culmination-signaling molecules, cyclic di-GMP and the spore differentiation factor SDF-1 and that addition of c-di-GMP rescues the gtaG- culmination and spore formation deficiencies. We propose that GtaG is a regulator of terminal differentiation that functions in concert with Dd-STATa and controls culmination through regulating c-di-GMP and SDF-1 production in prestalk cells. PMID- 26962012 TI - Weak-binding molecules are not drugs?-toward a systematic strategy for finding effective weak-binding drugs. AB - Designing maximally selective ligands that act on individual drug targets with high binding affinity has been the central dogma of drug discovery and development for the past two decades. However, many low-affinity drugs that aim for several targets at the same time are found more effective than the high affinity binders when faced with complex disease conditions, such as cancers, Alzheimer's disease and cardiovascular diseases. The aim of this study was to appreciate the importance and reveal the features of weak-binding drugs and propose an integrated strategy for discovering them. Weak-binding drugs can be characterized by their high dissociation rates and transient interactions with their targets. In addition, network topologies and dynamics parameters involved in the targets of weak-binding drugs also influence the effects of the drugs. Here, we first performed a dynamics analysis for 33 elementary subgraphs to determine the desirable topology and dynamics parameters among targets. Then, by applying the elementary subgraphs to the mitogen-activated protein kinase (MAPK) pathway, several optimal target combinations were obtained. Combining drug-target interaction prediction with molecular dynamics simulation, we got two potential weak-binding drug candidates, luteolin and tanshinone IIA, acting on these targets. Further, the binding affinity of these two compounds to their targets and the anti-inflammatory effects of them were validated through in vitro experiments. In conclusion, weak-binding drugs have real opportunities for maximum efficiency and may show reduced adverse reactions, which can offer a bright and promising future for new drug discovery. PMID- 26962011 TI - Illumina microRNA profiles reveal the involvement of miR397a in Citrus adaptation to long-term boron toxicity via modulating secondary cell-wall biosynthesis. AB - The mechanisms underlying tolerance to B-toxicity in plants are still controversial. Our previous studies indicated that B-toxicity is mainly limited to leaves in Citrus and that alternations of cell-wall structure in vascular bundles are involved in tolerance to B-toxicity. Here, miRNAs and their expression patterns were first identified in B-treated Citrus sinensis (tolerant) and C. grandis (intolerant) leaves via high-throughput sequencing. Candidate miRNAs were then verified with molecular and anatomical approaches. The results showed that 51 miRNAs in C. grandis and 20 miRNAs in C. sinensis were differentially expressed after B-toxic treatment. MiR395a and miR397a were the most significantly up-regulated miRNAs in B-toxic C. grandis leaves, but both were down-regulated in B-toxic C. sinensis leaves. Four auxin response factor genes and two laccase (LAC) genes were confirmed through 5'-RACE to be real targets of miR160a and miR397a, respectively. Up-regulation of LAC4 resulted in secondary deposition of cell-wall polysaccharides in vessel elements of C. sinensis, whereas down-regulation of both LAC17 and LAC4, led to poorly developed vessel elements in C. grandis. Our findings demonstrated that miR397a plays a pivotal role in woody Citrus tolerance to B-toxicity by targeting LAC17 and LAC4, both of which are responsible for secondary cell-wall synthesis. PMID- 26962014 TI - Telemonitoring in patients with chronic respiratory insufficiency: expectations deluded? PMID- 26962013 TI - Randomised crossover trial of telemonitoring in chronic respiratory patients (TeleCRAFT trial). AB - DESIGN: Randomised crossover trial with 6 months of standard best practice clinical care (control group) and 6 months with the addition of telemonitoring. PARTICIPANTS: 68 patients with chronic lung disease (38 with COPD; 30 with chronic respiratory failure due to other causes), who had a hospital admission for an exacerbation within 6 months of randomisation and either used long-term oxygen therapy or had an arterial oxygen saturation (SpO2) of <90% on air during the previous admission. Individuals received telemonitoring (second-generation system) via broadband link to a hospital-based care team. OUTCOME MEASURES: Primary outcome measure was time to first hospital admission for an acute exacerbation. Secondary outcome measures were hospital admissions, general practitioner (GP) consultations and home visits by nurses, quality of life measured by EuroQol-5D and hospital anxiety and depression (HAD) scale, and self efficacy score (Stanford). RESULTS: Median (IQR) number of days to first admission showed no difference between the two groups-77 (114) telemonitoring, 77.5 (61) control ( p=0.189). Hospital admission rate at 6 months increased (0.63 telemonitoring vs 0.32 control p=0.026). Home visits increased during telemonitoring; GP consultations were unchanged. Self-efficacy fell, while HAD depression score improved marginally during telemonitoring. CONCLUSIONS: Telemonitoring added to standard care did not alter time to next acute hospital admission, increased hospital admissions and home visits overall, and did not improve quality of life in chronic respiratory patients. TRIAL REGISTRATION NUMBER: NCT02180919 (ClinicalTrials.gov). PMID- 26962016 TI - Revealing Portraits. PMID- 26962015 TI - Understanding the impact of second-hand smoke exposure on clinical outcomes in participants with COPD in the SPIROMICS cohort. AB - BACKGROUND: Second-hand smoke (SHS) exposure has been linked to the development of and morbidity from lung disease. We sought to advance understanding of the impact of SHS on health-related outcomes in individuals with COPD. METHODS: Among the participants with COPD in SPIROMICS, recent SHS exposure was quantified as (1) hours of reported exposure in the past week or (2) reported living with a smoker. We performed adjusted regression for SHS with outcomes, testing for interactions with gender, race, smoking and obesity. RESULTS: Of the 1580 participants with COPD, 20% reported living with a smoker and 27% reported exposure in the past week. Living with a smoker was associated with worse St George's Respiratory Questionnaire score (SGRQ, beta 3.10; 95% CI 0.99 to 5.21), COPD Assessment Test score (beta 1.43; 95% CI 0.52 to 2.35) and increased risk for severe exacerbations (OR 1.51, 95% CI 1.04 to 2.17). SHS exposure in the past week was associated with worse SGRQ (beta 2.52; 95% CI 0.47 to 4.58), nocturnal symptoms (OR 1.58; 95% CI 1.19 to 2.10), wheezing (OR 1.34; 95% CI 1.02 to 1.77), chronic productive cough (OR 1.77; 95% CI 1.33 to 2.35) and difficulty with cough and sputum (Ease of Cough and Sputum scale, beta 0.84; 95% CI 0.42 to 1.25). SHS was associated with increased airway wall thickness on CT but not emphysema. Active smokers, obese individuals and individuals with less severe airflow obstruction also had higher susceptibility to SHS for some outcomes. CONCLUSION: Individuals with COPD, including active smokers, have significant SHS exposure, associated with worse outcomes and airway wall thickness. Active smokers and obese individuals may have worse outcomes associated with SHS. TRIAL REGISTRATION NUMBER: NCT01969344 (clinicaltrials.gov). PMID- 26962017 TI - M011L-deficient oncolytic myxoma virus induces apoptosis in brain tumor initiating cells and enhances survival in a novel immunocompetent mouse model of glioblastoma. AB - BACKGROUND: Myxoma virus (MYXV) is a promising oncolytic agent and is highly effective against immortalized glioma cells but less effective against brain tumor initiating cells (BTICs), which are believed to mediate glioma development/recurrence. MYXV encodes various proteins to attenuate host cell apoptosis, including an antiapoptotic Bcl-2 homologue known as M011L. Such proteins may limit the ability of MYXV to kill BTICs, which have heightened resistance to apoptosis. We hypothesized that infecting BTICs with an M011L deficient MYXV construct would overcome BTIC resistance to MYXV. METHODS: We used patient-derived BTICs to evaluate the efficacy of M011L knockout virus (vMyx M011L-KO) versus wild-type MYXV (vMyx-WT) and characterized the mechanism of virus-induced cell death in vitro. To extend our findings in a novel immunocompetent animal model, we derived, cultured, and characterized a C57Bl/6J murine BTIC (mBTIC0309) from a spontaneous murine glioma and evaluated vMyx-M011L KO efficacy with and without temozolomide (TMZ) in mBTIC0309-bearing mice. RESULTS: We demonstrated that vMyx-M011L-KO induces apoptosis in BTICs, dramatically increasing sensitivity to the virus. vMyx-WT failed to induce apoptosis as M011L protein prevented Bax activation and cytochrome c release. In vivo, intracranial implantation of mBTIC0309 generated tumors that closely recapitulated the pathological and molecular profile of human gliomas. Treatment of tumor-bearing mice with vMyx-M011L-KO significantly prolonged survival in immunocompetent-but not immunodeficient-mouse models, an effect that is significantly enhanced in combination with TMZ. CONCLUSIONS: Our data suggest that vMyx-M011L-KO is an effective, well-tolerated, proapoptotic oncolytic virus and a strong candidate for clinical translation. PMID- 26962018 TI - Oral Biofilm Architecture at the Microbial Scale. AB - The application of Spectral Imaging FISH to oral biofilm samples has permitted the direct, simultaneous observation of up to nine different bacterial taxa. This has revealed a complex yet organized microbial architecture, identifying the key microorganisms in the community and detecting the existing interspecies physical interactions at the micron scale. PMID- 26962019 TI - Pre-hospital electrocardiographic severity and acuteness scores predict left ventricular function in patients with ST elevation myocardial infarction. AB - OBJECTIVES: System delay (time from first medical contact to primary percutaneous coronary intervention) is associated with heart failure and mortality in patients with ST segment elevation myocardial infarction (STEMI). We evaluated the impact of system delay on left ventricular function (LVF) according to the combination of ischemia severity (Sclarovsky-Birnbaum grades) and acuteness (Anderson-Wilkins scores) in the pre-hospital electrocardiogram (ECG). METHODS: In a predefined secondary analysis of a prospective study, the severity and acuteness scores were performed on the pre-hospital ECG. Patients were assessed with respect to 4 classifications which were not mutually exclusive: severe ischemia (+SI) or non severe ischemia (-SI) and acute ischemia (+AI) or non-acute ischemia (-AI). LVF was assessed by global longitudinal strain (GLS) within 48hours of admission. Adjusted linear regression investigated the association of system delay with GLS in each group. RESULTS: In total 262 patients were eligible for analysis of the ECG, which resulted in 42 (16%) with (+SI, -AI), 110 (42%) with (-SI, -AI), 90 (34%) with (-SI, +AI), and 20 (8%) patients with (+SI, +AI). Although system delay did not differ between groups, patients with severe and non-acute ischemia had the most impaired LVF. System delay correlated weakly with GLS in the entire population (r=0.133, p=0.031), and well with GLS in the (+SI, +AI) group (r=0.456, p=0.04), while there was no correlation in the other groups. By adjusted analysis, system delay predicted impaired GLS only in the (+SI, +AI) group (beta=0.578, p=0.002). CONCLUSION: Pre-hospital risk stratification by ECG identifies patients with acute and severe ischemia who are at increased risk for reduced ventricular function (assessed by GLS) after STEMI. Optimizing reperfusion delays in these patients can therefore be of particular benefit in improving clinical outcome after STEMI. PMID- 26962020 TI - Scoping review of instruments measuring attitudes toward disability. AB - BACKGROUND: Negative attitudes toward disability cause difficulties in integrating persons with disabilities (PWDs) into society and limit their access to health care, education, employment, and leisure. Being aware of societal attitudes toward disability may help explain discrimination against PWDs and draw attention to the solutions needed to address these. Good measures of attitudes are vital for this purpose. OBJECTIVE: The aim is to synthesize published information, including evidences on psychometric properties and overall utility on instruments that measure attitudes toward disability. METHODS: A two-tiered search process was performed to identify instruments that measure attitudes toward disability and retrieve articles that describe their development and/or validation. The CanChild Outcome Measures Rating Form was utilized to determine the overall utility of the instruments. Results were synthesized using a self constructed data extraction form. RESULTS: Thirty-one instruments were included in the study. Five measured attitudes toward communication disability, 7 toward intellectual disability, 4 toward mental illness, and 15 toward disability in general. Target respondents ranged from children to adults, and included respondents from different occupations and cultural backgrounds. Twenty-three were found to have adequate overall utility, while 8 have poor overall utility. CONCLUSION: Several instruments are available in literature and all may be used for their intended purposes as long as their limitations are considered. Many still require further validation to ascertain their validity and responsiveness to change. PMID- 26962022 TI - A comprehensive analysis and functional characterization of naturally occurring non-synonymous variants of nuclear receptor PXR. AB - Pregnane & Xenobiotic Receptor (PXR) acts as a xenosensing transcriptional regulator of many drug metabolizing enzymes and transporters of the 'detoxification machinery' that coordinate in elimination of xenobiotics and endobiotics from the cellular milieu. It is an accepted view that some individuals or specific populations display considerable differences in their ability to metabolize different drugs, dietary constituents, herbals etc. In this context we speculated that polymorphisms in PXR gene might contribute to variability in cytochrome P450 (CYP450) metabolizing enzymes of phase I, drug metabolizing components of phase II and efflux components of the detoxification machinery. Therefore, in this study, we have undertaken a comprehensive functional analysis of seventeen naturally occurring non-synonymous variants of human PXR. When compared, we observed that some of the PXR SNP variants exhibit distinct functional and dynamic responses on parameters which included transcriptional function, sub-cellular localization, mitotic chromatin binding, DNA-binding properties and other molecular interactions. One of the unique SNP located within the DNA-binding domain of PXR was found to be functionally null and distinct on other parameters. Similarly, some of the non-synonymous SNPs in PXR imparted reduced transactivation function as compared to wild type PXR. Interestingly, PXR is reported to be a mitotic chromatin binding protein and such an association has been correlated to an emerging concept of 'transcription memory' and altered transcription output. In view of the observations made herein our data suggest that some of the natural PXR variants may have adverse physiological consequences owing to its influence on the expression levels and functional output of drug-metabolizing enzymes and transporters. The present study is expected to explain not only the observed inter-individual responses to different drugs but may also highlight the mechanistic details and importance of PXR in drug clearance, drug-drug interactions and diverse metabolic disorders. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. PMID- 26962025 TI - Deciphering ENCODE. AB - The ENCODE project represents a major leap from merely describing and comparing genomic sequences to surveying them for direct indicators of function. The astounding quantity of data produced by the ENCODE consortium can serve as a map to locate specific landmarks, guide hypothesis generation, and lead us to principles and mechanisms underlying genome biology. Despite its broad appeal, the size and complexity of the repository can be intimidating to prospective users. We present here some background about the ENCODE data, survey the resources available for accessing them, and describe a few simple principles to help prospective users choose the data type(s) that best suit their needs, where to get them, and how to use them to their best advantage. PMID- 26962026 TI - [Response to serum S100beta protein reference values in a paediatric population]. PMID- 26962024 TI - Methylene blue counteracts H2S toxicity-induced cardiac depression by restoring L type Ca channel activity. AB - We have previously reported that methylene blue (MB) can counteract hydrogen sulfide (H2S) intoxication-induced circulatory failure. Because of the multifarious effects of high concentrations of H2S on cardiac function, as well as the numerous properties of MB, the nature of this interaction, if any, remains uncertain. The aim of this study was to clarify 1) the effects of MB on H2S induced cardiac toxicity and 2) whether L-type Ca(2+) channels, one of the targets of H2S, could transduce some of the counteracting effects of MB. In sedated rats, H2S infused at a rate that would be lethal within 5 min (24 MUM.kg( 1).min(-1)), produced a rapid fall in left ventricle ejection fraction, determined by echocardiography, leading to a pulseless electrical activity. Blood concentrations of gaseous H2S reached 7.09 +/- 3.53 MUM when cardiac contractility started to decrease. Two to three injections of MB (4 mg/kg) transiently restored cardiac contractility, blood pressure, and Vo2, allowing the animals to stay alive until the end of H2S infusion. MB also delayed PEA by several minutes following H2S-induced coma and shock in unsedated rats. Applying a solution containing lethal levels of H2S (100 MUM) on isolated mouse cardiomyocytes significantly reduced cell contractility, intracellular calcium concentration ([Ca(2+)]i) transient amplitudes, and L-type Ca(2+) currents (ICa) within 3 min of exposure. MB (20 mg/l) restored the cardiomyocyte function, ([Ca(2+)]i) transient, and ICa The present results offer a new approach for counteracting H2S toxicity and potentially other conditions associated with acute inhibition of L-type Ca(2+) channels. PMID- 26962023 TI - Toward improved phosphorus efficiency in monogastrics-interplay of serum, minerals, bone, and immune system after divergent dietary phosphorus supply in swine. AB - Phosphorus (P) is of vital importance for many aspects of metabolism, including bone mineralization, blood buffering, and energy utilization. In order to identify molecular routes affecting intrinsic P utilization, we address processes covering P intake, uptake, metabolism, and excretion. In particular, the interrelation of bone tissue and immune features is of interest to approximate P intake to animal's physiology and health status. German Landrace piglets received different levels of digestible phosphorus: recommended, higher, or lower amounts. At multiple time points, relevant serum parameters were analyzed and radiologic studies on bone characteristics were performed. Peripheral blood mononuclear cells were collected to assess differential gene expression. Dietary differences were reflected by serum phosphorus, calcium, parathyroid hormone, and vitamin D. Bone reorganization was persistently affected as shown by microstructural parameters, cathepsin K levels, and transcripts associated with bone formation. Moreover, blood expression patterns revealed a link to immune response, highlighting bidirectional loops comprising bone formation and immune features, where the receptor-activator of NF-kappaB ligand/receptor-activator of NF-kappaB kinase system may play a prominent role. The modulated P supplementation provoked considerable organismal plasticity. Genes found to be differentially expressed due to variable P supply are involved in pathways relevant to P utilization and are potential candidate genes for improved P efficiency. PMID- 26962027 TI - Analysis of blink dynamics in patients with blepharoptosis. AB - Owing to the rapid movements of the human upper eyelid, a high-speed camera was used to record and characterize voluntary blinking and the blink dynamics of blepharoptosis patients were compared to a control group. Twenty-six blepharoptosis patients prior to surgery and 45 control subjects were studied and the vertical height of the palpebral aperture (PA) was measured manually at 2 ms intervals during each blink cycle. The PA and blinking speed were plotted with respect to time and a predictive model was generated. The blink dynamic was analysed in closing and opening phases, and revealed a reduced speed of the initial opening phase in ptotic patients, suggesting intrinsic muscle function change in ptosis pathogenesis. The PA versus time curve for each subject was reconstructed using custom-built parameters; however, there were significant differences between the two groups. Those parameters used included the rate of closure, the delay between opening and closing, rate of initial opening, rate of slow opening (nonlinear function) and the 'switch point' between those two rates of opening. The model was tested against a new group of subjects and was able to discriminate ptosis patients from controls with 80% accuracy. PMID- 26962028 TI - A model for competition for ribosomes in the cell. AB - A single mammalian cell includes an order of 10(4)-10(5) mRNA molecules and as many as 10(5)-10(6) ribosomes. Large-scale simultaneous mRNA translation induces correlations between the mRNA molecules, as they all compete for the finite pool of available ribosomes. This has important implications for the cell's functioning and evolution. Developing a better understanding of the intricate correlations between these simultaneous processes, rather than focusing on the translation of a single isolated transcript, should help in gaining a better understanding of mRNA translation regulation and the way elongation rates affect organismal fitness. A model of simultaneous translation is specifically important when dealing with highly expressed genes, as these consume more resources. In addition, such a model can lead to more accurate predictions that are needed in the interconnection of translational modules in synthetic biology. We develop and analyse a general dynamical model for large-scale simultaneous mRNA translation and competition for ribosomes. This is based on combining several ribosome flow models (RFMs) interconnected via a pool of free ribosomes. We use this model to explore the interactions between the various mRNA molecules and ribosomes at steady state. We show that the compound system always converges to a steady state and that it always entrains or phase locks to periodically time-varying transition rates in any of the mRNA molecules. We then study the effect of changing the transition rates in one mRNA molecule on the steady-state translation rates of the other mRNAs that results from the competition for ribosomes. We show that increasing any of the codon translation rates in a specific mRNA molecule yields a local effect, an increase in the translation rate of this mRNA, and also a global effect, the translation rates in the other mRNA molecules all increase or all decrease. These results suggest that the effect of codon decoding rates of endogenous and heterologous mRNAs on protein production is more complicated than previously thought. In addition, we show that increasing the length of an mRNA molecule decreases the production rate of all the mRNAs. PMID- 26962030 TI - Resilience in social insect infrastructure systems. AB - Both human and insect societies depend on complex and highly coordinated infrastructure systems, such as communication networks, supply chains and transportation networks. Like human-designed infrastructure systems, those of social insects are regularly subject to disruptions such as natural disasters, blockages or breaks in the transportation network, fluctuations in supply and/or demand, outbreaks of disease and loss of individuals. Unlike human-designed systems, there is no deliberate planning or centralized control system; rather, individual insects make simple decisions based on local information. How do these highly decentralized, leaderless systems deal with disruption? What factors make a social insect system resilient, and which factors lead to its collapse? In this review, we bring together literature on resilience in three key social insect infrastructure systems: transportation networks, supply chains and communication networks. We describe how systems differentially invest in three pathways to resilience: resistance, redirection or reconstruction. We suggest that investment in particular resistance pathways is related to the severity and frequency of disturbance. In the final section, we lay out a prospectus for future research. Human infrastructure networks are rapidly becoming decentralized and interconnected; indeed, more like social insect infrastructures. Human infrastructure management might therefore learn from social insect researchers, who can in turn make use of the mature analytical and simulation tools developed for the study of human infrastructure resilience. PMID- 26962021 TI - Nuclear receptors and nonalcoholic fatty liver disease. AB - Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic side effects. The impact of nuclear receptor crosstalk in NAFLD is likely to be profound, but requires further elucidation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. PMID- 26962029 TI - Network modules and hubs in plant-root fungal biomes. AB - Terrestrial plants host phylogenetically and functionally diverse groups of below ground microbes, whose community structure controls plant growth/survival in both natural and agricultural ecosystems. Therefore, understanding the processes by which whole root-associated microbiomes are organized is one of the major challenges in ecology and plant science. We here report that diverse root associated fungi can form highly compartmentalized networks of coexistence within host roots and that the structure of the fungal symbiont communities can be partitioned into semi-discrete types even within a single host plant population. Illumina sequencing of root-associated fungi in a monodominant south beech forest revealed that the network representing symbiont-symbiont co-occurrence patterns was compartmentalized into clear modules, which consisted of diverse functional groups of mycorrhizal and endophytic fungi. Consequently, terminal roots of the plant were colonized by either of the two largest fungal species sets (represented by Oidiodendron or Cenococcum). Thus, species-rich root microbiomes can have alternative community structures, as recently shown in the relationships between human gut microbiome type (i.e., 'enterotype') and host individual health. This study also shows an analytical framework for pinpointing network hubs in symbiont-symbiont networks, leading to the working hypothesis that a small number of microbial species organize the overall root-microbiome dynamics. PMID- 26962031 TI - Understanding individual routing behaviour. AB - Knowing how individuals move between places is fundamental to advance our understanding of human mobility (Gonzalez et al. 2008 Nature 453, 779-782. (doi:10.1038/nature06958)), improve our urban infrastructure (Prato 2009 J. Choice Model. 2, 65-100. (doi:10.1016/S1755-5345(13)70005-8)) and drive the development of transportation systems. Current route-choice models that are used in transportation planning are based on the widely accepted assumption that people follow the minimum cost path (Wardrop 1952 Proc. Inst. Civ. Eng. 1, 325 362. (doi:10.1680/ipeds.1952.11362)), despite little empirical support. Fine grained location traces collected by smart devices give us today an unprecedented opportunity to learn how citizens organize their travel plans into a set of routes, and how similar behaviour patterns emerge among distinct individual choices. Here we study 92 419 anonymized GPS trajectories describing the movement of personal cars over an 18-month period. We group user trips by origin destination and we find that most drivers use a small number of routes for their routine journeys, and tend to have a preferred route for frequent trips. In contrast to the cost minimization assumption, we also find that a significant fraction of drivers' routes are not optimal. We present a spatial probability distribution that bounds the route selection space within an ellipse, having the origin and the destination as focal points, characterized by high eccentricity independent of the scale. While individual routing choices are not captured by path optimization, their spatial bounds are similar, even for trips performed by distinct individuals and at various scales. These basic discoveries can inform realistic route-choice models that are not based on optimization, having an impact on several applications, such as infrastructure planning, routing recommendation systems and new mobility solutions. PMID- 26962032 TI - Correction to: 'The entropic basis of collective behaviour'. PMID- 26962033 TI - Assessing the appropriateness of prevention and management of venous thromboembolism in Australia: a cross-sectional study. AB - OBJECTIVES: The prevention and management of venous thromboembolism (VTE) is often at variance with guidelines. The CareTrack Australia (CTA) study reported that appropriate care (in line with evidence-based or consensus-based guidelines) is being provided for VTE at just over half of eligible encounters. The aim of this paper is to present and discuss the detailed CTA findings for VTE as a baseline for compliance with guidelines at a population level. SETTING: The setting was 27 hospitals in 2 states of Australia. PARTICIPANTS: A sample of participants designed to be representative of the Australian population was recruited. Participants who had been admitted overnight during 2009 and/or 2010 were eligible. Of the 1154 CTA participants, 481(42%) were admitted overnight to hospital at least once, comprising 751 admissions. There were 279 females (58%), and the mean age was 64 years. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary measure was compliance with indicators of appropriate care for VTE. The indicators were extracted from Australian VTE clinical practice guidelines and ratified by experts. Participants' medical records from 2009 to 2010 were analysed for compliance with 38 VTE indicators. RESULTS: Of the 35,145 CTA encounters, 1078 (3%) were eligible for scoring against VTE indicators. There were 2-84 eligible encounters per indicator at 27 hospitals. Overall compliance with indicators for VTE was 51%, and ranged from 34% to 64% for aggregated sets of indicators. CONCLUSIONS: The prevention and management of VTE was appropriate for only half of the at-risk patients in our sample; this provides a baseline for tracking progress nationally. There is a need for national and, ideally, international agreement on clinical standards, indicators and tools to guide, document and monitor care for VTE, and for measures to increase their uptake, particularly where deficiencies have been identified. PMID- 26962034 TI - Assessing comorbidity and correlates of wasting and stunting among children in Somalia using cross-sectional household surveys: 2007 to 2010. AB - OBJECTIVE: Wasting and stunting may occur together at the individual child level; however, their shared geographic distribution and correlates remain unexplored. Understanding shared and separate correlates may inform interventions. We aimed to assess the spatial codistribution of wasting, stunting and underweight and investigate their shared correlates among children aged 6-59 months in Somalia. SETTING: Cross-sectional nutritional assessments surveys were conducted using structured interviews among communities in Somalia biannually from 2007 to 2010. A two-stage cluster sampling methodology was used to select children aged 6-59 months from households across three livelihood zones (pastoral, agropastoral and riverine). Using these data and environmental covariates, we implemented a multivariate spatial technique to estimate the codistribution and divergence of the risks and correlates of wasting and stunting at the 1 * 1 km spatial resolution. PARTICIPANTS: 73,778 children aged 6-59 months from 1066 survey clusters in Somalia. RESULTS: Observed pairwise child level empirical correlations were 0.30, 0.70 and 0.73 between weight-for-height and height-for age; height-for-age and weight-for-age, and weight-for-height and weight-for-age, respectively. Access to foods with high protein content and vegetation cover, a proxy of rainfall or drought, were associated with lower risk of wasting and stunting. Age, gender, illness, access to carbohydrates and temperature were correlates of all three indicators. The spatial codistribution was highest between stunting and underweight with relative risk values ranging between 0.15 and 6.20, followed by wasting and underweight (range: 0.18-5.18) and lowest between wasting and stunting (range: 0.26-4.32). CONCLUSIONS: The determinants of wasting and stunting are largely shared, but their correlation is relatively variable in space. Significant hotspots of different forms of malnutrition occurred in the South Central regions of the country. Although nutrition response in Somalia has traditionally focused on wasting rather than stunting, integrated programming and interventions can effectively target both conditions to alleviate common risk factors. PMID- 26962035 TI - Ultra-processed foods and added sugars in the US diet: evidence from a nationally representative cross-sectional study. AB - OBJECTIVES: To investigate the contribution of ultra-processed foods to the intake of added sugars in the USA. Ultra-processed foods were defined as industrial formulations which, besides salt, sugar, oils and fats, include substances not used in culinary preparations, in particular additives used to imitate sensorial qualities of minimally processed foods and their culinary preparations. DESIGN: Cross-sectional study. SETTING: National Health and Nutrition Examination Survey 2009-2010. PARTICIPANTS: We evaluated 9317 participants aged 1+ years with at least one 24 h dietary recall. MAIN OUTCOME MEASURES: Average dietary content of added sugars and proportion of individuals consuming more than 10% of total energy from added sugars. DATA ANALYSIS: Gaussian and Poisson regressions estimated the association between consumption of ultra-processed foods and intake of added sugars. All models incorporated survey sample weights and adjusted for age, sex, race/ethnicity, family income and educational attainment. RESULTS: Ultra-processed foods comprised 57.9% of energy intake, and contributed 89.7% of the energy intake from added sugars. The content of added sugars in ultra-processed foods (21.1% of calories) was eightfold higher than in processed foods (2.4%) and fivefold higher than in unprocessed or minimally processed foods and processed culinary ingredients grouped together (3.7%). Both in unadjusted and adjusted models, each increase of 5 percentage points in proportional energy intake from ultra-processed foods increased the proportional energy intake from added sugars by 1 percentage point. Consumption of added sugars increased linearly across quintiles of ultra-processed food consumption: from 7.5% of total energy in the lowest quintile to 19.5% in the highest. A total of 82.1% of Americans in the highest quintile exceeded the recommended limit of 10% energy from added sugars, compared with 26.4% in the lowest. CONCLUSIONS: Decreasing the consumption of ultra-processed foods could be an effective way of reducing the excessive intake of added sugars in the USA. PMID- 26962036 TI - Total glucosides of paeony for rheumatoid arthritis: a protocol for a systematic review. AB - INTRODUCTION: Total glucosides of paeony (TGP) is a natural plant extract, which is widely used in China for treating rheumatoid arthritis (RA). Many relevant randomised controlled trials (RCTs) of TGP for RA are available, but they have not been systematically reviewed. This systematic review aims to examine the effectiveness and safety of TGP in patients with RA. METHODS AND ANALYSES: We will search for RCTs of TGP in the treatment of RA, performed up until February 2016, in PubMed, Embase, Cochrane Central Register of Controlled Trials, and four Chinese databases (Chinese Biomedical Database, China National Knowledge Infrastructure, Wanfang Database and Chinese Scientific Journal Database). Trial registers and reference lists of retrieved articles will also be searched to identify potential articles. RCTs comparing TGP with placebo, no treatment, or disease-modifying antirheumatic drugs for patients with RA will be retrieved. The primary outcomes will be disease improvement and disease remission. The secondary outcomes will be surrogate outcomes, symptoms, adverse effects, and quality of life. Two reviewers will independently extract data on participants, interventions, comparisons, outcomes, etc. The methodological quality of each included study will be evaluated using the Cochrane risk of bias tool, and the strength of evidence on prespecified outcomes will be assessed in accordance with the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Review Manager 5.3 software will be used for data analyses. Meta analyses will be performed if the data are sufficiently homogeneous, both statistically and clinically. Possible publication bias will also be checked using funnel plots once the number of included studies is sufficient. ETHICS AND DISSEMINATION: Ethics approval is not required, as this study will not involve patients. The results of this study will be submitted to a peer-reviewed journal for publication, to inform both clinical practice and further research. TRIAL REGISTRATION NUMBER: CRD42015026345. PMID- 26962037 TI - Why is there variation in the practice of evidence-based medicine in primary care? A qualitative study. AB - OBJECTIVE: To explore the factors, including barriers and facilitators, influencing the practice of evidence-based medicine (EBM) across various primary care settings in Malaysia based on the doctors' views and experiences. RESEARCH DESIGN: The qualitative study was used to answer the research question. 37 primary care physicians participated in six focus group discussions and six individual in-depth interviews. A semistructured topic guide was used to facilitate both the interviews and focus groups, which were audio recorded, transcribed verbatim, checked and analysed using a thematic approach. PARTICIPANTS: 37 primary care doctors including medical officers, family medicine specialists, primary care lecturers and general practitioners with different working experiences and in different settings. SETTING: The study was conducted across three primary care settings-an academic primary care practice, private and public health clinics in Klang Valley, Malaysia. RESULTS: The doctors in this study were aware of the importance of EBM but seldom practised it. Three main factors influenced the implementation of EBM in the doctors' daily practice. First, there was a lack of knowledge and skills in searching for and applying evidence. Second, workplace culture influenced doctors' practice of EBM. Third, some doctors considered EBM as a threat to good clinical practice. They were concerned that rigid application of evidence compromised personalised patient care and felt that EBM did not consider the importance of clinical experience. CONCLUSIONS: Despite being aware of and having a positive attitude towards EBM, doctors in this study seldom practised EBM in their routine clinical practice. Besides commonly cited barriers such as having a heavy workload and lack of training, workplace 'EBM culture' had an important influence on the doctors' behaviour. Strategies targeting barriers at the practice level should be considered when implementing EBM in primary care. PMID- 26962038 TI - Are migration patterns and mortality related among European regions? AB - Geographical inequalities in mortality across Europe may be influenced by migration between regions. The relationship between age- and sex-standardised death rates, 2008-2010, and population change resulting from migration 2000-2010, was analysed in 250 'Nomenclature of Statistical Territorial Units' (NUTS) level 2 regions in 26 European countries. Across Europe death rates were significantly higher in regions experiencing population loss. This association continued after adjustment for 2005 household income among all regions and Western regions but not among Eastern areas. This analysis suggests migration could contribute to Europe's persistent inequalities in mortality, and highlights the problems of Eastern regions with the highest death rates, lowest incomes and declining populations. PMID- 26962039 TI - Continuity of care in the ambulatory sector and hospital admissions among patients with heart failure in Germany. AB - BACKGROUND: Heart failure is one of the most cost-intensive chronic diseases and the most common cause of hospitalization. More than 60% of the treatment costs of heart failure are incurred in the inpatient sector in Germany. However, hospital admissions due to heart failure are considered to be potentially avoidable through effective and continuous ambulatory care. Our aim is to examine whether continuity in ambulatory care is associated with hospitalizations due to heart failure. METHODS: Using insurance claims data from Germany's biggest statutory health insurance company, we defined three measures of continuity of care: Continuity of Care Index (COCI), Usual Provider Index (UPC) and the Sequential Continuity Index (SECON). We analyzed whether these measures are associated with hospitalization due to heart failure using separate logistic regression models. We controlled for a wide range of covariates such as sex, age and the Charlson comorbidity index. RESULTS: Data of 382 118 heart failure patients were included in the analyses. Index values range from 0.77 to 0.89. Results of logistic regression analyses indicate that the continuity indices COCI, UPC and SECON based on visits to general practitioners (GPs), cardiologists and internists are negatively associated with the probability of hospitalization whereas of the continuity indices based on GP visits only SECON is significantly associated with hospitalization. CONCLUSION: The results indicate that the overall continuity in the ambulatory sector is high for heart failure patients in Germany. Public policy should, nevertheless, focus on increasing sequential continuity of specialist and generalist ambulatory care as this was found to be significantly associated with a reduced likelihood of hospitalization. PMID- 26962040 TI - Changes in psychosocial and physical working conditions and common mental disorders. AB - BACKGROUND: Previous studies on changes in working conditions and mental health are few and have typically focused only on psychosocial working conditions. We assessed the impact of changes in both psychosocial and physical working conditions on common mental disorders (CMDs) in a cohort of midlife and older employees. METHODS: Repeat data were derived from the Helsinki Health Study, which is a cohort study on employees of the City of Helsinki, Finland (aged 40-60 years at baseline). Changes in working conditions were assessed between Phase 1 (2000-2002) and Phase 2 (2007). CMD was assessed at Phase 1, Phase 2 and Phase 3 (2012) using the 12-item General Health Questionnaire. In total, 4946 participants (82% women) who were still employed at Phase 2 were available for the analyses. Logistic regression analyses using generalized estimating equations were conducted to examine the association between changes in working conditions and the likelihood of CMD. ORs and their 95% CIs were estimated. RESULTS: After adjustment for sex, age, marital status, health behaviours and obesity; increased and repeated exposure to low job control, high job demands and repetitive movements and repeated exposure to awkward postures and rotation of back were associated with a higher likelihood of CMD at Phases 1-3. Fully adjusted ORs ranged from 1.27 to 2.39 for psychosocial, and from 1.18 to 1.29 for physical working conditions. CONCLUSIONS: Repeated and increased exposures to several adverse psychosocial and physical working conditions are associated with a higher likelihood of CMD. PMID- 26962041 TI - Who stops selling? A systematic analysis of ex-tobacco retailers. AB - OBJECTIVE: There is evidence that wide distribution of cigarettes contributes to smoking, and multiple commentators have called for a review of tobacco retailing. This study analyses retailers who stop selling cigarettes, why they do so, and discusses the implications for tobacco control. METHOD: An audit of tobacco retailers in the Australian state of NSW was used to identify retailers who had stopped selling tobacco, and they were then compared with current retailers to determine how many, and what types of outlets stop selling tobacco. Attempts were made to contact and interview all former tobacco retailers identified in three audited regions. In-depth interviews were conducted with 13 ex-tobacco retailers, or 31% of the subset of ex-tobacco retailers. RESULTS: Low-volume outlet types were over-represented as a proportion of retailers exiting the market, and some had resumed selling within 18 months of the audit. Low profits were often cited as a contributor to stopping; however, in all but one case, the decision to stop selling was also influenced by a significant change in business circumstances either legislative or other business changes. CONCLUSIONS: Few retailers stop selling tobacco while continuing in the same business, and those who stop disproportionately represent retailer types with low sales volume. The results suggest that legislative changes provide a window where retailers could be prompted to exit the market. PMID- 26962042 TI - Electronic nicotine delivery systems: overheating, fires and explosions. AB - BACKGROUND: Electronic nicotine delivery system (ENDS)-associated overheating, fire or explosion (OH/F/EXP) events have occurred since at least 2009. OBJECTIVE: To identify the number and nature of ENDS OH/F/EXP events in the USA. METHODS: Center for Tobacco Products (CTP) scientists searched for event reports among five US federal agencies, scientific literature and media outlets. FINDINGS: 100 reference sources identified 92 OH/F/EXP events in the USA, of which 45 (49%) injured 47 people, and 67 (73%) involved property damage beyond the product. Events were identified in media outlets (n=50; 54%) and reported to four agencies (n=42; 46%). The report rate peaked at an average of six reports per month in late 2013 with a smaller peak of three to four reports per month in the second quarter of 2015. All reports were incomplete and events exhibited variability. International events in three countries are mentioned, and international responses to events are summarised. CONCLUSIONS: The scope, causes and trajectory of ENDS OH/F/EXP events remain incompletely defined. Some events have resulted in life-threatening injury, permanent disfigurement or disability, and major property damage, suggesting the need for ongoing surveillance and risk mitigation. More comprehensive reporting could assist future analyses and may help to identify root causes and contributors to the OH/F/EXP events. PMID- 26962043 TI - Pipeline embolization device induced collateral channels in elective flow diversion treatment. AB - The pipeline embolization device (PED) is a well recognized treatment for intracranial aneurysms. However, uncertainty remains regarding its effects on flow alteration, which is particularly highlighted by persistently perfused aneurysmal remnants and non-regressing, non-perfused aneurysmal masses. Here we present a 68-year-old woman with an incidental giant fusiform right paraophthalmic aneurysm electively treated with a PED. After lowering her antiplatelet therapy to promote aneurysm thrombosis, she was found to have a progressively enlarging perfused aneurysmal remnant. Angiography revealed PED occlusion, but curiously the development of a peri-construct collateral channel which feeds the aneurysmal remnant, and gives rise to distal branches and contributes to middle cerebral artery flow. The large 'thrombosed' aneurysmal mass showed tiny internal vessels on cone beam CT angiography as well as florid enhancement on MRI, further confirming that apparently thrombosed remnants are biologically active and may be remodeled depending on flow demand. PMID- 26962044 TI - Use of Pipeline Flex is associated with reduced fluoroscopy time, procedure time, and technical failure compared with the first-generation Pipeline embolization device. AB - BACKGROUND: Flow diversion with the Pipeline embolization device is a well established method of intracranial aneurysm treatment. However, deployment of the first-generation device (Pipeline Classic) can be technically challenging. The Pipeline Flex contains the same flow-diverting stent with a modified delivery system. OBJECTIVE: To compare procedural outcomes between the first-generation device (Pipeline Classic) and the Pipeline Flex. METHODS: Thirty-eight of the first 40 consecutive patients who underwent intracranial aneurysm treatment with the Pipeline Flex and 58 of the most recent 60 consecutive patients who underwent treatment with the Pipeline Classic at our institution were evaluated. Patient demographics, aneurysm characteristics, technical procedural details, and early outcomes were analyzed. RESULTS: The two groups were comparable for age, gender, and location of target aneurysms. Use of Pipeline Flex decreased procedure time by 44.2 min (p<=0.001) and fluoroscopy time by 22.0 min (p=0.001) compared with the Pipeline Classic. Similarly, radiation exposure was less in the Flex group with a mean difference of 3473.5 Gy cm2 (p=0.002), while contrast usage was decreased with a mean difference of 22.3 mL (p=0.007). These differences remained significant in multivariate regression analysis. Finally, the rate of device deployment failure was lower in the Flex group (7.1%) than in the Classic group (23.9%) (p=0.034). CONCLUSIONS: Use of Pipeline Flex significantly reduces the total procedure and fluoroscopy time, contrast usage, patient radiation exposure, and proportion of recaptured devices in comparison with the Pipeline Classic, probably owing to an enhanced delivery system that allows for more reliable and controlled deployment. PMID- 26962045 TI - Factors in use of family planning services by Syrian women in a refugee camp in Jordan. AB - BACKGROUND: The Syrian conflict presents the fastest growing refugee crisis in the world today, with over four million people now displaced outside the country. Existing literature suggests that family planning services are often still neglected in crisis response efforts. METHODS: A small-scale qualitative study conducted in May 2013, interviewing Syrian women residing in a Jordanian refugee camp about use and barriers to accessing family planning services. RESULTS: The study shows that significant barriers remain, and suggests that international attempts to address refugees' family planning needs remain inconsistent. CONCLUSIONS: Several practical measures are identified to address barriers to access, making the article of both practical and academic relevance. PMID- 26962046 TI - Sortilin is associated with the chlamydial inclusion and is modulated during infection. AB - Chlamydia species are obligate intracellular pathogens that have a major impact on human health. The pathogen replicates within an intracellular niche called an inclusion and is thought to rely heavily on host-derived proteins and lipids, including ceramide. Sortilin is a transmembrane receptor implicated in the trafficking of acid sphingomyelinase, which is responsible for catalysing the breakdown of sphingomyelin to ceramide. In this study, we examined the role of sortilin in Chlamydia trachomatis L2 development. Western immunoblotting and immunocytochemistry analysis revealed that endogenous sortilin is not only associated with the inclusion, but that protein levels increase in infected cells. RNAi-mediated depletion of sortilin, however, had no detectable impact on ceramide delivery to the inclusion or the production of infectious progeny. This study demonstrates that whilst Chlamydia redirects sortilin trafficking to the chlamydial inclusion, RNAi knockdown of sortilin expression is insufficient to determine if this pathway is requisite for the development of the pathogen. PMID- 26962047 TI - NGT-3D: a simple nematode cultivation system to study Caenorhabditis elegans biology in 3D. AB - The nematodeCaenorhabditiselegansis one of the premier experimental model organisms today. In the laboratory, they display characteristic development, fertility, and behaviors in a two dimensional habitat. In nature, however,C. elegansis found in three dimensional environments such as rotting fruit. To investigate the biology ofC. elegansin a 3D controlled environment we designed a nematode cultivation habitat which we term the nematode growth tube or NGT-3D. NGT-3D allows for the growth of both nematodes and the bacteria they consume. Worms show comparable rates of growth, reproduction and lifespan when bacterial colonies in the 3D matrix are abundant. However, when bacteria are sparse, growth and brood size fail to reach levels observed in standard 2D plates. Using NGT-3D we observe drastic deficits in fertility in a sensory mutant in 3D compared to 2D, and this defect was likely due to an inability to locate bacteria. Overall, NGT-3D will sharpen our understanding of nematode biology and allow scientists to investigate questions of nematode ecology and evolutionary fitness in the laboratory. PMID- 26962048 TI - Post-hatching development of mitochondrial function, organ mass and metabolic rate in two ectotherms, the American alligator (Alligator mississippiensis) and the common snapping turtle (Chelydra serpentina). AB - The ontogeny of endothermy in birds is associated with disproportionate growth of thermogenic organs and increased mitochondrial oxidative capacity. However, no similar study has been made of the development of these traits in ectotherms. For comparison, we therefore investigated the metabolism, growth and muscle mitochondrial function in hatchlings of a turtle and a crocodilian, two ectotherms that never develop endothermy. Metabolic rate did not increase substantially in either species by 30 days post-hatching. Yolk-free body mass and heart mass did not change through 30 days in alligators and heart mass was a constant proportion of body mass, even after 1 year. Yolk-free body mass and liver mass grew 36% and 27%, respectively, in turtles during the first 30 days post-hatch. The mass-specific oxidative phosphorylation capacity of mitochondria, assessed using permeabilized muscle fibers, increased by a non-significant 47% in alligator thigh and a non-significant 50% in turtle thigh over 30 days, but did not increase in the heart. This developmental trajectory of mitochondrial function is slower and shallower than that previously observed in ducks, which demonstrate a 90% increase in mass-specific oxidative phosphorylation capacity in thigh muscles over just a few days, a 60% increase in mass-specific oxidative phosphorylation capacity of the heart over a few days, and disproportionate growth of the heart and other organs. Our data thus support the hypothesis that these developmental changes in ducks represent mechanistic drivers for attaining endothermy. PMID- 26962049 TI - Cross-species functional analyses reveal shared and separate roles for Sox11 in frog primary neurogenesis and mouse cortical neuronal differentiation. AB - A well-functioning brain requires production of the correct number and types of cells during development; cascades of transcription factors are essential for cellular coordination. Sox proteins are transcription factors that affect various processes in the development of the nervous system. Sox11, a member of the SoxC family, is expressed in differentiated neurons and supports neuronal differentiation in several systems. To understand how generalizable the actions of Sox11 are across phylogeny, its function in the development of the frog nervous system and the mouse cerebral cortex were compared. Expression of Sox11 is largely conserved between these species; in the developing frog, Sox11 is expressed in the neural plate, neural tube and throughout the segmented brain, while in the mouse cerebral cortex, Sox11 is expressed in differentiated zones, including the preplate, subplate, marginal zone and cortical plate. In both frog and mouse, data demonstrate that Sox11 supports a role in promoting neuronal differentiation, with Sox11-positive cells expressing pan-neural markers and becoming morphologically complex. However, frog and mouse Sox11 cannot substitute for one another; a functional difference likely reflected in sequence divergence. Thus, Sox11 appears to act similarly in subserving neuronal differentiation but is species-specific in frog neural development and mouse corticogenesis. PMID- 26962050 TI - Genomic islands 1 and 2 play key roles in the evolution of extensively drug resistant ST235 isolates of Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa are noscomially acquired, opportunistic pathogens that pose a major threat to the health of burns patients and the immunocompromised. We sequenced the genomes of P. aeruginosa isolates RNS_PA1, RNS_PA46 and RNS_PAE05, which displayed resistance to almost all frontline antibiotics, including gentamicin, piperacillin, timentin, meropenem, ceftazidime and colistin. We provide evidence that the isolates are representatives of P. aeruginosa sequence type (ST) 235 and carry Tn6162 and Tn6163 in genomic islands 1 (GI1) and 2 (GI2), respectively. GI1 disrupts the endA gene at precisely the same chromosomal location as in P. aeruginosa strain VR-143/97, of unknown ST, creating an identical CA direct repeat. The class 1 integron associated with Tn6163 in GI2 carries a blaGES-5-aacA4-gcuE15-aphA15 cassette array conferring resistance to carbapenems and aminoglycosides. GI2 is flanked by a 12 nt direct repeat motif, abuts a tRNA-gly gene, and encodes proteins with putative roles in integration, conjugative transfer as well as integrative conjugative element-specific proteins. This suggests that GI2 may have evolved from a novel integrative conjugative element. Our data provide further support to the hypothesis that genomic islands play an important role in de novo evolution of multiple antibiotic resistance phenotypes in P. aeruginosa. PMID- 26962051 TI - Molecular architecture of the Dam1 complex-microtubule interaction. AB - Mitosis is a highly regulated process that allows the equal distribution of the genetic material to the daughter cells. Chromosome segregation requires the formation of a bipolar mitotic spindle and assembly of a multi-protein structure termed the kinetochore to mediate attachments between condensed chromosomes and spindle microtubules. In budding yeast, a single microtubule attaches to each kinetochore, necessitating robustness and processivity of this kinetochore microtubule attachment. The yeast kinetochore-localized Dam1 complex forms a direct interaction with the spindle microtubule. In vitro, the Dam1 complex assembles as a ring around microtubules and couples microtubule depolymerization with cargo movement. However, the subunit organization within the Dam1 complex, its higher-order oligomerization and how it interacts with microtubules remain under debate. Here, we used chemical cross-linking and mass spectrometry to define the architecture and subunit organization of the Dam1 complex. This work reveals that both the C termini of Duo1 and Dam1 subunits interact with the microtubule and are critical for microtubule binding of the Dam1 complex, placing Duo1 and Dam1 on the inside of the ring structure. Integrating this information with available structural data, we provide a coherent model for how the Dam1 complex self-assembles around microtubules. PMID- 26962053 TI - Iron and dopamine: a toxic couple. AB - Iron accumulation is a cardinal feature of degenerating regions in the Parkinson's disease brain. As a potent pro-oxidant, redox-active iron may be a key player in upstream mechanisms that precipitate cell death in this disorder. Although an elevation in brain iron levels is a normal feature of ageing, the increase is greater in Parkinson's disease; on the other hand, the effects of the disease are most marked in the nigrostriatal dopaminergic system. In this Update, we explain that neurodegeneration in the affected regions may result from the potent redox couple formed by iron and dopamine itself, and discuss the clinical implications of this molecular trait in this dynamic and rapidly moving area of Parkinson's disease research. PMID- 26962055 TI - Subtoxic Alterations in Hepatocyte-Derived Exosomes: An Early Step in Drug Induced Liver Injury? AB - Drug-induced liver injury (DILI) is a significant clinical and economic problem in the United States, yet the mechanisms that underlie DILI remain poorly understood. Recent evidence suggests that signaling molecules released by stressed hepatocytes can trigger immune responses that may be common across DILI mechanisms. Extracellular vesicles released by hepatocytes, principally hepatocyte-derived exosomes (HDEs), may constitute one such signal. To examine HDE alterations as a function of drug-induced stress, this work utilized prototypical hepatotoxicant acetaminophen (APAP) in male Sprague-Dawley (SD) rats, SD rat hepatocytes, and primary human hepatocytes. HDE were isolated using ExoQuick precipitation reagent and analyzed by quantification of the liver specific RNAs albumin and microRNA-122 (miR-122). In vivo, significant elevations in circulating exosomal albumin mRNA were observed at subtoxic APAP exposures. Significant increases in exosomal albumin mRNA were also observed in primary rat hepatocytes at subtoxic APAP concentrations. In primary human hepatocytes, APAP elicited increases in both exosomal albumin mRNA and exosomal miR-122 without overt cytotoxicity. However, the number of HDE produced in vitro in response to APAP did not increase with exosomal RNA quantity. We conclude that significant drug-induced alterations in the liver-specific RNA content of HDE occur at subtoxic APAP exposures in vivo and in vitro, and that these changes appear to reflect selective packaging rather than changes in exosome number. The current findings demonstrate that translationally relevant HDE alterations occur in the absence of overt hepatocellular toxicity, and support the hypothesis that HDE released by stressed hepatocytes may mediate early immune responses in DILI. PMID- 26962052 TI - Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. AB - SEE SARAZIN ET AL DOI101093/BRAIN/AWW041 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The advent of the positron emission tomography tracer (18)F-AV1451 provides the unique opportunity to visualize the regional distribution of tau pathology in the living human brain. In this study, we tested the hypothesis that tau pathology is closely linked to symptomatology and patterns of glucose hypometabolism in Alzheimer's disease, in contrast to the more diffuse distribution of amyloid-beta pathology. We included 20 patients meeting criteria for probable Alzheimer's disease dementia or mild cognitive impairment due to Alzheimer's disease, presenting with a variety of clinical phenotypes, and 15 amyloid-beta-negative cognitively normal individuals, who underwent (18)F-AV1451 (tau), (11)C-PiB (amyloid-beta) and (18)F-FDG (glucose metabolism) positron emission tomography, apolipoprotein E (APOE) genotyping and neuropsychological testing. Voxel-wise contrasts against controls (at P < 0.05 family-wise error corrected) showed that (18)F-AV1451 and (18)F-FDG patterns in patients with posterior cortical atrophy ('visual variant of Alzheimer's disease', n = 7) specifically targeted the clinically affected posterior brain regions, while (11)C-PiB bound diffusely throughout the neocortex. Patients with an amnestic predominant presentation (n = 5) showed highest (18)F-AV1451 retention in medial temporal and lateral temporoparietal regions. Patients with logopenic variant primary progressive aphasia ('language variant of Alzheimer's disease', n = 5) demonstrated asymmetric left greater than right hemisphere (18)F-AV1451 uptake in three of five patients. Across 30 FreeSurfer-defined regions of interest in 16 Alzheimer's disease patients with all three positron emission tomography scans available, there was a strong negative association between (18)F-AV1451 and (18)F FDG uptake (Pearson's r = -0.49 +/- 0.07, P < 0.001) and less pronounced positive associations between (11)C-PiB and (18)F-FDG (Pearson's r = 0.16 +/- 0.09, P < 0.001) and (18)F-AV1451 and (11)C-PiB (Pearson's r = 0.18 +/- 0.09, P < 0.001). Voxel-wise linear regressions thresholded at P < 0.05 (uncorrected) showed that, across all patients, younger age was associated with greater (18)F-AV1451 uptake in wide regions of the neocortex, while older age was associated with increased (18)F-AV1451 in the medial temporal lobe. APOE epsilon4 carriers showed greater temporal and parietal (18)F-AV1451 uptake than non-carriers. Finally, worse performance on domain-specific neuropsychological tests was associated with greater (18)F-AV1451 uptake in key regions implicated in memory (medial temporal lobes), visuospatial function (occipital, right temporoparietal cortex) and language (left > right temporoparietal cortex). In conclusion, tau imaging contrary to amyloid-beta imaging-shows a strong regional association with clinical and anatomical heterogeneity in Alzheimer's disease. Although preliminary, these results are consistent with and expand upon findings from post mortem, animal and cerebrospinal fluid studies, and suggest that the pathological aggregation of tau is closely linked to patterns of neurodegeneration and clinical manifestations of Alzheimer's disease. PMID- 26962054 TI - Perinatal Lead Exposure Alters Gut Microbiota Composition and Results in Sex specific Bodyweight Increases in Adult Mice. AB - Heavy metal pollution is a principle source of environmental contamination. Epidemiological and animal data suggest that early life lead (Pb) exposure results in critical effects on epigenetic gene regulation and child and adult weight trajectories. Using a mouse model of human-relevant exposure, we investigated the effects of perinatal Pb exposure on gut microbiota in adult mice, and the link between gut microbiota and bodyweight changes. Following Pb exposure during gestation and lactation via maternal drinking water, bodyweight in A(vy) strain wild-type non-agouti (a/a) offspring was tracked through adulthood. Gut microbiota of adult mice were characterized by deep DNA sequencing of bacterial 16S ribosomal RNA genes. Data analyses were stratified by sex and adjusted for litter effects. A Bayesian variable selection algorithm was used to analyze associations between bacterial operational taxonomic units and offspring adult bodyweight. Perinatal Pb exposure was associated with increased adult bodyweight in male (P < .05) but not in female offspring (P = .24). Cultivable aerobes decreased and anaerobes increased in Pb-exposed offspring (P < .005 and P < .05, respectively). Proportions of the 2 predominant phyla (Bacteroidetes and Firmicutes) shifted inversely with Pb exposure, and whole bacterial compositions were significantly different (analysis of molecular variance, P < .05) by Pb exposure without sex bias. In males, changes in gut microbiota were highly associated with adult bodyweight (P = .028; effect size = 2.59). Thus, perinatal Pb exposure results in altered adult gut microbiota regardless of sex, and these changes are highly correlated with increased bodyweight in males. Adult gut microbiota can be shaped by early exposures and may contribute to disease risks in a sex-specific manner. PMID- 26962056 TI - Vinyl Chloride Metabolites Potentiate Inflammatory Liver Injury Caused by LPS in Mice. AB - Vinyl chloride (VC) is a ubiquitous environmental contaminant for which human risk is incompletely understood. We have previously reported that high occupational exposure to VC directly caused liver damage in humans. However, whether VC may also potentiate liver injury from other causes is not known. C57Bl/6J mice were administered chloroethanol (CE), a major metabolite of VC, and lipopolysaccharide (LPS) 24 h after CE. Samples were harvested for determination of liver damage, inflammation, and changes in carbohydrate and lipid metabolism. In mice, CE exposure alone caused no detectable liver damage. LPS exposure caused inflammatory liver damage, oxidative stress, lipid accumulation, and glycogen depletion; the effect of all of these variables was potentiated by CE pre exposure. In vitro experiments suggest that VC metabolite chloroacetaldehyde (CAA) directly damages mitochondria, which may explain the sensitization effect observed in vivo Moreover, co-exposure of cells to CAA and TNFalpha caused increased cell death, supporting the hypothesis of sensitization by VC metabolites. Taken together, these data demonstrate that exposure to VC/metabolites at levels that are not overtly hepatotoxic can potentiate liver injury caused by another hepatotoxicant. This serves as proof-of-concept that VC hepatotoxicity may be modified by an additional metabolic stress such as endotoxemia, which commonly occurs in acute (eg, sepsis) and chronic (eg, NAFLD) diseases. PMID- 26962058 TI - Need for Intensive Nutrition Care After Bariatric Surgery. AB - Severe nutrition complications after bariatric surgery remain poorly described. The aim of this case series was to identify specific factors associated with nutrition complications after bariatric surgery and to characterize their nutrition disorders. We retrospectively reviewed all people referred to the clinical nutrition intensive care unit of our university hospital after bariatric surgery from January 2013 to June 2015. Twelve persons who required artificial nutrition supplies (ie, enteral nutrition or parenteral nutrition) were identified. Seven persons underwent a "one-anastomosis gastric bypass" (OAGB) or "mini gastric bypass," 2 underwent a Roux-en-Y gastric bypass, 2 had a sleeve gastrectomy, and 1 had an adjustable gastric band. This case series suggests that OAGB could overexpose subjects to severe nutrition complications requiring intensive nutrition care and therefore cannot be considered a "mini" bariatric surgery. Even if OAGB is often considered a simplified surgical technique, it obviously requires as the other standard bariatric procedures a close follow-up by experimented teams aware of its specific complications. PMID- 26962057 TI - Cancer Stem-Like Cells Accumulated in Nickel-Induced Malignant Transformation. AB - Nickel compounds are known as human carcinogens. Chronic environmental exposure to nickel is a worldwide health concern. Although the mechanisms of nickel induced carcinogenesis are not well understood, recent studies suggest that stem cells/cancer stem cells are likely important targets. This study examines the role of cancer stem cells in nickel-induced cell transformation. The nontransformed human bronchial epithelial cell line (Beas-2B) was chronically exposed to nickel chloride for 12 months to induce cell transformation. Nickel induced Beas-2B cell transformation, and cancer stem-like cells were enriched in nickel-transformed cell (BNiT) population. The BNiT cancer stem-like cells demonstrated enhanced self-renewal and distinctive differentiation properties. In vivo tumorigenesis studies show that BNiT cancer stem-like cells possess a high tumor-initiating capability. It was also demonstrated that superoxide dismutase 1 was involved in the accumulation of cancer stem-like cells; the regulation of superoxide dismutase 1 expression was different in transformed stem-like cells and nontransformed. Overall, the accumulation of stem-like cells and their enhanced stemness functions contribute to nickel-induced tumorigenesis. Our study provides additional insight into the mechanisms by which metals or other chemicals can induce carcinogenesis. PMID- 26962059 TI - Long-Term Fish Oil Lipid Emulsion Use in Children With Intestinal Failure Associated Liver Disease [Formula: see text]. AB - BACKGROUND: Fish oil lipid emulsion (FOLE) and multidisciplinary care for infants with intestinal failure (IF) have been associated with reduced morbidity and mortality due to IF-associated liver disease (IFALD). With increased survival, a greater proportion of infants with IF are now able to remain on parenteral nutrition (PN) in the long term. The purpose of this study was to examine outcomes in children with IFALD who have required long-term PN and FOLE therapy due to chronic IF. MATERIALS AND METHODS: A review of prospectively collected data was performed for children with IFALD who required at least 3 years of PN and FOLE therapy due to chronic IF. Outcomes examined include the incidence of death, transplantation, and essential fatty acid deficiency (EFAD), as well as growth parameters and the biochemical markers of liver disease. RESULTS: Of 215 patients with IFALD treated from 2004-2015, 30 required PN and FOLE therapy for at least 3 years (median, 4.6 years). To date, no patients have died, required transplantation, or developed EFAD. Biochemical markers of liver disease normalized within the first year of therapy with no recurrent elevations in the long term. Weight-for age and length-for-age z scores improved and PN dependence decreased in the first year of therapy, with a stable rate of growth in the long term. CONCLUSIONS: Children with IFALD who required long-term PN and FOLE for chronic IF had no mortality, need for transplantation, EFAD, or recurrence of liver disease in the long term, allowing for continued intestinal rehabilitation. PMID- 26962060 TI - Factors Affecting the Development of an Antibody Response to Hepatitis B Immunization in Children With Intestinal Failure: Before and After Small Bowel Transplantation (With and Without Liver Graft). AB - BACKGROUND: Small bowel transplant with or without a liver graft (SBTx +/- LTx) for children with intestinal failure involves checking their immunity to a range of microorganisms, including hepatitis B virus (HBV), at the time of assessment. HBV vaccination in the United Kingdom is recommended for transplant candidates. The aim of this audit was to find out how many SBTx +/- LTx candidates received HBV vaccination before transplantation and how the timing of vaccination influenced the development of immunity. MATERIALS AND METHODS: Retrospective review of case notes and hospital microbiology database formed the basis of the study. Vaccination history and serology were available in 56 of 87 subjects who had SBTx +/- LTx. RESULTS: All patients were seronegative for HBV when assessed for transplant. HBV vaccination was started before transplant in 25 children and after transplant in 31. Eight children died posttransplant before their immunity could be checked, but of the 48 survivors, 20 children developed immunity, of whom 13 (65%) received at least 1 vaccination before SBTx +/- LTx ( P = .008). Lack of response to HBV vaccine was significantly associated with isolated bowel transplantation and intensification of immune suppression. Of 11 children, 5 lost hepatitis B surface antibody (HbsAb), and 28 never made HBsAb, despite repeated vaccinations. CONCLUSION: Our study clearly shows that HBV vaccine before transplant is more effective. In line with renal failure patients, we suggest that children with chronic intestinal failure receive HBV vaccine when clinically stable, before referral for transplant. Higher-dose vaccines, accelerated schedules, and more frequent booster vaccinations are also strategies that may improve HBsAb levels after transplant. PMID- 26962061 TI - Validation of Bedside Ultrasound of Muscle Layer Thickness of the Quadriceps in the Critically Ill Patient (VALIDUM Study). AB - BACKGROUND: In critically ill patients, muscle atrophy is associated with long term disability and mortality. Bedside ultrasound may quantify muscle mass, but it has not been validated in the intensive care unit (ICU). Here, we compared ultrasound-based quadriceps muscle layer thickness (QMLT) with precise quantifications of computed tomography (CT)-based muscle cross-sectional area (CSA). METHODS: Patients >=18 years old with abdominal CT scans performed for clinical reasons were recruited from 9 ICUs for an ultrasound assessment of the quadriceps. CT scans of the third lumbar vertebra, performed <24 hours before or <72 hours after ICU admission, were analyzed for CSA. Low muscularity was defined as 170 cm2 for men and 110 cm2 for women. The ultrasound probe was maximally compressed against the skin and QMLT was measured on 2 sites of each quadriceps <72 hours of the CT scan. RESULTS: Mean CT-derived muscle CSA was 109 +/- 25 cm2 for women and 168 +/- 37 cm2 for men, where 58% of patients exhibited low muscularity; only 2.7% patients were underweight according to body mass index. QMLT was positively correlated with CT CSA ( r = 0.45, P < .001). Based on logistic regression to predict low muscularity, QMLT independently generated a concordance index ( c) of 0.67 ( P < .002), which increased to 0.77 ( P < .001) when age, sex, body mass index, Charlson Comorbidity Index, and admission type (surgical vs medical) were added. CONCLUSIONS: Our results suggest that QMLT alone with our current protocol may not accurately identify patients with low muscle mass. PMID- 26962063 TI - Some Concerns About the Design of Nutrition Support Trials. PMID- 26962062 TI - Parenteral Plant Sterols Accumulate in the Liver Reflecting Their Increased Serum Levels and Portal Inflammation in Children With Intestinal Failure. AB - BACKGROUND: Parenteral plant sterols (PSs) are considered hepatotoxic; however, liver PSs and their associations with liver injury in patients with intestinal failure (IF) have not been reported. MATERIALS AND METHODS: We analyzed liver and serum PS (avenasterol, campesterol, sitosterol, and stigmasterol) concentrations and ratios to cholesterol and their associations with biochemical and histologic liver damage in children with IF during (n = 7) parenteral nutrition (PN) and after weaning off it (n = 9), including vegetable oil-based lipid emulsions. RESULTS: Liver avenasterol, sitosterol, and total PS concentrations and cholesterol ratios were 2.4-fold to 5.6-fold higher in PN-dependent patients ( P < .05). Parenteral PS delivery reflected liver avenasterol and sitosterol ratios to cholesterol ( r = 0.83-0.89, P = .02-.04), while serum and liver total PS levels were positively interrelated ( r = 0.98, P < .01). Any liver histopathology was equally common while portal inflammation more frequent (57 vs 0%, P = .02) in PN-dependent patients. All liver PS fractions correlated positively with histologic portal inflammation ( r = 0.53-0.66, P < .05), and their total concentration was significantly ( P = .01) higher among patients with versus without portal inflammation. In PN-dependent patients, liver fibrosis and any histopathology correlated with liver campesterol and stigmasterol levels ( r = 0.79-0.87, P <= .03). CONCLUSION: Among children with IF, parenteral PSs accumulate in the liver, reflect their increased serum levels, and relate with biochemical liver injury, portal inflammation, and liver fibrosis, thus supporting their role in promoting liver damage. PMID- 26962064 TI - Nutrition Delivery Affects Outcomes in Pediatric Acute Respiratory Distress Syndrome. AB - BACKGROUND: Malnutrition is prevalent in critically ill children. We aim to describe nutrition received by children with acute respiratory distress syndrome (ARDS) and to determine whether provision of adequate nutrition is associated with improved clinical outcomes. MATERIALS AND METHODS: We studied characteristics and outcomes of 2 groups of patients: (1) those who received adequate calories (defined as >=80% of predicted resting energy expenditure) and (2) those who received adequate protein (defined as >=1.5g/kg/d of protein). Outcomes of interest were mortality, ventilator-free days (VFDs), intensive care unit (ICU)-free days, multiorgan dysfunction, and need for extracorporeal membrane oxygenation. Categorical variables were analyzed using the Fisher exact test, and continuous variables were analyzed using the Mann-Whitney U test. Univariate and multivariate logistic regression models were used to identify associated risk factors related to these outcomes of interest. RESULTS: In total, 107 patients with ARDS were identified. There was a reduction in ICU mortality in patients who received adequate calories (34.6% vs 60.5%, P = .025) and adequate protein (14.3% vs 60.2%, P = .002) compared with those that did not. Patients with adequate protein intake also had more VFDs (median [interquartile range], 12 [3.0-19.0] vs 0 [0.0-14.8] days; P = .005). After adjusting for severity of illness, adequate protein remained significantly associated with decreased mortality (adjusted odds ratio [95% confidence interval], 0.09 [0.01-0.94]; P = .044). CONCLUSION: Our study demonstrated that adequate nutrition delivery in children with ARDS was associated with improved clinical outcomes. Protein delivery may have potentially more impact than overall caloric delivery. PMID- 26962065 TI - End-of-life care preferences of nursing home residents: Results of a cross sectional study. AB - BACKGROUND: Palliative care services were not available in nursing homes in Singapore. Project CARE (Care At the end-of-life for Residents in homes for the Elderly) was a pilot programme that aimed to promote advance care planning and improve end-of-life care in nursing homes. AIM: We aimed to examine end-of-life care preferences among nursing home residents, and identify factors associated with preference for medical intervention, cardiopulmonary resuscitation and place of death. DESIGN AND SETTING/PARTICIPANTS: A cross-sectional study using data from advance care planning discussions was conducted from September 2009 to April 2012 across seven nursing homes. The advance care planning discussion was conducted with the resident (with a prognosis of 6 months or 1 year), their families and staff from the nursing home and hospital. RESULTS: A total of 600 residents and their families completed the advance care planning discussion. Majority (93.2%) preferred not to proceed with cardiopulmonary resuscitation, 52.3% opted for limited additional intervention at the nursing home with escalation to the hospital if necessary and 77.0% preferred to die at the nursing home. Residents 85+ years (relative risk ratio: 3.34, 95% confidence interval: 1.13-9.93, p = 0.030) were more likely to prefer medical intervention at the nursing home only. No associations were found with the preference for cardiopulmonary resuscitation. Residents who were single, or who were Christians or Catholics (adjusted odds ratio: 2.09, 95% confidence interval: 1.04-4.19, p = 0.039), were more likely to prefer to die at the nursing home. CONCLUSION: Preferences for medical interventions in nursing homes provide support to extend palliative care services to nursing homes, which may benefit residents who are older, single, or Christians or Catholics. PMID- 26962066 TI - Sex differences in comorbidity at diagnosis of multiple sclerosis: A population based study. AB - OBJECTIVE: To determine the prevalence of comorbidity in the multiple sclerosis (MS) population at the time of MS diagnosis. We also compared the prevalence of comorbidity in the MS population to that in a matched cohort from the general population. METHODS: Using population-based administrative health data from 4 Canadian provinces, we identified 23,382 incident MS cases and 116,638 age-, sex , and geographically matched controls. We estimated the prevalence of hypertension, diabetes, hyperlipidemia, heart disease, chronic lung disease, epilepsy, fibromyalgia, inflammatory bowel disease, depression, anxiety, bipolar disorder, and schizophrenia at MS diagnosis using validated case definitions. We compared the populations using rate ratios. RESULTS: Of the MS cases, 16,803 (71.9%) were female. The most prevalent comorbidity was depression (19.1%). Compared to the matched population, all comorbidities except hyperlipidemia were more common in the MS population. Relative to the matched populations, the prevalence of hypertension was 16% higher for women with MS and 48% higher for men with MS, thus there was a disproportionately higher prevalence of hypertension in men with MS than women. Men with MS also had a disproportionately higher prevalence than women with MS for diabetes, epilepsy, depression, and anxiety. CONCLUSIONS: Comorbidity is more common than expected in MS, even around the time of diagnosis. The prevalence of psychiatric comorbidity is particularly high and highlights the need for clinical attention to this issue. The observed sex-specific differences in the burden of comorbidity in MS, which differ from those in the matched population, warrant further investigation. PMID- 26962067 TI - Two different phenomena in basic motor speech performance in premanifest Huntington disease. AB - OBJECTIVE: Dysarthria is a common feature in Huntington disease (HD). The aim of this cross-sectional pilot study was the description and objective analysis of different speech parameters with special emphasis on the aspect of speech timing of connected speech and nonspeech verbal utterances in premanifest HD (preHD). METHODS: A total of 28 preHD mutation carriers and 28 age- and sex-matched healthy speakers had to perform a reading task and several syllable repetition tasks. Results of computerized acoustic analysis of different variables for the measurement of speech rate and regularity were correlated with clinical measures and MRI-based brain atrophy assessment by voxel-based morphometry. RESULTS: An impaired capacity to steadily repeat single syllables with higher variations in preHD compared to healthy controls was found (variance 1: Cohen d = 1.46). Notably, speech rate was increased compared to controls and showed correlations to the volume of certain brain areas known to be involved in the sensory-motor speech networks (net speech rate: Cohen d = 1.19). Furthermore, speech rate showed correlations to disease burden score, probability of disease onset, the estimated years to onset, and clinical measures like the cognitive score. CONCLUSIONS: Measurement of speech rate and regularity might be helpful additional tools for the monitoring of subclinical functional disability in preHD. As one of the possible causes for higher performance in preHD, we discuss huntingtin-dependent temporarily advantageous development processes of the brain. PMID- 26962069 TI - Monozygotic twins with de novo ZIC2 gene mutations discordant for the type of holoprosencephaly. PMID- 26962068 TI - Health-related quality of life in multiple sclerosis: Direct and indirect effects of comorbidity. AB - OBJECTIVE: To evaluate the direct and indirect influences of physical comorbidity, symptoms of depression and anxiety, fatigue, and disability on health-related quality of life (HRQoL) in persons with multiple sclerosis (MS). METHODS: A large (n = 949) sample of adults with MS was recruited from 4 Canadian MS clinics. HRQoL was assessed using the patient-reported Health Utilities Index Mark 3. Expanded Disability Status Scale scores, physical comorbidity, depression, anxiety, and fatigue were evaluated as predictors of HRQoL in a cross sectional path analysis. RESULTS: All predictors were significantly associated with HRQoL and together accounted for a large proportion of variance (63%). Overall, disability status most strongly affected HRQoL (beta = -0.52) but it was closely followed by depressive symptoms (beta = -0.50). The direct associations of physical comorbidity and anxiety with HRQoL were small (beta = -0.08 and 0.10, respectively), but these associations were stronger when indirect effects through other variables (depression, fatigue) were also considered (physical comorbidity: beta = -0.20; anxiety: beta = -0.34). CONCLUSIONS: Increased disability, depression and anxiety symptoms, fatigue, and physical comorbidity are associated with decreased HRQoL in MS. Disability most strongly diminishes HRQoL and, thus, interventions that reduce disability are expected to yield the most substantial improvement in HRQoL. Yet, interventions targeting other factors amenable to change, particularly depression but also anxiety, fatigue, and physical comorbidities, may all result in meaningful improvements in HRQoL, as well. Our findings point to the importance of further research confirming the efficacy of such interventions. PMID- 26962071 TI - Multiple sclerosis: A lifestyle disease? PMID- 26962070 TI - Network dysfunction predicts speech production after left hemisphere stroke. AB - OBJECTIVE: To investigate the role of multiple distributed brain networks, including the default mode, fronto-temporo-parietal, and cingulo-opercular networks, which mediate domain-general and task-specific processes during speech production after aphasic stroke. METHODS: We conducted an observational functional MRI study to investigate the effects of a previous left hemisphere stroke on functional connectivity within and between distributed networks as patients described pictures. Study design included various baseline tasks, and we compared results to those of age-matched healthy participants performing the same tasks. We used independent component and psychophysiological interaction analyses. RESULTS: Although activity within individual networks was not predictive of speech production, relative activity between networks was a predictor of both within-scanner and out-of-scanner language performance, over and above that predicted from lesion volume, age, sex, and years of education. Specifically, robust functional imaging predictors were the differential activity between the default mode network and both the left and right fronto-temporo parietal networks, respectively activated and deactivated during speech. We also observed altered between-network functional connectivity of these networks in patients during speech production. CONCLUSIONS: Speech production is dependent on complex interactions among widely distributed brain networks, indicating that residual speech production after stroke depends on more than the restoration of local domain-specific functions. Our understanding of the recovery of function following focal lesions is not adequately captured by consideration of ipsilesional or contralesional brain regions taking over lost domain-specific functions, but is perhaps best considered as the interaction between what remains of domain-specific networks and domain-general systems that regulate behavior. PMID- 26962072 TI - Domain general neurocognitive networks: A new player in poststroke recovery from aphasia? PMID- 26962073 TI - The Need for Global Regulation of Antibiotics: The Case of a Generic Oral Penem. PMID- 26962074 TI - Test of Cure for Anogenital Gonorrhoea Using Modern RNA-Based and DNA-Based Nucleic Acid Amplification Tests: A Prospective Cohort Study. AB - BACKGROUND: The use of nucleic acid amplification tests (NAATs) to diagnose Neisseria gonorrhoeae infections complicates the performance of a test of cure (TOC) to monitor treatment failure, if this is indicated. As evidence for the timing of TOC using modern NAATs is limited, we performed a prospective cohort study to assess time to clearance when using modern RNA- and DNA-based NAATs. METHODS: We included patients with anogenital gonorrhoea visiting the Sexually Transmitted Infection Clinic Amsterdam from March through October 2014. After treatment with ceftriaxone mono- or dual therapy (with azithromycin or doxycycline), anal, vaginal, or urine samples were self-collected during 28 consecutive days, and analyzed using an RNA-based NAAT (Aptima Combo 2) and a DNA based NAAT (Cobas 4800). Clearance was defined as 3 consecutive negative results, and blips as isolated positive results following clearance. RESULTS: We included 77 patients; 5 self-cleared gonorrhoea before treatment and 10 were lost to follow-up. Clearance rate of the remaining 62 patients was 100%. Median time to clearance was 2 days, with a range of 1-7 days for RNA-based NAAT and 1-15 days for DNA-based NAAT. The risk of finding a blip after clearance was 0.8% and 1.5%, respectively. One patient had a reinfection. CONCLUSIONS: If indicated, we recommend that TOC be performed for anogenital gonorrhoea at least 7 or 14 days after administering therapy, when using modern RNA- or DNA-based NAATs, respectively. When interpreting TOC results for possible treatment failure, both the occurrence of blips and a possible reinfection need to be taken into account. PMID- 26962076 TI - Human Polyomavirus-6 Infecting Lymph Nodes of a Patient With an Angiolymphoid Hyperplasia With Eosinophilia or Kimura Disease. AB - Human polyomavirus 6 (HPyV6) is most often detected at the skin surface of healthy individuals. Here, we demonstrate for the first time that HPyV6 also infects internal tissues. We provide direct evidence of HPyV6 infecting a lymph node of a patient with an angiolymphoid hyperplasia with eosinophilia or Kimura disease. PMID- 26962077 TI - Editorial Commentary: HIV Is Putting Up Less Resistance. PMID- 26962075 TI - Emergence of Acquired HIV-1 Drug Resistance Almost Stopped in Switzerland: A 15 Year Prospective Cohort Analysis. AB - BACKGROUND: Drug resistance is a major barrier to successful antiretroviral treatment (ART). Therefore, it is important to monitor time trends at a population level. METHODS: We included 11 084 ART-experienced patients from the Swiss HIV Cohort Study (SHCS) between 1999 and 2013. The SHCS is highly representative and includes 72% of patients receiving ART in Switzerland. Drug resistance was defined as the presence of >=1 major mutation in a genotypic resistance test. To estimate the prevalence of drug resistance, data for patients with no resistance test was imputed based on the patient's risk of harboring drug resistant viruses. RESULTS: The emergence of new drug resistance mutations declined dramatically from 401 to 23 patients between 1999 and 2013. The upper estimated prevalence limit of drug resistance among ART-experienced patients decreased from 57.0% in 1999 to 37.1% in 2013. The prevalence of 3-class resistance decreased from 9.0% to 4.4% and was always <0.4% for patients who initiated ART after 2006. Most patients actively participating in the SHCS in 2013 with drug-resistant viruses initiated ART before 1999 (59.8%). Nevertheless, in 2013, 94.5% of patients who initiated ART before 1999 had good remaining treatment options based on Stanford algorithm. CONCLUSIONS: Human immunodeficiency virus type 1 drug resistance among ART-experienced patients in Switzerland is a well-controlled relic from the era before combination ART. Emergence of drug resistance can be virtually stopped with new potent therapies and close monitoring. PMID- 26962078 TI - Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program. AB - BACKGROUND: When combined with ceftazidime, the novel non-beta-lactam beta lactamase inhibitor avibactam provides a carbapenem alternative against multidrug resistant infections. Efficacy and safety of ceftazidime-avibactam plus metronidazole were compared with meropenem in 1066 men and women with complicated intra-abdominal infections from 2 identical, randomized, double-blind phase 3 studies (NCT01499290 and NCT01500239). METHODS: The primary end point was clinical cure at test-of-cure visit 28-35 days after randomization, assessed by noninferiority of ceftazidime-avibactam plus metronidazole to meropenem in the microbiologically modified intention-to-treat (mMITT) population (in accordance with US Food and Drug Administration guidance), and the modified intention-to treat and clinically evaluable populations (European Medicines Agency guidance). Noninferiority was considered met if the lower limit of the 95% confidence interval for between-group difference was greater than the prespecified noninferiority margin of -12.5%. RESULTS: Ceftazidime-avibactam plus metronidazole was noninferior to meropenem across all primary analysis populations. Clinical cure rates with ceftazidime-avibactam plus metronidazole and meropenem, respectively, were as follows: mMITT population, 81.6% and 85.1% (between-group difference, -3.5%; 95% confidence interval -8.64 to 1.58); modified intention-to-treat, 82.5% and 84.9% (-2.4%; -6.90 to 2.10); and clinically evaluable, 91.7% and 92.5% (-0.8%; -4.61 to 2.89). The clinical cure rate with ceftazidime-avibactam plus metronidazole for ceftazidime-resistant infections was comparable to that with meropenem (mMITT population, 83.0% and 85.9%, respectively) and similar to the regimen's own efficacy against ceftazidime-susceptible infections (82.0%). Adverse events were similar between groups. CONCLUSIONS: Ceftazidime-avibactam plus metronidazole was noninferior to meropenem in the treatment of complicated intra-abdominal infections. Efficacy was similar against infections caused by ceftazidime-susceptible and ceftazidime resistant pathogens. The safety profile of ceftazidime-avibactam plus metronidazole was consistent with that previously observed with ceftazidime alone. CLINICAL TRIALS REGISTRATION: NCT01499290 and NCT01500239. PMID- 26962080 TI - Editorial Commentary: When to Perform a Test of Cure for Gonorrhea: Controversies and Evolving Data. PMID- 26962079 TI - Incidence, Duration, Persistence, and Factors Associated With High-risk Anal Human Papillomavirus Persistence Among HIV-negative Men Who Have Sex With Men: A Multinational Study. AB - BACKGROUND: Given high rates of anal disease, we investigated the natural history of high-risk anal human papillomavirus (HPV) among a multinational group of men who have sex with men (MSM) aged 18-64 years. METHODS: Anal specimens from human immunodeficiency virus-negative men from Brazil, Mexico, and the United States were genotyped. Over 2 years, 406 MSM provided evaluable specimens every 6 months for >=2 visits. These men were stratified into men who have sex only with men (MSOM, n = 70) and men who have sex with women and men (MSWM, n = 336). Persistence was defined as >=12 months' type-specific duration and could begin with either a prevalent or incident infection. Prevalence ratios and 95% confidence intervals were calculated by Poisson regression. RESULTS: Median follow-up time was 2.1 years. Retention was 82%. Annual cumulative incidence of 9 valent vaccine types was 19% and 8% among MSOM and MSWM, respectively (log-rank P = .02). Duration of anal HPV did not differ for MSOM and MSWM and was a median of 6.9 months for HPV-16 after combining men from the 2 groups. Among men with prevalent high-risk infection (n = 106), a total of 36.8%, retained the infection for at least 24 months. For those with prevalent HPV-16 (n = 27), 29.6% were persistent for at least 24 months. Persistence of high-risk HPV was associated with number of male anal sex partners and inversely associated with number of female sex partners. CONCLUSIONS: MSM with prevalent high-risk HPV infection should be considered at increased risk for nontransient infection. PMID- 26962081 TI - Capsular Typing Method for Streptococcus agalactiae Using Whole-Genome Sequence Data. AB - Group B streptococcus (GBS) capsular serotypes are major determinants of virulence and affect potential vaccine coverage. Here we report a whole-genome sequencing-based method for GBS serotype assignment. This method shows strong agreement (kappa of 0.92) with conventional methods and increased serotype assignment (100%) to all 10 capsular types. PMID- 26962083 TI - The Clinical Urine Culture: Enhanced Techniques Improve Detection of Clinically Relevant Microorganisms. AB - Enhanced quantitative urine culture (EQUC) detects live microorganisms in the vast majority of urine specimens reported as "no growth" by the standard urine culture protocol. Here, we evaluated an expanded set of EQUC conditions (expanded spectrum EQUC) to identify an optimal version that provides a more complete description of uropathogens in women experiencing urinary tract infection (UTI) like symptoms. One hundred fifty adult urogynecology patient-participants were characterized using a self-completed validated UTI symptom assessment (UTISA) questionnaire and asked "Do you feel you have a UTI?" Women responding negatively were recruited into the no-UTI cohort, while women responding affirmatively were recruited into the UTI cohort; the latter cohort was reassessed with the UTISA questionnaire 3 to 7 days later. Baseline catheterized urine samples were plated using both standard urine culture and expanded-spectrum EQUC protocols: standard urine culture inoculated at 1 MUl onto 2 agars incubated aerobically; expanded spectrum EQUC inoculated at three different volumes of urine onto 7 combinations of agars and environments. Compared to expanded-spectrum EQUC, standard urine culture missed 67% of uropathogens overall and 50% in participants with severe urinary symptoms. Thirty-six percent of participants with missed uropathogens reported no symptom resolution after treatment by standard urine culture results. Optimal detection of uropathogens could be achieved using the following: 100 MUl of urine plated onto blood (blood agar plate [BAP]), colistin-nalidixic acid (CNA), and MacConkey agars in 5% CO2 for 48 h. This streamlined EQUC protocol achieved 84% uropathogen detection relative to 33% detection by standard urine culture. The streamlined EQUC protocol improves detection of uropathogens that are likely relevant for symptomatic women, giving clinicians the opportunity to receive additional information not currently reported using standard urine culture techniques. PMID- 26962082 TI - Phylogenetic Analysis of Invasive Serotype 1 Pneumococcus in South Africa, 1989 to 2013. AB - Serotype 1 is an important cause of invasive pneumococcal disease in South Africa and has declined following the introduction of the 13-valent pneumococcal conjugate vaccine in 2011. We genetically characterized 912 invasive serotype 1 isolates from 1989 to 2013. Simpson's diversity index (D) and recombination ratios were calculated. Factors associated with sequence types (STs) were assessed. Clonal complex 217 represented 96% (872/912) of the sampled isolates. Following the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13), ST diversity increased in children <5 years (D, 0.39 to 0.63, P = 0.002) and individuals >14 years (D, 0.35 to 0.54, P < 0.001): ST-217 declined proportionately in children <5 years (153/203 [75%] versus 21/37 [57%], P = 0.027) and individuals >14 years (242/305 [79%] versus 96/148 [65%], P = 0.001), whereas ST-9067 increased (4/684 [0.6%] versus 24/228 [11%], P < 0.001). Three subclades were identified within ST-217: ST-217C1 (353/382 [92%]), ST-217C2 (15/382 [4%]), and ST-217C3 (14/382 [4%]). ST-217C2, ST-217C3, and single-locus variant (SLV) ST-8314 (20/912 [2%]) were associated with nonsusceptibility to chloramphenicol, tetracycline, and co-trimoxazole. ST-8314 (20/912 [2%]) was also associated with increased nonsusceptibility to penicillin (P < 0.001). ST-217C3 and newly reported ST-9067 had higher recombination ratios than those of ST-217C1 (4.344 versus 0.091, P < 0.001; and 0.086 versus 0.013, P < 0.001, respectively). Increases in genetic diversity were noted post-PCV13, and lineages associated with antimicrobial nonsusceptibility were identified. PMID- 26962084 TI - Molecular Diagnosis of Hemorrhagic Fever with Renal Syndrome Caused by Puumala Virus. AB - Rodent-borne hantaviruses cause two severe acute diseases: hemorrhagic fever with renal syndrome (HFRS) in Eurasia, and hantavirus pulmonary syndrome (HPS; also called hantavirus cardiopulmonary syndrome [HCPS]) in the Americas. Puumala virus (PUUV) is the most common causative agent of HFRS in Europe. Current routine diagnostic methods are based on serological analyses and can yield inconclusive results. Hantavirus-infected patients are viremic during the early phase of disease; therefore, detection of viral RNA genomes can be a valuable complement to existing serological methods. However, the high genomic sequence diversity of PUUV has hampered the development of molecular diagnostics, and currently no real time reverse transcription-quantitative (RT)-PCR assay is available for routine diagnosis of HFRS. Here, we present a novel PUUV RT-PCR assay. The assay was validated for routine diagnosis of HFRS on samples collected in Sweden during the winter season from 2013 to 2014. The assay allowed detection of PUUV RNA in 98.7% of confirmed clinical HFRS samples collected within 8 days after symptomatic onset. In summary, this study shows that real-time RT-PCR can be a reliable alternative to serological tests during the early phase of HFRS. PMID- 26962086 TI - Evaluation of Multiplex-Based Antibody Testing for Use in Large-Scale Surveillance for Yaws: a Comparative Study. AB - WHO has targeted yaws for global eradication by 2020. The program goals are to interrupt the transmission in countries where yaws is endemic and to certify countries as yaws free where yaws was endemic in the past. No new rapid plasmin reagin (RPR) seroreactivity in young children is required for certification of elimination at a country level. We sought to evaluate whether antibody responses to specific treponemal antigens measured in a high-throughput multiplex bead array (MBA) assay differentiate past versus current infection and whether a nontreponemal lipoidal antigen test can be incorporated into the MBA. Serum and dried blood spot specimens collected for yaws surveillance projects in Ghana, Vanuatu, and Papua New Guinea (PNG) were run on MBA to measure antibodies against recombinant p17 (rp17) and treponemal membrane protein A (TmpA) treponemal antigens. Results were compared to standard treponemal laboratory (TPPA or TPHA [TPP(H)A]) and quantitative RPR test data. Of 589 specimens, 241 were TPP(H)A(+)/RPR(+), 88 were TPP(H)A(+)/RPR(-), 6 were TPP(H)A(-)/RPR(+), and 254 were negative for both tests. Compared to TPP(H)A, reactive concordance of rp17 was 93.7%, while reactive concordance of TmpA was only 81.9%. TmpA-specific reactivity showed good correlation with RPR titers (R(2) = 0.41; P < 0.0001). IgG responses to the lipoidal antigen used in RPR testing (cardiolipin) were not detected in the MBA. Our results suggest that TmpA can be used as a treponemal antigen marker for recent or active infection and potentially replace RPR in a high-throughput multiplex tool for large-scale yaws surveillance. PMID- 26962085 TI - Mycobacterium arupense, Mycobacterium heraklionense, and a Newly Proposed Species, "Mycobacterium virginiense" sp. nov., but Not Mycobacterium nonchromogenicum, as Species of the Mycobacterium terrae Complex Causing Tenosynovitis and Osteomyelitis. AB - Mycobacterium terrae complex has been recognized as a cause of tenosynovitis, with M. terrae and Mycobacterium nonchromogenicum reported as the primary etiologic pathogens. The molecular taxonomy of the M. terrae complex causing tenosynovitis has not been established despite approximately 50 previously reported cases. We evaluated 26 isolates of the M. terrae complex associated with tenosynovitis or osteomyelitis recovered between 1984 and 2014 from 13 states, including 5 isolates reported in 1991 as M. nonchromogenicum by nonmolecular methods. The isolates belonged to three validated species, one new proposed species, and two novel related strains. The majority of isolates (20/26, or 77%) belonged to two recently described species: Mycobacterium arupense (10 isolates, or 38%) and Mycobacterium heraklionense (10 isolates, or 38%). Three isolates (12%) had 100% sequence identity to each other by 16S rRNA and 99.3 to 100% identity by rpoB gene region V sequencing and represent a previously undescribed species within the M. terrae complex. There were no isolates of M. terrae or M. nonchromogenicum, including among the five isolates reported in 1991. The 26 isolates were susceptible to clarithromycin (100%), rifabutin (100%), ethambutol (92%), and sulfamethoxazole or trimethoprim-sulfamethoxazole (70%). The current study suggests that M. arupense, M. heraklionense, and a newly proposed species ("M. virginiense" sp. nov.; proposed type strain MO-233 [DSM 100883, CIP 110918]) within the M. terrae complex are the major causes of tenosynovitis and osteomyelitis in the United States, with little change over 20 years. Species identification within this complex requires sequencing methods. PMID- 26962087 TI - In Vitro Antimicrobial Susceptibility of Staphylococcus pseudintermedius Isolates of Human and Animal Origin. AB - MIC results for 115 Staphylococcus intermedius group isolates are presented. Of these, 33% were methicillin resistant, among which 51.4% were susceptible to doxycycline, 29.7% to clindamycin, and 21.6% to trimethoprim-sulfamethoxazole. All of the isolates were susceptible to ceftaroline, daptomycin, linezolid, nitrofurantoin, quinupristin-dalfopristin, rifampin, tigecycline, and vancomycin. Of all the isolates, 82.6%, 67.8%, and 23.5% were susceptible to ciprofloxacin, erythromycin, and penicillin, respectively. No isolates harbored mupA or qacA/B genes, which suggested a lack of resistance to mupirocin or chlorhexidine. PMID- 26962089 TI - Complicated Urinary Tract Infections: What's a Lab To Do? AB - The article by Price et al. in this issue (T. K. Price et al., J Clin Microbiol 54:1216-1222, 2016, http://dx.doi.org/10.1128/JCM.00044-16) advocates for the use of a larger inoculum when culturing urine obtained by "in-and-out" catheterization in a selected female population. Their findings and the resulting challenges will afford clinical microbiologists and specialty physicians an opportunity to review what will or should be done with the additional microbiological culture data. PMID- 26962090 TI - Clostridium difficile Ribotype 023 Lacks the Ability To Hydrolyze Esculin, Leading to False-Negative Results on Chromogenic Agar. PMID- 26962088 TI - Multicenter Evaluation of Clinical Diagnostic Methods for Detection and Isolation of Campylobacter spp. from Stool. AB - The use of culture-independent diagnostic tests (CIDTs), such as stool antigen tests, as standalone tests for the detection of Campylobacter in stool is increasing. We conducted a prospective, multicenter study to evaluate the performance of stool antigen CIDTs compared to culture and PCR for Campylobacter detection. Between July and October 2010, we tested 2,767 stool specimens from patients with gastrointestinal illness with the following methods: four types of Campylobacter selective media, four commercial stool antigen assays, and a commercial PCR assay. Illnesses from which specimens were positive by one or more culture media or at least one CIDT and PCR were designated "cases." A total of 95 specimens (3.4%) met the case definition. The stool antigen CIDTs ranged from 79.6% to 87.6% in sensitivity, 95.9 to 99.5% in specificity, and 41.3 to 84.3% in positive predictive value. Culture alone detected 80/89 (89.9% sensitivity) Campylobacter jejuni/Campylobacter coli-positive cases. Of the 209 noncases that were positive by at least one CIDT, only one (0.48%) was positive by all four stool antigen tests, and 73% were positive by just one stool antigen test. The questionable relevance of unconfirmed positive stool antigen CIDT results was supported by the finding that noncases were less likely than cases to have gastrointestinal symptoms. Thus, while the tests were convenient to use, the sensitivity, specificity, and positive predictive value of Campylobacter stool antigen tests were highly variable. Given the relatively low incidence of Campylobacter disease and the generally poor diagnostic test characteristics, this study calls into question the use of commercially available stool antigen CIDTs as standalone tests for direct detection of Campylobacter in stool. PMID- 26962091 TI - Comparison of the Cytomegalovirus (CMV) Enzyme-Linked Immunosorbent Spot and CMV QuantiFERON Cell-Mediated Immune Assays in CMV-Seropositive and -Seronegative Pregnant and Nonpregnant Women. AB - Human cytomegalovirus (CMV) infection is a major cause of congenital infection leading to birth defects and sensorineural anomalies, including deafness. Recently, cell-mediated immunity (CMI) in pregnant women has been shown to correlate with congenital CMV transmission. In this study, two interferon gamma release assays (IGRA), the CMV enzyme-linked immunosorbent spot (ELISPOT) and CMV QuantiFERON assays, detecting CMV-specific CMI were compared. These assays were performed for 80 CMV-infected (57 primarily and 23 nonprimarily) pregnant women and 115 controls, including 89 healthy CMV-seropositive pregnant women without active CMV infection, 15 CMV-seronegative pregnant women, and 11 seropositive or seronegative nonpregnant women. Statistical tests, including frequency distribution analysis, nonparametric Kruskal-Wallis equality-of-populations rank test, Wilcoxon rank sum test for equality on unmatched data, and lowess smoothing local regression, were employed to determine statistical differences between groups and correlation between the assays. The CMV ELISPOT and CMV QuantiFERON assay data were not normally distributed and did not display equal variance. The CMV ELISPOT but not CMV QuantiFERON assay displayed significant higher values for primarily CMV-infected women than for the healthy seropositive pregnant and nonpregnant groups (P = 0.0057 and 0.0379, respectively) and those with nonprimary infections (P = 0.0104). The lowess local regression model comparing the assays on an individual basis showed a value bandwidth of 0.8. Both assays were highly accurate in discriminating CMV-seronegative pregnant women. The CMV ELISPOT assay was more effective than CMV-QuantiFERON in differentiating primary from the nonprimary infections. A substantial degree of variability exists between CMV ELISPOT and CMV QuantiFERON assay results for CMV-seropositive pregnant women. PMID- 26962093 TI - Erratum. PMID- 26962092 TI - New Gram-Positive Agents: the Next Generation of Oxazolidinones and Lipoglycopeptides. AB - The growing problem of antimicrobial resistance among bacterial pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococci (VRE), has reached a critical state. Tedizolid phosphate, dalbavancin, and oritavancin have recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and represent the next generation of oxazolidinones and lipoglycopeptides. All three agents exhibit in vitro activity and clinical efficacy against MRSA. Tedizolid phosphate and oritavancin demonstrate in vitro activity against VRE. These new Gram-positive agents are reviewed here. PMID- 26962094 TI - Prospective, Tissue-Specific Optimization of Ablation for Multiwavelet Reentry: Predicting the Required Amount, Location, and Configuration of Lesions. AB - BACKGROUND: Treatment of multiwavelet reentry (MWR) remains difficult. We previously developed a metric, the fibrillogenicity index, to assess the propensity of homogeneous, 2-dimensional tissues to support MWR. In this study, we demonstrate a method by which fibrillogenicity index can be generalized to heterogeneous tissues and validate an algorithm for prospective, tissue-specific optimization of ablation to reduce MWR burden. METHODS AND RESULTS: We used a computational model to simulate and measure the duration of MWR in tissues with heterogeneously distributed action potential durations and then assessed the relative efficacy of a variety of ablation strategies for reducing tissues' ability to support MWR. We then derived and tested a strategy in which multiple linear lesions partially divided a fibrillogenic tissue into functionally equivalent subsections. The composite action potential duration of heterogeneous tissue was well approximated by an inverse sum of cellular action potential durations (R(2)=0.82). Linear ablation more efficiently reduced MWR duration than branching ablation patterns and optimally reduced disease burden when positioned at a tissue's functional (rather than geometric) center. The duration of MWR after application of prospective, individually optimized ablation sets fell within 4.4% (95% confidence interval, 3-5.8) of the predicted target. CONCLUSIONS: We think that this study presents a novel approach for (1) quantifying the extent of a tissue's electric derangement, (2) prospectively determining the amount of ablation required to minimize the burden of MWR, and (3) predicting the most efficient distribution of these ablation lesions in tissue refractory to standard ablation strategies. PMID- 26962095 TI - Creating Order From Chaos: Practical Interventional Targets for the Multiple Wavelets of Atrial Fibrillation. PMID- 26962096 TI - Current Status of Supplemental Screening in Dense Breasts. PMID- 26962097 TI - Adjunct Screening With Tomosynthesis or Ultrasound in Women With Mammography Negative Dense Breasts: Interim Report of a Prospective Comparative Trial. AB - PURPOSE: Debate on adjunct screening in women with dense breasts has followed legislation requiring that women be informed about their mammographic density and related adjunct imaging. Ultrasound or tomosynthesis can detect breast cancer (BC) in mammography-negative dense breasts, but these modalities have not been directly compared in prospective trials. We conducted a trial of adjunct screening to compare, within the same participants, incremental BC detection by tomosynthesis and ultrasound in mammography-negative dense breasts. PATIENTS AND METHODS: Adjunct Screening With Tomosynthesis or Ultrasound in Women With Mammography-Negative Dense Breasts is a prospective multicenter study recruiting asymptomatic women with mammography-negative screens and dense breasts. Eligible women had tomosynthesis and physician-performed ultrasound with independent interpretation of adjunct imaging. Outcome measures included cancer detection rate (CDR), number of false-positive (FP) recalls, and incremental CDR for each modality; these were compared using McNemar's test for paired binary data in a preplanned interim analysis. RESULTS: Among 3,231 mammography-negative screening participants (median age, 51 years; interquartile range, 44 to 78 years) with dense breasts, 24 additional BCs were detected (23 invasive): 13 tomosynthesis detected BCs (incremental CDR, 4.0 per 1,000 screens; 95% CI, 1.8 to 6.2) versus 23 ultrasound-detected BCs (incremental CDR, 7.1 per 1,000 screens; 95% CI, 4.2 to 10.0), P = .006. Incremental FP recall occurred in 107 participants (3.33%; 95% CI, 2.72% to 3.96%). FP recall (any testing) did not differ between tomosynthesis (FP = 53) and ultrasound (FP = 65), P = .26; FP recall (biopsy) also did not differ between tomosynthesis (FP = 22) and ultrasound (FP = 24), P = .86. CONCLUSION: The Adjunct Screening With Tomosynthesis or Ultrasound in Women With Mammography-Negative Dense Breasts' interim analysis shows that ultrasound has better incremental BC detection than tomosynthesis in mammography-negative dense breasts at a similar FP-recall rate. However, future application of adjunct screening should consider that tomosynthesis detected more than 50% of the additional BCs in these women and could potentially be the primary screening modality. PMID- 26962098 TI - Hyperaldosteronism after decreased renal K+ excretion in KCNMB2 knockout mice. AB - The kidney is the primary organ ensuring K(+) homeostasis. K(+) is secreted into the urine in the distal tubule by two mechanisms: by the renal outer medullary K(+) channel (Kir1.1) and by the Ca(2+)-activated K(+) channel (KCa1.1). Here, we report a novel knockout mouse of the beta2-subunit of the KCa1.1 channel (KCNMB2), which displays hyperaldosteronism after decreased renal K(+) excretion. KCNMB2(-/-) mice displayed hyperaldosteronism, normal plasma K(+) concentration, and produced dilute urine with decreased K(+) concentration. The normokalemia indicated that hyperaldosteronism did not result from primary aldosteronism. Activation of the renin-angiotensin-aldosterone system was also ruled out as renal renin mRNA expression was reduced in KCNMB2(-/-) mice. Renal K(+) excretion rates were similar in the two genotypes; however, KCNMB2(-/-) mice required elevated plasma aldosterone to achieve K(+) balance. Blockade of the mineralocorticoid receptor with eplerenone triggered mild hyperkalemia and unmasked reduced renal K(+) excretion in KCNMB2(-/-) mice. Knockout mice for the alpha-subunit of the KCa1.1 channel (KCNMA1(-/-) mice) have hyperaldosteronism, are hypertensive, and lack flow-induced K(+) secretion. KCNMB2(-/-) mice share the phenotypic traits of normokalemia and hyperaldosteronism with KCNMA1(-/-) mice but were normotensive and displayed intact flow-induced K(+) secretion. Despite elevated plasma aldosterone, KNCMB2(-/-) mice did not display salt sensitive hypertension and were able to decrease plasma aldosterone on a high Na(+) diet, although plasma aldosterone remained elevated in KCNMB2(-/-) mice. In summary, KCNMB2(-/-) mice have a reduced ability to excrete K(+) into the urine but achieve K(+) balance through an aldosterone-mediated, beta2-independent mechanism. The phenotype of KCNMB2 mice was similar but milder than the phenotype of KCNMA1(-/-) mice. PMID- 26962100 TI - Renal blood flow autoregulation: what are the contributions for nitric oxide or superoxide to modulate the myogenic response? PMID- 26962099 TI - Metformin, an AMPK activator, stimulates the phosphorylation of aquaporin 2 and urea transporter A1 in inner medullary collecting ducts. AB - Nephrogenic diabetes insipidus (NDI) is characterized by production of very large quantities of dilute urine due to an inability of the kidney to respond to vasopressin. Congenital NDI results from mutations in the type 2 vasopressin receptor (V2R) in ~90% of families. These patients do not have mutations in aquaporin-2 (AQP2) or urea transporter UT-A1 (UT-A1). We tested adenosine monophosphate kinase (AMPK) since it is known to phosphorylate another vasopressin-sensitive transporter, NKCC2 (Na-K-2Cl cotransporter). We found AMPK expressed in rat inner medulla (IM). AMPK directly phosphorylated AQP2 and UT-A1 in vitro. Metformin, an AMPK activator, increased phosphorylation of both AQP2 and UT-A1 in rat inner medullary collecting ducts (IMCDs). Metformin increased the apical plasma membrane accumulation of AQP2, but not UT-A1, in rat IM. Metformin increased both osmotic water permeability and urea permeability in perfused rat terminal IMCDs. These findings suggest that metformin increases osmotic water permeability by increasing AQP2 accumulation in the apical plasma membrane but increases urea permeability by activating UT-A1 already present in the membrane. Lastly, metformin increased urine osmolality in mice lacking a V2R, a mouse model of congenital NDI. We conclude that AMPK activation by metformin mimics many of the mechanisms by which vasopressin increases urine-concentrating ability. These findings suggest that metformin may be a novel therapeutic option for congenital NDI due to V2R mutations. PMID- 26962101 TI - 2016 Robert W. Berliner Award for Excellence in Renal Physiology. PMID- 26962102 TI - ACTH action on podocytes: mystery solved? PMID- 26962103 TI - RAS and sex differences in diabetic nephropathy. AB - The incidence and progression of kidney diseases are influenced by sex. The renin angiotensin system (RAS) is an important regulator of cardiovascular and renal function. Sex differences in the renal response to RAS blockade have been demonstrated. Circulating and renal RAS has been shown to be altered in type 1 and type 2 diabetes; this enzymatic cascade plays a critical role in the development of diabetic nephropathy (DN). Angiotensin converting enzyme (ACE) and ACE2 are differentially regulated depending on its localization within the diabetic kidney. Furthermore, clinical and experimental studies have shown that circulating levels of sex hormones are clearly modulated in the context of diabetes, suggesting that sex-dependent RAS regulation may be also be affected in these individuals. The effect of sex hormones on circulating and renal RAS may be involved in the sex differences observed in DN progression. In this paper we will review the influence of sex hormones on RAS expression and its relation to diabetic kidney disease. A better understanding of the sex dimorphism on RAS might provide a new approach for diabetic kidney disease treatment. PMID- 26962104 TI - Renovascular remodeling and renal injury after extended angiotensin II infusion. AB - Chronic angiotensin II (ANG II) infusion for 1 or 2 wk leads to progressive hypertension and induces inward hypertrophic remodeling in preglomerular vessels, which is associated with increased renal vascular resistance (RVR) and decreased glomerular perfusion. Considering the ability of preglomerular vessels to exhibit adaptive responses, the present study was performed to evaluate glomerular perfusion and renal function after 6 wk of ANG II infusion. To address this study, male Wistar rats were submitted to sham surgery (control) or osmotic minipump insertion (ANG II 200 ng.kg(-1).min(-1), 42 days). A group of animals was treated or cotreated with losartan (10 mg.kg(-1).day(-1)), an AT1 receptor antagonist, between days 28 and 42 Chronic ANG II infusion increased systolic blood pressure to 185 +/- 4 compared with 108 +/- 2 mmHg in control rats. Concomitantly, ANG II-induced hypertension increased intrarenal ANG II level and consequently, preglomerular and glomerular injury. Under this condition, ANG II enhanced the total renal plasma flow (RPF), glomerular filtration rate (GFR), urine flow and induced pressure natriuresis. These changes were accompanied by lower RVR and enlargement of the lumen of interlobular arteries and afferent arterioles, consistent with impairment of renal autoregulatory capability and outward preglomerular remodeling. The glomerular injury culminated with podocyte effacement, albuminuria, tubulointerstitial macrophage infiltration and intrarenal extracellular matrix accumulation. Losartan attenuated most of the effects of ANG II. Our findings provide new information regarding the contribution of ANG II infusion over 2 wk to renal hemodynamics and function via the AT1 receptor. PMID- 26962105 TI - Mass spectrometric imaging of metabolites in kidney tissues from rats treated with furosemide. AB - In the kidney, metabolic processes are different among the cortex (COR), outer medulla (OM), and inner medulla (IM). Using matrix-assisted laser desorption/ionization (MALDI) and imaging mass spectrometry (IMS), we examined the change of metabolites in the COR, OM, and IM of the rat kidney after furosemide treatment compared with vehicle-treated controls. Osmotic minipumps were implanted in male Sprague-Dawley rats to deliver 12 mg.day(-1).rat(-1) of furosemide. Vehicle-treated (n = 14) and furosemide-treated (furosemide rats, n = 15) rats in metabolic cages received a fixed amount of rat chow (15 g.220 g body wt(-1).day(-1) for each rat) with free access to water intake for 6 days. At day 6, higher urine output (32 +/- 4 vs. 9 +/- 1 ml/day) and lower urine osmolality (546 +/- 44 vs. 1,677 +/- 104 mosmol/kgH2O) were observed in furosemide rats. Extracts of COR, OM, and IM were analyzed by ultraperformance liquid chromatography coupled with quadrupole time-of-flight (TOF) mass spectrometry, where multivariate analysis revealed significant differences between the two groups. Several metabolites, including acetylcarnitine, betaine, carnitine, choline, and glycerophosphorylcholine (GPC), were significantly changed. The changes of metabolites were further identified by MALDI-TOF/TOF and IMS. Their spatial distribution and relative quantitation in the kidneys were analyzed by IMS. Carnitine compounds were increased in COR and IM, whereas carnitine and acetylcarnitine were decreased in OM. Choline compounds were increased in COR and OM but decreased in IM from furosemide rats. Betaine and GPC were decreased in OM and IM. Taken together, MALDI-TOF/TOF and IMS successfully provide the spatial distribution and relative quantitation of metabolites in the kidney. PMID- 26962106 TI - Tetrahydrobiopterin ameliorates the exaggerated exercise pressor response in patients with chronic kidney disease: a randomized controlled trial. AB - Chronic kidney disease (CKD) patients have an exaggerated increase in blood pressure (BP) during rhythmic handgrip exercise (RHG 20%) and static handgrip exercise (SHG 30%). Nitric oxide levels increase during exercise and help prevent excessive hypertension by both increasing vasodilation and reducing sympathetic nerve activity (SNA). Therefore, we hypothesized that tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthase, would ameliorate the exaggerated exercise pressor response in CKD patients. In a randomized, double-blinded, placebo-controlled trial, we tested the effects of 12 wk of sapropterin dihydrochloride (6R-BH4; n = 18) versus placebo (n = 14) treatement on BP and muscle SNA (MSNA) responses during RHG 20% and SHG 30% in CKD patients. The 6R BH4-treated group had a significantly lower systolic BP (+6 +/- 1 vs. +13 +/- 2 mmHg, P = 0.002) and mean arterial pressure response (+5 +/- 1 vs. +10 +/- 2 mmHg, P = 0.020) during RHG 20% and a significantly lower systolic BP response (+19 +/- 3 vs. +28 +/- 3 mmHg, P = 0.043) during SHG 30%. Under baseline conditions, there was no significant difference in MSNA responses between the groups; however, when the BP response during exercise was equalized between the groups using nitroprusside, the 6R-BH4-treated group had a significantly lower MSNA response during RHG 20% (6R-BH4 vs. placebo, +12 +/- 1 vs. +21 +/- 2 bursts/min, P = 0.004) but not during SHG 30%. These findings suggest that 6R-BH4 ameliorates the augmented BP response during RHG 20% and SHG 30% in CKD patients. A reduction in reflex activation of SNA may contribute to the decreased exercise pressor response during RHG 20% but not during SHG 30% in CKD patients. PMID- 26962109 TI - Delivery of interleukin-10 via injectable hydrogels improves renal outcomes and reduces systemic inflammation following ischemic acute kidney injury in mice. AB - Injectable hydrogels can be used to deliver drugs in situ over a sustained period of time. We hypothesized that sustained delivery of interleukin-10 (IL-10) following acute kidney injury (AKI) would mitigate the local and systemic proinflammatory cascade induced by AKI and reduce subsequent fibrosis. Wild-type C57BL/6 mice underwent ischemia-reperfusion AKI with avertin anesthesia. Three days later, mice were treated with either hyaluronic acid injectable hydrogel with or without IL-10, or IL-10 suspended in saline, injected under the capsule of the left kidney, or hydrogel with IL-10 injected subcutaneously. Untreated AKI served as controls. Serial in vivo optical imaging tracked the location and degradation of the hydrogel over time. Kidney function was assessed serially. Animals were killed 28 days following AKI and the following were evaluated: serum IL-6, lung inflammation, urine neutrophil gelatinase-associated lipocalin, and renal histology for fibroblast activity, collagen type III deposition and fibrosis via Picrosirius Red staining and second harmonic imaging. Our model shows persistent systemic inflammation, and renal inflammation and fibrosis 28 days following AKI. The hydrogels are biocompatible and reduced serum IL-6 and renal collagen type III 28 days following AKI even when delivered without IL-10. Treatment with IL-10 reduced renal and systemic inflammation, regardless of whether the IL-10 was delivered in a sustained manner via the injectable hydrogel under the left kidney capsule, as a bolus injection via saline under the left kidney capsule, or via the injectable hydrogel subcutaneously. Injectable hydrogels are suitable for local drug delivery following renal injury, are biocompatible, and help mitigate local and systemic inflammation. PMID- 26962110 TI - In vivo protection studies of bis-quaternary 2-(hydroxyimino)- N-(pyridin-3-yl) acetamide derivatives against sarin poisoning in mice. AB - In vivo antidotal efficacy of new bis- quaternary 2-(hydroxyimino)- N-(pyridin 3yl) acetamide derivatives (HNK series), to counter multiples of lethal doses of nerve agent sarin (GB) and reactivation of acetylcholinesterase (AChE), was evaluated in Swiss albino mice. [Protection index PI; median lethal dose (LD50) of sarin with treatment/LD50 of sarin] was estimated, using 0.05, 0.10, and 0.20 LD50 as treatment doses of all the oximes with atropine against sarin poisoning. Dose-dependent time course study was conducted at 0.2, 0.4 and 0.8 LD50 dose of sarin for estimating maximum AChE inhibition. At optimized time (15 min), in vivo enzyme half inhibition concentration (IC50) was calculated. AChE reactivation efficacy of HNK series and pralidoxime (2-PAM) were determined by plotting shift of log IC50 doses. HNK-102 with atropine showed three fold higher PI compared to 2-PAM. In vivo IC50 of sarin for brain and serum AChE was found to be 0.87 LD50 (139.2 ug/kg) and 0.48 LD50 (77.23 ug/kg), respectively. Treatment with HNK-102 and HNK-111 (equal to their 0.20LD50) significantly reactivated sarin-intoxicated AChE ( p < 0.05) at 2* IC50 dose of sarin, compared to 2-PAM. The study revealed that HNK-102 oxime was three times more potent as antidote, for acute sarin poisoning compared to 2-PAM in vivo. PMID- 26962108 TI - The anti-inflammatory peptide Ac-SDKP is released from thymosin-beta4 by renal meprin-alpha and prolyl oligopeptidase. AB - N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural tetrapeptide with anti-inflammatory and antifibrotic properties. Previously, we have shown that prolyl oligopeptidase (POP) is involved in the Ac-SDKP release from thymosin beta4 (Tbeta4). However, POP can only hydrolyze peptides shorter than 30 amino acids, and Tbeta4 is 43 amino acids long. This indicates that before POP hydrolysis takes place, Tbeta4 is hydrolyzed by another peptidase that releases NH2-terminal intermediate peptide(s) with fewer than 30 amino acids. Our peptidase database search pointed out meprin-alpha metalloprotease as a potential candidate. Therefore, we hypothesized that, prior to POP hydrolysis, Tbeta4 is hydrolyzed by meprin-alpha. In vitro, we found that the incubation of Tbeta4 with both meprin-alpha and POP released Ac-SDKP, whereas no Ac-SDKP was released when Tbeta4 was incubated with either meprin-alpha or POP alone. Incubation of Tbeta4 with rat kidney homogenates significantly released Ac-SDKP, which was blocked by the meprin-alpha inhibitor actinonin. In addition, kidneys from meprin-alpha knockout (KO) mice showed significantly lower basal Ac-SDKP amount, compared with wild-type mice. Kidney homogenates from meprin-alpha KO mice failed to release Ac SDKP from Tbeta4. In vivo, we observed that rats treated with the ACE inhibitor captopril increased plasma concentrations of Ac-SDKP, which was inhibited by the coadministration of actinonin (vehicle, 3.1 +/- 0.2 nmol/l; captopril, 15.1 +/- 0.7 nmol/l; captopril + actinonin, 6.1 +/- 0.3 nmol/l; P < 0.005). Similar results were obtained with urinary Ac-SDKP after actinonin treatment. We conclude that release of Ac-SDKP from Tbeta4 is mediated by successive hydrolysis involving meprin-alpha and POP. PMID- 26962111 TI - Effect of repeated oral administration of levofloxacin, enrofloxacin, and meloxicam on antioxidant parameters and lipid peroxidation in rabbits. AB - The effect of 21 days of repeated oral administration of levofloxacin and enrofloxacin both alone and in combination with meloxicam, on the oxidative balance in blood was evaluated in rabbits. Rabbits were randomly allocated to six groups of four animals each. Control group was gavaged 5% dextrose and 2% benzyl alcohol. Three groups were exclusively gavaged meloxicam (0.2 mg/kg body weight o.d.), levofloxacin hemihydrate (10 mg/kg body weight b.i.d 12 h), and enrofloxacin (20 mg/kg body weight o.d.), respectively. Two other groups were co gavaged meloxicam with levofloxacin hemihydrate and enrofloxacin, respectively. A reduction ( p < 0.05) of reduced glutathione levels was observed in groups treated with meloxicam both alone and in combination with levofloxacin, whereas an increase ( p < 0.01) in the levels of this antioxidant was observed in the groups treated with enrofloxacin. The activities of enzymes, glutathione peroxidase and superoxide dismutase, were induced ( p < 0.05) in levofloxacin alone treated group. Superoxide dismutase was also induced ( p < 0.05) in meloxicam-alone treated group and inhibited ( p < 0.05) in enrofloxacin-meloxicam co-treated group. The activity of catalase was non-significantly different between various groups. Enrofloxacin-treated groups had higher ( p < 0.01) lipid peroxidation than control and levofloxacin-alone treated groups. Elevated lipid peroxidation was also observed in the groups treated with meloxicam both alone and in combination with levofloxacin ( p < 0.05). In conclusion, these drugs have potential to induce oxidative imbalance, however, compared to levofloxacin, more oxidative damage is produced by enrofloxacin and meloxicam. PMID- 26962112 TI - Behavior of Mouse Spermatozoa in the Female Reproductive Tract from Soon after Mating to the Beginning of Fertilization. AB - Using transgenic mice with spermatozoa expressing enhanced green fluorescent protein in their acrosome and red fluorescent protein in their midpiece mitochondria, we followed the behavior of spermatozoa within the female genital tract after natural mating. When examined 15 min after coitus, many spermatozoa were around the opening of the uterotubal junction. Spermatozoa that entered the uterotubal junction were seemingly not moving, yet they steadily migrated toward the isthmus at a speed only time-lapse video recording could demonstrate. Many spermatozoa reaching the lower isthmus were motile. The site where spermatozoa attached and detached from the isthmus epithelium shifted from the lower to the upper segment of the isthmus with time. Virtually all the live spermatozoa within the lower isthmus were acrosome intact, whereas many of the actively motile spermatozoa in the upper isthmus were acrosome reacted. As far as we could observe, all the spermatozoa we found within the lumen of the ampulla and the cumulus oophorus were acrosome reacted. Even though we saw only a very few spermatozoa within the ampulla during fertilization, all were associated with, or were already within, oocytes, indicating that mouse fertilization in vivo is extremely efficient. PMID- 26962107 TI - Bridging translation for acute kidney injury with better preclinical modeling of human disease. AB - The current lack of effective therapeutics for patients with acute kidney injury (AKI) represents an important and unmet medical need. Given the importance of the clinical problem, it is time for us to take a few steps back and reexamine current practices. The focus of this review is to explore the extent to which failure of therapeutic translation from animal studies to human studies stems from deficiencies in the preclinical models of AKI. We will evaluate whether the preclinical models of AKI that are commonly used recapitulate the known pathophysiologies of AKI that are being modeled in humans, focusing on four common scenarios that are studied in clinical therapeutic intervention trials: cardiac surgery-induced AKI; contrast-induced AKI; cisplatin-induced AKI; and sepsis associated AKI. Based on our observations, we have identified a number of common limitations in current preclinical modeling of AKI that could be addressed. In the long term, we suggest that progress in developing better preclinical models of AKI will depend on developing a better understanding of human AKI. To this this end, we suggest that there is a need to develop greater in-depth molecular analyses of kidney biopsy tissues coupled with improved clinical and molecular classification of patients with AKI. PMID- 26962113 TI - MiR-125b Regulates Primordial Follicle Assembly by Targeting Activin Receptor Type 2a in Neonatal Mouse Ovary. AB - The establishment of the primordial follicle pool is crucial for fertility in mammalian females, and the interruption of overall micro-RNA production byDicer1conditional knockout in the female reproductive system results in infertility. However, there are few reports about the functions of individual micro-RNA in regulating primordial follicle assembly. The present study aimed to investigate the function of miR-125b, which is conserved and preferentially expressed in mammalian ovary during primordial follicle assembly. Detection of miR-125b in the developing mouse ovaries by real-time PCR and in situ hybridization showed that it was highly expressed perinatally and specifically located in the ovarian somatic cells. MiR-125b overexpression blocked the process of primordial follicle assembly in cultured newborn mouse ovaries, while its knockdown promoted this process. Further studies showed that miR-125b regulated the activin/Smad2 signaling in neonatal mouse ovary by directly targeting the 3' untranslated region of activin receptor type 2a (Acvr2a). Overexpression of miR 125b in neonatal mouse ovary suppressed theAcvr2aprotein level, attenuating activin/Smad2 signaling, while knockdown of miR-125b showed the opposite effects. In addition, recombinant human activin A (rh-ActA) down-regulated miR-125b in the neonatal mouse ovary. Overexpression of miR-125b attenuated the promoting effects of rh-ActA on primordial follicle assembly. Taken together, these data suggest that miR-125b blocks the process of primordial follicle assembly, and miR-125b may play this role by regulating the expression ofAcvr2ain the activin/Smad2 signaling pathway. PMID- 26962115 TI - JEG-3 Trophoblast Cells Producing Human Chorionic Gonadotropin Promote Conversion of Human CD4+FOXP3- T Cells into CD4+FOXP3+ Regulatory T Cells and Foster T Cell Suppressive Activity. AB - The pregnancy hormone human Chorionic Gonadotropin (hCG) reportedly modulates innate and adaptive immune responses and contributes thereby to fetal survival. More precisely, hCG has been shown to support human Treg cell homing into the fetal-maternal interface and enhance number and function of Treg cells in murine pregnancy. Here, we aimed to study whether hCG and hCG-producing human trophoblast cell lines induce Treg cells from CD4+FOXP3- T cells and promote T cell suppressive activity. CD4+FOXP3- T cells were isolated from peripheral blood of normal pregnant women and cultured in the presence of hCG-producing (JEG-3, HTR-8) and non-producing (SWAN-71) cell lines. To confirm the participation of hCG in Treg cell conversion, the experiments were performed in the presence of anti-hCG and additional experiments were run with recombinant or urine-purified hCG. After culture the number of CD4+FOXP3+ Treg cells as well as the suppressive capacity of total T cells was assessed. hCG-producing JEG-3 cells as well as recombinant and urine-purified hCG induced CD4+FOXP3+ Treg cells from CD4+FOXP3- T cells. Blockage of hCG impaired Treg cell induction. Moreover, hCG-producing JEG-3 cells increased suppressive activity of CD4+FOXP3- T cells through an antigen-independent pathway. Our results propose another mechanism through which hCG modulates the female immune system during pregnancy in favor of the fetus. PMID- 26962116 TI - Unravelling the Link Between the Placental Epigenome and Pregnancy Outcomes. PMID- 26962114 TI - Maternal High-Fat Diet-Induced Loss of Fetal Oocytes Is Associated with Compromised Follicle Growth in Adult Rat Offspring. AB - Maternal obesity predisposes offspring to metabolic and reproductive dysfunction. We have shown previously that female rat offspring born to mothers fed a high-fat (HF) diet throughout pregnancy and lactation enter puberty early and display aberrant reproductive cyclicity. The mechanisms driving this reproductive phenotype are currently unknown thus we investigated whether changes in ovarian function were involved. Wistar rats were mated and randomized to: dams fed a control diet (CON) or dams fed a HF diet from conception until the end of lactation (HF). Ovaries were collected from fetuses at Embryonic Day (E) 20, and neonatal ovaries at Day 4 (P4), prepubertal ovaries at P27 and adult ovaries at P120. In a subset of offspring, the effects of a HF diet fed postweaning were evaluated. The present study shows that fetuses of mothers fed a HF diet had significantly fewer oocytes at E20, and in neonates, have reduced AMH signaling that may facilitate an increased number of assembled primordial follicles. Both prepubertally and in adulthood, ovaries show increased follicular atresia. As adults, offspring have reduced FSH responsiveness, low expression levels of estrogen receptor alpha (Eralpha), the oocyte-secreted factor, Gdf9, oocyte specific RNA binding protein, Dazl, and high expression levels of the granulosa cell derived factor, AMH, in antral follicles. Together, these data suggest that ovarian compromise in offspring born to HF-fed mothers may arise from changes already observable in the fetus and neonate and in the long term, associated with increased follicular atresia through adulthood. PMID- 26962118 TI - Surfing and Swimming of Ejaculated Sperm in the Mouse Oviduct. AB - To accomplish fertilization in the oviductal ampulla, ejaculated sperm are required to migrate through the female reproductive tract. However, this fundamental process largely remains unknown. In this study, we focused on the role of oviductal smooth muscle (myosalpinx) contractions in the sperm migration. Administration of prifinium bromide, padrin, to mice effectively suppressed myosalpinx contractions, resulting in a decreased rate of fertilization in a dose dependent manner, and an abrogation of high-speed back-and-forth/shuttling flows of oviductal fluids around the isthmus. Regardless of padrin administration, no shuttling flows were found near the ampulla. In the isthmus, sperm formed a tight assemblage that was synchronized with the shuttling flows. The sperm assemblage was gradually loosened and then completely abolished near the ampulla. No sperm assemblage was formed in the isthmus when padrin was administrated. These results suggest that myosalpinx contractions play important roles in the formation of sperm assemblage in the isthmus, and in the transport of the assemblage to the middle region of the oviduct. It is also suggested that the motility of sperm is essential for the migration of sperm from the middle oviductal region to the ampulla. PMID- 26962120 TI - Quantitative Glycopeptide Changes in Rat Sperm During Epididymal Transit. AB - Mammalian spermatozoa acquire fertilizing potential as they undergo a series of changes during epididymal transit. One major facet of such is the alterations in the sperm glycome. Modifications of the sialic acid content within glycan moieties are known to regulate epitope presentation and cellular adhesion and signaling, all of which may be critical for sperm to successfully reach and fertilize the egg. To date, there is paucity of information regarding the sialic acid changes that occur on spermatozoa during epididymal transit. Therefore, the aim of this study was to identify N-linked sialylated glycoproteins in rat epididymal sperm and investigate whether they are regulated during epididymal transit. Sialylated glycopeptides from caput, corpus, and cauda spermatozoa were enriched using titanium dioxide beads. Bound N-linked glycopeptides were released by enzymatic deglycosylation using PNGase F and then analyzed by liquid chromatography tandem-mass spectrometry. A total of 92 unique N-linked sialylated glycopeptides were identified from 65 different proteins. These included members of the disintegrin and metalloproteinase domain-containing protein family (ADAM), Basigin, and Testis-expressed protein 101 (TEX101). Remarkably, label-free quantification showed that more than half of these peptides (48/92) were regulated during epididymal transit. Of interest, the protein TEX101 exhibited PNGase F-resistant deglycosylation under the conditions used in this study. The results from this study showed that changes in the N-linked sialoglycoprotein profile is a major hallmark of sperm maturation in rats. PMID- 26962119 TI - Dietary-Induced Chronic Hypothyroidism Negatively Affects Rat Follicular Development and Ovulation Rate and Is Associated with Oxidative Stress. AB - The long-term effects of chronic hypothyroidism on ovarian follicular development in adulthood are not well known. Using a rat model of chronic diet-induced hypothyroidism initiated in the fetal period, we investigated the effects of prolonged reduced plasma thyroid hormone concentrations on the ovarian follicular reserve and ovulation rate in prepubertal (12-day-old) and adult (64-day-old and 120-day-old) rats. Besides, antioxidant gene expression, mitochondrial density and the occurrence of oxidative stress were analyzed. Our results show that continuous hypothyroidism results in lower preantral and antral follicle numbers in adulthood, accompanied by a higher percentage of atretic follicles, when compared to euthyroid age-matched controls. Not surprisingly, ovulation rate was lower in the hypothyroid rats. At the age of 120 days, the mRNA and protein content of superoxide dismutase 1 (SOD1) were significantly increased while catalase (CAT) mRNA and protein content was significantly decreased, suggesting a disturbed antioxidant defense capacity of ovarian cells in the hypothyroid animals. This was supported by a significant reduction in the expression of peroxiredoxin 3 ( ITALIC! Prdx3), thioredoxin reductase 1 ( ITALIC! Txnrd1), and uncoupling protein 2 ( ITALIC! Ucp2) and a downward trend in glutathione peroxidase 3 ( ITALIC! Gpx3) and glutathione S-transferase mu 2 ( ITALIC! Gstm2) expression. These changes in gene expression were likely responsible for the increased immunostaining of the oxidative stress marker 4-hydroxynonenal. Together these results suggest that chronic hypothyroidism initiated in the fetal/neonatal period results in a decreased ovulation rate associated with a disturbance of the antioxidant defense system in the ovary. PMID- 26962117 TI - Deletion of Arid1a in Reproductive Tract Mesenchymal Cells Reduces Fertility in Female Mice. AB - Women with endometriosis can suffer from decreased fecundity or complete infertility via abnormal oocyte function or impaired placental-uterine interactions required for normal pregnancy establishment and maintenance. Although AT-rich interactive domain 1A (SWI-like) (ARID1A) is a putative tumor suppressor in human endometrial cancers and endometriosis-associated ovarian cancers, little is known about its role in normal uterine function. To study the potential function of ARID1A in the female reproductive tract, we generated mice with a conditional knockout of Arid1a using anti-Mullerian hormone receptor 2-Cre Female Arid1a conditional knockout mice exhibited a progressive decrease in number of pups per litter, with a precipitous decline after the second litter. We observed no tumors in virgin mice, although one knockout mouse developed a uterine tumor after pregnancy. Unstimulated virgin female knockout mice showed normal oviductal, ovarian, and uterine histology. Uteri of Arid1a knockout mice showed a normal decidualization response and appropriate responses to estradiol and progesterone stimulation. In vitro studies using primary cultures of human endometrial stromal fibroblasts revealed that small interfering RNA knockdown of ARID1A did not affect decidualization in vitro. Timed pregnancy studies revealed the significant resorption of embryos at Embryonic Day 16.5 in knockout mice in the third pregnancy. In addition to evidence of implantation site hemorrhage, pregnant Arid1a knockout mice showed abnormal placental morphology. These results suggest that Arid1a supports successful pregnancy through its role in placental function. PMID- 26962121 TI - Dibutyl Phthalate Inhibits the Effects of Follicle-Stimulating Hormone on Rat Granulosa Cells Through Down-Regulation of Follicle-Stimulating Hormone Receptor. AB - Dibutyl phthalate (DBP) is used worldwide in solvents and plasticizers. The cytotoxicity and potential tumorigenic effect of DBP have been reported. DBP has also been shown to impact reproductive function. In this study, to further evaluate the effects of DBP on granulosa cells (GCs), we treated rat GCs in vitro with DBP before evaluation of the biological alterations of these GCs. We found that DBP did not induce significant GC death at the tested concentrations. However, follicle-stimulating hormone (FSH)-induced KIT ligand (KITLG) expression in GCs was significantly reduced at both mRNA and protein levels by DBP treatment in a dose-dependent manner. The down-regulation of KITLG was due to the down regulation of expression of FSH receptor (FSHR) in GCs. Down-regulation of FSHR impaired FSH-induced intracellular signaling in GCs, demonstrated by decreased phosphorylation of AKT and mechanistic target of rapamycin (mTOR). Furthermore, DBP treatment also reduced FSH-induced expression of hypoxia-inducible factor 1 alpha (HIF1A), which is an important signaling component for KITLG expression. Other FSH-induced biological effects, such as production of estradiol and progesterone, as well as GC proliferation, were also suppressed by DBP. Therefore, our study discovered a unique mechanism underlying the toxicity of DBP on GCs. These findings may initiate the development of novel therapeutic interventions for DBP-induced damage to GCs. PMID- 26962122 TI - Evaluation of care access and hypertension control in a community health worker driven non-communicable disease programme in rural Uganda: the chronic disease in the community project. AB - The burden of non-communicable diseases continues to grow throughout the developing world. Health systems in low- and middle-income regions face significant human resource shortages, which limit the ability to meet the growing need for non-communicable disease care. Specially trained community health workers may be useful in filling that provider gap. This study aimed to evaluate consistency of access to care and quality of hypertension control in a community health worker led, decentralized non-communicable disease programme operating in rural Uganda. Days between clinical evaluations and average systolic blood pressure were described for programme patients; these markers were also compared with patients seen in a central, hospital-based clinic. In 2013, community health worker programme patients were seen every 35.6 days and significantly more often than clinic patients (50.8 days, P < 0.001). From October to December 2013, hypertensive patients in the community health worker programme had a mean systolic blood pressure of 147.8 mmHg. This was lower than the average systolic pressure of clinic patients (156.7 mmHg, P < 0.001). Programme patients' blood pressures were also more frequently measured at below goal than clinic patients (71.2 vs 59.8%, P = 0.048). Decentralizing care and shifting significant clinical management responsibilities to community health workers improved consistency of access to care and did not come with a demonstrable cost in quality of hypertension control. Community health workers may have the potential to bridge the provider gap in low-income nations, providing expanded non-communicable disease care. PMID- 26962123 TI - Performance of retail pharmacies in low- and middle-income Asian settings: a systematic review. AB - In low- and middle-income countries (LMIC) in Asia, pharmacies are often patients' first point of contact with the health care system and their preferred channel for purchasing medicines. Unfortunately, pharmacy practice in these settings has been characterized by deficient knowledge and inappropriate treatment. This paper systematically reviews both the performance of all types of pharmacies and drug stores across Asia's LMIC, and the determinants of poor practice, in order to reflect on how this could best be addressed. Poor pharmacy practice in Asia appears to have persisted over the past 30 years. We identify a set of inadequacies that occur at key moments throughout the pharmacy encounter, including: insufficient history taking; lack of referral of patients who require medical attention; illegal sale of a wide range of prescription only medicines without a prescription; sale of medicines that are either clinically inappropriate and/or in doses that are outside of the therapeutic range; sale of incomplete courses of antibiotics; and limited provision of information and counselling. In terms of determinants of poor practice, first knowledge was found to be necessary but not sufficient to ensure correct management of patients presenting at the pharmacy. This is evidenced by large discrepancies between stated and actual practice; little difference in the treatment behaviour of less and more qualified personnel and the failure of training programmes to improve practice to a satisfactory level. Second, we identified a number of profit maximizing strategies employed by pharmacy staff that can be linked to poor practices. Finally, whilst the research is relatively sparse, the regulatory environment appears to play an important role in shaping behaviour. Future efforts to improve the situation may yield more success than historical attempts, which have tended to concentrate on education, if they address the profit incentives faced by pharmacy personnel and the regulatory system. PMID- 26962124 TI - A dynamic intron retention program in the mammalian megakaryocyte and erythrocyte lineages. AB - Intron retention (IR) is a form of alternative splicing that can impact mRNA levels through nonsense-mediated decay or by nuclear mRNA detention. A complex, dynamic IR pattern has been described in maturing mammalian granulocytes, but it is unknown whether IR occurs broadly in other hematopoietic lineages. We globally assessed IR in primary maturing mammalian erythroid and megakaryocyte (MK) lineages as well as their common progenitor cells (MEPs). Both lineages exhibit an extensive differential IR program involving hundreds of introns and genes with an overwhelming loss of IR in erythroid cells and MKs compared to MEPs. Moreover, complex IR patterns were seen throughout murine erythroid maturation. Similarly complex patterns were observed in human erythroid differentiation, but not involving the murine orthologous introns or genes. Despite the common origin of erythroid cells and MKs, and overlapping gene expression patterns, the MK IR program is entirely distinct from that of the erythroid lineage with regards to introns, genes, and affected gene ontologies. Importantly, our results suggest that IR serves to broadly regulate mRNA levels. These findings highlight the importance of this understudied form of alternative splicing in gene regulation and provide a useful resource for studies on gene expression in the MK and erythroid lineages. PMID- 26962125 TI - Impact of Improved Glycemic Control on Cardiac Function in Type 2 Diabetes Mellitus. AB - BACKGROUND: Patients with type 2 diabetes mellitus are at risk of heart failure. Specific therapeutic interventions for diabetic heart disease are still elusive. We aimed to examine the impact of improved glycemic control on left ventricular (LV) function in these patients. METHODS AND RESULTS: A total of 105 subjects with type 2 diabetes mellitus (aged 54+/-10 years) and poor glycemic control received optimization of treatment for blood glucose, blood pressure, and cholesterol to recommended targets for 12 months. LV systolic and diastolic function, measured by LV global longitudinal strain (GLS) and septal e' velocities, were compared before and after optimization. At baseline, patients had impaired LV systolic (GLS -14.9+/-3.2%) and diastolic function (e' 6.2+/-1.7 cm/s). After 12 months, glycated hemoglobin (HbA1c) decreased from 10.3+/-2.4% to 8.3+/-2.0%, which was associated with significant relative improvement in GLS of 21% and septal e' of 24%. There was a progressively greater improvement in GLS as patients achieved a lower final HbA1c. Patients achieving an HbA1c of <7.0% had the largest improvement. The 15 patients whose HbA1c worsened experienced a decline in GLS. Patients who improved their HbA1c by >=1.0% had a significantly higher relative improvement in e' than those who did not (32% versus 8%; P=0.003). Baseline GLS, decrease in body mass index, and treatment with metformin were additional independent predictors of GLS improvement. CONCLUSIONS: Improvements in glycemic control over a 12-month period led to improvements in LV systolic and diastolic function. This may have long-term prognostic implications. PMID- 26962126 TI - Right Ventricular Volumes and Systolic Function by Cardiac Magnetic Resonance and the Impact of Sex, Age, and Obesity in a Longitudinally Followed Cohort Free of Pulmonary and Cardiovascular Disease: The Framingham Heart Study. AB - BACKGROUND: Cardiac magnetic resonance is uniquely well suited for noninvasive imaging of the right ventricle. We sought to define normal cardiac magnetic resonance reference values and to identify the main determinants of right ventricular (RV) volumes and systolic function using a modern imaging sequence in a community-dwelling, longitudinally followed cohort free of clinical cardiovascular and pulmonary disease. METHODS AND RESULTS: The Framingham Heart Study Offspring cohort has been followed since 1971. We scanned 1794 Offspring cohort members using steady-state free precession cardiac magnetic resonance and identified a reference group of 1336 adults (64+/-9 years, 576 men) free of prevalent cardiovascular and pulmonary disease. RV trabeculations and papillary muscles were considered cavity volume. Men had greater RV volumes and cardiac output before and after indexation to body size (all P<0.001). Women had higher RV ejection fraction than men (68+/-6% versus 64+/-7%; P<0.0001). RV volumes and cardiac output decreased with advancing age. There was an increase in raw and height-indexed RV measurements with increasing body mass index, but this trend was weakly inverted after indexation of RV volumes to body surface area. Sex, age, height, body mass index, and heart rate account for most of the variability in RV volumes and function in this community-dwelling population. CONCLUSIONS: We report sex-specific normative values for RV measurements among principally middle aged and older adults. RV ejection fraction is greater in women. RV volumes increase with body size, are greater in men, and are smaller in older people. Body surface area seems to be appropriate for indexation of cardiac magnetic resonance-derived RV volumes. PMID- 26962127 TI - New Cardiac Magnetic Resonance Reference Ranges for Right Ventricular Volumes and Systolic Function: What Is New and Why Should We Care? PMID- 26962128 TI - Glycemic Control and Heart Failure: Separating the Contributors to Left Ventricular Dysfunction. PMID- 26962129 TI - Company is blamed for early halt of trial into obesity treatment. PMID- 26962130 TI - The anticipated and the lived experience of home and in-centre haemodialysis: Is there a disconnect? AB - This qualitative study aimed to explore home haemodialysis and in-centre haemodialysis patients' experience, to illuminate barriers and facilitators in the uptake and maintenance of home haemodialysis. Thirty-two semi-structured interviews with patients receiving home haemodialysis or in-centre haemodialysis were analysed using framework analysis. Four themes emerged: 'perceptions of self'; 'impact of haemodialysis on family'; 'perceived advantages and disadvantages of home haemodialysis and in-centre haemodialysis' and 'practical issues and negotiating haemodialysis'. The lived experience of home haemodialysis was in contrast to the lived experience of in-centre haemodialysis and to the anticipated experience of home haemodialysis, highlighting patient factors that contributed to under-usage of home haemodialysis. PMID- 26962132 TI - 'It might hurt, but still it's good': People with rheumatoid arthritis beliefs and expectations about physical activity interventions. AB - Many people who have rheumatoid arthritis report low levels of physical activity. We conducted 17 interviews with people who have rheumatoid arthritis to gain insight into how they view physical activity and to explore how their levels of activity may be increased. Interviews were transcribed verbatim and analysed using thematic analysis. Four main themes were generated: being active, barriers and facilitators, information and advice, and supporting physical activity. A lack of information about being active fostered negative emotions limiting physical activity participation. Improved provision of physical activity advice is warranted to promote physical activity in people who have rheumatoid arthritis. PMID- 26962131 TI - Patient and partner dispositional optimism as a long-term predictor of illness representations in autoimmune diseases. AB - We examined whether the dispositional optimism of patients suffering from an autoimmune disease as well as of their partners can predict, at a dyadic level, their representations of illness consequences, and personal and treatment control, assessed 1 year later. Patient optimism predicted several patient and partner illness representations. Partner optimism was unrelated to own or patient illness representations. Results highlight the strong long-term predictive power of patient optimism and underline the importance of the interpersonal function of personality traits. At the same time, study findings indicate that the dyadic effects of optimism are complex and probably conditional on several factors. PMID- 26962133 TI - Impact of Spironolactone on Longitudinal Changes in Health-Related Quality of Life in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial. AB - BACKGROUND: Heart failure (HF) with preserved ejection fraction patients have equally impaired health-related quality of life (HRQL) compared with those with HF with reduced ejection fraction, but limited studies have evaluated the impact of therapies on changes in HRQL. METHODS AND RESULTS: Patients >=50 years of age, with symptomatic HF and left ventricular ejection fraction >=45%, were enrolled in Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) and randomized to spironolactone or placebo. Patients completed the Kansas City Cardiomyopathy Questionnaire (KCCQ), which was the primary HRQL instrument, and EQ5D visual analog scale at baseline, 4 months, 12 months, and annually thereafter. McMaster Overall Treatment Evaluation was assessed at 4 and 12 months to assess global change scores. Change scores (+SD) were calculated to determine between-group differences, and multivariable repeated-measures models were created to identify other factors associated with change scores. Paired KCCQ data were available for 91.7% of 3445 TOPCAT patients. By 4 months, the mean change in KCCQ was 7.7+/-16 and mean change in EQ5D visual analog scale was 4.7+/-16. Adjusted mean changes in KCCQ for the spironolactone group were significantly better than those for the placebo group at 4-month (1.54 better; P=0.002), 12-month (1.35 better; P=0.02), and 36-month (1.86 better; P=0.02) visits. No between-group differences in EQ5D visual analog scale change scores or McMaster Overall Treatment Evaluation were noted. Older age, obesity, current smoking, New York Heart Association class III/IV, and comorbid illnesses were associated with declines in KCCQ scores. Use of spironolactone was an independent predictor of improved KCCQ scores. CONCLUSIONS: In symptomatic HF with preserved ejection fraction patients, use of spironolactone was associated with an improvement in HF-specific HRQL. Several modifiable risk factors were associated with HRQL deterioration. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302. PMID- 26962134 TI - Oceanographic drivers and mistiming processes shape breeding success in a seabird. AB - Understanding the processes driving seabirds' reproductive performance through trophic interactions requires the identification of seasonal pulses in marine productivity. We investigated the sequence of environmental and biological processes driving the reproductive phenology and performance of the storm petrel (Hydrobates pelagicus) in the Western Mediterranean. The enhanced light and nutrient availability at the onset of water stratification (late winter/early spring) resulted in annual consecutive peaks in relative abundance of phytoplankton, zooplankton and ichthyoplankton. The high energy-demanding period of egg production and chick rearing coincided with these successive pulses in food availability, pointing to a phenological adjustment to such seasonal patterns with important fitness consequences. Indeed, delayed reproduction with respect to the onset of water stratification resulted in both hatching and breeding failure. This pattern was observed at the population level, but also when confounding factors such as individuals' age or experience were also accounted for. We provide the first evidence of oceanographic drivers leading to the optimal time-window for reproduction in an inshore seabird at southern European latitudes, along with a suitable framework for assessing the impact of environmentally driven changes in marine productivity patterns in seabird performance. PMID- 26962136 TI - One crop breeding cycle from starvation? How engineering crop photosynthesis for rising CO2 and temperature could be one important route to alleviation. AB - Global climate change is likely to severely impact human food production. This comes at a time when predicted demand for primary foodstuffs by a growing human population and changing global diets is already outpacing a stagnating annual rate of increase in crop productivity. Additionally, the time required by crop breeding and bioengineering to release improved varieties to farmers is substantial, meaning that any crop improvements needed to mitigate food shortages in the 2040s would need to start now. In this perspective, the rationale for improvements in photosynthetic efficiency as a breeding objective for higher yields is outlined. Subsequently, using simple simulation models it is shown how predicted changes in temperature and atmospheric [CO2] affect leaf photosynthetic rates. The chloroplast accounts for the majority of leaf nitrogen in crops. Within the chloroplast about 25% of nitrogen is invested in the carboxylase, Rubisco, which catalyses the first step of CO2 assimilation. Most of the remaining nitrogen is invested in the apparatus to drive carbohydrate synthesis and regenerate ribulose-1:5-bisphosphate (RuBP), the CO2-acceptor molecule at Rubisco. At preindustrial [CO2], investment in these two aspects may have been balanced resulting in co-limitation. At today's [CO2], there appears to be over investment in Rubisco, and despite the counter-active effects of rising temperature and [CO2], this imbalance is predicted to worsen with global climate change. By breeding or engineering restored optimality under future conditions increased productivity could be achieved in both tropical and temperate environments without additional nitrogen fertilizer. Given the magnitude of the potential shortfall, better storage conditions, improved crop management and better crop varieties will all be needed. With the short time-scale at which food demand is expected to outpace supplies, all available technologies to improve crop varieties, from classical crop breeding to crop genetic engineering should be employed. This will require vastly increased public and private investment to support translation of first discovery in laboratories to replicated field trials, and an urgent re-evaluation of regulation of crop genetic engineering. PMID- 26962137 TI - Environmental drivers of crocodyliform extinction across the Jurassic/Cretaceous transition. AB - Crocodyliforms have a much richer evolutionary history than represented by their extant descendants, including several independent marine and terrestrial radiations during the Mesozoic. However, heterogeneous sampling of their fossil record has obscured their macroevolutionary dynamics, and obfuscated attempts to reconcile external drivers of these patterns. Here, we present a comprehensive analysis of crocodyliform biodiversity through the Jurassic/Cretaceous (J/K) transition using subsampling and phylogenetic approaches and apply maximum likelihood methods to fit models of extrinsic variables to assess what mediated these patterns. A combination of fluctuations in sea-level and episodic perturbations to the carbon and sulfur cycles was primarily responsible for both a marine and non-marine crocodyliform biodiversity decline through the J/K boundary, primarily documented in Europe. This was tracked by high extinction rates at the boundary and suppressed origination rates throughout the Early Cretaceous. The diversification of Eusuchia and Notosuchia likely emanated from the easing of ecological pressure resulting from the biodiversity decline, which also culminated in the extinction of the marine thalattosuchians in the late Early Cretaceous. Through application of rigorous techniques for estimating biodiversity, our results demonstrate that it is possible to tease apart the complex array of controls on diversification patterns in major archosaur clades. PMID- 26962135 TI - How habitat-modifying organisms structure the food web of two coastal ecosystems. AB - The diversity and structure of ecosystems has been found to depend both on trophic interactions in food webs and on other species interactions such as habitat modification and mutualism that form non-trophic interaction networks. However, quantification of the dependencies between these two main interaction networks has remained elusive. In this study, we assessed how habitat-modifying organisms affect basic food web properties by conducting in-depth empirical investigations of two ecosystems: North American temperate fringing marshes and West African tropical seagrass meadows. Results reveal that habitat-modifying species, through non-trophic facilitation rather than their trophic role, enhance species richness across multiple trophic levels, increase the number of interactions per species (link density), but decrease the realized fraction of all possible links within the food web (connectance). Compared to the trophic role of the most highly connected species, we found this non-trophic effects to be more important for species richness and of more or similar importance for link density and connectance. Our findings demonstrate that food webs can be fundamentally shaped by interactions outside the trophic network, yet intrinsic to the species participating in it. Better integration of non-trophic interactions in food web analyses may therefore strongly contribute to their explanatory and predictive capacity. PMID- 26962138 TI - Host persistence or extinction from emerging infectious disease: insights from white-nose syndrome in endemic and invading regions. AB - Predicting species' fates following the introduction of a novel pathogen is a significant and growing problem in conservation. Comparing disease dynamics between introduced and endemic regions can offer insight into which naive hosts will persist or go extinct, with disease acting as a filter on host communities. We examined four hypothesized mechanisms for host-pathogen persistence by comparing host infection patterns and environmental reservoirs for Pseudogymnoascus destructans (the causative agent of white-nose syndrome) in Asia, an endemic region, and North America, where the pathogen has recently invaded. Although colony sizes of bats and hibernacula temperatures were very similar, both infection prevalence and fungal loads were much lower on bats and in the environment in Asia than North America. These results indicate that transmission intensity and pathogen growth are lower in Asia, likely due to higher host resistance to pathogen growth in this endemic region, and not due to host tolerance, lower transmission due to smaller populations, or lower environmentally driven pathogen growth rate. Disease filtering also appears to be favouring initially resistant species in North America. More broadly, determining the mechanisms allowing species persistence in endemic regions can help identify species at greater risk of extinction in introduced regions, and determine the consequences for disease dynamics and host-pathogen coevolution. PMID- 26962140 TI - Histology and affinity of anaspids, and the early evolution of the vertebrate dermal skeleton. AB - The assembly of the gnathostome bodyplan constitutes a formative episode in vertebrate evolutionary history, an interval in which the mineralized skeleton and its canonical suite of cell and tissue types originated. Fossil jawless fishes, assigned to the gnathostome stem-lineage, provide an unparalleled insight into the origin and evolution of the skeleton, hindered only by uncertainty over the phylogenetic position and evolutionary significance of key clades. Chief among these are the jawless anaspids, whose skeletal composition, a rich source of phylogenetic information, is poorly characterized. Here we survey the histology of representatives spanning anaspid diversity and infer their generalized skeletal architecture. The anaspid dermal skeleton is composed of odontodes comprising spheritic dentine and enameloid, overlying a basal layer of acellular parallel fibre bone containing an extensive shallow canal network. A recoded and revised phylogenetic analysis using equal and implied weights parsimony resolves anaspids as monophyletic, nested among stem-gnathostomes. Our results suggest the anaspid dermal skeleton is a degenerate derivative of a histologically more complex ancestral vertebrate skeleton, rather than reflecting primitive simplicity. Hypotheses that anaspids are ancestral skeletonizing lampreys, or a derived lineage of jawless vertebrates with paired fins, are rejected. PMID- 26962139 TI - Substituting mouse transcription factor Pou4f2 with a sea urchin orthologue restores retinal ganglion cell development. AB - Pou domain transcription factor Pou4f2 is essential for the development of retinal ganglion cells (RGCs) in the vertebrate retina. A distant orthologue of Pou4f2 exists in the genome of the sea urchin (class Echinoidea) Strongylocentrotus purpuratus (SpPou4f1/2), yet the photosensory structure of sea urchins is strikingly different from that of the mammalian retina. Sea urchins have no obvious eyes, but have photoreceptors clustered around their tube feet disc. The mechanisms that are associated with the development and function of photoreception in sea urchins are largely unexplored. As an initial approach to better understand the sea urchin photosensory structure and relate it to the mammalian retina, we asked whether SpPou4f1/2 could support RGC development in the absence of Pou4f2. To answer this question, we replaced genomic Pou4f2 with an SpPou4f1/2 cDNA. In Pou4f2-null mice, retinas expressing SpPou4f1/2 were outwardly identical to those of wild-type mice. SpPou4f1/2 retinas exhibited dark adapted electroretinogram scotopic threshold responses, indicating functionally active RGCs. During retinal development, SpPou4f1/2 activated RGC-specific genes and in S. purpuratus, SpPou4f2 was expressed in photoreceptor cells of tube feet in a pattern distinct from Opsin4 and Pax6. Our results suggest that SpPou4f1/2 and Pou4f2 share conserved components of a gene network for photosensory development and they maintain their conserved intrinsic functions despite vast morphological differences in mouse and sea urchin photosensory structures. PMID- 26962141 TI - Trophic assimilation efficiency markedly increases at higher trophic levels in four-level host-parasitoid food chain. AB - Trophic assimilation efficiency (conversion of resource biomass into consumer biomass) is thought to be a limiting factor for food chain length in natural communities. In host-parasitoid systems, which account for the majority of terrestrial consumer interactions, a high trophic assimilation efficiency may be expected at higher trophic levels because of the close match of resource composition of host tissue and the consumer's resource requirements, which would allow for longer food chains. We measured efficiency of biomass transfer along an aphid-primary-secondary-tertiary parasitoid food chain and used stable isotope analysis to confirm trophic levels. We show high efficiency in biomass transfer along the food chain. From the third to the fourth trophic level, the proportion of host biomass transferred was 45%, 65% and 73%, respectively, for three secondary parasitoid species. For two parasitoid species that can act at the fourth and fifth trophic levels, we show markedly increased trophic assimilation efficiencies at the higher trophic level, which increased from 45 to 63% and 73 to 93%, respectively. In common with other food chains, delta(15)N increased with trophic level, with trophic discrimination factors (Delta(15)N) 1.34 and 1.490/00 from primary parasitoids to endoparasitic and ectoparasitic secondary parasitoids, respectively, and 0.780/00 from secondary to tertiary parasitoids. Owing to the extraordinarily high efficiency of hyperparasitoids, cryptic higher trophic levels may exist in host-parasitoid communities, which could alter our understanding of the dynamics and drivers of community structure of these important systems. PMID- 26962143 TI - Controlled comparison of species- and community-level models across novel climates and communities. AB - Species distribution models (SDMs) assume species exist in isolation and do not influence one another's distributions, thus potentially limiting their ability to predict biodiversity patterns. Community-level models (CLMs) capitalize on species co-occurrences to fit shared environmental responses of species and communities, and therefore may result in more robust and transferable models. Here, we conduct a controlled comparison of five paired SDMs and CLMs across changing climates, using palaeoclimatic simulations and fossil-pollen records of eastern North America for the past 21 000 years. Both SDMs and CLMs performed poorly when projected to time periods that are temporally distant and climatically dissimilar from those in which they were fit; however, CLMs generally outperformed SDMs in these instances, especially when models were fit with sparse calibration datasets. Additionally, CLMs did not over-fit training data, unlike SDMs. The expected emergence of novel climates presents a major forecasting challenge for all models, but CLMs may better rise to this challenge by borrowing information from co-occurring taxa. PMID- 26962142 TI - Ecological genomics of mutualism decline in nitrogen-fixing bacteria. AB - Anthropogenic changes can influence mutualism evolution; however, the genomic regions underpinning mutualism that are most affected by environmental change are generally unknown, even in well-studied model mutualisms like the interaction between legumes and their nitrogen (N)-fixing rhizobia. Such genomic information can shed light on the agents and targets of selection maintaining cooperation in nature. We recently demonstrated that N-fertilization has caused an evolutionary decline in mutualistic partner quality in the rhizobia that form symbiosis with clover. Here, population genomic analyses of N-fertilized versus control rhizobium populations indicate that evolutionary differentiation at a key symbiosis gene region on the symbiotic plasmid (pSym) contributes to partner quality decline. Moreover, patterns of genetic variation at selected loci were consistent with recent positive selection within N-fertilized environments, suggesting that N-rich environments might select for less beneficial rhizobia. By studying the molecular population genomics of a natural bacterial population within a long-term ecological field experiment, we find that: (i) the N environment is indeed a potent selective force mediating mutualism evolution in this symbiosis, (ii) natural variation in rhizobium partner quality is mediated in part by key symbiosis genes on the symbiotic plasmid, and (iii) differentiation at selected genes occurred in the context of otherwise recombining genomes, resembling eukaryotic models of adaptation. PMID- 26962144 TI - Selection for brain size impairs innate, but not adaptive immune responses. AB - Both the brain and the immune system are energetically demanding organs, and when natural selection favours increased investment into one, then the size or performance of the other should be reduced. While comparative analyses have attempted to test this potential evolutionary trade-off, the results remain inconclusive. To test this hypothesis, we compared the tissue graft rejection (an assay for measuring innate and acquired immune responses) in guppies (Poecilia reticulata) artificially selected for large and small relative brain size. Individual scales were transplanted between pairs of fish, creating reciprocal allografts, and the rejection reaction was scored over 8 days (before acquired immunity develops). Acquired immune responses were tested two weeks later, when the same pairs of fish received a second set of allografts and were scored again. Compared with large-brained animals, small-brained animals of both sexes mounted a significantly stronger rejection response to the first allograft. The rejection response to the second set of allografts did not differ between large- and small brained fish. Our results show that selection for large brain size reduced innate immune responses to an allograft, which supports the hypothesis that there is a selective trade-off between investing into brain size and innate immunity. PMID- 26962147 TI - Pre-eclampsia is linked to small increase in risk of cardiomyopathy in longer term. PMID- 26962145 TI - Matching loci surveyed to questions asked in phylogeography. AB - Although mitochondrial DNA (mtDNA) has long been used for assessing genetic variation within and between populations, its workhorse role in phylogeography has been criticized owing to its single-locus nature. The only choice for testing mtDNA results is to survey nuclear loci, which brings into contrast the difference in locus effective size and coalescence times. Thus, it remains unclear how erroneous mtDNA-based estimates of species history might be, especially for evolutionary events in the recent past. To test the robustness of mtDNA and nuclear sequences in phylogeography, we provide one of the largest paired comparisons of summary statistics and demographic parameters estimated from mitochondrial, five Z-linked and 10 autosomal genes of 30 avian species co distributed in the Caucasus and Europe. The results suggest that mtDNA is robust in estimating inter-population divergence but not in intra-population diversity, which is sensitive to population size change. Here, we provide empirical evidence showing that mtDNA was more likely to detect population divergence than any other single locus owing to its smaller Ne and thus faster coalescent time. Therefore, at least in birds, numerous studies that have based their inferences of phylogeographic patterns solely on mtDNA should not be readily dismissed. PMID- 26962148 TI - PATIENT EXPOSURE OPTIMISATION THROUGH TASK-BASED ASSESSMENT OF A NEW MODEL-BASED ITERATIVE RECONSTRUCTION TECHNIQUE. AB - The goal of the present work was to report and investigate the performances of a new iterative reconstruction algorithm, using a model observer. For that, a dedicated low-contrast phantom containing different targets was scanned at four volume computed tomography dose index (CTDIvol) levels on a Siemens SOMATOM Force computed tomography (CT). The acquired images were reconstructed using the ADMIRE algorithm and were then assessed by three human observers who performed alternative forced choice experiments. Next, a channelised hotelling observer model was applied on the same set of images. The comparison between the two was performed using the percentage correct as a figure of merit. The results indicated a strong agreement between human and model observer as well as an improvement in the low-contrast detection when switching from an ADMIRE strength of 1-3. Good results were also observed even in situations where the target was hard to detect, suggesting that patient dose could be further reduced and optimised. PMID- 26962146 TI - Defining individual size in the model filamentous fungus Neurospora crassa. AB - It is challenging to apply the tenets of individuality to filamentous fungi: a fungal mycelium can contain millions of genetically diverse but totipotent nuclei, each capable of founding new mycelia. Moreover, a single mycelium can potentially stretch over kilometres, and it is unlikely that its distant parts share resources or have the same fitness. Here, we directly measure how a single mycelium of the model ascomycete Neurospora crassa is patterned into reproductive units (RUs), meaning subpopulations of nuclei that propagate together as spores, and function as reproductive individuals. The density of RUs is sensitive to the geometry of growth; we detected 50-fold smaller RUs when mycelia had expanding frontiers than when they were constrained to grow in one direction only. RUs fragmented further when the mycelial network was perturbed. In mycelia with expanding frontiers, RU composition was strongly influenced by the distribution of genotypes early in development. Our results provide a concept of fungal individuality that is directly connected to reproductive potential, and therefore to theories of how fungal individuals adapt and evolve over time. Our data show that the size of reproductive individuals is a dynamic and environment-dependent property, even within apparently totally connected fungal mycelia. PMID- 26962149 TI - Darzi calls for overhaul of safety incident reporting. PMID- 26962150 TI - A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy. AB - Spinal and bulbar muscular atrophy (SBMA, also known as Kennedy's disease) is one of nine neurodegenerative disorders that are caused by expansion of polyglutamine encoding CAG repeats. Intracellular accumulation of abnormal proteins in these diseases, a pathological hallmark, is associated with defects in protein homeostasis. Enhancement of the cellular proteostasis capacity with small molecules has therefore emerged as a promising approach to treatment. Here, we characterize a novel curcumin analog, ASC-JM17, as an activator of central pathways controlling protein folding, degradation and oxidative stress resistance. ASC-JM17 acts on Nrf1, Nrf2 and Hsf1 to increase the expression of proteasome subunits, antioxidant enzymes and molecular chaperones. We show that ASC-JM17 ameliorates toxicity of the mutant androgen receptor (AR) responsible for SBMA in cell, fly and mouse models. Knockdown of the Drosophila Nrf1 and Nrf2 ortholog cap 'n' collar isoform-C, but not Hsf1, blocks the protective effect of ASC-JM17 on mutant AR-induced eye degeneration in flies. Our observations indicate that activation of the Nrf1/Nrf2 pathway is a viable option for pharmacological intervention in SBMA and potentially other polyglutamine diseases. PMID- 26962153 TI - Lost: Young Canadian physician-scientists need a map. AB - The termination of dedicated funding for integrated MD-PhD trainees has left biomedical researchers to question the future of physician-scientists in Canada. PMID- 26962154 TI - Back to the future: Rethinking global control of tuberculosis. AB - If the ultimate goal of controlling an infectious disease is to interrupt transmission, the current global tuberculosis strategy is not succeeding. PMID- 26962152 TI - Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease. AB - Genome-wide association studies (GWAS) of chronic periodontitis (CP) defined by clinical criteria alone have had modest success to-date. Here, we refine the CP phenotype by supplementing clinical data with biological intermediates of microbial burden (levels of eight periodontal pathogens) and local inflammatory response (gingival crevicular fluid IL-1beta) and derive periodontal complex traits (PCTs) via principal component analysis. PCTs were carried forward to GWAS (~2.5 million markers) to identify PCT-associated loci among 975 European American adult participants of the Dental ARIC study. We sought to validate these findings for CP in the larger ARIC cohort (n = 821 participants with severe CP, 2031-moderate CP, 1914-healthy/mild disease) and an independent German sample including 717 aggressive periodontitis cases and 4210 controls. We identified six PCTs with distinct microbial community/IL-1beta structures, although with overlapping clinical presentations. PCT1 was characterized by a uniformly high pathogen load, whereas PCT3 and PCT5 were dominated by Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, respectively. We detected genome-wide significant signals for PCT1 (CLEC19A, TRA, GGTA2P, TM9SF2, IFI16, RBMS3), PCT4 (HPVC1) and PCT5 (SLC15A4, PKP2, SNRPN). Overall, the highlighted loci included genes associated with immune response and epithelial barrier function. With the exception of associations of BEGAIN with severe and UBE3D with moderate CP, no other loci were associated with CP in ARIC or aggressive periodontitis in the German sample. Although not associated with current clinically determined periodontal disease taxonomies, upon replication and mechanistic validation these candidate loci may highlight dysbiotic microbial community structures and altered inflammatory/immune responses underlying biological sub-types of CP. PMID- 26962151 TI - Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram. AB - The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up. PMID- 26962155 TI - Staphylococcus aureus alpha toxin potentiates opportunistic bacterial lung infections. AB - Broad-spectrum antibiotic use may adversely affect a patient's beneficial microbiome and fuel cross-species spread of drug resistance. Although alternative pathogen-specific approaches are rationally justified, a major concern for this precision medicine strategy is that co-colonizing or co-infecting opportunistic bacteria may still cause serious disease. In a mixed-pathogen lung infection model, we find that the Staphylococcus aureus virulence factor alpha toxin potentiates Gram-negative bacterial proliferation, systemic spread, and lethality by preventing acidification of bacteria-containing macrophage phagosomes, thereby reducing effective killing of both S. aureus and Gram-negative bacteria. Prophylaxis or early treatment with a single alpha toxin neutralizing monoclonal antibody prevented proliferation of co-infecting Gram-negative pathogens and lethality while also promoting S. aureus clearance. These studies suggest that some pathogen-specific, antibody-based approaches may also work to reduce infection risk in patients colonized or co-infected with S. aureus and disparate drug-resistant Gram-negative bacterial opportunists. PMID- 26962156 TI - TarO-specific inhibitors of wall teichoic acid biosynthesis restore beta-lactam efficacy against methicillin-resistant staphylococci. AB - The widespread emergence of methicillin-resistant Staphylococcus aureus (MRSA) has dramatically eroded the efficacy of current beta-lactam antibiotics and created an urgent need for new treatment options. We report an S. aureus phenotypic screening strategy involving chemical suppression of the growth inhibitory consequences of depleting late-stage wall teichoic acid biosynthesis. This enabled us to identify early-stage pathway-specific inhibitors of wall teichoic acid biosynthesis predicted to be chemically synergistic with beta lactams. We demonstrated by genetic and biochemical means that each of the new chemical series discovered, herein named tarocin A and tarocin B, inhibited the first step in wall teichoic acid biosynthesis (TarO). Tarocins do not have intrinsic bioactivity but rather demonstrated potent bactericidal synergy in combination with broad-spectrum beta-lactam antibiotics against diverse clinical isolates of methicillin-resistant staphylococci as well as robust efficacy in a murine infection model of MRSA. Tarocins and other inhibitors of wall teichoic acid biosynthesis may provide a rational strategy to develop Gram-positive bactericidal beta-lactam combination agents active against methicillin-resistant staphylococci. PMID- 26962159 TI - The ASCO Provider Utilization File (ASCO PUF): A Closer Look. PMID- 26962158 TI - Development of a prosaposin-derived therapeutic cyclic peptide that targets ovarian cancer via the tumor microenvironment. AB - The vast majority of ovarian cancer-related deaths are caused by metastatic dissemination of tumor cells, resulting in subsequent organ failure. However, despite our increased understanding of the physiological processes involved in tumor metastasis, there are no clinically approved drugs that have made a major impact in increasing the overall survival of patients with advanced, metastatic ovarian cancer. We identified prosaposin (psap) as a potent inhibitor of tumor metastasis, which acts via stimulation of p53 and the antitumorigenic protein thrombospondin-1 (TSP-1) in bone marrow-derived cells that are recruited to metastatic sites. We report that more than 97% of human serous ovarian tumors tested express CD36, the receptor that mediates the proapoptotic activity of TSP 1. Accordingly, we sought to determine whether a peptide derived from psap would be effective in treating this form of ovarian cancer. To that end, we developed a cyclic peptide with drug-like properties derived from the active sequence in psap. The cyclic psap peptide promoted tumor regression in a patient-derived tumor xenograft model of metastatic ovarian cancer. Thus, we hypothesize that a therapeutic agent based on this psap peptide would have efficacy in treating patients with metastatic ovarian cancer. PMID- 26962160 TI - Chemotherapy for Bone Sarcoma in Adults. AB - The largest studies of chemotherapy for bone sarcomas are in the pediatric population. Although increasing age is often found to be an adverse prognostic factor in these clinical trials, few studies are aimed at assessing regimens specifically in the adult population. Osteosarcoma and Ewing sarcoma have peak incidences in the pediatric and young adult population but also occur in adults. Chondrosarcoma and giant cell tumor of bone are generally found in adults. In this review, we describe the current status of our knowledge about treating adults with cancers of bone origin. We also describe our experience treating patients in the adult Sarcoma Medical Oncology group at The University of Texas MD Anderson Cancer Center. PMID- 26962157 TI - Two-mAb cocktail protects macaques against the Makona variant of Ebola virus. AB - The 2014-2015 Ebola virus (EBOV) outbreak in West Africa highlighted the urgent need for specific therapeutic interventions for infected patients. The human mouse chimeric monoclonal antibody (mAb) cocktail ZMapp, previously shown to be efficacious in EBOV (variant Kikwit) lethally infected nonhuman primates (NHPs) when administration was initiated up to 5 days, was used in some patients during the outbreak. We show that a two-antibody cocktail, MIL77E, is fully protective in NHPs when administered at 50 mg/kg 3 days after challenge with a lethal dose of EBOV variant Makona, the virus responsible for the ongoing 2014-2015 outbreak, whereas a similar formulation of ZMapp protected two of three NHPs. The chimeric MIL77E mAb cocktail is produced in engineered Chinese hamster ovary cells and is based on mAbs c13C6 and c2G4 from ZMapp. The use of only two antibodies in MIL77E opens the door to a pan-ebolavirus cocktail. PMID- 26962161 TI - Contemporary Concerns in Managing Bone Sarcoma. PMID- 26962162 TI - Bones: The Adult Sarcoma Drama. PMID- 26962163 TI - Managing Liposarcomas: Cutting Through the Fat. AB - Liposarcomas are one of the most common of more than 50 histologic subtypes of soft tissue sarcomas that, themselves, are heterogeneous. Liposarcomas fall into four distinct histologic subtypes: atypical lipomatous tumor/well-differentiated liposarcoma, dedifferentiated liposarcoma, myxoid (round cell) liposarcoma, and pleomorphic liposarcoma. Definitive treatment remains surgical resection with negative margins for resectable disease. However, well-differentiated liposarcomas that are large or difficult to operate upon should be followed with close surveillance as long as there is no radiologic concern for a dedifferentiated component. In contrast, first-line chemotherapy with anthracycline with or without ifosfamide, or gemcitabine and docetaxel should be used for inoperable myxoid (round cell) or pleomorphic liposarcomas, which are relatively responsive to chemotherapy. In the second- and third-line setting, myxoid liposarcomas, in particular, seem to be sensitive to trabectedin, which was recently approved by the US Food and Drug Administration (FDA). Eribulin offered a survival benefit when compared with dacarbazine in the third-line setting in liposarcomas (other than the well-differentiated subtype) and is now FDA approved. Recent studies have identified distinct genetic aberrations that not only aid in the diagnosis of liposarcoma subtypes but represent actionable targets. Cyclin-dependent kinase 4 and murine double minute 2 are overexpressed in well-differentiated and dedifferentiated liposarcomas and offer opportunities that are being pursued in clinical trials. It is critical that liposarcomas are not approached by oncologists as one disease entity but rather subclassified into distinct subtypes using histologic and molecular tools before formalizing a treatment plan. PMID- 26962164 TI - Systemic Treatment of Liposarcomas: Light at the End of the Tunnel? PMID- 26962165 TI - New Approaches to Managing Liposarcoma: Will Cold Steel Remain the Only Way to Heal? PMID- 26962166 TI - A Clinician's Approach to Double-Hit Lymphoma: Identification, Evaluation, and Management. AB - Double-hit lymphomas have concurrent rearrangements of CMYC and BCL2 or occasionally BCL6. Although double-hit lymphomas are a part of the mature B-cell lymphoma lineage, they have an aggressive clinical course that is complicated by an extremely poor response to standard therapy for aggressive non-Hodgkin lymphoma. Overall survival is short for many patients with double-hit lymphomas, which reinforces the importance of identifying appropriate therapies for these patients. Fortunately, recent reports have demonstrated improved outcomes with the use of intensive induction therapies. This article discusses the biology, therapeutic considerations, treatment opinions, possible role of autologous stem cell transplant, and need for ongoing clinical trials for this subgroup of patients with lymphoma. PMID- 26962167 TI - Double-Hit Lymphoma: Practicing in a Data-Limited Setting. PMID- 26962168 TI - Optimal Management of Double-Hit Lymphoma. PMID- 26962169 TI - Who Should Be Tested for Double-Hit Lymphoma? PMID- 26962171 TI - Complete Durable Response From Carboplatin and Olaparib in a Heavily Pretreated Triple-Negative Metastatic Breast Cancer With Germline BRCA2 and "BRCAness" Mutations. PMID- 26962170 TI - Oncologists' Selection of Genetic and Molecular Testing in the Evolving Landscape of Stage II Colorectal Cancer. AB - PURPOSE: Little is known about the roles of genetic and molecular testing and Lynch syndrome screening in the formulation of predictive and prognostic assessments for patients with stage II colorectal cancer (CRC). METHODS: From 2012 to 2013, we surveyed medical oncologists in the Cancer Care Outcomes Research and Surveillance Consortium and evaluated oncologists' selection of microsatellite instability (MSI) and/or immunohistochemistry (IHC) for mismatch repair (MMR) proteins, germline testing for MMR genes, BRAF and KRAS mutation analysis, and Oncotype DX in stage II CRC. Physicians were randomly assigned to receive one of three vignettes that varied by strength of CRC family history. We used multivariable logistic regression to identify physician and practice characteristics associated with test selection. RESULTS: Among 327 oncologists, MSI and/or IHC for MMR proteins were most frequently selected (n = 205; 64%), with 82% versus 53% choosing MSI/IHC testing in patients with strong versus no CRC family history, respectively (adjusted odds ratio [OR], 3.87; 95% CI, 2.07 to 7.22). KRAS and Oncotype DX testing were chosen by 24% and 38% of oncologists, respectively. Graduates of non-US and Canadian medical schools and physicians compensated by fee-for-service or on the basis of productivity were more likely to choose KRAS testing versus those receiving salaries not on the basis of productivity (OR, 2.16; 95% CI, 1.17 to 3.99; and OR, 1.94; 95% CI, 1.02 to 3.66, respectively). Fee-for-service or productivity-based salaries were also associated with increased odds of Oncotype DX testing (OR, 2.04; 95% CI, 1.17 to 3.55). CONCLUSION: Among surveyed oncologists, we found undertesting and overtesting related to genetic and molecular testing and Lynch syndrome screening for patients with stage II CRC,highlighting the need for improved implementation, targeted education, and evaluation of organizational and financial arrangements to promote the appropriate use of such tests. PMID- 26962172 TI - Discovery and Characterization of a Novel Small-Molecule Agonist for Medium-Chain Free Fatty Acid Receptor G Protein-Coupled Receptor 84. AB - G protein-coupled receptor 84 (GPR84) is a free fatty acid receptor activated by medium-chain free fatty acids with 9-14 carbons. It is expressed mainly in the immune-related tissues, such as spleen, bone marrow, and peripheral blood leukocytes. GPR84 plays significant roles in inflammatory processes and may represent a novel drug target for the treatment of immune-mediated diseases. However, the lack of potent and specific ligands for GPR84 hindered the study of its functions and the development of potential clinical applications. Here, we report the screen of 160,000 small-molecule compounds with a calcium mobilization assay using a human embryonic kidney 293 cell line stably expressing GPR84 and Galpha16, and the identification of 2-(hexylthio)pyrimidine-4,6-diol (ZQ-16) as a potent and selective agonist of GPR84 with a novel structure. ZQ-16 activates several GPR84-mediated signaling pathways, including calcium mobilization, inhibition of cAMP accumulation, phosphorylation of extracellular signal regulated protein kinase 1/2, receptor desensitization and internalization, and receptor-beta-arrestin interaction. This compound may be a useful tool to study the functions of GPR84 and a potential candidate for further structural optimization. PMID- 26962173 TI - Dietary Protein Requirement of Men >65 Years Old Determined by the Indicator Amino Acid Oxidation Technique Is Higher than the Current Estimated Average Requirement. AB - BACKGROUND: The current estimated average requirement (EAR) and RDA for protein of 0.66 and 0.8 g ? kg-1 ? d-1, respectively, for adults, including older men, are based on nitrogen balance data analyzed by monolinear regression. Recent studies in young men and older women that used the indicator amino acid oxidation (IAAO) technique suggest that those values may be too low. This observation is supported by 2-phase linear crossover analysis of the nitrogen balance data. OBJECTIVE: The main objective of this study was to determine the protein requirement for older men by using the IAAO technique. METHODS: Six men aged >65 y were studied; each individual was tested 7 times with protein intakes ranging from 0.2 to 2.0 g ? kg-1 ? d-1 in random order for a total of 42 studies. The diets provided energy at 1.5 times the resting energy expenditure and were isocaloric. Protein was consumed hourly for 8 h as an amino acid mixture with the composition of egg protein with l-[1-13C]phenylalanine as the indicator amino acid. The group mean protein requirement was determined by applying a mixed effects change-point regression analysis to F13CO2 (label tracer oxidation in breath 13CO2), which identified a breakpoint in F13CO2 in response to graded intakes of protein. RESULTS: The estimated protein requirement and RDA for older men were 0.94 and 1.24 g ? kg-1 ? d-1, respectively, which are not different from values we published using the same method in young men and older women. CONCLUSIONS: The current intake recommendations for older adults for dietary protein of 0.66 g ? kg-1 ? d-1 for the EAR and 0.8 g ? kg-1 ? d-1 for the RDA appear to be underestimated by ~30%. Future longer-term studies should be conducted to validate these results. This trial was registered at clinicaltrials.gov as NCT01948492. PMID- 26962174 TI - Folic Acid Supplementation of Female Mice, with or without Vitamin B-12, before and during Pregnancy and Lactation Programs Adiposity and Vascular Health in Adult Male Offspring. AB - BACKGROUND: The developmental origins of health and disease theory suggest that disturbances in the fetal and early postnatal environment contribute to chronic adulthood diseases, such as type 2 diabetes and cardiovascular disease. Greater adiposity and insulin resistance have been reported in children of women with high erythrocyte folate but poor vitamin B-12 status during pregnancy. The mechanisms underlying this relation are not known. OBJECTIVE: The objective of this study was to investigate the effects of maternal supplemental folic acid, with or without vitamin B-12, on adiposity, glucose homeostasis, and vascular health in adult male offspring mice. METHODS: Female C57BL/6J mice were fed a control diet (M-CON, 2 mg folic acid/kg, 50 MUg vitamin B-12/kg) or a folic acid supplemented diet with [10 mg folic acid/kg, 50 MUg vitamin B-12/kg (SFA+B12)] or without [10 mg folic acid/kg, no vitamin B-12 (SFA-B12)] vitamin B-12 for 6 wk before mating and during pregnancy and lactation. The offspring were weaned onto a control diet (16% energy from fat) or a western diet (45% energy from fat) until 23 wk of age. The effects of maternal diet on adiposity, vascular function, and glucose tolerance were assessed in 6 groups of adult male offspring: control diet-fed M-CON, SFA+B12, and SFA-B12 and western diet-fed M-CON, SFA+B12, and SFA B12. RESULTS: Control and western diet-fed SFA-B12 and SFA+B12 offspring had smaller visceral and subcutaneous adipose tissue than M-CON offspring (P < 0.05). Control SFA-B12 and SFA+B12 offspring had lower serum total adiponectin and vitamin B-12 concentrations and lower NADPH oxidase 2 expression in aorta compared with M-CON offspring (P < 0.05). These effects were not observed in western diet-fed offspring. CONCLUSIONS: Folic acid supplementation of female mice before and during pregnancy and lactation, with or without dietary vitamin B 12, affects adult male offspring adiposity, vascular function, and one-carbon metabolism in those fed a control diet but not a western diet. PMID- 26962175 TI - Early Childhood Nutrition Is Positively Associated with Adolescent Educational Outcomes: Evidence from the Andhra Pradesh Child and Parents Study (APCAPS). AB - BACKGROUND: India's Integrated Child Development Scheme, which provides supplementary nutrition and other public health services to >91 million women and children aged <6 y, is the largest program of its kind in the world. OBJECTIVE: We estimated the long-term associations of maternal and early childhood nutrition provided under the Integrated Child Development Scheme with educational outcomes when the children became adolescents. METHODS: We used longitudinal data from a controlled nutrition trial conducted near the city of Hyderabad, India. From 1987 to 1990, a balanced protein-energy supplement (corn-soya meal, called upma) was offered to pregnant women and children aged <6 y in 15 intervention villages, whereas no supplementation was offered in 14 control villages. Both groups had equal access to other public programs such as immunization and anemia control in pregnancy. Children born during the original trial period were resurveyed (654 intervention and 511 control group children) in 2003-2005. We used propensity score matching methods to correct for estimation bias in our regression models to assess the associations of supplementary nutrition with school enrollment, schooling grades completed, and academic test performance of these adolescents. RESULTS: Children born in intervention villages were 7.8% (95% CI: 0.1%, 15.4%; P < 0.05) more likely to be enrolled in school and completed 0.84 (95% CI: 0.28, 1.39; P < 0.005) more schooling grades than children born in control villages. We found no association between supplementary nutrition and academic performance, as measured by school test scores. CONCLUSION: Offering a nutritional supplement to pregnant women and children <6 y of age during the Hyderabad Nutrition Trial was associated with improved school enrollment and completion of more schooling grades when the children became adolescents. PMID- 26962176 TI - The Dietary Inflammatory Index Is Associated with Prostate Cancer Risk in French Middle-Aged Adults in a Prospective Study. AB - BACKGROUND: Chronic inflammation is one of the mechanisms involved in carcinogenesis. Diet is a major source of pro- and anti-inflammatory compounds. The Dietary Inflammatory Index (DII) was designed to estimate its overall inflammatory potential. OBJECTIVE: Our objective was to investigate the associations between the DII and overall, breast, and prostate cancer risks. METHODS: This prospective study included 6542 participants [3771 women and 2771 men with a mean +/- SD age of 49.2 +/- 6.4 y and a BMI (in kg/m2) of 24.0 +/- 3.6 at baseline] from the Supplementation en VItamines et Mineraux AntioXydants (SU.VI.MAX) cohort who completed at least six 24-h dietary records during the first 2 y of follow-up. The DII was based on 36 food variables. Higher scores corresponded to more proinflammatory diets. A total of 559 incident cancers were diagnosed (median follow-up, 12.6 y), including 158 female breast and 123 prostate cancers (the 2 main cancer sites in this cohort). Associations were characterized by multivariable Cox proportional hazards models. Stratified analyses were performed according to the median of usual daily alcohol intake. RESULTS: Sex-specific quartiles of the DII were positively associated with prostate cancer risk [quartile (Q) 4 compared with Q1, HR: 2.08; 95% CI: 1.06, 4.09] but not with overall or breast cancer risks. There was an interaction between the DII and alcohol intake (grams per day) on overall cancer risk (P interaction = 0.02): the DII was positively associated with overall cancer risk in low-to-moderate alcohol drinkers (Q4 compared with Q1 HR: 1.75; 95% CI: 1.15, 2.68; P-trend = 0.02), whereas no association was detected in higher consumers of alcohol (P-trend = 0.8). This interaction was also observed for breast cancer (P interaction = 0.001). CONCLUSION: Consistent with mechanistic data, findings from this study indicated that proinflammatory diets are associated with increased prostate cancer risk and, in low-to-moderate alcohol drinkers, with increased overall and breast cancer risk. The SU.VI.MAX trial was registered at clinicaltrials.gov as NCT00272428. PMID- 26962177 TI - Prepregnancy Low to Moderate Alcohol Intake Is Not Associated with Risk of Spontaneous Abortion or Stillbirth. AB - BACKGROUND: Numerous studies have documented the negative effects of maternal alcohol consumption during pregnancy on risk of pregnancy loss, yet whether prepregnancy alcohol intake affects the risk of spontaneous abortion is still unclear. OBJECTIVE: This study aimed to assess prepregnancy alcohol intake and risk of spontaneous abortion and stillbirth. METHODS: Our prospective cohort study included 27,580 pregnancies reported by 17,929 women in the Nurses' Health Study II between 1990 and 2009. Alcohol intake was assessed in 1989 and 1991 and every 4 y thereafter with the use of a validated questionnaire. Women were classified into 5 categories of consumption: 0, 0.1-1.9, 2-4.9, 5-9.9, and >=10 g/d (1 serving = ~12 g). Pregnancies were self-reported, with case pregnancies lost spontaneously (spontaneous abortion after gestation of <20 wk and stillbirth after gestation of >=20 wk) and comparison pregnancies not ending in fetal loss (live birth, ectopic pregnancy, or induced abortion). Multivariable log-binomial regression models with generalized estimating equations were used to estimate RRs and 95% CIs. RESULTS: Incident spontaneous abortion and stillbirth were reported in 4326 (15.7%) and 205 (0.7%) pregnancies, respectively. Prepregnancy alcohol intake was not associated with spontaneous abortion. Compared with women who did not consume alcohol, the multivariable RRs (95% CIs) for increasing categories of alcohol intake among women who did consume alcohol were 1.04 (0.97, 1.12) for 0.1 1.9 g/d, 1.02 (0.94, 1.11) for 2-4.9 g/d, 1.01 (0.92, 1.10) for 5-9.9 g/d, and 0.98 (0.88, 1.09) for >=10 g/d (P-trend = 0.45). Women who consumed >=2 servings beer/wk before pregnancy had a 9% (95% CI: 1%, 17%) lower risk of spontaneous abortion than did women who consumed <1 serving beer/mo; however, this association did not persist in various sensitivity analyses. Prepregnancy consumption of wine and liquor were not associated with spontaneous abortion. Total alcohol and specific alcohol beverage intake before pregnancy were not associated with stillbirth. CONCLUSION: Prepregnancy alcohol intake was not related to risk of incident spontaneous abortion or stillbirth in women with no history of pregnancy loss. Our results provide reassuring evidence that low to moderate alcohol intake (<=12 g/d) before pregnancy initiation does not affect risk of pregnancy loss. PMID- 26962180 TI - The Microbiome, Intestinal Function, and Arginine Metabolism of Healthy Indian Women Are Different from Those of American and Jamaican Women. AB - BACKGROUND: Indian women have slower arginine flux during pregnancy compared with American and Jamaican women. Arginine is a semi-essential amino acid that becomes essential during periods of rapid lean tissue deposition. It is synthesized only from citrulline, a nondietary amino acid produced mainly in the gut. The gut is therefore a key site of arginine and citrulline metabolism, and gut microbiota may affect their metabolism. OBJECTIVE: The objective of this study was to identify differences in the gut microbiota of nonpregnant American, Indian, and Jamaican women and characterize the relations between the gut microbiota, gut function, and citrulline and arginine metabolism. METHODS: Thirty healthy American, Indian, and Jamaican women (n = 10/group), aged 28.3 +/- 0.8 y, were infused intravenously with [guanidino-15N2]arginine, [5,5-2H2]citrulline, and [15N2]ornithine and given oral [U-13C6]arginine in the fasting and postprandial states. Fecal bacterial communities were characterized by 16S rRNA gene sequencing. RESULTS: In the fasting state, Indian women had lower citrulline flux than did American and Jamaican women [7.0 +/- 0.4 compared with 9.1 +/- 0.4 and 8.9 +/- 0.2 MUmol ? kg fat-free mass (FFM)-1 ? h-1, P = 0.01] and greater enteral arginine conversion to ornithine than did American women (1.4 +/- 0.11 compared with 1.0 +/- 0.08 MUmol ? kg FFM-1 ? h-1, P = 0.04). They also had lower mannitol excretion than American and Jamaican women (154 +/- 37.1 compared with 372 +/- 51.8 and 410 +/- 39.6 mg/6 h, P < 0.01). Three dominant stool community types characterized by increased abundances of the genera Prevotella, Bacteroides, and Bacteroides with Clostridium were identified. Indian women had increased mean relative abundances of Prevotella (42%) compared to American and Jamaican women (7% and < 1%, P = 0.03) which were associated with diet, impaired intestinal absorptive capacity, and arginine flux. CONCLUSIONS: These findings suggest that dysregulated intestinal function and a unique gut microbiome may contribute to altered arginine metabolism in Indian women. PMID- 26962179 TI - Short-Term Vitamin B-6 Restriction Does Not Affect Plasma Concentrations of Hydrogen Sulfide Biomarkers Lanthionine and Homolanthionine in Healthy Men and Women. AB - BACKGROUND: Suboptimal vitamin B-6 status is associated with increased cardiovascular disease risk, although the mechanism is unknown. The synthesis of the vasodilator hydrogen sulfide occurs through side reactions of the transsulfuration enzymes cystathionine beta-synthase and cystathionine gamma lyase, with pyridoxal 5'-phosphate as a coenzyme. Two proposed hydrogen sulfide biomarkers, lanthionine and homolanthionine, are produced concurrently. OBJECTIVE: To determine whether hydrogen sulfide production is reduced by vitamin B-6 deficiency, we examined the relations between plasma concentrations of lanthionine and homolanthionine, along with other components of the transsulfuration pathway (homocysteine, cystathionine, and Cys), in a secondary analysis of samples from 2 vitamin B-6 restriction studies in healthy men and women. METHODS: Metabolite concentrations were measured in plasma from 23 healthy adults (12 men and 11 women) before and after 28-d controlled dietary vitamin B-6 restriction (0.37 +/- 0.04 mg/d). Vitamin B-6 restriction effects on lanthionine and homolanthionine concentrations were assessed. Associations between hydrogen sulfide biomarkers, transsulfuration metabolites, and functional indicators of vitamin B-6 deficiency were analyzed by linear regression. RESULTS: Preprandial plasma lanthionine and homolanthionine concentrations ranged from 89.0 to 372 nmol/L and 5.75 to 32.3 nmol/L, respectively, in healthy adults. Mean lanthionine and homolanthionine concentrations were not affected by vitamin B-6 restriction (P < 0.66), with marked heterogeneity of individual responses. After restriction, homolanthionine was positively associated with functional indicators of vitamin B 6 deficiency, which differed from hypothesized negative associations. Plasma lanthionine was positively correlated with the concentration of its precursor, Cys, before (R2 = 0.36; P = 0.002) and after (R2 = 0.37; P = 0.002) restriction. Likewise, homolanthionine concentration was positively correlated with its precursor homocysteine, but only in vitamin B-6 adequacy (R2 = 0.41; P < 0.001). CONCLUSIONS: The resiliency of plasma lanthionine and homolanthionine concentrations after short-term vitamin B-6 restriction suggests a minimal effect of moderate vitamin B-6 deficiency on hydrogen sulfide production. Additional research is needed to better understand the metabolism and disposal of these biomarkers in humans. This study was registered at clinicaltrials.gov as NCT00877812. PMID- 26962178 TI - Protective Effects of the Mediterranean Diet on Type 2 Diabetes and Metabolic Syndrome. AB - Several studies provide evidence supporting a beneficial effect from the traditional Mediterranean diet (MedDiet) on the risk of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). This review summarizes the current scientific evidence from epidemiologic studies and clinical trials on the relation between the MedDiet and T2DM and MetS and the possible mechanisms underlying the reported associations. A recent meta-analysis of prospective cohort studies showed that greater adherence to the MedDiet was associated with a significant reduction in the risk of diabetes. The MedDiet has also been found to be beneficial in the prevention of gestational diabetes. Four large prospective studies have observed inverse associations between the MedDiet and MetS or its components. Few randomized controlled trials (RCTs) have evaluated the effect of the MedDiet on T2DM and MetS. Results from the landmark PREvencion con DIeta MEDiterranea (PREDIMED) nutrition intervention trial showed that participants assigned to the MedDiet had a significant 30% reduction in the risk of T2DM and that it also promoted the reversion of MetS and its components, hyperglycemia and central obesity. In addition, 5 RCTs showed the beneficial effects of the MedDiet compared with other dietary patterns on glycemic control in patients with T2DM. A recent meta-analysis of RCTs revealed that, compared with a variety of control diets, the MedDiet was associated with beneficial effects on all MetS components. Bioactive components of the MedDiet synergize to affect various metabolic pathways, leading to a reduced cardiometabolic disease risk. The abundance of healthy, nutrient-dense foods that make up the plant-based MedDiet predicts its bioactivity and potential to beneficially influence metabolic pathways that lead to MetS and T2DM, as well as other chronic conditions. Abundant epidemiologic and clinical trial evidence supports the role of the MedDiet on the prevention and management of T2DM and MetS. PMID- 26962181 TI - Intake of Total Polyphenols and Some Classes of Polyphenols Is Inversely Associated with Diabetes in Elderly People at High Cardiovascular Disease Risk. AB - BACKGROUND: Higher consumption of some polyphenols has been associated with a reduced risk of diabetes. However, no studies have evaluated the relation between all polyphenol subclasses and the incidence of diabetes. OBJECTIVE: We aimed to prospectively examine the associations between the intake of total polyphenols and different groups of polyphenols (flavonoids, phenolic acids, stilbenes, lignans, and others) on the risk of incident diabetes in the PREDIMED (Prevencion con Dieta Mediterranea) trial. METHODS: This was an observational cohort analysis of the nondiabetic participants in the PREDIMED trial. This study was a multicenter, controlled, randomized, parallel-group feeding trial to assess the effects of either a Mediterranean diet that was supplemented with extra-virgin olive oil or nuts or advice to adhere to a low-fat control diet on cardiovascular outcomes in elderly men and women at high cardiovascular disease risk. From the 7447 randomly assigned participants, 3430 were selected because they were free of diabetes at baseline and filled out the food-frequency questionnaires (FFQs). Polyphenol intake was calculated by matching food consumption data from repeated FFQs with the Phenol-Explorer database on the polyphenol content of each reported food. HRs and 95% CIs for diabetes according to tertiles of polyphenol intake were estimated with the use of time-dependent Cox proportional hazards models. RESULTS: Over a mean of 5.51 y of follow-up (18,900 person-years), there were 314 new cases of diabetes. After multivariable adjustment, we observed a 28% reduction in new-onset diabetes in the highest compared with the lowest tertile of total polyphenol intake (HR: 0.72; 95% CI: 0.52, 0.99; P-trend = 0.05). The intake of subclasses of polyphenols also was inversely associated with diabetes risk, including for total flavonoids (HR: 0.67; 95% CI: 0.48, 0.93; P-trend = 0.02), stilbenes (HR: 0.57; 95% CI: 0.38, 0.84; P-trend = 0.003), dihydroflavonols (HR: 0.59; 95% CI: 0.40, 0.88; P-trend = 0.003), and flavanones (HR: 0.69; 95% CI: 0.49, 0.97; P-trend = 0.03). CONCLUSIONS: A high intake of total polyphenols, total flavonoids (specifically flavanones and dihydroflavonols), and stilbenes is associated with a reduced risk of diabetes in elderly persons at high risk of cardiovascular disease. This trial was registered at http://www.controlled-trials.com as ISRCTN35739639. PMID- 26962182 TI - Free Sugars and Total Fat Are Important Characteristics of a Dietary Pattern Associated with Adiposity across Childhood and Adolescence. AB - BACKGROUND: The importance of dietary sugar compared with fat in the development of obesity is currently a topic of debate. OBJECTIVE: We aimed to identify dietary patterns (DPs) characterized by high sugar content, high fat content, or both and their longitudinal associations with adiposity during childhood and adolescence. METHODS: Participants were 6722 children from the ALSPAC (Avon Longitudinal Study of Parents and Children) who were born in 1991-1992. DPs were characterized by percentage of total energy intake (%E) from free sugars, %E from total fat, and dietary energy density (DED) and fiber density by using reduced rank regression at 7, 10, and 13 y of age. Total body fat mass was measured at 11, 13, and 15 y of age. Regression analyses were used to adjust for dietary misreporting, physical activity, and maternal social class. RESULTS: Two major DPs were identified: higher z scores for DP1 were associated with greater DED, greater %E from free sugars and total fat, and lower fiber density; higher z scores for DP2 were associated with greater %E from free sugars but lower %E from total fat and DED. A 1-SD increase in z score for DP1 was associated with a mean increase in the fat mass index z score of 0.04 SD units (95% CI: 0.01, 0.07; P = 0.017) and greater odds of excess adiposity (OR: 1.12; 95% CI: 1.0, 1.25; P = 0.038). DP2 was not associated with adiposity. CONCLUSIONS: An energy-dense DP high in %E from total fat and free sugars is associated with greater adiposity in childhood and adolescence. This appears to confirm the role of both fat and sugar and provides a basis for food-based dietary guidelines to prevent obesity in children. PMID- 26962183 TI - Supplementation with alpha-Lipoic Acid Alone or in Combination with Eicosapentaenoic Acid Modulates the Inflammatory Status of Healthy Overweight or Obese Women Consuming an Energy-Restricted Diet. AB - BACKGROUND: The proinflammatory state induced by obesity plays an important role in obesity-related metabolic complications. OBJECTIVE: Our objective was to evaluate whether dietary supplementation with alpha-lipoic acid (LA) and eicosapentaenoic acid (EPA), separately or in combination, could improve inflammatory and cardiovascular disease risk markers in healthy overweight or obese women consuming an energy-restricted diet. METHODS: Within the context of the Effects of Lipoic Acid and Eicosapentaenoic Acid in Human Obesity (OBEPALIP) study, Caucasian women (n = 73) aged 20-50 y with a BMI (in kg/m2) between 27.5 and 40 consumed an energy-restricted diet for 10 wk after being randomly assigned to 1 of 4 parallel experimental groups: a control group or groups supplemented with 1.3 g EPA/d, 0.3 g LA/d, or both. Secondary outcomes were measured at baseline and at the end of the study. These included circulating inflammatory [C reactive protein (CRP), adiponectin, interleukin 6 (IL-6), chemerin, haptoglobin, amyloid A, and leukocytes] and cardiovascular disease risk markers (platelet count and circulating apelin, asymmetric dimethylarginine, vascular endothelial growth factor, and plasminogen activator inhibitor 1). Gene expression of IL6, adhesion G protein-coupled receptor E1 (ADGRE1), interleukin 10 (IL10), chemokine (C-C motif) ligand 2, and adiponectin was measured in subcutaneous abdominal adipose tissue biopsies at endpoint. RESULTS: Supplementation with LA caused a greater reduction in some circulating inflammatory risk markers, such as CRP ( 0.13 +/- 0.07 mg/dL compared with 0.06 +/- 0.07 mg/dL, P < 0.05) and leukocyte count (-0.74 +/- 0.18 * 103/mm3 compared with 0.06 +/- 0.18 * 103/mm3, P < 0.01), than in the groups that were not supplemented with LA. In contrast, the fall in apelin concentrations that accompanied weight loss was less pronounced in groups that were supplemented with LA (-1.1 +/- 4.9 pg/mL) than in those that were not ( 21.3 +/- 4.8 pg/mL, P < 0.01). In adipose tissue, compared with those who did not receive EPA, EPA-supplemented groups exhibited a downregulation of ADGRE1 (0.7 +/ 0.1-fold compared with 1.0 +/- 0.1-fold) (P < 0.05) and an upregulation of IL10 (1.8 +/- 0.2-fold compared with 1.0 +/- 0.2-fold) (P < 0.05) gene expression. CONCLUSIONS: Dietary supplementation with LA improves some systemic inflammatory and cardiovascular disease-related risk markers in healthy overweight or obese women independently of weight loss, whereas EPA modulates inflammation-related genes in adipose tissue. This trial was registered at clinicaltrials.gov as NCT01138774. PMID- 26962185 TI - Estimating Sodium and Potassium Intakes and Their Ratio in the American Diet: Data from the 2011-2012 NHANES. AB - BACKGROUND: The dietary sodium-to-potassium ratio (Na:K) is shown to be more strongly associated with an increased risk of cardiovascular disease (CVD) and CVD-related mortality than either sodium or potassium intake alone. OBJECTIVE: The aim was to estimate the Na:K in the diet of US adults. METHODS: Among US adults from the 2011-2012 NHANES (>=20 y; 2393 men and 2337 women), the National Cancer Institute method was used to estimate sodium and potassium intakes, Na:K, and the percentage of individuals with Na:K <1.0 utilizing the complex, stratified, multistage probability cluster sampling design. RESULTS: Overall, women had a significantly lower Na:K than men (mean +/- SE: 1.32 +/- 0.02 compared with 1.45 +/- 0.02). Non-Hispanic whites had a significantly lower Na:K than non-Hispanic blacks and non-Hispanic Asians (1.34 +/- 0.02 compared with 1.54 +/- 0.03 and 1.49 +/- 0.04, respectively). Only 12.2% +/- 1.5% of US adults had a Na:K < 1.0. The Na:K decreased linearly as age increased. Most adults (90% +/- 0.8%) had sodium intakes >2300 mg/d, whereas <3% had potassium intakes >4700 mg/d. Grains and vegetables were among the highest contributors to sodium intakes for adults with Na:K < 1.0, compared with protein foods and grains for those with Na:K >= 1.0. Vegetables and milk and dairy products constituted the primary dietary sources of potassium for individuals with Na:K < 1.0, whereas mixed dishes and protein foods contributed the most potassium for individuals with ratios >=1.0. Individuals with a Na:K < 1.0 were less likely to consume mixed dishes and condiments and were more likely to consume vegetables, milk and dairy products, and fruit than those with a Na:K >= 1.0. CONCLUSION: Only about one tenth of US adults have a Na:K consistent with the WHO guidelines for reduced risk of mortality. Continued efforts to reduce sodium intake in tandem with novel strategies to increase potassium intake are warranted. PMID- 26962184 TI - Intervention Trials with the Mediterranean Diet in Cardiovascular Prevention: Understanding Potential Mechanisms through Metabolomic Profiling. AB - Large observational epidemiologic studies and randomized trials support the benefits of a Mediterranean dietary pattern on cardiovascular disease (CVD). Mechanisms postulated to mediate these benefits include the reduction of low grade inflammation, increased adiponectin concentrations, decreased blood coagulation, enhanced endothelial function, lower oxidative stress, lower concentrations of oxidized LDL, and improved apolipoprotein profiles. However, the metabolic pathways through which the Mediterranean diet influences CVD risk remain largely unknown. Investigating specific mechanisms in the context of a large intervention trial with the use of high-throughput metabolomic profiling will provide more solid public health messages and may help to identify key molecular targets for more effective prevention and management of CVD. Although metabolomics is not without its limitations, the techniques allow for an assessment of thousands of metabolites, providing wide-ranging profiling of small molecules related to biological status. Specific candidate plasma metabolites that may be associated with CVD include branched-chain and aromatic amino acids; the glutamine-to-glutamate ratio; some short- to medium-chain acylcarnitines; gut flora metabolites (choline, betaine, and trimethylamine N-oxide); urea cycle metabolites (citrulline and ornithine); and specific lipid subclasses. In addition to targeted metabolites, the role of a large number of untargeted metabolites should also be assessed. Large intervention trials with the use of food patterns for the prevention of CVD provide an unparalleled opportunity to examine the effects of these interventions on plasma concentrations of specific metabolites and determine whether such changes mediate the benefits of the dietary interventions on CVD risk. PMID- 26962187 TI - Fermentable Carbohydrates Differentially Affect Colon Tumor Formation in Azoxymethane-Induced Male Fischer 344 Rats. AB - BACKGROUND: The role of fermentation compared with the source or type of the fermentable material in colon tumorigenesis remains an issue in refining the definition of dietary fiber (DF). OBJECTIVE: The aim of this study was to investigate the fermentation and source-specific effects of various carbohydrates in a medium-term colon tumorigenesis model. METHODS: Six-week-old male Fischer 344 rats were randomly allocated into 6 groups (n = 36/group) to receive either AIN-93G (control) or diets containing fructooligosaccharides, wheat bran (WB), oat bran (OB), polydextrose, or high-amylose maize starch (HAMS), each adjusted to contain a total DF concentration of 7% (wt:wt) and have a fermentability of 3% (wt:wt). After 2 wk, 24 rats/group received 2 subcutaneous doses of azoxymethane (at 15 mg/kg body weight) 1 wk apart while 12 rats/group were injected with a saline vehicle; all rats were maintained on the assigned diets for 24 wk postinjection and then killed. Colon tumor outcomes and pathology together with cecal short-chain fatty acid composition were assessed. RESULTS: No tumors were found in saline-injected rats, and all subsequent analyses were restricted to azoxymethane-injected rats. Colon tumor incidence was significantly lower in the polydextrose (21%) and WB (13%) groups than in the control group (63%; P < 0.05) but not different from the fructooligosaccharide (58%), HAMS (46%), and OB (33%) groups. In comparison to the control group (8 proximal/31 total tumors), fermentable materials reduced the number of tumors (P < 0.05) originating in the proximal colon: HAMS (5/15), polydextrose (2/7), OB (2/9), fructooligosaccharides (1/21), and WB (1/3). The mean +/- SEM number of tumors/tumor-bearing rats was significantly lower in the WB (1.00 +/- 0.00), OB (1.13 +/- 0.13), and HAMS (1.36 +/- 0.15) groups than in the control group (2.07 +/- 0.27; P < 0.02); other groups did not differ. The mean +/- SEM tumor burden/diet group was lower in the WB (1.2 +/- 0.7 mm2), polydextrose (6.7 +/- 3.2 mm2), and OB (7.0 +/- 3.0 mm2) groups than in the control (21.4 +/- 5.9 mm2) and fructooligosaccharide (22.1 +/- 7.1 mm2; P < 0.05) groups but not significantly different from the HAMS group (15.1 +/- 6.1 mm2). Total cecal SCFA concentrations did not differ among diet groups (overall mean +/- SEM: 81 +/- 4 MUmol/g wet weight). CONCLUSION: The rate and extent of fermentation of the carbohydrate material as well as the characteristics of the material in the lumen of the lower gastrointestinal tract all appear to have an important role in tumor outcomes in the azoxymethane induced rat colon tumorigenesis assay. PMID- 26962188 TI - Regulatory T Cell Depletion Abolishes the Protective Effect of Dietary Galacto Oligosaccharides on Eosinophilic Airway Inflammation in House Dust Mite-Induced Asthma in Mice. AB - BACKGROUND: In a murine model for house dust mite (HDM)-induced asthma, dietary galacto-oligosaccharides have been shown to suppress allergic symptoms. Previously, CD25+ regulatory T cells (Tregs) induced by nondigestible oligosaccharides were found to protect against allergy development. OBJECTIVE: The aim of the current study was to examine the effect of anti-CD25-induced Treg depletion in a murine HDM-induced asthma model and to study the contribution of Tregs in the protective effect of dietary intervention with galacto oligosaccharides. METHODS: Male BALB/c mice (aged 6-8 wk) were intranasally sensitized and challenged with phosphate-buffered saline (PBS) or HDM. Two weeks before sensitization and throughout the whole experiment, mice were fed a control or 1% w/w galacto-oligosaccharide diet. Tregs were depleted by anti-mouse CD25 antibody (intraperitoneally injected). On day 14, T helper cell subtypes in lung and spleen were analyzed and cytokines were measured. Leukocyte subtypes were analyzed in the bronchoalveolar lavage fluid, and interleukin (IL)-33 and chemokines were measured in lung homogenate supernatants. RESULTS: Anti-CD25 treatment depleted CD25+ Forkhead box P3+ Tregs in the lung and spleen of control and HDM-allergic mice (P < 0.0001) by >70% while increasing the percentage of activated T helper cells (P < 0.05) and type 2 T helper cells (P < 0.05). This was associated with increased IL-10, IL-4, and IL-13 concentrations in supernatants of ex vivo restimulated lung cells (P < 0.01). Bronchoalveolar lavage fluid leukocyte numbers and percentages of eosinophils and lymphocytes were greater in HDM-allergic mice compared with PBS mice (P < 0.01) but remained unaffected by the anti-CD25 treatment. Galacto-oligosaccharides decreased airway eosinophilia compared with HDM-allergic mice fed the control diet (from 47.8% +/- 6.7% to 26.6% +/- 8.5%, P < 0.01). This protective effect was lost in anti-CD25 treated mice (P < 0.05). In lung homogenates of HDM-allergic mice, IL-33 was increased compared with PBS mice (from 2.8 +/- 0.3 to 5.4 +/- 0.6 ng protein/mg, P < 0.01). Galacto-oligosaccharides abrogated the increase in IL-33 compared with HDM-allergic mice fed the control diet (3.0 +/- 0.6 ng protein/mg, P < 0.05), which was abolished by the anti-CD25 treatment (P < 0.01). CONCLUSIONS: Treg depletion enhances pulmonary type 2 T helper cell frequency and cytokine release in HDM-induced asthma in mice. Galacto-oligosaccharides decreased airway eosinophilia and IL-33 concentrations in the lung, which was abrogated by Treg depletion. This indicates that galacto-oligosaccharides have a beneficial effect in the prevention of HDM-induced allergic asthma by supporting pulmonary Treg function. PMID- 26962186 TI - Sequences of Regressions Distinguish Nonmechanical from Mechanical Associations between Metabolic Factors, Body Composition, and Bone in Healthy Postmenopausal Women. AB - BACKGROUND: There is increasing recognition of complex interrelations between the endocrine functions of bone and fat tissues or organs. OBJECTIVE: The objective was to describe nonmechanical and mechanical links between metabolic factors, body composition, and bone with the use of graphical Markov models. METHODS: Seventy postmenopausal women with a mean +/- SD age of 62.3 +/- 3.7 y and body mass index (in kg/m2) of 24.9 +/- 3.8 were recruited. Bone outcomes were peripheral quantitative computed tomography measures of the distal and diaphyseal tibia, cross-sectional area (CSA), volumetric bone mineral density (vBMD), and cortical CSA. Biomarkers of osteoblast and adipocyte function were plasma concentrations of leptin, adiponectin, osteocalcin, undercarboxylated osteocalcin (UCOC), and phylloquinone. Body composition measurements were lean and percent fat mass, which were derived with the use of a 4-compartment model. Sequences of Regressions, a subclass of graphical Markov models, were used to describe the direct (nonmechanical) and indirect (mechanical) interrelations between metabolic factors and bone by simultaneously modeling multiple bone outcomes and their relation with biomarker outcomes with lean mass, percent fat mass, and height as intermediate explanatory variables. RESULTS: The graphical Markov models showed both direct and indirect associations linking plasma leptin and adiponectin concentrations with CSA and vBMD. At the distal tibia, lean mass, height, and adiponectin-UCOC interaction were directly explanatory of CSA (R2 = 0.45); at the diaphysis, lean mass, percent fat mass, leptin, osteocalcin, and age-adiponectin interaction were directly explanatory of CSA (R2 = 0.49). The regression models exploring direct associations for vBMD were much weaker, with R2 = 0.15 and 0.18 at the distal and diaphyseal sites, respectively. Lean mass and UCOC were associated, and the global Markov property of the graph indicated that this association was explained by osteocalcin. CONCLUSIONS: This study, to our knowledge, offers a novel approach to the description of the complex physiological interrelations between adiponectin, leptin, and osteocalcin and the musculoskeletal system. There may be benefits to jointly targeting both systems to improve bone health. PMID- 26962189 TI - An Increase in Plasma Homovanillic Acid with Cocoa Extract Consumption Is Associated with the Alleviation of Depressive Symptoms in Overweight or Obese Adults on an Energy Restricted Diet in a Randomized Controlled Trial. AB - BACKGROUND: Obesity has been associated with various health disorders, including psychological alterations. Cocoa consumption and weight management may produce a beneficial effect on these problems. OBJECTIVE: The purpose of this study was to investigate the effect of cocoa extract supplementation as part of an energy restricted diet on psychological status and peripheral dopaminergic activity in overweight or obese middle-aged subjects. METHODS: In a 4-wk, double-blind, randomized, placebo-controlled parallel nutritional intervention, 22 men and 25 women [mean +/- SD age: 57 +/- 5 y; body mass index (kg/m2): 30.6 +/- 2.3] were studied. After a 1-wk run-in period, volunteers consumed 15% energy-restricted diets; one-half of the volunteers were randomly assigned to receive ready-to-eat meals supplemented with 1.4 g cocoa extract/d (645 mg total polyphenols/d), whereas the rest of the volunteers received the same meals without cocoa supplementation. Plasma monoamines [dopamine, dopac, and homovanillic acid (HVA)], monoamine oxidase (MAO), and psychological status (anxiety and depressive symptoms) were analyzed in fasting participants at baseline and endpoint. Data were analyzed over time, and regression and correlation analyses were conducted to determine the relation between variables. RESULTS: Depressive symptoms decreased in both groups after the intervention (control: -9.4%, P < 0.001; cocoa: -6.3%, P = 0.008), but anxiety symptoms did not. The increase in plasma HVA was 11.5% greater in the cocoa group than in the control group (P = 0.016), but plasma dopamine, dopac, and MAO changes did not differ between groups. A negative relation between changes in depressive symptoms and changes in plasma HVA was observed in the cocoa group (beta = -0.39, P = 0.029). Moreover, the change in plasma dopamine was positively associated with the change in methyl catechin-O-glucoronide in the cocoa-supplemented group (r = 0.69, P = 0.019). CONCLUSION: The intake of cocoa extract by participants consuming a 15% energy restricted diet contributed to an increase in plasma HVA concentrations. This change was associated with a reduction in depressive symptoms, suggesting a potential effect of cocoa extract intake on this relation. The present results are secondary analyses of a clinical trial that was registered at www.clinicaltrials.gov as NCT01596309. PMID- 26962191 TI - Future Perspectives of Personalized Weight Loss Interventions Based on Nutrigenetic, Epigenetic, and Metagenomic Data. AB - As obesity has become a major global public health challenge, a large number of studies have analyzed different strategies aimed at inducing a negative energy balance and, consequently, body weight loss. However, most existing weight loss programs are generally unsuccessful, so several interventions have been carried out to identify physiologic and behavioral factors concerning this variability in order to implement more personalized treatment. Nowadays, an individualized approach is being proposed through so-called personalized nutrition, whereby not only the phenotype but also the genotype is used for customized nutrition treatment. Regarding body weight regulation, ~70 polymorphisms have been identified in or near genes related to energy expenditure, appetite, adipogenesis, insulin resistance, and lipid metabolism. Although personalized nutrition refers mainly to genetic makeup, recent advances in the investigation of the epigenome and the microbiome open the door to implement more personalized recommendations for body weight management. In this context, recent studies have demonstrated the existence of several epigenetic markers that may modify gene expression and could be involved in the outcome of weight loss interventions. Moreover, different studies have shown that dietary interventions could affect the composition of gut microbiota and have an impact on body weight. The integration of nutrigenetic, epigenetic, and metagenomic data may lead to the design of more personalized dietary treatments to prevent chronic diseases and to optimize the individual's response to dietary interventions. PMID- 26962192 TI - Prevention of Aflatoxin B1 Hepatoxicity by Dietary Selenium Is Associated with Inhibition of Cytochrome P450 Isozymes and Up-Regulation of 6 Selenoprotein Genes in Chick Liver. AB - BACKGROUND: The involvement of cytochrome P450 (CYP450) isozymes and the selenogenome in selenium-mediated protection against aflatoxin B1 (AFB1)-induced adverse effects in broilers remains unclear. OBJECTIVE: This study was designed first to determine whether selenium could reduce AFB1-induced hepatotoxic effects and then to determine whether these effects were due to changes in the CYP450 isozymes and selenogenome expression in the liver of chicks. METHODS: Male avian broilers (aged 120 d) were allocated to 4 groups with 5 replicates of 6 birds to be included in a 2-by-2 factorial trial in which the main factors included supplementation of AFB1 (<5 compared with 100 MUg/kg) and selenium (0.2 compared with 0.5 mg/kg) in a corn/soybean-based diet for 4 wk. Serum biochemistry, hepatic histology, and mRNA and/or activities of hepatic antioxidant enzymes, CYP450 isozymes, and 26 selenoproteins were analyzed at week 2 and/or 4. RESULTS: Administration of AFB1 induced liver injury, decreasing (P < 0.05) total protein and albumin concentrations by 33.3-43.8% and increasing (P < 0.05) alanine aminotransferase and aspartate aminotransferase activities by 26.0-33.8% in serum, and induced hepatic necrosis and bile duct hyperplasia at week 2. AFB1 also decreased (P < 0.05) hepatic activities of glutathione peroxidase (GPX), thioredoxin reductase (TXNRD), and catalase, and the glutathione concentration by 13.1-59.9% and increased (P < 0.05) malondialdehyde, 8-hydroxydeoxyguanosine and exo-AFB1-8,9-epoxide (AFBO) DNA concentrations by 17.9-1200%. In addition, the mRNA and activity of enzymes responsible for the bioactivation of AFB1 into AFBO, which included CYP450 A1, 1A2, 2A6, and 3A4, were significantly induced (P < 0.05) by 29.2-271% in liver microsomes after 2-wk exposure to AFB1. These alterations induced by AFB1 were prevented by selenium supplementation. Dietary selenium supplementation increased (P < 0.05) mRNA and/or activities of 6 selenoprotein genes (Gpx3, Txnrd1, Txnrd2, Txnrd3, iodothyronine deiodinase 2, and selenoprotein N) in the liver of AFB1-treated groups at week 2. CONCLUSIONS: Dietary selenium protected chicks from AFB1-induced liver injury, potentially through the synergistic actions of inhibition of the pivotal CYP450 isozyme mediated activation of AFB1 to toxic AFBO, and increased antioxidant capacities by upregulation of selenoprotein genes coding for antioxidant proteins. PMID- 26962193 TI - Lipid-Based Nutrient Supplements Plus Malaria and Diarrhea Treatment Increase Infant Development Scores in a Cluster-Randomized Trial in Burkina Faso. AB - BACKGROUND: Adequate nutrition is necessary for the rapid brain development that occurs during infancy. OBJECTIVES: We tested the hypothesis that the provision of small-quantity, lipid-based nutrient supplements (SQ-LNSs) plus malaria and diarrhea treatment positively affects infant development. We also tested the effect of various doses of zinc provided in SQ-LNSs or in a tablet. METHODS: In a partially masked, cluster-randomized controlled trial, communities in rural Burkina Faso were stratified by selected characteristics and then randomly assigned within strata to the intervention (IC; 25 communities, 2435 children) or the nonintervention (NIC; 9 communities, 785 children) cohorts. IC children were randomly assigned to 4 groups. As secondary outcomes, a subsample of 3 of these 4 groups (n = 747) and of the NIC (n = 376) were assessed for motor, language, and personal-social development at age 18 mo by using the Developmental Milestones Checklist II. The 3 IC groups received 20 g SQ-LNSs/d containing 0 or 10 mg added zinc with a placebo tablet or 20 g SQ-LNSs/d containing 0 mg added zinc with a tablet containing 5 mg Zn. All IC groups received treatment of malaria and diarrhea from age 9 to 18 mo. Data collectors and participants were aware of allocation to the IC or NIC but did not know the particular IC subgroup. RESULTS: Children in the IC scored 0.34 (95% CI: 0.21, 0.46), 0.30 (95% CI: 0.15, 0.44), and 0.32 (95% CI: 0.16, 0.48) SDs higher in motor, language, and personal-social development, respectively, than did children in the NIC (All P < 0.001). Children who received different amounts of zinc did not differ significantly in any of the scores. No effect on caregiver-child interaction was found. CONCLUSION: In rural Burkina Faso, the provision of SQ-LNSs to infants from age 9 to 18 mo, regardless of added zinc content, plus malaria and diarrhea treatment positively affected motor, language, and personal-social development at age 18 mo. This trial was registered at clinicaltrials.gov as NCT00944281. PMID- 26962194 TI - A Healthy Nordic Diet Alters the Plasma Lipidomic Profile in Adults with Features of Metabolic Syndrome in a Multicenter Randomized Dietary Intervention. AB - BACKGROUND: A healthy Nordic diet is associated with improvements in cardiometabolic risk factors, but the effect on lipidomic profile is not known. OBJECTIVE: The aim was to investigate how a healthy Nordic diet affects the fasting plasma lipidomic profile in subjects with metabolic syndrome. METHODS: Men and women (n = 200) with features of metabolic syndrome [mean age: 55 y; body mass index (in kg/m2): 31.6] were randomly assigned to either a healthy Nordic (n = 104) or a control (n = 96) diet for 18 or 24 wk at 6 centers. Of the participants, 156 completed the study with plasma lipidomic measurements. The healthy Nordic diet consisted of whole grains, fruits, vegetables, berries, vegetable oils and margarines, fish, low-fat milk products, and low-fat meat. An average Nordic diet served as the control diet and included low-fiber cereal products, dairy fat-based spreads, regular-fat milk products, and a limited amount of fruits, vegetables, and berries. Lipidomic profiles were measured at baseline, week 12, and the end of the intervention (18 or 24 wk) by using ultraperformance liquid chromatography mass spectrometry. The effects of the diets on the lipid variables were analyzed with linear mixed-effects models. Data from centers with 18- or 24-wk duration were also analyzed separately. RESULTS: Changes in 21 plasma lipids differed significantly between the groups at week 12 (false discovery rate P < 0.05), including increases in plasmalogens and decreases in ceramides in the healthy Nordic diet group compared with the control group. At the end of the study, changes in lipidomic profiles did not differ between the groups. However, when the intervention lasted 24 wk, changes in 8 plasma lipids that had been identified at 12 wk, including plasmalogens, were sustained. There were no differences in changes in plasma lipids between groups with an intervention of 18 wk. By the dietary biomarker score, adherence to diet did not explain the difference in the results related to the duration of the study. CONCLUSIONS: A healthy Nordic diet transiently modified the plasma lipidomic profile, specifically by increasing the concentrations of antioxidative plasmalogens and decreasing insulin resistance-inducing ceramides. This trial was registered at clinicaltrials.gov as NCT00992641. PMID- 26962195 TI - Higher Childhood Red Meat Intake Frequency Is Associated with Earlier Age at Menarche. AB - BACKGROUND: Early age at menarche is associated with increased breast cancer risk. Red meat consumption in adolescence predicts breast cancer risk, but it is unknown whether it is also related to earlier menarche. OBJECTIVE: We studied the association between intake of red meat at ages 5-12 y and age at menarche in a prospective study. METHODS: We assessed usual diets with a food-frequency questionnaire in a group of 456 girls aged 8.4 +/- 1.7 y and followed them for a median 5.6 y in Bogota, Colombia. Girls were asked periodically about the occurrence and date of menarche. Median age at menarche was estimated with use of Kaplan-Meier survival probabilities by categories of red meat intake frequency. Cox proportional hazards models were used to compare the incidence of menarche by red meat intake frequency, adjusting for potential sociodemographic and dietary confounders including total energy intake and intake frequency of other animal food groups (dairy, poultry, freshwater fish, tuna/sardines, eggs, and innards). RESULTS: Median age at menarche was 12.4 y. After adjustment for total energy intake, maternal parity, and socioeconomic status, red meat intake frequency was inversely associated with age at menarche. When compared with girls with red meat intake <4 times/wk, those consuming it >=2 times/d had a significantly earlier age at menarche (HR: 1.64; 95% CI: 1.11, 2.41; P-trend = 0.0009). Incidentally, we found that girls with tuna/sardine intake >1 time/wk had a significantly later age at menarche (HR: 0.62; 95% CI: 0.42, 0.90; P = 0.01) than those with intake <1 time/mo. Intake frequency of other animal food groups was not significantly associated with age at menarche. CONCLUSION: Higher red meat intake frequency during childhood is associated with an earlier age at menarche, whereas greater fatty fish intake frequency is associated with a later menarcheal age. PMID- 26962197 TI - Therapeutic Drug Monitoring of Ganciclovir Treatment for Cytomegalovirus Infections Among Immunocompromised Children. PMID- 26962190 TI - Biomarkers of Nutrition for Development (BOND)-Zinc Review. AB - Zinc is required for multiple metabolic processes as a structural, regulatory, or catalytic ion. Cellular, tissue, and whole-body zinc homeostasis is tightly controlled to sustain metabolic functions over a wide range of zinc intakes, making it difficult to assess zinc insufficiency or excess. The BOND (Biomarkers of Nutrition for Development) Zinc Expert Panel recommends 3 measurements for estimating zinc status: dietary zinc intake, plasma zinc concentration (PZC), and height-for-age of growing infants and children. The amount of dietary zinc potentially available for absorption, which requires an estimate of dietary zinc and phytate, can be used to identify individuals and populations at risk of zinc deficiency. PZCs respond to severe dietary zinc restriction and to zinc supplementation; they also change with shifts in whole-body zinc balance and clinical signs of zinc deficiency. PZC cutoffs are available to identify individuals and populations at risk of zinc deficiency. However, there are limitations in using the PZC to assess zinc status. PZCs respond less to additional zinc provided in food than to a supplement administered between meals, there is considerable interindividual variability in PZCs with changes in dietary zinc, and PZCs are influenced by recent meal consumption, the time of day, inflammation, and certain drugs and hormones. Insufficient data are available on hair, urinary, nail, and blood cell zinc responses to changes in dietary zinc to recommend these biomarkers for assessing zinc status. Of the potential functional indicators of zinc, growth is the only one that is recommended. Because pharmacologic zinc doses are unlikely to enhance growth, a growth response to supplemental zinc is interpreted as indicating pre-existing zinc deficiency. Other functional indicators reviewed but not recommended for assessing zinc nutrition in clinical or field settings because of insufficient information are the activity or amounts of zinc-dependent enzymes and proteins and biomarkers of oxidative stress, inflammation, or DNA damage. PMID- 26962196 TI - Food environments of young people: linking individual behaviour to environmental context. AB - Background: We aimed to identify and characterize the food environments from which young people obtain food and to explore associations between the type of food environment and food intakes. Methods: Young people (n = 86, mean age 17 years; combined data of two sequential pilot studies (collected in 2008-09) and a study conducted in 2011-12) recorded in 4-day self-complete food diaries what food they consumed and where food was sourced. Nutrient, fruit and vegetable intake was calculated according to the source of food, categorized using a food environment classification tool. Results: Over 4 days, respondents sourced food from an average of 4.3 different food environments. Home food was used daily and was more favourable in terms of nutrient profile than out-of-home food. Food sourced from specialist outlets, convenience stores and retail bakers had the highest energy density. Food from retail bakers and 'takeaway and fast food' outlets were the richest sources of fat while vending machines and convenience stores had the highest percentage of energy from sugar. Conclusions: This work provides details of 'where' young people obtain food and the nutritional consequences of choosing those food environments. While home food was a significant contributor to total dietary intake, food was obtained from a broad range of environments; particularly takeaway, fast food and education establishments. PMID- 26962199 TI - An unusual case of spinal cord compression from concomitant spinal epidural lipomatosis and Hodgkin's lymphoma. AB - Spinal epidural lipomatosis (SEL) results from an abnormal accumulation of unencapsulated fat within the epidural space and is a rare cause of spinal cord compression, which needs to be considered with a high index of suspicion. It most commonly occurs secondary to chronic corticosteroid use and endocrinopathies. Idiopathic cases are highly associated with obesity. We report an unusual case of idiopathic thoracic SEL in a 69-year-old male, with an adjacent infiltrative Hodgkin's lymphoma and associated vertebral crush fracture, which resulted in ataxia and sensory loss. Magnetic resonance imaging scans displayed extensive SEL and an infiltrative disease process causing thoracic cord compression. Surgical decompression confirmed the presence of extensive epidural lipomatosis and Hodgkin's lymphoma and subsequently led to improvement in neurological symptoms. To our knowledge, this is the first reported case of concomitant SEL with an adjacent Hodgkin's lymphoma resulting in cord compression. PMID- 26962198 TI - Clinical applications of stereotactic radiation therapy for oligometastatic cancer patients: a disease-oriented approach. AB - Oligometastases from solid tumors are currently recognized as a distinct clinical entity, corresponding to an intermediate state between local and widespread disease. It has been suggested that local ablative therapies (including surgery, radiofrequency ablation and radiation therapy) play an important role in this setting, in combination or not with systemic therapies, particularly in delaying disease progression and hopefully in increasing the median survival time. Stereotactic body radiation therapy (SBRT) rapidly emerged in recent years as one of the most effective and less toxic local treatment modalities for lung, liver, adrenal, brain and bone metastases. The aim of this review was to focus on its clinical role for oligometastatic disease in four major cancer subtypes: lung, breast, colorectal and prostate. On the basis of the available evidence, SBRT is able to provide high rates of local tumor control without significant toxicity. Its global impact on survival is uncertain; however, in specific subpopulations of oligometastatic patients there is a trend towards a significant improvement in progression-free and overall survival rates; these important data might be used as a platform for clinical decision-making and establish the basis for the current and future prospective trials investigating its role with or without systemic treatments. PMID- 26962200 TI - Racial Patterns of Peripheral T-Cell Lymphoma Incidence and Survival in the United States. AB - PURPOSE: To compare incidence and survival of peripheral T-cell lymphoma (PTCL) subtypes among US racial/ethnic groups. METHODS: Patients with PTCL (age >= 15 years; 2000 to 2012) were identified in the Surveillance, Epidemiology, and End Results (SEER) registries. Race/ethnicity was categorized as non-Hispanic white, black, Asian/Pacific Islander, Hispanic white, or American Indian/Alaskan native. Age-standardized annual incidence rates and incidence rate ratios were estimated with 95% CIs, and case-case odds ratios were estimated by race/ethnicity using polytomous regression. Survival was estimated from SEER follow-up data with Cox regression. RESULTS: Thirteen thousand one hundred seven patients with PTCL were identified. Annual PTCL incidence was highest in blacks and lowest in Native Americans. Compared with non-Hispanic whites, blacks had a higher incidence of PTCL not otherwise specified (PTCL-NOS), anaplastic large-cell lymphoma, and adult T-cell leukemia/lymphoma (ATLL) and a lower incidence of angioimmunoblastic T-cell lymphoma (AITL); Asians/Pacific Islanders had a higher incidence of AITL, extranodal nasal-type natural killer/T-cell lymphoma and NK-cell leukemia (ENKCL), and ATLL and a lower incidence of anaplastic large-cell lymphoma; Hispanics had a higher incidence of AITL and ENKCL; and Native Americans had a lower incidence of PTCL-NOS (all P < .05). The ratio of ENKCL to PCTL-NOS among Native Americans, Asians/Pacific Islanders, and Hispanic whites was approximately three- to four-fold the same ratio among non-Hispanic whites. Survival varied significantly by race/ethnicity (P < .001), with blacks in particular experiencing shorter survival for most subtypes. CONCLUSION: Striking variation in incidence, proportions of PTCL subtypes, and survival was observed. Aspects of these PTCL subtype patterns, such as for ENKCL and ATLL, were similar to corresponding global populations. Despite the small population size and limited number of Native American patients, PTCL subtype frequencies in this group were distinct but most similar to Hispanic whites. Survival disparities were evident, especially for blacks compared with non-Hispanic whites. PMID- 26962202 TI - Physical, emotional and sexual adolescent abuse victimisation in South Africa: prevalence, incidence, perpetrators and locations. AB - BACKGROUND: Physical, emotional and sexual abuse of children is a major problem in South Africa, with severe negative outcomes for survivors. To date, no known studies have used data directly obtained from community-based samples of children to investigate prevalence, incidence, locations and perpetrators of child abuse victimisation. This study aims to investigate prevalence and incidence, perpetrators, and locations of child abuse victimisation in South Africa using a multicommunity sample. METHODS: 3515 children aged 10-17 years (56.6% female) were interviewed from all households in randomly selected census enumeration areas in two South African provinces. Child self-report questionnaires were completed at baseline and at 1-year follow-up (96.7% retention). RESULTS: Prevalence was 56.3% for lifetime physical abuse (18.2% past-year incidence), 35.5% for lifetime emotional abuse (12.1% incidence) and 9% for lifetime sexual abuse (5.3% incidence). 68.9% of children reported any type of lifetime victimisation and 27.1% reported lifetime multiple abuse victimisation. Main perpetrators of abuse were reported: for physical abuse, primary caregivers and teachers; for emotional abuse, primary caregivers and relatives; and for sexual abuse, girlfriend/boyfriends or other peers. CONCLUSIONS: This is the first study assessing current self-reported child abuse through a large, community-based sample in South Africa. Findings of high rates of physical, emotional and sexual abuse demonstrate the need for targeted and effective interventions to prevent incidence and re-victimisation. PMID- 26962205 TI - Hypertension Guidelines: Is It Time to Reappraise Blood Pressure Thresholds and Targets? PMID- 26962203 TI - Fukushima, mental health and suicide. PMID- 26962206 TI - Maternal Cardiovascular Function in Normal Pregnancy: Evidence of Maladaptation to Chronic Volume Overload. AB - The aim of this study was to investigate cardiac functional status in pregnancy using a comprehensive approach taking into account the simultaneous changes in loading and geometry, as well as maternal age and anthropometric indices. This was a prospective cross-sectional study of 559 nulliparous pregnant women assessed at 4 time points during pregnancy and at 1 year postpartum. All women underwent conventional echocardiography and tissue Doppler velocities and strain rate analysis at multiple cardiac sites. Mean arterial pressure and total vascular resistance index significantly decreased (both P<0.001) during the first 2 trimesters of pregnancy and increased thereafter. Stroke volume index and cardiac index showed the opposite trend compared with mean arterial pressure and total vascular resistance index (both P<0.05). Myocardial and ventricular function were significantly enhanced in the first 2 trimesters but progressively declined thereafter. By the end of pregnancy, significant chamber diastolic dysfunction and impaired myocardial relaxation was evident in 17.9% and 28.4% of women, respectively, whereas myocardial contractility was preserved. There was full recovery of cardiac function at 1 year postpartum. Cardiovascular changes during pregnancy are thought to represent a physiological adaptation to volume overload. The findings of a drop in stroke volume index, impaired myocardial relaxation with diastolic dysfunction, and a tendency toward eccentric remodeling in a significant proportion of cases at term are suggestive of cardiovascular maladaptation to the volume-overloaded state in some apparently normal pregnancies. These unexpected cardiovascular findings have important implications for the management of both normal and pathological pregnancy states. PMID- 26962207 TI - Correction. PMID- 26962208 TI - Jasmonic acid is a downstream component in the modulation of somatic embryogenesis by Arabidopsis Class 2 phytoglobin. AB - Previous studies have shown that the beneficial effect of suppression of the Arabidopsis phytoglobin 2 gene, PGB2, on somatic embryogenesis occurs through the accumulation of nitric oxide (NO) within the embryogenic cells originating from the cultured explant. NO activates the expression of Allene oxide synthase (AOS) and Lipoxygenase 2 (LOX2), genes encoding two key enzymes of the jasmonic acid (JA) biosynthetic pathway, elevating JA content within the embryogenic tissue. The number of embryos in the single aos1-1 mutant and pgb2-aos1-1 double mutant declined, and was not rescued by increasing levels of NO stimulating embryogenesis in wild-type tissue. NO also influenced JA responses by up regulating PLANT DEFENSIN 1 (PDF1) and JASMONATE-ZIM-PROTEIN (JAZ1), as well as down-regulating MYC2. The NO and JA modulation of MYC2 and JAZ1 controlled embryogenesis. Ectopic expression of JAZ1 or suppression of MYC2 promoted the formation of somatic embryos, while repression of JAZ1 and up-regulation of MYC2 reduced the embryogenic performance. Sustained expression of JAZ1 induced the transcription of several indole acetic acid (IAA) biosynthetic genes, resulting in higher IAA levels in the embryogenic cells. Collectively these data fit a model integrating JA in the PGB2 regulation of Arabidopsis embryogenesis. Suppression of PGB2 increases JA through NO. Elevated levels of JA repress MYC2 and induce JAZ1, favoring the accumulation of IAA in the explants and the subsequent production of somatic embryos. PMID- 26962209 TI - Phosphorylation of plastoglobular proteins in Arabidopsis thaliana. AB - Plastoglobules (PGs) are plastid lipid-protein particles with a small specialized proteome and metabolome. Among the 30 core PG proteins are six proteins of the ancient ABC1 atypical kinase (ABC1K) family and their locations in an Arabidopsis mRNA-based co-expression network suggested central regulatory roles. To identify candidate ABC1K targets and a possible ABC1K hierarchical phosphorylation network within the chloroplast PG proteome, we searched Arabidopsis phosphoproteomics data from publicly available sources. Evaluation of underlying spectra and/or associated information was challenging for a variety of reasons, but supported pSer sites and a few pThr sites in nine PG proteins, including five FIBRILLINS. PG phosphorylation motifs are discussed in the context of possible responsible kinases. The challenges of collection and evaluation of published Arabidopsis phosphorylation data are discussed, illustrating the importance of deposition of all mass spectrometry data in well-organized repositories such as PRIDE and ProteomeXchange. This study provides a starting point for experimental testing of phosho-sites in PG proteins and also suggests that phosphoproteomics studies specifically designed toward the PG proteome and its ABC1K are needed to understand phosphorylation networks in these specialized particles. PMID- 26962210 TI - Subcellular localization and trafficking of phytolongins (non-SNARE longins) in the plant secretory pathway. AB - SNARE proteins are central elements of the machinery involved in membrane fusion of eukaryotic cells. In animals and plants, SNAREs have diversified to sustain a variety of specific functions. In animals, R-SNARE proteins called brevins have diversified; in contrast, in plants, the R-SNARE proteins named longins have diversified. Recently, a new subfamily of four longins named 'phytolongins' (Phyl) was discovered. One intriguing aspect of Phyl proteins is the lack of the typical SNARE motif, which is replaced by another domain termed the 'Phyl domain'. Phytolongins have a rather ubiquitous tissue expression in Arabidopsis but still await intracellular characterization. In this study, we found that the four phytolongins are distributed along the secretory pathway. While Phyl2.1 and Phyl2.2 are strictly located at the endoplasmic reticulum network, Phyl1.2 associates with the Golgi bodies, and Phyl1.1 locates mainly at the plasma membrane and partially in the Golgi bodies and post-Golgi compartments. Our results show that export of Phyl1.1 from the endoplasmic reticulum depends on the GTPase Sar1, the Sar1 guanine nucleotide exchange factor Sec12, and the SNAREs Sec22 and Memb11. In addition, we have identified the Y48F49 motif as being critical for the exit of Phyl1.1 from the endoplasmic reticulum. Our results provide the first characterization of the subcellular localization of the phytolongins, and we discuss their potential role in regulating the secretory pathway. PMID- 26962212 TI - Mechanisms and challenges in translational stroke research. AB - Translating basic science advances into clinical meaning has been challenging for stroke research. This does not, however, mean that the investigation of basic mechanisms is irrelevant. Translation is difficult because the underlying mechanisms are complex and ill-defined. The original focus on neuroprotection has now evolved into a broader consideration of the role of non-neuronal cells in stroke pathophysiology. The neurovascular unit may provide a conceptual framework within which interactions between neural, glial, and vascular cells comprise a basis for function and dysfunction in the central nervous system. Importantly, these cell-cell signaling pathways are also biphasic in nature, that is, mechanisms that are deleterious in the acute phase may surprisingly be required for neurovascular remodeling and plasticity during stroke recovery. Furthermore, injury-into-repair gradients are significantly influenced by a host of modifying factors and comorbidities. Rigorous dissection of these complex and recursive mechanisms should be required before they can be rationally targeted for stroke. PMID- 26962211 TI - The Cer-cqu gene cluster determines three key players in a beta-diketone synthase polyketide pathway synthesizing aliphatics in epicuticular waxes. AB - Aliphatic compounds on plant surfaces, called epicuticular waxes, are the first line of defense against pathogens and pests, contribute to reducing water loss and determine other important phenotypes. Aliphatics can form crystals affecting light refraction, resulting in a color change and allowing identification of mutants in their synthesis or transport. The present study discloses three such Eceriferum (cer) genes in barley - Cer-c, Cer-q and Cer-u - known to be tightly linked and functioning in a biochemical pathway forming dominating amounts of beta-diketone and hydroxy-beta-diketones plus some esterified alkan-2-ols. These aliphatics are present in many Triticeae as well as dicotyledons such as Eucalyptus and Dianthus. Recently developed genomic resources and mapping populations in barley defined these genes to a small region on chromosome arm 2HS. Exploiting Cer-c and -u potential functions pinpointed five candidates, of which three were missing in apparent cer-cqu triple mutants. Sequencing more than 50 independent mutants for each gene confirmed their identification. Cer-c is a chalcone synthase-like polyketide synthase, designated diketone synthase (DKS), Cer-q is a lipase/carboxyl transferase and Cer-u is a P450 enzyme. All were highly expressed in pertinent leaf sheath tissue of wild type. A physical map revealed the order Cer-c, Cer-u, Cer-q with the flanking genes 101kb apart, confirming they are a gene cluster, Cer-cqu. Homology-based modeling suggests that many of the mutant alleles affect overall protein structure or specific active site residues. The rich diversity of identified mutations will facilitate future studies of three key enzymes involved in synthesis of plant apoplast waxes. PMID- 26962213 TI - 2C Proteins of Enteroviruses Suppress IKKbeta Phosphorylation by Recruiting Protein Phosphatase 1. AB - The NF-kappaB signaling network, which is an ancient signaling pathway, plays a pivotal role in innate immunity and constitutes a first line of defense against invading pathogens, including viruses. However, numerous viruses possess evolved strategies to antagonize the activation of the NF-kappaB signaling pathway. Our previous study demonstrated that the nonstructural protein 2C of enterovirus 71 (EV71), which is the major pathogen of hand, foot, and mouth disease, inhibits tumor necrosis factor alpha (TNF-alpha)-mediated activation of NF-kappaB by suppressing IkappaB kinase beta (IKKbeta) phosphorylation. Nevertheless, the mechanism underlying the inhibition of IKKbeta phosphorylation by EV71 2C remains largely elusive. We demonstrate that EV71 2C interacts with all isoforms of the protein phosphatase 1 (PP1) catalytic subunit (the PP1alpha, PP1beta, and PP1gamma isoforms) through PP1-docking motifs. EV71 2C has no influence on the subcellular localization of PP1. In addition, the PP1-binding-deficient EV71 2C mutant 3E3L nearly completely lost the ability to suppress IKKbeta phosphorylation and NF-kappaB activation was markedly restored in the mutant, thereby indicating that PP1 binding is efficient for EV71 2C-mediated inhibition of IKKbeta phosphorylation and NF-kappaB activation. We further demonstrate that 2C forms a complex with PP1 and IKKbeta to dephosphorylate IKKbeta. Notably, we reveal that other human enteroviruses, including poliovirus (PV), coxsackie A virus 16 (CVA16), and coxsackie B virus 3 (CVB3), use 2C proteins to recruit PP1, leading to the inhibition of IKKbeta phosphorylation. Our findings indicate that enteroviruses exploit a novel mechanism to inhibit IKKbeta phosphorylation by recruiting PP1 and IKKbeta to form a complex through 2C proteins, which ultimately results in the inhibition of the NF-kappaB signaling pathway. IMPORTANCE: The innate antiviral immunity system performs an essential function in recognizing and eliminating invading viruses. Enteroviruses include a number of important human pathogens, including poliovirus (PV), EV71, and coxsackieviruses (CVs). As 2C is the most conserved and complex nonstructural protein of enteroviruses, its biological function is largely unclear, whereas the 2A and 3C proteinases of enteroviruses are well characterized. We reveal that EV71 2C forms a complex with PP1 and IKKbeta to maintain IKKbeta in an unphosphorylated and inactive state, resulting in the inactivation of the TNF alpha-mediated NF-kappaB signaling pathway. We provide evidence that the 2C proteins of the enteroviruses PV, CVA16, and CVB3 suppress IKKbeta phosphorylation through the same mechanism involving PP1. We demonstrate that enteroviruses exploit a novel mechanism involving PP1 to regulate innate antiviral immunity, and our findings may be particularly important for understanding the pathogenicity of enteroviruses. PMID- 26962214 TI - Differential Persistence of Foot-and-Mouth Disease Virus in African Buffalo Is Related to Virus Virulence. AB - Foot-and-mouth disease (FMD) virus (FMDV) circulates as multiple serotypes and strains in many regions of endemicity. In particular, the three Southern African Territories (SAT) serotypes are maintained effectively in their wildlife reservoir, the African buffalo, and individuals may harbor multiple SAT serotypes for extended periods in the pharyngeal region. However, the exact site and mechanism for persistence remain unclear. FMD in buffaloes offers a unique opportunity to study FMDV persistence, as transmission from carrier ruminants has convincingly been demonstrated for only this species. Following coinfection of naive African buffaloes with isolates of three SAT serotypes from field buffaloes, palatine tonsil swabs were the sample of choice for recovering infectious FMDV up to 400 days postinfection (dpi). Postmortem examination identified infectious virus for up to 185 dpi and viral genomes for up to 400 dpi in lymphoid tissues of the head and neck, focused mainly in germinal centers. Interestingly, viral persistence in vivo was not homogenous, and the SAT-1 isolate persisted longer than the SAT-2 and SAT-3 isolates. Coinfection and passage of these SAT isolates in goat and buffalo cell lines demonstrated a direct correlation between persistence and cell-killing capacity. These data suggest that FMDV persistence occurs in the germinal centers of lymphoid tissue but that the duration of persistence is related to virus replication and cell killing capacity. IMPORTANCE: Foot-and-mouth disease virus (FMDV) causes a highly contagious acute vesicular disease in domestic livestock and wildlife species. African buffaloes (Syncerus caffer) are the primary carrier hosts of FMDV in African savannah ecosystems, where the disease is endemic. We have shown that the virus persists for up to 400 days in buffaloes and that there is competition between viruses during mixed infections. There was similar competition in cell culture: viruses that killed cells quickly persisted more efficiently in passaged cell cultures. These results may provide a mechanism for the dominance of particular viruses in an ecosystem. PMID- 26962215 TI - Effects of Filovirus Interferon Antagonists on Responses of Human Monocyte Derived Dendritic Cells to RNA Virus Infection. AB - Dendritic cells (DCs) are major targets of filovirus infection in vivo Previous studies have shown that the filoviruses Ebola virus (EBOV) and Marburg virus (MARV) suppress DC maturation in vitro Both viruses also encode innate immune evasion functions. The EBOV VP35 (eVP35) and the MARV VP35 (mVP35) proteins each can block RIG-I-like receptor signaling and alpha/beta interferon (IFN alpha/beta) production. The EBOV VP24 (eVP24) and MARV VP40 (mVP40) proteins each inhibit the production of IFN-stimulated genes (ISGs) by blocking Jak-STAT signaling; however, this occurs by different mechanisms, with eVP24 blocking nuclear import of tyrosine-phosphorylated STAT1 and mVP40 blocking Jak1 function. MARV VP24 (mVP24) has been demonstrated to modulate host cell antioxidant responses. Previous studies demonstrated that eVP35 is sufficient to strongly impair primary human monocyte-derived DC (MDDC) responses upon stimulation induced through the RIG-I-like receptor pathways. We demonstrate that mVP35, like eVP35, suppresses not only IFN-alpha/beta production but also proinflammatory responses after stimulation of MDDCs with RIG-I activators. In contrast, eVP24 and mVP40, despite suppressing ISG production upon RIG-I activation, failed to block upregulation of maturation markers or T cell activation. mVP24, although able to stimulate expression of antioxidant response genes, had no measurable impact of DC function. These data are consistent with a model where filoviral VP35 proteins are the major suppressors of DC maturation during filovirus infection, whereas the filoviral VP24 proteins and mVP40 are insufficient to prevent DC maturation. IMPORTANCE: The ability to suppress the function of dendritic cells (DCs) likely contributes to the pathogenesis of disease caused by the filoviruses Ebola virus and Marburg virus. To clarify the basis for this DC suppression, we assessed the effect of filovirus proteins known to antagonize innate immune signaling pathways, including Ebola virus VP35 and VP24 and Marburg virus VP35, VP40, and VP24, on DC maturation and function. The data demonstrate that the VP35s from Ebola virus and Marburg virus are the major suppressors of DC maturation and that the effects on DCs of the remaining innate immune inhibitors are minor. PMID- 26962216 TI - Human Papillomavirus E2 Regulates SRSF3 (SRp20) To Promote Capsid Protein Expression in Infected Differentiated Keratinocytes. AB - The human papillomavirus (HPV) life cycle is tightly linked to differentiation of the infected epithelial cell, suggesting a sophisticated interplay between host cell metabolism and virus replication. Previously, we demonstrated in differentiated keratinocytes in vitro and in vivo that HPV type 16 (HPV16) infection caused increased levels of the cellular SR splicing factors (SRSFs) SRSF1 (ASF/SF2), SRSF2 (SC35), and SRSF3 (SRp20). Moreover, the viral E2 transcription and replication factor that is expressed at high levels in differentiating keratinocytes could bind and control activity of the SRSF1 gene promoter. Here, we show that the E2 proteins of HPV16 and HPV31 control the expression of SRSFs 1, 2, and 3 in a differentiation-dependent manner. E2 has the greatest transactivation effect on expression of SRSF3. Small interfering RNA depletion experiments in two different models of the HPV16 life cycle (W12E and NIKS16) and one model of the HPV31 life cycle (CIN612-9E) revealed that only SRSF3 contributed significantly to regulation of late events in the virus life cycle. Increased levels of SRSF3 are required for L1 mRNA and capsid protein expression. Capsid protein expression was regulated specifically by SRSF3 and appeared independent of other SRSFs. Taken together, these data suggest a significant role of the HPV E2 protein in regulating late events in the HPV life cycle through transcriptional regulation of SRSF3 expression. IMPORTANCE: Human papillomavirus replication is accomplished in concert with differentiation of the infected epithelium. Virus capsid protein expression is confined to the upper epithelial layers so as to avoid immune detection. In this study, we demonstrate that the viral E2 transcription factor activates the promoter of the cellular SRSF3 RNA processing factor. SRSF3 is required for expression of the E4(^)L1 mRNA and so controls expression of the HPV L1 capsid protein. Thus, we reveal a new dimension of virus-host interaction crucial for production of infectious virus. SRSF proteins are known drug targets. Therefore, this study provides an excellent basis for developing strategies to regulate capsid protein production in the infected epithelium and the production of new virions. PMID- 26962218 TI - Vaccination with Live Attenuated Simian Immunodeficiency Virus (SIV) Protects from Mucosal, but Not Necessarily Intravenous, Challenge with a Minimally Heterologous SIV. AB - Few studies have evaluated the impact of the viral challenge route on protection against a heterologous simian immunodeficiency virus (SIV) challenge. We vaccinated seven macaques with a live attenuated SIV that differed from SIVmac239Deltanef by 24 amino acids, called m3KODeltanef. All animals were protected from an intrarectal SIVmac239 challenge, whereas only four animals were protected from subsequent intravenous SIVmac239 challenge. These data suggest that immune responses elicited by vaccination with live attenuated SIV in an individual animal can confer protection from intrarectal challenge while remaining insufficient for protection from intravenous challenge. IMPORTANCE: Our study is important because we show that vaccinated animals can be protected from a mucosal challenge with a heterologous SIV, but the same animals are not necessarily protected from intravenous challenge with the same virus. This is unique because in most studies, either vaccinated animals are challenged multiple times by the same route or only a single challenge is performed. An individually vaccinated animal is rarely challenged multiple times by different routes, so protection from different challenge routes cannot be measured in the same animal. Our data imply that vaccine-elicited responses in an individual animal may be insufficient for protection from intravenous challenge but may be suitable for protection from a mucosal challenge that better approximates human immunodeficiency virus (HIV) exposure. PMID- 26962219 TI - Respiratory Syncytial Virus (RSV) Pulmonary Infection in Humanized Mice Induces Human Anti-RSV Immune Responses and Pathology. AB - Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease, which causes high rates of morbidity and mortality in infants and the elderly. Models of human RSV pulmonary disease are needed to better understand RSV pathogenesis and to assess the efficacy of RSV vaccines. We assessed the RSV specific human innate, humoral, and cellular immune responses in humanized mice (mice with a human immune system [HIS mice]) with functional human CD4(+) T and B cells. These mice were generated by introduction of HLA class II genes, various human cytokines, and human B cell activation factor into immunodeficient NOD scid gamma (NSG) mice by the use of an adeno-associated virus vector, followed by engraftment of human hematopoietic stem cells. During the first 3 days of infection, HIS mice lost more weight and cleared RSV faster than NSG mice. Human chemokine (C-C motif) ligand 3 (CCL3) and human interleukin-1beta (IL-1beta) expression was detected in the RSV-infected HIS mice. The pathological features induced by RSV infection in HIS mice included peribronchiolar inflammation, neutrophil predominance in the bronchioalveolar lavage fluid, and enhanced airway mucus production. Human anti-RSV IgG and RSV-neutralizing antibodies were detected in serum and human anti-RSV mucosal IgA was detected in bronchioalveolar lavage fluid for up to 6 weeks. RSV infection induced an RSV-specific human gamma interferon response in HIS mouse splenocytes. These results indicate that human immune cells can induce features of RSV lung disease, including mucus hyperplasia, in murine lungs and that HIS mice can be used to elicit human anti RSV humoral and cellular immunity. IMPORTANCE: Infections with respiratory syncytial virus (RSV) are common and can cause severe lung disease in infants and the elderly. The lack of a suitable animal model with disease features similar to those in humans has hampered efforts to predict the efficacy of novel anti-RSV therapies and vaccines for use in humans. A murine model consisting of mice with a human immune system (HIS mice) could be useful for assessment of RSV disease and anti-RSV responses specific to humans. This study investigates an HIS mouse model to imitate human RSV disease and immune responses. We found that RSV lung infection in HIS mice results in an RSV-specific pathology that mimics RSV disease in humans and induces human anti-RSV immune responses. This model could be useful for better understanding of human RSV disease and for the development of RSV therapies. PMID- 26962220 TI - CD8+ T Cells Play a Bystander Role in Mice Latently Infected with Herpes Simplex Virus 1. AB - Based on an explant reactivation model, it has been proposed that CD8(+) T cells maintain latency in trigeminal ganglia (TG) of mice latently infected with herpes simplex virus 1 (HSV-1) [T. Liu, K. M. Khanna, X. Chen, D. J. Fink, and R. L. Hendricks, J Exp Med 191:1459-1466, 2000, doi:10.1084/jem.191.9.1459; K. M. Khanna, R. H. Bonneau, P. R. Kinchington, and R. L. Hendricks, Immunity 18:593 603, 2003, doi:10.1016/S1074-7613(03)00112-2]. In those studies, BALB/c mice were ocularly infected with an avirulent HSV-1 strain (RE) after corneal scarification. However, in our studies, we typically infect mice with a virulent HSV-1 strain (McKrae) that does not require corneal scarification. Using a combination of knockout mice, adoptive transfers, and depletion studies, we recently found that CD8alpha(+) dendritic cells (DCs) contribute to HSV-1 latency and reactivation in TG of ocularly infected mice (K. R. Mott, S. J. Allen, M. Zandian, B. Konda, B. G. Sharifi, C. Jones, S. L. Wechsler, T. Town, and H. Ghiasi, PLoS One 9:e93444, 2014, doi:10.1371/journal.pone.0093444). This suggested that CD8(+) T cells might not be the major regulators of HSV-1 latency in the mouse TG. To investigate this iconoclastic possibility, we used a blocking CD8 antibody and CD8(+) T cells in reactivated TG explants from mice latently infected with (i) the avirulent HSV-1 strain RE following corneal scarification or (ii) the virulent HSV-1 strain McKrae without corneal scarification. Independently of the strain or approach, our results show that CD8alpha(+) DCs, not CD8(+) T cells, drive latency and reactivation. In addition, adoptive transfer of CD8(+) T cells from wild-type (wt) mice to CD8alpha(-/-) mice did not restore latency to the level for wt mice or wt virus. In the presence of latency associated transcript (LAT((+)); wt virus), CD8(+) T cells seem to play a bystander role in the TG. These bystander T cells highly express PD-1, most likely due to the presence of CD8alpha(+) DCs. Collectively, these results support the notion that CD8(+) T cells do not play a major role in maintaining HSV-1 latency and reactivation. SIGNIFICANCE: This study addresses a fundamentally important and widely debated issue in the field of HSV latency reactivation. In this article, we directly compare the effects of anti-CD8 antibody, CD8(+) T cells, LAT, and CD8alpha(+) DCs in blocking explant reactivation in TG of mice latently infected with avirulent or virulent HSV-1. Our data suggest that CD8(+) T cells are not responsible for an increase or maintenance of latency in ocularly infected mice. However, they seem to play a bystander role that correlates with the presence of LAT, higher subclinical reactivation levels, and higher PD-1 expression levels. PMID- 26962217 TI - Zika Virus: New Clinical Syndromes and Its Emergence in the Western Hemisphere. AB - Zika virus (ZIKV) had remained a relatively obscure flavivirus until a recent series of outbreaks accompanied by unexpectedly severe clinical complications brought this virus into the spotlight as causing an infection of global public health concern. In this review, we discuss the history and epidemiology of ZIKV infection, recent outbreaks in Oceania and the emergence of ZIKV in the Western Hemisphere, newly ascribed complications of ZIKV infection, including Guillain Barre syndrome and microcephaly, potential interactions between ZIKV and dengue virus, and the prospects for the development of antiviral agents and vaccines. PMID- 26962221 TI - Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4 Mimetic Compounds. AB - The human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4 mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1 neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines. IMPORTANCE: Preventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine. PMID- 26962222 TI - Comparative Analysis of HIV-1 and Murine Leukemia Virus Three-Dimensional Nuclear Distributions. AB - Recent advances in fluorescence microscopy allow three-dimensional analysis of HIV-1 preintegration complexes in the nuclei of infected cells. To extend this investigation to gammaretroviruses, we engineered a fluorescent Moloney murine leukemia virus (MLV) system consisting of MLV-integrase fused to enhanced green fluorescent protein (MLV-IN-EGFP). A comparative analysis of lentiviral (HIV-1) and gammaretroviral (MLV) fluorescent complexes in the nuclei of infected cells revealed their different spatial distributions. This research tool has the potential to achieve new insight into the nuclear biology of these retroviruses. PMID- 26962223 TI - Functional Transplant of a Dengue Virus Serotype 3 (DENV3)-Specific Human Monoclonal Antibody Epitope into DENV1. AB - The four dengue virus (DENV) serotypes, DENV1 through 4, are endemic throughout tropical and subtropical regions of the world. While first infection confers long term protective immunity against viruses of the infecting serotype, a second infection with virus of a different serotype carries a greater risk of severe dengue disease, including dengue hemorrhagic fever and dengue shock syndrome. Recent studies demonstrate that humans exposed to DENV infections develop neutralizing antibodies that bind to quaternary epitopes formed by the viral envelope (E) protein dimers or higher-order assemblies required for the formation of the icosahedral viral envelope. Here we show that the quaternary epitope target of the human DENV3-specific neutralizing monoclonal antibody (MAb) 5J7 can be partially transplanted into a DENV1 strain by changing the core residues of the epitope contained within a single monomeric E molecule. MAb 5J7 neutralized the recombinant DENV1/3 strain in cell culture and was protective in a mouse model of infection with the DENV1/3 strain. However, the 5J7 epitope was only partially recreated by transplantation of the core residues because MAb 5J7 bound and neutralized wild-type (WT) DENV3 better than the DENV1/3 recombinant. Our studies demonstrate that it is possible to transplant a large number of discontinuous residues between DENV serotypes and partially recreate a complex antibody epitope, while retaining virus viability. Further refinement of this approach may lead to new tools for measuring epitope-specific antibody responses and new vaccine platforms. IMPORTANCE: Dengue virus is the most important mosquito-borne pathogen of humans worldwide, with approximately one-half the world's population living in regions where dengue is endemic. Dengue immunity following infection is robust and thought to be conferred by antibodies raised against the infecting virus. However, the specific viral components that these antibodies recognize and how they neutralize the virus have been incompletely described. Here we map a region on dengue virus serotype 3 recognized by the human neutralizing antibody 5J7 and then test the functional significance of this region by transplanting it into a serotype 1 virus. Our studies demonstrate a region on dengue virus necessary for 5J7 binding and neutralization. Our work also demonstrates the technical feasibility of engineering dengue viruses to display targets of protective antibodies. This technology can be used to develop new dengue vaccines and diagnostic assays. PMID- 26962226 TI - BPIFB6 Regulates Secretory Pathway Trafficking and Enterovirus Replication. AB - Bactericidal/permeability-increasing protein (BPI) fold-containing family B, member 3 (BPIFB3) is an endoplasmic reticulum (ER)-localized host factor that negatively regulates coxsackievirus B (CVB) replication through its control of the autophagic pathway. Here, we show that another member of the BPIFB family, BPIFB6, functions as a positive regulator of CVB, and other enterovirus, replication by controlling secretory pathway trafficking and Golgi complex morphology. We show that similar to BPIFB3, BPIFB6 localizes exclusively to the ER, where it associates with other members of the BPIFB family. However, in contrast to our findings that RNA interference (RNAi)-mediated silencing of BPIFB3 greatly enhances CVB replication, we show that silencing of BPIFB6 expression dramatically suppresses enterovirus replication in a pan-viral manner. Mechanistically, we show that loss of BPIFB6 expression induces pronounced alterations in retrograde and anterograde trafficking, which correlate with dramatic fragmentation of the Golgi complex. Taken together, these data implicate BPIFB6 as a key regulator of secretory pathway trafficking and viral replication and suggest that members of the BPIFB family participate in diverse host cell functions to regulate virus infections. IMPORTANCE: Enterovirus infections are associated with a number of severe pathologies, such as aseptic meningitis, dilated cardiomyopathy, type I diabetes, paralysis, and even death. These viruses, which include coxsackievirus B (CVB), poliovirus (PV), and enterovirus 71 (EV71), co-opt the host cell secretory pathway, which controls the transport of proteins from the endoplasmic reticulum to the Golgi complex, to facilitate their replication. Here we report on the identification of a novel regulator of the secretory pathway, bactericidal/permeability-increasing protein (BPI) fold containing family B, member 6 (BPIFB6), whose expression is required for enterovirus replication. We show that loss of BPIFB6 expression correlates with pronounced defects in the secretory pathway and greatly reduces the replication of CVB, PV, and EV71. Our results thus identify a novel host cell therapeutic target whose function could be targeted to alter enterovirus replication. PMID- 26962225 TI - Characterization of the Adeno-Associated Virus 1 and 6 Sialic Acid Binding Site. AB - The adeno-associated viruses (AAVs), which are being developed as gene delivery vectors, display differential cell surface glycan binding and subsequent tissue tropisms. For AAV serotype 1 (AAV1), the first viral vector approved as a gene therapy treatment, and its closely related AAV6, sialic acid (SIA) serves as their primary cellular surface receptor. Toward characterizing the SIA binding site(s), the structure of the AAV1-SIA complex was determined by X-ray crystallography to 3.0 A. Density consistent with SIA was observed in a pocket located at the base of capsid protrusions surrounding icosahedral 3-fold axes. Site-directed mutagenesis substitution of the amino acids forming this pocket with structurally equivalent residues from AAV2, a heparan sulfate binding serotype, followed by cell binding and transduction assays, further mapped the critical residues conferring SIA binding to AAV1 and AAV6. For both viruses five of the six binding pocket residues mutated (N447S, V473D, N500E, T502S, and W503A) abolished SIA binding, whereas S472R increased binding. All six mutations abolished or decreased transduction by at least 50% in AAV1. Surprisingly, the T502S substitution did not affect transduction efficiency of wild-type AAV6. Furthermore, three of the AAV1 SIA binding site mutants-S472R, V473D, and N500E escaped recognition by the anti-AAV1 capsid antibody ADK1a. These observations demonstrate that common key capsid surface residues dictate both virus binding and entry processes, as well as antigenic reactivity. This study identifies an important functional capsid surface "hot spot" dictating receptor attachment, transduction efficiency, and antigenicity which could prove useful for vector engineering. IMPORTANCE: The adeno-associated virus (AAV) vector gene delivery system has shown promise in several clinical trials and an AAV1-based vector has been approved as the first gene therapy treatment. However, limitations still exist with respect to transduction efficiency and the detrimental effects of preexisting host antibodies. This study aimed to identify key capsid regions which can be engineered to overcome these limitations. A sialic glycan receptor recognition pocket was identified in AAV1 and its closely related AAV6, using X ray crystallography. The site was confirmed by mutagenesis followed by cell binding and transduction assays. Significantly, residues controlling gene expression efficiency, as well as antibody escape variants, were also identified. This study thus provides, at the amino acid level, information for rational structural engineering of AAV vectors with improved therapeutic efficacy. PMID- 26962224 TI - Ion Channel Function and Cross-Species Determinants in Viral Assembly of Nonprimate Hepacivirus p7. AB - Nonprimate hepacivirus (NPHV), the closest homolog of hepatitis C virus (HCV) described to date, has recently been discovered in horses. Even though the two viruses share a similar genomic organization, conservation of the encoded hepaciviral proteins remains undetermined. The HCV p7 protein is localized within endoplasmic reticulum (ER) membranes and is important for the production of infectious particles. In this study, we analyzed the structural and functional features of NPHV p7 in addition to its role during virus assembly. Three dimensional homology models for NPHV p7 using various nuclear magnetic resonance spectroscopy (NMR) structures were generated, highlighting the conserved residues important for ion channel function. By applying a liposome permeability assay, we observed that NPHV p7 exhibited liposome permeability features similar to those of HCV p7, indicative of similar ion channel activity. Next, we characterized the viral protein using a p7-based trans-complementation approach. A similar subcellular localization pattern at the ER membrane was observed, although production of infectious particles was likely hindered by genetic incompatibilities with HCV proteins. To further characterize these cross-species constraints, chimeric viruses were constructed by substituting different regions of HCV p7 with NPHV p7. The N terminus and transmembrane domains were nonexchangeable and therefore constitute a cross-species barrier in hepaciviral assembly. In contrast, the basic loop and the C terminus of NPHV p7 were readily exchangeable, allowing production of infectious trans-complemented viral particles. In conclusion, comparison of NPHV and HCV p7 revealed structural and functional homology of these proteins, including liposome permeability, and broadly acting determinants that modulate hepaciviral virion assembly and contribute to the host-species barrier were identified. IMPORTANCE: The recent discovery of new relatives of hepatitis C virus (HCV) enables for the first time the study of cross-species determinants shaping hepaciviral pathogenesis. Nonprimate hepacivirus (NPHV) was described to infect horses and represents so far the closest homolog of HCV. Both viruses encode the same viral proteins; however, NPHV protein functions remain poorly understood. In this study, we aimed to dissect NPHV p7 on a structural and functional level. By using various NMR structures of HCV p7 as templates, three-dimensional homology models for NPHV p7 were generated, highlighting conserved residues that are important for ion channel function. A p7-based trans-complementation approach and the construction of NPHV/HCV p7 chimeric viruses showed that the N terminus and transmembrane domains were nonexchangeable. In contrast, the basic loop and the C terminus of NPHV p7 were readily exchangeable, allowing production of infectious viral particles. These results identify species-specific constraints as well as exchangeable determinants in hepaciviral assembly. PMID- 26962227 TI - Plum Pox Virus 6K1 Protein Is Required for Viral Replication and Targets the Viral Replication Complex at the Early Stage of Infection. AB - The potyviral RNA genome encodes two polyproteins that are proteolytically processed by three viral protease domains into 11 mature proteins. Extensive molecular studies have identified functions for the majority of the viral proteins. For example, 6K2, one of the two smallest potyviral proteins, is an integral membrane protein and induces the endoplasmic reticulum (ER)-originated replication vesicles that target the chloroplast for robust viral replication. However, the functional role of 6K1, the other smallest protein, remains uncharacterized. In this study, we developed a series of recombinant full-length viral cDNA clones derived from a Canadian Plum pox virus (PPV) isolate. We found that deletion of any of the short motifs of 6K1 (each of which ranged from 5 to 13 amino acids), most of the 6K1 sequence (but with the conserved sequence of the cleavage sites being retained), or all of the 6K1 sequence in the PPV infectious clone abolished viral replication. The trans expression of 6K1 or the cis expression of a dislocated 6K1 failed to rescue the loss-of-replication phenotype, suggesting the temporal and spatial requirement of 6K1 for viral replication. Disruption of the N- or C-terminal cleavage site of 6K1, which prevented the release of 6K1 from the polyprotein, either partially or completely inhibited viral replication, suggesting the functional importance of the mature 6K1. We further found that green fluorescent protein-tagged 6K1 formed punctate inclusions at the viral early infection stage and colocalized with chloroplast bound viral replicase elements 6K2 and NIb. Taken together, our results suggest that 6K1 is required for viral replication and is an important viral element of the viral replication complex at the early infection stage. IMPORTANCE: Potyviruses account for more than 30% of known plant viruses and consist of many agriculturally important viruses. The genomes of potyviruses encode two polyproteins that are proteolytically processed into 11 mature proteins, with the majority of them having been at least partially functionally characterized. However, the functional role of a small protein named 6K1 remains obscure. In this study, we showed that deletion of 6K1 or a short motif/region of 6K1 in the full-length cDNA clones of plum pox virus abolishes viral replication and that mutation of the N- or C-terminal cleavage sites of 6K1 to prevent its release from the polyprotein greatly attenuates or completely inhibits viral replication, suggesting its important role in potyviral infection. We report that 6K1 forms punctate structures and targets the replication vesicles in PPV-infected plant leaf cells at the early infection stage. Our data reveal that 6K1 is an important viral protein of the potyviral replication complex. PMID- 26962228 TI - MerTK Is a Functional Regulator of Myelin Phagocytosis by Human Myeloid Cells. AB - Multifocal inflammatory lesions featuring destruction of lipid-rich myelin are pathologic hallmarks of multiple sclerosis. Lesion activity is assessed by the extent and composition of myelin uptake by myeloid cells present in such lesions. In the inflamed CNS, myeloid cells are comprised of brain-resident microglia, an endogenous cell population, and monocyte-derived macrophages, which infiltrate from the systemic compartment. Using microglia isolated from the adult human brain, we demonstrate that myelin phagocytosis is dependent on the polarization state of the cells. Myelin ingestion is significantly enhanced in cells exposed to TGF-beta compared with resting basal conditions and markedly reduced in classically activated polarized cells. Transcriptional analysis indicated that TGF-beta-treated microglia closely resembled M0 cells. The tyrosine kinase phagocytic receptor MerTK was one of the most upregulated among a select number of differentially expressed genes in TGF-beta-treated microglia. In contrast, MerTK and its known ligands, growth arrest-specific 6 and Protein S, were downregulated in classically activated cells. MerTK expression and myelin phagocytosis were higher in CNS-derived microglia than observed in monocyte derived macrophages, both basally and under all tested polarization conditions. Specific MerTK inhibitors reduced myelin phagocytosis and the resultant anti inflammatory biased cytokine responses for both cell types. Defining and modulating the mechanisms that regulate myelin phagocytosis has the potential to impact lesion and disease evolution in multiple sclerosis. Relevant effects would include enhancing myelin clearance, increasing anti-inflammatory molecule production by myeloid cells, and thereby permitting subsequent tissue repair. PMID- 26962229 TI - KIR3DL1 and HLA-B Density and Binding Calibrate NK Education and Response to HIV. AB - NK cells recognize self-HLA via killer Ig-like receptors (KIR). Homeostatic HLA expression signals for inhibition via KIR, and downregulation of HLA, a common consequence of viral infection, allows NK activation. Like HLA, KIR are highly polymorphic, and allele combinations of the most diverse receptor-ligand pair, KIR3DL1 and HLA-B, correspond to hierarchical HIV control. We used primary cells from healthy human donors to demonstrate how subtype combinations of KIR3DL1 and HLA-B calibrate NK education and their consequent capacity to eliminate HIV infected cells. High-density KIR3DL1 and Bw4-80I partnerships endow NK cells with the greatest reactivity against HLA-negative targets; NK cells exhibiting the remaining KIR3DL1/HLA-Bw4 combinations demonstrate intermediate responsiveness; and Bw4-negative KIR3DL1(+) NK cells are poorly responsive. Cytotoxicity against HIV-infected autologous CD4(+) T cells strikingly correlated with reactivity to HLA-negative targets. These findings suggest that the programming of NK effector function results from defined features of receptor and ligand subtypes. KIR3DL1 and HLA-B subtypes exhibit an array of binding strengths. Like KIR3DL1, subtypes of HLA-Bw4 are expressed at distinct, predictable membrane densities. Combinatorial permutations of common receptor and ligand subtypes reveal binding strength, receptor density, and ligand density to be functionally important. These findings have immediate implications for prognosis in patients with HIV infection. Furthermore, they demonstrate how features of KIR and HLA modified by allelic variation calibrate NK cell reactive potential. PMID- 26962230 TI - TRIM21 Immune Signaling Is More Sensitive to Antibody Affinity Than Its Neutralization Activity. AB - Ab-coated viruses can be detected in the cytosol by the FcR tripartite motif containing 21 (TRIM21), which rapidly recruits the proteasomal machinery and triggers induction of immune signaling. As such, TRIM21 plays a key role in intracellular protection by targeting invading viruses for destruction and alerting the immune system. A hallmark of immunity is elicitation of a balanced response that is proportionate to the threat, to avoid unnecessary inflammation. In this article, we show how Ab affinity modulates TRIM21 immune function. We constructed a humanized monoclonal IgG1 against human adenovirus type 5 (AdV5) and a panel of Fc-engineered variants with a wide range of affinities for TRIM21. We found that IgG1-coated viral particles were neutralized via TRIM21, even when affinity was reduced by as much as 100-fold. In contrast, induction of NF-kappaB signaling was more sensitive to reduced affinity between TRIM21 and the Ab variants. Thus, TRIM21 mediates neutralization under suboptimal conditions, whereas induction of immune signaling is balanced according to the functional affinity for the incoming immune stimuli. Our findings have implications for engineering of antiviral IgG therapeutics with tailored effector functions. PMID- 26962231 TI - alpha-NAC-Specific Autoreactive CD8+ T Cells in Atopic Dermatitis Are of an Effector Memory Type and Secrete IL-4 and IFN-gamma. AB - Autoreactivity may play a critical role in the chronification of atopic dermatitis (AD). Several studies showed that AD patients produce IgE Abs specific for autoantigens, and we described Th as well as CD8(+) T cells specific for the autoallergen Hom s 2, the alpha-chain of the nascent polypeptide-associated complex (alpha-NAC). This study aimed to investigate the frequency and inflammatory phenotype of autoallergen-specific CD8(+) T cells. CD8(+) T cell immunodominant epitopes of alpha-NAC were mapped by applying prediction softwares, and binding affinity was confirmed by stabilization of empty MHC complexes. MHC class I tetramers were assembled and binding cells were analyzed directly ex vivo by flow cytometry and in terms of single-cell assessment by ChipCytometry. We report significantly elevated numbers of alpha-NAC-specific peripheral T cells in sensitized patients compared with nonatopic controls. These cells secrete IL-4 and IFN-gamma, and surface markers revealed significantly elevated frequencies of circulating terminally differentiated alpha-NAC-specific CD8(+) T cells in patients with AD compared with nonatopic donors. The observed phenotype of alpha-NAC-specific CD8(+) T cells indicates a role in the pathogenesis of AD. PMID- 26962234 TI - Reply to Gelfand and Cleveland. PMID- 26962233 TI - Deconstructing Chronic Low Back Pain in the Older Adult-Step by Step Evidence and Expert-Based Recommendations for Evaluation and Treatment. Part VI: Lumbar Spinal Stenosis. AB - OBJECTIVE: . To present the sixth in a series of articles designed to deconstruct chronic low back pain (CLBP) in older adults. This article focuses on the evaluation and management of lumbar spinal stenosis (LSS), the most common condition for which older adults undergo spinal surgery. METHODS: . The evaluation and treatment algorithm, a table articulating the rationale for the individual algorithm components, and stepped-care drug recommendations were developed using a modified Delphi approach. The Principal Investigator, a five member content expert panel and a nine-member primary care panel were involved in the iterative development of these materials. The illustrative clinical case was taken from the clinical practice of a contributor's colleague (SR). RESULTS: . We present an algorithm and supportive materials to help guide the care of older adults with LSS, a condition that occurs not uncommonly in those with CLBP. The case illustrates the importance of function-focused management and a rational approach to conservative care. CONCLUSIONS: . Lumbar spinal stenosis exists not uncommonly in older adults with CLBP and management often can be accomplished without surgery. Treatment should address all conditions in addition to LSS contributing to pain and disability. PMID- 26962235 TI - Reversion From Methicillin Susceptibility to Methicillin Resistance in Staphylococcus aureus. PMID- 26962232 TI - Age-Associated Resident Memory CD8 T Cells in the Central Nervous System Are Primed To Potentiate Inflammation after Ischemic Brain Injury. AB - Aging is associated with an increase in basal inflammation in the CNS and an overall decline in cognitive function and poorer recovery following injury. Growing evidence suggests that leukocyte recruitment to the CNS is also increased with normal aging, but, to date, no systematic evaluation of these age-associated leukocytes has been performed. In this work, the effect of aging on CNS leukocyte recruitment was examined. Aging was associated with more CD45(high) leukocytes, primarily composed of conventional CD8(+) T cells. These results were strain independent and seen in both sexes. Intravascular labeling and immunohistology revealed the presence of parenchymal CD8(+) T cells in several regions of the brain, including the choroid plexus and meninges. These cells had effector memory (CD44(+)CD62L(-)) and tissue-resident phenotypes and expressed markers associated with TCR activation. Analysis of TCRvbeta repertoire usage suggested that entry into the CNS is most likely stochastic rather than Ag driven. Correlational analyses revealed a positive association between CD8 T cell numbers and decreased proinflammatory function of microglia. However, the effects of cerebral ischemia and ex vivo stimulation of these cells dramatically increased production of TNF, IFN-gamma, and MCP-1/CCL2. Taken together, we identified a novel population of resident memory, immunosurveillant CD8 T cells that represent a hallmark of CNS aging and appear to modify microglia homeostasis under normal conditions, but are primed to potentiate inflammation and leukocyte recruitment following ischemic injury. PMID- 26962237 TI - Maintaining a Safe Blood Supply in an Era of Emerging Pathogens. AB - Coming shortly after outbreaks of dengue and chikungunya virus in related locations, the recent outbreak of Zika virus in the southern part of the western hemisphere is yet another reminder that infectious pathogens continue to emerge rapidly and can adversely affect public health, including the safety of the blood supply. In response to Zika virus, public health measures that rely largely on donor deferral and sourcing of blood from non-outbreak areas until a blood donor screening test becomes available have been implemented to address the safety of the blood supply in the United States. However, a more universal approach to ensuring blood safety in the setting of rapidly emerging infectious diseases is needed. PMID- 26962238 TI - Poverty and Child Health in the United States. AB - Almost half of young children in the United States live in poverty or near poverty. The American Academy of Pediatrics is committed to reducing and ultimately eliminating child poverty in the United States. Poverty and related social determinants of health can lead to adverse health outcomes in childhood and across the life course, negatively affecting physical health, socioemotional development, and educational achievement. The American Academy of Pediatrics advocates for programs and policies that have been shown to improve the quality of life and health outcomes for children and families living in poverty. With an awareness and understanding of the effects of poverty on children, pediatricians and other pediatric health practitioners in a family-centered medical home can assess the financial stability of families, link families to resources, and coordinate care with community partners. Further research, advocacy, and continuing education will improve the ability of pediatricians to address the social determinants of health when caring for children who live in poverty. Accompanying this policy statement is a technical report that describes current knowledge on child poverty and the mechanisms by which poverty influences the health and well-being of children. PMID- 26962236 TI - Inflammation and Change in Body Weight With Antiretroviral Therapy Initiation in a Multinational Cohort of HIV-Infected Adults. AB - BACKGROUND: Both wasting and obesity are associated with inflammation, but the extent to which body weight changes influence inflammation during human immunodeficiency virus infection is unknown. METHODS: Among a random virologically suppressed participants of the Prospective Evaluation of Antiretrovirals in Resource-Limited Settings trial, inflammatory markers were measured at weeks 0, 24, and 48 after antiretroviral therapy (ART) initiation. Associations between both baseline and change in body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared) and changes in inflammation markers were assessed using random effects models. RESULTS: Of 246 participants, 27% were overweight/obese (BMI, >= 25), and 8% were underweight (BMI < 18.5) at baseline. After 48 weeks, 37% were overweight/obese, and 3% were underweight. While level of many inflammatory markers decreased 48 weeks after ART initiation in the overall group, the decrease in C-reactive protein (CRP) level was smaller in overweight/obese participants (P = .01), and the decreases in both CRP (P = .01) and interleukin 18 (P = .02) levels were smaller in underweight participants. Each 1-unit gain in BMI among overweight/obese participants was associated with a 0.02-log10 increase in soluble CD14 level (P = .05), while each 1-unit BMI gain among underweight participants was associated with a 9.32-mg/L decrease in CRP level (P = .001). CONCLUSIONS: Being either overweight or underweight at ART initiation was associated with heightened systemic inflammation. While weight gain among overweight/obese persons predicted increased inflammation, weight gain among underweight persons predicted reduced inflammation. PMID- 26962239 TI - Mediators and Adverse Effects of Child Poverty in the United States. AB - The link between poverty and children's health is well recognized. Even temporary poverty may have an adverse effect on children's health, and data consistently support the observation that poverty in childhood continues to have a negative effect on health into adulthood. In addition to childhood morbidity being related to child poverty, epidemiologic studies have documented a mortality gradient for children aged 1 to 15 years (and adults), with poor children experiencing a higher mortality rate than children from higher-income families. The global great recession is only now very slowly abating for millions of America's children and their families. At this difficult time in the history of our nation's families and immediately after the 50th anniversary year of President Lyndon Johnson's War on Poverty, it is particularly germane for the American Academy of Pediatrics, which is "dedicated to the health of all children," to publish a research supported technical report that examines the mediators associated with the long recognized adverse effects of child poverty on children and their families. This technical report draws on research from a number of disciplines, including physiology, sociology, psychology, economics, and epidemiology, to describe the present state of knowledge regarding poverty's negative impact on children's health and development. Children inherit not only their parents' genes but also the family ecology and its social milieu. Thus, parenting skills, housing, neighborhood, schools, and other factors (eg, medical care) all have complex relations to each other and influence how each child's genetic canvas is expressed. Accompanying this technical report is a policy statement that describes specific actions that pediatricians and other child advocates can take to attenuate the negative effects of the mediators identified in this technical report and improve the well-being of our nation's children and their families. PMID- 26962240 TI - Interventions To Prevent Retinopathy of Prematurity: A Meta-analysis. AB - CONTEXT: The effectiveness of many interventions aimed at reducing the risk of retinopathy has not been well established. OBJECTIVE: To estimate the effectiveness of nutritional interventions, oxygen saturation targeting, blood transfusion management, and infection prevention on the incidence of retinopathy of prematurity (ROP). DATA SOURCES: A comprehensive search of several databases was conducted, including Medline, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through March 2014. STUDY SELECTION: We included studies that evaluated nutritional interventions, management of supplemental oxygen, blood transfusions, or infection reduction and reported the incidence of ROP and mortality in neonates born at <32 weeks. DATA EXTRACTION: We extracted patient characteristics, interventions, and risk of bias indicators. Outcomes of interest were any stage ROP, severe ROP or ROP requiring treatment, and mortality. RESULTS: We identified 67 studies enrolling 21 819 infants. Lower oxygen saturation targets reduced the risk of developing any stage ROP (relative risk [RR] 0.86, 95% confidence interval [CI], 0.77-0.97) and severe ROP or ROP requiring intervention (RR 0.58, 95% CI, 0.45-0.74) but increased mortality (RR 1.15, 95% CI, 1.04-1.29). Aggressive parenteral nutrition reduced the risk of any stage ROP but not severe ROP. Supplementation of vitamin A, E, or inositol and breast milk feeding were beneficial but only in observational studies. Use of transfusion guidelines, erythropoietin, and antifungal agents were not beneficial. LIMITATIONS: Results of observational studies were not replicated in randomized trials. Interventions were heterogeneous across studies. CONCLUSIONS: At the present time, there are no safe interventions supported with high quality evidence to prevent severe ROP. PMID- 26962241 TI - Patient age was an independent predictor of cancer-specific survival in male patients with upper tract urothelial carcinoma treated by radical nephroureterectomy. AB - OBJECTIVE: We hypothesized that there may be a prognostic difference in age between the genders and evaluated the influence of gender-adjusted age on prognosis in upper tract urothelial carcinoma patients. METHODS: A total of 839 patients with upper tract urothelial carcinoma from a retrospective multi institutional cohort were included. The patients were divided into four groups consisting of males (N = 610) and females (N = 229) according to age ((i) <60 years, (ii) 60-69.9 years, (iii) 70-79.9 years and (iv) >=80 years), and we evaluated the associations of patient age and gender with clinicopathological features and oncological outcomes following radical nephroureterectomy. The median follow-up duration was 34 months. RESULTS: Disease recurrence occurred in 249 patients and 192 patients died of upper tract urothelial carcinoma. The 3 year cancer-specific survival rates were (i) 84.3%, (ii) 80.2%, (iii) 77.1% and (iv) 71.5% in the entire patient population (P = 0.001); (i) 84.5%, (ii) 81.1%, (iii) 76.8% and (iv) 69.7% in males (P = 0.010); and (i) 83.3%, (ii) 76.9%, (iii) 77.7% and (iv) 72.9% in females (P = 0.287), respectively. No significant differences between disease recurrence and age were found in the male or female population. In multivariate analysis, older age was an independent predictor of cancer-specific survival, in addition to advanced pT stage, the presence of lymphovascular invasion and lymph node involvement in males. In contrast, age was not associated with cancer-specific survival in females, while high grade, advanced pT stage, the presence of lymph node involvement and multifocal tumor were independent predictors. CONCLUSION: The results indicate that gender adjusted age might be a new prognostic factor in upper tract urothelial carcinoma patients. PMID- 26962243 TI - Repeated biopsy results. PMID- 26962242 TI - The magnitude of best tumor shrinkage during second-line targeted therapy affects progression-free survival but not overall survival in patients with metastatic renal cell carcinoma. AB - OBJECTIVE: The present study aimed to evaluate the influence of the magnitude of best tumor shrinkage during second-line targeted therapy after first-line tyrosine kinase inhibitor failure on metastatic renal cell carcinoma prognosis. METHODS: Fifty-two patients were enrolled. The magnitude of tumor shrinkage was assessed according to the Response Evaluation Criteria in Solid Tumors v. 1.1, and evaluated as a continuous variable and by categorical classification: good responders (greater than or equal to -30%), mild responders (-0.1 to -29.9%), poor responders (0 to +19.9%) and non-responders (greater than or equal to +20% or new lesions). Overall survival and progression-free survival after second-line therapy initiation were evaluated according to the categorical classification. Factors predicting overall survival and progression-free survival were also examined. RESULTS: The mean magnitude of tumor shrinkage was -1.29%, and there were 9, 21, 11 and 11 good responders, mild responders, poor responders and non responders, respectively. The overall survival and progression-free survival significantly improved as the magnitude of tumor shrinkage increased according to the categorical classification (overall survival: not reached, 27.8, 18.2 and 4.67 months; progression-free survival: 13.4, 8.19, 5.18 and 1.84 months, respectively; P< 0.0001 for both). For overall survival, the magnitude of tomor shrinkage was not demonstrated as an independent indicator in the multivariate analysis (P= 0.0872 for the categorical classification, P= 0.133 for the continuous variable) whereas for second-line progression-free survival, the magnitude of tumor shrinkage according to both the categorical classification and continuous variable was found to be an independent factor in the multivariate analysis (P< 0.0001 for both). CONCLUSIONS: The magnitude of tumor shrinkage is an independent predictive factor for progression-free survival, and may represent a surrogate marker for overall survival. PMID- 26962244 TI - Predictive value of radiological response rate for pathological response to neoadjuvant chemotherapy and post-cystectomy survival of bladder urothelial cancer. AB - OBJECTIVE: To determine the predictive value of the radiological response rate assessed by serial pelvic computed tomography scans for pathological response to neoadjuvant chemotherapy and clinical outcomes after radical cystectomy in bladder urothelial cancer patients. METHODS: We retrospectively reviewed 59 patients with muscle-invasive bladder cancer who underwent radical cystectomy following neoadjuvant chemotherapy. Pretreatment and post-neoadjuvant chemotherapy computed tomography scans were evaluated by a single radiologist to determine the radiological response rate based on the largest diameter of the primary tumor. Association of the radiological response rate with pathological findings of the radical cystectomy specimen and post-radical cystectomy clinical outcomes were assessed. RESULTS: The pathological complete response rate was 25% (n = 15) and the median (range) radiological response rate was 0.58 (0.00-1.00). The radiological response rate was significantly associated with <=pT1. Patients with pathological downstaging to <=pTa/is or pT1, compared with those with pT2<= tumor, had significantly better post-radical cystectomy recurrence-free survival (2-year survival 92.0, 88.9, 36.8%, respectively, P < 0.0001), disease-specific survival (2-year survival 95.8, 88.9, 47.3%, respectively, P < 0.0001) and overall survival (2-year survival 91.7, 88.9, 40.1%, respectively, P < 0.0001). Patients with a higher radiological response rate (>=0.57) had significantly better post-radical cystectomy recurrence-free survival (2-year survival 89.7 vs. 48.1%, P = 0.0011), disease-specific survival (2-year survival 93.2 vs. 48.2%, P < 0.0001) and overall survival (2-year survival 90.0 vs. 39.0%, P < 0.0001). Multivariate analyses using the Cox proportional hazard model revealed that the radiological response rate was an independent predictor for favorable pT stage and recurrence-free survival. CONCLUSION: The radiological response rate determined by pretreatment and post-chemotherapy computed tomography scans predicts the pathological outcome and post-radical cystectomy prognosis, which is clinically relevant and useful for patient counselling and decision-making. PMID- 26962245 TI - SonoTip Pro EBUS-TBNA needle-the need for comparative studies with the Vizishot 21 gauge needle. PMID- 26962246 TI - A prospective multicenter study of intermittent chemotherapy with docetaxel and prednisolone for castration-resistant prostate cancer. AB - OBJECTIVE: The optimal schedule of docetaxel chemotherapy for castration resistant prostate cancer is unknown, although continuous administration is accepted as the standard. We conducted a Phase II trial to evaluate the outcome of intermittent docetaxel and prednisolone therapy in castration-resistant prostate cancer. METHODS: The patients were treated using a 28-day cycle of docetaxel (70 mg/m2 on Day 1) and oral prednisolone (10 mg/day). After three consecutive administrations of docetaxel, a holiday was taken until prostate specific antigen levels returned to the baseline. The therapy was continued intermittently until the disease progressed, drug toxicity occurred, or the patients refused further treatment. The primary endpoint was overall survival. Time to treatment failure, adverse events, the duration of chemotherapy holiday and quality of life were also evaluated. RESULTS: A total of 120 patients were enrolled. The median age and pretreatment prostate specific antigen level were 72 years and 37.5 ng/ml, respectively. Sixty (50.0%) patients resumed chemotherapy after the first holiday, and a maximum of six courses were administered to four patients. The median period of the first, second and third-to-fifth holiday was 18.6, 11.0 and 4.9 weeks, respectively. Toxicity was moderate, except for two fatal adverse events. The median time to treatment failure and overall survival from the initiation of docetaxel and prednisolone therapy in all patients were 17.5 and 35.0 months, respectively. All quality-of-life scores were unchanged statistically from the start of docetaxel and prednisolone therapy to the beginning of the second course. CONCLUSIONS: Intermittent docetaxel and prednisolone therapy might be a feasible treatment option for castration resistant prostate cancer with comparable outcome and successful chemotherapy holidays. PMID- 26962247 TI - The revised guidelines of the Medical Council of India for academic promotions: Need for a rethink. PMID- 26962248 TI - A quest for utilitarian approach in research. PMID- 26962249 TI - Preoperative cardiovascular investigations in liver transplant candidate: An update. AB - Cardiovascular complications are a major cause of morbidity and mortality in patients with end-stage liver disease (ESLD) undergoing liver transplantation. Identifying candidates at the highest risk of postoperative cardiovascular complications is the cornerstone for optimizing the outcome. Ischaemic heart disease contributes to major portion of cardiovascular complications and therefore warrants evaluation in the preoperative period. Patients of ESLD usually demonstrate increased cardiac output, compromised ventricular response to stress, low systemic vascular resistance and occasionally bradycardia. Despite various recommendations for preoperative evaluation of cardiovascular disease in liver transplant candidates, a considerable controversy on screening methodology persists. This review critically focuses on the rapidly expanding body of evidence for diagnosis and risk stratification of cardiovascular disorder in liver transplant candidates. PMID- 26962251 TI - A comparative study of attenuation of propofol-induced pain by lignocaine, ondansetron, and ramosetron. AB - BACKGROUND AND AIMS: Propofol is widely used for induction of anaesthesia, although the pain during its injection remains a concern for all anaesthesiologists. A number of techniques have been adopted to minimise propofol induced pain. Various 5-hydroxytryptamine-3 antagonists have shown to reduce propofol-induced pain. Hence, this placebo-controlled study was conducted to compare the efficacy of ondansetron, ramosetron and lignocaine in terms of attenuation of propofol-induced pain during induction of anaesthesia. METHODS: Hundred and fifty adult patients, aged 18-60 years, posted for various elective surgical procedures under general anaesthesia were randomly assigned to three groups of 50 each. Group R received 0.3 mg of ramosetron, Group L received 0.5 mg/kg of 2% lignocaine and Group O received 4 mg of ondansetron. After intravenous (IV) pre-treatment of study drug, manual occlusion of venous drainage was done at mid-arm with the help of an assistant for 1 min. This was followed by administration of propofol (1%) after release of venous occlusion. Pain was assessed with a four-point scale. Unpaired Student's t-test and Chi-square test/Fisher's exact test were used to analyse results. RESULTS: The overall incidence and intensity of pain were significantly less in Groups L and R compared to Group O (P <= 0.001). The incidence of mild to moderate pain in Groups O, R and L was 56%, 26% and 20%, respectively. The incidence of score '0' (no pain) was significantly higher in Group L (76%) and Group R (72%) than Group O (34%) (P < 0.001). CONCLUSION: Pre-treatment with IV ramosetron 0.3 mg is equally effective as 0.5 mg/kg of 2% lignocaine in preventing propofol-induced pain and both were better than ondansetron. PMID- 26962250 TI - Does tranexamic acid reduce blood loss during head and neck cancer surgery? AB - BACKGROUND AND AIMS: Transfusion of blood and blood products poses several hazards. Antifibrinolytic agents are used to reduce perioperative blood loss. We decided to assess the effect of tranexamic acid (TA) on blood loss and the need for transfusion in head and neck cancer surgery. METHODS: After Institutional Review Board approval, 240 patients undergoing supramajor head and neck cancer surgeries were prospectively randomised to either TA (10 mg/kg) group or placebo (P) group. After induction, the drug was infused by the anaesthesiologist, who was blinded to allocation, over 20 min. The dose was repeated every 3 h. Perioperative (up to 24 h) blood loss, need for transfusion and fluid therapy was recorded. Thromboelastography (TEG) was performed at fixed intervals in the first 100 patients. Patients were watched for post-operative complications. RESULTS: Two hundred and nineteen records were evaluable. We found no difference in intraoperative blood loss (TA - 750 [600-1000] ml vs. P - 780 [150-2600] ml, P = 0.22). Post-operative blood loss was significantly more in the placebo group at 24 h (P - 200 [120-250] ml vs. TA - 250 [50-1050] ml, P = 0.009), but this did not result in higher number of patients needing transfusions (TA - 22/108 and P - 27/111 patients, P = 0.51). TEG revealed faster clot formation and minimal fibrinolysis. Two patients died of causes unrelated to study drug. Incidence of wound complications and deep venous thrombosis was similar. CONCLUSION: In head and neck cancer surgery, TA did not reduce intraoperative blood loss or need for transfusions. Perioperative TEG variables were similar. This may be attributed to pre-existing hypercoagulable state and minimal fibrinolysis in cancer patients. PMID- 26962252 TI - Evaluation of caudal dexamethasone with ropivacaine for post-operative analgesia in paediatric herniotomies: A randomised controlled study. AB - BACKGROUND AND AIMS: Caudal analgesia is one of the most popular regional blocks in paediatric patients undergoing infra-umbilical surgeries but with the drawback of short duration of action after single shot local anaesthetic injection. We evaluated whether caudal dexamethasone 0.1 mg/kg as an adjuvant to the ropivacaine improved analgesic efficacy after paediatric herniotomies. METHODS: Totally 128 patients of 1-5 years age group, American Society of Anaesthesiologists physical status I and II undergoing elective inguinal herniotomy were randomly allocated to two groups in double-blind manner. Group A received 1 ml/kg of 0.2% ropivacaine caudally and Group B received 1 ml/kg of 0.2% ropivacaine, in which 0.1 mg/kg dexamethasone was added for caudal analgesia. Post operative pain by faces, legs, activity, cry and consolability tool score, rescue analgesic requirement and adverse effects were noted for 24 h. RESULTS: Results were statistically analysed using Student's t-test. Pain scores measured at 1, 2, 4, and 6 h post-operative, were lower in Group B as compared to Group A. Mean duration of analgesia in Group A was 248.4 +/- 54.1 min and in Group B was 478.046 +/- 104.57 min with P = 0.001. Rescue analgesic requirement was more in Group A as compared to Group B. Adverse effects after surgery were comparable between the two groups. CONCLUSION: Caudal dexamethasone added to ropivacaine is a good alternative to prolong post-operative analgesia with less pain score compared to caudal ropivacaine alone. PMID- 26962253 TI - Does dexmedetomidine improve analgesia of superficial cervical plexus block for thyroid surgery? AB - BACKGROUND AND AIMS: Bilateral superficial cervical plexus block (BSCPB) is effective in reducing pain following thyroid surgeries. We studied the effect of dexmedetomidine on duration and quality of analgesia produced by BSCPB with 0.5% ropivacaine in patients undergoing thyroid surgeries. METHODS: In this prospective double-blinded study, 60 adults undergoing thyroid surgeries were randomised into two equal groups to receive BSCPB, either with 20 ml 0.5% ropivacaine (Group A) or 20 ml 0.5% ropivacaine with 0.5 MUg/kg dexmedetomidine (Group B) after induction of anaesthesia. Visual analogue scale (VAS) was used to assess analgesia postoperatively at 0, 2, 4, 6, 12 and 24 h and patient satisfaction at 24 h. Haemodynamics were recorded peri-operatively. Wilcoxon signed rank test and Mann-Whitney U-test were applied for VAS and sedation scores. Unpaired t-test was applied for age, weight, duration of surgery and duration of post-operative analgesia. RESULTS: There was significantly longer duration of analgesia in Group B (1696.2 +/- 100.2 vs. 967.8 +/- 81.6 min; P < 0.001) and higher patient satisfaction at 24 h (7 [7-9] vs. 5 [4-6]; P < 0.001). While VAS score for pain were similar up to 6 h, they were lower in Group B at 12 h (0 [0-1] vs. 2 [1-2]; P < 0.001) and 24 h (2 [2-2] vs. 5 [5-6]; P < 0.001). Haemodynamic stability and sedation scores were similar across the groups. There were no adverse events. However, pain during swallowing persisted in both the groups. CONCLUSION: Combination of 0.5% ropivacaine and dexmedetomidine for BSCPB provided significantly prolonged and better quality of postoperative analgesia and patient satisfaction than with 0.5% ropivacaine alone in patients undergoing thyroidectomy. PMID- 26962254 TI - A prospective, comparative, randomised, double blind study on the efficacy of addition of clonidine to 0.25% bupivacaine in scalp block for supratentorial craniotomies. AB - BACKGROUND AND AIMS: Scalp blocks combined with general anaesthesia reduce pin and incision response, along with providing stable perioperative haemodynamics and analgesia. Clonidine has proved to be a valuable additive in infiltrative blocks. We studied the efficacy and safety of addition of clonidine 2 MUg/kg to scalp block with 0.25% bupivacaine (Group B) versus plain 0.25% bupivacaine (Group A) for supratentorial craniotomies. METHODS: Sixty patients were randomly divided into two groups to receive scalp block: Group A (with 0.25% bupivacaine) and Group B (with 0.25% bupivacaine and clonidine (2 MUg/kg). Bilateral scalp block was given immediately after induction. All the patients received propofol based general anaesthesia. Intraoperatively, propofol infusion was maintained at 75 to 100 MUg/kg/h up to dura closure and reduced to 50-75 MUg/kg/h up to skin closure with atracurium infusion stopped at dura closure. Heart rate (HR) and mean arterial pressure (MAP) were monitored at pin insertion, at 5 minute intervals from incision till dura opening and again at 5 minute interval from dura closure up to skin closure. Fentanyl 0.5 MUg/kg was given if a 20% increase in either HR and/or MAP was observed. Postoperative haemodynamics and verbal rating scores (VRS) were recorded. When the VRS score increased above 3, rescue analgesia was given. Any intraoperative haemodynamic complications were noted. RESULTS: Group A showed a significant increase in haemodynamic variables during the perioperative period as compared to group B (P < 0.05). Addition of clonidine 2 MUg/kg in the infiltrative block also provided significantly prolonged postoperative analgesia. CONCLUSIONS: Addition of clonidine to scalp block provided better perioperative haemodynamic stability and significantly prolonged analgesia. PMID- 26962255 TI - A randomized controlled study comparing intrathecal hyperbaric bupivacaine fentanyl mixture and isobaric bupivacaine-fentanyl mixture in common urological procedures. AB - BACKGROUND AND AIMS: Bupivacaine is available in isobaric and hyperbaric forms for intrathecal use and opioids are used as additives to modify their effects. The aim of this study was to compare the efficacy and haemodynamic effect of intrathecal isobaric bupivacaine-fentanyl mixture and hyperbaric bupivacaine fentanyl mixture in common urological procedures. METHODS: One hundred American Society of Anesthesiologists physical status 1 and 2 patients undergoing urological procedures were randomized into two groups. Group 1 received 3 ml of 0.5% isobaric bupivacaine with 25 MUg fentanyl while Group 2 received 3 ml of 0.5% hyperbaric bupivacaine with 25 MUg fentanyl. The parameters measured include heart rate, blood pressure, respiratory rate, onset and duration of motor and sensory blockade. Student's unpaired t-test and the chi(2) test were used to analyse the results, using the SPSS version 11.5 software. RESULTS: The haemodynamic stability was better with isobaric bupivacaine fentanyl mixture (Group 1) than with hyperbaric bupivacaine fentanyl mixture (Group 2). The mean onset time in Group 1 for both sensory block (4 min) and motor block (5 min) was longer compared with Group 2. The duration of sensory block (127.8 +/- 38.64 min) and motor block (170.4 +/- 27.8 min) was less with isobaric bupivacaine group compared with hyperbaric bupivacaine group (sensory blockade 185.4 +/- 16.08 min and motor blockade 201.6 +/- 14.28 min). Seventy percent of patients in Group 2 had maximum sensory block level of T6 whereas it was 53% in Group 1. More patients in Group 1 required sedation compared to Group 2. CONCLUSION: Isobaric bupivacaine fentanyl mixture was found to provide adequate anaesthesia with minimal incidence of haemodynamic instability. PMID- 26962256 TI - Anaesthetic considerations for liver transplantation in propionic acidemia. AB - Propionic acidemia (PA) is an autosomal recessive disorder of metabolism due to deficiency of the enzyme propionyl-CoA carboxylase (PCC) that converts propionyl CoA to methylmalonyl-CoA with the help of the cofactor biotin inside the mitochondria. The resultant accumulation of propionyl-CoA causes severe hyperammonaemia and life-threatening metabolic acidosis. Based on the positive outcomes, liver transplantation is now recommended for individuals with recurrent episodes of hyperammonaemia or acidosis that is not adequately controlled with appropriate medical therapies. We report anaesthetic management of two children with PA for liver transplantation at our institution. It is essential for the anaesthesiologist, caring for these individuals to be familiar with the manifestations of the disease, the triggers for decompensation and management of an acute episode. PMID- 26962257 TI - Anaesthesia for robotic thyroidectomy for thyroid cancer and review of literature. AB - Robotic thyroidectomy (RT) is a new gasless, scarless technique which utilises the da VinciTM surgical robot to excise thyroid tumours. Anaesthetic management must be modified according to the patient position and robotic surgery equipment. Anaesthesiologists need to be geared up to face the new challenges posed by advancements in surgical techniques in order to maintain patient safety. Another vital aspect of this surgery is documenting possible recurrent laryngeal nerve palsy, for which a C-Mac D-BladeTM video laryngoscope serves as a valuable tool. Post-operative pain management in RT also merits special attention. PMID- 26962258 TI - The efficacy of different methods of pre-operative counselling on perioperative anxiety in patients undergoing regional anaesthesia. PMID- 26962259 TI - Post-operative accidental diagnosis of intra-cerebellar astrocytoma in an emergency appendicectomy case. PMID- 26962260 TI - Effect of indocyanine green dye administration on cerebral oxygen saturation. PMID- 26962261 TI - Carbon dioxide embolism during endoscopic thyroidectomy. PMID- 26962262 TI - Defective heat moisture exchange filter causing 'block' in anaesthesia breathing circuit. PMID- 26962263 TI - Legg-Calve-Perthes disease: A must know entity for anaesthesiologists. PMID- 26962264 TI - Guidewire replacement of leaking paediatric intravenous cannula. PMID- 26962265 TI - Dandy Walker syndrome with giant occipital meningocele with craniovertebral anomalies: Challenges faced during anaesthesia. PMID- 26962266 TI - Sevoflurane in an infant with dilated cardiomyopathy due to myocarditis and hypocalcaemia. PMID- 26962267 TI - Migration, Social Organization, and the Sexual Partners of Mexican Men. AB - We build on recent developments in social organization theory to examine the sexual partnering of Mexican men in a new area of immigrant destination. We elaborate on two levels of contextual influence: 1) how differences in social capital between sending and receiving communities affect partner formation and 2) how neighborhood social cohesion influences immigrants' behavior. Data come from an original survey conducted in Durham, NC and migrant sending communities in Mexico. We show dramatic differences in sexual partnering between Mexico and the U.S. that are directly linked to lack of social networks and familial support. Neighborhood level social cohesion in part counteracts those effects. The role of social capital and neighborhoods, however, is highly gendered. The presence of women is a critical dimension of the social organization of immigrant communities and its effect extends beyond mere partner availability. PMID- 26962269 TI - Retirement migration, the 'other' story: caring for frail elderly British citizens in Spain. AB - Recent years have seen a growth in research on retirement/lifestyle migration to Spain, however this has tended to focus on the reasons for moving, as well as the lifestyles adopted as part of a healthy and active retirement. However, ageing in Spain can bring challenges as a person's resources for independent living diminish. This paper draws on narrative interviews with vulnerable older British people in Spain, focusing on those who have encountered a severe decline in health, are frail and in need of care. It looks at the formal and informal networks and agencies that support these individuals, in particular the resources and strategies they employ to access care. Drawing on a framework of care provision developed by Glucksmann and Lyons, four broad modes of provision for old age care used by older British people in Spain are identified: state/public, family/community, voluntary/not-for-profit and market/for-profit. The paper argues that there are language, cultural, spatial and financial barriers when accessing care in Spain as an older British citizen. It is concluded that there are some frail, vulnerable people that may fall through a support gap, whereby they are no longer the responsibility of UK welfare services, yet not fully recognised in their new country of residence, and asks if more should be done to support this population. PMID- 26962268 TI - Drug Design Strategies for GPCR Allosteric Modulators. PMID- 26962270 TI - Disability in U.S. Households, 2000-2010: Findings from the National Health Interview Survey. AB - Understanding the demographic structure of households containing members with disabilities is of key importance in policy planning for populations with disabilities at state and national levels. Yet, most, but not all, previous family-level studies of disability have excluded persons living alone or with unrelated persons (e.g., a housemate or an unmarried partner) because they are not considered families. To address this gap, the authors utilize National Health Interview Survey data to produce household-level estimates of disability using a detailed household type variable that includes households omitted from previous reports. Findings indicate that one-person households made up 24.7% of all households with an adult aged 18-64 with a disability, and 42.9% of all households with an adult aged 65 or older with a disability. Including nonfamily households provides a clearer picture of the association between living arrangements and disability in the U.S. PMID- 26962271 TI - Challenging biopower: "Liquid cuffs" and the "Junkie" habitus. AB - BACKGROUND: Methadone maintenance treatment program (MMTP) is associated with improved quality of life amongst many heroin users. Still, program adherence problems remain a fact. AIM: To improve our understanding of MMTP "adherence problems". METHODS: Using snowball sampling, two subgroups were recruited: MMTP enrollees and non-enrollees. A semi-structured questionnaire guided all in-depth interviews. Interviews were recorded, transcribed, hand-coded and analyzed using a grounded theory approach. FINDINGS: Of 28 participants, 23 were male and Fifteen were in MMTP. All were NYC residents. Most were Hispanic (57%) and Caucasian (32%). The average age was 38 years. Twenty-two had a General Educational Development or less. All were poor and 64% were homeless. Many do not enroll in MMTP to quit heroin but to avoid physical withdrawals. Once enrolled, problems emerge with program regulations and methadone's pharmacology. These they refer to as "liquid cuffs". Drawing on Michel Foucault, methadone may be considered a disciplinary biopower technology that participants challenge using specific strategies. A "Junkie" habitus, crystallized by emotional and identitarian heroin-dispositions, also challenges biopower. CONCLUSIONS: The "liquid cuffs" experience along with the "Junkie" habitus effectively challenge disciplinary biopower. Loosening program regulations may improve quality of services and reduce harm. PMID- 26962272 TI - Visceral pain modulation in female primary afferent sensory neurons. AB - The variations in symptoms and pain perception across the menstrual cycle in a large percentage of women diagnosed with functional syndromes such as Irritable Bowel Syndrome (IBS), Painful Bladder Syndrome (PBS), and Chronic Pelvic Pain (CPP), suggests the involvement of modulation of sex steroid hormones. Our recent studies have shown that estrogen modulation of visceral inputs of primary afferent nociceptors, located in the afferent primary sensory neurons of the dorsal root ganglia (DRG), accounts for the observed changes in nociception. Patients with CPP frequently experience pain from several organs. For patients with IBS, the most common co-morbid diagnoses include PBS and CPP. Pain is strongly associated with these diseases and the lack of awareness of their pathology is further illustrated by the fact that the average time between the onset of pain and the diagnosis is three to ten years. CPP patients may initially only have pain in the pelvis, but a multitude of mechanisms involving the peripheral and central nervous systems can lead to development of painful sensations in other adjacent organs; examples include lower colonic pain associated with IBS, and other viscera, such as the endometrium. In addition to the central regulation of pain, it is important to understand new pathways in which sex steroid hormones, such as estrogen, affect visceral nociception peripherally. PMID- 26962273 TI - "If Not Us, Then Who? If Not Now, Then When?" - The Need for Resource Stratified Guidelines. PMID- 26962274 TI - Experience in Strategic Networking to Promote Palliative Care in a Clinical Academic Setting in India. AB - BACKGROUND: Palliative care in low and middle-income countries is a new discipline, responding to a greater patient need, than in high-income countries. By its very nature, palliative as a specialty has to network with other specialties to provide quality care to patients. For any medical discipline to grow as a specialty, it should be well established in the teaching medical institutions of that country. Data show that palliative care is more likely to establish and grow in an academic health care institution. It is a necessity that multiple networking strategies are adopted to reach this goal. OBJECTIVES: (1) To describe a strategic approach to palliative care service development and integration into clinical academic setting. (2) To present the change in metrics to evaluate progress. DESIGN AND SETTING: This is a descriptive study wherein, the different strategies that are adopted by the Department of Palliative Medicine for networking in an academic health care institution and outside the institution are scrutinized. MEASUREMENT: The impact of this networking was assessed, one, at the level of academics and the other, at the level of service. The number of people who attended various training programs conducted by the department and the number of patients who availed palliative care service over the years were assessed. RESULTS: Ten different strategies were identified that helped with networking of palliative care in the institution. During this time, the referrals to the department increased both for malignant diseases (52-395) and nonmalignant diseases (5-353) from 2000 to 2013. The academic sessions conducted by the department for undergraduates also saw an increase in the number of hours from 6 to 12, apart from the increase in a number of courses conducted by the department for doctors and nurses. CONCLUSION: Networking is an essential strategy for the establishment of a relatively new medical discipline like palliative care in a developing and populous country like India, where the service is disproportionate to the demands. PMID- 26962276 TI - Pilot Testing of Triage Coding System in Home-based Palliative Care Using Edmonton Symptom Assessment Scale. AB - INTRODUCTION: Home-based palliative care is an essential model of palliative care that aims to provide continuity of care at patient's own home in an effective and timely manner. This study was a pilot test of triage coding system in home-based palliative care using Edmonton Symptom Assessment System (ESAS) scale. METHODS: Objective of the study was to evaluate if the triage coding system in home-based palliative care: (a) Facilitated timely intervention, (b) improved symptom control, and (c) avoided hospital deaths. Homecare services were coded as high (Group 1 - ESAS scores >=7), medium (Group 2 - ESAS scores 4-6), and low (Group 3 - ESAS scores 0-3) priority based on ESAS scores. In high priority group, patients received home visit in 0-3 working days; medium priority group, patients received home visit in 0-10 working days; and low priority group, patients received home visit in 0-15 working days. The triage duration of home visit was arbitrarily decided based on the previous retrospective audit and consensus of the experts involved in prioritization and triaging in home care. RESULTS: "High priority" patients were visited in 2.63 +/- 0.75 days; "medium priority" patients were visited in 7.00 +/- 1.5 days, and "low priority" patients were visited in 10.54 +/- 2.7 days. High and medium priority groups had a statistically significant improvement in most of the ESAS symptoms following palliative home care intervention. Intergroup comparison showed that improvement in symptoms was the highest in high priority group compared to medium and low priority group. There was an 8.5% increase in home and hospice deaths following the introduction of triage coding system. There was a significant decrease in deaths in the hospital in Group 1 (6.3%) (chi (2) = 27.3, P < 0.001) compared to Group 2 (28.6%) and Group 3 (15.4%). Group 2 had more hospital deaths. Interval duration from triaging to first intervention was a significant predictor of survival with odds ratio 0.75 indicating that time taken for intervention from triaging was more significantly affecting survival than group triaging. CONCLUSION: Pilot study of testing triaging coding system in home-based palliative care showed, triage coding system: (a) Facilitated early palliative home care intervention, (b) improved symptom control, (c) decreased hospital deaths, predominantly in high priority group, and (d) time taken for intervention from triaging was a significant predictor of survival. PMID- 26962275 TI - Development and Psychometric Assessment of a Spirituality Questionnaire for Indian Palliative Care Patients. AB - INTRODUCTION: There are only a few studies on spirituality among palliative care patients in India. This gap in research may be caused by the absence of relevant questionnaires and scales specifically designed for Indian palliative care populations. In this study, we describe the development of such a questionnaire and explain its psychometric characteristics. METHODS: We designed a questionnaire on the basis of a systematic review of the literature. After a review of the questionnaire by specialists and a subsequent pilot study, the questionnaire was amended. The final questionnaire consisted of a list of 36 spirituality items. It was administered to a sample of 300 cancer patients attending the pain clinic of a tertiary hospital in New Delhi. RESULTS: A factor analysis led to four factors explaining 54.6% of variance: Shifting moral and religious values (Factor 1), support from religious relationship (Factor 2), existential blame (Factor 3), and spiritual trust (Factor 4). The skewness and kurtosis for Factors 1, 3, and 4 were within a tolerable range for assuming a normal distribution, but Factor 2 was skewed. The alphas showed that the four factors have an acceptable internal consistency. Statistically significant associations were observed for age and Factor 3 (P = 0.004), gender and Factor 4 (P = 0.014), marital status and Factors 3 (P = 0.002) and 4 (P = 0.001), educational level and Factors 3 (P < 0.001) and 4 (P < 0.001), and pain scores and Factors 1 (P < 0.001), 2 (P < 0.001), and 3 (P = 0.001). CONCLUSION: The questionnaire offers promising prospects for the study of spirituality among palliative care patients in India. PMID- 26962277 TI - Social Determinants of Dementia and Caregivers' Perspectives in the Field Practice Villages of Rural Health Training Centre, Thiruvennainallur. AB - OBJECTIVES: (1) To find out the prevalence of dementia in the study population and its social determinants. (2) To explore the family caregivers' perceptions and their support needs. MATERIALS AND METHODS - STUDY SETTING: This study was undertaken in the field practice area of 55 villages of three Primary Health Centres in Villupuram District of Tamil Nadu. STUDY DESIGN: An exploratory mixed methods study design, where a qualitative method (key informant interview) was followed by a quantitative method (survey). SAMPLE SIZE: A representative sample of 1300 respondents was selected by two-stage sampling. ANALYSIS: Manual content analysis was done for qualitative data. Multiple logistic regression was performed on quantitative data. RESULTS: The prevalence of dementia among study sample was found to be 3.1%. The determinants for dementia were age, sex, socioeconomic status, and previous involvement in family decision making and cardiovascular risk factors. The family caregivers strongly felt that caregiving interferes with their personal and professional life; they also felt that caregiving is an integral part of Indian culture, and the elderly prefer home based care. Caregivers preferred government owned public health facility for medical care. All the responding caregivers strongly felt that they are not adequately trained in caregiving. CONCLUSIONS AND RECOMMENDATIONS: Routine screening of elderly for early identification of dementia and its medical and social risk factors should be initiated in primary health care facility. Care of caregivers should be seen as an integral part of dementia care program. PMID- 26962278 TI - Prevalence of Hyponatremia in Palliative Care Patients. AB - INTRODUCTION: Hyponatremia is an undertreated finding in clinical practice. It is the most common electrolyte abnormality. Hyponatremia can be asymptomatic or can cause symptoms ranging from nausea and lethargy to convulsions and coma. Palliative care patients have a multitude of symptoms and there are several contributing factors towards this. Hyponatremia could be one of the contributing factors. Looking at the prevalence of hyponatremia would highlight the magnitude of the problem and would prompt healthcare professionals to investigate and treat hyponatremia in palliative care patients, which in turn might reduce symptoms such as fatigue and nausea. This could improve the quality of life in palliative care patients. AIM: To assess the prevalence of hyponatremia among patients referred for palliative care in a tertiary care hospital. METHODOLOGY: This is a descriptive study, with retrospective analysis of consecutive patient charts for 5 years. The sodium levels at the time of referral for palliative care, was reviewed. Inferential statistics for the result was calculated using the Z-test. RESULTS: Of the 2666 consecutive patient charts that were reviewed, sodium values were recorded in 796 charts. Among the recorded charts, 28.8 % of patients showed hyponatremia at the time of referral which was significant with a P value of 0.000 (<0.05). Of these, 61.1 % had malignancy as their diagnosis and the rest had nonmalignant diseases, ranging from trauma to chronic obstructive pulmonary disease. CONCLUSIONS: Prevalence of hyponatremia is significant in palliative care patients. A prospective study looking at the causes and clinical outcomes associated with hyponatremia in palliative care patients is needed. PMID- 26962279 TI - Intensive Care Unit Physician's Attitudes on Do Not Resuscitate Order in Palestine. AB - BACKGROUND: There is some ambiguity concerning the do-not-resuscitate (DNR) orders in the Arabic world. DNR is an order written by a doctor, approved by the patient or patient surrogate, which instructs health care providers to not do CPR when cardiac or respiratory arrest occurs. Therefore, this research study investigated the attitudes of Intensive Care Unit physicians and nurses on DNR order in Palestine. MATERIALS AND METHODS: A total of 123 males and females from four different hospitals voluntarily participated in this study by signing a consent form; which was approved by the Ethical Committee at Birzeit University and the Ministry of Health. A non-experimental, quantitative, descriptive, and co relational method was used, the data collection was done by a three page form consisting of the consent form, demographical data, and 24 item-based questionnaire based on a 5-point-Likert scale from strongly agree (score 1) to strongly disagree (score 5). RESULTS: The Statistical Package for Social Sciences (SPSS) software program version 17.0 was used to analyze the data. Finding showed no significant relationship between culture and opinion regarding the DNR order, but religion did. There was statistical significance difference between the physicians' and nurses' religious beliefs, but there was no correlation. Moreover, a total of 79 (64.3%) physicians and nurses agreed with legalizing the DNR order in Palestine. CONCLUSION: There was a positive attitude towards the legalization of the DNR order in Palestine, and culture and religion did not have any affect towards their attitudes regarding the legalization in Palestine. PMID- 26962280 TI - Nurses' Perceptions of Spirituality and Spiritual Care Giving: A Comparison Study Among All Health Care Sectors in Jordan. AB - AIMS: This study aimed to describe nurses' perceptions of spirituality and spiritual care in Jordan, and to investigate the relationship between their perceptions and their demographic variables. METHODS: The study used a cross sectional descriptive design and recruited a convenience sample of 408 Jordanian registered nurses to complete the spiritual care giving scale. RESULTS: The findings of the study demonstrated that most of the participating nurses had a high level of spirituality and spiritual care perception. Significant differences were found between male and female nurses' perceptions of spirituality and spiritual care (P < 0.05); previous attendance of courses on spiritual care also made a significant difference to perceptions (P < 0.05). CONCLUSIONS: The research findings suggest that, Jordanian nurses' gender made a difference in their perceptions of spirituality and spiritual care. They had satisfactory levels of perception of spirituality and spiritual care. Moreover, spiritual care courses appeared to have a positive impact on their perception of spirituality and spiritual care. Enhancing nursing care by integrating standardized spiritual care into the current nursing care, training, and education should also be emphasized. PMID- 26962282 TI - Prescription Pattern of Analgesic Drugs for Patients Receiving Palliative Care in a Teaching Hospital in India. AB - BACKGROUND: Drugs used in the palliative care unit for managing symptoms are major contributors toward the expenditure occurring in palliative care. This study was conducted to understand the prescription pattern of analgesic drugs in the patients who are receiving palliative care in a teaching hospital in India by a retrospective study of case records. METHODS: Case record based, retrospective, descriptive study was conducted at the Pain and Palliative Care Department of St. John's Medical College Hospital, Bengaluru. Case record files of all patients referred to Pain and Palliative Care Department for the treatment of pain in the year of 2012 were studied. Patients' age, gender, diagnoses, numerical pain rating scale (0-10), drugs prescribed, dosage, frequency, route of administration were recorded. The difference in drug utilization between the genders was done using Chi-square test. Data were collected from 502 patients of which 280 (56%) were males and 222 (44%) were females. Twelve percent of patients had mild pain (1-3), 34% had moderate pain (4-6), and 54% had severe pain (7-10). The most commonly used analgesic drugs were opioids (47%), followed by nonsteroidal anti inflammatory drugs (36%). The opioids used were tramadol (56%), and morphine (38%). Ninety percent of patients with numerical pain scale more than 6 received morphine. There was no difference in analgesic drug utilization with regards to gender. Prescription pattern differed depending on the severity of pain. Opioids were the most commonly used drugs for pain management. CONCLUSION: The study shows that prescription pattern in palliative care unit of this hospital was in accordance with WHO pain management guidelines. The study showed the current trend in prescription of analgesic drugs in the teaching hospital where the study was conducted. PMID- 26962281 TI - Unilobar Versus Bilobar Biliary Drainage: Effect on Quality of Life and Bilirubin Level Reduction. AB - BACKGROUND: Percutaneous biliary drainage is an accepted palliative treatment for malignant biliary obstruction. PURPOSE: To assess the effect on quality of life (QOL) and bilirubin level reduction in patients with inoperable malignant biliary obstruction treated by unilobar or bilobar percutaneous transhepatic biliary drainage (PTBD). MATERIALS AND METHODS: Over a period of 2 years, 49 patients (age range, 22-75 years) of inoperable malignant biliary obstruction were treated by PTBD. Technical and clinical success rates, QOL, patency rates, survival rates, and complications were recorded. Clinical success rates, QOL, and bilirubin reduction were compared in patients treated with complete (n = 21) versus partial (n = 28) liver parenchyma drainage. QOL before and 1 month after biliary drainage were analyzed retrospectively between these two groups. RESULTS: Biliary drainage was successful in all 49 patients, with an overall significant reduction of the postintervention bilirubin levels (P < 0.001) resulting in overall clinical success rate of 89.97%. Clinical success rates were similar in patients treated with whole-liver drainage versus partial-liver drainage. Mean serum bilirubin level before PTBD was 19.85 mg/dl and after the procedure at 1 month was 6.02 mg/dl. The mean baseline functional score was 39.35, symptom scale score was 59.55, and global health score was 27.45. At 1 month, mean functional score was 61.25, symptom scale score was 36.0 4, and global health score was 56.33, with overall significant improvement in QOL (<0.001). There was a statistically significant difference in the improvement of the QOL scores (P = 0.002), among patients who achieved clinical success, compared with those patients who did not achieve clinical success at 1 month. We did not find any significant difference in the QOL scores in patients according to the amount of liver drained (unilateral or bilateral drainage), the type of internalization used (ring biliary or stent). Overall, minor and major complications rates were 14.3% and 8.1%, respectively. CONCLUSION: Percutaneous biliary drainage provides good palliation of malignant obstructive jaundice. Partial-liver drainage achieved results as good as those after complete liver drainage with significant improvements in QOL and reduction of the bilirubin level. PMID- 26962284 TI - Burning Mouth Syndrome. AB - Burning mouth syndrome (BMS) is multifactorial in origin which is typically characterized by burning and painful sensation in an oral cavity demonstrating clinically normal mucosa. Although the cause of BMS is not known, a complex association of biological and psychological factors has been identified, suggesting the existence of a multifactorial etiology. As the symptom of oral burning is seen in various pathological conditions, it is essential for a clinician to be aware of how to differentiate between symptom of oral burning and BMS. An interdisciplinary and systematic approach is required for better patient management. The purpose of this study was to provide the practitioner with an understanding of the local, systemic, and psychosocial factors which may be responsible for oral burning associated with BMS, and review of treatment modalities, therefore providing a foundation for diagnosis and treatment of BMS. PMID- 26962283 TI - Percutaneous Image-guided Radiofrequency Ablation of Tumors in Inoperable Patients - Immediate Complications and Overall Safety. AB - INTRODUCTION: Percutaneous destruction of cancer cells using a radiofrequency energy source has become an accepted part of the modern armamentarium for managing malignancies. Radiofrequency ablation (RFA) is a relatively novel procedure for treating recurrent and metastatic tumors. It is used for debulking tumors and as adjuvant therapy for palliative care apart from its role as a pain management tool. Its use in the third world countries is limited by various factors such as cost and expertise. In the remotest parts of India, where economic development has been slow, abject poverty with poor health care facilities advanced malignancies present a challenge to health care providers. We undertook this study to assess the safety of the percutaneous RFA tumor ablation as a therapeutic or palliative measure in patients where surgery was not possible. We observed that RFA may be an effective, alternative therapeutic modality for some inoperable tumors where other therapeutic modalities cannot be considered. CONTEXT: Palliative and therapeutic image-guided RFAs of tumors may be the only treatment option in patients who are inoperable for a variety of reasons. To assess the safety and complications of RFA in such a patient population is important before embarking upon any interventions given their physically, mentally, and socially compromised status in a country such as India. AIMS: To assess the safety of percutaneous image-guided radiofrequency tumor ablation and to note the various immediate and early complications of the intervention. SETTINGS AND DESIGN: This was a prospective, observational study conducted in Tata Main Hospital, Jamshedpur, Jharkhand, India. SUBJECTS AND METHODS: After approval by the Hospital Approval Committee all patients who consented for percutaneous RFA of their tumor admitted in the hospital were included after taking fully informed consent from patient/close relative keeping the following criteria in view. INCLUSION CRITERIA: Patients who were likely to derive a direct benefit in the survival or as a palliative measure for relief in their symptoms and patients who were inoperable because of any of the following reasons: (1) Exhausted conventional treatment options, (2) technical and anatomical contraindications to conventional treatment, (3) medical comorbidities precluding surgery, (4) patient refusal, (5) recurrent tumors, and (6) advanced tumor stage. Conventional Treatment has been defined as surgical resection, radiotherapy, and/or chemotherapy, although the patient eligibility for each treatment may vary. EXCLUSION CRITERIA: Patients with the following were excluded: (1) Severe coagulopathy, (2) heart, renal, or liver failure, (3) lesions within 1 cm of gall bladder, hilum, bowel wall, and major blood vessels, (4) patient with any metal implant, (5) patients in sepsis, and (6) tumor adjacent to structures at risk (main bile ducts, pericardium, stomach, or bowel). RESULTS: The duration of procedure as well as ablation of tumor free margin was significantly related to the size of the tumor. As the size of tumor increased, duration of procedure increased significantly. A good tumor-free margin also needs to be ablated for optimum results as it prevents residual tumors and recurrences in the future. We observed that tumors sized <3.1 cm were optimal in this regard. Most common adverse event in postprocedure period was pain in and around ablation site. Post-RFA syndrome is also a common and benign self-limiting side effect. Patient counseling and proper selection of patients in the early stages of malignancy can enhance the efficacy of the procedure and patient satisfaction. CONCLUSIONS: Percutaneous image-guided RFA is an option in patients where most other tumor management modalities have been exhausted or rejected. RFA may not be free from side effects such as postablation syndrome, pain, and there may be other serious complications such as bleeding, but based on our observations, percutaneous image-guided RFA of tumors is a safe palliative and therapeutic treatment option. PMID- 26962285 TI - Myofacial Trigger Points in Advanced Cancer Patients. AB - Myofascial pain syndrome is started to be recognized as one of important factors of pain in cancer patients. However, no reports on features of myofascial trigger points were found in terminally-ill cancer populations. This time, we encountered 5 patients with myofascial pain syndrome and terminal cancer in whom delirium developed due to increased doses of opioid without a diagnosis of myofascial pain syndrome on initial presentation. The delirium subsided with dose reductions of opioid and treatment of myofascial pain syndrome. The common reason for a delayed diagnosis among the patients included an incomplete palpation of the painful sites, which led to unsuccessful myofascial trigger points identification. The features of myofascial trigger points included single onset in the cancer pain management site with opioid and the contralateral abdominal side muscles of the non-common sites. Withdrawal reflexes associated with cancer pain in the supine position, which are increasingly seen in the terminal cancer patients, were considered to have contributed to this siuation. We consider that careful palpation of the painful site is important, in order to obtain greater knowledge and understanding of the features of myofascial trigger points. PMID- 26962287 TI - Gabapentin for Chronic Refractory Cancer Cough. AB - Vagal sensory neuropathy or vagal hypersensitivity has been implicated in the pathophysiology of chronic cough. Earlier reports have shown gabapentin to be effective in sensory laryngeal neuropathy and symptom conditions that have a proven neural origin. We present a case report of a patient with chronic refractory cough due to a soft tissue mass in the lung that caused compression of the mediastinal structures. The patient was successfully treated with gabapentin with reduction in the cough intensity, duration, and frequency. PMID- 26962286 TI - A New Perspective of Neuromyopathy to Explain Intractable Pancreatic Cancer Pains; Dry Needling as an Effective Adjunct to Neurolytic Blocks. AB - We present a new perspective of neuromyopathy in pancreatic cancer pain (PCP) referral to bodywall; proposal of new rationale to include ultrasound guided dry needling (USGDN) of body wall muscles as an effective adjunct to neurolytic coeliac plexus block (NCPB) or splanchnic nerve radiofrequency ablation (SRF) for comprehensive interventional management. METHODS: PCP response to SRF in 2 patients and NCPB in 3 patients was documented on numerical rating scale (NRS) on post procedure days 3 and 15. If the residual pain was >5 NRS on day 15, USGDN of abdominal and back muscles was started on a thrice weekly basis. The response to USGDN documented on day 30 after approximately 6 sessions of DN, showed a significant pain reduction (0-2 NRS) with 50% reduction of pre-treatment opioid consumption. This was sustained at 6 months or till their demise. Convergence of visceral and somatic nerves at the dorsal horn (viscerosomatic neurons) causes referral of visceral pain to the back and abdominal muscles. This leads to formation of myofascial trigger points (MTrPs) in the muscles which sets up a parallel network of sensitized peripheral and central motor nociceptive processing (neuromyopathy). USGDN specifically addressed the MTrPs that develop as an epiphenomenon of self-perpetuating neuromyopathy while SRF/NCPB, analgesics and neuromodulators could address only visceral nociceptive afferents (pain mediated through celiac plexus) which forms a meagre 10% of the total spinal cord afferent input. Thus, we conclude that combination of neuromyopathy and viscerosomatic convergence in PCP indicate a specific role for DN as an adjunct to SRF/NCPB in our patients. PMID- 26962288 TI - Retroperitoneal Endodermal Sinus Tumor Patient with Palliative Care Needs. AB - This article is a case reflection of a personal encounter on the palliative care treatment required after the removal of a complicated case of a primary extra gonadal retro-peritoneal endodermal sinus tumor (yolk sac tumor). This reflection is from the perspective of a recently graduated MD student who spent one month with an Indian pain management and palliative care team at the Institute Rotary Cancer Hospital (IRCH), All India Institute of Medical Sciences (AIIMS), New Delhi. PMID- 26962289 TI - Pregabalin in Chemotherapy Induced Neuropathic Pain. AB - Chemotherapeutic agents belonging to vinca alkaloids, taxanes, and antitubulins produce peripheral neuropathy for which there is no validated treatment. Pregabalin, a gamma-aminobutyric acid analog, is known to inhibit thealpha2delta subunit of the voltage-gated calcium channel. Earlier studies and case reports have shown pregabalin to be effective in treating neuropathic pain. We present a case series of patients with chemotherapy-induced peripheral neuropathy who were successfully treated with pregabalin with reduction in the hyperalgesia, allodynia, and improvement in the quality of life. PMID- 26962290 TI - Maintaining the Social Flow of Evidence-Informed Palliative Care: Use and Misuse of YouTube. AB - This review article is aimed to explore the use of the social media website YouTube (www.youtube.com) as an evidence resource in palliative care, for patients and caregivers, students and professionals, and providers and policy makers in developing countries' settings. The reviewed evidence reiterated the role of this social media website in palliative care practice, education and research in the area of cancer. Efficacy studies on impact of such media on palliative care delivery in developing countries are still lacking. PMID- 26962292 TI - I Wish I Could Prevent My Grandma's Suffering....!!! PMID- 26962291 TI - Smarter palliative care for cancer: Use of smartphone applications. AB - Smartphones are technologically advanced mobile phone devices which use software similar to computer-based devices as a user-friendly interface. This review article is aimed to inform the palliative care professionals, cancer patients and their caregivers about the role of smartphone applications (apps) in the delivery of palliative care services, through a brief review of existing literature on the development, feasibility, analysis, and effectiveness of such apps. There is a dearth need for sincere palliative care clinicians to work together with software professionals to develop the suitable smartphone apps in accordance with the family/caregivers' necessities and patients' biopsychosocial characteristics that influence the technology driven evidence informed palliative cancer care. PMID- 26962293 TI - Systematic Analysis of Yeast Proteome Reveals Peptide Detectability Factors for Mass Spectrometry. AB - Here we used a data-independent acquisition (DIA) method, Precursor Acquisition Independent from Ion Count (PAcIFIC), to systematically profile the S. cerevisiae proteome. Direct PAcIFIC analysis of a yeast whole cell lysate (WCL) yielded 90% reproducibility between replicates and detected approximately 2000 proteins. When combined with sub-cellular fractionation, reproducibility was equally high and the number of detected yeast proteins approached 5000. As noted previously, this unbiased DIA approach identified so-called "orphan" peptides that could only be detected by tandem mass spectra because there was no detectable precursor ion. Using this unique dataset we examined features associated with peptide detectability and demonstrated that orphans were more likely to arise from low copy number proteins than proteins with median or high copy number. Finally, an investigation into why some orphans also arose from high copy number proteins found that, aside from protein copy number, there was a bias toward physiochemical factors associated with regions flanking the proteolytic cleavage sites of orphan peptides. This suggested that those orphan peptides originating from high abundance proteins were likely the result of inefficient protease release, which has implications for quantitative bottom-up proteomics. PMID- 26962294 TI - Reduced PARP1 as a Serum Biomarker for Graft Rejection in Kidney Transplantation. AB - A serum proteomics platform enabling expression Profiling in transplantation associated clinical subsets gives an opportunity to identify non-invasive biomarkers that can accurately predict transplant outcome. In this study, we attempted to identify candidate serum biomarkers that could predict kidney allograft rejection/injury, regardless of its etiological and therapeutic heterogeneity. Using serum samples collected from kidney transplantation patients and healthy controls, we first employed Clontech-500 Ab microarrays to Profile acute rejection (AR) and chronic graft injury (CGI) versus stable graft function (SF) and normal kidneys (NK). Using GenePattern analysis of duplicate arrays on pooled samples, we identified gender-independent biomarkers PARP1, MAPK1, SRP54, DP1, and p57 (FDR ~ 25%), the concordant downregulation of which represented a detrimental Profile common for both rejection/ injury types (AR-CGI). The reverse phase arrays qualified a 2-fold upregulation of PARP1 with an ROC of 0.87 in individual samples from patients with SF vs. AR-CGI rendering serum PARP1 as a biomarker for early prognosis. Ingenuity Pathways Analysis (IPA) connected PARP1 to some other markers (MAPK1), elucidating their possible interactions and connections to the immune response and graft-versus-host disease signaling. The downregulation of serum PARP1 in the damaged graft tissues, represents a perspective non-invasive marker, predicting the failing kidney graft, regardless of rejection/injury causes or gender. Thus, the successful identification of PARP1 as a bio-marker in limited patient cohorts demonstrates that serum proteomics platform empowered by the GenePattern- and IPA-based Bioinformatics algorithm can guarantee a successful development of the clinically applicable prognostic biomarker panel. PMID- 26962295 TI - A Quantitative Proteomic Analysis of Urine from Gamma-Irradiated Non-Human Primates. AB - The molecular effects of total body gamma-irradiation exposure are of critical importance as large populations of people could be exposed either by terrorists, nuclear blast, or medical therapy. In this study, we aimed to identify changes in the urine proteome using a non-human primate model system, Rhesus macaque, in order to characterize effects of acute radiation syndrome following whole body irradiation (Co-60) at 6.7 Gy and 7.4 Gy with a twelve day observation period. The urine proteome is potentially a valuable and non-invasive diagnostic for radiation exposure. Using high-resolution mass spectrometry, we identified 2346 proteins in the urine proteome. We show proteins involved in disease, cell adhesion, and metabolic pathway were significantly changed upon exposure to differing levels and durations of radiation exposure. Cell damage increased at a faster rate at 7.4 Gy compared with 6.7 Gy exposures. We report sets of proteins that are putative biomarkers of time- and dose-dependent radiation exposure. The proteomic study presented here is a comprehensive analysis of the urine proteome following radiation exposure. PMID- 26962296 TI - The Influence of General Discrimination and Social Context on Young Urban Expecting Couples' Mental Health. AB - Young expecting parents face a great deal of challenges as they transition into parenthood. This paper sought to identify racial and gender differences in the relationship between general discrimination, neighborhood problems, neighborhood cohesion, and social support on the depressive and stress symptoms among young expecting couples. Results indicated perceived general discrimination and less social support was associated with increased stress and depression. More neighborhood problems were related to increased depression and more neighborhood cohesion was related to less stress. Moderator analyses showed that the influence of general discrimination and stress was stronger for women than men. In addition, neighborhood cohesion was protective on stress for Blacks and Whites but not for Hispanics. These results indicate the need to address the broader social context for young expectant couples. PMID- 26962300 TI - Functionalized Metallated Cavitands via Imidation and Late-Stage Elaboration. AB - Efficient methods for the preparation of functionalized metallated cavitands are described. Functional groups can be either introduced by an imidation of metal oxo complexes or by a late-stage elaboration of the imido ligands. By using diversified iminophosphorane (PPh3=NR) reagents, pi-conjugated pyrene, redox active ferrocene and polymerizable norbornene moieties were successfully introduced. Furthermore, the iodo and alkynyl groups on the imido ligands are capable of undergoing efficient Sonogashira cross-coupling and copper-catalyzed azide alkyne cycloaddition reactions, thereby providing facile access to complex architectures containing metallated cavitands. PMID- 26962301 TI - Perceived needs and level of satisfaction with care by family members of critically ill patients at Muhimbili National hospital intensive care units, Tanzania. AB - BACKGROUND: Earlier studies in developed and a few developing countries have documented experiences of family members with critically-ill patients. However, in Tanzania no documented studies could be found in this study area. The aim of this study was therefore to explore the Tanzanian family members' perceived needs and level of satisfaction with care of their critically-ill patients, in the intensive care units in the Muhimbili National Hospital. METHODS: A descriptive cross-sectional study was undertaken, using a quantitative approach. A semi structured questionnaire was used to collect data. The sample size was 110 respondents, comprised of individuals who visited critically-ill patients in the intensive care unit. Data were analyzed using SPSS Version 14. RESULTS: The study revealed that 72 % of the family members perceived having a specific person to call at the hospital when a related family member was not available at the hospital as a very important need. Only 23 % of the respondents perceived the need of talking about the possibility of their patients' death as very important. The nurses' provision of care to the patients of the family members was found to be satisfactory. CONCLUSION: The perceived needs and level of satisfaction of family members of critically-ill patients calls for nurses to improve the quality of care to patients' family members, which in return will enhance the patient's recovery. PMID- 26962302 TI - Transcription factor CCAAT/enhancer binding protein alpha up-regulates microRNA let-7a-1 in lung cancer cells by direct binding. AB - AIMS: The transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) and microRNA (miRNA) let-7a-1 act as tumor suppressors in many types of cancers including lung cancer. In the present study, we aim to investigate whether let-7a 1 is a novel important target of C/EBPalpha in lung cancer cells. METHODS: The DNA sequence of the 2.1 kb let-7a-1 promoter was analyzed with MatInspector 4.1 (http://www.genomatix.de). Human lung cancer cell lines A549 and H1299, and human cervical cancer cell line Hela were used for transfection. Total RNA was extracted from cells using Trizol reagent and pri-let-7a-1 mRNA expression was measured using quantitative real-time polymerase chain reaction. Western blotting was performed to detect C/EBPalpha protein expression. To test whether C/EBP alpha could up-regulate the expression level of let-7a at transcription level, dual-luciferase reporter gene assay was carried out. To determine whether C/EBPalpha could bind let-7a-1 promoter, electrophoretic mobility shift assay was employed. To further confirm the direct targeting let-7a-1 promoter by C/EBPalpha, chromatin immunoprecipitation was used. RESULTS: Both C/EBPalpha and let-7a-1 were down-regulated in lung cancer A549 and H1299 cells, but up regulated in Hela cells. Transfection and reporter gene assay showed that C/EBPalpha increased the expression of let-7a-1 at transcription level. Bioinformatics assay identified four putative C/EBP elements within let-7a-1 promoter. Dual-luciferase reporter gene, electrophoretic mobility shift assay and chromatin immunoprecipitation assays demonstrated that these four elements mediated the up-regulation effect of C/EBPalpha on let-7a-1. CONCLUSIONS: The present study reveals that decreased C/EBPalpha contributes to the down regulation of miRNA let-7a-1 in lung cancer cells. PMID- 26962298 TI - Role of Protein Tyrosine Phosphatases in Plants. AB - Reversible protein phosphorylation is a crucial regulatory mechanism that controls many biological processes in eukaryotes. In plants, phosphorylation events primarily occur on serine (Ser) and threonine (Thr) residues, while in certain cases, it was also discovered on tyrosine (Tyr) residues. In contrary to plants, extensive reports on Tyr phosphorylation regulating a large numbers of biological processes exist in animals. Despite of such prodigious function in animals, Tyr phosphorylation is a least studied mechanism of protein regulation in plants. Recently, various chemical analytical procedures have strengthened the view that Tyr phosphorylation is equally prevalent in plants as in animals. However, regardless of Tyr phosphorylation events occuring in plants, no evidence could be found for the existence of gene encoding for Tyr phosphorylation i.e. the typical Tyr kinases. Various methodologies have suggested that plant responses to stress signals and developmental processes involved modifications in protein Tyr phosphorylation. Correspondingly, various reports have established the role of PTPs (Protein Tyrosine Phosphatases) in the dephosphorylation and inactivation of mitogen activated protein kinases (MAPKs) hence, in the regulation of MAPK signaling cascade. Besides this, many dual specificity protein phosphatases (DSPs) are also known to bind starch and regulate starch metabolism through reversible phosphorylation. Here, we are emphasizing the significant progress on protein Tyr phosphatases to understand the role of these enzymes in the regulation of post-translational modification in plant physiology and development. PMID- 26962299 TI - Role of Genetic Factors in the Pathogenesis of Radial Deficiencies in Humans. AB - Radial deficiencies (RDs), defined as under/abnormal development or absence of any of the structures of the forearm, radial carpal bones and thumb, occur with a live birth incidence ranging from 1 out of 30,000 to 1 out 6,000 newborns and represent about one third/one fourth of all the congenital upper limb anomalies. About half of radial disorders have a mendelian cause and pattern of inheritance, whereas the remaining half appears sporadic with no known gene involved. In sporadic forms certain anomalies, such as thumb or radial hypoplasia, may occur either alone or in association with systemic conditions, like vertebral abnormalities or renal defects. All the cases with a mendelian inheritance are syndromic forms, which include cardiac defects (in Holt-Oram syndrome), bone marrow failure (in Fanconi anemia), platelet deficiency (in thrombocytopenia absent-radius syndrome), ocular motility impairment (in Okihiro syndrome). The genetics of radial deficiencies is complex, characterized by genetic heterogeneity and high inter- and intra-familial clinical variability: this review will analyze the etiopathogenesis and the genotype/phenotype correlations of the main radial deficiency disorders in humans. PMID- 26962303 TI - The acute effects of multi-ingredient pre-workout ingestion on strength performance, lower body power, and anaerobic capacity. AB - BACKGROUND: Multi-ingredient pre-workout supplements (MIPS) are popular among resistance trained individuals. Previous research has indicated that acute MIPS ingestion may increase muscular endurance when using a hypertrophy-based protocol but less is known in regard to their effects on strength performance and high intensity running capacity. Therefore, the purpose was to determine if short term, MIPS ingestion influences strength performance and anaerobic running capacity. METHODS: In a double-blind, randomized, placebo controlled, crossover design; 12 males (19 +/- 1 yrs.; 180 +/- 12 cm; 89.3 +/- 11 kg; 13.6 +/- 4.9 %BF) had their body composition assessed followed by 5-repetition maximum (5RM) determination of back squat (BS; 119.3 +/- 17.7 kg) and bench press (BP; 92.1 +/- 17.8 kg) exercises. On two separate occasions subjects ingested a MIPS or a placebo (P) 30-minutes prior to performing a counter movement vertical jump test, 5 sets of 5 repetitions at 85 % of 5RM of BS and BP, followed by a single set to failure, and an anaerobic capacity sprint test to assess peak and mean power. Subjective markers of energy levels and fatigue were also assessed. Subjects returned one week later for a second testing session using counter treatment. RESULTS: MIPS resulted in a greater number of repetitions performed in the final set to failure in the BP (MIPS, 9.8 +/- 1.7 repetitions; P, 9.1 +/- 2; p = 0.03, d = 0.38), which led to a greater total volume load (set x repetitions x load) in the MIPS (753 +/- 211 kg) compared to P (710 +/- 226 kg; p =0.03, d = .20). MIPS ingestion improved subjective markers of fatigue (p = 0.01, d = 3.78) and alertness (p = 0.048, d = 2.72) following a bout of resistance training. An increase in mean power was observed in the MIPS condition (p = 0.03, d = 0.25) during the anaerobic sprint test. CONCLUSION: Results suggest that acute ingestion of a MIPS study may increase upper body muscular endurance. In addition, acute MIPS ingestion improved mean power output during an anaerobic capacity sprint test. However, the practical significance of these performance related outcomes may be minimal due to the small effect sizes observed. MIPS ingestion does appear to positively influence subjective markers of fatigue and alertness during high-intensity exercise. PMID- 26962304 TI - Extracellular vesicle proteomes reflect developmental phases of Bacillus subtilis. AB - BACKGROUND: Extracellular vesicles (EV) are spherical membrane-bound vesicles with nano-scale diameters, which are shed to the extracellular region by most eukaryotic and prokaryotic cells. Bacterial EV are proposed to contribute to intercellular communication, bacterial survival and human pathogenesis as a novel secretion system. EV have been characterized from many Gram-negative species and, more recently, from several vegetative Gram-positive bacteria. Further characterization of EV and their molecular cargos will contribute to understanding bacterial physiology and to developing therapeutic approaches. RESULTS: Bacillus subtilis were observed to release EV to a similar extent during sporulation as during the vegetative growth phase. However, the two vesicular cargos show qualitatively and quantitatively different proteomes. Among 193 total proteins identified across both samples, 61 were shown to be significantly more abundant in EV shed by sporulating cells, with (log) ratio of spectral counts RSC > 1 and Fisher-exact test FDR < 5 %. Sixty-two proteins were found to be significantly more abundant in EV shed by vegetative cells. Membrane fusion was shown to take place between these EVs and Gram-positive cells. CONCLUSION: Biogenesis of EV is a continuous process over the entire life cycle of this sporulating bacterium. The formation of EV during sporulation is strongly supported by the delineation of protein content that differs from the proteome of EV formed by vegetative spores. PMID- 26962306 TI - A Prospective and Controlled Clinical Trial on Stromal Vascular Fraction Enriched Fat Grafts in Secondary Breast Reconstruction. AB - Background. Fat grafting is a tremendous tool in secondary breast reconstruction. Stromal vascular fraction (SVF) enriched fat grafts have been presenting promising results regarding volume maintenance. Methods. We developed a method that produces a superior SVF enrichment rate (2 : 1) in the operating theatre. This prospective and controlled trial analyzed quantitatively and qualitatively fat grafts with (stem cells group, SG) and without (control group, CG) SVF enrichment in secondary breast reconstruction, through MRI-based volumetry, immunophenotyping, and cell counting. Also, patient satisfaction, aesthetic outcomes, and complications were analyzed. Results. Volumetric persistence in the SG was 78,9% and 51,4% in the CG; however it did not reach statistical significant difference. CD90 was the only marker highly expressed in the SG and showed a positive correlation with volumetric persistence (r = 0.651, p = 0.03). Fat necrosis occurred in 4 patients in the SG and in none in the CG. Patients in the CG showed a trend to be more satisfied. Considering aesthetics, both groups presented improvements. No locoregional recurrences were observed. Conclusions. Results are encouraging despite the fact that SVF enrichment in a higher supplementation rate did not improve, with statistical significance, fat graft volumetric persistence. Enriched fat grafts have proven to be safe in a 3-year follow-up. PMID- 26962305 TI - Multidetector CT Enterography versus Double-Balloon Enteroscopy: Comparison of the Diagnostic Value for Patients with Suspected Small Bowel Diseases. AB - Aim. To compare the diagnostic value of multidetector CT enterography (MDCTE) and double-balloon enteroscopy (DBE) for patients with suspected small bowel diseases. Methods. From January 2009 to January 2014, 190 patients with suspected small bowel diseases were examined with MDCTE and DBE. The characteristics of the patients, detection rates, diagnostic yields, sensitivity, specificity, positive predictive value, and negative predictive value were described and analyzed. Results. The overall detection rates of DBE and MDCTE were 92.6% and 55.8%, respectively (P<0.05), while the overall diagnostic yields were 83.2% and 33.7%, respectively (P<0.05). The sensitivity, specificity, positive predictive value, and negative predictive value of DBE were all higher than those of MDCTE. DBE had a higher diagnostic yield for OGIB (87.3% versus 20.9%, P<0.05). The diagnostic yields of DBE were higher than those of MDCTE for inflammatory diseases, angioma/angiodysplasia, and diverticulums, while being not for gastrointestinal tumors/polyps. Conclusions. The diagnostic value of DBE for small bowel diseases is better than that of MDCTE as a whole, but if gastrointestinal tumors are suspected, MDCTE is also needed to gain a comprehensive and accurate diagnosis. PMID- 26962307 TI - Cellular Origins of Regenerating Nodules and Malignancy in the FAH Model of Liver Injury after Bone Marrow Cell Transplantation. AB - In previous reports, we and other groups have shown that proliferating hepatocytes are formed by the fusion of donor hematopoietic cells with host hepatocytes in the Fah(-/-) model. Thus, it would be interesting to determine whether cell fusion occurs during malignancy. However, it is difficult to demonstrate such processes using this model. Therefore, we established a new strain to study the processes of regenerating nodules and malignancy and their origins. The FAH(-/-) mouse model was crossed with the ROSAnZ strain and their offspring was genotyped for FAH(-/-) and ROSAnZ mutations to create a new strain (Fah(-/-) -ROSAnZ). Using this strain as recipients, we performed bone marrow transplantation experiments. As a result, we could not demonstrate the presence of any epithelial cells except hepatocytes that were of donor origin in regenerating tissue, and no evidence of cell fusion was found in tumors. The hepatic malignancy was of host origin in these mice. There was higher expression of extracellular matrix proteins and more inflammatory cells in liver tumor nodules than in regenerating normal liver nodules. Hepatocytes generated by fusion with bone marrow cells did not form malignant tumors. Extracellular matrix and inflammatory cells had significantly accumulated in liver tumors. PMID- 26962308 TI - Comparative evaluation of bispectral index system after sedation with midazolam and propofol combined with remifentanil versus ketamine in uncooperative during dental procedures. AB - BACKGROUND: Proper analgesic agents should be used in combination with sedative agents. Remifentanil is a synthetic narcotic/analgesic agent with a short duration effect and decreases the risk of apnea during recovery. Bispectral index system (BIS) is a new noninvasive technique for the evaluation of the depth of sedation. The aim of present clinical trial was to evaluate and compare the efficacy of intravenous sedation with propofol/midazolam/remifentanil (PMR) in comparison to propofol/midazolam/ketamine (PMK) for dental procedures in children 3-7 years of age. MATERIALS AND METHODS: In this clinical trial, 32 healthy uncooperative children who were candidates for dental treatments under sedation were randomly divided into two groups. Intravenous sedation was induced with PMR in one group and with PMK in the other group. After injection and during procedure BIS index, heart rate and respiratory rate, blood pressure, and oxygen saturation was evaluated every 5 min. After the procedure, recovery time was measured. Data were analyzed with ANOVA, Friedman, Wilcoxon, and t-test. RESULTS: The BIS value was significantly low in ketamin group (P = 0.003) but respiratory rates and heart rates were same in both groups with no statistical difference (P = 0.884, P = 0.775). The recovery time was significantly shorter in remifentanil group (P = 0.008 and P = 0.003). CONCLUSION: It can be concluded that intravenous sedation technique with PMR combination induces effective and safe sedation, with less pain and more forgetfulness and a shorter recovery time for children 3-7 years of age during dental procedures. PMID- 26962309 TI - Comparison of microleakage from stainless steel crowns margins used with different restorative materials: An in vitro study. AB - BACKGROUND: Obtaining optimal marginal adaption with prefabricated stainless steel crowns (SSCs) is difficult, especially after removing dental caries or defects in cervical areas. This situation requires the use of an SSC after tooth reconstruction. This study evaluated microleakage and material loss with five restorative materials at SSC margins. MATERIALS AND METHODS: One hundred and twenty primary molar teeth were randomly divided into six groups (n = 20). Class V cavities were prepared on the buccal surfaces of the teeth in groups 1-5. Cavities were restored with amalgam, resin-based composite, glass ionomer (GI), zinc phosphate, or reinforced zinc oxide eugenol (Zonalin). Group 6 without cavity preparation was used as a control. Restorations with SSCs were prepared according to standard methods. Then, SSCs were fitted so that the crown margins overlaid the restorative materials and cemented with GI. After thermocycling, the specimens were placed in 0.5% fuchsin and sectioned. The proportions of mircoleakage and material loss were evaluated with a digital microscope. Statistical analysis was performed with Kruskal-Wallis and Mann-Whitney tests. RESULTS: The groups differed significantly (P < 0.001). Amalgam and GI showed the least microleakage. Amalgam restorations had significantly less microleakage than the other materials (P < 0.05). Microleakage was greatest with resin-based composite, followed by Zonalin. Material loss was greater in samples restored with Zonalin and zinc phosphate. CONCLUSION: When SSC margins overlaid the restoration materials, cavity restoration with amalgam or GI before SSC placement led to less microleakage and material loss. Regarding microleakage and material loss, resin-based composite, zinc phosphate, and Zonalin were not suitable options. PMID- 26962310 TI - Influence of motion pattern on apical transportation and centering ability of WaveOne single-file technique in curved root canals. AB - BACKGROUND: The aim of this study was to evaluate apical transportation and centering ability of single-file instruments, WaveOne primary, with full rotation versus reciprocation movement using cone-beam computed tomography (CBCT) analysis in curved mesiobuccal (MB) root canal of human mandibular molars. MATERIALS AND METHODS: Thirty MB canals of mandibular molars were randomly divided into two groups according to the instrument motion (n = 15): Group 1, reciprocation/WaveOne primary; Group 2, continuous rotation/WaveOne primary. After preparation, the amount of apical transportation and centering ability were assessed by evaluating pre- and post-instrumentation CBCT scans in three section (1, 3, and 5 mm from apical foramen). Statistical analysis of the data was performed using Mann-Whitney U-test and Friedman test (alpha = 0.05). RESULTS: There was no statistically significant difference between two experimental groups in terms of apical transportation and centering ratio at 1, 3, and 5 mm from apical foramen (P > 0.05). CONCLUSION: Apical transportation and centering ability of WaveOne primary reciprocating instrument did not significantly differ between two motion patterns. PMID- 26962311 TI - Plasma levels of N-telopeptide of Type I collagen in periodontal health, disease and after treatment. AB - BACKGROUND: To determine plasma concentrations of bone resorption marker cross linked N-terminal telopeptide (NTx) of Type I collagen in periodontal health, disease and after nonsurgical periodontal therapy in chronic periodontitis group. In addition, to know the association between plasma NTx levels and the different clinical parameters. MATERIALS AND METHODS: Thirty subjects were divided on the basis of their periodontal status and were categorized as Group I: Healthy, Group II: Gingivitis, and Group III: Chronic periodontitis. Group III subjects were treated with scaling and root planing, 6-8 weeks later blood samples were analyzed, and they constituted Group IV. NTx levels in plasma were analyzed by competitive - enzyme-linked immunosorbent assay. All data were analyzed using statistical software (SPSS) (alpha = 0.05). RESULTS: All the samples tested positive for the presence of NTx. The mean NTx concentration was highest in Group III (18.77 nanomole Bone Collagen Equivalent [nm BCE]) and the lowest in Group IV (16.02 nm BCE). The values of Group I and Group II fell between the highest and the lowest values (16.23 nm BCE and 16.70 nm BCE, respectively). The difference in mean NTx levels in Group III and Group IV were statistically significant. NTx levels in all the groups positively correlated with the clinical parameters. All data were analyzed using statistical software (SPSS) (alpha = 0.05). CONCLUSION: Within the limits of this study, it may be suggested that plasma NTx levels may provide distinguishing data between periodontally healthy diseased sites and after nonsurgical therapy of diseased sites. PMID- 26962312 TI - The effect of low-level helium-neon laser on oral wound healing. AB - BACKGROUND: The effectiveness of low power lasers on incisional wound healing, because of conflicting results of previous studies, is uncertain. Therefore, the aim of this study was to evaluate the effects of low-level helium-neon (He-Ne) laser irradiation on wound healing in rat's oral mucosa. MATERIALS AND METHODS: Sixty-four standardized incisions were carried out on the buccal mucosa of 32 male Wistar divided into four groups of eight animals each. Each rat received two incisions on the opposite sides of the buccal mucosa by a steel scalpel. On the right side (test side), a He-Ne laser (632 nm) was employed on the incision for 40 s. Laser radiation was used just in 1(st) day, 1(st) and 2(nd) day, 1(st) and 3(rd) day, and continuous 3 days in groups of A, B, C, and D of rats, respectively. The left side (control side) did not receive any laser. Histological processing and hematoxylin and eosin staining were done on tissue samples after 5 days. Wilcoxon and Kruskal-Wallis tests were used for statistical analysis. RESULTS: Histological analysis showed that the tissue healing after continuous 3 days on the laser irradiated side was better than the control side, but there was no difference between the two sides in each groups (P > 0.05). CONCLUSION: This study showed that He-Ne laser had no beneficial effects on incisional oral wound healing particularly in 5 days after laser therapy. Future research in the field of laser effects on oral wound healing in human is recommended. PMID- 26962313 TI - Microbiological analysis after complete or partial removal of carious dentin using two different techniques in primary teeth: A randomized clinical trial. AB - BACKGROUND: The management of deep carious lesions can be done by various techniques but residual caries dilemma still persists and bacterial reduction in cavities treated by either partial or complete caries removal techniques is debatable. So the objective of the present randomized clinical trial was to compare microbial counts in cavities submitted to complete caries removal and partial caries removal using either hand instruments or burs before and after 3 weeks of restoration. MATERIALS AND METHODS: Primary molars with acute carious lesions in inner half of dentine and vital pulp were randomly divided into three groups of 14 each: Group A: Partial caries removal using hand instruments atraumatic restorative treatment (ART) only; Group B: Partial caries removal using bur; Group C: Complete caries removal using bur and caries detector dye. Dentine sample obtained after caries removal and 3 weeks after restoration, were subjected to microbial culture and counting (colony-forming units [CFU]/mg of dentine) for total viable bacterial count, Streptococcus spp., mutans streptococci, Lactobacillus spp. RESULTS: Three techniques of caries removal showed significant (P < 0.05) reduction in all microorganisms studied after 3 weeks of evaluation, but there was no statistically significant difference in percentage reduction of microbial count among three groups. CONCLUSION: Results suggest the use of partial caries removal in a single session as compared to complete caries removal as a part of treatment of deep lesions in deciduous teeth in order to reduce the risk of pulp exposure. Partial caries removal using ART can be preferred for community settings as public health procedure for caries management. PMID- 26962314 TI - Prediction of lip response to orthodontic treatment using a multivariable regression model. AB - BACKGROUND: This was a retrospective cephalometric study to develop a more precise estimation of soft tissue changes related to underlying tooth movment than simple relatioship betweenhard and soft tissues. MATERIALS AND METHODS: The lateral cephalograms of 61 adult patients undergoing orthodontic treatment (31 = premolar extraction, 31 = nonextraction) were obtained, scanned and digitized before and immediately after the end of treatment. Hard and soft tissues, angular and linear measures were calculated by Viewbox 4.0 software. The changes of the values were analyzed using paired t-test. The accuracy of predictions of soft tissue changes were compared with two methods: (1) Use of ratios of the means of soft tissue to hard tissue changes (Viewbox 4.0 Software), (2) use of stepwise multivariable regression analysis to create prediction equations for soft tissue changes at superior labial sulcus, labrale superius, stomion superius, inferior labial sulcus, labrale inferius, stomion inferius (all on a horizontal plane). RESULTS: Stepwise multiple regressions to predict lip movements showed strong relations for the upper lip (adjusted R (2) = 0.92) and the lower lip (adjusted R (2) = 0.91) in the extraction group. Regression analysis showed slightly weaker relations in the nonextraction group. CONCLUSION: Within the limitation of this study, multiple regression technique was slightly more accurate than the ratio of mean prediction (Viewbox4.0 software) and appears to be useful in the prediction of soft tissue changes. As the variability of the predicted individual outcome seems to be relatively high, caution should be taken in predicting hard and soft tissue positional changes. PMID- 26962315 TI - Evaluation of biofilm removal activity of Quercus infectoria galls against Streptococcus mutans. AB - BACKGROUND: Dental caries is one of the most prevalent infectious diseases affecting humans of all ages. Streptococcus mutans has an important role in the development of dental caries by acid production. The purpose of this study was to evaluate the antibacterial and biofilm disinfective effects of the oak tree Quercus infectoria galls against S. mutans. MATERIALS AND METHODS: The bacterial strain used in this study was S. mutans (ATCC: 35668). Two kinds of galls, Mazouj and Ghalghaf were examined. Galls were extracted by methanol, ethanol and acetone by Soxhlet apparatus, separately. Extracts were dissolved in sterile distilled water to a final concentration of 10.00, 5.00, 2.50, 1.25, 0.63, 0.31, and 0.16 mg/ml. Microdilution determined antibacterial activities. The biofilm removal activities of the extracts were examined using crystal violet-stained microtiter plate method. One-way ANOVA was used to compare biofilm formation in the presence or absence of the extracts. RESULTS: The methanolic, ethanolic, and acetonic extracts of Q. infectoria galls showed the strong inhibitory effects on S. mutans (P < 0.05). The minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values for the Mazouj and Ghalghaf gall extracts against S. mutans were identical. The MIC values ranged from 160 MUg/ml to 320 MUg/ml, whereas the MBC values ranged from 320 MUg/ml to 640 MUg/ml. All extracts of Q. infectoria galls significantly (P < 0.05) reduced biofilm biomass of S. mutans at the concentrations higher than 9.8 MUg/ml. CONCLUSION: Three different extracts of Q. infectoria galls were similar in their antibacterial activity against S. mutans. These extracts had the highest biofilm removal activities at 312.5 MUg/ml concentration. The galls of Q. infectoria are potentially good sources of antibacterial and biofilm disinfection agent. PMID- 26962316 TI - The effect of two remineralizing agents and natural saliva on bleached enamel hardness. AB - BACKGROUND: In order to compensate the adverse consequences of bleaching agents, the use of fluoride-containing remineralizing agents has been suggested by many researchers. The aim of this study was to compare the effect of applying two remineralizing materials on bleached enamel hardness and in comparison to natural saliva. MATERIALS AND METHODS: In this experimental study, 30 enamel samples of sound human permanent molars were prepared for this study. Microhardness (MH) of all specimens was measured and 35% hydrogen peroxide was applied 3 times to the specimens. After completion of the bleaching process, MH of samples was measured and then enamel specimens were divided into three groups each of 10, specimens of groups 1 and 2 were subjected to daily application of hydroxyl apatite (Remin Pro) and casein phosphopeptide amorphous calcium phosphate fluoride (CPP-ACPF) (MI Paste Plus) pastes, respectively, for 15 days. In group 3, the specimens were stored in the operators' natural saliva at room temperature in this period of time. Final MH of all groups was measured. The data were analyzed using repeated measures ANOVA (alpha = 0.05). RESULTS: The hardness significantly decreased in all groups following bleaching. Application of either Remin Pro, CPP-ACPF or natural saliva increased the hardness significantly. The hardness of the three test groups after 15 days were statistically similar to each other. CONCLUSION: The hardness of enamel increases eventually after exposure to either MI Paste Plus, Remin Pro or natural saliva. PMID- 26962317 TI - Surface microhardness of different thicknesses of a premixed bioceramic material with or without the application of a moist cotton pellet. AB - BACKGROUND: This study was conducted to assess the effect of thickness and hydration condition on the surface microhardness of Endosequence Root Repair Material putty (ERRM; Brasseler USA, Savannah, GA), a premixed bioceramic material. MATERIALS AND METHODS: Polymethyl methacrylate cylindrical molds with an internal diameter of 4 mm and three heights of 2, 4, and 6 mm were fabricated. In Group 1 (dry condition), the molds with heights of 2, 4, and 6 mm (10 molds of each) were filled with ERRM. In Groups 2 and 3 (wet condition), a distilled water or phosphate-buffered saline (PBS)-moistened cotton pellet was placed directly on the upper surface of ERRM, respectively. The lower surface of ERRM was in contact with floral foams soaked with human blood. After 4 days, Vickers microhardness of the upper surface of ERRM was tested. The data were analyzed using two-way analysis of variance. Significance level was set at P < 0.05. RESULTS: No significant difference was found between the microhardness of three thicknesses of ERRM (2, 4, and 6 mm) with or without placing a distilled water- or PBS-moistened cotton pellet over the material (P > 0.05). CONCLUSION: Based on the results of this study, it could be concluded that placing a moistened cotton pellet on ERRM putty up to 6 mm thick might be unnecessary to improve its surface microhardness and hydration characteristics. PMID- 26962318 TI - Bispectoral index scores of pediatric patients under dental treatment and recovery conditions: Study of children assigned for general anesthesia under propofol and isofloran regimes. AB - BACKGROUND: This study was planned to determine the relationship between bispectoral index (BIS) during dental treatment and recovery conditions in children undergoing two regimes of anesthesia of propofol and isoflurane. MATERIALS AND METHODS: In this single-blind clinical trial study, 57 4-7-year-old healthy children who had been referred for dental treatment under general anesthesia between 60 and 90 min were selected by convenience sampling and assigned to two groups, after obtaining their parents' written consent. The anesthesia was induced by inhalation. For the first group, the anesthesia was preserved by a mixture of oxygen (50%), nitrous oxide (50%), and isoflurane (1%). For the second group, the anesthesia was preserved by a mixture of oxygen (50%), nitrous oxide (50%), and propofol was administered intravenously at a dose of 100 Ng/kg/min. The patients' vital signs, BIS, and agitation scores were recorded every 10 min. The data were analyzed by repeated measure ANOVA and t-tests at a significance level of alpha = 0.05 using SPSS version 20. RESULTS: The results of independent t-test for anesthesia time showed no statistically significant difference between isoflurane and propofol (P = 0.87). Controlling age, the BIS difference between the two anesthetic agents was not significant (P > 0.05); however, it was negatively correlated with the duration of anesthesia and the discharge time (P = 0.001, r = -0.308) and (P < 0.001, r = -0.55). CONCLUSION: The same depth of anesthesia is produced by propofol and isoflurane, but lower recovery complications from anesthesia are observed with isoflurane. PMID- 26962321 TI - Clinical management of a fused mandibular lateral incisor with supernumerary tooth: A case report. AB - The purpose of this report is to present a rare case of a fused mandibular lateral incisor with supernumerary tooth with a follow-up for 18-months. A 35 year-old female patient was referred to our clinic with an extraoral sinus tract in the chin. The intraoral diagnosis revealed the fusion of her mandibular lateral incisors. Vitality pulp tests were negative for mandibular right central and lateral incisors. Radiographic examinations showed a fused tooth with two separate pulp chambers, two distinct roots, and two separate root canals. There were also periapical lesion of fused teeth and mandibular right central incisor, so endodontic treatment was carried out the related teeth. Radiographic examination revealed a complete healing of the lesion postoperatively at the end of 18-months. This paper reports the successful endodontic and restorative treatment of unilateral fused incisors. Because of the abnormal morphology of the crown and the complexity of the root canal system in fused teeth, treatment protocols require special attention. PMID- 26962319 TI - Salivary levels of interleukin-6 and tumor necrosis factor-alpha in patients undergoing hemodialysis. AB - BACKGROUND: Inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) are elevated in end-stage renal disease (ESRD). IL-6 and TNF-alpha are toxins which deteriorate renal function, and their pathogenic role has been confirmed in cardiovascular and oral diseases. This study was designed to investigate the salivary levels of IL-6 and TNF-alpha in patients with ESRD undergoing hemodialysis (HD). MATERIALS AND METHODS: Twenty patients with ESRD who were treated with 4 h HD sessions, with low flux membrane were included in this cross-sectional study. Average Kt/V index in patients was 1.19 +/- 0.1. Twenty age-sex-matched healthy controls with no infectious diseases during 1 month before saliva sampling were selected. Unstimulated whole saliva was collected and TNF-alpha and IL-6, concentrations were measured using human IL 6 and TNF-alpha ELISA kits. Independent t-test was used to analyze the data using SPSS (alpha = 0.05). RESULTS: There was a significant difference between dialysis and control groups regarding the salivary levels of TNF-alpha (P = 0.034) and IL 6 (P = 0.001). CONCLUSION: Considering the results of this study and reported role of inflammatory cytokines in the pathogenesis of cardiovascular and oral diseases, measurement of salivary IL-6 and TNF-alpha in HD patients may help in risk stratification of HD patients and in planning pertinent preventive strategies. PMID- 26962320 TI - Effect of dentifrices on their remineralizing potential in artificial carious lesions: An in situ study. AB - BACKGROUND: The eventual sequel of dental caries is determined by the dynamic equilibrium between pathological factors which lead to demineralization and protective elements, which in turn leads to remineralization. Remineralization is the natural process for noncavitated demineralized lesions and relies on calcium and phosphate ions assisted by fluoride to rebuild a new surface on existing crystal remnants in subsurface lesions remaining after demineralization. Hence, the present study was designed to evaluate the efficacy of fluoride dentifrices in remineralizing artificial caries-like lesions in situ. MATERIALS AND METHODS: A double-blind, randomized study with an initial washout period of 7 days was carried out for 3 weeks. Twenty volunteers were enrolled, who wore the intraoral cariogenicity test appliance having enamel slabs incorporated into them, for 3 weeks. 10 participants were instructed to use Group A dentifrice (fluoride) and the other 10 Group B dentifrice (nonfluoride) for brushing their teeth. The enamel slabs were analyzed by surface microhardness testing and scanning electron microscopy (SEM) at 3 intervals. RESULTS: No significant differences was seen in the microhardness values recorded for Group A and Group B at baseline and after demineralization (P > 0.05); however Group B exhibited lesser microhardness compared to Group A, after intra-oral exposure (P < 0.05). In the SEM analysis, the Group A enamel surfaces had more regular and longer crystallites to those of the Group B. CONCLUSION: Fluoride dentifrices avert the decrease in enamel hardness and loss of minerals from the enamel surface to a large extent as compared to the nonfluoride dentifrices. PMID- 26962322 TI - Cone-beam computed tomography as a surgical guide to impacted anterior teeth. AB - Surgical procedure for removal of impacted teeth is a challenge for clinicians as it involves accuracy in the diagnosis and localization of the dental elements. The cone-beam computed tomography (CBCT), compared to the conventional radiography, has a greater potential to provide complementary information because of its three-dimensional (3D) images, reducing the possibility of failures in surgical procedures. Two 10-year-old boys presented with aesthetic issues associated with the juxtaposition of ectopic teeth with the permanent ones. Both two-dimensional and 3D preoperative radiographic diagnostic sets were produced. The occlusal and panoramic radiographs were not enough for proper localization of impacted incisors. Thus, the CBCT was used as a surgical guide. After 2 years of longitudinal following, no lesion was recorded, and the orthodontic treatment has proven successful. In all cases, CBCT contributed to both diagnosis and correct localization of supernumerary teeth, aiding the professional in the treatment planning, and consequently in the clinical success. The surgeries were completely safe, avoiding damage in noble structures, and providing a better recovering of the patients. PMID- 26962324 TI - Modelling Needs for Mental Healthcare from Epidemiological Surveys with Validation Using Sociodemographic Census Data. AB - PURPOSE: To develop and validate a prediction model for mental health needs (MHN) and psychiatric needs (PN) using specific social indicators, obtainable from census data, within low-density departments (LDD) and high- density departments (HDD). METHODS: In a population-based study of 20,404 participants from 22 departments in France, mental health needs were defined into three categories (no needs, MHN, and PN) using the Composite International Diagnosis Interview Short Form, Sheehan disability scale, and presence of depressive and alcohol disorders. Within HDD (n=9) and LDD (n=13) departments, two separate logistic regression models, using MHN or PN as an endpoint, were fitted using available sociodemographic data. Model validation was performed using 2007 census data. Overall accuracy was evaluated using average residuals (AR) calculated within density stratum. RESULTS: In LDD and HDD respectively, 26.6% and 28.7% of persons had MHN and 9.8% and 11.3% had PN. In LDD, housing type, age, employment, living alone, housing support, and household size predicted MHN and PN. In HDD, housing type, living alone, household size, living in a marriage/partnership, and duration of dwelling habitation predicted MHN and PN. Predictions were more accurate in HDD, in which the AR was 30% lower for MHN and 40% lower for PN. Predictions were less accurate when using census data, yet they were consistently better in HDD. CONCLUSIONS: Sociodemographic indicators from either survey or census data may be useful in predicting MHN and PN in high-density settings. The ideal territorial size still needs to be evaluated when planning psychiatric and mental health resources. PMID- 26962323 TI - The Burden of Depressive and Bipolar Disorders in Celiac Disease. AB - INTRODUCTION: AIMS: to measure the association between Celiac Disease (CD) and affective disorders, particularly Bipolar Disorder (BD), since it has not been studied yet, and to measure how much the quality of life (QoL) of a person with CD is affected by comorbidity with these disorders. METHODS: DESIGN: Case control study. CASES: 60 consecutive patients with CD. CONTROLS: 240 subjects without CD, randomly selected after sex- and age-matching from a database of an epidemiological study. Psychiatric diagnoses according to DSM-IV carried out by physicians using structured interview tools (ANTAS-SCID). QoL was measured by means of SF-12. RESULTS: The lifetime prevalence of Major Depressive Disorder (MDD) was higher in CD than in controls (30.0% vs 8.3%, P<0.0001) as well as Panic Disorder (PD) (18.3% vs 5.4%, P<0.001) and BD (4.3% vs 0.4%, P<0.005). Patients with CD show a lower mean score than controls on SF12 (35.8+/-5.7 vs. 38.2+/-6.4; p=0.010), but those without comorbidity with MDD, PD and BD do not. The attributable burden of CD in worsening QoL - when comorbid with these disorders - was found comparable to that of serious chronic diseases like Wilson's Disease, and lower than Multiple Sclerosis only. CONCLUSION: MDD, PD and BD are strictly associated with CD. The comorbidity with these disorders is the key determinant of impaired quality of life in CD. Thus a preventive action on mood and anxiety disorders in patients suffering from CD is required. Moreover a screening for CD in people with affective disorders and showing key symptoms or family history of CD is recommended. PMID- 26962325 TI - A simple test for the cleavage activity of customized endonucleases in plants. AB - BACKGROUND: Although customized endonucleases [transcription activator-like effector nucleases (TALENs) and RNA-guided endonucleases (RGENs)] are known to be effective agents of mutagenesis in various host plants, newly designed endonuclease constructs require some pre-validation with respect to functionality before investing in the creation of stable transgenic plants. RESULTS: A simple, biolistics-based leaf epidermis transient expression test has been developed, based on reconstituting the translational reading frame of a mutated, non functional yfp reporter gene. Quantification of mutation efficacy was made possible by co-bombarding the explant with a constitutive mCherry expression cassette, thereby allowing the ratio between the number of red and yellow fluorescing cells to serve as a metric for mutation efficiency. Challenging either stable mutant alleles of a compromised version of gfp in tobacco and barley or the barley MLO gene with TALENs/RGENs confirmed the capacity to induce site-directed mutations. CONCLUSIONS: A convenient procedure to assay the cleavage activity of customized endonucleases has been established. The system is independent of the endonuclease platform and operates in both di- and monocotyledonous hosts. It not only enables the validation of a TALEN/RGEN's functionality prior to the creation of stable mutants, but also serves as a suitable tool to optimize the design of endonuclease constructs. PMID- 26962326 TI - Conserved antigenic sites between MERS-CoV and Bat-coronavirus are revealed through sequence analysis. AB - BACKGROUND: MERS-CoV is a newly emerged human coronavirus reported closely related with HKU4 and HKU5 Bat coronaviruses. Bat and MERS corona-viruses are structurally related. Therefore, it is of interest to estimate the degree of conserved antigenic sites among them. It is of importance to elucidate the shared antigenic-sites and extent of conservation between them to understand the evolutionary dynamics of MERS-CoV. RESULTS: Multiple sequence alignment of the spike (S), membrane (M), enveloped (E) and nucleocapsid (N) proteins was employed to identify the sequence conservation among MERS and Bat (HKU4, HKU5) coronaviruses. We used various in silico tools to predict the conserved antigenic sites. We found that MERS-CoV shared 30 % of its S protein antigenic sites with HKU4 and 70 % with HKU5 bat-CoV. Whereas 100 % of its E, M and N protein's antigenic sites are found to be conserved with those in HKU4 and HKU5. CONCLUSION: This sharing suggests that in case of pathogenicity MERS-CoV is more closely related to HKU5 bat-CoV than HKU4 bat-CoV. The conserved epitopes indicates their evolutionary relationship and ancestry of pathogenicity. PMID- 26962327 TI - Retrospective analysis of reproductive health indicators in the United Nations High Commissioner for Refugees post-emergency camps 2007-2013. AB - BACKGROUND: The United Nations Refugee Agency's Health Information System issues analytical reports on the current camp conditions and trends for priority reproductive health issues. The goal was to assess the status of reproductive health by analyzing seven indicators and comparing them to standards and host country estimates. METHODS: Data on seven indicators were extracted from the database during a seven-year period (2007 through 2013). A standardized country inclusion criterion was created based on the year of country implementation and the percentage of missing reports per camp and year. The unit of analysis was monthly camp reports by year within a country. To account for the lack of independence of monthly camp reports, the variance was computed using Taylor Series Linearization methods in SAS. RESULTS: Ten of the 23 eligible countries met the inclusion criterion. The mean camp maternal and neonatal mortality rates, except for two country years, were lower than the host country estimates for all countries and years. There was a significant increase in the percent of births attended by a skilled birth attendant (p < 0.0001), and 8 of 10 countries did not meet the standard of 100 % for all reporting years. The percent of births performed by Caesarian section (p < 0.001), were below the recommended minimum standard for nearly half of the countries every year. There was a significant increase in the percent of women screened for syphilis across years (p < 0.0001) and the percent of women who received post HIV exposure prophylaxis (p < 0.0001) and 10 % reached the standard for all reporting years, respectively. CONCLUSION: Comprehensive, consistent and comparable statistics on reproductive health provides an opportunity to assess progress towards indicator standards. Despite some improvements over time, this analysis confirms that most countries did not meet standards and that there were differences in reproductive health indicators between countries and across years. Consequently, the HIS periodic monitoring of key reproductive health indicators at the camp level should continue. Data should be used to improve intervention strategies. PMID- 26962328 TI - Bridging the gap: investigating challenges and way forward for intersectoral provision of psychosocial rehabilitation in South Africa. AB - BACKGROUND: Intersectoral collaboration between government sectors such as Health and Social Development and non-governmental organisations (NGOs) in communities is crucial for provision of psychosocial rehabilitation (PSR) for those with severe mental illness. This study aims to provide recommendations for strengthening such intersectoral collaboration in South Africa and with relevance to other low and middle income countries (LMIC), particularly African countries. METHODS: Twenty-four in-depth semi-structured interviews were conducted with 16 key informants from the South African Department of Health, two key informants from the Department of Social Development, four key informants from the NGO sector and one key informant from a service user organisation at national level. Framework analysis was conducted with NVivo 10 software. RESULTS: Challenges to intersectoral work identified were lack of communication between sectors, problems delineating roles, and each sector's perception of lack of support from other sectors. Participant-identified strategies for addressing these challenges included improving communication between sectors, promoting leadership from all levels and formalising intersectoral relationships through appropriate written agreements; as well as ensuring that the available resources for PSR are effectively re-directed to district level. CONCLUSIONS: This study has outlined several directions for progress to address challenges for intersectoral working for PSR in South Africa. These may be of relevance to other LMIC, particularly those in Africa. Political will and a long-term view will be necessary to realise these strategies. PMID- 26962329 TI - Cellular automata modeling depicts degradation of cellulosic material by a cellulase system with single-molecule resolution. AB - BACKGROUND: Enzymatic hydrolysis of cellulose involves the spatiotemporally correlated action of distinct polysaccharide chain cleaving activities confined to the surface of an insoluble substrate. Because cellulases differ in preference for attacking crystalline compared to amorphous cellulose, the spatial distribution of structural order across the cellulose surface imposes additional constraints on the dynamic interplay between the enzymes. Reconstruction of total system behavior from single-molecule activity parameters is a longstanding key goal in the field. RESULTS: We have developed a stochastic, cellular automata based modeling approach to describe degradation of cellulosic material by a cellulase system at single-molecule resolution. Substrate morphology was modeled to represent the amorphous and crystalline phases as well as the different spatial orientations of the polysaccharide chains. The enzyme system model consisted of an internally chain-cleaving endoglucanase (EG) as well as two processively acting, reducing and non-reducing chain end-cleaving cellobiohydrolases (CBHs). Substrate preference (amorphous: EG, CBH II; crystalline: CBH I) and characteristic frequencies for chain cleavage, processive movement, and dissociation were assigned from biochemical data. Once adsorbed, enzymes were allowed to reach surface-exposed substrate sites through "random walk" lateral diffusion or processive motion. Simulations revealed that slow dissociation of processive enzymes at obstacles obstructing further movement resulted in local jamming of the cellulases, with consequent delay in the degradation of the surface area affected. Exploiting validation against evidence from atomic force microscopy imaging as a unique opportunity opened up by the modeling approach, we show that spatiotemporal characteristics of cellulose surface degradation by the system of synergizing cellulases were reproduced quantitatively at the nanometer resolution of the experimental data. This in turn gave useful prediction of the soluble sugar release rate. CONCLUSIONS: Salient dynamic features of cellulose surface degradation by different cellulases acting in synergy were reproduced in simulations in good agreement with evidence from high-resolution visualization experiments. Due to the single-molecule resolution of the modeling approach, the utility of the presented model lies not only in predicting system behavior but also in elucidating inherently complex (e.g., stochastic) phenomena involved in enzymatic cellulose degradation. Thus, it creates synergy with experiment to advance the mechanistic understanding for improved application. PMID- 26962330 TI - Gender-specific associations of serum sex hormone-binding globulin with features of metabolic syndrome in children. AB - BACKGROUND: Sex hormone-binding globulin (SHBG) has been proposed as a biomarker of MetS in children and adults. We aim to determine the associations of SHBG with components of MetS in children from the Middle-East where the prevalence of MetS are on the rise. METHODS: In this cross-sectional study, a total of 509 randomly selected school children (226 boys and 283 girls) aged 12-16 years were recruited. Fasting blood glucose and lipid profile were determined using routine laboratory procedures. Serum SHBG is measured with Cobas e411 using an electrochemiluminescence immunoassay. The modified definition of ATP-III (NHANES III) was used for the diagnosis of MetS. RESULTS: Among 509 children, 23.4 % had metabolic syndrome. Boys had a significantly higher waist circumference and systolic blood pressure (p < 0.032, 0.024, respectively) than girls, while levels of glucose (p < 0.029), and SHBG (p < 0.003) were significantly higher in girls than in boys. In overall population, a significant inverse correlation of SHBG level with age, BMI, systolic blood pressure and triglycerides and a significant direct correlation between SHBG level and HDL-c was exhibited. Children with the lowest tertile of serum SHBG had significantly higher prevalence of MetS (p < 0.05). ROC curve shows SHBG level as more sensitive marker of MetS in boys (AUC = 0.70, p < 0.001). CONCLUSIONS: Serum SHBG is significantly more sensitive in identifying MetS in boys, not girls, indicating gender dimorphism. PMID- 26962331 TI - From the Editor's desk. PMID- 26962332 TI - Autism and sleep disorders. AB - "Autism Spectrum Disorders" (ASDs) are neurodevelopment disorders and are characterized by persistent impairments in reciprocal social interaction and communication. Sleep problems in ASD, are a prominent feature that have an impact on social interaction, day to day life, academic achievement, and have been correlated with increased maternal stress and parental sleep disruption. Polysomnography studies of ASD children showed most of their abnormalities related to rapid eye movement (REM) sleep which included decreased quantity, increased undifferentiated sleep, immature organization of eye movements into discrete bursts, decreased time in bed, total sleep time, REM sleep latency, and increased proportion of stage 1 sleep. Implementation of nonpharmacotherapeutic measures such as bedtime routines and sleep-wise approach is the mainstay of behavioral management. Treatment strategies along with limited regulated pharmacotherapy can help improve the quality of life in ASD children and have a beneficial impact on the family. PubMed search was performed for English language articles from January 1995 to January 2015. Following key words: Autism spectrum disorder, sleep disorders and autism, REM sleep and autism, cognitive behavioral therapy, sleep-wise approach, melatonin and ASD were used. Only articles reporting primary data relevant to the above questions were included. PMID- 26962334 TI - Pediatric encephaloceles: A series of 20 cases over a period of 3 years. AB - BACKGROUND: Encephalocele is the protrusion of the cranial contents beyond the normal confines of the skull through a defect in the calvarium and is far less common than spinal dysraphism. The exact worldwide frequency is not known. AIMS AND OBJECTIVES: To determine the epidemiological features, patterns of encephalocele, and its postsurgical results. MATERIALS AND METHODS: The study was carried from year July 2012 to June 2015. Patients with encephalocele were evaluated for epidemiological characteristics, clinical features, imaging characteristics, and surgical results. RESULTS: 20 encephaloceles patients were treated during the study period. Out of these 12 (60%) were male and 8 (40%) female. Age range was 1 day to 6 years. The most common type of encephalocele was occipital 12 (60%), occipito-cervical 4 (20%), parietal 2 (10%), fronto-nasal 1 (5%), and fronto-naso-ethmoidal 1 (5%). One patient had a double encephalocele (one atretic and other was occipital) with dermal sinus tract and limited dermal myeloschisis. Other associations: Chiari 3 malformation (2), meningomyeloceles (4), and syrinx (4). Three patients presented with rupture two of whom succumbed to meningitis and shock. Seventeen patients treated surgically did well with no immediate surgical mortality (except a case of Chiari 3 malformation who succumbed 6 months postsurgery to unrelated causes). Shunt was performed in 4 cases. CONCLUSION: The most common type of encephalocele is occipital in our set up. Early surgical management of encephalocele is not only for cosmetic reasons but also to prevent tethering, rupture, and future neurological deficits. PMID- 26962333 TI - Extended endoscopic endonasal transsphenoidal approach for retrochiasmatic craniopharyngioma: Surgical technique and results. AB - OBJECTIVE: Surgical treatment of retrochiasmatic craniopharyngioma still remains a challenge. While complete removal of the tumor with preservation of the vital neurovascular structures is often the goal of the treatment, there is no optimal surgical approach available to achieve this goal. Transcranial and transsphenoidal microsurgical approaches, commonly used in the past, have considerable technical limitations. The extended endonasal endoscopic surgical route, obtained by removal of tuberculum sellae and planum sphenoidale, offers direct midline access to the retrochiasmatic space and provides excellent visualization of the undersurface of the optic chiasm. In this report, we describe the technical details of the extended endoscopic approach, and review our results using this approach in the surgical management of retrochiasmatic craniopharyngiomas. METHODS: Fifteen children, including 9 girls and 6 boys, aged 8 to 15 years underwent surgery using extended endoscopic transsphenoidal approach between 2008 and 2014. Nine patients had a surgical procedure done previously and presented with recurrence of symptoms and regrowth of their residual tumors. RESULTS: A gross total or near total excision was achieved in 10 (66.7%) patients, subtotal resection in 4 (26.7%), and partial removal in 1 (6.7%) patient. Postoperatively, headache improved in 93.3%, vision recovered in 77.3%, and the hormonal levels stabilised in 66.6%. Three patients (20%) developed postoperative CSF leaks which were managed conservatively. Three (20%) patients with diabetes insipidus and 2 (13.3%) with panhypopituitarism required long-term hormonal replacement therapy. CONCLUSIONS: Our early experience suggests that the extended endonasal endoscopic approach is a reasonable option for removal of the retrochiasmal craniopharyngiomas. Compared to other surgical approaches, it provides better opportunities for greater tumor removal and visual improvement without any increase in risks. PMID- 26962335 TI - The relationship between obesity and symptomatic Chiari I malformation in the pediatric population. AB - BACKGROUND: Concomitant with the rise in childhood obesity in the United States is an increase in the diagnosis of Chiari I malformation (CM1). OBJECTIVE: To discern a correlation between obesity and CM1, defined as >5 mm of cerebellar tonsillar descent on sagittal magnetic resonance imaging. METHODS: Charts of CM1 patients aged 2-20 years were retrospectively reviewed. Chiari size, age, body mass index (BMI), and CM1 signs/symptoms were recorded. Patients were stratified by age: 2-9, 10-14, and 15-20 years. Mixed-effect linear models and linear regression analysis were applied to investigate the relationship between BMI-for age percentiles and CM1 signs/symptoms. RESULTS: One hundred sixty-seven patients were included (mean age 14.5 +/- 2.97 years, BMI 22.98 +/- 6.5, and Chiari size 12.27 mm +/- 5.91). When adjusted for age, 42% were overweight or obese-higher than normative BMI for children in the studied area (29.6%). When stratified by age, patients between 2 and 9 years were most commonly obese and presented the highest mean BMI (25.66), largest Chiari size (13.58), and highest incidence of headache (75%) and syringomyelia (66.67%). Patients between 15 and 20 years were most commonly overweight and presented the smallest Chiari size (11.76 mm), but the highest incidence of cerebellar (50%) and brainstem (8.55%) compression symptoms. A significant positive correlation existed between BMI and headache in the first two age groups: (R (2): 0.36, P = 0.03; R (2): 0.39, P = 0.01, respectively). Obese patients had higher incidence of headache in the 10-14 group (R (2): 0.37, P = 0.02) and the largest Chiari size in the 15-20 group (R (2): 0.40, P = 0.03). CONCLUSIONS: The pediatric CM1 population is more likely to be overweight or obese. Younger obese patients presented the highest incidence of Chiari-related headache symptoms, and older obese patients, the highest incidence of findings other than headache. Thus, body weight and age should be considered when evaluating children with CM1. PMID- 26962337 TI - Diphtheritic polyneuropathy in the wake of resurgence of diphtheria. AB - OBJECTIVE: To study the clinical profile and outcome in children with diphtheritic polyneuropathy (DP). METHODOLOGY: 13 children with polyneuropathy were included in this study. Their demographic profile, age, sex and immunization status were recorded. Detailed clinical and neurological examination was done. Investigations like CSF analysis, NCV studies, MRI brain were done. The results were tabulated and analyzed. RESULTS: All the children presented with bulbar palsy and had h/o membranous tonsillitis. Isolated palatal palsy was seen in 7 children (53%). 6 (46.1%) children developed quadriparesis. 1 child expired and recovery is complete in rest of the 12 children. Children with isolated bulbar palsy recovered within 2 to 4 weeks while children with quadriparesis recovered within 5-6 wks. CONCLUSIONS: Any child diagnosed with diphtheria should be followed for 3-6 months in anticipation of neurological complications. DP carries good prognosis hence timely diagnosis and differentiation from other neuropathies is a prerequisite for rational management. PMID- 26962336 TI - Does diffusion restriction changes in magnetic resonance imaging predict neurological outcome in neonatal seizures? AB - BACKGROUND: Neonatal seizures are a common manifestation of brain dysfunction. Neonatal magnetic resonance imaging (MRI) has rapidly become the study of choice for the evaluation of central nervous systems disorders in newborns. According to a study conducted in Wilhelmina Children's Hospital, University Medical Center Utrecht, diffusion Restriction (DR) changes in the MRI is a good indicator of cell dysfunction (reversible or irreversible) within one week of insult. OBJECTIVES: The main aim of this study was to find the association of DR changes in MRI of brain for neonatal seizures with long term neurodevelopment outcome. METHODS: This is a retrospective observational study conducted in Sri Ramachandra University. Retrospective data was collected for the time period of January 2010 to December 2011 from medical records department (MRD) for patient data, neonatal intensive care unit and reports from PACS for MRI images and the Karthikeyan child development unit for their developmental follow up reports. RESULTS: Comparison of composite score for various domains with DR changes was done with a t-test and comparison of babies with developmental delay and DR changes with Chi square test. MRI DR changes with developmental outcome in different domains namely cognition, language-receptive/expressive, fine and gross motor was studied. There is no statistical significance among those who have DR changes and with those who do not have DR changes. CONCLUSION: Though diffusion restriction changes in MRI may not predict adverse long term neuro developmental outcome, they can be of use with regards to individual etiological profile as in stroke. Larger group study and long term follow up is required to substantiate these findings. PMID- 26962338 TI - Brain tumors in infants. AB - BACKGROUND: Brain tumors in infants have different clinical presentations, anatomical distribution, histopathological diagnosis, and clinical prognosis compared with older children. MATERIALS AND METHODS: A retrospective analysis was done in patients <12 months old who were operated on for primary brain tumor in Children's Hospital Medical Center since 2008 to 2014. RESULTS: Thirty-one infants, 20 males and 11 females, with the mean age of 7.13 months (0.5-12) were enrolled. There were 16 supratentorial and 15 infratentorial tumors. The presenting symptoms included increased head circumference (16); bulge fontanel (15); vomiting (15); developmental regression (11); sunset eye (7); seizure (4); loss of consciousness (4); irritability (3); nystagmus (2); visual loss (2); hemiparesis (2); torticollis (2); VI palsy (3); VII, IX, X nerve palsy (each 2); and ptosis (1). Gross total and subtotal resection were performed in 19 and 11 cases, respectively. Fourteen patients needed external ventricular drainage in the perioperative period, from whom four infants required a ventriculoperitoneal shunt. One patient underwent ventriculoperitoneal shunting without tumor resection. The most common histological diagnoses were primitive neuroectodermal tumor (7), followed by anaplastic ependymoma (6) and grade II ependymoma. The rate of 30-day mortality was 19.3%. Eighteen patients are now well-controlled with or without adjuvant therapy (overall survival; 58%), from whom 13 cases are tumor free (disease free survival; 41.9%), 3 cases have residual masses with fixed or decreased size (progression-free survival; 9.6%), and 2 cases are still on chemotherapy. CONCLUSION: Brain tumors in infants should be treated with surgical resection, followed by chemotherapy when necessary. PMID- 26962339 TI - Survival with concurrent temozolomide and radiotherapy in pediatric brainstem glioma with relation to the tumor volume. AB - BACKGROUND: Brainstem gliomas account for approximately 25% of all posterior fossa tumors. In pediatric age group, it constitutes about 10% of all brain tumors. Brainstem glioma is an aggressive and lethal type of malignancy with poor outcome despite all treatments. AIM: We studied the incidence and treatment outcome in pediatric patients with brainstem glioma depending on their tumor volume presenting in our institution in last 5 years. Brain tumors comprised 2.95% of all cancers and brainstem gliomas were 8% of all brain tumors. MATERIALS AND METHODS: Nine pediatric patients were included in this analysis, who were treated with localized external radiotherapy 54-59.4 Gy along with temozolomide 75 mg/m(2) during the whole course of radiotherapy. RESULTS: The median survival in all these patients was 20 months and the overall 2 years survival is 44.4% (4/9). The median survival of patients with primary disease volume <40cc is 26 months whereas when the volume is more than 40cc the median survival is 13.5 months as calculated by Chi-square test. CONCLUSION: As this study includes a small number of patients with unknown histology and treated on the basis of magnetic resonance imaging findings, no definite opinion can be given as some patients may have a low-grade tumor. More studies are required to establish the relation of size of the tumor with survival. PMID- 26962340 TI - Merosin-negative congenital muscular dystrophy: Report of five cases. AB - CONTEXT: Congenital muscular dystrophy type 1A (MDC1A) is caused by mutations in the laminin alpha-2 gene encoding laminin-a2. AIMS: The purpose of this study is to determine clinical and genetic results in five Turkish patients with MDC1A. SETTING AND DESIGNS: Five children with MDC1A were retrospectively analyzed. RESULTS: Three (60%) were boys, and 2 (40%) were girls. Parental consanguinity was found in all the families. In all the patients, hypotonia, weakness, delayed motor milestones, markedly elevated creatine phosphokinase (CPK) concentration, and brain white matter abnormalities on magnetic resonance imaging were detected. Mutation analysis was performed in all the patients, and 3 different mutations were detected. However, a mutation in patient 1 and 2 has not been previously described in the literature. CONCLUSIONS: When a patient presents with severe congenital hypotonia, muscle weakness, high serum CPK levels, and white matter abnormalities, should be suspected as MDC1A. PMID- 26962341 TI - A clinical study to identify the possible etiology of complex partial seizures using magnetic resonance imaging brain findings and its implications on treatment. AB - CONTEXT: Epilepsy is one of the common neurological disorders worldwide. Fundamentally, there are two types of epilepsy-primary generalized epilepsy and localization-related epilepsy. Partial seizures account for about 40% of childhood seizures in some series and can be classified as simple or complex.[1] Partial seizures, more so the complex partial seizures (CPSs), are presumed to have a structural etiology. AIMS: (1) To study the magnetic resonance imaging (MRI) brain findings in CPSs in children aged 1-18 years. (2) To identify treatable causes of CPSs based on MRI findings and institute appropriate treatment. STATISTICAL ANALYSIS: Statistical analysis was performed using percentages and proportions. METHODS: Hospital based prospective study in which MRI brain was done on all newly diagnosed children with complex partial seizures, aged 1 to 18 yrs, during the study period. Final diagnosis was made correlating clinical features, radiological features and other supportive evidences, and appropriate treatment instituted. Follow up of cases was done until the completion of treatment (maximum 6 months). RESULTS: Among the 64 children who were clinically diagnosed to have CPSs and subjected to MRI study of the brain, 40(62.5%) children were detected to have structural lesions, of which neurocysticercosis (NCC) was noted in 17 (42.5%), tuberculoma in 12 (30%), hippocampal sclerosis (HS) in 6 (15%), gliosis in 4 (10%), and tumor in 1 (2.5%) patient. Sixty-two (96.8%) children were treated medically, and 2 (3.2%) children underwent surgery. CONCLUSIONS: Etiology of CPS based on MRI findings showed a substantial number of medically- and surgically-treatable pathologies. This study done on South Indian children showed neuro infections to be the most common cause of CPS, followed by HS, with NCC being the most common lesion noted. MRI not only identifies specific epileptogenic substrates, but also determines the specific treatment and predicts prognosis and should be the imaging modality of choice in the evaluation of CPS. PMID- 26962342 TI - Nonketotic hyperglycinemia case series. AB - To present three cases who presented with neonatal hiccups and who were later diagnosed with nonketotic hyperglycinemia (NKH). CASE SERIES: We present three babies who presented in neonatal life with hiccups who later were diagnosed with NKH. Two babies presented on the 2(nd) day of life with hypotonia, poor feeding, and abnormal movements including jitteriness, hiccups, and twitching. The third baby only had transient hiccups lasting for a couple of days in the 1(st) week of life but later presented at 3 months of age with poor feeding, drowsiness, and jerky movements. All three cases needed extensive investigations before reaching the diagnosis including metabolic screen, lumbar puncture, electroencephalography, and computed tomography/magnetic resonance imaging. The first two babies needed intubation on their 2(nd) day of life because of apneas in whom later, the care was withdrawn after reaching the diagnosis of NKH because of poor prognosis. The third baby was discharged home on oral dextromethorphan and ketogenic diet. We discuss the importance of early recognition of symptoms (frequent hiccups) and investigation needed to reach the diagnosis early as it helps in making decision to either carry on treatment or withdraw care because of poor prognosis. It also helps in genetic counseling and prenatal diagnosis can be offered at the subsequent pregnancy. PMID- 26962343 TI - Delayed diagnosis of Gorlin syndrome: Learning from mistakes! AB - Gorlin syndrome (GS) is a rare inherited multisystem disorder with predisposition to basal cell carcinomas and various other neoplasms. Characteristic features include falx calcification, multiple odontogenic keratocysts (OKCs), early onset medulloblastoma, craniofacial and skeletal malformations, cardiac and ovarian fibroma. We present a case of GS in a 9-year-old girl with recurrent dental infections which was overlooked for 8 years. Diagnosis was finally suggested by the incidental detection of multiple OKCs and ovarian fibromas on follow-up magnetic resonance imaging performed for surveillance of previous operated brain tumor. PMID- 26962344 TI - Spondylocostal dysostosis associated with right-sided polythelia, right-sided rib deformity and meningocoele: Case report with review of literature. AB - Spondylocostal dysostosis (SCD) is a rare anomaly of axial skeleton due to flawed embryological development. A newborn baby boy with right-sided polythelia, meningocoele, fan-like configuration of third and fourth rib, fused fifth and sixth rib and third thoracic hemivertebra was delivered to a second gravid mother by elective caesarean section. Baby was active, cried immediately after birth, had normal muscle tone and reflexes. He passed urine and meconium within 24 h of birth. Based on clinical examination and radiological picture, a diagnosis of SCD with meningocele with right-sided polythelia was made. Our case is the first SCD with polythelia and meningocele in newborn. SCD with right-sided polythelia and rib deformity with neural tube defect (NTD) may be due to a genetic defect with the culprit genes missing. Further genetic and embryological studies might find a link between right-sided rib defects, polythelia and NTD. PMID- 26962346 TI - Vesical calculi formation on the slit valves of a migrated distal end of ventriculoperitoneal shunt. AB - Various complications of distal end of the ventriculoperitoneal (VP) shunt have been described in the literature. We present, here, an extremely rare and potentially severe complication of vesical calculi formation on the slit valves of distal end of VP shunt which erosively migrated into the urinary bladder. Suprapubic cystolithotomy performed, peritoneal end of the tube found to be eroding and entering into the bladder with two calculi firmly stuck to slit valves in the distal end of the tubing were removed. Shunt was functional, therefore, it was pulled out and repositioned on the superior aspect of the liver; the urinary bladder was repaired. Patient did well postoperatively. This complication was revealed 1.5 years after the shunt was implanted. Although there were symptoms of dysuria and dribbling of urine of short duration, the patient did not show obvious peritoneal signs; suggesting that, penetration of a VP shunt into the urinary bladder can remain asymptomatic for a long period of time, disclosed late and can lead to considerable morbidity. Careful follow-up is important and management should be individualized. PMID- 26962345 TI - A rare case of abdominal compartment syndrome following repair of large myelomeningocele. AB - Abdominal compartment syndrome is a rare entity that can be life-threatening if not diagnosed and correctly managed in time. We report a case of abdominal compartment syndrome following an apparently uneventful excision and repair of myelomeningocele (MMC). Though MMC is the most complex congenital spinal cord malformation compatible with life and early surgery is recommended to decrease the risk of meningitis and sepsis but generally surgery is safe without major perioperative turbulence. The majority of the skin defects following excision of MMC are repaired by primary skin closure, but large defects may require secondary closure by skin grafts or rotational flaps. We report a case of an infant with large MMC, who developed abdominal compartment syndrome following excision and repair of the swelling. Intraoperatively, it manifested as bradycardia, hypotension, and ventilatory difficulty which were managed successfully. Subsequently, in the postoperative period, the presence of tight abdomen and fall in urine output raised strong suspicion regarding development of abdominal compartment syndrome. Condition of infant improved following the release of flap sutures. A high index of suspicion along with early management is imperative for a successful outcome in such cases. PMID- 26962347 TI - Cerebellopontine angle arachnoid cyst associated with mirror movements. AB - Arachnoid cysts are benign developmental collections of cerebrospinal fluid (CSF). They constitute approximately 1% of intracranial masses. The cerebellopontine angle (CPA) arachnoid cysts are rare and often asymptomatic. The onset of symptoms and signs is usually due to the compression of the brain, cranial nerves and obstruction of CSF circulation. The major clinical symptoms for CPA arachnoid cysts were reported as headache, ataxia and 8(th) cranial nerve palsy. We report a patient with a CPA arachnoid cyst. He presented with cranial nerve palsies and mirror movements found in upper extremities. We postulated that CPA arachnoid cyst compressing the brain stem and the pyramidal decussation may lead to mirror movements. We conclude that mirror movements can be associated with CPA arachnoid cyst. PMID- 26962348 TI - Occipital lobe seizures: Rare hyperglycemic sequelae of type 1 diabetes mellitus. AB - A 15-year-old boy presented with osmotic symptoms and photopsia. He had short term memory impairment, visual hallucinations, and headache. His random blood sugar was 474 mg/dl, HbA1c -9.4%, and glutamic acid decarboxylase -65 >2000 IU/ml. Magnetic resonance imaging brain and cerebrospinal fluid study were normal. Digital electroencephalography was suggestive of bilateral hemispheric occipital lobe seizures. He responded well to insulin and antiepileptic medications. PMID- 26962349 TI - A pediatric chronic subdural hematoma: More than meets the eye. AB - We present an unusual case of a 13-year-old child who following minor head injury presented with what appeared to be a thin chronic subdural hematoma on plain computed tomography imaging. The child was found to have an underlying arachnoid cyst. Intra- and extra-cystic bleeding had occurred simultaneously causing an isodense cyst with an accompanying subdural collection. This radiographically occult pathology should be excluded using magnetic resonance imaging in any child presenting with a subdural collection. PMID- 26962350 TI - Pediatric gliomatosis cerebri mimicking tubercular encephalitis. AB - Gliomatosis cerebri (GC) is a diffuse infiltrating glial neoplasm of astrocytic origin. GC in children is rare and difficult to diagnose, often presenting with a variety of signs and symptoms that may mimic myriad conditions. We discuss here the presentation and diagnosis of GC in a child who was initially treated on lines of tubercular encephalitis, with transient clinical relief and disappearance of enhancing component of the disease on magnetic resonance imaging. In this report, we highlight the limitations of clinical presentation and neuroimaging as well as the essential role of histological evaluation for the diagnosis of GC in children. Also is highlighted a more benign and protracted clinical course following radiotherapy in a subset of patients, with Ki index <10%, thereby stressing earliest possible diagnosis. A new prognostic classification can also be proposed for pediatric GC based on various parameters. Since these are rare cases, a combined effort is required for this. PMID- 26962351 TI - Atypical teratoid rhabdoid tumor of the lateral ventricle. AB - Atypical teratoid/rhabdoid tumors (AT/RTs) are rare and highly malignant embryonal central nervous system neoplasms, usually seen in very young children with rapid fatal outcome despite aggressive treatment. They are most commonly located in the posterior fossa. Intraventricular location is extremely rare. To the best of our knowledge, only 4 cases of lateral ventricle location were reported in the literature. We report the fifth case of lateral ventricle AT/RT in a 2-month-old male who presented with rapid increase of his head circumference. Brain computed tomography scan and magnetic resonance imaging showed heterogeneous huge mass within the left lateral ventricle extending to the parieto-occipital parenchyma and markedly enhancing by contrast. The baby underwent left transparietal approach with complete removal of the tumor. Histological examination confirmed the diagnosis of AT/RT. An aggressive chemotherapy was administrated postoperatively. The outcome is good without neurological deficit or recurrence after 3 years and half of follow-up. PMID- 26962352 TI - A case report of pontine glioblastoma presenting as subcutaneous metastasis in nape of neck in a child. AB - Glioblastoma (GBM) is the most common malignant tumor in adults. Extracranial metastasis of GBM is very rare. The incidence of brainstem glioblastoma is not known due to low biopsy and resection rates. In this case report, we experienced an 11-year-old male who was diagnosed as a case of pontine GBM after biopsy of lesion and underwent radiotherapy with adjuvant chemotherapy. He presented with a subcutaneous swelling in the nape of neck 1 year after the first procedure. Swelling was excised. Pathological examination and immunohistochemical staining confirmed it as GBM. This case shows us that GBM can at times present as a swelling in soft tissue. PMID- 26962354 TI - Primary intraventricular central nervous system lymphoma in an immunocompetent patient. AB - We report a young 15-year-old boy with 6 months history of headache, vomiting, and seizure. He underwent septostomy followed by right ventriculoperitoneal shunt for obstructive hydrocephalus and was managed with empirical antituberculosis treatment. Magnetic resonance imaging (MRI) revealed solid, nodular, enhancing masses in bilateral lateral ventricles and 4(th) ventricle. Surgical biopsy from 4(th) ventricular lesion confirmed a B-cell lymphoma. Staging evaluation with MRI positron emission tomography and bone marrow biopsy were normal suggesting an intraventricular primary central nervous system lymphoma. PMID- 26962353 TI - Primary parietal myeloid sarcoma. AB - Intracranial occurrence of myeloid sarcoma without any evidence of systemic hematological disorder is uncommon. We report the case of a 17-year-old girl who presented with features of raised intracranial pressure and paraparesis of short duration. Magnetic resonance imaging showed a 6 cm bilateral middle 1/3(rd) para sagittal contrast enhancing extra-axial mass with mass effect. The tumor was subtotally excised. Histology and immunohistochemistry proved to be a myelosarcoma. Further evaluation done with peripheral blood smear and bone marrow biopsy ruled out the possibility of leukemia or myeloproliferative disorder. She was referred for chemotherapy and clinically showed improvement after 6 months of follow-up. Authors report a case of intracranial myelosarcoma which closely resembled meningioma both radiologically and in intraoperative morphological appearance. Authors discuss in detail the radiological and histological features of myelosarcoma along with differential diagnoses and treatment options. PMID- 26962355 TI - Single staged complete length excision of the holocord ependymoma: Team work. AB - The authors present a case of a 15-year-old male patient who presented with gradually progressive quadriparesis for 3 years. Magnetic resonance imaging of the spine was suggestive of heterogeneously enhancing mass lesion extending from cervicomedullary junction to conus. This holocord spinal tumor was excised in a single stage with standard microsurgical technique. In immediate postoperative period, the patient had deterioration in power in both lower limbs which improved in follow-up at 6 months. Histopathology of the tumor was suggestive of ependymoma. Holocord ependymoma is a rare entity; until now, only six cases have been described in the literature. To the author's best knowledge, this is only the second case of holocord ependymoma excised in a single stage. PMID- 26962356 TI - Guillain-Barre syndrome masquerading as acute respiratory failure in an infant. AB - Guillain-Barre syndrome (GBS) is a rare entity in infants. We report a case of GBS in a 5-month-old girl. The child presented with cough, loose stools, breathing difficulty, and listlessness. The child was treated as pneumonia with respiratory failure. Due to difficulty in weaning from ventilation with areflexia, marked hypotonia, and reduced power in all four limbs; possibilities of spinal muscular atrophy, poliomyelitis, and myopathies were kept. Nerve conduction velocity study was suggestive of mixed sensory-motor, severe axonal, and demyelinating polyradiculoneuropathy. Cerebrospinal fluid study revealed albuminocytological dissociation. Child was diagnosed as GBS and treated with intravenous immunoglobulin. Child recovered completely on follow-up. GBS should be considered as a differential diagnosis in acute onset respiratory failure with neuromuscular weakness in infants. PMID- 26962358 TI - Paraneoplastic encephalitis as a first evidence of recurrent neuroblastoma: A rare case entity. AB - Prevalence of paraneoplastic encephalitis in association with recurrent neuroblastoma (NB) is rare. Here, we report a case of recurrent NB presented as paraneoplastic encephalitis, treated successfully with high dose steroids leading to complete neurological recovery. This case highlights the importance of early recognition, diagnosis, and treatment of paraneoplastic encephalitis in a pediatric patient with the new development of neurological symptoms in the background of NB. Paraneoplastic encephalitis also served as an early sign of disease relapse. PMID- 26962357 TI - Epstein-Barr virus encephalitis with substantia nigra involvement. AB - Infectious mononucleosis due to Epstein-Barr virus (EBV) is a usually benign systemic viral illness common in children. Many studies described nervous system manifestations of infectious mononucleosis with a wide spectrum of neurologic deficits. Neurologic complications of EBV are seen in both acute and reactivate infection. Herein, we describe a patient diagnosed by acute EBV encephalitis with substantia nigra involvement and excellent clinical recovery. PMID- 26962359 TI - Diffuse leptomeningeal spread of supratentorial recurrent pilocytic astrocytoma in a child. PMID- 26962360 TI - Faun tail associated with bony tail like projecting dysplastic sacral vertebral segments in natal cleft: Unique twin tails. PMID- 26962361 TI - Treatment-resistant mania in Dandy-Walker malformation with seizure disorder: A case report. PMID- 26962362 TI - Hypergonadotrophic hypogonadism and cerebellar ataxia in an Indian adolescent: A rare report. PMID- 26962363 TI - A rare cause of occipital headache. PMID- 26962364 TI - Febrile seizures in 1-5 aged infants in tropical practice: Frequency, etiology and outcome of hospitalization. PMID- 26962365 TI - Concurrent acute disseminated encephalomyelitis and Guillain-Barre syndrome in a child. PMID- 26962366 TI - Hsa-miR-375 is a predictor of local control in early stage breast cancer. AB - BACKGROUND: A long-term analysis by the Early Breast Cancer Trialist Group (EBCTG) revealed a strong correlation between local control and cancer-specific mortality. MicroRNAs (miRs), short (20-25 nucleotides) non-coding RNAs, have been described as prognosticators and predictors for breast cancer in recent years. The aim of the current study was to identify miRs that can predict local control after breast conserving therapy (BCT) in early stage breast cancer. RESULTS: Clinical data of 46 early stage breast cancer patients with local relapse after BCT were selected from the institutional database. These patients were matched to 101 control patients showing identical clinical features but without local relapse. The study was conducted in two steps. (1) In the pilot study, 32 patients (16 relapses versus 16 controls) were screened for the most de-regulated microRNAs (= candidate microRNAs) in a panel of 1250 miRs by microarray technology. Eight miRs were found to be significantly de-regulated. (2) In the validation study, the candidate microRNAs were analyzed in an independent cohort of 115 patients (30 relapses versus 85 controls) with reverse transcription quantitative polymerase chain reaction (RT-qPCR). From these eight candidates, hsa-miR-375 could be validated. Its median fold change was 2.28 (Mann-Whitney U test, corrected p value = 0.008). In the log-rank analysis, high expression levels of hsa-miR-375 correlated with a significantly higher risk of local relapse (p = 0.003). In a multivariate analysis (forward stepwise regression) including established predictors and prognosticators, hsa-miR-375 was the only variable that was able to distinguish the statistical significance between relapse and control groups (raw p value = 0.000195 HR = 0.76, 95 % CI 0.66-0.88; corrected p value = 0.005). CONCLUSIONS: Hsa-miR-375 predicts local control in patient with early stage breast cancer, especially in estrogen receptor alpha (ER alpha)-positive patients. It can therefore serve as an additional molecular marker for treatment choice independently from known predictors and prognosticators. Validation in larger prospective studies is warranted. PMID- 26962368 TI - Dentinal Tubule Disinfection with Propolis & Two Extracts of Azadirachta indica Against Candida albicans Biofilm Formed on Tooth Substrate. AB - AIM: This study evaluates the disinfection of dentinal tubules using Propolis, Azadirachta indica (alcoholic and aqueous extracts), 2% chlorhexidine gel and calcium hydroxide against Candida albicans biofilm formed on tooth substrate. MATERIALS & METHOD: One hundred and five human teeth were infected with Candida albicans for 2 days. Samples were divided into 7 groups. Group I- Propolis, Group II- Alcoholic extract of Azadirachta indica, Group III- Aqueous extract of Azadirachta indica, Group IV- 2% Chlorhexidine, Group V- Calcium hydroxide, Group VI- Ethanol and Group VII- Saline (negative control). At the end of 1,3 and 5 days, the antimicrobial efficacy of medicaments against Candida albicans was assessed at the depths of 200 um and 400 um. RESULTS: The overall percentage inhibition of fungal growth (at 200 um and 400 um depth) was 99.2% with 2% chlorhexidine gel. There was no statistical difference between propolis, alcoholic extract of Azadirachta indica (neem) and 2% chlorhexidine. CONCLUSION: Propolis and alcoholic extract of Azadirachta indica performed equally well as that of 2% Chlorhexidine. PMID- 26962367 TI - Discovery of new methylation markers to improve screening for cervical intraepithelial neoplasia grade 2/3. AB - BACKGROUND: Assessment of DNA promoter methylation markers in cervical scrapings for the detection of cervical intraepithelial neoplasia (CIN) and cervical cancer is feasible, but finding methylation markers with both high sensitivity as well as high specificity remains a challenge. In this study, we aimed to identify new methylation markers for the detection of high-grade CIN (CIN2/3 or worse, CIN2+) by using innovative genome-wide methylation analysis (MethylCap-seq). We focused on diagnostic performance of methylation markers with high sensitivity and high specificity considering any methylation level as positive. RESULTS: MethylCap-seq of normal cervices and CIN2/3 revealed 176 differentially methylated regions (DMRs) comprising 164 genes. After verification and validation of the 15 best discriminating genes with methylation-specific PCR (MSP), 9 genes showed significant differential methylation in an independent cohort of normal cervices versus CIN2/3 lesions (p < 0.05). For further diagnostic evaluation, these 9 markers were tested with quantitative MSP (QMSP) in cervical scrapings from 2 cohorts: (1) cervical carcinoma versus healthy controls and (2) patients referred from population-based screening with an abnormal Pap smear in whom also HPV status was determined. Methylation levels of 8/9 genes were significantly higher in carcinoma compared to normal scrapings. For all 8 genes, methylation levels increased with the severity of the underlying histological lesion in scrapings from patients referred with an abnormal Pap smear. In addition, the diagnostic performance was investigated, using these 8 new genes and 4 genes (previously identified by our group: C13ORF18, JAM3, EPB41L3, and TERT). In a triage setting (after a positive Pap smear), sensitivity for CIN2+ of the best combination of genes (C13ORF18/JAM3/ANKRD18CP) (74 %) was comparable to hrHPV testing (79 %), while specificity was significantly higher (76 % versus 42 %, p <= 0.05). In addition, in hrHPV-positive scrapings, sensitivity and specificity for CIN2+ of this best-performing combination was comparable to the population referred with abnormal Pap smear. CONCLUSIONS: We identified new CIN2/3-specific methylation markers using genome-wide DNA methylation analysis. The diagnostic performance of our new methylation panel shows higher specificity, which should result in prevention of unnecessary colposcopies for women referred with abnormal cytology. In addition, these newly found markers might be applied as a triage test in hrHPV positive women from population-based screening. The next step before implementation in primary screening programs will be validation in population based cohorts. PMID- 26962369 TI - Effects of Internal Bleaching on the Adhesion of Glass-Fiber Posts. AB - OBJECTIVE: We evaluated the effects of internal bleaching on the adhesion of glass-fiber posts (GFPs) luted with different resin cements. METHODS: Forty extracted human single-root teeth were endodontically treated and divided into four groups (n=10): G1- conventional resin cement (CRC); G2- self-adhesive resin cement (SARC); G3- bleaching + CRC; and G4- bleaching + SARC. Specimens were sectioned transversally into three slices to perform the push-out test at the coronal, middle and apical regions of the root canals. Data were analyzed using analysis of variance and Tukey's test (p<0.05). RESULTS: The push-out bond strength of GFPs luted with SARC after bleaching (G4) was significantly lower than that of the other groups (p<0.001). We found no statistically significant differences in push-out bond strength among the other groups. SIGNIFICANCE: Internal bleaching reduced the adhesion of GFPs luted with SARC. The adhesion of GFPs luted with CRC was not decreased after bleaching. PMID- 26962370 TI - Benign Orofacial Lesions in Libyan Population: A 17 Years Retrospective Study. AB - OBJECTIVES: To analyze the frequency and type of benign orofacial lesions submitted for diagnosis at Tripoli Medical Centre over 17 years period (1997 2013). MATERIALS AND METHODS: Entries for specimens from patients were retrieved and compiled into 9 diagnostic categories and 82 diagnoses. RESULTS: During the 17 years period, a total of 975 specimens were evaluated, it comprised a male female ratio of 0.76:1. The mean age of biopsied patients was 36.3+/-18.32 years. The diagnostic category with the highest number of specimens was skin and mucosal pathology (22.87%); and the most frequent diagnosis was pyogenic granuloma (14.05%). CONCLUSION: Pyogenic granuloma, lichen planus, radicular cyst and fibroepithelial polyp were found to be the most predominant diagnoses. Frequencies of most benign orofacial diseases were comparable to similar studies in the literature and to those reported from the eastern region of Libya. Further surveys are needed to define the epidemiology of orofacial diseases in Libyan population. PMID- 26962371 TI - Inhibitory Effect of Alpha-Mangostin on Adhesion of Candida albicans to Denture Acrylic. AB - OBJECTIVE: Candida-associated denture stomatitis is a very common disease affecting denture wearers. It is characterized by the presence of yeast biofilm on the denture, primarily associated with C. albicans. The investigation of agents that can reduce C. albicans adhesion may represent a significant advancement in the prevention and treatment of this disease. This study aims to investigate the effect of alpha-mangostin on the in vitro adhesion of C. albicans to denture acrylic and germ tube formation by C. albicans and to compare its activity with clotrimazole which is a topical antifungal agent commonly used for the treatment of Candida-associated denture stomatitis. MATERIALS AND METHODOLOGY: Alpha-mangostin was extracted by thin layer chromatography. The effect of alpha-mangostin on adhesion of C. albicans to denture acrylic was determined by using a colorimetric tetrazolium assay and germ tube formation by C. albicans was determined by using the counting chamber. RESULTS: A significant reduction of C. albicans adhesion to denture acrylic was evident after exposure to 2,000 ug/ml of alpha-mangostin for only 15 min. In addition, the 2,000 ug/ml of the alpha-mangostin-treated C. albicans had a reduced ability for germ tube formation. These inhibitory effects of alpha-mangostin were as effective as clotrimazole. CONCLUSION: Alpha-mangostin has antifungal property against C. albicans by inhibiting the adhesion to denture acrylic and germ tube formation in vitro. These results suggest the potential application of alpha-mangostin as a topical medication or a natural oral hygiene product for treatment of Candida associated denture stomatitis. PMID- 26962372 TI - Failure Rate of Direct High-Viscosity Glass-Ionomer Versus Hybrid Resin Composite Restorations in Posterior Permanent Teeth - a Systematic Review. AB - PURPOSE: Traditionally, resin composite restorations are claimed by reviews of the dental literature as being superior to glass-ionomer fillings in terms of restoration failures in posterior permanent teeth. The aim of this systematic review is to answer the clinical question, whether conventional high-viscosity glass-ionomer restorations, in patients with single and/or multi-surface cavities in posterior permanent teeth, have indeed a higher failure rate than direct hybrid resin composite restorations. METHODS: Eight databases were searched until December 02, 2013. Trials were assessed for bias risks, in-between datasets heterogeneity and statistical sample size power. Effects sizes were computed and statistically compared. A total of 55 citations were identified through systematic literature search. From these, 46 were excluded. No trials related to high-viscosity glass-ionomers versus resin composite restorations for direct head to-head comparison were found. Three trials related to high-viscosity glass ionomers versus amalgam and three trials related to resin composite versus amalgam restorations could be included for adjusted indirect comparison, only. RESULTS: The available evidence suggests no difference in the failure rates between both types of restoration beyond the play of chance, is limited by lack of head-to-head comparisons and an insufficient number of trials, as well as by high bias and in-between-dataset heterogeneity risk. The current clinical evidence needs to be regarded as too poor in order to justify superiority claims regarding the failure rates of both restoration types. Sufficiently large-sized, parallel-group, randomised control trials with high internal validity are needed, in order to justify any clinically meaningful judgment to this topic. PMID- 26962373 TI - The Dental Solid Waste Management in Different Categories of Dental Laboratories in Abha City, Saudi Arabia. AB - AIM: To study the awareness, attitude, practice and facilities among the different categories of dental laboratories in Abha city. MATERIALS AND METHODS: A total of 80 dental technicians were surveyed in the study. The dental laboratories included in the study were teaching institute (Group I), Government Hospital (Group II), Private Dental Clinic (Group III) and Independent laboratory (Group IV). The pre-tested anonymous questionnaire was used to understand knowledge, attitude, facilities, practice and orientation regarding biomedical waste management. RESULTS: The knowledge of biomedical waste categories, colour coding and segregation was better among Group I (55-65%) and Group II (65-75%). The lowest standard of waste disposal was practiced at Group IV (15-20%) and Group III (25-35%). The availability of disposal facilities was poor at Group IV. The continuous education on biomedical waste management lacked in all the Groups. CONCLUSION: The significant improvement in disposal facilities was required at Group III and Group IV laboratories. All dental technicians were in need of regular training of biomedical waste management. CLINICAL SIGNIFICANCE: The dental laboratories are an integral part of dental practice. The dental laboratories are actively involved in the generation, handling and disposal of biomedical waste. Hence, it is important to assess the biomedical waste management knowledge, attitude, facilities and practice among different categories of dental laboratories. PMID- 26962374 TI - Application of Behavior Management Techniques for Paediatric Dental Patients by Tanzanian Dental Practitioners. AB - BACKGROUND: Management of children's behavior is an integral component of pediatric dental practice. OBJECTIVE: To investigate the oral health care providers' awareness, use and factors for choice of behavior management techniques when attending paediatric dental patients. METHODS: A cross-sectional study among dental practitioners in Dar es Salaam, Tanzania. Data collection was done through interview using a structured questionnaire. The recorded information included: awareness and application of behavior management techniques (BMT) when attending a child dental patient, factors influencing choice of a particular technique, socio-demographics, level of professional training, working experience and facility profile. Using SPSS program version 18, frequency distributions and cross tabulations analyses were performed. RESULTS: 74 dental practitioners participated in the study, of whom 49 (66.2%) were males and 44 (59.5%) were graduates. Most participants were aware of the behavior management techniques, ranging from 100% for Tell-Show-Do to 86% for distraction. A small proportion (9.5%) reported to have adequate skills, all of them were graduates. The use of universally accepted BMTs was reported by 65% of experienced practitioners, 61% of graduates, 59% of those reporting to have received formal training and all of those reporting to have fair/inadequate skills to apply BMTs (p= 0.01). CONCLUSION: Most participants were aware of BMTs, although few acknowledged having adequate skills to apply the techniques. They use BMTs during treatment of paediatric dental patients and their choice of the technique is mainly influenced by children's factors. PMID- 26962375 TI - Caries Removal by Chemomechanical (CarisolvTM) vs. Rotary Drill: A Systematic Review. AB - BACKGROUND: Chemomechanical caries removal is an effective alternative to the traditional rotary drilling method. The advantages of chemomechanical techniques in terms of the need for anesthesia, pain perception and patient preference are systematically reviewed and a meta-analysis of the time required for caries removal is reported. METHOD: Randomized controlled studies of comparison of chemomechanical techniques with conventional rotary drill were selected from a systematic search of standard biomedical databases, including the PubMed and Cochrane clinical trials. Non-repeated search results were screened for relevance and risk of bias assessment, followed by methodology assessment. Statistical models were applied to the outcome parameters - time required, pain perception, need of anesthesia and patient preference - extracted from the studies. RESULTS: Out of the 111 non-repeated search results, 26 studies receiving a low bias score were selected for the review, and 16 randomized clinical trials of rotary and Carisolv techniques were considered for meta-analysis. Meta-analysis by fixed effect as well as random effect models indicate that Carisolv takes more time (3.65 +/- 0.05 and 4.09 +/- 0.29 min) than rotary drill (8.65 +/- 0.09 and 8.97 +/- 0.66 min) method. Advantages of reduced pain (14.67 for Carisolv vs. 6.76 for rotary drill), need for anesthesia (1.59% vs. 10.52%) outweigh the longer time requirement and make it the preferred (18.68% vs. 4.69%) method. CONCLUSION: Chemomechanical techniques stand out as a minimally invasive and preferred method based on the meta-analyses. Evaluation of pain experienced using robust methods is needed to strengthen the evidence for their use. PMID- 26962377 TI - Revascularization of an Immature Tooth with Apical Periodontitis Using Calcium Hydroxide: A 3-year Follow-up. AB - Root canal treatment of teeth presenting immature development is a great challenge for both the patient and the professional. The thinness of the root canal walls of immature teeth may lead to root fracture and thus the outcomes of such treatments are uncertain. Revascularization is based on root canal decontamination followed by the induction of blood migration from the periapical tissues and the development of new vascular tissue in the canal space. The principle of disinfection in regenerative endodontics is that it should be achieved with minimum root canal instrumentation; an intracanal medication is used to inhibit bacterial growth and appropriate sealing of the coronal portion is performed. The American Association of Endodontists (AAE) considerations for regenerative endodontics include calcium hydroxide as an alternative intracanal dressing. This material has also been claimed to diminish the possibility of dental staining during revascularization procedures. The relatively new treatment protocol has been widely reported in the last few years; however it should be performed only when other alternatives are not reasonable. This case report presents a 3-year follow-up of a case of revascularization of a maxillary central incisor using calcium hydroxide as a root canal disinfection dressing. PMID- 26962376 TI - Esthetic Prosthetic Restorations: Reliability and Effects on Antagonist Dentition. AB - Recent advances in ceramics have greatly improved the functional and esthetic properties of restorative materials. New materials offer an esthetic and functional oral rehabilitation, however their impact on opposing teeth is not welldocumented. Peer-reviewed articles published till December 2014 were identified through Pubmed (Medline and Elsevier). Scientifically, there are several methods of measuring the wear process of natural dentition which enhances the comparison of the complicated results. This paper presents an overview of the newly used prosthetic materials and their implication on antagonist teeth or prostheses, especially emphasizing the behavior of zirconia restorations. PMID- 26962378 TI - Bactericidal Efficacy of Cold Plasma at Different Depths of Infected Root Canals In Vitro. AB - OBJECTIVES: Cold plasma (CP) has been shown to be effective even against multiresistant microorganisms. As previous investigations on the effect of CP in root canals showed promising results, the aim of the present study was to analyze the bactericidal efficacy of CP in different depths of infected dentin. METHODS: 32 standardized root canals of human mandibular premolars were infected with Enterococcus faecalis and incubated for one week. Specimens were randomly selected for one of four disinfection methods: control (5mL NaCl), 5mL chlorhexidine (CHX), CP alone (CP), and a combination of 5mL CHX and cold plasma (CHX+CP). CHX was ultrasonically activated for 30s, while cold plasma was used for 60s in the root canals. Dentin samples at depths of 300, 500 and 800 um were obtained and diluted serially. Colony forming units (CFUs) were counted on agar plates after 24h of incubation. RESULTS: The highest overall logarithmic reduction factors (RF) were obtained from CHX+CP (log RF 3.56 p<0.01; Mann Whitney U test), followed by CP (log RF 3.27 p<0.01) and CHX alone (log RF 2.65 p<0.01) related to the control. All disinfection methods showed significantly lower CFU counts compared to the control group in 300 um and 800 um (both p<0.01, Kruskal-Wallis test). DISCUSSION: The adjuvant use of CP might be beneficial in highly infected root canals to improved disinfection. However, the disinfection effect against Enterococcus faecalis of CP is comparable to ultrasonically activated CHX. PMID- 26962379 TI - The Lateral Meniscus as a Guide to Anatomical Tibial Tunnel Placement During Anterior Cruciate Ligament Reconstruction. AB - PURPOSE: The aim of the study is to show, on an MRI scan, that the posterior border of the anterior horn of the lateral meniscus (AHLM) could guide tibial tunnel position in the sagittal plane and provide anatomical graft position. METHOD: One hundred MRI scans were analysed with normal cruciate ligaments and no evidence of meniscal injury. We measured the distance between the posterior border of the AHLM and the midpoint of the ACL by superimposing sagittal images. RESULTS: The mean distance between the posterior border of the AHLM and the ACL midpoint was -0.1mm (i.e. 0.1mm posterior to the ACL midpoint). The range was 5mm to -4.6mm. The median value was 0.0mm. 95% confidence interval was from -0.5 to 0.3mm. A normal, parametric distribution was observed and Intra- and inter observer variability showed significant correlation (p<0.05) using Pearsons Correlation test (intra-observer) and Interclass correlation (inter-observer). CONCLUSION: Using the posterior border of the AHLM is a reproducible and anatomical marker for the midpoint of the ACL footprint in the majority of cases. It can be used intra-operatively as a guide for tibial tunnel insertion and graft placement allowing anatomical reconstruction. There will inevitably be some anatomical variation. Pre-operative MRI assessment of the relationship between AHLM and ACL footprint is advised to improve surgical planning. LEVEL OF EVIDENCE: Level 4. PMID- 26962380 TI - Malik's Technique of Single Loop Fixation of Posterior Chamber Intraocular Lens in Presence of Partial Capsular Support. AB - Single loop fixation of posterior chamber intraocular lens in the presence of partial capsular support is usually performed by creation of additional scleral flap or tunnel. This extra port may expose the suture holding the intraocular lens or the tucked-in lens haptics to the outside environment thereby increasing the risk of endophthalmitis. We describe a technique of single loop fixation where the scleral tunnel is created adjacent to the site with the absent capsule, the leading haptic is placed on the capsular scaffold, the trailing haptic is tied to 9-0 polypropylene, and the suture is then secured to the inner edge of the scleral lip with enough tension to center the optics and the wound is then closed. The suture knot gets buried within the scleral tunnel with no external communication and does not require a separate port. It is an easy, safe, fast and reproducible technique with a lens tilt of less than 2 degrees . PMID- 26962382 TI - Macular Hole Formation After Intravitreal Ranibizumab Injection in Wet Age Related Macular Degeneration. AB - Ranibizumab is a monoclonal antibody fragment that inhibits angiogenesis by inhibiting vascular endothelial growth factor A, used as a treatment for patients with wet aged-related macular degeneration (ARMD). Adverse effects from intravitreal Ranibizumab injections are well recognised. Macular hole formation following Ranibizumab injection is a complication that has been recently reported in few case reports. We present a larger case series of five patients, who developed full thickness macular holes (FTMH) after intravitreal Ranibizumab injections for treatment of wet ARMD that we were aware of between 2009 and 2013. PMID- 26962381 TI - Prevalence of Keratoconus Among a Palestinian Tertiary Student Population. AB - PURPOSE: To screen for keratoconus and potential associated risk factors in a tertiary student population sample. POPULATION AND METHODS: This cross sectional study included 1234 students attending An-Najah National University (Nablus, West Bank, Palestine), that were randomly selected from a total of 20,000 university students. 634 (51.3%) student participants responded by completing a self administered questionnaire and were assessed by means of corneal topography. Following initial evaluation, participants were referred for Pentacam evaluation if they demonstrated either a mean keratometry of more than 45 diopters, corneal astigmatism of more than 2 diopters and/or if asymmetric topographic patterns were present. Pentacam images were analyzed by an experienced ophthalmologist based on a number of indices and the participants were classified as normal, keratoconus suspects, and keratoconus patients. RESULTS: A total of 620 participants (mean age, 20.1+/-1.6 years) were included in this study, 379 (61.1%) were females and 241 (38.9%) were males. Nine subjects were diagnosed with keratoconus, demonstrating a prevalence of 1.5%. 52 (8.4%) participants showed at least one abnormal pentacam index, and were considered as KC suspects. CONCLUSION: Keratoconus is a prevalent disease among the tertiary Palestinian student population. This may be related to a combination of genetic and environmental factors. The results of this study signal the need for public health outreach and intervention for keratoconus. PMID- 26962384 TI - Registration of wheat lines carrying the partial stripe rust resistance gene Yr36 without the Gpc-B1 high grain protein content allele. AB - While the high-temperature adult plant resistance gene Yr36 represents a promising source of quantitative and potentially race non-specific resistance to wheat stripe rust (causal organism Puccinia striiformis Westend. f. sp. tritici), its tight linkage (0.3 cM) with the high-grain protein content gene Gpc-B1 may hinder its introgression in certain cases, such as in soft wheat varieties requiring low grain protein content or in lines where the Gpc-B1 allele may be associated with a yield penalty. The development and registration of two donor lines, one tetraploid (Triticum turgidum L. ssp. durum; PI 656793) and one hexaploid (T. aestivum L. ssp. aestivum; PI 664549), each carrying the resistant wild emmer (T. turgidum ssp. dicoccoides) allele for Yr36 linked with the non functional Gpc-B1 allele, are intended to overcome this potential limitation. Meiotic recombination events breaking the linkage between these two genes were discovered during the systematic screening of a population of 4,500 F2 durum plants (cv. Langdon background) used to fine map Yr36. One of the critical recombination events was selected for fixation by self-pollination and transferred to a California adapted spring hexaploid background (breeding line UC11105+10) through five generations of backcrossing. Genotypic and phenotypic data confirm the presence of Yr36 and the non-functional Gpc-B1 allele in both registered lines. PMID- 26962385 TI - New England Faculty and College Students Differ in Their Views About Evolution, Creationism, Intelligent Design, and Religiosity. AB - Public acceptance of evolution in Northeastern U.S. is the highest nationwide, only 59%. Here, we compare perspectives about evolution, creationism, intelligent design (ID), and religiosity between highly educated New England faculty (n=244; 90% Ph.D. holders in 40 disciplines at 35 colleges/universities) and college students from public secular (n=161), private secular (n=298), and religious (n=185) institutions: 94/3% of the faculty vs. 64/14% of the students admitted to accepting evolution openly and/or privately, and 82/18% of the faculty vs. 58/42% of the students thought that evolution is definitely true or probably true, respectively. Only 3% of the faculty vs. 23% of the students thought that evolution and creationism are in harmony. Although 92% of faculty and students thought that evolution relies on common ancestry, one in every four faculty and one in every three students did not know that humans are apes; 15% of the faculty vs. 34% of the students believed, incorrectly, that the origin of the human mind cannot be explained by evolution, and 30% of the faculty vs. 72% of the students was Lamarckian (believed in inheritance of acquired traits). Notably, 91% of the faculty was very concerned (64%) or somehow concerned (27%) about the controversy evolution vs creationism vs ID and its implications for science education: 96% of the faculty vs. 72% of the students supported the exclusive teaching of evolution while 4% of the faculty vs. 28% of the students favored equal time to evolution, creationism and ID; 92% of the faculty vs. 52% of the students perceived ID as not scientific and proposed to counter evolution or as doctrine consistent with creationism. Although ~30% of both faculty and students considered religion to be very important in their lives, and ~20% admitted to praying daily, the faculty was less religious (Religiosity Index faculty=0.5 and students=0.75) and, as expected, more knowledgeable about science (Science Index faculty=2.27 and students=1.60) and evolution (Evolution Index faculty=2.48 and students=1.65) than the students. Because attitudes toward evolution correlate (1) positively with understanding of science/evolution and (2) negatively with religiosity/political ideology, we conclude that science education combined with vigorous public debate should suffice to increase acceptance of naturalistic rationalism and decrease the negative impact of creationism and ID on society's evolution literacy. PMID- 26962388 TI - The Effect of Melasma on the Quality of Life in a Sample of Women Living in Singapore. AB - INTRODUCTION: Melasma is a common disorder of acquired hyperpigmentation characterized by irregular brown macules and patches that occur primarily on sun exposed areas. METHODS: This was a prospective cross-sectional study that recruited 49 women clinically diagnosed with melasma from a tertiary dermatology referral center in Singapore. Trained investigators assessed the melasma severity objectively using the chromameter and mexameter and subjectively using the Melasma Area and Severity Index. The effect of melasma on the quality of life on the patients was assessed using the melasma quality of life scale and dermatology life quality index questionnaires. RESULTS: The mean +/- SD Melasma Area and Severity Index score was 12.1+/-6.5 (median 10.8). The mean +/- SD melasma quality of life scale score was 25.6+/-15.3 (median 24.0). Melasma quality of life scale scores are significantly correlated (Spearman's coefficient = 0.597, p value <0.001) with the dermatology life quality index scores. There was no correlation between Melasma Area and Severity Index with melasma quality of life scale or dermatology life quality index scores. There is no difference in the melasma quality of life scale scores with different demographic variables including age, duration of disease, levels of education, and employment. CONCLUSION: This study contributes to building evidence regarding the validity of melasma quality of life scale in accurately evaluating the effect of melasma on a patient's quality of life and the burden of disease in Singaporean women. PMID- 26962386 TI - International survey on skin patch test procedures, attitudes and interpretation. AB - BACKGROUND: Skin patch test is the gold standard method in diagnosing contact allergy. Although used for more than 100 years, the patch test procedure is performed with variability around the world. A number of factors can influence the test results, namely the quality of reagents used, the timing of the application, the patch test series (allergens/haptens) that have been used for testing, the appropriate interpretation of the skin reactions or the evaluation of the patient's benefit. METHODS: We performed an Internet -based survey with 38 questions covering the educational background of respondents, patch test methods and interpretation. The questionnaire was distributed among all representatives of national member societies of the World Allergy Organization (WAO), and the WAO Junior Members Group. RESULTS: One hundred sixty-nine completed surveys were received from 47 countries. The majority of participants had more than 5 years of clinical practice (61 %) and routinely carried out patch tests (70 %). Both allergists and dermatologists were responsible for carrying out the patch tests. We could observe the use of many different guidelines regardless the geographical distribution. The use of home-made preparations was indicated by 47 % of participants and 73 % of the respondents performed 2 or 3 readings. Most of the responders indicated having patients with adverse reactions, including erythroderma (12 %); however, only 30 % of members completed a consent form before conducting the patch test. DISCUSSION: The heterogeneity of patch test practices may be influenced by the level of awareness of clinical guidelines, different training backgrounds, accessibility to various types of devices, the patch test series (allergens/haptens) used for testing, type of clinical practice (public or private practice, clinical or research-based institution), infrastructure availability, financial/commercial implications and regulations among others. CONCLUSION: There is a lack of a worldwide homogeneity of patch test procedures, and this raises concerns about the need for standardization and harmonization of this important diagnostic procedure. PMID- 26962387 TI - World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Prebiotics. AB - BACKGROUND: The prevalence of allergic diseases in infants, whose parents and siblings do not have allergy, is approximately 10 % and reaches 20-30 % in those with an allergic first-degree relative. Intestinal microbiota may modulate immunologic and inflammatory systemic responses and, thus, influence development of sensitization and allergy. Prebiotics - non-digestible oligosaccharides that stimulate growth of probiotic bacteria - have been reported to modulate immune responses and their supplementation has been proposed as a preventive intervention. OBJECTIVE: The World Allergy Organization (WAO) convened a guideline panel to develop evidence-based recommendations about the use of prebiotics in the prevention of allergy. METHODS: The WAO guideline panel identified the most relevant clinical questions about the use of prebiotics for the prevention of allergy. We performed a systematic review of randomized controlled trials of prebiotics, and reviewed the evidence about patient values and preferences, and resource requirements (up to January 2015, with an update on July 29, 2015). We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. RESULTS: Based on GRADE evidence to decision frameworks, the WAO guideline panel suggests using prebiotic supplementation in not-exclusively breastfed infants and not using prebiotic supplementation in exclusively breastfed infants. Both recommendations are conditional and based on very low certainty of the evidence. We found no experimental or observational study of prebiotic supplementation in pregnant women or in breastfeeding mothers. Thus, the WAO guideline panel chose not to provide a recommendation about prebiotic supplementation in pregnancy or during breastfeeding, at this time. CONCLUSIONS: WAO recommendations about prebiotic supplementation for the prevention of allergy are intended to support parents, clinicians and other health care professionals in their decisions whether or not to use prebiotics for the purpose of preventing allergies in healthy, term infants. PMID- 26962389 TI - Addressing Free Radical Oxidation in Acne Vulgaris. AB - OBJECTIVE: Comparatively little attention has been paid to the role of free radical oxidation in acne vulgaris. Here, using the traditional abnormalities cited for acne, the authors address the role of free radical oxidation throughout the pathogenesis by detailing the chemistry that may contribute to clinical changes. To probe the effects of free radical oxidation and test an antioxidant, they conducted a preliminary study of topically applied vitamin E. METHODS: Seventeen patients with mild-to-moderate acne vulgaris were evaluated over an eight-week period in two private dermatology practices in this open-label study. All patients enrolled were on the same baseline regimen of salicylic acid and benzoyl peroxide. This regimen was then supplemented with topical vitamin E in sunflower seed oil. RESULTS: At the end of the eight-week period, all patients demonstrated clinical improvement, as indicated by a reduction in the number of lesions and global mean difference. A statistically significant reduction was noted as early as Week 2. Enrolled patients also expressed a positive experience due to good tolerability and easy application. CONCLUSION: Although the exact pathogenesis of acne vulgaris remains unknown, the presence of excessive reactive oxygen species can be implicated in each of the major abnormalities involved. This presence, along with the positive results of the authors' preliminary study, demonstrates the need for more exploration on the use of topical antioxidants in limiting free radical oxidation in the acne model. This paper is designed to stimulate academic discussion regarding a new way of thinking about the disease state of acne. PMID- 26962391 TI - United States Food and Drug Administration Product Label Changes. AB - Once a drug has been approved by the United States Food and Drug Administration and is on the market, the Food and Drug Administration communicates new safety information through product label changes. Most of these label changes occur after a spontaneous report to either the drug manufacturing companies or the Food and Drug Administration MedWatch program. As a result, 400 to 500 label changes occur every year. Actinic keratosis treatments exemplify the commonality of label changes throughout the postmarket course of a drug. Diclofenac gel, 5 fluorouracil cream, imiquimod, and ingenol mebutate are examples of actinic keratosis treatments that have all undergone at least one label revision. With the current system of spontaneous reports leading to numerous label changes, each occurrence does not necessarily signify a radical change in the safety of a drug. PMID- 26962390 TI - Aging Differences in Ethnic Skin. AB - Aging is an inevitable and complex process that can be described clinically as features of wrinkles, sunspots, uneven skin color, and sagging skin. These cutaneous effects are influenced by both intrinsic and extrinsic factors and often are varied based on ethnic origin given underlying structural and functional differences. The authors sought to provide updated information on facets of aging and how it relates to ethnic variation given innate differences in skin structure and function. Publications describing structural and functional principles of ethnic and aging skin were primarily found through a PubMed literature search and supplemented with a review of textbook chapters. The most common signs of skin aging despite skin type are dark spots, loss of elasticity, loss of volume, and rhytides. Skin of color has many characteristics that make its aging process unique. Those of Asian, Hispanic, and African American descent have distinct facial structures. Differences in the concentration of epidermal melanin makes darkly pigmented persons more vulnerable to dyspigmentation, while a thicker and more compact dermis makes facial lines less noticeable. Ethnic skin comprises a large portion of the world population. Therefore, it is important to understand the unique structural and functional differences among ethnicities to adequately treat the signs of aging. PMID- 26962392 TI - Periorbital Hyperpigmentation: A Comprehensive Review. AB - Periorbital hyperpigmentation is a commonly encountered condition. There is very little scientific data available on the clinical profile and pathogenesis of periorbital hyperpigmentation. Periorbital hyperpigmentation is caused by various exogenous and endogenous factors. The causative factors include genetic or heredity, excessive pigmentation, postinflammatory hyperpigmentation secondary to atopic and allergic contact dermatitis, periorbital edema, excessive vascularity, shadowing due to skin laxity and tear trough associated with aging. There are a number of treatment options available for periorbital hyperpigmentation. Among the available alternatives to treat dark circles are topical depigmenting agents, such as hydroquinone, kojic acid, azelaic acid, and topical retinoic acid, and physical therapies, such as chemical peels, surgical corrections, and laser therapy, most of which are tried scientifically for melasma, another common condition of hyperpigmentation that occurs on the face. The aim of treatment should be to identify and treat the primary cause of hyperpigmentation as well as its contributing factors. PMID- 26962393 TI - Muir-Torre Syndrome: A Case Associated with an Infrequent Gene Mutation. AB - Muir-Torre syndrome is a rare, autosomal dominant genodermatosis characterized by the presence of at least one sebaceous gland neoplasm, associated with an underlying visceral malignancy. Muir-Torre syndrome is believed to be a subtype of Lynch Syndrome. Affected individuals are found to have germline mutations predominantly in DNA mismatch repair gene MSH2, and much less frequently, MLH1. The authors report the case of a 55-year-old woman presenting with multiple cutaneous neoplasms including sebaceoma, basal cell carcinoma, and squamous cell carcinoma; personal history of colorectal and endometrial cancer; and family history of colorectal cancer; found to have a deletion at mismatch repair gene MLH1. It is important to recognize the role of these less common gene deletions in producing the Muir-Torre syndrome phenotype, and consider the correlation of cutaneous manifestations with internal disease. The authors discuss the clinical presentation of Muir-Torre syndrome, methods of diagnosis, and the importance of regular medical surveillance to detect and prevent disease progression in Muir Torre syndrome patients and their family members. PMID- 26962394 TI - Protection of Bovine Mammary Epithelial Cells from Hydrogen Peroxide-Induced Oxidative Cell Damage by Resveratrol. AB - The mammary epithelial cells (MECs) of high-producing dairy cows are likely to be subject to oxidative stress (OS) due to the intensive cell metabolism. The objectives of this study were to investigate the cytoprotective effects of resveratrol against hydrogen peroxide- (H2O2-) induced OS in cultured bovine MECs (MAC-T). Pretreatment of MAC-T cells with resveratrol could rescue the decrease in cell viability and resulted in lower intracellular reactive oxygen species (ROS) accumulation after H2O2 exposure. Resveratrol helped MAC-T cells to prevent H2O2-induced endoplasmic reticulum stress and mitochondria-related cell apoptosis. Moreover, resveratrol induced mRNA expression of multiple antioxidant defense genes in MAC-T cells under normal/oxidative conditions. Nuclear factor erythroid 2-related factor 2 (Nrf2) was required for the cytoprotective effects on MAC-T cells by resveratrol, as knockdown of Nrf2 significantly abolished resveratrol-induced cytoprotective effects against OS. In addition, by using selective inhibitors, we further confirmed that the induction of Nrf2 by resveratrol was mediated through the prolonged activation of PI3K/Akt and ERK/MAPK pathways but negatively regulated by p38/MAPK pathway. Overall, resveratrol has beneficial effects on bovine MECs redox balance and may be potentially used as a therapeutic medicine against oxidative insult in lactating animals. PMID- 26962395 TI - Memory Deficit Recovery after Chronic Vanadium Exposure in Mice. AB - Vanadium is a transitional metal with an ability to generate reactive oxygen species in the biological system. This work was designed to assess memory deficits in mice chronically exposed to vanadium. A total of 132 male BALB/c mice (4 weeks old) were used for the experiment and were divided into three major groups of vanadium treated, matched controls, and animals exposed to vanadium for three months and thereafter vanadium was withdrawn. Animals were tested using Morris water maze and forelimb grip test at 3, 6, 9, and 12 months of age. The results showed that animals across the groups showed no difference in learning but had significant loss in memory abilities after 3 months of vanadium exposure and this trend continued in all vanadium-exposed groups relative to the controls. Animals exposed to vanadium for three months recovered significantly only 9 months after vanadium withdrawal. There was no significant difference in latency to fall in the forelimb grip test between vanadium-exposed groups and the controls in all age groups. In conclusion, we have shown that chronic administration of vanadium in mice leads to memory deficit which is reversible but only after a long period of vanadium withdrawal. PMID- 26962398 TI - Burn injury induces histopathological changes and cell proliferation in liver of rats. AB - AIM: To investigate effects of severe burn injury (BI) in rat liver through the histopathological and inflammatory markers analysis. METHODS: Forty-two male Wistar rats were distributed into two groups, control (C) and subjected to scald BI (SBI). The animals were euthanized one, four and 14 d post sham or 45% of the total body surface BI. Liver fragments were submitted to histopathological, morphoquantitative (hepatocyte area and cell density), ciclooxigenase-2 (COX-2) immunoexpression, and gene expression [real-time polymerase chain reaction for tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS) and caspase-3] methods. RESULTS: Histopathological findings showed inflammatory process in all periods investigated and hepatocyte degeneration added to increased amount of connective tissue 14 d post injury. Hepatocyte area, the density of binucleated hepatocytes and density of sinusoidal cells of SBI groups were increased when compared with control. COX-2 immunoexpression was stronger in SBI groups. No differences were found in TNF-alpha, iNOS and caspase-3 gene expression. CONCLUSION: BI induces histopathological changes, upregulation of COX 2 immunoexpression, and cell proliferation in liver of rats. PMID- 26962399 TI - Boceprevir plus peginterferon/ribavirin for treatment of chronic hepatitis C in Russia. AB - AIM: To evaluate addition of boceprevir to peginterferon/ribavirin (PR) in Russian patients with chronic hepatitis C virus (HCV). METHODS: Treatment-naive (TN) and treatment-experienced (TE) patients (who had failed prior treatment with PR for >= 12 wk) with chronic HCV genotype 1 infection were enrolled in this placebo-controlled, double-blind study. All patients initially received PR for 4 wk. Patients randomized to control treatment then received PR for an additional 44 wk. TN patients randomized to triple therapy received boceprevir (800 mg three times daily) plus PR for 24 wk and then further therapy according to treatment week 8 (TW8) HCV RNA levels. TE patients received boceprevir plus PR for 32 wk and then further therapy according to TW8 HCV RNA levels. Treatment was discontinued for TN patients with detectable HCV RNA at TW24 and TE patients with detectable HCV RNA at TW12 because of futility. The primary efficacy end point was sustained virologic response (SVR) defined as undetectable HCV RNA 24 wk after completing all study therapy. RESULTS: SVR was 74.8% in the boceprevir plus PR arm compared with 46.2% in the control arm, with a stratification-adjusted treatment difference of 29.2% (95%CI: 16.4-41.5; P < 0.0001). Rates of SVR were higher in the boceprevir arm in both TN and TE patient groups (TN 78.4% vs 56.3%; TE 69.4% vs 30.0%). Within TE patients, the rates of SVR were higher with boceprevir plus PR compared with PR, regardless of treatment failure type (null responder, partial responder, and relapser). Most patients receiving boceprevir plus PR in both TN (86%) and TE (71%) populations were eligible for reduced treatment duration. Anemia was increased in patients receiving boceprevir plus PR vs PR alone (47.2% vs 24.4%); there was a corresponding increase in ribavirin dose reduction and erythropoietin use. Among patients receiving boceprevir plus PR, SVR rates were similar in patients with anemia (< 10 g/dL) and those without anemia (71.2% vs 77.4%). CONCLUSION: Regulatory approval has been obtained for boceprevir plus PR in Russian patients with HCV genotype 1 infection based on the results of this study. PMID- 26962396 TI - Relationship between the Peroxidation of Leukocytes Index Ratio and the Improvement of Postprandial Metabolic Stress by a Functional Food. AB - For the first time, we investigated the relationship between postprandial dysmetabolism and the Peroxidation of Leukocytes Index Ratio (PLIR), a test that measures the resistance of leukocytes to exogenous oxidative stress and their functional capacity of oxidative burst upon activation. Following a blind, placebo controlled, randomized, crossover design, ten healthy subjects ingested, in two different occasions, a high fat and high carbohydrates meal with Snello cookie (HFHCM-S) or with control cookies (HFHCM-C). Snello cookie, a functional food covered by dark chocolate and containing glucomannan, inulin, fructooligosaccharides, and Bacillus coagulans strain GanedenBC30, significantly improved postprandial metabolic stress (insulin, glucose, and triglycerides) and reduced the postprandial increase of uric acid. HFHCM-S improved PLIR of lymphocytes, but not of monocytes and granulocytes. Both meals increased granulocytes' count and reduced the lipoperoxidation induced by both exogenous free radicals and reactive oxygen species (ROS) produced by oxidative burst. Our results suggest that the healthy status of the subjects could be a limitation of this pilot study for PLIR evaluation on cells that produce ROS by oxidative burst. In conclusion, the relationship between PLIR and postprandial dysmetabolism requires further investigations. PMID- 26962400 TI - Primary hepatic amyloidosis: A case report and review of literature. AB - We describe a case of 42-year-old female presenting with abdominal pain associated with loss of weight and fever for 8 mo. On evaluation she had gross hepatomegaly with raised alkaline phosphatase and raised GGT levels with normal transaminases and bilirubin. On imaging she had diffuse enlargement of liver with heterogeneous contrast uptake in liver. Her viral marker and autoimmune markers were negative. Liver biopsy depicted massive deposition of amyloid in peri sinusoidal spaces which revealed apple green birefringence on polarizing microscopy after Congo red staining. Cardiac and renal evaluation was unremarkable. Abdominal fat pad and rectum biopsy was negative for amyloid deposit. There was no evidence of primary amyloidosis as bone marrow examination was normal. Serum and urine immunofixation electrophoresis were normal. Immunoperoxidase staining for serum amyloid associated protein for secondary amyloidosis was negative from liver biopsy. We present this rare case of primary hepatic amyloidosis and review the literature regarding varied presentations of hepatic involvement in amyloidosis. PMID- 26962397 TI - Bacterial infections in cirrhosis: A critical review and practical guidance. AB - Bacterial infection is common and accounts for major morbidity and mortality in cirrhosis. Patients with cirrhosis are immunocompromised and increased susceptibility to develop spontaneous bacterial infections, hospital-acquired infections, and a variety of infections from uncommon pathogens. Once infection develops, the excessive response of pro-inflammatory cytokines on a pre-existing hemodynamic dysfunction in cirrhosis further predispose the development of serious complications such as shock, acute-on-chronic liver failure, renal failure, and death. Spontaneous bacterial peritonitis and bacteremia are common in patients with advanced cirrhosis, and are important prognostic landmarks in the natural history of cirrhosis. Notably, the incidence of infections from resistant bacteria has increased significantly in healthcare-associated settings. Serum biomarkers such as procalcitonin may help to improve the diagnosis of bacterial infection. Preventive measures (e.g., avoidance, antibiotic prophylaxis, and vaccination), early recognition, and proper management are required in order to minimize morbidity and mortality of infections in cirrhosis. PMID- 26962402 TI - Endoscopic hemostasis state of the art - Nonvariceal bleeding. AB - New endoscopic techniques for hemostasis in nonvariceal bleeding were introduced and known methods further improved. Hemospray and Endoclot are two new compounds for topical treatment of bleeding. Initial studies in this area have shown a good hemostatic effect, especially in active large scale oozing bleeding, e.g., tumor bleedings. For further evaluation larger prospective studies comparing the substanced with other methods of endoscopic hemostasis are needed. For localized active arterial bleeding primary injection therapy in the area of bleeding as well as in the four adjacent quadrants offers a good method to reduce bleeding activity. The injection is technically easy to learn and practicable. After bleeding activity is reduced the bleeding source can be localized more clearly for clip application. Today many different through-the-scope (TTS) clips are available. The ability to close and reopen a clip can aid towards good positioning at the bleeding site. Even more important is the rotatability of a clip before application. Often multiple TTS clips are required for secure closure of a bleeding vessel. One model has the ability to use three clips in series without changing the applicator. Severe arterial bleeding from vessels larger than 2 mm is often unmanageable with these conventional methods. Here is the over the-scope-clip system another newly available method. It is similar to the ligation of esophageal varices and involves aspiration of tissue into a transparent cap before closure of the clip. Thus a greater vascular occlusion pressure can be achieved and larger vessels can be treated endoscopically. Patients with severe arterial bleeding from the upper gastrointestinal tract have a very high rate of recurrence after initial endoscopic treatment. These patients should always be managed in an interdisciplinary team of interventional radiologist and surgeons. PMID- 26962401 TI - Role of colonic stents in the management of colorectal cancers. AB - Colorectal cancer is one of the commonly encountered cancers across the Western World. In United Kingdom, this constitutes third most common ranked cancer and second most common ranked cause of cancer related deaths. Its acute presentation as a malignant colonic obstruction imposes challenges in its management. Colonic stent has been used for many years to alleviate acute obstruction in such cases allowing optimisation of patient's physiological status and adequate staging of cancer. In this review, current literature evidence regarding use of colonic stent in acute malignant colonic obstruction is critically appraised and recommendations on the use of colonic stent are advocated. PMID- 26962403 TI - Endoscopic management of esophageal stenosis in children: New and traditional treatments. AB - Post-esophageal atresia anastomotic strictures and post-corrosive esophagitis are the most frequent types of cicatricial esophageal stricture. Congenital esophageal stenosis has been reported to be a rare but typical disease in children; other pediatric conditions are peptic, eosinophilic esophagitis and dystrophic recessive epidermolysis bullosa strictures. The conservative treatment of esophageal stenosis and strictures (ES) rather than surgery is a well-known strategy for children. Before planning esophageal dilation, the esophageal morphology should be assessed in detail for its length, aspect, number and level, and different conservative strategies should be chosen accordingly. Endoscopic dilators and techniques that involve different adjuvant treatment strategies have been reported and depend on the stricture's etiology, the availability of different tools and the operator's experience and preferences. Balloon and semirigid dilators are the most frequently used tools. No high-quality studies have reported on the differences in the efficacies and rates of complications associated with these two types of dilators. There is no consensus in the literature regarding the frequency of dilations or the diameter that should be achieved. The use of adjuvant treatments has been reported in cases of recalcitrant stenosis or strictures with evidence of dysphagic symptoms. Corticosteroids (either systemically or locally injected), the local application of mitomycin C, diathermy and laser ES sectioning have been reported. Some authors have suggested that stenting can reduce both the number of dilations and the treatment length. In many cases, this strategy is effective when either metallic or plastic stents are utilized. Treatment complications, such esophageal perforations, can be conservatively managed, considering surgery only in cases with severe pleural cavity involvement. In cases of stricture relapse, even if such relapses occur following the execution of well-conducted conservative strategies, surgical stricture resection and anastomosis or esophageal substitution are the only remaining options. PMID- 26962405 TI - Efficiency and patient experience with propofol vs conventional sedation: A prospective study. AB - AIM: To determine whether anaesthesiologist-administered sedation with propofol (AAP) or endoscopist-administered conscious sedation (EAC) with fentanyl/midazolam shortens colonoscopy duration/total room time. METHODS: This is a prospective, non-randomized, comparative study that enrolled patients greater than 18 years of age undergoing colonoscopy in a single Canadian academic outpatient endoscopy unit over a three-month consecutive period. Colonoscopies in this unit are performed both with AAP and EAC. Patient demographics, procedure related data and adverse events were documented. Additionally, the level of procedure difficulty, and whether a staff endoscopist, trainee with assistance, or independent trainee, performed the procedure were documented. A validated modified 4-question, 5-point Likert scale telephone survey was used to assess patient satisfaction with colonoscopy. The telephone patient satisfaction survey was conducted 24-72 h following the procedure. RESULTS: Two hundred and thirty patients were enrolled during the study period with 126 patients in the AAP group and 104 patients in the EAC group. Mean procedure time was 18.3 +/- 10.1 min in the AAP group and 14.7 +/- 7.1 min in the EAC group (P = 0.002). Mean total room time was 36.8 +/- 13.7 with AAP and 30.1 +/- 11 min with EAC (P < 0.001). Multivariate analysis revealed the use of AAP (P = 0.002), resident participation (P < 0.001), diagnostic interventions (P = 0.033), therapeutic interventions (P < 0.001), lower body mass index (P = 0.008) and American Society of Anaesthesiologist class (P = 0.016), to be predictors of longer total room time. Patient age and gender were not significant predictors. After excluding cases in which trainees were involved, there was no significant difference in procedure time between the two groups (P = 0.941), however total room time was still prolonged in the AAP group (P = 0.019). The amount of pain experienced was lower with AAP (P = 0.02), with a trend toward overall higher patient satisfaction (P = 0.074). There were 2 sedation-related adverse events, both in the AAP group involving a patient with aspiration requiring hospitalization and a patient with hypoxia managed with bronchodilators. CONCLUSION: EAC results in reduced total room time compared to AAP. Resident participation doubles procedure time regardless of sedation type. PMID- 26962406 TI - Peroral endoscopic reduction of dilated gastrojejunal anastomosis after bariatric surgery: Techniques and efficacy. AB - AIM: To investigate the techniques and efficacy of peroral endoscopic reduction of dilated gastrojejunal anastomosis after bariatric surgery. METHODS: An extensive English language literature search was conducted using PubMed, MEDLINE, Medscape and Google to identify peer-reviewed original and review articles using the keywords "bariatric endoscopic suturing", "overstitch bariatric surgery", "endoscopic anastomotic reduction", "bariatric surgery", "gastric bypass", "obesity", "weight loss". We identified articles describing technical feasibility, safety, efficacy, and adverse outcomes of overstitch endoscopic suturing system for transoral outlet reduction in patients with weight regain following Roux-en-Y gastric bypass (RYGB). All studies that contained material applicable to the topic were considered. Retrieved peer-reviewed original and review articles were reviewed by the authors and the data extracted using a standardized collection tool. Data were analyzed using statistical analysis as percentages of the event. RESULTS: Four original published articles which met our search criteria were pooled. The total number cases were fifty-nine with a mean age of 46.75 years (34-63 years). Eight of the patients included in those studies were males (13.6%) and fifty-one were females (86.4%). The mean time elapsed since the primary bypass surgery was 5.75 years. The average pre-endoscopic procedure body mass index (BMI) was 38.68 (27.5-48.5). Mean body weight regained post-RYGB surgery was 13.4 kg from their post-RYGB nadir. The average pouch length at the initial upper endoscopy was 5.75 cm (2-14 cm). The pre-intervention anastomotic diameter was averaged at 24.85 mm (8-40 mm). Average procedure time was 74 min (50-164 min). Mean post endoscopic intervention anastomotic diameter was 8 mm (3-15 mm). Weight reduction at 3 to 4 mo post revision noted to be an average of 10.1 kg. Average overall post revision BMI was recorded at 37.7. The combined technical and clinical success rate was 94.9% (56/59) among studied participants. CONCLUSION: Endoscopic suturing can be technically feasible, effective and safe for transoral outlet reduction in patients with weight regain following RYGB. PMID- 26962404 TI - Role of endoscopic retrograde cholangiopancreatography in the management of benign biliary strictures: What's new? AB - Benign biliary strictures comprise a heterogeneous group of diseases. The most common strictures amenable to endoscopic treatment are post-cholecystectomy, post liver transplantation, related to primary sclerosing cholangitis and to chronic pancreatitis. Endoscopic treatment of benign biliary strictures is widely used as first line therapy, since it is effective, safe, noninvasive and repeatable. Endoscopic techniques currently used are dilation, multiple plastic stents insertion and fully covered self-expandable metal stents. The main indication for dilation alone is primary sclerosing cholangitis related strictures. In the vast majority of the remaining cases, temporary placement of multiple plastic stents with/without dilation is considered the treatment of choice. Although this approach is effective, it requires multiple endoscopic sessions due to the short duration of stent patency. Fully covered self-expandable metal stents appear as a good alternative to plastic stents, since they have an increased radial diameter, longer stent patency, easier insertion technique and similar efficacy. Recent advances in endoscopic technique and various devices have allowed successful treatment in most cases. The development of novel endoscopic techniques and devices is still ongoing. PMID- 26962407 TI - Gastric adenocarcinoma of fundic gland type: Endoscopic and clinicopathological features. AB - Gastric adenocarcinoma of fundic gland type (GA-FG) with chief cell differentiation was recently proposed as an extremely rare type of gastric adenocarcinoma. Here, we report 4 cases of GA-FG with chief cell differentiation. Endoscopic features included a submucosal tumor shape or a flat shape, whitish discoloration and dilated vessels on the surface. The tumors were located in the upper or middle third of the stomach. All cases were preoperatively diagnosed as GA-FG by biopsy, and endoscopic submucosal dissection was performed. Resected specimens revealed well-differentiated adenocarcinomas resembling chief cells. Tumor cells were diffusely positive for pepsinogen-I, but partially positive for H(+)/K(+)-ATPase in scattered locations around the tumor margin. Despite the presence of minimal invasion of the carcinoma into the submucosal layer, which was observed in two cases, neither lymphatic nor venous invasion was detected in any of the cases. Finally, all cases showed less aggressive clinical behavior with low grade malignancy. PMID- 26962408 TI - Recent Advances in Targeting Tumor Energy Metabolism with Tumor Acidosis as a Biomarker of Drug Efficacy. AB - Cancer cells employ a deregulated cellular metabolism to leverage survival and growth advantages. The unique tumor energy metabolism presents itself as a promising target for chemotherapy. A pool of tumor energy metabolism targeting agents has been developed after several decades of efforts. This review will cover glucose and fatty acid metabolism, PI3K/AKT/mTOR, HIF-1 and glutamine pathways in tumor energy metabolism, and how they are being exploited for treatments and therapies by promising pre-clinical or clinical drugs being developed or investigated. Additionally, acidification of the tumor extracellular microenvironment is hypothesized to be the result of active tumor metabolism. This implies that tumor extracellular pH (pHe) can be a biomarker for assessing the efficacy of therapies that target tumor metabolism. Several translational molecular imaging methods (PET, MRI) for interrogating tumor acidification and its suppression are discussed as well. PMID- 26962411 TI - Visceral Pain: Basic Research Concepts and Therapeutic Interventions. PMID- 26962410 TI - Glycosaminoglycan remodeling during diabetes and the role of dietary factors in their modulation. AB - Glycosaminoglycans (GAGs) play a significant role in various aspects of cell physiology. These are complex polymeric molecules characterized by disaccharides comprising of uronic acid and amino sugar. Compounded to the heterogeneity, these are variously sulfated and epimerized depending on the class of GAG. Among the various classes of GAG, namely, chondroitin/dermatan sulfate, heparin/heparan sulfate, keratan sulfate and hyaluronic acid (HA), only HA is non-sulfated. GAGs are known to undergo remodeling in various tissues during various pathophysiological conditions, diabetes mellitus being one among them. These changes will likely affect their structure thereby impinging on their functionality. Till date, diabetes has been shown to affect GAGs in organs such as kidney, liver, aorta, skin, erythrocytes, etc. to name a few, with deleterious consequences. One of the mainstays in the treatment of diabetes is though dietary means. Various dietary factors are known to play a significant role in regulating glucose homeostasis. Furthermore, in recent years, there has been a keen interest to decipher the role of dietary factors on GAG metabolism. This review focuses on the remodeling of GAGs in various organs during diabetes and their modulation by dietary factors. While effect of diabetes on GAG metabolism has been worked out quite a bit, studies on the role of dietary factors in their modulation has been few and far between. We have tried our best to give the latest reports available on this subject. PMID- 26962413 TI - Biomechanical Comparison of Spinal Fusion Methods Using Interspinous Process Compressor and Pedicle Screw Fixation System Based on Finite Element Method. AB - OBJECTIVE: To investigate the biomechanical effects of a newly proposed Interspinous Process Compressor (IPC) and compare with pedicle screw fixation at surgical and adjacent levels of lumbar spine. METHODS: A three dimensional finite element model of intact lumbar spine was constructed and two spinal fusion models using pedicle screw fixation system and a new type of interspinous devices, IPC, were developed. The biomechanical effects such as range of motion (ROM) and facet contact force were analyzed at surgical level (L3/4) and adjacent levels (L2/3, L4/5). In addition, the stress in adjacent intervertebral discs (D2, D4) was investigated. RESULTS: The entire results show biomechanical parameters such as ROM, facet contact force, and stress in adjacent intervertebral discs were similar between PLIF and IPC models in all motions based on the assumption that the implants were perfectly fused with the spine. CONCLUSION: The newly proposed fusion device, IPC, had similar fusion effect at surgical level, and biomechanical effects at adjacent levels were also similar with those of pedicle screw fixation system. However, for clinical applications, real fusion effect between spinous process and hooks, duration of fusion, and influence on spinous process need to be investigated through clinical study. PMID- 26962412 TI - The Similarities and Differences between Intracranial and Spinal Ependymomas : A Review from a Genetic Research Perspective. AB - Ependymomas occur in both the brain and spine. The prognosis of these tumors sometimes differs for different locations. The genetic landscape of ependymoma is very heterogeneous despite the similarity of histopathologic findings. In this review, we describe the genetic differences between spinal ependymomas and their intracranial counterparts to better understand their prognosis. From the literature review, many studies have reported that spinal cord ependymoma might be associated with NF2 mutation, NEFL overexpression, Merlin loss, and 9q gain. In myxopapillary ependymoma, NEFL and HOXB13 overexpression were reported to be associated. Prior studies have identified HIC-1 methylation, 4.1B deletion, and 4.1R loss as common features in intracranial ependymoma. Supratentorial ependymoma is usually characterized by NOTCH-1 mutation and p75 expression. TNC mutation, no hypermethylation of RASSF1A, and GFAP/NeuN expression may be diagnostic clues of posterior fossa ependymoma. Although MEN1, TP53, and PTEN mutations are rarely reported in ependymoma, they may be related to a poor prognosis, such as recurrence or metastasis. Spinal ependymoma has been found to be quite different from intracranial ependymoma in genetic studies, and the favorable prognosis in spinal ependymoma may be the result of the genetic differences. A more detailed understanding of these various genetic aberrations may enable the identification of more specific prognostic markers as well as the development of customized targeted therapies. PMID- 26962414 TI - The Effect of GCSB-5 a New Herbal Medicine on Changes in Pain Behavior and Neuroglial Activation in a Rat Model of Lumbar Disc Herniation. AB - OBJECTIVE: Lumbar disc herniation can induce sciatica by mechanical compression and/or chemical irritation. The aim of this study was to compare the effects of GCSB-5 (Shinbaro(r)) and NSAIDs on pain-related behavior and on the expressions of microglia, astrocytes, CGRP, TRPV1, IL-6, and CX3CL1 in a rat model of lumbar disc herniation. METHODS: 112 male Sprague-Dawley rats underwent implantation of nucleus pulposus to a dorsal root ganglion (DRG). Rats were divided into five groups as follows; a saline group (the vehicle control group) (n=27), a 10 mg/kg aceclofenac group (the aceclofenac group) (n=22), and 100, 300 or 600 mg/kg GCSB 5 groups (the GCSB-5 100, 300, or 600 groups) (n=21 for each group). Rats were tested for mechanical allodynia at 3 days after surgery and at 1 day, 3 days, 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, and 56 days after treatment commencement. Immunohistochemical staining of microglia (Iba1), astrocytes (GFAP), CGRP, and TRPV1, and PCR for IL-6 and CX3CL1 were performed on spinal dorsal horns and DRGs at 56 days after medication commencement. RESULTS: After 56 days of GCSB-5 300 administration, mechanical withdrawal thresholds were significantly increased (p<0.05), and immunohisto-chemical expressions of Iba1, GFAP, CGRP, and TRPV1 were reduced than other groups, but this difference was not statistically significant. CONCLUSION: These results indicate GCSB-5 reduces mechanical allodynia and downregulates neuroglial activity and the expressions of CGRP and TRPV1 in the spinal segments of a rat model of lumbar disc herniation. PMID- 26962409 TI - Management of diabolical diabetes mellitus and periodontitis nexus: Are we doing enough? AB - Periodontitis is the commonest oral disease affecting population worldwide. This disease is notorious for the devastation of tooth supporting structures, ensuing in the loss of dentition. The etiology for this disease is bacterial biofilm, which accumulates on the teeth as dental plaque. In addition to the biofilm microorganisms, other factors such as environmental, systemic and genetic are also responsible in progression of periodontitis. Diabetes mellitus (DM) is metabolic disorder which has an impact on the global health. DM plays a crucial role in the pathogenesis of periodontitis. Periodontitis is declared as the "sixth" major complication of DM. Evidence based literature has depicted an enhanced incidence and severity of periodontitis in subjects with DM. A "two way" relationship has been purported between periodontitis and DM. Mutual management of both conditions is necessary. Periodontal therapy (PT) may assist to diminish the progression of DM and improve glycemic control. Various advanced technological facilities may be utilized for the purpose of patient education and disease management. The present paper clarifies the etio-pathogenesis of periodontitis, establishing it as a complication of DM and elaborating the various mechanisms involved in the pathogenesis. The role of PT in amelioration of DM and application of digital communication will be discussed. Overall, it is judicious to create an increased patient cognizance of the periodontitis-DM relationship. Conjunctive efforts must be undertaken by the medical and oral health care professionals for the management of periodontitis affected DM patients. PMID- 26962416 TI - Recurrent Bleeding in Hemorrhagic Moyamoya Disease : Prognostic Implications of the Perfusion Status. AB - OBJECTIVE: Hemorrhagic moyamoya disease (hMMD) is associated with a poor clinical course. Furthermore, poorer clinical outcomes occur in cases of recurrent bleeding. However, the effect of hemodynamic insufficiency on rebleeding risk has not been investigated yet. This study evaluated the prognostic implications of the perfusion status during the clinical course of adult hMMD. METHODS: This retrospective study enrolled 52 adult hMMD patients between April 1995 and October 2010 from a single institute. Demographic data, clinical and radiologic characteristics, including hemodynamic status using single photon emission computed tomography (SPECT), and follow up data were obtained via a retrospective review of medical charts and imaging. Statistical analyses were performed to explore potential prognostic factors. RESULTS: Hemodynamic abnormality was identified in 44 (84.6%) patients. Subsequent revascularization surgery was performed in 22 (42.3%) patients. During a 58-month (median, range 3-160) follow up assessment period, 17 showed subsequent stroke (hemorrhagic n=12, ischemic n=5, Actuarial stroke rate 5.8+/-1.4%/year). Recurrent hemorrhage was associated with decreased basal perfusion (HR 19.872; 95% CI=1.196-294.117) and omission of revascularization (10.218; 95%; CI=1.532-68.136). CONCLUSION: Decreased basal perfusion seems to be associated with recurrent bleeding. Revascularization might prevent recurrent stroke in hMMD by rectifying the perfusion abnormality. A larger-sized, controlled study is required to address this issue. PMID- 26962415 TI - Bacitracin Inhibits the Migration of U87-MG Glioma Cells via Interferences of the Integrin Outside-in Signaling Pathway. AB - OBJECTIVE: Protein disulfide isomerase (PDI) acts as a chaperone on the cell surface, and it has been reported that PDI is associated with the tumor cell migration and invasion. The aims of this study are to investigate the anti migration effect of bacitracin, which is an inhibitor of PDI, and the associated factor in this process. METHODS: U87-MG glioma cells were treated with bacitracin in 1.25, 2.5, 3.75, and 5.0 mM concentrations. Western blot with caspase-3 was applied to evaluate the cytotoxicity of bacitracin. Adhesion, morphology, migration assays, and organotypic brain-slice culture were performed to evaluate the effect of bacitracin to the tumor cell. Western blot, PCR, and gelatin zymography were performed to investigate the associated factors. Thirty glioma tissues were collected following immunohistochemistry and Western blot. RESULTS: Bacitracin showed a cytotoxicity in 3rd (p<0.05) and 4th (p<0.001) days, in 5.0 Mm concentration. The cell adhesion significantly decreased and the cells became a round shape after treated with bacitracin. The migration ability, the expression of phosphorylated focal adhesion kinase (p-FAK) and matrix metalloproteinase-2 (MMP-2) decreased in a bacitracin dose- and time-dependent manner. The U87-MG cells exhibited low-invasiveness in the 2.5 mM, compared with the untreated in organotypic brain-slice culture. PDI was expressed in the tumor margin, and significantly increased with histological glioma grades (p<0.001). CONCLUSION: Bacitracin, as a functional inhibitor of PDI, decreased the phosphorylated FAK and the secreted MMP-2, which are the downstream of integrin and play a major role in cell migration and invasion, might become one of the feasible therapeutic strategies for glioblastoma. PMID- 26962417 TI - Single-Stage Posterior Subtotal Corpectomy and Circumferential Reconstruction for the Treatment of Unstable Thoracolumbar Burst Fractures. AB - OBJECTIVE: To illustrate the technique of single-stage posterior subtotal corpectomy and circumferential reconstruction for the treatment of unstable thoracolumbar burst fractures and to evaluate the radiographical and clinical outcomes of patients treated using this technique. METHODS: 16 consecutive patients with unstable thoracolumbar burst fractures were treated with single stage posterior subtotal corpectomy and circumferential reconstruction. The mean patient age was 54.8 years. The mean follower up period was 25 months. Five patients suffered from T12 fractures, 10 from L1, 1 from L2. The segmental kyphosis, neurologic status, visual analogue scale for back pain was evaluated before surgery and at follow up. RESULTS: The segmental kyphotic angle improved from 18.5 degrees before surgery to -9.2 degrees at the last follow up. The mean correction angle was 28.9 degrees. The mean surgical time was 255 minutes, and a mean intraoperative blood loss was 1073 mL. Intraoperative complications included two dural tears, and a superficial wound infection. There were no other severe complications. The mean visual analog scale of back pain decreased from a mean value of 6.6 to 2 at the last follow up. CONCLUSION: The single-stage posterior subtotal corpectomy and circumferential reconstruction achieved satisfactory kyphosis correction with direct visualization of the circumferentially decompressed spinal cord, as well as good fusion with less blood loss and complications. It is a safe and reliable surgical treatment option for unstable thoracolumbar burst fractures. PMID- 26962418 TI - Radiologic Findings and Risk Factors of Adjacent Segment Degeneration after Anterior Cervical Discectomy and Fusion : A Retrospective Matched Cohort Study with 3-Year Follow-Up Using MRI. AB - OBJECTIVE: The purpose of this study was to figure out the radiologic findings and risk factors related to adjacent segment degeneration (ASD) after anterior cervical discectomy and fusion (ACDF) using 3-year follow-up radiography, computed tomography (CT), and magnetic resonance image (MRI). METHODS: A retrospective matched comparative study was performed for 64 patients who underwent single-level ACDF with a cage and plate. Radiologic parameters, including upper segment range of motion (USROM), lower segment range of motion (LSROM), upper segment disc height (UDH), and lower segment disc height (LDH), clinical outcomes assessed with neck and arm visual analogue scale (VAS), and risk factors were analyzed. RESULTS: Patients were categorized into the ASD (32 patients) and non-ASD (32 patients) group. The decrease of UDH was significantly greater in the ASD group at each follow-up visit. At 36 months postoperatively, the difference for USROM value from the preoperative one significantly increased in the ASD group than non-ASD group. Preoperative other segment degeneration was significantly associated with the increased incidence of ASD at 36 months. However, pain intensity for the neck and arm was not significantly different between groups at any post-operative follow-up visit. CONCLUSION: The main factor affecting ASD is preoperative other segment degeneration out of the adjacent segment. In addition, patients over the age of 50 are at higher risk of developing ASD. Although there was definite radiologic degeneration in the ASD group, no significant difference was observed between the ASD and non-ASD groups in terms of the incidence of symptomatic disease. PMID- 26962420 TI - Postoperative Clinical Outcome and Risk Factors for Poor Outcome of Foraminal and Extraforaminal Lumbar Disc Herniation. AB - OBJECTIVE: We evaluated postoperative outcomes in patients who have lumbar foraminal or extraforaminal disc herniation (FELDH) and suggested the risk factors for poor outcomes. METHODS: A total of 234 patients were selected for this study. Pre- and post-operative Visual Analogue Scale (VAS) and Korean version Oswestry Disability Index (KODI) were evaluated and the changes of both score were calculated. Outcome was defined as excellent, good, fair, and poor based on Mcnab classification. The percentage of superior facetectomy was calculated by using the Maro-view 5.4 Picture Archiving Communication System (PACS). RESULTS: Paramedian lumbar discectomy was performed in 180 patients and combined lumbar discectomy was performed in 54 patients. Paramedian lumbar discectomy group showed better outcome compared with combined discectomy group. p value of VAS change was 0.009 and KODI was 0.013. The average percentage of superior facetectomy was 33% (range, 0-79%) and it showed negative correlation with VAS and KODI changes (Pearson coefficient : -0.446 and -0.498, respectively). Excellent or good outcome cases (Group I) were 136 (58.1%) and fair or poor outcome cases (Group II) were 98 (41.9%). The percentage of superior facetectomy was 26.5% at Group I and 42.5% at Group II. There was significant difference in superior facetectomy percentage between Group I and II (p=0.000). CONCLUSION: This study demonstrated that paramedian lumbar discectomy with preservation of facet joints is an effective and good procedure for FELDH. At least 60% of facet should be preserved for excellent or good outcomes. PMID- 26962419 TI - Early Bone Marrow Edema Pattern of the Osteoporotic Vertebral Compression Fracture : Can Be Predictor of Vertebral Deformity Types and Prognosis? AB - OBJECTIVE: To evaluate whether an early bone marrow edema pattern predicts vertebral deformity types and prognosis in osteoporotic vertebral compression fracture (OVCF). METHODS: This retrospective study enrolled 64 patients with 75 acute OVCFs who underwent early MRI and followed up MRI. On early MRI, the low SI pattern of OVCF on T1WI were assessed and classified into 3 types (diffuse, globular or patchy, band-like). On followed up MRI, the vertebral deformity types (anterior wedge, biconcave, crush), degree of vertebral body height loss, incidence of vertebral osteonecrosis and spinal stenosis were assessed for each vertebral fracture types. RESULTS: According to the early bone marrow edema pattern on T1WI, 26 vertebrae were type 1, 14 vertebrae were type 2 and 35 vertebrae were type 3. On followed up MRI, the crush-type vertebral deformity was most frequent among the type 1 OVCFs, the biconcave-type vertebral deformity was most frequent among the type 2 OVCFs and the anterior wedge-type vertebral deformity was most frequent among the type 3 OVCFs (p<0.001). In addition, type 1 early bone marrow edema pattern of OVCF on T1WI were associated with higher incidence of severe degree vertebral body height loss, vertebral osteonecrosis and spinal stenosis on the follow up MRI. CONCLUSION: Early bone marrow edema pattern of OVCF on T1WI, significant correlated with vertebral deformity types on the follow up MRI. The severe degree of vertebral height loss, vertebral osteonecrosis, and spinal stenosis were more frequent in patients with diffuse low SI pattern. PMID- 26962421 TI - Epidemiologic Impact of Rapid Industrialization on Head Injury Based on Traffic Accident Statistics in Korea. AB - OBJECTIVE: The aim of the present study is to estimate the incidence trend of head injury and the mortality based on traffic accident statistics and to investigate the impacts of rapid industrialization and economic growth on epidemiology of head injury in Korea over the period 1970-2012 including both pre industrialized and post-industrialized stages. METHODS: We collected data of head injury estimated from traffic accident statistics and seven hospital based reports to see incidence trends between 1970 and 2012. We also investigated the population structure and Gross National Income (GNI) per capita of Korea over the same period. The age specific data were investigated from 1992 to 2012. RESULTS: The incidence of head injury gradually rose in the 1970s and the 1980s but stabilized until the 1990s with transient rise and then started to decline slowly in the 2000s. The mortality grew until 1991 but gradually declined ever since. However, the old age groups showed rather slight increase in both rates. The degree of decrease in the mortality has been more rapid than the incidence on head injury. CONCLUSION: In Korea during the low income stage, rapid industrialization cause considerable increase in the mortality and the incidence of head injury. During the high income stage, the incidence of head injury gradually declined and the mortality dropped more rapidly than the incidence due to preventive measures and satisfactory medical care. Nevertheless, the old age groups revealed rather slight increase in both rates owing to the large population structure and the declining birth rate. PMID- 26962422 TI - Protocol Based Real-Time Continuous Electroencephalography for Detecting Vasospasm in Subarachnoid Hemorrhage. AB - A continuous electroencephalography (cEEG) can be helpful in detecting vasospasm and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage (SAH). We describe a patient with an aneurysmal SAH whose symptomatic vasospasm was detected promptly by using a real-time cEEG. Patient was immediately treated by intraarterial vasodilator therapy. A 50-year-old woman without any significant medical history presented with a severe bifrontal headache due to acute SAH with a ruptured aneurysm on the anterior communicating artery (Fisher grade 3). On bleed day 6, she developed a sudden onset of global aphasia and left hemiparesis preceded by cEEG changes consistent with vasospasm. A stat chemical dilator therapy was performed and she recovered without significant neurological deficits. A real-time and protocol-based cEEG can be utilized in order to avoid any delay in detection of vasospasm in aneurysmal SAH and thereby improve clinical outcomes. PMID- 26962423 TI - A Rare Case of Concomitant Intramedullary Gangliocytoma at the Cervicomedullary Junction in Patient with Neuroendocrine Tumor of Lung. AB - Ganglion cell tumors (GCT) are divided into two subtypes : gangliocytoma and ganglioglioma. Intramedullary gangliocytomas are extremely rare. A 20-year-old male patient with pain of neck, who also had a previously known neuroendocrine tumor of lung, was operated for mass found in the cervicomedullary junction with a presumptive diagnosis of metastases. Only partial resection could be performed. Pathological diagnosis had been reported as gangliocytoma. Only ten cases of intramedullary gangliocytoma have been reported in the literature. Although association with scoliosis and Von Recklinghausen's disease were previously reported in the literature, no gangliocytoma case concomitant with endocrine tumor of lung have been published. Pathological study is the most important diagnostic method for gangliocytomas. Surgical excision is the primary treatment, but difficulty in total surgical tumor resection is the most important problem. PMID- 26962424 TI - Preoperative Extrapontine Myelinolysis with Good Outcome in a Patient with Pituitary Adenoma. AB - Few preoperative extrapontine myelinolysis (EPM) cases with pituitary adenoma have been reported. No such case had long follow-up to see the outcome of EPM. We reported a 38-year-old man complaining of nausea, malaise and transient loss of consciousness who was found to have severe hyponatremia. Neurologic deficits including altered mental status, behavioral disturbances, dysarthria and dysphagia developed despite slow correction of hyponatremia. Endocrine and imaging studies revealed hypopituitarism, nonfunctional pituitary macroadenoma and extrapontine myelinolysis. Transsphenoidal surgery was performed after three weeks of supportive therapy, when neurological symptoms improved significantly. The patient recovered function completely 3 months after surgery. Our case indicates that outcome of EPM can be good even with prolonged periods of severe neurologic impairment. PMID- 26962425 TI - Case of Langerhans Cell Histiocytosis That Mimics Meningioma in CT and MRI. AB - Langerhans cell histiocytosis (LCH) is a rare disorder histologically characterized by the proliferation of Langerhans cells. Here we present the case of a 13-year-old girl with LCH wherein CT and MRI results led us to an initially incorrect diagnosis of meningioma. The diagnosis was corrected to LCH based on pathology findings. An intracranial mass was found mainly in the dura mater, with thickening of the surrounding dura. It appeared to be growing downward from the calvaria, pressing on underlying brain tissue, and had infiltrated the inner skull, causing a bone defect. The lesion was calcified with the typical dural tail sign. The dural origin of the lesion was verified upon surgical dissection. There are no previous reports in the literature describing LCH of dural origin presenting in young patients with typical dural tail signs and meningioma-like imaging findings. The current case report underscores the need for thorough histological and immunocytochemical examinations in LCH differential diagnosis. PMID- 26962426 TI - Growing Hemorrhagic Choroidal Fissure Cyst. AB - Choroidal fissure cysts are often incidentally discovered. They are usually asymptomatic. The authors report a case of growing and hemorrhagic choroidal fissure cyst which was treated surgically. A 22-year-old female presented with headache. Cranial MRI showed a left-sided choroidal fissure cyst. Follow-up MRI showed that the size of the cyst had increased gradually. Twenty months later, the patient was admitted to our emergency department with severe headache. MRI and CT showed an intracystic hematoma. Although such cysts usually have a benign course without symptoms and progression, they may rarely present with intracystic hemorrhage, enlargement of the cyst and increasing symptomatology. PMID- 26962427 TI - Foraminoplastic Superior Vertebral Notch Approach with Reamers in Percutaneous Endoscopic Lumbar Discectomy : Technical Note and Clinical Outcome in Limited Indications of Percutaneous Endoscopic Lumbar Discectomy. AB - To describe the details of the foraminoplastic superior vertebral notch approach (FSVNA) with reamers in percutaneous endoscopic lumbar discectomy (PELD) and to demonstrate the clinical outcomes in limited indications of PELD. Retrospective data were collected from 64 patients who underwent PELD with FSVNA from August 2012 to April 2014. Inclusion criteria were high grade migrated disc, high canal compromised disc, and disc protrusion combined with foraminal stenosis. The clinical outcomes were assessed using by the visual analogue scale (VAS), Oswestry Disability Index (ODI) and modified MacNab criteria. Complications related to the surgery were reviewed. The procedure used a unique approach, using the superior vertebral notch as the target and performing foraminoplasty with only reamers under C-arm control. The mean age of the 55 female and 32 male patients was 52.73 years. The mean F/U period was 12.2+/-4.2 months. Preoperative VAS (8.24+/-1.25) and ODI (67.8+/-15.4) score improved significantly at the last follow-up (VAS, 1.93+/-1.78; ODI, 17.14+/-15.7). Based on the modified MacNab criteria, excellent or good results were obtained in 95.3% of the patients. Postoperative transient dysthesia (n=2) and reoperation (n=1) due to recurred disc were reported. PELD with FSVNA could be a good method for treating lumbar disc herniation. This procedure may offer safe and efficacious results, especially in the relatively limited indications for PELD. PMID- 26962428 TI - Sudden Death Following Cranioplasty. PMID- 26962429 TI - Discovery of high affinity inhibitors of Leishmania donovani N myristoyltransferase. AB - N-Myristoyltransferase (NMT) is a potential drug target in Leishmania parasites. Scaffold-hopping from published inhibitors yielded the serendipitous discovery of a chemotype selective for Leishmania donovani NMT; development led to high affinity inhibitors with excellent ligand efficiency. The binding mode was characterised by crystallography and provides a structural rationale for selectivity. PMID- 26962431 TI - Post-operative rehabilitation in osteoarthritis. AB - Osteoarthritis (OA) is a degenerative process involving the progressive loss of articular cartilage, synovial inflammation and structural changes to the subchondral bone that lead to loss of synovial joint structural features and impaired functionality of the articular cartilage. OA represents one of the most common causes of physical disability in the world. Different OA treatments are usually considered in relation to the stage of the disease. However, in the earlier stages of the disease, it is possible to recommend physical activity programs that can maintain joint health and keep the patient mobile, as recommended by the Osteoarthritis Research Society International (OARSI) and the European League Against Rheumatism (EULAR). In the most severe and advanced cases of OA, surgical intervention is necessary. In early post-operative stages, it is essential to include rehabilitation exercise program therapies in order to restore the full function of the involved joint. Physical therapy is crucial for the success of any surgical procedure and can promote recovery of muscle strength, range of motion, coordinated walking, proprioception and mitigate joint pain. After discharge from the hospital, patients should continue the rehabilitation exercise program at home. In this review, we analyze articles from the most recent literature and provide a balanced and comprehensive overview of the latest discoveries in relation to the effects of physical exercise on post operative rehabilitation in OA. The literature search was conducted in April 2014 using PubMed, Scopus and Google Scholar using the keywords 'osteoarthritis', 'rehabilitation' and 'exercise', in a range of period 2002/2014 and out of 100 papers we have chosen 48 that we considered more appropriate. The available data suggests that physical exercise is effective, economical and accessible to everyone, and is one of the most important components of post-operative rehabilitation for OA. PMID- 26962432 TI - Case Report: "ADHD Trainer": the mobile application that enhances cognitive skills in ADHD patients. AB - We report the case of a 10 year old patient diagnosed with attention deficit hyperactivity disorder (ADHD) and comorbid video game addiction, who was treated with medication combined to a novel cognitive training method based on video games called TCT method. A great risk of developing video game or internet addiction has been reported in children, especially in children with ADHD. Despite this risk, we hypothesize that the good use of these new technologies might be useful to develop new methods of cognitive training. The cognitive areas in which a greater improvement was observed through the use of video games were the visuospatial working memory and fine motor skills. TCT method is a cognitive training method that enhances cognitive skills such as attention, working memory, processing speed, calculation ability, reasoning, and visuomotor coordination. The purpose of reviewing this case is to highlight that regular cognitive computerized training in ADHD patients can improve some of their cognitive symptoms and can help treating video game addition. PMID- 26962430 TI - Discovery of pyridyl-based inhibitors of Plasmodium falciparum N myristoyltransferase. AB - N-Myristoyltransferase (NMT) represents an attractive drug target in parasitic infections such as malaria due to its genetic essentiality and amenability to inhibition by drug-like small molecules. Scaffold simplification from previously reported inhibitors containing bicyclic cores identified phenyl derivative 3, providing a versatile platform to study the effects of substitution on the scaffold, which yielded pyridyl 19. This molecule exhibited improved enzyme and cellular potency, and reduced lipophilicity compared to inhibitor 3. Further structure-based inhibitor design led to the discovery of 30, the most potent inhibitor in this series, which showed single-digit nM enzyme affinity and sub MUM anti-plasmodial activity. PMID- 26918122 TI - Metabarcoding-based fungal diversity on coarse and fine particulate organic matter in a first-order stream in Nova Scotia, Canada. AB - Most streams receive substantial inputs of allochthonous organic material in the form of leaves and twigs (CPOM , coarse particulate organic matter). Mechanical and biological processing converts this into fine particulate organic matter (FPOM). Other sources of particles include flocculated dissolved matter and soil particles. Fungi are known to play a role in the CPOM conversion process, but the taxonomic affiliations of these fungi remain poorly studied. The present study seeks to shed light on the composition of fungal communities on FPOM and CPOM as assessed in a natural stream in Nova Scotia, Canada. Maple leaves were exposed in a stream for four weeks and their fungal community evaluated through pyrosequencing. Over the same period, four FPOM size fractions were collected by filtration and assessed. Particles had much lower ergosterol contents than leaves, suggesting major differences in the extent of fungal colonization. Pyrosequencing documented a total of 821 fungal operational taxonomic units (OTU), of which 726 were exclusive to particles and 47 to leaf samples. Most fungal phyla were represented, including yeast lineages (e.g., Taphrinaceae and Saccharomycotina), Basidiomycota, Chytridiomycota and Cryptomycota, but several classes of Pezizomycontina (Ascomycota) dominated. Cluster dendrograms clearly separated fungal communities from leaves and from particles. Characterizing fungal communities may shed some light on the processing pathways of fine particles in streams and broadens our view of the phylogenetic composition of fungi in freshwater ecosystems. PMID- 26962434 TI - Crambled: A Shiny application to enable intuitive resolution of conflicting cellularity estimates. AB - It is now commonplace to investigate tumour samples using whole-genome sequencing, and some commonly performed tasks are the estimation of cellularity (or sample purity), the genome-wide profiling of copy numbers, and the assessment of sub-clonal behaviours. Several tools are available to undertake these tasks, but often give conflicting results - not least because there is often genuine uncertainty due to a lack of model identifiability. Presented here is a tool, "Crambled", that allows for an intuitive visual comparison of the conflicting solutions. Crambled is implemented as a Shiny application within R, and is accompanied by example images from two use cases (one tumour sample with matched normal sequencing, and one standalone cell line example) as well as functions to generate the necessary images from any sequencing data set. Through the use of Crambled, a user may gain insight into why each tool has offered its given solution and combined with a knowledge of the disease being studied can choose between the competing solutions in an informed manner. PMID- 26962435 TI - The importance of selecting the appropriate reference genes for quantitative real time PCR as illustrated using colon cancer cells and tissue. AB - Quantitative real-time reverse-transcription polymerase chain reaction (RT-qPCR) remains the most sensitive technique for nucleic acid quantification. Its popularity is reflected in the remarkable number of publications reporting RT qPCR data. Careful normalisation within RT-qPCR studies is imperative to ensure accurate quantification of mRNA levels. This is commonly achieved through the use of reference genes as an internal control to normalise the mRNA levels between different samples. The selection of appropriate reference genes can be a challenge as transcript levels vary with physiology, pathology and development, making the information within the transcriptome flexible and variable. In this study, we examined the variation in expression of a panel of nine candidate reference genes in HCT116 and HT29 2-dimensional and 3-dimensional cultures, as well as in normal and cancerous colon tissue. Using normfinder we identified the top three most stable genes for all conditions. Further to this we compared the change in expression of a selection of PKC coding genes when the data was normalised to one reference gene and three reference genes. Here we demonstrated that there is a variation in the fold changes obtained dependent on the number of reference genes used. As well as this, we highlight important considerations namely; assay efficiency tests, inhibition tests and RNA assessment which should also be implemented into all RT-qPCR studies. All this data combined demonstrates the need for careful experimental design in RT-qPCR studies to help eliminate false interpretation and reporting of results. PMID- 26962436 TI - Towards an open science publishing platform. AB - The way science and research is done is rapidly becoming more open and collaborative. The traditional way of publishing new findings in journals is becoming increasingly outdated and no longer serves the needs of much of science. Whilst preprints can bring significant benefits of removing delay and selection, they do not go far enough if simply implemented alongside the existing journal system. We propose that we need a new approach, an Open Science Platform, that takes the benefits of preprints but adds formal, invited, and transparent post publication peer review. This bypasses the problems of the current journal system and, in doing so, moves the evaluation of research and researchers away from the journal-based Impact Factor and towards a fairer system of article-based qualitative and quantitative indicators. In the long term, it should be irrelevant where a researcher publishes their findings. What is important is that research is shared and made available without delay within a framework that encourages quality standards and requires all players in the research community to work as collaborators. PMID- 26962437 TI - Current Landscape of Antiviral Drug Discovery. AB - Continued discovery and development of new antiviral medications are paramount for global human health, particularly as new pathogens emerge and old ones evolve to evade current therapeutic agents. Great success has been achieved in developing effective therapies to suppress human immunodeficiency virus (HIV) and hepatitis B virus (HBV); however, the therapies are not curative and therefore current efforts in HIV and HBV drug discovery are directed toward longer-acting therapies and/or developing new mechanisms of action that could potentially lead to cure, or eradication, of the virus. Recently, exciting early clinical data have been reported for novel antivirals targeting respiratory syncytial virus (RSV) and influenza (flu). Preclinical data suggest that these new approaches may be effective in treating high-risk patients afflicted with serious RSV or flu infections. In this review, we highlight new directions in antiviral approaches for HIV, HBV, and acute respiratory virus infections. PMID- 26962439 TI - Management of children with prolonged diarrhea. AB - Prolonged diarrhea is usually defined as acute-onset diarrhea lasting 7 days or more, but less than 14 days. Its trend has been declining in recent years because of improvement in the management of acute diarrhea, which represents the ideal strategy to prevent prolonged diarrhea. The pathogenesis of prolonged diarrhea is multifactorial and essentially based on persistent mucosal damage due to specific infections or sequential infections with different pathogens, host-related factors including micronutrient and/or vitamin deficiency, undernutrition and immunodeficiency, high mucosal permeability due to previous infectious processes and nutrient deficiency with consequential malabsorption, and microbiota disruption. Infections seem to play a major role in causing prolonged diarrhea in both developing and developed areas. However, single etiologic pathogens have not been identified, and the pattern of agents varies according to settings, host risk factors, and previous use of antibiotics and other drugs. The management of prolonged diarrhea is complex. Because of the wide etiologic spectrum, diagnostic algorithms should take into consideration the age of the patient, clinical and epidemiological factors, and the nutritional status and should always include a search for enteric pathogens. Often, expensive laboratory evaluations are of little benefit in guiding therapy, and an empirical approach may be effective in the majority of cases. The presence or absence of weight loss is crucial for driving the initial management of prolonged diarrhea. If there is no weight loss, generally there is no need for further evaluation. If weight loss is present, empiric anti-infectious therapy or elimination diet may be considered once specific etiologies have been excluded. PMID- 26962440 TI - How special is the biochemical function of native proteins? AB - Native proteins perform an amazing variety of biochemical functions, including enzymatic catalysis, and can engage in protein-protein and protein-DNA interactions that are essential for life. A key question is how special are these functional properties of proteins. Are they extremely rare, or are they an intrinsic feature? Comparison to the properties of compact conformations of artificially generated compact protein structures selected for thermodynamic stability but not any type of function, the artificial (ART) protein library, demonstrates that a remarkable number of the properties of native-like proteins are recapitulated. These include the complete set of small molecule ligand binding pockets and most protein-protein interfaces. ART structures are predicted to be capable of weakly binding metabolites and cover a significant fraction of metabolic pathways, with the most enriched pathways including ancient ones such as glycolysis. Native-like active sites are also found in ART proteins. A small fraction of ART proteins are predicted to have strong protein-protein and protein DNA interactions. Overall, it appears that biochemical function is an intrinsic feature of proteins which nature has significantly optimized during evolution. These studies raise questions as to the relative roles of specificity and promiscuity in the biochemical function and control of cells that need investigation. PMID- 26962438 TI - Developmental gene regulatory networks in sea urchins and what we can learn from them. AB - Sea urchin embryos begin zygotic transcription shortly after the egg is fertilized. Throughout the cleavage stages a series of transcription factors are activated and, along with signaling through a number of pathways, at least 15 different cell types are specified by the beginning of gastrulation. Experimentally, perturbation of contributing transcription factors, signals and receptors and their molecular consequences enabled the assembly of an extensive gene regulatory network model. That effort, pioneered and led by Eric Davidson and his laboratory, with many additional insights provided by other laboratories, provided the sea urchin community with a valuable resource. Here we describe the approaches used to enable the assembly of an advanced gene regulatory network model describing molecular diversification during early development. We then provide examples to show how a relatively advanced authenticated network can be used as a tool for discovery of how diverse developmental mechanisms are controlled and work. PMID- 26962442 TI - Recent advances in the pathogenesis and treatment of paroxysmal nocturnal hemoglobinuria. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a very rare disease that has been investigated for over one century and has revealed unique aspects of the pathogenesis and pathophysiology of a hemolytic anemia. PNH results from expansion of a clone of hematopoietic cells that, as a consequence of an inactivating mutation of the X-linked gene PIG-A, are deficient in glycosylphosphatidylinositol (GPI)-linked proteins: since these include the surface membrane complement-regulatory proteins CD55 and CD59, the red cells arising from this clone are exquisitely sensitive to lysis by activated complement. Until a decade ago, the treatment options for PNH were either supportive treatment - often including blood transfusion, anti-thrombosis prophylaxis, and sometimes thrombolytic therapy - or allogeneic bone marrow transplantation. Since 2007, PNH has received renewed and much wider attention because a new form of treatment has become available, namely complement blockade through the anti-C5 monoclonal antibody eculizumab. This brief review focuses on two specific aspects of PNH: (1) response to eculizumab, variability of response, and how this new agent has impacted favorably on the outlook and on the quality of life of patients; and (2) with respect to pathogenesis, new evidence supports the notion that expansion of the PNH clone results from T-cell-mediated auto immune damage to hematopoietic stem cells, with the GPI molecule as target. Indeed, GPI-specific CD8+ T cells - which have been identified in PNH patients - would spare selectively GPI-negative stem cells, thus enabling them to re populate the marrow of a patient who would otherwise have aplastic anemia. PMID- 26962441 TI - Recent Advances in Urinary Tract Reconstruction for Neuropathic Bladder in Children. AB - Neuropathic bladder usually causes several limitations to patients' quality of life, including urinary incontinence, recurrent urinary tract infections, and upper urinary tract damage. Its management has significantly changed over the last few years. The aim of our paper is to address some salient features of recent literature dealing with reconstructive procedures in pediatric and adolescent patients with lower urinary tract dysfunction. PMID- 26962443 TI - Recent Advances in Understanding and Engineering Polyketide Synthesis. AB - Polyketides are a diverse group of natural products that form the basis of many important drugs. The engineering of the polyketide synthase (PKS) enzymes responsible for the formation of these compounds has long been considered to have great potential for producing new bioactive molecules. Recent advances in this field have contributed to the understanding of this powerful and complex enzymatic machinery, particularly with regard to domain activity and engineering, unique building block formation and incorporation, and programming rules and limitations. New developments in tools for in vitro biochemical analysis, full length megasynthase structural studies, and in vivo heterologous expression will continue to improve our fundamental understanding of polyketide synthesis as well as our ability to engineer the production of polyketides. PMID- 26962446 TI - Antimicrobial stewardship in long-term care facilities in Belgium: a questionnaire-based survey of nursing homes to evaluate initiatives and future developments. AB - BACKGROUND: The use of antimicrobials is intense and often inappropriate in long term care facilities. Antimicrobial resistance has increased in acute and chronic care facilities, including those in Belgium. Evidence is lacking concerning antimicrobial stewardship programmes in chronic care settings. The medical coordinator practicing in Belgian nursing homes is a general practitioner designated to coordinate medical activity. He is likely to be the key position for effective implementation of such programmes. The aim of this study was to evaluate past, present, and future developments of antimicrobial stewardship programmes by surveying medical coordinators working in long-term care facilities in Belgium. METHODS: We conducted an online questionnaire-based survey of 327 Belgian medical coordinators. The questionnaire was composed of 33 questions divided into four sections: characteristics of the respondents, organisational frameworks for implementation of the antimicrobial stewardship programme, tools to promote appropriate antimicrobial use and priorities of action. Questions were multiple choice, rating scale, or free text. RESULTS: A total of 39 medical coordinators (12 %) completed the questionnaire. Past or present antimicrobial stewardship initiatives were reported by 23 % of respondents. The possibility of future developments was rated 2.7/5. The proposed key role of medical coordinators was rated <3/5 by 36 % of respondents. General practitioners, nursing staff, and hospital specialists are accepted as important roles. The use of antimicrobial guidelines was reported by only 19 % of respondents. Education was considered the cornerstone for any future developments. Specific diagnostic recommendations were considered useful, but chest x-rays were judged difficult to undertake. The top priority identified was to reduce unnecessary treatment of asymptomatic urinary infections. CONCLUSIONS: Our study shows that the implementation of an antimicrobial stewardship programme is reported only in a minority of nursing homes. The possibility of future developments is uncertain. Nevertheless, the self-selected medical coordinators who responded to the survey reported a good knowledge of this complex problem. Despite a lack of optimism, medical coordinators seem to have the appropriate competencies to play a key role in antimicrobial stewardship in the future. PMID- 26962444 TI - Axonal maintenance, glia, exosomes, and heat shock proteins. AB - Of all cellular specializations, the axon is especially distinctive because it is a narrow cylinder of specialized cytoplasm called axoplasm with a length that may be orders of magnitude greater than the diameter of the cell body from which it originates. Thus, the volume of axoplasm can be much greater than the cytoplasm in the cell body. This fact raises a logistical problem with regard to axonal maintenance. Many of the components of axoplasm, such as soluble proteins and cytoskeleton, are slowly transported, taking weeks to months to travel the length of axons longer than a few millimeters after being synthesized in the cell body. Furthermore, this slow rate of supply suggests that the axon itself might not have the capacity to respond fast enough to compensate for damage to transported macromolecules. Such damage is likely in view of the mechanical fragility of an axon, especially those innervating the limbs, as rapid limb motion with high impact, like running, subjects the axons in the limbs to considerable mechanical force. Some researchers have suggested that local, intra-axonal protein synthesis is the answer to this problem. However, the translational state of axonal RNAs remains controversial. We suggest that glial cells, which envelop all axons, whether myelinated or not, are the local sources of replacement and repair macromolecules for long axons. The plausibility of this hypothesis is reinforced by reviewing several decades of work on glia-axon macromolecular transfer, together with recent investigations of exosomes and other extracellular vesicles, as vehicles for the transmission of membrane and cytoplasmic components from one cell to another. PMID- 26962448 TI - Activation of intracellular calcium signaling in osteoblasts colocalizes with the formation of post-yield diffuse microdamage in bone matrix. AB - Previous studies demonstrated that extracellular calcium efflux ([Ca(2+)]E) originates from the regions of bone extracellular matrix that are undergoing microdamage. Such [Ca(2+)]E is reported to induce the activation of intracellular calcium signaling ([Ca(2+)]I) in MC3T3-E1 cells. The current study investigated the association between microdamage and local activation of intracellular calcium signaling quantifiably in MC3T3-E1 cells. Cells were seeded on devitalized notched bovine bone samples to induce damage controllably within the field of observation. A sequential staining procedure was implemented to stain for intracellular calcium activation followed by staining for microdamage on the same sample. The increase in [Ca(2+)]I fluorescence in cells of mechanically loaded samples was greater than that of unloaded negative control cells. The results showed that more than 80% of the cells with increased [Ca(2+)]I fluorescence were located within the damage zone. In conclusion, the findings demonstrate that there are spatial proximity between diffuse microdamage induction and the activation of intracellular calcium ([Ca(2+)]I) signaling in MC3T3-E1 cells. The downstream responses to the observed activation in future research may help understand how bone cells repair microdamage. PMID- 26962445 TI - Particulate air pollution and impaired lung function. AB - Air pollution is a leading cause of morbidity and mortality throughout the world, particularly in individuals with existing lung disease. Of the most common air pollutants, particulate matter (PM) is associated with an increased risk of exacerbations and respiratory symptoms in individuals with existing lung disease, and to a lesser extent, in those without known respiratory issues. The majority of published research has focused on the effects of PM exposures on symptoms and health care utilization. Fewer studies focus on the impact of PM on objective measurements of pulmonary function. This review will focus on the effects of PM exposure on objective measurements of lung function in both healthy individuals and those with existing lung disease. PMID- 26962447 TI - Prevalence, risk factors and molecular epidemiology of highly resistant gram negative rods in hospitalized patients in the Dutch region Kennemerland. AB - BACKGROUND: This paper describes (1) the Highly Resistant Gram Negative Rod (HR GNR) prevalence rate, (2) their genotypes, acquired resistance genes and (3) associated risk factors of HR-GNR colonization among the hospitalized population in the Dutch region Kennemerland. METHODS: Between 1 October 2013 and 31 March 2014, cross-sectional prevalence measurements were performed in three regional hospitals as part of each hospitals infection control program. Rectal swabs were analyzed at the Regional Public Health Laboratory Kennemerland by direct culturing. Genotypes and acquired resistance genes of positive isolates were determined using Whole Genome Sequencing with the MiSeq instrument (Illumina). Association between several independent variables and HR-GNR positivity was examined using logistic regression models. RESULTS: Out of 427 patients, 24 HR GNR positive isolates were recovered from 22 patients, resulting in a regional HR GNR colonization prevalence (95 % CI) of 5.2 % (3.6-7.9). Of these 22 positive patients, 15 were Extended Spectrum Beta-Lactamase (ESBL) positive (3.5 % (2.1 5.7)), 7 patients were positive for a Fluoroquinolones and Aminoglycosides (Q&A) resistant Enterobacteriaceae (1.6 % (0.8-3.3)) and from one patient (0.2 % (0 1.3)) a Stenotrophomonas maltophilia resistant towards co-trimoxazole was isolated. No carbapenemase producing Enterobacteriaceae (CPE), multi-resistant Acinetobacter species or multi-resistant Pseudomonas aeruginosa were isolated. The ESBL genes found were bla CTX-M-1 (n = 4, 25.0 %), bla CTX-M-15 (n = 3, 18.8 %), bla CTX-M-27 (n = 2, 12.5 %), bla CTX-M-14b (n = 2, 12.5 %), bla CTX-M-9 (n = 2, 12.5 %), bla CTX-M-14 (n = 1, 6.3 %), bla CTX-M-3 (n = 1, 6.3 %), bla SHV-11 (n = 1, 6.3 %) and bla SHV-12 (n = 1, 6.3 %). Being known HR-GNR positive in the past was the only significant associated risk factor for HR-GNR positivity, odds ratio (95 % CI): 7.32 (1.82-29.35), p-value = 0.005. CONCLUSIONS: Similar ESBL prevalence rates and genotypes (3.5 %) were found in comparison to other Dutch studies. When previously HR-GNR positive patients are readmitted, they should be screened for HR-GNR colonization since colonization with GR-GNRs could be prolonged. We recommend for future studies to include all defined HR-GNRs in addition to ESBLs in prevalence studies, in order to obtain a more comprehensive overview of colonization with HR-GNRs. PMID- 26962449 TI - TBS and bone strength. PMID- 26962450 TI - Therapeutic actions of curcumin in bone disorders. AB - Curcumin is the active component of turmeric extract derived from the Curcuma longa plant. In the last decade, curcumin has raised a considerable interest in medicine owing to its negligible toxicity and multiple therapeutic actions including anti-cancer, anti-inflammatory and anti-microbial activities. Among the various molecular targets of curcumin, some are involved in bone remodeling, which strongly suggests that curcumin can affect the skeletal system. The review sheds light on the current and potential applications of curcumin to treat bone disorders characterized by an excessive resorption activity. Within the scope of this review, the novel formulations of curcumin to overcome its physico-chemical and pharmacokinetic constraints are also discussed. PMID- 26962451 TI - Peripartal rumen-protected methionine supplementation to higher energy diets elicits positive effects on blood neutrophil gene networks, performance and liver lipid content in dairy cows. AB - BACKGROUND: Main objectives were to determine to what extent Smartamine M (SM) supplementation to a prepartal higher-energy diet could alter neutrophil (PMN) and liver tissue immunometabolic biomarkers, and whether those responses were comparable to those in cows fed a prepartal lower-energy diet (CON). RESULTS: Twenty-eight multiparous Holstein cows were fed CON (NEL = 1.24 Mcal/kg DM) during d -50 to d -22 relative to calving. From d -21 to calving, cows were randomly assigned to a higher-energy diet (OVE, n = 9; NEL = 1.54 Mcal/kg DM), OVE plus SM (OVE + SM, n = 10; SM = 0.07 % of DM) or remained on CON (n = 9). All cows received the same basal lactation diet (NEL = 1.75 Mcal/kg DM). Supplementation of SM (OVE + SM) continued until 30 d postpartum. Liver biopsies were harvested at d -10, 7, and 21 relative to parturition. Blood PMN isolated at -10, 3, and 21 d relative to calving was used to evaluate gene expression. As expected, OVE increased liver lipid content postpartum; however, cows fed OVE + SM or CON had lower concentrations than OVE. Compared with OVE, cows in CON and OVE + SM had greater DMI postpartum and milk production. Furthermore, cows fed OVE + SM had the greatest milk protein and fat percentage and lowest milk SCC despite having intermediate PMN phagocytic capacity. Adaptations in PMN gene expression in OVE + SM cows associated with the lower SCC were gradual increases from -10 to 21 d in genes that facilitate migration into inflammatory sites (SELL, ITGAM), enzymes essential for reducing reactive oxygen metabolites (SOD1, SOD2), and a transcription factor(s) required for controlling PMN development (RXRA). The greater expression of TLR4 on d 3, key for activation of innate immunity due to inflammation, in OVE compared with CON cows suggests a more pronounced inflammatory state. Feeding OVE + SM dampened the upregulation of TLR4, despite the fact that these cows had similar expression of the pro inflammatory genes NFKB1 and TNF as OVE. Cows in CON had lower overall expression of these inflammation-related genes and GSR, which generates reduced glutathione, an important cellular antioxidant. CONCLUSIONS: Although CON cows appeared to have a less stressful transition into lactation, SM supplementation was effective in alleviating negative effects of energy-overfeeding. As such, SM was beneficial in terms of production and appeared to boost the response of PMN in a way that improved overall cow health. PMID- 26962452 TI - Warburg effect(s)-a biographical sketch of Otto Warburg and his impacts on tumor metabolism. AB - Virtually everyone working in cancer research is familiar with the "Warburg effect", i.e., anaerobic glycolysis in the presence of oxygen in tumor cells. However, few people nowadays are aware of what lead Otto Warburg to the discovery of this observation and how his other scientific contributions are seminal to our present knowledge of metabolic and energetic processes in cells. Since science is a human endeavor, and a scientist is imbedded in a network of social and academic contacts, it is worth taking a glimpse into the biography of Otto Warburg to illustrate some of these influences and the historical landmarks in his life. His creative and innovative thinking and his experimental virtuosity set the framework for his scientific achievements, which were pioneering not only for cancer research. Here, I shall allude to the prestigious family background in imperial Germany; his relationships to Einstein, Meyerhof, Krebs, and other Nobel and notable scientists; his innovative technical developments and their applications in the advancement of biomedical sciences, including the manometer, tissue slicing, and cell cultivation. The latter were experimental prerequisites for the first metabolic measurements with tumor cells in the 1920s. In the 1930s 1940s, he improved spectrophotometry for chemical analysis and developed the optical tests for measuring activities of glycolytic enzymes. Warburg's reputation brought him invitations to the USA and contacts with the Rockefeller Foundation; he received the Nobel Prize in 1931. World politics and world wars heavily affected Warburg's scientific survival in Berlin. But, after his second postwar recovery, Warburg's drive for unraveling the energetic processes of life, both in plants and in tumor cells, continued until his death in 1970. The legacy of Otto Warburg is not only the Warburg effect, but also the identification of the "respiratory ferment" and hydrogen-transferring cofactors and the isolation of glycolytic enzymes. His hypothesis of respiratory damage being the cause of cancer remains to be a provocative scientific issue, along with its implications for cancer treatment and prevention. Warburg is therefore still stimulating our thinking, as documented in a soaring increase in publications citing his name in the context of tumor metabolism. PMID- 26962454 TI - Intraperitoneal adipose tissue is strongly related to survival rate in a mouse cecal ligation and puncture model. AB - Cecal ligation and puncture (CLP) models exhibiting polymicrobial sepsis are considered as the gold standard in sepsis research. However, despite meticulous research being conducted in this field, only few treatment drugs are available, indicating that CLP sepsis models do not completely mimic human sepsis models. The greatest flaw in CLP models is abscess formation because the localization of inflammation caused by abscess formation increases the survival rate. Therefore, by resecting intraperitoneal adipose tissue, we developed a mouse CLP model wherein abscess formation was unlikely. Survival rates at 7 days postoperatively were compared using the Kaplan-Meier method for an intraperitoneal adipose tissue resection group (resection group, n=34), an intraperitoneal adipose tissue non resection group (non-resection group, n=35) and a sham group (n=10). Results indicated that the survival rate was significantly higher in the non-resection group compared with the resection group. Intraperitoneal macroscopic findings in the non-resection group revealed the localization of inflammation caused by abscesses formation covered in adipose tissue. The survival rate for the sham group was 100%. Measurement of interleukin 6 (IL-6) indicated that during the 12 h after the creation of the CLP model, the median level of IL-6 was 1300 (552 3000) pg ml(-1) in the non-resection group (n=19) and 3000 (1224-8595) pg ml(-1) in the resection group (n=19). Meanwhile, for the sham group, IL-6 values were below measurement sensitivity in most cases (9/10 mice). Thus our results suggest that, in CLP models, intraperitoneal adipose tissue has an important role in abscess formation and is strongly related to the survival rate. PMID- 26962455 TI - 'Feelings stronger than reason': conflicting experiences of exercise in women with anorexia nervosa. AB - BACKGROUND: Individuals with anorexia nervosa frequently feel ambivalent about treatment and weight restoration, and drop out and relapse rates in treatment are high. Increased insight into the function of the eating disorder is considered essential for achieving long-lasting, meaningful change. However, research investigating the functions of anorexia nervosa tends to focus on the role of the disease per se. Distinctions are rarely made across features. In particular, the subjective experience, understanding and sense making of the engagement in compulsive exercise in individuals with anorexia nervosa has received little attention. By using a qualitative methodological approach, this paper aims to expand on prior findings by examining how patients with anorexia nervosa understand and make sense of the experience of exercise in the context of their lives and treatment programme. METHODS: Semi-structured interviews were conducted with six females, four of whom were former athletes. Transcripts were subjected to interpretative phenomenological analysis (IPA). RESULTS: Two overarching themes emerged in the analysis of the larger study of which this paper is a part; 'paradoxical functions of exercise' and 'diverging experiences of exercise'. Diverging experiences of exercise is the focus of this paper. Firstly, in spite of being severely underweight and suffering from exhaustion, as well as having a clear awareness of the associated negative health effects, participants were engaged in a continuous cycle of rigorous and excessive exercise, which consumed extensive amounts of time and energy. Secondly, the results demonstrate how exercise routines negatively control and interfere with the participants' involvement in the social world. Thirdly, the manner in which participants speak about their exercise reveals their wording to be characterized by efforts to downplay the extent of their actual immersion in exercise. Issues of control and ambivalence about treatment and recovery can be considered potential triggers for the participants' engagement with exercise. Implicit meanings are elaborated upon and discussed in relation to existing literature. CONCLUSIONS: The material provides increased insight into the multi-layered meanings of exercise for individuals with anorexia nervosa. It also suggests alternatives to current ways of understanding and approaching exercise that may enable this issue to be addressed in a more meaningful way in therapy. Qualitative approaches can make a valuable contribution to furthering such understanding. PMID- 26962457 TI - Trends in research on indoor radon exposure and lung cancer in South Korea. PMID- 26962453 TI - Involvement of B cells in non-infectious uveitis. AB - Non-infectious uveitis-or intraocular inflammatory disease-causes substantial visual morbidity and reduced quality of life amongst affected individuals. To date, research of pathogenic mechanisms has largely been focused on processes involving T lymphocyte and/or myeloid leukocyte populations. Involvement of B lymphocytes has received relatively little attention. In contrast, B-cell pathobiology is a major field within general immunological research, and large clinical trials have showed that treatments targeting B cells are highly effective for multiple systemic inflammatory diseases. B cells, including the terminally differentiated plasma cell that produces antibody, are found in the human eye in different forms of non-infectious uveitis; in some cases, these cells outnumber other leukocyte subsets. Recent case reports and small case series suggest that B-cell blockade may be therapeutic for patients with non infectious uveitis. As well as secretion of antibody, B cells may promote intraocular inflammation by presentation of antigen to T cells, production of multiple inflammatory cytokines and support of T-cell survival. B cells may also perform various immunomodulatory activities within the eye. This translational review summarizes the evidence for B-cell involvement in non-infectious uveitis, and considers the potential contributions of B cells to the development and control of the disease. Manipulations of B cells and/or their products are promising new approaches to the treatment of non-infectious uveitis. PMID- 26962456 TI - Attitude and satisfaction of health care providers towards clinical pharmacy services in Ethiopia: A post-deployment survey. AB - BACKGROUND: Clinical pharmacy service has evolved steadily over the past few decades and is contributing to the 'patient care journey' at all stages. The service improves safety and effectiveness of medicines, thereby avoiding medication errors. As part of this global shift in pharmacy education and practice, Ethiopian Universities revamped the undergraduate pharmacy curriculum and the first graduates came out in July 2013. These graduates were immediately deployed in public hospital settings, with the ultimate aim of providing clinical pharmacy services. As such an initiative is new to the Ethiopian pharmacy sector, there is a need to do assessment of the health care providers' perception and satisfaction towards the service. METHODS: A cross-sectional survey using self administered questionnaire was conducted in six regions and one-city administration of the country. Physicians, Health officers and Nurses working along with the new pharmacy graduates formed the study population. A total of 650 healthcare professionals participated in the study. Data were entered, cleaned and analyzed using appropriate statistical tools. RESULTS: Majority of the health care providers agreed that clinical pharmacy service could have a significant contribution to the patient care. A large proportion of them (70-90 %) had a positive attitude, although there appeared to be some differences across professions. About 50 % of the professionals were of the opinion that patient care should be left to the health care providers and pharmacists should concentrate on drug products. In addition, the same proportion of respondents said that the setup in their respective hospital was appropriate for provision of clinical pharmacy service. Multivariable analysis indicated that attitude of the health care providers was significantly associated with year of experience. CONCLUSIONS: A large proportion of the health care providers had positive attitude towards the service, although the extent of the service was below their expectation. Hence, efforts should be in place to organize continuous professional training for pharmacists and awareness creation forums for other healthcare professionals. PMID- 26962458 TI - Radon exposure and lung cancer: risk in nonsmokers among cohort studies. AB - Eleven cohorts of miners occupationally exposed to relatively high concentrations of radon showed a statistically significantly high risk of lung cancer, while three cohorts from the general population showed a relatively low concentration, but the results were not statistically significant. However, the risk of lung cancer tended to increase with increased radon exposure. The risk is likely to have been underestimated due to low statistical power. Therefore, additional well designed studies on the risk of lung cancer in nonsmokers in the general population with relatively low concentrations of radon exposure are needed in the future. In addition, country-specific preventive policies are needed in order to actively reduce radon exposure and lung cancer incidence in nonsmokers. PMID- 26962459 TI - Determinants of overweight or obesity among ever-married adult women in Bangladesh. AB - BACKGROUND: The prevalence of overweight and obesity is increasing in Bangladesh. It is higher among Bangladeshi women than among men. This study was conducted to assess a host of demographic and socioeconomic correlates of overweight and obesity, separately for the urban and rural women of Bangladesh. METHODS: We used data from the Bangladesh Demographic and Health Survey (BDHS) 2011. The BDHS provides cross-sectional data on a wide range of indicators relating to population, health, and nutrition. We analyzed nutrition-related data to identify the factors associated with being overweight or obese among ever-married women aged 18-49 years. RESULTS: Of 16,493 women, about 18 % (95 % CI 17 . 80-18 . 99) were overweight or obese. Unemployed urban women were at 1 . 44 (95 % CI 1 . 18-1 . 76, p < 0 . 001) times higher risk of being overweight or obese than those women who were involved in manual-labored work. Watching television at least once a week was another significant predictor among urban women (OR 1 . 49; 95 % CI 1 . 24-1 . 80; p < 0 . 001) and rural women (OR 1 . 31; 95 % CI 1 . 14-1 . 51; p < 0 . 001). Household wealth index and food security were also strongly associated with overweight or obesity of both rural and urban women. CONCLUSIONS: The findings of the study indicate that a large number of women in Bangladesh are suffering from being overweight or obese, and multiple factors are responsible for this including, older age, being from wealthy households, higher education, being from food-secured households, watching TV at least once a week, and being an unemployed urban woman. Given the anticipated long-term effects, the factors that are associated with being overweight or obese should be considered while formulating an effective intervention for the women of Bangladesh. PMID- 26962461 TI - Contrast-enhanced synthetic MRI for the detection of brain metastases. AB - BACKGROUND: Synthetic magnetic resonance imaging (MRI), a technique that enables creation of various contrast-weighted images from a single MRI quantification scan, is a useful clinical tool. However, there are currently no reports examining the use of contrast-enhanced synthetic MRI for detecting brain metastases. PURPOSE: To assess whether contrast-enhanced synthetic MRI is suitable for detecting brain metastases. MATERIAL AND METHODS: Ten patients with a combined total of 167 brain metastases who underwent quantitative MRI and conventional T1-weighted inversion recovery fast spin-echo (conventional T1IR) MRI before and after administration of a contrast agent were included in the study. Synthetic T1IR and T1-weighted (synthetic T1W) images were produced after parameter quantification. Lesion-to-white matter contrast and contrast-to-noise ratio were calculated for each image. The number of visible lesions in each image was determined by two neuroradiologists. RESULTS: The mean lesion-to-white matter contrast and mean contrast-to-noise ratio of the synthetic T1IR images were significantly higher than those of the synthetic T1W (P < 0.001 and P < 0.001, respectively) and conventional T1IR (P = 0.04 and P = 0.002, respectively) images. Totals of 130 and 124 metastases were detected in the synthetic T1IR images by the first and second radiologists, respectively. The corresponding numbers were 91 and 85 in the synthetic T1W images and 119 and 119 in the conventional T1IR images. Statistical significance was not found among detected numbers of lesions. CONCLUSION: Synthetic T1IR imaging created better contrast compared with synthetic T1W or conventional T1IR imaging. The ability to detect brain metastases was comparable among these imaging. PMID- 26962460 TI - Ocular blood flow and cerebrospinal fluid pressure in glaucoma. AB - Disease mechanism underlying glaucoma remains unclear. Extensive research on this pathology has highlighted changes in vascular parameters and in circulation of the cerebrospinal fluid (CSF). Here, we review the most recent research on alterations in ocular blood flow and/or CSF flow in glaucoma. Ultrasound Doppler imaging studies have shown an increased resistive index in ophthalmic artery's in glaucoma. Furthermore, changes in optic nerve CSF circulation, which can be assessed with magnetic resonance imaging, may lead to a greater translaminar pressure difference, mechanical stress, and poor clearance of toxic substances. This constitutes a new approach for understanding blood-CSF interactions involved in glaucoma. PMID- 26962462 TI - Spontaneous brain tumor imaging of aged rat by crystal X-ray interferometer-based phase-contrast X-ray CT. AB - BACKGROUND: Crystal X-ray interferometer-based phase-contrast X-ray computed tomography (C-PCCT) enables the depiction of internal structures of biological tissue without contrast agents. PURPOSE: To determine the advantage of this technique in visualizing detailed morphological structures of a rare spontaneous brain tumor in an aged rat. MATERIAL AND METHODS: An aged rat's spontaneous brain tumor was imaged by C-PCCT without contrast agent. Three-dimensional (3D) images of the tumor microvasculature were reconstructed and compared with pathological pictures. RESULTS: C-PCCT depicted the tumor's various pathological features clearly, e.g. its cell density and vasculature, and blood clots caused by hemorrhaging and/or hematomas. The obtained images resembled pathological pictures with a magnification of *20 and were used to reconstruct 3D images of the tumor vascularity up to approximately 26 um in diameter. CONCLUSION: Since C PCCT is able to depict various pathological conditions, it might be useful for cancer research. PMID- 26962463 TI - Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model. AB - Accumulating evidence indicates that microglial TLR2 and TLR4 play a significant role in nociception. Experiments were conducted to evaluate the contribution of TLR2 and TLR4 and their adaptor molecules to neuropathy and their ability to amplify opioid effectiveness. Behavioral tests (von Frey's and cold plate) and biochemical (Western blot and qRT-PCR) analysis of spinal cord and DRG tissue were conducted after chronic constriction injury (CCI) to the sciatic nerve. Repeated intrathecal administration of LPS-RS (TLR2 and TLR4 antagonist) and LPS RS Ultrapure (TLR4 antagonist) attenuated allodynia and hyperalgesia. Biochemical analysis revealed time-dependent upregulation of mRNA and/or protein levels of TLR2 and TLR4 and MyD88 and TRIF adaptor molecules, which was paralleled by an increase in IBA-1/CD40-positive cells under neuropathy. LPS-RS and LPS-RS Ultrapure similarly influenced opioid analgesia by enhancing the effectiveness of buprenorphine but not morphine. Summing up, in light of their upregulation over the course of pain, both TLR2 and TLR4 may indeed play a significant role in neuropathy, which could be linked to the observed activation of IBA-1/CD40 positive cells. Blockade of TLR2 and TLR4 produced analgesia and enhanced buprenorphine's effectiveness, which suggests that they may be a putative target for future pharmacological pain relief tools, especially for opioid rotation, when the effect of morphine is tolerated. PMID- 26962465 TI - Characterization of genetically engineered mouse models carrying Col2a1-cre induced deletions of Lrp5 and/or Lrp6. AB - Mice carrying Collagen2a1-cre-mediated deletions of Lrp5 and/or Lrp6 were created and characterized. Mice lacking either gene alone were viable and fertile with normal knee morphology. Mice in which both Lrp5 and Lrp6 were conditionally ablated via Collagen2a1-cre-mediated deletion displayed severe defects in skeletal development during embryogenesis. In addition, adult mice carrying Collagen2a1-cre-mediated deletions of Lrp5 and/or Lrp6 displayed low bone mass suggesting that the Collagen2a1-cre transgene was active in cells that subsequently differentiated into osteoblasts. In both embryonic skeletal development and establishment of adult bone mass, Lrp5 and Lrp6 carry out redundant functions. PMID- 26962466 TI - Neurosurgery concepts: Key perspectives on embolectomy for stroke with emergent large vessel occlusion (MR CLEAN), endonasal endoscopic craniopharyngioma resection, gamma knife radiosurgery for meningiomas, therapeutic hypothermia for severe traumatic brain injury. PMID- 26962467 TI - Analysis of sphenoid sinus lateral pneumatization for endonasal endoscopic surgery. AB - BACKGROUND: The purpose of this study was to analyze sphenoid sinus lateral pneumatization (SSLP), especially in Asian populations, and to identify cautionary items when using the endoscopic endonasal approach (EEA) for parasellar/lateral lesions. METHODS: We analyzed SSLP and the width of SS (SSW) in 121 patients who had undergone EEA from 2008 to 2013 at the Division of Neurosurgery, Keio University Hospital. SSLP was defined as the distance between the SS lateral edge and the medial aspect of the pterygoid process on coronal reconstruction computed tomography. SSW was defined as the distance between the midline and lateral wall. We recorded SSLP and SSW for 242 sides. Further, we present two characteristic cases. RESULTS: The average SSLP and SSW were 7.0 mm ( 10.0-25.8 mm) and 21.8 mm (6.0-40.2 mm), respectively. No correlation between pneumatization and age was observed at age 15 or more. Sphenoid pneumatization was significantly wider in male than in female patients. There was no relationship between lateral and sagittal plane pneumatization. In a patient with recurrent chordoma who had an undeveloped SSLP, the tumor was removed via the medial space in the internal carotid artery. In another patient who had a giant pituitary adenoma and average SSLP, the tumor was located in the middle cranial fossa and was removed via the lateral internal carotid space through the left SSLP. CONCLUSIONS: Wide variations were observed in SSLP and SSW. For EEA, pneumatization is an instrument corridor. Preoperative assessment of SSLP is important, especially for parasellar lesions. PMID- 26962468 TI - Intra-bronchial migration of peritoneal catheter of lumboperitoneal shunt. AB - BACKGROUND: A rare case of intra-bronchial migration of peritoneal catheter of lumboperitoneal (LP) shunt was treated under the bronchoscopic and fluoroscopic observation. CASE DESCRIPTION: A 71-year-old man, who underwent LP shunt installation due to idiopathic normal pressure hydrocephalus a year before, presented with history of high fever and sputum production. Roentgenography and computed tomography of the chest revealed migration of distal end of the peritoneal catheter into the left main bronchus. Migrated catheter was gently extracted through the abdominal wound incision under the bronchoscopic and fluoroscopic observation. Contrast material infused into the catheter did not spread into the pleural cavity. The patient was free of the symptoms within 2 postoperative weeks. Moreover, he underwent the ventriculo-peritoneal shunt surgery 1-month later. CONCLUSION: This is the first case of the migration of peritoneal catheter of LP shunt into the main bronchus. PMID- 26962469 TI - Macrophage Polarization: Decisions That Affect Health. PMID- 26962464 TI - Current research on pharmacologic and regenerative therapies for osteoarthritis. AB - Osteoarthritis (OA) is a degenerative joint disorder commonly encountered in clinical practice, and is the leading cause of disability in elderly people. Due to the poor self-healing capacity of articular cartilage and lack of specific diagnostic biomarkers, OA is a challenging disease with limited treatment options. Traditional pharmacologic therapies such as acetaminophen, non-steroidal anti-inflammatory drugs, and opioids are effective in relieving pain but are incapable of reversing cartilage damage and are frequently associated with adverse events. Current research focuses on the development of new OA drugs (such as sprifermin/recombinant human fibroblast growth factor-18, tanezumab/monoclonal antibody against beta-nerve growth factor), which aims for more effectiveness and less incidence of adverse effects than the traditional ones. Furthermore, regenerative therapies (such as autologous chondrocyte implantation (ACI), new generation of matrix-induced ACI, cell-free scaffolds, induced pluripotent stem cells (iPS cells or iPSCs), and endogenous cell homing) are also emerging as promising alternatives as they have potential to enhance cartilage repair, and ultimately restore healthy tissue. However, despite currently available therapies and research advances, there remain unmet medical needs in the treatment of OA. This review highlights current research progress on pharmacologic and regenerative therapies for OA including key advances and potential limitations. PMID- 26962470 TI - The Metabolic Prospective and Redox Regulation of Macrophage Polarization. AB - Macrophage plasticity is an important feature of these innate immune cells. Macrophage phenotypes are divided into two categories, the classically activated macrophages (CAM, M1 phenotype) and the alternatively activated macrophages (AAM, M2 phenotype). M1 macrophages are commonly associated with the generation of proinflammatory cytokines, whereas M2 macrophages are anti-inflammatory and often associated with tumor progression and fibrosis development. Macrophages produce high levels of reactive oxygen species (ROS). Recent evidence suggests ROS can potentially regulate macrophage phenotype. In addition, macrophages phenotypes are closely related to their metabolic patterns, particularly fatty acid/cholesterol metabolism. In this review, we briefly summarize recent advances in macrophage polarization with special attention to their relevance to specific disease conditions and metabolic regulation of polarization. Understanding these metabolic switches can facilitate the development of targeted therapies for various diseases. PMID- 26962471 TI - Comparison of Two Methods of Estradiol Replacement: their Physiological and Behavioral Outcomes. AB - Fluctuating sex steroids during the estrous or menstrual cycle of mammalian females make it difficult to determine their role on behaviors and physiology. To avoid this, many investigators ovariectomize their animals and administer progesterone, estradiol or a combination of both. Several different strategies are used to administer estradiol, which confounds interpretation of results. This study compared two methods of estradiol replacement implants: Silastic tubes filled with crystalline estradiol benzoate (E2) and commercially available estradiol benzoate pellets. Implants were placed subcutaneously in adult ovariectomized (OVX) rats and blood samples obtained weekly. Control OVX rats received empty Silastic tubes or placebo pellets. Our data shows that E2 plasma levels from rats with Silastic implants peaked after one week and decreased slowly thereafter. In contrast, plasma E2 from commercial pellets peaked after two weeks, increasing and decreasing over time. To validate hormone release, body weight was monitored. All E2 treated animals maintained a similar body weight over the four weeks period whereas an increase in body weight over time was observed in the OVX group that received empty implants, confirming E2 release and supporting the role of E2 in the regulation of body weight. Furthermore, the effects of E2 on basal locomotor activity were assessed using animal activity cages. Results showed no difference between E2 and control group in several locomotor activities. These results indicate that Silastic implants achieve more stable plasma estradiol levels than pellets and thus are a better alternative for studies of estradiol on brain function and behavior. PMID- 26962473 TI - Fracture Forces of Dentin after Surface Treatment with High Speed Drill Compared to Er:YAG and Er,Cr:YSGG Laser Irradiation. AB - Dental tooth restorative procedures may weaken the structural integrity of the tooth, with the possibility of leading to fracture. In this study we present findings of coronal dentin strength after different techniques of surface modification. The fracture strength of dentin beams after superficial material removal with a fine diamond bur high speed drill hand piece, Er:YAG (2.94 MUm, 8 J/cm(2)), and Er,Cr:YSGG (2.78 MUm, 7.8 J/cm(2)) laser irradiation slightly above the ablation threshold was measured by a four-point bending apparatus. Untreated dentin beams served as a control. A total of 58 dentin beams were manufactured from sterilized human extracted molars using the coronal part of the available dentin. Mean values of fracture strength were calculated as 82.0 +/- 27.3 MPa for the control group (n = 10), 104.5 +/- 26.3 MPa for high speed drill treatment (n = 10), 96.1 +/- 28.1 MPa for Er,Cr:YSGG laser irradiation (n = 20), and 89.1 +/- 36.3 MPa for Er:YAG laser irradiation (n = 18). Independent Student's t-tests showed no significant difference between each two groups (p > 0.05). Within the parameter settings and the limits of the experimental setup used in this study, both lasers systems as well as the high speed drill do not significantly weaken coronal dentin after surface treatment. PMID- 26962472 TI - Special Considerations for Measuring Energy Expenditure with Doubly Labeled Water under Atypical Conditions. AB - The global increase in the prevalence of obesity has dramatically increased interest in understanding the factors that influence human total energy expenditure (TEE). This in turn has increased interest in the doubly labeled water (DLW) method, a technique for measurement of total energy expenditure in free-living humans. The increasing use of this method is attributed to its portability, objectivity, minimal invasiveness, high accuracy and good precision. Although a relatively standard protocol for the method has emerged, the new generation of users often is unfamiliar with rationale behind aspects of the protocol as well as the approaches to avoid or correct for in situations that are not covered by the standard protocol procedure. The primary uncommon situations like introduction of isotopically different diet and fluids with or without geographical relocation, seasonal and temperature variations, activity level of participants etc. during or prior to the DLW measurements can lead to shift in baseline abundance of 2H and 18O or tracer elimination, resulting in moderate to large errors in the measured TEE. These unique situations call for special modifications to the conventional protocol to minimize errors. The objective of the present review was to assemble a list of frequently asked questions and the issues they represent, and then examine the available literature to describe and explain the modifications to the standard DLW protocol to maintain the method's accuracy. This discussion of DLW protocol modification can be an excellent resource for investigators who intend to use this measurement technique for interesting and uncommon study designs. PMID- 26962474 TI - Burkholderia pseudomallei: First case of melioidosis in Portugal. AB - Burkholderia pseudomallei is a Gram-negative bacillus and the causative agent of melioidosis, a serious infection associated with high mortality rate in humans. It can be naturally found as an environmental saprophyte in soil or stagnant water, and rice paddies that predominate in regions of endemicity such as Northeast Thailand. B. pseudomallei is a Biosafety Level 3 organism due to risks of aerosolization and severe disease and is now included in formal emergency preparedness plans and guidelines issued by various authorities in the United States and Europe. Here, we report the first case of imported melioidosis in Portugal. B. pseudomallei was isolated from the patient's blood as well as from a left gluteal abscess pus. The isolate strain showed the unusual resistance profile to first-line eradication therapy trimethroprim/sulfamethoxazole. Whole genome sequencing revealed its similarity with isolates from Southeast Asia, suggesting the Thai origin of this Portuguese isolate, which is in agreement with a recent patient's travel to Thailand. PMID- 26962476 TI - It Is Time to Pay More Attention to Sperm Cryopreservation: Now More Than Ever! PMID- 26962475 TI - Increased utilisation of PEPFAR-supported laboratory services by non-HIV patents in Tanzania. AB - BACKGROUND: It is unknown to what extent the non-HIV population utilises laboratories supported by the President's Emergency Plan for AIDS Relief (PEPFAR). OBJECTIVES: We aimed to describe the number and proportion of laboratory tests performed in 2009 and 2011 for patients referred from HIV and non-HIV services (NHSs) in a convenience sample collected from 127 laboratories supported by PEPFAR in Tanzania. We then compared changes in the proportions of tests performed for patients referred from NHSs in 2009 vs 2011. METHODS: Haematology, chemistry, tuberculosis and syphilis test data were collected from available laboratory registers. Referral sources, including HIV services, NHSs, or lack of a documented referral source, were recorded. A generalised linear mixed model reported the odds that a test was from a NHS. RESULTS: A total of 94 132 tests from 94 laboratories in 2009 and 157 343 tests from 101 laboratories in 2011 were recorded. Half of all tests lacked a documented referral source. Tests from NHSs constituted 42% (66 084) of all tests in 2011, compared with 31% (29 181) in 2009. A test in 2011 was twice as likely to have been referred from a NHS as in 2009 (adjusted odds ratio: 2.0 [95% confidence interval: 2.0-2.1]). CONCLUSION: Between 2009 and 2011, the number and proportion of tests from NHSs increased across all types of test. This finding may reflect increased documentation of NHS referrals or that the laboratory scale-up originally intended to service the HIV-positive population in Tanzania may be associated with a 'spillover effect' amongst the general population. PMID- 26962477 TI - An Evaluation of the Historical Importance of Fertility and Its Reflection in Ancient Mythology. AB - Myths are reflective of human concerns and needs during ancient times. By reviewing them, it turns out that many human problems today, have a historical background. Among the main themes of ancient mythologies, fertility and reproduction have various representations in ancient civilizations. The purpose of this paper was to review myths and common symbols of fertility and reproduction in ancient civilizations and evaluate the reasons of their continuous importance in different cultures. The data in this review study was obtained by scrutinizing the related literature. The gathered data indicated the multiplicity and variety of fertility symbols in ancient myths. Most ancient fertility symbols were inspired by the nature and some of them like earth and water were common in mythology of different civilizations. Therefore, the symbols consolidate the concept of conformity between human reproductive concerns and the nature's necessities. PMID- 26962478 TI - Induction of Asherman's Syndrome in Rabbit. AB - BACKGROUND: Uterine synechiae or Asherman's syndrome is a condition that can cause infertility. The present experimental study was designed to establish the rabbit as an animal model for human Asherman's syndrome using the endometrial curettage. METHODS: In an experimental study, female adult rabbits (n=18) were randomly divided into intact and ovariectomized groups. One third of caudal part of both uteri was submitted to traumatic endometrial curettage. One group was simultaneously ovariectomized. The intact rabbits were artificially induced ovulation during 10 days after surgery. One third of cranial part of both uteri was selected as the control. Synechiae occurring, luminal area/total area (LA/TA), endometrial area/total area (EA/TA), myometrial and perimetrial area/total area (MPA/TA), endometrial area/uterine wall area (EA/UWA), and myometrial and perimetrial area/uterine wall area (MPA/UWA) ratios of both uteri in six subdivided groups (n=6) were analysed in curetted and intact control parts. On days 15, 30 and 45 following surgery by two-way ANOVA and LSD test (p<0.05). RESULTS: Histopathologic findings showed significant epithelial damage together with significant inflammatory reaction in the intact curettage group. The LA/TA ratios of the intact curettage group on days 15 and 45 were more than the intact control group on day 15. The EA/TA ratio of the intact curettage group on day 30 was less than the intact control group on day 30. CONCLUSION: Uterine fibrosis was observed in intact curettage group, and this modified animal model showed a pathogenesis condition similar to intrauterine adhesions observed in human. PMID- 26962479 TI - Male Sexual Dysfunction, Leptin, Pituitary and Gonadal Hormones in Nigerian Males with Metabolic Syndrome and Type 2 Diabetes Mellitus. AB - BACKGROUND: Pituitary and gonadal dysfunctions resulting from increased adiposity leading to disturbances of sexual and reproductive functions have been reported in males with metabolic syndrome (MS) and type 2 diabetes mellitus (DM2). The aim of this study was to evaluate sexual dysfunction, leptin, and reproductive hormones in Nigerian males with MS and DM2. METHODS: Participants were 104 men (34 males with DM2, 17 men with MS and 53 men with normal body mass index (18.5 24.9 Kg/m (2)) without MS (controls)). The International Diabetes Federation (2005) criteria were used for MS diagnosis. Reproductive history, anthropometry, blood pressure (BP) and 10 ml fasting blood samples were obtained by standard methods. Fasting plasma glucose, total cholesterol, triglycerides and high density lipoprotein cholesterol were determined by enzymatic methods while low density lipoprotein cholesterol was calculated. Leptin, follicle stimulating hormone (FSH), luteinising hormone (LH), prolactin, testosterone and oestrogen were determined by enzyme immunoassay (leptin by Diagnostic Automation, Inc.; others by Immunometrics (UK) Ltd.) while oestrogen-testosterone ratio was calculated. Data analyzed using ANOVA, Chi square and multiple regression were statistically significant at p<0.05. RESULTS: Testosterone was significantly lower in MS than controls while oestradiol and ETR were significantly higher in MS compared with controls and DM2 group (p<0.05). ETR significantly predicted testosterone in all groups (p<0.05). Significantly lower libido was observed in men in MS than controls and DM2 groups (p<0.05). CONCLUSION: Sexual and reproductive dysfunction may be related to increased conversion of testosterone to oestrogen in increased adipose mass in men with metabolic syndrome and type 2 diabetes mellitus. PMID- 26962480 TI - Sexual Dysfunction in Women Undergoing Fertility Treatment in Iran: Prevalence and Associated Risk Factors. AB - BACKGROUND: Sexual dysfunctions are one of the most fundamental difficulties for infertile women, which can be as the cause of infertility. This study investigated the prevalence of this disorder and associated factors in order to improve infertility treatment process and the quality of life of women referring to infertility center. METHODS: A cross sectional study was performed on 236 women who referred to Fatima Zahra infertility center of Babol, Iran. Data collection tool was a questionnaire contained two parts; demographic characteristics and infertility information. Also, data for sexual dysfunction was obtained through diagnostic interview based on the international classification DSM-IV. For data analysis, logistic and linear regression analysis were used. The p<0.05 was considered significant. RESULTS: Most of women (84.9%) suffered from primary infertility and the mean duration of infertility was 60.2+/ 8.4 months. The prevalence of sexual dysfunction was 55.5% (n=131); including dyspareunia in 28% (n=66), impaired sexual desire and lack of orgasm in 26.3% (n=62 patients), vaginismus in 15.2% (n=36) and lack of sexual stimulation in 13.6% (n=32). Binary logistic regression analysis showed that age, sexual satisfaction and history of mental illness had a significant effect on the probability of experiencing the sexual dysfunction. CONCLUSION: There is a high prevalence of sexual dysfunction among infertile women. Considering the interaction between sexual dysfunction and infertility, professional health care centers should be sensitive to this effect. Also, more attention must be paid on marital relationships, economic and social situation and infertility characteristics in order to prevent sexual dysfunction development through early screening and psychological interference. PMID- 26962481 TI - High Prevalence of Vitamin D Deficiency and Adverse Pregnancy Outcomes in Yazd, a Central Province of Iran. AB - BACKGROUND: There is a growing concern about the high prevalence of vitamin D deficiency and its relationship with variety of diseases worldwide. The objective of this study was to determine the prevalence of vitamin D deficiency and its relationship with pregnancy adverse effects in Yazd. METHODS: This was a cross sectional study conducted among 200 nulliparous women from October 2013 to April 2014. Data containing socio-demographic and personal details, vitamin D level, pregnancy complications and growth situation of newborns were collected and analyzed using Mann-Whitney, Kruskal-Wallis and Pearson's correlation coefficient by SPSS. p<0.05 was considered statistically significant. RESULTS: The mean serum 1, 25 (OH)2D3 concentration was 20.3+/-10.8 MUg/l. Totally, 78% of the women had less than sufficient levels. Mean of vitamin D was significantly higher in natural or elective cesarean in comparison with abortion and emergency cesarean (p=0.040). Risk of abortion was 3.1(1.39-6.8) and higher in severely deficient group in comparison to women with vitamin D deficiency (p=0.017) and mean of vitamin D group was significantly lower in women who had oligohydramnios or polyhydramnios complication (p=0.045). CONCLUSION: The study findings revealed that vitamin D deficiency is prevalent in pregnant women and it is significantly associated with elevated risk for abortion, and oligohydramnios or polyhydramnios. Probably, a targeted screening strategy can be suggested to detect and treat women at high risk of vitamin D deficiency in early pregnancy as a simple way to reduce the risk of these adverse pregnancy outcomes in Yazd. PMID- 26962482 TI - Comparison of the Effect of Dry Cupping Therapy and Acupressure at BL23 Point on Intensity of Postpartum Perineal Pain Based on the Short Form of McGill Pain Questionnaire. AB - BACKGROUND: Perineal pain is a major morbidity in the first few days after delivery. This study aimed to investigate the effect of dry cupping therapy and acupressure at BL23 point on the intensity of postpartum perineal pain based on the short-form of McGill pain questionnaire (SMPQ). METHODS: The present clinical trial was conducted on 150 subjects in 3 groups of 50 cases. After at least 4-8 hr of delivery, cupping therapy was performed for 15-20 min up to 3 times a week (once a day) and acupressure was performed for 15-20 min based on clockwise model. The short-form of McGill pain questionnaire was completed both before and after the intervention. The SPSS statistical software was used to analyze the data using repeated measures ANOVA. Besides, p<0.05 was considered statistically significant. RESULTS: In the cupping therapy group, mean of the perineal pain intensity reduced from 37.5+/-6.8 before the intervention to 11.1+/-6.1, 6.9+/ 4.7, and 3.8+/-3.6 immediately, 24 hr, and 2 weeks after the intervention, respectively. The results of study showed that the differences between the intervention and control groups were statistically significant (p<0.01). Mean difference of the perineal pain intensity in the acupressure group reached from 35.6+/-8.1 before the intervention to 10.4+/-5.5 two weeks after the intervention, so the variation between intervention and control groups was statistically significant. CONCLUSION: The study findings showed that cupping therapy and acupressure reduced perineal pain. Therefore, they may be considered as effective treatments for reducing pain intensity of allowing delivery. PMID- 26962483 TI - Attitudes About Sexual Activity Among Postmenopausal Women in Different Ethnic Groups: A Cross-sectional Study in Jahrom, Iran. AB - BACKGROUND: Sexual function is affected by personal and interpersonal factors, familial and social traditions, culture, religion, menopause, and aging. So, ethnicity is a determining factor in sexual function. The present study aimed to investigate the prevalence of sexual dysfunction and attitudes towards sexuality in postmenopausal women among three different ethnic groups in Iran. METHODS: This cross-sectional study was conducted on 746 postmenopausal women between 50 and 89 years who referred to Honoree clinic, Jahrom in 2013. Among the study participants, 42.4% were Arab, 33.5% were Persian, and 24.1% were Lor. Data were collected about women's socio-demographic characteristics, attitudes regarding sexuality and sexual function. The descriptive statistics were used for demographic variables. Moreover, ANOVA, post hoc (LSD) was used. Besides, p<0.05 was considered statistically significant. RESULTS: The participants' mean age was 60.10+/-6.89 years and the total mean score of Female Sexual Function Index (FSFI) was 19.31+/-8.5. In addition, 81.5% of the women had sexual dysfunction (FSFI <26.55) and only 147 women (18.5%) had normal sexual function (FSFI >26.55). Sexual dysfunction was 75.3% in Arabs, 83.2% in Persians, and 86.1% in Lors. Besides, the most prevalent sexual dysfunction was dyspareunia in Arabs and arousal disorder in Persians and Lors. CONCLUSION: The results of this study showed that sexual dysfunction is considerable among postmenopausal women. The most prevalent sexual dysfunction was dyspareunia in Arabs and arousal disorder in Persians and Lors. PMID- 26962484 TI - Studying the Relationship between the Attitude to Infertility and Coping Strategies in Couples Undergoing Assisted Reproductive Treatments. AB - BACKGROUND: Using appropriate coping strategies has a positive influence on moderating mental pressures caused by infertility and the stress during treatment. Using these strategies needs personal skills and they could be influenced by individual's inner psychological and environmental factors. The aim of this study was to assess the relationship between the attitude toward infertility and coping strategies considering the couple's social and financial situation. METHODS: This was a cross sectional study conducted on 133 volunteered couples undergoing assisted reproductive treatment. Coping strategies and the attitude toward infertility were assessed using a self-report questionnaire. Higher scores of attitude indicated positive attitudes. Data was analyzed using paired-samples t test and multiple regression model. RESULTS: Independent from demographic information and causes of infertility, using self-blame and self focused rumination coping strategies were negatively related to attitude toward infertility in both men and women (p<0.05). Also, using self-blame coping strategy had a positive correlation with female infertility and negative correlation with male infertility. CONCLUSION: Regardless of the economic and social conditions, in infertile couples, downward trend in attitude toward infertility is mostly associated with the use of maladaptive coping strategies. PMID- 26962485 TI - Frequency of Human Immunodeficiency Virus (HIV) in Trichomonas vaginalis Infected Women in Badagry, Lagos, Nigeria. AB - BACKGROUND: The interaction between HIV and Trichomonas vaginalis infection has been widely studied in most developed countries but with scanty information in sub-Saharan Africa. While many of these studies have examined the prevalence of T. vaginalis infection in HIV positive individuals, no study in Nigeria has shown the effect of T. vaginalis on HIV transmission. Therefore, the study aimed to determine the occurrence of HIV in T. vaginalis infected women. METHODS: A descriptive study was conducted among women attending STI clinic at the General Hospital, Badagry, Lagos, Nigeria. A total number of 201 (T. vaginalis infected) women were screened for HIV using rapid diagnostic test kits. RESULTS: The frequency of HIV in T. vaginalis infected women was 35.8%. CONCLUSION: The study showed that T. vaginalis infection in women may be a high risk factor of HIV infection. PMID- 26962486 TI - Existence of Microchimerism in Pregnant Women Carrying a Boy! PMID- 26962489 TI - Distal clavicle fractures in children. AB - OBJECTIVE: To analyze fractures of the distal clavicle region in pediatric patients. METHODS: Ten patients between the ages of five to eleven years (mean of 7.3 years) were observed. Nine patients were treated conservatively and one surgically. All the fractures were classified using the Nenopoulos classification system. RESULTS: All the fractures consolidated without complications. Conservative treatment was used for nine patients, of whom three were in group IIIB, three IIb, two IIa and one IV. The only patient who was treated surgically was a female patient of eleven years of age with a group IV fracture. CONCLUSION: The treatment indication for distal fractures of the clavicle in children should be based on the patient's age and the displacement of the fragments. PMID- 26962487 TI - Stress fractures: definition, diagnosis and treatment. AB - Stress fractures were first described in Prussian soldiers by Breithaupt in 1855. They occur as the result of repeatedly making the same movement in a specific region, which can lead to fatigue and imbalance between osteoblast and osteoclast activity, thus favoring bone breakage. In addition, when a particular region of the body is used in the wrong way, a stress fracture can occur even without the occurrence of an excessive number of functional cycles. The objective of this study was to review the most relevant literature of recent years in order to add key information regarding this pathological condition, as an updating article on this topic. PMID- 26962488 TI - Minimally invasive surgical treatment for unstable fractures of the proximal phalanx: intramedullary screw. AB - OBJECTIVE: To analyze the clinical-functional parameters and quality of life of patients undergoing minimally invasive surgical treatment for extra-articular fractures of the proximal phalanx, using an intramedullary screw (Acutrak((r))). METHODS: Between January 2011 and September 2014, a prospective study was conducted on 41 patients (48 fingers) with unstable extra-articular fractures of the proximal phalanx, who underwent minimally invasive surgical treatment using an intramedullary screw (Acutrak((r))). These patients were evaluated 12 months after the surgery by means of the DASH quality-of-life questionnaire, VAS pain scale, measurement of range of motion (ROM, in degrees) and radiographic assessment. RESULTS: All the patients achieved adequate reduction and consolidation of their fractures. There were statistically significant improvements in quality of life on the DASH scale, pain on the VAS scale and range of motion. CONCLUSION: The minimally invasive technique for treating unstable extra-articular fractures of the proximal phalanx using an intramedullary screw (Acutrak((r))) is effective and safe, and it presents satisfactory clinical-functional results. PMID- 26962490 TI - Evaluation of surgical treatment of carpal tunnel syndrome using local anesthesia. AB - OBJECTIVE: To evaluate the results and complications from surgical treatment of carpal tunnel syndrome by means of an open route, using a local anesthesia technique comprising use of a solution of lidocaine, epinephrine and sodium bicarbonate. MATERIAL AND METHODS: This was a cohort study conducted through evaluating the medical files of 16 patients who underwent open surgery to treat carpal tunnel syndrome, with use of local anesthesia consisting of 20 mL of 1% lidocaine, adrenaline at 1:100,000 and 2 mL of sodium bicarbonate. The DASH scores before the operation and six months after the operation were evaluated. Comparisons were made regarding the intensity of pain at the time of applying the anesthetic and during the surgical procedure, and in relation to other types of procedure. RESULTS: The DASH score improved from 65.17 to 16.53 six months after the operation (p < 0.01). In relation to the anesthesia, 75% of the patients reported that this technique was better than or the same as venous puncture and 81% reported that it was better than a dental procedure. Intraoperative pain occurred in two cases. There were no occurrences of ischemia. CONCLUSION: Use of local anesthesia for surgically treating carpal tunnel syndrome is effective for performing the procedure and for the final result. PMID- 26962491 TI - Are the good functional results from arthroscopic repair of massive rotator cuff injuries maintained over the long term? AB - OBJECTIVE: To evaluate whether the good and excellent functional results from arthroscopic repair of massive rotator cuff tears are maintained over the long term. METHODS: From the sample of the study conducted by our group in 2006, in which we evaluated the functional results from arthroscopic repair of massive rotator cuff tears, 35 patients were reassessed, 8 years after the first evaluation. The inclusion criteria were that these patients with massive rotator cuff tears operated by means of an arthroscopic technique, who participated in the previous study and achieved good or excellent outcomes according to the UCLA criteria. Patients whose results were not good or excellent in the first evaluation according to the UCLA criteria were excluded. RESULTS: Among the 35 patients reassessed, 91% of them continued to present good and excellent results (40% excellent and 51% good), while 3% presented fair results and 6% poor results. The time interval between the first and second evaluations was 8 years and the minimum length of follow-up since the immediate postoperative period was 9 years (range: 9-17 years), with an average of 11.4 years. CONCLUSION: The good and excellent results from arthroscopic repair of massive rotator cuff tears were mostly maintained (91%), with the same level of function and satisfaction, even though 8 years had passed since the first assessment, with a follow-up period averaging 11.4 years. PMID- 26962493 TI - Tendon of the long head of the biceps originating from the rotator cuff - An uncommon anatomical variation: case report. AB - Anatomical variations at the origin of the biceps tendon have been described by several authors, but occurrences of an origin in the supraspinatus are rare. It is unclear whether this variation might contribute toward pathological conditions of the shoulder. Our objective here was to describe a case of an anatomical variation in the origin of the tendon of the long head of the biceps. The clinical information, preoperative images and arthroscopic images relating to a patient with an aberrant origin of the long head of the biceps, which was observed during shoulder arthroscopy, were reviewed. In this case study, the origin of the biceps was found in the rotator cuff, without any origin from the supraglenoid tubercle or upper labrum. This variant did not seem to contribute toward the pathological condition of the shoulder, and standard treatment for the concomitant condition was sufficient for treating it. PMID- 26962492 TI - Comparative evaluation of patellar height methods in the Brazilian population. AB - OBJECTIVE: The methods most used for patellar height measurement were compared with the plateau-patella angle method. METHODS: A cross-sectional study was conducted, in which lateral-view radiographs of the knee were evaluated using the three methods already established in the literature: Insall-Salvati (IS), Blackburne-Peel (BP) and Caton-Deschamps (CD). These were compared with the plateau-patella angle method. One hundred and ninety-six randomly selected patients were included in the sample. RESULTS: The data were initially evaluated using the chi-square test. This analysis was deemed to be positive with p < 0.0001. We compared the traditional methods with the plateau-patella angle measurement, using Fisher's exact test. In comparing the IS index with the plateau-patella angle, we did not find any statistically significant differences in relation to the proportion of altered cases between the two groups. The traditional methods were compared with the plateau-patella angle with regard to the proportions of cases of high and low patella, by means of Fisher's exact test. This analysis showed that the plateau-patella angle identified fewer cases of high patella than did the IS, BP and CD methods, but more cases of low patella. In comparing pairs, we found that the IS and CD indices were capable of identifying more cases of high patella than was the plateau-patella angle. In relation to the cases of low patella, the plateau-patella angle was capable of identifying more cases than were the other three methods. CONCLUSIONS: The plateau-patella angle found more patients with low patella than did the classical methods and showed results that diverged from those of the other indices studied. PMID- 26962494 TI - Ossifying fibroma: report on a clinical case, with the imaging and histopathological diagnosis made and treatment administered. AB - The aim was to report on a case of ossifying fibroma, consisting of a benign fibro-osseous lesion characterized by slow growth and proliferation of fibrous cellular tissue, bone, cement or a combination. A 29-year-old male patient was attended at a hospital, after he had suffered a car accident. During the clinical examination, increased volume in the region of the right side of the mandible was observed, and a fracture in the middle third of the face was suspected. The tomographic examination showed an image suggestive of fracturing of the left-side zygomatic complex, without displacement, and with a well-delimited radiopaque image of the mandible. The patient was sent to a hospital where panoramic radiography, posteroanterior radiography of the face and teleradiography were performed in order to better document the case. An incisional biopsy was performed. Histopathological examination showed the presence of a benign bone lesion suggestive of ossifying fibroma. Surgery was performed in order to completely remove the lesion, with fixation using a reconstruction plate. A new anatomopathological examination confirmed the diagnosis. PMID- 26962495 TI - Presence of a long accessory flexor tendon of the toes in surgical treatment for tendinopathy of the insertion of the calcaneal tendon: case report. AB - The presence of accessory tendons in the foot and ankle needs to be recognized, given that depending on their location, they may cause disorders relating either to pain processes or to handling of the surgical findings. We describe the presence of an accessory flexor tendon of the toes, seen in surgical exposure for transferring the long flexor tendon of the hallux to the calcaneus, due to the presence of a disorder of tendinopathy of the insertion of the calcaneal tendon in association with Haglund's syndrome. PMID- 26962497 TI - Medical education. PMID- 26962496 TI - Congenital dislocation of the patella - clinical case. AB - Congenital patellar dislocation is a rare condition in which the patella is permanently dislocated and cannot be reduced manually. The patella develops normally as a sesamoid bone of the femur. This congenital dislocation results from failure of the internal rotation of the myotome that forms the femur, quadriceps muscle and extensor apparatus. It usually manifests immediately after birth, although in some rare cases, the diagnosis may be delayed until adolescence or adulthood. Early diagnosis is important, thereby allowing surgical correction and avoiding late sequelae, including early degenerative changes in the knee. A case of permanent dislocation of the patella is presented here, in a female child aged seven years. PMID- 26962498 TI - Statistical analysis on the concordance of the radiological evaluation of fractures of the distal radius subjected to traction. AB - OBJECTIVE: The objective of this study was to evaluate the current classifications for fractures of the distal extremity of the radius, since the classifications made using traditional radiographs in anteroposterior and lateral views have been questioned regarding their reproducibility. In the literature, it has been suggested that other options are needed, such as use of preoperative radiographs on fractures of the distal radius subjected to traction, with stratification by the evaluators. The aim was to demonstrate which classification systems present better statistical reliability. RESULTS: In the Universal classification, the results from the third-year resident group (R3) and from the group of more experienced evaluators (Staff) presented excellent correlation, with a statistically significant p-value (p < 0.05). Neither of the groups presented a statistically significant result through the Frykman classification. In the AO classification, there were high correlations in the R3 and Staff groups (respectively 0.950 and 0.800), with p-values lower than 0.05 (respectively <0.001 and 0.003). CONCLUSION: It can be concluded that radiographs performed under traction showed good concordance in the Staff group and in the R3 group, and that this is a good tactic for radiographic evaluations of fractures of the distal extremity of the radius. PMID- 26962499 TI - Effect of removal and reinsertion of force-closed stems on deformation of total hip arthroplasty. AB - OBJECTIVES: This study investigated removal of a force-closed stem, done in order to improve acetabular exposure during revision, with reinsertion afterwards. It is unknown how much this procedure modifies the stem/cement interface. METHODS: Three tapered stem models were implanted into composite femurs. Strain gauges were embedded in the medial aspect of the cement mantle and in several positions on the outer surface of the femurs. The deformation was measured during static loading, which was applied at two different times: after implantation and after one million loading cycles, followed by stem removal and reinsertion. The t test was performed. The differences in deformation were compared (at p <= 0.05) between the two static loading times and among the three stem designs. RESULTS: No significant differences in deformation were found after the two loading times for the three models. No significant differences in the initial deformations of the three models were found for most of the gauges attached to the femurs. CONCLUSIONS: Reinsertion of the force-closed stem does not alter the load transmission from the stem to the cement and to the surface of the femur, even after one million loading cycles. PMID- 26962500 TI - Evaluation of postoperative results from videoarthroscopic treatment for recurrent shoulder dislocation using metal anchors. AB - OBJECTIVE: To clinically and radiologically evaluate the results from videoarthroscopic treatment using metal anchors in patients with recurrent shoulder dislocation and its complications. METHODS: This was a retrospective study on 47 patients (47 shoulders) operated by the shoulder group of the orthopedic hospital between February 2010 and February 2012. A questionnaire, interview and physical and radiographic examinations were used, with the classification of Samilson and Pietro. The mean postoperative follow-up was 33 months (range 12-47 months). The statistical analysis consisted of using Fisher's exact test through the IBM SPSS 22 statistical software. The significance level used was 5%. RESULTS: Recurrence was observed in nine cases. The patients were, on average, 26.5 years old at the first episode, and 19.1% were aged 20 years or under. Among these, 55.6% presented recurrence. In relation to age at the time of the surgical procedure, the average age was 27 years, and 12.8% were aged 20 years or under. Nineteen patients presented prominent anchors and, of these, 21% manifested arthrosis. CONCLUSION: There was a statistically identified correlation between the recurrence rate and age less than or equal to 20 years at the times of first dislocation and the surgical procedure. Further studies should be conducted in order to compare the use of absorbable anchors, which despite higher cost, may provide lower risk of developing glenohumeral arthrosis in some cases. PMID- 26962502 TI - Use of superficial peroneal nerve graft for treating peripheral nerve injuries. AB - OBJECTIVE: To evaluate the clinical results from treating chronic peripheral nerve injuries using the superficial peroneal nerve as a graft donor source. METHODS: This was a study on eleven patients with peripheral nerve injuries in the upper limbs that were treated with grafts from the sensitive branch of the superficial peroneal nerve. The mean time interval between the dates of the injury and surgery was 93 days. The ulnar nerve was injured in eight cases and the median nerve in six. There were three cases of injury to both nerves. In the surgery, a longitudinal incision was made on the anterolateral face of the ankle, thus viewing the superficial peroneal nerve, which was located anteriorly to the extensor digitorum longus muscle. Proximally, the deep fascia between the extensor digitorum longus and the peroneal longus muscles was dissected. Next, the motor branch of the short peroneal muscle (one of the branches of the superficial peroneal nerve) was identified. The proximal limit of the sensitive branch was found at this point. RESULTS: The average space between the nerve stumps was 3.8 cm. The average length of the grafts was 16.44 cm. The number of segments used was two to four cables. In evaluating the recovery of sensitivity, 27.2% evolved to S2+, 54.5% to S3 and 18.1% to S3+. Regarding motor recovery, 72.7% presented grade 4 and 27.2% grade 3. There was no motor deficit in the donor area. A sensitive deficit in the lateral dorsal region of the ankle and the dorsal region of the foot was observed. None of the patients presented complaints in relation to walking. CONCLUSIONS: Use of the superficial peroneal nerve as a graft source for treating peripheral nerve injuries is safe and provides good clinical results similar to those from other nerve graft sources. PMID- 26962501 TI - Giant-cell tumor: analysis on the importance of early diagnosis and the epidemiological profile. AB - OBJECTIVE: This study aimed to ascertain the relationship between early diagnosis of giant-cell tumors (GCT) and their prognosis, by correlating the time of symptom onset with the staging of the injury (through the Campanacci classification at the time of diagnosis), and with the type of treatment. The secondary objective of the study was to outline the epidemiological profile of patients with GCT in the region where the data were gathered, and to compare them with data in the literature. METHODS: The authors present an evaluation on 61 patients diagnosed with bone GCT, with regard to the site of involvement, age, initial symptoms, time of symptom onset, classification and type of treatment, among patients attended between May 1994 and August 2009. RESULTS: The threshold indicated as the limit for Campanacci stage I tumors to be the commonest diagnosis, with a 98.2% chance that the treatment would be non-aggressive, was 2 months after symptom onset. This finding was statistically significant (p = 0.017). Every additional month increased the chance that a patient would be diagnosed with an advanced-stage tumor by 10.94%, in relation to the chances of having the other two stages of the tumor. CONCLUSION: The study result not only suggests that the alternative hypothesis that the earlier the diagnosis of GCT is, the less severe the lesion will be, has been confirmed; but also especially predicts the relationship between the time of symptom appearance and the severity of the tumor. PMID- 26962503 TI - Mesenchymal stromal cells from bone marrow treated with bovine tendon extract acquire the phenotype of mature tenocytes. AB - OBJECTIVE: This study evaluated in vitro differentiation of mesenchymal stromal cells isolated from bone marrow, in tenocytes after treatment with bovine tendon extract. METHODS: Bovine tendons were used for preparation of the extract and were stored at -80 degrees C. Mesenchymal stromal cells from the bone marrow of three donors were used for cytotoxicity tests by means of MTT and cell differentiation by means of qPCR. RESULTS: The data showed that mesenchymal stromal cells from bone marrow treated for up to 21 days in the presence of bovine tendon extract diluted at diminishing concentrations (1:10, 1:50 and 1:250) promoted activation of biglycan, collagen type I and fibromodulin expression. CONCLUSION: Our results show that bovine tendon extract is capable of promoting differentiation of bone marrow stromal cells in tenocytes. PMID- 26962504 TI - Reconstruction of medial patellofemoral ligament using quadriceps tendon combined with reconstruction of medial patellotibial ligament using patellar tendon: initial experience. AB - OBJECTIVE: To describe a surgical technique for anatomical reconstruction of the medial patellofemoral ligament using the quadriceps tendon, combined with reconstruction of the medial patellotibial ligament using the patellar tendon; and to present the initial results from a case series. METHOD: The proposed technique was used on a series of cases of patients with diagnoses of patellofemoral instability and indications for surgical treatment, who were attended by the Knee Group of HC-IOT, University of Sao Paulo. The following were evaluated before and after the operation: range of motion (ROM), apprehension test, lateral translation test, patellar inclination test, inverted J sign, subluxation upon extension, pain from compression of the patella and pain from contraction of the quadriceps. After the operation, the patients were asked whether any new episode of dislocation had occurred, what their degree of satisfaction with the surgery was (on a scale from 0 to 10) and whether they would be prepared to go through this operation again. RESULTS: Seven knees were operated, in seven patients, with a mean follow-up of 5.46 months (+/-2.07). Four patients who presented apprehension before the operation did not show this after the operation. The lateral translation test became normal for all the patients, while the patellar inclination test remained positive for two patients. The patients with an inverted J sign continued to be positive for this sign. Five patients were positive for subluxation upon extension before the operation, but all patients were negative for this after the operation. None of the patients presented any new episode of dislocation of the patella. All of them stated that they were satisfied: five gave a satisfaction score of 9 and two, a score of 10. All of them said that they would undergo the operation again. Only one patient presented a postoperative complication: dehiscence of the wound. CONCLUSION: Reconstruction of the medial patellofemoral ligament using the quadriceps tendon, combined with reconstruction of the medial patellotibial ligament using the patellar tendon, was technically safe and presented good objective and subjective clinical results in this case series with a short follow-up. PMID- 26962505 TI - Assessment of spontaneous correction of lumbar curve after fusion of the main thoracic in Lenke 1 adolescent idiopathic scoliosis. AB - OBJECTIVE: To evaluate the clinical and radiographic response of the lumbar curve after fusion of the main thoracic, in patients with adolescent idiopathic scoliosis of Lenke type 1. METHODS: Forty-two patients with Lenke 1 adolescent idiopathic scoliosis who underwent operations via the posterior route with pedicle screws were prospectively evaluated. Clinical measurements (size of the hump and translation of the trunk in the coronal plane, by means of a plumb line) and radiographic measurements (Cobb angle, distal level of arthrodesis, translation of the lumbar apical vertebral and Risser) were made. The evaluations were performed preoperatively, immediately postoperatively and two years after surgery. RESULTS: The mean Cobb angle of the main thoracic curve was found to have been corrected by 68.9% and the lumbar curve by 57.1%. Eighty percent of the patients presented improved coronal trunk balance two years after surgery. In four patients, worsening of the plumb line measurements was observed, but there was no need for surgical intervention. Less satisfactory results were observed in patients with lumbar modifier B. CONCLUSIONS: In Lenke 1 patients, fusion of the thoracic curve alone provided spontaneous correction of the lumbar curve and led to trunk balance. Less satisfactory results were observed in curves with lumbar modifier B, and this may be related to overcorrection of the main thoracic curve. PMID- 26962507 TI - Intraosseous lipoma of the iliac: case report. AB - Lipomas are benign tumors that attack fat cells and most often affecting soft tissues in adulthood. On rare occasions, they may affect bones, preferentially the metaphyses of the long bone. They are generally asymptomatic and radiography shows radiolucent lesions with a thin sclerotic rim or radiodense lesions with a thick sclerotic rim. Malignant transformation of these tumors is rare, as is their recurrence, and there is no need for surgery in most cases. In this report, we present a rare case of intraosseous lipoma in the iliac bone. PMID- 26962506 TI - Effects of platelet-rich plasma on lateral epicondylitis of the elbow: prospective randomized controlled trial. AB - OBJECTIVE: To evaluate the effects of platelet-rich plasma (PRP) infiltration in patients with lateral epicondylitis of the elbow, through analysis of the Disabilities of the Arm, Shoulder and Hand (DASH) and Patient-Rated Tennis Elbow Evaluation (PRTEE) questionnaires. METHODS: Sixty patients with lateral epicondylitis of the elbow were prospectively randomized and evaluated after receiving infiltration of three milliliters of PRP, or 0.5% neocaine, or dexamethasone. For the scoring process, the patients were asked to fill out the DASH and PRTEE questionnaires on three occasions: on the day of infiltration and 90 and 180 days afterwards. RESULTS: Around 81.7% of the patients who underwent the treatment presented some improvement of the symptoms. The statistical tests showed that there was evidence that the cure rate was unrelated to the substance applied (p = 0.62). There was also intersection between the confidence intervals of each group, thus demonstrating that the proportions of patients whose symptoms improved were similar in all the groups. CONCLUSION: At a significance level of 5%, there was no evidence that one treatment was more effective than another, when assessed using the DASH and PRTEE questionnaires. PMID- 26962508 TI - Letrozole as the first-line treatment of infertile women with poly cystic ovarian syndrome (PCOS) compared with clomiphene citrate: A clinical trial. AB - BACKGROUND: The purpose of this study was to determine the efficacy and safety of letrozole on ovulation induction and pregnancy in comparison with clomiphene citrate in PCOS patients. MATERIALS AND METHODS: The study was based on prospective randomized clinical trial comparing the efficacy of letrozole as the first-line management of the PCOS patients in comparison to clomiphene citrate during 2009 to 2011 and was performed in one private infertility clinic. The study included 100 patients divided into 2 equal groups. RESULTS: Pregnancy occurred in 29 of 50 patients in letrozole group (58%) and 24 of 51 patients in clomiphene group (47%). The difference was not statistically significant (P value = 0.23). Thirty patients in clomiphene group and 36 patients in letrozole group showed regular menses after or during the treatment course. No significant difference between the 2 groups was observed (P value = 0.21). CONCLUSION: Our findings suggest letrozole and clomiphene citrate are equally effective for induction of ovulation and achieving pregnancy in patients with PCOS. PMID- 26962509 TI - Effect of vitamin D supplementation in the reduce risk of preeclampsia in nulliparous women. AB - BACKGROUND: The exact role of vitamin D in the development and severity of preeclampsia is still unclear. The aim of the present study was to investigate the association between vitamin D supplement and preeclampsia in pregnant women. MATERIALS AND METHODS: In this randomized controlled trial, in 2012, 140 nulliparous pregnant women in two groups received supplementation with 600 IU/day of vitamin D or supplementation free of vitamin D at 16 week gestation until the delivery. The main outcomes included the frequency of preeclampsia and subtypes by clinical severity and infant birth weight. RESULTS: Mean of maternal age and gestational age at the delivery in all studied subjects were 25 +/- 4.1 years and 37.4 +/- 3 weeks, respectively, which were not statistically significant between the groups. Preeclampsia was observed in two subjects in case group compared to seven subjects in control group, which was not significant (P-value = 0.09). In case group, subjects with preeclampsia diagnosed as mild preeclampsia and in control group four subjects were mild, and three were severe. No significant differences were noted between the case and control groups in the frequency of preeclampsia subtypes by clinical severity. Infant birth weight in case group who was significantly higher than control group, which was statistically significant between groups (P-value = 0.09). CONCLUSION: In summary, our results demonstrated that vitamin D supplementation during the third trimester of pregnancy; despite the non-significant association between vitamin D supplementation and preeclampsia, reduce the risk of preeclampsia. However, further studies needs to be done. PMID- 26962510 TI - Study of pomegranate (Punica granatum L.) peel extract containing anthocyanins on fatty streak formation in the renal arteries in hypercholesterolemic rabbits. AB - BACKGROUND: The influence of the supplementation of pomegranate peel extract containing anthocyanins on atherosclerotic plaque formation induced by hypercholesterolemia was investigated in renal arteries in rabbits. MATERIALS AND METHODS: After the determination of polyphenol and anthocyanin's content of P. granatum peel hydroalcoholic extract, 30 male rabbits were randomly divided into three groups. They were fed basic diet, hypercholesterolemic diet and hypercholesterolemic diet along with P. granatum peel extract (polyphenolic content for each rabbit 1 g/kg diet) for 2 month. Blood samples were collected at the begging, middle and end of the study in order to measure lipid concentration and oxidative and antioxidative status variables, and renal arteries were taken for the assessment of atherosclerotic plaques at the end of the study. RESULTS: The results reveal that P. granatum peel extract significantly increases serum antioxidant capacity in the extract recipient group in comparison with hypercholesterolemic control (P < 0.05). No significant differences are observed in total cholesterol, triglyceride, low-density lipoprotein, high-density lipoprotein, very low-density lipoprotein and in mean size of accumulated fatty streaks in renal arteries in the extract treatment group in comparison with hypercholesterolemic control (P > 0.05). CONCLUSION: The results of this study indicate that consumption of pomegranate peel extract containing anthocyanins (polyphenol content 1 g/kg diet) despite of a significant increase in serum antioxidant capacity cannot protect the kidneys from hypercholesterolemia-induced damages during the treatment period. PMID- 26962511 TI - Common antigens between hydatid cyst and cancers. AB - BACKGROUND: Different research groups reported a negative correlation between cancers and parasitical infections. As an example, the prevalence of a hydatid cyst among patients with cancer was significantly lower than its prevalence among normal population. Tn antigens exist both in cancer and hydatid cyst. This common antigen may be involved in the effect of parasite on cancer growth. So in this work, common antigens between hydatid cyst and cancers have been investigated. MATERIALS AND METHODS: Different hydatid cyst antigens including hydatid fluid, laminated and germinal layer antigens, and excretory secretory antigens of protoscolices were run in SDS PAGE and transferred to NCP paper. In western immunoblotting, those antigens were probed with sera of patients with different cancer and also sera of non-cancer patients. Also, cross reaction among excretory secretory products of cancer cells and antisera raised against different hydatid cyst antigen was investigated. RESULTS: In western immunoblotting, antisera raised against laminated and germinal layers of hydatid cyst reacted with excretory secretory products of cancer cells. Also, a reaction was detected between hydatid cyst antigens and sera of patients with some cancers. CONCLUSION: Results of this work emphasize existence of common antigens between hydatid cyst and cancers. More investigation about these common antigens is recommended. PMID- 26962512 TI - Bevacizumab plus FOLFOX or FOLFIRI regimens on patients with unresectable liver only metastases of metastatic colorectal cancer. AB - BACKGROUND: The present study was aimed to evaluate the efficacy and safety of at least three cycles of Bevacizumab in combination with chemotherapy regimens, FOLFIRI or FOLFOX to treat liver metastatic colorectal cancer and improved response rates in these patients. MATERIALS AND METHODS: In this non-randomized clinical trial, 38 patients were enrolled and followed for 12-weeks period of chemotherapy. Fifteen patients under treated with FOLOFX (Group I), 15 patients under treated with FOLOFIRI (Group II), 4 patients under treated with FOLOFX + Bevacizumab (Group III), and 34 patients under treated with FOLOFIRI + Bevacizumab (Group IV). Response to treatment was assessed in all patients as main endpoint. Patients in groups I and II, who did not response to treatment after 12 weeks of chemotherapy, were followed by groups III and IV regimens, respectively, for 12 weeks. RESULTS: Overall response rate was 35% (19 of 54), and complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) rates in all patients were 18%, 17%, 35%, and 30%. PR, SD, and PD were different among groups, but no statistical significance was noted among groups (P-value >0.05). No patient achieved a CR in groups III and IV, although CR was observed in 4 patients (27%) and 6 patients (40%) in groups I and II, respectively. The rare of CR was statistically significant among studied groups (P-value = 0.013). CONCLUSION: Results showed that adding Bevacizumab to chemotherapy regimens, in patients who did not response to FOLFIRI or FOLFOX regimen, did not increase CR in these patients. PMID- 26962514 TI - Detection of secondary ossification centers by sonography. AB - BACKGROUND: To assess the validity of ultrasonography (US) in detection of secondary ossification centers (SOC) of the hand. Radiography is the standard technique for estimating skeletal bone age with its unwanted harmful effects mostly undesirable in little children. If efficient enough, US could be an appropriate substitute. MATERIALS AND METHODS: Left hand US was performed on 6-60 months children (n = 24, with 29 SOCs for each child in his/her hand and a total of 696 SOCs) referred for wrist radiography and bone age determination during a 4 months period. The presence of SOCs was investigated by US and radiography by two radiologists under blind conditions. RESULTS: US was evaluated 696 SOCs, and 446 SOCs were detected, by US and 436 by radiography without statistically significant difference. The results of US and radiography in detection of SOCs of distal forearm (23 SOCs were detected by both US and radiography) and carpi (87 SOCs) were identical. However, in metacarpi (94 for US, 88 for radiography) and phalanges (242 for US, 238 for radiography) US appeared better. CONCLUSION: On the base of our data, US is at least as effective as radiography in detection of SOCs and therefore can play a role in the skeletal age estimation. PMID- 26962513 TI - Evaluation of differences in HLA-DR4 gene and its subtypes prevalence among healthy people and RA patients in Isfahan province population. AB - BACKGROUND: There are a lot of evidences showing that genetic play an important role in RA disease. Inheritance of some subgroups of HLA-DR4 gene increases the propensity to RA disease. In this paper, the impact of HLA-DR4 gene and its subtypes or subgroups, be consistence on RA patient who lived in Isfahan province, has been evaluated. MATERIALS AND METHODS: In this survey, two groups of people (100 patients in case group and 100 normal persons in control group) have been selected. These two groups were similar in age and gender. Statistical population has been considered among people who visited Al Zahra rheumatology clinic. The participants were from Isfahan province and accepted to participate to the study voluntarily. The prevalence of HLA-DR4 and its 0401-0404 subtypes were evaluated between two groups; DNA was extracted from blood samples and studied using PCR SSCP method. RESULTS: It was found that 35% of RA patients had HLA-DR4 gene, of which 14 persons had 0401, 10 persons had 0404, and 11 persons had other subtypes, whereas 30 people in control group had HLA-DR4 gene, of which 10 people had 0401, 20 people had 0404, and nobody had other subtypes. CONCLUSION: The observed differences between prevalence of HLA-DR4 gene between the case and control group were not statistically significant (P = 0.45; OR = 1.256; 95% CI = 0.69-2.27), but a relation was between HLA-DR4 0404 subtypes and RA (P = 0.02; OR = 0.44; 95% CI = 0.196-0.992). PMID- 26962515 TI - Comparing the efficacy of routine H&E staining and cytokeratin immunohistochemical staining in detection of micro-metastasis on serial sections of dye-mapped sentinel lymph nodes in colorectal carcinoma. AB - BACKGROUND: The significance of techniques used for detecting micro-metastasis (MM) or isolated tumor cells (ITCs) is a controversial issue among investigators. We evaluated the different techniques used on sentinel lymph node (SLN) to detect MM/ITCs. MATERIALS AND METHODS: Ninety-one SLNs of 15 patients underwent serial section with 100 MUm interval. In each level, two sections were prepared. One section was stained with H&E and another with anti-cytokeratin antibody (immunohistochemistry). Then the sections were evaluated for detecting MM/ITCs. Results were analyzed by chi-square test. RESULTS: 1656 sections of 91 SLNs of 15 patients were evaluated by a pathologist; MM was found in 1 and ITCs in 1 case. Overall, 2 out of 15 cases (13.3% of the patients) showed MM/ITCs by IHC staining. So, serial section along with using IHC was superior than serial section and routine H&E staining. But it did not affect the 5-year survival of the patients (P = 0.47). CONCLUSION: Using the combined techniques of serial section and IHC staining could up-stage 13.3% of colon cancer patients who were lymph node negative. In other studies with different combination of serial section, IHC staining, and PCR, investigators were able to find MM/ITCs in 3-39% of the cases. In our study, although serial section and IHC staining could up stage 13.3% of patients, it could not affect the 5-year survival of the patients. PMID- 26962517 TI - Preparation of monoclonal antibodies against mannosylated lipoarabinomannan (ManLAM), a surface antigen of BCG vaccine produced in Iran. AB - BACKGROUND: Bacille Calmette-Guerin (BCG) vaccine is the only vaccine that is used against Mycobacterium tuberculosis, but its efficacy is limited in mycobacterium-endemic regions. One of the major antigens present on the cell envelope of the vaccine that suppresses the immune system is mannosylated lipoarabinomannan (ManLAM). MATERIALS AND METHODS: In this study, we immunized 4 week-old mice with sonicated BCG vaccine injected intraperitoneally two times at an interval of 2 weeks and with ManLAM antigen injected intravenously and then extracted the spleen cells of the immunized mice. They were fused with SP2/0 myeloma cells. RESULTS: Five cell line clones producing antibody against ManLAM antigens were prepared and each clone was tested for immunoreactivity against sonicated BCG and purified ManLAM by enzyme-linked immunosorbent assay (ELISA) and immunoblotting. The clones designated H13F33E11 and H23D91G4 reacted strongly with ManLAM. Immunoblotting using monoclonal antibodies (MAbs) H13F33E11 and H23D91G4 showed that these MAbs bind to ManLAM with a molecular weight of 35 kDa. CONCLUSIONS: In this study, we produced a monoclonal antibody of immunoglobulin G3 (IgG3) subclass. This MAb can be used for purification of ManLAM in culture media and detection of the antigen in patient's urine and for increasing the efficacy of BCG vaccine. PMID- 26962516 TI - Effect of enalapril in cisplatin-induced nephrotoxicity in rats; gender-related difference. AB - BACKGROUND: The function of renin angiotensin system (RAS) is gender-related, and this system affects cisplatin (CP)-induced nephrotoxicity. In this study, we compared the effect of enalapril as an angiotensin-converting enzyme (ACE) inhibitor on CP-induced nephrotoxicity between male and female rats. MATERIALS AND METHODS: Sixty-two adult male and female Wistar rats were divided into eight groups. Both genders received CP (2.5 mg/kg, i.p.) and enalapril (30 mg/kg, i.p.) for 7 days in compared with CP alone or enalapril alone or vehicle alone treated groups. At the end of the experiment, blood samples were obtained, and the kidney tissue was investigated for histopathological changes. RESULTS: CP increased the serum levels of blood urea nitrogen and creatinine as well as kidney weight and kidney tissue damage score in both genders (P < 0.05). However, not only enalapril failed to ameliorate the aforementioned parameters in both genders, but also it intensified nephrotoxicity in females (P < 0.05). In addition, enalapril enhanced body weight loss induced by CP in females (P < 0.05). CP alone decreased kidney level of nitrite in both genders (P < 0.05) and enalapril could not reverse this decreasing. The combination of enalapril and CP significantly increased serum level of nitrite in females, but this was not observed in males (P < 0.05). CONCLUSION: Enalapril as an ACE inhibitor failed to ameliorate nephrotoxicity induced by CP in both male and female rats. In addition, enalapril aggravated CP-induced nephrotoxicity in female possibly due to gender-dependent RAS response. PMID- 26962519 TI - Comparison of CRP and ALK-P serum levels in prediction of preterm delivery. AB - BACKGROUND: Preterm birth, defined as birth occurring before 37 weeks of gestation, is a common complication of pregnancy and may lead to death or long term disability in newborns. Accurate diagnosis is, therefore, crucial for identifying those women undergoing preterm labor who are at greatest risk of preterm delivery. This may allow transport to a regional obstetrical center and permit time for corticosteroid therapy. Recent study recommends several markers such as CRP (C-reactive protein) and ALK-P (alkaline phosphatase) to predict preterm delivery. MATERIALS AND METHODS: We select a total of 300 pregnant women that had symptoms of premature birth. All of them were under treatment with tocolytic and serum sample were taken to assess the level of CRP-ALKp. Cervix length and the time of response to tocolytic were measured. 110 pregnant of them had preterm labor. 110 patient that had a term labor selected as a control group. RESULTS: Qualitative evaluation of efficacy CRP level on preterm delivery showed a significant relationship with 27 as a cut of point of CRP (P < 0.00001 -OR = 7.5). Investigate of effect of ALK-P level on preterm delivery refers to a significant relationship with 399 as a cut of point of ALKP (P < 0.00001 -OR = 5). Inquire of efficacy of CRP level and ALK-P level on preterm delivery demonstrate a significant relationship (P < 0.0001 1OR = 9). CONCLUSIONS: Maternal concentrations of CRP and ALKP and cervix length can be used as appropriate biomarker for predicting preterm labor and response to tocolytic therapy in pregnant women. PMID- 26962518 TI - Effectiveness of splinting and splinting plus local steroid injection in severe carpal tunnel syndrome: A Randomized control clinical trial. AB - BACKGROUND: The Study aimed to compare the effectiveness of two commonly used conservative treatments, splinting and local steroid injection in improving clinical and nerve conduction findings of the patients with severe carpal tunnel syndrome (CTS). MATERIALS AND METHODS: In this randomized control clinical trial, the patients with severe CTS selected and randomized in two interventional groups. Group A was prescribed to use full time neutral wrist splint and group B was injected with 40 mg Depo-Medrol and prescribed to use the full time neutral wrist splint for 12 weeks. Clinical and nerve conduction findings of the patients was evaluated at baseline, 4 and 12 weeks after interventions. RESULTS: Twenty two and 21 patients were allocated in group A and B, respectively. Mean of clinical symptoms and functional status scores, nerve conduction variables and patients' satisfaction score were not significant between group at baseline and 4 and 12 weeks after intervention. Within the group comparison, there was significant improvement in the patients' satisfaction, clinical and nerve conduction items between the baseline level and 4 weeks after intervention and between the baseline and 12 weeks after intervention (P < 0.01). The difference was significant for functional status score between 4 and 12 weeks after intervention in group B (P = 0.02). CONCLUSION: considering some findings regarding the superior effect of splinting plus local steroid injection on functional status scale and median nerve distal motor latency, it seems that using combination therapy could be more effective for long-term period specially in the field of functional improvement of CTS. PMID- 26962520 TI - Lack of association between rs1800795 (-174 G/C) polymorphism in the promoter region of interleukin-6 gene and susceptibility to type 2 diabetes in Isfahan population. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is an inflammatory autoimmune disease that mostly affects older adults. The etiology of T2DM includes both genetic and environmental factors. rs1800795 (-174 G/C) single nucleotide polymorphism (SNP) linked with autoimmune disorders predispositions, identified by Genome-Wide Association Study among genes, which immunologically related is considerably over signified. The goal of this study was to evaluate the association between rs1800795 (-174 G/C) polymorphisms in the promoter of interleukin-6 (IL-6) gene with susceptibility to T2DM in a subset of the Iranian population. MATERIALS AND METHODS: In this case-control study, 120 healthy subjects and 120 patients with T2DM were included. Genomic DNA obtained from whole blood samples and the polymerase chain reaction was used to amplify the fragment of interest contain rs1800795 SNP, restriction fragment length polymorphism method was applied for genotyping of the DNA samples with NlaIII as a restriction enzyme. SPSS for Windows software (version 18.0, SPSS, Chicago, IL, USA) was performed for statistical analysis. RESULTS: No significant differences were found between healthy controls and T2DM patients with respect to the frequency distribution of the cytokine gene polymorphism investigated. Odds ratio, adjusted for sex, age, and smoking status has displayed similar outcomes. CONCLUSION: These results indicated that the rs1800795 SNP is not a susceptibility gene variant for the development of T2DM in the Isfahan population. Further studies using new data on complex transcriptional interactions between IL-6 polymorphic sites are necessary to determine IL-6 haplotype influence on susceptibility to T2DM. PMID- 26962521 TI - The effect of oral tizanidine on postoperative pain relief after elective laparoscopic cholecystectomy. AB - BACKGROUND: Cholecystectomy is considered as the most important and relatively common postoperative pain control often begins in recovery room by using systemic narcotics that may have some side effects. The aim of this study is to evaluate the effect of premedication with oral tizanidine on pain relief after elective laparoscopic cholecystectomy. MATERIALS AND METHODS: In this double-blinded clinical trial, 70 adults of American Society of Anesthesiologist physiologic state 1 and 2 scheduled for elective laparoscopic cholecystectomy under general anesthesia were studied and randomly divided in two study and control groups. Ninety minutes before the induction of anesthesia, patients received either 4 mg tizanidine (study group) orally in 50cc or the same volume of plain water as a placebo (control group). Then, the vital signs, pain intensity, duration of stay in recovery, and the analgesic consumption were measured and then compared in both groups during 24 h postoperatively. RESULTS: There was no significant difference in patient characteristics, with respect to age, weight, gender, and duration of anesthesia and surgery between the groups (P > 0.05). The pain intensity, need for analgesic drugs (34.57 +/- 8.88 mg vs. 101.86 +/- 5.08 mg), and the duration of stay in recovery room (67.43 +/- 1.59 min vs. 79.57 +/- 5.48 min) were significantly lower in tizanidine group than that of the control group. CONCLUSION: Oral administration of 4 mg tizanidine before laparoscopic cholecystectomy reduces postoperative pain, opioid consumption, and consequence of the duration of stay in recovery room without any complication. PMID- 26962522 TI - Effect of forced treadmill exercise and blocking of opioid receptors with naloxone on memory in male rats. AB - BACKGROUND: The forced treadmill running can influence the opioid contents of the brain, through both effects of exercise and the effects of stress caused by coercion. Since opioids can cause negative effects on brain functions, this study aimed to evaluate the effect of forced treadmill exercise and blocking of opioid receptors with naloxone on memory in male rats. MATERIALS AND METHODS: Experimental groups were the control, the exercise, the naloxone, and the naloxone exercise. The exercise program was treadmill running at 22 m/min at 0 degrees inclination for 50 min/day, 6 days/week, for 4 weeks. Naloxone (1 mg/kg) was injected 5 min before the treadmill running. Morris water maze and passive avoidance learning tests were used for evaluation of memory. Acquisition phase of both tests was performed before interventions, and memory was evaluated 1-day and 1-week after the last session of exercise and treatments. RESULTS: Our data showed that forced exercise impaired performance in passive avoidance learning test (P < 0.05 and P <0.01, 1-day, and 1-week after the last session of exercise and treatments, respectively). Spatial memory was only impaired after 1-week in the exercise group. Naloxone had no significant effect on memory in the control group. However, it improved memory in the exercise group, as there was no significant difference between the control and the naloxone exercise in both tests. CONCLUSION: The data correspond to the possibility that opioidergic system may have mediatory roles in exercise-induced responses in forced exercise. These roles are likely harmful for memory. PMID- 26962523 TI - Effect of the co-administration of glucose with morphine on glucoregulatory hormones and causing of diabetes mellitus in rats. AB - BACKGROUND: Morphine is related to dysregulation of serum hormone levels. In addition, addict subjects interest to sugar intake. Therefore, this study investigated the effect of co-administration of glucose with Mo on the glucoregulatory hormones and causing of diabetes mellitus in rats. MATERIALS AND METHODS: Male rats were randomly divided into four groups including, control, morphine, Morphine-Glucose and diabetes groups. Morphine was undergone through doses of 10, 20, 30, 40, 50, and 60 mg/kg, respectively on days 1, 2, 3, 4, 5, and 6. Then, dose of 60 mg/kg was used repeated for 20 extra days. The Morphine Glucose group received the same doses of morphine plus 1 g/kg glucose per day. Diabetes was induced by intraperitoneal injection of 65 mg/kg streptozotocin. At the end of experiment, the serum insulin, glucagon, growth hormone (GH), cortisol, and glucose levels were measured. The homeostasis model assessment (HOMA) indexes concluding the HOMA-insulin resistance (HOMA-IR) and HOMA-beta were evaluated. RESULTS: Morphine insignificantly induced a hyperglycemia condition and insulin resistance. Whereas, the beta-cell functions significantly (P < 0.05) decreased only in morphine group. The co-administration of glucose slightly increased the GH, and increased insulin and cortisol levels significantly (P < 0.05 and P < 0.01; respectively) in the Morphine-Glucose group. Furthermore, the co-administration of glucose with morphine could nearly modulate the morphine effects on body weight, glucose, and glucagon levels. CONCLUSION: It is probable that the co-administration of glucose with morphine modulate the serum glucose levels by stimulating the beta-cell functions and to increase insulin secretion. PMID- 26962524 TI - The role of biodegradable engineered random polycaprolactone nanofiber scaffolds seeded with nestin-positive hair follicle stem cells for tissue engineering. AB - BACKGROUND: Tissue engineering is a new approach to reconstruction and/or regeneration of lost or damaged tissue. The purpose of this study was to fabricate the polycaprolactone (PCL) random nanofiber scaffold as well as evaluation of the cell viability, adhesion, and proliferation of rat nestin positive hair follicle stem cells (HFSCs) in the graft material using electrospun PCL nanofiber scaffold in regeneration medicine. MATERIALS AND METHODS: The bulge HFSCs was isolated from rat whiskers and cultivated in Dulbecco's modified Eagle's medium/F12. To evaluate the biological nature of the bulge stem cells, flow cytometry using nestin, CD34 and K15 antibodies was performed. Electrospinning was used for the production of PCL nanofiber scaffolds. Furthermore, scanning electron microscopy (SEM) for HFSCs attachment, infiltration, and morphology, 3-(4, 5-di-methylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (MTT) assay for cell viability and cytotoxicity, tensile strength of the scaffolds mesh, and histology analysis were used. RESULTS: Flow cytometry showed that HFSCs were nestin and CD34 positive but K15 negative. The results of the MTT assay showed cell viability and cell proliferation of the HFSCs on PCL nanofiber scaffolds. SEM microscopy photographs indicated that HFSCs are attached and spread on PCL nanofiber scaffolds. Furthermore, tensile strength of the scaffolds mesh was measured. CONCLUSION: The results of this study revealed that modified PCL nanofiber scaffolds are suitable for HFSCs seeding, attachment, and proliferation. Furthermore, HFSCs are attached and proliferated on PCL nanofiber scaffolds. PMID- 26962525 TI - Vasomotor reactivity comparison in multiple sclerosis patients with white matter lesions and nonmultiple sclerosis subjects with white matter lesions in brain magnetic resonance imaging. AB - BACKGROUND: It has been recognized a close relationship between multiple sclerosis (MS) lesions and the cerebral vasculature. In this study, we observed cerebrovascular vasomotor reactivity difference between the MS patients and the non-MS migraine individuals. MATERIALS AND METHODS: This prospective study was conducted on 40 patients with MS referring to Neurology Clinic of Isfahan Al Zahra Hospital in 2012. The patients were compared with the same number of non-MS migraine individuals. Both groups had white matter lesions in brain magnetic resonance imaging. To evaluate the rate of cerebral artery vasomotor reactivity, transcranial Doppler device was used, and breath-holding index (BHI) was separately calculated for each middle cerebral artery. Main flow velocity (MFV) was determined by continuously recording of a period of 5 min of breathing the air in the room. The obtained data were analyzed using SPSS software version 18 and t-test, Chi-square and analysis of variance tests. RESULTS: The mean values of MFV at rest was not significantly different between cases and control groups (46.21 +/- 4.20 vs. 44.69 +/- 4.34, P = 0.115) but difference between cases and control groups in MFV apnea was significant (59.11 +/- 5.10 vs. 55.35 +/- 6.03, P = 0.004). BHI in the control group was 0.79 +/- 0.26 and in the case group was 0.93 +/- 0.20 and these differences was found to be significant (P < 0.05). CONCLUSION: The mean of BHI and cerebral vasomotor reactivity in MS patients was more than the non-MS migraine individuals, although the mechanism of this process still remains unknown. PMID- 26962526 TI - Coronary atherosclerosis evaluation among Iranian patients with zero coronary calcium score in computed tomography coronary angiography. AB - BACKGROUND: Coronary artery calcification (CAC) is a specific indicator of and a sensitive marker for the atherosclerotic disease process. However, calcium scoring may miss noncalcified plaques with clinical importance. The present study aimed to identify the presence and extent of coronary plaques in computed tomography coronary angiography (CTCA) in patients with a zero CAC score and the secondary endpoint was to evaluate the association between coronary risk factors and the presence of noncalcified plaques. MATERIALS AND METHODS: In a retrospective descriptive-analytic study, a total of 2000 consecutive patients who undergone CTCA between September 2012 and September 2014 at Alzahra Hospital in Isfahan, Iran were analyzed. Three hundred and eighty-five patients with a zero calcium score were included in the study. The demographic information and coronary artery disease (CAD), risk factors including diabetes mellitus (DM), hypertension, hyperlipidemia, smoking, and family history of CAD, were obtained from the questionnaire. Furthermore, the presence of plaques and extent of stenosis were evaluated in patients with zero CAC score. RESULTS: Of the 385 patients with a zero calcium score, 16 (4.2%) had atherosclerotic plaques. Among them, 6 (1.6%) had significant (>50%) coronary stenosis, and 10 (2.6%) had no significant (<50%) coronary stenosis. Hyperlipidemia, DM, and smoking were significantly associated with obstructive CAD. Furthermore, in patients with zero calcium score, DM, hyperlipidemia, and smoking had odds ratios of 5.9, 14, and 32.5 for the development of coronary artery plaques, respectively. CONCLUSION: Although, CAC scoring is a noninvasive and valuable method to evaluate CAD; but zero CAC score does not absolutely exclude the CAD, especially in the presence of risk factors such as diabetes, hyperlipidemia, and smoking. PMID- 26962527 TI - Extralevator Abdominoperineal Resection in the Prone Position. PMID- 26962528 TI - Impact of Visceral Fat Area in Colorectal Surgery. PMID- 26962529 TI - Quality of Life After a Low Anterior Resection in Elderly Patients. PMID- 26962530 TI - Vaginal Approaches Using Synthetic Mesh to Treat Pelvic Organ Prolapse. AB - Pelvic organ prolapse (POP) is a very common condition in elderly women. In women with POP, a sacrocolpopexy or a vaginal hysterectomy with anterior and posterior colporrhaphy has long been considered as the gold standard of treatment. However, in recent decades, the tendency to use a vaginal approach with mesh for POP surgery has been increasing. A vaginal approach using mesh has many advantages, such as its being less invasive than an abdominal approach and easier to do than a laparoscopic approach and its having a lower recurrence rate than a traditional approach. However, the advantages of a vaginal approach with mesh for POP surgery must be weighed against the disadvantages. Specific complications that have been reported when using mesh in POP procedures are mesh erosion, dyspareunia, hematomas, urinary incontinence and so on, and evidence supporting the use of transvaginal surgery with mesh is still lacking. Hence, surgeons should understand the details of the surgical pelvic anatomy, the various surgical techniques for POP surgery, including using mesh, and the possible side effects of using mesh. PMID- 26962531 TI - Short-term Outcomes of an Extralevator Abdominoperineal Resection in the Prone Position Compared With a Conventional Abdominoperineal Resection for Advanced Low Rectal Cancer: The Early Experience at a Single Institution. AB - PURPOSE: This study compared the perioperative and pathologic outcomes between an extralevator abdominoperineal resection (APR) in the prone position and a conventional APR. METHODS: Between September 2011 and March 2014, an extralevator APR in the prone position was performed on 13 patients with rectal cancer and a conventional APR on 26 such patients. Patients' demographics and perioperative and pathologic outcomes were obtained from the colorectal cancer database and electronic medical charts. RESULTS: Age and preoperative carcinoembryonic antigen (CEA) level were significantly different between the conventional and the extralevator APR in the prone position (median age, 65 years vs. 55 years [P = 0.001]; median preoperative CEA level, 4.94 ng/mL vs. 1.81 ng/mL [P = 0.011]). For perioperative outcomes, 1 (3.8%) intraoperative bowel perforation occurred in the conventional APR group and 2 (15.3%) in the extralevator APR group. In the conventional and extralevator APR groups, 12 (46.2%) and 6 patients (46.2%) had postoperative complications, and 8 (66.7%) and 2 patients (33.4%) had major complications (Clavien-Dindo III/IV), respectively. The circumferential resection margin involvement rate was higher in the extralevator APR group compared with the conventional APR group (3 of 13 [23.1%] vs. 3 of 26 [11.5%]). CONCLUSION: The extralevator APR in the prone position for patients with advanced low rectal cancer has no advantages in perioperative and pathologic outcomes over a conventional APR for such patients. However, through early experience with a new surgical technique, we identified various reasons for the lack of favorable outcomes and expect sufficient experience to produce better peri- or postoperative outcomes. PMID- 26962532 TI - Distribution and Impact of the Visceral Fat Area in Patients With Colorectal Cancer. AB - PURPOSE: The purposes of this study were to investigate the distribution of the visceral fat area (VFA) and general obesity and to compare visceral and general obesity as predictors of surgical outcomes of a colorectal cancer resection. METHODS: The prospectively collected data of 102 patients with preoperatively diagnosed sigmoid colon or rectal cancer who had undergone a curative resection at Pusan National University Yangsan Hospital between April 2011 and September 2012 were reviewed retrospectively. Men with a VFA of >130 cm(2) and women with a VFA of >90 cm(2) were classified as obese (VFA-O, n = 22), and the remaining patients were classified as nonobese (VFA-NO, n = 80). RESULTS: No differences in morbidity, mortality, postoperative bowel recovery, and readmission rate after surgery were observed between the 2 groups. However, a significantly higher number of harvested lymph nodes was observed in the VFA-NO group compared with the VFA-O group (19.0 +/- 1.0 vs. 13.5 +/- 1.2, respectively, P = 0.001). CONCLUSION: Visceral obesity has no influence on intraoperative difficulties, postoperative complications, and postoperative recovery in patients with sigmoid colon or rectal cancer. PMID- 26962533 TI - Quality of Life After a Low Anterior Resection for Rectal Cancer in Elderly Patients. AB - PURPOSE: Fecal incontinence is a major concern, and its incidence increases with age. Quality of life may decrease due to fecal incontinence after both sphincter saving surgery and a rectal resection with a permanent stoma. This study investigated quality of life, with regard to fecal incontinency, in elderly patients after rectal-cancer surgery. METHODS: All patients who underwent elective rectal surgery with anastomosis for rectal cancer between December 2008 and June 2012 at two Dutch hospitals were eligible for inclusion. The Wexner and the fecal incontinence quality of life (FIQoL) scores were collected. Young (<70 years of age) and elderly (>=70 years of age) patients were compared. RESULTS: Seventy-nine patients were included, of whom 19 were elderly patients (24.1%). All diverting stomas that had been placed (n = 60, 75.9%) had been closed at the time of the study. There were no differences in Wexner or FIQoL scores between the young and the elderly patients. Also, there were no differences between patients without a diverting stoma and patients in whom bowel continuity had been restored. Elderly females had significantly worse scores on the FIQoL subscales of coping/behavior (P = 0.043) and depression/self-perception (P = 0.004) than young females. Elderly females scored worse on coping/behavior (P = 0.010) and depression/self-perception (P = 0.036) than elderly males. Young and elderly males had comparable scores. CONCLUSION: Quality of life with regard to fecal incontinency is worse in elderly females after sphincter-preserving surgery for rectal cancer. Patients should be informed of this impact, and a definite stoma may be considered in this patient group. PMID- 26962535 TI - Spontaneous Transomental Hernia. AB - A transomental hernia through the greater or lesser omentum is rare, accounting for approximately 4% of internal hernias. Transomental hernias are generally reported in patients aged over fifty. In such instances, acquired transomental hernias are usual, are commonly iatrogenic, and result from surgical interventions or from trauma or peritoneal inflammation. In rare cases, such as the one described in this study, internal hernias through the greater or lesser omentum occur spontaneously as the result of senile atrophy without history of surgery, trauma, or inflammation. A transomental hernia has a high postoperative mortality rate of 30%, and emergency diagnosis and treatment are critical. We report a case of a spontaneous transomental hernia of the small intestine causing intestinal obstruction. An internal hernia with strangulation of the small bowel in the lesser sac was suspected from the image study. After an emergency laparotomy, a transomental hernia was diagnosed. PMID- 26962534 TI - Primary Retroperitoneal Mucinous Cystadenoma. AB - Mucinous cystadenomas and cystadenocarcinomas of the ovary are clinically and histopathologically well-established common tumors. However, primary retroperitoneal mucinous cystic tumors are extremely rare, and although their histopathogenesis is still uncertain, several theories have been proposed. Most authors suggest that they develop through mucinous metaplasia in a preexisting mesothelium-lined cyst. An accurate preoperative diagnosis of these tumors is difficult because no effective diagnostic measures have been established. Delay in diagnosis and treatment of this tumor may be fatal for the patient because of complications such as rupture, infection, and malignant transformation. We describe the case of a 31-year-old woman with abdominal pain and a palpable mass. Computed tomography of the abdomen revealed a retroperitoneal cystic mass, which was resected successfully through laparoscopy. Histopathological examination of the resected mass confirmed the diagnosis of a primary retroperitoneal mucinous cystadenoma. The patient was discharged on postoperative day 5 without any complications. PMID- 26962536 TI - Investigation on Furan Levels in Pressure-Cooked Foods. AB - Furan is a food processing contaminant classified as possibly carcinogenic to humans. As the occurrence of furan has been reported in a variety of foods processed in sealed containers, the objective of this work was to investigate if the contaminant can be found in home-cooked foods prepared in a pressure cooker. For that, several foods including beans, soy beans, whole rice, beef, pork, potato, and cassava were pressure-cooked and analyzed for the furan content by gas chromatography coupled to mass spectrometry preceded by a headspace solid phase microextraction (HS-SPME-GC/MS). Furan was not found above the limit of quantification in the pressure-cooked samples. No furan has either been found in reheated samples after 24 hours under cold storage. Although levels up to 173 MUg/kg were already reported for commercial canned/jarred foods, it seems that the cooking in a pressure cooker may not represent a concern in relation to the occurrence of furan in foods. PMID- 26962538 TI - Hyperinsulinism Hyperammonemia Syndrome, a Rare Clinical Constellation. AB - We present the unique case of adult hyperinsulinism hyperammonemia syndrome (HI/HA). This condition is rarely seen in children and even more infrequently in adults. A 27-year-old female with HI/HA, generalized tonic-clonic seizures, staring spells, and gastroesophageal reflux disease presented with diffuse abdominal pain, hypoglycemia, confusion, and sweating. She reported a history of significant nausea, vomiting, and diarrhea, which had been present intermittently over the past year. On examination, she was found to have a soft, nontender, and mildly distended abdomen without splenomegaly or masses. She had a normal blood pressure and was tachycardic (130 bpm). Her initial complete blood count and basic metabolic panel, excluding glucose, were within normal limits. She was found to have an elevated peripherally drawn venous ammonia (171 mmol/L) and near hypoglycemia (blood glucose 61 mg/dL), which were drawn given her history of HI/HA. She was continued on home carglumic acid and diazoxide, glucose was supplemented intravenously, and she was started on levetiracetam for seizure prophylaxis. An upper endoscopy (esophagogastroduodenoscopy [EGD]) was performed and was unremarkable, and biopsies taken were within normal limits. Following the EGD, she underwent a gastric emptying study that showed delayed emptying (216 minutes), consistent with a new diagnosis of gastroparesis, the likely etiology of her initial abdominal pain on presentation. This was subsequently treated with azithromycin oral solution. We present this case to raise awareness of this rarely encountered syndrome and to provide the basic principles of treatment. PMID- 26962537 TI - JNK1 Deficient Insulin-Producing Cells Are Protected against Interleukin-1beta Induced Apoptosis Associated with Abrogated Myc Expression. AB - The relative contributions of the JNK subtypes in inflammatory beta-cell failure and apoptosis are unclear. The JNK protein family consists of JNK1, JNK2, and JNK3 subtypes, encompassing many different isoforms. INS-1 cells express JNK1alpha1, JNK1alpha2, JNK1beta1, JNK1beta2, JNK2alpha1, JNK2alpha2, JNK3alpha1, and JNK3alpha2 mRNA isoform transcripts translating into 46 and 54 kDa isoform JNK proteins. Utilizing Lentiviral mediated expression of shRNAs against JNK1, JNK2, or JNK3 in insulin-producing INS-1 cells, we investigated the role of individual JNK subtypes in IL-1beta-induced beta-cell apoptosis. JNK1 knockdown prevented IL-1beta-induced INS-1 cell apoptosis associated with decreased 46 kDa isoform JNK protein phosphorylation and attenuated Myc expression. Transient knockdown of Myc also prevented IL-1beta-induced apoptosis as well as caspase 3 cleavage. JNK2 shRNA potentiated IL-1beta-induced apoptosis and caspase 3 cleavage, whereas JNK3 shRNA did not affect IL-1beta-induced beta-cell death compared to nonsense shRNA expressing INS-1 cells. In conclusion, JNK1 mediates INS-1 cell death associated with increased Myc expression. These findings underline the importance of differentiated targeting of JNK subtypes in the development of inflammatory beta-cell failure and destruction. PMID- 26962539 TI - Prevalence of Scapular Dyskinesis in Overhead and Nonoverhead Athletes: A Systematic Review. AB - BACKGROUND: Scapular dyskinesis, or abnormal dynamic scapular control, is a condition that is commonly associated with shoulder pathology but is also present in asymptomatic individuals. Literature varies on whether it represents a cause or symptom of shoulder pathology, but it is believed to be a risk factor for further injury. Clinical identification focuses on visual observation and examination maneuvers. Treatment of altered scapular motion has been shown to improve shoulder symptoms. It is thought to be more common in overhead athletes due to their reliance on unilateral upper extremity function but the incidence within nonoverhead athletes is unknown. HYPOTHESIS: Overhead athletes will have a greater prevalence of scapular dyskinesis when compared with nonoverhead athletes. STUDY DESIGN: Systematic review; Level of evidence, 3. METHODS: After PROSPERO registration, a systematic review was performed using PRISMA guidelines through the PubMed database looking for studies published before October 2014. All studies containing the search terms scapular, scapulothoracic, dyskinesis, dyskinesia, shoulder athlete, or overhead athlete were included. Studies that did not include prevalence data for scapular dyskinesis were excluded. Study methodological quality was evaluated using the modified Coleman methodology score. Descriptive statistics and 2-proportion 2-tailed z-tests were used to compare the reported prevalence of scapular dyskinesis between overhead and nonoverhead athletes. RESULTS: Twelve studies were analyzed including 1401 athletes (1257 overhead and 144 nonoverhead; mean age, 24.4 +/- 7.1 years; 78% men). All the studies were evidence level 2 (33%) or level 3 (67%). The reported prevalence of scapular dyskinesis was significantly (P < .0001) higher in overhead athletes (61%) compared with nonoverhead athletes (33%). CONCLUSION: Scapular dyskinesis was found to have a greater reported prevalence (61%) in overhead athletes compared with nonoverhead athletes (33%). CLINICAL RELEVANCE: Prevalence data for scapular dyskinesis are scarce within the literature. Information on the reported prevalence, laterality, and association with the dominant extremity will allow for better allocation of diagnostic and therapeutic interventions. Recognition and treatment will help athletes to optimize functional performance and decrease the risk of further shoulder injury. PMID- 26962540 TI - The Prevalence of Obesity and Elevated Blood Pressure in Adolescent Student Athletes From the State of Mississippi. AB - BACKGROUND: Over the past 30 years, there has been a dramatic increase in the prevalence of childhood obesity and hypertension in the United States. The prevalence of these diagnoses among individuals participating in school sanctioned sports has not been clearly defined. PURPOSE: To identify the prevalence of obesity and elevated blood pressure (BP) among student athletes and investigate associations between race, sex, type and number of sports played, and the prevalence of these diseases. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Pre-sports participation medical examinations (N = 7705) performed between 2009 and 2013 were reviewed to identify the prevalence of obesity and elevated BP and examine relationships between the type of sports played, participation in multiple sports versus a single sport, and the athlete's body weight and body mass index (BMI). RESULTS: The prevalence of obesity was 23.5%. There was a significant association (P < .001) between the number of sports played by the student and BMI. The risk of obesity among single-sport athletes was more than 2-fold the risk (relative risk [RR], 2.13) compared with >=3-sport athletes and 1.42 times greater compared with 2-sport athletes (RR, 1.42). The prevalence of elevated BP was 21.2%. There was a significant association (P < .001) between the number of sports played by the student and elevated BP. The risk of elevated BP among single-sport athletes was 1.59 times greater (RR, 1.59) than >=3-sport athletes and 1.30 times greater compared with 2 sport athletes (RR, 1.30). Finally, obese students were 2.40 times more likely to have elevated BP compared with nonobese students (P < .001). CONCLUSION: The result of this study confirms the progressive nature of the obesity epidemic and identifies the contribution of obesity to the worsening cardiometabolic profiles in student athletes. The study also identifies that participation in multiple sports and running sports decreases the individual's risk for obesity and hypertension. CLINICAL RELEVANCE: The present study emphasizes the importance of screening for obesity and elevated blood pressure during the athlete's preparticipation physical examination. PMID- 26962541 TI - Upper Extremity Injuries in NASCAR Drivers and Pit Crew: An Epidemiological Study. AB - BACKGROUND: Understanding the position-specific musculoskeletal forces placed on the body of athletes facilitates treatment, prevention, and return-to-play decisions. While position-specific injuries are well documented in most major sports, little is known about the epidemiology of position-specific injuries in National Association for Stock Car Automobile Racing (NASCAR) drivers and pit crew. PURPOSE: To investigate position-specific upper extremity injuries in NASCAR drivers and pit crew members. STUDY DESIGN: Descriptive epidemiological study. METHODS: A retrospective chart review was performed to assess position specific injuries in NASCAR drivers and pit crew members. Included in the study were patients seen by a single institution between July 2003 and October 2014 with upper extremity injuries from race-related NASCAR events or practices. Charts were reviewed to identify the diagnosis, mechanism of injury, and position of each patient. RESULTS: A total of 226 NASCAR team members were treated between July 2003 and October 2014. Of these, 118 injuries (52%) occurred during NASCAR racing events or practices. The majority of these injuries occurred in NASCAR changers (42%), followed by injuries in drivers (16%), carriers (14%), jack men (11%), fuel men (9%), and utility men (8%). The majority of the pit crew positions are at risk for epicondylitis, while drivers are most likely to experience neuropathies, such as hand-arm vibration syndrome. The changer sustains the most hand-related injuries (42%) on the pit crew team, while carriers commonly sustain injuries to their digits (29%). CONCLUSION: Orthopaedic injuries in NASCAR vary between positions. Injuries in NASCAR drivers and pit crew members are a consequence of the distinctive forces associated with each position throughout the course of the racing season. Understanding these forces and position-associated injuries is important for preventive measures and facilitates diagnosis and return-to-play decisions so that each team can function at its maximal efficiency. PMID- 26962542 TI - How Accurate Are Patients at Diagnosing the Cause of Their Knee Pain With the Help of a Web-based Symptom Checker? AB - BACKGROUND: Researching medical information is the third most popular activity online, and there are a variety of web-based symptom checker programs available. PURPOSE: This study evaluated a patient's ability to self-diagnose their knee pain from a list of possible diagnoses supplied by an accurate symptom checker. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: All patients older than 18 years who presented to the office of 7 different fellowship-trained sports medicine surgeons over an 8-month period with a complaint of knee pain were asked to participate. A web-based symptom checker for knee pain was used; the program has a reported accuracy of 89%. The symptom checker generates a list of potential diagnoses after patients enter symptoms and links each diagnosis to informative content. After exploring the informative content, patients selected all diagnoses they felt could explain their symptoms. Each patient was later examined by a physician who was blinded to the differential generated by the program as well as the patient-selected diagnoses. A blinded third party compared the diagnoses generated by the program with those selected by the patient as well as the diagnoses determined by the physician. The level of matching between the patient-selected diagnoses and the physician's diagnoses determined the patient's ability to correctly diagnose their knee pain. RESULTS: There were 163 male and 165 female patients, with a mean age of 48 years (range, 18-76 years). The program generated a mean 6.6 diagnoses (range, 2-15) per patient. Each patient had a mean 1.7 physician diagnoses (range, 1-4). Patients selected a mean 2 diagnoses (range, 1-9). The patient-selected diagnosis matched the physician's diagnosis 58% of the time. CONCLUSION: With the aid of an accurate symptom checker, patients were able to correctly identify the cause of their knee pain 58% of the time. PMID- 26962543 TI - Design and implementation of coded aperture coherent scatter spectral imaging of cancerous and healthy breast tissue samples. AB - A scatter imaging technique for the differentiation of cancerous and healthy breast tissue in a heterogeneous sample is introduced in this work. Such a technique has potential utility in intraoperative margin assessment during lumpectomy procedures. In this work, we investigate the feasibility of the imaging method for tumor classification using Monte Carlo simulations and physical experiments. The coded aperture coherent scatter spectral imaging technique was used to reconstruct three-dimensional (3-D) images of breast tissue samples acquired through a single-position snapshot acquisition, without rotation as is required in coherent scatter computed tomography. We perform a quantitative assessment of the accuracy of the cancerous voxel classification using Monte Carlo simulations of the imaging system; describe our experimental implementation of coded aperture scatter imaging; show the reconstructed images of the breast tissue samples; and present segmentations of the 3-D images in order to identify the cancerous and healthy tissue in the samples. From the Monte Carlo simulations, we find that coded aperture scatter imaging is able to reconstruct images of the samples and identify the distribution of cancerous and healthy tissues (i.e., fibroglandular, adipose, or a mix of the two) inside them with a cancerous voxel identification sensitivity, specificity, and accuracy of 92.4%, 91.9%, and 92.0%, respectively. From the experimental results, we find that the technique is able to identify cancerous and healthy tissue samples and reconstruct differential coherent scatter cross sections that are highly correlated with those measured by other groups using x-ray diffraction. Coded aperture scatter imaging has the potential to provide scatter images that automatically differentiate cancerous and healthy tissue inside samples within a time on the order of a minute per slice. PMID- 26962545 TI - Mix Infections of Helicobacter pylori: A Major Risk Factor Affecting Genotyping Studies. PMID- 26962544 TI - Optimal Decomposition of Service Level Objectives into Policy Assertions. AB - WS-agreement specifies quality objectives that each partner is obligated to provide. To meet quality objectives, the corresponding partner should apply appropriate policy assertions to its web services and adjust their parameters accordingly. Transformation of WS-CDL to WSBPEL is addressed in some related works, but neither of them considers quality aspects of transformation nor run time adaptation. Here, in conformance with web services standards, we propose an optimal decomposition method to make a set of WS-policy assertions. Assertions can be applied to WSBPEL elements and affect their run-time behaviors. The decomposition method achieves the best outcome for a performance indicator. It also guarantees the lowest adaptation overhead by reducing the number of service reselections. We considered securities settlement case study to prototype and evaluate the decomposition method. The results show an acceptable threshold between customer satisfaction-the targeted performance indicator in our case study-and adaptation overhead. PMID- 26962546 TI - Why isn't Contrast Enhanced Ultrasound for Focal Liver Lesions used more in daily practice? PMID- 26962547 TI - Feasibility of Transient Elastography with M and XL probes in real life. AB - AIM: Reliable liver stiffness measurements (RLSM) using Transient Elastography (TE) with the standard M probe are difficult to obtain in overweight (BMI>=25kg/m2) and obese (BMI>30kg/m2) patients. The aim of our paper was to assess the feasibility of TE in daily practice using both M and XL probes. MATERIAL AND METHOD: We studied retrospectively 3235 patients with chronic liver disease assessed by TE first by the M probe (standard probe - transducer frequency 3.5 MHz), and if the measurements were unreliable, with the XL probe (transducer frequency 2.5 MHz). Reliable measurements were defined as the median of 10 valid measurements with a success rate >= 60% and an interquartile range < 30%. Results of liver elasticity were expressed in kilo Pascals (kPa). RESULTS: RLSM by M probe were obtained in 62.2% (2015/3235) patients, and by XL probe in 1011/1220 (80%) of patients with unreliable measurements by M probe; thus we obtained RLSM in 93.5% of 3235 cases. In overweight patients we obtained RLSM in 89.9% (1039/1156) cases: in 63.1% (729) by M probe and in 26.8% (310) by XL probe. In obese patients we obtained RLSM in 83.8% (746/890): in 18.4% (164) by M probe and in 65.4% (582) by XL probe. Thus, by using both probes, RLSM were obtained in 1785 (87.2%) of overweight and obese patients. CONCLUSION: The feasibility of the M probe was 62.2% in our Department. Reliable measurements using M or XL probe allowed the evaluation of liver stiffness in 93.5% of cases. By using both M and XL probes, reliable LSM by TE can be obtained in the majority of obese and overweight patients (87.2%). PMID- 26962548 TI - Is the spleen stiffness value acquired using acoustic radiation force impulse (ARFI) technology predictive of the presence of esophageal varices in patients with cirrhosis of various etiologies? AB - AIM: This study's aimwas to determine the accuracy of the spleen stiffness value acquired using acoustic radiation force impulse (ARFI) technology, to predict the presence of esophageal varices (EVs) in patients with liver cirrhosis of various etiologies. MATERIAL AND METHODS: Of the 366 enrolled patients, 192 had hepatitis B virus, 74 had hepatitis C virus, and 100 had alcohol-related cirrhosis. All patients underwent biochemical tests, gastrointestinal endoscopy, and liver and spleen elastography by ARFI. We evaluated the correlation between the presence of EVs and factors including liver and spleen stiffness measured by ARFI, biochemical tests, and other noninvasive measurements, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count (PLT), spleen diameter (SD), PLT to SD ratio, AST to ALT ratio (AAR) score, the AST to PLT ratio index (APRI) score. RESULTS: A univariate analysis revealed that the AAR score, APRI score, PLT, PLT/SD ratio, and spleen elastography variables were all independently associated with EVs (p<0.05). On multivariate analysis, only spleen elastography was associated with EVs (p=0.001). However, in cases of alcohol-induced liver cirrhosis, spleen stiffness was not reliable for the prediction of EVs. CONCLUSION: Spleen elastography measured using ARFI may serve as a non-invasive method for determining the presence of EVs. However, it is not an appropriate predictor for EVs in alcoholic cirrhosis. PMID- 26962549 TI - Clinical impact of EUS elastography followed by contrast-enhanced EUS in patients with focal pancreatic masses and negative EUS-guided FNA. AB - AIMS: It is well known that endoscopic ultrasound guided fine needle aspiration (EUS-FNA) has a high sensitivity (over 85%) and specificity (100%) for diagnosis of pancreatic cancer. The aim of the study was to establish a EUS based clinical diagnostic algorithm in patients with pancreatic masses and negative cytopathology after EUS-FNA, based on previously published results and cut-offs of real-time elastographic (RTE) EUS and contrast-enhanced harmonic (CEH) EUS. MATERIAL AND METHODS: We included in the study a subgroup of 50 consecutive patients with focal pancreatic masses which underwent EUS examinations with negative EUS-FNA. RTE-EUS and CEH-EUS were performed sequentially in all patients. The sensitivity, specificity and accuracy of these methods were calculated separately. A clinical decision algorithm based on elastography followed by CEH was established. RESULTS: For the diagnosis of possible malignancy, the sensitivity, specificity and accuracy of RTE-EUS were: 97.7%, 77.4%, and 84% respectively. CEH-EUS had similar results: 89.5%, 80.7%, and 84%, respectively. In 25 patients with soft/mixed appearance during elastography,sequential assessment using contrast-enhanced EUSwas performed. The specificity of CEH-EUS for detection of chronic pancreatitis in this sub-set of patients was excellent (100%). In other 25 patients with hard appearance in elastography (low strain) CEH-EUS had an excellent specificity (100%) and accuracy (93%) in the detection of pancreatic cancer. CONCLUSIONS: The proposed algorithm with sequential use of elastography followed by CEH could be a good clinical tool in the set of patients with negative EUS-FNA results for the differentiation between benign and malignant focal pancreatic masses. PMID- 26962550 TI - Tumor protrusion with intensive blood signals on ultrasonography is a strongly suggestive finding of follicular thyroid carcinoma. AB - AIM: It is difficult to differentiate follicular carcinomas (FC) from follicular adenomas (FA) because ultrasonography and cytology provide very similar findings. FC is histopathologically diagnosed to have capsular and/or vascular invasion. In a few patients, tumor protrusions are observed by preoperative ultrasonography as large forms of capsular invasion of follicular carcinomas. The aim of the study was to clarify the predictive value of tumor protrusions on preoperative ultrasonography for follicular carcinomas. MATERIAL AND METHODS: A total of 531 patients (FC: 184 patients, FA: 347 patients) undergoing thyroid surgery were included in this study. A tumor protrusion on ultrasonography was defined as follows: 1) a solid tumor extending beyond a marginal line of capsular zone of the main tumor on B-mode ultrasonography; 2) intensive blood signals observed within the protrusion area on Doppler ultrasonography. The large form of capsular invasion was defined if the protrusion lesion was histopathologically diagnosed to be a capsular invasion of follicular carcinoma. RESULTS: The sensitivity of tumor protrusion was 0.071, specificity 0.994, positive predictive value 0.867, and negative predictive value 0.669 for FC diagnosis. For the large form of capsular invasion in FC the sensitivity of tumor protrusion was 0.813, specificity 0.982, positive predictive value 0.684, and negative predictive value 0.982. CONCLUSIONS: A tumor protrusion with intensive blood signals extending from the main tumor on ultrasonography strongly suggests a large form of capsular invasion of follicular carcinoma. PMID- 26962551 TI - Structural tendon changes in patients with acromegaly: assessment of Achilles tendon with sonoelastography. AB - AIMS: To describe the sonoelastographic appearance of the Achilles tendon in acromegalic patients and to determine whether the blood concentrations of growth hormone (GH) and insulin-like growth factor (IGF-1) are associated with the various sonographic elasticity types of Achilles tendons. MATERIAL AND METHODS: Eighty-four Achilles tendons of 42 acromegaly patients and 84 Achilles tendons of 42 healthy volunteers were assessed with sonoelastography. The tendons were classified into two main types according to the elasticity features: type 1 blue/green (hard tissue) and type 2 yellow/red within green (intermediate-soft tissue). Two subtypes of these types were also defined. According to the definition, the elasticity of the tissue was in a spectrum ranging from hard to soft as the type progressed from 1a to 2b. RESULTS: The mean thickness of Achilles tendons in patients with acromegaly was significantly higher compared with healthy Achilles tendons (5.1+/-0.7 mm vs. 4.4+/-0.5, p<0.001), and patients with active disease had thicker Achilles tendons (5.5+/-0.8 mm vs. 4.8+/-0.5 mm in inactive disease, p=0.003). A significantly higher proportion of acromegaly patients had type 2 sonoelastographic appearance of the Achilles tendon (124/252 third; 49.2% vs. 81/252 third; 32.1%, p=0.0001). Activity status of acromegaly and GH/IGF-I levels were similar in patients with different types of elasticity (p>0.05). CONCLUSIONS: Sonoelastography revealed structural changes in the tendinous tissue of patients with acromegaly, but it was not sensitive enough to reflect changes in the serum levels of GH/IGF-1. PMID- 26962552 TI - Ultrasonographic evaluation of the median nerve at the level of the carpal tunnel outlet and mid forearm in patients with type II Mucopolysaccharidosis. AB - AIMS: The ultrasonographic (US) evaluation of the median nerve at the level of the carpal tunnel outlet (CTO) and mid forearm in pediatric patients with mucopolysaccharidosis type II (MPS II) and comparison with healthy subjects. MATERIAL AND METHOD: Fifteen children with MPS II and 44 healthy children were included in the study and they were divided into three age groups. The cross sectional area, the appearance of the nerve, and the ratio of the cross-sectional areas were evaluated by US. RESULTS: At the level of the CTO the mean area of the nerve was increased in all MPS II groups compared with the correspondent healthy age groups and the differences were statistically significant (p<0.01). At the level of the mid forearm the differences were statistically significant only for the first age group. Other US findings at the level of the CTO in the MPS II groups were represented by hypoechogenicity (86.67 % on the right and 93.33% on the left), thickened fascicles (80% bilaterally), irregular contour (53.33% bilaterally) and the presence of the Doppler signal including the nerve (26.67 % on the right and 33.33 % on the left). The CTO/mid forearm cross-sectional area ratio was higher in all MPS II age groups and the differences were statistically significant (p<0.001). CONCLUSION: In patients with MPS II there are significant US changes in the size and aspect of the median nerve. PMID- 26962553 TI - EFSUMB COMPASS for Rheumatologists dissemination and implementation--an international survey. AB - AIM: The European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) competency assessment (COMPASS) for rheumatologists performing musculoskeletal ultrasound (MSUS) was developed and published 2 years ago. It consists of a 3 level competency system. The objective of this study was to evaluate how the EFSUMB COMPASS has been disseminated and implemented and to assess the potential obstacles encountered. MATERIALS AND METHODS: A questionnaire was developed and distributed by e-mail to all rheumatologists certified as EFSUMB level 3. RESULTS: Seventeen (85%) rheumatologists considered that the EFSUMB COMPASS is useful for training MSUS. The majority of them (17; 85%) had informed their colleagues or national rheumatology societies about the EFSUMB COMPASS. The most common obstacle encountered for the implementation of the COMPASS was the lack of time for supervision of the trainees (9; 45%). A total of 83 rheumatologists had been trained and assessed for competency in the three EFSUMB levels. CONCLUSION: This survey highlights the current status of EFSUMB COMPASS implementation in European countries with an expected increased number of rheumatologists being able to train and assess new trainees. Still, more efforts should be done for a higher implementation of EFSUMB COMPASS across European countries. PMID- 26962554 TI - Subclinical myocardial impairment in SLE: insights from novel ultrasound techniques and clinical determinants. AB - AIMS: Myocardial damage is frequent and often silent in systemic lupus erythematosus (SLE). The aim of the study was to determine the prevalence of myocardial damage by novel ultrasound techniques and to systematically assess the relationship between subclinical cardiac dysfunction and SLE-related clinical parameters. MATERIAL AND METHODS: Seventy-five consecutive SLE patients without evidence of cardiac disease and seventy-three controls underwent standard transthoracic echocardiography using classical and novel ultrasound techniques: tissue Doppler imaging and speckle tracking echocardiography. Patient characteristics, cumulative organ damage and laboratory data were retrieved by medical chart review. RESULTS: Within the cohort, 89.3% of the patients were female; mean+/-SD age and median (IQR) disease duration were 43.2+/-12.5 years and 8.03(6.3) years, respectively. SLE patients exhibited a significant decrement in endocardial longitudinal strain (-18.4% vs 19.3%, p=0.001) compared with controls. Diastolic dysfunction was detected in 34 (45.3%) of SLE patients. Major determinants of systolic and diastolic dysfunction were hypertension (p=0.023 and p<0.001, respectively), associated antiphospholipid syndrome (APS) (p<0.001 and p<0.001, respectively), cumulative damage accrual (p<0.001 and p=0.003, respectively), and disease duration (p=0.03 and p<0.001, respectively). Notably, anti-Ro antibodies were present in 37% of the SLE patients who had better systolic longitudinal performance. Neither disease activity, nor specific organ involvement, were associated with myocardial impairment. CONCLUSION: Systolic longitudinal and diastolic performance impairments are frequent findings in SLE patients without overt cardiovascular disease. Cumulative organ damage, disease duration, APS, and hypertension are major determinants for early heart involvement in SLE patients. PMID- 26962557 TI - A novel approach to assessing fetal tissue stiffness using virtual touch tissue quantification. AB - AIMS: Virtual touch tissue quantification (VTTQ) has been widely used in adults, but its application in fetuses has not been reported. The purposes of this study were to describe the normal shear wave velocity (SWV) values of fetal brain, lung, and liver by VTTQ and to examine the clinical usefulness of this procedure in THE evaluation of gestational age-related SWV changes in the fetal brain, lung and liver. MATERIAL AND METHODS: One hundred fetuses were enrolled in this study and were evaluated at 18 weeks (second trimester) and 35 weeks (third trimester) during pregnancy. The SWV was measured at the cerebral parenchyma, thalamus, cerebellum, choroid plexus, left lung, right lung, right and left lobe of the liver in each participant. RESULTS: The SWV at the cerebral parenchyma were all significantly greater in the third trimesters than in the second trimesters (3.29+/-1.05 vs. 2.22+/-0.97 m/s, p<0.001), while the velocities at thalamus, cerebellum, choroid plexus, left lung, right lung, right lobe of the liver and left lobe of the liver did not differ between the second and the third trimesters (p>0.05). Moreover, the SWV at the cerebral parenchyma correlated significantly with gestational age (r=0.47, p<0.001). CONCLUSIONS: VTTQ can provide numerical measurements of fetal brain, lung and liver stiffness and can effectively and objectively indicate gestational age-related changes in cerebral parenchyma stiffness by measuring SWV values. PMID- 26962556 TI - Ultrasound in diagnosis of anatomical variation of anterior and posterior tibial arteries. AB - AIMS: Knowledge about branching pattern of the popliteal artery is very important in any clinical settings involving the anterior and posterior tibial arteries. This study aims to elucidate the anatomical variation patterns and common types of anterior tibial artery (ATA) and posterior tibial arteries (PTA) in the general population in China. MATERIAL AND METHODS: Anatomical variations of ATA, PTA, and peroneal artery were evaluated with ultrasound in a total of 942 lower extremity arteries in 471 patients. RESULTS: Three patterns of course in the PTA were ultrasonographically identified: 1) PTA1: normal anatomy with posterior tibial artery entering tarsal tunnel to perfuse the foot (91.5%), 2) PTA2: tibial artery agenetic, and replaced by communicating branches of peroneal artery entering tarsal tunnel above the medial malleolus to perfuse the foot (5.9%), and 3) PTA3: hypoplastic or aplastic posterior tibial artery communicating above the medial malleolus with thick branches of peroneal artery to form a common trunk entering into the tarsal tunnel (2.4%). In cases where ATA was hypoplastic or aplastic, thick branches of the peroneal artery replaced the anterior tibial artery to give rise to dorsalis pedis artery, with a total incidence of 3.2 % in patients, and were observed more commonly in females than in males. Hypoplastic or aplastic termini of ATA and PTA, with perfusion of the foot solely by the peroneal artery, was identified in 1 case. In another case, both communicating branches of the peroneal artery and PTA entered the tarsal tunnel to form lateral and medial plantar arteries. CONCLUSIONS: Anatomical variation of ATA and PTA is relatively common in the normal population. Caution should be exercised with these variations when preparing a peroneal artery vascular pedicle flap grafting. Ultrasound evaluation provides accurate and reliable information on the variations. PMID- 26962555 TI - Nitroglycerin mediated dilation evaluated by ultrasound is associated with sTWEAK in hemodialysis patients. AB - AIMS: The main cause of death in hemodialysis (HD) patients is cardiovascular disease. Ultrasound assessment of the brachial artery dysfunction is easily achievable and can non-invasively detect atherosclerosis in various stages. In HD patients the cardiovascular risk profile is different and the determinants of brachial arterial function can be distinct comparing with general population. The aim of the study is to assess the determinants of arterial brachial function (flow-mediated and nitroglycerin-mediated dilation) evaluated by ultrasound in HD patients and their relation with tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) described as atherosclerotic marker in chronic kidney disease patients. MATERIAL AND METHODS: We conducted a cross-sectional observational study on 54 hemodialysis patients. We recorded clinical and biological data and we measured sTWEAK serum levels by ELISA. We evaluated the arterial brachial function by measurement of flow-mediated and nitroglycerin-mediated dilation, using B mode ultrasound. RESULTS: The determinants of flow-mediated dilation were: Kt/V (r=0.47, p<0.001), LDL-cholesterol (r=0.29, p=0.04), and total cholesterol (r=0.31, p=0.02). Flow-mediated dilation correlated with nitroglycerin-mediated dilation (r=0.70, p<0.001). In multivariate analysis kt/V was the only significant predictor for flow-mediated dilation (p=0.04). Nitroglycerin-mediated dilation correlates with sTWEAK (r=-0.30, p=0.03), systolic blood pressure (r=-0.28, p=0.04) and pulse pressure (r=-0.31, p=0.02). In multivariate analysis sTWEAK was the only significant predictor for nitroglycerin-mediated dilation (p=0.04). CONCLUSIONS: The main determinant of nitroglycerin-mediated dilation was sTWEAK. In addition, decreased nitroglycerin mediated dilation was associated with higher systolic blood pressure and pulse pressure. The main determinant of FMD was Kt/V. Increased flow-mediated dilation was associated with better dialysis efficiency and high total cholesterol and LDL cholesterol. PMID- 26962558 TI - Multimodal endocavitary ultrasound versus MRI and clinical findings in pre- and post-treatment advanced cervical cancer. Preliminary report. AB - AIMS: The aim of this study was to evaluate the use of pre and post-therapy transrectal and transvaginal ultrasonography (TRUS, TVUS) with contrast enhancement and strain elastography compared with clinical examination and magnetic resonance imaging (MRI) in the assessment of advanced stage cervical cancer. MATERIAL AND METHODS: This was a prospective study, carried out over a period of nine months on subjects with advanced-stage cervical cancer (stage >/= IIB). All included patients were examined clinically and underwent abdomino pelvic contrast enhanced MRI and multimodal US examinations (TRUS with strain elastography and contrast enhanced TVUS) at the time of diagnosis and after radiochemotherapy. Tumor size and staging at TRUS and TVUS was compared with the same data obtained by clinical examination and MRI. Pathology was the golden standard. RESULTS: Eight patients accomplished the inclusion criteria. In five cases the tumor stage was identical on clinical and MRI examinations. In all cases parametrial infiltration was diagnosed by all pre-treatment examinations. No significant differences were observed in tumor size between clinical, US and MRI exams either at baseline or post-therapy, in native or post-contrast examinations. The size of the tumor evaluated pre-treatment proved to be significantly smaller post-contrast in both US and MRI examinations compared with the native images. Post-therapy, no significant differences were observed on US measured tumor dimensions when comparing native with post-contrast images. Oppositely, significant smaller dimensions were observed on post-contrast MRI compared with native scans. CONCLUSIONS: TRUS is accurate in the estimation of pre-therapy cervical cancer dimension. The post therapy tumor evaluation is better performed with MRI. The use of intravenous contrast agents on both examinations did not improved the accuracy of tumor evaluation pre or post therapy. PMID- 26962559 TI - Concepts in monitoring enthesitis in patients with spondylarthritis--the role of musculoskeletal ultrasound. AB - Enthesitis is the key pathological lesion in the spondyloarthritides group and an important element for early diagnosis with a predictive and prognostic value. The recognition of enthesitis on a clinical basis alone remains a challenge and creates unnecessary delays in diagnosis and adequate treatment commencement. Musculoskeletal ultrasound is a valid, reliable, and feasible imaging tool valuable for identifying inflammatory and structural lesions at enthesis level, helpful in establishing a diagnosis, evaluating disease activity and therapy monitoring. This paper focuses on the most relevant aspects of current literature regarding enthesitis and highlights the musculoskeletal ultrasound added value in enthesis assessment. PMID- 26962560 TI - Ultrasonography in the diagnosis and management of non inflammatory conditions of the hand and wrist. AB - High resolution ultrasonography has already become an important tool in the diagnosis and management of inflammatory arthritis of the hand and wrist but lately it has been proven to be the method of choice in the evaluation of traumatic lesions of tendons, annular pulleys, nerves, and ligaments and at the same time in detecting foreign bodies. The objective of this paper is to review and describe the current knowledge on these US findings and to highlight the ultrasonography role in the evaluation of non-inflammatory conditions of the hand and wrist. PMID- 26962561 TI - Contrast enhanced ultrasonography in assessing the treatment response to transarterial chemoembolization in patients with hepatocellular carcinoma. AB - The last decades have known continuous development of therapeutic strategies in hepatocellular carcinoma (HCC). Unfortunately the disease it still not diagnosed until it is already at an intermediate or even an advanced disease. In these circumstances transarterial chemoembolization (TACE) is considered an effective treatment for HCC. The most important independent prognostic factor of both disease free survival and overall survival is the presence of complete necrosis. Therefore, treatment outcomes are dictated by the proper use of radiological imaging. Current guidelines recommend contrast enhanced computer tomography (CECT) as the standard imaging technique for evaluating the therapeutic response in patients with HCC after TACE. One of the most important disadvantage of CECT is the overestimation of tumor response. As an attempt to overcome this limitation contrast enhanced ultrasound (CEUS) has gained particular attention as an imaging modality in HCC patients after TACE. Of all available imaging modalities, CEUS performs better in the early and very early assessment of TACE especially after lipiodol TACE. As any other imaging techniques CEUS has disadvantages especially in hypovascular tumors or in cases of tumor multiplicity. Not far from now the current limitations of CEUS will be overcome by the new CEUS techniques that are already tested in clinical practice such as dynamic CEUS with quantification, three-dimensional CEUS or fusion techniques. PMID- 26962562 TI - The usefulness of fetal Doppler evaluation in early versus late onset intrauterine growth restriction. Review of the literature. AB - Intrauterine growth restriction (IUGR) represents a serious condition that can lead to increased perinatal morbidity, mortality and postnatal impaired neurodevelopment. There are two distinct phenotypes of IUGR: early onset and late onset IUGR with different onset, patterns of evolution and fetal Doppler profile. In early onset preeclampsia the main Doppler modifications are at the level of umbilical artery, with progressive augmentation of the pulsatility index to absent or reverse end diastolic flow. The modifications of the cerebral, cardiac and ductus venosus circulation are generally present, but with different sequences. The late onset IUGR is determined by third trimester placental insufficiency that entails fetal hypoxia. The cerebro-placental ratio (CPR) and the pulsatility index of the middle cerebral artery (PI MCA) seems to be the main markers for both diagnosis and obstetrical management while umbilical Doppler PI is frequently normal. Also the sequence of Doppler alterations is neither specific nor complete. New protocols for the diagnosis and management of late onset IUGR need to be implemented. PMID- 26962563 TI - Contrast enhanced harmonic ultrasonography for the evaluation of acute scrotal pathology. A pictorial essay. AB - Conventional ultrasonographic evaluation (grey scale and Doppler) represents the first line investigation in the acute pathology of the scrotum. Its diagnosis value in acute scrotal pathology is undoubted in regard with hypervascular lesions, but in the evaluation of isoechoic and hypo/avascular lesions i.v. contrast-enhanced harmonic ultrasonography (CEUS) is recommended in establishing a firm and certain diagnosis. Besides these, CEUS has an important role in the evaluation of the remaining viable testicular tissue in cases of testicular trauma, thus guiding a limited excision surgery. This paper aims to discuss the added diagnosis value of CEUS and to illustrate this through various ultrasonographic images suggestive for acute scrotum pathology. PMID- 26962564 TI - Celiac disease in toddler with atypical onset. Case report. AB - Celiac disease is a chronic immune-mediated disorder induced in genetically susceptible individuals after ingestion of gluten proteins. An early diagnosis is of highest importance. Ultrasound might show small-bowel intussusception. We present a toddler with one month history of diarrhea and abdominal ultrasound showing ileo-ileal intussusception. Specific serological markers for celiac disease were positive. The duodenal endoscopy showed normal architecture but pathology indicated fully developed celiac disease (Marsh 3c). In conclusion, toddlers, who have even a short history of diarrhea with ultrasound showing ileo ileal intussusception, can be suspected of celiac disease by positive serologic markers and can be confirmed by duodenal biopsy and pathology. PMID- 26962565 TI - Diagnostic imaging findings of pelvic retroperitoneal ganglioneuroma in a child: a case report with the emphasis on initial ultrasound findings. AB - Ganglioneuromas are rare benign tumors of neural crest origin developed along the sympathetic chain. The pelvic retroperitoneum is the rarest location of these tumors. Clinically these tumors are commonly asypmtomatic even if they reach large sizes. Here we report the radiological features of a 16 year old boy with pathologically proven retroperitoneal ganglioneuroma that was detected initially by ultrasound. Relevant literature is also discussed. PMID- 26962566 TI - Unilateral temporal myositis heralding polymyositis: ultrasonographic and elastographic findings. Case report. AB - Temporal myositis is a rare inflammatory disease of the temporal muscle. We report a case of unilateral temporal myositis, in which a polymyositis was diagnosed two years thereafter. Although focal myositis may rarely herald polymyositis, isolated temporal myositis preceding inflammatory myopathies has not been described, to our knowledge. In the setting of a temporal pain and swelling, ultrasonography may help in diagnosis, biopsy guidance, disease extension, and progression assessment. Further studies are necessary to establish the role of elastography in differentiating between muscle inflammation and hypertrophy. PMID- 26962567 TI - The use of Doppler ultrasonography for pre- and post-surgery monitoring of abdominal aortic aneurysm. Case report. AB - A 75 year old male patient was monitored for 3 years by Doppler Ultrasonography (US) for an abdominal aorta aneurysm (AAA). Because the aneurysm increased significantly, an aortic prosthesis was installed via an endovascular procedure. After one month of post-surgery monitoring, both Doppler US exam and contrast enhancement US (CEUS) suspected the presence of a leak at the level of the prosthesis. A new surgical procedure was scheduled and intraoperative arteriography confirmed an endoleak type II. Although not always able to specify the correct type of linkage, CEUS remains a reliable method for investigating the postoperative complications of AAA. PMID- 26962568 TI - How useful is ARFI elastography for predicting the significant fibrosis and compensated liver cirrhosis? PMID- 26962569 TI - Author's response. PMID- 26962570 TI - Usefulness of ultrasound for the diagnosis of dermatofibroma. PMID- 26962571 TI - Refractory knee synovitis due to suprapatellar plica persistence--the role of ultrasonography in diagnosis and management. PMID- 26962572 TI - Cesarean scar pregnancy: role of serial transabdominal ultrasonography in the diagnosis and treatment response following dilation and curettage. PMID- 26962573 TI - In situ grown, self-supported iron-cobalt-nickel alloy amorphous oxide nanosheets with low overpotential toward water oxidation. AB - Electrocatalytic water oxidation by in situ grown iron-cobalt-nickel ternary alloy amorphous oxides is reported. This catalytic material was prepared by simple anodization of an alloy plate followed by low-temperature annealing, which shows superior electrocatalytic activity toward oxygen evolution reaction with an overpotential of only 170 mV and a low Tafel slope. PMID- 26962575 TI - Pure white light emission from organic molecules using solvent induced selective self-assembly. AB - Organic materials generating pure white light emission have attracted considerable attention in recent times due to their potential applications in lighting and display devices. We have used anthracene carboxylic acid (AnA) and anthracene carbaldehyde (AnC) to generate white light using solvent induced selective self-assembly (SISSA). Mechanistically, SISSA prevents a fast intersystem crossing of the AnC monomer and generates an emissive state from the self-assembled AnC. While AnA emits in the blue region, the self-assembled AnC emits in the greenish yellow region with identical emission intensity. CIE coordinates (0.33, 0.33) of pure white light have been achieved by incorporating orange emitting rhodamine B. More importantly, the pure white light formation has been demonstrated at desired temperatures in both aqueous medium as well as in an agar-agar hydrogel. PMID- 26962574 TI - A novel dimethylformamide (DMF) free bar-cast method to deposit organolead perovskite thin films with improved stability. AB - We report a solvent-free approach to synthesizing organolead perovskites by using solid state reactions to coat perovskite crystals onto Al2O3 or TiO2 nanoparticles followed by addition of terpineol affording perovskite inks. We have bar cast these inks to produce photoactive perovskite thin films which are significantly more stable to humidity than solution-processed films. This new method also avoids the use of toxic DMF solvent. PMID- 26962576 TI - A comparative study of the electrorheological properties of various N-doped nanomaterials using ammonia plasma treatment. AB - A new, simple method is reported to enhance the electrorheological (ER) activity of nanomaterials. Plasma treatment was the ideal technique owing to its ease of use, versatility, and common usage in mass production. Multi-gram quantities of ER nanomaterials with different morphologies, sizes, and compositions were successfully treated by ammonia plasma. PMID- 26962577 TI - Multiple linear regression. PMID- 26962578 TI - Death by super-resolution imaging. PMID- 26962579 TI - fMRI goes individual. PMID- 26962580 TI - Structure in the cellular context. PMID- 26962581 TI - STOMPing at the bits. PMID- 26962582 TI - New kid on the CRISPR block. PMID- 26962583 TI - Nanopores and the helicase two-step. PMID- 26962584 TI - Guest Editorial--Special Issue on Selected Papers From IEEE BioCAS 2014. PMID- 26962585 TI - Owl's eye sign: A rare neuroimaging finding in flail arm syndrome. PMID- 26962586 TI - Epilepsy after aneurysmal subarachnoid hemorrhage: A population-based, long-term follow-up study. PMID- 26962587 TI - The William Harvey Lecture on Basic Science at ESC London. PMID- 26962588 TI - Emerging role of the gut microbiome for cardiovascular disease. PMID- 26962589 TI - For the first time! By Caveman. PMID- 26962635 TI - Correction to Catalytic Enantioselective Desymmetrization of 1,3-Diazido-2 propanol via Intramolecular Interception of Alkyl Azides with Diazo(aryl)acetates. PMID- 26962590 TI - Professor Sir Henry Harris (1925-2014). PMID- 26962636 TI - A prospective study analyzing the application of radiofrequency energy and high voltage, ultrashort pulse duration electrical fields on the quantitative reduction of adipose tissue. AB - Noninvasive fat reduction is claimed by many device manufacturers, but proof of efficacy has been difficult to establish. This prospective study was designed to measure the reduction of fat thickness and actual volume reduction in 20 female patients treated with an external radiofrequency (RF) device. This device combines RF heat, suction coupled vacuum, and oscillating electrical pulses that induce adipocyte death over time. Patients underwent pre- and post-treatment and intercurrent measurements of weight, body mass index, ultrasonic transcutaneous fat thickness, and 2D and 3D Vectra photography with independent calculation of circumferential and volumetric change. Mean transcutaneous ultrasound thickness at reproducible points was 2.78 cm; at 1-month post-treatment, the mean fat thickness was 1.71 cm. At 3-month post-treatment, the mean fat thickness reduction was 39.6%. Vectra circumference measurements were taken at 10-mm intervals, with postural and breathing cycle control. Independent analysis of serial measurements from + 60 to - 70 mm showed mean abdominal circumference measurement of 2.3 cm. Mean abdominal volume loss was 202.4 and 428.5 cc at 1- and 3-month post-treatment, respectively. Scanning electron microscopy confirmed that permanent cell destruction was caused by irreversible electroporation. Pyroptosis appears to be the mechanism of action. PMID- 26962637 TI - Mitochondria-targeted ruthenium (II) polypyridyl complexes with benzofuran group for live cell imaging. AB - Labeling and imaging mitochondria have attracted considerable interest because of its involvement in early stage apoptosis and necrotic cell death. Various highly specific and photostable fluorescent probes for mitochondria are in demand. In the present study, two novel Ru(II) polypyridine complexes Ru1 and Ru2 were developed to act as mitochondrial fluorescence probes. In comparison with the commercially available mitochondrial trackers, Ru1 possesses high mitochondria specificity, superior photostability, high resistance to the loss of mitochondrial membrane potential and appreciable tolerance to environmental change, allowing imaging of the mitochondrial morphological changes over long periods of time. Combined results indicate that Ru1 may contribute to the future development of staining agents for organelle-selective imaging in living cells. PMID- 26962638 TI - Origin of Photocarrier Losses in Iron Pyrite (FeS2) Nanocubes. AB - Iron pyrite has received significant attention due to its high optical absorption. However, the loss of open circuit voltage (Voc) prevents its further application in photovoltaics. Herein, we have studied the photophysics of pyrite by ultrafast laser spectroscopy to understand fundamental limitation of low Voc by quantifying photocarrier losses in high quality, stoichiometric, and phase pure {100} faceted pyrite nanocubes. We found that fast carrier localization of photoexcited carriers to indirect band edge and shallow trap states is responsible for major carrier loss. Slow relaxation component reflects high density of defects within the band gap which is consistent with the observed Mott variable range hopping (VRH) conduction from transport measurements. Magnetic measurements strikingly show the magnetic ordering associated with phase inhomogeneity, such as FeS2-delta (0 <= delta <= 1). This implies that improvement of iron pyrite solar cell performance lies in mitigating the intrinsic defects (such as sulfur vacancies) by blocking the fast carrier localization process. Photocarrier generation and relaxation model is presented by comprehensive analysis. Our results provide insight into possible defects that induce midgap states and facilitate rapid carrier relaxation before collection. PMID- 26962673 TI - Capture of CO2 on gamma-Al2O3 materials prepared by solution-combustion and ball milling processes. AB - A series of porous gamma-Al2O3 materials was prepared by solution-combustion and ball-milling processes. The as-prepared powders were physicochemically characterized by x-ray diffraction (XRD), scanning electron microscopy (SEM), and N2 physisorption measurements and their performances in CO2 adsorption at different pressures (0.5 to 1.5 MPa) and temperatures (40 to 60oC) were investigated. It was found that gamma-Al2O3 synthesized by the solution combustion process and ball milled at 10 hr exhibited the best CO2 adsorption performance at 60oC and 1.5 MPa, achieving a maximum of 1.94 mmol/g compared to the four studied materials, as a result of their interesting microstructure and surface properties (i.e., nanocrystallinity, specific surface area, narrow pore size distribution, and large total pore volume). Our study shows that the gamma Al2O3 prepared by solution combustion followed by ball milling presents a fairly good potential adsorbent for efficient CO2 capture. IMPLICATIONS: In this work, gamma-Al2O3 materials were successfully obtained by solution combustion and modified via ball milling. These improved materials were systematically investigated as solid adsorbents of accessible surface areas, large pore volumes, and narrow pore size distribution for the CO2 capture. These studied solid adsorbents can provide an additional contribution and effort to develop an efficient CO2 capture method as means of alleviating the serious global warning problem. PMID- 26962674 TI - Long-Term Effects of Multiwalled Carbon Nanotubes and Graphene on Microbial Communities in Dry Soil. AB - Little is known about the long-term effects of engineered carbonaceous nanomaterials (ECNMs) on soil microbial communities, especially when compared to possible effects of natural or industrial carbonaceous materials. To address these issues, we exposed dry grassland soil for 1 year to 1 mg g(-1) of either natural nanostructured material (biochar), industrial carbon black, three types of multiwalled carbon nanotubes (MWCNTs), or graphene. Soil microbial biomass was assessed by substrate induced respiration and by extractable DNA. Bacterial and fungal communities were examined by terminal restriction fragment length polymorphism (T-RFLP). Microbial activity was assessed by soil basal respiration. At day 0, there was no treatment effect on soil DNA or T-RFLP profiles, indicating negligible interference between the amended materials and the methods for DNA extraction, quantification, and community analysis. After a 1-year exposure, compared to the no amendment control, some treatments reduced soil DNA (e.g., biochar, all three MWCNT types, and graphene; P < 0.05) and altered bacterial communities (e.g., biochar, carbon black, narrow MWCNTs, and graphene); however, there were no significant differences across the amended treatments. These findings suggest that ECNMs may moderately affect dry soil microbial communities but that the effects are similar to those from natural and industrial carbonaceous materials, even after 1-year exposure. PMID- 26962676 TI - Two-Photon Activation of p-Hydroxyphenacyl Phototriggers: Toward Spatially Controlled Release of Diethyl Phosphate and ATP. AB - Two-photon activation of the p-hydroxyphenacyl (pHP) photoactivated protecting group is demonstrated for the first time using visible light at 550 nm from a pulsed laser. Broadband two-photon absorption measurements reveal a strong two photon transition (>10 GM) near 4.5 eV that closely resembles the lowest-energy band at the same total excitation energy in the one-photon absorption spectrum of the pHP chromophore. The polarization dependence of the two-photon absorption band is consistent with excitation to the same S3 ((1)pipi*) excited state for both one- and two-photon activation. Monitoring the progress of the uncaging reaction under nonresonant excitation at 550 nm confirms a quadratic intensity dependence and that two-photon activation of the uncaging reaction is possible using visible light in the range 500-620 nm. Deprotonation of the pHP chromophore under mildly basic conditions shifts the absorption band to lower energy (3.8 eV) in both the one- and two-photon absorption spectra, suggesting that two-photon activation of the pHP chromophore may be possible using light in the range 550 720 nm. The results of these measurements open the possibility of spatially and temporally selective release of biologically active compounds from the pHP protecting group using visible light from a pulsed laser. PMID- 26962675 TI - Evaluation of the immunoradiometric and electrochemiluminescence method for the measurement of serum insulin in children. AB - Human insulin is a polypeptide hormone produced, stored, and secreted by the beta cells in the pancreatic islets of Langerhans. Its secretion is stimulated by an increase of the glucose concentration in circulation. Non-radioactive assays are frequently used in many laboratories to measure hormone concentrations, as an alternative to the traditional "gold standard" radioimmuno- and immunoradiometric assays. The precise and reliable determination of the insulin concentration is an important concern in numerous diagnostic procedures. The aim of this study was to compare two commercially available assays (manual and automated) for measurement of serum insulin concentrations. Aliquots of the 86 randomly selected serum samples were measured by Elecsys Insulin Assay (cobas e411 immunoassay analyzer, Roche Diagnostics GmbH, Mannheim, Germany) and DIAsource INS-IRMA Kit (DIAsource ImmunoAssays S.A., Louvain-la-Neuve, Belgium). Compared assays exhibit good correlation (r = 0.996). Insulin concentrations were on average 4.2 MU IU/mL lower (p < 0.05) with the cobas e411 immunoassay analyzer when compared to those measured with DIAsouce Immunoassay. Our findings suggest that electrochemiluminescence method on the cobas e411 analyzer and manual IRMA method offered by the DIAsource for the serum insulin determination could be considered interchangeable. PMID- 26962679 TI - Neuropilin Controls Endothelial Differentiation by Mesenchymal Stem Cells From the Periodontal Ligament. AB - BACKGROUND: Periodontal ligament (PDL) has been reported to be a source of mesenchymal stem cells (MSCs).New vascular networks from undifferentiated cells are essential for repair/regeneration of specialized tissues, including PDL. The current study aims to determine potential of CD105(+)-enriched cell subsets of periodontal ligament cells (PDLSCs) to differentiate into endothelial cell (EC) like cells and to give insights into the mechanism involved. METHODS: CD105(+) enriched PDLSCs were induced to EC differentiation by endothelial growth medium 2 (EGM-2) for 3, 7, 14, and 21 days, with mRNA/protein levels and functional activity assessed by: 1) real-time polymerase chain reaction; 2) Western blotting; 3) fluorescence-activated cell sorting; 4) immunohistochemistry; 5) immunofluorescence; 6) matrigel; and 7) small interfering RNA assays. RESULTS: Data analyses demonstrated that EGM-2 treated PDLSCs presented increased expression of EC markers, including: 1) CD105; 2) kinase domain-containing receptor; and 3) Ulex europaeus agglutinin 1, and were able to form cord/tube like structures. Gene and protein expression analysis showed that neuropilin 2 (NRP2), a key factor for vascular development, was significantly downregulated during EC differentiation. NRP2 was constitutively expressed in mouse PDL tissues by immunohistochemistry analysis, and NRP2 knockdown in CD105(+)-enriched PDLSCs resulted in increased cord/tube-like structures in a matrigel assay. CONCLUSION: These findings demonstrated the potential of CD105(+)-enriched PDLSCs to support angiogenesis, and NRP2 as a pivotal factor regulating this process. PMID- 26962678 TI - Long-Term Follow-Up of Testicular Microlithiasis in Children and Adolescents: Multicenter Prospective Cohort Study of the Italian Society of Pediatric Urology. AB - Introduction Testicular microlithiasis (TM), characterized by the presence of intratubular calcifications in a single or both the gonads, is an uncommon entity with unknown etiology and outcome in pediatric and adolescent age. In this study, the results of a multicenter long-term survey are presented. Materials and Methods From 11 units of pediatric urology/surgery, patients with TM were identified and yearly, followed up in a 7-year period, adopting a specific database. The recorded items were: age at diagnosis, presenting symptoms/associated abnormalities, ultrasonographic finding, surgery and histology at biopsy, if performed. Results Out of 85 patients, 81 were evaluated yearly (4 patients lost to follow-up). TM was bilateral in 66.6% of the patients. Associate genital abnormalities were present in 90%, more frequently undescended/retractile testis (23.4%) and varicocele (22.2%). TM remained unchanged at 4.7 years follow-up in 77 patients (93.8%) and was reduced in 4 patients after 1 to 5 years of inguinoscrotal surgery. Orchiectomy was performed in three patients (3.7%), one for severe testicular hypoplasia and two for seminoma (2.5%), respectively, concurrent and metachronous to diagnosis of TM. Tumorectomy with parenchymal sparing surgery was performed in a teratoma associated with TM. Conclusion TM is a controversial entity, often associated with several inguinogenital features, which rarely can recover. Testicular malignancy, although present in TM, has not proven definitively associated to microliths. Proper counseling, yearly ultrasound, and self-examination are long term recommended. PMID- 26962677 TI - Why individual thermo sensation and pain perception varies? Clue of disruptive mutations in TRPVs from 2504 human genome data. AB - Every individual varies in character and so do their sensory functions and perceptions. The molecular mechanism and the molecular candidates involved in these processes are assumed to be similar if not same. So far several molecular factors have been identified which are fairly conserved across the phylogenetic tree and are involved in these complex sensory functions. Among all, members belonging to Transient Receptor Potential (TRP) channels have been widely characterized for their involvement in thermo-sensation. These include TRPV1 to TRPV4 channels which reveal complex thermo-gating behavior in response to changes in temperature. The molecular evolution of these channels is highly correlative with the thermal response of different species. However, recent 2504 human genome data suggest that these thermo-sensitive TRPV channels are highly variable and carry possible deleterious mutations in human population. These unexpected findings may explain the individual differences in terms of complex sensory functions. PMID- 26962680 TI - Zn-Cu-In-Se Quantum Dot Solar Cells with a Certified Power Conversion Efficiency of 11.6%. AB - The enhancement of power conversion efficiency (PCE) and the development of toxic Cd-, Pb-free quantum dots (QDs) are critical for the prosperity of QD-based solar cells. It is known that the properties (such as light harvesting range, band gap alignment, density of trap state defects, etc.) of QD light harvesters play a crucial effect on the photovoltaic performance of QD based solar cells. Herein, high quality ~4 nm Cd-, Pb-free Zn-Cu-In-Se alloyed QDs with an absorption onset extending to ~1000 nm were developed as effective light harvesters to construct quantum dot sensitized solar cells (QDSCs). Due to the small particle size, the developed QD sensitizer can be efficiently immobilized on TiO2 film electrode in less than 0.5 h. An average PCE of 11.66% and a certified PCE of 11.61% have been demonstrated in the QDSCs based on these Zn-Cu-In-Se QDs. The remarkably improved photovoltaic performance for Zn-Cu-In-Se QDSCs vs Cu-In-Se QDSCs (11.66% vs 9.54% in PCE) is mainly derived from the higher conduction band edge, which favors the photogenerated electron extraction and results in higher photocurrent, and the alloyed structure of Zn-Cu-In-Se QD light harvester, which benefits the suppression of charge recombination at photoanode/electrolyte interfaces and thus improves the photovoltage. PMID- 26962681 TI - Rescue from early-onset hearing loss in a mouse model lacking the cyclin dependent kinase inhibitor p19Ink4d. PMID- 26962682 TI - Critical B-lymphoid cell intrinsic role of endogenous MCL-1 in c-MYC-induced lymphomagenesis. AB - Evasion of apoptosis is critical for tumorigenesis, and sustained survival of nascent neoplastic cells may depend upon the endogenous levels of pro-survival BCL-2 family members. Indeed, previous studies using gene-targeted mice revealed that BCL-XL, but surprisingly not BCL-2, is critical for the development of c-MYC induced pre-B/B lymphomas. However, it remains unclear whether another pro survival BCL-2 relative contributes to their development. MCL-1 is an intriguing candidate, because it is required for cell survival during early B-lymphocyte differentiation. It is expressed abnormally high in several types of human B-cell lymphomas and is implicated in their resistance to chemotherapy. To test the B cell intrinsic requirement for endogenous MCL-1 in lymphoma development, we conditionally deleted Mcl-1 in B-lymphoid cells of EMU-Myc transgenic mice. We found that MCL-1 loss in early B-lymphoid progenitors delayed MYC-driven lymphomagenesis. Moreover, the lymphomas that arose when MCL-1 levels were diminished appeared to have been selected for reduced levels of BIM and/or increased levels of BCL-XL. These results underscore the importance of MCL-1 in lymphoma development and show that alterations in the levels of other cell death regulators can compensate for deficiencies in MCL-1 expression. PMID- 26962683 TI - IL10 inhibits starvation-induced autophagy in hypertrophic scar fibroblasts via cross talk between the IL10-IL10R-STAT3 and IL10-AKT-mTOR pathways. AB - Hypertrophic scar (HS) is a serious skin fibrotic disease characterized by excessive hypercellularity and extracellular matrix (ECM) component deposition. Autophagy is a tightly regulated physiological process essential for cellular maintenance, differentiation, development, and homeostasis. Previous studies show that IL10 has potential therapeutic benefits in terms of preventing and reducing HS formation. However, no studies have examined IL10-mediated autophagy during the pathological process of HS formation. Here, we examined the effect of IL10 on starvation-induced autophagy and investigated the molecular mechanism underlying IL10-mediated inhibition of autophagy in HS-derived fibroblasts (HSFs) under starvation conditions. Immunostaining and PCR analysis revealed that a specific component of the IL10 receptor, IL10 alpha-chain (IL10Ralpha), is expressed in HSFs. Transmission electron microscopy and western blot analysis revealed that IL10 inhibited starvation-induced autophagy and induced the expression of p-AKT and p-STAT3 in HSFs in a dose-dependent manner. Blocking IL10R, p-AKT, p-mTOR, and p-STAT3 using specific inhibitors (IL10RB, LY294002, rapamycin, and cryptotanshinone, respectively) showed that IL10 inhibited autophagy via IL10Ralpha-mediated activation of STAT3 (the IL10R-STAT3 pathway) and by directly activating the AKT-mTOR pathway. Notably, these results suggest that IL10 mediated inhibition of autophagy is facilitated by the cross talk between STAT3, AKT, and mTOR; in other words, the IL10-IL10R-STAT3 and IL10-AKT-mTOR pathways. Finally, the results also indicate that mTOR-p70S6K is the molecule upon which these two pathways converge to induce IL10-mediated inhibition of autophagy in starved HSFs. In summary, the findings reported herein shed light on the molecular mechanism underlying IL10-mediated inhibition of autophagy and suggest that IL10 is a potential therapeutic agent for the treatment of HS. PMID- 26962684 TI - The oncolytic peptide LTX-315 triggers immunogenic cell death. AB - LTX-315 is a cationic amphilytic peptide that preferentially permeabilizes mitochondrial membranes, thereby causing partially BAX/BAK1-regulated, caspase independent necrosis. Based on the observation that intratumorally injected LTX 315 stimulates a strong T lymphocyte-mediated anticancer immune response, we investigated whether LTX-315 may elicit the hallmarks of immunogenic cell death (ICD), namely (i) exposure of calreticulin on the plasma membrane surface, (ii) release of ATP into the extracellular space, (iii) exodus of HMGB1 from the nucleus, and (iv) induction of a type-1 interferon response. Using a panel of biosensor cell lines and robotized fluorescence microscopy coupled to automatic image analysis, we observed that LTX-315 induces all known ICD characteristics. This conclusion was validated by several independent methods including immunofluorescence stainings (for calreticulin), bioluminescence assays (for ATP), immunoassays (for HMGB1), and RT-PCRs (for type-1 interferon induction). When injected into established cancers, LTX-315 caused a transiently hemorrhagic focal necrosis that was accompanied by massive release of HMGB1 (from close-to all cancer cells), as well as caspase-3 activation in a fraction of the cells. LTX-315 was at least as efficient as the positive control, the anthracycline mitoxantrone (MTX), in inducing local inflammation with infiltration by myeloid cells and T lymphocytes. Collectively, these results support the idea that LTX 315 can induce ICD, hence explaining its capacity to mediate immune-dependent therapeutic effects. PMID- 26962685 TI - Overcoming MITF-conferred drug resistance through dual AURKA/MAPK targeting in human melanoma cells. AB - MITF (microphthalmia-associated transcription factor) is a frequently amplified lineage-specific oncogene in human melanoma, whose role in intrinsic drug resistance has not been systematically investigated. Utilizing chemical inhibitors for major signaling pathways/cellular processes, we witness MITF as an elicitor of intrinsic drug resistance. To search kinase(s) targets able to bypass MITF-conferred drug resistance, we employed a multi-kinase inhibitor-directed chemical proteomics-based differential affinity screen in human melanocytes carrying ectopic MITF overexpression. A subsequent methodical interrogation informed mitotic Ser/Thr kinase Aurora Kinase A (AURKA) as a crucial regulator of melanoma cell proliferation and migration, independent of the underlying molecular alterations, including TP53 functional status and MITF levels. Crucially, assessing the efficacy of investigational AURKA inhibitor MLN8237, we pre-emptively witness the procurement of a molecular program consistent with acquired drug resistance. This involved induction of multiple MAPK (mitogen activated protein kinase) signaling pathway components and their downstream proliferation effectors (Cyclin D1 and c-JUN) and apoptotic regulators (MITF and Bcl-2). A concomitant AURKA/BRAF and AURKA/MEK targeting overcame MAPK signaling activation-associated resistance signature in BRAF- and NRAS-mutated melanomas, respectively, and elicited heightened anti-proliferative activity and apoptotic cell death. These findings reveal a previously unreported MAPK signaling-mediated mechanism of immediate resistance to AURKA inhibitors. These findings could bear significant implications for the application and the success of anti-AURKA approaches that have already entered phase-II clinical trials for human melanoma. PMID- 26962687 TI - MiR-125a-5p decreases after long non-coding RNA HOTAIR knockdown to promote cancer cell apoptosis by releasing caspase 2. AB - HOTAIR (homeobox transcript antisense RNA), one of the prototypical long non coding RNAs, has been verified overexpressed in multiple carcinomas and has emerged as a promising novel anticancer target. Its well-established role is acting as a predictor of poor prognosis and promoting cancer cell metastasis. Recently, another important mission of HOTAIR was uncovered that targeting HOTAIR caused cancer cell apoptosis. Nevertheless, so far there is no published data elaborating the mechanism. Here, we report that microRNA miR-125a-5p decreases and releases caspase 2 to promote cancer cell apoptosis after HOTAIR knockdown. We applied siRNAs targeting HOTAIR to various cancer cells, and observed apoptosis in all of these cell lines. RNA sequencing detected that miR-125a-5p was decreased after HOTAIR knockdown and miR-125a-5p mimics could rescue the apoptosis induced by HOTAIR deficiency. Luciferase assays identified caspase 2, an initiator caspase, to be a new target of miR-125a-5p. Elevated expression and subsequent cleavage of caspase 2 was observed after HOTAIR knockdown or inhibition of miR-125a-5p. RNAi of caspase 2 could attenuate the apoptosis induced by HOTAIR knockdown. In 80 clinical colon cancer tissues, HOTAIR and miR 125a-5p levels were higher than adjacent tissues, whereas caspase 2 was lower. MiR-125a-5p expression level was significantly correlated with colon tumor size, lymph node metastasis and clinical stage. These findings indicate that miR-125a 5p decreases after HOTAIR knockdown to promote cancer cell apoptosis by releasing caspase 2. Our work reveals a previously unidentified apoptotic mechanism, which might be exploitable in anticancer drug development. PMID- 26962689 TI - NGF FLIPs TrkA onto the death TRAIL in neuroblastoma cells. PMID- 26962688 TI - Diet-driven interferon-gamma enhances malignant transformation of primary bovine mammary epithelial cells through nutrient sensor GCN2-activated autophagy. PMID- 26962686 TI - Wnt activation protects against neomycin-induced hair cell damage in the mouse cochlea. AB - Recent studies have reported the role of Wnt/beta-catenin signaling in hair cell (HC) development, regeneration, and differentiation in the mouse cochlea; however, the role of Wnt/beta-catenin signaling in HC protection remains unknown. In this study, we took advantage of transgenic mice to specifically knockout or overactivate the canonical Wnt signaling mediator beta-catenin in HCs, which allowed us to investigate the role of Wnt/beta-catenin signaling in protecting HCs against neomycin-induced damage. We first showed that loss of beta-catenin in HCs made them more vulnerable to neomycin-induced injury, while constitutive activation of beta-catenin in HCs reduced HC loss both in vivo and in vitro. We then showed that loss of beta-catenin in HCs increased caspase-mediated apoptosis induced by neomycin injury, while beta-catenin overexpression inhibited caspase mediated apoptosis. Finally, we demonstrated that loss of beta-catenin in HCs led to increased expression of forkhead box O3 transcription factor (Foxo3) and Bim along with decreased expression of antioxidant enzymes; thus, there were increased levels of reactive oxygen species (ROS) after neomycin treatment that might be responsible for the increased aminoglycoside sensitivity of HCs. In contrast, beta-catenin overexpression reduced Foxo3 and Bim expression and ROS levels, suggesting that beta-catenin is protective against neomycin-induced HC loss. Our findings demonstrate that Wnt/beta-catenin signaling has an important role in protecting HCs against neomycin-induced HC loss and thus might be a new therapeutic target for the prevention of HC death. PMID- 26962690 TI - A long non-coding RNA interacts with Gfra1 and maintains survival of mouse spermatogonial stem cells. AB - Spermatogonial stem cells (SSCs) are unique male germline stem cells that support spermatogenesis and male fertility. Long non-coding RNAs (lncRNA) have been identified as key regulators of stem cell fate; however, their role in SSCs has not been explored. Here, we report that a novel spermatogonia-specific lncRNA (lncRNA033862) is essential for the survival of murine SSCs. LncRNA033862 is expressed in early spermatogonia including SSC and was among 805 lncRNAs identified by global expression profiling as responsive to glial cell-derived neurotrophic factor (GDNF), a growth factor required for SSC self-renewal and survival. LncRNA033862 is an antisense transcript of the GDNF receptor alpha1 (Gfra1) that lacks protein coding potential and regulates Gfra1 expression levels by interacting with Gfra1 chromatin. Importantly, lncRNA033862 knockdown severely impairs SSC survival and their capacity to repopulate recipient testes in a transplantation assay. Collectively, our data provide the first evidence that long non-coding RNAs (lncRNAs) regulate SSC fate. PMID- 26962691 TI - Genetic Analysis of the Rhodopsin Gene Identifies a Mosaic Dominant Retinitis Pigmentosa Mutation in a Healthy Individual. AB - PURPOSE: Retinitis pigmentosa (RP) is a group of clinically and genetically heterogeneous hereditary retinal diseases that result in blindness due to photoreceptor degeneration. Mutations in the rhodopsin (RHO) gene are the most common cause of autosomal dominant RP (adRP) and are responsible for 16% to 35% of adRP cases in the Western population. Our purpose was to investigate the contribution of RHO to adRP in the Israeli and Palestinian populations. METHODS: Thirty-two adRP families participated in the study. Mutation detection was performed by whole exome sequencing (WES) and Sanger sequencing of RHO exons. Fluorescence PCR reactions of serially diluted samples were used to predict the percentage of mosaic cells in blood samples. RESULTS: Eight RHO disease-causing mutations were identified in nine families, with only one novel mutation, c.548 638dup91bp, identified in a family where WES failed to detect any causal variant. Segregation analysis revealed that the origin of the mutation is in a mosaic healthy individual carrying the mutation in approximately 13% of blood cells. CONCLUSIONS: This is the first report of the mutation spectrum of a known adRP gene in the Israeli and Palestinian populations, leading to the identification of seven previously reported mutations and one novel mutation. Our study shows that RHO mutations are a major cause of adRP in this cohort and are responsible for 28% of adRP families. The novel mutation exhibits a unique phenomenon in which an unaffected individual is mosaic for an adRP-causing mutation. PMID- 26962692 TI - The Stereoscopic Anisotropy Develops During Childhood. AB - PURPOSE: Human vision has a puzzling stereoscopic anisotropy: horizontal depth corrugations are easier to detect than vertical depth corrugations. To date, little is known about the function or the underlying mechanism responsible for this anisotropy. Here, we aim to find out whether this anisotropy is independent of age. To answer this, we compare detection thresholds for horizontal and vertical depth corrugations as a function of age. METHODS: The depth corrugations were defined solely by the horizontal disparity of random dot patterns. The disparities depicted a horizontal or vertical sinusoidal depth corrugation of spatial frequency 0.1 cyc/deg. Detection thresholds were obtained using Bayesian adaptive staircases from a total of 159 subjects aged from 3 to 73 years. For each participant we computed the anisotropy index, defined as the log10-ratio of the detection threshold for vertical corrugations divided by that for horizontal. RESULTS: Anisotropy index was highly variable between individuals but was positive in 87% of the participants. There was a significant correlation between anisotropy index and log-age (r = 0.21, P = 0.008) mainly driven by a significant difference between children and adults. In 67 children aged 3 to 13 years, the mean anisotropy index was 0.34 +/- 0.38 (mean +/- SD, meaning that vertical thresholds were on average 2.2 times the horizontal ones), compared with 0.59 +/- 0.55 in 84 adults aged 18 to 73 years (vertical 3.9 times horizontal). This was mainly driven by a decline in the sensitivity to vertical corrugations. Children had poorer stereoacuity than adults, but had similar sensitivity to adults for horizontal corrugations and were actually more sensitive than adults to vertical corrugations. CONCLUSIONS: The fact that adults show stronger stereo anisotropy than children raises the possibility that visual experience plays a critical role in developing and strengthening the stereo anisotropy. PMID- 26962693 TI - Paclitaxel Associated With Lipid Nanoparticles as a New Antiscarring Agent in Experimental Glaucoma Surgery. AB - PURPOSE: To investigate the effects of paclitaxel associated with lipid nanoemulsions (LDE-PTX) on postoperative scarring in rabbits undergoing trabeculectomy. METHODS: Thirty-four rabbits that underwent trabeculectomy were allocated to four groups: LDE-PTX/SC (n = 9), treated with LDE-PTX (1.5 mg, intraoperative subconjunctival injection); LDE-PTX/IV (n = 9), treated with LDE PTX (4 mg/kg per day intravenously) at the end of the surgery and once per week for 3 weeks; MMC (n = 9), treated with intraoperative 0.4 mg/mL mitomycin-C for 3 minutes; and control group (CTL, n = 7), without treatment. Bleb characteristics and IOP were evaluated over 4 weeks. Animals were killed on day 28. Histologic analyses were performed to assess the amount of scarring and toxicity to the conjunctiva and ciliary body. RESULTS: Groups were similar with respect to IOP and anterior chamber depth during the 28-day observation period. The LDE-PTX/SC, LDE-PTX/IV, and MMC groups showed greater bleb height than CTL on days 14 and 21 (P < 0.001). The LDE-PTX/SC, LDE-PTX/IV, and MMC groups showed longer bleb survival time than CTL (P < 0.001). The LDE-PTX/SC, LDE-PTX/IV, and MMC groups were equally effective in reducing fibrosis (P < 0.001), number of blood vessels (P < 0.001), and chronic inflammatory cells (P < 0.01) at the surgical site. However, LDE-PTX/SC and LDE-PTX/IV treatments had lower conjunctival (P < 0.001) and ciliary body toxicity (P < 0.01), compared with MMC. CONCLUSIONS: The LDE PTX/SC was effective in reducing the scarring process following trabeculectomy to the same extent as MMC, but with considerably less toxicity to the conjunctiva and ciliary body. The LDE-PTX/IV was somewhat less effective than LDE-PTX/SC or MMC, but could have potential as a postoperative adjuvant treatment. Therefore, the LDE-PTX preparation in both administration routes may offer promising options for wound-healing modulation in the surgical treatment of glaucoma. PMID- 26962694 TI - Prevalence and Associations of Anisometropia in Children. AB - PURPOSE: To describe prevalence and associations of anisometropia in children. METHODS: The cross-sectional school-based study included children aged 4 to 18 years. RESULTS: The study included 6025 (94.7%) of 6364 eligible children. Mean refractive anisometropia was 0.37 +/- 0.57 diopters (median: 0.25 diopters; range: 0-7.88 diopters; prevalence [>=1 diopter]: 7.0% +/- 0.3%). In multivariate analysis (regression coefficient r: 0.66), higher refractive anisometropia was associated with older age (P < 0.001; beta: 0.07; B: 0.01; 95% CI: 0.01-0.02), higher maternal education level (P < 0.001; beta: 0.04; B: 0.02; 95% CI: 0.01 0.03), more total time spent indoors reading or writing (P = 0.001; beta: 0.04; B: 0.01; 95% CI: 0.01-0.02), larger intereye difference in axial length (P < 0.001; beta: 0.57; B: 1.20; 95% CI: 1.15-1.24), shorter mean axial length of both eyes (P = 0.03; beta: -0.03; B: -0.02; 95% CI: -0.03 to -0.001), larger intereye difference in best corrected visual acuity (BCVA) (P < 0.001; beta: 0.14; B: 1.83; 95% CI: 1.54-2.12), and lower stereoacuity (P < 0.001; beta: 0.08; B: 0.31; 95% CI: 0.22-0.39). Refractive anisometropia showed a U-shaped correlation with refractive error. Higher anisomyopia was associated (r: 0.57) with older age (P = 0.001; beta: 0.05; B: 0.006; 95% CI: 0.002-0.009), higher level of paternal education (P = 0.001; beta: 0.01; B: 0.01; 95% CI: 0.01-0.02), more total time spent indoors reading or writing (P = 0.01; beta: 0.03; B: 0.01; 95% CI: 0.00 0.01), larger intereye difference in axial length (P < 0.001; beta: 0.22; B: 0.26; 95% CI: 0.23-0.29), greater myopic refractive error (P < 0.001; beta: 0.46; B: -0.07; 95% CI: -0.08 to -0.07), and lower corneal astigmatism (P < 0.001; beta: -0.10; B: -0.06; 95% CI: -0.08 to -0.05). In the same multivariate model, hyperopic anisometropia was not significantly associated with time spent indoors with reading (P = 0.18). Cylindrical anisometropia (mean: 0.30 +/- 0.32 diopters; prevalence [>=1 diopter]: 3.7% +/- 0.2%) increased with higher refractive anisometropia (P < 0.001; beta: 0.16; B: 0.09; 95% CI: 0.08-0.11), greater myopic refractive error (P < 0.001; beta: -0.06; B: -0.01; 95% CI: -0.01 to -0.01), higher corneal astigmatism (P < 0.001; beta: -0.22; B: -0.15; 95% CI: 0.17 to -0.13), and lower mean BCVA (P < 0.001; beta: 0.11; B: 0.90; 95% CI: 0.68 1.17). CONCLUSIONS: In 4- to 18-year-old children, refractive anisometropia and anisomyopia increased with systemic parameters such as age, parental education level, and lifestyle of the children, for example, more time spent indoors reading or writing. In contrast, hyperopic anisometropia and cylindrical anisometropia were not related with lifestyle parameters. PMID- 26962695 TI - Formation of Macular Inner Nuclear Layer Cysts in Optic Atrophy. PMID- 26962697 TI - Comparison of the Pattern of Macular Ganglion Cell-Inner Plexiform Layer Defect Between Ischemic Optic Neuropathy and Open-Angle Glaucoma. AB - PURPOSE: To compare the pattern of macular ganglion cell plus inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (RNFL) thickness changes in moderate to severe primary open-angle glaucoma (POAG) with nonarteritic anterior ischemic optic neuropathy (NAION) using optical coherence tomography (OCT) auto-segmentation. METHODS: A total of 138 eyes (42 eyes with chronic unilateral NAION and their 42 unaffected fellow eyes, 32 eyes of 32 moderate to severe glaucoma patients, and 22 eyes of 22 healthy normal subjects) underwent neuro-ophthalmologic examinations and spectral-domain OCT in a cross sectional study at a single academic institution. GCIPL and total retinal thicknesses were obtained from 20 degrees by 20 degrees cube scans of the macula centered around the fovea. The scanned region was divided into two concentric regions (inner and outer, with diameters of 3 and 6 mm, respectively) and eight sectors (four sectors in each of the inner and outer regions). Peripapillary RNFL thickness was also measured. RESULTS: Peripapillary RNFL, total macula, and GCIPL were significantly thinner in NAION and POAG eyes compared to unaffected fellow eyes of NAION and to age-matched healthy control eyes in all eight sectors (P < 0.001). There was no significant difference in peripapillary RNFL, total macula, and outer region GCIPL thicknesses between the affected eyes of the patients with NAION and glaucoma patients. However, the inner region GCIPL was significantly thinner in NAION eyes compared to POAG eyes after adjusting for age, sex, and mean deviation of the visual field (P = 0.001). Also, the GCIPL sector thicknesses were more strongly correlated with visual acuity than were the macular sectors in all patients (most sectors P <= 0.001). CONCLUSIONS: Patients with NAION show differences in the tissue damage with greater loss of parafoveal GCIPL tissue thickness compared to patients with POAG. PMID- 26962696 TI - The Ocular Surface in Medically Controlled Glaucoma: An In Vivo Confocal Study. AB - PURPOSE: To study clinical and in vivo laser scanning confocal microscopy (LSCM) ocular surface findings in stable, medically controlled primary open-angle glaucoma (MCPOAG) patients. METHODS: We recruited 100 consecutive patients with MCPOAG and 50 healthy controls. Patients had to have been treated with the same medical regimen without variation for the 18 months before enrollment and were excluded if there was a history of dry eye prior to glaucoma diagnosis. Each participant underwent ocular surface clinical and LSCM examination. RESULTS: In MCPOAG patients, subbasal nerve length and tortuosity and dendritic cell density were increased compared to controls (P < 0.01), but there were no clinical abnormalities. Patients treated with preserved drugs (n = 80) had reduced tear film breakup time (P < 0.05, ANOVA), and those preserved with benzalkonium chloride (n = 72) had reduced Schirmer test values (P < 0.001). Patients (n = 50) treated with two or more drugs had increased lissamine green conjunctival staining (P < 0.001, LSD post hoc test). Patients (n = 29) treated with three or more eye drops daily had decreased Schirmer test values. Laser scanning confocal microscopy showed subbasal changes related to preservatives, type and number of drugs, and number of eye drops. CONCLUSIONS: In stable MCPOAG patients without dry eye history, the ocular surface changes due to antiglaucoma medications are mostly subclinical. Active ingredients, preservatives, number of concomitant drugs, and number of eye drops instilled per day are all elements that can induce ocular surface changes. The clinical relevance of these changes remains to be determined. PMID- 26962698 TI - Potential Therapeutic Agents Against Retinal Diseases Caused by Aberrant Metabolism of Retinoids. AB - The retinoid (visual) cycle is a complex enzymatic pathway that operates in the retina for the regeneration of 11-cis-retinal (11-cis-Ral), the inherent visual chromophore indispensable for vision. Deficiencies in the retinoid metabolism are involved in pathologic mechanisms of several forms of retinal diseases including age-related macular degeneration, Stargardt's disease, and Leber's congenital amaurosis, for which no effective cures presently exist. Nevertheless, the interference of abnormal retinoid metabolism with chemicals has been considered to be a promising strategy aimed at alleviating these retinal dysfunctions. Moreover, since gene therapy is gaining increasing importance in clinical practice, the modulation of key enzymes implicated with the retinoid cycle at a genetic level will hold great promise for the treatment of patients with degenerative diseases of the retina. PMID- 26962699 TI - The Effect of Electric Cross-Talk in Retinal Neurostimulation. AB - PURPOSE: To investigate the efficacy of electric field shaping in modulating the extent and activation threshold in retinal neurostimulation. This study aims to quantify the interference of neighboring stimulation sites by assessing the shift in the activation threshold produced by a concomitant interfering stimulus. METHODS: Electrical stimuli were applied to healthy retinae in a feline model (n = 4) using a 24-channel electrode array surgically implanted in the suprachoroidal space. A 96-channel penetrating electrode array was used for recording cortical responses to a number of stimulation paradigms. Data were analyzed offline. Concurrent monopolar and hexapolar stimuli were delivered at primary and interfering sites separated by up to 2.19 mm to evaluate electric cross-talk. The spike rate was fit to a sigmoidal curve to estimate the P50 threshold. The slope of the linear regression of the P50 value versus interfering current level was considered as a measure of cross-talk. RESULTS: Concurrent monopolar stimulation produced a proportional drop in the P50 of approximately 20% of the interfering current level in presence of a primary monopolar and hexapolar stimulus. On the other hand, hexapolar interference did not alter activation thresholds at the primary site. CONCLUSIONS: Hexapolar stimulation reduces electric cross-talk between neighboring sites and represents a technique to reduce interference between individual stimulation sites. In contrast, concurrent monopolar stimulation produces a reduction of the activation threshold of stimuli delivered nearby. Thus, a single source of subthreshold monopolar charge injection can provide benefit in the form of significant threshold reduction simultaneously at multiple stimulation sites. PMID- 26962701 TI - A Diagnostic Calculator for Detecting Glaucoma and False Positive Using Cirrus OCT. PMID- 26962700 TI - PGC-1alpha Induces Human RPE Oxidative Metabolism and Antioxidant Capacity. AB - PURPOSE: Oxidative stress and metabolic dysregulation of the RPE have been implicated in AMD; however, the molecular regulation of RPE metabolism remains unclear. The transcriptional coactivator, peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) is a powerful mediator of mitochondrial function. This study examines the ability of PGC-1alpha to regulate RPE metabolic program and oxidative stress response. METHODS: Primary human fetal RPE (hfRPE) and ARPE-19 were matured in vitro using standard culture conditions. Mitochondrial mass of RPE was measured using MitoTracker staining and citrate synthase activity. Expression of PGC-1 isoforms, RPE-specific genes, oxidative metabolism proteins, and antioxidant enzymes was analyzed by quantitative PCR and Western blot. Mitochondrial respiration and fatty-acid oxidation were monitored using the Seahorse extracellular flux analyzer. Expression of PGC-1alpha was increased using adenoviral delivery. ARPE-19 were exposed to hydrogen peroxide to induce oxidative stress. Reactive oxygen species were measured by CM-H2DCFDA fluorescence. Cell death was analyzed by LDH release. RESULTS: Maturation of ARPE 19 and hfRPE was associated with significant increase in mitochondrial mass, expression of oxidative phosphorylation (OXPHOS) genes, and PGC-1alpha gene expression. Overexpression of PGC-1alpha increased expression of OXPHOS and fatty acid beta-oxidation genes, ultimately leading to the potent induction of mitochondrial respiration and fatty-acid oxidation. PGC-1alpha gain of function also strongly induced numerous antioxidant genes and, importantly, protected RPE from oxidant-mediated cell death without altering RPE functions. CONCLUSIONS: This study provides important insights into the metabolic changes associated with RPE functional maturation and identifies PGC-1alpha as a potent driver of RPE mitochondrial function and antioxidant capacity. PMID- 26962704 TI - Rediscovering the therapeutic use of glucocorticoids in rheumatoid arthritis. AB - PURPOSE OF REVIEW: This review will focus on new information obtained on how to apply glucocorticoids in the treatment of rheumatoid arthritis, aiming at an optimal risk-benefit ratio. Moreover, advances in the development of new preparations such as liposomal glucocorticoids will be discussed. RECENT FINDINGS: In early rheumatoid arthritis, treatment regimens with a disease modifying drug and initially medium-dose glucocorticoids (>7.5 but <=30 mg prednisone equivalent) are noninferior compared with regimens with disease modifying drugs and initially high-dose glucocorticoids (>30 mg prednisone equivalent) and have repeatedly been proven to be more effective than methotrexate monotherapy. Use of glucocorticoids following such a scheme during a period of 6 months to 2 years was not associated with increased mortality, nor with substantial bone loss if bone protective measures had been taken. New drug delivery systems, and in particular long-circulating liposomes, aiming at enhancing the biodistribution and the target site accumulation of glucocorticoids and thereby improving the balance between their efficacy and toxicity, are promising; more results on the effects in rheumatoid arthritis patients are expected to be reported during the years to come. SUMMARY: Combination therapy including methotrexate and glucocorticoids should be the initial treatment in patients with early rheumatoid arthritis. Treatment regimens including medium dose glucocorticoids are noninferior compared with regimens with initially high dose glucocorticoids. Studies on new glucocorticoid preparations and new drug delivery systems improving the balance between efficacy and toxicity of glucocorticoid therapy are ongoing. PMID- 26962702 TI - Immunization practices in acute lymphocytic leukemia and post-hematopoietic stem cell transplant in Canadian Pediatric Hematology/Oncology centers. AB - There are no Canadian immunization guidelines for children treated for malignancy. Guidelines do exist for patients who underwent hematopoietic stem cell transplant (HSCT), but they provide broad timeframes for initiating vaccination; there is no standard schedule. The optimal approach to immunization in these populations is unclear. We sought to describe immunization practices at Canadian Pediatric Hematology/Oncology centers. A 43-item online questionnaire was distributed to the 16 programs in the C(17) research network of pediatric hematology/oncology centers to capture information on timing and criteria for immunization of patients with acute lymphocytic leukemia (ALL) and those who have undergone HSCT. At each center, 1-2 physicians or pharmacists completed the survey to reflect center-wide immunization practices. Responses were received from 11/16 (69%) programs; 11 respondents reported on practices for patients with ALL and 9 reported on practices for patients who are post-HSCT. In 5/11 ALL programs (45%) re-immunization is recommended routinely after chemotherapy, starting 3-6 months post-chemotherapy. In HSCT programs, timing of pneumococcal conjugate vaccination (PCV) varied from 3 months post-HSCT (4 programs) to 12 months post-HSCT (4 programs). Live vaccines were administered 24 months post HSCT in 8/9 programs. All HSCT programs considered graft-versus-host-disease and 7 considered discontinuation of immunosuppression in immunization decisions. Pediatric hematology/oncology programs were divided in regards to re-immunization of patients with ALL post-chemotherapy. After HSCT, timing of PCV administration varied, with 4 programs initiating immunization later than Canadian guidelines recommend (3-9 months post-HSCT). These findings suggest a need to standardize immunization practices in these populations. PMID- 26962706 TI - Adult hypophosphatasia. PMID- 26962705 TI - What is the evidence for Sjogren's syndrome being triggered by viral infection? Subplot: infections that cause clinical features of Sjogren's syndrome. AB - PURPOSE OF REVIEW: To clarify the involvement of viral infections in the pathogenesis of Sjogren's syndrome and to discuss whether viruses can be a trigger for the development of Sjogren's syndrome. RECENT FINDINGS: Although some viruses are candidate triggers of Sjogren's syndrome, we focus on human T lymphotropic virus type I (HTLV-I). Clinicoepidemiological studies show a relationship between HTLV-I and Sjogren's syndrome with a low frequency of salivary gland damage in magnetic resonance imaging, autoantibody production and ectopic germinal center in HTLV-I-associated myelopathy (HAM) patients with Sjogren's syndrome. Our recent study showed that HTLV-I has the potential to infect salivary gland epithelial cells (SGECs). After a coculture of HCT-5 (an HTLV-I-infected T-cell line derived from the cerebrospinal fluid) of an HAM patient and SGECs, we observed time-dependent increases in the levels of soluble intracellular adhesion molecule1, interferon gamma-induced protein 10 kDa and regulated on activation, normal T-cell expressed and secreted. In addition, SGECs themselves express these molecules along with the expression of HTLV-I proteins. SUMMARY: HTLV-I is involved in the pathogenesis of HTLV-I-seropositive patients with Sjogren's syndrome. By infecting CD4 T cells in vivo, HTLV-I induces specific clinicopathological conditions. In addition, HTLV-I-infected SGECs have the potential to augment the expression of molecules involved in cell adhesion, inflammation and migration. PMID- 26962707 TI - Recent advances in the management of pulmonary sarcomatoid carcinoma. AB - Pulmonary sarcomatoid carcinoma (PSC) is a unique and biologically fascinating group of poorly differentiated non-small cell lung cancer (NSCLC), however it is highly aggressive with poor overall survival compared to other types of NSCLC. Radical surgery remains the standard of care for early localized disease but this has shown to result in high recurrence rates. Traditional palliative chemotherapy is associated with poor response in advanced/metastatic PSC. Recent comprehensive genetic studies and clinical observations are starting to elucidate the key oncogenic underpinnings of PSC. In particular, the recent identification of frequent genetic alterations of the MET gene leading to exon 14 skipping have yielded actionable targets for intervention with available MET inhibitors for a subset of PSC patients. Immunotherapy against immune checkpoints, such as anti PD1/PD-L1 agents, have also raised great interest for the management of PSC. A growing understanding of the molecular pathogenesis of PSC is rapidly yielding novel approaches for the treatment of this deadly malignancy. PMID- 26962703 TI - Loss of the integral nuclear envelope protein SUN1 induces alteration of nucleoli. AB - A supervised machine learning algorithm, which is qualified for image classification and analyzing similarities, is based on multiple discriminative morphological features that are automatically assembled during the learning processes. The algorithm is suitable for population-based analysis of images of biological materials that are generally complex and heterogeneous. Here we used the algorithm wndchrm to quantify the effects on nucleolar morphology of the loss of the components of nuclear envelope in a human mammary epithelial cell line. The linker of nucleoskeleton and cytoskeleton (LINC) complex, an assembly of nuclear envelope proteins comprising mainly members of the SUN and nesprin families, connects the nuclear lamina and cytoskeletal filaments. The components of the LINC complex are markedly deficient in breast cancer tissues. We found that a reduction in the levels of SUN1, SUN2, and lamin A/C led to significant changes in morphologies that were computationally classified using wndchrm with approximately 100% accuracy. In particular, depletion of SUN1 caused nucleolar hypertrophy and reduced rRNA synthesis. Further, wndchrm revealed a consistent negative correlation between SUN1 expression and the size of nucleoli in human breast cancer tissues. Our unbiased morphological quantitation strategies using wndchrm revealed an unexpected link between the components of the LINC complex and the morphologies of nucleoli that serves as an indicator of the malignant phenotype of breast cancer cells. PMID- 26962708 TI - Changes in hydraulic conductance cause the difference in growth response to short term salt stress between salt-tolerant and -sensitive black gram (Vigna mungo) varieties. AB - Black gram (Vigna mungo) is an important crop in Asia, However, most black gram varieties are salt-sensitive. The causes of varietal differences in salt-induced growth reduction between two black gram varieties, 'U-Taung-2' (salt-tolerant; BT) and 'Mut Pe Khaing To' (salt-sensitive; BS), were examined the potential for the first step toward the genetic improvement of salt tolerance. Seedlings grown in vermiculite irrigated with full-strength Hoagland solution were treated with 0mM NaCl (control) or 225 mM NaCl for up to 10 days. In the 225 mM NaCl treatment, plant growth rate, net assimilation rate, mean leaf area, leaf water potential, and leaf photosynthesis were reduced more in BS than in BT plants. Leaf water potential was closely related to leaf photosynthesis, net assimilation rate, and increase in leaf area. In response to salinity stress, hydraulic conductance of the root, stem, and petiole decreased more strongly in BS than in BT plants. The reduction in stem and petiole hydraulic conductance was caused by cavitation, whereas the reduction in root hydraulic conductance in BS plants was caused by a reduction in root surface area and hydraulic conductivity. We conclude that the different reduction in hydraulic conductance is a cause of the differences in the growth response between the two black gram varieties under short-term salt stress. PMID- 26962709 TI - Alternative oxidase pathway is involved in the exogenous SNP-elevated tolerance of Medicago truncatula to salt stress. AB - Exogenous application of sodium nitroprusside (SNP) would enhance the tolerance of plants to stress conditions. Some evidences suggested that nitric oxide (NO) could induce the expression of alternative oxidase (AOX). In this study, Medicago truncatula (Medicago) was chosen to study the role of AOX in the SNP-elevated resistance to salt stress. Our results showed that the expression of AOX genes (especially AOX1 and AOX2b1) and cyanide-resistant respiration rate (Valt) could be significantly induced by salt stress. Exogenous application of SNP could further enhance the expression of AOX genes and Valt. Exogenous application of SNP could alleviate the oxidative damage and photosynthetic damage caused by salt stress. However, the stress resistance was significantly decreased in the plants which were pretreated with n-propyl gallate (nPG). More importantly, the damage in nPG-pretreated plants could not be alleviated by application of SNP. Further study showed that effects of nPG on the activities of antioxidant enzymes were minor. These results showed that AOX pathway played an important role in the SNP elevated resistance of Medicago to salt stress. AOX could contribute to regulating the accumulation of reactive oxygen (ROS) and protect of photosystem, and we proposed that all these were depend on the ability of maintaining the homeostasis of redox state. PMID- 26962710 TI - Suppression of tomato SlNAC1 transcription factor delays fruit ripening. AB - Fruit ripening is a complex process involving many physiological and biochemical changes, including those for ethylene, carotenoid, and cell wall metabolism. Tomato (Solanum lycopersicum) serves as a research model for fruit development and ripening because it possesses numerous favorable genetic features. In this study, SlNAC1 was cloned. An antisense (AS) vector was constructed and transferred to tomato to further explore the function of SlNAC1. The results showed that AS fruits exhibited delayed ripening and a deeper red appearance when these fruits were fully ripened. Fully ripened AS fruits also produced higher total carotenoid and lycopene contents than those of the wild-type (WT) line. Ethylene production of AS fruits was delayed but occurred to a higher extent than that of WT fruits. The softening of AS fruits was slower than that of WT fruits. Endogenous abscisic acid (ABA) level in AS-4 fruits was lower than that in WT fruits. Exogenous ABA accelerated the softening of AS fruits. Furthermore, AS fruits demonstrated up-regulated expression of genes related to lycopene and ethylene biosynthesis but down-regulated expression of genes related to cell wall metabolism and ABA synthesis. Therefore, SlNAC1 is likely implicated in fruit ripening. PMID- 26962711 TI - Work Habits Are Valid Components of Evaluations of Anesthesia Residents Based on Faculty Anesthesiologists' Daily Written Comments About Residents. AB - BACKGROUND: In our department, faculty anesthesiologists routinely evaluate the resident physicians with whom they worked in an operative setting the day before, providing numerical scores to questions. The faculty can also enter a written comment if so desired. Because residents' work habits are important to anesthesiology program directors, and work habits can improve with feedback, we hypothesized that faculty comments would include the theme of the anesthesia resident's work habits. METHODS: We analyzed all 6692 faculty comments from January 1, 2011, to June 30, 2015. We quantified use of the theme of Dannefer et al.'s work habit scale, specifically the words and phrases in the scale, and synonyms to the words. RESULTS: Approximately half (50.7% [lower 99.99% confidence limit, 48.4%]) of faculty comments contained the theme of work habits. Multiple sensitivity analyses were performed excluding individual faculty, residents, and words. The lower confidence limits for comments containing the theme were each >42.7%. CONCLUSIONS: Although faculty anesthesiologists completed (numerical) questions based on the American College of Graduate Medical Education competencies to evaluate residents, an important percentage of written comments included the theme of work habits. The implication is that the theme has validity as one component of the routine evaluation of anesthesia residents. PMID- 26962713 TI - Electroacupuncture Enhances the Antiallodynic and Antihyperalgesic Effects of Milnacipran in Neuropathic Rats. AB - BACKGROUND: Milnacipran, a selective serotonin/norepinephrine-reuptake inhibitor, has been shown to elicit a beneficial effect in various models of neuropathic pain. Previously, we reported that repetitive electroacupuncture (EA) significantly ameliorates neuropathic pain induced by L5 spinal nerve ligation (SNL). In the present study, we sought to determine whether a single treatment with EA produces analgesia and whether EA in combination with a subeffective dosage of milnacipran exhibits an additive effect in SNL rats. METHODS: Mechanical allodynia and thermal hyperalgesia were assessed by measuring paw withdrawal thresholds and latencies in response to mechanical and thermal stimuli, respectively, 1 day before and 5 days after neuropathic surgery. In addition, on day 5 post-SNL, time courses of behaviors were assessed at 0, 1, 2, 4, 6, and 8 hours after intrathecal (i.t.) milnacipran (1, 5, and 20 MUg) administration. EA (10 Hz/1 mA) was administered at the ST36 and GB34 acupoints for 30 minutes on day 5 and the time courses of behaviors were also assessed at 0, 1, 2, 4, 6, and 8 hours later. Similarly, when treated in combination (milnacipran [5 MUg, i.t.] and EA [10 Hz/1 mA]), time courses of behaviors were assessed at the same time points. RESULTS: Intrathecal injection of milnacipran at 5 or 20 MUg exerted dose-dependent effects on thermal hyperalgesia but had similar efficacies on mechanical allodynia. Furthermore, EA itself detectably attenuated hyperalgesia at 4 hours after the application, but no statistically significant difference was found in mechanical allodynia. Importantly, cotreatment with EA and milnacipran (5 MUL) produced more potent antiallodynic and antihyperalgesic effects than those obtained from EA or milnacipran alone at 1, 2, and 4 hours after treatment, indicating an additive effect. In addition, the analgesic effect of EA plus milnacipran was almost completely abolished by the catecholamine neurotoxin 6-hydroxydopamine hydrobromide (25 MUg), which depletes spinal norepinephrine, and by yohimbine (an alpha2-adrenoceptor antagonist, 30 MUg, i.t.). Somewhat surprisingly, the analgesic effect of milnacipran plus EA lasted for 6 hours. CONCLUSIONS: The study shows that, in male rats with SNL, spinal administration of milnacipran effectively alleviates mechanical allodynia and thermal hyperalgesia, and that a single treatment of EA has an antihyperalgesic effect. Furthermore, our findings suggest that coapplication of EA and milnacipran enhanced antiallodynia and antihyperalgesia by activating spinal noradrenergic systems coupled with spinal alpha2 adrenoceptors and prolongs the duration of analgesia. PMID- 26962714 TI - The Effects of Lidocaine on Central Respiratory Neuron Activity and Nociceptive Related Responses in the Brainstem-Spinal Cord Preparation of the Newborn Rat. AB - BACKGROUND: Lidocaine is widely used in the clinical setting as a local anesthetic and antiarrhythmic drug. Although it has been suggested that lidocaine exerts inhibitory effects on the central and peripheral neurons, there are no reports on its effects on central respiratory activity in vertebrates. In this study, we examined the effects of lidocaine on respiratory rhythm generation and nociceptive response in brainstem-spinal cord preparations from the newborn rats. METHODS: Preparations were isolated from Wistar rats (postnatal day 0-3) and superfused with artificial cerebrospinal fluid equilibrated with 95% O2 and 5% CO2, pH 7.4, at 25 degrees C to 26 degrees C. We examined the effects of lidocaine on the fourth cervical ventral root (C4)-inspiratory activity and on the preinspiratory and inspiratory neurons in the rostral medulla. We also examined the effects on the C4/C5 reflex responses induced by ipsilateral C7/C8 dorsal root stimulation, which are thought to be related to the nociceptive response. RESULTS: The application of low doses of lidocaine (10-20 MUM) resulted in a slight increase of the C4 burst rate, whereas high doses of lidocaine (100 400 MUM) decreased the burst rate in a dose-dependent manner, eventually resulting in the complete cessation of respiratory rhythm. High doses of lidocaine decreased the burst duration and negative slope conductance of preinspiratory neurons, suggesting that lidocaine blocked persistent Na+ current. After the burst generation of the respiratory neurons ceased, depolarizing current stimulation continued to induce action potentials; however, the induction of the spike train was depressed because of strong adaptation. A low dose of lidocaine (20 MUM) depressed C4/C5 spinal reflex responses. CONCLUSIONS: Our findings indicate that lidocaine depressed nociception-related responses at lower concentrations than those that induced respiratory depression. Our report provides the basic neuronal mechanisms to support the clinical use of lidocaine, which shows antinociceptive effects with minimal side effects on breathing. PMID- 26962712 TI - Continuous Popliteal Sciatic Blocks: Does Varying Perineural Catheter Location Relative to the Sciatic Bifurcation Influence Block Effects? A Dual-Center, Randomized, Subject-Masked, Controlled Clinical Trial. AB - BACKGROUND: Multiple studies have demonstrated that, for single-injection popliteal sciatic nerve blocks, block characteristics are dependent upon local anesthetic injection relative to the sciatic nerve bifurcation. In contrast, this relation remains unexamined for continuous popliteal sciatic nerve blocks. We, therefore, tested the hypothesis that postoperative analgesia is improved with the perineural catheter tip at the level of the bifurcation compared with 5 cm proximal to the bifurcation. METHODS: Preoperatively, subjects having moderately painful foot or ankle surgery were randomly assigned to receive an ultrasound guided subepimyseal perineural catheter inserted either at or 5 cm proximal to the sciatic nerve bifurcation. Subjects received a single injection of mepivacaine 1.5% either via the insertion needle preoperatively or the perineural catheter postoperatively, followed by an infusion of ropivacaine 0.2% (6 mL/h basal, 4 mL bolus, and 30-min lockout) for the study duration. The primary end point was the average pain measured on a numeric rating scale (0-10) in the 3 hours before a data collection telephone call the morning after surgery. RESULTS: The average numeric rating scale of subjects with a catheter inserted at the sciatic nerve bifurcation (n = 64) was a median (10th, 25th to 75th, and 90th quartiles) of 3.0 (0.0, 2.4-5.0, and 7.0) vs 2.0 (0.0, 1.0-4.0, and 5.0) for subjects with a catheter inserted proximal to the bifurcation (n = 64; P = 0.008). Similarly, maximum pain scores were greater in the group at the bifurcation: 6.0 (3.0, 4.4-8.0, and 9.0) vs 5.0 (0.0, 3.0-8.0, and 10.0) (P = 0.019). Differences between the groups for catheter insertion time, opioid rescue dose, degree of numbness in the foot/toes, catheter dislodgement, and fluid leakage did not reach statistical significance. CONCLUSIONS: For continuous popliteal sciatic nerve blocks, a catheter inserted 5 cm proximal to the sciatic nerve bifurcation provides superior postoperative analgesia in subjects having moderately painful foot or ankle surgery compared with catheters located at the bifurcation. This is in marked contrast with single-injection popliteal sciatic nerve blocks for which benefits are afforded to local anesthetic injection distal, rather than proximal, to the bifurcation. PMID- 26962715 TI - Bacterial Contamination of the Anesthesia Workplace and Efficiency of Routine Cleaning Procedures: A Prospective Cohort Study. AB - In this prospective cohort study, 200 decontamination (cleaning and disinfection) procedures of the anesthesia workplace either by anesthesia nurses or by specially trained housekeeping staff were monitored. Time used by housekeeping staff was shorter (1.2 +/- 0.1 vs 2.6 +/- 0.2 minutes on average, data are mean +/- SEM; P < 0.0001) with less visible marker spots (14.4 +/- 0.68 [55%] vs 17.3 +/- 0.75 [66.7%] on average, data are mean +/- SEM; P = 0.0041), and the bacterial load showed a decrease (?67%, P < 0.0001) compared with anesthesia nurses. Specially trained housekeeping staff outperformed anesthesia nurses in cleaning the anesthesia workplace. Specific training for anesthesia workplace cleaning is supported by these findings. PMID- 26962716 TI - Isolation and (111)In-Oxine Labeling of Murine NK Cells for Assessment of Cell Trafficking in Orthotopic Lung Tumor Model. AB - A noninvasive in vivo imaging method for NK cell trafficking is essential to gain further understanding of the pathogenesis of NK cell mediated immune response to the novel cancer treatment strategies, and to discover the homing sites and physiological distribution of NK cells. Although human NK cells can be labeled for in vivo imaging, little is known about the murine NK cell labeling and its application in animal models. This study describes the isolation and ex vivo radiolabeling of murine NK cells for the evaluation of cell trafficking in an orthotopic model of human lung cancer in mice. Scid-Tg(FCGR3A)Blt transgenic SCID mice were used to isolate NK cells from mouse splenocytes using the CD49b (DX5) MicroBeads positive selection method. The purity and viability of the isolated NK cells were confirmed by FACS analysis. Different labeling buffers and incubation times were evaluated to optimize (111)In-oxine labeling conditions. Functionality of the radiolabeled NK cell was assessed by (51)Cr-release assay. We evaluated physiological distribution of (111)In-oxine labeled murine NK cells in normal SCID mice and biodistribution in irradiated and nonirradiated SCID mice with orthotopic A549 human lung tumor lesions. Imaging findings were confirmed by histology. Results showed that incubation with 0.011 MBq of (111)In-oxine per million murine NK cells in PBS (pH 7.4) for 20 min is the best condition that provides optimum labeling efficiency without affecting cell viability and functionality. Physiological distribution in normal SCID mice demonstrated NK cells homing mainly in the spleen, while (111)In released from NK cells was excreted via kidneys into urine. Biodistribution studies demonstrated a higher lung uptake in orthotopic lung tumor-bearing mice than control mice. In irradiated mice, lung tumor uptake of radiolabeled murine NK cells decreased between 24 h and 72 h postinjection (p.i.), which was accompanied by tumor regression, while in nonirradiated mice, radiolabeled NK cells were retained in the lung tumor lesions up to 72 h p.i. without tumor regression. In tumor-bearing mice that were only irradiated but did not receive radiolabeled murine NK cells, a high tumor burden was observed at 72 h p.i., which indicates that irradiation in combination with murine NK cell allocation, but not irradiation alone, induced a remarkable antitumor effect in the orthotopic A549 lung tumor bearing mouse model. In conclusion, we describe a method to evaluate murine NK cell trafficking and biodistribution, which can be used to determine potential effects of immune mediated therapeutic agents on NK cell biodistribution. PMID- 26962718 TI - Excellent microwave-absorbing properties of elliptical Fe3O4 nanorings made by a rapid microwave-assisted hydrothermal approach. AB - High-quality elliptical polycrystalline Fe3O4 nanorings (NRs) with continuously tunable size have been synthesized in large amounts via a rapid microwave assisted hydrothermal approach. The surface-protected glucose reducing/etching/Ostwald ripening mechanism is responsible for the formation of NRs. Ring size can be modulated by selecting iron glycolate nanosheets with various sizes as precursors. The size-dependent magnetic behavior of the NRs was observed. Our research gives insights into the understanding of the microwave absorption mechanism of elliptical Fe3O4 NRs. Owing to their large specific surface area, shape anisotropy, and closed ring-like configuration, elliptical polycrystalline Fe3O4 NRs exhibited significantly enhanced microwave absorption performance compared with Fe3O4 circular NRs, nanosheets, microspheres, nanospindles, and nanotubes. An optimal reflection loss value of -41.59 dB is achieved at 5.84 GHz and R(L) values (<=-20 dB) are observed at 3.2-10.4 GHz. Some new mechanisms including multiple scattering, oscillation resonance absorption, microantenna radiation, and interference are also crucial to the enhanced absorption properties of NRs. These findings indicate that ring-like nanostructures are a promising structure for devising new and effective microwave absorbers. PMID- 26962717 TI - A mixed-methods exploration of the quality of life of Chinese breast cancer survivors. AB - Quality of life (QOL) in cancer survivorship is a multidimensional and subjective concept, which represents the personal sense of the physical, psychological, social, and spiritual consequences of cancer diagnosis and its treatment. This mixed method study aimed to explore the QOL of Chinese breast cancer survivors. Participants were recruited from a cancer self-help organization in the central area of China. QOL was assessed using the QOL-Cancer Survivor Scale and subsequently elicited by in-depth interviews. Results showed that participants had good overall QOL but with unfavorable aspects in psychological and social well-being. Interview data revealed that participants seldom attended spiritual activities. Instead, they actively reconnected with their "self" to create a positive meaning from their cancer experience. Understanding how Chinese breast cancer survivors perceive QOL is important for health professionals to address survivorship in this population. PMID- 26962720 TI - In vivo and in vitro metabolism of the designer anabolic steroid furazadrol in thoroughbred racehorses. AB - Furazadrol ([1',2']isoxazolo[4',5':2,3]-5alpha-androstan-17beta-ol) is a designer anabolic androgenic steroid that is readily available via the internet. It contains an isoxazole fused to the steroid A-ring which offers metabolic stability and noteworthy anabolic activity raising concerns over the potential for abuse of this compound in equine sports. The metabolism of furazadrol was studied by in vivo and in vitro methods for the first time. Urinary furazadrol 17 sulfate and furazadrol 17-glucuronide metabolites were detected in vivo after a controlled administration and compared with synthetically-derived reference materials in order to confirm their identities. They were quantified to establish the excretion profile and a suitable limit of detection. Minor metabolites were also detected, including epifurazadrol, hydroxylated furazadrol, and hydroxylated and oxidised furazadrol, present as the sulfate and glucuronide conjugates. Phase II metabolites were subjected to enzymatic hydrolysis by Escherichia coli beta glucuronidase and Pseudomonas aeruginosa arylsulfatase to further confirm the identity of the corresponding phase I metabolites. The metabolism profile was compared to the products obtained from an in vitro phase I metabolism study, with all but two of the minor in vivo phase I metabolites observed in the in vitro system. These investigations identify the key urinary metabolites of furazadrol following oral administration, which can be incorporated into anti-doping screening and confirmation procedures. PMID- 26962721 TI - Raman spectroscopy for the analytical quality control of low-dose break-scored tablets. AB - Quality control of solid dosage forms involves the analysis of end products according to well-defined criteria, including the assessment of the uniformity of dosage units (UDU). However, in the case of break-scored tablets, given that tablet splitting is widespread as a means to adjust doses, the uniform distribution of the active pharmaceutical ingredient (API) in all the possible fractions of the tablet must be assessed. A general procedure to accomplish with both issues, using Raman spectroscopy, is presented. It is based on the acquisition of a collection of spectra in different regions of the tablet, that later can be selected to determine the amount of API in the potential fractions that can result after splitting. The procedure has been applied to two commercial products, Sintrom 1 and Sintrom 4, with API (acenocoumarol) mass proportion of 2% and 0.7% respectively. Partial Least Squares (PLS) calibration models were constructed for the quantification of acenocoumarol in whole tablets using HPLC as a reference analytical method. Once validated, the calibration models were used to determine the API content in the different potential fragments of the scored Sintrom 4 tablets. Fragment mass measurements were also performed to estimate the range of masses of the halves and quarters that could result after tablet splitting. The results show that Raman spectroscopy can be an alternative analytical procedure to assess the uniformity of content, both in whole tablets as in its potential fragments, and that Sintrom 4 tablets can be perfectly split in halves, but some cautions have to be taken when considering the fragmentation in quarters. A practical alternative to the use of UDU test for the assessment of tablet fragments is proposed. PMID- 26962719 TI - Pilot trial of gabapentin for the treatment of benzodiazepine abuse or dependence in methadone maintenance patients. AB - BACKGROUND: Benzodiazepine use disorders are a common clinical problem among methadone maintenance treatment patients and have adverse effects on clinical outcomes. OBJECTIVES: To evaluate gabapentin for the outpatient treatment of benzodiazepine abuse or dependence in methadone maintenance patients. METHODS: Participants (n = 19) using benzodiazepines at least 4 days per week were enrolled into an 8-week randomized double-blind placebo-controlled outpatient pilot trial. All participants received a manual-guided supportive psychotherapy aimed to promote abstinence. Study medication was titrated over a 2-week period to a maximum dose of gabapentin 1200 mg or placebo three times a day. Benzodiazepine use was assessed using urine toxicology confirmed self-report. Benzodiazepines were not provided as part of study participation; participants were provided guidance to gradually reduce benzodiazepine intake. RESULTS: Sixteen participants had post-randomization data for analysis. Retention at week eight was 50%. The mean dose of gabapentin achieved by titration was 2666 mg/day (SD = +/- 1446). There were no significant between group differences on benzodiazepine use outcomes (amount benzodiazepine per day [Mann-Whitney U = 27, p = 0.745], abstinent days per week [U = 28, p = 0.811]) and Clinical Instrument Withdrawal Assessment (CIWA)-benzodiazepines scale (U = 29.0, p = 0.913). One participant in the gabapentin group discontinued study medication because of peripheral edema. Two participants in the placebo group requested admission for inpatient detoxification treatment. CONCLUSION: In outpatient methadone maintained patients with benzodiazepine use disorder, gabapentin did significantly decrease benzodiazepine use relative to placebo. The small sample recruited for this trial may have limited the ability to detect a group difference. PMID- 26962722 TI - The different fate of satellite cells on conductive composite electrospun nanofibers with graphene and graphene oxide nanosheets. AB - Electrospinning of composite polymer solutions provides fantastic potential to prepare novel nanofibers for use in a variety of applications. The addition of graphene (G) and graphene oxide (GO) nanosheets to bioactive polymers was found to enhance their conductivity and biocompatibility. Composite conductive nanofibers of polyaniline (PANI) and polyacrylonitrile (PAN) with G and GO nanosheets were prepared by an electrospinning process. The fabricated membranes were investigated by physical and chemical examinations including scanning electron microscopy (SEM), Raman spectroscopy, x-ray diffraction (XRD) and tensile assay. The muscle satellite cells enriched by a pre-plating technique were cultured in the following and their proliferation and differentiation behavior studied by MTT, Real-Time PCR assays and 4', 6-diamidino-2-phenylindole (DAPI) staining. The cultured cells on composite nanofibrous PAN/PANI-CSA/G confirmed a higher proliferation and differentiation value compared to other groups including PAN/PANI-CSA/GO and PAN/PANI-CSA scaffolds. Furthermore, the higher stiffness of the former scaffold showed a lower cell spreading as a function of stem cell activation into more proliferative cells. It is supposed that the enhanced conductivity value in addition to relative higher stiffness of the PAN/PANI-CSA/G composite nanofibers plays a favorable role for proliferation and differentiation of satellite cells. PMID- 26962724 TI - Toward Lower Costs and Better Care--Averting a Collision between Consumer- and Provider-Focused Reforms. PMID- 26962723 TI - Multicenter clinical evaluation of the new 3rd generation assay for detection of antibodies against hepatitis C virus on the VIDAS((r)) system. AB - BACKGROUND: Detection of antibodies (anti-HCV) against hepatitis C virus (HCV) is indispensable for screening and diagnosis of viral hepatitis and for the viral safety of blood, tissue or organ donations. It gains additional importance by the new HCV drugs which improve the therapeutic possibilities dramatically. OBJECTIVE: To evaluate the performance of a newly developed immune assay for anti HCV based on the well-established VIDAS platform. STUDY DESIGN: The assay was evaluated with samples from anti-HCV negative blood donors and from patients with or without HCV markers in six centres in France, Spain and Egypt. The status of the samples was determined by using CE-marked immune assays (Architect, AxSym, Prism, Vitros), two immunoblots (RIBA, Inno-Lia) and/or HCV RNA results. RESULTS: Specificity was 99.67% in 10,320 French blood donors without anti-HCV, 99.5% in 200 anti-HCV negative hospitalized European patients and 99.0% in 198 negative patients from Egypt. Sensitivity was 99.7% in 1054 patients pretested positive by other assays; 345 patients with known genotype had genotype 1-6; 61 patients were co-infected with HIV. VIDAS was reactive in 78% of 91 patients with uncertain or very weak anti-HCV. It became on average positive at day 37 with seroconversion panels. CONCLUSIONS: This multicentric, international study with >12,000 samples show that the new VIDAS anti-HCV assay is very suitable for screening and confirmation of HCV infection. Sensitivity, specificity and recognition of seroconversion compare favorably with well-established CE-marked tests and help to clarify discrepant results obtained with other assays. PMID- 26962725 TI - The Physician Payments Sunshine Act--Two Years of the Open Payments Program. PMID- 26962726 TI - Disheartening Disparities. PMID- 26962727 TI - Four Artemisinin-Based Treatments in African Pregnant Women with Malaria. AB - BACKGROUND: Information regarding the safety and efficacy of artemisinin combination treatments for malaria in pregnant women is limited, particularly among women who live in sub-Saharan Africa. METHODS: We conducted a multicenter, randomized, open-label trial of treatments for malaria in pregnant women in four African countries. A total of 3428 pregnant women in the second or third trimester who had falciparum malaria (at any parasite density and regardless of symptoms) were treated with artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, or dihydroartemisinin-piperaquine. The primary end points were the polymerase-chain-reaction (PCR)-adjusted cure rates (i.e., cure of the original infection; new infections during follow-up were not considered to be treatment failures) at day 63 and safety outcomes. RESULTS: The PCR-adjusted cure rates in the per-protocol analysis were 94.8% in the artemether-lumefantrine group, 98.5% in the amodiaquine-artesunate group, 99.2% in the dihydroartemisinin piperaquine group, and 96.8% in the mefloquine-artesunate group; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2%, 96.9%, 98.0%, and 95.5%, respectively. There was no significant difference among the amodiaquine artesunate group, dihydroartemisinin-piperaquine group, and the mefloquine artesunate group. The cure rate in the artemether-lumefantrine group was significantly lower than that in the other three groups, although the absolute difference was within the 5-percentage-point margin for equivalence. The unadjusted cure rates, used as a measure of the post-treatment prophylactic effect, were significantly lower in the artemether-lumefantrine group (52.5%) than in groups that received amodiaquine-artesunate (82.3%), dihydroartemisinin piperaquine (86.9%), or mefloquine-artesunate (73.8%). No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups. Drug-related adverse events such as asthenia, poor appetite, dizziness, nausea, and vomiting occurred significantly more frequently in the mefloquine-artesunate group (50.6%) and the amodiaquine-artesunate group (48.5%) than in the dihydroartemisinin-piperaquine group (20.6%) and the artemether lumefantrine group (11.5%) (P<0.001 for comparison among the four groups). CONCLUSIONS: Artemether-lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest post-treatment prophylaxis, whereas dihydroartemisinin-piperaquine had the best efficacy and an acceptable safety profile. (Funded by the European and Developing Countries Clinical Trials Partnership and others; ClinicalTrials.gov number, NCT00852423.). PMID- 26962730 TI - Mesenteric Ischemia. PMID- 26962731 TI - IMAGES IN CLINICAL MEDICINE. Midline Destructive Lesions in a Cocaine User. PMID- 26962728 TI - Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy. AB - BACKGROUND: Intermittent treatment with sulfadoxine-pyrimethamine is widely recommended for the prevention of malaria in pregnant women in Africa. However, with the spread of resistance to sulfadoxine-pyrimethamine, new interventions are needed. METHODS: We conducted a double-blind, randomized, controlled trial involving 300 human immunodeficiency virus (HIV)-uninfected pregnant adolescents or women in Uganda, where sulfadoxine-pyrimethamine resistance is widespread. We randomly assigned participants to a sulfadoxine-pyrimethamine regimen (106 participants), a three-dose dihydroartemisinin-piperaquine regimen (94 participants), or a monthly dihydroartemisinin-piperaquine regimen (100 participants). The primary outcome was the prevalence of histopathologically confirmed placental malaria. RESULTS: The prevalence of histopathologically confirmed placental malaria was significantly higher in the sulfadoxine pyrimethamine group (50.0%) than in the three-dose dihydroartemisinin-piperaquine group (34.1%, P=0.03) or the monthly dihydroartemisinin-piperaquine group (27.1%, P=0.001). The prevalence of a composite adverse birth outcome was lower in the monthly dihydroartemisinin-piperaquine group (9.2%) than in the sulfadoxine pyrimethamine group (18.6%, P=0.05) or the three-dose dihydroartemisinin piperaquine group (21.3%, P=0.02). During pregnancy, the incidence of symptomatic malaria was significantly higher in the sulfadoxine-pyrimethamine group (41 episodes over 43.0 person-years at risk) than in the three-dose dihydroartemisinin-piperaquine group (12 episodes over 38.2 person-years at risk, P=0.001) or the monthly dihydroartemisinin-piperaquine group (0 episodes over 42.3 person-years at risk, P<0.001), as was the prevalence of parasitemia (40.5% in the sulfadoxine-pyrimethamine group vs. 16.6% in the three-dose dihydroartemisinin-piperaquine group [P<0.001] and 5.2% in the monthly dihydroartemisinin-piperaquine group [P<0.001]). In each treatment group, the risk of vomiting after administration of any dose of the study agents was less than 0.4%, and there were no significant differences among the groups in the risk of adverse events. CONCLUSIONS: The burden of malaria in pregnancy was significantly lower among adolescent girls or women who received intermittent preventive treatment with dihydroartemisinin-piperaquine than among those who received sulfadoxine-pyrimethamine, and monthly treatment with dihydroartemisinin piperaquine was superior to three-dose dihydroartemisinin-piperaquine with regard to several outcomes. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT02163447.). PMID- 26962732 TI - CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 7-2016. An 80-Year-Old Man with Weight Loss, Abdominal Pain, Diarrhea, and an Ileocecal Mass. PMID- 26962733 TI - Treatment of Malaria in Pregnancy. PMID- 26962734 TI - HLA-Incompatible Kidney Transplantation--Worth the Risk? PMID- 26962735 TI - N-of-1 Policymaking--Tragedy, Trade-offs, and the Demise of Morcellation. PMID- 26962729 TI - Survival Benefit with Kidney Transplants from HLA-Incompatible Live Donors. AB - BACKGROUND: A report from a high-volume single center indicated a survival benefit of receiving a kidney transplant from an HLA-incompatible live donor as compared with remaining on the waiting list, whether or not a kidney from a deceased donor was received. The generalizability of that finding is unclear. METHODS: In a 22-center study, we estimated the survival benefit for 1025 recipients of kidney transplants from HLA-incompatible live donors who were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting-list-or-transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting-list-only control group). We analyzed the data with and without patients from the highest volume center in the study. RESULTS: Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0%, vs. 94.0% for the waiting-list-or-transplant control group and 89.6% for the waiting-list-only control group), 3 years (91.7% vs. 83.6% and 72.7%, respectively), 5 years (86.0% vs. 74.4% and 59.2%), and 8 years (76.5% vs. 62.9% and 43.9%) (P<0.001 for all comparisons with the two control groups). The survival benefit was significant at 8 years across all levels of donor-specific antibody: 89.2% for recipients of kidney transplants from incompatible live donors who had a positive Luminex assay for anti-HLA antibody but a negative flow cytometric cross-match versus 65.0% for the waiting-list-or-transplant control group and 47.1% for the waiting-list-only control group; 76.3% for recipients with a positive flow-cytometric cross-match but a negative cytotoxic cross-match versus 63.3% and 43.0% in the two control groups, respectively; and 71.0% for recipients with a positive cytotoxic cross-match versus 61.5% and 43.7%, respectively. The findings did not change when patients from the highest-volume center were excluded. CONCLUSIONS: This multicenter study validated single-center evidence that patients who received kidney transplants from HLA-incompatible live donors had a substantial survival benefit as compared with patients who did not undergo transplantation and those who waited for transplants from deceased donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.). PMID- 26962736 TI - Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. PMID- 26962737 TI - Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. PMID- 26962738 TI - Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. PMID- 26962739 TI - Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. PMID- 26962740 TI - The Genetic Evolution of Melanoma. PMID- 26962741 TI - The Genetic Evolution of Melanoma. PMID- 26962742 TI - The Genetic Evolution of Melanoma. PMID- 26962744 TI - Lymph-Node Palpation--No Laughing Matter. PMID- 26962743 TI - The Genetic Evolution of Melanoma. PMID- 26962746 TI - Subclinical Atrial Fibrillation and the Risk of Stroke. PMID- 26962747 TI - Chimeric Antigen Receptor-Modified T Cells in Chronic Lymphoid Leukemia; Chimeric Antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia; Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia. PMID- 26962745 TI - Hyponatremia among Triathletes in the Ironman European Championship. PMID- 26962748 TI - IMAGES IN CLINICAL MEDICINE. Tinea Versicolor. PMID- 26962749 TI - Self-care Management Intervention to Improve Psychological Wellbeing for Jordanian Patients with Type Two Diabetes Mellitus. AB - The purpose of the study is to evaluate the effectiveness of self-care management intervention on psychological wellbeing for Jordanian patients with type two diabetes mellitus. A quasi-experimental design was used. The study was conducted in a diabetes clinic of a specialized diabetes center in Amman. One hundred and forty-nine participants completed the three-month post-treatment assessments (76 in the intervention group and 73 in the control group). Both the control and intervention groups received a standard diabetic educational program. The intervention group received the following additional interventions: (1) Diabetes Self-care Management booklet, (2)DVD viewing, (3) counseling rehearsal session, and (4) a telephone follow-up. The main study instrument was an Arabic version 20 of the depression anxiety stress scales: To assess the group differences of dependent variable changes, repeated measure ANOVA was used. It was found that psychological wellbeing was not significant at 2-week post-intervention and significant change was observed at 3-month post-intervention. The findings from this study can guide the health providers to be trained to provide relevant diabetic interventions into their nursing interventions, education, and research. PMID- 26962750 TI - Erratum. PMID- 26962757 TI - Propensity score analysis with missing data. AB - Propensity score analysis is a method that equates treatment and control groups on a comprehensive set of measured confounders in observational (nonrandomized) studies. A successful propensity score analysis reduces bias in the estimate of the average treatment effect in a nonrandomized study, making the estimate more comparable with that obtained from a randomized experiment. This article reviews and discusses an important practical issue in propensity analysis, in which the baseline covariates (potential confounders) and the outcome have missing values (incompletely observed). We review the statistical theory of propensity score analysis and estimation methods for propensity scores with incompletely observed covariates. Traditional logistic regression and modern machine learning methods (e.g., random forests, generalized boosted modeling) as estimation methods for incompletely observed covariates are reviewed. Balance diagnostics and equating methods for incompletely observed covariates are briefly described. Using an empirical example, the propensity score estimation methods for incompletely observed covariates are illustrated and compared. (PsycINFO Database Record PMID- 26962758 TI - A power analysis for fidelity measurement sample size determination. AB - The importance of assessing fidelity has been emphasized recently with increasingly sophisticated definitions, assessment procedures, and integration of fidelity data into analyses of outcomes. Fidelity is often measured through observation and coding of instructional sessions either live or by video. However, little guidance has been provided about how to determine the number of observations needed to precisely measure fidelity. We propose a practical method for determining a reasonable sample size for fidelity data collection when fidelity assessment requires observation. The proposed methodology is based on consideration of the power of tests of the treatment effect of outcome itself, as well as of the relationship between fidelity and outcome. It makes use of the methodology of probability sampling from a finite population, because the fidelity parameters of interest are estimated over a specific, limited time frame using a sample. For example, consider a fidelity measure defined as the number of minutes of exposure to a treatment curriculum during the 36 weeks of the study. In this case, the finite population is the 36 sessions, the parameter (number of minutes over the entire 36 sessions) is a total, and the sample is the observed sessions. Software for the sample size calculation is provided. PMID- 26962759 TI - Confidence intervals for population reliability coefficients: Evaluation of methods, recommendations, and software for composite measures. AB - A composite score is the sum of a set of components. For example, a total test score can be defined as the sum of the individual items. The reliability of composite scores is of interest in a wide variety of contexts due to their widespread use and applicability to many disciplines. The psychometric literature has devoted considerable time to discussing how to best estimate the population reliability value. However, all point estimates of a reliability coefficient fail to convey the uncertainty associated with the estimate as it estimates the population value. Correspondingly, a confidence interval is recommended to convey the uncertainty with which the population value of the reliability coefficient has been estimated. However, many confidence interval methods for bracketing the population reliability coefficient exist and it is not clear which method is most appropriate in general or in a variety of specific circumstances. We evaluate these confidence interval methods for 4 reliability coefficients (coefficient alpha, coefficient omega, hierarchical omega, and categorical omega) under a variety of conditions with 3 large-scale Monte Carlo simulation studies. Our findings lead us to generally recommend bootstrap confidence intervals for hierarchical omega for continuous items and categorical omega for categorical items. All of the methods we discuss are implemented in the freely available R language and environment via the MBESS package. PMID- 26962760 TI - Serum adiponectin is a negative predictor of central arterial stiffness in kidney transplant patients. AB - BACKGROUND: The role of adiponectin in arterial stiffness and its relationship to cardiovascular disease is not fully demonstrated and needs further elaboration. In this study, the association between adiponectin level and arterial stiffness is studied among kidney transplant patients. MATERIAL AND METHODS: Anthropometric data and biochemical data including fasting glucose, lipid profile, renal function and serum adiponectin were determined in 55 kidney transplant patients. Central arterial stiffness was measured and presented by carotid-femoral pulse wave velocity. RESULTS: Univariate linear analysis showed that body weight, waist circumference, brachial pulse pressure and body mass index were correlated positively with carotid-femoral pulse wave velocity in this patient group. However, logarithmically transformed adiponectin level (log-adiponectin) correlated negatively with carotid-femoral pulse wave velocity. In multivariate regression analysis of factors significantly associated with carotid-femoral pulse wave velocity, it showed that both log-adiponectin (beta = -0.427; R(2) = 0.205, p = 0.001) and body weight (beta = 0.327; R(2 )=( )0.106, p = 0.007) were independently predictive of central arterial stiffness. CONCLUSION: Our study suggests that fasting serum adiponectin is negatively associated with carotid femoral pulse wave velocity, hence arterial stiffness, in kidney transplant patients. PMID- 26962761 TI - Stimuli-responsive poly(N-isopropyl acrylamide)-co-tyrosine@gadolinium: Iron oxide nanoparticle-based nanotheranostic for cancer diagnosis and treatment. AB - In this paper, we have prepared a stimuli-responsive polymer modified gadolinium doped iron oxide nanoparticle (poly@Gd-MNPs) as cancer theranostic agent. The responsive polymer is composed of the poly(N-isopropyl acrylamide)-co-tyrosine unit, which shows excellent loading for the anti-cancer drug (methotrexate) and stimuli dependent release (change in pH and temperature). The in vitro experiment revealed that the poly@Gd-MNPs exhibited T1-weighted MRI capability (r1=11.314mM( 1)s(-1)) with good in-vitro hyperthermia response. The prepared poly@Gd-MNPs has generated quick heating (45 degrees C in 2min) upon exposure to an alternating magnetic field and able to travel a distance of 35cm in 1min in the presence of an external magnet. The poly@Gd-MNPs shows 86% of drug loading capacity with 70% drug release in first 2h. The cytotoxic assay (MTT) demonstrated that the nanoparticle did not affect the viability of normal human fibroblast and efficiently kill the MCF7 cancer cells in the presence of an external magnetic field. To explore the uptake of poly@Gd-MNPs in the cells, bright field cell imaging study was also performed. This study provides a valuable approach for the design of highly sensitive polymer modified gadolinium doped iron oxide-based T1 contrast agents for cancer theranostics. PMID- 26962762 TI - Heat shock mediated labelling of Pseudomonas aeruginosa with quantum dots. AB - Biocompatible nanoparticles are good candidates to label bacteria for imaging and diagnosis purposes. A high labeling efficiency reduces the concentration of nanoparticles required for labeling and allows the labeled bacteria to be tracked for longer periods. This report explores the optimal labeling strategy for Pseudomonas aeruginosa, a common gram-negative opportunistic pathogen, with quantum dots. Three strategies including direct incubation, calcium chloride treatment, and heat shock are compared and the labeling efficiency is assessed through fluorescence microscopy and flow cytometry analysis. Of the three, heat shock is finally selected due to its comparable labeling efficiency and simplicity. Through the assay of the respiration rate of bacteria together with morphology analysis, the heat shock process does not show any negative effect over the cells activity even at sub-toxic concentrations. PMID- 26962763 TI - Dopamine modulated ionic permeability in mesoporous silica sphere based biomimetic compartment. AB - The building of artificial systems with similar structure and function as cellular compartments will expand our understanding of compartmentalization related biological process and facilitate the construction of biomimetic highly functional structures. Herein, surface phenylboronic acid functionalized mesoporous silica sphere was developed as a biomimetic dopamine gated compartment, in which the ionic permeability can be well modulated through the dopamine-binding induced charge reversal. As the phenylboronic acid is negatively charged, the negatively charged 1, 3, 6, 8-pyrenetetrasulfonic acid (TPSA) was hindered from permeation into the biomimetic compartment. However, the presence of dopamine and its binding with phenylboronic acid reversed the gatekeeper shell from negative to positive charged and gated the permeation of TPSA into the interior. The dopamine gated permeation phenomenon resembles that in biological system, and thus the phenylboronic acid functionalized mesoporous silica sphere was taken as a simple model for dopamine gated ion channel decorated biological compartment. It will also contribute to the development of artificial cell and responsive nanoreactor. PMID- 26962764 TI - On the interaction of alginate-based core-shell nanocarriers with keratinocytes in vitro. AB - Calcium alginate nanocarriers (CaANCs) were developed as a potential tool for delivery of hydrophobic active molecules such as pharmaceutical and cosmetic active ingredients. In this study, we focused on interactions between CaANCs and keratinocytes in culture and examined toxicity, internalization and drug release. Prior to cellular interactions, cryogenic transmission electron microscopy images showed that CaANCs appear as regular, spherical and dense particles, giving evidence of the surface gelation of CaANCs. Their size, around 200nm, was stable under tested conditions (temperature, culture media, presence of serum and presence of encapsulated dye), and their toxicity on keratinocytes was very low. Flow cytometry assays showed that CaANCs are internalized into keratinocytes by endocytosis with a predominant implication of the caveolae-mediated route. Forster resonance energy transfer (FRET) demonstrated that after a 2h contact, the release of CaANC contents in the cytoplasm of keratinocytes was almost complete. The endocytosis of CaANCs by a lysosome-free pathway, and the rapid release of their contents inside keratinocytes, will allow vectorized molecules to fully exhibit their pharmacological or cosmetic activity. PMID- 26962765 TI - Biostability enhancement of oil core - polysaccharide multilayer shell via photoinitiator free thiol-ene 'click' reaction. AB - Layer-by-layer of polyelectrolytes has emerged as one of the easiest and most controlled techniques to deposit ultrathin polymer layers mainly driven by electrostatic interactions. However, this kind of interaction results to be weak and easily breakable in physiological environment. Here we report on the preparation of nanocapsules completely made of natural biomaterials: a lipophilic core (soybean oil and egg lecithin as surfactant) as nanometric template and a polysaccharide-based multilayer shell (glycol chitosan and heparin) covalently cross-linked. We first modified glycol chitosan with a thiol moiety and heparin with an alkene moiety, respectively, and then we built a polymer multilayer film with a covalent cross-linkage among layers, exploiting the light initiated thiol ene reaction, known as click chemistry. We showed the possibility to perform the covalent cross-linkage without any photoinitiator or metal catalyst, thus avoiding cytotoxic effects and further purification steps. The so realized nanocapsules resulted to be stable and completely biocompatible and, therefore, of interest for the biotechnology fields, mainly for drug delivery. PMID- 26962767 TI - Sticky Palms Following Use of Proton-Pump Inhibitors. PMID- 26962768 TI - Microbiological Assessment of Bile and Corresponding Antibiotic Treatment: A Strobe-Compliant Observational Study of 1401 Endoscopic Retrograde Cholangiographies. AB - The aim of this study was to determine the antibiotic susceptibility profiles of bacteria in bile samples and to analyze the clinical relevance of the findings as only limited information about risk factors for elevated frequence of bacterial and fungal strains in routinely collected bile samples has been described so far.A prospective cohort study at a tertiary care center was conducted. Seven hundred forty-four patients underwent 1401 endoscopic retrograde cholangiographies (ERCs) as indicated by liver transplantation (427/1401), primary sclerosing cholangitis (222/1401), choledocholithiasis only (153/1401), obstruction due to malignancy (366/1401), or other conditions (233/1401). Bile samples for microbiological analysis were obtained in all patients.The 71.6% (823/1150) samples had a positive microbiological finding, and 57% (840/1491) of the bacterial isolates were gram-positive. The main species were Enterococcus spp (33%; 494/1491) and Escherichia coli (12%; 179/1491). Of the samples, 53.8% had enteric bacteria and 24.7% had Candida spp; both were associated with clinical and laboratory signs of cholangitis (C-reactive proteins 35.0 +/- 50.1 vs 44.8 +/ 57.6; 34.5 +/- 51.2 vs 52.9 +/- 59.7; P < 0.001), age, previous endoscopic intervention, and immunosuppression. Multi-resistant (MR) strains were found in 11.3% of all samples and were associated with clinical and laboratory signs of cholangitis, previous intervention, and immunocompromised status. In subgroup analysis, strain-specific antibiotic therapy based on bile sampling was achieved in 56.3% (89/158) of the patients. In cases with a positive bile culture and available blood culture, blood cultures were positive in 29% of cases (36/124), and 94% (34/36) of blood cultures had microbial species identical to the bile cultures.Bactobilia and fungobilia can usually be detected by routine microbiological sampling, allowing optimized, strain-specific antibiotic treatment. Previous endoscopic intervention, clinical and laboratory signs of cholangitis, and age are independent risk factors. MR bacteria and fungi are an evolving problem in cholangitis, especially in immunocompromised patients. PMID- 26962769 TI - Experience With Fenestrated Endovascular Repair of Juxtarenal Abdominal Aortic Aneurysms at a Single Center. AB - To present the early and mid-term results of fenestrated endovascular aneurysm repair (FEVAR) using the Zenith fenestrated device for juxtarenal abdominal aortic aneurysms (JAAAs) at our center in China. DESIGN: Retrospective study.The study included 15 male patients with JAAAs, who underwent FEVAR using the Zenith fenestrated device at our center between February 2011 and June 2015.All custom made Zenith fenestrated devices were designed according to computed tomography angiography (CTA) images obtained preoperatively. The patients with renal insufficiency underwent duplex ultrasonography, while the patients with normal renal function underwent 3 CT data acquisitions including nonenhanced CT, arterial phase, and venous phase. These examinations and blood examinations were completed at 3, 6, and 12 months after discharge, and annually thereafter.The mean age of the patients was 73.13 +/- 9.06 years (range, 57-86 years), and the median follow-up period was 30 months (8-52 months). Small fenestrations were used in 27 renal arteries, scallops were used in 7 superior mesenteric arteries (SMAs) and 2 renal arteries, and large fenestrations were used in 2 SMAs. Conversion to an open procedure was not required in any of the patients, and the technical success rate was 100%. The mean length of hospital stay was 11.33 +/- 2.02 days (7-15 days). No patient died within the 1st 30 days after the operation. One patient had a type Ia endoleak, which disappeared at 6 months after the operation, 1 patient had a type Ib endoleak, which was detected at 17 months after the operation, and 2 patients had type II endoleaks. One patient died at 17 months and another patient died at 30 months after the operation. Therefore, the all-cause mortality rate was 13.33% (2/15). The target vessel patency rate was 100% without occlusion.The early and mid-term results of FEVAR using the Zenith fenestrated device were good, demonstrating that this procedure is effective for the treatment of JAAAs. PMID- 26962770 TI - Total Hemi-overgrowth in Pigmentary Mosaicism of the (Hypomelanosis of) Ito Type: Eight Case Reports. AB - Pigmentary mosaicism of the (hypomelanosis of) Ito type is an umbrella term, which includes phenotypes characterized by mosaic hypopigmentation in the form of streaks, whorls, patchy, or more bizarre skin configurations (running along the lines of Blaschko): these cutaneous patterns can manifest as an isolated skin disorder (pigmentary mosaicism of the Ito type) or as a complex malformation syndrome in association with extracutaneous anomalies (most often of the musculoskeletal and/or nervous systems) (hypomelanosis of Ito). Affected individuals are anecdotally reported to have also partial or total body hemi overgrowth (HOG), which often causes moderate to severe complications.We studied the occurrence and features of HOG in the 114 children and adults with mosaic pigmentary disorders of the Ito type diagnosed and followed up (from 2 to 22 years; average follow-up 16 years) at our Institutions.Eight patients (5 M, 3 F; aged 4 to 25 years; median age 16 years) out of the 114 analyzed (7%) fulfilled the criteria for unilateral HOG, with differences in diameter ranging from 0.4 to 4.0 cm (upper limbs) and 1.0 to 9.0 cm (lower limbs). Moreover, among these 8 patients, 5/8 filled in the 75th to 90th percentile for height; 6/8 had associated kyphoscoliosis; and 5/8 showed cognitive delays. No tumour complications were recorded. Overall, 6/8 HOG patients presented with additional (extracutaneous) syndromic manifestations, apart from the HOG (ie, with a clinical phenotype of hypomelanosis of Ito).The present study, which includes children and adults with the longest follow-up so far recorded, confirms the association between pigmentary mosaicism of the Ito type and HOG lowering previous estimates (7% vs 16%) for HOG in the context of mosaic hypopigmentation. A careful examination, looking at subtle to moderate asymmetries and associated complications within the spectrum of these mosaic pigmentary disorders, is recommended. PMID- 26962771 TI - Prevalence and Clustering of Major Cardiovascular Risk Factors in China: A Recent Cross-Sectional Survey. AB - Cardiovascular disease is the leading cause of death in the Chinese population. Although general prevalence estimates of cardiovascular risk factors (CVRFs) are available for Chinese adults, prevalence estimates covering all adult age groups by race/ethnicity have not been reported. The aim of this study is to estimate the current prevalence and clustering of major CVRFs in Chinese adults, including a plurality of ethnic minorities.A cross-sectional survey was conducted in a nationally representative sample of 23,010 adults aged 18 years and older from 2007 to 2011. Questionnaires and physical examinations were performed, and fasting blood was collected for laboratory measurements. The prevalence of traditional CVRFs, including hypertension, diabetes, dyslipidemia, overweight, and current smoking, were determined.The prevalence of the major CVRFs, including hypertension, diabetes, dyslipidemia, overweight, and current smoking were 24.3%, 4.3%, 49.3%, 32.0%, and 21.7%, respectively. These risk factors were significantly associated with sex, age, region, ethnicity, and education levels. Overall, 70.3%, 40.3%, and 16.7% of Chinese adults had >=1, >=2, or >=3 CVRFs, respectively. Men, northern and rural residents were more likely to have clustered CVRFs compared with women, southern and urban residents, respectively. Compared with Han residents, Hui and Mongolian residents were more likely, and Tujia and Miao residents were less likely, to have >=1, >=2, or >=3 risk factors. The prevalence of Chinese women having >=1, >=2, or >=3 CVRFs decreased with increasing levels of education.The prevalence and clustering of CVRFs is still high in Chinese adults >=18 years old, especially in men and in individuals living in the northern and rural areas. Of note, there are differences in cardiovascular risk among different ethnic groups. Therefore, targeted and enhanced intervention measures are required to reduce the risk of cardiovascular disease and the corresponding economic burden of disease in China. PMID- 26962772 TI - Colorectal Cancer Screening Based on Age and Gender: A Cost-Effectiveness Analysis. AB - We evaluated whether age- and gender-based colorectal cancer screening is cost effective.Recent studies in the United States identified age and gender as 2 important variables predicting advanced proximal neoplasia, and that women aged <60 to 70 years were more suited for sigmoidoscopy screening due to their low risk of proximal neoplasia. Yet, quantitative assessment of the incremental benefits, risks, and cost remains to be performed.Primary care screening practice (2008-2015).A Markov modeling was constructed using data from a screening cohort. The following strategies were compared according to the Incremental Cost Effectiveness Ratio (ICER) for 1 life-year saved: flexible sigmoidoscopy (FS) 5 yearly; colonoscopy 10 yearly; FS for each woman at 50- and 55-year old followed by colonoscopy at 60- and 70-year old; FS for each woman at 50-, 55-, 60-, and 65 year old followed by colonoscopy at 70-year old; FS for each woman at 50-, 55-, 60-, 65-, and 70-year old. All male subjects received colonoscopy at 50-, 60-, and 70-year old under strategies 3 to 5.From a hypothetical population of 100,000 asymptomatic subjects, strategy 2 could save the largest number of life-years (4226 vs 2268 to 3841 by other strategies). When compared with no screening, strategy 5 had the lowest ICER (US$42,515), followed by strategy 3 (US$43,517), strategy 2 (US$43,739), strategy 4 (US$47,710), and strategy 1 (US$56,510). Strategy 2 leads to the highest number of bleeding and perforations, and required a prohibitive number of colonoscopy procedures. Strategy 5 remains the most cost effective when assessed with a wide range of deterministic sensitivity analyses around the base case.From the cost effectiveness analysis, FS for women and colonoscopy for men represent an economically favorable screening strategy. These findings could inform physicians and policy-makers in triaging eligible subjects for risk-based screening, especially in countries with limited colonoscopic resources. Future research should study the acceptability, feasibility, and feasibility of this risk-based strategy in different populations. PMID- 26962773 TI - Measuring Resource Utilization: A Systematic Review of Validated Self-Reported Questionnaires. AB - A variety of methods may be used to obtain costing data. Although administrative data are most commonly used, the data available in these datasets are often limited. An alternative method of obtaining costing is through self-reported questionnaires. Currently, there are no systematic reviews that summarize self reported resource utilization instruments from the published literature.The aim of the study was to identify validated self-report healthcare resource use instruments and to map their attributes.A systematic review was conducted. The search identified articles using terms like "healthcare utilization" and "questionnaire." All abstracts and full texts were considered in duplicate. For inclusion, studies had to assess the validity of a self-reported resource use questionnaire, to report original data, include adult populations, and the questionnaire had to be publically available. Data such as type of resource utilization assessed by each questionnaire, and validation findings were extracted from each study.In all, 2343 unique citations were retrieved; 2297 were excluded during abstract review. Forty-six studies were reviewed in full text, and 15 studies were included in this systematic review. Six assessed resource utilization of patients with chronic conditions; 5 assessed mental health service utilization; 3 assessed resource utilization by a general population; and 1 assessed utilization in older populations. The most frequently measured resources included visits to general practitioners and inpatient stays; nonmedical resources were least frequently measured. Self-reported questionnaires on resource utilization had good agreement with administrative data, although, visits to general practitioners, outpatient days, and nurse visits had poorer agreement.Self-reported questionnaires are a valid method of collecting data on healthcare resource utilization. PMID- 26962774 TI - Baseline Characteristics and Risk Factors of Pulmonary Arterial Hypertension in Systemic Lupus Erythematosus Patients. AB - Peking Union Medical College Hospital (PUMCH) has started a single-center right heart catheterization (RHC)-based pulmonary arterial hypertension (PAH) study in systemic lupus erythematosus (SLE) since 2006. The baseline characteristics of these patients were described and the risk factor for PAH in lupus was identified.The demographic, clinical, laboratory, and treatment characteristics of SLE patients with PAH when they were registered were collected as the baseline data. A case-control study was conducted by taking the admitted SLE-non-PAH patients adjusted for age and gender in a 4:1 ratio during the same period as the controls. The associated variables were examined by binary multivariate logistic regression analysis to identify possible risk factors. A total of 111 RHC confirmed SLE-PAH patients were enrolled, with the onset age of 34.6 +/- 8.6 years old and the average SLE duration of 5 years. RHC revealed mPAP as 46.4 +/- 11.4 mm Hg, CI as 2.7 +/- 0.8 L/min * m, and PVR as 10.5 +/- 4.8 WU. 46% of patients were WHO Fc I-II. All patients were treated with immunosuppressive agents and 65% patients had PAH-targeted therapy. The case-control study had confirmed 2 independent risk factors previously published: pericardial effusion (OR = 21.290, P < 0.001) and anti-RNP antibody (OR = 12.399, P < 0.001). Meanwhile, 6 independent variables were discovered: baseline SLE duration (OR = 1.118, P = 0.007), interstitial lung disease (OR = 17.027, P < 0.001=, without acute rash (OR = 3.258, P = 0.019), anti-SSA antibody (OR = 4.836, P = 0.004), SLEDAI<=9 (OR = 26.426, P < 0.001), ESR<=20 mm/h (OR = 12.068, P < 0.001), and uric acid > 357 MUmol/L (OR = 9.666, P < 0.001) to be associated with PAH in SLE patients.The PUMCH study has shown that SLE patients complicated with PAH are usually earlier diagnosed and have less disease severity than patients without PAH. The immunosuppressive therapy rate and the PAH target therapy rate were high, which is consistent with reports from Western countries. This study has confirmed that pericardial effusion and positive anti-RNP antibody are risk factors for SLE-associated PAH. Long SLE disease duration, the presence of interstitial lung disease, without acute skin rash, positive anti-SSA antibody, low SLEDAI and ESR, and high uric acid levels are also associated with PAH in SLE patients. PMID- 26962775 TI - Increased Risk of Endometriosis in Patients With Lower Genital Tract Infection: A Nationwide Cohort Study. AB - Endometriosis results from the ectopic invasion of endometrial glands and stroma in the peritoneal cavity. The exact etiology of endometriosis is still unknown. It has, however, been shown that there are higher numbers of Escherichia coli in menstrual blood, and higher endotoxin levels in menstrual fluid, as well as, in the peritoneal fluid of patients with endometriosis. In this study, we aimed to determine whether lower genital tract infections could increase the risk of endometriosis.We used the Taiwan National Health Insurance database to conduct a population-based cohort study. We included patients diagnosed with inflammatory diseases of the cervix, vagina, and vulva, and a control group comprising patients matched by age, sex, and comorbidities but without inflammatory diseases of the cervix, vagina, or vulva.A total of 79,512 patients were included in the inflammatory disease group and an equal number of control individuals were selected. The incidence of endometriosis (hazard ratio, 2.01; 95% confidence interval, 1.91-2.12; P < 0.001) was higher among patients than controls. Cox proportional hazards models showed that irrespective of comorbidities, lower genital tract infection was an independent risk factor for endometriosis.Patients with lower genital tract infections exhibit a substantially higher risk for developing endometriosis. PMID- 26962776 TI - Insulin Resistance is Associated With Total Bile Acid Level in Type 2 Diabetic and Nondiabetic Population: A Cross-Sectional Study. AB - Bile acid metabolism was reported to be involved in glucose metabolism homeostasis. However, the exact relationship between bile acid and glucose metabolism as well as insulin sensitivity is not clarified. Therefore, we sought to investigate the association between insulin sensitivity and hyperbileacidemia in type 2 diabetic and nondiabetic population.This community-based cross sectional study included 9603 residents from Jiading, Shanghai, China, who were 40 years and older. Standardized questionnaire, anthropometric measurements and laboratory tests were conducted. Homeostasis model assessment of insulin resistance (HOMA-IR) >= 2.7 was defined as insulin resistance and fasting TBA >= 10 mmol/L was defined as hyperbileacidemia.Multivariate stepwise regression analysis revealed that HOMA-IR, age, and male sex were positively associated with hyperbileacidemia in both nondiabetic and diabetic participants. In multivariate logistic models, participants with insulin resistance had significantly higher risk of hyperbileacidemia compared to those who have no insulin resistance, in both nondiabetic and diabetic population (nondiabetic: OR = 1.76; 95% CI 1.42 2.19; P < 0.001; diabetic: OR = 1.56; 95% CI 1.06 - 2.31; P = 0.025, respectively). Further adjustment for the HbA1c level in diabetic population did not change the significant association (OR = 1.59; 95% CI 1.06 - 2.40; P = 0.024). In nondiabetic participants, each 1-unit increment of HOMA-IR conferred an 18% higher risk of hyperbileacidemia (95% CI 1.04-1.35; P = 0.013), whereas in diabetic participants, this association was similar but not significant (95% CI 0.95-1.59; P = 0.117).Insulin resistance was positively associated with hyperbileacidemia in both nondiabetic and diabetic population. The increase in the bile acid level in insulin-resistant population regardless of status of diabetes and glucose level indicated the important role of insulin resistance in the regulation of bile acid metabolism in human. PMID- 26962777 TI - Preoperative Anxiety in Patients With Myasthenia Gravis and Risk for Myasthenic Crisis After Extended Transsternal Thymectomy: A CONSORT Study. AB - A thymectomy can ameliorate the symptoms of myasthenia gravis (MG) and prevent the progression of ocular MG (OMG) to generalized MG (GMG). However, postoperative myasthenic crisis (POMC) is a serious post-thymectomy complication. Preoperative anxiety (POA) is common but typically neglected in MG patients. The association of POA with POMC has not yet been examined.From June 2007 to December 2013, 541 cases of MG were admitted to the First Affiliated Hospital of Sun Yat sen University (Guangzhou, China). All cases underwent extended transsternal thymectomy (ETT). The clinical and pathological characteristics of these patients, including POA and POMC, were analyzed.A total of 179 patients experienced POA and 67 patients experienced POMC. Patients with POA were more likely to have POMC, a thymoma, and an ectopic thymus. Univariate analysis showed that POMC correlated with POA, presence of an ectopic thymus, dose of pyridostigmine bromide (PYR), presence of a thymoma, MGFA stage, preoperative myasthenic crisis, and postoperative pneumonia. Multivariate logistic regression analysis showed that the independent risk factors for POMC were POA, preoperative myasthenic crisis, higher dose of PYR, and postoperative pneumonia.Our results suggest that clinicians should consider the risk factors for POMC-especially preoperative anxiety-before performing a thymectomy in patients with MG. PMID- 26962779 TI - Primary Intestinal Lymphangiectasia Manifested as Unusual Edemas and Effusions: A Case Report. AB - Primary intestinal lymphangiectasia (PIL) is a rare disorder of unknown etiology characterized by diffuse or localized dilation and eventual rupture of the enteric lymphatic vessels in mucosa, submucosa, and/or subserosa. Lymph, rich in all kinds of proteins and lymphocytes, leaks into the gastrointestinal tract via the affected lymphatic vessels causing hypoproteinemia and lymphopenia. The main symptom is variable degrees of pitting edemas of bilateral lower limbs. But edemas of any other parts of body, and mild serous effusions may also occur sometimes. PIL occurs in conjunction with a right hemifacial edema, a right upper limb lymphedema, asymmetric bilateral calves edemas, and a unilateral massive pleural effusion seems never to be reported before. In addition, increased enteric protein loss that may cause severe hypoproteinemia usually get overlooked, and the lymphatic system disorders always put the diagnoses in a dilemma.We described a case of a 17-year-old Chinese girl with a history of gradually progressive swellings of right-sided face, right upper limb, and bilateral calves since 3 to 4 months of age. A right-sided massive pleural effusion, a moderate pericardial effusion, and a mild ascites have been proved unchanged by a series of computerized tomography (CT) scans since 5 years ago. The diagnosis of PIL was finally confirmed by severe hypoproteinemia, endoscopic changes, and histology of jejunum biopsy. Further lymphoscintigraphy and lymphangiography also identified lymph leakage in her bowel and several abnormal lymphatic vessels. A high-protein, low-fat diet supplemented with medium-chain triglycerides (MCT) showed some benefit.This case suggested that PIL was a rare but important etiology of hypoproteinemia, effusions, and edemas. PIL, effusions, and lymphedema can be the features of multisegmental generalized lymphatic dysplasia. In addition, both lymphoscintigraphy and intranodal lymphangiography could be considered when lymphatic system disorders are suspected. PMID- 26962778 TI - High Throughput Sequencing of T Cell Antigen Receptors Reveals a Conserved TCR Repertoire. AB - The T-cell receptor (TCR) repertoire is a mirror of the human immune system that reflects processes caused by infections, cancer, autoimmunity, and aging. Next generation sequencing has become a powerful tool for deep TCR profiling. Herein, we used this technology to study the repertoire features of TCR beta chain in the blood of healthy individuals.Peripheral blood samples were collected from 10 healthy donors. T cells were isolated with anti-human CD3 magnetic beads according to the manufacturer's protocol. We then combined multiplex-PCR, Illumina sequencing, and IMGT/High V-QUEST to analyze the characteristics and polymorphisms of the TCR.Most of the individual T cell clones were present at very low frequencies, suggesting that they had not undergone clonal expansion. The usage frequencies of the TCR beta variable, beta joining, and beta diversity gene segments were similar among T cells from different individuals. Notably, the usage frequency of individual nucleotides and amino acids within complementarity determining region (CDR3) intervals was remarkably consistent between individuals. Moreover, our data show that terminal deoxynucleotidyl transferase activity was biased toward the insertion of G (31.92%) and C (27.14%) over A (21.82%) and T (19.12%) nucleotides.Some conserved features could be observed in the composition of CDR3, which may inform future studies of human TCR gene recombination. PMID- 26962780 TI - Comparing Burnout Across Emergency Physicians, Nurses, Technicians, and Health Information Technicians Working for the Same Organization. AB - Studies on the topic of burnout measure the effects of emotional exhaustion (EE), depersonalization (DP) (negative or cynical attitudes toward work), and reduced sense of personal accomplishment (PA). While the prevalence of burnout in practicing emergency medicine (EM) professionals has been studied, little is known of the prevalence and factors across physicians, nurses, technicians, and health information technicians working for the same institution. The aim of this study was to assess burnout differences across EM professional types.The total population of 250 EM professionals at 2 public urban hospitals in Turkey were surveyed using the Maslach Burnout Inventory and basic social- and work-related demographics. Descriptive statistics, ANOVA, and additional post hoc tests were computed.Findings show that EE and DP scores were high across all occupational groups, while scores on PA were low. There was a statistically significant difference between nurses and medical technicians (P < 0.05) for EE; and between physicians and both nurses and medical technicians (P < 0.05) for PA; while no group differences were found for DP. Age, gender, economic well-being, and income level were all significant; while patient load and marital status showed no significance.Burnout can be high across occupational groups in the emergency department. Burnout is important for EM administrators to assess across human resources. Statistically significant differences across socio-demographic groups vary across occupational groups. However, differences between occupational groups may not be explained effectively by the demographic factors assessed in this or other prior studies. Rather, the factors associated with burnout are incomplete and require further institutional, cultural, and organizational analyses including differentiating between job tasks carried out by each EM job type. PMID- 26962781 TI - Diagnosis of Transverse Sinus Hypoplasia in Magnetic Resonance Venography: New Insights Based on Magnetic Resonance Imaging in Combined Dataset of Venous Outflow Impairment Case-Control Studies: Post Hoc Case-Control Study. AB - In previous studies of transverse sinus (TS) hypoplasia, discrepancies between TS diameter measured by magnetic resonance venography (MRV) and contrast T1-weighted magnetic resonance (contrast T1) were observed. To investigate these discrepancies, and considering that TS hypoplasia is associated with neurological disorders, we performed a post hoc analysis of prospectively collected data from 3 case-control studies on transient global amnesia (TGA), transient monocular blindness (TMB), and panic disorders while retaining the original inclusion and exclusion criteria. Magnetic resonance (MR) imaging of 131 subjects was reviewed to evaluate TS diameter and the location and degree of venous flow stenosis and obstruction.MRV without contrast revealed that TS hypoplasia was observed in 69 subjects, whom we classified into 2 subgroups according to the concordance with contrast T1 observations: concordance indicated anatomically small TS (30 subjects), and discrepancy indicated that the MRV diagnosis is in fact flow related and that TS is not anatomically small (39 subjects). The latter subgroup was associated with at least 1 site of venous compression/stenosis in the internal jugular vein (IJV) or the left brachiocephalic vein (BCV) (P < 0.001), which was significantly larger in patients than controls. Compensatory dilatation of contralateral TS diameter was only observed with MRV, not with contrast T1 imaging.The clinical implication of these results is that using MRV only, IJV/BCV compression/stenosis may be misdiagnosed as TS hypoplasia. And contralateral TS have no compensatory dilatation in its diameter in contrast T1 imaging, just compensatory increased flow volume. PMID- 26962782 TI - A Matched Influenza Vaccine Strain Was Effective in Reducing the Risk of Acute Myocardial Infarction in Elderly Persons: A Population-Based Study. AB - The aim of this study was to explore whether matched or mismatched strains of influenza vaccines (IVs) are beneficial at reducing the risk of acute myocardial infarction (AMI) in elderly persons.Data were obtained from the Longitudinal Health Database 2005 (LHID 2005) which is maintained by the National Health Insurance Research Institute in Taiwan. The analytical data included individuals who were vaccinated with mismatched vaccines during the October 2007 to December 2007 season and individuals vaccinated with matched strains during the October 2008 to December 2008 season. All participants were 65 years of age and older. In this analysis, individuals were considered to be exposed if their records showed that they were vaccinated against influenza, and they were considered to be nonexposed if they were not vaccinated during these seasons. A Cox hazard model was used to estimate AMI hazard ratio.This study enrolled 93,051 exposed and 109,007 unexposed individuals. The AMI hazards ratios (HRs) for the men and women exposed to mismatched vaccine (in 2007) were 0.990 (95% confidence interval [CI], 0.745-1.316) and 1.102 (95% CI: 0.803-1.513), respectively. Men exposed to matched vaccines (in 2008) had significant HRs (HR: 0.681; 95% CI: 0.509-0.912) while the HRs in the women were barely significant (HR: 0.737; 95% CI: 0.527 1.029).AMI risk could be particularly reduced in men if the IV matches well with the circulating strains in elderly people 65 years of age and older. PMID- 26962783 TI - Patient With Severe Hyponatremia Caused by Adrenal Insufficiency Due to Ectopic Posterior Pituitary Lobe and Miscommunication Between Hypothalamus and Pituitary: A Case Report. AB - Hyponatremia may be one of the clinical manifestations of adrenal insufficiency (AI) and during the diagnostic workup of hyponatremic patients investigation of AI should be included.We report the case of an 82-year-old patient who was admitted to our hospital with clinical symptoms and laboratory findings of hyponatremia. Following the diagnostic algorithm of hyponatremia we reached the diagnosis of AI. Clinician's attention must focus on the underlying cause of AI which in this case was hidden in a miscommunication between hypothalamus and pituitary due to an ectopic posterior pituitary lobe and became apparent by a pituitary magnetic resonance imaging (MRI) scan. Treatment with oral hydrocortisone resulted in full clinical recovery and electrolyte balance, which was maintained after 7 months of follow-up.Secondary AI is related with hyponatremia through increased ADH secretion. Although a hyponatremic episode may be the first presentation of AI, clinical suspicion is of high importance in order to place the right diagnosis. Disruption of communication between hypothalamus and pituitary is a rare but considerable cause of AI. PMID- 26962784 TI - Genetic Association Between Androgen Receptor Gene CAG Repeat Length Polymorphism and Male Infertility: A Meta-Analysis. AB - The association between polymorphism of androgen receptor gene CAG (AR-CAG) and male infertility in several studies was controversial. Based on studies on association between AR-CAG repeat length and male infertility in recent years, an updated meta-analysis is needed. We aimed to evaluate the association between AR CAG repeat length and male infertility in advantage of the data in all published reports.We searched for reports published before August 2015 using PubMed, CNKI, VIP, and WanFang. Data on sample size, mean, and standard deviation (SD) of AR CAG repeat length were extracted independently by 3 investigators.Forty-four reports were selected based on criteria. The overall infertile patients and azoospermic patients were found to have longer AR-CAG repeat length (standard mean difference (SMD) = 0.19, 95% confidence interval (CI): 0.10-0.28, P < 0.01; SMD = 0.36, 95% CI: 0.10-0.61, P < 0.01). AR-CAG repeat length was longer in infertile men in Asian, Caucasian, and mixed races (SMD = 0.25, 95% CI: 0.08 0.43, P <0.01; SMD = 0.13, 95% CI: 0.02-0.25, P <0.05; SMD = 0.39, 95% CI: 0.15 0.63, P <0.01). The overall study shows that increased AR-CAG repeat length was associated with male infertility. The subgroup study on races shows that increased AR-CAG repeat length was associated with male infertility in Asian, Caucasian, and mixed races. Increased AR-CAG repeat length was also associated with azoospermia.This meta-analysis supports that increased androgen receptor CAG length is capable of causing male infertility susceptibility. PMID- 26962785 TI - Correlation Between the Integrity of the Circle of Willis and the Severity of Initial Noncardiac Cerebral Infarction and Clinical Prognosis. AB - The quality of collateral circulation affects the severity and prognosis of stroke patients. The effect of the circle of Willis, which is the primary collateral circulation, on ischemic stroke has attracted significant attention. This study was designed to investigate the effect of different circles of Willis types on stroke severity and prognosis in patients with noncardiac stroke.A total of 376 patients with noncardiac ischemic stroke, who were treated by the specialty team of cerebrovascular diseases at the First Affiliated Hospital of Sun Yat-sen Hospital, were successively enrolled in this study. The detailed clinical characteristics of the patients were recorded upon admission, including risk factors of vascular disease and National Institutes of Health Stroke Scale (NIHSS) scores. The patients were divided into groups of different circles of Willis types based on magnetic resonance angiography (MRA) that was performed within 3 days of admission-type I: complete circle of Willis; type II: complete anterior half of the circle of Willis and incomplete posterior half of the circle of Willis; type III: incomplete anterior half of the circle of Willis and complete posterior half of the circle of Willis; and type IV: incomplete anterior and posterior halves of the circle of Willis. Patients were re-evaluated for NIHSS scores at discharge and after discharge. The modified Rankin score (mRS) was recorded for 90 days, and stroke recurrence and death after 90 days were also recorded until the end of the study.The 376 patients were divided into 4 groups based on the MRA-type I group: 92 patients (24.5%); type II group: 215 patients (57.2%); type III group: 12 patients (3.2%), and type IV group: 57 patients (15.2%). NIHSS scores at admission and discharge were significantly lower for the type I group compared with those for the type II and type IV groups (P < 0.05). NIHSS scores were higher in the groups with an incomplete circle of Willis compared with the group with a complete circle of Willis. A poor recovery rate was highest for the type IV group, whereas a good recovery rate was highest for the type I group. The logistic regression analysis showed that a complete circle of Willis was one of the predictors of suitable recovery (odds ratio [OR] = 0.708, 95% confidence interval [CI]: 0.554-0.906).Circle of Willis type was associated with stroke severity and patient prognosis, whereas an incomplete circle of Willis was associated with more severe conditions and a higher 90-day poor diagnosis rate. A complete circle of Willis was an independent predictor of good prognosis. PMID- 26962787 TI - Burkitt-Type Acute Lymphoblastic Leukemia With Precursor B-Cell Immunophenotype and Partial Tetrasomy of 1q: A Case Report. AB - Burkitt-type acute lymphoblastic leukemia (B-ALL) is thought as a variant of Burkitt lymphoma/leukemia and derived from mature B-cell lymphoblast.B-ALL was developed in a 10-year-old girl. Two characteristics were apparent in this case. First, the lymphoblastic cells were positive for CD10, CD19, CD20, and CD22, but negative for terminal deoxynucleotidyl transferase and surface immunoglobulins, indicating a B-cell immunophenotype. The detection of t(8;14)(q24;q32) with a chromosomal analysis is required for a diagnosis of B-ALL. Second, der(1)(pter -> q32.1::q32.1 -> q21.1::q11 -> qter) was detected, in which 1q21.1 to 1q32.1 was inverted and inserted. Finally, partial tetrasomy of 1q was also present. Because B-ALL with abnormal chromosome 1 has been reported poor outcome, the usual chemotherapy for stage 4 Burkitt lymphoma with added rituximab was administered for our patient.We report B-ALL with precursor B-cell immunophenotype and interesting partial tetrasomy of 1q. PMID- 26962786 TI - Interaction Between Dietary Vitamin K Intake and Anticoagulation by Vitamin K Antagonists: Is It Really True?: A Systematic Review. AB - Educational advice is often given to patients starting treatment with vitamin K Antagonists (VKAs). A great emphasis is made on nutritional information. Common belief is that dietary vitamin K intake could counteract the anticoagulant effect by VKAs and for many years, patients have been discouraged to consume vitamin-K rich foods, such as green leafy vegetables.The objective of this study is to summarize the current evidence supporting the putative interaction between dietary vitamin K intake and changes in INR with the VKAs.Data sources are MEDLINE via PubMed and Cochrane database.All clinical studies investigating the relationship between dietary vitamin K and measures of anticoagulation were included. We excluded all studies of supplementation of vitamin K alone.We performed a systematic review of the literature up to October 2015, searching for a combination of "food," "diet," "vitamin K," "phylloquinone," "warfarin," "INR," "coagulation," and "anticoagulant."Two dietary interventional trials and 9 observational studies were included. We found conflicting evidence on the effect of dietary intake of vitamin K on coagulation response. Some studies found a negative correlation between vitamin K intake and INR changes, while others suggested that a minimum amount of vitamin K is required to maintain an adequate anticoagulation. Median dietary intake of vitamin K1 ranged from 76 to 217 MUg/day among studies, and an effect on coagulation may be detected only for high amount of vitamin intake (>150 MUg/day).Most studies included patients with various indications for VKAs therapy, such as atrial fibrillation, prosthetic heart valves, and venous thromboembolism. Thus, INR target was dishomogeneous and no subanalyses for specific populations or different anticoagulants were conducted. Measures used to evaluate anticoagulation stability were variable.The available evidence does not support current advice to modify dietary habits when starting therapy with VKAs. Restriction of dietary vitamin K intake does not seem to be a valid strategy to improve anticoagulation quality with VKAs. It would be, perhaps, more relevant to maintain stable dietary habit, avoiding wide changes in the intake of vitamin K. PMID- 26962788 TI - Estimated Glomerular Filtration Rate and Systolic Time Intervals in Risk Stratification for Increased Left Ventricular Mass Index and Left Ventricular Hypertrophy. AB - Either decreased renal function or increased systolic time interval is associated with cardiac hypertrophy and poor cardiac outcome. The aim of this study was to evaluate combination of renal function and brachial systolic time intervals were associated with increased left ventricular mass index (LVMI) and left ventricular hypertrophy (LVH).In total of 990 patients were consecutively included in this study from January 2011 to December 2012. All study participants were further classified into 4 groups by the values of estimated glomerular filtration rate (eGFR) and ratio of brachial preejection period (bPEP) to brachial ejection time (bET). The classification of 4 groups were eGFR >= 45 mL/min/1.73 m and bPEP/bET < 0.38 (group 1), eGFR >= 45 ml/min/1.73 m and bPEP/bET >= 0.38 (group 2), eGFR < 45 mL/min/1.73 m and bPEP/bET < 0.38 (group 3), and eGFR < 45 mL/min/1.73 m and bPEP/bET >= 0.38 (group 4), respectively. Patients in groups 1 and 4 had the lowest and highest LVMI among 4 groups, respectively (P < 0.001). In multivariable analyses, increased LVMI and LVH were significantly associated with patients in groups 2, 3 and 4 (vs group 1) (P <= 0.019).Our study demonstrated that joined parameter of renal function and systolic time intervals, in terms of eGFR and bPEP/bET, might be an alternative method in risk stratification for increased LVMI and LVH. PMID- 26962790 TI - A Rare Case of Isolated Cystic Hydatid of Thyroid Gland. AB - Hydatid cysts are most frequently localized within the liver and lungs, although they can also be found in highly vascularized tissues such as the brain, muscle, heart, pancreas, adrenal, and thyroid glands.A 65-year-old female patient was admitted to our clinic with complaints of a progressively growing mass that was compressing the surrounding tissues and causing respiratory distress. The pathological result was obtained as cytic hydatid.In patients with diagnosed hydatid cysts in the liver, systemic evaluation is necessary to rule out involvement of other organs. Among patients presenting with growths located in the neck, primary hydatid cyst of the thyroid gland must be considered in endemic regions. PMID- 26962789 TI - Effect of Dexmedetomidine in Preventing Postoperative Side Effects for Laparoscopic Surgery: A Meta-Analysis of Randomized Controlled Trials and Trial Sequential Analysis (PRISMA). AB - Dexmedetomidine (DEX) has been used extensively for patients during surgery. Some studies found that DEX could reduce the incidence of postoperative side effects in laparoscopic surgical patients. However, no firm conclusions were made about it.The authors searched for randomized controlled trials (RCTs) in PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials testing DEX administrated in laparoscopic surgical patients and reporting on postoperative nausea, vomiting, shivering, heart rate, mean arterial pressure (MAP), or extubation time after surgery or within 1 hour in postoperative care unit. Trial sequential analysis (TSA) was used for RCTs comparing DEX with placebo or no treatment in laparoscopic surgery patients. A protocol for this meta-analysis has been registered on PROSPERO (http://www.crd.york.ac.uk/prospero) and the registration number is CRD42015020226.Fifteen studies (899 patients) were included. DEX could significantly reduce the incidence of postoperative nausea (risk ratio [RR] and 95% confidence interval [CI], 0.43 [0.28, 0.66], P < 0.0001), vomiting (RR and 95% CI, 0.36 [0.18, 0.72], P = 0.004), shivering (RR and 95% CI, 0.19 [0.11, 0.35], P < 0.00001), rescue antiemetic (RR and 95% CI, 0.18 [0.07, 0.47], P = 0.0006), and increase the incidence of dry mouth (RR and 95% CI, 7.40 [2.07, 26.48], P = 0.002) comparing with the control group. In addition, firm conclusions can be made on the results of postoperative nausea according to the TSA. Meta-analysis showed that DEX group had a significantly lower heart rate (mean difference [MD] and 95% CI, -14.21 [-18.85, -9.57], P < 0.00001) and MAP (MD and 95% CI, -12.35 [-15.28, -9.42], P < 0.00001) than the control group, and firm conclusions can be made according to the TSA. No significance was observed on extubation time between 2 groups (MD and 95% CI, 0.70 [-0.89, 2.28], P = 0.39).The results from this meta-analysis indicated that perioperative DEX decreased postoperative nausea and shivering in laparoscopic surgical patients. However, common adverse effects were lower heart rate and MAP. Firm conclusions cannot be made on postoperative shivering, rescue antiemetic, and dry mouth until more RCTs were included. PMID- 26962791 TI - Cadmium Exposure and Risk of Any Fracture: A PRISMA-Compliant Systematic Review and Meta-Analysis. AB - Several observational studies have investigated the relation between cadmium exposure and risk of any fracture. However, the results from epidemiological studies for the association are inconsistent.We conducted a meta-analysis to evaluate the relationship between cadmium exposure and risk of any fracture. The pertinent studies were identified by a search of PubMed and Embase databases from 1966 to June 2015.Seven articles involving 21,941 fracture cases and 504,346 participants were included. The meta-analysis showed that the pooled relative risk of any fracture for the highest versus lowest category of cadmium concentration was 1.30 (95% confidence interval = 1.13-1.49). In subgroup analyses, the significant association remained consistent when stratified by study type, geographical region, method of cadmium exposure assessment, and gender.Our meta-analysis showed that a high cadmium exposure may be a risk factor for any fracture. However, this result should be interpreted cautiously because of the heterogeneity among studies and existence of publication bias. Additional large, high-quality prospective studies are needed to evaluate the association between cadmium exposure and the risk of development of fracture. PMID- 26962792 TI - dCK Expression and Gene Polymorphism With Gemcitabine Chemosensitivity in Patients With Pancreatic Ductal Adenocarcinoma: A Strobe-Compliant Observational Study. AB - The aim of this study was to investigate the relationship of deoxycytidine kinase (dCK) protein expression and gene single-nucleotide polymorphisms to gemcitabine chemosensitivity in patients with pancreatic ductal adenocarcinoma (PDAC).In total, 54 patients with resectable PDAC, who received postoperative gemcitabine based therapy, were enrolled in this study, from January 2011 to April 2013. The dCK protein expression was measured retrospectively by immunohistochemistry. Furthermore, 5 single-nucleotide polymorphisms (C1205T, A9846G, A70G, C356G, and C364T) of the dCK gene were detected in PDAC cells by PCR amplification and sequencing.The dCK protein expression was found to be negatively correlated with age (P = 0.006), but correlated positively with overall survival (OS) (P = 0.000) and disease-free survival (DFS) (P = 0.003). The A9846G AA genotype in the dCK gene was significantly associated with reduced mortality compared with AG and GG genotypes. The OS and DFS were longer in patients with the A9846G AA genotype than the AG and GG genotypes. In univariate and multivariate analyses, we found that the dCK protein expression and A9846G genotype were significant predictors of both OS and DFS.Our study suggests that the dCK protein expression and A9846G genotype may act as prognostic biomarkers in identifying patients who are likely to benefit from postoperative gemcitabine therapy in PDAC. PMID- 26962793 TI - Cholesteatoma in the Sellar Region Presenting as Hypopituitarism and Diabetes Insipidus. AB - Clinically significant sellar cysts unrelated to pituitary adenomas are uncommon. Intracranial cholesteatomas are also rare and are most common in the middle ear and mastoid region. We report an even rarer case of cholesteatoma in the sellar region-a challenging diagnosis guided by clinical presentations, radiological signs, and biopsy, aiming at emphasize the importance of considering cholesteatoma when making differential diagnoses of sellar lesions.We present a case of cholesteatoma in the sellar region in a 56-year-old man with hypopituitarism, diabetes insipidus, and cystic imaging findings. It was difficult to make an accurate diagnosis before surgery. We present detailed analysis of the patient's disease course and review pertinent literature.The patient underwent a surgical exploration and tumor resection through a transsphenoidal approach. Pathologic results revealed a cholesteatoma. The patient's symptoms improved a lot after surgery, and the postoperative period was uneventful. Taken together, the lesion's imaging appearance, pathological characteristics, and clinical features were all unique features that lead to a diagnosis of cholesteatoma.As we did not see such reports by Pubmed and EMBASE, we believe this is the first reported case of sellar cholesteatoma presenting in this manner. This article emphasized that cholesteatomas, although rare, should be considered part of the differential diagnosis of sellar lesions. PMID- 26962794 TI - Nonmuscle-invasive and Muscle-invasive Urinary Bladder Cancer: Image Quality and Clinical Value of Reduced Field-of-view Versus Conventional Single-shot Echo planar Imaging DWI. AB - This study compared the imaging quality, diagnostic accuracy, and apparent diffusion coefficient (ADC) values of reduced field-of-view (rFOV) diffusion weighted imaging (DWI) and full field-of-view (fFOV) single-shot echo-planar imaging with regard to patients with nonmuscle-invasive or muscle-invasive bladder cancer.Thirty-nine patients with 60 bladder tumors underwent rFOV and fFOV DWI in this internal review board-approved study. Pathologic and histologic grades were determined for all tumors. Two observers rated DWI image quality using a 4-point scale. Two radiologists who were blinded to the pathology findings reviewed 3 image sets (T2-weighted alone, T2-weighted plus fFOV DWI, and T2-weighted plus rFOV DWI) and assigned T stages and confidence levels for tumors of stage T2 or higher. The image quality scores for the 2 DWI sequences were assessed using the Wilcoxon signed-rank test. Differences in the diagnostic accuracy, sensitivity, and specificity for each image set were evaluated using the McNemar test. Differences in performance were analyzed by comparing the areas under the receiver-operating characteristic curves (ie, the Az values). A Mann Whitney U test was used to compare the mean ADCs and the relationship between tumor stage and histologic grade.Image quality scores were significantly higher for rFOV (mean = 3.62) than for fFOV DWI (2.98; P < 0.001). The pooled diagnostic accuracies were 57%, 70%, and 78% for the T2-weighted alone images, the T2 weighted plus fFOV DWI images, and the T2-weighted plus rFOV DWI images, respectively. The overall accuracy, specificity, and Az for diagnosing T2 or higher stages were significantly improved by adding rFOV DWI (P < 0.05). The mean ADC values of the muscle-invasive and G3 grade bladder cancers were significantly lower than those of the nonmuscle-invasive tumors and G1 grade cancers, regardless of DWI sequence (P < 0.01).rFOV DWI is superior to fFOV DWI with respect to image quality and diagnostic accuracy. ADC values might be useful for distinguishing nonmuscle-invasive from muscle-invasive cancers, and G1 from G3 grade lesions. PMID- 26962795 TI - Leukemia Risk After Cardiac Fluoroscopic Interventions Stratified by Procedure Number, Exposure Latent Time, and Sex: A Nationwide Population-Based Case-Control Study. AB - A number of cardiac fluoroscopic interventions have increased rapidly worldwide over the past decade. Percutaneous transluminal coronary angioplasty (PTCA) and stent implantation have become increasingly popular, and these advancements have allowed patients to receive repetitive treatments for restenosis. However, these advancements also significantly increase radiation exposure that may lead to higher cumulative doses of radiation. In the present study, a nationwide population-based case-controlled study was used to explore the risk of leukemia after cardiac angiographic fluoroscopic intervention.A total of 5026 patients with leukemia and 100,520 control patients matched for age and sex (1:20) by a propensity score method without any cancer history were enrolled using the Registry Data for Catastrophic Illness and the National Health Insurance Research Database (NHIRD) of Taiwan between 2008 and 2010. All subjects were retrospectively surveyed (from year 2000) to determine receipt of cardiac fluoroscopic interventions. Data were analyzed using conditional logistic regression models, and estimated crude and adjusted odds ratios (95% confidence interval).After adjusting for age, gender, and comorbidities, PTCA was found to be associated with an increased risk of leukemia with an adjusted OR of 1.566 (95% CI, 1.282-1.912), whereas coronary angiography alone without PTCA and cardiac electrophysiologic study were not. Our results also showed that an increased frequency of PTCA and coronary angiography was associated with a higher risk of leukemia (adjusted OR: 1.326 to 1.530 [all P < 0.05]). Gender subgroup analyses demonstrated that men were associated with a higher risk of leukemia compared with women.These results provide additional data in the quantification of the long-term health effects of radiation exposure derived from the cardiac fluoroscopic diagnostic and therapeutic intervention. PTCA alone or PTCA with coronary angiography was associated with an elevated risk of leukemia. Continued follow-up of existing cohorts will be valuable to help assess lifetime risks of cancer. PMID- 26962796 TI - Intratumoral Macroscopic Fat and Hemorrhage Combination Useful in the Differentiation of Benign and Malignant Solid Renal Masses. AB - To evaluate the value of combining the detection of intratumoral macroscopic fat and hemorrhage in the differentiation of the benign from malignant solid renal masses.Conventional magnetic resonance imaging (MRI), chemical shift (CS)-MRI, and susceptibility-weighted imaging were performed in 152 patients with 152 solid renal masses, including 48 benign and 104 malignant masses all pathologically confirmed. The presence of macroscopic fat detected by CS-MRI and hemorrhage detected by susceptibility-weighted imaging were evaluated in all masses. The rates of macroscopic fat and hemorrhage observed between benign and malignant masses were compared by a chi test. All masses found to contain macroscopic fat with or without hemorrhage were considered to be benign. The remaining masses (without macroscopic fat) found not to contain hemorrhage were considered to be benign. Only those found to contain hemorrhage alone were considered to be malignant. The evaluation indexes for differentiating and forecasting the benign and malignant masses were calculated.Significant differences in the rate of macroscopic fat (observed in 85.42% of benign masses vs. 0% of malignant masses) and hemorrhage (observed in 4.17% of benign masses vs. 95.19% of malignant masses) were measured in the benign and malignant groups (P < 0.005, for both). The 41 masses containing macroscopic fat with or without hemorrhage and 11 masses containing neither macroscopic fat nor hemorrhage were considered to be benign. The 100 masses containing no macroscopic fat and only hemorrhage were considered to be malignant. By combining the results for the macroscopic fat and hemorrhage, the accuracy, sensitivity, and specificity in the differential diagnosis of the benign and malignant masses were 96.05%, 95.19%, and 97.92%, respectively, and the accuracy and error rate of forecasting the benign and malignant masses were 95.39% and 4.61%, respectively.Combining the detection intratumoral macroscopic fat and hemorrhage can be used to differentiate the benign from malignant solid renal masses. PMID- 26962797 TI - Relationship Between Determinants of Arterial Stiffness Assessed by Diastolic and Suprasystolic Pulse Oscillometry: Comparison of Vicorder and Vascular Explorer. AB - Pulse wave velocity (PWV) and augmentation index (AI) are independent predictors of cardiovascular health. However, the comparability of multiple oscillometric modalities currently available for their assessment was not studied in detail. In the present study, we aimed to evaluate the relationship between indices of arterial stiffness assessed by diastolic and suprasystolic oscillometry.In total, 56 volunteers from the general population (23 males; median age 70 years [interquartile range: 65-72 years]) were recruited into observational feasibility study to evaluate the carotid-femoral/aortic PWV (cf/aoPWV), brachial-ankle PWV (baPWV), and AI assessed by 2 devices: Vicorder (VI) applying diastolic, right sided oscillometry for the determination of all 3 indices, and Vascular explorer (VE) implementing single-point, suprasystolic brachial oscillometry (SSBO) pulse wave analysis for the assessment of cfPWV and AI. Within- and between-device correlations of measured parameters were analyzed. Furthermore, agreement of repeated measurements, intra- and inter-observer concordances were determined and compared for both devices.In VI, both baPWV and cfPWV inter-correlated well and showed good level of agreement with bilateral baPWV measured by VE (baPWV[VI] baPWV[VE]R: overall concordance correlation coefficient [OCCC] = 0.484, mean difference = 1.94 m/s; cfPWV[VI]-baPWV[VE]R: OCCC = 0.493, mean difference = 1.0 m/s). In contrast, SSBO-derived aortic PWA (cf/aoPWA[VE]) displayed only weak correlation with cfPWV(VI) (r = 0.196; P = 0.04) and ipsilateral baPWV (cf/aoPWV[VE]R-baPWV[VE]R: r = 0.166; P = 0.08). cf/aoPWA(VE) correlated strongly with AI(VE) (right-sided: r = 0.725, P < 0.001). AI exhibited marginal between device agreement (right-sided: OCCC = 0.298, mean difference: 6.12%). All considered parameters showed good-to-excellent repeatability giving OCCC > 0.9 for 2-point-PWV modes and right-sided AI(VE). Intra- and inter-observer concordances were similarly high except for AI yielding a trend toward better reproducibility in VE (interobserver-OCCC[VI] vs [VE] = 0.774 vs 0.844; intraobserver-OCCC[VI] vs [VE] = 0.613 vs 0.769).Both diastolic oscillometry derived PWV modes, and AI measured either with VI or VE, are comparable and reliable alternatives for the assessment of arterial stiffness. Aortic PWV assessed by SSBO in VE is not related to the corresponding indices determined by traditional diastolic oscillometry. PMID- 26962798 TI - Prognosis Can Be Predicted More Accurately Using Pre- and Postchemoradiotherapy Carcinoembryonic Antigen Levels Compared to Only Prechemoradiotherapy Carcinoembryonic Antigen Level in Locally Advanced Rectal Cancer Patients Who Received Neoadjuvant Chemoradiotherapy. AB - We aimed to evaluate the prognostic value of a change in the carcinoembryonic antigen (CEA) level during neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer. A total of 110 patients with clinical T3/T4 or node-positive disease underwent nCRT and curative total mesorectal resection from February 2006 to December 2013. Serum CEA level was measured before nCRT, after nCRT, and then again after surgery. A cut-off value for CEA level to predict prognosis was determined using the maximally selected log-rank test. According to the test, patients were classified into 3 groups, based on their CEA levels (Group A: pre-CRT CEA <=3.2; Group B: pre-CRT CEA level >3.2 and post-CRT CEA <=2.8; and Group C: pre-CRT CEA >3.2 and post-CRT CEA >2.8). The median follow-up time was 31.1 months. The 3-year disease-free survival (DFS) rates of Group A and Group B were similar, while Group C showed a significantly lower 3-year DFS rate (82.5% vs. 89.5% vs. 55.1%, respectively, P = 0.001). Other clinicopathological factors that showed statistical significance on univariate analysis were pre-CRT CEA, post-CRT CEA, tumor distance from the anal verge, surgery type, downstage, pathologic N stage, margin status and perineural invasion. The CEA group (P = 0.001) and tumor distance from the anal verge (P = 0.044) were significant prognostic factors for DFS on multivariate analysis. Post-CRT CEA level may be a useful prognostic factor in patients whose prognosis cannot be predicted exactly by pre-CRT CEA levels alone in the neoadjuvant treatment era. Combined pre-CRT CEA and post-CRT CEA levels enable us to predict prognosis more accurately and determine treatment and follow-up policies. Further large-scale studies are necessary to validate the prognostic value of CEA levels. PMID- 26962799 TI - Assessment of Choroidal Microstructure and Subfoveal Thickness Change in Eyes With Different Stages of Age-Related Macular Degeneration. AB - Age-related macular degeneration (AMD) is a major cause of irreversible blindness. Choroidal structural changes seem to be inevitable in AMD pathogenesis. Our study revealed associated choroidal microstructural changes in AMD eyes.The aim of the study was to compare choroidal microstructural changes in eyes with AMD of different stages.The study was a retrospective, cross-sectional case series.The participants comprised of 32 age-matched normal eyes as controls, and 26 fellow uninvolved eyes of intermediate/late AMD, 29 of early AMD, 28 of intermediate AMD, and 39 of late AMD.All subjects underwent comprehensive ophthalmologic examination. The choroid images, including subfoveal choroidal thickness, percentage of Sattler layer area, and en face images of the choroid, were obtained using spectral-domain optical coherence tomography.The main outcome measures were subfoveal choroidal thickness changes, percentage of Sattler layer area changes, and en face images of the choroid in AMD eyes.One hundred fifty four eyes of 96 individuals with mean age of 67.1+/-9.2 years were included. The mean subfoveal choroidal thickness was 295.4 +/- 56.8 MUm in age-matched normal eyes, 306.7 +/- 68.4 MUm in fellow uninvolved eyes with AMD, 293.8 +/- 80.4 MUm in early AMD, 215.6 +/- 80.4 MUm in intermediate AMD, and 200.4 +/- 66.6 MUm in late AMD (F = 14.2, all P < 0.001). Choroidal thickness was greater in early AMD eyes than in intermediate/late AMD eyes (P < 0.001). Mean percentage of Sattler layer area in each group showed a similar tendency. Microstructure of the choroid showed reduced vascular density of Sattler layer areas in late AMD eyes compared with normal eyes.Decreasing subfoveal choroidal thickness and percentage of Sattler layer area were demonstrated in the progression of AMD. The choroidal change was related to atrophy of the microstructural changes of underlying capillaries and medium-sized vessels. PMID- 26962800 TI - Nonmedical Use of Cough Syrup Among Secondary Vocational School Students: A National Survey in China. AB - Nonmedical use of cough syrup (NUCS) among secondary vocational school (SVS) students has been an increasing concern for public health in China, but no data were available. This cross-sectional study aimed to investigate the epidemiological characters of NUCS as well as its risk factors among SVS students in China.From September 2013 to December 2014, a total of 13,614 SVS students were purposively selected through multistage sampling in 6 cities of China. Information on NUCS, demographics, family background, smoking and alcohol consumption, impulsiveness, sensation seeking, and parental monitoring were collected. Logistic regression was used to explore factors related to NUCS.The 12,923 (94.9%) valid responses (16.3 +/- 1.0 years old, and 52.6% men) reported 3.47% (95% confidence interval: 3.15-3.79%) lifetime NUCS. Logistic regression indicated that smoking, part-time job experience, high level of impulsiveness, and sensation seeking were risk factors for NUCS, whereas urban living and high parental monitoring were protective ones.NUCS was prevalent among SVS students. Interventions that target on smoking, impulsiveness and sensation seeking control, improvement on parental monitoring may have considerable impact on NUCS among SVS students. PMID- 26962801 TI - Genetic Variation in the Human SORBS1 Gene is Associated With Blood Pressure Regulation and Age at Onset of Hypertension: A SAPPHIRe Cohort Study. AB - Essential hypertension is a complex disease involving multiple genetic and environmental factors. A human gene containing a sorbin homology domain and 3 SH3 domains in the C-terminal region, termed SORBS1, plays a significant role in insulin signaling. We previously found a significant association between the T228A polymorphism and insulin resistance, obesity, and type 2 diabetes. It has been hypothesized that a set of genes responsible for insulin resistance may be closely linked with genes susceptible to the development of hypertension. Identification of insulin resistance-related genetic factors may, therefore, enhance our understanding of essential hypertension. This study aimed to examine whether common SORBS1 genetic variations are associated with blood pressure and age at onset of hypertension in an ethnic Chinese cohort.We genotyped 9 common tagged single nucleotide polymorphisms of the SORBS1 gene in 1136 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance family study. Blood pressure was measured upon enrolment. The associations of the SORBS1 single nucleotide polymorphisms with blood pressure and the presence of hypertension were analyzed with a generalized estimating equation model. We used the false-discovery rate measure Q value with a cutoff <0.1 to adjust for multiple comparisons. In the Cox regression analysis for hypertension-free survival, a robust sandwich variance estimator was used to deal with the within-family correlations with age at onset of hypertension. Gender, body mass index, and antihypertension medication were adjustment covariates in the Cox regression analysis.In this study, genetic variants of rs2281939 and rs2274490 were significantly associated with both systolic and diastolic blood pressure. A genetic variant of rs2274490 was also significantly associated with the presence of hypertension. Furthermore, genetic variants of rs2281939 and rs2274490 were associated with age at onset of hypertension after adjustment for gender, body mass index, and antihypertension medication.In conclusion, we provide evidence for an association between common SORBS1 genetic variations and blood pressure, presence of hypertension, and age at onset of hypertension. The biological mechanism of genetic variation associated with blood pressure regulation needs further investigation. PMID- 26962802 TI - Effect of Beta Blockers and Renin-Angiotensin System Inhibitors on Survival in Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention. AB - Because it remains uncertain whether beta-blockers (BBs) and/or renin-angiotensin system inhibitors benefit a broad population of acute myocardial infarction (AMI) patients, we sought to evaluate the effectiveness of these drugs in improving survival for post-AMI patients who underwent a percutaneous coronary intervention (PCI).From the nationwide data of the South Korea National Health Insurance, 33,390 patients with a diagnosis of AMI who underwent a PCI between 2009 and 2013 and survived at least 30 days were included in this study. We evaluated the risk of all-cause death for patients treated with both BB and angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor antagonist (ARB) (n = 16,280), only BB (n = 3683), and only ACEI/ARB (n = 9849), with the drug-untreated patients (n = 3578) as the reference.Over a median follow-up of 2.4 years, although treated patients displayed a trend toward improved survival, there were no significant differences in the adjusted risk of all-cause death when patients were treated with both drugs (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.70-1.06, P = 0.154), BB (HR 0.88, 95% CI 0.68-1.14, P = 0.325), or ACEI/ARB (HR 0.84, 95% CI 0.68-1.04, P = 0.111). No additional benefit was found for the combination therapy compared with either isolated BB (HR 0.98, 95% CI 0.80-1.21, P = 0.856) or ACEI/ARB (HR 1.03, 95% CI 0.89-1.19, P = 0.727) therapy.Treatment with BB and/or ACEI/ARB has limited effect on survival in unselected nonfatal AMI patients who undergo PCI. PMID- 26962803 TI - Graves Disease Is Associated With Endometriosis: A 3-Year Population-Based Cross Sectional Study. AB - The aim of this cross-sectional study was to compare the prevalence of thyroid diseases between women with and without endometriosis.We established the endometriosis group according to diagnosis codes, surgery codes, and gonadotropin releasing hormone agonist codes using the Korean Health Insurance Review and Assessment Service-National Inpatients Sample (HIRA-NIS) from 2009 to 2011. Four controls were randomly matched to each endometriosis case. Thyroid disease cases were selected using the thyroid disease diagnosis code (E0X).Among the 1,843,451 women sampled, 5615 had endometriosis; 22,460 controls were matched to the endometriosis cases. After adjustment for age and sampling year, Graves disease was associated with endometriosis (odds ratio [OR]: 2.52; 95% CI: 1.30-4.88; P < 0.01), while hypothyroidism was not (OR: 1.17; 95% CI: 0.90-1.52; P = 0.25). Autoimmune hypothyroidism was also not associated with endometriosis (OR: 1.61; 95% CI: 0.88-2.94; P = 0.12).This study revealed an association between Graves disease and endometriosis. PMID- 26962804 TI - Biodex Fall Risk Assessment in the Elderly With Ataxia: A New Age-Dependent Derived Index in Rehabilitation: An Observational Study. AB - The aim of this study was to evaluate if the Biodex Fall Risk Assessment could provide an age-adjusted index useful for classifying patients at "risk of fall."This was a cohort study conducted on 61 chronic patients, in stable conditions, having a history of ataxia, difficulty in walking or loss of balance, and aged >64 years. These patients were coming from home to our Institute undergoing a period of in-hospital standard rehabilitation. Assessment of clinical parameters was performed at entry. Functional scales (Functional Independence Measure [FIM] for motor and cognitive function, Barthel G, Tinetti POMA), and the Biodex Fall Risk Index (FRI) were performed at entry and discharge. The Normalized FRI, obtained adjusting FRI to the reported maximum predictive FRI for the relevant age, identified 2 types of patients: those with a greater risk of fall than expected for that age, labeled Case 1 (Normalized FRI>1); and those with an equal or even lesser risk of fall than expected for that age, labeled Case 0 (Normalized FRI<=1).FRI, Normalized FRI as well as independent variables as age, sex, pathology group, FIM, BarthelG, were considered in a multiple regression analysis to predict the functional improvement (i.e., delta Tinetti Total score) after rehabilitation.Normalized FRI is useful in assessing patients at risk of falls both before and after rehabilitation. At admission, the Normalized FRI evidenced high fall risk in 46% of patients (Case 1) which decreased to 12% after rehabilitation, being greater than age-predicted in 7 patients (Case 1-1) despite the functional improvement observed after the rehabilitation treatment. Normalized FRI evidenced Case 1-1 patients as neurological, "very old" (86% in age-group 75-84 years), and with serious events at 18 to 24 months' follow-up. Normalized FRI, but not FRI, at admission was a predictor of improvement in Tinetti Total scores.The normalized FRI effectively indicated patients at higher risk of fall, in whom health deterioration, falls, or cognitive decline was later documented at follow-up. The normalized FRI could be a standardized measure for identifying frailer patients becoming a further criterium of discharge home and marker of fall risk at home. PMID- 26962805 TI - Impact of Palliative Care Consultation Service on Terminally Ill Cancer Patients: A 9-Year Observational Cohort Study in Taiwan. AB - The palliative care consultation service (PCCS) that has been enthusiastically promoted in Taiwan since 2005 was designed to provide comprehensive end-of-life care for terminally ill patients with qualified interdisciplinary specialists in acute care ward setting. This study aims to evaluate the impact of PCCS on terminally ill cancer patients.A total of 10,594 terminal cancer patients who were referred to PCCS from a single medical center in Taiwan between 2006 and 2014 were enrolled. The percentages of patients' and their families' disease awareness, do-not-resuscitate (DNR) designation, refusal and acceptance of palliative care among terminally ill cancer patients were analyzed retrospectively.At the beginning of PCCS, the percentages of disease awareness among patients and their family were increased from 25.4% to 37.9% (P = 0.007) and from 61.2% to 84.7% between 2006 and 2014 (P = 0.001), respectively. Patients' disease awareness after PCCS referral between 2006 and 2014 was increased from 47.1% to 64.5% (P = 0.016). Family's awareness of diagnosis and prognosis after PCCS referral researched to a steady plateau, 94.1% to 97.8% in different year cohort (P = 0.34). The percentage of DNR designation rate at the beginning of PCCS (in 2006) was 15.5%, and the designation rate was increased annually and finally reached to 42.0% in 2014 (P = 0.004). The percentage of DNR consents after PCCS was also improved from 44.0% in 2006 up to 80.0% in 2014 (P = 0.005). PCCS refusal rate decreased gradually and dropped to 1.6% in 2014 (P = 0.005). The percentage of PCCS utilization was increased 5-fold during the 9-year period after the promotion of PCCSIn the program of PCCS promotion, an increasing trend of PCCS utilization, better patients' and their families' awareness of diagnosis and prognosis, more consent to DNR, more patients were discharged with stable condition at the end of PCCS and a decrease refusal rate of end-of-life palliative care among terminal cancer patients were observed in Taiwan between 2006 and 2014. PMID- 26962807 TI - Capsular Outcomes After Pediatric Cataract Surgery Without Intraocular Lens Implantation: Qualitative Classification and Quantitative Measurement. AB - The objective of this study was to investigate capsular outcomes 12 months after pediatric cataract surgery without intraocular lens implantation via qualitative classification and quantitative measurement.This study is a cross-sectional study that was approved by the institutional review board of Zhongshan Ophthalmic Center of Sun Yat-sen University in Guangzhou, China.Digital coaxial retro illumination photographs of 329 aphakic pediatric eyes were obtained 12 months after pediatric cataract surgery without intraocular lens implantation. Capsule digital coaxial retro-illumination photographs were divided as follows: anterior capsule opening area (ACOA), posterior capsule opening area (PCOA), and posterior capsule opening opacity (PCOO). Capsular outcomes were qualitatively classified into 3 types based on the PCOO: Type I-capsule with mild opacification but no invasion into the capsule opening; Type II-capsule with moderate opacification accompanied by contraction of the ACOA and invasion to the occluding part of the PCOA; and Type III-capsule with severe opacification accompanied by total occlusion of the PCOA. Software was developed to quantitatively measure the ACOA, PCOA, and PCOO using standardized DCRPs. The relationships between the accurate intraoperative anterior and posterior capsulorhexis sizes and the qualitative capsular types were statistically analyzed.The DCRPs of 315 aphakic eyes (95.8%) of 191 children were included. Capsular outcomes were classified into 3 types: Type I-120 eyes (38.1%); Type II-157 eyes (49.8%); Type III-38 eyes (12.1%). The scores of the capsular outcomes were negatively correlated with intraoperative anterior capsulorhexis size (R = -0.572, P < 0.001), but no significant correlation with intraoperative posterior capsulorhexis size (R = -0.16, P = 0.122) was observed. The ACOA significantly decreased from Type I to Type II to Type III, the PCOA increased in size from Type I to Type II, and the PCOO increased from Type II to Type III (all P < 0.05).Capsular outcomes after pediatric cataract surgery can be qualitatively classified and quantitatively measured by acquisition, division, definition, and user-friendly software analyses of high-quality digital coaxial retro-illumination photographs. PMID- 26962806 TI - Pre-existing Pulmonary Diseases and Survival in Patients With Stage-dependent Lung Adenocarcinoma: A STROBE-compliant Article. AB - Asthma, chronic obstructive pulmonary disease (COPD), and pulmonary tuberculosis (TB) are common lung diseases associated with lung cancer mortality. This study evaluated sex disparities in pre-existing pulmonary diseases and stage-dependent lung adenocarcinoma survival.Patients newly diagnosed with lung adenocarcinoma between 2003 and 2008 were identified using the National Health Insurance Research Database and Cancer Registry. Cases with lung adenocarcinoma were followed until the end of 2010. Survival curves were estimated by the Kaplan Meier method. Cox proportional-hazard regression was used to calculate the hazard ratio (HR) of pre-existing asthma, COPD, and/or TB, and to estimate all-cause mortality risk in patients with different stages of lung adenocarcinoma.A total of 14,518 cases were identified with lung adenocarcinoma. Specifically, among men, the HRs for TB were 1.69 (95% confidence interval [CI], 1.10-2.58), 1.48 (95% CI, 1.14-1.93), and 1.27 (95% CI, 1.08-1.49) for individuals with stage I + II, III, and IV diseases, respectively. The HRs for asthma were 1.41 (95% CI, 1.00-1.99) in women with stage I + II and 1.14 (95% CI, 1.04-1.26) in men with stage IV disease. For pulmonary disease combinations in men, the HRs were 1.45 (95% CI, 1.12-1.89) for asthma + COPD + TB, 1.35 (95% CI, 1.12-1.63) for COPD + TB, 1.28 (95% CI, 1.01-1.63) for TB, and 1.15 (95%CI, 1.04-1.27) for asthma + COPD, respectively. For women with stage I + II disease, the HR was 6.94 (95% CI, 2.72-17.71) for asthma + COPD + TB.Coexistence of pre-existing pulmonary diseases increased mortality risk in men with adenocarcinoma. TB is at elevated risk of mortality among men with different stages of adenocarcinoma. Asthmatic women with early-stage adenocarcinoma had increased risk of mortality. PMID- 26962808 TI - Pancreatic Stent or Rectal Indomethacin-Which Better Prevents Post-ERCP Pancreatitis?: A Propensity Score Matching Analysis. AB - We investigated and compared 2 clinical strategies to prevent postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP).We retrospectively reviewed data from patients who underwent ERCP between 2008 and 2014. Of 623 patients at high risk for PEP, 145 were treated with prophylactic pancreatic stent placement (PSP) only, and 478 were treated with rectal indomethacin (RI) only, for PEP prevention. Patients were matched by one-to-one propensity score matching (PSM) by risk factors, with overall PEP incidence as primary outcome, and moderate or severe PEP and complication rates as secondary outcomes.Of 623 patients with high-risk factors, 145 pairs were generated after PSM. Thirty-two patients developed pancreatitis-10 (6.9 %) in the PSP group and 22 (15.2 %) in the RI group (P = 0.025). Moderate-to-severe pancreatitis developed in 5 patients (2.8%) in the PSP group and 14 patients (9.7 %) in the RI group (P = 0.047).Although indomethacin represents an easy, inexpensive treatment, prophylactic PSP is still the better prevention strategy for PEP. PMID- 26962809 TI - Hepatitis B Surface Antigen Loss and Hepatocellular Carcinoma Development in Patients With Dual Hepatitis B and C Infection. AB - Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are 2 major causes of chronic viral hepatitis. It is still unclear how HCV coinfection affects HBV replication and clinical outcomes in HBV/HCV coinfected patients.We conducted a longitudinal study, which enrolled 111 patients with HBV/HCV coinfection and 111 propensity score-matched controls with HBV monoinfection. Both groups had comparable baseline age, sex, fibrosis stage, levels of HBV DNA, and HBV surface antigen (HBsAg). The HCV coinfection and other host/viral factors were correlated with various outcomes, including HBsAg loss and cirrhosis/hepatocellular carcinoma (HCC) development.After a 10-year follow-up, we found that HCV coinfection itself was not associated with HBsAg loss. However, coinfected patients with alanine aminotransferase (ALT) level >80 U/L had a higher chance of HBsAg loss than those with ALT level <=80 U/L [hazard ratio (95% confidence interval): 4.41 (1.75-11.15)] or matched controls with HBV monoinfection [hazard ratio (95% confidence interval): 3.40 (1.54-7.50)]. Besides, both HCV coinfection and higher ALT levels were associated with higher HCC risks and the HCC risks remained even after HBsAg loss in HBV/HCV con-infected patient.HCV coinfection is not associated with HBsAg loss. A higher ALT level is a major determinant of HBsAg loss in patients with HBV/HCV coinfection. Both HCV coinfection and a higher ALT level were independent risk factors of HCC. PMID- 26962811 TI - Altered Th17/Treg Ratio in Nasal Polyps With Distinct Cytokine Profile: Association With Patterns of Inflammation and Mucosal Remodeling. AB - Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease that can be classified as eosinophilic or noneosinophilic. Nasal polyps can exhibit different types of mucosal inflammation and responses to treatment. Imbalanced ratios of T-helper 17(Th17) and regulatory T (Treg) cells may contribute to the pathogenesis of nasal polyps.This study assessed the frequency of Th17 and Treg cells and related cytokines in patients with nasal polyps and tested for associations with mucosal remodeling.Surgical samples from 12 controls and 33 CRSwNP patients were analyzed histopathologically. The frequency of Th17 and Treg cells in peripheral blood mononuclear cells (PBMCs) and tissues were determined using flow cytometry. Th17 and Treg cells-related cytokines in plasma were measured by Cytometric Bead Array (CBA) multiplex assays and enzyme-linked immunosorbent assays (ELISAs).Eosinophilic CRSwNP (ECRSwNP) patients exhibited robust eosinophilia, whereas non-ECRSwNP patients were characterized by neutrophilia. Compared with non-ECRSwNP, an increased Th17/Treg ratio in ECRSwNP was associated with a less increased frequency of Th17 cells and a more striking reduction of Treg cells. An altered Th17/Treg cell ratio was positively correlated with eosinophilic and neutrophilic infiltration, submucosal basement membrane thickness, and the degree of subepithelial collagen deposition. Compared with non-ECRSwNP, ECRSwNP had higher levels of IL-17A and IL-4, and lower levels of IL-10 and TGF-beta1, whereas non-ECRSwNP showed higher levels of IFN-gamma and IL-6.Th17/Treg cell imbalance in nasal polyps (both in tissues and PBMCs) with distinct cytokine profile may contribute to different inflammatory patterns (eosinophilic versus neutrophilic inflammation) and corresponding features of mucosal remodeling. Effective strategies can be designed to target a Th17/Treg imbalance to restore immune homeostasis in nasal polyps. PMID- 26962812 TI - Assessment of the Addition of Hypoalbuminemia to ACS-NSQIP Surgical Risk Calculator in Colorectal Cancer. AB - The aim of this study was to evaluate the benefit of adding hypoalbuminemia to the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) Surgical Risk Calculator when predicting postoperative outcomes in colorectal cancer patients.The ACS-NSQIP Surgical Risk Calculator offers qualified risk evaluation in surgical decision-making and informed patient consent. To date, malnutrition defined as hypoalbuminemia, an important independent surgical risk factor in colorectal cancer, is not included.This is a retrospective, multi-institutional study of ACS-NSQIP patients (n = 18,532) who received colorectal surgery from 2009 to 2012. Models were constructed for predicting postoperative mortality and morbidity using the risk factors of the ACS-NSQIP Surgical Risk Calculator before and after adding hypoalbuminemia as a risk factor. The 2 models' performance was then compared using c-statistics and Brier scores. The ACS-NSQIP database in 2008 was used for validation of the created models.The prevalence of hypoalbuminemia (27.8%) is higher in colorectal cancer, when compared with other most common cancers. In univariate analyses, hypoalbuminemia was significantly associated with postoperative mortality and morbidity in colorectal cancer patients. In multivariate logistic regression analyses, 15 postoperative complications, including mortality and serious morbidities, were significantly predicted by hypoalbuminemia. Most of the models with hypoalbuminemia showed better performance and validation in predicting postoperative complications than those without hypoalbuminemia.In colorectal cancer, hypoalbuminemia, with levels below 3.5 g/dL, serves as an excellent assessment tool and preoperative predictor of postoperative outcomes. When combined with hypoalbuminemia as a risk factor, the ACS-NSQIP Surgical Risk Calculator offers more accurate information and estimation of surgical risks to patients and surgeons when choosing treatment options. PMID- 26962810 TI - Hedgehog Signaling in Pancreatic Fibrosis and Cancer. AB - The hedgehog signaling pathway was first discovered in the 1980s. It is a stem cell-related pathway that plays a crucial role in embryonic development, tissue regeneration, and organogenesis. Aberrant activation of hedgehog signaling leads to pathological consequences, including a variety of human tumors such as pancreatic cancer. Multiple lines of evidence indicate that blockade of this pathway with several small-molecule inhibitors can inhibit the development of pancreatic neoplasm. In addition, activated hedgehog signaling has been reported to be involved in fibrogenesis in many tissues, including the pancreas. Therefore, new therapeutic targets based on hedgehog signaling have attracted a great deal of attention to alleviate pancreatic diseases. In this review, we briefly discuss the recent advances in hedgehog signaling in pancreatic fibrogenesis and carcinogenesis and highlight new insights on their potential relationship with respect to the development of novel targeted therapies. PMID- 26962813 TI - Surgery or Peroral Esophageal Myotomy for Achalasia: A Systematic Review and Meta Analysis. AB - To date very few studies with small sample size have compared peroral esophageal myotomy (POEM) with the current surgical standard of care, laparoscopic Heller myotomy (LHM), in terms of efficacy and safety, and no recommendations have been proposed.To investigate the efficacy and safety of POEM compared with LHM, for the treatment of achalasia.The databases of Pubmed, Medline, Cochrane, and Ovid were systematically searched between January 1, 2005 and January 31, 2015, with the medical subject headings (MeSH) and keywords "achalasia," "POEM," "per oral endoscopic myotomy," and "peroral endoscopic myotomy," "laparoscopic Heller myotomy" (LHM), "Heller myotomy."All types of study designs including adult patients with diagnosis of achalasia were selected. Studies that did not report the comparison between endoscopic and surgical treatment, experimental studies in animal models, single case reports, technical reports, reviews, abstracts, and editorials were excluded.The total number of included patients was 486 (196 in POEM group and 290 in LHM group).There were no differences between POEM and LHM in reduction in Eckardt score (MD = -0.659, 95% CI: -1.70 to 0.38, P = 0.217), operative time (MD = -0.354, 95% CI: -1.12 to 0.41, P = 0.36), postoperative pain scores (MD = -1.86, 95% CI: -5.17 to 1.44, P = 0.268), analgesic requirements (MD = -0.74, 95% CI: -2.65 to 1.16, P = 0.445), and complications (OR = 1.11, 95% CI: 0.5-2.44, P = 0.796). Length of hospital stay was significantly lower for POEM (MD = -0.629, 95% CI: -1.256 to -0.002, P = 0.049). There was a trend toward significant reduction in symptomatic gastroesophageal reflux rate in favors of LHM compared to POEM group (OR = 1.81, 95% CI: 1.11-2.95, P = 0.017).All included studied were not randomized. Furthermore all selected studies did not report the results of follow-up longer than 1 year and most of them included patients who were both treatment naive and underwent previous endoscopic or surgical interventions for achalasia.POEM represents a safe and efficacy procedure comparable to the safety profile of LHM for achalasia at a short-term follow-up. Long-term clinical trials are urgently needed. PMID- 26962814 TI - Comparing the Clinical Outcomes Between Insulin-treated and Non-insulin-treated Patients With Type 2 Diabetes Mellitus After Coronary Artery Bypass Surgery: A Systematic Review and Meta-analysis. AB - Several studies have shown coronary artery bypass surgery (CABG) to be beneficial in patients with type 2 diabetes mellitus (T2DM) and multivessel coronary artery diseases. Patients with insulin-treated T2DM (ITDM) are usually patients with poor glycemic control and are expected to suffer more complications compared with patients with non-insulin-treated T2DM (NITDM). However, the adverse clinical outcomes in patients with ITDM and NITDM after CABG are still not very clear. Hence, to solve this issue, we aim to compare the short-and long-term adverse clinical outcomes in a larger number of patients with ITDM and NITDM after CABG, respectively.Randomized controlled trials and observational studies comparing the adverse clinical outcomes such as mortality, major adverse events (MAEs), stroke, myocardial infarction, and repeated revascularization in patients with ITDM and NITDM after CABG have been searched from Medline, EMBASE, Cochrane, and PubMed databases. A short-term follow-up (<=30 days) and a long-term follow-up (>=1 year) were considered. Odds ratio (OR) with 95% confidence interval (CI) was used to express the pooled effect on discontinuous variables and the pooled analyses were performed with RevMan 5.3.Eleven studies involving a total of 64,152 patients with T2DM (23,781 patients with ITDM and 40,371 patients with NITDM) have been included in this meta-analysis. During the short-term follow-up period, patients with ITDM had a significantly higher mortality (OR: 1.47; 95% CI: 1.33 1.61, P < 0.00001) and MAEs (OR: 1.66; 95% CI: 1.48-1.87, P < 0.00001). During the long-term follow-up period, patients with ITDM still had a significantly higher rate of mortality, MAEs, and stroke (OR: 1.23, 95% CI: 1.02-1.49, P = 0.03; OR: 1.50, 95% CI: 1.07-2.12, P = 0.02; OR: 1.39, 95% CI: 1.22-1.59, P < 0.00001, respectively) after CABG. However, our results showed similar repeated revascularization rate between the ITDM and NITDM groups after CABG (OR: 1.31, 95% CI: 0.81-2.12, P = 0.27).According to this study, patients with ITDM had a significantly higher rate of mortality and MAEs compared with patients with NITDM after CABG. Stroke was also significantly higher in patients with ITDM during a long-term follow-up period. However, since the result for the long-term mortality had a higher heterogeneity as compared with the other subgroups, and because a similar revascularization rate was observed between the ITDM and NITDM groups after CABG maybe because of a limited number of patients analyzed, further studies still need to be conducted to completely solve this issue. PMID- 26962815 TI - Plasma Uromodulin Correlates With Kidney Function and Identifies Early Stages in Chronic Kidney Disease Patients. AB - Uromodulin, released from tubular cells of the ascending limb into the blood, may be associated with kidney function. This work studies the relevance of plasma uromodulin as a biomarker for kidney function in an observational cohort of chronic kidney disease (CKD) patients and subjects without CKD (CKD stage 0). It should be further evaluated if uromodulin allows the identification of early CKD stages.Plasma uromodulin, serum creatinine, cystatin C, blood-urea-nitrogen (BUN) concentrations, and estimated glomerular filtration rate (eGFR CKD-EPIcrea cystatin) were assessed in 426 individuals of whom 71 were CKD stage 0 and 355 had CKD. Besides descriptive statistics, univariate correlations between uromodulin and biomarkers/eGFR were calculated using Pearson-correlation coefficient. Multiple linear regression modeling was applied to establish the association between uromodulin and eGFR adjusted for demographic parameters and pharmacologic treatment. Receiver-operating-characteristic (ROC) analysis adjusted for demographic parameters was performed to test if uromodulin allows differentiation of subjects with CKD stage 0 and CKD stage I.Mean uromodulin plasma levels were 85.7 +/- 60.5 ng/mL for all CKD stages combined. Uromodulin was correlated with all biomarkers/eGFR in univariate analysis (eGFR: r = 0.80, creatinine: r = -0.76, BUN: r = -0.72, and cystatin C: r = -0.79). Multiple linear regression modeling showed significant association between uromodulin and eGFR (coefficient estimate beta = 0.696, 95% confidence interval [CI] 0.603 0.719, P < 0.001). In ROC analysis uromodulin was the only parameter that significantly improved a model containing demographic parameters to differentiate between CKD 0 degrees and I degrees (area under the curve [AUC] 0.831, 95% CI 0.746-0.915, P = 0.008) compared to creatinine, cystatin C, BUN, and eGFR (AUC for creatinine: 0.722, P = 0.056, cystatin C: 0.668, P = 0.418, BUN: 0.653, P = 0.811, and eGFR: 0.634, P = 0.823).Plasma uromodulin serves as a robust biomarker for kidney function and uniquely allows the identification of early stages of CKD. As a marker of tubular secretion it might represent remaining nephron mass and therefore intrinsic "kidney function" rather than just glomerular filtration, the latter only being of limited value to represent kidney function as a whole. It therefore gives substantial information on the renal situation in addition to glomerular filtration and potentially solves the problem of creatinine-blind range of CKD, in which kidney impairment often remains undetected. PMID- 26962816 TI - Laparoscopic Splenectomy for the Elderly Liver Cirrhotic Patients With Hypersplenism: A Retrospective Comparable Study. AB - A growing body of evidence has supported the benefits of laparoscopic splenectomy (LS) for hypersplenism due to liver cirrhosis. With the increased proportion of elderly persons worldwide, it is necessary to investigate the risks and benefits of LS in elderly liver cirrhotic patients.From September 2003 to March 2012, LS and open splenectomy (OS) were performed for 21 (Group 1) and 19 (Group 3) patients, respectively, all of whom were 65 years of age and older; in addition, 39 patients who were <65 years old were treated with LS and referred to as Group 2. Data (i.e., demographic characteristics and preoperative, intraoperative, and postoperative information) were retrospectively collected. Between-group comparisons were performed for the above-mentioned data.Compared with the patients in Group 3, the patients in Group 1 required longer operative times, fewer transfusions, less intensive care, a shorter postoperative course, and a shorter time to the first oral intake, and they had less blood loss and fewer postoperative short-term complications. During the follow-up period, compared with the preoperative status, significant changes in hemoglobin, leukocyte, platelet, and albumin levels were observed in all groups, whereas changes in the total BILirubin (BIL), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels were inconspicuous.Patients >65 years of age with hypersplenism caused by liver cirrhosis can safely undergo LS. PMID- 26962817 TI - The Increasing Challenge of Multidrug-Resistant Gram-Negative Bacilli: Results of a 5-Year Active Surveillance Program in a Neonatal Intensive Care Unit. AB - Colonization and infection by multidrug-resistant gram-negative bacilli (MDR GNB) in neonatal intensive care units (NICUs) are increasingly reported.We conducted a 5-year prospective cohort surveillance study in a tertiary NICU of the hospital "Paolo Giaccone," Palermo, Italy. Our objectives were to describe incidence and trends of MDR GNB colonization and the characteristics of the most prevalent organisms and to identify the risk factors for colonization. Demographic, clinical, and microbiological data were prospectively collected. Active surveillance cultures (ASCs) were obtained weekly. Clusters of colonization by extended spectrum beta-lactamase (ESBL) producing Escherichia coli and Klebsiella pneumoniae were analyzed by conventional and molecular epidemiological tools.During the study period, 1152 infants were enrolled in the study. Prevalences of colonization by MDR GNB, ESBL-producing GNB and multiple species/genera averaged, respectively, 28.8%, 11.7%, and 3.7%. Prevalence and incidence density of colonization by MDR GNB and ESBL-producing GNB showed an upward trend through the surveillance period. Rates of ESBL-producing E coli and K pneumoniae colonization showed wide fluctuations peaking over the last 2 years. The only independent variables associated with colonization by MDR GNB and ESBL producing organisms and multiple colonization were, respectively, the days of NICU stay (odds ratio [OR] 1.041), the days of exposure to ampicillin-sulbactam (OR 1.040), and the days of formula feeding (OR 1.031). Most clusters of E coli and K pneumoniae colonization were associated with different lineages. Ten out of 12 clusters had an outborn infant as their index case.Our study confirms that MDR GNB are an increasing challenge to NICUs. The universal once-a-week approach allowed us to understand the epidemiology of MDR GNB, to timely detect new clones and institute contact precautions, and to assess risk factors. Collection of these data can be an important tool to optimize antimicrobials use and control the emergence and dissemination of resistances in NICU. PMID- 26962818 TI - Impact of Treatment Modalities on Survival of Patients With Locoregional Esophageal Squamous-Cell Carcinoma in Taiwan. AB - The optimal treatment modality for locoregional esophageal squamous-cell carcinoma (ESCC) is still undetermined. This study investigated the treatment modalities affecting survival of patients with ESCC in Taiwan.Data on 6202 patients who underwent treatment for locoregional esophageal squamous-cell carcinoma during 2008 to 2012 in Taiwan were collected from the Taiwan Cancer Registry. Patients were stratified by clinical stage. The major treatment approaches included definitive chemoradiotherapy, preoperative chemoradiation followed by esophagectomy, esophagectomy followed by adjuvant therapy, and esophagectomy alone. The impact of different treatment modalities on overall survival was analyzed.The majority of patients had stage III disease (n = 4091; 65.96%), followed by stage II (n = 1582, 25.51%) and stage I cancer (n = 529, 8.53%). The 3-year overall survival rates were 60.65% for patients with stage I disease, 36.21% for those with stage II cancer, and 21.39% for patients with stage III carcinoma. Surgery alone was associated with significantly better overall survival than the other treatment modalities for patients with stage I disease (P = 0.029) and was associated with significantly worse overall survival for patients with stage III cancer (P < 0.001). There was no survival risk difference among the different treatment methods for patients with clinical stage II disease.Multimodality treatment is recommended for patients with stage II-III esophageal squamous-cell carcinoma. Patients with clinical stage I disease can be treated with esophagectomy without preoperative therapy. PMID- 26962820 TI - More Severe Extratemporal Damages in Mesial Temporal Lobe Epilepsy With Hippocampal Sclerosis Than That With Other Lesions: A Multimodality MRI Study. AB - Mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) presents different clinical presentations from that with other lesions (OL). It is significant to investigate the neural mechanism underlying the different clinical presentations using neuroimaging study.Thirty mTLE patients with mTLE-HS, 30 mTLE patients with other lesions (mTLE-OL), and 30 age- and sex-matched healthy controls were involved. Amplitude of low-frequency fluctuation (ALFF) analysis based resting-state functional magnetic resonance imaging (fMRI) and voxel-based morphometry (VBM) based morphometric MRI were employed to describing functional and structural imaging alterations in mTLE. Imaging parameters of ALFF and gray matter volume (GMV) were compared among groups and correlated with clinical variables and cognitive scores.For parameter of ALFF, both patient groups of mTLE HS and mTLE-OL showed decrease in the frontal cortices relative to the healthy controls; mTLE-HS showed more decrease in the prefrontal and brain default regions relative to mTLE-OL. For GMV, both patient groups showed decrease in the frontal cortex, thalamus, and cerebellum; mTLE-HS showed more GMV decrease relative to the mTLE-OL, also mainly in the prefrontal and brain default regions. In both patient groups, the prefrontal regions showed negative correlation between GMV and epilepsy duration.This work revealed distinct alteration patterns of functional and structural brain organizations in mTLEs with different forms. MTLE-HS, despite with smaller lesion size of the pathological focus, presented more severe functional and structural damages in the extratemporal regions than mTLE-OL. The findings provided imaging evidence to support the proposal that mTLE HS is a special epilepsy syndrome. PMID- 26962821 TI - Comparative Analysis of Interval, Skipped, and Key-vertebral Pedicle Screw Strategies for Correction in Patients With Lenke Type 1 Adolescent Idiopathic Scoliosis. AB - Pedicle screw constructs have become the mainstay for surgical correction in patients with spinal deformities. To reduce or avoid the risk of pedicle screw based complications and to decrease the costs associated with pedicle screw instrumentation, some authors have introduced interval, skipped, and key vertebral pedicle screw strategies for correction. However, there have been no comparisons of outcomes among these 3 pedicle screw-placement strategies.The aim of this study was to compare the correlative clinical outcomes of posterior correction and fusion with pedicle screw fixation using these 3 surgical strategies.Fifty-six consecutive patients with Lenke type 1 adolescent idiopathic scoliosis were included in this study. Twenty patients were treated with the interval pedicle screw strategy (IPSS), 20 with the skipped pedicle screw strategy (SPSS), and 16 with the key-vertebral pedicle screw strategy (KVPSS). Coronal and sagittal radiographs were analyzed before surgery, at 1 week after surgery, and at the last follow-up after surgery.There were no significant differences among the 3 groups regarding preoperative radiographic parameters. No significant difference was found between the IPSS and SPSS groups in correction of the main thoracic curve (70.8% vs 70.0%; P = 0.524). However, there were statistically significant differences between the IPSS and KVPSS groups (70.8% vs 64.9%) and between the SPSS and KVPSS groups (70.0% vs 64.9%) in correction of the main thoracic curve (P < 0.001 for both). Additionally, there were no significant differences among the 3 strategies for sagittal parameters at the immediate postoperative and last postoperative follow-up periods, though there were significant differences in the Cobb angle between the preoperative and immediate postoperative periods among the 3 groups, but not between the immediate postoperative and last follow-up periods. The amount of hospital charges in the SPSS group was significantly higher than those in the IPSS (P < 0.001) and KVPSS groups (P < 0.001). There were also significant differences in operative time between the IPSS and KVPSS groups (P < 0.001) and between the SPSS and KVPSS groups (P < 0.001).Each of the 3 types of pedicle screw strategies for correction in patients with Lenke type 1 adolescent idiopathic scoliosis are effective, with satisfactory coronal and acceptable sagittal plane results. Although the KVPSS does not provide superior operative correction compared with the IPSS and SPSS, it can achieve a satisfactory clinical outcome and is more cost-effective. PMID- 26962819 TI - GC Gene Polymorphism and Unbound Serum Retinol-Binding Protein 4 Are Related to the Risk of Insulin Resistance in Patients With Chronic Hepatitis C: A Prospective Cross-Sectional Study. AB - Insulin resistance (IR) is found in chronic hepatitis C (CHC) more frequently than in other chronic liver diseases.Prospective cross-sectional study to evaluate a wide multitest panel to identify factors related with IR in CHC and their possible interactions.In 76 patients with CHC we performed a series of routine laboratory analysis as well as specifically designed serum biochemical tests [retinol, retinol-binding protein 4 (RBP4), 25-OH vitamin D, Vitamin E, lipopolysaccharide-binding protein (LBP), interleukin-6 (IL-6), and cystatin C]. The single nucleotide polymorphisms rs7041 and rs4588 GC-DBP (group-specific component-Vitamin D-binding protein), rs738409 PNPLA3 (patatin-like phospholipase domain containing 3), and rs12979860 IL28B (interleukin-28 B) genes were determined. Insulin sensitivity was established with the HOMA-IR and IR was diagnosed when HOMA-IR > 3. Fibrosis staging was assessed with liver biopsy or transient elastography.After backward logistic regression analysis, independent variables associated with IR were Gc1s/Gc1s DBP phenotype, that results from the homozygous carriage of the rs7041G/rs4588C haplotype (P = 0.033); low retinol/RBP4 ratio, reflecting a greater rate of unbound RBP4 (P = 0.005); older age (P = 0.01); high serum tryglicerides (P = 0.026); and advanced (F3-F4) fibrosis stage. The AUROC provided by the multivariate model was 0.950 (95% CI = 0.906-0.993).In addition to previously known ones, the Gc1s/Gc1s phenotype variant of DBP and the unbound fraction of plasma RBP4 may be considered as factors related with the incidence, and possibly the risk, of IR in CHC patients. PMID- 26962823 TI - A New Modified Twist Drill Craniostomy Using a Novel Device to Evacuate Chronic Subdural Hematoma. AB - Compared with burr hole craniostomy (BHC), twist drill craniostomy (TDC) is increasingly popular because of its minimal invasiveness in evacuating chronic subdural hematoma (CSDH). However, the TDC technique varies and is continually developing; moreover, no consensus yet exists regarding the optimal protocol, and the efficacy and safety of TDC is still controversial, especially with respect to a specific method. This article introduces a new modified TDC technique using a novel device, the YL-1 puncture needle, and evaluates its efficacy and advantages compared with BHC.A retrospective study involving 121 patients with CSDH who underwent surgery at a single center was conducted, involving 68 patients undergoing modified TDC (TDC group) and 53 patients treated by BHC (BHC group). The neurological outcome was studied to evaluate the surgery efficacy, and the radiological outcome was assessed as a supplement to the surgery efficacy. In addition, complications, recurrence, and reoperation, as well as pneumocrania, operation duration, and length of stay, were studied to evaluate the advantages of the modified TDC compared with BHC. Independent sample t tests or rank-sum tests were used to compare the outcomes between the 2 groups.The neurological and radiological outcomes did not differ significantly between the TDC and BHC groups (P = 0.852 and P = 0.232, respectively), while the rates of complication and pneumocrania in patients who underwent the modified TDC were significantly lower than that in those who underwent BHC (P = 0.021 and P < 0.001, respectively). The recurrence and reoperation rates in patients from the 2 groups were similar (P = 0.566 and P = 0.715, respectively). The operation duration and length of hospital stay of the patients who underwent the modified TDC were significantly shorter than those of the patients who underwent BHC (both P < 0.001).Modified TDC with a YL-1 puncture needle is a minimally invasive surgical technique to treat CSDH; this procedure is as effective as BHC, but safer and simpler than BHC, and should be considered for patients with CSDH, especially the elderly. PMID- 26962822 TI - Cadence Feedback With ECE PEDO to Monitor Physical Activity Intensity: A Pilot Study. AB - The purpose of this study was to examine the monitoring capabilities of the equipment for clever exercise pedometer (ECE PEDO) that provides audible feedback when the person exceeds the upper and lower limits of the target step numbers per minute and to compare step counts with Yamax SW-200 (YX200) as the criterion pedometer.A total of 30 adult volunteers (15 males and 15 females) were classified as normal weight (n = 10), overweight (n = 10), and obese (n = 10). After the submaximal exercise test on a treadmill, the moderate intensity for walking was determined by using YX200 pedometer and then the number of steps taken in a minute was measured. Lower and upper limits of steps per minute (cadence) were recorded in ECE PEDO providing audible feedback when the person's walking speed gets out of the limits. Volunteers walked for 30 minutes in the individual step count range by attaching the ECE PEDO and YX200 pedometer on both sides of the waist belt in the same session. Step counts of the volunteers were recorded. Wilcoxon, Spearman correlation, and Bland-Altman analyses were performed to show the relationship and agreement between the results of 2 devices.Subjects took an average of 3511 +/- 426 and 3493 +/- 399 steps during 30 minutes with ECE PEDO and criterion pedometer, respectively. About 3500 steps taken by ECE PEDO reflected that this pedometer has capability of identifying steps per minute to meet moderate intensity of physical activity. There was a strong correlation between step counts of both devices (P < 0.001, r = 0.96). Correlations across all three BMI categories and both sex remained consistently high ranging from 0.92 to 0.95. There was a high level of agreement between the ECE PEDO and YX200 pedometer in the Bland-Altman analysis.Although both devices showed a strong similarity in counting steps, the ECE PEDO provides monitoring of intensity such that a person can walk in a specified time with a desired speed. PMID- 26962824 TI - Pretreatment Intra-Voxel Incoherent Motion Diffusion-Weighted Imaging (IVIM-DWI) in Predicting Induction Chemotherapy Response in Locally Advanced Hypopharyngeal Carcinoma. AB - The aim of this study was to predict response to induction chemotherapy in patients with locally advanced hypopharyngeal carcinoma by IVIM values.Twenty eight patients with locally advanced hypopharyngeal carcinoma underwent IVIM studies using 12 different b values (b = 0, 10, 20, 30, 50, 70 100, 150, 200, 400, 800, and 1000 s/ mm). All patients underwent 2 MRI studies: a baseline exam before any treatment and a mid-treatment exam 3 weeks after induction chemotherapy. In the IVIM approach, D, f, and D were extracted from a bi exponential fit. For comparison, the ADC map were extracted from a mono exponential fit. At the end of induction chemotherapy, patients were classified as responders or nonresponders group according to the Response Evaluation Criteria in Solid Tumors criteria (RECIST), based on their MRI measurement. The patients were classified into high grade group (G1), moderate grade group (G2), and low grade group (G3) according to the tumor pathological grading. The predictive value of IVIM parameters were examined with Student's t test, analysis of variance (ANOVA), and receiver operating characteristic (ROC) curves.After 2 cycles of induction chemotherapy, 18 patients were categorized into the responder group whereas the other 10 patients were considered nonresponders. Compared with the pretreatment value, the post-treatment ADC value and D value was significantly higher and the posttreatment D value was significantly lower (all P < 0.05). In contrast, post-treatment f parameter only changed slightly (P > 0.05). Compared with nonresponders, a notably lower pretreatment ADC value, D value, posttreatment D value, and higher posttreatment ADC value, D value, DeltaADC, DeltaD, and DeltaD were observed in responders (all P < 0.05), but no significant change in Delta f among the 2 group (P > 0.05). The ROC curve analysis indicated that the cutoff of pretreatment D value in best predicting tumor's chemotherapeutic response was 0.847 * 10 mm/s, and the corresponding AUC, sensitivity, and specificity were 0.806, 75.0%, and 88.9%, respectively. Although pretreatment IVIM-derived parameters had no significant differences between high grade, moderate grade, and low grade group, a trend towards lower D was observed with increasing tumor grading from G3 to G1.IVIM-DWI can potentially predict the treatment response to induction chemotherapy for hypopharyngeal carcinoma. PMID- 26962825 TI - Discordances Between Serology and Culture for Strongyloides in an Ethiopian Adopted Child With Multiple Parasitic Infections: A Case Report. AB - RATIONALE: infectious diseases screening of international adoptees is complex because of the concurrence of different pathogens in a child at same time. We describe an international adopted child born at Ethiopia infected by 5 different pathogens (Hymenolepis nana, Giardia intestinalis, Entamoeba histolytica, Strongyloides stercoralis, and Trichuris trichiura), 2 of them S. stercoralis and E. histolytica with a capacity to develop severe clinical complications if not detected promptly with appropriate diagnosis tests.Concerns of the patient: according to the screening protocol a stool sample is always processed for culture addressed to find out protozoan and helminthic pathogens but not specifically for S. stercoralis. Only, when eosinophilia is detected 3 serial stool samples are collected to rule out intestinal parasitic infection including S. stercoralis. INTERVENTIONS: in our case, S. stercoralis would not have been detected if we had followed the protocol because eosinophilia was absent and its specific serology was negative. Fortunately, the initial inclusion of the feces charcoal culture for S. stercoralis allowed us to detect this infection. OUTCOMES: discordances between direct methods such as culture and indirect as serology or antigen test forces us to be very cautious before ruling out S. stercoralis or E. histolytica infection, respectively. Also, if a child from tropical areas has persistent symptoms (such as diarrhea or fever) that have not been treated we have to rule out other infections that have not been detected yet.Main lessons: The introduction of different sequencing tests and the insistence to find out pathogens such as S. stercoralis or E. histolytica was determinant to be able to cure this symptomatic child and to prevent potential severe clinical forms in case of immunosuppression. PMID- 26962826 TI - Primary Non-Hodgkin's Lymphoma of the Vulva: A Case Report and Literature Review. AB - The aim of this study was to add a new case of primary non-Hodgkin's malignant lymphoma of the vulva to the literature and to review the current literature.We searched the PubMed/MEDLINE databases for previous case reports using the key words "non-Hodgkin's malignant lymphoma of the vulva," "vulvar lymphoma," and "primary vulvar non-Hodgkin's lymphoma." We found 29 cases of primary vulvar non Hodgkin's malignant lymphoma of the vulva reported until 2015. Among them, only 8 cases of diffuse large B-cell lymphoma (DLBCL), classified according to the most recent 2008 WHO classification, were reported.Moreover, only few studies reported the therapeutic management and clinical follow-up of patients affected by this condition.Due to its uncommon presentation, the primary non-Hodgkin's malignant lymphoma of the vulva can be undiagnosed; thus gynecologists, oncologists, and pathologists should be aware of this condition, as a correct diagnosis is essential for an appropriate therapeutic management. PMID- 26962827 TI - Clinical and Molecular Characterization of NF1 Patients: Single-Center Experience of 32 Patients From China. AB - Neurofibromatosis type 1 (NF1) is a hereditary disorder caused by mutations in the NF1 gene. Detecting mutation in NF1 is hindered by the gene's large size, the lack of mutation hotspots, and the presence of pseudogenes.Our goal was to establish a sensitive, feasible, and comparatively economical protocol to detect NF1 mutations using blood samples.We developed a method to screen patients for mutations. Thirty-two NF1 patients from 32 unrelated families and 120 unrelated population-match controls were investigated in this study. Specific primers were designed for NF1 to avoid pseudogenes. NF1 mutations were detected by sequencing at the deoxyribonucleic acid (DNA) and complementary DNA (cDNA) levels, and multiplex ligation-dependent probe amplification (MLPA) and familial segregation analyses were used.Forty-four specific primers designed according to the NF1 structure were successfully used for polymerase chain reaction (PCR) and DNA sequencing, which was more feasible and useful than cDNA sequencing. Thirty distinct NF1 mutations were identified in 32 patients. Thirteen mutations were novel and most were frameshift mutations (33.3%). Mutations were detected at a rate of 93.8%.Our study suggests that this sensitive, feasible, and comparatively economical protocol is effective for the detection of NF1 mutations. PMID- 26962828 TI - Identifying Thoracic Malignancies Through Pleural Fluid Biomarkers: A Predictive Multivariate Model. AB - The diagnosis of malignant pleural effusions may be challenging when cytological examination of aspirated pleural fluid is equivocal or noncontributory. The purpose of this study was to identify protein candidate biomarkers differentially expressed in the pleural fluid of patients with mesothelioma, lung adenocarcinoma, lymphoma, and tuberculosis (TB).A multiplex protein biochip comprising 120 biomarkers was used to determine the pleural fluid protein profile of 29 mesotheliomas, 29 lung adenocarcinomas, 12 lymphomas, and 35 tuberculosis. The relative abundance of these predetermined biomarkers among groups served to establish the differential diagnosis of: malignant versus benign (TB) effusions, lung adenocarcinoma versus mesothelioma, and lymphoma versus TB. The selected putative markers were validated using widely available commercial techniques in an independent sample of 102 patients.Significant differences were found in the protein expressions of metalloproteinase-9 (MMP-9), cathepsin-B, C-reactive protein, and chondroitin sulfate between malignant and TB effusions. When integrated into a scoring model, these proteins yielded 85% sensitivity, 100% specificity, and an area under the curve (AUC) of 0.98 for labeling malignancy in the verification sample. For lung adenocarcinoma-mesothelioma discrimination, combining CA19-9, CA15-3, and kallikrein-12 had maximal discriminatory capacity (65% sensitivity, 100% specificity, AUC 0.94); figures which also refer to the validation set. Last, cathepsin-B in isolation was only moderately useful (sensitivity 89%, specificity 62%, AUC 0.75) in separating lymphomatous and TB effusions. However, this last differentiation improved significantly when cathepsin-B was used with respect to the patient's age (sensitivity 72%, specificity 100%, AUC 0.94).In conclusion, panels of 4 (i.e., MMP-9, cathepsin-B, C-reactive protein, chondroitin sulfate), or 3 (i.e., CA19-9, CA15-3, kallikrein 12) different protein biomarkers on pleural fluid samples are highly discriminative for signaling a malignant versus tuberculous effusion, or lung adenocarcinoma versus mesothelioma, respectively. Cathepsin-B could also be helpful in establishing the presence of a lymphomatous effusion versus that of TB, if the patient's age is simultaneously taken into consideration. PMID- 26962829 TI - Does Previous Hip Surgery Effect the Outcome of Tonnis Triple Periacetabular Osteotomy? Mid-Term Results. AB - Hip dysplasia (HD) is 1 of the major reasons of coxarthrosis. The goal of the treatment of HD by Tonnis triple pelvic osteotomy (TPAO) is to improve the function of hip joint while relieving pain, delaying and possibly preventing end stage arthritis. The aim of this study is to compare the clinical and radiological results of TPAO to determine if previous surgery has a negative effect on TPAO.Patients operated with TPAO between 2005 and 2010, included in this study. Patients divided into 2 groups: primary acetabular dysplasia (PAD) and residual acetabular dysplasia (RAD). Prepostoperatively, hip range of motion, Harris hip score (HHS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) hip score, visual analog scores (VAS), impingement tests, and also the presence of Trendelenburg sign (TS) were investigated for clinical evaluation. For radiological analysis pre-postoperative, anterior-posterior (AP) pelvis and faux profile radiographs were used. Acetabular index, lateral center edge (LCE) angle, and Sharp angles were measured by AP pelvis; anterior center edge (ACE) angle were measured by faux profile radiography. All the clinical and radiological data of the groups were analyzed separately for the pre postoperative scores also the amount of improvement in all parameters were analyzed.SPSS20 (SPSS Inc., Chicago, IL) was used for statistical analysis. Wilcoxon test, McNemar test, paired t tests, and Mann-Whitney U tests were used to compare the groups. P < 0.05 were defined as statistically significant.Study included 27 patients: 17 patients were in PAD and 10 patients were in RAD. The mean follow-up period was 6.2 years (5.2-10.3 years). In all patients, the radiological and the clinical outcomes were better after TPAO except the flexion of the hip parameter. When the patient groups were evaluated as pre postoperatively, more statistically significant parameters were found in the PAD group when compared with RAD group. Extension, impingement, TS, VAS, HHS, WOMAC score parameters in clinical outcome and LCE, ACE, Sharp angle, coverage ratio in radiological results were significantly better in PAD group postoperatively but in RAD group; only extension, VAS, HHS, and WOMAC parameters were clinically and LCE and Coverage ratio were significantly different compared with the preoperative measurements. The change of the parameters that used for the evaluation of clinical and radiological results did not show a significant difference between groups.Our data suggest that TPAO can be performed on patients with HD for both groups. Although there were fewer parameters which changed significantly after TPAO in RAD patients; the improvement of radiological and clinical results was similar for groups. Further long-term follow-up studies with large number of patients are needed to determine the proper results of TPAO. PMID- 26962830 TI - Predictive Value of Glucose Parameters Obtained From Oral Glucose Tolerance Tests in Identifying Individuals at High Risk for the Development of Diabetes in Korean Population. AB - Previous studies suggest that the future risk for type 2 diabetes is not similar among subjects in the same glucose tolerance category. In this study, we aimed to evaluate simple intuitive indices to identify subjects at high risk for future diabetes development by using 0, 30, 120 minute glucose levels obtained during 75 g OGTTs from participants of a prospective community-based cohort in Korea.Among subjects enrolled at the Chungju Metabolic disease Cohort, those who performed an OGTT between 2007 and 2010 and repeated the test between 2011 and 2014 were recruited after excluding subjects with diabetes at baseline. Subjects were categorized according to their 30 minute glucose (G30) and the difference between 120 and 0 minute glucose (G(120-0)) levels with cutoffs of 9.75 and 2.50 mmol/L, respectively.Among 1126 subjects, 117 (10.39%) developed type 2 diabetes after 4 years. In diabetes nonconverters, increased insulin resistance was accompanied by compensatory insulin secretion, but this was not observed in converters during 4 years of follow-up. Subjects with G(120-0) >= 2.50 mmol/L or G30 >= 9.75 mmol/L demonstrated lower degrees of insulin secretion, higher degrees of insulin resistance, and ~6-fold higher risk of developing future diabetes compared to their lower counterparts after adjustment for possible confounding factors. Moreover, subjects with high G(120-0) and high G30 demonstrated 22-fold higher risk for diabetes development compared to subjects with low G(120-0) and low G30.By using the G(120-0) and G30 values obtained during the OGTT, which are less complicated measurements than previously reported methods, we were able to select individuals at risk for future diabetes development. Further studies in different ethnicities are required to validate our results. PMID- 26962831 TI - Atrial Fibrillation is Associated With Poor Outcomes in Thrombolyzed Patients With Acute Ischemic Stroke: A Systematic Review and Meta-Analysis. AB - The influence of atrial fibrillation (AF) on the clinical outcomes of patients with ischemic stroke (IS) has not been completely determined. We aimed to perform a systematic review and meta-analysis to assess the relationship between AF and adverse events in patients with acute IS treated with thrombolysis.PubMed, EMBASE, and the Cochrane Library were searched for relevant studies regarding the association between AF and the outcomes of patients with IS treated with thrombolysis. Random and fixed effect models were used for pooling data.Twelve cohort studies involving 14,801 patients with acute IS were included. Meta analysis revealed that patients with AF were more likely to die within 90 days after thrombolysis (odds ratio [OR], 2.13; 95% confidence interval [CI]: 1.68 2.70, P < 0.001), whereas this association was not observed in hospitalized patients (OR, 1.50; 95% CI, 0.86-2.60; P = 0.150). AF was associated with a reduced incidence of favorable outcomes (modified Rankin Scale <= 2) (OR, 1.95; 95% CI: 1.33-2.85, P = 0.001) and an increased risk of symptomatic intracerebral hemorrhage (OR, 1.28; 95% CI: 1.08-1.52, P = 0.006). No evident publication bias was found by Begg's test or Egger's test.Comorbidity of AF may increase the risk of adverse outcomes for patients with IS undergoing thrombolysis. Further well designed trials are warranted to confirm this association. PMID- 26962832 TI - Association Between Peripheral Vascular Endothelial Function and Progression of Open-Angle Glaucoma. AB - The aim of the study is to evaluate the relationship between Humphrey visual field progression and peripheral vascular endothelial function in patients with open-angle glaucoma (OAG), assessed by noninvasive endothelium-dependent flow mediated vasodilation (FMD).Forty OAG patients, among which 22 had normal-tension glaucoma (NTG) and 18 had primary open-angle glaucoma (POAG) were enrolled. Each enrolled patient underwent a thorough ophthalmological examination including the Humphrey visual field test and measurement of FMD via high-resolution 2 dimensional ultrasonographic imaging of the brachial artery. Blood samples were evaluated for biochemistry and lipid profiles as well as levels of high sensitivity C-reactive protein (hsCRP). The annual change of threshold sensitivity of the visual field in each test location were analyzed with pointwise linear regression. The correlation between long-term visual field progression and FMD was evaluated.A mean follow-up of 7.47 +/- 1.84 years revealed a faster progression rate over the superior visual field in all 40 OAG patients (superior field -0.24 +/- 0.67 dB/y, inferior field -0.10 +/- 0.59 dB/y, P = 0.37). However, only the annual sensitivity change of the inferior peripheral field showed correlation with baseline FMD. There was no significant difference in the change slope of visual field between NTG and POAG patients.A correlation between baseline brachial artery FMD and visual field progression was observed in the inferior peripheral field in patients with NTG and POAG. This result suggests that peripheral vascular endothelial dysfunction may be related to glaucoma progression. PMID- 26962834 TI - High Mortality of Cirrhotic Patients With End-Stage Renal Disease. AB - Ascites, hepatic encephalopathy (HE), and esophageal variceal bleeding (EVB) are 3 major complications in patients with cirrhosis. Limited data exist with which to evaluate the long-term mortality of end-stage renal disease (ESRD) in cirrhotic patients with or without complications.The National Health Insurance Database in Taiwan was used to identify patients with cirrhosis hospitalized between January 1, 2007, and December 31, 2007. The study group consisted of 1068 cirrhotic patients with ESRD, and the control group consisted of 10,680 randomly selected cirrhotic patients without baseline renal function impairment.The overall 1-year and 3-year mortality rates were 48.5% and 73.1% in the ESRD group, and 32.9% and 55.6% in the control group, respectively. After adjusting for other comorbid disorders, the cirrhotic patients with ESRD showed a statistically significant increase in 3-year mortality (hazard ratio [HR], 1.65; P < 0.001). The HR for 3-year mortality of ESRD cirrhotic patients with recurrent complications was 1.98 (P < 0.001), compared to those with no recent or past complications. The HR of ESRD for 3-year mortality was 1.48 (P < 0.001) in cirrhotic patients with ascites, 1.67 (P < 0.001) in patients with EVB, and 1.19 (P = 0.147) in patients with HE.ESRD increases the mortality rate in patients with cirrhosis. Recurrent complications can account for a 2-fold increase in the 3-year mortality of ESRD cirrhotic patients. ESRD has a smaller impact on the 3 year mortality of cirrhotic patients with HE compared to those with ascites or EVB. PMID- 26962833 TI - Prolong Exposure of NSAID in Patients With RA Will Decrease the Risk of Dementia: A Nationwide Population-Based Cohort Study. AB - Rheumatoid arthritis (RA), a chronic, systemic inflammatory disorder, primarily affects joints. Several studies have indicated that early inflammation, cardiovascular disease, and depression in patients were associated with a considerably increased risk of dementia. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for treating RA. NSAIDs facilitate alleviating RA associated chronic pain, inflammation, and swelling. Therefore, we conducted this nationwide study for evaluating the association between the dementia risk and NSAID treatment in patients with RA.The RA cohort comprised patients aged 20 years and older who were newly diagnosed with RA between 2000 and 2011, with data obtained from the Registry of Catastrophic Illnesses Patient Database (RCIPD). Patients without RA were frequency matched with the RA cohort at a 1:4 ratio according to age, sex, and year of RA diagnosis. The relative risks of dementia were estimated using Cox proportional hazard models.The risk of dementia in the RA cohort was not significantly higher than that in the non-RA cohort (adjusted HR [hazard ratio] = 0.95, 95% confidence interval [CI] = 0.87-1.02). Regarding the duration of NSAID treatment, the risk of dementia was significantly lower when the RA cohort used NSAIDs for >2191 days (HR = 0.56, 95% CI = 0.45-0.68).A longer duration of NSAID treatment possibly reduces the risk of dementia. Additional studies are warranted for verifying the association of dementia risk with NSAID treatment in patients with RA. PMID- 26962836 TI - Distal Pancreatectomy With En Bloc Celiac Axis Resection for Locally Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis. AB - Although distal pancreatectomy with en bloc celiac resection (DP-CAR) is used to treat locally advanced pancreatic cancer, the advantages and disadvantages of this surgical procedure remain unclear. The purpose of this study was to evaluate its clinical safety and efficacy.Studies regarding DP-CAR were retrieved from the following databases: PubMed, EMBASE, Web of Science, Cochrane Library, and Chinese electronic databases. Articles were selected according to predesigned inclusion criteria, and data were extracted according to predesigned sheets. Clinical, oncologic, and survival outcomes of DP-CAR were systematically reviewed by hazard ratios (HRs) or odds ratio (OR) using fixed- or random-effects models.Eighteen studies were included. DP-CAR had a longer operating time and greater intraoperative blood loss compared to distal pancreatectomy (DP). A high incidence of vascular reconstruction occurred in DP-CAR: 11.53% (95%CI: 6.88 18.68%) for artery and 33.28% (95%CI: 20.45-49.19%) for vein. The pooled R0 resection rate of DP-CAR was 72.79% (95% CI, 46.19-89.29%). Higher mortality and morbidity rates were seen in DP-CAR, but no significant differences were detected compared to DP; the pooled OR was 1.798 for mortality (95% CI, 0.360-8.989) and 2.106 for morbidity (95% CI, 0.828-5.353). The pooled incidence of postoperative pancreatic fistula (POPF) was 31.31% (95%CI, 23.69-40.12%) in DP-CAR, similar to that of DP (OR = 1.07; 95%CI, 0.52-2.20). The pooled HR against DP-CAR was 5.67 (95%CI, 1.48-21.75) for delayed gastric emptying. The pooled rate of reoperation was 9.74% (95%CI, 4.56-19.59%) in DP-CAR. The combined 1-, 2-, and 3-year survival rates in DP-CAR were 65.22% (49.32-78.34%), 30.20% (21.50-40. 60%), and 18.70% (10.89-30.13%), respectively. The estimated means and medians for survival time in DP-CAR patients were 24.12 (95%CI, 18.26-29.98) months and 17.00 (95%CI, 13.52-20.48) months, respectively. There were no significant differences regarding postoperative 1-, 2-, and 3-year survival rates between DP-CAR and DP, whereas DP-CAR had a better 1-year survival rate compared to palliative treatments. The pooled HR for overall survival between DP-CAR and DP was 1.36 (95%CI: 0.997-1.850); the pooled HR favoring DP-CAR was 0.38 (95%CI: 0.25-0.58) for overall survival compared to palliative treatments. The rate of cancer related pain relief from DP-CAR was 89.20% (95%CI, 77.85-95.10%). The pooled incidence of postoperative diarrhea was 37.10% (95%CI, 20.79-57.00%); however, most diarrhea was effectively controlled.DP-CAR is feasible and acceptable in terms of its survival benefits and improved quality of life. However, it should be performed with caution due to its high postoperative morbidity. PMID- 26962835 TI - Pathophysiology of Small-Fiber Sensory System in Parkinson's Disease: Skin Innervation and Contact Heat Evoked Potential. AB - Sensory symptoms are frequent nonmotor complaints in patients with Parkinson's disease (PD). However, few investigations integrally explored the physiology and pathology of the thermonociceptive pathway in PD. We aim to investigate the involvement of the thermonociceptive pathway in PD.Twenty-eight PD patients (16 men, with a mean age and standard deviation of 65.6 +/- 10.7 years) free of neuropathic symptoms and systemic disorders were recruited for the study and compared to 23 age- and gender-matched control subjects (12 men, with a mean age and standard deviation of 65.1 +/- 9.9 years). We performed skin biopsy, contact heat-evoked potential (CHEP), and quantitative sensory tests (QST) to study the involvement of the thermonociceptive pathway in PD.The duration of PD was 7.1 +/- 3.2 (range 2-17 years) years and the UPDRS part III score was 25.6 +/- 9.7 (range 10-48) during the off period. Compared to control subjects, PD patients had reduced intra-epidermal nerve fiber (IENF) density (2.48 +/- 1.65 vs 6.36 +/- 3.19 fibers/mm, P < 0.001) and CHEP amplitude (18.02 +/- 10.23 vs 33.28 +/- 10.48 MUV, P < 0.001). Twenty-three patients (82.1%) had abnormal IENF densities and 18 (64.3%) had abnormal CHEP. Nine patients (32.1%) had abnormal thermal thresholds in the feet. In total 27 patients (96.4%) had at least 1 abnormality in IENF, CHEP, or thermal thresholds of the foot, indicating dysfunctions in the small fiber nerve system. In control subjects, CHEP amplitude linearly correlated with IENF density (P < 0.001). In contrast, this relationship disappeared in PD (P = 0.312) and CHEP amplitude was negatively correlated with motor severity of PD independent of age, gender, and anti-PD medication dose (P = 0.036), suggesting the influences of central components on thermonociceptive systems in addition to peripheral small-fiber nerves in PD.The present study suggested impairment of small-fiber sensory system at both peripheral and central levels is an intrinsic feature of PD, and skin biopsy, CHEP, and QST provided an integral approach for assessing such dysfunctions. PMID- 26962837 TI - Pituicytoma Coexisting With Corticotroph Hyperplasia: Literature Review With One Case Report. AB - Pituicytoma is a rare, low-grade glial neoplasm that arises in the neurohypophysis or infundibulum and usually presents as pituitary gland enlargement. They are often misdiagnosed as pituitary adenomas. Causes have varied for high serum adrenocorticotropic hormone level reported in a few patients with pituicytoma.We report a rare case of pituicytoma accompanied by corticotroph hyperplasia-a challenging diagnosis guided by clinical presentations, radiological signs, and biopsy.We present a case of pituicytoma with corticotroph hyperplasia in a 46-year-old woman with typical Cushing syndrome. Magnetic resonance imaging revealed a lesion in the sellar area with equal T1 and T2 signals and marked homogeneous enhancement. We present detailed analysis of the patient's disease course and review pertinent literature. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. Because of this, there is no need to conduct special ethic review and the ethical approval is not necessary.The patient underwent a surgical exploration and tumor resection through a trans sphenoidal approach. Pathologic results revealed pituicytoma and corticotroph hyperplasia. As adrenocorticotropic hormone and cortisol levels did not decrease to normal, the patient received radiotherapy and recovered uneventfully. No recurrence was found over 8 years of follow-up.Pituicytoma is a rare type of sellar tumor. Pituicytomas in patients with Cushing syndrome are rarer still. To our knowledge, this is the first report of Cushing syndrome caused by corticotroph hyperplasia in a pituicytoma patient. PMID- 26962838 TI - A Nationwide Population-Based Cohort Study of Migraine and Organic-Psychogenic Erectile Dysfunction. AB - As chronic illnesses and chronic pain are related to erectile dysfunction (ED), migraine as a prevalent chronic disorder affecting lots of people all over the world may negatively affect quality of life as well as sexual function. However, a large-scale population-based study of erectile dysfunction and other different comorbidities in patients with migraine is quite limited. This cohort longitudinal study aimed to estimate the association between migraine and ED using a nationwide population-based database in Taiwan.The data used for this cohort study were retrieved from the Longitudinal Health Insurance Database 2000 in Taiwan. We identified 5015 patients with migraine and frequency matched 20,060 controls without migraine from 2000 to 2011. The occurrence of ED was followed up until the end of 2011. We used Cox proportional hazard regression models to analyze the risks of ED.The overall incidence of ED was 1.78-fold greater in the migraine cohort than in the comparison cohort (23.3 vs 10.5 per 10,000 person years; 95% confidence interval [CI] = 1.31-2.41). Furthermore, patients with migraine were 1.75-fold more likely to develop organic ED (95% CI = 1.27-2.41) than were the comparison cohort. The migraine patients with anxiety had a 3.6 fold higher HR of having been diagnosed with ED than the comparison cohort without anxiety (95% CI, 2.10-6.18).The results support that patients with migraine have a higher incidence of being diagnosed with ED, particularly in the patient with the comorbidity of anxiety. PMID- 26962839 TI - Risk of Chronic Obstructive Pulmonary Disease in Female Adults With Primary Sjogren Syndrome: A Nationwide Population-Based Cohort Study. AB - No large-scale population-based cohort study has ever investigated the risk of developing chronic obstructive pulmonary disease (COPD) in patients with Sjogren syndrome (SS). This study evaluated the risk of COPD in women with primary SS (pSS) in a nationwide population.We used the data of the National Health Insurance Research Database of Taiwan to establish a pSS group consisting of 3013 female adults diagnosed between 2000 and 2005, and a non-SS group consisting of 12,052 women without SS matched by a propensity score. Incident COPD cases were identified to the end of 2011. The pSS group to non-SS group adjusted hazard ratios (aHRs) of COPD were estimated using multivariable Cox proportional hazards regression analysis.After a mean follow-up period of 7.99 years, the incidence of COPD was 1.4-fold greater in the pSS group than in the non-SS group (3.87 vs 2.77 per 1000 person-years) with an aHR of 1.39 (95% confidence interval [CI] = 1.10 1.75, P = 0.007). The COPD incidence was 7-fold greater for women aged 50 years and above than women aged 20 to 49, with the aHR of 4.24 (95% CI = 3.06-5.88, P < 0.001). Comorbidity increased the COPD risk further for women with pSS. Women with both pSS and comorbidity had an aHR of 3.11 (95% CI = 2.23-4.33, P < 0.001) for COPD, compared to those free of both pSS and comorbidity.Women with pSS are at a greater risk of developing COPD than those without SS. Patients with SS require close monitoring to prevent COPD development, particularly for those with comorbidity. PMID- 26962840 TI - Molecular Identification of Biliary Isospora Belli: A Case Report. AB - This report describes the novel sampling of bile from the biliary endoscopic intervention for the molecular identification of parasite infection.A 63-year-old Vietnamese man underwent travel health examination in our hospital. Physical examination showed that his height was 159 cm and weight was 41 kg. He had a 15 year history of intermittent abdominal pain and frequent episodes of diarrhea. Laboratory tests revealed raised eosinophil count (23%, normal range [NR] 0-5), absolute eosinophil count (1899/MUL, NR 50-350), and levels of serum immunoglobulin E (3770 IU/mL, NR < 100), aspartate transaminase (270 U/L, NR 0 37), alanine transaminase (210 U/L, NR 0-40), and total bilirubin (1.8 mg/dL, NR 0.2-1.4); however, the serum alkaline phosphatase level was normal (65 U/L, NR 28 94) and non-reactive result for serum human insufficiency virus antibody.Magnetic resonance cholangiopancreatography revealed diffuse dilatation of the biliary tree; the common hepatic and pancreatic duct diameters increased to 1.86 cm and 0.61 cm, respectively.Endoscopic retrograde cholangiopancreatography was performed and a 10-Fr model plastic biliary stent was inserted and flushed with 20 cc normal saline; thereafter, the bile was collected and sent for DNA sequencing. Isospora belli (IB) infection was identified by a polymerase chain reaction.Trimethoprim-sulfamethoxazole 800 mg q6h was administered for 1 month. Liver enzyme levels normalized and negative for concentration method of ova study. The patient was doing well and weighed 51 kg at the outpatient clinic visit 3 months later.This bile sampling with molecular identification has not been described in the literature. We believe that an acute IB infection through fecal-oral transmission may progress to chronic infection of the hepatobiliary system, leading to biliary obstruction and jaundice. PMID- 26962841 TI - Does Orthodontic Treatment Affect the Alveolar Bone Density? AB - Few studies involving human participants have been conducted to investigate the effect of orthodontic treatment on alveolar bone density around the teeth. Our previous study revealed that patients who received 6 months of active orthodontic treatment exhibited an ~24% decrease in alveolar bone density around the teeth. However, after an extensive retention period following orthodontic treatment, whether the bone density around the teeth can recover to its original state from before the treatment remains unclear, thus warranting further investigation.The purpose of this study was to assess the bone density changes around the teeth before, during, and after orthodontic treatment.Dental cone-beam computed tomography (CBCT) was used to measure the changes in bone density around 6 teeth in the anterior maxilla (maxilla central incisors, lateral incisors, and canines) of 8 patients before and after orthodontic treatment. Each patient underwent 3 dental CBCT scans: before treatment (T0); at the end of 7 months of active orthodontic treatment (T1); after several months (20-22 months) of retention (T2). The Friedman test was applied to evaluate the changes in the alveolar bone density around the teeth according to the 3 dental CBCT scans.From T0 to T1, a significant reduction in bone density was observed around the teeth (23.36 +/- 10.33%); by contrast, a significant increase was observed from T1 to T2 (31.81 +/ 23.80%). From the perspective of the overall orthodontic treatment, comparing the T0 and T2 scans revealed that the bone density around the teeth was relatively constant (a reduction of only 0.75 +/- 19.85%). The results of the statistical test also confirmed that the difference in bone density between T0 and T2 was nonsignificant.During orthodontic tooth movement, the alveolar bone density around the teeth was reduced. However, after a period of bone recovery, the reduced bone density recovered to its previous state from before the orthodontic treatment. However, the bone density around ~10% of the teeth in this region could not recover to 80% of its state from before the orthodontic treatment. PMID- 26962843 TI - Redislocation After a Failed Surgery to Treat C6/7 Fracture-Dislocation With Pedicular Fracture of the C6 Vertebra: Case Report of a Successful Revision Surgery, Analysis of the Causes, and Discussion of Revision Surgical Strategies. AB - Cervical spinal fracture-dislocation with pedicular fracture of the vertebra has been little reported and the management of such a patient is difficult. Considering the little knowledge of this area, we present this special case of a successful revision surgery for the treatment of redislocation after a failed surgery to treat C6/7 fracture-dislocation with pedicular fracture of the C6 vertebra to share our experience.A 45-year-old male patient presented to our hospital with history of neck pain for 4 months. According to his medical records, he was involved in an architectural accident and diagnosed with C6/7 fracture-dislocation with pedicular fracture of the C6 vertebra (ASIA: D). A surgery of posterior lateral mass screw fixation (bilateral in C5 and C7; left side in C6) was performed in a different institution. However, 4 months after his primary surgery, he was still troubled by serious neck pain and muscle weakness in all right side limbs. The physical examination of the patient showed hypoesthesia in the right side limbs, myodynamia of the right side limbs weakened to Grade 4. Cervical X-rays, computed tomography (CT), and magnetic resonance imaging confirmed the redislocation of C6/7. A successful revision surgery of anterior cervical corpectomy and fusion (ACCF) with nanohydroxyapatite/polyamide 66 composite fulfilled with vertebral autograft plus anterior plate was performed. The 3 months postoperative X-rays and CT scan showed the good position of the implant and bony fusion. The patient's neck pain was relived and the neurological function recovered to ASIA E grade at the 3rd month follow-up.ACCF with nanohydroxyapatite/polyamide 66 composite fulfilled with vertebral autograft plus anterior plate is effective for the treatment of redislocation after a failed surgery in patients of fracture-dislocation with pedicular fracture. The best method to avoid such a failed surgery is a combined anterior-posterior approach surgery in our opinion. PMID- 26962842 TI - Life-Threatening Hypercalcemia Revealing Diffuse and Isolated Acute Sarcoid-Like Myositis: A New Entity? (A Case-Series). AB - Up to 50% patients with sarcoidosis display extra-pulmonary disease. However, initial and isolated (ie, without lung disease) acute muscular involvement associated with pseudo-malignant hypercalcemia is very uncommon. We report on 3 cases of life-threatening hypercalcemia revealing florid and isolated acute sarcoid-like myositis.All patients complained of fatigue, progressive general muscle weakness, and weight loss. Laboratory tests showed a severe life threatening hypercalcemia (>3.4 mmol/L). Hypercalcemia was associated with increased serum level of 1,25-(OH)2 vitamin D and complicated with acute renal failure. One patient displayed acute pancreatitis due to hypercalcemia.In all cases, PET-scan, performed for malignancy screening, incidentally revealed an intense, diffuse, and isolated muscular fluorodeoxyglucose (FDG) uptake consistent with diffuse non-necrotizing giant cells granulomatous myositis demonstrated by muscle biopsy. Of note, creatine phosphokinase blood level was normal in all cases. No patients displayed the usual thoracic features of sarcoidosis.All patients were treated with high dose steroids and achieved rapid, complete, and sustained remission. A review of English and French publications in Medline revealed 5 similar published cases.Steroid-sensitive acute sarcoid-like myositis causing high calcitriol levels and life-threatening hypercalcemia should be recognized as a separate entity. PMID- 26962844 TI - A heart for interaction: Shared physiological dynamics and behavioral coordination in a collective, creative construction task. AB - Interpersonally shared physiological dynamics are increasingly argued to underlie rapport, empathy, and even team performance. Inspired by the model of interpersonal synergy, we critically investigate the presence, temporal development, possible mechanisms and impact of shared interpersonal heart rate (HR) dynamics during individual and collective creative LEGO(r) construction tasks. In Study 1 we show how shared HR dynamics are driven by a plurality of sources, including task constraints and behavioral coordination. Generally, shared HR dynamics are more prevalent in individual trials (involving participants doing the same things) than in collective ones (involving participants taking turns and performing complementary actions). However, when contrasted against virtual pairs, collective trials display more stable shared HR dynamics suggesting that online social interaction plays an important role. Furthermore, in contrast to individual trials, shared HR dynamics are found to increase across collective trials. Study 2 investigates which aspects of social interaction might drive these effects. We show that shared HR dynamics are statistically predicted by interpersonal speech and building coordination. In Study 3, we explore the relation between HR dynamics, behavioral coordination, and self-reported measures of rapport and group competence. Although behavioral coordination predicts rapport and group competence, shared HR dynamics do not. Although shared physiological dynamics were reliably observed in our study, our results warrant not to consider HR dynamics a general driving mechanism of social coordination. Behavioral coordination-on the other hand-seems to be more informative of both shared physiological dynamics and collective experience. (PsycINFO Database Record PMID- 26962845 TI - Gaze direction aftereffects are surprisingly long-lasting. AB - Adaptation to gaze direction induces aftereffects in the perception of gaze in subsequently presented faces. Gaze adaptation calibrates neural responses to the most frequently occurring gaze signals and therefore frees up capacity to respond to more novel signals, likely enhancing gaze discrimination and supporting novelty detection. The longevity of aftereffects can provide some insight into the temporal window over which this calibration occurs. Since gaze direction is a rapidly changing signal in the face, one might expect gaze aftereffects to also be very short-lived. Here we show that this is not the case. In Experiment 1, we measured participants' aftereffects immediately after gaze adaptation and 24 h later. We found significant aftereffects at both times. In Experiment 2, we tested whether long-term adaptation also occurred when aftereffects were measured only once, 24 h after adaptation. Again, we found significant long-term aftereffects. These results demonstrate that gaze adaptation can integrate information over remarkably long periods. We discuss the implications of the longevity of gaze direction aftereffects on our understanding of their functionality, and the functionality of face aftereffects more generally. (PsycINFO Database Record PMID- 26962846 TI - The guidance of spatial attention during visual search for color combinations and color configurations. AB - Representations of target-defining features (attentional templates) guide the selection of target objects in visual search. We used behavioral and electrophysiological measures to investigate how such search templates control the allocation of attention in search tasks where targets are defined by the combination of 2 colors or by a specific spatial configuration of these colors. Target displays were preceded by spatially uninformative cue displays that contained items in 1 or both target-defining colors. Experiments 1 and 2 demonstrated that, during search for color combinations, attention is initially allocated independently and in parallel to all objects with target-matching colors, but is then rapidly withdrawn from objects that only have 1 of the 2 target colors. In Experiment 3, targets were defined by a particular spatial configuration of 2 colors, and could be accompanied by nontarget objects with a different configuration of the same colors. Attentional guidance processes were unable to distinguish between these 2 types of objects. Both attracted attention equally when they appeared in a cue display, and both received parallel focal attentional processing and were encoded into working memory when they were presented in the same target display. Results demonstrate that attention can be guided simultaneously by multiple features from the same dimension, but that these guidance processes have no access to the spatial-configural properties of target objects. They suggest that attentional templates do not represent target objects in an integrated pictorial fashion, but contain separate representations of target-defining features. (PsycINFO Database Record PMID- 26962847 TI - Adults with Fetal Alcohol Spectrum Disorder: Factors Associated with Positive Outcomes and Contact with the Criminal Justice System. AB - BACKGROUND: Adults with FASD are at increased risk for contact with the criminal justice system (CJS). To date, there has been limited research devoted to development of supports for adults with FASD and it is unclear what supports are required to improve outcomes and reduce CJS contact. OBJECTIVES: To examine the services and supports experienced by a small group of adults with FASD living in both rural and urban locations in Ontario, and their contact with the CJS. METHODS: A sample of 14 individuals with FASD and 11 support persons participated in the study. Semi-structured interviews were conducted and coded according to key themes which were qualitatively analysed using quotations that supported each key theme. A reliability analysis was conducted for the interview coding. RESULTS: Early diagnosis and lower substance use were found to be factors associated with reduced contact with the CJS. Participants reported on: knowledge of their diagnosis and caregiver training and education about FASD; interdependence; routine, structure, and supervision; evidence of a strength based approach; effective communication; and collaborative services. Few participants had received training and education around FASD and further research is needed to determine the training required for more successful interventions and outcomes. CONCLUSION: As has been found previously, early diagnosis of FASD is associated with more positive outcomes including reduced amount of contact with the CJS. It is likely that early diagnosis leads to the receipt of more supports throughout childhood and contributes to a better understanding of FASD by family and caregivers. PMID- 26962848 TI - Bioelectrochemical Chromium(VI) Removal in Plant-Microbial Fuel Cells. AB - Plant-microbial fuel cell (PMFC) is a renewable and sustainable energy technology that generates electricity with living plants. However, little information is available regarding the application of PMFC for the remediation of heavy metal contaminated water or soil. In this study, the potential for the removal of heavy metal Cr(VI) using PMFC was evaluated, and the performance of the PMFC at various initial Cr(VI) contents was investigated. The Cr(VI) removal efficiency could reached 99% under various conditions. Both the Cr(VI) removal rates and the removal efficiencies increased with the increasing initial Cr(VI) concentration. Furthermore, the long-term operation of the PMFC indicated that the system was stable and sustainable for Cr(VI) removal. The mass balance results and XPS analysis results demonstrate that only a small amount of soluble Cr(III) remained in the PMFC and that most Cr(III) precipitated in the form of the Cr(OH)3(s) or was adsorbed onto the electrodes. The PMFC experiments of without acetate addition also show that plants can provide carbon source for MFC through secrete root exudates and bioelectrochemical reduction of Cr(VI) was the main mechanism for the Cr(VI) removal. These results extend the application fields of PMFC and might provide a new insight for Cr(VI) removal from wastewater or soil. PMID- 26962849 TI - Kangaroo-mother care method and neurobehavior of preterm infants. AB - OBJECTIVE: To evaluate the effect of kangaroo-mother care (KMC) in preterm (PT) neurobehavior between 36 and 41 weeks post-conceptual age (PCA). METHOD: A prospective cohort of 61 preterm infants with gestational age (GA) of 28-32 w evaluated by the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS), with 36-41 w PCA. Infants with clinical instability were excluded. They were analyzed in 2 groups: - Kangaroo (KAN): KMC for 7 or more days; Conventional (CON): did not receive KMC. Scores of the 13 NNNS variables were compared between groups and the effect of KMC in the scores of the variables of NNNS were evaluated by multiple linear regression, controlling for confounders. RESULTS: The KAN groups (n=24) and CON (n=37) were similar regarding main demographic and clinical maternal and neonatal characteristics. Mean GA was 30.3 w; and birth weight was 1170 g for both groups. PT of KAN group were admitted in KMC with PCA of 35.8 w (38.5 days of life) and remained with this care for 14.3 days. The NNNS was applied 13 days after the start of KMC. PT submitted to KMC showed higher quality of movements (KAN: 4.98 +/- 0.53 vs CON: 4.53 +/- 0.47; p=0.001) and lower scores on Signs of stress and abstinence (KAN: 0.03 +/- 0.03 vs CON: 0.05 +/- 0.03; p=0.001). Controlling for confounders, the KMC was associated with higher scores on the variables Attention, Quality of movements, and lower scores on Asymmetry and Signs of stress and abstinence. CONCLUSION: PT submitted to the KMC, compared to those non-submitted, have better neurobehavior performance between 36 and 41 weeks of post-conceptual age. PMID- 26962850 TI - Changes in Kidney Function and in the Rate of Tubular Dysfunction After Tenofovir Withdrawal or Continuation in HIV-Infected Patients. AB - INTRODUCTION: Longitudinal data on the changes in kidney function and tubular abnormalities in case of tenofovir disoproxil fumarate (TDF) withdrawal or continuation are scarce. METHODS: Prospective study of 228 patients receiving TDF, with 3 sequential determinations of serum creatinine, estimated glomerular filtration rate (eGFR), phosphatemia, and different urinary parameters (protein, albumin, phosphaturia, uricosuria, and glycosuria). Changes were analyzed in patients who interrupted TDF as compared to those who continued the same regimen. Proximal renal tubular dysfunction (PRTD) was defined as >=2 tubular abnormalities. RESULTS: After a median follow-up of 59.5 months, 78 patients (34%) had PRTD, mainly proteinuria (40%) and phosphaturia (61%), and time on TDF explains the severity of tubular alterations and eGFR slopes. In 35 switching patients, there was a rapid and significant eGFR improvement (median +4.1 ml/min per 1.73 m; P = 0.02), leading to a 39%-83% reduction in the prevalence of tubular abnormalities and of PRTD in less than 1 year (66%-39%). In comparison, 193 patients continuing the same regimen for 21.2 months had a small but significant and progressive eGFR decrease (-2.9 mL.min.1.73 m; P < 0.01), and a progressive rise in the prevalence of phosphaturia, uricosuria, and glycosuria (+9%-56%). In linear mixed-effect model, subsequent eGFR impairment was associated with proteinuria and time on TDF, and eGFR improvement with TDF discontinuation. CONCLUSIONS: Our data support the role of use and time on TDF in eGFR decline and tubular dysfunction. In contrast, TDF withdrawal is followed by a rapid and significant, although partial, recovery of eGFR and tubular abnormalities. PMID- 26962851 TI - Semi-quantitative method for the assessment of debris supply from slopes to river in ungauged catchments. AB - This paper presents an integrated empirical methodology for assessing the amount of sediment transported from slopes to the main river in absence of a sediment transport monitoring system. The amount of transported sediment is calculated through the characterization of the sediment source areas including the identification of the slope phenomena responsible for the sediment propagation to the main river: shallow landslides, channelized debris flows and deep-seated rotational slides. On this basis, several scenarios related to the climatic conditions are defined: they indicate the number of possible slope phenomena and potential volumes of mobilized unconsolidated material from sediment source areas to the main river. This methodology was finalized and tested in the Maira River basin (south-western Italian Alps) with quite good results. PMID- 26962852 TI - Long-acting recombinant factor VIII Fc fusion protein (rFVIIIFc) for perioperative haemostatic management in severe haemophilia A. AB - The Phase 3 A-LONG and Kids A-LONG studies demonstrated the prolonged half-life of rFVIIIFc compared with rFVIII, and the safety and efficacy of rFVIIIFc in subjects with severe haemophilia A. Eligible subjects from A-LONG and Kids A-LONG continued rFVIIIFc treatment by enrolling in ASPIRE, an ongoing extension study. Based on combined data from the primary studies and ASPIRE interim data, the safety and efficacy of rFVIIIFc in subjects requiring surgery were evaluated. Perioperative dosing regimens were determined by investigators with guidance based on pharmacokinetic data and recommendations from a clinical dosing committee. In addition to dosing frequency, factor consumption, blood loss, transfusions, bleeding episodes, and haemostatic response were assessed. Across studies, 21 subjects underwent 23 evaluable major surgeries, including 19 orthopaedic surgeries; 41 subjects underwent 52 minor surgeries, including 30 dental procedures. No major and 10 minor surgeries were performed in paediatric subjects. Of the major (n = 22) and minor (n = 32) surgeries assessed for haemostatic response, all were rated as excellent or good by the investigator/surgeon. During most major surgeries (95.7 %), haemostasis was maintained with one rFVIIIFc infusion. Blood loss in major surgeries was consistent with similar surgeries in subjects without haemophilia. Across studies, rFVIIIFc was well tolerated; no subject developed an inhibitor. PMID- 26962853 TI - Unraveling the Relationship between Motor Symptoms, Affective States and Contextual Factors in Parkinson's Disease: A Feasibility Study of the Experience Sampling Method. AB - BACKGROUND: In Parkinson's disease (PD), the complex relationship between motor symptoms, affective states, and contextual factors remains to be elucidated. The Experience Sampling Method provides (ESM) a novel approach to this issue. Using a mobile device with a special purpose application (app), motor symptoms, affective states and contextual factors are assessed repeatedly at random moments in the flow of daily life, yielding an intensive time series of symptoms and experience. The aim of this study was to study the feasibility of this method. METHOD: We studied the feasibility of a five-day period of ESM in PD and its ability to objectify diurnal fluctuations in motor symptom severity and their relation with affect and contextual factors in five PD patients with motor fluctuations. RESULTS: Participants achieved a high compliance, with 84% of assessment moments completed without disturbance of daily activities. The utility of the device was rated 8 on a 10-point scale. We were able to capture extensive diurnal fluctuations that were not revealed by routine clinical assessment. In addition, we were able to detect clinically relevant associations between motor symptoms, emotional fluctuations and contextual factors at an intra-individual level. CONCLUSIONS: ESM represents a viable and novel approach to elucidate relationships between motor symptoms, affective states and contextual factors at the level of individual subjects. ESM holds promise for clinical practice and scientific research. PMID- 26962854 TI - High-Density Lipoprotein-Associated miR-223 Is Altered after Diet-Induced Weight Loss in Overweight and Obese Males. AB - BACKGROUND AND AIMS: microRNAs (miRNAs) are small, endogenous non-coding RNAs that regulate metabolic processes, including obesity. The levels of circulating miRNAs are affected by metabolic changes in obesity, as well as in diet-induced weight loss. Circulating miRNAs are transported by high-density lipoproteins (HDL) but the regulation of HDL-associated miRNAs after diet-induced weight loss has not been studied. We aim to determine if HDL-associated miR-16, miR-17, miR 126, miR-222 and miR-223 levels are altered by diet-induced weight loss in overweight and obese males. METHODS: HDL were isolated from 47 subjects following 12 weeks weight loss comparing a high protein diet (HP, 30% of energy) with a normal protein diet (NP, 20% of energy). HDL-associated miRNAs (miR-16, miR-17, miR-126, miR-222 and miR-223) at baseline and after 12 weeks of weight loss were quantified by TaqMan miRNA assays. HDL particle sizes were determined by non denaturing polyacrylamide gradient gel electrophoresis. Serum concentrations of human HDL constituents were measured immunoturbidometrically or enzymatically. RESULTS: miR-16, miR-17, miR-126, miR-222 and miR-223 were present on HDL from overweight and obese subjects at baseline and after 12 weeks of the HP and NP weight loss diets. The HP diet induced a significant decrease in HDL-associated miR-223 levels (p = 0.015), which positively correlated with changes in body weight (r = 0.488, p = 0.032). Changes in miR-223 levels were not associated to changes in HDL composition or size. CONCLUSION: HDL-associated miR-223 levels are significantly decreased after HP diet-induced weight loss in overweight and obese males. This is the first study reporting changes in HDL-associated miRNA levels with diet-induced weight loss. PMID- 26962855 TI - Optogenetic Inhibition of the Subthalamic Nucleus Reduces Levodopa-Induced Dyskinesias in a Rat Model of Parkinson's Disease. AB - BACKGROUND: The inhibition of neuronal activity by electrical deep brain stimulation is one of the mechanisms explaining the amelioration of levodopa induced dyskinesia. However, electrical deep brain stimulation cannot specifically activate or inactivate selected types of neurons. OBJECTIVES: We applied optogenetics as an alternative treatment to deep brain stimulation for levodopa-induced dyskinesia, and also to confirm that the mechanism of levodopa induced dyskinesia amelioration by subthalamic nucleus deep brain stimulation is mediated through neuronal inhibition. METHODS: 6-hydroxydopamine-induced hemiparkinsonian rats received injections of hSynapsin1-NpHR-YFP adeno-associated virus (AAV) or hSynapsin1-YFP AAV. Two weeks after viral injections, all rats were treated with daily injections of levodopa. Then, the optic fiber was implanted into the ipsilateral subthalamic nucleus. We performed various behavioral tests to evaluate the changes in levodopa-induced dyskinesias after optogenetic expression and illumination in the subthalamic nucleus. RESULTS: The behavioral tests revealed that optical inhibition of the subthalamic nucleus significantly ameliorated levodopa-induced dyskinesia by reducing the duration of the dyskinesias as well as the severity of axial dyskinesia. CONCLUSIONS: These findings will provide a useful foundation for the future development of optogenetic modulation systems that could be considered as an approach to dyskinesia therapy. PMID- 26962857 TI - Avian Assemblages at Bird Baths: A Comparison of Urban and Rural Bird Baths in Australia. AB - Private gardens provide habitat and resources for many birds living in human dominated landscapes. While wild bird feeding is recognised as one of the most popular forms of human-wildlife interaction, almost nothing is known about the use of bird baths. This citizen science initiative explores avian assemblages at bird baths in private gardens in south-eastern Australia and how this differs with respect to levels of urbanisation and bioregion. Overall, 992 citizen scientists collected data over two, four-week survey periods during winter 2014 and summer 2015 (43% participated in both years). Avian assemblages at urban and rural bird baths differed between bioregions with aggressive nectar-eating species influenced the avian assemblages visiting urban bird baths in South Eastern Queensland, NSW North Coast and Sydney Basin while introduced birds contributed to differences in South Western Slopes, Southern Volcanic Plains and Victorian Midlands. Small honeyeaters and other small native birds occurred less often at urban bird baths compared to rural bird baths. Our results suggest that differences between urban versus rural areas, as well as bioregion, significantly influence the composition of avian assemblages visiting bird baths in private gardens. We also demonstrate that citizen science monitoring of fixed survey sites such as bird baths is a useful tool in understanding large-scale patterns in avian assemblages which requires a vast amount of data to be collected across broad areas. PMID- 26962856 TI - Supply- and Demand-Side Factors Influencing Utilization of Infant and Young Child Feeding Counselling Services in Viet Nam. AB - Adequate utilization of services is critical to maximize the impact of counselling on infant and young child feeding (IYCF), but little is known about factors affecting utilization. Our study examined supply- and demand-side factors associated with the utilization of IYCF counselling services in Viet Nam. We used survey data from mothers with children <2y (n = 1,008) and health staff (n = 60) from the evaluation of a program that embedded IYCF counseling into the existing government health system. The frequency of never users, one-time users, repeat users, and achievers of the recommended minimum number of visits at health facilities were 45.1%, 13.0%, 28.4% and 13.5%, respectively. Poisson regression showed that demand-generation strategies, especially invitation cards, were the key factors determining one-time use (Prevalence ratio, PR 3.0, 95% CI: 2.2-4.2), repeated use (PR 3.2, 95% CI: 2.4-4.2), and achievement of minimum visits (PR 5.5, 95% CI: 3.6-8.4). Higher maternal education was associated with higher utilization both for one-time and repeated use. Being a farmer, belonging to an ethnic minority, and having a wasted child were associated with greater likelihood of achieving the minimum recommended number of visits, whereas child stunting or illness were not. Distance to health center was a barrier to repeated visits. Among supply-side factors, good counselling skills (PR: 1.3-1.8) was the most important factor associated with any service use, whereas longer employment duration and greater work pressure of health center staff were associated with lower utilization. Population attributable risk estimations showed that an additional 25% of the population would have achieved the minimum number of visits if exposed to three demand-generation strategies, and further increased to 49% if the health staff had good counseling skills and low work pressure. Our study provides evidence that demand-generation strategies are essential to increase utilization of facility-based IYCF counselling services in Viet Nam, and may be relevant for increasing and sustaining use of nutrition services in similar contexts. PMID- 26962859 TI - Human FGF-21 Is a Substrate of Fibroblast Activation Protein. AB - FGF-21 is a key regulator of metabolism and potential drug candidate for the treatment of type II diabetes and other metabolic disorders. However, the half life of active, circulating, human FGF-21 has recently been shown to be limited in mice and monkeys by a proteolytic cleavage between P171 and S172. Here, we show that fibroblast activation protein is the enzyme responsible for this proteolysis by demonstrating that purified FAP cleaves human FGF-21 at this site in vitro, and that an FAP-specific inhibitor, ARI-3099, blocks the activity in mouse, monkey and human plasma and prolongs the half-life of circulating human FGF-21 in mice. Mouse FGF-21, however, lacks the FAP cleavage site and is not cleaved by FAP. These findings indicate FAP may function in the regulation of metabolism and that FAP inhibitors may prove useful in the treatment of diabetes and metabolic disorders in humans, but pre-clinical proof of concept studies in rodents will be problematic. PMID- 26962862 TI - Correction: Transcriptome Analysis of Plant Hormone-Related Tomato (Solanum lycopersicum) Genes in a Sunlight-Type Plant Factory. PMID- 26962858 TI - Changes in the miRNA-mRNA Regulatory Network Precede Motor Symptoms in a Mouse Model of Multiple System Atrophy: Clinical Implications. AB - Multiple system atrophy (MSA) is a fatal rapidly progressive alpha synucleinopathy, characterized by alpha-synuclein accumulation in oligodendrocytes. It is accepted that the pathological alpha-synuclein accumulation in the brain of MSA patients plays a leading role in the disease process, but little is known about the events in the early stages of the disease. In this study we aimed to define potential roles of the miRNA-mRNA regulatory network in the early pre-motor stages of the disease, i.e., downstream of alpha synuclein accumulation in oligodendroglia, as assessed in a transgenic mouse model of MSA. We investigated the expression patterns of miRNAs and their mRNA targets in substantia nigra (SN) and striatum, two brain regions that undergo neurodegeneration at a later stage in the MSA model, by microarray and RNA-seq analysis, respectively. Analysis was performed at a time point when alpha synuclein accumulation was already present in oligodendrocytes at neuropathological examination, but no neuronal loss nor deficits of motor function had yet occurred. Our data provide a first evidence for the leading role of gene dysregulation associated with deficits in immune and inflammatory responses in the very early, non-symptomatic disease stages of MSA. While dysfunctional homeostasis and oxidative stress were prominent in SN in the early stages of MSA, in striatum differential gene expression in the non-symptomatic phase was linked to oligodendroglial dysfunction, disturbed protein handling, lipid metabolism, transmembrane transport and altered cell death control, respectively. A large number of putative miRNA-mRNAs interaction partners were identified in relation to the control of these processes in the MSA model. Our results support the role of early changes in the miRNA-mRNA regulatory network in the pathogenesis of MSA preceding the clinical onset of the disease. The findings thus contribute to understanding the disease process and are likely to pave the way towards identifying disease biomarkers for early diagnosis of MSA. PMID- 26962860 TI - Genetic Divergence between Camellia sinensis and Its Wild Relatives Revealed via Genome-Wide SNPs from RAD Sequencing. AB - Tea is one of the most popular beverages across the world and is made exclusively from cultivars of Camellia sinensis. Many wild relatives of the genus Camellia that are closely related to C. sinensis are native to Southwest China. In this study, we first identified the distinct genetic divergence between C. sinensis and its wild relatives and provided a glimpse into the artificial selection of tea plants at a genome-wide level by analyzing 15,444 genomic SNPs that were identified from 18 cultivated and wild tea accessions using a high-throughput genome-wide restriction site-associated DNA sequencing (RAD-Seq) approach. Six distinct clusters were detected by phylogeny inferrence and principal component and genetic structural analyses, and these clusters corresponded to six Camellia species/varieties. Genetic divergence apparently indicated that C. taliensis var. bangwei is a semi-wild or transient landrace occupying a phylogenetic position between those wild and cultivated tea plants. Cultivated accessions exhibited greater heterozygosity than wild accessions, with the exception of C. taliensis var. bangwei. Thirteen genes with non-synonymous SNPs exhibited strong selective signals that were suggestive of putative artificial selective footprints for tea plants during domestication. The genome-wide SNPs provide a fundamental data resource for assessing genetic relationships, characterizing complex traits, comparing heterozygosity and analyzing putatitve artificial selection in tea plants. PMID- 26962861 TI - Whole Genome Sequencing of Newly Established Pancreatic Cancer Lines Identifies Novel Somatic Mutation (c.2587G>A) in Axon Guidance Receptor Plexin A1 as Enhancer of Proliferation and Invasion. AB - The genetic profile of human pancreatic cancers harbors considerable heterogeneity, which suggests a possible explanation for the pronounced inefficacy of single therapies in this disease. This observation has led to a belief that custom therapies based on individual tumor profiles are necessary to more effectively treat pancreatic cancer. It has recently been discovered that axon guidance genes are affected by somatic structural variants in up to 25% of human pancreatic cancers. Thus far, however, some of these mutations have only been correlated to survival probability and no function has been assigned to these observed axon guidance gene mutations in pancreatic cancer. In this study we established three novel pancreatic cancer cell lines and performed whole genome sequencing to discover novel mutations in axon guidance genes that may contribute to the cancer phenotype of these cells. We discovered, among other novel somatic variants in axon guidance pathway genes, a novel mutation in the PLXNA1 receptor (c.2587G>A) in newly established cell line SB.06 that mediates oncogenic cues of increased invasion and proliferation in SB.06 cells and increased invasion in 293T cells upon stimulation with the receptor's natural ligand semaphorin 3A compared to wild type PLXNA1 cells. Mutant PLXNA1 signaling was associated with increased Rho-GTPase and p42/p44 MAPK signaling activity and cytoskeletal expansion, but not changes in E-cadherin, vimentin, or metalloproteinase 9 expression levels. Pharmacologic inhibition of the Rho-GTPase family member CDC42 selectively abrogated PLXNA1 c.2587G>A-mediated increased invasion. These findings provide in-vitro confirmation that somatic mutations in axon guidance genes can provide oncogenic gain-of-function signals and may contribute to pancreatic cancer progression. PMID- 26962863 TI - Fluctuations, Correlations and the Estimation of Concentrations inside Cells. AB - Information transmission in cells occurs quite accurately even when concentration changes are "read" by individual binding sites. In this paper we study ligand number and site occupancy fluctuations when ligands diffuse and react going beyond the analyses that focus on their asymptotic decay. In this way we show that, for immobile binding sites, fluctuations in the number of bound molecules decay on a relatively fast scale before the asymptotic behavior kicks in. This result can explain the observed co-existence of highly fluctuating instantaneous transcriptional activities with accumulated mRNA concentrations that have relatively small noise levels. We also show that the initial stages of the decay in the bound molecule number fluctuations have one or two characteristic timescales depending on the concentration of free molecules. This transition can explain the changes in enzyme activity observed at the single molecule level. PMID- 26962864 TI - Quantitative Trait Locus Based Virulence Determinant Mapping of the HSV-1 Genome in Murine Ocular Infection: Genes Involved in Viral Regulatory and Innate Immune Networks Contribute to Virulence. AB - Herpes simplex virus type 1 causes mucocutaneous lesions, and is the leading cause of infectious blindness in the United States. Animal studies have shown that the severity of HSV-1 ocular disease is influenced by three main factors; innate immunity, host immune response and viral strain. We previously showed that mixed infection with two avirulent HSV-1 strains (OD4 and CJ994) resulted in recombinants that exhibit a range of disease phenotypes from severe to avirulent, suggesting epistatic interactions were involved. The goal of this study was to develop a quantitative trait locus (QTL) analysis of HSV-1 ocular virulence determinants and to identify virulence associated SNPs. Blepharitis and stromal keratitis quantitative scores were characterized for 40 OD4:CJ994 recombinants. Viral titers in the eye were also measured. Virulence quantitative trait locus mapping (vQTLmap) was performed using the Lasso, Random Forest, and Ridge regression methods to identify significant phenotypically meaningful regions for each ocular disease parameter. The most predictive Ridge regression model identified several phenotypically meaningful SNPs for blepharitis and stromal keratitis. Notably, phenotypically meaningful nonsynonymous variations were detected in the UL24, UL29 (ICP8), UL41 (VHS), UL53 (gK), UL54 (ICP27), UL56, ICP4, US1 (ICP22), US3 and gG genes. Network analysis revealed that many of these variations were in HSV-1 regulatory networks and viral genes that affect innate immunity. Several genes previously implicated in virulence were identified, validating this approach, while other genes were novel. Several novel polymorphisms were also identified in these genes. This approach provides a framework that will be useful for identifying virulence genes in other pathogenic viruses, as well as epistatic effects that affect HSV-1 ocular virulence. PMID- 26962865 TI - Successful Treatment of Human Visceral Leishmaniasis Restores Antigen-Specific IFN-gamma, but not IL-10 Production. AB - One of the key immunological characteristics of active visceral leishmaniasis (VL) is a profound immunosuppression and impaired production of Interferon-gamma (IFN-gamma). However, recent studies from Bihar in India showed using a whole blood assay, that whole blood cells have maintained the capacity to produce IFN gamma. Here we tested the hypothesis that a population of low-density granulocytes (LDG) might contribute to T cell responses hyporesponsiveness via the release of arginase. Our results show that this population is affected by the anticoagulant used to collect blood: the frequency of LDGs is significantly lower when the blood is collected with heparin as compared to EDTA; however, the anticoagulant does not impact on the levels of arginase released. Next, we assessed the capacity of whole blood cells from patients with active VL to produce IFN-gamma and IL-10 in response to antigen-specific and polyclonal activation. Our results show that whole blood cells produce low or levels below detection limit of IFN-gamma and IL-10, however, after successful treatment of VL patients, these cells gradually regain their capacity to produce IFN-gamma, but not IL-10, in response to activation. These results suggest that in contrast to VL patients from Bihar, India, whole blood cells from VL patients from Gondar, Ethiopia, have lost their ability to produce IFN-gamma during active VL and that active disease is not associated with sustained levels of IL-10 production following stimulation. PMID- 26962867 TI - Using Seroprevalence and Immunisation Coverage Data to Estimate the Global Burden of Congenital Rubella Syndrome, 1996-2010: A Systematic Review. AB - BACKGROUND: The burden of Congenital Rubella Syndrome (CRS) is typically underestimated in routine surveillance. Updated estimates are needed following the recent WHO position paper on rubella and recent GAVI initiatives, funding rubella vaccination in eligible countries. Previous estimates considered the year 1996 and only 78 (developing) countries. METHODS: We reviewed the literature to identify rubella seroprevalence studies conducted before countries introduced rubella-containing vaccination (RCV). These data and the estimated vaccination coverage in the routine schedule and mass campaigns were incorporated in mathematical models to estimate the CRS incidence in 1996 and 2000-2010 for each country, region and globally. RESULTS: The estimated CRS decreased in the three regions (Americas, Europe and Eastern Mediterranean) which had introduced widespread RCV by 2010, reaching <2 per 100,000 live births (the Americas and Europe) and 25 (95% CI 4-61) per 100,000 live births (the Eastern Mediterranean). The estimated incidence in 2010 ranged from 90 (95% CI: 46-195) in the Western Pacific, excluding China, to 116 (95% CI: 56-235) and 121 (95% CI: 31-238) per 100,000 live births in Africa and SE Asia respectively. Highest numbers of cases were predicted in Africa (39,000, 95% CI: 18,000-80,000) and SE Asia (49,000, 95% CI: 11,000-97,000). In 2010, 105,000 (95% CI: 54,000-158,000) CRS cases were estimated globally, compared to 119,000 (95% CI: 72,000-169,000) in 1996. CONCLUSIONS: Whilst falling dramatically in the Americas, Europe and the Eastern Mediterranean after vaccination, the estimated CRS incidence remains high elsewhere. Well-conducted seroprevalence studies can help to improve the reliability of these estimates and monitor the impact of rubella vaccination. PMID- 26962866 TI - Cyclin B Translation Depends on mTOR Activity after Fertilization in Sea Urchin Embryos. AB - The cyclin B/CDK1 complex is a key regulator of mitotic entry. Using PP242, a specific ATP-competitive inhibitor of mTOR kinase, we provide evidence that the mTOR signalling pathway controls cyclin B mRNA translation following fertilization in Sphaerechinus granularis and Paracentrotus lividus. We show that PP242 inhibits the degradation of the cap-dependent translation repressor 4E-BP (eukaryotic initiation factor 4E-Binding Protein). PP242 inhibits global protein synthesis, delays cyclin B accumulation, cyclin B/CDK1 complex activation and consequently entry into the mitotic phase of the cell cycle triggered by fertilization. PP242 inhibits cyclin B mRNA recruitment into active polysomes triggered by fertilization. An amount of cyclin B mRNA present in active polysomes appears to be insensitive to PP242 treatment. Taken together, our results suggest that, following sea urchin egg fertilization, cyclin B mRNA translation is controlled by two independent mechanisms: a PP242-sensitive and an additional PP242-insentitive mechanism. PMID- 26962868 TI - Clusterin/Akt Up-Regulation Is Critical for GATA-4 Mediated Cytoprotection of Mesenchymal Stem Cells against Ischemia Injury. AB - BACKGROUND: Clusterin (Clu) is a stress-responding protein with multiple biological functions. Our preliminary microarray studies show that clusterin was prominently upregulated in mesenchymal stem cells (MSCs) overexpressing GATA-4 (MSCGATA-4). We hypothesized that the upregulation of clusterin is involved in overexpression of GATA-4 mediated cytoprotection. METHODS: MSCs harvested from bone marrow of rats were transduced with GATA-4. The expression of clusterin in MSCs was further confirmed by real-time PCR and western blotting. Simulation of ischemia was achieved by exposure of MSCs to a hypoxic environment. Lactate dehydrogenase (LDH) released from MSCs was served as a biomarker of cell injury and MTs uptake was used to estimate cell viability. Mitochondrial function was evaluated by measuring mitochondrial membrane potential (DeltaPsim) and caspase 3/7 activity. RESULTS: (1) Clusterin expression was up-regulated in MSCGATA-4 compared to control MSCs transfected with empty-vector (MSCNull). MSCGATA-4 were tolerant to 72 h hypoxia exposure as shown by reduced LDH release and higher MTs uptake. This protection was abrogated by transfecting Clu-siRNA into MSCGATA-4. (2) Exogenous clusterin significantly decreased LDH release and increased MSC survival in hypoxic environment. Moreover, DeltaPsim was maintained and caspase 3/7 activity was reduced by clusterin in a concentration-dependent manner. (3) p Akt expression in MSCs was upregulated following pre-treatment with clusterin, with no change in total Akt. Moreover, cytoprotection mediated by clusterin was partially abrogated by Akt inhibitor LY294002. CONCLUSIONS: Clusterin/Akt signaling pathway is involved in GATA-4 mediated cytoprotection against hypoxia stress. It is suggested that clusterin may be therapeutically exploited in MSC based therapy for cardiovascular diseases. PMID- 26962870 TI - Stimulating Effect of Manumycin A on Suicidal Erythrocyte Death. AB - BACKGROUND/AIMS: The streptomycete derived farnesyltransferase inhibitor Manumycin A triggers apoptosis of tumor cells and is thus considered for the treatment of malignancy. The present study explored whether Manumycin A could similarly stimulate eryptosis, the suicidal death of erythrocytes characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include Ca2+ entry as well as activation of staurosporine sensitive protein kinase C and SB203580 sensitive p38 kinase. The present study explored, whether Manumycin A induces eryptosis and, if so, to shed some light on the mechanisms involved. METHODS: Phosphatidylserine abundance at the human erythrocyte surface was estimated from annexin-V-binding, cell volume from forward scatter, and hemolysis from hemoglobin concentration in the supernatant. RESULTS: A 48 hours exposure of human erythrocytes to Manumycin A (>= 5 ug/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter and significantly incrased hemolysis. The effect of Manumycin A on annexin-V binding was significantly blunted by removal of extracellular Ca2+, by addition of staurosporine (1 uM) and by addition of SB203580 (2 uM). CONCLUSIONS: Manumycin A triggers hemolysis, cell shrinkage and phospholipid scrambling of the human erythrocyte cell membrane. The effect on cell membrane scrambling was in part but not fully dependent on entry of extracellular Ca2+, as well as activity of staurosporine and SB203580 sensitive kinases. PMID- 26962869 TI - Genetic Passive Immunization with Adenoviral Vector Expressing Chimeric Nanobody Fc Molecules as Therapy for Genital Infection Caused by Mycoplasma hominis. AB - Developing pathogen-specific recombinant antibody fragments (especially nanobodies) is a very promising strategy for the treatment of infectious disease. Nanobodies have great potential for gene therapy application due to their single gene nature. Historically, Mycoplasma hominis has not been considered pathogenic bacteria due to the lack of acute infection and partially due to multiple studies demonstrating high frequency of isolation of M. hominis samples from asymptomatic patients. However, recent studies on the role of latent M. hominis infection in oncologic transformation, especially prostate cancer, and reports that M. hominis infects Trichomonas and confers antibiotic resistance to Trichomonas, have generated new interest in this field. In the present study we have generated specific nanobody against M. hominis (aMh), for which the identified target is the ABC-transporter substrate-binding protein. aMh exhibits specific antibacterial action against M. hominis. In an attempt to improve the therapeutic properties, we have developed the adenoviral vector-based gene therapy approach for passive immunization with nanobodies against M. hominis. For better penetration into the mucous layer of the genital tract, we fused aMh with the Fc fragment of IgG. Application of this comprehensive approach with a single systemic administration of recombinant adenovirus expressing aMh-Fc demonstrated both prophylactic and therapeutic effects in a mouse model of genital M. hominis infection. PMID- 26962871 TI - Integrating Transgenic Vector Manipulation with Clinical Interventions to Manage Vector-Borne Diseases. AB - Many vector-borne diseases lack effective vaccines and medications, and the limitations of traditional vector control have inspired novel approaches based on using genetic engineering to manipulate vector populations and thereby reduce transmission. Yet both the short- and long-term epidemiological effects of these transgenic strategies are highly uncertain. If neither vaccines, medications, nor transgenic strategies can by themselves suffice for managing vector-borne diseases, integrating these approaches becomes key. Here we develop a framework to evaluate how clinical interventions (i.e., vaccination and medication) can be integrated with transgenic vector manipulation strategies to prevent disease invasion and reduce disease incidence. We show that the ability of clinical interventions to accelerate disease suppression can depend on the nature of the transgenic manipulation deployed (e.g., whether vector population reduction or replacement is attempted). We find that making a specific, individual strategy highly effective may not be necessary for attaining public-health objectives, provided suitable combinations can be adopted. However, we show how combining only partially effective antimicrobial drugs or vaccination with transgenic vector manipulations that merely temporarily lower vector competence can amplify disease resurgence following transient suppression. Thus, transgenic vector manipulation that cannot be sustained can have adverse consequences-consequences which ineffective clinical interventions can at best only mitigate, and at worst temporarily exacerbate. This result, which arises from differences between the time scale on which the interventions affect disease dynamics and the time scale of host population dynamics, highlights the importance of accounting for the potential delay in the effects of deploying public health strategies on long-term disease incidence. We find that for systems at the disease-endemic equilibrium, even modest perturbations induced by weak interventions can exhibit strong, albeit transient, epidemiological effects. This, together with our finding that under some conditions combining strategies could have transient adverse epidemiological effects suggests that a relatively long time horizon may be necessary to discern the efficacy of alternative intervention strategies. PMID- 26962873 TI - A High-Throughput Screening Strategy to Identify Protein-Protein Interaction Inhibitors That Block the Fanconi Anemia DNA Repair Pathway. AB - Induction of the Fanconi anemia (FA) DNA repair pathway is a common mechanism by which tumors evolve resistance to DNA crosslinking chemotherapies. Proper execution of the FA pathway requires interaction between the FA complementation group M protein (FANCM) and the RecQ-mediated genome instability protein (RMI) complex, and mutations that disrupt FANCM/RMI interactions sensitize cells to DNA crosslinking agents. Inhibitors that block FANCM/RMI complex formation could be useful therapeutics for resensitizing tumors that have acquired chemotherapeutic resistance. To identify such inhibitors, we have developed and validated high throughput fluorescence polarization and proximity assays that are sensitive to inhibitors that disrupt interactions between the RMI complex and its binding site on FANCM (a peptide referred to as MM2). A pilot screen of 74,807 small molecules was performed using the fluorescence polarization assay. Hits from the primary screen were further tested using the proximity assay, and an orthogonal proximity assay was used to assess inhibitor selectivity. Direct physical interaction between the RMI complex and the most selective inhibitor identified through the screening process was measured by surface plasmon resonance and isothermal titration calorimetry. Observation of direct binding by this small molecule validates the screening protocol. PMID- 26962872 TI - Focal Adhesion Kinase Inhibitors in Combination with Erlotinib Demonstrate Enhanced Anti-Tumor Activity in Non-Small Cell Lung Cancer. AB - Blockade of epidermal growth factor receptor (EGFR) activity has been a primary therapeutic target for non-small cell lung cancers (NSCLC). As patients with wild type EGFR have demonstrated only modest benefit from EGFR tyrosine kinase inhibitors (TKIs), there is a need for additional therapeutic approaches in patients with wild-type EGFR. As a key component of downstream integrin signalling and known receptor cross-talk with EGFR, we hypothesized that targeting focal adhesion kinase (FAK) activity, which has also been shown to correlate with aggressive stage in NSCLC, would lead to enhanced activity of EGFR TKIs. As such, EGFR TKI-resistant NSCLC cells (A549, H1299, H1975) were treated with the EGFR TKI erlotinib and FAK inhibitors (PF-573,228 or PF-562,271) both as single agents and in combination. We determined cell viability, apoptosis and 3 dimensional growth in vitro and assessed tumor growth in vivo. Treatment of EGFR TKI-resistant NSCLC cells with FAK inhibitor alone effectively inhibited cell viability in all cell lines tested; however, its use in combination with the EGFR TKI erlotinib was more effective at reducing cell viability than either treatment alone when tested in both 2- and 3-dimensional assays in vitro, with enhanced benefit seen in A549 cells. This increased efficacy may be due in part to the observed inhibition of Akt phosphorylation when the drugs were used in combination, where again A549 cells demonstrated the most inhibition following treatment with the drug combination. Combining erlotinib with FAK inhibitor was also potent in vivo as evidenced by reduced tumor growth in the A549 mouse xenograft model. We further ascertained that the enhanced sensitivity was irrespective of the LKB1 mutational status. In summary, we demonstrate the effectiveness of combining erlotinib and FAK inhibitors for use in known EGFR wild-type, EGFR TKI resistant cells, with the potential that a subset of cell types, which includes A549, could be particularly sensitive to this combination treatment. As such, further evaluation of this combination therapy is warranted and could prove to be an effective therapeutic approach for patients with inherent EGFR TKI-resistant NSCLC. PMID- 26962874 TI - High-Throughput Screening Platform for the Discovery of New Immunomodulator Molecules from Natural Product Extract Libraries. AB - It is widely accepted that central nervous system inflammation and systemic inflammation play a significant role in the progression of chronic neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, neurotropic viral infections, stroke, paraneoplastic disorders, traumatic brain injury, and multiple sclerosis. Therefore, it seems reasonable to propose that the use of anti-inflammatory drugs might diminish the cumulative effects of inflammation. Indeed, some epidemiological studies suggest that sustained use of anti-inflammatory drugs may prevent or slow down the progression of neurodegenerative diseases. However, the anti-inflammatory drugs and biologics used clinically have the disadvantage of causing side effects and a high cost of treatment. Alternatively, natural products offer great potential for the identification and development of bioactive lead compounds into drugs for treating inflammatory diseases with an improved safety profile. In this work, we present a validated high-throughput screening approach in 96-well plate format for the discovery of new molecules with anti-inflammatory/immunomodulatory activity. The in vitro models are based on the quantitation of nitrite levels in RAW264.7 murine macrophages and interleukin-8 in Caco-2 cells. We have used this platform in a pilot project to screen a subset of 5976 noncytotoxic crude microbial extracts from the MEDINA microbial natural product collection. To our knowledge, this is the first report on an high-throughput screening of microbial natural product extracts for the discovery of immunomodulators. PMID- 26962876 TI - Multifunctional Nanotherapeutics with All-in-One Nanoentrapment of Drug/Gene/Inorganic Nanoparticle. AB - It is challenging but imperative to merge together specific inorganic nanomaterials with macromolecular and small-molecule therapeutics into one nanoentity for all-in-one theranostic/remedy. We establish a versatile nanotechnology to nanoentrap magnetic nanoparticles, doxorubicin, and DNA, thus allowing the combination of magnetic targeting, magnetic resonance (MR) imaging, gene transport, and bioresponsive chemotherapy. We hope this nanotechnology can prompt the development of complex inorganic/organic nanosystems for various applications. PMID- 26962877 TI - Inherited Platelet Function Disorders: Algorithms for Phenotypic and Genetic Investigation. AB - Inherited platelet function disorders (IPFDs) manifest with mucocutaneous bleeding and are frequently difficult to diagnose due to their heterogeneity, the complexity of the platelet activation pathways and a lack of standardization of the platelet function laboratory assays and of their use for this purpose. A rational diagnostic approach to IPFDs should follow an algorithm where clinical examination and a stepwise laboratory evaluation play a crucial role. A streamlined panel of laboratory tests, with consecutive steps of increasing level of complexity, allows the phenotypic characterization of most IPFDs. A first-line diagnosis of a significant fraction of the IPFD may be made also at nonspecialized centers by using relatively simple tests, including platelet count, peripheral blood smear, light transmission aggregometry, measurement of platelet granule content and release, and the expression of glycoproteins by flow cytometry. Some of the most complex, second- and third-step tests may be performed only in highly specialized laboratories. Genotyping, including the widespread application of next-generation sequencing, has enabled discovery in the last few years of several novel genes associated with platelet disorders and this method may eventually become a first-line diagnostic approach; however, a preliminary clinical and laboratory phenotypic characterization nowadays still remains crucial for diagnosis of IPFDs. PMID- 26962879 TI - Synergistic Acid-Catalyzed Synthesis of N-Aryl-Substituted Azacycles from Anilines and Cyclic Ethers. AB - A metal-free and efficient approach to N-aryl-substituted azacycles from arylamines and cyclic ethers is described. In this synthesis, the synergistic effect between Lewis and Bronsted acids is crucial to the ring-opening of cyclic ethers and the subsequent cyclization. The use of B(C6F5)3 enabled the formation of frustrated Lewis pairs (FLPs) from the reactants, and the resulting FLPs allowed ready access to the N-arylazacycles in moderate to good yields via further cyclization. Water is the sole waste resulting from the reaction, thereby making it an environmentally benign process. PMID- 26962878 TI - Triboelectric Nanogenerator as a Self-Powered Communication Unit for Processing and Transmitting Information. AB - In this paper, we demonstrate an application of a triboelectric nanogenerator (TENG) as a self-powered communication unit. An elaborately designed TENG is used to translate a series of environmental triggering signals into binary digital signals and drives an electronic-optical device to transmit binary digital data in real-time without an external power supply. The elaborately designed TENG is built in a membrane structure that can effectively drive the electronic-optical device in a bandwidth from 1.30 to 1.65 kHz. Two typical communication modes (amplitude-shift keying and frequency-shift keying) are realized through the resonant response of TENG to different frequencies, and two digital signals, i.e., "1001" and "0110", are successfully transmitted and received through this system, respectively. Hence, in this study, a simple but efficient method for directly transmitting ambient vibration to the receiver as a digital signal is established using an elaborately designed TENG and an optical communication technique. This type of the communication system, as well as the implementation method presented, exhibits great potential for applications in the smart city, smart home, password authentication, and so on. PMID- 26962880 TI - Synthesis of High-Quality alpha-MnSe Nanostructures with Superior Lithium Storage Properties. AB - High-quality alpha-MnSe nanocubes were successfully prepared for the first time by an effective hot injection synthesis strategy. This approach was simple but robust and had been applied to the controllable synthesis of different sizes and diverse morphologies of alpha-MnSe nanostructures. The crystal phases, compositions, and microstructures of these nanostructures had been systematically characterized with a series of techniques. As a proof-of-concept application, the as-prepared alpha-MnSe nanocubes were used as an anode material for a lithium ion battery, which exhibited superior rate ability and ultralong cycle stability in half-cell and full-cell tests. Importantly, the phase transition from alpha-MnSe to beta-MnSe during the electrochemical process was proved by ex situ X-ray diffraction and selected area electron diffraction. The excellent electrochemical performance of alpha-MnSe endowed its potential as an anode material candidate for high performance lithium storage. PMID- 26962875 TI - A Perspective on Implementing a Quantitative Systems Pharmacology Platform for Drug Discovery and the Advancement of Personalized Medicine. AB - Drug candidates exhibiting well-defined pharmacokinetic and pharmacodynamic profiles that are otherwise safe often fail to demonstrate proof-of-concept in phase II and III trials. Innovation in drug discovery and development has been identified as a critical need for improving the efficiency of drug discovery, especially through collaborations between academia, government agencies, and industry. To address the innovation challenge, we describe a comprehensive, unbiased, integrated, and iterative quantitative systems pharmacology (QSP) driven drug discovery and development strategy and platform that we have implemented at the University of Pittsburgh Drug Discovery Institute. Intrinsic to QSP is its integrated use of multiscale experimental and computational methods to identify mechanisms of disease progression and to test predicted therapeutic strategies likely to achieve clinical validation for appropriate subpopulations of patients. The QSP platform can address biological heterogeneity and anticipate the evolution of resistance mechanisms, which are major challenges for drug development. The implementation of this platform is dedicated to gaining an understanding of mechanism(s) of disease progression to enable the identification of novel therapeutic strategies as well as repurposing drugs. The QSP platform will help promote the paradigm shift from reactive population-based medicine to proactive personalized medicine by focusing on the patient as the starting and the end point. PMID- 26962881 TI - Fractional 532-nm Q-switched Nd:YAG laser: One of the safest novel treatment modality to treat cafe-au-lait macules. AB - Cafe-au-lait macules (CALMs) are benign epidermal basilar hyperpigmentations that can be found in an isolated form or in association with neurocutaneous syndromes. Frequency-doubled Q-switched neodymium-doped yttrium aluminum garnet laser (532 nm QSNYL) does not penetrate deeply into the skin and is therefore suitable for epidermal pigmented lesion. Fractional photothermolysis (FP) targets only very small areas of the skin, without injuring adjacent areas of healthy, normal skin. Herein, we report a case of CALMs successfully treated with fractional 532-nm QSNYL. By applying FP to 532-nm QSNYL, we could treat CALMs safely with less downtime as compared to conventional laser treatments and expect more energy delivery for each microscopic hole, thereby allowing higher response rate. PMID- 26962883 TI - Optical Response of Terpyridine Ligands to Zinc Binding: A Close Look at the Substitution Effect by Spectroscopic Studies at Low Temperature. AB - Terpyridine (tpy) ligands are popular building blocks to bind metal ions. Several tpy ligands with different substituents were synthesized and examined for their binding with zinc cation. The study revealed a large substituent effect on the zinc binding-induced fluorescence quenching. With the aid of a liquid nitrogen Dewar, the tpy molecules were frozen to their ground-state conformation, preventing (or minimizing) molecular reorganization in the photoinduced excited state. This allowed us to detect the fluorescence spectra from the locally excited state (having a minimum of charge transfer interaction) and the temperature-dependent fluorescence. The fluorescence response to low temperature provided useful information about the intramolecular charge transfer (ICT) interaction between the donor and acceptor groups. Furthermore, a strong donor substituent (such as Me2N) played an essential role in observed fluorescence quenching. The study also provides a useful example to elucidate the ICT mechanism by using low-temperature fluorescence spectroscopy. PMID- 26962884 TI - Technology selection for infectious medical waste treatment using the analytic hierarchy process. AB - The overall objective of this paper was to evaluate five different technologies used for infectious medical waste treatment and select the optimum one by means of multicriteria analysis. Steam disinfection was selected as the optimum treatment technology, among others using incineration, microwave disinfection, chemical disinfection with sodium hypochlorite, and reverse polymerization with microwaves. The evaluation was based on four groups of criteria, specifically, environmental, economic, technical, and social criteria, using the analytic hierarchy process. Selection among four commercial systems using steam disinfection was not possible, because it required additional site-specific criteria, e.g., loading capacity and requirements of local regulations. IMPLICATIONS: The paper can help health care facilities to select the system for infectious waste treatment that best fits their needs. It was concluded that steam disinfection was the optimum technology, using environmental, economic, technical, and social criteria. PMID- 26962885 TI - A painful tale about synthetic scorpion toxins. PMID- 26962886 TI - Understanding Oxadiazolothiazinone Biological Properties: Negative Inotropic Activity versus Cytochrome P450-Mediated Metabolism. AB - We present a series of oxadiazolothiazinones, selective inotropic agents on isolated cardiac tissues, devoid of chronotropy and vasorelaxant activity. Functional and binding data for the precursor of the series (compound 1) let us hypothesize LTCC blocking activity and the existence of a recognition site specific for this scaffold. We synthesized and tested 22 new derivatives: introducing a para-methoxyphenyl at C-8 led to compound 12 (EC50 = 0.022 MUM), twice as potent as its para-bromo analogue (1). For 10 analogues, we extended the characterization of the biological properties by including the assessment of metabolic stability in human liver microsomes and cytochrome P450 inhibition potential. We observed that the methoxy group led to active compounds with low metabolic stability and high CYP inhibition, whereas the protective effect of bromine resulted in enhanced metabolic stability and reduced CYP inhibition. Thus, we identified two para-bromo benzothiazino-analogues as candidates for further studies. PMID- 26962887 TI - Graphdiyne: A Metal-Free Material as Hole Transfer Layer To Fabricate Quantum Dot Sensitized Photocathodes for Hydrogen Production. AB - Graphdiyne (GDY), a novel large pi-conjugated carbon material, for the first time, is introduced as the hole transfer layer into a photoelectrochemical water splitting cell (PEC). Raman and ultraviolet photoelectron spectroscopic studies indicate the existence of relatively strong pi-pi interactions between GDY and 4 mercaptopyridine surface-functionalized CdSe quantum dots, beneficial to the hole transportation and enhancement of the photocurrent performance. Upon exposure to a Xe lamp, the integrated photocathode produces a current density of nearly -70 MUA cm(-2) at a potential of 0 V vs NHE in neutral aqueous solution. Simultaneously, the photocathode evolves H2 with 90 +/- 5% faradic efficiency over three times and exhibits good stability within 12 h. All of the results indicate that GDY is a promising hole transfer material to fabricate a PEC device for water splitting by solar energy. PMID- 26962888 TI - Authors' Response. PMID- 26962889 TI - Re: Comparison of Azithromycin and Amoxicillin Before Dental Implant Placement: An Exploratory Study of Bioavailability and Resolution of Postoperative Inflammation. PMID- 26962890 TI - Setting the agenda for the journal's new direction. PMID- 26962891 TI - AOSW CONFERENCE ABSTRACTS. PMID- 26962892 TI - Associations between neuropsychiatric symptoms and cognition in Chinese patients with amyotrophic lateral sclerosis. AB - Our objective was to explore features of the neuropsychiatric symptoms in Chinese patients with amyotrophic lateral sclerosis (ALS) and the associations between these neuropsychiatric symptoms and cognition. A total of 91 ALS patients were evaluated using three recommended scales including the Neuropsychiatric Inventory (NPI), Addenbrooke's Cognitive Examination Revised (ACE-R), and Frontal Assessment Battery (FAB) tests. The mean age of onset was 52.5 +/- 10.8 years. The median NPI score of all patients was 2.0. The most common neuropsychiatric symptom was dysphoria/depression (59.3%), followed by anxiety (41.8%) and irritability/lability (26.4%). There were no significant differences in the frequency of neuropsychiatric symptoms in terms of gender, age of onset, onset form and disease duration. There were no significant differences in NPI total score, ACE-R total score and FAB total score in terms of gender, age of onset, onset form and disease duration, except for a higher ACE-R score observed in patients with a shorter disease duration. The NPI score had a strong correlation with the ACE-R score but not with the FAB score. In conclusion, neuropsychiatric symptoms appear to be quite common in Chinese ALS patients, who were likely to present with the emotional states of depression or anxiety. The neuropsychiatric symptoms in ALS are closely related to global cognition dysfunction. PMID- 26962894 TI - IAEA Isotope-enabled coupled catchment-lake water balance model, IWBMIso: description and validation. AB - The International Atomic Energy Agency (IAEA) Water Balance Model with Isotopes (IWBMIso) is a spatially distributed monthly water balance model that considers water fluxes and storages and their associated isotopic compositions. It is composed of a lake water balance model that is tightly coupled with a catchment water balance model. Measured isotope compositions of precipitation, rivers, lakes, and groundwater provide data that can be used to make an improved estimate of the magnitude of the fluxes among the model components. The model has been developed using the Object Modelling System (OMS). A variety of open source geographic information systems and web-based tools have been combined to provide user support for (1) basin delineation, characterization, and parameterization; (2) data pre-processing; (3) model calibration and application; and (4) visualization and analysis of model results. In regions where measured data are limited, the model can use freely available global data sets of climate, isotopic composition of precipitation, and soils and vegetation characteristics to create input data files and estimate spatially distributed model parameters. The OMS model engine and support functions, and the spatial and web-based tool set are integrated using the Colorado State University Environmental Risk Assessment and Management System (eRAMS) framework. The IWBMIso can be used to assess the spatial and temporal variability of annual and monthly water balance components for input to water planning and management. PMID- 26962895 TI - Quality of Life Outcomes in Community-based Mental Health Consumers: Comparisons with Population Norms and Changes over Time. AB - Quality of life is shown to be lower in people diagnosed with mental illness in comparison to the general population. The aim of this study is to examine the Quality of life in a subset of people accessing mental health services in a regional Queensland Centre. Thirty-seven people accessing mental health services completed the SF36 Health Survey on three occasions. Differences and relationships between Physical Composite Scores and Mental Composite Scores, comparisons with Australian population norms, and temporal change in Quality of Life were examined. Physical Composite Scores were significantly different to, but significantly correlated with, Mental Composite Scores on each occasion. Physical Composite Scores and Mental Composite Scores were significantly different to population norms, and did not vary significantly across time. The poor Quality of life of people with mental illness remains a significant challenge for the mental health workforce. PMID- 26962893 TI - Identification of chromatin accessibility domains in human breast cancer stem cells. AB - Epithelial-to-mesenchymal transition (EMT) is physiological in embryogenesis and wound healing but also associated with the formation of cancer stem cells (CSCs). Many EMT signaling pathways are implicated in CSC formation, but the precise underlying mechanisms of CSC formation remain elusive. We have previously demonstrated that PKC is critical for EMT induction and CSC formation in inducible breast EMT/CSC models. Here, we used formaldehyde-assisted isolation of regulatory elements-sequencing (FAIRE-seq) to investigate DNA accessibility changes after PKC activation and determine how they influence EMT and CSC formation. During EMT, DNA accessibility principally increased in regions distant from transcription start sites, low in CpG content, and enriched with chromatin enhancer marks. ChIP-sequencing revealed that a subset of these regions changed from poised to active enhancers upon stimulation, with some even more acteylated in CSCs. While regions with increased accessibility were enriched for FOX, AP-1, TEAD, and TFAP2 motifs, those containing FOX and AP-1 motif were associated with increased expression of CSC-associated genes, while those with TFAP2 were associated with genes with increased expression in non-CSCs. Silencing of 2 members of the FOX family, FOXN2 and FOXQ1, repressed CSCs and the mesenchymal phenotype and inhibited the CSC gene signature. These novel, PKC-induced DNA accessibility regions help explain how the epigenomic plasticity of cells undergoing EMT leads to CSC gene activation. PMID- 26962896 TI - Characterisation of caecum and crop microbiota of Indian indigenous chicken targeting multiple hypervariable regions within 16S rRNA gene. AB - A comparative analysis of caecum and crop microbiota of chick, grower and adult stages of Indian indigenous chickens was conducted to investigate the role of the microbiota of the gastrointestinal tract, which play an important role in host performance, health and immunity. High-throughput Illumina sequencing was performed for V3, V4 and V4-V6 hypervariable regions of the 16S rRNA gene. M5RNA and M5NR databases under MG-RAST were used for metagenomic datasets annotation. In the crop, Firmicutes (~78%) and Proteobacteria (~16%) were the predominant phyla whereas in the caecum, Firmicutes (~50%), Bacteroidetes (~29%) and Actinobacteria (~10%) were predominant. The Shannon-Wiener diversity index suggested that sample richness and diversity increased as the chicken aged. For the first time, the presence of Lactobacillus species such as L. frumenti, L. antri, L. mucosae in the chicken crop along with Kineococcus radiotolerans, Desulfohalobium retbaense and L. jensenii in the caecum are reported. Many of these bacterial species have been found to be involved in immune response modulation and disease prevention in pigs and humans. The gut microbiome of the indigenous chicken was enriched with microbes having probiotic potential which might be essential for their adaptability. PMID- 26962898 TI - Protecting and Expanding Access to Birth Control. PMID- 26962897 TI - Drug Delivery Research: The Invention Cycle. AB - Controlled drug delivery systems have been successful in introducing improved formulations for better use of existing drugs and novel delivery of biologicals. The initial success of producing many oral products and some injectable depot formulations, however, reached a plateau, and the progress over the past three decades has been slow. This is likely due to the difficulties of formulating hydrophilic, high molecular weight drugs, such as proteins and nucleic acids, for targeting specific cells, month-long sustained delivery, and pulsatile release. Since the approaches that have served well for delivery of small molecules are not applicable to large molecules, it is time to develop new methods for biologicals. The process of developing future drug delivery systems, termed as the invention cycle, is proposed, and it starts with clearly defining the problems for developing certain formulations. Once the problems are well-defined, creative imagination examines all potential options and selects the best answer and alternatives. Then, innovation takes over to generate unique solutions for developing new formulations that resolve the previously identified problems. Ultimately, the new delivery systems will have to go through a translational process to produce the final formulations for clinical use. The invention cycle also emphasizes examining the reasons for success of certain formulations, not just the reasons for failure of many systems. Implementation of the new invention cycle requires new mechanisms of funding the younger generation of scientists and a new way of identifying their achievements, thereby releasing them from the burden of short-termism. PMID- 26962899 TI - Menopause Management--Getting Clinical Care Back on Track. PMID- 26962900 TI - Uber's Message for Health Care. PMID- 26962901 TI - Stroke and t-PA--Triggering New Paradigms of Care. PMID- 26962903 TI - Trimethoprim-Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess. AB - BACKGROUND: U.S. emergency department visits for cutaneous abscess have increased with the emergence of methicillin-resistant Staphylococcus aureus (MRSA). The role of antibiotics for patients with a drained abscess is unclear. METHODS: We conducted a randomized trial at five U.S. emergency departments to determine whether trimethoprim-sulfamethoxazole (at doses of 320 mg and 1600 mg, respectively, twice daily, for 7 days) would be superior to placebo in outpatients older than 12 years of age who had an uncomplicated abscess that was being treated with drainage. The primary outcome was clinical cure of the abscess, assessed 7 to 14 days after the end of the treatment period. RESULTS: The median age of the participants was 35 years (range, 14 to 73); 45.3% of the participants had wound cultures that were positive for MRSA. In the modified intention-to-treat population, clinical cure of the abscess occurred in 507 of 630 participants (80.5%) in the trimethoprim-sulfamethoxazole group versus 454 of 617 participants (73.6%) in the placebo group (difference, 6.9 percentage points; 95% confidence interval [CI], 2.1 to 11.7; P=0.005). In the per-protocol population, clinical cure occurred in 487 of 524 participants (92.9%) in the trimethoprim-sulfamethoxazole group versus 457 of 533 participants (85.7%) in the placebo group (difference, 7.2 percentage points; 95% CI, 3.2 to 11.2; P<0.001). Trimethoprim-sulfamethoxazole was superior to placebo with respect to most secondary outcomes in the per-protocol population, resulting in lower rates of subsequent surgical drainage procedures (3.4% vs. 8.6%; difference, -5.2 percentage points; 95% CI, -8.2 to -2.2), skin infections at new sites (3.1% vs. 10.3%; difference, -7.2 percentage points; 95% CI, -10.4 to -4.1), and infections in household members (1.7% vs. 4.1%; difference, -2.4 percentage points; 95% CI, 4.6 to -0.2) 7 to 14 days after the treatment period. Trimethoprim sulfamethoxazole was associated with slightly more gastrointestinal side effects (mostly mild) than placebo. At 7 to 14 days after the treatment period, invasive infections had developed in 2 of 524 participants (0.4%) in the trimethoprim sulfamethoxazole group and in 2 of 533 participants (0.4%) in the placebo group; at 42 to 56 days after the treatment period, an invasive infection had developed in 1 participant (0.2%) in the trimethoprim-sulfamethoxazole group. CONCLUSIONS: In settings in which MRSA was prevalent, trimethoprim-sulfamethoxazole treatment resulted in a higher cure rate among patients with a drained cutaneous abscess than placebo. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00729937.). PMID- 26962905 TI - CLINICAL PRACTICE. Peripheral Artery Disease. PMID- 26962902 TI - Randomized Trial of Labor Induction in Women 35 Years of Age or Older. AB - BACKGROUND: The risk of antepartum stillbirth at term is higher among women 35 years of age or older than among younger women. Labor induction may reduce the risk of stillbirth, but it also may increase the risk of cesarean delivery, which already is common in this older age group. METHODS: We conducted a randomized, controlled trial involving primigravid women who were 35 years of age or older. Women were randomly assigned to labor induction between 39 weeks 0 days and 39 weeks 6 days of gestation or to expectant management (i.e., waiting until the spontaneous onset of labor or until the development of a medical problem that mandated induction). The primary outcome was cesarean delivery. The trial was not designed or powered to assess the effects of labor induction on stillbirth. RESULTS: A total of 619 women underwent randomization. In an intention-to-treat analysis, there were no significant between-group differences in the percentage of women who underwent a cesarean section (98 of 304 women in the induction group [32%] and 103 of 314 women in the expectant-management group [33%]; relative risk, 0.99; 95% confidence interval [CI], 0.87 to 1.14) or in the percentage of women who had a vaginal delivery with the use of forceps or vacuum (115 of 304 women [38%] and 104 of 314 women [33%], respectively; relative risk, 1.30; 95% CI, 0.96 to 1.77). There were no maternal or infant deaths and no significant between-group differences in the women's experience of childbirth or in the frequency of adverse maternal or neonatal outcomes. CONCLUSIONS: Among women of advanced maternal age, induction of labor at 39 weeks of gestation, as compared with expectant management, had no significant effect on the rate of cesarean section and no adverse short-term effects on maternal or neonatal outcomes. (Funded by the Research for Patient Benefit Programme of the National Institute for Health Research; Current Controlled Trials number, ISRCTN11517275.). PMID- 26962906 TI - IMAGES IN CLINICAL MEDICINE. Right Ventricular Infarction. PMID- 26962904 TI - Declines in Unintended Pregnancy in the United States, 2008-2011. AB - BACKGROUND: The rate of unintended pregnancy in the United States increased slightly between 2001 and 2008 and is higher than that in many other industrialized countries. National trends have not been reported since 2008. METHODS: We calculated rates of pregnancy for the years 2008 and 2011 according to women's and girls' pregnancy intentions and the outcomes of those pregnancies. We obtained data on pregnancy intentions from the National Survey of Family Growth and a national survey of patients who had abortions, data on births from the National Center for Health Statistics, and data on induced abortions from a national census of abortion providers; the number of miscarriages was estimated using data from the National Survey of Family Growth. RESULTS: Less than half (45%) of pregnancies were unintended in 2011, as compared with 51% in 2008. The rate of unintended pregnancy among women and girls 15 to 44 years of age declined by 18%, from 54 per 1000 in 2008 to 45 per 1000 in 2011. Rates of unintended pregnancy among those who were below the federal poverty level or cohabiting were two to three times the national average. Across population subgroups, disparities in the rates of unintended pregnancy persisted but narrowed between 2008 and 2011; the incidence of unintended pregnancy declined by more than 25% among girls who were 15 to 17 years of age, women who were cohabiting, those whose incomes were between 100% and 199% of the federal poverty level, those who did not have a high school education, and Hispanics. The percentage of unintended pregnancies that ended in abortion remained stable during the period studied (40% in 2008 and 42% in 2011). Among women and girls 15 to 44 years of age, the rate of unintended pregnancies that ended in birth declined from 27 per 1000 in 2008 to 22 per 1000 in 2011. CONCLUSIONS: After a previous period of minimal change, the rate of unintended pregnancy in the United States declined substantially between 2008 and 2011, but unintended pregnancies remained most common among women and girls who were poor and those who were cohabiting. (Funded by the Susan Thompson Buffett Foundation and the National Institutes of Health.). PMID- 26962907 TI - CLINICAL PROBLEM-SOLVING. Too Much of a Good Thing. PMID- 26962908 TI - Induction of Labor and Cesarean Delivery. PMID- 26962909 TI - CLINICAL DECISIONS. Skin Abscess. PMID- 26962910 TI - Burning Fat by Bugging the System. PMID- 26962911 TI - Treatment of Advanced Renal-Cell Carcinoma. PMID- 26962912 TI - Treatment of Advanced Renal-Cell Carcinoma. PMID- 26962913 TI - Treatment of Advanced Renal-Cell Carcinoma. PMID- 26962915 TI - Soluble Urokinase Receptor and Chronic Kidney Disease. PMID- 26962914 TI - Soluble Urokinase Receptor and Chronic Kidney Disease. PMID- 26962916 TI - Soluble Urokinase Receptor and Chronic Kidney Disease. PMID- 26962917 TI - Polymer-free Drug-Coated Coronary Stents. PMID- 26962918 TI - Polymer-free Drug-Coated Coronary Stents. PMID- 26962919 TI - Polymer-free Drug-Coated Coronary Stents. PMID- 26962920 TI - Polymer-free Drug-Coated Coronary Stents. PMID- 26962921 TI - Progesterone in Women with Recurrent Miscarriages. PMID- 26962922 TI - Progesterone in Women with Recurrent Miscarriages. PMID- 26962923 TI - Functional Dyspepsia. PMID- 26962924 TI - Functional Dyspepsia. PMID- 26962925 TI - Functional Dyspepsia. PMID- 26962926 TI - Functional Dyspepsia. PMID- 26962928 TI - IMAGES IN CLINICAL MEDICINE. Vertebral-Body Erosion in Thoracic Aortic Aneurysm. PMID- 26962927 TI - Tumor Regression and Allograft Rejection after Administration of Anti-PD-1. PMID- 26962934 TI - Kinetic limitation of chemical ordering in Bi2Te3-x Se x layers grown by molecular beam epitaxy. AB - We study the chemical ordering in Bi2Te3-x Se x grown by molecular beam epitaxy on Si substrates. We produce films in the full composition range from x = 0 to 3, and determine their material properties using energy dispersive x-ray spectroscopy, x-ray diffraction and Raman spectroscopy. By fitting the parameters of a kinetic growth model to these results, we obtain a consistent description of growth at a microscopic level. Our main finding is that despite the incorporation of Se in the central layer being much more probable than that of Te, the formation of a fully ordered Te-Bi-Se-Bi-Te layer is prevented by kinetic of the growth process. Indeed, the Se concentration in the central layer of Bi2Te2Se1 reaches a maximum of only ~ 75% even under ideal growth conditions. A second finding of our work is that the intensity ratio of the 0 0 12 and 0 0 6 x-ray reflections serves as an experimentally accessible quantitative measure of the degree of ordering in these films. PMID- 26962935 TI - Actin' on HIV: How Dendritic Cells Spread Infection. AB - Dendritic cells (DCs) capture HIV particles and transmit them to CD4 T cells. In a recent article published in Cell, Menager and Littman (2016) perform an shRNA screen in DCs and find that actin nucleation and stabilization regulate HIV uptake and maintain the virus on membrane protrusions for efficient transfer. PMID- 26962936 TI - The HIV-Associated Enteric Microbiome Has Gone Viral. AB - HIV infection is associated with dramatic alterations in enteric bacteria, but little is known about other microbiome components. In this issue of Cell Host & Microbe, studies by Monaco et al. (2016) and Handley et al. (2016) reveal an under-appreciated role of the enteric virome in HIV-associated gastroenteritis and pathogenesis. PMID- 26962937 TI - Type I Interferon Keeps IL-1beta in Check. AB - Type I interferons have diametric roles in the host defense against pathogens. In this issue of Cell Host & Microbe, Castiglia et al. (2016) demonstrate that type I interferons produced during Streptococcus pyogenes infection are required to prevent inflammation-associated tissue damage and host lethality driven by the pro-inflammatory cytokine IL-1beta. PMID- 26962938 TI - A Drug-Free Zone--Lymph Nodes as a Safe Haven for HIV. AB - Understanding where and how the HIV latent reservoir persists is essential for developing rational HIV cure strategies. In a recent paper in Nature, Lorenzo Redondo et al. (2016) demonstrate that HIV persists and actively evolves within lymph nodes due to low antiretroviral drug penetration, revealing the need to target these drug-privileged sites. PMID- 26962939 TI - CMV and NK Cells: An Unhealthy Tryst? AB - Cytomegalovirus (CMV) has been associated with autoimmune diseases, but linking this common virus to disease pathology has been difficult. In this issue of Cell Host & Microbe, Liu et al. (2016) identify a CMV-cross-reactive autoantibody that also recognizes CIP2A on natural killer cells, possibly affecting their function in autoimmune patients. PMID- 26962940 TI - Dissecting How CD4 T Cells Are Lost During HIV Infection. AB - Although the replicative life cycle of HIV within CD4 T cells is understood in molecular detail, less is known about how this human retrovirus promotes the loss of CD4 T lymphocytes. It is this cell death process that drives clinical progression to acquired immune deficiency syndrome (AIDS). Recent studies have highlighted how abortive infection of resting and thus nonpermissive CD4 T cells in lymphoid tissues triggers a lethal innate immune response against the incomplete DNA products generated by inefficient viral reverse transcription in these cells. Sensing of these DNA fragments results in pyroptosis, a highly inflammatory form of programmed cell death, that potentially further perpetuates chronic inflammation and immune activation. As discussed here, these studies cast CD4 T cell death during HIV infection in a different light. Further, they identify drug targets that may be exploited to both block CD4 T cell demise and the chronic inflammatory response generated during pyroptosis. PMID- 26962941 TI - Macrophages and HIV-1: An Unhealthy Constellation. AB - Lentiviruses have a long-documented association with macrophages. Abundant evidence exists for in vitro and, in a tissue-specific manner, in vivo infection of macrophages by the primate lentiviruses HIV-1 and SIV. However, macrophage contribution to aspects of HIV-1 and SIV pathogenesis, and their role in viral persistence in individuals on suppressive antiretroviral therapy, remains unclear. Here we discuss recent evidence implicating macrophages in HIV-1 mediated disease and highlight directions for further investigation. PMID- 26962942 TI - Altered Virome and Bacterial Microbiome in Human Immunodeficiency Virus Associated Acquired Immunodeficiency Syndrome. AB - Human immunodeficiency virus (HIV) infection is associated with increased intestinal translocation of microbial products and enteropathy as well as alterations in gut bacterial communities. However, whether the enteric virome contributes to this infection and resulting immunodeficiency remains unknown. We characterized the enteric virome and bacterial microbiome in a cohort of Ugandan patients, including HIV-uninfected or HIV-infected subjects and those either treated with anti-retroviral therapy (ART) or untreated. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and this increase was independent of ART treatment. Additionally, the enteric bacterial microbiome of patients with lower CD4 T counts exhibited reduced phylogenetic diversity and richness with specific bacteria showing differential abundance, including increases in Enterobacteriaceae, which have been associated with inflammation. Thus, immunodeficiency in progressive HIV infection is associated with alterations in the enteric virome and bacterial microbiome, which may contribute to AIDS-associated enteropathy and disease progression. PMID- 26962943 TI - SIV Infection-Mediated Changes in Gastrointestinal Bacterial Microbiome and Virome Are Associated with Immunodeficiency and Prevented by Vaccination. AB - AIDS caused by simian immunodeficiency virus (SIV) infection is associated with gastrointestinal disease, systemic immune activation, and, in cross-sectional studies, changes in the enteric virome. Here we performed a longitudinal study of a vaccine cohort to define the natural history of changes in the fecal metagenome in SIV-infected monkeys. Matched rhesus macaques were either uninfected or intrarectally challenged with SIV, with a subset receiving the Ad26 vaccine, an adenovirus vector expressing the viral Env/Gag/Pol antigens. Progression of SIV infection to AIDS was associated with increased detection of potentially pathogenic viruses and bacterial enteropathogens. Specifically, adenoviruses were associated with an increased incidence of gastrointestinal disease and AIDS related mortality. Viral and bacterial enteropathogens were largely absent from animals protected by the vaccine. These data suggest that the SIV-associated gastrointestinal disease is associated with the presence of both viral and bacterial enteropathogens and that protection against SIV infection by vaccination prevents enteropathogen emergence. PMID- 26962944 TI - HIV-1 Nucleocapsid Mimics the Membrane Adaptor Syntenin PDZ to Gain Access to ESCRTs and Promote Virus Budding. AB - HIV-1 recruits cellular endosomal sorting complexes required for transport (ESCRTs) to bud virions from the membrane. Disruption of the viral nucleocapsid (NC) domain integrity affects HIV-1 budding. However, the molecular mechanisms of NC's involvement in HIV budding remain unclear. We find that NC mimics the PDZ domains of syntenin, a membrane-binding adaptor involved in cell-to-cell contact/communication, to capture the Bro1 domain of ALIX, which is an ESCRTs recruiting cellular adaptor. NC binds membranes via basic residues in either the distal or proximal zinc fingers, and NC-membrane binding is essential for Bro1 capture and HIV-1 budding. Removal of RNA enhances NC membrane binding, suggesting a dynamic competition between membrane lipids and RNA for the same binding sites in NC. Remarkably, syntenin PDZ can substitute for NC function in HIV-1 budding. Thus, NC mimics syntenin PDZs to function as a membrane-binding adaptor critical for HIV-1 budding at specific microdomains of the membrane. PMID- 26962945 TI - Phosphatidic Acid-Mediated Signaling Regulates Microneme Secretion in Toxoplasma. AB - The obligate intracellular lifestyle of apicomplexan parasites necessitates an invasive phase underpinned by timely and spatially controlled secretion of apical organelles termed micronemes. In Toxoplasma gondii, extracellular potassium levels and other stimuli trigger a signaling cascade culminating in phosphoinositide-phospholipase C (PLC) activation, which generates the second messengers diacylglycerol (DAG) and IP3 and ultimately results in microneme secretion. Here we show that a delicate balance between DAG and its downstream product, phosphatidic acid (PA), is essential for controlling microneme release. Governing this balance is the apicomplexan-specific DAG-kinase-1, which interconverts PA and DAG, and whose depletion impairs egress and causes parasite death. Additionally, we identify an acylated pleckstrin-homology (PH) domain containing protein (APH) on the microneme surface that senses PA during microneme secretion and is necessary for microneme exocytosis. As APH is conserved in Apicomplexa, these findings highlight a potentially widely used mechanism in which key lipid mediators regulate microneme exocytosis. PMID- 26962946 TI - Type I Interferon Signaling Prevents IL-1beta-Driven Lethal Systemic Hyperinflammation during Invasive Bacterial Infection of Soft Tissue. AB - Type I interferons (IFN-Is) are fundamental for antiviral immunity, but their role in bacterial infections is contradictory and incompletely described. Streptococcus pyogenes activates IFN-I production in innate immune cells, and IFN I receptor 1 (Ifnar1)-deficient mice are highly susceptible to S. pyogenes infection. Here we report that IFN-I signaling protects the host against invasive S. pyogenes infection by restricting inflammation-driven damage in distant tissues. Lethality following infection in Ifnar1-deficient mice is caused by systemically exacerbated levels of the proinflammatory cytokine IL-1beta. Critical cellular effectors of IFN-I in vivo are LysM+ and CD11c+ myeloid cells, which exhibit suppression of Il1b transcription upon Ifnar1 engagement. These cells are also the major source of IFN-beta, which is significantly induced by S. pyogenes 23S rRNA in an Irf5-dependent manner. Our study establishes IL-1beta and IFN-I levels as key homeostatic variables of protective, yet tuned, immune responses against severe invasive bacterial infection. PMID- 26962948 TI - A Cytomegalovirus Peptide-Specific Antibody Alters Natural Killer Cell Homeostasis and Is Shared in Several Autoimmune Diseases. AB - Human cytomegalovirus (hCMV), a ubiquitous beta-herpesvirus, has been associated with several autoimmune diseases. However, the direct role of hCMV in inducing autoimmune disorders remains unclear. Here we report the identification of an autoantibody that recognizes a group of peptides with a conserved motif matching the Pp150 protein of hCMV (anti-Pp150) and is shared among patients with various autoimmune diseases. Anti-Pp150 also recognizes the single-pass membrane protein CIP2A and induces the death of CD56(bright) NK cells, a natural killer cell subset whose expansion is correlated with autoimmune disease. Consistent with this finding, the percentage of circulating CD56(bright) NK cells is reduced in patients with several autoimmune diseases and negatively correlates with anti Pp150 concentration. CD56(bright) NK cell death occurs via both antibody- and complement-dependent cytotoxicity. Our findings reveal that a shared hCMV-induced autoantibody is involved in the decrease of CD56(bright) NK cells and may thus contribute to the onset of autoimmune disorders. PMID- 26962947 TI - Bacterial Peptidoglycan Traverses the Placenta to Induce Fetal Neuroproliferation and Aberrant Postnatal Behavior AB - Maternal infection during pregnancy is associated with adverse outcomes for the fetus, including postnatal cognitive disorders. However, the underlying mechanisms are obscure. We find that bacterial cell wall peptidoglycan (CW), a universal PAMP for TLR2, traverses the murine placenta into the developing fetal brain. In contrast to adults, CW-exposed fetal brains did not show any signs of inflammation or neuronal death. Instead, the neuronal transcription factor FoxG1 was induced, and neuroproliferation leading to a 50% greater density of neurons in the cortical plate was observed. Bacterial infection of pregnant dams, followed by antibiotic treatment, which releases CW, yielded the same result. Neuroproliferation required TLR2 and was recapitulated in vitro with fetal neuronal precursor cells and TLR2/6, but not TLR2/1, ligands. The fetal neuroproliferative response correlated with abnormal cognitive behavior in CW exposed pups following birth. Thus, the bacterial CW-TLR2 signaling axis affects fetal neurodevelopment and may underlie postnatal cognitive disorders. PMID- 26962951 TI - Figure/Ground Segmentation via a Haptic Glance: Attributing Initial Finger Contacts to Objects or Their Supporting Surfaces. AB - The current study addresses the well-known "figure/ground" problem in human perception, a fundamental topic that has received surprisingly little attention from touch scientists to date. Our approach is grounded in, and directly guided by, current knowledge concerning the nature of haptic processing. Given inherent figure/ground ambiguity in natural scenes and limited sensory inputs from first contact (a "haptic glance"), we consider first whether people are even capable of differentiating figure from ground (Experiments 1 and 2). Participants were required to estimate the strength of their subjective impression that they were feeling an object (i.e., figure) as opposed to just the supporting structure (i.e., ground). Second, we propose a tripartite factor classification scheme to further assess the influence of kinetic, geometric (Experiments 1 and 2), and material (Experiment 2) factors on haptic figure/ground segmentation, complemented by more open-ended subjective responses obtained at the end of the experiment. Collectively, the results indicate that under certain conditions it is possible to segment figure from ground via a single haptic glance with a reasonable degree of certainty, and that all three factor classes influence the estimated likelihood that brief, spatially distributed fingertip contacts represent contact with an object and/or its background supporting structure. PMID- 26962950 TI - High Expression of Cullin7 Correlates with Unfavorable Prognosis in Epithelial Ovarian Cancer Patients. AB - Ubiquitin ligase Cullin7 has been has been suggested to act as an oncogene in some tumors; however, the prognostic role of Cullin7 has not been evaluated in cancer patients. In this study, we observed that the expression of Cullin7 mRNA was significantly higher in epithelial ovarian cancer (EOC) compared with normal ovarian surface tissues. In addition, Cullin7 expression was related to FIGO stage (p = .001) and lymph node metastasis (p = .033). Furthermore, Cullin7 overexpression inhibited the migration and invasion of ovarian cancer cells. These results suggest that Cullin7 may serve as an indicator of poor prognosis in patients with EOC. PMID- 26962953 TI - Perception and Haptic Rendering of Friction Moments. AB - This paper considers moments due to friction forces on the human fingertip. A computational technique called the friction moment arc method is presented. The method computes the static and/or dynamic friction moment independent of a friction force calculation. In addition, a new finger holder to display friction moment is presented. This device incorporates a small brushless motor and disk, and connects the human's finger to an interface finger of the five-fingered haptic interface robot HIRO II. Subjects' perception of friction moment while wearing the finger holder, as well as perceptions during object manipulation in a virtual reality environment, were evaluated experimentally. PMID- 26962952 TI - Five-Fingered Haptic Interface Robot: HIRO III. AB - This paper presents the design and characteristics of a five-fingered haptic interface robot named HIRO III. The aim of the development of HIRO III is to provide a high-precision three-directional force at the five human fingertips. HIRO III consists of a 15-degrees-of-freedom (DOF) haptic hand, a 6-DOF interface arm, and a control system. The haptic interface, which consists of a robot arm and hand, can be used in a large workspace and can provide multipoint contact between the user and a virtual environment. However, the following problems peculiar to a multi-DOF robot have arisen: a large amount of friction, a backlash, and the presence of many wires for many motors and sensors. To solve these problems, a new mechanism and a wire-saving control system have been designed and developed. Furthermore, several experiments have been carried out to investigate the performance of HIRO III. These results show the high-precision force display and great potential of HIRO III. PMID- 26962949 TI - A Broad RNA Virus Survey Reveals Both miRNA Dependence and Functional Sequestration. AB - Small non-coding RNAs have emerged as key modulators of viral infection. However, with the exception of hepatitis C virus, which requires the liver-specific microRNA (miRNA)-122, the interactions of RNA viruses with host miRNAs remain poorly characterized. Here, we used crosslinking immunoprecipitation (CLIP) of the Argonaute (AGO) proteins to characterize strengths and specificities of miRNA interactions in the context of 15 different RNA virus infections, including several clinically relevant pathogens. Notably, replication of pestiviruses, a major threat to milk and meat industries, critically depended on the interaction of cellular miR-17 and let-7 with the viral 3' UTR. Unlike canonical miRNA interactions, miR-17 and let-7 binding enhanced pestivirus translation and RNA stability. miR-17 sequestration by pestiviruses conferred reduced AGO binding and functional de-repression of cellular miR-17 targets, thereby altering the host transcriptome. These findings generalize the concept of RNA virus dependence on cellular miRNAs and connect virus-induced miRNA sequestration to host transcriptome regulation. PMID- 26962955 TI - The Role of Haptics in Medical Training Simulators: A Survey of the State of the Art. AB - This review paper discusses the role of haptics within virtual medical training applications, particularly, where it can be used to aid a practitioner to learn and practice a task. The review summarizes aspects to be considered in the deployment of haptics technologies in medical training. First, both force/torque and tactile feedback hardware solutions that are currently produced commercially and in academia are reviewed, followed by the available haptics-related software and then an in-depth analysis of medical training simulations that include haptic feedback. The review is summarized with scrutiny of emerging technologies and discusses future directions in the field. PMID- 26962954 TI - Physics-Based Haptic Simulation of Bone Machining. AB - We present a physics-based training simulator for bone machining. Based on experimental studies, the energy required to remove a unit volume of bone is a constant for every particular bone material. We use this physical principle to obtain the forces required to remove bone material with a milling tool rotating at high speed. The rotating blades of the tool are modeled as a set of small cutting elements. The force of interaction between a cutting element and bone is calculated from the energy required to remove a bone chip with an estimated thickness and known material stiffness. The total force acting on the cutter at a particular instant is obtained by integrating the differential forces over all cutting elements engaged. A voxel representation is used to represent the virtual bone and removed chips for calculating forces of machining. We use voxels that carry bone material properties to represent the volumetric haptic body and to apply underlying physical changes during machining. Experimental results of machining samples of a real bone confirm the force model. A real-time haptic implementation of the method in a dental training simulator is described. PMID- 26962956 TI - Haptic Recognition of Emotions in Raised-Line Drawings by Congenitally Blind and Sighted Adults. AB - 15 sighted and 15 congenitally blind adults were to classify raised-line pictures of emotional faces through haptics. Whereas accuracy did not vary significantly between the two groups, the blind adults were faster at the task. These results suggest that raised-line pictures of emotional faces are intelligible to blind adults. PMID- 26962957 TI - Adult-onset phenylketonuria with rapidly progressive dementia and parkinsonism. AB - Phenylketonuria (PKU) is an autosomal recessive metabolic disorder due to mutations in the phenylalanine hydroxylase (PAH) gene, which converts phenylalanine (PHE) to tyrosine. Although it is principally a childhood disorder, in rare cases, the first signs of PKU may develop in late adulthood resembling common neurological diseases. Here we report a 59-year-old, previously normal functioning man who was admitted with blurred vision, cognitive problems, and gait difficulty that began 8 months before. He had brisk reflexes and left side dominant parkinsonism. His Mini-Mental State Examination (MMSE) score was 25/30, and neuropsychological evaluation revealed a dysexecutive syndrome with simultanagnosia and constructional apraxia. His Clinical Dementia Rating score (CDR) was 1. Cranial MRI revealed bilateral diffuse hyperintense lesions in parietal and occipital white matter in T2, fluid-attenuated inversion recovery, and diffusion weighted images. Diagnostic workup for rapidly progressive dementias was all normal except PHE level which was found to be highly elevated (1075 MUmol/L, normal 39-240 MUmol/L) with normal tyrosine level (61.20 MUmol/L, normal 35-100 MUmol/L). Three months after PHE-restricted diet, his cognitive impairment and signs of parkinsonism significantly improved, with MRI scan unchanged. This case demonstrates that late-onset PKU is a rare, treatable cause of rapidly progressive dementia and parkinsonism with certain constellations such as consanguinity and white matter abnormalities (WMAs) in imaging. PMID- 26962958 TI - The quantification of game-induced muscle fatigue in amputee soccer players. AB - BACKGROUND: This study quantified the degree of game-induced muscular fatigue in amputee soccer players. METHODS: Thirty-three male amputee soccer players performed muscular tests (Push Up Test [PUT], Countermovement Jump Test [CMJ] and medicine-ball throw [MBT]) before and after a competitive match. Five players served as a control group. The rating of perceived exertion was recorded after each battery. RESULTS: Control group demonstrated no differences between the two testing batteries (P>0.05, effect size [ES]: 0.1-0.4). However, match group illustrated markedly lower performances for PUT (-17%, P<0.01, ES: 0.9) with less pronounced declines in MBT (-8%, P<0.01, ES: 0.7) and CMJ (-5%, P<0.01, ES: 0.3) compared to pre-match values. The rating of perceived exertion were higher after the match compared to baseline values (+60%, P<0.01, ES: 2.4). CONCLUSIONS: The data demonstrate that the fatigue experienced after amputee soccer matches causes impairments in muscular performance and this could be different to able-bodied players. PMID- 26962960 TI - Listening to accented speech in a second language: First language and age of acquisition effects. AB - Bilingual speakers must acquire the phonemic inventory of 2 languages and need to recognize spoken words cross-linguistically; a demanding job potentially made even more difficult due to dialectal variation, an intrinsic property of speech. The present work examines how bilinguals perceive second language (L2) accented speech and where accommodation to dialectal variation takes place. Dialectal effects were analyzed at different levels: An AXB discrimination task tapped phonetic-phonological representations, an auditory lexical-decision task tested for effects in accessing the lexicon, and an auditory priming task looked for semantic processing effects. Within that central focus, the goal was to see whether perceptual adjustment at a given level is affected by 2 main linguistic factors: bilinguals' first language and age of acquisition of the L2. Taking advantage of the cross-linguistic situation of the Basque language, bilinguals with different first languages (Spanish or French) and ages of acquisition of Basque (simultaneous, early, or late) were tested. Our use of multiple tasks with multiple types of bilinguals demonstrates that in spite of very similar discrimination capacity, French-Basque versus Spanish-Basque simultaneous bilinguals' performance on lexical access significantly differed. Similarly, results of the early and late groups show that the mapping of phonetic phonological information onto lexical representations is a more demanding process that accentuates non-native processing difficulties. L1 and AoA effects were more readily overcome in semantic processing; accented variants regularly created priming effects in the different groups of bilinguals. (PsycINFO Database Record PMID- 26962961 TI - The role of verb repetition in cumulative structural priming in comprehension. AB - Recently processed syntactic information is likely to play a fundamental role in online sentence comprehension. For example, there is now a good deal of evidence that the processing of a syntactic structure (the target) is facilitated if the same structure was processed on the immediately preceding trial (the prime), a phenomenon known as structural priming. However, compared with structural priming in production, structural priming in comprehension remains relatively understudied. We investigate an aspect of structural priming in comprehension that is comparatively well understood in production but has received little attention in comprehension: the cumulative effect of structural primes on subsequently processed sentences. We further ask whether this effect is modulated by lexical overlap between preceding primes and the target. In 3 self-paced reading experiments, we find that structural priming effects in comprehension are cumulative and of similar magnitude both with and without lexical overlap. We discuss the relevance of our results to questions about the relationship between recent experience and online language processing. (PsycINFO Database Record PMID- 26962959 TI - Difficulty in learning similar-sounding words: A developmental stage or a general property of learning? AB - How are languages learned, and to what extent are learning mechanisms similar in infant native-language (L1) and adult second-language (L2) acquisition? In terms of vocabulary acquisition, we know from the infant literature that the ability to discriminate similar-sounding words at a particular age does not guarantee successful word-meaning mapping at that age (Stager & Werker, 1997). However, it is unclear whether this difficulty arises from developmental limitations of young infants (e.g., poorer working memory) or whether it is an intrinsic part of the initial word learning, L1 and L2 alike. In this study, we show that adults of particular L1 backgrounds-just like young infants-have difficulty learning similar-sounding L2 words that they can nevertheless discriminate perceptually. This suggests that the early stages of word learning, whether L1 or L2, intrinsically involve difficulty in mapping similar-sounding words onto referents. We argue that this is due to an interaction between 2 main factors: (a) memory limitations that pose particular challenges for highly similar sounding words, and (b) uncertainty regarding the language's phonetic categories, because the categories are being learned concurrently with words. Overall, our results show that vocabulary acquisition in infancy and adulthood shares more similarities than previously thought, thus supporting the existence of common learning mechanisms that operate throughout the life span. (PsycINFO Database Record PMID- 26962962 TI - Life Expectancy of People with Fetal Alcohol Syndrome. AB - OBJECTIVES: To estimate the life expectancy and specify the causes of death among people with fetal alcohol syndrome (FAS). METHODS: Included were all patients recorded in Alberta provincial databases of inpatients, outpatients, or practitioner claims from 2003 to 2012. People with FAS were identified by ICD-9 code 760.71 and ICD-10 codes Q86.0 and P04.3, and were linked to the Vital Statistics Death Registry to get information about mortality. Life expectancy was estimated by using the life table template developed in the United Kingdom, which is recommended for estimating life expectancy in small areas or populations. RESULTS: The life expectancy at birth of people with FAS was 34 years (95% confidence interval: 31 to 37 years), which was about 42% of that of the general population. The leading causes of death for people with FAS were "external causes" (44%), which include suicide (15%), accidents (14%), poisoning by illegal drugs or alcohol (7%), and other external causes (7%). Other common causes of death were diseases of the nervous and respiratory systems (8% each), diseases of the digestive system (7%), congenital malformations (7%), mental and behavioural disorders (4%), and diseases of the circulatory system (4%). CONCLUSION: The life expectancy of people with FAS is considerably lower than that of the general population. As the cause of FAS is known and preventable, more attention devoted to the prevention of FAS is urgently needed. PMID- 26962963 TI - Increased von Willebrand factor, P-selectin and fibrin content in occlusive thrombus resistant to lytic therapy. AB - Therapeutic fibrinolysis is ineffective in 40 % of ST-segment elevation acute myocardial infarction (STEMI) patients, but understanding of the mechanisms is incomplete. It was our aim to compare the composition of coronary thrombus in lysis-resistant STEMI patients with that of lysis-sensitive patients. Intracoronary thrombi (n=64) were obtained by aspiration in consecutive STEMI patients. Of them, 20 had received fibrinolysis and underwent rescue percutaneous coronary intervention (r-PCI, lysis-resistant patients) and 44 underwent primary PCI (p-PCI). Lysis-sensitivity was determined in vitro by clot permeability measurements and turbidimetric lysis in plasma of 44 patients undergoing p-PCI and 20 healthy donors. Clot-lysis sensitivity was defined as a clot-lysis time not greater than 1 SD over the mean of healthy donors. Coronary thrombus composition in 20 lysis-resistant and in 20 lysis-sensitive patients was analysed by immunofluorescence with confocal microscopy. Plasma biomarkers (P-selectin, VWF, PAI-1, t-PA, D-dimer, TF pathway markers, plasmin and CD34+) were measured simultaneously on peripheral blood. Lysis-resistant clots had higher levels of fibrin (p=0.02), P-selectin (p=0.03) and VWF (p=0.01) than lysis-sensitive clots. Among thrombi obtained <= 6 hours after onset of symptoms, those from lysis resistant patients showed a higher content in fibrin than those from p-PCI patients (p=0.01). Plasma PAI-1 (p=0.02) and D-dimer levels were significantly higher (p=0.003) in lysis-resistant patients, whereas plasmin levels were lower (p=0.03). Multivariate analysis showed the content of fibrin and VWF within thrombus as predictors of thrombolysis resistance. In conclusion, coronary thrombi in STEMI patients resistant to fibrinolysis are characterised by higher fibrin, P-selectin and VWF content than lysis-sensitive thrombi. PMID- 26962965 TI - Lead and manganese levels in serum and erythrocytes in Alzheimer's disease and mild cognitive impairment: results from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. AB - We examined serum and erythrocyte lead and manganese levels in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL), which contains over 1000 registrants including over 200 cases of Alzheimer's disease (AD) and 100 mildly cognitively impaired (MCI) individuals. After correcting for confounding effects of age, collection site and sex, we found a significant decrease in serum manganese levels in AD subjects compared to healthy controls. Analysis of smaller subset of erythrocytes revealed no difference in either lead or manganese levels in AD. Although lead and manganese have neurotoxic effects and may be involved in AD pathology, our results showed that neither metal in serum nor erythrocytes are suitable biomarkers in our cohort. However, prospective studies might reveal whether the burden of either metal modifies disease outcomes. PMID- 26962966 TI - Hybrid plasmonic gap modes in metal film-coupled dimers and their physical origins revealed by polarization resolved dark field spectroscopy. AB - Plasmonic gap modes sustained by metal film-coupled nanostructures have recently attracted extensive research attention due to flexible control over their spectral response and significantly enhanced field intensities at the particle film junction. In this work, by adopting an improved dark field spectroscopy methodology - polarization resolved spectral decomposition and colour decoding - we are able to "visualize" and distinguish unambiguously the spectral and far field radiation properties of the complex plasmonic gap modes in metal film coupled nanosphere monomers and dimers. Together with full-wave numerical simulation results, it is found that while the monomer-film system supports two hybridized dipole-like plasmon modes having different oscillating orientations and resonance strengths, the scattering spectrum of the dimer-film system features two additional peaks, one strong yet narrow resonant mode corresponding to a bonding dipolar moment and one hybridized higher order resonant mode, both polarized along the dimer axis. In particular, we demonstrate that the polarization dependent scattering radiation of the film-coupled nanosphere dimer can be used to optically distinguish from monomers and concurrently determine the spatial orientation of the dimer with significantly improved accuracy at the single-particle level, illustrating a simple yet highly sensitive plasmon resonance based nanometrology method. PMID- 26962967 TI - Free-Standing Photonic Crystal Films with Gradient Structural Colors. AB - Hydrogel colloidal crystal composite materials have a demonstrated value in responsive photonic crystals (PhCs) via controllable stimuli. Although they have been successfully exploited to generate a gradient of color distribution, the soft hydrogels have limitations in terms of stability and storage caused by dependence on environment. Here, we present a practical strategy to fabricate free-standing PhC films with a stable gradient of structural colors using binary polymer networks. A colloidal crystal hydrogel film was prepared for this purpose, with continuously varying photonic band gaps corresponding to the gradient of the press. Then, a second polymer network was used to lock the inside non-close-packed PhC structures and color distribution of the hydrogel film. It was demonstrated that our strategy could bring about a solution to the angle dependent structural colors of the PhC films by coating the surface with special microstructures. PMID- 26962968 TI - Evaluation of Pericardial Fluid C-Type Natriuretic Peptide Levels in Patients Undergoing Coronary Bypass Surgery. AB - Background Neurohumoral and hemodynamic mechanisms have an effect on cardiac activity. C-type natriuretic peptide (CNP) is accessible in the cardiovascular system. The aim of this study was to determine whether CNP concentrations in pericardial fluid and blood are related to cardiac dysfunction in patients undergoing coronary artery bypass graft surgery. Materials and Methods In this study, 40 patients undergoing coronary artery bypass grafting were enrolled. The patients were separated into two groups according to left ventricular (LV) ejection fraction (EF): group 1 contained 28 patients with normal LV systolic function (LVEF >= 50%) and group 2 contained 12 patients with impaired LV systolic function (LVEF < 45%). Plasma and pericardial fluid samples were acquired during surgery to measure CNP levels. Results In group 1, CNP levels were detected to be 0.46 +/- 0.10 ng/mL in plasma and 0.66 +/- 0.8 ng/mL in pericardial liquid. In group 2, these levels were 0.51 +/- 0.09 and 0.79 +/- 0.12 ng/mL, respectively. CNP levels were determined to be significantly higher in patients with low EF compared with those with normal EF in pericardial fluid concentrations (p = 0.013). Conclusions CNP level in pericardial fluid is a more sensitive and proper marker of LV dysfunction than CNP levels in plasma. To the best of our knowledge, this study is the first to examine pericardial fluid CNP levels in patients undergoing coronary artery bypass surgery. It may have a valuable role in organizing cardiac remodeling and hypertrophy. PMID- 26962970 TI - Diastereomerization Dynamics of a Bistridentate Ru(II) Complex. AB - The unsymmetrical nature of a new tridentate ligand bis(quinolinyl)-1,3-pyrazole (DQPz) is exploited in a bistridentate Ru(II) complex [Ru(DQPz)2](2+) to elucidate an unexpected dynamic diastereomerism. Structural characterization based on a combination of nuclear magnetic resonance spectroscopy and density functional theory calculations reveals the first quantifiable diastereomerization dynamics for Ru complexes with fully conjugated tridentate heteroaromatic ligands. A mechanism that involves a large-scale twisting motion of the ligands is proposed to explain the dynamic interconversion between the observed diastereomers, and the analysis of both experiments and calculations reveals a potential energy landscape with a transition barrier for the diastereomerization of ~70 kJ mol(-1). The structural flexibility demonstrated around the central transition metal ion has implications for integration of complexes into catalytic and photochemical applications. PMID- 26962969 TI - Forty-Two Years' Experience with Pulmonary Resections of Metastases from Colorectal Cancer. AB - Background Pulmonary metastasectomy is a commonly performed surgery in patients with controlled metastatic colorectal cancer (CRC). We reviewed our long-term single institution experience with lung resections for colorectal metastases to assess the factors influencing patient survival. Materials and Methods A cohort of 220 patients (138 men and 82 women; median age, 59 years) who underwent complete pulmonary metastasectomy for CRC with curative intent between 1972 and 2014 was retrospectively analyzed. The impact of factors related to primary tumor, metastases, and associated therapy on patient survival was assessed. Results Two postoperative inhospital deaths occurred. The median interoperative interval was 26 months. The overall 5-year survival rate after pulmonary metastasectomy was 49.4%. In univariable analysis, bilateral pulmonary metastases (log rank p = 0.02), multiple metastases (log rank p = 0.005), and stage IV UICC (the International Union Against Cancer) CRC at the time of initial presentation (log rank p = 0.008) were significantly associated with poor outcome. Multivariable Cox analysis demonstrated that stage IV CRC (p = 0.02) and multiple metastases (p = 0.0019) were statistically significant predictors of survival after the pulmonary metastasectomy. There was no significant difference in survival between patients with high versus low preoperative carcinoembryonic antigen serum level (p = 0.149), high versus low preoperative carbohydrate antigen 19-9 serum level (p = 0.291), and primary tumor location in rectum versus colon (p = 0.845). Conclusion Patients with unilateral metastasis and stages I to III primary tumor benefited most from pulmonary metastasectomy for CRC. PMID- 26962971 TI - The use of lasers in cutaneous sarcoid: Is there a role? AB - Sarcoid is a granulomatous disease that can affect the skin solely or as part of a systemic involvement. Cutaneous lesions of sarcoid may be difficult to treat and lasers are rarely used. In this article we report our case series and review the literature on the use of lasers in cutaneous sarcoid. PMID- 26962972 TI - Cardiovascular and other causes of death as a function of lifestyle habits in a quasi extinct middle-aged male population. A 50-year follow-up study. AB - OBJECTIVES: To relate major causes of death with lifestyle habits in an almost extinct male middle-aged population. MATERIAL AND METHODS: A 40-59 aged male population of 1712 subjects was examined and followed-up for 50 years. Baseline smoking habits, working physical activity and dietary habits were related to 50 years mortality subdivided into 12 simple and 3 composite causes of death by Cox proportional hazard models. Duration of survival was related to the same characteristics by a multiple linear regression model. RESULTS: Death rate in 50 years was of 97.5%. Out of 12 simple groups of causes of death, 6 were related to smoking habits, 3 to physical activity and 4 to dietary habits. Among composite groups of causes of death, hazard ratios (and their 95% confidence limits) of never smokers versus smokers were 0.68 (0.57-0.81) for major cardiovascular diseases; 0.65 (0.52-0.81) for all cancers; and 0.72 (0.64-0.81) for all-cause deaths. Hazard ratios of vigorous physical activity at work versus sedentary physical activity were 0.63 (0.49-0.80) for major cardiovascular diseases; 1.01 (0.72-1.41) for all cancers; and 0.76 (0.64-0.90) for all-cause deaths. Hazard ratios of Mediterranean Diet versus non-Mediterranean Diet were 0.68 (0.54-0.86) for major cardiovascular diseases; 0.54 (0.40-0.73) for all cancers; and 0.67 (0.57-0.78) for all-cause deaths. Expectancy of life was 12 years longer for men with the 3 best behaviors than for those with the 3 worst behaviors. CONCLUSIONS: Some lifestyle habits are strongly related to lifetime mortality. PMID- 26962973 TI - Formation Mechanism of Fe Nanocubes by Magnetron Sputtering Inert Gas Condensation. AB - In this work, we study the formation mechanisms of iron nanoparticles (Fe NPs) grown by magnetron sputtering inert gas condensation and emphasize the decisive kinetics effects that give rise specifically to cubic morphologies. Our experimental results, as well as computer simulations carried out by two different methods, indicate that the cubic shape of Fe NPs is explained by basic differences in the kinetic growth modes of {100} and {110} surfaces rather than surface formation energetics. Both our experimental and theoretical investigations show that the final shape is defined by the combination of the condensation temperature and the rate of atomic deposition onto the growing nanocluster. We, thus, construct a comprehensive deposition rate-temperature diagram of Fe NP shapes and develop an analytical model that predicts the temporal evolution of these properties. Combining the shape diagram and the analytical model, morphological control of Fe NPs during formation is feasible; as such, our method proposes a roadmap for experimentalists to engineer NPs of desired shapes for targeted applications. PMID- 26962975 TI - Coevolution of adolescent friendship networks and smoking and drinking behaviors with consideration of parental influence. AB - Friendship tie choices in adolescent social networks coevolve simultaneously with youths' cigarette smoking and drinking. We estimate direct and multiplicative relationships between both peer influence and peer selection with salient parental factors affecting both friendship tie choice and the use of these 2 substances. We utilize 1 sample of 12 small schools and a single large school extracted from the National Longitudinal Study of Adolescent to Adult Health. Using a Stochastic Actor-Based modeling approach over 3 waves, we find: (a) a peer selection effect, as adolescents nominated others as friends based on cigarette and alcohol use levels across samples; (b) a peer influence effect, as adolescents adapted their smoking and drinking behaviors to those of their best friends across samples; (c) reciprocal effect between cigarette and alcohol usage in the small school sample; (d) a direct effect of parental support and the home smoking environment on adolescent friendship tie choice in the small school sample; (e) a direct effect of the home smoking environment on smoking across samples; (f) a direct effect of the home drinking environment on alcohol use across samples; and (g) a direct effect of parental monitoring on alcohol use across samples. We observed an interaction between parental support and peer influence in affecting drinking, and an interaction between the home drinking environment and peer influence on drinking, in the small school sample. Our findings suggested the importance of delineating direct and synergistic pathways linking network processes and parental influence as they affect concurrent cigarette and alcohol use. (PsycINFO Database Record PMID- 26962976 TI - Enhanced removal of Cr(VI) from aqueous solutions using polypyrrole wrapped oxidized MWCNTs nanocomposites adsorbent. AB - Polypyrrole wrapped oxidized multiwalled carbon nanotubes nanocomposites (PPy/OMWCNTs NCs) were prepared via in situ chemical polymerization of pyrrole (Py) monomer in the presence of OMWCNTs using FeCl3 as oxidant for the effective removal of hexavalent chromium [Cr(VI)]. The as-prepared PPy/OMWCNTs NCs were characterized by FE-SEM, HR-TEM, ATR-FTIR, XRD, XPS and BET method. Characterization results suggested that PPy was uniformly covered on the OMWCNTs surface and resulted in enhanced specific surface area. Adsorption experiments were carried out in batch sorption mode to investigate the effect of pH, dose of adsorbent, contact time, concentration of Cr(VI) and temperature. The adsorption of Cr(VI) on the nanocomposite surface was highly pH dependent and the kinetics of the adsorption followed the pseudo-second-order model. The adsorption isotherm data were in good conformity with the Langmuir isothermal model. The maximum adsorption capacity of the PPy/OMWCNTs NCs for Cr(VI) was 294mg/g at 25 degrees C. The calculated values of the thermodynamic parameters such as DeltaG(0) ( 0.237kJ/mol), DeltaH(0) (13.237kJ/mol) and DeltaS(0) (0.0452kJ/mol/K) revealed that the adsorption process is spontaneous, endothermic and marked with an increase in randomness at the solid-liquid interface. The presence of co-existing ions slightly affected the Cr(VI) removal efficiency of the PPy/OMWCNTs. PMID- 26962974 TI - Moderating effects of perceived social benefits on inhalant initiation among American Indian and White youth. AB - This study examined whether perceived social benefits moderated the relationship between social influence variables (school attachment, peer inhalant use, perceived family caring, and parental monitoring) and stage of inhalant initiation (Study 1) and lifetime inhalant use (Study 2). Participants were 7th to 12th grade students attending schools on or near American Indian reservations, with comparisons made between American Indian and White students. A total of 3,498 American Indian and 1,596 White students were surveyed. Differences in mean levels of social influence variables were found across ethnicity and stage of inhalant initiation and lifetime inhalant use. Structural equation models were evaluated to examine variable relationships for the 2 studies. For Study 1, social influence variables did not clearly differentiate early versus later inhalant initiators, and perceived social benefits failed to serve as a moderator. More differences were observed between users and nonusers across measures of social influence (Study 2). Perceived social benefits generally did not moderate the relationships, with 2 exceptions. Low perceived social benefits provided greater protection against the influence of peers on lifetime inhalant use among White students, whereas high perceived social benefits increased risk of peer influence among American Indian students. (PsycINFO Database Record PMID- 26962977 TI - Green synthesis of seashell supported silver nanoparticles using Bunium persicum seeds extract: Application of the particles for catalytic reduction of organic dyes. AB - In the present work, silver nanoparticles were immobilized on the surface of seashell using Bunium persicum seeds extract as a reducing and stabilizing agent. The seashell supported silver nanoparticles was characterized by FT-IR spectroscopy, X-ray diffraction (XRD) pattern, field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM) and Thermogravimetric-differential thermal analysis (TG DTA). The diameter of Ag NPs on the seashell was predominantly found within the range 20-50nm. The catalytic performance of the prepared catalyst was investigated for reduction of 4-Nitrophenol (4-NP), Methyl Orange (MO), Congo Red (CR) and Methylene Blue (MB) at room temperature. It was found that the Ag NPs/seashell is a highly active and recyclable catalyst for related reactions and can be recovered and reused several times without significant loss of its catalytic activity. PMID- 26962978 TI - Silica nanoparticles functionalized with polyamidoamine (PAMAM) dendrimers as platforms for photoluminescence (PL) sensing of copper and cyanide ions. AB - Functionalized nanoparticles for photoluminescence (PL) applications are a promising technology for biomedical imaging and as sensors for small molecules. This work presents a new method to modify silica nanoparticles (SNP) using the bifunctional linker 1,1'-carbonyldiimidazole (CDI) with a series of polyamidoamine (PAMAM) dendrimer molecules followed by grafting of fluorescein isothiocyanate (FITC) or rhodamine B isothiocyanate (RITC) to create platforms for photoluminescence (PL) sensors. A dendrimer size and charge-variable response to only copper(II) ions confirmed the prediction of a selective turn-off sensor via proximity quenching. Both dye density and Cu(2+) quenching efficiency peaked with SNP-dendrimer generation 4 (64 terminal amines). In addition, changing the terminal dendrimer arms to carboxylic acid end groups increased the copper quenching suggesting that more metal ion binding sites were created in close proximity to the dyes. Of the small anions tested for a turn-off sensor, only cyanide ion fully restored the PL when reaching a 2:1 CN(-):Cu(2+) ratio, while EDTA was not as effective at the same ratio. Therefore, dendrimer size and surface charge on the nanoparticles controlled the dye loading and copper quenching efficiency, while creating multiple binding sites for cyanide over other metal binding anions. PMID- 26962980 TI - Design of a 3T preamplifier which stability is insensitive to coil loading. AB - In MRI (magnetic resonance imaging), preamplifiers are needed to amplify signals obtained from MRI receiver coils. Under various loading conditions of the corresponding receiver coils, preamplifiers see different source impedance at their input and may become unstable. Therefore preamplifiers which stability is not sensitive to coil loading are desirable. In this article, a coil-loading insensitive preamplifier for MRI is presented, derived from an unstable preamplifier. Different approaches to improve stability were used during this derivation. Since a very low noise factor is essential for MRI preamplifiers, noise contributions from passive components in the MRI preamplifier have to be considered during the stabilization process. As a result, the initially unstable preamplifier became stable with regard to coil loading, while other MRI requirements, as the extremely low noise factor, were still fulfilled. The newly designed preamplifier was manufactured, characterized and tested in the MRI spectrometer. Compared to a commercially available preamplifier, the newly designed preamplifier has similar imaging performance but other advantages like smaller size and better stability. Furthermore, presented stabilization approaches can be generalized to stabilize other unstable low-noise amplifiers. PMID- 26962979 TI - Characterizing implicit mental health associations across clinical domains. AB - BACKGROUND AND OBJECTIVES: Implicit associations are relatively uncontrollable associations between concepts in memory. The current investigation focuses on implicit associations in four mental health domains (alcohol use, anxiety, depression, and eating disorders) and how these implicit associations: a) relate to explicit associations and b) self-reported clinical symptoms within the same domains, and c) vary based on demographic characteristics (age, gender, race, ethnicity, and education). METHODS: Participants (volunteers over age 18 to a research website) completed implicit association (Implicit Association Tests), explicit association (self + psychopathology or attitudes toward food, using semantic differential items), and symptom measures at the Project Implicit Mental Health website tied to: alcohol use (N = 12,387), anxiety (N = 21,304), depression (N = 24,126), or eating disorders (N = 10,115). RESULTS: Within each domain, implicit associations showed small to moderate associations with explicit associations and symptoms, and predicted self-reported symptoms beyond explicit associations. In general, implicit association strength varied little by race and ethnicity, but showed small ties to age, gender, and education. LIMITATIONS: This research was conducted on a public research and education website, where participants could take more than one of the studies. CONCLUSIONS: Among a large and diverse sample, implicit associations in the four domains are congruent with explicit associations and self-reported symptoms, and also add to our prediction of self-reported symptoms over and above explicit associations, pointing to the potential future clinical utility and validity of using implicit association measures with diverse populations. PMID- 26962981 TI - Edoxaban, a direct factor Xa inhibitor, suppresses tissue-factor induced human platelet aggregation and clot-bound factor Xa in vitro: Comparison with an antithrombin-dependent factor Xa inhibitor, fondaparinux. AB - INTRODUCTION: Tissue factor-induced platelet aggregation and factor Xa (FXa) activity bound to clot contribute to the formation and growth of thrombus. The effects of edoxaban, a direct FXa inhibitor, on these responses were determined and compared with that of fondaparinux, an antithrombin-dependent (indirect) FXa inhibitor. MATERIAL AND METHODS: Human platelet aggregation was induced by human tissue factor (Dade Innovin or RecombiPlasTin) in platelet-rich plasma spiked with edoxaban or fondaparinux. Clot formed from human whole blood was incubated with 0.9MUM prothrombin in the absence or presence of FXa inhibitors. As the index of FXa activity, the amount of prothrombin fragment F1+2 was measured with an ELISA. Free FXa activity was measured using human FXa and its chromogenic substrate S-2222. RESULTS: Edoxaban inhibited tissue factor-induced platelet aggregation in a concentration-dependent manner with the IC50 values of 150 and 110nM for Dade Innovin and RecombiPlasTin-induced platelet aggregation, respectively. At 1MUM, edoxaban completely inhibited the aggregation. Fondaparinux inhibited RecombiPlasTin-induced aggregation with the IC50 of 9.3MUM, but did not show complete inhibition up to 30MUM and had no effect on Dade Innovin-induced aggregation. Edoxaban inhibited both free and clot-bound FXa with the IC50 of 2.3 and 8.2nM, respectively. Fondaparinux inhibited free FXa (IC50 5.4nM), but 40-times higher concentration were required to inhibit clot bound FXa (IC50 217nM). CONCLUSIONS: Edoxaban, a direct FXa inhibitor, was a more potent inhibitor of tissue factor-induced platelet aggregation and clot-bound FXa than fondaparinux, an indirect FXa inhibitor. PMID- 26962982 TI - Isotypic analysis of antibodies against activated Factor VII in patients with Factor VII deficiency using the x-MAP technology. AB - While the immune response to hemophilic factors in hemophilia has been widely studied, little is known about the development of anti-Factor VII (FVII) antibodies in FVII deficiency. We developed a robust technique based on the x-MAP technology to detect the presence of antibodies against FVII and characterize their isotype and validated this method using blood samples from 100 patients with FVII deficiency (median FVII clotting activity [FVII:C]: 6%) and 95 healthy controls. Anti-FVII antibodies were detected in patients but also in some controls, although the concentration of total immunoglobulin G (IgGt) and IgG1 and IgG4 subclasses was significantly different between groups. The IgG1 subclass concentrations remained significantly different also when only untreated patients were compared with controls. This difference could partially be related to the F7 genotype, particularly in patients harboring the p.Arg139Gln mutation. This x-MAP based method might be useful for assessing the immunogenicity of novel FVII compounds and of activated FVII (FVIIa) concentrates. Further prospective studies are needed to better understand the clinical relevance of these antibodies in the management of patients with FVII deficiency. PMID- 26962983 TI - Association of PEAR1 genetic variants with platelet reactivity in response to dual antiplatelet therapy with aspirin and clopidogrel in the Chinese patient population after percutaneous coronary intervention. AB - INTRODUCTION: Platelet Endothelial Aggregation Receptor-1 (PEAR1) is a recently reported platelet transmembrane protein which plays an important role in platelet aggregation. The aim of this study was to investigate whether PEAR1 genetic variations were associated with platelet reactivity as assessed by adenosine diphosphate(ADP)-induced platelet aggregation in Chinese patients treated with aspirin and clopidogrel. METHODS: Patients with coronary heart disease (CHD) who underwent percutaneous coronary intervention (PCI) were enrolled in the study. All patients were on dual antiplatelet therapy with aspirin and clopidogrel. ADP induced platelet aggregation was measured by thromboelastography and defined as percent inhibition of platelet aggregation (IPA). Patients (n=204) with IPA <30% were identified as high on-treatment platelet reactivity (HPR). Patients (n=201) with IPA >70% were identified as low on-treatment platelet reactivity (LPR). Sixteen single nucleotide polymorphisms (SNPs) of PEAR1 were determined by a method of improved multiple ligase detection reaction. RESULTS: Among the 16 SNPs examined by univariate analysis, 5 SNPs were significantly associated with ADP induced platelet aggregation. Minor allele C at rs11264580 (p=0.033), minor allele G at rs2644592 (p=0.048), minor allele T at rs3737224 (p=0.033) and minor allele T at rs41273215 (p=0.025) were strongly associated with HPR, whereas homozygous TT genotype at rs57731889 (p=0.009) was associated with LPR. Multivariate logistic regression analysis further revealed that the minor allele T at rs41273215 (p=0.038) was an independent predictor of HPR and the homozygous TT genotype at rs57731889 (p=0.003) was an independent predictor of LPR. CONCLUSIONS: PEAR1 genetic variations were strongly associated with ADP-induced platelet aggregation in Chinese patients with CHD treated with aspirin and clopidogrel. These genetic variations may contribute to the variability in platelet function. The utility of PEAR1 genetic variants in the assessment and prediction of cardiovascular risk warrants further investigation. PMID- 26962984 TI - Risk factors for venous thromboembolism in adults with hemoglobin SC or Sbeta(+) thalassemia genotypes. AB - INTRODUCTION: Venous thromboembolism (VTE) is common in sickle cell disease (SCD); however, the risk factors associated with VTE in patients with sickle variant syndromes are not known. The primary aim of this study was to determine hematologic and clinical risk factors for VTE in adults with hemoglobin SC or Sbeta(+) thalassemia genotypes. MATERIALS AND METHODS: We conducted a retrospective cross-sectional analysis of patients with hemoglobin SC and Sbeta(+) thalassemia genotypes followed at the Sickle Cell Center for Adults from 2008 to 2012. Data on baseline hematologic parameters and SCD-specific comorbidities were collected from review of electronic records. RESULTS: A total of 116 patients, 85 (73%) with hemoglobin SC disease and 31 (27%) with Sbeta(+) thalassemia, were included for analysis. Thirty-two (28%) patients had a verified history of non-catheter related VTE. Mean baseline hemoglobin levels were higher among individuals with a history of VTE compared to those without (11.7g/dL vs. 11.0g/dL, p=0.003). In addition, the prevalence of surgical splenectomy was higher among patients with VTE compared to those without (25.0% vs. 4.8%, p=0.001). On multivariate analysis, elevated baseline hemoglobin (odds ratio [OR] 2.45 (95% confidence interval [CI] 1.42-4.23)) and history of surgical splenectomy (OR 5.76 [CI 1.43-23.22]) were independently associated with VTE risk. CONCLUSIONS: Higher baseline hemoglobin is a risk factor for non-catheter related VTE in patients with hemoglobin SC or Sbeta(+) thalassemia genotypes. Surgical splenectomy, which is a known risk factor for VTE in other hemoglobinopathies such as beta-thalassemia intermedia, is also associated with VTE in sickle variant syndromes. Future studies are needed to validate these findings and to investigate the mechanisms of hypercoagulability observed in patients with hemoglobin SC and Sbeta(+) thalassemia. PMID- 26962995 TI - Fibulin-5 as a potential therapeutic target in COPD. PMID- 26962996 TI - Use of evidence-based assessment for childhood anxiety disorders in community practice. AB - High-quality assessment is essential to the delivery of effective treatment for childhood anxiety disorders. However, relatively little is known about how frequently child clinicians utilize evidence-based assessment (EBA) techniques in practice, and even less is known about the factors that influence EBA use in such settings. Thus, the current study presents data from a survey of 339 clinicians from a variety of professional backgrounds concerning their use of EBA for childhood anxiety disorders and explores issues preventing EBA implementation. Results indicated infrequent EBA use with clinicians citing practical barriers (i.e., time, access, knowledge, cost) and negative beliefs about EBA techniques (i.e., unhelpful) as issues preventing implementation. Implications for future EBA dissemination and implementation efforts are discussed. PMID- 26962997 TI - Epigenetic alteration of imprinted genes during neural differentiation of germline-derived pluripotent stem cells. AB - Spermatogonial stem cells (SSCs), which are unipotent stem cells in the testes that give rise to sperm, can be converted into germline-derived pluripotent stem (gPS) by self-induction. The androgenetic imprinting pattern of SSCs is maintained even after their reprogramming into gPS cells. In this study, we used an in vitro neural differentiation model to investigate whether the imprinting patterns are maintained or altered during differentiation. The androgenetic patterns of H19, Snrpn, and Mest were maintained even after differentiation of gPS cells into NSCs (gPS-NSCs), whereas the fully unmethylated status of Ndn in SSCs was altered to somatic patterns in gPS cells and gPS-NSCs. Thus, our study demonstrates epigenetic alteration of genomic imprinting during the induction of pluripotency in SSCs and neural differentiation, suggesting that gPS-NSCs can be a useful model to study the roles of imprinted genes in brain development and human neurodevelopmental disorders. PMID- 26962998 TI - Teacher ratings of resilience and peer relationships of preschoolers whose fathers died unexpectedly. AB - This study endeavors to compare resilience and peer relationships of children who lost their fathers in a major mining accident in Soma with those who did not. Teachers rated 51 preschoolers whose fathers died, and 53 preschoolers whose fathers were alive. On the negative side, bereaved children had lower resilience and higher exclusion; on the positive side, bereaved children had lower peer victimization and higher prosocial behavior. Death of fathers is associated with lower resilience and more exclusion among young children, but others treat them better as well. PMID- 26962999 TI - Photophysics of the LOV-Based Fluorescent Protein Variant iLOV-Q489K Determined by Simulation and Experiment. AB - Light, oxygen, voltage (LOV) based fluorescent proteins (FPs) represent a promising alternative to fluorescent reporters of the green fluorescent protein family. For certain applications like multicolor imaging or the design of FRET based biosensors, the generation of spectrally shifted LOV-based FPs would be required. In a recent theoretical study ( Khrenova J. Phys. Chem. B 2015 , 119 ( 16 ), pp 5176 - 5183 ), the photophysical properties of a variant of the LOV based fluorescent protein iLOV were predicted using quantum mechanics/molecular mechanics (QM/MM) approaches. The variant contained a lysine residue at the position of a highly conserved glutamine residue (Q489K), which directly interacts with the O4 and N5 atom of the flavin mononucleotide (FMN) chromophore. On the basis of QM/MM calculations, iLOV-Q489K was suggested to possess substantially red-shifted absorption and fluorescence-emission maxima with respect to parental iLOV. Here, we describe the experimental characterization of this variant, which, surprisingly contrary to the theoretical prediction, shows blue-shifted absorption and fluorescence-emission maxima. Using molecular dynamics (MD) simulations and QM/MM calculations, the molecular basis for the contradictory theoretical and experimental results is presented. Essentially, our computational analysis suggests that, in the Q489K variant, two possible side chain conformers exist: (i) a least populated conformer K489in forming a hydrogen bond with the O4 atom of FMN chromophore and (ii) a most populated conformer K489out with the side-chain amino group flipped away from the FMN chromophore forming a new hydrogen bond with the backbone oxygen of G487. QM/MM calculated spectra of the K489out conformer are blue-shifted compared to the calculated spectra of parental iLOV, which is in accordance with experimental data. This suggests that the change in the conformation of K489 from K498in to K489out accounts for the change in the direction of the spectral shift from red to blue, thus reconciling theory and experiment. PMID- 26963000 TI - Cytomegalovirus-Related Hospitalization Is Associated With Adverse Outcomes and Increased Health-Care Resource Utilization in Inflammatory Bowel Disease. AB - OBJECTIVES: Impact of cytomegalovirus (CMV)-related hospitalization in inflammatory bowel disease (IBD) patients is unknown. The aim of this study was to determine hospital outcomes of CMV-related hospitalization in IBD patients in a large national in-patient administrative data set. METHODS: This was a cross sectional study using data from the Nationwide In-patient Sample database. IBD- and CMV-related hospitalizations between 2003 and 2011 were identified using appropriate ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) codes. Impact of CMV-related hospitalization on in hospital mortality, length of stay (LOS), and hospital charges were quantified. RESULTS: CMV-related hospitalization was associated with higher in-hospital mortality (odds ratio (OR) 7.09, 95% confidence interval (CI) 3.38-14.85), prolonged LOS (7.77 days, P<0.0001), and more hospital charge (US$66,495, P<0.0001) in IBD patients. CONCLUSIONS: CMV-related hospitalization in IBD is associated with high in-hospital mortality, prolonged LOS, and hospital care costs. PMID- 26963002 TI - Expression Profiles of miRNA Subsets Distinguish Human Colorectal Carcinoma and Normal Colonic Mucosa. AB - OBJECTIVES: MicroRNAs (miRNAs) are small, non-protein-coding RNA molecules that are commonly dysregulated in colorectal tumors. The objective of this study was to identify smaller subsets of highly predictive miRNAs. METHODS: Data come from population-based studies of colorectal cancer conducted in Utah and the Kaiser Permanente Medical Care Program. Tissue samples were available for 1,953 individuals, of which 1,894 had carcinoma tissue and 1,599 had normal mucosa available for statistical analysis. Agilent Human miRNA Microarray V.19.0 was used to generate miRNA expression profiles; validation of expression levels was carried out using quantitative PCR. We used random forest analysis and verified findings with logistic modeling in separate data sets. Important microRNAs are identified and bioinformatics tools are used to identify target genes and related biological pathways. RESULTS: We identified 16 miRNAs for colon and 17 miRNAs for rectal carcinoma that appear to differentiate between carcinoma and normal mucosa; of these, 12 were important for both colon and rectal cancer, hsa-miR 663b, hsa-miR-4539, hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-21-5p, hsa-miR-4506, hsa-miR-92a-3p, hsa-miR-93-5p, hsa-miR-145-5p, hsa-miR-3651, hsa-miR-378a-3p, and hsa-miR-378i. Estimated misclassification rates were low at 4.83% and 2.5% among colon and rectal observations, respectively. Among independent observations, logistic modeling reinforced the importance of these miRNAs, finding the primary principal components of their variation statistically significant (P<0.001 among both colon and rectal observations) and again producing low misclassification rates. Repeating our analysis without those miRNAs initially identified as important identified other important miRNAs; however, misclassification rates increased and distinctions between remaining miRNAs in terms of classification importance were reduced. CONCLUSIONS: Our data support the hypothesis that while many miRNAs are dysregulated between carcinoma and normal mucosa, smaller subsets of these miRNAs are useful and informative in discriminating between these tissues. PMID- 26963001 TI - Tracking the Correlation Between CpG Island Methylator Phenotype and Other Molecular Features and Clinicopathological Features in Human Colorectal Cancers: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: The controversy of CpG island methylator phenotype (CIMP) in colorectal cancers (CRCs) persists, despite many studies that have been conducted on its correlation with molecular and clinicopathological features. To drive a more precise estimate of the strength of this postulated relationship, a meta analysis was performed. METHODS: A comprehensive search for studies reporting molecular and clinicopathological features of CRCs stratified by CIMP was performed within the PubMed, EMBASE, and Cochrane Library. CIMP was defined by either one of the three panels of gene-specific CIMP markers (Weisenberger panel, classic panel, or a mixture panel of the previous two) or the genome-wide DNA methylation profile. The associations of CIMP with outcome parameters were estimated using odds ratio (OR) or weighted mean difference (WMD) or hazard ratios (HRs) with 95% confidence interval (CI) for each study using a fixed effects or random effects model. RESULTS: A total of 29 studies involving 9,393 CRC patients were included for analysis. We observed more BRAF mutations (OR 34.87; 95% CI, 22.49-54.06) and microsatellite instability (MSI) (OR 12.85 95% CI, 8.84-18.68) in CIMP-positive vs. -negative CRCs, whereas KRAS mutations were less frequent (OR 0.47; 95% CI, 0.30-0.75). Subgroup analysis showed that only the genome-wide methylation profile-defined CIMP subset encompassed all BRAF mutated CRCs. As expected, CIMP-positive CRCs displayed significant associations with female (OR 0.64; 95% CI, 0.56-0.72), older age at diagnosis (WMD 2.77; 95% CI, 1.15-4.38), proximal location (OR 6.91; 95% CI, 5.17-9.23), mucinous histology (OR 3.81; 95% CI, 2.93-4.95), and poor differentiation (OR 4.22; 95% CI, 2.52-7.08). Although CIMP did not show a correlation with tumor stage (OR 1.10; 95% CI, 0.82-1.46), it was associated with shorter overall survival (HR 1.73; 95% CI, 1.27-2.37). CONCLUSIONS: The meta-analysis highlights that CIMP positive CRCs take their own molecular feature, especially overlapping with BRAF mutations, and clinicopathological features and worse prognosis from CIMP negative CRCs, suggesting CIMP could be used as an independent prognostic marker for CRCs. PMID- 26963003 TI - Investigation of the antigen recognition and presentation capacity of pecteneal hyalocytes in the chicken (gallus gallus domesticus). AB - We investigated at different developmental stages the antigen recognition and presentation capacity of pecteneal hyalocytes that adhere to the pecten oculi in the eye of domestic chickens. Forty-eight fertilized eggs were used to investigate embryonic stages and 12 6-week-old chickens were used to investigate adults. Tissue samples from both embryos and adults were stained with monoclonal antibodies against MHC-II, TLR2/CD282 and TLR4, and also with RCA-1, WGA and SNA lectins. The developmental stage of the pecteneal hyalocytes was determined using Masson's triple staining. Pecteneal hyalocytes first appeared at Hamburger Hamilton stages 30 34 and remained unchanged from their first appearance to adulthood. Chicken pecteneal hyalocytes were stained by monoclonal antibodies against TLR2 and TLR4, and were unstained by monoclonal antibodies for MHC-II. Hyalocytes were positive for RCA-I, WGA and SNA lectins. We found that pecteneal hyalocytes that adhere to the pecten oculi in domestic chickens recognized antigens, but could not present them. These cells have been assumed to be of monocyte/macrophage lineage; their functions in the immune response are not fully understood. PMID- 26963004 TI - Epidemiologic, Clinicopathologic, Diagnostic, and Management Challenges of Pityriasis Rubra Pilaris: A Case Series of 100 Patients. AB - IMPORTANCE: Pityriasis rubra pilaris (PRP) is a rare papulosquamous disorder with limited epidemiologic and clinicopathologic data. Little information is available on long-term outcomes, comorbidities, and treatment efficacy. OBJECTIVE: To evaluate objective and subjective disease experience metrics from the perspectives of patients and clinicians. DESIGN, SETTING, AND PARTICIPANTS: One hundred patients with a putative diagnosis of PRP and who elected to participate completed a comprehensive survey, followed by acquisition of their medical records, including histopathology slides and reports. The data were analyzed separately from the health care clinician and the patient perspectives. Two academic dermatologists examined clinical notes, pathology reports, and photographs, confirming diagnoses via predetermined criteria. Patients were categorized into 4 levels of diagnostic certainty to allow stratification of the findings for subgroup analysis. Patients with a diagnosis of PRP were solicited through patient support organization websites. MAIN OUTCOMES AND MEASURES: Clinical outcomes, unexpected association of comorbidities, and efficacy (or lack of it) of various treatment modalities. RESULTS: Among the 100 patients, 50 were diagnosed as having classic, unquestionable PRP. The patients were a median of 61 years old (range, 5-87 years), and 46% were female. Fifty were categorized as level 1 diagnostic certainty, 15 as level 2, 30 as level 3, and 5 as level 4. Of the level 1 patients, 13 (26%) were correctly diagnosed at initial presentation; diagnosis was delayed, on average, by 29 months (range, 0.25-288 months; median, 2 months); and 27 (54%) having undergone 2 or more biopsies. At enrollment, PRP symptoms had persisted in 36 patients (72%) for an average of 58 months (range, 1 300 months; median, 30 months). Thirty-one patients (62%) had comorbidities, including hypothyroidism (20%). Nearly all patients (98%) received some form of therapy. Patients cited topical emollients, corticosteroids, and salicylic acid along with oral retinoids, methotrexate, and tumor necrosis factor inhibitors as most helpful. CONCLUSIONS AND RELEVANCE: Pityriasis rubra pilaris remains a challenging diagnosis without established and specific treatment. Our data highlight new potential avenues for research with therapeutic perspective. PMID- 26963007 TI - ACSM Clinician Profile. PMID- 26963005 TI - Hydrothermal gases in a shallow aquifer at Mt. Amiata, Italy: insights from stable isotopes and geochemical modelling. AB - We investigate the interaction between hydrothermal gases and groundwater in a major aquifer exploited for potable supply in the geothermal-volcanic area of Mt. Amiata, Central Italy. Two springs and two wells located on different sides of the volcanic edifice have been repeatedly sampled over the last 11 years. More than 160 chemical analyses and 10 isotopic analyses of total dissolved carbon (delta(13)C - total dissolved inorganic carbon (TDIC) = -15.9 to -7.8 0/00 vs. V PDB) and sulphate (delta(34)S-SO4 = -6.9 to 5.1 0/00 vs. V-CDT) have been processed with geochemical modelling techniques. Best-fitting conditions between analytical data and model outputs have been achieved by numerical optimization, allowing for a quantitative description of gas-water-rock interactions occurring in this aquifer. Numerical calculations support a conceptual model that considers water-rock interactions to occur in the volcanic aquifer after inflow of deep seated gases (CO2(g) and H2S(g)), and total conversion of H2S(g) to SO4, in the absence of mixing with geothermal waters from reservoirs currently exploited for electricity generation. PMID- 26963006 TI - Preparticipation Cardiovascular Screening--Finding the Middle Ground. PMID- 26963008 TI - Never Take Your Heart by Surprise: Heart Attack Triggers. PMID- 26963010 TI - Thoracic Outlet Syndrome. PMID- 26963011 TI - Sacral Stress Fractures: They See You, But Are You Seeing Them? PMID- 26963012 TI - Boxer Safety: Reducing System Errors in the Ring. PMID- 26963013 TI - Cardiovascular Screening in Young Athletes: Evidence for the Electrocardiogram. AB - : The objective of this study is to review the evidence for cardiovascular screening inclusive of an electrocardiogram (ECG) in young athletes. Sudden cardiac death (SCD) in athletes is the leading cause of death during exercise and occurs at a rate that is substantially higher than initially recognized. There is widespread agreement that cardiovascular screening should be performed prior to athletic competition. The primary purpose of preparticipation cardiovascular screening is to identify athletes with conditions that predispose them to SCD. Unfortunately, the traditional model in the United States of a medical history and a physical examination has limited sensitivity to detect cardiovascular disease and provides false reassurance to athletes, parents, and team officials. The addition of an ECG enhances the ability to identify disease, and modern athlete-specific ECG interpretation standards used by experienced physicians provide low false-positive rates, improving the cost-effectiveness while preserving sensitivity. The evidence is clear that if athletes are screened, ECG inclusive strategies are most likely to meet the primary aim of preparticipation cardiovascular screening. These advanced protocols have the potential to improve health and safety during sport events and should be considered the best practice in high-risk athletes when the sports cardiology infrastructure and oversight are readily available. PMID- 26963014 TI - The Evidence Against Cardiac Screening Using Electrocardiogram in Athletes. AB - Sudden cardiac death (SCD) in young athletes is publicly remarkable and tragic because of the loss of a seemingly healthy young person. Because many of the potential etiologies may be identified with a preparticipation electrocardiogram (ECG), the possible use of an ECG as a screening tool has received much attention. A good screening test should be cost-effective and should influence a disease or health outcome that has a significant impact on public health. The reality is that the prevalence of SCD is low and no outcome-based data exist to determine whether early detection saves lives. Further, there is insufficient screening infrastructure, and the risk of screening and follow-up may be higher than that of the actual disease. Until outcomes data demonstrate a benefit with regard to SCD, universal screening cannot be recommended. PMID- 26963015 TI - The Use of Musculoskeletal Ultrasound for the Diagnosis of Groin and Hip Pain in Athletes. AB - Athletes are particularly predisposed to injuries in the groin and pelvic region. Men in particular are predisposed to injuries like hernias in the inguinal region. The increased demands and training load on today's athletes combined with individual factors may create the environment for these injuries. Five areas categorize the pain present from different pathological entities in this region: adductor-related, iliopsoas-related, inguinal-related, pubic-related, and hip related groin pain. It has been extremely difficult in the past to accurately diagnose what has been previously labeled sports hernia, sportsman's groin, or inguinal disruption. Therefore, this article describes the methods and procedures used for diagnostic ultrasound (US) and differentiation between these entities from one practice based on the most current research in musculoskeletal US. PMID- 26963016 TI - Drowning Injuries: An Update on Terminology, Environmental Factors, and Management. PMID- 26963017 TI - A Tale of Two Heat Strokes: A Comparative Case Study. PMID- 26963018 TI - Tick-Borne Illnesses. AB - Tick-borne diseases are prevalent throughout the United States. These illnesses are caused by a variety of different pathogens that use ticks as vectors, including bacteria, viruses, rickettsia, and protozoa. Some of the most common illnesses caused by ticks are Lyme disease, Rocky Mountain spotted fever, babesiosis, ehrlichiosis, anaplasmosis, tularemia, Colorado tick fever, tick borne relapsing fever, and Powassan disease. Unique skin changes, fever, and influenza-like symptoms may indicate tick-borne disease. Early diagnosis can be difficult as well as nonspecific and can resemble overtraining syndrome. Diagnosis is important to facilitate early treatment to decrease morbidity and mortality and should often be initiated before a definitive diagnosis is made. Treatment guidelines are published by the Centers for Disease Control and Prevention. As tick-borne diseases increase and their geographic regions expand, it is important for providers to distinguish the often overlapping and diverse presentations of these diseases. PMID- 26963020 TI - Acupuncture for the Treatment of Sports Injuries in an Austere Environment. AB - For sports injuries in an austere environment, narcotic pain medications are often unavailable or have limiting side effects like sedation or constipation. Meanwhile, nonsteroidal anti-inflammatory medications are frequently associated with gastrointestinal side effects and acetaminophen liver toxicity. A trained physician can rapidly use certain acupuncture techniques in an austere environment with potentially fewer side effects. Current medical literature notes low to moderate quality evidence for the use of acupuncture in lower back pain and osteoarthritis of the knee. There is emerging evidence for the use of acupuncture in traumatic brain injury. The U.S. military uses acupuncture in deployed settings to treat battlefield injuries with promising results. This article reviews the military's current use of acupuncture to treat injuries in a deployed setting and how this may translate to the care of a sports injury in an austere environment. PMID- 26963019 TI - Wilderness Travel in Nonpregnant Females: Differences in Physiology, Counseling, and Common Issues. AB - Interest in wilderness travel has been increasing in women of all ages and can lead to multiple health benefits. In order to optimize a woman's experience in the wilderness, providers should be aware of both common and special conditions unique to women that may be impacted by wilderness travel. Both anatomic and physiologic differences set women apart from men and should be carefully considered in a wilderness setting. Special conditions pertaining to women in the wilderness include high altitude exposure and temperature sensitivity. Before wilderness travel, each patient should complete a physical examination, review medical history with a provider, and receive an overview of counseling for their desired area of travel. PMID- 26963021 TI - Spinal Cord Injuries in Wave-Riding Sports: The Influence of Environmental and Sport-Specific Factors. AB - Spinal cord injury is a nonfatal, catastrophic consequence of wave-riding sports. With surfing at the core, a multitude of activities have evolved that attempt to harness the power of ocean waves. The unique qualities of each wave-riding sport, in combination with the environmental factors of the ocean, define the risk for potential injuries. As wave-riding sports have become more advanced, athletes continue to push physical barriers. Taller waves are attempted while incorporating aerial maneuvers, all without protective equipment. PMID- 26963022 TI - Asymmetric Alkylation of N-Sulfonylbenzamides with Vinyl Ethers via C-H Bond Activation Catalyzed by Hydroxoiridium/Chiral Diene Complexes. AB - Asymmetric alkylation of N-sulfonylbenzamides with vinyl ethers via a directed C H bond activation gave high yields of the corresponding addition products with high branch- and enantioselectivity. PMID- 26963023 TI - Exploring the Relationship Between Resilience and Ostomy Adjustment in Adults With a Permanent Ostomy. AB - PURPOSE: The aims of this study were to describe the relationship between resilience and ostomy adjustment in adults with permanent stomas and to determine if participants who report higher levels of resilience also report higher levels of adjustment to a permanent ostomy. DESIGN: Descriptive, correlational research design utilizing the Roy Adaptation Model as the theoretical framework was used. SUBJECTS AND SETTING: Persons with permanent stomas were recruited from ostomy support groups on the East Coast of the United States. The study sample included 48 respondents. Their mean age was 66 +/- 12.7 years (mean +/- SD); the majority (60.4%) were women, had an ileostomy (62.5%), and had a history of inflammatory bowel disease (62.5%). METHODS: Respondents completed a questionnaire that queried demographic and pertinent clinical data, along with 2 previously validated instruments, the Resilience Scale and Ostomy Adjustment Inventory-23. The relationships between levels of resilience, levels of adjustment to an ostomy, and demographic characteristics were examined. RESULTS: Participants with higher levels of ostomy adjustment had higher levels of resilience than respondents who reported lower levels of ostomy adjustment (r = 0.65, P <= .01). CONCLUSIONS: Findings from this study suggest that higher levels of resilience facilitate adjustment to a permanent ostomy. PMID- 26963024 TI - Quality of Life in US Residents With Ostomies Assessed via the SF36v2: Role Physical, Bodily Pain, and General Health Domain. AB - PURPOSE: The purpose of this study was to investigate the physical-role, bodily pain, and general health domains of health-related quality of life in the adult with ostomies living in the United States and to compare findings to population based norms established using the Short Form 36 version 2 (SF36v2). SUBJECTS AND SETTING: Study participants were identified by randomly sampling from proprietary databases. Within the United States, 2,329 completed the survey for a response rate of 14.9% and a margin of error of 2.03%. METHODS: Secondary analysis of data from a propietary database. RESULTS: A greater proportion of persons living with an ostomy experienced limitations in the physical component summary levels of the SF36v2, indicating greater impairment than the general population. In contrast, no differences in pain interference with work or other activities reductions were found between the 2 groups. Persons with ostomies reported similar levels of general health, but they were more likely to indicate they "got sick a little easier than others." CONCLUSIONS: Persons with ostomies report more limitations in physical activities than do individuals within the general population. In contrast, they were no more likely to report bodily pain than the general population of the United States, and no more likely to indicate pain interferes with physical activity than the general population. Additional research is needed to elucidate the nature of these limitations and potential interventions to ameliorate these effects of ostomy creation. PMID- 26963025 TI - Insulin-degrading enzyme secretion from astrocytes is mediated by an autophagy based unconventional secretory pathway in Alzheimer disease. AB - The secretion of proteins that lack a signal sequence to the extracellular milieu is regulated by their transition through the unconventional secretory pathway. IDE (insulin-degrading enzyme) is one of the major proteases of amyloid beta peptide (Abeta), a presumed causative molecule in Alzheimer disease (AD) pathogenesis. IDE acts in the extracellular space despite having no signal sequence, but the underlying mechanism of IDE secretion extracellularly is still unknown. In this study, we found that IDE levels were reduced in the cerebrospinal fluid (CSF) of patients with AD and in pathology-bearing AD-model mice. Since astrocytes are the main cell types for IDE secretion, astrocytes were treated with Abeta. Abeta increased the IDE levels in a time- and concentration dependent manner. Moreover, IDE secretion was associated with an autophagy-based unconventional secretory pathway, and depended on the activity of RAB8A and GORASP (Golgi reassembly stacking protein). Finally, mice with global haploinsufficiency of an essential autophagy gene, showed decreased IDE levels in the CSF in response to an intracerebroventricular (i.c.v.) injection of Abeta. These results indicate that IDE is secreted from astrocytes through an autophagy based unconventional secretory pathway in AD conditions, and that the regulation of autophagy is a potential therapeutic target in addressing Abeta pathology. PMID- 26963027 TI - Haemostasis monitored in stored red blood cells, plasma and platelet concentrates in the proportion of 4 : 4 : 1 diluted with crystalloids and colloids. AB - The aim of this in-vitro study was to evaluate haemostasis analysed with thromboelastometry and blood gas and blood count variables, in stored blood components and the effects after dilution with Ringer[Combining Acute Accent]s acetate, albumin and hydroxyethyl starch (HES). Aliquots from stored red blood cells, plasma and platelet concentrates were mixed in the proportion of 4 : 4 : 1 and analysed with rotational thromboelastometry (ROTEM), blood count [haemoglobin (Hb), haematocrit, platelet count] and blood gas (pH, calcium, sodium, potassium, glucose levels). The blood mix was thereafter diluted 20 and 33% with Ringer's acetate, albumin or HES. The stored blood component mix in a ratio of 4 : 4 : 1 had a low pH (7.11 +/- 0.03, mean +/- standard deviation), nonmeasurable calcium level, and high concentrations of sodium, potassium and glucose but ROTEM curves within normal range after recalcification. With Ringer's acetate dilution, the ROTEM variables changed almost linearly with increasing dilution volume. When albumin was used in the 33% dilution, the clot firmness of the fibrin clot (FibTEM) was further reduced, and with HES dilution, there was a pronounced impairment. The stored blood mix had a low pH and calcium level, both of which might have a significant influence on the coagulation process but normal ROTEM curves after recalcification. Dilution with Ringer's acetate and albumin resulted in moderate deterioration, while dilution with HES showed severely impaired haemostasis. PMID- 26963028 TI - Benefit and risk of primary thromboprophylaxis in ambulatory patients with advanced pancreatic cancer receiving chemotherapy: a systematic review and meta analysis of randomized controlled trials. AB - As vascular thromboembolism (VTE) is a leading cause of death in cancer patients, it has been postulated that primary thromboprophylaxis (PTP) in cancer patients might improve survival by reducing VTE occurrence. We performed a systemic review and meta-analysis of randomized controlled trials (RCTs) to investigate the benefit and risk of PTP with low-molecular-weight heparins (LMWHs) in ambulatory advanced pancreatic cancer (APC) patients receiving chemotherapy. We undertook a literature search using MEDLINE and EMBASE databases through May 2015. RCTs with reduction in symptomatic VTE as a primary or secondary endpoints were included. Mantel-Haenszel method was used to estimate the pooled event-based risk ratio as well as the pooled absolute risk difference with 95% confidence interval (CI). Seven hundred and thirty-eight APC patients were eligible for analysis. PTP lasted 3-6 months. The crude VTE incidence was 2.1 and 11.2% in LMWH and in control groups, respectively (risk ratio, 0.18; 95% CI, 0.083-0.39; P < 0.0001). The absolute risk difference in VTE was -0.092 (95% CI, -0.127 to -0.057; P < 0.0001), with an estimated number needed to treat of 11 patients to prevent one symptomatic VTE event. The pooled risk ratio for major bleeding was 1.25 (95% CI, 0.48-3.3, P = 0.65). Although these findings are encouraging to deploy PTP in APC patients receiving chemotherapy, uncertainties remain as to its survival benefit, optimal PTP duration, type and dose of LMWH, and costs of care. Therefore, adequately powered randomized phase III studies are warranted to address these questions. PMID- 26963029 TI - RN-BS Writing Project: A Successful Academic-Community Partnership. PMID- 26963030 TI - In Our Own "Campus-Yard": A Creative Approach to Learning About Culture. PMID- 26963031 TI - Linking Root Cause Analysis to Practice Using Problem-Based Learning. PMID- 26963032 TI - Using Metacognitive Wrappers to Help Students Enhance Their Prioritization and Test-Taking Skills. PMID- 26963033 TI - Broadening the Reach of Standardized Patients in Nurse Practitioner Education to Include the Distance Learner. AB - Using standardized patients (SP) presenting with a specific complaint has been a mainstay in health care education. Increased use of technology has facilitated the move of instruction from the on-campus classroom to distance learning for many nurse practitioner programs. Using interactive case studies provides distance learners SP encounters. This technologically facilitated encounter gives the distance learner the opportunity for integrative thinking and development of problem solving and clinical reasoning skills. PMID- 26963026 TI - Recent advances in understanding nuclear size and shape. AB - Size and shape are important aspects of nuclear structure. While normal cells maintain nuclear size within a defined range, altered nuclear size and shape are associated with a variety of diseases. It is unknown if altered nuclear morphology contributes to pathology, and answering this question requires a better understanding of the mechanisms that control nuclear size and shape. In this review, we discuss recent advances in our understanding of the mechanisms that regulate nuclear morphology, focusing on nucleocytoplasmic transport, nuclear lamins, the endoplasmic reticulum, the cell cycle, and potential links between nuclear size and size regulation of other organelles. We then discuss the functional significance of nuclear morphology in the context of early embryonic development. Looking toward the future, we review new experimental approaches that promise to provide new insights into mechanisms of nuclear size control, in particular microfluidic-based technologies, and discuss how altered nuclear morphology might impact chromatin organization and physiology of diseased cells. PMID- 26963034 TI - Multiagency Online Preceptor Education: Design, Implementation, and Outcomes. AB - This article describes the design, implementation, feedback, problems, and solutions of a fully online Preceptor Development Program designed to help nurses acquire knowledge, attitudes, and skills key to the preceptor role. This program uses a variety of active learning experiences that support preceptor development. PMID- 26963035 TI - Effectiveness of an Adaptive Quizzing System as an Institutional-Wide Strategy to Improve Student Learning and Retention. AB - Exploring ways to help students achieve success in nursing programs is critical to increase retention and the number of nurse graduates. This study examined the impact of an adaptive quizzing system implemented as a strategy to support student persistence and performance measured by use, grades, and graduation. Results indicated that use of the system increased course content mastery and predicted final course grades. Retention and program completion rates were also positively influenced. PMID- 26963036 TI - Developing a Foundation for Interprofessional Education Within Nursing and Medical Curricula. AB - Effective teamwork is essential to foster patient safety and promote quality patient care. Students may have limited to no exposure to interprofessional education (IPE) or collaborative practice, therefore making it challenging to learn how to work in teams. This article describes how a nursing and a medical school collaborated to systematically integrate IPE simulations into the curricula so that every graduate from the respective schools received TeamSTEPPS(r) education and participated in a standardized IPE simulation experience. PMID- 26963037 TI - Comparison of the mineral and fatty acid profiles of ostrich, turkey and broiler chicken livers. AB - The aim of this study was to determine the mineral and lipid profiles in ostrich, turkey and broiler chicken livers. The highest concentrations of phosphorus, potassium and magnesium were found in turkey livers, at 3751.50, 2153.05 and 363.98 mg/kg fresh weight (FW), respectively, whereas ostrich livers were the richest in calcium (82.77 mg/kg FW). Ostrich liver was the richest source of iron, calcium, zinc and silicon, at 947.8, 82.77, 47.50, 36.69 mg/kg FW, respectively. Ostrich livers proved to be the richest source of long-chain fatty acids (5.18% C20:4n+6, 0.48% EPA and 1.08% DHA). PMID- 26963038 TI - Photoinduced Electron Transfer in the Strong Coupling Regime: Waveguide-Plasmon Polaritons. AB - Reversible exchange of photons between a material and an optical cavity can lead to the formation of hybrid light-matter states where material properties such as the work function [ Hutchison et al. Adv. Mater. 2013 , 25 , 2481 - 2485 ], chemical reactivity [ Hutchison et al. Angew. Chem., Int. Ed. 2012 , 51 , 1592 - 1596 ], ultrafast energy relaxation [ Salomon et al. Angew. Chem., Int. Ed. 2009 , 48 , 8748 - 8751 ; Gomez et al. J. Phys. Chem. B 2013 , 117 , 4340 - 4346 ], and electrical conductivity [ Orgiu et al. Nat. Mater. 2015 , 14 , 1123 - 1129 ] of matter differ significantly to those of the same material in the absence of strong interactions with the electromagnetic fields. Here we show that strong light-matter coupling between confined photons on a semiconductor waveguide and localized plasmon resonances on metal nanowires modifies the efficiency of the photoinduced charge-transfer rate of plasmonic derived (hot) electrons into accepting states in the semiconductor material. Ultrafast spectroscopy measurements reveal a strong correlation between the amplitude of the transient signals, attributed to electrons residing in the semiconductor and the hybridization of waveguide and plasmon excitations. PMID- 26963045 TI - The PGF2alpha agonists luprostiol and d-cloprostenol reliably induce luteolysis in luteal phase mares without evoking clinical side effects or a stress response. AB - In the present study we have evaluated a possible stress reaction in response to two different PGF2alpha analogs-luprostiol and D-cloprostenol--and their effects on estrous cycle characteristics. In a cross-over-design eight mares received in alternating order either luprostiol (Treatment LUP; 3.75 mg im), D-cloprostenol (Treatment CLO; 22.5MUg im) or saline (Treatment CON; NaCl 0.9% 0.5ml im) on day 8 after ovulation. Injection of either LUP or CLO, but not of CON resulted in a significant decline of progesterone concentration in plasma to baseline concentrations within two days (time: p<0.001, treatment: p<0.01, time * treatment: p<0.05). The treatment to ovulation interval was significantly shorter in LUP and CLO than in CON cycles (LUP: 9.4 +/- 0.4 d; CLO: 9.4 +/- 1.3 d; CON: 16.1 +/- 0.8 d; p<0.001). Injection of either LUP or CLO, but not of CON significantly increased salivary cortisol concentration (immediately before injection: CON 1.3 +/- 0.2, LUP 1.4 +/- 0.3, CLO 1.4 +/- 0.3 ng/ml; 60 min after injection: CON 1.0 +/- 0.3, LUP 8.0 +/- 1.4, CLO 4.2 +/- 0.7 ng/ml; time: p<0.01, treatment: p<0.001, time * treatment: p<0.001). Heart rate decreased over time (p<0.05) independent of treatment and no changes in heart rate variability were detected. Injection of the PGF2alpha analogs CLO and LUP reliably induced luteolysis and apart from a transient increase in salivary cortisol concentration no signs of a physiological stress response or apparent side effects occurred. PMID- 26963047 TI - Finite-time full counting statistics and factorial cumulants for transport through a quantum dot with normal and superconducting leads. AB - We study the finite-time full counting statistics for subgap transport through a single-level quantum dot tunnel-coupled to one normal and one superconducting lead. In particular, we determine the factorial and the ordinary cumulants both for finite times and in the long-time limit. We find that the factorial cumulants violate the sign criterion, indicating a non-binomial distribution, even in absence of Coulomb repulsion due to the presence of superconducting correlations. At short times the cumulants exhibit oscillations which are a signature of the coherent transfer of Cooper pairs between the dot and the superconductor. PMID- 26963046 TI - Epididymal protein markers and fertility. AB - The last stages of male gamete differentiation occur outside the gonad in a specific environment controlled by the epididymal epithelium. All the fundamental characteristics of a fertile spermatozoon are acquired sequentially during transit through the epididymal tubule. Full understanding of the mechanisms involved in these gamete modifications is a key to understanding and controlling such important stages in male fertility. With the development of new large scale technologies, large amounts of information give hope of identifying the fundamental elements involved in such cellular events and of being able to obtain some markers predictive of male fertility that would be valuable both in human and/or animal reproduction. PMID- 26963048 TI - Probenecid Sensitizes Neuroblastoma Cancer Stem Cells to Cisplatin. AB - We used both in vitro cultures of neuroblastoma cell lines and nude-mice xenotransplants to explore the effects of co-administration of cisplatin and probenecid. Probenecid sensitized neuroblastoma cells, including tumor cells with stem features, to the effects of cisplatin, both in vitro and in vivo. This effect was mediated by an increase in the apoptotic cell death and a concomitant decrease in cell proliferation. This effect is accompanied by modulation of the mRNA and protein of the drug efflux transporters MDR1, MRP2, and BCRP. The co administration of probenecid with cisplatin should be explored as a possible therapeutic strategy. PMID- 26963050 TI - The beneficial influence of inattention on visual interference in schizophrenia. AB - OBJECTIVE: Schizophrenia is associated with poor spatial attention. However, although this deficit undermines the perception of target information, it may be helpful for ignoring irrelevant inputs. The present study examined whether event related brain potential (ERP) indices of visual spatial attention predicted the magnitude of the brain response to interference in schizophrenia. METHOD: ERPs were recorded in 16 schizophrenia patients and 20 healthy control participants who had to indicate whether the target E was global or local in compound letter stimuli. The nontarget could be either highly similar to the target (i.e., a global E composed of local Ss and vice versa) and thus produce more interference, or it could be dissimilar (i.e., a global E composed of local Hs and vice versa) and generate less interference. RESULTS: Both groups' responses were slowed by interference. Voltage amplitudes of the P1, and of ERP interference effects from 300-500 ms after stimulus onset, were significantly smaller in schizophrenia patients than in healthy participants when the target was global. In patients, larger P1 amplitudes were correlated with larger interference effects and with more severe symptoms of attentional deficits and conceptual disorganization. Schizophrenia participants thus exhibited abnormal ERPs to interference despite normal behavioral performance. CONCLUSIONS: Schizophrenia patients likely pay less attention to stimuli in general; however, the impact of this impairment on target detection is compensated by relatively greater inattention to irrelevant components of the stimuli, and this explains why they are not more influenced by interference than healthy participants at the behavioral level. (PsycINFO Database Record PMID- 26963049 TI - Stochastic modeling of central apnea events in preterm infants. AB - A near-ubiquitous pathology in very low birth weight infants is neonatal apnea, breathing pauses with slowing of the heart and falling blood oxygen. Events of substantial duration occasionally occur after an infant is discharged from the neonatal intensive care unit (NICU). It is not known whether apneas result from a predictable process or from a stochastic process, but the observation that they occur in seemingly random clusters justifies the use of stochastic models. We use a hidden-Markov model to analyze the distribution of durations of apneas and the distribution of times between apneas. The model suggests the presence of four breathing states, ranging from very stable (with an average lifetime of 12 h) to very unstable (with an average lifetime of 10 s). Although the states themselves are not visible, the mathematical analysis gives estimates of the transition rates among these states. We have obtained these transition rates, and shown how they change with post-menstrual age; as expected, the residence time in the more stable breathing states increases with age. We also extrapolated the model to predict the frequency of very prolonged apnea during the first year of life. This paradigm-stochastic modeling of cardiorespiratory control in neonatal infants to estimate risk for severe clinical events-may be a first step toward personalized risk assessment for life threatening apnea events after NICU discharge. PMID- 26963051 TI - Two cases of food aversion with semantic dementia. AB - Accounts of altered eating behavior in semantic dementia generally emphasize gluttony and abnormal food preferences. Here we describe two female patients with no past history of eating disorders who developed early prominent aversion to food in the context of an otherwise typical semantic dementia syndrome. One patient (aged 57) presented features in line with anorexia nervosa while the second patient (aged 58) presented with a syndrome more suggestive of bulimia nervosa. These cases add to the growing spectrum of apparently dichotomous behavior patterns in the frontotemporal dementias and illustrate a potentially under-recognized cause of eating disorders presenting in later life. PMID- 26963052 TI - Health Care, Family, and Community Factors Associated with Mental, Behavioral, and Developmental Disorders in Early Childhood - United States, 2011-2012. AB - Sociodemographic, health care, family, and community attributes have been associated with increased risk for mental, behavioral, and developmental disorders (MBDDs) in children (1,2). For example, poverty has been shown to have adverse effects on cognitive, socio-emotional, and physical development (1). A safe place to play is needed for gross motor development, and accessible health care is needed for preventive and illness health care (3). Positive parenting and quality preschool interventions have been shown to be associated with prosocial skills, better educational outcomes, and fewer health risk behaviors over time (2). Protective factors for MBDDs are often shared (4) and conditions often co occur; therefore, CDC considered MBDDs together to facilitate the identification of factors that could inform collaborative, multidisciplinary prevention strategies. To identify specific factors associated with MBDDs among U.S. children aged 2-8 years, parent-reported data from the most recent (2011-2012) National Survey of Children's Health (NSCH) were analyzed. Factors associated with having any MBDD included inadequate insurance, lacking a medical home, fair or poor parental mental health, difficulties getting by on the family's income, employment difficulties because of child care issues, living in a neighborhood lacking support, living in a neighborhood lacking amenities (e.g., sidewalks, park, recreation center, and library), and living in a neighborhood in poor condition. In a multivariate analysis, fair or poor parental mental health and lacking a medical home were significantly associated with having an MBDD. There was significant variation in the prevalence of these and the other factors by state, suggesting that programs and policies might use collaborative efforts to focus on specific factors. Addressing identified factors might prevent the onset of MBDDs and improve outcomes among children who have one or more of these disorders. PMID- 26963053 TI - NOX 5 is expressed in platelets from patients with chronic granulomatous disease. PMID- 26963054 TI - Dermatoscopy as a Helpful Tool in Plastic Surgeon's Practice - A Preliminary Study. AB - The aim of the study was to examine the utility of dermatoscopy in plastic surgeons' practice in pigmented and non-pigmented skin lesions management. MATERIAL AND METHODS: The examined group consisted of 68 patients with 132 lesions (50 women and 18 men) aged from 12 to 75 years (the mean: 47.2 years +/- 16.9 years), who underwent dermatoscopy. Dermatoscopic photographs were analysed according to the ABCD and 7-point scales and then, a further treatment (surgical excision, electro resection or regular follow-up and observations) was planned. RESULTS: The mean score of all lesions according to ABCD scale was 2.34 while in 7-point scale it was 0.62. In male and female groups the number of lesions and their ABCD and 7-point scale scores were similar (p>0.05). Histopathological examination revealed that all excised lesions were benign (compound melanocytic nevi) which corresponded with dermatoscopic evaluation. CONCLUSIONS: Dermatoscopy seems to be helpful in surgeons' dealing with skin lesions practise and in many cases it enables to choose less invasive technique of lesions' removal (electro resection), which gives better aesthetic results. PMID- 26963055 TI - Treatment of Perianal Fistulas in Poland. AB - A perianal fistula is a pathological canal covered by granulation tissue connecting the anal canal and perianal area epidermis. The above-mentioned problem is the reason for the patient to visit the surgeonproctologist. Unfortunately, the disease is characterized by a high recurrence rate, even despite proper management. The aim of the study was to determine the current condition of perianal fistula treatment methods in everyday surgical practice, considering members of the Society of Polish Surgeons. MATERIAL AND METHODS: 1523 members of the Society of Polish Surgeons received an anonymous questionnaire comprising 15 questions regarding perianal fistula treatment in everyday practice. RESULTS: Results were obtained from 807 (53%) members. After receiving answers, questionnaire results were collected, analysed, and presented in a descriptive form. CONCLUSIONS: Study results showed that most Polish surgeons choose the fistulectomy/fistulotomy method. Considering treatment of perianal fistulas the most important issue is to find the correct, primary fistula canal. Further methods should be individually selected for each patient. One should also remember that every fistula is different. Surgical departments that operate a small number of perianal fistulas should direct such patients to reference centers. PMID- 26963056 TI - Assessment of Pharmacological Prophylaxis for Acute Pancreatitis Following ERCP in Patients with Choledoholithiasis. AB - Endoscopic retrograde cholangiopancreatography (ERCP) is an effective tool in the diagnostics and treatment of bile duct diseases. Although minimally invasive, the procedure is associated with a risk of complications, with acute pancreatitis being the most serious. In recent years, high hopes have been placed on pharmacological prevention of acute pancreatitis after ERCP. The aim of the study was assessment of the efficacy of low-molecular-weight heparin and somatostatin in combination with diclofenac in the prevention of acute pancreatitis after ERCP. MATERIAL AND METHODS: The study enrolled three groups of 30 patients diagnosed with cholelithiasis; group I: patients who received low-molecular weight heparin prior to ERCP, group II: patients who received somatostatin and diclofenac, group III: control group. The study assessed the incidence of acute pancreatitis, hyperamylasemia and increased CRP levels. RESULTS: Acute pancreatitis was observed in 13.3% of group I patients, 10% of group II patients and 16.7% of group III patients (no statistical significance). Hyperamylasemia was observed in 16.7% of group I patients, 16.7% of group II patients and 43.3% of group III patients. These differences were statistically significant. No significant differences were found in the occurrence of increased CRP levels among the study groups. CONCLUSIONS: No significant reduction in the occurrence of acute pancreatitis after ERCP was observed in patients who received pharmacological prophylaxis. A significant reduction in the occurrence of hyperamylasemia was found in drug-treated patients. PMID- 26963057 TI - Long-Term Results of Partial Nasal Reconstructions with Indian Flap. AB - The aim of the study was clinical evaluation of the results following reconstruction with the Indian flap in patients with partial nasal defects, and estimation of their postoperative life quality in functional and aesthetic aspects. MATERIAL AND METHODS: We analyzed results in 38 patients who underwent reconstructions with the Indian flap in the Department of Plastic, Reconstructive and Aesthetic Surgery between years 2000-2013. The patients were followed-up for at least 2 years. We estimated their life quality in aesthetic and functional aspects after surgery. RESULTS: Observed complications of nasal reconstruction were alar asymmetry in 6 patients (15.8%), nasal obstruction in 6 persons (15.8%), wide postoperative scar in 4 (10.5%), and non-aesthetic appearance of the donor site in two cases (5.3%). Estimation of life quality post surgery in the examined group of patients revealed significant postoperative improvement in both functional and aesthetic aspects. CONCLUSIONS: 1. Reconstructions of nasal defects with the Indian flap resulted in satisfactory longterm postoperative results, which confirms the efficiency of the applied technique. 2. Reconstructive surgery with Indian flap of individuals with partial nasal defects contributed to significant postoperative improvement in both functional and aesthetic aspects and their life quality. PMID- 26963058 TI - Laparosocopic Appendectomy, Cost-Effectiveness of Three Different Techniques Used to Close the Appendix Stump. AB - It is generally agreed that laparoscopic appendectomy is a valuable operative method. The aim of the study was to evaluate cost-effectiveness of three different techniques used to close the appendix stump. MATERIAL AND METHODS: We conducted a retrospective study that compared three groups of patients who were operated on laparoscopically for acute appendicitis in 2013 at our institution. We used an endoscopic clip to close the appendix stump in the first group (n=20), endoscopic stapler was applied in the second group (n=20), and in the third group of patients the appendix base was closed with a laparoscopic suture (n=20). These groups were matched by age, sex and BMI. RESULTS: The average operative cost was the highest in the second group. Cost of the laparoscopic appendectomy with the application of the endoscopic clip was significantly lower (first group) and comparable to the third group. Observed differences in total hospitalization costs were associated only with the chosen appendix stump closure technique. CONCLUSIONS: Clip closure of the appendix base is an easy and cost-effective procedure. The laparoscopic suture technique is the cheapest but technically demanding. According to our experience endoscopic stapler may be useful in some cases, although it is the most expensive method. PMID- 26963059 TI - Consent for Surgery in View of an Ambigious Court Decision - Case Report. AB - Guardianship courts seem to issue decisions in case of the need to obtain consent for surgery, amongst other things, when the patient is unable to consciously express written consent, and at the same time does not have a legal representative or a statutory representative does exist, but settlement with him is impossible. The presented study case demonstrated the abnormalities of applying court procedures, as well as the responsibilities and dilemmas posed in front of a surgeon. A specialist surgeon wanted to help the patient and he was able to accomplish his mission. PMID- 26963060 TI - Bleeding Liver Tumor in a Patient on Anticoagulation Therapy - Case Report. AB - Intraabdominal bleeding is a serious surgical problem, particularly in elderly patients following an anticoagulant therapy. It occurs, that abdominal haemorrhage is the first symptom of hepatocellular carcinoma, mostly in Asians and Africans, occasionally in Europeans. The article's author shows a case of an elderly man, treated by Acenocumarolum, in a haemorrhagic shock. During an operation a bleeding liver tumor was revealed. The surgical team performed an effectual tumor resection and stoped the bleeding. PMID- 26963061 TI - Preoperative Evaluation; New Attempt. PMID- 26963062 TI - Resistant multiple sparse canonical correlation. AB - Canonical correlation analysis (CCA) is a multivariate technique that takes two datasets and forms the most highly correlated possible pairs of linear combinations between them. Each subsequent pair of linear combinations is orthogonal to the preceding pair, meaning that new information is gleaned from each pair. By looking at the magnitude of coefficient values, we can find out which variables can be grouped together, thus better understanding multiple interactions that are otherwise difficult to compute or grasp intuitively. CCA appears to have quite powerful applications to high-throughput data, as we can use it to discover, for example, relationships between gene expression and gene copy number variation. One of the biggest problems of CCA is that the number of variables (often upwards of 10,000) makes biological interpretation of linear combinations nearly impossible. To limit variable output, we have employed a method known as sparse canonical correlation analysis (SCCA), while adding estimation which is resistant to extreme observations or other types of deviant data. In this paper, we have demonstrated the success of resistant estimation in variable selection using SCCA. Additionally, we have used SCCA to find multiple canonical pairs for extended knowledge about the datasets at hand. Again, using resistant estimators provided more accurate estimates than standard estimators in the multiple canonical correlation setting. R code is available and documented at https://github.com/hardin47/rmscca. PMID- 26963063 TI - Comparative study of polyvinylidene fluoride and polypropylene suburethral slings in the treatment of female stress urinary incontinence. AB - Aims Evaluate the effectiveness and safety of polyvinylidene fluoride (PVDF) transobturator suburethral slings/tapes (TOTs) in the treatment of stress urinary incontinence, and compare them to polypropylene (PP) slings. Material and Methods A retrospective cohort study was performed on women treated with a TOT procedure at Vall d'Hebron Hospital between February 2010 and May 2013. A PVDF sling was used in surgeries on 23 women. A comparison group was randomly selected among all women treated with a PP sling in a 1:4 ratio (n = 92). Failure incidence was analyzed by Kaplan-Meier survival functions and a multivariate Cox regression model. Results Both groups were similar in their initial characteristics. The median follow-up was 24.6 months in the PP group and 21.3 months in the PVDF group. The survival functions showed a higher incidence of failures in the PP group, primarily because of obstructive symptoms. However, the differences were not statistically significant (hazard ratio of failure of PP vs PVDF 4.31; 95% confidence interval 0.56-33.05). Complication rates did not differ between the two groups. More cases of voiding dysfunction were observed in the PP group. Conclusions Polyvinylidene fluoride suburethral tapes have been found to have an effectiveness and safety comparable to PP tapes. PMID- 26963066 TI - Probing the Self-Assembly Mechanism of Lanthanide-Containing Sandwich-Type Silicotungstates [{Ln(H2O)n}2{Mn4(B-alpha-SiW9O34)2(H2O)2}](6-) Using Time Resolved Mass Spectrometry and X-ray Crystallography. AB - The reaction of [gamma-SiW10O36](8-) with Mn(2+) and Ln(3+) in an aqueous solution led to the isolation of a series of new lanthanide-containing sandwich type polyoxometalates (POMs) [{Ln(H2O)n}2{Mn4(B-alpha-SiW9O34)2(H2O)2}](6-) (1 5a) (Ln = La (1), Nd (2), Gd (3), Dy (4), Er (5); n = 5, 6), which crystallize in the space groups C2/c with a = 33.0900(2)-32.9838(15) A, b = 12.8044(10) 12.7526(6) A, c = 22.8273(17)-22.6368(11) A, V = 9669.2(12)-9519.7(8) A(3), Z = 2 (1, 2); P1 with a = 11.9502(4)-11.8447(6) A, b = 13.2203(4)-13.1164(5) A, c = 15.8291(5)-15.8524(7) A, V = 2221.25(13)-2189.95(18) A(3), Z = 1 (3, 4, 5), respectively. X-ray diffraction analysis reveals that they consist of two dimensional networks based on a sandwich-type polyanion [Mn4(B-alpha SiW9O34)2(H2O)2](12-) (6a, {Mn4(SiW9)2}) and lanthanide cations (Ln(3+)), which are further connected into three-dimensional frameworks by potassium cations for 3, 4, and 5. The unprecedented combination of time-resolved electrospray ionization mass spectrometry (ESI-MS) studies and X-ray crystallography allows us not only to directly observe the in-solution rearrangement of divant anion [gamma SiW10O36](8-) into the sandwich-type POM 6a via an intermediate species [Mn3(B beta-SiW8O30(OH))(B-beta-SiW9O33(OH))(H2O)](12-) (7a, {Mn3(SiW8)(SiW9)}) from ESI MS results, but also to gain the solid-state structures of intermediate and final product isolated from reaction solutions from X-ray crystallography results, from which the self-assembly mechanism of the lanthanide-containing sandwich-type POMs 1-5a was proposed. PMID- 26963065 TI - Molecular Dynamics Simulation of DNA Capture and Transport in Heated Nanopores. AB - The integration of local heat sources with solid-state nanopores offers new means for controlling the transmembrane transport of charged biomacromolecules. In the case of electrophoretic transport of DNA, recent experimental studies revealed unexpected temperature dependences of the DNA capture rate, the DNA translocation velocity, and the ionic current blockades produced by the presence of DNA in the nanopore. Here, we report the results of all-atom molecular dynamics simulations that elucidated the effect of temperature on the key microscopic processes governing electric field-driven transport of DNA through nanopores. Mimicking the experimental setup, we simulated the capture and subsequent translocation of short DNA duplexes through a locally heated nanopore at several temperatures and electrolyte conditions. The temperature dependence of ion mobility at the DNA surface was found to cause the dependence of the relative conductance blockades on temperature. To the first order, the effective force on DNA in the nanopore was found to be independent of temperature, despite a considerable reduction of solution viscosity. The temperature dependence of the solution viscosity was found to make DNA translocations faster for a uniformly heated system but not in the case of local heating that does not affect viscosity of solution surrounding the untranslocated part of the molecule. Increasing solution temperature was also found to reduce the lifetime of bonds formed between cations and DNA. Using a flow suppression algorithm, we were able to separate the effects of electro osmotic flow and direct ion binding, finding the reduced durations of DNA-ion bonds to increase, albeit weakly, the effective force experienced by DNA in an electric field. Unexpectedly, our simulations revealed a considerable temperature dependence of solvent velocity at the DNA surface-slip velocity, an effect that can alter hydrodynamic coupling between the motion of DNA and the surrounding fluid. PMID- 26963067 TI - Combined Medial Patellofemoral Ligament Reconstruction and Tibial Tubercle Transfer Results at a Follow-Up of 2 years. AB - There is limited data on the effectiveness of combined medial patellofemoral ligament (MPFL) reconstruction and tibial tubercle transfer (TTT) in patients with patella instability. The aim of our study was to analyze the functional outcome in patients treated with MPFL reconstruction and TTT. Between July 2008 and April 2013, 18 patients (21 knees) underwent combined MPFL reconstruction and TTT; 15 patients (16 knees) with a mean age of 24 years (16-41) had a mean follow up of 30 months (26-55). There was significant improvement in outcome scores in 12 out of 15 patients. KOOS score improved from 68.25 (44-93.9) to 77.05 (48.8 96.4) and KUJALA score improved from 63.3 (41-88) to 78.06 (45-99). Nine patients achieved at least a preinstability level of activity. Out of these nine patients, four had activity level better than the preinstability level. The remaining six patients had a lower activity level than preinstability level (2-lack of confidence and 4-lifestyle modification). Fourteen patients were satisfied and happy to recommend this procedure. There were three postoperative complications, with two cases of stiffness and one case of nonunion of the tibial tuberosity. Thus, the restoration of tibial tubercle to trochlear groove distance, patella height, and MPFL reconstruction yields good results in carefully selected patients. PMID- 26963068 TI - Does Timing of Arthroscopic Partial Meniscectomy in Stable Knees Matter? AB - The timing of arthroscopic partial meniscectomy (APM) is not well defined. The purpose of this study was to evaluate the impact of early surgical intervention on the short-term improvement in clinical outcome. Between June 2012 and July 2013, patients who had APM for symptomatic irreparable meniscal tears in stable knees with no preoperative radiographic osteoarthrosis were included (n = 187). The mean age was 45.6 +/- 14.5 years. Early surgical intervention (duration of symptoms of less than 3 months) was evaluated together with various preoperative and operative variables in a multivariable stepwise regression analysis, while the improvement in Lysholm knee score was modeled as a function of these predictors. At the last follow-up, the mean Lysholm knee score improved by 14.7 points and 79% of all patients declared they were satisfied to have had the operation; however, of the various predictors in the regression analysis, patients who had shorter duration of symptoms or better clinical function before surgical intervention had greater improvement in clinical score. In conclusion, early APM for symptomatic irreparable tears in stable knees without preoperative arthrosis had better improvement in clinical results than in delayed intervention. PMID- 26963069 TI - Knee Arthroscopy in the Setting of Knee Arthroplasty. AB - Knee arthroplasty is an effective and reproducible way of treating advanced knee arthritis; however, results are not always favorable. Knee arthroscopy has been described in symptomatic knee arthroplasty, but opinion is divided over its utility. The purpose of this systematic review is to examine existing evidence supporting knee arthroscopy in the setting of knee arthroplasty. Predetermined inclusion criteria were used to search the databases EMBASE, MEDLINE, and PubMed for articles addressing knee arthroplasty patients who subsequently underwent arthroscopy. Inclusion criteria limited our search to human and English language studies with clearly described surgical indications. Article screening was conducted in duplicate. Before duplicate screening, 2,179 studies were retrieved and 52 ultimately satisfied the inclusion criteria. A total of 609 patients underwent knee arthroscopy of a symptomatic knee arthroplasty and 120 patients went on to require further surgery post-arthroscopy. Peripatellar fibrosis and pain with no clear diagnosis were the most commonly described indications for surgery. Knee arthroscopy is a safe diagnostic and therapeutic tool in symptomatic knee arthroplasty with variable efficacy depending on indication. It has diagnostic utility in painful knee arthroplasty patients and is a reliable therapeutic option for those with post-arthroplasty diagnoses; although 20% of the patients go on to require further surgery. This is a systematic review of level IV studies. PMID- 26963070 TI - Arthroscopic Suture Pull-Out Fixation of Displaced Tibial Spine Avulsion Fracture. AB - The aim of this study is to assess the clinical and radiological outcomes of arthroscopic reduction and fixation of tibial spine avulsion in patients with either open physis or closed physis, using high strength nonabsorbable sutures utilizing intravenous cannula needle as suture passer and retriever. Twenty-six patients of mean age 24.5 years were included in the study with a mean follow-up period of 31 months. Twelve patients had McKeever type III avulsion fracture and 14 had type IV. A follow-up analysis was performed using fracture union time, range of motion assessment, and Lysholm and IKDC (International Knee Documentation Committee) scores with instrumental (KT-1000 arthrometer) laxity assessment. All avulsion fractures showed union at the end of a 3-month follow up. Mean (+/- standard deviation [SD]) postoperative Lysholm and IKDC subjective scores were 97.7 (+/- 3.62, range, 89-100) and 95.55 (+/- 4.21, 82.8-100), respectively. All patients were graded IKDC grade A except one with grade B. The Lysholm score of open physis group was better than the closed physis group (99.6 vs. 96.5, p < 0.03), whereas IKDC scores of open versus closed physis group (both subjective and objective) and type III and IV McKeever groups did not reveal any statistical difference. KT-1000 assessment revealed mean (+/- SD) anterior translation of the tibia as 0.85 (+/-0.9) mm. At the final follow-up, all patients achieved complete range of movement with no symptom of instability. Two patients underwent adhesiolysis for postoperative stiffness in their knee at 4th month postoperatively. Arthroscopic suture pull-out fixation for type III and IV tibial spine avulsion results in excellent clinical and radiological outcomes in patient with open and closed physis without any significant complications. This is a prospective case series with level of evidence IV. PMID- 26963071 TI - The Impact of Prior Surgery after Total Knee Arthroplasty. AB - The number of total knee arthroplasty (TKA) procedures performed continues to rise. This is the first 1:1 matched cohort analysis of functional outcomes from a large prospective total joint registry. Our hypothesis is that a previous ipsilateral knee surgery is not associated with worse outcome scores following TKA. A total of 1,473 patients who underwent TKA were reviewed: 469 with a history of previous ipsilateral knee surgery and 1,004 without. After 1:1 matching, 469 patients were included in each cohort. Patients in both cohorts had statistically similar postoperative functional outcome scores, although patients without previous ipsilateral knee surgery had an increased Western Ontario and McMaster Universities Arthritis Index stiffness score. This study supports the hypothesis that previous ipsilateral knee surgery is not associated with worse functional outcomes following primary TKA. PMID- 26963072 TI - Polyethylene Insert Exchange Is Crucial in Debridement for Acute Periprosthetic Infections following Total Knee Arthroplasty. AB - This study aims to report our experience of managing acute periprosthetic joint infection (PJI) following total knee arthroplasty (TKA) with surgical debridement and prostheses retention. A review of patients in our prospective joint replacement register from 1998 to 2013 was performed. In this study, 34 patients with 35 TKAs were included; 25 were infections after primary TKA and 10 were after revision TKA. For primary TKA infections, after a mean follow-up of 53.8 +/ 42.6 months, 11 were successfully treated, while 14 failed, including 10 required reoperations and 4 needed lifelong antibiotic suppression. The success rate of debridement was 44.0%. Statistical analyses showed no significant differences between the two groups on patients' age, time lag between symptoms onset and debridement, preoperative C-reactive protein, erythrocyte sedimentation rate, white blood cell count, hemoglobin, albumin, glucose, or synovial fluid total cell count. Patients' primary diagnoses or staphylococcal infections had no significant impact on the surgical outcomes either. Debridement with polyethylene insert exchange had significantly higher success rate than debridement alone, with all 13 cases without exchange failed. All 10 cases with infections after revision TKA had failed. We concluded that debridement with prostheses retention has a low success rate for acute PJI following primary TKA. The polyethylene insert should be exchanged during surgery. For acute infections after revision TKA, total revision should be contemplated. PMID- 26963073 TI - Gait Using Pneumatic Brace for End-Stage Knee Osteoarthritis. AB - More than 20 million individuals in the United States are affected by knee osteoarthritis (OA), which can lead to altered biomechanics and excessive joint loading. The use of an unloader pneumatic brace with extension assist has been proposed as a nonoperative treatment modality that may improve gait mechanics and correct knee malalignment. We assessed the following parameters in patients who have knee OA treated with and without a brace: (1) changes in temporospatial parameters in gait; (2) knee range of motion, knee extension at heel strike, and foot placement; (3) knee joint moments and impulse; and (4) changes in dynamic stiffness and rate of change of knee flexion during midstance to terminal stance. This 2:1 prospective, randomized, single-blinded trial evaluated 36 patients (24 brace and 12 matching). OA knee patients were randomized to receive either a pneumatic unloader brace or a standard nonoperative treatment regimen as the matching cohort for a 3-month period. They underwent evaluation of gait parameters using a three-dimensional gait analysis system at their initial appointment and at 3 months follow-up. All the testing, pre- and postbracing were performed without wearing the brace to examine for retained effects. Treatment with the brace led to significant improvements versus standard treatment in various gait parameters. Patients in the brace group had improvements in walking speed, knee extension at heel strike, total range of motion, knee joint forces, and rate of knee flexion from midstance to terminal stance when compared with the matching cohort. Knee OA patients who used a pneumatic unloader brace for 3 months for at least 3 hours per day had significant improvements various gait parameters when compared with a standard nonoperative therapy cohort. Braced patients demonstrated gait-modifying affects when not wearing the brace. These results are encouraging and suggest that this device represents a promising treatment modality for knee OA that may improve gait, knee pain, and strength in knee OA patients. PMID- 26963074 TI - Rehabilitative Guidelines after Total Knee Arthroplasty: A Review. AB - Rehabilitation following total knee arthroplasty (TKA) continues to pose a challenge for both patients and providers. In addition, guidelines vary considerably between institutions, which often leave therapy regimens to the discretion of the provider. The lack of clear guidelines for rehabilitation may contribute to inadequate recovery of strength and range-of-motion, resulting in less optimal functional outcomes. Therefore, the aim of this review was to highlight and discuss a variety of post-TKA rehabilitative modalities currently available and to provide evidence regarding efficacy and practicality. Specifically, we assessed the role of and evidence for exercise therapy, aquatic therapy, balance training, continuous passive motion, cold therapy and compression, neuromuscular electrical stimulation, transcutaneous electrical nerve stimulation, and instrument-assisted soft-tissue therapy. Additionally, we proposed general recommendations for rehabilitation after TKA, and as we specifically described active and obese patients, we have included guidelines for these subsets as well. Our review examines the various rehabilitative modalities to offer suggestions for recovery of strength and range-of-motion after TKA, with a focus on the early incorporation of exercise therapy, balance training, aquatic therapy, cryopneumatic therapy, neuromuscular electrical stimulation, and transcutaneous electrical nerve stimulation. Dedication and commitment to rehabilitation may help patients attain and exceed their preoperative activity levels. PMID- 26963075 TI - In Reply. PMID- 26963076 TI - Comment on: "Cervical Necrotizing Fasciitis-The Value of the Laboratory Risk Indicator for Necrotizing Fasciitis Score as an Indicative Parameter". PMID- 26963077 TI - Among Patients With Facial Fractures, Geriatric Patients Have an Increased Risk for Associated Injuries. AB - PURPOSE: It is hypothesized that facial trauma-associated injuries (AIs) are more frequent and severe in elderly than in younger adult patients. The purpose of this study was to determine the occurrence of, reasons for, and severity of AI in geriatric facial fractures and to compare the differences between geriatric and younger adult patients. MATERIALS AND METHODS: Two patient cohorts were included in this cross-sectional retrospective study. Geriatric patients were at least 65 years old (n = 117) and younger controls were 20 to 50 years old (n = 136). The main predictor was age, the primary outcome was AI, and secondary outcomes were affected organ system, multiple AIs, polytrauma, and mortality during hospitalization. The other explanatory variables were gender, trauma mechanism, and type of facial fracture. Statistical methods included chi(2) tests, risk analyses with 2 * 2 table, and logistic regression analyses. RESULTS: AIs were significantly more common in geriatric patients (44.0%) than in younger controls (25.0%; P < .001). Also, multiple AIs (P = .003), polytrauma (P = .039), mortality (P = .008), limb injuries (P = .005), and spine injuries (P = .041) were significantly more common in the elderly. In the risk analyses, geriatric patients had a 1.8-fold risk for AI, a 2.6-fold risk for multiple AIs, and a 2.2 fold risk for polytrauma. CONCLUSIONS: AIs are much more frequent and severe in geriatric patients, and the elderly die more often of their injuries. The results emphasize that elderly patients require specific attention and multi-professional collaboration in the diagnosis and sequencing of trauma treatment. PMID- 26963078 TI - Fractional non-ablative laser treatment at 1410 nm wavelength for periorbital wrinkles - reviscometrical and clinical evaluation. AB - OBJECTIVE: The aim of the research was to establish the influence of 1410-nm fractional non-ablative laser treatment on skin aging in the eye area. The reviscometer reference test is an objective method of estimating the flexibility of the skin. The photographic records were used as the auxiliary method of the therapy quality effectiveness. MATERIALS AND METHODS: The study involved the group of 13 people (12 females and 1 male, aged 33-47 with prototype II and III according to the Fitzpatrick scale), who underwent two sessions of fractional non ablative laser therapy (wavelength of 1410 nm) with a 2-week interval. In order to evaluate the effectiveness of the quality of the treatment a reviscometer probe was used to measure the skin elasticity (Reviscometer RVM 600). The measurements were taken twice: directly before and two weeks after the treatment. Furthermore, to facilitate the clinical evaluation an anonymous photographical documentation was prepared. RESULTS: An improvement of the skin flexibility in the eye area was observed and the fact was confirmed by values obtained using the reviscometer probe (significant statistic differences: P < 0.0001) as well as clinical assessment based on photographical records. CONCLUSION: On the basis of the reviscometer measurements analysis and photographical records, 1410-nm fractional non-ablative laser treatment appears to be an efficient method contributing to the improvement of the skin flexibility of the eyes area as well as to the reduction of the number of wrinkles. The post-treatment observation proves that the method is well-tolerated in the sensitive eyes area and does not cause any significant side effects. PMID- 26963080 TI - Identified ambivalence: When cognitive conflicts can help individuals overcome cognitive traps. AB - In this article we investigate the functional effects of ambivalence on decision making processes. We build on the misattribution literature and recent work on ambivalence to propose that individuals who properly identify the causes of their ambivalence (i.e., identified ambivalence) can systematically process relevant situational cues to make more effective decisions. The results of 4 studies demonstrate that individuals experiencing identified ambivalence are less influenced by cognitive biases (i.e., the framing effect, availability bias, and conjunction bias) than individuals experiencing no ambivalence or felt ambivalence. Notably, we find that contextual awareness accounts for the effect of identified ambivalence on decision effectiveness. We then investigate the role of trait self-control as a specific contingency in our model; our results indicate that identified ambivalence leads to effective decisions when individuals are low in trait self-control. Taken together, we advance theory and offer robust, consistent empirical evidence that explains why and how ambivalence can result in functional outcomes. (PsycINFO Database Record PMID- 26963079 TI - Everything that you have ever been told about assessment center ratings is confounded. AB - Despite a substantial research literature on the influence of dimensions and exercises in assessment centers (ACs), the relative impact of these 2 sources of variance continues to raise uncertainties because of confounding. With confounded effects, it is not possible to establish the degree to which any 1 effect, including those related to exercises and dimensions, influences AC ratings. In the current study (N = 698) we used Bayesian generalizability theory to unconfound all of the possible effects contributing to variance in AC ratings. Our results show that <=1.11% of the variance in AC ratings was directly attributable to behavioral dimensions, suggesting that dimension-related effects have no practical impact on the reliability of ACs. Even when taking aggregation level into consideration, effects related to general performance and exercises accounted for almost all of the reliable variance in AC ratings. The implications of these findings for recent dimension- and exercise-based perspectives on ACs are discussed. (PsycINFO Database Record PMID- 26963081 TI - Departures from optimality when pursuing multiple approach or avoidance goals. AB - This article examines how people depart from optimality during multiple-goal pursuit. The authors operationalized optimality using dynamic programming, which is a mathematical model used to calculate expected value in multistage decisions. Drawing on prospect theory, they predicted that people are risk-averse when pursuing approach goals and are therefore more likely to prioritize the goal in the best position than the dynamic programming model suggests is optimal. The authors predicted that people are risk-seeking when pursuing avoidance goals and are therefore more likely to prioritize the goal in the worst position than is optimal. These predictions were supported by results from an experimental paradigm in which participants made a series of prioritization decisions while pursuing either 2 approach or 2 avoidance goals. This research demonstrates the usefulness of using decision-making theories and normative models to understand multiple-goal pursuit. (PsycINFO Database Record PMID- 26963082 TI - Recognizing "me" benefits "we": Investigating the positive spillover effects of formal individual recognition in teams. AB - Many organizations use formal recognition programs (e.g., "employee of the month") as a way to publically acknowledge an individual employee's outstanding performance and motivate continued high performance. However, it remains unclear whether emphasizing individual achievement in a team context is beneficial or detrimental for recipients' teammates and, by extension, the team as a whole. Drawing on a social influence perspective, we examine potential spillover effects of individual formal recognition programs in teams. We hypothesize that a single team member's recognition will produce positive spillover effects on other team members' performance, as well as overall team performance, via social influence processes, especially when the award recipient is located in a central position in a team. Findings from 2 lab experiments of 24 teams and 40 teams (Study 1 and Study 2, respectively) and a field experiment of 52 manufacturing teams (Study 3) reveal that formally recognizing a team member leads to positive changes in her/his teammates' individual and collective performance. Thus, formal social recognition programs can potentially provide a motivational effect beyond individual recipients. (PsycINFO Database Record PMID- 26963083 TI - Illusion of agency in patients with Gilles de la Tourette Syndrome. AB - The sense of agency refers to the conscious experience of authorship and control over actions. The voluntary or involuntary nature of tics, which are the hallmark of Gilles de la Tourette Syndrome (GTS), is unclear. Here, we studied metacognitive processing of agency in an explicit agency task on non-medicated and medicated GTS patients compared to matched controls. In this task, the participants made judgements of control and performance after completion of a computerized game where they had to catch targets with a cursor by moving the computer mouse. The task included several conditions, where the objective control over the cursor could be normal, disrupted or artificially enhanced. We show that GTS patients, independently of medication status, based their judgments of agency predominantly on the matching between their intention and the outcome, i.e., had an illusion of agency in the task condition where their performance was artificially enhanced. Nevertheless, they recognized not to be fully in control in conditions of disrupted control. The propensity to illusions of agency was negatively correlated with global disease severity. Our findings suggest alterations of metacognition of agency in GTS patients. This illusion of agency could reflect a compensatory mechanism related to tic control, but is more likely to be related to deviant brain maturation in GTS. PMID- 26963084 TI - Performing two different actions simultaneously: The critical role of interhemispheric interactions during the preparation of bimanual movement. AB - Even though it has been suggested that the dorsolateral prefrontal cortex (DLPFC) and dorsal premotor cortex (PMd) are highly involved in the planning of bimanual movements, the exact nature (facilitatory or inhibitory) of their role is not well understood. Using a dual-site transcranial magnetic stimulation (TMS) paradigm, we examined the functional influence from DLPFC and PMd to the contralateral primary cortex (M1) during the preparation of a complex bimanual coordination task in which inter-hand movement frequency was manipulated. Only the left PMd showed inter-hand frequency-specific modulations in the interaction with the contralateral M1. Left PMd-right M1 interaction became facilitatory during the preparation phase when the left hand had to move faster than the right hand, while inhibitory modulation was observed when the movement frequency arrangement was reversed. Interestingly, bilateral DLPFC showed a facilitatory interaction with the contralateral M1s during the preparation period only in difficult conditions, irrespective of the inter-hand frequency ratio, suggesting a less task-specific role in the organization of complex bimanual actions. Observed task-related modulations in DLPFC-M1 and left PMd-right M1 interactions during preparation were significantly correlated with up-coming performance, predicting successful bimanual movements. These observations highlight the distinct roles of DLPFC and left PMd in the preparation of bimanual movements that require a differential contribution of each limb. PMID- 26963086 TI - Personality characteristics in MS patients: The role of avoidant personality. AB - OBJECTIVES: Quality of life (QOL) is markedly affected by multiple sclerosis (MS). Particular personality characteristics (PC) of MS patients can affect their QOL. We designed the present study to determine the role of various PCs on QOL in MS patients accounting for other clinical factors. METHODS: QOL, PC, physical disability, and mental status were recorded in 83 MS patients referred to two academic hospitals of Tehran University of Medical Sciences in 2011-2012. RESULTS: The mean age of enrolled patients was 31.54+/-7.38 (range: 14-50) years and 74 (89.2%) were female. Mean disease duration was 4.55+/-4.70 years. Seventy seven patients (92.8%) had relapsing-remitting disease, five (6%) had primary progressive, and one showed a secondary progressive course. Correlation between total QOL scores in MS patients and disease duration, cognitive impairment, and physical disability was significant (all p<0.001). Obsessive-compulsive personality was the most frequent PC (43.4%) in our patients. Only avoidant personality had a significant negative correlation with all components of QOL (Beta: 0.33, p<0.00). In addition, avoidant personality, physical disability, and mental status were found to be three predictors of QOL with all its components. CONCLUSION: Avoidant personality appears to be an important predictor of poor QOL in MS patients. In addition, avoidant coping strategies appear to be associated with adverse response to stressful events in these patients. These findings suggest the need for psychological intervention for improving the coping strategies and QOL in MS patients. PMID- 26963085 TI - Perceived egocentric distance sensitivity and invariance across scene-selective cortex. AB - Behavioral studies in many species and studies in robotics have demonstrated two sources of information critical for visually-guided navigation: sense (left right) information and egocentric distance (proximal-distal) information. A recent fMRI study found sensitivity to sense information in two scene-selective cortical regions, the retrosplenial complex (RSC) and the occipital place area (OPA), consistent with hypotheses that these regions play a role in human navigation. Surprisingly, however, another scene-selective region, the parahippocampal place area (PPA), was not sensitive to sense information, challenging hypotheses that this region is directly involved in navigation. Here we examined how these regions encode egocentric distance information (e.g., a house seen from close up versus far away), another type of information crucial for navigation. Using fMRI adaptation and a regions-of-interest analysis approach in human adults, we found sensitivity to egocentric distance information in RSC and OPA, while PPA was not sensitive to such information. These findings further support that RSC and OPA are directly involved in navigation, while PPA is not, consistent with the hypothesis that scenes may be processed by distinct systems guiding navigation and recognition. PMID- 26963087 TI - Predictors of good functional outcomes and mortality in patients with severe rebleeding after aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: Aneurysmal rebleeding is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH); however, limited data on severity of rebleeding and outcomes after severe rebleeding are available. We aimed to determine predictors of good outcome and mortality after severe rebleeding. MATERIALS AND METHODS: In a multicenter poor-grade aneurysm study, 60 patients with severe rebleeding, defined as new hemorrhage with poor clinical condition caused by rebleeding, were identified. Good functional outcome was defined as a modified Rankin scale (mRS) of <=2, and mortality was defined as a mRS of 6. Multivariate logistic analyses were used to determine predictors of good outcome and mortality. RESULTS: Of the 58 patients included in this report, 24 (41.3%) patients experienced rebleeding within 24h after ictus. 42 (72.4%) patients had died at 12 months. The rate of good outcome increased from 5.2% at discharge to 13.8% at 6 months and 19.0% at 12 months. In multivariate analysis, World Federation of Neurosurgical Societies (WFNS) grade IV after rebleeding (P=0.007) and aggressive treatment (P=0.039) were independently associated with good outcome. A higher modified Fisher grade before rebledding (P=0.040), larger aneurysms (P=0.005), and lower Glasgow coma score after rebleeding (P=0.003) were independently associated with increased mortality. CONCLUSIONS: A better clinical condition after rebleeding were independently associated with good outcome and inversely associated with morality after severe rebleeding. Despite high mortality of rebleeding, patients with WFNS grade IV treated with aggressive treatment were more likely to have good outcomes regardless of their condition before rebleeding. PMID- 26963089 TI - IRLT: Integrating Reputation and Local Trust for Trustworthy Service Recommendation in Service-Oriented Social Networks. AB - With the prevalence of Social Networks (SNs) and services, plenty of trust models for Trustworthy Service Recommendation (TSR) in Service-oriented SNs (S-SNs) have been proposed. The reputation-based schemes usually do not contain user preferences and are vulnerable to unfair rating attacks. Meanwhile, the local trust-based schemes generally have low reliability or even fail to work when the trust path is too long or does not exist. Thus it is beneficial to integrate them for TSR in S-SNs. This work improves the state-of-the-art Combining Global and Local Trust (CGLT) scheme and proposes a novel Integrating Reputation and Local Trust (IRLT) model which mainly includes four modules, namely Service Recommendation Interface (SRI) module, Local Trust-based Trust Evaluation (LTTE) module, Reputation-based Trust Evaluation (RTE) module and Aggregation Trust Evaluation (ATE) module. Besides, a synthetic S-SN based on the famous Advogato dataset is deployed and the well-known Discount Cumulative Gain (DCG) metric is employed to measure the service recommendation performance of our IRLT model with comparing to that of the excellent CGLT model. The results illustrate that our IRLT model is slightly superior to the CGLT model in honest environment and significantly outperforms the CGLT model in terms of the robustness against unfair rating attacks. PMID- 26963088 TI - Parallel improvement in anxiety and tics after DBS for medically intractable Tourette syndrome: A long-term follow-up. PMID- 26963090 TI - A New Application of Parallel Synthesis Strategy for Discovery of Amide-Linked Small Molecules as Potent Chondroprotective Agents in TNF-alpha-Stimulated Chondrocytes. AB - As part of an effort to profile potential therapeutics for the treatment of inflammation-related diseases, a diversity of amide-linked small molecules was synthesized by using parallel synthesis strategy. Moreover, these new compounds were also evaluated for their inhibitory effects on nitric oxide (NO) by using tumor necrosis factor alpha (TNF-alpha)-induced inflammatory responses in chondrocytes. Among the tested compounds, N-(3-chloro-4-fluorophenyl)-2 hydroxybenzamide (HS-Ck) was the most potent inhibitor of NO production and inducible nitric oxide synthase (iNOS) expression in TNF-alpha-stimulated chondrocytes. In addition, our biological results indicated that HS-Ck might suppress the expression levels of iNOS and matrix metalloproteinases-13 (MMP-13) activities through downregulating the activation of nuclear factor kappa B (NF kappaB) and signal transducer and activator of transcription 3 (STAT-3) transcriptional factors. Therefore, the parallel synthesis was successful used to develop a new class of potential anti-inflammatory agents as chondroprotective candidates for the treatment of osteoarthritis. PMID- 26963093 TI - A Secure and Robust Compressed Domain Video Steganography for Intra- and Inter Frames Using Embedding-Based Byte Differencing (EBBD) Scheme. AB - This paper presents a novel secure and robust steganographic technique in the compressed video domain namely embedding-based byte differencing (EBBD). Unlike most of the current video steganographic techniques which take into account only the intra frames for data embedding, the proposed EBBD technique aims to hide information in both intra and inter frames. The information is embedded into a compressed video by simultaneously manipulating the quantized AC coefficients (AC QTCs) of luminance components of the frames during MPEG-2 encoding process. Later, during the decoding process, the embedded information can be detected and extracted completely. Furthermore, the EBBD basically deals with two security concepts: data encryption and data concealing. Hence, during the embedding process, secret data is encrypted using the simplified data encryption standard (S-DES) algorithm to provide better security to the implemented system. The security of the method lies in selecting candidate AC-QTCs within each non overlapping 8 * 8 sub-block using a pseudo random key. Basic performance of this steganographic technique verified through experiments on various existing MPEG-2 encoded videos over a wide range of embedded payload rates. Overall, the experimental results verify the excellent performance of the proposed EBBD with a better trade-off in terms of imperceptibility and payload, as compared with previous techniques while at the same time ensuring minimal bitrate increase and negligible degradation of PSNR values. PMID- 26963091 TI - Identification and Analysis of the Role of Superoxide Dismutases Isoforms in the Pathogenesis of Paracoccidioides spp. AB - The ability of Paracoccidioides to defend itself against reactive oxygen species (ROS) produced by host effector cells is a prerequisite to survive. To counteract these radicals, Paracoccidioides expresses, among different antioxidant enzymes, superoxide dismutases (SODs). In this study, we identified six SODs isoforms encoded by the Paracoccidioides genome. We determined gene expression levels of representative isolates of the phylogenetic lineages of Paracoccidioides spp. (S1, PS2, PS3 and Pb01-like) using quantitative RT-PCR. Assays were carried out to analyze SOD gene expression of yeast cells, mycelia cells, the mycelia-to yeast transition and the yeast-to-mycelia germination, as well as under treatment with oxidative agents and during interaction with phagocytic cells. We observed an increased expression of PbSOD1 and PbSOD3 during the transition process, exposure to oxidative agents and interaction with phagocytic cells, suggesting that these proteins could assist in combating the superoxide radicals generated during the host-pathogen interaction. Using PbSOD1 and PbSOD3 knockdown strains we showed these genes are involved in the response of the fungus against host effector cells, particularly the oxidative stress response, and in a mouse model of infection. Protein sequence analysis together with functional analysis of knockdown strains seem to suggest that PbSOD3 expression is linked with a pronounced extracellular activity while PbSOD1 seems more related to intracellular requirements of the fungus. Altogether, our data suggests that P. brasiliensis actively responds to the radicals generated endogenously during metabolism and counteracts the oxidative burst of immune cells by inducing the expression of SOD isoforms. PMID- 26963092 TI - Arthrobacter pokkalii sp nov, a Novel Plant Associated Actinobacterium with Plant Beneficial Properties, Isolated from Saline Tolerant Pokkali Rice, Kerala, India. AB - A novel yellow colony-forming bacterium, strain P3B162T was isolated from the pokkali rice rhizosphere from Kerala, India, as part of a project study aimed at isolating plant growth beneficial rhizobacteria from saline tolerant pokkali rice and functionally evaluate their abilities to promote plant growth under saline conditions. The novel strain P3B162T possesses plant growth beneficial traits such as positive growth on 1-aminocyclopropane-1-carboxylic acid (ACC), production of indole acetic acid (IAA) and siderophore. In addition, it also showed important phenotypic characters such as ability to form biofilm and utilization of various components of plant root exudates (sugars, amino acids and organic acids), clearly indicating its lifestyle as a plant rhizosphere associated bacterium. Taxonomically, the novel strain P3B162T was affiliated to the genus Arthrobacter based on the collective results of phenotypic, genotypic and chemotaxonomic analyses. Moreover, molecular analysis using 16S rRNA gene showed Arthrobacter globiformis NBRC 12137T, Arthrobacter pascens DSM 20545T and Arthrobacter liuii DSXY973T as the closely related phylogenetic neighbours, showing more than 98% 16S rRNA similarity values, whereas the recA gene analysis displayed Arthrobacter liuii JCM 19864T as the nearest neighbour with 94.7% sequence similarity and only 91.7% to Arthrobacter globiformis LMG 3813T and 88.7% to Arthrobacter pascens LMG 16255T. However, the DNA-DNA hybridization values between strain P3B162T, Arthrobacter globiformis LMG 3813T, Arthrobacter pascens LMG 16255T and Arthrobacter liuii JCM 19864T was below 50%. In addition, the novel strain P3B162T can be distinguished from its closely related type strains by several phenotypic characters such as colony pigment, tolerance to NaCl, motility, reduction of nitrate, hydrolysis of DNA, acid from sucrose, cell wall sugars and cell wall peptidoglycan structure. In conclusion, the combined results of this study support the classification of strain P3B162T as a novel Arthrobacter species and we propose Arthrobacter pokkalii sp.nov.as its name. The type strain is P3B162T (= KCTC 29498T = MTCC 12358T). PMID- 26963094 TI - Identification of Dw1, a Regulator of Sorghum Stem Internode Length. AB - Sorghum is an important C4 grain and grass crop used for food, feed, forage, sugar, and biofuels. In its native Africa, sorghum landraces often grow to approximately 3-4 meters in height. Following introduction into the U.S., shorter, early flowering varieties were identified and used for production of grain. Quinby and Karper identified allelic variation at four loci designated Dw1 Dw4 that regulated plant height by altering the length of stem internodes. The current study used a map-based cloning strategy to identify the gene corresponding to Dw1. Hegari (Dw1dw2Dw3dw4) and 80M (dw1dw2Dw3dw4) were crossed and F2 and HIF derived populations used for QTL mapping. Genetic analysis identified four QTL for internode length in this population, Dw1 on SBI-09, Dw2 on SBI-06, and QTL located on SBI-01 and SBI-07. The QTL on SBI-07 was ~3 Mbp upstream of Dw3 and interacted with Dw1. Dw1 was also found to contribute to the variation in stem weight in the population. Dw1 was fine mapped to an interval of ~33 kbp using HIFs segregating only for Dw1. A polymorphism in an exon of Sobic.009G229800 created a stop codon that truncated the encoded protein in 80M (dw1). This polymorphism was not present in Hegari (Dw1) and no other polymorphisms in the delimited Dw1 locus altered coding regions. The recessive dw1 allele found in 80M was traced to Dwarf Yellow Milo, the progenitor of grain sorghum genotypes identified as dw1. Dw1 encodes a putative membrane protein of unknown function that is highly conserved in plants. PMID- 26963095 TI - Genome-Wide Investigation Using sRNA-Seq, Degradome-Seq and Transcriptome-Seq Reveals Regulatory Networks of microRNAs and Their Target Genes in Soybean during Soybean mosaic virus Infection. AB - MicroRNAs (miRNAs) play key roles in a variety of cellular processes through regulation of their target gene expression. Accumulated experimental evidence has demonstrated that infections by viruses are associated with the altered expression profile of miRNAs and their mRNA targets in the host. However, the regulatory network of miRNA-mRNA interactions during viral infection remains largely unknown. In this study, we performed small RNA (sRNA)-seq, degradome-seq and as well as a genome-wide transcriptome analysis to profile the global gene and miRNA expression in soybean following infections by three different Soybean mosaic virus (SMV) isolates, L (G2 strain), LRB (G2 strain) and G7 (G7 strain). sRNA-seq analyses revealed a total of 253 soybean miRNAs with a two-fold or greater change in abundance compared with the mock-inoculated control. 125 transcripts were identified as the potential cleavage targets of 105 miRNAs and validated by degradome-seq analyses. Genome-wide transcriptome analysis showed that total 2679 genes are differentially expressed in response to SMV infection including 71 genes predicted as involved in defense response. Finally, complex miRNA-mRNA regulatory networks were derived using the RNAseq, small RNAseq and degradome data. This work represents a comprehensive, global approach to examining virus-host interactions. Genes responsive to SMV infection are identified as are their potential miRNA regulators. Additionally, regulatory changes of the miRNAs themselves are described and the regulatory relationships were supported with degradome data. Taken together these data provide new insights into molecular SMV-soybean interactions and offer candidate miRNAs and their targets for further elucidation of the SMV infection process. PMID- 26963097 TI - Push Force Analysis of Anchor Block of the Oil and Gas Pipeline in a Single-Slope Tunnel Based on the Energy Balance Method. AB - In this paper, a single-slope tunnel pipeline was analysed considering the effects of vertical earth pressure, horizontal soil pressure, inner pressure, thermal expansion force and pipeline-soil friction. The concept of stagnation point for the pipeline was proposed. Considering the deformation compatibility condition of the pipeline elbow, the push force of anchor blocks of a single slope tunnel pipeline was derived based on an energy method. Then, the theoretical formula for this force is thus generated. Using the analytical equation, the push force of the anchor block of an X80 large-diameter pipeline from the West-East Gas Transmission Project was determined. Meanwhile, to verify the results of the analytical method, and the finite element method, four categories of finite element codes were introduced to calculate the push force, including CAESARII, ANSYS, AutoPIPE and ALGOR. The results show that the analytical results agree well with the numerical results, and the maximum relative error is only 4.1%. Therefore, the results obtained with the analytical method can satisfy engineering requirements. PMID- 26963096 TI - Metformin Induces Cell Cycle Arrest, Reduced Proliferation, Wound Healing Impairment In Vivo and Is Associated to Clinical Outcomes in Diabetic Foot Ulcer Patients. AB - BACKGROUND: Several epidemiological studies in diabetic patients have demonstrated a protective effect of metformin to the development of several types of cancer. The underlying mechanisms of such phenomenon is related to the effect of metformin on cell proliferation among which, mTOR, AMPK and other targets have been identified. However, little is known about the role that metformin treatment have on other cell types such as keratinocytes and whether exposure to metformin of these cells might have serious repercussions in wound healing delay and in the development of complications in diabetic patients with foot ulcers or in their exacerbation. MATERIAL AND METHODS: HaCaT Cells were exposed to various concentrations of metformin and cell viability was evaluated by a Resazurin assay; Proliferation was also evaluated with a colony formation assay and with CFSE dilution assay by flow cytometry. Cell cycle was also evaluated by flow cytometry by PI staining. An animal model of wound healing was used to evaluate the effect of metformin in wound closure. Also, an analysis of patients receiving metformin treatment was performed to determine the effect of metformin treatment on the outcome and wound area. Statistical analysis was performed on SPSS v. 18 and GraphPad software v.5. RESULTS: Metformin treatment significantly reduces cell proliferation; colony formation and alterations of the cell cycle are observed also in the metformin treated cells, particularly in the S phase. There is a significant increase in the area of the wound of the metformin treated animals at different time points (P<0.05). There is also a significant increase in the size and wound area of the patients with diabetic foot ulcers at the time of hospitalization. A protective effect of metformin was observed for amputation, probably associated with the anti inflammatory effects reported of metformin. CONCLUSIONS: Metformin treatment reduces cell proliferation and reduces wound healing in an animal model and affects clinical outcomes in diabetic foot ulcer patients. Chronic use of this drug should be further investigated to provide evidence of their security in association with DFU. PMID- 26963098 TI - Cervical Cancer Screening Service Uptake and Associated Factors among Age Eligible Women in Mekelle Zone, Northern Ethiopia, 2015: A Community Based Study Using Health Belief Model. AB - INTRODUCTION: Cervical cancer is the third most common cancer among women worldwide, with about 500,000 new patients diagnosed and over 250,000 deaths every year. Cervical cancer screening offers protective benefits and is associated with a reduction in the incidence of invasive cervical cancer and cervical cancer mortality. But there is very low participation rate in screening for cervical cancer among low and middle-income countries. OBJECTIVE: This study aimed to determine cervical cancer screening service uptake and its associated factor among age eligible women in Mekelle zone, northern Ethiopia, 2015. METHODS: A community based cross-sectional study was conducted in Mekelle zone among age eligible women from February to June 2015. Systematic sampling technique was used to select 1286 women in to the study. A pre-tested structured questionnaire was used to collect relevant data. Data was entered and cleaned using EPINFO and analyzed using SPSS version 20 software package. Bivariate and Multivariate logistic regression was performed to assess association between dependent and independent variables with 95% CI and p-value less than 0.05 was set for association. RESULTS: The study revealed that among 1186 age eligible women, only 235(19.8%) have been screened for cervical cancer. Age (AOR = 1.799, 95%CI = 1.182-2.739), history of multiple sexual partners (AOR = 1.635, 95%CI = 1.094-2.443), history of sexually transmitted disease (AOR = 1.635,95%CI = 1.094 2.443), HIV sero status (AOR = 5.614, 95%CI = 2.595-12.144), perceived susceptibility to cervical cancer (AOR = 2.225, 95%CI = 1.308-3.783), perceived barriers to premalignant cervical lesions screening (AOR = 2.256, 95%CI = 1.447 3.517) and knowledge on cervical cancer and screening (AOR = 2.355, 95%CI = 1.155 4.802) were significant predictors of cervical cancer screening service uptake. CONCLUSION: Magnitude of cervical cancer screening service uptake among age eligible women is still unacceptably low. Age of the women, history of multiple sexual partners and sexually transmitted disease, HIV sero-positivity, Knowledge, Perceived susceptibility and Perceived Barrier were important predictors of cervical cancer screening service uptake. PMID- 26963099 TI - Simulated Microgravity Using a Rotary Culture System Compromises the In Vitro Development of Mouse Preantral Follicles. AB - BACKGROUND: Growing cells in simulated weightlessness condition might be a highly promising new technique to maintain or generate tissue constructs in a scaffold free manner. There is limited evidence that microgravity condition may affect development of ovarian follicles. The objective of the present study was to investigate the effects of simulated microgravity on the in vitro development of mouse preantral follicles. METHODS AND RESULTS: Ovarian tissue from 14-day-old mice, or preantral follicles mechanically isolated from 14-day-old mouse ovaries were cultured at a simulated microgravity condition generated using a rotating wall vessel apparatus. Follicle survival was assessed quantitatively using H&E staining. Follicle diameter and oocyte diameter were measured under an inverted microscope. Ultrastructure of oocytes was evaluated using transmission electron microscopy. We observed that simulated microgravity compromised follicle survival in vitro, downregulated PCNA and GDF-9 expressions, and caused ultrastructural abnormalities in oocytes. CONCLUSION: This study showed for the first time that three-dimensional culture condition generated by simulated microgravity is detrimental to the initial stage development of mouse preantral follicles in vitro. The experimental setup provides a model to further investigate the mechanisms involved in the in vitro developmental processes of oocytes/granulosa cells under the microgravity condition. PMID- 26963100 TI - Evidence for Status Epilepticus and Pro-Inflammatory Changes after Intranasal Kainic Acid Administration in Mice. AB - Kainic acid (KA) is routinely used to elicit status epilepticus (SE) and epileptogenesis. Among the available KA administration protocols, intranasal instillation (IN) remains understudied. Dosages of KA were instilled IN in mice. Racine Scale and Video-EEG were used to assess and quantify SE onset. Time spent in SE and spike activity was quantified for each animal and confirmed by power spectrum analysis. Immunohistochemistry and qPCR were performed to define brain inflammation occurring after SE, including activated microglial phenotypes. Long term video-EEG recording was also performed. Titration of IN KA showed that a dose of 30 mg/kg was associated with low mortality while eliciting SE. IN KA provoked at least one behavioral and electrographic SE in the majority of the mice (>90%). Behavioral and EEG SE were accompanied by a rapid and persistent microglial-astrocytic cell activation and hippocampal neurodegeneration. Specifically, microglial modifications involved both pro- (M1) and anti inflammatory (M2) genes. Our initial long-term video-EEG exploration conducted using a small cohort of mice indicated the appearance of spike activity or SE. Our study demonstrated that induction of SE is attainable using IN KA in mice. Typical pro-inflammatory brain changes were observed in this model after SE, supporting disease pathophysiology. Our results are in favor of the further development of IN KA as a means to study seizure disorders. A possibility for tailoring this model to drug testing or to study mechanisms of disease is offered. PMID- 26963101 TI - Pathologic Evaluation of Type 2 Porcine Reproductive and Respiratory Syndrome Virus Infection at the Maternal-Fetal Interface of Late Gestation Pregnant Gilts. AB - The pathogenesis of fetal death caused by porcine reproductive and respiratory syndrome virus (PRRSV) remains unclear. The objective of this study was to improve our understanding of the pathogenesis by assessing potential relationships between specific histopathological lesions and PRRSV RNA concentration in the fetuses and the maternal-fetal interface. Pregnant gilts were inoculated with PRRSV (n = 114) or sham inoculated (n = 19) at 85+/-1 days of gestation. Dams and their litters were humanely euthanized and necropsied 21 days later. PRRSV RNA concentration was measured by qRT-PCR in the maternal-fetal interface and fetal thymus (n = 1391). Presence of fetal lesions was positively related to PRRSV RNA concentration in the maternal-fetal interface and fetal thymus (P<0.05 for both), but not to the distribution or severity of vasculitis, or the severity of endometrial inflammation. The presence of fetal and umbilical lesions was associated with greater odds of meconium staining (P<0.05 for both). The distribution and severity of vasculitis in endometrium were not significantly related to PRRSV RNA concentration in maternal-fetal interface or fetal thymus. Endometrial inflammation severity was positively related to distribution and severity of vasculitis in endometrium (P<0.001 for both). Conclusions from this study suggest that type 2 PRRSV infection in pregnant gilts induces significant histopathological lesions at maternal-fetal interface, but they are not associated with presence of PRRSV in the maternal-fetal interface at 21 days post infection. Conversely, fetal pathological lesions are associated with presence of PRRSV in the maternal-fetal interface and fetal thymus, and meconium staining is significantly associated with the presence of both fetal and umbilical lesions observed 21 days post infection. PMID- 26963102 TI - Synchronization and Propagation of Global Sleep Spindles. AB - Sleep spindles occur thousands of times during normal sleep and can be easily detected by visual inspection of EEG signals. These characteristics make spindles one of the most studied EEG structures in mammalian sleep. In this work we considered global spindles, which are spindles that are observed simultaneously in all EEG channels. We propose a methodology that investigates both the signal envelope and phase/frequency of each global spindle. By analysing the global spindle phase we showed that 90% of spindles synchronize with an average latency time of 0.1 s. We also measured the frequency modulation (chirp) of global spindles and found that global spindle chirp and synchronization are not correlated. By investigating the signal envelopes and implementing a homogeneous and isotropic propagation model, we could estimate both the signal origin and velocity in global spindles. Our results indicate that this simple and non invasive approach could determine with reasonable precision the spindle origin, and allowed us to estimate a signal speed of 0.12 m/s. Finally, we consider whether synchronization might be useful as a non-invasive diagnostic tool. PMID- 26963109 TI - Imaging in Dermatology. Introduction. PMID- 26963103 TI - Versatile Trans-Replication Systems for Chikungunya Virus Allow Functional Analysis and Tagging of Every Replicase Protein. AB - Chikungunya virus (CHIKV; genus Alphavirus, family Togaviridae) has recently caused several major outbreaks affecting millions of people. There are no licensed vaccines or antivirals, and the knowledge of the molecular biology of CHIKV, crucial for development of efficient antiviral strategies, remains fragmentary. CHIKV has a 12 kb positive-strand RNA genome, which is translated to yield a nonstructural (ns) or replicase polyprotein. CHIKV structural proteins are expressed from a subgenomic RNA synthesized in infected cells. Here we have developed CHIKV trans-replication systems, where replicase expression and RNA replication are uncoupled. Bacteriophage T7 RNA polymerase or cellular RNA polymerase II were used for production of mRNAs for CHIKV ns polyprotein and template RNAs, which are recognized by CHIKV replicase and encode for reporter proteins. CHIKV replicase efficiently amplified such RNA templates and synthesized large amounts of subgenomic RNA in several cell lines. This system was used to create tagged versions of ns proteins including nsP1 fused with enhanced green fluorescent protein and nsP4 with an immunological tag. Analysis of these constructs and a matching set of replicon vectors revealed that the replicases containing tagged ns proteins were functional and maintained their subcellular localizations. When cells were co-transfected with constructs expressing template RNA and wild type or tagged versions of CHIKV replicases, formation of characteristic replicase complexes (spherules) was observed. Analysis of mutations associated with noncytotoxic phenotype in CHIKV replicons showed that a low level of RNA replication is not a pre-requisite for reduced cytotoxicity. The CHIKV trans-replicase does not suffer from genetic instability and represents an efficient, sensitive and reliable tool for studies of different aspects of CHIKV RNA replication process. PMID- 26963110 TI - Current state of imaging in dermatology. AB - Medical imaging has dramatically transformed the practice of medicine, especially the field of dermatology. Imaging is used to facilitate the transfer of information between providers, document cutaneous disease, assess response to therapy, and plays a crucial role in monitoring and diagnosing skin cancer. Advancements in imaging technology and overall improved quality of imaging have augmented the utility of photography. We provide an overview of current imaging technologies used in dermatology with a focus on their role in skin cancer diagnosis. Future technologies include three-dimensional, total-body photography, mobile smartphone applications, and computerassisted diagnostic devices. With these advancements, we are better equipped to capture and monitor skin conditions longitudinally and achieve improved diagnostic accuracy of skin cancer. PMID- 26963104 TI - Understanding Genotype-Phenotype Effects in Cancer via Network Approaches. AB - Cancer is now increasingly studied from the perspective of dysregulated pathways, rather than as a disease resulting from mutations of individual genes. A pathway centric view acknowledges the heterogeneity between genomic profiles from different cancer patients while assuming that the mutated genes are likely to belong to the same pathway and cause similar disease phenotypes. Indeed, network centric approaches have proven to be helpful for finding genotypic causes of diseases, classifying disease subtypes, and identifying drug targets. In this review, we discuss how networks can be used to help understand patient-to-patient variations and how one can leverage this variability to elucidate interactions between cancer drivers. PMID- 26963111 TI - The role of imaging in the prevention of wrong-site surgery in dermatology. AB - Wrong-site surgery in dermatology often results from inaccurate identification of a skin cancer biopsy site. Factors making biopsy-site identification difficult include background actinic damage, delays from biopsy to surgery, and lack of photographic documentation. While other methods exist for biopsy-site identification, photography is the most helpful tool available. Although modern technology has made high-quality photographic equipment ubiquitous and easy to use, photography for biopsy-site identification continues to be underutilized. The authors recommend that photographic documentation of biopsy sites become the standard of care. PMID- 26963112 TI - Self-acquired patient images: the promises and the pitfalls. AB - Self-acquired patient images, also known as selfies, are increasingly utilized in the practice of dermatology; however, research on their utility is somewhat limited. While the implementation of selfies has yet to be universally accepted, their role in triage appears to be especially useful. The potential for reducing office wait times, expediting referrals, and providing dermatologic services to patients with limited access to care is promising. In addition, as technology advances, the number of smartphone applications related to dermatology that are available to the general public has risen exponentially. With appropriate standardization, regulation, and confidentiality measures, these tools can be feasible adjuncts in clinical practice, dermatologic surgery, and teledermatology. Selfies likely will have a large role in dermatologic practice and delivery in the future. PMID- 26963113 TI - Advances in noninvasive imaging of melanoma. AB - Melanoma is the most dangerous type of skin cancer and its incidence has risen sharply in recent decades. Early detection of disease is critical for improving patient outcomes. Any pigmented lesion that is clinically concerning must be removed by biopsy for morphologic investigation on histology. However, biopsies are invasive and can cause significant morbidity, and their accuracy in detecting melanoma may be limited by sampling error. The advent of noninvasive imaging devices has allowed for assessment of intact skin, thereby minimizing the need for biopsy; and these technologies are increasingly being used in the diagnosis and management of melanoma. Reflectance confocal microscopy, optical coherence tomography, ultrasonography, and multispectral imaging are noninvasive imaging techniques that have emerged as diagnostic aids to physical exam and/or conventional dermoscopy. This review summarizes the current knowledge about these techniques and discusses their practical applications and limitations. PMID- 26963114 TI - Computer-assisted diagnosis of melanoma. AB - The computer-assisted diagnosis of melanoma is an exciting area of research where imaging techniques are combined with diagnostic algorithms in an attempt to improve detection and outcomes for patients with skin lesions suspicious for malignancy. Once an image has been acquired, it undergoes a processing pathway which includes preprocessing, enhancement, segmentation, feature extraction, feature selection, change detection, and ultimately classification. Practicality for everyday clinical use remains a vital question. A successful model must obtain results that are on par or outperform experienced dermatologists, keep costs at a minimum, be user-friendly, and be time efficient with high sensitivity and specificity. PMID- 26963115 TI - Noninvasive imaging for nonmelanoma skin cancer. AB - The development of noninvasive optical technologies is revolutionizing the diagnosis of skin tumors. Nonmelanoma skin cancer, the most frequent neoplasm, has become an important health and economic issue, and proper management can avoid unnecessary morbidity and mutilating treatment or relapses. Noninvasive treatment modalities and the recently approved systemic therapies for advanced basal cell carcinoma cases make noninvasive monitoring techniques necessary. Current knowledge, applications, and limitations of the tools most clinically implemented, such as dermoscopy, reflectance confocal microscopy, high frequency ultrasonography, and optical coherence tomography will be reviewed in this article. In addition to the improvement of diagnostic accuracy of skin cancer, using these tools individually or in combination facilitates better management of certain patients and tumors. PMID- 26963116 TI - Radiographic imaging for skin cancer. AB - Radiographic imaging is important for the full evaluation of high-risk cutaneous tumors. The correct modality should be chosen based on tumor subtype and clinical question. Locally advanced tumors may require imaging to evaluate the extent of disease, such as bony involvement, orbital infiltration, or perineural invasion. Tumors at high risk for regional and distant metastasis require imaging to identify local and distant tumor burden. PMID- 26963118 TI - Influence of sulphate on the reduction of cadmium toxicity in the microalga Chlamydomonas moewusii. AB - Cadmium is considered as one of the most hazardous metals for living organism and ecosystems. Environmental factors play an important role since they alter the toxicity of metals by varying the bioavailability of these elements for the organisms. The aim of the present study was to investigate, using the freshwater microalga Chlamydomonas moewusii, the existence of an interaction between cadmium and sulphate as a factor that varied the toxicity of this metal. Different cell parameters such as cell growth, content of chlorophylls and biosynthesis of phytochelatins (PCs) were determined. A two-way ANOVA showed that the interaction had a significant effect size of 21% (p<0.001) for the growth of this microalga and around of a 6% on the content of chlorophylls/cell. The effect of this inhibition was that when the concentration of sulphate increased, a lower toxic effect of cadmium on the growth and on the content of chlorophylls was observed. In addition, the increase of sulphate concentration allowed the biosynthesis of a higher amount of PCs and/or PCs with higher chain length. This higher biosynthesis was responsible for the reduction of the toxic effect of cadmium and explained the interaction. PMID- 26963117 TI - Epilepsy, Behavioral Abnormalities, and Physiological Comorbidities in Syntaxin Binding Protein 1 (STXBP1) Mutant Zebrafish. AB - Mutations in the synaptic machinery gene syntaxin-binding protein 1, STXBP1 (also known as MUNC18-1), are linked to childhood epilepsies and other neurodevelopmental disorders. Zebrafish STXBP1 homologs (stxbp1a and stxbp1b) have highly conserved sequence and are prominently expressed in the larval zebrafish brain. To understand the functions of stxbp1a and stxbp1b, we generated loss-of-function mutations using CRISPR/Cas9 gene editing and studied brain electrical activity, behavior, development, heart physiology, metabolism, and survival in larval zebrafish. Homozygous stxbp1a mutants exhibited a profound lack of movement, low electrical brain activity, low heart rate, decreased glucose and mitochondrial metabolism, and early fatality compared to controls. On the other hand, homozygous stxbp1b mutants had spontaneous electrographic seizures, and reduced locomotor activity response to a movement-inducing "dark flash" visual stimulus, despite showing normal metabolism, heart rate, survival, and baseline locomotor activity. Our findings in these newly generated mutant lines of zebrafish suggest that zebrafish recapitulate clinical phenotypes associated with human syntaxin-binding protein 1 mutations. PMID- 26963129 TI - Inhibition of Sonic Hedgehog Signaling Pathway by Thiazole Antibiotic Thiostrepton Attenuates the CD44+/CD24-Stem-Like Population and Sphere-Forming Capacity in Triple-Negative Breast Cancer. AB - BACKGROUND/AIM: Triple-negative breast cancer (TNBC) represents a particular clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents. The lack of effective agents and obvious targets are major challenges in treating TNBC. In this study we explored the cytostatic effect of thiazole ring containing antibiotic drug thiostrepton on TNBC cell lines and investigated the molecular mechanism. METHODS: Cell viability was measured by MTT assay. Cell surface marker was monitored by FCM. Western blot was applied to assess the protein expression levels of target genes. RESULTS: We found that thiostrepton remarkably suppressed the CD44+/CD24- stem-like population and sphere forming capacity of TNBC cell lines. Notably, we showed for the first time that thiostrepton exerted its pharmacological action by targeting sonic hedgehog (SHH) signaling pathway. Thiostrepton repressed SHH ligand expression and reduced Gli-1 nuclear localization in TNBC cell line. Furthermore, the downstream target of SHH signaling undergone dose-dependent, rapid, and sustained loss of mRNA transcript level after thiostrepton treatment. Finally, we showed that SHH ligand was essential for maintaining CD44+/CD24- stem-like population in TNBC cell line. CONCLUSION: We conclude that thiostrepton suppresses the CD44+/CD24- stem-like population through inhibition of SHH signaling pathway. Our results give a new insight into the mechanism of thiostrepton anti-tumor activity and suggest thiostrepton as a promising agent that targets hedgehog signaling pathway in TNBC. PMID- 26963119 TI - Reduced DNA double-strand break repair capacity and risk of squamous cell carcinoma of the head and neck--A case-control study. AB - Tobacco smoke and alcohol use play important roles in the etiology of squamous cell carcinoma of the head and neck (SCCHN). Smoking causes DNA damage, including double-strand DNA breaks (DSBs), that leads to carcinogenesis. To test the hypothesis that suboptimal DSB repair capacity is associated with risk of SCCHN, we applied a flow cytometry-based method to detect the DSB repair phenotype first in four EBV-immortalized human lymphoblastoid cell lines and then in human peripheral blood T-lymphocytes (PBTLs). With this blood-based laboratory assay, we conducted a pilot case-control study of 100 patients with newly diagnosed, previously untreated SCCHN and 124 cancer-free controls of non-Hispanic whites. We found that the mean DSB repair capacity level was significantly lower in cases (42.1%) than that in controls (54.4%) (P<0.001). When we used the median DSB repair capacity level in the controls as the cutoff value for calculating the odds ratios (ORs) with adjustment for age, sex, smoking and drinking status, the cases were more likely than the controls to have a reduced DSB repair capacity (adjusted OR=1.93; 95% confidence interval, CI=1.04-3.56, P=0.037), especially for those subjects who were ever drinkers (adjusted OR=2.73; 95% CI=1.17-6.35, P=0.020) and had oropharyngeal tumors (adjusted OR=2.17; 95% CI=1.06-4.45, P=0.035). In conclusion, these findings suggest that individuals with a reduced DSB repair capacity may be at an increased risk of developing SCCHN. Larger studies are warranted to confirm these preliminary findings. PMID- 26963130 TI - Laparoscopic Transperitoneal Lateral Adrenalectomy for Large Adrenal Tumors. AB - BACKGROUND: Laparoscopic adrenalectomy is the gold standard for treatment of benign adrenal lesions. Tumor size is a factor that might influence decision making concerning the use of laparoscopic approach. The aim of this study was to analyze the results of adrenalectomy for tumors >=6 cm in diameter. METHODS: Two groups of patients were analyzed: first group comprised 441 patients with tumors <6 cm in diameter and second group consisted of 89 patients with tumors >=6 cm. Both groups were compared with regard to the duration of surgery, intraoperative blood loss, conversion and complications rate. RESULTS: Median duration of surgery in groups 1 and 2 amounted to 86.6 and 111.9 min (p < 0.0001), respectively. Median intraoperative blood loss in groups 1 and 2 was 56.5 and 172.8 ml (p < 0.0001), respectively. There was a linear relationship between tumor size and the duration of surgery, and between tumor size and intraoperative blood loss (p < 0.0001). There were 2 (0.5%) and 6 (6.7%) conversions in groups 1 and 2, respectively. There were 41 (9.3%) and 14 (15.7%) complications in groups 1 and 2 (p = 0.0692), respectively. CONCLUSIONS: Laparoscopic adrenalectomy of tumors >=6 cm is more difficult, but it can be regarded safe and beneficial for patients. PMID- 26963131 TI - Evidence-based guidelines for recommending cochlear implantation for postlingually deafened adults. AB - OBJECTIVE: Adult selection criteria for cochlear implantation have been developed based on analysis of the post-operative performance of a large group of postlingually deafened adults. Original criteria published in 2004 were reviewed and amended to reflect outcomes currently being achieved by implant recipients. DESIGN: Retrospective review of 12-month post-operative speech perception performance of adults implanted at the Eye and Ear Hospital, Melbourne, Australia. STUDY SAMPLE: A total of 382 postlingually deafened adults, using a Freedom, Nucleus 5, or CI422 Slim Straight cochlear implant were used to create a comparative set of data. RESULTS: Revised guidelines suggest that adults with postlingual hearing loss can now be considered cochlear implant candidates if they obtain scores of up to 55% for open-set phonemes in quiet in the ear to be implanted. Functional benefit may vary depending on the recipients' contralateral hearing. CONCLUSIONS: This study supports the provision of cochlear implants to candidates with significant residual hearing when at least one ear meets the criterion outlined above. Patient-specific counseling is required to ensure the potential to benefit predicted by the current model is acceptable to the individual patient and their family. Counseling regarding functional benefit must take into consideration hearing in the contralateral ear. PMID- 26963132 TI - New developments for antibody-drug conjugate-based therapeutic approaches. AB - The clinical success of Adcetris((r)) (brentuximab vedotin) and Kadcyla((r)) (ado trastuzumab emtansine) has sparked clinical development of novel ADCs. These powerful anti-cancer agents are designed to allow specific targeting of highly potent cytotoxic agents to tumor cells while sparing healthy tissues. Despite the use of tumor-specific antibodies, the emerging clinical data with ADCs indicates that adverse effects frequently occur before ADCs have reached their optimal therapeutic dose, resulting in a relatively narrow therapeutic window. This review summarizes the therapeutic window of ADCs currently in clinical development, along with some strategies that may help to widen the window. PMID- 26963134 TI - Ultrastructural features of spermatozoa and their phylogenetic application in Zaprionus (Diptera, Drosophilidae). AB - The genus Zaprionus consists of approximately 60 species of drosophilids that are native to the Afrotropical region. The phylogenetic position of Zaprionus within the Drosophilidae family is still unresolved. In the present study, ultrastructural features of spermatozoa of 6 species of Zaprionus as well as the species Drosophila willistoni and Scaptodrosophila latifasciaeformis were analyzed. The ultrastructure revealed that the species have the same flagellar ultrastructure. Two mitochondrial derivatives, one larger than the other, close to the axoneme were present, primarily in D. willistoni (subgenus Sophophora). Except for Z. davidi and Z. tuberculatus, the analyzed species had paracrystalline material in both mitochondrial derivatives. Moreover, the testes showed 64 spermatozoa per bundle in all of the species. In the cluster analysis, 6 Zaprionus species were grouped closely, but there were some incongruent positions in the cladogram. The results indicated that sperm ultrastructure is an important tool for elucidating the phylogeny and taxonomy of insects. PMID- 26963135 TI - Gender Differences in C-Reactive Protein and Muscle Strengthening Activity. AB - BACKGROUND: Few studies have examined the gender differences between C-reactive protein (CRP) and muscle strengthening activity (MSA). METHODS: The sample (n = 7533) included U.S. adult (>=20 years of age).participants in the 1999-2004 National Health and Nutrition Examination Survey (NHANES). Created categories of MSA participation included no MSA (referent group), some MSA (>=1 to <2 days/week), and meeting the 2008 Department of Health and Human Services (DHHS) recommendation (>=2 days/week). The dependent variable was elevated CRP (>3 to 10 mg/L). RESULTS: Analysis revealed significantly lower odds of having elevated CRP for women reporting some MSA (OR 0.64; 95% CI 0.44-0.93, P = .0191). Significantly lower odds of men having elevated CRP was observed in those reporting MSA volumes meeting the DHHS recommendation (OR 0.72; 95% CI 0.59-0.88, P = .0019). Following adjustment for waist circumference (WC) these odds remained significant in men but not women. CONCLUSIONS: These results suggest that WC may mediate the associations between MSA and CRP and this relationship may be stronger in women. PMID- 26963136 TI - To share or not to share? The contribution of self-disclosure to stress-related growth among suicide survivors. AB - This study examined to what extent suicide survivors can experience growth in the aftermath of suicide loss, as well as the role of self-disclosure and coping strategies in stress-related growth (SRG) among suicide survivors, compared to bereavement following sudden and expected death types. One hundred forty-five bereaved individuals (aged 18-73) completed questionnaires measuring SRG, self disclosure, and coping strategies. Significant interaction between self disclosure and types of death was found, in which suicide survivors with low levels of self-disclosure manifested the lowest level of SRG compared to other subgroups. This finding suggests that sharing intimate information can be beneficial in struggling with a situation of suicide in the family. PMID- 26963133 TI - Bispecific antibodies and CARs: generalized immunotherapeutics harnessing T cell redirection. AB - To realize the full potential of cancer immunotherapy, the latest generation immunotherapeutics are designed to harness the potent tumor-killing capacity of T cells. Thus, to mobilize T cells, new optimized bispecific antibody (BsAb) designs, enabling efficient polyclonal redirection of cytotoxic activity through binding to CD3 and a Tumor Associated Antigen (TAA) and refined genetically modified T cells have recently expanded the arsenal of available options for cancer treatment. This review presents the current understanding of the parameters crucial to the design of optimal T cell redirecting BsAb and chimeric antigen receptor (CAR)-modified T cells. However, there are additional questions that require thorough elucidation. Both modalities will benefit from design changes that may increase the therapeutic window. One such approach could employ the discrimination afforded by multiple TAA to significantly increase selectivity. PMID- 26963137 TI - Mapping and Tuning the Fluorescence of Perfluorinated Polyanilines Synthesized through Liquid-Liquid Interfaces. AB - A series of light-emitting perfluorinated polyanilines were synthesized by the oxidative polymerization of 3-perfluorooctyl aniline through a variety of aqueous/organic interfaces. According to the interfacial tension between the two solvents (the organic being chloroform, dichloromethane, perfluorinated ether, toluene, or o-dichlorobenzene), we obtain distinctive classes of materials based on the crystal packing, protonation, and oxidation state of the polymeric chains. We distinguish between soluble fractions with a distinctive, strong, and red shifted photoluminescence pattern and an insoluble precipitate which can be subsequently solubilized in a mixture of acetone and toluene. The emission maximum for the insoluble fraction is located in the ultraviolet or blue region with a small Stokes shift; maxima for the soluble counterparts are in the green to yellow region. The soluble derivatives demonstrate a significantly smaller band gap compared to the monomer and large Stokes shifts up to 163 nm; the emission maximum for the most red-shifted emission was located at lambda(em) = 548 nm. Their redox activity toward silver nanoparticles, their sensor reactivity with organic acid and bases, and the subsequent changes in the optical properties were demonstrated and the structure of the materials was evaluated with NMR, X ray diffraction, and FTIR/Raman spectroscopy. PMID- 26963139 TI - Irisin immunohistochemistry in gastrointestinal system cancers. AB - Cancer is the leading cause of morbidity and mortality worldwide. Some studies have shown that high heat kills cancer cells. Irisin is a protein involved in heat production by converting white into brown adipose tissue, but there is no information about how its expression changes in cancerous tissues. We used irisin antibody immunohistochemistry to investigate changes in irisin expression in gastrointestinal cancers compared to normal tissues. Irisin was found in human brain neuroglial cells, esophageal epithelial cells, esophageal epidermoid carcinoma, esophageal adenocarcinoma and neuroendocrine esophageal carcinoma, gastric glands, gastric adenosquamous carcinoma, gastric neuroendocrine carcinoma, gastric signet ring cell carcinoma, neutrophils in vascular tissues, intestinal glands of colon, colon adenocarcinoma, mucinous colon adenocarcinoma, hepatocytes, hepatocellular carcinoma, islets of Langerhans, exocrine pancreas, acinar cells and interlobular and interlobular ducts of normal pancreas, pancreatic ductal adenocarcinoma, and intra- and interlobular ducts of cancerous pancreatic tissue. Histoscores (area * intensity) indicated that irisin was increased significantly in gastrointestinal cancer tissues, except liver cancers. Our findings suggest that the relation of irisin to cancer warrants further investigation. PMID- 26963140 TI - Electrical Characterization of Ultrathin RF-Sputtered LiPON Layers for Nanoscale Batteries. AB - Ultrathin lithium phosphorus oxynitride glass (LiPON) films with thicknesses down to 15 nm, deposited by reactive sputtering in nitrogen plasma, were found to be electronically insulating. Such ultrathin electrolyte layers could lead to high power outputs and increased battery energy densities. The effects of stoichiometry, film thickness, and substrate material on the ionic conductivity were investigated. As the amount of nitrogen in the layers increased, the activation energy of the ionic conductivity decreased from 0.63 to 0.53 eV, leading to a maximum conductivity of 1 * 10(-6) S/cm. No dependence of the ionic conductivity on the film thickness or substrate material could be established. A detailed analysis of the equivalent circuit model used to fit the impedance data is provided. Polarization measurements were performed to determine the electronic leakage in these ultrathin films. A 15-nm LiPON layer on a TiN substrate showed electronically insulating properties with electronic resistivity values around 10(15) Omega.cm. To our knowledge, this is the thinnest RF-sputtered LiPON layer shown to be electronically insulating while retaining good ionic conductivity. PMID- 26963138 TI - Current status and recent advances of next generation sequencing techniques in immunological repertoire. AB - To ward off a wide variety of pathogens, the human adaptive immune system harbors a vast array of T-cell receptors (TCRs) and B-cell receptors (BCRs), collectively referred to as the immune repertoire. High-throughput sequencing (HTS) of TCR/BCR genes allows in-depth molecular analysis of T/B-cell clones, providing an unprecedented level of detail when examining the T/B-cell repertoire of individuals. It can evaluate TCR/BCR complementarity-determining region 3 (CDR3) diversity and assess the clonal composition, including the size of the repertoire; similarities between repertoires; V(D)J segment use; nucleotide insertions and deletions; CDR3 lengths; and amino acid distributions along the CDR3s at sequence-level resolution. Deep sequencing of B-cell and T-cell repertoires offers the potential for a quantitative understanding of the adaptive immune system in healthy and disease states. Recently, paired sequencing strategies have also been developed, which can provide information about the identity of immune receptor pairs encoded by individual T or B lymphocytes. HTS technology provides a previously unimaginable amount of sequence data, accompanied, however, by numerous challenges associated with error correction and interpretation that remain to be solved. The review details some of the technologies and some of the recent achievements in this field. PMID- 26963142 TI - Bougainvinones A-H, Peltogynoids from the Stem Bark of Purple Bougainvillea spectabilis and Their Cytotoxic Activity. AB - Eight new peltogynoids, named bougainvinones A-H (1-8), were obtained from the stem bark of Bougainvillea spectabilis. Their structures were elucidated by means of physical data (1D and 2D NMR, HRESIMS) and single-crystal X-ray crystallographic analyses. The peltogynoids, a rare type of modified flavonoids, are reported for the first time from this species of the genus Bougainvillea. All isolated compounds were evaluated for their cytotoxic effects against five cancer cell lines including KB, Hela S-3, HT-29, MCF-7, and HepG2. Among them, compound 7 showed cytotoxicity against five cancer cell lines with IC50 values in the 7.4 9.7 MUM range, and compounds 2 and 3 exhibited cytotoxicity against the KB cell line with IC50 values of 6.6 and 9.0 MUM. PMID- 26963141 TI - Biological Properties of a 3',3"-Bis-Peptide-siRNA Conjugate in Vitro and in Vivo. AB - This study proposes an effective melanoma small interfering RNA (siRNA), named siMB3, which targets the mRNA of mutant BRAF protein. We found that Bis-pep siMB3, with peptide KALLAL-conjugated siMB3 at the 3'-termini of both strands, inhibited translation of the target genes and expression of the related protein as effectively as siMB3, but for substantially longer, and the conjugates could alleviate off-target effects. Further studies on the mechanisms of action showed that the stability of Bis-pep-siMB3 in fetal bovine serum improved and the half life period of Bis-pep-siMB3 was increased 21-fold over that of siMB3. Peptide conjugation could improve the combination of siRNA and cationic lipid vectors. Bis-pep-siMB3 is likely to reach the lysosome earlier and stay longer, and appears to increase the release of siRNA from the endosome. At the animal level, application of Bis-pep-siMB3 showed good therapeutic potential, inhibiting the growth of xenograft tumors in athymic mice slightly better than siMB3 and greatly prolonging the circulating time in vivo. Moreover, it distributed widely in mice. These results show the promising potential of Bis-pep-siRNA conjugates as therapeutic siRNAs for cancer treatment. PMID- 26963144 TI - Elderly Woman With Acute Abdomen and Gastric Mass on Imaging. PMID- 26963145 TI - Long-Pulsed Dye Laser of 595 nm in Combination With Pigment-Specific Modalities for a Patient Exhibiting Increased Vascularity Within Lesions of Melasma. PMID- 26963143 TI - Beta cell specific probing with fluorescent exendin-4 is progressively reduced in type 2 diabetic mouse models. AB - Probes based on GLP-1R agonist exendin-4 have shown promise as in vivo beta cell tracers. However, questions remain regarding the beta cell specificity of exendin 4 probes, and it is unclear if the expression levels of the GLP-1R are affected in a type 2 diabetic state. Using in vivo probing followed by ex vivo imaging we found fluorescent exendin-4 probes to distinctly label the pancreatic islets in mice in a Glp-1r dependent manner. Furthermore, a co-localization study revealed a near 100 percent beta cell specificity with less than one percent probing in other analyzed cell types. We then tested if probing was affected in models of type 2 diabetes using the Lepr(db/db) (db/db) and the Diet-Induced Obese (DIO) mouse. Although nearly all beta cells continued to be probed, we observed a progressive decline in probing intensity in both models with the most dramatic reduction seen in db/db mice. This was paralleled by a progressive decrease in Glp-1r protein expression levels. These data confirm beta cell specificity for exendin-4 based probes in mice. Furthermore, they also suggest that GLP-1R targeting probes may provide a tool to monitor beta cell function rather than mass in type 2 diabetic mouse models. PMID- 26963146 TI - Clinical and Histopathologic Assessment of Facial Melasma After Low-Fluence Q Switched Neodymium-Doped Yttrium Aluminium Garnet Laser. AB - BACKGROUND: Melasma is a frequent and difficult to treat skin disorder. Results of laser therapy are inconsistent. OBJECTIVE: To determine the safety and efficacy of low-fluence Q-switched neodymium-doped yttrium aluminum garnet (QS Nd:YAG) laser for melasma treatment and assess recurrence rates and histopathologic findings before and after treatment. METHODS: Twenty patients were treated with 10 weekly sessions of low-fluence 1064-nm QS Nd:YAG laser at 1 week intervals. The modified Melasma Area and Severity Index (mMASI) score was evaluated at baseline; 1 week; and 1, 3, and 6 months after treatment. Epidermal melanin quantification was performed on 10 biopsy samples and compared before and after treatment. RESULTS: All patients showed improvement by mMASI scores, range (21%-75%) compared with that at baseline. No permanent side effects occurred. The recurrence rate was 81%. By histopathology, a slight, nonsignificant (p = .305) decrease in melanin deposition was seen in all layers of the epidermis 1 week after the laser treatments ended. CONCLUSION: The results confirm the safety and effectiveness of low-fluence QS Nd:YAG laser for treating melasma; however, the high recurrence suggests poor long-term results when the laser is used as a monotherapy. PMID- 26963147 TI - The Effect of Neodymium: Yttrium Aluminum Garnet and Fractional Carbon Dioxide Lasers on Alopecia Areata: A Prospective Controlled Clinical Trial. AB - BACKGROUND: Effective treatment options for alopecia areata (AA) are missing. Whether lasers might be effective is a topic of debate. OBJECTIVE: We aimed to evaluate whether neodymium: yttrium aluminum garnet (Nd:YAG) or fractional carbon dioxide lasers might stimulate the development of new hair. MATERIALS AND METHODS: Thirty-two patients who had long-standing and treatment refractory diseases were recruited for the study. Three different patches on the scalp were selected, 1 of which served as control. The mean outcome measure was the hair count, which was calculated with the digital phototrichogram. Response was defined as at least 25% increase in the mean hair count at the treated patch compared with the control patch. RESULTS: At the end of the study, there was no statistically significant difference in the mean hair count for the 3 patches. In 7 of 32 patients (22%), an increase in the mean hair count was observed on the whole scalp including the control patch, which resulted in an improved Severity of Alopecia Tool (SALT) score. CONCLUSION: We have observed that Nd:YAG or fractional carbon dioxide lasers did not increase the mean hair count on the treated AA patches when compared with the control patch. However, an SALT score improvement in 22% of the patients suggested spontaneous remission. PMID- 26963148 TI - Processes governing the stable isotope composition of water in the St. Lawrence river system, Canada. AB - Linkages between delta(18)O-delta(2)H and hydrological processes have been investigated from isotopic time series recorded in the St. Lawrence River basin. Three stations were monitored from 1997 to 2008. They include the Ottawa River, the St. Lawrence River main channel at Montreal and the fluvial estuary. All sites depict seasonal isotopic cycles characterized by heavy isotope depletions during the snowmelt period and heavy isotope enrichments throughout the ice-free period. The data define delta(2)H-delta(18)O regression lines falling below the meteoric water line. In the Ottawa River, calculations suggest that approximately 8 % of the total inflow to the basin is lost through evaporation. In the St. Lawrence River main channel, seasonal isotopic fluctuations most likely reflect hydrological processes occurring within the Great Lakes and mixing with tributaries located downstream. In the St. Lawrence River fluvial estuary, isotopic data allow partitioning streamflow components and suggest that the recorded seasonal variations mainly respond to mixing processes. PMID- 26963149 TI - Concise Total Synthesis of Lundurines A-C Enabled by Gold Catalysis and a Homodienyl Retro-Ene/Ene Isomerization. AB - The total synthesis of lundurines A-C has been accomplished in racemic and enantiopure forms in 11-13 and 12-14 steps, respectively, without protection/deprotection of functional groups, by a novel tandem double condensation/Claisen rearrangement, a gold(I)-catalyzed alkyne hydroarylation, a cyclopropanation via formal [3 + 2] cycloaddition/nitrogen extrusion, and a remarkable olefin migration through a vinylcyclopropane retro-ene/ene reaction that streamlines the endgame. PMID- 26963150 TI - Recent HCV genotype changing pattern in the Khyber Pakhtunkhwa province of Pakistan; is it pointing out a forthcoming problem? PMID- 26963151 TI - Cytotoxic factor secreted by Escherichia coli associated with sepsis facilitates transcytosis through human umbilical vein endothelial cell monolayers. AB - Culture supernatant of sepsis-associated Escherichia coli (SEPEC) isolated from patients with sepsis caused loss of intercellular junctions and elongation of human umbilical vein endothelial cells (HUVEC). The cytotoxic factor was purified from culture supernatant of SEPEC 15 (serogroup O153) by liquid chromatography process. PAGE (polyacrylamide gel electrophoresis) showed that the purified SEPEC cytotoxic factor had a molecular mass of ~150kDa and consisted of at least two subunits. At the concentration of 1 CD50 (40MUg/mL) did facilitate transcytosis through the HUVEC cells monolayer of SEPEC 15 as much as E. coli K12 within 30min without affecting cell viability. These results suggest that this cytotoxic factor, named as SPF (SEPEC's permeabilizing factor), may be an important SEPEC virulence factor that facilitates bacterial access to the bloodstream. PMID- 26963153 TI - Safety of testosterone replacement therapy. PMID- 26963154 TI - Zarxio--a filgrastim biosimilar. PMID- 26963152 TI - Aspergillus niger - a possible new etiopathogenic agent in Tinea capitis? Presentation of two cases. AB - Tinea capitis is generally considered as the most frequent fungal infection in childhood, as it accounts for approximately 92% of all mycosis in children. The epidemiology of this disease varies widely ranging from antropophillic, zoophilic, and geophillic dermatophytes, as the main causative agent in different geographic areas, depending on several additional factors. Nowadays, the etiology is considered to vary with age, as well with gender, and general health condition. The former reported extraordinary Tinea capitis case reports have been replaced by original articles and researches dealing with progressively changing patterns in etiology and clinical manifestation of the disease. This fact is indicative that under the umbrella of the well-known disease there are facts still hidden for future revelations. Herein, we present two rare cases of Tinea capitis in children, which totally differ from the recently established pattern, in their clinical presentation, as well as in the etiological aspect, as we discuss this potential new etiological pattern of the disease, focusing on our retrospective and clinical observation. Collected data suggest that pathogenic molds should be considered as a potential source of infection in some geographic regions, which require total rationalization of the former therapeutic conception, regarding the molds' higher antimitotic resistance compared to dermatophytes. Molds-induced Tinea capitis should be also considered in clinically resistant and atypical cases, with further investigations of the antifungal susceptibility of the newest pathogens in the frame of the old disease. Further investigations are still needed to confirm or reject this proposal. PMID- 26963155 TI - Low-dose meloxicam (Vivlodex) for osteoarthritis pain. PMID- 26963156 TI - Isavuconazonium sulfate (Cresemba)--a new antifungal. PMID- 26963157 TI - The growing pipeline of natural aminoacyl-tRNA synthetase inhibitors for malaria treatment. AB - Malaria remains a major global health problem. Parasite resistance to existing drugs makes development of new antimalarials an urgency. The protein synthesis machinery is an excellent target for the development of new anti-infectives, and aminoacyl-tRNA synthetases (aaRS) have been validated as antimalarial drug targets. However, avoiding the emergence of drug resistance and improving selectivity to target aaRS in apicomplexan parasites, such as Plasmodium falciparum, remain crucial challenges. Here we discuss such issues using examples of known inhibitors of P. falciparum aaRS, namely halofuginone, cladosporin and borrelidin (inhibitors of ProRS, LysRS and ThrRS, respectively). Encouraging recent results provide useful guidelines to facilitate the development of novel drug candidates which are more potent and selective against these essential enzymes. PMID- 26963159 TI - A Comparative Study of Haptic Stiffness Identification by Veterinarians and Students. AB - Palpation is an important clinical skill in both veterinary and medical health professions. The present study compares the ability of practicing veterinarians and veterinary students to identify the stiffness of virtual surfaces through palpation. An absolute identification paradigm was used where a force-feedback haptic device rendered virtual surfaces with five levels of stiffness within a "clinically relevant" range (0.2-0.5 N/mm). The mean information transfer was 0.97 bits (almost two perfectly identifiable stiffness levels) for 12 veterinarians and 0.58 bits (one correctly identified level) for 14 veterinary students. Although the difference between the two groups was significant (p <; 0.001), neither group was able to reliably identify more than two levels of stiffness, indicating that the success of veterinarians in clinical practice probably relies on additional properties such as size, shape, and texture. Analyses of force versus time and displacement versus time recordings suggest that the superior performance of the veterinarians may be partially attributable to motor strategy. Specifically, veterinarians used a greater mean maximum force (2.0 N) compared to students (1.6 N) (p <; 0.05). However, further studies are required to investigate motor strategy in more detail. The implications of our findings for veterinary education and quantitative skill assessment are discussed. PMID- 26963160 TI - Exploration of Tactile Contact in a Haptic Display: Effects of Contact Velocity and Transient Vibrations. AB - Experiments were conducted using a novel tactile contact rendering device to explore important factors of the tactile contact event. The effects of contact velocity and event-based transient vibrations were explored. Our research was motivated by a need to better understand the perception of the tactile contact event and to develop a means of rendering stiff surfaces with a nonspecialized haptic device. A passive tactile display, suitable for mounting on a Phantom robot, was developed and is capable of rendering the tactile sensation of contact on a fingertip over a range of velocities commonly experienced during everyday manipulation and tactile exploration. Experiments were conducted with this device to explore how tactile contact dynamics affect the perceived stiffness of a virtual surface. It was found that contact velocity does not have a significant effect on perceived stiffness. These results can be explained by prior research that defines perceived hardness (akin to stiffness) in terms of rate-hardness. However, in agreement with prior literature with stylus-based studies, the addition of transient vibrations to the contact event can, in some cases, increase the perceived stiffness. PMID- 26963158 TI - Protein aggregates stimulate macropinocytosis facilitating their propagation. AB - Temporal and spatial patterns of pathological changes such as loss of neurons and presence of pathological protein aggregates are characteristic of neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Alzheimer's disease and Parkinson's disease. These patterns are consistent with the propagation of protein misfolding and aggregation reminiscent of the prion diseases. There is a surge of evidence that suggests that large protein aggregates of a range of proteins are able to enter cells via macropinocytosis. Our recent work suggests that this process is activated by the binding of aggregates to the neuron cell surface. The current review considers the potential role of cell surface receptors in the triggering of macropinocytosis by protein aggregates and the possibility of utilizing macropinocytosis pathways as a therapeutic target. PMID- 26963161 TI - Feeling through Tactile Displays: A Study on the Effect of the Array Density and Size on the Discrimination of Tactile Patterns. AB - Tactile arrays are devices that can provide spatially distributed cutaneous signals delivering crucial information during virtual haptic exploration or remote manipulation procedures. Two of the key specifications of a tactile array are the tactor spacing and array size that are believed to directly affect the device performance. In most of the systems developed so far, these two parameters have been chosen by trial and error or by trying to match the tactor density to the spatial resolution in the human fingertip. The objective of this work is to study the effect of tactor spacing and array size on the tactile arrays performance by measuring human tactile discrimination ability. Psychophysical experiments were performed to obtain the differential threshold for discrimination of a ridge angle and the shape recognition performance while exploring edge-based patterns. The patterns were explored through different passive (nonactuated) tactile arrays of vertically moving pins and also directly with the finger. Results indicate that a tactile array of 1.8 mm tactor spacing and 1 cm(2) array size transmits the pattern information with a good level of accuracy. This work shows that tactile devices with low complexity (small number of tactors) are still effective in conveying tactile cues. Moreover, this work provides performance measures that determinate the capabilities of tactile pin arrays to convey accurately tactile information. PMID- 26963162 TI - Geodesic Spline Interface for Haptic Curve Rendering. AB - Several haptic devices have been developed in recent years in order to reproduce the sensation of physical contact with virtual objects. Many of these devices are point-based, and some haptic interfaces behave like small surfaces that conform to a virtual shape. None of these allow a full-hand contact with the shape, and they are, in general, too small to render big surfaces. The simulation of tasks, such as the exploration of aesthetic surfaces made by industrial designers in order to check the quality of prototypes, require full-hand contact with the shape on a one-to-one scaled representation of the object. These explorations follow trajectories that can be approximated with planar or geodesic curves. In this paper, we describe the design and implementation of a linear haptic device that is able to render these trajectories. The device is part of a multimodal system including stereoscopic visualization that allows visual representation of the entire surface. Industrial designers use the system for checking the quality of shapes while exploiting their manual and visual skills. The system has been tested by industrial designers and the results are reported in this paper. PMID- 26963163 TI - Roughness Perception in Virtual Textures. AB - Haptic devices allow the production of virtual textured surfaces for psychophysical experiments. Some studies have shown inconsistencies between virtual and real textures with respect to their psychophysical functions for roughness, leading to speculation that virtual textures differ in some way from real ones. We have determined the psychophysical function for roughness using textures rendered with a high-fidelity magnetic levitation haptic device. A constraint surface algorithm was used to simulate the motion of a spherical probe over trapezoidal gratings and randomly dithered cones. The shape of the psychophysical functions for roughness is consistent between subjects but varies with changes in texture and probe geometry. For dithered cones, inverted "U" shaped functions were found nearly identical, in maxima and curvature, to those in the literature for real textures with similar geometry. PMID- 26963164 TI - What you can't feel won't hurt you: Evaluating haptic hardware using a haptic contrast sensitivity function. AB - In this paper, we extend the concept of the contrast sensitivity function - used to evaluate video projectors - to the evaluation of haptic devices. We propose using human observers to determine if vibrations rendered using a given haptic device are accompanied by artifacts detectable to humans. This determination produces a performance measure that carries particular relevance to applications involving texture rendering. For cases in which a device produces detectable artifacts, we have developed a protocol that localizes deficiencies in device design and/or hardware implementation. In this paper, we present results from human vibration detection experiments carried out using three commercial haptic devices and one high performance voice coil motor. We found that all three commercial devices produced perceptible artifacts when rendering vibrations near human detection thresholds. Our protocol allowed us to pinpoint the deficiencies, however, and we were able to show that minor modifications to the haptic hardware were sufficient to make these devices well suited for rendering vibrations, and by extension, the vibratory components of textures. We generalize our findings to provide quantitative design guidelines that ensure the ability of haptic devices to proficiently render the vibratory components of textures. PMID- 26963165 TI - The Influence of Exposure Amount on the Persistence of Short-Term, Haptically Acquired Sensorimotor Memorial Representations. AB - This study investigates the influence that the amount of exposure has on the persistence of sensorimotor memories. Participants acquired memories of an unexpectedly heavy object in one of four groups that varied in the number lifts of the object they each performed. All participants followed this acquisition period with retention lifts immediately and after 2-second and 10-second intervals, as well as after 15 minutes and 24 hours. Grasp force profiles were evaluated for the maintenance of memory-dependent adaptations. A lack of any group effects indicates that the quantity of exposure offers the sensorimotor memory system no temporal advantage in the maintenance of short-term representations. The results are discussed in light of the possibility that, within a short time frame, only the information from the preceding lift has functional relevance to the current lift. PMID- 26963166 TI - The relationship between trait positive empathy and brain structure: a voxel based morphometry study. AB - Although studies relating to positive empathy have received increased attention in recent years, no studies have been carried out to explore the neural basis of positive empathy. Using a voxel-based morphometry analysis, this study investigates the relationship between trait positive empathy (as measured by the Positive Empathy Scale) and its association with brain structure in 86 healthy college students. The results indicate that an individual's ability to show positive empathy is positively correlated with the volume of gray matter in the right insula, left anterior cingulate cortex, dorsolateral prefrontal cortex, and medial prefrontal cortex. It may be suggested that the differences between the abilities of emotion processing and regulating play important roles in shaping an individual's positive empathy traits from the perspective of brain morphometry. PMID- 26963167 TI - PARP-1-modulated AIF translocation is involved in streptomycin-induced cochlear hair cell death. AB - Conclusion SM-induced dose- and location-dependent cochlear hair cell death in vitro. AIF might be translocated from mitochondria to nucleus and cytoplasm within SM-treated hair cells. The translocation of AIF might be modulated by PARP 1. Objective Streptomycin (SM), one of the widely used aminoglycoside nowadays, is still causing significant permanent sensorineural hearing loss owing to sensory hair cell death. This study was designed to investigate the role of apoptosis-inducing factor (AIF), an important mitochondrial cell death regulator, in SM ototoxicity within neonatal rat cochleae and HEI-OC1 cells. Methods The viability of HEI-OC1 cells was quantified by MTT assay. AIF, PARP-1, and myosin VIIa distributions were achieved by immunofluorescence. mRNA and protein expression of AIF and PARP-1 were examined by q-PCR and Western-blot. Results The hair cell loss was concomitant with the SM concentration variation, and aggravated from apical to basal turn. AIF was detected in nuclear region and AIF mRNA was up-regulated after SM incubation. Besides, AIF protein expression in mitochondria was decreased, whereas in cytosol it was increased. PARP-1 mRNA and protein were also up-regulated. 3-AB could attenuate the cell death and reverse the changes of AIF distribution by blocking PARP-1. PMID- 26963175 TI - Symbolic dynamics of heart rate variability - a promising tool to investigate cardiac sympathovagal control in attention deficit/hyperactivity disorder (ADHD)? AB - We aimed to evaluate complex cardiac sympathovagal control in attention deficit/hyperactivity disorder (ADHD) by using heart rate variability (HRV) nonlinear analysis - symbolic dynamics. We examined 29 boys with untreated ADHD and 25 healthy boys (age 8-13 years). ADHD symptoms were evaluated by ADHD-RS-IV scale. ECG was recorded in 3 positions: baseline supine position, orthostasis, and clinostasis. Symbolic dynamics indices were used for the assessment of complex cardiac sympathovagal regulation: normalised complexity index (NCI), normalised unpredictability index (NUPI), and pattern classification measures (0V%, 1V%, 2LV%, 2UV%). The results showed that HRV complexity was significantly reduced at rest (NUPI) and during standing position (NCI, NUPI) in ADHD group compared to controls. Cardiac-linked sympathetic index 0V% was significantly higher during all posture positions and cardiovagal index 2LV% was significantly lower to standing in boys suffering from ADHD. Importantly, ADHD symptom inattention positively correlated with 0V%, and negatively correlated with NCI, NUPI. Concluding, symbolic dynamics revealed impaired complex neurocardiac control characterised by potential cardiac beta-adrenergic overactivity and vagal deficiency at rest and to posture changes in boys suffering from ADHD that is correlated with inattention. We suggest that symbolic dynamics indices could represent promising cardiac biomarkers in ADHD. PMID- 26963176 TI - Tracking micro-optical resonances for identifying and sensing novel procaspase-3 protein marker released from cell cultures in response to toxins. AB - The response of cells to toxins is commonly investigated by detecting intracellular markers for cell death, such as caspase proteins. This requires the introduction of labels by the permeabilization or complete lysis of cells. Here we introduce a non-invasive tool for monitoring a caspase protein in the extracellular medium. The tool is based on highly sensitive optical micro devices, referred to as whispering-gallery mode biosensors (WGMBs). WGMBs are functionalized with antibodies for the specific and label-free detection of procaspase-3 released from human embryonic kidney HEK293 and neuroglioma H4 cells after introducing staurosporine and rotenone toxins, respectively. Additional tests show that the extracellular accumulation of procaspase-3 is concomitant with a decrease in cell viability. The hitherto unknown release of procaspase-3 from cells in response to toxins and its accumulation in the medium is further investigated by Western blot, showing that the extracellular detection of procaspase-3 is interrelated with cytotoxicity of alpha-synuclein protein (aSyn) overexpressed in H4 cells. These studies provide evidence for procaspase-3 as a novel extracellular biomarker for cell death, with applications in cytotoxicity tests. Such WGMBs could be applied to further identify as-yet unknown extracellular biomarkers using established antibodies against intracellular antigens. PMID- 26963177 TI - MicroRNAs in bone development and their diagnostic and therapeutic potentials in osteoporosis. AB - MicroRNAs (miRNAs) are small non-coding RNAs approximately 22 nucleotides in length. miRNAs play an important role in the posttranscriptional regulation of gene expression via translational repression and targeting messenger RNA for degradation. In vivo and in vitro evidence has established the importance of miRNAs in physiology and developmental processes such as cell proliferation, differentiation, survival and apoptosis. miRNA dysregulation is associated with the pathogenesis of cardiovascular diseases, metabolic syndromes, and degenerative diseases. An increasing number of miRNAs have been found to play an important role in bone homeostasis. In this review, the roles of miRNAs in the regulation of bone formation and resorption as well as miRNAs that regulate key transcription factors of osteogenesis are discussed. A special emphasis is given to miRNAs whose direct targets have been identified. The miRNAs that contribute to the pathogenesis of osteoporosis and their therapeutic potential are also considered. PMID- 26963178 TI - Improving psychology students' attitudes toward people with schizophrenia: A quasi-randomized controlled study. AB - Despite scientific evidence that the majority of people with schizophrenia (PWS) have personal histories of traumatic life events and adversities, their needs for psychological support often remain unmet. Poor availability of nonpharmacological therapies in schizophrenia may be partly because of professionals' attitudes toward people diagnosed with this disorder. As future health professionals, psychology students represent a target population for efforts to increase the probability that PWS will be offered effective psychological therapies. This quasi-randomized controlled study investigated the effect of an educational intervention, addressing common prejudices via scientific evidence and prerecorded audio-testimony from PWS, on the attitudes of psychology students toward PWS. Students in their fifth year of a master's degree in Psychology at the Second University of Naples, Italy were randomly assigned to an experimental group-which attended two 3-hr sessions a week apart-or to a control group. Compared with their baseline assessment, at 1-month reassessment the 76 educated students endorsed more psychosocial causes and more of them recommended psychologists in the treatment of schizophrenia. They were also more optimistic about recovery, less convinced that PWS are recognizable and unpredictable, and more convinced that treatments, pharmacological and psychological, are useful. No significant changes were found, from baseline to 1-month reassessment, in the 112 controls. At 1-month reassessment, educated students were more optimistic about recovery and less convinced that PWS are unpredictable than controls. These findings suggest that psychology students' attitudes toward PWS can be improved by training initiatives including education and indirect contact with users. (PsycINFO Database Record PMID- 26963180 TI - New frontiers in building mental, emotional and behavioral health in children and youth: Introduction to the special section. AB - The passage of the Patient Protection and Affordable Care Act (ACA; 2010) has had tremendous influence on behavioral health in the United States (Alker & Chester, 2015). Shortly after its passage, the editors of this special section became interested in examining the provisions of the ACA related to care for mental, emotional, and behavioral disorders in children and youth and synthesizing their implications in the context of other contemporary trends in children's behavioral health promotion. We first developed a white paper with the goal of increasing our own understanding of these issues and their possible influence on the status quo of designing, implementing, financing, and evaluating behavioral health services for children and their families. From our discussions came the idea of developing a special section in the American Journal of Orthopsychiatry featuring input from researchers who have been exploring these issues and who have tangible and relevant examples of "new frontiers" in building mental, emotional, and behavioral health for children and youth. The result is the current special section, the purpose of which is to highlight the importance of prevention in behavioral health and to explore examples of efforts that have used a broad public health approach to prevention and early intervention in mental, emotional, and substance use disorders in children and youth. Before introducing the seven articles in this special section, we describe in detail our foundational thinking about building mental, emotional, and behavioral health for children and youth, as expressed in our initial white paper on this topic. (PsycINFO Database Record PMID- 26963179 TI - Major discriminatory events and risk for psychotic experiences among Black Americans. AB - Racism is a multidimensional construct that impacts risk for psychosis through various complex pathways. Previous research has yet to fully explore how major racial discriminatory events contribute to risk for psychotic experiences in the general population. We examined the National Survey of American Life to analyze the effects of 9 major racial discriminatory events on lifetime psychotic experiences among Black Americans. By examining each event separately, we found that police discrimination was associated with increased risk for lifetime psychotic experiences after adjusting for demographic variables, socioeconomic status, and co-occurring psychological or social problems. Being denied a promotion, being a victim of police abuse, and being discouraged from pursuing education were associated with lifetime visual hallucinations, and being discouraged from pursuing education was also associated with lifetime delusional ideation. None of the events were associated with lifetime auditory hallucinations. As a count of events, experiencing a greater range of major racial discriminatory events was associated with higher risk, particularly for lifetime visual hallucinations. Our findings point to the need for early detection and intervention efforts in community settings and multilevel efforts to eliminate racial discrimination. (PsycINFO Database Record PMID- 26963181 TI - Toxic stress, behavioral health, and the next major era in public health. AB - Before the development of the germ theory in the late 19th century, infectious illnesses were largely uncontrollable and caused significant mortality. Implementing public hygiene, preventive, and treatment interventions created remarkable improvements in population health. Today's U.S. public health crises involve threats to health and human capital evidenced by multiple indicators of deteriorating wellbeing. These problems result from the interaction of risk and protective factors. Specifically, we argue that the interaction of genetic vulnerability and toxic stress are antecedents to a developmental cascade that undermines healthy development and human capital. We review relevant literature, summarize effective strategies to prevent or ameliorate this deterioration, and outline a theory of the mechanisms currently undermining our health. A series of strategies that we believe will constitute the next major era in public health are discussed, involving actions at the individual/family, community and societal level to reduce risk and strengthen protective factors. (PsycINFO Database Record PMID- 26963182 TI - Launching forward: The integration of behavioral health in primary care as a key strategy for promoting young child wellness. AB - In 2008, the Substance Abuse and Mental Health Services Administration (SAMHSA) created a national grant program, Project LAUNCH (Linking Actions for Unmet Needs in Children's Health), to improve behavioral health and developmental outcomes for young children through the incorporation of prevention and wellness promotion practices in key early childhood settings. Project LAUNCH supports states, tribal nations, and territories to improve coordination across early childhood systems and implement 5 core strategies of prevention and promotion. This article focuses on the lessons learned from 1 of the 5 core strategies: integration of behavioral health into primary care for young children. This paper analyzes the experiences of a sample of Project LAUNCH grantees, describing 10 common elements of integration approaches and exploring some of the challenges of promoting health and preventing social, emotional, and behavioral problems at a population level. (PsycINFO Database Record PMID- 26963183 TI - Building an evidence-based multitiered system of supports for high-risk youth and communities. AB - The mental, emotional and behavioral health problems of high-risk youth and youth living in high-risk communities are not inevitable and can be prevented. A shift from the nation's focus on treating disease and illness after it occurs to a concentrated effort on preventing the root causes of these problems is needed. Prevention science suggests a comprehensive multitiered approach that provides evidence-based prevention supports for children and youth at each developmental stage and across multiple social contexts is likely to result in the greatest health impact and return on investment. However, actually implementing this approach at a neighborhood level has remained a challenge and an ongoing research gap especially in high-risk communities. This article describes a process and provides a case study example for implementing a comprehensive, multitiered approach in a high-risk community. This includes assessing and prioritizing the specific needs of individuals and communities; selecting evidence-based programs based upon assessed needs; and creating a continuum of programs to improve the health and well-being of youth across developmental age spans, social contexts, and levels of risk. Operational details and challenges for organizing and implementing this comprehensive approach are also described. We estimate that the collective impact of a multitiered evidence-based approach, implemented with fidelity, could conservatively result in a 30 to 40% reduction in problem behaviors. (PsycINFO Database Record PMID- 26963184 TI - Using communities that care for community child maltreatment prevention. AB - The prevention of mental, emotional, and behavioral (MEB) disorders among children and adolescents is a national priority. One mode of implementing community-wide MEB prevention efforts is through evidence-based community mobilization approaches such as Communities That Care (CTC). This article provides an overview of the CTC framework and discusses the adaptation process of CTC to prevent development of MEBs through preventing child abuse and neglect and bolstering child well-being in children aged 0 to 10. Adaptations include those to the intervention itself as well as those to the evaluation approach. Preliminary findings from the Keeping Families Together pilot study of this evolving approach suggest that the implementation was manageable for sites, and community board functioning and community adoption of a science-based approach to prevention in pilot sites looks promising. Implications and next steps are outlined. (PsycINFO Database Record PMID- 26963186 TI - Using public health strategies to shape early childhood policy. AB - There is clear evidence that ensuring safe, stimulating, and nurturing caregiving environments for young children may be one of the most impactful health promotion strategies available, with lifelong and intergenerational benefits. Supports and interventions in the early years of life may in fact be the most effective way to improve school performance, increase high school graduation rates, job performance, and adult productivity. A public health approach to early childhood well-being, as opposed to the needs of children being addressed in multiple siloes, may be a more effective strategy that will lead to smarter investments and increasing financial commitments. Louisiana is used as a case study, with examples of strategies organized by the 3 core functions of public health. (PsycINFO Database Record PMID- 26963187 TI - Can behavioral health drive its own reformation? The challenges of shifting direction. AB - This paper is designed to provide a broad-view perspective on at least some of the implications of the Affordable Care Act for children's behavioral health. Historical trends in behavioral health have tended to isolate both consumers of services (including children, youth and families) and practitioners from the larger world of healthcare, with decidedly mixed results. This paper uses the concept of path dependence to highlight the multiple challenges facing child behavioral health as it moves forward. The paper builds its recommendations on the 4 pillars of sustainable change: politics, practice, economics, and science. In a changing health care environment, behavioral health has to transform. The paper concludes with some observations on the kinds of transformative change required to move in new directions. (PsycINFO Database Record PMID- 26963185 TI - Fostering SMART partnerships to develop an effective continuum of behavioral health services and supports in schools. AB - The education sector offers compelling opportunities to address the shortcomings of traditional mental health delivery systems and to prevent and treat youth mental, emotional, and behavioral (MEB) problems. Recognizing that social and emotional wellness is intrinsically related to academic success, schools are moving to adopt multi-tier frameworks based on the public health model that provide a continuum of services to all children, including services to address both academic and MEB problems. In this article, we review the potential value of multi-tier frameworks in facilitating access to, and increasing the effectiveness of, mental health services in schools, and review the empirical support for school-based mental health interventions by tier. We go on to describe a community-academic partnership between the Seattle Public Schools and the University of Washington School Mental Health Assessment, Research, and Training (SMART) Center that exemplifies how multi-tier educational frameworks, research and evidence, and purposeful collaboration can combine to improve development and implementation of a range of school-based strategies focused on MEB needs of students. Finally, we present a set of 10 recommendations that may help guide other research and practice improvement efforts to address MEB problems in youth through effective school mental health programming. (PsycINFO Database Record PMID- 26963188 TI - Reducing primary and secondary traumatic stress symptoms among educators by training them to deliver a resiliency program (ERASE-Stress) following the Christchurch earthquake in New Zealand. AB - The current investigation evaluated the impact of a universal school-based resiliency intervention (ERASE-Stress) on educators who were working with elementary schoolchildren exposed to the Canterbury earthquake in New Zealand. In the context of major disasters, educators may suffer from "dual trauma"; they can experience symptoms of both primary trauma (as a result of the disaster itself) and secondary trauma (as a result of working with traumatized students). Sixty three educators were randomly assigned to either the ERASE-Stress intervention or an alternative Managing Emergencies and Traumatic Incidents (METI) program which served as a control group. Efficacy of the program was evaluated at the end of the training as well as at 8 months follow-up. Compared with educators in the control group, those in the ERASE-Stress intervention significantly reduced their posttraumatic distress and secondary traumatization symptoms, improved their perceived level of professional self-efficacy as a helper of earthquake survivors, developed an optimistic outlook regarding their personal future and enhanced their sense of hope, and honed some of their positive coping strategies and reduced the utilization of some maladaptive coping methods. These beneficial consequences of the ERASE-Stress training make it a potentially useful tool for educators working with traumatized students in the context of major disasters. (PsycINFO Database Record PMID- 26963194 TI - Nonlinear mixed effects modelling for the analysis of longitudinal body core temperature data in healthy volunteers. AB - Many longitudinal studies have collected serial body core temperature (T c) data to understand thermal work strain of workers under various environmental and operational heat stress environments. This provides the opportunity for the development of mathematical models to analyse and forecast temporal T c changes across populations of subjects. Such models can reduce the need for invasive methods that continuously measure T c. This current work sought to develop a nonlinear mixed effects modelling framework to delineate the dynamic changes of T c and its association with a set of covariates of interest (e.g. heart rate, chest skin temperature), and the structure of the variability of T c in various longitudinal studies. Data to train and evaluate the model were derived from two laboratory investigations involving male soldiers who participated in either a 12 (N = 18) or 15 km (N = 16) foot march with varied clothing, load and heat acclimatisation status. Model qualification was conducted using nonparametric bootstrap and cross validation procedures. For cross validation, the trajectory of a new subject's T c was simulated via Bayesian maximum a posteriori estimation when using only the baseline T c or using the baseline T c as well as measured T c at the end of every work (march) phase. The final model described T c versus time profiles using a parametric function with its main parameters modelled as a sigmoid hyperbolic function of the load and/or chest skin temperature. Overall, T c predictions corresponded well with the measured data (root mean square deviation: 0.16 degrees C), and compared favourably with those provided by two recently published Kalman filter models. PMID- 26963193 TI - Fine Particulate Matter and Emergency Room Visits for Respiratory Illness. Effect Modification by Oxidative Potential. AB - RATIONALE: Fine particulate air pollution (PM2.5; particulate matter 2.5 MUm or less in diameter) is thought to contribute to acute respiratory morbidity in part through oxidative stress. OBJECTIVES: To examine the association between PM2.5 oxidative burden and emergency room visits for respiratory illnesses. METHODS: We conducted a case-crossover study in Ontario, Canada between 2004 and 2011, including 127,836 cases of asthma, 298,751 cases of chronic obstructive pulmonary disease, and more than 1.1 million cases of all respiratory illnesses. Daily air pollution data were collected from ground monitors, and city-level PM2.5 oxidative potential was measured on the basis of a synthetic respiratory tract lining fluid containing the antioxidants glutathione and ascorbate. Conditional logistic regression was used to estimate associations between air pollution concentrations and emergency room visits, adjusting for time-varying covariates. MEASUREMENTS AND MAIN RESULTS: Three-day mean PM2.5 concentrations were consistently associated with emergency room visits for all respiratory illnesses. Among children (<9 yr), each interquartile change (5.92 MUg/m(3)) in 3-day mean PM2.5 was associated with a 7.2% (95% confidence interval, 4.2-10) increased risk of emergency room visits for asthma. Glutathione-related oxidative potential modified the impact of PM2.5 on emergency room visits for respiratory illnesses (P = 0.001) but only at low concentrations (<=10 MUg/m(3)). Between-city differences in ascorbate-related oxidative potential did not modify the impact of PM2.5 on respiratory outcomes. CONCLUSIONS: Between-city differences in glutathione-related oxidative potential may modify the impact of PM2.5 on acute respiratory illnesses at low PM2.5 concentrations. This may explain in part how small changes in ambient PM2.5 mass concentrations can contribute to acute respiratory morbidity in low-pollution environments. PMID- 26963195 TI - Evaluation of a National Call Center and a Local Alerts System for Detection of New Cases of Ebola Virus Disease - Guinea, 2014-2015. AB - The epidemic of Ebola virus disease (Ebola) in West Africa began in Guinea in late 2013 (1), and on August 8, 2014, the World Health Organization (WHO) declared the epidemic a Public Health Emergency of International Concern (2). Guinea was declared Ebola-free on December 29, 2015, and is under a 90 day period of enhanced surveillance, following 3,351 confirmed and 453 probable cases of Ebola and 2,536 deaths (3). Passive surveillance for Ebola in Guinea has been conducted principally through the use of a telephone alert system. Community members and health facilities report deaths and suspected Ebola cases to local alert numbers operated by prefecture health departments or to a national toll free call center. The national call center additionally functions as a source of public health information by responding to questions from the public about Ebola. To evaluate the sensitivity of the two systems and compare the sensitivity of the national call center with the local alerts system, the CDC country team performed probabilistic record linkage of the combined prefecture alerts database, as well as the national call center database, with the national viral hemorrhagic fever (VHF) database; the VHF database contains records of all known confirmed Ebola cases. Among 17,309 alert calls analyzed from the national call center, 71 were linked to 1,838 confirmed Ebola cases in the VHF database, yielding a sensitivity of 3.9%. The sensitivity of the national call center was highest in the capital city of Conakry (11.4%) and lower in other prefectures. In comparison, the local alerts system had a sensitivity of 51.1%. Local public health infrastructure plays an important role in surveillance in an epidemic setting. PMID- 26963196 TI - Genetic Variants in Folate and Cobalamin Metabolism-Related Genes in Nonsyndromic Cleft Lip and/or Palate. AB - The aim of this study was to evaluate the association of the polymorphisms in TCN2 (rs1801198) gene and in MTRR (rs1801394) gene with nonsyndromic cleft lip and/or palate (NSCL/P) in a Brazilian population. Genomic DNA was extracted from buccal cells. The polymorphisms in TCN2 (rs1801198) and MTRR (rs1801394) genes were genotyped by carrying out real-time PCR and Taqman assay. Chi-square test was used to determine the association between genotype and allele frequencies with NSCL/P and NSCL/P subgroups (cleft lip only, cleft lip and palate, and cleft palate only). Eight hundred and sixty seven unrelated individuals (401 cases with NSCL/P and 466 individuals without cleft) were evaluated. Genotype distributions of TCN2 and MTRR polymorphisms were in Hardy-Weinberg equilibrium. The TCN2 polymorphic genotype GG was identified in 16.7% of the NSCL/P group and in 14.1% of the non-cleft group (p>0.05). Similarly, the frequency of MTRR genotype (GG) was similar in NSCL/P group (15.5%) and control group (17.8%) (p>0.05). Multivariate analysis showed an association between MTRR and the subgroup that the mother smoked during pregnancy (p=0.039). Our findings did not demonstrate an association between TCN2 polymorphisms and NSCL/P, however suggests an association between MTRR and NSCL/P etiology. PMID- 26963197 TI - Vital Pulp Therapies in Clinical Practice: Findings from a Survey with Dentist in Southern Brazil. AB - Studies based on dentists' clinical practice possess vital relevance to understand factors leading the clinicians to choose by a specific technique over another. This study investigated which clinical conduct therapies are adopted by dentists in front of deep caries. Was evaluated how the place of work, post graduate training and years since complete graduation influenced their decisions. A cross-sectional study was performed using a self-applied questionnaire with dentists (n=276) in Southern Brazil. Information regarding post-graduation training (specialization, master's or PhD), clinical experience (years since completing graduation) and place of work were investigated. The information regarding pulp vital therapies (materials for direct pulp capping; techniques for caries removal in deep cavities and strategies for indirect pulp capping) were collected by specific questions. Data were submitted to descriptive analysis and Exact Fischer Test. Response rate was 68% (187). The majority of dentists selected the calcium hydroxide (CH) as first material for direct (86.3%) and indirect (80.3%) pulp protection. Partial caries removal was reported by 61.9% of dentists. Less experienced clinical dentists choose partial caries removal more frequently (p=0.009), if compared with dentists graduated 10 years and up ago. The use of MTA was more common among professionals working at academic environment. Besides, MTA was not mentioned by professionals working exclusively in the public health service (p=0.003). In conclusion, the time since graduation influenced the clinical conduct related to caries removal. The choice of liner materials was influenced by dentists' workplace. PMID- 26963198 TI - Non-Pedicled Buccal Fat Pad Grafts to Treatment for Class I and II Gingival Recessions: A Clinical Trial. AB - The aim of this study was to analyze the transplant efficiency of non-pedicled buccal fat pad graft (BFPG) for the treatment of Miller Class I or II gingival recessions (GRs) and to compare these results with those of subepithelial connective tissue graft (SCTG), which is considered the gold standard. Twelve patients with Miller Class I or II (>=2 mm) bilateral recessions in maxillary premolars or canines were selected. Recessions were randomly assigned to receive SCTG or BFPG. The clinical parameters evaluated at baseline and at 1, 3, and 6 months postoperatively included gingival index, plaque index, probing depth, GR, clinical attachment level, width of keratinized tissue, thickness of keratinized tissue and gingival margin to the acrylic guide. None of the evaluated clinical parameters differed significantly between the groups. At all evaluated postoperative time-points, both groups exhibited statistically significant differences in GR and gingival margin to the acrylic guide compared to baseline. Six months after surgery, the mean percentages of root coverage were 67.5% and 87.5% in the BFPG and SCTG groups respectively. In both groups, complete root coverage was observed in 50% of cases 6 months after surgery. The results presented herein indicate that the use of BFPG transplant has clinical similarities with SCTG and both may be considered as clinically successful methods for treating Miller Class I and II GRs. PMID- 26963199 TI - Autofluorescence and Diagnostic Accuracy of Lesions of Oral Mucosa: A Pilot Study. AB - The purpose of this study was to determine the accuracy of autofluorescence techniques for diagnosing oral mucosa lesions, using as reference pattern for comparison the visual diagnosis made by a clinical specialist. A pilot study was conducted with 60 patients divided in a control group without mucosal pathology and a study group with known clinical history for mucosal pathology. Both groups were examined by an oral medicine specialist and by a general dentist who used VELscope(r) system, which applies tissue fluorescence visualization to identify oral mucosal abnormalities. Using the VELscope(r) system, the general dentist made overdiagnosis in two cases and underdiagnosis in one case. The sensitivity and specificity for the oral medicine specialist were 1 (95% CI: 0.884 to 1). For the general dentist, the sensitivity did not improve significantly with the use of VELscope(r) system [0.53 (95% CI: 0.343 to 0.717) versus 0.49 (95% CI: 0.406 to 0.773)] and the specificity was 0.80 (95% CI: 0.614 to 0.923). A limitation of the study is the small sample size, which does not fully represent a population and extrapolation of the data should be done carefully. Based on the obtained results, no clinical benefits were obtained using this VELscope(r) system. PMID- 26963200 TI - Experimental Calcium Silicate-Based Cement with and without Zirconium Oxide Modulates Fibroblasts Viability. AB - The aim of this study was to verify whether the use of zirconium oxide as a radiopacifier of an experimental calcium silicate-based cement (WPCZO) leads to cytotoxicity. Fibroblasts were treated with different concentrations (10 mg/mL, 1 mg/mL, and 0.1 mg/mL) of the cements diluted in Dulbecco's modified Eagle's medium (DMEM) for periods of 12, 24, and 48 h. Groups tested were white Portland cement (WPC), white Portland cement with zirconium oxide (WPCZO), and white mineral trioxide aggregate Angelus (MTA). Control group cells were not treated. The cytotoxicity was evaluated through mitochondrial-activity (MTT) and cell density (crystal violet) assays. All cements showed low cytotoxicity. In general, at the concentration of 10 mg/mL there was an increase in viability of those groups treated with WPC and WPCZO when compared to the control group (p<0.05). A similar profile for the absorbance values was noted among the groups: 10 mg/mL presented an increase in viability compared to the control group. On the other hand, smaller concentrations presented a similar or lower viability compared to the control group, in general. A new dental material composed of calcium silicate based cement with 20% zirconium oxide as the radiopacifier showed low cytotoxicity as a promising material to be exploited for root-end filling. PMID- 26963202 TI - An Indirect Method to Measure Abutment Screw Preload: A Pilot Study Based on Micro-CT Scanning. AB - This study aimed to measure the preload in different implant platform geometries based on micro-CT images. External hexagon (EH) implants and Morse Tapered (MT) implants (n=5) were used for the preload measurement. The abutment screws were scanned in micro-CT to obtain their virtual models, which were used to record their initial length. The abutments were screwed on the implant with a 20 Ncm torque and the set composed by implant, abutment screw and abutment were taken to the micro-CT scanner to obtain virtual slices of the specimens. These slices allowed the measurement of screw lengths after torque application and based on the screw elongation. Preload values were calculated using the Hooke's Law. The preloads of both groups were compared by independent t-test. Removal torque of each specimen was recorded. To evaluate the accuracy of the micro-CT technique, three rods with known lengths were scanned and the length of their virtual model was measured and compared with the original length. One rod was scanned four times to evaluate the measuring method variation. There was no difference between groups for preload (EH = 461.6 N and MT = 477.4 N), but the EH group showed higher removal torque values (13.8 +/- 4.7 against 8.2 +/- 3.6 N cm for MT group). The micro-CT technique showed a variability of 0.053% and repeatability showed an error of 0.23 to 0.28%. Within the limitations of this study, there was no difference between external hexagon and Morse taper for preload. The method using micro-CT may be considered for preload calculation. PMID- 26963201 TI - Evaluation of Chair-Side Assays in High Microbiological Caries-Risk Subjects. AB - The aim of this study was to evaluate the commercial chair-side assays Saliva Check Mutans and ClinproTM Cario L-PopTM in high microbiological caries-risk dental students compared with conventional semi-quantitative colony counting culture-based technique as the reference method. Saliva samples from 93 subjects of both sexes aged 18-26 years were seeded (Kohler and Bratthall method) on plates containing SB-20M culture medium method and 12 subjects with high caries risk were selected. These 12 individuals were subjected to determination of caries risk using two commercial rapid detection chair-side assays (Saliva-Check Mutans and ClinproTM Cario L-PopTM) according to the manufacturers' instructions. The results were analyzed by the Kappa correlation test using SAS statistical software. There was a perfect agreement (Kappa=1) among the three caries risk evaluation methods - chair-side assays and semi-quantitative CFU count (control) in all subjects. The results suggest that the commercial chair-side assays evaluated in this study may be practical and useful to identify high microbiological caries-risk subjects. PMID- 26963203 TI - Evaluation of the Biological Behavior of Mucograft(r) in Human Gingival Fibroblasts: An In Vitro Study. AB - Mucograft(r) is a resorbing porcine matrix composed of type I and type III collagen, used for soft tissue augmentation in guided tissue bony regeneration procedures. This in vitro study aimed to evaluate the biological behavior of Mucograft(r) in human gingival fibroblasts, as well as the ability of the matrix to induce production of extracellular matrix. Six resorbing Mucograft(r) matrices (MCG) were cut into 3 x 2 mm rectangles and 5 x 5 mm squares and were placed in 96- and 24-well plates, respectively. The control group (CTRL) consisted of cells plated on polystyrene without the MCG. After one, two, three and seven days, cell proliferation and viability were assessed using the Trypan exclusion method and MTT test, respectively. Type III collagen (COL 3A1) and vimentin (VIM) expression were also evaluated at 10 and 14 days, using Western blotting. Statistical analysis, using ANOVA with post hoc Bonferroni test, revealed that human gingival fibroblasts from MCG showed similar results (p>0.05) for proliferation and viability as the cells cultured on CTRL. After 14 days, a significant decrease in COL 3A1 expression (p<0.05) was observed when cultured with the MCG. VIM expression showed no significant difference at any time period (p>0.05). Although no increase in extracellular matrix secretion was observed in this in vitro study, Mucograft(r) presented cellular compatibility, being an option for a scaffold whenever it is required. PMID- 26963204 TI - Three-dimensional Quantitative Porosity Characterization of Syringe- versus Hand mixed Set Epoxy Resin Root Canal Sealer. AB - The aim of the present study was to compare the porosity characteristics of AH Plus Jet(tm) syringe-mix and the conventional hand-mixed AH Plus root canal sealers by three-dimensional quantitative high-resolution micro-computed tomography (micro-CT). Seven test specimens were prepared from each tested sealer by a single operator following the manufacturer's instructions and poured into pre-lubricated plastic split-ring moulds. Set sealer test specimens were scanned using a micro-CT device and the shadow images were reconstructed into cross sectional slices. The evaluated parameters were (i) total pore count, (ii) total pore volume and mean pore volume, (iii) total porosity (% of pore volume in relation to total sealer volume) and (iv) mean pore distance to the sealer lateral external surface. In both groups, most pores were localized within the external sealer perimeter (0.05 mm from the external surface). Hand-mixed AH Plus specimens showed statistically significant higher mean total pore count, total pore volume and total porosity (p=0.001) than the syringe-mixed specimens. However, mean pore sizes in AH Plus syringe-mixed specimens were significantly higher (p=0.046) than the AH Plus hand-mixed counterparts. Hand-mixed AH Plus was associated with higher total mean pore count, volume and total porosity compared to syringe mixed AH Plus. PMID- 26963205 TI - Micro-CT Evaluation of Root Filling Removal after Three Stages of Retreatment Procedure. AB - The aim of this study was to quantify the residual filling material after filling removal, re-preparation with rotary or reciprocating files and passive ultrasonic irrigation (PUI). Twenty maxillary molars were prepared using ProTaper instruments up to F1. The teeth were filled with AH Plus and ProTaper gutta percha points using the single-cone technique. Thereafter, the specimens were scanned using a micro-computed tomography system (Micro-CT #1). Then, the root canal filling was removed using ProTaper Retreatment files, and a new scan was performed (Micro-CT #2). The specimens were divided into two groups according to the instrument used for re-preparation: ProTaper rotary or WaveOne reciprocating files (Micro-CT #3). Finally, PUI was performed, and a new micro-CT scan was performed (Micro-CT #4). Intragroup and intergroup analyses were performed using Friedman and Dunn's post hoc test and the Kruskal-Wallis and Dunn post hoc tests, respectively. Palatal canal presented the highest volume of residual filling material in all stages of endodontic retreatment (p<0.05). The main reduction of filling volume was achieved after using ProTaper Retreament (p<0.05). The amount of remaining filling material after using ProTaper Retreatment was similar to that achieved with rotary and reciprocating files and after PUI (p>0.05). Rotary and reciprocating files achieved similar removal of the root canal filling (p>0.05). The greatest reduction in filling material was achieved after using ProTaper Retreatment files. Rotary and reciprocating instruments and PUI did not improve the removal of root canal filling materials. PMID- 26963206 TI - A 3-Year Retrospective Evaluation of the Clinical Performance of Fiber Posts. AB - This retrospective study evaluated the clinical outcome of 139 teeth restored with carbon fiber posts after 3 years of placement, considering the amount of remaining dentin as the main variable. Eighty-one patients received the fiber posts within a period of 16 months and were recalled after 3 years. The tooth type, amount of remaining dentin, and prosthetic crown material were evaluated. No loss of post or core retention was detected after 3 years of follow up. During the observed time, root or post fracture and secondary caries were not recorded. Only one failure concerning endodontic treatment was detected. The amount of remaining dentin was not an important characteristic in the restorative failure of endodontically treated teeth restored with carbon fiber posts within 3 years. PMID- 26963207 TI - Micro-CT Evaluation of Non-instrumented Canal Areas with Different Enlargements Performed by NiTi Systems. AB - The aim of this study was to compare the percentage of non-instrumented area of root canals prepared with different enlargements using single-file reciprocating systems (Reciproc and WaveOne) and a conventional multi-file rotary (BioRaCe) system by micro-computed tomographic analysis. Thirty mesial roots of mandibular molars with moderate curvature (10 degrees to 20 degrees ) presenting a type II Vertucci canal configuration and similar internal volume were chosen and scanned at an isotropic resolution of 14.16 um. The sample was assigned to 3 groups (n=10) according to the system used for root canal preparation: Reciproc, WaveOne, and BioRaCe groups. Second and third scans were taken after the canals were prepared with instruments sizes 25 and 40, respectively. The recorded images of the surface area voxels of the canals, before and after preparation were examined from the furcation level to the apex to quantify the non-instrumented surface. Statistical data were compared using GLM for repeated-measures with a significance level set at 5%. Instrumentation systems did not influence the percentage of untouched root canal surfaces (p=0.690) whilst a significant reduction in the percentage of static voxels was observed after the enlargement of the root canal (p=0.010) in all groups (p=0.507). None of the systems was able to prepare the entire surface area of the mesial root canal of mandibular molars. The increased final apical size resulted in a significant positive effect on the shaping ability of the tested systems. PMID- 26963208 TI - Effect of Resin Cement Porosity on Retention of Glass-Fiber Posts to Root Dentin: An Experimental and Finite Element Analysis. AB - The aim of this study was to evaluate the effect of porosity of self-adhesive resin on the stress distribution, post retention and failure mode of fiber post cemented to human root dentin. Ten human central upper incisors with circular root canal were selected. They were sectioned with 15 mm and were endodontically filled. The roots were scanned using micro-CT after post space preparation for root filling remaining evaluation. Fiber posts were cemented using self-adhesive resin cement (Rely X U200, 3M-ESPE). Two 1-mm-thick slices from the cervical, medium and apical thirds were scanned for resin cement bubbles volume measurements and submitted to a push-out test (PBS). Three operators using stereomicroscopy and confocal laser microscopy classified the failure mode. Stress distributions during the push-out test were analyzed using 3D finite element analysis. PBS values (MPa) were submitted to one-way ANOVA and Tukey's post hoc tests and the failure modes using the Kappa coefficient to assess inter operator agreement. Chi-square test was used to determine significant differences between the methods (? = 0.05). Push-out bond strength was significantly affected by the bubbles presence in all root depth (p<0.05). The stress concentration was higher when the bubbles were present. Adhesive dentin/resin cement interface failure was the most frequent type of failure. Confocal microscopy was better than stereomicroscopy for failure analysis. Bubbles generated during resin cement insertion into the root canal negatively affect the stress distribution and the bond strength. The use of confocal microscopy is recommended for failure analysis. PMID- 26963209 TI - Influence of Temporary Cements on the Bond Strength of Self-Adhesive Cement to the Metal Coronal Substrate. AB - This research evaluated the influence of temporary cements (eugenol-containing [EC] or eugenol-free [EF]) on the tensile strength of Ni-Cr copings fixed with self-adhesive resin cement to the metal coronal substrate. Thirty-six temporary crowns were divided into 4 groups (n=9) according to the temporary cements: Provy, Dentsply (eugenol-containing), Temp Cem, Vigodent (eugenol-containing), RelyX Temp NE, 3M ESPE (eugenol-free) and Temp Bond NE, Kerr Corp (eugenol-free). After 24 h of temporary cementation, tensile strength tests were performed in a universal testing machine at a crosshead speed of 0.5 mm/min and 1 kN (100 kgf) load cell. Afterwards, the cast metal cores were cleaned by scraping with curettes and air jet. Thirty-six Ni-Cr copings were cemented to the cast metal cores with self-adhesive resin cement (RelyX U200, 3M ESPE). Tensile strength tests were performed again. In the temporary cementation, Temp Bond NE (12.91 +/- 2.54) and Temp Cem (12.22 +/- 2.96) presented the highest values of tensile strength and were statistically similar to each other (p>0.05). Statistically significant difference (p<0.05) was observed only between Provy (164.44 +/- 31.23) and Temp Bond NE (88.48 +/- 21.83) after cementation of Ni-Cr copings with self-adhesive resin cement. In addition, Temp Cem (120.68 +/- 48.27) and RelyX Temp NE (103.04 +/- 26.09) showed intermediate tensile strength values. In conclusion, the Provy eugenol-containing temporary cement was associated with the highest bond strength among the resin cements when Ni-Cr copings were cemented to cast metal cores. However, the eugenol cannot be considered a determining factor in increased bond strength, since the other tested cements (1 eugenol-containing and 2 eugenol-free) were similar. PMID- 26963210 TI - Effect of Chlorhexidine on Dentin Bond Strength of Two Adhesive Systems after Storage in Different Media. AB - The aim of this study was to evaluate the effect of 2% chlorhexidine (CHX) application during the bonding protocol on microshear bond strength of two adhesive systems, after storage in different media. Seventy-two human molars had their crowns cut in half and embedded in PVC cylinders with acrylic resin. The specimens were randomly divided into experimental groups (n=12) according to the adhesive system (Ambar and Single Bond 2), use of CHX in the bonding protocol, and time interval (24 h and 15 days) in the storage media (distilled water, mineral oil and 1% sodium hypochlorite - NaOCl). Adhesive systems were applied in accordance to manufacturers' recommendations, with or without the use of CHX, and resin composite (Z350 XT) cylinders were placed on the hybridized dentin. After photoactivation, the specimens were stored in distilled water, mineral oil and 1% NaOCl for 24 h and 15 days. Microshear bond strength was determined at a crosshead speed of 0.5 mm/min until fracture. The bond strength data were analyzed statistically by 4-way ANOVA and Tukey's test (alpha=5%). Use of CHX in the bonding protocol did not cause loss of bond strength in any of the evaluated situations, irrespective of time and storage medium. The storage medium had no influence on bond strength values after 15 days when the bond protocol without CHX application was used. However, the use of CHX in the protocol influenced negatively the bond strength values for Single Bond 2 after 15 days storage in distilled water and 1% NaOCl. PMID- 26963211 TI - LED and Halogen Light Transmission through a CAD/CAM Lithium Disilicate Glass Ceramic. AB - The effect of thickness, shade and translucency of CAD/CAM lithium disilicate glass-ceramic on light transmission of light-emitting diode (LED) and quartz tungsten-halogen units (QTH) were evaluated. Ceramic IPS e.max CAD shades A1, A2, A3, A3.5, high (HT) and low (LT) translucency were cut (1, 2, 3, 4 and 5 mm). Light sources emission spectra were determined. Light intensity incident and transmitted through each ceramic sample was measured to determine light transmission percentage (TP). Statistical analysis used a linear regression model. There was significant interaction between light source and ceramic translucency (p=0.008) and strong negative correlation (R=-0.845, p<0.001) between ceramic thickness and TP. Increasing one unit in thickness led to 3.17 reduction in TP. There was no significant difference in TP (p=0.124) between shades A1 (beta1=0) and A2 (beta1=-0.45) but significant reduction occurred for A3 (beta1=-0.83) and A3.5 (beta1=-2.18). The interaction QTH/HT provided higher TP (beta1=0) than LED/HT (beta1=-2.92), QTH/LT (beta1=-3.75) and LED/LT (beta1= 5.58). Light transmission was more effective using halogen source and high translucency ceramics, decreased as the ceramic thickness increased and was higher for the lighter shades, A1 and A2. From the regression model (R2=0.85), an equation was obtained to estimate TP value using each variable beta1 found. A maximum TP of 25% for QTH and 20% for LED was found, suggesting that ceramic light attenuation could compromise light cured and dual cure resin cements polymerization. PMID- 26963212 TI - Effectiveness of Combination of Dentin and Enamel Layers on the Masking Ability of Porcelain. AB - This study evaluated the masking ability of different porcelain thicknesses and combination of enamel and/or dentin porcelain layers over simulated background dental substrates with higher (A2) and lower (C4) color values. Combination of the enamel (E) and dentin (D) monolayer porcelain disks with different thicknesses (0.5 mm, 0.8 mm, and 1 mm) resulted in the following bilayer groups (n=10): D1E1, D1E0.8; D1E0.5; D0.8E0.8; D0.8E0.5, and D0.5E0.5. CIELAB color coordinates were measured with a spectrophotometer. The translucency parameter of mono and bilayer specimens and the masking ability estimated by color variation (DeltaE*ab) of bilayer specimens over simulated dental substrates were evaluated. Linear regression analysis was used to investigate the relationships translucency parameter * DeltaE*, translucency parameter * porcelain thickness, and DeltaE* * porcelain thickness. Data were analyzed statistically (alpha= 0.05). Thinner porcelain disks were associated with higher translucency. Porcelain monolayers were considerably more translucent than bilayers (enamel + dentin). Dentin porcelain was less translucent than enamel porcelain with same thickness. DeltaE* was always lower when measured over A2 background. Higher DeltaE* was observed for the C4 background, indicating poorer masking ability. Increased DeltaE* was significantly associated with increased translucency for both backgrounds. Decreased translucency and DeltaE* were associated with increased total porcelain thickness or increased dentin thickness for both backgrounds. In conclusion, increased porcelain thickness (particularly increased dentin layer) and increased porcelain opacity resulted in better masking ability of the dental backgrounds. PMID- 26963213 TI - Effects of Peracetic Acid on the Corrosion Resistance of Commercially Pure Titanium (grade 4). AB - The aim of this study was to evaluate the corrosion resistance of pure titanium grade 4 (cp-Ti-4), subjected to disinfection with 0.2% and 2% peracetic acid during different immersion periods using anodic potentiodynamic polarization test in acid and neutral artificial saliva. Cylindrical samples of cp-Ti-4 (5 mm x 5 mm) were used to fabricate 24 working electrodes, which were mechanically polished and divided into eight groups (n=3) for disinfection in 2% and 0.2% peracetic acid for 30 and 120 min. After disinfection, anodic polarization was performed in artificial saliva with pH 4.8 and 6.8 to assess the electrochemical behavior of the electrodes. A conventional electrochemical cell, constituting a reference electrode, a platinum counter electrode, and the working electrode (cp Ti specimens) were used with a scanning rate of 1 mV/s. Three curves were obtained for each working electrode, and corrosion was characterized by using scanning electron microscopy (SEM) and energy dispersive x-ray spectrometry (EDS). Data of corrosion potential (Ecorr) and passive current (Ipass) obtained by the polarization curves were analyzed statistically by Student's t-test (a=0.05). The statistical analysis showed no significant differences (p>0.05) between artificial saliva types at different concentrations and periods of disinfection, as well as between control and experimental groups. No surface changes were observed in all groups evaluated. In conclusion, disinfection with 0.2% and 2% peracetic acid concentrations did not cause corrosion in samples manufactured with cp-Ti-4. PMID- 26963214 TI - Reliability of FEA on the Results of Mechanical Properties of Materials. AB - The present study evaluated the reliability of FEA on the results of different mechanical properties (E and v) of materials. Two 3D models of a maxillary canine with endodontic treatment, intracanal post, composite resin core and restored with porcelain-fused-to-metal crown were generated according to micro-CT images. Two groups with different E and nu values for porcelain, metal coping alloy, resin cement and composite resin were established. The materials' properties for group GL were based on literature data, while for group GIE the impulse excitation technique was used. A load of 180 N was applied at 45 degrees on the incisal third of the lingual surface of the canine tooth. All models were supported by the periodontal ligament (x=y=z=0). The von Mises stress (VMS) was calculated. The stress values revealed differences between the groups for both VMS distribution and value. The porcelain (GL: 5.966 MPa; GIE: 7.478 MPa), metal coping (GL: 3.811 MPa; GIE: 0.973 MPa) and core (GL: 4.771 MPa; GIE: 0.026 MPa) were significantly affected. In conclusion, this study showed that the determination of mechanical properties (E and nu) of materials is essential for the reliability on the results of FEA. PMID- 26963215 TI - Effect of Fluoride Varnish Combined with Er:YAG Laser on the Permeability of Eroded Dentin: An In Situ Study. AB - This study evaluated the combined effect of fluoride varnish and Er:YAG laser on the permeability of eroded bovine root dentin. After initial erosive challenge followed by a remineralization period, the specimens were divided in two groups according to the treatment - fluoride varnish and non-fluoride varnish - and were subdivided according to the irradiation protocol: Er:YAG laser (100 mJ, 3 Hz, 12.8 J/cm2per pulse, non-contact and defocus mode) and non-irradiated. After a lead-in period, 7 volunteers wore a palatal device containing 4 specimens that were subjected to erosive challenges. At the first experimental phase, 4 volunteers used specimens treated with fluoride varnish and fluoride varnish+Er:YAG laser and 3 volunteers used specimens treated with non-fluoride varnish and non-fluoride varnish+Er:YAG laser. After a washout period, volunteers were crossed to treatments, characterizing a 2x2 crossover experiment. At the end of the experimental phase, the quantitative response variable was obtained by permeability analysis and the qualitative response by scanning electron microscopy (SEM). Two-way ANOVA and Tukey-Kramer's test revealed that specimens treated with fluoride varnish+Er:YAG laser showed the lowest permeability and a significant difference was found between this group and the others. When varnish (fluoride/non-fluoride) was applied in the absence of Er:YAG laser, higher permeability was found when compared to the laser-treated groups. SEM evaluations showed partially or completely obliterated dentinal tubules when specimens were treated with fluoride varnish+Er:YAG laser. It may be concluded that Er:YAG laser was able to control the permeability of eroded root dentin and the combination with fluoride varnish increased laser action. PMID- 26963216 TI - A Two-Year Clinical Evaluation of Fluoride and Non-Fluoride Resin-Based Pit-and Fissure Sealants. AB - The aim of this study was to evaluate and compare for 24 months, the retention and surface characteristics of two pit-and-fissure sealants: Helioseal Clear and Helioseal F (Ivoclar Vivadent). The correlation between the different stages of eruption and sealant retention was also verified. Fifty children aged 6 to 8 years participated in the study, totalizing 153 teeth divided into two groups: HC (Helioseal Clear) and HF (Helioseal F). After 6, 12, 18 and 24 months, a clinical examination was performed by previously calibrated examiners. The surface characteristics and the retention of the sealants (modified RYGE & SNYDER criteria) were assessed. Analyzing the occlusal surface, HC exhibited a statistically significant higher retention at 12 (p=0.0345) and 24 months (p=0.0076). Concerning the surface characteristics, only the superficial discoloration of HC was smaller than HF, during the entire studied period. For all the other characteristics, the results of the Mann-Whitney test were highly significant at different periods (p=0.0000 to 0.0421). The frequency of air bubbles within the sealant surfaces, determined by Chi-square test, was significantly higher in HF (p=0.000:12 and 18 months to p=0.002: 6 and 24 months). HC sealant material exhibited the best performance regarding the retention and surface characteristics on the occlusal surface. PMID- 26963218 TI - Racial Differences in Oral Health-Related Quality of Life: A Multilevel Analysis in Brazilian Children. AB - This cross-sectional study aimed to assess the influence of race/ethnicity on Brazilian children' oral health-related quality of life (OHRQoL). A multistage random sampling selected a representative sample of 1,134 twelve-years-old children from public schools of Santa Maria, a city in Southern Brazil. Participants were examined by 4 calibrated clinicians (minimum Kappa-value for inter-examiner agreement of 0.8) and the Brazilian short version of the Child Perceptions Questionnaire (CPQ11-14) was administered. The children's parents or guardians answered questions regarding their demographics and socioeconomic status. Associations were analyzed using multilevel Poisson regression models. Children from racial/ethnic minority groups had poorer OHRQoL. The mean CPQ11-14 score was 1.08 times higher for non-white children than their white counterparts' score. "Social" and "Emotional well-being" were the most affected domains for non white children, with significantly higher mean scores as compared to white children (RR 1.19, 95% CI, 1.07-1.33; and RR 1.14; 95% CI 1.04-1.24). This association remained significant even after adjusting for individual and contextual covariates. OHRQoL disparities are prevalent among children from racial/ethnic minority groups. Non-white children have lower OHRQoL compared to white children. PMID- 26963217 TI - Influence of Light Source, Thermocycling and Silane on the Shear Bond Strength of Metallic Brackets to Ceramic. AB - The objective of this study was to evaluate the effects of different light sources, thermocycling and silane on the bond strength of metallic brackets to ceramic. Cylinders of feldspathic ceramic were etched with 10% hydrofluoric acid for 60 s. Half of the cylinders (Groups 1 to 4) received two layers of silane. Metallic brackets were bonded to the cylinders using Transbond XT and divided into 8 groups (n=20), according to light source (Radii Plus LED - 40 s; Groups 1, 2, 5 and 6 and XL 2500 halogen light - 40 s; Groups 3, 4, 7 and 8) and experimental conditions with (Groups 2, 4, 6 and 8) without thermocycling (Groups 1, 3, 5 and 7). Shear bond testing was carried out after 24 h of deionized water storage (Groups 1, 3, 5 and 7) and thermocycling (Groups 2, 4, 6 and 8; 7,000 cycles - 5 degrees /55 degrees C). Date were submitted to three-way ANOVA and Tukey's post hoc test (alpha=0.05). The Adhesive Remnamt Index (ARI) was evaluated at 8* magnification. The application of silane was effective in increasing the shear bond strength of the brackets to ceramic (p<0.05). Significant difference (p<0.05) on the bond strength was observed between light sources with or without thermocycling. The ARI showed a predominance of scores 0 for all groups, with an increase in scores 1, 2 and 3 for the silane groups. In conclusion, silane improved significantly the shear bond strength of the brackets to ceramic. The thermocycling and light sources influence on the bond strength. PMID- 26963219 TI - Definitive Presurgical CAD/CAM-Guided Implant-Supported Crown in an Esthetic Area. AB - This paper describes the digital workflow from cone beam computer tomography (CBCT) to the installation of a definitive presurgical zirconium individual crown in a 19-year-old woman requiring implant replacement of a maxillary right lateral incisor. The patient had agenesis of this tooth and had completed the orthodontic treatment. CBCT was conducted and diagnostic casts were digitized. Virtual planning was completed by defining a prosthetically driven implant and a stereolithographic surgical template was produced. Good adaptation of a stereolithographic surgical template was verified in the working cast. Implant and abutment were installed in this cast using a stereolithographic surgical template, and a CAD/CAM definitive zirconium crown was produced. Flapless computer-guided implant surgery was performed. The abutment was connected, and a definitive zirconium crown was cemented using resin cement. The digital workflow presented herein shows high accuracy for a virtually planned implant with flapless guided placement, allowing the successful delivery of a definitive presurgical zirconium single crown in an esthetic area in a single visit. The patient was revaluated after 1 year of function with an excellent outcome of the treatment. PMID- 26963220 TI - Tutankhamun's Dentition: The Pharaoh and his Teeth. AB - Tutankhamun was a Pharaoh of the 18th Dynasty (New Kingdom) in ancient Egypt. Medical and radiological investigations of his skull revealed details about the jaw and teeth status of the mummy. Regarding the jaw relation, a maxillary prognathism, a mandibular retrognathism and micrognathism have been discussed previously. A cephalometric analysis was performed using a lateral skull X-ray and a review of the literature regarding King Tutankhamun's mummy. The results imply diagnosis of mandibular retrognathism. Furthermore, third molar retention and an incomplete, single cleft palate are present. PMID- 26963221 TI - What constitutes Homo sapiens? Morphology versus received wisdom. AB - Although Linnaeus coined Homo sapiens in 1735, it was Blumenbach forty years later who provided the first morphological definition of the species. Since humans were not then allowed to be ante-Diluvian, his effort applied to the genus, as well. After the Feldhofer Grotto Neanderthal disproved this creationist notion, and human-fossil hunting became legitimate, new specimens were allocated either to sapiens or new species within Homo, or even to new species within new genera. Yet as these taxonomic acts reflected the morphological differences between specimens, they failed to address the question: What constitutes H. sapiens? When in 1950 Mayr collapsed all human fossils into Homo, he not only denied humans a diverse evolutionary past, he also shifted the key to identifying its species from morphology to geological age - a practice most paleoanthropologists still follow. Thus, for example, H. erectus is the species that preceded H. sapiens, and H. sapiens is the species into which H. erectus morphed. In order to deal with a growing morass of morphologically dissimilar specimens, the non-taxonomic terms "archaic" (AS) and "anatomically modern" (AMS) were introduced to distinguish between the earlier and later versions of H. sapiens, thereby making the species impossible to define. In attempting to disentangle fact from scenario, I begin from the beginning, trying to delineate features that may be distinctive of extant humans (ES), and then turning to the fossils that have been included in the species. With the exception of Upper Paleolithic humans - e.g. from Cro-Magnon, Dolni Vestonice, Mladec - I argue that many specimens regarded as AMS, and all those deemed AS, are not H. sapiens. The features these AMS do share with ES suggest the existence of a sapiens clade. Further, restudy of near-recent fossils, especially from southwestern China (~11 14.5 ka), reinforces what discoveries such as H. floresiensis indicate: "If it's recent, it's not necessarily H. sapiens". PMID- 26963222 TI - The evolution of language and thought. AB - Language primarily evolved as a vocal medium that transmits the attributes of human culture and the necessities of daily communication. Human language has a long, complex evolutionary history. Language also serves as an instrument of thought since it has become evident that in the course of this process neural circuits that initially evolved to regulate motor control, motor responses to external events, and ultimately talking were recycled to serve tasks such as working memory, cognitive flexibility linguistic tasks such as comprehending distinctions in meaning conveyed by syntax. This precludes the human brain possessing an organ devoted exclusively to language, such as the Faculty of Language proposed by Chomsky (1972, 2012). In essence like Fodor's (1983) modular model, a restatement of archaic phrenological theories (Spurzheim, 1815). The subcortical basal ganglia can be traced back to early anurans. Although our knowledge of the neural circuits of the human brain is at a very early stage and incomplete, the findings of independent studies over the past 40 years, discussed here, have identified circuits linking the basal ganglia with various areas of prefrontal cortex, posterior cortical regions and other subcortical structures. These circuits are active in linguistic tasks such as lexical access, comprehending distinctions in meaning conferred by syntax and the range of higher cognitive tasks involving executive control and play a critical role in conferring cognitive flexibility. The cingulate cortex which appeared in Therapsids, transitional mammal-like reptiles who lived in age of the dinosaurs, most likely enhanced mother-infant interaction, contributing to success in the Darwinian (1859) "Struggle for Existence" - the survival of progeny. They continue to fill that role in present-day mammals as well as being involved in controlling laryngeal phonation during speech and directing attention (Newman & MacLean, 1983; Cummings, 1993". The cerebellum and hippocampus, archaic structures, play role in cognition. Natural selection acting on genetic and epigenetic events in the last 500,000 years enhanced human cognitive and linguistic capabilities. It is clear that human language did not suddenly come into being 70,000 to 100,000 years as Noam Chomsky (Bolhuis et al., 2014) and others claim. The archeological record and analyses of fossil and genetic evidence shows that Neanderthals, who diverged from the human line at least 500,000 years ago possessed some form of language. Nor did the human population suddenly acquire the capability to relate two seemingly unrelated concepts by means of associative learning 100,000 years ago, re-coined "Merge" by Chomsky and his adherents, Merge supposedly is the key to syntax but associative learning, one of the cognitive processes by which children learn languages and the myriad complexities of their cultures, is a capability present in dogs and virtually all animals. PMID- 26963224 TI - Copper-Doped Titanium Dioxide Bronze Nanowires with Superior High Rate Capability for Lithium Ion Batteries. AB - Pristine and Cu-doped TiO2-B nanowires are synthesized by the microwave assisted hydrothermal method. The doped oxide exhibits a highly porous structure with a specific surface area of 160.7 m(2) g(-1). As evidenced by X-ray photoelectron spectroscopy and X-ray energy dispersive spectroscopy, around 2.0 atom % Cu(2+) cations are introduced into TiO2-B, which leads to not only a slightly expanded lattice network but also, more importantly, a modified electronic structure. The band gap of TiO2-B is reduced from 2.94 to 2.55 eV, resulting in enhanced electronic conductivity. Cyclic voltammetry and electrochemical impedance spectroscopy reveal improved electrochemical kinetic properties of TiO2-B due to the Cu doping. The doped nanowires show a specific capacity of 186.8 mAh g(-1) at the 10 C rate with a capacity retention of 64.3% after 2000 cycles. Remarkably, our material exhibits a specific capacity of 150 mAh g(-1) at the 60 C rate, substantiating its superior high rate capability for rechargeable lithium batteries. PMID- 26963226 TI - Hurricane Sandy's impact on the predisaster homeless and homeless shelter services in New Jersey. AB - Presently, there is little research on how people experiencing homelessness prepare for, respond to, and recover from disasters. Existing emergency management literature does not provide an understanding of how disasters affect homeless shelter services. The present study seeks to fill these gaps by examining how Hurricane Sandy impacted homeless shelters and their guests in New Jersey. Presenting findings from ethnographic research in Atlantic City and Hoboken, this study identifies several areas in which homeless shelters and their guests may be able to assist in emergency response and disaster recovery such as preparing meals for victims, sorting and processing donated items, and assisting victims in filing for emergency assistance. PMID- 26963227 TI - A proposed emergency management program for acute care facilities in response to a highly virulent infectious disease. AB - To address the organizational complexities associated with a highly virulent infectious disease (HVID) hazard, such as Ebola Virus Disease (EVD), an acute care facility should institute an emergency management program rooted in the fundamentals of mitigation, preparedness, response, and recovery. This program must address all known facets of the care of a patient with HVID, from unannounced arrival to discharge. The implementation of such a program not only serves to mitigate the risks from an unrecognized exposure but also serves to prepare the organization and its staff to provide for a safe response, and ensure a full recovery. Much of this program is based on education, training, and infection control measures along with resourcing for appropriate personal protective equipment which is instrumental in ensuring an organized and safe response of the acute care facility in the service to the community. This emergency management program approach can serve as a model in the care of not only current HVIDs such as EVD but also future presentations in our healthcare setting. PMID- 26963228 TI - The National Capital Region closed circuit television video interoperability project. AB - OBJECTIVE: The National Capital Region (NCR) includes many government jurisdictions and agencies using different closed circuit TV (CCTV) cameras and video management software. Because these agencies often must work together to respond to emergencies and events, a means of providing interoperability for CCTV video is critically needed. DESIGN: Video data from different CCTV systems that are not inherently interoperable is represented in the "data layer." An "integration layer" ingests the data layer source video and normalizes the different video formats. It then aggregates and distributes this video to a "presentation layer" where it can be viewed by almost any application used by other agencies and without any proprietary software. A native mobile video viewing application is also developed that uses the presentation layer to provide video to different kinds of smartphones. SETTING: The NCR includes Washington, DC, and surrounding counties in Maryland and Virginia. RESULTS: The video sharing architecture allows one agency to see another agency's video in their native viewing application without the need to purchase new CCTV software or systems. A native smartphone application was also developed to enable them to share video via mobile devices even when they use different video management systems. CONCLUSIONS: A video sharing architecture has been developed for the NCR that creates an interoperable environment for sharing CCTV video in an efficient and cost effective manner. In addition, it provides the desired capability of sharing video via a native mobile application. PMID- 26963229 TI - Factors influencing mine rescue team behaviors. AB - A focus group study of the first moments in an underground mine emergency response was conducted by the National Institute for Occupational Safety and Health (NIOSH), Office for Mine Safety and Health Research. Participants in the study included mine rescue team members, team trainers, mine officials, state mining personnel, and individual mine managers. A subset of the data consists of responses from participants with mine rescue backgrounds. These responses were noticeably different from those given by on-site emergency personnel who were at the mine and involved with decisions made during the first moments of an event. As a result, mine rescue team behavior data were separated in the analysis and are reported in this article. By considering the responses from mine rescue team members and trainers, it was possible to sort the data and identify seven key areas of importance to them. On the basis of the responses from the focus group participants with a mine rescue background, the authors concluded that accurate and complete information and a unity of purpose among all command center personnel are two of the key conditions needed for an effective mine rescue operation. PMID- 26963230 TI - A course in disaster mitigation. AB - While endeavors are underway within the emergency management discipline to develop a unique body of foundational knowledge, widespread acknowledgement and agreement within the emergency management scholarly community of the existence of theoretical foundations and the consistent incorporation of these elements into emergency management research and teaching are still lacking. This article offers an outline of a US-based undergraduate course in mitigation theory and practice that is based on a synthesis of the academic literature related to disaster mitigation as a means to advance the discourse on foundational knowledge and curriculum development. The course outline proposes a set of concepts, theories, propositions, and empirical data that would arguably be fundamental for students in gaining a comprehensive understanding of mitigation in the United States and suggests how that information can be organized and presented in a meaningful way. PMID- 26963231 TI - Continuity of operations planning in college athletic programs: The case for incorporating Federal Emergency Management Guidelines. AB - College athletic departments have a responsibility to provide a safe environment for student-athletes; however, most colleges do not have a crisis management plan that includes procedures for displaced student-athletes or alternate facilities to perform athletic events. Continuity of operations planning ensures athletic programs are equipped to maintain essential functions during, or shortly after, a disruption of operations due to possible hazards. Previous studies have identified a lack of emergency preparedness and continuity planning in college athletic departments. The purpose of this article is to illustrate in detail one approach to disaster planning for college athletic departments, namely the Federal Emergency Management Agency (FEMA) continuity of operations framework. By adhering to FEMA guidelines and promoting a best practices model, athletic programs can effectively plan to address potential hazards, as well as protect the organization's brand, image, and financial sustainability after a crisis event. PMID- 26963232 TI - Reduction in unavailable-for-response episodes in a private emergency medical services agency. AB - OBJECTIVE: Increased demand for emergency medical services (EMS), financial constraints, emergency department overcrowding, EMS crews kept in hospital, all result in ambulance unavailability. This study seeks to identify daily temporal patterns for unavailable-for-response episodes, impact of increasing staffing during peak periods, and evaluating the extent of reduction in unavailable-for response episodes due to temporally precise increases in staffing during critical time periods and the resulting cost/benefit analysis. DESIGN: The authors evaluated all EMS responses during a 7-month time period and recorded all unavailable-for-response episodes. This identified clusters of unavailable-for response episodes for which incremental staffing changes were implemented. Internal audit of cost/revenues was recorded. SETTING: Midsized private EMS agency in Northwest Pennsylvania. SUBJECTS/PARTICIPANTS: EMS Responders/Agency calls. INTERVENTIONS: Temporally precise increases in staffing during critical time periods/unavailable-for-response episodes. MAIN OUTCOME MEASURE(S): Reduction in unavailable-for-response episodes, cost effectiveness. RESULTS: Evaluating 23,833 EMS responses that occurred during the study period, staffing changes resulted in a 93 percent average reduction and 100 percent maximum reduction in unavailable-for-response episodes and were cost effective, based on evaluation of cost versus revenue, in this EMS agency. CONCLUSIONS: Identification of opportunities for system staffing improvement in a midsized EMS agency demonstrated feasibility and usability of mapping temporal patterns of unavailable-for-response episodes to substantially reduce the number of unavailable-for-response episodes and was cost effective. PMID- 26963233 TI - Increasing topical anesthetic efficacy with microneedle application. AB - INTRODUCTION: Since topical anesthetics alone seldom provide adequate analgesia for laser resurfacing procedures, injectable forms of anesthesia are often required. However, their application is uncomfortable for the patient. In this study, it is investigated whether microneedle application would enhance the efficacy of topical anesthetics. METHODS: Forty-seven patients participated in the study. Topical anesthetic agent EMLA was applied to the whole face of the patients. Microneedle treatment was applied to one side of the face with a roller type device. Whole-face carbon dioxide laser resurfacing therapy was carried out then. The pain that patients experienced was assessed by using visual analog scale (VAS) method. VAS scores of two sides of the face were compared by using Wilcoxon signed-rank test. RESULTS: The mean of VAS score of the microneedle treated side was 2.1 +/- 1.1 while that of the untreated side was 5.9 +/- 0.9 and this difference was statistically significant (Wilcoxon signed-rank test, the Z value is - 5.9683 and the p-value is < 0.001). SUMMARY: This study revealed that microneedle application, with a roller-type device, is a safe and easy procedure in providing sufficient anesthesia for facial laser resurfacing without the need for supplementary nerve blocks or injections. PMID- 26963235 TI - Ozonation of chlortetracycline in the aqueous phase: Degradation intermediates and pathway confirmed by NMR. AB - Chlortetracycline (CTC) degradation mechanism in aqueous phase ozonation was evaluated for degradation mechanism and its correlation with the biodegradability and mineralization. CTC was removed within 8 and 4 min of ozonation at pH 2.2 and 7.0, respectively. At pH 2.2, HPLC-triple quadrupole mass spectrometry (MS) detected 30 products. The structures for some of these products were proposed on the basis of ozonation chemistry, CTC structure and MS data; these structures were then confirmed by nuclear magnetic resonance (NMR) spectra. Double bond cleavages, dimethyl amino group oxidation, opening and removal of the aromatic ring and dechlorination, mostly direct ozonation reactions, gave products with molecular weights (m.w.) 494, 510, 524, 495 and 413, respectively. Subsequent degradations gave products with m.w. 449, 465, 463 and 415. These products were arranged into a degradation pathway. At pH 7.0, the rate of reaction was increased, though the detected products were similar. Direct ozonation at pH 2.2 increased the biodegradability by altering the structures of CTC and its products. Nevertheless, direct ozonation alone remained insufficient for the mineralization, which was efficient at pH 7.0 due to the production of free radicals. PMID- 26963234 TI - Sleep disturbance in mild cognitive impairment is associated with alterations in the brain's default mode network. AB - This study aimed to identify default mode network (DMN) functional connectivity deficits in patients with mild cognitive impairment (MCI) and sleep disturbance, relative to those with MCI and no sleep disturbance. A control group was included to aid in identifying DMN changes specific to MCI. A cross-sectional, single center study was performed at the Brain and Mind Research Centre in Sydney, Australia. Participants (95 adults over the age of 65: 38 controls and 57 meeting criteria for MCI) underwent resting-state functional MRI along with comprehensive neuropsychological, medical, and psychiatric assessment. Self-report data were collected including sleep quality assessment via the Pittsburgh Sleep Quality Index. A total score of greater than 5 on the Pittsburgh Sleep Quality Index was used to signify the presence of significant sleep disturbance, as per commonly used methodology. Using this criterion, 53% (n = 30) of our MCI group were classified as sleep-disturbed. Whereas the total group of MCI subjects and controls demonstrated no significant differences, sleep-disturbed MCIs demonstrated increased connectivity between temporal and parietal regions, and decreased connectivity between the prefrontal cortex and the temporoparietal junction relative to sleep-disturbed controls. Relative to those MCIs without sleep disturbance, sleep-disturbed MCI participants demonstrated significantly diminished DMN connectivity between temporal and parietal regions, a finding that was particularly pronounced in amnestic MCI. Sleep disturbance in MCI is associated with distinct alterations in DMN functional connectivity in brain regions underpinning salient memory and sleep systems. Future studies may build on these results via experimental manipulation and objective measurement of sleep. (PsycINFO Database Record PMID- 26963236 TI - Semi-nitritation process producing optimum influent for anammox process in treatment of domestic wastewater. AB - The process of anaerobic ammonium oxidation (Anammox) requires a proper ratio of NH4(+)-N and NO2(-)-N in the influent, which is difficult to control upon treating domestic wastewater. In this study, a control strategy of semi nitritation (SN) process based on monitoring the pH profile and NH4(+)-N concentration in a sequencing batch reactor (SBR) was developed. The aeration time of each cycle in SN-SBR was calculated using the established equation tSN=tCOD+0.56alphanS0/(S0-Sn). To verify the suitability of the control strategy, SN-SBR was operated continuously for 20 cycles, fed with real domestic wastewater with a fluctuating COD of 200-400 mg L(-1) and NH4(+)-N of 65-80 mg L(-1). The nitrogen removal performance of SN-anammox system using the developed control strategy was also monitored. Results showed that SN-SBR was able to generate a suitable ratio of NH4(+)-N to NO2(-)-N for the following anammox process, the TN removal rate of the SN-anammox system achieved 91.7 +/- 0.4% and the average ammonium, nitrite and nitrate concentration of effluent was only 0.50 +/- 0.24, 0.13 +/- 0.09 and 4.9 +/- 0.22 mg L(-1), respectively. This study has potential application in the treatment of domestic wastewater using combined SN-anammox process. PMID- 26963237 TI - Effects of gamma-irradiation of original and organic matter-amended soils on the sorption of triclosan and diuron from aqueous solutions. AB - Soil gamma-irradiation is a well-known method of inhibiting microbial activity in studies of the soil sorption of organic compounds. However, few studies have addressed the possible effect of gamma-irradiation on the sorptive ability of soils enriched with different types of organic matter (OM). The objective of this study was to probe the effect of soil gamma-irradiation on organic compound-soil interactions in two different situations representing adding OM to soils through land disposal of (a) OM-rich sewage sludge-originating biosolids and (b) olive mill wastewater (OMW). Both situations describe frequent environmental and agricultural scenarios. Comparisons of aqueous sorption on cobalt-60 gamma irradiated and non-irradiated soil sorbents were carried out for (a) triclosan (in a series of three soils and their lab-incubated mixtures with three different types of biosolids), and (b) the pesticide diuron (in two different untreated and OMW-affected soils). In each case, sodium azide was used as a biocide. Soil gamma irradiation affected the sorption of organic compounds by a factor generally not exceeding 2-3. Specifically, for triclosan, the sorbed concentration ratio between irradiated and non-irradiated soils when averaged over all the soil samples was 0.94. No significant effects of gamma-irradiation on soil organic carbon or total nitrogen contents were observed. The effect of gamma-irradiation on a soil sorbent may be less important when a rough estimate of a soil sorption coefficient of an organic compound is needed. However, it may need to be taken into account in mechanistic sorption studies, specifically, when the shape of sorption isotherms is of interest. PMID- 26963238 TI - Phenyl-functionalized magnetic palm-based powdered activated carbon for the effective removal of selected pharmaceutical and endocrine-disruptive compounds. AB - Triethoxyphenylsilane (TEPS)-functionalized magnetic palm-based powdered activated carbon (MPPAC-TEPS) was prepared and characterized using various spectroscopic methods, and then tested for the removal of bisphenol A, carbamazepine, ibuprofen and clofibric acid. Magnetite film on MPPAC-TEPS was homogeneously coated on the outer surface of palm-based powdered activated carbon (PPAC) through a hydrothermal co-precipitation technique. Followed by silanization of phenyl-functionalized organosilane on MPPAC's magnetic film. As results, micro/mesopore surface area and volume increased without significant pore clogging and iron (Fe) dissolution under the acidic conditions was greatly decreased. The unique structural and chemical features of MPPAC-TEPS were found to be the main reasons for the enhanced adsorption rates and removal capacities of POPs. The presence of electrolytes and different pH values greatly affected the sorption efficiencies. The dominant sorption mechanism of POPs by MPPAC-TEPS was determined to be pi-pi interaction (physisorption), based on thermodynamic (DeltaG degrees ) and differential scanning calorimetry (DSC). Thermal regeneration at a low temperature (350 degrees C) was an effective method to desorb the retained POPs and enabled to reactivate MPPAC-TEPS with sustained sorption rates and capacities, whereas PPAC was largely exhausted. As a new type of sorbent for POPs, MPPAC-TEPS has operational advantages, such as magnetic separation and stable regeneration. PMID- 26963239 TI - Mesoporous silica nanoparticles enhance seedling growth and photosynthesis in wheat and lupin. AB - The application of mesoporous silica nanoparticles (MSNs) as a smart delivery system to agricultural crops is gaining attention but the release of nanoparticles into the environment may pose a potential threat to biological systems. We investigated the effects of MSNs on the growth and development of wheat and lupin plants grown under controlled conditions. We report a dramatic increase in the growth of wheat and lupin plants exposed to MSNs. We also found that, in leaves, MSNs localised to chloroplasts and that photosynthetic activity was significantly increased. In addition, absorption and cellular distribution of MSNs by the two plant species following root uptake were observed using scanning electron microscopy equipped with energy dispersive spectroscopy (SEM-EDS). Following uptake of MSNs at 500 and 1000 mg L(-1), there was enhancement of seed germination, increased plant biomass, total protein and chlorophyll content. Treatment of both species with MSNs at the highest concentration (2000 mg L(-1)) did not result in oxidative stress or cell membrane damage. These findings show that MSNs can be used as novel delivery systems in plants and that over the range of concentrations tested, MSNs do not have any negative impacts on plant growth or development. PMID- 26963241 TI - Separation of the metallic and non-metallic fraction from printed circuit boards employing green technology. AB - The generation of electrical and electronic waste is increasing day by day; recycling is attractive because of the metallic fraction containing these. Nevertheless, conventional techniques are highly polluting. The comminution of the printed circuit boards followed by an inverse flotation process is a clean technique that allows one to separate the metallic fraction from the non-metallic fraction. It was found that particle size and superficial air velocity are the main variables in the separation of the different fractions. In this way an efficient separation is achieved by avoiding the environmental contamination coupled with the possible utilization of the different fractions obtained. PMID- 26963240 TI - Dioxins, DL-PCB and NDL-PCB accumulation profiles in livers from sheep and cattle reared in North-western Italy. AB - Products of animal origin represent the main route of human exposure to dioxins and dioxin-like PCBs (DL-compounds). Recently, concerns have been raised about ovine products, particularly the liver, in which relatively high levels of DL compounds have been reported. We surveyed ovine and bovine livers in areas with no known sources of dioxin or DL-PCB contamination, in order to assess accumulation patterns for both DL-compounds and non-DL (NDL-) PCBs. None of the ovine and bovine samples exceeded the current Maximum Limits (MLs) for DL compounds. Liver DL-compound TEQ concentrations were up to 5-fold higher in sheep than in cows. No statistically significant differences in total NDL-PCBs levels were found. The main contributors to TEQ levels were the Penta- and Hexa chlorinated PCDFs and PCB 126. The results confirm the increased bioaccumulation in ovine liver towards specific DL-compounds even in ewes reared in areas with no known sources of PCDD/Fs or DL-PCBs contamination. PMID- 26963242 TI - Benzo(a)pyrene induces interleukin (IL)-6 production and reduces lipid synthesis in human SZ95 sebocytes via the aryl hydrocarbon receptor signaling pathway. AB - In this study, we determined the effects of benzo(a)pyrene (BaP) on the expression of aryl hydrocarbon receptor (AhR) and cytochrome P450 1A1 (CYP1A1), and assessed the action of BaP on inflammatory cytokine expression and lipid synthesis in SZ95 sebocytes in vitro. BaP (10(-8), 10(-7), 10(-6) and 10(-5)M) was not cytotoxic for SZ95 sebocytes after 24h exposure. Expression of AhR was promoted in mRNA lever, while was inhibited in protein lever after BaP (10(-5)M) exposure. CYP1A1 expression was up-regulated in both mRNA and protein levels. BaP (10(-5)M) exerted a stimulatory action on interleukin (IL)-6 secretion, while a dose-dependently inhibitory effect on lipid synthesis from 10(-8)M to 10(-5)M in SZ95 sebocytes. Both actions were partly antagonized in AhR-knockdowned SZ95 sebocytes. This study demonstrates that BaP can activate AhR signaling pathway, and exhibits pro-inflammatory effects and inhibitory effects on sebum production in human sebocytes. PMID- 26963243 TI - Endocrine Disruption: Computational Perspectives on Human Sex Hormone-Binding Globulin and Phthalate Plasticizers. AB - Phthalates are a class of high volume production chemicals used as plasticizers for household and industrial use. Several members of this chemical family have endocrine disrupting activity. Owing to ubiquitous environmental distribution and exposure of human population at all stages of life, phthalate contamination is a continuous global public health problem. Clinical and experimental studies have indicated that several phthalates are associated with adverse effects on development and function of human and animal systems especially the reproductive system and exposures during pregnancy and early childhood are by far of utmost concern. Sex hormone-binding globulin (SHBG) is a plasma carrier protein that binds androgens and estrogens and represents a potential target for phthalate endocrine disruptor function in the body. In the present study, the binding mechanism of the nine phthalates i.e. DMP, DBP, DIBP, BBP, DNHP, DEHP, DNOP, DINP, DIDP with human SHBG was delineated by molecular docking simulation. Docking complexes of the nine phthalates displayed interactions with 15-31 amino acid residues of SHBG and a commonality of 55-95% interacting residues between natural ligand of SHBG, dihydrotestosterone, and the nine phthalate compounds was observed. The binding affinity values were more negative for long chain phthalates DEHP, DNOP, DINP, and DIDP compared to short chain phthalates such as DMP and DBP. The Dock score and Glide score values were also higher for long chain phthalates compared to short chain phthalates. Hence, overlapping of interacting amino acid residues between phthalate compounds and natural ligand, dihydrotestosterone, suggested potential disrupting activity of phthalates in the endocrine homeostasis function of SHBG, with long chain phthalates expected to be more potent than the short chain phthalates. PMID- 26963244 TI - Epidemiology, Diagnosis and Management of Extra-Pulmonary Tuberculosis in a Low Prevalence Country: A Four Year Retrospective Study in an Australian Tertiary Infectious Diseases Unit. AB - OBJECTIVES: Extra-pulmonary tuberculosis (EPTB) is relatively neglected and increasing in incidence, in comparison to pulmonary tuberculosis (PTB) in low burden settings. It poses particular diagnostic and management challenges. We aimed to determine the characteristics of EPTB in Western Sydney, Australia, and to conduct a quality assurance investigation of adherence to guidelines among Infectious Diseases (ID) practitioners managing EPTB cases. METHODS: All adult EPTB cases managed by a large ID service during 01/01/2008-31/12/2011 were eligible for inclusion in the retrospective review. Data were extracted from patient medical records on demographic, diagnostic, clinical and management details, and on clinician adherence to local and international TB guidelines. RESULTS: 129 cases managed by the ID service were identified, with files available for 117. 98 cases were managed by the Respiratory service and were excluded. 98.2%(112/114) had been born in a country other than Australia. HIV status was tested or previously known in 97 people, and positive in 4 (4%). Microbiological confirmation was obtained in 68/117 (58.1%), an additional 24 had histopathological findings considered confirmatory (92/117, 78.6%), with the remainder diagnosed on clinical and/or radiological grounds. Median time to diagnosis post-migration from a high TB-burden country was 5 years (range 0-41). 95 cases were successfully treated, 11 cases defaulted, refused therapy or transferred, 2 cases relapsed and outcomes unknown or pending in 9 cases. No deaths occurred in the sample analysed. Clinician adherence to guidelines was high, but with scope for improvement in offering testing for co-infections, performing eye checks, monitoring blood glucose in patients receiving adjunctive corticosteroids, and considering drug interactions. CONCLUSIONS: Despite excellent TB outcomes in this setting, the low proportion of cases with susceptibility data is worrying in this era of increasing drug resistance, and illustrates the diagnostic difficulties faced even in a well-resourced setting. Vigilance for EPTB needs to remain high in those moving from high prevalence countries to Australia, even decades after immigration. PMID- 26963245 TI - Unbiased Characterization of Anopheles Mosquito Blood Meals by Targeted High Throughput Sequencing. AB - Understanding mosquito host choice is important for assessing vector competence or identifying disease reservoirs. Unfortunately, the availability of an unbiased method for comprehensively evaluating the composition of insect blood meals is very limited, as most current molecular assays only test for the presence of a few pre-selected species. These approaches also have limited ability to identify the presence of multiple mammalian hosts in a single blood meal. Here, we describe a novel high-throughput sequencing method that enables analysis of 96 mosquitoes simultaneously and provides a comprehensive and quantitative perspective on the composition of each blood meal. We validated in silico that universal primers targeting the mammalian mitochondrial 16S ribosomal RNA genes (16S rRNA) should amplify more than 95% of the mammalian 16S rRNA sequences present in the NCBI nucleotide database. We applied this method to 442 female Anopheles punctulatus s. l. mosquitoes collected in Papua New Guinea (PNG). While human (52.9%), dog (15.8%) and pig (29.2%) were the most common hosts identified in our study, we also detected DNA from mice, one marsupial species and two bat species. Our analyses also revealed that 16.3% of the mosquitoes fed on more than one host. Analysis of the human mitochondrial hypervariable region I in 102 human blood meals showed that 5 (4.9%) of the mosquitoes unambiguously fed on more than one person. Overall, analysis of PNG mosquitoes illustrates the potential of this approach to identify unsuspected hosts and characterize mixed blood meals, and shows how this approach can be adapted to evaluate inter-individual variations among human blood meals. Furthermore, this approach can be applied to any disease transmitting arthropod and can be easily customized to investigate non-mammalian host sources. PMID- 26963246 TI - Contributions of Subsurface Cortical Modulations to Discrimination of Executed and Imagined Grasp Forces through Stereoelectroencephalography. AB - Stereoelectroencephalographic (SEEG) depth electrodes have the potential to record neural activity from deep brain structures not easily reached with other intracranial recording technologies. SEEG electrodes were placed through deep cortical structures including central sulcus and insular cortex. In order to observe changes in frequency band modulation, participants performed force matching trials at three distinct force levels using two different grasp configurations: a power grasp and a lateral pinch. Signals from these deeper structures were found to contain information useful for distinguishing force from rest trials as well as different force levels in some participants. High frequency components along with alpha and beta bands recorded from electrodes located near the primary motor cortex wall of central sulcus and electrodes passing through sensory cortex were found to be the most useful for classification of force versus rest although one participant did have significant modulation in the insular cortex. This study electrophysiologically corroborates with previous imaging studies that show force-related modulation occurs inside of central sulcus and insular cortex. The results of this work suggest that depth electrodes could be useful tools for investigating the functions of deeper brain structures as well as showing that central sulcus and insular cortex may contain neural signals that could be used for control of a grasp force BMI. PMID- 26963247 TI - Minimum Wage and Overweight and Obesity in Adult Women: A Multilevel Analysis of Low and Middle Income Countries. AB - OBJECTIVES: To describe the relationship between minimum wage and overweight and obesity across countries at different levels of development. METHODS: A cross sectional analysis of 27 countries with data on the legislated minimum wage level linked to socio-demographic and anthropometry data of non-pregnant 190,892 adult women (24-49 y) from the Demographic and Health Survey. We used multilevel logistic regression models to condition on country- and individual-level potential confounders, and post-estimation of average marginal effects to calculate the adjusted prevalence difference. RESULTS: We found the association between minimum wage and overweight/obesity was independent of individual-level SES and confounders, and showed a reversed pattern by country development stage. The adjusted overweight/obesity prevalence difference in low-income countries was an average increase of about 0.1 percentage points (PD 0.075 [0.065, 0.084]), and an average decrease of 0.01 percentage points in middle-income countries (PD 0.014 [-0.019, -0.009]). The adjusted obesity prevalence difference in low-income countries was an average increase of 0.03 percentage points (PD 0.032 [0.021, 0.042]) and an average decrease of 0.03 percentage points in middle-income countries (PD -0.032 [-0.036, -0.027]). CONCLUSION: This is among the first studies to examine the potential impact of improved wages on an important precursor of non-communicable diseases globally. Among countries with a modest level of economic development, higher minimum wage was associated with lower levels of obesity. PMID- 26963249 TI - Biannual Spawning and Temporal Reproductive Isolation in Acropora Corals. AB - Coral spawning on the oceanic reef systems of north-western Australia was recently discovered during autumn and spring, but the degree to which species and particularly colonies participated in one or both of these spawnings was unknown. At the largest of the oceanic reef systems, the participation by colonies in the two discrete spawning events was investigated over three years in 13 species of Acropora corals (n = 1,855 colonies). Seven species spawned during both seasons; five only in autumn and one only in spring. The majority of tagged colonies (n = 218) spawned once a year in the same season, but five colonies from three species spawned during spring and autumn during a single year. Reproductive seasonality was not influenced by spatial variation in habitat conditions, or by Symbiodinium partners in the biannual spawner Acropora tenuis. Colonies of A. tenuis spawning during different seasons separated into two distinct yet cryptic groups, in a bayesian clustering analysis based on multiple microsatellite markers. These groups were associated with a major genetic divergence (G"ST = 0.469), despite evidence of mixed ancestry in a small proportion of individuals. Our results confirm that temporal reproductive isolation is a common feature of Acropora populations at Scott Reef and indicate that spawning season is a genetically determined trait in at least A. tenuis. This reproductive isolation may be punctuated occasionally by interbreeding between genetic groups following favourable environmental conditions, when autumn spawners undergo a second annual gametogenic cycle and spawn during spring. PMID- 26963248 TI - In Vitro and In Vivo Characterization of the Alkaloid Nuciferine. AB - RATIONALE: The sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays. METHODS: Nuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms. RESULTS: Nuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy. CONCLUSIONS: The molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions. PMID- 26963250 TI - Genetic and Functional Analysis of the Biosynthesis of a Non-Ribosomal Peptide Siderophore in Burkholderia xenovorans LB400. AB - B. xenovorans LB400 is a model bacterium for the study of the metabolism of aromatic compounds. The aim of this study was the genomic and functional characterization of a non-ribosomal peptide synthetase containing gene cluster that encodes a siderophore in B. xenovorans LB400. The mba gene cluster from strain LB400 encodes proteins involved in the biosynthesis and transport of a hydroxamate-type siderophore. Strain LB400 has a unique mba gene organization, although mba gene clusters have been observed in diverse Burkholderiales. Bioinformatic analysis revealed the presence of promoters in the mba gene cluster that strongly suggest regulation by the ferric uptake regulator protein (Fur) and by the alternative RNA polymerase extracytoplasmic function sigma factor MbaF. Reverse transcriptase PCR analyses showed the expression of iron-regulated transcriptional units mbaFGHIJKL, mbaN, mbaABCE, mbaO, mbaP and mbaD genes under iron limitation. Chrome azurol S (CAS) assay strongly suggests that strain LB400 synthesized a siderophore under iron limitation. Mass spectrometry ESI-MS and MALDI-TOF-MS analyses revealed that the siderophore is a non-ribosomal peptide, and forms an iron complex with a molecular mass of 676 Da. Based on bioinformatic prediction, CAS assay and MS analyses, we propose that the siderophore is L Ndelta-hydroxy-Ndelta-formylOrn-D-beta-hydroxyAsp-L-Ser-L-Ndelta-hydroxy-Ndelta formylOrn-1,4-diaminobutane that is closely related to malleobactin-type siderophores reported in B. thailandensis. PMID- 26963251 TI - Investigating Sources of Heterogeneity in Randomized Controlled Trials of the Effects of Pharmacist Interventions on Glycemic Control in Type 2 Diabetic Patients: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To assess the effect of pharmacist interventions on glycemic control in type 2 diabetic patients and to examine factors that could explain the variation across studies. METHODS: A comprehensive literature search was performed in PubMed, Scopus, and LILACS databases for randomized controlled trials (RCTs) published up to July 2015. The search strategy included the use of MeSH terms or text words related to pharmacist interventions, type 2 diabetes, and randomized controlled trials. RCTs published in English, Portuguese, or Spanish that evaluated the effect of pharmacist intervention on glycemic control in type 2 diabetic outpatients were included. Two independent authors executed study selection, data extraction, and risk of bias assessment. Mean differences in glycosylated hemoglobin (HbA1c) were estimated using random-effect models, and heterogeneity was evaluated by subgroup and meta-regression analyses. RESULTS: The literature search yielded 963 records of potential interest, of which 30 were included in the systematic review and 22 in the meta-analysis. Most of these RCTs were conducted in the United States in patients in outpatient clinics using face to-face contact only. All RCTs performed patient education, and most executed the medication review. The appraised sample showed uncertain or high risk of bias in most of the items evaluated, resulting in low-quality studies. In comparison with usual care, pharmacist interventions were associated with significant reductions in HbA1c levels (-8.5% [95% CI: -1.06, -0.65]; P < 0.0001; I2 = 67.3%). Subgroup analysis indicated differences of heterogeneity by country, baseline HbA1c levels, setting, intervention frequency, and random allocation. Age and HbA1c levels partly explained the variability across studies by meta-regression. CONCLUSIONS: Our findings confirmed that pharmacist interventions improve glycemic control in patients with type 2 diabetes compared with usual care and suggest that younger patients or with higher baseline HbA1c levels may be the main beneficiaries of pharmacist care. PROTOCOL PROSPERO REGISTRATION NUMBER: CRD42014007457. PMID- 26963252 TI - Evaluating and Quantifying User and Carer Involvement in Mental Health Care Planning (EQUIP): Co-Development of a New Patient-Reported Outcome Measure. AB - International and national health policy seeks to increase service user and carer involvement in mental health care planning, but suitable user-centred tools to assess the success of these initiatives are not yet available. The current study describes the development of a new reliable and valid, interval-scaled service user and carer reported outcome measure for quantifying user/carer involvement in mental health care planning. Psychometric development reduced a 70-item item bank to a short form questionnaire using a combination of Classical Test, Mokken and Rasch Analyses. Test-retest reliability was calculated using t-tests of interval level scores between baseline and 2-4 week follow-up. Items were worded to be relevant to both service users and carers. Nine items were removed following cognitive debriefing with a service user and carer advisory group. An iterative process of item removal reduced the remaining 61 items to a final 14-item scale. The final scale has acceptable scalability (Ho = .69), reliability (alpha = .92), fit to the Rasch model (chi2(70) = 97.25, p = .02), and no differential item functioning or locally dependent items. Scores remained stable over the 4 week follow-up period, indicating good test-retest reliability. The 'Evaluating the Quality of User and Carer Involvement in Care Planning (EQUIP)' scale displays excellent psychometric properties and is capable of unidimensional linear measurement. The scale is short, user and carer-centred and will be of direct benefit to clinicians, services, auditors and researchers wishing to quantify levels of user and carer involvement in care planning. PMID- 26963253 TI - Introduced Amino Terminal Epitopes Can Reduce Surface Expression of Neuronal Nicotinic Receptors. AB - Epitopes accessible on the surface of intact cells are extremely valuable in studies of membrane proteins, allowing quantification and determination of the distribution of proteins as well as identification of cells expressing large numbers of proteins. However for many membrane proteins there are no suitable antibodies to native sequences, due to lack of availability, low affinity or lack of specificity. In these cases the use of an introduced epitope at specific sites in the protein of interest can often provide a suitable tool for studies. However, the introduction of the epitope sequence has the potential to affect protein expression, the assembly of multisubunit proteins or transport to the surface membrane. We find that surface expression of heteromeric neuronal nicotinic receptors containing the alpha4 and beta4 subunits can be affected by introduced epitopes when inserted near the amino terminus of a subunit. The FLAG epitope greatly reduces surface expression when introduced into either alpha4 or beta4 subunits, the V5 epitope has little effect when placed in either, while the Myc epitope reduces expression more when inserted into beta4 than alpha4. These results indicate that the extreme amino terminal region is important for assembly of these receptors, and demonstrate that some widely used introduced epitopes may severely reduce surface expression. PMID- 26963254 TI - Prioritizing Avian Species for Their Risk of Population-Level Consequences from Wind Energy Development. AB - Recent growth in the wind energy industry has increased concerns about its impacts on wildlife populations. Direct impacts of wind energy include bird and bat collisions with turbines whereas indirect impacts include changes in wildlife habitat and behavior. Although many species may withstand these effects, species that are long-lived with low rates of reproduction, have specialized habitat preferences, or are attracted to turbines may be more prone to declines in population abundance. We developed a prioritization system to identify the avian species most likely to experience population declines from wind facilities based on their current conservation status and their expected risk from turbines. We developed 3 metrics of turbine risk that incorporate data on collision fatalities at wind facilities, population size, life history, species' distributions relative to turbine locations, number of suitable habitat types, and species' conservation status. We calculated at least 1 measure of turbine risk for 428 avian species that breed in the United States. We then simulated 100,000 random sets of cutoff criteria (i.e., the metric values used to assign species to different priority categories) for each turbine risk metric and for conservation status. For each set of criteria, we assigned each species a priority score and calculated the average priority score across all sets of criteria. Our prioritization system highlights both species that could potentially experience population decline caused by wind energy and species at low risk of population decline. For instance, several birds of prey, such as the long-eared owl, ferruginous hawk, Swainson's hawk, and golden eagle, were at relatively high risk of population decline across a wide variety of cutoff values, whereas many passerines were at relatively low risk of decline. This prioritization system is a first step that will help researchers, conservationists, managers, and industry target future study and management activity. PMID- 26963255 TI - Interactive Data Visualization for HIV Cohorts: Leveraging Data Exchange Standards to Share and Reuse Research Tools. AB - OBJECTIVE: To develop and disseminate tools for interactive visualization of HIV cohort data. DESIGN AND METHODS: If a picture is worth a thousand words, then an interactive video, composed of a long string of pictures, can produce an even richer presentation of HIV population dynamics. We developed an HIV cohort data visualization tool using open-source software (R statistical language). The tool requires that the data structure conform to the HIV Cohort Data Exchange Protocol (HICDEP), and our implementation utilized Caribbean, Central and South America network (CCASAnet) data. RESULTS: This tool currently presents patient-level data in three classes of plots: (1) Longitudinal plots showing changes in measurements viewed alongside event probability curves allowing for simultaneous inspection of outcomes by relevant patient classes. (2) Bubble plots showing changes in indicators over time allowing for observation of group level dynamics. (3) Heat maps of levels of indicators changing over time allowing for observation of spatial-temporal dynamics. Examples of each class of plot are given using CCASAnet data investigating trends in CD4 count and AIDS at antiretroviral therapy (ART) initiation, CD4 trajectories after ART initiation, and mortality. CONCLUSIONS: We invite researchers interested in this data visualization effort to use these tools and to suggest new classes of data visualization. We aim to contribute additional shareable tools in the spirit of open scientific collaboration and hope that these tools further the participation in open data standards like HICDEP by the HIV research community. PMID- 26963256 TI - Function approximation in inhibitory networks. AB - In performance-optimized artificial neural networks, such as convolutional networks, each neuron makes excitatory connections with some of its targets and inhibitory connections with others. In contrast, physiological neurons are typically either excitatory or inhibitory, not both. This is a puzzle, because it seems to constrain computation, and because there are several counter-examples that suggest that it may not be a physiological necessity. Parisien et al. (2008) showed that any mixture of excitatory and inhibitory functional connections could be realized by a purely excitatory projection in parallel with a two-synapse projection through an inhibitory population. They showed that this works well with ratios of excitatory and inhibitory neurons that are realistic for the neocortex, suggesting that perhaps the cortex efficiently works around this apparent computational constraint. Extending this work, we show here that mixed excitatory and inhibitory functional connections can also be realized in networks that are dominated by inhibition, such as those of the basal ganglia. Further, we show that the function-approximation capacity of such connections is comparable to that of idealized mixed-weight connections. We also study whether such connections are viable in recurrent networks, and find that such recurrent networks can flexibly exhibit a wide range of dynamics. These results offer a new perspective on computation in the basal ganglia, and also perhaps on inhibitory networks within the cortex. PMID- 26963258 TI - Systems Approaches to the Eukaryotic Stress Response. PMID- 26963259 TI - Fish Rejections in the Marine Aquarium Trade: An Initial Case Study Raises Concern for Village-Based Fisheries. AB - A major difficulty in managing wildlife trade is the reliance on trade data (rather than capture data) to monitor exploitation of wild populations. Collected organisms that die or are rejected before a point of sale often go unreported. For the global marine aquarium trade, identifying the loss of collected fish from rejection, prior to export, is a first step in assessing true collection levels. This study takes a detailed look at fish rejections by buyers before export using the Papua New Guinea marine aquarium fishery as a case study. Utilizing collection invoices detailing the species and quantity of fish (Actinopteri and Elasmobranchii) accepted or rejected by the exporting company it was determined that, over a six month period, 24.2% of the total fish catch reported (n = 13,886) was rejected. Of the ten most collected fish families, rejection frequency was highest for the Apogonidae (54.2%), Chaetodontidae (26.3%), and Acanthuridae (18.2%) and lowest for Labridae (6.6%) and Hemiscylliidae (0.7%). The most frequently cited reasons for rejection were fin damage (45.6% of cases), undersized fish (21.8%), and fish deemed too thin (11.1%). Despite fishers receiving feedback on invoices explaining rejections, there was no improvement in rejection frequencies over time (r = -0.33, P = 0.15) with weekly rejection frequencies being highly inconsistent (range: 2.8% to 79.4%; s = 16.3%). These findings suggest that export/import statistics can greatly underestimate collection for the marine aquarium trade as additional factors such as fisher discards, escapees, post-collection mortalities, and unregulated domestic trade would further contribute to this disparity. PMID- 26963260 TI - Case report of non-traumatic spontaneous intrahepatic bile duct rupture in an adult. AB - INTRODUCTION: Spontaneous rupture of the biliary duct, a rare condition in adults, is difficult to diagnose preoperatively and presents with acute abdominal symptoms. The treatment of this rare condition should be based on the individual's clinical status. We present peripheric biliary duct rupture (segment three) treated with external segment III drainage and postoperative endoscopic removal of the stones. PRESENTATION OF CASE: An 82-year-old male patient presented with abdominal pain and fever. An ultrasound (US) revealed a solid gall stone lesion, 3cm in diameter, in liver segments three and four with additional intra-abdominal fluid accumulation without coexisting free air. A diagnostic laparotomy was then performed because the patient had signs of peritonitis. Exploration revealed a biliary leakage from the posterior surface of segment three. An external biliary drainage catheter was inserted to the perforated segment III duct via a 6 French (6F) feeding catheter. He was discharged after 10 days and his intracholedocal stent was removed postoperative after three months. The patient continues to be monitored. DISCUSSION: Spontaneous rupture of the intrahepatic biliary duct is a rare condition. Although occurrence is frequently reported as spontaneous, the majority of cases are related to choledocholithiasis. The role of surgical treatment in cases of spontaneous bile duct rupture is unclear. When biliary peritonitis is present, drainage of contaminated biliary fluid, T-tube drainage, closure of the biliary duct, as well as primary disease conditions, should be reviewed prior to treatment. CONCLUSION: Surgical treatment of spontaneous biliary duct rupture should be indicated only after careful consideration of the patient's clinical and comorbidity status. PMID- 26963257 TI - HIV/AIDS Competent Households: Interaction between a Health-Enabling Environment and Community-Based Treatment Adherence Support for People Living with HIV/AIDS in South Africa. AB - In the context of severe human resource shortages in HIV care, task-shifting and especially community-based support are increasingly being cited as potential means of providing durable care to chronic HIV patients. Socio-ecological theory clearly stipulates that-in all social interventions-the interrelatedness and interdependency between individuals and their immediate social contexts should be taken into account. People living with HIV/AIDS (PLWHA) seldom live in isolation, yet community-based interventions for supporting chronic HIV patients have largely ignored the social contexts in which they are implemented. Research is thus required to investigate such community-based support within its context. The aim of this study is to address this research gap by examining the way in which HIV/AIDS competence in the household hampers or facilitates community-based treatment adherence support. The data was analyzed carefully in accordance with the Grounded Theory procedures, using Nvivo 10. More specifically, we analyzed field notes from participatory observations conducted during 48 community-based treatment adherence support sessions in townships on the outskirts of Cape Town, transcripts of 32 audio-recorded in-depth interviews with PLWHA and transcripts of 4 focus group discussions with 36 community health workers (CHWs). Despite the fact that the CHWs try to present themselves as not being openly associated with HIV/AIDS services, results show that the presence of a CHW is often seen as a marker of the disease. Depending on the HIV/AIDS competence in the household, this association can challenge the patient's hybrid identity management and his/her attempt to regulate the interference of the household in the disease management. The results deepen our understanding of how the degree of HIV/AIDS competence present in a PLWHA's household affects the manner in which the CHW can perform his or her job and the associated benefits for the patient and his/her household members. In this respect, a household with a high level of HIV/AIDS competence will be more receptive to treatment adherence support, as the patient is more likely to allow interaction between the CHW and the household. In contrast, in a household which exhibits limited characteristics of HIV/AIDS competence, interaction with the treatment adherence supporter may be difficult in the beginning. In such a situation, visits from the CHW threaten the hybrid identity management. If the CHW handles this situation cautiously and the patient acting as a gate keeper-allows interaction, the CHW may be able to help the household develop towards HIV/AIDS competence. This would have a more added value compared to a household which was more HIV/AIDS competent from the outset. This study indicates that pre-existing dynamics in a patient's social environment, such as the HIV/AIDS competence of the household, should be taken into account when designing community-based treatment adherence programs in order to provide long-term quality care, treatment and support in the context of human resource shortages. PMID- 26963261 TI - Efficacy of octreotide against chylothorax following lateral neck dissection for thyroid cancer: A case report. AB - INTRODUCTION: Postsurgical chylothorax is a rare complication of cervical dissection for thyroid cancer. We report that octreotide, a synthetic analog of somatostatin, is effective in treating chylothorax after thyroid carcinoma surgery. PRESENTATION OF CASE: The patient was a 48-year-old woman who presented to our institution complaining of a left anterior cervical mass. We diagnosed this as thyroid papillary carcinoma and performed a subtotal excision of the thyroid gland with left cervical lymph node dissection. The patient developed dyspnea, and a chest X-ray revealed bilateral chylothorax on Day 4 post-surgery. Octreotide was administered since bilateral chylothorax was noted. A marked decrease in chyle effusion was noted just 3 days after starting octreotide, and after a total of 9 days of treatment, there were no further signs of chylous effusion. DISCUSSION: Octreotide is effective against postsurgical chylothorax; however, if there are no signs of improvement, we believe surgical treatment should be considered. CONCLUSION: Octreotide should be administered first to treat postsurgical chylothorax before surgical treatment is considered. PMID- 26963274 TI - Comorbidities and recurrence of benign paroxysmal positional vertigo: personal experience. AB - OBJECTIVE: The aim of this study is to evaluate the correlation between clinical features of benign paroxysmal positional vertigo (BPPV) and age, sex, trauma, presence of one or more comorbidities such as cardiovascular, neurological, endocrinological, metabolic, psychiatric diseases. DESIGN: Retrospective review of medical records (chart review). STUDY SAMPLE: A total of 475 patients aged from 14 to 87 years, affected by BPPV. RESULTS: Recurrence of BPPV occurred in 139/475 patients (29.2%). The recurrence rate was significantly higher in female and older patients. Comorbidities were present in 72.6% of subjects with recurrent BPPV vs. 48.9% of patients with no recurrence (p < 0.01). Forty-two patients (8.8%) reported a cranial trauma as a triggering event. Post-traumatic patients showed a significantly higher persistence rate (45.2%) compared to patients affected by non-traumatic BPPV (20.5%). Recurrence rates are overlapping between the two groups. CONCLUSION: Our results confirm the association between recurrence of BPPV and age, female sex, and presence of comorbidities. The correlation is stronger in patients affected by multiple associated diseases; the most frequently involved pathologies are psychiatric disorders, followed by neurological and vascular diseases. Collecting a complete medical history is important for prognostic stratification and detection of potential underlying pathological conditions. PMID- 26963275 TI - A Study of Differential Expression of Testicular Genes in Various Reproductive Phases of Hemidactylus flaviviridis (Wall Lizard) to Derive Their Association with Onset of Spermatogenesis and Its Relevance to Mammals. AB - Testis of Hemidactylus flaviviridis, commonly known as Indian wall lizard, displays a lack of cellular and metabolic activity in regressed phase of testis during non-breeding season of the year. Retracted Sertoli cells (Sc), fibroid myoid cells and pre-meiotic resting spermatogonia are observed in such testis. This situation is akin to certain forms of infertility in men where hormone supplementation fails to generate sperm despite the presence of Sc and germ cells (Gc) in testis. In testis of lizard, spermatogenesis is reinitiated upon increased level of hormones during appropriate season (phase of recrudescence). Study of genes associated with generation of sperm, from regressed adult testis in lizard, may provide valuable information for understanding certain forms of male idiopathic infertility. Subtractive hybridization using testicular RNA obtained from the regressed and active phases of lizard reproductive cycle led to identify eight partial mRNA sequences that showed sequence homology with mice genes. We further evaluated the gene expression prolife by real-time PCR in three different reproductive phases of H. flaviviridis: regressed (pre-meiotic), recrudescent (meiotic) and active (post meiotic), for comparison with the corresponding testicular phases found in testis of 5 days (pre-meiotic), 20 days (meiotic) and 60 days (post-meiotic) old mouse. This is the first report where genes associated with progression of spermatogenesis during active phase, which follows a regressed state of adult testis, were identified in lizard and found to be conserved in mouse. Six important genes, Hk1, Nme5, Akap4, Arih1, Rassf7 and Tubb4b were found to be strictly associated with active spermatogenesis in both mouse and lizard. Factors interfering with the expression of any of these genes may potentially abrogate the process of spermatogenesis leading to infertility. Such information may shed light on unknown causes of idiopathic male infertility. PMID- 26963276 TI - Uniquely designed nuclear structures of lower eukaryotes. AB - The nuclear structures of lower eukaryotes, specifically protists, often vary from those of yeasts and metazoans. Several studies have demonstrated the unique and fascinating features of these nuclear structures, such as a histone independent condensed chromatin in dinoflagellates and two structurally distinct nuclear pore complexes in ciliates. Despite their unique molecular/structural features, functions required for formation of their cognate molecules/structures are highly conserved. This provides important information about the structure function relationship of the nuclear structures. In this review, we highlight characteristic nuclear structures found in lower eukaryotes, and discuss their attractiveness as potential biological systems for studying nuclear structures. PMID- 26963277 TI - Impact of probiotic supplements on microbiome diversity following antibiotic treatment of mice. AB - Shifts in microbial populations of the intestinal tract have been associated with a multitude of nutritional, autoimmune, and infectious diseases. The limited diversity following antibiotic treatments creates a window for opportunistic pathogens, diarrhea, and inflammation as the microbiome repopulates. Depending on the antibiotics used, microbial diversity can take weeks to months to recover. To alleviate this loss of diversity in the intestinal microbiota, supplementation with probiotics has become increasingly popular. However, our understanding of the purported health benefits of these probiotic bacteria and their ability to shape the microbiome is significantly lacking. This study examined the impact of probiotics concurrent with antibiotic treatment or during the recovery phase following antibiotic treatment of mice. We found that probiotics did not appear to colonize the intestine themselves or shift the overall diversity of the intestinal microbiota. However, the probiotic supplementation did significantly change the types of bacteria which were present. In particular, during the recovery phase the probiotic caused a suppression of Enterobacteriaceae outgrowth (Shigella and Escherichia) while promoting a blooming of Firmicutes, particularly from the Anaerotruncus genus. These results indicate that probiotics have a significant capacity to remodel the microbiome of an individual recovering from antibiotic therapy. PMID- 26963280 TI - Response to Cunningham et al. PMID- 26963279 TI - Response to Biesecker. PMID- 26963281 TI - Archibald E. Garrod: the father of precision medicine. PMID- 26963282 TI - Role of medical food in MMA. PMID- 26963283 TI - Towards a more representative morphology: clinical and ethical considerations for including diverse populations in diagnostic genetic atlases. AB - An important gap exists in textbooks (or atlases) of dysmorphology used by health care professionals to help diagnose genetic syndromes. The lack of varied phenotypic images in available atlases limits the utility of these atlases as diagnostic tools in globally diverse populations, causing geneticists difficulty in diagnosing conditions in individuals of different ancestral backgrounds who may present with variable morphological features. Proposals to address the underinclusion of images from diverse populations in existing atlases can take advantage of the Internet and digital photography to create new resources that take into account the broad global diversity of populations affected by genetic disease. Creating atlases that are more representative of the global population will expand resources available to care for diverse patients with these conditions, many of whom have been historically underserved by the medical system. However, such projects also raise ethical questions that are grounded in the complex intersection of imagery, medicine, history, and race and ethnicity. We consider here the benefits of producing such a resource while also considering ethical and practical concerns, and we offer recommendations for the ethical creation, structure, equitable use, and maintenance of a diverse morphological atlas for clinical diagnosis.Genet Med 18 11, 1069-1074. PMID- 26963284 TI - The complex behavioral phenotype of 15q13.3 microdeletion syndrome. AB - BACKGROUND: Chromosome 15q13.3 represents a hotspot for genomic rearrangements due to repetitive sequences mediating nonallelic homologous recombination. Deletions of 15q13.3 have been identified in the context of multiple neurological and psychiatric disorders, but a prospective clinical and behavioral assessment of affected individuals has not yet been reported. METHODS: Eighteen subjects with 15q13.3 microdeletion underwent a series of behavioral assessments, along with clinical history and physical examination, to comprehensively define their behavioral phenotypes. RESULTS: Cognitive deficits are the most prevalent feature in 15q13.3 deletion syndrome, with an average nonverbal IQ of 60 among the patients studied. Autism spectrum disorder was highly penetrant, with 31% of patients meeting clinical criteria and exceeding cutoff scores on both ADOS-2 and ADI-R. Affected individuals exhibited a complex pattern of behavioral abnormalities, most notably hyperactivity, attention problems, withdrawal, and externalizing symptoms, as well as impairments in functional communication, leadership, adaptive skills, and activities of daily living. CONCLUSIONS: The 15q13.3 deletion syndrome encompasses a heterogeneous behavioral phenotype that poses a major challenge to parents, caregivers, and treating providers. Further work to more clearly delineate genotype-phenotype relationships in 15q13.3 deletions will be important for anticipatory guidance and development of targeted therapies.Genet Med 18 11, 1111-1118. PMID- 26963286 TI - Retrospective Analysis of Fifth-Line Targeted Therapy Efficacy in Patients with Metastatic Renal Cell Carcinoma. AB - OBJECTIVES: Current evidence of sequence-targeted therapy (TT) for patients with metastatic renal cell carcinoma (mRCC) beyond fourth-line is sparse. The aim of this study was to describe the efficacy and toxicity of fifth-line TT in patients with mRCC. METHODS: Out of 406 patients treated in first-line, 25 patients (6.16%) with more than 4 lines of TT were retrospectively reviewed at a German academic high-volume cancer center. Response was assessed by the use of standard Response Evaluation Criteria in Solid Tumors version 1.0, and toxicity was graded according to the Common Toxicity Criteria for Adverse Events version 3.0. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Cox proportional hazard models were applied to explore predictors of PFS and OS in univariable and multivariable analyses. RESULTS: Disease control rate for fifth-line treatment was 20%. Median OS from the beginning of first-line therapy was 50.2 months (IQR (interquartile range) 38.9 76.7). Median OS from the time of initiation of fifth-line therapy was 6.2 months (IQR 3.1-23.8). Median PFS for fifth-line TT was 4.1 months (IQR 1.81-9.07) and did not correlate to treatment response in first-line TT. CONCLUSIONS: Highly selected patients might benefit from fifth-line treatment independently from treatment response in first-line TT. PMID- 26963285 TI - Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis. AB - PURPOSE: We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients. METHODS: WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls. RESULTS: We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo. CONCLUSION: Mutations in LRP6 cause TA in humans.Genet Med 18 11, 1158-1162. PMID- 26963287 TI - IL-10 Induces T Cell Exhaustion During Transplantation of Virus Infected Hearts. AB - BACKGROUND/AIMS: Unexpected transmissions of viral pathogens during solid organ transplantation (SOT) can result in severe, life-threatening diseases in transplant recipients. Immune activation contributes to disease onset. However mechanisms balancing the immune response against transmitted viral infection through organ transplantation remain unknown. Methods & RESULTS: Here we found, using lymphocytic choriomeningitis virus (LCMV), that transplantation of LCMV infected hearts led to exhaustion of virus specific CD8+ T cells, viral persistence in organs and survival of graft and recipient. Genetic depletion of Interleukin-10 (IL-10) resulted in strong immune activation, graft dysfunction and death of mice, suggesting that IL-10 was a major regulator of CD8+ T cell exhaustion during SOT. In the presence of memory CD8+ T cells, virus could be controlled. However sufficient antiviral immune response resulted in acute rejection of transplanted heart. CONCLUSION: We found that virus transmitted via SOT could not be controlled by naive mice recipients due to IL-10 mediated CD8+ T cell exhaustion which thereby prevented immunopathology and graft failure whereas memory mice recipients were able to control the virus and induced graft failure. PMID- 26963288 TI - The Effect of Molecular Conformation on the Accuracy of Theoretical (1)H and (13)C Chemical Shifts Calculated by Ab Initio Methods for Metabolic Mixture Analysis. AB - NMR spectroscopy is a powerful method for analyzing metabolic mixtures. The information obtained from an NMR spectrum is in the form of physical parameters, such as chemical shifts, and construction of databases for many metabolites will be useful for data interpretation. To increase the accuracy of theoretical chemical shifts for development of a database for a variety of metabolites, the effects of sets of conformations (structural ensembles) and the levels of theory on computations of theoretical chemical shifts were systematically investigated for a set of 29 small molecules in the present study. For each of the 29 compounds, 101 structures were generated by classical molecular dynamics at 298.15 K, and then theoretical chemical shifts for 164 (1)H and 123 (13)C atoms were calculated by ab initio quantum chemical methods. Six levels of theory were used by pairing Hartree-Fock, B3LYP (density functional theory), or second order Moller-Plesset perturbation with 6-31G or aug-cc-pVDZ basis set. The six average fluctuations in the (1)H chemical shift were +/-0.63, +/- 0.59, +/- 0.70, +/- 0.62, +/- 0.75, and +/-0.66 ppm for the structural ensembles, and the six average errors were +/-0.34, +/- 0.27, +/- 0.32, +/- 0.25, +/- 0.32, and +/-0.25 ppm. The results showed that chemical shift fluctuations with changes in the conformation because of molecular motion were larger than the differences between computed and experimental chemical shifts for all six levels of theory. In conclusion, selection of an appropriate structural ensemble should be performed before theoretical chemical shift calculations for development of an accurate database for a variety of metabolites. PMID- 26963289 TI - Prevalence of traumatic brain injury and epilepsy among prisoners in France: Results of the Fleury TBI study. AB - OBJECTIVE: The first aim of this study was to estimate the prevalence of TBI and epilepsy in a French prison population and to study variables known to be associated with TBI. The second aim was to compare prisoners with and without a history of TBI. PARTICIPANTS: All offenders (females, males and juveniles) admitted consecutively to Fleury-Merogis prison over a period of 3 months were included in the study. DESIGN: During the admission procedure, offenders were interviewed by healthcare staff using a self-reported questionnaire. RESULTS: In all, 1221 prisoners were included. The rates of TBI and epilepsy were high, with a prevalence of 30.6% and 5.9%, respectively. Psychiatric care, anxiolytic and antidepressant treatment, use of alcohol and cannabis were all significantly higher among offenders with a history of TBI. Moreover, the number of times in custody and the total time spent in jail over the preceding 5 years were significantly higher among offenders with a history of TBI. CONCLUSIONS: These results provide further evidence that specific measures need to be developed such as, first of all, screening for TBI upon arrival in prison. PMID- 26963290 TI - A Preoperative Scale for Determining Surgical Readmission Risk After Total Hip Replacement. AB - IMPORTANCE: Total hip replacement is a commonly performed orthopedic procedure for the treatment of painful arthritis, osteonecrosis, or fracture. OBJECTIVE: To develop and verify a scale for predicting readmission rates for total hip replacement patients and allow for the development and implementation of readmission risk-reduction strategies. DESIGN, SETTING, AND PARTICIPANTS: Discharge data on 268 518 patients from New York and California (derivation cohort) and 153 560 patients from Florida and Washington (validation cohort) were collected from the State Inpatient Database, a part of the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality (2006 2011). Analysis of the derivation cohort was performed in July 2013 and analysis of the validation cohort was performed in August 2014. Demographic and clinical characteristics of patients undergoing total hip replacement were abstracted. The Readmission After Total Hip Replacement Risk Scale was developed to predict readmission risk. MAIN OUTCOME AND MEASURE: Readmission rate. RESULTS: Of the 268 518 patients from New York and California (derivation cohort), 151 009 (56.2%) were women and 216 477 (80.6%) were white. Of the 153 560 patients from Florida and Washington (validation cohort), 86 534 (56.3%) were women and 120 591 (78.5%) were white. Overall 30-day readmission rate was 5.89% for the derivation cohort and 5.82% for the validation cohort. Readmission rates for men and women were 5.79% and 6.08% for the derivation cohort (odds ratio [OR], 1.05; 95% CI, 1.02 1.09) and 5.80% and 5.84% for the validation cohort (OR, 0.99; 95% CI, 0.95 1.04), respectively. The following were all determined to be associated with increased risk of readmission after total hip replacement: being older than 71 years (OR, 1.83; 95% CI, 1.77-1.89), African American (OR, 1.23; 95% CI, 1.15 1.31), and in the lowest income quartile (OR, 1.18; 95% CI, 1.12-1.24); revision replacement (OR, 1.82, 95% CI, 1.75-1.90); liver disease (OR, 1.57; 95% CI, 1.39 1.77); congestive heart failure (OR, 1.49; 95% CI, 1.38-1.61); chronic pulmonary disease (OR, 1.33; 95% CI, 1.27-1.39); renal failure (OR, 1.26; 95% CI, 1.18 1.36); diabetes (OR, 1.21; 95% CI, 1.16-1.27); fluid and electrolyte disorder (OR, 1.21; 95% CI, 1.14-1.27); anemia (OR, 1.19; 95% CI, 1.15-1.25); rheumatoid arthritis (OR, 1.19; 95% CI, 1.10-1.29); coagulopathy (OR, 1.19; 95% CI, 1.08 1.32); hypertension (OR, 1.17; 95% CI, 1.12-1.21); and obesity (OR, 1.15; 95% CI 1.09-1.21). They were used to create the Readmission After Total Hip Replacement Risk Scale, which was applied to the validation cohort and explained 89.1% of readmission variability in that cohort. CONCLUSIONS AND RELEVANCE: Data derived from patients in the New York and California State Inpatient Database were reliably able to explain readmission variability for patients in the Florida and Washington State Inpatient Database at a rate of 89.1% based on known preoperative risk factors. Risk-stratification models, such as the Readmission After Total Hip Replacement Risk Scale, can identify high-risk patients for readmission and permit implementation of patient-specific readmission-reduction strategies to reduce readmissions and health care expenditures. PMID- 26963291 TI - Targeted Estimation of Marginal Absolute and Relative Associations in Case Control Data: An Application in Social Epidemiology. AB - BACKGROUND: Case-control studies are useful for rare outcomes, but typical analyses limit investigators to parametric estimation of conditional odds ratios. Several methods exist for obtaining marginal risk differences and risk ratios in a case-control setting, including a recently described semiparametric targeted approach optimized for rare outcomes. METHODS: Using case-control data from a study of neighborhood poverty and very preterm birth, we demonstrate estimation of marginal risk differences and risk ratios and compare a parametric substitution estimator based on maximum likelihood estimation with targeted maximum likelihood estimation (TMLE), and a refinement of TMLE for rare outcomes that incorporates bounds on the conditional risk. RESULTS: In this illustration, living in a neighborhood with high poverty was associated with a higher risk of very preterm birth for white women. The estimated risk differences (cases/100) were 0.6 (95% confidence interval [CI]: 0.1, 1.1) from maximum likelihood estimation, 0.5 (95% CI: -1.1, 2.1) from TMLE, and 0.5 (95% CI: 0.0, 1.0) from the rare outcomes refinement. The rare outcomes refinement, which incorporates knowledge that the conditional risk is small, produced more precise estimates than TMLE. A similar pattern was observed for the relative risk. CONCLUSION: Absolute and relative associations estimated from case-control data using a semiparametric targeted approach allow the scientific question to determine the analysis and avoid unwarranted parametric assumptions. A rare outcomes refinement provided more precise estimates than TMLE, and thus is well suited for the study of rare outcomes. PMID- 26963292 TI - Transportability in Network Meta-analysis. AB - Network meta-analysis is an extension of the conventional pair wise meta-analysis to include treatments that have not been compared head to head. It has in recent years caught the interest of clinical investigators in comparative effectiveness research. While allowing a simultaneous comparison of a large number of treatment effects, an inclusion of indirect effects (i.e., estimating effects using treatments that have not been randomized head to head) may introduce bias. This bias occurs from not accounting for covariates differences in the analysis, in a way that allows transfer of causal information across trials. Although this problem might not be entirely new to network meta-analysis researchers, it has not been given a formal treatment. Occasionally it is tackled by fitting a meta regression model to account for imbalance of covariates. However, this approach may still produce biased estimates if covariates responsible for disparity across studies are post-treatment variables. To address the problem, we use the graphical method known as transportability to demonstrate whether and how indirect treatment effects can validly be estimated in network meta-analysis. See Video Abstract at http://links.lww.com/EDE/B37. PMID- 26963293 TI - Online induction heating for determination of isotope composition of woody stem water with laser spectrometry: a methods assessment. AB - Application of stable isotopes of water to studies of plant-soil interactions often requires a substantial preparatory step of extracting water from samples without fractionating isotopes. Online heating is an emerging approach for this need, but is relatively untested and major questions of how to best deliver standards and assess interference by organics have not been evaluated. We examined these issues in our application of measuring woody stem xylem of sagebrush using a Picarro laser spectrometer with online induction heating. We determined (1) effects of cryogenic compared to induction-heating extraction, (2) effects of delivery of standards on filter media compared to on woody stem sections, and (3) spectral interference from organic compounds for these approaches (and developed a technique to do so). Our results suggest that matching sample and standard media improves accuracy, but that isotopic values differ with the extraction method in ways that are not due to spectral interference from organics. PMID- 26963295 TI - The Vision for Preparing the Next Generation of Reviewers for the Scholarly Scientific Publication Process. PMID- 26963294 TI - P450-Mediated Coupling of Indole Fragments To Forge Communesin and Unnatural Isomers. AB - Dimeric indole alkaloids are structurally diverse natural products that have attracted significant attention from the synthetic and biosynthetic communities. Here, we describe the characterization of a P450 monooxygenase CnsC from Penicillium that catalyzes the heterodimeric coupling between two different indole moieties, tryptamine and aurantioclavine, to construct vicinal quaternary stereocenters and yield the heptacyclic communesin scaffold. We show, via biochemical characterization, substrate analogues, and computational methods that CnsC catalyzes the C3-C3' carbon-carbon bond formation and controls the regioselectivities of the pair of subsequent aminal bond formations to yield the communesin core. Use of omega-N-methyltryptamine and tryptophol in place of tryptamine led to the enzymatic synthesis of isocommunesin compounds, which have not been isolated to date. PMID- 26963296 TI - Focusing Quality Improvement Initiatives in Pediatric Plastic Surgery: A Descriptive Study Using the Pediatric National Surgical Quality Improvement Program. AB - BACKGROUND: The American College of Surgeons National Surgical Quality Improvement Program - Pediatrics uses a risk-adjusted, case-mix-adjusted methodology to compare quality of hospital-level surgical performance. This paper aims to focus quality improvement efforts on diagnoses that have large patient volume and high morbidity for pediatric plastic surgery. METHODS: Frequency statistics were generated for a cohort of patients under age 18 who underwent plastic surgery procedures at participating National Surgical Quality Improvement Program - Pediatrics hospitals from January 1, 2011 to December 31, 2012. RESULTS: Cleft lip and palate procedures were the leading contributor to serious adverse events (45.00%), and the second largest contributor to composite morbidity (37.73%) as well as hospital-acquired infections (21.23%). CONCLUSIONS: When focusing resources for relevant data collection and quality improvement efforts, it is important to consider procedures that are both substantial volume and result in relatively higher morbidity. A balance must be made between what is relevant to collect and what is feasible given finite resources. Cleft lip and/or palate procedures might provide an ideal opportunity for coordinated efforts that could ultimately improve care for pediatric plastic surgery patients. PMID- 26963297 TI - The Tsao Fellowship in Global Health: A Model for International Fellowships in a Surgery Residency. AB - OBJECTIVE: To present a model for integrated global health fellowships in plastic surgical residency training. BACKGROUND: National surveys have found that North American surgical residents have significant interest in international training. While global health training opportunities exist, less than a third of these are housed within surgical residency programs; even fewer are designed specifically for plastic surgery residents. METHODS: The Tsao Fellowship was created through a partnership between Operation Smile, Children's Hospital Los Angeles, Shriners Hospital for Children, and the University of Southern California. Designed for Accreditation Council for Graduate Medical Education accredited plastic surgery residents between their third and fourth years of residency, the fellowship curriculum is completed over 24 months and divided into 3 areas: clinical research, international reconstructive surgery fieldwork, and the completion of a Master of Science in Clinical and Biomedical Investigations. RESULTS: The Tsao Fellowship has matriculated 4 fellows: 3 have graduated from the program and 1 is in the current cycle. Fellows completed 4 to 7 international missions each cycle and have performed an aggregate total of 684 surgical procedures. Each fellow also conducted 2 to 6 research projects and authored several publications. All fellows continue to assume leadership roles within the field of global reconstructive surgery. CONCLUSIONS: Comprehensive global health fellowships provide invaluable opportunities beyond surgical residency. The Tsao Fellowship is a model for integrating international surgical training with global health research in plastic surgical residency that can be applied to other residency programs and different surgical specialties. PMID- 26963298 TI - Comparison of Intracranial Volume and Cephalic Index After Correction of Sagittal Synostosis With Spring-assisted Surgery or Pi-plasty. AB - BACKGROUND: The aim of the current study was to determine the intracranial volume (ICV) and cephalic index (CI) in patients operated for sagittal synostosis, and to compare the outcome of 2 different surgical techniques: craniotomy combined with springs and modified pi-plasty. METHODS: The authors studied all patients who had been operated for isolated sagittal synostosis and registered in the Gothenburg Craniofacial Registry until the end of 2012 and who had undergone a preoperative and/or postoperative (at 3 years of age) computed tomography examination. Sex- and age-matched controls were identified from children who had undergone computed tomography for other reasons. RESULTS: Craniotomy combined with springs increased the ICV and CI from 802 +/- 127 mL (mean +/- SD) and 70.1 +/- 4.0 to 1300 +/- 158 mL and 73.1 +/- 3.3, respectively. The corresponding values for controls were 796 +/- 136 mL and 83.6 +/- 7.3 preoperatively and 1334 +/- 136 mL and 80.0 +/- 4.5 at 3 years of age. Pi-plasty increased the ICV and CI from 1014 +/- 115 mL and 69.7 +/- 3.3 to 1286 +/- 122 mL and 74.1 +/- 2.6, respectively. Corresponding values for controls were 1043 +/- 153 mL and 83.4 +/- 7.0 preoperatively and 1362 +/- 122 mL and 79.6 +/- 3.9 at 3 years of age. CONCLUSIONS: There was no significant difference between craniotomy combined with springs in children younger than 6 months and pi-plasty in older children regarding the efficacy of improving ICV and CI. Neither of the techniques fully normalized the head shape. PMID- 26963299 TI - Postoperative Complications in Craniomaxillofacial Reconstruction With Medpor. AB - Bone reconstruction in craniofacial surgery is a challenge for surgeons, who most commonly adopt the autogenous bone grafting and alloplastic implants in such procedures. Among the alloplastic materials, the high-density porous polyethylene is highlighted-Medpor (Medpor, Porex Surgical Inc, Newman, GA), considered to be pure polyethylene, with only 1 manufacturing process and standard pore size. The purpose of the current study has been to present through a review of literature and the types of complications derived from the use of Medpor in craniomaxillofacial bone surgery. A specific and sensitive database was initially created via PubMed, focusing on studies published in English peer-reviewed journals between 2004 and 2014, including case reports, experimental studies in humans, and prospective and retrospective studies. Forty articles were found at PubMed database. After analyzing their abstracts, 19 were selected, totaling 1453 patients and 121 complications, being the most commonly reported diplopia with 56 patients and infection with 6 patients. Most of the complications reported in the articles used for the development of the current review are not directly related to the use of the Medpor implant. The only complications directly related to the use of this biomaterial were cases of infection. PMID- 26963300 TI - Aesthetic Unit-Based Reconstruction of Periorbital Defects. AB - PURPOSE: The aim of this study was to perform a retrospective analysis of patients who underwent periorbital area reconstructions, determine their sociodemographic characteristics, analyze the effects of defect etiologies and locations classified according to periorbital subunits on our reconstruction options, and to present our treatment outcomes and clinical experience. METHODS: A retrospective chart review of 23 patients operated in our department between January 2010 and March 2013 and underwent periorbital area reconstructions, was performed. In addition to the demographic characteristics of the patients; defect etiologies, locations according to Spinelli aesthetic subunits, and the degrees of involvement were determined. RESULT: Analysis of the reconstructive methods showed that primary closure with lateral cantholysis was performed in 1 patient with a defect involving less than 50% of zone 1 along with a partial defect involving less than 50% of zone 2. In another patient with a full-thickness defect involving 75% of zone 1, reconstruction was made with a temporally based monopedicle forehead transposition (Fricke) flap prepared from the lower eyelid, and a conchal cartilage graft. In 2 other patients with partial defects involving more than 50% of zone 2; reconstruction was made with full-thickness skin grafts taken from the retroauricular area. Four patients had full-thickness defects that involved 50% to 75% of zone 2; 3 of them were reconstructed with a Tenzel lateral semicircular rotation flap and 1 with a Tripier flap. In 3 patients who had full thickness defects involving 75% of zone 2; reconstruction was made with a paramedian forehead flap and conchal cartilage graft. In 3 patients with full thickness defects involving more than 75% of zone 2, a Mustarde cheek rotation flap was used for reconstruction. Six patients had defects in zone 3, 3 of them were reconstructed with a glabellar flap, 2 with a paramedian forehead flap, and 1 with a bilobed flap. One patient with a defect that involved 50% of zone 4 was reconstructed with a McGregor flap. CONCLUSIONS: Construction of a reconstructive algorithm by separation of the eyelid into aesthetic units and use of local healthy tissues provide functionally and aesthetically acceptable results. PMID- 26963302 TI - Botulinum Toxin A Upregulates Rac1, Cdc42, and RhoA Gene Expression in a Dose Dependent Manner: In Vivo and in Vitro Study. AB - Angiogenesis is the development of new capillaries from existing blood vessels and is a prerequisite for the wound-healing process. Many lines of scientific evidences have shown that complicated roles of small guanosine triphosphatases (GTPases) (ras-related C3 botulinum toxin substrate 1 [Rac1], cell division control protein 42 [Cdc42], and ras homolog gene family, member A [RhoA]) in regulation of signal transduction pathways exist to transmit distinct cellular effects on the modulation of actin cytoskeleton remodeling such as cell cycle progression, cell survival, and cell motility. In addition, these small GTPases activate mitogen-activated protein kinase kinase kinases (MAP3Ks) leading to activated mitogen-activated protein kinase kinases (MAPKK), mitogen-activated protein kinase (MAPK), and various transcription factors such as vascular endothelial growth factor with involvement of MAPK signaling pathways.In this study, the authors hypothesized that botulinum toxin A increases angiogenesis via the expression of small GTPases in vivo and in vitro studies.In vivo experiment, 24 Sprague-Dawley rats were randomly divided into 2 groups: a control group and a botulinum toxin A group. Five days prior to superiorly based transverse rectus abdominis myocutaneous flap elevation, the botulinum toxin A (BoTA) group was pretreated with BoTA, while the control group was pretreated with normal saline. quantitative real-time polymerase chain reaction was performed to evaluate the expression of Rac1, RhoA, and Cdc42.The angiogenic effects of botulinum toxin A on human dermal fibroblasts were measured in vitro experiment. To understand the mechanism of botulinum toxin A on small GTPases production of fibroblasts, Rac1, Cdc42, and RhoA were measured using qRT-PCR.The relative messenger ribonucleic acid expression of Rac1, RhoA, and Cdc42 was significantly higher in the BoTA group than in the control group, in every zone and pedicle muscle, on postoperative days 1, 3, and 5. Levels of these molecules increased significantly in human dermal fibroblasts grown in the presence of BoTA compared with control group over 5 IU.Our in vivo and in vitro studies suggest that administration of BoTA upregulates the expression of RhoA, Rac1, and Cdc42 in a dose-dependent manner. MAPK signaling pathway might be involved in BoTA-induced angiogenesis mechanism. LEVEL OF EVIDENCE: N/A. PMID- 26963303 TI - Unusual Adenomatoid Odontogenic Tumor. AB - The adenomatoid odontogenic tumor is a rare benign neoplasm. It can, however, have locally aggressive behavior. This is a case of an adenomatoid odontogenic tumor of unusual location and behavior in a 15-year-old female patient. A panoramic radiograph revealed a large radiolucent lesion involving the retained tooth 33. Teeth involved in this lesion were displaced and with apparent root resorption. A prototype of the mandible showed a marked expansion of cortical bone, fenestration points in the lingual cortex, and fragility of the base of the mandible. Therefore, because of the risk of postoperative pathologic fracture the placement of a 2.4-mm reconstruction plate was indicated. Total enucleation of the lesion, as well as placement of a reconstruction plate were performed. Despite the large bone destruction, with the correct surgical procedure and the use of the reconstruction plate the patient recovered without incidents and a 24 month postoperative radiography showed satisfactory bone formation. PMID- 26963301 TI - Age-Related Changes Between the Level of Velopharyngeal Closure and the Cervical Spine. AB - The primary focus of this study was to assess age-related changes in the vertical distance of the estimated level of velopharyngeal closure in relation to a prominent landmark of the cervical spine: the anterior tubercle of cervical vertebra 1 (C1). Midsagittal anatomic magnetic resonance images were examined across 51 participants with normal head and neck anatomy between 4 and 17 years of age. Results indicate that age is a strong predictor (P = 0.002) of the vertical distance between the level of velopharyngeal closure relative to C1. Specifically, as age increases, the vertical distance between the palatal plane and C1 becomes greater resulting in the level of velopharyngeal closure being located higher above C1 (range 4.88-10.55 mm). Results of this study provide insights into the clinical usefulness of using C1 as a surgical landmark for placement of pharyngoplasties in children with repaired cleft palate and persistent hypernasal speech. Clinical implications and future directions are discussed. PMID- 26963304 TI - Approach of pulmonologists in Turkey to noninvasive mechanical ventilation use in acute respiratory failure. AB - INTRODUCTION: Noninvasive mechanical ventilation (NIV) has been increasingly used worldwide for acute respiratory failure (ARF), especially in patients with chronic lung disorders. We aimed to define the approach of pulmonologists in Turkey to NIV use for ARF management. MATERIALS AND METHODS: A 38-question survey, developed and tested by authors, was distributed by e-mail to a total of 2.205 pulmonologists in Turkey. RESULT: Response rate was 27% (n= 596). Seventy one percent of responders were practicing NIV in clinic. NIV use was found to be associated with responder's academic title, age, duration of medical license, type of physician's hospital and its region, patient load, NIV experience during residency, and duration of NIV and intensive care unit (ICU) experience (p< 0.001). Based on sub-group analysis of responders using NIV, median number of NIV patients followed-up per week was 4 [interquartile range (IQR): 2-6]. Most of the NIV users reported employment of wards (90%) and/or ICUs (86%) to follow-up patients, while 8.4% of the responders were applying NIV only in ICU's. Chronic obstructive lung disease (COPD) (99.5%), obesity hypoventilation syndrome (93.7%) and restrictive lung disease (89.4%) were the most common indications. Majority of NIV users (87%) were applying NIV to > 60% of patients with COPD, and success rate in COPD was reported as over 60% by 93% of users. Oronasal mask (median and IQR 90, 80-100%, respectively) and home care NIV ventilators (median and IQR 50, 10-85%, respectively) were the most commonly utilized equipment. CONCLUSIONS: NIV use in ARF varies based on hospital type, region and, especially, experience of the physician. Although consistent with guidelines and general practice, NIV use can still be improved and increased. PMID- 26963305 TI - [Storage mite sensitivity and related factors in asthmatic patients]. AB - INTRODUCTION: The aim of the study was to investigate the storage mite sensitivity and related factors in patients with asthma or asthma and rhinitis. PATIENTS AND METHODS: 149 patients with asthma or asthma and rhinitis were included to the study. Prick test was performed after addition of Acarus siro (A. siro), Lepidoglyphus destructor (L. destructor), Glycophagus domesticus (G. domesticus) and Tyrophagus putrescentiae (T. putrescentiae) to the standart prick test. Living conditions, smoking history, allergic diseases status, seasonal variations in symptoms were evaluated by a questionnaire. Besides, respiratory screening spesific IgE, L. destructor spesific IgE was examined in a group of patients who were allergic to storage mites according to prick tests. RESULT: Prick test results showed that; 115 of the patients were sensitized while 34 of them were not. House dust mite sensitivity was detected as mite 58.3%.The storage mite sensitivity for at least one of the studied species was detected in 61.7% of patients. The sensitivity rates were 50.4%, 48.7%, 47%, %40 for A. siro, L. destructor, G. domesticus and T. putrescentiae, respectively. The storage mite sensivity was found higher in the patients from the rural areas (p< 0.05). L. destructor IgE positiveness was detected in 9.1% of the group that antibody levels were examined. Positive reaction was detected for at least one of the storage mite species in %22.7 of the patients who were considered as not sensitized according to the results of the standart prick tests. CONCLUSIONS: As a result, storage mites are important allergens in subjects who live in rural areas and close contact with barn, haymow, bin and pantry. Addition of storage mite allergens to the standart prick test panel of patients living in rural area is suitable. PMID- 26963306 TI - Analysis of rpsL and rrs genes mutations related to streptomycin resistance in Mdr and Xdr clinical isolates of Mycobacterium tuberculosis. AB - INTRODUCTION: Streptomycin is a bactericidal and aminoglycoside antibiotic. It is one of the most effective drugs for treatment of multi-drug Tuberculosis disease. Incidence of resistance is increasingly reported. Its action mechanism is by inhibition of binding aminoacyl tRNA to position "A" in elongation phase, which finally it causes to stop bacterial protein synthesis. In this study, resistance rapid investigation to streptomycin was conducted in clinical strains of Mycobacterium tuberculosis. MATERIALS AND METHODS: In this study, among 105 strains of phlegm-positive and culture-positive Mycobacterium tuberculosis, 45 strains of resistant and sensitive to streptomycin were selected for possible mutations examination in genes rrs and rpsL. Specific primers that used for PCR were named rpsL 1, rpsL 2 and rrsR, Frrs. PCR products were sequenced. RESULT: PCR Products represents 504 bp band for gene rpsL and 1027 bp for gene rrs that shows proper selection of primers and determining an amplification appropriate program. From 26 resistant strains to streptomycin 26 strain have mutation in rpsL gene and 1 strain have alteration in rrs gene. In this study 19 strains were sensitive to streptomycin that have no mutation in these gene. CONCLUSIONS: Streptomycin resistance is mainly related to mutation at codons 43 and 88 "rpsL" gene and to a lesser extent "rrs" that are the greatest cause of drug resistance to streptomycin. PMID- 26963307 TI - The comparative value of pleural fluid adenosine deaminase and neopterin levels in diagnostic utility of pleural tuberculosis. AB - INTRODUCTION: The aim of the present study was to evaluate and compare the diagnostic accuracy of pleura levels of adenosine deaminase (ADA) and neopterin for the differential diagnosis of pleural tuberculosis (TP). PATIENTS AND METHODS: The study included 50 patients with TB, 27 patients with malignancies, and 24 patients with pleural effusion of non-tuberculous and non-malignant origin as controls. ADA and neopterin levels in pleural fluid were measured by spectrofotometric and ELISA method, respectively. RESULT: Pleural neopterin levels were significantly higher in patients with pleural TB than patients with malignancy (p< 0.001). Pleural ADA levels were significantly higher in patients with pleural TB than patients with malignancy (p< 0.001) and patients with benign non-tuberculosis effusions (p< 0.001). The mean levels of ADA and neopterin in pleural effusion were evaluated according to their underlying diseases for the diagnostic accuracy. As for pleural TB receiving operating characteristic curves identified the following results; The best cut-off value for pleural neopterin was 4.7 U/L and yielded a sensitivity and specificity of 86% and 72.55%, respectively. Taking a cut-off value of 42 U/L for pleural ADA, the sensitivity and the specificity were found to be 88% and 68.63%, respectively. CONCLUSIONS: In the diagnosis of pleural TB pleural neopterin level has a comparable sensitivity to pleural ADA activity. Both markers may find a place as a routine investigation in the coming days for early detection of TB. However, these tests should not be considered an alternative to biopsy and culture. PMID- 26963308 TI - Psychometric properties of the Turkish version of the Fagerstrom test for nicotine dependence. AB - INTRODUCTION: The Fagerstrom Test for Nicotine Dependence (FTND), modified from Fagerstrom Tolerance Questionnairre (FTQ), is used to determine whether a smoker trying to quit will need nicotine replacement therapy to treat with drawal symptoms. The FTND has been translated into many languages and has been referred to in the smoking literature worldwide. However, only a few studies have examined the psychometric propertiesof the non-English FTND versions. This study aimed to assess the psychometric properties of the Turkish version of the FTND. MATERIALS AND METHODS: Confirmatory factor analysis (CFA) was used to test the factor structure of the Turkish version of the questionnaire using a large sample from two smoking cessation clinics in Istanbul, Turkey. Our study comprised 502 smokers who entered one of these smoking cessation clinics between October 1 and December 31, 2011. All subjects gave informed consent to the study. We assessed the validity of the FTND using CFA, and we calculated Cronbach's alpha coefficients to determine reliability. RESULT: One-factor CFA included all of the items on the FTND. All items loaded on this factor with a score of 0.40 or higher. The goodness of fit statistics were adequate, with a Comparative Fit Index (CFI) of 0.922, a Tucker-Lewis Index (TLI) of 0.902, and a root-mean-square error of approximation (RMSEA) of 0.081. Two-factor CFA comprised the three "morning smoking" items, and the three "smoking pattern" items. The factor loadings and the goodness-of-fit statistics confirmed that the FTND has a two factor structure. CONCLUSIONS: Analyses confirmed that the Turkish version of the FTND has a two-factor structure with moderate reliability. This study found that using a total score as an estimate of nicotine dependence may limit the assessment of specific smoking dependency and tailoring intervention approaches. We suggest that a two-factor FTND in clinical practice would more accurately determine the nicotine dependence of patients. PMID- 26963309 TI - [Computed tomography findings in pulmonary involvement of Wegener's granulomatosis: pictorial review]. AB - Wegener's granulomatosis is a necrotising granulomatous vasculitis which has a variable manifestations in the chest that are best described on computed tomography. Imaging findings may include masses or nodules, which may cavitate; consolidations and ground-glass opacities. Wegener's granulomatosis can mimic pneumonia, malignancy, and noninfectious inflammatory diseases. The purpose of this pictorial essay is to demonstrate the characteristic computed tomography findings of pulmonary Wegener's granulomatosis. PMID- 26963310 TI - [Asthma-COPD overlap syndrome]. AB - Asthma and chronic obstructive pulmonary disease (COPD) are common lung diseases characterized by chronic airway inflammation and airway obstruction. Among patient with COPD and asthma; there is a group of patients with an overlap between clinical, functional characteristics and airway inflammation patterns, named "Asthma-COPD Overlap Syndrome" (ACOS). ACOS is a syndrome characterized by reversible but persistant airflow limitation (postbronchodilator FEV1/FVC < 70%) which has some features of both asthma and COPD. ACOS should be suspected in a patient > 40 years, with smoking history, previous asthma diagnosis or history of childhood asthma who has persistant airflow limitation and reversible ariway obstruction (defined by an increase of > %12 of FEV1 pred or increase of FEV1 > 200 mL after inhalation of 400 mcg salbutamol or 1000 mcg terbutaline). The prevalence for ACOS has been reported 11-55% in different case series to date and increases by age and is more frequent in females in different age groups. Patients with ACOS are younger than COPD patients and older than asthma patients. Frequent and severe exacerbations and related hospitalization and emergency room visits are common in ACOS and this causes an impaired quality of life. Current recommendations of guidelines for pharmacologic treatment of ACOS have been composed of a combination with optimal COPD and asthma treatment. Future therapeutic approaches should be based on endotypes. Clinical phenotype and underlying endotype driven clinical studies may be the base of ACOS guidelines. PMID- 26963311 TI - [Current management of idiopathic pulmonary fibrosis]. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible and eventually fatal chronic interstitial pneumonia limited to the lung and associated with the histological and/or radiological pattern of usual interstitial pneumonia.The mean age of the disease is 65 and it is more frequent in men than women. The disease was historically considered as an inflammatory disease, but currently this has shifted towards a prominent role of impaired wound healing process. The diagnosis of disease requires exclusion of other known causes of interstitial lung disease, the presence of a usual interstitial pneumonia pattern on high -resolution computed tomography (HRCT) in patients or specific combinations of HRCT and surgical lung biopsy patterns. The patients are considered as mild, moderate and severe according to the symptoms, radiological and pulmonary function tests. It is difficult to predict the course of the disease; clinical exacerbation can be seen after a long stable period. Average median survival is approximately 3 years. Advanced age, smoking, low body mass index, widespread radiological involvement, comorbidities and complications (pulmonary hypertension, emphysema, and bronchogenic cancer) are considered as poor prognostic factors. The treatment approach is the basis on the severity of the disease and patient preference. The recent positive result of the pirfenidone and nintedanib phase II and III clinical trials based on the prevailing mechanism of IPF pathogenesis particularly targeted fibroblast activation and myofibroblast differentiation have currently been reported. Initiating therapy with pirfenidone and nintedanib is recommended for the patients with mild and moderate IPF who do not have underlying liver disease and who live in area where these drugs are available. Nausea and rashes are more common in treatment with pirfenidone while diarrhea and deterioration in liver function tests are seen more frequently in nintedanib. The information regarding participation in randomized trials should be given to all patients and also early referral for transplantation should be considered. PMID- 26963313 TI - [Diffusion weighted imaging of the chest]. PMID- 26963312 TI - [A case of Takayasu's arteritis with endobronchial involvement]. AB - Takayasu arteritis (TA) is a large vessel vasculitis especially seen in young women. Because of nonspecific symptoms diagnois is difficult and confused with other diseases. Delayed treatment increase morbidity and mortality. It effects primarly pulmonary artery in lung involvement. To our knowledge endobronchial involvement has not been reported previously in the literature. Due to rarity we present our patient whom we observed with the diagnosis of endobronchial tuberculosis and confirmed the diagnosis of Takayasu arteritis after 9 months. PMID- 26963314 TI - Homozygous methylene tetra hydro folate reductase-677TT gene mutation: case of pulmonary thromboembolism. PMID- 26963315 TI - [Does diabetic neuropathy affect cyclic alternating pattern rates in patients with obstructive sleep apnea syndrome?]. PMID- 26963316 TI - Effects of Sugammadex and Neostigmine on Renal Biomarkers. AB - BACKGROUND: Neostigmine, the currently commonly used agent for reversal of neuromuscular blockade. Sugammadex is a novel and unique compound designed as an antagonist of steroidal neuromuscular blockers. In this study, we evaluated the effects of sugammadex or neostigmine on kidney functions in patients scheduled for elective surgery. MATERIAL/METHODS: Patients scheduled for a surgical procedure under desflurane/opioid anesthesia received an intubating dose rocuronium. Patients were divided into 2 groups receiving either sugammadex or neostigmine atropine to reverse neuromuscular blockade. Cystatin C, creatinine, urea, blood urea nitrogen, sodium, potassium, and calcium levels in the blood and alpha1microglobulin, beta2microglobulin, and microalbumin levels in the urine were measured. RESULTS: There was no significant difference between the groups with regard to the demographic data. In the Neostigmine Group, although beta2microglobulin and microalbumin were similar, a significant increase was found in the postoperative alpha1microglobulin and cystatin C values. In the Sugammadex Group, although beta2-microglobulin and cystatin C were similar, a significant increase was found in the postoperative alpha1-microglobulin and microalbumin values. The only significant difference was cystatin C value variation in the Neostigmine Group compared to the Sugammadex Group. CONCLUSIONS: We believe that the use of more specific and sensitive new-generation markers like cystatin C to evaluate kidney function will provide a better understanding and interpretation of our results. Sugammadex has more tolerable effects on kidney function in patients than does neostigmine. However, when compared to preoperative values, there is a negative alteration of postoperative values. Neostigmine and sugammadex do not cause renal failure but they may affect kidney function. PMID- 26963317 TI - Does iron deficiency anemia affect olfactory function? AB - Conclusion This study found a negative effect of IDA on olfactory function. IDA leads to a reduction in olfactory function, and decreases in hemoglobin levels result in further reduction in olfactory function. Objective This study examined the effects of iron-deficiency anemia (IDA) on olfactory function. Method The study enrolled 50 IDA patients and 50 healthy subjects. Olfactory function was evaluated using the Sniffin' Sticks olfactory test. The diagnosis of IDA was made according to World Health Organization (WHO) criteria. Results Patients with IDA had a significantly lower threshold, discrimination, and identification (TDI) value, and a lower threshold compared with the control group. However, there were no significant differences between the groups in terms of smell selectivity values. PMID- 26963318 TI - Intratracheal Administration of Small Interfering RNA Targeting Fas Reduces Lung Ischemia-Reperfusion Injury. AB - OBJECTIVES: Lung ischemia-reperfusion injury is the main cause of primary graft dysfunction after lung transplantation and results in increased morbidity and mortality. Fas-mediated apoptosis is one of the pathologic mechanisms involved in the development of ischemia-reperfusion injury. We hypothesized that the inhibition of Fas gene expression in lungs by intratracheal administration of small interfering RNA could reduce lung ischemia-reperfusion injury in an ex vivo model reproducing the procedural sequence of lung transplantation. DESIGN: Prospective, randomized, controlled experimental study. SETTING: University research laboratory. SUBJECTS: C57/BL6 mice weighing 28-30 g. INTERVENTIONS: Ischemia-reperfusion injury was induced in lungs isolated from mice, 48 hours after treatment with intratracheal small interfering RNA targeting Fas, control small interfering RNA, or vehicle. Isolated lungs were exposed to 6 hours of cold ischemia (4 degrees C), followed by 2 hours of warm (37 degrees C) reperfusion with a solution containing 10% of fresh whole blood and mechanical ventilation with constant low driving pressure. MEASUREMENTS AND MAIN RESULTS: Fas gene expression was significantly silenced at the level of messenger RNA and protein after ischemia-reperfusion in lungs treated with small interfering RNA targeting Fas compared with lungs treated with control small interfering RNA or vehicle. Silencing of Fas gene expression resulted in reduced edema formation (bronchoalveolar lavage protein concentration and lung histology) and improvement in lung compliance. These effects were associated with a significant reduction of pulmonary cell apoptosis of lungs treated with small interfering RNA targeting Fas, which did not affect cytokine release and neutrophil infiltration. CONCLUSIONS: Fas expression silencing in the lung by small interfering RNA is effective against ischemia-reperfusion injury. This approach represents a potential innovative strategy of organ preservation before lung transplantation. PMID- 26963319 TI - Effects of Tocilizumab on Experimental Severe Acute Pancreatitis and Associated Acute Lung Injury. AB - OBJECTIVE: To examine the therapeutic effects of tocilizumab, an antibody against interleukin-6 receptor, on experimental severe acute pancreatitis and associated acute lung injury. The optimal dose of tocilizumab and the activation of interleukin-6 inflammatory signaling were also investigated. DESIGN: Randomized experiment. SETTING: Research laboratory at a university hospital. SUBJECT: Experimental severe acute pancreatitis in rats. INTERVENTIONS: Severe acute pancreatitis was induced by retrograde injection of sodium taurocholate (50 mg/kg) into the biliopancreatic duct. In dose-study, rats were administered with different doses of tocilizumab (1, 2, 4, 8, and 16 mg/kg) through the tail vein after severe acute pancreatitis induction. In safety-study, rats without severe acute pancreatitis induction were treated with high doses of tocilizumab (8, 16, 32, and 64 mg/kg). Serum and tissue samples of rats in time-study were collected for biomolecular and histologic evaluations at different time points (2, 6, 12, 18, and 24 hr). MEASUREMENTS AND MAIN RESULTS: 1) Under the administration of tocilizumab, histopathological scores of pancreas and lung were decreased, and severity parameters related to severe acute pancreatitis and associated lung injury, including serum amylase, C-reactive protein, lung surfactant protein level, and myeloperoxidase activity, were all significant alleviated in rat models. 2) Dose-study demonstrated that 2 mg/kg tocilizumab was the optimal treatment dose. 3) Basing on multi-organ pathologic evaluation, physiological and biochemical data, no adverse effect and toxicity of tocilizumab were observed in safety-study. 4) Pancreatic nuclear factor-kappaB and signal transducer and activator of transcription 3 were deactivated, and the serum chemokine (C-X-C motif) ligand 1 was down-regulated after tocilizumab administration. CONCLUSIONS: Our study demonstrated tocilizumab, as a marketed drug commonly used for immune mediated diseases, was safe and effective for the treatment of experimental severe acute pancreatitis and associated acute lung injury. Our findings provide experimental evidences for potential clinical application of tocilizumab in severe acute pancreatitis and associated complications. PMID- 26963321 TI - Lung Functional and Biologic Responses to Variable Ventilation in Experimental Pulmonary and Extrapulmonary Acute Respiratory Distress Syndrome. AB - OBJECTIVES: The biologic effects of variable ventilation may depend on the etiology of acute respiratory distress syndrome. We compared variable and conventional ventilation in experimental pulmonary and extrapulmonary acute respiratory distress syndrome. DESIGN: Prospective, randomized, controlled experimental study. SETTINGS: University research laboratory. SUBJECTS: Twenty four Wistar rats. INTERVENTIONS: Acute respiratory distress syndrome was induced by Escherichia coli lipopolysaccharide administered intratracheally (pulmonary acute respiratory distress syndrome, n = 12) or intraperitoneally (extrapulmonary acute respiratory distress syndrome, n = 12). After 24 hours, animals were randomly assigned to receive conventional (volume-controlled ventilation, n = 6) or variable ventilation (n = 6). Nonventilated animals (n = 4 per etiology) were used for comparison of diffuse alveolar damage, E-cadherin, and molecular biology variables. Variable ventilation was applied on a breath-to-breath basis as a sequence of randomly generated tidal volume values (n = 600; mean tidal volume = 6 mL/kg), with a 30% coefficient of variation (normal distribution). After randomization, animals were ventilated for 1 hour and lungs were removed for histology and molecular biology analysis. MEASUREMENTS AND MAIN RESULTS: Variable ventilation improved oxygenation and reduced lung elastance compared with volume controlled ventilation in both acute respiratory distress syndrome etiologies. In pulmonary acute respiratory distress syndrome, but not in extrapulmonary acute respiratory distress syndrome, variable ventilation 1) decreased total diffuse alveolar damage (median [interquartile range]: volume-controlled ventilation, 12 [11-17] vs variable ventilation, 9 [8-10]; p < 0.01), interleukin-6 expression (volume-controlled ventilation, 21.5 [18.3-23.3] vs variable ventilation, 5.6 [4.6-12.1]; p < 0.001), and angiopoietin-2/angiopoietin-1 ratio (volume controlled ventilation, 2.0 [1.3-2.1] vs variable ventilation, 0.7 [0.6-1.4]; p < 0.05) and increased relative angiopoietin-1 expression (volume-controlled ventilation, 0.3 [0.2-0.5] vs variable ventilation, 0.8 [0.5-1.3]; p < 0.01). In extrapulmonary acute respiratory distress syndrome, only volume-controlled ventilation increased vascular cell adhesion molecule-1 messenger RNA expression (volume-controlled ventilation, 7.7 [5.7-18.6] vs nonventilated, 0.9 [0.7-1.3]; p < 0.05). E-cadherin expression in lung tissue was reduced in volume-controlled ventilation compared with nonventilated regardless of acute respiratory distress syndrome etiology. In pulmonary acute respiratory distress syndrome, E-cadherin expression was similar in volume-controlled ventilation and variable ventilation; in extrapulmonary acute respiratory distress syndrome, however, it was higher in variable ventilation than in volume-controlled ventilation. CONCLUSIONS: Variable ventilation improved lung function in both pulmonary acute respiratory distress syndrome and extrapulmonary acute respiratory distress syndrome. Variable ventilation led to more pronounced beneficial effects in biologic marker expressions in pulmonary acute respiratory distress syndrome compared with extrapulmonary acute respiratory distress syndrome but preserved E-cadherin in lung tissue only in extrapulmonary acute respiratory distress syndrome, thus suggesting lower damage to epithelial cells. PMID- 26963320 TI - Sirtuin 1 Stimulation Attenuates Ischemic Liver Injury and Enhances Mitochondrial Recovery and Autophagy. AB - OBJECTIVES: Hepatic ischemia-reperfusion is a major clinical problem with limited treatment options. The pathophysiology of hepatic ischemia-reperfusion is characterized by mitochondrial dysfunction and cellular energy deficits. Sirtuin 1 is an energy-sensing enzyme known to modulate mitochondrial biogenesis. We hypothesized that pharmacologic activation of sirtuin 1 is protective after hepatic ischemia-reperfusion injury. DESIGN: Animal study. SETTING: University based experimental laboratory. SUBJECTS: Wild-type C57BL/6 mice. INTERVENTIONS: C57BL/6 mice were subjected to 60-minute partial hepatic ischemia-reperfusion and posttreated with sirtuin 1 activator, SRT1720 (20 mg/kg), or vehicle. Blood and liver were collected at 24 hours after ischemia-reperfusion for analyses of hepatic injury, adenosine triphosphate levels, mitochondrial mass, autophagy, inflammation, and oxidative stress. H4IIE hepatoma cells and rat primary hepatocytes were incubated with oxyrase to induce hypoxia followed by reoxygenation in the presence or absence of SRT1720 for assessment of mitochondrial mass, mitochondrial membrane potential, and autophagy. MEASUREMENTS AND MAIN RESULTS: SRT1720 restored the reduction in mitochondrial mass, enhanced autophagy, and preserved adenosine triphosphate levels in the liver after ischemia-reperfusion, which was associated with a decrease in ischemia reperfusion-induced hepatic injury, apoptosis, and necrosis. Ischemia-reperfusion induced inflammation was also significantly reduced by SRT1720 as measured by systemic and hepatic cytokine and chemokine levels, as well as a decrease in neutrophil infiltration to the liver. Furthermore, oxidative stress was markedly attenuated in the SRT1720-treated mice compared with the vehicle. SRT1720 treatment increased adenosine triphosphate levels and survival of cultured hepatocytes after hypoxia-reoxygenation. SRT1720 not only increased the mitochondrial mass but also increased mitochondrial membrane potential per cell in cultured hepatocytes after hypoxia-reoxygenation. Moreover, SRT1720 prevented the hypoxia-reoxygenation-induced mitochondrial depolarization and resulted in an enhancement of autophagy in cultured hepatocytes after hypoxia-reoxygenation. CONCLUSIONS: Pharmacologic stimulation of sirtuin 1 attenuates liver injury after hepatic ischemia-reperfusion by restoring mitochondrial mass and membrane potential, which is associated with the enhancement of autophagy. PMID- 26963322 TI - Inhibition of Plexin C1 Protects Against Hepatic Ischemia-Reperfusion Injury. AB - OBJECTIVES: Hepatic ischemia-reperfusion injury is a disease pattern that is associated with an acute inflammatory reaction. It is well known that neutrophils play an essential role in the early phase of hepatic ischemia-reperfusion injury and determine the extent of tissue damage. Hepatic ischemia-reperfusion injury can result in organ failure, which is linked to high mortality. Recent data indicate that the neuronal guidance receptor Plexin C1 is involved in the control of the acute inflammatory response and, as such, modulates the transmigration of neutrophils. Hence, we investigated the functional role of Plexin C1 in a mouse model of early hepatic ischemia-reperfusion injury. DESIGN: Animal study. SETTING: University experimental laboratory. SUBJECTS: Wild-type, PLXNC1 and chimeric mice. INTERVENTIONS: Hepatic ischemia-reperfusion injury or sham operation. MEASUREMENTS AND MAIN RESULTS: We found that the functional inhibition of Plexin C1 in wild-type mice treated with an anti-Plexin C1 antibody and a Semaphorin 7A peptide reduced hepatic ischemia-reperfusion injury, as measured by the levels of lactate dehydrogenase, aspartate, and alanine aminotransferase. This reduction in ischemia-reperfusion injury was accompanied by reduced numbers of neutrophils in ischemic hepatic tissue and reduced serum levels of inflammatory cytokines. Experiments using Plexin C1 receptor-deficient (PLXNC1) mice also demonstrated decreased hepatic ischemia-reperfusion injury. Studies of chimeric mice revealed that the hematopoietic Plexin C1 knockout is crucial for reducing the extent of hepatic ischemia-reperfusion injury. CONCLUSIONS: These results describe a role for Plexin C1 during ischemia-reperfusion injury, highlight the role of hematopoietic Plexin C1 in the development of hepatic ischemia-reperfusion injury, and suggest that Plexin C1 is a potential drug target. PMID- 26963323 TI - Triiodothyronine Administration in a Model of Septic Shock: A Randomized Blinded Placebo-Controlled Trial. AB - OBJECTIVES: Triiodothyronine concentration in plasma decreases during septic shock and may contribute to multiple organ dysfunction. We sought to determine the safety and efficacy of administering triiodothyronine, with and without hydrocortisone, in a model of septic shock. DESIGN: Randomized blinded placebo controlled trial. SETTING: Preclinical research laboratory. SUBJECTS: Thirty-two sheep rendered septic with IV Escherichia coli and receiving protocol-guided sedation, ventilation, IV fluids, and norepinephrine infusion. INTERVENTIONS: Two hours following induction of sepsis, 32 sheep received a 24-hour IV infusion of 1) placebo + placebo, 2) triiodothyronine + placebo, 3) hydrocortisone + placebo, or 4) triiodothyronine + hydrocortisone. MEASUREMENTS AND MAIN RESULTS: Primary outcome was the total amount of norepinephrine required to maintain a target mean arterial pressure; secondary outcomes included hemodynamic and metabolic indices. Plasma triiodothyronine levels increased to supraphysiological concentrations with hormonal therapy. Following 24 hours of study drug infusion, the amount of norepinephrine required was no different between the study groups (mean +/- SD MUg/kg; placebo + placebo group 208 +/- 392; triiodothyronine + placebo group 501 +/- 370; hydrocortisone + placebo group 167 +/- 286; triiodothyronine + hydrocortisone group 466 +/- 495; p = 0.20). There was no significant treatment effect on any hemodynamic variable, metabolic parameter, or measure of organ function. CONCLUSIONS: A 24-hour infusion of triiodothyronine, with or without hydrocortisone, in an ovine model of septic shock did not markedly alter norepinephrine requirement or any other physiological parameter. PMID- 26963324 TI - Impact of a Sequential Intervention on Albumin Utilization in Critical Care. AB - OBJECTIVES: Literature generally finds no advantages in mortality risk for albumin over cheaper alternatives in many settings. Few studies have combined financial and nonfinancial strategies to reduce albumin overuse. We evaluated the effect of a sequential multifaceted intervention on decreasing albumin use in ICU and explore the effects of different strategies. DESIGN: Prospective prepost cohort study. SETTING: Eight ICUs at two hospitals in an academic healthcare system. PATIENTS: Adult patients admitted to study ICUs from September 2011 to August 2014 (n = 22,004). INTERVENTIONS: Over 2 years, providers in study ICUs participated in an intervention to reduce albumin use involving monthly feedback and explicit financial incentives in the first year and internal guidelines and order process changes in the second year. MEASUREMENTS AND MAIN RESULTS: Outcomes measured were albumin orders per ICU admission, direct albumin costs, and mortality. Mean (SD) utilization decreased 37% from 2.7 orders (6.8) per admission during the baseline to 1.7 orders (4.6) during the intervention (p < 0.001). Regression analysis revealed that the intervention was independently associated with 0.9 fewer orders per admission, a 42% relative decrease. This adjusted effect consisted of an 18% reduction in the probability of using any albumin (p < 0.001) and a 29% reduction in the number of orders per admission among patients receiving any (p < 0.001). Secondary analysis revealed that probability reductions were concurrent with internal guidelines and order process modification while reductions in quantity occurred largely during the financial incentives and feedback period. Estimated cost savings totaled $2.5M during the 2 year intervention. There was no significant difference in ICU or hospital mortality between baseline and intervention. CONCLUSIONS: A sequential intervention achieved significant reductions in ICU albumin use and cost savings without changes in patient outcomes, supporting the combination of financial and nonfinancial strategies to align providers with evidence-based practices. PMID- 26963325 TI - Different Mortality Time Points in Critical Care Trials: Current Practice and Influence on Effect Estimates in Meta-Analyses. AB - OBJECTIVE: Mortality is frequently used as an outcome in critical care trials, being a patient-orientated variable and robust against information/selection bias. Mortality frequency, however, should be measured at a defined time point of follow-up. Practice of meta-analysis shows that follow-up times of trials in critical care medicine differ substantially. This may have substantial implications on potential pooling of effect estimates. We aimed to describe the current practice of mortality follow-up time definitions in a representative sample of published critical care randomized controlled trials and to analyze the influence of different follow-up times on subsequently pooled effect estimates. DATA SOURCES: Cochrane CENTRAL, EMBASE, MEDLINE, PASCAL Biomed, and PsycINFO. STUDY SELECTION: Databases were searched for critical care randomized controlled trials published after 2000. A random sample of 50% was drawn for further review. DATA EXTRACTION: Study characteristics were extracted, as well as the number and time points of mortality ascertainment. Additional data were extracted from Kaplan-Meier plots, as available. DATA SYNTHESIS: Meta-regression and multilevel mixed-effects linear regression were used to analyze the influence of follow-up time (independent variable) on deviation of pooled risk ratios from study baseline (dependent variable). From 9,246 retrieved references, we included 106 studies representing 63,713 participants. Among these, 45 studies (43%) reported more than one time point, with 24 different time points at all, only three (28, 30, and 90 d) being reported in more than 10% of studies. Limiting meta-analyses to only one predefined time point would reduce the number of eligible studies by at least 60%. No influence of time points on meta-analytic summary effect estimates was found. CONCLUSIONS: In a large sample of critical care randomized controlled trials, numerous different mortality time points are reported. Mortality time points did not influence pooled point estimates of the effects. Consequently, it seems possible to pool effect estimates, which in turn will increase the precision of these effect estimates. PMID- 26963326 TI - The Fragility Index in Multicenter Randomized Controlled Critical Care Trials. AB - OBJECTIVES: Recent literature has drawn attention to the potential inadequacy of frequentist analysis and threshold p values as tools for reporting outcomes in clinical trials. The fragility index, which is a measure of how many events the statistical significance of a result depends on, has been suggested as a means to aid the interpretation of trial results. This study aimed to calculate the fragility index of clinical trials in critical care medicine reporting a statistically significant effect on mortality (increasing or decreasing mortality). DATA SOURCES: Literature search (PubMed/MEDLINE) to identify all multicenter randomized controlled trials in critical care medicine. STUDY SELECTION: We identified 862 trials; of which 56 fulfilled eligibility criteria and were included in our analysis. DATA EXTRACTION: Calculation of fragility index for trials reporting a statistically significant effect on mortality, and analysis of the relationship between trial characteristics and fragility index. DATA SYNTHESIS: The median fragility index was 2 (interquartile range, 1-3.5), and greater than 40% of trials had a fragility index of less than or equal to 1. 12.5% of trials reported loss to follow-up greater than their fragility index. Trial sample size was positively correlated, and reported p value was negatively correlated, with fragility index. CONCLUSIONS: In critical care trials reporting statistically significant effects on mortality, the findings often depend on a small number of events. Critical care clinicians should be wary of basing decisions on trials with a low fragility index. We advocate the reporting of fragility index for future trials in critical care to aid interpretation and decision making by clinicians. PMID- 26963327 TI - Glucocorticoid Sensitivity Is Highly Variable in Critically Ill Patients With Septic Shock and Is Associated With Disease Severity. AB - OBJECTIVES: To measure tissue glucocorticoid sensitivity in patients with septic shock and determine its relationship to standard measurements of adrenal function and of outcome. DESIGN: Prospective observational trial. SETTING: Teaching hospital ICU. SUBJECTS: Forty-one patients and 20 controls were studied. INTERVENTIONS: Glucocorticoid sensitivity was measured by in vitro suppression of cytokine production from lipopolysaccharide-stimulated leukocytes. MEASUREMENTS AND MAIN RESULTS: There was no significant difference between the groups in the relative suppression of cytokine production, although there was a greater range and variance in the patient data. Patients in the lowest quartile of glucocorticoid sensitivity had higher Acute Physiology and Chronic Health Evaluation II scores (25 [24-28] vs 20 [14-23]; p = 0.02) and a trend toward higher mortality (30% vs 0%; p = 0.2) compared to those in the highest. The mRNA expression of the beta variant of the glucocorticoid receptor and the 11-beta hydroxysteroid dehydrogenase 2 isozyme were significantly higher in patients compared to controls (8.6-fold, p = 0.002 and 10.1-fold, p = 0.0002, respectively). Changes in mRNA expression of these genes did not correlate with measurements of glucocorticoid sensitivity. CONCLUSIONS: Patients with septic shock and controls do not differ in their median glucocorticoid sensitivity. However, patients exhibited a greater variability in glucocorticoid responsiveness and had evidence of association between increased sickness sensitivity and reduced glucocorticoid sensitivity. Sensitivity to glucocorticoids did not appear to be mediated by changes in the expression of the beta variant of the glucocorticoid receptor or the 11-beta hydroxysteroid dehydrogenase 2 isozyme. PMID- 26963328 TI - Melioidosis Causing Critical Illness: A Review of 24 Years of Experience From the Royal Darwin Hospital ICU. AB - OBJECTIVES: Melioidosis is increasing in incidence with newly recognized foci of melioidosis in the Americas, Africa, and elsewhere. This review describes the demographics, management, and outcomes of a large cohort of critically ill patients with melioidosis. DESIGN: Data were extracted from two prospective databases-the Menzies School of Health Research Melioidosis Database (1989-2013) and the Royal Darwin Hospital ICU Melioidosis Database (2001-2013). SETTING AND PATIENTS: The Royal Darwin Hospital ICU is the only ICU in the tropical Top End of Northern Territory of Australia, an endemic area for melioidosis. The study included all patients with melioidosis admitted to Royal Darwin Hospital ICU from 1989 to 2013. MEASUREMENTS AND MAIN RESULTS: From 1989 to 2013, 207 patients with melioidosis required admission to ICU. Mortality reduced from 92% (1989-1997) to 26% (1998-2013) (p < 0.001). The reduced mortality coincided with the introduction of an intensivist-led service, meropenem, and adjuvant granulocyte colony-stimulating factor for confirmed melioidosis sepsis in 1998. Pneumonia was the presenting illness in 155 of 207 (75%). ICU melioidosis patients (2001-2013) had an Acute Physiology and Chronic Health Evaluation II score of 23, median length of stay in the ICU of 7 days, and median ventilation hours of 130 and one third required renal replacement therapy. CONCLUSIONS: The mortality for critically ill patients with melioidosis in the Top End of the Northern Territory of Australia has substantially reduced over the past 24 years. The reduction in mortality coincided with the introduction of an intensivist-led model of care, the empiric use of meropenem, and adjunctive treatment with granulocyte colony stimulating factor in 1998. PMID- 26963330 TI - The Levels of Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase L1 During the First Week After a Traumatic Brain Injury: Correlations With Clinical and Imaging Findings. AB - BACKGROUND: Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) are promising biomarkers of traumatic brain injury (TBI). OBJECTIVE: We investigated the relation of the GFAP and UCH-L1 levels to the severity of TBI during the first week after injury. METHODS: Plasma UCH-L1 and GFAP were measured from 324 consecutive patients with acute TBI and 81 control subject enrolled in a 2-center prospective study. The baseline measures included initial Glasgow Coma Scale (GCS), head computed tomographic (CT) scan at admission, and blood samples for protein biomarkers that were collected at admission and on days 1, 2, 3, and 7 after injury. RESULTS: Plasma levels of GFAP and UCH-L1 during the first 2 days after the injury strongly correlated with the initial severity of TBI as assessed with GCS. Additionally, levels of UCH-L1 on the seventh day after the injury were significantly related to the admission GCS scores. At admission, both biomarkers were capable of distinguishing mass lesions from diffuse injuries in CT, and the area under the curve of the receiver operating characteristic curve for prediction of any pathological finding in CT was 0.739 (95% confidence interval, 0.636-0.815) and 0.621 (95% confidence interval, 0.517-0.713) for GFAP and UCH-L1, respectively. CONCLUSION: These results support the prior findings of the potential role of GFAP and UCH-L1 in acute-phase diagnostics of TBI. The novel finding is that levels of GFAP and UCH L1 correlated with the initial severity of TBI during the first 2 days after the injury, thus enabling a window for TBI diagnostics with latency. ABBREVIATIONS: AUC, area under the curveCI, confidence intervalED, emergency departmentGCS, Glasgow Coma ScaleGRAP, glial fibrillary acidic proteinIMPACT, International Mission for Prognosis and Clinical TrialROC, receiver-operating characteristicTBI, traumatic brain injuryTRACK-TBI, Transforming Research and Clinical Knowledge in Traumatic Brain InjuryUCH-L1, ubiquitin C-terminal hydrolase-L1. PMID- 26963333 TI - Paraventricular nucleus is involved in the central pathway of adipose afferent reflex in rats. AB - Increasing evidence indicates a link between sympathetic nervous system activation and obesity, but the underlying mechanisms remain elusive. The adipose afferent reflex (AAR) is a sympathoexcitatory reflex that is activated by afferent neurotransmission from the white adipose tissue (WAT). This study aimed to investigate whether the hypothalamic paraventricular nucleus (PVH) is an important component of the central neurocircuitry of the AAR. In anesthetized rats, the discharge activity of individual PVH neurons was recorded in vivo. Activation of WAT afferents was initiated by capsaicin injection, and the AAR was evaluated by monitoring renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses. The responses of PVH neurons to activation of WAT afferents were evaluated by c-fos immunoreactivity and the discharge activity of individual PVH neurons, which was recorded using extracellular single-unit recording. After activation of WAT afferents, both individual PVH neuron discharge activity and c-fos immunoreactivity increased. Bilateral selective lesions of the neurons in the PVH with kainic acid abolished the AAR. These results indicate that PVH is an important component of the central neurocircuitry of the AAR. PMID- 26963341 TI - Piezoelectric potential in axial (In,Ga)N/GaN nanowire heterostructures. AB - We derive analytic expressions for the built-in electrostatic potential arising from piezo- and pyroelectricity in a cylindrical axial In(x)Ga(1-x)N/GaN nanowire (NW) heterostructure. Our simulations show that, for sufficiently thin NWs, a significant reduction of the built-in potential is reached in comparison to the planar heterostructure of the same In content, thickness, and orientation. This specific feature of axial NW heterostructures makes the aspect ratio of the embedded In(x)Ga(1-x)N/GaN disks an important additional degree of freedom to control the recombination energies. We furthermore show that the magnitude of the polarization potential decreases again above a certain value of the aspect ratio and that the extrema of the potential move from the central axis of the NW towards the side facets when the thickness of the disk is increased. PMID- 26963342 TI - Evaluation of the posttraumatic growth inventory after severe burn injury in Western Australia: clinical implications for use. AB - PURPOSE: Posttraumatic growth (PTG) is "the subjective experience of positive psychological change reported as a result of the struggle with trauma". Very few studies have explored PTG after burn injury. The Posttraumatic Growth Inventory (PTGI) is a 21-item questionnaire which assesses five domains in which PTG has been found. First, the aim of this study was to assess how PTG presented after a severe burn, and second, whether it could be measured by the PTGI in Australian burn survivors. METHODS: A mixed method approach was used. Seventeen patients who had a severe burn injury at least 2 years previously were interviewed and completed the PTGI. The interviews were analyzed, then compared to the PTGI responses. RESULTS: PTG in burn survivors had similarities to PTG arising from other trauma. Burn-specific context such as heat intolerance and functional problems influenced the type of changes made. Barriers to PTG in relationships were related to guilt burden and visible scarring. CONCLUSION: PTG presents similarly after burn to other trauma types, but has other features to consider when devising intervention strategies. The PTGI is a 5-min screening tool that adequately identifies the presence or absence of PTG in burn survivors in Western Australia, and can guide intervention. IMPLICATIONS FOR REHABILITATION: The Posttraumatic Growth Inventory is a 5-min screening tool that adequately identifies the degree of PTG in burn survivors in Western Australia. It is a quick and easy tool to use to identify the need for clinical intervention. It will also evaluate the effectiveness of strategies designed to target PTG. A mean score of 2.5 can be used as a threshold to guide intervention strategy. PMID- 26963329 TI - Evaluating Physical Outcomes in Acute Respiratory Distress Syndrome Survivors: Validity, Responsiveness, and Minimal Important Difference of 4-Meter Gait Speed Test. AB - OBJECTIVE: To examine the reliability, validity, responsiveness, and minimal important difference of the 4-m gait speed test in acute respiratory distress syndrome survivors. DESIGN: Secondary analyses of data from two longitudinal follow-up studies of acute respiratory distress syndrome survivors. Test-retest and inter-rater reliability, construct validity (convergent, discriminant, and known group), predictive validity, and responsiveness were examined. The minimal important difference was estimated using anchor- and distribution-based approaches. SETTING: A national multicenter prospective study (ARDSNet Long-Term Outcome Study) and a multisite prospective study in Baltimore, MD (Improving Care of Acute Lung Injury Patients). PATIENTS: Acute respiratory distress syndrome survivors with 4-m gait speed assessment up to 60 months after acute respiratory distress syndrome (ARDSNet Long-Term Outcome Study, n = 184; Improving Care of Acute Lung Injury Patients, n = 122). INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: Four-meter gait speed was assessed at 6- and 12-month follow-up (ARDSNet Long-Term Outcome Study) and 36-, 48-, and 60-month follow-up (Improving Care of Acute Lung Injury Patients). Excellent test-retest (intraclass correlation, 0.89-0.99 across studies and follow-up) and inter-rater (intraclass correlation, 0.97) reliability were found. Convergent validity was supported by moderate-to-strong correlations (69% of 32 > 0.40) with other physical function measures. Discriminant validity was supported by weak correlations (86% of 28 < 0.30) with mental health measures. Survivors with impaired versus nonimpaired measures of muscle strength and pulmonary function had significantly slower 4-m gait speed (all but one p < 0.05). Furthermore, 4-m gait speed significantly predicted future hospitalization and health-related quality of life. Gait speed changes were consistent with reported changes in function, supporting responsiveness. The estimated 4-m gait speed minimal important difference was 0.03-0.06 m/s. CONCLUSIONS: The 4-m gait speed is a reliable, valid, and responsive measure of physical function in acute respiratory distress syndrome survivors. The estimated minimal important difference will facilitate sample size calculations for clinical studies evaluating the 4-m gait speed test in acute respiratory distress syndrome survivors. PMID- 26963343 TI - Serum Osteopontin as a Novel Biomarker for Muscle Regeneration in Duchenne Muscular Dystrophy. AB - Duchenne muscular dystrophy is a lethal X-linked muscle disorder. We have already reported that osteopontin (OPN), an inflammatory cytokine and myogenic factor, is expressed in the early dystrophic phase in canine X-linked muscular dystrophy in Japan, a dystrophic dog model. To further explore the possibility of OPN as a new biomarker for disease activity in Duchenne muscular dystrophy, we monitored serum OPN levels in dystrophic and wild-type dogs at different ages and compared the levels to other serum markers, such as serum creatine kinase, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1. Serum OPN levels in the dystrophic dogs were significantly elevated compared with those in wild-type dogs before and 1 hour after a cesarean section birth and at the age of 3 months. The serum OPN level was significantly correlated with the phenotypic severity of dystrophic dogs at the period corresponding to the onset of muscle weakness, whereas other serum markers including creatine kinase were not. Immunohistologically, OPN was up-regulated in infiltrating macrophages and developmental myosin heavy chain-positive regenerating muscle fibers in the dystrophic dogs, whereas serum OPN was highly elevated. OPN expression was also observed during the synergic muscle regeneration process induced by cardiotoxin injection. In conclusion, OPN is a promising biomarker for muscle regeneration in dystrophic dogs and can be applicable to boys with Duchenne muscular dystrophy. PMID- 26963344 TI - Posttraumatic stress symptoms in context: Examining trauma responses to violent exposures and homicide death among Black males in urban neighborhoods. AB - Concentrated disadvantage in urban communities places young Black men at disproportionate risk for exposure to violence and trauma. Homicide, a health disparity, positions Black males vulnerable to premature violent death and traumatic loss, particularly when peers are murdered. Posttraumatic stress disorder (PTSD) has been demonstrated as a health consequence for middle-income and White homicide survivors; however, understandings of traumatic stress among young Black men situated in contexts of chronic violence exposure remains limited. Guided by phenomenological variant of ecological systems theory (PVEST), the current study used in-depth qualitative interviews (average length: 90 min) to examine the presence and expression of traumatic stress symptoms among 37 young Black men (18-24) in Baltimore who experienced the homicide death of a loved one. Participants were recruited over 18 months through fieldwork at a large organization that serves Baltimore youth and young adults. Confidential participant interviews were audio recorded, transcribed verbatim, coded, and analyzed in ATLAS.ti. Pseudonyms were assigned to all participants. More than 70% of participants reported experiencing 2 or more Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V)-defined posttraumatic stress symptoms. Hypervigilance was most frequently experienced and expressed as being on point. Findings identify the prevalence of traumatic stress symptoms among young Black men in urban contexts; identify contextually specific expressions of traumatic stress; and, present implications for the mental health and clinical treatment of Black males living in environments where no "post" exists. (PsycINFO Database Record PMID- 26963349 TI - Comparison of NIRS, laser Doppler flowmetry, photoplethysmography, and pulse oximetry during vascular occlusion challenges. AB - Monitoring changes in blood volume, blood flow, and oxygenation in tissues is of vital importance in fields such as reconstructive surgery and trauma medicine. Near infrared spectroscopy (NIRS), laser Doppler (LDF) flowmetry, photoplethysmography (PPG), and pulse oximetry (PO) contribute to such fields due to their safe and noninvasive nature. However, the techniques have been rarely investigated simultaneously or altogether. The aim of this study was to investigate all the techniques simultaneously on healthy subjects during vascular occlusion challenges. Sensors were attached on the forearm (NIRS and LDF) and fingers (PPG and PO) of 19 healthy volunteers. Different degrees of vascular occlusion were induced by inflating a pressure cuff on the upper arm. The responses of tissue oxygenation index (NIRS), tissue haemoglobin index (NIRS), flux (LDF), perfusion index (PPG), and arterial oxygen saturation (PO) have been recorded and analyzed. Moreover, the optical densities were calculated from slow varying dc PPG, in order to distinguish changes in venous blood volumes. The indexes showed significant changes (p < 0.05) in almost all occlusions, either venous or over-systolic occlusions. However, differentiation between venous and arterial occlusion by LDF may be challenging and the perfusion index (PI) may not be adequate to indicate venous occlusions. Optical densities may be an additional tool to detect venous occlusions by PPG. PMID- 26963350 TI - Looking to the Future. Equality in Health and Marriage. PMID- 26963351 TI - Imaging Biomarkers in Lymphangioleiomyomatosis Clinical Trials. A Wolf in Sheep's Clothing? PMID- 26963352 TI - Disruptive Technology. Can Electronic Portals Promote Communication in the Intensive Care Unit? PMID- 26963353 TI - Implementation of Lung Cancer Screening Programs with Low-Dose Computed Tomography in Clinical Practice. PMID- 26963354 TI - A 37-Year-Old Woman with Dyspnea and Stridor. PMID- 26963355 TI - An 87-Year-Old Man with Acute Catastrophic Pneumonia. PMID- 26963356 TI - Acute Hypoxemic Respiratory Failure after Large-Volume Thoracentesis. Mechanisms of Pleural Fluid Formation and Reexpansion Pulmonary Edema. PMID- 26963357 TI - Ultrasound Diagnosis of Hemodynamic Compromise in a Patient with Hepatic Hydrothorax. PMID- 26963358 TI - The Undefined Value of Pleural Interventions in Advanced Heart Failure and Recurrent Pleural Effusions. PMID- 26963359 TI - Differential Risk Factors for Chronic Obstructive Pulmonary Disease 30-Day Readmissions According to Indication for Readmission. PMID- 26963360 TI - Reply: The Undefined Value of Pleural Interventions in Advanced Heart Failure and Recurrent Pleural Effusions. PMID- 26963363 TI - Update: Providing Quality Family Planning Services - Recommendations from CDC and the U.S. Office of Population Affairs, 2015. AB - In 2014, CDC published Providing Quality Family Planning Services: Recommendations of CDC and the U.S. Office of Population Affairs (QFP), which describes the scope of services that should be offered in a family planning visit, and how to provide those services (e.g., periodicity of screening, which persons are considered to be at risk, etc.). The sections in QFP include Contraceptive Services, Pregnancy Testing and Counseling, Clients Who Want to Become Pregnant, Basic Infertility Services, Preconception Health Services, Sexually Transmitted Disease Services, Related Preventive Health Services, and Screening Services for Which Evidence Does Not Support Screening. PMID- 26963362 TI - An Official American Thoracic Society Workshop Report. A Framework for Addressing Multimorbidity in Clinical Practice Guidelines for Pulmonary Disease, Critical Illness, and Sleep Disorders. AB - Coexistence of multiple chronic conditions (i.e., multimorbidity) is the most common chronic health problem in adults. However, clinical practice guidelines have primarily focused on patients with a single disease, resulting in uncertainty about the care of patients with multimorbidity. The American Thoracic Society convened a workshop with the goal of establishing a strategy to address multimorbidity within clinical practice guidelines. In this Workshop Report, we describe a framework that addresses multimorbidity in each of the key steps of guideline development: topic selection, panel composition, identifying clinical questions, searching for and synthesizing evidence, rating the quality of that evidence, summarizing benefits and harms, formulating recommendations, and rating the strength of the recommendations. For the consideration of multimorbidity in guidelines to be successful and sustainable, the process must be both feasible and pragmatic. It is likely that this will be achieved best by the step-wise addition and refinement of the various components of the framework. PMID- 26963364 TI - Moderators of Remission in Patients With Late-Life Depression: Where Do We Go Next? PMID- 26963365 TI - Biopolymeric agents for skin wrinkle treatment. AB - Skin aging is caused by several factors capable of deteriorating dermal matrix and is visibly noticed in skin color and skin contour deformities. In addition to the prevention of skin aging by application of antioxidants and sunscreens, treatment of skin wrinkles with those of dermal fillers is also recommended. Dermal filler products with enhanced injectability and longer duration are being developed continuously. Biodegradable polymers such as skin elastic fibers and dermal matrix mimetic used for treatment of skin wrinkle are summarized in this article. Additionally, the importance of amino acids, enzymes, and proteins in aesthetic of skin is addressed. Thus, elective agents are proposed for the dermatologists, cosmetic formulators, and the individuals facing skin aging problems. The candidate natural peptides from marine sources are additionally presented for widening the choice of actives application for treating aging. PMID- 26963367 TI - Properties of Polyvinylpyrrolidone in a Deep Eutectic Solvent. AB - Deep eutectic solvents (DES) are mixtures of two or more components with high melting temperatures, which form a liquid at room temperature. These DES hold great promise as green solvents for chemical processes, as they are inexpensive and environmentally friendly. Specifically, they present a unique solvating environment to polymers that is different from water. Here, we use small angle neutron scattering to study the polymer properties of the common, water-soluble, polyvinylpyrrolidone (PVP) in the prominent DES formed by a 1:2 molar mixture of choline chloride and urea. We find that the polymer adopts a slightly different structure in DES than in water, so that at higher concentrations the polymer favors a more expanded conformation compared to the same concentration in water. Yet, the osmotic pressure of PVP solutions in DES is very similar to that in water, indicating that both solvents are of comparable quality and that the DES components interact favorably with PVP. The osmotic pressure measurements within this novel class of promising solvents should be of value toward future technological applications as well as for osmotic stress experiments in nonaqueous environments. PMID- 26963368 TI - Reaction of PerR with Molecular Oxygen May Assist H2O2 Sensing in Anaerobes. AB - PerR is the peroxide resistance regulator found in several pathogenic bacteria and governs their resistance to peroxide stress by inducing enzymes that destroy peroxides. However, it has recently been implicated as a key component of the aerotolerance in several facultative or strict anaerobes, including the highly pathogenic Staphylococcus aureus. By combining (18)O labeling studies to ESI- and MALDI-TOF MS detection and EMSA experiments, we demonstrate that the active form of PerR reacts with dioxygen, which leads ultimately to disruption of the PerR/DNA complex and is thus physiologically meaningful. Moreover, we show that the presence of O2 assists PerR sensing of H2O2, another feature likely to be important for anaerobic organisms. These results allow one to envisage different scenarios for the response of anaerobes to air exposure. PMID- 26963369 TI - Anxiety and working memory capacity: A meta-analysis and narrative review. AB - Cognitive deficits are now widely recognized to be an important component of anxiety. In particular, anxiety is thought to restrict the capacity of working memory by competing with task-relevant processes. The evidence for this claim, however, has been mixed. Although some studies have found restricted working memory in anxiety, others have not. Within studies that have found impairments, there is little agreement regarding the boundary conditions of the anxiety/WMC association. The aim of this review is to critically evaluate the evidence for anxiety-related deficits in working memory capacity. First, a meta-analysis of 177 samples (N = 22,061 individuals) demonstrated that self-reported measures of anxiety are reliably related to poorer performance on measures of working memory capacity (g = -.334, p < 10-29). This finding was consistent across complex span (e.g., OSPAN; g = -.342, k = 30, N = 3,196, p = .000001), simple span (e.g., digit span; g = -.318, k = 127, N = 17,547, p < 10-17), and dynamic span tasks (e.g., N-Back; g = -.437, k = 20, N = 1,318, p = .000003). Second, a narrative review of the literature revealed that anxiety, whether self-reported or experimentally induced, is related to poorer performance across a wide variety of tasks. Finally, the review identified a number of methodological limitations common in the literature as well as avenues for future research. (PsycINFO Database Record PMID- 26963370 TI - Linking micellar structures to hydrogelation for salt-triggered dipeptide gelators. AB - Some functionalised dipeptides can form hydrogels when salts are added to solutions at high pH. We have used surface tension, conductivity, rheology, optical, confocal and scanning electron microscopy, (1)H NMR and UV-Vis spectroscopy measurements to characterise fully the phase behaviour of solutions of one specific gelator, 2NapFF, at 25 degrees C at pH 10.5. We show that this specific naphthalene-dipeptide undergoes structural transformations as the concentration is increased, initially forming spherical micelles, then worm-like micelles, followed by association of these worm-like micelles. On addition of a calcium salt, gels are generally formed as long as worm-like micelles are initially present in solution, although there are structural re-organisations that occur at lower concentrations, allowing gelation at lower than expected concentration. Using IR and SANS, we show the differences between the structures present in the solution and hydrogel phases. PMID- 26963371 TI - WITHDRAWN: Antidepressants for generalised anxiety disorder (GAD). PMID- 26963373 TI - Change in parent-child conflict and the HPA-axis: Where should we be looking and for how long? AB - OBJECTIVE: Salivary cortisol is increasingly used as a longitudinal indicator of change in neuroendocrine regulation and as a predictor of health outcomes in youth. The purpose of this study was to describe which indices of HPA-axis functioning are sensitive to changes in parent-child conflict over a three week period and to explore the time course under which these changes can be measured. METHODS: Youth (n=47; ages 8-13) completed daily diaries of their conflict with parents for 56 days. On days 17-18 and 38-39, youth contributed saliva samples upon waking, 30-minutes post-waking, afternoon, and bedtime. We assessed change in average diurnal HPA-axis functioning between day 17-18 and day 38-39 as a function of the slopes of change in parent-child conflict over 3 weeks. RESULTS: Increasing parent-child conflict was positively associated with concurrent increases in total cortisol output (AUCg), flattening of the diurnal slope, and increases in cortisol at bedtime, but not with change in the cortisol awakening response (CAR). Further, associations between parent-child conflict and both AUCg and bedtime cortisol were observed with at least 14 days of daily diary reporting, whereas any additional ratings of conflict beyond 3 days of daily diaries did not improve model fit for changes in diurnal slope. CONCLUSIONS: This study demonstrates the within-subject up-regulation of the HPA-axis across three weeks in a healthy sample of youth exposed to natural increases in family conflict. In particular, cortisol at bedtime may be the HPA-axis index that is most sensitive to change over time in parent-child conflict, above and beyond conflict occurring that day. Further, when testing associations between family stressors and diurnal cortisol, the optimal schedule for assessing parent-child conflict varies for different indices of HPA-axis functioning. PMID- 26963372 TI - Radiation-induced changes in DNA methylation of repetitive elements in the mouse heart. AB - DNA methylation is a key epigenetic mechanism, needed for proper control over the expression of genetic information and silencing of repetitive elements. Exposure to ionizing radiation, aside from its strong genotoxic potential, may also affect the methylation of DNA, within the repetitive elements, in particular. In this study, we exposed C57BL/6J male mice to low absorbed mean doses of two types of space radiation-proton (0.1 Gy, 150 MeV, dose rate 0.53 +/- 0.08 Gy/min), and heavy iron ions ((56)Fe) (0.5 Gy, 600 MeV/n, dose rate 0.38 +/- 0.06 Gy/min). Radiation-induced changes in cardiac DNA methylation associated with repetitive elements were detected. Specifically, modest hypomethylation of retrotransposon LINE-1 was observed at day 7 after irradiation with either protons or (56)Fe. This was followed by LINE-1, and other retrotransposons, ERV2 and SINE B1, as well as major satellite DNA hypermethylation at day 90 after irradiation with (56)Fe. These changes in DNA methylation were accompanied by alterations in the expression of DNA methylation machinery and affected the one-carbon metabolism pathway. Furthermore, loss of transposable elements expression was detected in the cardiac tissue at the 90-day time-point, paralleled by substantial accumulation of mRNA transcripts, associated with major satellites. Given that the one-carbon metabolism pathway can be modulated by dietary modifications, these findings suggest a potential strategy for the mitigation and, possibly, prevention of the negative effects exerted by ionizing radiation on the cardiovascular system. Additionally, we show that the methylation status and expression of repetitive elements may serve as early biomarkers of exposure to space radiation. PMID- 26963374 TI - Depressive symptoms are associated with worsened severity of the metabolic syndrome in African American women independent of lifestyle factors: A consideration of mechanistic links from the Jackson heart study. AB - BACKGROUND: Depression and the metabolic syndrome (MetS) are both risk factors for cardiovascular disease and type 2 diabetes mellitus. Prior studies in predominantly White populations demonstrated that individuals with depressive symptoms at baseline are more likely to develop future MetS. We tested the hypothesis that depressive symptoms would contribute to a more pronounced increase in MetS severity among African Americans in the Jackson Heart Study (JHS). METHODS: We used repeated-measures modeling among 1743 JHS participants during Visits 1-3 over 8 years of follow-up to evaluate relations between depressive symptom score (Center for Epidemiologic Survey-Depression (CES-D)) at baseline and a sex- and race/ethnicity-specific MetS severity Z-score at each visit. RESULTS: 20.3% of participants had a CES-D score >=16, consistent with clinically-relevant depressive symptoms. Higher depressive-symptom scores were associated with higher MetS severity in women but not men (p=0.005 vs. p=0.490). There was no difference by depressive symptom score with rate of change in MetS severity over time. Both depressive-symptom score and MetS severity Z-score were associated with lower levels of physical activity and higher levels of C-reactive protein; however, addition of these to the regression model did not attenuate the association between depressive symptoms and MetS severity. CONCLUSION: African American women but not men in the JHS exhibit relationships between baseline depressive symptoms and MetS severity over an 8-year period. These data may have implications for targeting of MetS-associated lifestyle changes among individuals with depressive symptoms. PMID- 26963375 TI - Recurrent short sleep, chronic insomnia symptoms and salivary cortisol: A 10-year follow-up in the Whitehall II study. AB - Although an association between both sleep duration and disturbance with salivary cortisol has been suggested, little is known about the long term effects of poor quality sleep on diurnal cortisol rhythm. The aim of this study was to examine the association of poor quality sleep, categorised as recurrent short sleep duration and chronic insomnia symptoms, with the diurnal release of cortisol. We examined this in 3314 participants from an occupational cohort, originally recruited in 1985-1989. Salivary cortisol was measured in 2007-2009 and six saliva samples were collected: (1) waking, (2) waking+0.5h, (3) +2.5h, (4) +8h, (5) +12h and (6) bedtime, for assessment of the cortisol awakening response and the diurnal slope in cortisol secretion. Participants with the first saliva sample collected within 15min of waking and not on steroid medication were examined. Short sleep duration (<=5h) and insomnia symptoms (Jenkins scale, highest quartile) were measured in 1997-1999, 2003-2004 and 2007-2009. Recurrent short sleep was associated with a flatter diurnal cortisol pattern. A steeper morning rise in cortisol was observed among those reporting chronic insomnia symptoms at three time points and among those reporting short sleep twice, compared to those who never reported sleep problems. Participants reporting short sleep on three occasions had higher levels of cortisol later in the day, compared to those never reporting short sleep, indicated by a positive interaction with hours since waking (beta=0.02 (95% CI: 0.01, 0.03)). We conclude that recurrent sleep problems are associated with adverse salivary cortisol patterns throughout the day. PMID- 26963376 TI - Examining multiple sleep behaviors and diurnal salivary cortisol and alpha amylase: Within- and between-person associations. AB - Sleep has been linked to the daily patterns of stress-responsive physiological systems, specifically the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). However, extant research examining sleep and diurnal patterns of cortisol, the primary end product of the HPA axis, has primarily focused on sleep duration with limited attention on other facets of sleep. For example, it is not clear how specific aspects of sleep (e.g., sleep quality, sleep duration variability) are related to specific components of diurnal cortisol rhythms. Salivary alpha-amylase (sAA) has been recognized as a surrogate marker of ANS activity, but limited research has explored relations between sleep and sAA diurnal rhythms. The current study utilized an ecological momentary assessment protocol to examine within- and between-person relations between several facets of sleep behavior using multiple methods (e.g., subjective report, actigraphy) and salivary cortisol and sAA. Older adolescents (N=76) provided saliva samples and diary entries five times per day over the course of three days. Sleep was assessed via questionnaire, through daily diaries, and monitored objectively using actigraphy over a four day period. Between-person results revealed that shorter average objective sleep duration and greater sleep duration variability were related to lower levels of waking cortisol and flatter diurnal slopes across the day. Within-person results revealed that on nights when individuals slept for shorter durations than usual they also had lower levels of waking cortisol the next day. Sleep was not related to the cortisol awakening response (CAR) or diurnal patterns of sAA, in either between-person or within person analyses. However, typical sleep behaviors measured via questionnaire were related to waking levels of sAA. Overall, this study provides a greater understanding of how multiple components of sleep, measured in naturalistic environments, are related to cortisol and sAA diurnal rhythms, and how day-to day, within-person changes in sleep duration contribute to daily variations in cortisol. PMID- 26963378 TI - Structure-based design and confirmation of peptide ligands for neuronal polo-like kinase to promote neuroregeneration. AB - Neuronal polo-like kinase (nPLK) is an essential regular of cell cycle and differentiation in nervous system, and targeting nPLK has been established as a promising therapeutic strategy to treat neurological disorders and to promote neuroregeneration. The protein contains an N-terminal kinase domain (KD) and a C terminal Polo-box domain (PBD) that are mutually inhibited by each other. Here, the intramolecular KD-PBD complex in nPLK was investigated at structural level via bioinformatics analysis, molecular dynamics (MD) simulation and binding affinity scoring. From the complex interface two regions representing separately two continuous peptide fragments in PBD domain were identified as the hot spots of KD-PBD interaction. Structural and energetic analysis suggested that one (PBD peptide 1) of the two peptides can bind tightly to a pocket nearby the active site of KD domain, which is thus potential as self-inhibitory peptide to target and suppress nPLK kinase activity. The knowledge harvesting from computational studies were then used to guide the structural optimization and mutation of PBD peptide 1. Consequently, two of three peptide mutants separately exhibited moderately and considerably increased affinity as compared to the native peptide. The computationally modeled complex structures of KD domain with these self inhibitory peptides were also examined in detail to unravel the structural basis and energetic property of nPLK-peptide recognition and interaction. PMID- 26963377 TI - Body Mass Index Is Better than Other Anthropometric Indices for Identifying Dyslipidemia in Chinese Children with Obesity. AB - BACKGROUND: Body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) are used in screening and predicting obesity in adults. However, the best identifier of metabolic complications in children with obesity remains unclear. This study evaluated lipid profile distribution and investigated the best anthropometric parameter in association with lipid disorders in children with obesity. METHODS: A total of 2243 school children aged 7-17 years were enrolled in Guangzhou, China, in 2014. The anthropometric indices and lipid profiles were measured. Dyslipidemia was defined according to the US Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. The association between anthropometry (BMI, WC, and WHR) and lipid profile values was examined using chi-square analysis and discriminant function analysis. Information about demography, physical activity, and dietary intake was provided by the participant children and their parents. RESULTS: Children aged 10-14 and 15-17 years old generally had higher triglyceride values but lower median concentration of total cholesterol, high-density lipoprotein cholesterol, and low density lipoprotein cholesterol compared with children aged 7-9 years old (all P < 0.001). These lipid parameters fluctuated in children aged 10-14 years old. The combination of age groups, BMI, WC and WHR achieved 65.1% accuracy in determining dyslipidemic disorders. BMI correctly identified 77% of the total dyslipidemic disorders in obese children, which was higher than that by WHR (70.8%) (P< 0.05). CONCLUSION: The distribution of lipid profiles in Chinese children differed between younger and older age groups, and the tendency of these lipid levels remarkably fluctuated during 10 to 14 years old. BMI had better practical utility in identifying dyslipidemia among school-aged children with obesity compared with other anthropometric measures. PMID- 26963379 TI - A computational model for predicting fusion peptide of retroviruses. AB - As a pivotal domain within envelope protein, fusion peptide (FP) plays a crucial role in pathogenicity and therapeutic intervention. Taken into account the limited FP annotations in NCBI database and absence of FP prediction software, it is urgent and desirable to develop a bioinformatics tool to predict new putative FPs (np-FPs) in retroviruses. In this work, a sequence-based FP model was proposed by combining Hidden Markov Method with similarity comparison. The classification accuracies are 91.97% and 92.31% corresponding to 10-fold and leave-one-out cross-validation. After scanning sequences without FP annotations, this model discovered 53,946 np-FPs. The statistical results on FPs or np-FPs reveal that FP is a conserved and hydrophobic domain. The FP software programmed for windows environment is available at https://sourceforge.net/projects/fptool/files/?source=navbar. PMID- 26963380 TI - Does Stigmatized Social Risk Lead to Denialism? Results from a Survey Experiment on Race, Risk Perception, and Health Policy in the United States. AB - In this article, we report findings from an original survey experiment investigating the effects of different framings of disease threats on individual risk perceptions and policy priorities. We analyze responses from 1,946 white and African-American participants in a self-administered, web-based survey in the United States. We sought to investigate the effects of: 1) frames emphasizing disparities in the racial prevalence of disease and 2) frames emphasizing non normative (blameworthy or stigmatized) behavioral risk factors. We find some evidence that when treated with the first frame, African-Americans are more likely to report higher risk of infection (compared to an African-American control group and to whites receiving the same treatment); and that whites are more likely to report trust in government data (compared to a White control group and to African-Americans receiving the same treatment). Notwithstanding, we find no support for our hypotheses concerning the interactive effects of providing both frames, which was a central motivation for our study. We argue that this may be due to very large differences in risk perception at baseline (which generate limits on possible treatment effects) and the fact that in the context of American race relations, it may not be possible to fully differentiate racialized and stigmatized frames. PMID- 26963383 TI - Can surface electromyography improve surgery planning? Electromyographic assessment and intraoperative verification of the nerve bundle entry point location of the gracilis muscle. AB - PURPOSE: To verify the precision of surface electromyography (sEMG) in locating the innervation zone of the gracilis muscle, by comparing the location of the IZ estimated by means of sEMG with in vivo location of the nerve bundle entry point in patients before graciloplasty procedure due to fecal incontinence. METHODS: Nine patients who qualified for the graciloplasty procedure underwent sEMG on both gracilis muscle before their operations. During surgery the nerve bundle was identified by means of electrical stimulation. The distance between the proximal attachment and the nerve entry point into the muscle's body was measured. Both measurements (sEMG and in vivo identification) were compared for each subject. RESULTS: On average, the IZ was located 65.5mm from the proximal attachment. The mean difference in location of the innervation zones in each individual was 10+/ 9.7mm, maximal - 30mm, the difference being statistically significant (p=0.017). It was intraoperatively confirmed, that the nerve entered the muscle an average of 62mm from the proximal attachment. The largest difference between the EMG IZ estimation and nerve bundle entry point was 5mm (mean difference 2.8mm, p=0.767). CONCLUSION: Preoperative surface electromyography of both gracilis muscles is a safe, precise and reliable method of assessing the location of the innervation zones of the gracilis muscles. The asymmetry of the IZ location in left and right muscles may be important in context of technical aspects of the graciloplasty procedure. PMID- 26963381 TI - Genomic Analysis of Companion Rabbit Staphylococcus aureus. AB - In addition to being an important human pathogen, Staphylococcus aureus is able to cause a variety of infections in numerous other host species. While the S. aureus strains causing infection in several of these hosts have been well characterised, this is not the case for companion rabbits (Oryctolagus cuniculus), where little data are available on S. aureus strains from this host. To address this deficiency we have performed antimicrobial susceptibility testing and genome sequencing on a collection of S. aureus isolates from companion rabbits. The findings show a diverse S. aureus population is able to cause infection in this host, and while antimicrobial resistance was uncommon, the isolates possess a range of known and putative virulence factors consistent with a diverse clinical presentation in companion rabbits including severe abscesses. We additionally show that companion rabbit isolates carry polymorphisms within dltB as described as underlying host-adaption of S. aureus to farmed rabbits. The availability of S. aureus genome sequences from companion rabbits provides an important aid to understanding the pathogenesis of disease in this host and in the clinical management and surveillance of these infections. PMID- 26963382 TI - Relaxin Treatment in an Ang-II-Based Transgenic Preeclamptic-Rat Model. AB - Relaxin is a peptide related to pregnancy that induces nitric oxide-related and gelatinase-related effects, allowing vasodilation and pregnancy-related adjustments permitting parturition to occur. Relaxin controls the hemodynamic and renovascular adaptive changes that occur during pregnancy. Interest has evolved regarding relaxin and a therapeutic principle in preeclampsia and heart failure. Preeclampsia is a pregnancy disorder, featuring hypertension, proteinuria and placental anomalies. We investigated relaxin in an established transgenic rat model of preeclampsia, where the phenotype is induced by angiotensin (Ang)-II production in mid pregnancy. We gave recombinant relaxin to preeclamtic rats at day 9 of gestation. Hypertension and proteinuria was not ameliorated after relaxin administration. Intrauterine growth retardation of the fetus was unaltered by relaxin. Heart-rate responses and relaxin levels documented drug effects. In this Ang-II-based model of preeclampsia, we could not show a salubrious effect on preeclampsia. PMID- 26963384 TI - The Annexin a2 Promotes Development in Arthritis through Neovascularization by Amplification Hedgehog Pathway. AB - The neovascularization network of pannus formation plays a crucial role in the development of rheumatoid arthritis (RA). Annexin a2 (Axna2) is an important mediating agent that induces angiogenesis in vascular diseases. The correlation between Axna2 and pannus formation has not been studied. Here, we provided evidence that compared to osteoarthritis (OA) patients and healthy people, the expression of Axna2 and Axna2 receptor (Axna2R) were up-regulated in patients with RA. Joint swelling, inflammation and neovascularization were increased significantly in mice with collagen-induced arthritis (CIA) that were exogenously added Axna2. Cell experiments showed that Axna2 promoted HUVEC proliferation by binding Axna2R, and could activate Hedgehog (HH) signaling and up-regulate the expression of Ihh and Gli. Besides, expression of Ihh, Patched (Ptc), Smoothened (Smo) and Gli and matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), angiogenic growth factor of HH signaling downstream, were down-regulated after inhibition of expression Axna2R on HUVEC. Together, our research definitely observed that over-expression of Axna2 could promote the development of CIA, especially during the process of pannus formation for the first time. Meanwhile, Axna2 depended on combining Axna2R to activate and enlarge HH signaling and the expression of its downstream VEGF, Ang-2 and MMP-2 to promote HUVEC proliferation, and eventually caused to angiogenesis. Therefore, the role of Axna2 is instructive for understanding the development of RA, suppress the effect of Axna2 might provide a new potential measure for treatment of RA. PMID- 26963387 TI - Periodontitis and Cognitive Decline in Alzheimer's Disease. AB - Periodontitis is common in the elderly and may become more common in Alzheimer's disease because of a reduced ability to take care of oral hygiene as the disease progresses. Elevated antibodies to periodontal bacteria are associated with an increased systemic pro-inflammatory state. Elsewhere raised serum pro inflammatory cytokines have been associated with an increased rate of cognitive decline in Alzheimer's disease. We hypothesized that periodontitis would be associated with increased dementia severity and a more rapid cognitive decline in Alzheimer's disease. We aimed to determine if periodontitis in Alzheimer's disease is associated with both increased dementia severity and cognitive decline, and an increased systemic pro inflammatory state. In a six month observational cohort study 60 community dwelling participants with mild to moderate Alzheimer's Disease were cognitively assessed and a blood sample taken for systemic inflammatory markers. Dental health was assessed by a dental hygienist, blind to cognitive outcomes. All assessments were repeated at six months. The presence of periodontitis at baseline was not related to baseline cognitive state but was associated with a six fold increase in the rate of cognitive decline as assessed by the ADAS-cog over a six month follow up period. Periodontitis at baseline was associated with a relative increase in the pro inflammatory state over the six month follow up period. Our data showed that periodontitis is associated with an increase in cognitive decline in Alzheimer's Disease, independent to baseline cognitive state, which may be mediated through effects on systemic inflammation. PMID- 26963385 TI - Pathway Implications of Aberrant Global Methylation in Adrenocortical Cancer. AB - CONTEXT: Adrenocortical carcinomas (ACC) are a rare tumor type with a poor five year survival rate and limited treatment options. OBJECTIVE: Understanding of the molecular pathogenesis of this disease has been aided by genomic analyses highlighting alterations in TP53, WNT, and IGF signaling pathways. Further elucidation is needed to reveal therapeutically actionable targets in ACC. DESIGN: In this study, global DNA methylation levels were assessed by the Infinium HumanMethylation450 BeadChip Array on 18 ACC tumors and 6 normal adrenal tissues. A new, non-linear correlation approach, the discretization method, assessed the relationship between DNA methylation/gene expression across ACC tumors. RESULTS: This correlation analysis revealed epigenetic regulation of genes known to modulate TP53, WNT, and IGF signaling, as well as silencing of the tumor suppressor MARCKS, previously unreported in ACC. CONCLUSIONS: DNA methylation may regulate genes known to play a role in ACC pathogenesis as well as known tumor suppressors. PMID- 26963389 TI - Maternal Genetic Composition of a Medieval Population from a Hungarian-Slavic Contact Zone in Central Europe. AB - The genetic composition of the medieval populations of Central Europe has been poorly investigated to date. In particular, the region of modern-day Slovakia is a blank spot in archaeogenetic research. This paper reports the study of mitochondrial DNA (mtDNA) in ancient samples from the 9th-12th centuries originating from the cemeteries discovered in Nitra-Sindolka and Cakajovce, located in western Slovakia (Central Europe). This geographical region is interesting to study because its medieval multi-ethnic population lived in the so called contact zone of the territory of the Great Moravian and later Hungarian state formations. We described 16 different mtDNA haplotypes in 19 individuals, which belong to the most widespread European mtDNA haplogroups: H, J, T, U and R0. Using comparative statistical and population genetic analyses, we showed the differentiation of the European gene pool in the medieval period. We also demonstrated the heterogeneous genetic characteristics of the investigated population and its affinity to the populations of modern Europe. PMID- 26963388 TI - Visuospatial Attention to Single and Multiple Objects Is Independently Impaired in Parkinson's Disease. AB - Parkinson's disease (PD) is associated with deficits in visuospatial attention. It is as yet unknown whether these attentional deficits begin at a perceptual level or instead reflect disruptions in oculomotor or higher-order processes. In the present study, non-demented individuals with PD and matched normal control adults (NC) participated in two tasks requiring sustained visuospatial attention, both based on a multiple object tracking paradigm. Eye tracking was used to ensure central fixation. In Experiment 1 (26 PD, 21 NC), a pair of identical red dots (one target, one distractor) rotated randomly for three seconds at varied speeds. The task was to maintain the identity of the sole target, which was labeled prior to each trial. PD were less accurate than NC overall (p = .049). When considering only trials where fixation was maintained, however, there was no significant group difference, suggesting that the deficit's origin is closely related to oculomotor processing. To determine whether PD had additional impairment in multifocal attention, in Experiment 2 (25 PD, 15 NC), two targets were presented along with distractors at a moderate speed, along with a control condition in which dots remained stationary. PD were less accurate than NC for moving (p = 0.02) but not stationary targets. This group difference remained significant when considering only trials where fixation was maintained, suggesting the source of the PD deficit was independent from oculomotor processing. Taken together, the results implicate separate mechanisms for single vs. multiple object tracking deficits in PD. PMID- 26963390 TI - Monitoring of Heart and Breathing Rates Using Dual Cameras on a Smartphone. AB - Some smartphones have the capability to process video streams from both the front and rear-facing cameras simultaneously. This paper proposes a new monitoring method for simultaneous estimation of heart and breathing rates using dual cameras of a smartphone. The proposed approach estimates heart rates using a rear facing camera, while at the same time breathing rates are estimated using a non contact front-facing camera. For heart rate estimation, a simple application protocol is used to analyze the varying color signals of a fingertip placed in contact with the rear camera. The breathing rate is estimated from non-contact video recordings from both chest and abdominal motions. Reference breathing rates were measured by a respiration belt placed around the chest and abdomen of a subject; reference heart rates (HR) were determined using the standard electrocardiogram. An automated selection of either the chest or abdominal video signal was determined by choosing the signal with a greater autocorrelation value. The breathing rate was then determined by selecting the dominant peak in the power spectrum. To evaluate the performance of the proposed methods, data were collected from 11 healthy subjects. The breathing ranges spanned both low and high frequencies (6-60 breaths/min), and the results show that the average median errors from the reflectance imaging on the chest and the abdominal walls based on choosing the maximum spectral peak were 1.43% and 1.62%, respectively. Similarly, HR estimates were also found to be accurate. PMID- 26963392 TI - Investigation of Adaptive Optics Imaging Biomarkers for Detecting Pathological Changes of the Cone Mosaic in Patients with Type 1 Diabetes Mellitus. AB - PURPOSE: To investigate a set of adaptive optics (AO) imaging biomarkers for the assessment of changes of the cone mosaic spatial arrangement in patients with type 1 diabetes mellitus (DM1). METHODS: 16 patients with >=20/20 visual acuity and a diagnosis of DM1 in the past 8 years to 37 years and 20 age-matched healthy volunteers were recruited in this study. Cone density, cone spacing and Voronoi diagrams were calculated on 160x160 MUm images of the cone mosaic acquired with an AO flood illumination retinal camera at 1.5 degrees eccentricity from the fovea along all retinal meridians. From the cone spacing measures and Voronoi diagrams, the linear dispersion index (LDi) and the heterogeneity packing index (HPi) were computed respectively. Logistic regression analysis was conducted to discriminate DM1 patients without diabetic retinopathy from controls using the cone metrics as predictors. RESULTS: Of the 16 DM1 patients, eight had no signs of diabetic retinopathy (noDR) and eight had mild nonproliferative diabetic retinopathy (NPDR) on fundoscopy. On average, cone density, LDi and HPi values were significantly different (P<0.05) between noDR or NPDR eyes and controls, with these differences increasing with duration of diabetes. However, each cone metric alone was not sufficiently sensitive to discriminate entirely between membership of noDR cases and controls. The complementary use of all the three cone metrics in the logistic regression model gained 100% accuracy to identify noDR cases with respect to controls. CONCLUSION: The present set of AO imaging biomarkers identified reliably abnormalities in the spatial arrangement of the parafoveal cones in DM1 patients, even when no signs of diabetic retinopathy were seen on fundoscopy. PMID- 26963393 TI - Anaphylaxis Imaging: Non-Invasive Measurement of Surface Body Temperature and Physical Activity in Small Animals. AB - In highly sensitized patients, the encounter with a specific allergen from food, insect stings or medications may rapidly induce systemic anaphylaxis with potentially lethal symptoms. Countless animal models of anaphylaxis, most often in BALB/c mice, were established to understand the pathophysiology and to prove the safety of different treatments. The most common symptoms during anaphylactic shock are drop of body temperature and reduced physical activity. To refine, improve and objectify the currently applied manual monitoring methods, we developed an imaging method for the automated, non-invasive measurement of the whole-body surface temperature and, at the same time, of the horizontal and vertical movement activity of small animals. We tested the anaphylaxis imaging in three in vivo allergy mouse models for i) milk allergy, ii) peanut allergy and iii) egg allergy. These proof-of-principle experiments suggest that the imaging technology represents a reliable non-invasive method for the objective monitoring of small animals during anaphylaxis over time. We propose that the method will be useful for monitoring diseases associated with both, changes in body temperature and in physical behaviour. PMID- 26963391 TI - The Role of Epithelial Sodium Channel ENaC and the Apical Cl-/HCO3- Exchanger Pendrin in Compensatory Salt Reabsorption in the Setting of Na-Cl Cotransporter (NCC) Inactivation. AB - BACKGROUND: The absence of NCC does not cause significant salt wasting in NCC deficient mice under basal conditions. We hypothesized that ENaC and pendrin play important roles in compensatory salt absorption in the setting of NCC inactivation, and their inhibition and/or downregulation can cause significant salt wasting in NCC KO mice. METHODS: WT and NCC KO mice were treated with a daily injection of either amiloride, an inhibitor of ENaC, or acetazolamide (ACTZ), a blocker of salt and bicarbonate reabsorption in the proximal tubule and an inhibitor of carbonic anhydrases in proximal tubule and intercalated cells, or a combination of acetazolamide plus amiloride for defined durations. Animals were subjected to daily balance studies. At the end of treatment, kidneys were harvested and examined. Blood samples were collected for electrolytes and acid base analysis. RESULTS: Amiloride injection significantly increased the urine output (UO) in NCC KO mice (from 1.3 ml/day before to 2.5 ml/day after amiloride, p<0.03, n = 4) but caused only a slight change in UO in WT mice (p>0.05). The increase in UO in NCC KO mice was associated with a significant increase in sodium excretion (from 0.25 mmol/24 hrs at baseline to 0.35 mmol/24 hrs after amiloride injection, p<0.05, n = 4). Daily treatment with ACTZ for 6 days resulted in >80% reduction of kidney pendrin expression in both WT and NCC KO mice. However, ACTZ treatment noticeably increased urine output and salt excretion only in NCC KO mice (with urine output increasing from a baseline of 1.1 ml/day to 2.3 ml/day and sodium excretion increasing from 0.22 mmole/day before to 0.31 mmole/day after ACTZ) in NCC KO mice; both parameters were significantly higher than in WT mice. Western blot analysis demonstrated significant enhancement in ENaC expression in medulla and cortex of NCC KO and WT mice in response to ACTZ injection for 6 days, and treatment with amiloride in ACTZ-pretreated mice caused a robust increase in salt excretion in both NCC KO and WT mice. Pendrin KO mice did not display a significant increase in urine output or salt excretion after treatment with amiloride or ACTZ. CONCLUSION: 1. ENaC plays an important role in salt reabsorption in NCC KO mice. 2. NCC contributes to compensatory salt reabsorption in the setting of carbonic anhydrase inhibition, which is associated with increased delivery of salt from the proximal tubule and the down regulation of pendrin. 3. ENaC is upregulated by ACTZ treatment and its inhibition by amiloride causes significant diuresis in NCC KO and WT mice. Despite being considered mild agents individually, we propose that the combination of acetazolamide and amiloride in the setting of NCC inhibition (i.e., hydrochlorothiazide) will be a powerful diuretic regimen. PMID- 26963394 TI - SMOG 2: A Versatile Software Package for Generating Structure-Based Models. AB - Molecular dynamics simulations with coarse-grained or simplified Hamiltonians have proven to be an effective means of capturing the functionally important long time and large-length scale motions of proteins and RNAs. Originally developed in the context of protein folding, structure-based models (SBMs) have since been extended to probe a diverse range of biomolecular processes, spanning from protein and RNA folding to functional transitions in molecular machines. The hallmark feature of a structure-based model is that part, or all, of the potential energy function is defined by a known structure. Within this general class of models, there exist many possible variations in resolution and energetic composition. SMOG 2 is a downloadable software package that reads user-designated structural information and user-defined energy definitions, in order to produce the files necessary to use SBMs with high performance molecular dynamics packages: GROMACS and NAMD. SMOG 2 is bundled with XML-formatted template files that define commonly used SBMs, and it can process template files that are altered according to the needs of each user. This computational infrastructure also allows for experimental or bioinformatics-derived restraints or novel structural features to be included, e.g. novel ligands, prosthetic groups and post-translational/transcriptional modifications. The code and user guide can be downloaded at http://smog-server.org/smog2. PMID- 26963395 TI - Low Herbivory among Targeted Reforestation Sites in the Andean Highlands of Southern Ecuador. AB - Insect herbivory constitutes an important constraint in the viability and management of targeted reforestation sites. Focusing on young experimental stands at about 2000 m elevation in southern Ecuador, we examined foliar damage over one season as a function of tree species and habitat. Native tree species (Successional hardwood: Cedrela montana and Tabebuia chrysantha; fast-growing pioneer: Heliocarpus americanus) have been planted among prevailing local landcover types (abandoned pasture, secondary shrub vegetation, and a Pinus patula plantation) in 2003/4. Plantation trees were compared to conspecifics in the spontaneous undergrowth of adjacent undisturbed rainforest matched for height and foliar volume. Specifically, we tested the hypotheses that H. americanus as a pioneer species suffers more herbivory compared to the two successional tree species, and that damage is inversely related to habitat complexity. Overall leaf damage caused by folivorous insects (excluding leafcutter ants) was low. Average leaf loss was highest among T. chrysantha (7.50% +/- 0.19 SE of leaf area), followed by H. americanus (4.67% +/- 0.18 SE) and C. montana (3.18% +/- 0.15 SE). Contrary to expectations, leaf area loss was highest among trees in closed-canopy natural rainforest, followed by pine plantation, pasture, and secondary shrub sites. Harvesting activity of leafcutter ants (Acromyrmex sp.) was strongly biased towards T. chrysantha growing in open habitat (mean pasture: 2.5%; shrub: 10.5%) where it could result in considerable damage (> 90.0%). Insect folivory is unlikely to pose a barrier for reforestation in the tropical Andean mountain forest zone at present, but leafcutter ants may become problematic if local temperatures increase in the wake of global warming. PMID- 26963396 TI - Patterns and Trends in Accidental Poisoning Deaths: Pennsylvania's Experience 1979-2014. AB - INTRODUCTION: The purpose of this study was to examine county and state-level accidental poisoning mortality trends in Pennsylvania from 1979 to 2014. METHODS: Crude and age-adjusted death rates were formed for age group, race, sex, and county for accidental poisonings (ICD 10 codes X40-X49) from 1979 to 2014 for ages 15+ using the Mortality and Population Data System housed at the University of Pittsburgh. Rate ratios were calculated comparing rates from 1979 to 2014, overall and by sex, age group, and race. Joinpoint regression was used to detect statistically significant changes in trends of age-adjusted mortality rates. RESULTS: Rate ratios for accidental poisoning mortality in Pennsylvania increased more than 14-fold from 1979 to 2014. The largest rate ratios were among 35-44 year olds, females, and White adults. The highest accidental poisoning mortality rates were found in the counties of Southwestern Pennsylvania, those surrounding Philadelphia, and those in Northeast Pennsylvania near Scranton. CONCLUSIONS: The patterns and locations of accidental poisoning mortality by race, sex, and age group provide direction for interventions and policy makers. In particular, this study found the highest rate ratios in PA among females, whites, and the age group 35-44. PMID- 26963397 TI - Understanding Spatio-Temporal Variability in the Reproduction Ratio of the Bluetongue (BTV-1) Epidemic in Southern Spain (Andalusia) in 2007 Using Epidemic Trees. AB - Andalusia (Southern Spain) is considered one of the main routes of introduction of bluetongue virus (BTV) into Europe, evidenced by a devastating epidemic caused by BTV-1 in 2007. Understanding the pattern and the drivers of BTV-1 spread in Andalusia is critical for effective detection and control of future epidemics. A long-standing metric for quantifying the behaviour of infectious diseases is the case-reproduction ratio (Rt), defined as the average number of secondary cases arising from a single infected case at time t (for t>0). Here we apply a method using epidemic trees to estimate the between-herd case reproduction ratio directly from epidemic data allowing the spatial and temporal variability in transmission to be described. We then relate this variability to predictors describing the hosts, vectors and the environment to better understand why the epidemic spread more quickly in some regions or periods. The Rt value for the BTV 1 epidemic in Andalusia peaked in July at 4.6, at the start of the epidemic, then decreased to 2.2 by August, dropped below 1 by September (0.8), and by October it had decreased to 0.02. BTV spread was the consequence of both local transmission within established disease foci and BTV expansion to distant new areas (i.e. new foci), which resulted in a high variability in BTV transmission, not only among different areas, but particularly through time, which suggests that general control measures applied at broad spatial scales are unlikely to be effective. This high variability through time was probably due to the impact of temperature on BTV transmission, as evidenced by a reduction in the value of Rt by 0.0041 for every unit increase (day) in the extrinsic incubation period (EIP), which is itself directly dependent on temperature. Moreover, within the range of values at which BTV-1 transmission occurred in Andalusia (20.6 degrees C to 29.5 degrees C) there was a positive correlation between temperature and Rt values, although the relationship was not linear, probably as a result of the complex relationship between temperature and the different parameters affecting BTV transmission. Rt values for BTV-1 in Andalusia fell below the threshold of 1 when temperatures dropped below 21 degrees C, a much higher threshold than that reported in other BTV outbreaks, such as the BTV-8 epidemic in Northern Europe. This divergence may be explained by differences in the adaptation to temperature of the main vectors of the BTV-1 epidemic in Andalusia (Culicoides imicola) compared those of the BTV 8 epidemic in Northern Europe (Culicoides obsoletus). Importantly, we found that BTV transmission (Rt value) increased significantly in areas with higher densities of sheep. Our analysis also established that control of BTV-1 in Andalusia was complicated by the simultaneous establishment of several distant foci at the start of the epidemic, which may have been caused by several independent introductions of infected vectors from the North of Africa. We discuss the implications of these findings for BTV surveillance and control in this region of Europe. PMID- 26963398 TI - Psychometric properties of a Mandarin version of the tinnitus questionnaire. AB - OBJECTIVE: To develop a Mandarin version of the tinnitus questionnaire (MTQ) and determine the reliability and validity, and to assess whether it could be used clinically in the Chinese population. DESIGN: The MTQ, short-form (36) health survey, hospital anxiety and depression scale, Mandarin (Chinese) tinnitus handicap inventory, and visual analogue scale were completed by the participants. STUDY SAMPLE: We included 192 adults seeking treatment for primary or secondary tinnitus. RESULTS: Five factors, namely, emotional distress, auditory perceptual difficulties, cognitive distress, sleep disturbance, and intrusiveness, were extracted from the MTQ. Thirty-seven items were included. The MTQ had high test retest reliability (Spearman correlation coefficients: 0.87-1.00). The MTQ and its subscales had good internal consistency and reliability (total alpha = 0.93, subscales alpha = 0.71-0.86). A single measure of severity can be acquired by summing the five subscale scores. The MTQ was significantly correlated with psychological distress and tinnitus-related handicap. CONCLUSION: Our results demonstrated that the MTQ is a reliable and valid measure of tinnitus-related psychopathological symptoms and could be used clinically to evaluate tinnitus related psychological problems. Questionnaires designed to explore tinnitus related depression and other symptoms not covered by the scope of the MTQ are needed. PMID- 26963408 TI - CDR3 motif generation and selection in the BV19-utilizing subset of the human CD8 T cell repertoire. AB - The amino acids at the V-J rearrangement junction of TCR are encoded by the D region and by N or P nucleotides. Together they comprise the NDN region, the specific pMHC selection surface of the TCR beta-chain. As an extension of our earlier work on the recall response to influenza M158-66 in HLA-A2 individuals, we have been analyzing the circulating BV19 CD8 T cell repertoires. We observed that NDN regions of the CDR3 often start at positions that are V-region encoded. Here we examine NDN encoded amino acid motifs of BV19 rearrangements in circulating CD8 T cells based on the CDR3 length, the CDR3 start position of the NDN, and the motif length. Motifs that start at V region-encoded positions could be expected to be CDR3 length independent as indeed is the case. Motifs that included sequential proline and glycine showed a CDR3 length independent distribution and examining codon usage indicates that a large proportion of these can be explained by P-nucleotide addition from the 5' end of the D region. Other examples of skewed codon usage were observed indicating possible additional rearrangement mechanisms. Another pattern of motif distributions was a shift of position along the CDR3 as a function of the CDR3 length. As these data were collected from an older healthy individual they can be used to model successful repertoire selection and to further define characteristics associated with a positive history of responses to pathogen exposures. PMID- 26963409 TI - Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. AB - The formation of SCFA is the result of a complex interplay between diet and the gut microbiota within the gut lumen environment. The discovery of receptors, across a range of cell and tissue types for which short chain fatty acids SCFA appear to be the natural ligands, has led to increased interest in SCFA as signaling molecules between the gut microbiota and the host. SCFA represent the major carbon flux from the diet through the gut microbiota to the host and evidence is emerging for a regulatory role of SCFA in local, intermediary and peripheral metabolism. However, a lack of well-designed and controlled human studies has hampered our understanding of the significance of SCFA in human metabolic health. This review aims to pull together recent findings on the role of SCFA in human metabolism to highlight the multi-faceted role of SCFA on different metabolic systems. PMID- 26963411 TI - [Chemotherapy-related Cognitive Impairment and Quality of Life in People with Colon Cancer: The Mediating Effect of Psychological Distress]. AB - PURPOSE: The purpose of this study was to test the mediating effect of psychological distress in the relationship between chemotherapy related cognitive impairment (CRCI) and quality of life (QOL) in people with cancer. METHODS: A purposive sample of 130 patients undergoing chemotherapy was recruited for the cross-sectional survey design. Data were collected from November 2014 to June 2015. The instruments were K-MMSE (Korean Mini-Mental State Examination), Everyday Cognition (ECog), Hospital Anxiety Depression Scale (HADS), and Functional Assessment of Cancer Therapy-General (FACT-G). Data were analyzed using descriptive statistics, correlation, and multiple regression using Baron and Kenny steps for mediation. RESULTS: The mean score for objective cognitive function was 27.95 and 69.32 for perceived cognitive decline. Overall quality of life was 91.74. The mean score was 17.52 for psychological distress. The prevalence was 56.2% for anxiety and 63.1% for depression, and 20.0% for CRCI. There were significant correlations among the variables, objective cognitive function and self-reported cognitive decline, psychological distress, and quality of life. Psychological distress was directly affected by CRCI. (R2=29%). QOL was directly affected by CRCI. Psychological distress and CRCI effected QOL (R2=43%). Psychological distress had a partial mediating effect (beta=-.56, p<.001) in the relationship between self-reported cognitive decline and quality of life (Sobel test: Z=-5.08, p<.001). CONCLUSION: Based on the findings of this study, nursing intervention programs focusing on managing cognitive decline, and decreasing psychological distress are highly recommended to improve quality of life in cancer patients. PMID- 26963410 TI - [Correlates of Cognitive Impairment of Rheumatic Disease: Systematic Review and Meta-analysis]. AB - PURPOSE: This study was conducted to synthesis the results of research on relationships of cognitive impairment with multi-dimensional correlates of rheumatic disease through a systematic literature review and meta-analysis. METHODS: For the study purpose, 23 studies were selected through a systematic process of searching the literature. RESULTS: The study results showed that among general characteristics, age and education were the variables having a significant relationship with cognitive impairment. Among health risk factors, obesity appeared to have a significant positive relationship with cognitive impairment. For past history, diabetes and hypertension were shown to have a significant positive relationship with cognitive impairment. It was noted also that aPL, one of the physiological factor, had significant association with cognitive impairment. None of the medication related factors had a significant relationship with cognitive impairment. Results showed that among disease related factors, disease activity had the highest relationship with cognitive impairment. Depression, among psychological factors, was the only variable having a significant relationship with cognitive impairment. CONCLUSION: The findings indicate that the variables strongly impacting on cognitive impairment in rheumatic disease are depression and disease activity. PMID- 26963412 TI - [Reliability and Validity of the Korean Version of the Perinatal Post-Traumatic Stress Disorder Questionnaire]. AB - PURPOSE: The Perinatal Post-Traumatic Stress Disorder Questionnaire (PPQ) was designed to measure post-traumatic symptoms related to childbirth and symptoms during postnatal period. The purpose of this study was to develop a translated Korean version of the PPQ and to evaluate reliability and validity of the Korean PPQ. METHODS: Participants were 196 mothers at one to 18 months after giving childbirth and data were collected through e-mails. The PPQ was translated into Korean using translation guideline from World Health Organization. For this study Cronbach's alpha and split-half reliability were used to evaluate the reliability of the PPQ. Exploratory Factor Analysis (EFA), Confirmatory Factor Analysis (CFA), and known-group validity were conducted to examine construct validity. Correlations of the PPQ with Impact of Event Scale (IES), Beck Depression Inventory II (BDI-II), and Beck Anxiety Inventory (BAI) were used to test a criterion validity of the PPQ. RESULTS: Cronbach's alpha and Spearman-Brown split half correlation coefficient were 0.91 and 0.77, respectively. EFA identified a 3 factor solution including arousal, avoidance, and intrusion factors and CFA revealed the strongest support for the 3-factor model. The correlations of the PPQ with IES, BDI-II, and BAI were .99, .60, and .72, respectively, pointing to criterion validity of a high level. CONCLUSION: The Korean version PPQ is a useful tool for screening and assessing mothers' experiencing emotional distress related to child birth and during the postnatal period. The PPQ also reflects Post Traumatic Stress Disorder's diagnostic standards well. PMID- 26963413 TI - [Development of Patient Transfer Techniques based on Postural-stability Principles for the Care Helpers in Nursing Homes and Evaluation of Effectiveness]. AB - PURPOSE: This study was done to develop a postural-stability patient transfer technique for care helpers in nursing homes and to evaluate its effectiveness. METHODS: Four types of patient transfer techniques (Lifting towards the head board of the bed, turning to the lateral position, sitting upright on the bed, transferring from wheel chair to bed) were practiced in accordance with the following three methods; Care helpers habitually used transfer methods (Method 1), patient transfer methods according to care helper standard textbooks (Method 2), and a method developed by the author ensuring postural-stability (Method 3). The care helpers' muscle activity and four joint angles were measured. The collected data were analyzed using the program SPSS Statistic 21.0. To differentiate the muscle activity and joint angle, the Friedman test was executed and the post-hoc analysis was conducted using the Wilcoxon Signed Rank test. RESULTS: Muscle activity was significantly lower during Method 3 compared to Methods 1 and 2. In addition, the joint angle was significantly lower for the knee and shoulder joint angle while performing Method 3 compared to Methods 1 and 2. DISCUSSION: Findings indicate that using postural-stability patient transfer techniques can contribute to the prevention of musculoskeletal disease which care helpers suffer from due to physically demanding patient care in nursing homes. PMID- 26963414 TI - [A Study on the Knowledge Structure of Cancer Survivors based on Social Network Analysis]. AB - PURPOSE: The purpose of this study was to identify the knowledge structure of cancer survivors. METHODS: For data, 1099 articles were collected, with 365 keywords as a Noun phrase extracted from the articles and standardized for analyzing. Co-occurrence matrix were generated via a cosine similarity measure, and then the network analysis and visualization using PFNet and NodeXL were applied to visualize intellectual interchanges among keywords. RESULTS: According to the result of the content analysis and the cluster analysis of author keywords from cancer survivors articles, keywords such as 'quality of life', 'breast neoplasms', 'cancer survivors', 'neoplasms', 'exercise' had a high degree centrality. The 9 most important research topics concerning cancer survivors were 'cancer-related symptoms and nursing', 'cancer treatment-related issues', 'late effects', 'psychosocial issues', 'healthy living managements', 'social supports', 'palliative cares', 'research methodology', and 'research participants'. CONCLUSION: Through this study, the knowledge structure of cancer survivors was identified. The 9 topics identified in this study can provide useful research direction for the development of nursing in cancer survivor research areas. The Network analysis used in this study will be useful for identifying the knowledge structure and identifying general views and current cancer survivor research trends. PMID- 26963415 TI - [Development of a Korean Geriatric Suicidal Risk Scale (KGSRS)]. AB - PURPOSE: Increase in suicide rate for senior citizens which has become widespread in our society today. It is not a normal social phenomenon and is beyond the danger level. The contents of this study include Korean senior citizens' suicide related risk factors and warning signs, and the development of a simple Geriatric Suicide Risk Scale. METHODS: This study is Methodological Research to verify reliability and validity of the Geriatric Suicide Risk Scale according to the tool development process suggested by Devellis (2012). RESULTS: For predictive validity assessment, high suicide screening accuracy was showed with an Area under the ROC curve (AUC) of .93. For the optimal cutoff point of 11, sensitivity was 93.9%, and specificity, 75.7% which are excellence levels. Cross validity for assessment of generalization possibility showed the Area under the ROC curve (AUC) as .82 and in case of a cutoff point of 11, sensitivity was 73.7%, and specificity, 65.9%. CONCLUSION: When it comes to practical nursing, it is significant that the Korean Geriatric Suicide Risk Scale has high reliability and validity through adequate tool development and the tool assessment step to select degree of suicide risk of senior citizens. Also, it can be easily applied and does not take a long time to administer. Further, it can be used by health care personnel or the general public. PMID- 26963416 TI - [Development of a Wellness Index for Workers]. AB - PURPOSE: The purpose of this study was to develop a wellness index for workers (WIW) and examine the validity and reliability of the WIW for assessing workers' wellness. METHODS: The developmental process for the instrument included construction of a conceptual framework based on a wellness model, generation of initial items, verification of content validity, preliminary study, extraction of final items, and psychometric testing. Content validity was verified by 4 experts from occupational health nursing and wellness disciplines. The construct validity, convergent validity and discriminant validity were examined with confirmatory factor analysis. The reliability was examined with Cronbach's alpha. The participants were 494 workers from two workplaces. RESULTS: Eighteen items were selected for the final scale, and the results of the confirmatory factor analysis supported a five-factor model of wellness with acceptable model fit, and factors named as physical . emotional . social . intellectual . occupational wellness. The convergent and discriminant validity were also supported. The Cronbach's alpha coefficient was .91. CONCLUSION: The results indicate that the WIW is a valid and reliable instrument to comprehensively assess workers' wellness, and to provide basic directions for developing workplace wellness program. PMID- 26963417 TI - [Effects of a Hospital Based Follow-Up Program for Mothers with Very Low Birth Weight Infants]. AB - PURPOSE: This paper reports the results of a hospital centered follow-up program on parenting stress, parenting efficacy and coping for mothers with very low birth weight (VLBW) infants. METHODS: The follow-up program consisted of home visiting by an expert group and self-help program for 1 year. A non-equivalent control group pre-post quasi-experimental design was used. Participants were 70 mothers with low birth weight infants and were assigned to one of two groups, an experimental groups (n=28), which received the family support program; and a control group (n=27), which received the usual discharge education. Data were analyzed using chi2-test, t-test, and ANCOVA with IBM SPSS statistics 20.0. RESULTS: Mothers' parenting stress (F=5.66, p=.004) was significantly decreased in the experimental group. There were also significant increases in parenting efficacy (F=13.05, p<.001) and coping (F=8.91, p=.002) in the experimental group. CONCLUSION: The study findings suggest that a follow-up program for mothers with VLBW infants is an effective intervention to decrease mothers' parenting stress and to enhance parenting efficacy and coping. PMID- 26963418 TI - [Effects of Learning Activities on Application of Learning Portfolio in Nursing Management Course]. AB - PURPOSE: This study was conducted to examine effects of a learning portfolio by identifying the learning of nursing students taking a learning portfolio-utilized nursing management class. METHODS: A non-equivalent control group pretest posttest design was used. Participants were 83 senior students taking the nursing management course in one of the Departments of Nursing at 2 Universities. Experimental group (n=42) received a learning portfolio-utilized nursing management class 15 times over 15 weeks (3 hours weekly). Self-directed learning abilities, approaches to learning and learning flow of the participants were examined with self-report structured questionnaires. Data were collected between September 2 and December 16, 2014, and were analyzed using chi-square test, Fisher's exact test, independent t-test and ANCOVA with SPSS/PC version 21.0. RESULTS: After the intervention the experimental group showed significant increases in self-directed learning abilities, deep approaches to learning and learning flow compared to the control group. However, no significant difference was found between groups for surface approaches to learning. CONCLUSION: Learning activities using the learning portfolios could be effective in cultivating the learning competency for growth of knowledge, technology and professionalism by increasing personal concentration and organization ability of the nursing students so that they can react to the rapidly changing environment. PMID- 26963419 TI - [Influence of Nurse Managers' Authentic Leadership on Nurses' Organizational Commitment and Job Satisfaction: Focused on the Mediating Effects of Empowerment]. AB - PURPOSE: The aim of this study was to examine the mediating effect of empowerment in the relationship of nurse managers' authentic leadership, with nurses' organizational commitment and job satisfaction. METHODS: The participants in this study were 273 registered nurses working in five University hospitals located in Seoul and Gyeonggi Province. The measurements included the Authentic Leadership Questionnaire, Condition of Work Effectiveness Questionnaire-II, Organizational Commitment Questionnaire and Korea-Minnesota Satisfaction Questionnaire. Data were analyzed using t-test, ANOVA, Scheffe test, Pearson correlation coefficients, simple and multiple regression techniques with the SPSS 18.0 program. Mediation analysis was performed according to the Baron and Kenny method and Sobel test. RESULTS: There were significant correlations among authentic leadership, empowerment, organizational commitment and job satisfaction. Empowerment showed perfect mediating effects in the relationship between authentic leadership and organizational commitment. It had partial mediating effects in the relationship between authentic leadership and job satisfaction. CONCLUSION: In this study, nurse managers' authentic leadership had significant influences on nurses organizational commitment and job satisfaction via empowerment. Therefore, to enhance nurses' organizational commitment and job satisfaction, it is necessary to build effective strategies to enhance nurse manager's authentic leadership and to develop empowering education programs for nurses. PMID- 26963420 TI - [Psychometric Properties and Item Evaluation of Korean Version of Night Eating Questionnaire (KNEQ)]. AB - PURPOSE: The aim of this study was to develop a Korean version of Night Eating Questionnaire (KNEQ) and test its psychometric properties and evaluate items according to item response theory. METHODS: The 14-item NEQ as a measure of severity of the night eating syndrome was translated into Korean, and then this KNEQ was evaluated. A total of 1171 participants aged 20 to 50 completed the KNEQ on the Internet. To test reliability and validity, Cronbach's alpha, correlation, simple regression, and factor analysis were used. Each item was analyzed according to Rasch-Andrich rating scale model and item difficulty, discrimination, infit/outfit, and point measure correlation were evaluated. RESULTS: Construct validity was evident. Cronbach's alpha was .78. The items of evening hyperphagia and nocturnal ingestion showed high ability in discriminating people with night eating syndrome, while items of morning anorexia and mood/sleep provided relatively little information. The results of item analysis showed that item2 and item7 needed to be revised to improve the reliability of KNEQ. CONCLUSION: KNEQ is an appropriate instrument to measure severity of night eating syndrome with good validity and reliability. However, further studies are needed to find cut-off scores to screen persons with night eating syndrome. PMID- 26963421 TI - [Structural Equation Modeling for Public Hospital Quality of Care, Image, Role Performance, Satisfaction, Intent to (Re)visit, and Intent to Recommend Hospital as Perceived by Community Residents]. AB - PURPOSE: The study purposes were to construct and test structural equation modeling on the causal relationship of community residents' perceived quality of care, image, and role performance with satisfaction, intention to (re)visit and intention to recommend hospital. METHODS: A cross-sectional survey was conducted with 3,900 community residents from 39 district public hospitals. The questionnaire was designed to collected information on personal characteristics and community awareness of public hospitals. Community awareness consisted of 6 factors and 18 items. The data were collected utilizing call-interview by a survey company. Research data were collected via questionnaires and analyzed using SPSS version 20.0 and AMOS version 20.0. RESULTS: Model fit indices for the hypothetical model were suitable for the recommended level: chi2=796.40 (df=79, p<.001), GFI=.93, AGFI=.90, RMSR=.08, NFI=.94. Quality of care, image, and role performance explained 68.1% of variance in community awareness. Total effect of quality of care process factors on satisfaction (path coefficients=3.67), intention to (re)visit (path coefficients=2.67) and intention to recommend hospital (coefficients=2.45) were higher than other factors. CONCLUSION: Findings show that public hospitals have to make an effort to improve community image through the provision of quality care, and excellent role performance. Support for these activities is available from both Central and Local Governments. PMID- 26963423 TI - [The Effects of Urban Forest-walking Program on Health Promotion Behavior, Physical Health, Depression, and Quality of Life: A Randomized Controlled Trial of Office-workers]. AB - PURPOSE: This study was performed to determine the physical and psychological effects of an urban forest-walking program for office workers. For many workers, sedentary lifestyles can lead to low levels of physical activity causing various health problems despite an increased interest in health promotion. METHODS: Fifty four office workers participated in this study. They were assigned to two groups (experimental group and control group) in random order and the experimental group performed 5 weeks of walking exercise based on Information-Motivation-Behavioral skills Model. The data were collected from October to November 2014. SPSS 21.0 was used for the statistical analysis. RESULTS: The results showed that the urban forest walking program had positive effects on the physical activity level (U=65.00, p<.001), health promotion behavior (t=-2.20, p=.033), and quality of life (t=-2.42, p=.020). However, there were no statistical differences in depression, waist size, body mass index, blood pressure, or bone density between the groups. CONCLUSION: The current findings of the study suggest the forest walking program may have positive effects on improving physical activity, health promotion behavior, and quality of life. The program can be used as an effective and efficient strategy for physical and psychological health promotion for office workers. PMID- 26963422 TI - [Effects of an Individual Breast-feeding Promotion Program for Married Immigrant Women]. AB - PURPOSE: This study was designed to evaluate the effects of an individual breast feeding promotion program to address breast-feeding knowledge, attitude, method and rate of practice for married immigrant women. METHODS: A non-equivalent control group quasi-experimental design was used (experimental group=16, control group=17). The intervention consisted of 3 phases: (1) Within 2 hours of delivery - individual breast-feeding training through video/verbal/practical training education and demonstration (2) After 1~2 days - group training using video, model doll, and breast models (3) After 7 days - family visit, counseling, retraining and reinforcement training. The data were analyzed using non parametric tests with the SPSS program. RESULTS: Married immigrant women who participated in the individual breast-feeding program scored high in knowledge, attitude, method and rate of practice compared to the control group. CONCLUSION: The results indicate that the individual breast-feeding program is very effective in increasing breast-feeding knowledge, attitude, method and rate of practicing breast feeding for married immigrant women. So, nurses are encouraged to aggressively utilize individual breast-feeding programs to help married immigrant women, who are exposed to vulnerability due to various situations. PMID- 26963424 TI - [Development of Korean Intensive Care Delirium Screening Tool (KICDST)]. AB - PURPOSE: This study was done to develop of the Korean intensive care delirium screening tool (KICDST). METHODS: The KICDST was developed in 5 steps: Configuration of conceptual frame, development of preliminary tool, pilot study, reliability and validity test, development of final KICDST. Reliability tests were done using degree of agreement between evaluators and internal consistency. For validity tests, CVI (Content Validity Index), ROC (Receiver Operating Characteristics) analysis, known group technique and factor analysis were used. RESULTS: In the reliability test, the degree of agreement between evaluators showed .80~1.00 and the internal consistency was KR-20=.84. The CVI was .83~1.00. In ROC analysis, the AUC (Area Under the ROC Curve) was .98. Assessment score was 4 points. The values for sensitivity, specificity, correct classification rate, positive predictive value, and negative predictive value were found to be 95.0%, 93.7%, 94.4%, 95.0% and 93.7%, respectively. In the known group technique, the average delirium screening tool score of the non-delirium group was 1.25+/-0.99 while that of delirium group was 5.07+/-1.89 (t=-16.33, p<.001). The factors were classified into 3 factors (cognitive change, symptom fluctuation, psychomotor retardation), which explained 67.4% of total variance. CONCLUSION: Findings show that the KICDST has high sensitivity and specificity. Therefore, this screening tool is recommended for early identification of delirium in intensive care patients. PMID- 26963425 TI - Residues of carbosulfan and its metabolites carbofuran and 3-hydroxy carbofuran in rice field ecosystem in China. AB - The fate of carbosulfan (seed treatment dry powder) was studied in rice field ecosystem, and a simple and reliable analytical method was developed for determination of carbosulfan, carbofuran, and 3-hydroxyl carbofuran in brown rice, rice straw, paddy water, and soil. The target compounds were extracted using acetonitrile or dichloromethane, cleaned up on acidic alumina or florisil solid phase extraction (SPE) cartridge, and analyzed by gas chromatography. The average recoveries of carbosulfan, carbofuran and 3-hydroxy carbofuran in brown rice, rice straw, paddy water, and soil ranged from 72.71% to 105.07%, with relative standard deviations of 2.00-8.80%. The limits of quantitation (LOQs) of carbosulfan, carbofuran and 3-hydroxy carbofuran in the samples (brown rice, rice straw, paddy water and soil) were 0.011, 0.0091, 0.014, 0.010 mg kg(-1), 0.016, 0.019, 0.025, 0.013 mg kg(-1), and 0.031, 0.039, 0.035, 0.036 mg kg(-1), respectively. The trials results showed that the half-lives of carbosulfan, carbofuran and 3-hydroxy carbofuran in rice straw were 4.0, 2.6 days, 3.9, 6.0 days, and 5.8, 7.0 days in Zhejiang and Hunan, respectively. Carbosulfan, carbofuran and 3-hydroxy carbofuran were detected in soils. Carbosulfan and 3 hydroxy carbofuran were almost undetectable in paddy water. Carbofuran was detected in paddy water. The final residues of carbosulfan, carbofuran and 3 hydroxy carbofuran in brown rice were lower than 0.05 mg kg(-1), which were lower than 0.5 mg kg(-1) (MRL of carbosulfan) or 0.1 mg kg(-1) (MRL of carbofuran). Therefore, a dosage of 420 g active ingredient per 100 kg seed was recommended, which could be considered as safe to human beings and animals. These would contribute to provide the scientific basis of using this insecticide. PMID- 26963426 TI - Three- and four-dimensional ultrasound in fetal echocardiography: an up-to-date overview. AB - Congenital heart diseases (CHD) are the most commonly overlooked lesions in prenatal screening programs. Real-time two-dimensional ultrasound (2DUS) is the conventionally used tool for fetal echocardiography. Although continuous improvements in the hardware and post-processing software have resulted in a good image quality even in late first trimester, 2DUS still has its limitations. Four dimensional ultrasound with spatiotemporal image correlation (STIC) is an automated volume acquisition, recording a single three-dimensional (3D) volume throughout a complete cardiac cycle, which results in a four-dimensional (4D) volume. STIC has the potential to increase the detection rate of CHD. The aim of this study is to provide a practical overview of the possibilities and (dis)advantages of STIC. A review of literature and evaluation of the current status and clinical value of 3D/4D ultrasound in prenatal screening and diagnosis of congenital heart disease are presented. PMID- 26963427 TI - Fetal cardiology: changing the definition of critical heart disease in the newborn. AB - Infants born with congenital heart disease (CHD) may require emergent treatment in the newborn period. These infants are likely to benefit the most from a prenatal diagnosis, which allows for optimal perinatal planning. Several cardiac centers have created guidelines for the management of these high-risk patients with CHD. This paper will review and compare several prenatal CHD classification systems with a particular focus on the most critical forms of CHD in the fetus and newborn. A contemporary definition of critical CHD is one which requires urgent intervention in the first 24 h of life to prevent death. Such cardiac interventions may be not only life saving for the infant but also decrease subsequent morbidity. Critical CHD cases may require delivery at specialized centers that can provide perinatal, obstetric, cardiology and cardiothoracic surgery care. Fetuses diagnosed in mid-gestation require detailed fetal diagnostics and serial monitoring during the prenatal period, in order to assess for ongoing changes and identify progression to a more severe cardiac status. Critical CHD may progress in utero and there is still much to be learned about how to best predict those who will require urgent neonatal interventions. Despite improved therapeutic capabilities, newborns with critical CHD continue to have significant morbidity and mortality due to compromise that begins in the delivery room. Fetal echocardiography is the best way to predict the need for specialized care at birth to improve outcome. Once the diagnosis is made of critical CHD, delivery at the proper time and in appropriate institution with specific care protocols should be initiated. More work needs to be done to better delineate the risk factors for progression of critical CHD and to determine which newborns will require specialized care. The most frequently described forms of critical CHD requiring immediate intervention include hypoplastic left heart syndrome with intact or severely restricted atrial septum, obstructed total anomalous pulmonary venous return and transposition of the great arteries with restrictive atrial septum. PMID- 26963429 TI - Workplace air quality: International consensus standards. PMID- 26963428 TI - Predicting death or extended length of stay in infants with congenital diaphragmatic hernia. AB - OBJECTIVE: To predict mortality or length of stay (LOS) >109 days (90th percentile) among infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: We conducted a retrospective analysis using the Children's Hospital Neonatal Database during 2010 to 2014. Infants born >34 weeks gestation with CDH admitted at 22 participating regional neonatal intensive care units were included; patients who were repaired or were at home before admission were excluded. The primary outcome was death before discharge or LOS >109 days. Factors associated with this outcome were used to develop a multivariable equation using 80% of the cohort. Validation was performed in the remaining 20% of infants. RESULTS: The median gestation and age at referral in this cohort (n=677) were 38 weeks and 6 h, respectively. The primary outcome occurred in 242 (35.7%) infants, and was distributed between mortality (n=180, 27%) and LOS >109 days (n=66, 10%). Regression analyses showed that small for gestational age (odds ratio (OR) 2.5, P=0.008), presence of major birth anomalies (OR 5.9, P<0.0001), 5 min Apgar score ?3 (OR 7.0, P=0.0002), gradient of acidosis at the time of referral (P<0.001), the receipt of extracorporeal support (OR 8.4, P<0.0001) and bloodstream infections (OR 2.2, P=0.004) were independently associated with death or LOS >109 days. This model performed well in the validation cohort (area under curve (AUC)=0.856, goodness-of-fit (GF) chi(2), P=0.16) and acted similarly even after omitting extracorporeal support (AUC=0.82, GF chi(2), P=0.05). CONCLUSIONS: Six variables predicted death or LOS ?109 days in this large, contemporary cohort with CDH. These results can assist in risk adjustment for comparative benchmarking and for counseling affected families. PMID- 26963430 TI - Fluorescence investigations on choline phospholipid binding and chemical unfolding of HSP-1/2, a major protein of horse seminal plasma. AB - Seminal fibronectin type-II (Fn-II) proteins interact with choline phospholipids present on the sperm plasma membrane and play a crucial role in sperm capacitation. Crystal structure of phosphorylcholine (PrC) complex of PDC-109, the major bovine Fn-II protein, together with fluorescence spectroscopic studies has shown that tryptophan residues are crucial for its specific interaction with choline phospholipids. In the present study, the heterogeneity and microenvironment of tryptophan residues in HSP-1/2, a major protein of horse seminal plasma (which is homologous to PDC-109) were investigated in the native state, in the presence of PrC and phosphatidylcholines (PCs) with short (valeryl, C-5) and long (myristoyl, C-14) chains, and upon denaturation using fluorescence quenching, time-resolved fluorescence and red-edge excitation shift (REES) measurements. The results obtained show that the environment of tryptophan residues in HSP-1/2 is more heterogeneous as compared to that in PDC-109. Binding of choline containing ligands afforded a protection to the tryptophan residues with the shielding order being: PrC<=divalaroyl PC= 18 and admitted <= 24 hours from injury and stratified them as 'transfer' vs 'direct' admission. Demographics, transfer distance, transfer times and outcomes were compared using Chi-square, t-test and multivariable logistic regression; p < 0.05 was significant. RESULTS: During the study period, 1845 patients met inclusion criteria: 947 'direct' and 898 'transfers'. For transfers, median distance was 60.1 miles; mean time to initial care was 1.2 +/- 2.7 hours and time to Level 1 care was 5.0 +/- 2.4 hours. Transfer patients were older (56 vs 49 years; p < 0.01) and had more comorbidities, but had lower mean ISS (15.9 vs 18.8; p < 0.01) and lower mortality (7.0 vs 10.3%; p < 0.03), complications and LOS. Neurosurgical intervention was comparable (p = 0.88), as was mortality for patients with ISS >= 15 (12.4% vs 14.8%; p = 0.28). After regression analysis, advanced age and increasing ISS, not distance or time, predicted mortality. CONCLUSION: Neither transfer distance nor time independently contributed to mortality for TBI after rural injury. An established regional trauma system, with initial local stabilization using ATLS principles, may help reduce negative outcomes for injured patients in rural settings. PMID- 26963434 TI - Effects of Ischemic Reperfusion Injury and Remote Conditioning on Passive Leg Raising-Induced Brachial-Artery Dilation. AB - OBJECTIVES: Passive leg raising (PLR) has been proposed to assess arterial vasodilator reserve and possibly endothelial function. Since endothelial function is sensitive to ischemic-reperfusion (I-R) injury, we determined the effects of I R injury and ischemic conditioning on PLR-induced brachial-artery dilation (BAD), i.e. PLR-BAD. METHODS: We induced PLR-BAD before and after ipsilateral arm I-R injury (7.5 min of occlusion) in 20 healthy males aged 29 +/- 6 years. The protocol was repeated in combination with remote conditioning stimuli (3 * 30 s of contralateral arm occlusions). RESULTS: PLR resulted in significant BAD (3.85%, p < 0.001) before but not after prolonged ischemia (0.25%, p = 0.38). I-R injury, along with either preischemic or postischemic conditioning restored the PLR-BAD response (before: 3.11%, p < 0.001 and after: 3.74%, p < 0.001). CONCLUSIONS: I-R injury blunts the BAD induced by PLR. Remote pre- and postconditioning restore this response. These findings are similar to those previously reported using hyperemia and ultrasound to assess BAD. PMID- 26963436 TI - Ambulatory Extracorporeal Membrane Oxygenation: A Surgical Innovation for Adult Respiratory Distress Syndrome. PMID- 26963435 TI - Phage display revisited: Epitope mapping of a monoclonal antibody directed against Neisseria meningitidis adhesin A using the PROFILER technology. AB - There is a strong need for rapid and reliable epitope mapping methods that can keep pace with the isolation of increasingly larger numbers of mAbs. We describe here the identification of a conformational epitope using Phage-based Representation OF ImmunoLigand Epitope Repertoire (PROFILER), a recently developed high-throughput method based on deep sequencing of antigen-specific lambda phage-displayed libraries. A novel bactericidal monoclonal antibody (mAb 9F11) raised against Neisseria meningitidis adhesin A (NadA), an important component of the Bexsero((r)) anti-meningococcal vaccine, was used to evaluate the technique in comparison with other epitope mapping methods. The PROFILER technology readily identified NadA fragments that were capable of fully recapitulating the reactivity of the entire antigen against mAb 9F11. Further analysis of these fragments using mutagenesis and hydrogen-deuterium exchange mass-spectrometry allowed us to identify the binding site of mAb 9F11 (A250-D274) and an adjoining sequence (V275-H312) that was also required for the full functional reconstitution of the epitope. These data suggest that, by virtue of its ability to detect a great variety of immunoreactive antigen fragments in phage-displayed libraries, the PROFILER technology can rapidly and reliably identify epitope-containing regions and provide, in addition, useful clues for the functional characterization of conformational mAb epitopes. PMID- 26963437 TI - Autologous Serum Eye Drops Combined With Silicone Hydrogen Lenses for the Treatment of Postinfectious Corneal Persistent Epithelial Defects. AB - OBJECTIVE: To evaluate the clinical effect of combined topical autologous serum eye drops (ASEs) and silicone hydrogel contact lens (CLs) for the treatment of corneal persistent epithelial defects (PEDs) after infectious corneal ulcers. METHODS: We conducted a retrospective chart review of 12 patients with postinfectious corneal PEDs who were unsuccessfully treated with conventional medical management and were then treated with combined topical 20% (v/v) ASEs and silicone hydrogel CLs from July 1, 2011, to June 30, 2014. The corneal ulcers were all initially managed with antibiotic eye drops until the infiltrates resolved but the lesions failed to epithelialize. The clinical effects of the combined treatment were evaluated. RESULTS: The PEDs healed in all 12 patients within 2 weeks. The combined treatment was associated with an improvement of best corrected visual acuity (BCVA) at the final 3-month follow-up examination. All patients responded well to the combined treatment and no adverse events were noted in any patient. CONCLUSIONS: The combined use of silicone hydrogel CLs and ASEs can successfully treat postinfectious corneal PEDs and prevent continuous corneal melting during acute disease. PMID- 26963438 TI - Symptomatic Dry Eye and Its Associated Factors: A Study of University Undergraduate Students in Ghana. AB - BACKGROUND: To estimate the prevalence and risk factors of symptomatic dry eye disease (DED) among undergraduate students in a Ghanaian university. METHODS: This cross-sectional study included 700 undergraduate students of the University of Cape Coast, aged 18 to 34 years. Participants completed questionnaires delivered directly to randomly and systematically selected subjects to detect symptomatic dry eye and its predictive factors. Symptomatic dry eye was defined as any reported symptom on the Standard Patient Evaluation Eye Dryness (SPEED) questionnaire reported as often or constant or if any symptom on the Ocular Surface Disease Index (OSDI) was reported as most of the time or all of the time. Furthermore, OSDI >=13 and SPEED >=6 were used to defined symptomatic dry eye and prevalence were also estimated with these criteria as secondary measures. Current symptoms of dry eye and possible risk factors such as age, gender, current alcohol drinking, use of oral contraceptives, use of computer more than an hour daily, environmental conditions, allergies, and self-medication with over-the counter eye drops were the main outcome measures. We used logistic regression analysis to examine the associations between dry eye and its predictive factors. RESULTS: Of the 700 participants, 650 completed the questionnaire. The prevalence of symptomatic dry eye was 44.3% (95% confidence interval [CI], 40.6%-48.2%). There was a significant association between symptomatic dry eye and discomfort with eyes in windy conditions (chi=110.1; df=4; P<0.001), areas with low humidity (chi=91.6; df=4; P<0.001), and air-conditioned rooms (chi=89.0; df=4; P<0.001). Self-medication with over-the-counter eye drops (OR 4.20; 95% CI, 2.61-6.74; P<0.001), any allergies (OR 2.46; 95% CI, 1.42-4.29; P=0.001), and use of oral contraceptives (OR 4.04; 95% CI, 1.02-16.01; P=0.047) were predictive factors of symptomatic dry eye. Sex was predictive in univariate analysis but was not significantly associated in multivariate analysis. CONCLUSIONS: The prevalence of symptomatic dry eye among undergraduate students in Ghana is high and it is associated with self-medication with over-the-counter eye drops, allergies, use of oral contraceptive, windy conditions, very low humid areas, air-conditioned rooms, and sex. Relevant input directed against modifiable risks factors may have a positive impact on the well-being of undergraduate students in Ghana. PMID- 26963439 TI - Spatial analysis of annual mean stable isotopes in precipitation across Japan based on an intensive observation period throughout 2013. AB - Spatial distribution of annual mean stable isotopes in precipitation (delta(18)O, delta(2)H) was observed at 56 sites across Japan throughout 2013. Annual mean delta(18)O values showed a strong latitude effect, from -12.4 0/00 in the north to -5.1 0/00 in the south. Annual mean d-excess values ranged from 8 to 21 0/00, and values on the Sea of Japan side in Northern and Eastern Japan were relatively higher than those on the Pacific Ocean side. The local meteoric water line (LMWL) and isotope effects were based on the annual mean values from all sites across Japan as divided into distinct regions: the Sea of Japan side to the Pacific Ocean side and Northeastern to Southwestern Japan. Slopes and intercepts of LMWL ranged from 7.4 to 7.8 and 9.8 to 13.0, respectively. Slopes for latitude, altitude, and temperature effects ranged from -0.27 to -0.48 0/00/ degrees N, 0.0034 to -0.0053 0/00/m, and 0.36 to 0.46 0/00/ degrees C, respectively, with statistically significance at the 99 % level. However, there was no precipitation amount effect. From the result of a multiple regression analysis, the empirical formula of annual mean delta(18)O in precipitation from latitude and altitude for all sites across Japan was determined to be delta(18) O = -0.348 (LAT) - 0.00307 (ALT) + 4.29 (R(2) = 0.59). Slopes for latitude and altitude ranged from - 0.28 to - 0.51, and - 0.0019 to - 0.0045, respectively. Even though site distribution was uneven, these equations are the first trial estimation for annual mean stable isotopes in precipitation across Japan. Further research performed on the monthly basis is required to elucidate factors controlling the spatiotemporal variability of stable isotopes in precipitation across Japan. PMID- 26963440 TI - Collective Rayleigh-Plateau Instability: A Mimic of Droplet Breakup in High Internal Phase Emulsion. AB - Using a microfluidic multi-inlet coflow system, we show the Rayleigh-Plateau instability of adjacent, closely spaced fluid threads to be collective. Although droplet size distributions and breakup frequencies are unaffected by cooperativity when fluid threads are identical, breakup frequencies and wavelengths between mismatched fluid threads become locked due to this collective instability. Locking narrows the size distribution of drops that are produced from dissimilar threads, and thus the polydispersity of the emulsion. These observations motivate a hypothesized two-step mechanism for high internal phase emulsification, wherein coarse emulsion drops are elongated into close-packed fluid threads, which break into smaller droplets via a collective Rayleigh Plateau instability. Our results suggest that these elongated fluid threads break cooperatively, whereupon wavelength-locking reduces the ultimate droplet polydispersity of high-internal phase emulsions, consistent with experimental observations. PMID- 26963441 TI - A Tale of 2 Units: Lessons in Changing the Care Delivery Model. AB - In response to patient care quality and satisfaction concerns, a hospital determined the need to change the care delivery model on some inpatient units. Two pilot units adopted 2 different models of care. The authors describe the change project, successful outcomes, and lessons learned. PMID- 26963442 TI - Partnering With a Patient and Family Advisory Council to Improve Patient Care Experiences With Pain Management. AB - Patient-centered care is a key driver for the nation's health system, yet patient experience surveys indicate that hospitals are far from achieving favorable outcomes. Partnering with patients and families through a patient and family advisory council (PFAC) advances the practice of patient-centered care to improve outcomes and experiences. This article describes the process of implementing a PFAC and presents outcomes related to patients' perception of pain management in the acute care hospital setting. PMID- 26963443 TI - Implementation Analysis of a Nurse-Led Observation Unit. AB - OBJECTIVE: This implementation analysis of a nurse-led observation unit describes the development process and analyzes patients' characteristics, patient satisfaction, and provider perceptions. BACKGROUND: A nurse-led observation unit was developed to create more inpatient bed capacity and place patients in the clinical area best suited to their needs. METHODS: Descriptive statistics and content analysis were used for analysis. RESULTS: The average length of stay of 467 patients was 1.1 days; 68.1% (n = 318) were female. Elective surgery was the most frequent reason for admission. All of the patients rated the observation unit patient feedback survey factors favorably except for noise. All healthcare providers (n = 64) reported that they communicated well with each other and had resources to provide quality care but rated the environment less favorably. CONCLUSIONS: A nurse-led observation unit was found to be an effective and efficient approach to providing postoperative and postprocedure care, which was generally well received by patients and healthcare providers. PMID- 26963444 TI - 320-Row Multidetector CT Angiography in the Detection of Critical Cerebrovascular Anomalies. AB - BACKGROUND: The acquisition of a new 320-row multidetector computed tomography angiography (CTA) scanner at the Montreal Neurological Institute and Hospital has provided higher quality imaging with less radiation exposure and shorter time of acquisition. However, its reliability has not been fully proven in critical vascular lesions when it comes to replacing a more invasive examination such as cerebral angiography. We wished to validate the accuracy of this equipment to investigate four common indications for patients to undergo conventional digital subtraction angiography: subarachnoid hemorrhage, vasospasm, unusual intracerebral hemorrhage, and unruptured aneurysm. METHODS: Radiological reports and relevant imaging from 82 consecutive subjects who underwent a 320-row multidetector CTA followed by cerebral angiography from February 2010 to February 2014 were retrospectively analysed. A total of 102 cerebrovascular anomalies were found. Reports from both imaging modalities were compared to determine the diagnostic accuracy of CTA. RESULTS: The overall sensitivity and specificity of 320-row multidetector CTA for detecting cerebrovascular abnormalities were, respectively, 97.60% and 63.20%. Similar results were obtained for all four categories of clinical indications. CONCLUSION: Results obtained from CTA were consistent with those obtained on digital subtraction angiography regardless of the vascular pathology. To our knowledge, this study is the first validating the accuracy of 320-row CTA in diagnosing critical cerebrovascular lesions. PMID- 26963445 TI - Immediate and long-term clinical performance of bioresorbable vascular scaffolds in a real world population. AB - BACKGROUND: The aim of this study was to evaluate the safety and efficacy of bioresorbable vascular scaffolds (BVS) in terms of acute success and long-term clinical events in a real world population according to the most updated technical recommendations. METHODS: Perspective, single-center registry involving symptomatic patients treated with BVS from February 2013 to January 2016. Primary end-point was the occurrence of MACCEs at one year: death, target vessel related myocardial infarction, target vessel revascularization, stroke, major bleeding. Secondary endpoints were acute device and procedural clinical success, and occurrence of MACCEs at long-term follow-up. RESULTS: In total, 112 patients were treated on 173 lesions. Average age was 55.53+/-12.4 years and acute coronary syndrome was the admission diagnosis for 79.5% patients. Nine patients presented cardiac allograft vasculopathy after cardiac transplantation. Multi-vessel disease was treated in 50% of cases. Predilatation and post-dilatation were performed respectively in 96% and 88.4% of lesions. Intravascular imaging was used in 41 patients (37%). Angiographic success rate and procedural success rate were 100% and 97.3% respectively. Clinical follow-up was completed in 100 patients with an average follow-up of 10.5+/-8.3 months. Including peri procedural and in-hospital MACCEs, target vessel failure was noticed in 7% of patients in the first year of follow up and in 11% of patients at long-term follow-up. Two cases of target lesion revascularization occurred 25 and 26 months after the index procedure. No cases of definite stent thrombosis were reported. CONCLUSIONS: Strict adherence to expert recommendation for BVS placement may minimize device related peri-procedural and mid-to-long term MACCEs in a real world population. PMID- 26963446 TI - Analysis of audio-vestibular assessment in acute low-tone hearing loss. AB - Conclusion This study demonstrated excellent hearing recovery following the combined treatment of diuretic and oral steroid, and electrocochleography (ECoG) was significantly higher than normal side. This study reports characteristics of acute low-tone hearing loss (ALHL) that show the greater low-tone hearing loss, the higher ECoG, and excellent recovery, even-though low-tone hearing loss is worse, which can be different compared with sudden deafness. Objective To analyze ALHL without vertigo, this study compared the ALHL group with all patients exhibiting low-tone hearing loss and ear fullness. Hearing changes and vestibular functions were analyzed. Materials and methods ALHL was defined as a mean hearing loss of >= 30 dB at 125, 250, and 500 Hz, and <= 20 dB at 2, 4, and 8 kHz. From 156 cases of low-tone hearing loss of more than 10 dB without vertigo, 31 met the ALHL criteria and were subjected to audio-vestibular assessments including PTA, ECoG, vestibular evoked myogenic potential (VEMP) testing, and caloric testing. Results In ALHL, low-tone hearing loss was 42.7 +/- 9.5 dB, and 83.9% of ALHL significantly recovered by more than 10 dB. The ECoG in ALHL was 0.334 +/- 0.11 (higher than 0.25 +/- 0.08 on the normal side) and ECoG abnormality was 35.5% (the greater low-tone hearing loss, the higher ECoG value). PMID- 26963448 TI - Tomosynthesis-detected Architectural Distortion: Management Algorithm with Radiologic-Pathologic Correlation. AB - As use of digital breast tomosynthesis becomes increasingly widespread, new management challenges are inevitable because tomosynthesis may reveal suspicious lesions not visible at conventional two-dimensional (2D) full-field digital mammography. Architectural distortion is a mammographic finding associated with a high positive predictive value for malignancy. It is detected more frequently at tomosynthesis than at 2D digital mammography and may even be occult at conventional 2D imaging. Few studies have focused on tomosynthesis-detected architectural distortions to date, and optimal management of these distortions has yet to be well defined. Since implementing tomosynthesis at our institution in 2011, we have learned some practical ways to assess architectural distortion. Because distortions may be subtle, tomosynthesis localization tools plus improved visualization of adjacent landmarks are crucial elements in guiding mammographic identification of elusive distortions. These same tools can guide more focused ultrasonography (US) of the breast, which facilitates detection and permits US guided tissue sampling. Some distortions may be sonographically occult, in which case magnetic resonance imaging may be a reasonable option, both to increase diagnostic confidence and to provide a means for image-guided biopsy. As an alternative, tomosynthesis-guided biopsy, conventional stereotactic biopsy (when possible), or tomosynthesis-guided needle localization may be used to achieve tissue diagnosis. Practical uses for tomosynthesis in evaluation of architectural distortion are highlighted, potential complications are identified, and a working algorithm for management of tomosynthesis-detected architectural distortion is proposed. PMID- 26963449 TI - Developing Asymmetries at Mammography: A Multimodality Approach to Assessment and Management. AB - A developing asymmetry is a focal asymmetry that is new or increased in conspicuity compared with the previous mammogram. It is challenging to evaluate, as it often looks similar to fibroglandular tissue at mammography. A developing asymmetry should be viewed with suspicion because it is an uncommon manifestation of breast cancer. Diagnostic mammography forms the foundation of diagnostic evaluation of a developing asymmetry and begins with additional spot compression, lateral, and/or rolled views to evaluate and localize it in three-dimensional space. Digital breast tomosynthesis can aid in evaluation by improving radiologists' sensitivity and specificity, as well as allowing localization of the lesion. Once the developing asymmetry has been fully characterized and localized with diagnostic mammography, targeted ultrasonography (US) should be performed to identify potentially benign causes of the developing asymmetry or identify a target for biopsy. However, lack of a US correlate should not preclude biopsy of a developing asymmetry. Diagnostic breast magnetic resonance imaging can be used in a minority of cases for problem solving or biopsy planning if no US correlate is identified and stereotactic biopsy is not feasible. The purpose of this article is to review the definition of developing asymmetry, describe the multimodality diagnostic tools available to the radiologist for evaluation of this challenging entity, and review the various causes, both benign and malignant. PMID- 26963451 TI - Commentary on "Hypertrophic Cardiomyopathy from A to Z," with Response from Dr Baxi and Colleagues. PMID- 26963450 TI - Hypertrophic Cardiomyopathy from A to Z: Genetics, Pathophysiology, Imaging, and Management. AB - Hypertrophic cardiomyopathy (HCM) is a heterogeneous group of diseases related to sarcomere gene mutations exhibiting heterogeneous phenotypes with an autosomal dominant mendelian pattern of inheritance. The disorder is characterized by diverse phenotypic expressions and variable natural progression, which may range from dyspnea and/or syncope to sudden cardiac death. It is found across all racial groups and is associated with left ventricular hypertrophy in the absence of another systemic or cardiac disease. The management of HCM is based on a thorough understanding of the underlying morphology, pathophysiology, and clinical course. Imaging findings of HCM mirror the variable expressivity and penetrance heterogeneity, with the added advantage of diagnosis even in cases where a specific mutation may not yet be found. The diagnostic information obtained from imaging varies depending on the specific stage of HCM-phenotype manifestation, including the prehypertrophic, hypertrophic, and later stages of adverse remodeling into the burned-out phase of overt heart failure. However, subtle or obvious, these imaging findings become critical components in diagnosis, management, and follow-up of HCM patients. Although diagnosis of HCM traditionally relies on clinical assessment and transthoracic echocardiography, recent studies have demonstrated increased utility of multidetector computed tomography (CT) and particularly cardiac magnetic resonance (MR) imaging in diagnosis, phenotype differentiation, therapeutic planning, and prognostication. In this article, we provide an overview of the genetics, pathophysiology, and clinical manifestations of HCM, with the spectrum of imaging findings at MR imaging and CT and their contribution in diagnosis, risk stratification, and therapy. PMID- 26963452 TI - Use of Dual-Energy CT and Iodine Maps in Evaluation of Bowel Disease. AB - Dual-energy computed tomography (CT) relies on material-dependent x-ray absorption behavior from concurrently acquired high- and low-kilovolt peak data and has a range of imaging applications. This article focuses on use of dual energy CT in assessment of bowel disease. After a summary of relevant dual-energy CT image acquisition and postprocessing principles, the authors describe dual energy techniques of greatest utility in evaluation of benign and malignant pathologic conditions in the bowel, including neoplastic, vascular, infectious, and inflammatory disorders, as well as in assessment of abdominopelvic trauma. The dual-energy postprocessing techniques of iodine-selective imaging and virtual monochromatic imaging have the broadest applicability in bowel imaging. They may be used for improved visualization of subtle differences in bowel wall enhancement or for quantitative assessment of altered enhancement for evaluation of a neoplasm or bowel ischemia. Iodine images and virtual monochromatic low kiloelectron volt images are particularly helpful for assessment of a neoplasm, ischemia, infection, or inflammation, while iodine maps paired with virtual nonenhanced images are most helpful to differentiate iodine from other dense materials, as in gastrointestinal bleeding or trauma. In most applications, radiation doses at dual-energy CT are comparable to those at traditional CT. However, dual-energy CT may allow reduction in radiation dose by using virtual nonenhanced images that obviate an additional nonenhanced CT acquisition. Limitations of dual-energy CT are discussed, including potential challenges in acquisition, postprocessing, and interpretation. PMID- 26963453 TI - Benign Multicystic Peritoneal Mesothelioma: AIRP Best Cases in Radiologic Pathologic Correlation. AB - RadioGraphics continues to publish radiologic-pathologic case material selected from the American Institute for Radiologic Pathology (AIRP) "best case" presentations. The AIRP conducts a 4-week Radiologic Pathology Correlation Course, which is offered five times per year. On the penultimate day of the course, the best case presentation is held at the American Film Institute Silver Theater and Cultural Center in Silver Spring, Md. The AIRP faculty identifies the best cases, from each organ system, brought by the resident attendees. One or more of the best cases from each of the five courses are then solicited for publication in RadioGraphics. These cases emphasize the importance of radiologic pathologic correlation in the imaging evaluation and diagnosis of diseases encountered at the institute and its predecessor, the Armed Forces Institute of Pathology (AFIP). PMID- 26963454 TI - The Wheel of the Mesentery: Imaging Spectrum of Primary and Secondary Mesenteric Neoplasms--How Can Radiologists Help Plan Treatment?: Resident and Fellow Education Feature. PMID- 26963455 TI - Cardiopulmonary and Gastrointestinal Manifestations of Eosinophil- associated Diseases and Idiopathic Hypereosinophilic Syndromes: Multimodality Imaging Approach. AB - Eosinophil-associated diseases (EADs) are a diverse group of disorders characterized by an increase in circulating or tissue eosinophils. Cardiopulmonary and gastrointestinal system involvement can be due to primary EAD with no known cause or can be secondary to known systemic disease. The cardiopulmonary spectrum of EADs comprises simple pulmonary eosinophilia, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis, bronchocentric granulomatosis, parasitic infections, and idiopathic hypereosinophilic syndrome. Eosinophilic gastrointestinal disorders include eosinophilic esophagitis, eosinophilic gastroenteritis, and eosinophilic colitis. Diagnosis is often challenging and requires a combination of clinical and imaging features along with laboratory findings. The absolute eosinophil count in peripheral blood and the percentage of eosinophils in bronchoalveolar lavage fluid are crucial in evaluation of various eosinophilic lung diseases. Although chest radiography is the initial imaging modality used in suspected cases of pulmonary EAD, multidetector computed tomography may demonstrate more characteristic pulmonary patterns, nodules, and subtle parenchymal abnormalities. Barium esophagography is used to assess mucosal abnormalities and the length and diameter of esophageal strictures. Magnetic resonance imaging is superior in providing valuable information in select patients, especially in evaluation of cardiac and gastrointestinal system involvement. Many patients require a multimodality imaging approach to enable diagnosis, guide treatment, and assess treatment response. Knowledge of the clinical features and imaging findings of the spectrum of EADs involving the lungs, heart, and gastrointestinal tract permits optimal patient care. PMID- 26963456 TI - US of the Peripheral Nerves of the Upper Extremity: A Landmark Approach. AB - Ultrasonography (US) has become a first-line modality for the evaluation of the peripheral nerves of the upper extremity. The benefits of US over magnetic resonance (MR) imaging include higher soft-tissue resolution, cost effectiveness, portability, real-time and dynamic imaging, and the ability to scan an entire extremity quickly and efficiently. US can be performed on patients who are not eligible for MR imaging. Metallic implant artifacts are usually not problematic. US has been shown to have equal specificity and greater sensitivity than MR imaging in the evaluation of peripheral nerves. Any abnormal findings can be easily compared with the contralateral side. The published literature has shown that US has demonstrated clinical utility in patients with suspected peripheral nerve disease by guiding diagnostic and therapeutic decisions as well as by confirming electrodiagnostic findings. Common indications for upper extremity peripheral nerve US are the evaluation for injury due to penetrating trauma, entrapment by scar tissue, and tumor. US of the upper extremity is most commonly performed to evaluate carpal and cubital tunnel syndrome. It is important for the radiologist or sonographer to have a detailed knowledge of anatomy and specific anatomic landmarks for each nerve to efficiently and accurately perform an examination. The goal of this article is to introduce readers to the basics of US of the peripheral nerves of the upper extremity with a focus on the median, ulnar, and radial nerves. Common sites of disease and the location of important anatomic landmarks will be reviewed. PMID- 26963457 TI - Artifacts at Musculoskeletal US: Resident and Fellow Education Feature. PMID- 26963459 TI - Two Classic Patterns of Pediatric Renal Neoplasia. PMID- 26963458 TI - Role of Optimal Quantification of FDG PET Imaging in the Clinical Practice of Radiology. AB - The combination of fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and computed tomography (CT) for dual-modality imaging (PET/CT) plays a key role in the diagnosis and staging of FDG-avid malignancies. FDG uptake by the tumor cells offers an opportunity to detect cancer in organs that appear normal at anatomic imaging and to differentiate viable tumor from posttreatment effects. Quantification of FDG uptake has multiple clinical applications, including cancer diagnosis and staging. Dedicated FDG PET/CT-based visual and quantitative criteria have been developed to evaluate treatment response. Furthermore, the level of tumor FDG uptake reflects the biologic aggressiveness of the tumor, predicting the risk of metastasis and recurrence. FDG uptake can be measured with qualitative, semiquantitative, and quantitative methods. Qualitative or visual assessment of PET/CT images is the most common clinical approach for describing the level of FDG uptake. Standardized uptake value (SUV) is the most commonly used semiquantitative tool for measuring FDG uptake. SUV can be measured as maximum, mean, or peak SUV and may be normalized by using whole or lean body weight. SUV measurements provide the basis for quantitative response criteria; however, SUVs have not been widely adopted as diagnostic thresholds for discriminating malignant and benign lesions. Volumetric FDG uptake measurements such as metabolic tumor volume and total lesion glycolysis have shown substantial promise in providing accurate tumor assessment. SUV measurement and other quantification techniques can be affected by many technical, physical, and biologic factors. Familiarity with FDG uptake quantification approaches and their pitfalls is essential for clinical practice and research. PMID- 26963460 TI - Renal Tumors of Childhood: Radiologic-Pathologic Correlation Part 1. The 1st Decade: From the Radiologic Pathology Archives. AB - Wilms tumor is the second most common pediatric solid tumor and by far the most common renal tumor of infants and young children. As most tumors are large at presentation and are treated with nephrectomy, the role of imaging is primarily in preoperative planning and evaluation for metastatic disease. However, with treatment protocols increasingly involving use of preoperative (neoadjuvant) chemotherapy (the standard in Europe) and consideration of nephron-sparing surgery, the role of imaging is evolving to include providing initial disease staging information and a presumptive diagnosis to guide therapy. Differential diagnostic considerations include lesions that are clinically benign and others that require more intensive therapy than is used to treat Wilms tumor. In part 1 of this article, the unique histologic spectrum of renal neoplasms of infants and young children is reviewed with emphasis on radiologic-pathologic correlation. Part 2 will focus on renal tumors of older children and adolescents. PMID- 26963461 TI - 4D Contrast-enhanced MR Angiography with the Keyhole Technique in Children: Technique and Clinical Applications. AB - Unlike in adults, contrast agent-enhanced magnetic resonance (MR) angiography in the pediatric population raises unique challenges such as faster heart rates, more rapid arteriovenous transit, smaller structures, smaller volumes of contrast agent used, and more complex disease processes. A need exists for a rapid contrast-enhanced MR angiographic technique that can separate the arterial and venous phases of contrast enhancement in sedated pediatric patients breathing freely during the course of an examination. In time-resolved contrast-enhanced MR angiography with the keyhole method (four-dimensional [4D] contrast-enhanced MR angiography), various spatial and temporal frequency undersampling schemes are used to substantially reduce the time of acquisition without markedly compromising spatial resolution. The keyhole method can be briefly described as an undersampling approach in which only a small region of the k-space (keyhole) around the center is repeatedly sampled while the periphery is sampled only once during acquisition. This method provides a wide range of options that can be used to overcome conventional limitations of contrast-enhanced MR angiography in children and opens the door for several new pediatric applications, including evaluation of congenital heart disease in neonates and infants, thoracic and extremity vascular pathologic conditions, high-flow vascular malformations, systemic vein thrombosis, and pediatric portal hypertension. This review provides a technical overview of 4D contrast-enhanced MR angiography, outlines its advantages and pitfalls in the pediatric population, and also describes various applications in children, including modifications of the technique needed for each application. PMID- 26963462 TI - Radiation Therapy for Soft-Tissue Sarcomas: A Primer for Radiologists. AB - Radiation therapy (RT) plays an important role in multimodality therapy for soft tissue sarcomas (STS). RT treatment paradigms have evolved significantly in recent years, and many different complex RT modalities are commonly used in STS. These include external-beam RT, intensity-modulated RT, stereotactic body RT, and brachytherapy. Imaging is essential throughout the treatment process. Plain radiographs, computed tomography (CT), magnetic resonance imaging, ultrasonography, and positron emission tomography/CT all play potential roles in the management of STS. Before RT, high-quality imaging is needed to direct management decisions, both by global tumor staging and detailed assessment of the extent of local disease. At the time of RT, precise planning imaging is required to delineate tumor volumes, including gross tumor volume, clinical target volume, and planning target volume, which are used to direct therapy. In addition, imaging at the time of RT must outline the location of adjacent vital organs, to optimize treatment efficacy and minimize toxicity. After RT, imaging is needed to assess the patient for tumor response to therapy. In addition, imaging at regular intervals is often required to monitor for recurrence of disease and potential complications of therapy. The purpose of this review is to familiarize radiologists with the indications for RT in STS, common therapeutic modalities used, roles of imaging throughout the treatment process, and complications of therapy. PMID- 26963463 TI - Testing "Saintly" Authenticity: Investigations on Two Catacomb Saints. PMID- 26963465 TI - Invited Commentary on "US of the Nongravid Cervix with Multimodality Imaging Correlation". PMID- 26963464 TI - US of the Nongravid Cervix with Multimodality Imaging Correlation: Normal Appearance, Pathologic Conditions, and Diagnostic Pitfalls. AB - The adult uterine cervix may exhibit a wide variety of pathologic conditions that include benign entities (eg, cervicitis, hyperplasia, nabothian cysts, cervical polyps, leiomyomas, endometriosis, and congenital abnormalities) as well as malignant lesions, particularly cervical carcinoma. In addition, lesions that arise in the uterine body may secondarily involve the cervix, such as endometrial carcinoma and prolapsed intracavitary masses. Many of these conditions can be identified and characterized at ultrasonography (US), which is considered the first-line imaging examination for the female pelvis. However, examination of the cervix is often cursory during pelvic US, such that cervical disease may be overlooked or misdiagnosed. Transabdominal US of the cervix may not afford sufficient spatial resolution to depict cervical disease in many patients; therefore, endovaginal US is considered the optimal technique. Use of supplemental imaging techniques, particularly the application of transducer pressure on the cervix, may be helpful. This review describes the normal appearance of the cervix at US, the appearance of cervical lesions and conditions that mimic abnormalities at US, and optimal US techniques for evaluation of the cervix. This information will help radiologists detect and diagnose cervical abnormalities more confidently at pelvic US. Online supplemental material is available for this article. PMID- 26963466 TI - Consider Risk for Gadolinium Retention in the Brain When Using Gadolinium-based Contrast Media. PMID- 26963467 TI - Clinical significance of thyroid incidentalomas identified by 18F-FDG PET/CT: correlation of ultrasonograpy findings with cytology results. AB - AIM: The aim of this study was to investigate the clinical importance of incidental focal or diffuse fluorine-18 fluorodeoxyglucose (F-FDG) uptake in the thyroid gland on positron emission tomography (PET)/computed tomography (CT) and to evaluate the additive value of thyroid ultrasonography (US) in defining the malignancy potential of thyroid incidentalomas. PATIENTS AND METHODS: A total of 1450 patients, who had undergone a PET/CT scan for staging or restaging of various malignancies, were screened retrospectively and 52 (3.6%) patients with focal or diffuse F-FDG uptake in the thyroid gland on PET/CT were enrolled in the study. None of the patients had any history of thyroid diseases. Thyroid US with elastography for a thyroid nodule was performed for all the patients cross sectionally. Thyroid fine-needle aspiration biopsy (FNAB) was also applied at the same time as the thyroid US to 34 patients with a nodule(s) 10 mm or more in diameter or less than 10 mm, but with malignancy potential ultrasonographically. The cytology results were compared with the thyroid US and F-FDG PET/CT findings. RESULTS: Although 39 patients had focal (group 1) F-FDG uptake in the thyroid gland, the remaining 13 patients had diffuse (group 2) uptake. In group 1, FNAB was performed in 32 patients. In 10 of 32 (31%) patients, FNAB results were concordant with malignant cytology (seven primary thyroid malignancy and three metastasis to thyroid). In group 2, in one of two patients who had undergone FNAB, malignant cytology (metastasis to thyroid) was detected. Although the difference between the maximum standardized uptake value (SUVmax) of malignant and benign nodules was statistically significant (10.2+/-8.9 vs. 5.6+/-3.0, P=0.013), the difference between the nodule sizes was not statistically significant (20.0+/-7.3 vs. 16.7+/-7.4, P=0.923). The presence of suspicious US findings and a high elastography score (>=4) were also statistically significant (P<0.001 and P=0.035, respectively). In the receiver-operator characteristic analysis, a 5.3 cut-off SUVmax was calculated with 82% sensitivity and 65% specificity for predicting malignant cytology. CONCLUSION: Focal F-FDG uptake was associated with a higher prevalence of malignant thyroid nodule compared with diffuse F-FDG uptake. In particular, if a focal thyroid incidentaloma with high SUVmax (>5.5), suspicious US findings, and a high elastography score (>=4) is detected, a pathological diagnosis, either by histology or by cytology examination, should be made, especially when the patient has a long life expectancy. PMID- 26963468 TI - Radiosensitizing effect of irisquinone on glioma through the downregulation of HIF-1alpha evaluated by 18F-FDG and 18F-FMISO PET/CT. AB - OBJECTIVE: The aim of this study was to elucidate the radiosensitizing mechanism of irisquinone (IQ) and evaluate the utility of F-fluorodeoxyglucose (F-FDG) and F-fluoromisonidazole (F-FMISO) PET/computed tomography (CT) in assessing the radiosensitizing effect of IQ. MATERIALS AND METHODS: In an in-vitro experiment, C6 rat glioma cells were treated with IQ, radiation, or both. The viability and radiosensitivity of C6 cells were detected using the MTT assay and clonogenic survival assay. The expression of hypoxia-inducible factor-1alpha (HIF-1alpha) was evaluated by real-time PCR and western blot. In an in-vivo experiment, C6 rat glioma cells were implanted into the right flank of rats and treated with IQ, radiation, both, or no treatment. F-FDG and F-FMISO PET/CT images were obtained before and after treatment. The expression of HIF-1alpha was detected by immunohistochemistry staining. RESULTS: In the in-vitro experiment, the results of the MTT assay showed that the half-inhibition concentration (IC50) of IQ for normoxic and hypoxic C6 tumor cells was 17.2 and 21.0 nmol/l, respectively. Clonogenic survival assay showed that IQ could improve the radiosensitivity of both normoxic and hypoxic C6 tumor cells. When the concentration of irradiation was 20% IC50 (4.2 nmol/l), the sensitive enhancement ratio of normoxic and hypoxic C6 tumor cells was 1.18 and 1.33, respectively. The mRNA and protein expression levels of HIF-1alpha decreased significantly when treated with IQ plus radiation compared with the other groups.In the in-vivo experiment, 24 or 48 h after different treatments, the maximum standardized uptake values (SUVmax) of F FDG or F-FMISO uptake decreased in the radiation group and the IQ plus radiation group, whereas these values increased in the control and IQ groups. The SUVmax of F-FDG or F-FMISO uptake in IQ plus radiation group were lower than those of the radiation group (t=3.28, 2.62, P<0.05). However, there was no significant decrease in tumor volumes in the radiation group and the IQ plus radiation treatment group early after treatment.Immunohistochemistry staining showed that there were significant differences in the expression of HIF-1alpha in the four groups (F=87.1, P<0.01). The SUVmax of both F-FDG and F-FMISO uptake showed a significant correlation with the expression of HIF-1alpha. F-FMISO provided a higher correlation coefficient with HIF-1alpha than F-FDG (r=0.93, 0.82, P<0.01). CONCLUSION: The present experiments indicated that IQ enhanced the radiosensitivity of C6 rat glioma cells both in vitro and in vivo. The primary mechanism of this radiosensitizing effect involves the downregulation of HIF 1alpha. F-FDG and F-FMISO PET/CT were sensitive and noninvasive for monitoring the early radiosensitizing effect of IQ. Meanwhile, F-FMISO PET/CT provided more information on the changes in tumor hypoxic status. PMID- 26963469 TI - Does major surgery induce immune suppression and increase the risk of postoperative infection? AB - PURPOSE OF REVIEW: Infection is the commonest cause of a postoperative complication. Following major surgery alterations in immune function are commonplace and these may contribute to an enhanced susceptibility to acquire nosocomial infections. This review will discuss postoperative infections in the context of an altered perioperative immune response and the factors influencing this response. RECENT FINDINGS: Up to 10% of patients undergoing elective in patient surgery may develop a postoperative infection. Laboratory advances now permit systematic monitoring of single-cell immune signatures, which enable a clearer description of the interaction between tissue damage, immune modulation and clinical outcomes. Traditional candidate gene expression has identified pathways that define the detrimental immune modulating effects of perioperative allogeneic blood transfusion. Large clinical studies have demonstrated that the choice of anaesthetic technique may have an impact on postoperative infections through differential immune modulation. SUMMARY: Point of care tests are emerging that allow monitoring of the perioperative immune response. These could be further developed to introduce personalised care pathways. Consideration must also be given to anaesthesia techniques and perioperative treatments that may be associated with poor outcomes through immune modulation. PMID- 26963470 TI - The use of remifentanil during general anesthesia for caesarean section. AB - PURPOSE OF REVIEW: The purpose is to review the neonatal and maternal effects of remifentanil given at induction of general anesthesia for caesarean section and prior to delivery of the baby. MAIN FINDINGS: Remifentanil seems to have short lived respiratory depressant effects in approximately 50% of neonates, requiring short periods of mask ventilation or tactile stimulation of the neonate. Remifentanil produces excellent maternal hemodynamic stability avoiding tachycardia and hypertension, possibly reducing the risk of maternal awareness. SUMMARY: Remifentanil can be safely used at induction of general anesthesia provided healthcare workers are available to manage short-lived neonatal depression. PMID- 26963471 TI - Robotic surgery and anesthesia for pediatric urologic procedures. AB - PURPOSE OF REVIEW: Minimally invasive approaches to pediatric surgery have become increasingly popular over the last 15 years. With the advent of robotically controlled instruments, common pediatric urologic surgeries such as pyeloplasty and ureteral reimplantation, which were previously technically challenging, are now commonly performed laparoscopically. It is important to recognize the unique physiologic considerations with this approach and how to provide safe and effective anesthesia for these procedures. RECENT FINDINGS: Although there are multiple studies in the surgical literature describing robot-assisted laparoscopic approaches for pediatric urologic surgery, there are few articles that describe the anesthetic considerations for this type of surgery in children. As the first pediatric hospital in the USA to obtain a surgical robot in 2001, a consistent, collaborative approach has been developed to care for infants and children undergoing robot-assisted laparoscopic surgery. SUMMARY: Robot-assisted laparoscopic surgery is increasingly utilized for common pediatric urologic surgeries. To provide safe and effective anesthesia for this type of surgery, it is important to have a thorough understanding of the multiple physiologic derangements that occur with robot-assisted laparoscopic surgery in infants and children, the potential complications that can occur with this approach and have a consistent approach to the anesthetic management and postoperative pain control for these procedures. PMID- 26963474 TI - Influence of the active layer nanomorphology on device performance for ternary PbS(x)Se(1-x) quantum dots based solution-processed infrared photodetector. AB - In this paper, the influence of the active layer nanomorphology on device performance for ternary PbS(x)Se(1-x) quantum dot-based solution-processed infrared photodetector is presented. Firstly, ternary PbS(x)Se(1-x) quantum dots (QDs) in various chemical composition were synthesized and the bandgap of the ternary PbS(x)Se(1-x) QDs can be controlled by the component ratio of S/(S + Se), and then field-effect transistor (FET) based photodetectors Au/PbS0.4Se0.6:P3HT/PMMA/Al, in which ternary PbS0.4Se0.6 QDs doped with poly(3 hexylthiophene) (P3HT) act as the active layer and poly(methyl methacrylate) (PMMA) as the dielectric layer, were presented. By changing the weight ratio of P3HT to PbS0.4Se0.6 QDs (K = M(P3HT):M(QDs)) in dichlorobenzene solution, we found that the device with K = 2:1 shows optimal electrical property in dark; however, the device with K = 1:2 demonstrated optimal performance under illumination, showing a maximum responsivity and specific detectivity of 55.98 mA W(-1) and 1.02 * 10(10) Jones, respectively, at low V(DS) = -10 V and V(G) = 3 V under 980 nm laser with an illumination intensity of 0.1 mW cm(-2). By measuring the atomic force microscopy phase images of PbS0.4Se0.6:P3HT films in different weight ratio K, our experimental data show that the active layer nanomorphology has a great influence on the device performance. Also, it provides an easy way to fabricate high performance solution-processed infrared photodetector. PMID- 26963472 TI - Centrally Synthesized Estradiol Is a Potent Anti-Inflammatory in the Injured Zebra Finch Brain. AB - In homeotherms, injury to the brain, such as a penetrating wound, increases microglial cytokine expression and astroglial aromatase (estrogen synthase). In songbirds, injury-induced synthesis of estrogens is neuroprotective as aromatase inhibition and replacement with estradiol (E2) exacerbates and mitigates the extent of damage, respectively. The influence of induced aromatization on inflammation, however, remains unstudied. We hypothesized that injury-induced aromatization, via E2 synthesis, may affect neuroinflammation after a penetrating brain injury. Using adult zebra finches, we first documented an increase in the transcription of cytokines but not aromatase, 2 hours after the injury. Twenty four hours after the injury, however, aromatase was dramatically elevated and cytokine expression had returned to baseline, suggesting that aromatization may be involved in the decrease of cytokines and neuroinflammation. In two subsequent experiments, we tested the influence of the inhibition of induced aromatization and aromatase inhibition with concomitant central E2 replacement on the transcription of the cytokines TNF-alpha, IL-1beta, and IL-6, the enzyme cyclooxygenase-2 (cox-2), and its product prostaglandin E2 (PGE2). Administration of fadrozole, an aromatase inhibitor, caused a sustained elevation of IL-1beta in females and TNF-alpha, cox-2, and PGE2 in both sexes. This prolonged neuroinflammation appears to be due to a failure to synthesize E2 locally because intracranial E2 replacement lowered IL-1beta in females, TNF-alpha in males, and cox-2 and PGE2 in both sexes. IL-6 was not affected by injury, aromatase inhibition, or E2 replacement in either sex. These data suggest that E2 synthesis after a penetrating brain injury is a potent and inducible anti-inflammatory signal, with specific modulation of discrete cytokine signaling. PMID- 26963473 TI - A Role for Androgens in Epithelial Proliferation and Formation of Glands in the Mouse Uterus. AB - The endometrium consists of stromal and epithelial compartments (luminal and glandular) with distinct functions in the regulation of uterine homeostasis. Ovarian sex steroids, namely 17beta-estradiol and progesterone, play essential roles in modulating uterine cell proliferation, stromal-epithelial cross-talk and differentiation in preparation for pregnancy. The effect of androgens on uterine function remains poorly understood. The current study investigated the effect of the non-aromatizable androgen dihydrotestosterone (DHT) on mouse endometrial function. Ovx female mice were given a single sc injection (short treatment) or 7 daily injections (long treatment) of vehicle alone (5% ethanol, 0.4% methylcellulose) or vehicle with the addition of 0.2 mg DHT (n=8/group) and a single injection of bromodeoxyuridine 2 hours prior to tissue recovery. Treatment with DHT increased uterine weight, the area of the endometrial compartment and immunoexpression of the androgen receptor in the luminal and glandular epithelium. Treatment-dependent proliferation of epithelial cells was identified by immunostaining for MKi67 and bromodeoxyuridine. Real-time PCR identified significant DHT-dependent changes in the concentrations of mRNAs encoded by genes implicated in the regulation of the cell cycle (Wee1, Ccnd1, Rb1) and stromal epithelial interactions (Wnt4, Wnt5a, Wnt7a, Cdh1, Vcl, Igf1, Prl8, Prlr) as well as a striking effect on the number of endometrial glands. This study has revealed a novel role for androgens in regulating uterine function with an effect on the glandular compartment of the endometrium. This previously unrecognized role for androgens has implications for our understanding of the role of androgens in regulation of endometrial function and fertility in women. PMID- 26963478 TI - A method for early detection of the initiation of sit-to-stand posture transitions. AB - A powered lower extremity orthotic brace can potentially be used to assist frail elderly during daily activities. This paper presents a method for an early detection of the initiation of sit-to-stand (SiSt) posture transition that can be used in the control of the powered orthosis. Unlike the methods used in prosthetic devices that rely on surface electromyography (EMG), the proposed method uses only sensors embedded into the orthosis brace attached to the limb. The method was developed and validated using data from a human study with 10 individuals. Each human trial included different sets of sitting, standing and walking activities originating from various initial postures. Features from the sensor signal were extracted and aggregated in lagged epochs to incorporate the time history. Principal component analysis (PCA) was used to reduce the feature set. The principal components were then used in a leave-one-out manner to train a linear support vector machine (SVM) classifier to perform early detection of the SiSt posture transition. The proposed method achieved the sensitivity of 100% and the specificity 92.94% of trials without false positives. The average detection time (DT) of 0.1341 +/- 0.3310 s following the start of transition demonstrated early recognition of the initiation of SiSt transition. PMID- 26963477 TI - Using the international classification of functioning to examine the impact of trigger finger. AB - PURPOSE: To evaluate the impact of trigger finger (TF) on hand motor function, activity and participation (A&P) and quality of life (QOL), and to evaluate the association between personal factors (age and gender, disease severity) and body functions (dexterity and strength) with A&P and QOL in patients with TF. METHODS: Sixty-six patients with TF (study group) and 66 healthy volunteers (control group) participated in the study. TF symptoms were graded using the Quinnell classification. A&P was evaluated using the Disabilities of Arm Shoulder and Hand questionnaire and the QOL using the World Health Organization Quality of Life questionnaire. Dexterity was evaluated using the Functional Dexterity Test and the Purdue Pegboard Test; hand strength was evaluated using the Jamar Dynamometer and Pinch Gauge. RESULTS: The comparisons between the study and control groups revealed significant differences in all measures. The study group reported lower perceived QOL, A&P and reduced hand strength and dexterity. Hierarchical regression analyses revealed that (a) the severity of TF contributed significantly to the explained variance of QOL, while demographics and hand functioning did not; (b) demographics, TF severity and hand function all contributed significantly to the explained variance of A&P. CONCLUSION: The findings of the study point to the importance of addressing the functional implications and QOL of individuals with TF. Implications for Rehabilitation Although trigger finger is considered to be a mild hand pathology, it has a wide ranging impact on hand functioning, daily activities and quality of life. Clinicians should include assessments of these outcomes in the treatment of individuals with trigger finger. Treatment efficacy should be evaluated with International Classification of Functioning outcomes, and not limited to symptomatology. PMID- 26963481 TI - Adult age differences in information foraging in an interactive reading environment. AB - When learning about a single topic in natural reading environments, readers are confronted with multiple sources varying in the type and amount of information. In this situation, readers are free to adaptively respond to the constraints of the environment (e.g., through selection of resources and time allocation for study), but there may be costs of exploring and switching between sources (e.g., disruption of attention, opportunity costs for study). From an ecological perspective, such properties of the environment are expected to influence learning strategies. In the current study, we used a novel reading paradigm to investigate age differences in the effects of information richness (i.e., sentence elaboration) and costs of switching between texts (i.e., time delay) on selection of sources and study time allocation. Consistent with the ecological view, participants progressed from less informative to more informative texts. Furthermore, increased switch cost led to a tendency to allocate more effort to easier materials and to greater persistence in reading, which in turn, led to better memory in both immediate and delayed recall. Older adults showed larger effects of switch cost, such that the age difference in delayed recall was eliminated in the high switch cost condition. Based on an ecological paradigm of reading that affords choice and self-regulation, our study provided evidence for preservation with age in the ability to adapt to changing learning environments so as to improve performance. (PsycINFO Database Record PMID- 26963482 TI - A Model Using Local Weather Data to Determine the Effective Sampling Volume for PCB Congeners Collected on Passive Air Samplers. AB - We have developed and evaluated a mathematical model to determine the effective sampling volumes (Veff) of PCBs and similar compounds captured using polyurethane foam passive air samplers (PUF-PAS). We account for the variability in wind speed, air temperature, and equilibrium partitioning over the course of the deployment of the samplers. The model, provided as an annotated Matlab script, predicts the Veff as a function of physical-chemical properties of each compound and meteorology from the closest Integrated Surface Database (ISD) data set obtained through NOAA's National Centers for Environmental Information (NCEI). The model was developed to be user-friendly, only requiring basic Matlab knowledge. To illustrate the effectiveness of the model, we evaluated three independent data sets of airborne PCBs simultaneously collected using passive and active samplers: at sites in Chicago, Lancaster, UK, and Toronto, Canada. The model provides Veff values comparable to those using depuration compounds and calibration against active samplers, yielding an average congener specific concentration method ratio (active/passive) of 1.1 +/- 1.2. We applied the model to PUF-PAS samples collected in Chicago and show that previous methods can underestimate concentrations of PCBs by up to 40%, especially for long deployments, deployments conducted under warming conditions, and compounds with log Koa values less than 8. PMID- 26963483 TI - Effects and feasibility of exercise therapy combined with branched-chain amino acid supplementation on muscle strengthening in frail and pre-frail elderly people requiring long-term care: a crossover trial. AB - This study examined the effects and feasibility of a twice-weekly combined therapy of branched-chain amino acids (BCAAs) and exercise on physical function improvement in frail and pre-frail elderly people requiring long-term care. We used a crossover design in which the combination of exercise and nutritional interventions was carried out twice a week during cycles A (3 months) and B (3 months) and the exercise intervention alone was performed during the washout period. The exercise intervention entailed the following 5 training sets: 3 sets of muscle training at 30% of maximum voluntary contraction, 1 set of aerobic exercise, and 1 set of balance training. For the nutritional intervention, 6 g of BCAAs or 6 g of maltodextrin was consumed 10 min before starting the exercise. We determined upper and lower limb isometric strength, performance on the Functional Reach Test (FRT) and the Timed Up and Go test, and activity level. In the comparison between the BCAA group and the control group after crossover, the improvement rates in gross lower limb muscle strength (leg press, knee extension) and FRT performance were significantly greater (by approximately 10%) in the BCAA group. In the comparison between different orders of BCAA administration, significant effects were shown for the leg press in both groups only when BCAAs were given. The combination of BCAA intake and exercise therapy yielded significant improvements in gross lower limb muscle strength and dynamic balance ability. PMID- 26963484 TI - Effect of Grip Force and Training in Unstable Dynamics on Micromanipulation Accuracy. AB - This paper investigates whether haptic error amplification using unstable dynamics can be used to train accuracy in micromanipulation. A preliminary experiment first examines the possible confounds of visual magnification and grip force. Results show that micromanipulation precision is not affected by grip force in both naive and experienced subjects. On the other hand, precision is increased by visual magnification of up to 10*, but not further for larger magnifications. The main experiment required subjects to perform small-range point-to-point movements in 3D space in an unstable environment which amplified position errors to the straight line between start and end point. After having trained in this environment, subjects performing in the free conditions show an increase in success rate and a decrease in error and its standard deviation relative to the control subjects. This suggests that this technique can improve accuracy and reliability of movements during micromanipulation. PMID- 26963485 TI - Constraint-Based Haptic Rendering of Multirate Compliant Mechanisms. AB - The paper is dedicated to haptic rendering of complex physics-based environment in the context of surgical simulation. A new unified formalism for modeling the mechanical interactions between medical devices and anatomical structures and for computing accurately the haptic force feedback is presented. The approach deals with the mechanical interactions using appropriate force and/or motion transmission models named compliant mechanisms. These mechanisms are formulated as a constraint-based problem that is solved in two separate threads running at different frequencies. The first thread processes the whole simulation including the soft-tissue deformations, whereas the second one only deals with computer haptics. This method builds a bridge between the so-called virtual mechanisms (that were proposed for haptic rendering of rigid bodies) and intermediate representations (used for rendering of complex simulations). With this approach, it is possible to describe the specific behavior of various medical devices while relying on a unified method for solving the mechanical interactions between deformable objects and haptic rendering. The technique is demonstrated in interactive simulation of flexible needle insertion through soft anatomical structures with force feedback. PMID- 26963486 TI - Haptic Simulator for Prostate Brachytherapy with Simulated Needle and Probe Interaction. AB - This paper presents a haptic simulator for prostate brachytherapy. Both needle insertion and the manipulation of the transrectal ultrasound (TRUS) probe are controlled via haptic devices. Tissue interaction forces that are computed by a deformable tissue model based on the finite element method (FEM) are rendered to the user by these devices. The needle insertion simulation employs 3D models of needle flexibility and asymmetric tip bevel. The needle-tissue simulation allows a trainee to practice needle insertion and targeting. The TRUS-tissue interaction simulation allows a trainee to practice the 3D intraoperative TRUS placement for registration with the preoperative volume study and to practice TRUS axial translation and rotation for imaging needles during insertions. Approaches to computational acceleration for realtime haptic performance are presented. Trade offs between accuracy and speed are discussed. A graphics-card implementation of the numerically intensive mesh-adaptation operation is also presented. The simulator can be used for training, rehearsal, and treatment planning. PMID- 26963487 TI - Integrating Haptics with Augmented Reality in a Femoral Palpation and Needle Insertion Training Simulation. AB - This paper presents a virtual environment for training femoral palpation and needle insertion, the opening steps of many interventional radiology procedures. A novel augmented reality simulation called PalpSim has been developed that allows the trainees to feel a virtual patient using their own hands. The palpation step requires both force and tactile feedback. For the palpation haptics effect, two off-the-shelf force feedback devices have been linked together to provide a hybrid device that gives five degrees of force feedback. This is combined with a custom built hydraulic interface to provide a pulse like tactile effect. The needle interface is based on a modified PHANTOM Omni end effector that allows a real interventional radiology needle to be mounted and used during simulation. While using the virtual environment, the haptics hardware is masked from view using chroma-key techniques. The trainee sees a computer generated patient and needle, and interacts using their own hands. This simulation provides a high level of face validity and is one of the first medical simulation devices to integrate haptics with augmented reality. PMID- 26963488 TI - Tool Contact Acceleration Feedback for Telerobotic Surgery. AB - Minimally invasive telerobotic surgical systems enable surgeons to perform complicated procedures without large incisions. Unfortunately, these systems typically do not provide the surgeon with sensory feedback aside from stereoscopic vision. We have, thus, developed VerroTouch, a sensing and actuating device that can be added to Intuitive Surgical's existing da Vinci S Surgical System to provide auditory and vibrotactile feedback of tool contact accelerations. These cues let the surgeon feel and hear contact with rough textures as well as the making and breaking of contact with objects and other tools. To evaluate the merits of this approach, we had 11 surgeons use an augmented da Vinci S to perform three in vitro manipulation tasks under four different feedback conditions: with no acceleration feedback, with audio feedback, with haptic feedback, and with both audio and haptic. Subjects expressed a significant preference for the inclusion of tool contact acceleration feedback, although they disagreed over which sensory modality was best. Other survey responses and qualitative written comments indicate that the feedback may have improved the subject's concentration and situational awareness by strengthening the connection between the surgeon and the surgical instruments. Analysis of quantitative task metrics shows that the feedback neither improves nor impedes the performance of the chosen tasks. PMID- 26963489 TI - Vital Signs: Preventing Antibiotic-Resistant Infections in Hospitals - United States, 2014. AB - BACKGROUND: Health care-associated antibiotic-resistant (AR) infections increase patient morbidity and mortality and might be impossible to successfully treat with any antibiotic. CDC assessed health care-associated infections (HAI), including Clostridium difficile infections (CDI), and the role of six AR bacteria of highest concern nationwide in several types of health care facilities. METHODS: During 2014, approximately 4,000 short-term acute care hospitals, 501 long-term acute care hospitals, and 1,135 inpatient rehabilitation facilities in all 50 states reported data on specific infections to the National Healthcare Safety Network. National standardized infection ratios and their percentage reduction from a baseline year for each HAI type, by facility type, were calculated. The proportions of AR pathogens and HAIs caused by any of six resistant bacteria highlighted by CDC in 2013 as urgent or serious threats were determined. RESULTS: In 2014, the reductions in incidence in short-term acute care hospitals and long-term acute care hospitals were 50% and 9%, respectively, for central line-associated bloodstream infection; 0% (short-term acute care hospitals), 11% (long-term acute care hospitals), and 14% (inpatient rehabilitation facilities) for catheter-associated urinary tract infection; 17% (short-term acute care hospitals) for surgical site infection, and 8% (short-term acute care hospitals) for CDI. Combining HAIs other than CDI across all settings, 47.9% of Staphylococcus aureus isolates were methicillin resistant, 29.5% of enterococci were vancomycin-resistant, 17.8% of Enterobacteriaceae were extended spectrum beta-lactamase phenotype, 3.6% of Enterobacteriaceae were carbapenem resistant, 15.9% of Pseudomonas aeruginosa isolates were multidrug resistant, and 52.6% of Acinetobacter species were multidrug resistant. The likelihood of HAIs caused by any of the six resistant bacteria ranged from 12% in inpatient rehabilitation facilities to 29% in long-term acute care hospitals. CONCLUSIONS: Although there has been considerable progress in preventing some HAIs, many remaining infections could be prevented with implementation of existing recommended practices. Depending upon the setting, more than one in four of HAIs excluding CDI are caused by AR bacteria. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Physicians, nurses, and health care leaders need to consistently and comprehensively follow all recommendations to prevent catheter- and procedure related infections and reduce the impact of AR bacteria through antimicrobial stewardship and measures to prevent spread. PMID- 26963490 TI - How MicroRNAs Are Involved in Splitting the Mind. PMID- 26963491 TI - Bioinspired roft robotics: preface to the special issue. PMID- 26963492 TI - Erbium YAG laser treatment of periorbital syringomas by using the multiple ovoid shape ablation method. AB - INTRODUCTION: Syringomas are benign tumours that develop predominantly in the periorbital areas of women. As periorbital syringoma is adjacent to the appendages, Erbium YAG (Er:YAG) laser treatment should be an ideal tool for its precise ablation, although its use has not previously been reported. We retrospectively analysed our new ovoid-shape Er:YAG laser ablation method for the treatment of syringoma. MATERIALS AND METHODS: We developed an extirpation method in which multiple, 2- to 4-mm, egg-shaped ablation fields were created. This method was used to treat 49 patients, 35 of whom had predominantly accumulated syringomas, and 14 had disseminated syringomas. Treatment was repeated every 2 months. RESULTS: Our approach was successful in both disseminated- and accumulated-type syringoma as well as plaque-type syringoma, which is considered to be the most difficult to treat. After an average of 3.77 treatments, more than 75% of the syringoma in the treated area had disappeared in 43 of 49 patients. CONCLUSION: Our ovoid-shape ablation method gives good cosmetic results even in the most difficult type of syringoma. PMID- 26963493 TI - DNA Stains as Surrogate Nucleobases in Fluorogenic Hybridization Probes. AB - The increasing importance assigned to RNA dynamics in cells and tissues calls for probe molecules that enable fluorescence microscopy imaging in live cells. To achieve this goal, fluorescence dyes are conjugated with oligonucleotides so as to provide strong emission upon hybridization with the target molecule. The impressive 10(3)-fold fluorescence intensification observed when DNA stains such as thiazole orange (TO) interact with double-stranded DNA is intriguing and prompted the exploration of oligonucleotide conjugates. However, nonspecific interactions of DNA stains with polynucleotides tend to increase background, which would affect the contrast achievable in live-cell imaging. This Account describes the development of DNA-stain-labeled hybridization probes that provide high signal-to-background. We focus on our contributions in context with related advances from other laboratories. The emphasis will be on the requirements of RNA imaging in live cells. To reduce background, intercalator dyes such as TO were appended to peptide nucleic acid (PNA), which is less avidly recognized by DNA stains than DNA/RNA. Constraining the TO dye as a nucleobase surrogate in "forced intercalation (FIT) probes" improved the target specificity, presumably by helping to prevent unspecific interactions. The enforcement of TO intercalation between predetermined base pairs upon formation of the probe-target duplex provided for high brightness and enabled match/mismatch selectivity beyond stringency of hybridization. We show examples that highlight the use of PNA FIT probes in the imaging of mRNA, miRNA, and lncRNA in living cells. The "FIT approach" was recently extended to DNA probes. Signal brightness can become limiting when low-abundance targets ought to be visualized over cellular autofluorescence. We discuss strategies that further the brightness of signaling by FIT probes. Multilabeling with identical dyes does not solve the brightness issue. To avoid self-quenching, we combined two different yet spectrally overlapping fluorescent base surrogates. A hybridization-sensitive dye serves as a light collector that transfers energy to a brightly emissive acceptor dye. To improve the brilliance of single-dye probes, the "TO-nucleotide" was accompanied by an adjacent locked nucleic acid (LNA) unit. The LNA-constrained FIT probes are responsive and bright, enabling the tracking of mRNA transport in living tissue. We also show that the color repertoire of FIT probes is not restricted to the green-emissive TO but can be expanded to cyan and red. A new base surrogate (4,4 linked bisquinoline) provided up to 195-fold enhancement of the fluorescence. PMID- 26963494 TI - Piperlongumine as a direct TrxR1 inhibitor with suppressive activity against gastric cancer. AB - Piperlongumine (PL), a natural alkaloid isolated from the fruit of long pepper, is known to selectively kill tumor cells while sparing their normal counterparts. However, the cellular target and potent anticancer efficacy of PL in numerous types of human cancer cells have not been fully defined. We report here that PL may interact with the thioredoxin reductase 1 (TrxR1), an important selenocysteine (Sec)-containing antioxidant enzyme, to induce reactive oxygen species (ROS)-mediated apoptosis in human gastric cancer cells. By inhibiting TrxR1 activity and increasing intracellular ROS levels, PL induces a lethal endoplasmic reticulum stress and mitochondrial dysfunction in human gastric cancer cells. Importantly, knockdown of TrxR1 sensitizes cells to PL treatment, and PL displays synergistic lethality with GSH inhibitors (BSO and Erastin) against gastric cancer cells. In vivo, PL treatment markedly reduces the TrxR1 activity and tumor cell burden. Remarkably, TrxR1 was significantly overexpressed in gastric cancer cell lines and human gastric cancer tissues. Targeting TrxR1 with PL thus discloses a previously unrecognized mechanism underlying the biological activity of PL and provides an in-depth insight into the action of PL in the treatment of gastric cancer. PMID- 26963495 TI - [(11)C]Ascorbic and [(11)C]dehydroascorbic acid, an endogenous redox pair for sensing reactive oxygen species using positron emission tomography. AB - Here we report the radiosynthesis of an endogenous redox pair, [(11)C]ascorbic acid ([(11)C]VitC) and [(11)C]dehydroascorbic acid ([(11)C]DHA), the reduced and oxidized forms of vitamin C, and their application to ROS sensing. These results provide the basis for in vivo detection of ROS using positron emission tomography (PET). PMID- 26963496 TI - Electrophoretic Separation of Single Particles Using Nanoscale Thermoplastic Columns. AB - Phenomena associated with microscale electrophoresis separations cannot, in many cases, be applied to the nanoscale. Thus, understanding the electrophoretic characteristics associated with the nanoscale will help formulate relevant strategies that can optimize the performance of separations carried out on columns with at least one dimension below 150 nm. Electric double layer (EDL) overlap, diffusion, and adsorption/desorption properties and/or dielectrophoretic effects giving rise to stick/slip motion are some of the processes that can play a role in determining the efficiency of nanoscale electrophoretic separations. We investigated the performance characteristics of electrophoretic separations carried out in nanoslits fabricated in poly(methyl methacrylate), PMMA, devices. Silver nanoparticles (AgNPs) were used as the model system with tracking of their transport via dark field microscopy and localized surface plasmon resonance. AgNPs capped with citrate groups and the negatively charged PMMA walls (induced by O2 plasma modification of the nanoslit walls) enabled separations that were not apparent when these particles were electrophoresed in microscale columns. The separation of AgNPs based on their size without the need for buffer additives using PMMA nanoslit devices is demonstrated herein. Operational parameters such as the electric field strength, nanoslit dimensions, and buffer composition were evaluated as to their effects on the electrophoretic performance, both in terms of efficiency (plate numbers) and resolution. Electrophoretic separations performed at high electric field strengths (>200 V/cm) resulted in higher plate numbers compared to lower fields due to the absence of stick/slip motion at the higher electric field strengths. Indeed, 60 nm AgNPs could be separated from 100 nm particles in free solution using nanoscale electrophoresis with 100 MUm long columns. PMID- 26963504 TI - Ordered mesoporous CoMOx (M = Al or Zr) mixed oxides for Fischer-Tropsch synthesis. AB - A superior structural stability of the ordered mesoporous CoMOx synthesized by using the KIT-6 template was observed under Fischer-Tropsch reaction conditions. The enhanced stability was attributed to a strong interaction of the irreducible metal oxides with the mesoporous Co3O4 by forming Co3O4-ZrO2 (or Co3O4-Al2O3), which resulted in showing a stable activity. PMID- 26963497 TI - Development and validation of a high-throughput stereoselective LC-MS/MS assay for bupropion, hydroxybupropion, erythrohydrobupropion, and threohydrobupropion in human plasma. AB - A stereoselective analytical method was developed and validated for the quantification of bupropion, and principle metabolites hydroxybupropion, erythrohydrobupropion and threohydrobupropion in human plasma. Separation of individual enantiomers (R)-bupropion, (S)-bupropion, (R,R)-hydroxybupropion, (S,S hydroxybupropion), (1S,2S)-threohydrobupropion, (1R,2R)-threohydrobupropion, (1R,2S)-erythrohydrobupropion, and (1S,2R)-erythrohydrobupropion was achieved utilizing an alpha1-acid glycoprotein column within a 12-min run time. Chromatograph separation was significantly influenced by mobile phase pH and variability between columns. Analytes were quantified by positive ion electrospray tandem mass spectrometry following plasma protein precipitation with 20% trichloroacetic acid. Identification of erythrohydrobupropion enantiomer peaks and threohydrobupropion enantiomer peaks was achieved by sodium borohydride reduction of enantiopure (R)- and (S)-bupropion. Initial assay validation and sensitivity determination was on AB Sciex 3200, 4000 QTRAP, and 6500 mass spectrometers. Accuracy and precision were within 15% for each analyte. The assay was fully validated over analyte-specific concentrations using an AB Sciex 3200 mass spectrometer. Intra- and inter-assay precision and accuracy were within 12% for each analyte. The limits of quantification for bupropion (R and S), hydroxybupropion (R,R and S,S), threohydrobupropion (1S,2S and 1R,2R), and erythrohydrobupropion (1R,2S and 1S,2R) were 0.5, 2, 1, and 1ng/mL, respectively. All analytes were stable following freeze thaw cycles at -80 degrees C and while stored at 4 degrees C in the instrument autosampler. This method was applicable to clinical pharmacokinetic investigations of bupropion in patients. This is the first chromatographic method to resolve erythrohydrobupropion and threohydrobupropion enantiomers, and the first stereoselective LC-MS/MS assay to quantify bupropion, and principle metabolites hydroxybupropion, erythrohydrobupropion, and threohydrobupropion in human plasma. PMID- 26963498 TI - Do People Take Stimulus Correlations into Account in Visual Search? AB - In laboratory visual search experiments, distractors are often statistically independent of each other. However, stimuli in more naturalistic settings are often correlated and rarely independent. Here, we examine whether human observers take stimulus correlations into account in orientation target detection. We find that they do, although probably not optimally. In particular, it seems that low distractor correlations are overestimated. Our results might contribute to bridging the gap between artificial and natural visual search tasks. PMID- 26963507 TI - Health Extension Workers' and Mothers' Attitudes to Maternal Health Service Utilization and Acceptance in Adwa Woreda, Tigray Region, Ethiopia. AB - BACKGROUND: The maternal health system in Ethiopia links health posts in rural communities (kebeles) with district (woreda) health centres, and health centres with primary hospitals. At each health post two Health Extension Workers (HEWs) assist women with birth preparedness, complication readiness, and mobilize communities to facilitate timely referral to mid-level service providers. This study explored HEWs' and mother's attitudes to maternal health services in Adwa Woreda, Tigray Region. METHODS: In this qualitative study, we trained 16 HEWs to interview 45 women to gain a better understanding of the social context of maternal health related behaviours. Themes included barriers to health services; women's social status and mobility; and women's perceptions of skilled birth attendant's care. All data were analyzed thematically. FINDINGS: There have been substantial efforts to improve maternal health and reduce maternal mortality in Adwa Woreda. Women identified barriers to healthcare including distance and lack of transportation due to geographical factors; the absence of many husbands due to off-woreda farming; traditional factors such as zwar (some pregnant women are afraid of meeting other pregnant women), and discouragement from mothers and mothers-in-law who delivered their children at home. Some women experienced disrespectful care at the hospital. Facilitators to skilled birth attendance included: identification of pregnant women through Women's Development Groups (WDGs), and referral by ambulance to health facilities either before a woman's Expected Due Date (EDD) or if labour started at home. CONCLUSION: With the support of WDGs, HEWs have increased the rate of skilled birth attendance by calling ambulances to transfer women to health centres either before their EDD or when labour starts at home. These findings add to the growing body of evidence that health workers at the community level can work with women's groups to improve maternal health, thus reducing the need for emergency obstetric care in low-income countries. PMID- 26963505 TI - Safety, Acceptability and Adherence of Dapivirine Vaginal Ring in a Microbicide Clinical Trial Conducted in Multiple Countries in Sub-Saharan Africa. AB - BACKGROUND: This was the first microbicide trial conducted in Africa to evaluate an antiretroviral-containing vaginal ring as an HIV prevention technology for women. OBJECTIVES: The trial assessed and compared the safety, acceptability and adherence to product use of a 4-weekly administered vaginal ring containing the antiretroviral microbicide, dapivirine, with a matching placebo ring among women from four countries in sub-Saharan Africa. METHODS: 280 Healthy, sexually active, HIV-negative women, aged 18 to 40 years were enrolled with 140 women randomised to a dapivirine vaginal ring (25 mg) and 140 women to a matching placebo ring, inserted 4-weekly and used over a 12-week period. Safety was evaluated by pelvic examination, colposcopy, clinical laboratory assessments, and adverse events. Blood samples for determination of plasma concentrations of dapivirine were collected at Weeks 0, 4 and 12. Residual dapivirine levels in returned rings from dapivirine ring users were determined post-trial. Participant acceptability and adherence to ring use were assessed by self-reports. RESULTS: No safety concerns or clinically relevant differences were observed between the dapivirine and placebo ring groups. Plasma dapivirine concentrations immediately prior to ring removal were similar after removal of the first and third ring, suggesting consistent ring use over the 12-week period. No clear relationship was observed between the residual amount of dapivirine in used rings and corresponding plasma concentrations. Self-reported adherence to daily use of the vaginal rings over the 12-week trial period was very high. At the end of the trial, 96% of participants reported that the ring was usually comfortable to wear, and 97% reported that they would be willing to use it in the future if proven effective. CONCLUSIONS: The dapivirine vaginal ring has a favourable safety and acceptability profile. If proven safe and effective in large-scale trials, it will be an important component of combination HIV prevention approaches for women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01071174. PMID- 26963506 TI - Pediatric Primitive Neuroectodermal Tumors of the Central Nervous System Differentially Express Granzyme Inhibitors. AB - BACKGROUND: Central nervous system (CNS) primitive neuroectodermal tumors (PNETs) are malignant primary brain tumors that occur in young infants. Using current standard therapy, up to 80% of the children still dies from recurrent disease. Cellular immunotherapy might be key to improve overall survival. To achieve efficient killing of tumor cells, however, immunotherapy has to overcome cancer associated strategies to evade the cytotoxic immune response. Whether CNS-PNETs can evade the immune response remains unknown. METHODS: We examined by immunohistochemistry the immune response and immune evasion strategies in pediatric CNS-PNETs. RESULTS: Here, we show that CD4+, CD8+, gammadelta-T-cells, and Tregs can infiltrate pediatric CNS-PNETs, although the activation status of cytotoxic cells is variable. Pediatric CNS-PNETs evade immune recognition by downregulating cell surface MHC-I and CD1d expression. Intriguingly, expression of SERPINB9, SERPINB1, and SERPINB4 is acquired during tumorigenesis in 29%, 29%, and 57% of the tumors, respectively. CONCLUSION: We show for the first time that brain tumors express direct granzyme inhibitors (serpins) as a potential mechanism to overcome cellular cytotoxicity, which may have consequences for cellular immunotherapy. PMID- 26963508 TI - Speech Databases of Typical Children and Children with SLI. AB - The extent of research on children's speech in general and on disordered speech specifically is very limited. In this article, we describe the process of creating databases of children's speech and the possibilities for using such databases, which have been created by the LANNA research group in the Faculty of Electrical Engineering at Czech Technical University in Prague. These databases have been principally compiled for medical research but also for use in other areas, such as linguistics. Two databases were recorded: one for healthy children's speech (recorded in kindergarten and in the first level of elementary school) and the other for pathological speech of children with a Specific Language Impairment (recorded at a surgery of speech and language therapists and at the hospital). Both databases were sub-divided according to specific demands of medical research. Their utilization can be exoteric, specifically for linguistic research and pedagogical use as well as for studies of speech-signal processing. PMID- 26963509 TI - Polymorphisms of Dectin-1 and TLR2 Predispose to Invasive Fungal Disease in Patients with Acute Myeloid Leukemia. AB - BACKGROUND: Patients with acute myeloid leukemia (AML) who undergo induction chemotherapy are at high risk for invasive fungal disease (IFD). Dectin-1, a C type lectin family member represents one of the most important pattern recognition receptors of the innate immune system and single nucleotide polymorphisms (SNPs) in the Dectin-1 gene have been associated with an increased risk of infectious complications. We sought to investigate the impact of three different Dectin-1 SNPs and one TLR2 SNP on developing IFD in 186 adult patients with newly diagnosed AML following anthracycline-based induction chemotherapy. PATIENTS AND METHODS: Genotyping of Dectin-1 SNPs (rs16910526, rs3901533 and rs7309123) and TLR2 SNP (rs5743708) was performed by TaqMan method and pyrosequencing. IFD was defined according to the EORTC/MSG consensus guidelines. Multiple logistic regression analyses were applied to evaluate the association between the polymorphisms and the occurrence of pulmonary infections. Dectin-1 expression studies with SNP genotyped human monocytes were performed to elucidate susceptibility to IFD following chemotherapy. RESULTS: We could demonstrate that patients carrying the Dectin-1 SNP rs7309123 G/G (n = 47) or G/G and C/G (n = 133) genotype revealed a significant higher risk for developing both pneumonia in general (adjusted odds ratio (OR): 2.5; p = 0.014 and OR: 3.0, p = 0.004) and pulmonary IFD (OR: 2.6; p = 0.012 and OR: 2.4, p = 0.041, respectively). Patients carrying the TLR2 SNP rs5743708 (R753Q, GA/AA genotype, n = 12) also revealed a significantly higher susceptibility to pneumonia including IFD. Furthermore, Dectin-1 mRNA expression in human monocytes was lower following chemotherapy. CONCLUSION: To our best knowledge, this study represents the first analysis demonstrating that harbouring polymorphisms of Dectin-1 (rs7309123) or TLR2 (rs5743708) represents an independent risk factor of developing IFD in patients with AML undergoing induction chemotherapy. PMID- 26963512 TI - Age at Menarche, Level of Education, Parity and the Risk of Hysterectomy: A Systematic Review and Meta-Analyses of Population-Based Observational Studies. AB - BACKGROUND: Although rates have declined, hysterectomy is still a frequent gynaecological procedure. To date, there has been no systematic quantification of the relationships between early/mid-life exposures and hysterectomy. We performed a systematic review and meta-analyses to quantify the associations between age at menarche, education level, parity and hysterectomy. METHODS: Eligible studies were identified by searches in PubMed and Embase through March 2015. Study specific estimates were summarised using random effects meta-analysis. Heterogeneity was explored using sub-group analysis and meta-regression. RESULTS: Thirty-two study populations were identified for inclusion in at least one meta analysis. Each year older at menarche was associated with lower risk of hysterectomy-summary hazard ratio 0.86 (95% confidence interval: 0.78, 0.95; I2 = 0%); summary odds ratio 0.88 (95% confidence interval: 0.82, 0.94; I2 = 61%). Low education levels conferred a higher risk of hysterectomy in the lowest versus highest level meta-analysis (summary hazard ratio 1.87 (95% confidence interval: 1.25, 2.80; I2 = 86%), summary odds ratio 1.51 (95% confidence interval: 1.35, 1.69; I2 = 90%)) and dose-response meta-analysis (summary odds ratio 1.17 (95% confidence interval: 1.12, 1.23; I2 = 85%) per each level lower of education). Sub-group analysis showed that the birth cohort category of study participants, the reference category used for level of education, the year the included article was published, quality of the study (as assessed by the authors) and control for the key variables accounted for the high heterogeneity between studies in the education level meta-analyses. In the meta-analyses of studies of parity and hysterectomy the results were not statistically significant. CONCLUSIONS: The present meta-analyses suggest that the early life factors of age at menarche and lower education level are associated with hysterectomy, although this evidence should be interpreted with some caution due to variance across the included studies. PMID- 26963510 TI - Blockade of Thrombopoietin Reduces Organ Damage in Experimental Endotoxemia and Polymicrobial Sepsis. AB - BACKGROUND AND PURPOSE: Thrombopoietin (TPO), a growth factor primarily involved in thrombopoiesis may also have a role in the pathophysiology of sepsis. In patients with sepsis, indeed, TPO levels are markedly increased, with disease severity being the major independent determinant of TPO concentrations. Moreover, TPO increases and correlates with ex vivo indices of platelet activation in patients with burn injury upon sepsis development, and may contribute to depress cardiac contractility in septic shock. Still, the role of TPO in sepsis pathophysiology remains controversial, given the protective role of TPO in other experimental disease models, for instance in doxorubicin-induced cardiotoxicity and myocardial ischemia/reperfusion injury. The aim of our study was to define the contribution of TPO in the development of organ damage induced by endotoxemia or sepsis, and to investigate the effects of inhibiting TPO in these conditions. METHODS: We synthesized a chimeric protein able to inhibit TPO, mTPOR-MBP, and studied its effect in two murine experimental models, acute endotoxemia and cecal ligation and puncture (CLP) model. RESULTS: In both models, TPO levels markedly increased, from 289.80+/-27.87 pg/mL to 465.60+/-45.92 pg/mL at 3 hours in the LPS model (P<0.01), and from 265.00+/-26.02 pg/mL to 373.70+/-26.20 pg/mL in the CLP model (P<0.05), respectively. Paralleling TPO levels, also platelet-monocyte aggregates increased, from 32.86+/-2.48% to 46.13+/-1.39% at 3 hours in the LPS model (P<0.01), and from 43.68+/-1.69% to 56.52+/-4.66% in the CLP model (P<0.05). Blockade of TPO by mTPOR-MBP administration reduced histological damage in target organs, namely lung, liver, and gut. In particular, neutrophil infiltration and lung septal thickening were reduced from a score of 1.86+/-0.34 to 0.60+/-0.27 (P<0.01) and from 1.43+/-0.37 to 0.40+/-0.16 (P<0.05), respectively, in the LPS model at 3 hours, and from a score of 1.75+/-0.37 to 0.38+/-0.18 (P<0.01) and from 1.25+/-0.31 to 0.13+/-0.13 (P<0.001), respectively, in the CLP model. Similarly, the number of hepatic microabscesses was decreased from 14.14+/-1.41 to 3.64+/-0.56 in the LPS model at 3 hours (P<0.001), and from 1.71+/-0.29 to 0.13+/-0.13 in the CLP model (P<0.001). Finally, the diameter of intestinal villi decreased from 90.69+/-3.95 MUm to 70.74+/-3.60 MUm in the LPS model at 3 hours (P<0.01), and from 74.29+/-4.29 MUm to 57.50+/-1.89 MUm in the CLP model (P<0.01). This protective effect was associated with the blunting of the increase in platelet-monocyte adhesion, and, on the contrary, with increased platelet-neutrophil aggregates in the circulation, which may be related to decreased neutrophil sequestration into the inflamed tissues. Conversely, circulating cytokine levels were not significantly changed, in both models, by mTPOR-MBP administration. CONCLUSION: Our results demonstrate that TPO participates in the development of organ damage induced by experimental endotoxemia or polymicrobial sepsis via a mechanism involving increased platelet leukocyte adhesion, but not cytokine release, and suggest that blocking TPO may be useful in preventing organ damage in patients affected by systemic inflammatory response or sepsis. PMID- 26963513 TI - Correction: A Comparison of the Beneficial Effects of Live and Heat-Inactivated Baker's Yeast on Nile Tilapia: Suggestions on the Role and Function of the Secretory Metabolites Released from the Yeast. PMID- 26963511 TI - Non-Dioxin-Like Polychlorinated Biphenyls Inhibit G-Protein Coupled Receptor Mediated Ca2+ Signaling by Blocking Store-Operated Ca2+ Entry. AB - Polychlorinated biphenyls (PCBs) are ubiquitous pollutants which accumulate in the food chain. Recently, several molecular mechanisms by which non-dioxin-like (NDL) PCBs mediate neurodevelopmental and neurobehavioral toxicity have been elucidated. However, although the G-protein coupled receptor (GPCR) is a significant target for neurobehavioral disturbance, our understanding of the effects of PCBs on GPCR signaling remains unclear. In this study, we investigated the effects of NDL-PCBs on GPCR-mediated Ca2+ signaling in PC12 cells. We found that ortho-substituted 2,2',6-trichlorinated biphenyl (PCB19) caused a rapid decline in the Ca2+ signaling of bradykinin, a typical Gq- and phospholipase Cbeta-coupled GPCR, without any effect on its inositol 1,4,5-trisphosphate production. PCB19 reduced thapsigargin-induced sustained cytosolic Ca2+ levels, suggesting that PCB19 inhibits SOCE. The abilities of other NDL-PCBs to inhibit store-operated Ca2+ entry (SOCE) were also examined and found to be of similar potencies to that of PCB19. PCB19 also showed a manner equivalent to that of known SOCE inhibitors. PCB19-mediated SOCE inhibition was confirmed by demonstrating the ability of PCB19 to inhibit the SOCE current and thapsigargin induced Mn2+ influx. These results imply that one of the molecular mechanism by which NDL-PCBs cause neurobehavioral disturbances involves NDL-PCB-mediated inhibition of SOCE, thereby interfering with GPCR-mediated Ca2+ signaling. PMID- 26963514 TI - Inhibition of TREM-1 and Dectin-1 Alleviates the Severity of Fungal Keratitis by Modulating Innate Immune Responses. AB - PURPOSE: To explore the possibility that inhibiting triggering receptor expressed on myeloid cells-1 (TREM-1) and Dendritic cell-associated C-type lectin-1(Dectin 1) could modulate the innate immune response and alleviate the severity of corneal fungal keratitis. METHOD: TREM-1 and Dectin-1 expression was detected in fungus-infected human corneal specimens by real-time PCR. C57BL/6 (B6) mice were injected with Aspergillus fumigatus and divided into 4 groups that received subconjunctival injections of PBS and IgG as a control (group I), mTREM-1/IgG fusion protein (group II), the soluble beta-glucan antagonist laminarin (group III), or mTREM-1/Fc and laminarin (group IV). Corneal virulence was evaluated based on clinical scores. TREM-1 and Dectin-1 mRNA levels were assayed using real time PCR. The distribution patterns of TREM-1, Dectin-1 and cellular infiltrates in fungus-infected corneas were examined by immunohistochemistry. Moreover, changes in T Helper Type1 (Th1)-/ T Helper Type1 (Th2)- type cytokines and proinflammatory cytokines were measured. RESULTS: The expression of TREM-1 and Dectin-1 increased significantly and correlated positively with the progression of fungal keratitis. Most infiltrated cells were neutrophils and secondarily macrophages in infected cornea. The clinical scores decreased after interfering with TREM-1 and Dectin-1 expression in infected mouse corneas. Levels of Th1-type cytokines including interleukin-12 (IL-12), IL-18 and interferon-gamma (IFN gamma) were decreased in the cornea, while the levels of Th2-type cytokines, including IL-4, IL-5 and IL-10, showed obvious increases. CONCLUSION: TREM-1 and Dectin-1 function concurrently in the corneal innate immune response by regulating inflammatory cytokine expression in fungal keratitis. Inhibition of TREM-1 and Dectin-1 can alleviate the severity of corneal damage by downregulating the excessive inflammatory response. PMID- 26963515 TI - Methanol Production by a Broad Phylogenetic Array of Marine Phytoplankton. AB - Methanol is a major volatile organic compound on Earth and serves as an important carbon and energy substrate for abundant methylotrophic microbes. Previous geochemical surveys coupled with predictive models suggest that the marine contributions are exceedingly large, rivaling terrestrial sources. Although well studied in terrestrial ecosystems, methanol sources are poorly understood in the marine environment and warrant further investigation. To this end, we adapted a Purge and Trap Gas Chromatography/Mass Spectrometry (P&T-GC/MS) method which allowed reliable measurements of methanol in seawater and marine phytoplankton cultures with a method detection limit of 120 nanomolar. All phytoplankton tested (cyanobacteria: Synechococcus spp. 8102 and 8103, Trichodesmium erythraeum, and Prochlorococcus marinus), and Eukarya (heterokont diatom: Phaeodactylum tricornutum, coccolithophore: Emiliania huxleyi, cryptophyte: Rhodomonas salina, and non-diatom heterokont: Nannochloropsis oculata) produced methanol, ranging from 0.8-13.7 micromolar in culture and methanol per total cellular carbon were measured in the ranges of 0.09-0.3%. Phytoplankton culture time-course measurements displayed a punctuated production pattern with maxima near early stationary phase. Stabile isotope labeled bicarbonate incorporation experiments confirmed that methanol was produced from phytoplankton biomass. Overall, our findings suggest that phytoplankton are a major source of methanol in the upper water column of the world's oceans. PMID- 26963517 TI - D-methionine (D-met) significantly reduces kanamycin-induced ototoxicity in pigmented guinea pigs. AB - OBJECTIVE: Test D-methionine (D-met) as an otoprotectant from kanamycin-induced ototoxicity and determine the lowest maximally protective D-met dose. DESIGN: Auditory brainstem responses (ABR) were measured at 4, 8, 14, and 20 kHz at baseline and two, four, and six weeks after kanamycin and D-met administration initiation. ABR threshold shifts assessed auditory function. Following six-week ABR testing, animals were decapitated and cochleae collected for outer hair cell (OHC) quantification. STUDY SAMPLE: Eight groups of 10 male pigmented guinea pigs were administered a subcutaneous kanamycin (250 mg/kg/dose) injection once per day and an intraperitoneal D-met injection (0 (saline), 120, 180, 240, 300, 360, 420, or 480 mg/kg/day) twice per day for 23 days. RESULTS: Significant ABR threshold shift reductions and increased OHC counts (p <= 0.01) were measured at multiple D-met-dosed groups starting at two-week ABR assessments. A 300 mg/kg/day optimal otoprotective D-met dose provided 34-41 dB ABR threshold shift reductions and OHC protection. Lesser, but significant, D-met otoprotection was measured at lower and higher D-met doses. CONCLUSIONS: D-met significantly reduced ABR threshold shifts and increased OHC percentages compared to kanamycin-treated controls. Results may be clinically significant particularly for multidrug resistant tuberculosis patients who frequently suffer from kanamycin-induced hearing loss in developing countries. PMID- 26963516 TI - Pharmacological and Genetic Modulation of REV-ERB Activity and Expression Affects Orexigenic Gene Expression. AB - The nuclear receptors REV-ERBalpha and REV-ERBbeta are transcription factors that play pivotal roles in the regulation of the circadian rhythm and various metabolic processes. The circadian rhythm is an endogenous mechanism, which generates entrainable biological changes that follow a 24-hour period. It regulates a number of physiological processes, including sleep/wakeful cycles and feeding behaviors. We recently demonstrated that REV-ERB-specific small molecules affect sleep and anxiety. The orexinergic system also plays a significant role in mammalian physiology and behavior, including the regulation of sleep and food intake. Importantly, orexin genes are expressed in a circadian manner. Given these overlaps in function and circadian expression, we wanted to determine whether the REV-ERBs might regulate orexin. We found that acute in vivo modulation of REV-ERB activity, with the REV-ERB-specific synthetic ligand SR9009, affects the circadian expression of orexinergic genes in mice. Long term dosing with SR9009 also suppresses orexinergic gene expression in mice. Finally, REV-ERBbeta-deficient mice present with increased orexinergic transcripts. These data suggest that the REV-ERBs may be involved in the repression of orexinergic gene expression. PMID- 26963518 TI - Mechanistic insights into induction of vitellogenin gene expression by estrogens in Sydney rock oysters, Saccostrea glomerata. AB - Marine molluscs, such as oysters, respond to estrogenic compounds with the induction of the egg yolk protein precursor, vitellogenin (Vtg), availing a biomarker for estrogenic pollution. Despite this application, the precise molecular mechanism through which estrogens exert their action to induce molluscan vitellogenesis is unknown. As a first step to address this question, we cloned a gene encoding Vtg from the Sydney rock oyster Saccostrea glomerata (sgVtg). Using primers designed from a partial sgVtg cDNA sequence available in Genbank, a full-length sgVtg cDNA of 8498bp was obtained by 5'- and 3'-RACE. The open reading frame (ORF) of sgVtg was determined to be 7980bp, which is substantially longer than the orthologs of other oyster species. Its deduced protein sequence shares the highest homology at the N- and C-terminal regions with other molluscan Vtgs. The full-length genomic DNA sequence of sgVtg was obtained by genomic PCR and genome walking targeting the gene body and flanking regions, respectively. The genomic sequence spans 20kb and consists of 30 exons and 29 introns. Computer analysis identified three closely spaced half-estrogen responsive elements (EREs) in the promoter region and a 210-bp CpG island 62bp downstream of the transcription start site. Upregulation of sgVtg mRNA expression was observed in the ovaries following in vitro (explants) and in vivo (tank) exposure to 17beta-estradiol (E2). Notably, treatment with an estrogen receptor (ER) antagonist in vitro abolished the upregulation, suggesting a requirement for an estrogen-dependent receptor for transcriptional activation. DNA methylation of the 5' CpG island was analysed using bisulfite genomic sequencing of the in vivo exposed ovaries. The CpG island was found to be hypomethylated (with 0-3% methylcytosines) in both control and E2-exposed oysters. However, no significant differential methylation or any correlation between methylation and sgVtg expression levels was observed. Overall, the results support the possible involvement of an ERE-containing promoter and an estrogen-activated receptor in estrogen signalling in marine molluscs. PMID- 26963519 TI - Thyroid active agents T3 and PTU differentially affect immune gene transcripts in the head kidney of rainbow trout (Oncorynchus mykiss). AB - In mammals, numerous reports describe an immunomodulating effect of thyroid active compounds. In contrast, only few reports have been published on this subject in fish. We previously demonstrated that immune cells of rainbow trout (Oncorhynchus mykiss) possess thyroid hormone receptors (THRs) and that exposure of trout to the thyroid hormone 3,3',5-triiodo-l-thyronine (T3) or the antithyroid drug propylthiouracil (PTU) alters immune cell transcript levels of THR and several immune genes. The present study aims to further characterize the immunomodulating action of thyroid-active compounds in trout immune cells. We report here the use of a custom-designed 60-mer oligo immune-targeted microarray for rainbow trout to analyze the gene expression profiles induced in the head kidney by T3 and PTU. Morphometric analyses of the thyroid showed that PTU exposure increased the size of the epithelial cells, whereas T3 induced no significant effects. Both T3 and PTU had diverse and partly contrasting effects on immune transcript profiles. The strongest differential effects of T3 and PTU on gene expressions were those targeting the Mitogen Associated Protein Kinase (MAPK), NFkB, Natural Killer (NK) and Toll-Like Receptor (TLR) pathways, a number of multipath genes (MPG) such as those encoding pleiotropic transcription factors (atf1, junb, myc), as well as important pro-inflammatory genes (tnfa, tnf6, il1b) and interferon-related genes (ifng, irf10). With these results we show for the first time in a fish species that the in vivo thyroidal status modulates a diversity of immune genes and pathways. This knowledge provides the basis to investigate both mechanisms and consequences of thyroid hormone- and thyroid disruptor-mediated immunomodulation for the immunocompetence of fish. PMID- 26963521 TI - Stability of Ensemble Models Predicts Productivity of Enzymatic Systems. AB - Stability in a metabolic system may not be obtained if incorrect amounts of enzymes are used. Without stability, some metabolites may accumulate or deplete leading to the irreversible loss of the desired operating point. Even if initial enzyme amounts achieve a stable steady state, changes in enzyme amount due to stochastic variations or environmental changes may move the system to the unstable region and lose the steady-state or quasi-steady-state flux. This situation is distinct from the phenomenon characterized by typical sensitivity analysis, which focuses on the smooth change before loss of stability. Here we show that metabolic networks differ significantly in their intrinsic ability to attain stability due to the network structure and kinetic forms, and that after achieving stability, some enzymes are prone to cause instability upon changes in enzyme amounts. We use Ensemble Modelling for Robustness Analysis (EMRA) to analyze stability in four cell-free enzymatic systems when enzyme amounts are changed. Loss of stability in continuous systems can lead to lower production even when the system is tested experimentally in batch experiments. The predictions of instability by EMRA are supported by the lower productivity in batch experimental tests. The EMRA method incorporates properties of network structure, including stoichiometry and kinetic form, but does not require specific parameter values of the enzymes. PMID- 26963522 TI - Advancing probiotic research in humans in the United States: Challenges and strategies. AB - This is a summary from a workshop convened as part of the 13(th) annual meeting of the International Scientific Association for Probiotics and Prebiotics. A group of 24 stakeholders, including clinical experts, researchers, federal government officials, funding agencies, lawyers and industry experts met to review the challenges of the current regulatory approach to human research on probiotics in the USA and to discuss ways to move research forward. There was agreement that some of the current regulatory requirements imposed on probiotic research in the United States hindered research progress and increased cost without improving study subject safety. Many situations were outlined by clinical investigators demonstrating the impact of regulatory delays on research progress. Additionally, research is compromised when study designs and outcomes require manipulation so as to invoke less burdensome regulatory requirements. These responses by investigators to regulatory requirements have placed United States' researchers at a disadvantage. The public ultimately suffer when research to clarify the role of these products on health is stalled. Workshop participants concurred that regulatory oversight should balance study subject vulnerability with documented safety for the intended use for the probiotic strain, and that human research on foods and supplements should not be be regulated as drug research. Challenges and potential improvement strategies are discussed. PMID- 26963520 TI - Does nutrient enrichment compensate fungicide effects on litter decomposition and decomposer communities in streams? AB - Nutrient and pesticide pollution are widespread agricultural stressors. Fungicides may affect freshwater fungi, which play an important role in litter decomposition (LD), whereas moderate nutrient enrichment can stimulate LD. We examined potential interaction effects of nutrients and fungicides on decomposer communities and LD in a 14-day two-factorial (fungicide and nutrient treatments) mesocosm experiment. Fungicide exposure was limited to 4days to simulate episodic contamination. Only the microbial community responded significantly to the experimental factors, though non-significant increases >20% were found for invertebrate decomposer weight gain and LD under high-nutrient conditions. Fungal community structure responded more strongly to fungicides than sporulation. Sporulation responded strongest to nutrients. Bacterial community structure was affected by both factors, although only nutrients influenced bacterial density. Our results suggest effects from fungicides at field-relevant levels on the microbial community. Whether these changes propagate to invertebrate communities and LD remains unclear and should be analysed under longer and recurrent fungicide exposure. PMID- 26963523 TI - Uncertainty in Ecohydrological Modeling in an Arid Region Determined with Bayesian Methods. AB - In arid regions, water resources are a key forcing factor in ecosystem circulation, and soil moisture is the critical link that constrains plant and animal life on the soil surface and underground. Simulation of soil moisture in arid ecosystems is inherently difficult due to high variability. We assessed the applicability of the process-oriented CoupModel for forecasting of soil water relations in arid regions. We used vertical soil moisture profiling for model calibration. We determined that model-structural uncertainty constituted the largest error; the model did not capture the extremes of low soil moisture in the desert-oasis ecotone (DOE), particularly below 40 cm soil depth. Our results showed that total uncertainty in soil moisture prediction was improved when input and output data, parameter value array, and structure errors were characterized explicitly. Bayesian analysis was applied with prior information to reduce uncertainty. The need to provide independent descriptions of uncertainty analysis (UA) in the input and output data was demonstrated. Application of soil moisture simulation in arid regions will be useful for dune-stabilization and revegetation efforts in the DOE. PMID- 26963524 TI - Fast and Controllable Crystallization of Perovskite Films by Microwave Irradiation Process. AB - The crystal growth process significantly influences the properties of organic inorganic halide perovskite films along with the performance of solar cell devices. In this paper, we adopted the microwave irradiation to treat perovskite films through a one-step deposition method for several minutes at a fixed output power. It is found that the specific microwave irradiation process can evaporate the solvent directly and heat perovskite film quickly. In comparison with the conventional thermal annealing process, a microwave irradiation process assisted fast and controllable crystallization of perovskite films with less energy-loss and time-consumption and therefore resulted in the enhancement in the photovoltaic performance of the corresponding solar cells. PMID- 26963525 TI - Correction: External Quality Assessment of Molecular Detection of Ebola Virus in China. PMID- 26963527 TI - Synthesis and antifungal activity of 2H-1,4-benzoxazin-3(4H)-one derivatives. AB - A series of 2-alkyl-2H-1,4-benzoxazin-3(4H)-ones (4a-l) was easily synthesized by two-step process involving O-alkylation of 2-nitrophenols with methyl 2 bromoalkanoates and next "green" catalytic reductive cyclization of the obtained 2-nitro ester intermediates (3a-l). Further, 6,7-dibromo (5a-c) and N-acetyl (6) derivatives were prepared by bromination and acetylation of unsubstituted 2-alkyl 2H-1,4-benzoxazin-3(4H)-ones (4a-c). The novel compounds (3a-l, 4d-l, 5a-c and 6) were fully characterized by spectroscopic methods (MS, (1)H and (13)C NMR). 2 Alkyl-2H-1,4-benzoxazin-3(4H)-ones (4a-l, 5a-c and 6) were screened for antifungal activity. Preliminary assays were performed using two methods: in vitro against seven phytopathogenic fungi-Botrytis cinerea, Phythophtora cactorum, Rhizoctonia solani, Phoma betae, Fusarium culmorum, Fusarium oxysporum and Alternaria alternata-and in vivo against barley powdery mildew Blumeria graminis. The tested compounds displayed moderate to good antifungal activity at high concentration (200 mg L(-1)). The most potent compounds were 2-ethyl-2H-1,4 benzoxazin-3(4H)-one (4a), 2-ethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (4g) and 4-acetyl-2-ethyl-2H-1,4-benzoxazin-3(4H)-one (6), which completely inhibited the mycelial growth of seven agricultural fungi at the concentration of 200 mg L(-1) in the in vitro tests. Moreover, 2-ethyl-2H-1,4-benzoxazin-3(4H)-one (4a) and 4 acetyl-2-ethyl-2H-1,4-benzoxazin-3(4H)-one (6) were also screened for antifungal activity at concentrations of 100 mg L(-1) and 20 mg L(-1). In the concentration of 100 mg L(-1), the N-acetyl derivative (6) completely inhibited the growth of three strains of fungi (F. culmorum, P. cactorum and R. solani), while 2-ethyl-2H 1,4-benzoxazin-3(4H)-one (4a) completely inhibited only R. solani strain. At the concentration of 20 mg L(-1), compound 6 showed good activity only against P. cactorum strain (72%). PMID- 26963526 TI - Computational Research on Mobile Pastoralism Using Agent-Based Modeling and Satellite Imagery. AB - Dryland pastoralism has long attracted considerable attention from researchers in diverse fields. However, rigorous formal study is made difficult by the high level of mobility of pastoralists as well as by the sizable spatio-temporal variability of their environment. This article presents a new computational approach for studying mobile pastoralism that overcomes these issues. Combining multi-temporal satellite images and agent-based modeling allows a comprehensive examination of pastoral resource access over a realistic dryland landscape with unpredictable ecological dynamics. The article demonstrates the analytical potential of this approach through its application to mobile pastoralism in northeast Nigeria. Employing more than 100 satellite images of the area, extensive simulations are conducted under a wide array of circumstances, including different land-use constraints. The simulation results reveal complex dependencies of pastoral resource access on these circumstances along with persistent patterns of seasonal land use observed at the macro level. PMID- 26963529 TI - Breaking out of the bubble. PMID- 26963530 TI - Immune profiling players shift gear to guide cancer drug development. PMID- 26963528 TI - HIV testing, risk perception, and behaviour in the British population. AB - OBJECTIVE: To examine the relationship between HIV risk behaviour, risk perception and testing in Britain. DESIGN: A probability sample survey of the British population. METHODS: We analyzed data on sexual behaviour, self-perceived HIV risk and HIV testing (excluding testing because of blood donation) from 13 751 sexually experienced men and women aged 16-74, interviewed between 2010 and 2012 using computer-assisted face-to-face and self-interviewing. RESULTS: Altogether, 3.5% of men and 5.4% of women reported having an HIV test in the past year. Higher perceived risk of HIV was associated with sexual risk behaviours and with HIV testing. However, the majority of those rating themselves as 'greatly' or 'quite a lot' at risk of HIV (3.4% of men, 2.5% of women) had not tested in the past year. This was also found among the groups most affected by HIV: MSM and black Africans. Within these groups, the majority reporting sexual risk behaviours did not perceive themselves as at risk and had not tested for HIV. Overall, 29.6% of men and 39.9% of women who tested for HIV in the past year could be classified as low risk across a range of measures. CONCLUSION: Most people who perceive themselves as at risk of HIV have not recently tested, including among MSM and black Africans. Many people tested in Britain are at low risk, reflecting current policy that aims to normalize testing. Strategies to further improve uptake of testing are needed, particularly in those at greatest risk, to further reduce undiagnosed HIV infection at late diagnoses. PMID- 26963532 TI - Natural killer cells blaze into immuno-oncology. PMID- 26963531 TI - Drug developers refocus efforts on RAS. PMID- 26963533 TI - FDA head Califf spurned. PMID- 26963534 TI - GM salmon shut out of US. PMID- 26963535 TI - GM mosquitoes fire first salvo against Zika virus. PMID- 26963536 TI - Bial incident raises FAAH suspicions. PMID- 26963537 TI - Seed spy pleads guilty. PMID- 26963538 TI - Sanofi drops MannKind's inhaled insulin. PMID- 26963540 TI - Aligning needs. PMID- 26963541 TI - Deciphering the EU clinical trials regulation. PMID- 26963542 TI - A call for industry to embrace green biopharma. PMID- 26963543 TI - Marketplace response to GM animal products. PMID- 26963544 TI - Digital medicine's march on chronic disease. PMID- 26963545 TI - Estimating the biotech sector's contribution to the US economy. PMID- 26963546 TI - 20 years of Nature Biotechnology research tools. PMID- 26963547 TI - 20 years of Nature Biotechnology biomedical research. PMID- 26963548 TI - 20 years of Nature Biotechnology bioengineering research. PMID- 26963551 TI - When biotech goes bad. PMID- 26963549 TI - Voices of biotech. PMID- 26963550 TI - Community crystal gazing. PMID- 26963552 TI - The changing life science patent landscape. PMID- 26963553 TI - From clinical imaging to implantation of 3D printed tissues. PMID- 26963555 TI - Cas9 loosens its grip on off-target sites. PMID- 26963554 TI - Haplotypes drop by drop. PMID- 26963557 TI - Towards sustaining a culture of mental health and wellness for trainees in the biosciences. PMID- 26963560 TI - Extending the Hydrophobic Mismatch Concept to Amphiphilic Membranolytic Peptides. AB - A series of nine amphiphilic, pore-forming alpha-helical KIA peptides (KIAGKIA repeats) with lengths between 14 and 28 residues were studied by solid-state (15)N NMR to determine their alignment in oriented lipid bilayers. In a 2:1 mixture of 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) with its corresponding 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (lyso-MPC), which has a highly positive spontaneous curvature, the helix tilt angle was found to vary steadily with peptide length. The shortest peptide was aligned transmembrane and upright, while the longer ones successively became tilted away from the membrane normal. This behavior is in agreement with the hydrophobic matching concept, conceived so far only for hydrophobic helices. In 1,2-dioleoyl-sn glycero-3-phosphatidylcholine, with a negative spontaneous curvature, all KIA peptides remained flat on the bilayer surface, while the cylindrical DMPC lipids permitted a slight tilt. Peptide insertion thus depends critically on the intrinsic lipid curvature, and helix orientation is then fine-tuned by membrane thickness. A refined toroidal pore model is proposed. PMID- 26963561 TI - Comparison of two quantitative fit-test methods using N95 filtering facepiece respirators. AB - Current regulations require annual fit testing before an employee can wear a respirator during work activities. The goal of this research is to determine whether respirator fit measured with two TSI Portacount instruments simultaneously sampling ambient particle concentrations inside and outside of the respirator facepiece is similar to fit measured during an ambient aerosol condensation nuclei counter quantitative fit test. Sixteen subjects (ten female; six male) were recruited for a range of facial sizes. Each subject donned an N95 filtering facepiece respirator, completed two fit tests in random order (ambient aerosol condensation nuclei counter quantitative fit test and two-instrument real time fit test) without removing or adjusting the respirator between tests. Fit tests were compared using Spearman's rank correlation coefficients. The real-time two-instrument method fit factors were similar to those measured with the single instrument quantitative fit test. The first four exercises were highly correlated (r > 0.7) between the two protocols. Respirator fit was altered during the talking or grimace exercise, both of which involve facial movements that could dislodge the facepiece. Our analyses suggest that the new real-time two instrument methodology can be used in future studies to evaluate fit before and during work activities. PMID- 26963562 TI - Relationship between quality-of-life after 1-year follow-up and severity of traumatic brain injury assessed by computerized tomography. AB - PURPOSE: This paper studies the relationship between computed tomography (CT) scan on admission, according to Marshall's tomographic classification, and quality-of-life (QoL) after 1 year in patients admitted to the Intensive Care Unit (ICU) with traumatic brain injury (TBI). METHODS: This study used validated scales including the Glasgow Outcome Scale and the PAECC (Project for the Epidemiologic Analysis of Critical Care Patients) QoL questionnaire. RESULTS: We enrolled 531 patients. After 1 year, 171 patients (32.2%) had died (missing data = 6.6%). Good recovery was seen in 22.7% of the patients, while 20% presented moderate disability. The PAECC score after 1 year was 9.43 +/- 8.72 points (high deterioration). Patients with diffuse injury I had a mean of 5.08 points vs 7.82 in those with diffuse injury II, 11.76 in those with diffuse injury III and 19.29 in those with diffuse injury IV (p < 0.001). Multivariate analysis found that QoL after 1 year was associated with CT Marshall classification, depth of coma, age, length of stay, spinal injury and tracheostomy. CONCLUSIONS: Patients with TBI had a high mortality rate 1 year after admission, deterioration in QoL and significant impairment of functional status, although more than 40% were normal or self-sufficient. QoL after 1 year was strongly related to cranial CT findings on admission. PMID- 26963563 TI - Length-independent structural similarities enrich the antibody CDR canonical class model. AB - Complementarity-determining regions (CDRs) are antibody loops that make up the antigen binding site. Here, we show that all CDR types have structurally similar loops of different lengths. Based on these findings, we created length independent canonical classes for the non-H3 CDRs. Our length variable structural clusters show strong sequence patterns suggesting either that they evolved from the same original structure or result from some form of convergence. We find that our length-independent method not only clusters a larger number of CDRs, but also predicts canonical class from sequence better than the standard length-dependent approach. To demonstrate the usefulness of our findings, we predicted cluster membership of CDR-L3 sequences from 3 next-generation sequencing datasets of the antibody repertoire (over 1,000,000 sequences). Using the length-independent clusters, we can structurally classify an additional 135,000 sequences, which represents a ~20% improvement over the standard approach. This suggests that our length-independent canonical classes might be a highly prevalent feature of antibody space, and could substantially improve our ability to accurately predict the structure of novel CDRs identified by next-generation sequencing. PMID- 26963564 TI - The Emerging Zika Virus Epidemic in the Americas: Research Priorities. PMID- 26963565 TI - How to Assess and Document Endoscopies in IBD Patients by Including Standard Scoring Systems. AB - Endoscopy has become an essential tool for effective management of patients with inflammatory bowel disease, including Crohn's disease and ulcerative colitis. The endoscopic management of inflammatory bowel disease ranges from diagnosing the disease, assessing the disease's extent, and activity to monitor the responses to various medical therapies with assessment of mucosal healing, serving as a predictor of disease course and response to therapy to finally treating the disease's complications. In general, the use of endoscopic scoring systems has been recommended for assessing the activity of the disease, and the prognosis and efficacy of medical treatment. However, many of currently available endoscopic scoring systems are often too complicated for their routine use in clinical practice, lacking adequate interobserver agreement and formal validation. In this review, we will discuss how we should be assessing and documenting endoscopies in inflammatory bowel disease patients and incorporating standard scoring systems into patients' care. PMID- 26963566 TI - Use of Cancer Stem Cells to Investigate the Pathogenesis of Colitis-associated Cancer. AB - Colitis-associated cancer (CAC) can develop in patients with inflammatory bowel disease with long-term uncontrolled inflammation. The mutational history and tumor microenvironment observed in CAC patients is distinct from that observed in sporadic colon cancer and suggests a different etiology. Recently, much attention has been focused on understanding the cellular origin of cancer and the cancer stem cells, which is key to growth and progression. Cancer stem cells are often chemo-resistant making them attractive targets for improving patient outcomes. New techniques have rapidly been evolving allowing for a better understanding of the normal intestinal stem cell function and behavior in the niche. Use of these new technologies will be crucial to understanding cancer stem cells in both sporadic and CAC. In this review, we will explore emerging methods related to the study of normal and cancer stem cells in the intestine, and examine potential avenues of investigation and application to understanding the pathogenesis of CAC. PMID- 26963568 TI - Gibbon Aggression During Introductions: An International Survey. AB - Little is known regarding the prevalence of aggression seen during introductions of captive gibbons (Hylobatidae). In this study, an online survey was developed to quantify and collect contextual details regarding the frequency and types of aggression seen during introductions of captive gibbons (Hylobatidae). Nineteen percent of institutions (17 institutions) reported observing aggression, and 6 of these institutions recorded multiple instances of aggression, though a vast majority of these cases resulted in mild injuries or none at all. The female was the primary aggressor in 23% of cases, the male was the primary aggressor in 58% of cases, and both were the primary aggressor in 1 case. Although these aggressive interactions were often not associated with a known cause, 27% of cases were associated with food displacement. In most cases, management changes, including trying new pairings, greatly reduced situational aggression, suggesting that individual personalities may play a factor in aggression. These data begin to explain the extent of aggression observed in captive gibbons; future studies will address possible correlations with aggression and introduction techniques. PMID- 26963567 TI - Respective Roles of Hematopoietic and Nonhematopoietic Nod2 on the Gut Microbiota and Mucosal Homeostasis. AB - BACKGROUND: NOD2 mutations are associated with Crohn's disease (CD). Both CD (in human) and Nod2 deficiency (in mice) are characterized by increased mucosal CD4 T cells, an altered permeability and a microbial dysbiosis. However, the respective roles of the gut epithelial and immune compartments on the phenotype are not known. METHODS: Microbial composition, epithelial peptide secretion, intestinal permeability, and immune cell composition of Peyer patches were studied in Nod2 knock-out mice transplanted with wild-type bone marrow cells and vice versa. RESULTS: The nonhematopoietic cells control the microbiota composition and epithelial secretion of mucins and antimicrobial peptides. These parameters are correlated with recurrent associations between bacterial species and luminal products. In contrast, Nod2 in the hematopoietic compartment regulates the epithelial permeability and the gut-associated lymphoid tissue independently of the bacterial composition. CONCLUSIONS: The immune system and the gut permeability in one hand and the microbial and epithelial peptide compositions in the other hand are separate couples of interdependent parameters, both controlled by Nod2 in either the hematopoietic or nonhematopoietic lineages. PMID- 26963569 TI - Long-Term Effects of Individually Tailored Physical Training and Activity on Physical Function, Well-Being and Cognition in Scandinavian Nursing Home Residents: A Randomized Controlled Trial. AB - BACKGROUND: The preservation of physical functions such as muscle strength, balance and mobility is fundamental to maintaining independence in activities of daily living (ADL). The physical activity level of most nursing home residents is very low, which implies that they are often subject to a decline in health, mobility, autonomy and social contacts and are also at risk of suffering a decline in mental well-being. In a previous study, we demonstrated that transfers, balance and physical activity level improved after 3 months of individually tailored intervention in nursing home residents. OBJECTIVE: To evaluate the long-term effects on ADL, balance function, physical activity level, physical performance, falls-related self-efficacy, well-being and cognitive function 3 months after the completion of our intervention in nursing home residents. METHODS: The study was a multicenter randomized, controlled clinical trial with a parallel-group design. It was conducted in nursing homes in Sweden, Norway and Denmark, with an intervention period lasting 3 months and a follow-up at 6 months. Initially, 322 nursing home residents with a mean age of 85 years were included; 85 from Sweden, 171 from Norway and 66 from Denmark. Of these, 241 [129 intervention group (IG), 112 control group (CG)] were eligible for the 6 month follow-up tests. The level of dependence in ADL, physical activity level, several dimensions of physical function, well-being, falls-related self-efficacy and cognitive function were assessed with reliable and valid instruments at baseline, immediately after 3 months of intervention and 3 months later at the 6 month follow-up. RESULTS: After 3 months of intervention and an additional period of 3 months without intervention, only the following 2 variables demonstrated significant group differences: social and cognitive function, measured by the Functional Independence Measure n-r, where the IG deteriorated while the CG was almost stable. However, regarding transfers, the IG deteriorated significantly less than the CG. CONCLUSION: Without supervised physical exercise that challenged the individuals' capability, gains in ADL function, balance and transfer ability deteriorated during the 3 months following the intervention period. Thus, continuous, individually adjusted and supported physical activity seems crucial for the maintenance of physical functions in these vulnerable elderly persons. PMID- 26963570 TI - Correction to Influence of Coffee Genotype on Bioactive Compounds and the in Vitro Capacity To Scavenge Reactive Oxygen and Nitrogen Species. PMID- 26963572 TI - Electronic Structures of Anti-Ferromagnetic Tetraradicals: Ab Initio and Semi Empirical Studies. AB - The energy relationships and electronic structures of the lowest-lying spin states in several anti-ferromagnetic tetraradical model systems are studied with high-level ab initio and semi-empirical methods. The Full-CI method (FCI), the complete active space second-order perturbation theory (CASPT2), and the n electron valence state perturbation theory (NEVPT2) are employed to obtain reference results. By comparing the energy relationships predicted from the Heisenberg and Hubbard models with ab initio benchmarks, the accuracy of the widely used Heisenberg model for anti-ferromagnetic spin-coupling in low-spin polyradicals is cautiously tested in this work. It is found that the strength of electron correlation (|U/t|) concerning anti-ferromagnetically coupled radical centers could range widely from strong to moderate correlation regimes and could become another degree of freedom besides the spin multiplicity. Accordingly, the Heisenberg-type model works well in the regime of strong correlation, which reproduces well the energy relationships along with the wave functions of all the spin states. In moderately spin-correlated tetraradicals, the results of the prototype Heisenberg model deviate severely from those of multi-reference electron correlation ab initio methods, while the extended Heisenberg model, containing four-body terms, can introduce reasonable corrections and maintains its accuracy in this condition. In the weak correlation regime, both the prototype Heisenberg model and its extended forms containing higher-order correction terms will encounter difficulties. Meanwhile, the Hubbard model shows balanced accuracy from strong to weak correlation cases and can reproduce qualitatively correct electronic structures, which makes it more suitable for the study of anti-ferromagnetic coupling in polyradical systems. PMID- 26963571 TI - Dopamine Polymerization in Liquid Marbles: A General Route to Janus Particle Synthesis. AB - Coating a liquid with a particle shell not only renders a droplet superhydrophobic but also isolates a well-confined microenvironment for miniaturized chemical processes. Previously, we have demonstrated that particles at the liquid marble interface provide an ideal platform for the site-selective modification of superhydrophobic particles. However, the need for a special chemical reaction limits their potential use for the fabrication of Janus particles with various properties. Herein, we combine the employment of liquid marbles as microreactors with the remarkable adhesive ability of polydopamine to develop a general route for the synthesis of Janus particles from micrometer sized superhydrophobic particles. We demonstrate that dopamine polymerization and deposition inside liquid marbles could be used for the selective surface modification of microsized silica particles, resulting in the formation of Janus particles. Moreover, it is possible to manipulate the Janus balance of the particles via the addition of surfactants and/or organic solvents to tune the interfacial energy. More importantly, owing to the many functional groups in polydopamine, we show that versatile strategies could be introduced to use these partially polydopamine-coated silica particles as platforms for further modification, including nanoparticle immobilization, metal ion chelation and reduction, as well as for chemical reactions. Given the flexibility in the choice of cores and the modification strategies, this developed method is distinctive in its high universality, good controllability, and great practicability. PMID- 26963573 TI - Cases of Ischemic Optic Neuropathy Associated With Phosphodiesterase-5 Inhibitor Use Reported to the Food and Drug Administration Adverse Event Reporting System. PMID- 26963574 TI - Sulphur-containing compounds in the essential oil of Ferula alliacea roots and their mass spectral fragmentation patterns. AB - Context GC-MS analysis is the best way to characterize volatile sulphur containing compounds. Ferula (Apiaceae) is a genus of perennial herbs. Due to the occurrence of essential oils or oleoresins in the Ferula species, these plants usually possess strong aromatic scent. Terpenoid compounds were the most abundant constituents of Ferula oils, however, in some of Ferula species, the essential oils were dominated by volatile sulphur-containing compounds. Objectives Ferula alliacea Boiss. is considered one of the sources of the oleo-gum-resin asafoetida. In this study, we analyzed the hydrodistilled essential oil from its dried roots and provide new data about retention indices and mass fragmentation patterns of some volatile sulphur-containing compounds that are useful for future studies on this class of compounds. Materials and methods The roots of F. alliacea were collected during the flowering stage of plant, from Bezgh, Kashmar to Neishabour road, Khorasan-Razavi province, Iran, in June 2012. The oil was obtained by hydrodistillation using a Clevenger apparatus and analyzed by GC-MS. Results This is the first report on phytochemical analysis of F. alliacea roots. Seventy-six components, representing 99.5% of the oil, were characterized. The major components were 10-epi-gamma-eudesmol (22.3%), valerianol (12.5%), hinesol (8.3%), guaiol (7.3%) and Z-propenyl-sec-butyl trisulphide (6.5%). Predominant mass fragment ions of the identified sulphur-containing compounds are explained in this paper. Conclusion The volatile oil of F. alliacea mostly contains oxygenated sesquiterpenes, however, its odour was dominated by sulphur-containing compounds. The most abundant sulphur-containing compound includes Z-propenyl-sec butyl trisulphide (6.5%). PMID- 26963575 TI - A history of the Scandinavian Journal of Work, Environment & Health. PMID- 26963576 TI - Brain MR Imaging in Patients with Lower Motor Neuron-Predominant Disease. AB - Purpose To investigate the patterns of cortical thinning and white matter tract damage in patients with lower motor neuron (LMN)-predominant disease compared with healthy control subjects and those with classic amyotrophic lateral sclerosis (ALS) and to evaluate the relationship between brain structural changes and clinical and cognitive features in these patients. Materials and Methods This study was approved by the local ethical committee, and written informed consent was obtained from all subjects before enrollment. Twenty-eight patients with LMN predominant disease were compared with 55 patients with ALS and 56 healthy control subjects. Patients underwent a clinical and neuropsychological assessment and T1-weighted and diffusion-tensor magnetic resonance (MR) imaging. Surface based morphometry was used to assess cortical thickness. Tract-based spatial statistics and tractography were used to study white matter tract damage. Results Patients with LMN-predominant disease did not show differences compared with healthy control subjects in cortical thickness and diffusion-tensor MR imaging metrics. Patients with ALS showed cortical thinning of the motor-related cortices and a distributed involvement of the prefrontal, temporal, and parietal gyri (P < .05, false discovery rate corrected). Patients with ALS also showed white matter damage along motor and extramotor tracts compared with control subjects and patients with LMN-predominant disease (tract-based spatial statistics: P < .05, family-wise error corrected; tractography: P values < .001 to .05, false discovery rate corrected). In patients with LMN-predominant disease, cognitive deficits correlated with alterations in diffusivity in the left cingulum (r = 0.66, P = .01) and superior longitudinal fasciculus (r = -0.65, P = .05). Conclusion Motor and extramotor cortical thinning and diffusion-tensor MR imaging alterations were specific for motor neuron disease phenotypes, with clinically overt upper motor neuron involvement. However, the lack of significant differences in cortical thickness between subjects with LMN-predominant disease and those with ALS and cognitive deficits associated with alterations in diffusivity in patients with LMN-predominant disease suggest that investigating brain structural and microstructural MR imaging features may provide markers of central nervous system damage in patients with rare motor neuron disease. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 26963578 TI - Focusing on lower extremity DVT. PMID- 26963577 TI - Diagnostic Yield and Clinical Utility of Abdominopelvic CT Following Emergent Laparotomy for Trauma. AB - Purpose To determine the incidence of unexpected injuries that are diagnosed with computed tomography (CT) after emergent exploratory laparotomy for trauma and whether identification of such injuries results in additional surgery or angiography. Materials and Methods This HIPAA-compliant retrospective study was approved by the institutional review board, and the requirement for informed consent was waived. The trauma databases of two urban level 1 trauma centers were queried over a period of more than 5 years for patients who underwent abdominopelvic CT within 48 hours of emergent exploratory laparotomy for trauma. Comparisons were made between CT findings and those described in the surgical notes. Descriptive statistics were generated, and 95% confidence intervals (CIs) were determined by using an exact method based on a binomial distribution. Results The study cohort consisted of 90 patients, including both blunt and penetrating trauma victims with a median injury severity score of 17.5 (interquartile range, 9.25-34). Seventy-three percent (66 of 90) of patients sustained penetrating trauma, 82% (74 of 90) of whom were male. A total of 19 patients (21.1%; 95% CI: 13.2, 31.0) had additional injuries within the surgical field that were not identified during laparotomy. There were 17 unidentified solid organ injuries, and eight patients had active bleeding within the surgical field. Eight patients (8.9%; 95% CI: 3.9, 16.8) had unexpected injuries at CT that were substantial enough to warrant additional surgery or angiography. In addition, previously undiagnosed fractures were found in 45 patients (50%; 95% CI: 39.3, 60.7). Conclusion Performing CT after emergent exploratory laparotomy for trauma is useful in identifying unexpected injuries and confirming suspected injuries that were not fully explored at initial surgery. ((c)) RSNA, 2016. PMID- 26963579 TI - Nutritional support and the role of the stress response in critically ill children. AB - PURPOSE OF REVIEW: Nutrition impacts outcome in critically ill children. Based on evolving neuro-endocrine, immunologic and metabolic alterations, three different phases can be proposed during the course of illness. The different phases each demand for tailored macronutrient intakes in critically ill children. RECENT FINDINGS: Early enteral nutrition is associated with decreased morbidity and mortality, but several misconceptions concerning the provision of enteral nutrition prevent adequate intake. Parenteral nutrition in critically ill children is associated with potential disadvantages, as nosocomial infections, but evidence on the effect on clinical outcome is lacking. Nutrient restriction early during critical illness might be beneficial for short and long-term outcomes by decreasing the incidence of side-effects and possibly by amplifying the acute catabolic stress response and stimulating autophagy and muscle integrity. Higher caloric and protein intake via the enteral route are associated with higher 60-day survival, asking for a more aggressive feeding approach in subsequent phases. SUMMARY: Understanding the stress response to critical illness and its phases is essential for nutritional recommendations in critically ill children. Although parenteral nutrient restriction during the acute phase might be beneficial, inclining requirements ask for a more aggressive approach during the stable and recovery phase to enable recovery, growth and catch-up growth. PMID- 26963580 TI - Severe acute malnutrition. AB - PURPOSE OF REVIEW: The mortality and morbidity associated with severe acute malnutrition (SAM) remain high. A summary of recent studies that are of interest to clinicians treating children with SAM is provided. RECENT FINDINGS: Three important themes emerged in 2015: the use of anthropometry in the diagnosis of SAM and its correlation with body composition; the composition of ready-to-use therapeutic feeds (RUTF); and an improved understanding of the pathophysiology of SAM. SUMMARY: Standard anthropometry does not accurately predict body composition and mid-upper arm circumference more accurately reflects fat mass in children. As single measure, mid-upper arm circumference identifies those children who are most likely to die from SAM and is not influenced by dehydration. However, a significant proportion of SAM children requiring treatment will not be detected. Present RUTF formulations are deficient in long chain polyunsaturated fatty acids. Current evidence suggests that preformed docosahexaenoic acid should be added and/or the content of linoleic acid reduced in RUTF. In contrast to an animal model, stabile children with SAM have the same cardiac index as children without SAM. The situation in haemodynamically unstable children is unknown, continued conservative use of intravenous fluids seems advisable. A reduction in variability of the faecal DNA virome may account for increased susceptibility to malnutrition in vulnerable children. PMID- 26963581 TI - Oral zinc provision in acute diarrhea. AB - PURPOSE OF REVIEW: The clinical management of acute diarrhea is based on the use of oral rehydration salts and appropriate nutrition. In addition, the WHO and The United Nations Children's Fund recommend zinc supplementation for diarrhea in children below 5 years. This article aims at reviewing recent literature on the effects of oral zinc for treating acute diarrhea in children. RECENT FINDINGS: Recent studies confirm that zinc supplementation has a benefit in children below 5 years with acute diarrhea in countries at medium or high risk of zinc deficiency. A few small trials have reported a benefit of zinc in children at low risk of zinc deficiency, with heterogeneity in results. No recent study has explored the effects of zinc in children younger than 6 months, and in this age group previous research refuted any benefit from zinc. SUMMARY: Current literature supports the use of oral zinc in treating diarrhea in children older than 6 months, especially if at risk of zinc deficiency, such as children with poor diets exposed to recurrent gastrointestinal infections. More research is needed to confirm findings in children at low risk of zinc deficiency. Currently there is no evidence that zinc benefits children younger than 6 months. PMID- 26963582 TI - A potent antibacterial indole alkaloid from Psychotria pilifera. AB - A new strychnine alkaloid, 16,17,19,20-tetrahydro-2,16-dehydro-18 deoxyisostrychnine (1), and fourteen known alkaloids were isolated from the leaves of Psychotria pilifera. Their structures were identified on the basis of extensive spectroscopic analysis, as well as by comparison with the reported spectroscopic data. The new alkaloid (1) exhibited potent antibacterial activity against Escherichia coli, equivalent to cefotaxime with MIC value of 0.781 MUg/ml. PMID- 26963583 TI - Thickness-dependent charge transport in few-layer MoS2 field-effect transistors. AB - Molybdenum disulfide (MoS2) is currently under intensive study because of its exceptional optical and electrical properties in few-layer form. However, how charge transport mechanisms vary with the number of layers in MoS2 flakes remains unclear. Here, exfoliated flakes of MoS2 with various thicknesses were successfully fabricated into field-effect transistors (FETs) to measure the thickness and temperature dependences of electrical mobility. For these MoS2 FETs, measurements at both 295 K and 77 K revealed the maximum mobility for layer thicknesses between 5 layers (~3.6 nm) and 10 layers (~7 nm), with ~70 cm(2) V( 1) s(-1) measured for 5 layer devices at 295 K. Temperature-dependent mobility measurements revealed that the mobility rises with increasing temperature to a maximum. This maximum occurs at increasing temperature with increasing layer thickness, possibly due to strong Coulomb scattering from charge impurities or weakened electron-phonon interactions for thicker devices. Temperature-dependent conductivity measurements for different gate voltages revealed a metal-to insulator transition for devices thinner than 10 layers, which may enable new memory and switching applications. This study advances the understanding of fundamental charge transport mechanisms in few-layer MoS2, and indicates the promise of few-layer transition metal dichalcogenides as candidates for potential optoelectronic applications. PMID- 26963585 TI - Translation, cross-cultural adaptation and psychometric properties of the Back Beliefs Questionnaire in Modern Standard Arabic. AB - Purpose To translate and cross-culturally adapt the Back Beliefs Questionnaire (BBQ) into modern standard Arabic and examine its validity, acceptability and reliability in Arabic-speaking patients with low back pain (LBP). Method The BBQ was forward, back-translated and reviewed by an expert committee. Seventeen bilingual patients completed Arabic and English BBQs. LBP patients (n = 199) completed the Arabic BBQ. Sixty-four repeated it a week later, and 151 completed the Arabic Fear-avoidance Beliefs Questionnaire (FABQ). Results The expert committee followed advice from the developers to maintain Arabic equivalence of "back trouble(s)". Patients found the questionnaire comprehensible and acceptable. Agreement between the English and Arabic versions of the BBQ was acceptable, ICC = 0.65 (0.25-0.86). Most item-by-item agreement ranged from fair to moderate (K = 0.12-0.54). Mean (SD) of BBQ, FABQ total, work and physical activity subscales were 25.31(6.13), 44.76(19.49), 21.17(10.10) and 13.95(6.65). The BBQ correlated with the FABQ at r = -0.33, work subscale r = -0.29 and physical activity r = -0.30 (all p < 0.01). Cronbach's alpha = 0.73 indicated high internal consistency. Test-retest reliability was high, ICC = 0.80 (0.68 0.87). Item-by-item agreement ranged from fair to acceptable (K = 0.31-0.66). Conclusions The Arabic BBQ has good comprehensibility and acceptability, acceptable agreement with the English BBQ, high internal consistency and test retest reliability. We recommend its use with Arabic-speaking LBP patient to determine their beliefs and attitudes about their back pain, as they have been shown to be important predictors of persistent LBP disability. Implications for Rehabilitation There are limited valid and reliable outcome measures for back pain in Arabic. The Back Beliefs Questionnaire (BBQ) is a tool that measures attitudes and beliefs about back pain. We recommend the use of our valid and reliable, translated and cross-culturally adapted tool with Arabic-speaking patients. The tool can measure attitudes and beliefs concerning the future consequences of LBP, with regards to recovery and return to work in this sample. Findings will improve back pain management options aimed at reducing back pain disability though challenging and modifying beliefs in the Middle East or with migrant populations in the West. PMID- 26963588 TI - Self-Limiting Oxides on WSe2 as Controlled Surface Acceptors and Low-Resistance Hole Contacts. AB - Transition metal oxides show much promise as effective p-type contacts and dopants in electronics based on transition metal dichalcogenides. Here we report that atomically thin films of under-stoichiometric tungsten oxides (WOx with x < 3) grown on tungsten diselenide (WSe2) can be used as both controlled charge transfer dopants and low-barrier contacts for p-type WSe2 transistors. Exposure of atomically thin WSe2 transistors to ozone (O3) at 100 degrees C results in self-limiting oxidation of the WSe2 surfaces to conducting WOx films. WOx-covered WSe2 is highly hole-doped due to surface electron transfer from the underlying WSe2 to the high electron affinity WOx. The dopant concentration can be reduced by suppressing the electron affinity of WOx by air exposure, but exposure to O3 at room temperature leads to the recovery of the electron affinity. Hence, surface transfer doping with WOx is virtually controllable. Transistors based on WSe2 covered with WOx show only p-type conductions with orders of magnitude better on-current, on/off current ratio, and carrier mobility than without WOx, suggesting that the surface WOx serves as a p-type contact with a low hole Schottky barrier. Our findings point to a simple and effective strategy for creating p-type devices based on two-dimensional transition metal dichalcogenides with controlled dopant concentrations. PMID- 26963589 TI - Chemical Pollutants Sorbed to Ingested Microbeads from Personal Care Products Accumulate in Fish. AB - The prevalence of microplastics (<5 mm) in natural environments has become a widely recognized global problem. Microplastics have been shown to sorb chemical pollutants from their surrounding environment, thus raising concern as to their role in the movement of these pollutants through the food chain. This experiment investigated whether organic pollutants sorbed to microbeads (MBs) from personal care products were assimilated by fish following particle ingestion. Rainbow fish (Melanotaenia fluviatilis) were exposed to MBs with sorbed polybrominated diphenyl ethers (PBDEs; BDE-28, -47, -100, -99, -153, -154, -183, 200 ng g(-1); BDE-209, 2000 ng g(-1)) and sampled at 0, 21, 42, and 63 days along with two control treatments (food only and food + clean MBs). Exposed fish had significantly higher Sigma8PBDE concentrations than both control treatments after just 21 days, and continued exposure resulted in increased accumulation of the pollutants over the experiment (ca. 115 pg g(-1) ww d(-1)). Lower brominated congeners showed the highest assimilation whereas higher brominated congeners did not appear to transfer, indicating they may be too strongly sorbed to the plastic or unable to be assimilated by the fish due to large molecular size or other factors. Seemingly against this trend, however, BDE-99 did not appear to bioaccumulate in the fish, which may be due to partitioning from the MBs or it being metabolized in vivo. This work provides evidence that MBs from personal care products are capable of transferring sorbed pollutants to fish that ingest them. PMID- 26963591 TI - Norms for developmental milestones using VABS-II and association with anthropometric measures among apparently healthy urban Indian preschool children. AB - Assessment of developmental milestones based on locally developed norms is critical for accurate estimate of overall development of a child's cognitive, behavioral, social, and emotional development. A cross-sectional study was done to develop age specific norms for developmental milestones using Vineland Adaptive Behavior Scales (VABS-II) (Sparrow, Cicchetti, & Balla, 2005) for apparently healthy children from 2 to 5 years from urban Bangalore, India, and to examine its association with anthropometric measures. Mothers (or caregivers) of 412 children participated in the study. Age-specific norms using inferential norming method and adaptive levels for all domains and subdomains were derived. Low adaptive level, also called delayed developmental milestone, was observed in 2.3% of the children, specifically 2.7% in motor and daily living skills and 2.4% in communication skills. When these children were assessed on the existing U.S. norms, there was a significant overestimation of delayed development in socialization and motor skills, whereas delay in communication and daily living skills were underestimated (all p < .01). Multiple linear regression revealed that stunted and underweight children had significantly lower developmental scores for communication and motor skills compared with normal children (beta coefficient ranges from 2.6-5.3; all p < .01). In the absence of Indian normative data for VABS-II in preschool children, the prevalence of developmental delay could either be under- or overestimated using Western norms. Thus, locally referenced norms are critical for reliable assessments of development in children. Stunted and underweight children are more likely to have poorer developmental scores compared with healthy children. (PsycINFO Database Record PMID- 26963590 TI - Factor structure of the ARIC-NCS Neuropsychological Battery: An evaluation of invariance across vascular factors and demographic characteristics. AB - Neuropsychological test batteries are designed to assess cognition in detail by measuring cognitive performance in multiple domains. This study examines the factor structure of tests from the ARIC-NCS battery overall and across informative subgroups defined by demographic and vascular risk factors in a population of older adults. We analyzed neuropsychological test scores from 6,413 participants in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) examined in 2011-2013. Confirmatory factor analysis (CFA) was used to assess the fit of an a priori hypothesized 3-domain model, and fit statistics were calculated and compared to 1- and 2-domain models. Additionally, we tested for stability (invariance) of factor structures among different subgroups defined by diabetes, hypertension, age, sex, race, and education. Mean age of participants was 76 years, 76% were White, and 60% were female. CFA on the a priori hypothesized 3-domain structure, including memory, sustained attention and processing speed, and language, fit the data better (comparative fit index [CFI] = 0.973, root mean square error of approximation [RMSEA] = 0.059) than the 2 domain (CFI = 0.960, RMSEA = 0.070) and 1-domain (CFI = 0.947, RMSEA = 0.080) models. Bayesian information criterion value was lowest, and quantile-quantile plots indicated better fit, for the 3-domain model. Additionally, multiple-group CFA supported a common structure across the tested demographic subgroups, and indicated strict invariance by diabetes and hypertension status. In this community-based population of older adults with varying levels of cognitive performance, the a priori hypothesized 3-domain structure fit the data well. The identified factors were configurally invariant by age, sex, race, and education, and strictly invariant by diabetes and hypertension status. (PsycINFO Database Record PMID- 26963593 TI - Increase in Reported Prevalence of Microcephaly in Infants Born to Women Living in Areas with Confirmed Zika Virus Transmission During the First Trimester of Pregnancy - Brazil, 2015. AB - Widespread transmission of Zika virus by Aedes mosquitoes has been recognized in Brazil since late 2014, and in October 2015, an increase in the number of reported cases of microcephaly was reported to the Brazil Ministry of Health.* By January 2016, a total of 3,530 suspected microcephaly cases had been reported, many of which occurred in infants born to women who lived in or had visited areas where Zika virus transmission was occurring. Microcephaly surveillance was enhanced in late 2015 by implementing a more sensitive case definition. Based on the peak number of reported cases of microcephaly, and assuming an average estimated pregnancy duration of 38 weeks in Brazil (1), the first trimester of pregnancy coincided with reports of cases of febrile rash illness compatible with Zika virus disease in pregnant women in Bahia, Paraiba, and Pernambuco states, supporting an association between Zika virus infection during early pregnancy and the occurrence of microcephaly. Pregnant women in areas where Zika virus transmission is occurring should take steps to avoid mosquito bites. Additional studies are needed to further elucidate the relationship between Zika virus infection in pregnancy and microcephaly. PMID- 26963592 TI - Influence of a low-carbohydrate diet on endothelial microvesicles in overweight women. AB - Low-carbohydrate diets (LCD) are increasing in popularity, but their effect on vascular health has been questioned. Endothelial microvesicles (EMV) are membrane derived vesicles with the potential to act as a sensitive prognostic biomarker of vascular health and endothelial function. The aim of this study was to examine the influence of a LCD on EMV and other endothelial biomarkers of protein origin. Twenty-four overweight women (age, 48.4 +/- 0.6 years; height, 1.60 +/- 0.07 m; body mass, 76.5 +/- 9.1 kg; body mass index, 28.1 +/- 2.7 kg.m(-2); waist circumference, 84.1 +/- 7.4 cm; mean +/- standard deviation) were randomised to either 24 weeks on their normal diet (ND) or a LCD, after which they crossed over to 24 weeks on the alternative diet. Participants were assisted in reducing carbohydrate intake, but not below 40 g.day(-1). Body composition and endothelial biomarkers were assessed at the crossover point and at the end of the study. Daily carbohydrate intake (87 +/- 7 versus 179 +/- 11 g) and the percentage of energy derived from carbohydrate (29% versus 44%) were lower (p < 0.05) on the LCD compared to the ND, but absolute fat and saturated fat intake were unchanged. Body mass and waist circumference were 3.7 +/- 0.8 kg and 3.5 +/- 1.0 cm lower (p < 0.05), respectively, after the LCD compared with the ND phases. CD31(+)CD41( )EMV, soluble (s) thrombomodulin, sE-selectin, sP-selectin, serum amyloid A and C reactive protein were lower (p < 0.05) after the LCD compared to the ND, but serum lipids and apolipoproteins were not different. EMV along with a range of endothelial and inflammatory biomarkers are reduced by a LCD that involves modest weight loss. PMID- 26963594 TI - Fine-Needle Aspiration Followed by Core-Needle Biopsy in the Same Setting: Modifying Our Approach. AB - Fine-needle aspiration biopsy (FNAB) is a well-established initial diagnostic tool. However, in some instances limitations and shortcomings arise, making it insufficient for determining a specific diagnosis. Consequently, patients have to undergo another diagnostic procedure. The second procedure is either repeat FNAB, core-needle or open biopsy, and can be inconvenient and costly. In some centers, the FNAB is immediately followed by core-needle biopsy (CNB) in the same setting after assuring adequacy on the initial FNAB utilizing rapid on-site specimen evaluation (ROSE). It is argued that implementing such an approach will eventually have additional critical advantages that include the following: (a) it is more convenient to patients to have both procedures in one visit, (b) the tissue procured by both procedures will be more adequate, enabling cytopathologists to reach an accurate diagnosis, and (c) it is ultimately a cost effective approach if we take into consideration the avoidance of a potential second more invasive diagnostic procedure. Since we are living in an era of patient-centered medicine coupled with cost-cutting strategies, we present here a brief review of the topic with analysis of this alternative approach, review of the pertinent literature and shed light on a few scenarios that justify this approach. PMID- 26963595 TI - Analyzing the Role of MicroRNAs in Schizophrenia in the Context of Common Genetic Risk Variants. AB - IMPORTANCE: The recent implication of 108 genomic loci in schizophrenia marked a great advancement in our understanding of the disease. Against the background of its polygenic nature there is a necessity to identify how schizophrenia risk genes interplay. As regulators of gene expression, microRNAs (miRNAs) have repeatedly been implicated in schizophrenia etiology. It is therefore of interest to establish their role in the regulation of schizophrenia risk genes in disease relevant biological processes. OBJECTIVE: To examine the role of miRNAs in schizophrenia in the context of disease-associated genetic variation. DESIGN, SETTING, AND PARTICIPANTS: The basis of this study was summary statistics from the largest schizophrenia genome-wide association study meta-analysis to date (83 550 individuals in a meta-analysis of 52 genome-wide association studies) completed in 2014 along with publicly available data for predicted miRNA targets. We examined whether schizophrenia risk genes were more likely to be regulated by miRNA. Further, we used gene set analyses to identify miRNAs that are regulators of schizophrenia risk genes. MAIN OUTCOMES AND MEASURES: Results from association tests for miRNA targetomes and related analyses. RESULTS: In line with previous studies, we found that similar to other complex traits, schizophrenia risk genes were more likely to be regulated by miRNAs (P < 2 * 10-16). Further, the gene set analyses revealed several miRNAs regulating schizophrenia risk genes, with the strongest enrichment for targets of miR-9-5p (P = .0056 for enrichment among the top 1% most-associated single-nucleotide polymorphisms, corrected for multiple testing). It is further of note that MIR9-2 is located in a genomic region showing strong evidence for association with schizophrenia (P = 7.1 * 10-8). The second and third strongest gene set signals were seen for the targets of miR-485 5p and miR-137, respectively. CONCLUSIONS AND RELEVANCE: This study provides evidence for a role of miR-9-5p in the etiology of schizophrenia. Its implication is of particular interest as the functions of this neurodevelopmental miRNA tie in with established disease biology: it has a regulatory loop with the fragile X mental retardation homologue FXR1 and regulates dopamine D2 receptor density. PMID- 26963596 TI - Softworms: the design and control of non-pneumatic, 3D-printed, deformable robots. AB - Robots that can easily interact with humans and move through natural environments are becoming increasingly essential as assistive devices in the home, office and hospital. These machines need to be safe, effective, and easy to control. One strategy towards accomplishing these goals is to build the robots using soft and flexible materials to make them much more approachable and less likely to damage their environment. A major challenge is that comparatively little is known about how best to design, fabricate and control deformable machines. Here we describe the design, fabrication and control of a novel soft robotic platform (Softworms) as a modular device for research, education and public outreach. These robots are inspired by recent neuromechanical studies of crawling and climbing by larval moths and butterflies (Lepidoptera, caterpillars). Unlike most soft robots currently under development, the Softworms do not rely on pneumatic or fluidic actuators but are electrically powered and actuated using either shape-memory alloy microcoils or motor tendons, and they can be modified to accept other muscle-like actuators such as electroactive polymers. The technology is extremely versatile, and different designs can be quickly and cheaply fabricated by casting elastomeric polymers or by direct 3D printing. Softworms can crawl, inch or roll, and they are steerable and even climb steep inclines. Softworms can be made in any shape but here we describe modular and monolithic designs requiring little assembly. These modules can be combined to make multi-limbed devices. We also describe two approaches for controlling such highly deformable structures using either model-free state transition-reward matrices or distributed, mechanically coupled oscillators. In addition to their value as a research platform, these robots can be developed for use in environmental, medical and space applications where cheap, lightweight and shape-changing deformable robots will provide new performance capabilities. PMID- 26963597 TI - Selective recognition of c-MYC G-quadruplex DNA using prolinamide derivatives. AB - Herein we report the design, synthesis, biophysical and biological evaluation of triazole containing prolinamide derivatives as selective c-MYC G-quadruplex binding ligands. A modular synthetic route has been devised for prolinamide derivatives using a copper(i) catalyzed azide-alkyne cycloaddition (CuAAC). The Forster resonance energy transfer (FRET) melting assay indicates that prolinamide trimers can significantly stabilize G-quadruplex structures over duplex DNA compared to prolinamide dimers. The fluorescent intercalator displacement (FID) assay shows that a trimer with prolinamide side chains at the para-position of the benzene ring can discriminate between different quadruplex structures and exhibits the highest binding affinity towards the c-MYC G-quadruplex structure. Molecular modeling studies reveal that the prolinamide trimer stacks upon the terminal G-quartet of the c-MYC G-quadruplex. Atomic force microscopy (AFM) analysis reveals that the tris-prolinamide ligand can be used to regulate the assembly of novel supramolecular nanoarchitectures. Further, in vitro cellular studies with human hepatocellular carcinoma (HepG2) cells indicate that the tris prolinamide derivatives can inhibit cell proliferation and reduce c-MYC expression in cancer cells. PMID- 26963598 TI - A prospective study of safety and efficacy of combination therapy with bipolar radiofrequency-based intense pulsed light, infrared light, and diode laser in Chinese subjects with photoaged skin. AB - OBJECTIVE: To further evaluate the safety and effectiveness of bipolar RF-based optical therapy combining intense pulsed light (IPL), infrared light, and diode laser in the treatment of photoaged skin in Chinese subjects. METHODS: Twenty seven subjects received five treatments at 3-week intervals. Triple therapy was applied in one session to the face. Images and data were obtained 30 and 180 days after the last treatment. Objective measurements (including photometric analysis of skin pigmentation, texture and wrinkles, ultrasonic measurement of dermal thickness and dermal echo intensity, and public and self-assessment of apparent age), clinical assessment, and safety were evaluated. RESULTS: Objective measurements of pigmentation, texture, wrinkles, and dermal echo intensity improved significantly, regardless of age. Self-assessment of apparent age at 30 and 180 days was reduced by an average of 2.7 and 2.2 years, respectively, and public assessment of apparent age was reduced by an average of 3.14 years and 2.95 years, respectively. Global scores for photoaging were improved in all patients. Adverse events were generally transient and mild. CONCLUSION: Sequential combination treatment reported here could significantly reduce skin pigmentation, texture and wrinkles, improve dermal intensity, and reduce the self and publicly perceived age. This therapy is safe and well tolerated. PMID- 26963599 TI - Heated hatha yoga to target cortisol reactivity to stress and affective eating in women at risk for obesity-related illnesses: A randomized controlled trial. AB - OBJECTIVE: Cortisol reactivity to stress is associated with affective eating, an important behavioral risk factor for obesity and related metabolic diseases. Yoga practice is related to decreases in stress and cortisol levels, thus emerging as a potential targeted complementary intervention for affective eating. This randomized controlled trial examined the efficacy of a heated, hatha yoga intervention for reducing cortisol reactivity to stress and affective eating. METHOD: Females (N = 52; ages 25-46 years; 75% White) at risk for obesity and related illnesses were randomly assigned to 8 weeks of Bikram Yoga practice or to waitlist control. Cortisol reactivity to a laboratory stress induction were measured at Weeks 0 (pretreatment) and 9 (posttreatment). Self-reported binge eating frequency and coping motives for eating were assessed at Weeks 0, 3, 6, and 9. RESULTS: Among participants with elevated cortisol reactivity at pretreatment ("high reactors"), those randomized to the yoga condition evidenced greater pre- to posttreatment reductions in cortisol reactivity (p = .042, d = .85), but there were not significant condition differences for the "low reactors" (p = .178, d = .53). Yoga participants reported greater decreases in binge eating frequency (p = .040, d = .62) and eating to cope with negative affect (p = .038, d = .54). CONCLUSIONS: This study provides preliminary support for the efficacy of heated hatha yoga for treating physiological stress reactivity and affective eating among women at risk for obesity-related illnesses. (PsycINFO Database Record PMID- 26963600 TI - Impact of comorbid anxiety and depressive disorders on treatment response to cognitive behavior therapy for insomnia. AB - OBJECTIVE: To evaluate the impact of comorbid anxiety or depressive disorders on treatment response to cognitive-behavior therapy (CBT) for insomnia, behavior therapy (BT), or cognitive therapy (CT). METHOD: Participants were 188 adults (117 women; Mage = 47.4 years) with chronic insomnia, including 45 also presenting a comorbid anxiety or mild to moderate depressive disorder. They were randomized to BT (n = 63), CT (n = 65), or CBT (n = 60). Outcome measures were the proportion of treatment responders (decrease of >=8 points on the Insomnia Severity Index; ISI) and remissions (ISI score < 8) and depression and anxiety symptoms. RESULTS: Proportion of treatment responders and remitters in the CBT condition was not significantly different between the subgroups with and without comorbidity. However, the proportion of responders was lower in the comorbidity subgroup compared to those without comorbidity in both the BT (34.4% vs. 81.6%; p = .007) and CT (23.6% vs. 57.6%; p = .02) alone conditions, although remission rates and prepost ISI change scores were not. Pre to post change scores on the depression (-10.6 vs. -3.9; p < .001) and anxiety measures (-9.2 vs. -2.5; p = .01) were significantly greater in the comorbidity subgroup relative to the subgroup without comorbidity but only for those treated with the full CBT; no difference was found for those treated with either BT or CT alone. CONCLUSIONS: The presence of a comorbid anxiety or mild to moderate depressive disorder did not reduce the efficacy of CBT for insomnia, but it did for its single BT and CT components when used alone. (PsycINFO Database Record PMID- 26963601 TI - A randomized clinical trial of group versus standard behavioral couples therapy plus individually based treatment for patients with alcohol dependence. AB - OBJECTIVE: Multiple studies show that behavioral couples therapy (BCT) is more efficacious than individually based therapy (IBT) for substance use and relationship outcomes among patients with alcohol use disorder. To facilitate dissemination, a multicouple, rolling admission Group BCT (G-BCT) format has been suggested as an alternative to the 1 couple at a time, conjoint Standard BCT (S BCT) format. This randomized study compared outcomes of G-BCT versus S-BCT over a 1-year follow-up. The authors predicted that G-BCT, as compared to S-BCT, would have equivalent (i.e., noninferior) improvements on substance and relationship outcomes. METHOD: Participants were patients (N = 101) with alcohol dependence and their heterosexual relationship partners without substance use disorder. Participants were mostly White, in their 40s, and 30% of patients were women. Patients were randomized to either G-BCT plus 12-step-oriented IBT or S-BCT plus IBT. Primary outcomes included Timeline Followback Interview percentage days abstinent and Inventory of Drug Use Consequences measure of substance-related problems. Secondary outcome was Dyadic Adjustment Scale. Outcome data were collected at baseline, posttreatment, and quarterly for 1-year follow-up. RESULTS: Results overall found no support for the predicted statistical equivalency of G-BCT and S-BCT. Rather than the predicted equivalent outcomes, substance and relationship outcomes were significantly worse for G-BCT than S-BCT in the last 6-9 months of the 12-month follow-up period, because G-BCT deteriorated and S-BCT maintained gains during follow-up. CONCLUSION: This was the first study of the newer rolling admission group format for BCT. It proved to have worse not equivalent outcomes compared to standard conjoint BCT. (PsycINFO Database Record PMID- 26963602 TI - Highly pathogenic porcine reproductive and respiratory syndrome virus infection and induction of apoptosis in bone marrow cells of infected piglets. AB - Highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) has been shown to have a wide range of tissue tropism, and can directly and indirectly induce cellular apoptosis. However, the impact of HP-PRRSV infection on the bone marrow (BM) of piglets remains unclear. In this study, we investigated the BM as a novel site of infection by the HP-PRRSV strain in piglets. HP-PRRSV infected SWC3+SWC8- cells in the BM and induced BM cells to undergo apoptosis. The number of apoptotic cells highlights the striking effects of HP-PRRSV on the central immune organs (BM and thymus) that may enhance the susceptibility of pigs to secondary infections and lead to high mortality. This study is, to the best of our knowledge, the first to report the impact of HP PRRSV on the BM and implicate the depletion of BM cells during HP-PRRSV infection in the development of immunosuppression in this disease. PMID- 26963604 TI - Kinetic Rate Determination via Electrophoresis along a Varying Cross-Section Microchannel. AB - High throughput, efficient, and readily adoptable analytical tools for the validation and selection of reliable antibody reagents would impact the life sciences, clinical chemistry, and clinical medicine. To directly quantify antibody-antigen association and dissociation rate constants, kon and koff, in a single experiment, we introduce a microfluidic free-standing kinetic polyacrylamide gel electrophoresis (fsKPAGE) assay. Here, an antibody is immobilized in zones along the length of a single freestanding polyacrylamide gel lane of varying cross-sectional width. Fluorescently labeled antigen is electrophoresed through each immobilized antibody zone, with local cross sectional area determining the local electric field strength and, thus, the local interaction time between immobilized antibody and electromigrating antigen. Upon crossing, the interaction yields immobilized immunocomplex. The kon is quantified by assessing the amount of immunocomplex formed at each interaction time. To quantify koff, immobilized zones of fluorescently labeled immunocomplex are subjected to a buffer dilution and monitored over time. We determine kon and koff for prostate-specific antigen (PSA) and make a comparison to gold-standard values. The fsKPAGE assay determines kon and koff in a single experiment of less than 20 min, using 45 ng of often limited antibody material and standard laboratory equipment. We see the fsKPAGE assay as forming the basis for rapid, quantitative antibody-screening tools. PMID- 26963603 TI - Regulation of the fetal hemoglobin silencing factor BCL11A. AB - The clinical severity of sickle cell disease and beta-thalassemia, the major disorders of beta-globin, can be ameliorated by increased production of fetal hemoglobin (HbF). Here, we provide a brief overview of the fetal-to-adult hemoglobin switch that occurs in humans shortly after birth and review our current understanding of one of the most potent known regulators of this switching process, the multiple zinc finger-containing transcription factor BCL11A. Originally identified in genome-wide association studies, multiple orthogonal lines of evidence have validated BCL11A as a key regulator of hemoglobin switching and as a promising therapeutic target for HbF induction. We discuss recent studies that have highlighted its importance in silencing the HbF encoding genes and discuss opportunities that exist to further understand the regulation of BCL11A and its mechanism of action, which could provide new insight into opportunities to induce HbF for therapeutic purposes. PMID- 26963605 TI - The yield and decay coefficients of exoelectrogenic bacteria in bioelectrochemical systems. AB - In conventional wastewater treatment, waste sludge management and disposal contribute the major cost for wastewater treatment. Bioelectrochemical systems, as a potential alternative for future wastewater treatment and resources recovery, are expected to produce small amounts of waste sludge because exoelectrogenic bacteria grow on anaerobic respiration and form highly populated biofilms on bioanode surfaces. While waste sludge production is governed by the yield and decay coefficient, none of previous studies have quantified these kinetic constants for exoelectrogenic bacteria. For yield coefficient estimation, we modified McCarty's free energy-based model by using the bioanode potential for the free energy of the electron acceptor reaction. The estimated true yield coefficient ranged 0.1 to 0.3 g-VSS (volatile suspended solids) g-COD(-1) (chemical oxygen demand), which is similar to that of most anaerobic microorganisms. The yield coefficient was sensitively affected by the bioanode potential and pH while the substrate and bicarbonate concentrations had relatively minor effects on the yield coefficient. In lab-scale experiments using microbial electrolysis cells, the observed yield coefficient (including the effect of cell decay) was found to be 0.020 +/- 0.008 g-VSS g-COD(-1), which is an order of magnitude smaller than the theoretical estimation. Based on the difference between the theoretical and experimental results, the decay coefficient was approximated to be 0.013 +/- 0.002 d(-1). These findings indicate that bioelectrochemical systems have potential for future wastewater treatment with reduced waste sludge as well as for resources recovery. Also, the found kinetic information will allow accurate estimation of wastewater treatment performance in bioelectrochemical systems. PMID- 26963606 TI - UV254 absorbance as real-time monitoring and control parameter for micropollutant removal in advanced wastewater treatment with powdered activated carbon. AB - This study investigates the applicability of UV absorbance measurements at 254 nm (UVA254) to serve as a simple and reliable surrogate parameter to monitor and control the removal of organic micropollutants (OMPs) in advanced wastewater treatment applying powdered activated carbon (PAC). Correlations between OMP removal and corresponding UVA254 reduction were determined in lab-scale adsorption batch tests and successfully applied to a pilot-scale PAC treatment stage to predict OMP removals in aggregate samples with good accuracy. Real-time UVA254 measurements were utilized to evaluate adapted PAC dosing strategies and proved to be effective for online monitoring of OMP removal. Furthermore, active PAC dosing control according to differential UVA254 measurements was implemented and tested. While precise removal predictions based on real-time measurements were not accurate for all OMPs, UVA254-controlled dynamic PAC dosing was capable of achieving stable OMP removals. UVA254 can serve as an effective surrogate parameter for OMP removal in technical PAC applications. Even though the applicability as control parameter to adjust PAC dosing to water quality changes might be limited to applications with fast response between PAC adjustment and adsorptive removal (e.g. direct filtration), UVA254 measurements can also be used to monitor the adsorption efficiency in more complex PAC applications. PMID- 26963607 TI - Upgrade of deep bed filtration with activated carbon dosage for compact micropollutant removal from wastewater in technical scale. AB - The removal of micropollutants from drinking and wastewater by powdered activated carbon (PAC) adsorption has received considerable attention in research over the past decade with various separation options having been investigated. With Switzerland as the first country in the world having adopted a new legislation, which forces about 100 wastewater treatment plants to be upgraded for the removal of organic micropollutants from municipal wastewater, the topic has reached practical relevance. In this study, the process combination of powdered activated carbon (PAC) adsorption and deep bed filtration (DBF) for advanced municipal wastewater treatment was investigated over an extended period exceeding one year of operation in technical scale. The study aimed to determine optimum process conditions to achieve sufficient micropollutant removal in agreement with the new Swiss Water Ordinance under most economic process design. It was shown that the addition of PAC and Fe(3+) as combined coagulation and flocculation agent improved effluent water quality with respect to dissolved organic pollutants as well as total suspended solids (TSS), turbidity and PO4-P concentration in comparison to a DBF operated without the addition of PAC and Fe(3+). Sufficient micropollutant (MP) removal of around 80% was achieved at PAC dosages of 10 mg/L revealing that PAC retained in the filter bed maintained considerable adsorption capacity. In the investigated process combination the contact reactor serves for adsorption as well as for flocculation and allowed for small hydraulic retention times of minimum 10 min while maintaining sufficient MP removal. The flocculation of two different PAC types was shown to be fully concluded after 10-15 min, which determined the flocculation reactor size while both PAC types proved suitable for the application in combination with DBF and showed no significant differences in MP removal. Finally, the capping of PAC dosage during rain water periods, which resulted in lower dosage concentrations, was efficient in limiting PAC consumption during these events without suffering from negative effects on process performance or effluent quality. PMID- 26963608 TI - Mass spectrometric characterization of a two-glycosyltransferase tandem reaction for assembly of tetrasaccharide repeating unit of Escherichia coli O77 O-antigen. AB - The wbaD gene and wbaC gene from Escherichia coli O77 O-antigen gene cluster encoding mannosyltransferases were functionally characterized in vitro. A synthetic acceptor P(1)-(11-phenoxyundecyl)-P(2)-(2-acetamido-2-deoxy-alpha-D glucopyranosyl) diphosphate (GlcNAc-PP-PhU) was used as an acceptor and GDP-Man as a donor substrate; the activities of WbaD and WbaC were confirmed by detailed structural characterization of their lipooligosacharide enzyme products using high-sensitivity negative-ion electrospray ionization (ESI) collision-induced dissociation tandem mass spectrometry (CID) MS-MS. The extensive fragmentation unequivocally demonstrated that the Man(1-3)-GlcNAc linkage in WbaD catalyzed reaction product and two Man(1-2)-Man linkages in tandem WbaD/WbaC catalyzed reaction product are present, respectively. This study provided valuable information for the understanding of diversified glycosyltransferase (GT) functions and the two GTs characterized can serve as additional enzyme sources for possible pharmaceutical related applications. PMID- 26963609 TI - Non-Euclidean classification of medically imaged objects via s-reps. AB - Classifying medically imaged objects, e.g., into diseased and normal classes, has been one of the important goals in medical imaging. We propose a novel classification scheme that uses a skeletal representation to provide rich non Euclidean geometric object properties. Our statistical method combines distance weighted discrimination (DWD) with a carefully chosen Euclideanization which takes full advantage of the geometry of the manifold on which these non-Euclidean geometric object properties (GOPs) live. Our method is evaluated via the task of classifying 3D hippocampi between schizophrenics and healthy controls. We address three central questions. 1) Does adding shape features increase discriminative power over the more standard classification based only on global volume? 2) If so, does our skeletal representation provide greater discriminative power than a conventional boundary point distribution model (PDM)? 3) Especially, is Euclideanization of non-Euclidean shape properties important in achieving high discriminative power? Measuring the capability of a method in terms of area under the receiver operator characteristic (ROC) curve, we show that our proposed method achieves strongly better classification than both the classification method based on global volume alone and the s-rep-based classification method without proper Euclideanization of non-Euclidean GOPs. We show classification using Euclideanized s-reps is also superior to classification using PDMs, whether the PDMs are first Euclideanized or not. We also show improved performance with Euclideanized boundary PDMs over non-linear boundary PDMs. This demonstrates the benefit that proper Euclideanization of non-Euclidean GOPs brings not only to s rep-based classification but also to PDM-based classification. PMID- 26963611 TI - A Further Investigation of the Effects of Extremely Low Frequency Magnetic Fields on Alkaline Phosphatase and Acetylcholinesterase. AB - Using a custom build spectrophotometer equipped with Helmholtz coils and designed to study the effects of magnetic fields on enzyme reactions in real-time we have investigated the influence of fields, from 100 MUT to 10 mT and at a variety of field frequencies, on the membrane bound enzymes alkaline phosphatase and acetylcholinesterase. We have also employed other methods to apply a magnetic field, e.g. Biostim. In contrast to earlier reports we have been unable to detect any field effects on these enzymes under any field/frequency regime. We discuss possible reasons for the discrepancy between this and earlier work and note the particularly complex influence of small temperature changes that may confound analysis. PMID- 26963610 TI - Association of Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Thyroglobulin (TG) Genetic Variants with Autoimmune Hypothyroidism. AB - Autoimmune hypothyroidism is known to be caused by immune responses related to the thyroid gland and its immunological feature includes presence of autoimmune antibodies. Therefore the aim was to analyze presence of anti-TPO antibodies in hypothyroidism patients in Gujarat. Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) is one of the susceptibility genes for various autoimmune diseases. Hence, exon1 +49A/G and 3'UTR CT60A/G single nucleotide polymorphisms (SNPs) in CTLA4 and its mRNA expression levels were investigated in autoimmune hypothyroidism patients. Thyroglobulin (TG) is known to be associated with autoimmune thyroid disorders and thus exon 33 (E33) SNP in TG was investigated. We analyzed the presence of anti-TPO antibodies in the plasma samples of 84 hypothyroidism patients and 62 controls by ELISA. PCR-RFLP technique was used for genotyping of polymorphisms. sCTLA4 and flCTLA4 mRNA expression levels were assessed by real time PCR. 59.52% of hypothyroid patients had anti-TPO antibodies in their circulation. The genotype and allele frequencies differed significantly for +49A/G (p = 0.0004 for +49AG, p = 0.0019 for +49GG & p = 0.0004 for allele), CT60 (p = 0.0110 for CT60AG, p = 0.0005 for CT60GG & p<0.0001 for allele) and TG E33 (p = 0.0003 for E33TC p<0.0001 for E33CC& p<0.0001 for allele) SNPs between patients and controls. Patients had significantly decreased mRNA levels of both sCTLA4 (p = 0.0017) and flCTLA4 (p<0.0001) compared to controls. +49A/G and CT60 polymorphisms of CTLA4 were in moderate linkage disequilibrium. Logistic regression analysis indicated significant association of CT49A/G, CT60A/G and TG exon 33 polymorphisms with susceptibility to autoimmune hypothyroidism when adjusted for age and gender. Our results suggest +49A/G and CT60 polymorphism of CTLA4 and E33 polymorphism of TG may be genetic risk factors for autoimmune hypothyroidism susceptibility and down regulation of both forms of CTLA4 advocates the crucial role of CTLA4 in pathogenesis of autoimmune hypothyroidism. PMID- 26963612 TI - Drosophila Cyclin G Is a Regulator of the Notch Signalling Pathway during Wing Development. AB - Notch signalling regulates a multitude of differentiation processes during Drosophila development. For example, Notch activity is required for proper wing vein differentiation which is hampered in mutants of either the receptor Notch, the ligand Delta or the antagonist Hairless. Moreover, the Notch pathway is involved in several aspects of Drosophila oogenesis as well. We have identified Drosophila Cyclin G (CycG) as a molecular interaction partner of Hairless, the major antagonist in the Notch signalling pathway, in vitro and in vivo. Loss of CycG was shown before to cause female sterility and to disturb the architecture of the egg shell. Nevertheless, Notch dependent processes during oogenesis appeared largely unaffected in cycG mutant egg chambers. Loss of CycG modified the dominant wing phenotypes of Notch, Delta and Hairless mutants. Whereas the Notch loss of function phenotype was ameliorated by a loss of CycG, the phenotypes of either Notch gain of function or of Delta or Hairless loss of function were enhanced. In contrast, loss of CycG had only a minor effect on the wing vein phenotype of mutants affecting the EGFR signalling pathway emphasizing the specificity of the interaction of CycG and Notch pathway members. PMID- 26963615 TI - A home-based eyebrows lifting effect using a novel device that emits electrostatic pulses containing RF energy, resulting in high frequency, low level transdermal microcurrent pulsations: Double blind, randomized clinical study of efficacy and safety. AB - BACKGROUND: As the appearance of the face is a primary concern of many people, ways in which to tighten the skin are increasingly in demand. In recent years, radiofrequency (RF) has become a promising nonablative, non-invasive, technique for facial rejuvenation. OBJECTIVE: To assess the safety and the efficacy of a unipolar RF-based device for home use in increasing skin tightness (lifting effect) in the eyebrows area. METHODS: Subjects (N = 50) aged between 30 and 70 years old showing skin wrinkledness all over the face and skin laxity in the eyebrows area were enrolled. The primary endpoint was the assessment of the eyebrow to hairline distance by means of a morphometric digital image analysis technique. RESULTS: The eyebrows to hairline distance was statistically significant (both vs. basal condition and placebo) decreased by 1.338 +/- 0.170 cm in the treated eyebrow. CONCLUSION: The obtained results confirm the safety and the efficacy of the tested device in decreasing skin laxity in the eyebrows area. The treatment is not time-consuming (about 6 minutes) and can be done at home. The device seems to be then a useful tool to delay skin laxity or to prolong the time to the first surgical facial lift. PMID- 26963613 TI - Dapagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor, Acutely Reduces Energy Expenditure in BAT via Neural Signals in Mice. AB - Selective sodium glucose cotransporter-2 inhibitor (SGLT2i) treatment promotes urinary glucose excretion, thereby reducing blood glucose as well as body weight. However, only limited body weight reductions are achieved with SGLT2i treatment. Hyperphagia is reportedly one of the causes of this limited weight loss. However, the effects of SGLT2i treatment on systemic energy expenditure have not been fully elucidated. Herein, we investigated the acute effects of dapagliflozin, a SGLT2i, on systemic energy expenditure in mice. Eighteen hours after dapagliflozin treatment oxygen consumption and brown adipose tissue (BAT) expression of ucp1, a thermogenesis-related gene, were significantly decreased as compared to those after vehicle treatment. In addition, dapagliflozin significantly suppressed norepinephrine (NE) turnover in BAT and c-fos expression in the rostral raphe pallidus nucleus (rRPa) which contains the sympathetic premotor neurons responsible for thermogenesis. These findings indicate that the dapagliflozin-mediated acute decrease in energy expenditure involves a reduction in BAT thermogenesis via decreased sympathetic nerve activity from the rRPa. Furthermore, common hepatic branch vagotomy abolished the reductions in ucp1 expression and NE contents in BAT and c-fos expression in the rRPa. In addition, alterations in hepatic carbohydrate metabolism, such as decreases in glycogen contents and upregulation of phosphoenolpyruvate carboxykinase, manifested prior to the suppression of BAT thermogenesis, e.g. 6 hours after dapagliflozin treatment. Collectively, these results suggest that SGLT2i treatment acutely suppresses energy expenditure in BAT via regulation of an inter-organ neural network consisting of the common hepatic vagal branch and sympathetic nerves. PMID- 26963614 TI - Association between Physical Fitness and Successful Aging in Taiwanese Older Adults. AB - Population aging is escalating in numerous countries worldwide; among them is Taiwan, which will soon become an aged society. Thus, aging successfully is an increasing concern. One of the factors for achieving successful aging (SA) is maintaining high physical function. The purpose of this study was to determine the physical fitness factors associated with SA in Taiwanese older adults (OAs), because these factors are intervenable. Community-dwelling OAs aged more than 65 years and residing in Northern Taiwan were recruited in this study. They received a comprehensive geriatric assessment, which includes sociodemographic data, health conditions and behaviors, activities of daily living (ADL) and instrumental ADL (IADL) function, cognitive and depressive status, and quality of life. Physical fitness tests included the grip strength (GS), 30-second sit-to stand (30s STS), timed up-and-go (TUG), functional reach (FR), one-leg standing, chair sit-and-reach, and reaction time (drop ruler) tests as well as the 6-minute walk test (6MWT). SA status was defined as follows: complete independence in performing ADL and IADL, satisfactory cognitive status (Mini-Mental State Examination >= 24), no depression (Geriatric Depression Scale < 5), and favorable social function (SF subscale >= 80 in SF-36). Adjusted multiple logistic regression analyses were performed. Among the total recruited OAs (n = 378), 100 (26.5%) met the aforementioned SA criteria. After adjustment for sociodemographic characteristics and health condition and behaviors, some physical fitness tests, namely GS, 30s STS, 6MWT, TUG, and FR tests, were significantly associated with SA individually, but not in the multivariate model. Among the physical fitness variables tested, cardiopulmonary endurance, mobility, muscle strength, and balance were significantly associated with SA in Taiwanese OAs. Early detection of deterioration in the identified functions and corresponding intervention is essential to ensuring SA. PMID- 26963617 TI - Effects of Metformin on Tissue Oxidative and Dicarbonyl Stress in Transgenic Spontaneously Hypertensive Rats Expressing Human C-Reactive Protein. AB - Inflammation and oxidative and dicarbonyl stress play important roles in the pathogenesis of type 2 diabetes. Metformin is the first-line drug of choice for the treatment of type 2 diabetes because it effectively suppresses gluconeogenesis in the liver. However, its "pleiotropic" effects remain controversial. In the current study, we tested the effects of metformin on inflammation, oxidative and dicarbonyl stress in an animal model of inflammation and metabolic syndrome, using spontaneously hypertensive rats that transgenically express human C-reactive protein (SHR-CRP). We treated 8-month-old male transgenic SHR-CRP rats with metformin (5 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR CRP rats were fed a standard diet without metformin. In a similar fashion, we studied a group of nontransgenic SHR treated with metformin and an untreated group of nontransgenic SHR controls. In each group, we studied 6 animals. Parameters of glucose and lipid metabolism and oxidative and dicarbonyl stress were measured using standard methods. Gene expression profiles were determined using Affymetrix GeneChip Arrays. Statistical significance was evaluated by two way ANOVA. In the SHR-CRP transgenic strain, we found that metformin treatment decreased circulating levels of inflammatory response marker IL-6, TNFalpha and MCP-1 while levels of human CRP remained unchanged. Metformin significantly reduced oxidative stress (levels of conjugated dienes and TBARS) and dicarbonyl stress (levels of methylglyoxal) in left ventricles, but not in kidneys. No significant effects of metformin on oxidative and dicarbonyl stress were observed in SHR controls. In addition, metformin treatment reduced adipose tissue lipolysis associated with human CRP. Possible molecular mechanisms of metformin action-studied by gene expression profiling in the liver-revealed deregulated genes from inflammatory and insulin signaling, AMP-activated protein kinase (AMPK) signaling and gluconeogenesis pathways. It can be concluded that in the presence of high levels of human CRP, metformin protects against inflammation and oxidative and dicarbonyl stress in the heart, but not in the kidney. Accordingly, these cardioprotective effects of metformin might be especially effective in diabetic patients with high levels of CRP. PMID- 26963616 TI - Wnt5a Regulates the Assembly of Human Adipose Derived Stromal Vascular Fraction Derived Microvasculatures. AB - Human adipose-derived stromal vascular fraction (hSVF) cells are an easily accessible, heterogeneous cell system that can spontaneously self-assemble into functional microvasculatures in vivo. However, the mechanisms underlying vascular self-assembly and maturation are poorly understood, therefore we utilized an in vitro model to identify potential in vivo regulatory mechanisms. We utilized passage one (P1) hSVF because of the rapid UEA1+ endothelium (EC) loss at even P2 culture. We exposed hSVF cells to a battery of angiogenesis inhibitors and found that the pan-Wnt inhibitor IWP2 produced the most significant hSVF-EC networking decrease (~25%). To determine which Wnt isoform(s) and receptor(s) may be involved, hSVF was screened by PCR for isoforms associated with angiogenesis, with only WNT5A and its receptor, FZD4, being expressed for all time points observed. Immunocytochemistry confirmed Wnt5a protein expression by hSVF. To see if Wnt5a alone could restore IWP2-induced EC network inhibition, recombinant human Wnt5a (0-150 ng/ml) was added to IWP2-treated cultures. The addition of rhWnt5a significantly increased EC network area and significantly decreased the ratio of total EC network length to EC network area compared to untreated controls. To determine if Wnt5a mediates in vivo microvascular self-assembly, 3D hSVF constructs containing an IgG isotype control, anti-Wnt5a neutralizing antibody or rhWnt5a were implanted subcutaneously for 2w in immune compromised mice. Compared to IgG controls, anti-Wnt5a treatment significantly reduced vessel length density by ~41%, while rhWnt5a significantly increased vessel length density by ~62%. However, anti-Wnt5a or rhWnt5a did not significantly affect the density of segments and nodes, both of which measure vascular complexity. Taken together, this data demonstrates that endogenous Wnt5a produced by hSVF plays a regulatory role in microvascular self-assembly in vivo. These findings also suggest that manipulating Wnt signaling could enhance control of hSVF vascularization in tissue engineering applications. PMID- 26963618 TI - Vagal response during pulmonary vein isolation: Re-recognized its characteristics and implications in lone paroxysmal atrial fibrillation. AB - BACKGROUND: The role of autonomic innervation around the pulmonary vein (PV) antrum in the genesis of atrial fibrillation (AF) has been demonstrated but the characteristics of radiofrequency induced vagal response (VR) in the PV antrum and its clinical impact on pulmonary vein isolation (PVI) for paroxysmal AF need to be further elucidated. METHOD: Of 995 consecutive patients with symptomatic paroxysmal AF undergoing PVI at a single center over a 2-year period, 516 met exclusion criteria and the remaining 479 patients, 156 positive VR (PVR) and 323 negative VR (NVR), underwent 12-month follow-up. The primary endpoint was freedom from AF or other sustained atrial tachycardia (AT), verified by monthly visits and electrocardiographic monitoring. The frequency-domain analysis was performed to evaluate the autonomic activity before and after the procedure. RESULTS: VR was most commonly elicited during PVI at the LSPV roof (65.4%) and anterior RSPV (44.9%, with a >5s sinus pause in 37/70 [52.8%] cases). Compared with the NVR group, ablation was associated with reduced AF recurrence at 12 months in the PVR (hazard ratio: 0.53, 95% confidence interval: 0.22-0.89). Furthermore, the PVR group showed a significantly abbreviated AF cycle length at the left PV, and significantly lower HF and LF parameters with stable LF/HF ratio during follow up. CONCLUSION: Complete elimination of vagal response, most commonly elicited by radiofrequency application around the roof of LSPV and anterior RSPV, appeared associated with reduced 12-month recurrence of AF and with marked heart rate variability changes consistent with autonomic nervous withdrawal. PMID- 26963619 TI - Genotypic and Phenotypic Detection of AmpC beta-lactamases in Enterobacter spp. Isolated from a Teaching Hospital in Malaysia. AB - OBJECTIVES: The objective of this study was to determine the occurrence of chromosomal and plasmid-mediated beta-lactamases (AmpC) genes in a collection of Malaysian isolates of Enterobacter species. Several phenotypic tests for detection of AmpC production of Enterobacter spp. were evaluated and the agreements between tests were determined. METHODS: Antimicrobial susceptibility profiles for 117 Enterobacter clinical isolates obtained from the Medical Microbiology Diagnostic Laboratory, University Malaya Medical Centre, Malaysia, from November 2012-February 2014 were determined in accordance to CLSI guidelines. AmpC genes were detected using a multiplex PCR assay targeting the MIR/ACT gene (closely related to chromosomal EBC family gene) and other plasmid mediated genes, including DHA, MOX, CMY, ACC, and FOX. The AmpC beta-lactamase production of the isolates was assessed using cefoxitin disk screening test, D69C AmpC detection set, cefoxitin-cloxacillin double disk synergy test (CC-DDS) and AmpC induction test. RESULTS: Among the Enterobacter isolates in this study, 39.3% were resistant to cefotaxime and ceftriaxone and 23.9% were resistant to ceftazidime. Ten (8.5%) of the isolates were resistant to cefepime, and one isolate was resistant to meropenem. Chromosomal EBC family gene was amplified from 36 (47.4%) E. cloacae and three (25%) E. asburiae. A novel blaDHA type plasmid-mediated AmpC gene was identified for the first time from an E. cloacae isolate. AmpC beta-lactamase production was detected in 99 (89.2%) of 111 potential AmpC beta-lactamase producers (positive in cefoxitin disk screening) using D69C AmpC detection set. The detection rates were lower with CC-DDS (80.2%) and AmpC induction tests (50.5%). There was low agreement between the D69C AmpC detection set and the other two phenotypic tests. Of the 40 isolates with AmpC genes detected in this study, 87.5%, 77.5% and 50.0% of these isolates were positive by the D69C AmpC detection set, CC-DDS and AmpC induction tests, respectively. CONCLUSIONS: Besides MIR/ACT gene, a novel plasmid-mediated AmpC gene belonging to the DHA-type was identified in this study. Low agreement was noted between the D69C AmpC detection set and two other phenotypic tests for detection of AmpC production in Enterobacter spp. As plasmid-mediated genes may serve as the reservoir for the emergence of antibiotic resistance in a clinical setting, surveillance and infection control measures are necessary to limit the spread of these genes in the hospital. PMID- 26963620 TI - Breastfeeding and Immunohistochemical Expression of ki-67, p53 and BCL2 in Infiltrating Lobular Breast Carcinoma. AB - BACKGROUND/AIM: Invasive lobular breast carcinoma is the second most common type of breast cancer after invasive ductal carcinoma. According to the American Cancer Society, more than 180,000 women in the United States find out they have invasive breast cancer each year. Personal history of breast cancer and certain changes in the breast are correlated with an increased breast cancer risk. The aim of this work was to analyze breastfeeding in patients with infiltrating lobular breast carcinoma, in relation with: 1) clinicopathological parameters, 2) hormonal receptors and 3) tissue-based tumor markers. MATERIALS AND METHODS: The study included 80 women with ILC, 46 of which had breastfeed their children. Analyzed parameters were: age, tumor size, axillary lymph node (N), distant metastasis (M), histological grade (HG), estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), Ki-67, p53 and BCL2. RESULTS: ILC of non lactating women showed a larger (p = 0.009), lymph node involvement (p = 0.051) and distant metastasis (p = 0.060). They were also more proliferative tumors measured by Ki-67 (p = 0.053). Breastfeeding history did not influence the subsequent behavior of the tumor regardless of histological subtype. CONCLUSION: Lactation seems to influence the biological characteristics of ILC defining a subgroup with more tumor size, axillary lymph node involvement, distant metastasis and higher proliferation measured by ki-67 expression. PMID- 26963621 TI - Positive Feeling, Negative Meaning: Visualizing the Mental Representations of In Group and Out-Group Smiles. AB - Even though smiles are seen as universal facial expressions, research shows that there exist various kinds of smiles (i.e., affiliative smiles, dominant smiles). Accordingly, we suggest that there also exist various mental representations of smiles. Which representation is employed in cognition may depend on social factors, such as the smiling person's group membership: Since in-group members are typically seen as more benevolent than out-group members, in-group smiles should be associated with more benevolent social meaning than those conveyed by out-group members. We visualized in-group and out-group smiles with reverse correlation image classification. These visualizations indicated that mental representations of in-group smiles indeed express more benevolent social meaning than those of out-group smiles. The affective meaning of these visualized smiles was not influenced by group membership. Importantly, the effect occurred even though participants were not instructed to attend to the nature of the smile, pointing to an automatic association between group membership and intention. PMID- 26963623 TI - Carbon Abatement and Emissions Associated with the Gasification of Walnut Shells for Bioenergy and Biochar Production. AB - By converting biomass residue to biochar, we could generate power cleanly and sequester carbon resulting in overall greenhouse gas emissions (GHG) savings when compared to typical fossil fuel usage and waste disposal. We estimated the carbon dioxide (CO2) abatements and emissions associated to the concurrent production of bioenergy and biochar through biomass gasification in an organic walnut farm and processing facility in California, USA. We accounted for (i) avoided-CO2 emissions from displaced grid electricity by bioenergy; (ii) CO2 emissions from farm machinery used for soil amendment of biochar; (iii) CO2 sequestered in the soil through stable biochar-C; and (iv) direct CO2 and nitrous oxide (N2O) emissions from soil. The objective of these assessments was to pinpoint where the largest C offsets can be expected in the bioenergy-biochar chain. We found that energy production from gasification resulted in 91.8% of total C offsets, followed by stable biochar-C (8.2% of total C sinks), offsetting a total of 107.7 kg CO2-C eq Mg-1 feedstock. At the field scale, we monitored gas fluxes from soils for 29 months (180 individual observations) following field management and precipitation events in addition to weekly measurements within three growing seasons and two tree dormancy periods. We compared four treatments: control, biochar, compost, and biochar combined with compost. Biochar alone or in combination with compost did not alter total N2O and CO2 emissions from soils, indicating that under the conditions of this study, biochar-prompted C offsets may not be expected from the mitigation of direct soil GHG emissions. However, this study revealed a case where a large environmental benefit was given by the waste-to-bioenergy treatment, addressing farm level challenges such as waste management, renewable energy generation, and C sequestration. PMID- 26963622 TI - Up Regulation of cystathione gamma lyase and Hydrogen Sulphide in the Myocardium Inhibits the Progression of Isoproterenol-Caffeine Induced Left Ventricular Hypertrophy in Wistar Kyoto Rats. AB - Hydrogen sulphide (H2S) is an emerging molecule in many cardiovascular complications but its role in left ventricular hypertrophy (LVH) is unknown. The present study explored the effect of exogenous H2S administration in the regression of LVH by modulating oxidative stress, arterial stiffness and expression of cystathione gamma lyase (CSE) in the myocardium. Animals were divided into four groups: Control, LVH, Control-H2S and LVH-H2S. LVH was induced by administering isoprenaline (5mg/kg, every 72 hours, S/C) and caffeine in drinking water (62mg/L) for 2 weeks. Intraperitoneal NaHS, 56MUM/kg/day for 5 weeks, was given as an H2S donor. Myocardial expression of Cystathione gamma lyase (CSE) mRNA was quantified using real time polymerase chain reaction (qPCR).There was a 3 fold reduction in the expression of myocardial CSE mRNA in LVH but it was up regulated by 7 and 4 fold in the Control-H2S and LVH-H2S myocardium, respectively. Systolic blood pressure, mean arterial pressure, pulse wave velocity were reduced (all P<0.05) in LVH-H2S when compared to the LVH group. Heart, LV weight, myocardial thickness were reduced while LV internal diameter was increased (all P<0.05) in the LVH-H2S when compared to the LVH group. Exogenous administration of H2S in LVH increased superoxide dismutase, glutathione and total antioxidant capacity but significantly reduced (all P<0.05) plasma malanodialdehyde in the LVH-H2S compared to the LVH group. The renal cortical blood perfusion increased by 40% in LVH-H2S as compared to the LVH group. Exogenous administration of H2S suppressed the progression of LVH which was associated with an up regulation of myocardial CSE mRNA/ H2S and a reduction in pulse wave velocity with a blunting of systemic hemodynamic. This CSE/H2S pathway exhibits an antihypertrophic role by antagonizing the hypertrophic actions of angiotensin II(Ang II) and noradrenaline (NA) but attenuates oxidative stress and improves pulse wave velocity which helps to suppress LVH. Exogenous administration of H2S augmented the reduced renal cortical blood perfusion in the LVH state. PMID- 26963624 TI - Micronutrient Deficiencies and Plasmodium vivax Malaria among Children in the Brazilian Amazon. AB - BACKGROUND: There is a growing body of evidence linking micronutrient deficiencies and malaria incidence arising mostly from P. falciparum endemic areas. We assessed the impact of micronutrient deficiencies on malaria incidence and vice versa in the Brazilian state of Amazonas. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated children <10 years old living in rural communities in the state of Amazonas, Brazil, from May 2010 to May 2011. All children were assessed for sociodemographic, anthropometric and laboratory parameters, including vitamin A, beta-carotene, zinc and iron serum levels at the beginning of the study (May 2010) and one year later (May 2011). Children were followed in between using passive surveillance for detection of symptomatic malaria. Those living in the study area at the completion of the observation period were reassessed for micronutrient levels. Univariate Cox-proportional Hazards models were used to assess whether micronutrient deficiencies had an impact on time to first P. vivax malaria episode. We included 95 children median age 4.8 years (interquartile range [IQR]: 2.3-6.6), mostly males (60.0%) and with high maternal illiteracy (72.6%). Vitamin A deficiencies were found in 36% of children, beta-carotene deficiency in 63%, zinc deficiency in 61% and iron deficiency in 51%. Most children (80%) had at least one intestinal parasite. During follow-up, 16 cases of vivax malaria were diagnosed amongst 13 individuals. Micronutrient deficiencies were not associated with increased malaria incidence: vitamin A deficiency [Hazard ratio (HR): 1.51; P-value: 0.45]; beta-carotene [HR: 0.47; P value: 0.19]; zinc [HR: 1.41; P-value: 0.57] and iron [HR: 2.31; P-value: 0.16]). Upon reevaluation, children with al least one episode of malaria did not present significant changes in micronutrient levels. CONCLUSION: Micronutrient serum levels were not associated with a higher malaria incidence nor the malaria episode influenced micronutrient levels. Future studies targeting larger populations to assess micronutrients levels in P. vivax endemic areas are warranted in order to validate these results. PMID- 26963627 TI - Enhanced Thermionic Emission and Low 1/f Noise in Exfoliated Graphene/GaN Schottky Barrier Diode. AB - Temperature-dependent electrical transport characteristics of exfoliated graphene/GaN Schottky diodes are investigated and compared with conventional Ni/GaN Schottky diodes. The ideality factor of graphene/GaN and Ni/GaN diodes are measured to be 1.33 and 1.51, respectively, which is suggestive of comparatively higher thermionic emission current in graphene/GaN diode. The barrier height values for graphene/GaN diode obtained using thermionic emission model and Richardson plots are found to be 0.60 and 0.72 eV, respectively, which are higher than predicted barrier height ~0.40 eV as per the Schottky-Mott model. The higher barrier height is attributed to hole doping of graphene due to graphene-Au interaction which shifts the Fermi level in graphene by ~0.3 eV. The magnitude of flicker noise of graphene/GaN Schottky diode increases up to 175 K followed by its decrease at higher temperatures. This indicates that diffusion currents and barrier inhomogeneities dominate the electronic transport at lower and higher temperatures, respectively. The exfoliated graphene/GaN diode is found to have lower level of barrier inhomogeneities than conventional Ni/GaN diode, as well as earlier reported graphene/GaN diode fabricated using chemical vapor deposited graphene. The lesser barrier inhomogeneities in graphene/GaN diode results in lower flicker noise by 2 orders of magnitude as compared to Ni/GaN diode. Enhanced thermionic emission current, lower level of inhomogeneities, and reduced flicker noise suggests that graphene-GaN Schottky diodes may have the underlying trend for replacing metal-GaN Schottky diodes. PMID- 26963626 TI - The serine protease Pic as a virulence factor of atypical enteropathogenic Escherichia coli. AB - Autotransporter proteins (AT) are associated with bacterial virulence attributes. Originally identified in enteroaggregative Escherichia coli (EAEC), Shigella flexneri 2a and uropathogenic E. coli, the serine protease Pic is one of these AT. We have previously detected one atypical enteropathogenic E. coli strain (BA589) carrying the pic gene. In the present study, we characterized the biological activities of Pic produced by BA589 both in vitro and in vivo. Contrarily to other Pic-producers bacteria, pic in BA589 is located on a high molecular weight plasmid. PicBA589 was able to agglutinate rabbit erythrocytes, cleave mucin and degrade complement system molecules. BA589 was able to colonize mice intestines, and an intense mucus production was observed. The BA589Deltapic mutant lost the capacity to colonize as well as the above-mentioned in vitro activities. Thus, Pic represents an additional virulence factor in aEPEC strain BA589, associated with adherence, colonization and evasion from the innate immune system. PMID- 26963628 TI - Pollution characteristics of 23 veterinary antibiotics in livestock manure and manure-amended soils in Jiangsu province, China. AB - The aim of this study was to investigate the pollution characteristics of typical veterinary antibiotics in manure and soil of livestock farms in Jiangsu province. This investigation employed solid-phase extraction (SPE) coupled with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A total of 53 manure and 50 amended soil samples from 16 livestock farms in Jiangsu province were collected for analysis. In the manure samples, the highest detected frequencies and concentrations were those of tetracyclines (TCs, 54.1 +/- 5775.6 MUgkg(-1)), followed by fluoroquinolones (FQs, 8.4 +/- 435.6 MUgkg(-1)), sulphonamides (SAs, 3.2 +/- 5.2 MUgkg(-1)) and macrolides (MACs, 0.4 +/- 110.5 MUgkg(-1)). Statistical analysis was used to illuminate the pollution characteristics of 23 veterinary antibiotics for various animal types and different regions in Jiangsu province. The results showed that the pollution level in cow manure was relatively lower compared with pig and chicken manure due to the relative restriction of medication. Furthermore, contamination was serious in amended soil from chicken farms. The pollution level in manure among different regions was higher to the south and north compared with the centre of the region. The same outcome was found for soil. Antibiotic residues in organic fertilizer were also investigated in this study. We found that although the detected concentration was lower in organic fertilizer than in fresh manure, detection frequencies (10-90%) were high, especially for roxithromycin (90%) in MACs (30 90%). This finding suggests attention should be paid to the pollution levels in organic fertilizer. This study is the first extensive investigation of the occurrence and distribution of many kinds of typical veterinary antibiotics in manure and soil from livestock farms of Jiangsu province. This investigation systematically assesses veterinary antibiotics usage and related emissions in southeast China. PMID- 26963629 TI - Sudden Death Due to Undiagnosed Wilkie Syndrome. AB - A 56-year-old transgender woman with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes syndrome and diabetes presented to hospital with headaches and experiencing with malnutrition. She was agitated and refused medical and physical assistance. Soon after admission, she started to vomit and developed abdominal pain, becoming rapidly unresponsive on the ward after attending the radiology department, and was pronounced deceased. Autopsy revealed a cachectic transgender woman with a grossly distended stomach and proximal duodenum containing 2 L of liquid. The postmortem computed tomography scan showed compression of the duodenum by the superior mesenteric artery, diagnostic of Wilkie syndrome. Superior mesenteric artery syndrome, or Wilkie syndrome, was first described in 1861 by Von Rokitansky. It is an uncommon but well-recognized clinical entity characterized by compression of the third, or transverse, portion of the duodenum between the aorta and the superior mesenteric artery. This results in chronic, intermittent, or acute complete or partial duodenal obstruction. It is a well-recognized complication of anorexia. PMID- 26963625 TI - Cdkn1c Boosts the Development of Brown Adipose Tissue in a Murine Model of Silver Russell Syndrome. AB - The accurate diagnosis and clinical management of the growth restriction disorder Silver Russell Syndrome (SRS) has confounded researchers and clinicians for many years due to the myriad of genetic and epigenetic alterations reported in these patients and the lack of suitable animal models to test the contribution of specific gene alterations. Some genetic alterations suggest a role for increased dosage of the imprinted CYCLIN DEPENDENT KINASE INHIBITOR 1C (CDKN1C) gene, often mutated in IMAGe Syndrome and Beckwith-Wiedemann Syndrome (BWS). Cdkn1c encodes a potent negative regulator of fetal growth that also regulates placental development, consistent with a proposed role for CDKN1C in these complex childhood growth disorders. Here, we report that a mouse modelling the rare microduplications present in some SRS patients exhibited phenotypes including low birth weight with relative head sparing, neonatal hypoglycemia, absence of catch up growth and significantly reduced adiposity as adults, all defining features of SRS. Further investigation revealed the presence of substantially more brown adipose tissue in very young mice, of both the classical or canonical type exemplified by interscapular-type brown fat depot in mice (iBAT) and a second type of non-classic BAT that develops postnatally within white adipose tissue (WAT), genetically attributable to a double dose of Cdkn1c in vivo and ex-vivo. Conversely, loss-of-function of Cdkn1c resulted in the complete developmental failure of the brown adipocyte lineage with a loss of markers of both brown adipose fate and function. We further show that Cdkn1c is required for post transcriptional accumulation of the brown fat determinant PR domain containing 16 (PRDM16) and that CDKN1C and PRDM16 co-localise to the nucleus of rare label retaining cell within iBAT. This study reveals a key requirement for Cdkn1c in the early development of the brown adipose lineages. Importantly, active BAT consumes high amounts of energy to generate body heat, providing a valid explanation for the persistence of thinness in our model and supporting a major role for elevated CDKN1C in SRS. PMID- 26963632 TI - Microfluidic differential immunocapture biochip for specific leukocyte counting. AB - Enumerating specific cell types from whole blood can be very useful for research and diagnostic purposes-e.g., for counting of CD4 and CD8 T cells in HIV/AIDS diagnostics. We have developed a biosensor based on a differential immunocapture technology to enumerate specific cells in 30 min using 10 MUl of blood. This paper provides a comprehensive stepwise protocol to replicate our biosensor for CD4 and CD8 cell counts. The biochip can also be adapted to enumerate other specific cell types such as somatic cells or cells from tissue or liquid biopsies. Capture of other specific cells requires immobilization of their corresponding antibodies within the capture chamber. Therefore, this protocol is useful for research into areas surrounding immunocapture-based biosensor development. The biosensor production requires 24 h, a one-time cell capture optimization takes 6-9 h, and the final cell counting experiment in a laboratory environment requires 30 min to complete. PMID- 26963633 TI - Contrasting Effects of Water on the Barriers to Decarboxylation of Two Oxalic Acid Monohydrates: A Combined Rotational Spectroscopic and Ab Initio Study. AB - Using rotational spectroscopy, we have observed two isomers of the monohydrate of oxalic acid, the most abundant dicarboxylic acid in the atmosphere. In the lowest energy isomer, water hydrogen-bonds to both carboxylic acid groups, and the barrier to decarboxylation decreases. In the second isomer, water bonds to only one carboxylic acid group, and the barrier increases. Though the lower barrier in the former is not unequivocal evidence that water acts as a photocatalyst, the higher barrier in the latter indicates that water acts as an inhibitor in this topology. Oxalic acid is unique among dicarboxylic acids: for the higher homologues calculated, the inhibiting topology of the monohydrate is lowest in energy and most abundant under atmospheric conditions. Consequently, oxalic acid is the only dicarboxylic acid for which single-water catalysis of overtone induced decarboxylation in the atmosphere is plausible. PMID- 26963634 TI - Correction: Development and Testing of a Magnetically Actuated Capsule Endoscopy for Obesity Treatment. PMID- 26963631 TI - Near-IR photoactivation using mesoporous silica-coated NaYF4:Yb,Er/Tm upconversion nanoparticles. AB - Photoactivation is a process in which light is used to 'activate' photolabile therapeutics. As a therapeutic strategy, its advantages are that it is noninvasive and that a high degree of spatial and temporal control is possible. However, conventional photoactivation techniques are hampered by the limited penetration depth of the UV and visible lights to which the photosensitive compounds are responsive. Here we describe a protocol for the use of upconversion nanoparticles (UCNs) as light transducers to convert deeply penetrating near infrared (NIR) light to UV-visible wavelengths matching that of the absorption spectrum of photosensitive therapeutics. This allows the use of deep-penetrating and biologically friendly NIR light instead of low-penetrating and/or toxic visible or UV lights for photoactivation. In this protocol, we focus on two photoactivation applications: photodynamic therapy (PDT) and photoactivated control of gene expression. We describe how to prepare and characterize the UCNs, as well as how to check their function in biochemical assays and in cells. For both applications, the UCNs are coated with mesoporous silica for easy loading of the therapeutics. For PDT, the UCNs are coated with polyethylene glycol (PEG) for stabilization and folic acid for tumor targeting and then loaded with photosensitizers that would be expected to kill cells by singlet oxygen production; the nanoparticles are injected intravenously. For photoactivated control of gene expression, knockdown of essential tumor genes is achieved using UCNs loaded with caged nucleic acids, which are injected intratumorally. The whole process from nanoparticle synthesis to animal studies takes ~36 d. PMID- 26963630 TI - Using Raman spectroscopy to characterize biological materials. AB - Raman spectroscopy can be used to measure the chemical composition of a sample, which can in turn be used to extract biological information. Many materials have characteristic Raman spectra, which means that Raman spectroscopy has proven to be an effective analytical approach in geology, semiconductor, materials and polymer science fields. The application of Raman spectroscopy and microscopy within biology is rapidly increasing because it can provide chemical and compositional information, but it does not typically suffer from interference from water molecules. Analysis does not conventionally require extensive sample preparation; biochemical and structural information can usually be obtained without labeling. In this protocol, we aim to standardize and bring together multiple experimental approaches from key leaders in the field for obtaining Raman spectra using a microspectrometer. As examples of the range of biological samples that can be analyzed, we provide instructions for acquiring Raman spectra, maps and images for fresh plant tissue, formalin-fixed and fresh frozen mammalian tissue, fixed cells and biofluids. We explore a robust approach for sample preparation, instrumentation, acquisition parameters and data processing. By using this approach, we expect that a typical Raman experiment can be performed by a nonspecialist user to generate high-quality data for biological materials analysis. PMID- 26963635 TI - Diversity, Mutation and Recombination Analysis of Cotton Leaf Curl Geminiviruses. AB - The spread of cotton leaf curl disease in China, India and Pakistan is a recent phenomenon. Analysis of available sequence data determined that there is a substantial diversity of cotton-infecting geminiviruses in Pakistan. Phylogenetic analyses indicated that recombination between two major groups of viruses, cotton leaf curl Multan virus (CLCuMuV) and cotton leaf curl Kokhran virus (CLCuKoV), led to the emergence of several new viruses. Recombination detection programs and phylogenetic analyses showed that CLCuMuV and CLCuKoV are highly recombinant viruses. Indeed, CLCuKoV appeared to be a major donor virus for the coat protein (CP) gene, while CLCuMuV donated the Rep gene in the majority of recombination events. Using recombination free nucleotide datasets the substitution rates for CP and Rep genes were determined. We inferred similar nucleotide substitution rates for the CLCuMuV-Rep gene (4.96X10-4) and CLCuKoV-CP gene (2.706X10-4), whereas relatively higher substitution rates were observed for CLCuMuV-CP and CLCuKoV-Rep genes. The combination of sequences with equal and relatively low substitution rates, seemed to result in the emergence of viral isolates that caused epidemics in Pakistan and India. Our findings also suggest that CLCuMuV is spreading at an alarming rate, which can potentially be a threat to cotton production in the Indian subcontinent. PMID- 26963637 TI - Human PIEZO1 Ion Channel Functions as a Split Protein. AB - PIEZO1 is a mechanosensitive eukaryotic cation-selective channel that rapidly inactivates in a voltage-dependent manner. We previously showed that a fluorescent protein could be encoded within the hPIEZO1 sequence without loss of function. In this work, we split the channel into two at this site and asked if coexpression would produce a functional channel or whether gating and permeation might be contained in either segment. The split protein was expressed in two segments by a bicistronic plasmid where the first segment spanned residues 1 to 1591, and the second segment spanned 1592 to 2521. When the "split protein" is coexpressed, the parts associate to form a normal channel. We measured the whole cell, cell-attached and outside-out patch currents in transfected HEK293 cells. Indentation produced whole-cell currents monotonic with the stimulus. Single channel recordings showed voltage-dependent inactivation. The Boltzmann activation curve for outside-out patches had a slope of 8.6/mmHg vs 8.1 for wild type, and a small leftward shift in the midpoint (32 mmHg vs 41 mmHg). The association of the two channel domains was confirmed by FRET measurements of mCherry on the N-terminus and EGFP on the C-terminus. Neither of the individual protein segments produced current when expressed alone. PMID- 26963636 TI - Interactive Effects of Anxiety Sensitivity and Subjective Social Status on Psychological Symptomatology in Black Adults. AB - Anxiety sensitivity is the fear of anxiety-related sensations and subjective social status is a self-perception of social standing relative to others: both constructs have been linked to psychological symptomatology. This study investigated the interactive effects of anxiety sensitivity and social status in relation to anxiety and depressive symptomatology expression among 124 black adults. Participants provided sociodemographics and completed self-report questionnaires. The interactive associations between anxiety sensitivity and social status on anxiety symptomatology and depressive symptomatology were examined with hierarchical linear regressions adjusted for sociodemographics and negative affectivity. Significant interactions between anxiety sensitivity and social status were evident only for anxiety symptoms: specifically, the association between anxiety sensitivity and anxiety symptoms was much stronger for individuals with lower (versus higher) subjective social status. Black adults with this higher anxiety sensitivity/lower social status phenotype may be at heightened risk for the expression of anxiety symptomatology, and may benefit from interventions to reduce anxiety sensitivity. PMID- 26963640 TI - Outcomes of an International Audiology Service-Learning Study-Abroad Program. AB - PURPOSE: The purpose of this study was to evaluate students' academic and civic learning, with particular interest in cultural competence, gained through participation in the Speech, Language, and Hearing Sciences in Zambia study abroad program. METHOD: Twelve female students participated in the program. Quantitative data collected included pre- and postprogram administration of the Public Affairs Scale (Levesque-Bristol & Cornelius-White, 2012) to measure changes in participants' civic learning. Qualitative data included journals, end of-program reflection papers, videos, and researcher field notes. Feedback was also obtained from community-partner organizations via a questionnaire and rating scale. RESULTS: Comparison of the pre- and postprogram Public Affairs Scale data showed a significant increase in cultural competence and a marginal increase in community engagement at the conclusion of the program. Qualitative data showed that participants' cultural awareness was increased, they benefited from hands-on learning, and they experienced a variety of emotions and emotional and personal growth. CONCLUSIONS: Results show that a short-term study-abroad program with a service-learning component can be a mechanism for students to enhance academic and civic learning, specifically cultural competence and clinical skills. Sustainability of programs is a challenge that needs to be addressed. PMID- 26963638 TI - Longitudinal sex and stress hormone profiles among reproductive age and post menopausal women after severe TBI: A case series analysis. AB - PRIMARY OBJECTIVES: To describe hormone profiles for pre-/post-menopausal women, to monitor time to resumption of menstruation among pre-menopausal women and to describe cortisol associated LH suppression and phasic variation in other sex hormones over timeMethods and procedures: This study determined amenorrhea duration and characterized acute (days 0-7) and chronic (months 1-6) gonadotropins [luteinizing hormone and follicle stimulating hormone (LH, FSH)], sex hormones (progesterone, estradiol) and stress hormone (cortisol) profiles. Women were pre-menopausal (n = 3) or post-menopausal (n = 3). Among pre menopausal women, menstrual cycle resolution and phase association (luteal/follicular) was monitored using self-report monthly reproductive history questionnaires. This study compared post-TBI hormone profiles, stratified by menopausal status, to hormone levels from seven controls and described 6- and 12 month outcomes for these women. MAIN OUTCOMES AND RESULTS: Consistent with functional hypothalamic amenorrhea (FHA), menstruation resumption among pre menopausal women occurred when serum cortisol normalized to luteal phase control levels. For post-menopausal women, serum cortisol reductions corresponded with resolution of suppressed LH levels. CONCLUSIONS: The stress of TBI results in anovulation and central hypothalamic-pituitary-ovarian (HPG) axis suppression. Future work will examine acute/chronic consequences of post-TBI hypercortisolemia and associated HPG suppression, the temporal association of HPG suppression with other neuroendocrine adaptations and how HPG suppression impacts multidimensional recovery for women with TBI. PMID- 26963641 TI - Recovery of motor imagery ability in the first year after stroke. AB - The aim of this study was to examine the level and recovery of motor imagery ability (MIA) in the first year after stroke and whether the recovery of MIA is related to that of arm/hand function. Twenty-three patients with diminished arm/hand function were included. The accuracy score on the hand laterality judgment task was used to assess MIA and the Fugl-Meyer Assessment was used to evaluate the recovery of arm/hand function. The patients were assessed 3, 6, 16, 26, and 52 weeks after stroke. In the first year after stroke, the percentage of patients with moderate to good MIA improved from 78% after 3 weeks to 94% after 1 year. The recovery of MIA took place in the first 6 weeks after stroke. No correlation was found between the recovery of MIA and arm/hand function, despite the fact that the greatest improvement in both occurred in the first 6 weeks. PMID- 26963639 TI - Improving the CH1-CK heterodimerization and pharmacokinetics of 4Dm2m, a novel potent CD4-antibody fusion protein against HIV-1. AB - We previously described 4Dm2m, an exceptionally potent broadly neutralizing CD4 antibody fusion protein against HIV-1. It was generated by fusing the engineered single human CD4 domain mD1.22 to both the N and C termini of the human IgG1 heavy chain constant region and the engineered single human antibody domain m36.4, which targets the CD4-induced coreceptor binding site of the viral envelope glycoprotein, to the N terminus of the human antibody kappa light chain constant region via the (G4S)3 polypeptide linkers. However, therapeutic use of 4Dm2m was limited by its short in vivo half-life. Here, we show that a combination of three approaches have successfully increased the persistence of 4Dm2m in mice. First, to stabilize the scaffold, we enhanced heterodimerization between the heavy chain constant domain 1 (CH1) and kappa light chain constant domain (CK) by using structure-guided design and phage-display library technologies. Second, to address the possibility that long polypeptide linkers might render fusion proteins more susceptible to proteolysis, we shortened the (G4S)3 linkers or replaced them with the human IgG1 hinge sequence, which is naturally designed for both flexibility and stability. Third, we introduced two amino acid mutations into the crystallizable fragment (Fc) of the scaffold previously shown to increase antibody binding to the neonatal Fc receptor (FcRn) and prolong half-lives in vivo. Collectively, these approaches markedly increased the serum concentrations of 4Dm2m in mice while not affecting other properties of the fusion protein. The new 4Dm2m variants are promising candidates for clinical development to prevent or treat HIV-1 infection. To our knowledge, this is the first report on stabilized CH1-CK, which is potentially useful as a new heterodimerization scaffold for generation of bispecific and multispecific antibodies or proteins with a more favorable pharmacokinetic profile. PMID- 26963649 TI - Tearing down to build up: Metalloenzymes in the biosynthesis lincomycin, hormaomycin and the pyrrolo [1,4]benzodiazepines. AB - The metabolic pathways for the production of lincomycin, hormaomycin and the antitumor pyrrolo [1,4] benzodiazepines share a vinyl substituted pyrroline carboxylic acid (3-vinyl-2,3-pyrroline-5-carboxylic acid, VPCA) as a common intermediate. Biosynthesis of this vinyl substituted pyrroline carboxylic acid intermediate requires a short, three-enzyme pathway containing two metalloenzymes: a heme-dependent l-tyrosine hydroxylase and a non-heme Fe(2+) dependent l-DOPA dioxygenase. The l-tyrosine hydroxylase is an unprecedented type of peroxidase that specifically monohydroxylates tyrosine, while the l-DOPA extradiol cleaving enzyme is a single-domain vicinal-oxygen-chelate (VOC) dioxygenase. The dioxygenase product subsequently undergoes an, as yet uncharacterized, C-C bond cleavage reaction. This mini-pathway demonstrates the use of metal-dependent chemistry typically associated with natural product degradation in order to build a compact, functionalized building block for larger, bioactive molecules. PMID- 26963650 TI - Characterization of Polyphenols from Lycium ruthenicum Fruit by UPLC-Q-TOF/MS(E) and Their Antioxidant Activity in Caco-2 Cells. AB - The fruit of Lycium ruthenicum Murr. (LRF) has long been used in folk medicine. Nevertheless, detailed information related to its polyphenol compositions remains scarce. In this study, we confirmed that the total phenolic and anthocyanin contents of LRF fruit extracts (LRFEs) were 4906.5 +/- 60.6 mg of gallic acid equivalents/100 g DW and 787.6 +/- 34.1 mg of cyanindin-3-glucoside equivalents/100 g DW, respectively. A characterization of LRFEs was performed by ultrahigh performance liquid chromatography/quadrupole time-of-flight mass spectrometry using an MS(E) data acquisition. A total of 26 polyphenols were tentatively identified, of which 19 represent the first reports of these polyphenols in LRFEs. Furthermore, the cellular antioxidant array showed that LRFEs could protect Caco-2 cells against H2O2-induced oxidative damage based on microscopic fluorometric imaging. PMID- 26963651 TI - Liquid-Mercury-Supported Langmuir Films of Ionic Liquids: Isotherms, Structure, and Time Evolution. AB - Ionic liquids have been intensively developed for the last few decades and are now used in a wide range of applications, from electrochemistry to catalysis and nanotechnology. Many of these applications involve ionic liquid interfaces with other liquids and solids, the subnanometric experimental study of which is highly demanding, and has been little studied to date. We present here a study of mercury-supported Langmuir films of imidazolium-based ionic liquids by surface tensiometry and X-ray reflectivity. The charge-delocalized ionic liquids studied here exhibit no 2D lateral order but show diffuse surface-normal electron density profiles exhibiting gradual mercury penetration into the ionic liquid film, and surface-normal structure evolution over a period of hours. The effect of increasing the nonpolar alkyl chain length was also investigated. The results obtained provide insights into the interactions between these ionic liquids and liquid mercury and about the time evolution of the structure and composition of their interface. PMID- 26963642 TI - Investigation Into the Humaneness of Slaughter Methods for Guinea Pigs (Cavia porcelus) in the Andean Region. AB - Guinea pigs (Cavia porcelus) are an important source of nonhuman animal protein in the Andean region of South America. Specific guidelines regarding the welfare of guinea pigs before and during slaughter have yet to be developed. This study critically assessed the humaneness of 4 different stunning/slaughter methods for guinea pigs: cervical neck dislocation (n = 60), electrical head-only stunning (n = 83), carbon dioxide (CO2) stunning (n = 21), and penetrating captive bolt (n = 10). Following cervical neck dislocation, 97% of guinea pigs had at least 1 behavioral or cranial/spinal response. Six percent of guinea pigs were classified as mis-stunned after electrical stunning, and 1% were classified as mis-stunned after captive bolt. Increased respiratory effort was observed during CO2 stunning. Apart from this finding, there were no other obvious behavioral responses that could be associated with suffering. Of the methods assessed, captive bolt was deemed the most humane, effective, and practical method of stunning guinea pigs. Cervical neck dislocation should not be recommended as a slaughter method for guinea pigs. PMID- 26963652 TI - Design and Evaluation of Identifiable Key-Click Signals for Mobile Devices. AB - As touch based input becomes more popular in mobile devices, there is an increasing need for haptic feedback on key-less input surface. Four experiments were conducted to design and evaluate identifiable emulated key-click signals using a piezoelectric actuator. Experiments I and II assessed the information transmission capacity for the amplitude, frequency, and number of cycles of raised cosine waveforms used to drive the piezo actuators under fixed- and roving background conditions, respectively. Experiment III estimated the total information transfer for all three parameters. The results were used to reduce the number of stimulus alternatives in the key-click signal set with the goal to achieve perfect identification performance. Experiment IV verified that up to 5 to 6 identifiable key-click signals could be achieved with the experimental setup. The present study outlines an information theoretic approach to conducting identification experiments to guide the design of and to evaluate a perfectly identifiable stimulus set. The methodology can be applied to other applications in need of perceptually identifiable stimulation patterns. PMID- 26963653 TI - Exploratory Strategies in Haptic Softness Discrimination Are Tuned to Achieve High Levels of Task Performance. AB - Haptic perception essentially depends on the executed exploratory movements. It has been speculated that spontaneously executed movements are optimized for the computation of associated haptic properties. We investigated to what extent people strategically execute movements that are tuned for softness discrimination of objects with deformable surfaces. In Experiment 1, we investigated how movement parameters depend on expected stimulus compliance. In a discrimination task, we measured exploratory forces for less compliant (hard) stimuli and for more compliant (soft) stimuli. In Experiment 2, we investigated whether exploratory force also depends on the expected compliance difference between the two stimuli. The results indicate that participants apply higher forces when expecting harder objects as compared to softer objects, and they apply higher forces for smaller compliance differences than for larger ones. Experiment 3 examined how applied force influences differential sensitivity for softness as assessed by just noticeable differences (JNDs). For soft stimuli, JNDs did not depend on force. For hard stimuli, JNDs were "worse" (higher) if participants applied less force than they use naturally. We conclude that applying high force is a robust strategy to obtain high differential sensitivity, and that participants used this strategy if it was required for successful discrimination performance. PMID- 26963654 TI - Improved Tactile Shear Feedback: Tactor Design and an Aperture-Based Restraint. AB - Tactile feedback could replace or augment visual and auditory communication in a range of important applications. This paper advances the field of tactile communication by presenting performance data on a variety of tactors and a finger restraint that is suitable for use in portable devices. Tactors, the contact elements between the device and the skin, and finger restraints were evaluated using a tangential skin displacement direction identification task. We tested tactors of three sizes and two different textures. Rough textured tactors improved communication accuracy compared to smooth tactors, but tactor size did not have a statistically significant effect. Aperture-based restraints of three sizes were evaluated on both the index finger and the thumb. The aperture-based restraint was effective when used on both the index finger and the thumb, with performances on par with our previously tested thimble-based restraint. Participants performed better with larger apertures than with smaller apertures, but there was no interaction between aperture size and finger size, meaning that the same aperture could be used with a range of finger sizes. Subjects' perceptual acuity varied with stimulus direction. We discuss the effects of contact force, finger size, and differences in perceptual acuity between the index finger and thumb. PMID- 26963655 TI - Tactile and Haptic Illusions. AB - This paper surveys the research literature on robust tactile and haptic illusions. The illusions are organized into two categories. The first category relates to objects and their properties, and is further differentiated in terms of haptic processing of material versus geometric object properties. The second category relates to haptic space, and is further differentiated in terms of the observer's own body versus external space. The illusions are initially described and where possible addressed in terms of their functional properties and/or underlying neural processes. The significance of these illusions for the design of tactile and haptic displays is also discussed. We conclude by briefly considering a number of important general themes that have emerged in the materials surveyed. PMID- 26963656 TI - The Role of Gesture Types and Spatial Feedback in Haptic Communication. AB - The sense of touch is a fundamental part of social interaction as even a short touch from another person can elicit emotional experiences. Previous studies on haptic communication indicate that the benefits of interpersonal touch exist even when touch is artificially mediated between people that are physically apart. In the current study an evaluation of three input gestures (i.e., moving, squeezing, and stroking) was conducted to identify preferred methods for creating haptic messages using a hand-held device. Furthermore, two output methods (i.e., one or four haptic actuators) were investigated in order to determine whether representing spatial properties of input gestures haptically provides additional benefit for communication. Participants created haptic messages in four example communication scenarios. The results of subjective ratings, postexperimental interviews, and observations showed that squeezing and stroking were the preferred ways to interact with the device. Squeezing was an unobtrusive and quick way to create haptic content. Stroking, on the other hand, enabled crafting of more detailed haptic messages. Spatial haptic output was appreciated especially when using the stroking method. These findings can help in designing haptic communication methods for hand-held devices. PMID- 26963658 TI - Characterization of the Haptic Shape-Weight Illusion with 3D Objects. AB - The present study shows an effect of 3D shape on perceived weight of objects. This effect could be explained partly by the size-weight and the shape-size illusions, suggesting that the perceived size is not the only factor responsible for the shape-weight illusion. PMID- 26963657 TI - Vibrotactile Stimuli Applied to Finger Pads as Biases for Perceived Inertial and Viscous Loads. AB - The perception of the mass and viscosity of an object is based on the dynamic forces applied to our hands when we jiggle or lift the object [1], [2], [3]. This force is commonly assumed to be sensed by kinetic receptors [4] in our muscles or tendons. When jiggling objects, we also experience the cutaneous deformation of our finger pads. In this study, we show that the dynamic vibration on the finger pad influences our perception of mass and viscosity. We experimentally confirm that the vibration on the finger pad, that synchronizes with the hand's accelerations or velocities, enhances the perceived changes in the mass or viscosity when the vibrotactile stimuli and the changes in the mass and viscosity are in the same perceptual direction. For example, when the increased mass and an acceleration-synchronized tactile stimulus-which is a positive bias for the mass are simultaneously presented to the experiment participants, they respond that the perceived increase in the mass is enhanced. In contrast, when the tactile and proprioceptive stimuli are in perceptually opposite directions, the vibrotactile stimuli cancel the perceived changes in the mass and viscosity. In particular, the effect of the velocity-synchronized vibration on perception is stronger than the effect of the actual viscosity. PMID- 26963659 TI - Collocation Accuracy of Visuo-Haptic System: Metrics and Calibration. AB - Human resolution of collocation error between haptic and stereoscopic displays influences the design of visuo-haptic rendering algorithms, yet it is not well characterized. In the present study, we propose quantified metrics to measure the visuo-haptic collocation error and a prototype based on half-silvered mirror is established to validate the metrics. After defining collocation error in terms of the spatial correspondence between a tool and a surface, a mathematical model is derived that relates collocation error to the visual and haptic rendering modules within the computational pipeline. A calibration method consisting of Perspective Calibration (PC) and Model Calibration (MC) is then proposed to compensate for manufacturing and assembly tolerances. Based on measurement values by a precise measurement apparatus, i.e., the FARO Arm, parameters for the PC and MC were determined. System performance is evaluated by measuring the collocation error between a real handle and its visual avatar. The average collocation error was 1.8 mm within the XwYwOw plane, and the error never exceeded 7 mm within an 80 mm * 80 mm * 80 mm workspace. PMID- 26963660 TI - Modeling and Compensation of the Internal Friction Torque of a Travelling Wave Ultrasonic Motor. AB - This paper deals with the control and experimentation of a one-degree-of-freedom haptic stick, actuated by a travelling wave ultrasonic motor. This type of actuator has many interesting properties such as low-speed operation capabilities and a high torque-to-weight ratio, making it appropriate for haptic applications. However, the motor used in this application displays nonlinear behavior due to the necessary contact between its rotor and stator. Moreover, due to its energy conversion process, the torque applied to the end-effector is not a straightforward function of the supply current or voltage. This is why a force feedback control strategy is presented, which includes an online parameter estimator. Experimental runs are then presented to examine the fidelity of the interface. PMID- 26963661 TI - The Economics of Cognitive Impairment: Volunteering and Cognitive Function in the HILDA Survey. AB - BACKGROUND: The economic impact of older-age cognitive impairment has been estimated primarily by the direct and indirect costs associated with dementia care. Other potential costs associated with milder cognitive impairment in the community have received little attention. OBJECTIVE: To quantify the cost of nonclinical cognitive impairment in a large population-based sample in order to more fully inform cost-effectiveness evaluations of interventions to maintain cognitive health. METHODS: Volunteering by seniors has economic value but those with lower cognitive function may contribute fewer hours. Relations between hours volunteering and cognitive impairment were assessed using the Household, Income and Labour Dynamics in Australia (HILDA) survey data. These findings were extrapolated to the Australian population to estimate one potential cost attributable to nonclinical cognitive impairment. RESULTS: In those aged >=60 years in HILDA (n = 3,127), conservatively defined cognitive impairment was present in 3.8% of the sample. Impairment was defined by performance >=1 standard deviation below the age- and education-adjusted mean on both the Symbol Digit Modalities Test and Backwards Digit Span test. In fully adjusted binomial regression models, impairment was associated with the probability of undertaking 1 h 9 min less volunteering a week compared to being nonimpaired (beta = -1.15, 95% confidence interval -1.82 to -0.47, p = 0.001). In the population, 3.8% impairment equated to probable loss of AUD 302,307,969 per annum estimated by hours of volunteering valued by replacement cost. CONCLUSION: Nonclinical cognitive impairment in older age impacts upon on the nonmonetary economy via probable loss of volunteering contribution. Valuing loss of contribution provides additional information for cost-effectiveness evaluations of research and action directed toward maintaining older-age cognitive functioning. PMID- 26963662 TI - The management of hypophysitis. AB - Hypophysitis is generally accepted as an autoimmune disease which is characterized by inflammation and cellular infiltration of the pituitary gland. It can be either primary or secondary. In this review, treatment of primary hypophysitis of various histological subtypes are discussed. Management of primary hypophysitis is usually symptomatic aiming to reduce the size of the pituitary mass and/or replace deficient pituitary hormones. Observation with replacement for deficient pituitary hormones can be applied in some group of patients. Keeping the complications of surgery in mind, surgical intervention should be limited to cases with severe and/or deteriorating compressive signs or cases with inconclusive findings of hypophysitis in whom treatment would be based on histopathological examination. The most commonly used drugs in the treatment of hypophysitis are glucocorticoids. They are able to reduce the size of the mass lesion with their anti-inflammatory effects and sometimes pituitary functions may also recover. However, there is no consensus about the optimal duration and dose of glucocorticoid use. When glucocorticoids and/or surgery fail, azathioprine, methotrexate, cyclosporin A and novel immunotherapies can be tried as third or forth line treatment. Radiotherapy and radiosurgery have been seldom used for treatment of hypophysitis in order to reduce the mass effect. PMID- 26963663 TI - Anastomotic complications after robot-assisted laparoscopic and open radical prostatectomy. AB - Objective Anastomotic complications are well known after radical prostatectomy (RP). The vesicourethral anastomotic technique is handled differently between open and robotic RP. The aim of the study was to investigate whether the frequency of anastomotic leakages and strictures differed between patients undergoing retropubic radical prostatectomy (RRP) and robot-assisted radical prostatectomy (RARP) and to identify risk factors associated with these complications. Materials and methods The study included 735 consecutive patients who underwent RRP (n = 499) or RARP (236) at the Department of Urology, Rigshospitalet, Denmark, in a complete 3 year period from 2010 to 2012. Univariate and multivariate logistic regression analysis was used to analyse associations between surgical procedure (RRP vs RARP) and anastomotic complications. Analyses included age, smoking status, diabetes, hypertension, surgeon, prostate volume and anastomotic leakage as variables. Owing to a low number of events, multivariable analyses only included smoking status, diabetes and prostate volume for anastomotic leakage, and age, smoking status, prostate volume and anastomotic leakage for anastomotic strictures. Results The frequency of anastomotic leakage was 2.9%. Anastomotic stricture was seen in 4.9% of patients during follow-up. No differences were found in the frequency of anastomotic leakage (p = 0.35) or strictures (p = 0.35) between RRP and RARP. Univariate analysis demonstrated an association between surgeon and the risk of anastomotic strictures in RRP patients (p = 0.02). No other independent risk factors were identified. Conclusion Overall, the anastomotic complication rate in this cohort is similar to other published reports. No obvious risk factors for anastomotic complications could be identified, which in part was due to the low number of events. PMID- 26963664 TI - Reproductive decisions in the lives of West Bank Palestinian women: Dimensions and contradictions. AB - Palestinian women have one of the highest fertility rates in the world, averaging 4.38 births per woman. However, Palestinian fertility patterns are distinct from those of other developing nations, in that high fertility rates coexist alongside high levels of education and low levels of infant mortality - both of which have been established elsewhere as predictors of low total fertility rates. This study explores the dimensions and context of the contradictions between fertility predictors and rates, isolating main factors that shape Palestinian reproductive behaviour. Furthermore, while this study addresses factors that influence the high fertility in the Palestinian Territories, it also addresses factors that contribute to the steady decline of this trend. In-depth interviews were conducted with Palestinian women in urban refugee communities and key informant interviews with experts on Palestinian reproductive health. The findings indicate that five factors shape women's reproductive behaviour: (1) the fear of losing one's children in the ongoing conflict; (2) socio-economic factors including poverty and density of space; (3) the marital relationship; (4) religious values; and (5) generational differences. These results highlight the influence of socio political conditions on reproductive behaviour and the significance of women's agency in manoeuvring their fertility outcomes. PMID- 26963665 TI - Emergence of Binaural Summation After Surgical Correction of Unilateral Congenital Aural Atresia. AB - OBJECTIVE: To investigate the emergence of binaural summation in patients with unilateral congenital aural atresia undergoing surgical correction. STUDY DESIGN: Preoperative and postoperative audiometric testing in a prospective cohort of 10 patients with unilateral congenital aural atresia. SETTING: University-based tertiary care center. PATIENTS: Ten patients (ages 6-53) with an average 69 dB (+/-9 dB sd) unilateral conductive hearing loss, normal hearing in the nonatretic ear, and normal bone conduction in the atretic ear. INTERVENTIONS: Pre- and postoperative hearing in noise test in quiet and in noise. MAIN OUTCOME MEASURES: Levels of sentences presented from a single central speaker were adaptively varied to determine a speech reception threshold (SRT), first in quiet and then with simultaneous multitalker babble at 65 dB SPL from the same speaker. RESULTS: Preoperative SRT was worse than normal controls in both quiet (p = 0.001) and in noise (p = 0.05), as expected. Postoperative SRT in quiet improved 3.5 dB (marginally significant with one-tailed p value of 0.05); thresholds in noise improved an insignificant 0.8 dB (one-tailed p = 0.2). Converting results to dB worse-than normal, atresia patients did better in noise (relative to normal) than in quiet (p = 0.008). CONCLUSION: The expected summation effect (3 dB) occurs after atresia surgery in quiet but not in noise. Relative to normal, these patients performed better in noise than quiet, perhaps because these patients develop skills attending to threshold-level speech in noise during their years without binaural benefit. PMID- 26963666 TI - High Frequency Ex Vivo Ultrasound Imaging of the Middle Ear to Show Simulated Ossicular Pathology. AB - HYPOTHESIS: To illustrate the ability of high frequency ultrasound (HFUS) using a transducer array to demonstrate a variety of simulated clinical scenarios involving the ossicular chain. BACKGROUND: HFUS (>20 MHz) is a relatively new area of ultrasonic imaging that provides an order of magnitude better image resolution than the conventional low-frequency systems. HFUS may be a real-time imaging system that could be used in the clinic and would complement computed tomography (CT) and magnetic resonance imaging (MRI) to enhance the decision making process for patients with middle ear pathology. METHODS: Using a commercially available HFUS scanner, we imaged a variety of simulated clinical scenarios to demonstrate the ability of HFUS to image middle ear pathology. RESULTS: We were able to clearly demonstrate real-time visualization of ossicular pathology in human temporal bones, whereas there are some limitations in the current technique to be addressed before it is used in vivo. CONCLUSION: HFUS allows excellent visualization of middle ear anatomy and pathology through an intact tympanic membrane (TM), and these experiments go some way towards giving the otologist access to high resolution, real-time imaging of the middle ear in the clinic. PMID- 26963667 TI - Economic Evaluation of Treatments for Pediatric Bilateral Severe to Profound Sensorineural Hearing Loss: An Australian Perspective. AB - OBJECTIVES: In Australia, surgical treatment options for children with bilateral severe to profound sensorineural hearing loss exist in a continuum ranging from unilateral cochlear implantation (CI), sequential bilateral CI through to simultaneous bilateral CI, depending on the condition. When treatment options are mutually exclusive, the mean costs and benefits of each treatment group are summed together to obtain the total mean costs and benefits. This enables an incremental analysis of treatment options in the context of the treated populations.The objective was to evaluate the cost-utility of current Australian CI treatment practices in children using domestic costs and consequences when compared with bilateral hearing aids (HAs). RESEARCH DESIGN: Economic evaluation including a Markov model based on secondary sources. SETTING: The base case modeled a government health payer perspective over a child's lifetime. Primary and secondary school education costs were also assessed. INTERVENTION: Bilateral HAs compared with CI, including unilateral, sequential bilateral, or simultaneous bilateral CI weighted according to treatment. MAIN OUTCOME MEASURES: Incremental costs per quality adjusted life year. RESULTS: Approximately 42% of children in Australia with unilateral CI did not transition to sequential bilateral nor undergo simultaneous bilateral implantation. This differs from previous economic evaluations that assumed 100% of children transitioned to sequential bilateral CI treatment or were treated with simultaneous bilateral CI.The incremental cost utility of unilateral cochlear implantation compared with HAs was AUD 21,947/QALY. The weighted average incremental cost utility of the combined cochlear implantation treatment groups was AUD 31,238/QALY when compared with HAs. CONCLUSION: Previous economic evaluations of cochlear implantation assumed 100% of unilaterally treated patients would transition to sequential bilateral or be treated with simultaneous bilateral implantation. This approach does not take into account the total treated population, where a proportion of patients are treated with unilateral CI.CI was cost effective when compared with HAs, and included children treated with unilateral, sequential bilateral, and simultaneous bilateral CI.The model was sensitive to the number of assessment and habilitation visits. Alternative health service models with cost efficiencies are needed to reduce after care costs. PMID- 26963668 TI - Cost-Utility Analysis of Cochlear Implantation in Australian Adults. AB - OBJECTIVES: Sequential and simultaneous bilateral cochlear implants are emerging as appropriate treatment options for Australian adults with sensory deficits in both cochleae. Current funding of Australian public hospitals does not provide for simultaneous bilateral cochlear implantation (CI) as a separate surgical procedure. Previous cost-effectiveness studies of sequential and simultaneous bilateral CI assumed 100% of unilaterally treated patients' transition to a sequential bilateral CI. This assumption does not place cochlear implantation in the context of the generally treated population. When mutually exclusive treatment options exist, such as unilateral CI, sequential bilateral CI, and simultaneous bilateral CI, the mean costs of the treated populations are weighted in the calculation of incremental cost-utility ratios. The objective was to evaluate the cost-utility of bilateral hearing aids (HAs) compared with unilateral, sequential, and simultaneous bilateral CI in Australian adults with bilateral severe to profound sensorineural hearing loss. RESEARCH DESIGN: Cost utility analysis of secondary sources input to a Markov model. SETTING: Australian health care perspective, lifetime horizon with costs and outcomes discounted 5% annually. INTERVENTION: Bilateral HAs as treatment for bilateral severe to profound sensorineural hearing loss compared with unilateral, sequential, and simultaneous bilateral CI. MAIN OUTCOME MEASURES: Incremental costs per quality adjusted life year (AUD/QALY). RESULTS: When compared with bilateral hearing aids the incremental cost-utility ratio for the CI treatment population was AUD11,160/QALY. The incremental cost-utility ratio was weighted according to the number of patients treated unilaterally, sequentially, and simultaneously, as these were mutually exclusive treatment options. CONCLUSION: No peer-reviewed articles have reported the incremental analysis of cochlear implantation in a continuum of care for surgically treated populations with bilateral severe to profound sensorineural hearing loss. Unilateral, sequential, and simultaneous bilateral CI were cost-effective when compared with bilateral hearing aids. Technologies that reduce the total number of visits for a patient could introduce additional cost efficiencies into clinical practice. PMID- 26963669 TI - Microvascular head and neck reconstruction after (chemo)radiation: facts and prejudices. AB - PURPOSE OF REVIEW: This article critically analyzes the recent literature on microvascular head and neck reconstruction after (chemo)radiation [(C)RT], taking into consideration both the underlying pathogenetic mechanisms and their clinical consequences. RECENT FINDINGS: Microvascular reconstruction has gradually become a mainstay in the management of head and neck cancer both in primary and salvage scenarios. However, limited data are available concerning the influence of previous radiotherapy/chemoradiation therapy (CRT) on free flap survival and surgical complications. Molecular studies show that the effects of radiotherapy/CRT may be essentially reduced to three components: inflammation, a prothrombotic state and fibrosis. From a clinical point of view, this is reflected in a moderate increase in free flaps failure and surgical complications. Nevertheless, free flaps continue to offer clear advantages even in such an unfavorable condition. SUMMARY: Radiotherapy/CRT induce a less favorable tissue environment, potentially leading to a higher risk of complications. In this scenario, however, free tissue transfer still plays the role of favoring wound healing bringing well vascularized tissue to less vascularized microenvironments. PMID- 26963670 TI - Early detection of oral cancers: current status and future prospects. AB - PURPOSE OF REVIEW: This article reviews the current literature and summarizes the latest developments in screening and early detection of oral cancers and looks at the future possibilities. RECENT FINDINGS: Oral cancer is the best model for screening and prevention. The screening for oral cancer can be population based, opportunistic, or targeted. A long-term 15-year follow-up data of a randomized controlled study from a developing country setting indicated a sustained reduction in oral cancer mortality in high-risk individuals. Visual oral examination remains the mainstay in the screening. Several adjunctive techniques have been described to aid in the clinical examination of these lesions. A Cochrane review revealed that there is no evidence to recommend these adjuncts in clinically visible lesions. Salivary biomarkers seem to be promising as a tool for screening in the future. A Targeted Evidence Update for the US Preventive Services Task Force found no evidence on screening either in the general or selected high-risk population for oral cancer in the United States or on benefit of any adjunctive device affecting the performance of the screening examination. SUMMARY: Current evidence shows that community based screening has a value in reducing the oral cancer mortality in high-risk group of population. But this evidence may not be universally applicable. PMID- 26963671 TI - Current understanding of the tumor microenvironment of laryngeal dysplasia and progression to invasive cancer. AB - PURPOSE OF REVIEW: This review examines the historical tumor progression genetic model of laryngeal carcinomas, from dysplasia to invasive carcinoma and the role of infiltrating immune and inflammatory cells as contributors to this process. RECENT FINDINGS: Classically, the genetic model of carcinogenesis describes overexpression of oncogenes and/or silencing of tumor suppressor genes which, when combined with exposure to environmental carcinogens over the course of time, results in damage to cellular DNA. Increasing evidence indicates that innate and adaptive immune mediators also play an important role in tumor progression of laryngeal carcinomas. Cellular mediators of immune suppression are often over represented in the tumor microenvironment and these cells release cytokines, which perpetuate immune suppression allowing for tumor immune evasion. SUMMARY: Future therapies targeting laryngeal malignancies should focus on a combined approach which targets both genetic variations and immune mediators. PMID- 26963672 TI - Reasonable limits for transoral laser microsurgery in laryngeal cancer. AB - PURPOSE OF REVIEW: Transoral laser microsurgery (TLM) is widely acknowledged to offer several advantages in the treatment of early and selected intermediate advanced laryngeal cancers. Nevertheless, a number of issues are still under debate. The purpose of this review is to discuss the reasonable limits for TLM in laryngeal cancer to highlight its most appropriate and reproducible indications, putting this therapeutic tool in the right perspective within a comprehensive frame of alternative treatment strategies such as open partial laryngectomies and nonsurgical organ preservation protocols. RECENT FINDINGS: Inadequate laryngeal exposure, anterior commissure involvement in the cranio-caudal plane (T2), invasion of the posterior paraglottic space with arytenoid fixation, massive infiltration of the preepiglottic space, and even minor thyroid cartilage erosion (T3) represent the most controversial applications of TLM in management of glottic and supraglottic cancer. SUMMARY: Published oncological results appear to be satisfactory when TLM is applied to T1-T2 and accurately selected T3 glottic and supraglottic cancers with favourable exposure. Caution should be used for more advanced tumours. PMID- 26963673 TI - Contribution of animal models to contemporary understanding of Attention Deficit Hyperactivity Disorder. AB - Attention Deficit Hyperactivity Disorder (ADHD) is a poorly understood neurodevelopmental disorder of multifactorial origin. Animal-based research has been used to investigate ADHD aetiology, pathogenesis and treatment, but the efficacy of this research for patients has not yet been systematically evaluated. However, such evaluation is important, given the resource consumption and ethical concerns incurred by animal use. Accordingly, we used the citation tracking facility within Web of Science to locate original research performed on animal models related to ADHD, prior to 2010. Human medical papers citing those animal studies were carefully analyzed by two independent raters to evaluate the contribution of the animal to the human studies. 211 publications describing relevant animal studies were located. Approximately half (3,342) of their 6,406 citations were by other animal studies. 446 human medical papers cited 121 of these 211 animal studies, a total of 500 times. 254 of these 446 papers were human studies of ADHD. However, only eight animal papers (cited 10 times) were relevant to the hypothesis of the human medical study in question. Three of these eight papers described results from both human and animal studies, but their citations solely referred to the human data. Five animal research papers were relevant to the hypotheses of the applicable human medical papers. Citation analysis indicates that animal research has contributed very little to contemporary understanding of ADHD. To ensure optimal allocation of Research & Development funds targeting this disease the contribution of other research methods should be similarly evaluated. PMID- 26963674 TI - A 44 bp intestine-specific hermaphrodite-specific enhancer from the C. elegans vit-2 vitellogenin gene is directly regulated by ELT-2, MAB-3, FKH-9 and DAF-16 and indirectly regulated by the germline, by daf-2/insulin signaling and by the TGF-beta/Sma/Mab pathway. AB - The Caenorhabditis elegans vitellogenin genes are transcribed in the intestine of adult hermaphrodites but not of males. A 44-bp region from the vit-2 gene promoter is able largely to reconstitute this tissue-, stage- and sex-specific expression. This "enhancer" contains a binding site for the DM-domain factor MAB 3, the male-specific repressor of vitellogenesis, as well as an activator site that we show is the direct target of the intestinal GATA factor ELT-2. We further show that the enhancer is directly activated by the winged-helix/forkhead-factor FKH-9, (whose gene has been shown by others to be a direct target of DAF-16), by an unknown activator binding to the MAB-3 site, and by the full C. elegans TGF beta/Sma/Mab pathway acting within the intestine. The vit-2 gene has been shown by others to be repressed by the daf-2/daf-16 insulin signaling pathway, which so strongly influences aging and longevity in C. elegans. We show that the activity of the 44 bp vit-2 enhancer is abolished by loss of daf-2 but is restored by simultaneous loss of daf-16. DAF-2 acts from outside of the intestine but DAF-16 acts both from outside of the intestine and from within the intestine where it binds directly to the same non-canonical target site that interacts with FKH-9. Activity of the 44 bp vit-2 enhancer is also inhibited by loss of the germline, in a manner that is only weakly influenced by DAF-16 but that is strongly influenced by KRI-1, a key downstream effector in the pathway by which germline loss increases C. elegans lifespan. The complex behavior of this enhancer presumably allows vitellogenin gene transcription to adjust to demands of body size, germline proliferation and nutritional state but we suggest that the apparent involvement of this enhancer in aging and longevity "pathways" could be incidental. PMID- 26963676 TI - High-density ordered Ag@Al2O3 nanobowl arrays in applications of surface-enhanced Raman spectroscopy. AB - In this paper, we demonstrate a high-performance surface-enhanced Raman scattering (SERS) substrate based on high-density ordered Ag@Al2O3 nanobowl arrays. By ion beam etching (IBE) the anodized aluminum oxide (AAO) and subsequent Ag coating, ordered Ag@Al2O3 nanobowl arrays were created on the Si substrate. Unlike the 'hot spots' generated between adjacent metallic nanostructures, the Ag@Al2O3 nanobowl introduced 'hot spots' on the metal boundary of its hemispherical cavity. Based on the analysis of SERS signals, the optimized SERS substrate of Ag@Al2O3 nanobowl arrays had both high sensitivity and large-area uniformity. A detection limit as low as 10(-10) M was obtained using chemisorbed p-thiocresol (p-Tc) molecules, and the SERS signal was highly reproducible with a small standard deviation. The method opens up a new way to create highly sensitive SERS sensors with high-density 'hot spots', and it could play an important role in device design and corresponding biological and food safety monitoring applications. PMID- 26963685 TI - Anisotropic Electron-Photon and Electron-Phonon Interactions in Black Phosphorus. AB - Orthorhombic black phosphorus (BP) and other layered materials, such as gallium telluride (GaTe) and tin selenide (SnSe), stand out among two-dimensional (2D) materials owing to their anisotropic in-plane structure. This anisotropy adds a new dimension to the properties of 2D materials and stimulates the development of angle-resolved photonics and electronics. However, understanding the effect of anisotropy has remained unsatisfactory to date, as shown by a number of inconsistencies in the recent literature. We use angle-resolved absorption and Raman spectroscopies to investigate the role of anisotropy on the electron-photon and electron-phonon interactions in BP. We highlight, both experimentally and theoretically, a nontrivial dependence between anisotropy and flake thickness and photon and phonon energies. We show that once understood, the anisotropic optical absorption appears to be a reliable and simple way to identify the crystalline orientation of BP, which cannot be determined from Raman spectroscopy without the explicit consideration of excitation wavelength and flake thickness, as commonly used previously. PMID- 26963675 TI - Centroacinar cells: At the center of pancreas regeneration. AB - The process of regeneration serves to heal injury by replacing missing cells. Understanding regeneration can help us replace cell populations lost during disease, such as the insulin-producing beta cells lost in diabetic patients. Centroacinar cells (CACs) are a specialized ductal pancreatic cell type that act as progenitors to replace beta cells in the zebrafish. However, whether CACs contribute to beta-cell regeneration in adult mammals remains controversial. Here we review the current understanding of the role of CACs as endocrine progenitors during regeneration in zebrafish and mammals. PMID- 26963686 TI - Enhancement in Secondary Organic Aerosol Formation in the Presence of Preexisting Organic Particle. AB - Atmospheric models of secondary organic aerosol (SOA) typically assume organic species form a well-mixed phase. As a result, partitioning of semivolatile oxidation products into the particle phase to form SOA is thought to be enhanced by preexisting organic particles. In this work, the physicochemical properties that govern such enhancement in SOA yield were examined. SOA yields from alpha pinene ozonolysis were measured in the presence of a variety of organic seeds which were chosen based on polarity and phase state at room temperature. Yield enhancement was only observed with seeds of medium polarities (tetraethylene glycol and citric acid). Solid hexadecanol seed was observed to enhance SOA yields only in chamber experiments with longer mixing time scales, suggesting that the mixing process for SOA and hexadecanol may be kinetically limited at shorter time scales. Our observations indicate that, in addition to kinetic limitations, intermolecular interactions also play a significant role in determining SOA yields. Here we propose for the first time to use the Hansen solubility framework to determine aerosol miscibility and predict SOA yield enhancement. These results highlight that current models may overestimate SOA formation, and parametrization of intermolecular forces is needed for accurate predictions of SOA formation. PMID- 26963687 TI - Female Japanese quail with high levels of estradiol demonstrate cocaine-induced conditioned place preference. AB - Preclinical research has indicated that females may be more sensitive to the rewarding properties of cocaine. However, the majority of this research has been done in rodent species. Environmental cues associated with human drug-taking behavior tend to be visual. Because rodents do not rely on the visual system as their primary sense modality, the use of a visually oriented species may add to our understanding of cue-elicited drug cravings and relapse. The present study examined the potential role of the steroid hormone, estradiol, in the rewarding properties of cocaine in female Japanese quail using a conditioned place preference (CPP) procedure. In the current experiment, female quail were housed on either an 8L:16D (light:dark) or 16L:8D (light:dark) cycle for 21 days to induce photoregression or photostimulation, respectively. They then received 10, 20, or 30 mg/kg cocaine, or saline during conditioning. Conditioning trials were carried out for 8 days, once per day for 30 min, for a total of 4 cocaine and 4 saline alternating conditioning trials. Results indicated that female quail housed in long-light conditions (16L:8D) had significantly higher levels of estradiol than short-cycle females. Additionally, photostimulated female quail developed a CPP to 10 and 20 mg/kg cocaine. Short-cycle females did not show cocaine-induced CPP to any dose tested. Results indicate that cocaine is dose dependently rewarding to photostimulated female Japanese quail. Furthermore, the current findings suggest that estradiol may enhance the rewarding properties of cocaine in female quail. (PsycINFO Database Record PMID- 26963688 TI - Notes from the Field: Lymphocytic Choriomeningitis Virus Meningoencephalitis from a Household Rodent Infestation - Minnesota, 2015. AB - On April 20, 2015, a female aged 15 years sought care at her pediatrician's office after 5 days of fever, myalgia, left parietal headache, and photophobia. A rapid influenza assay was negative, and erythrocyte sedimentation rate and total white blood cell count were normal. She improved with symptomatic care at home, but returned to her pediatrician's office on April 28, reporting recurrence of her headache and photophobia and new onset of a stiff neck. She was admitted to the hospital, where she was febrile to 102.9 degrees F (39.4 degrees C) and had meningismus. Computed tomography scan of her head was normal, and a cerebrospinal fluid (CSF) analysis showed a markedly elevated white blood cell count with 68% lymphocytes, low glucose, and a negative Gram stain. She was treated empirically for both bacterial and herpes simplex virus meningitis. The patient's hospital course was notable for hypotension (blood pressure 81/50), irritability, and pancreatitis with a peak lipase of 8,627 U/L. CSF cultures yielded no growth, and CSF polymerase chain reaction (PCR) testing for herpes simplex virus was negative. Nucleic acid amplification testing, acid-fast bacilli stain, and acid fast bacilli cultures of CSF were negative for Mycobacterium tuberculosis. Results of investigations for human immunodeficiency virus, syphilis, Lyme disease, human herpesvirus 6 and 7, and species of Babesia, Toxoplasma, Histoplasma, Cryptococcus, Blastomyces, and Brucella were negative. She recovered and was discharged on hospital day 11 with no apparent sequelae. PMID- 26963690 TI - COSMO-RSC: Second-Order Quasi-Chemical Theory Recovering Local Surface Correlation Effects. AB - The conductor-like screening model for realistic solvation (COSMO-RS) was introduced 20 years ago and meanwhile has become an important tool for the prediction of fluid phase equilibrium properties. Starting from quantum chemical information about the surface polarity of solutes and solvents, it solves the statistical thermodynamics of molecules in liquid phases by the very efficient approximation of independently pairwise interacting surfaces, which meanwhile was shown to be equivalent to Guggenheim's quasi-chemical theory. One of the basic limitations of COSMO-RS, as of any quasi-chemical model, is the neglect of neighbor information, i.e., of local correlations of surface types on the molecular surface. In this paper we present the completely novel concept of using the first-order COSMO-RS contact probabilities for the construction of local surface correlation functions. These are fed as an entropic correction for the pair interactions into a second COSMO-RS self-consistency loop, which yields new contact probabilities, enthalpies, free energies and activity coefficients recovering much of the originally lost neighbor effects. By a novel analytic correction for concentration dependent interactions, the resulting activity coefficients remain exactly Gibbs-Duhem consistent. The theory is demonstrated on the example of a lattice Monte Carlo fluid of dimerizing pseudomolecules. In this showcase the strong deviations of the lattice Monte Carlo fluid from quasi chemical theory are almost perfectly reproduced by COSMO-RSC. PMID- 26963691 TI - Insights into the catalytic mechanism of N-acetylglucosaminidase glycoside hydrolase from Bacillus subtilis: a QM/MM study. AB - The peptidoglycan (PG) metabolic process is essential for bacterial growth. beta N-Acetylglucosaminidases (NagZ enzymes) are involved in the PG process and they catalyze the removal of terminal N-acetylglucosamine in PG fragments. According to the amino acid sequence and secondary structures, NagZ enzymes should belong to the glycoside hydrolase family GH3. However, a recent experimental study revealed that NagZ enzymes are glycoside phosphorylases rather than glycoside hydrolases. To further understand the catalytic process of NagZs at the atomistic level, the reaction mechanism of NagZ from Bacillus subtilis (BsNagZ) has been studied by using a QM/MM approach. Our calculation results show that the glycosylation of the substrate is the rate limiting step of the whole catalytic cycle with an energy barrier of 19.3 kcal mol(-1), which is close to the free energy barrier (16.4 kcal mol(-1)) estimated from the experimental rate constant. For deglycosylation, both the hydrolysis and phosphorylation of the glycosyl enzyme intermediate were explored. The phosphorylation corresponds to the lower energy barrier than hydrolysis (1.8 vs. 17.7 kcal mol(-1)), giving theoretical support to the previously suggested phosphorylase activity of NagZ enzymes. In both the glycosylation and deglycosylation steps, the oxocarbenium-ion-like transition states are always involved, and the substrate distortion in the active site can significantly facilitate the reaction, in which residue D123 plays a key role in this distortion. This is the first computational report for understanding the phosphorylase activity of NagZ enzymes. PMID- 26963692 TI - Successful removal of freckles with the bipolar radiofrequency and optical energy. AB - OBJECTIVES: Freckles are melanocytic lesions frequently seen on the face with red or blond hair. We aim to determine the effectiveness of combined bipolar radiofrequency (RF) and optical energy. METHODS: Thirty patients with facial freckles received four treatment at 3-week intervals with RF and optical energy, combination of broadband light (580-980 nm) + bipolar RF energy 100 J/cm(3). The improvement of the freckles was evaluated using the Freckles Area and Severity Index (FASI), and physician and patient assessment at the end of the sessions, at Months 3 and 12 after the treatment. RESULTS: By the end of the study, assessment of results by physician for 83% at Week 12 and by patients for 70% at Week 52 was excellent or good. On the other hand, 88% at Week 12 and 76% at Week 52 of the patients reported that they were extremely or very satisfied. FASI was noted to be 65.15 at pre-treatment, 25.60 at 12th week, and 27.40 at the end of the follow up (one year). Mean improvement rate (n = 30), as determined from the difference in mean FASI score, was 70% at 3 months and 66% at 12 months. CONCLUSION: Bipolar radiofrequency and optical energy can be accepted as an alternative treatment modality for the therapy of freckles with few adverse effects and high satisfaction levels. PMID- 26963689 TI - Predictors and Moderators of Remission With Aripiprazole Augmentation in Treatment-Resistant Late-Life Depression: An Analysis of the IRL-GRey Randomized Clinical Trial. AB - IMPORTANCE: Safe, efficacious, second-line pharmacological treatment options exist for the large portion of older adults with major depressive disorder who do not respond to first-line pharmacotherapy. However, limited evidence exists to aid clinical decision making regarding which patients will benefit from which second-line treatments. OBJECTIVE: To test the moderating role of pretreatment executive function, severity of anxiety, and severity of medical comorbidity in remission of treatment-resistant late-life depression after aripiprazole augmentation. DESIGN, SETTING, AND PARTICIPANTS: As follow-up to a 12-week randomized clinical trial of aripiprazole augmentation for first-line treatment resistant late-life depression (Incomplete Response in Late-Life Depression: Getting to Remission [IRL-GRey]), we evaluated the effects of the following potential moderators and their interactions with treatment: baseline assessments of executive function (set shifting measured by the Trail Making Test) and response inhibition control (measured by a Color-Word Interference task), anxiety symptoms, and medical comorbidity. Analyses were conducted in May and June 2015. INTERVENTIONS: Aripiprazole or placebo tablets were started at 2 mg daily and titrated as tolerated, to a maximal dose of 15 mg daily. MAIN OUTCOMES AND MEASURES: Remission of treatment-resistant late-life depression (defined as a Montgomery-Asberg Depression Rating Scale score of <=10 at both of the last 2 consecutive visits). RESULTS: Of 181 trial participants (103 female [56.9%]) who were 60 years of age or older and whose major depression had failed to remit with venlafaxine hydrochloride monotherapy, 91 received aripiprazole and 90 received placebo. Remission occurred in 40 (43%) who received aripiprazole and 26 (29%) who received placebo. Baseline set shifting moderated the efficacy of aripiprazole augmentation (odds ratio [OR], 1.66 [95% CI, 1.05-2.62]; P = .03 for interaction with treatment). Among participants with a Trail Making Test scaled score of 7 or higher, the odds of remission were significantly higher with aripiprazole than with placebo (53% vs 28%; number needed to treat, 4; OR, 4.11 [95% CI, 1.83-9.20]). Among participants with a Trail Making Test scaled score of less than 7, aripiprazole and placebo were equally efficacious (OR, 0.64 [95% CI, 0.15-2.80]). Greater severity of anxiety at baseline predicted a lower remission rate but did not moderate aripiprazole efficacy; each standard deviation greater anxiety severity was associated with 50% reduced odds of remission in both aripiprazole and placebo arms. Medical comorbidity and Color-Word Interference test performance were neither general predictors nor treatment-moderating factors. CONCLUSIONS AND RELEVANCE: Set-shifting performance indicates which older adults with treatment-resistant depression may respond favorably to augmentation with aripiprazole and thus may help to personalize treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00892047. PMID- 26963693 TI - A bio-inspired device for drag reduction on a three-dimensional model vehicle. AB - In this paper, we introduce a bio-mimetic device for the reduction of the drag force on a three-dimensional model vehicle, the Ahmed body (Ahmed et al 1984 SAE Technical Paper 840300). The device, called automatic moving deflector (AMD), is designed inspired by the movement of secondary feathers on bird's wing suction surface: i.e., secondary feathers pop up when massive separation occurs on bird's wing suction surface at high angles of attack, which increases the lift force at landing. The AMD is applied to the rear slanted surface of the Ahmed body to control the flow separation there. The angle of the slanted surface considered is 25 degrees at which the drag coefficient on the Ahmed body is highest. The wind tunnel experiment is conducted at Re H = 1.0 * 10(5)-3.8 * 10(5), based on the height of the Ahmed body (H) and the free-stream velocity (U infinity). Several AMDs of different sizes and materials are tested by measuring the drag force on the Ahmed body, and showed drag reductions up to 19%. The velocity and surface pressure measurements show that AMD starts to pop up when the pressure in the thin gap between the slanted surface and AMD is much larger than that on the upper surface of AMD. We also derive an empirical formula that predicts the critical free-stream velocity at which AMD starts to operate. Finally, it is shown that the drag reduction by AMD is mainly attributed to a pressure recovery on the slanted surface by delaying the flow separation and suppressing the strength of the longitudinal vortices emanating from the lateral edges of the slanted surface. PMID- 26963694 TI - Stimulating Effect of Elvitegravir on Suicidal Erythrocyte Death. AB - BACKGROUND/AIMS: The antiviral drug Elvitegravir is used for the treatment of Human Immunodeficiency Virus (HIV) infections. The present study explored whether the drug is able to trigger eryptosis, the suicidal death of erythrocytes. Eryptosis is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, ceramide, activated p38 kinase and activated caspases. The present study explored, whether Elvitegravir induces eryptosis and, if so, to shed light on the mechanisms involved. METHODS: Phosphatidylserine abundance at the erythrocyte surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, abundance of reactive oxygen species (ROS) from DCFDA dependent fluorescence, and ceramide abundance at the erythrocyte surface utilizing specific antibodies. RESULTS: A 48 hours exposure of human erythrocytes to Elvitegravir (>= 1.5 ug/ml) significantly increased the percentage of annexin V-binding cells, and significantly decreased forward scatter. Elvitegravir (2.5 ug/ml) significantly increased Fluo3-fluorescence, but did not significantly modify DCFDA fluorescence or ceramide abundance. The effect of Elvitegravir on annexin-V-binding was significantly blunted by removal of extracellular Ca2+, but not in the presence of p38 kinase inhibitor SB203580 (2 uM) or in the presence of pancaspase inhibitor zVAD (10 uM). CONCLUSIONS: Elvitegravir triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect in part due to entry of extracellular Ca2+. PMID- 26963696 TI - Enantioselective iridium-catalyzed hydrogenation of beta,beta-disubstituted nitroalkenes. AB - An iridium complex with a newly prepared chiral spiro amino-phosphine ligand efficiently catalyzed the hydrogenation of both beta-aryl-beta-methyl nitroalkenes and beta-alkyl-beta-methyl-nitroalkenes to the corresponding saturated nitroalkanes, which represents the first report of a chiral catalyst that exhibits high enantioselectivity for the challenging hydrogenation of beta,beta-dialkyl-nitroalkenes. PMID- 26963695 TI - Profiles of cognitive appraisals and triangulation into interparental conflict: Implications for adolescent adjustment. AB - Youth appraisals and triangulation into conflicts are key mechanisms by which interparental conflict places youth at risk for psychological maladjustment. Although evidence suggests that there are multiple mechanisms at work (e.g., Fosco & Feinberg, 2015; Grych, Harold, & Miles, 2003), this body of work has relied on variable-centered analyses that are limited to the unique contributions of each process to the variance in outcomes. In reality, it is possible that different combinations of these risk mechanisms may account for multifinality in risk outcomes. Using latent profile analysis (LPA) we examined profiles of threat appraisals, self-blaming attributions, and triangulation in relation to internalizing and externalizing problems in a sample of 285, ethnically diverse high school students. The current analyses revealed 5 distinct profiles of appraisals and triangulation, including an overall low-risk group and a global high-risk group, in which all 3 processes were below average or above average, respectively. Additional profiles included combinations of threat and blame, threat and triangulation, and blame and triangulation. Links between these profiles and emotional distress, problem behavior, and academic outcomes are discussed. (PsycINFO Database Record PMID- 26963697 TI - Quantitative and qualitative study of STR DNA from ethanol and formalin fixed tissues. AB - Complete and concordant autosomal short tandem repeat (STR) DNA profiles were obtained from 2.0mg human tissue samples of various types after they were preserved for 24 weeks in 100% ethanol and amplified with the GlobalFiler((r)) and the PowerPlex((r)) Fusion Amplification Kits. When 4.0mg of the same tissues were preserved for 12 weeks in 10% Neutral Buffered Formalin (NBF) they yielded partial profiles when amplified with the same kits. However, these NBF preserved tissues yielded complete autosomal profiles when amplified with the AmpFlSTR((r)) MiniFilerTM Amplification Kit. Six tissue specimens from the male donor were also amplified with the PowerPlex((r)) Y-23 System. Y-STR profiles were successfully generated from 2.0mg tissue specimens when preserved for 12 weeks in 100% Ethanol. Only partial profiles were obtained when the fixation time was increased to 24 weeks. Only partial Y-STR profiles were also obtained from 4.0mg tissue specimen from the same donor when preserved in 10% NBF. In an attempt to optimize the method, the preserved samples that yielded partial profiles were homogenized using the BioMasher III disposable homogenizer and BioMasher III homogenizer and filter. These homogenized tissues did not yield significantly better or more complete profiles when using the GlobalFiler((r)), AmpFlSTR((r)) MiniFilerTM Amplification Kits, the PowerPlex((r)) Fusion System or the PowerPlex((r)) Y23 System. A total number of 240 tissue samples were analyzed in this project. The amplification of the tissues preserved in 10% NBF with kits such as AmpFlSTR((r)) MiniFilerTM and GlobalFiler((r)) Amplification Kits that contain mini STR primers can be beneficial in forensic testing. The results of the study indicate that in cases such as when a victim or a suspect is missing, the profiles obtained from minute amounts of chemically fixed tissues can be used as reference samples and compared to evidence found at the crime scene. PMID- 26963698 TI - Cardiac complications in thalassemia major. AB - The myocardium is particularly susceptible to complications from iron loading in thalassemia major. In the first years of life, severe anemia leads to high-output cardiac failure and death if not treated. The necessary supportive blood transfusions create loading of iron that cannot be naturally excreted, and this iron accumulates within tissues, including the heart. Free unbound iron catalyzes the formation of toxic hydroxyl radicals, which damage cells and cause cardiac dysfunction. Significant cardiac siderosis may present by the age of 10 and may lead to acute clinical heart failure, which must be treated urgently. Atrial fibrillation is the most frequently encountered iron-related arrhythmia. Iron chelation is effective at removing iron from the myocardium, at the expense of side effects that hamper compliance to therapy. Monitoring of myocardial iron content is mandatory for clinical management of cardiac risk. T2* cardiac magnetic resonance measures myocardial iron and is the strongest biomarker for prediction of heart failure and arrhythmic events. It has been calibrated to human myocardial tissue iron concentration and is highly reproducible across all magnetic resonance scanner vendors. As survival and patient age increases, endothelial dysfunction and diabetes may become new factors in the cardiovascular health of thalassemia patients. Promising new imaging technology and therapies could ameliorate the long-term prognosis. PMID- 26963699 TI - Son et lumiere: Sound and light effects on spatial distribution and swimming behavior in captive zebrafish. AB - Aquatic and terrestrial habitats are heterogeneous by nature with respect to sound and light conditions. Fish may extract signals and exploit cues from both ambient modalities and they may also select their sound and light level of preference in free-ranging conditions. In recent decades, human activities in or near water have altered natural soundscapes and caused nocturnal light pollution to become more widespread. Artificial sound and light may cause anxiety, deterrence, disturbance or masking, but few studies have addressed in any detail how fishes respond to spatial variation in these two modalities. Here we investigated whether sound and light affected spatial distribution and swimming behavior of individual zebrafish that had a choice between two fish tanks: a treatment tank and a quiet and light escape tank. The treatments concerned a 2 * 2 design with noisy or quiet conditions and dim or bright light. Sound and light treatments did not induce spatial preferences for the treatment or escape tank, but caused various behavioral changes in both spatial distribution and swimming behavior within the treatment tank. Sound exposure led to more freezing and less time spent near the active speaker. Dim light conditions led to a lower number of crossings, more time spent in the upper layer and less time spent close to the tube for crossing. No interactions were found between sound and light conditions. This study highlights the potential relevance for studying multiple modalities when investigating fish behavior and further studies are needed to investigate whether similar patterns can be found for fish behavior in free-ranging conditions. PMID- 26963701 TI - Nicolau syndrome due to hyaluronic acid injections. AB - Six cases of vascular compromise after hyaluronic injection are reported. Clinical symptoms realized a Nicolau syndrome, which is characterized by immediate pain, livedoid pattern and a few days later by the appearance of scabs and skin necrosis. This type of complication is rare, but may be dramatic and injectors must be aware of that. A thorough knowledge of facial anatomy is mandatory to avoid the risky facial areas. The use of a flexible cannula instead of a sharp needle has much less risk of hurting vessels and must be preferred. The support of the patient is discussed and a treatment protocol is proposed. PMID- 26963700 TI - Fresh insight to functioning of selected enzymes of the nitrogen cycle. AB - The global nitrogen cycle is the process in which different forms of environmental N are interconverted by microorganisms either for assimilation into biomass or in respiratory energy-generating pathways. This short review highlights developments over the last 5 years in our understanding of functionality of nitrogenase, Cu-nitrite reductase, NO reductase and N2O reductase, complex metalloenzymes that catalyze electron/proton-coupled substrate reduction reactions. PMID- 26963702 TI - Plant Quantity Affects Development and Survival of a Gregarious Insect Herbivore and Its Endoparasitoid Wasp. AB - Virtually all studies of plant-herbivore-natural enemy interactions focus on plant quality as the major constraint on development and survival. However, for many gregarious feeding insect herbivores that feed on small or ephemeral plants, the quantity of resources is much more limiting, yet this area has received virtually no attention. Here, in both lab and semi-field experiments using tents containing variably sized clusters of food plants, we studied the effects of periodic food deprivation in a tri-trophic system where quantitative constraints are profoundly important on insect performance. The large cabbage white Pieris brassicae, is a specialist herbivore of relatively small wild brassicaceous plants that grow in variable densities, with black mustard (Brassica nigra) being one of the most important. Larvae of P. brassicae are in turn attacked by a specialist endoparasitoid wasp, Cotesia glomerata. Increasing the length of food deprivation of newly molted final instar caterpillars significantly decreased herbivore and parasitoid survival and biomass, but shortened their development time. Moreover, the ability of caterpillars to recover when provided with food again was correlated with the length of the food deprivation period. In outdoor tents with natural vegetation, we created conditions similar to those faced by P. brassicae in nature by manipulating plant density. Low densities of B. nigra lead to potential starvation of P. brassicae broods and their parasitoids, replicating nutritional conditions of the lab experiments. The ability of both unparasitized and parasitized caterpillars to find corner plants was similar but decreased with central plant density. Survival of both the herbivore and parasitoid increased with plant density and was higher for unparasitized than for parasitized caterpillars. Our results, in comparison with previous studies, reveal that quantitative constraints are far more important that qualitative constraints on the performance of gregarious insect herbivores and their gregarious parasitoids in nature. PMID- 26963704 TI - The WEPP Model Application in a Small Watershed in the Loess Plateau. AB - In the Loess Plateau, soil erosion has not only caused serious ecological and environmental problems but has also impacted downstream areas. Therefore, a model is needed to guide the comprehensive control of soil erosion. In this study, we introduced the WEPP model to simulate soil erosion both at the slope and watershed scales. Our analyses showed that: the simulated values at the slope scale were very close to the measured. However, both the runoff and soil erosion simulated values at the watershed scale were higher than the measured. At the slope scale, under different coverage, the simulated erosion was slightly higher than the measured. When the coverage is 40%, the simulated results of both runoff and erosion are the best. At the watershed scale, the actual annual runoff of the Liudaogou watershed is 83 m(3); sediment content is 0.097 t/m(3), annual erosion sediment 8.057 t and erosion intensity 0.288 t ha(-1) yr(-1). Both the simulated values of soil erosion and runoff are higher than the measured, especially the runoff. But the simulated erosion trend is relatively accurate after the farmland is returned to grassland. We concluded that the WEPP model can be used to establish a reasonable vegetation restoration model and guide the vegetation restoration of the Loess Plateau. PMID- 26963703 TI - All in the first glance: first fixation predicts individual differences in valence bias. AB - Surprised expressions are interpreted as negative by some people, and as positive by others. When compared to fearful expressions, which are consistently rated as negative, surprise and fear share similar morphological structures (e.g. widened eyes), but these similarities are primarily in the upper part of the face (eyes). We hypothesised, then, that individuals would be more likely to interpret surprise positively when fixating faster to the lower part of the face (mouth). Participants rated surprised and fearful faces as either positive or negative while eye movements were recorded. Positive ratings of surprise were associated with longer fixation on the mouth than negative ratings. There were also individual differences in fixation patterns, with individuals who fixated the mouth earlier exhibiting increased positive ratings. These findings suggest that there are meaningful individual differences in how people process faces. PMID- 26963705 TI - Visuomotor Dissociation in Cerebral Scaling of Size. AB - Estimating size and distance is crucial in effective visuomotor control. The concept of an internal coordinate system implies that visual and motor size parameters are scaled onto a common template. To dissociate perceptual and motor components in such scaling, we performed an fMRI experiment in which 16 right handed subjects copied geometric figures while the result of drawing remained out of sight. Either the size of the example figure varied while maintaining a constant size of drawing (visual incongruity) or the size of the examples remained constant while subjects were instructed to make changes in size (motor incongruity). These incongruent were compared to congruent conditions. Statistical Parametric Mapping (SPM8) revealed brain activations related to size incongruity in the dorsolateral prefrontal and inferior parietal cortex, pre-SMA / anterior cingulate and anterior insula, dominant in the right hemisphere. This pattern represented simultaneous use of a 'resized' virtual template and actual picture information requiring spatial working memory, early-stage attention shifting and inhibitory control. Activations were strongest in motor incongruity while right pre-dorsal premotor activation specifically occurred in this condition. Visual incongruity additionally relied on a ventral visual pathway. Left ventral premotor activation occurred in all variably sized drawing while constant visuomotor size, compared to congruent size variation, uniquely activated the lateral occipital cortex additional to superior parietal regions. These results highlight size as a fundamental parameter in both general hand movement and movement guided by objects perceived in the context of surrounding 3D space. PMID- 26963707 TI - Letter to the Editor. PMID- 26963706 TI - Ultrasound melted polymer sleeve for improved screw anchorage in trabecular bone- A novel screw augmentation technique. AB - BACKGROUND: Screw anchorage in osteoporotic bone is still limited and makes treatment of osteoporotic fractures challenging for surgeons. Conventional screws fail in poor bone quality due to loosening at the screw-bone interface. A new technology should help to improve this interface. In a novel constant amelioration process technique, a polymer sleeve is melted by ultrasound in the predrilled screw hole prior to screw insertion. The purpose of this study was to investigate in vitro the effect of the constant amelioration process platform technology on primary screw anchorage. METHODS: Fresh frozen femoral heads (n=6) and vertebrae (n=6) were used to measure the maximum screw insertion torque of reference and constant amelioration process augmented screws. Specimens were cut in cranio-caudal direction, and the screws (reference and constant amelioration process) were implanted in predrilled holes in the trabecular structure on both sides of the cross section. This allowed the pairwise comparison of insertion torque for constant amelioration process and reference screws (femoral heads n=18, vertebrae n=12). Prior to screw insertion, a micro-CT scan was made to ensure comparable bone quality at the screw placement location. FINDINGS: The mean insertion torque for the constant amelioration process augmented screws in both, the femoral heads (44.2 Ncm, SD 14.7) and the vertebral bodies (13.5 Ncm, SD 6.3) was significantly higher than for the reference screws of the femoral heads (31.7 Ncm, SD 9.6, p<0.001) and the vertebral bodies (7.1 Ncm, SD 4.5, p<0.001). INTERPRETATION: The interconnection of the melted polymer sleeve with the surrounding trabecular bone in the constant amelioration process technique resulted in a higher screw insertion torque and can improve screw anchorage in osteoporotic trabecular bone. PMID- 26963708 TI - Restoring lumbar spine stiffness using an interspinous implant in an ovine model of instability. AB - BACKGROUND: The objective of this study was to determine the effect of an interspinous implant on lumbar spine stability and stiffness during dorsoventral loading. METHODS: Twelve Merino lambs were mechanically tested in vivo. Oscillatory (2 Hz) loads were applied to L2 under load control while displacements were monitored. Tri-axial accelerometers further quantified adjacent L3-L4 accelerations. Dorsoventral lumbar spine stiffness and L3 and L4 dorsoventral and axial displacements were determined over six trials of 20 cycles of loading. Four conditions were examined: 1) initial intact, 2) following destabilization at L3-L4, 3) following the insertion of an InSwing((r)) interspinous device at L3-L4, and 4) with the implant secured with a tension band. Comparisons were performed using a one-way ANOVA with repeated measures and post-hoc Bonferroni correction. FINDINGS: Compared to the intact condition, destabilization significantly decreased lumbar stiffness by 4.5% (P=.001) which was only recovered by the interspinous device with tension band. The interspinous device caused a significant 9.75% (P=.001) increase in dorsoventral stiffness from destabilization that increased 14% with the tension band added (P=.001). The tension band was responsible for decreased displacements from the intact (P=.038), instability (P=.001), and interspinous device (P=.005) conditions. Dorsoventral L3-L4 motion significantly improved with the interspinous device (P=.01) and the addition of the tension band (P=.001). No significant differences in L3-L4 intersegmental stability were noted for axial motion in the sagittal plane. INTERPRETATION: This ovine model provided objective in vivo biomechanical evidence of lumbar instability and its restoration by means of an interspinous implant during dorsoventral spinal loading. PMID- 26963709 TI - Effects of aging and Parkinson's disease on joint coupling, symmetry, complexity and variability of lower limb movements during gait. AB - BACKGROUND: Natural aging and disease processes such as Parkinson's disease often lead to gait impairment. This impairment often manifests as changes in symmetry, complexity, and variability of lower limb joint movements during gait as compared to young healthy adults. Current gait assessment tools primarily focus on discrete events during gait or are based on univariate statistical techniques. Therefore, they fall short in examining spatiotemporally complex gait characteristics including interactions across multiple segments and joints. METHODS: Treadmill walking data from ten healthy older adults and ten individuals with idiopathic Parkinson's disease were collected at their self-selected speed. Additionally treadmill walking data from previously collected gait studies on 20 young adults were also used. This study utilized new gait assessment techniques that quantitatively examined joint coupling characteristics (via Condition Signature Analysis), variability and complexity of joint variables (via Phase Portrait Analysis), and movement asymmetry (via Regions of Deviation analysis) of the three different groups. FINDINGS: People with Parkinson's disease had the highest asymmetry among the three groups. Aging and Parkinson's disease significantly decreased complexity of hip and ankle joint movements, respectively, while there were no significant differences in variability measures among the three groups. The Condition Signature Analysis method suggested significant differences of joint coupling patterns due to aging and Parkinson's disease. INTERPRETATION: These new gait assessment techniques successfully captured changes in asymmetry, variability, complexity, and joint coupling patterns. Quantitative gait assessment using these tools can be used to detect various types of gait impairments. PMID- 26963710 TI - Parameterization for In-Silico Modeling of Ion Channel Interactions with Drugs. AB - Since the first Hodgkin and Huxley ion channel model was described in the 1950s, there has been an explosion in mathematical models to describe ion channel function. As experimental data has become richer, models have concomitantly been improved to better represent ion channel kinetic processes, although these improvements have generally resulted in more model complexity and an increase in the number of parameters necessary to populate the models. Models have also been developed to explicitly model drug interactions with ion channels. Recent models of drug-channel interactions account for the discrete kinetics of drug interaction with distinct ion channel state conformations, as it has become clear that such interactions underlie complex emergent kinetics such as use-dependent block. Here, we describe an approach for developing a model for ion channel drug interactions. The method describes the process of extracting rate constants from experimental electrophysiological function data to use as initial conditions for the model parameters. We then describe implementation of a parameter optimization method to refine the model rate constants describing ion channel drug kinetics. The algorithm takes advantage of readily available parallel computing tools to speed up the optimization. Finally, we describe some potential applications of the platform including the potential for gaining fundamental mechanistic insights into ion channel function and applications to in silico drug screening and development. PMID- 26963711 TI - Information Thermodynamics of Cytosine DNA Methylation. AB - Cytosine DNA methylation (CDM) is a stable epigenetic modification to the genome and a widespread regulatory process in living organisms that involves multicomponent molecular machines. Genome-wide cytosine methylation patterning participates in the epigenetic reprogramming of a cell, suggesting that the biological information contained within methylation positions may be amenable to decoding. Adaptation to a new cellular or organismal environment also implies the potential for genome-wide redistribution of CDM changes that will ensure the stability of DNA molecules. This raises the question of whether or not we would be able to sort out the regulatory methylation signals from the CDM background ("noise") induced by thermal fluctuations. Here, we propose a novel statistical and information thermodynamic description of the CDM changes to address the last question. The physical basis of our statistical mechanical model was evaluated in two respects: 1) the adherence to Landauer's principle, according to which molecular machines must dissipate a minimum energy epsilon = kBT ln2 at each logic operation, where kB is the Boltzmann constant, and T is the absolute temperature and 2) whether or not the binary stretch of methylation marks on the DNA molecule comprise a language of sorts, properly constrained by thermodynamic principles. The study was performed for genome-wide methylation data from 152 ecotypes and 40 trans-generational variations of Arabidopsis thaliana and 93 human tissues. The DNA persistence length, a basic mechanical property altered by CDM, was estimated with values from 39 to 66.9 nm. Classical methylome analysis can be retrieved by applying information thermodynamic modelling, which is able to discriminate signal from noise. Our finding suggests that the CDM signal comprises a language scheme properly constrained by molecular thermodynamic principles, which is part of an epigenomic communication system that obeys the same thermodynamic rules as do current human communication systems. PMID- 26963712 TI - The Evolution and Development of Cephalopod Chambers and Their Shape. AB - The Ammonoidea is a group of extinct cephalopods ideal to study evolution through deep time. The evolution of the planispiral shell and complexly folded septa in ammonoids has been thought to have increased the functional surface area of the chambers permitting enhanced metabolic functions such as: chamber emptying, rate of mineralization and increased growth rates throughout ontogeny. Using nano computed tomography and synchrotron radiation based micro-computed tomography, we present the first study of ontogenetic changes in surface area to volume ratios in the phragmocone chambers of several phylogenetically distant ammonoids and extant cephalopods. Contrary to the initial hypothesis, ammonoids do not possess a persistently high relative chamber surface area. Instead, the functional surface area of the chambers is higher in earliest ontogeny when compared to Spirula spirula. The higher the functional surface area the quicker the potential emptying rate of the chamber; quicker chamber emptying rates would theoretically permit faster growth. This is supported by the persistently higher siphuncular surface area to chamber volume ratio we collected for the ammonite Amauroceras sp. compared to either S. spirula or nautilids. We demonstrate that the curvature of the surface of the chamber increases with greater septal complexity increasing the potential refilling rates. We further show a unique relationship between ammonoid chamber shape and size that does not exist in S. spirula or nautilids. This view of chamber function also has implications for the evolution of the internal shell of coleoids, relating this event to the decoupling of soft-body growth and shell growth. PMID- 26963714 TI - Spontaneous K-Complex Density in Slow-Wave Sleep. AB - PURPOSE: To study spontaneous K-complex (KC) densities during slow-wave sleep. The secondary objective was to estimate intra-non-rapid eye movement (NREM) sleep differences in KC density. MATERIALS AND METHODS: It is a retrospective study using EEG data included in polysomnographic records from the archive at the sleep research laboratory of the Centre for Physiotherapy and Rehabilitation Sciences, Jamia Millia Islamia, India. The EEG records of 4459 minutes were used. The study presents a manual identification investigation of KCs in 17 healthy young adult male volunteers (age = 23.82+/-3.40 years and BMI = 23.42+/-4.18 kg/m2). RESULTS: N3 had a higher KC density than N2 (Z = -2.485, p = 0.013) for all of the probes taken together. Four EEG probes had a higher probe-specific KC density during N3. The inter-probe KC density differed significantly during N2 (chi2 = 67.91, p < .001), N3 (chi2 = 70.62, p < .001) and NREM (chi2 = 68.50, p < .001). The percent distribution of KC decreased uniformly with sleep cycles. CONCLUSION: The inter probe differences during N3 establish the fronto-central dominance of the KC density regardless of sleep stage. This finding supports one local theory of KC generation. The significantly higher KC density during N3 may imply that the neuro-anatomical origin of slow-wave activity and KC is the same. This temporal alignment with slow-wave activity supports the sleep-promoting function of the KC. PMID- 26963713 TI - Bacterial species involved in the conversion of dietary flavonoids in the human gut. AB - The gut microbiota plays a crucial role in the conversion of dietary flavonoids and thereby affects their health-promoting effects in the human host. The identification of the bacteria involved in intestinal flavonoid conversion has gained increasing interest. This review summarizes available information on the so far identified human intestinal flavonoid-converting bacterial species and strains as well as their enzymes catalyzing the underlying reactions. The majority of described species involved in flavonoid transformation are capable of carrying out the O-deglycosylation of flavonoids. Other bacteria cleave the less common flavonoid-C-glucosides and/or further degrade the aglycones of flavonols, flavanonols, flavones, flavanones, dihydrochalcones, isoflavones and monomeric flavan-3-ols. To increase the currently limited knowledge in this field, identification of flavonoid-converting bacteria should be continued using culture dependent screening or isolation procedures and molecular approaches based on sequence information of the involved enzymes. PMID- 26963715 TI - Feature Selection via Chaotic Antlion Optimization. AB - BACKGROUND: Selecting a subset of relevant properties from a large set of features that describe a dataset is a challenging machine learning task. In biology, for instance, the advances in the available technologies enable the generation of a very large number of biomarkers that describe the data. Choosing the more informative markers along with performing a high-accuracy classification over the data can be a daunting task, particularly if the data are high dimensional. An often adopted approach is to formulate the feature selection problem as a biobjective optimization problem, with the aim of maximizing the performance of the data analysis model (the quality of the data training fitting) while minimizing the number of features used. RESULTS: We propose an optimization approach for the feature selection problem that considers a "chaotic" version of the antlion optimizer method, a nature-inspired algorithm that mimics the hunting mechanism of antlions in nature. The balance between exploration of the search space and exploitation of the best solutions is a challenge in multi-objective optimization. The exploration/exploitation rate is controlled by the parameter I that limits the random walk range of the ants/prey. This variable is increased iteratively in a quasi-linear manner to decrease the exploration rate as the optimization progresses. The quasi-linear decrease in the variable I may lead to immature convergence in some cases and trapping in local minima in other cases. The chaotic system proposed here attempts to improve the tradeoff between exploration and exploitation. The methodology is evaluated using different chaotic maps on a number of feature selection datasets. To ensure generality, we used ten biological datasets, but we also used other types of data from various sources. The results are compared with the particle swarm optimizer and with genetic algorithm variants for feature selection using a set of quality metrics. PMID- 26963716 TI - Atomic Layer Deposition of p-Type Epitaxial Thin Films of Undoped and N-Doped Anatase TiO2. AB - Employing atomic layer deposition, we have grown p-type epitaxial undoped and N doped anatase TiO2(001) thin films on c-axis Al2O3 substrate. From X-ray diffraction and transmission electron microscopy studies, crystallographic relationships between the film and the substrate are found to be (001)TiO2//(0001)Al2O3 and [110]TiO2//[0110]Al2O3. N-doping in TiO2 thin films enhances the hole concentration and mobility. The optical band gap of anatase TiO2 (3.23 eV) decreases to 3.07 eV upon N-doping. The epitaxial films exhibit room-temperature ferromagnetism and photoresponse. A TiO2-based homojunction diode was fabricated with rectification from the p-n junction formed between N doped p-TiO2 and n-TiO2. PMID- 26963717 TI - Age Effects and Temporal Trends in HPV-Related and HPV-Unrelated Oral Cancer in the United States: A Multistage Carcinogenesis Modeling Analysis. AB - Differences in prognosis in HPV-positive and HPV-negative oral (oropharyngeal and oral cavity) squamous cell carcinomas (OSCCs) and increasing incidence of HPV related cancers have spurred interest in demographic and temporal trends in OSCC incidence. We leverage multistage clonal expansion (MSCE) models coupled with age period-cohort (APC) epidemiological models to analyze OSCC data in the SEER cancer registry (1973-2012). MSCE models are based on the initiation-promotion malignant conversion paradigm in carcinogenesis and allow for interpretation of trends in terms of biological mechanisms. APC models seek to differentiate between the temporal effects of age, period, and birth cohort on cancer risk. Previous studies have looked at the effect of period and cohort on tumor initiation, and we extend this to compare model fits of period and cohort effects on each of tumor initiation, promotion, and malignant conversion rates. HPV related, HPV-unrelated except oral tongue, and HPV-unrelated oral tongue sites are best described by placing period and cohort effects on the initiation rate. HPV-related and non-oral-tongue HPV-unrelated cancers have similar promotion rates, suggesting similar tumorigenesis dynamics once initiated. Estimates of promotion rates at oral tongue sites are lower, corresponding to a longer sojourn time; this finding is consistent with the hypothesis of an etiology distinct from HPV or alcohol and tobacco use. Finally, for the three subsite groups, men have higher initiation rates than women of the same race, and black people have higher promotion than white people of the same sex. These differences explain part of the racial and sex differences in OSCC incidence. PMID- 26963718 TI - Confocal Analysis of Nuclear Lamina Behavior during Male Meiosis and Spermatogenesis in Drosophila melanogaster. AB - Lamin family proteins are structural components of a filamentous framework, the nuclear lamina (NL), underlying the inner membrane of nuclear envelope. The NL not only plays a role in nucleus mechanical support and nuclear shaping, but is also involved in many cellular processes including DNA replication, gene expression and chromatin positioning. Spermatogenesis is a very complex differentiation process in which each stage is characterized by nuclear architecture dramatic changes, from the early mitotic stage to the sperm differentiation final stage. Nevertheless, very few data are present in the literature on the NL behavior during this process. Here we show the first and complete description of NL behavior during meiosis and spermatogenesis in Drosophila melanogaster. By confocal imaging, we characterized the NL modifications from mitotic stages, through meiotic divisions to sperm differentiation with an anti-laminDm0 antibody against the major component of the Drosophila NL. We observed that continuous changes in the NL structure occurred in parallel with chromatin reorganization throughout the whole process and that meiotic divisions occurred in a closed context. Finally, we analyzed NL in solofuso meiotic mutant, where chromatin segregation is severely affected, and found the strict correlation between the presence of chromatin and that of NL. PMID- 26963720 TI - The mycotoxin definition reconsidered towards fungal cyclic depsipeptides. AB - Currently, next to the major classes, cyclic depsipeptides beauvericin and enniatins are also positioned as mycotoxins. However, as there are hundreds more fungal cyclic depsipeptides already identified, should these not be considered as mycotoxins as well? The current status of the mycotoxin definition revealed a lack of consistency, leading to confusion about what compounds should be called mycotoxins. Because this is of pivotal importance in risk assessment prioritization, a clear and quantitatively expressed mycotoxin definition is proposed, based on data of widely accepted mycotoxins. Finally, this definition is applied to a set of fungal cyclic depsipeptides, revealing that some of these should indeed be considered as mycotoxins. PMID- 26963719 TI - Association between Blood Dioxin Level and Chronic Kidney Disease in an Endemic Area of Exposure. AB - BACKGROUND: Dioxin is an industrial pollutant related to various diseases, but epidemiological data on its effects on the kidney are limited. Therefore, we conducted a study to evaluate the association between dioxin exposure and chronic kidney disease (CKD) and identify the related factors. METHODS: We conducted a community-based cross-sectional study and recruited participants from an area where the residents were exposed to dioxin released from a factory. We defined a "high dioxin level" as polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) >= 20 pg WHO98-TEQDF/g lipid in the serum and defined CKD as having an estimated glomerular filtration rate (e-GFR) <= 60 mL/min/1.73m2 or a diagnosis of CKD by a physician. The renal function was assessed between 2005 and 2010, and we excluded those who had had kidney diseases before the study started. Comparisons between patients of CKD and those who did not have CKD were made to identify the risk factors for CKD. RESULTS: Of the 2898 participants, 1427 had high dioxin levels, and 156 had CKD. In the univariate analyses, CKD was associated with high dioxin levels, age, gender, metabolic syndrome, diabetes mellitus, hypertension, and high insulin and uric acid levels. After adjusting for other factors, we found high dioxin levels (adjusted odds ratio [AOR] = 1.76, 95% confidence interval [CI]: 1.04-2.99), female gender (AOR = 1.74, 95%CI: 1.20 2.53), hypertension (AOR = 1.68, 95%CI: 1.17-2.42), high insulin levels (AOR = 2.14, 95% CI: 1.26-3.61), high uric acid levels (AOR = 4.25, 95% CI: 2.92-6.20), and older age (AOR = 4.66, 95% CI: 1.87-11.62 for 40-64 year and AOR = 26.66, 95% CI: 10.51-67.62 for age >= 65 year) were independent predictors of CKD. CONCLUSION: A high dioxin level was associated with an increased prevalence of CKD. Therefore, the kidney function of populations with exposure to dioxin should be monitored. PMID- 26963721 TI - Anti-Inflammatory Action of Angiotensin 1-7 in Experimental Colitis. AB - BACKGROUND: There is evidence to support a role for angiotensin (Ang) 1-7 in reducing the activity of inflammatory signaling molecules such as MAPK, PKC and SRC. Enhanced angiotensin converting enzyme 2 (ACE2) expression has been observed in patients with inflammatory bowel disease (IBD) suggesting a role in its pathogenesis, prompting this study. METHODS: The colonic expression/activity profile of ACE2, Ang 1-7, MAS1-receptor (MAS1-R), MAPK family and Akt were determined by western blot and immunofluorescence. The effect of either exogenous administration of Ang 1-7 or pharmacological inhibition of its function (by A779 treatment) was determined using the mouse dextran sulfate sodium model. RESULTS: Enhanced colonic expression of ACE2, Ang1-7 and MAS1-R was observed post-colitis induction. Daily Ang 1-7 treatment (0.01-0.06 mg/kg) resulted in significant amelioration of DSS-induced colitis. In contrast, daily administration of A779 significantly worsened features of colitis. Colitis-associated phosphorylation of p38, ERK1/2 and Akt was reduced by Ang 1-7 treatment. CONCLUSION: Our results indicate important anti-inflammatory actions of Ang 1-7 in the pathogenesis of IBD, which may provide a future therapeutic strategy to control the disease progression. PMID- 26963722 TI - Molecular Evolution and Functional Divergence of Trace Amine-Associated Receptors. AB - Trace amine-associated receptors (TAARs) are a member of the G-protein-coupled receptor superfamily and are known to be expressed in olfactory sensory neurons. A limited number of molecular evolutionary studies have been done for TAARs so far. To elucidate how lineage-specific evolution contributed to their functional divergence, we examined 30 metazoan genomes. In total, 493 TAAR gene candidates (including 84 pseudogenes) were identified from 26 vertebrate genomes. TAARs were not identified from non-vertebrate genomes. An ancestral-type TAAR-like gene appeared to have emerged in lamprey. We found four therian-specific TAAR subfamilies (one eutherian-specific and three metatherian-specific) in addition to previously known nine subfamilies. Many species-specific TAAR gene duplications and losses contributed to a large variation of TAAR gene numbers among mammals, ranging from 0 in dolphin to 26 in flying fox. TAARs are classified into two groups based on binding preferences for primary or tertiary amines as well as their sequence similarities. Primary amine-detecting TAARs (TAAR1-4) have emerged earlier, generally have single-copy orthologs (very few duplication or loss), and have evolved under strong functional constraints. In contrast, tertiary amine-detecting TAARs (TAAR5-9) have emerged more recently and the majority of them experienced higher rates of gene duplications. Protein members that belong to the tertiary amine-detecting TAAR group also showed the patterns of positive selection especially in the area surrounding the ligand binding pocket, which could have affected ligand-binding activities and specificities. Expansions of the tertiary amine-detecting TAAR gene family may have played important roles in terrestrial adaptations of therian mammals. Molecular evolution of the TAAR gene family appears to be governed by a complex, species-specific, interplay between environmental and evolutionary factors. PMID- 26963724 TI - Comparison of Intraoperative Indicators and Postoperative Efficacy in Treatment of Benign Ovarian Tumor: Laparoscopy Versus Open Surgery. AB - This study aimed to compare intraoperative indicators and postoperative efficacy between laparoscopy and open surgery managing benign ovarian tumors. A total of 180 patients with benign ovarian tumor were enrolled; 105 underwent laparoscopy (LA group) and 75 underwent open surgery (OS group). Postoperative parameters were recorded. Preoperative and postoperative serum follicle-stimulating hormone, luteinizing hormone, and estradiol (E2) levels were determined using a BHP9507 chemiluminescence analyzer. The preoperative and postoperative serum C-reactive protein (CRP) level was examined using a QuikRead go CRP analyzer. Serum white blood cell and neutrophil (Ne) percentage were determined using an XT-2000i hematology analyzer. Compared with the OS group, intraoperative blood loss was less and the postoperative anal exhaust time, active time spent out of bed, length of hospitalization, time of indwelling catheter, and time of body temperature returning to normal were shorter in the LA group (all P < 0.001); the number of cases of intraoperative and postoperative complications and analgesia was less in the LA group (all P < 0.05). Six months after operation, serum follicle-stimulating hormone, luteinizing hormone, and E2 levels in the LA group were higher than those in the OS group (all P < 0.05). On day 1 and day 3 after operation, serum white blood cell and CRP levels and Ne percentage in the LA group were lower than those in the OS group (all P < 0.05). Laparoscopy is efficient and safe for managing benign ovarian tumors with comparable results to open surgery, and it is able to alleviate postoperative inflammation and minimize damage to the ovaries. PMID- 26963723 TI - Misuse of Prescribed Pain Medication in a Military Population-A Self-Reported Survey to Assess a Correlation With Age, Deployment, Combat Illnesses, or Injury? AB - Opioid misuse is a growing epidemic among the civilian and military communities. Five hundred prospective, anonymous surveys were collected in the emergency department waiting room of a military tertiary care hospital over 3 weeks. Demographics, medical and military characteristics were investigated for association with opioid use. Univariate logistic models were used to characterize the probability of misuse in relation to the demographic, medical, and military specific variables. Traumatic brain injury (TBI) and posttraumatic stress disorder were investigated within different age cohorts with adjustment for deployment. The opioid misuse rate disclosed by the subject was 31%. Subjects with TBI were less likely to misuse opioids. We found a trend among younger cohorts to have a higher likelihood for misusing opioids when diagnosed with TBI or posttraumatic stress disorder with history of deployment in the past 5 years. The most common form of misuse was using a previously prescribed medication for a new pain. Traumatic brain injury and/or enrollment in post-deployment recovery programs maybe protective against opioid misuse. Chronic opioid use among young soldiers maybe viewed as a weakness that could influence opioid misuse. Younger cohorts of active duty service members could be at higher risk for misuse. Efforts to enhance close monitoring of misuse should address these at-risk populations. PMID- 26963725 TI - The Selective Advantage of Synonymous Codon Usage Bias in Salmonella. AB - The genetic code in mRNA is redundant, with 61 sense codons translated into 20 different amino acids. Individual amino acids are encoded by up to six different codons but within codon families some are used more frequently than others. This phenomenon is referred to as synonymous codon usage bias. The genomes of free living unicellular organisms such as bacteria have an extreme codon usage bias and the degree of bias differs between genes within the same genome. The strong positive correlation between codon usage bias and gene expression levels in many microorganisms is attributed to selection for translational efficiency. However, this putative selective advantage has never been measured in bacteria and theoretical estimates vary widely. By systematically exchanging optimal codons for synonymous codons in the tuf genes we quantified the selective advantage of biased codon usage in highly expressed genes to be in the range 0.2-4.2 x 10-4 per codon per generation. These data quantify for the first time the potential for selection on synonymous codon choice to drive genome-wide sequence evolution in bacteria, and in particular to optimize the sequences of highly expressed genes. This quantification may have predictive applications in the design of synthetic genes and for heterologous gene expression in biotechnology. PMID- 26963726 TI - Autoimmunity: An evolving autoantibody response in RA? PMID- 26963728 TI - The effect of thermal treatment on the enhancement of detection of adulteration in extra virgin olive oils by synchronous fluorescence spectroscopy and chemometric analysis. AB - In this study the effect of thermal treatment on the enhancement of synchronous fluorescence spectroscopic method for discrimination and quantification of pure extra virgin olive oil (EVOO) samples from EVOO samples adulterated with refined oil was investigated. Two groups of samples were used. One group was analyzed at room temperature (25 degrees C) and the other group was thermally treated in a thermostatic water bath at 75 degrees C for 8h, in contact with air and with light exposure, to favor oxidation. All the samples were then measured with synchronous fluorescence spectroscopy. Synchronous fluorescence spectra were acquired by varying the wavelength in the region from 250 to 720 nm at 20 nm wavelength differential interval of excitation and emission. Pure and adulterated olive oils were discriminated by using partial least-squares discriminant analysis (PLS-DA). It was found that the best PLS-DA models were those built with the difference spectra (75 degrees C-25 degrees C), which were able to discriminate pure from adulterated oils at a 2% level of adulteration of refined olive oils. Furthermore, PLS regression models were also built to quantify the level of adulteration. Again, the best model was the one built with the difference spectra, with a prediction error of 3.18% of adulteration. PMID- 26963727 TI - New perspectives on femoroacetabular impingement syndrome. AB - Femoroacetabular impingement (FAI) is characterized by an abnormality in the shape of the femoral head-neck or acetabulum that results in impingement between these two structures. Arthroscopic treatment has become the preferred method of management of FAI owing to its minimally invasive approach. Surgical correction involves resection of impinging osseous structures as well as concurrent management of the associated chondral and labral pathology. Research from the past 5 years has shown that repair of the labrum results in a better anatomic correction and improved outcomes compared with labral debridement. Research is underway to improve cartilage assessment by using innovative imaging techniques and biochemical tests to inform predictions of prognosis. Several ongoing randomized controlled trials, including the Femoroacetabular Impingement Trial (FAIT) and the Femoroacetabular Impingement Randomized Controlled Trial (FIRST), will provide critical information regarding the diagnosis, management and prognosis of patients undergoing arthroscopic management of FAI. PMID- 26963729 TI - Investigation on the protein-binding properties of icotinib by spectroscopic and molecular modeling method. AB - Icotinib is a highly-selective epidermal growth factor receptor tyrosine kinase inhibitor with preclinical and clinical activity in non-small cell lung cancer, which has been developed as a new targeted anti-tumor drug in China. In this work, the interaction of icotinib and human serum albumin (HSA) were studied by three-dimensional fluorescence spectra, ultraviolet spectra, circular dichroism (CD) spectra, molecular probe and molecular modeling methods. The results showed that icotinib binds to Sudlow's site I in subdomain IIA of HSA molecule, resulting in icotinib-HSA complexes formed at ground state. The number of binding sites, equilibrium constants, and thermodynamic parameters of the reaction were calculated at different temperatures. The negative enthalpy change (DeltaH(theta)) and entropy change (DeltaS(theta)) indicated that the structure of new complexes was stabilized by hydrogen bonds and van der Waals power. The distance between donor and acceptor was calculated according to Forster's non radiation resonance energy transfer theory. The structural changes of HSA caused by icotinib binding were detected by synchronous spectra and circular dichroism (CD) spectra. Molecular modeling method was employed to unfold full details of the interaction at molecular level, most of which could be supported by experimental results. The study analyzed the probability that serum albumins act as carriers for this new anticarcinogen and provided fundamental information on the process of delivering icotinib to its target tissues, which might be helpful in understanding the mechanism of icotinib in cancer therapy. PMID- 26963730 TI - A sensitive "turn-on" fluorescent assay for quantification of ceftriaxone based on L-tryptophan-Pd(II) complex fluorophore. AB - Based on L-tryptophan-Pd(II) system, a sensitive and selective fluorimetric assay for the quantification of ceftriaxone (CTRX) had been developed. The experimental results showed that in pH 4.0 Britton-Robinson (BR) buffer medium, the fluorescence of L-tryptophan (L-Trp) (lambdaex/lambdaem=276 nm/352 nm) could be efficiently quenched by Pd(II). When CTRX was added to the mixed solution of the L-tryptophan and Pd(II), the fluorescence of L-Trp recovered. The reaction mechanism and the reasons for the fluorescence recovery were also discussed. Pd(II) reacted with L-Trp to form a 1:1 chelate complex, and then, after CTRX was added in L-Try-Pd(II) system, the ligand exchange reaction occurred between L-Trp and CTRX, which resulted in the fluorescence recovery. Under the optimized experimental conditions, the recovered fluorescence intensities at 352 nm showed excellent linear relationship with the concentration of CTRX over the range of 6.0 * 10(-8)-2.4 * 10(-)(6) mol L(-1) (0.040-1.59 MUg mL(-1)). The correlation coefficient (R) was 0.9997 and the detection limit was 1.8 * 10(-8) mol L(-1) (11.9 ng mL(-1)). Furthermore, the assay had been applied to determine trace amount of CTRX human urine samples with satisfactory results. PMID- 26963731 TI - Ab initio MRCI+Q calculations on the low-lying excited states of the MgBr radical including spin-orbit coupling. AB - Accurate theoretical calculations on the MgBr radical have been carried out by using the high-level relativistic multireference configuration interaction method with Davidson correction (MRCI+Q) using correlation-consistent Quintuple-zeta quality basis set. The potential energy curves (PECs) of the 14 Lambda-S states of MgBr have been computed. In order to improve the PECs, the core-valence correlation, scalar relativistic effect, and spin-orbit coupling effect are taken into account in the computations. The spectroscopic constants of the bound states have been determined from the computed PECs. The results of the ground state X(2)Sigma(+) and the first excited state A(2)Pi are in good agreement with those from the available experiments, while spectroscopic constants of the other electronic states are firstly reported. The low-lying ion-pair state B(2)Sigma(+) correlated to ion-pair dissociation limit Mg(+) ((2)Sg)+Br(-) ((1)Sg) is characterized. The permanent dipole moments (PDMs) of Lambda-S states and the R dependent spin-orbit (SO) matrix elements are computed. The results indicate that the abrupt changes of PDMs and the SO matrix elements are attributed to the changes of the electronic configurations near the avoided crossing point. After taking the SOC effect into account, the 14 Lambda-S states split into 30Omega states, and the SOC splitting for the A(2)Pi is calculated to be 102.58cm(-1). The SOC effect, leading to the double-well potential of the Omega=(3)1/2 state, is found to be substantial for MgBr. In order to further illustrate the SOC effect and the avoided crossing phenomenon of the PECs, the Lambda-S compositions in the Omega state wavefunctions are analyzed in detail. Finally, the transition dipole moments (TDMs) of several transitions from upper Omega states to the ground X(2)Sigma(+)1/2 state and the corresponding radiative lifetimes have been studied. It is shown that the (1)3/2-X(2)Sigma(+)1/2 and (2)3/2-X(2)Sigma(+)1/2 are particularly important to the observed transitions A(2)Pi-X(2)Sigma(+) and C(2)Pi-X(2)Sigma(+). The present study should shed more light on the electronic structures and transition properties of electronic states of the MgBr radical. PMID- 26963732 TI - Solving the Tautomeric Equilibrium of Purine through Analysis of the Complex Hyperfine Structure of the Four (14)N Nuclei. AB - The rotational spectra of two tautomers of purine have been measured by pulsed jet Fourier transform microwave spectroscopy coupled to a UV ultrafast vaporization system. The population ratio of the two main tautomers [N(7)H]/[N(9)H] is about 1/40 in the gas phase. It contrasts with the solid state where only the N(7)H species is present, or in solution where a mixture of both tautomers is observed. For both species, a full quadrupolar hyperfine analysis has been performed. This has led to the determination of the full sets of diagonal quadrupole coupling constants of the four (14)N atoms, which have provided crucial information for the unambiguous identification of both species. This work shows the great potential of microwave spectroscopy to study isolated biomolecules in the gas phase. All the work was supported by theoretical calculations. PMID- 26963733 TI - Problem Internet Overuse Behaviors in College Students: Readiness-to-Change and Receptivity to Treatment. AB - This mixed methods study explores college students' readiness-to-change and receptivity to treatment for problem Internet overuse behaviors. Focus groups were conducted with 27 college students who self-identified as Internet over users, and had experienced biopsychosocial problems related to Internet overuse. Participants completed standardized questionnaires assessing their Internet use and sociodemographic forms. Focus groups explored readiness to change problem Internet overuse behaviors and receptivity to treatment. Similar to college students with other addictive behaviors, students with problem Internet overuse fall along a continuum vis-a-vis readiness-to-change their behaviors. Over half of the participants were receptive to treatment for their problem Internet overuse behaviors. PMID- 26963734 TI - Correction: Soil Respiration in Semiarid Temperate Grasslands under Various Land Management. PMID- 26963735 TI - Altering the Mitochondrial Fatty Acid Synthesis (mtFASII) Pathway Modulates Cellular Metabolic States and Bioactive Lipid Profiles as Revealed by Metabolomic Profiling. AB - Despite the presence of a cytosolic fatty acid synthesis pathway, mitochondria have retained their own means of creating fatty acids via the mitochondrial fatty acid synthesis (mtFASII) pathway. The reason for its conservation has not yet been elucidated. Therefore, to better understand the role of mtFASII in the cell, we used thin layer chromatography to characterize the contribution of the mtFASII pathway to the fatty acid composition of selected mitochondrial lipids. Next, we performed metabolomic analysis on HeLa cells in which the mtFASII pathway was either hypofunctional (through knockdown of mitochondrial acyl carrier protein, ACP) or hyperfunctional (through overexpression of mitochondrial enoyl-CoA reductase, MECR). Our results indicate that the mtFASII pathway contributes little to the fatty acid composition of mitochondrial lipid species examined. Additionally, loss of mtFASII function results in changes in biochemical pathways suggesting alterations in glucose utilization and redox state. Interestingly, levels of bioactive lipids, including lysophospholipids and sphingolipids, directly correlate with mtFASII function, indicating that mtFASII may be involved in the regulation of bioactive lipid levels. Regulation of bioactive lipid levels by mtFASII implicates the pathway as a mediator of intracellular signaling. PMID- 26963737 TI - The effects of neuromuscular facilitation techniques on osteoporosis of hemiplegia limbs and serum leptin level in patients or rats with cerebral infarction. AB - PRIMARY OBJECTIVE: This study was to investigate the effect of proprioceptive neuromuscular facilitation techniques (NFT) on osteoporosis and serum leptin level in cerebral infarction patients or rats. RESEARCH DESIGN: Forty cerebral infarction rats were randomly grouped into control, sham operation, conventional treatment (CT) group and CT+NFT group. Fifty-two stroke patients with hemiplegia were included in this study. METHODS AND PROCEDURES: The bone mineral densities (BMD) of proximal hemiplegia limbs and serum ALP, BALP, BGP, IL-6 and leptin levels were detected using commercial kits. MAIN OUTCOMES AND RESULTS: In cerebral infarction rats, the BMD, BGP, BALP, ALP and leptin concentrations in the CT+NFT group was higher compared with the control and CT group, while serum IL-6 level was more reduced by CT+NFT than control and CT. In cerebral infarction patients, both CT and CT+NFT increased the BMD, ALP, BGP and leptin levels. In addition, compared with CT, the BMD, ALP, BGP and leptin levels were markedly increased by CT+NFT. C Conclusion: NFC elevated the BMD of hemiplegia limbs, serum ALP, BGP, IL-6 and leptin levels and, thus, alleviated osteoporosis in rats and patients with cerebral infarction. PMID- 26963736 TI - Specific Detection of Two Divergent Simian Arteriviruses Using RNAscope In Situ Hybridization. AB - Simian hemorrhagic fever (SHF) is an often lethal disease of Asian macaques. Simian hemorrhagic fever virus (SHFV) is one of at least three distinct simian arteriviruses that can cause SHF, but pathogenesis studies using modern methods have been scarce. Even seemingly straightforward studies, such as examining viral tissue and cell tropism in vivo, have been difficult to conduct due to the absence of standardized SHFV-specific reagents. Here we report the establishment of an in situ hybridization assay for the detection of SHFV and distantly related Kibale red colobus virus 1 (KRCV-1) RNA in cell culture. In addition, we detected SHFV RNA in formalin-fixed, paraffin-embedded tissues from an infected rhesus monkey (Macaca mulatta). The assay is easily performed and can clearly distinguish between SHFV and KRCV-1. Thus, if further developed, this assay may be useful during future studies evaluating the mechanisms by which a simian arterivirus with a restricted cell tropism can cause a lethal nonhuman primate disease similar in clinical presentation to human viral hemorrhagic fevers. PMID- 26963738 TI - Phenylboronic-Acid-Based Polymeric Micelles for Mucoadhesive Anterior Segment Ocular Drug Delivery. AB - Topical drug delivery to the front of the eye is extremely inefficient due to effective natural protection mechanisms such as precorneal tear turnover and the relative impermeability of the cornea and sclera tissues. This causes low ocular drug bioavailability, requiring large frequent doses that result in high systemic exposure and side effects. Mucoadhesive drug delivery systems have the potential to improve topical drug delivery by increasing pharmaceutical bioavailability on the anterior eye surface. We report the synthesis and characterization of a series of poly(L-lactide)-b-poly(methacrylic acid-co-3-acrylamidophenylboronic acid) block copolymer micelles for use as mucoadhesive drug delivery vehicles. Micelle properties, drug release rates, and mucoadhesion were shown to depend on phenylboronic acid content. The micelles showed low in vitro cytotoxicity against human corneal epithelial cells and undetectable acute in vivo ocular irritation in Sprague-Dawley rats, suggesting good biocompatibility with the corneal surface. The micelles show the potential to significantly improve the bioavailability of topically applied ophthalmic drugs, which could reduce dosage, frequency of administration, and unintentional systemic exposure. This would greatly improve the delivery of the ocular drugs such as the potent immunosuppressive cyclosporine A used in the treatment of severe dry eye disease. PMID- 26963740 TI - Remodeling of the Mandibular Bone Induced by Overdentures Supported by Different Numbers of Implants. AB - The objective of this study was to investigate the process of mandibular bone remodeling induced by implant-supported overdentures. computed tomography (CT) images were collected from edentulous patients to reconstruct the geometry of the mandibular bone and overdentures supported by implants. Based on the theory of strain energy density (SED), bone remodeling models were established using the user material subroutine (UMAT) in abaqus. The stress distribution in the mandible and bone density change was investigated to determine the effect of implant number on the remodeling of the mandibular bone. The results indicated that the areas where high Mises stress values were observed were mainly situated around the implants. The stress was concentrated in the distal neck region of the distal-most implants. With an increased number of implants, the biting force applied on the dentures was almost all taken up by implants. The stress and bone density in peri-implant bone increased. When the stress reached the threshold of remodeling, the bone density began to decrease. In the posterior mandible area, the stress was well distributed but increased with decreased implant numbers. Changes in bone density were not observed in this area. The computational results were consistent with the clinical data. The results demonstrate that the risk of bone resorption around the distal-most implants increases with increased numbers of implants and that the occlusal force applied to overdentures should be adjusted to be distributed more in the distal areas of the mandible. PMID- 26963741 TI - A Comparison of Walking Rates Between Wild and Zoo African Elephants. AB - With increased scrutiny surrounding the welfare of elephants in zoological institutions, it is important to have empirical evidence on their current welfare status. If elephants are not receiving adequate exercise, it could lead to obesity, which can lead to many issues including acyclicity and potentially heart disease. The goal of the current study was to compare the walking rates of elephants in the wild versus elephants in zoos to determine if elephants are walking similar distances relative to their wild counterparts. Eleven wild elephants throughout different habitats and locations in Botswana were compared to 8 elephants at the San Diego Zoo Safari Park. Direct comparisons revealed no significant difference in average walking rates of zoo elephants when compared with wild elephants. These results suggest that elephants at the San Diego Zoo Safari Park walk similar rates to those of wild elephants and may be meeting their exercise needs. PMID- 26963739 TI - Humanized mouse G6 anti-idiotypic monoclonal antibody has therapeutic potential against IGHV1-69 germline gene-based B-CLL. AB - In 10-20% of the cases of chronic lymphocytic leukemia of B-cell phenotype (B CLL), the IGHV1-69 germline is utilized as VH gene of the B cell receptor (BCR). Mouse G6 (MuG6) is an anti-idiotypic monoclonal antibody discovered in a screen against rheumatoid factors (RFs) that binds with high affinity to an idiotope expressed on the 51p1 alleles of IGHV1-69 germline gene encoded antibodies (G6 id(+)). The finding that unmutated IGHV1-69 encoded BCRs are frequently expressed on B-CLL cells provides an opportunity for anti-idiotype monoclonal antibody immunotherapy. In this study, we first showed that MuG6 can deplete B cells encoding IGHV1-69 BCRs using a novel humanized GTL mouse model. Next, we humanized MuG6 and demonstrated that the humanized antibodies (HuG6s), especially HuG6.3, displayed ~2-fold higher binding affinity for G6-id(+) antibody compared to the parental MuG6. Additional studies showed that HuG6.3 was able to kill G6 id(+) BCR expressing cells and patient B-CLL cells through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Finally, both MuG6 and HuG6.3 mediate in vivo depletion of B-CLL cells in NSG mice. These data suggest that HuG6.3 may provide a new precision medicine to selectively kill IGHV1-69-encoding G6-id(+) B-CLL cells. PMID- 26963742 TI - Metabolic dysfunction and adipose tissue macrophages: is there more to glean from studying the lean?: Comment on "Adipose tissue infiltration in normal-weight subjects and its impact on metabolic function" by Moreno-Indias et al. PMID- 26963744 TI - Buccal Bone Thickness in the Esthetic Zone of Postmenopausal Women: A CBCT Analysis. AB - PURPOSE: To compare bone thickness buccal to the teeth in the esthetic zone of postmenopausal women, premenopausal women, younger men and older men. METHODS: Retrospective data were randomly selected from 4 groups: 59 premenopausal women, 60 postmenopausal women, 60 men less than age 50, and 60 men more than 50. Half root and bone crest landmarks were identified on each participant's cone beam computed tomography for teeth 7 to 10 and 23 to 26. Buccal bone thickness was measured by calibrated examiners. Group averages were calculated and compared between groups using analysis of variance (P < 0.05). RESULTS: When comparing premenopausal to postmenopausal women and postmenopausal women to older men, anterior bone thickness was significantly different for tooth maxillary and mandibular lateral incisors and overall maxillary and mandibular central incisors. In addition, significant differences were observed between these groups within the maxilla comparing lateral incisors, central incisors (P < 0.05), and within the mandible when comparing lateral and central incisors at (P < 0.05) at bone crest and half-root, respectively. CONCLUSION: Buccal bone in the anterior esthetic zone bone is thin in all segments of the population, but significantly thinner in postmenopausal women. In this cohort, when anterior implants are planned, it is essential to make informed treatment planning decisions. Strategies are available to manage the thinner bony housing, but require further research specific to this growing consumer cohort. PMID- 26963743 TI - Differential impact of mechanical unloading on structural and nonstructural components of the extracellular matrix in advanced human heart failure. AB - Adverse remodeling of the extracellular matrix (ECM) is a significant characteristic of heart failure. Reverse remodeling of the fibrillar ECM secondary to mechanical unloading of the left ventricle (LV) by left ventricular assist device (LVAD) has been subject of intense investigation; however, little is known about the impacts on nonfibrillar ECM and matricellular proteins that also contribute to disease progression. Explanted failing hearts were procured from patients with nonischemic dilated cardiomyopathy (DCM) with or without LVAD support, and compared to nonfailing control hearts. LV free wall specimens were formalin-fixed, flash-frozen or optimum cutting temperature-mount frozen. Histologic and biochemical assessment of fibrillar ECM showed that LVAD support was associated with lower levels of insoluble collagen, collagen type I mRNA, and collagen I/III ratio compared with no-LVAD hearts. A disintegrin and Metalloproteinase with Thrombospondin Motifs-2 (ADAM-TS2), a procollagen endopeptidase, was reduced in no-LVAD but not in LVAD hearts. The rise in ECM proteolytic activities was significantly lower in LVAD hearts. Matrix metalloproteinases (MMP1, MMP2, MMP8, MMP13, and MT1-MMP/MMP14) were comparable between DCM hearts. Tissue inhibitor of metalloproteinase (TIMP)3 and TIMP4 messenger RNA and protein showed the greatest reduction in no-LVAD hearts. Basement membrane proteins exhibited less severe disarray of laminin and fibronectin-1 in LVAD-supported hearts. The rise in matricellular protein, osteopontin, was suppressed in LVAD hearts, whereas secreted protein, acidic, cysteine-rich (SPARC) levels was unaffected by LVAD. Mechanical unloading of the failing DCM hearts can restore the fibrillar ECM and the basement membrane, contributing toward improved clinical outcomes. However, persistent elevation of matricellular proteins such as SPARC could contribute to the relapse of failing hearts on removal of LVAD support. PMID- 26963745 TI - Influence of Metal and Ceramic Abutments on the Stress Distribution Around Narrow Implants: A Photoelastic Stress Analysis. AB - PURPOSE: This study aimed to compare, through photoelastic analysis, the distribution of stresses around narrow implants with external hexagon (EH) and Morse taper (MT) connections, when single crowns made with metal and ceramic abutments were used. MATERIALS AND METHODS: Six photoelastic models were prepared, simulating the use of narrow EH and MT implants replacing a lateral incisor. These 2 groups received 3 different abutments: prefabricated metal abutments, customized metal abutments, and customized zirconia abutments. All crowns were identical and made with a leucite reinforced glass-ceramic. Vertical loads of 0 to 100 N were applied on the palatal surface of the crowns, and the photoelastic stress fringes developed in each model were captured in a high definition video, and digital photographs were taken at 100 N. RESULTS: The abutment type and material influenced the stress distribution patterns around narrow implants with EH and MT connections. Stresses were generated mainly around the apical and lingual regions of the implants. CONCLUSIONS: For both connections, the prefabricated metal abutments presented better stress distribution around the implants when compared to customized metal and zirconia abutments because low stress levels were developed in smaller areas around the implants. PMID- 26963747 TI - Clay/Polyaniline Hybrid through Diazonium Chemistry: Conductive Nanofiller with Unusual Effects on Interfacial Properties of Epoxy Nanocomposites. AB - The concept of conductive network structure in thermoset matrix without sacrificing the inherent mechanical properties of thermoset polymer (e.g., epoxy) is investigated here using "hairy" bentonite fillers. The latter were prepared through the in situ polymerization of aniline in the presence of 4-diphenylamine diazonium (DPA)-modified bentonite (B-DPA) resulting in a highly exfoliated bentonite-DPA/polyaniline (B-DPA/PANI). The nanocomposite filler was mixed with diglycidyl ether of bisphenol A (DGEBA), and the curing agent (4,4' diaminodiphenylsulfone) (DDS) at high temperature in order to obtain nanocomposites through the conventional melt mixing technique. The role of B-DPA in the modification of the interface between epoxy and B-DPA/polyaniline (B DPA/PANI) is investigated and compared with the filler B/PANI prepared without any diazonium modification of the bentonite. Synergistic improvement in dielectric properties and mechanical properties points to the fact that the DPA aryl groups from the diazonium precursor significantly modify the interface by acting as an efficient stress transfer medium. In DPA-containing nanocomposites, unique fibril formation was observed on the fracture surface. Moreover, dramatic improvement (210-220%) in fracture toughness of epoxy composite was obtained with B-DPA/PANI filler as compared to the weak improvement of 20-30% noted in the case of the B/PANI filler. This work shows that the DPA diazonium salt has an important effect on the improvement of the interfacial properties and adhesion of DGEBA and clay/PANI nanofillers. PMID- 26963746 TI - Platelet-Rich Plasma in Grafted Maxillae: Growth Factor Quantification and Dynamic Histomorphometric Evaluation. AB - PURPOSE: Validation of platelet-rich plasma (PRP) system and assessing its enhancing effect on the healing of iliac crest grafts before implant placement. MATERIALS AND METHODS: Patients randomly allocated to test (n = 13) and control (n = 9) groups. Iliac crest grafts were mixed with PRP in the test group. Tetracycline labeling preceded implant placement. Bone samples were harvested for histomorphometrical analysis. Platelet and growth factor quantifications were performed. ANALYSIS: Data were analyzed using SPSS software package. Independent t test was used and statistical significance was set at 5%. RESULTS: The PRP group showed significantly higher platelet counts, PDGF-BB, and TGF-beta1 concentrations. Tendency to higher volume of woven bone was observed in the PRP group (13 +/- 11 vs 4 +/- 6, P = 0.1). Histomorphometry showed increased seam separation in the PRP group (8.8 +/- 9 MUm vs 1.5 +/- 3 MUm, P = 0.039). Remodeling activity was higher in PRP-woven bone sections and comparable in trabecular sections. CONCLUSION: PRP significantly increased platelet and growth factor concentrations and was of possible enhancing effect on the rate of bone formation at 3 to 4 months of grafting. The clinical significance of this enhancement is yet to be established. PMID- 26963748 TI - Characteristics of Spirituality and Religion Among Suicide Attempters. AB - Spirituality and religiousness are associated with a lower risk of suicide. A detailed assessment of spirituality among 88 suicide attempters hospitalized after a suicide attempt was performed. Factors associated with the recurrence of suicide attempts over 18 months were looked into. Spirituality was low among most suicide attempters in comparison with the general population. Two groups were identified: those with a high score of depression who featured "low" in spirituality and those with a more heterogeneous profile, for example, involving personality disorders, characterized by a "high" spirituality. At the follow-up, the "meaning in life" score appeared to correlate with recurrence of suicide. Clinical implications are discussed herein. PMID- 26963750 TI - Long non-coding RNA-LET can indicate metastasis and a poor prognosis: a meta analysis. AB - INTRODUCTION: Recent studies have reported that long non-coding RNA low expression in tumor (lncRNA-LET) was down-regulated in several cancers. The current meta-analysis aims to determine whether lncRNA-LET can be used as a potential biomarker for metastasis and prognosis. EVIDENCE ACQUISITION: We collected all relevant papers by searching multiple electronic databases (PubMed, EMBASE, Google Scholar, CNKI, Wanfang Database) and explored the association between the expression levels of lncRNA-LET and lymph node metastasis (LNM), distant metastasis (DM) and overall survival (OS). EVIDENCE SYNTHESIS: A total of 383 patients from four studies were finally included. The meta-analysis results showed that LNM occurred more frequently in patients from the lncRNA-LET low expression group than in patients from the lncRNA-LET overexpression group (OR=4.56, 95% CI 2.92-7.12, P<0.00001), and a similar result was observed between lncRNA-LET expression and DM (OR=4.77, 95% CI 2.29-9.94, P<0.0001). Additionally, we found that patients with low expression of lncRNA-LET had a poorer OS than those with lncRNA-LET overexpression (HR=2.39, 95% CI 1.57-3.21, P=0.000). CONCLUSIONS: lncRNA-LET may serve as a common molecular marker for metastasis and prognosis in human cancers. PMID- 26963749 TI - The ciliary GTPase Arl13b regulates cell migration and cell cycle progression. AB - The GTPase ARL13B is localized to primary cilia; small cellular protrusions that act as antennae. Its defective ARL13B hennin (HNN) variant is linked causally with Joubert Syndrome, a developmental ciliopathy attributed to poor sensing of extracellular chemical gradients. We tested the hypothesis that impaired detection of extracellular voltage gradients also contributes to the HNN phenotype. In vitro, extracellular electric fields stimulated migration of wild type (WT) and HNN fibroblasts toward the cathode but the field only increased the migration speed of WT cells. Cilia on WT cells did not align to the field vector. HNN cells divided more slowly than WT cells, arresting at the G2/M phase. Mechanistically, HNN cells had reduced phospho-ERK1/2 signaling and elevated levels of Suppressor of Fused protein. These suggest that cells may not be able to read extracellular chemical cues appropriately, resulting in deficits in cell migration and proliferation. Finally, an increase in tubulin stabilization (more detyrosinated tubulin) confirmed the general stagnation of HNN cells, which may further contribute to slower migration and cell cycle progression. We conclude that Arl13b dysfunction resulted in HNN cell stagnation due to poor growth factor signaling and impaired detection of extracellular electrical gradients, and that the role of Arl13b in cell proliferation may be understated. PMID- 26963751 TI - Unique C-terminal region of Hap3 is required for methanol-regulated gene expression in the methylotrophic yeast Candida boidinii. AB - The Hap complex of the methylotrophic yeast Candida boidinii was found to be required for methanol-regulated gene expression. In this study, we performed functional characterization of CbHap3p, one of the Hap complex components in C. boidinii. Sequence alignment of Hap3 proteins revealed the presence of a unique extended C-terminal region, which is not present in Hap3p from Saccharomyces cerevisiae (ScHap3p), but is found in Hap3p proteins of methylotrophic yeasts. Deletion of the C-terminal region of CbHap3p (Delta256-292 or Delta107-237) diminished activation of methanol-regulated genes and abolished the ability to grow on methanol, but did not affect nuclear localization or DNA-binding ability. However, deletion of the N-terminal region of CbHap3p (Delta1-20) led to not only a growth defect on methanol and a decreased level of methanol-regulated gene expression, but also impaired nuclear localization and binding to methanol regulated gene promoters. We also revealed that CbHap3p could complement the growth defect of the Schap3Delta strain on glycerol, although ScHap3p could not complement the growth defect of a Cbhap3Delta strain on methanol. We conclude that the unique C-terminal region of CbHap3p contributes to maximum activation of methanol-regulated genes, whilst the N-terminal region is required for nuclear localization and binding to DNA. PMID- 26963752 TI - Obstetric Admissions to the Intensive Care Unit in a Tertiary Hospital. AB - AIMS: A better understanding of the characteristics of obstetric patients admitted to an intensive care unit (ICU) could guide where the focus of obstetric training and awareness should be directed at to reduce further maternal mortality and morbidity. METHODS: We retrospectively assessed the charts of all women admitted during pregnancy or postpartum to a tertiary ICU over a 12-year period. We retrieved whether women were followed locally or referred from another hospital and whether the ICU admission was prophylactic or therapeutic. RESULTS: There were 190 admissions in 183 women. One-hundred and four admissions were in referred women and 86 in women cared for locally. Seventy-eight admissions (41.1%) were for direct obstetric causes (primarily postpartum hemorrhage (n = 14), hypertensive disorders of pregnancy (n = 12) and peripartum cardiomyopathy (n = 10)). Indirect obstetric admissions (n = 89; 46.8%) were primarily for cardiopathies (n = 35) and pulmonary diseases (n = 18). Among non-obstetric admissions, trauma (n = 6; 26.1%) and neurologic tumors (n = 6; 26.1%) were the most common. CONCLUSION: Pre-existing and acquired cardiopathies are the main reason for admission to an ICU in a developed country and have surpassed hypertensive disorders and hemorrhage. This should become a focus of obstetric care provider training. PMID- 26963754 TI - Optimization of Salmonella Typhi biofilm assay on polypropylene microtiter plates using response surface methodology. AB - The objective of this study was to develop an optimized assay for Salmonella Typhi biofilm that mimics the environment of the gallbladder as an experimental model for chronic typhoid fever. Multi-factorial assays are difficult to optimize using traditional one-factor-at-a-time optimization methods. Response surface methodology (RSM) was used to optimize six key variables involved in S. Typhi biofilm formation on cholesterol-coated polypropylene 96-well microtiter plates. The results showed that bile (1.22%), glucose (2%), cholesterol (0.05%) and potassium chloride (0.25%) were critical factors affecting the amount of biofilm produced, but agitation (275 rpm) and sodium chloride (0.5%) had antagonistic effects on each other. Under these optimum conditions the maximum OD reading for biofilm formation was 3.4 (lambda600 nm), and the coefficients of variation for intra-plate and inter-plate assays were 3% (n = 20) and 5% (n = 8), respectively. These results showed that RSM is an effective approach for biofilm assay optimization. PMID- 26963755 TI - Cyclotorsion Measured in a Patient Population Using Three Different Methods: A Comparative Study. AB - PURPOSE: To establish if cyclotorsion measurements obtained in a patient population using different methods of testing give equivalent results, and if the results from each test are repeatable over time. METHODS: Twenty referrals, from the orthoptic waiting list at Sahlgrenska University Hospital, Molndal, Sweden, with vertical deviation stated as the primary reason for referral, were examined. Subjective cyclotorsion measurements using three different methods were performed. The methods included two standard tests: a synoptophore, with slides A17a/18a, the single Maddox rod test (SMR), and a new test method: the KMScreen method. Measurements were repeated 3 times for fixing either eye, and on two separate test occasions, for repeatability within each of the methods. RESULTS: During the first test measurements, 11 (55%) showed excyclotorsion measured with the synoptophore method, 18 (90%) with the SMR test, and 15 (75%) with the KMScreen method. During the second set of measurements, 11 (55%) showed excyclotorsion with the synoptophore method, 17 (85%) with the SMR test, and 10 (50%) with the KMScreen test. Median perceived torsional measurements at the first visit for the synoptophore, SMR, and KMScreen tests were -1 degrees , -5 degrees , and -1 degrees , respectively. There were significant differences between the synoptophore and SMR (P=0.025), and the SMR and KMScreen (P=0.025), but not between the synoptophore and KMScreen (P=0.90) methods on measuring the affected eye. All three tests showed repeatable values. The 95% limits of agreement (LoAs) between visits, defined as mean torsional difference +/- 1.96 SD of difference, for the synoptophore, SMR, and KMScreen methods were -0.5 degrees +/- 4.5 degrees , -0.3 degrees +/- 5 degrees , and -0.7 degrees +/- 3.5 degrees , respectively. P values for differences between visits were P=0.45, P=0.75, and P=0.90, respectively, using an exact permutation test. CONCLUSION: In this small study group, the three different methods used for testing cyclotorsion showed significantly different results. However, all methods showed significant repeatability (test-retest reliability) over time. This finding is of clinical importance when investigating cyclotorsion in patients. Clinicians need to be aware of the differences between methods when monitoring recovery or changes in patients, and in particular when planning surgical correction for cyclotorsion. PMID- 26963756 TI - 'I am not a man': Trans-specific barriers and facilitators to PrEP acceptability among transgender women. AB - The frequent conflation of transgender ('trans') women with 'men who have sex with men (MSM)' in HIV prevention obscures trans women's unique gender identities, social and behavioural vulnerabilities, and their disproportionately high rates of HIV infection. Pre-exposure prophylaxis (PrEP) is an efficacious biomedical HIV prevention approach. However, trans women are underrepresented in PrEP research, and are often aggregated with MSM without consideration for their unique positions within sociocultural contexts. This study examined PrEP acceptability among trans women via three focus groups and nine individual interviews (total N = 30) in San Francisco. While knowledge of PrEP was low, interest was relatively high once participants were informed. Due to past negative healthcare experiences, ability to obtain PrEP from a trans-competent provider was cited as essential to PrEP uptake and adherence. Participants noted that PrEP could address situations in which trans women experience reduced power to negotiate safer sex, including sex work. Trans-specific barriers included lack of trans-inclusive marketing of PrEP, prioritisation of hormone use, and medical mistrust due to transphobia. Findings underscore the importance of disaggregating trans women from MSM in HIV prevention strategies to mitigate disparate risk among this highly vulnerable population. PMID- 26963757 TI - Risk Factors for Venous Thromboembolism in Pediatric Trauma Patients and Validation of a Novel Scoring System: The Risk of Clots in Kids With Trauma Score. AB - OBJECTIVES: Identify risk factors for venous thromboembolism and develop venous thromboembolism risk assessment models for pediatric trauma patients. DESIGN: Single institution and national registry retrospective cohort studies. SETTING: John Hopkins level 1 adult and pediatric trauma center and National Trauma Data Bank. PATIENTS: Patients 21 years and younger hospitalized following traumatic injuries at John Hopkins (1987-2011). Patients 21 years and younger in the National Trauma Data Bank (2008-2010 and 2011-2012). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical characteristics of Johns Hopkins patients with and without venous thromboembolism were compared, and multivariable logistic regression analysis was used to identify independent venous thromboembolism risk factors. Weighted risk assessment scoring systems were developed based on these and previously identified factors from National Trauma Data Bank patients (2008 2010); the scoring systems were validated in this cohort from Johns Hopkins and a cohort from the National Trauma Data Bank (2011-2012). Forty-nine of 17,366 pediatric trauma patients (0.28%) were diagnosed with venous thromboembolism after admission to our trauma center. After adjusting for potential confounders, venous thromboembolism was independently associated with older age, surgery, blood transfusion, higher Injury Severity Score, and lower Glasgow Coma Scale score. These and additional factors were identified in 402,329 pediatric patients from the National Trauma Data Bank from 2008 to 2010; independent risk factors from the logistic regression analysis of this National Trauma Data Bank cohort were selected and incorporated into weighted risk assessment scoring systems. Two models were developed and were cross-validated in two separate pediatric trauma cohorts: 1) 282,535 patients in the National Trauma Data Bank from 2011 to 2012 and 2) 17,366 patients from Johns Hopkins. The receiver operating curve using these models in the validation cohorts had area under the curves that ranged 90 94%. CONCLUSIONS: Venous thromboembolism is infrequent after trauma in pediatric patients. We developed weighted scoring systems to stratify pediatric trauma patients at risk for venous thromboembolism. These systems may have potential to guide risk-appropriate venous thromboembolism prophylaxis in children after trauma. PMID- 26963758 TI - Strain Echocardiography Parameters Correlate With Disease Severity in Children and Infants With Sepsis. AB - OBJECTIVES: In the progression of severe sepsis, sepsis-induced myocardial dysfunction contributes to severity of illness and ultimate mortality. Identification of sepsis-induced myocardial dysfunction causing depressed cardiac function during critical illness has implications for ongoing patient management. However, assessing pediatric cardiac function traditionally relies on echocardiographic qualitative assessment and measurement of left ventricular ejection fraction or fractional shortening. These metrics are often insensitive for detecting early or regional myocardial dysfunction. Strain echocardiography is a contemporary echocardiographic modality that may be more sensitive to perturbations in cardiac function. This investigation hypothesizes that strain echocardiography metrics correlate with severity of illness in pediatric sepsis despite normal fractional shortening. DESIGN: Single-center retrospective observational study. SETTING: Tertiary 36-bed medical/surgical PICU. PATIENTS: Pediatric patients admitted with sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-three children with sepsis received an echocardiogram in the study period. Patients with sepsis demonstrated abnormal peak systolic longitudinal strain for age (mean = -0.13 +/- 0.07; p < 0.01) and low normal peak systolic circumferential strain (mean = -0.17 +/- 0.14; p = 0.02) compared with internal controls as well as previously published normal values. Depressed strain was demonstrated in the septic patients despite having normal fractional shortening (mean = 0.41; 95% CI, 0.38-0.43). On initial echocardiographic imaging, worsening peak systolic longitudinal strain was associated with increasing lactate (p = 0.04). CONCLUSIONS: Pediatric patients with sepsis demonstrate evidence of depressed strain echocardiography parameters not shown by fractional shortening that correlate with clinical indices of sepsis severity. Whether strain echocardiography could eventually assist in grading pediatric sepsis severity and affect management is an area for potential future investigation. PMID- 26963760 TI - Ethanol flame synthesis of carbon nanotubes in deficient oxygen environments. AB - In this study, carbon nanotubes (CNTs) were synthesized using ethanol diffusion flames in a stagnation-flow system composed of an upper oxidizer duct and a lower liquid pool. In the experiments, a gaseous mixture of oxygen and nitrogen flowed from the upper oxidizer duct, and then impinged onto the vertically aligned ethanol pool to generate a planar and steady diffusion flame in a deficient oxygen environment. A nascent nickel mesh was used as the catalytic metal substrate to collect deposited materials. The effect of low oxygen concentration on the formation of CNTs was explored. The oxygen concentration significantly influenced the flame environment and thus the synthesized carbon products. Lowering the oxygen concentration increased the yield, diameter, and uniformity of CNTs. The optimal operating conditions for CNT synthesis were an oxygen concentration in the range of 15%-19%, a flame temperature in the range of 460 degrees C-870 degrees C, and a sampling position of 0.5-1 mm below the upper edge of the blue flame front. It is noteworthy that the concentration gradient of C2 species and CO governed the CNT growth directly. CNTs were successfully fabricated in regions with uniform C2 species and CO distributions. PMID- 26963761 TI - Determining clinical practice of expert physiotherapy for patients undergoing lumbar spinal fusion: a cross-sectional survey study. AB - PURPOSE: To determine the content of current Dutch expert hospital physiotherapy practice for patients undergoing lumbar spinal fusion (LSF), to gain insight into expert-based clinical practice. METHODS: At each hospital where LSF is performed, one expert physiotherapist received an e-mailed questionnaire, about pre- and postoperative physiotherapy and discharge after LSF. The level of uniformity in goals and interventions was graded on a scale from no uniformity (50-60 %) to very strong uniformity (91-100 %). RESULTS: LSF was performed at 34 of the 67 contacted hospitals. From those 34 hospitals, 28 (82 %) expert physiotherapists completed the survey. Twenty-one percent of the respondents saw patients preoperatively, generally to provide information. Stated postoperative goals and administered interventions focused mainly on performing transfers safely and keeping the patient informed. Outcome measures were scarcely used. There was no uniformity regarding advice on the activities of daily living. CONCLUSION: Dutch perioperative expert physiotherapy for patients undergoing LSF is variable and lacks structural outcome assessment. Studies evaluating the effectiveness of best practice physiotherapy are warranted. PMID- 26963759 TI - Assignment of Functional Relevance to Genes at Type 2 Diabetes-Associated Loci Through Investigation of beta-Cell Mass Deficits. AB - Type 2 diabetes (T2D) has been associated with a large number of genomic loci, many of which encompass multiple genes without a definitive causal gene. This complexity has hindered efforts to clearly identify functional candidate genes and interpret their role in mediating susceptibility to disease. Here we examined the relevance of individual genes found at T2D-associated loci by assessing their potential contribution to a phenotype relevant to the disease state: production and maintenance of beta-cell mass. Using transgenic zebrafish in which beta-cell mass could be rapidly visualized in vivo, we systematically suppressed the expression of orthologs of genes found at T2D-associated genomic loci. Overall, we tested 67 orthologs, many of which had no known relevance to beta-cell mass, at 62 human T2D-associated loci, including eight loci with multiple candidate genes. In total we identified 25 genes that were necessary for proper beta-cell mass, providing functional evidence for their role in a physiological phenotype directly related to T2D. Of these, 16 had not previously been implicated in the regulation of beta-cell mass. Strikingly, we identified single functional candidate genes at the majority of the loci for which multiple genes were analyzed. Further investigation into the contribution of the 25 genes to the adaptive capacity of beta-cells suggested that the majority of genes were not required for glucose-induced expansion of beta-cell mass but were significantly necessary for the regeneration of beta-cells. These findings suggest that genetically programmed deficiencies in beta-cell mass may be related to impaired maintenance. Finally, we investigated the relevance of our findings to human T2D onset in diabetic individuals from the Old Order Amish and found that risk alleles in beta-cell mass genes were associated with significantly younger age of onset and lower body mass index. Taken together, our study offers a functional approach to assign relevance to genes at T2D-associated loci and offers experimental evidence for the defining role of beta-cell mass maintenance in genetic susceptibility to T2D onset. PMID- 26963762 TI - Relationship between cervical sagittal alignment and health-related quality of life in adolescent idiopathic scoliosis. AB - PURPOSE: Little information is available on the relationship between cervical sagittal alignment and health-related quality of life (HRQOL) in adolescent idiopathic scoliosis (AIS) patients. The aim of this study was to identify relationships between postoperative cervical sagittal alignment and HRQOL in AIS. METHODS: The study and control groups comprised 67 AIS patients (51 girls and 16 boys). All underwent anteroposterior and lateral plain radiography and completed clinical questionnaires. The radiographic parameters investigated were pre- and postoperative C2-C7 lordosis, C2-C7 sagittal vertical axis (SVA), T1 slope, T1 slope minus C2-C7 lordosis (TS-CL), thoracic kyphosis (TK), lumbar lordosis (LL), pelvic tilt (PT), sacral slope (SS), and pelvic incidence (PI). The Korean version of the SRS-22 questionnaire and the previously validated Short Form-36 (SF-36) outcome questionnaire were administered to evaluate HRQOL at last follow up visits. Statistical analysis was performed to determine the significances of differences between preoperative and last follow-up radiological findings. In addition, correlations between radiological parameters and clinical questionnaire scores were sought. RESULTS: Radiological sagittal parameters were found to be significantly increased after surgical correction in terms of C2-C7 lordosis (3.5 +/- 11.4), C2-C7 SVA (1.5 +/- 6.0), T1 slope (3.5 +/- 6.1), and TK (6.0 +/- 8.1). However, no significant difference was observed for TS-CL, LL, PT, SS, and PI (P > 0.05). Correlation analysis revealed significant relationships between radiographic parameters and questionnaire scores. Multiple regression analysis was performed to identify predictors of HRQOL, and the results obtained revealed that postoperative T1 slope significantly predicted SRS, PCS, and MCS scores and that postoperative C2-C7 SVA predicted SRS scores. CONCLUSIONS: Changes in cervical sagittal parameters were significant after deformity correction in AIS patients. Correlation analysis revealed significant relationships between postoperative radiographic parameters and HRQOL. In particular, T1 slope and C2 C7 SVA were found to be significant predictors of HRQOL in AIS patient. PMID- 26963763 TI - They see us as less than human: Metadehumanization predicts intergroup conflict via reciprocal dehumanization. AB - Although the act of dehumanizing an outgroup is a pervasive and potent intergroup process that drives discrimination and conflict, no formal research has examined the consequences of being dehumanized by an outgroup-that is, "metadehumanization." Across 10 studies (N = 3,440) involving several real-world conflicts spanning 3 continents, we provide the first empirical evidence that metadehumanization (a) plays a central role in outgroup aggression that is (b) mediated by outgroup dehumanization, and (c) distinct from metaprejudice. Studies 1a and 1b demonstrate experimentally that Americans who learn that Arabs (Study 1a) or Muslims (Study 1b) blatantly dehumanize Americans are more likely to dehumanize that outgroup in return; by contrast, experimentally increasing outgroup dehumanization did not increase metadehumanization (Study 1c). Using correlational data, Study 2 documents indirect effects of metadehumanization on Americans' support for aggressive policies toward Arabs (e.g., torture) via Arab dehumanization. In the context of Hungarians and ethnic minority Roma, Study 3 shows that the pathway for Hungarians from metadehumanization to aggression through outgroup dehumanization holds controlling for outgroup prejudice. Study 4 examines Israelis' metaperceptions with respect to Palestinians, showing that: (a) feeling dehumanized (i.e., metadehumanization) is distinct from feeling disliked (i.e., metaprejudice), and (b) metadehumanization uniquely influences aggression through outgroup dehumanization, controlling for metaprejudice. Studies 5a and 5b explore Americans' metaperceptions regarding ISIS and Iran. We document a dehumanization-specific pathway from metadehumanization to aggressive attitudes and behavior that is distinct from the path from metaprejudice through prejudice to aggression. In Study 6, American participants learning that Muslims humanize Americans (i.e., metahumanization) humanize Muslims in turn. Finally, Study 7 experimentally contrasts metadehumanization and metahumanization primes, and shows that resulting differences in outgroup dehumanization are mediated by (a) perceived identity threat, and (b) a general desire to reciprocate the outgroup's perceptions of the ingroup. In summary, our research outlines how and why metadehumanization contributes to cycles of ongoing violence and animosity, providing direction for future research and policy. (PsycINFO Database Record PMID- 26963764 TI - How being busy can increase motivation and reduce task completion time. AB - This research tests the hypothesis that being busy increases motivation and reduces the time it takes to complete tasks for which people miss a deadline. This effect occurs because busy people tend to perceive that they are using their time effectively, which mitigates the sense of failure people have when they miss a task deadline. Studies 1 and 2 show that when people are busy, they are more motivated to complete a task after missing a deadline than those who are not busy, and that the perception that one is using time effectively mediates this effect. Studies 3 and 4 show that this process makes busy people more likely to complete real tasks than people who are not busy. Study 5 uses data from over half a million tasks submitted by thousands of users of a task management software application to show that busy people take less time to complete a task after they miss a deadline for completing it. The findings delineate the conditions under which being busy can mitigate the negative effects of missing a deadline and reduce the time it takes to complete tasks. (PsycINFO Database Record PMID- 26963765 TI - Editorial. PMID- 26963768 TI - Strongly Coupled Ternary Hybrid Aerogels of N-deficient Porous Graphitic-C3N4 Nanosheets/N-Doped Graphene/NiFe-Layered Double Hydroxide for Solar-Driven Photoelectrochemical Water Oxidation. AB - Developing photoanodes with efficient sunlight harvesting, excellent charge separation and transfer, and fast surface reaction kinetics remains a key challenge in photoelectrochemical water splitting devices. Here we report a new strongly coupled ternary hybrid aerogel that is designed and constructed by in situ assembly of N-deficient porous carbon nitride nanosheets and NiFe-layered double hydroxide into a 3D N-doped graphene framework architecture using a facile hydrothermal method. Such a 3D hierarchical structure combines several advantageous features, including effective light-trapping, multidimensional electron transport pathways, short charge transport time and distance, strong coupling effect, and improved surface reaction kinetics. Benefiting from the desirable nanostructure, the ternary hybrid aerogels exhibited remarkable photoelectrochemical performance for water oxidation. Results included a record high photocurrent density that reached 162.3 MUA cm(-2) at 1.4 V versus the reversible hydrogen electrode with a maximum incident photon-to-current efficiency of 2.5% at 350 nm under AM 1.5G irradiation, and remarkable photostability. The work represents a significant step toward the development of novel 3D aerogel-based photoanodes for solar water splitting. PMID- 26963769 TI - Leaching of Terbutryn and Its Photodegradation Products from Artificial Walls under Natural Weather Conditions. AB - Terbutryn is a commonly used biocide in construction materials. Especially polymer-resin-based renders and paints, used in external thermal insulation composite systems, are very susceptible to microbial deterioration. Previous studies have shown that biocides leach out of the material when contacted with rainwater; thus, they reach surface waters where they might have adverse effects on aquatic organisms. The knowledge on the long-term leaching performance and especially the formation and fate of degradation products is rare. In the present study, the leaching of terbutryn from artificial walls equipped with two types of render was observed for 19 months. In addition to concentration and mass load determinations for terbutryn, photodegradation products were identified and studied in the leachate and render. The results show that terbutryn leached mainly within the first 6-12 months. During the exposure, only 3% of the initial terbutryn was emitted to the runoff, while 64-80% remained in the coating. The overall mass balance could be closed by including several degradation products. Contrary to expectations, the major fraction of transformation products remained in the material and was not washed off immediately, which is of high importance for the long-term assessment of biocides in coating materials. PMID- 26963770 TI - Biotechnological potential of microbial inulinases: Recent perspective. AB - Among microbial enzymes, inulinases or fructo-furanosylhydrolases have received considerable attention in the past decade, and as a result, a variety of applications based on enzymatic hydrolysis of inulin have been documented. Inulinases are employed for generation of fructose and inulo-oligosaccharides (IOS) in a single-step reaction with specificity. The high fructose syrup can be biotransformed into value-added products such as ethanol, single cell protein, while IOS are indicated in nutraceutical industry as prebiotic. Myriad microorganisms produce inulinases, and a number of exo- and endo-inulinases have been characterized and expressed in heterologous hosts. Initially, predominated by Aspergilli, Penicillia, and some yeasts (Kluyveromyces spp.), the list of prominent inulinase producers has gradually expanded and now includes extremophilic prokaryotes and marine-derived microorganisms producing robust inulinases. The present paper summarizes important developments about microbial inulinases and their applications made in the last decade. PMID- 26963771 TI - Ultraviolet Photodissociation Dynamics of the 1-Propenyl Radical. AB - Ultraviolet (UV) photodissociation dynamics of jet-cooled 1-propenyl radical (CHCHCH3) were investigated at the photolysis wavelengths from 224 to 248 nm using high-n Rydberg atom time-of-flight (HRTOF) technique. The 1-propenyl radicals were produced from 193 nm photolysis of 1-chloropropene and 1 bromopropene precursors. The photofragment yield (PFY) spectra of the H atom product have a broad peak centered at 230 nm. The H + C3H4 product translational energy P(ET) distribution's peak near ~8 kcal/mol, and the fraction of average translational energy in the total available energy, ?fT?, is nearly a constant of ~0.12 from 224 to 248 nm. The H atom product has an isotropic angular distribution with the anisotropy parameter beta ~ 0. Quasiclassical trajectory calculations were also carried out using an ab initio ground-state potential energy surface for dissociation of 1-propenyl at the excitation energy of 124 kcal/mol (230 nm). The calculated branching ratios are 60% to the methyl + acetylene products, 16% to H + propyne, 4% to H + allene, and 1% to H + cyclopropene. The experimental and calculated P(ET) distributions of the H + C3H4 products at 230 nm are in a qualitative agreement, suggesting that the H + propyne dissociation is the main H atom product channel. The calculated dissociation time scale on the ground electronic state is ~1 ps, shorter than but close to the time scale of >10 ps for the overall UV photodissociation implied by the isotropic H atom product angular distribution. The UV photodissociation mechanism of 1-propenyl can be described as unimolecular decomposition of hot 1 propenyl radical on the ground electronic state following internal conversion from the electronically excited states of 1-propenyl. PMID- 26963773 TI - Errata: Vol. 65, No. 6. AB - In the report, "Notes from the Field: Administration Error Involving a Meningococcal Conjugate Vaccine - United States, March 1, 2010-September 22, 2015," on page 162, the end of the first paragraph should contain an additional sentence as follows: "However, because serogroup A meningococcal disease is rare in the United States, patients only receiving the liquid MenCYW-135 component of Menveo might not need revaccination, unless international travel is anticipated (especially travel to Africa) (3,6)." PMID- 26963772 TI - Blaschkoid Skin Lesions in a Young Girl. PMID- 26963774 TI - Efficient decellularization of whole porcine kidneys improves reseeded cell behavior. AB - Combining patient-specific cells with the appropriate scaffold to create functional kidneys is a promising technology to provide immunocompatible kidneys for the 100,000+ patients on the organ waiting list. For proper recellularization to occur, the scaffold must possess the critical microstructure and an intact vascular network. Detergent perfusion through the vasculature of a kidney is the preferred method of decellularization; however, harsh detergents could be damaging to the microstructure of the renal tissue and may undesirably solubilize the endogenous growth and signaling factors. In this study, automated decellularization of whole porcine kidneys was performed using an improved method that combined physical and chemical steps to efficiently remove cellular materials while producing minimal damage to the collagenous extracellular matrix (ECM). Freezing/thawing, incremental increases in flow rate under constant pressure, applying osmotic shock to the cellular membranes, and low concentrations of the detergent sodium dodecyl sulfate (SDS) were factors used to decrease SDS exposure time during the decellularization process from 36 to 5 h, which preserved the microstructure while still removing 99% of the DNA. The well preserved glycosaminoglycans (GAGs) and collagen fibers enhanced cell-ECM interactions. Human renal cortical tubular epithelium (RCTE) cells grew more rapidly when cultured on the ECM obtained from the improved decellularization process and also demonstrated more in vivo-like gene expression patterns. The optimized, automated process that resulted from this work is now used routinely in our laboratory to rapidly decellularize porcine kidneys and could be adapted to other large organs (e.g. heart, liver, and lung). PMID- 26963775 TI - Emotional distress and burden among caregivers of children with oncological/hematological disorders. AB - INTRODUCTION: Caring for children with oncological and hematological disorders may lead to caregiver emotional distress and caregiver burden; however, little work has examined the relationship between children's symptoms and caregiver's distress and burden. METHOD: This study used self-report survey data from caregivers (N = 96) and a cross-sectional design to examine correlates of caregiver emotional distress and burden. Data collected included caregiver and child demographic data, child symptoms (i.e., sleep problems, pain, and emotional/behavioral problems), caregiver emotional distress, and caregiver burden. RESULTS: Multiple linear regression found that parent reported financial difficulty (beta = 0.29, t = 3.13, p = .003), greater child sleep problems (beta = 0.29 t = 2.81, p = .007), greater child pain (beta = 0.33 t = 3.48, p = .001), and greater child emotional/behavioral problems (beta = 0.27, t = 2.71, p = .009) were all related to higher levels of caregiver emotional distress. Only financial difficulties (beta = -0.35, t = -2.03, p = .04) and child pain (beta = -0.30, t = -2.33, p = .02) were related to caregiver burden. DISCUSSION: Child symptoms may play an important role in the development of caregiver distress and caregiver burden; future research should utilize longitudinal designs to examine temporal and casual relationships. (PsycINFO Database Record PMID- 26963776 TI - The Tri-Optic II: Embracing the family voice. AB - In June, 2015, for the issue marking the passing of Donald Bloch, the intellectual founder of the collaborative health care movement, we wrote an editorial called, "The Tri-Optic: Next step for Collaborative Family Healthcare" (Mauksch & Fogarty, 2015). Bloch had famously proposed the "dual optic": the partnership of Dr. Biomedicine and Dr. Psychosocial (Bloch, 1988). Our readers, including many Collaborative Family Healthcare Association (CFHA) members, understand the value of a family perspective and are grappling with the next steps to truly integrate family and systems thinking into all levels of health care. A current exploration about the last 10 years of articles published in the journal by Tai Mendenhall, a member or our editorial board (personal communication, 2015), has found that the most common topic of focus is family health and functioning in 28% of the articles. This focus was also evident to varying degrees in all the plenaries at the 2015 CFHA conference held in Portland, Oregon. we pose the following questions to the FSH readership and CFHA community: Where are we, individually and collectively, with our knowledge about families as resources in and influences on health care? How are we teaching our learners about family-oriented care? How do we integrate family thinking into our various models of care? How do models of behavioral health integration include the family context in patient care? PMID- 26963778 TI - Privacy versus care--The shifting balance in mental health. AB - Mental health professionals are now debating client confidentiality and its relationship to care coordination. History tells us there is a need to protect the privacy of people who are diagnosed with mental health issues in a world filled with stigma and misperceptions. People with mental illness and substance use problems may be legitimately concerned that employers, insurance companies, financial institutions, medical practices, and educational institutions could use their health information to discriminate against them, often without their knowledge. The protection of jobs and health information is a real, justifiable benefit of privacy legislation. However, there are also a host of negative consequences, including fragmented health care, lack of prevention, uninformed families, and even early death, because of a lack of coordination with medical treatment. The legal situation can be very confusing, but the upshot is that we are shifting from an environment of strict confidentiality to one of better care coordination. In short, we are moving toward a system that allows for better coordination because it improves the quality of care for our clients. At the policy level, we must lead the change process and actively support the revision and reinterpretation of existing laws and regulations. These changes will require earning the trust of the people being served. Many are wary, and some even scared, of their perceived loss of privacy. Health-care professionals must commit to the concept of coordinating care, making communication about shared care plans a priority. PMID- 26963777 TI - Benefits of integrated behavioral health services: The physician perspective. AB - INTRODUCTION: There are benefits of integrating a behavioral health specialist in primary care; however, little is known about the physicians' perspectives. The purpose of this study was to explore primary care physicians' beliefs regarding the benefits of integrated care for both patients and themselves. METHOD: Fifteen senior staff physicians and 78 residents completed surveys regarding their opinions of referring to a psychologist in a patient-centered medical home. RESULTS: The top reasons that physicians believed their patients followed through with a visit with an integrated psychologist included that they recommended it (79.5%) and that patients can be seen in the same primary care clinic (76.9%). The overwhelming majority of physicians were satisfied with having access to an integrated psychologist (97.4%). Physicians believed that integrated care directly improves patient care (93.8%), is a needed service (90.3%), and helps provide better care to patients (80.9%). In addition, physicians reported that having an integrated psychologist reduces their personal stress level (90.1%). CONCLUSION: Primary care physicians may be motivated to integrate behavioral health services into their clinics knowing that other physicians believe that it directly and indirectly improves patient care and physician stress. PMID- 26963779 TI - Medicaid expansion and mental health: A Minnesota case study. AB - INTRODUCTION: The health status and psychosocial needs of the Medicaid expansion population have been estimated but not measured. This population includes childless adults predicted to have high rates of mental illness, especially among the homeless. Given limitations in access to mental health services, it is unclear how prepared the U.S. health care system is to care for the needs of the expansion population. METHOD: Using enrollment and claims data from the Minnesota Department of Human Services, this study presents prevalence rates of mental illness diagnoses and measures of unstable housing in Minnesota's childless-adult early Medicaid expansion population. Rates are compared with prior predictions of serious psychological distress and mental illness constructed from the National Survey on Drug Use and Health (NSDUH) using chi2 and t tests. RESULTS: Diagnoses of mental illness in Minnesota's childless-adult early Medicaid expansion population were more than 15% higher than prevalence measures of mental illness/distress for the current Medicaid population. Diagnosis rates fell within confidence intervals of estimates of mental illness for Minnesota's Medicaid expansion population. Almost 1 in 3 enrollees had a marker of unstable housing; of this group, half had mental illness and/or distress. DISCUSSION: Findings support predictions of the high burden of mental illness and unstable housing among the Medicaid expansion population. Minnesota offers lessons to other regions working to care for such populations: (a) the use of flexible financing structures to build integrated care systems and (b) passage of legislation to allow data sharing among mental health, social services, and medical care. PMID- 26963780 TI - A breath of fresh air: A family ceremony. AB - Healing rituals and ceremonies are conducted with the hope of ushering a sick or impaired person back to wellness or preserving health against perceived threats (Burns, 1996). In medical settings, healing ceremonies can address biopsychosocial, existential, and spiritual aspects of difficult situations (Hammerschlag, 1989; Johnson, Feldman, Lubin, & Southwick, 1995; Mehl-Madrona, 1999). This article describes presents the case history of Lisa H. and her son, Anthony. Anthony experienced two medical crises within the first five days of his birth. The author suggested a healing ceremony might be valuable for Anthony's family. The ceremony opened the door to a candid conversation regarding everything that had transpired. It decreased the family's fear, anxiety, frustration, and guilt, and helped them cope better with the situation. Anthony sailed smoothly through his surgery and went home from the hospital a week later. The author notes that health care professionals generally set aside their spirituality while trying to help people, thus broaching the subject of ceremonies might make the care provider or the family feel uncomfortable. Care providers who are uncomfortable with participating could still provide a valuable service by presenting the notion of a ceremony as an option the patient or family may wish to consider, and directing them to useful resources. PMID- 26963787 TI - Looking back and looking forward. AB - As the author's tenure as President of the Board of Collaborative Family Healthcare Association (CFHA) comes to a close it's time for some reflection on CFHA's past year and where the field of integrated behavioral health care is going. In summary, CFHA is growing, maturing and broadening its partners and its reach. CFHA's accomplishments are increasing, but there is an abundance of work still to do. PMID- 26963788 TI - Structural studies of beta-turn-containing peptide catalysts for atroposelective quinazolinone bromination. AB - We describe herein a crystallographic and NMR study of the secondary structural attributes of a beta-turn-containing tetra-peptide, Boc-Dmaa-D-Pro-Acpc-Leu-NMe2, which was recently reported as a highly effective catalyst in the atroposelective bromination of 3-arylquinazolin-4(3H)-ones. Inquiries pertaining to the functional consequences of residue substitutions led to the discovery of a more selective catalyst, Boc-Dmaa-D-Pro-Acpc-Leu-OMe, the structure of which was also explored. This new lead catalyst was found to exhibit a type I'beta-turn secondary structure both in the solid state and in solution, a structure that was shown to be an accessible conformation of the previously reported catalyst, as well. PMID- 26963789 TI - Fabricating photoelectrochemical aptasensor for selectively monitoring microcystin-LR residues in fish based on visible light-responsive BiOBr nanoflakes/N-doped graphene photoelectrode. AB - The presence of microcystins in fish has been augmenting the risk of toxicity to animal and human health. Herein, a selective and sensitive method for detecting microcystin-LR (MC-LR) in fish samples by integrating the photoelectrochemical (PEC) technique and the specific recognition ability of aptamer was developed. Specifically, as an efficient PEC transducer, the BiOBr nanoflakes/N-doped graphene p-n heterojunction electrode was utilized as the aptamer immobilization platform via the pi-pi stacking interaction, which would be a biosensor enabling the convenient and exquisite PEC analysis. Subsequently, the PEC response of constructed aptasensor was specific binding to MC-LR. Other isoforms did not interfere with the detection process, and thus, it could be applied for the highly selective determination of MC-LR level. Under the optimized condition, the PEC signal versus the logarithm of the MC-LR concentration was in good linear relationship ranging from 0.1pM to 100nM with detection limit about 0.03pM. The constructed method was employed to analyze fish samples collected from the local supermarket. The overall analytical recovery of MC-LR in the fish matrices ranged from 97.8 to 101.6%, with relative standard deviation (RSD) of 2.52-5.14%, implying it would have great potential in farm product analysis. PMID- 26963790 TI - Single cell studies of mouse embryonic stem cell (mESC) differentiation by electrical impedance measurements in a microfluidic device. AB - Biological populations of cells show considerable cell-to-cell variability. Study of single cells and analysis of cell heterogeneity are considered to be critical in understanding biological processes such as stem cell differentiation and cancer development. Recent advances in lab-on-a-chip techniques have allowed single-cell capture in microfluidic channels with the possibility of precise environmental control and high throughput of experiments with minimal usage of samples and reagents. In recent years, label-free techniques such as electrical impedance spectroscopy have emerged as a non-invasive approach to studying cell properties. In this study, we have designed and fabricated a microfluidic device that combines hydrodynamic trapping of single cells in pre-defined locations with the capability of running electrical impedance measurements within the same device. We have measured mouse embryonic stem cells (mESCs) at different states during differentiation (t=0h, 24h and 48h) and quantitatively analysed the changes in electrical parameters of cells during differentiation. A marked increase in the magnitude of the cell impedance is found during cell differentiation, which can be attributed to an increase in cell size. The analysis of the measurements shows that the nucleus-to-cytoplasm ratio decreases during this process. The degree of cell heterogeneity is observed to be the highest when the cells are at the transition state (24h), compare with cells at undifferentiated (0h) and fully differentiated (48h) states. The device enables highly efficient single cell trapping and provides sensitive, label-free electrical impedance measurements of individual cells, enabling the possibility of quantitatively analysing their physical state as well as studying the associated heterogeneity of a cell population. PMID- 26963791 TI - Peptide-Conjugated Quantum Dots Act as the Target Marker for Human Pancreatic Carcinoma Cells. AB - BACKGROUND/AIMS: In the present study, we describe a novel and straightforward approach to produce a cyclic- arginine-glycine-aspartic (RGD)-peptide-conjugated quantum dot (QD) probe as an ideal target tumor biomarker. Due to its specific structure, the probe can be used for targeted imaging of pancreatic carcinoma cells. METHODS: Pancreatic carcinoma cells were routinely cultured and marked with QD-RGD probe. The QD-RGD probe on the fluorescence-labeled cancer cell was observed by fluorescence microscopy and laser confocal microscopy. Cancer cell viability was detected by MTT assay after culturing with QD-RGD probe. RESULTS: Fluorescence microscopy and laser confocal microscopy displayed that 10nmol/L QD RGD probe was able to effectively mark pancreatic carcinoma cells. In comparison with organic dyes and fluorescent proteins, the quantum dot-RGD probe had unique optical and electronic properties. CONCLUSION: QD-RGD probe has a low cytotoxicity with an excellent optical property and biocompatibility. These findings support further evaluation of QD-RGD probes for the early detection of pancreatic cancer. PMID- 26963792 TI - Mindfulness-based interventions for coping with cancer. AB - Work in the development and evaluation of mindfulness-based interventions (MBIs) for cancer care has been underway for the last 20 years, and a growing body of literature now supports their efficacy. MBIs are particularly helpful in dealing with common experiences related to cancer diagnosis, treatment, and survivorship, including loss of control, uncertainty about the future, and fears of recurrence, as well as a range of physical and psychological symptoms, including depression, anxiety, insomnia, and fatigue. Our adaptation, mindfulness-based cancer recovery (MBCR), has resulted in improvements across a range of psychological and biological outcomes, including cortisol slopes, blood pressure, and telomere length, in various groups of cancer survivors. In this paper, I review the rationale for MBIs in cancer care and provide an overview of the state of the current literature, with a focus on results from three recent clinical trials conducted by our research group. These include a comparative efficacy trial comparing MBCR to supportive-expressive therapy in distressed breast cancer survivors, a non-inferiority trial comparing MBCR to cognitive behavioral therapy for insomnia in cancer survivors with clinical insomnia, and an online adaptation of MBCR for rural and remote cancer survivors without access to in-person groups. I conclude by outlining work in progress and future directions for MBI research and applications in cancer care. PMID- 26963793 TI - Early pelvic floor muscle training after obstetrical anal sphincter injuries for the reduction of anal incontinence. AB - OBJECTIVES: Between 0.5 and 5% of vaginal deliveries involve obstetrical anal sphincter injuries (OASIS). Thirty to forty percent of patients with OASIS will suffer from anal incontinence in the subacute postpartum period. The aim of the present study was to assess the effectiveness of early pelvic floor muscle training (PFMT) combined with standard rehabilitation on anal incontinence after vaginal deliveries complicated by OASIS. STUDY DESIGN: The present work was a retrospective quantitative study performed in a tertiary-level maternity hospital. Women with 3rd or 4th degree obstetric tears were included. Women who gave birth between January 1st, 2011 and December 31st, 2012 underwent standard pelvic-perineal rehabilitation within 6-8 weeks postpartum. Women who gave birth between January 1st, 2013 and July 1st, 2014 had early rehabilitation (within 30 days after delivery) followed by the same standard rehabilitation received by the other group. Rehabilitation was performed by physiotherapists specialized in perineology. No electrostimulation was done in early rehabilitation. An in-house validated modification of the Jorge and Wexner questionnaire was sent by mail to the patients to assess symptoms. The main judgment criterion was anal incontinence to gas, loose stools and/or solid stool. RESULTS: Two hundred and thirty patients were diagnosed with OASIS. Nineteen women (8.3%) were lost to follow-up. The intention-to-treat analysis included 211 patients, 109 of whom underwent standard rehabilitation and 102 early rehabilitation plus standard rehabilitation. The two groups were comparable in terms of parity, birth weight, assisted delivery, epidural anesthesia and rates of mediolateral episiotomy. Multivariate analyses adjusted for type of perineal lesion were performed. Early rehabilitation significantly reduced gas leakage: OR 0.51 [0.29-0.90] (p=0.02), liquid stool leakage: OR 0.22 [0.08-0.58] (p=0.02) and urinary stress incontinence: OR 0.43 [0.24-0.77] (p=0.004). CONCLUSIONS: We recommend early (during the first month postpartum) PFMT after vaginal deliveries associated with OASIS. Rehabilitation should be carried out by a physiotherapist specialized in perineology in order to prevent medium-term functional consequences. A longer follow-up may be necessary to confirm the stability of results. PMID- 26963794 TI - Human papillomavirus 16 E2 interacts with neuregulin receptor degradation protein 1 affecting ErbB-3 expression in vitro and in clinical samples of cervical lesions. AB - The ErbB tyrosine kinase receptors play a key role in regulating many cellular functions and human papillomaviruses (HPVs) may interact with transductional pathway of different growth factor receptors. Here, these interactions were analysed in W12 cell line carrying HPV 16 genome and in clinical samples. W12 cells, in which HPV16 becomes integrated during passages, were utilised to detect viral and ErbB family expression at early (W12E) and late passages (W12G). Interestingly, a strong reduction of ErbB-3 expression was observed in W12G. Loss of the E2 and E5 viral genes occurs in W12G and this may affect ErbB-3 receptor expression. E2 and E5 rescue experiments demonstrated that only E2 gene was able to restore ErbB-3 expression. E2 is a transcriptional factor but the expression levels of ErbB3 were unaffected and ErbB-3 promoter did not show any consensus sequence for E2, thus E2 may interact in another way with ErbB3. Indeed, HPV 16 E2 can modulate ErbB-3 by interacting with the ubiquitin ligase neuregulin receptor degradation protein 1 (Nrdp-1) that is involved in the regulation of this receptor, via ubiquitination and degradation. E2 co-immunoprecipitated in a complex with Nrdp-1 leading to hypothesise an involvement of this interaction in ErbB-3 regulation. In addition, 90% of the clinical samples with integrated virus and E2 loss showed no or low ErbB-3 positivity, confirming in vitro results. In conclusion, the new discovered interaction of HPV-16 E2 with Nrdp-1 may affect ErbB-3 expression. PMID- 26963795 TI - Ribosomal RNA Genes in the Protozoan Parasite Leishmania major Possess a Nucleosomal Structure. AB - Little is known about nucleosome structure and epigenetic regulation of transcription of rRNA genes in early-branched eukaryotes. Here we analyze the chromatin architecture and distribution of some histone modifications in the rRNA genes in the parasitic protozoon Leishmania major. Southern blots of MNase partially-digested chromatin with DNA probes spanning the whole rRNA gene repeat showed that the intergenic spacer presents a tight nucleosomal structure, whereas the promoter region is practically devoid of nucleosomes. Intermediate levels of nucleosomes were found in the rRNA coding regions. ChIP assays allowed us to determine that H3K14ac, H3K23ac and H3K27ac, epigenetics marks that are generally associated with activation of transcription, are enriched in the promoter region. In contrast, H4K20me3, which is generally related to transcriptional silencing, was absent from the promoter region and intergenic spacer and enriched in the coding region. Interestingly, the distribution pattern for H3K9me3, generally linked to heterochromatin formation, was very similar to the distribution observed with the euchromatin marks, suggesting that this modification could be involved in transcriptional activation of rRNA genes in L. major. PMID- 26963802 TI - Treatment of atrophic facial acne scars with fractional Er:YAG laser in skin phototype III-IV: A pilot study. AB - BACKGROUND: Fractional ablative lasers have recently been used for the treatment of skin scars. The objective of this study was to assess the efficacy and safety of the fractional erbium-doped yttrium aluminum garnet (Er:YAG) laser (2940 nm) in the treatment of skin scars. MATERIALS AND METHODS: A total of 9 patients (8 female, 1 male) with Fitzpatrick skin types III and IV suffering from atrophic facial acne scars were treated with a fractional Er:YAG laser for 2-5 (mean 3.3) sessions 4-6 weeks apart. One independent investigator assessed the efficacy, using standardized photographs, before and 1 month after the last treatment. The patients' satisfaction rate was also evaluated. RESULTS: The treatment was well tolerated by all patients without any anesthesia. The downtime was 2-3 days. All patients showed improvement in scars: excellent in 1, good in 1, and fair in 7 patients. Six patients were highly satisfied and 3 were satisfied with treatment. No adverse effect was noted. CONCLUSION: A fractional Er:YAG laser can deliver an effective and minimally invasive treatment for acne scars. PMID- 26963803 TI - The beneficial and detrimental effects of major depression on intuitive decision making. AB - Intuitions play a central role in everyday life decision-making but little is known regarding this capacity during depression. Thus, in Study 1, N = 39 depressed in-patients completed two well-established tasks, assessing intuitions of visual and semantic coherence. In the semantic coherence task, patients judged whether presented words triads were coherent (e.g. SALT DEEP FOAM, related to SEA) or not (e.g. DREAM BALL BOOK, no denominator). In the visual coherence task, patients judged whether blurred pictures depicted real-life objects (coherent) or not (incoherent). Results showed that higher depressive symptomatology was associated with impaired intuitions of semantic coherence but with enhanced intuitions of visual coherence. In Study 2, visual coherence intuitions of depressed patients (n = 27) were compared to healthy control participants (n = 30). Depressed patients outperformed the healthy control subjects in the visual coherence task. This pattern of findings shows both detrimental and beneficial decisional consequences of depression. PMID- 26963805 TI - Salt Reduction Interventions in Sub-Saharan Africa: A Systematic Review. AB - BACKGROUND: Salt intake is associated with hypertension, the leading risk factor for cardiovascular disease. To promote population-level salt reduction, the World Health Organization recommends intervention around three core pillars: Reformulation of processed foods, consumer awareness, and environmental changes to increase availability and affordability of healthy food. This review investigates salt reduction interventions implemented and evaluated in sub Saharan Africa (SSA). METHODS: MEDLINE and google scholar electronic databases were searched for articles meeting inclusion criteria. Studies that reported evaluation results of a salt intervention in SSA were identified. Titles and abstracts were screened, and articles selected for full-text review. Quality of included articles was assessed, and a narrative synthesis of the findings undertaken. PROSPERO registration number CRD42015019055. RESULTS: Seven studies representing four countries-South Africa, Nigeria, Ghana, and Tanzania-were included. Two examined product reformulation, one in hypertensive patients and the other in normotensive volunteers. Four examined consumer awareness interventions, including individualised counselling and advisory health sessions delivered to whole villages. One study used an environmental approach by offering discounts on healthy food purchases. All the interventions resulted in at least one significantly improved outcome measure including reduction in systolic blood pressure (BP), 24 hour urinary sodium excretion, or mean arterial BP. CONCLUSIONS: More high quality studies on salt reduction interventions in the region are needed, particularly focused on consumer awareness and education in urban populations given the context of rapid urbanisation; and essentially, targeting product reformulation and environmental change, for greater promise for propagation across a vast, diverse continent. PMID- 26963806 TI - Continuous Glucose Monitoring in Patients Undergoing Extracorporeal Ventricular Assist Therapy. AB - BACKGROUND: Dysregulations of blood glucose (BG) are associated with adverse outcome in critical illness; controlling BG to target appears to improve outcome. Since BG-control is challenging in daily intensive care practice BG-control remains poor especially in patients with rapidly fluctuating BG. To improve BG control and to avoid deleterious hypoglycemia, automated online-measurement tools are advocated. We thus evaluated the point-accuracy of the subcutaneous Sentrino(r) Continuous Glucose Monitoring System (CGM, Medtronic Diabetes, Northridge, California) in patients undergoing extracorporeal cardiac life support (ECLS) for cardiogenic shock. METHODS: Management of BG was performed according to institute's standard aiming at BG-levels between 100-145 mg/dl. CGM values were recorded without taking measures into therapeutic account. Point accuracy in comparison to intermittent BG-measurement by the ABL-blood-gas analyzer was determined. RESULTS: CGM (n = 25 patients) correlated significantly with ABL-values (r = 0.733, p<0.001). Mean error from standard was 15.0 mg/dl (11.9%). 44.2% of the readings were outside a 15% range around ABL-values. In one of 635 paired data-points, ABL revealed hypoglycemia (BG 32 mg/dl) whereas CGM did not show hypoglycemic values (132mg/dl). CONCLUSIONS: CGM reveals minimally invasive BG-values in critically ill adults with dynamically impaired tissue perfusion. Because of potential deviations from standard, CGM-readings must be interpreted with caution in specific ICU-populations. PMID- 26963804 TI - The microbiome of the oral mucosa in irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a poorly understood disorder characterized by persistent symptoms, including visceral pain. Studies have demonstrated oral microbiome differences in inflammatory bowel diseases suggesting the potential of the oral microbiome in the study of non-oral conditions. In this exploratory study we examine whether differences exist in the oral microbiome of IBS participants and healthy controls, and whether the oral microbiome relates to symptom severity. The oral buccal mucosal microbiome of 38 participants was characterized using PhyloChip microarrays. The severity of visceral pain was assessed by orally administering a gastrointestinal test solution. Participants self-reported their induced visceral pain. Pain severity was highest in IBS participants (P = 0.0002), particularly IBS-overweight participants (P = 0.02), and was robustly correlated to the abundance of 60 OTUs, 4 genera, 5 families and 4 orders of bacteria (r2 > 0.4, P < 0.001). IBS-overweight participants showed decreased richness in the phylum Bacteroidetes (P = 0.007) and the genus Bacillus (P = 0.008). Analysis of beta-diversity found significant separation of the IBS overweight group (P < 0.05). Our oral microbial results are concordant with described fecal and colonic microbiome-IBS and -weight associations. Having IBS and being overweight, rather than IBS-subtypes, was the most important factor in describing the severity of visceral pain and variation in the microbiome. Pain severity was strongly correlated to the abundance of many taxa, suggesting the potential of the oral microbiome in diagnosis and patient phenotyping. The oral microbiome has potential as a source of microbial information in IBS. PMID- 26963807 TI - Synthesis of Hydrophilic CuInS2/ZnS Quantum Dots with Different Polymeric Shells and Study of Their Cytotoxicity and Hemocompatibility. AB - In this work, there is a detailed description of the whole process of biocompatible CIS/ZnS QDs production. Special attention was paid to the stability of QDs against photooxidation. It was shown that Cu/In ratio greatly affected not only nanocrystals PLQYs but photostability as well. CIS/ZnS QDs with Cu/In = 1:4 ratio showed high photostability under UV illumination both in toluene and aqueous solutions. Meanwhile, photoluminescence of CIS/ZnS QDs with Cu/In = 1:1 ratio was completely quenched after several hours under UV illumination, though their initial QY was as high as 40% with peak maximum at 740 nm. QDs were transferred to water by polymer encapsulation and were subsequently modified with polyethers Jeffamines, cheap analogues of PEG-derivatives. Three types of hydrophilic QDs differing in size, PEG content, and surface charge were obtained for further investigation and comparison of their cytotoxicity and hemocompatibility. It was shown that both leucocytes size distribution and coagulation activation change after introduction of polyethers into QDs polymeric shell, while red blood cells and platelets size distribution as well as hemolysis rate did not show any different results among different QDs and the polymer itself. All three types of QDs showed only slight cytotoxicity. Confocal microscopy proves penetration of hydrophilic CIS/ZnS QDs inside cells, so the low QDs cytotoxocity cannot be explained by low cellular uptake of the QDs and indicated low QDs toxicity in general. PMID- 26963808 TI - Safety and Efficacy Studies of Vertebroplasty, Kyphoplasty, and Mesh-Container Plasty for the Treatment of Vertebral Compression Fractures: Preliminary Report. AB - To evaluate the clinical safety and efficacies of percutaneous vertebroplasty (PVP), percutaneous kyphoplasty (PKP), and percutaneous mesh-container-plasty (PMCP) for the treatment of vertebral compression fractures (VCFs), a retrospective study of 90 patients with VCFs who had been treated by PVP (n = 30), PKP (n = 30), and PMCP (n = 30) was conducted. The clinical efficacies of these three treatments were evaluated by comparing their PMMA cement leakages, cement patterns, height restoration percentages, wedge angles, visual analogue scales (VAS), and oswestry disability index (ODI) at the pre- and post-operative time points. 6.67%, 3.33%, and 0% of patients had PMMA leakage in PVP, PKP, and PMCP groups, respectively. Three (solid, trabecular, and mixed patterns), two (solid and mixed patterns), and one (mixed patterns) types of cement patterns were observed in PVP, PKP, and PMCP groups, respectively. PKP and PMCP treatments had better height restoration ability than PVP treatment. PVP, PKP, and PMCP treatments had significant and similar ability in pain relief and functional recovery ability for the treatment of VCFs. These results indicate minimally invasive techniques were effective methods for the treatment of VCFs. Moreover, these initial outcomes suggest PMCP treatment may be better than both PVP treatment and PKP treatment. PMID- 26963810 TI - Correction: Immune Parameters That Distinguish Multiple Sclerosis Patients from Patients with Other Neurological Disorders at Presentation. PMID- 26963809 TI - Unique Insights in the Cervicovaginal Lactobacillus iners and L. crispatus Proteomes and Their Associations with Microbiota Dysbiosis. AB - BACKGROUND: A Lactobacillus-dominated cervicovaginal microbiota (VMB) protects women from adverse reproductive health outcomes, but the role of L. iners in the VMB is poorly understood. Our aim was to explore the association between the cervicovaginal L. iners and L. crispatus proteomes and VMB composition. METHODS: The vaginal proteomes of 50 Rwandan women at high HIV risk, grouped into four VMB groups (based on 16S rDNA microarray results), were investigated by mass spectrometry using cervicovaginal lavage (CVL) samples. Only samples with positive 16S results for L. iners and/or L. crispatus within each group were included in subsequent comparative protein analyses: Lactobacillus crispatus dominated VMB cluster (with 16S-proven L. iners (ni) = 0, and with 16S-proven L. crispatus (nc) = 5), L. iners-dominated VMB cluster (ni = 11, nc = 4), moderate dysbiosis (ni = 12, nc = 2); and severe dysbiosis (ni = 8, nc = 2). The relative abundances of proteins that were considered specific for L. iners and L. crispatus were compared among VMB groups. RESULTS: Forty Lactobacillus proteins were identified of which 7 were specific for L. iners and 11 for L. crispatus. The relative abundances of L. iners DNA starvation/stationary phase protection protein (DPS), and the glycolysis enzymes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glucose-6-phosphate isomerase (GPI), were significantly decreased in women with L. iners-containing dysbiosis compared to women with a L. iners-dominated VMB, independent of vaginal pH and L. iners abundance. Furthermore, L. iners DPS, GAPDH, GPI, and fructose-bisphosphate aldolase (ALDO) were significantly negatively associated with vaginal pH. Glycolysis enzymes of L. crispatus showed a similar negative, but nonsignificant, trend related to dysbiosis. CONCLUSIONS: Most identified Lactobacillus proteins had conserved intracellular functions, but their high abundance in CVL supernatant might imply an additional extracellular (moonlighting) role. Our findings suggest that these proteins can be important in maintaining a Lactobacillus-dominated VMB. Functional studies are needed to investigate their roles in vaginal bacterial communities and whether they can be used to prevent vaginal dysbiosis. PMID- 26963811 TI - Development of a Microemulsion Formulation for Antimicrobial SecA Inhibitors. AB - In our previous study, we have identified five antimicrobial small molecules via structure based design, which inhibit SecA of Candidatus Liberibacter asiaticus (Las). SecA is a critical protein translocase ATPase subunit and is involved in pre-protein translocation across and integration into the cellular membrane in bacteria. In this study, eleven compounds were identified using similarity search method based on the five lead SecA inhibitors identified previously. The identified SecA inhibitors have poor aqueous solubility. Thus a microemulsion master mix (MMX) was developed to address the solubility issue and for application of the antimicrobials. MMX consists of N-methyl-2-pyrrolidone and dimethyl sulfoxide as solvent and co-solvent, as well as polyoxyethylated castor oil, polyalkylene glycol, and polyoxyethylene tridecyl ether phosphate as surfactants. MMX has significantly improved the solubility of SecA inhibitors and has no or little phytotoxic effects at concentrations less than 5.0% (v/v). The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the SecA inhibitors and streptomycin against eight bacteria including Agrobacterium tumefaciens, Liberibacter crescens, Rhizobium etli, Bradyrhizobium japonicum, Mesorhizobium loti, and Sinorhizobium meliloti phylogenetically related to Las were determined using the broth microdilution method. MIC and MBC results showed that the 16 SecA inhibitors have antibacterial activities comparable to that of streptomycin. Overall, we have identified 11 potent SecA inhibitors using similarity search method. We have developed a microemulsion formulation for SecA inhibitors which improved the antimicrobial activities of SecA inhibitors. PMID- 26963813 TI - Fast Mode Decision in the HEVC Video Coding Standard by Exploiting Region with Dominated Motion and Saliency Features. AB - The emerging High Efficiency Video Coding (HEVC) standard introduces a number of innovative and powerful coding tools to acquire better compression efficiency compared to its predecessor H.264. The encoding time complexities have also increased multiple times that is not suitable for realtime video coding applications. To address this limitation, this paper employs a novel coding strategy to reduce the time complexity in HEVC encoder by efficient selection of appropriate block-partitioning modes based on human visual features (HVF). The HVF in the proposed technique comprise with human visual attention modelling based saliency feature and phase correlation-based motion features. The features are innovatively combined through a fusion process by developing a content-based adaptive weighted cost function to determine the region with dominated motion/saliency (RDMS)- based binary pattern for the current block. The generated binary pattern is then compared with a codebook of predefined binary pattern templates aligned to the HEVC recommended block-paritioning to estimate a subset of inter-prediction modes. Without exhaustive exploration of all modes available in the HEVC standard, only the selected subset of modes are motion estimated and motion compensated for a particular coding unit. The experimental evaluation reveals that the proposed technique notably down-scales the average computational time of the latest HEVC reference encoder by 34% while providing similar rate distortion (RD) performance for a wide range of video sequences. PMID- 26963812 TI - Characterization of Small RNAs Derived from tRNAs, rRNAs and snoRNAs and Their Response to Heat Stress in Wheat Seedlings. AB - Small RNAs (sRNAs) derived from non-coding RNAs (ncRNAs), such as tRNAs, rRNAs and snoRNAs, have been identified in various organisms. Several observations have indicated that cleavage of tRNAs and rRNAs is induced by various stresses. To clarify whether sRNAs in wheat derived from tRNAs (stRNAs), rRNAs (srRNAs) and snoRNAs (sdRNAs) are produced specifically in association with heat stress responses, we carried out a bioinformatic analysis of sRNA libraries from wheat seedlings and performed comparisons between control and high-temperature-treated samples to measure the differential abundance of stRNAs, srRNAs and sdRNAs. We found that the production of sRNAs from tRNAs, 5.8S rRNAs, and 28S rRNAs was more specific than that from 5S rRNAs and 18S rRNAs, and more than 95% of the stRNAs were processed asymmetrically from the 3' or 5' ends of mature tRNAs. We identified 333 stRNAs and 8,822 srRNAs that were responsive to heat stress. Moreover, the expression of stRNAs derived from tRNA-Val-CAC, tRNA-Thr-UGU, tRNA Tyr-GUA and tRNA-Ser-UGA was not only up-regulated under heat stress but also induced by osmotic stress, suggesting that the increased cleavage of tRNAs might be a mechanism that developed in wheat seedlings to help them cope with adverse environmental conditions. PMID- 26963814 TI - Factors that Affect Pancreatic Islet Cell Autophagy in Adult Rats: Evaluation of a Calorie-Restricted Diet and a High-Fat Diet. AB - Aging may be a risk factor for type 2 diabetes in the elderly. Dietary intervention can affect glucose tolerance in adults, which may be due to body composition and islet cell autophagy. The aim of this study was to determine the effects of various dietary interventions on islet cell autophagy. Pancreatic tissue and blood samples were collected from Sprague Dawley rats (14-16 months old, n = 15 for each group) that received a normal diet (ND), a high-fat diet (HFD), or a calorie-restricted diet (CRD). The body weight (BW), visceral fat, serum lipid levels, fasting serum glucose, insulin levels, and beta/alpha cell area were determined in 14-16-(0-w), 16-18-(8-w), and 18-20(16-w)-month-old rats. Pancreatic islet autophagy (LC3B and LAMP2), AP (Acid Phosphatase) and apoptosis (apoptosis index, AI (TUNEL assay) and cleaved caspase-3) were detected using immunohistochemistry, ELISA and western blot. At 16 weeks, the expressions of LC3B, LAMP2 and AP markedly increased in both the HFD (P<0.01) and CRD (P<0.05) groups; however, an increase in the AI (P<0.05), cleaved caspase-3 and Beclin1 expression and a decrease in the expressions of BCL2 and BCLXL (P<0.05) were observed in only the HFD group. FFA, triglyceride levels, HOMA-IR, insulin levels and glucagon levels were significantly increased in the HFD group but decreased in the CRD group at 16 weeks (P<0.05). The degree of islet cell autophagy was potentially regulated by the levels of FFA and islet cell insulin and glucagon, which may have been due to the effects of Beclin1/BCL2. PMID- 26963815 TI - Characterization of Natural and Simulated Herbivory on Wild Soybean (Glycine soja Seib. et Zucc.) for Use in Ecological Risk Assessment of Insect Protected Soybean. AB - Insect-protected soybean (Glycine max (L.) Merr.) was developed to protect against foliage feeding by certain Lepidopteran insects. The assessment of potential consequences of transgene introgression from soybean to wild soybean (Glycine soja Seib. et Zucc.) is required as one aspect of the environmental risk assessment (ERA) in Japan. A potential hazard of insect-protected soybean may be hypothesized as transfer of a trait by gene flow to wild soybean and subsequent reduction in foliage feeding by Lepidopteran insects that result in increased weediness of wild soybean in Japan. To assess this potential hazard two studies were conducted. A three-year survey of wild soybean populations in Japan was conducted to establish basic information on foliage damage caused by different herbivores. When assessed across all populations and years within each prefecture, the total foliage from different herbivores was <= 30%, with the lowest levels of defoliation (< 2%) caused by Lepidopteran insects. A separate experiment using five levels of simulated defoliation (0%, 10%, 25%, 50% and 100%) was conducted to assess the impact on pod and seed production and time to maturity of wild soybean. The results indicated that there was no decrease in wild soybean plants pod or seed number or time to maturity at defoliation rates up to 50%. The results from these experiments indicate that wild soybean is not limited by lepidopteran feeding and has an ability to compensate for defoliation levels observed in nature. Therefore, the potential hazard to wild soybean from the importation of insect-protected soybean for food and feed into Japan is negligible. PMID- 26963817 TI - Vein of Galen Malformation and High-output Cardiac Failure. PMID- 26963816 TI - Clinical Assessment of Lamina Cribrosa Curvature in Eyes with Primary Open-Angle Glaucoma. AB - PURPOSE: Quantitative evaluation of lamina cribrosa (LC) posterior bowing in primary open-angle glaucoma (POAG) eyes using swept-source optical coherence tomography. METHODS: Patients with POAG (n = 123 eyes) and healthy individuals of a similar age (n = 92 eyes) were prospectively recruited. Anterior laminar insertion depth (ALID) was defined as the vertical distance between the anterior laminar insertion and a reference plane connecting the Bruch's membrane openings (BMO). The mean LC depth (mLCD) was approximated by dividing the area enclosed by the anterior LC, the BMO reference plane, and the two vertical lines for ALID measurement by the length between those two vertical lines. The LC curvature index was defined as the difference between the mLCD and the ALID. The factors influencing the LC curvature index were evaluated. RESULTS: The ALID and mLCD were significantly larger in POAG eyes than in healthy controls (P < 0.05). The LC curvature index was significantly larger in POAG eyes than in healthy controls on both the horizontal (85.8 +/- 34.1 vs. 68.2 +/- 32.3 MUm) and vertical meridians (49.8 +/- 38.5 vs. 32.2 +/- 31.1 MUm, all P < 0.001). Multivariate regression showed significant associations of greater disc area (P < 0.001), vertical C/D ratio (P < 0.001) and mLCD (P < 0.001), smaller rim area (P = 0.001), thinner average RNFLT (P < 0.001), and myopic refraction (P = 0.049) with increased LC curvature index. There was no difference in the LC curvature index between mild (MD > -6 dB) and moderate-to-advanced glaucoma (MD < -6 dB, P = 0.95). CONCLUSIONS: LC posterior bowing was increased in POAG eyes, and was significantly associated with structural optic nerve head (ONH) changes but not with functional glaucoma severity. Quantitative evaluation of LC curvature can facilitate assessment of glaucomatous ONH change. PMID- 26963818 TI - NK Cells Respond to Haptens by the Activation of Calcium Permeable Plasma Membrane Channels. AB - Natural Killer (NK) cells mediate innate immunity to infected and transformed cells. Yet, NK cells can also mount hapten-specific recall responses thereby contributing to contact hypersensitivity (CHS). However, since NK cells lack antigen receptors that are used by the adaptive immune system to recognize haptens, it is not clear if NK cells respond directly to haptens and, if so, what mediates these responses. Here we show that among four haptens the two that are known to induce NK cell-dependent CHS trigger the rapid influx of extracellular Ca2+ into NK cells and lymphocyte cell lines. Thus lymphocytes can respond to haptens independent of antigen presentation and antigen receptors. We identify the Ca2+-permeable cation channel TRPC3 as a component of the lymphocyte response to one of these haptens. These data suggest that the response to the second hapten is based on a distinct mechanism, consistent with the capacity of NK cells to discriminate haptens. These findings raise the possibility that antigen receptor independent activation of immune cells contributes to CHS. PMID- 26963819 TI - Preclinical Evidence for the Efficacy of Ischemic Postconditioning against Renal Ischemia-Reperfusion Injury, a Systematic Review and Meta-Analysis. AB - BACKGROUND: Renal ischemia-reperfusion injury (IRI) is a major cause of kidney damage after e.g. renal surgery and transplantation. Ischemic postconditioning (IPoC) is a promising treatment strategy for renal IRI, but early clinical trials have not yet replicated the promising results found in animal studies. METHOD: We present a systematic review, quality assessment and meta-analysis of the preclinical evidence for renal IPoC, and identify factors which modify its efficacy. RESULTS: We identified 39 publications studying >250 control animals undergoing renal IRI only and >290 animals undergoing renal IRI and IPoC. Healthy, male rats undergoing warm ischemia were used in the vast majority of studies. Four studies applied remote IPoC, all others used local IPoC. Meta analysis showed that both local and remote IPoC ameliorated renal damage after IRI for the outcome measures serum creatinine, blood urea nitrogen and renal histology. Subgroup analysis indicated that IPoC efficacy increased with the duration of index ischemia. Measures to reduce bias were insufficiently reported. CONCLUSION: High efficacy of IPoC is observed in animal models, but factors pertaining to the internal and external validity of these studies may hamper the translation of IPoC to the clinical setting. The external validity of future animal studies should be increased by including females, comorbid animals, and transplantation models, in order to better inform clinical trial design. The severity of renal damage should be taken into account in the design and analysis of future clinical trials. PMID- 26963821 TI - Q and Soret Band Photoexcitation of Isolated Palladium Porphyrin Tetraanions Leads to Delayed Emission of Nonthermal Electrons over Microsecond Time Scales. AB - We have used both action and photoelectron spectroscopy to study the response of isolated Pd(II) meso-tetra(4-sulfonatophenyl)porphyrin tetraanions ([PdTPPS](4-)) to electronic excitation over the 2.22-2.98 eV photon energy range. The action spectrum obtained by recording the wavelength-dependent intensity of charged decay products closely resembles the absorption spectrum of PdTPPS in aqueous solution (which shows pronounced Q and Soret absorption bands). The two main decay channels observed are sulfonate group loss and, predominantly, electron emission. To better understand the electron emission channel, we have also acquired photoelectron spectra at multiple detachment photon energies covering the range probed in action spectroscopy. Upon both Q and Soret band excitation, we find that electrons are emitted in three characteristic kinetic energy ranges. The corresponding detachment processes are identified as (delayed) tunneling emission from both excited singlet and triplet states (each of which is accessed by/after one-photon absorption) as well as resonant two-photon detachment. The first triplet state lifetime of isolated [PdTPPS](4-) is significantly longer than 10 MUs, possibly on the 100 MUs time scale. We estimate that more than 50% of the electron emission observed upon photoexcitation occurs by way of this triplet state. PMID- 26963820 TI - Hospital care for mental health and substance abuse in children with epilepsy. AB - BACKGROUND: Reducing the burden of pediatric mental illness requires greater knowledge of mental health and substance abuse (MHSA) outcomes in children who are at an increased risk of primary psychiatric illness. National data on hospital care for psychiatric illness in children with epilepsy are limited. METHODS: We used the Kids' Inpatient Database (KID), the Healthcare Cost and Utilization Project (HCUP), and the Agency for Healthcare Research and Quality from 2003 to 2009 to examine MHSA hospitalization patterns in children with comorbid epilepsy. Nonparametric and regression analyses determined the association of comorbid epilepsy with specific MHSA diagnoses and examined the impact of epilepsy on length of stay (LOS) for such MHSA diagnoses while controlling for demographic, payer, and hospital characteristics. RESULTS: We observed 353,319 weighted MHSA hospitalizations of children ages 6-20; 3280 of these involved a child with epilepsy. Depression was the most common MHSA diagnosis in the general population (39.5%) whereas bipolar disorder was the most common MHSA diagnosis among children with epilepsy (36.2%). Multivariate logistic regression models revealed that children with comorbid epilepsy had greater adjusted odds of bipolar disorder (AOR: 1.17, 1.04-1.30), psychosis (AOR: 1.78, 1.51-2.09), sleep disorder (AOR: 5.90, 1.90-18.34), and suicide attempt/ideation (AOR: 3.20, 1.46-6.99) compared to the general MHSA inpatient population. Epilepsy was associated with a greater LOS and a higher adjusted incidence rate ratio (IRR) for prolonged LOS (IRR: 1.12, 1.09-1.17), particularly for suicide attempt/ideation (IRR: 3.74, 1.68-8.34). CONCLUSIONS: Children with epilepsy have distinct patterns of hospital care for mental illness and substance abuse and experience prolonged hospitalization for MHSA conditions. Strategies to reduce psychiatric hospitalizations in this population may require disease-specific approaches and should measure disease-relevant outcomes. Hospitals caring for large numbers of children with neurological disease (such as academic centers) may have inaccurate measurements of mental health-care quality unless the impact of key comorbid conditions such as epilepsy is considered. PMID- 26963822 TI - The Moderation of Blood Alcohol Levels on Higher Odds of Survival among American Indians with Violent, Blunt-Force Traumatic Brain Injuries. AB - This study assessed the moderation of blood alcohol level (BAL) and American Indian race on survival of patients with violent traumatic brain injury (TBI). An initial logistic regression model indicated that those who were American Indian and insured had higher odds of survival and those with higher injury severity scores and low-medium BAL were less likely to survive. A second logistic regression model including a relationship between American Indians and BAL found that American Indians had a higher odds of survival which tripled when they have no BAL. Low-medium and high BAL were associated with less likelihood of survival among White patients. PMID- 26963823 TI - Correction: Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study. PMID- 26963824 TI - Electrotactile Feedback for Handheld Devices with Touch Screen and Simulation of Roughness. AB - We present a novel electrotactile display that can be integrated into current handheld devices with touch screens. In this display, tactile information is presented to the fingertip of the user by transmitting small currents through electrodes. Experiments were conducted to investigate the perception of simulated textures using this electrotactile display technique. One fundamental feature of texture, which is the focus of this study, is roughness. The aim of the first experiment was to investigate the relationship between electrotactile stimulation parameters such as current and pulse frequency and the perception of roughness. An increase in the current magnitude resulted in an increase in perceived roughness. The aim of the second experiment was to investigate parameter combinations of electrotactile stimuli can be used to simulate textures. Subjects adjusted the intensity and frequency of the current stimuli until the simulated textures were perceived as being equal to reference textures such as sandpapers of varying grit numbers and grooved woods with varying groove widths. Subjects tended to find an electrotactile stimulus with a high current magnitude and a low pulse frequency more suitable to represent rough surfaces. They tended to find just-perceptible current magnitudes suitable for very smooth surfaces and did not show a preference for any frequency. PMID- 26963825 TI - Vibrotactile Rendering for a Traveling Vibrotactile Wave Based on a Haptic Processor. AB - Mobile device users can now experience diverse graphical content ranging from a simple static object to an object having complex dynamic behavior. A user who manipulates and plays with such "objects" wants to haptically "feel" the presence of a static object or the motion of a dynamic object. To satisfy this demand, we previously proposed a vibrotactile rendering method based on a vibrotactile traveling wave. Although the proposed method can haptically simulate the dynamic behavior of a target object, it is not easy to delicately generate the traveling vibrotactile wave. The reason is that the sampling rate of the haptic loop in the system determines the performance of the traveling vibrotactile wave. In this study, we develop a haptic processor that can control multiple motors, and furthermore we discuss how we could create traveling vibrotactile waves in mobile devices. PMID- 26963826 TI - Smooth Vibrotactile Flow Generation Using Two Piezoelectric Actuators. AB - This paper proposes a method for generating a smooth directional vibrotactile flow on a thin plate. While actuating two piezoelectric actuators spatially across the plate, temporal sweeping of the input excitation frequency from zero to the first mode of the resonance frequency can smooth the perceived directional vibrotactile flow, as compared to a vibrotactile flow generated by conventional apparent tactile movement and phantom sensation methods. In order to ascertain important factors in the excitation pattern, a user study was conducted for three factors (amplitude (constant versus modulated), frequency (constant versus swept), and ending shape (sharp versus smooth)). The results showed that frequency sweeping in addition to amplitude modulation and smooth ending were the most important factors in smoothing vibrotactile flows. Moreover, an excitation signal with a smooth ending shape was important for generating nonspiky flows at the midpoint. In this study, a vibration isolation design is also proposed in order to substantially decrease the transmission of the actuator vibration to the mockup housing. As such, it is expected that the proposed vibrotactile flow generation method and vibration isolation design may be useful in applications including generating directional information in navigation maps or for identifying callers in mobile devices. PMID- 26963827 TI - Mobile Navigation Using Haptic, Audio, and Visual Direction Cues with a Handheld Test Platform. AB - This paper reports on a series of user experiments evaluating the design of a multimodal test platform capable of rendering visual, audio, vibrotactile, and directional skin-stretch stimuli. The test platform is a handheld, wirelessly controlled device that will facilitate experiments with mobile users in realistic environments. Stimuli rendered by the device are fully characterized, and have little variance in stimulus onset timing. A series of user experiments utilizing navigational cues validates the function of the device and investigates the user response to all stimulus modes. Results show users are capable of interpreting all stimuli with high accuracy and can use the direction cues for mobile navigation. Tests included both stationary (seated) and mobile (walking a simple obstacle course) tasks. Accuracy and response time patterns are similar in both seated and mobile conditions. This device provides a means of designing and evaluating multimodal communication methods for handheld devices and will facilitate experiments investigating the effects of stimulus mode on device usability and situation awareness. PMID- 26963828 TI - Negative Feedback for Small Capacitive Touchscreen Interfaces: A Usability Study for Data Entry Tasks. AB - Touchscreen technology has become pervasive in the consumer product arena over the last decade, offering some distinct advantages such as software reconfigurable interfaces and the removal of space consuming mice and keyboards. However, there are significant drawbacks to these devices that have limited their adoption by some users. Most notably, standard touchscreens demand the user's visual attention and require them to look at the input device to avoid pressing the wrong button. This issue is particularly important for mobile, capacitive sensing, nonstylus devices, such as the iPhone where small button sizes can generate high error rates. While previous work has shown the benefits of augmenting such interfaces with audio or vibrotactile feedback, only positive feedback (confirmation of button presses) has been considered. In this paper, we present a simple prototype interface that provides negative vibrotactile feedback. By negative, we mean feedback is generated when an inactive or ambiguous part of the screen, such as the area between two buttons, is touched. First, we present a usability study comparing positive and negative vibrotactile feedback for a benchmark numerical data entry task. The difference in performance is not statistically significant, implying negative feedback provides comparable benefits. Next, based on the experimenter's observations and the users comments, we introduce a multimodal feedback strategy-combining complementary positive audio and negative vibrotactile signals. User tests on a text entry experiment show that, with multimodal feedback, users exhibit a (statistically significant) 24 percent reduction in corrective key presses, as compared to positive audio feedback alone. Exit survey comments indicate that users favor multimodal feedback. PMID- 26963829 TI - Dynamic Physical Constraints: Emulating Hard Surfaces with High Realism. AB - In this paper, we present a novel haptic technique for emulating hard surfaces with high realism; such a technique has significant potential utility in certain orthopedic surgery applications such as joint replacement surgery where the goal is to prevent incursions beyond a virtual surface during bone cutting operations. The Dynamic Physical Constraint (DPC) concept uses a unidirectional physical constraint that is actively positioned to limit movement between two manipulator links; the concept is applicable to providing virtual constraints in both 2D and 3D workspaces. Simulation results demonstrate the potential feasibility of the concept, and a prototype device was built for testing. The DPC device provides a convincing sensation of a real, hard virtual surface which can be smoothly tracked when the end effector is in contact with the surface. Incursion across the surface with the prototype was well submillimetric and within the accuracy constraints required for joint replacement applications. PMID- 26963830 TI - Influence of Local Properties on the Perception of Global Object Orientation. AB - In previous studies, the effect on perception of individual features such as curvature and edges have been studied with specifically designed stimuli. However, the effect of local properties on the perception of the global object has so far received little attention. In this study, cylinders with an elliptical cross section and rectangular blocks were used to investigate the effect and relative importance of curvature, change in curvature and edges, as local properties, on the ability of subjects to determine the orientation of the stimuli, which is a global property. We found that when curvature was present the threshold to determine the orientation was 43 percent lower than when curvature was absent. When, in addition, the change in curvature could be felt, the threshold was 37 percent lower than when only curvature could be felt. Finally, when edges were felt during exploration, the threshold increased by 46 percent compared to when the subjects were instructed to avoid the edges in the blocks. We conclude that the perception of curvature and change in curvature improve the performance of humans in perception of the whole shape, whereas edges, when not directly contributing to the task, disrupt performance. PMID- 26963831 TI - Perceptually Augmented Simulator Design. AB - Training simulators have proven their worth in a variety of fields, from piloting to air-traffic control to nuclear power station monitoring. Designing surgical simulators, however, poses the challenge of creating trainers that effectively instill not only high-level understanding of the steps to be taken in a given situation, but also the low-level "muscle-memory" needed to perform delicate surgical procedures. It is often impossible to build an ideal simulator that perfectly mimics the haptic experience of a surgical procedure, but by focussing on the aspects of the experience that are perceptually salient we can build simulators that effectively instill learning. We propose a general method for the design of surgical simulators that augment the perceptually salient aspects of an interaction. Using this method, we can increase skill-transfer rates without requiring expensive improvements in the capability of the rendering hardware or the computational complexity of the simulation. In this paper, we present our decomposition-based method for surgical simulator design, and describe a user study comparing the training effectiveness of a haptic-search-task simulator designed using our method versus an unaugmented simulator. The results show that perception-based task decomposition can be used to improve the design of surgical simulators that effectively impart skill by targeting perceptually significant aspects of the interaction. PMID- 26963832 TI - Rendering Virtual Tumors in Real Tissue Mock-Ups Using Haptic Augmented Reality. AB - Haptic augmented reality (AR) is an emerging research area, which targets the modulation of haptic properties of real objects by means of virtual feedback. In our research, we explore the feasibility of using this technology for medical training systems. As a possible demonstration example, we currently examine the use of augmentation in the context of breast tumor palpation. The key idea in our prototype system is to augment the real feedback of a silicone breast mock-up with simulated forces stemming from virtual tumors. In this paper, we introduce and evaluate the underlying algorithm to provide these force augmentations. This includes a method for the identification of the contact dynamics model via measurements on real sample objects. The performance of our augmentation is examined quantitatively as well as in a user study. Initial results show that the haptic feedback of indenting a real silicone tumor with a rod can be approximated reasonably well with our algorithm. The advantage of such an augmentation approach over physical training models is the ability to create a nearly infinite variety of palpable findings. PMID- 26963833 TI - Virtual Active Touch: Perception of Virtual Gratings Wavelength through Pointing Stick Interface. AB - Tactile feedback enhances the usability and enjoyment of human-computer interfaces. Many feedback techniques have been devised to present tactile stimuli corresponding to a user's hand movements taking account of the concept of active touch. However, hand movements may not necessarily be required for achieving natural tactile feedback. Here, we propose a virtual-active-touch method that achieves haptic perception without actual/direct hand movements. In this method, a cursor manipulated by a force-input device is regarded as a virtual finger of the operator on the screen. Tactile feedback is provided to the operator in accordance with cursor movements. To validate the translation of virtual roughness gratings, we compare the virtual-active-touch interface with an interface that involves actual hand movements. By using the appropriate force-to velocity gain for the pointing-stick interface, we show that the virtual-active touch method presents the surface wavelengths of the gratings, which is a fundamental property for texture roughness, and that the gain significantly influences the textures experienced by the operators. Furthermore, we find that the perceived wavelengths of objects scaled and viewed on a small screen are skewed. We conclude that although some unique problems remain to be solved, we may be able to perceive the surface wavelengths solely with the intentions of active touch through virtual-active-touch interfaces. PMID- 26963834 TI - Synthesis of Carbazoles and Carbazole-Containing Heterocycles via Rhodium Catalyzed Tandem Carbonylative Benzannulations. AB - Polycyclic aromatic compounds are important constituents of pharmaceuticals and other materials. We have developed a series of Rh-catalyzed tandem carbonylative benzannulations for the synthesis of tri-, tetra-, and pentacyclic heterocycles from different types of aryl propargylic alcohols. These tandem reactions provide efficient access to highly substituted carbazoles, furocarbazoles, pyrrolocarbazoles, thiophenocarbazoles, and indolocarbazoles. While tricyclic heterocycles could be derived from vinyl aryl propargylic alcohols, tetra- and pentacyclic heterocycles were synthesized from diaryl propargylic alcohols. The tandem carbonylative benzannulation is initiated by a pi-acidic rhodium(I) catalyst-mediated nucleophilic addition to alkyne to generate a key metal-carbene intermediate, which is then trapped by carbon monoxide to form a ketene species for 6pi electrocyclization. Overall, three bonds and two rings are formed in all of these tandem carbonylative benzannulation reactions. PMID- 26963835 TI - Inflammatory and endothelial markers during the menstrual cycle. AB - BACKGROUND: The menstrual cycle exhibits a pattern of repeated inflammatory activity. The present study aims to evaluate inflammatory and endothelial markers during the two phases of a menstrual cycle. METHODS: The study cohort consisted of 102 women with regular menstrual cycles. Inflammatory and endothelial markers (interleukin-6 [IL-6], pentraxin-3 [PTX-3], hs-C reactive protein [hs-CRP], sE selectin, sP-selectin, intracellular and vascular cell adhesion molecules [ICAM-1 and VCAM-1] and cathepsins L, B and S) were measured during the early follicular and the late luteal phase of a normal menstrual cycle. RESULTS: Pentraxin-3 (PTX 3) and hs-CRP were significantly higher during the follicular phase compared to the luteal phase (p < 0.001 respectively p = 0.025). The other inflammatory and endothelial markers, with the exception of cathepsin B, were higher, albeit not significantly, during the follicular phase. CONCLUSIONS: Inflammatory activity, expressed mainly by members of the pentraxin family, is higher during the early follicular compared to the luteal phase. This could be associated to menstruation but the exact mechanisms behind this pattern are unclear and might involve the ovarian hormones or an effect on hepatocytes. PMID- 26963836 TI - Bronsted-Lowry Acid Strength of Metal Hydride and Dihydrogen Complexes. AB - Transition metal hydride complexes are usually amphoteric, not only acting as hydride donors, but also as Bronsted-Lowry acids. A simple additive ligand acidity constant equation (LAC for short) allows the estimation of the acid dissociation constant Ka(LAC) of diamagnetic transition metal hydride and dihydrogen complexes. It is remarkably successful in systematizing diverse reports of over 450 reactions of acids with metal complexes and bases with metal hydrides and dihydrogen complexes, including catalytic cycles where these reactions are proposed or observed. There are links between pKa(LAC) and pKa(THF), pKa(DCM), pKa(MeCN) for neutral and cationic acids. For the groups from chromium to nickel, tables are provided that order the acidity of metal hydride and dihydrogen complexes from most acidic (pKa(LAC) -18) to least acidic (pKa(LAC) 50). Figures are constructed showing metal acids above the solvent pKa scales and organic acids below to summarize a large amount of information. Acid base features are analyzed for catalysts from chromium to gold for ionic hydrogenations, bifunctional catalysts for hydrogen oxidation and evolution electrocatalysis, H/D exchange, olefin hydrogenation and isomerization, hydrogenation of ketones, aldehydes, imines, and carbon dioxide, hydrogenases and their model complexes, and palladium catalysts with hydride intermediates. PMID- 26963839 TI - Correction: Effect of Voluntary Ethanol Consumption Combined with Testosterone Treatment on Cardiovascular Function in Rats: Influence of Exercise Training. PMID- 26963838 TI - Reduced Biaxial Contractility in the Descending Thoracic Aorta of Fibulin-5 Deficient Mice. AB - The precise role of smooth muscle cell contractility in elastic arteries remains unclear, but accumulating evidence suggests that smooth muscle dysfunction plays an important role in the development of thoracic aortic aneurysms and dissections (TAADs). Given the increasing availability of mouse models of these conditions, there is a special opportunity to study roles of contractility ex vivo in intact vessels subjected to different mechanical loads. In parallel, of course, there is a similar need to study smooth muscle contractility in models that do not predispose to TAADs, particularly in cases where disease might be expected. Multiple mouse models having compromised glycoproteins that normally associate with elastin to form medial elastic fibers present with TAADs, yet those with fibulin-5 deficiency do not. In this paper, we show that deletion of the fibulin 5 gene results in a significantly diminished contractility of the thoracic aorta in response to potassium loading despite otherwise preserved characteristic active behaviors, including axial force generation and rates of contraction and relaxation. Interestingly, this diminished response manifests around an altered passive state that is defined primarily by a reduced in vivo axial stretch. Given this significant coupling between passive and active properties, a lack of significant changes in passive material stiffness may help to offset the diminished contractility and thereby protect the wall from detrimental mechanosensing and its sequelae. PMID- 26963837 TI - Development of purification processes for fully human bispecific antibodies based upon modification of protein A binding avidity. AB - There is strong interest in the design of bispecific monoclonal antibodies (bsAbs) that can simultaneously bind 2 distinct targets or epitopes to achieve novel mechanisms of action and efficacy. Multiple bispecific formats have been proposed and are currently under development. Regeneron's bispecific technology is based upon a standard fully human IgG antibody in order to minimize immunogenicity and improve the pharmacokinetic profile. A single common light chain and 2 distinct heavy chains combine to form the bispecific molecule. One of the heavy chains contains a chimeric Fc sequence form (called Fc*) that ablates binding to Protein A via the constant region. As a result of co-expression of the 2 heavy chains and the common light chain, 3 products are created, 2 of which are homodimeric for the heavy chains and one that is the desired heterodimeric bispecific product. The Fc* sequence allows selective purification of the FcFc* bispecific product on commercially available affinity columns, due to intermediate binding affinity for Protein A compared to the high avidity FcFc heavy chain homodimer, or the weakly binding Fc*Fc* homodimer. This platform requires the use of Protein A chromatography in both a capture and polishing modality. Several challenges, including variable region Protein A binding, resin selection, selective elution optimization, and impacts upon subsequent non affinity downstream unit operations, were addressed to create a robust and selective manufacturing process. PMID- 26963840 TI - Expression of ODC Antizyme Inhibitor 2 (AZIN2) in Human Secretory Cells and Tissues. AB - Ornithine decarboxylase (ODC) antizyme inhibitor 2 (AZIN2), originally called ODCp, is a regulator of polyamine synthesis that we originally identified and cloned. High expression of ODCp mRNA was found in brain and testis. We reported that AZIN2 is involved in regulation of cellular vesicle transport and / or secretion, but the ultimate physiological role(s) of AZIN2 is still poorly understood. In this study we used a peptide antibody (K3) to human AZIN2 and by immunohistochemistry mapped its expression in various normal tissues. We found high expression in the nervous system, in type 2 pneumocytes in the lung, in megakaryocytes, in gastric parietal cells co-localized with H,K-ATPase beta subunit, in selected enteroendocrine cells, in acinar cells of sweat glands, in podocytes, in macula densa cells and epithelium of collecting ducts in the kidney. The high expression of AZIN2 in various cells with secretory or vesicle transport activity indicates that the polyamine metabolism regulated by AZIN2 is more significantly involved in these events than previously appreciated. PMID- 26963841 TI - Varicella-Zoster Virus in Perth, Western Australia: Seasonality and Reactivation. AB - BACKGROUND: Identification of the factors affecting reactivation of varicella zoster virus (VZV) largely remains an open question. Exposure to solar ultra violet (UV) radiation is speculated to facilitate reactivation. Should the role of UV in reactivation be significant, VZV reactivation patterns would generally be expected to be synchronous with seasonal UV profiles in temperate climates. METHODS: We analysed age and gender specific VZV notification time series data from Perth, Western Australia (WA). This city has more daily sunshine hours than any other major Australian city. Using the cosinor and generalized linear models, we tested these data for seasonality and correlation with UV and temperature. RESULTS: We established significant seasonality of varicella notifications and showed that while herpes-zoster (HZ) was not seasonal it had a more stable seasonal component in males over 60 than in any other subpopulation tested. We also detected significant association between HZ notifications and UV for the entire Perth population as well as for females and males separately. In most cases, temperature proved to be a significant factor as well. CONCLUSIONS: Our findings suggest that UV radiation may be important for VZV reactivation, under the assumption that notification data represent an acceptably accurate qualitative measure of true VZV incidence. PMID- 26963842 TI - The effect of brexpiprazole (OPC-34712) and aripiprazole in adult patients with acute schizophrenia: results from a randomized, exploratory study. AB - The aim of this study was to explore the effects of brexpiprazole and aripiprazole on efficacy, cognitive functioning, and safety in patients with acute schizophrenia. Patients who would benefit from hospitalization/continued hospitalization for acute relapse of schizophrenia were enrolled and randomized (2 : 1) to target doses of open-label brexpiprazole 3 mg/day or aripiprazole 15 mg/day for 6 weeks. Outcomes included change from baseline to week 6 in the Positive and Negative Syndrome Scale total score, Barratt Impulsiveness Scale 11 item score, and Cogstate computerized cognitive test battery scores. Patients treated with brexpiprazole (n=64) or aripiprazole (n=33) showed reductions in symptoms of schizophrenia as assessed by Positive and Negative Syndrome Scale total score (-22.9 and -19.4, respectively). A modest reduction in impulsivity was observed with brexpiprazole, but not aripiprazole (mean change in the Barratt Impulsiveness Scale 11-item total score: -2.7 and 0.1, respectively). No change in Cogstate scores was observed for either treatment. Brexpiprazole was well tolerated and the incidence of akathisia was lower in patients treated with brexpiprazole (9.4%) than aripiprazole (21.2%). Clinically relevant improvements in psychopathology were observed in patients with acute schizophrenia treated with brexpiprazole or aripiprazole. Brexpiprazole was well tolerated, with a lower incidence of akathisia than aripiprazole. PMID- 26963843 TI - Supramolecular Surface Photochemistry: Cascade Energy Transfer between Encapsulated Dyes Aligned on a Clay Nanosheet Surface. AB - Three coumarin derivatives (7-propoxy coumarin, coumarin-480, and coumarin-540a, 2, 3, and 4, respectively) having different absorption and emission spectra were encapsulated within a water-soluble organic capsule formed by the two positively charged ammonium-functionalized cavitand octaamine (OAm, 1). Guests 2, 3, and 4 absorb in ultraviolet, violet, and blue regions and emit in violet, blue, and green regions, respectively. Energy transfer between the above three coumarin@(OAm)2 complexes assembled on the surface of a saponite clay nanosheet was investigated by steady-state and time-resolved emission techniques. Judging from their emission and excitation spectra, we concluded that the singlet-singlet energy transfer proceeded from 2 to 3, from 2 to 4, and from 3 to 4 when OAm encapsulated 2, 3, and 4 were aligned on a clay surface as two-component systems. Under such conditions, the energy transfer efficiencies for the paths 2* to 3, 2* to 4, and 3* to 4 were calculated to be 33, 36, and 50% in two-component systems. When all three coumarins were assembled on the surface and 2 was excited, the energy transfer efficiencies for the paths 2* to 3, 2* to 4, and 3* to 4 were estimated to be 32, 34, and 33%. A comparison of energy transfer efficiencies of the two-component and three-component systems revealed that excitation of 2 leads to emission from 4. Successful merging of supramolecular chemistry and surface chemistry by demonstrating novel multi-step energy transfer in a three-component dye encapsulated system on a clay surface opens up newer opportunities for exploring such systems in an artificial light-harvesting phenomenon. PMID- 26963845 TI - Obstacles to activity pacing: assessment, relationship to activity and functioning. AB - Activity pacing is frequently included among the strategies provided to individuals with chronic pain to manage pain and improve functioning. Individuals with chronic pain may, however, limit their use of activity pacing because they perceive significant obstacles to its use. This study describes the development of a measure to assess obstacles to activity pacing and examines the relationship of this measure to activity patterns and functioning. A sample of 637 individuals with chronic pain completed items describing potential obstacles to activity pacing as part of their pretreatment assessment. Item analyses were used to construct a 14-item measure of obstacles to activity pacing. A subset of these individuals completed the measure again after completion of a group treatment program. The resulting measure demonstrated excellent internal consistency and was minimally affected by social desirability. Correlations with measures of activity and psychosocial functioning provided initial construct validity for the measure. Sex differences were found with women initially identifying more obstacles to activity pacing. Fewer obstacles were identified by both men and women after treatment, and these changes were related to modest changes in activity patterns and functioning. The present results identify a number of obstacles that may limit the use of activity pacing by individuals with chronic pain. Treatment may result in a decrease in the number of obstacles identified, and this change is related to changes in the individual's activity pattern and psychosocial functioning. PMID- 26963846 TI - Helping motivation and well-being of chronic pain couples: a daily diary study. AB - Receiving support from a romantic partner may yield benefits for individuals with chronic pain (ICPs), but may also carry unintended side effects. The conditions under which partner support provision yields (mal)adaptive effects deserve greater attention. Grounded in Self-determination theory, partners may provide help for autonomous or volitional (eg, enjoyment, full commitment) or rather controlled or pressured (eg, avoiding guilt and criticism) motives. This study examined associations between day-to-day fluctuations in partners' type of helping motivation and several outcomes, among partners and ICPs. Seventy couples, with 1 partner having chronic pain (75.7% female), completed a diary for 14 consecutive days. Daily helping motivation was assessed together with daily affect, relational conflict, and relationship-based need satisfaction. Partners (Mage = 55.14) additionally reported on daily helping exhaustion, whereas ICPs (Mage = 54.71) reported on daily pain intensity, disability, satisfaction with received help, and amount of received help. Providing autonomous help related to improvements in partners' affective (eg, positive affect), relational (eg, conflict), and help-specific (eg, exhaustion) functioning, which were accounted for by improvements in daily relationship-based psychological need satisfaction. Similarly, daily autonomously motivated help yielded a direct (ie, relational conflict; perceived amount of help) or indirect (ie, positive and negative affects; relational conflict; satisfaction with help, disability) contribution in explaining ICP outcomes-through improvements in ICPs' relationship-based psychological need satisfaction. Findings highlight the importance of a motivational and dynamic perspective on help provision within chronic pain couples. Considering reasons why a partner provides help is important to understand when partners and ICPs may benefit from daily support. PMID- 26963844 TI - A randomized controlled trial of gabapentin for chronic low back pain with and without a radiating component. AB - Gabapentin is prescribed for analgesia in chronic low back pain, yet there are no controlled trials supporting this practice. This randomized, 2-arm, 12-week, parallel group study compared gabapentin (forced titration up to 3600 mg daily) with inert placebo. The primary efficacy measure was change in pain intensity from baseline to the last week on treatment measured by the Descriptor Differential Scale; the secondary outcome was disability (Oswestry Disability Index). The intention-to-treat analysis comprised 108 randomized patients with chronic back pain (daily pain for >=6 months) whose pain did (43%) or did not radiate into the lower extremity. Random effects regression models which did not impute missing scores were used to analyze outcome data. Pain intensity decreased significantly over time (P < 0.0001) with subjects on gabapentin or placebo, reporting reductions of about 30% from baseline, but did not differ significantly between groups (P = 0.423). The same results pertained for disability scores. In responder analyses of those who completed 12 weeks (N = 72), the proportion reporting at least 30% or 50% reduction in pain intensity, or at least "Minimal Improvement" on the Physician Clinical Global Impression of Change did not differ significantly between groups. There were no significant differences in analgesia between participants with radiating (n = 46) and nonradiating (n = 62) pain either within or between treatment arms. There was no significant correlation between gabapentin plasma concentration and pain intensity. Gabapentin appears to be ineffective for analgesia in chronic low back pain with or without a radiating component. PMID- 26963847 TI - Brief time-based activity pacing instruction as a singular behavioral intervention was not effective in participants with symptomatic osteoarthritis. AB - Osteoarthritis (OA) of the lower extremities is a prevalent cause of disability in which symptoms interfere with mobility and activity participation. Behavioral self-management for OA symptomatology is commonly recommended; but these interventions are underutilized, unstandardized in application, and at times, unavailable in the context of clinical care. For people with chronic pain, rehabilitation professionals may select to apply activity pacing instruction as one behavioral strategy to manage symptoms. Activity pacing is widely used in combination with other pharmacological and behavioral interventions but has not been studied as a singular behavioral intervention for people with OA. The purpose of this study was to evaluate the effectiveness of an occupational therapist-delivered, time-based activity pacing program for treatment of pain, fatigue, and physical function in people with symptomatic knee or hip OA. A 3-arm randomized controlled trial was conducted in which 193 people were randomized into tailored activity pacing, general activity pacing, or usual care arms. Assessments were done at 10 weeks and 6 months after baseline. Using linear mixed models, Western Ontario and McMaster Universities Osteoarthritis Index pain scores changed over time, decreasing the most in the general and usual care groups; only the usual care group had decreased pain over 6 months. The tailored and general activity pacing groups reported higher frequency of pacing behaviors than the usual care group at 10 weeks, but pacing was not sustained at 6 months. This trial does not support the use of time-based pacing as a singular behavioral strategy for people with knee or hip OA. PMID- 26963848 TI - Defining problematic pharmaceutical opioid use among people prescribed opioids for chronic noncancer pain: do different measures identify the same patients? AB - The International Classification of Diseases (ICD) and the Diagnostic and Statistical Manual (DSM) are routinely used in diagnosing illicit substance use disorders, but for people taking prescribed opioids they remain controversial. In pain medicine, the concept of "Addiction" is preferred with reduced emphasis on tolerance and withdrawal. This article examines the prevalence and characteristics of pharmaceutical opioid dependence/disorder according to ICD, DSM, and the pain medicine concept of "Addiction," among chronic noncancer pain (CNCP) patients prescribed opioids. In the current study, we used data from a national sample of 1134 people prescribed opioids for CNCP. Past 12-month "Addiction" (based on Pain Medicine definition), DSM, and ICD dependence definitions were assessed using the Composite International Diagnostic Interview. Twenty-four percent of the cohort met the criteria for "Addiction," 18% for DSM-5 use disorder and 19% for ICD-11 dependence. There was "substantial" concordance between "Addiction" and both DSM-5 use disorder and ICD-11 dependence, although concordance was much greater with ICD-11 dependence (kappa = 0.63 and 0.79, respectively). Participants meeting the criteria for "Addiction" only were older, less likely to engage in nonadherent behaviours, self-reported fewer problems or concerns with their medication, and had lower rates of psychological distress than those who also met the DSM-5 and ICD-11 criteria. The definition of "Addiction" captures a larger group of patients than other classification systems and includes people with fewer "risk" behaviours. Despite removal of tolerance and withdrawal for prescribed opioid use for DSM-5, we found that "Addiction" was more closely related to an ICD-11 diagnosis of pharmaceutical opioid dependence. PMID- 26963849 TI - Depression in patients with chronic pain attending a specialised pain treatment centre: prevalence and impact on health care costs. AB - This cross-sectional study aimed to determine the prevalence and impact of depression on health care costs in patients with complex chronic pain. The sample included 1204 patients attending a tertiary pain management service for people with chronic disabling pain, unresponsive to medical treatment. As part of routine care, patients completed a web-based questionnaire assessing mental and physical health, functioning, and service use in the preceding 3 months. Depression was assessed using the 9-item Patient Health Questionnaire. Self report health care utilisation was measured across 4 domains: general practitioner contacts, contacts with secondary/tertiary care doctors, accident and emergency department visits, and days hospitalised. The participation rate was 89%. Seven hundred and thirty-two patients (60.8%; 95% CI 58.0-63.6) met criteria for probable depression, and 407 (33.8%) met the threshold for severe depression. Patients with depression were more likely to be unable to work because of ill health and reported greater work absence, greater pain-related interference with functioning, lower pain acceptance, and more generalised pain. Mean total health care costs per 3-month period were L731 (95% CI L646-L817) for patients with depression, compared with L448 (95% CI L366-L530) for patients without depression. A positive association between severe depression and total health care costs persisted after controlling for key demographic, functional, and clinical covariates using multiple linear regression models. These findings reveal the extent, severity, and impact of depression in patients with chronic pain and make evident a need for action. Effective treatment of depression may improve patient health and functioning and reduce the burden of chronic pain on health care services. PMID- 26963851 TI - A randomized, double-blind, placebo-controlled trial of injected capsaicin for pain in Morton's neuroma. AB - Intermetatarsal neuroma or Morton's neuroma is a painful condition of the foot resulting from an entrapment of the common digital nerve typically in the third intermetatarsal space. The pain can be severe and especially problematic with walking. Treatment options are limited and surgery may lead to permanent numbness in the toes. Capsaicin, the pungent ingredient of hot peppers, produces analgesia by inducing retraction of nociceptive afferents from the area of innervation and is effective in treating certain neuropathic pain disorders. A randomized double blind placebo-controlled study was conducted to test the efficacy, tolerability, and safety of a single 0.1 mg dose of capsaicin vs placebo injected into the region of the neuroma. A total of 58 subjects diagnosed with Morton's neuroma with foot pain >=4 (0-10 numerical pain rating scale) were injected with 2 mL of lidocaine into the intermetatarsal space proximal to the neuroma to provide local anesthesia. After 5 minutes, 0.1 mg capsaicin or placebo was injected into the intermetatarsal space containing the painful neuroma. Average foot pain was rated for 2 weeks before through 4 weeks after injection. At weeks 1 and 4, the decrease in pain was significantly greater in the subjects treated with capsaicin (P = 0.021 and P = 0.019, respectively). A trend toward significance was noted at weeks 2 and 3. Improvements in functional interference scores and reductions in oral analgesic use were also seen in the capsaicin-treated group. These findings suggest that injection of capsaicin is an efficacious treatment option for patients with painful intermetatarsal neuroma. PMID- 26963850 TI - Epac-protein kinase C alpha signaling in purinergic P2X3R-mediated hyperalgesia after inflammation. AB - Sensitization of purinergic P2X3 receptors (P2X3Rs) is a major mechanism contributing to injury-induced exaggerated pain responses. We showed in a previous study that cyclic adenosine monophosphate (cAMP)-dependent guanine nucleotide exchange factor 1 (Epac1) in rat sensory dorsal root ganglia (DRGs) is upregulated after inflammatory injury, and it plays a critical role in P2X3R sensitization by activating protein kinase C epsilon (PKCepsilon) inside the cells. protein kinase C epsilon has been established as the major PKC isoform mediating injury-induced hyperalgesic responses. On the other hand, the role of PKCalpha in receptor sensitization was seldom considered. Here, we studied the participation of PKCalpha in Epac signaling in P2X3R-mediated hyperalgesia. The expression of both Epac1 and Epac2 and the level of cAMP in DRGs are greatly enhanced after complete Freund adjuvant (CFA)-induced inflammation. The expression of phosphorylated PKCalpha is also upregulated. Complete Freund adjuvant (CFA)-induced P2X3R-mediated hyperalgesia is not only blocked by Epac antagonists but also by the classical PKC isoform inhibitors, Go6976, and PKCalpha-siRNA. These CFA effects are mimicked by the application of the Epac agonist, 8-(4-chlorophenylthio)-2 -O-methyl-cAMP (CPT), in control rats, further confirming the involvement of Epacs. Because the application of Go6976 prior to CPT still reduces CPT-induced hyperalgesia, PKCalpha is downstream of Epacs to mediate the enhancement of P2X3R responses in DRGs. The pattern of translocation of PKCalpha inside DRG neurons in response to CPT or CFA stimulation is distinct from that of PKCepsilon. Thus, in contrast to prevalent view, PKCalpha also plays an essential role in producing complex inflammation-induced receptor-mediated hyperalgesia. PMID- 26963852 TI - Pain modulatory phenotypes differentiate subgroups with different clinical and experimental pain sensitivity. AB - Pain biomarkers are warranted for individualized pain management. Based on different pain modulatory phenotypes, the objectives of this study were to explore the existence of subgroups within patients with nonmalignant chronic pain and to investigate differences in clinical pain and pain hypersensitivity between subgroups. Cuff algometry was performed on lower legs in 400 patients with chronic pain to assess pressure pain threshold, pressure pain tolerance, temporal summation of pain (TSP: increase in pain scores to 10 repeated stimulations), and conditioned pain modulation (CPM: increase in cuff pressure pain threshold during cuff pain conditioning on the contralateral leg). Heat detection and heat pain thresholds at clinical painful and nonpainful body areas were assessed. Based on TSP and CPM, 4 distinct groups were formed: group 1 (n = 85) had impaired CPM and facilitated TSP; group 2 (n = 148) had impaired CPM and normal TSP; group 3 (n = 45) had normal CPM and facilitated TSP; and group 4 (n = 122) had normal CPM and normal TSP. Group 1 showed more pain regions than the other 3 groups (P < 0.001), indicating that impaired CPM and facilitated TSP play an important role in widespread pain. Groups 1 and 2 compared with group 4 had lower heat pain threshold at nonpainful areas and lower cuff pressure pain tolerance (P < 0.02), indicating that CPM plays a role for widespread hyperalgesia. Moreover, group 1 demonstrated higher clinical pain scores than group 4 (P < 0.05). Although not different between subgroups, patients were profiled on demographics, disability, pain catastrophizing, and fear of movement. Future research should investigate interventions tailored towards these subgroups. PMID- 26963854 TI - Neonatal medicine: past, present, and future. PMID- 26963855 TI - Neonatal nephrology. PMID- 26963856 TI - Perinatal programming of renal function. AB - PURPOSE OF REVIEW: Perinatal programming of renal function reflects the epigenetic alteration of genetically determined development by environmental factors. These include intrauterine malnutrition, pre and postnatal overnutrition, glucocorticoids, and certain toxins such as smoking. This review aims to summarize the most important findings. RECENT FINDINGS: Human studies may show an increased susceptibility toward the general prevalence of renal failure in already small for gestational age children and adolescents. In particular, glomerular diseases present with a more severe clinical course. Partially related, partially independently, arterial hypertension is found in this at-risk group. The findings can mostly be confirmed in animal models. Both intrauterine nutrient deprived and overfed rodents show a tendency toward developing glomerulosclerosis and other renal disorders. Animal studies attempt to imitate clinical conditions, however, there are difficulties in transferring the findings to the human setting. The reduction of nephron number, especially in intrauterine growth-restricted humans and animals, is one mechanism of perinatal programming in the kidneys. In addition, vascular and endocrine alterations are prevalent. The molecular changes behind these mechanisms include epigenetic changes such as DNA-methylation, microRNAs, and histone modifications. SUMMARY: Future research will have to establish clinical studies with clear and well defined inclusion criteria which also reflect prenatal life. The use of transgenic animal models might help to obtain a deeper insight into the underlying mechanisms. PMID- 26963853 TI - TGF-beta activates APC through Cdh1 binding for Cks1 and Skp2 proteasomal destruction stabilizing p27kip1 for normal endometrial growth. AB - We previously reported that aberrant TGF-beta/Smad2/3 signaling in endometrial cancer (ECA) leads to continuous ubiquitylation of p27(kip1)(p27) by the E3 ligase SCF-Skp2/Cks1 causing its degradation, as a putative mechanism involved in the pathogenesis of this cancer. In contrast, normal intact TGF-beta signaling prevents degradation of nuclear p27 by SCF-Skp2/Cks1 thereby accumulating p27 to block Cdk2 for growth arrest. Here we show that in ECA cell lines and normal primary endometrial epithelial cells, TGF-beta increases Cdh1 and its binding to APC/C to form the E3 ligase complex that ubiquitylates Cks1 and Skp2 prompting their proteasomal degradation and thus, leaving p27 intact. Knocking-down Cdh1 in ECA cell lines increased Skp2/Cks1 E3 ligase activity, completely diminished nuclear and cytoplasmic p27, and obviated TGF-beta-mediated inhibition of proliferation. Protein synthesis was not required for TGF-beta-induced increase in nuclear p27 and decrease in Cks1 and Skp2. Moreover, half-lives of Cks1 and Skp2 were extended in the Cdh1-depleted cells. These results suggest that the levels of p27, Skp2 and Cks1 are strongly or solely regulated by proteasomal degradation. Finally, an inverse relationship of low p27 and high Cks1 in the nucleus was shown in patients in normal proliferative endometrium and grade I-III ECAs whereas differentiated secretory endometrium showed the reverse. These studies implicate Cdh1 as the master regulator of TGF-beta-induced preservation of p27 tumor suppressor activity. Thus, Cdh1 is a potential therapeutic target for ECA and other human cancers showing an inverse relationship between Cks1/Skp2 and p27 and/or dysregulated TGF-beta signaling. PMID- 26963858 TI - Using Electronic Health Record Data for Healthy Weight Surveillance in Children, San Diego, California, 2014. PMID- 26963859 TI - Integrating Tobacco Control and Obesity Prevention Initiatives at Retail Outlets. AB - Tobacco products are sold in approximately 375,000 US retail outlets, including convenience stores and pharmacies, which often sell energy-dense, low-nutrient foods and beverages. The Food and Drug Administration's (FDA's) increased authority over tobacco product sales and marketing, combined with declining smoking rates, provides an opportunity to transition tobacco retailers toward healthier retail environments. Unfortunately, research into improving consumer retail environments is often conducted in isolation by researchers working in tobacco control, nutrition, and physical activity. Interdisciplinary efforts are needed to transform tobacco retailers from stores that are dependent on a declining product category, to the sale and promotion of healthful foods and creating environments conducive to active living. The objective of this article is to describe the potential for interdisciplinary efforts to transition retailers away from selling and promoting tobacco products and toward creating retail environments that promote healthful eating and active living. PMID- 26963861 TI - The toxicology of ion-shedding zinc oxide nanoparticles. AB - Zinc oxide nanoparticles (ZnO NPs) are nanomaterials that are widely used in many fields. ZnO NPs are ion-shedding particles, and zinc ions produce important and potent effects that differ from those of other metal or metal oxide NPs. Several studies have reported the toxicological effects of ZnO NPs administered via several different routes, including orally, dermally, by pulmonary absorption, intraperitoneally, and intravenously. Some potential routes for human exposure have produced various toxic effects in animal models. Moreover, several in vitro studies using a range of cell lines have reported the mechanisms underlying ZnO NP toxicity. Zinc ions play a very important role in ZnO NP toxicity, although the effects of the particulate form cannot be excluded. A crucial determinant of toxicity is the solubility of ZnO NPs, which is influenced by various factors, including the pH of the environment in tissues, cells, and organelles. In addition to the inflammatory responses and oxidative stress known to be induced by ZnO NPs, these NPs also exhibit some positive anti-inflammatory, anti diabetic, and pro-coagulant effects at sub-toxic doses; these effects are probably induced by zinc ions, which are an essential element in cell homeostasis. It is highly likely that there are additional distinct mechanisms at sub-toxic doses and concentrations, which may be concealed or altered by the toxic effects observed at higher levels of ZnO NPs. Furthermore, many signaling pathway molecules associated with necrosis and apoptosis can be activated, leading to cell death. This review presents the status of ZnO NP toxicology and highlights areas requiring further investigation. PMID- 26963860 TI - Increasing Community Access to Fresh Fruits and Vegetables: A Case Study of the Farm Fresh Market Pilot Program in Cobb County, Georgia, 2014. AB - BACKGROUND: Ecological models of health suggest that to effectively prevent chronic disease, community food environments must support healthy eating behaviors. However, disparities in access to healthy foods persist in the United States. COMMUNITY CONTEXT: The Farm Fresh Market (FFM) was a fruit and vegetable market that sold low-cost fresh produce in Cobb County, Georgia in 2014. METHODS: This case study describes the development of the FFM through a community engagement process and presents evaluation results from the project's pilot implementation. Community engagement strategies included forming a community advisory board, conducting a needs assessment, and contracting with a community based organization to implement the FFM. OUTCOME: In the pilot year, the FFM served an average of 28.7 customers and generated an average of $140.20 in produce sales per market day. Most returning customers lived in the local community and reported a range of socioeconomic backgrounds. Most returning customers strongly agreed that the FFM made it easier (69.0%) and less expensive (79.0%) for them to buy fresh fruits and vegetables, reported that they ate more vegetables (65.0%) and fruit (55.0%) as a result of the FFM, and reported that they were very satisfied with the FFM overall (92.0%). INTERPRETATION: Results from this community case study underscore the importance of engaging communities in the development of community food environment interventions. Results also suggest that the FFM initiative was a feasible and acceptable way to respond to the community-identified public health priority of increasing access to healthy foods. PMID- 26963862 TI - Epithelial cell detachment by Porphyromonas gingivalis biofilm and planktonic cultures. AB - Porphyromonas gingivalis is present as a biofilm at the sites of periodontal infections. The detachment of gingival epithelial cells induced by P. gingivalis biofilms was examined using planktonic cultures as a comparison. Exponentially grown planktonic cultures or 40-h biofilms were co-incubated with epithelial cells in a 24-well plate for 4 h. Epithelial cell detachment was assessed using imaging. The activity of arginine-gingipain (Rgp) and gene expression profiles of P. gingivalis cultures were examined using a gingipain assay and quantitative PCR, respectively. P. gingivalis biofilms induced significantly higher cell detachment and displayed higher Rgp activity compared to the planktonic cultures. The genes involved in gingipain post-translational modification, but not rgp genes, were significantly up-regulated in P. gingivalis biofilms. The results underline the importance of including biofilms in the study of bacterial and host cell interactions. PMID- 26963868 TI - Surface-plasmon mediated photoluminescence enhancement of Pt-coated ZnO nanowires by inserting an atomic-layer-deposited Al2O3 spacer layer. AB - Surface-plasmon mediated photoluminescence emission enhancement has been investigated for ZnO nanowire (NW)/Pt nanoparticle (NP) nanostructures by inserting an Al2O3 spacer layer. The thickness of the Al2O3 spacer layer and of the Pt NPs capped on the ZnO NWs are well controlled by atomic layer deposition. It is found that the photoluminescence property of the ZnO NW/Al2O3/Pt hybrid structure is highly tunable with respect to the thickness of the inserted Al2O3 spacer layer. The highest enhancement (~14 times) of the near band emission of ZnO NWs is obtained with an optimized Al2O3 spacer layer thickness of 10 nm leading to a ultraviolet-visible emission ratio of 271.2 compared to 18.8 for bare ZnO NWs. The enhancement of emission is influenced by a Forster-type non radiative energy transfer process of the exciton energy from ZnO NWs to Pt NPs as well as the coupling effect between excitons of ZnO NWs and surface plasmons of Pt NPs. The highly versatile and tunable photoluminescence properties of Pt coated ZnO NWs achieved by introducing an Al2O3 spacer layer demonstrate their potential application in highly efficient optoelectronic devices. PMID- 26963867 TI - The influence of humanitarian crises on social functioning among civilians in low and middle-income countries: A systematic review. AB - Our aim was to systematically review how social functioning is measured, conceptualised, impacted, and associated with mental disorders in populations affected by humanitarian crises. Quantitative studies conducted with civilian populations affected by humanitarian crises in low- and middle-income countries with outcomes of social functioning were examined up to 2014. Data sources included Medline, Embase, PsycInfo, and Global Health, and 8 grey literature sources, yielding 14,350 records, of which 20 studies met inclusion criteria. A descriptive synthesis analysis was used, and the final selected studies assessed for quality using a modified Newcastle-Ottawa Scale. In the 20 studies, social functioning was conceptualised in 6 categories: family functioning, friendship quality, functional impairment, overall social functioning, social adaptation, and social relations. Seventeen studies were cross-sectional, two were cohort, and one a controlled trial. The quality of the studies was generally moderate. The limited evidence suggests that social functioning is a relevant variable. Greater crisis exposure is associated with more severe depression and lower social functioning. The protective role of familial and social resources for social functioning is highlighted in different crisis settings. However, greater research on social functioning and mental health is required. PMID- 26963869 TI - Aging-related gains and losses associated with word production in connected speech. AB - Older adults have been observed to use more nonnormative, or atypical, words than younger adults in connected speech. We examined whether aging-related losses in word-finding abilities or gains in language expertise underlie these age differences. Sixty younger and 60 older adults described two neutral photographs. These descriptions were processed into word types, and textual analysis was used to identify interrupted speech (e.g., pauses), reflecting word-finding difficulty. Word types were assessed for normativeness, with nonnormative word types defined as those used by six (5%) or fewer participants to describe a particular picture. Accuracy and precision ratings were provided by another sample of 48 high-vocabulary younger and older adults. Older adults produced more interrupted and, as predicted, nonnormative words than younger adults. Older adults were more likely than younger adults to use nonnormative language via interrupted speech, suggesting a compensatory process. However, older adults' nonnormative words were more precise and trended for having higher accuracy, reflecting expertise. In tasks offering response flexibility, like connected speech, older adults may be able to offset instances of aging-related deficits by maximizing their expertise in other instances. PMID- 26963875 TI - How to approach sleep disordered breathing in heart failure patients. AB - Sleep disordered breathing (SDB) is a major public health problem and is highly prevalent in patients with heart failure (HF) disease. In these patients, a thorough pre-test probability evaluation and appropriate selection of overnight sleep study should be performed before treatment evaluation. A high index of suspicion for SDB should exist when an HF patient presents with the associated clinical features or risk factors for SDB. With a high index of suspicion, polysomnography (PSG), as a gold standard, is able to confirm or rule out the disease; however, portable monitoring devices may also be appropriate and represent more cost effective diagnosis strategies to confirm the diagnosis in adequately selected patients among a HF cohort. The choice of treatment largely depends on the type and severity of SDB demonstrated by validated sleep recording. The treatment of OSA in HF with CPAP is well established, while the optimal treatment of CSA still to be defined. PMID- 26963876 TI - Carpal Tunnel Syndrome in an Adolescent With Obesity. AB - PURPOSE: Carpal tunnel syndrome (CTS) is typically found in adults and may be associated with a variety of metabolic conditions including obesity. Obesity is a growing problem among today's youth, and adult diseases often associated with obesity are now being found in a younger population. This case study describes a young adolescent girl with obesity and CTS. SUMMARY OF KEY POINTS: A history and examination were completed before electrophysiologic testing, and the patient had no evidence of any contributory pathology. STATEMENT OF CONCLUSIONS: There was electrophysiologic evidence of bilateral median nerve compromise at the wrist. The patient's diagnosis of CTS may be obesity related. RECOMMENDATIONS FOR CLINICAL PRACTICE: Management of patients with obesity and CTS should also include education about weight management in addition to traditional interventions. This may be even more important for a child or adolescent with obesity and CTS. PMID- 26963877 TI - Hair and Scalp Care in African American Women Who Exercise. PMID- 26963878 TI - Highly Directional Room-Temperature Single Photon Device. AB - One of the most important challenges in modern quantum optical applications is the demonstration of efficient, scalable, on-chip single photon sources, which can operate at room temperature. In this paper we demonstrate a room-temperature single photon source based on a single colloidal nanocrystal quantum dot positioned inside a circular bulls-eye shaped hybrid metal-dielectric nanoantenna. Experimental results show that 20% of the photons are emitted into a very low numerical aperture (NA < 0.25), a 20-fold improvement over a free standing quantum dot, and with a probability of more than 70% for a single photon emission. With an NA = 0.65 more than 35% of the single photon emission is collected. The single photon purity is limited only by emission from the metal, an obstacle that can be bypassed with careful design and fabrication. The concept presented here can be extended to many other types of quantum emitters. Such a device paves a promising route for a high purity, high efficiency, on-chip single photon source operating at room temperature. PMID- 26963879 TI - Global challenges keynote address in memoriam to colleagues lost in the Malaysia airlines 17 crash. AB - Six colleagues working in the HIV field were killed when their flight en route to Kuala Lumpur was shot down over the Ukraine. This report is drawn from the in memoriam keynote opening address given at the 12th International AIDS Impact conference in Amsterdam in 2015. It highlights their tangible and valued roles in the HIV response and looks forward to the road ahead. It describes the ways in which we can build on their legacy to address current global challenges in HIV prevention and treatment and to mobilise the intensified, focused resources that are needed to turn the HIV epidemic on its head. PMID- 26963880 TI - How Many Environmental Impact Indicators Are Needed in the Evaluation of Product Life Cycles? AB - Numerous indicators are currently available for environmental impact assessments, especially in the field of Life Cycle Impact Assessment (LCIA). Because decision making on the basis of hundreds of indicators simultaneously is unfeasible, a nonredundant key set of indicators representative of the overall environmental impact is needed. We aimed to find such a nonredundant set of indicators based on their mutual correlations. We have used Principal Component Analysis (PCA) in combination with an optimization algorithm to find an optimal set of indicators out of 135 impact indicators calculated for 976 products from the ecoinvent database. The first four principal components covered 92% of the variance in product rankings, showing the potential for indicator reduction. The same amount of variance (92%) could be covered by a minimal set of six indicators, related to climate change, ozone depletion, the combined effects of acidification and eutrophication, terrestrial ecotoxicity, marine ecotoxicity, and land use. In comparison, four commonly used resource footprints (energy, water, land, materials) together accounted for 84% of the variance in product rankings. We conclude that the plethora of environmental indicators can be reduced to a small key set, representing the major part of the variation in environmental impacts between product life cycles. PMID- 26963881 TI - EFFECTS CRYOPRESERVATION OF IONOTROPIC GLUTAMATERGIC RECEPTOR MECHANISMS IN VITRO. AB - BACKGROUND: We assayed hypothesis of cryopreservation of small volumes of nervous tissue (olfactory cortex slices). OBJECTIVE: Effect of freezing (-10(0)C) and rewarming to +37(0)C studied on glutamatergic mechanisms. MATERIALS AND METHODS: Viability slices determined from the change of the amplitudes of glutamatergic synaptic transmission: action potential of lateral olfactory tract (AP LOT), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPAR) and N-methyl-D aspartate (NMDAR) receptor-dependent mechanisms. Effects of two rates freezing/rewarming: slow (0.1(0)C/min) and rapid (9.0(0)C/min) were studied. RESULTS: Activity AP LOT and AMPARs restored at slow rate freezing/rewarming, and at rapid rate, these indicators were increased. Activity NMDARs decreased at slow rate both at slow and at rapid rates after freezing/rewarming were blocked. At rewarming water swelling content ofin slices was maximal at rapid rate of freezing/rewarming. CONCLUSION: The protocol of cryopreservation with slow rate (0.1(0)C/min) freezing/rewarming and a depth of freezing -10(0)C is optimal for the cryopreservation of small volumes of nervous tissue. PMID- 26963882 TI - DESIGN OF A SIMPLE SLOW COOLING DEVICE FOR CRYOPRESERVATION OF SMALL BIOLOGICAL SAMPLES. AB - BACKGROUND: Slow cooling is a cryopreservation methodology where samples are cooled to its storage temperature at controlled cooling rates. OBJECTIVE: Design, construction and evaluation of a simple and low cost device for slow cooling of small biological samples. MATERIALS AND METHODS: The device was constructed based on Pye's freezer idea. A Dewar flask filled with liquid nitrogen was used as heat sink and a methanol bath containing the sample was cooled at constant rates using copper bars as heat conductor. RESULTS: Sample temperature may be lowered at controlled cooling rate (ranging from 0.4 degrees C/min to 6.0 degrees C/min) down to ~-60 degrees C, where it could be conserved at lower temperatures. An example involving the cryopreservation of Neuro-2A cell line showed a marked influence of cooling rate over post preservation cell viability with optimal values between 2.6 and 4.6 degrees C/min. CONCLUSION: The cooling device proved to be a valuable alternative to more expensive systems allowing the assessment of different cooling rates to evaluate the optimal condition for cryopreservation of such samples. PMID- 26963883 TI - BACTERIA IN CRYOPRESERVED SPERM MASS OF THE WHITE SHRIMP Penaeus vannamei. AB - BACKGROUND: Cryopreservation and global trading of P. vannamei sperm will become a potential and important biotechnological tool. Nevertheless, information of the possible transfer of bacteria in cryopreserved shrimp sperm has not been registered yet. OBJECTIVE: The objective of this work was to determine the type of bacteria that could be cryopreserved together with white shrimp sperm masses. MATERIALS AND METHODS: Sixteen sperm masses were cryopreserved in 10% DMSO and 0.5 M trehalose and sixteen fresh sperm masses were used for bacterial analysis. Bacterial colonies were isolated and selected for sequencing. RESULTS: Strains were seawater borne and facultative aerobic bacteria from the genera Bacillus, Micrococcus, Paracoccus, Ruegeria and Staphylococcus. Most of them have been related with benefits to its host. None were pathogenic for P. vannamei. CONCLUSION: Cryopreservation implies preserving pathogenic or beneficial bacteria together with the sample. Therefore, it is possible to enhance cryopreserved samples or disperse pathogenic bacteria, which needs to be prevented. PMID- 26963884 TI - ULTRASTRUCTURAL RESPONSE OF EMBRYONIC AXES OF Fortunella polyandra TO DEHYDRATION AND CRYOPRESERVATION. AB - BACKGROUND: To further understand the survival characteristics of desiccation sensitive excised embryonic axes of Fortunella polyandra to desiccation and cryopreservation it is necessary to study the impact of drying rates on both the ultrastructure and electrolyte leakage. OBJECTIVE: To examine the effects of two different drying regimes (silica gel and ultra-rapid) on the survival, ultrastructure and membrane leakage characteristics of excised embryonic axes of F. polyandra before and after cryopreservation. MATERIALS AND METHODS: The effects of the drying regimes on the survival, ultrastructure and membrane integrity of the excised embryonic axes of F. polyandra was determined. Survival was assessed in vitro, and the integrity of membranes following drying was estimated by electrolyte leakage and observation under the transmission electron microscope (TEM). Survival and ultrastructural changes were also observed after cryopreservation. RESULTS: Electrolyte leakage increased with decreasing water content of the embryonic axes, indicative of substantial subcellular damage, after both ultra-rapid dehydration (to water contents of <0.16 g H2O g(-1) dw) and silica gel dehydration (to <0.28 g H2O g(-1) dw water content). Ultrastructurally, axes showed increasing cytoplasm and vacuole shrinkage and disruption of cell membranes with longer dehydration periods. Normal seedling recovery of 50 to 47% for cryopreserved embryonic axes of F. polyandra was observed after ultra-rapid and silica gel drying respectively. Extreme cell injury was observed after exposure to liquid nitrogen at high moisture content. Although cells of dehydrated axes encountered stress during cryopreservation, the main damage occurred during the dehydration step. CONCLUSION: For surviving axes, the damage was less severe and the axes grew to become normal seedlings. Ultrastructural studies reveal the damage of the cells at different rates of dehydration and during cryopreservation. PMID- 26963885 TI - A SIMPLE AND EFFICIENT VITRIFICATION METHOD FOR IN-STRAW DILUTION AND DIRECT TRANSFER OF BOVINE EMBRYOS. AB - BACKGROUND: An easy and user friendly protocol that produces consistent results will facilitate the commercial application of embryo vitrification technology in the field. OBJECTIVE: This study was designed to develop a simple and efficient vitrification, in-straw dilution and direct transfer method for bovine embryos. METHODS: After being vitrified and in-straw thawed, in vivo-derived and in vitro produced bovine embryos were subjected to in vitro culture or embryo transplantation. RESULTS: There were no significant differences (P > 0.05) in survival rates (100.0% vs. 93.9%) and expansion rates (93.8% vs. 87.5%) between in vivo-derived and in vitro-produced blastocysts after vitrification and in straw dilution. And there was also no significant difference (P > 0.05) in conception rates (56.5% vs. 58.8%) after ET between cryopreserved and fresh in vivo-derived blastocysts. CONCLUSION: Vitrification using EG-based vitrification solution and in-straw dilution with PBS-based diluent is a simple and efficient method for cryopreservation and direct transfer of bovine embryos. PMID- 26963886 TI - GERMPLASM BANKING AND ITS ROLE IN THE DEVELOPMENT OF THE FISH GENETIC IMPROVEMENT PROGRAMME IN BRAZIL. AB - BACKGROUND: Over the last ten years, Brazilian fish farming has become more focused, resulting in the development of genetic improvement programmes (GIP) for two South American species Colossoma macropomum (tambaqui) and Pseudoplatystoma reticulatum (cachara). OBJECTIVE: To describe the action plan used for setting up the GIP and to detail the germplasm bank composition. MATERIALS AND METHODS: Semen of both species was collected, frozen and transported between locations in Brazil. To start the programme, full and half-sib families of both species were established from 120 males and 60 females. RESULTS: New species-specific protocols for semen cryopreservation s were established of value to commercial application in fish farming. CONCLUSION: Germplasm banking has enabled the exchange of biological material and reduced the overall GIP costs. Germplasm banking can be very important to the dissemination of the selected genetic material of these species among fish farmers. PMID- 26963887 TI - EFFECT OF SEMEN EXTENDER ON PROTEIN CONCENTRATION IN EACH FRACTION OF CRYOPRESERVED HUMAN SEMEN. AB - BACKGROUND: Semen extender is liquid diluents which are added to semen to preserve its fertilizing ability. The addition of extender to semen protects the sperm against possible damage by toxic seminal plasma, as well as providing nutrients. AIM AND OBJECTIVE: The hypotheses of the study are to evaluate, if there is any significant change in the protein concentration in each fractions of human semen before and after freezing with prepared semen extender. Then we are going to correlate the semen parameters with thee fresh semen total protein concentration. RESULTS: After preserving with the extender, all the semen samples show statistically significant (p < 0.001) in case of protein concentration. CONCLUSION: There is a significant different (p < 0.001) in protein concentration in various fractions before and after freezing. Also the prepared semen extender can be used in Assisted Reproductive centres (ART). PMID- 26963888 TI - DETERMINATION OF HEAT TRANSFER COEFFICIENTS FOR FRENCH PLASTIC SEMEN STRAW SUSPENDED IN STATIC NITROGEN VAPOR OVER LIQUID NITROGEN. AB - BACKGROUND: The use of mathematical models describing heat transfer during the freezing process is useful for the improvement of cryopreservation protocols. A widespread practice for cryopreservation of spermatozoa of domestic animal species consists of suspending plastic straws in nitrogen vapor before plunging into liquid nitrogen. Knowledge of surface heat transfer coefficient (h) is mandatory for computational modelling; however, h values for nitrogen vapor are not available. OBJECTIVE: In the present study, surface heat transfer coefficients for plastic French straws immersed in nitrogen vapor over liquid nitrogen was determined; vertical and horizontal positions were considered. MATERIALS AND METHODS: Heat transfer coefficients were determined from the measurement of time-temperature curves and from numerical solution of heat transfer partial differential equation under transient conditions using finite elements. The h values experimentally obtained for horizontal and vertically placed straws were compared to those calculated using correlations based on the Nusselt number for natural convection. RESULTS: For horizontal straws the average obtained value was h=12.5 +/- 1.2 W m(2) K and in the case of vertical straws h=16 +/- 2.48 W m(2) K. The numerical simulation validated against experimental measurements, combined with accurate h values provides a reliable tool for the prediction of freezing curves of semen-filled straws immersed in nitrogen vapor. CONCLUSION: The present study contributes to the understanding of the cryopreservation techniques for sperm freezing based on engineering concepts, improving the cooling protocols and the manipulation of the straws. PMID- 26963890 TI - Screening for Metabolic Syndrome in Mental Health Consumers Using an Electronic Metabolic Monitoring Form. AB - Metabolic syndrome is more prevalent in people with serious mental illness, compared to the general population. The main purpose of this study was to determine the extent electronic metabolic monitoring forms were being completed in a regional mental health service and the extent to which diagnoses of metabolic syndrome could be made using the data available. A retrospective file audit of 721 electronic mental health consumer records was undertaken. Metabolic monitoring data were recorded for 261 (36%) consumers, of which 57 (21.8%) met the clinical criteria for metabolic syndrome, 61 (23.4%) did not meet clinical criteria, and diagnoses could not be made for 143 (54.8%) consumers due to missing data. The limited use of electronic health records may inhibit the detection of risk factors for the diagnosis of metabolic syndrome. PMID- 26963891 TI - Heparin-immobilized hydroxyapatite nanoparticles as a lactoferrin delivery system for improving osteogenic differentiation of adipose-derived stem cells. AB - The aim of this study is to fabricate lactoferrin (LF)-carrying hydroxyapatite nanoparticles (HAp NPs) to enhance osteogenic differentiation of rabbit adipose derived stem cells (rADSCs). HAp NPs were modified with heparin-dopamine (Hep DOPA) (Hep-HAp) and further immobilized with LF (LF/Hep-HAp). Heparin immobilization on HAp NPs prevented aggregation of HAp NPs in aqueous solution and prolonged the release of LF from LF/Hep-HAp NPs. In vitro studies of rADSCs have demonstrated that LF-Hep/HAp NPs significantly increase alkaline phosphatase (ALP) activity, calcium deposition, and both mRNA expression of osteocalcin (OCN) and osteopontin (OPN) in comparison with HAp and Hep-HAp NPs. These results suggest that LF/Hep-HAp NPs can effectively induce osteogenic differentiation of rADSCs. PMID- 26963892 TI - Tetracene Formation by On-Surface Reduction. AB - We present the on-surface reduction of diepoxytetracenes to form genuine tetracene on Cu(111). The conversion is achieved by scanning tunneling microscopy (STM) tip-induced manipulation as well as thermal activation and is conclusively demonstrated by means of atomic force microscopy (AFM) with atomic resolution. We observe that the metallic surface plays an important role in the deoxygenation and for the planarization after bond cleavage. PMID- 26963893 TI - Correction: Enantioselective total synthesis of (+)-methoxystemofoline and (+) isomethoxystemofoline. PMID- 26963894 TI - Hormone-dependent adolescent organization of socio-sexual behaviors in mammals. AB - The adolescent transition from childhood to adulthood requires both reproductive and behavioral maturation as individuals acquire the ability to procreate. Gonadal steroid hormones are key players in the maturation of behaviors required for reproductive success. Beyond activating behavior in adulthood, testicular and ovarian hormones organize the adolescent brain and program adult-typical and sex typical expression of sociosexual behaviors. Testicular hormones organize sexual and agonistic behaviors, including social proficiency-the ability to adapt behavior as a function of social experience. Ovarian hormones organize behaviors related to energy balance and maternal care. These sex differences in the behaviors that are programmed by gonadal hormones during adolescence suggest that evolution has selected for hormone-dependent sex-specific organization of behaviors that optimize reproductive fitness. PMID- 26963895 TI - Soluble tumor necrosis factor-alpha receptors in the serum of endometriosis patients. AB - INTRODUCTION: We examine serum levels sTNFR-I and sTNFR-II in endometriosis patients, and their role as biomarkers of endometriosis. MATERIAL AND METHODS: Women were diagnosed with endometriosis during laparoscopy to investigate pelvic pain and/or infertility (N=62). Control group included women with pelvic pain and/or infertility, whose laparoscopy showed no abnormalities (N=55). Serum concentrations of sTNFR-I and sTNFR-II were measured using Bioplex Protein Array system. Non-parametric statistics were used. RESULTS: Endometriosis patients had significantly higher levels of sTNFR-I than controls (257.46pg/ml, IQR=2.37 1048.92 versus 130.39pg/ml, IQR=0.99-361.1 respectively, P value=0.01). For TNFR II, difference between women with (232pg/ml, IQR=0.0-624.4), and women without (132.93pg/ml, IQR=0.0-312.81) endometriosis was not significant (P value=0.05). Early stage endometriosis patients had significantly higher level of sTNFR-I (559.13, IQR=1.82-1289.86) and sTNFR-II (248.8, IQR=0-644.65) than control women (P value is 0.01 for TNFR-I and 0.04 for TNFR-II). Levels of sTNFR-I and sTNFR-II were comparable for advanced endometriosis and controls, and between early and advanced endometriosis. As a biomarker for all- stage endometriosis, sTNFR-I produces AUC of 0.62, sensitivity of 61%, and specificity of 47.3%, at a cutoff of 81.87pg/ml. For early stage disease, sTNFR-I yields AUC of 0.68, sensitivity of 60.7%, specificity of 75%, at a cutoff of 351.22pg/ml. CONCLUSION: sTNFR-I is significantly higher in serum of endometriosis patients than controls. As an endometriosis biomarker, sTNFR-I achieves better performance for early stage disease. PMID- 26963896 TI - Hyperemesis in Pregnancy Study: a pilot randomised controlled trial of midwife led outpatient care. AB - OBJECTIVE: To assess the feasibility of implementing a complex intervention involving rapid intravenous rehydration and ongoing midwifery support as compared to routine in-patient care for women suffering from severe nausea and vomiting in pregnancy, (NVP)/hyperemesis gravidarum (HG). STUDY DESIGN: 53 pregnant women attending the Maternity Assessment Unit (MAU), Newcastle upon Tyne NHS Foundation Trust, Newcastle, UK with moderate-severe NVP, (as determined by a Pregnancy Unique Quantification of Emesis and Vomiting [PUQE] score >=nine), consented to participate in this pilot randomised controlled trial (RCT). Subsequently 27 were randomised to the intervention group, 26 to the control group. Women in the intervention group received rapid rehydration (three litres Hartman's solution over 6h) and symptom relief on the MAU followed by ongoing midwifery telephone support. The control group were admitted to the antenatal ward for routine in patient care. Quality of life (QoL) determined by SF36.V2 score and PUQE score were measured 7 days following randomisation. Completion rates, readmission rate, length of hospital stay and pregnancy outcomes data were collected. RESULTS: Groups were comparable at baseline. Questionnaire two return rate was disappointing, only 18 women in the control group (69%) and 13 women in the intervention groups (44%). Nonetheless there were no differences between groups on Day 7 in terms of QoL, mean PUQE score, satisfaction with care, obstetric and neonatal outcomes or readmission rates. However, total combined admission time was higher in the control group (94h versus 27h, p=0.001). CONCLUSIONS: This study suggests that day-case management plus ongoing midwifery support may be an effective alternative for treating women with severe NVP/HG. A larger trial is needed to determine if this intervention affects women's QoL. PMID- 26963897 TI - Does dehydroepiandrosterone improve pregnancy rate in women undergoing IVF/ICSI with expected poor ovarian response according to the Bologna criteria? A randomized controlled trial. AB - OBJECTIVE: To provide the best available evidence on the role of dehydroepiandrosterone (DHEA) treatment in improving the outcome of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in women with poor ovarian response (POR). STUDY DESIGN: A randomized controlled trial conducted in Cairo University hospitals and Dar Al-Teb subfertility and assisted conception centre, Giza, Egypt. 140 women undergoing IVF/ICSI with POR according to the Bologna criteria were randomly divided into 2 equal groups. The study group received DHEA 25mg three times daily for 12 weeks before the IVF/ICSI cycles and the control group did not receive DHEA. Controlled ovarian stimulation (COH) was started on the second day of menstruation using human menopausal gonadotropins, cetrotide 0.25mg was started when the leading follicle reached 14mm. The main outcome measures were the clinical pregnancy rate, ongoing pregnancy rate, retrieved oocytes, fertilization rate, gonadotropins doses and COH days. RESULTS: The DHEA group had significantly higher clinical pregnancy rate (32.8% vs 15.7%, p=0.029), ongoing pregnancy rate (28.5% vs 12.8%), retrieved oocytes (6.9+/-3 vs 5.8+/-3.1, p=0.03), fertilization rate (62.3+/-27.4 vs 52.2+/-29.8, p=0.039), significantly less gonadotropins doses (3383+/-717.5IU vs 3653.5+/-856IU, p=0.045) and COH days (11.6+/-1.8 vs 12.6+/-1.06, p=0.001). CONCLUSION: DHEA increases the number of oocytes, fertilization rate, fertilized oocytes, and clinical pregnancy rate and ongoing pregnancy rate in women with POR according to the Bologna criteria. DHEA was well tolerated by the patients and was associated with less COH days and gonadotropins doses. REGISTRATION NUMBER: www.clinicaltrials.govNCT02151006. PMID- 26963898 TI - Ryanodine Receptor 2 Plays a Critical Role in Spinal Cord Injury via Induction of Oxidative Stress. AB - BACKGROUND/AIMS: Spinal cord injury (SCI) is a severe health problem worldwide. Ryanodine receptors (RyRs) are a class of intracellular calcium channels in various excitable tissues such as muscles and nervous tissues. The current study was designed to investigate the possible role of RyR2 upregulation in SCI and to elucidate the possible molecular mechanisms. METHODS: Rats were injected with LVshRNAi- RyR2 and then exposed to spinal cord contusion injury. RESULTS: The results showed that knockdown of RyR2 significantly promoted the recovery of structural and functional injury in spinal cord, as evidenced by reduction of lesion volume and increase of Basso, Beattie and Bresnahan (BBB) and combined behavioral score (CBS) scores. Knockdown of RyR2 inhibited the increase of proinflammatory cytokines, including IL-1beta and TNFalpha. Moreover, downregulation of RyR2 increased oxygen consumption rate and decreased the expression of glucose-regulated protein 78 (GRP78), activating transcription factor 3 (ATF3) and ATF6, indicating the improvement of mitochondrial dysfunction and endoplasmic reticulum stress after SCI. Furthermore, silence of RyR2 reduced oxidative stress, as reflected by decrease of TBARS and GSSG content and increase of GSH level. The expression of NADPH oxidase 2 (NOX2), NOX4 and p66(shc) were increased in SCI rats. Knockdown of RyR2 significantly decreased NOX2 expression, but had no evident effect on NOX4 and p66shc expression. These results indicated NOX2 may be involved in RyR2-induced ROS generation which mediated contusion induced spinal cord injury. CONCLUSION: The data provide novel insights into the mechanism of RyR2-mediated injury and the potential therapeutic targets for injury in spinal cord. PMID- 26963899 TI - Arsenic stress induces changes in lipid signalling and evokes the stomata closure in soybean. AB - Soybean (Glycine max) is often exposed to high arsenic (As) level in soils or through irrigation with groundwater. In previous studies on As-treated soybean seedlings we showed deleterious effect on growth, structural alterations mainly in root vascular system and induction of antioxidant enzymes. However, there are not reports concerning signal transduction pathways triggered by the metalloid in order to develop adaptive mechanisms. Phosphatidic acid (PA), a key messenger in plants, can be generated via phospholipase D (PLD) or via phospholipase C (PLC) coupled to diacylglycerol kinase (DGK). Thus, changes in PA and in an enzyme involved in its metabolism (PLD) were analysed in soybean seedlings treated with 25 MUM AsV or AsIII. The present study demonstrated that As triggers the PA signal by PLD and also via PLC/DGK mainly after 48 h of As treatment. DGPP, other lipid messenger produced by phosphorylation of PA by PAK increased in As treated roots. Arsenic also induced rapid and significant stomatal closure after 1.5 h of treatment, mainly with AsIII, probably as an adaptive response to the metalloid to reduce water loss by transpiration. This report constitute the first evidence that shows the effects of As on lipid signalling events in soybean seedlings which would be crucial in adaptation and survival of soybean seedlings under As stress. PMID- 26963900 TI - Biofunctionalized PEDOT-coated microfibers for the treatment of spinal cord injury. AB - Poly(3, 4-ethylenedioxythiophene)-coated carbon microfibers (PEDOT-MFs) hold promise for developing advanced neuroprostheses and neural repair devices. We investigated the chronic cellular responses to PEDOT-MFs implanted into the uninjured and the transected rat spinal cord, and compared the effects of polymer surface biofunctionalization with covalently attached polylysine (PLL) or a multimolecular complex of PLL, heparin, basic fibroblast growth factor (bFGF), and fibronectin. An alginate gel was used to facilitate microfiber implantation and reduce connective tissue scarring after spinal cord injury (SCI). PLL/heparin/bFGF/fibronectin-functionalized PEDOT-MFs showed excellent integration within the uninjured and injured spinal cord, frequently establishing contact with neuronal somas, axons, dendrites and glial cells, accompanied by very little or absent scarring response. On the contrary, non-functionalized and PLL-functionalized microfibers provoked inflammation and fibrosis with loss of neural elements in the surrounding tissue. Within the lesion, the PEDOT-MFs by themselves facilitated longitudinal alignment of migratory cells and growing axons, and their modification with PLL/heparin/bFGF/fibronectin promoted tissue healing, enhancing blood vessel formation and axonal regeneration without increasing inflammation. These results support the incorporation of biofunctionalized electroconducting microfibers in neuro-electronic interfaces and lesion-bridging systems for the treatment of SCI. PMID- 26963902 TI - Hierarchical photocatalysts. AB - As a green and sustainable technology, semiconductor-based heterogeneous photocatalysis has received much attention in the last few decades because it has potential to solve both energy and environmental problems. To achieve efficient photocatalysts, various hierarchical semiconductors have been designed and fabricated at the micro/nanometer scale in recent years. This review presents a critical appraisal of fabrication methods, growth mechanisms and applications of advanced hierarchical photocatalysts. Especially, the different synthesis strategies such as two-step templating, in situ template-sacrificial dissolution, self-templating method, in situ template-free assembly, chemically induced self transformation and post-synthesis treatment are highlighted. Finally, some important applications including photocatalytic degradation of pollutants, photocatalytic H2 production and photocatalytic CO2 reduction are reviewed. A thorough assessment of the progress made in photocatalysis may open new opportunities in designing highly effective hierarchical photocatalysts for advanced applications ranging from thermal catalysis, separation and purification processes to solar cells. PMID- 26963901 TI - Perfusion-decellularized skeletal muscle as a three-dimensional scaffold with a vascular network template. AB - There exists a great need for repair grafts with similar volume to human skeletal muscle that can promote the innate ability of muscle to regenerate following volumetric muscle loss. Perfusion decellularization is an attractive technique for extracellular matrix (ECM) scaffold from intact mammalian organ or tissue which has been successfully used in tissue reconstruction. The perfusion decellularization of skeletal muscle has been poorly assessed and characterized, but the bioactivity and functional capacity of the obtained perfusion skeletal muscle ECM (pM-ECM) to remodel in vivo is unknown. In the present study, pM-ECM was prepared from porcine rectus abdominis (RA). Perfusion-decellularization of porcine RA effectively removed cellular and nuclear material while retaining the intricate three-dimensional microarchitecture and vasculature networks of the native RA, and many of the bioactive ECM components and mechanical properties. In vivo, partial-thickness abdominal wall defects in rats repaired with pM-ECM showed improved neovascularization, myogenesis and functional recellularization compared to porcine-derived small intestinal submucosa (SIS). These findings show the biologic potential of RA pM-ECM as a scaffold for supporting site appropriate, tissue reconstruction, and provide a better understanding of the importance maintaining the tissue-specific complex three-dimensional architecture of ECM during decellularization and regeneration. PMID- 26963903 TI - Topical immunotherapy with diphenylcyclopropenone-induced vitiligo. AB - Topical immunotherapy made by diphenylcyclopropenone (DPCP) is an alternative treatment that can be used safely and efficaciously in recalcitrant alopecia areata patients. DPCP-induced vitiligo is a rare, but documented, unwanted side effect. The real mechanism of DPCP-induced vitiligo is not well known. PMID- 26963904 TI - Implementation of a hospital-integrated general practice--a successful way to reduce the burden of inappropriate emergency-department use. AB - PRINCIPLES: Emergency departments (EDs) are overcrowded by lower acuity patients, which might be more efficiently treated by general practitioners (GPs). This study evaluated the impact of triaging lower acuity patients to a new hospital integrated general practice (HGP) on ED case-load and the reasons for choosing the ED/HGP. METHODS AND RESULTS: Patients were consecutively assessed according to the emergency severity index (ESI) to triage lower acuity patients to the HGP. Consultation numbers at the emergency centre (ED and HGP) increased by 43% between 2007 (n = 16 974) and 2011 (n = 24 331) (implementation of HGP in 2009). Although self-referrals increased significantly at the emergency centre from 54% to 63% (p <0.001), the proportion of self-referrals at the ED was significantly reduced to 48% (p = 0.007). The HGP was able to reduce the burden of increasing total consultations by 36%; 4.6% were referred back to the ED after triaging to the HGP. Overall, 95% of HGP patients were self-referred, Swiss nationals (65%) and with a personal GP (82%) they attended regularly (69%). The most common reason for presenting at the emergency centre was not being able to reach the GP (60%). Diagnoses were injury- (29%) and infection- (23%) related problems affecting the musculoskeletal (27%) system and skin (21%). CONCLUSION: The HGP succeeded in reducing the burden of inappropriate ED use: the majority of low acuity self-referred patients were conclusively treated at the HGP. The HGP does not represent competition to the GP out-of-hours care service, since the main reason for presenting at the hospital was not lacking a relationship but the GPs' inaccessibility. PMID- 26963905 TI - Impact of traumatic brain injury on social cognition in adolescents and contribution of other higher order cognitive functions. AB - Social cognition impairments can contribute to social participation difficulties following traumatic brain injury (TBI). However, little attention has been given to these impairments during adolescence, a period of life when peer relationships are central. The aim of the current study was to examine the impact of a moderate to severe TBI sustained in adolescence on multiple facets of social cognition. Twenty-three adolescents who had sustained a moderate-to-severe TBI were compared with a group of 23 typically developing peers. The Integrated Social Cognition Battery (mentalising, social knowledge, emotion recognition) and the Interpersonal Reactivity Index were administered, along with non-social cognition tests (selective attention, working memory, executive functions), IQ estimation, and a socio-demographic questionnaire. Adolescents with TBI reported having a significantly lower ability to take other people's perspectives versus controls. They also presented significantly lower levels of mentalising. After controlling for non-social higher-order cognitive variables, the group effect on mentalising remained marginally significant, whereas the effect on perspective taking remained significant. Our findings suggest the presence of primary deficits in social cognition following TBI in adolescence. These deficits could partially underlie the social reintegration difficulties encountered following TBI. A systematic assessment of social cognition in clinical practice is necessary. PMID- 26963906 TI - Immobilization of biofilms of Pseudomonas aeruginosa NY3 and their application in the removal of hydrocarbons from highly concentrated oil-containing wastewater on the laboratory scale. AB - To explore the potential of Pseudomonas aeruginosa NY3 for the treatment of highly concentrated crude oil-contaminated water, the immobilization of strain NY3 on the surface of polyurethane foam (PUF), the conditions for using these biofilms and the possibility of recovering the used biofilms were studied. The results demonstrated that the biofilm formation process for strain NY3 was quick and easy. Under optimum conditions, the biomass immobilized on the PUF surface could reach 488.32 mg dry cell/g dry PUF. The results demonstrated that when the degradation time was 12 h, the average oil removal rate in 2 g crude oil/L contaminated water was approximately 90% for 40d. Meanwhile, the biofilms could be recovered for reuse. The recovery ability and the high and steady oil removal rate facilitated the application of the biofilms for the removal of concentrated oil from wastewater. PMID- 26963907 TI - Conferring Natural-Derived Porous Microspheres with Surface Multifunctionality through Facile Coordination-Enabled Self-Assembly Process. AB - In this study, multifunctional chitin microspheres are synthesized and utilized as a platform for multiple potential applications in enzyme immobilization, catalytic reduction and adsorption. Porous chitin microspheres with an average diameter of 111.5 MUm and a porous architecture are fabricated through a thermally induced phase separation method. Then, the porous chitin microspheres are conferred with surface multifunctionality through facile coordination-enabled self-assembly of tannic acid (TA) and titanium (Ti(IV)) bis(ammonium lactate)dihydroxide (Ti-BALDH). The multipoint hydrogen bonds between TA and chitin microspheres confer the TA-Ti(IV) coating with high adhesion capability to adhere firmly to the surface of the chitin microspheres. In view of the biocompatibility, porosity and surface activity, the multifunctional chitin microspheres are used as carriers for enzyme immobilization. The enzyme conjugated multifunctional porous microspheres exhibit high catalytic performance (102.8 U.mg(-1) yeast alcohol dehydrogenase). Besides, the multifunctional chitin microspheres also find potential applications in the catalytic reduction (e.g., reduction of silver ions to silver nanoparticles) and efficient adsorption of heavy metal ions (e.g., Pb(2+)) taking advantages of their porosity, reducing capability and chelation property. PMID- 26963908 TI - The Bipolar II Depression Questionnaire: A Self-Report Tool for Detecting Bipolar II Depression. AB - Bipolar II (BP-II) depression is often misdiagnosed as unipolar (UP) depression, resulting in suboptimal treatment. Tools for differentiating between these two types of depression are lacking. This study aimed to develop a simple, self report screening instrument to help distinguish BP-II depression from UP depressive disorder. A prototype BP-II depression questionnaire (BPIIDQ-P) was constructed following a literature review, panel discussions and a field trial. Consecutively assessed patients with a diagnosis of depressive disorder or BP with depressive episodes completed the BPIIDQ-P at a psychiatric outpatient clinic in Hong Kong between October and December 2013. Data were analyzed using discriminant analysis and logistic regression. Of the 298 subjects recruited, 65 (21.8%) were males and 233 (78.2%) females. There were 112 (37.6%) subjects with BP depression [BP-I = 42 (14.1%), BP-II = 70 (23.5%)] and 182 (62.4%) with UP depression. Based on family history, age at onset, postpartum depression, episodic course, attacks of anxiety, hypersomnia, social phobia and agoraphobia, the 8-item BPIIDQ-8 was constructed. The BPIIDQ-8 differentiated subjects with BP II from those with UP depression with a sensitivity/specificity of 0.75/0.63 for the whole sample and 0.77/0.72 for a female subgroup with a history of childbirth. The BPIIDQ-8 can differentiate BP-II from UP depression at the secondary care level with satisfactory to good reliability and validity. It has good potential as a screening tool for BP-II depression in primary care settings. Recall bias, the relatively small sample size, and the high proportion of females in the BP-II sample limit the generalization of the results. PMID- 26963910 TI - Correction: Expression of Human NSAID Activated Gene 1 in Mice Leads to Altered Mammary Gland Differentiation and Impaired Lactation. PMID- 26963909 TI - Inter-Reader Reliability of Early FDG-PET/CT Response Assessment Using the Deauville Scale after 2 Cycles of Intensive Chemotherapy (OEPA) in Hodgkin's Lymphoma. AB - PURPOSE: The five point Deauville (D) scale is widely used to assess interim PET metabolic response to chemotherapy in Hodgkin lymphoma (HL) patients. An International Validation Study reported good concordance among reviewers in ABVD treated advanced stage HL patients for the binary discrimination between score D1,2,3 and score D4,5. Inter-reader reliability of the whole scale is not well characterised. METHODS: Five international expert readers scored 100 interim PET/CT scans from paediatric HL patients. Scans were acquired in 51 European hospitals after two courses of OEPA chemotherapy (according to the EuroNet-PHL-C1 study). Images were interpreted in direct comparison with staging PET/CTs. RESULTS: The probability that two random readers concord on the five point D score of a random case is only 42% (global kappa = 0.24). Aggregating to a three point scale D1,2 vs. D3 vs. D4,5 improves concordance to 60% (kappa = 0.34). Concordance if one of two readers assigns a given score is 70% for score D1,2 only 36% for score D3 and 64% for D4,5. Concordance for the binary decisions D1,2 vs. D3,4,5 is 67% and 86% for D1,2,3 vs D4,5 (kappa = 0.36 resp. 0.56). If one reader assigns D1,2,3 concordance probability is 92%, but only 64% if D4,5 is called. Discrepancies occur mainly in mediastinum, neck and skeleton. CONCLUSION: Inter-reader reliability of the five point D-scale is poor in this interobserver analysis of paediatric patients who underwent OEPA. Inter-reader variability is maximal in cases assigned to D2 or D3. The binary distinction D1,2,3 versus D4,5 is the most reliable criterion for clinical decision making. PMID- 26963911 TI - Comparison of Algorithms for Prediction of Protein Structural Features from Evolutionary Data. AB - Proteins have many functions and predicting these is still one of the major challenges in theoretical biophysics and bioinformatics. Foremost amongst these functions is the need to fold correctly thereby allowing the other genetically dictated tasks that the protein has to carry out to proceed efficiently. In this work, some earlier algorithms for predicting protein domain folds are revisited and they are compared with more recently developed methods. In dealing with intractable problems such as fold prediction, when different algorithms show convergence onto the same result there is every reason to take all algorithms into account such that a consensus result can be arrived at. In this work it is shown that the application of different algorithms in protein structure prediction leads to results that do not converge as such but rather they collude in a striking and useful way that has never been considered before. PMID- 26963912 TI - Relationship between Erythrocyte Fatty Acid Composition and Psychopathology in the Vienna Omega-3 Study. AB - This study investigated the relationship between erythrocyte membrane fatty acid (FA) levels and the severity of symptoms of individuals at ultra-high risk (UHR) for psychosis. Subjects of the present study consisted of 80 neuroleptic-naive UHR patients. Partial correlation coefficients were calculated between baseline erythrocyte membrane FA levels, measured by gas chromatography, and scores on the Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning Scale, and Montgomery-Asberg Depression Rating Scale (MADRS) after controlling for age, sex, smoking and cannabis use. Subjects were divided into three groups according to the predominance of positive or negative symptoms based on PANSS subscale scores; membrane FA levels in the three groups were then compared. More severe negative symptoms measured by PANSS were negatively correlated with two saturated FAs (myristic and margaric acids), one omega-9 monounsaturated FA (MUFA; nervonic acid), and one omega-3 polyunsaturated FA (PUFA; docosapentaenoic acid), and were positively correlated with two omega-9 MUFAs (eicosenoic and erucic acids) and two omega-6 PUFAs (gamma-linolenic and docosadienoic acids). More severe positive symptoms measured by PANSS were correlated only with nervonic acid. No associations were observed between FAs and MADRS scores. In subjects with predominant negative symptoms, the sum of the omega-9 MUFAs and the omega-6:omega-3 FA ratio were both significantly higher than in those with predominant positive symptoms, whereas the sum of omega-3 PUFAs was significantly lower. In conclusion, abnormalities in FA metabolism may contribute to the neurobiology of psychopathology in UHR individuals. In particular, membrane FA alterations may play a role in negative symptoms, which are primary psychopathological manifestations of schizophrenia-related disability. PMID- 26963913 TI - Lowered Diversity and Increased Inbreeding Depression within Peripheral Populations of Wild Rice Oryza rufipogon. AB - BACKGROUND: The distribution of genetic variability from the interior towards the periphery of a species' range is of great interest to evolutionary biologists. Although it has been long presumed that population genetic variation should decrease as a species' range is approached, results of empirical investigations still remain ambiguous. Knowledge regarding patterns of genetic variability as well as affected factors is particularly not conclusive in plants. METHODOLOGY/PRINCIPAL FINDINGS: To determine genetic divergence in peripheral populations of the wild rice Oryza rufipogon Griff. from China, genetic diversity and population structure were studied in five northern & northeastern peripheral and 16 central populations using six microsatellite loci. We found that populations resided at peripheries of the species possessed markedly decreased microsatellite diversity than those located in its center. Population size was observed to be positively correlated with microsatellite diversity. Moreover, there are significantly positive correlations between levels of microsatellite diversity and distances from the northern and northeastern periphery of this species. To investigate genetic structure and heterozygosity variation between generations of O. rufipogon, a total of 2382 progeny seeds from 186 maternal families were further assayed from three peripheral and central populations, respectively. Peripheral populations exhibited significantly lower levels of heterozygosities than central populations for both seed and maternal generations. In comparisons with maternal samples, significantly low observed heterozygosity (HO) and high heterozygote deficit within populations (FIS) values were detected in seed samples from both peripheral and central populations. Significantly lower observed heterozygosity (HO) and higher FIS values were further observed in peripheral populations than those in central populations for seed samples. The results indicate an excess of homozygotes and thus high inbreeding depression in peripheral populations. CONCLUSIONS/SIGNIFICANCE: Our results together suggest that historical contraction of geographical range, demographic changes, and environmental conditions near the northern and northeastern margins of O. rufipogon favor inbreeding and possibly selfing, leading to the rapidly decreased effective population size. Genetic drift, reduced gene flow, and possible local selection, consequently lead to lowered gene diversity, accelerated genetic divergence and increased inbreeding depression found in peripheral populations of O. rufipogon. Given these characteristics observed, northern and northeastern peripheral populations deserve relatively different conservation strategies for either germplasm sampling of ex situ conservation or setting in situ reserves for the adaptation to possible environmental changes and the future germplasm utilization of wild rice. PMID- 26963915 TI - Social Suppressive Behavior Is Organized by the Spatiotemporal Integration of Multiple Cortical Regions in the Japanese Macaque. AB - Under social conflict, monkeys develop hierarchical positions through social interactions. Once the hierarchy is established, the dominant monkey dominates the space around itself and the submissive monkey tries not to violate this space. Previous studies have shown the contributions of the frontal and parietal cortices in social suppression, but the contributions of other cortical areas to suppressive functions remain elusive. We recorded neural activity in large cortical areas using electrocorticographic (ECoG) arrays while monkeys performed a social food-grab task in which a target monkey was paired with either a dominant or a submissive monkey. If the paired monkey was dominant, the target monkey avoided taking food in the shared conflict space, but not in other areas. By contrast, when the paired monkey was submissive, the target monkey took the food freely without hesitation. We applied decoding analysis to the ECoG data to see when and which cortical areas contribute to social behavioral suppression. Neural information discriminating the social condition was more evident when the conflict space was set in the area contralateral to the recording hemisphere. We found that the information increased as the social pressure increased during the task. Before food presentation, when the pressure was relatively low, the parietal and somatosensory-motor cortices showed sustained discrimination of the social condition. After food presentation, when the monkey faced greater pressure to make a decision as to whether it should take the food, the prefrontal and visual cortices started to develop buildup responses. The social representation was found in a sustained form in the parietal and somatosensory-motor regions, followed by additional buildup form in the visual and prefrontal cortices. The representation was less influenced by reward expectation. These findings suggest that social adaptation is achieved by a higher-order self-regulation process (incorporating motor preparation/execution processes) in accordance with the embodied social contexts. PMID- 26963914 TI - Pediatric in-Hospital Death from Infectious Disease in Uganda: Derivation of Clinical Prediction Models. AB - BACKGROUND: Pediatric hospital mortality from infectious diseases in resource constrained countries remains unacceptably high. Improved methods of risk stratification can assist in referral decision making and resource allocation. The purpose of this study was to create prediction models for in-hospital mortality among children admitted with suspected infectious diseases. METHODS: This two-site prospective observational study enrolled children between 6 months and 5 years admitted with a proven or suspected infection. Baseline clinical and laboratory variables were collected on enrolled children. The primary outcome was death during admission. Stepwise logistic regression minimizing Akaike's information criterion was used to identify the most promising multivariate models. The final model was chosen based on parsimony. RESULTS: 1307 children were enrolled consecutively, and 65 (5%) of whom died during their admission. Malaria, pneumonia and gastroenteritis were diagnosed in 50%, 31% and 8% of children, respectively. The primary model included an abnormal Blantyre coma scale, HIV and weight-for-age z-score. This model had an area under the curve (AUC) of 0.85 (95% CI, 0.80-0.89) with a sensitivity and specificity of 83% and 76%, respectively. The positive and negative predictive values were 15% and 99%, respectively. Two alternate models with similar performance characteristics were developed withholding HIV and weight-for-age z-score, for use when these variables are not available. CONCLUSIONS: Risk stratification of children admitted with infectious diseases can be calculated based on several easily measured variables. Risk stratification at admission can be used for allocation of scarce human and physical resources and to guide referral among children admitted to lower level health facilities. PMID- 26963916 TI - Differences in Trait Impulsivity Indicate Diversification of Dog Breeds into Working and Show Lines. AB - Impulsiveness describes the inability to inhibit behaviour in the presence of salient cues. Trait-level impulsivity exists on a continuum and individual differences can be adaptive in different contexts. While breed related differences in behavioural tendency in the domestic dog (Canis familiaris) are well established, the phenomenon within lines of a breed which have been selected more recently is not well studied, although it may challenge the popular notion of breed-typical behaviour. We describe differences in impulsivity between and within two dog breeds with working and show lines selected for different levels of impulsivity: Border Collies (herding work) and Labrador Retrievers (gun work). Recent show line selection might have lessened differences in impulsivity between breeds. We tested this hypothesis on a dataset of 1161 individuals assessed using a validated psychometric tool (Dog Impulsivity Assessment Scale--DIAS). Collies were more impulsive on average, consistent with the original purpose of breed selection. Regarding line, working Collies differed from working Labradors, but show lines from the two breeds were not significantly different. Altered or relaxed artificial selection for behavioural traits when appearance rather than behaviour become the primary focus for breeders may reduce average differences in impulsivity between breeds in show lines. PMID- 26963917 TI - From Grapheme to Phonological Output: Performance of Adults Who Stutter on a Word Jumble Task. AB - PURPOSE: The purpose of the present study was to extend previous research by analyzing the ability of adults who stutter to use phonological working memory in conjunction with lexical access to perform a word jumble task. METHOD: Forty English words consisting of 3-, 4-, 5-, and 6-letters (n = 10 per letter length category) were randomly jumbled using a web-based application. During the experimental task, 26 participants were asked to silently manipulate the scrambled letters to form a real word. Each vocal response was coded for accuracy and speech reaction time (SRT). RESULTS: Adults who stutter attempted to solve fewer word jumble stimuli than adults who do not stutter at the 4-letter, 5 letter, and 6-letter lengths. Additionally, adults who stutter were significantly less accurate solving word jumble tasks at the 4-letter, 5-letter, and 6-letter lengths compared to adults who do not stutter. At the longest word length (6 letter), SRT was significantly slower for the adults who stutter than the fluent controls. CONCLUSION: Results of the current study lend further support to the notion that differences in various aspects of phonological processing, including vision-to-sound conversions, sub-vocal stimulus manipulation, and/or lexical access are compromised in adults who stutter. PMID- 26963920 TI - Atomic Layer Deposition-Confined Nonstoichiometric TiO2 Nanocrystals with Tunneling Effects for Solar Driven Hydrogen Evolution. AB - Ti(3+) self-doped TiO2 nanocrystals (TNCs) confined with controllable atomic layer deposition (ALD) amorphous layers were developed to provide a novel model of metal-insulator-semiconductor (MIS) photocatalysts for hydrogen generation in the ultraviolet to near-infrared region. Photoexcitation of optimized MIS nanostructures consisting of a metal cocatalyst (Pt), electron tunneling layer (ALD TiO2), and photoactive nonstoichiometric core (Ti(3+)-doped TNC) exhibited efficient hydrogen generation (52 MUmol h(-1).g(-1)), good reusability (16 h), and long-term stability (>7 d). The charge-transfer dynamics were examined using transient absorption spectroscopy to clarify the relationship between the photocatalytic activity and the tunneling effect. Our strategies highlight defect engineering in fabricating MIS photocatalysts with improved charge separation and tailored solar energy conversion properties. PMID- 26963918 TI - Daily Activity and Nest Occupation Patterns of Fox Squirrels (Sciurus niger) throughout the Year. AB - The authors investigated the general activity and nest occupation patterns of fox squirrels in a natural setting using temperature-sensitive data loggers that measure activity as changes in the microenvironment of the animal. Data were obtained from 25 distinct preparations, upon 14 unique squirrels, totaling 1385 recording days. The animals were clearly diurnal, with a predominantly unimodal activity pattern, although individual squirrels occasionally exhibited bimodal patterns, particularly in the spring and summer. Even during the short days of winter (9 hours of light), the squirrels typically left the nest after dawn and returned before dusk, spending only about 7 hours out of the nest each day. Although the duration of the daily active phase did not change with the seasons, the squirrels exited the nest earlier in the day when the days became longer in the summer and exited the nest later in the day when the days became shorter in the winter, thus tracking dawn along the seasons. During the few hours spent outside the nest each day, fox squirrels seemed to spend most of the time sitting or lying. These findings suggest that fox squirrels may have adopted a slow life history strategy that involves long periods of rest on trees and short periods of ground activity each day. PMID- 26963921 TI - Chronic Wasting Disease: Transmission Mechanisms and the Possibility of Harvest Management. AB - We develop a model of CWD management by nonselective deer harvest, currently the most feasible approach available for managing CWD in wild populations. We use the model to explore the effects of 6 common harvest strategies on disease prevalence and to identify potential optimal harvest policies for reducing disease prevalence without population collapse. The model includes 4 deer categories (juveniles, adult females, younger adult males, older adult males) that may be harvested at different rates, a food-based carrying capacity, which influences juvenile survival but not adult reproduction or survival, and seasonal force of infection terms for each deer category under differing frequency-dependent transmission dynamics resulting from environmental and direct contact mechanisms. Numerical experiments show that the interval of transmission coefficients beta where the disease can be controlled is generally narrow and efficiency of a harvest policy to reduce disease prevalence depends crucially on the details of the disease transmission mechanism, in particular on the intensity of disease transmission to juveniles and the potential differences in the behavior of older and younger males that influence contact rates. Optimal harvest policy to minimize disease prevalence for each of the assumed transmission mechanisms is shown to depend on harvest intensity. Across mechanisms, a harvest that focuses on antlered deer, without distinguishing between age classes reduces disease prevalence most consistently, whereas distinguishing between young and older antlered deer produces higher uncertainty in the harvest effects on disease prevalence. Our results show that, despite uncertainties, a modelling approach can determine classes of harvest strategy that are most likely to be effective in combatting CWD. PMID- 26963922 TI - Nativity and Health Disparities: Predictors of Immigrant Health. AB - This study examines the differences in the social determinants of health and chronic health conditions of immigrants and nonimmigrants. The logistic regression results indicate that employment, education, poverty, residential status, and neighborhood safety have strong influence on the health of immigrants and native-born Americans; however, gender and place of residence are significant to only nonimmigrant health. For chronic health conditions, age and employment status are significant predictors for immigrants whereas race/ethnicity, age, gender, insurance coverage, and education are important predictors of chronic health conditions among nonimmigrants. Neighborhood safety, English proficiency, and marital status were not significant determinants of the health conditions of both subgroups. The study points to the importance of education, poverty/income, and neighborhood safety as essential determinants of immigrant and nonimmigrant health. However, there are variations in the health predictors for each group. PMID- 26963919 TI - EEG Theta Dynamics within Frontal and Parietal Cortices for Error Processing during Reaching Movements in a Prism Adaptation Study Altering Visuo-Motor Predictive Planning. AB - Modulation of frontal midline theta (fmtheta) is observed during error commission, but little is known about the role of theta oscillations in correcting motor behaviours. We investigate EEG activity of healthy partipants executing a reaching task under variable degrees of prism-induced visuo-motor distortion and visual occlusion of the initial arm trajectory. This task introduces directional errors of different magnitudes. The discrepancy between predicted and actual movement directions (i.e. the error), at the time when visual feedback (hand appearance) became available, elicits a signal that triggers on-line movement correction. Analysis were performed on 25 EEG channels. For each participant, the median value of the angular error of all reaching trials was used to partition the EEG epochs into high- and low-error conditions. We computed event-related spectral perturbations (ERSP) time-locked either to visual feedback or to the onset of movement correction. ERSP time-locked to the onset of visual feedback showed that fmtheta increased in the high- but not in the low-error condition with an approximate time lag of 200 ms. Moreover, when single epochs were sorted by the degree of motor error, fmtheta started to increase when a certain level of error was exceeded and, then, scaled with error magnitude. When ERSP were time-locked to the onset of movement correction, the fmtheta increase anticipated this event with an approximate time lead of 50 ms. During successive trials, an error reduction was observed which was associated with indices of adaptations (i.e., aftereffects) suggesting the need to explore if theta oscillations may facilitate learning. To our knowledge this is the first study where the EEG signal recorded during reaching movements was time-locked to the onset of the error visual feedback. This allowed us to conclude that theta oscillations putatively generated by anterior cingulate cortex activation are implicated in error processing in semi-naturalistic motor behaviours. PMID- 26963924 TI - An approach to standardization of urine sediment analysis via suggestion of a common manual protocol. AB - INTRODUCTION: The results of urine sediment analysis have been reported semiquantitatively. However, as recent guidelines recommend quantitative reporting of urine sediment, and with the development of automated urine sediment analyzers, there is an increasing need for quantitative analysis of urine sediment. Here, we developed a protocol for urine sediment analysis and quantified the results. METHODS: Based on questionnaires, various reports, guidelines, and experimental results, we developed a protocol for urine sediment analysis. The results of this new protocol were compared with those obtained with a standardized chamber and an automated sediment analyzer. Reference intervals were also estimated using new protocol. RESULTS: We developed a protocol with centrifugation at 400 g for 5 min, with the average concentration factor of 30. The correlation between quantitative results of urine sediment analysis, the standardized chamber, and the automated sediment analyzer were generally good. The conversion factor derived from the new protocol showed a better fit with the results of manual count than the default conversion factor in the automated sediment analyzer. CONCLUSIONS: We developed a protocol for manual urine sediment analysis to quantitatively report the results. This protocol may provide a mean for standardization of urine sediment analysis. PMID- 26963923 TI - Preserving Subjective Wellbeing in the Face of Psychopathology: Buffering Effects of Personal Strengths and Resources. AB - BACKGROUND: Many studies on resilience have shown that people can succeed in preserving mental health after a traumatic event. Less is known about whether and how people can preserve subjective wellbeing in the presence of psychopathology. We examined to what extent psychopathology can co-exist with acceptable levels of subjective wellbeing and which personal strengths and resources moderate the association between psychopathology and wellbeing. METHODS: Questionnaire data on wellbeing (Manchester Short Assessment of Quality of Life/Happiness Index), psychological symptoms (Depression Anxiety Stress Scales), and personal strengths and resources (humor, Humor Style questionnaire; empathy, Empathy Quotient questionnaire; social company; religion; daytime activities, Living situation questionnaire) were collected in a population-based internet study (HowNutsAreTheDutch; N = 12,503). Data of the subset of participants who completed the above questionnaires (n = 2411) were used for the present study. Regression analyses were performed to predict wellbeing from symptoms, resources, and their interactions. RESULTS: Satisfactory levels of wellbeing (happiness score 6 or higher) were found in a substantial proportion of the participants with psychological symptoms (58% and 30% of those with moderate and severe symptom levels, respectively). The association between symptoms and wellbeing was large and negative (-0.67, P < .001), but less so in persons with high levels of self-defeating humor and in those with a partner and/or pet. Several of the personal strengths and resources had a positive main effect on wellbeing, especially self-enhancing humor, having a partner, and daytime activities. CONCLUSIONS: Cultivating personal strengths and resources, like humor, social/animal company, and daily occupations, may help people preserve acceptable levels of wellbeing despite the presence of symptoms of depression, anxiety, and stress. PMID- 26963925 TI - Coinfection of Leishmania (Viannia) braziliensis and Streptococcus pneumoniae in Multiple Cutaneous Lesions. PMID- 26963932 TI - Potential Projective Material on the Rorschach: Comparing Comprehensive System Protocols to Their Modeled R-Optimized Administration Counterparts. AB - Exner ( 1989 ) and Weiner ( 2003 ) identified 3 types of Rorschach codes that are most likely to contain personally relevant projective material: Distortions, Movement, and Embellishments. We examine how often these types of codes occur in normative data and whether their frequency changes for the 1st, 2nd, 3rd, 4th, or last response to a card. We also examine the impact on these variables of the Rorschach Performance Assessment System's (R-PAS) statistical modeling procedures that convert the distribution of responses (R) from Comprehensive System (CS) administered protocols to match the distribution of R found in protocols obtained using R-optimized administration guidelines. In 2 normative reference databases, the results indicated that about 40% of responses (M = 39.25) have 1 type of code, 15% have 2 types, and 1.5% have all 3 types, with frequencies not changing by response number. In addition, there were no mean differences in the original CS and R-optimized modeled records (M Cohen's d = -0.04 in both databases). When considered alongside findings showing minimal differences between the protocols of people randomly assigned to CS or R-optimized administration, the data suggest R-optimized administration should not alter the extent to which potential projective material is present in a Rorschach protocol. PMID- 26963933 TI - The Developmental Biology of Parasitic Nematodes. PMID- 26963934 TI - Observations and impacts of transported Canadian wildfire smoke on ozone and aerosol air quality in the Maryland region on June 9-12, 2015. AB - Canadian wildfire smoke impacted air quality across the northern Mid-Atlantic (MA) of the United States during June 9-12, 2015. A multiday exceedance of the new 2015 70-ppb National Ambient Air Quality Standard (NAAQS) for ozone (O3) followed, resulting in Maryland being incompliant with the Environmental Protection Agency's (EPA) revised 2015 O3 NAAQS. Surface in situ, balloon-borne, and remote sensing observations monitored the impact of the wildfire smoke at Maryland air quality monitoring sites. At peak smoke concentrations in Maryland, wildfire-attributable volatile organic compounds (VOCs) more than doubled, while non-NOx oxides of nitrogen (NOz) tripled, suggesting long range transport of NOx within the smoke plume. Peak daily average PM2.5 was 32.5 ug m(-3) with large fractions coming from black carbon (BC) and organic carbon (OC), with a synonymous increase in carbon monoxide (CO) concentrations. Measurements indicate that smoke tracers at the surface were spatially and temporally correlated with maximum 8-hr O3 concentrations in the MA, all which peaked on June 11. Despite initial smoke arrival late on June 9, 2015, O3 production was inhibited due to ultraviolet (UV) light attenuation, lower temperatures, and nonoptimal surface layer composition. Comparison of Community Multiscale Air Quality (CMAQ) model surface O3 forecasts to observations suggests 14 ppb additional O3 due to smoke influences in northern Maryland. Despite polluted conditions, observations of a nocturnal low-level jet (NLLJ) and Chesapeake Bay Breeze (BB) were associated with decreases in O3 in this case. While infrequent in the MA, wildfire smoke may be an increasing fractional contribution to high-O3 days, particularly in light of increased wildfire frequency in a changing climate, lower regional emissions, and tighter air quality standards. IMPLICATIONS: The presented event demonstrates how a single wildfire event associated with an ozone exceedance of the NAAQS can prevent the Baltimore region from complying with lower ozone standards. This relatively new problem in Maryland is due to regional reductions in NOx emissions that led to record low numbers of ozone NAAQS violations in the last 3 years. This case demonstrates the need for adequate means to quantify and justify ozone impacts from wildfires, which can only be done through the use of observationally based models. The data presented may also improve future air quality forecast models. PMID- 26963935 TI - Crystal Structure of the Fab Fragment of an Anti-ofloxacin Antibody and Exploration of Its Specific Binding. AB - The limited knowledge on the mechanism of interactions between small contaminants and the corresponding antibodies greatly inhibits the development of enzyme linked immunosorbent assay methods. In this study, the crystal structure of a Fab fragment specific for ofloxacin was obtained. On the basis of the crystal characteristics, the modeling of the interactions between ofloxacin and the Fab revealed that TYR31 and HIS99 of the heavy chain and MET20 and GLN79 of the light chain formed a hydrophobic region and that SER52 and ALA97 of the heavy chain and TYR35 of the light chain formed a salt bridge and two hydrogen bonds for specific binding. The key roles of SER52 and ALA97 were further confirmed by site-directed mutation. A specificity analysis using 14 ofloxacin analogues indicates that the length of the bond formed between the piperazine ring and the antibody plays key roles in specific recognition. This work helps to clarify the mechanisms through which antibodies recognize small molecules and improve immune detection methods. PMID- 26963936 TI - Predicting Prostate Biopsy Outcomes: A Preliminary Investigation on Screening with Ultrahigh B-Value Diffusion-Weighted Imaging as an Innovative Diagnostic Biomarker. AB - BACKGROUND: Routine screening of prostate specific antigen (PSA) is no longer recommended because of a high rate of over-diagnosis of prostate cancer (PCa). OBJECTIVE: To evaluate the efficacy of diffusion-weighted magnetic resonance imaging (DW-MRI) for PCa detection, and to explore the clinical utility of ultrahigh b-value DW-MRI in predicting prostate biopsy outcomes. METHODOLOGY: 73 male patients were selected for the study. They underwent 3T MRI using T2WI conventional DW-MRI with b-value 1000 s/mm2, and ultrahigh b-value DW-MRI with b values of 2000 s/mm2 and 3000 s/mm2. Two radiologists evaluated individual prostate gland images on a 5-point rating scale using PI-RADS, for the purpose of region-specific comparisons among modalities. Sensitivity, specificity, accuracy, positive predictive value (PPV), negative predictive value (NPV) and likelihood ratios (LR) were investigated for each MRI modality. The area under the receiver operating characteristic (ROC) curve (AUC) was also calculated. RESULTS: Results showed the improved diagnostic value of ultrahigh b-value DWI-MRI for detection of PCa when compared to other b values and conventional MRI protocols. Sensitivity values for 3000 s/mm2 in both peripheral zone (PZ) and transition zone (TZ) were significantly higher than those observed with conventional DW-MRI Specificity values for 3000 s/mm2 in the TZ were significantly higher than other b-value images, whereas specificity values using 3000 s/mm2 in the PZ were not significantly higher than 2000 s/mm2 images. PPV and NPV between 3000 s/mm2 and the other three modalities were significantly higher for both PZ and TZ images. The PLRs and NLRs of b-value 3000 s/mm2 DW-MRI in the PZ and TZ were also recorded. ROC analysis showed greater AUCs for the b value 3000 s/mm2 DWI than for the other three modalities. CONCLUSIONS: DW-MRI with a b-value of 3000 s/mm2 was found to be the most accurate and reliable MRI modality for PCa tumor detection and localization, particularly for TZ lesion discrimination. It may be stated that the b-value of 3000 s/mm2 is a novel, improved diagnostic biomarker with greater predictive accuracy for PCa prior to biopsy. PMID- 26963937 TI - Seasonality of Influenza A(H7N9) Virus in China-Fitting Simple Epidemic Models to Human Cases. AB - BACKGROUND: Three epidemic waves of influenza A(H7N9) (hereafter 'H7N9') human cases have occurred between March 2013 and July 2015 in China. However, the underlying transmission mechanism remains unclear. Our main objective is to use mathematical models to study how seasonality, secular changes and environmental transmission play a role in the spread of H7N9 in China. METHODS: Data on human cases and chicken cases of H7N9 infection were downloaded from the EMPRES-i Global Animal Disease Information System. We modelled on chicken-to-chicken transmission, assuming a constant ratio of 10-6 human case per chicken case, and compared the model fit with the observed human cases. We developed three different modified Susceptible-Exposed-Infectious-Recovered-Susceptible models: (i) a non-periodic transmission rate model with an environmental class, (ii) a non-periodic transmission rate model without an environmental class, and (iii) a periodic transmission rate model with an environmental class. We then estimated the key epidemiological parameters and compared the model fit using Akaike Information Criterion and Bayesian Information Criterion. RESULTS: Our results showed that a non-periodic transmission rate model with an environmental class provided the best model fit to the observed human cases in China during the study period. The estimated parameter values were within biologically plausible ranges. CONCLUSIONS: This study highlighted the importance of considering secular changes and environmental transmission in the modelling of human H7N9 cases. Secular changes were most likely due to control measures such as Live Poultry Markets closures that were implemented during the initial phase of the outbreaks in China. Our results suggested that environmental transmission via viral shedding of infected chickens had contributed to the spread of H7N9 human cases in China. PMID- 26963938 TI - Value of Gamma-Glutamyl Transpeptidase for Diagnosis of Biliary Atresia by Correlation With Age. AB - OBJECTIVES: The aim of the study was to analyze the value of gamma-glutamyl transpeptidase (GGT) for distinguishing biliary atresia (BA) from non-BA for patients suspected of having neonatal obstructive jaundice by correlation with age. METHODS: From January 2003 to March 2014, cholangiography and/or surgical exploration were undertaken in 1469 patients with suspicion of having neonatal obstructive jaundice. A total of 1338 patients were diagnosed with BA intraoperatively. Preoperative medical records were compared between BA and non BA patients. RESULTS: Preoperative levels of total bilirubin, direct bilirubin, and GGT were significantly higher in the BA group (P < 0.05), whereas the non-BA group had higher alkaline phosphatase levels (P = 0.0003). The area under the receiver operating characteristic curve of total bilirubin, direct bilirubin, GGT, and alkaline phosphatase was 0.584, 0.614, 0.843, and 0.398, respectively. In all age groups (i: 31-60 days; ii: 61-90 days; iii: 91-120 days; iv: >=121 days), BA groups had higher GGT levels (in IU/L) (i: 725.3 +/- 549.9; ii: 927.0 +/- 679.8; iii: 1114.3 +/- 823.1; iv: 767.5 +/- 666.7). The level of GGT in patients with BA younger than 30 days was 834.2 +/- 475.3 IU/L. GGT levels had the highest diagnostic value (0.869) in group ii (61-90 days) and the lowest diagnosis value (0.712) in group iv (>=121 days). At a cutoff of >303 IU/L in group ii (61-90 days), GGT had 82.8% sensitivity and 81.6% specificity for the discrimination of BA. CONCLUSIONS: GGT levels contribute to the diagnosis of BA before 120 days. Age must be considered if using GGT levels as a diagnostic test for BA. PMID- 26963939 TI - Parenteral Nutrition of Preterm Infants May Lead to Inadequate Phosphorus Supply. PMID- 26963941 TI - Effects of 10-week eccentric overload training on kinetic parameters during change of direction in football players. AB - The aim of the current study was to analyse the effect of 10-week eccentric overload training on kinetic parameters during change of direction (COD) in U-19 football players. The outcome measured included relative peak braking (rPB) and propulsive force (rPF), contact time (CT), time spent during braking (BT) and propulsive phase (PT), relative total (rTOT_IMP), braking (rB_IMP) and propulsive (rP_IMP) impulses. Between-group results showed a substantial better improvement (likely) in CT (ES: 0.72) and BT (ES: 0.74) during side-step cutting, and in rPB (ES: 0.84) and rB_IMP (ES: 0.72) during crossover cutting, in the experimental group (EXP) in comparison to control group (CON). Within-group analysis showed a substantially better performance (likely to almost certain) in CT (ES: 1.19), BT (ES: 1.24), PT (ES: 0.70), rPB (ES: 0.75), rPF (ES: 0.68), rTOT_IMP (ES: 0.48) and rB_IMP (ES: 0.50) in EXP during side-step cutting. Regarding crossover cutting, within-group analysis showed a substantial better performance (likely to almost certain) in CT (ES: 0.75), rPB (ES: 0.75), rPF (ES: 1.34), rTOT_IMP (ES: 0.61), rB_IMP (ES: 0.76) and rP_IMP (ES: 0.46) in EXP. In conclusion, the eccentric overload-based programme led to an improvement in kinetic parameters during COD football tasks. PMID- 26963942 TI - Study on the disparate transition behaviors of the electrical/physical properties in PEDOT:PSS film depending on solvent species under a follow-up solution treatment process. AB - In most solution-processed organic devices, a poly(3,4-ethylenedioxythiophene) (PEDOT) polymerized with poly(4-styrenesulfonate) (PSS) film is inevitably affected by various conditions during the subsequent solution-coating processes. To investigate the effects of direct solvent exposure on the properties of PEDOT polymerized with PSS (PEDOT:PSS) films, photoemission spectroscopy-based analytical methods were used before and after solvent-coating processes. Our results clearly indicate that PEDOT: PSS films undergo a different transition mechanism depending on the solubility of the solvent in water. The water-miscible solvents induce the solvation of hydrophilic PSS chains. As a result, this process allows the solvent to diffuse into the PEDOT: PSS film, and a conformational change between PEDOT and PSS occurs. On the other hand, the water immiscible organic solvents cause the partial adsorption of solvent molecules at the PE surface, which leads to changes in the surface properties, including work function. Based on our finding, we demonstrate that the energy-level alignments at the organic semiconductor/electrode interface for the PEDOT: PSS films can be controlled by simple solvent treatments. PMID- 26963940 TI - Golimumab Therapy in Six Patients With Severe Pediatric Onset Crohn Disease. AB - Anti-tumor necrosis factor-alpha (TNF-alpha) blockade is so far the most effective therapy for extensive pediatric Crohn disease (CD), but loss of response is frequently encountered. We describe here the use of golimumab (Simponi) in 6 pediatric CD patients with antibody formation/loss of response to infliximab and adalimumab. Most patients had undergone surgery but had poor disease control. After introduction of golimumab, the levels of inflammatory markers and fecal calprotectin declined at first, but the response was not sustained. Each patient needed dose escalation of golimumab from 4 to 2 week intervals, to maintain response and to increase trough levels. Importantly, most patients were able to attend school when undergoing golimumab therapy. As with other anti-TNFalpha drugs, follow-up of drug levels is advisable. Although golimumab therapy failed in most patients, it is an alternate treatment option in pediatric patients with severe CD. The therapeutic response, however, is suboptimal in anti-TNFalpha exposed patients. PMID- 26963943 TI - An efficient technique for estimating the two-dimensional temperature distributions around multiple cryo-surgical probes based on combining contributions of unit circles. AB - This study presents an efficient, fast and accurate method for estimating the two dimensional temperature distributions around multiple cryo-surgical probes. The identical probes are inserted into the same depth and are operated simultaneously and uniformly. The first step in this method involves numerical derivation of the temporal performance data of a single probe, embedded in a semi-infinite, tissue like medium. The results of this derivation are approximated by algebraic expressions that form the basis for computing the temperature distributions of multiple embedded probes by combining the data of a single probe. Comparison of isothermal contours derived by this method to those computed numerically for a variety of geometrical cases, up to 15 inserted probes and 2-10 min times of operation, yielded excellent results. Since this technique obviates the solution of the differential equations of multiple probes, the computational time required for a particular case is several orders of magnitude shorter than that needed for obtaining the full numerical solution. Blood perfusion and metabolic heat generation rates are demonstrated to inhibit the advancement of isothermal fronts. Application of this method will significantly shorten computational times without compromising the accuracy of the results. It may also facilitate expeditious consideration of the advantages of different modes of operation and the number of inserted probes at the early design stage. PMID- 26963944 TI - Low level laser therapy in non-surgical management of osteoradionecrosis of the jaws. PMID- 26963945 TI - A computer-guided minimally-invasive technique for orthodontic forced eruption of impacted canines. AB - BACKGROUND: The aim of this study was to develop a computer-guided minimally invasive protocol for the surgical application of an orthodontic traction during the forced eruption of an impacted canine. METHODS: 3Diagnosys(r) software was used to evaluate impacted canines position and to plan the surgical access, taking into account soft and hard tissues thickness, orthodontic traction path and presence of possible obstacles. Geomagic(r) software was used for reverse engineering and RhinocerosTM software was employed as three-dimensional modeller in preparing individualized surgical guides. Surgical access was gained flapless through the use of a mucosal punch for soft tissues, followed by a trephine bur with a pre-adjusted stop for bone path creation. A diamond bur mounted on SONICflex(r) 2003/L handpiece was used to prepare a 2-mm-deep calibrated hole into the canine enamel where a titanium screw connected with a stainless steel ligature was screwed. In-vitro pull-out tests, radiological and SEM analysis were realized in order to investigate screw stability and position. RESULTS: In two out of ten samples the screw was removed after the application of a 1-kg pull-out force. Radiological and SEM analysis demonstrated that all the screws were inserted into the enamel without affecting dentine integrity. CONCLUSIONS: This computer-guided minimally-invasive technique allowed a precise and reliable positioning of screws utilized during the orthodontic traction of impacted canines. PMID- 26963946 TI - The genetic predisposition to bronchopulmonary dysplasia. AB - PURPOSE OF REVIEW: Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease in premature infants. Twin studies have shown strong heritability underlying this disease; however, the genetic architecture of BPD remains unclear. RECENT FINDINGS: A number of studies employed different approaches to characterize the genetic aberrations associated with BPD, including candidate gene studies, genome-wide association studies, exome sequencing, integrative omics analysis, and pathway analysis. Candidate gene studies identified a number of genes potentially involved with the development of BPD, but the etiological contribution from each gene is not substantial. Copy number variation studies and three independent genome-wide association studies did not identify genetic variations significantly and consistently associated with BPD. A recent exome sequencing study pointed to rare variants implicated in the disease. In this review, we summarize these studies' methodology and findings, and suggest future research directions to better understand the genetic underpinnings of this potentially life-long lung disease. SUMMARY: Genetic factors play a significant role in the development of BPD. Recent studies suggested that rare variants in genes participating in lung development pathways could contribute to BPD susceptibility. PMID- 26963948 TI - Surgical options for the management of severe functional constipation in children. AB - PURPOSE OF REVIEW: Constipation is a very common problem in pediatrics with both the severity of presentations and treatments varying across a broad spectrum. The majority of children with functional constipation are managed successfully without the need for specialized testing and surgical intervention. Those who present with intractable constipation, with or without fecal soiling, require referrals for motility testing that helps determine both medical and surgical management, and interventions. The literature was reviewed for publications on surgical approaches to children with severe constipation, including assessing the quality and levels of evidence and the use of objective measures to determine outcomes. RECENT FINDINGS: There is very little in the way of recent studies evaluating surgical indications or treatment approaches for functional constipation, apart from one systematic review and one recent expert review. Although the systematic review was published in the last year, most of the studies it analyzes are older. The vast majority of studies comprise level 4 and 5 evidence. SUMMARY: The indication for most surgical procedures is 'failed' medical management, yet no standardized definition for this exists. Many surgical procedures are proposed with little evidence to show outcomes. We recommend that the surgical evaluation and treatment of children with constipation needs to be protocolized and studied in a prospective manner using validated outcomes measures. Our center's current protocol is described. PMID- 26963947 TI - Anaphylaxis in children. AB - PURPOSE OF REVIEW: Anaphylaxis is a serious allergic reaction that can be life threatening. We will review the most recent evidence regarding the diagnosis, treatment, monitoring, and prevention of anaphylaxis in children. RECENT FINDINGS: Histamine and tryptase are not sufficiently accurate for the routine diagnosis of anaphylaxis, so providers should continue to rely on clinical signs. Platelet-activating factor shows some promise in the diagnosis of anaphylaxis. Intramuscular is the best route for epinephrine administration for children of all weights. Glucocorticoids may reduce prolonged hospitalizations for anaphylaxis. Children with anaphylaxis who have resolving symptoms and no history of asthma or previous biphasic reactions may be observed for as few as 3-4 h before emergency department discharge. Early peanut introduction reduces the risk of peanut allergy. SUMMARY: Epinephrine remains the mainstay of anaphylaxis treatment, and adjuvant medications should not be used in its place. All patients with anaphylaxis should be prescribed and trained to use an epinephrine autoinjector. Clinically important biphasic reactions are rare. Observation in the emergency department for most anaphylaxis patients is recommended, with the duration determined by risk factors. Admission is reserved for patients with unimproved or worsening symptoms, or prior biphasic reaction. PMID- 26963949 TI - Pediatric Differentiated Thyroid Carcinoma in The Netherlands: A Nationwide Follow-Up Study. AB - INTRODUCTION: Treatment for differentiated thyroid carcinoma (DTC) in pediatric patients is based mainly on evidence from adult series due to lack of data from pediatric cohorts. Our objective was to evaluate presentation, treatment-related complications, and long-term outcome in patients with pediatric DTC in The Netherlands. PATIENTS AND METHODS: In this nationwide study, presentation, complications, and outcome of patients with pediatric DTC (age at diagnosis <=18 y) treated in The Netherlands between 1970 and 2013 were assessed using medical records. RESULTS: We identified 170 patients. Overall survival was 99.4% after a median follow-up of 13.5 years (range 0.3-44.7 y). Extensive follow-up data were available for 105 patients (83.8% women), treated in 39 hospitals. Median age at diagnosis was 15.6 years (range 5.8-18.9 y). At initial diagnosis, 43.8% of the patients had cervical lymph node metastases; 13.3% had distant metastases. All patients underwent total thyroidectomy. Radioiodine was administered to 97.1%, with a median cumulative activity of 5.66 GBq (range 0.74-35.15 GBq). Life-long postoperative complications (permanent hypoparathyroidism and/or recurrent laryngeal nerve injury) were present in 32.4% of the patients. At last known follow-up, 8.6% of the patients had persistent disease and 7.6% experienced a recurrence. TSH suppression was not associated with recurrences (odds ratio 2.00, 95% confidence interval 0.78-5.17, P = .152). CONCLUSIONS: Survival of pediatric DTC is excellent. Therefore, minimizing treatment-related morbidity takes major priority. Our study shows a frequent occurrence of life-long postoperative complications. Adverse effects may be reduced by the centralization of care, which is crucial for children with DTC. PMID- 26963951 TI - Acromegaly Is More Severe in Patients With AHR or AIP Gene Variants Living in Highly Polluted Areas. AB - CONTEXT: An increased prevalence of acromegaly was found some years ago in a highly polluted area in North-Eastern Sicily, where high concentration of nonmethane hydrocarbons, volatile organic compounds, and cadmium was found. Aryl hydrocarbon receptor (AHR) pathway has a key role in detoxification of these compounds and in tumorigenesis. OBJECTIVE: We correlated the occurrence of AHR and/or AHR-interacting protein (AIP) gene variants with acromegaly severity according to pollution exposition. DESIGN, SETTING, and PATIENTS: This was an observational, perspective study conducted over 7 years in four Italian referral centers for pituitary diseases in which 210 patients with acromegaly were enrolled between 2008 and 2015. INTERVENTION: Genetic screening of patients for AHR and AIP variants. MAIN OUTCOME MEASURES: Clinical, biochemical, and radiological data of patients with and without AIP and/or AHR gene variants, living in polluted (high-risk for health, [HR]) or nonpolluted (NP) areas of five Italian regions were evaluated and compared. RESULTS: Among the 23 patients from HR areas, nine showed AHR or AIP variants. Mean IGF-I levels and pituitary tumor diameter were significantly higher in these nine patients (HR/VAR+) than in the other 14 (HR/VAR-) and in the 187 from NP areas (44 NP/VAR+). Somatostatin analogs significantly decreased mean GH and IGF-I levels in patients from NP areas and in HR/VAR- (GH P < .05; IGF-I times the upper limit of normal P < .01) but not in HR/VAR+ group. CONCLUSIONS: Genetic variants potentially inducing functional abnormalities of the aryl hydrocarbon receptor (AHR) pathway are associated with a more severe acromegaly, increased pituitary tumor size, and somatostatin analog resistance in patients living in HR areas. PMID- 26963950 TI - Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences. AB - CONTEXT: Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous condition resembling primary hyperparathyroidism (PHPT) but not curable by surgery; FHH types 1, 2, and 3 are due to loss-of-function mutations of the CASR, GNA11, or AP2S1 genes, respectively. OBJECTIVE: This study aimed to compare the phenotypes of patients with genetically proven FHH types 1 or 3 or PHPT. DESIGN, SETTING, AND PATIENTS: This was a mutation analysis in a large cohort, a cross-sectional comparison of 52 patients with FHH type 1, 22 patients with FHH type 3, 60 with PHPT, and 24 normal adults. INTERVENTION: There were no interventions. MAIN OUTCOME MEASURES: Abnormalities of the CASR, GNA11, and AP2S1 genes, blood calcium, phosphate, and PTH concentrations, urinary calcium excretion were measured. RESULTS: In 133 families, we detected 101 mutations in the CASR gene, 68 of which were previously unknown, and in 19 families, the three recurrent AP2S1 mutations. No mutation was detected in the GNA11 gene. Patients with FHH type 3 had higher plasma calcium concentrations than patients with FHH type 1, despite having similar PTH concentrations and urinary calcium excretion. Renal tubular calcium reabsorption levels were higher in patients with FHH type 3 than in those with FHH type 1. Plasma calcium concentration was higher whereas PTH concentration and urinary calcium excretion were lower in FHH patients than in PHPT patients. In patients with FHH or PHPT, all data groups partially overlapped. CONCLUSION: In our population, AP2S1 mutations affect calcium homeostasis more severely than CASR mutations. Due to overlap, the risk of confusion between FHH and PHPT is high. PMID- 26963952 TI - A Subset of Men With Age-Related Decline in Testosterone Have Gonadotroph Autoantibodies. AB - CONTEXT: Age-related decline in serum testosterone (T) is being increasingly diagnosed. In most men, it associates with low or inappropriately normal gonadotropin levels, which suggests a hypothalamic-pituitary etiology. Autoantibodies against adenohypophyseal cells have been associated with pituitary dysfunction; however, the prevalence of pituitary autoimmunity in this age related T decline has not been assessed. OBJECTIVES: This is a proof-of-concept study with the objective of determining the prevalence of antibodies to gonadotrophs in older men with age-related low T and compare it with healthy young and older eugonadal men. STUDY DESIGN: This is a cross-sectional case control study of 182 men. Cases included 100 older men (>=65 years) with age related low T levels; the control groups were composed of 50 young and 32 older healthy eugonadal men. Serum antibodies against the anterior pituitary gland were measured using a two-step approach: 1) single indirect immunofluorescence (ie, participant serum only) to determine the pattern of cytosolic staining; and 2) double indirect immunofluorescence (ie, participant serum plus a commercial adenohypophyseal hormone antibody) to identify the anterior pituitary cell type recognized by the patient's antibodies). RESULTS: In participants with positive antipituitary antibodies, the granular cytosolic pattern (highly predictive of pituitary autoimmunity) was only seen in older men with age-related low T (4%) and none in control groups (0%, P = .001). Double indirect immunofluorescence confirmed that pituitary antibodies were exclusively directed against the gonadotrophs. CONCLUSION: A subset of older men with age-related low T levels have specific antibodies against the gonadotrophs. Whether these antibodies are pathogenic and contributory to the age-related decline in T remains to be established. PMID- 26963953 TI - Temporal Changes in Androgens and Estrogens Are Associated With All-Cause and Cause-Specific Mortality in Older Men. AB - CONTEXT: The dynamic temporal relationship between changes in serum reproductive hormones and mortality in men has not been reported. OBJECTIVE: The objective of the study was to examine the relationship between progressive changes in circulating reproductive hormones over time with all-cause and cause-specific mortality in older men. DESIGN, SETTING, AND PARTICIPANTS: Community-dwelling men aged 70 years and older from the Concord Health and Ageing in Men Project study were assessed at baseline (2005-2007, n = 1705) and at 2-year (n = 1367) and 5 year follow-up (n = 958). MAIN OUTCOMES AND MEASURES: At all three time-points, T, DHT, estradiol (E2), and estrone (E1) were measured by liquid chromatography tandem mass spectrometry, and SHBG, LH, and FSH were determined by immunoassay and calculated free T (cFT) was calculated. Mortality was ascertained through the state death registry. Statistical modeling was by general estimating equations with the Poisson regression. RESULTS: Serum T over time (relative risk [RR] per 1 SD decrease in concentration: 1.18, 95% confidence interval [CI] 1.05-1.32), DHT (RR 1.17, 95% CI 1.05-1.32), and E2 (RR 1.46, 95% CI 1.30-1.63) as well as cFT (RR 1.27, 95% CI 1.13-1.41) was associated with all-cause mortality. After adjusting for multiple covariables, the decline in serum T (RR 1.17, 95% CI 1.03 1.32), DHT (RR 1.17, 95% CI 1.03-1.32), and cFT (RR 1.13, 95% CI 1.08-1.19) remained significantly associated with all-cause mortality. Similar relationships were observed for cancer but not cardiovascular mortality. Progressive decline in serum E2 levels remained significantly associated with all-cause (RR 1.49, 95% CI 1.31-1.69), cancer (RR 1.82, 95% CI 1.45-2.28), and cardiovascular (RR 1.37, 95% CI 1.13-1.66) mortality, even after adjustment for covariables. Serum E1, LH, FSH, and SHBG were not associated with all-cause, cancer, or cardiovascular mortality. CONCLUSION: Dynamic temporal changes in serum T, cFT, DHT, and E2 (but not E1, LH, FSH, and SHBG) in older men are associated with all-cause and cause specific mortality in distinct patterns. PMID- 26963954 TI - Association of Mutations in SLC12A1 Encoding the NKCC2 Cotransporter With Neonatal Primary Hyperparathyroidism. AB - CONTEXT: Primary hyperparathyroidism with hypercalciuria has not been described in the newborn period. OBJECTIVE: Our objectives are to identify the genetic basis for neonatal primary hyperparathyroidism in a family with 2 affected children. SUBJECTS: An African American boy presenting with mild neonatal primary hyperparathyroidism and hypercalciuria was evaluated at The Children's Hospital of Philadelphia. His older brother with neonatal primary hyperparathyroidism had died in infancy of multiple organ failure. METHODS: We collected clinical and biochemical data and performed exome sequencing analysis on DNA from the patient and his unaffected mother after negative genetic testing for known causes of primary hyperparathyroidism. RESULTS: Exome sequencing followed by Sanger sequencing disclosed 2 heterozygous mutations, c.1883C>A, p.(A628D) and c.2786_2787insC, p.(T931fsX10), in the SLC12A1 gene, which was previously implicated in antenatal type 1 Bartter syndrome. Sanger sequencing confirmed the 2 mutations in the proband and his deceased brother; both parents were heterozygous for different mutations and an unaffected sister was homozygous for wild-type alleles. CONCLUSIONS: These results demonstrate a previously unrecognized association between neonatal primary hyperparathyroidism and mutation of SLC12A1, the cause of antenatal Bartter syndrome type 1, and suggest that the loss of sodium-potassium-chloride cotransporter-2 cotransporter activity influences parathyroid gland function. PMID- 26963955 TI - Outcomes from eye movement desensitization and reprocessing in active-duty service members with posttraumatic stress disorder. AB - OBJECTIVE: Eye movement desensitization and reprocessing (EMDR) is one of the therapy interventions recommended by the Veterans Affairs and Department of Defense Clinical Practice Guidelines. However, the literature concerning the effectiveness of this treatment modality in military service members is sparse. This study investigated the efficacy of EMDR in active-duty service members. METHOD: We conducted an effectiveness study with a record review from active-duty military mental health clinics where clinical outcomes had been monitored over a 10-week period using self-report measures of posttraumatic stress and disability. Symptom scores were examined over time in 331 service members who met presumptive criteria for the disorder on the PTSD Checklist-Military Version (PCL-M), who were in psychotherapy, and who received (n = 46) or didn't receive (n = 285) EMDR. RESULTS: Results indicated that patients receiving EMDR had significantly fewer therapy sessions over 10 weeks but had significantly greater gains in their PCL-M scores than did individuals not receiving EMDR. CONCLUSIONS: Randomized, controlled trials are still needed, but these findings provide further support for the use of EMDR in service members with PTSD. (PsycINFO Database Record PMID- 26963956 TI - Within-unit relationship quality mediates the association between military sexual trauma and posttraumatic stress symptoms in veterans separating from military service. AB - OBJECTIVE: Few studies have examined the impact of military sexual trauma (MST) on social functioning during deployment. Yet consideration of unit relationships during deployment may be important, given that military unit cohesion and support can provide protective effects against the stress of combat, and reduce the likelihood of developing posttraumatic stress disorder. METHOD: Although prior research has posited that depleted social resources are one pathway through which MST is associated with posttraumatic stress symptoms (PTSS), no studies have statistically tested this theory. This study examined the association of MST and PTSS and evaluated the potential mediating role of decreased unit relationship quality. Mediational analyses were conducted on a sample of veterans following discharge from military service (N = 818; 328 women, 490 men). RESULTS: Women were significantly more likely to experience MST than men. As hypothesized, experiences of MST during deployment were associated with higher PTSS. MST experiences were associated with less trust in and support from one's military unit, which partially mediated the association between MST and PTSS. The indirect effect of MST on PTSS through lower unit relationship quality accounted for 20.4% of the total effect of MST on PTSS. CONCLUSIONS: While the retrospective study design precludes tests of causality, mediational findings provided statistical evidence that lower unit relationship quality partially explains the association between MST and PTSS. This finding is consistent with interpersonal theories of trauma response suggesting that the deleterious effects of MST may be in part due to its erosion of social resources during deployment. (PsycINFO Database Record PMID- 26963957 TI - Racial discrimination as race-based trauma, coping strategies, and dissociative symptoms among emerging adults. AB - OBJECTIVE: The race-based traumatic stress theory (Carter, 2007) suggests that some racial- and ethnic-minority individuals experience racial discrimination as psychological trauma, as it may elicit a response comparable to posttraumatic stress. In the present study, we examined this further by determining the relation between racial discrimination and dissociation, a common response to trauma exposure. Further, we examined whether active coping strategies specifically employed to cope with racial discrimination related to less dissociative symptomatology. METHOD: The predominant racial- and ethnic-minority sample (N = 743) of emerging adults, ages 18-29, recruited from a public university in northeastern United States completed a battery of self-report measures on racial discrimination, responses to racial discrimination, traumatic life events, and dissociative symptoms. RESULTS: Frequency of racial discrimination was positively associated with dissociative symptoms in regression analyses adjusted for demographics and other traumatic life events. In addition, more active coping strategies in response to racial discrimination were negatively associated with dissociative symptoms. CONCLUSION: Racial- and ethnic minority emerging adults who experience racial discrimination, possibly as traumatic, may be more vulnerable to dissociative symptoms. However, different strategies of coping with racial discrimination may differentially impact risk for dissociation. (PsycINFO Database Record PMID- 26963958 TI - Types of trauma in adolescence and their relation to dissociation: A mixed methods study. AB - OBJECTIVE: To study adolescent traumatization and the impact of various types of trauma on dissociative experiences in a sample of 239 Swedish youngsters, 13 to 20 years of age, with diverse socioeconomic and migration backgrounds. We also evaluated whether the type of worst lifetime trauma was associated with higher rates of dissociation. METHOD: Quantitative and qualitative data on posttraumatic stress, dissociative experiences, and potentially traumatic events (PTEs), including participants' written descriptions of their worst lifetime trauma. RESULTS: Most (92%) of the participants had been exposed to at least 1 PTE and 51% to 4 or more, during their life. Number of PTEs correlated with symptoms of posttraumatic stress and dissociation. There were higher rates of dissociation among economically vulnerable and second-generation war refugee participants. Emotional abuse by others (mostly peers) was the only significant predictor of dissociation when controlling for gender, age, total PTEs, posttraumatic stress, and poverty. Moderation analyses showed that lifetime worst traumas categorized as primarily emotional moderated and amplified the relation between total PTEs and dissociation, but only among girls. CONCLUSIONS: Our findings indicate that traumatization is very common among adolescents, with greater prevalence of dissociation among vulnerable groups, and that emotional traumas are linked to higher rates of dissociation, especially among girls. Researchers, clinicians, and school personnel need to focus more on immigrant status and low SES as vulnerability factors, and address the consequences of emotional abuse, including bullying, among adolescents. (PsycINFO Database Record PMID- 26963959 TI - FOCAL CHOROIDAL EXCAVATION AND CHOROIDAL NEOVASCULARIZATION WITH ASSOCIATED PACHYCHOROID. AB - PURPOSE: To report a case of focal choroidal excavation and choroidal neovascularization in the setting of pachychoroid disease. METHODS: Multimodal imaging, including fundus photography, fundus autofluorescence, enhanced depth imaging optical coherence tomography, indocyanine green angiography, and en face structural and angiographic optical coherence tomography. RESULTS: The authors describe a 39-year-old female with moderately high myopia presenting with focal choroidal excavation and associated choroidal neovascularization. Multimodal imaging demonstrated pachychoroid features with dilated choroidal vessels surrounding the lesion. Optical coherence tomography angiography showed Type 2 neovascularization. CONCLUSION: Some cases of focal choroidal excavation and associated neovascularization may be related to structural abnormalities of the associated choroidal vasculature. PMID- 26963960 TI - DIFFUSE PERIPAPILLARY CHOROIDAL MELANOMA THAT EVOLVED FROM A SMALL PRESUMED CHOROIDAL NEVUS SUCCESSFULLY TREATED WITH GAMMA KNIFE RADIOTHERAPY. AB - PURPOSE: To report a case of diffuse peripapillary choroidal melanoma which began as a small choroidal nevus and was successfully treated with gamma knife radiotherapy. METHODS: Observational case report. RESULTS: A 31-year-old visually asymptomatic man presented for a routine eye examination and was noted to have a small choroidal nevus. Six years later, the lesion had become a diffuse juxtapapillary choroidal melanoma with a thickness of 1.9 mm. Given the peripapillary location of the tumor with involvement of about 6 clock hours of the disk, Leksell Gamma Knife radiotherapy was performed. At 5.5 years after radiation therapy, visual acuity remained 20/20. The lesion thickness had decreased to 1.5 mm, and there was no interval growth of any margins. CONCLUSION: Small choroidal nevi carry low malignant potential but still deserve photographic documentation when possible with regular follow intervals. Gamma knife radiotherapy can be considered for tumors abutting the optic nerve, especially when plaque radiotherapy may be technically difficult. PMID- 26964003 TI - Influence of Proton and Salt Concentration on the Chromonic Liquid Crystal Phase Diagram of Disodium Cromoglycate Solutions: Prospects and Limitations of a Host for DNA Nanostructures. AB - Lyotropic chromonic liquid crystals have recently been suggested for use as a self-organized host for dispersing and aligning self-organized DNA origami nanostructures. However, an appropriate pH value and a suitable cation concentration are necessary to stabilize such nanostructures and to avoid unfolding of the DNA. The present study shows that the nematic and columnar liquid crystal phases appearing in aqueous solutions of disodium cromoglycate are robust against the replacement of deionized water by a neutral or alkaline buffer solution. However, disodium cromoglycate precipitates when an acidic buffer is used or when the concentration of magnesium cations exceeds a critical concentration of about 0.6-0.7 mmol/L. PMID- 26964004 TI - Cutaneous Neonatal Lupus Arising in an Infant Conceived From an Oocyte Donation Pregnancy. PMID- 26964005 TI - Protective Effects of Colivelin Against Alzheimer's Disease in a PDAPP Mouse Model. AB - BACKGROUND: Alzheimer's disease (AD) is characterized with progressive memory loss and severe cognitive impairments, which affect everyday life and human health in the elderly. It is required that an effective and safe protective reagent against AD should be developed. It has been reported that humanin (HN) exerts neuroprotective effects against AD. In this study, we investigated the effect of a novel and more effective HN derivative, Colivelin (CLN) on AD. METHODS: PDAPP(V717I) transgenic AD model mice (derived from parental C57/BL6 mice) were used in our study as AD model. Morris water maze test was used to test the memory impairment of AD mice and the levels of Abeta40 and Abeta42 were determined by an Elisa assay. We used an Immunohistochemistry and Immunofluorescence staining method to check the GFAP and MAP2 positive cells, and TUNEL to assess the apoptotic cells. Western blot assay was used to check the expression and phosphorylation level of p38. RESULTS: We found that CLN improved the memory impairment induced by AD and reduced the deposit of Abeta40 and Abeta42. CLN also inhibited cell apoptosis and activation of caspase 3 in brain tissues of AD mice. Inflammation in AD mice was alleviated by CLN treatment, including the accumulation of GFAP positive cells and the inflammatory cytokines. With both structure of AGA-HNG and ANDF, CLN exhibited significantly stronger effects than synchronously administration of AGA-HNG and ADNF, suggesting CLN as a novel potential effective therapeutic reagent for AD patients. Finally, we found that CLN inhibited phosphorylation of p38 in AD mice and p38 inhibitor, SB203580 weakened the therapeutic effect of CLN. CONCLUSION: CLN effectively improved the memory dysfunction in PDAPP mice, and our data suggests CLN as a novel and effective reagent which may have great potentials in AD therapy. PMID- 26964008 TI - Editorial Comment. PMID- 26964007 TI - Dynamic nuclear polarization in a magnetic resonance force microscope experiment. AB - We report achieving enhanced nuclear magnetization in a magnetic resonance force microscope experiment at 0.6 tesla and 4.2 kelvin using the dynamic nuclear polarization (DNP) effect. In our experiments a microwire coplanar waveguide delivered radiowaves to excite nuclear spins and microwaves to excite electron spins in a 250 nm thick nitroxide-doped polystyrene sample. Both electron and proton spin resonance were observed as a change in the mechanical resonance frequency of a nearby cantilever having a micron-scale nickel tip. NMR signal, not observable from Curie-law magnetization at 0.6 T, became observable when microwave irradiation was applied to saturate the electron spins. The resulting NMR signal's size, buildup time, dependence on microwave power, and dependence on irradiation frequency was consistent with a transfer of magnetization from electron spins to nuclear spins. Due to the presence of an inhomogeneous magnetic field introduced by the cantilever's magnetic tip, the electron spins in the sample were saturated in a microwave-resonant slice 10's of nm thick. The spatial distribution of the nuclear polarization enhancement factor epsilon was mapped by varying the frequency of the applied radiowaves. The observed enhancement factor was zero for spins in the center of the resonant slice, was epsilon = +10 to +20 for spins proximal to the magnet, and was epsilon = -10 to -20 for spins distal to the magnet. We show that this bipolar nuclear magnetization profile is consistent with cross-effect DNP in a ~10(5) T m(-1) magnetic field gradient. Potential challenges associated with generating and using DNP-enhanced nuclear magnetization in a nanometer-resolution magnetic resonance imaging experiment are elucidated and discussed. PMID- 26964009 TI - Editorial Comment. PMID- 26964010 TI - Vacuum characteristics of the sucking cycle and relationships with milk removal from the breast in term infants. AB - BACKGROUND: The importance of an infant's intra-oral vacuum in milk removal from the breast has been established. However, the relationship between the vacuum curve and milk transfer is not well understood. AIMS: To investigate the parameters of the infant suck cycle in relation to the volume of milk removed from the breast. STUDY DESIGN: Cross-sectional study to elucidate the role of infant intra-oral vacuum in efficient milk removal from the breast. SUBJECTS: Nineteen fully breastfed term infants. METHODS: Intra-oral vacuum was recorded during monitored breastfeeds using a pressure transducer. Ultrasound imaging (milk flow) and respiratory inductive plethysmography (swallowing) were used to determine the nutritive sucking (NS) portion of the feed. Milk intake was determined by weighing infants before and after feeds. Vacuum traces of the first and next 2min of NS from the first breast were analysed. RESULTS: The volumes of milk removed during both NS periods were negatively associated with peak vacuum (p<0.001) and rate of vacuum application (p<0.001), and positively related to area under first half of the suck cycle (p<0.001). Most parameters changed significantly from the first 2min of NS to the next 2min including significant reduction in peak vacuum and area under first half of the suck cycle. CONCLUSION: These results further support the role of intra-oral vacuum, specifically optimal peak vacuum, in effective and efficient milk removal during breastfeeding. It also appears that infants modify their sucking dynamics to adapt to changes in milk flow during milk ejection as the breast empties. PMID- 26964011 TI - Neurobehaviour and neurological development in the first month after birth for infants born between 32-42 weeks' gestation. AB - AIMS: The objective of this study was to generate reference values for infants born moderate preterm (MPT), late preterm (LPT) and full term (FT) for three newborn neurobehavioural/neurological examinations in the first weeks after birth. STUDY DESIGN: Prospective cohort study to examine the expected range of values for MPT (born 32(+0) to 33(+6)), LPT (34(+0) to 36(+6)) and FT (born 37 to 42weeks' gestation) infants' performance on the Hammersmith Neonatal Neurological Examination (HNNE), the Neonatal Intensive Care Unit Network Neurobehavioural Scale (NNNS) and Prechtl's General Movements Assessment (GMA) in the first weeks after birth. Further, to determine the effects of sex, gestational age at birth, and postmenstrual age at assessment on the 3 different assessments within the gestational age groups. SUBJECTS: 80 MPT, 129 LPT and 201 FT infants were recruited shortly after birth from a tertiary hospital. RESULTS: The means, standard deviations and 5th, 10th, 25th, 50th, 75th, 90th and 95th centiles are presented for the HNNE and NNNS for each of the three gestational age groups. Overall, FT infants performed better than MPT and LPT infants. The rate of normal GMA within the first few weeks after birth was 25% for MPT, 32% for LPT, and 90% for FT infants. The effects of sex, gestational age at birth, and postmenstrual age at assessment varied between test and gestational age groups. CONCLUSIONS: This study provides normative data for the HNNE, NNNS, and GMA administered within the first weeks after birth in a sample of MPT, LPT and healthy FT infants. PMID- 26964012 TI - Large Spatially Resolved Rectification in a Donor-Acceptor Molecular Heterojunction. AB - We demonstrate that rectification ratios (RR) of ?250 (?1000) at biases of 0.5 V (1.2 V) are achievable at the two-molecule limit for donor-acceptor bilayers of pentacene on C60 on Cu using scanning tunneling spectroscopy and microscopy. Using first-principles calculations, we show that the system behaves as a molecular Schottky diode with a tunneling transport mechanism from semiconducting pentacene to Cu-hybridized metallic C60. Low-bias RRs vary by two orders-of magnitude at the edge of these molecular heterojunctions due to increased Stark shifts and confinement effects. PMID- 26964013 TI - Gate-Tunable Spin Exchange Interactions and Inversion of Magnetoresistance in Single Ferromagnetic ZnO Nanowires. AB - Electrical control of ferromagnetism in semiconductor nanostructures offers the promise of nonvolatile functionality in future semiconductor spintronics. Here, we demonstrate a dramatic gate-induced change of ferromagnetism in ZnO nanowire (NW) field-effect transistors (FETs). Ferromagnetism in our ZnO NWs arose from oxygen vacancies, which constitute deep levels hosting unpaired electron spins. The magnetic transition temperature of the studied ZnO NWs was estimated to be well above room temperature. The in situ UV confocal photoluminescence (PL) study confirmed oxygen vacancy mediated ferromagnetism in the studied ZnO NW FET devices. Both the estimated carrier concentration and temperature-dependent conductivity reveal the studied ZnO NWs are at the crossover of the metal insulator transition. In particular, gate-induced modulation of the carrier concentration in the ZnO NW FET significantly alters carrier-mediated exchange interactions, which causes even inversion of magnetoresistance (MR) from negative to positive values. Upon sweeping the gate bias from -40 to +50 V, the MRs estimated at 2 K and 2 T were changed from -11.3% to +4.1%. Detailed analysis on the gate-dependent MR behavior clearly showed enhanced spin splitting energy with increasing carrier concentration. Gate-voltage-dependent PL spectra of an individual NW device confirmed the localization of oxygen vacancy-induced spins, indicating that gate-tunable indirect exchange coupling between localized magnetic moments played an important role in the remarkable change of the MR. PMID- 26964015 TI - Three-dimensional poly (epsilon-caprolactone)/hydroxyapatite/collagen scaffolds incorporating bone marrow mesenchymal stem cells for the repair of bone defects. AB - We previously demonstrated that three-dimensional (3D) hydroxyapatite (HAP) collagen (COL)-coated poly(epsilon-caprolactone) (PCL) scaffolds (HAP-COL-PCL) possess appropriate nano-structures, surface roughness, and nutrients, providing a favorable environment for osteogenesis. However, the effect of using 3D HAP-COL PCL scaffolds incorporating BMSCs for the repair of bone defects in rats has been not evaluated. 3D PCL scaffolds coated with HAP, collagen or HAP/COL and incorporating BMSCs were implanted into calvarial defects. At 12 weeks after surgery, the rats were sacrificed and crania were harvested to assess the bone defect repair using microcomputed tomography (micro-CT), histology, immunohistochemistry and sequential fluorescent labeling analysis. 3D micro-CT reconstructed images and quantitative analysis showed that HAP-COL-PCL groups possessed better bone-forming capacity than HAP-PCL groups or COL-PCL groups. Fluorescent labeling analysis revealed the percentage of tetracycline labeling, alizarin red labeling, and calcein labeling in HAP-COL-PCL groups were all greater than in the other two groups (P < 0.05), and the result was confirmed by immunohistochemical staining and histological analysis of bone regeneration. This study demonstrates that 3D HAP-COL-PCL scaffolds incorporating BMSCs markedly enhance bone regeneration of bone defects in rats. PMID- 26964014 TI - Alcohol-antiretroviral therapy interactive toxicity beliefs and daily medication adherence and alcohol use among people living with HIV. AB - Alcohol-antiretroviral therapy (ART) interactive toxicity beliefs reflect perceived adverse outcomes of mixing alcohol and ART. Previous research has shown a significant relationship between alcohol-ART interactive toxicity beliefs and ART non-adherence, over and above other correlates of non-adherence such as human immunodeficiency virus (HIV)symptoms and frequency of alcohol use. Most past studies have collected data over extended periods and have not determined if alcohol use and missed medications occur at the day-level among people holding interactive toxicity beliefs. Previous daily analyses, however, have been limited by self-reported adherence and relatively short periods of observation. To address these gaps in the literature, men and women living with HIV in Atlanta, GA, were enrolled in a 45-day observational cohort study. Daily alcohol use was collected using two-way interactive text message surveys and daily adherence was collected via the Wisepill device. Fifty-seven participants completed a measure of alcohol-ART interactive toxicity beliefs and contributed 2565 days of daily data. Participants who endorsed high levels of interactive toxicity beliefs had significantly more days when they missed doses of medication. Alcohol antiretroviral toxicity beliefs predicted missing doses of medication on days when participants were drinking and on days when they were not drinking. Multilevel multivariate regressions showed that these toxicity beliefs predicted daily missed doses of medication over and above quantity of alcohol consumed, depression and general medication concerns. This study replicates and extends previous literature and indicates the necessity of addressing alcohol-ART toxicity beliefs within adherence interventions. PMID- 26964016 TI - Design, synthesis and biological evaluation of novel coumarin thiazole derivatives as alpha-glucosidase inhibitors. AB - A new series of coumarin thiazole derivatives 7a-7t were synthesized, characterized by (1)H NMR, (13)C NMR and element analysis, evaluated for their alpha-glucosidase inhibitory activity. The majority of the screened compounds displayed potent inhibitory activities with IC50 values in the range of 6.24+/ 0.07-81.69+/-0.39MUM, when compared to the standard acarbose (IC50=43.26+/ 0.19MUM). Structure-activity relationship (SAR) studies suggest that the pattern of substitution in the phenyl ring is closely related to the biological activity of this class of compounds. Among all the tested molecules, compound 7e (IC50=6.24+/-0.07MUM) was found to be the most active compound in the library of coumarin thiazole derivatives. Enzyme kinetic studies showed that compound 7e is a non-competitive inhibitor with a Ki of 6.86MUM. Furthermore, the binding interactions of compound 7e with the active site of alpha-glucosidase were confirmed through molecular docking. This study has identified a new class of potent alpha-glucosidase inhibitors for further investigation. PMID- 26964017 TI - Anti-HIV cytotoxicity enzyme inhibition and molecular docking studies of quinoline based chalcones as potential non-nucleoside reverse transcriptase inhibitors (NNRT). AB - A series of fourteen (A1 - A14) qunioline based chalcones were screened for reverse transcriptase inhibitors (RT) and found potentially active against RT. Bioassay, theoretical and dockings studies with RT (the enzyme required for reverse transcription of viral RNA) results showed that the type and positions of the substituents seemed to be critical for their inhibition against RT. The bromo and chloro substituted chalcone displayed high degree of inhibition against RT. The A4 andA6 showed high interaction with RT, contributing high free binding energy (DeltaG -9.30 and -9.13kcal) and RT inhibition value (IC50 0.10MUg/ml and 0.11MUg/ml). PMID- 26964018 TI - Effect of Polycyclic Aromatic Hydrocarbon Source Materials and Soil Components on Partitioning and Dermal Uptake. AB - The bioavailability of polycyclic aromatic hydrocarbons (PAHs) in soils can be influenced by the source material they are emitted within, the properties of the receiving soil, weathering processes, and the concentration of PAHs. In this study 30 contaminated soils were constructed with common PAH sources (fuel oil, soot, coal tar based skeet particles) and direct spike with a solvent added to different types and contents of soil organic matter and minerals to achieve PAH concentrations spanning 4 orders of magnitude. Source material had the greatest impact on PAH partitioning. Soils containing skeet generally exhibited the highest KD values, followed by soot, fuel oil, and solvent spiked soils. Among all soil compositions, the presence of 2% charcoal had the largest enhancement of KD. Partitioning behavior could not be predicted by an organic carbon and black carbon partitioning model. Including independently measured partitioning behavior of the soil components and PAH sources allowed better prediction but still suffered from issues of interaction (oil sorption in peat) and highly nonlinear partitioning with depletion (for skeet). Dermal absorption of PAHs measured using pig skin was directly related to the freely dissolved aqueous concentration in soil and not the total concentration in the soil. Overall, we show that PAH source materials have a dominating influence on partitioning, highlighting the importance of using native field soils in bioavailability and risk assessments. PMID- 26964019 TI - CRYOTHERAPY AS A METHOD FOR REDUCING THE VIRUS INFECTION OF APPLES (Malus sp.). AB - BACKGROUND: There is an urgent need in Kazakhstan for virus-free nursery stock to reinvigorate the industry and preserve historic cultivars. An in vitro collection of apples could be used for virus testing and elimination and to provide virus free elite stock plants to nurseries. METHODS: Malus sieversii Ledeb. M. Roem. and Malus domestica Borkh. accessions were initiated in vitro for virus identification and elimination. Reverse transcription and multiplex PCR were used to test for five viruses. PVS2 vitrification was used as a tool for cryotherapy. RESULTS: Four viruses, Apple chlorotic leaf spot virus (ACLSV), Apple stem pitting virus (ASPV), Apple stem grooving virus (ASGV) and Apple mosaic virus (ApMV) were detected in 17 accessions. Tomato ringspot virus (ToRSV) was not detected. ACLSV affected 53.8% of the accessions, ASPV 30.8%, ASGV 5.1%, and ApMV was found only in 'Aport Alexander'. Cryotherapy produced virus-free shoot tips for seven of nine cultivars tested. Six cultivars had 60-100% elimination of ACLSV. CONCLUSIONS: An in vitro collection of 59 accessions was established. Virus elimination using cryotherapy produced virus-free shoots for seven of nine cultivars and is a promising technique for developing a virus-free apple collection. PMID- 26964020 TI - HEAT INDUCIBLE EXPRESSION OF ANTIFREEZE PROTEIN GENES FROM THE BEETLES Tenebrio molitor AND Microdera punctipennis. AB - BACKGROUND: Antifreeze proteins (AFPs) play important roles in protecting poikilothermic organisms from cold damage. The expression of AFP genes (afps) is induced by low temperature. However, it is reported that heat can influence the expression of afps in the desert beetle Microdera punctipennis. OBJECTIVE: To further detect whether heat also induce the expression of afps in other insects, and to determine the expression profiling of insect afps at different temperatures. MATERIALS AND METHODS: The expression of antifreeze protein genes in the two beetles, Microdera punctipennis and Tenebrio molitor that have quite different living environment, under different temperatures were studied by using real-time quantitative PCR. RESULTS: Mild low temperatures (5~15 degree C), high temperature (38~47 degree C for M. punctipennis, or 37~42 degree C for T. molitor) and temperature difference (10~30 degree C) all stimulated strongly to the expression of AFP genes (Mpafps) in M. punctipennis which lives in the wild filed in desert. The mRNA level of Mpafps after M. punctipennis were exposed to these temperatures for 1h~5h was at least 30-fold of the control at 25 degree C. For T. molitor which is breeding in door with wheat bran all these temperatures stimulated significantly to the expression of Tmafps, while the extent and degree of the temperature stimulation on Tmafps expression were much lower than on Mpafps. After T. molitor were exposed to 5 degree C and 15 degree C for 1h~5h, the mRNA level of Tmafps was over 6-fold and 45-fold of the control at 25 degree C. High temperature (37~42 degree C) for 1h~3h treatments increased Tmafps mRNA level 4.8-fold of the control. Temperature difference of 10 degree C was effective in stimulating Tmafps expression. CONCLUSION: The expression of insect antifreeze protein genes both in M. punctipennis and T. molitor was induced by heat, suggesting that this phenomenon may be common in insects; the extent and degree of the influence differ in species that have different living conditions. The heat inducible expression of antifreeze protein genes hints that antifreeze proteins may involve in other functions except for antifreeze. PMID- 26964021 TI - VISCOSITIES OF CONCENTRATED NaCl-H2O AND Me2SO-NaCl-H2O SOLUTIONS AT SUBZERO TEMPERATURES. AB - BACKGROUND: Viscosity is an important property of cryoprotectant solutions because it directly influences diffusion and reaction at liquid state. OBJECTIVE: To measure the viscosities of concentrated NaCl-H(2)O and Me(2)SO-NaCl-H(2)O solutions at subzero temperatures down to -50 degree C. MATERIALS AND METHODS: Solution viscosity was measured with a rotary viscometer coupled with a thermostat bath. Two viscosity models, Laliberte model and Williams-Landel-Ferry (WLF) model, were employed in the correlation and prediction. RESULTS AND CONCLUSION: The Laliberte model performed well to correlate the viscosities of NaCl- H(2)O solutions measured here and the viscosities of Me(2)SO-H(2)O solutions found in the literature. The parameters obtained were used to predict the viscosities of Me(2)SO-NaCl-H(2)O solutions. The average discrepancy between the calculation and the experimental data was 19.0%. With the WLF model, the average discrepancy between the calculation and the experimental data for ternary solution was 5.4%. PMID- 26964022 TI - HIGH INCIDENCE OF POLYSPERMIC FERTILIZATION IN BOVINE OOCYTES MATURED IN VITRO AFTER CRYOTOP VITRIFICATION. AB - BACKGROUND: Vitrification with the Cryotop device is the most promising technique for oocyte cryopreservation, but the high post-warming morphological survival of bovine oocytes does not guarantee high developmental competence after in vitro fertilization (IVF). OBJECTIVE: This study was designed to examine achievement of normal fertilization in bovine oocytes vitrified-warmed with the Cryotop device. MATERIALS AND METHODS: Oocytes were matured in vitro and vitrified-warmed after complete removal of the cumulus layers. Distribution of cortical granules (CGs) was assessed by Lens culinaris agglutinin (LCA) lectin staining. Ten hours after IVF, presumptive zygotes were analyzed for pronuclear formation. Day-8 blastocysts were harvested and stained with Hoechst-33342 for total cell counting. RESULTS: Both yield and mean cell number of the blastocysts were impaired by Cryotop vitrification. Incidence of polyspermic fertilization was three-times higher in vitrified oocytes compared to fresh oocytes. No difference in CG distribution was found between vitrified and fresh oocytes. CONCLUSION: Polyspermic fertilization induced in vitrified-warmed bovine oocytes may be one of the possible causes responsible for their low developmental potential. PMID- 26964023 TI - PROTECTIVE EFFECTS OF GLUTATHIONE SUPPLEMENTATION AGAINST OXIDATIVE STRESS DURING CRYOPRESERVATION OF HUMAN SPERMATOZOA. AB - BACKGROUND: Freeze damage is one of the most important factors which impair the membrane and DNA integrity of sperm cells. OBJECTIVE: The present study aims to investigate glutathione (GSH) supplementation on human spermatozoa cryopreservation. We determined sperm motility and viability, sperm lipid peroxidation, DNA damage, and the amount of hydrogen peroxide (H(2)O(2)) and superoxide (O(2)(-)). MATERIALS AND METHODS: Twenty pooled semen samples were freeze with 5mM GSH for 10 minute (test) and without GSH as control and stored in liquid nitrogen. RESULTS: After thawing, cryovials supplemented with 5mM GSH led to higher sperm viability compared with control samples (p < 0.05). Furthermore, the addition of 5mM GSH decreased sperm lipid peroxidation, DNA fragmentation, and H(2)O(2) and O(2)(-) content compared with controls (p < 0.05). CONCLUSION: GSH can be a good free radical scavenger in the freezing media and can support function of sperm cell after a cycle of freezing and thawing. PMID- 26964024 TI - CRYOPRESERVATION OF GOLDFISH (Carassius auratus) SPERMATOZOA: EFFECTS OF EXTENDER SUPPLEMENTED WITH TAURINE ON SPERM MOTILITY AND DNA DAMAGE. AB - BACKGROUND: Amino acids, present in seminal plasma at high concentration, protect spermatozoa against cell damage during cryopreservation. OBJECTIVE: Experiments were designed to analyze the effect of semen extender supplemented with taurine on post-thawed sperm motility and duration, as well as DNA damage. MATERIALS AND METHODS: Extenders were supplemented with 1, 2 or 4 mM taurine. Semen samples were diluted at the ratio of 1:9 with the extenders. Diluted samples were aspirated into 0.25 ml French straws and 0.1 ml pellets. DNA damage was assessed with the comet assay after cryopreservation. RESULTS: The percentage and duration of sperm motility were significantly increased by taurine. Additionally, sperm motility and the motility period in pellets were higher than in straws. The best concentration of taurine was 4 mM, and the highest post-thaw motility rate (72.50 +/- 3.54 %) and duration (17.50 +/- 0.71 s) were obtained from the extender with 4 mM in pellets. DNA damage was decreased after taurine supplementation. CONCLUSION: Pellets could be used for goldfish sperm cryopreservation. The addition of 4 mM taurine increases the post-thaw motility and decreases DNA damage on goldfish semen. PMID- 26964026 TI - EFFECTS OF LYOPHILIZATION AND REHYDRATION ON MEMBRANE SURFACE ANTIGENS OF HUMAN RED BLOOD CELLs. AB - BACKGROUND: Previous studies have demonstrated that human RBCs can survival from freeze-drying, but there is still some uncertainty on whether and how the cell properties change during the processes. OBJECTIVE: The present study is to evaluate the effects of lyophilization and rehydration on the membrane surface antigens, such as CD antigens and blood group antigens, of human RBCs. MATERIALS AND METHODS: Human RBCs were lyophilized first through a simplified protocol, in which glycerol were used in the lyoprotectant solution instead of trehalose. Upon rehydration, a series of in-vitro experiments were performed to examine the variation of cell count, cell level of ATP and 2,3 DPG, and the surface antigens on cell membrane. RESULTS: The cell count recovery was 58.87%+/-0.74%, and the cell levels of ATP and 2, 3 DPG maintained well upon rehydration. Those results are comparable to the literature, demonstrating the simplified protocol has similar effects on RBCs comparing with the reported approaches. Flow cytometry assays demonstrated that there were no significant difference in CD35, CD44, CD45, CD47 and CD71 expressions before and after freeze-drying. In blood group tests, most of the blood group antigens maintained after lyophilization and rehydration, except that Le(a), Le(b) and JK1 showed high probabilities of falling off during the processes. PMID- 26964025 TI - FIRST STEPS TOWARDS ORGAN BANKS: VITRIFICATION OF RENAL PRIMORDIAL. AB - BACKGROUND: Kidney transplantation from deceased or living human donors has been limited by donor availability as opposed to the increasing demand, by the risks of allograft loss rejection and immunosuppressive therapy toxicity and by limitations of organ preservation protocols, which is essential to organise staff and facilities, transport organs, and perform necessary laboratory tests. However, the cryopreservation of composite tissues poses technical challenges beyond those seen in the preservation of single tissue types or organs. OBJECTIVE: The purpose of our study was to establish a protocol for long-term storing of renal primordia, that generates new adult kidneys after transplant into a syngeneic non-immunosuppressed host. MATERIALS AND METHODS: Metanephroi from 16-days-old embryos were microdissected and vitrified following the minimum essential volume method and using Cryotop as a device and VM3 as vitrification solution. After 3 months of storage in liquid nitrogen (-196 degree C), 20 metanephroi were warmed and transplanted using minimally invasive laparoscopic surgery into retroperitoneal fat of 5-month-old immune-competent New Zealand rabbits. In the same way, 22 fresh metanephroi were transplanted. Twenty-one days after transplantation, hosts were euthanized and developed kidneys were recovered and evaluated morphologically and histologically. RESULTS: Significant growth and fully differentiated mature glomeruli and tubule were observed in all kidney graft explants recovered. In total, 5 metanephroi (25.0%) were successfully grown after vitrification. In the same way, 12 metanephroi (54.5%) were successfully grown in the fresh group. CONCLUSION: These encouraging results reported that metanephroi not only survive vitrification, but they vascularized and developed morphologically normal glomeruli after their allotransplantation. These results suggest that it's possible to create a long-term biobank of kidney precursors as an unlimited source of organs for transplantation, and open new therapeutic possibilities for the patients with chronic renal failure. PMID- 26964027 TI - IMPROVED SURVIVAL AND DEVELOPMENTAL RATES IN VITRIFIED-WARMED PIG OOCYTES AFTER RECOVERY CULTURE WITH COENZYME Q10. AB - BACKGROUND: The primary problems with porcine oocyte vitrification are their low viability and development; both need improvement. OBJECTIVE: This study was designed to improve the survival and developmental rates in vitrified-warmed porcine oocytes. MATERIALS AND METHODS: Porcine oocytes matured in vitro were vitrified-warmed with Cryotop. Then the oocytes were supplemented with Q10 during recovery culture. RESULTS: The survival rates immediately after warming were 92.9% by morphological inspection and 39.3% by fluorescein diacetate (FDA) assay. The group of recovery culture with Q10 (VC+Q10) showed significantly higher viability compared to the group of recovery culture without Q10 (VC+) analyzed by morphology and the FDA. The VC+Q10 group showed a low Bax/Bcl-xl ratio and a high expression of MAP3K12 and TGFB3 compared to the VC+. The cleavage rate did not differ in both groups but, blastocyst yield was higher in VC+Q10 than the VC+ group. CONCLUSION: Supplementation of Q10 during recovery culture led to a higher blastocyst yield by increasing survival rates and regulating mRNA expressions. PMID- 26964028 TI - Direct oral anticoagulants: a guide for daily practice. AB - In recent years, small oral compounds that specifically block activated coagulation factor X (FXa) or thrombin (FIIa) have become alternatives to the anticoagulants that had been used for several decades. As of today, these direct oral anticoagulants (DOACs) include dabigatran etexilate (thrombin inhibitor) and apixaban, edoxaban and rivaroxaban (inhibitors of FXa). While there is no doubt that DOACs represent a major step forward in the management of patients with venous thromboembolic disease and atrial fibrillation, new challenges have arisen. They need to be addressed with the necessary pragmatism on the basis of evidence. Indeed, a better understanding of the management of these last generation antithrombotics will favour safer use and increase confidence of the practitioner for the prescription of these drugs. The aim of this article is to present practical suggestions for the prescription and use of these drugs in everyday clinical practice, based on clinical experience and recently updated recommendations of the European Heart Rhythm Association and the American College of Chest Physicians among other scientific organisations. We address issues such as pharmacokinetics, dosing, side effects, limitations of use, drug interactions, switching from and to other anticoagulants, renal function, concomitant administration of antiplatelet agents and perioperative use. We also address the issue of monitoring and reversal, taking advantage of the most recent development in this latter area. Rather than being one additional set of recommendations, our narrative review aims at assisting the practicing physician in his or her daily handling of these novel anticoagulant compounds, based on frequently asked questions to the authors, a group of experienced specialists in the field who have, however, no commitment to issue guidelines. PMID- 26964029 TI - Calcified amorphous tumor of the left atrial appendage. AB - A 57-year-old female with end-stage renal dysfunction was admitted to our hospital. The echocardiogram revealed a 9mm*22mm hyperechoic mass in the left atrial appendage (LAA). The mass was extremely mobile. Considering the high risk of embolic events, we decided on a surgical resection. Microscopic examination of the mass revealed a nodular focus of calcification and fibrosis with focal chronic inflammation of the atrial endocardium. The endocardium was uniformly thickened with no evidence of neoplastic proliferation. The mass was diagnosed with a calcified amorphous tumor (CAT). This is first report of CAT of the LAA. PMID- 26964031 TI - Triapine potentiates platinum-based combination therapy by disruption of homologous recombination repair. AB - BACKGROUND: Platinum resistance may be attributable to inherent or acquired proficiency in homologous recombination repair (HRR) in epithelial ovarian cancer (EOC). The objective of this study was to evaluate the efficacy of the small molecule inhibitor triapine to disrupt HRR and sensitise BRCA wild-type EOC cells to platinum-based combination therapy in vitro and in vivo. METHODS: The sensitivity of BRCA wild-type cancer cells to olaparib, cisplatin, carboplatin, doxorubicin, or etoposide in combination with triapine was evaluated by clonogenic survival assays. The effects of triapine on HRR activity in cells were measured with a DR-GFP reporter assay. The ability of triapine to enhance the effects of the carboplatin-doxil combination on EOC tumour growth delay was determined using a xenograft tumour mouse model. RESULTS: Platinum resistance is associated with wild-type BRCA status. Triapine inhibits HRR activity and enhances the sensitivity of BRCA wild-type cancer cells to cisplatin, olaparib, and doxorubicin. However, sequential combination of triapine and cisplatin is necessary to achieve synergism. Moreover, triapine potentiates platinum-based combination therapy against BRCA wild-type EOC cells and produces significant delay of EOC tumour growth. CONCLUSIONS: Triapine promises to augment the clinical efficacy of platinum-based combination regimens for treatment of platinum-resistant EOC with wild-type BRCA and proficient HRR activity. PMID- 26964032 TI - Long-term impact of preeclampsia on maternal endometrial cancer risk. AB - BACKGROUND: Endometrial cancer is mainly dependent on oestrogen exposure. Preeclampsia has shown to reduce oestrogen levels hence preeclampsia may affect later endometrial cancer risk. METHODS: We conducted a case-control study of 523 Danish women with endometrial cancer and 52 299controls during 1978-2010. The association between preeclampsia and later endometrial cancer was evaluated overall and according to preeclampsia onset and type of endometrial cancer in conditional logistic regression models. RESULTS: We observed no overall association between preeclampsia and endometrial cancer risk (OR=1.11 (95% CI 0.68-1.81)). This was true for all endometrial cancer subtypes. In an analysis of preeclampsia onset, however, we report a markedly increased risk of endometrial cancer following early-onset preeclampsia (OR=2.64 (95% CI 1.29-5.38)). CONCLUSIONS: Although we report no obvious association between preeclampsia and endometrial cancer, studying the subset of early-onset preeclampsia may prove fruitful in further understanding the aetiology of endometrial cancer. PMID- 26964034 TI - Does Nucleos(t)ide Analogues Treatment Affect Renal Function in Chronic Hepatitis B Patients Who Have Already Decreased eGFR? A Longitudinal Study. AB - This study aimed to assess the renal function in chronic hepatitis B (CHB) patients who received nucleos(t)ide analogues (NAs) therapy using estimated glomerular filtration rate (eGFR) titer. We performed a longitudinal observational study of 37 tenofovir-, 42 telbivudine-, and 62 entecavir-naive CHB patients, who had impaired renal function (eGFR, 90-30 ml/min/1.73m2) without history of diabetes, hypertension, and chemotherapy. Calculation and evaluation of eGFR was performed with the Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, and Cockcroft-Gault formula at pretreatment, at baseline, and after the 1st and 2nd year of treatment. The eGFR was significantly increased in patients given telbivudine or entecavir (p = 0.003 and p = 0.012, respectively), but the eGFR was decreased in patients given tenofovir (p = 0.001) after 2 years of treatment. Of all patients, eGFR was stable one year prior to treatment. If we analyzed the renal function by change of chronic kidney disease (CKD) category with a change of 25% of eGFR, the proportion of uncertain drop (drop in CKD category with <25% decrease in eGFR) and certain drop (drop in CKD category with ?25% decrease in eGFR) in tenofovir group was smaller (5.4%) than those of telbivudine (12.9%) or entecavir (6.5%). Furthermore, telbivudine had the lowest stable rate (76.2%), the highest certain rise rate (9.5%), and certain drop rate (7.1%) compared to the other groups (p = 0.049). In conclusion, in NAs-naive CHB patients with impaired renal function, telbivudine and entecavir resulted in a significant increase in eGFR while tenofovir resulted in a significant decrease after a 2-year treatment. Interestingly, TDF had the lowest proportion of patients reclassified to certain and uncertain drop groups; in contrast, LdT had a higher proportion in both raise and drop groups. The outcomes of this renal effect remain to be determined. PMID- 26964035 TI - A Model-Based Joint Identification of Differentially Expressed Genes and Phenotype-Associated Genes. AB - Over the last decade, many analytical methods and tools have been developed for microarray data. The detection of differentially expressed genes (DEGs) among different treatment groups is often a primary purpose of microarray data analysis. In addition, association studies investigating the relationship between genes and a phenotype of interest such as survival time are also popular in microarray data analysis. Phenotype association analysis provides a list of phenotype-associated genes (PAGs). However, it is sometimes necessary to identify genes that are both DEGs and PAGs. We consider the joint identification of DEGs and PAGs in microarray data analyses. The first approach we used was a naive approach that detects DEGs and PAGs separately and then identifies the genes in an intersection of the list of PAGs and DEGs. The second approach we considered was a hierarchical approach that detects DEGs first and then chooses PAGs from among the DEGs or vice versa. In this study, we propose a new model-based approach for the joint identification of DEGs and PAGs. Unlike the previous two step approaches, the proposed method identifies genes simultaneously that are DEGs and PAGs. This method uses standard regression models but adopts different null hypothesis from ordinary regression models, which allows us to perform joint identification in one-step. The proposed model-based methods were evaluated using experimental data and simulation studies. The proposed methods were used to analyze a microarray experiment in which the main interest lies in detecting genes that are both DEGs and PAGs, where DEGs are identified between two diet groups and PAGs are associated with four phenotypes reflecting the expression of leptin, adiponectin, insulin-like growth factor 1, and insulin. Model-based approaches provided a larger number of genes, which are both DEGs and PAGs, than other methods. Simulation studies showed that they have more power than other methods. Through analysis of data from experimental microarrays and simulation studies, the proposed model-based approach was shown to provide a more powerful result than the naive approach and the hierarchical approach. Since our approach is model-based, it is very flexible and can easily handle different types of covariates. PMID- 26964037 TI - Correction: Identification of Molecular Markers of Delayed Graft Function Based on the Regulation of Biological Ageing. PMID- 26964036 TI - Frontal Lobe Contusion in Mice Chronically Impairs Prefrontal-Dependent Behavior. AB - Traumatic brain injury (TBI) is a major cause of chronic disability in the world. Moderate to severe TBI often results in damage to the frontal lobe region and leads to cognitive, emotional, and social behavioral sequelae that negatively affect quality of life. More specifically, TBI patients often develop persistent deficits in social behavior, anxiety, and executive functions such as attention, mental flexibility, and task switching. These deficits are intrinsically associated with prefrontal cortex (PFC) functionality. Currently, there is a lack of analogous, behaviorally characterized TBI models for investigating frontal lobe injuries despite the prevalence of focal contusions to the frontal lobe in TBI patients. We used the controlled cortical impact (CCI) model in mice to generate a frontal lobe contusion and studied behavioral changes associated with PFC function. We found that unilateral frontal lobe contusion in mice produced long-term impairments to social recognition and reversal learning while having only a minor effect on anxiety and completely sparing rule shifting and hippocampal-dependent behavior. PMID- 26964039 TI - Estimation of Soil Erosion Dynamics in the Koshi Basin Using GIS and Remote Sensing to Assess Priority Areas for Conservation. AB - High levels of water-induced erosion in the transboundary Himalayan river basins are contributing to substantial changes in basin hydrology and inundation. Basin wide information on erosion dynamics is needed for conservation planning, but field-based studies are limited. This study used remote sensing (RS) data and a geographic information system (GIS) to estimate the spatial distribution of soil erosion across the entire Koshi basin, to identify changes between 1990 and 2010, and to develop a conservation priority map. The revised universal soil loss equation (RUSLE) was used in an ArcGIS environment with rainfall erosivity, soil erodibility, slope length and steepness, cover-management, and support practice factors as primary parameters. The estimated annual erosion from the basin was around 40 million tonnes (40 million tonnes in 1990 and 42 million tonnes in 2010). The results were within the range of reported levels derived from isolated plot measurements and model estimates. Erosion risk was divided into eight classes from very low to extremely high and mapped to show the spatial pattern of soil erosion risk in the basin in 1990 and 2010. The erosion risk class remained unchanged between 1990 and 2010 in close to 87% of the study area, but increased over 9.0% of the area and decreased over 3.8%, indicating an overall worsening of the situation. Areas with a high and increasing risk of erosion were identified as priority areas for conservation. The study provides the first assessment of erosion dynamics at the basin level and provides a basis for identifying conservation priorities across the Koshi basin. The model has a good potential for application in similar river basins in the Himalayan region. PMID- 26964038 TI - Viruses as Sole Causative Agents of Severe Acute Respiratory Tract Infections in Children. AB - BACKGROUND: Respiratory syncytial virus (RSV) and influenza A viruses are known to cause severe acute respiratory tract infections (SARIs) in children. For other viruses like human rhinoviruses (HRVs) this is less well established. Viral or bacterial co-infections are often considered essential for severe manifestations of these virus infections. OBJECTIVE: The study aims at identifying viruses that may cause SARI in children in the absence of viral and bacterial co-infections, at identifying disease characteristics associated with these single virus infections, and at identifying a possible correlation between viral loads and disease severities. STUDY DESIGN: Between April 2007 and March 2012, we identified children (<18 year) with or without a medical history, admitted to our paediatric intensive care unit (PICU) with SARI or to the medium care (MC) with an acute respiratory tract infection (ARTI) (controls). Data were extracted from the clinical and laboratory databases of our tertiary care paediatric hospital. Patient specimens were tested for fifteen respiratory viruses with real-time reverse transcriptase PCR assays and we selected patients with a single virus infection only. Typical bacterial co-infections were considered unlikely to have contributed to the PICU or MC admission based on C-reactive protein-levels or bacteriological test results if performed. RESULTS: We identified 44 patients admitted to PICU with SARI and 40 patients admitted to MC with ARTI. Twelve viruses were associated with SARI, ten of which were also associated with ARTI in the absence of typical bacterial and viral co-infections, with RSV and HRV being the most frequent causes. Viral loads were not different between PICU-SARI patients and MC-ARTI patients. CONCLUSION: Both SARI and ARTI may be caused by single viral pathogens in previously healthy children as well as in children with a medical history. No relationship between viral load and disease severity was identified. PMID- 26964040 TI - Clinical Efficacy of Simulated Vitreoretinal Surgery to Prepare Surgeons for the Upcoming Intervention in the Operating Room. AB - PURPOSE: To evaluate the efficacy of the virtual reality training simulator Eyesi to prepare surgeons for performing pars plana vitrectomies and its potential to predict the surgeons' performance. METHODS: In a preparation phase, four participating vitreoretinal surgeons performed repeated simulator training with predefined tasks. If a surgeon was assigned to perform a vitrectomy for the management of complex retinal detachment after a surgical break of at least 60 hours it was randomly decided whether a warmup training on the simulator was required (n = 9) or not (n = 12). Performance at the simulator was measured using the built-in scoring metrics. The surgical performance was determined by two blinded observers who analyzed the video-recorded interventions. One of them repeated the analysis to check for intra-observer consistency. The surgical performance of the interventions with and without simulator training was compared. In addition, for the surgeries with simulator training, the simulator performance was compared to the performance in the operating room. RESULTS: Comparing each surgeon's performance with and without warmup trainingshowed a significant effect of warmup training onto the final outcome in the operating room. For the surgeries that were preceeded by the warmup procedure, the performance at the simulator was compared with the operating room performance. We found that there is a significant relation. The governing factor of low scores in the simulator were iatrogenic retinal holes, bleedings and lens damage. Surgeons who caused minor damage in the simulation also performed well in the operating room. CONCLUSIONS: Despite the large variation of conditions, the effect of a warmup training as well as a relation between the performance at the simulator and in the operating room was found with statistical significance. Simulator training is able to serve as a warmup to increase the average performance. PMID- 26964041 TI - De Novo Occurrence of a Variant in ARL3 and Apparent Autosomal Dominant Transmission of Retinitis Pigmentosa. AB - BACKGROUND: Retinitis pigmentosa is a phenotype with diverse genetic causes. Due to this genetic heterogeneity, genome-wide identification and analysis of protein altering DNA variants by exome sequencing is a powerful tool for novel variant and disease gene discovery. In this study, exome sequencing analysis was used to search for potentially causal DNA variants in a two-generation pedigree with apparent dominant retinitis pigmentosa. METHODS: Variant identification and analysis of three affected members (mother and two affected offspring) was performed via exome sequencing. Parental samples of the index case were used to establish inheritance. Follow-up testing of 94 additional retinitis pigmentosa pedigrees was performed via retrospective analysis or Sanger sequencing. RESULTS AND CONCLUSIONS: A total of 136 high quality coding variants in 123 genes were identified which are consistent with autosomal dominant disease. Of these, one of the strongest genetic and functional candidates is a c.269A>G (p.Tyr90Cys) variant in ARL3. Follow-up testing established that this variant occurred de novo in the index case. No additional putative causal variants in ARL3 were identified in the follow-up cohort, suggesting that if ARL3 variants can cause adRP it is an extremely rare phenomenon. PMID- 26964043 TI - Evolution of E. coli on [U-13C]Glucose Reveals a Negligible Isotopic Influence on Metabolism and Physiology. AB - 13C-Metabolic flux analysis (13C-MFA) traditionally assumes that kinetic isotope effects from isotopically labeled compounds do not appreciably alter cellular growth or metabolism, despite indications that some biochemical reactions can be non-negligibly impacted. Here, populations of Escherichia coli were adaptively evolved for ~1000 generations on uniformly labeled 13C-glucose, a commonly used isotope for 13C-MFA. Phenotypic characterization of these evolved strains revealed ~40% increases in growth rate, with no significant difference in fitness when grown on either labeled (13C) or unlabeled (12C) glucose. The evolved strains displayed decreased biomass yields, increased glucose and oxygen uptake, and increased acetate production, mimicking what is observed after adaptive evolution on unlabeled glucose. Furthermore, full genome re-sequencing revealed that the key genetic changes underlying these phenotypic alterations were essentially the same as those acquired during adaptive evolution on unlabeled glucose. Additionally, glucose competition experiments demonstrated that the wild type exhibits no isotopic preference for unlabeled glucose, and the evolved strains have no preference for labeled glucose. Overall, the results of this study indicate that there are no significant differences between 12C and 13C glucose as a carbon source for E. coli growth. PMID- 26964042 TI - NMR Methods to Study Dynamic Allostery. AB - Nuclear magnetic resonance (NMR) spectroscopy provides a unique toolbox of experimental probes for studying dynamic processes on a wide range of timescales, ranging from picoseconds to milliseconds and beyond. Along with NMR hardware developments, recent methodological advancements have enabled the characterization of allosteric proteins at unprecedented detail, revealing intriguing aspects of allosteric mechanisms and increasing the proportion of the conformational ensemble that can be observed by experiment. Here, we present an overview of NMR spectroscopic methods for characterizing equilibrium fluctuations in free and bound states of allosteric proteins that have been most influential in the field. By combining NMR experimental approaches with molecular simulations, atomistic-level descriptions of the mechanisms by which allosteric phenomena take place are now within reach. PMID- 26964044 TI - Comparative Proteomic Identification of Mature and Immature Sperm in the Catfish Cranoglanis bouderius. AB - To understand the molecular responses of mature and immature sperm in the catfish Cranoglanis bouderius, we used the iTRAQ proteomics approach to perform proteomic profiling of spermatogenesis in C. bouderius. As a result, 1,941 proteins were identified, including 361 differentially expressed proteins, 157 upregulated proteins and 204 downregulated proteins in mature sperm relative to immature sperm. All of the identified proteins were categorized into seven types of subcellular localizations and three molecular functions and were found to be involved in nine biological processes. All of the differential proteins were involved in 235 different pathways. Moreover, we found that the tricarboxylic acid (TCA) pathway played an important role in the energy metabolism of sperm and that the EABB pathway was involved in the mechanism of spermatogenesis. Our study is the first to use the iTRAQ-based proteomic approach to analyze the catfish sperm proteome, and the results we obtained using this approach are valuable for understanding the molecular mechanisms of fish spermatogenesis. PMID- 26964045 TI - Hyperlipidemia Is Associated with Chronic Urticaria: A Population-Based Study. AB - The etiology of chronic urticaria (CU) is diverse, with chronic infections and inflammation being reported as considerable contributing factors. Although the prevalence of metabolic syndrome was found to be significantly elevated in patients with CU, no one has specifically estimated the effects on CU following hyperlipidemia. This study aimed to examine the association between hyperlipidemia and CU using a population-based dataset in Taiwan. This study included 9798 adults with CU as cases and 9798 sex- and age-matched controls. These patients were examined for whether they had received a prior diagnosis of hyperlipidemia. We used conditional logistic regression analyses to calculate the odds ratio (OR) and its corresponding 95% confidence interval (CI) for having been previously diagnosed with hyperlipidemia between cases and controls. In total, 7066 (36.1%) patients had received a prior diagnosis of hyperlipidemia, including 4287 (43.8%) among CU cases and 2779 (28.4%) among controls. The conditional logistic regression revealed that the OR of prior hyperlipidemia for cases was 1.97 (95% CI: 1.85~2.09) compared to the controls. Furthermore, compared to patients without CU, patients with CU independently experienced a 1.65-fold (95% CI = 1.55~1.76; p<0.001) increased risk of having a prior hyperlipidemia diagnosis, after adjustments were made. We concluded that CU was associated with having received a prior diagnosis of hyperlipidemia. PMID- 26964050 TI - Healing the Bee's Knees--On Honey and Wound Healing. PMID- 26964046 TI - The Role of Oxidative Stress in the Longevity and Insecticide Resistance Phenotype of the Major Malaria Vectors Anopheles arabiensis and Anopheles funestus. AB - Oxidative stress plays numerous biological roles, both functional and pathological. The role of oxidative stress in various epidemiologically relevant biological traits in Anopheles mosquitoes is not well established. In this study, the effects of oxidative stress on the longevity and insecticide resistance phenotype in the major malaria vector species An. arabiensis and An. funestus were examined. Responses to dietary copper sulphate and hydrogen peroxide were used as proxies for the oxidative stress phenotype by determining the effect of copper on longevity and hydrogen peroxide lethal dose. Glutathione peroxidase and catalase activities were determined colorimetrically. Oxidative burden was quantified as protein carbonyl content. Changes in insecticide resistance phenotype were monitored by WHO bioassay. Insecticide resistant individuals showed an increased capacity for coping with oxidative stress, mediated by increased glutathione peroxidase and catalase activity. This effect was observed in both species, as well as in laboratory strains and F1 individuals derived from wild-caught An. funestus mothers. Phenotypic capacity for coping with oxidative stress was greatest in strains with elevated Cytochrome P450 activity. Synergism of oxidative stress defence enzymes by dietary supplementation with haematin, 3 Amino-1, 2, 4-triazole and Sodium diethyldithiocarbamate significantly increased pyrethroid-induced mortality in An. arabiensis and An. funestus. It is therefore concluded that defence against oxidative stress underlies the augmentation of the insecticide resistance phenotype associated with multiple blood-feeding. This is because multiple blood-feeding ultimately leads to a reduction of oxidative stress in insecticide resistant females, and also reduces the oxidative burden induced by DDT and pyrethroids, by inducing increased glutathione peroxidase activity. This study highlights the importance of oxidative stress in the longevity and insecticide resistance phenotype in malaria vectors. PMID- 26964047 TI - beta-Cyclodextrin-Based Inclusion Complexation Bridged Biodegradable Self Assembly Macromolecular Micelle for the Delivery of Paclitaxel. AB - In this study, a novel adamantanamine-paclitaxel (AD-PTX) incorporated oligochitosan- carboxymethyl-beta-cyclodextrin (CSO-g-CM-beta-CD) self-assembly macromolecular (CSO-g-CM-beta-CD@AD-PTX) micelle was successfully prepared in water through sonication. The formed molecules were characterized by Fourier transform infrared spectroscopy, proton nuclear magnetic resonance (NMR) spectroscopy, two-dimensional NMR, elemental analysis, and liquid chromatography mass spectrometry, while the correspondent micelles were characterized by dynamic light scattering and transmission electron microscopy. We showed that the macromolecular micelle contained a spherical core-shell structure with a diameter of 197.1 +/- 3.3 nm and zeta potential of -19.1 +/- 4.3 mV. The CSO-g-CM-beta CD@AD-PTX micelle exhibited a high drug-loading efficacy up to 31.3%, as well as a critical micelle concentration of 3.4 * 10-7 M, which indicated good stability. Additionally, the in vitro release profile of the CSO-g-CM-beta-CD@AD-PTX micelle demonstrated a long-term release pattern, 63.1% of AD-PTX was released from the micelle during a 30-day period. Moreover, the CSO-g-CM-beta-CD@AD-PTX micelle displayed cytotoxicity at a sub-MUM scale similar to PTX in U87 MG cells, and CSO g-CM-beta-CD exhibited a good safety profile by not manifesting significant toxicity at concentrations up to 100 MUM. These results indicated that beta-CD based inclusion complexation resulting in biodegradable self-assembled macromolecular micelles can be utilized as nanocarrier, and may provide a promising platform for drug delivery in the future medical applications. PMID- 26964051 TI - History That Will Make Your Skin Crawl--Insect Use in Dermatology. PMID- 26964052 TI - Henna--A Temporary Body of Art. PMID- 26964054 TI - The Softest Rock on Earth. PMID- 26964053 TI - The Pus Pioneers. PMID- 26964055 TI - Enjoying Opera, Dermatology Style. PMID- 26964057 TI - Online Reviews of Physicians--Reply. PMID- 26964056 TI - Online Reviews of Physicians. PMID- 26964058 TI - Graft-vs-Host Disease. PMID- 26964060 TI - The Relationship Between Functional Movement, Balance Deficits, and Previous Injury History in Deploying Marine Warfighters. AB - Screening for primary musculoskeletal injury (MSK-I) is costly and time consuming. Both the Functional Movement Screen (FMS) and the Y-Balance Test (YBT) have been shown to predict future MSK-I. With a goal of optimizing the efficiency of primary MSK-I screening, we studied associations between performance on the FMS and YBT and whether history of MSK-I influenced FMS and YBT scores. In total, 365 deploying Marines performed the FMS and YBT as prescribed. Composite and individual scores were each categorized as high risk or low risk using published injury thresholds: High-risk FMS included composite scores <=14 and right-to-left (R/L) asymmetry for Shoulder Mobility, In-Line Lunge, Straight Leg Raise, Hurdle Step, or Rotary Stability. High-risk YBT consisted of anterior, posteromedial, and/or posterolateral R/L differences >4 cm and/or composite differences >=12 cm. Pearson's chi tests evaluated associations between: (a) all FMS and YBT risk groups and (b) previous MSK-I and all FMS and YBT risk groups. Marines with high risk FMS were twice as likely to have high-risk YBT posteromedial scores (chi = 10.2, p = 0.001; odds ratio [OR] = 2.1, 95% confidence interval [CI] = 1.3-3.2). History of any MSK-I was not associated with high-risk FMS or high-risk YBT. However, previous lower extremity MSK-I was associated with In-Line Lunge asymmetries (chi = 9.8, p = 0.002, OR = 2.2, 95% CI = 1.3-3.6). Overall, we found limited overlap in FMS and YBT risk. Because both methods seem to assess different risk factors for injury, we recommend FMS and YBT continue to be used together in combination with a thorough injury history until their predictive capacities are further established. PMID- 26964059 TI - A Mycobacterial Perspective on Tuberculosis in West Africa: Significant Geographical Variation of M. africanum and Other M. tuberculosis Complex Lineages. AB - BACKGROUND: Phylogenetically distinct Mycobacterium tuberculosis lineages differ in their phenotypes and pathogenicity. Consequently, understanding mycobacterial population structures phylogeographically is essential for design, interpretation and generalizability of clinical trials. Comprehensive efforts are lacking to date to establish the West African mycobacterial population structure on a sub continental scale, which has diagnostic implications and can inform the design of clinical TB trials. METHODOLOGY/PRINCIPAL FINDINGS: We collated novel and published genotyping (spoligotyping) data and classified spoligotypes into mycobacterial lineages/families using TBLineage and Spotclust, followed by phylogeographic analyses using statistics (logistic regression) and lineage axis plot analysis in GenGIS, in which a phylogenetic tree constructed in MIRU VNTRplus was analysed. Combining spoligotyping data from 16 previously published studies with novel data from The Gambia, we obtained a total of 3580 isolates from 12 countries and identified 6 lineages comprising 32 families. By using stringent analytical tools we demonstrate for the first time a significant phylogeographic separation between western and eastern West Africa not only of the two M. africanum (West Africa 1 and 2) but also of several major M. tuberculosis sensu stricto families, such as LAM10 and Haarlem 3. Moreover, in a longitudinal logistic regression analysis for grouped data we showed that M. africanum West Africa 2 remains a persistent health concern. CONCLUSIONS/SIGNIFICANCE: Because of the geographical divide of the mycobacterial populations in West Africa, individual research findings from one country cannot be generalized across the whole region. The unequal geographical family distribution should be considered in placement and design of future clinical trials in West Africa. PMID- 26964030 TI - Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array. AB - BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of B100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. METHODS: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA repair genes. RESULTS: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. CONCLUSIONS: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers. PMID- 26964061 TI - Impact of Short and Moderate Rest Intervals on the Acute Immunometabolic Response to Exhaustive Strength Exercise: Part II. AB - The purpose of this study was to investigate the influence of short and moderate recovery intervals during heavy strength exercise on performance, inflammatory, and metabolic responses in recreational weightlifters. Eight healthy subjects (age = 24.6 +/- 4.1 years) performed 2 randomized sequences with different rest intervals: short = 90% of 1RM and 30 seconds rest allowed between sets; moderate = 90% of 1RM and 90 seconds rest allowed between sets. All sequences of exercises were performed over 4 sets until movement failure in the squat and bench press exercises, respectively. Glucose, TNF-alpha, IL-6, IL-10, IL-10/TNF-alpha ratio, and nonester fatty acid concentrations were assessed at the baseline, immediately postexercise, post-15 and post-30 minutes. We observed a statistically significant decrease after 30 seconds on maximum number of repetitions (p = 0.003) and total weight lifted (p = 0.006) after the bench press, and there was a marginal decrease in the squat (p = 0.055). The glucose concentrations showed a significant increase post-15 minutes in the 30-second condition (pre-exercise = 86.1 +/- 9.1, immediately = 85.3 +/- 8.2, post-15 = 97.0 +/- 9.0, post-30 = 87.1 +/- 5.3 mg/dl; p = 0.015); on the other hand, IL-10 increased post-30 minutes in the 90-second condition (pre-exercise = 18.2 +/- 12.7, immediately = 16.4 +/- 10.7, post-15 = 16.8 +/- 12.2, post-30 = 35.0 +/- 13.1 pg/ml; p < 0.001). In addition, the 90-second condition showed anti-inflammatory effects (as indicated by IL-10/TNF-alpha ratio: pre-exercise = 1.08 +/- 1.32, immediately = 1.23 +/- 1.20, post-15 = 1.15 +/- 1.14, post-30 = 2.48 +/- 2.07; p = 0.020) compared with the 30-second condition (pre-exercise = 1.30 +/- 2.04, immediately = 0.99 +/- 1.27, post-15 = 1.23 +/- 1.82, post-30 = 1.28 +/- 1.28; p = 0.635). Thus, we concluded that a moderate interval of recovery (90 seconds) during heavy strength exercise allowed higher workload, IL-10 levels, and IL-10/TNF-alpha ratio in recreational weightlifters. PMID- 26964062 TI - The Herpes Simplex Virus Neurovirulence Factor gamma34.5: Revealing Virus-Host Interactions. PMID- 26964063 TI - The Formulation of Bacteriophage in a Semi Solid Preparation for Control of Propionibacterium acnes Growth. AB - AIMS: To isolate and characterise phage which could lyse P. acnes and to formulate the phage into a delivery form for potential application in topical treatment of acne infection. METHODS AND RESULTS: Using standard phage isolation techniques, ten phage capable of lysing P. acnes were isolated from human skin microflora. Their genomes showed high homology to previously reported P. acnes phage. These phage were formulated into cetomacrogol cream aqueous at a concentration of 2.5x108 PFU per gram, and shown to lyse underlying P. acnes cells grown as lawn cultures. These phage formulations remained active for at least 90 days when stored at four degrees Celsius in a light protected container. CONCLUSIONS: P. acnes phage formulated into cetomacrogol cream aqueous will lyse surrounding and underlying P. acnes bacteria, and are effective for at least 90 days if stored appropriately. SIGNIFICANCE AND IMPACT OF THE STUDY: There are few reports of phage formulation into semi solid preparations for application as phage therapy. The formulation method described here could potentially be applied topically to treat human acne infections. The potential exists for this model to be extended to other phage applied to treat other bacterial skin infections. PMID- 26964066 TI - Abdominal Palpation Haptic Device for Colonoscopy Simulation Using Pneumatic Control. AB - In this paper, we describe the development of a haptic device to be used in a simulator aiming to train the skills of gastroenterology assistants in abdominal palpation during colonoscopy, as well as to train team interaction skills for the colonoscopy team. To understand the haptic feedback forces to be simulated by the haptic device, we conducted an experiment with five participants of varying BMI. The applied forces and displacements were measured and hysteresis modeling was used to characterize the experimental data. These models were used to determine the haptic feedback forces required to simulate a BMI case in response to the real-time user interactions. The pneumatic haptic device consisted of a sphygmomanometer bladder as the haptic interface and a fuzzy controller to regulate the bladder pressure. The haptic device showed good steady state and dynamic response was adequate for simulating haptic interactions. Tracking accuracy averaged 94.2 percent within 300 ms of the reference input while the user was actively applying abdominal palpation and minor repositioning. PMID- 26964067 TI - Creating Realistic Virtual Textures from Contact Acceleration Data. AB - Modern haptic interfaces are adept at conveying the large-scale shape of virtual objects, but they often provide unrealistic or no feedback when it comes to the microscopic details of surface texture. Direct texture-rendering challenges the state of the art in haptics because it requires a finely detailed model of the surface's properties, real-time dynamic simulation of complex interactions, and high-bandwidth haptic output to enable the user to feel the resulting contacts. This paper presents a new, fully realized solution for creating realistic virtual textures. Our system employs a sensorized handheld tool to capture the feel of a given texture, recording three-dimensional tool acceleration, tool position, and contact force over time. We reduce the three-dimensional acceleration signals to a perceptually equivalent one-dimensional signal, and then we use linear predictive coding to distill this raw haptic information into a database of frequency-domain texture models. Finally, we render these texture models in real time on a Wacom tablet using a stylus augmented with small voice coil actuators. The resulting virtual textures provide a compelling simulation of contact with the real surfaces, which we verify through a human subject study. PMID- 26964065 TI - Assessment of the Cardiac Autonomic Nervous System in Mercury-Exposed Individuals via Post-Exercise Heart Rate Recovery. AB - OBJECTIVE: The aim of this study was to assess exercise heart rate recovery (HRR) indices in mercury-exposed individuals when evaluating their cardiac autonomic function. SUBJECTS AND METHODS: Twenty-eight mercury-exposed individuals and 28 healthy controls were enrolled. All the subjects underwent exercise testing and transthoracic echocardiography. The HRR indices were calculated by subtracting the first- (HRR1), second- (HRR2) and third-minute (HRR3) heart rates from the maximal heart rate. The two groups were evaluated in terms of exercise test parameters, especially HRR, and a correlation analysis was performed between blood, 24-hour urine and hair mercury levels and the test parameters. RESULTS: The mercury-exposed and control groups were similar in age (37.2 +/- 6.6 vs. 36.9 +/- 9.0 years), had an identical gender distribution (16 females and 12 males) and similar left ventricular ejection fractions (65.5 +/- 3.1 vs. 65.4 +/- 3.1%). The mean HRR1 [25.6 +/- 6.5 vs. 30.3 +/- 8.2 beats per min (bpm); p = 0.009], HRR2 (43.5 +/- 5.3 vs. 47.8 +/- 5.5 bpm; p = 0.010) and HRR3 (56.8 +/- 5.1 vs. 59.4 +/- 6.3 bpm; p = 0.016) values were significantly lower in the mercury exposed group than in the healthy controls. However, there were no significant correlations between blood, urine and hair mercury levels and exercise test parameters. CONCLUSIONS: Mercury-exposed individuals had lower HRR indices than normal subjects. In these individuals, mercury exposure measurements did not show correlations with the exercise test parameters, but age did show a negative correlation with these parameters. Therefore, cardiac autonomic functions might be involved in cases of mercury exposure. PMID- 26964064 TI - Activation of Myenteric Glia during Acute Inflammation In Vitro and In Vivo. AB - BACKGROUND: Enteric glial cells (EGCs) are the main constituent of the enteric nervous system and share similarities with astrocytes from the central nervous system including their reactivity to an inflammatory microenvironment. Previous studies on EGC pathophysiology have specifically focused on mucosal glia activation and its contribution to mucosal inflammatory processes observed in the gut of inflammatory bowel disease (IBD) patients. In contrast knowledge is scarce on intestinal inflammation not locally restricted to the mucosa but systemically affecting the intestine and its effect on the overall EGC network. METHODS AND RESULTS: In this study, we analyzed the biological effects of a systemic LPS induced hyperinflammatory insult on overall EGCs in a rat model in vivo, mimicking the clinical situation of systemic inflammation response syndrome (SIRS). Tissues from small and large intestine were removed 4 hours after systemic LPS-injection and analyzed on transcript and protein level. Laser capture microdissection was performed to study plexus-specific gene expression alterations. Upon systemic LPS-injection in vivo we observed a rapid and dramatic activation of Glial Fibrillary Acidic Protein (GFAP)-expressing glia on mRNA level, locally restricted to the myenteric plexus. To study the specific role of the GFAP subpopulation, we established flow cytometry-purified primary glial cell cultures from GFAP promotor-driven EGFP reporter mice. After LPS stimulation, we analyzed cytokine secretion and global gene expression profiles, which were finally implemented in a bioinformatic comparative transcriptome analysis. Enriched GFAP+ glial cells cultured as gliospheres secreted increased levels of prominent inflammatory cytokines upon LPS stimulation. Additionally, a shift in myenteric glial gene expression profile was induced that predominantly affected genes associated with immune response. CONCLUSION AND SIGNIFICANCE: Our findings identify the myenteric GFAP-expressing glial subpopulation as particularly susceptible and responsive to acute systemic inflammation of the gut wall and complement knowledge on glial involvement in mucosal inflammation of the intestine. PMID- 26964069 TI - Haptic Detection of Artificial Tumors by Hand and with a Tool in a MIS Environment. AB - Minimally invasive surgery uses optical cameras and special surgical tools in order to operate from an environment one step removed from the body cavity of interest to the surgeon. It has been suggested that constraints posed by this arrangement, in particular the lack of direct haptic feedback to the surgeon, may affect the surgeon's ability to identify tissues and accurately maneuver inside the body cavity. In the present study, the ability of laypeople to detect artificial tumors of various hardness values embedded in silicone gels was assessed in a simulated MIS environment. Participants explored the gels under three conditions all with remote viewing; using the unrestricted bare finger, using a stick-like surgical tool also unrestricted, and using the surgical tool restricted by its insertion through an operating port as in MIS. Participants were significantly more accurate and more efficient at tumor detection with the finger as compared to the other methods of exploration, and they were also better at detecting harder tumors as compared to softer ones. The potential implications of these results for the role of haptic perception in minimally invasive surgery are discussed. PMID- 26964068 TI - Haptic-Assisted Target Acquisition in a Visual Point-and-Click Task for Computer Users with Motion Impairments. AB - Haptic assistance is the process of using force feedback to aid the operator in human-computer interaction (HCI). This may take the form of guiding the operator toward a target or assisting them in its selection. Haptic feedback has previously been investigated to assist motion-impaired computer users; however, limitations of previous 2 DOF haptic target acquisition techniques such as gravity wells and high-friction-targets have hampered progress. In this paper, two new haptic-assistive techniques are presented that utilize the 3 DOF capabilities of the Phantom Omni to produce assistance that is designed specifically for motion-impaired computer users. These include haptic cones and V shaped funnels. To evaluate the effectiveness of the new haptic techniques, a series of point-and-click experiments were undertaken in parallel with cursor analysis to compare the levels of performance. The task required the operator to produce a predefined sentence on the Windows-On-Screen Keyboard. The results of the study prove that higher performance levels can be achieved using techniques that are less constricting than traditional assistance and without many of the drawbacks. Haptic cones produced the most significant results when compared to an unassisted interface with a mean improvement of 53 percent in the number of missed clicks and 145 percent improvement in throughput. PMID- 26964070 TI - Please Touch: Object Properties that Invite Touch. AB - Touch has received increasing interest in marketing, given research indicating that contact with products influences evaluation and the tendency to purchase. However, little is known from the marketing or psychophysical literature about visible attributes of objects that elicit touch for hedonic purposes. In these studies, participants rated the tendency of pictured objects to invite touch, or "touch-ability." Rated touch-ability varied reliably with structural attributes of objects, and the structural influences were distinct from those on other ratings such as attractiveness and apparent expense. Although the trends varied across object sets, touch-ability generally declined as surface textures became markedly rough and shape complexity became extreme. Holding stimulus factors constant, touch-ability also varied with the specific hand movements that were anticipated. Finally, mean touch-ability ratings were correlated across participants with the "Need for Touch" scale, which measures an individual's tendency to touch products. The studies point to touch-ability as a potential factor that might be incorporated into product design. PMID- 26964071 TI - Stable and Intuitive Control of an Intelligent Assist Device. AB - Safety and dependability are of the utmost importance for physical human-robot interaction due to the potential risks that a relatively powerful robot poses to human beings. From the control standpoint, it is possible to improve safety by guaranteeing that the robot will never exhibit any unstable behavior. However, stability is not the only concern in the design of a controller for such a robot. During human-robot interaction, the resulting cooperative motion should be truly intuitive and should not restrict in any way the human performance. For this purpose, we have designed a new variable admittance control law that guarantees the stability of the robot during constrained motion and also provides a very intuitive human interaction. The former characteristic is provided by the design of a stability observer while the latter is based on a variable admittance control scheme that uses the time derivative of the contact force to assess human intentions. The stability observer is based on a previously published stability investigation of cooperative motion which implies the knowledge of the interaction stiffness. A method to accurately estimate this stiffness online using the data coming from the encoder and from a multiaxis force sensor at the end effector is also provided. The stability and intuitivity of the control law are verified in a user study involving a cooperative drawing task with a 3 degree of-freedom (dof) parallel robot as well as in experiments performed with a prototype of an industrial Intelligent Assist Device. PMID- 26964072 TI - The Effect of Interaction Force Estimation on Performance in Bilateral Teleoperation. AB - Measuring interaction forces in bilateral teleoperation systems may be difficult, due to size and cost restrictions on the force sensors. Obtaining the interaction forces by estimation can be a viable alternative. The primary contribution of this paper is the study of the effect of interaction force estimation on performance in bilateral teleoperation. A distinction is made between the obvious effect as a result of inaccurate estimation, and the less obvious effect as a result of the inherent theoretical properties of a system that has two points of interaction with its surroundings (a teleoperator) as opposed to one point of interaction (single robot). Specifically, the existence of a singularity property is pointed out, at which interaction force estimation is impossible, and close to which it may be infeasible. The secondary contribution of the paper is the Force Sensor Free (FSF) transformation for linear teleoperation systems, which is an automated procedure that turns a teleoperation controller with force sensing into an equivalent controller with force estimation. An experiment is reported whose objective is to validate the operation of the FSF transformation on a real teleoperator. PMID- 26964073 TI - The Haptic Deictic System-HDS: Bringing Blind Students to Mainstream Classrooms. AB - Mathematics instruction and discourse typically involve two modes of communication: speech and graphical presentation. For the communication to remain situated, dynamic synchrony must be maintained between the speech and dynamic focus in the graphics. In sighted people, vision is used for two purposes: access to graphical material and awareness of embodied behavior. This embodiment awareness keeps communication situated with visual material and speech. Our goal is to assist students who are blind or visually impaired (SBVI) in the access to such instruction/communication. We employ the typical approach of sensory replacement for the missing visual sense. Haptic fingertip reading can replace visual material. We want to make the SBVI aware of the deictic gestures performed by the teacher over the graphic in conjunction with speech. We employ a haptic glove interface to facilitate this embodiment awareness. We address issues from the conception through the design and implementation to the effective and successful use of our Haptic Deictic System (HDS) in inclusive classrooms. PMID- 26964074 TI - Electrotactile Display with Real-Time Impedance Feedback Using Pulse Width Modulation. AB - An electrotactile display is a tactile interface composed of skin surface electrodes. The use of such a device is limited by the variability of the elicited sensation. One possible solution to this problem is to monitor skin electrical impedance. Previous studies revealed a correlation between impedance and threshold, but did not construct real-time feedback loops. In this study, an electrotactile display was constructed using a 1.45 MUs feedback loop. Real-time pulse width modulation was proposed, and the relationship between skin resistance and absolute threshold was measured to find a function for determining a suitable pulse width from skin resistance. An evaluation experiment revealed that the proposed algorithm suppressed spatial variation and reduced temporal change. PMID- 26964076 TI - Subclinical cardiac involvement in Crohn's disease and ulcerative colitis: an echocardiographic case-control study. AB - BACKGROUND: Cardiovascular manifestations of inflammatory bowel disease (IBD) are considered rare. The aim of the present study was to assess cardiac structure and function by means of traditional Doppler echocardiography and tissue Doppler imaging in order to better appreciate myocardial subclinical alterations and their future implications for these kind of patients. METHODS: Twenty-seven patients affected by Crohn's disease (CD) and 43 suffering from ulcerative colitis (UC) were enrolled. They were selected without cardiovascular diseases nor risk factors. They were compared with 24 healthy subjects matched for sex and age. Everyone underwent transthoracic echocardiography. RESULTS: IBD patients had larger left atrial anterior-posterior dimension (34+/-7 vs. 31+/-2 mm; P=0.001) and volume (46+/-7 vs. 41+/-6; P=0.002), reduced left ventricular (LV) ejection fraction (59+/-6 vs. 63+/-5%; P=0.006) and higher pulmonary artery systolic pressure (26+/-6 vs. 22+/-2 mmHg; P<0.001) than healthy volunteers. Moreover, LV diastolic function was slightly altered in patients in respect of controls. Atrioventricular valve regurgitation was prevalent in IBD. Finally, we found that 18 (25.7%) patients had mitral valve prolapse, 35 (50.0%) mitral valve leaflets thickening and 3 (4.3%) pericardial effusion. We did not find differences in echocardiographic parameters between CD and UC. CONCLUSIONS: Our study suggests that subclinical cardiac involvement is frequent among IBD patients. The underlying mechanisms require further evaluation, but might be due to a systemic increase in cytokines and profibrotic factors. PMID- 26964075 TI - Safety of Gadobutrol: Results From 42 Clinical Phase II to IV Studies and Postmarketing Surveillance After 29 Million Applications. AB - OBJECTIVE: The aim of this study was to provide a systematic safety analysis of gadobutrol after more than 29 million applications in clinical routine. MATERIALS AND METHODS: Forty-two clinical development phase II to IV studies on gadobutrol or comparator and the postmarketing safety surveillance database for gadobutrol (1998-2015) were analyzed. Adverse events (AEs) and drug-related AEs were evaluated in the clinical development database and spontaneous adverse drug reactions (ADRs) in the postmarketing database. Subgroup analyses were run on patients with special medical history and on patients of different age groups. RESULTS: In the clinical development studies, 6809 and 2184 patients received gadobutrol or comparators, respectively. The incidence of drug-related AEs was 3.5% for both groups. With the exception of nausea (0.7% related cases in both groups), all other drug-related AEs were 0.3% or less in both groups. Hypersensitivity reactions were sporadic (<0.1%). Patients with history of allergies to contrast agents experienced slightly more drug-related AEs. No differences were seen between age groups.The overall reporting rate of ADRs from postmarketing surveillance was 0.05%. The most frequent ADRs were anaphylactoid/hypersensitivity reactions, nausea, vomiting, and dyspnea.For 3 single-agent reports of nephrogenic systemic fibrosis, using a conservative approach, association with gadobutrol could not be excluded. CONCLUSIONS: Gadobutrol is well tolerated and has a favorable safety profile for patients of all age groups. PMID- 26964077 TI - The association of HOTAIR expression with clinicopathological features and prognosis in gastric cancer patients. AB - INTRODUCTION: A number of studies in gastric carcinoma have demonstrated that cancerous tissues have a significant higher HOTAIR level than that in noncancerous tissues. Overexpression of HOTAIR is associated with the development in gastric cancer. EVIDENCE ACQUISITION: We collected all relevant articles and explored the association of HOTAIR expression with clinicopathological features and prognosis in patients with gastric cancer. Literature collections were conducted by searching a number of electronic databases (up to November 15, 2015). The meta-analysis was conducted by using RevMan v.5.3 software and Stata SE 12.0. EVIDENCE SYNTHESIS: A total of 832 patients with gastric cancer based on 10 studies were included. The Meta-analysis results showed that high-expression of HOTAIR is significantly associated with clinicopathological features in gastric cancer patients, especially in the depth of tumor invasion, lymph node metastasis, vessel invasion, lymphatic vessel involvement and TNM stage, but there is no association between HOTAIR overexpression and other clinicopathological features. In addition, aberrant HOTAIR expression is also significantly associated with the prognosis in gastric cancer patients. CONCLUSIONS: There is an association between HOTAIR expression and clinicopathological features and prognosis in gastric cancer patients. High expression of HOTAIR in cancerous tissue could predict poor clinical outcome in gastric cancer, suggesting HOTAIR abundance may serve as a novel candidate biomarker for the clinical outcome in gastric cancers. PMID- 26964078 TI - The lung microbiome and exacerbations of COPD. AB - PURPOSE OF REVIEW: Traditional culture methods have identified airway bacterial pathogens that cause acute exacerbations of chronic obstructive pulmonary disease (COPD), and contribute to airway inflammation and COPD progression. However, conventional microbiology is limited by low sensitivity and bias toward predetermined and predominant pathogens. Highly sensitive, unbiased microbiome techniques overcome these limitations. Here, we present recent lung microbiome data, specifically in the context of smoking, COPD, and exacerbations. RECENT FINDINGS: In contrast to the sterile lung environment found with conventional microbiology, microbiome techniques demonstrate a lower respiratory tract microbiome in health. Alterations in the lung microbiome with smoking and COPD have been clearly demonstrated by culture techniques, however, the findings in microbiome studies are limited and controversial. Increasing COPD disease severity is associated with a reduction in microbial diversity. Though microbial community structure does not change with exacerbation, there are notable changes in its composition. Antibiotic and corticosteroid treatment of acute exacerbations of COPD have significant but opposing effects on microbiome composition. SUMMARY: The composition of the lung microbiome changes with smoking, the severity of COPD, during acute exacerbations and with the use of steroids and/or antibiotics. Understanding the role of the microbiome in disease progression and development of exacerbations will lead to novel therapies. PMID- 26964079 TI - Outcomes of double-balloon enteroscopy-assisted direct percutaneous endoscopic jejunostomy tube placement. AB - BACKGROUND AND STUDY AIMS: In a large series, conventional direct percutaneous endoscopic jejunostomy (DPEJ) tube placement with push endoscopes failed in approximately one-third of patients. In a pilot study, double-balloon enteroscopy (DBE)-assisted DPEJ tube placement was successful in all patients in whom attempted conventional DPEJ had failed. The study aim was to assess the technical success of and adverse events related to DBE-DPEJ tube placement in a large cohort of patients. PATIENTS AND METHODS: The medical records of all patients who underwent DBE-DPEJ tube placement between July 2010 and November 2013 were reviewed using a prospectively maintained electronic database. Data were abstracted for patient demographics, indications for DPEJ, gut anatomy, technical success rate, causes of failure, and adverse events. RESULTS: The study comprised a total of 94 patients (39 men; mean age 56 years; body mass index [BMI] 23 +/- 6.4 kg/m(2)). The most common indication for DPEJ was gastroparesis (n = 29). Altered gut anatomy was present in 36 patients (38 %). DBE-DPEJ tube placement was technically successful in 87 patients (93 %). The mean procedure duration was 33 minutes (range 15 - 88). DBE-DPEJ tube placement failed in seven patients (7 %), primarily because of limited instrument advancement in the setting of presumed surgical adhesions. Post-procedural adverse events occurred in eight patients (9 %), with one serious adverse event, which was a gastric interposition requiring surgical repair. CONCLUSIONS: Compared with the published outcomes of DPEJ by conventional endoscopy, DBE-DPEJ tube placement was technically successful in a high proportion of patients (93 %) and with a relatively low rate of significant adverse events. PMID- 26964080 TI - New Hope for Liver Xenotransplantation. PMID- 26964088 TI - Development and Preliminary Face and Content Validation of the "Which Health Approaches and Treatments Are You Using?" (WHAT) Questionnaires Assessing Complementary and Alternative Medicine Use in Pediatric Rheumatology. AB - OBJECTIVE: Complementary and alternative medicine (CAM) is commonly used by children with juvenile idiopathic arthritis (JIA), yet no validated questionnaires assess that use. The objective of this study was to develop child self- and parent proxy-report questionnaires assessing CAM use and to determine the face and content validity of the "Which Health Approaches and Treatments are you using?" (WHAT) questionnaires in pediatric rheumatology. METHODS: A sequential phased mixed methods approach was used to develop the questionnaires. A Delphi Survey of 126 experts followed by an interdisciplinary consensus conference of 14 stakeholders in CAM, general pediatrics and pediatric rheumatology was held to develop consensus on the content of the questionnaires using a nominal group technique. To determine face and content validity of the questionnaires, two groups, including (a) a purposive sample of 22 children with JIA 8 to 18 years and their parents from the Children's Hospital of Eastern Ontario and the Hospital for Sick Children, and (b) 21 Canadian pediatric rheumatology experts, participated in interviews. Participants were independently asked about the goal, understandability and comprehensiveness of the WHAT questionnaires, as well as the relevance of items. RESULTS: Consensus was reached on 17 items of the WHAT questionnaires. The domains found to be relevant were child's CAM use, factors associated with CAM use, perceived impact of CAM use, and communication about CAM. A total of 15 items in the parent proxy-report questionnaire and 13 items in the child report questionnaire showed adequate content validity. CONCLUSIONS: Consensus was reached by experts on the content of a pediatric CAM questionnaire. Face and content validity testing and modifications made to the WHAT questionnaires have helped ensure adequate preliminary validity for use in pediatric rheumatology. This constitutes the basis for further testing of these questionnaires in pediatric rheumatology and for adaptation to other chronic diseases. PMID- 26964091 TI - Correction: Peptidyl Prolyl Isomerase PIN1 Directly Binds to and Stabilizes Hypoxia-Inducible Factor-1alpha. PMID- 26964090 TI - Specific Activation of A3, A2A and A1 Adenosine Receptors in CD73-Knockout Mice Affects B16F10 Melanoma Growth, Neovascularization, Angiogenesis and Macrophage Infiltration. AB - CD73 (ecto-5'-nucleotidase), a cell surface enzyme hydrolyzing AMP to adenosine, was lately demonstrated to play a direct role in tumor progression including regulation of tumor vascularization. It was also shown to stimulate tumor macrophage infiltration. Interstitial adenosine, accumulating in solid tumors due to CD73 enzymatic activity, is recognized as a main mediator regulating the production of pro- and anti-angiogenic factors, but the engagement of specific adenosine receptors in tumor progression in vivo is still poorly researched. We have analyzed the role of high affinity adenosine receptors A1, A2A, and A3 in B16F10 melanoma progression using specific agonists (CCPA, CGS-21680 and IB-MECA, respectively). We limited endogenous extracellular adenosine background using CD73 knockout mice treated with CD73 chemical inhibitor, AOPCP (adenosine alpha,beta-methylene 5'-diphosphate). Activation of any adenosine receptor significantly inhibited B16F10 melanoma growth but only at its early stage. At 14th day of growth, the decrease in tumor neovascularization and MAPK pathway activation induced by CD73 depletion was reversed by all agonists. Activation of A1AR primarily increased angiogenic activation measured by expression of VEGF-R2 on tumor blood vessels. However, mainly A3AR activation increased both the microvessel density and expression of pro-angiogenic factors. All agonists induced significant increase in macrophage tumor infiltration, with IB-MECA being most effective. This effect was accompanied by substantial changes in cytokines regulating macrophage polarization between pro-inflammatory and pro-angiogenic phenotype. Our results demonstrate an evidence that each of the analyzed receptors has a specific role in the stimulation of tumor angiogenesis and confirm significantly more multifaceted role of adenosine in its regulation than was already observed. They also reveal previously unexplored consequences to extracellular adenosine signaling depletion in recently proposed anti-CD73 cancer therapy. PMID- 26964089 TI - Uropathogenic E. coli (UPEC) Infection Induces Proliferation through Enhancer of Zeste Homologue 2 (EZH2). AB - Host-pathogen interactions can induce epigenetic changes in the host directly, as well as indirectly through secreted factors. Previously, uropathogenic Escherichia coli (UPEC) was shown to increase DNA methyltransferase activity and expression, which was associated with methylation-dependent alterations in the urothelial expression of CDKN2A. Here, we showed that paracrine factors from infected cells alter expression of another epigenetic writer, EZH2, coordinate with proliferation. Urothelial cells were inoculated with UPEC, UPEC derivatives, or vehicle (mock infection) at low moi, washed, then maintained in media with Gentamycin. Urothelial conditioned media (CM) and extracellular vesicles (EV) were isolated after the inoculations and used to treat naive urothelial cells. EZH2 increased with UPEC infection, inoculation-induced CM, and inoculation induced EV vs. parallel stimulation derived from mock-inoculated urothelial cells. We found that infection also increased proliferation at one day post infection, which was blocked by the EZH2 inhibitor UNC1999. Inhibition of demethylation at H3K27me3 had the opposite effect and augmented proliferation. CONCLUSION: Uropathogen-induced paracrine factors act epigenetically by altering expression of EZH2, which plays a key role in early host cell proliferative responses to infection. PMID- 26964092 TI - The Contribution of Ionic Currents to Rate-Dependent Action Potential Duration and Pattern of Reentry in a Mathematical Model of Human Atrial Fibrillation. AB - Persistent atrial fibrillation (PeAF) in humans is characterized by shortening of action potential duration (APD) and attenuation of APD rate-adaptation. However, the quantitative influences of particular ionic current alterations on rate dependent APD changes, and effects on patterns of reentry in atrial tissue, have not been systematically investigated. Using mathematical models of human atrial cells and tissue and performing parameter sensitivity analysis, we evaluated the quantitative contributions to action potential (AP) shortening and APD rate adaptation of ionic current remodeling seen with PeAF. Ionic remodeling in PeAF was simulated by reducing L-type Ca2+ channel current (ICaL), increasing inward rectifier K+ current (IK1) and modulating five other ionic currents. Parameter sensitivity analysis, which quantified how each ionic current influenced APD in control and PeAF conditions, identified interesting results, including a negative effect of Na+/Ca2+ exchange on APD only in the PeAF condition. At high pacing rate (2 Hz), electrical remodeling in IK1 alone accounts for the APD reduction of PeAF, but at slow pacing rate (0.5 Hz) both electrical remodeling in ICaL alone ( 70%) and IK1 alone (+100%) contribute equally to the APD reduction. Furthermore, AP rate-adaptation was affected by IKur in control and by INaCa in the PeAF condition. In a 2D tissue model, a large reduction (-70%) of ICaL becomes a dominant factor leading to a stable spiral wave in PeAF. Our study provides a quantitative and unifying understanding of the roles of ionic current remodeling in determining rate-dependent APD changes at the cellular level and spatial reentry patterns in tissue. PMID- 26964093 TI - IL-10 Production Is Critical for Sustaining the Expansion of CD5+ B and NKT Cells and Restraining Autoantibody Production in Congenic Lupus-Prone Mice. AB - The development and progression of systemic lupus erythematosus is mediated by the complex interaction of genetic and environmental factors. To decipher the genetics that contribute to pathogenesis and the production of pathogenic autoantibodies, our lab has focused on the generation of congenic lupus-prone mice derived from the New Zealand Black (NZB) strain. Previous work has shown that an NZB-derived chromosome 4 interval spanning 32 to 151 Mb led to expansion of CD5+ B and Natural Killer T (NKT) cells, and could suppress autoimmunity when crossed with a lupus-prone mouse strain. Subsequently, it was shown that CD5+ B cells but not NKT cells derived from these mice could suppress the development of pro-inflammatory T cells. In this paper, we aimed to further resolve the genetics that leads to expansion of these two innate-like populations through the creation of additional sub-congenic mice and to characterize the role of IL-10 in the suppression of autoimmunity through the generation of IL-10 knockout mice. We show that expansion of CD5+ B cells and NKT cells localizes to a chromosome 4 interval spanning 91 to 123 Mb, which is distinct from the region that mediates the majority of the suppressive phenotype. We also demonstrate that IL-10 is critical to restraining autoantibody production and surprisingly plays a vital role in supporting the expansion of innate-like populations. PMID- 26964094 TI - Contrasting Effects of Historical Sea Level Rise and Contemporary Ocean Currents on Regional Gene Flow of Rhizophora racemosa in Eastern Atlantic Mangroves. AB - Mangroves are seafaring taxa through their hydrochorous propagules that have the potential to disperse over long distances. Therefore, investigating their patterns of gene flow provides insights on the processes involved in the spatial genetic structuring of populations. The coastline of Cameroon has a particular geomorphological history and coastal hydrology with complex contemporary patterns of ocean currents, which we hypothesize to have effects on the spatial configuration and composition of present-day mangroves within its spans. A total of 982 trees were sampled from 33 transects (11 sites) in 4 estuaries. Using 11 polymorphic SSR markers, we investigated genetic diversity and structure of Rhizophora racemosa, a widespread species in the region. Genetic diversity was low to moderate and genetic differentiation between nearly all population pairs was significant. Bayesian clustering analysis, PCoA, estimates of contemporary migration rates and identification of barriers to gene flow were used and complemented with estimated dispersal trajectories of hourly released virtual propagules, using high-resolution surface current from a mesoscale and tide resolving ocean simulation. These indicate that the Cameroon Volcanic Line (CVL) is not a present-day barrier to gene flow. Rather, the Inter-Bioko-Cameroon (IBC) corridor, formed due to sea level rise, allows for connectivity between two mangrove areas that were isolated during glacial times by the CVL. Genetic data and numerical ocean simulations indicated that an oceanic convergence zone near the Cameroon Estuary complex (CEC) presents a strong barrier to gene flow, resulting in genetic discontinuities between the mangrove areas on either side. This convergence did not result in higher genetic diversity at the CEC as we had hypothesized. In conclusion, the genetic structure of Rhizophora racemosa is maintained by the contrasting effects of the contemporary oceanic convergence and historical climate change-induced sea level rise. PMID- 26964096 TI - The Sclerotic Scatter Limbal Arc Is More Easily Elicited under Mesopic Rather Than Photopic Conditions. AB - INTRODUCTION: We aimed to determine the limbal lighting illuminance thresholds (LLITs) required to trigger perception of sclerotic scatter at the opposite non illuminated limbus (i.e. perception of a light limbal scleral arc) under different levels of ambient lighting illuminance (ALI). MATERIAL AND METHODS: Twenty healthy volunteers were enrolled. The iris shade (light or dark) was graded by retrieving the median value of the pixels of a pre-determined zone of a gray-level iris photograph. Mean keratometry and central corneal pachymetry were recorded. Each subject was asked to lie down, and the ALI at eye level was set to mesopic values (10, 20, 40 lux), then photopic values (60, 80, 100, 150, 200 lux). For each ALI level, a light beam of gradually increasing illuminance was applied to the right temporal limbus until the LLIT was reached, i.e. the level required to produce the faint light arc that is characteristic of sclerotic scatter at the nasal limbus. RESULTS: After log-log transformation, a linear relationship between the logarithm of ALI and the logarithm of the LLIT was found (p<0.001), a 10% increase in ALI being associated with an average increase in the LLIT of 28.9%. Higher keratometry values were associated with higher LLIT values (p = 0.008) under low ALI levels, but the coefficient of the interaction was very small, representing a very limited effect. Iris shade and central corneal thickness values were not significantly associated with the LLIT. We also developed a censored linear model for ALI values <= 40 lux, showing a linear relationship between ALI and the LLIT, in which the LLIT value was 34.4 times greater than the ALI value. CONCLUSION: Sclerotic scatter is more easily elicited under mesopic conditions than under photopic conditions and requires the LLIT value to be much higher than the ALI value, i.e. it requires extreme contrast. PMID- 26964095 TI - A Comparative Assessment of the Influences of Human Impacts on Soil Cd Concentrations Based on Stepwise Linear Regression, Classification and Regression Tree, and Random Forest Models. AB - Soil cadmium (Cd) contamination has attracted a great deal of attention because of its detrimental effects on animals and humans. This study aimed to develop and compare the performances of stepwise linear regression (SLR), classification and regression tree (CART) and random forest (RF) models in the prediction and mapping of the spatial distribution of soil Cd and to identify likely sources of Cd accumulation in Fuyang County, eastern China. Soil Cd data from 276 topsoil (0 20 cm) samples were collected and randomly divided into calibration (222 samples) and validation datasets (54 samples). Auxiliary data, including detailed land use information, soil organic matter, soil pH, and topographic data, were incorporated into the models to simulate the soil Cd concentrations and further identify the main factors influencing soil Cd variation. The predictive models for soil Cd concentration exhibited acceptable overall accuracies (72.22% for SLR, 70.37% for CART, and 75.93% for RF). The SLR model exhibited the largest predicted deviation, with a mean error (ME) of 0.074 mg/kg, a mean absolute error (MAE) of 0.160 mg/kg, and a root mean squared error (RMSE) of 0.274 mg/kg, and the RF model produced the results closest to the observed values, with an ME of 0.002 mg/kg, an MAE of 0.132 mg/kg, and an RMSE of 0.198 mg/kg. The RF model also exhibited the greatest R2 value (0.772). The CART model predictions closely followed, with ME, MAE, RMSE, and R2 values of 0.013 mg/kg, 0.154 mg/kg, 0.230 mg/kg and 0.644, respectively. The three prediction maps generally exhibited similar and realistic spatial patterns of soil Cd contamination. The heavily Cd affected areas were primarily located in the alluvial valley plain of the Fuchun River and its tributaries because of the dramatic industrialization and urbanization processes that have occurred there. The most important variable for explaining high levels of soil Cd accumulation was the presence of metal smelting industries. The good performance of the RF model was attributable to its ability to handle the non-linear and hierarchical relationships between soil Cd and environmental variables. These results confirm that the RF approach is promising for the prediction and spatial distribution mapping of soil Cd at the regional scale. PMID- 26964097 TI - Construction of High-Density Linkage Maps of Populus deltoides * P. simonii Using Restriction-Site Associated DNA Sequencing. AB - Although numerous linkage maps have been constructed in the genus Populus, they are typically sparse and thus have limited applications due to low throughput of traditional molecular markers. Restriction-site associated DNA sequencing (RADSeq) technology allows us to identify a large number of single nucleotide polymorphisms (SNP) across genomes of many individuals in a fast and cost effective way, and makes it possible to construct high-density genetic linkage maps. We performed RADSeq for 299 progeny and their two parents in an F1 hybrid population generated by crossing the female Populus deltoides 'I-69' and male Populus simonii 'L3'. A total of 2,545 high quality SNP markers were obtained and two parent-specific linkage maps were constructed. The female genetic map contained 1601 SNPs and 20 linkage groups, spanning 4,249.12 cM of the genome with an average distance of 2.69 cM between adjacent markers, while the male map consisted of 940 SNPs and also 20 linkage groups with a total length of 3,816.24 cM and an average marker interval distance of 4.15 cM. Finally, our analysis revealed that synteny and collinearity are highly conserved between the parental linkage maps and the reference genome of P. trichocarpa. We demonstrated that RAD sequencing is a powerful technique capable of rapidly generating a large number of SNPs for constructing genetic maps in outbred forest trees. The high-quality linkage maps constructed here provided reliable genetic resources to facilitate locating quantitative trait loci (QTLs) that control growth and wood quality traits in the hybrid population. PMID- 26964098 TI - Tissue Distribution of Porcine FTO and Its Effect on Porcine Intramuscular Preadipocytes Proliferation and Differentiation. AB - The fat mass and obesity associated (FTO) gene plays an important role in adipogenesis. However, its function during porcine intramuscular preadipocyte proliferation and differentiation remains poorly understood. In this study, we prepared the antiserum against porcine FTO (pFTO), which was used to determine its subcellular localization and tissue distribution. Our data indicated that pFTO was localized predominantly in the nucleus. Real-time quantitative PCR and western blot analysis showed that pFTO was highly expressed in the lung and subcutaneous adipose tissue. Overexpression of pFTO in porcine intramuscular preadipocytes significantly promoted cell proliferation and lipid deposition. Furthermore, overexpression of pFTO in differentiating porcine intramuscular preadipocytes also significantly increased the mRNA levels of adipocyte differentiation transcription factors peroxisome proliferators-activated receptor gamma (PPARgamma), CCAAT/enhancer binding protein alpha (C/EBPalpha), lipoprotein lipase (LPL) and fatty acid synthase (FAS). Our findings provide the first functional evidence to reveal a role of pFTO in porcine intramuscular preadipocyte proliferation and differentiation. PMID- 26964099 TI - Native Magnetic Resonance T1-Mapping Identifies Diffuse Myocardial Injury in Hypothyroidism. AB - BACKGROUND AND AIM: Hypothyroidism (HT) is characterized by thyroid hormone deficiencies, which can lead to diffuse myocardial interstitium lesions in patients with HT. Myocardial longitudinal relaxation time (T1) mapping is a potential diagnostic tool for quantifying diffuse myocardial injury. This study aimed to assess the usefulness of T1 mapping in identifying myocardial involvement in HT, and determine the relationship between T1 values and myocardial function. METHODS: A cross-sectional study was conducted with 30 untreated HT patients alongside 23 age- and sex-matched healthy controls. All subjects underwent cardiac magnetic resonance (CMR) with non-contrast (native) T1 mapping using a modified Look-Locker inversion-recovery (MOLLI) sequence to assess the native T1 values of myocardium and cardiac function. RESULTS: Native myocardial T1 values were significantly increased in HT patients, especially those with pericardial effusion (p < 0.05), compared with healthy controls. In addition, significantly reduced peak filling rate (PFR) and prolonged peak filling time (PFT) were obtained (p < 0.05) in HT patients compared with controls. Furthermore, stroke volume (SV) and cardiac index (CI) were significantly lower in HT patients than controls (all p < 0.05). Interestingly, native T1 values were negatively correlated with free triiodothyronine (FT3), PFR, SV and CI (all p < 0.05). CONCLUSION: Diffuse myocardial injuries are common in HT patients, and increased T1 values are correlated with FT3 and cardiac function impairment. These findings indicate that T1 mapping might be useful in evaluating myocardial injuries in HT patients. PMID- 26964101 TI - Association of Soil Aggregation with the Distribution and Quality of Organic Carbon in Soil along an Elevation Gradient on Wuyi Mountain in China. AB - Forest soils play a critical role in the sequestration of atmospheric CO2 and subsequent attenuation of global warming. The nature and properties of organic matter in soils have an influence on the sequestration of carbon. In this study, soils were collected from representative forestlands, including a subtropical evergreen broad-leaved forest (EBF), a coniferous forest (CF), a subalpine dwarf forest (DF), and alpine meadow (AM) along an elevation gradient on Wuyi Mountain, which is located in a subtropical area of southeastern China. These soil samples were analyzed in the laboratory to examine the distribution and speciation of organic carbon (OC) within different size fractions of water-stable soil aggregates, and subsequently to determine effects on carbon sequestration. Soil aggregation rate increased with increasing elevation. Soil aggregation rate, rather than soil temperature, moisture or clay content, showed the strongest correlation with OC in bulk soil, indicating soil structure was the critical factor in carbon sequestration of Wuyi Mountain. The content of coarse particulate organic matter fraction, rather than the silt and clay particles, represented OC stock in bulk soil and different soil aggregate fractions. With increasing soil aggregation rate, more carbon was accumulated within the macroaggregates, particularly within the coarse particulate organic matter fraction (250-2000 MUm), rather than within the microaggregates (53-250MUm) or silt and clay particles (< 53MUm). In consideration of the high instability of macroaggregates and the liability of SOC within them, further research is needed to verify whether highly-aggregated soils at higher altitudes are more likely to lose SOC under warmer conditions. PMID- 26964100 TI - Experimental Cerebral Malaria Spreads along the Rostral Migratory Stream. AB - It is poorly understood how progressive brain swelling in experimental cerebral malaria (ECM) evolves in space and over time, and whether mechanisms of inflammation or microvascular sequestration/obstruction dominate the underlying pathophysiology. We therefore monitored in the Plasmodium berghei ANKA-C57BL/6 murine ECM model, disease manifestation and progression clinically, assessed by the Rapid-Murine-Coma-and-Behavioral-Scale (RMCBS), and by high-resolution in vivo MRI, including sensitive assessment of early blood-brain-barrier-disruption (BBBD), brain edema and microvascular pathology. For histological correlation HE and immunohistochemical staining for microglia and neuroblasts were obtained. Our results demonstrate that BBBD and edema initiated in the olfactory bulb (OB) and spread along the rostral-migratory-stream (RMS) to the subventricular zone of the lateral ventricles, the dorsal-migratory-stream (DMS), and finally to the external capsule (EC) and brainstem (BS). Before clinical symptoms (mean RMCBS = 18.5+/-1) became evident, a slight, non-significant increase of quantitative T2 and ADC values was observed in OB+RMS. With clinical manifestation (mean RMCBS = 14.2+/-0.4), T2 and ADC values significantly increased along the OB+RMS (p = 0.049/p = 0.01). Severe ECM (mean RMCBS = 5+/-2.9) was defined by further spread into more posterior and deeper brain structures until reaching the BS (significant T2 elevation in DMS+EC+BS (p = 0.034)). Quantitative automated histological analyses confirmed microglial activation in areas of BBBD and edema. Activated microglia were closely associated with the RMS and neuroblasts within the RMS were severely misaligned with respect to their physiological linear migration pattern. Microvascular pathology and ischemic brain injury occurred only secondarily, after vasogenic edema formation and were both associated less with clinical severity and the temporal course of ECM. Altogether, we identified a distinct spatiotemporal pattern of microglial activation in ECM involving primarily the OB+RMS axis, a distinct pathway utilized by neuroblasts and immune cells. Our data suggest significant crosstalk between these two cell populations to be operative in deeper brain infiltration and further imply that the manifestation and progression of cerebral malaria may depend on brain areas otherwise serving neurogenesis. PMID- 26964102 TI - Feature Integration and Task Switching: Diminished Switch Costs after Controlling for Stimulus, Response, and Cue Repetitions. AB - This report presents data from two versions of the task switching procedure in which the separate influence of stimulus repetitions, response key repetitions, conceptual response repetitions, cue repetitions, task repetitions, and congruency are considered. Experiment 1 used a simple alternating runs procedure with parity judgments of digits and consonant/vowel decisions of letters as the two tasks. Results revealed sizable effects of stimulus and response repetitions, and controlling for these effects reduced the switch cost. Experiment 2 was a cued version of the task switch paradigm with parity and magnitude judgments of digits as the two tasks. Results again revealed large effects of stimulus and response repetitions, in addition to cue repetition effects. Controlling for these effects again reduced the switch cost. Congruency did not interact with our novel "unbiased" measure of switch costs. We discuss how the task switch paradigm might be thought of as a more complex version of the feature integration paradigm and propose an episodic learning account of the effect. We further consider to what extent appeals to higher-order control processes might be unnecessary and propose that controls for feature integration biases should be standard practice in task switching experiments. PMID- 26964103 TI - Funding and Innovation in Diseases of Neglected Populations: The Paradox of Cryptococcal Meningitis. PMID- 26964106 TI - Toward Perceiving Robots as Humans: Three Handshake Models Face the Turing-Like Handshake Test. AB - In the Turing test a computer model is deemed to "think intelligently" if it can generate answers that are indistinguishable from those of a human. We developed an analogous Turing-like handshake test to determine if a machine can produce similarly indistinguishable movements. The test is administered through a telerobotic system in which an interrogator holds a robotic stylus and interacts with another party - artificial or human with varying levels of noise. The interrogator is asked which party seems to be more human. Here, we compare the human-likeness levels of three different models for handshake: (1) Tit-for-Tat model, (2) lambda model, and (3) Machine Learning model. The Tit-for-Tat and the Machine Learning models generated handshakes that were perceived as the most human-like among the three models that were tested. Combining the best aspects of each of the three models into a single robotic handshake algorithm might allow us to advance our understanding of the way the nervous system controls sensorimotor interactions and further improve the human-likeness of robotic handshakes. PMID- 26964107 TI - The Task-Dependent Efficacy of Shared-Control Haptic Guidance Paradigms. AB - Shared-control haptic guidance is a common form of robot-mediated training used to teach novice subjects to perform dynamic tasks. Shared-control guidance is distinct from more traditional guidance controllers, such as virtual fixtures, in that it provides novices with real-time visual and haptic feedback from a real or virtual expert. Previous studies have shown varying levels of training efficacy using shared-control guidance paradigms; it is hypothesized that these mixed results are due to interactions between specific guidance implementations ("paradigms") and tasks. This work proposes a novel guidance paradigm taxonomy intended to help classify and compare the multitude of implementations in the literature, as well as a revised proxy rendering model to allow for the implementation of more complex guidance paradigms. The efficacies of four common paradigms are compared in a controlled study with 50 healthy subjects and two dynamic tasks. The results show that guidance paradigms must be matched to a task's dynamic characteristics to elicit effective training and low workload. Based on these results, we provide suggestions for the future development of improved haptic guidance paradigms. PMID- 26964105 TI - Molecular and Epigenetic Mechanism Regulating Hypothalamic Kiss1 Gene Expression in Mammals. AB - After the discovery of hypothalamic kisspeptin encoded by the Kiss1 gene, the central mechanism regulating gonadotropin-releasing hormone (GnRH) secretion, and hence gonadotropin secretion, is gradually being unraveled. This has increased our understanding of the central mechanism regulating puberty and subsequent reproductive performance in mammals. Recently, emerging evidence has indicated the molecular and epigenetic mechanism regulating hypothalamic Kiss1 gene expression. Here we compile data regarding DNA and histone modifications in the Kiss1 promoter region and provide a hypothetic scheme of the molecular and epigenetic mechanism regulating Kiss1 gene expression in two populations of hypothalamic kisspeptin neurons, which govern puberty and subsequent reproductive performance via GnRH/gonadotropin secretion. PMID- 26964108 TI - Simultaneous Perception of Forces and Motions Using Bimanual Interactions. AB - When teaching physical skills, experts or robotic assistants commonly move a novice through a task. However, this guiding motion is only partially effective at portraying the full experience because the guided person is only performing the task passively and the guidance and task forces can become ambiguously intertwined. The interaction evaluated in this paper separates the task and guidance forces by guiding one hand so the user can actively recreate the motion with their other hand that receives task-related forces. This method is based on the ability of humans to easily move their hands through similar paths, such as drawing circles, compared to the difficulty of simultaneously drawing a square with one hand and a circle with the other. Several experiments were first performed to characterize the reference frames, interaction stiffnesses, and trajectories that humans can recreate. Visual Symmetry and Joint-Space Symmetry proved to be easier than Point Mirror Symmetry and participants' recreated motions typically lagged by approximately 50-100 ms. Based on these results, participants used bimanual guidance to identify the orientation of a hard rod embedded in a soft material. The results show that participants could identify the orientation of the rod equally well when working independently compared to being bimanually guided through a desired motion. PMID- 26964104 TI - Loss of ATP-Sensitive Potassium Channel Surface Expression in Heart Failure Underlies Dysregulation of Action Potential Duration and Myocardial Vulnerability to Injury. AB - The search for new approaches to treatment and prevention of heart failure is a major challenge in medicine. The adenosine triphosphate-sensitive potassium (KATP) channel has been long associated with the ability to preserve myocardial function and viability under stress. High surface expression of membrane KATP channels ensures a rapid energy-sparing reduction in action potential duration (APD) in response to metabolic challenges, while cellular signaling that reduces surface KATP channel expression blunts APD shortening, thus sacrificing energetic efficiency in exchange for greater cellular calcium entry and increased contractile force. In healthy hearts, calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylates the Kir6.2 KATP channel subunit initiating a cascade responsible for KATP channel endocytosis. Here, activation of CaMKII in a transaortic banding (TAB) model of heart failure is coupled with a 35-40% reduction in surface expression of KATP channels compared to hearts from sham operated mice. Linkage between KATP channel expression and CaMKII is verified in isolated cardiomyocytes in which activation of CaMKII results in downregulation of KATP channel current. Accordingly, shortening of monophasic APD is slowed in response to hypoxia or heart rate acceleration in failing compared to non-failing hearts, a phenomenon previously shown to result in significant increases in oxygen consumption. Even in the absence of coronary artery disease, failing myocardium can be further injured by ischemia due to a mismatch between metabolic supply and demand. Ischemia-reperfusion injury, following ischemic preconditioning, is diminished in hearts with CaMKII inhibition compared to wild type hearts and this advantage is largely eliminated when myocardial KATP channel expression is absent, supporting that the myocardial protective benefit of CaMKII inhibition in heart failure may be substantially mediated by KATP channels. Recognition of CaMKII-dependent downregulation of KATP channel expression as a mechanism for vulnerability to injury in failing hearts points to strategies targeting this interaction for potential preventives or treatments. PMID- 26964109 TI - Wrist Coordination in a Kinematically Redundant Stabilization Task. AB - We investigated how the control of a compliant object is realized by the redundancy of wrist anatomy. Subjects had to balance a one degree-of-freedom inverted pendulum using elastic linkages controlled by wrist flexion/extension (FE) and forearm pronation/supination (PS). Haptic feedback of the interaction forces between the pendulum and the wrist was provided by a robotic interface. By tuning the mechanical properties of the virtual pendulum and the stiffness of the elastic linkages it was possible to study various dynamical regimes of the simulated object. Twenty subjects (divided in two groups) were tested in four days performing the same task but with different presentation order. The stabilization strategy adopted by the subjects was characterized by primarily using the PS DoF when the pendulum was linked to stiff springs and characterized by a relatively fast dynamic response; in contrast, the stabilization task was shared by both DoFs in case of lower spring stiffness and slower dynamics of the virtual object. PMID- 26964110 TI - Evaluation of Tactile Feedback Methods for Wrist Rotation Guidance. AB - Tactile motion guidance systems aim to direct the user's movement toward a target pose or trajectory by delivering tactile cues through lightweight wearable actuators. This study evaluates 10 forms of tactile feedback for guidance of wrist rotation to understand the traits that influence the effectiveness of such systems. We present five wearable actuators capable of tapping, dragging across, squeezing, twisting, or vibrating against the user's wrist; each actuator can be controlled via steady or pulsing drive algorithms. Ten subjects used each form of feedback to perform three unsighted movement tasks: directional response, position targeting, and trajectory following. The results show that directional responses are fastest when direction is conveyed through the location of the tactile stimulus or steady lateral skin stretch. Feedback that clearly conveys movement direction enables subjects to reach target positions most quickly, though tactile magnitude cues (steady intensity and especially pulsing frequency) can also be used when direction is difficult to discern. Subjects closely tracked arbitrary trajectories only when both movement direction and cue magnitude were subjectively rated as very easy to discern. The best overall performance was achieved by the actuator that repeatedly taps on the subject's wrist on the side toward which they should turn. PMID- 26964111 TI - A High Performance Tactile Feedback Display and Its Integration in Teleoperation. AB - This paper presents the development of a compact tactile display and its integration in teleoperation. The system's operation is based on the display of surface shape to an area of the fingertip through a 4 * 4 array of tactors moving perpendicularly to the skin surface. The tactors are spring loaded and are actuated remotely by dc motors through a flexible tendon transmission. This novel implementation of conventional actuation principles achieves a compact design with superior performance compared to devices of a similar footprint, demonstrating an excellent combination of tactor spatiotemporal resolution, force, and amplitude. The display's ergonomic design and high performance make it suitable for integration on haptic devices for tactile feedback in VR and in Teleoperation. This paper presents the design, control, and performance of the tactile display and of the transmission system. It also demonstrates its integration on an Omega7 force feedback device for the teleoperation of an LWR KUKA manipulator. An experiment is presented where users teleoperated the stylus of the robot in a 3D contour following task with and without tactile feedback. In this experiment, force feedback from the slave is fused with model-based local tactile feedback. Subjects' performances indicate an improvement in teleoperation when both tactile and force feedback are present. PMID- 26964112 TI - Control of a Robot Dancer for Enhancing Haptic Human-Robot Interaction in Waltz. AB - Haptic interaction between a human leader and a robot follower in waltz is studied in this paper. An inverted pendulum model is used to approximate the human's body dynamics. With the feedbacks from the force sensor and laser range finders, the robot is able to estimate the human leader's state by using an extended Kalman filter (EKF). To reduce interaction force, two robot controllers, namely, admittance with virtual force controller, and inverted pendulum controller, are proposed and evaluated in experiments. The former controller failed the experiment; reasons for the failure are explained. At the same time, the use of the latter controller is validated by experiment results. PMID- 26964113 TI - Supporting Negotiation Behavior with Haptics-Enabled Human-Computer Interfaces. AB - An active research goal for human-computer interaction is to allow humans to communicate with computers in an intuitive and natural fashion, especially in real-life interaction scenarios. One approach that has been advocated to achieve this has been to build computer systems with human-like qualities and capabilities. In this paper, we present insight on how human-computer interaction can be enriched by employing the computers with behavioral patterns that naturally appear in human-human negotiation scenarios. For this purpose, we introduce a two-party negotiation game specifically built for studying the effectiveness of haptic and audio-visual cues in conveying negotiation related behaviors. The game is centered around a real-time continuous two-party negotiation scenario based on the existing game-theory and negotiation literature. During the game, humans are confronted with a computer opponent, which can display different behaviors, such as concession, competition, and negotiation. Through a user study, we show that the behaviors that are associated with human negotiation can be incorporated into human-computer interaction, and the addition of haptic cues provides a statistically significant increase in the human-recognition accuracy of machine-displayed behaviors. In addition to aspects of conveying these negotiation-related behaviors, we also focus on and report game-theoretical aspects of the overall interaction experience. In particular, we show that, as reported in the game-theory literature, certain negotiation strategies such as tit-for-tat may generate maximum combined utility for the negotiating parties, providing an excellent balance between the energy spent by the user and the combined utility of the negotiating parties. PMID- 26964127 TI - Cutaneous Force Feedback as a Sensory Subtraction Technique in Haptics. AB - A novel sensory substitution technique is presented. Kinesthetic and cutaneous force feedback are substituted by cutaneous feedback (CF) only, provided by two wearable devices able to apply forces to the index finger and the thumb, while holding a handle during a teleoperation task. The force pattern, fed back to the user while using the cutaneous devices, is similar, in terms of intensity and area of application, to the cutaneous force pattern applied to the finger pad while interacting with a haptic device providing both cutaneous and kinesthetic force feedback. The pattern generated using the cutaneous devices can be thought as a subtraction between the complete haptic feedback (HF) and the kinesthetic part of it. For this reason, we refer to this approach as sensory subtraction instead of sensory substitution. A needle insertion scenario is considered to validate the approach. The haptic device is connected to a virtual environment simulating a needle insertion task. Experiments show that the perception of inserting a needle using the cutaneous-only force feedback is nearly indistinguishable from the one felt by the user while using both cutaneous and kinesthetic feedback. As most of the sensory substitution approaches, the proposed sensory subtraction technique also has the advantage of not suffering from stability issues of teleoperation systems due, for instance, to communication delays. Moreover, experiments show that the sensory subtraction technique outperforms sensory substitution with more conventional visual feedback (VF). PMID- 26964128 TI - Design and Evaluation of a Novel Haptic Interface for Endoscopic Simulation. AB - Inspection of the colon with an endoscope for early signs of cancer (colonoscopy) has become an extremely widespread procedure, since early treatment radically improves the outlook of patients. The procedure requires a close coordination between the sense of touch and vision to navigate the endoscope along the colon. This raises the need to develop efficient training methods for physicians. Training simulators based on virtual reality, where realistic graphics are combined with a mechatronic system providing haptic feedback, are alternative to traditional training methods. To provide physicians with realistic haptic sensations of an endoscopic procedure, we have designed a haptic interface, instrumented a clinical endoscope and combined them with a simulation software for colonoscopy. In this contribution, we present the mechatronic components of the simulator. The haptic interface is able to generate high forces using the combination of electrical motors and brakes in a compact design. Experiments were performed to determine the characteristics of the device. A model-based control has been implemented and the results show that the control successfully compensates for the device nonlinearities, such as friction. The proposed haptic interface, together with the virtual reality, form a highly realistic training simulator for endoscopic surgeons, applicable not only to colonoscopy, but also to similar interventions. PMID- 26964129 TI - Force Parameters for Skills Assessment in Laparoscopy. AB - When equipped with motion and force sensors, box-trainers can be good alternatives for relatively expensive Virtual Reality (VR) trainers. As in VR trainers, the sensors in a box trainer could provide the trainee with objective information about his performance. Recently, multiple tracking systems were developed for classification of participants based on motion and time parameters. The aim of this study is the development of force parameters that reflect the trainee's performance in a suture task. Our second goal is to investigate if the level of the participant's skills can be classified as experts or novice level. In the experiment, experts (n = 11) and novices (n = 21) performed a two-handed needle driving and knot tying task on artificial tissue inside a box trainer. The tissue was mounted on the Force platform that was used to measure the force, which the subject applied on the tissue in three directions. We evaluated the potential of 16 different performance parameters, related to the magnitude, direction, and variability of applied forces, to distinguish between different levels of surgical expertise. Nine of the parameters showed significant differences between experts and novices. Principal Component Analysis was used to convert these nine partly correlating parameters, such as peak force, mean force, and main direction of force, into two uncorrelated variables. By performing a Leave-One-Out-Cross Validation with Linear Discriminant Analysis on each participants' score on these two variables, it was possible to correctly classify 84 percent of all participants as an expert or novice. We conclude that force measurements in a box trainer can be used to classify the level of performance of trainees and can contribute to objective assessment of suture skills. PMID- 26964130 TI - Haptic Edge Sharpness Perception with a Contact Location Display. AB - The effect of contact location information on virtual edge perception was investigated in two experiments. In Experiment 1, participants discriminated edge sharpness under force-alone and force-plus-contact-location conditions using a 4.8 mm radius contact roller. Virtual objects were 2D profiles of edges with two adjoining surfaces. For both conditions, the Just Noticeable Difference (JND) in change of edge radius increased from 2.3 to 7.4 mm as edge radii increased from 2.5 to 20.0 mm; there was no significant difference between the two conditions. A follow-up experiment with contact location alone resulted in higher edge sharpness JNDs. In Experiment 2, the same edge sharpness discrimination task was performed using a smaller contact roller (R = 1.5 mm) to investigate the effect of roller size. The JNDs for the smaller roller were not statistically significant from those of the larger roller. Our results suggest that 1) contact location cues alone are capable of conveying edge sharpness information, but that force cues are dominant when both types of cues are available; and 2) the radius of the contact roller does not significantly affect the user's ability to discriminate edge sharpness, indicating that the participants could use the changes in contact location to judge curvature. PMID- 26964131 TI - iDental: A Haptic-Based Dental Simulator and Its Preliminary User Evaluation. AB - Performance evaluation is indispensable for a surgical simulator to become acceptable. A haptics-based dental simulator (iDental) has been developed and preliminary user evaluation on its first-generation prototype has been carried out to gain the knowledge. Based on detailed requirement analysis of Periodontics procedures, a combined evaluation method including qualitative and quantitative analysis was designed. Construct validity was used to compare the performance difference between two groups of participants (faculty members and dental graduate students). These participants were required to perform three periodontal examination and treatment procedures including periodontal pocket probing, calculus detection, and removal. From the evaluation results, we found that penetration between tool and teeth or cheek will greatly decrease the fidelity of the simulation, therefore, it is necessary to utilize 6-DOF haptic device with both force and torque feedback in dental simulator, and accordingly it is needed to extend point-based rendering to 6-DOF haptic rendering of multiregion contacts. Furthermore, several other key research topics that will enable haptic technology to be effective in a practical dental simulator were identified, including simulation of deformable body such as tongue and gingival, and simulation of occlusion of tongue and cheek on teeth, etc. PMID- 26964132 TI - Impulse-Based Rendering Methods for Haptic Simulation of Bone-Burring. AB - Bone-burring is a common procedure in orthopedic, dental, and otologic surgeries. Virtual reality (VR)-based surgical simulations with both visual and haptic feedbacks provide novice surgeons with a feasible and safe way to practice their burring skill. However, creating realistic haptic interactions between a high speed rotary burr and stiff bone is a challenging task. In this paper, we propose a novel interactive haptic bone-burring model based on impulse-based dynamics to simulate the contact forces, including resistant and frictional forces. In order to mimic the lateral and axial burring vibration forces, a 3D vibration model has been developed. A prototype haptic simulation system for the bone-burring procedure has been implemented to evaluate the proposed haptic rendering methods. Several experiments of force evaluations and task-oriented tests were conducted on the prototype system. The results demonstrate the validity and feasibility of the proposed methods. PMID- 26964133 TI - The Enactive Torch: A New Tool for the Science of Perception. AB - The cognitive sciences are increasingly coming to terms with the embodied, embedded, extended, and experiential aspects of the mind. Exemplifying this shift, the enactive approach points to an essential role of goal-directed bodily activity in the generation of meaningful perceptual experience, i.e., sense making. Here, building on recent insights into the transformative effects of practical tool-use, we make use of the enactive approach in order to provide a definition of an enactive interface in terms of augmented sense-making. We introduce such a custom-built interface, the Enactive Torch, and present a study of its experiential effects. The results demonstrate that the user experience is not adequately captured by any standardly assumed perceptual modality; rather, it is a new feeling that is mediated by the design of the device and shaped by the overall situation of the task. Taken together these findings show that there is much to be gained by synergies between engineering and the cognitive sciences in the creation of new experience-centered technology. We suggest that the guiding principle should be the design of interfaces that serve as a transparent medium for augmenting our natural skills of interaction with the world, instead of requiring conscious attention to the interface as an opaque object in the world. PMID- 26964134 TI - Training Toddlers Seated on Mobile Robots to Steer Using Force-Feedback Joystick. AB - The broader goal of our research is to train infants with special needs to safely and purposefully drive a mobile robot to explore the environment. The hypothesis is that these impaired infants will benefit from mobility in their early years and attain childhood milestones, similar to their healthy peers. In this paper, we present an algorithm and training method using a force-feedback joystick with an "assist-as-needed" paradigm for driving training. In this "assist-as-needed" approach, if the child steers the joystick outside a force tunnel centered on the desired direction, the driver experiences a bias force on the hand. We show results with a group study on typically developing toddlers that such a haptic guidance algorithm is superior to training with a conventional joystick. We also provide a case study on two special needs children, under three years old, who learn to make sharp turns during driving, when trained over a five-day period with the force-feedback joystick using the algorithm. PMID- 26964142 TI - Corrections to "Relevance Metric Learning for Person Re-Identification by Exploiting Listwise Similarities" [Dec 15 4741-4755]. AB - Corrections are presented for the above paper (ibid., vol. 24, no. 12, pp. 4741 4755, Dec. 2015). PMID- 26964143 TI - PPARbeta/delta directs the therapeutic potential of mesenchymal stem cells in arthritis. AB - OBJECTIVES: To define how peroxisome proliferator-activated receptor (PPAR) beta/delta expression level in mesenchymal stem cells (MSCs) could predict and direct both their immunosuppressive and therapeutic properties. PPARbeta/delta interacts with factors such as nuclear factor-kappa B (NF-kappaB) and regulates the expression of molecules including vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1. Since these molecules are critical for MSC function, we investigated the role of PPARbeta/delta on MSC immunosuppressive properties. METHODS: We either treated human MSCs (hMSCs) with the irreversible PPARbeta/delta antagonist (GSK3787) or derived MSCs from mice deficient for PPARbeta/delta (PPARbeta/delta-/- MSCs). We used the collagen induced arthritis (CIA) as model of immune-mediated disorder and the MSC-immune cell coculture assays. RESULTS: Modulation of PPARbeta/delta expression in hMSCs either using GSK3787 or hMSCs from different origin reveals that MSC immunosuppressive potential is inversely correlated with Ppard expression. This was consistent with the higher capacity of PPARbeta/delta-/- MSCs to inhibit both the proliferation of T lymphocytes, in vitro, and arthritic development and progression in CIA compared with PPARbeta/delta+/+ MSCs. When primed with proinflammatory cytokines to exhibit an immunoregulatory phenotype, PPARbeta/delta-/- MSCs expressed a higher level of mediators of MSC immunosuppression including VCAM-1, ICAM-1 and nitric oxide (NO) than PPARbeta/delta+/+ MSCs. The enhanced NO2 production by PPARbeta/delta-/- MSCs was due to the increased retention of NF-kappaB p65 subunit on the kappaB elements of the inducible nitric oxide synthase promoter resulting from PPARbeta/delta silencing. CONCLUSIONS: Our study is the first to show that the inhibition or knockdown of PPARbeta/delta in MSCs primes their immunoregulatory functions. Thus, the regulation of PPARbeta/delta expression provides a new strategy to generate therapeutic MSCs with a stable regulatory phenotype. PMID- 26964145 TI - Can genetics explain the higher risk of worsening knee pain in offspring of people with total knee replacement for severe primary knee osteoarthritis? PMID- 26964144 TI - The changing landscape of biosimilars in rheumatology. AB - Biosimilars remain a hot topic in rheumatology, and some physicians are cautious about their application in the real world. With many products coming to market and a wealth of guidelines and recommendations concerning their use, there is a need to understand the changing landscape and the real clinical and health economic potential offered by these agents. Notably, rheumatologists will be at the forefront of the use of biosimilar monoclonal antibodies/soluble receptors. Biosimilars offer cost savings and health gains for our patients and will play an important role in treating rheumatic diseases. We hope that these lower costs will compensate for inequities in access to therapy based on economic differences across countries. Since approved biosimilars have already demonstrated highly similar efficacy, it will be most important to establish pharmacovigilance databases across countries that are adequate to monitor long-term safety after marketing approval. PMID- 26964146 TI - Resistance training reduces systolic blood pressure in metabolic syndrome: a systematic review and meta-analysis of randomised controlled trials. AB - AIM: To evaluate the effects of resistance training on metabolic syndrome risk factors through comparison with a control group. DESIGN: Meta-analysis comparing resistance training interventions with control groups. Two independent reviewers selected the studies and assessed their quality and data. The pooled mean differences between resistance training and the control group were calculated using a fixed-effects model. DATA SOURCES: The MEDLINE, PEDro, EMBASE, SPORTDiscus and The Cochrane Library databases were searched from their earliest records to 10 January 2015. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials that compared the effect of resistance training on metabolic syndrome risk factors with a control group were included. All types of resistance training, irrespective of intensity, frequency or duration, were eligible. RESULTS: Only systolic blood pressure was significantly reduced, by 4.08 mm Hg (95% CI 1.33 to 6.82; p<0.01), following resistance training. The pooled effect showed a reduction of 0.04 mmol/L (95% CI -0.12, 0.21; p>0.05) for fasting plasma glucose, 0.00 (95% CI -0.05, 0.04; p>0.05) for high-density lipoprotein (HDL) cholesterol, 0.03 (95% CI -0.14, 0.20; p>0.05) for triglycerides, 1.39 mm Hg (95% CI -0.19, 2.98; p=0.08) for diastolic blood pressure and 1.09 cm (95% CI -0.12, 2.30; p=0.08) for waist circumference. Inconsistency (I2) for all meta-analysis was 0%. CONCLUSIONS: Resistance training may help reduce systolic blood pressure levels, stroke mortality and mortality from heart disease in people with metabolic syndrome. TRIAL REGISTRATION NUMBER: CRD42015016538. PMID- 26964147 TI - Population attributable fraction: names, types and issues with incorrect interpretation of relative risks. PMID- 26964148 TI - [Appropriate technology: a driver to eliminate schistosomiasis in China. In- sights gained from the First Forum on Schistosomiasis Control in China]. AB - This paper described the First Forum on Schistosomiasis Control in China. With "Appropriate technology is essential to schistosomiasis prevention and control" as the topic, the forum shared the main interventions and experiences for schistosomiasis control and elimination, exhibited the recent achievements gained from the development of appropriate technology for schistosomiasis control, showed the technical support of appropriate technology for schistosomiasis elimination, and proposed the priority for the future research and development of appropriate technology for schistosomiasis control and elimination in China. It is considered that the forum builds a bridge for communicating information between the administrative sectors and specialized prevention and control institutions, between research institutions and manufactures, and between experts/professors and grassroots professional staff, and provides a platform to communicate the national schistosomiasis control knowledge of China. PMID- 26964149 TI - [Warm needling combined with external application of mirabilite for 27 cases of early fat liquefaction after gynecological operation]. PMID- 26964150 TI - INTRODUCTION. PMID- 26964151 TI - Schedules of Controlled Substances: Extension of Temporary Placement of 10 Synthetic Cathinones in Schedule I of the Controlled Substances Act. Final order. AB - The Administrator of the Drug Enforcement Administration is issuing this final order to extend the temporary schedule I status of 10 synthetic cathinones pursuant to the temporary scheduling provisions of the Controlled Substances Act. The 10 substances are: 4-methyl-N-ethylcathinone (4-MEC); 4-methyl-alpha pyrrolidinopropiophenone (4-MePPP); alpha-pyrrolidinopentiophenone ([alpha]-PVP); 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butan-1-one (butylone); 2-(methylamino)-1 phenylpentan-1-one (pentedrone); 1-(1,3-benzodioxol-5-yl)-2-(methylamino)pentan-1 one (pentylone); 4-fluoro-N-methylcathinone (4-FMC); 3-fluoro-N-methylcathinone (3-FMC); 1-(naphthalen-2-yl)-2-(pyrrolidin-1-yl)pentan-1-one (naphyrone); and alpha-pyrrolidinobutiophenone ([alpha]-PBP) [hereinafter 4-MEC, 4-MePPP, [alpha] PVP, butylone, pentedrone, pentylone, 4-FMC, 3-FMC, naphyrone, and [alpha]-PBP, respectively], including their optical, positional, and geometric isomers, salts, and salts of isomers. The current final order temporarily placing 4-MEC, 4-MePPP, [alpha]-PVP, butylone, pentedrone, pentylone, 4-FMC, 3-FMC, naphyrone, and [alpha]-PBP into schedule I is in effect through March 6, 2016. This final order will extend the temporary scheduling of 4-MEC, 4-MePPP, [alpha]-PVP, butylone, pentedrone, pentylone, 4-FMC, 3-FMC, naphyrone, and [alpha]-PBP for one year, or until the permanent scheduling action for these 10 substances is completed, whichever occurs first. PMID- 26964152 TI - TRICARE; Revision of Nonparticipating Providers Reimbursement Rate; Removal of Cost Share for Dental Sealants; TRICARE Dental Program. Final rule. AB - This final rule revises the benefit payment provision for nonparticipating providers to more closely mirror industry practices by requiring TDP nonparticipating providers to be reimbursed (minus the appropriate cost-share) at the lesser of billed charges or the network maximum allowable charge for similar services in that same locality (region) or state. This rule also updates the regulatory provisions regarding dental sealants to clearly categorize them as a preventive service and, consequently, eliminate the current 20 percent cost-share applicable to sealants to conform with the language in the regulation to the statute. PMID- 26964153 TI - Patient Protection and Affordable Care Act; HHS Notice of Benefit and Payment Parameters for 2017. Final rule. AB - This final rule sets forth payment parameters and provisions related to the risk adjustment, reinsurance, and risk corridors programs; cost-sharing parameters and cost-sharing reductions; and user fees for Federally-facilitated Exchanges. It also provides additional amendments regarding the annual open enrollment period for the individual market for the 2017 and 2018 benefit years; essential health benefits; cost sharing; qualified health plans; Exchange consumer assistance programs; network adequacy; patient safety; the Small Business Health Options Program; stand-alone dental plans; third-party payments to qualified health plans; the definitions of large employer and small employer; fair health insurance premiums; student health insurance coverage; the rate review program; the medical loss ratio program; eligibility and enrollment; exemptions and appeals; and other related topics. PMID- 26964154 TI - Diagnostic Performance of Positron Emission Tomography for the Presurgical Evaluation of Patients with Non-lesional Intractable Partial Epilepsy: Comparison among 18F-FDG, 11C-Flumazenil, and 11C-Flumazenil Binding Potential Imaging Using Statistical Imaging Analysis. AB - To compare the diagnostic performance of 18F-FDG PET, 11C-FMZ PET, and 11C-FMZ BP imaging for the evaluation of patients with intractable partial epilepsy whose MRI findings are normal by using statistical imaging analysis. Ten patients underwent comprehensive presurgical evaluation, including PET studies, to assess the epileptic foci. The extent of cortical resection was based on the results of intracranial video-electroencephalography (IVEEG) monitoring and brain mapping under stimulation. The images of 10 patients and 30 controls were spatially normalized to templates generated in-house by non-rigid registration and the standardized images of the patients and controls were statistically compared. Epileptic focus candidates were visualized on a color map of axial images of each template and the focus site was identified in candidates for lobar location. In patients with Engel I postoperative seizure outcomes we assessed the sensitivity and specificity of the imaging methods for lobar focus localization. We also compared the concordance scores of patients with Engel I and Engel II-IV postoperative seizures. The sensitivity and specificity for lobar focus localization on 18F-FDG PET scans was 90.0% and 84.8%, respectively; it was 30.0% and 81.4% for 11C-FMZ PET, 40.0% and 66.7% for 11C-FMZ BP images, and 100.0% and 51.4% for 18F-FDG PET/11C-FMZ PET/11C-FMZ BP images. In one patient the epileptic focus not detected on 18F-FDG PET scans was shown on 11C-FMZ BP images. In patients with Engel I post-treatment seizures the concordance scores were significantly higher for 18F-FDG PET than 11C-FMZ PET and 11C-FMZ BP images (p < 0.05). With respect to sensitivity and specificity, 18F-FDG PET was superior to 11C-FMZ PET and 11C-FMZ BP imaging. However, in some patients with normal MRI results, 11C-FMZ BP studies may complement 18F-FDG PET findings in efforts to identify the epileptogenic lobar regions. PMID- 26964156 TI - Complete Response Obtained with S-1 Plus CDDP Therapy in a Patient with Multiple Liver Metastases from Gastric Cancer. AB - A 58-year-old woman with advanced gastric cancer underwent total gastrectomy in May 2012. The histological diagnosis was poorly differentiated adenocarcinoma, cT4a (SE), pN1, cM0; fStage IIIA. Chemotherapy by S-1 was started after surgery. Six months after the operation, two metastatic nodules were noticed on the liver. Therefore, the chemotherapy was switched to S-1 plus cisplatin (CDDP) in November 2012. TS-1 (80 mg/body) was administrated from day 1 to 21 followed by 14 days rest as one course. CDDP (70 mg/body) was infused on day 1. After 3 courses of this combination chemotherapy, remarkable diminution of the metastatic lesions on CT images was observed. Because of the adverse event of Grade 2 nausea, the patient was forced to discontinue chemotherapy. The patient underwent partial resection of the liver (Hr-0: S8, S7) at 1 year after the first operation. The resected specimens showed no sign of malignancy, although uneven fatty deposition was observed more frequently than in the surroundings, and designated as histologically complete response (CR). The patient has been alive 30 months after the second operation without any recurrent sites. Thus, combined use of peroral S 1 and CDDP should be recommended for multiple liver metastases after gastrectomy. PMID- 26964155 TI - Solitary Cranial Langerhans Cell Histiocytosis: Two case reports. AB - Langerhans cell histiocytosis (LCH) is a proliferation of Langerhans cells intermixed with inflammatory cells, in particular eosinophils, that may manifest as a unisystem (unifocal or multifocal) or multisystem disease. We describe the clinical and histologic spectrum of LCH of the orbit and skull in our two cases. Both cases had unifocal erosive skull lesions with a history of trauma. Typical histologic features included numerous histiocytes with varying degrees of giant cell formation and scattered eosinophilic granulocytes. The presence of Langerhans cells was confirmed by CD1a and S100 immunohistochemistry. LCH has an excellent prognosis when treated with surgical resection, steroids and radiotherapy or chemotherapy. One of our patients is disease free at 7 year follow-up and one patient had regression of lesion on follow-up. PMID- 26964157 TI - [Moderate and severe persistent allergic rhinitis treated with acupuncture: a randomized controlled trial]. AB - OBJECTIVE: To observe the clinical efficacy and safety on moderate and severe persistent allergic rhinitis treated with acupuncture. METHODS: Sixty-six patients of moderate and severe persistent allergic rhinitis were randomized into an acupuncture group (34 cases) and a western medication group (32 cases). In the acupuncture, group, acupuncture was applied to Dazhui (GV 14), Feishu (BL 13), Pishu (BL 20), Ganshu (BL 18) and Shenshu (BL 23) in the prone, retained for 20 min; then in the supine, at Baihui (GV 20), Yintang (GV 29), yingxiang (LI20) Taichong (LR 3) and Hegu (LI 4), retained for 20 min. Acupuncture was given once every two days, three times a week, continuously for 8 weeks. In the western medication group, cetirizine hydrochloride was taken orally, 10 mg each time, once every day, continuously for 8 weeks. Separately, before treatment, after the treatment of 1 and 2 months and in 1 month after treatment, the total nasal symptom score (TNSS), the scores in the emotion rating scale for Ganzangxiang of TCM (ERSG) and the rhinoconjunctivitis quality of life questionnaire (RQLQ) were observed in the patients of the two groups. The clinical efficacy was compared between the two groups. RESULTS: (1) For TNSS, the results after 1 and 2 months treatment and in 1 month after treatment were all, reduced as compare with that before treatment separately in the two groups (P < 0.05, P < 0.01) The result after 2 months treatment was lower than that after 1 month treatment in the acupuncture group (P < 0.05). In 1 month after treatment, the result in the acupuncture group was lower than that in the western medication group (P < 0.05). (2) For ERSG, the score after 2 months treatment was lower than that before treatment in the two groups (both P < 0.05). The score after 2 months treatment in the acupuncture group was lower than that in the western medication group (P < 0.05). (3) For RQLQ, the score after 1 month treatment was lower than that before treatment and the score after 2 months treatment was lower than that after 1 month treatment in the two groups (all P < 0.05). The score after 1 and 2 months treatment and in 1 month after treatment in the acupuncture group was lower than that in the western medication group separately (all P < 0.05). (4) The total effective rate was 91.2% (31/34) in the acupuncture group and was 90.6% (29/32) in the western medication group, without significant difference between the two groups (P > 0.05). CONCLUSION: Acupuncture is the safe and effective intervention on moderate and severe persistent allergic rhinitis. Compared with the western medicine group, the efficacy in the acupuncture group presents much more advantageous at its durability. PMID- 26964158 TI - [Discussion on point Shuzhe for treatment of Periarthritis of shoulder]. PMID- 26964159 TI - [Impacts on the life quality of the patients with allergic rhinitis treated with warming acupuncture in winter and summer]. AB - OBJECTIVE: To explore the impacts on the life quality and the effect mechanism in the patients of allergic rhinitis (AR) treated with warm acupuncture in winter and summer. METHODS: Two hundred and forty patients of AR were randomized into a summer and winter acupuncture group, a non-summer and winter acupuncture group and a western medication group, 80 cases in each one. In the two acupuncture groups, Dazhui (GV 14), Fengmen (BL 12), Feishu (BL 13), Pishu (BL 20) and Shenshu (BL 23) were selected. In the summer and winter acupuncture group, the warm acupuncture started at the first day of the three periods of hot season and the first day of the third nine-day period after the winter solstice. The treatment was given once every two days, continuously for 15 times. Totally, 30 treatments were required a year. In the non-summer and winter acupuncture group, the warm acupuncture was applied out of the three periods of the hot season and the third nine-day period after the winter solstice. The treatment was given once every two days and 30 treatments for a year. In the western medication group, cetirizine was taken orally, continuously for 30 days as one session. In the three groups, the treatment for 1 year was taken as one session. The second session started in the next year. Totally, 2 sessions were required. The score of rhinoconjunctivitis quality of life questionnaire (RQLQ) and the level of serum immunoglobulin E (IgE) were compared in the patients' of each group before treatment and in 1 and 2 sessions of treatment. RESULTS: After treatment, the scores of 7 domains, named activities, common complaints, practical problems, sleep, ocular symptoms, nasal symptoms and emotions were all improved as compared with those before treatment, in the patients of the three groups (all P < 0.05). After 2 sessions treatment, the results in the summer and winter acupuncture group were better than those in the other two groups (all P < 0.05), and the results in the non-summer and winter acupuncture group were better than those in the western medication group (all P < 0.05). After treatment, serum IgE level was lower averagely than that before treatment in the three groups (all P < 0.05). After 2 sessions treatment, the result in the summer and winter acupuncture group was lower than that in the other two groups (both P < 0.05), and the result in the non-summer and winter acupuncture group was lower than that in the western medication group (P < 0.05). After treatment, the total effective rate was 92.3% (72/78) in the summer and winter acupuncture group, better than 80.5% (62/77) in the non-summer and winter acupuncture group and 69.7% (53/76) in the western medication group (both P < 0.05). CONCLUSION: The warm acupuncture in both summer and winter achieves the definite efficacy on AR and the effect mechanism is relevant with reducing serum IgE level. PMID- 26964160 TI - [Case of intractable scalp pain]. PMID- 26964161 TI - [Clinical observation of fire needle for facial spasm]. AB - OBJECTIVE: To compare the effects between fire needle combined with acupuncture and simple acupuncture for facial spasm. METHODS: Sixty patients with facial spasm were randomly divided into a fire needle group and an acupuncture group, 30 cases in each one. In the two groups, acupuncture was used at Fengchi (GB 20), Baihui(GV 20), Shenting (GV 24), Zusanli(ST 36) and Yanglingquan(GB 34). The needles were retained for 30 min. In the fire needle group, ashi points in the spasm areas were pricked by fire needles without retaining. In the acupuncture group, acupuncture was retained at ashi points. In the first two weeks,the treatment was given once a day, totally 10 times, and there were two days to have a rest after 5-day treatment. But patients were treated once every other day, three times a week, and totally 20 times from the third week. Fire needle and acupuncture were applied at ashi points until spasm was relieved. The facial spasm degree and frequency were observed after the 15th treatment and the 30th treatment,and the clinical effects were assessed in the two groups. RESULTS: After treatment the facial spasm degree and frequency were relieved than those before treatment in the two groups (all P < 0.05). Ones in the fire needle group were declined more apparently than those in the acupuncture group (both P < 0.05). After the 15th treatment and the 30th treatment,the cured rates and the total effective rates in the fire needle group were better than those in the acupuncture group [after the 15th treatment: 20.0% (6/30) vs. 10.0% (3/30), 80.0% (24/30) vs. 63.3% (19/30), both P < 0.05; after the 30th treatment: 33.3% (10/30) vs. 20.0% (6/30), 93.3% (28/30) vs. 80.0% (24/30), both P < 0.05]. CONCLUSION: The efficacy of fire needle is superior to that of simple acupuncture for facial spasm. PMID- 26964162 TI - [Analysis of optimal plan of multiple acupuncture manipulations for shoulder pain after stroke at different stages]. AB - OBJECTIVE: To observe the effects between acupuncture combined with rehabilitation and simple rehabilitation for shoulder pain after stroke, and to select the best plan of acupuncture manipulations at different stages by orthogonal design. METHODS: Ninety patients were treated with comprehensive rehabilitation, and nine cases without acupuncture were arranged into a control group. Eighty-one patients of orthogonal design were applied by acupuncture with the same acupoints and course. The VAS score and its weighted value were regarded as the observation indices,and the effects between the acupuncture group and the control group were compared. The optimal plans of acupuncture manipulations of the early stage and the later stage were chosen after the first course treatment and the third course treatment separately. The acupuncture depth (factor A:A: shallow depth less than 25 mm, A(II): modest depth 25-40 mm, A(III): deep depth 40-50 mm), the acupuncture angle (factor B:B(I): perpendicular insertion, B(II): horizontal insertion, B(III): oblique insertion), needle manipulated frequency (factor C: C(I): zero time, C(II): one time, C(III): three times) and needle retained time(factor D:D(I):20 min, D(II): 30 min, D(III): 60 min) were studied. The differences among all factors and the diversity among major factors at different stages were analyzed. RESULTS: (1) Acupuncture combined with rehabilitation at the early and the later stage acquired better improvement than simple rehabilitation (all P < 0.01). (2) The optimal acupuncture manipulation plan at the early stage was A(III) B(III) C(I) D(I), which was deep acupuncture and oblique insertion for 20 min with zero-time manipulation; the optimal acupuncture manipulation plan at the later stage was A(III) B(III) C(III) D(I), which was deep acupuncture and oblique insertion for 20 min with three-time manipulation. (3) There was significance for acupuncture depth and angle at the early stage (both P < 0.01) and there was significance for insertion depth, acupuncture angle and manipulating frequency at the later stage (all P < 0.05). (4) At the early stage, the insertion depth was statistically significant between A(I) and A(II), A(I) and A(III), A(II) and A(III) (P < 0.05, P < 0.01), and the statistical significance was existed between B(I) and B(III) (P < 0.01). At the later stage, the insertion depth was statistically significant between A(I) and A(III), A(III) and A(II), A(I) and A(II) (P < 0.05, P < 0.01), and the statistical significance was existed between C(I) and C(III), C(II) and C(III) (P < 0.05). CONCLUSION: Acupuncture combined with rehabilitation acquire apparent effect for shoulder pain after stroke. At the early stage,the optimal plan is deep and oblique insertion for 20 min with zero-time manipulation. At the later stage, the best plan is deep and oblique insertion for 20 min with 3-time manipulation. PMID- 26964163 TI - [Efficacy of hooking therapy and safflower injection on lumbar disc herniation and the impact on IL-6 and NO in the patients]. AB - OBJECTIVE: To explore the clinical efficacy and the effect mechanism of hooking therapy and safflower injection in the treatment of lumbar disc herniation (LDH). METHODS: Sixty patients of LDH were randomized into an observation group and a control group at ratio of 1 to 1, 30 cases in each one. In the control group, safflower injection was applied to three points of lumbar region, once a day. Seven treatments made one session, and totally 2 sessions were required. In the observation group, under local anesthesia, the big hook needle was used to stimulate the three points of lumbar region first, followed by the safflower injection, once every 6 to 7 days. If the efficacy was not satisfactory enough, the second treatment was given. The visual analogue scale (VAS) and the modified Japanese Orthopaedic Association (M-JOA) scores were observed before and after treatment in the patients of the two groups and the clinical efficacy was evaluated. The levels of peripheral interleukin-6 (IL-6) and nitric oxide (NO) were determined. RESULTS: VAS and M-JOA scores were all improved apparently after treatment as compared with those before treatment in the patients of the two groups (both P < 0.01). The improvements in the observation group were much more obvious than those in the control group (both P < 0.01). In the observation group, the curative and remarkably effective rate was 76.7% (23/30) and the total effective rate was 96.7% (29/ 30), better than 43.3% (13/30) and 70.0% (21/30) in the control group separately (both P < 0.05). After treatment, the levels of IL-6 and NO were all reduced as compared with those before treatment in the two groups; (both P < 0.01). The above indices were changed more obviously in the observation group as compared with those in the control group (both P < 0.01). CONCLUSION: The combined therapy of hooking therapy and safflower injection apparently relieves pain and clinical symptoms of LDH. The effect mechanism is relevant with reducing the levels of IL-6 and NO in the peripheral blood. PMID- 26964165 TI - [Clinical observation of type III prostatitis treated with acupuncture and isolated-ginger moxibustion]. AB - OBJECTIVE: To compare the difference in the clinical efficacy on type M prostatitis between the combined therapy of acupuncture and isolated-ginger moxibustion and tamsulosin. METHODS: One hundred and ten patients of type III prostatitis were randomized into an acupuncture and moxibustion group and a tamsulosin group, 55 cases in each one. In the acupuncture and moxibustion group, acupuncture and isolated-ginger moxibustion were adopted. Two groups of acupoints were selected, named (1) Guanyuan (CV 4), Qugu (CV 2) and Sanyinjiao (SP 6); (2) Yaoyangguan (GV 3), Pangguangshu (BL 28) and Zhibian (BL 54). The two groups of points were used by acupuncture alternatively and only one group was selected a day. Isolated-ginger moxibustion was applied to Guanyuan (CV 4) and Zhibian (BL 54), once a day, 10 treatments made one session, and totally 3 sessions were required. In the tamsulosin group, tamsulosin was prescribed for oral administration, 0.2 mg, twice a day for 1 month. The National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score and expressed prostatic secretion (EPS) score were observed in the patients of the two groups. RESULTS: NIH-CPSI and EPS scores after treatment were all reduced apparently as compared with those before treatment in the two groups (all P < 0.05). The improvements in the acupuncture and moxibustion group were more obvious than those in the tamsulosin group (all P < 0.05). In 3 months follow-up, NIH-CPSI score in the acupuncture and moxibustion group was reduced apparently as compared with the tamsulosin group (P < 0.05). The curative rate and total effective, rate were 20.0% (11/55) and 85.5% (47/55) in the acupuncture and moxibustion group, and were 3.6% (2/55) and 61.8% (34/55) in the tamsulosin group respectively (both P < 0.05). CONCLUSION: The combined therapy of acupuncture and isolated-ginger moxibustion achieves the good effect of relieving the symptoms of type III prostatitis and recovery of EPS, better than those treated with tamsulosin. This combined therapy spresents the better long-term efficacy. PMID- 26964164 TI - [Clinical observation of acupoint application therapy on senile female bladder neck obstruction]. AB - OBJECTIVE: To observe the clinical efficacy on senile female bladder neck obstruction treated with acupoint application, therapy and western medication. METHODS: Fifty cases of senile female bladder neck observation were randomized into an obstrvation group and a control group, 25 cases in each one. Tamsulosin hydrochloride capsules were taken orally in the two groups, 0.2 mg every night, continuously for 100 days. In the observation group, with radix aconiti lateralis preparata, semen brassicae and fructus ligustri lucidi contained, bushentongyu plaster was used at Shenque (CV 8), Sanyinjiao (SP 6), Pangguangshu (BL 28), Zhongji (CV 3) and Sanjiaoshu (BL 22), once every two days. Eight treatments made one session and 6 sessions were required totally. The international prostate symptom score (IPSS), the bother score (BS), the residual volume (RV) and the maximal urinary flow rate (MFR) were observed before and after treatment in the two groups. The clinical efficacy was compared between the two groups. RESULTS: Every score in IPSS after treatment was reduced apparently as compared with that before treatment in the two groups (all P < 0.01). The improvements in feeling of incomplete, bladder emptying, intermittency < 2 h, urgency, interupted urination and nocturia in the observation group were more advantageous than those in the control group (all P < 0.05). The total effective rate was 95.65% (22/23) in the observation group, higher than 85.71% (18/21) in the control group (P < 0.05). After treatment, RV, MFR and BS were significantly different as compared with those before treatment (all P < 0.05). CONCLUSION: The combined therapy of acupoint application of bushentongyu plaster and oral administration of tamsulosin hydrochloride capsules achieves the significant efficacy on senile female bladder neck obstruction as compared with the simple administration of tamsulosin hydrochloride capsules. PMID- 26964167 TI - [Multiple dredging method combined with regulating internal organs and spinal cord for 18 cases of neurodermatitis]. PMID- 26964166 TI - [Clinical observation of recurrent oral ulcer of heat accumulation in the heart and spleen treated with acupoint injection and fire needling therapy]. AB - OBJECTIVE: To compare the clinical efficacy between the combined acupuncture therapy of acupoint injection and fire needling and the oral administration of vitamin C and B2 as well as subcutaneous injection of transfer factor. METHODS: One hundred and fifty-eight patients of recurrent oral ulcer (ROU) differentiated as heat accumulation in the heart and spleen were randomized into an observation group and a control group, 79 cases in each, one. In the observation group, Xinshu (BL 15), Pishu (BL 20) and Zusanli (ST 36) were selected for acupoint injection of shuang huanglian injection, 1 mL at each point, three times a week, for 2 weeks totally. Additionally, fire needling was applied to the ulcer lesion and peripheral mucosa, once a day, totally for 3 times. In the control group, vitamin C 100 mg and vitamin B2 20 mg were prescribed for oral administration, three times a day; and subcutaneous injection of transfer factor was applied, 2 mL (3 mg), twice a week, for 2 weeks totally. The score of symptoms and physical signs and the visual analogue scale (VAS) were observed before and after treatment, as well as the time of ulcer healing and ulcer recurrence in the patients of the two groups. The clinical efficacy was compared between the two groups. RESULTS: The total effective rate was 92.4% (73/79) in the observation group, better than 77.2% (61/79) in the control group (P < 0.01). The differences in the score of symptoms and physical signs and VAS score before and after treatment were significant statistically in the observation group and the control group (all P < 0.01). The score of symptoms and physical signs and VAS score after treatment in the observation group were reduced significantly as compared with those in the control group (both P < 0.01). The time of ulcer healing in the observation group was earlier than that in the control group [(3.87 +/- 1.01) d vs. (6.22 +/- 0.53) d, P < 0.01]. The recurrence rate in the observation was lower than that in the control group [22.7% (17/75) vs. 50.0% (36/72), P < 0.01]. CONCLUSION: The combined therapy of acupoint injection and fire needling achieves the better efficacy on ROU compared with oral administration of vitamin and subcutaneous injection of transfer factor. This therapy has the good and quick effect of analgesia, relieves the relevant symptoms, shortens the time of ulcer healing and reduces the recurrence rate. PMID- 26964169 TI - [Hyperplasia of mammary glands treated with acupuncture combined with bleeding stasis collaterals therapy: a clinical study of 30 cases]. PMID- 26964168 TI - [Eighty cases of peripheral facial paralysis sequela treated with mian kou three needle touci]. PMID- 26964170 TI - [Clinical observation of therapeutic methods of different sensitive types for lumbar disc herniation]. AB - OBJECTIVE: To observe the acupoint distribution and clinical efficacy of lumbar disc herniationi (LDH) with different sensitive types. METHODS: Eighty patients with LDH were randomly divided into a heat-sensitive moxibustion group (group A), a heat-sensitive acupuncture group (group B), a force-sensitive acupuncture group (group C) and a force-sensitive moxibustion group (group D), 20 cases in each one. In the group A and the group B, moxibustion and acupuncture were applied at two or three heat-sensitive acupoints separately. In the group C and the group D,acupuncture and moxibustion were used at two or three force-sensitive acupoints respectively. The treatment was given once a day, totally 10 times. The distribution law of the heat-sensitive acupoints and the force-sensitive acupoints and the change of M-JOA before and after treatment were recorded in the four groups. RESULTS: The frequent heat-sensitive acupoints areas of LDH were at Yaoyangguan (GV 3), Dachangshu (BL 25), Zhiyang(GV 9), Guanyuanshu(BL 26) and Weizhong(BL 40). The major force-sensitive acupoints areas were at Shenshu (BL 23), Dachangshu (BL 25), Tianshu (ST 25), Guilai (ST 29) and Weizhong (BL 40). After treatment, the heat-sensitive acupoints in the group A and the group B were all reduced than those before treatment and the force-sensitive acupoints in the group C and the group D were declined as well (P < 0.01, P < 0.05). The M-JOA scores were obviously lower than those before treatment in the four groups (all P < 0.01). The score in the group A was reduced more apparently than that in the group B (P < 0.05). The score in the group C was declined more markedly than that in the group D (P < 0.05). CONCLUSION: There are diverse acupoints for LDH patients due to different sensitive types. All forms of stimulation can change the functional state of acupoints. Moxibustion is more suitable for heat sensitive acupoints and acupuncture is optimal for force-sensitive acupoints. PMID- 26964171 TI - [Case of stiff-person syndrome]. PMID- 26964172 TI - [Midnight-noon ebb-flow acupuncture at stomach meridian of foot-yangming: a fMRI study]. AB - The status change of brain functional region of functional magnetic resonance imaging (fMRI) of midnight-noon ebb-flow acupuncture method at stomach meridian was explored. Ten healthy volunteers were recruited. With identical sequence of magnetic resonance scans, fMRI data was collected respectively in the timely acupoint group, untimely acupoint group and timely non-acupoint group. Volunteers in the timely acupoint group were treated at Zusanli (ST 36) and Chongyang (ST 42) between 7:02:53 A.M. to 9:02:52 A.M.; volunteers in the untimely acupoint group were treated with Zusanli (ST 36) and Chongyang (ST 42) between 3:02 P.M. to 5:02 P.M.; volunteers in the timely non-acupoint group were treated at non acupoints 1 to 2 cm outside Zusanli (ST 36) and Chongyang (ST 42) between 7:02:53 A. M. to 9:02:52 A.M.. All fMRI data was analyzed with SPM5 software, and intra group comparison and among-group comparison of timely acupoint group, untimely acupoint group and timely non-acupoint group were performed. The tonsil of cerebellum, the right-side insular cortex showed strengthened function in the timely acupoint group; the right-side medial frontal gyrus showed weakened function in the untimely acupoint group; the right-sided insular cortex showed strengthened function in the timely non-acupoint group. The comparison among groups indicated that there was different brain change in three groups. The midnight-noon ebb-flow acupuncture method at stomach meridian is likely to activate the function of cerebellum and insular lobe, which can have a positive effect on patients with flaccidity syndrome and stomach diseases. PMID- 26964173 TI - [Exploration and analysis on the "similar-indication acupoints"]. AB - The concept, connotation and extension of "similar-indication acupoints" which is proposed by Professor WANG Fuchun are introduced in this paper. It is noted that "similar-indication acupoints" is one category of acupoints that hass similar effects for one symptom or disease, which is the basic element for acupoints compatibility, while acupoint compatibility is the foundation of acupuncture acupoints prescription. The proposal and application of "similar-indication acupoints" has provided a new method for the transition from specificity study to generality study, also lay a solid theoretical foundation for acupoints compatibility search. PMID- 26964174 TI - [Case of primary thrombocythemia]. PMID- 26964175 TI - [Case of moyamoya disease complicated with bilateral posterior cerebral artery occlusion]. PMID- 26964176 TI - [Effects of moxibustion on cell proliferative factors in gastric mucosa in rats with precancerous lesions of chronic atrophic gastritis]. AB - OBJECTIVE: To explore the molecular mechanism of moxibustion at stomach meridian acupoints for precancerous lesions of chronic atrophic gastritis (CAG). METHODS: Fifty male SD rats were randomly divided into a normal group, a model group, a stomach meridian group, a control point group and a vitacoenzyme group, 10 rats in each group. The CAG precancerous lesion model was made in all the groups except the normal group. The rats in the normal group and model group were bundled for 30 min per day; the rats in the stomach meridian group and control point group were bundled and treated with moxibustion at stomach meridian acupoints or control points for 30 min per day; the rats in the vitacoenzyme group were treated with intragastric administration of vitacoenzyme, once per day. All the treatment was given for 20 weeks. The pathological morphological change of gastric mucosa was observed under optical microscope; the expression of epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), vascular endothelial growth factor (VEGF), gastric mucosal proliferatig cell nuclear antigen (PCNA), argyrophilic protein of nucleolar organizer regions (Ag NORs) in gastric mucosal cells were detected by enzyme linked immuno sorbent assay (ELISA). RESULTS: Compared with the normal group, in the model group the gastric mucosal cells showed dysplasia and the expression of EGF, TGF-alpha, PCNA, VEGF, Ag-NORs in gastric mucosa cells in the model group was increased significantly (all P < 0.05). Compared with the model group, the gastric mucosa lesion gradually recovered and the expression of EGF, TGF-alpha, PCNA, VEGF, Ag NORs in gastric mucosal cells was gradually decreased in the stomach meridian group, control point group and vitacoenzyme group, in which the stomach meridian group had the most significant effects (all P < 0.05). CONCLUSION: Moxibustion at stomach meridian acupoints can obviously decrease the expression of cell proliferative factors in gastric mucosa in rats with CAG precancerous lesions, inhibit the gastric mucosal cell dysplasia, and promote the recovery of gastric mucosa. PMID- 26964177 TI - [Case of venous ulcer of right lower extremity]. PMID- 26964179 TI - [Case of acute Guillain-Barre syndrome]. PMID- 26964178 TI - [Effect of electroacupuncture at different acupoints on hormones and neurotransmitters of hypotha- lamic-pituitary-adrenal axis in rats under simulated weightlessness]. AB - OBJECTIVE: To explore the change pattern of hypothalamic-pituitary-adrenal (HPA) axis and related neurotransmitters under simulated weightlessness. METHODS: A total of 40 clean-grade male Wistar rats were randomly divided into a normal group, a tail-suspension group, an electroacupuncture (EA) at Neiguan (PC 6) group, an EA at Sanyinjiao (SP 6) group, 10 rats in each group. Rats in the tail suspension group, EA at "Neiguan" (PC 6) group and EA at "Sanyinjiao" (SP 6) group were treated with tail suspension to simulate weightlessness effect. Rats in the normal group were treated with normal diet. Rats in the tail-suspension group were treated with tail suspension for 28 d. During the time of tail suspension, rats in the EA at "Neiguan" (PC 6) group were treated with EA at "Neiguan" (PC 6), 30 min per treatment, once every two days for 14 treatments, while rats in the EA at "Sanyinjiao" (SP 6) group were treated with EA at "Sanyinjiao" (SP 6), 30 min per treatment, once every two days for 14 treatments. Samples were all collected after 4 weeks. The contents of corticotropin releasing hormone (CRH) , adrenocorticotropic hormone (ACTH), corticosterone (CORT) in as well as 5-hydroxy tryptamine (5-HT), dopamine (DA), norepinephrine (NE) were measured by using radioimmunoassay. RESULTS: Compared with the normal group, in the tail-suspension group the content of ACTH in pituitary was significantly decreased (P< 0.05), and the content of 5-HT in hypothalamus was significantly decreased (P < 0.01); the content of CRH and 5-HT in hypothalamus was significantly decreased (P < 0.01, P < 0.05) in the EA at "Neiguan" (PC 6) group; the content of CRH and 5-HT in hypothalamus was significantly decreased (P < 0.01), and the content of CORT in serum was significantly decreased (P < 0.05) in the EA at "Sanyinjiao" (SP 6) group. Compared with the tail-suspension group, the content of ACTH in hypothalamus was significantly decreased (P< 0.05) in the EA at "Neiguan" (PC 6) group; the content of CRH, ACTH and CORT was significantly decreased (P < 0.01, P < 0.05) in the EA at "Sanyinjiao" (SP 6) group. Compared with the EA at "Neiguan" (PC 6) group, the content of CORT was decreased (P < 0.05) in the EA at "Sanyinjiao" (SP 6) group. CONCLUSION: EA can regulate the content of 5-HT in hypothalamus in tail-suspension rats, inhibit the hyperactivity of the HPA axis, in which EA at "Sanyinjiao" (SP 6) had more significant effects than "Neiguan" (PC 6), but no obvious effects on NE and DA were observed. PMID- 26964180 TI - [Clinical observation on controlling antihypertension with the general anesthesia of TEAS and anesthetics in endoscopic endonasal surgery]. AB - OBJECTIVE: To study whether the dose of controlling antihypertensive drug is reduced by transcutaneous electrical acupoint stimulation (TEAS) and the anesthetics, as well as the control of blood pressure (BP) and heart rate (HR) in endoscopic endonasal surgery with general anesthesia. METHODS: Sixty patients for selective endoscopic endonasal surgery with general anesthetics and controlling antihypertension involved were selected and randomized into a TEAS group, a sham TEAS group, 30 cases in each one. The electric pads were attached to bilateral Hegu (LI 4), Zusanli (ST 36), Sanyinjiao (SP 6) and Quchi (LI 11), stimulated with Hans-200 apparatus, 3 to 5 mA, 2 Hz/100 Hz in the TEAS group based on the patients' response to comfort. No electric stimulation was applied to the sham TEAS group. The general anesthesia started after 30 min intervention and lasted till the end of surgery. The BP and HR were observed and recorded at the end of monitoring in operation room, 10 min after tranquilization (T0), 30 min after intervention (Tj, after induction~of general anestiesa (T2), 30 min after surgery start (T3), 60 min after surgery start (T4) and 30 min after extubation (T5). The doses of vecuronium bromide, propofol and nitroglycerin were recorded statistically in surgery, as well as the operative bleeding volume, the operative time, the resuscitation time and the visual analogue scale (VAS) score after resuscitation. RESULTS: Compared with that at T0, the mean arterial pressure (MAP) at T2, T3, T4 and T5 in the TEAS group and at T3 and T4 in the sham-TEAS group was all reduced, indicating the significant difference (all P < 0.01). MAP at T2 and T5 in the TEAS group was lower than that in the sham-TEAS group (both P < 0.01). Compared, with that at T5, except at T2 in the TEAS group (P<0. 05), HR was not different significantly at the rest time points (all P > 0.05). HR was different at T2 to Ts in the sham-TEAS group statistically (all P < 0.01). The doses of vecuronium bromide, propofol and nitroglycerin, the operative bleeding volume, the operative time, the resuscitation time and VAS after resuscitation were not different significantly between the two groups (all P > 0.05). CONCLUSION: The general anesthesia with TEAS and anesthetics involved for controlling antihypertension contributes to the control of BP and HR in the patients in endoscopic endonasal surgery. The impacts are not obvious on the doses of antihypertensive drug, the general anesthetics, the operative bleeding volume, the time of resuscitation and the postoperative analgesia. PMID- 26964181 TI - [Professor GAO Yuchun's experience of acupuncture for headache]. AB - As one of the important founders of GAO's acupuncture academic school in YanZhao area, Professor GAO Yuchun 's experience of acupuncture for headache is summarized in this paper. In the opinion of Professor GAO, the treatment of headache should focus on eliminating evil and relieving pain, and the syndrome differentiation should be based on meridian differentiation, especially on three yang meridians of foot as well as liver meridian and kidney meridian. In the acupoint prescription, attention should be placed on strengthening the spleen and stomach. The midnight-midday ebb flow acupuncture is advocated. The combination between acupuncture order and movement of qi is emphasized. In the manipulation, the role of pressing hand, the stimulation during reinforcing and reducing methods, and needle-retention time are important. The breathing reinforcing and reducing method of acupuncture are also advocated. PMID- 26964182 TI - [Case of varicocele]. PMID- 26964183 TI - [Professor LIN Guohua's experience of gold implantation at acupoint for rheumatoid arthritis]. AB - Based on the pathogenesis and symptom of rheumatoid arthritis (RA), professor LIN Guohua's unique opinion and method for RA in clinical treatment are summarized and analyzed. In the opinion of Professor Lin, RA is considered as "Jinbi" and "Gubi" in TCM, which is caused by deficient root with superficial excess. Based on the symptoms of RA, attention should be focused on lung-kidney diagnosis and treatment, and gold and catgut implantation at acupoint can be mutually combined, which is aimed to provide a special and effective method for clinical treatment of RA. PMID- 26964185 TI - [Analysis on the accuracy of simple selection method of Fengshi (GB 31)]. AB - To explore the accuracy of simple selection method of Fengshi (GB 31). Through the study of the ancient and modern data,the analysis and integration of the acupuncture books,the comparison of the locations of Fengshi (GB 31) by doctors from all dynasties and the integration of modern anatomia, the modern simple selection method of Fengshi (GB 31) is definite, which is the same as the traditional way. It is believed that the simple selec tion method is in accord with the human-oriented thought of TCM. Treatment by acupoints should be based on the emerging nature and the individual difference of patients. Also, it is proposed that Fengshi (GB 31) should be located through the integration between the simple method and body surface anatomical mark. PMID- 26964184 TI - [Exploration and analysis on the mechanism of sinew acupuncture]. AB - In order to explore the mechanism of sinew acupuncture (SA), related literature is reviewed and analyzed in combination with clinical practice. It is believed that the clinical indications of SA mainly include sinew injury and sinew injury related diseases. Sinew and channel tissue is similar to the superficial and deep fascia, which has a close relationship with defensive qi. The pathogenesis of sinew injury results from the deficiency of defense qi, leading to stagnation of evil qi in sinew tissue. The manipulation of SA is featured with the floating and superficial needling, transverse needling at points without arrival of qi. SA treatment can activate the defense qi, regulate sinew and channels and disperse the evil qi in sinew and channels, by which it exerts therapeutic effects. The SA will have a promotion effects on acupuncture popularization. PMID- 26964186 TI - [Acupoints selection rules analysis of ancient acupuncture for urinary incontinence based on data mining technology]. AB - Based on ancient literature of acupuncture in Canon of Chinese Medicine (4th edition), the articles regarding acupuncture for urinary incontinence were retrieved and collected to establish a database. By Weka data mining software, the multi-level association rules analysis method was applied to analyze the acupoints selection characteristics and rules of ancient acupuncture for treatment of urinary incontinence. Totally 356 articles of acupuncture for urinary incontinence were collected, involving 41 acupoints with a total frequency of 364. As a result, (1) the acupoints in the yin-meridian of hand and foot were highly valued, as the frequency of acupoints in yin-meridians was 2.6 times than that in yang-meridians, and the frequency of acupoints selected was the most in the liver meridian of foot-jueyin; (2) the acupoints in bladder meridian of foot-taiyang were also highly valued, and among three yang-meridians of foot, the frequency of acupoints in the bladder meridian of foot-taiyang was 54, accounting for 65.85% (54/82); (3) more acupoints selected were located in the lower limbs and abdomen; (4) specific acupoints in above meridians were mostly selected, presenting 73.2% (30/41) to the ratio of number and 79.4% (289/364) to the frequency, respectively; (5) Zhongji (CV 3), the front-mu point of bladder meridian, was seldom selected in the ancient acupuncture literature, which was different from modern literature reports. The results show that urinary incontinence belongs to external genitalia diseases, which should be treated from yin, indicating more yin-meridians be used and special acupoints be focused on. It is essential to focus inheritance and innovation in TCM clinical treatment, and applying data mining technology to ancient literature of acupuncture could provide classic theory basis for TCM clinical treatment. PMID- 26964187 TI - [Case of myofibril myopathy]. PMID- 26964188 TI - [Analysis on the contribution of HUA Tuo to acupuncture]. AB - The academic contribution of HUA Tuo to acupuncture, such as HUA Tuo Jiaji points, the drawing of viscera and channels, "diagnosis by observing the eyes", focusing on the clinical application of moxibustion, being the first to treat headache with Geshu (BL 17), selecting essential acupoints and paying attention to spirit management, etc. were summarized in this paper. It was believed that HUA Tuo made an outstanding contribution to acupuncture, which still had important guiding significance and academic value for clinical acupuncture and research work. PMID- 26964189 TI - [Query of simple position method at Yaoyangguan (GV 3)]. PMID- 26964191 TI - [Application and case analysis on the problem-based teaching of Jingluo Shuxue Xue (Science of Meridian and Acupoint) in reference to the team oriented learning method]. AB - The problem based teaching (PBT) has been the main approach to the training in the universities o the world. Combined with the team oriented learning method, PBT will become the method available to the education in medical universities. In the paper, based on the common questions in teaching Jingluo Shuxue Xue (Science of Meridian and Acupoint), the concepts and characters of PBT and the team oriented learning method were analyzed. The implementation steps of PBT were set up in reference to the team oriented learning method. By quoting the original text in Beiji Qianjin Yaofang (Essential recipes for emergent use worth a thousand gold), the case analysis on "the thirteen devil points" was established with PBT. PMID- 26964190 TI - [Statistical analysis of acupuncture-moxibustion literature based on SCIE and GoPubMed]. AB - By bibliometric method, acupuncture-moxibustion literature from 2003 to 2013 included by SCIE and GoPubMed was analyzed. The number of annually published literature, distribution of country, agency and area, author, journal, subject category, high-frequency words and H index were analyzed to explore the current situation and development trend of acupuncture and moxibustion. PMID- 26964192 TI - [Case of greater occipital neuralgia after high fever]. PMID- 26964194 TI - [Study on the Supercontinuum Generation with Femtosecond Pulse in Photonic Crystal Fiber]. AB - Physical mechanism of supercontinuum generation in photonic crystal fiber by femtosecond laser pulse has been investigated experimentally. In this study, we used the tunable output wavelength Ti: sapphire optical parametric amplifier as the pump source and the fiber spectrometer acquired the spectrogram of supercontinuum generation in photonic crystal fiber under different power and wavelength conditions, then we normalized the spectrograms and make a comparison of them. PCF supercontinuum differences affected by physical mechanisms were analyzed. We found that when increasing the incident pump pulse power, the spectral width will be gradually widened, there are more peaks, part of the energy will transfer in to the short-wave- length region; as long as it reaches a certain intensity, width of supercontinuum finally saturated, the shape of supercontinuum was also stabilized. As the incident power was settled at 300 milliwatt and the length of PCF was settled at 105 millimeter, experimental results show that width and shape of supercontinuum are affected by the wavelength of pump pulse, in the range of 760 to 840 nm, there appears more and more peaks with the increase of incident wavelength; at anomalous dispersion the spectrogram of supercontinuum generation will be more flat and more wider as the wavelength of pump pulse closer to zero point. PMID- 26964193 TI - [Research progress of secondary infection cases by acupuncture]. AB - The common pathogens and cases of secondary infection by acupuncture were classified and described, including staphylococcus aureus, mycobacteria, hepatitis virus and some sporadic infections. The above; cases were summed up according to the common pathogens of the secondary infection by acupuncture. Thus it illustrates the features of the secondary infection cases by acupuncture comprehensively and aims to enhance the infection knowledge of the medical staff in the hospital, so that the infection is effectively prevented in medical work. PMID- 26964195 TI - [Photoelectron Spectra of CCl2-: Ab Initio Calculation and Franck-Condon Analysis]. AB - Geometry optimization and harmonic vibrational frequency calculations were performed on the X1A1 state of CCl2 and X2B1 state of CCl2- at the B3LYP, MP2, CCSD levels. Franck-Condon analysis and spectral simulations were carried out on the photoelectron band of CCl2- including Duschinsky effects. The simulated spectra obtained are in excellent agreement with the experiment. Note that Duschinsky effect between bending vibration and the symmetric stretch modes should be considered in the CCl2 (X1A1)-CCl2- (X2B1) photodetachment process. By combining ab initio calculations with Franck-Condon analyses, the assignment of spectrum observed is firmly established to the X1A1-X2B1 photodetachment process of the CCl2- radical, and the recommended geometric parameters of which in the literature are confirmed again base on ab initio theory and IFCA process. PMID- 26964196 TI - [Ce3+/Tb3+ Doped Alkaline-Earth Borate Glasses Employed in Enhanced Solar Cells]. AB - Ce3+ and Tb3+ doped alkaline earth borate (LKZBSB) glasses and the photoluminescence properties of glass system have been fabricated and investigated, and the observed violet and green fluorescences are originated from Ce3+ and Tb3+ emit- ting centers, respectively. Four emission bands peaked at 487, 543, 586 and 621 nm are attributed to the emission transitions 5D4-->7F6, 5D4-->7F5, 5D4-->7F4 and 5D4-->7F3 of Tb3+, respectively, and consists of a broad emission band peaking at 389 nm attributed to 5d--4f electric dipole allowed transition of Ce3+. With the introduction of Ce3+, the effective excitation wavelength range of Tb3+ in LKZBSB glasses are remarkably expanded, and the enhanced factor of green fluorescence of Tb3+ in Ce3+/Tb3+ co-doped LKZBSB glasses is up to 73 times in medium-wavelength ultraviolet (UVB) excitation region, compared with that in Tb3+ single-doped case. The results show that the conversion from ultraviolet (UV) radiation to visible light is efficient in Ce3+/ Tb3+ doped LKZBSB glasses, demonstrating that the glasses have potential values in developing enhanced solar cell as a conver- sion layer. PMID- 26964197 TI - [Highly Efficient Bilayer-Structure Yellow-Green OLED with MADN Hole-Transport Layer and the Impedance Spectroscopy Analysis]. AB - Abstract Highly efficient bilayer-structure yellow-green organic light-emitting device (OLED) has been demonstrated based on MADN as hole-transport layer (HTL) and host-guest coped system of [Alq3: 0.7 Wt% rubrene] as emitting and electron trans- port layer. The device gives yellow-green emission through incomplete energy transfer from the host of Alq3 to the guest of ru- brene. An electroluminescent peak of 560 nm, 1931 CIE color coordinates of (0.46, 0.52) and a maximum current efficiency of 7.63 cd . A-1 (which has been enhanced by 30% in comparison with the counterpart having conventional NPB HTL) are ob- served. The hole-transporting characteristics of MADN and NPB have been systematically investigated by constructing hole-only devices and employing impedance spectroscopy analysis. Our results indicate that MADN can be served as an effective hole-trans- port material and its hole-transporting ability is slightly inferior to NPB. This overcomes the shortcoming of hole transporting more quickly than electron in OLED and improves carrier balance in the emitting layer. Consequently, the device current efficien- cy is promoted. In addition, the current efficiency of bilayer-structure OLED with MADN as HTL is comparable to that of conv- entinol trilayer-structure device with MADN as HTL and Alq3 as electron-transport layer. This indicates that the simplified bi- layer-structure device can be achieved without sacrificing current efficiency. The emitting layer of [Alq: 0.7 Wt% rubrene possesses superior elecron-transporting ability. PMID- 26964198 TI - [The Different Phase, Morphology Controllable Synthesis and Luminescent Properties Investigation of NaYF4: Yb, Er]. AB - Using sodium fluoride and rare earth nitrate as raw materials and sodium citrate as surfactant, micron grade NaYF4 upconversion luminescent materials were prepared by hydrothermal method. By X-ray diffraction(XRD), scanning electron microscope(SEM) and fluorescence spectrometer, the crystal phase, morphology and luminescent characteristics of the prepared samples were investigated. The results showed that the phase of the samples could generate a transition from cubic phase to hexagonal phase by adjusting the proportion (5, 6, 7, 8, 9, 11) of NaF/RE , and the X ray diffraction peaks for the cubic and hexagonal phase of samples exactly matched with those of the standard card of PDF# 77-2042 and PDF# 16-0334, respectively. The SEM photographs showed that the crystallinity of samples was high and the dispersibility was favourable, the morphology were translated from microrods to hexagonal microplates. The samples upconversion luminescent spectra showed the intensity enhancement of red and green light emission peaks with increasement of the ratio of NaF/RE3+. The green emission peaks of samples at 520 and 539 nm corresponded to the 2H11/2-4-->I15/2 and 4S3/2 ->4I15/2 level transition of Er3+ ion, and the red light emission peaks of samples at 653 nm corresponded to the 4F9/2-->4I15/2 levelt ransition of Er+ ion. The chromaticity coordinate diagram exhibited that the change of the luminescent color of samples could be achieved by adjusting the ratio of NaF/RE3+. With the increasing of NaF/RE3+ ratio, for the whole light-emitting colors of samples, the shift from yellow region to near red region could be realized. It can be concluded that through the relatively simple experimental procedure and lower cost materials, the change of phase and morphology, the moving of light-emitting color for sample NaYF4:Yb3+, Er3+ could be well controlled only by changing the single component (NaF) molar ratio in the raw materials. The effect of phase and morphology of fluorescent materials on their upconversion luminescence has great potential applications in photonic devices and bioanalysis research. PMID- 26964199 TI - [Investigation on the Spectral Characteristics of a Plasma Jet in Atmospheric Argon Glow Discharge]. AB - Plasma jet is a kind of important plasma source at atmospheric pressure. In recent years, it becomes an important hot topic in the field of low temperature plasma. In this paper, using a tungsten needle and a tungsten wire mesh, a direct current excited jet is developed to operate in argon at atmospheric pressure. In the atmospheric pressure argon, the plasma jet can produce a stable plasma plume. By using the method of emission spectroscopy, the parameters of the plasma plume are investigated. The discharge emits dazzling white light from the area between the tungsten needle electrode and the wire mesh electrode. A plasma plume with a flame shape appears outside the tungsten wire mesh electrode. For a constant value of voltage (U = 13.5 kV), the length of the plasma plume increases with the gas flow rate. For a constant value of the gas flow rate(10 L . min-1), the length of the plasma plume increases with the voltage. The voltage is inversely proportional to the current under the constant gas flow rate. In other words, the voltage decreases with the discharge current, which indicates that a glow discharge is formed in the plasma jet. Optical emission spectrum in 300 to 800 nm is collected from the direct-current excited plasma jet. By Boltzmann plot method, the excited electron temperature of the plasma plume is investigated as a function of the applied voltage or the gas flow rate. Results show that the excited electron temperature increases with decreasing applied voltage under the constant gas flow. Moreover, it increases with decreasing the gas flow under the constant voltage. Based on the discharge theory, these experimental phenomena are explained qualitatively. These results are of great importance to the development of atmospheric pressure uniform discharge plasma source and its application in industrial field. PMID- 26964201 TI - [Study of Terahertz Amplitude Imaging Based on the Mean Absorption]. AB - A new method of terahertz (THz) imaging based on the mean absorption is proposed. Terahertz radiation is an electromagnetic radiation in the range between millimeter waves and far infrared. THz pulse imaging emerges as a novel tool in many fields because of its low energy and non-ionizing character, such as material, chemical, biological medicine and food safety. A character of THz imaging technique is it can get large amount of information. How to extract the useful parameter from the large amount of information and reconstruct sample's image is a key technology in THz imaging. Some efforts have been done for advanced visualization methods to extract the information of interest from the raw data. Both time domain and frequency domain visualization methods can be applied to extract information on the physical properties of samples from THz imaging raw data. The process of extracting useful parameter from raw data of the new method based on the mean absorption was given in this article. This method relates to the sample absorption and thickness, it delivers good signal to noise ratio in the images, and the dispersion effects are cancelled. A paper with a "THz" shape hole was taken as the sample to do the experiment. Traditional THz amplitude imaging methods in time domain and frequency domain are used to achieve the sample's image, such as relative reduction of pulse maximum imaging method, relative power loss imaging method, and relative power loss at specific frequency imaging method. The sample's information that reflected by these methods and the characteristics of these methods are discussed. The method base on the mean absorption within a certain frequency is also used to reconstruct sample's image. The experimental results show that this new method can well reflect the true information of the sample. And it can achieve a clearer image than the other traditional THz amplitude imaging methods. All the experimental results and theoretical analyses indicate that the method base on the mean absorption within a certain frequency can reflects sample absorb and thickness information, it can achieve good signal to noise ratio in the images. Because the absorption is mean absorption within in a certain frequency, so the method proposed in this article is especially suitable for samples with simple structure. And this new method can be a useful added tool for the other traditional THz amplitude imaging methods. PMID- 26964200 TI - [Methane Concentration Detection System for Cigarette Smoke Based on TDLAS Technology]. AB - Rapid and real-time analysis of cigarette smoke is of great significance to study the puff-by-puff transfer rules in the suction process and to explore the relationship between smoking and health. By combining with the modified commercial smoking machine herein, cigarette smoke online analysis system was established based on the TDLAS technology. The puff-by-puff stability of this system was verified by simulated cigarette composed of a pocket containing CH4 (volume fraction of 0.4), of which the second harmonic peaks are near 1.39. Using this system, the concentration of CH4 in four different kinds of cigarettes was analyzed puff-by-puff by a semiconductor laser, of which center wavelength was at 1 653.72 nm. The results showed that the CH4 concentration of cigarette smoke increased puff-by-puff. CH4 concentration in the flue-cured cigarette is obviously higher than that of blended cigarette by comparing the content of all and puff-by-puff concentration. The puff-by-puff concentration of flue-cured cigarette increased from 400 to 900 ppm, however, the puff-by-puff concentration of blended cigarette increased from 200 to 600 ppm. Simultaneously, there was significant difference between different kinds of the flue-cured. Comparing to tradi- tional analysis methods, this system can effectively avoid the interference of other gases in the smoke cigarette as a result of its strong anti interference. At the same time, it can finish analysis between suction interval without sample pretreatment. The technology has a good prospect in the online puff-by-puff analysis of cigarette smoke. PMID- 26964202 TI - [Experimental Study of PMI Foam Composite Properties in Terahertz]. AB - Polymethacrylimide (PMI) foam composite has many excellent properties. Currently, PMI is heat-resistant foam, with the highest strength and stiffness. It is suitable as a high-performance sandwich structure core material. It can replace the honeycomb structure. It is widely used in aerospace, aviation, military, marine, automotive and high-speed trains, etc. But as new sandwich materials, PMI performance testing in the THz band is not yet visible. Based on the Terahertz (THz) time-domain spectroscopy technique, we conducted the transmission and reflection experiments, got the time domain waveforms and power density spectrum. And then we analyzed and compared the signals. The MATALB and Origin 8. 0 was used to calculate and obtain the transmittance (transfer function), absorptivity Coefficient, reflectance and the refractive index of the different thickness Degussa PMI (Model: Rohacell WF71), which were based on the application of the time-domain and frequency-domain analysis methods. We used the data to compared with the THz refractive index and absorption spectra of a domestic PMI, Baoding Meiwo Technology Development Co. , Ltd. (Model: SP1D80-P-30). The result shows that the impact of humidity on the measurement results is obvious. The refractive index of PMI is about 1. 05. The attenuation of power spectrum is due to the signal of the test platform is weak, the sample is thick and the internal scattering of PMI foam microstructure. This conclusion provides a theoretical basis for the THz band applications in the composite PMI. It also made a good groundwork for THz NDT (Non-Destructive Testing, NDT) technology in terms of PMI foam composites. PMID- 26964203 TI - [Terahertz Spectroscopic Identification with Deep Belief Network]. AB - Feature extraction and classification are the key issues of terahertz spectroscopy identification. Because many materials have no apparent absorption peaks in the terahertz band, it is difficult to extract theirs terahertz spectroscopy feature and identify. To this end, a novel of identify terahertz spectroscopy approach with Deep Belief Network (DBN) was studied in this paper, which combines the advantages of DBN and K-Nearest Neighbors (KNN) classifier. Firstly, cubic spline interpolation and S-G filter were used to normalize the eight kinds of substances (ATP, Acetylcholine Bromide, Bifenthrin, Buprofezin, Carbazole, Bleomycin, Buckminster and Cylotriphosphazene) terahertz transmission spectra in the range of 0.9-6 THz. Secondly, the DBN model was built by two restricted Boltzmann machine (RBM) and then trained layer by layer using unsupervised approach. Instead of using handmade features, the DBN was employed to learn suitable features automatically with raw input data. Finally, a KNN classifier was applied to identify the terahertz spectrum. Experimental results show that using the feature learned by DBN can identify the terahertz spectrum of different substances with the recognition rate of over 90%, which demonstrates that the proposed method can automatically extract the effective features of terahertz spectrum. Furthermore, this KNN classifier was compared with others (BP neural network, SOM neural network and RBF neural network). Comparisons showed that the recognition rate of KNN classifier is better than the other three classifiers. Using the approach that automatic extract terahertz spectrum features by DBN can greatly reduce the workload of feature extraction. This proposed method shows a promising future in the application of identifying the mass terahertz spectroscopy. PMID- 26964204 TI - [Research on Improving the Measurement Speed of THz-TDS Instruments]. AB - The measurement speed is an important parameter of terahertz time-domain spectroscopy (THz-TDS) instruments. To improve the measurement speed of the spectrometer we need to increase the scanning speed of the delay line. In this paper, we study the influence of the scanning speed, the time constant of lock-in amplifier and the sampling rate on the signal quality. The results show that, when the time constant equal to 10 ms, increasing the scanning speed does not cause significant changes in the amplitude of the signal. But when the time constant equal to 30, 100 and 300 ms, with the increasing of the scanning speed the signal amplitude decreases rapidly. Therefore, the time constant should be set as small as possible to avoid deterioration of signal quality. On the other hand, higher the scanning speed is, fewer data points are collected with a same time-domain length. Therefore, when the scanning speed increase, not only the time constant should be reduced, but also the sampling rate should be increased to avoid the distortion of signal waveform caused by the number reduction of data points. The conclusions can provide a reference for improving the measurement speed of THz-TDS instrument. PMID- 26964205 TI - [Vernier Anode Design and Image Simulation]. AB - Based-MCP position-sensitive anode photon-counting imaging detector is good at detecting extremely faint light, which includes micro-channel plate (MCP), position-sensitive anode and readout, and the performances of these detectors are mainly decided by the position-sensitive anode. As a charge division anode, Vernier anode using cyclically varying electrode areas which replaces the linearly varying electrodes of wedge-strip anode can get better resolution and greater electrode dynamic range. Simulation and design of the Vernier anode based on Vernier's decode principle are given here. Firstly, we introduce the decode and design principle of Vernier anode with nine electrodes in vector way, and get the design parameters which are the pitch, amplitude and the coarse wavelength of electrode. Secondly, we analyze the effect of every design parameters to the imaging of the detector. We simulate the electron cloud, the Vernier anode and the detector imaging using Labview software and get the relationship between the pitch and the coarse wavelength of the anode. Simultaneously, we get the corresponding electron cloud for the designing parameters. Based on the result of the simulation and the practical machining demand, a nine electrodes Vernier anode was designed and fabricated which has a pitch of 891 um, insulation width of 25 um, amplitude of 50 um, coarse pixel numbers of 5. PMID- 26964206 TI - [Tri-Level Infrared Spectroscopic Identification of Hot Melting Reflective Road Marking Paint]. AB - In order to detect the road marking paint from the trace evidence in traffic accident scene, and to differentiate their brands, we use Tri-level infrared spectroscopic identification, which employs the Fourier transform infrared spectroscopy (FTIR), the second derivative infrared spectroscopy(SD-IR), two dimensional correlation infrared spectroscopy(2D-IR) to identify three different domestic brands of hot melting reflective road marking paints and their raw materials in formula we Selected. The experimental results show that three labels coatings in ATR and FTIR spectrograms are very similar in shape, only have different absorption peak wave numbers, they have wide and strong absorption peaks near 1435 cm-1, and strong absorption peak near 879, 2955, 2919, 2870 cm-1. After enlarging the partial areas of spectrograms and comparing them with each kind of raw material of formula spectrograms, we can distinguish them. In the region 700-970 and 1370-1 660 cm-1 the spectrograms mainly reflect the different relative content of heavy calcium carbonate of three brands of the paints, and that of polyethylene wax (PE wax), ethylene vinyl acetate resin (EVA), dioctyl phthalate (DOP) in the region 2800-2960 cm-1. The SD-IR not only verify the result of the FTIR analysis, but also further expand the microcosmic differences and reflect the different relative content of quartz sand in the 512-799 cm-1 region. Within the scope of the 1351 to 1525 cm-1, 2D-IR have more significant differences in positions and numbers of automatically peaks. Therefore, the Tri level infrared spectroscopic identification is a fast and effective method to distinguish the hot melting road marking paints with a gradually improvement in apparent resolution. PMID- 26964207 TI - [Analysis of the Influence of Temperature on the Retrieval of Ozone Vertical Profiles Using the Thermal Infrared CrIS Sounder]. AB - Ozone is a particularly critical trace gas in the Earth's atmosphere, since this molecule plays a key role in the photochemical reactions and climate change. The TIR measurements can capture the variability of ozone and are weakly sensitive to the lowermost tropospheric ozone content but can provide accurate measurements of tropospheric ozone and higher vertical resolution ozone profiles, with the additional advantage that measurements are also possible during the night. Because of the influence of atmospheric temperature, the ozone profile retrieval accuracy is severely limited. This paper analyze and discuss the ozone absorption spectra and weighting function sensitivity of temperature and its influence on ozone profile retrieval in detail. First, we simulate the change of atmospheric transmittance and radiance by importing 1 K temperature uncertainty, using line by-line radiative transfer mode under 6 different atmosphere modes. The results show that the transmittance change ratio for 1 K temperature variation was consistent with the transmittance change ratio for 5%-6% change of ozone density variation in all layers of the profile. Then, we calculate the change of weighting function by a temperature error of 1 K, using the Community Radiative Transfer Model (CRTM) for the Cross-track Infrared Sounder (CrIS) on the Suomi National Polar-orbiting Partnership (Suomi NPP) satellite and calculate the corresponding change of retrieval result. The results demonstrate that CrIS is sensitive to Ozone in the middle to upper stratosphere, with the peak vertical sensitivity between 10-100 hPa and the change of weighting function for 1 K temperature variation was consistent with 6% change in the ozone profile. Finally, the paper retrieves ozone profiles from the CrIS radiances with a nonlinear Newton iteration method and use the eigenvector regression algorithm to construct the a priori state. In order to resolve the problem of temperature uncertainty and get high accuracy ozone profile, atmospheric temperature profile and ozone profile are simultaneously retrieved. Comparison of the CrIS retrieved ozone profile with high-vertical-resolution ozonesonde profiles provided by the World Ozone and Ultraviolet Radiation Data Centre (WOUDC) and ERA-Interim ozone profiles indicated that the retrieved ozone profiles are in good agreement with the ozonesonde profiles, and a notable improvement in this algorithm than the retrieval without atmospheric temperature profile, are also better than the ECMWF model profiles. The relative differences are less than 20% for the stratosphere and 50% for the lower troposphere. PMID- 26964208 TI - [Study on RBC Oxygen-Carrying Function with the Incubation Time]. AB - The cycle of Hemoglobin oxygenation and deoxidation plays an important role in driving structure and regulating function of red blood cell in vivo, has attracted wide attention. But it has not yet been reported about any studies on the oxygen-carrying function of individual living RBC in vitro with the incubation time. This study involved that using confocal Raman scanning microscopic technique, collecting the Raman spectra of living erythrocyte cultured in vitro at different time, analysing the peaks (1636, 1562 cm-1) with characterization of hemoglobin oxygen carrying capacity and the amide III band (1240-1300 cm-1) with sensitivity to conformation for understanding those changes both of hemoglobin oxygen carrying capacity and protein conformation over time. Meanwhile, its corresponding surface micromorphology was observed via scanning electron microscopy (SEM). The results indicated that the during 24 h hemoglobin with stable structure and normal allosteric collaborative function occurred alternately with the oxygen uptake of increase and decrease and conformation K state and T state, while double concave disk red blood cells observed under SEM also alternately between stretch and shrink. The conclusion not only provides a multi-level characteristic parameter from a single living cell for the study of RBC oxygen-carrying function in vitro, but also the potential research ideas for the screening of the active component, the evaluation of drug efficacy and toxicity for RBC in vitro. PMID- 26964209 TI - [Modified Mechanism of Cell Walls from Chinese Fir Treated with Low-Molecular Weight Phenol Formaldehyde Resin]. AB - Study on the modified mechanism of wood cell walls, it is very important for improving treatment reagents, optimizing treatment technology, and enhancing wood density, mechanical properties, dimensional stability, and so on. Samples of plantation Chinese fir were treated gradually with synthesized water-soluble low molecular-weight phenol formaldehyde (PF) resins under vacuum and pressure. The correlated physical and chemical properties of the treated and untreated reference samples were determined by X-ray diffractometer (XRD), Fourier transform infrared spectrometer (FTIR), and nuclear magnetic resonance spectrometer(NMR) (Using method of Cross Polarization/Magic Angle Spinning for continuous testing) with high precision and resolution. The results showed that, after treated with water-soluble low-molecular-weight PF resin, the average values of crystallinity from the treated samples were decreased obviously, and the average reduction rate was 12.67%, 11.91% and 6.26%, respectively. Comparing water-soluble, low-molecular-weight PF resin modified Chinese fir with untreated reference samples, no new chemical shifts and characteristic peaks of functional groups from esters, ethers, etc. were present by using FTIR and 13C NMR spectrum. It was considered that there was no distinct chemical reaction between the water soluble low-molecular-weight PF resin and Chinese Fir cell walls. But water soluble low-molecular-weight PF resin could enter into the structure relatively loose, large size spaces, relatively area large amorphous regions in cell walls of Chinese fir tracheids, and form physical filling, which resulting in the decreasing of relative crystallinity. This study has important reference value for the development of new wood modification reagents and the optimization of wood modification process. The findings also provide important theoretical foundation for further proving the modification mechanisms of wood cell walls and enriching the modified theories of wood cell walls. PMID- 26964210 TI - [Study on the Calibration Transfer of Near Infrared Spectroscopy Model for Soil Organic Matter Content Prediction by Using FIR]. AB - Calibration transfer of near infrared spectroscopy model is a key problem in the field of near infrared spectroscopy research. In this study, calibration transfer of near infrared spectroscopy model for soil organic matter prediction by using Finite Impulse Response (FIR) was analyzed. The specific research work and conclusions were as follows: Firstly, 59 soil samples were collected and detected by using ASD Fieldspec3 in different times. 50 soil samples called "master soil samples" were detected at the same time in 2012, and the other 9 soil samples called "target soil samples" were detected at the same time in 2013. Secondly, 41 soil samples as calibration samples were randomly selected from the "master soil samples", and soil organic matter prediction model was built by using partial least square (PLS) analysis. The other 9 "master soil samples" were predicted. The result shows that the prediction correlation coefficient is 0. 961, Root Mean Standard Error of Prediction(RMSEP) is 0.600%, and Standard Error of Prediction(SEP) is 0.597%. It indicates that it is feasible to predict "master soil samples" by using above PLS model. Then, 9 "target soil samples" were predicted by using above PLS model. The result shows that it is infeasible to predict "target soil samples" by using above PLS model. Finally, FIR was applied to realize calibration transfer. The result shows that, when the window size was 516, higher prediction accuracy was obtained. The prediction correlation coefficient is 0.706, RMSEP is 0.662%, and SEP is 0.430%. It indicates that it is feasible to realize calibration transfer by using FIR. PMID- 26964211 TI - [A Quantitative Analysis Method of Water-Soluble Inorganic Ions with ATR-FTIR Spectroscopy]. AB - A method of fast nondestructive determination of three kinds of water-soluble inorganic ions including SO42-, NO3- NH4+ in aerosol was disscussed. The method of IC measurement values was used on the control of the three kinds of inorganic ion content. The quantitative calibration models of the inorganic ions were developed by using ATR-FTIR spectroscopy combined with PLS algorithm and the model was evaluated. Markov distance discriminant method was used to identify and eliminate outliers, different mathematical treatments for spectra processing and different wavelength ranges were compared to determine the best model and the optimal model parameters was determined. The results showed that second derivative analysis after eliminating outliers can improve the prediction, PLS analysis can get better results for SO42- in the range of 1220-900 cm-1, for NO3- in the range of 1521-900 cm-1 and for NH in the range of 1521-1220 cm-1, the RMSEP were 1.736 7, 1.023 9 and 1.482 3, respectively. The foundation of real time fast quantitative analysis of the three kinds of inorganic ion in a large number of aerosol samples was established. PMID- 26964212 TI - [The Classification of Wheat Varieties Based on Near Infrared Hyperspectral Imaging and Information Fusion]. AB - Hyperspectral imaging technology has great potential in the identification of crop varieties because it contains both image information and spectral information for the object. But so far most studies only used the spectral information, the image information has not been effectively utilized. In this study, hyperspectral images of single seed of three types including strong gluten wheat, medium gluten wheat, and weak gluten wheat were collected by near infrared hyperspectra imager, 12 morphological characteristics such as length, width, rectangularity, circularity and eccentricity were extracted, the average spectra of endosperm and embryo were acquired by the mask which was created by image segmentation. Partial least squares discriminant analysis (PLADA) and least squares support vector machine (LSSVM) were used to construct the classification model with image information, results showed that the binary classification accuracy between strong gluten wheat and weak gluten wheat could achieve 98%, for strong gluten wheat and medium gluten wheat, it was only 74.22%, which indicated that hyperspectral images could reflect the differences of varieties, but the accuracy might be poor when recognizing the varieties just by image information. Soft independent modeling of class analogy (SIMCA), PLSDA and LSSVM were used to established the classification model with spectral information, the classification effect of endosperm is slightly better than the embryo, it demonstrated that the grain shape could influence the classification accuracy. Then, we fused the spectral and image information, SIMCA, PLSDA and LSSVM were used to established the identification model, the fusion model showed better performance than the individual image model and spectral model, the classification accuracy which used the PLSDA raise from 96.67% to 98.89%, it showed that digging the morphological and spectral characteristics of the hyperspectral image could effectively improve the classification effect. PMID- 26964213 TI - [Study on Paddy Soil Chronosequences Based on Visiblc-Near Infrared Diffuse Reflectance Spectra]. AB - To investigate spectral characteristics of different soil compositions, eight soil profiles from two paddy soil chronosequences developed on red clays and red sandstones respectively were collected in Jiangxi Province. A total of 37 soil samples were taken from each soil horizons of the profiles. The paddy soil chronosequences were chosen mainly because all soil profiles have the same land management and thus parent materials and rice cultivation time would be two major soil formative factors. This makes it possible to study spectral response characteristics of soil organic matter (SOM) and parent material characteristics. We measured diffuse reflectance spectra data of soil samples using the Cary 5000 spectrophotometer at 350-2500 nm spectral range. Spectral response characteristics of SOM and inorganic minerals in paddy soils were analyzed according to different soil horizons, soil forming times and parent materials. Experiment results showed that for soil samples from a single parent material, overall reflectance presented by PC_1 score can be calibrated for soil organic matter (SOM) content with high precision (R(RC)2 = 0.91, R(RS)2 = 0.79), even though the SOM content was low (not more than 20 g . kg-1). The absorption strength (AS) at 1400, 1900 and 2200 nm was mainly affected by the minerals inherited from parent materials. And the more the sample was near to bottom of a soil profile, the higher the AS value. Samples with the same mineral components had the similar AS ratio among these three wavelength locations. The differences in parent materials can significantly affect spectral curve shape and spectral absorption strength. To make the calibration more interpretative, parent material factors should be considered. PMID- 26964214 TI - [Potential Applicability of Fecal NIRs: A Review]. AB - Near-infrared reflectance spectroscopy (NIRS) is an inexpensive, rapid, environment-friendly and non-invasive analytical technique that has been extensively applied in the analysis of the dietary attributes and the animal products. Acquisition of dietary attributes is essential for nutritional diagnoses to provide animals with reasonable diet. Traditionally, the calibration equations for the prediction of dietary attributes (e. g. crude protein) are developed from feed NIR spectra and the results of conventional chemical analysis (i. e. reference data). It is difficult to obtain the NIR spectra of forages consumed by grazing animals, so the method of this calibration is inappropriate for free-grazing herbivores. Feces, as the animal's metabolites, contain the information about both the animal's diet and the animal itself. Recently, Fecal NIRS (F. NIRS) has been directly used to monitor diet information (botanical composition, chemical composition and digestibility), based on correlation between reference data and fecal NIR profile. Subsequently, some additional application (such as sex and species discrimination, reproductive and parasite status) of F. NIRS also is outlined. In the last, application of NIRS in animal manure is summarized. NIRS was shown to be an alternative to conventional wet chemical methods for analyzing some nutrient concentrations in animal manure rapidly. Overall, this paper proves that F. NIRS is a rapid and valid tool for the determination of the dietary attributes and of the physiological status of animal, although more efforts need to be done to improve the accuracy of the F. NIRS technique. Several researchers in English have reviewed the applications of F. NIRS. In China, however, there is a paucity of research and application regarding F. NIRS. We expect that this paper in Chinese will be helpful to the development of F. NIRS in China. At the same time, we propose NIRS as a simple and rapid analytical method for predicting the main chemical composition (dry matter, organ matter, total solid, volatile solid, total nitrogen, total Kjeldahl nitrogen and ammonium nitrogen) in animal manure. PMID- 26964215 TI - [Maize Hybrid Seed Purity Identification Based on Near Infrared Reflectance (NIR) and Transmittance (NIT) Spectra]. AB - This article explore the feasibility of using Near Infrared Reflectance (NIR) and Transmittance (NIT) Spectroscopy (908.1-1677.2 nm wavelength range) to identify maize hybrid purity, and compare the performance of NIR and NIT spectroscopy. Principle Component Analysis (PCA) and Orthogonal Linear Discriminant Analysis (OLDA) were used to reduce the dimension of spectra which have been pretreated by first derivative and vector normalization. The hybrid purity identification model of Nonghua101 and Jingyu16 were built by SVM. Models based on NIR spectra obtained correct identification rate as 100% and 90% for Nonghua101 and Jingyu16 respectively. But NIR spectra were greatly influenced by the placement of seeds, and there existed significant difference between NIR spectra of embryo and non embryo side. Models based on NIT spectroscopy yielded correct identification rate as 98% both for Nonghua101 and Jingyu16. NIT spectra of embryo and non-embryo side were highly similar. The results indicate that it is feasible to identify maize hybrid purity based on NIR and NIT spectroscopy, and NIT spectroscopy is more suitable to analyze single seed kernel than NIR spectroscopy. PMID- 26964216 TI - [Application of FTIR Microspectroscopy in the Study of Lignocellulosic Cell Walls]. AB - The development and utilization of lignocellulosic biomass resource becomes a major subject of widespread concern at home and abroad. To make better use of this resource and reduce cost, a thorough understanding of recalcitrance mechanism as well as chemical compositional and structural characteristics of lignocellulosic cell walls seems desiderated. With the property of fast testing, high sensitivity and simple sample preparation, FTIR microspectroscopy can provide microanalysis and nondestructive test. It has been proved to accurately present compositional and structural information of lignocellulosic cell walls and be suitable for the study of topochemistry of main components at the cellular level. After a brief introduction of the principle of FTIR microspectroscopy and its detailed experimental procedure, this review provides an overview on the feasibility of FTIR microspectroscopy in monitoring as well as evaluating the composition and structure of lignocellulosic cell walls from three aspects, including in situ distribution, changes after pretreatment and molecular orientation of the major components in cell walls. Some prospects, for example development of the magnification of the microscope and the spatial resolution of chemical imaging, combination with various analysis methods and instruments are also proposed. This technology can act as a new approach in characterizing lignocellulosic cell walls. PMID- 26964217 TI - [FTIR Spectroscopic Analysis of Humic-Like Substances Extracted from the Microbial Residues]. AB - Drived by the soil microorganisms, the decomposition and transformation of cellulose plays an important role in the formation of humic substances. The techniques of infrared spectrum combining with element analysis were adopted to compare the structural differences of humic-like substances (HLA, humic-like acid; Hu, humin) extracted from the microbial residues formed in the liquid shake flask culture (70 days), in which the single fungi (Trichoderma viride, Penicillium and Aspergillus niger) and mixed strains participated. The results showed that: (1) The combination of two techniques could clarify the molecu- lar structure of HLA extracted from the microbial residues, however, it remained to be further discussed in terms of analyzing the structures of Hu; (2) Trichoderma viride was beneficial to the condensation of HLA extracted from its microbial residue, but Penicillium was more favorable to the degradation of HLA. (3) The oxidative degradation of HLA fractions extracted the microbial residues was implemented by Penicillium and mixed strains. Both of the mixed strains and Aspergillus niger were helpful to transfer the inorganic N compounds from the culture media into the organic N components of HLA and Hu extracted from the microbial residues, simultaneously increase their amino C contents and then provide the indispensable N source for the humification process. PMID- 26964218 TI - [Research on Early Diagnosis of Gastric Cancer by the Surface Enhanced Raman Spectroscopy of Human Hemoglobin]. AB - Early diagnosis have great positive effect on the treatment of gastric cancer patients. Raman spectroscopy can provide a useful monitor for hemoglobin dynamics. Besides, Raman spectroscopy has notable advantages in the fields of abnormal hemoglobin diagnosis, hemoglobin oxygen saturation deter mination and blood methemoglobin analysis. In this paper, novel silver colloid was synthesized by microwave heated method. The surface enhanced Raman spectrums of hemoglobin from 11 normal persons and 20 gastric cancer patients are measured and analyzed in order to obtain spectrums which are high repeatability and characteristic peaks protruding. By analyzing the assignations of the SERS bands, it found that the content of asparagine, tyrosine and phenylalanine in the hemoglobin are significantly lower than healthy people. Discussing the structure of hemoglobin, when hemoglobin combines with oxygen, Fe2+ is in a low spin state, ionic radius shrinks and moves 0. 075 nm and fall into the pore in the middle of the heme porphyrin ring plane. This spatial variation affects F8His connected with the iron, will narrow the gap between the globin in the two strands of the helix, as a result, HC2 tyrosine pushed out of the void. Using this mechanism, the absorption peak of 1 560 cm-1 confirmed that the tyrosine content in patients with gastric cancer was lower than that of normal people. Principal component analysis(PCA) is employed to get a three-dimensional scatter plot of PC scores for the health and cancer groups, and it can be learned that they are distributed in separate areas. By using the method of discriminate analysis, it is found that the diagnostic algorithm separates the two groups with sensitivity of 90.0% and diagnostic specificity of 90.9%, the overall diagnostic accuracy was 90.3%. The results from this exploratory study demonstrate that, SERS detection of oxyhemoglobin combined with multivariate analysis would be an effective method for early diagnosis of gastric cancer. PMID- 26964219 TI - [Research on the Method of Eliminating Noise and Background in the Meantime in Detecting Ethanol Contention Based on Raman Spectra]. AB - In the process of detecting ethanol content by Raman spectra, the precision of correction model prediction is affected by noise and baseline drift, which is caused by the spectral fluorescence and sample pool's background. Use ensemble empirical mode decomposition to decompose spectrum into several intrinsic mode functions, which are without aliasing. The permutation entropy is employed to judge the intrinsic mode functions. Set the intrinsic mode functions which are on behalf of noise and background to zero, and then the signal is without noise and background. In this paper combine ensemble empirical mode decomposition and permutation entropy, and apply to the Raman spectrum, which are used to detect ethanol content. At the same time compare with wavelet transform and average smoothing filter. The experimental result shows that the application of empirical mode decomposition and permutation entropy can effectively eliminate the noise and background. The precision of correction model prediction is improved. This method simply employs and doesn't need to set parameters, which has great value of application in the process of detecting ethanol content by Raman spectra. PMID- 26964220 TI - [Diagnosing Low Health and Wood Borer Attacked Trees of Chinese Arborvitae by Using Thermography]. AB - Water and energy metabolism of plants is very important actions in their lives. Although the studies about these actions by using thermography were often reported, seldom were found in detecting the health status of forest trees. In this study, we increase the measurement accuracy and comparability of thermo images by creating the difference indices. Based on it, we exam the water and energy status in stem of Chinese arborvitae (Platycladus orientalis (L.) Franco) by detecting the variance of far infrared spectrum between sap-wood and heart wood of the cross-section of felling trees and the cores from an increment borer using thermography. The results indicate that the sap rate between sapwood and heartwood is different as the variance of the vigor of forest trees. Meanwhile, the image temperature of scale leaves from Chinese arborvitae trees with different vigor is also dissimilar. The far infrared spectrum more responds the sap status not the wood percentage in comparing to the area rate between sapwood and heartwood. The image temperature rate can be used in early determining the health status of Chinese arborvitae trees. The wood borers such as Phloeosinus aubei Perris and Semanotus bifasciatus Motschulsky are the pests which usually attack the low health trees, dying trees, wilted trees, felled trees and new cultivated trees. This measuring technique may be an important index to diagnose the health and vigor status after a large number of measurements for Chinese arborvitae trees. Therefore, there is potential to be an important index to check the tree vigor and pest damage status by using this technique. It will be a key in the tending and management of ecological and public Chinese arborvitae forest. PMID- 26964221 TI - [Quantification of Agricultural In-Situ Surface Soil Moisture Content Using Near Infrared Diffuse Reflectance Spectroscopy: A Comparison of Modeling Methods]. AB - At field scale, surface soil had special characteristics of volumetric moisture content (VMC) with a relatively little difference and spatial heterogeneity induced by physical and chemical properties, roughness, straw residues, etc. It has been a great challenge for near infrared diffuse reflectance spectroscopy (NIR-DRS) measurement of surface soil moisture in situ. In this study, exonential decay models based on seven water-related wavelengths (1200, 1400, 1450, 1820, 1940, 2000 and 2250 nm), linear models of normalized difference soil moisture index (NSMI) and relative absorption depth (RAD) based on wave-length combinations, linear or quadratic model of width of the inflection (sigma), center amplitude of the function (Rd) and area under the Gaussian curve (A) from soil moisture Gaussian model (SMGM), and partial least square (PLS) regression models based on bands were used to quantify VMC. The results indicated that (1) of all the single wavelengths, 2 000 nm showed the best validation result, indicated by the lowest RMSEp (2.463) and the highest RPD value (1.060). (2) Comparing with RAD, the validation of NSMI was satisfactory with higher R2 (0.312), lower RMSEp (2.133) and higher RPD value (1.224). (3) In the validation results of SMGM parameters and PLS fitting, Rd was found to produce the best fitting quality identified by the highest R2 (0.253), the lowest RMSEp (2.222), and the highest RPD value (1.175). (4) Comprehensively, a linear model based on NSMI showed the highest validation accuracy of all the methods. What is more, its calculation process is simple and easy to operate, and therefore become the preferred method to quantify surface soil moisture content in situ. PMID- 26964222 TI - [Rapid and Dynamic Determination Models of Amino Acids and Catechins Concentrations during the Processing Procedures of Keemun Black Tea]. AB - Tea is one of the most popular beverages in the world. For the contribution to the taste and healthy functions of tea, amino acids and catechins are important components. Among different kinds of black teas in the world, Keemun black tea has the famous and specific fragrance, "Keemun aroma". During the processing procedure of Keemun black tea, the contents of amino acids and catechins changed greatly, and the differences of these concentrations during processing varied significantly. However, a rapid and dynamic determination method during the processing procedure was not existed up to now. In order to find out a rapid determination method for the contents of amino acids and catechins during the processing procedure of Keemun black tea, the materials of fresh leaves, withered leaves, twisted leaves, fermented leaves, and crude tea (after drying) were selected to acquire their corresponding near infrared spectroscopy and obtain their contents of amino acids and catechins by chemical analysis method. The original spectra data were preprocessed by the Standard Normal Variate Transformation (SNVT) method. And the model of Near Infrared (NIR) spectroscopy with the contents of amino acids and catechins combined with Synergy Interval Partial Least squares (Si-PLS) was established in this study. The correlation coefficients and the cross validation root mean square error are treated as the efficient indexes for evaluating models. The results showed that the optimal prediction model of amino acids by Si-PLS contained 20 spectral intervals combined with 4 subintervals and 9 principal component factors. The correlation coefficient and the root mean square error of the calibration set were 0. 955 8 and 1. 768, respectively; the correlation coefficient and the root mean square error of the prediction set were 0. 949 5 and 2. 16, respectively. And the optimal prediction model of catechins by Si-PLS contained 20 spectral intervals combined with 3 subintervals and 10 principal component factors. The correlation coefficient and the root mean square error of the calibration set were 0. 940 1 and 1. 22, respectively; the correlation coefficient and the root mean square error of the prediction set were 0. 938 5 and 1. 17, respectively. The results showed that the established models had good accuracy which could provide a theoretical foundation for the online determination of tea chemical components during processing. PMID- 26964223 TI - [A Set of Infrared Cells for the Determination of Titanium Oxychloride in Refined Titanium Tetrachloride]. AB - The content control of the impurities in refined TiCl4 becomes the key part for the quality control of titanium material. Refined TiCl4 is the key procedure in producing titanium sponge. Besides, the content of the impurities in titanium sponge and that of the impurities in refined TiCl4 presents the 4-times enrichment relationship. Therefore, control the content of the oxygen, there is the need to analyze the source of oxygen impurities so that strict control can be conducted over the impurities of refined TiCl4. Determination of TiOCl2 in refined TiCl4 was significant for analysis of its impurities. TiOCl2 could be determined by infrared spectroscopy due to its infrared characteristic spectrum line. However, normal infrared absorption cell was not fit for the sample analysis, because TiCl4 easily reacted with moisture in the air and immediately was hydrolyzed to form highly corrosive hydrochloric acid smoke. According to Lambert-Beer Law, which means the concentration (c(x)) and absorbance (A)-length (L) curve's slope have direct ratio. The infrared absorption cell with the window film of ZnSe (Phi10 x 1 mm, wavenumers: 7800-440 cm-1) and the glass cell (optical path: 22, 12, 7 and 4 mm) was assembled and utilized in determination of the TiOCl2 in refined TiCl4 by standard addition method. The detection limit of TiOCl2 was 17.8 mg . kg-1, the regression equation was Y = 1.011 8X, R = 0.9963; With standard addition method, the regression equation of TiOCl2 was Y = 1.940 0X, R = 0.997 0, it' s good in linearity relation, the TiOCl2 content in refined TiCl4 is determined to be 833.8 mg . kg-1 and SD up to 40.0 mg . kg-1. RSD of the method precision is between 0.95%-1.94%, while recovery rate is between 88.5% 93.1%. This infrared absorption device was safe, simple and convenient, easily removable and washable, and re-useable. The method could conduct the quantitative analysis over the TiOCl2 content in refined TiCl4 through adding standard sample for one time, it could meet the requirement of determination of TiOCl2 in refined TiCl4. PMID- 26964224 TI - [Study on the Color Determination of Tomato Leaves Stressed by the High Temperature Based on Hyperspectral Imaging]. AB - Determination of color values on tomato leaves stressed by the high temperature using hyperspectral imaging technique was studied in this paper. Hyperspectral images of sixty healthy and sixty unhealthy tomato leaves in the wavelengths of 380-1023 nm were acquired by the hyperspectral imaging system. Simultaneously, three color parameters (L*, a* and b*) were measured by a colorimeter. Reflectance of all pixels in the region of interest (ROI) was extracted from the corrected hyperspectral image. Partial Least Squares (PLS) models were established based on different preprocessing methods. Successive Projections Algorithm (SPA) was identified to select effective wavelengths. Finally, Partial Least Squares-Discriminant Analysis (PLS-DA) models were built to classify different types of samples. The results showed that the determination coefficient (R2) were 0. 818, 0. 109 and 0. 896 in the prediction sets of PLS modes; 0.591, 0.244 and 0.673 in the prediction sets of SPA-PLS models. The overall classification accuracy in the prediction sets of PLS-DA models were over 77.50%. It demonstrated that it is feasible to measure color values on tomato leaves and identify different types of samples using hyperspectral imaging technique. PMID- 26964225 TI - [Inversion of True Protein Content in Milk Based on Hyperspectral Data]. AB - As an indispensable drink of people's daily life, milk's quality has been also increasingly concerned by consumers. Rapid and accurate detection of milk and its products is the indispensable step for improving the quality of milk and daily products in production. However, traditional methods cannot meet the need. In this paper, rapid quantitative detection of true protein in pure milk was studied by using visible/near-infrared (VIS/NIR) reflectance spectroscopy (350-2500 nm). The spectral data and the protein content data of the pure milk samples were collected by ASD spectrometer and CEM rapid protein analyzer, respectively. Based on the analysis and comparison of different spectrum preprocessing methods and band selection methods, the feature bands were determined. Finally, using the Principle Component Regression (PCR) and Least Squares Support Vector Machine (LS SVM) model, the regression models between the reflectance spectroscopy and the protein content in milk were presented for pure milk samples and the predictive ability was also analyzed. In this way, the optimal inversion model for true protein content in milk was established. The results were shown as follows: (1) In the process of spectral pretreatment, the combination of multiple scatter correction and second derivative achieved a better result; (2) Compared with the modeling of whole spectral, appropriate variable optimization models had the ability to improve the accuracy of the inversion results and reduce the modeling time; (3) The analysis results between PCR model and LS-SVM model demonstrated that the prediction accuracy of LS-SVM model was better than PCR model. The coefficient of determination (R(P)2) of PCR and LS-SVM were 0.952 2 and 0.958 0 respectively, and the root mean square error of prediction (RMSEP) of PCR and LS SVM were 0.048 7 and 0.048 2 respectively. The result of this research is expected to provide a novel method for nondestructive and rapid detection of true protein in milk. PMID- 26964226 TI - [Aqueous Fingerprint of Printing and Dyeing Wastewater]. AB - Aqueous fingerprint has an advantage to represent the organic components of water samples as compared to traditional parameters such as chemical oxygen demand (COD) and total organic carbon (TOC). Printing and dyeing wastewater is one of the major types of industrial wastewater in China. It is of huge volume and heavy pollution, containing large numbers of luminescent components and being difficult to be degraded. In this study the aqueous fingerprint of printing and dyeing wastewater was investigated with the fluorescent spectrometry. The experimental results showed that there existed two peaks in the aqueous fingerprint of the printing and dyeing wastewater, locating at the excitation/emission wavelength around 230/340 nm and 280/310 nm respectively. The intensity of the excitation/emission wavelength at 230/340 nm was higher than that of 280/310 nm. The locations and intensities of peaks varied within small range. The intensities of the two peaks linearly correlated with coefficient of 0.910 8 and slope of 1.506. The intensity ratio of Peak at 280/310 nm to Peak at 230/340 nm averagely was 0.777, ranging between 0.712 and 0.829. It was found that the aqueous fingerprints of sewage and aniline compounds were significantly different from that of the printing and dyeing wastewater, but the aqueous fingerprints of several types of widely-used dye were similar to that of the printing and dyeing wastewater. Thus dye may be the main luminescent components in the wastewater. The aqueous fingerprint can be used as a novel tool of early warning of waterbodies. PMID- 26964227 TI - [The Study on the Characteristics of Organic Pollution in Typical Herbicide Plant Wastewater]. AB - Herbicide wastewater is one of tne industrial wastewater, it has high salt content, poor biodegradability, biodegradable characteristics. Nitrogen containing organic compounds are dominated in dissolved organic matter and dissolved organic matter of wastewater, BOD: COD = 0.045, C:N:P = 692:426:1. Applying static headspace, purg and trap, solid-phase extraction, solid-phase microextraction and liquid-liquid extraction as pretreatment methods combined with gas chromatography/mass spectrometry (GC/MS), which qualitatively analyzed the organic components of the Atrazine, acetochlor herbicide production wastewater and researched the UV spectrum, three-dimensional fluorescence spectroscopy of the wastewater and its major pollutants. The study of GC/MS indicated that Wastewater contained chlorinated hydrocarbons, BTEX and triazines, amides herbicides etc. 38 kinds of volatile and semi-volatile organic compounds, atrazine and acetochlor herbicides accounted for 87. 99%. Affected monocyclic or heterocyclic substances, the ultraviolet absorption spectrum of the wastewater in 210-230 and 250-270 nm in that the amino group lead to the UV absorption red shift 20 nm. Wastewater generated 5 fluorescence peak in lambda(ex)/lambda(em) = 200-280/300-400 nm, such as a(225/305 nm), b(265/365 nm), c(275/305 nm), d(285/390 nm), e(320/375 nm). Based on three-dimensional fluorescence results of the different functional groups of the characteristics organic, fluorescent area of unsaturated bond is in lambda(ex)/lambda(em) = 215-230/290-340 nm, the main contribution of the fluorescent substance in the region were olefins, benzene, heterocyclic in the wastewater; fluorescent area of Phenolic hydroxyl and carbonyl is in lambda(ex)/lambda(em) = 270/300 nm, the main contribution of the fluorescent substance in the region were phenols, ketones. PMID- 26964228 TI - [Identification of Prepared Rehmannia Root in Different Regions by Using Derivative Synchronous Fluorescence Spectrum]. AB - Three-dimensional synchronous fluorescence spectrum of prepared rehmannia root from different regions were measured and feature parameters were extracted. It can be found that the effective fluorescent compositions of prepared rehmannia root from different regions are similar. The relationships between the spectrum effect were established. This study can provide reference for clinicaldosage. First order derivative and second order derivative of prepared rehmanniaroot from different regions can be got by programming respectively. Magnifing synchronous emission spectrum of the shoulder strap, the subtle differences of the spectrum can be distinguished and the method, derivative synchronous fluorescence spectrum, to identify different regions of prepared rehmannia root are acquired. PMID- 26964229 TI - [Qualitative Determination of Organic Vapour Using Violet and Visible Spectrum]. AB - Vapours of organic matters were determined qualitatively employed with ultraviolet-visible absorption spectroscopy. Vapours of organic matters were detected using ultraviolet-visible spectrophotometer employing polyethylene film as medium, the ultraviolet and visible absorption spectra of vegetable oil vapours of soybean oil, sunflower seed oil, peanut oil, rapeseed oil, sesame oil, cotton seed oil, tung tree seed oil, and organic compound vapours of acetone, ethyl acetate, 95% ethanol, glacial acetic acid were obtained. Experimental results showed that spectra of the vegetable oil vapour and the organic compound vapour could be obtained commendably, since ultra violet and visible spectrum of polyethylene film could be deducted by spectrograph zero setting. Different kinds of vegetable oils could been distinguished commendably in the spectra since the lambda(max), lambda(min), number of absorption peak, position, inflection point in the ultra violet and visible spectra obtained from the vapours of the vegetable oils were all inconsistent, and the vapours of organic compounds were also determined perfectly. The method had a good reproducibility, the ultraviolet and visible absorption spectra of the vapours of sunflower seed oil in 10 times determination were absolutely the same. The experimental result indicated that polyethylene film as a kind of medium could be used for qualitative analysis of ultraviolet and visible absorption spectroscopy. The method for determination of the vapours of the vegetable oils and organic compounds had the peculiarities of fast speed analysis, well reproducibility, accuracy and reliability and low cost, and so on. Ultraviolet and visible absorption spectrum of organic vapour could provide feature information of material vapour and structural information of organic compound, and provide a novel test method for identifying vapour of compound and organic matter. PMID- 26964230 TI - [Study on Enhancing Characteristic Vibration of the Molecular Vibration Spectrum for BDE-15 Based on Solvent Effect]. AB - In this paper, the molecular vibrational spectra (IR spectra and Raman spectra) of 4, 4'-dibrominated diphenyl ethers (BDE-15) in atmosphere and 24 kinds of solvents were calculated, at the B3LYP/6-31+G(d) level by density functional theory and self-consistent reaction field separately. Taking the spectra in atmosphere as benchmark, the spectra information of selected characteristic vibrations which were sensitive to the polarity of solvent were used to establish the solvent effect index system for BDE-15, evaluate the specific solvent effect on vibrational frequency, IR vibrational intensity, Raman vibrational intensity and comprehensive solvent effect of each solvent and search the organic solvent which significantly affected the frequency shift/intensity. From the view of molecular vibrational frequency, the characteristic vibrations sensitive to polarity of solvent (frequency shift > 1 cm-1) are all correlated with stretching and out-surface bending vibrations, the solvent effect on the vibrational frequency of BDE-15 of 24 kinds of solvents are all insignificant, with the index values between 1.01-1.03, compared with standard index value 1 of atmosphere spectra. From the view of molecular vibrational intensity, 24 kinds of solvents have all strengthen the vibrational intensities of most of vibrations, locating at the high frequency region of Raman spectra and the middle/low frequency region of IR spectra. The solvents which enhance the vibrational intensities significantly (index value greater than 6 and 5 for IR and Raman intensity separately) include alcohols, acetonitrile, dimethyl sulfoxide, nitrobenzene, dimethyl sulfoxide. The solvent effect index values on Raman vibrational intensity of BDE-15 increase along with the dielectric constant of solvents from linear to logarithmic growth trend, while the solvent effect index values on IR vibrational intensity only leaving the linear relationship. The comprehensive solvent effect index values have presented the similar change trend with Raman vibrational intensities. The spectra information of BDE-153, BDE-154, BDE-209 were used to authenticate the application on PBDEs of the analysis method above for BDE-15, obtaining the solvent effect index values on vibrational intensities on BDE-153, BDE-154, BDE-209 of alcohols, acetonitrile, dimethyl sulfoxide, nitrobenzene are all greater than 6 or 5, which indicate the enhancing vibrational intensities method can be used to identification research on PBDEs based on molecule vibrational spectra further. PMID- 26964231 TI - [Orthogonal Vector Projection Algorithm for Spectral Unmixing]. AB - Spectrum unmixing is an important part of hyperspectral technologies, which is essential for material quantity analysis in hyperspectral imagery. Most linear unmixing algorithms require computations of matrix multiplication and matrix inversion or matrix determination. These are difficult for programming, especially hard for realization on hardware. At the same time, the computation costs of the algorithms increase significantly as the number of endmembers grows. Here, based on the traditional algorithm Orthogonal Subspace Projection, a new method called. Orthogonal Vector Projection is prompted using orthogonal principle. It simplifies this process by avoiding matrix multiplication and inversion. It firstly computes the final orthogonal vector via Gram-Schmidt process for each endmember spectrum. And then, these orthogonal vectors are used as projection vector for the pixel signature. The unconstrained abundance can be obtained directly by projecting the signature to the projection vectors, and computing the ratio of projected vector length and orthogonal vector length. Compared to the Orthogonal Subspace Projection and Least Squares Error algorithms, this method does not need matrix inversion, which is much computation costing and hard to implement on hardware. It just completes the orthogonalization process by repeated vector operations, easy for application on both parallel computation and hardware. The reasonability of the algorithm is proved by its relationship with Orthogonal Sub-space Projection and Least Squares Error algorithms. And its computational complexity is also compared with the other two algorithms', which is the lowest one. At last, the experimental results on synthetic image and real image are also provided, giving another evidence for effectiveness of the method. PMID- 26964232 TI - [Label-Free Resonance Light Scattering Detection of Hg2+ Based on Specific Structure Thymine-Hg2+-Thymine]. AB - A new label-free resonance light scattering method for the highly selective and sensitive detection of mercury ion was designed. This strategy makes use of the target-induced DNA conformational change to enhance the resonance light scattering intensity leading to an amplified optical signal. The Hg2+ ion, which possesses a unique property to bind specifically to two DNA thymine (T) bases, in the presence of Hg2+, the specific oligonucleotide probes form a conformational reorganization of the oligonucleotide probes from single-chain structure to duplex-like complexes, which can greatly enhance the resonance light scattering intensity. Under the optimum experimental conditions, the enhanced resonance light scattering intensity at 566 nm was in proportion of mercury ion concentration in the range 7.2 x 10-9 x 10-8 mol . L-1 with the linear regression equation was DeltaI = 5.12c+3.55 (r = 0.999 5). This method was successfully applied to detection of Hg2+ in enviro nmental water samples, the RSD were less than 1.9% and recoveries were 99.4%-104.3%. This label-free strategy uses the mercury specific oligonucleotide probes as recognition elements and control the strength of resonance light scattering by changing the concentration of Hg2+. It translating the small molecule detection into the DNA hybridization behavior leading to an amplified resonance light scattering signal can well enhance the sensitive detection of Hg2+. With amplification by DNA hybridization behavior, the sensitivity for the detection of Hg2+ can achieve 2.16 x 10-9 mol . L(-1). In this study, the stacked T-Hg2+-Tfunctioned not only as amplification property but also as an selective recognition. The highly specific detection of Hg2+ is attributed to the formation of a stable T-Hg2+-T complex. PMID- 26964233 TI - [Observation and Analysis of Ground Daylight Spectra of China's Different Light Climate Partitions]. AB - The territory of China is vast, so the daylight climates of different regions are not the same. In order to expand theutilization scope and improve the utilization efficiency of solar energy and daylight resources, this article observed and analyzed the ground daylight spectra of China's different light climate partitions. Using a portable spectrum scanner, this article did a tracking observation of ground direct daylight spectra in the period of 380-780 nm visible spectrum of different solar elevation angles during one day in seven representative cities of china's different light climate partitions. The seven representative cities included Kunming, Xining, Beijing, Shenzhen, Nanjing, Nanchang and Chongqing. According to the observation results, this article analyzed the daylight spectrum changing law, compared the daylight spectrum curves of different light climate partitions cities, and summarized the influence factors of daylight spectral radiation intensity. The Analysis of the ground direct daylight spectra showed that the daylight spectral radiation intensity of different solar elevation angles during one day of china's different light climate partitions cities was different, but the distribution and trend of daylight power spectra were basically the same which generally was first increased and then decreased. The maximum peak of spectral power distribution curve appeared at about 475 nm, and there were a steep rise between 380-475 nm and a smooth decline between 475-700 nm while repeatedly big ups and downs appearing after 700 nm. The distribution and trend of daylight power spectra of china's different light climate partitions cities were basically the same, and there was no obvious difference between the daylight spectral power distribution curves and the different light climate partitions. The daylight spectral radiation intensity was closely related to the solar elevation angle and solar surface condition. PMID- 26964234 TI - [Segmentation of Winter Wheat Canopy Image Based on Visual Spectral and Random Forest Algorithm]. AB - Digital image analysis has been widely used in non-destructive monitoring of crop growth and nitrogen nutrition status due to its simplicity and efficiency. It is necessary to segment winter wheat plant from soil background for accessing canopy cover, intensity level of visible spectrum (R, G, and B) and other color indices derived from RGB. In present study, according to the variation in R, G, and B components of sRGB color space and L*, a*, and b* components of CIEL* a* b* color space between wheat plant and soil background, the segmentation of wheat plant from soil background were conducted by the Otsu's method based on a* component of CIEL* a* b* color space, and RGB based random forest method, and CIEL* a* b* based random forest method, respectively. Also the ability to segment wheat plant from soil background was evaluated with the value of segmentation accuracy. The results showed that all three methods had revealed good ability to segment wheat plant from soil background. The Otsu's method had lowest segmentation accuracy in comparison with the other two methods. There were only little difference in segmentation error between the two random forest methods. In conclusion, the random forest method had revealed its capacity to segment wheat plant from soil background with only the visual spectral information of canopy image without any color components combinations or any color space transformation. PMID- 26964235 TI - [Morphology and Spectral Properties Study of LaCeF3:Tb Microcrystalline]. AB - LaCeF3:Tb microcrystalline was synthesized by microemulsion method, oleic acid assisted solvothermal method, ultrasonic-assisted solvothermal method separately. LaCeF3:Tb microcrystalline synthesized by ultrasonic-assisted solvothermal method is rarely reported. Using X-ray diffraction (XRD), scanning electron microscope (SEM), fluorescence spectroscopy (PL) method such as the crystal phase, morphology and luminescence properties of the samples have been characterized. XRD results show that the crystallization product is good, microcrystalline and standard card PDF# 38-0452 (the six-party LaCeF3) is corresponding, SEM images showing the product has uniform size and morphology, under 250 nm excitation nanoparticlesshows strong green light, the main emission peaks respectively belonged to 5D4-->7F6 (489 nm), 5D4-->7F5 (545 nm), 5D4-->7F4 (585 nm) and 5D4- >7F3 (621 nm) transition of Tb3+. Through LaCeF3 and LaCeF3:Tb spectral studies prove the existence of the Ce-Tb energy transfer. Calculated the critical doping concentration of Tb in LaCeF3microcrystalline synthesized by different methods. PMID- 26964236 TI - [Gas Concentration Measurement Based on the Integral Value of Absorptance Spectrum]. AB - The absorptance spectrum of a gas is the basis for the qualitative and quantitative analysis of the gas by the law of the Lambert-Beer. The integral value of the absorptance spectrum is an important parameter to describe the characteristics of the gas absorption. Based on the measured absorptance spectrum of a gas, we collected the required data from the database of HIT-RAN, and chose one of the spectral lines and calculated the integral value of the absorptance spectrum in the frequency domain, and then substituted the integral value into Lambert-Beer's law to obtain the concentration of the detected gas. By calculating the integral value of the absorptance spectrum we can avoid the more complicated calculation of the spectral line function and a series of standard gases for calibration, so the gas concentration measurement will be simpler and faster. We studied the changing trends of the integral values of the absorptance spectrums versus temperature. Since temperature variation would cause the corresponding variation in pressure, we studied the changing trends of the integral values of the absorptance spectrums versus both the pressure not changed with temperature and changed with the temperature variation. Based on the two cases, we found that the integral values of the absorptance spectrums both would firstly increase, then decrease, and finally stabilize with temperature increasing, but the ranges of specific changing trend were different in the two cases. In the experiments, we found that the relative errors of the integrated values of the absorptance spectrum were much higher than 1% and still increased with temperature when we only considered the change of temperature and completely ignored the pressure affected by the temperature variation, and the relative errors of the integrated values of the absorptance spectrum were almost constant at about only 1% when we considered that the pressure were affected by the temperature variation. As the integral value of the absorptance spectrum varied with temperature and the calculating error for the integral value fluctuates with ranges of temperature, in the gas measurement when we usd integral values of the absoptance spectrum, we should select a suitable temperature variation and obtain a more accurate measurement result. PMID- 26964237 TI - [A New Method to Decline the SWC Effect on the Accuracy for Monitoring SOM with Hyperspectral Technology]. AB - Soil organic matter (SOM) is one of the most important indexes to reflect the soil fertility, and soil moisture is a main factor to limit the application of hyperspectral technology in monitoring soil attributes. To study the effect of soil moisture on the accuracy for monitoring SOM with hyperspectral remote sensing and monitor the SOM quickly and accurately, SOM, soil water content (SWC) and soil spectrum for 151 natural soil samples in winter wheat field were measured and the soil samples were classified with the method of traditional classification of SWC and Normalized Difference Soil Moisture Index (NSMI) based on the hyperspectral technology. Moreover, the relationship among SWC, SOM and NSMI were analyzed. The results showed that the accuracy of spectral monitor for SOM among the classifications were significantly different, its accuracy was higher than the soils (5%-25%) which was not classified. It indicated that the soil moisture affected the accuracy for monitoring the SOM with hyperspectral technology and the study proved that the most beneficent soil water content for monitoring the SOM was less 10% and higher 20%. On the other hand, the four models for monitoring the SOM by the hyperspectral were constructed by the classification of NSMI, and its accuracy was higher than the classification of SWC. The models for monitoring the SOM by the classification of NSMI were calibrated with the validation parameters of R2, RMSE and RPD, and it showed that the four models were available and reliable to quickly and conveniently monitor the SOM by heperspectral. However, the different classifiable ways for soil samples mentioned in the study were naturally similar as all soil samples were classified again with another way. Namely, there may be another optimal classifiable way or method to overcome and eliminate the SWC effect on the accuracy for monitoring SOM. The study will provide some theoretical technology to monitor the SWC and SOM by remote sensing. PMID- 26964238 TI - [Determination of Cu in Shell of Preserved Egg by LIBS Coupled with PLS]. AB - In this work, the content of copper in the shell of preserved eggs were determined directly by Laser induced breakdown spectroscopy (LIBS), and the characteristics lines of Cu was obtained. The samples of eggshell were pretreated by acid wet digestion, and the real content of Cu was obtained by atomic absorption spectrophotometer (AAS). Due to the test precision and accuracy of LIBS was influenced by a serious of factors, for example, the complex matrix effect of sample, the enviro nment noise, the system noise of the instrument, the stability of laser energy and so on. And the conventional unvariate linear calibration curve between LIBS intensity and content of element of sample, such as by use of Schiebe G-Lomakin equation, can not meet the requirement of quantitative analysis. In account of that, a kind of multivariate calibration method is needed. In this work, the data of LIBS spectra were processed by partial least squares (PLS), the precision and accuracy of PLS model were compared by different smoothing treatment and five pretreatment methods. The result showed that the correlation coefficient and the accuracy of the PLS model were improved, and the root mean square error and the average relative error were reduced effectively by 11 point smoothing with Multiplicative scatter correction (MSC) pretreatment. The results of the study show that, heavy metal Cu in preserved egg shells can be direct detected accurately by laser induced breakdown spectroscopy, and the next step batch tests will been conducted to find out the relationship of heavy metal Cu content in the preserved egg between the eggshell, egg white and egg yolk. And the goal of the contents of heavy metals in the egg white, egg yolk can be knew through determinate the eggshell by the LIBS can be achieved, to provide new method for rapid non-destructive testing technology for quality and satety of agricultural products. PMID- 26964239 TI - [Study on Contents and Budgets of Cu, Zn and Cd in an Arable Soil Using AAS]. AB - Based on a long-term experiment in Shenyang Experimental Station, the effect of manure application on the contents and budgets of Cu, Zn and Cd in the arable soil was studied. The experiment included four treatments: no mature addition (CK), mature addition 10 t . ha-1 year-1(M1), 25 t . ha-1 year-1 (M2), and 50 t . ha-1 year-1(M3). The result showed that Cu, Zn and Cd in soil were accumulated with manure application and prolongation of experiment, and the accumulative magnitude increased with increasing of manure application. The average annual growth rates of the heavy metals in the four treatments (CK, M1, M2, M3) were 2.83%, 6.56%, 7.54%, 8.96%; 0.03%, 3.44%, 4.53%, 6.64% and 1.51%, 8.01%, 10. 27%, 16. 08% for Cu, Zn and Cd, respectively. After six years of the experiment, the content of Cd in the M3 treatment was quite close to the threshold of Chinese Soil Quality Standard Grade III (1 mg . kg-1, GB15618-1995). After 12 years of the experiment, the contents of Cu in the mature-amended treatments fell in the Chinese Soil Quality Standard Grade III, which should be paid more attention. Although the heavy metals in soil were gradually accumulated, the Cu, Zn and Cd levels in crop grain were still below the National Food Contamination Standards (GB2762-2005; GB13106-91; GB15199-94), indicating the contents of heavy metals in crop produced from contaminated soil might not exceed the corresponding standards. The contents of Cu, Zn and Cd in the straw were much greater than those in the grain. The removal of heavy metal by crop was in the order of M3 > M2 > M1 > CK. The average amounts of Cu, Zn and Cd annually removed from the soil in the four treatments (CK, M1, M2 and M3) were 35.68, 47.80, 63.65, 69.64; 249.14, 375.22, 375.16, 444.44, and 0.83, 1.39, 1.64, 1.66 g . ha-1, respectively. The contents of heavy metals in organic manure varied in different years: the contents of Cu and Zn increased year by year, while Cd presented a decreasing trend. The average amounts of Cu, Zn and Cd annually remained in the soil in the treatments M1, M2 and M3 were 2 283.0, 5 763.7, 11585.4; 2 483.3, 6 771.4, 13 849.2 and 4.8, 13.9, 29.5 g . ha-1, respectively. Since the heavy metals in organic manure markedly fluctuated in different years, the average residuals can only reflect the changing trend. Therefore, the residuals of heavy metals in the soil could be accurately predicted only according to status of manure in a given year. PMID- 26964240 TI - [Matrix Effect of Fe and Ca on EDXRF Analysis of Ce Concentration in Bayan Obo Ores]. AB - When Energy-Dispersive X-RayFluorescence (EDXRF) used for measuring cerium (Ce) content in the Bayan Obo ores, matrix effect mainly comes from iron (Fe) and calcium (Ca). Due to extensive concentration variability of the two elements, commonly employed standard sample method for matrix effect correction is invalid. To overcome the problem, testing samples were prepared based on the average contents of elements in the Bayan Obo ores, and the influence of Fe and Ca on the coefficient in a linear relationship between Ce content and XRF signal was determined by linear least squares fitting for multivariate analysis. The coefficients thus determined reflected the matrix effect on Ce emitted fluorescence from Fe emitted fluorescence and Ca absorption. When the coefficients were used in analyzing Ce content in Bayan Obo mine by EDXRF, the relative error is less than 10%. PMID- 26964241 TI - [The Application of X-Ray Photoelectron Spectroscopy on Refining Catalyst]. AB - Abstract XPS analysis provides qualitative, quantitative and chemical state information for surface elements of solid materials. Therefore, XPS is widely applied in the characterization of refining catalyst. In the present paper, the applications of XPS in the field of typical refining catalysts, including hydrogenation catalyst, S Zorb sorbent and rare-earth modified Y zeolite, are illustrated and exemplified. For sulfided Co (Ni)-Mo (W)/Al2O3(-SiO2) hydrodesulfurization catalysts, the anhydrous oxygen-free transfer process from the reactor to XPS chamber was illustrated. The identification and peak fitting of S(2p) , Mo(3d), W (4f), Co(2p) and Ni(2p) XPS spectra were summarized. The typical chemical states of the active elements were described. Based on these results, the sulfidation extents of the active metals and the cause for the sulfidation inadequency of the catalysts were deduced. As for the application of XPS in S Zorb sorbent, the existence form of zinc was obtained from ZnLMM Auger spectra, and the fracture mechanism and deactivation reason of the sorbent were derived. The distribution of sulfur along the vertical direction was investigated using XPS and argon ion sputtering XPS. Besides, in situ XPS was applied to study the conversion of sulfur- and nickel-containing species for spent sorbent under hydrogen condition. Finally, for cerium modified Y zeolite, the location of cerium ion inside and outside Y zeolite cage was investigated. The results indicate that the liquid phase method is more suitable for the migration of cerium ion toward zeolite as compared with the solid phase method. PMID- 26964242 TI - [Study on Non-Destructive Testing of Guqin Interior Structure Based on Computed Tomography]. AB - The wood property and production process affect quality of Guqin. At the same time, Guqin shape with cavity layout relations to the improvement of Guqin technology and inheritance, so it's very important to get the internal cavity characteristics and parameters on the condition of non-destructive the structure of Guqin. The image of interior structure in Guqin was investigated by overall scanning based on non-destructive testing technology of computed tomography, which texture of faceplate, connection method between faceplate and soleplate and interior defects were studied. The three-dimensional reconstruction of Guqin cavity was achieved through Mimics software of surface rendering method and put the two-dimensional CT tomography images convert into three-dimensional, which more complete show interior structural form in Guqin, and finally the parameter of cavity dimensions was obtained. Experimental research shows that there is significant difference in Guqin interior structure between Zhong-ni and Luo-xia type, in which the fluctuation of the interior surfacein Zhong-ni type's is larger than that in Luo-xia type; the interior volume of Zhong-ni typeis less than that of Luo-xia type, especially in Guqin neck. The accurate internal information of Guqin obtained through the computed tomography (CT) technology will provide technical support for the Guqin manufacture craft and the quality examination, as well as provide the reference in the aspect of non-destructive testing for other traditional precious internal structure research. PMID- 26964243 TI - [A New Distance Metric between Different Stellar Spectra: the Residual Distribution Distance]. AB - Distance metric is an important issue for the spectroscopic survey data processing, which defines a calculation method of the distance between two different spectra. Based on this, the classification, clustering, parameter measurement and outlier data mining of spectral data can be carried out. Therefore, the distance measurement method has some effect on the performance of the classification, clustering, parameter measurement and outlier data mining. With the development of large-scale stellar spectral sky surveys, how to define more efficient distance metric on stellar spectra has become a very important issue in the spectral data processing. Based on this problem and fully considering of the characteristics and data features of the stellar spectra, a new distance measurement method of stellar spectra named Residual Distribution Distance is proposed. While using this method to measure the distance, the two spectra are firstly scaled and then the standard deviation of the residual is used the distance. Different from the traditional distance metric calculation methods of stellar spectra, when used to calculate the distance between stellar spectra, this method normalize the two spectra to the same scale, and then calculate the residual corresponding to the same wavelength, and the standard error of the residual spectrum is used as the distance measure. The distance measurement method can be used for stellar classification, clustering and stellar atmospheric physical parameters measurement and so on. This paper takes stellar subcategory classification as an example to test the distance measure method. The results show that the distance defined by the proposed method is more effective to describe the gap between different types of spectra in the classification than other methods, which can be well applied in other related applications. At the same time, this paper also studies the effect of the signal to noise ratio (SNR) on the performance of the proposed method. The result show that the distance is affected by the SNR. The smaller the signal-to-noise ratio is, the greater impact is on the distance; While SNR is larger than 10, the signal-to-noise ratio has little effect on the performance for the classification. PMID- 26964244 TI - [The Study of PDMS Grating Structure Gradient Preparation Techniques]. AB - Because traditional method for tunable grating fabrication has harsh process condition, complex fabrication process, high costs and long cycle. Proposed a low cost, simple process, can be prepared in large quantities gradient grating process method, based on self-assembly process using the rigid film/flexible substrate and oxygen plasma method prepared a micron scale gradient grating. Use of plasma free time controllability and excellent elastic of PDMS obtained the desired grating. First, polyethylene terephthalate (PET) was spin-coated layer of polydimethylsiloxane (PDMS) film on the thin film, two-layer film to be cured PDMS film after bending and treated with an oxygen plasma (plasma), in generating a rigid surface oxide layer, With flexible PET rigid layer applied uniform stress, when the stress exceeds the critical value, the PDMS substrate to form a self-assembled structure grating fold. Due to changes in prestressed bending, so the PDMS film formation period and height of the grating stepped fold, which is graded grating. Using visible light as the performance test light source for graded grating and selecting first-order diffracted as the detection target. The authors can see the grating has a good diffraction effects and achieves good spectral effect. Experiments show that graded grating has obvious diffraction grating, and the diffraction angle varies significantly, and can be widely used for stress measurement, the flexible gradient grating prepared by this method can also be used to detect changes in the stress strain as a miniature device, the future is expected for miniature spectrometer, scanners, optical communications and other fields. PMID- 26964245 TI - [High Precision Spectral Calibration Method of Fourier Interferometric Spectrometer]. AB - The Fourier interferometric spectrometer (FIS) acquires the interference data information of the spectrum and during the spectrum data processing, a series of spectrum reconstruction will be performed on the interference information to obtain the final spectrum information data. The spectral calibration is the key step to spectrum reconstruction of FIS, which directly determines accuracy and availability of the spectrum results. This paper introduces the basic ideas and calibration accuracy about the spectral calibration for the FIS and puts forward a new spectral calibration method based on calculating the precise value of the total optical path difference (TOPD). The TOPD of FIS is difficult to be precisely measured, but it is the core and key to the spectral calibration. In order to calculate the precise TOPD, this paper proposes the idea how to traverse the TOPD and analyzes the spectrum drift. During the calibration, all the possible values of the TOPD participate in the spectrum reconstruction flow to carry out spectrum recovery and analysis. Ultimately the TOPD with the minimum spectrum drift will be achieved, namely solution value of the TOPD. This method can accurately resolve the TOPD of the FIS and then calibrate the spectrum with high accuracy. In addition, the paper introduces the detailed and complete spectral calibration flow and obtains the center wavelength value of every band and wavenumber resolution. Moreover, the paper designs the main parameters of the typical FIS and generates its simulation interference data. Using the above method to calibrate the simulation data, the analysis and verification of the spectral calibration results proves that the calibration precision of wavenumber resolution achieves 0.000 25 cm-1 or above. PMID- 26964246 TI - Spectrophotometric Methods for Simultaneous Determination of Amlodipine Besylate and Atenolol in Their Tablet Dosage Form. AB - Three simple, specific, accurate and precise spectrophotometric methods are developed for simultaneous determination of amlodipine besylate (AM) and atenolol (AT) in tablets. The first method is dual wavelength spectrophotometry (DW). The second method is ratio subtraction (RS) which depends on subtraction of the plateau values from the ratio spectrum, coupled to first derivative of ratio spectra (1DD). The third method applies bivariate calibration method using 210 and 225 nm as an optimum pair of wavelength for amlodipine and atenolol. The calibration curves are linear over the concentration range of 4-40 ug . mL-1 for both drugs. The specificity of the developed methods is investigated by analyzing laboratory prepared mixtures of the two drugs and their combined dosage form. The two methods are validated as per ICH guidelines and can be applied for routine quality control testing. PMID- 26964247 TI - Measurement of L(III) Subshell Absorption Jump Parameters of Hafnium. AB - The L(III) subshell absorption jump ratio and jump factor of hafnium have been measured using two different ways which are X-ray attenuation method and Energy Dispersive X-ray Fluorescence technique. The results obtained both ways have been compared with theoretical values. They are in good agreement with each other. PMID- 26964248 TI - A New Method for the Determination of Potassium Sorbate Combining Fluorescence Spectra Method with PSO-BP Neural Network. AB - In this paper, fluorescence spectra properties of potassium sorbate in aqueous solution and orange juice are studied, and the result.shows that in two solution there are many difference in fluorescence spectra of potassium sorbate, but the fluorescence characteristic peak exists in lambda(ex)/lambda(em) = 375/490 nm. It can be seen from the two dimensional fluorescence spectra that the relationship between the fluorescence intensity and the concentration of potassium sorbate is very complex, so there is no linear relationship between them. To determine the concentration of potassium sorbate in orange juice, a new method combining Particle Swarm Optimization (PSO) algorithm with Back Propagation (BP) neural network is proposed. The relative error of two predicted concentrations is 1.83% and 1.53% respectively, which indicate that the method is feasible. The PSO-BP neural network can accurately measure the concentration of potassium sorbate in orange juice in the range of 0.1-2.0 g . L-1. PMID- 26964249 TI - Lipid Composition of Native Milk Fat Globules by Confocal Raman Microscopy. AB - Native fat globules composed mainly of triglycerides are secreted as droplets of variable size. The size of fat globules affects the form of fat in dairy products and final functionality, which depends mainly on the composition of the globules and membrane. However, the relation between the composition and size of fat globules has not been studied in detail. In this study, differences in the lipid content and fatty acid composition related to the size of native fat globules were investigated using confocal Raman spectroscopy, which offers the possibility of acquisition and analysis of the Raman signal without disruption of a single fat globule in natural suspension. The results showed small fat globules (SFG) had a higher ratio of band intensities at 2885/2850 cm-1, indicating SFG tend to have a triglyceride core in a fluid state with a milk fat globule membrane in a crystalline state. In addition, the SFG had a higher level of unsaturation compared to large fat globules, shown by a lower ratio at 1655/1443 cm-1. Using cream with selected SFG would allow a harder and more costly churning process but lead to a softer butter. PMID- 26964250 TI - Effect of REAu on Silver Staining Results and Their UV-Vis Absorption Spectra. AB - La, Ce, Nd, Sm, Eu, Gd, Dy particles and gold nanoparticles were prepared. Effects of La-Au, Ce-Au, Nd-Au, Sm-Au, Eu-Au, Gd-Au and Dy-Au particles on silver staining results were studied, respectively, and UV-Vis absorption spectra of La Au, Ce-Au, Nd-Au, Sm-Au, Eu-Au, Gd-Au and Dy-Au particles were studied. Times and colors of sports with La-Au, Ce-Au, Nd-Au, Sm-Au, Eu-Au, Gd-Au, Dy-Au particles are longer and darker than that of with gold nanoparticles, respectively. The time of sport with Nd-Au particles is as long as 30 min, which is 2.7 times as long as with gold nanoparticles. Although amount of gold nanoparticles reduced 80%, the color of sport with Nd-Au particles is darker than that of with gold nanoparticles. In 200.00-800.00 nm, La, Ce, Nd, Sm, Eu, Gd, Dy particles and gold nanoparticles has one absorption peak, respectively, and lambda(max) is 275, 277, 276, 276, 278, 277, 278 and 521 nm, respectively. La-Au, Ce-Au, Nd-Au, Sm-Au, Eu Au, Gd-Au, Dy-Au particles have two absorption peaks, respectively, lambda(max)(RE) and lambda(max) are 276 and 522 nm, 276 and 522 nm, 276 and 523 nm, 276 and 523 nm, 276 and 522 nm, 276 and 522 nm, 276 and 523 nm, respectively. lambda(max) of Au nanoparticles and La particles occurs red moving respectively, and lambda(max) of Ce, Eu, Gd and Dy particles occurs blue moving, respectively, and lambda(max) of Nd and Sm particles is constant respectively. Rare earths particles and gold nanoparticles may have interaction, respectively. PMID- 26964251 TI - Match Solution to the Problem. PMID- 26964252 TI - Bullying and Incivility in Our Health Care Environments. PMID- 26964253 TI - From Solidarity Comes Power--From Power Comes Change. PMID- 26964254 TI - 2015 Legislative Session Review. Staffing Law Improvements Top List of Legislative Successes. PMID- 26964255 TI - Anti-Worker Attacks in 2016 Threaten the Future of Unions for Public Sector Nurses. PMID- 26964256 TI - Building a Better Oregon. PMID- 26964257 TI - Sick Days Law Passes after Four Years of Advocacy. PMID- 26964258 TI - Advocate Profile Lynda Coats, RNC. PMID- 26964259 TI - Organizing for Our Patients. PMID- 26964260 TI - Nurse Assistance Network Conducts a Successful Nurse Peer Advocate Training. PMID- 26964262 TI - Opportunities and Challenges for Clinical Nurse Specialist Practice. PMID- 26964261 TI - Speak up for Safety Has Positive Impact on Chemeketa Community College Student Nurses. PMID- 26964263 TI - The Value of Lifelong Learning. PMID- 26964264 TI - New Resources Improve Members' Experience. PMID- 26964266 TI - Nurses' Role in the Regionalized Hospital. PMID- 26964265 TI - Defending our Voice: Anti-Worker Measures in Oregon. PMID- 26964267 TI - 2016 Legislative Priorities. PMID- 26964269 TI - Teaching the Next Nurse Advocates: Teri Mills, MS, RN, CNE. PMID- 26964268 TI - ONF Education Program Reduces Stigma of Substance Abuse. PMID- 26964270 TI - New Education Chair Brings Team-Based Approach: Nancy Ronan, DNP. PMID- 26964271 TI - Seasonal Influenza Vaccination Effectiveness and Compliance among Hospital Health Care Workers. AB - BACKGROUND: Recent studies show that vaccination of health care workers (HCW) might reduce influenza transmission and mortality among hospitalized patients. No studies have compared the incidence of laboratory-proven influenza in vaccinated versus unvaccinated hospital HCW. OBJECTIVES: To evaluate the effectiveness of influenza vaccination among hospital HCW and to examine the attitudes of this population towards influenza vaccination. METHODS: We performed a prospective cohort study between 1 January and 30 April 2014 of 1641 HCW at our medical center; 733 were vaccinated and 908 were not. A random sample of 199 subjects was obtained: 97 vaccinated and 102 non-vaccinated. Participating individuals were contacted on a weekly basis during the flu season and were asked to report any respiratory or flu symptoms and, if positive, to undergo a polymerase chain reaction (PCR) test for influenza. Results: In the general HCW population vaccination was more frequent among physicians (298/498, 58%) than among nurses (324/862, 38%) and among males than females. Flu symptoms were reported by 20 of 199 participants, 13 in the non-vaccinated group (12.7%) and 7 in the vaccinated group (7.2%). A positive PCR test for influenza A virus was present in 4 of 20 people tested (20%). All positive cases were from the non-vaccinated group (P = 0.0953). CONCLUSIONS: Non-vaccinated HCW showed a higher, although not statistically significant, tendency for contracting laboratory-proven influenza than the vaccinated population. The main reasons for vaccination and non vaccination were personal beliefs and habits. Education efforts are needed to improve compliance. Larger studies could further clarify this issue. PMID- 26964272 TI - Interval Laparoscopic Cholecystectomy: What is the Best Timing for Surgery? AB - BACKGROUND: The timing of interval laparoscopic cholecystectomy continues to be a matter of debate. OBJECTIVES: To evaluate the best timing for performing this procedure after an episode of acute cholecystitis. METHODS: In this retrospective analysis, we divided 213 patients into three groups based on the time that elapsed from an episode of acute cholecystitis to surgery: Group 1: 1-6 weeks, Group II: 6-12 weeks, Group III: > 12 weeks. RESULTS: The mean operative time ranged from 51 to 59 minutes, complication rate 2.6%-5.9%, conversion rate 2.6% 10.8%, length of hospitalization 1.55-2.2 days, and the 30 day readmission rate 2.7%-7.9%. There were no statistically significant differences between the study groups in the primary outcome parameters. CONCLUSIONS: Due to the lack of statistically significant differences between the groups, interval laparoscopic cholecystectomy can be performed safely and without increasing the complication rate within 6 weeks after the acute episode as well as 12 weeks after. However, a trend towards higher conversion and complication rates was observed in Group II (6-12 weeks). PMID- 26964273 TI - Transapical Transcatheter Valve-in-Valve Implantation for Failed Mitral Valve Bioprosthesis. AB - Background: The rate of mitral bioprosthesis implantation in clinical practice is increasing. Transcatheter valve-in- valve implantation has been described for high risk patients requiring redo valve surgery. OBJECTIVES: To report our experience with transapical valve-in-valve implantation for failed mitral bioprosthesis. METHODS: Since 2010, 10 patients have undergone transapical valve in-valve implantation for failed bioprosthesis in our center. Aortic valve-in valve implantation was performed in one of them and mitral valve-in-valve implantation in nine. Mean age was 82 +/- 4 years and 6 were female (67%). Mean time from original mitral valve (MV) replacement to valve-in-valve procedure was 10.5 +/- 3.7 years. Follow-up was completed by all patients with a mean duration of 13 +/- 12 months. RESULTS: Preoperatively, all patients presented with significant mitral regurgitation, two with mitral stenosis due to structural valve failure. All nine patients underwent successful transapical valve-in-valve implantation with an Edwards Sapien balloon expandable valve. There was no in hospital mortality. Mean and median hospital duration was 15 +/- 18 and 7 days respectively. Valve implantation was successful in all patients and there were no major complications, except for major femoral access bleeding in one patient. At last follow-up, all patients were alive and in NYHA functional class I or II. Echocardiography follow-up demonstrated that mitral regurgitation was absent or trivial in seven patients and mild in two. At follow-up, peak and mean gradients changed from 26 +/- 4 and 8 +/- 2 at baseline to 16.7 +/- 3 and 7.3 +/- 1.5, respectively. CONCLUSIONS: Transcatheter transapical mitral valve-in-valve implantation for failed bioprosthesis is feasible in selected high risk patients. Our early experience with this strategy is encouraging. Larger randomized trials with long-term clinical and echocardiographic follow-up are recommended. PMID- 26964275 TI - Bicycle-Related Shoulder Injuries: Etiology and the Need for Protective Gear. AB - BACKGROUND: The popularity of bicycle riding for recreation, exercise and transportation has grown enormously in recent years, which has led to an increased incidence of bicycle-related injuries. While these injuries involve mainly the musculoskeletal system, data on shoulder-specific injuries incurred while bike riding are lacking. Classifying these shoulder injuries may provide insight and assistance in the creation and implementation of effective protective gear and measures. OBJECTIVES: To investigate the types and mechanisms of shoulder injuries among cyclists. METHODS: This study retrospectively examined all cyclists who incurred shoulder injuries while riding and were admitted to the emergency department and shoulder clinic between January 2008 and November 2013. The study included 157 subjects with various bicycle-related shoulder injuries treated with either conservative or surgical measures. RESULTS: Eighty-four percent of injuries were caused by a direct blow to the shoulder, 7% by falling on an outstretched hand, 6% were traction injuries, and 3% were due to hyperabduction. Nine different clinical types of injury were observed; the most common injuries were clavicle fractures (32%), followed by acromioclavicular joint dislocations (22%), rotator cuff tears (22%), and humeral fractures (8%). Fifty-one percent of subjects were managed with conservative care and the remaining patients required surgical interventions. CONCLUSIONS: Shoulder injuries incurred while riding a bicycle span the entire spectrum of shoulder injuries and often result in debilitating conditions. Although the use of helmets is increasing, there is currently no effective protective gear or measures to prevent riders from suffering shoulder injuries. PMID- 26964274 TI - Tricuspid Regurgitation following Lead Extraction: Risk Factors and Clinical Course. AB - BACKGROUND: Transvenous lead extraction can lead to tricuspid valve damage. OBJECTIVES: To assess the incidence, risk factors and clinical outcome of tricuspid regurgitation (TR) following lead extraction. METHODS: We prospectively collected data on patients who underwent lead extraction at the Sheba Medical Center prior to laser use (i.e., before 2012). Echocardiography results before and following the procedure were used to confirm TR worsening, defined as an echocardiographic increase of at least one TR grade. Various clinical and echocardiographic parameters were analyzed as risk factors for TR. Clinical and echocardiographic follow-up was conducted to assess the clinical significance outcome of extraction-induced TR. RESULTS: Of 152 patients who underwent lead extraction without laser before 2012, 86 (56%) (192 electrodes) had echocardiography results before and within one week following the procedure. New or worsening TR was discovered in 13 patients (15%). Use of mechanical tools and younger age at extraction were found on multivariate analysis to be factors for TR development (P = 0.04 and P = 0.03 respectively). Average follow-up was 22.25 +/- 21.34 months (range 8-93). There were no significant differences in the incidence of right-sided heart failure (50% vs. 23%, P = 0.192) or hospitalizations due to heart failure exacerbations (37.5% vs. 11%, P = 0.110). No patient required tricuspid valve repair or replacement. Death rates were similar in the TR and non-TR groups (20% vs. 33%). CONCLUSIONS: TR following lead extraction is not uncommon but does not seem to affect survival or outcomes such as need for valve surgery. Its long-term effects remain to be determined. PMID- 26964276 TI - Ocular Paintball Injuries. AB - Background: One of the most alarming ocular injury trends in recent years has been the proliferation of paintball guns and the proportional increase in the number of ocular eye injuries caused by paintballs. OBJECTIVES: To describe five cases of paintball eye injuries that resulted in loss of functional vision in four of them. METHODS: We conducted a retrospective review of the clinical course in five patients with paintball eye injuries treated in the ophthalmology departments of two medical centers. RESULTS: Five young males were evaluated for paintball injuries caused by blunt trauma. There was one case of full-thickness laceration (globe rupture). Four patients required one to five surgical interventions: three of these involved the removal of traumatic cataract including two eyes with significant zonular dehiscence treated by lens capsule conservation using anchoring devices, one retinal surgery and two glaucoma filtration surgeries. However, final visual outcome was not favorable due to irreversible retinal damage. CONCLUSIONS: Paintball trauma often results in significant ocular injury and loss of functional vision despite successful surgical intervention. Most injuries occur in under-supervised settings and are easily preventable. Improved safety measures, strict regulation enforcement and appropriate public education could prevent such serious damage. PMID- 26964277 TI - Mammographic Breast Density as a Predictor of Radiological Findings Requiring Further Investigation. AB - BACKGROUND: High density breast mammography has been associated with a greater risk for breast cancer and an increased likelihood of false negative results. OBJECTIVES: To assess whether the degree of mammographic breast density correlates with increased risk for the presence of radiographic findings requiring further histological investigation. METHODS: Included in the study were 2760 consecutive screening mammograms performed in a large volume, early detection mammography unit. All mammograms were complemented by high resolution ultrasound and interpreted by a single expert radiologist. Breast density (BD) was evaluated using a semi-quantitative 5 grade scale and grouped into low breast density (LBD) and high breast density (HBD) mammograms. Demographic and all relevant obstetric, personal and family history of breast cancer data were recorded. RESULTS: Of the 2760 mammograms 2096 (76%) were LBD and 664 (24%) were HBD. Mean age of the LBD and HBD groups was 59 +/- 10.5 and 50.9 +/- 9.3 years respectively (P = 0001). Breast density significantly correlated with presence of mammographic findings requiring further histological assessment (8.7% and 12.3% for LBD and HBD respectively, P < 0.01). In women younger than 60 years in whom histological assessment was required due to these findings, malignant pathology was significantly more prevalent in the HBD group (2.3% and 4.1% respectively, P = 0.03). Age, parity, patient history and HBD were identified as independent risk factors for any pathological mammographic finding. CONCLUSIONS: Highly dense mammography, aside from being an indicator of higher risk for breast cancer, appears to be associated with a significantly higher incidence of findings that will prompt further investigation to achieve a definite diagnosis. PMID- 26964278 TI - High Success Rates Using Ultrasound for Neuraxial Block in Obese Patients. AB - BACKGROUND: Successful neuraxial block performance relies on assessment and palpation of surface landmarks, potentially challenging in patients with a high body mass index (BMI). OBJECTIVES: To evaluate the use of ultrasound-assisted neuraxial bock in a non-obstetric population with BMI above versus below 30 kg/m2. METHODS: Healthy adult patients undergoing extracorporeal shock wave lithotripsy (ESWL) under neuraxial block were observed in this quality assurance study. Prior to the neuraxial block, an ultrasound examination was performed to identify the puncture site. Neuraxial anesthesia block was performed under aseptic surgical conditions with the patient in the sitting position. Following block placement, external landmarks were palpated. Our primary study outcome was the number of attempts (skin insertions with the needle) after pre-puncture ultrasound identification of the insertion point, comparing patients with BMI above versus below 30 kg/m2. Our secondary outcome was assessment by palpation of external anatomical landmarks. RESULTS: Our study group included 63 consecutive patients undergoing neuraxial block for ESWL. Data were assessed according to BMI (above versus below 30 kg/m2). An overall success rate at the first attempt of 90.5% (CI 0.8-0.95) was achieved using ultrasound-guided neuraxial block. This block placement success rate was similar for all patients, regardless of BMI above versus below 30 kg/m2. In contrast, the ease of palpation of anatomic landmarks, P = 0.001, and the ease of palpation of iliac crest, P < 0.001, differed significantly between the patients above versus below 30 kg/m2. The reported verbal pain scores (VPS) due to block insertion was similar among all patients regardless of BMI category (above versus below 30 kg/m2). CONCLUSIONS: We observed high success rates when ultrasound-assisted neuraxial block is performed, regardless of BMI above versus below 30 kg/m2, despite expected differences in surface landmark palpation. PMID- 26964279 TI - Fetal Biometry in the Israeli Population: New Reference Charts. AB - BACKGROUND: Selection of appropriate reference charts for fetal biometry is mandatory to ensure an accurate diagnosis. Most hospitals and clinics in Israel use growth curves from the United States. Charts developed in different populations do not perform well in the Israeli population. OBJECTIVES: To construct new reference charts for fetal biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL), using a large sample of fetuses examined at 14-42 weeks gestational age in a medical center and a community ultrasound unit located in two different regions of Israel. METHODS: Data from the medical center and the community clinic were pooled. The mean and standard error of each measure for each week was calculated. Based on these, reference charts were calculated using quantiles of the normal distribution. The performance of the reference charts was assessed by comparing the new values to empiric quantiles. RESULTS: Biometric measurements were obtained for 79,328 fetuses. Growth charts were established based on these measurements. The overall performance of the curves was very good, with only a few exceptions among the higher quantiles in the third trimester in the medical center subsample. CONCLUSIONS: We present new local reference charts for fetal biometry, derived from a large and minimally selected Israeli population. We suggest using these new charts in routine daily obstetric practice. PMID- 26964280 TI - Maternal Sleep Disordered Breathing and Neonatal Outcome. AB - BACKGROUND: It has been suggested that sleep disordered breathing (SDB) during pregnancy may adversely influence maternal as well as fetal well being. OBJECTIVES: To examine the effect of maternal SDB on neonatal neurological examination and perinatal complications. METHODS: Pregnant women of singleton uncomplicated pregnancies were prospectively recruited from a community and hospital low risk obstetric surveillance. All participants completed a sleep questionnaire in the second trimester and underwent ambulatory sleep evaluation (WatchPAT, Itamar Medical, Caesarea, Israel). They were categorized as SDB (apnea hypopnea index > 5) and non-SDB. Maternal and newborn records were reviewed and a neonatal neurologic examination was conducted during the first 48 hours. RESULTS: The study group included 44 women and full-term infants; 11 of the women (25%) had SDB. Mean maternal age of the SDB and non-SDB groups was 32.3 +/- 2.8 and 32.5 +/- 4.7 years, respectively (P = 0.86). Mean body mass index before the pregnancy in the SDB and non-SDB groups was 25.8 +/- 4.7 and 22.0 +/- 2.5 kg/m2, respectively (P = 0.028). No differences were found between infants born to mothers with SDB and non-SDB in birth weight (3353.8 +/- 284.8 vs. 3379.1 +/- 492.4 g), gestational age (39.5 +/- 0.9 vs. 39.2 +/- 1.5 weeks), 5 minute Apgar scores (9.8 +/- 0.6 vs. 9.9 +/- 0.3), and neurologic examination scores (95.2 +/- 3.9 vs. 94.6 +/- 4.1). P value for all was not significant. CONCLUSIONS: Our preliminary results suggest that maternal mild SDB during pregnancy has no adverse effect on neonatal neurologic examination or on perinatal complications. PMID- 26964281 TI - Impact of Androgen Deprivation Therapy on Sexual and Hormonal Function in Patients Receiving Radiation Therapy for Prostate Cancer. AB - BACKGROUND: Androgen deprivation therapy (ADT) added to radiation therapy (RT) in intermediate to high risk prostate cancer negatively impacts quality of life. OBJECTIVES: To compare health-related quality of life (HR-QOL) in patients receiving combined RT with and without ADT METHODS: The study population comprised patients treated with definitive RT for prostate cancer who completed the Expanded Prostate Cancer Index Composite-26 form between 3 and 24 months after completing RT. Covariance and a stepwise backward logistic regression model was used. RESULTS: Data were available for 143 patients who received RT+ADT and 70 who received RT alone. The sexual function and hormonal vitality scores of patients receiving RT+ADT were significantly lower than those receiving RT alone (P < 0.0001). Patients with only compulsory school education had significantly lower sexual function scores than patients with university level education (P <= 0.005). Patients with depression had significantly lower hormonal vitality scores than those without depression (P <= 0.0001). CONCLUSIONS: The addition of ADT to RT is responsible for decrements in quality of life in the sexual and hormonal vitality domains, which is further compounded by depression and lack of education. This underlines the need to improve education, identify and treat depression, and develop strategies to improve the quality of life of patients receiving combination therapy. PMID- 26964282 TI - Autommune Diseases in Low and Middle Income Countries: A Neglected Issue in Global Health. PMID- 26964283 TI - Deep Frostbite: the Question of Adjuvant Treatment. PMID- 26964284 TI - Refractory Hypoparathyroidism in a Child with Celiac Disease. PMID- 26964285 TI - Extracorporeal Cardiopulmonary Resuscitation for Out-of-Hospital Cardiac Arrest. PMID- 26964286 TI - Skin and Visceral Manifestations in Tuberous Sclerosis. PMID- 26964287 TI - Dermographic Urticaria. PMID- 26964288 TI - European Academy of Allergy/Clinical Immunology Annual Congress: View of a Senior Allergist. PMID- 26964289 TI - [Extension of the concept of withdrawal signs]. AB - If the conditions including normal-dose dependence in which withdrawal signs are observed in the absence of definite psychic dependence are classified as dependence, this classification should be regarded as inappropriate extension of the concept of drug dependence. These conditions should be diagnosed as 'withdrawal' as specified by the DSM-5 or ICD-10. Advancements of research have clarified that an increased number of drugs cause withdrawal signs. Some Japanese researchers use the concept of 'withdrawal signs of psychic dependence.' Their definition of drug dependence and concept of withdrawal signs, however, are different from the definition established by the WHO and the researchers specializing in this field. Thus, the concept of 'withdrawal signs of psychic dependence' raises a lot of questions. PMID- 26964290 TI - Psychological Evaluation of Animal-assisted Intervention (AAI) Programs Involving Visiting Dogs and Cats for Alcohol Dependents: A Pilot Study. AB - The purpose of this study was to develop an evaluation method for animal-assisted intervention (AAI) programs involving Mood Check List-Short form.2 (MCL-S.2) and the State-Trait Anxiety Inventory (STAI) for psychiatric daycare of Japanese alcohol. dependents. A total of 36 alcohol dependents completed the study and questionnaires assessing their state. A single session of AAI reduced both subjective and physiological measures of state anxiety (A-State); and this program induced a significant reduction in the anxiety after an AAI program session with the dogs and cats involved in the intervention (p = 0.001). The Wilcoxon t-test showed that there were also significant differences in the "anxiety", "pleasantness", and "relaxation". scores for MCL-S.2 among the alcohol dependents, before and after AAI; a significantly decreased "anxiety" score (p = 0.006), and increased "pleasantness" (p = 0.002) and "relaxation" (p=0.012) scores for MCL-S.2 after AAI. The results of this study indicated that alcohol dependents who experienced a group AAI session-program exhibited significant improvements in their feeling; decreased anxiety, and increased pleasantness and relaxation. PMID- 26964291 TI - [Effectiveness of brief intervention for substance use disorder in Japan--a pilot study]. AB - BACKGROUND: Relatively few hospitals can treat substance use disorder in Japan and the options for treatment are limited. Previous studies in the West have shown the effectiveness of brief intervention for substance use disorder. However, such treatment has not been sufficiently implemented in Japan. For this study, we developed brief intervention tools for substance use disorder, and conducted a pilot study to evaluate the efficacy of treatment. METHODS: Participants in this study were recruited from those admitted for substance use disorder in the addiction treatment unit of Tokyo Metropolitan Matsuzawa Hospital, and the recruitment period was from October 2013 through March 2014. The brief intervention consisted of one 30-min individual session. Four self rating scales measuring motivation, relapse risk and self-efficacy were administered pre- and post-intervention: SOCRATES-8D, Stimulants Relapse Risk Scale, Drug Abuse Self-efficacy Scale and Visual Analogue Scale. RESULTS: Forty patients participated in this study. Subscale Scores at post-intervention that improved significantly compared to those at pre-intervention were Recognition (SOCRATES-8D); Total score and Anxiety and intention to use drug (Stimulants Relapse Risk Scale); Generalized self-efficacy (Drug Abuse Self-efficacy Scale); and Knowledge about drug abuse (Visual Analogue Scale). CONCLUSION: These results indicate that brief interventions may offer effective treatment for substance use disorder. A randomized controlled trial that contains an evaluation of abstinence rate in the follow-up period is needed to ascertain the efficacy of brief intervention for substance use disorder in Japan. PMID- 26964292 TI - [Reliability and validity of the Japanese version of the DAST-20]. AB - OBJECTIVE: Assessing the degree of problems related to drug abuse is important in each treatment setting. The Drug Abuse Screening Test-20 (DAST-20) is a brief, simple 20-item instrument to measure the degree of problems related to drug use. The objective of the present study is to examine the reliability and validity of the Japanese version of the DAST-20. METHODS: We translated the DAST-20 into Japanese using back translation. The anonymous self-administered questionnaire was completed by 310 drug users at the Drug Addiction Rehabilitation Centers (DARC group, n = 113) and at HIV/AIDS regional hospitals (HIV group, n = 197) in Japan. RESULTS: The average DAST-20 score was 7.6 (DARC group = 14.7, HIV group = 2.8). Each item score was highly correlated with the total score (r = 0.45-0.88). A high internal consistency (Cronbach's alpha = 0.95) was observed (men = 0.95, women = 0.84). Overall test-retest reliability was 0.86 (men = 0.85, women = 0.90). The total DAST-20 score was strongly positively correlated with the Severity of Dependence Scale-J score (r = 0.85), but moderately positively correlated with the Alcohol Use Disorders Identification Test score (r = 0.41). In addition, confirmatory factor analysis indicated an acceptable fit to the data (goodness-of-fit index [GFI] = 0.893, adjusted goodness-of-fit index [AGFI] = 0.854, comparative fit index [CFI] = 0.948, root mean square residual [RMR] = 0.008, root mean square error of approximation [RMSEA] = 0.073). CONCLUSION: Our results clearly suggest that the Japanese version of the DAST-20 has sufficient internal consistency and acceptable levels of concurrent validity and construct validity. PMID- 26964293 TI - [Research of Effective Network of Emotion Electroencephalogram Based on Sparse Bayesian Network]. AB - Exploring the functional network during the interaction between emotion and cognition is an important way to reveal the underlying neural connections in the brain. Sparse Bayesian network (SBN) has been used to analyze causal characteristics of brain regions and has gradually been applied to the research of brain network. In this study, we got theta band and alpha band from emotion electroencephalogram (EEG) of 22 subjects, constructed effective networks of different arousal, and analyzed measurements of complex network including degree, average clustering coefficient and characteristic path length. We found that: (1) compared with EEG signal of low arousal, left middle temporal extensively interacted with other regions in high arousal, while right superior frontal interacted less; (2) average clustering coefficient was higher in high arousal and characteristic path length was shorter in low arousal. PMID- 26964294 TI - [Study on Brain Functional Connectivity Using Resting State Electroencephalogram Based on Synchronization Likelihood in Alzheimer's Disease]. AB - Alzheimer's disease (AD) is the most common type of dementia and a neurodegenerative disease with progressive cognitive dysfunction as the main feature. How to identify the early changes of cognitive dysfunction and give appropriate treatments is of great significance to delay the onset of dementia. Some other researches have shown that AD is associated with abnormal changes of brain networks. To study human brain functional connectivity characteristics in AD, 16 channels electroencephalogram (EEG) were recorded under resting and eyes closed condition in 15 AD patients and 15 subjects in the control group. The synchronization likelihood of the full-band and alpha-band (8-13 Hz) data were evaluated, which resulted in the synchronization likelihood coefficient matrices. Considering a threshold T, the matrices were converted into binary graphs. Then the graphs of two groups were measured by topological parameters including the clustering coefficient and global efficiency. The results showed that the global efficiency of the network in full-band EEG was significantly smaller in AD group for the values of T = 0.06 and T = 0.07, but there was no statistically significant difference in the clustering coefficients between the two groups for the values of T (0.05-0.07). However, the clustering coefficient and global efficiency were significantly lower in AD patients at alpha-band for the same threshold range than those of subjects in the control group. It suggests that there may be decreases of the brain connectivity strength in AD patients at alpha band of the resting-state EEG. This study provides a support for quantifying functional brain state of AD from the brain network perspective. PMID- 26964295 TI - [Study on the Optimum Order of Autoregressive Models for Heart Rate Variability Analysis]. AB - Heart rate variability (HRV) analysis technology based on an autoregressive (AR) model is widely used in the assessment of autonomic nervous system function. The order of AR models has important influence on the accuracy of HRV analysis. This article presents a method to determine the optimum order of AR models. After acquiring the ECG signal of 46 healthy adults in their natural breathing state and extracting the beat-to-beat intervals (RRI) in the ECG, we used two criteria, i. e. final prediction error (FPE) criterion to estimate the optimum model order for AR models, and prediction error whiteness test to decide the reliability of the model. We compared the frequency domain parameters including total power, power in high frequency (HF), power in low frequency (LF), LF power in normalized units and ratio of LF/HF of our HRV analysis to the results of Kubios-HRV. The results showed that the correlation coefficients of the five parameters between our methods and Kubios-HRV were greater than 0.95, and the Bland-Altman plot of the parameters was in the consistent band. The results indicate that the optimization algorithm of HRV analysis based on AR models proposed in this paper can obtain accurate results, and the results of this algorithm has good coherence with those of the Kubios-HRV software in HRV analysis. PMID- 26964296 TI - [Group Lasso Penalized Classifier for Diagnosis of Diseases with Categorical Data]. AB - Six kinds of erythemato-squamous diseases have been common skin diseases, but the diagnosis of them has always been a problem. The quantitative data processing method is not suitable for erythemato-squamous data because they are categorical qualitative data. This paper proposed a new method based on group lasso penalized classification for the feature selection and classification for erythemato squamous data with categorical qualitative data. The first categorical data of 33 dimensions were changed by the virtual code, and then 34th dimension age data were discretized and changed by the virtual code. Then the encoded data were grouped according to class group and variable group. Lastly Group Lasso penalized classification was executed. The classified accuracy of 10-fold cross validation was 98.88% +/- 0.002 3%. Compared with those of other method in the literature, this new method is simpler, and better for effect and efficiency, and has stronger interpretability and stronger stability. PMID- 26964297 TI - [An Improved Empirical Mode Decomposition Algorithm for Phonocardiogram Signal De noising and Its Application in S1/S2 Extraction]. AB - In this paper, an improved empirical mode decomposition (EMD) algorithm for phonocardiogram (PCG) signal de-noising is proposed. Based on PCG signal processing theory, the S1/S2 components can be extracted by combining the improved EMD-Wavelet algorithm and Shannon energy envelope algorithm. Firstly, by applying EMD-Wavelet algorithm for pre-processing, the PCG signal was well filtered. Then, the filtered PCG signal was saved and applied in the following processing steps. Secondly, time domain features, frequency domain features and energy envelope of the each intrinsic mode function's (IMF) were computed. Based on the time frequency domain features of PCG's IMF components which were extracted from the EMD algorithm and energy envelope of the PCG, the S1/S2 components were pinpointed accurately. Meanwhile, a detecting fixed method, which was based on the time domain processing, was proposed to amend the detection results. Finally, to test the performance of the algorithm proposed in this paper, a series of experiments was contrived. The experiments with thirty samples were tested for validating the effectiveness of the new method. Results of test experiments revealed that the accuracy for recognizing S1/S2 components was as high as 99.75%. Comparing the results of the method proposed in this paper with those of traditional algorithm, the detection accuracy was increased by 5.56%. The detection results showed that the algorithm described in this paper was effective and accurate. The work described in this paper will be utilized in the further studying on identity recognition. PMID- 26964298 TI - [Research on Reconstruction of Ultrasound Diffraction Tomography Based on Compressed Sensing]. AB - Ultrasound diffraction tomography (UDT) possesses the characteristics of high resolution, sensitive to dense tissue, and has high application value in clinics. To suppress the artifact and improve the quality of reconstructed image, classical interpolation method needs to be improved by increasing the number of projections and channels, which will increase the scanning time and the complexity of the imaging system. In this study, we tried to accurately reconstruct the object from limited projection based on compressed sensing. Firstly, we illuminated the object from random angles with limited number of projections. Then we obtained spatial frequency samples through Fourier diffraction theory. Secondly, we formulated the inverse problem of UDT by exploring the sparsity of the object. Thirdly, we solved the inverse problem by conjugate gradient method to reconstruct the object. We accurately reconstructed the object using the proposed method. Not only can the proposed method save scanning time to reduce the distortion by respiratory movement, but also can reduce cost and complexity of the system. Compared to the interpolation method, our method can reduce the reconstruction error and improve the structural similarity. PMID- 26964299 TI - [Method for Extracting Vascular Perfusion Region Based on Ultrasound Contrast Agent]. AB - Vascular perfusion distribution in fibroids contrast-enhanced ultrasound images provides useful pathological and physiological information, because the extraction of the vascular perfusion area can be helpful to quantitative evaluation of uterine fibroids blood supply. The pixel gray scale in vascular perfusion area of fibroids contrast-enhanced ultrasound image sequences is different from that in other regions, and, based on this, we proposed a method of extracting vascular perfusion area of fibroids. Firstly, we denoised the image sequence, and then we used Brox optical flow method to estimate motion of two adjacent frames, based on the results of the displacement field for motion correction. Finally, we extracted vascular perfusion region from the surrounding background based on the differences in gray scale for the magnitude of the rich blood supply area and lack of blood supply area in ultrasound images sequence. The experimental results showed that the algorithm could accurately extract the vascular perfusion area, reach the precision of identification of clinical perfusion area, and only small amount of calculation was needed and the process was fairly simple. PMID- 26964300 TI - [Research of Feedback Algorithm and Deformable Model Based on Improved Spring mass Model]. AB - A new diamond-based variable spring-mass model has been proposed in this study. It can realize the deformation simulation for different organs by changing the length of the springs, spring coefficient and initial angle. The virtual spring joined in the model is used to provide constraint and to avoid hyperelastic phenomenon when excessive force appears. It is also used for the calculation of force feedback in the deformation process. With the deformation force feedback algorithm, we calculated the deformation area of each layer through screening effective particles, and contacted the deformation area with the force. This simplified the force feedback algorithm of traditional spring-particle model. The deformation simulation was realized by the PHANTOM haptic interaction devices based on this model. The experimental results showed that the model had the advantage of simple structure and of being easy to implement. The deformation force feedback algorithm reduces the number of the deformation calculation, improves the real-time deformation and has a more realistic deformation effect. PMID- 26964301 TI - [Three-dimensional Finite Element Analysis to T-shaped Fracture of Pelvis in Sitting Position]. AB - We developed a three-dimensional finite element model of the pelvis. According to Letournel methods, we established a pelvis model of T-shaped fracture with its three different fixation systems, i. e. double column reconstruction plates, anterior column plate combined with posterior column screws and anterior column plate combined with quadrilateral area screws. It was found that the pelvic model was effective and could be used to simulate the mechanical behavior of the pelvis. Three fixation systems had great therapeutic effect on the T-shaped fracture. All fixation systems could increase the stiffness of the model, decrease the stress concentration level and decrease the displacement difference along the fracture line. The quadrilateral area screws, which were drilled into cortical bone, could generate beneficial effect on the T-type fracture. Therefore, the third fixation system mentioned above (i. e. the anterior column plate combined with quadrilateral area screws) has the best biomechanical stability to the T-type fracture. PMID- 26964302 TI - [Finite Element Analysis of Intravascular Stent Based on ANSYS Software]. AB - This paper adopted UG8.0 to bulid the stent and blood vessel models. The models were then imported into the finite element analysis software ANSYS. The simulation results of ANSYS software showed that after endothelial stent implantation, the velocity of the blood was slow and the fluctuation of velocity was small, which meant the flow was relatively stable. When blood flowed through the endothelial stent, the pressure gradually became smaller, and the range of the pressure was not wide. The endothelial shear stress basically unchanged. In general, it can be concluded that the endothelial stents have little impact on the flow of blood and can fully realize its function. PMID- 26964303 TI - [Combined Probe for Determining Canal Filing Cutting Path]. AB - In order to help a surgeon to determine a proper canal filing cutting path in a hip replacement operation conveniently, this paper presents a kind of probe with combined structure. Firstly, the doctor can use this kind of combined probe to choose canal filing cutting path. Then, the doctor can use computer to guide the surgeon to file femoral cavity along the selected canal filing cutting path. Through hip replacement corpse experiments, filing effects and used time of using combined probe group and separate control group were analyzed. The experiment results showed that the methods introduced in this paper could lower the difficulty of hip replacement operations, improve the implantation of hip stem prostheses further, and reduce the incidence of surgical complications. PMID- 26964304 TI - [Stability Analysis of Susceptible-Infected-Recovered Epidemic Model]. AB - With the range of application of computational biology and systems biology gradually expanding, the complexity of the bioprocess models is also increased. To address this difficult problem, it is required to introduce positive alternative analysis method to cope with it. Taking the dynamic model of the epidemic control process as research object, we established an evaluation model in our laboratory. Firstly, the model was solved with nonlinear programming method. The results were shown to be good. Based on biochemical systems theory, the ODE dynamic model was transformed into S-system. The eigen values of the model showed that the system was stable and contained oscillation phenomenon. Next the sensitivities of rate constant and logarithmic gains of the three key parameters were analyzed, as well as the robust of the system. The result indicated that the biochemical systems theory could be applied in different fields more widely. PMID- 26964305 TI - [Research on Barrier-free Home Environment System Based on Speech Recognition]. AB - The number of people with physical disabilities is increasing year by year, and the trend of population aging is more and more serious. In order to improve the quality of the life, a control system of accessible home environment for the patients with serious disabilities was developed to control the home electrical devices with the voice of the patients. The control system includes a central control platform, a speech recognition module, a terminal operation module, etc. The system combines the speech recognition control technology and wireless information transmission technology with the embedded mobile computing technology, and interconnects the lamp, electronic locks, alarms, TV and other electrical devices in the home environment as a whole system through a wireless network node. The experimental results showed that speech recognition success rate was more than 84% in the home environment. PMID- 26964306 TI - [Software Design for a Portable Ultrasound Bone Densitometer]. AB - In order to meet the requirements of ultrasound bone density measurement, we designed a sofware based on Visual Studio C+ + 2008. The software includes interface design, acquisition and control, data processing and parameter extraction, data storage and printing. Excellent human-computer interface (HCI) will give users a convenient experience. Auto gain control (AGC) and digital filter can improve the precision effectively. In addition, we can observe waveform clearly in real time. By using USB communication, we can send control commands to the acquisition and get data effectively, which can shorten the measuring time. Then we calculated the speed of sound (SOS) and broadband ultrasound attenuation (BUA). Patients' information can be accessed by using XML document. Finally, the software offers printing function. PMID- 26964307 TI - [Exploration Research of Treatment Effect Improvement of Transcutaneous Electrical Nerve Stimulation Using Parameter-changing Chaotic Signal]. AB - This article presents a transcutaneous electric stimulator that is based on chaotic signal. Firstly, we in the study used the MATLAB platform in the PC to generate chaotic signal through the chaos equation, and then we transferred the signal out by data acquisition equipment of USB-6251 manufactured by NI Company. In order to obtain high-power signal for transcutaneous electric stimulator, we used the chip of LM3886 to amplify the signal. Finally, we used the power amplified chaotic signal to stimulate the internal nerve of human through the electrodes fixed on the skin. We obtained different stimulation effects of transcutaneous electric stimulator by changing the parameters of chaotic model. The preliminary test showed that the randomness of chaotic signals improved the applicability of electrical stimulation and the rules of chaos ensured that the stimulation was comfort. The method reported in this paper provides a new way for the design of transcutaneous electric stimulator. PMID- 26964308 TI - [Change of Volume and Mechanical Properties of Femoral Bone in Rabbits at Different Ages with Knee Osteoarthritis under Sand-therapy]. AB - The present paper is aimed to study the effect of sand-therapy with Uyghur medicine on biomechanical properties and femoral bone volume of the femur of osteoarthritis (OA) rabbits at two different ages. In the experiments, we injected Papain through the joint space of right knees into the bodies of New Zealand rabbits (16 in the growing group, and 16 in the mature group), and established an OA model. The 16 rabbits in the mature group were divided randomly into 2 sub-groups: 8 in control group (no sand therapy), and 8 sand-therapy group. The 16 rabbits in the growing group were divided randomly into 2 groups as well: 8 in the control group (no sand therapy), and 8 in the sand-therapy group. We carried out CT scanning four times (1 day before, 13th, 27th and 41st days after the establishment of the model, respectively). After importing the CT data to MIMICS, the different volumes of each sclerotin were recorded and change of the percentage of each sclerotins in total femur bone volume were analyzed. Finally the rabbit femurs were given three-point bending test, the elastic load and the elastic deflection were obtained and the inertia of the section, the maximum bending stresses, the bending modulus of elasticity and the structural rigidity were calculated. The experimental results showed that (1) Compared with 1 day before and 13th day after establishment of model at maturity, the cancellous bone volume increased and cortical bone volume decreased (P < 0.05), but compared with those in the control group, the cancellous bone volume of femurs decrease and cortical bone volume increased under sand-therapy (P < 0.05). Compared with those in the control group, there were no significant changes in the deflection and cross-sectional moment of inertia in the sand-therapy group (P > 0.05), but the maximum bending normal stress, maximum load, elastic modulus, and structural stiffness (P < 0.05) in the sand therapy group were larger than those in the control group. The study showed that sand-therapy in Uyghur medicine has benign effect on bone volume of the OA rabbit femur in two ages and the mechanical properties of the OA rabbit femur at the two ages induced by sand therapy in Uyghur medicine have been improved. PMID- 26964309 TI - [Extraction, Purification and Identification of a Dexamethasone-degrading Enzymes Generated by Pseudomonas Alcaligenes]. AB - In this research a strain of isolated Pseudomonas alcaligenes which causes degradation of dexamethasone was acclimated further and its proteins of every position in the bacterium were separated by the osmotic shock method. The separated intracellular proteins which had the highest enzyme activity were extracted by the salting out with ammonium sulfate and were purified with the cation exchange chromatography and gel chromatography. The purified proteins which was active to cause degradation of dexamethasone had been detected were cut with enzyme and were analyzed with mass spectrometry. The results showed that the degradation rate to dexamethasone by acclimated Pseudomonas alcaligenes were increased from 23.63% to 52.84%. The degrading enzymes were located mainly in the intracellular of the bacteria and its molecular weight was about 41 kD. The specific activity of the purified degrading enzymes were achieved to 1.02 U x mg( 1). Its 5-peptide amino acid sequences were consistent with some sequences of the isovaleryl-CoA dehydrogenase. The protein enzyme may be a new kind degrading enzyme of steroidal compounds. Our experimental results provided new strategies for cleanup of dexamethasone in water environment with microbial bioremediation technique. PMID- 26964311 TI - [Promotion of Pink1S Auto-phosphorylation with CK2beta]. AB - The aim of this study is to determine the regulatory mechanism of PTEN-induced putative kinase protein 1 short isoform (PINK1S) in cytoplasm. By co immunoprecipitation (Co-IP) assay, we identified that PINK1S interacted with the beta regulatory subunit of Casein Kinase 2 (CK2beta), but not with the catalytic subunits CK2alpha1 and CK2alpha2. Furthermore, cells were transfected with PINK1S and CK2beta, and then PINK1S was purified by immunoprecipitation. After detecting the phosphorylated proteins by Phos-tag Biotin, we found that CK2beta overexpression increased auto-phosphorylation of PINK1S. Finally, we generated CK2beta knockdown cell lines by RNA interference. Purified PINK1S from CK2beta knockdown cells significantly reduced its auto-phosphorylation compared with control cells. These results suggested that CK2beta functions as a regulatory subunit of PINK1S kinase complex promoted its activation by self-phosphorylation. PMID- 26964310 TI - [Optimization of Prokaryotic Expression Conditions of Human beta2-microglobulin in E. Coli and Its Purification]. AB - To obtain recombinant human beta2-microglobulin (rhbeta2M) with properties of good solubility and high purity from E. coli, prokaryotic expression conditions were optimized and protein purification was performed in this study. After testing the effect of different IPTG concentrations, temperatures and induction times on the production of rhbeta2M, the optimum expression conditions were determined, i. e. joining IPTG to final concentration being 0.8 mmol/L and inducing time 6 h and at temperature of 25 degrees C. Under the optimum induction conditions, the ratio of soluble rhbeta2M to soluble bacterial protein was 63.7%. After purified by Ni Sepharose 6 Fast Flow, the purity of rhbeta2M achieved a greater value of 95%. Western blot analysis revealed that rhbeta2M possessed the antigen property that specifically interacted with anti-beta2M antibody. PMID- 26964312 TI - [Effect of Conditioned Medium from Endothelial Cells on Cancer Stem Cell Phenotype of Hepatoma Cells]. AB - In this study, we aimed to investigate the influences of conditioned medium from human umbilical vein endothelial cells (HUVEC) on cancer stem cell phenotype of human hepatoma cells. HUVEC and human hepatoma cells (MHCC97H) were cultured, respectively, and then the MHCC97H cells were co-cultured with conditioned medium from HUVEC (EC-CM) with Transwell system. Anti-cancer drug sensitivity, colony formation, migration/invasion ability, expression of cancer stem cell marker and sphere formation were performed to determine the cancer stem cell phenotype in MHCC97H cells. We found that MHCC97H cells co-cultured with EC-CM exhibited significantly higher colony-formation ability and lower sensitivity of anti cancer drugs 5-FU and Cis. Transwell assay showed that treatment with EC-CM obviously increased migration and invasion of MHCC97H cells. Moreover, increased sphere forming capability and expression of CD133 in MHCC97H cells were observed after co-cultured with EC-CM. These results suggested that EC-CM could promote cancer stem cell phenotype of hepatoma cells. PMID- 26964313 TI - [Molecular Image of Superparamagnetic Iron Oxide Nanopariticle Labeled with hATF in Colon Tumor Models]. AB - Urokinase plasminogen activator receptor (uPAR) is a membrane protein which is attached to the cellular external membrane. The uPAR expression can be observed both in tumor cells and in tumor-associated stromal cells. Thus, in the present study, the human amino-terminal fragment (hATF), as a targeting element to uPAR, is used to conjugate to the surface of superparamagnetic iron nanoparticle (SPIO). Flowcytometry was used to examine the uPAR expression in different tumor cell lines. The specificity of hATF-SPIO was verified by Prussian blue stain and cell phantom test. The imaging properties of hATF-SPIO were confirmed in vivo magnetic resonance imaging (MRI) of uPAR-elevated colon tumor. Finally, the distribution of hATF-SPIO in tumor tissue was confirmed by pathological staining. Results showed that the three cells in which we screened, presented different expression characteristics, i. e., Hela cells strongly expressed uPAR, HT29 cells moderately expressed uPAR, but Lovo cells didn't express uPAR. In vitro, after incubating with Hela cells, hATF-SPIO could specifically combined to and be subsequently internalized by uPAR positive cells, which could be observed via Prussian blue staining. Meanwhile T2WI signal intensity of Hela cells, after incubation with targeted probe, significantly decreased, and otherwise no obvious changes in Lovo cells both by Prussian blue staining and MRI scans. In vivo, hATF SPIO could be systematically delivered to HT29 xenograft and accumulated in the tumor tissue which was confirmed by Prussian Blue stain compared to Lovo xenografts. Twenty-four hours after injection of targeting probe, the signal intensity of HT29 xenografts was lower than Lovo ones which was statistically significant. This targeting nanoparticles enabled not only in vitro specifically combining to uPAR positive cells but also in vivo imaging of uPAR moderately elevated colon cancer lesions. PMID- 26964314 TI - [Temporal Pattern of DNA Breaks in Human Ovarian Cancer Cells after Exposure to Nanosecond Electric Pulses]. AB - This study aims to explore the temporal pattern of DNA breaks induced by nanosecond electric pulses (nsEP) in cisplatin-sensitive and cisplatin-resistant human ovarian cancer cells. Human ovarian cancer cells A2780 (cisplatin-sensitive subline) and C30 (cisplatin-resistant subline) were exposed to nsEP. Sham exposed groups were shame exposed to nsEP. Cell viability was determined using CCK-8 assay after 0 h, 4 h, 8 h, 12 h and 24 h, respectively, and the percentage of dead cells was calculated. The DNA break was detected with the alkaline single cell gel electrophoresis (comet assay), and the 75th percentiles of TL (tail length), TM (tail moment) and OTM (Olive tail moment) were measured. Cell viability displayed an early decrease and late increase, with the valley value seen at 8 h. Percentages of cell death and comet-formed in A2780 cells were higher than those in C30 cells (P < 0.05) at 8 h, respectively. TL, TM and OTM in C30 cells were less than those in A2780 cells (P < 0.05). The percentage of comet formed correlated with that of cell death in either A2780 (r = 0.997, P < 0.05) or C30 (r = 0.998, P < 0.05) cells. DNA breaks induced by nsEP in cisplatin sensitive cells differred from that in resistant cells, and DNA break resulted in fraction of cell death. PMID- 26964315 TI - [Effect of the Combination of Xiyanping and Cefazolin on the Function of Neutrophils in Mice]. AB - Xiyanping is used to treat infectious diseases with antibiotics in clinic. The aim of this study is to investigate the mechanism of Xiyanping through studying the effect of the combination of Xiyanping with Cefazolin on the chemotaxis and phagocytic function of peripheral blood neutrophils in mice. Ten healthy mice were in control group. Forty healthy mice in experimental group were infected with staphylococcus aureus, and were randomly divided further into four groups, i. e. model group, Xiyanping group, Cefazolin group and combination group (Xiyanping with Cefazolin). Mice in the control group and model group were given normal saline (NS) through abdomen while those in other groups were given Xiyanping, Cefazolin, and Xiyanping with Cefazolin, respectively. The chemotaxis of peripheral blood neutrophils was detected with the transwell method, and the phagocytic function of peripheral blood neutrophils was analyzed with flow cytometry (FCM). In the present study, there was no significance on the chemotactic index of peripheral blood neutrophils in all the groups (P > 0.05). The actual phagocytotic rate and index of peripheral blood neutrophils in the blank group, Xiyanping group, and the combination group were significantly higher than those of the model group and Cefazolin group (P < 0.05). However, those were not significant in the blank group, Xiyanping group, and the combination group (P > 0.05) or between the model group and Cefazolin group (P> 0.05). Our results suggested the combination of Xiyanping and Cefazolin could enhance the therapeutic effect by improving the phagocytic function of peripheral blood neutrophils. PMID- 26964317 TI - [Comparison Study of Left Ventricular Function Assessment by 18F-FDG PET, Gated SPECT and 2D-Echocardiography in Patients with Myocardial Infarction]. AB - The aim of this study is to analyze the concordance between EDV, ESV and LVEF values derived from 18F-FDG PET, GSPECT and ECHO in patients with myocardial infarction. Sixty-four patients with coronary artery disease (CAD) and myocardial infarction were enrolled in the study. Each patient underwent at least two of the above mentioned studies within 2 weeks. LVEF, EDV and ESV values were analyzed with dedicated software. Statistical evaluation of correlation and agreement was carried out EDV was overestimated by 18F-FDG PET compared with GSPECT [(137.98 +/ 61.71) mL and (125.35 +/- 59.34) mL]; ESV was overestimated by 18F-FDG PET (85.89 +/- 55.21) mL and GSPECT (82.39 +/- 55.56) mL compared with ECHO (68.22 +/ 41.37) mL; EF was overestimated by 18F-FDG PET (41.96% +/- 15.08%) and ECHO (52.18% +/- 13.87%) compared with GSPECT (39.75% +/- 15.64%), and EF was also overestimated by 18F-FDG PET compared with GSPECT. The results of linear regression analysis showed good correlation between EDV, ESV and LVEF values derived from 18F-FDG PET, GSPECT and ECHO (r = 0.643-0.873, P = 0.000). Bland Altman analysis indicated that 18F-FDG PET correlated well with ECHO in the Left ventricular function parameters. While GSPECT correlated well with 18F-FDG PET in ESV, GSPECT had good correlation with Echo in respect of EDV and EF; whereas GSPECT had poor correlation with PET/ECHO in the remaining left ventricular function parameters. Therefore, the clinical physicians should decide whether they would use the method according to the patients' situation and diagnostic requirements. PMID- 26964316 TI - [Effects of Plasmid Fibroblast Growth Factor-2 Magnetic Chitosan Gelatin Microspheres on Proliferation and Differentiation of Mesenchymal Stem Cells]. AB - The purpose of this study is to investigate the effect of superparamagnetic chitosan FGF-2 gelatin microspheres (SPCFGM) on the proliferation and differentiation of mouse mesenchymal stem cells. The superparamagnetic iron oxide chitosan nanoparticles (SPIOCNs) were synthesized by means of chemical co precipitation, combined with FGF-2. Then The SPCFGM and superparamagnetic chitosan gelatin microspheres (SPCGM) were prepared by means of crosslinking emulsion. The properties of SPCFGM and SPIONs were measured by laser diffraction particle size analyser and transmisson electron microscopy. The SPCFGM were measured for drug loading capacity, encapsulation efficiency and release pharmaceutical properties in vitro. The C3H10 cells were grouped according to the different ingredients being added to the culture medium: SPCFGM group, SPCGM group and DMEM as control group. Cell apoptosis was analyzed by DAPI staining. The protein expression level of FGF-2 was determined by Western blot. The proliferation activity and cell cycle phase of C3H10 were examined by CCK8 and flow cytometry. The results demonstrated that both of the SPIOCNs and SPCFGM were exhibited structure of spherical crystallization with a diameter of (25 +/- 9) nm and (140 +/- 12) MUm, respectively. There were no apoptosis cells in the three group cells. Both the protein expression level of FGF-2 and cell proliferation activity increased significantly in the SPCFGM group cells (P < 0.05). The SPCFGM is successfully constructed and it can controlled-release FGF-2, remained the biological activity of FGF-2, which can promote proliferation activity of C3H10 cells, and are non-toxic to the cell. PMID- 26964319 TI - [New Approach of Fundus Image Segmentation Evaluation Based on Topology Structure]. AB - In view of the evaluation of fundus image segmentation, a new evaluation method was proposed to make up insufficiency of the traditional evaluation method which only considers the overlap of pixels and neglects topology structure of the retinal vessel. Mathematical morphology and thinning algorithm were used to obtain the retinal vascular topology structure. Then three features of retinal vessel, including mutual information, correlation coefficient and ratio of nodes, were calculated. The features of the thinned images taken as topology structure of blood vessel were used to evaluate retinal image segmentation. The manually labeled images and their eroded ones of STARE database were used in the experiment. The result showed that these features, including mutual information, correlation coefficient and ratio of nodes, could be used to evaluate the segmentation quality of retinal vessel on fundus image through topology structure, and the algorithm was simple. The method is of significance to the supplement of traditional segmentation evaluation of retinal vessel on fundus image. PMID- 26964318 TI - [Rectovaginal Fistula Stage-one Repair Device Based on Magnetic Compression Technique]. AB - The magnamosis device for stage-one repair of the rectovaginal tistula consists of two arc magnets. Drawing the interrupting thread along the fistula margin via the vaginal side, and pulling the string to arrange the magnets at the fistula base along the long axis of the vagina, we made the magnamosis device automatically clipped to seal the fistula. After removing the threads we kept the device for 2-4 weeks till the natural detachment of it when the compressed tissue in between healed after vascular necrosis. This device utilizing the unique ability of magnamosis to fulfill anastomosis under inflammatory infected state reduces the current high relapse rate and colostomy drawbacks of the conventional rectovaginal neoplasty. PMID- 26964320 TI - [An Algorithm for Correcting Fetal Heart Rate Baseline]. AB - Fetal heart rate (FHR) baseline estimation is of significance for the computerized analysis of fetal heart rate and the assessment of fetal state. In our work, a fetal heart rate baseline correction algorithm was presented to make the existing baseline more accurate and fit to the tracings. Firstly, the deviation of the existing FHR baseline was found and corrected. And then a new baseline was obtained finally after treatment with some smoothing methods. To assess the performance of FHR baseline correction algorithm, a new FHR baseline estimation algorithm that combined baseline estimation algorithm and the baseline correction algorithm was compared with two existing FHR baseline estimation algorithms. The results showed that the new FHR baseline estimation algorithm did well in both accuracy and efficiency. And the results also proved the effectiveness of the FHR baseline correction algorithm. PMID- 26964321 TI - [Research on the Method of Blood Pressure Monitoring Based on Multiple Parameters of Pulse Wave]. AB - In order to improve the accuracy of blood pressure measurement in wearable devices, this paper presents a method for detecting blood pressure based on multiple parameters of pulse wave. Based on regression analysis between blood pressure and the characteristic parameters of pulse wave, such as the pulse wave transit time (PWTT), cardiac output, coefficient of pulse wave, the average slope of the ascending branch, heart rate, etc. we established a model to calculate blood pressure. For overcoming the application deficiencies caused by measuring ECG in wearable device, such as replacing electrodes and ECG lead sets which are not convenient, we calculated the PWTT with heart sound as reference (PWTT(PCG)). We experimentally verified the detection of blood pressure based on PWTT(PCG) and based on multiple parameters of pulse wave. The experiment results showed that it was feasible to calculate the PWTT from PWTT(PCG). The mean measurement error of the systolic and diastolic blood pressure calculated by the model based on multiple parameters of pulse wave is 1.62 mm Hg and 1.12 mm Hg, increased by 57% and 53% compared to those of the model based on simple parameter. This method has more measurement accuracy. PMID- 26964322 TI - [Integrated Development of Full-automatic Fluorescence Analyzer]. AB - In view of the fact that medical inspection equipment sold in the domestic market is mainly imported from abroad and very expensive, we developed a full-automatic fluorescence analyzer in our center, presented in this paper. The present paper introduces the hardware architecture design of FPGA/DSP motion controlling card+PC+ STM32 embedded micro processing unit, software system based on C# multi thread, design and implementation of double-unit communication in detail. By simplifying the hardware structure, selecting hardware legitimately and adopting control system software to object-oriented technology, we have improved the precision and velocity of the control system significantly. Finally, the performance test showed that the control system could meet the needs of automated fluorescence analyzer on the functionality, performance and cost. PMID- 26964323 TI - [Segmentation Method for Liver Organ Based on Image Sequence Context]. AB - In view of the problems of more artificial interventions and segmentation defects in existing two-dimensional segmentation methods and abnormal liver segmentation errors in three-dimensional segmentation methods, this paper presents a semi automatic liver organ segmentation method based on the image sequence context. The method takes advantage of the existing similarity between the image sequence contexts of the prior knowledge of liver organs, and combines region growing and level set method to carry out semi-automatic segmentation of livers, along with the aid of a small amount of manual intervention to deal with liver mutation situations. The experiment results showed that the liver segmentation algorithm presented in this paper had a high precision, and a good segmentation effect on livers which have greater variability, and can meet clinical application demands quite well. PMID- 26964324 TI - [Research Progress of Quantitative Susceptibility Mapping in MRI]. AB - Magnetic susceptibility is an intrinsic physical quantity which describes the relationship between material magnetization and applied external magnetic field. Quantitative susceptibility mapping (QSM) is an MRI technology which can quantify the buck magnetic susceptibility of tissue in vivo. It is particularly effective at elucidating anatomy with paramagnetic or diamagnetic components. QSM technology is a method for solving the ill-pose problem of unconventional de convolution of the measured tissue magnetic field with the unit magnetic dipole field to obtain the susceptibility source map. Many multi orientation scan based QSM and clinically acceptable single orientation QSM methods have been proposed to solve this ill-posed problem. In this paper, the QSM concept is introduced and the various QSM methods are systematically categorized and discussed. The aim of this paper is to summarize the current research progress of QSM, popularize the knowledge of QSM and promote the improvements and the rational application of QSM in clinical field. PMID- 26964325 TI - [Research Progress on the Interaction Effects and Its Neural Mechanisms between Physical Fatigue and Mental Fatigue]. AB - Fatigue is an exhaustion state caused by prolonged physical work and mental work, which can reduce working efficiency and even cause industrial accidents. Fatigue is a complex concept involving both physiological and psychological factors. Fatigue can cause a decline of concentration and work performance and induce chronic diseases. Prolonged fatigue may endanger life safety. In most of the scenarios, physical and mental workloads co-lead operator into fatigue state. Thus, it is very important to study the interaction influence and its neural mechanisms between physical and mental fatigues. This paper introduces recent progresses on the interaction effects and discusses some research challenges and future development directions. It is believed that mutual influence between physical fatigue and mental fatigue may occur in the central nervous system. Revealing the basal ganglia function and dopamine release may be important to explore the neural mechanisms between physical fatigue and mental fatigue. Future effort is to optimize fatigue models, to evaluate parameters and to explore the neural mechanisms so as to provide scientific basis and theoretical guidance for complex task designs and fatigue monitoring. PMID- 26964326 TI - [Research Progress on the Development and Regulation of Embryonic Hematopoietic Stem Cells]. AB - Hematopoietic stem cells (HSCs) are tissue specific stem cells that replenish all mature blood lineages during the lifetime of an individual. Hematopoietic cell clusters in the aorta of vertebrate embryos play a pivotal role in the formation of the adult blood system. Recently, people have learned a lot about the embryonic HSCs on their development and homing. During their differentiation, HSCs are regulated by the transcription factors, such as Runx1 and Notch signaling pathway, etc. MicroRNAs also regulate the self-renewal and differentiation of hematopoietic stem/progenitor cells on the post transcriptional levels. Since the onset of circulation, the formation of HSCs and their differentiation into blood cells, especially red blood cells, are regulated by the hemodynamic forces. It would be of great significance if we could treat hematologic diseases with induced HSCs in vitro on the basis of fully understanding of hemotopoietic stem cell development. This review is focused on the advances in the research of HSCs' development and regulation. PMID- 26964327 TI - [A Review of Methods for Early Evaluation of Alzheimer's Disease]. AB - With the intensified aging problem, the study of age-related diseases is becoming more and more significant. Alzheimer's disease is a kind of dementia, with senile plaques and neurofibrillary tangles as the main pathological features, and has become one of the major diseases that endanger the health of the elderly. This review is concentrated on the research of the early assessment of Alzheimer's disease. The current situation of early diagnosis of the disease is analyzed, and a prospect of the future development of early assessment means of the disease is also made in the paper. PMID- 26964328 TI - [Research Progress of Intestinal Microbiome Detection Method]. AB - Microorganism distributes in the organs of human body which connect with external environment, especially those organs in the gastrointestinal tracts, and it also plays a fundamental role in the physiopathology of the host's body. Because the microorganism is very small and has a great variety, it is difficult to reveal the significance of microorganism in the human physiopathology comprehensively and deeply. With the development of molecular biology, genomics, bioinformatics and other disciplines, the microbiome research will be more possible and easier. There are two key contents of microecology. One of these is to identify and quantify the diversity of microorganism, and the other is to reveal activity and the physiopathological function of microorganism in the host. Microbiome research methods, therefore, can be summarized as the traditional detection methods, construction of gene library, the genetic fingerprint analysis and molecular hybridization techniques and so on. PMID- 26964329 TI - [Research Progress of Automatic Sleep Staging Based on Electroencephalogram Signals]. AB - The research of sleep staging is not only a basis of diagnosing sleep related diseases but also the precondition of evaluating sleep quality, and has important clinical significance. In recent years, the research of automatic sleep staging based on computer has become a hot spot and got some achievements. The basic knowledge of sleep staging and electroencephalogram (EEG) is introduced in this paper. Then, feature extraction and pattern recognition, two key technologies for automatic sleep staging, are discussed in detail. Wavelet transform and Hilbert Huang transform, two methods for feature extraction, are compared. Artificial neural network and support vector machine (SVM), two methods for pattern recognition are discussed. In the end, the research status of this field is summarized, and development trends of next phase are pointed out. PMID- 26964330 TI - [Utilization of Three-dimensional Printing Technology for Manufacture of Artificial Organs]. AB - In this article, we introduce the principle, describe the utilization and discuss the future development of three-dimensional printing technology for manufacturing artificial organs. PMID- 26964331 TI - [Preface for special issue on bioenergy (2015)]. AB - Research and industrial application of bioenergy have developed quickly with the systematic and multifocal trends in recent years. The 4th International Conference on Biomass Energy Technologies-8th World Bioenergy Symposium (ICBT-WBS 2014) and Joint Biomass Energy Symposium of Chinese Renewable Energy Society (CRES) were held in Changsha, China, 17-19 October, 2014, with American Institute of Chemical Engineers (AIChE), Biomass Energy Innovation Alliance, European Biomass Industry Association, AIChE and United Nations Development Programme (UNDP). This special issue on bioenergy is based on selected excellent papers from the submissions, together with free submissions. The special issue consists of reviews and original papers, mainly involving the aspects closely related to the bioenergy and related fields, including resource analyses, pretreatment, fuel/chemicals production, byproduct disposal and strategy investigation. PMID- 26964332 TI - [Trends of microalgal biotechnology: a view from bibliometrics]. AB - Microalgae is a single-cell organism with the characteristics of high light energy utilization rate, fast growth rate, high-value bioactive components and high energy material content. Therefore, microalgae has broad application prospects in food, feed, bioenergy, carbon sequestration, wastewater treatment and other fields. In this article, the microalgae biotechnology development in recent years were fully consulted, through analysis from the literature and patent. The progress of microalgal biotechnology at home and abroad is compared and discussed. Furthermore, the project layout, important achievements and development bottlenecks of microalgae biotechnology in our country were also summarized. At last, future development directions of microalgae biotechnology were discussed. PMID- 26964333 TI - [Transcriptome analysis of bioenergy plant Miscanthus sinensis Anderss by RNA Seq]. AB - Miscanthus sinensis Anderss is a perennial C4-grass. It is a promising bioenergy plant, which has been proposed as general feedstock for biomass and lignocellulosic biofuel production. In this study, the flower and leaf buds transcriptomes of Miscanthus sinensis Anderss were sequenced by the platform of Illumina HiSeq 2000. In total 98 326 Unigenes were generated by de novo assembly with an average length of 822 bp and N50 of 1 023 bp. Based on the NR, NT, Swiss Prot, KEGG, GO and COG databases (Evalue < le-5), 74 134 (75.40%) Unigenes were annotated. A total of 45 507 Unigenes were mapped into different GO terms. In KEGG pathways identification, 36 710 sequences were assigned to 128 KEGG pathways. Sorghum bicolor (37 731, 60.86%), Zea mays (16 258, 26.22%), and Oryza sativa (3 065, 4.94%) showed high similarity to Miscanthus sinensis Anderss. And 24 photosynthesis-related enzyme genes were identified. The result provides a foundation for further characterizing the functional genes in Miscanthus sinensis Anderss. PMID- 26964334 TI - [Effect of pretreatment by solid-state fermentation of sawdust on the pelletization and pellet's properties]. AB - We pretreated sawdust (Castanopsis fissa Rehd.et Wils) by solid state fermentation (SSF) with Phanerochaete chrysosporium, and then compressed it into pellets with the moisture content of 15% and the pressure of 98 MPa, to solve the problem of low density, low Meyer hardness, high water uptake, and short storage period of pellet in the woody pellet industry. We studied the effects of fermentation time on pelletization and pellets's characteristics (including energy consumption, density, Meyer hardness, and hydrophobicity). SSF affected the heating values of pellet. Compared with fresh sawdust, SSF consumed more energy at the maximal value by 6.98% but saved extrusion energy by 32.19% at the maximum. Meanwhile, SSF could improve the density, Meyer hardness and hydrophobicity of pellet. Pellet made of sawdust pretreated by SSF for 48 d had best quality, beneficial for long-term transportation and storage of pellets. PMID- 26964335 TI - [Effects of hot-NaOH pretreatment on Jerusalem artichoke stalk composition and subsequent enzymatic hydrolysis]. AB - In order to explore the possibility of Jerusalem artichoke stalk for bioenergy conversion, we analyzed the main composition of whole stalk, pitch, and core of the stalk. Meanwhile, these parts were pretreated with different NaOH concentrations at 121 degrees C. Afterwards, enzymatic hydrolysis was performed to evaluate the pretreatment efficiency. Jerusalem artichoke stalk was characterized by relatively high lignin content (32.0%) compared with traditional crop stalks. The total carbohydrate content was close to that of crop stalks, but with higher cellulose content (40.5%) and lower hemicellulose (19.6%) than those of traditional crop stalks. After pretreatment, the lignin content in the whole stalk, pitch, and core decreased by 13.1%-13.4%, 8.3%-13.5%, and 19.9%-27.2%, respectively, compared with the unpretreated substrates. The hemicellulose content in the whole stalk, pitch, and core decreased 87.8%-96.9%, 87.6%-95.0%, and 74.0%-90.2%, respectively. Correspondingly, the cellulose content in the pretreated whole stalk, pitch, and core increased by 56.5%-60.2%, 52.2%-55.4%, and 62.7%-73.2%, respectively. Moreover, increase of NaOH concentration for pretreatment could improve the enzymatic hydrolysis of the whole stalk and pitch by 2.3-2.6 folds and 10.3-18.5 folds, respectively. The hydrolysis of pretreated stalk core decreased significantly as 2.0 mol/L NaOH was employed, although the increased NaOH concentration can also improve its hydrolysis performance. Based on these results, hot-NaOH can be regarded as an option for Jerusalem artichoke stalk pretreatment. Increasing NaOH concentration was beneficial to hemicellulose and lignin removal, and consequently improved sugar conversion. However, the potential decrease of sugar conversion of the pretreated core by higher NaOH concentration suggested further optimization on the pretreatment conditions should be performed. PMID- 26964336 TI - [High titer ethanol production from an atmospheric glycerol autocatalytic organosolv pretreated wheat straw]. AB - The expensive production of bioethanol is because it has not yet reached the 'THREE-HIGH' (High-titer, high-conversion and high-productivity) technical levels of starchy ethanol production. To cope with it, it is necessary to implement a high-gravity mash bioethanol production (HMBP), in which sugar hydrolysates are thick and fermentation-inhibitive compounds are negligible. In this work, HMBP from an atmospheric glycerol autocatalytic organosolv pretreated wheat straw was carried out with different fermentation strategies. Under an optimized condition (15% substrate concentration, 10 g/L (NH4)2SO4, 30 FPU/g dry matter, 10% (V/V) inoculum ratio), HMBP was at 31.2 g/L with a shaking simultaneous saccharification and fermentation (SSF) at 37 degrees C for 72 h, and achieved with a conversion of 73% and a productivity of 0.43 g/(L x h). Further by a semi SFF with pre-hydrolysis time of 24 h, HMBP reached 33.7 g/L, the conversion and productivity of which was 79% and 0.47 g/(L x h), respectively. During the SSF and semi-SSF, more than 90% of the cellulose in both substrates were hydrolyzed into fermentable sugars. Finally, a fed-batch semi-SFF was developed with an initial substrate concentration of 15%, in which dried substrate (= the weight of the initial substrate) was divided into three portions and added into the conical flask once each 8 h during the first 24 h. HMBP achieved at 51.2 g/L for 72 h with a high productivity of 0.71 g/(L x h) while a low cellulose conversion of 62%. Interestingly, the fermentation inhibitive compound was mainly acetic acid, less than 3.0 g/L, and there were no other inhibitors detected, commonly furfural and hydroxymethyl furfural existing in the slurry. The data indicate that the lignocellulosic substrate subjected to the atmospheric glycerol autocatalytic organosolv pretreatment is very applicable for HMBP. The fed-batch semi-SFF is effective and desirable to realize an HMBP. PMID- 26964337 TI - [Effects of furfural on the growth and lipid production of oleaginous yeast Rhodotorula glutinis]. AB - In order to illustrate the effects of furfural, one of the most common inhibitory compounds in lignocellulosic hydrolysate, on oleaginous yeast Rhodotorula glutinis, we investigated the effects of different concentrations of furfural (0.1, 0.4, 0.6 and 1.5 g/L) on the biomass and lipid production of R. glutinis, as well as the effects of 1.0 g/L furfural on the utilization of glucose and xylose. Results showed that: when the furfural concentration reached 1.5 g/L, the lag phrase time was extended to 96 h, and the residual glucose was up to 17.7 g/L, with maximum biomass of only 6.6 g/L, which accounted for 47% of that in the basic medium (furfural-free), and the corresponding lipid content was reduced about 50%. Furfural showed lighter inhibitory degree on R. glutinis when xylose acted as the carbon source than glucose was the carbon source; more C18 fatty acids or unsaturated C18 fatty acids were generated in the presence of furfural. PMID- 26964338 TI - [Adsorption mechanism of furfural onto modified rice husk charcoals]. AB - To evaluate the absorptive characteristics of furfural onto biomass charcoals derived from rice husk pyrolysis, we studied the information of the structure and surface chemistry properties of the rice husk charcoals modified by thermal treatment under nitrogen and carbon dioxide flow and adsorption mechanism of furfural. The modified samples are labeled as RH-N2 and RH-CO2. Fresh rice husk charcoal sample (RH-450) and modified samples were characterized by elemental analysis, nitrogen adsorption-desorption isotherms, Fourier-transform infrared spectroscopy and Boehm titration. The results show that fresh rice husk charcoal obtained at 450 degrees C had a large number of organic groups on its surface and poor pore structure. After the modification under nitrogen and carbon dioxide flow, oxygenic organics in rice husk charcoals decompose further, leading to the reduction of acidic functional groups on charcoals surface, and the increase of the pyrone structures of the basic groups. Meanwhile, pore structure was improved significantly and the surface area was increased, especially for the micropores. This resulted in the increase of pi-pi dispersion between the surfaces of rice husk charcoals and furfural molecular. With making comprehensive consideration of pi-pi dispersion and pore structure, the best removal efficiency of furfural was obtained by rice husk charcoal modified under carbon dioxide flow. PMID- 26964339 TI - Biomass fast pyrolysis for bio-oil production in a fluidized bed reactor under hot flue atmosphere. AB - Fast pyrolysis experiments of corn stalk were performed to investigate the optimal pyrolysis conditions of temperature and bed material for maximum bio-oil production under flue gas atmosphere. Under the optimized pyrolysis conditions, furfural residue, xylose residue and kelp seaweed were pyrolyzed to examine their yield distributions of products, and the physical characteristics of bio-oil were studied. The best flow rate of the flue gas at selected temperature is obtained, and the pyrolysis temperature at 500 degrees C and dolomite as bed material could give a maximum bio-oil yield. The highest bio-oil yield of 43.3% (W/W) was achieved from corn stalk under the optimal conditions. Two main fractions were recovered from the stratified bio-oils: light oils and heavy oils. The physical properties of heavy oils from all feedstocks varied little. The calorific values of heavy oils were much higher than that of light oils. The pyrolysis gas could be used as a gaseous fuel due to a relatively high calorific value of 6.5-8.5 MJ/m3. PMID- 26964340 TI - [Pyrolytic depolymerization mechanism of a lignin model compound with alpha-O-4 linkage]. AB - To understand the pyrolysis mechanism of lignin with alpha-O-4 linkage, 4-(3 hydroxy-1-phenoxypropyl)-phenol was selected as an alpha-O-4 type lignin dimer model compound, and its pyrolysis process was studied by density functional theory with M06-2X method at 6-31+G (d,p) level. Equilibrium geometries of the reactant, intermediates, transition states and products were fully optimized. The activation energies in each pyrolysis pathway were calculated. The dimer decomposed mainly through the homolytic cleavage and concerted decomposition of the C(alpha)-O linkage. Pyrolytic products mainly included various phenolic compounds such as phenol, 4-methylphenol, 4-vinylphenol and p-coumaryl alcohol, as well as light compounds such as ethanol, methanol and formaldehyde. Pyrolytic depolymerization process has its potential in biomass-based fuels. PMID- 26964341 TI - [Automatically feeding strategy for 1,3-propanediol fermentation of Klebsiella pneumoniae LDH526]. AB - 1,3-propanediol is an important chemical used as building block for the synthesis of highly promising polyesters such as polytrimethylene terephthalate. A genetically modified Klebsiella pneumoniae LDH526 can use glycerol as sole carbon source and produce 1,3-propanediol with the titer above 90 g/L. A key factor affecting the production of 1,3-propanediol by the mutant K. pneumoniae is the accurate control of the feeding of glycerol. To generate a robust and reproducible fermentation process of 1,3-propanediol, we designed and optimized an automatically feeding strategy of glycerol based on fermentation kinetics. By coupling the substrate feeding rate with easily observed variables -pH and fermentation time, we have achieved self-starting glycerol feeding and dynamic control of the glycerol concentration during the fermentation process. This automated system allowed us to generate a reproducible, consistent and operator independent process from lab-scale to production scale. The final concentration of 1,3-propanediol was above 95 g/L after 72 h. PMID- 26964342 TI - [Influence of Professional Contact with Plutonium-239 on Indicators of the Immune Status of the Personnel at Siberian Chemical Plant]. AB - The results of the examination and monitoring of the personnel at the Siberian Chemical Plant (SChP) and adult population of Seversk are presented. The results of primary examination of the personnel who professionally contact the ionizing radiation (IR) from external sources and incorporated 239Pu showed that clinical symptoms of dysfunction of the immune system manifested themselves with a frequency of 75.30%. Infectious-inflammatory diseases (46.95%) and the combined pathology of infectious and allergic character (20.12%) were the most widespread. The allergic diseases (AD) without manifestations of an infectious component were observed not often (7.62%). The monitoring which was carried out for 10 years revealed a decrease in a percentage of persons with clinical signs of disorders of the immune system up to 60.68% among the personnel at the Chemical-Steel Plant and even more among the whole group of the studied personnel at SChP--49.68% (389 : 783). Among the population their frequency made up 51.78%. Features of clinical manifestations of dysfunction ofthe immune system depending on accumulation of 239Pu in the organism are established. Similar dynamics of infectious and infectious and allergic syndromes is revealed when the activity of 239Pu is 40 nCi. AD frequency reliably increased .when the activity of 239Pu is 20 nCi, but if accumulation is higher than 20-40 nCi it decreases and again increases when the activity is over 40 nCi. Pathologies of infectious and allergic genesis are most often observed when the content of 239Pu in an organism is over 40 nCi. Indicators of the immune status (IS) of the personnel at SChP with incorporated 239Pu are analyzed. 59 people--carriers of 239Pu and 408 people without 239Pu accumulated in an organism are examined. In comparison with the control, IS indicators characteristic for all dose loading groups are revealed: increase of lymphocytes, existence of dissociation in indicators of relative and absolute values of the T-cellular link, CD16+56+(-) NK-cells and B-lymphocytes with increase of absolute values, decrease in markers of activation of HLA-DR+ and CD95+, increase of B-lymphocytes and low level of serum IgM. Features of IS in comparison with the group of the personnel with the absence of 239Pu in an organism and indicators of IS which depend on the activity of 239Pu are established. Among them are a decrease in the percentage of persons with increased number of lymphocytes with increased beam loading; increase of NK-T cells when the activity of 239Pu is 10-20 nCi and the highest value at doses over40 nCi; the dynamics of CD16+56(+)-lymphocytes with the increase of the contents and a percentage of persons with the increase of the activity above 40 nCi; the highest frequenc of a regulatory imbalance with high frequency decrease of CD8(+)-T-lymphocytes at the content of 239Pu > 0-10 nCi; decrease in indicators of B-lymphocytes and serum IgA with an increase in the activity of 239Pu with the lowest values under internal radiation over 40 nCi; decrease in the percentage of persons with a weakening expression of HLA-DR+ with the increase in dose loading. PMID- 26964343 TI - [Comparative Evaluation of Healing Wounds at a Local and Combined Radiation Injury in an Experiment]. AB - Wound healing activity of 20 different means of conservative treatment of radiation burns was studies in the experiments on the rats subjected to local beta-radiation (at a dose of 60 Gy) and combined radiation damage (beta-radiation at a dose of 60 Gy and the whole-body gamma-irradiation at a dose of 4 Gy). It was found that reparative processes in the irradiated,skin in the case of the local radiation injuries are most effectively accelerated by ointments Biopin, Panthenol-Ratiopharm, IL-1beta and Iruksol; Dimexidum solution; aerosols Olazol, Gipozol and Polkortolon; wound coverings Procell-super and Selenopol. Ointments containing IL-1beta, Dimexidum solution, aerosols and wound coverings have a healing effect in the case of combined radiation injury. PMID- 26964344 TI - [The Combined Effects of Ionizing Radiation and Dendritic Polymers Loaded with Doxorubicin on the MCF-7 Breast Cancer Cell Line]. AB - The dendritic polymers (dendrimers) are perspective nanocontainers for transportation of anticancer drugs into cells and a controlled release of the delivered substances. However, the combined effect of ionizing radiation and dendrimers loaded with anticancer drugs has been poorly studied and is the aim of this research. We used poliamidoamin (PAMAM) dendrimers of the second generation (G2) covalently conjugated with doxorubicin (Dox) via an acid labile linker, cis aconitic anhydride. We compared the intracellular accumulation of Dox and growth rate of the MCF-7 cell culture under the single and combined action of ionizing radiation at a dose of 4 Gy, free Dox and G2-Dox. It was found that within 2 hours free Dox accumulated in cancer cells better than Dox connected with G2 dendrimers (p < 0.05 in the concentration range of 1-5 MUmol/l). The intracellular accumulation of Dox was higher by 1.7 times for the free Dox than that connected with dendrimers (for concentration 0.5 MUmol/l p = 0.02) after 26 hours of incubation. Like the intracellular accumulation of Dox, inhibition of the cell culture growth was more pronounced when using free Dox than G2-Dox in the case of both a single and combined action of these drugs. Subadditivity effects of the combined action of both drugs and ionizing radiation are shown in terms of reducing the number of tumor cells 24 hours after irradiation. The results indicate the need for further development of selective delivery systems for Doxin tumor cells, providing a more intense accumulation of anticancer drug in target cells. PMID- 26964345 TI - [Effects of Intensity of Acting Agents on the Manifestation of Synergistic Interaction]. AB - The universal dependence of the synergistic interaction on the intensity of the acting agents was demonstrated. This dependence is not associated with the biological object, as well as the nature of the physical or chemical agents used in the combined exposures. In all cases, with a decrease in the intensity of one of the agents the intensity of the other factor should be also decreased to ensure the greatest synergistic effect. Such relationship of synergy and the intensity of the acting agents is of interest for radiation safety. This regularity indicates the principal possibility of synergistic interaction of harmful environmental factors actually occurring in the biosphere at their low intensities. PMID- 26964347 TI - [Structural and Functional Modifications of Human Lymphocytes in Dynamics of UV Induced Development of Their Apoptosis]. AB - The flow-cytometric analysis of condition of human peripheral blood lymphocytes in dynamics of development of the apoptosis induced by exposure to UV-light (240 390 nanometers) at a dose of 1510 J/m2 was carried out. Superficial architectonics and changes of the level of a membrane potential and functional activity of succinatedehydrogenase of mitochondrions are studied. The contribution of extracellular calcium to the processes of lymphocyte cellular death is revealed. The ideas about dynamics of the intracellular events leading to the death of photomodified lymphocytes 1-6 h after their UV-radiation exposure are specified and added on the basis of the analysis of our new and already published results. PMID- 26964346 TI - [Modification of Barley Development at Early Stages after Exposure of Seeds to gamma-Irradiation]. AB - The reaction of barley seeds (Nur and Grace varieties) to gamma-irradiation in the dose range of 2-50 Gy was studied. The length and weight of a root, the length of a seedling and germination rate were investigated. The dose range in which we observed stimulation of plant development was evaluated. It was shown that the increase of root and seedling sizes after irradiation of seeds at stimulating doses is associated with the rise in the developmental speed, rather than with their earlier germination. Also the effects of a dose rate, a quality of seeds, humidity and a period of storage on the manifestation of radiation exposure were studied. PMID- 26964348 TI - [Effect of Low-Intensity 900 MHz Frequency Electromagnetic Radiation on Rat Brain Enzyme Activities Linked to Energy Metabolism]. AB - The research deals with the effect of low-intensity 900 MHz frequency electromagnetic radiation (EMR), power density 25 MUW/cm2, on the following rat brain and blood serum enzyme activities: creatine kinase (CK), playing a central role in the process of storing and distributing the cell energy, as well as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) that play a key role in providing the conjunction of carbohydrate and amino acid metabolism. The comparative analysis of the changes in the enzyme activity studied at different times following the two-hour single, as well as fractional, radiation equivalent of the total time showed that the most radiosensitive enzyme is the brain creatine kinase, which may then be recommended as a marker of the radio frequency radiation impact. According to the analysis of the changing dynamics of the CK, ALT and AST activity level, with time these changes acquire the adaptive character and are directed to compensate the damaged cell energy metabolism. PMID- 26964349 TI - [The Patterns of Behavior of Radioactive Particles in the Food Chain of Cattle and Transport in the Gastrointestinal Tract of Animals]. AB - The analysis of the patterns of behavior of polydisperse radioactive silicate particles in the components of the food chain of cattle is presented. It is shown that the composition of the size distribution of radioactive particles taken into animal organisms differs from the original composition of the particles deposited on the surface of pasture vegetation, and from dispersion of the particles in the aboveground biomass of vegetation at the time of grazing. The intake of particles into animal organisms is reduced with the increase of their size, and for the particle fraction of 400-800 microns it is about 10 times less than for the fine fraction (< 100 microns). The mathematical compartment model ofthe transport of polydisperse radioactive particles in the digestive tract of cattle has been developed. It is found that the elimination rate of radioactive particles from the animal organism depends on their sizes. Deposition of particles on the fundic surface of the wall ventral sac of rumen and reticulum as well as their long stay in comparison with the chyme in abomasum was noted. The maximum levels of irradiation are formed in these parts of the digestive tract of cattle. PMID- 26964350 TI - [Accumulation of 238, 239 + 240Pu and 241Am in Boar Organs and Tissues on the Territory of the Belarusian Part of the ChNPP Exclusion Zone]. AB - The paper is devoted to determination of alpha-emitting radionuclides of 238, 239 + 240Pu and 241Am in liver, lungs, muscular and bone tissues of the boars on the territory of the Belarusian part of the ChNPP exclusion zone. It is shown that the content of Pu and Am isotopes in boar organs and tissues decreases in the following order: liver > bone tissues > lungs >= muscular tissues. The results received allow evaluation of penetration of 238, 239 + 240Pu and 241Am through the biological chain "soil-ration-organs and tissues". It is calculated that 1.7% of a boar's ration falls on the soil getting into the stomach with food. Translocation and accumulation coefficients characterizing the transfer of radionuclides through the chain "soil-vegetation-organs and tissues" were calculated. The conclusion about accumulation of Pu in the boar's body is made. PMID- 26964351 TI - [Specific Features of Radioactive Pollution of Soils of Catchment Areas of Lake Shablish (Distant Zone of the East Ural Radioactive Trace)]. AB - Specific features of 90Sr and 137Cs distribution and accumulation in soil cuts of superaqueous and eluvial positions of catchment areas of Lake Shablish located in a distant zone of the East Ural radioactive trace are considered. Some physical and chemical characteristics of the soils were defined. It is established that the signs typical for the lake ecosystems of distant East-Ural radioactive trace zone which underwent impact of technogenic influence are common for soils of catchment areas of Lake Shablish. The distinctions in some characteristic features of the specific activity of long-living radionuclides for the soils of superaqueous and eluvial positions of catchment areas connected with the character of the water regime of soils are shown. PMID- 26964352 TI - [Study on Tritium Content in Soil at Sites of Nuclear Explosions on the Territory of Semipalatinsk Test Site]. AB - As a result of investigations carried out on the territory of Semipalatinsk Test Site, tritium was found in different environmental objects--surface and ground waters, vegetation, air environment, and snow cover. The analysis of the data obtained has shown that contamination of environmental objects at the Semipalatinsk Test Site with tritium is associated with the places where underground nuclear tests were performed. Since tritium can originate from an activation reaction and be trapped by pock particles during a test, it was decided to examine the soil in the sites where surface and excavation tests took place. It was found that the concentration of tritium in soil correlates with the concentration of europium. Probably, the concentration of tritium in the soil depends on the character and yield of the tests performed. Findings of the study have revealed that tritium can be found in soil in significant amounts not only in sites where underground nuclear tests took place but also in sites where surface and excavation nuclear tests were carried out. PMID- 26964353 TI - [Multi-Species Biofilms in Ecology, Medicine, and Biotechnology]. AB - The structure, composition, and developmental patterns of multi-species biofilms are analyzed, as well as the mechanisms of interaction of their microbial components. The main methodological approaches used for analysis of multi-species biofilms, including omics technologies, are characterized. Environmental communities (cyanobacterial mats and methanotrophic communities), as well as typical multi-species communities of medical importance (oral cavity, skin, and gut microbiomes) are described. A special section deals with the role of multi species biofilms in such biotechnological processes as wastewater treatment, heavy metal removal, corrosion control, and environmental bioremediation. PMID- 26964354 TI - [Surviving Forms in Antibiotic-Treated Pseudomonas aeruginosa]. AB - Survival of bacterial populations treated with lethal doses of antibiotics is ensured by the presence of very small numbers of persister cells. Unlike antibiotic-resistant cells, antibiotic tolerance of persisters is not inheritable and reversible. The present work provides evidence supporting the hypothesis of transformation (maturation) of persisters of an opportunistic pathogen Pseudomonas aeruginosa revealed by ciprofloxacin (CF) treatment (25-100 MUg/mL) into dormant cystlike cells (CLC) and non-culturable cells (NC), as was described previously for a number. of non-spore-forming bacteria. Subpopulations of type 1 and type 2 persisters, which survived antibiotic treatment and developed into dormant forms, were heterogeneous in their capacity to form colonies or microcolonies upon germination, in resistance to heating at 70 degrees C, and in cell morphology Type 1 persisters, which were formed after 1-month incubation in the stationary-phase cultures in the medium with decreased C and N concentrations, developed in several types of surviving cells, including those similar to CLC in cell morphology. In the course of 1-month incubation of type 2 persisters, which were formed in exponentially growing cultures, other types of surviving cells developed: immature CLC and L-forms. Unlike P. aeruginosa CLC formed in the control post-stationary phase cultures without antibiotic treatment, most of 1-month persisters, especially type 2 ones, were characterized by the loss of colony-forming capacity, probably due to transition into an uncultured state with relatively high numbers of live intact cells (Live/Dead test). Another survival strategy of P. aeruginosa populations was ensured by a minor subpopulation of CF-tolerant and CF-resistant cells able to grow in the form of microcolonies or regular colonies of decreased size in the presence of the antibiotic. The described P. aeruginosa dormant forms may be responsible for persistent forms in bacteria carriers and latent infections and, together with antibiotic-resistant cells, are important as components of test systems to assay the of efficiency of potential pharmaceuticals against resistant infections. PMID- 26964355 TI - [Effect of Inherent Immunity Factors of Development of Antibiotic Tolerance and Survival of Bacterial Populations under Antibiotic Attack]. AB - Effect of human inherent immunity factors of, a gene-encoded antibacterial peptide indolicidin (Ind) and a cytokine interleukin 1 (IL1) on formation of antibiotic-tolerant persister cells surviving in the presence of ciprofloxacin (Cpf, 100 MUg/mL) and ampicillin (Amp, 100 MUg/mL) in submerged bacterial cultures (Staphylococcus aureus FGA 209P, Escherichia coli K12, and Pseudomonas aeruginosa PAO1) was studied. While Ind in physiological concentrations (0.3 and 3.0 MUg/mL) introduced to the lag- or exponential-phase cultures of test organisms exhibited no reliable effect on population growth, the number of persisters increased at 3.0 MUg/mL. Bactericidal Ind concentrations (9 MUg/mL) suppressed S. aureus growth (-0.1% of surviving cells) with subsequent recovery due to development of the more antibiotic-tolerant white variant. Treatment with Cpf after Ind addition resulted in mutual potentiation of their antimicrobial activity, with the number of S. aureus persisters 2 to 3 orders of magnitude lower than in the case of the antibiotic alone. IL1, another immunity factor, when introduced (0.1-1 ng/mL) to the exponentially growing S. aureus culture (but not to the lag phase culture) had a temporary growth-static effect, with the number of persisters surviving Cpf treatment (100 MUg/mL) increasing by 1 to 2 orders of magnitude. Electron microscopy revealed significant alterations in the outer cell envelope layer of surviving S. aureus cells, which should be associated with their changed antigenic properties. Thus, the factors of human inherent immunity have a dose-dependent effect on the growth of bacterial populations. In combination with antibiotics, they exhibit synergism of antimicrobial action (indolicidin) and minimize (indolicidin) or increase (interleukin 1) the frequency of formation of persister cells responsible for survival of a population subjected to an antibiotic attack. PMID- 26964356 TI - [Effect of Distant Interactions on Growth and Development of Streptomycetes]. AB - Regulation of streptomycete growth and development by distant interactions of physical nature was shown using a vial-in-vial experimental setup, providing physical isolation of the inducer and detector cultures. Some effects of distant interaction were observed with Streptomyces netropsis proliferating submerged culture as an inducer and a surface culture of the same strain as a detector. The growth rate of the detector strain doubled. Spore germination was stimulated, as was indicated by a 30% increase in the number of colony-forming units (CRU) in the detector culture plated as a spore suspension. The phase variation spectrum also changed, with an increased share of the colonies of the morphotype predominant under the standard conditions. PMID- 26964357 TI - [Characterization of the Lipopolysaccharides of Pseudomonas chlororaphis]. AB - Lipopolysaccharides (LPS) from two strains ot Pseudomonas chlororaphis subsp. aureofaciens,UCM B-111 and UCM B-306, were isolated and characterized. The LPS preparations exhibited low toxicity, high pyrogenicity and high antiviral activity. Mild acid hydrolysis was used to obtain the O-specific polysaccharides. Their structures were established by monosaccharide analysis and determination of absolute configurations, as well as by 1D and 2D NMR spectroscopy. The O polysaccharides were shown to contain the linear tri- or tetrasaccharide repeating units. Both O-polysaccharides were structurally heterogeneous: P. chlororaphis subsp. aureofaciens UCM B-111--> 4)-alphaD-GalpNAc6Ac-(1 --> 3)-beta D-QuipNAc-(1 --> 6)-alphaD-GlcpNAc-(l --> betaD-GlcpNAc-(l --> 3)] GalNAc -60%; degree of the non-stoichiometric 6-O-acetylation of GalNAc -60%; P. chlorophis subsp. aureofaciens UCM B-306 --> 3)-alpha-D-Rhap-(1 --> 4)-alpha-D-GalpNAcAN-(1 -> 3)-alphaD-QuipNAc4NAc-(1 -->, where GalNAcAN is 2-acetamido-2-deoxy-D galacturonamide, the degree of non-stoichiometric amidation of the GalNAcA residue -60%. PMID- 26964358 TI - [Ligninolytic Activity of Bacteria of the Genera Azospirillum and Niveispirillum]. AB - Capacity of associative soil bacteria of the genera Azospirillum and Niveispirillum for degradation of lignin model compounds was demonstrated. Lignin and Mn-peroxidases were detected in the culture liquid of the type strains of these genera. The data on involvement of nonspecific bacterial peroxidases in lignin degradation were obtained. PMID- 26964359 TI - [Functionality of the xoxF Gene in Methylobacterium dichloromethanicum DM4]. AB - Activation of expression of the xoxFgene encoding PQQ-dependent methanol/ethanol dehydrogenase (METDI2492) in dichloromethane- (DCM) -grown Methylobacterium dichloromethanicum DM4 was first demonstrated. The sequence of the only XoxF homolog found in the genome of strain DM4 exhibited 50% identity to that of the protein (MxaF) of the large subunit of methanol dehydrogenase (MDH). A knockout mutant with the inactivate xoxF gene (DeltaxoxF) was found to be unable to grow on methanol due to the absence of the expression of the gene cluster of the classical MDH, as was confirmed by the GFP test. When grown of succinate, the DeltaxoxF mutant exhibited a lower growth rate on DCM than the original strain and was more sensitive to various stress factors (oxidative, osmotic, and heat shock). Based on these data, the xoxF gene was hypothesized to belong to a group of genes affecting expression of the proteins of general stress response. PMID- 26964360 TI - [Role of Bacterial Adhesin RAPA1 in Formation of Efficient Symbiosis of Rhizobium leguminosarum with Bean Plants]. AB - Bacterial adhesins, the proteins responsible for attachment of plant growth promoting rhizobacteria to plant roots, are involved in formation of stable associative symbioses. In the present work enhanced expression of the rapA1 adhesin gene in Rhizobium leguminosarum PVu5 was shown to improve the efficiency of nodulation on bean roots inoculated with the modified strain. The rapA1 gene was cloned into the pJN105Turbo plasmid, this construct was used for transformation of R. leguminosarum PVu5, bean plants were inoculated by this transgenic strain, and efficiency of root nodule formation was determined. In the plants treated with rapA1-transgenic rhizobia, the number of root nodules was on average two times higher than in the plants inoculated with the original strain. Aggregation of R. leguminosarum was achieved when the rapA1 gene expression was enhanced either in rhizobia or in the co-cultured modified strain E. coli pJN105TurboRapA1. PMID- 26964361 TI - [Monitoring of the Moskva River Water Using Microbiological Parameters and Chlorophyll a Fluorescence]. AB - The results of investigations of three Moskva River sites with different degree of pollution using a complex of microbiological characteristics and the parameters of chlorophyll a fluorescence are presented. We determined that the bacterioplankton seasonal dynamics at less polluted waters (Tushino and Vorobyovy Gory) were similar and differed significantly from one in more polluted waters (Dzerzhinskii). The number of bacteria with active electron transport chain, as well as their share in the bacterioplankton structure, was higher in the water of Dzerzhinskii (average annual values of 0.23 x 10(6) cells/mL and 14%), that in the less polluted water of Tushino and Vorobyovy Gory (0.14 x 10(6) cells/mL; 6% and 0.15 x 10(6) cells/mL; 7%, respectively). From April to October, the content of chlorophyll a and its photosynthetic activity were the highest in Tushino. In Dzerzhinskii, during spring the increase in photosynthetic activity commenced earlier and was more intensive that the increase in chlorophyll a content, i.e., the increase in phytoplankton biomass was temporarily suppressed. We suggest association of this phenomenon with suppression of organic matter synthesis by phytoplankton due to the high water pollution in Dzerzhinskii. The second autumn peak of chlorophyll a content, that was typical of clear water and was observed in Tushino, did not occur in Dzerzhinskii. We recommend combined application of these microbiological parameters and characteristics of chlorophyll a fluorescence for a monitoring. PMID- 26964363 TI - [Analysis of Phytoplankton in Tsimlyansk Reservoir (RUSSIA) for the Presence of Cyanobacterial Hepato- and Neurotoxins]. AB - Although the water bodies of southern Russia experience the most extreme effects of cyanobacterial blooms, molecular genetic data on the composition of toxigenic cyanobacteria in this region have been absent. Screening for the genes responsible for the synthesis of hepatotoxins (microcystins and cylindrospermopsin) and neurotoxins (anatoxin-a and saxitoxins) in cyanobacteria from the Tsimlyansk reservoir on the Don River was carried out. The presence of microcystin-producing Microcystis and Planktothrix populations, as well as of cyanobacteria capable of synthesis of a neurotoxin anatoxin-a was revealed by polymerase chain reaction (PCR). A hypothesis of the presence of anatoxin-a producing Planktothrix rubescens population in the phytoplankton of the Tsimlyansk reservoir is proposed. The obtained PCR data were confirmed by the results of enzyme-linked immunosorbent assay (ELISA) and liquid chromatography/mass-spectrometry (LC/MS). Anatoxin-a and five microcystin variants were identified in the phytoplankton biomass. PMID- 26964362 TI - [Effect of Methylmercury on the Light Dependence Fluorescence Parameters in a Green Alga Chlamydomonas moewusii]. AB - The effect of a dangerous toxic substance, methylmercury, on light dependence curves of chlorophyll fluorescence in Chlamydomonas moewusii was studied. We found low concentration of methylmercury (10(-7) M) to cause a decrease in the relative rate of the non-cyclic electron transport activity of PS 2, a decline in the maximum utilization of light energy (alpha), and a decline in the saturation light intensity (E(s)). Non-photochemical fluorescence quenching increased after short-term exposure and decreased in the course of prolonged incubation. These parameters were more sensitive to the action of the toxic substance than the widely used parameter F(V)/F(M), which reflects the maximum quantum yield of PS 2. We propose the use of the method of fast measurement of light dependence curves of fluorescence to detect the changes in algal cells at the early stages of exposure to mercury salts. PMID- 26964365 TI - ["Current Problems in Microbial Physiology, Ecology, and Biotechnology", an all Russian symposium with international participation (Biological Faculty, Lomonosov Moscow State University, December 24-27, 2014)]. PMID- 26964364 TI - [Microbial Processes and Genesis of Methane Gas Jets in the Coastal Areas of the Crimea Peninsula]. AB - Hydroasoustic techniques were used for detection and mapping of gas jet areas in the coastal regions of the Crimean peninsula. Gas seep areas in the bays Laspi, Khersones, and Kazach'ya were chosen for detailed microbiological investigation. The first type of gas jets, observed in the Laspi Bay, was probably associated with discarge of deep thermogenic methane along the faults. Methane isotopic composition was char- acterized by Delta13C of -35.3 degrees. While elevated rates of aerobic methane oxidation were revealed in the sandy sediments adjacent to the methane release site, no evidence of bacterial mats was found. The second type of gas emission, observed in the Khersones Bay, was accompanied by formation of bacterial biofilms of the "Thiodendron" microbial community type, predominated by filamentous, spirochete-like organisms, in the areas of gas seepage. The isotopic composition of methane was there considerably lower (-60.4 degrees), indicating a considerable contribution of modern microbial methane to the gas bubbles discharged in this bay. Activity of the third type of gas emission, the seeps of the Kazach'ya Bay, probably depended directly on modern microbial processes of organic matter degradation in the upper sediment layers. The rates of sulfate reduction and methanogenesis were 260 and 34 MUmol dm(-3) day(-1), respectively. Our results indicate different mechanisms responsible for formation of methane jets in the Laspi Bay and in the coastal areas of the Heracles Peninsula, where the bays Kazach'ya and Khersones are located. PMID- 26964366 TI - [The role of intrusive and deliberate ruminations for meaning making in stressful events]. AB - This study examined the relationship between meaning making and rumination regarding stressful events. We focused on two facets of rumination: intrusive and deliberate. Participants (N = 121) completed a questionnaire about a stressful event in their life that assessed the possibility of preventing the event, probability of the event occurring, perceived threat of the event, and meaning making. They also completed scales that assessed intrusive and deliberate ruminations about the event, posttraumatic growth after the event, as well as dispositions of self-rumination and self-reflection, and executive function. The results revealed that disposition of self-reflection was positively correlated with deliberate rumination about the event. Furthermore, deliberate rumination at the time of the experience was positively correlated with current positive meaning making, which was associated with current posttraumatic growth. Additionally, current intrusive rumination promoted current negative meaning making, but intrusive rumination at the time of the experience did not. Thus, this study suggests the important role of both intrusive and deliberate ruminations in the process of meaning making and several issues for future research. PMID- 26964367 TI - [Association between approach-avoidance commitment to romantic relationships, emotional experiences in romantic relationships, and personal mental health]. AB - The present study examined the association between approach-avoidance commitment, emotional experiences in romantic relationships, and mental health. It was hypothesized that the association between avoidance commitment and emotional experiences was moderated by approach commitment. Two hundred and three undergraduates who were involved in romantic relationships participated in a questionnaire survey. Results revealed that approach commitment was associated with greater positive emotion and less negative emotion, and these emotional experiences were associated with higher mental health. On the other hand, the association between avoidance commitment and emotional experiences was moderated by approach commitment. That is, only when approach commitment was weak, avoidance commitment was associated with fewer positive emotions and greater negative emotions, and that these emotional experiences were associated with lower mental health. These results reveal that approach-avoidance commitment was associated with mental health via emotional experiences in romantic relationships, and verified Johnson's (1999) and Levinger's (1999) theoretical argument. PMID- 26964368 TI - [A factor analysis method for contingency table data with unlimited multiple choice questions]. AB - The purpose of this study is to propose a method of factor analysis for analyzing contingency tables developed from the data of unlimited multiple-choice questions. This method assumes that the element of each cell of the contingency table has a binominal distribution and a factor analysis model is applied to the logit of the selection probability. Scree plot and WAIC are used to decide the number of factors, and the standardized residual, the standardized difference between the sample, and the proportion ratio, is used to select items. The proposed method was applied to real product impression research data on advertised chips and energy drinks. Since the results of the analysis showed that this method could be used in conjunction with conventional factor analysis model, and extracted factors were fully interpretable, and suggests the usefulness of the proposed method in the study of psychology using unlimited multiple-choice questions. PMID- 26964369 TI - [Effects of planning and executive functions on young children's script change strategy: A developmental perspective]. AB - This research examined the effects of planning and executive functions on young children's (ages 3-to 5-years) strategies in changing scripts. Young children (N = 77) performed a script task (doll task), three executive function tasks (DCCS, red/blue task, and nine box task), a planning task, and a receptive vocabulary task. In the doll task, young children first enacted a "changing clothes" script, and then faced a situation in which some elements of the script were inappropriate. They needed to enact a script by compensating inappropriate items for the other-script items or by changing to the other script in advance. The results showed that shifting, a factor of executive function, had a positive influence on whether young children could compensate inappropriate items. In addition, planning was also an important factor that helped children to change to the other script in advance. These findings suggest that shifting and planning play different roles in using the two strategies appropriately when young children enact scripts in unexpected situations. PMID- 26964370 TI - [Emotional competence in the multiple intelligences theory from the perspective of laypersons]. AB - Emotional competence has recently, become a widespread concern in schools and workplaces, both which deeplyinvolve laypersons. While academic researchers have discussed the status of emotional competence comparedto the traditional intelligence, it is very important to elucidate how laypersons regard emotional competencecompared to traditional intelligence as well. The present study investigated the position of emotional competencein the multiple intelligences theory by assessing laypersons' self-estimates of their abilities and their rating ofthe importance of emotional competence for thriving in society. Participants (N = 584) answered a questionnaireonline. Results showed that laypersons regarded emotional competence as a distinct construct, and most stronglyrelated it to personal intelligence. Moreover, their ratings of the importance of emotional competence and personalintelligence for thriving in society were higher than that of traditional intelligence. PMID- 26964372 TI - [An examination of a revised psycho-educational program for preventing depression among female undergraduates]. AB - The present study revised a psycho-educational program designed to prevent depression (Oikawa & Sakamoto, 2007) and to enhance interpersonal coping resources for depression. The effects of the revised program on female undergraduates were examined. One hundred and seventy two udergraduates were assigned either to an experimental group or a control group. The experimental group participated in the revised program for ten weeks as part of a psychological class, while the control group did not. All participants were asked to complete a self-report questionnaire about self-efficacy for cognitive, behavioral, and interpersonal coping for depression, the state of their mental health, and perceived social support from their family and friends before and after the program. The experimental group's ratings and responses indicated that the program were interesting and meaningful. Moreover, self-efficacy for coping with depression and perceived support from friends at the post intervention were significantly increased in the experimental group compared with the control group. These results suggest the effectiveness of the revised program for increasing interpersonal coping resources. PMID- 26964371 TI - [Development of the Trait Respect-Related Emotions Scale for late adolescence]. AB - This study developed a scale to measure the respect-related emotional traits (the Trait Respect-Related Emotions Scale) for late adolescence and examined the reliability and validity. In study 1,368 university students completed the items of the Trait Respect-Related Emotions Scale and other scales of theoretically important personality constructs including adult attachment style, the "Big Five," self-esteem, and two types of narcissistic personality. Factor analysis indicated that there are three factors of trait respect-related emotions: (a) trait (prototypical) respect; (b) trait idolatry (worship and adoration); and (c) trait awe. The three traits associated differentially with the daily experience (frequency) of the five basic respect-related emotions (prototypical respect, idolatry, awe, admiration, and wonder), and other constructs. In Study 2, a test retest correlation of the new scale with 60 university students indicated good reliability. Both studies generally supported the reliability and validity of the new scale. These findings suggest that, at Ieast in late adolescence, there are large individual differences in respect-related emotion experiences and the trait of respect should be considered as multi-dimensional structure. PMID- 26964374 TI - [The relationship between perceived personality and Ieading/following roles in university students' close friendships, using Gitaigo personality scale]. AB - Based on the recently developed Gitaigo personality scale (Komatsu, Sakai, Nishioka, & Mukoyama, 2012), we investigated the relationship between perceived personality and leading/following roles in close friend dyads. Primary participants rated their own and one of their close friend's personality with Gitaigo personality scale. They also described who takes the role of leader in the relationship with the friend they rated. When one in the pair is reported as leader, the other is considered as follower. Subsidiary participants who were cited as close friends rated their own personality. Our analysis of the 215 pairs showed that the participants taking the role of follower were rated higher in the traits of Cowardliness and Mildness by the primary participants. Regarding Mildness, this tendency was also clear in subsidiary participants' self-ratings. Primary participants rated the Preciseness and Candidness of their friends lower if their friend was considered a follower. Gitaigo personality scale describes the perceived personality well, at least for several traits. PMID- 26964373 TI - [Did a 16th century Christian missionary observe that the Japanese were collectivists?]. AB - Volpi (2004) pointed out that Alessandro Valignano, a 16th century Christian missionary, had considered the Japanese extreme collectivists. According to Volpi, his remark was based on Valignano's reports (1583, 1592) edited by Alvares Taladriz (1954). However, it is highly questionable whether Volpi examined these texts directly because the information about them provided by Volpi involved many serious errors. A thorough inspection of Valignano's translated reports found no mention of Japanese collectivism. On the contrary, he had actually reported exceedingly individualistic behaviors of Japanese warriors. Such behaviors are consistent with what is widely known about the 16th century Civil Wars in Japan. It has thus turned out that no reliable evidence is present for the alleged observation by Valignano. PMID- 26964375 TI - [Which comes first for interpersonal stress, coping or support?]. AB - This study used structural equation modeling to investigate directional relationships between coping with interpersonal stress and received support. One hundred and seventy-seven undergraduates who had experienced interpersonal stress during the past month answered questions about coping with interpersonal stress and received support. Structural equation modeling based on third-order moment structures was used to examine the directionality of the relationship between these two variables. The results revealed interactive associations between distancing and emotional support. Received support affected coping with interpersonal stress in terms of active coping, planning and monitoring, and positive reappraisal. These results suggest that received support functions as a coping resource. PMID- 26964376 TI - [The role of the orbitofrontal cortex in delayed reinforcement choice in rats]. AB - Previous studies have reported that lesions of the orbitofrontal cortex (OFC) in rats induce impulsive choices in delayed reinforcement tasks. However, some studies have suggested that the OFC is not related to impulsivity but instead to compulsivity. In this study, we investigated the effects of OFC lesions on choice in a T-maze. First, 14 rats were trained to discriminate spatially between a high reward arm with a delay of 15 seconds and a low-reward arm without a delay. The high-reward arm contained 10 food pellets, whereas the low-reward arm contained only one pellet. In the presurgery test, all rats chose the high-reward arm in most trials. In the postsurgery test, both OFC lesioned (n = 7) and control (sham lesioned and intact; n = 7) rats continued to choose the high-reward arm in most trials. Following the postsurgery test, the high- and low-reward arms were reversed. In the reversal test, OFC lesioned rats made significantly fewer high reward choices than did control rats. These results indicate that OFC lesions induced compulsive choices rather than impulsive choices. PMID- 26964377 TI - We take a look back to make a more successful step forward. PMID- 26964378 TI - Vacuum-assisted wound closure in vascular surgery--clinical and cost benefits in a developing country. AB - BACKGROUND/AIM. Surgical and chronic wounds in vascular patients might contribute to limb loss and death. Vacuum-assisted closure (VAC)--Kinetic Concepts, Inc. (KCI), has been increasingly used in Western Europe and the U.S.A. clinical practice for 15 years. Advantages of this method are faster wound healing, wound approximation, lower wound related treatment costs and improved quality of life during treatment. Evidence related to the usage of VAC therapy in vascular patients and cost effectiveness of VAC therapy in a developing country are lacking. The aim of this study was to explore results of VAC therapy in vascular surgery comparing to conventional methods and to test cost effects in a developing country like Serbia. METHODS: All patients with wound infection or dehiscence operated at the tertiary vascular university clinic in the period from January 2011-January 2012, were treated with VAC therapy. The primary endpoint was wound closure, while secondary endpoints were hospital stay, the number of weekly dressings, costs of wound care, working time of medical personnel. The patients were divided into groups according to the wound type and location: wound with exposed synthetic vascular implant (25%), laparotomy (13%), foot amputation (29%), major limb amputation (21%), fasciotomy (13%). The results of primary and secondary endpoint were compared with the results of conventional treatment during the previous year. RESULTS: There was one death (1/42, 2.38%) and one limb loss (1/12, 2.38%) in the VAC group, and 8 deaths (8/38, 21.05%) and 5 (5/38, 13.15%) limb losses in the patients treated with conventional therapy. In the VAC group there was one groin bleeding (1/12, 2.38%), one groin reinfection (1/12, 2.38%) and one resistance to therapy with a consequent limb loss. Costs of hospital stay (p < 0.001) and nursing time (p < 0.001) were reduced with VAC therapy in the group with exposed graft. CONCLUSION: VAC therapy is the effective method for care of complicated wounds in vascular surgery. Patients with infection of wound with the exposed synthetic graft significantly benefit form this therapy. Cost effectiveness of VAC therapy is applicable to a developing country scenario, however cautious selection of patients contributes to the effectiveness. PMID- 26964379 TI - The expression and significance of p53 protein and Ki-67 protein in pterygium. AB - BACKGROUND/AIM: Pterygium is considered to be a degenerative disease of the conjunctiva, however, the presence of tumor markers in pterygium reinforces the hypothesis that this lesion is similar to tumor. Inactivation of p53 function removes an obstacle to increased proliferation. Factors affecting the prevalence of p53 expression in pterygium deserve investigation. The aim of the study was to investigate the expression of p53 and Ki-67 proteins in pterygium and normal conjunctiva, the effects of gender and age on p53 expression, and the relationship between the expression of p53 and Ki-67 proteins. METHODS: A total of 34 samples of pterygium and 34 samples of the normal conjunctiva were analyzed. The samples were studied by immunohistochemistry using antibodies against p53 and Ki-67. RESULTS: Totally 15 (44%) samples of pterygia were p53 positive. Correlations between the expression of p53 protein and sex, and age were not established. The number of Ki-67 positive cells in pterygium (9.74%) was significantly higher than the number of Ki-67 positive cells in the normal conjunctiva (1.74%), (P = 0.001). Between the expression of p53 protein and Ki-67 protein in pterygium there was a significant positive correlation (p = 0.000). CONCLUSION: The prevalence of p53 positive samples of pterygium was 44%. The influence of sex and age on p53 protein expression in pterygium was not found. The increased proliferative acivity was present in the epithelium of pterygium. The expression of Ki-67 protein is associated with the expression of p53 protein in pterygium. The findings of our study support the thesis of pterygium as tissue growth disorder. PMID- 26964380 TI - Fever of unknown origin: Most frequent causes in adults patients. AB - BACKGROUND/AIM: The differential diagnosis of fever of unknown origin (FUO) includes more than 200 different diseases and conditions. The aim of this study was to identify the most frequent causes of FUO among adult patients according to gender and age. METHODS: The study included 74 patients examined from June 2010 to June 2013 at the Infectious Disease Clinic, Clinical Center Kragujevac in Serbia, according to the defined criteria for FUO. The patients were divided according to the diagnosis into four groups: infectious, malignant, rheumatic and "other diseases". A cause of febricity could not be estabilshed in a portion of subjects, and they comprised the group of undiagnosed cases. RESULTS: Infectious diseases were dominant in the study, followed by rheumatic diseases, which were most frequently found in women and the elderly. The diseases recognised as the most common causes of febricity were subacute thyroiditis, subacute endocarditis, Still's disease, rheumatic polymyalgia with or without temporal arteritis, and cytomegalovirus infection. In 44% of the patients, the final diagnosis was composed of only six clinical entities. CONCLUSION: The importance of establishing the diagnosis of rheumatic disease is especially emphasised, in line with other authors' research indicating the number of these diseases is on the rise. The diagnostic approach to FUO should always be directed to the known frequency of diseases. PMID- 26964381 TI - Cost effectiveness comparison of dutasteride and finasteride in patients with benign prostatic hyperplasia--The Markov model based on data from Montenegro. AB - BACKGROUND/AIM: Benign prostatic hyperplasia (BPH) is one of the most common disease among males aging 50 years and more. The rise of the prevalence of BPH is related to aging, and since duration of life time period has the tendency of rising the prevalence of BPH will rise as costs of BPH treatment will and its influence on health economic budget. Dutasteride is a new drug similar to finasteride, inhibits enzyme testosterone 5-alpha reductase, diminish symptoms of BPH, reduce risk of the complications and increases quality of life in patients with BPH. But, the use of dutasteride is limited by its high costs. The aim of this study was to compare cost effectiveness of dutasteride and finasteride from the perspective of a purchaser of health care service (Republic Institute for Health Insuranse, Montenegro). METHODS: We constructed a Markov model to compare cost effectivenss of dutasteride and finasteride using data from the available pharmacoeconomic literature and data about socioeconomic sphere actual in Montenegro. A time horizon was estimated to be 20 years, with the duration of 1 year per one cycle. The discount rate was 3%. We performed Monte Carlo simulation for virtual cohort of 1,000 patients with BPH. RESULTS: The total costs for one year treatment of BPH with dutasteride were estimated to be 6,458.00 ? which was higher comparing with finasteride which were 6,088.56 ?. The gain in quality adjusted life years (QALY) were higher with dutasteride (11.97 QALY) than with finasteride (11.19 QALY). The results of our study indicate that treating BPH with dutasteride comparing to finasteride is a cost effective option since the value of incremental cost-effectiveness ratio (ICER) is 1,245.68 ?/QALY which is below estimated threshold (1,350.00 ? per one gained year of life). CONCLUSION: Dutasteride is a cost effective option for treating BPH comparing to finasteride. The results of this study provide new information for health care decision makers about treatment of BPH in socioeconomic environment which is actual both in Montenegro and other countries with a recent history of socioeconomic transition. PMID- 26964382 TI - Risk factors and the prevalence of anorexia nervosa among female students in Serbia. AB - BACKGROUND/AIM: The widespread symptoms of anorexia netvosa (AN) in young women require to draw professional attention to this problem in Serbia. In previous research on AN, insecure attachment styles, perfectionism and concerns about body shape were identified as notable risk factors. The aim of this study was to identify the prevalence of AN among female students and assess the importance of these factors in its development. METHODS: The Eating Attitudes Test (EAT-40), the Experiences in Close Relationships Scale (ECR), the Frost Multidimensional Perfectionism Scale (FMPS) and the Body Shape Questionnaire (BSQ) were applied to a sample of 500 randomly selected female students of the University of Belgrade, the mean age of 22.44 years (min 18, max 35). In addition, Body Mass Index (BMI) was also calculated. RESULTS: Although 38 (7.6%) female students displayed symptoms of AN (EAT > 30) and 13 (2.6%) had BMI indicating anorexia nervosa syndrome (B4I < or = 17.50 kg/m2), only 1 (0.2%) student fulfilled both criteria. The majority of female students (60.4%) had some type of insecure attachment style. There is a significant influence of attachment styles on symptoms of AN: female students with insecure attachment styles have a significantly higher mean score on the EAT compared to those with secure attachment style (F = 7.873; p < 0.01). There was a positive correlation between scores on the EAT and FMPS (r = 0.217;p < 0.01), and scores on the EAT and BSQ (r = 0.388; p < 0.01). CONCLUSIONS: The obtained results show the prevalence of AN of 0.2% among female students and indicate the importance of insecure attachment styles, perfectionism and concern about body shape as risk factors. Activities for the prevention of AN in this subpopulation should include internet-based therapy and special counseling services with specific programs focusing on emotion-regulation skills through mindfulness, acceptance and commitment techniques, as well as specific cognitive-behavioral techniques. PMID- 26964383 TI - Quality of life of elderly people living in a retirement home. AB - BACKGROUND/AIM: The World Health Organization (WHO) identified four broad domains as being universally relevant to the quality of life, namely physical, and psychological health, social relationships, and environment. The aim of this study was to assess the relationship between sociodemographic characteristics and quality of life of old people. METHODS: The World Health Organization Quality of Life BREF questionnaire (WHOQOL-BREF) was used to assess quality of life on a random sample of 200 people aged 60 years and over who lived in the Retirement Home in Novi Sad. Items within the questionnaire were organized into four domains: physical, psychological, social relationships and environment. RESULTS: The majority of the participants were women (69.8%). The mean age was 79.2 years (SD = 6.6 years). Most of them were widowed (73.4%). More than two thirds of participants (68.8%) reported that they were ill at that moment and almost half of them (48.8%) had cardiovascular, 18.5% musculoskeletal, 9.6% endocrine and 5.9% neurological disease. In the social relations domain scores were lower in males (t = 2.4; p = 0.017). Scores of other domains did not differ significantly with regard to the age, educational level and the marital status of the participants. Participants who reported the presence of a disease had significantly lower mean scores of physical, psychological and environment domain. CONCLUSION: The presence of disease is a relevant factor for quality of life, whereas age, education and marital status do not reflect on physical health, psychological and environmental domain of quality of life. PMID- 26964384 TI - Choice of root canal irrigants by Serbian dental practitioners. AB - BACKGROUND/AIM: Root canal treatment is considered to be the one of the most important procedures in endodontic treatment. To irrigate the root canal it is most common to use sodium hypochlorite (NaOCl), chlorhexodine, ethylenediaminetetraacetic acid (EDTA), local anesthetic solution, while the most used in Serbia is hydrogen peroxide (H2O2). The aim of this survey was to reveal the preferred root canal irrigants used by general dental practitioners in Serbia and to determine the influence of the continuing education program, delivered over the 3-year observation period, on work habits of dental practitioners. This was the first comprehensive survey of this nature carried out in Serbia. METHODS: The survey was conducted in two instances, a 4-month observation period each, from November 1, 2009 to March 1, 2010 and from November 1, 2012 to March 1, 2013. Internet Web Page Survey was posted on the official web site of the Serbian Association of Private Dentists. In the first survey, 569 completed questionnaires were subjected to analysis. In the next attempt (3 years later), the survey was launched again and 615 completed questionnaires were analyzed using the same criteria. The statistical analysis was carried out with simple descriptive statistics applying the x2 test, at a significance level of p < 0.05. RESULTS: The first survey included 569 dental practitioners, while 3 years later the number of them was 615. Analyzing the questionnaires revealed the number of 10 to 30 interventins on the root canal montly. The most commonly used irrigant solution was H2O2 in 2009, while in 2012 it was yet H2O2, but also NaOCl, chlorhexodine, and a little less EDTA. CONCLUSION: This study shows significant changes in the irrigation protocol applied in Serbian dental community. After 3 years of observation, NaOCl became widely accepted as the irrigant of choice, whereas H2O2 lost its popularity. PMID- 26964385 TI - Lip, oral cavity and pharyngeal cancers in the population of the city of Belgrade in the period 1999-2010. AB - BACKGROUND/AIM: Cancers of the lip, oral cavity and pharynx (LOCP) are frequently grouped together mainly because they have similar risk factors. The incidence rate of these cancers varies worldwide depending on the geographic location. The aim of this study was to determine trends in age-standardized incidence rates of LOCP cancers in the Belgrade population during a 12-year period, from 1999 to 2010. METHODS: From The Serbian Cancer Registry (The Registry), we extracted all cases of LOCP cancers registered in Belgrade from January 1, 1999 to December 31, 2010. Joinpoint regression analysis was used to define trends and annual percentage change (APC). RESULTS: A total number of 2,025 (1,509 in men and 516 in women) LOCP cancers were reported to the Registry during the study period. The age standardized rate (ASR) for the entire period and for all LOCP cancers, was 6.24 per 100,000 persons (10.35 for men and 2.86 for women). ASR for lip cancers decreased (p < 0.001) during the study period with APC of -8.4%. The ASR for oral cavity and pharyngeal cancers increased (p < 0.05). CONCLUSION: Our results show a significantly decreasing trend of the incidence rate for lip cancers in the population of the city of Belgrade between 1999 and 2010. On the contrary, the incidence of oral cavity and pharyngeal cancers increased for both men and women. PMID- 26964387 TI - Medico-legal expertise of pain in dental trauma. PMID- 26964386 TI - Respiratory syncytial virus infection and bronchial hyperreactivity in children up to two years of age in correlation with atopy. AB - BACKGROUND/AIM: Bronchiolitis in early childhood caused by respiratory syncytial virus (RSV) is considered to be important risk factor of the recurrent wheezing and asthma development. The aim of this study was to examine the frequency of RSV infection and atopy in children up to two years of age and to determine their correlation with bronchial hyperreactivity. METHODS: The study included 175 children aged 5-24 months. The presence of RSV infection was identified by serum levels of IgA and IgG determined by ELISA. Bronchial hyperreactivity (BHR) has been defined as the existence of chronic bronchial disease and/or three or more previous suspected diagnosis of acute bronchial disease. Atopy was confirmed by detection of the specific serum IgE using quantitative multitest Phadiatop infant (cut off 0.35 kUA/L). RESULTS: The children with atopy were more frequently infected with RSV (43.3%) than those without atopy (22.8%; p = 0.02). The higher frequency of RSV infection was found in children with BHR in comparison with those without it but only in the group who also had atopy (77.8% vs. 28.6%, p = 0.018). In the female children, BHR and RSV infection were associated in 62.5% of cases, regardless the atopy. In the male children with atopy, RSV infection was associated with BHR in 83.3% of the cases, while in those without atopy, RSV infection with BHR was found in only 17.4% of the cases. CONCLUSION: Children up to two years of age with atopy are more frequently infected with RSV (43.3%) than nonatopic children. Every third child with atopy develops BHR and 77.8% of them also have RSV infection. Atopic children are at higher risk for development of BHR when infected with RSV also. PMID- 26964388 TI - Successful primary percutaneous coronary interventions in a patient with two consecutive ST-segment elevation myocardial infarctions and dual left anterior descending artery (type IV). AB - INTRODUCTION: Dual left anterior descending (LAD) artery is a very rare inherited anomaly. It can be incidentally revealed during primary percutaneous coronary intervention (pPCI) and may produce difficulties in detecting and treating the culprit lesion. CASE REPORT: We presented a 52-year-old male patient with ST segment elevation myocardial infarction (STEM1) of inferior wall, in whom dual LAD anomaly was revealed during pPCI: a short LAD artery originated from the left main coronary artery and a long LAD artery originated from the proximal part of the right coronary artery (RCA). A bare metal stent was successfully implanted in the place of the culprit lesion in RCA and ST-segment resolution was achieved in ECG. After two hours, the patient was referred again to the catheter lab due to new STEMI of anteroseptal wall. Another bare metal stent was implanted in new infarction related artery, this time it was proximal part of the short LAD. CONCLUSION: Careful and correct interpretation of ECG is very helpful in detection and treatment of the culprit lesion in cases with dual LAD. PMID- 26964389 TI - Prenatal diagnosis of lissencephaly: A case report. AB - INTRODUCTION: Lissencephaly ("smooth brain") forms a major group of brain malformations due to abnormal neuronal migration. It can cause severe intellectual and motor disability and epilepsy in children. The prenatal diagnosis of this malformation is rare. CASE REPORT: We presented a case of the prenatal diagnosis of lissencephaly. A 30-year-old pregnant woman was reffered to the hospital at the week 35 of gestation for magnetic resonance imaging (MRI after an ultrasound examination demonstrated fetal cerebral ventriculomegaly. Fetal MRI of the brain showed "smooth", agyrya cortex. The female infant was born at term with birth weight of 2,500 g and Apgar score 8, showing global developmental delay. Postnatal ultrasound and MRI confirmed classical lissencephaly. She is now 8 years old and has spastic quadriparesis, mental retardation and epilepsy. CONCLUSION: Confirmation of the ultrasound diagnosis with MRI is desirable for the prenatal diagnosis of lissencephaly. PMID- 26964390 TI - Successful treatment with cladribine of Erdheim-Chester disease with orbital and central nervous system involvement developing after treatment of Langerhans cell histiocytosis. AB - INTRODUCTION: Erdheim-Chester disease (ECD) is a rare, systemic form of non Langerhans cell histiocytosis of the juvenile xanthogranuloma family with characteristic bilateral symmetrical long bone osteosclerosis, associated with xanthogranulomatous extra skeletal organ involvement. In ECD, central nervous system (CNS) and orbital lesions are frequent, and more than half of ECD pa tients carry the V600E mutation of the protooncogene BRAF. The synchronous or metachronous development of ECD and Langerhans cell histiocytosis (LCH) in the same patients is rare, and the possible connection between them is still obscure. Cladribine is a purine substrate analogue that is toxic to lymphocytes and monocytes with good hematoencephalic penetration. CASE REPORT: We presented a 23 year-old man successfully treated with cladribine due to BRAF V600E-mutation negative ECD with bilateral orbital and CNS involvement ECD developed metachronously, 6 years after chemotherapy for multisystem LCH with complete disease remission and remaining central diabetes insipidus. During ECD treatment, the patient received 5 single-agent chemotherapy courses of cladribine (5 mg/m2 for 5 consecutive days every 4 weeks), with a reduction in dose to 4 mg/m2 in a fifth course, delayed due to severe neutropenia and thoracic dermatomal herpes zoster infection following the fourth course. Radiologic signs of systemic and CNS disease started to resolve 3 months after the end of chemotherapy, and CNS lesions completely resolved within 2 years after the treatment After 12-year follow-up, there was no recurrence or appearance of new systemic or CNS xanthogranulomatous lesions or second malignancies. CONCLUSION: In accordance with our findings and recommendations provided by other authors, cladribine can be considered an effective alternative treatment for ECD, especially with CNS involvement and BRAF V600E-mutation-negative status, when interferon-alpha as the first-line therapy fails. PMID- 26964391 TI - Failure of intravenous lipid emulsion in treatment of cardiotoxicity caused by mixed overdose including dihydropyridine calcium channel blockers. AB - INTRODUCTION: Calcium channel blockers and beta-blockers are among the most frequently ingested cardiovascular drugs in self-poisoning causing significant mortality. Intravenous lipid emulsion (ILE) is reported as a potentially novel antidote for treatment of acute poisoning caused by some of these drugs. CASE REPORT: We presented two cases of poisoning with these drugs. The case 1, a 24 year-old woman ingested amplodipine, metformin and gliclazide for self-poisoning. She presented with tachycardia and hypotension. Laboratory analyses revealed hyperglycaemia and metabolic acidosis. Despite the treatment which included fluid resuscitation, vasopressors, intravenous calcium, glucagon and ILE, circulatory shock occurred. The patient died 10 hours after admission due to cardiac arrest refractory to cardiopulmonary resuscitation. The case 2, a 41-year-old man, was found in a coma with empty packages of nifedipine, metoprolol and diazepam tablets. On admission vital signs included Glasgow Coma Scale (GCS) of 3, weak palpable pulses, undetectable blood pressure, and irregular breathing with oxygen saturation of 60%. An electrocardiography showed AV block (Mobitz II) with ventricular rate of 44/min with progression to third degree of AV block. In attempt to increase heart rate and blood pressure the following agents were administered: atropine boluses, normal saline with dopamine, glucagon, calcium chloride and ILE. Temporary transvenous pacemaker was placed, electrical capture was recorded, but without improvement in haemodynamics. Three hours after admission cardiac arrest happened and cardiopulmonary resuscitation was unsuccessful. CONCLUSION: Intravenous lipid emulsion may be ineffective in acute poisonings with amlodipine, nifedipine or metoprolol. PMID- 26964392 TI - A comment on the article: Rabrenovic M, Tresnjic S, Rabrenovic V, Cikiriz N, Masic S, Matunovic R. Neurotoxic effects of oxygen in hyperbaric environment. Vojnosanit Pregl 2015; 72(9): 827-30. PMID- 26964393 TI - Authors' reply. PMID- 26964395 TI - [Adverse Events of Sublingual Immunotherapy in 207 Patients with Japanese Cedar Pollinosis]. AB - Sublingual immunotherapy (SLIT) for Japanese cedar pollinosis is effective, however, caution must be exercised against allergen-specific adverse events (AEs) during SLIT. PURPOSE: The purpose of this study was to clarify the AEs of SLIT in a large cohort of patients with Japanese cedar pollinosis. METHODS: We conducted a detailed survey, by both questionnaires and direct interviews, of 207 patients receiving SLIT at our clinic. RESULTS: Eighty-four of the 207 patients (40.5%) developed AEs, with AEs involving the oral cavity and throat being the most common (56 patients; 27.1%). Sixteen patients (7.9%) had local mucosal swelling, but the swelling resolved in all the cases. Other allergen-induced symptoms such as nasal symptoms (29 events, 14.0%), eye symptoms (14 events, 6.8%) and ear symptoms (20 events, 9.7%) were also recognized. All the AEs were minor, and discontinuation of SLIT was not necessitated in any of the patients because of AEs. There were 52 AEs (25.0%) in the up-dose phase and 61 AEs (29.3%) in the maintenance phase. However, only 4 of the 161 patients (2.5%) developed AEs during the pollen season. Most AEs developing during the maintenance phase occurred in the first few weeks. In 60% of the cases, the AEs disappeared within 2 weeks, and in 6.0% (5 events), they persisted for longer than 2 months. There were no age-or sex-related differences in the prevalence of cedar pollen-specific IgE, or in the adherence to the treatment. CONCLUSION: AEs in SLIT were shown in many patients, however, the severity of AEs was mild and no events interfered SLIT. PMID- 26964394 TI - [Clinical Analysis of Evaluation of the Swallowing Function before Gastrostomy in an Acute-care Hospital for Elderly People]. AB - The Ministry of Health, Labour and Welfare, while defining a significant reduction of the medical fee points for gastrostomy in the medical fee revision of fiscal year 2014, assigned additional fee points for evaluation of the swallowing function by videofluoroscopy (VF) or videoendoscopy (VE) prior to gastrostomy. In addition, for facilities that carried out more than 50 gastrostomy operations, evaluation of the swallowing function was made mandatory in all cases and 35% of oral ingestion recovery rate to require the full amount calculation. Therefore, we evaluated the data on swallowing function evaluation in patients and gastrostomy at our hospital. During a 3-year period from February 2012, 114 patients who underwent gastrostomy at our hospital were enrolled. We evaluated the background disease, indications for gastrostomy, conduct/non conduct of swallowing function tests prior to gastrostomy, videoendoscopic score (VE score), and the functional oral intake score before and after gastrostomy in the patients. The predominant background diseases were cerebrovascular disease (33%), Parkinson's syndrome (26%), and Alzheimer's disease (11%). The indications for gastrostomy were dysphagia (38%), request for gastrostomy from other hospitals or nursing care home (24%), and malnutrition due to anorexia (18%). The severity of the dysfunction was classified based on the VE score as mild (28%), moderate (47%), or severe (25%). Dysphagia did not reach the majority of reasons for gastrostomy and not few of background diseases were progressive neurological diseases such as Parkinson's disease. Therefore, it remains under debate whether it is necessary to perform swallowing functional evaluation by VE or VF in all cases prior to gastrostomy. In some cases in which gastrostomy was indicated, the VE scores were not so high. Therefore, a comprehensive evaluation based on the pathophysiology and social background is needed to judge the indication for gastrostomy. Leading support and participation in the calculation of additional fee points for the evaluation of swallowing function is an urgent issue for otolaryngologists. PMID- 26964396 TI - [A Case of Stevens-Johnson Syndrome Developing during Chemoradiotherapy for Maxillary Sinus Cancer]. AB - Herein, we report a case of drug-induced Stevens Johnson syndrome. (SJS). A 56 year old female visited our hospital complaining of right cheek pain. Local examination revealed that the right ostium of the maxillary sinus was open and that the maxillary sinus mucosa was invaded by tumor. Biopsy revealed a histopathological diagnosis of squamous cell carcinoma. We therefore diagnosed the patient as a case of maxillary sinus carcinoma (T3N0M0) based on the CT, MRI and FDG-PET findings. During chemoradiotherapy for maxillary sinus cancer, the patient developed oral mucosal inflammation of progressively worsening severity; we initially thought that the symptom was a side effect of the treatment; however, several days later, skin lesions appeared throughout the body. We consulted a dermatologist, who suspected SJS. The patient was initiated on high dose steroid therapy (steroid pulse therapy), and the symptoms improved. Because of SJS is a fatal drug eruption, early diagnosis and prompt treatment are important. In patients receiving chemoradiotherapy showing severe oral mucosal inflammation outside the irradiation area or oral mucosal inflammation associated with skin lesions throughout the body, it is necessary to bear in mind the possibility of SJS. PMID- 26964397 TI - [Introduction of Percutaneous Dilational Tracheotomy in Otolaryngology Residency Training]. AB - In 2009, we introduced percutaneous dilational tracheotomy (PDT) in otolaryngology residency training. PDT was performed in 21 cases and five residents had an opportunity to learn PDT. No major complications occurred. Decannulation was achieved in 17 of the 18 cases, excluding 3 mortalities. All residents felt that their knowledge of PDT had advanced. Introduction of PDT has great significance in otolaryngology residency training. PMID- 26964398 TI - [Evaluation of the Effectiveness and Safety in a Multi-center Clinical Trial of VIBRANT SOUNDBRIDGE in Japan]. AB - Middle ear implants (MEIs) such as the Vibrant Soundbridge (VSB) are attractive and alternative treatments for patients with conductive, sensorineural, and mixed hearing loss who do not benefit from, or who choose not to wear, conventional hearing aids (HAs). Recent studies suggest that MEIs can provide better improvements in functional gain, speech perception, and quality of life than HAs, although there are certain risks associated with the surgery which should be taken into consideration, including facial nerve or chorda tympanic nerve damage, dysfunctions of the middle and inner ears, and future device failure/explantation. In Japan, a multi-center clinical trial of VSB was conducted between 2011-2014. A round window vibroplasty via the transmastoid approach was adopted in the protocol. The bony lip overhanging the round window membrane (RWM) was extensively but very carefully drilled to introduce the Floating Mass Transducer (FMT). Perichondrium sheets were used to stabilize the FMT onto the RWM. According to the audiological criteria, the upper limit of bone conduction should be 45 dB, 50 dB, and 65 dB from 500 Hz to 4, 000 Hz. Twenty five patients underwent the surgery so far at 13 different medical centers. The age at the surgery was between 26-79 years old, and there were 15 males and 10 females. The cause of conductive or mixed hearing loss was middle ear diseases in 23 cases and congenital aural atresia in two cases. The data concerning on the effectiveness and safety of VSB was collected before the surgery and 20 weeks after the surgery. Significant improvements of free-field Pure Tone Audiogram (PTA) from 250 Hz to 8, 000 Hz were confirmed (p < 0.001). Hearing gain up to 40 dB was achieved in the 1, 000 Hz to 4, 000 Hz range. No deterioration in either air conduction or bone conduction at PTA was noted at 20 weeks after the surgery. Monosyllable speech perception in both quiet and noisy conditions improved significantly (p < 0.001). The speech discrimination score in both quiet and noisy conditions improved significantly too (p < 0.001). In the future, it is likely that there will be an increasing population even in Japan that will meet the criteria for MEIs such as VSB. However, the long-term efficacy and safety of these devices should be established. PMID- 26964399 TI - [Use of a novel polymer, the in-situ gelling mucoadhesive thiolated poly(aspartic acid) in ophthalmic drug delivery]. AB - The bioavailability of drugs used on mucosal surfaces can be increased by the use of mucoadhesive polymers. A new type of mucoadhesive polymers is the group of thiolated polymers with thiol group containing side chains. These polymers are able to form covalent bonds (disulphide linkages) with the mucin glycoproteins. For the formulation of an ocular drug delivery system (DDS) thiolated poly(aspartic acid) polymer (ThioPASP) was used. Our aim was to determine their biocompatibility, mucoadhesion and drug release property. According to the results it can be established that the thiolated poly(aspartic acid) polymers can be a potential vehicle of an ocular drug delivery system due to their biocompatibility, good mucoadhesive property and drug release profile. Thanks to their properties controlled drug delivery can be achieved and bioavailability of the ophthalmic formulation can be increased, while the usage frequency can be decreased. PMID- 26964400 TI - [Resveratrol in Pharmaceutical Chemistry]. AB - Resveratrol is a polyphenol that can be found in various plants, including grapes. Wines therefore also contain this compound. The famous phenomenon, named "French paradox" is considered to be an effect of resveratrol: the regular, modest consumption of red wine causes low incidence of cardiovascular diseases. Resveratrol is also reported to have anti-carcinogenic, anti-inflammatory, neuroprotective, and several further beneficial effects. As yet, resveratrol is not a registered drug in Hungary; nevertheless it is a common food supplement. Paradoxically, this is the very danger of its use: it can have harmful side effects with several drugs. The bioavailability of resveratrol is, however, not favorable, due to its poor water-solubility and extensive metabolism. Our current knowledge is still far from being sufficient to understand its mode of action at a molecular level. Only a few of the most important physicochemical properties has been determined so far. The two major directions of pharmaceutical research of resveratrol are the elaboration of formulation systems that can improve the water solubility; the other is the development of analogous agents of enhanced effects. PMID- 26964401 TI - [Development possibilities of hormone-containing implants for gynecological applications: A review]. AB - Implantable gynecological drug delivery devices are applied for contraceptive, hormone replacement purposes and for the treatments of other gynecological diseases, e.g. endometriosis. The review provides a comprehensive overview about the indications, advantages, limitation of application and the applied technologies of hormone-containing implants, as well. The study comprises the relevant patents and the recently published papers. PMID- 26964402 TI - [Development of new magistral method for the preparation of artificial tears]. AB - Nowadays, large part of the population in Hungary is affected by the dry eye disease or symptom. Most of these magistral pharmaceuticals (FoNo VI) compared to the industrial products have disadvantages. They are not compatible with contact lenses, because of the preservatives and after opening they can be used only for seven days. In our experiments we used sodium-perborate as preservative, which could be a solution for the problems mentioned above. Our results indicate that the sodium-perborate sterilized the solution and resists against microbiological contamination. Its preservative effect maintained for more than four weeks. Our further purpose is to develop a new pharmacy drug preparation method to find an effective solution for the microbiological stability-related problems of artificial tears. PMID- 26964405 TI - Silent Voices: Current and Future Roles of African Research Ethics Committee Administrators. PMID- 26964403 TI - Waivers and Alterations to Consent in Pragmatic Clinical Trials: Respecting the Principle of Respect for Persons. PMID- 26964404 TI - Exploitation of Prisoners in Clinical Research: Perceptions of Study Participants. PMID- 26964406 TI - Meaningful use presents opportunity for measuring quality. PMID- 26964407 TI - Health system screens all patients for suicide risk. PMID- 26964408 TI - Money-back guarantee aimed at patient satisfaction. PMID- 26964409 TI - App lets patients check ED wait times before leaving home. PMID- 26964410 TI - NPSF says patient safety still a serious concern. PMID- 26964411 TI - Discharge planning proposed rule focuses on patient preferences. PMID- 26964412 TI - Readmissions are focus of Joint Commission resources. PMID- 26964413 TI - Financial stakes rising as auditors set their sights on providers. AB - The Centers for Medicare & Medicaid Services (CMS) is continuing to tweak its various audit programs, and the changes make it imperative that case managers stay current so they can educate the rest of the staff. Hospitals have got to get patient status right up front, and that means case managers should review every patient who comes in from every point of access. Hospitals should eliminate the silos within their various departments and outside the hospital walls with post acute providers so everyone can work together for better patient care. Case managers should work closely with their physician advisors and admitting physicians as well as being involved in revenue cycle activities. PMID- 26964414 TI - Get status right up front for fewer headaches later on. PMID- 26964415 TI - CMS gives the RA program a makeover with more changes in store. AB - CMS has made changes in the scope of work for the Recovery Auditor program and has proposed a number of other changes to be implemented when new RA contracts are issued. CMS has restricted the number of additional documentation requests, has shortened the "look-back" period for patient status reviews, and announced penalties for RAs with high error rates. The new contracts shorten the time RAs have to complete complex reviews, requires RAs to wait 30 days before referring cases to the Medicare Administrative Contractors, and postpones contingency payments to RAs until after the second level of appeals. The Audit and Appeal Fairness, Integrity, and Reforms in Medicare (AFIRM) bill, introduced in the Senate in December, revamps the appeals process, adding an Ombudsman for Medicare Reviews to assist in resolving complaints by hospitals that have appealed and those considering appeals, and establishes an Appeals Medicare Magistrate program with attorneys who will handle appeals of denials for $1,500 or less. PMID- 26964416 TI - Safety net hospital, community providers collaborate to improve transitions. AB - A Care Transitional Task Force at San Francisco General Hospital created a cross continuum program that has reduced readmissions and increased timely primary care visits for discharged patients. A basic bundle of services includes communication between inpatient and outpatient providers, providing the right information to the next level of providers, and giving patients and family members the right level of education. Transitional care nurses work with heart failure patients of any age and patients over 55 with chronic obstructive pulmonary disease, diabetes, renal failure, or who are recovering from a myocardial infarction. The nurses work closely with patients and family members during the hospital stay and follow up weekly for 30 days after discharge. PMID- 26964417 TI - CASE MANAGEMENT INSIDER. Thinking of Separating Utilization Management and Case Management? Think Again! AB - Case management should be designed as a fully patient-centric model with all the roles and functions of the case manager and social worker performed as part of a package of services provided to the patient, not as a series of tasks that are disjointed and performed in isolation of each other. When case management models separate these roles, they create an environment in which these roles no longer interface and no longer are applied with the patient's current and long-term care needs in mind. Be very cautious when implementing such models and as you can see above, the argument that the collaborative model is less expensive simply does not hold true. Whenever possible, try to keep your case management roles and functions as integrated as possible for the greatest success and achievement of outcomes! PMID- 26964418 TI - Transitional coordinator nurses focus on at-risk patients with chronic diseases. AB - Tucson Medical Center keeps its readmission rates low by having transitional coordinators work closely for patients with chronic disease who are at risk for readmissions. An analysis of readmitted patients determined that many who were rehospitalized were elderly with chronic diseases. The transitional coordinators are three experienced nurses with knowledge of chronic disease who work closely with the care team and follow patients for up to 30 days after discharge. The hospital arranges for post-acute providers to come to the hospital to see the patients referred to them for services. PMID- 26964419 TI - In Memoriam--Denis Carrier. PMID- 26964420 TI - Nagweyaab Geebawug: A retrospective autoethnography of the lived experience of kidney donation. AB - "Get the camera!" I yelled. As my young son came running towards me with the camera, I pointed up to the sky. Therethey were, four magnificent gleaming rainbows. The cloudssurrounding were a moody bluish black and the sun swiftly andgracefully beamed through them. The shimmering and glistening rainbows in that brief moment of sunshine pierced throughmy own darkness. In the last few months in my First Nationscommunity, we had experienced many deaths. Some of thesedeaths were relatives and friends. Years later, I would gaze atthe picture taken through hot tears, Nagweyaab geebawug orrainbow spirits I thought--these are the ancestors, those whohave passed reminding us to never give up. This is a story and inthis story an autoethnographical narrative emerges that is richwith contextual cultural interpretations of myself as a kidneydonor to my son. Through this autoethnographical narrative,there is the potential to further illuminate the lived experienceof chronic kidney disease (CKD) and kidney transplantation. Inthis paper, the terms First Nations and Indigenous are utilizedinterchangeably. PMID- 26964421 TI - An introduction to chemotherapy-associated nephrotoxicity. PMID- 26964422 TI - The Canadian Organ Replacement Register: Nursing's important contribution. AB - You are a charge nurse in a large hemodialysis unit in Ontario.One of the clerical staff has approached you today to assist withan update to her statistics on new and existing patients in yourunit. You are asked to clarify the cause of death for one patientand to clarify the date of transfer to the home dialysis programfor peritoneal dialysis on another patient. Finally, you are asked toremind the nurse practitioner (NP) to complete a registration formfor another patient who has just started chronic hemodialysis inyour unit. While you know the collection of data is important, thereare lots of patients to look after and you feel frustrated by havingto take time away from planning urgent hemodialysis requests--which are your priority--to source out information to complete aform. You reflect on this need for statistical data and wonder wherethe information on this form ends up and how it helps your patientswho are living with end stage kidney disease (ESKD). PMID- 26964423 TI - The dialysis technologist: What is our role? PMID- 26964424 TI - Development of competencies for the use of bedside ultrasound for assessment and cannulation of hemodialysis vascular access. AB - Use of ultrasound for hemodialysis vascular access assessment and real-time cannulation requires specialized training. In order to obtain basic hand-eye coordination, theoretical sessions on ultrasound use, as well as practical sessions using phantom models are recommended prior to its use in the clinical setting with patients. New users of this technology need to consider that all competencies can be achieved with daily use of ultrasound at the bedside. It takes approximately 500 guided cannulations to achieve the highest level of competency described above. PMID- 26964425 TI - Erythema nodosum leprosum research: ENLISTing support. PMID- 26964426 TI - Leprosy: a review on elimination, reducing the disease burden, and future research. AB - Leprosy, one of the oldest diseases known to man, is a stigmatising, potentially disabling disease. Throughout history, leprosy has been associated with fear, prejudice and immense social stigma. It remains one of the leading causes of deformity and physical disability from an infectious disease. Tremendous advances in leprosy control were made by the World Health Organization, and the 'elimination of leprosy', defined as a decrease of disease prevalence to less than 1 case per 10,000 population, was achieved by 2000. However, the reality is that true 'elimination' is yet to be achieved. Despite almost 30 years of effective multidrug treatment, the prevalence and incidence of leprosy have plateaued since 2005. Moreover, new cases with Grade 2 disability and new cases occurring in children remain unchanged since 2010, reflecting a failure in early leprosy detection, and indicating that transmission is clearly continuing. This review examines the challenges of elimination, and proposes further measures to reduce the disease burden, including future research possibilities. PMID- 26964427 TI - The decline of leprosy in the Republic of Korea; patterns and trends 1977-2013. AB - BACKGROUND: Though the World Health Organization declared the 'elimination of leprosy as public health problem' in 2000, the disease remains endemic in many countries. Current trends in incidence of infection and disease are unclear. METHODS: Data on leprosy prevalence between 1977-2013 and data on new leprosy cases detected in the Republic of Korea between 1989-2013 were analysed by age, sex, clinical types, mode of detection, family history, disability grading and geographical distribution. RESULTS: Both prevalence and incidence have declined greatly. There has been a shift to an increased proportion of multibacillary disease, and older age groups, consistent with a dramatic decrease in infection transmission in recent decades. An increase in proportion of cases with family history of disease is consistent with these declines. There is evidence that declines in infection and disease have been greater in the north of the country, as revealed in patterns by place of birth over time. Cases in immigrants now form a substantial proportion of leprosy disease in the Republic of Korea. CONCLUSIONS: Leprosy has declined dramatically in the Republic of Korea in recent decades, and transmission of M. leprae may have effectively stopped. There remains a burden of care for individuals whose disease developed in the past, and there may be some additional newly detected cases among immigrants and among older individuals who acquired autochthonous infections decades ago. PMID- 26964428 TI - Hidden leprosy cases in tribal population groups and how to reach them through a collaborative effort. AB - BACKGROUND: Tribal populations are an underserved population group and access to health services is a major challenge for them. Since leprosy treatment is integrated with the general health services, identifying leprosy cases is not be easy in these settings and they remain as endemic reservoirs, unless greater efforts are made to reach them. METHODOLOGY: An active search operation was conducted in the tribal colonies in four pre-identified Health & Nutrition Clusters, Nellore district, Andhra Pradesh, India, in 2013. After a brief training, village health nurses and selected volunteers covered all the households, showing flash cards with photos of leprosy cases and enquiring if there was any resident with a similar condition. Suspects were listed and examined by the district leprosy supervisor and field coordinators from Damien Foundation. Follow up interviews were done after one year to assess the treatment completion rate. RESULTS: Village health workers covered 47,574 people living in the tribal colonies and identified 325 leprosy suspects. Among them, 70 were confirmed as new leprosy cases. The prevalence of previously undetected leprosy cases was found to be 14.7/10,000. Out of 70 cases, 19 (27%) were children, 35 (50%) were female, 32 (45.7%) were classified as MB leprosy, 6 (8.6%) had a leprosy reaction and 11 (15.7%) persons had Grade 2 disability at the time of diagnosis. The treatment completion rate was found to be 74% at the end of one year. CONCLUSION: The study reveals a very high burden of leprosy among the tribal population and demonstrates how resources can be mobilized from government, NGO and local community sources to promote early case detection among underserved population groups. PMID- 26964429 TI - Human migration, railways and the geographic distribution of leprosy in Rio Grande do Norte State--Brazil. AB - INTRODUCTION: Leprosy is a public health problem in Brazil where 31,044 new cases were detected in 2013. Rio Grande do Norte is a small Brazilian state with a rate of leprosy lower than other areas in the same region, for unknown reasons. OBJECTIVES: We present here a review based on the analysis of a database of registered leprosy cases in Rio Grande do Norte state, comparing leprosy's geographic distribution among municipalities with local socio-economic and public health indicators and with historical documents about human migration in this Brazilian region. RESULTS: The current distribution of leprosy in Rio Grande do Norte did not show correlation with socio-economic or public health indicators at the municipal level, but it appears related to economically emerging municipalities 100 years ago, with spread facilitated by railroads and train stations. Drought-related migratory movements which occurred from this state to leprosy endemic areas within the same period may be involved in the introduction of leprosy and with its present distribution within Rio Grande do Norte. CONCLUSIONS: Leprosy may disseminate slowly, over many decades in certain circumstances, such as in small cities with few cases. This is a very unusual situation currently and a unique opportunity for epidemiologic studies of leprosy as an emerging disease. PMID- 26964430 TI - Relapse and deformity among 2177 leprosy patients released from treatment with MDT between 2005 and 2010 in South India: A retrospective cohort study. AB - OBJECTIVE: To estimate the incidence of relapse among leprosy patients released after completing multi-drug therapy (MDT) during 2005-2010 under India's National Leprosy Eradication Programme in South India. METHODS: We conducted a retrospective cohort study of leprosy patients who were released from treatment (RFT) with MDT during April 2005 and March 2010 in four purposely selected districts from South India. We clinically examined them for signs of relapse, persistence and deformity. We collected slit skin smears from those reporting signs of relapse or persistence. We computed relapse rate per 1000 person years by dividing the number of relapses by person years of follow-up and 95% confidence intervals (CI) for rates. FINDINGS: We tracked 3791 RFT patients and examined 58% of them. The examined and those who were not examined were similar in terms of leprosy type, year of completing MDT and gender. We identified 58 relapses (relapse rate 6.1 per 1000 person years) among the examined. Majority of these relapses occurred within 3 years post-MDT. Eighteen (31%) of the relapsed patients had deformity. CONCLUSION: While low level of relapse indicates effectiveness of MDT, the burden of deformity is of concern. For maximizing treatment effectiveness and minimizing transmission, we recommend educating leprosy patients at treatment completion for self-monitoring of signs of relapse and advising them to visit nearby public health facilities or Community health workers for immediate evaluation and intervention. PMID- 26964431 TI - Non-adherence to steroid therapy in leprosy reaction and neuritis. PMID- 26964432 TI - Leprosy associated with psoriasis. AB - Reported cases of leprosy and psoriasis coexistence are uncommon in the literature. Studies suggest a negative association between these two diseases. A case of association between these disorders has been reported. PMID- 26964433 TI - Report on a month course in clinical and surgical leprosy for undergraduate students of physiotherapy. PMID- 26964434 TI - Effectiveness of Methotrexate in prednisolone and thalidomide resistant cases of Type 2 lepra reaction: report on three cases. PMID- 26964435 TI - Presence of an index case in households of newly registered leprosy patients: experience from a leprosy referral centre in South India. AB - The global leprosy burden in terms of new case detection does not seem to show a declining trend. India continues to be one of the major contributors to the leprosy burden. It is well known that the presence of an index case is a risk factor for leprosy among household contacts. The Blue Peter Health and Research centre (BPHRC), a leprosy referral centre in South India, observed the presence of an index case in 27.6% of leprosy patients newly diagnosed during 2009-2013. A majority of the index cases were either parents or siblings. Early case detection is recommended in global and national strategies, but active contact screening is not in the purview of integrated leprosy services in India. Active contact screening may be considered as one of the major activities to further reduce the leprosy burden. PMID- 26964436 TI - Bullous Erythema Nodosum Leprosum masquerading as systemic onset juvenile idiopathic arthritis: A case report. PMID- 26964438 TI - Borderline Hansen complicated by a metastatic cold abscess. PMID- 26964437 TI - Single patch, mononeuritic multibacillary leprosy: A case report. PMID- 26964439 TI - Hemophagocytic lymphohistiocytosis in leprosy. AB - A patient from Southeast Asia was diagnosed with systemic lupus erythematosus. One year later, she experienced exacerbation of skin lesions and was diagnosed with erythema nodosum leprosum. Upon treatment, the patient developed hemophagocytic lymphohistiocytosis with multi-organ failure and died from invasive fungal infection. Hemophagocytic lymphohistiocytosis has to our knowledge, not previously been reported in leprosy. PMID- 26964440 TI - Erythema Nodosum Leprosum International Study Group: 3rd ENLIST Meeting Report, Mumbai, 7th-9th April 2015. PMID- 26964441 TI - Absent. PMID- 26964442 TI - Regulators and regulations: who will guard the guards? (or 'Quis custodiet ipsos custodes' as old Juvenal used to say). AB - Overbearing regulators with their various labyrinthine regulations have had adverse impacts on dentists and their teams' behaviours. This has produced the perverse outcomes of demoralizing dental teams as well as reducing their capacity and/or desire to deliver compassionate oral healthcare. These adverse outcomes do not seem to have benefited patients, or dentists, or their teams, in any sensible or measurable way. CPD/CLINICAL RELEVANCE: The vastly increased burdens on the UK dental profession of intrusive, bullying regulations, emanating from the various UK agencies, such as the supposedly fair and independent GDC, but including the increasingly politically controlled NHS and the CQC, have had unfortunate, perverse, effects on many dentists' clinical practices and affected dental teams' desires, or willingness, to be as compassionate as they used to be about helping to solve some patients' dental or oral problems. PMID- 26964443 TI - Minimally Invasive Long-Term Management of Direct Restorations: the '5 Rs'. AB - The assessment and operative long-term management of direct restorations is a complex and controversial subject in conservative dentistry. Employing a minimally invasive (MI) approach helps preserve natural tooth structure and maintain endodontic health for as long as possible during the restorative cycle. This paper discusses how minimally invasive techniques may be applied practically to reviewing, resealing, refurbishing, repairing or replacing deteriorating/failed direct coronal restorations (the'5 Rs') and provides an update of contemporary MI clinical procedures. CPD/CLINICAL RELEVANCE: The assessment and long-term clinical management of deteriorating/failing direct restorations is a major component of the general dental practice workload and NHS UK budget expenditure for operative dentistry. PMID- 26964444 TI - Rehabilitation of Oncology Patients with Hard Palate Defects Part 2: Principles of Obturator Design. AB - The first part of this series on the conventional rehabilitation of oncology patients with hard palate defects discussed the dental challenges posed by oncology patients and the surgical/restorative planning interface for conventional dental rehabilitation. This article will describe Aramany's classification of hard palate defects, Brown's classification of palatal defects and focus on the basic principles of obturator design which need to be appreciated when prosthetically rehabilitating a patient with a hard palate defect. CPD/CLINICAL RELEVANCE: A good understanding of basic removable prosthodontic theory relating to denture design, dental materials science and head and neck anatomy is a prerequisite when designing an obturator for a patient. PMID- 26964445 TI - Denosumab, an Alternative to Bisphosphonates but also Associated with Osteonecrosis of the Jaw--What is the Risk?. AB - Most dental professionals will have, or will soon, encounter patients prescribed this novel alternative antiresorptive drug to bisphosphonates, denosumab (Prolia(r), Xgeva(r)). Denosumab is licensed in the UK for the prevention of osteoporotic fractures in postmenopausal women and the prevention of skeletal related events (SRE) in adults with bone metastases. The presence of osteonecrosis of the jaw in patients receiving non-bisphosphonate antiresorptives has led to the introduction of the term antiresorptive-related osteonecrosis of the jaw or ARONJ. This paper discusses the basic physiology of bone remodelling, the pharmacology of bisphosphonates and denosumab, and the risk of ARONJ. CPD/CLINICAL RELEVANCE: What is the potential risk of ARONJ arising from dental treatment that we should be advising for our patients? PMID- 26964446 TI - Pain Part 3: Acute Orofacial Pain. AB - Acute trigeminal pain is a common presentation in the dental surgery, with a reported 22% of the US adult population experiencing orofacial pain more than once during a 6-month period. This article discusses the mechanisms underlying the pain experience, diagnosis and subsequent management of acute trigeminal pain, encompassing pre-, peri- and post-operative analgesia. The dental team spend most of their working lives managing patients and acute pain. The patient may present to the clinician in existing pain, which may often provide a diagnostic challenge. Prevention and managing intra-operative and post-surgical pain are implicit in providing your patient with optimum care. CPD/CLINICAL RELEVANCE: This paper aims to provide an overview of conditions that may present with acute orofacial pain and their management using the most recent evidence base. Intra-operative and post-surgical pain management are also scrutinized and evidence based treatment is recommended. PMID- 26964447 TI - Dementia and Dentistry. AB - Dementia is increasing in prevalence: by 2025 it is estimated that there will be over a million people in the UK with this diagnosis. The condition is likely to affect us all as healthcare providers, whether in our patients, our relatives or ourselves. This article gives an overview of dementia: causes, treatment, how it affects people and provides advice on how to manage patients with dementia who require dental care. CPD/CLINICAL RELEVANCE: By identifying the patient with dementia and being aware of the challenges in providing care the clinician can provide better treatment and reduce the chance of dental problems as the condition progresses. PMID- 26964448 TI - An Unusual Extranodal Presentation of Mycobacterium Tuberculosis in the Upper Lip. AB - Tuberculosis (TB) is a leading cause of morbidity and mortality worldwide, with a peak incidence in South-East Asia and Sub- Saharan Africa. A significant number of patients in the UK are affected. Extra-pulmonary TB presentation varies, and includes head and neck manifestations that can present on routine examination in the dental practice setting. We report an unusual case of extra-nodal TB in the upper lip, and provide some guidance to general dental practitioners on the presenting features of such lesions, and what to refer for further investigation where TB is included in the differential diagnosis. CPD/CLINICAL RELEVANCE: This case report highlights important factors in TB diagnosis, with particular emphasis on presenting features relevant to general dental practitioners, and informs on the accepted and current treatment regimen. PMID- 26964449 TI - Mouth Cancer for Clinicians Part 3: Risk Factors (Traditional: Tobacco). AB - A MEDLINE search early in 2015 revealed more than 250,000 papers on head and neck cancer; over 100,000 on oral cancer; and over 60,000 on mouth cancer. Not all publications contain robust evidence. We endeavour to encapsulate the most important of the latest information and advances now employed in practice, in a form comprehensible to healthcare workers, patients and their carers. This series offers the primary care dental team, in particular, an overview of the aetiopathogenesis, prevention, diagnosis and multidisciplinary care of mouth cancer, the functional and psychosocial implications, and minimization of the impact on the quality of life of patient and family. CPD/CLINICAL RELEVANCE: This article offers the dental team an overview of the main cancer risk factors, tobacco and alcohol, betel and other chewing habits, and environmental factors. PMID- 26964450 TI - Infraoccluded Upper Deciduous Second Molars Leading to Caries in the Permanent Dentition. AB - Infraocclusion of primary teeth is a problem that can be recognized early by the general dental practitioner. Allowing affected teeth to deteriorate beyond a point where active intervention would be recommended can make treatment of the condition more complex or may lead to unexpected sequelae. The case described in this report of infraoccluded primary teeth, suffered pathology in adjacent teeth, leading to multiple extractions and fixed orthodontic treatment post surgery. This case highlights the need for early recognition of infraocclusion by the GDP and will suggest interceptive treatment options. CPD/CLINICAL RELEVANCE: To highlight the need of interceptive orthodontics in primary care when required. PMID- 26964451 TI - Decision-Making for Residual Periodontal Pockets after Aetiological Treatment. AB - The practitioner may have difficulties making decisions regarding the most appropriate therapeutic approach in the case of the persistence of periodontal pockets after initial periodontal treatment. Several options may be considered: aetiologic retreatment, maintenance, surgery of the pocket or extraction of the tooth for strategic reasons or when the conservation of the tooth is impossible. There are no clear guidelines for the treatment decision. The aim of this article is to present the main factors involved in making a treatment decision. An algorithm and its background rationale are presented to help the practitioner make a decision about residual periodontal pockets after aetiological treatment. PMID- 26964452 TI - Articaine hydrochloride: is it the solution?. PMID- 26964453 TI - Authors' response. PMID- 26964454 TI - Dentistry + paediatrics + Maxillofacial Surgery = not so ordinary. PMID- 26964455 TI - Keep an eye out for the bifid uvula: yes please--as it is not always just an isolated congenital anomaly. PMID- 26964456 TI - Placement of Class II composites. PMID- 26964457 TI - Clinical Challenges Q&A 11. Ulcers. PMID- 26964458 TI - Technique Tips--The Cost of One Bond Failure? PMID- 26964459 TI - [PANCREATIC CANCER: TERRA INCOGNITA IN MODERN GASTROENTEROLOGY]. AB - The author presents definition of pancreatic cancer (PC), epidemiological data on its prevalence, risk factors (chronic pancreatitis, viral hepatitis B, smoking, etc.), and clinical symptoms. Modern laboratory and instrumental differential diagnostic methods are discussed. Morphological classification and stages of the neoplastic process are considered with special reference to the methods of its surgical treatment and adjuvant therapy. PMID- 26964460 TI - [POSSIBLE CAUSES OF INEFFICIENT MONOTHERAPY OF SUBCLINICAL HYPOTHYROIDISM WITH L THYROXIN]. AB - Substitution therapy with L-thyroxin was recognized in 2012 to be the method of choice for the treatment of subclinical hypothyroidism. However it does not always allow to achieve normalization of all metabolic parameters. The aim of our work was to search for and analyze data on the possible mechanisms responsible for the failure of replacement hormonal therapy with L-thyroxin with a view to changing the therapeutic strategy for patients with subclinical hypothyroidism. PMID- 26964461 TI - [STRUCTURAL, FUNCTIONAL, AND VEGETATIVE CONDITIONS OF PATIENTS WITH STABLE ARTERIAL HYPERTENSION, ITS MASKED FORM, AND WHITE COAT HYPERTENSION]. AB - The character of changing of functional and vegetative characteristics in different clinical variants of arterial hypertension thus far remains obscure. The aim of this work was to study patients with stable arterial hypertension (SAH), its masked form (MH), and white coat hypertension (WCH). We examined 125 patients who were divided into these 3 groups based on results of 24 hr AP monitoring by cardiac rhythm measurement and echocardiography. The study revealed different risk factors of each of the three forms of AH. The main risk factors of WCH are age and disturbed rhythm variability, those of MH are overweigh, obesity, and myocardial dysfunction, while SAH is associated with the advanced age, overweight, obesity, the history of concomitant cardiovascular diseases, and disordered daily profile of AP. It is concluded that different clinical variants of AH result from the changes in the functioning of cardiovascular and vegetative nervous systems associated with different risk factors. PMID- 26964462 TI - [THE RELATIONSHIP BETWEEN DISORDERS-OF EXTERNAL RESPIRATION AND RIGHT HEART REMODELING IN PATIENTS WITH ATOPIC BRONCHIAL ASTHMA]. AB - This study aimed at the evaluation of the state of the respiratory system and its possible influence on the structural and functional characteristics of the right heart in patients with atopic bronchial asthma (BA) with a view to optimizing diagnostics and prevention of cardiovascular complications. The study included 189 subjects of whom 148 with BA were divided into 3 groups depending on the severity of the disease. Forty practically healthy volunteers comprised the control group. The external respiration function and right ventricle functional parameters were the main variables measured in all the participants of the study. It was shown that disorders of external respiration and pulmonary hyperinflation progressed with severity of BA and thereby promoted right ventricular myocardium remodeling and dysfunction that in turn led to chronic cardiac insufficiency. It is concluded that functional changes in the right heart in of patients with BA of different severity are associated with remodeling of the respiratory tract. PMID- 26964463 TI - [MORPHOFUNCTIONAL MYOCARDIAL CHARACTERISTICS IN PATIENTS WITH MASKED ARTERIAL HYPERTENSION AND WHITE COAT HYPERTENSION]. AB - The aim of this work was to study morpho-functional myocardial characteristics in patients with masked arterial hypertension (AH) and white coat hypertension (WCH) given antihypertensive therapy (AHT) and without it. This cross-sectional cohort study included employees of a large industrial enterprise who annually underwent routine medical examination supplemented by 24 hr AP monitoring and echocardiography carried out at specified time of the working day. The participants of the study were divided into 6 groups based on the relationship between clinical AP and mean AP during work. Group I comprised 20 (7%) subjects with normal AP, group 2--20 (7%) with masked AH, group 3--40 (14%) with WCH, group 4--81 (28.3%) with optimal A HT effect, group 5--64 (22.4%) with unmanifest inefficiency of AHT, group 6--40 (14%) with WCH during AHT. Criteria for masked AH and unmanifest AHT inefficiency were clinical AP below 140 and 90 mm Hg in combination with mean AP during work 135 and/or 85 mm Hg and higher. Echocardiography was performed in a standard positions in M- and B-modes as well as in three Doppler regimes. One-factor ANOVA was used to analyze differences between the groups and Pearson's Chi-square test to determine the relationship between categorical variables. 206 (72%) of the 286 employees of the large industrial enterprise had a diagnosis of AH. It was shown that ambulatory AP values obtained by 24 hr monitoring better characterized the patient's condition than clinical AP since they correlated with the frequency of disorders in the target organs and the risk of cardiovascular complications in patients with AH. Patients with masked AH more frequently developed left ventricular hypertrophy and diastolic dysfunction than those having normal clinical and ambulatory AP. The mean width of the left ventricle wall and left ventricular isovolumic relaxation time (therefore, the degree of LV hypertrophy and diastolic dysfunction) in the patients with unmanifest inefficiency of AHT were greater than in those with optimal AHT effect. The occurrence of WCH was comparable in the two groups. These data were used to determine intensity of preventive AHT at the workplace with a view to improving medical and occupational prognosis. PMID- 26964464 TI - [CHRONODIAGNOSTICS AND CHRONOTHERAPY OF COGNITIVE DISORDERS IN ELDERLY SUBJECTS]. AB - Cognitive disorders in elderly subjects with cerebral atherosclerosis confirmed by paraclinical methods and psychological tests are accompanied by sympathicotonia and rhythm desynchronization of RR-intervals in ECG. Biocontrolled IR laser therapy in the projection of frontal and temporal lobes of both hemispheres, internal carotid and vertebral arteries, and superior cervical node reduces sympaticotonia, restores circumhoralian and circadian rhythms of RR intervals, improved cognitive functions and quality of sleep. PMID- 26964465 TI - [REFERENCE RANGES OF ANTITHROMBINE III IN ASSOCIATION WITH THE USE OF A STA COMPACT AUTOMATED COAGULOMETER]. AB - Domestic andforeign professional diagnostic communities recommend to develop new or confirm literature reference ranges for each laboratory parameter. Bearing in mind the importance of antithrombin-III levels for anticoagulation therapy, we determined their reference ranges for the adult population of the Astrakhan region and compared them with those obtained by other authors and presented in the instructions for use of commercial kits for measuring ant ithrombin-III. Our reference ranges differ from those cited in the said instructions. PMID- 26964466 TI - [MORPHO-FUNCTIONAL CHARACTERISTICS OF BLOOD CELL MITOCHONDRIA IN BRONCHIAL ASTHMA]. AB - We undertook a structural and functional study of blood cell mitochondria in 25 patients with controlled mild bronchial asthma (BA) including evaluation of blood saturation with oxygen, carboxyhemoglobin level in blood and carbon monoxide content in the exhaled air. Membrane potential of leukocyte mitochondria was determined based on the results of flow cytofluorimetry and fatty acid (FA) composition in platelet mitochondrial membranes measured by GLC. It was shown that the absence of clinical symptoms of BA during remission was associated with a reduction of membrane potential and a change of FA composition resulting in the depletion of the basal pool of saturated (12:0, 14:0, 18:0) and polyunsaturated (20:4n-6, 20:5n-3, 22:5n-3, 22:4n-6) FA. These changes in the structural and functional state of blood cell mitochondria in patients with BA are signs of disordered energy-producing activity, membrane permeability and transmembrane transport suggesting the development of mitochondrial dysfunction and cellular hypoxia. A deeper insight into the role of the structural and functional state of blood cell mitochondria in the formation of respiratory disorders will facilitate early detection of the risk and complications of bronchial obstruction. PMID- 26964467 TI - [RISK FACTORS OF CARDIOVASCULAR DISEASES AND COMORBID PATHOLOGY AS CAUSES OF MYOCARDIAL INFARCTION IN A YOUNG PATIENT]. AB - This paper deals with the problem of high prevalence of coronary heart disease and potential mortality of young patients with this pathology with reference to the role of metabolic, physiological, cultural, and behavioral factors and their combination influencing the risk of myocardial infarction in young patients. A 37 year-old patient is reported in whom a combination of multiple "traditional" risk factors of cardiovascular pathology and social factors resulted in extensive transmural myocardial infarction and death. PMID- 26964468 TI - [PULMONARY THROMBOEMBOLISM IN WOMEN USING ORAL HORMONAL CONTRACEPTIVES]. AB - Pulmonay thromboembolism is a common difficult-to-diagnose pathology not infrequently with a lethal outcome. There are many factors leading to hypercoagulation. One of them is intake of hormonal contraceptives to which doctors sometimes do not pay due attention. This paper reports two cases of acute coagulopathy with massive pulmonary thromboembolism in young women using these agents during a long period. PMID- 26964469 TI - [POSTPARTUM ACQUIRED HEMOPHILIA]. AB - This review deals with etiology, pathogenesis, clinical picture, diagnostic algorithm, and treatment of acquired hemophilia. In addition, a case of successful treatment of a patient with postpartum acquired hemophilia is reported. PMID- 26964470 TI - [ETACISIN-INDUCED BRUGADA SYNDROME IN A PATIENT WITH LONG-STANDING SUPRAVENTRICULAR EXTRASYSTOLE]. AB - Brugada syndrome is a commonest cause of malignant disorders of cardiac rhythm associated with sudden death. It is diagnosed based on characteristic ECG signs and ventricular arrhythmia. This paper reports a 49 year-old patient with long standing latent BS manifest as supraventricular and transient blockade of the right branch of the His bundle. The ECG pattern of BS became apparent in association with a 7 day treatment with class IC antiarrhythmic agent etacisin. Diagnostic difficulties account for the fact that the disease was initially described as myocardial infarction. Diagnosis of BS was confirmed by an electrophysiological study in which stable ventricular tachycardia and fibrillation were induced by etacisin. A cardioverter defibrillator was implanted to the patient. PMID- 26964471 TI - [FORMATION OF CLINICAL MENTALITY--AN IMPORTANT COMPONENT OF POST-GRADUATE MEDICAL TRAINING]. AB - The notion of clinical mentality is considered from the standpoint of its semantic meaning and significance for efficient medical activity. The main signs and implications of this notion are determined. It is shown, based on pedagogical methods (observations, conversations, solution of clinical problems, testing, etc.), that clinical mentality forms after 10 years of work in a given field. Criteria are proposed for distinguishing between health providers with and without clinical mentality. The free association method demonstrated that 37% of the doctors with a period of clinical work over 10 years have peculiarities of clinical mentality described as "internal medical mentality". Clinicians with the experience of work over 15 years exhibit empathy as a component of clinical mentality. The methods are proposed for the formation of clinical mentality during post-graduate education taking account of the modern differentiation of medical disciplines and the necessity to reconcile standards of medical aid and their application on an individual basis. PMID- 26964472 TI - Electric and acoustic stimulation during movement preparation can facilitate movement execution in healthy participants and stroke survivors. AB - There has been increasing interest in the use of loud acoustic stimulation (LAS) to gain insight into the preparation and initiation of motor actions. Typically, LAS presented during movement preparation in healthy participants culminates in the earlier than normal initiation of the prepared movement and an increase in the magnitude of the response. Recent reports have shown LAS can also facilitate movement in chronic stroke survivors. This suggests that current therapies for motor recovery after stroke might benefit from employing such alternate methods of triggering movement. In this study we sought to test a new way to facilitate motor actions that could be of relevance in clinical settings. Five individuals with chronic motor impairments due to stroke and eight healthy young adults performed a functional reaching task in response to a visual go-signal. On 30% of the trials, LAS or electric stimuli (collectively, sensory stimuli) were unexpectedly presented in synchrony with the go-signal. Both healthy and stroke participants reacted with shorter latencies and executed faster responses when sensory stimulation was synchronized with the go-signal. We have replicated previous findings showing acoustic stimuli can aid movement execution in chronic stroke survivors and demonstrated the same type of effect can be achieved using electric stimulation. Thus, these two types of sensory stimuli can be easily integrated with current devices available to assist people with stroke to engage in rehabilitation efforts. PMID- 26964473 TI - Investigating the psychosocial determinants of physical activity in older adults: A qualitative approach. AB - OBJECTIVE: Despite the benefits of physical activity (PA), only one-third of older adults meet the recommended levels. The present study focused on psychosocial determinants of PA following retirement. Social cognitive theory (SCT) was used to better understand pre- and post-retirement adults' thoughts about PA, the reasons why some individuals are more active than others, and how PA is incorporated into daily life after retirement. DESIGN: Seven focus groups of older adults (N = 37, M = 64, SD = 5.20; males = 20) representing a range of PA levels and retirement length participated in one of seven focus groups. RESULTS: Aligned with SCT, self-efficacy beliefs along with perceptions about barriers and benefits of PA were among the major determinants of PA. Findings highlighted the importance of social support, positive outcome expectations and self-regulatory strategies as motivators. The lack of structure in retirement was a hindrance to incorporating PA into daily routine but, when incorporated, PA provided a sense of purpose in the lives of retired individuals. CONCLUSION: It is important to understand the meaning of retirement as a life transition and how it affects beliefs about PA to inform SCT-based health promotion interventions targeting individuals in retirement age. PMID- 26964474 TI - Hemiballismus as a complication of an intratumoral chemotherapy catheter. AB - We report an unusual case of delayed bilateral, right greater than left hemiballismus in a 15-year-old female patient with a history of a craniopharyngioma 2years following the insertion of a right intratumoral chemotherapy catheter. Following cyst decompression, the catheter was found to have changed position, traversing the basal ganglia structures, namely the right subthalamic nucleus. Her movement disorder near-completely resolved immediately following removal of the catheter. A review of the current literature and proposed pathophysiological mechanisms are discussed. PMID- 26964475 TI - Rapidly-progressive catatonia responsive to zolpidem in a patient with ovarian teratoma-associated paraneoplastic encephalitis. AB - Psychiatric symptoms and catatonia are key components of the clinical presentation of paraneoplastic encephalitis; additionally symptoms can be long lasting and often difficult to treat. We report a 73-year-old patient with rapidly progressive catatonia not responsive to immunotherapy, tumor resection, electroconvulsive therapy, or benzodiazepines who had significant improvement after zolpidem administration. This report suggests that zolpidem is an option in the treatment of patients with refractory catatonia and paraneoplastic encephalitis. PMID- 26964477 TI - Oral delivery of diabetes peptides - Comparing standard formulations incorporating functional excipients and nanotechnologies in the translational context. AB - While some orally delivered diabetes peptides are moving to late development with standard formulations incorporating functional excipients, the demonstration of the value of nanotechnology in clinic is still at an early stage. The goal of this review is to compare these two drug delivery approaches from a physico chemical and a biopharmaceutical standpoint in an attempt to define how nanotechnology-based products can be differentiated from standard oral dosage forms for oral bioavailability of diabetes peptides. Points to consider in a translational approach are outlined to seize the opportunities offered by a better understanding of both the intestinal barrier and of nano-carriers designed for oral delivery. PMID- 26964476 TI - Intraoperative high-field MRI maximizes the extent of resection in intraventricular central neurocytoma surgery. AB - Central neurocytoma (CN) is a rare benign neuronal tumor of the ventricular system. Microsurgical resection is considered to be the mainstay of treatment for intraventricular CN, and the extent of resection is the most important prognostic factor. We describe our initial experience in the management of intraventricular CN with intraoperative MRI together with microscope-based neuronavigation. During a 5year period between February 2009 and June 2014, 18 consecutive patients with histologically proven CN were included in this study. Gross total tumor resection was achieved in 88.9% (16/18) of patients. There were no perioperative deaths, and the overall complication rate was 61.1% (11/18). The Karnofsky Performance Status score at the last follow-up was 100 in eight (44.4%), 90 in seven (38.9%), and ?70 in three patients (16.7%). We conclude that intraoperative high-field MRI combined with microscope-based neuronavigation can maximize the extent of resection in intraventricular CN surgery and minimize the risks of neurological impairment. PMID- 26964478 TI - Solution-Processed CuS NPs as an Inorganic Hole-Selective Contact Material for Inverted Planar Perovskite Solar Cells. AB - Organic-inorganic hybrid perovskite solar cells (PSCs) have drawn worldwide intense research in recent years. Herein, we have first applied another p-type inorganic hole-selective contact material, CuS nanoparticles (CuS NPs), in an inverted planar heterojunction (PHJ) perovskite solar cell. The CuS NP modification of indium tin oxide (ITO) has successfully tuned the surface work function from 4.9 to 5.1 eV but not affect the surface roughness and transmittance, which can effectively reduce the interfacial carrier injection barrier and facilitate high hole extraction efficiency between the perovskite and ITO layers. After optimization, the maximum power conversion efficiency (PCE) has been over 16% with low J-V hysteresis and excellent stability. Therefore, the low cost solution-processed and stable CuS NPs would be an alternative interfacial modification material for industrial production in perovskite solar cells. PMID- 26964479 TI - Cardiovascular aspects of geriatric medicines in traditional Persian medicine; a review of phytochemistry and pharmacology. AB - BACKGROUND: Geriatrics are a group of patients over 65 years and with multiple comorbidities and different functional impairments. Apart from decline in body mass, presence of exhaustion and general fatigue, an aged person may also suffer from various disorders. Approximately, around 30% of geriatric subjects have significant cardiovascular ailments. Apart from the intensive management of cardiovascular aspects in elderly, monitoring of the complementary cardiac medicine in those people should be received more attention. PURPOSE: There are many management lines for a cardio-geriatric condition in Traditional Persian Medicine (TPM). Accordingly, this paper aimed to deal with those medicaments as well as evidence-based clinical aspects and phytochemistry. METHODS: By searching through main pharmaceutical manuscripts of Persian medicine during 10th-18th centuries (A.D.), concurrently, natural medicines for geriatrics and remedies for cardiovascular ailments were derived. On the other side, related phytochemical and pharmacological aspects of those remedies were highlighted. RESULTS: In all, 38 cardiovascular and 34 geriatric medicaments were found in those manuscripts. Antihyperlipidemic and cholesterol lowering activities of those medicines were the most reported activities in current medicine. However, other pharmacological reports were related to hypotensive, coagulant, cardio-protective and cardiotonic activities. In regard of the chemical composition, medicaments were mainly of polyphenols and flavonoids and also most of the employed extracts and fractions were yielded from polar or semi-polar solvents. CONCLUSION: With reference to these findings, flavonoid-rich medicaments from Persian medicine may be selected as considerable herbs for geriatrics with cardiovascular ailments. PMID- 26964481 TI - Drug functionalized microbial polysaccharide based nanofibers as transdermal substitute. AB - In order to promote the natural healing process, drug-functionalized nanofibrous transdermal substitute was fabricated using gellan as chief polymer and polyvinyl alcohol (PVA) as supporting polymer via electrospinning technique. These fabricated nanofibers physiochemically mimic the extracellular matrix (ECM) which supports the cell growth. For neo-tissue regeneration in a sterilized environment, amoxicillin (Amx) was entrapped within these nanofibers. Entrapment of Amx in the nanofibers was confirmed by FESEM, FTIR, XRD and TG analysis. In vitro cell culture studies revealed that the fabricated non-cytotoxic nanofibers promoted enhance cell adherence and proliferation of human keratinocytes. A preliminary in vivo study performed on rat model for full thickness skin excision wound demonstrated the prompt re-epithelialization in early phase and quicker collagen deposition in later phases of wound healing in case of Amx functionalized gellan/PVA nanofibers. Data collectively confirmed the potential usage of gellan based electrospun nanofibers as transdermal substitute for faster skin restoration. PMID- 26964480 TI - GC-MS and LC-MS approaches for determination of tocopherols and tocotrienols in biological and food matrices. AB - Tocopherols and tocotrienols, widely described as vitamin E derivatives, have been proven to take part in a number of important biological functions. Among them, antioxidant properties had been investigated and documented in the literature. Since tocochromanols have revealed their plausible beneficial impact on several pathological processes, such as cancerogenesis or cognitive impairment diseases, there is a growing interest in quantitative determination of these compounds in biological fluids, tissues and plant organs. However, due to vitamin E chemical features, such as lipophilic and non-polar characteristics, quantitative determination of the compounds seems to be problematic. In this paper we present current analytical approaches in tocopherols and tocotrienols determination in biological and food matrices with the use of chromatographic techniques, especially gas chromatography (GC) and high performance liquid chromatography (HPLC) coupled with mass spectrometry. Derivatization techniques applied for GC-MS analysis in the case of tocol derivatives, especially silylation and acylation, are described. Significant attention is paid to ionization process of tocopherols and tocotrienols. PMID- 26964482 TI - iRGD decorated lipid-polymer hybrid nanoparticles for targeted co-delivery of doxorubicin and sorafenib to enhance anti-hepatocellular carcinoma efficacy. AB - The combination of doxorubicin (DOX) with sorafenib (SOR) has proven an effective strategy to enhance anti-hepatocellular carcinoma (HCC) efficacy. However, respective in vivo pharmacokinetic profiles and different endocytosis capacities of these two drugs greatly hinder their current application. Herein, the tumor targeting peptide iRGD decorated lipid-polymer hybrid nanoparticles (NPs) with a shell-core structure were developed for co-delivery of DOX and SOR (DOX+SOR/iRGD NPs). After the drug ratio was optimized, the stabilized DOX+SOR/iRGD NPs were prepared. Through the iRGD-integrin recognition, DOX+SOR/iRGD NPs showed synergistic cytotoxicity, pro-apoptotic ability and enhanced internalization rate in human liver cancer HepG2 cells. In vivo pharmacokinetic result demonstrated that an extended circulation and bioavailability of DOX+SOR/iRGD NPs than free drugs. More importantly, DOX+SOR/iRGD NPs significantly enhanced antitumor efficiency in HCC xenograft mouse models. Overall, this study describes a promising nanoparticulate drug co-delivery strategy to combine clinical anticancer drugs and enhance anti-HCC efficacy. PMID- 26964484 TI - Skeletal Muscle and Physical Activity in Portuguese Community-Dwelling Older Adults. AB - The aims of this study were to describe age- and sex-related differences in total body skeletal muscle (TB-SM) mass and to determine the variance explained by physical activity (PA). This cross-sectional study included 401 males and 402 females, aged 60-79 years. TB-SM was determined by dual-energy x-ray absorptiometry (DXA) and PA by Baecke questionnaire. Statistical analysis included t test, ANOVAs, Pearson correlations, and multiple regression analysis. TB-SM mass was higher in the youngest age group when compared with the oldest in males and females. Males had greater TB-SM values than females. PA made a significant and positive contribution to the variation in TB-SM, beta = 0.071; p = .016. Sex, height, fat mass, and PA explained 77% of the variance in TB-SM. The oldest cohorts and females had lower TB-SM than the younger cohorts and males. This study suggests that PA exerts a significant role in the explanation of TB SM. PMID- 26964483 TI - Tracking inflammation in the epileptic rat brain by bi-functional fluorescent and magnetic nanoparticles. AB - Correct localization of epileptic foci can improve surgical outcome in patients with drug-resistant seizures. Our aim was to demonstrate that systemically injected nanoparticles identify activated immune cells, which have been reported to accumulate in epileptogenic brain tissue. Fluorescent and magnetite-labeled nanoparticles were injected intravenously to rats with lithium-pilocarpine induced chronic epilepsy. Cerebral uptake was studied ex vivo by confocal microscopy and MRI. Cellular uptake and biological effects were characterized in vitro in murine monocytes and microglia cell lines. Microscopy confirmed that the nanoparticles selectively accumulate within myeloid cells in the hippocampus, in association with inflammation. The nanoparticle signal was also detectable by MRI. The in vitro studies demonstrate rapid nanoparticle uptake and good cellular tolerability. We show that nanoparticles can target myeloid cells in epileptogenic brain tissue. This system can contribute to pre-surgical and intra surgical localization of epileptic foci, and assist in detecting immune system involvement in epilepsy. PMID- 26964486 TI - De ontwikkelingsneurologische theorie van schizofrenie: bewijsmateriaal betreffende structuur en neuropsychologic. AB - Severe schizophrenics as a group show subtle abnormalities of cerebral structure. Cerebral ventricular enlargement is the best replicated finding, and this tends to be associated with impairment of neuropsychological performance. The idea that these abnormalities have a neurodevelopmental origin gains indirect support from the, admittedly less consistent, evidence of abnormalities of cerebral asymmetry and of neuronal migration in adult schizophrenics, as well as from the behavioural, psychomotor, and cognitive impairments reported in preschizophrenic children. However, the relationship between childhood and adult neuropsychological and brain structural findings has not been proven, and we do not know whether only some schizophrenics have a developmental origin, or whether patients differ only in the degree of developmental impairment that they show. PMID- 26964487 TI - rCBF-activatie en neuronale circuits gerelateerd aan visuele waarneming. AB - Three principles of neuronal interaction within cortically distributed networks are discussed. PET-rCBF activation methods provide an opportunity to acquire insight in the distribution of functionally related areas of the human brain in vivo. The distinction of visual areas, activated by either motion or color within an observed scenery, points at a segregation in neuronal information processing. Such a segregation extends into both a dorsal and a ventral route towards consequently the parietal and temporal cortex. Simultaneous activation over the dorsal and ventral route, which for example occurs in relation to the perception of complex motion (optic flow), or motion perception after lesion of V5, suggests integration by means of cross-connectivity. The third principle, i.e. "top-down" integration, appears by analysis of V5-V1 interaction, attentional effects on V4, frontal activation in prosopagnosia, and by analysis of hallucinations. Such "top down" integration indicates the presence of momentaneous effect on cortical areas, intimately related to the primary sensory cortex, by neuronal activity of remote "association" cortex, the latter being connected by direct (synaps restricted) bypass from early stations of information processing. PMID- 26964488 TI - Psychofarmakologika XIII. AB - Inleiding In deze rubriek zal worden ingegaan op recente observaties betreffende de psychofarmakologie in de breedst mogelijke zin. Vaak zullen zaken uit de literatuur worden behandeld. De gekozen onderwerpen dienen altijd klinische relevantie te hebben. Ook zal deze rubriek gaan over gewoontes die in psychofarmakologische behandeling of in onderzoek zijn geslopen die volgens de auteur lang niet altijd logisch zijn. Soms zal deze rubriek een oproep bevatten om te reageren op een bijdrage gepubliceerd in dit of in een ander tijdschrift. Ook zal de lezer worden aangemoedigd hier zijn eigen ervaringen mee te delen. Het is niet de bedoeling in deze rubriek onderzoeken uitvoerig te rapporteren. Daarvoor staan andere pagina 's van de Acta Neuropsychiatrica voor u open. PMID- 26964485 TI - Measures of Sleep-Wake Patterns and Risk of Mild Cognitive Impairment or Dementia in Older Women. AB - OBJECTIVE: Sleep disturbances are common in older adults. Little is known about the sleep of cognitively intact older adults and its relationship to subsequent cognitive impairment. The objective of this study was to examine the association between objective sleep-wake measures and risk of incident cognitive impairment. METHODS: In this prospective cohort study encompassing four U.S. sites, 1,245 women (mean age: 82.6 years) without dementia participated in the Study of Osteoporotic Fractures and completed actigraphy at the baseline visit and comprehensive cognitive assessment at follow-up. The association between sleep wake patterns measured by actigraphy and risk of incident mild cognitive impairment (MCI) and dementia was examined. RESULTS: A total of 473 women (38%) developed cognitive impairment during an average (SD) follow-up of 4.9 (0.6) years; 290 (23.3%) developed MCI and 183 (14.7%) developed dementia. After controlling for multiple potential confounders, women in the lowest quartile of average sleep efficiency (<74%) had a 1.5-fold higher odds of developing MCI or dementia compared with women in the highest quartile of sleep efficiency (>86%) (odds ratio: Q1 versus Q4 1.53; 95% CI: 1.07, 2.19; Wald chi(2) [1, N = 1,223] = 5.34 for p for trend = 0.03). Longer average sleep latency, but not total sleep time, was also associated with higher odds of developing cognitive impairment. Greater variability in both sleep efficiency and total sleep time was associated with an increased odds of developing MCI or dementia. CONCLUSION: Lower average sleep efficiency, longer average sleep latency, and greater variability in sleep efficiency and total sleep time are associated with increased odds of developing cognitive impairment. Further research is needed to explore the mechanisms underlying these associations. PMID- 26964493 TI - Host suitability and diet mixing influence activities of detoxification enzymes in adult Japanese beetles. AB - Induction of cytochrome P450, glutathione S transferase (GST), and carboxylesterase (CoE) activity was measured in guts of the scarab Popillia japonica Newman, after consumption of single or mixed plant diets of previously ranked preferred (rose, Virginia creeper, crape myrtle and sassafras) or non preferred hosts (boxelder, riverbirch and red oak). The goal of this study was to quantify activities of P450, GST and CoE enzymes in the midgut of adult P. japonica using multiple substrates in response to host plant suitability (preferred host vs non-preferred hosts), and single and mixed diets. Non preferred hosts were only sparingly fed upon, and as a group induced higher activities of P450, GST and CoE than did preferred hosts. However, enzyme activities for some individual plant species were similar across categories of host suitability. Similarly, beetles tended to have greater enzyme activities after feeding on a mixture of plants compared to a single plant type, but mixing per se does not seem as important as the species represented in the mix. Induction of detoxification enzymes on non-preferred hosts, or when switching between hosts, may explain, in part, the perceived feeding preferences of this polyphagous insect. The potential consequences of induced enzyme activities on the ecology of adult Japanese beetles are discussed. PMID- 26964494 TI - Surface Landau levels and spin states in bismuth (111) ultrathin films. AB - The development of next-generation electronics is much dependent on the discovery of materials with exceptional surface-state spin and valley properties. Because of that, bismuth has attracted a renewed interest in recent years. However, despite extensive studies, the intrinsic electronic transport properties of Bi surfaces are largely undetermined due to the strong interference from the bulk. Here we report the unambiguous determination of the surface-state Landau levels in Bi (111) ultrathin films using scanning tunnelling microscopy under magnetic fields perpendicular to the surface. The Landau levels of the electron-like and the hole-like carriers are accurately characterized and well described by the band structure of the Bi (111) surface from density functional theory calculations. Some specific surface spin states with a large g-factor are identified. Our findings shed light on the exploiting surface-state properties of Bi for their applications in spintronics and valleytronics. PMID- 26964495 TI - The cytochrome P450 inhibitor SKF-525A disrupts autophagy in primary rat hepatocytes. AB - The cytochrome P450 (CYP) inhibitor SKF-525A is commonly used to study drug metabolism and toxicity, particularly hepatotoxicity. By using Western blot and immunofluorescence staining, we unexpectedly found that SKF-525A at 2-20 MUM caused remarkable accumulation of microtubule-associated protein light chain 3 II (LC3-II) in primary rat hepatocytes at 1, 4 and 24 h, indicating that autophagy was disrupted. SKF-525A showed no effects on chloroquine induced LC3-II accumulation, suggesting that autophagic flux was blocked, which is further supported by the increased level of the p62 protein after SKF-525A treatment. SKF 525A did not affect proteasome activities or gene expression of LC3-II or p62. Immunofluorescence of green fluorescent protein fused lysosomal-associated membrane protein 1 (LAMP1, a specific protein marker for lysosomes) and LC3-II showed that co-localization of these two proteins was partially abolished by SKF 525A, indicating that autophagosome-lysosome fusion was blocked. The other five CYP inhibitors, metyrapone, 1-aminobenzotriazole, alpha-naphthoflavone, ticlopidine, and ketoconazole, showed no effects in parallel experiments. These findings provide novel insights into the mechanisms by which various CYP inhibitors differentially affect a same drug's toxicity in hepatocytes. The data also indicate that SKF-525A is not an ideal chemical inhibitor for probing the relation between CYP mediated metabolism and toxicity in primary hepatocytes. PMID- 26964496 TI - SINU 2015 Congress Report. PMID- 26964497 TI - A word from the SINU Past President. PMID- 26964499 TI - Re: Chokkappan K, Chinchure D, Chawla A, Subramanian M, Krishnan V, Narayana Shenoy J, Srinivasan S. An approach to various gastric pathologies using an "image appearance-based classification" on computed tomography. Curr Probl Diagn Radiol. 2016;45(1):23-38. PMID- 26964498 TI - Optimization of novel pentablock copolymer based composite formulation for sustained delivery of peptide/protein in the treatment of ocular diseases. AB - This manuscript is focussed on the development of pentablock (PB) copolymer based sustained release formulation for the treatment of posterior segment ocular diseases. We have successfully synthesised biodegradable and biocompatible PB copolymers for the preparation of nanoparticles (NPs) and thermosensitive gel. Achieving high drug loading with hydrophilic biotherapeutics (peptides/proteins) is a challenging task. Moreover, small intravitreal injection volume (<=100 MUL) requires high loading to develop a long term (six months) sustained release formulation. We have successfully investigated various formulation parameters to achieve maximum peptide/protein (octreotide, insulin, lysozyme, IgG-Fab, IgG, and catalase) loading in PB NPs. Improvement in drug loading can facilitate delivery of larger doses of therapeutic proteins via limited injection volume. A composite formulation comprised of NPs in gel system exhibited sustained release (without burst effect) of peptides and proteins, may serve as a platform technology for the treatment of posterior segment ocular diseases. PMID- 26964501 TI - Sedaxicenes: potential new antifungal ferrocene-based agents? AB - Fungal infections are a group of diseases spread all over the world with an extremely high morbidity. Worryingly, although several pathogenic fungi were found to develop resistance towards traditional therapy, research towards the discovery of novel antimycotic agents is very limited. Considering the promising results obtained with the ferrocene-based drug candidates Ferroquine and Ferrocifen as antimalarial and anticancer drug candidates, respectively, we envisaged derivatizing the organic scaffold of a new broad-spectrum fungicide, namely sedaxane, with a ferrocenyl moiety in order to obtain new metal-based antifungal agents. The new ferrocenyl sedaxane derivatives called herein Sedaxicenes (, and ) were characterized using different analytical techniques and the structures were confirmed by X-ray crystallography. As expected for antimycotic agents, , and were found to have a low or even no toxicity towards human cells (IC50 > 100 MUM). Interestingly, while the parent drug did not display any mycotoxicity (EC50 > 100 MUM), complex was found to have some antifungal activity with an IC50 value of 43 MUM under the same experimental conditions. In order to investigate the possible redox-mediated mode of action of , we synthesized the ruthenocene analogue of , namely . Ruthenocene is known to have a completely different electrochemical behaviour from ferrocene although both the compounds are isostructural. As anticipated, complex was found to induce an increase of the reactive oxygen species level in S. cerevisiae, contrary to its analogue and to the parent compound sedaxane. PMID- 26964502 TI - Reusable nanosilver-coated magnetic particles for ultrasensitive SERS-based detection of malachite green in water samples. AB - A novel nanosilver-deposited silica-coated Fe3O4 magnetic particle (Fe3O4@SiO2@Ag) with uniform size, good SERS activity and magnetic responsiveness was synthesized using amination polymer. The Fe3O4@SiO2@Ag magnetic particles have been successfully applied for ultrasensitive SERS detection of malachite green (MG) in water samples. The mechanism is that MG can be adsorbed on the silver surface of nanosilver-coated magnetic particles via one nitrogen atom, and the Raman signal intensity of MG is significantly enhanced by the nanosilver layer formed on the magnetic particles. The developed sensing system exhibited a sensitive response to MG in the range of 10 fM to 100 MUM with a low limit of detection (LOD) 2 fM under optimal conditions. The LOD was several orders of magnitude lower than those of other methods. This SERS-based sensor showed good reproducibility and stability for MG detection. The silver-coated magnetic particles could easily be regenerated as SERS substrates only using low pH solution for multiple sensing events. The recovery of MG added to several water samples at different concentrations ranged from 90% to 110%. The proposed method facilitates the ultrasensitive analysis of dyes to satisfy the high demand for ensuring the safety of water sources. PMID- 26964500 TI - Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis. AB - Ductal occlusion has been postulated to precipitate focal pancreatic inflammation, while the nature of the primary occluding agents has remained elusive. Neutrophils make use of histone citrullination by peptidyl arginine deiminase-4 (PADI4) in contact to particulate agents to extrude decondensed chromatin as neutrophil extracellular traps (NETs). In high cellular density, NETs form macroscopically visible aggregates. Here we show that such aggregates form inside pancreatic ducts in humans and mice occluding pancreatic ducts and thereby driving pancreatic inflammation. Experimental models indicate that PADI4 is critical for intraductal aggregate formation and that PADI4-deficiency abrogates disease progression. Mechanistically, we identify the pancreatic juice as a strong instigator of neutrophil chromatin extrusion. Characteristic single components of pancreatic juice, such as bicarbonate ions and calcium carbonate crystals, induce aggregated NET formation. Ductal occlusion by aggregated NETs emerges as a pathomechanism with relevance in a plethora of inflammatory conditions involving secretory ducts. PMID- 26964504 TI - Pushing Forward: Remyelination as the New Frontier in CNS Diseases. AB - The evolutionary acquisition of myelin sheaths around large caliber axons in the central nervous system (CNS) represented a milestone in the development of vertebrate higher brain function. Myelin ensheathment of axons enabled saltatory conduction and thus accelerated information processing. However, a number of CNS diseases harm or destroy myelin and oligodendrocytes (myelin-producing cells), ultimately resulting in demyelination. In the adult CNS, new oligodendrocytes can be generated from a quiescent pool of precursor cells, which - upon differentiation - can replace lost myelin sheaths. The efficiency of this spontaneous regeneration is limited, which leads to incomplete remyelination and residual clinical symptoms. Here, we discuss CNS pathologies characterized by white matter degeneration and regeneration and highlight drugs that could potentially serve as remyelination therapies. PMID- 26964505 TI - Hypertension Health Promotion via Text Messaging at a Community Health Center in South Africa: A Mixed Methods Study. AB - BACKGROUND: The use of mobile phones to deliver health care (mHealth) is increasing in popularity due to the high prevalence of mobile phone penetration. This is seen in developing countries, where mHealth may be particularly useful in overcoming traditional access barriers. Non-communicable diseases may be particularly amenable to mHealth interventions, and hypertension is one with an escalating burden in the developing world. OBJECTIVE: The objective of this study was to test whether the dissemination of health information via a short message service (SMS) led to improvements in health knowledge and self-reported health related behaviors. METHODS: A mixed methods study was carried out among a cohort of 223 hypertension clinic patients, in a resource-poor setting in Cape Town, South Africa, in 2012. Hypertensive outpatients were recruited at the clinic and administered a baseline questionnaire to establish existing knowledge of hypertension. Participants were then randomly assigned to intervention or control groups. The intervention group received 90 SMSes over a period of 17 weeks. Thereafter, the baseline questionnaire was readministered to both groups to gauge if any improvements in health knowledge had occurred. Those who received SMSes were asked additional questions about health-related behavior changes. A focus group was then conducted to obtain in-depth feedback about participants' experience with, and response to, the SMS campaign. RESULTS: No statistically significant changes in overall health knowledge were observed between the control and intervention groups. The intervention group had positive increases in self reported behavior changes. These were reaffirmed by the focus groups, which also revealed a strong preference for the SMS campaign and the belief that the SMSes acted as a reminder to change, as opposed to providing new information. CONCLUSIONS: Although the content of the SMSes was not new, and did not improve health knowledge, SMSes were effective in motivating positive self-reported behavior change among hypertensive patients. TRIAL REGISTRATION: Pan African Clinical Trials Registry Number: PACTR201412000968462. Registered 18 December 2014 (Archived by WebCite at http://www.webcitation.org/6fhtyLRcO). PMID- 26964503 TI - Pathways for Modulating Exosome Lipids Identified By High-Density Lipoprotein Like Nanoparticle Binding to Scavenger Receptor Type B-1. AB - Exosomes are produced by cells to mediate intercellular communication, and have been shown to perpetuate diseases, including cancer. New tools are needed to understand exosome biology, detect exosomes from specific cell types in complex biological media, and to modify exosomes. Our data demonstrate a cellular pathway whereby membrane-bound scavenger receptor type B-1 (SR-B1) in parent cells becomes incorporated into exosomes. We tailored synthetic HDL-like nanoparticles (HDL NP), high-affinity ligands for SR-B1, to carry a fluorescently labeled phospholipid. Data show SR-B1-dependent transfer of the fluorescent phospholipid from HDL NPs to exosomes. Modified exosomes are stable in serum and can be directly detected using flow cytometry. As proof-of-concept, human serum exosomes were found to express SR-B1, and HDL NPs can be used to label and isolate them. Ultimately, we discovered a natural cellular pathway and nanoparticle-receptor pair that enables exosome modulation, detection, and isolation. PMID- 26964506 TI - Treatment for osteoporosis in people with beta-thalassaemia. AB - BACKGROUND: Osteoporosis is a systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis represents an important cause of morbidity in people with beta-thalassaemia and its pathogenesis is multifactorial. Factors include bone marrow expansion due to ineffective erythropoiesis, resulting in reduced trabecular bone tissue with cortical thinning; endocrine dysfunction secondary to excessive iron loading, leading to increased bone turnover; and lastly, a predisposition to physical inactivity due to disease complications with a subsequent reduction in optimal bone mineralization.A number of therapeutic strategies have been applied to treat osteoporosis in people with beta-thalassaemia, which include bisphosphonates, with or without, hormone replacement therapy. There are various forms of bisphosphonates, such as clodronate, pamidronate, alendronate and zoledronic acid. Other treatments include calcitonin, calcium, zinc supplementation, hydroxyurea and hormone replacement therapy for preventing hypogonadism. OBJECTIVES: To review the evidence on the efficacy and safety of treatment for osteoporosis in people with beta-thalassaemia. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of most recent search: 04 February 2016. SELECTION CRITERIA: Randomised, placebo-controlled trials in people with thalassaemia with a bone mineral density z score of less than -2 standard deviations for: children less than 15 years old; adult males (15 to 50 years old); and all pre-menopausal females above 15 years and a bone mineral density t score of less than -2.5 standard deviations for post-menopausal females and males above 50 years old. DATA COLLECTION AND ANALYSIS: Two review authors assessed the eligibility and risk of bias of the included trials, extracted and analysed data and completed the review. We summarised results using risk ratios or rate ratios for dichotomous data and mean differences for continuous data. We combined trial results where appropriate. MAIN RESULTS: Four trials (with 211 participants) were included; three trials investigated the effect of bisphosphonate therapies and one trial investigated the effect of zinc supplementation. Only one trial was judged to be of good quality (low risk of bias); the remaining trials had a high or unclear risk of bias in at least one key domain.One trial (data not available for analysis) assessing the effect of neridronate (118 participants) reported significant increases in favour of the bisphosphonate group for bone mineral density at the lumbar spine and hip at both six and 12 months. For the femoral neck, a significant difference was noted at 12 months only. A further trial (25 participants) assessed the effect of alendronate and clodronate and found that after two years, bone mineral density increased significantly in the alendronate and clodronate groups as compared to placebo at the lumbar spine, mean difference 0.14 g/cm(2) (95% confidence interval 0.05 to 0.22) and at the femoral neck, mean difference 0.40 g/cm(2) (95% confidence interval 0.22 to 0.57). One 12-month trial (26 participants) assessed the effects of different doses of pamidronate (30 mg versus 60 mg) and found a significant difference in bone mineral density in favour of the 60 mg dose at the lumbar spine and forearm, mean difference 0.43 g/cm(2) (95% CI 0.10 to 0.76), mean difference 0.87 g/cm(2) (95% CI 0.23 to 1.51), respectively, but not at the femoral neck.In a zinc sulphate supplementation trial (42 participants), bone mineral density increased significantly compared to placebo at the lumbar spine after 12 months (37 participants), mean difference 0.15 g/cm(2) (95% confidence interval 0.10 to 0.20) and after 18 months (32 participants), mean difference 0.34 g/cm(2) (95% confidence interval 0.28 to 0.40). The same was true for bone mineral density at the hip after 12 months, mean difference 0.15 g/cm(2) (95% confidence interval 0.11 to 0.19) and after 18 months, mean difference 0.26 g/cm(2) (95% confidence interval 0.21 to 0.31).Fractures were not observed in one trial and not reported in three trials. There were no major adverse effects reported in two of the bisphosphonate trials; in the neridronate trial there was a reduction noted in the use of analgesic drugs and in the reported back pain score in favour of bisphosphonate treatment. Adverse effects were not reported in the trial of different doses of pamidronate or the zinc supplementation trial. AUTHORS' CONCLUSIONS: There is evidence to indicate an increase in bone mineral density at the femoral neck, lumbar spine and forearm after administration of bisphosphonates and at the lumbar spine and hip after zinc sulphate supplementation. The authors recommend that further long-term randomised control trials on different bisphosphonates and zinc supplementation therapies in people with beta-thalassaemia and osteoporosis are undertaken. PMID- 26964507 TI - Structural health monitoring (vibration) as a tool for identifying structural alterations of the lumbar spine: a twin control study. AB - Structural health monitoring (SHM) is an engineering technique used to identify mechanical abnormalities not readily apparent through other means. Recently, SHM has been adapted for use in biological systems, but its invasive nature limits its clinical application. As such, the purpose of this project was to determine if a non-invasive form of SHM could identify structural alterations in the spines of living human subjects. Lumbar spines of 10 twin pairs were visualized by magnetic resonance imaging then assessed by a blinded radiologist to determine whether twin pairs were structurally concordant or discordant. Vibration was then applied to each subject's spine and the resulting response recorded from sensors overlying lumbar spinous processes. The peak frequency, area under the curve and the root mean square were computed from the frequency response function of each sensor. Statistical analysis demonstrated that in twins whose structural appearance was discordant, peak frequency was significantly different between twin pairs while in concordant twins, no outcomes were significantly different. From these results, we conclude that structural changes within the spine can alter its vibration response. As such, further investigation of SHM to identify spinal abnormalities in larger human populations is warranted. PMID- 26964509 TI - Reinterpreting the best biomarker of oxidative stress: The 8-iso-prostaglandin F2alpha/prostaglandin F2alpha ratio shows complex origins of lipid peroxidation biomarkers in animal models. AB - Oxidative stress is elevated in numerous environmental exposures and diseases. Millions of dollars have been spent to try to ameliorate this damaging process using anti-oxidant therapies. Currently, the best accepted biomarker of oxidative stress is the lipid oxidation product 8-iso-prostaglandin F2alpha (8-iso PGF2alpha), which has been measured in over a thousand human and animal studies. 8-iso-PGF2alpha generation has been exclusively attributed to nonenzymatic chemical lipid peroxidation (CLP). However, 8-iso-PGF2alpha can also be produced enzymatically by prostaglandin-endoperoxide synthases (PGHS) in vivo. When failing to account for PGHS-dependent generation, 8-iso-PGF2alpha cannot be interpreted as a selective biomarker of oxidative stress. We investigated the formation of 8-iso-PGF2alpha in rats exposed to carbon tetrachloride (CCl4) or lipopolysaccharide (LPS) using the 8-iso-PGF2alpha/PGF2alpha ratio to quantitatively determine the source(s) of 8-iso-PGF2alpha. Upon exposure to a 120mg/kg dose of CCl4, the contribution of CLP accounted for only 55.6+/-19.4% of measured 8-iso-PGF2alpha, whereas in the 1200mg/kg dose, CLP was the predominant source of 8-iso-PGF2alpha (86.6+/-8.0% of total). In contrast to CCl4, exposure to 0.5mg/kg LPS was characterized by a significant increase in both the contribution of PGHS (59.5+/-7.0) and CLP (40.5+/-14.0%). In conclusion, significant generation of 8-iso-PGF2alpha occurs through enzymatic as well as chemical lipid peroxidation. The distribution of the contribution is dependent on the exposure agent as well as the dose. The 8-iso-PGF2alpha/PGF2alpha ratio accurately determines the source of 8-iso-PGF2alpha and provides an absolute measure of oxidative stress in vivo. PMID- 26964510 TI - Early recurrence of cardioembolic stroke successfully treated with a second thrombectomy. PMID- 26964512 TI - Psychomotor delay, hypotonia, and behavioural disorders: A case of succinic semialdehyde dehydrogenase deficiency. PMID- 26964508 TI - Mitochondrial poly(ADP-ribose) polymerase: The Wizard of Oz at work. AB - Among multiple members of the poly(ADP-ribose) polymerase (PARP) family, PARP1 accounts for the majority of PARP activity in mammalian cells. Although PARP1 is predominantly localized to the nucleus, and its nuclear regulatory roles are most commonly studied and are the best characterized, several lines of data demonstrate that PARP1 is also present in the mitochondria, and suggest that mitochondrial PARP (mtPARP) plays an important role in the regulation of various cellular functions in health and disease. The goal of the current article is to review the experimental evidence for the mitochondrial localization of PARP1 and its intra-mitochondrial functions, with focus on cellular bioenergetics, mitochondrial DNA repair and mitochondrial dysfunction. In addition, we also propose a working model for the interaction of mitochondrial and nuclear PARP during oxidant-induced cell death. MtPARP is similar to the Wizard of Oz in the sense that it is enigmatic, it has been elusive for a long time and it remains difficult to be interrogated. mtPARP - at least in some cell types - works incessantly "behind the curtains" as an orchestrator of many important cellular functions. PMID- 26964511 TI - Analysis of Sturge-Weber syndrome: A retrospective study of multiple associated variables. AB - INTRODUCTION: Sturge-Weber syndrome is a congenital vascular disorder characterised by facial capillary malformation (port-wine stain) associated with venous and capillary malformations in the brain and eye. Neurological symptoms and alterations in other locations may also be observed. OBJECTIVES: This study describes the clinical and epidemiological characteristics and different treatments in a cohort of patients diagnosed with Sturge-Weber syndrome in a tertiary hospital. MATERIAL AND METHODS: This comparative, retrospective and cross-sectional study was conducted by reviewing the medical records of patients diagnosed with Sturge-Weber syndrome between 1998 and 2013. RESULTS: The study included 13 patients (54% male, 46% female) diagnosed with Sturge-Weber syndrome. The mean age at diagnosis was 15 months. Leptomeningeal angiomatosis was present in 100% of cases: right hemisphere (46%), left hemisphere (38%), and bilateral (15%). Facial angioma was present in 61% of the cases: right (23%), left (38%) and bilateral (7%). Other skin disorders were found in 23% of the cases, including 2 with hemilateral involvement on the side where facial and leptomeningeal angiomatosis was present and one case of generalised cutis marmorata. Ocular disease was found in 77% of patients; the most common conditions were glaucoma (46%), strabismus (23%) and choroidal angioma (23%). Epilepsy was present in 100% of the cases, with partial seizures (simple or complex) being the most frequent (62%). Seizure control was highly variable; 31% of the patients had needed to try more than 3 drugs, 15% 3 drugs, and 31% 2 drugs, while 23% experienced good seizure control with monotherapy. One patient required surgery for epilepsy (left hemispherectomy) and has been seizure-free since then. The most frequent observations in electroencephalograms were spikes, polyspikes, and wave spikes in the lobes affected by leptomeningeal angiomatosis (46%). Other neurological symptoms were hemiparesis (39%), recurrent headaches (39%), stroke-like episodes (23%), psychomotor retardation (46%), and mental retardation (46%). Leptomeningeal calcifications could be seen in 85% of patient MRIs, as well as increased calcification in 70%; 54% of the patients had been treated with aspirin. CONCLUSIONS: There are multiple clinical manifestations of Sturge-Weber syndrome. Being familiar with all of them is vitally important for diagnosing and for monitoring and treating the condition correctly, which will improve the quality of life of these patients. PMID- 26964513 TI - Cerebral cavernous malformation in a woman presenting with hemichorea: Response to haloperidol. PMID- 26964516 TI - Development of a web application for recording bacterial etiologic agents and their antimicrobial susceptibility to improve the treatment of urinary tract infections and monitor resistance to antibiotics. AB - OBJECTIVE: We describe the development of a web platform that provides an updated record of the etiology and antimicrobial susceptibility of the different microorganisms responsible for urinary tract infections. METHODS: The MicrobDinamyc system (Francisco Soria Melguizo, SA, Madrid, Spain) is employed for the management of information derived from the urine culture results. The web application database automatically gathers the results of urine cultures conducted in the laboratory. RESULTS: Results. The user can consult the distribution of bacterial etiologies and antimicrobial susceptibilities in the different clinical settings during a specific time window. CONCLUSIONS: Using susceptibility data obtained in previous studies and stored on the web platform, it is possible to deduce the clinical activity of a given antibiotic in a specific setting. PMID- 26964515 TI - [Surveillance of antimicrobial susceptibility of Escherichia coli producing urinary tract infections in Galicia (Spain)]. AB - OBJECTIVE: Escherichia coli is the microorganism responsible for most of the community-acquired urinary tract infections (UTI). Our purpose was to determine the susceptibility of E. coli associated with UTI in Galicia and consider the most appropriate antibiotics for empirical treatment. METHODS: Retrospective study during the period 2011- 2012 of the isolation of E. coli in urine samples from almost all the Galician population. Demographic variables, minimum inhibitory concentration, and reading data were collected: amoxicillin clavulanate, cefotaxime, gentamicin, amikacin, ciprofloxacin, cotrimoxazole, nitrofurantoin and fosfomycin. The identification and susceptibility studies were mainly conducted by automated systems. The interpretation of the results was performed according to CLSI criteria. RESULTS: During the study period 55,046 E. coli were isolated in UTI. The percentages of resistance were: cotrimoxazole, 30%; ciprofloxacin, 33%; amoxicillin-clavulanate, 23% and 10% for 3rd generation cephalosporins. Fosfomycin and nitrofurantoin showed the highest activity with more than 96% of susceptibility in our study. The linear trend of resistance regarding age was statistically significant (p <0.0001) as it was regarding males (p <0.00001) for all antibiotics. CONCLUSIONS: In Galicia, the most active antibiotics against E. coli associated with UTI are fosfomycin and nitrofurantoin so they should be considered as empirical treatment of choice by the community acquired UTI not complicated by E. coli. PMID- 26964514 TI - Secreted APE1/Ref-1 inhibits TNF-alpha-stimulated endothelial inflammation via thiol-disulfide exchange in TNF receptor. AB - Apurinic apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) is a multifunctional protein with redox activity and is proved to be secreted from stimulated cells. The aim of this study was to evaluate the functions of extracellular APE1/Ref-1 with respect to leading anti-inflammatory signaling in TNF-alpha-stimulated endothelial cells in response to acetylation. Treatment of TNF-alpha-stimulated endothelial cells with an inhibitor of deacetylase that causes intracellular acetylation, considerably suppressed vascular cell adhesion molecule-1 (VCAM-1). During TSA-mediated acetylation in culture, a time-dependent increase in secreted APE1/Ref-1 was confirmed. The acetyl moiety of acetylated APE1/Ref-1 was rapidly removed based on the removal kinetics. Additionally, recombinant human (rh) APE1/Ref-1 with reducing activity induced a conformational change in rh TNF-alpha receptor 1 (TNFR1) by thiol-disulfide exchange. Following treatment with the neutralizing anti-APE1/Ref-1 antibody, inflammatory signals via the binding of TNF-alpha to TNFR1 were remarkably recovered, leading to up regulation of reactive oxygen species generation and VCAM-1, in accordance with the activation of p66(shc) and p38 MAPK. These results strongly indicate that anti-inflammatory effects in TNF-alpha-stimulated endothelial cells by acetylation are tightly linked to secreted APE1/Ref-1, which inhibits TNF-alpha binding to TNFR1 by reductive conformational change, with suggestion as an endogenous inhibitor of vascular inflammation. PMID- 26964517 TI - A meta-analysis on pain sensitivity in self-injury. AB - Individuals engaging in self-injurious behavior (SIB) frequently report absence of pain during acts of SIB. While altered pain sensitivity is discussed as a risk factor for the engagement in SIB, results have been mixed with considerable variance across reported effect sizes, in particular with respect to the effect of co-morbid psychopathology. The present meta-analysis aimed to summarize the current evidence on pain sensitivity in individuals engaging in SIB and to identify covariates of altered pain processing. Three databases were searched without restrictions. Additionally a hand search was performed and reference lists of included studies were checked for potential studies eligible for inclusion. Thirty-two studies were identified after screening 720 abstracts by two independent reviewers. Studies were included if they reported (i) an empirical investigation, in (ii) humans, including a sample of individuals engaging in (iii) SIB and a group of (iv) healthy controls, (v) receiving painful stimulation. Random-effects meta-analysis was performed on three pain-related outcomes (pain threshold, pain tolerance, pain intensity) and several population- and study-level covariates (i.e. age, sex, clinical etiology) were subjected to meta-regression. Meta-analysis revealed significant main effects associated with medium to large effect sizes for all included outcomes. Individuals engaging in SIB show greater pain threshold and tolerance and report less pain intensity compared to healthy controls. Clinical etiology and age are significant covariates of pain sensitivity in individuals engaging in SIB, such that pain threshold is further increased in borderline personality disorder compared to non suicidal self-injury. Mechanisms underlying altered pain sensitivity are discussed. PMID- 26964518 TI - Optimizing Preconception Health among Young Women: What Are We Missing? AB - STUDY OBJECTIVE: To evaluate whether receipt of specific preconception counseling topics differs between teen, young adult, and older mothers. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: A survey of 291 primarily low-income, minority mothers with young children at pediatric practices in Baltimore, Maryland was conducted. Multivariable logistic regression models generated relative odds of preconception counseling receipt comparing teens (ages 14-19 years) and young adults (ages 20-24 years) to adult women (age >=25 years) controlling for demographic characteristics, parity, and pregnancy intention. RESULTS: Teen mothers were less than half as likely to be counseled about taking folic acid, 4 times more likely to be counseled about vaccines, and twice as likely to be counseled about mental health before pregnancy compared with adult mothers. CONCLUSION: Adolescent preventive care might promote some aspects of preconception health, but topics related specifically to pregnancy outcomes might be missed. Because of the high rate of unplanned teen pregnancy in the United States, additional strategies to promote preconception health in this population are warranted. PMID- 26964519 TI - Age at Menarche and Its Association with Excess Weight and Body Fat Percentage in Girls in the Southwestern Region of the Brazilian Amazon. AB - STUDY OBJECTIVE: To analyze age at menarche and its association with excess weight and body fat percentage. DESIGN: School-based cross-sectional survey. SETTING: Southwestern region of the Brazilian Amazon. PARTICIPANTS: The sample was made up of 727 girls, in the 8- to 16-year age range, divided into 3 groups: early, normal, and late menarche, from public and private schools, selected through proportional stratified random sampling. INTERVENTIONS AND MAIN OUTCOME MEASURES: Bioimpedance was used to measure body fat percentage and body mass index, applying the Global School-Based Student Health Survey questionnaire to categorize behavior variables. Age at menarche was determined using the status quo method. Sexual maturity was assessed through self-assessment according to criteria described by Tanner. RESULTS: Overall age at menarche was 11.52 (+/ 1.35), early 10.48 (+/-0.78), normal 12.39 (+/-0.50) and late 14.27 (+/-0.51) years. Prevalence of excess weight and body fat was 28.3% (206/727) and 44.3% (322/727), among those with menarche. There was a positive association between excess weight and body fat with age at early menarche (P = .000 and .015). CONCLUSION: Age at menarche among girls from the Amazon region is similar to that of industrialized countries. Prevalence of excess weight and body fat was high, and there was evidence of an association between age with early menarche and excess weight. Trends in age at menarche and stage of sexual maturation should be monitored with related factors, to adopt obesity control strategies from an early age. PMID- 26964520 TI - Artificial supramolecular protein assemblies as functional high-order protein scaffolds. AB - Supramolecular assemblies of protein building blocks potentially offer unique biomaterials with unmatched functionalities as well as atomic level structural accuracy. An increasing number of assembling strategies have been reported for the fabrication of diverse artificial protein assemblies, ranging from rather heterogeneous protein oligomers to computationally designed discrete protein architectures. In this perspective, we discuss these artificial protein supramolecules in terms of their use as highly potent high-order protein scaffolds that can display various functional proteins with precise structural and valency control. Following a brief overview of current approaches for protein assembly, several examples of functional protein assemblies have been introduced, with a particular focus on our recent report of valency-controlled green fluorescent protein nano-assemblies. Our supramolecular protein scaffolds allow building a series of polygonal assemblies of functional binding proteins, which provide unprecedented ways to study multivalent protein interactions. Even with many remaining challenges, there is unlimited potential of artificial protein scaffolds in many fields from nanotechnology to vaccine development. PMID- 26964521 TI - Prevalence of dyslipidemia in school children of Kashmir valley. AB - AIM: Increased incidence of CVD has been observed in recent years in the Kashmir valley (North India). Since the risk factor development of the cardiovascular diseases (CVD) takes place during childhood, we undertook an epidemiological survey to assess the prevalence of dyslipidemia in the school children of Kashmir valley. MATERIALS AND METHODS: 1131 children of 5-19 years of age were selected and evaluated for BMI, cholesterol, TGs, LDL and HDL levels from different areas of Srinagar city (urban) region of the Kashmir valley from June 2011-June 2014. RESULTS: The frequency of dyslipidemia in Kashmiri children varied along the subjects. Hypertriglyceridemia was seen in 82.6% of the males and 47.6% of females in the age group of 5-9 years, 38.5% of males and 51.1% of females in the age group of 10-14 years and 24.7% of males and 35.9% of the females in the age group of 15-19 years. Low levels of HDL than normal were seen in 34.7% of males and 19% of females in the age group of 5-9 years. Similarly low HDL levels were seen in 17.9% of males and 15.5% of females in the age group of 10-14 years. The incidence of low HDL was also seen in 4.9% of males and 10.8% of females in the age group of 15-19 years. CONCLUSIONS: In the present study dyslipidemia was more common in centrally obese children and the most common component was high triglycerides and low HDL's. Female school children were at higher risk of developing CVD than males. PMID- 26964522 TI - Half-oxidized phosphorene: band gap and elastic properties modulation. AB - Based on a first principles approach, we study structural, electronic and elastic properties, as well as stabilities of all possible half-oxidized phosphorene conformers. Stability analysis reveals that oxygen chemisorption is an exothermic process in the six configurations despite the formation of interstitial oxygen bridges in three of them. Electronic structure calculations show that oxidation induces a band gap modulation ranging between 0.54 and 1.57 eV in the generalized gradient approximation corrected to 1.19 and 2.88 eV using GW. The mechanical response of the conformers is sensitively dependent on direction and indicates that the new derivatives are incompressible materials and one configuration has an auxetic behavior. The present results provide a basis for tailoring the electronic and elastic properties of phosphorene via half oxidation. PMID- 26964523 TI - Letter to Editor Re: Asgari SA, Safarinejad MR, Poorreza F, Safaei Asi A, Mansour Ghanaie M, Shahab E. The effect of parenteral testosterone administration prior to hypospadias surgery: A prospective, randomized and controlled study. J Pediatr Urol 11:143, 2015. PMID- 26964524 TI - An organizing principle for two-dimensional strongly correlated superconductivity. AB - Superconductivity in the cuprates exhibits many unusual features. We study the two-dimensional Hubbard model with plaquette dynamical mean-field theory to address these unusual features and relate them to other normal-state phenomena, such as the pseudogap. Previous studies with this method found that upon doping the Mott insulator at low temperature a pseudogap phase appears. The low temperature transition between that phase and the correlated metal at higher doping is first-order. A series of crossovers emerge along the Widom line extension of that first-order transition in the supercritical region. Here we show that the highly asymmetric dome of the dynamical mean-field superconducting transition temperature Tc(d), the maximum of the condensation energy as a function of doping, the correlation between maximum Tc(D) and normal-state scattering rate, the change from potential-energy driven to kinetic-energy driven pairing mechanisms can all be understood as remnants of the normal state first order transition and its associated crossovers that also act as an organizing principle for the superconducting state. PMID- 26964525 TI - Immobilization of pectinase on silica-based supports: Impacts of particle size and spacer arm on the activity. AB - The pectinase was separately immobilized onto Florisil and nano silica supports through both glutaraldehyde and 3-glyoxypropyltrietoxysilane spacer arms. The effects of spacer arm, particle size of support and ionic liquids on the activities of pectinase preparations were investigated. The immobilization of pectinase onto Florisil and nano silica through 3-glyoxypropyltrietoxysilane spacer arm completely led to inactivation of enzyme; however, 10 and 75% pectinase activity were retained when it was immobilized through glutaraldehyde spacer arm onto Florisil and nano silica, respectively. The pectinase immobilized onto nano silica through glutaraldehyde spacer arm showed 6.3-fold higher catalytic efficiency than that of the pectinase immobilized onto Florisil through same spacer arm. A 2.3-fold increase in thermal stability of pectinase was provided upon immobilization onto nano silica at 35 degrees C. The effects of IL/buffer mixture and volume ratio of IL/buffer mixture on the catalytic activities of free and immobilized pectinase preparations were also tested. All the pectinase preparations showed highest activity in 10% (v/v) 1-butyl-3 methylimidazolium hexafluorophosphate containing medium and their activities significantly affected from the concentration of 1-butyl-3-methylimidazolium hexafluorophosphate. PMID- 26964526 TI - Protein adsorption using novel carboxymethyl-curdlan microspheres. AB - Carboxymethyl-curdlan as a water soluble curdlan derivative, was synthesized in an aqueous alkaline medium using monochloroacetic acid. Novel carboxymethyl curdlan (CC) microspheres were prepared by the method of W/O/W emulsion. The chemical and morphological structures of CC microspheres were investigated by scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR) and particle size analysis. The CC microspheres were spherical, free flowing, non-aggregated and uniform mono-disperse with diameter of 260MUm. The prepared CC microspheres were applied to adsorbing Bovine serum albumin (BSA) as model protein. Factors influencing the adsorption of BSA such as solution pH, temperature, initial BSA concentration and ionic strength were examined by batch experiments. The maximum adsorption capacity was calculated as 168mg/g under optimal conditions including BSA initial concentration (4mg/mL), pH (4.7), adsorption time (9h) and temperature (35 degrees C). The adsorption isotherm followed the Langmuir model and the adsorption kinetics fitted the pseudo-second order model. In addition, the CC microspheres can be also regenerated and re used. PMID- 26964527 TI - An Innovative Rapid Method for Analysis of 10 Organophosphorus Pesticide Residues in Wheat by HS-SPME-GC-FPD/MSD. AB - The rapid detection of pesticide residues in wheat has become a top food security priority. A solvent-free headspace solid-phase microextraction (HS-SPME) has been evaluated for rapid screening of organophosphorus pesticide (OPP) residues in wheat with high sensitivity. Individual wheat samples (1.7 g), spiked with 10 OPPs, were placed in a 4 mL sealed amber glass vial and heated at 60 degrees C for 45 min. During this time, the OPP residues were extracted with a 50 MUm/30 MUm divinylbenzene (DVB)/carboxen (CAR)/plasma desorption mass spectroscopy polydimethylsiloxane (PDMS) fiber from the headspace above the sample. The fiber was then removed and injected into the GC injection port at 250 degrees C for desorption of the extracted chemicals. The multiple residues were identified by a GC mass spectrometer detector (GC-MSD) and quantified with a GC flame photometric detector (GC-FPD). Seven spiked levels of 10 OPPs on wheat were analyzed. The GC responses for a 50 MUm/30 MUm DVB/CAR/PDMS fiber increased with increasing spiking levels, yielding significant (R(2) > 0.98) linear regressions. The lowest LODs of the multiple pesticide standards were evaluated under the conditions of the validation study in a range of levels from 0 (control) to 100 ng of pesticide residue per g of wheat that separated on a low-polar GC capillary column (Agilent DB-35UI). The results of the HS-SPME method were compared with the QuEChERS AOAC 2007.01 method and they showed several advantages over the latter. These included improved sensitivity, selectivity, and simplicity. PMID- 26964528 TI - Determinants of host feeding success by Anopheles farauti. AB - BACKGROUND: The proportion of blood meals that mosquitoes take from a host species is a function of the interplay of extrinsic (abundance and location of potential hosts) and intrinsic (innate preference) factors. A mark-release recapture experiment addressed whether host preference in a population of Anopheles farauti was uniform or if there were anthropophilic and zoophilic subpopulations. The corresponding fitness associated with selecting different hosts for blood meals was compared by measuring fecundity. METHODS: The attractiveness of humans for blood meals by An. farauti in the Solomon Islands was compared to pigs using tent traps. Host fidelity was assessed by mark-release recapture experiments in which different colour dusts were linked to the host to which the mosquito was first attracted. Outdoor resting An. farauti were captured on barrier screens and the human blood index (HBI) as well as the feeding index were calculated. The fecundity of individual An. farauti after feeding on either humans or pigs was assessed from blood-fed mosquitoes held in individual oviposition chambers. RESULTS: Anopheles farauti were more attracted to humans than pigs at a ratio of 1.31:1.00. The mark-release-recapture experiment found evidence for An. farauti being a single population regarding host preference. The HBI of outdoor resting An. farauti was 0.93 and the feeding index was 1.29. Anopheles farauti that fed on a human host laid more eggs but had a longer oviposition time compared to An. farauti that had blood fed on a pig. CONCLUSIONS: One of the strongest drivers for host species preference was the relative abundance of the different host species. Here, An. farauti have a slight preference for humans over pigs as blood meal sources. However, the limited availability of alternative hosts relative to humans in the Solomon Islands ensures a very high proportion of blood meals are obtained from humans, and thus, the transmission potential of malaria by An. farauti is high. PMID- 26964529 TI - Prosthetic joint infection caused by Trueperella bernardiae. AB - Trueperella bernardiae is a Gram-positive coryneform bacilli which role as human pathogen is unknown because it has been usually considered a contaminant. Furthermore its identification by biochemical test was difficult. We describe a prosthetic joint infection in a women who years ago underwent a total knee replacement with superinfection and necrosis of the patellar tendon as major complications. In the sample of synovial fluid collected grew a gram-positive bacilli which was identified by matrix-assisted laser desorption/ionization time of-flight (MALDI-TOF) as T. bernardiae. The patient was treated with ciprofloxacin and currently preserves the prosthesis without signs of infection. PMID- 26964530 TI - Vacuum plasma sprayed coatings using ionic silver doped hydroxyapatite powder to prevent bacterial infection of bone implants. AB - Fast and efficient osseointegration of implants into bone is of crucial importance for their clinical success; a process that can be enhanced by coating the implant surface with hydroxyapatite (HA) using the vacuum plasma spray technology (VPS). However, bacterial infections, especially the biofilm formation on implant surfaces after a surgery, represent a serious complication. With ever increasing numbers of antibiotic-resistant bacteria, there is great interest in silver (Ag) as an alternative to classical antibiotics due to its broad activity against Gram-positive and Gram-negative bacterial strains. In the present study, silver ions were introduced into HA spray powder by ion exchange and the HA-Ag powder was applied onto titanium samples by VPS. The Ag-containing surfaces were evaluated for the kinetics of the silver release, its antibacterial effect against Staphylococcus aureus as well as Escherichia coli, and possible cytotoxicity against human bone cells. The HA-Ag coatings with different concentrations of Ag displayed mechanical and compositional properties that fulfill the regulatory requirements. Evaluation of the Ag release kinetic showed a high release rate in the first 24 h followed by a decreasing release rate over the four subsequent days. The HA-Ag coatings showed no cytotoxicity to primary human bone cells while exhibiting antibacterial activity to E. coli and S. aureus. PMID- 26964531 TI - What is really driving cell-surface interactions? Layer-by-layer assembled films may help to answer questions concerning cell attachment and response to biomaterials. AB - Layer-by-layer (LbL) assembled multicomponent films offer the opportunity to control and to fine-tune cell attachment and behavior on solid surfaces [Layer-by Layer Films for Biomedical Applications, edited by Picart et al. (Wiley, Weinheim, 2014) and El-Khouri et al., "Multifunctional layer-by-layer architectures for biological applications," in Functional Polymeric Ultrathin Films, edited by Advincula and Knoll (Wiley, Weinheim, 2011), Vol. 1]. At the same time, these films allow for quite detailed physicochemical characterization of static and dynamic surface properties that are typically not available in classic cell culture. In this report, the authors investigate cell adhesion and cytocompatibility of compositionally and morphologically similar thin films composed of oppositely charged synthetic or natural polyelectrolytes in which different physical parameters such as surface charge or water content are varied through chemical composition and deposition conditions. Human adult dermal fibroblasts were chosen as a model because of the need for chemically defined matrix in the field of primary cell amplification. The growth and the stability of the multilayer films in the incubation media were studied dissipation-enhanced quartz crystal micobalance (QCM-D) and ellipsometry. The QCM-D signals observed during the film deposition were analyzed qualitatively to estimate the viscoelastic properties of the films. The authors used contact angle measurements with water to study the contribution of the chemical functionalities to wetting behavior of the films. Most importantly, they also studied the interaction of the films with serum components. Our results underline that cell adhesion is a highly complex process which is not only governed by the functionality of a surface but also by its morphology, its affinity for serum components, and also by changes of surface properties brought about by adsorbing molecules. Of the many LbL-films tested, poly(4-styrenesulfonate)/poly(allyl amine) multilayers were best suited for our fibroblast cultures, which opens a way to avoid gelatin based and similar substrates whose exact chemical composition is unknown. PMID- 26964532 TI - Study of cholesterol and vitamin E levels in broiler meat from different feeding regimens by TOF-SIMS. AB - The quality of chicken meat, which is one of the most widely consumed meats in the world, has been the subject of research and studies for many years. There are several ways to improve the quality of this type of meat, including changing the concentrations of individual molecular components. Such important components of meat are inter alia, cholesterol, vitamin E, and some fatty acids such as omega-3 and omega-6. Manipulation of ingredient levels may be achieved by enriching chicken feed with elements of different types such as vegetable oils, garlic, or selenium. Thus far, various biochemical and biophysical methods have been used to study quality of different meat types, especially broiler meat. Here, the authors demonstrate the use of high-resolution time-of-flight secondary ion mass spectrometry (TOF-SIMS) mass spectrometry to assess how variations in animal nutrition affect concentrations of specific lipids in the meat, such as cholesterol and vitamin E. In the presented experiment, there were four different dietary treatments. Feed for animals in the first group was supplemented with soy oil in 50%, the second group's feed was supplemented with linseed oil in 50%, a combination of these two oils in the proportion of 44%:56% was used for the third group, and in the reference group, animals were fed with beef tallow. From each group, four individuals were selected for further analysis. Positive and negative ion mass spectra were generated from the pectoralis superficialis muscle tissue of the left carcass side of each one animal. Using TOF-SIMS with a bismuth cluster ion source (Bi3 (+)), and based on characteristic peaks for cholesterol in the positive mode and vitamin E in the negative mode, the authors have illustrated the relationship of these lipids levels to the various feeding regimens. Simultaneously, the authors characterized the varying dependences on the concentrations of measured lipids in fat and muscle fibers. The cholesterol concentration in muscle fibers was the lowest in the group fed with soybean oil and the highest in reference group IV (tallow feed). In the fatty region, the highest level of cholesterol was found in the third group. The highest concentrations of vitamin E were found in the fibers of the first group and the fat region of the second group. The obtained results show that SIMS imaging is a useful approach for assessing changes in lipid concentrations in the meat tissue from animals on different diets and provides a foundation for future research. PMID- 26964535 TI - Relationships between lumbar inter-vertebral motion and lordosis in healthy adult males: a cross sectional cohort study. AB - BACKGROUND: Intervertebral motion impairment is widely thought to be related to chronic back disability, however, the movements of inter-vertebral pairs are not independent of each other and motion may also be related to morphology. Furthermore, maximum intervertebral range of motion (IV-RoMmax) is difficult to measure accurately in living subjects. The purpose of this study was to explore possible relationships between (IV-RoMmax) and lordosis, initial attainment rate and IV-RoMmax at other levels during weight-bearing flexion using quantitative fluoroscopy (QF). METHODS: Continuous QF motion sequences were recorded during controlled active sagittal flexion of 60 degrees in 18 males (mean age 27.6 SD 4.4) with no history of low back pain in the previous year. IV-RoMmax, lordotic angle, and initial attainment rate at all inter-vertebral levels from L2-S1 were extracted. Relationships between IV-RoMmax and the other variables were explored using correlation coefficients, and simple linear regression was used to determine the effects of any significant relationships. Within and between observer repeatability of IV-RoMmax and initial attainment rate measurements were assessed in a sub-set of ten participants, using the intra-class correlation coefficient (ICC) and standard error of measurement (SEM). RESULTS: QF measurements were highly repeatable, the lowest ICC for IV-RoMmax, being 0.94 (0.80-0.99) and highest SEM (0.76 degrees ). For initial attainment rate the lowest ICC was 0.84 (0.49-0.96) and the highest SEM (0.036). The results also demonstrated significant positive and negative correlations between IV-RoMmax and IV-RoMmax at other lumbar levels (r = -0.64-0.65), lordosis (r = -0.52-0.54), and initial attainment rate (r = -0.64-0.73). Simple linear regression analysis of all significant relationships showed that these predict between 28 and 42 % of the variance in IV-RoMmax. CONCLUSIONS: This study found weak to moderate effects of individual kinematic variables and lumbar lordosis on IV-RoMmax at other intervertebral levels. These effects, when combined, may be important when such levels are being considered by healthcare professionals as potential sources of pain generation. Multivariate investigations in larger samples are warranted. PMID- 26964534 TI - Aggressive breast cancer in western Kenya has early onset, high proliferation, and immune cell infiltration. AB - BACKGROUND: Breast cancer incidence and mortality vary significantly among different nations and racial groups. African nations have the highest breast cancer mortality rates in the world, even though the incidence rates are below those of many nations. Differences in disease progression suggest that aggressive breast tumors may harbor a unique molecular signature to promote disease progression. However, few studies have investigated the pathology and clinical markers expressed in breast tissue from regional African patient populations. METHODS: We collected 68 malignant and 89 non-cancerous samples from Kenyan breast tissue. To characterize the tumors from these patients, we constructed tissue microarrays (TMAs) from these tissues. Sections from these TMAs were stained and analyzed using immunohistochemistry to detect clinical breast cancer markers, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2 receptor (HER2) status, Ki67, and immune cell markers. RESULTS: Thirty-three percent of the tumors were triple negative (ER-, PR-, HER2 ), 59% were ER+, and almost all tumors analyzed were HER2-. Seven percent of the breast cancer patients were male, and 30% were <40 years old at diagnosis. Cancer tissue had increased immune cell infiltration with recruitment of CD163+ (M2 macrophage), CD25+ (regulatory T lymphocyte), and CD4+ (T helper) cells compared to non-cancer tissue. CONCLUSIONS: We identified clinical biomarkers that may assist in identifying therapy strategies for breast cancer patients in western Kenya. Estrogen receptor status in particular should lead initial treatment strategies in these breast cancer patients. Increased CD25 expression suggests a need for additional treatment strategies designed to overcome immune suppression by CD25+ cells in order to promote the antitumor activity of CD8+ cytotoxic T cells. PMID- 26964533 TI - MicroRNAs in colorectal carcinoma--from pathogenesis to therapy. AB - BACKGROUND: Acting as inflammatory mediators, tumor oncogenes or suppressors, microRNAs are involved in cell survival, death, epithelial-mesenchymal transition and metastasis, etc. Investigating the communication between microRNAs and tumorigenesis is critical to our understanding of the pathogenesis of multiple disease states. MAIN BODY: Currently, colorectal carcinoma (CRC), one of the most common malignancies worldwide, has a poor prognosis due to lack of an effective therapeutic option. Increasing evidence has identified altered profiles and regulatory potential of microRNAs in conditions related to environmentally-caused colorectal inflammation and colitis-associated cancer. Many studies have shed light on a more thorough understanding of the function and distribution of microRNAs in CRC initiation and emergence. However, the molecular mechanisms by which microRNAs modulate cellular processes still need to be further elucidated and may offer a foundation for evaluating microRNA-based therapeutic potential for CRC in both animal models and clinical trials. CONCLUSION: In this review, the roles and mechanisms of microRNAs involved in CRC from pathogenesis to therapy are summarized and discussed, which may provide more useful hints for CRC prevention and therapy. PMID- 26964536 TI - Bioprospecting potential of halogenases from Arctic marine actinomycetes. AB - BACKGROUND: Halometabolites, an important group of natural products, generally require halogenases for their biosynthesis. Actinomycetes from the Arctic Ocean have rarely been investigated for halogenases and their gene clusters associated, albeit great potential of halometabolite production has been predicted. Therefore, we initiated this research on the screening of halogenases from Arctic marine actinomycetes isolates to explore their genetic potential of halometabolite biosynthesis. RESULTS: Nine halogenase genes were discovered from sixty Arctic marine actinomycetes using in-house designed or previously reported PCR primers. Four representative genotypes were further cloned to obtain full coding regions through genome walking. The resulting halogenases were predicted to be involved in halogenation of indole groups, antitumor agent ansamitocin-like substrates, or unknown peptide-like compounds. Genome sequencing revealed a potential gene cluster containing the halogenase predicted to catalyze peptide like compounds. However, the gene cluster was probably silent under the current conditions. CONCLUSIONS: PCR-based screening of halogenase genes is a powerful and efficient tool to conduct bioprospecting of halometabolite-producing actinomycetes from the Arctic. Genome sequencing can also identify cryptic gene clusters potentially producing new halometabolites, which might be easily missed by traditional isolation and chemical characterization. In addition, our study indicates that great genetic potential of new halometabolites can be expected from mostly untapped actinomycetes from the polar regions. PMID- 26964537 TI - Ground-glass nodule in a patient with echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK)-positive lung cancer: a case report. AB - BACKGROUND: Grand-glass nodule for CT image has thought to be less aggressive tumor in lung cancer. Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-positive lung cancer presenting with Ground-glass nodules (GGNs) is relatively rare, and few such cases have been reported. CASE PRESENTATION: An asymptomatic 56-year-old woman exhibited a 1.1-cm GGN in the lower lobe of the left lung on computed tomography during a medical checkup. Positron emission tomography showed no difference in uptake by the nodule compared with other organs. We elected to perform surgery because the nodule included a solid component and had grown only slightly during the last 2 years according to thin-section computed tomography. Partial resection of the lower left lung was performed by video-assisted thoracic surgery. Pathological examination revealed mucus-producing high columnar epithelium forming an irregular tubular-acinar-like structure partly replacing the alveolar epithelium on hematoxylin and eosin staining. More than 50 % of the tumor demonstrated a lepidic growth pattern. The tumor was negative for epidermal growth factor receptor mutation but positive for the EML4-ALK fusion oncogene according to fluorescence in situ hybridization. CONCLUSIONS: We herein report a case of EML4 ALK-positive lung cancer presenting with a GGN along with a review of the relevant literature, including histopathological findings and imaging features. We consider that EML4-ALK-positive lung cancer is often highly progressive and that careful follow-up is therefore essential in these patients. PMID- 26964539 TI - Plasma exchange response in 34 patients with severe optic neuritis. AB - Optic neuritis could lead to severe visual impairment despite corticosteroids. Our aim was to evaluate the rate of visual improvement in patients treated with plasma exchange (PLEX) for severe steroid unresponsive optic neuritis and to identify predictive factors of outcome. Thirty-four patients (41 optic nerves damaged) with remaining visual acuity of 0.1 or less despite steroid pulse therapy were treated with PLEX from September 2010 to May 2015. Demographic and clinical neuro-ophthalmic findings, and spectral domain-optical coherence tomography data before PLEX treatment were analyzed. The mean symptom duration before PLEX was 34.6 days (median 28 days; range 6-92 days). After PLEX, the median final visual acuity was 0.8 and in 56 % of cases, final acuity was 0.5 or better. Past history of ipsilateral optic neuritis was associated significantly with poor outcome defined as final acuity less than 0.5. No significant difference in the visual outcome after PLEX was found between multiple sclerosis and neuromyelitis optica. In conclusion, this observational study showed that PLEX as second-line therapy led to a functionally important visual recovery in more than half patients with severe optic neuritis. PMID- 26964538 TI - Infections in travellers returning to Turkey from the Arabian peninsula: a retrospective cross-sectional multicenter study. AB - Mass gatherings pooling people from different parts of the world-the largest of which is to Mecca, Saudi Arabia, for Hajj-may impose risks for acquisition and dissemination of infectious diseases. A substantial number of pilgrims to Hajj and Umrah are Turkish citizens (456,000 in 2014) but data are lacking on scale of the problem. We did a retrospective cross-sectional multicenter study in Turkey to explore the range of infections among inpatients who had recently returned from the Arabian Peninsula. Our inclusion criteria were patients who had acquired an infection during their trip to an Arabian Peninsula country, or who became symptomatic within 1 week of their return. The data were collected retrospectively for January 1, 2013 and March 1, 2015. 185 Turkish patients were recruited to the study across 15 referral centers with travel associated infectious diseases after returning from Arabian Peninsula countries (predominantly Saudi Arabia 163 [88.1 %] for religious purposes 162 [87.5 %]). Seventy four (40.0 %) of them were >= 65 years old with numerous comorbidities including diabetes (24.3 %) and COPD (14.1 %). The most common clinical diagnosis was respiratory tract infections (169 [91.5 %]), followed by diarrheal diseases (13 [7 %]), and there was one case of MERS-CoV. Patients spent a median of 5 (3 7) days as hospital inpatients and overall mortality was 1.1 %. Returning travellers from the Arabian Peninsula present as inpatients with a broad range of infectious diseases similar to common community acquired infections frequently seen in daily medical practices in Turkey. PMID- 26964540 TI - Impulsive compulsive behaviours in Parkinson's disease: patients' versus caregivers' perceptions. PMID- 26964541 TI - Clinical phenotype and risk of levodopa-induced dyskinesia in Parkinson's disease. AB - It is unclear whether patients with different clinical phenotypes of Parkinson's disease (PD) differ in their risk of developing levodopa-induced dyskinesia. We evaluated the possible association between clinical phenotypes and risk of levodopa-induced dyskinesia in PD patients using a case-control design. The FRAGAMP study is a large Italian multicenter study. Patients affected by PD diagnosed according to the Gelb's criteria were enrolled and underwent a face-to face interview. Clinical scales were used to evaluate motor and cognitive impairment. Presence of dyskinesia was assessed by the item 32 of the UPDRS section IV. On the basis of the most prominent motor symptoms at onset PD, patients were classified as tremor-dominant, akinetic-rigid, or mixed type. 485 PD patients (292 men; mean age 65.6 +/- 9.8) were enrolled in the study of whom 128 (26.4 %) presented levodopa-induced dyskinesia. Of the 485 patients, 311 (64.1 %) were classified as tremor-dominant, 104 (21.4 %) as Akinetic-Rigid and 70 (14.4 %) as mixed type. Multivariate logistic regression analysis showed a significant negative association between tremor-dominant phenotype and levodopa induced dyskinesia (adjusted OR 0.48; 95 % CI 0.23-1.00; p value 0.05). When analysis was stratified by age at onset a stronger negative association was found among the late onset (>50 years) PD patients (OR 0.28; 95 % CI 0.11-0.70; p value 0.007) while no association was found among patients with an early onset. Our findings support the hypothesis that the occurrence of resting tremor as an initial manifestation of PD may predict a lower probability of developing levodopa-induced dyskinesia. PMID- 26964543 TI - Quantifying the burden of caregiving in Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a rare pediatric neuromuscular disease associated with progressive muscle degeneration and extensive care needs. Our objective was to estimate the caregiver burden associated with DMD. We made cross sectional assessments of caregiver health-related quality of life (HRQL) and burden using the EuroQol EQ-5D, a Visual Analogue Scale (VAS), the SF-12 Health Survey, and the Zarit Caregiver Burden Interview (ZBI) administered online. Results were stratified by disease stage (early/late ambulatory/non-ambulatory) and caregivers' rating of patients' health and mental status. In total, caregivers to 770 patients participated. Mean EQ-5D utility ranged between 0.85 (95 % CI 0.82-0.88) and 0.77 (0.74-0.80) across ambulatory classes and 0.88 (0.85 0.90) and 0.57 (0.39-0.74) across caregivers' rating of patients' health and mental status. Mean VAS score was 0.74 (0.73-0.75), mean SF-12 Mental Health Component Summary score 44 (43-45), and mean ZBI score 29 (28-30). Anxiety and depression, recorded in up to 70 % of caregivers depending on patients' health and mental status, was significantly associated with annual household cost burden (>$5000 vs. <$1000, odds ratio 1.76, 95 % CI 1.18-2.63) and hours of leisure time devoted to informal care per week (25-50 vs. <25 h 2.01, 1.37-2.94; >50 vs. <25 h 3.35, 2.32-4.83) (p < 0.007). We show that caring for a person with DMD can be associated with a substantial burden and impaired HRQL. Our findings suggest that caregivers to patients with DMD should be screened for depression and emphasize the need for a holistic approach to family mental health in the context of chronic childhood disease. PMID- 26964542 TI - Long-term impact on quality of life of subthalamic nucleus stimulation in Parkinson's disease. AB - Long-term impact of bilateral subthalamic nucleus deep brain stimulation (STN DBS) on health-related quality of life (HRQOL) and associated factors in patients with Parkinson's disease (PD) are not clear. In this prospective study, we included 69 PD patients (64 % men, mean age 61.3 +/- 7.4 and disease duration 13.2 +/- 5.7 years) undergoing STN-DBS. They were evaluated preoperatively (baseline), 1 and 5 years postoperatively assessing 39-item Parkinson's Disease Questionnaire (PDQ-39), Schwab and England Activities of Daily Living Scale (SEADL), Unified Parkinson's Disease Rating Scale (UPDRS) off- and on-medication, patient diaries, dopaminergic treatment, mortality and surgical complications. Five years postoperatively, off-medication, there were improvements from baseline in UPDRS-II and III total (27.2 and 26.7 %, respectively) and SEADL (18.6 % more completely independent patients) (p < 0.05) scores, while on-medication, there was a deterioration in UPDRS-III (37.8 %, mainly axial signs) (p < 0.05) and minor improvements in SEADL (3.7 %). While at 1 year PDQ-39, the summary index improved substantially (36.5 %) (p < 0.05), at 5 years patients regressed (only 8.8 %) (p < 0.05), though changes in PDQ-39 subscores remained significant, with improvements in ADL (18.8 %), emotional well-being (19.0 %), stigma (36.4 %) and discomfort (20.6 %), despite worsening in communication (47.8 %) (p < 0.05). Lower preoperative PDQ-39 summary index and greater 1-year UPDRS-III-off total score gain predicted better long-term HRQOL. STN-DBS produces long-term improvements in HRQOL in PD. Preoperative HRQOL and short-term postoperative changes in off-medication motor status may predict long-term HRQOL in PD following STN-DBS. PMID- 26964544 TI - The Merits of a Two-Day Evidence-Based Medicine Course for Surgical Residents. AB - BACKGROUND: Over 10 years ago, we introduced a two-day, evidence-based surgery course for surgical residents. During the last 4 years, we evaluated its effect on the participants' evidence-based medicine (EBM) knowledge and skills. METHODS: Between 2012 and 2015, six courses were organised for residents of various surgical specialties of allied hospitals in the Amsterdam educational district. The courses covered the literature search, critical appraisal of surgical papers, and how to communicate and weigh the benefits and harms of surgical interventions. Proficiency regarding interpreting evidence was tested before and directly after the course using a modified Berlin questionnaire. RESULTS: One hundred participants attended the courses, comprising residents in surgery (61 %), orthopaedics (16 %), urology (7 %), plastic surgery (7 %), and surgical PhD students (9 %), most of whom had already been taught EBM during their medical curriculum. Pre-course score levels were already fairly high (6.19 out of 10), but scores after the course were significantly higher (7.04); mean difference 0.85 (95 % confidence interval 0.4-1.3). No significant differences were observed among the surgical specialties. Attendees highly appreciated the course. CONCLUSIONS: A two-day, evidence-based surgery course improved EBM aptitude of surgical residents. Hence, the course appears useful to refresh the EBM paradigm among future Dutch surgeons. PMID- 26964545 TI - Erratum to: Translational Modeling in Schizophrenia: Predicting Human Dopamine D2 Receptor Occupancy. PMID- 26964546 TI - Development of Long-Circulating pH-Sensitive Liposomes to Circumvent Gemcitabine Resistance in Pancreatic Cancer Cells. AB - PURPOSES: To develop pH-sensitive liposomes (PSL) containing a high content of gemcitabine; and to investigate whether drug loading (DL) would alter the in vitro and pharmacokinetic properties. METHODS: PSL with a high DL were obtained using a modified small-volume incubation method. The DL effects on drug release rate and in vitro cytotoxicity of PSL were evaluated using MIA PaCa-2 pancreatic cancer cells and their pharmacokinetics investigated in rats. RESULTS: The highest DL of 4.5 +/- 0.1% was achieved for gemcitabine in PSL with 145 +/- 5 nm diameter. DL did not alter the in vitro release rate from PSL. The IC50 (48 h) of PSL (DL 0.5 and 4.5%) and non pH-sensitive liposomes (NPSL, DL 4.2%) were 1.1 +/- 0.1, 0.7 +/- 0.1 and 37.0 +/- 7.5 MUM, respectively. The PSL resulted in a 4.2 fold increase in its elimination half-life (6.2 h) compared to gemcitabine solution (1.4 h) in rats. No significant difference in pharmacokinetic parameters was observed between the two PSL (DL 0.5 and 4.5%). CONCLUSION: The PSL offered advantages over NPSL in restoring the sensitivity of pancreatic cancer cells to gemcitabine without requiring a high DL. DL in the PSL did not alter release rate, cytotoxicity or their long-circulating properties. Graphical Abstract ?. PMID- 26964549 TI - Relationships between fatty infiltration in the thigh and calf in women with knee osteoarthritis. AB - BACKGROUND: In individuals with knee osteoarthritis (OA), fatty infiltration into thigh muscle is associated with poor physical performance and strength. However, it is not known whether this also occurs in the calf and if this impacts physical function. AIMS: We investigated the relationships between volumes of intramuscular fat (intraMF), intermuscular fat (IMF), subcutaneous fat (SCF), lean muscle and muscle adiposity, in the thighs compared to the calves of women with knee OA. METHODS: MRI scans of the thigh and calf were acquired from 20 women over 55 years with knee OA (3.0T Discovery MR750, GE Healthcare). Axial IDEAL (iterative decomposition of water and fat with echo asymmetry and least squares estimation) fat-separated images were segmented to quantify intraMF, IMF, SCF and lean muscle volumes (SliceOmatic 5.0, Tomovision). Correlation and linear regression analyses were run. RESULTS: We found a positive relationship between thigh and calf intraMF (R 2 = 0.592; B = 5.49; p = 0.001), muscle adiposity (R 2 = 0.539; B = 0.567; p = 0.001), and SCF volume (R 2 = 0.699; B = 12.847; p = 0.001), controlling for waist-to-hip ratio. Relationships between thigh and calf IMF (R 2 = 0.239; B = 7.743; p = 0.061), lean muscle (R 2 = 0.245; B = 4.149; p = 0.047) and combined intraMF and IMF volume (R 2 = 0.242; B = 6.162; p = 0.044) were not significant. DISCUSSION: Although a correlation exists between thigh and calf muscle adiposity, intraMF and SCF, this does not hold true for IMF or lean muscle. A greater amount of intraMF infiltration occurs in the thigh compared to the calf of women with knee OA. CONCLUSION: The calf and thigh may both be involved in pathologic changes in muscle composition in knee OA. PMID- 26964547 TI - An In Vitro Thrombolysis Study Using a Mixture of Fast-Acting and Slower Release Microspheres. AB - PURPOSE: To test the hypothesis that a mixture combining fast and slower release rate microspheres can restore blood flow rapidly and prevent formation of another blockage in thrombolysis. METHODS: We used polyethylene glycol (PEG) microspheres which provide the release of the encapsulated streptokinase (SK) on the scale of minutes, and Eudragit FS30D (Eud), a polymethacrylate polymer, for development of delayed release microspheres which were desirable to prevent a putative second thrombus. Eud microspheres were coated with chitosan (CS) to further extend half life. Experiments included the development, characterization of Eud/SK and CS Eud/SK microspheres, and in vitro thrombolytic studies of the mixtures of PEG/SK and Eud /SK microspheres and of PEG/SK and CS-Eud/SK microspheres. RESULTS: CS Eud/SK microspheres have slightly lower encapsulation efficiency, reduced activity of SK, and a much slower release of SK when compared with microspheres of Eud/SK microspheres. Counter-intuitively, slower release leads to faster thrombolysis after reocclusion as a result of greater retention of agent and the mechanism of distributed intraclot thrombolysis. CONCLUSIONS: A mixture of PEG/SK and CS-Eud/SK microspheres could break up the blood clot rapidly while providing clot-lytic efficacy in prevention of a second blockage up to 4 h. PMID- 26964551 TI - Pediatric Interventional Radiology: Vascular Interventions. AB - Pediatric interventional radiology (PIR) comprises a range of minimally invasive diagnostic and therapeutic procedures that are performed using image guidance. PIR has emerged as an essential adjunct to various surgical and medical conditions. Over the years, technology has undergone dramatic and continuous evolution, making this speciality grow. In this review, the authors will discuss various vascular interventional procedures undertaken in pediatric patients. It is challenging for the interventional radiologist to accomplish a successful interventional procedure. There are many vascular interventional radiology procedures which are being performed and have changed the way the diseases are managed. Some of the procedures are life saving and have become the treatment of choice in those patients. The future is indeed bright for the practice and practitioners of pediatric vascular and non-vascular interventions. As more and more of the procedures that are currently being performed in adults get gradually adapted for use in the pediatric population, it may be possible to perform safe and successful interventions in many of the pediatric vascular lesions that are otherwise being referred for surgery. PMID- 26964548 TI - Synthesis and Characterization of Poly(2-hydroxyethylmethacrylate) Contact Lenses Containing Chitosan Nanoparticles as an Ocular Delivery System for Dexamethasone Sodium Phosphate. AB - PURPOSE: Dexamethasone sodium phosphate (DXP) is an anti-inflammatory drug commonly used to treat acute and chronic ocular diseases. It is routinely delivered using eye-drops, where typically only 5% of the drug penetrates the corneal epithelium. The bioavailability of such ophthalmic drugs can be enhanced significantly using contact lenses incorporating drug-loaded nanoparticles (NPs). METHODS: The mechanism of release from chitosan NPs (CS-NPs), synthesized by ionic gelation, was studied in vitro. The DXP loaded CS-NPs were subsequently entrapped in contact lenses and the optical and drug-release properties were assessed. RESULTS: DXP release from CS-NPs followed diffusion and swelling controlled mechanisms, with an additional proposed impact from the electrostatic interaction between the drug and the CS-NPs. The release rate was found to increase with an increase in drug loading from 20 to 50 wt%. However, an inverse effect was observed when initial loading increased to 100 wt%. NP-laden lenses were optically clear (95-98% transmittance relative to the neat contact lens) and demonstrated sustained DXP release, with approximately 55.73% released in 22 days. CONCLUSIONS: The release profile indicated that drug levels were within the therapeutic requirement for anti-inflammatory use. These results suggest that these materials might be a promising candidate for the delivery of DXP and other important ophthalmic therapeutics. PMID- 26964550 TI - Role of Computed Tomography in Pediatric Abdominal Conditions. AB - In the pediatric patient, computed tomography (CT) scan as an imaging modality for evaluation of the abdomen is to be used judiciously. The use of correct scanning protocols, single phase scanning, scanning only when required are key factors to minimize radiation doses to the child, while providing diagnostic quality. CT is the preferred modality in the evaluation of trauma, to assess extent of solid organ or bowel injury. It is also useful in several inflammatory conditions such as inflammatory bowel diseases and acute pancreatitis. CT also has an important role in evaluating intra-abdominal tumors, although magnetic resonance imaging (MRI) can be used as an alternative to CT. PMID- 26964553 TI - Idiopathic CD4 T-Cell Lymphocytopenia: A Case Report of a Young Boy With Recalcitrant Warts. AB - IMPORTANCE: Idiopathic CD4 T-cell lymphocytopenia (ICL) is an immunodeficiency disorder that presents with a decrease in CD4(+) T cells without evidence of a human immunodeficiency virus infection. It is most commonly diagnosed after a patient presents with an opportunistic infection and can also be associated with malignancies and autoimmune diseases. This case presentation and literature review highlights the common skin findings in patients with ICL, mainly recalcitrant warts, and discusses the treatment options available. OBSERVATIONS: The patient described is the youngest reported with ICL presenting with isolated cutaneous findings of recalcitrant warts and psoriasis. Many treatment options were tried for the warts, with the most significant response to acitretin. CONCLUSIONS AND RELEVANCE: This case highlights the importance of considering underlying immunodeficiency in patients with recalcitrant warts as well as developing treatment plans. Such patients require close follow-up by both dermatology and immunology to monitor for the development of other diseases related to ICL. PMID- 26964552 TI - Presence of host-seeking Ixodes ricinus and their infection with Borrelia burgdorferi sensu lato in the Northern Apennines, Italy. AB - Host-seeking ticks were collected in the Northern Apennines, Italy, by dragging at 35 sites, at altitudes ranging from 680 and 1670 m above sea level (asl), from April to November, in 2010 and 2011. Ixodes ricinus (4431 larvae, 597 nymphs and 12 adults) and Haemaphysalis punctata (11,209 larvae, 313 nymphs, and 25 adults) were the most abundant species, followed by Haemaphysalis sulcata (20 larvae, five nymphs, and 13 adults), Dermacentor marginatus (42 larvae and two adults) and Ixodes hexagonus (one nymph). Greatest numbers of ticks were collected at locations characterised by southern exposure and limestone substratum, at altitudes <1400 m asl; I. ricinus was most abundant in Turkey oak (Quercus cerris) wood, whereas H. punctata was mostly collected in hop hornbeam (Ostrya carpinifolia) wood and on exposed rocks. Ixodes ricinus was also found up to 1670 m asl, in high stand beech (Fagus sylvatica) wood. The overall prevalence of Borrelia burgdorferi sensu lato (sl) in 294 host-seeking I. ricinus nymphs was 8.5 %. Borrelia garinii was the most frequently identified genospecies (64.0 % of positive nymphs), followed by B. valaisiana, B. burgdorferi sensu stricto, B. afzelii, and B. lusitaniae. Based upon the comparison with the results of previous studies at the same location, these research findings suggest the recent invasion of the study area by the tick vector and the agents of Lyme borreliosis. PMID- 26964555 TI - Letter regarding article 'Focal stenosis of the sigmoid sinus causing intracranial venous hypertension: Case report, endovascular management and review of the literature'. PMID- 26964554 TI - Epicardial fat thickness regression with continuous positive airway pressure therapy in patients with obstructive sleep apnea: assessment by two-dimensional echocardiography. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a common syndrome in patients with metabolic syndrome (MetS). Epicardial fat thickness (EFT), an indicator of visceral adiposity, is a novel parameter for studying patients with OSA. Our aim was to investigate the effects of continuous positive airway pressure therapy (CPAP) therapy on EFT. METHODS: A total of 162 subjects (68 women and 94 men) were included and divided into three groups: Group I: Apnea-hypopnea index (AHI) < 5 (n = 45), Group II: AHI 5-15 (n = 22), and Group III: AHI > 15 (n = 95). All participants underwent full-night polysomnography and transthoracic echocardiography. There were 28 symptomatic patients with AHI > 15 who received compliant CPAP therapy for 24 weeks. RESULTS: MetS was more frequent, and systolic blood pressure (SBP), diastolic blood pressure (DBP), blood glucose were higher in Group III compared with I (p < 0.05). High-density lipoprotein (HDL) levels were lower in Group III compared with I (p < 0.05). Triglyceride levels and waist circumference were higher in Group III compared with I and II (p < 0.05). EFT was higher in Group III compared with I and higher in Group II compared with I (p < 0.05). EFT was predicted by MetS and AHI. After CPAP therapy high-sensitive C-reactive protein (hsCRP) and EFT were reduced (p < 0.05). CONCLUSION: EFT was significantly higher in patients with AHI > 15 and predicted by MetS and AHI. CPAP therapy reduced hsCRP levels and EFT. PMID- 26964556 TI - Primary care management of patients after weight loss surgery. PMID- 26964558 TI - Quantitative Evaluation of the Dispersion of Graphene Sheets With and Without Functional Groups Using Molecular Dynamics Simulations. AB - Nanofluids with enhanced thermal properties are candidates for thermal management in automotive systems, with scope for improving energy efficiency. In particular, many studies have reported on dispersions of nanoparticles with long-term stability in the base fluid, with qualitative evaluations of the dispersion stability via either the naked eye or optical instruments. Additives such as surfactants can be used to enhance the dispersion of nanoparticles; however, this may diminish their intrinsic thermal properties. Here, we describe molecular dynamics simulations of nanofluids containing graphene sheets dispersed in ethylene glycol and water. We go on to suggest a quantitative evaluation method for the degree of dispersion, based on the ratio of the total number of nanoparticles to the number of clustered nanoparticles. Moreover, we investigate the effects of functional groups on the surface of graphene, which are expected to improve the dispersion without requiring additives such as surfactants due to steric hindrance and chemical affinity for the surrounding fluid. We find that, for pure graphene, the degree of dispersion decreased as the quantity of graphene sheets increased, which is attributed to an increased probability of aggregation at higher loadings; however, the presence of functional groups inhibited the graphene sheets from forming aggregates. PMID- 26964559 TI - Impacts of Thermal Atomic Layer-Deposited AlN Passivation Layer on GaN-on-Si High Electron Mobility Transistors. AB - Thermal atomic layer deposition (ALD)-grown AlN passivation layer is applied on AlGaN/GaN-on-Si HEMT, and the impacts on drive current and leakage current are investigated. The thermal ALD-grown 30-nm amorphous AlN results in a suppressed off-state leakage; however, its drive current is unchanged. It was also observed by nano-beam diffraction method that thermal ALD-amorphous AlN layer barely enhanced the polarization. On the other hand, the plasma-enhanced chemical vapor deposition (PECVD)-deposited SiN layer enhanced the polarization and resulted in an improved drive current. The capacitance-voltage (C-V) measurement also indicates that thermal ALD passivation results in a better interface quality compared with the SiN passivation. PMID- 26964557 TI - Intraoperative Laparoscopic Near-Infrared Fluorescence Cholangiography to Facilitate Anatomical Identification: When to Give Indocyanine Green and How Much. AB - Recent technological advances have enabled real-time near-infrared fluorescence cholangiography (NIRFC) with indocyanine green (ICG). Whereas several studies have shown its feasibility, dosing and timing for practical use have not been optimized. We undertook a prospective study with systematic variation of dosing and timing from injection of ICG to visualization. Adult patients undergoing laparoscopic biliary and hepatic operations were enrolled. Intravenous ICG (0.02 0.25 mg/kg) was administered at times ranging from 10 to 180 minutes prior to planned visualization. The porta hepatis was examined using a dedicated laparoscopic system equipped to detect NIRFC. Quantitative analysis of intraoperative fluorescence was performed using a scoring system to identify biliary structures. A total of 37 patients were enrolled. Visualization of the extrahepatic biliary tract improved with increasing doses of ICG, with qualitative scores improving from 1.9 +/- 1.2 (out of 5) with a 0.02-mg/kg dose to 3.4 +/- 1.3 with a 0.25-mg/kg dose (P < .05 for 0.02 vs 0.25 mg/kg). Visualization was also significantly better with increased time after ICG administration (1.1 +/- 0.3 for 10 minutes vs 3.4 +/- 1.1 for 45 minutes, P < .01). Similarly, quantitative measures also improved with both dose and time. There were no complications from the administration of ICG. These results suggest that a dose of 0.25 mg/kg administered at least 45 minutes prior to visualization facilitates intraoperative anatomical identification. The dosage and timing of administration of ICG prior to intraoperative visualization are within a range where it can be administered in a practical, safe, and effective manner to allow intraoperative identification of extrahepatic biliary anatomy using NIRFC. PMID- 26964560 TI - Validity of an Accelerometer-Based Activity Monitor System for Measuring Physical Activity in Frail Older Adults. AB - This study aimed to investigate the validity of the accelerometer-based DynaPort system to detect physical activity in frail, older subjects. Eighteen home dwelling subjects (Groningen Frailty Indicator [GFI] score >= 4, >= 75 years) were included. Activities in their home environment were simultaneously observed by two researchers and measured with the DynaPort system during six consecutive hours. Primary outcome measures were the sensitivity and specificity of the DynaPort for locomotion (90% considered as sufficient agreement). Other outcome measures were overall agreement, and sensitivity and specificity for other activities. Sensitivity and specificity for locomotion were 83.3% and 100.0%, respectively. Overall agreement was 74.6%. Sensitivity was sufficient for sitting (94.4%), but not for lying and standing (59.2% and 69.6%, respectively). Specificity was sufficient for lying and standing (100.0% and 93.3%, respectively), but not for sitting (80.7%). In conclusion, the DynaPort system is not a valid method for assessing physical activity in frail, older subjects. PMID- 26964562 TI - The clinical dilemma of heart failure with preserved ejection fraction: an update on pathophysiology and management for physicians. AB - The prevalence of heart failure with preserved ejection fraction (HFpEF) continues to grow at alarming rates and is predicted to become the most prevalent phenotype of heart failure over the next decade. Recent data show a higher non cardiac comorbidity burden associated with HFpEF, and similar overall hospitalisation rates when compared with patients with heart failure with reduced ejection fraction (HFrEF). Unfortunately, clinicians mainly focus their efforts in diagnosis of HFrEF despite HFpEF accounting for 50% of the cases of heart failure. Therefore, this review is intended to create awareness on the pathophysiology, risk factors, diagnosis and management of patients with HFpEF and its core mechanical abnormality left ventricular diastolic dysfunction. Clinical distinction between HFpEF and HFrEF should be of particular interest to internal medicine physicians and general practitioners as this distinction is seldom made and early diagnosis can lag if appropriate risk factors are not promptly recognised. PMID- 26964563 TI - Taut teachings: history and physical examination tips for examinations. PMID- 26964561 TI - Role of apolipoprotein B100 and oxidized low-density lipoprotein in the monocyte tissue factor induction mediated by anti-beta2 glycoprotein I antibodies. AB - OBJECTIVE: The objective of this paper is to elucidate the not yet known plasma molecule candidates involved in the induction of tissue factor (TF) expression mediated by beta2GPI-dependent anticardiolipin antibody (aCL/beta2GPI) on monocytes. METHODS: Human serum incubated with FLAG-beta2GPI was applied for affinity chromatography with anti- FLAG antibody. Immunopurified proteins were analyzed by a liquid chromatography coupled with mass spectrometry (LC-MS). TF mRNA induced by the identified molecules on monocytes was also analyzed. RESULTS: Apolipoprotein B100 (APOB) was the only identified serum molecule in the MS search. Oxidized LDL, containing APOB as well as ox-Lig1 (a known ligand of beta2GPI), was revealed as a beta2GPI-binding molecule in the immunoprecipitation assay. TF mRNA was markedly induced by oxidized LDL/beta2GPI complexes with either WBCAL-1 (monoclonal aCL/beta2GPI) or purified IgG from APS patients. The activities of lipoprotein-associated phospholipase A2, one of the component molecules of oxidized LDL, were significantly higher in serum from APS patients than in those from controls. CONCLUSION: APOB (or oxidized LDL) was detected as a major beta2GPI binding serum molecule by LC-MS search. Oxidized LDL/aCL/beta2GPI complexes significantly induced TF expressions on monocytes. These data suggest that complexes of oxidized LDL and aCL/beta2GPI may have a crucial role in the pathophysiology of APS. PMID- 26964564 TI - CRISPR/Cas9-mediated somatic correction of a novel coagulator factor IX gene mutation ameliorates hemophilia in mouse. AB - The X-linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR/Cas9 system was used to generate distinct genetically modified mouse models and confirmed that the novel Y371D mutation resulted in a more severe hemophilia B phenotype than the previously identified Y371S mutation. To develop therapeutic strategies targeting this mutation, we subsequently compared naked DNA constructs versus adenoviral vectors to deliver Cas9 components targeting the F9 Y371D mutation in adult mice. After treatment, hemophilia B mice receiving naked DNA constructs exhibited correction of over 0.56% of F9 alleles in hepatocytes, which was sufficient to restore hemostasis. In contrast, the adenoviral delivery system resulted in a higher corrective efficiency but no therapeutic effects due to severe hepatic toxicity. Our studies suggest that CRISPR/Cas-mediated in situ genome editing could be a feasible therapeutic strategy for human hereditary diseases, although an efficient and clinically relevant delivery system is required for further clinical studies. PMID- 26964567 TI - Metal-Catalyzed Chemical Reaction of Single Molecules Directly Probed by Vibrational Spectroscopy. AB - The study of heterogeneous catalytic reactions remains a major challenge because it involves a complex network of reaction steps with various intermediates. If the vibrational spectra of individual molecules could be monitored in real time, one could characterize the structures of the intermediates and the time scales of reaction steps without ensemble averaging. Surface-enhanced Raman scattering (SERS) spectroscopy does provide vibrational spectra with single-molecule sensitivity, but typical single-molecule SERS signals exhibit spatial heterogeneities and temporal fluctuations, making them difficult to be used in single-molecule kinetics studies. Here we show that SERS can monitor the single molecule catalytic reactions in real time. The surface-immobilized reactants placed at the junctions of well-defined nanoparticle-thin film structures produce time-resolved SERS spectra with discrete, step-transitions of photoproducts. We interpret that such SERS-steps correspond to the reaction events of individual molecules occurring at the SERS hotspot. The analyses of the yield, dynamics, and the magnitude of such SERS steps, along with the associated spectral characteristics, fully support our claim. In addition, a model that is based on plasmonic field enhancement and surface photochemistry reproduces the key features of experimental observation. Overall, the result demonstrates that it is possible, under well-controlled conditions, to differentiate the chemical and physical processes contributing to the single-molecule SERS signals, and thus shows the use of single-molecule SERS as a tool for studying the metal-catalyzed organic reactions. PMID- 26964565 TI - Long non-coding RNA MALAT1 regulates retinal neurodegeneration through CREB signaling. AB - The nervous and vascular systems, although functionally different, share many common regulators of function maintenance. Long non-coding RNAs (lncRNAs) are important players in many biological processes and human disorders. We previously identified a role of MALAT1 in microvascular dysfunction. However, its role in neurodegeneration is still unknown. Here, we used the eye as the model to investigate the role of MALAT1 in retinal neurodegeneration. We show that MALAT1 expression is significantly up-regulated in the retinas, Muller cells, and primary retinal ganglion cells (RGCs) upon stress. MALAT1 knockdown reduces reactive gliosis, Muller cell activation, and RGC survival in vivo and in vitro MALAT1-CREB binding maintains CREB phosphorylation by inhibiting PP2A-mediated dephosphorylation, which leads to continuous CREB signaling activation. Clinical and animal experimentation suggests that MALAT1 dysfunction is implicated in neurodegenerative processes and several human disorders. Collectively, this study reveals that MALAT1 might regulate the development of retinal neurodegeneration through CREB signaling. PMID- 26964568 TI - The Moorean argument for the full moral status of those with profound intellectual disability: a rejoinder to Roberts. AB - In a recent paper we argued that a Moorean strategy can be employed to justify our continuing to believe the following proposition, even in the presence of philosophical views that entail it is false, without any philosophical argument against those views, and without any positive philosophical argument in its favour: H>A: Humans have an equal moral status that is higher than the moral status of non-human animals. The basic idea is that our confidence in the truth of this proposition is greater than our confidence in the propositions that make up those philosophical views that entail that it is false, and that this is sufficient to justify rejecting those views and to continue to believe H>A. Roberts has recently responded to our argument by claiming that (i) although the Moorean strategy is valid, it is not powerful and (ii) a resort to the Moorean strategy reflects too great a pessimism about the accounts available that purport to justify H>A. In this short rejoinder we explain why Roberts fails to establish his two claims. PMID- 26964566 TI - Hyaluronan: More than just a wrinkle filler. AB - Dermatology is a field that strives not only to alleviate skin disease (therapeutics) but also to improve the perception of wellness (cosmetics). Thus, in this special issue of Glycobiology, it seems appropriate to discuss the biology of a glycosaminoglycan, called hyaluronic acid (hyaluronan, or HA), that has become the most popular agent today for intradermal injections to improve wrinkles and other cosmetic defects. HA is a simple linear polymer in which a simple disaccharide is repeated thousands of time, thereby creating a huge hydrophilic molecule that confers a large volume of hydration and contributes to the turgor and flexibility of healthy skin. Beyond cosmetic considerations, however, HA also has important biological and physiological functions that were largely under-appreciated until recently. New research has confirmed that HA is dynamically produced by most skin cells, not only fibroblasts (the cells that make most of the skin's extracellular matrix) but also by keratinocytes in the outer protective layer (epidermis). For both fibroblasts and keratinocytes, HA plays a regulatory role in controlling cell physiology through interaction of extracellular HA with a major cell-surface receptor, CD44. This interaction mediates intracellular signaling both directly and indirectly, through CD44 interactions with the cytoskeleton and with EGF and TGFbeta receptors. Furthermore, degradation of HA by specific hyaluronidase enzymes produces HA fragments that can help to regulate inflammatory processes. In this review, current knowledge about the role of HA in skin inflammation and wound healing are reviewed and possible future applications of such knowledge discussed. PMID- 26964569 TI - Are patients with amyotrophic lateral sclerosis at risk of a therapeutic misconception? AB - OBJECTIVES: To assess whether persons with amyotrophic lateral sclerosis (ALS) are at risk of a therapeutic misconception (TM) in which they misconceive research as treatment or overestimate the likelihood of its benefit. METHODS: 72 patients with ALS recruited via academic and patient organisations were surveyed using a hypothetical first-in-human intervention study scenario. We elicited their understanding of the purpose of the study ('purpose-of-research question') and then asked how they interpreted the question. We then asked for an estimate of the likelihood that their ALS would improve by participating and asked them to explain the meaning of their estimates. RESULTS: Although 10 of 72 (14%) subjects incorrectly said that the intervention study was 'mostly intending to help [me]' in response to the purpose-of-research question, 7 of those 10 thought that the question was asking them about their own motivations for participating. Overall, only one of 72 respondents (1.4%) both understood the purpose-of-research question as intended and gave the incorrect response. Subjects' mean estimate of likelihood of benefit was 31% (SD 26). This was due to 29 of 72 of respondents providing high estimates (50%-54% likelihood), which they said were expressions of hope and need for a positive attitude; among those who said their estimates meant 'those are the facts' or 'there is a lot of uncertainty', the estimates were much lower (12.6% and 18.5%, respectively). CONCLUSIONS: In this group of patients with ALS considering a hypothetical first-in-human intervention study, apparent TM responses have alternative explanations and the risk of true TM appears low. PMID- 26964570 TI - Integrated Whole Genome and Transcriptome Analysis Identified a Therapeutic Minor Histocompatibility Antigen in a Splice Variant of ITGB2. AB - PURPOSE: In HLA-matched allogeneic hematopoietic stem cell transplantation (alloSCT), donor T cells recognizing minor histocompatibility antigens (MiHAs) can mediate desired antitumor immunity as well as undesired side effects. MiHAs with hematopoiesis-restricted expression are relevant targets to augment antitumor immunity after alloSCT without side effects. To identify therapeutic MiHAs, we analyzed the in vivo immune response in a patient with strong antitumor immunity after alloSCT. EXPERIMENTAL DESIGN: T-cell clones recognizing patient, but not donor, hematopoietic cells were selected for MiHA discovery by whole genome association scanning. RNA-sequence data from the GEUVADIS project were analyzed to investigate alternative transcripts, and expression patterns were determined by microarray analysis and qPCR. T-cell reactivity was measured by cytokine release and cytotoxicity. RESULTS: T-cell clones were isolated for two HLA-B*15:01-restricted MiHA. LB-GLE1-1V is encoded by a nonsynonymous SNP in exon 6 of GLE1 For the other MiHAs, an associating SNP in intron 3 of ITGB2 was found, but no SNP disparity was present in the normal gene transcript between patient and donor. RNA-sequence analysis identified an alternative ITGB2 transcript containing part of intron 3. qPCR demonstrated that this transcript is restricted to hematopoietic cells and SNP-positive individuals. In silico translation revealed LB-ITGB2-1 as HLA-B*15:01-binding peptide, which was validated as hematopoietic MiHA by T-cell experiments. CONCLUSIONS: Whole genome and transcriptome analysis identified LB-ITGB2-1 as MiHAs encoded by an alternative transcript. Our data support the therapeutic relevance of LB-ITGB2-1 and illustrate the value of RNA-sequence analysis for discovery of immune targets encoded by alternative transcripts. Clin Cancer Res; 22(16); 4185-96. (c)2016 AACR. PMID- 26964572 TI - Development, Validation, and Evaluation of Web-Based Iranian Diabetic Personal Health Record: Rationale for and Protocol of a Randomized Controlled Trial. AB - BACKGROUND: Diabetes is one of the four main types of noncommunicable or chronic diseases. Iran is among the countries with the highest incidence of diabetic patients. A study demonstrated that the collection of diabetic data is neither organized nor standardized. There is currently no instance of electronic personal health records particularly used for diabetic patients in Iran, hence the need for one, which will be useful for self-care of diabetic patients. OBJECTIVE: The objective of the study is to examine the impact of a Web-based diabetic personal health record (DPHR) on the self-care status of diabetic patients as compared with the control group. METHODS: This study is a randomized control trial, which involves a systematic review of literature of the preferred data elements regarding a DPHR, and reevaluating the results with the opinions of local endocrinologists. Inclusion criteria were as follows: type 2 diabetic patients between 20-70 of age who live in the Mashhad City and having the disease for at least one year. The sample size is 72 people that were randomly assigned to the control and intervention groups. The participants in the intervention group were allowed access to the Web-based DPHR system, while those in the control group will continue to receive the usual care for 4 months. The study primary outcome measures include self-care status of participants and planned visit adherence. RESULTS: At the moment, there is an ongoing recruitment of participants, and preliminary results will be published in early 2016. CONCLUSIONS: We expect the final DPHR model, developed and tested during this study, to help diabetic patients to actively participate in their care management process, and also to empower the physician in providing more quality informed decisions regarding their patients. TRIAL REGISTRATION: irct.ir IRCT2013082914522N1; http://www.irct.ir/searchresult.php?id=14522&number=1 (Archived by WebCite at http://www.webcitation.org/6cC4PCcau). PMID- 26964573 TI - Confustication. PMID- 26964571 TI - HDAC Inhibitors Enhance T-Cell Chemokine Expression and Augment Response to PD-1 Immunotherapy in Lung Adenocarcinoma. AB - PURPOSE: A significant limitation of checkpoint blockade immunotherapy is the relatively low response rate (e.g., ~20% with PD-1 blockade in lung cancer). In this study, we tested whether strategies that increase T-cell infiltration to tumors can be efficacious in enhancing immunotherapy response. EXPERIMENTAL DESIGN: We performed an unbiased screen to identify FDA-approved oncology agents with an ability to enhance T-cell chemokine expression with the goal of identifying agents capable of augmenting immunotherapy response. Identified agents were tested in multiple lung tumor models as single agents and in combination with PD-1 blockade. Additional molecular and cellular analysis of tumors was used to define underlying mechanisms. RESULTS: We found that histone deacetylase (HDAC) inhibitors (HDACi) increased expression of multiple T-cell chemokines in cancer cells, macrophages, and T cells. Using the HDACi romidepsin in vivo, we observed increased chemokine expression, enhanced T-cell infiltration, and T-cell-dependent tumor regression. Importantly, romidepsin significantly enhanced the response to PD-1 blockade immunotherapy in multiple lung tumor models, including nearly complete rejection in two models. Combined romidepsin and PD-1 blockade also significantly enhanced activation of tumor infiltrating T cells. CONCLUSIONS: These results provide evidence for a novel role of HDACs in modulating T-cell chemokine expression in multiple cell types. In addition, our findings indicate that pharmacologic induction of T-cell chemokine expression represents a conceptually novel approach for enhancing immunotherapy response. Finally, these results suggest that combination of HDAC inhibitors with PD-1 blockade represents a promising strategy for lung cancer treatment. Clin Cancer Res; 22(16); 4119-32. (c)2016 AACR. PMID- 26964575 TI - Implant dentistry: Understanding CBCTs. PMID- 26964574 TI - Antimicrobial resistance: The need to train clinical microbiologists. PMID- 26964576 TI - A very big nut to crack. PMID- 26964577 TI - Dental education: Too many graduates in India. PMID- 26964578 TI - Student burnout. PMID- 26964579 TI - Orthodontics: Fast removal of claims. PMID- 26964580 TI - Dental trauma: Splinting with wire and composite. PMID- 26964581 TI - Workforce planning: The specialist map. PMID- 26964582 TI - Fluoridated milk approved for Blackpool children. PMID- 26964584 TI - Conference review: BAOMS Junior Trainee Group 2016. PMID- 26964585 TI - Child protection: The tenth anniversary of CPDT. PMID- 26964586 TI - Investigation: 'Our goal is to improve their quality of life'. PMID- 26964587 TI - Success for Dental Alcohol Reduction Trial. PMID- 26964591 TI - Real junk tooth pilot is a success. PMID- 26964592 TI - 'What has been your experience of providing short-term orthodontics?'--A pilot survey of GDPs in East Sussex. AB - Short-term orthodontics (STO) aims to enhance a patient's smile by aligning their anterior teeth. It is considered a quicker alternative to conventional orthodontics and less destructive than veneers. As such, it has recently gained much popularity in cosmetic dentistry worldwide. STO is provided almost exclusively by general dental practitioners (GDPs), however, the current literature on this subject focuses largely on the opinions of orthodontists and cosmetic dentists, respectively. The aim of this paper, on the other hand, is to examine the opinions of GDPs and what experience they have had of providing STO. It concludes that GDPs performing STO in East Sussex have expressed a wish to receive more teaching and support from their local orthodontists. It also suggests a need for orthodontic professional bodies to issue guidelines on case selection for STO in order to assist GDPs in recognising which malocclusions are beyond their scope of practice. PMID- 26964593 TI - The potential role of dentists in HIV screening. AB - Recent evidence suggests there is a role for the dental team, particularly dentists, in offering chairside HIV screening to patients during dental appointments. HIV is no longer a death sentence with early diagnosis and effective treatment contributing to a good prognosis. Despite the availability of both venipuncture diagnostic and rapid saliva/finger prick screening tests for HIV infection, 25% of people living with HIV in the United Kingdom are undiagnosed and remain at risk of transmitting their infection if having unprotected sex. This paper highlights the international evidence that supports dentists' willingness to conduct HIV screening and dental patient acceptance, and explores whether this is an opportunity or a step too far. PMID- 26964594 TI - Exodontia in dual antiplatelet therapy: the evidence. AB - BACKGROUND: Haemostasis is crucial for the success of oral surgical treatment as bleeding problems can cause complications both pre- and post-operatively. Patients on antiplatelet drugs present a challenge due to their increased risk of bleeding. AIMS: To identify a protocol for the management of oral surgery patients on dual antiplatelet therapy (aspirin and clopidogrel). METHODS: A literature review was conducted in January 2016 of free-text and MESH searches (keywords: aspirin, clopidogrel and dental extractions) in the Cochrane Library, PubMed and CINAHL. Trial registers, professional bodies for guidelines and OpenGrey for unpublished literature were also searched. Studies were selected for appraisal after limits were applied (adult, human and English only studies) and inclusion/exclusion criteria imposed. RESULTS: Eight studies were identified for critical appraisal using the CASP tools. These were a combination of retrospective, prospective, cohort and case control studies. Napenas et al. and Park et al. found no statistically significant risk of postoperative bleeding complications in patients on dual antiplatelet therapy. Girotra et al., Lillis et al., Omar et al. and Olmos-Carrasco et al., however, found statistically significant risk of postoperative bleeding in this group of patients, all of which can be controlled with local measures. CONCLUSION: Patients on dual antiplatelet therapy - although at an increased risk of postoperative bleeding complications - can be managed safely with local haemostatic measures and without the need to discontinue antiplatelet therapy. PMID- 26964600 TI - The place of James Arnott (1797-1883) in the development of local anaesthesia in dentistry. AB - Dental disease in the form of caries and abscesses has been known since antiquity. Before the advent of anaesthesia, operations upon the mouth were painful. The introduction of general anaesthesia in the form of ether and chloroform seemed to provide a solution, but there was an unacceptable level of mortality. James Arnott introduced local anaesthesia by means of freezing with ice, which he considered safer. He waged a long campaign and his method received recognition and was used in France and the USA. His method stimulated the development of pharmacological anaesthesia. PMID- 26964599 TI - Retrospective study of combined splinting restorations in the aesthetic zone of periodontal patients. AB - AIMS: This retrospective study evaluated the clinical performance of combining a fiber-reinforced, composite-resin (FRC) bonded splint; bridge; fiber post; and/or resin veneer for the restoration of periodontally-involved anterior teeth. METHODS: Sixty-three patients with periodontally-involved anterior teeth each received one of the following splinting restorations: FRC-bonded splint-bridges (SB), a combination of an FRC-bonded splint and resin veneer (SV), or FRC-bonded splints (S). Six patients with healthy periodontal teeth received orthodontic retainers with FRC-bonded splints (OS) as a control. Modified USPHS criteria were used to evaluate the effects of rehabilitation, and the periodontal pocket depth (PPD) and clinical attachment level (CAL) of the natural teeth were measured. RESULTS: All restorations resulted in good aesthetic outcomes. SV, S in combination with fiber posts and OS all resulted in 100% acceptable ratings for each category that was directly evaluated at each follow-up. The mean PPD was 3.5 +/- 1.0 mm at baseline, decreased to 3.3 +/- 1.0 mm after one year (p <0.05), and subsequently increased to 3.5+/-1.0 mm again after four years (p >0.05). These changes were similar to those in the mean CAL. CONCLUSION: A combination of a FRC bonded splint, bridge, fiber post and/or resin veneer for minimally invasive prosthodontic treatment in the aesthetic zone is a good choice for periodontal patients. PMID- 26964602 TI - Resuscitation in the dental practice. AB - The Resuscitation Council (UK) published new resuscitation guidelines in October 2015. The aim of this article is to understand these new guidelines and how dental practices should implement them. A 'resuscitation in the dental practice poster' has been designed which incorporates the new Resuscitation Council (UK) adult basic life support algorithm. This poster, endorsed by the British Dental Association, is included with this issue of the British Dental Journal. Further copies can be downloaded from: https://www.walsallhealthcare.nhs.uk/Data/Sites/1/media/documents/health-and safety/resus.pdf. PMID- 26964601 TI - The healthcare system and provision of oral healthcare in European Union member states. Part 4: Greece. AB - This paper presents a description of the healthcare system and how oral healthcare is organised and provided in Greece, a country in a deep economic and social crisis. The national health system is underfunded, with severe gaps in staffing levels and the country has a large private healthcare sector. Oral healthcare has been largely provided in the private sector. Most people are struggling to survive and have no money to spend on general and oral healthcare. Unemployment is rising and access to healthcare services is more difficult than ever. Additionally, there has been an overproduction of dentists and no development of team dentistry. This has led to under or unemployment of dentists in Greece and their migration to other European Union member states, such as the United Kingdom, where over 600 Greek dentists are currently working. PMID- 26964604 TI - Check before you travel: Zika virus--another emerging global health threat. AB - We now know that mosquitoes can transmit arboviruses such as the Zika virus (ZIKV) which is pandemic in Latin America. In order to avoid infection it is advised to avoid mosquitoes, but ZIKV can also be transmitted through blood donation, perinatally and sexually and has been detected in urine and saliva. Prevention against mosquito bites (particularly daytime bites) is best offered by avoiding mosquitoes and bites. To prevent the risk of transmission of ZIKV, standard infection control of all recent travellers to Zika affected areas should be conducted during dental care. This article will discuss how healthcare workers could contract diseases especially whilst working in the tropics or subtropics due to disease vectors such as mosquitoes and suggests prevention measures for this group. PMID- 26964605 TI - Practical application of composite resin techniques in the posterior dentition. AB - Posterior direct resin restorations are the combination of appreciation of anatomy, form and art. We require an understanding of the ideal form and metrics to control occlusal forces whilst layering our composite resin in the most amenable fashion to enable a predictable and asymptomatic restoration which looks and functions much like that of the natural dentition. In this article, and his associated presentation at the British Dental Conference and Exhibition 2016, Dr Chandrapal will discuss the methodology and practical based tips required to form clinical success within the environment of limited time, thus avoiding unnecessary complexities. PMID- 26964618 TI - Two-Dimensional Covalent Triazine Framework Membrane for Helium Separation and Hydrogen Purification. AB - Ultrathin membranes with intrinsic pores are highly desirable for gas separation applications, because of their controllable pore sizes and homogeneous pore distribution and their intrinsic capacity for high flux. Two-dimensional (2D) covalent organic frameworks (COFs) with layered structures have periodically distributed uniform pores and can be exfoliated into ultrathin nanosheets. As a representative of 2D COFs, a monolayer triazine-based CTF-0 membrane is proposed in this work for effective separation of helium and purification of hydrogen on the basis of first-principles calculations. With the aid of diffusion barrier calculations, it was found that a monolayer CTF-0 membrane can exhibit exceptionally high He and H2 selectivities over Ne, CO2, Ar, N2, CO, and CH4, and the He and H2 permeances are excellent at appropriate temperatures, superior to those of conventional carbon and silica membranes. These observations demonstrate that a monolayer CTF-0 membrane may be potentially useful for helium separation and hydrogen purification. PMID- 26964619 TI - Oral fluid drug analysis in the age of new psychoactive substances. AB - Oral fluid has become an important matrix for drugs of abuse analysis. These days the applicability is challenged by the fact that an increasing number of new psychoactive drugs are coming on the market. Synthetic cannabinoids and synthetic cathinones have been the main drug classes, but the diversity is increasing and other drugs like piperazines, phenethylamines, tryptamines, designer opioids and designer benzodiazepines are becoming more prevalent. Many of the substances are very potent, and low doses ingested will lead to low concentrations in biological media, including oral fluid. This review will highlight the phenomenon of new psychoactive substances and review methods for oral fluid drug testing analysis using on-site tests, immunoassays and chromatographic methods. PMID- 26964620 TI - Ca2O3Fe2.6S2: an antiferromagnetic Mott insulator at proximity to bad metal. AB - We report here the first layered iron oxychalcogenide Ca2O3Fe2.6S2 that contains both planar [Ca2FeO2](2+) and [Fe2OS2](2-) layers with the shortest Fe-Fe bond length. This compound is a narrow band gap (~0.073 eV) Mott insulator. The observed antiferromagnetic (AFM) transition at 77 K is due to the ordered Fe vacancies, which can be suppressed by partial substitution of Se for S. We show that the vacancy-free phase Ca2O3Fe3S2 may become a metal with moderate electron correlation comparable to the parent compound LaOFeAs of corresponding superconductors. Our results imply that iron oxychalcogenide can be converted from an AFM Mott insulator into a bad metal like iron pnictides through Fe-Fe bond length shrinking. PMID- 26964621 TI - STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation. AB - Cytosolic DNA sensing is an important process during the innate immune response that activates the stimulator of interferon genes (STING) adaptor and induces IFN I. STING incites spontaneous immunity during immunogenic tumor growth and accordingly, STING agonists induce regression of therapy-resistant tumors. However DNA, STING agonists, and apoptotic cells can also promote tolerogenic responses via STING by activating immunoregulatory mechanisms such as indoleamine 2,3 dioxygenase (IDO). Here, we show that IDO activity induced by STING activity in the tumor microenvironment (TME) promoted the growth of Lewis lung carcinoma (LLC). Although STING also induced IDO in tumor-draining lymph nodes (TDLN) during EL4 thymoma growth, this event was insufficient to promote tumorigenesis. In the LLC model, STING ablation enhanced CD8(+) T-cell infiltration and tumor cell killing while decreasing myeloid-derived suppressor cell infiltration and IL10 production in the TME. Depletion of CD8(+) T cells also eliminated the growth disadvantage of LLC tumors in STING-deficient mice, indicating that STING signaling attenuated CD8(+) T-cell effector functions during tumorigenesis. In contrast with native LLC tumors, STING signaling neither promoted growth of neoantigen-expressing LLC, nor did it induce IDO in TDLN. Similarly, STING failed to promote growth of B16 melanoma or to induce IDO activity in TDLN in this setting. Thus, our results show how STING-dependent DNA sensing can enhance tolerogenic states in tumors characterized by low antigenicity and how IDO inhibition can overcome this state by attenuating tumor tolerance. Furthermore, our results reveal a greater complexity in the role of STING signaling in cancer, underscoring how innate immune pathways in the TME modify tumorigenesis in distinct tumor settings, with implications for designing effective immunotherapy trials. Cancer Res; 76(8); 2076-81. (c)2016 AACR. PMID- 26964622 TI - GSK-3 Inhibition Sensitizes Acute Myeloid Leukemia Cells to 1,25D-Mediated Differentiation. AB - 1,25-dihydroxyvitamin D3 (1,25D), the biologically active form of vitamin D, is widely considered a promising therapy for acute myeloid leukemia (AML) based on its ability to drive differentiation of leukemic cells. However, clinical trials have been disappointing in part to dose-limiting hypercalcemia. Here we show how inhibiting glycogen synthase kinase 3 (GSK3) can improve the differentiation response of AML cells to 1,25D-mediated differentiation. GSK3 inhibition in AML cells enhanced the differentiating effects of low concentrations of 1,25D. In addition, GSK3 inhibition augmented the ability of 1,25D to induce irreversible growth inhibition and slow the progression of AML in mouse models. Mechanistic studies revealed that GSK3 inhibition led to the hyperphosphorylation of the vitamin D receptor (VDR), enabling an interaction between VDR and the coactivator, SRC-3 (NCOA3), thereby increasing transcriptional activity. We also found that activation of JNK-mediated pathways in response to GSK3 inhibition contributed to the potentiation of 1,25D-induced differentiation. Taken together, our findings offer a preclinical rationale to explore the repositioning of GSK3 inhibitors to enhance differentiation-based therapy for AML treatment. Cancer Res; 76(9); 2743-53. (c)2016 AACR. PMID- 26964623 TI - Mutant p53 Promotes Epithelial Ovarian Cancer by Regulating Tumor Differentiation, Metastasis, and Responsiveness to Steroid Hormones. AB - Mutations in the tumor protein p53 (TP53) are the most frequently occurring genetic events in high-grade ovarian cancers, especially the prevalence of the Trp53(R172H)-mutant allele. In this study, we investigated the impact of the Trp53(R172H)-mutant allele on epithelial ovarian cancer (EOC) in vivo We used the Pten/Kras(G12D)-mutant mouse strain that develops serous EOC with 100% penetrance to introduce the mutant Trp53(R172H) allele (homolog for human Trp53(R172H)). We demonstrate that the Trp53(R172H) mutation promoted EOC but had differential effects on disease features and progression depending on the presence or absence of the wild-type (WT) TP53 allele. Heterozygous WT/Trp53(R172H) alleles facilitated invasion into the ovarian stroma, accelerated intraperitoneal metastasis, and reduced TP53 transactivation activity but retained responsiveness to nutlin-3a, an activator of WT TP53. Moreover, high levels of estrogen receptor alpha in these tumors enhanced the growth of both primary and metastatic tumors in response to estradiol. Ovarian tumors homozygous for Trp53(R172H) mutation were undifferentiated and highly metastatic, exhibited minimal TP53 transactivation activity, and expressed genes with potential regulatory functions in EOC development. Notably, heterozygous WT/Trp53(R172H) mice also presented mucinous cystadenocarcinomas at 12 weeks of age, recapitulating human mucinous ovarian tumors, which also exhibit heterozygous TP53 mutations (~50%-60%) and KRAS mutations. Therefore, we present the first mouse model of mucinous tumor formation from ovarian cells and supporting evidence that mutant TP53 is a key regulator of EOC progression, differentiation, and responsiveness to steroid hormones. Cancer Res; 76(8); 2206-18. (c)2016 AACR. PMID- 26964630 TI - Benzodiazepinen in perspectief (I): De GABAA-benzodiazepine-receptor. AB - In this first part of a review on recent insights into the structure and function of the gamma-aminobuty rie acid type A - benzodiazepine receptor system, the gamma-aminobutyric acid type A (GABAA) receptor and the different types of benzodiazepine (BDZ) receptors known at this moment are dicussed. GABAA- and BDZ receptors are coupled in a supramolecular GABAA-BDZ-ionophore receptor complex, each consisting of five acidic glycoprotein molecules called subunits. These subunits can be classified into five groups: alpha, beta, gamma, sigma and rho. Present evidence indicates the existence of multiple subtypes of these subunits. Multiple GABAA-BDZ receptors exist in the brain that show differential distribution and developmental patterns. These receptors differ from their subunit composition. The final functional properties of the receptor are determined by the different subunits constituting this receptor. Heterogeneity among alpha- subunits may determine the diversity of BDZ pharmacology in different regions of the nervous system. PMID- 26964624 TI - Cytochrome P450 Allele CYP3A7*1C Associates with Adverse Outcomes in Chronic Lymphocytic Leukemia, Breast, and Lung Cancer. AB - CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially affecting drug effectiveness. Here, we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated SNP was rs45446698, an SNP that tags the CYP3A7*1C allele; this SNP was associated with a 54% decrease in urinary E1G levels. Genotyping this SNP in 1,008 breast cancer, 1,128 lung cancer, and 347 CLL patients, we found that rs45446698 was associated with breast cancer mortality (HR, 1.74; P = 0.03), all-cause mortality in lung cancer patients (HR, 1.43; P = 0.009), and CLL progression (HR, 1.62; P = 0.03). We also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (Pinteraction = 0.06). The CYP3A7*1C allele, which results in adult expression of the fetal CYP3A7 gene, is likely to be the functional allele influencing levels of circulating endogenous sex hormones and outcome in these various malignancies. Further studies confirming these associations and determining the mechanism by which CYP3A7*1C influences outcome are required. One possibility is that standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximately 8% of cancer patients who are CYP3A7*1C carriers. PMID- 26964631 TI - De Widlocher Remmingsschaal, een Nederlandse Schaal Voor het Meten van Psychomotorische Remming. AB - AIM: Translation of a specific instrument to measure psychomotor retardation, the "Widlocher Retardation Rating Scale" and validation of this Dutch translation (Widlocher remmingsschaal, WRS). METHOD: In three separate studies, we studied reliability (n = 26), concurrent and divergent validity (n = 25) and predictive validity (n = 28) of the WRS. In- and outpatients with a depressive disorder or schizophrenia participated, and scores on the WRS were compared with those on the Montgomery Asberg Depression Rating Scale (MADRS) and retardation items of the Comprehensive Psychopathological Rating Scale (CPRS). RESULTS: The internal consistency was good (Cronbach alpha = 0.86), interrater reliability was sufficient to good, the correlation between the sumscores of both raters was r = 0.84, n = 23, p <0.01 and the kappa's were between 0.23 and 0.80. Convergent and divergent validity showed in comparing the correlation between the sum scores on the WRS and the CPRS retardation items (r = 0.91, n = 25, p < 0.01 ) with the correlation between the sumscores on the WRS and the MADRS (r = 0.40, n = 25, p = 0.1). The decrease of the sum scores on the WRS after two weeks of treatment with antide-pressants predicted remission after six weeks. A subgroup of the patients who were not in remission after six weeks, showed a predominance of retardation signs over mood disturbances. The same clinical picture was seen in a group of patients with a chronic disorder. CONCLUSION: De Widlocher Retardation Rating Scale in this Dutch translation is a usefull instrument to measure psychomotor retardation. The connection between remaining retardation symptoms and longterm prognosis deserves further investigation. PMID- 26964632 TI - Magneto-encefalografie. AB - A magnetoencephalogram (MEG) is the registration of the magnetic field in points near the head. Because MEG's are weak fields, they have to be measured by means of superconducting sensors. The electric active population of neurons can be computed from the distribution of the magnetic field at a certain instant of time. This is called the inverse problem. In order to solve this probem, both the generators and the head have to be modelled. Usually, a patch of active neurons is modelled as a current dipole. Commonly, the head is described by three compartments, representing the brain, the skull and the scalp. The compartments may have the shape of spheres or they may have a realistic shape. Integration of EEG and MEG with MRI leads to a technique for functional imaging of the brain with a time resolution of one millisecond and a spatial resolution of one centimetre. Clinical applications are the non-invasive localization of an epileptic focus or the presurgical mapping of the sensorimotor cortex. PMID- 26964625 TI - Kruppel-like Pluripotency Factors as Modulators of Cancer Cell Therapeutic Responses. AB - Tumor cells inherit from their normal precursors an extensive stress response machinery that is critical for survival in response to challenges including oxidative stress, wounding, and shear stress. Kruppel-like transcription factors, including KLF4 and KLF5, are rarely affected by genetic alteration during tumorigenesis, but compose key components of the stress response machinery in normal and tumor cells and interact with critical survival pathways, including RAS, p53, survivin, and the BCL2 family of cell death regulators. Within tumor cells, KLF4 and KLF5 play key roles in tumor cell fate, regulating cell proliferation, cell survival, and the tumor-initiating properties of cancer stem like cells. These factors can be preferentially expressed in embryonic stem cells or cancer stem-like cells. Indeed, specific KLFs represent key components of a cross-regulating pluripotency network in embryonic stem cells and induce pluripotency when coexpressed in adult cells with other Yamanaka factors. Suggesting analogies between this pluripotency network and the cancer cell adaptive reprogramming that occurs in response to targeted therapy, recent studies link KLF4 and KLF5 to adaptive prosurvival signaling responses induced by HER2-targeted therapy. We review literature supporting KLFs as shared mechanisms in stress adaptation and cellular reprogramming and address the therapeutic implications. Cancer Res; 76(7); 1677-82. (c)2016 AACR. PMID- 26964633 TI - Letter to the Editor: Self-injurious thoughts and behaviours: low predictive power, yet important risk factors? PMID- 26964634 TI - Ligand-controlled product selectivity in palladium-catalyzed domino post-Ugi construction of (spiro)polyheterocycles. AB - A novel diversity-oriented access to (spiro)polyheterocycles possessing two adjacent quaternary carbon stereocenters is described. By combining an Ugi 4-CR with Pd-catalysis, the possible mode of cyclization is controlled by the appropriate choice of ligands. Using XantPhos, spirooxindoles are selectively generated, while with BINAP fused polycyclic cis-dihydrobenzofurans are obtained with high diastereoselectivity. PMID- 26964635 TI - Synthesis of indole-annulated sulfur heterocycles using copper-catalysed C-N coupling and palladium-catalysed direct arylation. AB - A simple and efficient method for the synthesis of biologically relevant 5H benzo[4,5][1,3]thiazino[3,2-a]indoles and 5,7-dihydroisothiochromeno[3,4 b]indoles has been developed via intramolecular copper catalysed Ullmann-type C-N coupling and palladium catalysed direct arylation from the corresponding precursors 2-(2-bromobenzylthio)-1H-indole and 2-(2-bromobenzylthio)-1-methyl-1H indole, respectively, in good to excellent yields. PMID- 26964636 TI - Superconductivity of novel tin hydrides (Sn(n)H(m)) under pressure. AB - With the motivation of discovering high-temperature superconductors, evolutionary algorithm USPEX is employed to search for all stable compounds in the Sn-H system. In addition to the traditional SnH4, new hydrides SnH8, SnH12 and SnH14 are found to be thermodynamically stable at high pressure. Dynamical stability and superconductivity of tin hydrides are systematically investigated. I4m2-SnH8, C2/m-SnH12 and C2/m-SnH14 exhibit higher superconducting transition temperatures of 81, 93 and 97 K compared to the traditional compound SnH4 with Tc of 52 K at 200 GPa. An interesting bent H3-group in I4m2-SnH8 and novel linear H in C2/m SnH12 are observed. All the new tin hydrides remain metallic over their predicted range of stability. The intermediate-frequency wagging and bending vibrations have more contribution to electron-phonon coupling parameter than high-frequency stretching vibrations of H2 and H3. PMID- 26964638 TI - GIS-NaP1 zeolite microspheres as potential water adsorption material: Influence of initial silica concentration on adsorptive and physical/topological properties. AB - GIS-NaP1 zeolite samples were synthesized using seven different Si/Al ratios (5 11) of the hydrothermal reaction mixtures having chemical composition Al2O3:xSiO2:14Na2O:840H2O to study the impact of Si/Al molar ratio on the water vapour adsorption potential, phase purity, morphology and crystal size of as synthesized GIS-NaP1 zeolite crystals. The X-ray diffraction (XRD) observations reveal that Si/Al ratio does not affect the phase purity of GIS-NaP1 zeolite samples as high purity GIS-NaP1 zeolite crystals were obtained from all Si/Al ratios. Contrary, Si/Al ratios have remarkable effect on the morphology, crystal size and porosity of GIS-NaP1 zeolite microspheres. Transmission electron microscopy (TEM) evaluations of individual GIS-NaP1 zeolite microsphere demonstrate the characteristic changes in the packaging/arrangement, shape and size of primary nano crystallites. Textural characterisation using water vapour adsorption/desorption, and nitrogen adsorption/desorption data of as-synthesized GIS-NaP1 zeolite predicts the existence of mix-pores i.e., microporous as well as mesoporous character. High water storage capacity 1727.5 cm(3) g(-1) (138.9 wt.%) has been found for as-synthesized GIS-NaP1 zeolite microsphere samples during water vapour adsorption studies. Further, the total water adsorption capacity values for P6 (1299.4 mg g(-1)) and P7 (1388.8 mg g(-1)) samples reveal that these two particular samples can absorb even more water than their own weights. PMID- 26964637 TI - Chloroquine enhances TRAIL-mediated apoptosis through up-regulation of DR5 by stabilization of mRNA and protein in cancer cells. AB - Chloroquine (CQ), an anti-malarial drug, has immune-modulating activity and lysosomotropic activity. In this study, we investigated CQ sensitizes TRAIL mediated apoptosis in human renal cancer Caki cells. Combination of CQ and TRAIL significantly induces apoptosis in human renal cancer Caki cells and various human cancer cells, but not in normal mouse kidney cells (TMCK-1) and human mesangial cells (MC). CQ up-regulates DR5 mRNA and protein expression in a dose- and time- dependent manner. Interestingly, CQ regulates DR5 expression through the increased stability in the mRNA and protein of DR5, rather than through the increased transcriptional activity of DR5. Moreover, we found that CQ decreased the expression of Cbl, an E3 ligase of DR5, and knock-down of Cbl markedly enhanced DR5 up-regulation. Other lysosomal inhibitors, including monensin and nigericin, also up-regulated DR5 and sensitized TRAIL-mediated apoptosis. Therefore, this study demonstrates that lysosomal inhibition by CQ may sensitize TRAIL-mediated apoptosis in human renal cancer Caki cells via DR5 up-regulation. PMID- 26964639 TI - Extensible Multiplex Real-time PCR of MicroRNA Using Microparticles. AB - Multiplex quantitative real-time PCR (qPCR), which measures multiple DNAs in a given sample, has received significant attention as a mean of verifying the rapidly increasing genetic targets of interest in single phenotype. Here we suggest a readily extensible qPCR for the expression analysis of multiple microRNA (miRNA) targets using microparticles of primer-immobilized networks as discrete reactors. Individual particles, 200~500 MUm in diameter, are identified by two-dimensional codes engraved into the particles and the non-fluorescent encoding allows high-fidelity acquisition of signal in real-time PCR. During the course of PCR, the amplicons accumulate in the volume of the particles with high reliability and amplification efficiency over 95%. In a quick assay comprising of tens of particles holding different primers, each particle brings the independent real-time amplification curve representing the quantitative information of each target. Limited amount of sample was analyzed simultaneously in single chamber through this highly multiplexed qPCR; 10 kinds of miRNAs from purified extracellular vesicles (EVs). PMID- 26964640 TI - A subunit of the oligosaccharyltransferase complex is required for interspecific gametophyte recognition in Arabidopsis. AB - Species-specific gamete recognition is a key premise to ensure reproductive success and the maintenance of species boundaries. During plant pollen tube (PT) reception, gametophyte interactions likely allow the species-specific recognition of signals from the PT (male gametophyte) by the embryo sac (female gametophyte), resulting in PT rupture, sperm release, and double fertilization. This process is impaired in interspecific crosses between Arabidopsis thaliana and related species, leading to PT overgrowth and a failure to deliver the sperm cells. Here we show that ARTUMES (ARU) specifically regulates the recognition of interspecific PTs in A. thaliana. ARU, identified in a genome-wide association study (GWAS), exclusively influences interspecific--but not intraspecific- gametophyte interactions. ARU encodes the OST3/6 subunit of the oligosaccharyltransferase complex conferring protein N-glycosylation. Our results suggest that glycosylation patterns of cell surface proteins may represent an important mechanism of gametophyte recognition and thus speciation. PMID- 26964641 TI - Hexose enhances oligonucleotide delivery and exon skipping in dystrophin deficient mdx mice. AB - Carbohydrate-based infusion solutions are widely used in the clinic. Here we show that co-administration of phosphorodiamidate morpholino oligomers (PMOs) with glucose enhances exon-skipping activity in Duchenne muscular dystrophy (DMD) mdx mice. We identify a glucose-fructose (GF) formulation that potentiates PMO activity, completely corrects aberrant Dmd transcripts, restores dystrophin levels in skeletal muscles and achieves functional rescue without detectable toxicity. This activity is attributed to enhancement of GF-mediated PMO uptake in the muscle. We demonstrate that PMO cellular uptake is energy dependent, and that ATP from GF metabolism contributes to enhanced cellular uptake of PMO in the muscle. Collectively, we show that GF potentiates PMO activity by replenishing cellular energy stores under energy-deficient conditions in mdx mice. Our findings provide mechanistic insight into hexose-mediated oligonucleotide delivery and have important implications for the development of DMD exon-skipping therapy. PMID- 26964643 TI - Molecular Dynamics of Dimethyldioxirane C-H Oxidation. AB - We report molecular dynamics simulations of the reaction of dimethyldioxirane (DMDO) with isobutane. The reaction involves hydrogen atom abstraction in the transition state, and trajectories branch to the oxygen rebound pathway, which gives tert-butanol and acetone, or a separated radical pair. In the gas phase, only 10% of the reactive trajectories undergo the oxygen rebound pathway, but this increases to 90% in simulations in an implicit acetone solvent (SMD) because the oxygen rebound becomes barrierless in solution. Short-lived diradical species were observed in the oxygen rebound trajectories. The time gap between C-H bond breaking and C-O bond formation ranges from 30 to 150 fs, close to the <200 fs lifetime of radical pairs from DMDO hydroxylation of trans-1-phenyl-2 ethylcyclopropane measured by Newcomb. PMID- 26964642 TI - Antioxidants inhibit advanced glycosylation end-product-induced apoptosis by downregulation of miR-223 in human adipose tissue-derived stem cells. AB - Advanced glycosylation end products (AGEs) are endogenous inflammatory mediators that induce apoptosis of mesenchymal stem cells. A potential mechanism includes increased generation of reactive oxygen species (ROS). MicroRNA-223 (miR-223) is implicated in the regulation of cell growth and apoptosis in several cell types. Here, we tested the hypothesis that antioxidants N-acetylcysteine (NAC) and ascorbic acid 2-phosphate (AAP) inhibit AGE-induced apoptosis via a microRNA dependent mechanism in human adipose tissue-derived stem cells (ADSCs). Results showed that AGE-HSA enhanced apoptosis and caspase-3 activity in ADSCs. AGE-HSA also increased ROS generation and upregulated the expression of miR-223. Interestingly, reductions in ROS generation and apoptosis, and upregulation of miR-223 were found in ADSCs treated with antioxidants NAC and AAP. Furthermore, miR-223 mimics blocked antioxidant inhibition of AGE-induced apoptosis and ROS generation. Knockdown of miR-223 amplified the protective effects of antioxidants on apoptosis induced by AGE-HSA. miR-223 acted by targeting fibroblast growth factor receptor 2. These results indicate that NAC and AAP suppress AGE-HSA induced apoptosis of ADSCs, possibly through downregulation of miR-223. PMID- 26964644 TI - An Acute Bout of Exercise Improves the Cognitive Performance of Older Adults. AB - There is evidence that an acute bout of exercise confers cognitive benefits, but it is largely unknown what the optimal mode and duration of exercise is and how cognitive performance changes over time after exercise. We compared the cognitive performance of 31 older adults using the Stroop test before, immediately after, and at 30 and 60 min after a 10 and 30 min aerobic or resistance exercise session. Heart rate and feelings of arousal were also measured before, during, and after exercise. We found that, independent of mode or duration of exercise, the participants improved in the Stroop Inhibition task immediately postexercise. We did not find that exercise influenced the performance of the Stroop Color or Stroop Word Interference tasks. Our findings suggest that an acute bout of exercise can improve cognitive performance and, in particular, the more complex executive functioning of older adults. PMID- 26964646 TI - Proteasome inhibitory, antioxidant, and synergistic antibacterial and anticandidal activity of green biosynthesized magnetic Fe3O4 nanoparticles using the aqueous extract of corn (Zea mays L.) ear leaves. AB - Herein, Fe3O4 nanoparticles synthesized using aqueous extract of corn ear leaves were investigated for proteasome inhibitory activity, antioxidant activity, synergistic antibacterial, and anticandidal potential. The UV-Vis spectrum displayed an absorption band at 355 nm that indicated the formation of nano-sized Fe3O4 particles. Vibrating sample magnetometer analysis revealed its superparamagnetic nature. Fe3O4 nanoparticles exhibited strong proteasome inhibitory potential and antioxidant activity and exerted strong synergistic antibacterial and anticandidal activity. Its significant proteasome inhibitory potential could be useful in cancer treatment and drug delivery. Furthermore, strong antioxidant, antibacterial, and anticandidal activity make them a promising candidate for biomedical and pharmaceutical applications. PMID- 26964645 TI - Integrative analysis of microRNA and mRNA expression profiles in non-small-cell lung cancer. AB - Non-small-cell lung cancer (NSCLC) represents the most common deadly disease. Emerging evidences suggest that abnormal epigenetic modulation via mRNAs and microRNAs (miRNAs) might be involved in the tumorigenesis. To explore novel therapeutic target of NSCLC, a more detailed mRNAs and miRNA expression profiling study is needed. High-quality total RNA including miRNA was isolated from NSCLC tissue and para-carcinoma tissue and used for RNA and small RNA sequencing. Results were analyzed bioinformatically and validated using quantitative real time (qRT)-PCR. A total of 3530 genes (1977 up-regulated and 1553 down-regulated) and 211 miRNAs (171 up-regulated and 30 down-regulated) were differentially expressed (DE) in NSCLC tissue versus adjacent normal tissues. Furthermore, 157 novel miRNAs were predicted in our samples. Of these, 918 significant miRNA-mRNA pairs were identified, consisting of 100 miRNAs and 443 mRNAs. Gene ontology analysis revealed that most of the target genes were enriched in the terms of plasma membrane, binding, and multiple biological-molecular signaling processes. Pathway analysis of these miRNA signatures highlights their critical roles in calcium signaling pathway. Using qRT-PCR, the expression of several DE genes (KRAS and RBM5) and miRNAs (miR-1-5p, let-7b-5p, miR-21-5p, miR-1290, miR-149-5p, chr8_28846, chrX_31594, and chr9_29897) were confirmed. The integrative analysis based on mRNA and miRNA profiling may provide more potential molecular for the tumorigenesis and development of NSCLC. PMID- 26964647 TI - A prospective longitudinal survey of erectile function status in symptomatic benign prostatic hyperplasia patients treated with dutasteride. AB - We prospectively evaluated erectile function (EF) using the Sexual Health Inventory for Men (SHIM) and the erectile hardness score (EHS) as well as urinary statuses using the International Prostate Symptom Score (IPSS) and Overactive Bladder Symptom Score (OABSS) before and 3, 6, and 12 months after a daily treatment with 0.5 mg dutasteride (DUT). Significant improvements were observed in IPSS and OABSS in 98 patients with the DUT treatment, and the effects were similar between 28 patients with potency with baseline SHIM of 8 or greater and 70 severe erectile dysfunction (ED) patients at baseline. In the 28 patients with potency, significant decreases were observed in SHIM and EHS after 3, 6, and 12 months of the DUT treatment, with the severity of ED according to SHIM deteriorating in half of these patients after 12 months of the DUT treatment. Eighteen out of 28 patients (64.3%) with potency at baseline had awareness of the occurrence of ED before the DUT treatment, were younger, and had higher SHIM and EHS just before the DUT treatment than their counterparts. Regular assessments of EF may be needed, especially in younger patients and those with higher levels of EF before the administration of DUT. PMID- 26964648 TI - Unveiling the Hybrid n-Si/PEDOT:PSS Interface. AB - We investigated the buried interface between monocrystalline n-type silicon (n Si) and the highly conductive polymer poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate) ( PEDOT: PSS), which is successfully applied as a hole selective contact in hybrid solar cells. We show that a post-treatment of the polymer films by immersion in a suitable solvent reduces the layer thickness by removal of excess material. We prove that this post-treatment does not affect the functionality of the hybrid solar cells. Through the thin layer we are probing the chemical structure at the n-Si/ PEDOT: PSS interface with synchrotron-based hard X-ray photoelectron spectroscopy (HAXPES). From the HAXPES data we conclude that the Si substrate of a freshly prepared hybrid solar cell is already oxidized immediately after preparation. Moreover, we show that even when storing the sample in inert gas such as, e.g., nitrogen the n-Si/SiOx/ PEDOT: PSS interface continues to further oxidize. Thus, without further surface treatment, an unstable Si suboxide will always be present at the hybrid interface. PMID- 26964649 TI - Sensitive assays enable detection of serum IgG antibodies against Clostridium difficile toxin A and toxin B in healthy subjects and patients with Clostridium difficile infection. AB - BACKGROUND: Pathogenic Clostridium difficile produces two proinflammatory exotoxins, toxin A and toxin B. Low level of serum antitoxin IgG antibodies is a risk factor for the development of primary and recurrent C. difficile infection (CDI). RESULTS: We developed and validated two sensitive, titer-based electrochemiluminescence assays for the detection of serum antibody levels against C. difficile toxins A and B. These assays demonstrated excellent precision. The sensitivity of the assays allowed the detection of antitoxin A and antitoxin B IgG antibodies in all tested serum samples during assay validation. CONCLUSION: The validated titer-based assays enable assessment of antitoxin A and antitoxin B IgG antibodies as potential biomarkers to identify patients with CDI at increased risk for CDI recurrence. PMID- 26964650 TI - Magnetic phase diagram of the helimagnetic spinel compound ZnCr2Se4 revisited by small-angle neutron scattering. AB - We performed small-angle neutron scattering (SANS) measurements on the helimagnetic spinel compound ZnCr2Se4. The ground state of this material is a multi-domain spin-spiral phase, which undergoes domain selection in a magnetic field and reportedly exhibits a transition to a proposed spin-nematic phase at higher fields. We observed a continuous change in the magnetic structure as a function of field and temperature, as well as a weak discontinuous jump in the spiral pitch across the domain-selection transition upon increasing field. From our SANS results we have established the absence of any long-range magnetic order in the high-field (spin-nematic) phase. We also found that all the observed phase transitions are surprisingly isotropic with respect to the field direction. PMID- 26964655 TI - Treatmentstrategies in refractory panic disorder. AB - A considerable amount of patients with panic disorder (25 - 30%) is refractory for the first line of treatment, mostly antidepressants, and for psychotherapy. Augmentation and combination strategies are discussed; and a protocol for the treatment of refractory patients with panic disorder is proposed with consists of five steps. No patients is considered treatment refractory until they have had a trial with monoamine oxidase inhibitors. PMID- 26964656 TI - Norharman and anxiety disorders. AB - Norharman is a beta-carboline, possibly of endogenous origin, although cigarette smoking and food are sources too. In brain specific binding sites have been demonstrated. In higher doses norharman binds to benzodiazepine receptors and has MAO-B inhibitory activity. From animal experiments it can be concluded that norharman induces sedation and muscle relaxation. A role in psychosis is unclear, a role in the pathogenesis in anxiety is possible, but has to be further substantiated. As current research suggests, norharman may be an important factor in addiction and withdrawal. PMID- 26964654 TI - Dynamic magnetic resonance imaging and spectroscopie of experimental brain injury. AB - This article describes the use of non-invasive magnetic resonance (MR) methods for the characterization and monitoring of the pathophysiology of experimental brain injury in laboratory animals as a function of time and treatment. The impact of MR in brain research is primarily due to its non-invasive nature, thereby enabling repeated measurements in long-term studies, and due to the type of information that it provides. MR imaging (MRI) enables the measurement of the morphology/anatomy as well as the functional status of tissues under in vivo conditions. Compared to other in vivo imaging modalities, MRI has a high spatial resolution and allows for a remarkable soft tissue differentiation. MR spectroscopy (MRS) provides information on the biochemical/metabolic status of tissues. MR methods which have proven valuable in animal studies, can be readily translated to the clinical situation where MR-based diagnosis and treatment planning play a rapidly increasing role. After a short introduction into the principles of MR, we will illustrate the remarkable versatility of MR in research on brain injury from recent animal studies. Examples will be mainly drawn from experiments on early injury in focai cerebral ischemia and from research on mechanical brain trauma and excitotoxic lesions. The article ends with a brief description of the perspectives of MR in neuropsychiatry. PMID- 26964657 TI - Psychological and biological aspects of anxiety disorders. AB - The research on anxiety disorders of the department of psychiatry of the Vrije Universiteit is briefly reviewed. Studies have included comparisons between pharmacotherapy and cognitive behaviour therapy and combination treatments of panic disorder and of obsessive-compulsive disorder. Also, the hyperventilation model of panic disorder could be rejected as a result of an ambulatory monitoring study. Provocation studies with adrenalin in panic disorder have shown less support for a psychological model of panic than expected. Recommendations for future research include studies on anxiety in the very young and in the elderly, studies on comorbidity in anxiety, especially with alcoholism and depression and the development of treatment manuals for general practice. The issue is raised whether investing in neuroimaging studies will critically advance our knowledge in the near future. PMID- 26964658 TI - The role of the 'central' cholecystokinin-B receptor in panic disorder. AB - Research investigating the neurobiological underpinnings of anxiety disorder have mainly been focused on dysfunction of the GABA, noradrenergic and serotonergic (5 HT) neuronal systems. Just recently, in both animal and human studies, evidence has been found for a possible role of the cholecystokinin (CCK) neuronal system in the pathogenesis of anxiety disorder. Behaviorally, animal studies revealed anxiogenic-like properties for the 'central' CCKB receptor agonists, while CCKB receptor antagonists displayed intrinsic anxiolytic properties. Similarly, in man, CCKB receptor agonists, like pentagastrin and CCK4, were found to be able to elicited panic attacks in both panic disorder (PD) patients and healthy volunteers. These effects appear due to stimulation of the CCKB receptor. In addition, clinically effective panicolytic agents reduce the sensitivity to CCK4 in PD patients. Taken together, these findings may suggest a role for CCK in the neurobiology of PD. On the other hand, there is circumstantial evidence for involvement of several other neuronal systems, such as the serotonergic, noradrenergic and GABA-ergic system, in the regulation of anxiety. Interestingly, evidence has been found for an interaction between CCK and 5-HT and that this interaction plays a role in the mediation of anxiety. This presentation will critically discuss the evidence for the role of the CCKB receptor in anxiety and in addition, will focus on the putative evidence that the role of CCK in anxiety is mediated by its interaction with the serotonergic neuronal system. PMID- 26964659 TI - The prediction of response in the anxiety disorders. AB - In this review the results are discussed on the prediction of response to pharmacotherapy in panic disorder (PD) and social phobia (SP). From the literature it appears that in PD variables indicative of illness severity are predictors of non-response. In our own studies we found that non-responders to pharmacotherapy in PD are characterised by a higher score on the Blood-Injury subscale of the Fear Questionnaire, a higher plasma MHPG and a higher heart rate. In SP non-responders to pharmacotherapy were also characterised by a higher heart rate. They also appeared to have a higher blood pressure. Furthermore non responders to pharmacotherapy in SP had higher scores on several psychometric scales, indicative of illness severity. PMID- 26964660 TI - Is CO2 inhalation a specific marker for panic disorder? An experimental panic model. AB - Patients with panic disorder (PD) report a transient feeling of anxiety upon inhalation of CO2 enriched air. They rate this experience as similar to symptoms of a panic attack. This hypersensitivity has been proposed as an experimental disease model. This paper examines the validity of single breath inhalation of 35% CO2 as a model for PD. PMID- 26964662 TI - Parents and their children's variable language: Is it acquisition or more? AB - This study compares the use of the variable (q), which is realized as rural [q] and urban [?], in the speech of twenty-two parents and their twenty-one children from the village of Oyoun Al-Wadi in Syria. The study shows that children acquire the general gendered linguistic pattern of the community but do not replicate the linguistic frequencies that exist in their immediate environment. Boys and girls exhibit different linguistic behavior. Boys deviate from the non-local caregivers' proportions and approach men's local linguistic behavior, although their local variant proportions remain lower; girls, even those with local mothers, approach the women's supralocal variant proportions. The study shows that sociolinguistic variation is not acquired from adults from a very early age; it is acquired later in life after accepting and ascertaining the gendered linguistic differences and appropriateness norms. PMID- 26964663 TI - Advances in identification and validation of protein targets of natural products without chemical modification. AB - Covering: up to February 2016Identification of the target proteins of natural products is pivotal to understanding the mechanisms of action to develop natural products for use as molecular probes and potential therapeutic drugs. Affinity chromatography of immobilized natural products has been conventionally used to identify target proteins, and has yielded good results. However, this method has limitations, in that labeling or tagging for immobilization and affinity purification often result in reduced or altered activity of the natural product. New strategies have recently been developed and applied to identify the target proteins of natural products and synthetic small molecules without chemical modification of the natural product. These direct and indirect methods for target identification of label-free natural products include drug affinity responsive target stability (DARTS), stability of proteins from rates of oxidation (SPROX), cellular thermal shift assay (CETSA), thermal proteome profiling (TPP), and bioinformatics-based analysis of connectivity. This review focuses on and reports case studies of the latest advances in target protein identification methods for label-free natural products. The integration of newly developed technologies will provide new insights and highlight the value of natural products for use as biological probes and new drug candidates. PMID- 26964664 TI - The facile synthesis of 1-benzoazepine derivatives via gold-catalyzed regioselective cycloisomerization reactions of N-(o-alkynylaryl)-N-vinyl sulfonamides. AB - Gold-catalyzed, regioselective cycloisomerization of N-(o-alkynylaryl)-N-vinyl sulfonamides afforded high yields of 2-sulfonylmethyl-1-benzoazepine derivatives. This 7-endo-dig selective cyclization proceeds via the incorporation of an exocyclic double bond by a labile 1-benzoazepine intermediate. The cyclization substrates were assembled in two steps from readily available materials using Sonogashira coupling and a Cs2CO3-mediated formal vinylic substitution. PMID- 26964665 TI - Synthesis of nitriles from amines using nanoscale Co3O4-based catalysts via sustainable aerobic oxidation. AB - The selective oxidation of amines for the benign synthesis of nitriles under mild conditions is described. Key to success for this transformation is the application of reusable cobalt oxide-based nanocatalysts. The resulting nitriles constitute key precursors and central intermediates in organic synthesis. PMID- 26964661 TI - Psychosocial Factors Are Associated With Blood Pressure Progression Among African Americans in the Jackson Heart Study. AB - BACKGROUND: Research that examines the associations of psychosocial factors with incident hypertension among African Americans (AA) is limited. Using Jackson Heart Study (JHS) data, we examined associations of negative affect and stress with incident hypertension and blood pressure (BP) progression among AA. METHODS: Our sample consisted of 1,656 normotensive participants at baseline (2000-2004) (mean age 47+/-12; 61% women). We investigated associations of negative affect (cynical distrust, anger-in, anger-out, and depressive symptoms) and stress (perceived stress, weekly stress inventory (WSI)-event, WSI-impact, and major life events) with BP progression (an increase by one BP stage as defined by JNC VII) and incident hypertension by examination 2 (2005-2008). Poisson regression analysis was utilized to examine the prevalence ratios (PRs; 95% confidence interval (CI)) of BP tracking and incident hypertension with psychosocial factors, adjusting for baseline age, sex, socioeconomic status (SES), and hypertension risk factors. RESULTS: Fifty-six percentage of the sample (922 cases) had BP progression from 2005 to 2008. After adjustment for age, sex, and SES, a high anger-out score was associated with a 20% increased risk of BP progression compared to a low anger-out score (PR 1.20; 95% CI 1.05-1.36). High depressive symptoms score was associated with BP progression in the age, sex, and SES-adjusted model (PR 1.14; 95% CI 1.00-1.30). High WSI-event scores were associated with BP progression in the fully adjusted model (PR 1.21; 95% CI 1.04 1.40). We did not observe significant associations with any of the psychosocial measures and incident hypertension. CONCLUSIONS: Psychosocial factors were associated with BP progression, with the strongest evidence for number of stressful events that occurred. PMID- 26964666 TI - Peltaster fructicola genome reveals evolution from an invasive phytopathogen to an ectophytic parasite. AB - Sooty blotch and flyspeck (SBFS) fungi are unconventional plant pathogens that cause economic losses by blemishing the surface appearance of infected fruit. Here, we introduce the 18.14-Mb genome of Peltaster fructicola, one of the most prevalent SBFS species on apple. This undersized assembly contains only 8,334 predicted protein-coding genes and a very small repertoire of repetitive elements. Phylogenomics and comparative genomics revealed that P. fructicola had undergone a reductive evolution, during which the numbers of orphan genes and genes involved in plant cell wall degradation, secondary metabolism, and secreted peptidases and effectors were drastically reduced. In contrast, the genes controlling 1,8-dihydroxynaphthalene (DHN)-melanin biosynthesis and appressorium mediated penetration were retained substantially. Additionally, microscopic examination of the surfaces of infected apple indicated for the first time that P. fructicola can not only dissolve epicuticular waxes but also partially penetrate the cuticle proper. Our findings indicate that genome contraction, characterized mainly by the massive loss of pathogenicity-related genes, has played an important role in the evolution of P. fructicola (and by implication other SBFS species) from a plant-penetrating ancestor to a non-invasive ectophyte, displaying a novel form of trophic interaction between plants and fungi. PMID- 26964667 TI - Activation of c-Jun predicts a poor response to sorafenib in hepatocellular carcinoma: Preliminary Clinical Evidence. AB - We determined the mitogen-activated protein kinase (MAPK) gene expression profile of acquired resistance in sorafenib-sensitive hepatocellular carcinoma (HCC) cells and aimed to identify c-Jun as an important molecule mediating the efficacy of sorafenib. Differences in gene expression of the MAPK signaling between untreated and sorafenib-treated HCC cell lines were investigated using real-time polymerase chain reaction array. Western blot and real-time PCR further evaluated the expression of c-Jun. Pathological specimens from 50 patients with advanced HCC were collected to measure p-c-Jun expression. Sorafenib-resistant HCC cells demonstrated greater levels of basal c-Jun mRNA and protein compared with sorafenib-sensitive HCC cells. Sorafenib activated p-c-Jun in a dose- and time dependent manner in PLC/PRF/5 and MHCC97H cell lines. Decreased expression levels of 6 genes after sorafenib treatment suggested a robust inhibitory impact of sorafenib on MAPK signaling in HCC cells. c-Jun and p-c-Jun expression levels were inversely correlated with the efficacy of sorafenib; a high expression level of p-c-Jun was associated with resistance to sorafenib and poor overall survival in patients with clinical HCC. p-c-Jun may act as a biomarker for predicting responses of sorafenib treatment, thus advocating targeting of JNK/c-Jun signaling as an optimal therapeutic strategy in a subset of HCC. PMID- 26964668 TI - Sensorimotor Peripheral Nerve Function and Physical Activity in Older Men. AB - We determined whether sensorimotor peripheral nerve (PN) function was associated with physical activity (PA) in older men. The Osteoporotic Fractures in Men Study Pittsburgh, PA, site (n = 328, age 78.8 +/- 4.7 years) conducted PN testing, including: peroneal motor and sural sensory nerve conduction (latencies, amplitudes: CMAP and SNAP for motor and sensory amplitude, respectively), 1.4g/10g monofilament (dorsum of the great toe), and neuropathy symptoms. ANOVA and multivariate linear regression modeled PN associations with PA (Physical Activity Scale for the Elderly [PASE] and SenseWear Armband). After multivariable adjustment, better motor latency was associated with higher PASE scores (160.5 +/ 4.8 vs. 135.6 +/- 6.7, p < .01). Those without versus with neuropathy symptoms had higher PASE scores (157.6 +/- 5.3 vs. 132.9 +/- 7.1, p < .01). Better versus worse SNAP was associated with slightly more daily vigorous activity (9.5 +/- 0.8 vs. 7.3 +/- 0.7, p = .05). Other PN measures were not associated with PA. Certain PN measures were associated with lower PA, suggesting a potential pathway for disability. PMID- 26964670 TI - Washoff of Residual Photosystem II Herbicides from Sugar Cane Trash under a Rainfall Simulator. AB - Herbicides are often applied to crop residues, but their fate has not been well studied. We measured herbicide washoff from sugar cane trash during simulated rainfall, at 1, 8, and 40 days after spraying (DAS), to provide insight into herbicide fate and for use in modeling. Herbicides included are commonly used in the sugar industry, either in Australia or in Brazil. Concentrations of all herbicides and applied Br tracer in washoff declined exponentially over time. The rate of washoff during rainfall declined with increasing DAS. Cumulative washoff as a function of rainfall was similar for most herbicides, although the most soluble herbicides did have more rapid washoff. Some but not all herbicides became more resistant to washoff with increasing DAS. Of the total mass washed off, 80% washed off in the first 30 mm (~40 min) of rainfall for most herbicides. Little herbicide remained on the trash after rainfall, implying nearly complete washoff. PMID- 26964669 TI - IL-15-dependent balance between Foxp3 and RORgammat expression impacts inflammatory bowel disease. AB - The ability of CD4+ T cells to change their phenotype and to specialize into different functional subsets may enhance the risk of autoimmune diseases. Here we investigate how a pleiotropic cytokine interleukin (IL)-15 may modify the functional commitment of CD4+ T cells expressing the lineage-associated transcription factors: forkhead box P3 (Foxp3; Treg) and RORgammat (Th17) in the context of inflammatory bowel disease (IBD). We demonstrate in mice that impaired delivery of IL-15 to CD4+ T cells in the colon downmodulates Foxp3 expression (diminishing STAT5 phosphorylation) and enhances RORgammat expression (by upregulating the expression of Runx1). In consequence, CD4+ T cells deprived of IL-15 rapidly trigger IBD characterized by enhanced production of pro inflammatory cytokines (interferon-gamma, IL-6) and accumulation of Th1/Th17 cells. Overall, our findings indicate a potentially beneficial role of IL-15 in IBD by fine-tuning the balance between Treg and Th17 cells and controlling intestinal inflammation. PMID- 26964672 TI - Novel tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one: Design, synthesis, model and use as hMAO-B inhibitors. AB - Based on our recently reported selective hMAO-A inhibitors, on which, the intramolecular cyclization led to a very interesting change of isoform selectivity. A series of selective hMAO-B inhibitors (3a-3u) with novel scaffold of tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one were designed and synthesized. Compound 3u (IC50=221 nM) exhibited the best inhibitory activity and isoform selectivity against hMAO-B, superior to selegiline (IC50=321 nM), which is a commercial selective hMAO-B inhibitor used to Parkinson's disease. Modeling study indicated that the selectivity of our compounds to hMAO-B is determined by at least two residues, i.e., Ile 199 and Cys 172 (or corresponded Phe 208 and Asn 181 of hMAO-A). These data support further studies to assess rational design of more efficiently selective hMAO-B inhibitors. PMID- 26964674 TI - Antiretroviral (HIV-1) activity of azulene derivatives. AB - The antiretroviral activity of azulene derivatives was detected for the first time. A series of eighteen diversely substituted azulenes was synthesized and tested in vitro using HIV-1 based virus-like particles (VLPs) and infectious HIV 1 virus in U2OS and TZM-bl cell lines. Among the compounds tested, the 2 hydroxyazulenes demonstrated the most significant activity by inhibiting HIV-1 replication with IC50 of 2-10 and 8-20 MUM for the VLPs and the infectious virus, respectively. These results indicate that azulene derivatives may be potentially useful candidates for the development of antiretroviral agents. PMID- 26964671 TI - Propagation phasor approach for holographic image reconstruction. AB - To achieve high-resolution and wide field-of-view, digital holographic imaging techniques need to tackle two major challenges: phase recovery and spatial undersampling. Previously, these challenges were separately addressed using phase retrieval and pixel super-resolution algorithms, which utilize the diversity of different imaging parameters. Although existing holographic imaging methods can achieve large space-bandwidth-products by performing pixel super-resolution and phase retrieval sequentially, they require large amounts of data, which might be a limitation in high-speed or cost-effective imaging applications. Here we report a propagation phasor approach, which for the first time combines phase retrieval and pixel super-resolution into a unified mathematical framework and enables the synthesis of new holographic image reconstruction methods with significantly improved data efficiency. In this approach, twin image and spatial aliasing signals, along with other digital artifacts, are interpreted as noise terms that are modulated by phasors that analytically depend on the lateral displacement between hologram and sensor planes, sample-to-sensor distance, wavelength, and the illumination angle. Compared to previous holographic reconstruction techniques, this new framework results in five- to seven-fold reduced number of raw measurements, while still achieving a competitive resolution and space bandwidth-product. We also demonstrated the success of this approach by imaging biological specimens including Papanicolaou and blood smears. PMID- 26964673 TI - Compound profiling and 3D-QSAR studies of hydrazone derivatives with activity against intracellular Trypanosoma cruzi. AB - Chagas disease is a tropical disease caused by the parasite Trypanosoma cruzi, which is endemic in Central and South America. Few treatments are available with effectiveness limited to the early (acute) stage of disease, significant toxicity and widespread drug resistance. In this work we report the outcome of a HTS-ready assay chemical library screen to identify novel, nontoxic, small-molecule inhibitors of T. cruzi. We have selected 50 compounds that possess hydrazone as a common group. The compounds were screened using recombinant T. cruzi (Tulahuen strain) expressing beta-galactosidase. A 3D quantitative structure-activity relationship (QSAR) analysis was performed using descriptors calculated from comparative molecular field analysis (CoMFA). Our findings show that of the fifty selected hydrazones, compounds LpQM-19, 28 and 31 displayed the highest activity against T. cruzi, leading to a selectivity index (SI) of 20-fold. The 3D-QSAR analysis indicates that a particular electrostatic arrangement, where electron deficient atoms are aligned along the molecule main axis positively correlates with compound biological activity. These results provide new candidate molecules for the development of treatments against Chagas disease. PMID- 26964675 TI - Synthesis, and docking studies of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors. AB - Four series of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3 b]pyridine moiety (14a-e, 15a-g, 16a-e and 17a-g) were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, PC-3 and MCF 7). Four selected compounds (15e, 16a-b and 17a) were further evaluated for the activity against c-Met kinase, HepG2 and Hela cell lines. Most of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 valuables in single-digit MUM to nanomole range. Eleven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15e showed superior activity to Foretinib against A549, PC-3 and MCF-7 cell lines, with the IC50 values of 0.14 +/- 0.08 MUM, 0.24 +/- 0.07 MUM and 0.02 +/- 0.01 MUM, which were 4.6, 1.6 and 473.5 times more active than Foretinib (0.64 +/- 0.26 MUM, 0.39 +/- 0.11 MUM, 9.47 +/- 0.22 MUM), respectively. Structure-activity relationships (SARs) and docking studies indicated that the replacement of phenylpicolinamide scaffold with phenylpyrimidine fragment of the target compounds was benefit for the activity. What's more, the introduction of fluoro atom to the aminophenoxy part played no significant impact on the activity and any substituent group on aryl group is unfavourable for the activity. PMID- 26964676 TI - Development of a fluorescent cardiomyocyte specific binding probe. AB - Cardiomyocytes are the major component of the heart. Their dysfunction or damage could lead to serious cardiovascular diseases, which have claimed numerous lives around the world. A molecule able to recognize cardiomyocytes would have significant value in diagnosis and treatment. Recently a novel peptide termed myocyte targeting peptide (MTP), with three residues of a non-natural amino acid biphenylalanine (Bip), showed good affinity to cardiomyocytes. Its selectivity towards cardiac tissues was concluded to be due to the ability of Bip to bind cardiac troponin I. With the aim of optimizing the affinity and the specificity towards cardiac myocytes and to better understand structure-activity relationship, a library of MTP derivatives was designed. Exploiting a fluorescent tag, the selectivity of the MTP analogs to myocardium over skeletal and stomach muscle tissues was assayed by fluorescence imaging. Among the tested sequences, the peptide probe Bip2, H-Lys(FITC)-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Gly-Ser-Gly-Ser Bip-Bip-NH2, displayed the best selectivity for cardiomyocytes. PMID- 26964677 TI - Structure-Based Virtual Ligand Screening on the XRCC4/DNA Ligase IV Interface. AB - The association of DNA Ligase IV (Lig4) with XRCC4 is essential for repair of DNA double-strand breaks (DSBs) by Non-homologous end-joining (NHEJ) in humans. DSBs cytotoxicity is largely exploited in anticancer therapy. Thus, NHEJ is an attractive target for strategies aimed at increasing the sensitivity of tumors to clastogenic anticancer treatments. However the high affinity of the XRCC4/Lig4 interaction and the extended protein-protein interface make drug screening on this target particularly challenging. Here, we conducted a pioneering study aimed at interfering with XRCC4/Lig4 assembly. By Molecular Dynamics simulation using the crystal structure of the complex, we first delineated the Lig4 clamp domain as a limited suitable target. Then, we performed in silico screening of ~95,000 filtered molecules on this Lig4 subdomain. Hits were evaluated by Differential Scanning Fluorimetry, Saturation Transfer Difference-NMR spectroscopy and interaction assays with purified recombinant proteins. In this way we identified the first molecule able to prevent Lig4 binding to XRCC4 in vitro. This compound has a unique tripartite interaction with the Lig4 clamp domain that suggests a starting chemotype for rational design of analogous molecules with improved affinity. PMID- 26964680 TI - The Brain Prize 2016: A prize not to forget. PMID- 26964678 TI - Intrinsic plasticity induced by group II metabotropic glutamate receptors via enhancement of high-threshold KV currents in sound localizing neurons. AB - Intrinsic plasticity has emerged as an important mechanism regulating neuronal excitability and output under physiological and pathological conditions. Here, we report a novel form of intrinsic plasticity. Using perforated patch clamp recordings, we examined the modulatory effects of group II metabotropic glutamate receptors (mGluR II) on voltage-gated potassium (KV) currents and the firing properties of neurons in the chicken nucleus laminaris (NL), the first central auditory station where interaural time cues are analyzed for sound localization. We found that activation of mGluR II by synthetic agonists resulted in a selective increase of the high-threshold KV currents. More importantly, synaptically released glutamate (with reuptake blocked) also enhanced the high threshold KV currents. The enhancement was frequency-coding region dependent, being more pronounced in low-frequency neurons compared to middle- and high frequency neurons. The intracellular mechanism involved the Gbetagamma signaling pathway associated with phospholipase C and protein kinase C. The modulation strengthened membrane outward rectification, sharpened action potentials, and improved the ability of NL neurons to follow high-frequency inputs. These data suggest that mGluR II provides a feedforward modulatory mechanism that may regulate temporal processing under the condition of heightened synaptic inputs. PMID- 26964679 TI - Expression and localization of Inter-alpha Inhibitors in rodent brain. AB - Inter-alpha Inhibitor Proteins (IAIPs) are a family of related serine protease inhibitors. IAIPs are important components of the systemic innate immune system. We have identified endogenous IAIPs in the central nervous system (CNS) of sheep during development and shown that treatment with IAIPs reduces neuronal cell death and improves behavioral outcomes in neonatal rats after hypoxic-ischemic brain injury. The presence of IAIPs in CNS along with their exogenous neuroprotective properties suggests that endogenous IAIPs could be part of the innate immune system in CNS. The purpose of this study was to characterize expression and localization of IAIPs in CNS. We examined cellular expressions of IAIPs in vitro in cultured cortical mouse neurons, in cultured rat neurons, microglia, and astrocytes, and in vivo on brain sections by immunohistochemistry from embryonic (E) day 18 mice and postnatal (P) day 10 rats. Cultured cortical mouse neurons expressed the light chain gene Ambp and heavy chain genes Itih-1, 2, 3, 4, and 5 mRNA transcripts and IAIP proteins. IAIP proteins were detected by immunohistochemistry in cultured cells as well as brain sections from E18 mice and P10 rats. Immunoreactivity was found in neurons, microglia, astrocytes and oligodendroglia in multiple brain regions including cortex and hippocampus, as well as within both the ependyma and choroid plexus. Our findings suggest that IAIPs are endogenous proteins expressed in a wide variety of cell types and regions both in vitro and in vivo in rodent CNS. We speculate that endogenous IAIPs may represent endogenous neuroprotective immunomodulatory proteins within the CNS. PMID- 26964681 TI - The microbiota-gut-brain axis and its potential therapeutic role in autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a series of neurodevelopmental disorders that are characterized by deficits in both social and cognitive functions. Although the exact etiology and pathology of ASD remain unclear, a disorder of the microbiota-gut-brain axis is emerging as a prominent factor in the generation of autistic behaviors. Clinical studies have shown that gastrointestinal symptoms and compositional changes in the gut microbiota frequently accompany cerebral disorders in patients with ASD. A disturbance in the gut microbiota, which is usually induced by a bacterial infection or chronic antibiotic exposure, has been implicated as a potential contributor to ASD. The bidirectional microbiota-gut brain axis acts mainly through neuroendocrine, neuroimmune, and autonomic nervous mechanisms. Application of modulators of the microbiota-gut-brain axis, such as probiotics, helminthes and certain special diets, may be a promising strategy for the treatment of ASD. This review mainly discusses the salient observations of the disruptions of the microbiota-gut-brain axis in the pathogenesis of ASD and reveals its potential therapeutic role in autistic deficits. PMID- 26964682 TI - Electrical stimulation of the frontal cortex enhances slow-frequency EEG activity and sleepiness. AB - Our aim was to enhance the spontaneous slow-frequency EEG activity during the resting state using oscillating transcranial direct currents (tDCS) with a stimulation frequency that resembles the spontaneous oscillations of sleep onset. Accordingly, in this preliminary study, we assessed EEG after-effects of a frontal oscillatory tDCS with different frequency (0.8 vs. 5 Hz) and polarity (anodal, cathodal, and sham). Two single-blind experiments compared the after effects on the resting EEG of oscillatory tDCS [Exp. 1=0.8 Hz, 10 subjects (26.2 +/- 2.5 years); Exp. 2=5 Hz, 10 subjects (27.4 +/- 2.4 years)] by manipulating its polarity. EEG signals recorded (28 scalp derivations) before and after stimulation [slow oscillations (0.5-1 Hz), delta (1-4 Hz), theta (5-7 Hz), alpha (8-12 Hz), beta 1 (13-15 Hz) and beta 2 (16-24 Hz)] were compared between conditions as a function of polarity (anodal vs. cathodal vs. sham) and frequency of stimulation (0.8 vs. 5 Hz). We found a significant relative enhancement of the delta activity after the anodal tDCS at 5 Hz compared to that at 0.8 Hz. This increase, even though not reaching the statistical significance compared to sham, is concomitant to a significant increase of subjective sleepiness, as assessed by a visual analog scale. These two phenomena are linearly related with a regional specificity, correlations being restricted to cortical areas perifocal to the stimulation site. We have shown that a frontal oscillating anodal tDCS at 5 Hz results in an effective change of both subjective sleepiness and spontaneous slow frequency EEG activity. These changes are critically associated to both stimulation polarity (anodal) and frequency (5 Hz). However, evidence of frequency-dependence seems more unequivocal than evidence of polarity-dependence. PMID- 26964684 TI - Cholinergic modulation of auditory steady-state response in the auditory cortex of the freely moving rat. AB - As disturbance in auditory steady-state response (ASSR) has been consistently found in many neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, there is considerable interest in the development of translational rat models to elucidate the underlying neural and neurochemical mechanisms involved in ASSR. This is the first study to investigate the effects of the non selective muscarinic antagonist scopolamine and the cholinesterase inhibitor donepezil (also in combination with scopolamine) on ASSR. We recorded the local field potentials through the chronic microelectrodes implanted in the auditory cortex of freely moving rat. ASSRs were recorded in response to auditory stimuli delivered over a range of frequencies (10-80 Hz) and averaged over 60 trials. We found that a single dose of scopolamine produced a temporal attenuation in response to auditory stimuli; the most attenuation occurred at 40 Hz. Time frequency analysis revealed deficits in both power and phase-locking to 40 Hz. Donepezil augmented 40-Hz steady-state power and phase-locking. Scopolamine combined with donepezil had an enhanced effect on the phase-locking, but not power of ASSR. These changes induced by cholinergic drugs suggest an involvement of muscarinic neurotransmission in auditory processing and provide a rodent model investigating the neurochemical mechanism of neurophysiological deficits seen in patients. PMID- 26964683 TI - Attenuation of cocaine self-administration by chronic oral phendimetrazine in rhesus monkeys. AB - Chronic treatment with the monoamine releaser d-amphetamine has been consistently shown to decrease cocaine self-administration in laboratory studies and clinical trials. However, the abuse potential of d-amphetamine is an obstacle to widespread clinical use. Approaches are needed that exploit the efficacy of the agonist approach but avoid the abuse potential associated with dopamine releasers. The present study assessed the effectiveness of chronic oral administration of phendimetrazine (PDM), a pro-drug for the monoamine releaser phenmetrazine (PM), to decrease cocaine self-administration in four rhesus monkeys. Each day, monkeys pressed a lever to receive food pellets under a 50 response fixed-ratio (FR) schedule of reinforcement and self-administered cocaine (0.003-0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule in the evening. After completing a cocaine self-administration dose-response curve, sessions were suspended and PDM was administered (1.0-9.0 mg/kg, p.o., b.i.d.). Cocaine self-administration was assessed using the PR schedule once every 7 days while food-maintained responding was studied daily. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was re determined. Daily PDM treatment decreased cocaine self-administration by 30-90% across monkeys for at least 4 weeks. In two monkeys, effects were completely selective for cocaine. Tolerance developed to initial decreases in food maintained responding in the third monkey and in the fourth subject, fluctuations were observed that were lower in magnitude than effects on cocaine self administration. Cocaine dose-effect curves were shifted down and/or rightward in three monkeys. These data provide further support for the use of agonist medications for cocaine abuse, and indicate that the promising effects of d amphetamine extend to a more clinically viable pharmacotherapy. PMID- 26964685 TI - Thermosensing mechanisms and their impairment by high-fat diet in orexin neurons. AB - In homeotherms, the hypothalamus controls thermoregulatory and adaptive mechanisms in energy balance, sleep-wake and locomotor activity to maintain optimal body temperature. Orexin neurons may be involved in these functions as they promote thermogenesis, food intake and behavioral arousal, and are sensitive to temperature and metabolic status. How thermal and energy balance signals are integrated in these neurons is unknown. Thus, we investigated the cellular mechanisms of thermosensing in orexin neurons and their response to a change in energy status using whole-cell patch clamp on rat brain slices. We found that warming induced an increase in miniature excitatory postsynaptic current (EPSC) frequency, which was blocked by the transient receptor potential vanilloid-1 (TRPV1) receptor antagonist AMG9810 and mimicked by its agonist capsaicin, suggesting that the synaptic effect is mediated by heat-sensitive TRPV1 channels. Furthermore, warming inhibits orexin neurons by activating ATP-sensitive potassium (KATP) channels, an effect regulated by uncoupling protein 2 (UCP2), as the UCP2 inhibitor genipin abolished this response. These properties are unique to orexin neurons in the lateral hypothalamus, as neighboring melanin concentrating hormone neurons showed no response to warming within the physiological temperature range. Interestingly, in rats fed with western diet for 1 or 11weeks, orexin neurons had impaired synaptic and KATP response to warming. In summary, this study reveals several mechanisms underlying thermosensing in orexin neurons and their attenuation by western diet. Overeating induced by western diet may in part be due to impaired orexin thermosensing, as post prandial thermogenesis may promote satiety and lethargy by inhibiting orexin neurons. PMID- 26964686 TI - Early increase in dopamine release in the ipsilateral striatum after unilateral intranigral administration of lactacystin produces spontaneous contralateral rotations in rats. AB - Since the discovery of the role of the ubiquitin-proteasome system (UPS) in the pathogenesis of Parkinson's disease, UPS inhibitors, such as lactacystin have been used to investigate the relationship between UPS impairment and degeneration of dopamine (DA) neurons. However, mostly long-term neurotoxic effects of lactacystin have been studied in animal models. Therefore, the aim of our study was to investigate behavioral and biochemical changes related to the DA system during the first week following unilateral intranigral injection of lactacystin to rats. We found that lactacystin produced early spontaneous contralateral rotations which were inhibited by combined administration of DA D1 and D2 receptor antagonists. Simultaneously, an increase in the extracellular level of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) was found in the ipsilateral striatum. In contrast, one week after lesion, when turning behavior was no longer visible, a decrease in the extracellular level of DA, DOPAC and HVA was demonstrated. It was accompanied by a substantial reduction in the tissue levels of DA and its metabolites in the lesioned substantia nigra and striatum. We concluded that unilateral intranigral administration of lactacystin produces an early increase in DA neurotransmission which precedes a decrease in the striatal and nigral tissue DA content. It is manifested by the appearance of spontaneous contralateral rotations and an elevation of the extracellular DA level in the ipsilateral striatum. Since similar behavior was previously observed after intranigral administration of rotenone and MPP(+) but not 6-hydroxydopamine (6-OHDA), it may indicate a common mechanism of action shared by these neurotoxins. PMID- 26964688 TI - Timing of high-frequency cortical stimulation in a genetic absence model. AB - INTRODUCTION: Seizure control is one of the ultimate aims of epileptology: here acute and prolonged effects of closed loop high-frequency stimulation of the somatosensory cortex on the expression of spontaneously occurring spike-wave discharges (SWD) were investigated in a genetic absence model. Effects of closed loop stimulation in the experimental group were compared with a yoked control group allowing to investigate the effect of timing related to SWD occurrence, while controlling for amount and intensity of stimulation. METHODS: WAG/Rij rats were implanted with stimulation electrodes in the deep layers of the somatosensory cortex, and recording electrodes in the cortex and thalamus. Closed loop and yoked stimulation (1 sec trains, biphasic 0.4 msec pulses, 130 Hz) sessions lasted 24h. The stimulation sessions were preceded and followed by baseline and post stimulation 24-h recordings. RESULTS: Closed-loop stimulation interrupted SWD and duration of SWD was shortened. Both types of stimulation resulted in a reduction in SWD number during stimulation sessions. Closed-loop stimulation also resulted in less SWD during the last eight hours of the post stimulation recording session. Sometimes yoked stimulation induced low-frequency afterdischarges. DISCUSSION: SWD can be aborted by closed-loop stimulation of the somatosensory cortex, and at the same time the number of SWD was reduced. It can be regarded as a relatively safe neuromodulatory technique without habituation. The reduction of SWD during yoked stimulation session might be caused by 3 Hz afterdischarges. The reduction of SWD on the stimulation and post-stimulation sessions demonstrates the critical relevance of timing for the induction of longer lasting neuromodulatory effects: it suggests that absence seizures themselves might be involved in their reoccurrence. PMID- 26964687 TI - Third trimester-equivalent ethanol exposure causes micro-hemorrhages in the rat brain. AB - Exposure to ethanol during fetal development produces long-lasting neurobehavioral deficits caused by functional alterations in neuronal circuits across multiple brain regions. Therapeutic interventions currently used to treat these deficits are only partially efficacious, which is a consequence of limited understanding of the mechanism of action of ethanol. Here, we describe a novel effect of ethanol in the developing brain. Specifically, we show that exposure of rats to ethanol in vapor chambers during the equivalent to the third trimester of human pregnancy causes brain micro-hemorrhages. This effect was observed both at low and high doses of ethanol vapor exposure, and was not specific to this exposure paradigm as it was also observed when ethanol was administered via intra esophageal gavage. The vast majority of the micro-hemorrhages were located in the cerebral cortex but were also observed in the hypothalamus, midbrain, olfactory tubercle, and striatum. The auditory, cingulate, insular, motor, orbital, retrosplenial, somatosensory, and visual cortices were primarily affected. Immunohistochemical experiments showed that the micro-hemorrhages caused neuronal loss, as well as reactive astrogliosis and microglial activation. Analysis with the Catwalk test revealed subtle deficits in motor function during adolescence/young adulthood. In conclusion, our study provides additional evidence linking developmental ethanol exposure with alterations in the fetal cerebral vasculature. Given that this effect was observed at moderate levels of ethanol exposure, our findings lend additional support to the recommendation that women abstain from consuming alcoholic beverages during pregnancy. PMID- 26964689 TI - The influence of a high-fat meal on fat taste thresholds. AB - A high-fat diet for four weeks has been shown to attenuate fat taste sensitivity in healthy weight individuals. However, there is minimal evidence as to whether a single high-fat meal immediately prior to fat taste threshold testing has an effect on thresholds. Therefore, the aim of the study was to determine the effect of a high-fat meal immediately prior to detection threshold testing for oleic acid (C18:1). Thirty-two participants (15 males, 17 females, aged 39.1 +/- 3.1 years, Body Mass Index 23.1 +/- 0.7 kg/m(2)) attended three laboratory sessions. In each session, participants were randomly assigned to one of three different types of breakfast: a high-fat (60% energy from fat), or low-fat (20% energy from fat) or macronutrient balanced (33% energy from fat) frittata. Fat taste thresholds were evaluated using ascending forced choice triangle tests on two occasions each day; once one-hour post breakfast and then one-hour post the completion of the first threshold test. There was no effect of breakfast type on fat taste detection thresholds for the first testing session of each day (P = 0.288), or the second testing session of each day (P = 0.754). There was also no effect of breakfast within each day (day 1: P = 0.198, day 2: P = 0.199, day 3: P = 0.125). There was no effect of macronutrient composition on the ability of participants to rank the level of fat in food (P = 0.345), or preference for the level of fat in food (P = 0.187-0.868). This study provides preliminary evidence that the composition of the meal consumed by a participant immediately prior to testing does not affect fat taste thresholds. PMID- 26964690 TI - Understanding fruit and vegetable intake of Native American children: A mixed methods study. AB - Native American children experience greater rates of obesity and risk for chronic diseases in comparison to their counterparts in other ethnic groups. Contributing to this risk may be inadequate consumption of fruits and vegetables. The objective of this study was to investigate the fruit and vegetable consumption of Native American children between the ages of 2 and 5 by using an exploratory sequential mixed methods research design. This study first collected qualitative data from caregivers of Native American children (n = 45) and stakeholders in Native American communities (n = 10) to gain perspectives of fruit and vegetable consumption. Data was then utilized to develop a fruit and vegetable survey which was administered with a fruit and vegetable food frequency questionnaire. These quantitative assessments were administered to caregivers of Native American children (n = 92) to gain an understanding of predictors of fruit and vegetable intake among this population. This study was guided by the Information-Motivation Behavioral Skills (IMB) model of health behavior. Findings from the mixed methods analysis demonstrate that, while the IMB model may be a useful tool to utilize in explaining the complex relationship between factors that impact fruit and vegetable consumption among Native American children, a revised model may be appropriate to use in future intervention development. PMID- 26964691 TI - How do people define moderation? AB - Eating in moderation is considered to be sound and practical advice for weight maintenance or prevention of weight gain. However, the concept of moderation is ambiguous, and the effect of moderation messages on consumption has yet to be empirically examined. The present manuscript examines how people define moderate consumption. We expected that people would define moderate consumption in ways that justified their current or desired consumption rather than view moderation as an objective standard. In Studies 1 and 2, moderate consumption was perceived to involve greater quantities of an unhealthy food (chocolate chip cookies, gummy candies) than perceptions of how much one should consume. In Study 3, participants generally perceived themselves to eat in moderation and defined moderate consumption as greater than their personal consumption. Furthermore, definitions of moderate consumption were related to personal consumption behaviors. Results suggest that the endorsement of moderation messages allows for a wide range of interpretations of moderate consumption. Thus, we conclude that moderation messages are unlikely to be effective messages for helping people maintain or lose weight. PMID- 26964692 TI - The usefulness of measuring tear periostin for the diagnosis and management of ocular allergic diseases. AB - BACKGROUND: Chronic ocular allergic diseases such as vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) are accompanied by serious comorbidities; however, the underlying pathogenesis remains obscure. Furthermore, diagnosing conjunctival lesions in patients with atopic dermatitis and estimating the severity in AKC are important for the treatment of ocular allergic diseases. OBJECTIVE: We addressed whether periostin, a novel mediator and biomarker in allergic inflammation, is involved in the pathogenesis of ocular allergic diseases and whether periostin can be a biomarker for these diseases. METHODS: We investigated tear periostin in patients with seasonal allergic conjunctivitis (SAC), VKC, and AKC and allergic patients without conjunctivitis and compared it with tear IL-13 and serum periostin. Furthermore, in patients with AKC, we measured tear periostin before and after topical treatment with tacrolimus. RESULTS: Tears from patients with ocular allergic disease showed significantly high periostin levels than did tears from allergic patients without conjunctivitis and from patients with AKC, VKC, and SAC in descending order. Tear periostin was associated with serious comorbidities such as large papilla formation and corneal damage in AKC, although both tear IL-13 and serum periostin had little to no such abilities. Furthermore, after topical tacrolimus treatment, tear periostin tended to decrease in most patients with AKC along with their clinical improvement. CONCLUSIONS: Periostin produced in conjunctival tissues stimulated by IL-13 may contribute to the pathogenesis of ocular allergic diseases. Furthermore, tear periostin can be potentially applied as a biomarker to diagnose conjunctivitis in allergic patients and to evaluate disease severity as well as the efficacy of treatments in AKC. PMID- 26964693 TI - Effective energy storage from a triboelectric nanogenerator. AB - To sustainably power electronics by harvesting mechanical energy using nanogenerators, energy storage is essential to supply a regulated and stable electric output, which is traditionally realized by a direct connection between the two components through a rectifier. However, this may lead to low energy storage efficiency. Here, we rationally design a charging cycle to maximize energy-storage efficiency by modulating the charge flow in the system, which is demonstrated on a triboelectric nanogenerator by adding a motion-triggered switch. Both theoretical and experimental comparisons show that the designed charging cycle can enhance the charging rate, improve the maximum energy-storage efficiency by up to 50% and promote the saturation voltage by at least a factor of two. This represents a progress to effectively store the energy harvested by nanogenerators with the aim to utilize ambient mechanical energy to drive portable/wearable/implantable electronics. PMID- 26964695 TI - Evaluation of the toxicity of selenium from hydroponically produced selenium enriched kale sprout in laying hens. AB - Hydroponically produced Se-enriched kale sprouts (HPSeKS) are studied for their use as an alternative dietary Se supplement for poultry. The study experimented with different levels and sources of Se to determine toxicity and how the toxicity may affect productive performance, Se concentration in egg and tissues, and physiological responses of laying hens. One-hundred and twenty hens, 59 weeks of age, were divided into 5 groups. Each group consisted of 4 replicates and each replicate had 6 birds according to a 2 * 2 + 1 Augmented Factorial Experiment in a Completely Randomized Design. The experiment was conducted over a 4 week period, and 5 dietary treatments (T) were used: T1 basal diet, T2 and T3 basal diet plus 5 and 10mg Se/kg from sodium selenite (SS), T4 and T5 basal diet plus 5 and 10mg Se/kg from HPSeKS, respectively. The results make clear that Se from HPSeKS, at 5-10mg/kg, did not affect (P>0.05) feed intake and egg production; however, Se bioavailability decreased (P<0.05). Egg, tissue and plasma Se concentrations, and GSH-Px activity in red blood cells increased (P<0.05) compared to those in T1. Final body weight, feed intake, Se bioavailability, concentration of Se in breast muscle and plasma of hens fed Se from SS were lower (P<0.05) than those of hens fed Se from HPSeKS. The findings demonstrate that dietary Se from HPSeKS at 5-10mg/kg is not considered a toxic level for laying hens. The toxicity of Se from HPSeKS was less than the toxicity of Se from SS. PMID- 26964694 TI - YiXin-Shu, a ShengMai-San-based traditional Chinese medicine formula, attenuates myocardial ischemia/reperfusion injury by suppressing mitochondrial mediated apoptosis and upregulating liver-X-receptor alpha. AB - Positive evidence from clinical trials has fueled growing acceptance of traditional Chinese medicine (TCM) for the treatment of cardiac diseases; however, little is known about the underlying mechanisms. Here, we investigated the nature and underlying mechanisms of the effects of YiXin-Shu (YXS), an antioxidant-enriched TCM formula, on myocardial ischemia/reperfusion (MI/R) injury. YXS pretreatment significantly reduced infarct size and improved viable myocardium metabolism and cardiac function in hypercholesterolemic mice. Mechanistically, YXS attenuated myocardial apoptosis by inhibiting the mitochondrial mediated apoptosis pathway (as reflected by inhibition of mitochondrial swelling, cytochrome c release and caspase-9 activity, and normalization of Bcl-2 and Bax levels) without altering the death receptor and endoplasmic reticulum-stress death pathways. Moreover, YXS reduced oxidative/nitrative stress (as reflected by decreased superoxide and nitrotyrosine content and normalized pro- and anti-oxidant enzyme levels). Interestingly, YXS upregulated endogenous nuclear receptors including LXRalpha, PPARalpha, PPARbeta and ERalpha, and in-vivo knockdown of cardiac-specific LXRalpha significantly blunted the cardio-protective effects of YXS. Collectively, these data show that YXS is effective in mitigating MI/R injury by suppressing mitochondrial mediated apoptosis and oxidative stress and by upregulating LXRalpha, thereby providing a rationale for future clinical trials and clinical applications. PMID- 26964696 TI - Diagnostic Value of Elastography in the Diagnosis of Intermetatarsal Neuroma. AB - The objective of the present study was to characterize the ultrasound and elastographic properties of intermetatarsal neuroma (interdigital neuroma) and their contribution to diagnosis. Eighteen patients with metatarsalgia, who had presented to an orthopedic clinic from April 2013 to February 2015, were diagnosed with 25 intermetatarsal neuromas (11 unilateral [61.11%], 7 bilateral [38.89%]). These patients underwent evaluation with ultrasonography and simultaneous ultrasound strain elastography to assess the elastographic properties of the tissues in the intermetatarsal space. The intermetatarsal neuroma diagnosis was confirmed by histopathologic inspection. The lesion contours, localization, dimensions, and vascularization were evaluated before surgical excision. The elasticity and strain ratio values were compared between the neuroma and adjacent healthy intermetatarsal space. Of the 25 intermetatarsal neuromas, 1 (4%) was not detected by ultrasonography (incidence of detection of 96%). The mean neuroma width was 6.35 (range 3.7 to 13) mm in the coronal plane, and the mean elasticity and strain ratio values were 3.44 (range 1.1 to 5.1) and 9.47 (range 2.3 to 19.3), respectively. The elasticity and strain ratio values were significantly greater in the presence of an interdigital neuroma than in the adjacent healthy intermetatarsal spaces (Z = -3.964, p = .0001 and Z = -3.927, p = .0001, respectively). The diagnostic cutoff values were calculated as 2.52 for elasticity and 6.1 for the strain ratio. Four neuromas (16%) were not demarcated, and the elasticity and strain ratio values for these were lower than those for neuromas with demarcated contours but were greater than those for healthy intermetatarsal spaces (p < .006 and p < .005, respectively). Patients with clinically suspected intermetatarsal neuromas that do not show demarcation and with smaller lesions might benefit from the use of ultrasound elastography for diagnosis. PMID- 26964697 TI - Calcaneonavicular Coalition Resection With Pes Planovalgus Reconstruction. AB - Calcaneonavicular coalitions can lead to a painful, rigid pes planovalgus deformity. Historical treatment of coalitions recommends resection. A newer concept in coalition treatment includes concomitant flatfoot reconstruction. In the present study, we hoped to demonstrate the ability to reconstruct a flatfoot deformity with concomitant calcaneonavicular coalition resection. We performed a retrospective comparative study of patients undergoing isolated calcaneonavicular bar excision (group A) with those undergoing calcaneonavicular bar excision and concomitant pes planovalgus reconstruction (group B). The radiographic parameters of pes planovalgus correction were measured on the pre- and postoperative radiographs, including talar head uncoverage, calcaneal inclination, and anteroposterior and lateral talo-first metatarsal angle. Calcaneonavicular coalition resection was performed using a standard technique with or without biologic spacers. Associated flatfoot reconstruction included posterior muscle group lengthening, calcaneal osteotomy, and/or midfoot osteotomy. Of the 27 patients, 20 were included in group A and 7 in group B. Their mean age was 18.1 years. Improvement was seen in the radiographic parameters for patients undergoing calcaneonavicular bar excision with concomitant flatfoot procedures, with statistical significance found in the calcaneal inclination (p = .013). Talar head uncoverage improved in both groups (p = .011). No change was found in the radiographic angles in patients undergoing isolated calcaneonavicular bar excision. No patients in either group developed recurrence of the coalition. The results of the present study demonstrated radiographic improvement in patients undergoing calcaneonavicular bar excision with concomitant pes planovalgus reconstruction. Hindfoot reconstruction with joint sparing osteotomies during coalition excision is a reasonable option to improve alignment and avoid arthrodesis. PMID- 26964699 TI - Update on Providing Re-Essure-ance to the Nickel-Allergic Patient Considering Hysteroscopic Sterilization. PMID- 26964700 TI - [Hepatitis B and pregnancy. Part 1. Thirteen practical issues in antenatal period]. AB - In France, the prevalence of chronic hepatitis B is about 1% in pregnant women (usually asymptomatic carriers of HBsAg). The risk of maternal-fetal transmission of hepatitis B is particularly high when viral load measured by PCR is higher in mothers (above 7 log) or HBeAg is present. In case of maternal-fetal transmission of hepatitis B, the risk to the newborn of developing subsequent chronic hepatitis B is very high (90%), with long-term complications such as cirrhosis and hepatocellular carcinoma. The prevention of maternal-fetal transmission is based on systematic testing for hepatitis B during pregnancy, followed by serovaccination of the newborn at birth. If necessary, amniocentesis can be realised but will avoid the realization of a transplacental gesture. In case of high viral load, the establishment of a maternal antiviral treatment with lamivudine or tenofovir from 28SA can further reduce the risk of transmission. Given the low resistance it induces, tenofovir should be used preferentially. PMID- 26964698 TI - Outcomes of Allogeneic Hematopoietic Cell Transplantation in Children and Young Adults with Chronic Myeloid Leukemia: A CIBMTR Cohort Analysis. AB - Chronic myeloid leukemia (CML) in children and young adults is uncommon. Young patients have long life expectancies and low morbidity with hematopoietic cell transplantation (HCT). Prolonged tyrosine kinase inhibitor (TKI) use may cause significant morbidity. In addition, indication for HCT in patients in the first chronic phase is not established. We hence retrospectively evaluated outcomes in 449 CML patients with early disease receiving myeloablative HCT reported to the CIBMTR. We analyzed various factors affecting outcome, specifically the effect of age and pre-HCT TKI in pediatric patients (age < 18 years, n = 177) and young adults (age 18 to 29 years, n = 272) with the goal of identifying prognostic factors. Post-HCT probability rates of 5-year overall survival (OS) and leukemia free survival (LFS) were 75% and 59%, respectively. Rates of OS and LFS were 76% and 57% in <18-year and 74% and 60% in 18- to 29-year group, respectively, by univariate analysis (P = .1 and = .6). Five-year rates of OS for HLA matched sibling donor (MSD) and bone marrow (BM) stem cell source were 83% and 80%, respectively. In multivariate analysis there was no effect of age (<18 versus 18 to 29) or pre-HCT TKI therapy on OS, LFS, transplant related mortality, or relapse. Favorable factors for OS were MSD (P < .001) and recent HCT (2003 to 2010; P = .04). LFS was superior with MSD (P < .001), BM as graft source (P = .001), and performance scores > 90 (P = .03) compared with unrelated or mismatched peripheral blood stem cells donors and recipients with lower performance scores. Older age was associated with increased incidence of chronic graft-versus-host disease (P = .0002). In the current era, HCT outcomes are similar in young patients and children with early CML, and best outcomes are achieved with BM grafts and MSD. PMID- 26964701 TI - [Gynaecologic follow up, physicians involved and cervical smears: An accumulation of social disparities]. AB - OBJECTIVES: This study analysed how social disparities are built in the health process leading to the achievement of cervical smears. MATERIALS AND METHODS: A cross-sectional study included women over 40 years eligible for cervical cancer screening and recruited randomly in the patient base of 52 volunteer general practitioners (GP). Judgement criteria were (1) the existence of a gynaecological follow up, (2) provided by a GP (versus gynaecologist), and (3) the "up to date" status for the cervical smear. Occupational class, education, and perceived financial condition evaluated social position. RESULTS: Among 1092 women (participation 74%), 86% had a gynaecological follow up. It was associated with a higher social position and to more "up to date" status. The follow up was performed by the GP for 10% of the patients who mainly had a lower social position. The "up to date" status was more prevalent when the follow up was done by the gynaecologist than by a GP but was socially differentiated. CONCLUSION: Having a gynaecological follow up, especially by a gynaecologist, improved cervical screening but social inequalities were linked to its achievement at every part of this process. PMID- 26964702 TI - The cardiac matrix revolution: Post-translational modification of Scleraxis. PMID- 26964704 TI - Are some children with empyema at risk for treatment failure with fibrinolytics? A multicenter cohort study. AB - BACKGROUND: Guidelines recommend that children with empyema be treated initially with chest tube insertion and intrapleural fibrinolytics. Some patients have poor outcomes with this approach, and it is unclear which factors are associated with treatment failure. METHODS: Possible risk factors were identified through a review of the literature. Treatment failure was defined as need for repeat pleural drainage and/or total length of stay greater than 2weeks. RESULTS: We retrospectively identified 314 children with empyema treated with fibrinolytics at The Hospital for Sick Children (2000-2013, n=195), Children's Hospital, London Health Sciences Centre (2009-2013, n=39), and McMaster Children's Hospital (2007 2014, n=80). Median length of stay was 11days (range 5-69days). Thirteen percent of children required repeat drainage procedures, and 34% experienced treatment failure. There were no deaths. White blood cell count, erythrocyte sedimentation rate, C-reactive protein, albumin, urea to creatinine ratio, and signs of necrosis on initial chest x-ray were not associated with treatment failure. Multivariable logistic regression demonstrated increased risk with positive blood culture (odds ratio=2.7), immediate admission to intensive care (odds ratio=2.6), and absence of complex septations on baseline ultrasound (odds ratio=2.1). Male gender and platelet count were associated with treatment failure in the univariate analysis but not in the multivariable model. CONCLUSIONS: Predicting which children with empyema are at risk for treatment failure with fibrinolytics remains challenging. Risk factors include positive blood culture, immediate admission to intensive care, and absence of complex septations on ultrasound. Routine blood work and inflammatory markers have little prognostic value. PMID- 26964703 TI - Cholesterol lipids and cholesterol-containing lipid rafts in bacteria. AB - Sterols are important components of eukaryotic membranes, but rare in bacteria. Some bacteria obtain sterols from their host or environment. In some cases, these sterols form membrane domains analogous the lipid rafts proposed to exist in eukaryotic membranes. This review describes the properties and roles of sterols in Borrelia and Helicobacter. PMID- 26964705 TI - A novel therapeutic approach for central sleep apnea: Phrenic nerve stimulation by the remede(r) System. AB - Central sleep apnea is a devastating disease which occurs in approximately 40% of patients with heart failure as well as patients with a history of stroke, opioid use and neurological conditions. It is associated with increased morbidity and mortality in heart failure likely due to the recurrent episodes of hypoxia and nor-epinephrine release. There have historically been few therapeutic options; positive airway pressure therapies have been the most common treatment to date. However, the adoption of positive airway pressure therapies has been limited due to poor patient adherence and acceptance and recent evidence of increased cardiovascular mortality in low ejection fraction heart failure patients with CSA. The remede(r) System, utilizing transvenous stimulation of the phrenic nerve, offers a novel physiologic approach to therapy that eliminates the need for positive airway pressure and patient adherence. Studies have shown that this therapy improves sleep, oxygenation, and quality of life and ongoing trials are expected to give additional randomized data to support the therapeutic benefit of the remede(r) System. PMID- 26964706 TI - Portability of therapeutic effects (letter commenting: J Clin Epidemiol. 2015;68(11):1251--1260.). PMID- 26964708 TI - Lacking portability of therapeutic effects: the hierarchy of internal validity is insufficient-A response to Hans J. Trampisch. PMID- 26964707 TI - Adequate sample size for developing prediction models is not simply related to events per variable. AB - OBJECTIVES: The choice of an adequate sample size for a Cox regression analysis is generally based on the rule of thumb derived from simulation studies of a minimum of 10 events per variable (EPV). One simulation study suggested scenarios in which the 10 EPV rule can be relaxed. The effect of a range of binary predictors with varying prevalence, reflecting clinical practice, has not yet been fully investigated. STUDY DESIGN AND SETTING: We conducted an extended resampling study using a large general-practice data set, comprising over 2 million anonymized patient records, to examine the EPV requirements for prediction models with low-prevalence binary predictors developed using Cox regression. The performance of the models was then evaluated using an independent external validation data set. We investigated both fully specified models and models derived using variable selection. RESULTS: Our results indicated that an EPV rule of thumb should be data driven and that EPV >= 20 generally eliminates bias in regression coefficients when many low-prevalence predictors are included in a Cox model. CONCLUSION: Higher EPV is needed when low-prevalence predictors are present in a model to eliminate bias in regression coefficients and improve predictive accuracy. PMID- 26964709 TI - Impact of nutritional risk screening in hospitalized patients on management, outcome and costs: A retrospective study. AB - BACKGROUND & AIMS: Hospitalized patients should be screened for nutritional risk and adequately managed. Being nutritionally 'at-risk' increases in-hospital mortality, length of stay (LOS) and costs, but the impact on actual costs has seldom been assessed. We aimed to determine nutritional risk screening and management in a Swiss university hospital. The impact of being nutritionally 'at risk' on in-hospital mortality, LOS and costs was also assessed. METHODS: Retrospective analysis of administrative data for years 2013 and 2014 from the department of internal medicine of the Lausanne university hospital (8541 hospitalizations, mean age 72.8 +/- 16.5 years, 50.4% women). Being nutritionally 'at-risk' was defined as a Nutritional risk screening-2002 score >= 3 and nutritional managements were collected from medical records. RESULTS: Screening increased from 16.5% in 2013 to 41.9% in 2014 (p < 0.001), while prevalence of 'at-risk' patients remained stable (64.6% in 2013 and 62.7% in 2014, p = 0.37). Prevalence of 'at-risk' patients was highest in patients with cancer (85.3% in 2013 and 70.2% in 2014) and lowest in patients with disease of skin (42% in 2013 and 44.8% in 2014). Less than half of patients 'at-risk' received any nutritional management, and this value decreased between 2013 and 2014 (46.9% vs. 40.3%, p < 0.05). After multivariate adjustment, 'at-risk' patients had a 3.7-fold (95% confidence interval: 1.91; 7.03) higher in-hospital mortality and higher costs (excess 5642.25 +/- 1479.80 CHF in 2013 and 5529.52 +/- 847.02 CHF in 2014, p < 0.001) than 'not at-risk' patients, while no difference was found for LOS. CONCLUSION: Despite an improvement in screening, management of nutritionally 'at risk' patients is not totally covered yet. Being nutritionally 'at-risk' affects three in every five patients and is associated with increased mortality and hospitalization costs. PMID- 26964710 TI - Cloning of Litopenaeus vannamei CD63 and it's role in white spot syndrome virus infection. AB - White Spot Syndrome Virus (WSSV) is currently the most serious shrimp pathogen, which has brought huge losses to shrimp industry worldwide. CD63 of shrimp belongs to the tetraspanin superfamily, which plays an important role in signal transduction and immune process. In this paper, CD63 cDNA sequence of Litopenaeus vannamei was cloned using RACE method. The amplified sequence is 1472 bp, with its ORF 744 bp, encoding 247 amino acids. Bioinformatics analysis showed that the sequence of LvCD63 has 93% similarity with Penaeus monodon and 92% similarity with Fenneropenaeus chinensis. Real-time PCR analysis showed that the mRNA levels of LvCD63 expressed in the tissues of hemocytes, gill, epithelial tissue, heart, lymphoid, hepatopancreas, stomach, intestines, muscle and nerve. Among these tissues the highest expression level was showed in the tissue of haemolymph, followed by epithelial tissue, hepatopancreas, and nerve. The lowest expression level of LvCD63 was appeared in the muscle tissue. After WSSV challenge, the expression levels of LvCD63 were both up-regulated in the tissues of gill and epithelial. However the expression level of LvCD63 in hepatopancreas was down regulated. Far-western blot analysis showed that LvCD63 interacts with VP28, and both VP28N and VP28C fragments interact with LvCD63. Flow cytometry analysis showed that LvCD63 was present on the surface of hemocytes and it is required for binding of WSSV virions. Neutral experiments in vivo showed that LvCD63LEL delayed WSSV infection in shrimp. PMID- 26964711 TI - Assessment of reference genes for reliable analysis of gene transcription by RT qPCR in ovine leukocytes. AB - With the availability of genetic sequencing data, quantitative reverse transcription PCR (RT-qPCR) is increasingly being used for the quantification of gene transcription across species. Too often there is little regard to the selection of reference genes and the impact that a poor choice has on data interpretation. Indeed, RT-qPCR provides a snapshot of relative gene transcription at a given time-point, and hence is highly dependent on the stability of the transcription of the reference gene(s). Using ovine efferent lymph cells and peripheral blood mono-nuclear cells (PBMCs), the two most frequently used leukocytes in immunological studies, we have compared the stability of transcription of the most commonly used ovine reference genes: YWHAZ, RPL-13A, PGK1, B2M, GAPDH, HPRT, SDHA and ACTB. Using established algorithms for reference gene normalization "geNorm" and "Norm Finder", PGK1, GAPDH and YWHAZ were deemed the most stably transcribed genes for efferent leukocytes and PGK1, YWHAZ and SDHA were optimal in PBMCs. These genes should therefore be considered for accurate and reproducible RT-qPCR data analysis of gene transcription in sheep. PMID- 26964712 TI - Tissue-specific mRNA expression profiles of porcine Toll-like receptors at different ages in germ-free and conventional pigs. AB - Toll-like receptors (TLRs), key initiators of innate immune responses, recognize antigens and are essential in linking innate and adaptive immune responses. Misrecognition and over-stimulation/expression of TLRs may contribute to the development of chronic inflammatory diseases and autoimmune diseases. However, appropriate and mature TLR responses are associated with the establishment of resistance against some infectious diseases. In this study, we assessed the mRNA expression profile of TLRs 1-10 in splenic and ileal mononuclear cells (MNCs) and dendritic cells (DCs) of germ-free (GF) and conventional pigs at different ages. We found that the TLR mRNA expression profiles were distinct between GF and conventional pigs. The expression profiles were also significantly different between splenic and ileal MNCs/DCs. Comparison of the TLR expression profiles in GF and conventional newborn and young pigs demonstrated that exposure to commensal microbiota may play a more important role than age in TLR mRNA expression profiles. To our knowledge, this is the first report that systematically assesses porcine TLRs 1-10 mRNA expression profiles in MNCs and DCs from GF and conventional pigs at different ages. These results further highlighted that the commensal microbiota of neonates play a critical role through TLR signaling in the development of systemic and mucosal immune systems. PMID- 26964713 TI - Natural resistance to experimental feline infectious peritonitis virus infection is decreased rather than increased by positive genetic selection. AB - A previous study demonstrated the existence of a natural resistance to feline infectious peritonitis virus (FIPV) among 36% of randomly bred laboratory cats. A genome wide association study (GWAS) on this population suggested that resistance was polygenic but failed to identify any strong specific associations. In order to enhance the power of GWAS or whole genome sequencing to identify strong genetic associations, a decision was made to positively select for resistance over three generations. The inbreeding experiment began with a genetically related parental (P) population consisting of three toms and four queens identified from among the survivors of the earlier study and belonging to a closely related subgroup (B). The subsequent effects of inbreeding were measured using 42 genome-wide STR markers. P generation cats produced 57 first filial (F1) kittens, only five of which (9.0%) demonstrated a natural resistance to FIPV infection. One of these five F1 survivors was then used to produce six F1/P backcrosses kittens, only one of which proved resistant to FIP. Six of eight of the F1 and F1/P survivors succumbed to a secondary exposure 4-12 months later. Therefore, survival after both primary and secondary infection was decreased rather than increased by positive selection for resistance. The common genetic factor associated with this diminished resistance was a loss of heterozygosity. PMID- 26964715 TI - Immunomodulatory properties of gamithromycin and ketoprofen in lipopolysaccharide challenged calves with emphasis on the acute-phase response. AB - Macrolide antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to be modulators of the innate immune response, irrespectively of their antimicrobial and anti-inflammatory actions. Therefore, it was our objective to evaluate whether the macrolide gamithromycin (GAM) and the NSAID ketoprofen (KETO) attenuate the acute-phase response in calves, and whether their combined administration is beneficial due to synergistic and/or additive effects. To this end, both drugs, as well as their combination, were studied in a previously developed inflammation model, i.e., the induction of an acute-phase response by an intravenous lipopolysaccharide (LPS) challenge (0.5 MUg/kg body weight). Sixteen 4-week-old Holstein-Friesian calves were randomized into 4 groups: a positive control (+CONTR) group, receiving LPS but no pharmacological treatment (n=4) and a GAM (n=4), a KETO (n=4) and a GAM-KETO (n=4) group, receiving the respective drugs 1h prior to LPS administration. Clinical scoring and blood collection were performed at regular time points until 72 h post LPS challenge. Plasma concentrations of the selected cytokines (tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6)), acute-phase protein (serum amyloid A (SAA)) and prostaglandin E2 (PGE2) were subsequently quantified. Pre treatment with GAM had no effect in the inflammation model compared to the +CONTR group. KETO, on the other hand, completely inhibited depression, anorexia and fever. This remarkable influence was associated with a significant reduction of PGE2 synthesis by KETO, while the effect on TNF-alpha, IL-6 and SAA was not straightforward. The combined administration of GAM and KETO provided no synergistic or additive effects in this model, neither clinically nor regarding the studied inflammatory mediators. In conclusion, KETO entirely inhibited PGE2 synthesis, fever development and depression, while GAM did not exert any effect in this model. These results promote the concomitant use of an antimicrobial drug and a NSAID in the treatment of calf diseases associated with LPS, both to enhance clinical recovery and to improve animal welfare. PMID- 26964714 TI - Bovine natural antibodies in antibody-dependent bactericidal activity against Escherichia coli and Salmonella Typhimurium and risk of mastitis. AB - Natural antibodies (NAbs) are mostly IgM antibodies produced without antigenic stimulation and serve as a first line of defence of the immune system. As both natural and specific antibodies are present in animals, NAbs are studied by determining the IgM response to naive antigens like keyhole limpet hemocyanin (KLH). In this study, we selected cows based on high and low anti-KLH IgM titers, reflecting high and low NAb titers, and determined if the anti-KLH IgM titers were indicative for the recognition of common microbial structures (lipopolysaccharide, lipoteichoic acid and peptidoglycan) and intact bacteria (Escherichia coli and Salmonella Typhimurium). Sera with high NAbs titers showed more IgM and IgG binding to common microbial structures and S. Typhimurium bacteria than sera with low NAbs titers. The same association was observed for IgM binding to E. coli, but not for IgG binding to E. coli. Antibody-mediated complement killing of E. coli and S. Typhimurium in a newly developed bactericidal test was equal between high and low NAb cows. However, relating the outcome of the bactericidal test to the development of mastitis within one and even four years after sampling showed a significant negative correlation implying cows that were less potent in bacterial killing had a higher chance on developing mastitis. In conclusion, sera with high NAbs titers had more antibodies binding to common microbial structures and intact bacteria. Furthermore, the bactericidal test might provide a useful prognostic tool for the development of mastitis. PMID- 26964717 TI - Canine placenta: A promising potential source of highly proliferative and immunomodulatory mesenchymal stromal cells? AB - In veterinary medicine, therapeutic mesenchymal stromal cells (MSC) have been traditionally isolated from adult bone marrow or adipose tissue. Neonatal tissues, normally discarded at birth from all species have become an alternative source of cells for regenerative medicine in the human clinic. These cells have been described as being more primitive, proliferative and immunosuppressive than their adult counterparts. Our objective was to examine if this phenomena holds true in dogs. Little information exists regarding canine neonatal MSC characterisation. In this study, we were able to both isolate, phenotype and assess the differentiation and immunomodulatory properties of MSC from canine foetal adnexa allowing us to compare their characteristics to their more well known bone marrow (BM) cousins. Neonatal tissues, including amnion (AM), placenta (PL), and umbilical cord matrix (UCM) were collected from 6 canine caesarean sections. Primary cells were expanded in vitro for 5 consecutive passages and their proliferation measured. BM-MSC were isolated from 5 control dogs euthanised from other studies and grown in vitro using an identical protocol. All MSC lines were systematically evaluated for their ability to differentiate into 3 mesodermal lineages (adipocyte, osteocyte and chondrocyte) and phenotyped by cytometry and qPCR. In addition, the enzymatic activity of the key immunomodulatory marker indoleamine 2,3-dioxygenase (IDO) was evaluated for each MSC line. MSC displaying a fibroblastic appearance were successfully grown from all neonatal tissues. PL-MSC exhibited significantly higher proliferation rates than AM- and UCM-MSC (p=0.05). Cytometric analysis showed that all MSC express CD90, CD29, and CD44, while no expression of CD45, CD34 and MHC2 was detected. Molecular profiling showed expression of CD105 and CD73 in all MSC. Low levels of SOX2 mRNA was observed in all MSC, while neither NANOG, nor OCT4 were detected. All MSC differentiate into 3 mesodermal lineages. Following inflammatory stimulation, the activity of the immunomodulatory enzyme IDO was significantly higher in neonatal MSC compared to BM-MSC (p=0.009). Our results show that canine foetal adnexa cells share very similar properties to their adult equivalents but upon stimulation show significantly higher IDO immunomodulatory activity. Further studies will be needed to confirm the potential therapeutic benefits of these cells. PMID- 26964716 TI - Effects of heat stress on the formation of splenic germinal centres and immunoglobulins in broilers infected by Clostridium perfringens type A. AB - Avian necrotic enteritis (NE) induced by Clostridium perfringens is a disease that affects mainly the first weeks of poultry's life. The pathogenesis of NE is complex and involves the combination of several factors, such as co-infection with different species of coccidia, immunosuppression and stress. Stress is one of the main limiting factors in poultry production. Although several studies emphasized the effects of stress on immunity, few works analyzed these effects on immunoglobulins and on germinal centres (GCs), which are specialized microenvironments, responsible for generating immune cells with high affinity antibodies and memory B-lymphocytes. Thus, the effects of heat stress associated or not with thioglycolate broth culture medium intake and/or C. perfringens infection on corticosterone serum levels, spleen GCs development and immunoglobulin production in broilers were evaluated. Results showed that heat stress, thioglycolate and C. perfringens per se increased corticosterone serum levels, although this was not observed in heat stressed and thioglycolate and C. perfringens-treated chickens. The serum levels of IgA, IgM and IgY were differently affected by heat stress and/or infection/thioglycolate. Heat stress decreased the duodenal concentrations of sIgA, which was accompanied by a reduction in GCs number in the duodenal lamina propria; a trend to similar findings of sIgA concentrations was observed in the chickens' jejunum. Changes in spleen and Bursa of Fabricius relative weights as well as in spleen morphometry were also noted in heat stressed animals, infected or not. Together, these data suggest that heat stress change GCs formation in chickens infected or not, which that may lead to failures in vaccination protocols as well as in the poultries' host resistance to infectious diseases during periods of exposure to heat stress. PMID- 26964718 TI - Effect of inflammatory environment on equine bone marrow derived mesenchymal stem cells immunogenicity and immunomodulatory properties. AB - Mesenchymal stem cells (MSCs) are being investigated for the treatment of equine joint diseases because of their regenerative potential. Recently, the focus mainly has addressed to their immunomodulatory capacities. Inflammation plays a central role in joint pathologies, since the release of proinflammatory mediators to the synovial fluid (SF) leads to the activation of enzymatic degradation of the cartilage. MSCs can modulate the local immune environment through direct or paracrine interaction with immune cells, suppressing their proliferation and re addressing their functions. Proinflammatory molecules can induce MSC immunoregulatory potential, but they could also increase the expression of immunogenic molecules. Studying the effect of inflammatory environment on MSC immunomodulation and immunogenicity profiles is mandatory to improve cellular therapies. The aim of this study was to analyse the response of equine bone marrow MSCs (eBM-MSCs) to three inflammatory conditions. Equine BM-MSCs from three animals were exposed to: (a) 20% allogeneic inflammatory SF (SF); (b) 50 ng/ml of TNFalpha and IFNgamma (CK50) and (c) 20 ng/ml of TNFalpha and IFNgamma (CK20). After 72 h of exposure, expression of immunogenic and immunomodulation related molecules, including cell-to-cell contact and paracrine signalling molecules, were analysed by RT-qPCR and flow cytometry. The gene expression of adhesion molecules was upregulated whereas MSC migration-related genes were downregulated by all inflammatory conditions tested. CK culture conditions significantly upregulated the expression of COX-2, iNOS, IDO and IL-6. MHC-I gene expression was upregulated by all conditions, whereas MHC-II was upregulated only after CK priming. The expression of CD40 did not significantly change, whereas the ligand, CD40L, was downregulated in CK conditions. Flow cytometry showed an increase in the percentage of positive cells and mean fluorescence intensity (MFI) of the MHC-I and MHC-II molecules at CK50 conditions, supporting the gene expression results. These outcomes reinforce the change of the immunophenotype of the eBM-MSCs according to the surrounding conditions. Inflammatory synovial environment did not lead to significant changes, so the environment found by eBM MSCs when they are intraarticular administered may not be enough to activate their immunomodulatory potential. CK priming at tested doses enhances the immunoregulatory profile of eBM-MSCs, which may promote a therapeutic benefit. Even if CK priming induced an upregulation of MHC expression, costimulatory molecule expression however was not upregulated, suggesting that immunogenicity might not be increased. This study provides a better understanding about the behaviour of eBM-MSCs inside the inflamed joint and constitutes a first step to improve MSC-based therapies for equine joint diseases. PMID- 26964720 TI - Gilthead seabream (Sparus aurata) Mx gene promoters respond differentially to IPNV and VHSV infections in RTG-2 cells. AB - The understanding of virus-host interactions relies on the knowledge of the regulatory mechanisms of the type I interferon (IFN I)-stimulated genes (ISGs). Among ISGs, those coding Mx proteins play a main role due to their direct antiviral activity. The study of these genes in gilthead seabream is interesting, since this species displays high natural resistance to viral diseases, being asymptomatic carrier of infectious pancreatic necrosis virus (IPNV) and viral haemorrhagic septicaemia virus (VHSV). Gilthead seabream has three Mx genes (Mx1, Mx2, and Mx3), encoding proteins with a wide spectrum of antiviral activity. The structure of the three promoters (pMx1, pMx2 and pMx3) has been previously disclosed, and their response to poly I:C in RTG-2 cells characterized. To further analyze these promoters, their response to two viral infections has been evaluated in the present study. For that purpose, RTG-2 cells transiently transfected with the luciferase gene under the control of each promoter were inoculated with either IPNV or VHSV at two different doses. The highest and lowest fold induction values were recorded for pMx2 and pMx3, respectively. The promoter induction was always stronger after VHSV inoculation than in IPNV inoculated cells. In addition, the higher dose of VHSV tested induced higher response of the three promoters, whereas in IPNV-infected cells the highest induction was recorded after inoculation with the lower viral dose. To further study the response of the Mx2 promoter, RTG-2 cells stably transfected with the luciferase gene under the control of pMx2 were stimulated with poly I:C and subsequently infected with IPNV or VHSV. Interestingly, IPNV infection inhibited the induction caused by poly I:C, suggesting an antagonistic activity of IPNV on Mx2 transcription. In contrast, VHSV infection did not alter the response triggered by poly I:C. These results highlight the specific regulation that controls the activity of each promoter, and support the existence of complex interactions between host cells, specific Mx promoters, and viruses, which are responsible for the final outcome of a viral infection. PMID- 26964719 TI - Oxidative stress in hoof laminar tissue of horses with lethal gastrointestinal diseases. AB - Tissue damage caused by oxidative stress is involved in the pathogenesis of several diseases in animals and man, and is believed to play a role in the development of laminitis in horses. The aim of this study was to investigate the oxidative stress associated with laminar lesions in horses with lethal gastrointestinal disorders. Laminar tissue samples of the hoof of 30 horses were used. Tissue samples were divided as follows: six healthy horses (control group CG), and 24 horses that died after complications of gastrointestinal diseases (group suffering from gastrointestinal disorders-GDG). Superoxide dismutase (SOD2) and nitrotyrosine immunostaining and the severity of laminar lesions were evaluated. Presence of laminar lesions and immunostaining for nitrotyrosine and SOD2 were only evident in horses from the GDG group. Thus, oxidative stress may play a role in the pathogenesis of laminar lesions secondary to gastrointestinal disorders. PMID- 26964721 TI - A review of the basis of the immunological diagnosis of ruminant brucellosis. AB - Bacteria of the genus Brucella cause brucellosis, the most common bacterial zoonosis worldwide. The diagnosis of Brucella abortus and Brucella melitensis ruminant brucellosis is based on bacteriological and immunological tests, the latter being routinely used in control and eradication and surveillance programs. Infections by smooth and rough Brucella spp., the use of smooth and rough vaccines, and the false-positive serological reactions caused by Yersinia enterocolitica O:9 and other cross-reacting bacteria represent the immunological contexts in which those tests are used. This complex context explains the large number of brucellosis tests that have been developed, and that vary in antigen type, antigen presentation, antibody and conditions for the reaction, the response detected and the sample required. This wealth of information and an imperfect understanding of Brucella antigens and of the peculiarities of the immunoresponse to Brucella has created confusion and led to several misconceptions on the usefulness and limitations of the brucellosis diagnostic tests. In this review, Brucella antigens are examined focusing on cellular topology, supramolecular properties, epitopic structure and lipopolysaccharide and protein cross-reactivity in the various contexts of the immune response in ruminants. Then, the significance of these features in diagnostic tests that use whole bacteria is discussed with respect to the activities of ruminant immunoglobulins, and the effect of pH on unspecific agglutinations, non agglutinating and blocking antibodies, pseudo-prozones and complement activation. Similarly, the bacterial surface lipopolysaccharides and cognate polysaccharides are discussed with regards to topological effects, epitope exposure, ionic strength and antibody avidity in immunoprecipitation, immunosorbent and fluorescence polarization assays. Finally, the search for immunodominant protein antigens and their use in immunological tests is reviewed. Critical review of the existing information is necessary both to select optimal tests according to the logistical means available and the epidemiological context, and to focus the development of new tests. PMID- 26964722 TI - Recombinant Mycoplasma mycoides proteins elicit protective immune responses against contagious bovine pleuropneumonia. AB - Mycoplasma mycoides subsp. mycoides (Mmm) is the causative agent of contagious bovine pleuropneumonia (CBPP), a devastating respiratory disease mainly affecting cattle in sub-Saharan Africa. The current vaccines are based on live-attenuated Mmm strains and present problems with temperature stability, duration of immunity and adverse reactions, thus new vaccines are needed to overcome these issues. We used a reverse vaccinology approach to identify 66 Mmm potential vaccine candidates. The selection and grouping of the antigens was based on the presence of specific antibodies in sera from CBPP-positive animals. The antigens were used to immunize male Boran cattle (Bos indicus) followed by a challenge with the Mmm strain Afade. Two of the groups immunized with five proteins each showed protection after the Mmm challenge (Groups A and C; P<0.05) and in one group (Group C) Mmm could not be cultured from lung specimens. A third group (Group N) showed a reduced number of animals with lesions and the cultures for Mmm were also negative. While immunization with some of the antigens conferred protection, others may have increased immune-related pathology. This is the first report that Mmm recombinant proteins have been successfully used to formulate a prototype vaccine and these results pave the way for the development of a novel commercial vaccine. PMID- 26964723 TI - Severe sensitivity loss in an influenza A molecular assay due to antigenic drift variants during the 2014/15 influenza season. AB - The 2014-2015 influenza season in Belgium was dominated by the circulation of 2 influenza A(H3N2) subgroups: 3C.2a and 3C.3b. Analysis of 166 nasopharyngeal aspirates, collected in patients with respiratory illness at the start of the epidemic season, showed a decreased sensitivity for the detection of influenza A(H3N2)/3C.2a using a commercially available multiplex assay. Gene sequencing of the matrix protein showed a point mutation (C163T) leading to a mismatch with the assay probes. PMID- 26964724 TI - Bacteria-host relationship: ubiquitin ligases as weapons of invasion. AB - Eukaryotic cells utilize the ubiquitin (Ub) system for maintaining a balanced functioning of cellular pathways. Although the Ub system is exclusive to eukaryotes, prokaryotic bacteria have developed an armory of Ub ligase enzymes that are capable of employing the Ub systems of various hosts, ranging from plant to animal cells. These enzymes have been acquired through the evolution and can be classified into three main classes, RING (really interesting new gene), HECT (homologous to the E6-AP carboxyl terminus) and NEL (novel E3 ligases). In this review we describe the roles played by different classes of bacterial Ub ligases in infection and pathogenicity. We also provide an overview of the different mechanisms by which bacteria mimic specific components of the host Ub system and outline the gaps in our current understanding of their functions. Additionally, we discuss approaches and experimental tools for validating this class of enzymes as potential novel antibacterial therapy targets. PMID- 26964725 TI - Repetitive Transcranial Magnetic Stimulation Educes Frequency-Specific Causal Relationships in the Motor Network. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has the potential to treat brain disorders by modulating the activity of disease-specific brain networks, yet the rTMS frequencies used are delivered in a binary fashion - excitatory (>1 Hz) and inhibitory (<=1 Hz). OBJECTIVE: To assess the effective connectivity of the motor network at different rTMS stimulation rates during positron-emission tomography (PET) and confirm that not all excitatory rTMS frequencies act on the motor network in the same manner. METHODS: We delivered image-guided, supra-threshold rTMS at 3 Hz, 5 Hz, 10 Hz, 15 Hz and rest (in separate randomized sessions) to the primary motor cortex (M1) of the lightly anesthetized baboon during PET imaging. Each rTMS/PET session was analyzed using normalized cerebral blood flow (CBF) measurements. Path analysis - using structural equation modeling (SEM) - was employed to determine the effective connectivity of the motor network at all rTMS frequencies. Once determined, the final model of the motor network was used to assess any differences in effective connectivity at each rTMS frequency. RESULTS: The exploratory SEM produced a very well fitting final network model (chi(2) = 18.04, df = 21, RMSEA = 0.000, p = 0.647, TLI = 1.12) using seven nodes of the motor network. 5 Hz rTMS produced the strongest path coefficients in four of the seven connections, suggesting that this frequency is the optimal rTMS frequency for stimulation the motor network (as a whole); however, the premotor cerebellum connection was optimally stimulated at 10 Hz rTMS and the supplementary motor area caudate connection was optimally driven at 15 Hz rTMS. CONCLUSION(S): We have demonstrated that 1) 5 Hz rTMS revealed the strongest path coefficients (i.e. causal influence) on the nodes of the motor network, 2) stimulation at "excitatory" rTMS frequencies did not produce increased CBF in all nodes of the motor network, 3) specific rTMS frequencies may be used to target specific none-to-node interactions in the stimulated brain network, and 4) more research needs to be performed to determine the optimum frequency for each brain circuit and/or node. PMID- 26964726 TI - Predictive value of serum dihomo-gamma-linolenic acid level and estimated Delta-5 desaturase activity in patients with hepatic steatosis. AB - BACKGROUND: Hepatic steatosis is considered one of the features of metabolic syndrome (MetS). Polyunsaturated fatty acid (PUFA) metabolism is modulated in obesity. However, it has yet to be fully elucidated whether a serum PUFA profile is associated with hepatic steatosis. OBJECTIVE: We aimed to clarify the relationship between a serum PUFA profile and liver lipid content. METHODS: A cross-sectional study was conducted on 288 patients with dyslipidemia, diabetes, or coronary artery disease on statin therapy. Several PUFAs were measured, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), dihomo-gamma linolenic acid (DGLA) and arachidonic acid (AA) in serum lipids, and Delta-5 desaturase (D5D) activity was estimated by AA to DGLA ratio. Abdominal computed tomography (CT) measured visceral fat area (VFA) and the ratio of CT attenuation for liver to spleen (L/S). RESULTS: The L/S ratio showed significant correlations with serum DGLA level and D5D activity (p<0.0001 for both). Serum DGLA level and D5D activity were significantly correlated with body mass index (BMI) or VFA, and with Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) (p<0.0001 for all). Multivariate logistic analysis revealed that a high DGLA level or low D5D activity was a significant determinant for hepatic steatosis (p<0.0001 for both) independent of BMI and HOMA-IR. ROC analysis revealed that they significantly enhanced the value of MetS-related factors in predicting hepatic steatosis (p<0.05 for both). CONCLUSIONS: A high DGLA level and low D5D activity in serum lipids may be useful markers predicting hepatic steatosis incrementally to MetS related conventional factors. PMID- 26964727 TI - The Etiology and Clinical Features of Non-CAH Gonadotropin-Independent Precocious Puberty: A Multicenter Study. AB - AIM: The causes of gonadotropin-independent precocious puberty are diverse, and often have overlapping clinical and biochemical features. With the exception of congenital adrenal hyperplasia (CAH), disorders that cause gonadotropin independent precocious puberty (GIPP) are uncommon. The literature is devoid of any large-scale studies on the etiologic distribution of GIPP. The aim of this study was to determine the frequency of each etiology in a cohort of patients with GIPP (excluding those with CAH), and to evaluate the clinical and laboratory features of these patients. MATERIALS AND METHODS: This multicenter, nationwide web-based study collected data on patients who presented with non-CAH GIPP in Turkey. RESULTS: Data were collected for 129 patients (102 girls and 27 boys) from 29 centers. Based on the data collected, the estimated prevalence of non-CAH GIPP in the studied population was 14 in 1 000 000 children. Functional ovarian cyst was the most common etiology, accounting for 37% of all cases, followed by McCune-Albright syndrome (MAS) (26%). Among the patients with MAS, 11.7% had fibrous dysplasia, 32.3% had cafe-au-lait spots, and 52.9% had both. Human chorionic gonadotrophin-secreting tumors included choriocarcinoma of the liver, hepatoblastoma, and germ cell tumors of the sellar-suprasellar region and mediastinum. Patients with adrenocortical tumors presented at an earlier age than those with other etiologies. Ovarian tumors included mature cystic teratoma, dysgerminoma, juvenile granulosa tumor, and steroid cell tumor. Despite overlapping features, it was possible to identify some unique clinical and laboratory features associated with each etiology. CONCLUSION: This largest cohort of patients with non-CAH GIPP to date yielded an estimation of the frequency of non-CAH GIPP in the general pediatric population and showed that girls were affected at a rate 4-fold greater than that of boys owing to functional ovarian cysts and MAS, which were the two most common etiologies. The data collected also provided some unique characteristics associated with each etiology. PMID- 26964728 TI - Defining Hyperandrogenism in Women With Polycystic Ovary Syndrome: A Challenging Perspective. AB - OBJECTIVE: This study was designed to assess the steroid profiling by liquid chromatography coupled with tandem mass spectrometry in PCOS women with different phenotypes. DESIGN: Cross-sectional study. SETTING: University hospital of Bologna, Italy. PATIENTS AND METHODS: A total of 156 PCOS women and 141 controls comparable for age were investigated. All underwent a steroid profiling by liquid chromatography coupled with tandem mass spectrometry. Metabolic parameters were also investigated and hirsutism was measured by the modified Ferriman-Gallwey (mF G) score. RESULTS: Three distinct phenotypes were initially defined according to the combination of hirsutism (mF-G >= 8) and/or high testosterone (T) (HA), oligo amenorrhea (OA), and polycystic ovarian morphology (PCOm); OA + PCOm (n = 43), HA + OA (n = 65), and HA + OA + PCOm (n = 45). T, androstenedione (A), and free androgen index (FAI) levels progressively increased in the 3 PCOS phenotypes with respect to the controls, with the highest values in the HA + OA + PCOm phenotype. The various combinations of hirsutism, high T, high A, and high FAI made it possible to categorize the 3 original phenotypes into 8 hyperandrogenic subgroups, characterized by divergent additional steroid profile and metabolic pattern. A total of 90% of patients with PCOS thus proved hyperandrogenic. Interestingly, half the PCOS women originally classified as having the OA-PCOm phenotype were categorized in a hyperandrogenic subgroup. No significant correlation was found between T, A, and the mF-G score. In contrast, significant correlation was found between A and both T and FAI. CONCLUSIONS: This study provides evidence that, by including a steroid profile in the definition of hyperandrogenemia, the majority of women with PCOS are hyperandrogenic, although a clinical and biochemical heterogeneity exists. In addition, these data demonstrate that hirsutism and high androgen levels cannot be used indifferently to define hyperandrogenism. PMID- 26964729 TI - Differential Effects of Oral and Intravenous Lipid Administration on Key Molecules Related to Energy Homeostasis. AB - CONTEXT: The spectrum of lipid-induced changes in the secretion of hormones important in energy homeostasis has not yet been fully elucidated. OBJECTIVE: To identify potential incretin-like effects in response to lipid administration, we examined the short-term effect of iv vs oral lipids on key molecules regulating energy homeostasis. Design, Intervention, and Participants: After a 10-hour overnight fast, 26 subjects were randomized to receive an oral lipid load, a 10% iv lipid emulsion, a 20% iv lipid emulsion, or an iv saline infusion. We obtained blood samples at 30-minute intervals for the first 2 hours and hourly thereafter for a total of 6 hours. MAIN OUTCOME MEASURES: Circulating levels of insulin, glucose, c-peptide, free fatty acids, incretins (glucagon-like peptide-1, gastric inhibitory polypeptide), glucagon, peptide YY, ghrelin, fibroblast growth factor 21, fetuin A, irisin, omentin, and adiponectin were measured. RESULTS: Oral lipid ingestion resulted in higher glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon, and peptide YY levels, compared with the other three groups (incremental area under the curve P = .003, P < .001, P < .001, P < .001, respectively). The 20% lipid emulsion, leading to higher free fatty acid levels, resulted in greater insulin, c-peptide, and fibroblast growth factor 21 responses compared with placebo and the other two groups (incremental area under the curve P = .002, P = .005, P < .001, P < .001, respectively). Omentin, adiponectin, fetuin A, and irisin levels were not affected by either mode of lipid administration. CONCLUSIONS: Metabolic responses to lipids depend on the route of administration. Only iv lipids trigger a dose-dependent fibroblast growth factor 21 secretion, which is nonglucagon mediated. Intravenous lipids also induce hyperinsulinemia without concurrent decreases in glucose, a phenomenon observed in insulin-resistant states. Orally administered lipids mostly affect gastrointestinal tract-secreted molecules important in glucose and energy homeostasis such as glucagon, incretins, and peptide YY. PMID- 26964730 TI - PDE5 Inhibition Ameliorates Visceral Adiposity Targeting the miR-22/SIRT1 Pathway: Evidence From the CECSID Trial. AB - CONTEXT: Visceral adiposity plays a significant role in cardiovascular risk. PDE5 inhibitors (PDE5i) can improve cardiac function and insulin sensitivity in type 2 diabetes patients. OBJECTIVE: To investigate whether PDE5i affect visceral adipose tissue (VAT), specifically epicardial fat (epicardial adipose tissue [EAT]), and what mechanism is involved, using microarray-based profiling of pharmacologically modulated microRNA (miRNAs). DESIGN: Randomized, double-blind, placebo-controlled study in type 2 diabetes. PATIENTS AND INTERVENTION: A total of 59 diabetic patients were randomized to receive 100-mg/d sildenafil or placebo for 12 weeks. Fat biopsies were collected in a subgroup of patients. In a parallel protocol, db/db mice were randomized to 12 weeks of sildenafil or vehicle, and VAT was collected. MAIN OUTCOME AND MEASURES: Anthropometric and metabolic parameters, EAT quantification through cardiac magnetic resonance imaging, array of 2005 circulating miRNAs, quantitative PCR, and flow cytometry of VAT. RESULTS: Compared with placebo, sildenafil reduced waist circumference (P = .024) and EAT (P = .045). Microarray analysis identified some miRNAs differentially regulated by sildenafil, including down-regulation of miR-22-3p, confirmed by real-time quantitative PCR (P < .001). Sildenafil's modulation of miR-22-3p expression was confirmed in vitro in HL1 cardiomyocytes. Up-regulation of SIRT1, a known target of miR-22-3p, was found in both serum and sc fat in sildenafil-treated subjects. Compared with vehicle, 12-week sildenafil treatment down-regulated miR-22-3p and up-regulated Sirtuin1 (SIRT1) gene expression in VAT from db/db mice, shifting adipose tissue cell composition toward a less inflamed profile. CONCLUSIONS: Treatment with PDE5i in humans and murine models of diabetes improves VAT, targeting SIRT1 through a modulation of miR-22-3p expression. PMID- 26964731 TI - Effects of Two Years of Teriparatide, Denosumab, or Both on Bone Microarchitecture and Strength (DATA-HRpQCT study). AB - CONTEXT: In postmenopausal osteoporosis, combining denosumab and teriparatide increases hip and spine bone mineral density more than either monotherapy. OBJECTIVE: The objective of the study was to determine the effects of 2 years of combination therapy on bone microarchitecture and estimated strength. DESIGN: This was an open-label, randomized controlled trial. PARTICIPANTS AND METHODS: We performed high-resolution peripheral quantitative computed tomography at the distal tibia and radius in 94 postmenopausal osteoporotic women randomized to 2 years of teriparatide 20 MUg sc daily, denosumab 60 mg sc every 6 months, or both. RESULTS: Total volumetric bone mineral density (vBMD) at the radius and tibia, trabecular vBMD at the radius, and cortical vBMD at the tibia all increased more in the combination group than both monotherapy groups (P < .002 for all comparisons with combination). Cortical thickness at the tibia also increased more in the combination group (8.1% +/- 4.3%) than both other groups (P < .001). Cortical porosity at both the radius and tibia increased progressively over the 24-month treatment period in the teriparatide group but was stable in both other groups (P < .001 teriparatide vs both other groups). Trabecular vBMD at the tibia increased similarly in all groups, whereas radius trabecular vBMD increased more in the combination group than the other groups (P < .01 for both comparisons). Finite element analysis-estimated strength improved or was maintained by all treatments at both the radius and tibia. CONCLUSIONS: Two years of combined teriparatide and denosumab improves bone microarchitecture and estimated strength more than the individual treatments, particularly in cortical bone. These findings suggest that this regimen may be beneficial in postmenopausal osteoporosis. PMID- 26964732 TI - Thyroid Stimulating Antibodies Are Highly Prevalent in Hashimoto's Thyroiditis and Associated Orbitopathy. AB - CONTEXT: Thyroid-associated orbitopathy (TAO) rarely occurs in patients with Hashimoto's thyroiditis (HT). OBJECTIVE: There is evidence that TSH receptor stimulating antibodies (TSAb) play a role in the pathogenesis of TAO. In this report, the prevalence of TSAb in HT patients with and without TAO was studied. DESIGN: This is a longitudinal observational study. SETTING: The study took place in an academic joint thyroid-eye clinic. SUBJECTS: A total of 1055 subjects were included. METHODS: TSAb was measured with a Food and Drug Administration-cleared bioassay that uses Chinese hamster ovary cells expressing a chimeric TSH receptor and a cAMP response element-dependent luciferase. Results of TSAb activity were reported as percentage of specimen-to-reference ratio (SRR%, cutoff >140%). MAIN OUTCOME MEASURE: We measured the association of TSAb with the risk of TAO in patients with HT. RESULTS: Of 700 consecutive and unselected patients with HT, 44 (6%) had overt TAO. Patients with HT+TAO were older (P < .001), heavier smokers (P = .032), and clustered less with autoimmune diseases (P = .005). All healthy controls were TSAb negative. In contrast, serum was TSAb positive in 30/44 (68.2%) and 36/656 (5.5%, P < .001) patients with HT+TAO and HT, respectively. Compared to patients with HT only, serum TSAb levels were higher in HT+TAO (median SRR%, 25th and 75th percentiles): 45, 35-65 vs 192.5, 115-455.3, P < .001. Highest TSAb values were noted in patients with active and severe TAO vs those with mild and inactive TAO: 486, 392-592 vs 142, 73-192.5; P < .001. The odds ratio of TSAb positivity for the risk of TAO adjusted for gender and age was 55.9 (95% confidence interval [CI], 24.6-127, P < .0001), whereas the odds ratio per 10-fold change in TSAb SRR% (quantitative TSAb) was 133 (95% CI, 45-390, P < .0001). The area under the receiver operating characteristic curve for qualitative and quantitative TSAb was 87.2% (95% CI, 80.6-93.8) and 89.4% (95% CI, 84.1-94.7), respectively. CONCLUSIONS: TSAb is strongly associated with TAO in HT and TSAb may contribute to the pathophysiology of TAO. PMID- 26964734 TI - CORRIGENDUM. PMID- 26964733 TI - Puberty and Pubertal Growth in GH-treated SGA Children: Effects of 2 Years of GnRHa Versus No GnRHa. AB - CONTEXT: Most studies on puberty in children born small for gestational age (SGA) report height and age at onset of puberty. GH-treated SGA children with an adult height (AH) expectation below -2.5 SDS at onset of puberty can benefit from an additional 2 years of GnRH analog (GnRHa) treatment. There are no data on puberty and growth after discontinuation of GnRHa treatment in GH-treated SGA children. OBJECTIVE: This study aimed to investigate the effects on puberty and pubertal growth of 2 years GnRHa vs no GnRHa in GH-treated SGA children. METHODS: This was a GH trial involving 76 prepubertal short SGA children (36 girls) treated with GH. Thirty-two children received additional GnRHa for 2 years. Pubertal stages were 3-monthly assessed according to Tanner. RESULTS: Age, bone age, and median height at pubertal onset were lower in girls and boys in the GH/GnRHa group compared with the GH group. In girls and boys treated with GH/GnRHa, pubertal duration after stop of GnRHa treatment was shorter than pubertal duration in those with GH only (40.9 vs 46.7 mo; P = .044; 50.8 vs 57.5 months; P = .006; respectively). Height gain from onset of puberty until AH, including height gain during 2 years of GnRHa treatment, was 25.4 cm in girls and 33.0 cm in boys, which was 6.6 cm more than girls and boys treated with GH only. AH was similar in children treated with GH/GnRHa compared with those with GH only. CONCLUSIONS: GH treated SGA children who start puberty with an AH expectation below -2.5 SDS and are treated with 2 years of GnRHa have a shorter pubertal duration after discontinuation of GnRHa compared with pubertal duration in children treated with GH only. Height gain from onset of puberty until AH is, however, more due to adequate growth during 2 years of GnRHa treatment resulting in a similar AH as children treated with GH only. PMID- 26964735 TI - Co3O4-SnO2 Hollow Heteronanostructures: Facile Control of Gas Selectivity by Compositional Tuning of Sensing Materials via Galvanic Replacement. AB - Co3O4 hollow spheres prepared by ultrasonic spray pyrolysis were converted into Co3O4-SnO2 core-shell hollow spheres by galvanic replacement with subsequent calcination at 450 degrees C for 2 h for gas sensor applications. Gas selectivity of the obtained spheres can be controlled by varying the amount of SnO2 shells (14.6, 24.3, and 43.3 at. %) and sensor temperatures. Co3O4 sensors possess an ability to selectively detect ethanol at 275 degrees C. When the amount of SnO2 shells was increased to 14.6 and 24.3 at. %, highly selective detection of xylene and methylbenzenes (xylene + toluene) was achieved at 275 and 300 degrees C, respectively. Good selectivity of Co3O4 hollow spheres to ethanol can be explained by a catalytic activity of Co3O4; whereas high selectivity of Co3O4-SnO2 core-shell hollow spheres to methylbenzenes is attributed to a synergistic effect of catalytic SnO2 and Co3O4 and promotion of gas sensing reactions by a pore-size control of microreactors. PMID- 26964736 TI - Endogenously-expressed NH2-terminus of circumsporozoite protein interferes with sporozoite invasion of mosquito salivary glands. AB - BACKGROUND: The circumsporozoite protein is the most abundant polypeptide expressed by sporozoites, the malaria parasite stage capable of infecting humans. Sporozoite invasion of mosquito salivary glands prior to transmission is likely mediated by a receptor/ligand-like interaction of the parasites with the target tissues, and the amino (NH2)-terminal portion of CSP is involved in this interaction but not the TSR region on the carboxyl (C)-terminus. Peptides based on the NH2-terminal domain could compete with the parasites for the salivary gland receptors and thus inhibit penetration. METHODS: Peptides based on the NH2 terminus and TSR domains of the CSP from avian or human malaria parasites, Plasmodium gallinaceum and Plasmodium falciparum, respectively, were expressed endogenously in mosquito haemolymph using a transient (Sindbis virus-mediated) or stable (piggyBac-mediated transgenesis) system. RESULTS: Transient endogenous expression of partial NH2-terminus peptide from P. falciparum CSP in P. gallinaceum-infected Aedes aegypti resulted in a reduced number of sporozoites in the salivary glands. When a transgenic approach was used to express a partial CSP NH2-terminal domain from P. gallinaceum the number of sporozoites in the salivary glands did not show a difference when compared to controls. However, a significant difference could be observed when mosquitoes with a lower infection were analysed. The same result could not be observed with mosquitoes endogenously expressing peptides based on the TSR domain from either P. gallinaceum or P. falciparum. CONCLUSION: These results support the conclusion that CSP partial NH2 terminal domain can be endogenously expressed to promote a competition for the receptor used by sporozoites to invade salivary glands, and they could be used to block this interaction and reduce parasite transmission. The same effect cannot be obtained with peptides based on the TSR domain. PMID- 26964737 TI - Predictors of early versus late mortality in pelvic trauma patients. AB - BACKGROUND: Risks of predicting time-related in-hospital mortality varies in pelvic trauma patients. We aim to identify potential independent risks predictive of time-related (early versus late) mortality among pelvic trauma patients. METHODS: Local trauma registry data from 2004 through 2013 were reviewed. Mortality causes and timing of death were investigated. Multivariate logistic regression identified independent risks predictive of early versus late mortality in pelvic trauma patients while adjusting for patient demographics (age, sex, race), clinical variables (initial vital signs, mental status, injury severity, associated injuries, comorbidities), and hospital outcomes (surgical interventions, crystalloid resuscitations, blood transfusions). RESULTS: We retrospectively collected data on 1566 pelvic trauma patients with a mortality rate of 9.96% (156/1566). Approximately 74% of patients died from massive hemorrhage within the first 24 h of hospitalization (early mortality). Revised trauma score (RTS), injury severity score (ISS), initial hemoglobin, direct transfer to operating room, and blood transfusion administration in the Emergency Department were considered independent risk factors predictive of early mortality. Age, ISS, and Glasgow Coma Scale (GCS) were deemed risk factors predictive of death after 24 h (late mortality). DISCUSSION: Given the fact of a substantial number of patients died within the first 24 h of hospital arrival, it is reasonable to consider the first 24 h of hospitalization as the appropriate window within which early mortality may be expected to occur in pelvic trauma patients. The risk factors associated with massive hemorrhage were strong predictors of early mortality, whereas late mortality predictors were more closely linked with comorbidities or in-hospital complications. CONCLUSIONS: While risk factors predictive of early versus late mortality vary, ISS seems to predict both early and late mortality accurately in pelvic trauma patients. PMID- 26964740 TI - Atypical leptospirosis: an overlooked cause of aseptic meningitis. AB - BACKGROUND: Leptospirosis, probably the most common zoonosis in the world, is caused by pathogenic Leptospira species. Clinical presentations range from nonspecific fevers to fulminant diseases such as Weil's syndrome. Neurological forms of leptospirosis (neuroleptospirosis) are usually underestimated, and many cases of leptospirosis are overlooked because of the lack of specificity of signs and symptoms. Diagnosis confirmation is difficult because of the challenges associated with isolating the organism and positive serologic testing. A comprehensive understanding of the clinical presentation of leptospirosis and risk factors for exposure to leptospirae are required for early diagnosis, in order to initiate appropriate treatment immediately. CASE PRESENTATION: Here we present one male patient with anicteric leptospirosis that manifested as neuroleptospirosis with aseptic meningitis, although he did not have impaired kidney function or thrombocytopenia. He recovered well after an early investigation and treatment for leptospirosis based on suspected relevant risk factors and clinical manifestations. CONCLUSION: To facilitate optimal use of antibiotic treatments and prevent lethal complications of leptospirosis, we report this case of leptospirosis, which highlights the importance of knowing the occupational history and environmental exposures of patients living in leptospirosis-endemic areas and presenting meningeal signs. PMID- 26964739 TI - Dynamic modulation of phosphoprotein expression in ovarian cancer xenograft models. AB - BACKGROUND: The dynamic changes that occur in protein expression after treatment of a cancer in vivo are poorly described. In this study we measure the effect of chemotherapy over time on the expression of a panel of proteins in ovarian cancer xenograft models. The objective was to identify phosphoprotein and other protein changes indicative of pathway activation that might link with drug response. METHODS: Two xenograft models, platinum-responsive OV1002 and platinum unresponsive HOX424, were used. Treatments were carboplatin and carboplatin paclitaxel. Expression of 49 proteins over 14 days post treatment was measured by quantitative immunofluorescence and analysed by AQUA. RESULTS: Carboplatin treatment in the platinum-sensitive OV1002 model triggered up-regulation of cell cycle, mTOR and DDR pathways, while at late time points WNT, invasion, EMT and MAPK pathways were modulated. Estrogen receptor-alpha (ESR1) and ERBB pathways were down-regulated early, within 24 h from treatment administration. Combined carboplatin-paclitaxel treatment triggered a more extensive response in the OV1002 model modulating expression of 23 of 49 proteins. Therefore the cell cycle and DDR pathways showed similar or more pronounced changes than with carboplatin alone. In addition to expression of pS6 and pERK increasing, components of the AKT pathway were modulated with pAKT increasing while its regulator PTEN was down regulated early. WNT signaling, EMT and invasion markers were modulated at later time points. Additional pathways were also observed with the NFkappaB and JAK/STAT pathways being up-regulated. ESR1 was down-regulated as was HER4, while further protein members of the ERBB pathway were upregulated late. By contrast, in the carboplatin-unresponsive HOX 424 xenograft, carboplatin only modulated expression of MLH1 while carboplatin-paclitaxel treatment modulated ESR1 and pMET. CONCLUSIONS: Thirteen proteins were modulated by carboplatin and a more robust set of changes by carboplatin-paclitaxel. Early changes included DDR and cell cycle regulatory proteins associating with tumor volume changes, as expected. Changes in ESR1 and ERBB signaling were also observed. Late changes included components of MAPK signaling, EMT and invasion markers and coincided in time with reversal in tumor volume reduction. These results suggest potential therapeutic roles for inhibitors of such pathways that may prolong chemotherapeutic effects. PMID- 26964741 TI - An efficient design strategy for logistic regression using outcome- and covariate dependent pooling of biospecimens prior to assay. AB - Potential reductions in laboratory assay costs afforded by pooling equal aliquots of biospecimens have long been recognized in disease surveillance and epidemiological research and, more recently, have motivated design and analytic developments in regression settings. For example, Weinberg and Umbach (1999, Biometrics 55, 718-726) provided methods for fitting set-based logistic regression models to case-control data when a continuous exposure variable (e.g., a biomarker) is assayed on pooled specimens. We focus on improving estimation efficiency by utilizing available subject-specific information at the pool allocation stage. We find that a strategy that we call "(y,c)-pooling," which forms pooling sets of individuals within strata defined jointly by the outcome and other covariates, provides more precise estimation of the risk parameters associated with those covariates than does pooling within strata defined only by the outcome. We review the approach to set-based analysis through offsets developed by Weinberg and Umbach in a recent correction to their original paper. We propose a method for variance estimation under this design and use simulations and a real-data example to illustrate the precision benefits of (y,c)-pooling relative to y-pooling. We also note and illustrate that set-based models permit estimation of covariate interactions with exposure. PMID- 26964742 TI - Elective implant removal in symptomatic patients after internal fixation of proximal humerus fractures improves clinical outcome. AB - BACKGROUND: Operative treatment is the standard for severely displaced proximal humerus fractures, but functional impairment can persist. Retaining of the implant can be a reason and in other fracture situations has proved to ameliorate patient satisfaction. The aim of this study was to analyse the functional outcome after locking plate removal in proximal humerus fractures. METHODS: In a two-year period, all symptomatic patients with plate osteosynthesis for proximal humerus fracture and hardware removal were retrospectively evaluated clinically and radiologically pre- and post-implant removal. Evaluation included Constant score, height of plate position and possible impingement, as well as intraoperative complications. RESULTS: Twenty patients met the inclusion criteria. The mean age was 56 +/- 12 years. The plates were placed 6.9 +/- 3 mm distal to the greater tubercle. The operation was performed in 35 +/- 10 min and no intraoperative complications were reported. The Constant score improved significantly after implant removal from 71 to 76 (p = 0.008). CONCLUSION: Symptomatic patients after locked plate osteosynthesis for proximal humerus fractures showed statistically significant improvement of the Constant score after implant removal. PMID- 26964743 TI - Strengthening health professions regulation in Cambodia: a rapid assessment. AB - BACKGROUND: This paper describes a rapid assessment of Cambodia's current system for regulating its health professions. The assessment forms part of a co-design process to set strategic priorities for strengthening health profession regulation to improve the quality and safety of health services. A health system approach for strengthening health professions' regulation is underway and aims to support the Government of Cambodia's plans for scaling up its health workforce, improving health services' safety and quality, and meeting its Association of South East Asian Nations (ASEAN) obligations to facilitate trade in health care services. METHODS: The assessment used a mixed methods approach including: A desktop review of key laws, plans, reports and other documents relating to the regulation of the health professions in Cambodia (medicine, dentistry, midwifery, nursing and pharmacy); Key informant interviews with stakeholders in Cambodia (The term "stakeholders" refers to government officials, people working on health professional regulation, people working for the various health worker training institutions and health workers at the national and provincial level); Surveys and questionnaires to assess Cambodian stakeholder knowledge of regulation; Self assessments by members of the five Cambodian regulatory councils regarding key capacities and activities of high-performing regulatory bodies; and A rapid literature review to identify: The key functions of health professional regulation; The key issues affecting the Cambodian health sector (including relevant developments in the wider ASEAN region); and "Smart" health profession regulation practices of possible relevance to Cambodia. RESULTS: We found that the current regulatory system only partially meets Cambodia's needs. A number of key regulatory functions are being performed, but overall, the current system was not designed with Cambodia's specific needs in mind. The existing system is also overly complex, with considerable duplication and overlap between governance and regulatory arrangements for the five regulated professions. CONCLUSIONS: There is considerable scope for reform to the current regulatory system to better align the system to Cambodia's: Current needs and circumstances; Health system strategic priorities; and International obligations. Cambodia is also well placed to base its reformed regulatory system on recent developments of "smart regulatory practices" for health professionals. PMID- 26964738 TI - Genome-wide analysis identifies gain and loss/change of function within the small multigenic insecticidal Albumin 1 family of Medicago truncatula. AB - BACKGROUND: Albumin 1b peptides (A1b) are small disulfide-knotted insecticidal peptides produced by Fabaceae (also called Leguminosae). To date, their diversity among this plant family has been essentially investigated through biochemical and PCR-based approaches. The availability of high-quality genomic resources for several fabaceae species, among which the model species Medicago truncatula (Mtr), allowed for a genomic analysis of this protein family aimed at i) deciphering the evolutionary history of A1b proteins and their links with A1b nodulins that are short non-insecticidal disulfide-bonded peptides involved in root nodule signaling and ii) exploring the functional diversity of A1b for novel bioactive molecules. RESULTS: Investigating the Mtr genome revealed a remarkable expansion, mainly through tandem duplications, of albumin1 (A1) genes, retaining nearly all of the same canonical structure at both gene and protein levels. Phylogenetic analysis revealed that the ancestral molecule was most probably insecticidal giving rise to, among others, A1b-nodulins. Expression meta-analysis revealed that many A1b coding genes are silent and a wide tissue distribution of the A1 transcripts/peptides within plant organs. Evolutionary rate analyses highlighted branches and sites with positive selection signatures, including two sites shown to be critical for insecticidal activity. Seven peptides were chemically synthesized and folded in vitro, then assayed for their biological activity. Among these, AG41 (aka MtrA1013 isoform, encoded by the orphan TA24778 contig.), showed an unexpectedly high insecticidal activity. The study highlights the unique burst of diversity of A1 peptides within the Medicago genus compared to the other taxa for which full-genomes are available: no A1 member in Lotus, or in red clover to date, while only a few are present in chick pea, soybean or pigeon pea genomes. CONCLUSION: The expansion of the A1 family in the Medicago genus is reminiscent of the situation described for another disulfide-rich peptide family, the "Nodule-specific Cysteine-Rich" (NCR), discovered within the same species. The oldest insecticidal A1b toxin was described from the Sophorae, dating the birth of this seed-defense function to more than 58 million years, and making this model of plant/insect toxin/receptor (A1b/insect v-ATPase) one of the oldest known. PMID- 26964748 TI - Analytical detection and characterization of biopharmaceutical glycosylation by MS. AB - Glycosylation plays an important role in ensuring the proper structure and function of most biotherapeutic proteins. Even small changes in glycan composition, structure, or location can have a drastic impact on drug safety and efficacy. Recently, glycosylation has become the subject of increased focus as biopharmaceutical companies rush to create not only biosimilars, but also biobetters based on existing biotherapeutic proteins. Against this backdrop of ongoing biopharmaceutical innovation, updated methods for accurate and detailed analysis of protein glycosylation are critical for biopharmaceutical companies and government regulatory agencies alike. This review summarizes current methods of characterizing biopharmaceutical glycosylation, including compositional mass profiling, isomer-specific profiling and structural elucidation by MS and hyphenated techniques. PMID- 26964749 TI - PeTTSy: a computational tool for perturbation analysis of complex systems biology models. AB - BACKGROUND: Over the last decade sensitivity analysis techniques have been shown to be very useful to analyse complex and high dimensional Systems Biology models. However, many of the currently available toolboxes have either used parameter sampling, been focused on a restricted set of model observables of interest, studied optimisation of a objective function, or have not dealt with multiple simultaneous model parameter changes where the changes can be permanent or temporary. RESULTS: Here we introduce our new, freely downloadable toolbox, PeTTSy (Perturbation Theory Toolbox for Systems). PeTTSy is a package for MATLAB which implements a wide array of techniques for the perturbation theory and sensitivity analysis of large and complex ordinary differential equation (ODE) based models. PeTTSy is a comprehensive modelling framework that introduces a number of new approaches and that fully addresses analysis of oscillatory systems. It examines sensitivity analysis of the models to perturbations of parameters, where the perturbation timing, strength, length and overall shape can be controlled by the user. This can be done in a system-global setting, namely, the user can determine how many parameters to perturb, by how much and for how long. PeTTSy also offers the user the ability to explore the effect of the parameter perturbations on many different types of outputs: period, phase (timing of peak) and model solutions. PeTTSy can be employed on a wide range of mathematical models including free-running and forced oscillators and signalling systems. To enable experimental optimisation using the Fisher Information Matrix it efficiently allows one to combine multiple variants of a model (i.e. a model with multiple experimental conditions) in order to determine the value of new experiments. It is especially useful in the analysis of large and complex models involving many variables and parameters. CONCLUSIONS: PeTTSy is a comprehensive tool for analysing large and complex models of regulatory and signalling systems. It allows for simulation and analysis of models under a variety of environmental conditions and for experimental optimisation of complex combined experiments. With its unique set of tools it makes a valuable addition to the current library of sensitivity analysis toolboxes. We believe that this software will be of great use to the wider biological, systems biology and modelling communities. PMID- 26964751 TI - Identifying the cellular targets of natural products using T7 phage display. AB - Covering: up to the end of 2015While Nature continues to deliver a myriad of potent and structurally diverse biologically active small molecules, the cellular targets and modes of action of these natural products are rarely identified, significantly hindering their development as new chemotherapeutic agents. This article provides an introductory tutorial on the use of T7 phage display as a tool to rapidly identify the cellular targets of natural products and is aimed specifically at natural products chemists who may have only limited experience in molecular biology. A brief overview of T7 phage display is provided, including its strengths, weaknesses, and the type of problems that can and cannot be tackled with this technology. Affinity probe construction is reviewed, including linker design and natural product derivatisation strategies. A detailed description of the T7 phage biopanning procedure is provided, with valuable tips for optimising each step in the process, as well as advice for identifying and avoiding the most commonly encountered challenges and pitfalls along the way. Finally, a brief discussion is provided on techniques for validating the cellular targets identified using T7 phage display. PMID- 26964752 TI - Aromaticity of the doubly charged [8]circulenes. AB - Magnetically induced current densities and current pathways have been calculated for a series of fully annelated dicationic and dianionic tetraphenylenes, which are also named [8]circulenes. The gauge including magnetically induced current (GIMIC) method has been employed for calculating the current density susceptibilities. The aromatic character and current pathways are deduced from the calculated current density susceptibilities showing that the neutral [8]circulenes have two concentric pathways with aromatic and antiaromatic character, respectively. The inner octatetraene core (the hub) is found to sustain a paratropic (antiaromatic) ring current, whereas the ring current along the outer part of the macrocycle (the rim) is diatropic (aromatic). The neutral [8]circulenes can be considered nonaromatic, because the sum of the ring-current strengths of the hub and the rim almost vanishes. The aromatic character of the doubly charged [8]circulenes is completely different: the dianionic [8]circulenes and the OC-, CH-, CH2-, SiH-, GeH-, SiH2-, and GeH2-containing dicationic species sustain net diatropic ring currents i.e., they are aromatic, whereas the O-, S-, Se-, NH-, PH- and AsH-containing dicationic [8]circulenes are strongly antiaromatic. The present study also shows that GIMIC calculations on the [8]circulenes provide more accurate information about the aromatic character than that obtained using local indices such as nuclear-independent chemical shifts (NICSs) and (1)H NMR chemical shifts. PMID- 26964750 TI - Quantifying the incidence and cost of acute gastrointestinal illness in Sweden, 2013-2014. AB - In Sweden, acute gastrointestinal illness (AGI) incidence, severity, impact on productivity, related healthcare usage and associated costs are not ascertained. We measured these in 2013-2014 using a population-based cohort reporting weekly. We defined AGI as ?3 episodes of loose stools or vomiting/24 h; or loose stools or vomiting with ?2 other gastrointestinal symptoms. After each AGI episode, we collected information about perceived severity, healthcare use and absenteeism. We calculated incidence rates, AGI absenteeism and costs comprising direct healthcare costs and productivity loss due to work/school absenteeism. A total of 3241 participants reported 1696 AGI episodes [incidence 360/1000 person-years, 95% confidence interval (CI) 326-395; highest in the <5 years age group]. In the <5 years age group, 31% of episodes were perceived as mild, 61% as moderate and 8% as severe; 9.4% led to primary-care consultations, and 1.4% to hospital admissions. In the ?5 years age group, 18% of episodes were perceived as mild, 64% as moderate and 18% as severe; 6.4% led to primary-care consultations, and 1.9% to hospital admissions. AGI caused 8 891 000 days of absenteeism (95% CI 6 009 000-12 780 000). AGI cost ?1 005 885 000 (95% CI 754 309 000-1 257 195 000) nationally for the year. In Sweden, a minority of cases perceive AGI as a mild illness. AGI is a burden on the healthcare system and causes productivity loss, with high costs. Countries may consider these estimates when prioritizing health interventions. PMID- 26964753 TI - N,N-Dicarboxymethyl hydrazine: an old but neglected reagent for chemoselective derivatization of carbonyl compounds. AB - N,N-Dicarboxymethyl hydrazine (DCMH) was found to be a chemoselective derivatization reagent of carbonyl compounds and its potential applications in organic synthesis was investigated for the first time. DCMH could be employed as a chemoselective protective reagent of aldehydes and gave the parent aldehydes in satisfactory yields. In proof-of-concept systems, DCMH could play the role of a scavenger to remove aldehydes in the presence of ketones. It was also used as a tagging reagent in the selective isolation of aldehyde from the complex mixture. PMID- 26964755 TI - Uncertainty-based Optimization Algorithms in Designing Fractionated Spacecraft. AB - A fractionated spacecraft is an innovative application of a distributive space system. To fully understand the impact of various uncertainties on its development, launch and in-orbit operation, we use the stochastic missioncycle cost to comprehensively evaluate the survivability, flexibility, reliability and economy of the ways of dividing the various modules of the different configurations of fractionated spacecraft. We systematically describe its concept and then analyze its evaluation and optimal design method that exists during recent years and propose the stochastic missioncycle cost for comprehensive evaluation. We also establish the models of the costs such as module development, launch and deployment and the impacts of their uncertainties respectively. Finally, we carry out the Monte Carlo simulation of the complete missioncycle costs of various configurations of the fractionated spacecraft under various uncertainties and give and compare the probability density distribution and statistical characteristics of its stochastic missioncycle cost, using the two strategies of timing module replacement and non-timing module replacement. The simulation results verify the effectiveness of the comprehensive evaluation method and show that our evaluation method can comprehensively evaluate the adaptability of the fractionated spacecraft under different technical and mission conditions. PMID- 26964754 TI - Study of individual erythrocyte deformability susceptibility to INFeD and ethanol using a microfluidic chip. AB - Human red blood cells (RBCs) deformability in vitro was assessed during iron dextran (INFeD) loading and/or ethanol co-administration using microfluidic deformability screening. The results showed donor-specific variations in dose dependent deformability shift were revealed below 500 MUg/mL iron dextran. Two out of nine blood samples exhibited significant cell stiffening at 500 MUg/mL iron dextran loading concentration (p < 0.05, Tukey test). More interestingly, co administration of moderate amount of ethanol was identified to have significant protective effects on RBC deformability. We also noted that ethanol can reverse the deformability of impaired RBCs. Meanwhile obvious donor dependent response to ethanol administration on RBC deformability was noted using our biomimetic microfluidic chip. PMID- 26964757 TI - Accuracy of Direct Observation to Assess Physical Activity in Older Adults. AB - The purpose of the study was to evaluate the accuracy of direct observation (DO) to estimate MET level and intensity category during laboratory-based and free living activity in older adults. Older adults engaged in unstructured laboratory and free-living activity. Participants wore a portable metabolic system to measure energy expenditure and were directly observed. DO recorded MET-level point estimates. 32,401 in-laboratory and 87,715 free-living data points (9 participants, 67% male, 71.0 +/- 6.9 years, 27.1 +/- 4.3 kg.m-2) were included in final analysis. Results revealed 45.4% of in-laboratory and 61.1% of free-living mean DO activities fell within 0.5 METs of the measured MET values. DO accurately classified intensity category 45.0% of the time in-laboratory and 50.9% of free living observations. DO-estimated activity cost resulted in low point estimate accuracy however there was low variability between the mean measured and estimated METs. This suggests, dependent on the desired outcome, DO could provide a viable option for activity assessment, however, the low point estimate accuracy presents a need for further research to continue to refine the approach to increase accuracy. PMID- 26964759 TI - Precession and nutation dynamics of nonlinearly coupled non-coaxial three dimensional matter wave vortices. AB - Nonlinearity is the driving force for numerous important effects in nature typically showing transitions between different regimes, regular, chaotic or catastrophic behavior. Localized nonlinear modes have been the focus of intense research in areas such as fluid and gas dynamics, photonics, atomic and solid state physics etc. Due to the richness of the behavior of nonlinear systems and due to the severe numerical demands of accurate three-dimensional (3D) numerical simulations presently only little knowledge is available on the dynamics of complex nonlinear modes in 3D. Here, we investigate the dynamics of 3D non coaxial matter wave vortices that are trapped in a parabolic potential and interact via a repulsive nonlinearity. Our numerical simulations demonstrate the existence of an unexpected and fascinating nonlinear regime that starts immediately when the nonlinearity is switched-on and is characterized by a smooth dynamics representing torque-free precession with nutations. The reported motion is proven to be robust regarding various effects such as the number of particles, dissipation and trap deformations and thus should be observable in suitably designed experiments. Since our theoretical approach, i.e., coupled nonlinear Schrodinger equations, is quite generic, we expect that the obtained novel dynamical behavior should also exist in other nonlinear systems. PMID- 26964760 TI - Is the new comer always better? PMID- 26964758 TI - Antibacterial Diamines Targeting Bacterial Membranes. AB - Antibiotic resistance is a growing threat to human health exacerbated by a lack of new antibiotics. We now describe a series of substituted diamines that produce rapid bactericidal activity against both Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus and stationary phase bacteria. These compounds reduce biofilm formation and promote biofilm dispersal in Pseudomonas aeruginosa. The most potent analogue, 3 (1,13-bis{[(2,2 diphenyl)-1-ethyl]thioureido}-4,10-diazatridecane), primarily acts by depolarization of the cytoplasmic membrane and permeabilization of the bacterial outer membrane. Transmission electron microscopy confirmed that 3 disrupts membrane integrity rapidly. Compound 3 is also synergistic with kanamycin, demonstrated by the checkerboard method and by time-kill kinetic experiments. In human cell toxicity assays, 3 showed limited adverse effects against the HEK293T human kidney embryonic cells and A549 human adenocarcinoma cells. In addition, 3 produced no adverse effects on Caenorhabditis elegans development, survival, and reproduction. Collectively, diamines related to 3 represent a new class of broad spectrum antibacterials against drug-resistant pathogens. PMID- 26964756 TI - Epigenetic regulation of diacylglycerol kinase alpha promotes radiation-induced fibrosis. AB - Radiotherapy is a fundamental part of cancer treatment but its use is limited by the onset of late adverse effects in the normal tissue, especially radiation induced fibrosis. Since the molecular causes for fibrosis are largely unknown, we analyse if epigenetic regulation might explain inter-individual differences in fibrosis risk. DNA methylation profiling of dermal fibroblasts obtained from breast cancer patients prior to irradiation identifies differences associated with fibrosis. One region is characterized as a differentially methylated enhancer of diacylglycerol kinase alpha (DGKA). Decreased DNA methylation at this enhancer enables recruitment of the profibrotic transcription factor early growth response 1 (EGR1) and facilitates radiation-induced DGKA transcription in cells from patients later developing fibrosis. Conversely, inhibition of DGKA has pronounced effects on diacylglycerol-mediated lipid homeostasis and reduces profibrotic fibroblast activation. Collectively, DGKA is an epigenetically deregulated kinase involved in radiation response and may serve as a marker and therapeutic target for personalized radiotherapy. PMID- 26964761 TI - Masculinised Behaviour of XY Females in a Mammal with Naturally Occuring Sex Reversal. AB - Most sex differences in phenotype are controlled by gonadal hormones, but recent work on laboratory strain mice that present discordant chromosomal and gonadal sex showed that sex chromosome complement can have a direct influence on the establishment of sex-specific behaviours, independently from gonads. In this study, we analyse the behaviour of a rodent with naturally occurring sex reversal: the African pygmy mouse Mus minutoides, in which all males are XY, while females are of three types: XX, XX* or X*Y (the asterisk represents an unknown X-linked mutation preventing masculinisation of X*Y embryos). X*Y females show typical female anatomy and, interestingly, have greater breeding performances. We investigate the link between sex chromosome complement, behaviour and reproductive success in females by analysing several behavioural features that could potentially influence their fitness: female attractiveness, aggressiveness and anxiety. Despite sex chromosome complement was not found to impact male mate preferences, it does influence some aspects of both aggressiveness and anxiety: X(*)Y females are more aggressive than the XX and XX*, and show lower anxiogenic response to novelty, like males. We discuss how these behavioural differences might impact the breeding performances of females, and how the sex chromosome complement could shape the differences observed. PMID- 26964763 TI - Combination of oviduct fluid and heparin to improve monospermic zygotes production during porcine in vitro fertilization. AB - In vivo, the oviduct provides appropriate microenvironment conditions for monospermic fertilization and early embryo development. In addition, glycosaminoglycans such as heparin are present in the oviduct and have been shown to modulate the activity of oviduct-secreted proteins on the regulation of sperms parameters. Thus, the present study was designed to evaluate the effect of porcine oocytes exposure to oviduct fluid (OF) before in vitro fertilization (IVF; incubation of oocytes in OF for 30 minutes before IVF), during IVF (supplementation of IVF medium with 10% OF), and during IVF in combination with heparin (10% OF + 10-MUg/mL heparin) on IVF parameters. Regardless of sperm concentration used (0.5, 1.5, or 4.5 * 10(5) cells/mL), exposure of oocytes to OF led to an increased (P < 0.05) monospermy rate, without alteration (P > 0.05) of the penetration rate in comparison with the control group. This resulted in a general increase (P < 0.05) in the final output of the IVF system in terms of zygotes with two pronuclei in OF-exposed groups: 56 +/- 9% (OF before) and 60 +/- 7% (10% OF during IVF), compared with control (21 +/- 8%), when IVF was performed with 4.5 * 10(5) cells/mL. The combination of 10% OF with heparin during IVF induced a decrease (P < 0.05) of the penetration rate, with no effect (P > 0.05) on the monospermy rate in comparison with 10% OF alone. This resulted in a general reduction (P < 0.05) in the final output of the IVF system (%), which was 33 +/- 6% and 52 +/- 8%, for 10% OF + heparin and 10% OF, respectively. In conclusion, the OF, used in porcine IVF, exerted a beneficial effect on oocytes by reducing the incidence of polyspermy without decreasing the penetration rate. However, the association of the OF with heparin reduced the efficiency of monospermic zygotes' production. PMID- 26964762 TI - Diet of dingoes and other wild dogs in peri-urban areas of north-eastern Australia. AB - Knowledge of the resource requirements of urban predators can improve our understanding of their ecology and assist town planners and wildlife management agencies in developing management approaches that alleviate human-wildlife conflicts. Here we examine food and dietary items identified in scats of dingoes in peri-urban areas of north-eastern Australia to better understand their resource requirements and the potential for dingoes to threaten locally fragmented populations of native fauna. Our primary aim was to determine what peri-urban dingoes eat, and whether or not this differs between regions. We identified over 40 different food items in dingo scats, almost all of which were mammals. Individual species commonly observed in dingo scats included agile wallabies, northern brown bandicoots and swamp wallabies. Birds were relatively common in some areas but not others, as were invertebrates. Dingoes were identified as a significant potential threat to fragmented populations of koalas. Dietary overlap was typically very high or near-identical between regions, indicating that peri-urban dingoes ate the same types or sizes of prey in different areas. Future studies should seek to quantify actual and perceived impacts of, and human attitudes towards, peri-urban dingoes, and to develop management strategies with a greater chance of reducing human-wildlife conflicts. PMID- 26964764 TI - Thermal selectivity of intermolecular versus intramolecular reactions on surfaces. AB - On-surface synthesis is a promising strategy for engineering heteroatomic covalent nanoarchitectures with prospects in electronics, optoelectronics and photovoltaics. Here we report the thermal tunability of reaction pathways of a molecular precursor in order to select intramolecular versus intermolecular reactions, yielding monomeric or polymeric phthalocyanine derivatives, respectively. Deposition of tetra-aza-porphyrin species bearing ethyl termini on Au(111) held at room temperature results in a close-packed assembly. Upon annealing from room temperature to 275 degrees C, the molecular precursors undergo a series of covalent reactions via their ethyl termini, giving rise to phthalocyanine tapes. However, deposition of the tetra-aza-porphyrin derivatives on Au(111) held at 300 degrees C results in the formation and self-assembly of monomeric phthalocyanines. A systematic scanning tunnelling microscopy study of reaction intermediates, combined with density functional calculations, suggests a [2+2] cycloaddition as responsible for the initial linkage between molecular precursors, whereas the monomeric reaction is rationalized as an electrocyclic ring closure. PMID- 26964765 TI - In vitro, molecular modeling and behavioral studies of 3-{[4-(5-methoxy-1H-indol 3-yl)-1,2,3,6-tetrahydropyridin-1-yl]methyl}-1,2-dihydroquinolin-2-one (D2AAK1) as a potential antipsychotic. AB - Antipsychotics currently available to treat schizophrenia suffer several limitations: (1) they are efficient against positive but not negative and cognitive symptoms of the disease; (2) they help only a half of patients; (3) they have severe side effects including neurological and metabolic side effects. Thus, novel drugs to treat schizophrenia are highly demanded. We identified a novel dopamine D2 receptor antagonist, D2AAK1, with Ki of 58 nM using structure based virtual screening. D2AAK1 possesses additional nanomolar or low micromolar affinity to D1, D3, 5-HT1A and 5-HT2A receptors, making it an ideal candidate for a multi-target drug. Here we present homology modeling, molecular docking and molecular dynamics of D2AAK1 and its molecular targets and animal studies of D2AAK1 as a potential antipsychotic. The main contact of D2AAK1 and all the receptors studied is the electrostatic interaction between the protonable nitrogen atom of the ligand and the conserved Asp(3.32) as typical for orthosteric ligands of aminergic GPCRs. We confirmed antagonistic/partial agonistic properties of D2AAK1 towards all the receptors in in vitro essays and in in silico studies as the ligand stabilizes the ionic lock interaction. We also demonstrated neuroleptic, anxiolytic and, importantly, procognitive properties of D2AAK1 in mouse models. PMID- 26964767 TI - Auricular vagus nerve stimulation promotes functional recovery and enhances the post-ischemic angiogenic response in an ischemia/reperfusion rat model. AB - Electrical stimulation of the vagus nerve, which has been used to treat epilepsy patients since 1997, also enhances long-term restoration after central nervous system (CNS) injury. Angiogenesis is a complex restorative mechanism that occurs in response to ischemic stroke, and it positively affects the recovery of neurological functions in a rat model of stroke. The aims of our study were to determine whether auricular vagus nerve stimulation (aVNS) promoted functional recovery and enhanced angiogenesis in the ischemic boundary following ischemia/reperfusion and to uncover the possible molecular mechanisms that are involved. Adult male Sprague-Dawley (SD) rats underwent transient middle cerebral artery occlusion (tMCAO) surgery and received repeated electrical stimulation of the left cavum concha starting 30 min after ischemia. For the following 21 days, we evaluated functional recovery at different time points using neurological deficit scores, the beam-walking test and the staircase test. The infarct volume was measured using TTC staining at 24 h post reperfusion, neuronal survival in the ischemic penumbra was assessed using hematoxylin and eosin (HE) staining. Microvessel density and endothelial cell proliferation in the ischemic boundary were assessed using immunofluorescence. The expression levels of brain-derived neurotrophic factor (BDNF), endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) in the ischemic penumbra were also evaluated. Our results showed that aVNS had significant neuroprotective effects and enhanced angiogenesis, which was demonstrated by improvements in the behavioral scores and brain histopathology, including increased levels of microvessel density and endothelial cell proliferation surrounding the infarct area. Furthermore, BDNF, eNOS and VEGF were expressed at higher levels in the I/R + aVNS group than in the I/R group or the I/R + sham aVNS group (p < 0.05). Our findings suggest that repeated aVNS promoted post-ischemic functional recovery and angiogenesis, possibly in conjunction with the up-regulated expression of BDNF, eNOS and VEGF in the rat brain. PMID- 26964766 TI - Autophagy regulates intracerebral hemorrhage induced neural damage via apoptosis and NF-kappaB pathway. AB - Autophagy can be a pro-survival or a pro-death mechanism depending on the context. The role of autophagy in intracerebral hemorrhage (ICH) remains elusive. In this study, in vivo and in vitro experiments have been carried out to investigate the role of autophagy after ICH. Collagenase-induced ICH model in mouse was made for in vivo experiments. Primary cortical neurons cultures were exposed to hemin to mimic ICH in vitro. 3-Methyladenine (3-MA) and rapamycin (RAP) were administrated both in vivo and in vitro. We first measured brain water content and cell death after ICH in model. Expression of LC3, p62/SQSTM1 (p62), Beclin1, Caspase3 and Bcl-2, which have been found related to autophagy and apoptosis, were assessed both in vivo and in vitro. Furthermore, NF-kappaB was detected to explore the potential mechanisms. We found brain edema in ICH model in mouse and the number of Propidium Iodide (PI)-positive cells both in vivo and in vitro were decreased by 3-MA pretreated. Simultaneously, both in vivo and in vitro, 3-MA significantly decreased the expression of LC3-II and Beclin-1, and maintained p62 at high level after ICH. Furthermore, pretreatment with 3-MA downregulated the level of cleaved caspase-3 but upregulated the Bcl-2 level. Conversely, RAP pretreatment reversed all these results above. These data indicated that autophagy activation may deprave ICH induced brain injury in ICH model and neuro-damage may be related to regulating of NF-kappaB pathway and thereby promote inflammation and apoptosis, thus might provide novel therapeutic interventions for ICH. PMID- 26964769 TI - Commentary on "AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer." Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J, Division of Urologic Oncology, Department of Urology, University of Michigan, MI. N Engl J Med 2014; 371(11):1028-38. PMID- 26964768 TI - Hypocholesterolemic effect of emodin by simultaneous determination of in vitro and in vivo bile salts binding. AB - Emodin is an active anthraquinone derivative from Rheum palmatum and some other Chinese herbs and it is traditionally used for treating a variety of diseases. In this study, we investigated the hypocholesterolemic effects and mechanism of emodin on hypercholesterolemia rats. In vitro, capability of emodin binding to sodium deoxycholate which is one kind of bile salts (BAs) was evaluated by detection of surplus content of sodium deoxycholate. In vivo, hypocholesterolemic effects were assessed by determining total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) level of serum and TC, TG level of the liver. Oil red O staining was employed to determine lipid droplet of the liver. The mechanism was explored by BAs in feces, the liver and small intestine. Furthermore, cholesterol 7alpha-hydroxylase (CYP7A1) activity was measured to evaluate cholesterol's transforming to BAs. The results indicated that TC level of emodin group apparently decreased comparing with model group (p<0.05). Emodin could bind to BAs both in vivo (p<0.05) and in vitro. CYP7A1 activity in emodin group apparently increased comparing with model group (p<0.05). Data suggested that emodin had the potential value for treatment of hypercholesterolemia. The underlying mechanism is probably associated with binding capability to BAs and subsequent increasing expression of CYP7A1. PMID- 26964770 TI - Centralspindlin in Rappaport's cleavage signaling. AB - Cleavage furrow in animal cell cytokinesis is formed by cortical constriction driven by contraction of an actomyosin network activated by Rho GTPase. Although the role of the mitotic apparatus in furrow induction has been well established, there remain discussions about the detailed molecular mechanisms of the cleavage signaling. While experiments in large echinoderm embryos highlighted the role of astral microtubules, data in smaller cells indicate the role of central spindle. Centralspindlin is a constitutive heterotetramer of MKLP1 kinesin and the non motor CYK4 subunit and plays crucial roles in formation of the central spindle and recruitment of the downstream cytokinesis factors including ECT2, the major activator of Rho during cytokinesis, to the site of division. Recent reports have revealed a role of this centralspindlin-ECT2 pathway in furrow induction both by the central spindle and by the astral microtubules. Here, a unified view of the stimulation of cortical contractility by this pathway is discussed. Cytokinesis, the division of the whole cytoplasm, is an essential process for cell proliferation and embryonic development. In animal cells, cytokinesis is executed using a contractile network of actin filaments driven by a myosin-II motor that constricts the cell cortex (cleavage furrow ingression) into a narrow channel between the two daughter cells, which is resolved by scission (abscission) [1-3]. The anaphase-specific organization of the mitotic apparatus (MA, spindle with chromosomes plus asters) positions the cleavage furrow and plays a major role in spatial coupling between mitosis and cytokinesis [4-6]. The nucleus and chromosomes are dispensable for furrow specification [7-10], although they contribute to persistent furrowing and robust completion in some cell types [11,12]. Likewise, centrosomes are not essential for cytokinesis, but they contribute to the general fidelity of cell division [10,13-15]. Here, classical models of cleavage furrow induction are outlined, and a unified view of the stimulation of cortical contractility by the centralspindlin-ECT2 pathway is discussed. PMID- 26964773 TI - Management of Barrett's esophagus: From screening to newer treatments. AB - Barrett's esophagus is a premalignant condition of the esophagus in which the squamous epithelium of the lower end of the esophagus is replaced with columnar epithelium. Since the incidence of esophageal adenocarcinoma is on the rise, the major gastroenterology societies have come up with their recommendations for screening and surveillance. Specific factors like obesity, white race, age over 50 years, early age of onset of GERD, smoking and hiatal hernia have been identified as increasing the risk of Barrett's esophagus and adenocarcinoma. The diagnosis requires both endoscopic identification of columnar-lined mucosa and histological confirmation with biopsy. Most medical societies recommend screening people with GERD and other risk factors with endoscopy, but other alternatives employing less invasive methods are currently being studied. Surveillance strategies vary depending on the endoscopic findings and the Seattle biopsy protocol with random 4-quadrant sampling is recommended. Biomarkers have shown promising results, but more studies are needed in the future. White light endoscopy is the standard practice, but other advanced imaging modalities have shown variable results and hence more studies are awaited for further validation. Endoscopic eradication techniques, including both resection and ablation, have shown good but variable results for treating dysplastic lesions confined to the mucosa. Resection procedures to remove visible lesions followed by ablation of the dysplastic mucosa have shown the best results with higher eradication rates and lower recurrence rates. Surgical management is reserved for lesions with sub mucosal invasion and lymph node spread with increased risk of metastasis. PMID- 26964771 TI - Phase II Study of a Non-Platinum-Containing Doublet of Paclitaxel and Pemetrexed with Bevacizumab as Initial Therapy for Patients with Advanced Lung Adenocarcinomas. AB - INTRODUCTION: Many patients with lung cancers cannot receive platinum-containing regimens owing to comorbid medical conditions. We designed the PPB (paclitaxel, pemetrexed, and bevacizumab) regimen to maintain or improve outcomes while averting the unique toxicities of platinum-based chemotherapies. METHODS: We enrolled patients with untreated, advanced lung adenocarcinomas with measurable disease and no contraindications to bevacizumab. Participants received paclitaxel, 90 mg/m(2), pemetrexed, 500 mg/m(2), and bevacizumab, 10 mg/kg, every 14 days for 6 months and continued to receive pemetrexed and bevacizumab every 14 days until progression or unacceptable toxicity. RESULTS: Of the 44 patients treated, 50% were women; the median age was 61 years and 89% had a Karnofsky performance status of at least 80%. We genotyped 38 patients with the following results: Kirsten rat sarcoma viral oncogene homolog gene (KRAS), 16; anaplastic lymphoma receptor tyrosine kinase gene (ALK), three; B-Raf proto-oncogene, serine/threonine kinase gene (BRAF) V600E, two; erb-b2 receptor tyrosine kinase 2 gene (HER2)/phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), one; epidermal growth factor receptor gene (EGFR) exon 20 insertion, one; and driver 15, none. A total of 23 patients achieved a PR (52%, 95% confidence interval: 37-68), including seven of 16 with KRAS-mutant tumors. The overall survival rate at 2 years was 43% with a median of 17 months (95% confidence interval: 10-29). Grade 3/4 treatment-related toxicities included elevated alanine transaminase level (16%), fatigue (16%), leukopenia (9%), anemia (7%), elevated aspartate transaminase level (7%), edema (5%), and pleural effusions (5%). Two patients died of respiratory failure without disease progression. CONCLUSIONS: The PPB regimen produced a high response rate in patients with lung adenocarcinomas regardless of mutational status. Survival and toxicities were comparable to those in the phase II reports testing platinum containing doublets with bevacizumab. These results justify use of the PPB regimen in fit patients in whom three-drug regimens including bevacizumab are appropriate. PMID- 26964772 TI - Pulse Afatinib for ERBB2 Exon 20 Insertion-Mutated Lung Adenocarcinomas. AB - INTRODUCTION: Genomic aberrations involving the erb-b2 receptor tyrosine kinase 2 gene (ERBB2) are driver oncogenes in approximately 2% of lung adenocarcinomas. However, the use of daily dosing of ERBB2 tyrosine kinase inhibitors (TKIs) including afatinib-has been fraught with plasma concentrations that barely achieve preclinical model inhibition, significant patient-reported toxicities, and limited clinical activity. We hypothesized that alternative dosing strategies could improve tolerability and efficacy. METHODS: We profiled lung cancer cell lines against TKIs and retrospectively evaluated the toxicity of and response to pulse afatinib (280 mg once weekly) in lung cancers with ERBB2 mutations. RESULTS: An ERBB2 exon 20 insertion-mutated lung cancer cell line had a 50% inhibitory concentration in response to afatinib that was higher than the reported plasma concentration of afatinib, 40 mg daily. Three patients with advanced ERBB2-mutated lung adenocarcinomas were treated with off-label pulse afatinib. The 280-mg weekly dose was well tolerated with no reported rash and minimal diarrhea. One TKI-naive patient achieved a partial response for 5 months and another achieved stable disease for 11 months. CONCLUSIONS: Pulse afatinib at a weekly dosing scheme induced antitumor activity in ERBB2 exon 20 insertion mutated lung adenocarcinomas. Future clinical trials of alternative dosing schemes of ERBB TKIs as monotherapy or in combination with other therapies are warranted for ERBB2-mutated tumors. PMID- 26964774 TI - Fractal analysis and Gray level co-occurrence matrix method for evaluation of reperfusion injury in kidney medulla. AB - Fractal analysis and Gray level co-occurrence matrix method represent two novel mathematical algorithms commonly used in medical sciences as potential parts of computer-aided diagnostic systems. In this study, we tested the ability of these methods to discriminate the kidney medullar tissue suffering from reperfusion injury, from normal tissue. A total of 320 digital micrographs of Periodic acid Schiff (PAS) - stained kidney medulla from 16 Wistar albino mice (20 per animal), were analyzed using National Institutes of Health ImageJ software (NIH, Bethesda, MD) and its plugins. 160 micrographs were obtained from the experimental group with induced reperfusion injury, and another 160 were obtained from the controls. For each micrograph we calculated the values of fractal dimension, lacunarity, as well as five GLCM features: angular second moment, entropy, inverse difference moment, GLCM contrast, and GLCM correlation. Discriminatory value of the parameters was tested using receiver operating characteristic (ROC) analysis, by measuring the area below ROC curve. The results indicate that certain features of GLCM algorithm have excellent discriminatory ability in evaluation of damaged kidney tissue. Fractal dimension and lacunarity as parameters of fractal analysis also had a relatively good discriminatory value in differentiation of injured from the normal tissue. Both methods have potentially promising application in future design of novel techniques applicable in cell physiology, histology and pathology. PMID- 26964776 TI - Special program and abstract issue of the 12th Annual Congress of the European Cardiac Arrhythmia Society (ECAS). PMID- 26964775 TI - Short-term storage of sterlet Acipenser ruthenus testicular cells at -80 degrees C. AB - The conservation of sturgeons is of critical importance, and optimization of long term storage is crucial to cell survival. This study aimed to examine the viability rates of several variations of sturgeon testicular cells storage at -80 degrees C for purpose of a short-term storage in a deep freezer or shipment on dried ice. Testes extracted from three immature fish were cut into small pieces, immersed in a cryomedium composed of phosphate buffered saline with 0.5% bovine serum albumin, 50 mM glucose, and 1.5 M ethylene glycol as a cryoprotectant, chilled from 10 to -80 degrees C at a cooling rate of 1 degrees C per min, and stored under varying conditions. Our results revealed a significant effect of storage conditions on the number of living and dead cells (p > 0.05). Samples that were stored for 7 days at -80 degrees C showed a considerable decline in terms of cell viability compared to samples stored for 2 days storage at -80 degrees C or in LN. This result indicated that testicular cells can be stored at 80 degrees C and/or on dry ice, for 2 days with minimum loss of viability. PMID- 26964778 TI - Guest editorial: Institute of Hematology and Blood Diseases Hospital in China. PMID- 26964777 TI - HFSRT of the resection cavity in patients with brain metastases. AB - PURPOSE: Aim of this single center, retrospective study was to assess the efficacy and safety of linear accelerator-based hypofractionated stereotactic radiotherapy (HFSRT) to the resection cavity of brain metastases after surgical resection. Local control (LC), locoregional control (LRC = new brain metastases outside of the treatment volume), overall survival (OS) as well as acute and late toxicity were evaluated. PATIENTS AND METHODS: 46 patients with large (> 3 cm) or symptomatic brain metastases were treated with HFSRT. Median resection cavity volume was 14.16 cm(3) (range 1.44-38.68 cm(3)) and median planning target volume (PTV) was 26.19 cm(3) (range 3.45-63.97 cm(3)). Patients were treated with 35 Gy in 7 fractions prescribed to the 95-100 % isodose line in a stereotactic treatment setup. LC and LRC were assessed by follow-up magnetic resonance imaging. RESULTS: The 1-year LC rate was 88 % and LRC was 48 %; 57% of all patients showed cranial progression after HFSRT (4% local, 44% locoregional, 9% local and locoregional). The median follow-up was 19 months; median OS for the whole cohort was 25 months. Tumor histology and recursive partitioning analysis score were significant predictors for OS. HFSRT was tolerated well without any severe acute side effects > grade 2 according to CTCAE criteria. CONCLUSION: HFSRT after surgical resection of brain metastases was tolerated well without any severe acute side effects and led to excellent LC and a favorable OS. Since more than half of the patients showed cranial progression after local irradiation of the resection cavity, close patient follow-up is warranted. A prospective evaluation in clinical trials is currently being performed. PMID- 26964779 TI - Lung Shunt Fraction prior to Yttrium-90 Radioembolization Predicts Survival in Patients with Neuroendocrine Liver Metastases: Single-Center Prospective Analysis. AB - OBJECTIVE: To investigate survival outcomes following radioembolization with Yttrium-90 (Y90) for neuroendocrine tumor liver metastases (NETLMs). This study was designed to assess the efficacy of Y90 radioembolization and to evaluate lung shunt fraction (LSF) as a predictor for survival. METHODS: A single-center, prospective study of 44 consecutive patients (median age: 58.5 years, 29.5 % male) diagnosed with pancreatic (52.3 %) or carcinoid (47.7 %) NETLMs from 2006 to 2012 who underwent Y90 radioembolization was performed. Patients' baseline characteristics, including LSF and median overall survival (OS) from first Y90 radioembolization, were recorded and compared between patients with high (>=10 %) and low (<10 %) LSF. Baseline comparisons were performed using Fisher's exact tests for categorical and Mann-Whitney U test for continuous variables. Survival was calculated using the Kaplan-Meier method. Univariate (Wilcoxon rank-sum test) and multivariate analyses (Cox Proportional Hazard Model) for risk factor analysis were performed. RESULTS: There was no statistically significant difference in age, gender, race, tumor properties, or previous treatments between patients with high (n = 15) and low (n = 29) LSF. The median OS was 27.4 months (95 %CI 12.73-55.23), with 4.77 months (95 %CI 2.87-26.73) for high and 42.77 months (95 %CI 18.47-59.73) for low LSF (p = 0.003). Multivariate analysis identified high LSF (p = 0.001), total serum bilirubin >1.2 mg (p = 0.016), and lack of pretreatment with octreotide (p = 0.01) as independent prognostic factors for poorer survival. Tumor type and total radiation dose did not predict survival. CONCLUSIONS: LSF >=10 %, elevated bilirubin levels, and lack of pretreatment with octreotide were found to be independent prognostic factors for poorer survival in patients with NETLMs. PMID- 26964780 TI - "Born Like This / Into This": Tuberculosis, Justice, and Futuristic Dinosaurs. PMID- 26964781 TI - Best practice strategies to safeguard drug prescribing and drug administration: an anthology of expert views and opinions. AB - BACKGROUND: While evidence on implementation of medication safety strategies is increasing, reasons for selecting and relinquishing distinct strategies and details on implementation are typically not shared in published literature. OBJECTIVE: We aimed to collect and structure expert information resulting from implementing medication safety strategies to provide advice for decision-makers. SETTING: Medication safety experts with clinical expertise from thirteen hospitals throughout twelve European and North American countries shared their experience in workshop meetings, on-site-visits and remote structured interviews. METHODS: We performed an expert-based, in-depth assessment of implementation of best-practice strategies to improve drug prescribing and drug administration. MAIN OUTCOME MEASURES: Workflow, variability and recommended medication safety strategies in drug prescribing and drug administration processes. RESULTS: According to the experts, institutions chose strategies that targeted process steps known to be particularly error-prone in the respective setting. Often, the selection was channeled by local constraints such as the e-health equipment and critically modulated by national context factors. In our study, the experts favored electronic prescribing with clinical decision support and medication reconciliation as most promising interventions. They agreed that self-assessment and introduction of medication safety boards were crucial to satisfy the setting specific differences and foster successful implementation. CONCLUSION: While general evidence for implementation of strategies to improve medication safety exists, successful selection and adaptation of a distinct strategy requires a thorough knowledge of the institute-specific constraints and an ongoing monitoring and adjustment of the implemented measures. PMID- 26964782 TI - Convergence Science Arrives: How Does It Relate to Psychiatry? PMID- 26964783 TI - Public reporting on quality, waiting times and patient experience in 11 high income countries. AB - This article maps current approaches to public reporting on waiting times, patient experience and aggregate measures of quality and safety in 11 high-income countries (Australia, Canada, England, France, Germany, Netherlands, New Zealand, Norway, Sweden, Switzerland and the United States). Using a questionnaire-based survey of key national informants, we found that the data most commonly made available to the public are on waiting times for hospital treatment, being reported for major hospitals in seven countries. Information on patient experience at hospital level is also made available in many countries, but it is not generally available in respect of primary care services. Only one of the 11 countries (England) publishes composite measures of overall quality and safety of care that allow the ranking of providers of hospital care. Similarly, the publication of information on outcomes of individual physicians remains rare. We conclude that public reporting of aggregate measures of quality and safety, as well as of outcomes of individual physicians, remain relatively uncommon. This is likely to be due to both unresolved methodological and ethical problems and concerns that public reporting may lead to unintended consequences. PMID- 26964786 TI - Editorial Comment. PMID- 26964784 TI - Anterior transarticular atlantoaxial screw fixation in combination with dens screw fixation for type II odontoid fractures with associated atlanto-odontoid osteoarthritis. AB - PURPOSE: The purpose of this study was to evaluate the 1-year outcome after anterior transarticular atlantoaxial fixation and odontoid fusion (TAFOF) for type II odontoid fractures and atlanto-odontoid osteoarthritis (AO) in elderly patients. METHODS: All geriatric patients, age 70 or older, with acute traumatic type II odontoid fractures and moderate or severe AO treated by TAFOF were included. The study was performed at a single institution between June 2008 and August 2013. Patients were evaluated clinically and radiologically after 1 year. Main parameter of interest were in-hospital and 1-year mortality rates, complication rates (re-operations, prolonged hospital stay, blood transfusion; non-union), and the patients' pain (0: no pain; 10: maximal pain) and satisfaction level (0: lowest satisfaction; 10: highest satisfaction) after 1 year. RESULTS: A total of 83 patients were included with an average age of 84.7 years (range 70-101 years). 39 patients were subdivided as "old" with an age 70 84 years and 44 patients were defined as "very old" with an age of 85 or higher. The average operation time was 64.7 min. Three patients died during the inpatient stay (3.6 %). Twenty patients (24.1 %) were lost contact follow-up. The 1-year mortality was 25.4 % with a significantly higher mortality rate in very old patient group (p = 0.01). At the 1-year follow-up, the mean pain level was 3.3 and the mean patient satisfaction level was 6.5. Osseous consolidation of the dens was visible in 90.2 % of patients. Revision surgery was performed in three patients (3.6 %). Generally, a significantly higher complication rate was seen after single-screw fixation of the dens compared to a double-screw fixation in combination with TAF (p = 0.042). CONCLUSIONS: Anterior TAFOF leads to promising 1-year results with low in-hospital mortality and a high fusion rate in geriatric patients with type II odontoid fractures and relevant AO. Double-screw dens fixation seems to reduce the complication rate. PMID- 26964785 TI - Risk of revision surgery for adult idiopathic scoliosis: a survival analysis of 517 cases over 25 years. AB - PURPOSE: Little is known about the long-term status of patients operated for spine deformities. The aim of this study was to determine the survival of primary fusion in adult idiopathic scoliosis and identify the risk factors of revision surgery. METHODS: Adult patients who underwent primary fusion for idiopathic scoliosis between 1983 and 2011 were included in a continuous monocentric retrospective series. Any additional surgery was registered for survival analysis. Survival and follow-up were estimated by the Kaplan-Meier method and an analysis was performed to identify the risk factors of revision surgery. RESULTS: This series included 447 women (86.5 %) and 70 men (13.5 %) reviewed after a mean follow-up of 7 years (range 0-26.4). Mean age was 44.4 years. Fusion was performed on a median 11 levels (range 3-15); revision rate was 13 % (CI 10-17), 18 % (CI 14-23) and 20 % (CI 16-26) at 5, 10 and 15 years, respectively. Revision surgery was associated with age, anterior release, length of fusion, the inferior limit of fusion, post-operative sagittal balance and junctional kyphosis. The length of fusion (HR 1.13 per vertebrae fused, p = 0.007) and the lower limit of fusion (HR 5.9, p < 0.001) remained independent predictors of revision surgery on multivariate analysis. CONCLUSION: This series evaluated the risk of revision surgery following spinal fusion for idiopathic scoliosis. Our results show that the risk seemed to increase linearly with a rate of nearly 20 % after 10 years. The length and lower limit of fusion are the main risk factors for revision surgery. Level IV (e.g. case series). PMID- 26964787 TI - Author Reply. PMID- 26964788 TI - Editorial Comment. PMID- 26964789 TI - Author Reply. PMID- 26964790 TI - Editorial Comment. PMID- 26964791 TI - Author Reply. PMID- 26964792 TI - Editorial Comment. PMID- 26964793 TI - Author Reply. PMID- 26964794 TI - Perceived Challenges and Rewards of Forming a Sexual Agreement Among HIV-Negative Male Couples. AB - Sexual agreements, explicit mutual understandings made between two partners about which sexual and related behaviors they agree to engage in within and/or outside of their relationship, are common among male couples. However, little is known about the perceived rewards and challenges partnered men face in the process of forming a sexual agreement. Such knowledge may be useful for the development of future HIV preventive and sexual health programs that encourage male couples to establish a sexual agreement in their relationship. By using qualitative dyadic data from a sample of 29 self-reported concordant HIV-negative male couples who had a sexual agreement, the present qualitative study sought to assess partnered men's perceived rewards and challenges of forming a sexual agreement in their relationship and examine whether both men in the couple concurred about their perceived rewards and challenges of forming a sexual agreement. Themes for perceived rewards were (1) being honest, (2) improving communication, (3) increasing understanding about expectations and permitted behaviors, (4) enhancing intimacy and relational bond, and (5) building trust. Themes for perceived challenges were: (1) stigma about having an open agreement; (2) awkwardness about the topic and talking about it; (3) jealousy; and (4) no perceived challenges. Few couples had both partners concur about their perceived rewards or challenges toward establishing a sexual agreement. The variety of perceived rewards and challenges highlight the need for tailoring given that a variety of factors may influence partnered men's establishment of a sexual agreement in their relationship. PMID- 26964795 TI - The polyphenols resveratrol and epigallocatechin-3-gallate restore the severe impairment of mitochondria in hippocampal progenitor cells from a Down syndrome mouse model. AB - Mitochondrial dysfunctions critically impair nervous system development and are potentially involved in the pathogenesis of various neurodevelopmental disorders, including Down syndrome (DS), the most common genetic cause of intellectual disability. Previous studies from our group demonstrated impaired mitochondrial activity in peripheral cells from DS subjects and the efficacy of epigallocatechin-3-gallate (EGCG) - a natural polyphenol major component of green tea - to counteract the mitochondrial energy deficit. In this study, to gain insight into the possible role of mitochondria in DS intellectual disability, mitochondrial functions were analyzed in neural progenitor cells (NPCs) isolated from the hippocampus of Ts65Dn mice, a widely used model of DS which recapitulates many major brain structural and functional phenotypes of the syndrome, including impaired hippocampal neurogenesis. We found that, during NPC proliferation, mitochondrial bioenergetics and mitochondrial biogenic program were strongly compromised in Ts65Dn cells, but not associated with free radical accumulation. These data point to a central role of mitochondrial dysfunction as an inherent feature of DS and not as a consequence of cell oxidative stress. Further, we disclose that, besides EGCG, also the natural polyphenol resveratrol, which displays a neuroprotective action in various human diseases but never tested in DS, restores oxidative phosphorylation efficiency and mitochondrial biogenesis, and improves proliferation of NPCs. These effects were associated with the activation of PGC-1alpha/Sirt1/AMPK axis by both polyphenols. This research paves the way for using nutraceuticals as a potential therapeutic tool in preventing or managing some energy deficit-associated DS clinical manifestations. PMID- 26964796 TI - The TIR/BB-loop mimetic AS-1 attenuates mechanical stress-induced cardiac fibroblast activation and paracrine secretion via modulation of large tumor suppressor kinase 1. AB - The TIR/BB-loop mimetic AS-1 has been reported to prevent cardiac hypertrophy by inhibiting interleukin-1 receptor (IL-1R)-mediated myeloid differentiation primary response gene 88 (MyD88)-dependent signaling. To date, it remains unknown whether and if so how AS-1 contributes to mechanical stress (MS)-induced cardiac fibroblast activation, a key process in pressure overload-induced cardiac remodeling and heart failure. Here, we show that phosphorylation and expression of large tumor suppressor kinase 1 (LATS1), a key molecule in the Hippo-Yes associated protein (YAP) signaling pathway, were down-regulated in primary neonatal rat cardiac fibroblasts (NRCFs) in response to MS and in the hearts of mice subjected to transverse aortic constriction (TAC) procedure; AS-1 treatment was able to restore LATS1 phosphorylation and expression both in vitro and in vivo. AS-1 treatment suppressed the induction of proliferation, differentiation and collagen synthesis in response to MS in NRCFs. AS-1 also ameliorated cardiomyocyte hypertrophy and apoptosis through dampening paracrine secretion of stretched cardiac fibroblasts. In mice, AS-1 treatment could protect against TAC induced cardiac hypertrophy, myocardial fibrosis and heart failure. Of note, LATS1 depletion using siRNA completely abrogated the inhibitory effects of AS-1 on NRCFs under MS including accelerated proliferation, differentiation, enhanced ability to produce collagen and augmented paracrine secretion of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) to induce cardiomyocyte hypertrophy. Therefore, our results delineate a previously unrecognized role for LATS1 in cardiac fibroblast to mediate the beneficial effects of AS-1 in preventing pressure overload-induced cardiac remodeling and heart failure. PMID- 26964797 TI - The impact of Er:YAG laser enamel conditioning on the microleakage of a new hydrophilic sealant--UltraSeal XT hydro. AB - UltraSeal XT hydro is a new hydrophilic, light-cured, methacrylate-based pit and fissure sealant which has been developed by Ultradent Products, USA. The sealant is highly filled with a 53 wt.% mixture of inorganic particles which confer both thixotropy and radiopacity. The principal purpose of this study was to investigate the microleakage of UltraSeal XT hydro as a function of different enamel etching techniques. The occlusal surfaces of sound, extracted human molars were either acid etched, Er:YAG laser irradiated or successively laser irradiated and acid etched. UltraSeal XT hydro was applied to each group of teeth (n = 10) which were subjected to a thermocycling process consisting of 2500 cycles between 5 and 50 degrees C with a dwell time of 30 s. Microleakage assessments were then carried out using 0.5% fuchsin dye and optical microscopy. The microleakage score data were analysed using the Kruskal-Wallis, Mann-Whitney U test with Bonferroni adjustment. No significant differences in microleakage were noted between the individually acid etched and laser-irradiated groups (p > 0.05); however, teeth treated with a combination of laser irradiation and acid etching demonstrated significantly lower microleakage scores (p < 0.001). Electron microscopy with energy-dispersive X-ray analysis revealed that the mineral filler component of UltraSeal XT hydro essentially comprises micrometre-sized particles of inorganic silicon-, aluminium- and barium-bearing phases. Laser etching increases the roughness of the enamel surface which causes a concentrated zoning of the filler particles at the enamel-sealant interface. PMID- 26964798 TI - Effect of low-level laser therapy on tooth sensitivity induced by in-office bleaching. AB - This study aimed to investigate the effect of low-level laser therapy (LLLT) on tooth sensitivity induced by in-office bleaching. Sixty-six patients enrolled in this randomized clinical trial. Following the in-office procedure with 40% hydrogen peroxide, the participants were randomly divided into three groups. The patients in group 1 received irradiation from a low-level red laser (LLRL; 660 nm, 200 mW, 15 s, 12 J/cm(2)), whereas participants in group 2 were subjected to a low-level infrared laser (LLIL; 810 nm) under similar conditions as in group 1. In group 3 (placebo), the laser treatment was the same as that in groups 1 and 2, but without energy output. The degree of tooth sensitivity was recorded at 1, 24, and 48 h after bleaching using a visual analog scale (VAS). The change in tooth shade was measured 30 days after tooth whitening. The intensity of tooth sensitivity was not significantly different between groups at 1 h after bleaching (p > 0.05). At 24 h after therapy, pain level was significantly lower in the LLIL group compared to the LLRL and placebo groups (p < 0.05). At 48 h after bleaching, VAS scores in the LLIL and LLRL groups were comparable to each other (p > 0.05) and both were significantly lower than that of the placebo group (p < 0.05). There was no significant difference in the efficacy of tooth whitening among groups (p > 0.05). LLLT with an infrared diode laser could be recommended as a suitable strategy to reduce the intensity of tooth sensitivity after in office bleaching. PMID- 26964801 TI - Brachytherapy: a dying art or missed opportunity? PMID- 26964799 TI - Evaluation of the effects of pulsed wave LLLT on tibial diaphysis in two rat models of experimental osteoporosis, as examined by stereological and real-time PCR gene expression analyses. AB - Osteoporosis (OP) and osteoporotic fracture are major public health issues for society; the burden for the affected individual is also high. Previous studies have shown that pulsed wave low-level laser therapy (PW LLLT) has osteogenic effects. This study intended to evaluate the impacts of PW LLLT on the cortical bone of osteoporotic rats' tibias in two experimental models, ovariectomized and dexamethasone-treated. We divided the rats into four ovariectomized induced OP (OVX-d) and four dexamethasone-treated (glucocorticoid-induced OP, GIOP) groups. A healthy (H) group of rats was considered for baseline evaluations. At 14 weeks following ovariectomy, we subdivided the OVX-d rats into the following groups: (i) control which had OP, (ii) OVX-d rats treated with alendronate (1 mg/kg), (iii) OVX-d rats treated with LLLT, and (iv) OVX-d rats treated with alendronate and PW LLLT. The remaining rats received dexamethasone over a 5-week period and were also subdivided into four groups: (i) control rats treated with intramuscular (i.m.) injections of distilled water (vehicle), (ii) rats treated with subcutaneous alendronate injections (1 mg/kg), (iii) laser-treated rats, and (iv) rats simultaneously treated with laser and alendronate. The rats received alendronate for 30 days and underwent PW LLLT (890 nm, 80 Hz, 0.972 J/cm(2)) three times per week during 8 weeks. Then, the right tibias were extracted and underwent a stereological analysis of histological parameters and real-time polymerase chain reaction (RT-PCR). A significant increase in cortical bone volume (mm(3)) existed in all study groups compared to the healthy rats. There were significant decreases in trabecular bone volume (mm(3)) in all study groups compared to the group of healthy rats. The control rats with OP and rats from the vehicle group showed significantly increased osteoclast numbers compared to most other groups. Alendronate significantly decreased osteoclast numbers in osteoporotic rats. Concurrent treatments (compounded by PW LLLT and alendronate) produce the same effect on osteoporotic bone. PMID- 26964802 TI - Colorectal Cancer: Epidemiology, Disease Mechanisms and Interventions to Reduce Onset and Mortality. AB - Colorectal cancer (CRC) is a multifactorial disease resulting from lifestyle, genetic, and environmental factors. There are hereditary and non-hereditary CRC types; however, the majority are non-hereditary and mainly caused by somatic mutations in response to environmental factors. In past years, researchers have focused their attention on the mechanisms behind these factors and the methods of improving disease prevention and treatment. Improving the awareness of the population with regard to the benefits of a healthy lifestyle, including a balanced diet associated with exercise, could globally reduce CRC risk. The present review aims to address the current knowledge on CRC, taking into consideration the common molecular alterations upon different environmental and non-environmental factors, current and promising treatment interventions, and how all these factors may interact to positively or negatively influence CRC risk. PMID- 26964800 TI - The dark art of light measurement: accurate radiometry for low-level light therapy. AB - Lasers and light-emitting diodes are used for a range of biomedical applications with many studies reporting their beneficial effects. However, three main concerns exist regarding much of the low-level light therapy (LLLT) or photobiomodulation literature; (1) incomplete, inaccurate and unverified irradiation parameters, (2) miscalculation of 'dose,' and (3) the misuse of appropriate light property terminology. The aim of this systematic review was to assess where, and to what extent, these inadequacies exist and to provide an overview of 'best practice' in light measurement methods and importance of correct light measurement. A review of recent relevant literature was performed in PubMed using the terms LLLT and photobiomodulation (March 2014-March 2015) to investigate the contemporary information available in LLLT and photobiomodulation literature in terms of reporting light properties and irradiation parameters. A total of 74 articles formed the basis of this systematic review. Although most articles reported beneficial effects following LLLT, the majority contained no information in terms of how light was measured (73%) and relied on manufacturer stated values. For all papers reviewed, missing information for specific light parameters included wavelength (3%), light source type (8%), power (41%), pulse frequency (52%), beam area (40%), irradiance (43%), exposure time (16%), radiant energy (74%) and fluence (16%). Frequent use of incorrect terminology was also observed within the reviewed literature. A poor understanding of photophysics is evident as a significant number of papers neglected to report or misreported important radiometric data. These errors affect repeatability and reliability of studies shared between scientists, manufacturers and clinicians and could degrade efficacy of patient treatments. Researchers need a physicist or appropriately skilled engineer on the team, and manuscript reviewers should reject papers that do not report beam measurement methods and all ten key parameters: wavelength, power, irradiation time, beam area (at the skin or culture surface; this is not necessarily the same size as the aperture), radiant energy, radiant exposure, pulse parameters, number of treatments, interval between treatments and anatomical location. Inclusion of these parameters will improve the information available to compare and contrast study outcomes and improve repeatability, reliability of studies. PMID- 26964805 TI - Meal Supervision During Medical Hospitalization for Eating Disorders. AB - The focus of medical hospitalization for restrictive eating disorders is weight gain; however, no guidelines exist on how to achieve successful and safe weight gain. Meal supervision may be a supportive intervention to aid in meal completion and weight gain. The aim of this study was to examine the effect of standardized meal supervision on weight gain, length of stay, vital signs, electrolytes, and use of liquid caloric supplementation in hospitalized adolescents and young adults with restrictive eating disorders. A chart review compared patients who received meal supervision from admission through discharge to an earlier cohort who received meal supervision as needed. There were no differences in weight, electrolytes, or vital signs between the two cohorts. Length of stay for those who received meal supervision from admission was 3 days shorter than earlier cohort. Nursing supervised meals beginning at admission may shorten length of stay and decrease health care costs. PMID- 26964804 TI - Sex differences in healthy human heart rate variability: A meta-analysis. AB - The present meta-analysis aimed to quantify current evidence on sex differences in the autonomic control of the heart, indexed by measures of heart rate variability (HRV) in healthy human subjects. An extensive search of the literature yielded 2020 titles and abstracts, of which 172 provided sufficient reporting of sex difference in HRV. Data from 63,612 participants (31,970 females) were available for analysis. Meta-analysis yielded a total of 1154 effect size estimates (k) across 50 different measures of HRV in a cumulated total of 296,247 participants. Females showed a significantly lower mean RR interval and standard deviation of RR intervals (SDNN). The power spectral density of HRV in females is characterized by significantly less total power that contains significantly greater high- (HF) and less low-frequency (LF) power. This is further reflected by a lower LF/HF ratio. Meta-regression revealed significant effects of age, respiration control and the length of recording available for analysis. Although women showed greater mean heart rate, they showed greater vagal activity indexed by HF power of HRV. Underlying mechanisms of these findings are discussed. PMID- 26964803 TI - PROSPECT Eligibility and Clinical Outcomes: Results From the Pan-Canadian Rectal Cancer Consortium. AB - BACKGROUND: The PROSPECT trial (N1048) is evaluating the selective use of chemoradiation in patients with cT2N1 and cT3N0-1 rectal cancer undergoing sphincter-sparing low anterior resection. We evaluated outcomes of PROSPECT eligible and -ineligible patients from a multi-institutional database. PATIENTS AND METHODS: Data from patients with locally advanced rectal cancer who received chemoradiation and low anterior resection from 2005 to 2014 were retrospectively collected from 5 Canadian centers. Overall survival, disease-free survival (DFS), recurrence-free survival (RFS), and time to local recurrence (LR) were estimated using the Kaplan-Meier method, and a multivariate analysis was performed adjusting for prognostic factors. RESULTS: A total of 566 (37%) of 1531 patients met the PROSPECT eligibility criteria. Eligible patients were more likely to have better PS (P = .0003) and negative circumferential resection margin (P < .0001). PROSPECT eligibility was associated with improved DFS (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.61-0.91), overall survival (HR, 0.73; 95% CI, 0.57-0.95), and RFS (HR, 0.68; 95% CI, 0.54-0.86) in univariate analyses. In multivariate analysis, only RFS remained significantly improved for PROSPECT eligible patients (HR, 0.75; 95% CI, 0.57-1.00, P = .0499). The 3-year DFS and freedom from LR for PROSPECT-eligible patients were 79.1% and 97.4%, respectively, compared to 71.1% and 96.8% for PROSPECT-ineligible patients. CONCLUSION: Real-world data corroborate the eligibility criteria used in the PROSPECT study; the criteria identify a subgroup of patients in whom risk of recurrence is lower and in whom selective use of chemoradiation should be actively examined. PMID- 26964806 TI - Mapping the epidemiology and trends of extra-pulmonary tuberculosis in Saudi Arabia. AB - An extra-pulmonary tuberculosis (EPTB) infection rate of 30% in Saudi Arabia remains above the global rate. A variable rate of infection in each province has been reported and the involvement of most organs has been cited. Nationwide collective data on the current trends of infection are scarce and the factors behind the increased rate of EPTB are perplexing. This review endeavors to shed light into the epidemiology of EPTB, various types of infections sites, geographical differences in the infection rate, known risk factors, and challenges in the diagnosis and management of EPTB in Saudi Arabia. PMID- 26964807 TI - Diagnosis of lymph node tuberculosis using the GeneXpert MTB/RIF in Tunisia. AB - INTRODUCTION: GeneXpert MTB/RIF is a fully-automated diagnostic molecular test which simultaneously detects tuberculosis (TB) and rifampicin (RIF) drug resistance. The purpose of this study is to evaluate the performance of the GeneXpert MTB/RIF test for the detection of Mycobacterium tuberculosis complex (MTBC) in lymph node specimens and to show the place of Mycobacterium bovis as a major cause of TB lymphadenitis. MATERIAL AND METHODS: This study was conducted simultaneously in the National Reference Laboratory for Mycobacteria of Ariana and the Central Laboratory of Sfax, from January to December 2013. In total, 174 lymph node specimens were processed simultaneously for Ziehl-Neelsen, auramine and immuno-histochemical staining. Conventional culture on both Lowenstein-Jensen and liquid medium (Bactec MGIT 960 BD system) and the new molecular-based GeneXpert MTB/RIF assay system were performed. Positive cultures were confirmed using molecular identification (Genotype MTBC Hain Lifescience). RESULTS: Among the 174 samples tested, the GeneXpert detected the DNA of MTBC in 134 samples (77%). Standard bacteriological assays, including AFB microscopy and culture, were positive, respectively, in 41 (23.6%) and 79 (45.4%) specimens. M. bovis was isolated in 76% of positive cultures. GeneXpert sensitivity and specificity results were assessed according to smear and culture results, clinical and histological findings. The sensitivity and specificity of the Xpert assay were 87.5% (126/144) and 73.3%, respectively. CONCLUSION: The implementation of the GeneXpert MTB/RIF assay may dramatically improve the rapid diagnosis of lymph node TB. PMID- 26964808 TI - Study of mechanism of interaction of truncated isoniazid-nicotinamide adenine dinucleotide adduct against multiple enzymes of Mycobacterium tuberculosis by a computational approach. AB - OBJECTIVE/BACKGROUND: Isoniazid (INH) is one of the effective antituberculosis (TB) drugs used for TB treatment. However, most of the drug-resistant Mycobacterium tuberculosis (MTB) clinical strains are resistant to INH, a first line antituberculous drug. Certain metabolic enzymes such as adenosylhomocysteinase (Rv3248c), universal stress protein (Rv2623), nicotinamide adenine dinucleotide (reduced)-dependent enoyl-acyl carrier protein reductase (Rv1484), oxidoreductase (Rv2971), dihydrofolate reductase (Rv2763c), pyrroline-5 carboxylate dehydrogenase (Rv1187) have been identified to bind INH-nicotinamide adenine dinucleotide (INH-NAD) and INH-nicotinamide adenine dinucleotide phosphate adducts coupled to Sepharose resin. These enzymes are reported to be involved in many important biochemical processes of MTB, including cysteine and methionine metabolism, mycobacterial growth regulation, mycolic acid biosynthesis, detoxification of toxic metabolites, folate biosynthesis, etc. The truncated INH-nicotinamide adenine dinucleotide (oxidized) adduct, 4 isonicotinoylnicotinamide, isolated from urine samples of human TB patients treated with INH therapy is proposed to have antimycobacterial activity. METHODS: To understand the mechanism of interaction of the truncated INH-NAD adduct, binding energy studies were carried out on the aforementioned six enzymes with known three-dimensional structures using AutoDock4.2. RESULTS: In silico docking analysis of these MTB enzymes with the truncated INH-NAD adduct showed favorable binding interactions with docking energies ranging from -5.29 to -7.07 kcal/mol. CONCLUSION: Thus, in silico docking study revealed that the INH-NAD adduct, which is generated in vivo after INH activation, may undergo spontaneous hydrolysis to form the truncated INH-NAD adduct and further binds and inhibits multiple enzymes of MTB, in addition to InhA, confirming that INH is an effective anti-TB drug acting at multiple enzymes. Further analysis of amino acid residues in the active site of INH-NAD-binding proteins showed the probable presence of catalytic triad in four enzymes possibly involved in INH binding to the enzyme. PMID- 26964809 TI - Comparison of four DNA extraction methods for the detection of Mycobacterium leprae from Ziehl-Neelsen-stained microscopic slides. AB - OBJECTIVE/BACKGROUND: The diagnosis of leprosy has been a challenge due to the low sensibility of the conventional methods and the impossibility of culturing the causative organism. In this study, four methods for Mycobacterium leprae nucleic-acid extraction from Ziehl-Neelsen-stained slides (ZNS slides) were compared: Phenol/chloroform, Chelex 100 resin, and two commercial kits (Wizard Genomic DNA Purification Kit and QIAamp DNA Mini Kit). METHODS: DNA was extracted from four groups of slides: a high-codification-slide group (bacteriological index [BI]?4), a low-codification-slide group (BI=1), a negative-slide group (BI=0), and a negative-control-slide group (BI=0). Quality DNA was evidenced by the amplification of specific repetitive element present in M. leprae genomic DNA (RLEP) using a nested polymerase chain reaction. RESULTS: This is the first report comparing four different extraction methods for obtaining M. leprae DNA from ZNS slides in Cuban patients, and applied in molecular diagnosis. Good quality DNA and positive amplification were detected in the high-codification slide group with the four methods, while from the low-codification-slide group only the QIAGEN and phenol-chloroform methods obtained amplification of M. leprae. In the negative-slide group, only the QIAGEN method was able to obtain DNA with sufficient quality for positive amplification of the RLEP region. No amplification was observed in the negative-control-slide group by any method. Patients with ZNS negative slides can still transmit the infection, and molecular methods can help identify and treat them, interrupting the chain of transmission and preventing the onset of disabilities. CONCLUSION: The ZNS slides can be sent easily to reference laboratories for later molecular analysis that can be useful not only to improve the diagnosis, but also for the application of other molecular techniques. PMID- 26964810 TI - Genetic diversity of Mycobacterium tuberculosis strains isolated in Algeria: Results of spoligotyping. AB - OBJECTIVE/BACKGROUND: Molecular typing tools, including spoligotyping, are currently widely used in the monitoring and study of the dynamics of tuberculosis epidemics. METHODS: A study of the molecular profile of a sample of 129 Myobacterium tuberculosis strains isolated during 2011 was carried out in the National Reference Laboratory for Tuberculosis and Mycobacteria at the Pasteur Institute of Algeria. This sample was selected at random from a set of 350 strains isolated from tuberculosis patients from central and eastern areas of the country. RESULTS: Genotypic analysis helped to clarify the frequencies of the different genotypes in the current study population: H family, 29%; LAM family, 26%; T family, 25%; S family, 5%, and other genomic families, including orphan strains, 15%. CONCLUSION: The study of strains isolated between January and December 2011 has allowed insight into the frequency of different genomic families and the importance of existing clusters in the population of central and eastern Algeria. PMID- 26964811 TI - Morphological changes in experimental tuberculosis resulting from treatment with quercetin and polyvinylpyrrolidone. AB - RESEARCH OBJECTIVE: Morphological study of tissue necrosis stages in experimental organ-preserving tuberculosis pharmacotherapy using Quercetin and Polyvinylpyrrolidone (QP). BACKGROUND AND METHODS: 32 laboratory mice of C57BL/6JLacSto strain were used in the experiment. The animals were divided into five groups, six to seven mice in each: group 1- Mycobacterium tuberculosis (MBT) uninfected mice; group 2- MBT infected mice; group 3- MBT infected and treated with antituberculosis preparation (ATP); group 4- MBT infected and QP treated; group 5- MBT infected and treated with ATP and QP. The mice were infected through caudal vein injection with MTB H37Rv strain. The preparation QP, which belongs to the capillary-stabilizing-remedy group, was used for the research. The ATP were izoniazid and streptomycin. RESULTS: QP produced a strict delineation of caseous necrosis from the unaffected parts of the connective tissue with fibrosis in the center and a large number of Langerhans cells, which was not observed in the control groups without QP. The combination of QP and ATP had more pronounced effects. In MBT-infected mice, where QP was not used, unlike the group where QP was used, adipose dystrophy of hepatocytes was observed. Thus, the hepatoprotective effect of QP against TB can be suggested. CONCLUSION: QP produces a clear delineation of caseous necrosis from an uninfected tissue by connective-tissue formation, and by forming fibrotic tissue in the center of epithelioid cells that prevents further TB dissemination by enhancing TB pharmacotherapy. PMID- 26964812 TI - Mycobacterium tuberculosis resistance pattern against first-line drugs in patients from urban area. AB - OBJECTIVE/BACKGROUND: Tuberculosis (TB) infection is still a major public health burden in Indonesia. TB cases in Indonesia constitute 35% of all the TB cases detected worldwide and the prevalence of TB drug resistance in this country is approximately 3%. The aim of this study was to evaluate the resistance of Mycobacterium tuberculosis to first-line TB drugs among isolates from clinical specimens from a hospital in an urban area. METHODS: This laboratory-based study was conducted in Tangerang District, Indonesia, from January 2011 to December 2014. Sputum and other clinical specimens were obtained from patients with pulmonary and extrapulmonary TB. The specimens were stained with Ziehl-Neelsen, inoculated on Lowenstein-Jensen media for 6-8 weeks, and tested for sensitivity against first-line TB drugs [isoniazid (INH), rifampicin (RIF), ethambutol (EMB), and streptomycin (SM)]. RESULTS: All TB patients in this study lived in urban areas with male preponderance. Of the 127 M. tuberculosis isolates collected, 22% showed resistance to first-line TB drugs. Among these resistant isolates, 20.5% showed resistance to at least one of the first-line TB drugs and 0.8% showed multidrug resistance (MDR). Resistance to EMB, INH, RIF, and SM was seen in 6.3% 6.3%, 4.7%, and 1.6% of isolates, respectively. Polyresistance to EMB and INH, EMB and RIF, and EMB, INH, and RIF was seen in 0.8% of the isolates, respectively. CONCLUSION: Our study confirms that drug resistance, including MDR, observed against all first-line TB drugs was a real threat in the management of TB infection in Indonesia. The resistance pattern identified in this study could assist clinicians in providing appropriate treatment regimen to TB patients and improve their clinical outcome. PMID- 26964813 TI - In vitro antimycobacterial activity of six Cameroonian medicinal plants using microplate alamarBlue assay. AB - OBJECTIVE/BACKGROUND: The latest incidence of tuberculosis (TB) (per 100,000 people) in Cameroon was 243.00 as of 2011. Over the past 21 years, the value for this indicator has fluctuated between 112.00 in 1990 and 320.00 in 2003. Worldwide, this incidence has also increased, bringing back TB as a reemerging disease. On the same note, resistance to anti-TB drugs has increased, urging the search for new molecules. METHODS: This study was carried out to evaluate the antimycobacterial activity of six medicinal plants on the virulent strain, H37Rv, using the microplate alamarBlue assay. Mycobacterium tuberculosis (H37Rv strain) was incubated with decreased concentrations of six plant extracts, ranging from 250 MUg/mL to 31.25 MUg/mL. After 7 days of incubation at 37 degrees C, the effects of these plant extracts on the viability of the mycobacteria were evaluated. For each plant extract, the minimal inhibitory concentration was determined. RESULTS: The results showed that the compounds MBC1, MBC24, MBC68, MBC81, MBC117, and MBC118 were the best candidates with minimal inhibitory concentrations of 31.25, 62.5, 125, 62.5, and 125 MUg/mL, respectively. CONCLUSION: These results confirm and validate the traditional use of these plants to treat respiratory diseases, which could be good sources and alternatives of plant metabolites for anti-TB-drug development. PMID- 26964814 TI - Nested reverse transcriptase-polymerase chain reactions targeting the messenger RNA of icl2, hspx, and rRNAP1 genes to detect viable Mycobacterium tuberculosis directly from clinical specimens. AB - There is an urgent need for a rapid and reliable test to detect actively multiplying Mycobacterium tuberculosis directly from clinical specimens for an early initiation of the appropriate antituberculous treatment. This study was aimed at the optimization and application of nested reverse transcriptase-PCR (nRT-PCR) targeting the messenger RNA of the icl2, hspx, and rRNAP1 genes directly from sputum specimens, and their evaluation against the culture by the BACTEC MicroMGIT mycobacterial culture system. 203 Sputum samples from clinically suspected tuberculosis patients and 30 control specimens (clinically proven viral or bacterial infections other than tuberculosis) were included in this study. The mycobacterial culture was performed by the BACTEC MicroMGIT system following the manufacturer's instructions. The primers for nRT-PCRs targeting icl2, hspx, and rRNAP1 genes were indigenously designed using the Primer-BLAST software, and optimized for sensitivity and specificity. The icl2, hspx, and rRNAP1 genes were able to pick up 63.9%, 67.2%, and 58.75%, respectively, of culture-negative sputum specimens collected from clinically suspected tuberculosis patients. However, three (1.4%) were negative for nRT-PCR, but M. tuberculosis culture positive. All the 30 controls were negative for culture by the BACTEC MicroMGIT method and all three nRT-PCR. The novel nRT-PCRs targeting icl2, hspx, and rRNAP1 genes developed in this study are rapid and reliable diagnostic tools to detect viable M. tuberculosis directly from sputum specimens. However, further study by including a larger number of sputum specimens needs to be carried out to ascertain the diagnostic utility of the novel nRT-PCRs optimized in the study. PMID- 26964815 TI - Hookworm infection among patients with pulmonary tuberculosis: Impact of co infection on the therapeutic failure of pulmonary tuberculosis. AB - OBJECTIVE/BACKGROUND: The aim of this study is to determine the rate of hookworm infection among patients with pulmonary tuberculosis (TB) and to find out if there is a relation between hookworm infection and the therapeutic failure of pulmonary TB. METHODS: We carried out a prospective, hospital-based study. The study included 231 naive patients with pulmonary TB, consecutively. Patients were evaluated at the 4th month of therapy for persistence of Mycobacterium tuberculosis infection. All patients had clinical evaluation, laboratory investigations (including sputum culture and stool microscopic examination), and imaging studies (abdominal ultrasonography and chest radiography). RESULTS: The study population mean age was 42.7+/-13.9 years old with 26.8% of them 40 years old or more. Out of 231 patients, 133 (57.6%) were men. Therapeutic failure rate of pulmonary TB was 29.4%. Hookworm infection was diagnosed among 16.5% of patients and 27.7% had diabetes mellitus (DM). Using multivariate analysis, it was found that age of 40 years or more (odds ratio [OR] 8.4; 95% confidence interval [CI] 1.7-41.3; p=.009), hookworm infection (OR 7.6; 95% CI 1.2-49.9; p=.034), and DM (OR 5.9; 1.2-28; p=.027) were independently associated with therapeutic failure of pulmonary TB among the study population with pulmonary TB. CONCLUSION: In conclusion, the rate of therapeutic failure of pulmonary TB is high. Besides older age and DM, hookworm infection can reduce the therapeutic response of pulmonary TB. Screening for and control of DM and hookworm infection among patients with pulmonary TB may improve their therapeutic response. PMID- 26964816 TI - Diabetes mellitus and its influence on sputum smear positivity at the 2nd month of treatment among pulmonary tuberculosis patients in Kuala Lumpur, Malaysia: A case control study. AB - OBJECTIVE/BACKGROUND: Many studies have suggested that sputum smear conversion after 2 months of antituberculosis treatment is an important determinant of treatment success and can be a predictor for relapse. The objective of this study is to determine the factors that influence sputum smear conversion after 2 months of treatment among pulmonary tuberculosis patients receiving treatment in the Institute of Respiratory Medicine in Kuala Lumpur, Malaysia. METHODS: A total of 75 cases and 75 controls were interviewed, and their medical records were retrieved in order to extract the information needed. All analyses were conducted using SPSS version 17, and binary logistic regression analysis was used to determine the predictors of sputum smear nonconversion. RESULTS: Results showed that the following factors were associated with sputum smear positivity after 2 months of intensive treatment: diabetes mellitus (p=.013, odds ratio [OR]=2.59, 95% confidence interval [CI] 1.27-5.33), underweight body mass index (p=.025, OR=1.67, 95% CI 0.80-3.49), nonadherent to tuberculosis treatment (p=.024, OR=2.85, 95% CI 1.21-6.74), and previous history of tuberculosis (p=.043, OR=2.53, 95% CI 1.09-5.83). Multivariable analysis identified diabetes mellitus (p=.003, OR=4.01, 95% CI 1.61-9.96) as being independently associated with the risk of persistent sputum smear positivity after 2 months of intensive treatment. CONCLUSION: Based on the findings, identification of these factors is valuable in strengthening the management and treatment of tuberculosis in Malaysia in the future. This study emphasizes the importance of diabetes screening and integration of diabetic controls among tuberculosis patients in achieving better treatment outcome. PMID- 26964817 TI - Virtual screening studies to identify novel inhibitors for Sigma F protein of Mycobacterium tuberculosis. AB - Tuberculosis (TB) is one of the oldest threats to public health. TB is caused by the pathogen Mycobacterium tuberculosis (MTB). The Sigma factors are essential for the survival of MTB. The Sigma factor Sigma F (SigF) regulates genes expression under stress conditions. The SigF binds to RNA polymerase and forms a holoenzyme, which initiates the transcription of various genes. The Usfx, an anti SigF protein, binds to SigF and alters the transcription initiation and gene expression. In the present work, virtual screening studies are taken up to identify the interactions between SigF and small molecular inhibitors which can inhibit the formation of holoenzyme. The studies reveal that ARG 104 and ARG 224 amino acid residues of SigF protein are forming important binding interactions with the ligands. The in silico ADME properties for the ligand data set are calculated to check the druggability of the molecules. PMID- 26964818 TI - Reactivation of pulmonary tuberculosis during cancer treatment. AB - Reactivation of Mycobacterium tuberculosis can occur in patients with latent tuberculosis (TB) with risk factors including chronic disease (i.e., malignancy). We herein describe the case of an immigrant from Hong Kong with lung cancer and no known TB disease who presents with reactivation of TB in the setting of chemotherapy and radiation therapy. PMID- 26964819 TI - Sequence comparison of six human microRNAs genes between tuberculosis patients and healthy individuals. AB - OBJECTIVE/BACKGROUND: MicroRNAs (miRNAs) play an important role in diseases development. Therefore, human miRNAs may be able to inhibit the survival of Mycobacterium tuberculosis (Mtb) in the human host by targeting critical genes of the pathogen. Mutations within miRNAs can alter their target selection, thereby preventing them from inhibiting Mtb genes, thus increasing host susceptibility to the disease. METHODS: This study was undertaken to investigate the genetic association of pulmonary tuberculosis (TB) with six human miRNAs genes, namely, hsa-miR-370, hsa-miR-520d, hsa-miR-154, hsa-miR-497, hsa-miR-758, and hsa-miR 593, which have been predicted to interact with Mtb genes. The objective of the study was to determine the possible sequence variation of selected miRNA genes that are potentially associated with the inhibition of critical Mtb genes in TB patients. RESULTS: The study did not show differences in the sequences compared with healthy individuals without antecedents of TB. CONCLUSION: This result could have been influenced by the sample size and the selection of miRNA genes, which need to be addressed in future studies. PMID- 26964820 TI - Tuberculous flexor tenosynovitis of the hand. AB - Tuberculosis is a major public health problem in developing countries. Flexor tenosynovitis of the fingers constitutes an exceptional tuberculosis localization (Gabl et al., 1997; Senda et al., 2011) [1,2]. Unusual presentations, such as tuberculous tenosynovitis, often go undetected and are associated with a diagnostic and therapeutic delay, especially when bacteriological research proves to be negative. Here, we report a case of tuberculous flexor tenosynovitis of the hand. PMID- 26964821 TI - A 7-year-old girl with multiple skin ulcers: Case report and literature review. AB - INTRODUCTION: There has been an increase in the number of tuberculosis (TB) cases worldwide, but TB of the skin remains rare. CASE PRESENTATION: A case of 7-year old girl with multiple ulcerating nodules who presented with four ulcers in the skin of the left elbow. The patient was unresponsive to broad-spectrum antibiotics treatment initially. Because of poor clinical response to conventional therapy, TB was suspected. Although tuberculin skin test was negative, positive QuantiFERON TB Gold test and clinical picture strongly indicated TB. Clinical diagnosis was confirmed by positive culture for Mycobacterium tuberculosis. CONCLUSION: A high index of clinical suspicion is necessary to suspect TB of the skin. Positive culture remains the gold standard for diagnosis. PMID- 26964822 TI - Efficacy and safety of isoniazid preventive therapy in light of increasing multi drug resistance in tuberculosis. PMID- 26964823 TI - Very brief training for laypeople in hands-only cardiopulmonary resuscitation. Effect of real-time feedback. AB - BACKGROUND: Bystander cardiopulmonary resuscitation (CPR) improves survival from out-of-hospital cardiac arrest, but rates and performance quality remain low. Although training laypeople is a primary educational goal, the optimal strategy is not well defined. This study aimed to determine whether a short training with real-time feedback was able to improve hands-only CPR among untrained citizens. METHODS: On the occasion of the 2015 World Heart Day and the European Restart a Heart Day, a pilot study involving 155 participants (81 laypeople, 74 health care professionals) was conducted. Participants were invited to briefly practice hands only CPR on a manikin and were after evaluated during a 2-minute chest compression (CC) test. During training brief instructions regarding hand position, compression rate and depth according to the current guidelines were given and real-time feedback was provided by a Laerdal SkillReporting System. RESULTS: Mean CC rate was significantly higher among health care professionals than among laypeople (119.07 +/- 12.85 vs 113.02 +/- 13.90 min(-1); P = .006), although both met the 100-120 CC min(-1) criterion. Laypeople achieved noninferior results regarding % of CC at adequate rate (51.46% +/- 35.32% vs health care staff (55.97% +/- 36.36%; P = .43) and depth (49.88% +/- 38.58% vs 50.46% +/- 37.17%; P = .92), % of CC with full-chest recoil (92.77% +/- 17.17% vs 0.91% +/- 18.84; P = .52), and adequate hand position (96.94% +/- 14.78% vs 99.74 +/- 1.98%; P = .11). The overall quality performance was greater than 70%, noninferior for citizens (81.23% +/- 20.10%) vs health care staff (85.95% +/- 14.78%; P = .10). CONCLUSION: With a very brief training supported by hands-on instructor-led advice and visual feedback, naive laypeople are able to perform good-quality CC-CPR. Simple instructions, feedback, and motivation were the key elements of this strategy, which could make feasible to train big numbers of citizens. PMID- 26964824 TI - The development and experimental application of a new thoracostomy trocar. PMID- 26964825 TI - Negative pressure wound therapy for serious dog bites of extremities: a prospective randomized trial. AB - OBJECTIVES: The objectives were to investigate the emergency treatment of serious dog bite lacerations on limbs and to identify whether negative pressure wound therapy (NPWT) was beneficial in these instances. METHODS: A total of 580 cases with serious limb lacerations due to dog bites were randomly divided into 2 groups. After thorough debridement, the limb lacerations of group A (n = 329) were left open. The remaining cases (n = 251) were randomly divided into 2 subgroups, group B and group C, which were treated with 125 and 75 mm Hg of continuous negative pressure, respectively. Antibiotics were only used in cases where there were systemic signs of wound infection, and were not given prophylactically. The infection rate, infection time, and healing time were analyzed. RESULTS: The wound infection rates of groups A, B, and C were 9.1%, 4.1%, and 3.9%, respectively. The infection times of the 3 groups were 26.3 +/- 11.6, 159.8 +/- 13.4, and 166.4 +/- 16.2 hours, respectively. The recovery times of the infection patients in the 3 groups were 19.2 +/- 4.6, 13.2 +/- 2.1, and 12.7 +/- 2.3 days, respectively, and in the noninfection patients, the recovery times were 15.6 +/- 2.7, 10.1 +/- 2.3, and 10.5 +/- 1.9 days, respectively. In groups B (-125 mm Hg) and C (-75 mm Hg), the infection rate, infection time, and healing time showed no significant differences. CONCLUSION: Patients with serious dog bite laceration on limbs could benefit from NPWT. Compared with the traditional treatment of leaving the wounds open, NPWT reduced the infection rate and shortened recovery time. When NPWT was performed, low negative pressure (-75 mm Hg) had the same positive effects as high pressure (-125 mm Hg). Prophylactic antibiotics administration is not recommended for treating this kind of laceration. LEVEL OF EVIDENCE: Therapeutic/care management, level II. PMID- 26964826 TI - The need to use the elevated sniffing position for endotracheal intubation. PMID- 26964827 TI - The effect of nebulized magnesium sulfate in the treatment of moderate to severe asthma attacks: a randomized clinical trial. AB - OBJECTIVE: Thirty percent of people with asthma do not respond to standard treatment, and complementary therapies are needed. The objective of this study was to investigate the impact of inhaled magnesium sulfate on the treatment response in emergency department (ED) patients with moderate to severe attacks of asthma. METHODS: This study is a randomized controlled trial, enrolling patients with moderate to severe asthma in the ED. Subjects allocated to the study group were treated with the standard, plus 3 ml of 260 mmol/L solution of magnesium sulfate every 20 to 60 minutes. The control group was treated with nebulized saline as a placebo in addition to standard protocol. The study results included admission rate and changes in peak expiratory flow rate (PEFR) (primary outcomes) as well as dyspnea severity score, respiratory rate and peripheral oxygen saturation. RESULTS: A total of 50 patients were enrolled (25 allocated to the study group and 25 to the control group). The study group as compared to the control group had significantly more improvement in the intensity of dyspnea, PEFR and Spo2 20, 40 and 60 minutes after intervention. In the control group, 11 patients (44%) required admission as compared to 18 (72%) in the control group (P=.02). CONCLUSION: Adding nebulized magnesium sulfate to standard therapy in patients with moderate to severe asthma attacks leads to greater and faster improvement in PEFR, respiratory rate, oxygen saturation and respiratory rate. It also reduces hospitalization rates in this patient population. PMID- 26964829 TI - Analysing indicators of performance, satisfaction, or safety using empirical logit transformation. PMID- 26964828 TI - An unusual presentation of disseminated Mycobacterium tuberculosis in the ED. PMID- 26964830 TI - Dynamic cross talk between metabolic organs in obesity and metabolic diseases. PMID- 26964831 TI - Heterogeneity of white adipose tissue: molecular basis and clinical implications. AB - Adipose tissue is a highly heterogeneous endocrine organ. The heterogeneity among different anatomical depots stems from their intrinsic differences in cellular and physiological properties, including developmental origin, adipogenic and proliferative capacity, glucose and lipid metabolism, insulin sensitivity, hormonal control, thermogenic ability and vascularization. Additional factors that influence adipose tissue heterogeneity are genetic predisposition, environment, gender and age. Under obese condition, these depot-specific differences translate into specific fat distribution patterns, which are closely associated with differential cardiometabolic risks. For instance, individuals with central obesity are more susceptible to developing diabetes and cardiovascular complications, whereas those with peripheral obesity are more metabolically healthy. This review summarizes the clinical and mechanistic evidence for the depot-specific differences that give rise to different metabolic consequences, and provides therapeutic insights for targeted treatment of obesity. PMID- 26964832 TI - Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism. AB - Accumulated evidence from genetic animal models suggests that the brain, particularly the hypothalamus, has a key role in the homeostatic regulation of energy and glucose metabolism. The brain integrates multiple metabolic inputs from the periphery through nutrients, gut-derived satiety signals and adiposity related hormones. The brain modulates various aspects of metabolism, such as food intake, energy expenditure, insulin secretion, hepatic glucose production and glucose/fatty acid metabolism in adipose tissue and skeletal muscle. Highly coordinated interactions between the brain and peripheral metabolic organs are critical for the maintenance of energy and glucose homeostasis. Defective crosstalk between the brain and peripheral organs contributes to the development of obesity and type 2 diabetes. Here we comprehensively review the above topics, discussing the main findings related to the role of the brain in the homeostatic regulation of energy and glucose metabolism. PMID- 26964834 TI - Regulation of glucose metabolism from a liver-centric perspective. AB - Glucose homeostasis is tightly regulated to meet the energy requirements of the vital organs and maintain an individual's health. The liver has a major role in the control of glucose homeostasis by controlling various pathways of glucose metabolism, including glycogenesis, glycogenolysis, glycolysis and gluconeogenesis. Both the acute and chronic regulation of the enzymes involved in the pathways are required for the proper functioning of these complex interwoven systems. Allosteric control by various metabolic intermediates, as well as post translational modifications of these metabolic enzymes constitute the acute control of these pathways, and the controlled expression of the genes encoding these enzymes is critical in mediating the longer-term regulation of these metabolic pathways. Notably, several key transcription factors are shown to be involved in the control of glucose metabolism including glycolysis and gluconeogenesis in the liver. In this review, we would like to illustrate the current understanding of glucose metabolism, with an emphasis on the transcription factors and their regulators that are involved in the chronic control of glucose homeostasis. PMID- 26964833 TI - Crosstalk between the heart and peripheral organs in heart failure. AB - Mediators from peripheral tissues can influence the development and progression of heart failure (HF). For example, in obesity, an altered profile of adipokines secreted from adipose tissue increases the incidence of myocardial infarction (MI). Less appreciated is that heart remodeling releases cardiokines, which can strongly impact various peripheral tissues. Inflammation, and, in particular, activation of the nucleotide-binding oligomerization domain-like receptors with pyrin domain (NLRP3) inflammasome are likely to have a central role in cardiac remodeling and mediating crosstalk with other organs. Activation of the NLRP3 inflammasome in response to cardiac injury induces the production and secretion of the inflammatory cytokines interleukin (IL)-1beta and IL-18. In addition to having local effects in the myocardium, these pro-inflammatory cytokines are released into circulation and cause remodeling in the spleen, kidney, skeletal muscle and adipose tissue. The collective effects of various cardiokines on peripheral organs depend on the degree and duration of myocardial injury, with systematic inflammation and peripheral tissue damage observed as HF progresses. In this article, we review mechanisms regulating myocardial inflammation in HF and the role of factors secreted by the heart in communication with peripheral tissues. PMID- 26964838 TI - [Use of hyaluronidase to correct hyaluronic acid injections in aesthetic medicine]. AB - Hyaluronic acid (HA) is the most commonly used filler in aesthetic medicine. However, overcorrections are frequent even with experienced practitioner. Hyaluronidase is an enzyme that hydrolyzes HA. Hyaluronidase has been recently proposed to correct unsatisfactory results of HA injections in aesthetic medicine (overcorrection, asymmetry, Tyndall effect) and to treat immediate complications such as arterial or venous thrombosis. The objective of this technical note was to summarize the literature data regarding the efficacy, safety and technique of use of hyaluronidase. Hyaluronidase may be responsible for allergies. The practitioner should take this risk and the possible drug interactions into account before using this antidote in order to weigh up the risk/benefit ratio. PMID- 26964836 TI - Recent progress in genetic and epigenetic research on type 2 diabetes. AB - Type 2 diabetes (T2DM) is a common complex metabolic disorder that has a strong genetic predisposition. During the past decade, progress in genetic association studies has enabled the identification of at least 75 independent genetic loci for T2DM, thus allowing a better understanding of the genetic architecture of T2DM. International collaborations and large-scale meta-analyses of genome-wide association studies have made these achievements possible. However, whether the identified common variants are causal is largely unknown. In addition, the detailed mechanism of how these genetic variants exert their effect on the pathogenesis of T2DM requires further investigation. Currently, there are ongoing large-scale sequencing studies to identify rare, functional variants for T2DM. Environmental factors also have a crucial role in the development of T2DM. These could modulate gene expression via epigenetic mechanisms, including DNA methylation, histone modification and microRNA regulation. There is evidence that epigenetic changes are important in the development of T2DM. Recent studies have identified several DNA methylation markers of T2DM from peripheral blood and pancreatic islets. In this review, we will briefly summarize the recent progress in the genetic and epigenetic research on T2DM and discuss how environmental factors, genetics and epigenetics can interact in the pathogenesis of T2DM. PMID- 26964837 TI - [Harlequin syndrome in a melanoderm patient]. AB - INTRODUCTION: Harlequin's syndrome is a neurological disorder due to a dysfunction of the sympathetic innervation of the face. It has been rarely reported in the literature. The authors report one case occurring in a melanoderm patient. OBSERVATION: A 38-year-old melanoderm man, without any history of surgery or neck trauma, consulted for a strictly right unilateral facial hyperhidrosis. Clinical and radiological investigations concluded to an idiopathic Harlequin's syndrome. Therapeutic abstention was proposed because of non-invalidating symptoms. DISCUSSION: Harlequin's syndrome is a rare sudoral and vaso-motor disorder. On dark skin, flush and erythrosis may be subtle and the diagnosis less obvious. Etiologies are varied but essentially idiopathic. Its association with others dysautonomic facial syndromes is possible. Main differential diagnosis is the Frey's syndrome. Treatment is not clearly codified. PMID- 26964839 TI - [Kimura's disease of the hard palate]. AB - INTRODUCTION: Kimura's disease is an inflammatory and autoimmune disease that is endemic in Middle East and Asian countries but remains rare in Europe. It usually presents as subcutaneous nodules combined with cervical lymphadenopathies in the cervicofacial region. The oral mucosa localization is extremely rare. We report for the first time a case of hard palate localization. OBSERVATION: A 61-year-old male patient from Martinique consulted for a recent median, extensive and poorly defined black area localized on the hard palate. It was painless and did not cause any discomfort. We performed a biopsy to rule out a melanoma. The pathology report led to diagnosing Kimura's disease. The biological parameters, especially the renal status, were normal. A simple medical supervision was prescribed. DISCUSSION: This was the first time Kimura's disease was observed as a pigmented area located on the hard palate. The diagnosis of melanoma first had to be ruled out. The histological and immunohistological parameters are mandatory to make a diagnosis. PMID- 26964840 TI - [Reached multifocal secondary syphilis: A case presentation]. AB - INTRODUCTION: Syphilis is a sexually transmitted infection (STI) related to Treponema pallidum. Secondary syphilis is the blood-borne systemic spread of Treponema. OBSERVATION: We report the case of secondary syphilis in a patient without risk of STIs factor. The clinical picture began with a genital affection followed by oral erosions and ulcers and an anterior and then posterior uveitis. Serology established the diagnosis and intravenous penicillin G treatment allowed for healing. DISCUSSION: Called the "great pretender" because of its clinical polymorphism, secondary syphilis can lead to formidable neurological and ophthalmological complications. Serological diagnosis is based on the use of treponemal and a nontreponemal tests. Penicillin G remains the treatment of choice and must be adapted according to the clinical damage. PMID- 26964841 TI - [A cervical necrotizing cellulitis revealing a Lemierre syndrome]. AB - INTRODUCTION: Lemierre syndrome is characterized by a septic thrombophlebitis of the internal jugular vein (IJV) following an oropharyngeal infection. CASE REPORT: We report a case of Lemierre syndrome that occurred in a context of angina and necrotizing cellulitis of the neck in a 45-year-old patient. The Doppler ultrasound exam of the neck vessels and a neck CT showed an IJV thrombophlebitis. No germ could be isolated in the samples (blood culture, pus). The treatment associated antibiotics, heparin and surgical debridement of the necrotic tissues with extraction of the thrombus after ligation and section of the IJV. The postoperative course was uneventful. DISCUSSION: Lemierre syndrome is a rare but serious disease. Its low incidence makes him a forgotten disease. It should be systematically suspected in any oropharyngeal infection with the presence of a large painful swelling of the neck. PMID- 26964843 TI - Eu(III)-Sensitized Luminescence Probe for Determination of Tolnaftate in Pharmaceuticals and Biological Fluids. AB - A highly selective, sensitive, accurate, and reproducible luminescence procedure for determination of antifungal drug tolnaftate was developed. The introduced method was based on the formation of Europa Universalis III (Eu(III))-tolnaftate complex using sodium sulfite as a deoxygenated agent in the presence of acetate buffer (pH = 6) and micellar solution of anionic surfactant sodium dodecyl sulfate. The optimum conditions (effect of pH, buffer, surfactant, Eu(III), and sodium sulfite concentrations) for the luminescence signal were investigated and optimized. The luminescence signals were recorded at lambdaex = 270 nm and lambdaem = 460 nm. The method has a good linear response (0.2-130 MUg/mL(-1)) between the luminescence intensity and the concentrations of the drug (r = 0.999), with a LOD 0.07 MUg/mL(-1) and LOQ 0.2 MUg/mL(-1). The luminescence signals of Eu (III)-tolnaftate-sodium dodecyl sulfate were found to be 200-fold more sensitive without the presence of micelle solution. The interferences of some additives, metals, amino acids, sugars, and other related pharmacological action drugs were examined and no interference was recorded. The proposed method was used for quick and simple determination of tolnaftate in its pharmaceuticals and biological fluids. PMID- 26964842 TI - Pathogenicity of IgG in patients with IgG4-related disease. AB - OBJECTIVE: IgG4-related disease (IgG4-RD) is a systemic disease characterised by elevated serum IgG4 and IgG4-positive lymphoplasmacytic infiltration in the affected tissues. The pathogenic role of IgGs, including IgG4, in patients with IgG4-RD, however, is unknown. DESIGN: We examined the pathogenic activity of circulating IgGs in patients with IgG4-RD by injecting their IgGs into neonatal male Balb/c mice. Binding of patient IgGs to pancreatic tissue was also analysed in an ex vivo mouse organ culture model and in tissue samples from patients with autoimmune pancreatitis (AIP). RESULTS: Subcutaneous injection of patient IgG, but not control IgG, resulted in pancreatic and salivary gland injuries. Pancreatic injury was also induced by injecting patient IgG1 or IgG4, with more destructive changes induced by IgG1 than by IgG4. The potent pathogenic activity of patient IgG1 was significantly inhibited by simultaneous injection of patient IgG4. Binding of patient IgG, especially IgG1 and IgG4, to pancreatic tissue was confirmed in both the mouse model and AIP tissue samples. CONCLUSIONS: IgG1 and IgG4 from patients with IgG4-RD have pathogenic activities through binding affected tissues in neonatal mice. PMID- 26964845 TI - Flame Atomic Absorption Spectrometric Determination of Gold After Solid-Phase Extraction of Its 2-Aminobenzothiazole Complex on Diaion SP-207. AB - An SPE of Au (III) on a 2-aminobenzothiazole-coated Diaion SP 207-column system has been developed. The parameters, including pH of solution, amount of 2 aminobenzothiazole, eluent type, sample volume, and flow rates, were examined. The effects of alkali, alkali earth, and some metals were also studied. The recovery values at optimal conditions and detection limits for Au (III) were found as >95% and 3.8 MUg L(-1), respectively. The factor of preconcentration was 250. The RSD value was <5%. The capacity of adsorption for the resin was 10.4 mg g(-1). The accuracy of the method was evaluated by the use of CDN-GS-3D gold certified reference material. The proposed procedure for the determination of gold was applied to water, mine, soil, and anodic slime samples. PMID- 26964835 TI - Pancreatic regulation of glucose homeostasis. AB - In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed. PMID- 26964844 TI - Urinary Stone Disease: Advancing Knowledge, Patient Care, and Population Health. AB - Expanding epidemiologic and physiologic data suggest that urinary stone disease is best conceptualized as a chronic metabolic condition punctuated by symptomatic, preventable stone events. These acute events herald substantial future chronic morbidity, including decreased bone mineral density, cardiovascular disease, and CKD. Urinary stone disease imposes a large and growing public health burden. In the United States, 1 in 11 individuals will experience a urinary stone in their lifetime. Given this high incidence and prevalence, urinary stone disease is one of the most expensive urologic conditions, with health care charges exceeding $10 billion annually. Patient care focuses on management of symptomatic stones rather than prevention; after three decades of innovation, procedural interventions are almost exclusively minimally invasive or noninvasive, and mortality is rare. Despite these advances, the prevalence of stone disease has nearly doubled over the past 15 years, likely secondary to dietary and health trends. The NIDDK recently convened a symposium to assess knowledge and treatment gaps to inform future urinary stone disease research. Reducing the public health burden of urinary stone disease will require key advances in understanding environmental, genetic, and other individual disease determinants; improving secondary prevention; and optimal population health strategies in an increasingly cost-conscious care environment. PMID- 26964846 TI - Exploring midwifery prescribing in Australia. AB - BACKGROUND: Midwifery prescribing was introduced in Australia in 2010 and is available to those notated as Medicare Eligible. Only 59% of Medicare Eligible midwives are endorsed prescribers. AIM: To explore and describe Australian midwives views of prescribing including the barriers and enablers to prescribing. METHODS: Online survey. Eligible participants were Australian midwives who had completed an educational programme required for endorsement as a midwifery prescriber (n=131). Descriptive statistics and content analysis were used to analyse the data set. RESULTS: Sixty-six midwives entered data (50% response rate). Twelve midwives (18%) had commenced prescribing. Prescribers agreed that being able to prescribe enhanced women's access to medicines and role satisfaction. The most common barriers to initiating prescribing were regulatory issues and processes, and no pathway to support midwifery prescribing in the public sector. The enabling factors most commonly reported were supportive relationships, education and personal factors such as motivation, knowledge and confidence. CONCLUSION: Prescribing was viewed positively by midwives, but only a small proportion of suitably educated midwives were able to translate this into prescribing. Prolonged and complicated registration processes, restrictive drug formularies, and a lack of prescribing roles for public sector midwives were clear barriers. Supportive professional relationships, quality education and personal motivation and confidence assisted midwives in overcoming these barriers. Offering mentoring may help midwives to move into prescribing practice and use it in a manner that best meets the health needs of women and infants in midwifery care. PMID- 26964848 TI - Benchmarking management practices in Australian public healthcare. AB - PURPOSE: The purpose of this paper is to investigate the quality of management practices of public hospitals in the Australian healthcare system, specifically those in the state-managed health systems of Queensland and New South Wales (NSW). Further, the authors assess the management practices of Queensland and NSW public hospitals jointly and globally benchmark against those in the health systems of seven other countries, namely, USA, UK, Sweden, France, Germany, Italy and Canada. DESIGN/METHODOLOGY/APPROACH: In this study, the authors adapt the unique and globally deployed Bloom et al. (2009) survey instrument that uses a "double blind, double scored" methodology and an interview-based scoring grid to measure and internationally benchmark the management practices in Queensland and NSW public hospitals based on 21 management dimensions across four broad areas of management - operations, performance monitoring, targets and people management. FINDINGS: The findings reveal the areas of strength and potential areas of improvement in the Queensland and NSW Health hospital management practices when compared with public hospitals in seven countries, namely, USA, UK, Sweden, France, Germany, Italy and Canada. Together, Queensland and NSW Health hospitals perform best in operations management followed by performance monitoring. While target management presents scope for improvement, people management is the sphere where these Australian hospitals lag the most. PRACTICAL IMPLICATIONS: This paper is of interest to both hospital administrators and health care policy-makers aiming to lift management quality at the hospital level as well as at the institutional level, as a vehicle to consistently deliver sustainable high quality health services. ORIGINALITY/VALUE: This study provides the first internationally comparable robust measure of management capability in Australian public hospitals, where hospitals are run independently by the state-run healthcare systems. Additionally, this research study contributes to the empirical evidence base on the quality of management practices in the Australian public healthcare systems of Queensland and NSW. PMID- 26964847 TI - Sustaining organizational culture change in health systems. AB - PURPOSE: The questions addressed by this review are: first, what are the guiding principles underlying efforts to stimulate sustained cultural change; second, what are the mechanisms by which these principles operate; and, finally, what are the contextual factors that influence the likelihood of these principles being effective? The paper aims to discuss these issues. DESIGN/METHODOLOGY/APPROACH: The authors conducted a literature review informed by rapid realist review methodology that examined how interventions interact with contexts and mechanisms to influence the sustainability of cultural change. Reference and expert panelists assisted in refining the research questions, systematically searching published and grey literature, and helping to identify interactions between interventions, mechanisms and contexts. FINDINGS: Six guiding principles were identified: align vision and action; make incremental changes within a comprehensive transformation strategy; foster distributed leadership; promote staff engagement; create collaborative relationships; and continuously assess and learn from change. These principles interact with contextual elements such as local power distributions, pre-existing values and beliefs and readiness to engage. Mechanisms influencing how these principles sustain cultural change include activation of a shared sense of urgency and fostering flexible levels of engagement. PRACTICAL IMPLICATIONS: The principles identified in this review, along with the contexts and mechanisms that influence their effectiveness, are useful domains for policy and practice leaders to explore when grappling with cultural change. These principles are sufficiently broad to allow local flexibilities in adoption and application. ORIGINALITY/VALUE: This is the first study to adopt a realist approach for understanding how changes in organizational culture may be sustained. Through doing so, this review highlights the broad principles by which organizational action may be organized within enabling contextual settings. PMID- 26964849 TI - Contradicting logics in everyday practice. AB - PURPOSE: Performance management is criticised as a direct challenge to the dominant logic of professionalism in health care organisations. The purpose of this paper is to report an ethnographic study that investigates how performance management and professionalism as contradicting logics are interpreted and implemented by managers and nurses in everyday practice within Norwegian nursing homes. DESIGN/METHODOLOGY/APPROACH: The paper presents an analysis of 18 semistructured interviews and 100 hours of observation of managers and nurses from three nursing homes. The study draws on the institutional logic perspective as a theoretical framework. In the analysis, the authors searched for patterns of activities and interactions that reflected managers and nurses' coping strategies for handling contradicting logics. Qualitative content analysis was used to systematically code the data, supported by NVIVO software. FINDINGS: The authors identified three forms of coping strategies: the adjustment of professionalism to standards, the reinforcement of professional flexibility and problem solving, and the strategic adoption of documentation. These patterns of activities and interactions reflect new organisational structures that allowed contradicting logics to co-exist. The study demonstrates that a new complex dimension of governing processes within nursing homes is the way in which managers and nurses handle the tension between contradicting logics in their daily work and clinicians' everyday practice. ORIGINALITY/VALUE: The study provides new insight into how managers and nurses reshape internal organisational structures to cope with contradicting logics in nursing homes. PMID- 26964850 TI - Measuring effective capacity in an emergency department. AB - PURPOSE: The purpose of this paper is to show how elements from queueing theory can be used to obtain objective measures of effective capacity in the triage function at Skaraborg Hospital in Sweden without direct observation of the function itself. DESIGN/METHODOLOGY/APPROACH: Approximately 30,000 patients arrived to the emergency department at Skaraborg Hospital in Sweden during 2011. The exact time of arrival and the exact time of triage were recorded for each patient on an individual level. Basic queueing theory uses arrival rates and system capacity measures to derive average queueing times. The authors use the theoretical relation between these three measures to derive system capacity measures based on observed arrival rates and observed average queueing times. FINDINGS: The effective capacity in the triage process is not a linear function of the number of nurses. However, the management of capacity seems well adapted to the actual demand, even though service levels vary substantially during the day and night. ORIGINALITY/VALUE: This paper uses elements from queueing theory in an innovative way to measure the effective capacity of a service process without direct observation, thereby also avoiding the potential risk of the Hawthorne effect. PMID- 26964851 TI - Improving care coordination using organisational routines. AB - PURPOSE: The purpose of this paper is to systematically apply theory of organisational routines to standardised care pathways. The explanatory power of routines is used to address open questions in the care pathway literature about their coordinating and organising role, the way they change and can be replicated, the way they are influenced by the organisation and the way they influence health care professionals. DESIGN/METHODOLOGY/APPROACH: Theory of routines is systematically applied to care pathways in order to develop theoretically derived propositions. FINDINGS: Care pathways mirror routines by being recurrent, collective and embedded and specific to an organisation. In particular, care pathways resemble standard operating procedures that can give rise to recurrent collective action patterns. In all, 11 propositions related to five categories are proposed by building on these insights: care pathways and coordination, change, replication, the organisation and health care professionals. Research limitations/implications - The paper is conceptual and uses care pathways as illustrative instances of hospital routines. The propositions provide a starting point for empirical research. PRACTICAL IMPLICATIONS: The analysis highlights implications that health care professionals and managers have to consider in relation to coordination, change, replication, the way the organisation influences care pathways and the way care pathways influence health care professionals. Originality/value - Theory on organisational routines offers fundamental, yet unexplored, insights into hospital processes, including in particular care coordination. PMID- 26964852 TI - Between substance and governance. AB - PURPOSE: Many developed countries have seen significant reforms of their health systems for the last few decades. Despite extensive investment in these changes, health systems still face a range of challenges which reform efforts do not seem to have overcome. The purpose of this paper is to argue that there are two particular reasons, which go beyond the standard explanations of changing demographics and disease profiles. DESIGN/METHODOLOGY/APPROACH: The paper is a commentary based on the literature. FINDINGS: The first explanation relates to the relationship between substantive health care reform and governance reform. These are intertwined processes and the pattern of interaction has distorted both types of reform. Second, reform has multiple meanings and may sometimes be more of an intra-organizational ritual and routine than a coherent plan aiming to bring about particular changes. As such, part of the reason why reform so frequently fails to bring about change is that it was not actually intended to bring about specific changes in the first place. The limited success of reform in recent years, the authors argue, has been a result of the fact that reform has focused too much on the substantive aspects of healthcare, while ignoring the governance aspect of the sector. ORIGINALITY/VALUE: As a result, governance has often been obstructed by interest groups inside the system, resulting in paralysis. The authors conclude by arguing that substantive reform of public organizations without an accompanying reassessment of the governance of these organizations are more likely to fail, compared to more comprehensive reform efforts. PMID- 26964853 TI - Planes, straws and oysters: the use of metaphors in healthcare reform. AB - PURPOSE: The purpose of the paper is to examine the metaphors used by senior managers and clinicians in the delivery of healthcare reform. DESIGN/METHODOLOGY/APPROACH: A study of healthcare reform in England carried out a series of semi structured interviews with senior managers and clinicians leading primary and secondary care organisations. Qualitative data analysis examines instances where metaphorical language is used to communicate how particular policy reforms are experienced and the implications these reforms have for organisational contexts. FINDINGS: The findings show how metaphorical language is used to explain the interactions between policy reform and organisational contexts. Metaphors are used to illustrate both the challenges and opportunities associated with the reform proposals for organisational change. ORIGINALITY/VALUE: The authors provide the first systematic study of patterns and meanings of metaphors within English healthcare contexts and beyond. The authors argue that these metaphors provide important examples of "generative" dialogue in their illustration of the opportunities associated with reform. Conversely, these metaphors also provide examples of "degenerative" dialogue in their illustration of a demarcation between the reform policy proposals and existing organisational contexts. PMID- 26964855 TI - Investigation of nurses' intention to leave: a study of a sample of UK nurses. AB - PURPOSE: The purpose of this paper is to provide an evaluation of the key antecedents of leave intention demonstrated by nurses employed in UK National Health Service (NHS). DESIGN/METHODOLOGY/APPROACH: Survey assessment of a sample of 433 nurses employed within the NHS was undertaken, potential relationships relating to both affective commitment and leave intention and work-place experiences assessed through leader-member exchange (LMX) and perceived organisational support (POS) have been evaluated quantitatively, using confirmatory factor analysis (CFA) and structural equations modelling (SEM). FINDINGS: The study indicates that both LMX and POS act as direct antecedents to nurses' leave intention. Additionally, both LMX and POS in combination, significantly effect employees' affective commitment, the latter further impacting on employee leave intention. This would suggest that both LMX and POS have a significant role to play in employee leave intention that is partially mediated by affective commitment, further analysis confirming this to be the case. Research limitations/implications - The sample of nurses is large in absolute terms, permitting the CFA/SEM analysis undertaken, although the data represented only two NHS trusts, hence generalisation across the NHS should be done so cautiously. Various other drivers of leave intention, personal and organisational, have not been assessed here. PRACTICAL IMPLICATIONS: The implications of these results are that to safeguard nurse retention, appropriate line manager engagement is crucial, but this requires organisational support that is recognised by the employees, especially to enhance their levels of affective commitment. ORIGINALITY/VALUE: This is given by providing NHS-based assessment of the role of both POS and LMX in the realisation of both affective commitment and desire to remain with their current organisations amongst members of the UK nursing profession. PMID- 26964854 TI - Quality improvement in large healthcare organizations. AB - PURPOSE: The purpose of this paper is to investigate the obstacles and challenges associated with organizational monitoring and follow-up (M & F) processes related to health care quality improvement (QI) and development. DESIGN/METHODOLOGY/APPROACH: A longitudinal case study of a large health care organization during a system-wide QI intervention. Content analysis was conducted of repeated interviews with key actors and archival data collected over a period of four years. FINDINGS: The demand for improved M & F strategies, and what and how to monitor were described by the respondents. Obstacles and challenges for achieving M & F strategies that enables system-wide and coherent development were found in three areas: monitoring, processing, and feedback and communication. Also overarching challenges were found. PRACTICAL IMPLICATIONS: A model of important aspects of M & F systems is presented that can be used for analysis and planning and contribute to shared cognition of such systems. Approaches for systematic analysis and follow-up of identified problems have to be developed and fully incorporated in the organization's measurement systems. A systematic M & F needs analytic and process-oriented competence, and this study highlights the potential in an organizational function with capacity and mandate for such tasks. ORIGINALITY/VALUE: Most health care systems are flooded with a vast amount of registers, records, and measurements. A key issue is how such data can be processed and refined to reflect the needs and the development process of the health care system and how rich data can be used for improvement purposes. This study presents key organizational actor's view on important factors to consider when building a coherent organizational M & F strategy. PMID- 26964856 TI - Entrepreneurs ' perspective on public-private partnership in health care and social services. AB - PURPOSE: The purpose of this paper is to probe experiences of entrepreneurs in the social and health care service provision. DESIGN/METHODOLOGY/APPROACH: Information was collected regarding entrepreneurs' views on the factors affecting the collaboration between public and private sectors. A sample of social and health care entrepreneurs was interviewed using open-ended questions. The interviews were transcribed and analysed using inductive content analysis. FINDINGS: Three main categories of factors affecting the success of partnership were identified: the nature of partnership, business aspects and tension builders. Research LIMITATIONS/IMPLICATIONS: The research was undertaken in rural Finland and the sample consisted 13 entrepreneurs. The results must be considered as observations with more generalised conclusions. PRACTICAL implications - The results of this study support municipalities in their social and health care service strategy work and especially in consideration of how to also facilitate a fruitful public-private partnership (PPP)-framework, which will largely depend on mutual understanding and consensus. ORIGINALITY/VALUE: The reform of the social and health care system has raised intensive public debate throughout Europe. Key issues include the reorganising of social and health care processes as well as PPPs in provision of services. This study observes the views and experiences of private entrepreneurs and points out where some potential problems and solutions of social and health care PPPs are. PMID- 26964857 TI - Comparative Study of Acceptance and Adaptation to New Complete Dentures, Using Two Construction Protocols. AB - PURPOSE: To validate patients' acceptance and adaptation to new complete dentures, fabricated using two construction protocols. Evaluation was achieved by means of two psychometric questionnaires and registration of total number of sore spots. MATERIALS AND METHODS: Twenty complete denture wearers, who sought replacement dentures because of complaints (material degradation or unsatisfactory repaired fracture) associated with them, were selected according to specific inclusion criteria. The denture construction protocols were randomly assigned to the study participants. Ten participants received complete dentures using a duplication construction protocol with a bilateral balanced occlusal (BBO) scheme (duplicate complete denture group); ten participants received complete dentures using a traditional construction protocol with BBO (traditional complete denture group). All study participants completed the Complete Denture Satisfaction and the Oral Health Impact Profile-20 (OHIP-20) questionnaires before they received the new complete dentures (pretreatment) and at 3 and 6 months post-treatment. At the initial adaptation/adjustment visits, the location and number of sore spots were identified. Statistical analysis was performed to evaluate differences between groups and within each group pre- and post treatment. RESULTS: Denture satisfaction and oral health related quality of life scores were independent of the complete denture construction protocol. Within the traditional complete denture group there was a statistically significant increase in denture satisfaction and equivalent decrease (improvement) in OHIP-20 scores between pre- and post-treatment (both at 3-month and 6-month visits). This finding was consistent for OHIP-20 scores within the duplicate complete denture group, but not for denture satisfaction, which was not statistically significant. The total number of recorded sore spots was approximately double for the traditional complete denture group compared to the duplicate complete denture group. CONCLUSIONS: According to the results of the study, patients' overall acceptance of their newly constructed complete dentures improved significantly for both groups (traditional and duplication construction protocols). Study participants adapted dissimilarly to their newly constructed complete dentures regarding comfort, as assessed by the total number of sore spots, although the recorded mean number of initial adaptation/adjustment visits was equal. PMID- 26964859 TI - Marginal regression analysis of recurrent events with coarsened censoring times. AB - Motivated by an ongoing pediatric mental health care (PMHC) study, this article presents weakly structured methods for analyzing doubly censored recurrent event data where only coarsened information on censoring is available. The study extracted administrative records of emergency department visits from provincial health administrative databases. The available information of each individual subject is limited to a subject-specific time window determined up to concealed data. To evaluate time-dependent effect of exposures, we adapt the local linear estimation with right censored survival times under the Cox regression model with time-varying coefficients (cf. Cai and Sun, Scandinavian Journal of Statistics 2003, 30, 93-111). We establish the pointwise consistency and asymptotic normality of the regression parameter estimator, and examine its performance by simulation. The PMHC study illustrates the proposed approach throughout the article. PMID- 26964858 TI - Design of Highly Potent Lipid-Functionalized Peptidomimetics for Efficient in Vivo siRNA Delivery. AB - RNA interference (RNAi) is a highly efficient approach for gene silencing. Regulation of gene expression at post-transcriptional level provides great potential for curing diseases caused by abnormal overexpression of disease related genes. However, the application of RNAi in the clinic has been hindered by the lack of efficient and biocompatible delivery systems. Therefore, the development of a safe and tissue-targeted double-stranded interfering RNA (siRNA) carrier for clinical application is urgently needed. Here we report the discovery of a highly efficient liposomal siRNA delivery agent based on a novel peptidomimetic built from natural amino acids. Fine tuning of the composition of amino acids, the type of amide linkage in the peptidomimetic, as well as the formulation and the physicochemical parameters of the novel lipoplex resulted in a lipid nanoparticle (LNP) that efficiently encapsulates and carries siRNA to mouse liver. In vivo experiments showed that a single injection of unmodified siRNA complexed to one of the peptidomimetics at a clinically feasible dose induced significant RNAi in mouse liver, resulting in a 90% decrease in apolipoprotein B (ApoB) mRNA level, as well as a 60% decrease in serum ApoB protein level. Analysis of mouse serum by ELISA indicated that the novel peptidomimetic based lipoplex did not elevate the level of liver enzymes (ALT, AST) in the serum. Our novel peptidomimetic-based lipoplex demonstrated great potential for the development of a safe and efficient siRNA delivery agent for clinical applications. PMID- 26964860 TI - The impact of a bundled policy intervention on improving the performance of rural healthcare in China. AB - BACKGROUND: The strategy of health policy has been changed for improving the performances to meeting the increasing healthcare demands. However, limited evidences were found to prove that the bundled payment was valid for service delivering in public sector. This study was designed to evaluate the effectiveness of a bundled policy on strengthening the county-village communication and improving the quality of chronic disease management. METHODS: This is a retrospective cohort study using the data collected in 2011, 2012 and 2014 from the Rural Health Development Project in China. The policy intervention included performance-related contract with health facilities, developing technical guideline for doctors and nurses, routine monitoring of performance, and efforts to increase public awareness about the services. There were two intervention counties in Henan Province, China, while one county with similar characteristics in Henan was selected as control. Funding allocation, work load and salary for health care workers, volume of township-to-village technical assistance were reported before and after the policy was implemented. Our study also examined the policy impacts on improving treatment outcomes of diabetes and hypertension care. RESULTS: There were substantial increases in the provision of the basic package of services including 96.6 % of patients with hypertension, 91.2 % of patients with diabetes under the health management system. After the intervention, there were 34.3 % (hypertension) and 42.0 % (diabetes) increase in regular follow-up visit rates, 24.6 and 17.2 % increase in blood pressure and blood glucose control rates, respectively. The family health records system covered 96 % of the rural families. Technical assistance between township health centres and village clinics were enhanced. Compared with baseline, the monthly training meeting and field supervision & guidance between township health centres and village clinics increased 1.0 meeting, 1.5 field visits, respectively, while the increases in the control county were only 0.3 meeting and 0.3 field visits. At the end of this study, 93.8 % of health workers achieved their performance goals. More patients were referred to appropriate levels of care. CONCLUSION: This bundled policy intervention effectively improved rural health care delivery. The result of our study can be used for local governments to implement performance-based health system management in developing country. PMID- 26964866 TI - Facile synthesis and photoluminescence characteristics of blue-emitting nitrogen doped graphene quantum dots. AB - A one-step hydrothermal method for synthesizing nitrogen-doped graphene quantum dots (N-GQDs) from organic carbon sources is presented in this paper. The high quality N-GQDs can be obtained via tuning the degree of dehydration/carbonization of citric acid and doping of nitrogen atoms into the graphene lattice. The micromorphology, chemical structure, composition and photoluminescence (PL) characteristics of the N-GQDs were characterized systematically. The size of the obtained N-GQDs is about 5-10 nm with typical topographic heights of 0.8-2.5 nm. There is intense blue emission and excitation-independent PL behavior when the N GQDs are in aqueous solution. The most remarkable innovation is that the fluorescence quantum yield (FL QY) of our N-GQDs is up to 75.2%, which is much higher than that of most reported GQDs (less than 25%). Thus, it is initially believed that synthesis parameters, hydrothermal process and nitrogen doping may greatly influence the surface state and bandgap of the GQDs, which are important in determining the PL characteristics of the N-GQDs. PMID- 26964868 TI - Event-Related Potentials for Diagnosing Children and Adults With ADHD. AB - OBJECTIVE: The diagnosis of ADHD is based on behavioral criteria, which allow for subjective variability and invite criticism regarding the reality of the disorder. In this situation, more objective criteria would be desirable. We review the scientific literature for diagnostic tests based on event-related potentials (ERPs). METHOD: Seven studies met the inclusion criteria of reporting the sensitivity and specificity of an ERP-based classifier discriminating participants with ADHD from healthy controls. Study quality was rated using the second version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS 2) system. RESULTS: Overall, study quality was acceptable. The largest biases were lack of representativeness and overfitting. Sensitivities and specificities ranged from 57% to 96%, and 63% to 92%, respectively. However, no two studies used the same diagnostic test. CONCLUSION: There is a serious lack of coordination in worldwide efforts to find more objective ERP-based criteria for the diagnosis of ADHD. Concerted action is needed. PMID- 26964861 TI - The impact of retractor SPONGE-assisted laparoscopic surgery on duration of hospital stay and postoperative complications in patients with colorectal cancer (SPONGE trial): study protocol for a randomized controlled trial. AB - BACKGROUND: To achieve an adequate visual working field during laparoscopic colorectal surgery without disturbance of the small intestine, patients are positioned in the Trendelenburg position. This position results in hemodynamic changes that may increase the risk of cardiopulmonary complications and prolonged hospital stay. Recently, an intraoperative retractor sponge was introduced as an alternative to the Trendelenburg position during laparoscopic surgery. The objective of this trial is to study the impact of the use of an intraoperative retractor sponge on the duration of the hospital stay and risk of perioperative complications in patients undergoing laparoscopic surgery for colorectal cancer. METHODS/DESIGN: The SPONGE trial is a monocenter study and follows the cohort multiple randomized controlled trial (cmRCT) design. It will be conducted within a multicenter prospective observational cohort of colorectal cancer patients of all stages, for whom longitudinal clinical data and patient-reported outcomes are collected. Patients within the cohort, who will undergo laparoscopic surgery for distal colon or rectal cancer, are eligible for inclusion and form a subcohort. From this subcohort, a 1:1 random sample will be offered to undergo surgery with the use of the retractor sponge. Patients from the subcohort who are not selected will undergo standard treatment, that is, surgery in the Trendelenburg position. The primary endpoint is the duration of the postoperative hospital stay. Secondary outcomes are duration of surgery; intraoperative blood loss and fluid balance; and postoperative body temperature, oxygenation and complications. Both arms require 94 patients. DISCUSSION: This study is the first randomized controlled trial to evaluate the effect of sponge-assisted laparoscopic colorectal surgery in comparison with standard Trendelenburg position on hospital stay and peri- and postoperative complications. Results of this study will also be relevant for other surgical procedures in the pelvic region. The present study is the second randomized controlled trial according to the cmRCT design, which is embedded within our colorectal cancer cohort. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02574013 . Registered 27 September 2015. PMID- 26964869 TI - Amygdala Abnormalities in Adults With ADHD. AB - OBJECTIVE: The suggested neurobiological bases of ADHD focus on the amygdala as a center of emotions processing. Therefore, we hypothesize that patients with ADHD will show an irregular pattern of emotional-related activity of the amygdala region as well as some structural abnormalities. METHOD: Nine adult patients with ADHD and nine group-matched healthy volunteers were studied using a 1.5-T magnetic resonance imaging (MRI) scanner. Morphometric measurements were obtained manually, and they were later processed and compared. Absolute volumes of several structures and nuclei were calculated with FSL-FIRST. For the functional magnetic resonance examination, a set of two paradigms was prepared, using a block design, incorporating images of the International Affective Picture System (IAPS). The patients were unmedicated at the time of the MRI scan. RESULTS: Negative correlation was found between the right amygdala volume and Barrat's impulsivity scores ( r = -.756, p = .018). The age of patients did not turn out to be a significant factor. No significantly higher activation areas were found in patients with unpleasant content images. For the left amygdala, an Region Of Interest (ROI)-based analysis showed moderately higher level of activation in the patients than in the controls with pleasant content images. CONCLUSION: Patients with ADHD tend to have smaller amygdala volumes. ADHD patients presented less activation in the area of the left frontal pole than the controls. There was no amygdala activation stated when presenting the pleasant images. Whereas bigger activation of the left amygdala was found in patients while presenting them unpleasant images. These results might suggest that lower emotional processing and less control of impulsivity is associated with dysfunctional amygdala in ADHD patients. PMID- 26964867 TI - Genome-wide association mapping for root traits in a panel of rice accessions from Vietnam. AB - BACKGROUND: Despite recent sequencing efforts, local genetic resources remain underexploited, even though they carry alleles that can bring agronomic benefits. Taking advantage of the recent genotyping with 22,000 single-nucleotide polymorphism markers of a core collection of 180 Vietnamese rice varieties originating from provinces from North to South Vietnam and from different agrosystems characterized by contrasted water regimes, we have performed a genome wide association study for different root parameters. Roots contribute to water stress avoidance and are a still underexploited target for breeding purpose due to the difficulty to observe them. RESULTS: The panel of 180 rice varieties was phenotyped under greenhouse conditions for several root traits in an experimental design with 3 replicates. The phenotyping system consisted of long plastic bags that were filled with sand and supplemented with fertilizer. Root length, root mass in different layers, root thickness, and the number of crown roots, as well as several derived root parameters and shoot traits, were recorded. The results were submitted to association mapping using a mixed model involving structure and kinship to enable the identification of significant associations. The analyses were conducted successively on the whole panel and on its indica (115 accessions) and japonica (64 accessions) subcomponents. The two associations with the highest significance were for root thickness on chromosome 2 and for crown root number on chromosome 11. No common associations were detected between the indica and japonica subpanels, probably because of the polymorphism repartition between the subspecies. Based on orthology with Arabidopsis, the possible candidate genes underlying the quantitative trait loci are reviewed. CONCLUSIONS: Some of the major quantitative trait loci we detected through this genome-wide association study contain promising candidate genes encoding regulatory elements of known key regulators of root formation and development. PMID- 26964870 TI - Mouse models for ROS1-fusion-positive lung cancers and their application to the analysis of multikinase inhibitor efficiency. AB - ROS1-fusion genes, resulting from chromosomal rearrangement, have been reported in 1-2% of human non-small cell lung cancer cases. More than 10 distinct ROS1 fusion genes, including break-point variants, have been identified to date. In this study, to investigate the in vivo oncogenic activities of one of the most frequently detected fusions, CD74-ROS1, as well as another SDC4-ROS1 fusion that has also been reported in several studies, we generated transgenic (TG) mouse strains that express either of the two ROS1-fusion genes specifically in lung alveolar type II cells. Mice in all TG lines developed tumorigenic nodules in the lung, and a few strains of both TG mouse lines demonstrated early-onset nodule development (multiple tumor lesions present in the lung at 2-4 weeks after birth); therefore, these two strains were selected for further investigation. Tumors developed progressively in the untreated TG mice of both lines, whereas those receiving oral administration of an ALK/MET/ROS1 inhibitor, crizotinib, and an ALK/ROS1 inhibitor, ASP3026, showed marked reduction in the tumor burden. Collectively, these data suggest that each of these two ROS1-fusion genes acts as a driver for the pathogenesis of lung adenocarcinoma in vivo The TG mice developed in this study are expected to serve as valuable tools for exploring novel therapeutic agents against ROS1-fusion-positive lung cancer. PMID- 26964871 TI - Transcriptional activation of FN1 and IL11 by HMGA2 promotes the malignant behavior of colorectal cancer. AB - Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide, and metastasis is the principle reason for its poor prognosis. Overexpression of high-mobility gene group A2 (HMGA2) contributes to the aggressiveness of CRC. However, the underlying molecular mechanism of its overexpression is still elusive. In this study, we showed that ectopic expression of HMGA2 significantly enhanced cell migration and invasion in vitro and promoted tumor growth and distant metastasis in vivo In contrast, the silencing of HMGA2 produced the opposite effects in vitro and in vivo Chromatin immunoprecipitation-PCR and luciferase assays revealed that HMGA2 bound directly to the promoters of FN1 and IL11 and significantly induced their transcriptional activities. Moreover, as the direct downstream target of HMGA2, IL11 modulated cell migration and invasion through a pSTAT3-dependent signaling pathway. Furthermore, a strong positive correlation between HMGA2 and IL11 expression was identified in 122 CRC tissues. High IL11 expression was associated with poor differentiation, a large tumor size, lymph node metastasis and low overall survival in CRC patients. Collectively, our data reveal novel insights into the molecular mechanisms underlying HMGA2-mediated CRC metastasis and highlight the possibility of targeting HMGA2 and IL11 for treating CRC patients with metastasis. PMID- 26964873 TI - Should commonly prescribed drugs be avoided as internal standard choices in new assays for clinical samples? PMID- 26964872 TI - Cerebral infarction in advanced non-small cell lung cancer: a case control study. AB - BACKGROUND: Advanced non-small cell lung cancer (NSCLC) patients often develop thromboembolic events, including cerebral infarction (CI). However, the relationship between advanced NSCLC and CI has not been thoroughly investigated. We examined the association between advanced NSCLC and CI and risk factors for CI in advanced or post-operative recurrent NSCLC patients. METHODS: We retrospectively investigated 515 patients diagnosed with advanced or post operative recurrent NSCLC at Juntendo University Hospital between April 2009 and March 2014. RESULTS: Among the 515 patients evaluated, 15 patients (2.9%) developed CI after diagnosis of advanced or post-operative recurrent NSCLC. Univariate and multivariate analyses were conducted, and brain metastasis was the only significant independent risk factor for CI (odds ratio 5.24, 95% confidence interval 1.72-16.10, p = 0.004). The incidence was 6.3% in these patients. The median survival time was 36 days, and 1-year survival rate was 6.7% after development of CI. Overall survival from diagnosis of advanced NSCLC or post operative recurrence was significantly shorter in patients with CI than in patients without CI (223 days versus 895 days; HR, 3.46; 95% confidence interval, 2.04-6.02; p = 0.001). CONCLUSIONS: The incidence of CI is high in advanced or post-operative recurrent NSCLC, and is especially higher in patients with brain metastasis than in those without brain metastasis. Moreover, CI may affect patient's prognosis. Careful monitoring for the development of CI in patients with advanced or post-operative recurrent NSCLC is needed, especially for patients with brain metastasis. PMID- 26964874 TI - Microsatellite loci for Urochloa decumbens (Stapf) R.D. Webster and cross amplification in other Urochloa species. AB - BACKGROUND: Forage grasses of the African genus Urochloa (syn. Brachiaria) are the basis of Brazilian beef production, and there is a strong demand for high quality, productive and adapted forage plants. Among the approximately 100 species of the genus Urochloa, Urochloa decumbens is one of the most important tropical forage grasses used for pastures due to several of its agronomic attributes. However, the level of understanding of these attributes and the tools with which to control them at the genetic level are limited, mainly due to the apomixis and ploidy level of this species. In this context, the present study aimed to identify and characterize molecular microsatellite markers of U. decumbens and to evaluate their cross-amplification in other Urochloa species. FINDINGS: Microsatellite loci were isolated from a previously constructed enriched library from one U. decumbens genotype. Specific primers were designed for one hundred thirteen loci, and ninety-three primer pairs successfully amplified microsatellite regions, yielding an average of 4.93 alleles per locus. The polymorphism information content (PIC) values of these loci ranged from 0.26 to 0.85 (average 0.68), and the associated discriminating power (DP) values ranged from 0.22 to 0.97 (average 0.77). Cross-amplification studies demonstrated the potential transferability of these microsatellites to four other Urochloa species. Structure analysis revealed the existence of three distinct groups, providing evidence in the allelic pool that U. decumbens is closely related to Urochloa ruziziensis and Urochloa brizantha. The genetic distance values determined using Jaccard's coefficient ranged from 0.06 to 0.76. CONCLUSIONS: The microsatellite markers identified in this study are the first set of molecular markers for U. decumbens species. Their availability will facilitate understanding the genetics of this and other Urochloa species and breeding them, and will be useful for germplasm characterization, linkage mapping and marker assisted selection. PMID- 26964875 TI - Metabolic activity of sperm cells: correlation with sperm cell concentration, viability and motility in the rabbit. AB - The resazurin reduction test (RRT) is a useful technique to assess the metabolic rate of sperm cells. RRT depends on the ability of metabolically active cells to reduce the non-fluorescent dye resazurin to the fluorescent resorufin. The aim of this study was to develop a vital fluorometric method to evaluate metabolic activity of rabbit sperm cells. Twenty-five rabbit males were included in the study. Viability and morphology, motility and metabolic activity were evaluated using an eosin-nigrosin staining, a computer-assisted semen analysis (CASA) and the RRT, respectively. Spearman rank correlation analysis was used to determine the correlation between RRT and semen parameters. After evaluation, a concentration of 10 * 106 sperm cells/ml was selected for further experiments with RRT. No significant correlation was found between the RRT results and the motility parameters. However, after RRT a significant positive correlation between relative fluorescence units and the percentage of alive spermatozoa (r = 0.62; P = 0.001) and a negative one with the percentage of sperm cells with acrosomic abnormalities (r = -0.45; P < 0.05) were detected. The vital assessment of metabolic rate of sperm cells by RRT could provide more information about semen quality than other routine semen analysis, correlating with sperm viability and acrosome status information. PMID- 26964877 TI - A Patient-Centered Approach to Informed Consent: Results from a Survey and Randomized Trial. AB - PURPOSE: Traditional informed consent documents tend to be too lengthy and technical to facilitate proper patient engagement. Patient-centered, short informed consent content could be equally informative, while minimizing patient burden and producing greater patient engagement. This study aimed to develop and evaluate patient-centered, patient-designed paper and video informed consent formats. METHODS: Two studies were conducted. In study 1, 118 self-identifying asthma patients recruited from a national, online pool completed survey tasks from their personal computers. Participants in study 1 were randomly assigned to examine sections of a standard informed consent document for an asthma trial and to select information they deemed critical to their decision making. In study 2, a sample of 83 self-identifying asthma patients completed experimental tasks in a university laboratory. Participants in study 2 were randomly assigned to a full informed consent document; a shortened, patient-designed informed consent document created from study 1; or a video with content matched to the shortened paper form. RESULTS: Study 1 yielded a more readable, concise version of a standard informed consent document (5 v. 17 pages). This shortened, patient designed form closely met normative criteria for good clinical practice. In study 2, participants who viewed either the shortened paper consent or video reported greater engagement than those viewing the standard paper consent, without lowered performance on any other decision-relevant variables (i.e., comprehension, judged risk/benefit, feelings of trust). The video consent format did not cause increased enrollment. CONCLUSIONS: Results suggest that providing concise informed consent content, systematically developed from patients' self-reported information needs, may be more effective at engaging and informing clinical trial participants than the traditional consent approach, without detriment to trial comprehension, risk assessment, or enrollment. PMID- 26964876 TI - Contemporary Context of Drug-Eluting Stents in Brazil: A Cost Utility Study. AB - BACKGROUND: Although drug-eluting stents (DES) have been widely incorporated into clinical practice in developed countries, several countries restrict their use mainly because of their high cost and unfavorable incremental cost-effectiveness ratios (ICER). OBJECTIVE: To evaluate the cost-effectiveness of DES in comparison with bare-metal stents (BMS) for treatment of coronary artery disease (CAD). DESIGN: Markov model. DATA SOURCES: Published literature, government database, and CAD patient cohort. TARGET POPULATION: Single-vessel CAD patients. TIME HORIZON: One year and lifetime. PERSPECTIVE: Brazilian Public Health System (SUS). INTERVENTION: Six strategies composed of percutaneous intervention with a BMS or 1 of 5 DES (paclitaxel, sirolimus, everolimus, zotarolimus, and zotarolimus resolute). OUTCOME MEASURES: Cost for target vessel revascularization avoided and cost for quality-adjusted life year gained. BASE CASE ANALYSIS: In the short-term analysis, sirolimus was the most effective and least costly among DES (ICER of I$20,642 per target vessel revascularization avoided), with all others DES dominated by sirolimus. Lifetime cumulative costs ranged from I$18,765 to I$21,400. In the base case analysis, zotarolimus resolute had the most favorable ICER among the DES (ICER I$62,761), with sirolimus, paclitaxel, and zotarolimus being absolute dominated and everolimus extended dominated by zotarolimus resolute, although all the results were above the willingness-to-pay threshold of 3 times the gross domestic product per capita (I$35,307). SENSITIVITY ANALYSIS: In deterministic sensitivity analysis, results were sensitive to cost of DES, number of stents used per patient, baseline probability, and duration of stent thrombosis risk. The probabilistic sensitivity analysis demonstrated a probability of 81% for BMS being the strategy of choice, with 9% for everolimus and 9% zotarolimus resolute, at the willingness-to-pay threshold. CONCLUSION: DES is not a good value for money in SUS perspective, despite its benefit in reducing target vessel revascularization. Since the cost effectiveness of DES is mainly driven by the stents' cost difference, they should cost less than twice the BMS price to become a cost-effective alternative. PMID- 26964878 TI - Odonto-onycho-dermal dysplasia in a patient homozygous for a WNT10A nonsense mutation and mild manifestations of ectodermal dysplasia in carriers of the mutation. AB - BACKGROUND: Odonto-onycho-dermal dysplasia (OODD) is a rare form of ectodermal dysplasia characterized by severe oligodontia, onychodysplasia, palmoplantar hyperkeratosis, dry skin, hypotrichosis, and hyperhidrosis of the palms and soles. The ectodermal dysplasias resulting from biallelic mutations in the WNT10A gene result in highly variable phenotypes, ranging from isolated tooth agenesis to OODD and Schopf-Schulz-Passarge syndrome (SSPS). CASE PRESENTATION: We identified a female patient, with consanguineous parents, who was clinically diagnosed with OODD. Genetic testing showed that she was homozygous for a previously reported pathogenic mutation in the WNT10A gene, c.321C > A, p.Cys107*. The skin and nail abnormalities were for many years interpreted as psoriasis and treated accordingly. A thorough clinical examination revealed hypotrichosis and hyperhidrosis of the soles and dental examination revealed agenesis of permanent teeth except the two maxillary central incisors. Skin biopsies from the hyperkeratotic palms and soles showed the characteristic changes of eccrine syringofibroadenomatosis, which has been described in patients with ectodermal dysplasias. Together with a family history of tooth anomalies, this lead to the clinical suspicion of a hereditary ectodermal dysplasia. CONCLUSION: This case illustrates the challenges of diagnosing ectodermal dysplasia like OODD and highlights the relevance of interdisciplinary cooperation in the diagnosis of rare conditions. PMID- 26964879 TI - Transmembrane delivery of anticancer drugs through self-assembly of cyclic peptide nanotubes. AB - Breaking the natural barriers of cell membranes achieves fast entry of therapeutics, which leads to enhanced efficacy and helps overcome multiple drug resistance. Herein, transmembrane delivery of a series of small molecule anticancer drugs was achieved by the construction of artificial transmembrane nanochannels formed by self-assembly of cyclic peptide (cyclo[Gln-(d-Leu-Trp)4-d Leu], CP) nanotubes (CPNTs) in the lipid bilayers. Our in vitro study in liposomes indicated that the transport of molecules with sizes smaller than 1.0 nm, which is the internal diameter of the CPNTs, could be significantly enhanced by CPNTs in a size-selective and dose-dependent manner. Facilitated uptake of 5 fluorouracil (5-FU) was also confirmed in the BEL7402 cell line. On the contrary, CPs could facilitate neither the transport across liposomal membranes nor the uptake by cell lines of cytarabine, a counterevidence drug with a size of 1.1 nm. CPs had a very weak anticancer efficacy, but could significantly reduce the IC50 of 5-FU in BEL7402, HeLa and S180 cell lines. Analysis by a q test revealed that a combination of 5-FU and CP had a synergistic effect in BEL7402 at all CP levels, in S180 at CP levels higher than 64 MUg mL(-1), but not in HeLa, where an additive effect was observed. Temporarily, intratumoral injection is believed to be the best way for CP administration. In vivo imaging using (125)I radio labelled CP confirmed that CPNPTs were completely localized in the tumor tissues, and translocation to other tissues was negligible. In vivo anticancer efficacy was studied in the grafted S180 solid tumor model in mice, and the results indicated that tumor growth was greatly inhibited by the combinatory use of 5-FU and CP, and a synergistic effect was observed at CP doses of 0.25 mg per kg bw. It is concluded that facilitated transmembrane delivery of anticancer drugs with sizes smaller than 1.0 nm was achieved, and the synergistic anticancer effect was confirmed both in cell lines and in vivo through the combinatory use of 5-FU and CP. PMID- 26964881 TI - Photoisomerization mechanisms from trans, trans-1,4-diphenyl-1,3-butadiene: CASSCF on-the-fly trajectory surface hopping dynamic simulations. AB - We have employed the SA2-CAS(4,4)/6-31G ab initio method together with an on-the fly global-switching trajectory surface hopping algorithm to simulate photoisomerization reaction dynamics from reactant trans, trans-1,4-diphenyl-1,3 butadiene (DPB) to products cis,trans-DPB and cis,cis-DPB. This topic has been extensively studied experimentally and the present theoretical study is the first to simulate DPB photoisomerization reaction dynamics as far as we know. With total 600 sampling trajectories, 300 actively contribute to isomerization reaction via two conical intersections between the electronic ground and the first excited states. Simulated quantum yields of photoisomerization to cis, trans-DPB and cis, cis-DPB are 0.09 and 0.045, which are in good agreement with the experimental values of 0.07-0.25 and 0.02, respectively. The lifetime of the first excited state is estimated as 702 fs. The present simulation has shown two reactive photoisomerization mechanisms, namely one bond twist (OBT) and bicycle pedal (BP), and two non-reactive photoisomerization mechanisms, namely single bond torsion (SBT) and reverse torsion (RT) with respect to the central backbone CC bonds. We believe that the present theoretical work can benefit the experiments on photoisomerization of DPB derivates. PMID- 26964880 TI - A review and content analysis of engagement, functionality, aesthetics, information quality, and change techniques in the most popular commercial apps for weight management. AB - BACKGROUND: There are thousands of apps promoting dietary improvement, increased physical activity (PA) and weight management. Despite a growing number of reviews in this area, popular apps have not been comprehensively analysed in terms of features related to engagement, functionality, aesthetics, information quality, and content, including the types of change techniques employed. METHODS: The databases containing information about all Health and Fitness apps on GP and iTunes (7,954 and 25,491 apps) were downloaded in April 2015. Database filters were applied to select the most popular apps available in both stores. Two researchers screened the descriptions selecting only weight management apps. Features, app quality and content were independently assessed using the Mobile App Rating Scale (MARS) and previously-defined categories of techniques relevant to behaviour change. Inter-coder reliabilities were calculated, and correlations between features explored. RESULTS: Of the 23 popular apps included in the review 16 were free (70%), 15 (65%) addressed weight control, diet and PA combined; 19 (83%) allowed behavioural tracking. On 5-point MARS scales, apps were of average quality (Md = 3.2, IQR = 1.4); "functionality" (Md = 4.0, IQR = 1.1) was the highest and "information quality" (Md = 2.0, IQR = 1.1) was the lowest domain. On average, 10 techniques were identified per app (range: 1-17) and of the 34 categories applied, goal setting and self-monitoring techniques were most frequently identified. App quality was positively correlated with number of techniques included (rho = .58, p < .01) and number of "technical" features (rho = .48, p < .05), which was also associated with the number of techniques included (rho = .61, p < .01). Apps that provided tracking used significantly more techniques than those that did not. Apps with automated tracking scored significantly higher in engagement, aesthetics, and overall MARS scores. Those that used change techniques previously associated with effectiveness (i.e., goal setting, self-monitoring and feedback) also had better "information quality". CONCLUSIONS: Popular apps assessed have overall moderate quality and include behavioural tracking features and a range of change techniques associated with behaviour change. These apps may influence behaviour, although more attention to information quality and evidence-based content are warranted to improve their quality. PMID- 26964882 TI - Rhodium-catalyzed pyridannulation of indoles with diazoenals: a direct approach to pyrido[1,2-a]indoles. AB - A novel rhodium catalyzed pyridannulation of 3-substituted indoles with diazoenals furnished privileged pyrido[1,2-a]indoles. The reaction is proposed to involve a [4 + 2]-annulation of the diacceptor rhodium enalcarbenoid via C-2 functionalization of the indole. The utility of the methodology was demonstrated with a short synthesis of the tetrahydropyrido[1,2-a]indole core, present in a large number of biologically important polycyclic indole alkaloids. PMID- 26964883 TI - Directly tailoring photon-electron coupling for sensitive photoconductance. AB - The coupling between photons and electrons is at the heart of many fundamental phenomena in nature. Despite tremendous advances in controlling electrons by photons in engineered energy-band systems, control over their coupling is still widely lacking. Here we demonstrate an unprecedented ability to couple photon electron interactions in real space, in which the incident electromagnetic wave directly tailors energy bands of solid to generate carriers for sensitive photoconductance. By spatially coherent manipulation of metal-wrapped material system through anti-symmetric electric field of the irradiated electromagnetic wave, electrons in the metals are injected and accumulated in the induced potential well (EIW) produced in the solid. Respective positive and negative electric conductances are easily observed in n-type and p-type semiconductors into which electrons flow down from the two metallic sides under light irradiation. The photoconductivity is further confirmed by sweeping the injected electrons out of the semiconductor before recombination applied by sufficiently strong electric fields. Our work opens up new perspectives for tailoring energy bands of solids and is especially relevant to develop high effective photon detection, spin injection, and energy harvesting in optoelectronics and electronics. PMID- 26964884 TI - Optical responses of a metal with sub-nm gaps. AB - If the size of a metallic structure is reduced to be comparable to or even smaller than the typical quantum-mechanical lengths such as the Fermi wavelength or Thomas-Fermi wavelength, the electronic structure and optical responses are modulated by quantum effects. Here, we calculate the optical responses of a metal with sub-nm gaps using the eigenstates obtained from an effective-mass quantum theory. According to our simulation, the dielectric responses can be significantly modified by tuning the inter-gap distances. Remarkably, sub-nm gaps occupying a 0.3% volumetric fraction can elongate the penetration depth by an order of magnitude in the terahertz regime. We find that the detailed dependences of electron-photon interaction matrix elements on the involved electronic wavefunctions play an important role in the optical responses. The results draw our attention to these recently fabricated systems. PMID- 26964885 TI - A unified mechanism for proteolysis and autocatalytic activation in the 20S proteasome. AB - Biogenesis of the 20S proteasome is tightly regulated. The N-terminal propeptides protecting the active-site threonines are autocatalytically released only on completion of assembly. However, the trigger for the self-activation and the reason for the strict conservation of threonine as the active site nucleophile remain enigmatic. Here we use mutagenesis, X-ray crystallography and biochemical assays to suggest that Lys33 initiates nucleophilic attack of the propeptide by deprotonating the Thr1 hydroxyl group and that both residues together with Asp17 are part of a catalytic triad. Substitution of Thr1 by Cys disrupts the interaction with Lys33 and inactivates the proteasome. Although a Thr1Ser mutant is active, it is less efficient compared with wild type because of the unfavourable orientation of Ser1 towards incoming substrates. This work provides insights into the basic mechanism of proteolysis and propeptide autolysis, as well as the evolutionary pressures that drove the proteasome to become a threonine protease. PMID- 26964887 TI - Physical Activity Measurement by Accelerometry Among Older Malay Adults Living in Semi-Rural Areas-A Feasibility Study. AB - We evaluated feasibility of physical activity measurement by accelerometry among older Malay adults living in semi-rural areas in Malaysia. Results showed that 95% of 146 participants (aged [SD] 67.6 [6.4] years) were compliant in wearing the accelerometer for at least five days. Fifteen participants were asked for re wear the accelerometer because they did not have enough valid days during the first assessment. Participants wore the accelerometer an average of 15.3 hr in a 24-hr day, with 6.5 (1.2) valid wear days. No significant difference in valid wear day and time was found between men and women. Participants who are single provide more valid wear days compared with married participants (p < .05), and participants with higher levels of education provide longer periods of accelerometer wearing hours (p < .01). Eighty-seven percent of participants reported 'no issues' with wearing the meter. This study suggests that accelerometry is a feasible method to assess the physical activity level among older Malay adults living in semi-rural areas. PMID- 26964888 TI - Fast and Efficient Fragment-Based Lead Generation by Fully Automated Processing and Analysis of Ligand-Observed NMR Binding Data. AB - NMR binding assays are routinely applied in hit finding and validation during early stages of drug discovery, particularly for fragment-based lead generation. To this end, compound libraries are screened by ligand-observed NMR experiments such as STD, T1rho, and CPMG to identify molecules interacting with a target. The analysis of a high number of complex spectra is performed largely manually and therefore represents a limiting step in hit generation campaigns. Here we report a novel integrated computational procedure that processes and analyzes ligand observed proton and fluorine NMR binding data in a fully automated fashion. A performance evaluation comparing automated and manual analysis results on (19)F- and (1)H-detected data sets shows that the program delivers robust, high confidence hit lists in a fraction of the time needed for manual analysis and greatly facilitates visual inspection of the associated NMR spectra. These features enable considerably higher throughput, the assessment of larger libraries, and shorter turn-around times. PMID- 26964890 TI - Lymphocytic meningitis caused by herpes simplex virus type 2. PMID- 26964889 TI - Rise in differentiated thyroid cancer incidence in our hospital is not related with an increased incidental microcarcinoma detection. PMID- 26964891 TI - A scurvy case in a XXI century young men. PMID- 26964886 TI - Spatiotemporal patterns of sortilin and SorCS2 localization during organ development. AB - BACKGROUND: Sortilin and SorCS2 are part of the Vps10p receptor family. They have both been studied in nervous tissue with several important functions revealed, while their expression and possible functions in developing peripheral tissue remain poorly understood. Here we deliver a thorough characterization of the prenatal localization of sortilin and SorCS2 in mouse peripheral tissue. RESULTS: Sortilin is highly expressed in epithelial tissues of the developing lung, nasal cavity, kidney, pancreas, salivary gland and developing intrahepatic bile ducts. Furthermore tissues such as the thyroid gland, developing cartilage and ossifying bone also show high expression of sortilin together with cell types such as megakaryocytes in the liver. SorCS2 is primarily expressed in mesodermally derived tissues such as striated muscle, adipose tissue, ossifying bone and general connective tissue throughout the body, as well as in lung epithelia. Furthermore, the adrenal gland and liver show high expression of SorCS2 in embryos 13.5 days old. CONCLUSIONS: The possible functions relating to the expression patterns of Sortilin and SorCS2 in development are numerous and hopefully this paper will help to generate new hypotheses to further our understanding of the Vps10p receptor family. PMID- 26964892 TI - Ecosystem services provided by a complex coastal region: challenges of classification and mapping. AB - A variety of ecosystem services classification systems and mapping approaches are available in the scientific and technical literature, which needs to be selected and adapted when applied to complex territories (e.g. in the interface between water and land, estuary and sea). This paper provides a framework for addressing ecosystem services in complex coastal regions. The roadmap comprises the definition of the exact geographic boundaries of the study area; the use of CICES (Common International Classification of Ecosystem Services) for ecosystem services identification and classification; and the definition of qualitative indicators that will serve as basis to map the ecosystem services. Due to its complexity, the Ria de Aveiro coastal region was selected as case study, presenting an opportunity to explore the application of such approaches at a regional scale. The main challenges of implementing the proposed roadmap, together with its advantages are discussed in this research. The results highlight the importance of considering both the connectivity of natural systems and the complexity of the governance framework; the flexibility and robustness, but also the challenges when applying CICES at regional scale; and the challenges regarding ecosystem services mapping. PMID- 26964893 TI - Ovarian cancer: Status of homologous recombination pathway as a predictor of drug response. AB - Epithelial ovarian cancer (EOC), particularly high-grade serous subtype, is associated with germline mutations in BRCA1/BRCA2 genes in up to 20% of the patients. BRCA1/BRCA2 proteins are important components of the homologous recombination (HR) pathway, a vital DNA repair process that protects the genome from double-strand DNA damage. Recent studies revealed frequent somatic mutations of BRCA1/BRCA2 and hypermethylation of the promoter of BRCA1 in EOC, in addition to germline mutations. Comparison of DNA copy number changes in tumors with or without BRCA1/BRCA2 alterations, lead to the identification of several signatures that detect HR pathway defects, here named "HRness". These signatures predict platinum-sensitivity and survival in EOC, as it was previously shown for germline mutations of BRCA1/BRCA2. They are currently investigated in clinical trials as potential predictive biomarker for response to poly(ADP- ribose) polymerase inhibitors. PMID- 26964894 TI - The refugee crisis challenges national health care systems: Countries accepting large numbers of refugees are struggling to meet their health care needs, which range from infectious to chronic diseases to mental illnesses. PMID- 26964896 TI - Exhibition A: scientist at work: Science museums are shifting their focus away from educating and elating their audiences to fostering dialogue with scientists. PMID- 26964895 TI - A novel cytoprotective function for the DNA repair protein Ku in regulating p53 mRNA translation and function. AB - Ku heterodimer is a DNA binding protein with a prominent role in DNA repair. Here, we investigate whether and how Ku impacts the DNA damage response by acting as a post-transcriptional regulator of gene expression. We show that Ku represses p53 protein synthesis and p53-mediated apoptosis by binding to a bulged stem-loop structure within the p53 5' UTR However, Ku-mediated translational repression of the p53 mRNA is relieved after genotoxic stress. The underlying mechanism involves Ku acetylation which disrupts Ku-p53 mRNA interactions. These results suggest that Ku-mediated repression of p53 mRNA translation constitutes a novel mechanism linking DNA repair and mRNA translation. PMID- 26964897 TI - Niclosamide blocks glucagon phosphorylation of Ser552 on beta-catenin in primary rat hepatocytes via PKA signalling. AB - Recently, it has been found that glucagon is able to activate the beta-catenin signalling pathway leading to increased cyclin D1 and c-Myc expression in liver. Therefore the main aim of the present study is to determine whether the effect of glucagon activating beta-catenin signalling leading to increased target gene expression is mediated through cAMP activation of PKA (protein kinase A). Primary rat hepatocytes were incubated with insulin, glucagon or adrenaline (epinephrine) and a range of inhibitors of PI3K (phosphoinositide 3-kinase), Wnt, mitochondrial uncoupler (niclosamide) or PKA inhibitors to dissect out the pathway leading to increased Ser(552) phosphorylation on beta-catenin following glucagon exposure. In primary rat hepatocytes, we found that short exposure to glucagon or adrenaline caused a rapid increase in Ser(552) phosphorylation on beta-catenin that leads to increased cyclin D1 and c-Myc expression. A range of PI3K and Wnt inhibitors were unable to block the effect of glucagon phosphorylating beta catenin. Interestingly, both niclosamide and the PKA inhibitor H89 blocked the glucagon effect on beta-catenin signalling, leading to a reduction in target gene expression. Likewise, niclosamide inhibited cAMP levels and the direct addition of db-cAMP (dibutyryl-cAMP sodium salt) also resulted in Ser(552) phosphorylation of beta-catenin. We have identified a new pathway via glucagon signalling that leads to increased beta-catenin activity that can be reversed with the antihelminthic drug niclosamide, which has recently shown promise as a potential treatment of T2D (Type 2 diabetes). This novel finding could be useful in liver cancer treatment, particularly in the context of T2D with increased beta-catenin activity. PMID- 26964898 TI - Exploring the structure of glutamate racemase from Mycobacterium tuberculosis as a template for anti-mycobacterial drug discovery. AB - Glutamate racemase (MurI) is responsible for providing D-glutamate for peptidoglycan biosynthesis in bacteria and has been a favoured target in pharmaceutical drug design efforts. It has recently been proven to be essential in Mycobacterium tuberculosis, the causative organism of tuberculosis, a disease for which new medications are urgently needed. In the present study, we have determined the protein crystal structures of MurI from both M. tuberculosis and Mycobacterium smegmatis in complex with D-glutamate to 2.3 A and 1.8 A resolution respectively. These structures are conserved, but reveal differences in their active site architecture compared with that of other MurI structures. Furthermore, compounds designed to target other glutamate racemases have been screened but do not inhibit mycobacterial MurI, suggesting that a new drug design effort will be needed to develop inhibitors. A new type of MurI dimer arrangement has been observed in both structures, and this arrangement becomes the third biological dimer geometry for MurI found to date. The mycobacterial MurI dimer is tightly associated, with a KD in the nanomolar range. The enzyme binds D- and L glutamate specifically, but is inactive in solution unless the dimer interface is mutated. We created triple mutants of this interface in the M. smegmatis glutamate racemase (D26R/R105A/G194R or E) that have appreciable activity (kcat=0.056-0.160 min(-1) and KM=0.26-0.51 mM) and can be utilized to screen proposed antimicrobial candidates for inhibition. PMID- 26964899 TI - miR-434-3p and DNA hypomethylation co-regulate eIF5A1 to increase AChRs and to improve plasticity in SCT rat skeletal muscle. AB - Acetylcholine receptors (AChRs) serve as connections between motor neurons and skeletal muscle and are essential for recovery from spinal cord transection (SCT). Recently, microRNAs have emerged as important potential biotherapeutics for several diseases; however, whether miRNAs operate in the modulation of AChRs remains unknown. We found increased AChRs numbers and function scores in rats with SCT; these increases were reduced following the injection of a eukaryotic translation initiation factor 5A1 (eIF5A1) shRNA lentivirus into the hindlimb muscle. Then, high-throughput screening for microRNAs targeting eIF5A1 was performed, and miR-434-3p was found to be robustly depleted in SCT rat skeletal muscle. Furthermore, a highly conserved miR-434-3p binding site was identified within the mRNA encoding eIF5A1 through bioinformatics analysis and dual luciferase assay. Overexpression or knockdown of miR-434-3p in vivo demonstrated it was a negative post-transcriptional regulator of eIF5A1 expression and influenced AChRs expression. The microarray-enriched Gene Ontology (GO) terms regulated by miR-434-3p were muscle development terms. Using a lentivirus, one functional gene (map2k6) was confirmed to have a similar function to that of miR 434-3p in GO terms. Finally, HRM and MeDIP-PCR analyses revealed that DNA demethylation also up-regulated eIF5A1 after SCT. Consequently, miR-434-3p/eIF5A1 in muscle is a promising potential biotherapy for SCI repair. PMID- 26964901 TI - Efficacy of Ketorolac Buccal Infiltrations and Inferior Alveolar Nerve Blocks in Patients with Irreversible Pulpitis: A Prospective, Double-blind, Randomized Clinical Trial. AB - INTRODUCTION: The purpose of this prospective, randomized, double-blind, placebo controlled study was to determine whether ketorolac buccal infiltrations (BIs) helped to improve the success of inferior alveolar nerve blocks (IANBs) in patients with acute irreversible pulpitis (AIP). METHODS: Forty adult volunteers with AIP in a mandibular molar were included in this study. Patients were instructed to evaluate their pain by using a Heft-Parker visual analog scale. They were randomly divided into 2 groups (n = 20). All patients received standard IANB injection and after that a BI of 4% articaine with 1:100,000 epinephrine. After 5 minutes, 20 patients received a BI of 30 mg/mL ketorolac, and the other received a BI of normal saline (control group). Endodontic access cavity preparation (ACP) was initiated 15 minutes after the IANB when the patient reported lip numbness and had 2 electric pulp tests with no responses. The patient's pain during caries and dentin removal, ACP, and canal length measurements (CLM) was recorded by using Heft-Parker visual analog scale. Successful anesthesia was defined as no or mild pain during any of these steps, without the need for additional injection. Data were statistically analyzed by using Mann-Whitney U and chi(2) tests. RESULTS: Successful anesthesia after an IANB plus BI of articaine was obtained in 15% of patients in the control group at the end of CLM. Adding BI of ketorolac significantly increased the success rate to 40% (P < .05). Patient's pain during ACP and CLM was significantly lower in the ketorolac group (P < .05). CONCLUSIONS: Ketorolac BI can increase the success rate of anesthesia after IANB and BI with articaine in patients with AIP. PMID- 26964900 TI - Novel function of LHFPL2 in female and male distal reproductive tract development. AB - Congenital reproductive tract anomalies could impair fertility. Female and male reproductive tracts are developed from Mullerian ducts and Wolffian ducts, respectively, involving initiation, elongation and differentiation. Genetic basis solely for distal reproductive tract development is largely unknown. Lhfpl2 (lipoma HMGIC fusion partner-like 2) encodes a tetra-transmembrane protein with unknown functions. It is expressed in follicle cells of ovary and epithelial cells of reproductive tracts. A spontaneous point mutation of Lhfpl2 (LHFPL2(G102E)) leads to infertility in 100% female mice, which have normal ovarian development, ovulation, uterine development, and uterine response to exogenous estrogen stimulation, but abnormal upper longitudinal vaginal septum and lower vaginal agenesis. Infertility is also observed in ~70% mutant males, which have normal mating behavior and sperm counts, but abnormal distal vas deferens convolution resulting in complete and incomplete blockage of reproductive tract in infertile and fertile males, respectively. On embryonic day 15.5, mutant Mullerian ducts and Wolffian ducts have elongated but their duct tips are enlarged and fail to merge with the urogenital sinus. These findings provide a novel function of LHFPL2 and a novel genetic basis for distal reproductive tract development; they also emphasize the importance of an additional merging phase for proper reproductive tract development. PMID- 26964902 TI - Prevalence and risk factors associated with HIV and tuberculosis in people who use drugs in Abidjan, Ivory Coast. AB - BACKGROUND: The number of people who use drugs (PWUD) has dramatically increased in West Africa over the last 15 years, but targeted interventions are falling behind, notably because of the lack of awareness of the health needs of PWUD. We aimed to assess prevalence and factors associated with HIV and other infections in PWUD in Abidjan, Ivory Coast, one of the countries most affected by HIV in Western Africa. METHODS: We used respondent-driven-sampling to obtain a representative sample of heroin or cocaine/crack users aged 18 years or more. Socio-behavioral data were obtained by face-to-face questionnaires. Blood samples were collected and tested for HIV. Two sputa were obtained in tuberculosis (TB) symptomatic participants for acid-fast-bacilli (AFB) smear testing. After a descriptive analysis, crude prevalence were calculated, then weighted to take account of the sampling method. Factors associated with HIV and TB were studied using adjusted log-binomial regression. Population size was estimated by capture recapture. RESULTS: 450 PWUD were recruited in May 2014. The mean age was 33.5 years; 10.9% were women. Smoking was the main mode of consumption, ever injecting was reported by 12.7% of the participants (3.6% in the past month). Sex work was reported by 15.8% of the PWUD (13.7% of the men), and 10.2% of the men reported sexual relationships with other men (MSM). We found a weighted prevalence of 9.5% for HIV. Women were 3.4 times more likely to be infected than men. Among men, being a sex worker (SW) (adjusted OR 2.9 [95CI 1.06-7.98]) or MSM (adjusted OR 11.5 [95CI 4.22-31.42]) were the main factors associated with HIV infection in adjusted analysis. Injection was not associated with HIV. TB weighted prevalence was 1.8%, associated with poor living arrangements in adjusted analysis. We estimated that 3521; 95CI 3049-3993 PWUD live in Abidjan. CONCLUSION: PWUD in Abidjan are at high risk of HIV due to sexual transmission, especially in women, SW and MSM who also use drugs. Interventions should be developed to improve HIV prevention and linkage to care in these specific populations. More generally, improving the health of PWUD involves a broader reflection on the living environment and access to health care of slum residents in large African cities. PMID- 26964904 TI - Rehebbilitating Memory. PMID- 26964903 TI - Joel Elkes. PMID- 26964905 TI - The effects of physical activity on impulsive choice: Influence of sensitivity to reinforcement amount and delay. AB - Impulsive choice is a diagnostic feature and/or complicating factor for several psychological disorders and may be examined in the laboratory using delay discounting procedures. Recent investigators have proposed using quantitative measures of analysis to examine the behavioral processes contributing to impulsive choice. The purpose of this study was to examine the effects of physical activity (i.e., wheel running) on impulsive choice in a single-response, discrete-trial procedure using two quantitative methods of analysis. To this end, rats were assigned to physical activity or sedentary groups and trained to respond in a delay-discounting procedure. In this procedure, one lever always produced one food pellet immediately, whereas a second lever produced three food pellets after a 0, 10, 20, 40, or 80-s delay. Estimates of sensitivity to reinforcement amount and sensitivity to reinforcement delay were determined using (1) a simple linear analysis and (2) an analysis of logarithmically transformed response ratios. Both analyses revealed that physical activity decreased sensitivity to reinforcement amount and sensitivity to reinforcement delay. These findings indicate that (1) physical activity has significant but functionally opposing effects on the behavioral processes that contribute to impulsive choice and (2) both quantitative methods of analysis are appropriate for use in single response, discrete-trial procedures. PMID- 26964906 TI - The role of MAO in personality and drug use. AB - Monoamine oxidases, both MAO-A and MAO-B, have been implicated in personality traits and complex behaviour, including drug use. Findings supporting the involvement of MAO-A and MAO-B in shaping personality and in the development of strategies of making behavioural choices come from a variety of studies that have examined either prevalence of gene variants in clinical groups or population derived samples, estimates of enzyme activity in blood or, by positron emission tomography, in the brain and, most recently, measurement of methylation of the gene. Most of the studies converge in associating MAO-A and MAO-B with impulsive, aggressive or antisocial personality traits or behaviours, including alcohol related problems, and for MAO-A available evidence strongly supports interaction with adverse environmental exposures in childhood. What is known about genotype effects, and on expression and activity of the enzyme in the brain and in blood has not yet been possible to unite into a mechanistic model of the role of monoamine systems, but the reason for this low degree of generalization is likely caused by the cross-sectional nature of investigation that has not incorporated the developmental effects of MAO-s in critical time windows, including the foetal period. The "risk variants" of both MAO-s appear to increase behavioural plasticity, as supportive environments may particularly well enhance the hidden potential of their carriers. Importantly, male and female brain and behaviours have been found very different with regard to MAO*life events interaction. Future studies need to take into consideration these developmental aspects and sex/gender, as well as to specify the role of different types of environmental factors. PMID- 26964907 TI - Development and characterization of microsatellite markers for the oomyceta Aphanomyces euteiches. AB - Aphanomyces euteiches Drechsler is a serious pathogen of leguminous crops that causes devastating root rot of pea worldwide. Given that A. euteiches is a diploid organism, robust, codominant markers are needed for population genetics studies. We have developed and screened a microsatellite-enriched small-insert genomic library for identification of A. euteiches SSR containing sequences. Fourteen out of the 48 primer pairs designed to amplify SSR, produced unambiguous polymorphic products in our test population of 94 isolates. The number of alleles at each locus ranged from one to four. The identification of new markers would enhance the ability to evaluate the genetic structure of A. euteiches populations, and pathogen evolution. PMID- 26964908 TI - Genetic variants at 18q11.2 and 8q24 identified by genome-wide association studies were not associated with pulmonary tuberculosis risk in Chinese population. AB - OBJECTIVE: Genome-wide association study (GWAS) recently identified several susceptibility loci in ASAP1 gene on chromosome 8q24 for tuberculosis (TB) in a Russian population, but no relevant studies have been performed to validate these findings. In addition, previous GWAS in Ghana and Gambia found that the variant rs4331426 at 18q11.2 was a susceptibility locus for TB. However, the follow-up studies reported conflicting results. Herein, we investigated the contribution of genetic variants at 8q24 and 18q11.2 to TB in Chinese population. METHODS: We genotyped four genetic variants at 8q24 (rs10956514 and rs11774633) and 18q11.2 (rs4331426 and rs6507226) in a case-control study with 355 newly bacteriologically confirmed pulmonary TB cases and 395 healthy controls using TaqMan allelic discrimination assay. Subsequently, we conducted a meta-analysis including 4 reported studies in Chinese populations and our case-control study with a total of 3118 cases and 3226 controls to further evaluate the relationship between rs4331426 at 18q11.2 and TB risk. RESULTS: We did not find significant association between genetic variants at 8q24 and risk of TB (rs10956514: OR=0.89, 95%CI: 0.72-1.09, P=0.253; rs11774633: OR=0.86, 95%CI: 0.69-1.08, P=0.206). We did not observe significant association for genetic variants at 18q11.2 (rs4331426: OR=0.62, 95%CI: 0.34-1.14, P=0.122; and rs6507226: OR=0.98, 95%CI: 0.80-1.20, P=0.853). Moreover, the pooled results from the Meta-analysis further supported that rs4331426 at 18q11.2 was not associated with TB risk in Chinese population (OR=0.90, 95% CI: 0.63-1.29). CONCLUSIONS: Our findings indicate that TB risk-associated loci at 8q24 and 18q11.2 identified by GWAS from the other populations may not contribute to TB susceptibility in Chinese population. PMID- 26964909 TI - Molecular analysis and MIRU-VNTR typing of Mycobacterium avium subsp. avium, 'hominissuis' and silvaticum strains of veterinary origin. AB - Besides Mycobacterium avium subsp. paratuberculosis (MAP), M. avium subsp. avium (MAA), M. avium subsp. silvaticum (MAS), and 'M. avium subsp. hominissuis' (MAH) are equally important members of M. avium complex, with worldwide distribution and zoonotic potential. Genotypic discrimination is a prerequisite to epidemiological studies which can facilitate disease prevention through revealing infection sources and transmission routes. The primary aim of this study was to identify the genetic diversity within 135 MAA, 62 MAS, and 84 MAH strains isolated from wild and domestic mammals, reptiles and birds. Strains were tested for the presence of large sequence polymorphism LSP(A)17 and were submitted to Mycobacterial interspersed repetitive units-variable-number tandem repeat (MIRU VNTR) analysis at 8 loci, including MIRU1, 2, 3, and 4, VNTR25, 32, and 259, and MATR9. In 12 strains hsp65 sequence code type was also determined. LSP(A)17 was present only in 19.9% of the strains. All LSP(A)17 positive strains belonged to subspecies MAH. The discriminatory power of the MIRU-VNTR loci set used reached 0.9228. Altogether 54 different genotypes were detected. Within MAH, MAA, and MAS strains 33, 16, and 5 different genotypes were observed. The described genotypes were not restricted to geographic regions or host species, but proved to be subspecies specific. Our knowledge about MAS is limited due to isolation and identification difficulties. This is the first study including a large number of MAS field strains. Our results demonstrate the high diversity of MAH and MAA strains and the relative uniformity of MAS strains. PMID- 26964910 TI - Separate pulmonary venous anastomoses using a left atrial appendage in a left single lung transplantation. PMID- 26964911 TI - Evaluation of robotic cardiac surgery simulation training: A randomized controlled trial. AB - OBJECTIVE: To compare the currently available simulation training modalities used to teach robotic surgery. METHODS: Forty surgical trainees completed a standardized robotic 10-cm dissection of the internal thoracic artery and placed 3 sutures of a mitral valve annuloplasty in porcine models and were then randomized to a wet lab, a dry lab, a virtual reality lab, or a control group that received no additional training. All groups trained to a level of proficiency determined by 2 expert robotic cardiac surgeons. All assessments were evaluated using the Global Evaluative Assessment of Robotic Skills in a blinded fashion. RESULTS: Wet lab trainees showed the greatest improvement in time-based scoring and the objective scoring tool compared with the experts (mean, 24.9 +/- 1.7 vs 24.9 +/- 2.6; P = .704). The virtual reality lab improved their scores and met the level of proficiency set by our experts for all primary outcomes (mean, 24.9 +/- 1.7 vs 22.8 +/- 3.7; P = .103). Only the control group trainees were not able to meet the expert level of proficiency for both time-based scores and the objective scoring tool (mean, 24.9 +/- 1.7 vs 11.0 +/- 4.5; P < .001). The average duration of training was shortest for the dry lab and longest for the virtual reality simulation (1.6 hours vs 9.3 hours; P < .001). CONCLUSIONS: We have completed the first randomized controlled trial to objectively compare the different training modalities of robotic surgery. Our data demonstrate the significant benefits of wet lab and virtual reality robotic simulation training and highlight key differences in current training methods. This study can help guide training programs in investing resources in cost-effective, high-yield simulation exercises. PMID- 26964913 TI - Every step matters. PMID- 26964912 TI - Outcomes in patients undergoing coronary artery bypass graft surgery in the United States based on hospital volume, 2007 to 2011. AB - OBJECTIVE: To examine national trends in coronary artery bypass grafting (CABG) volume between 2007 and 2011, and analyze in-hospital outcomes after CABG surgery stratified according to hospital volume. METHODS: We analyzed all patients who underwent isolated CABG surgery between 2007 and 2011 in the National Inpatient Sample database. Trends in procedure volume and rates of adverse in-hospital outcomes were examined. Multivariate propensity-score adjusted analysis was performed to compare in-hospital mortality for hospitals based on quartiles of CABG volume. RESULTS: The frequency of isolated CABG decreased by 25.4% from 2007 to 2011 (from 326 cases per million adults to 243 cases per million adults), with the most marked decline at higher-volume centers. Patients in the highest-volume quartile were more likely to have a history of previous CABG, previous percutaneous coronary intervention, peripheral vascular disease, hypertension, or chronic renal failure. In-hospital mortality was highest in low-volume centers. In multivariate logistic regression analysis, low hospital volume was an independent predictor of in-hospital all-cause mortality (adjusted odds ratio, 1.39; 95% confidence interval, 1.24-1.56; P < .001). CONCLUSIONS: The rate of CABG procedures has declined, mainly at high-volume centers. Low CABG volume is associated with an increase in in-hospital mortality. PMID- 26964914 TI - Is conventional coronary artery surgery being replaced by the hybrid approach? PMID- 26964915 TI - Postinfarction ventricular septal defect: Beyond patching the hole. PMID- 26964916 TI - Controlled Outcomes for Achievement of Urinary Continence among Boys Treated for Posterior Urethral Valves. AB - PURPOSE: We evaluated the age at which boys with a history of posterior urethral valves after no or minimal anticholinergic medication achieve urinary continence and the factors contributing to continence. MATERIALS AND METHODS: We reviewed the hospital records of all males treated for posterior urethral valves at a single institution between 1990 and 2008. Continence was considered to have been attained if no weekly wetting episodes occurred. We evaluated the influence of patient characteristics, including reduced kidney function and primary ring type ureteral stoma, on age at which continence was achieved. RESULTS: A total of 76 patients were assessed. Achievement of daytime and nighttime urinary continence was markedly delayed in patients (mean +/- SD age 5.5 +/- 3.3 years and 5.4 +/- 3.0 years, respectively) compared to the reference population (2.3 +/- 0.5 and 2.9 +/- 1.2, p <0.001). Increased serum creatinine levels at age 5 years were associated with later daytime and nighttime continence (mean +/- SD 6.0 +/- 3.2 and 5.5 +/- 2.6 years, respectively, vs 4.1 +/- 2.3 and 3.7 +/- 1.4 years, respectively, in patients with normal serum creatinine, p <=0.05). Prenatal or neonatal diagnosis of posterior urethral valves was associated with significantly delayed achievement of daytime continence compared to cases diagnosed later (mean +/- SD 5.9 +/- 3.6 vs 4.1 +/- 1.8 years, p = 0.02). Patients with high nadir serum creatinine and vesicoureteral reflux initially also were at increased risk for urinary tract infections (p = 0.003 and p <0.001, respectively). CONCLUSIONS: Patients with posterior urethral valves achieve daytime and nighttime urinary continence significantly later than their healthy peers. Prenatal or neonatal diagnosis and high serum creatinine are associated with later attainment of continence. PMID- 26964918 TI - Ultrasound-enhanced chemiluminescence tomography in biological tissue. AB - This paper reports ultrasound-assisted optical imaging of chemiluminescent probes in biological tissue. A focused low power ultrasound sonochemically enhances a peroxyoxalate chemiluminescence (CL) that involves indocyanine green (ICG) as luminescent pigments. By scanning the focus, it produces tomographic images of CL in scattering media. The authors demonstrate imaging using a slab of porcine muscle measuring 50 * 50 * 75 mm, in which a capsuled CL reagent is embedded at 25 mm depth. Spatial resolution of imaging and concentration characteristics of CL reagents to enhanced CL intensity are also studied to evaluate the potential for use in bio-imaging applications with exploring the CL enhancement mechanisms. CL enhancement ratio, defined as the ratio of ultrasonically enhanced CL intensity to the base intensity without ultrasound irradiation, was found to be constant even in varying ICG and oxidizer concentrations, implying to be applicable for quantitative determination of these molecules. PMID- 26964917 TI - Systemic Radioligand Therapy with (177)Lu Labeled Prostate Specific Membrane Antigen Ligand for Imaging and Therapy in Patients with Metastatic Castration Resistant Prostate Cancer. AB - PURPOSE: We report our initial clinical experience with beta -emitting (177)Lu PSMA-I&T ((177)Lu labeled prostate specific membrane antigen ligand for imaging and therapy) for systemic treatment of metastatic castration resistant prostate cancer. MATERIALS AND METHODS: Patients with metastatic castration resistant prostate cancer who experienced treatment failure with chemotherapy and novel androgen receptor targeted therapy were treated for 8 weeks with up to 4 cycles of (177)Lu-PSMA-I&T. We report safety data, the antitumor response with prostate specific antigen decreases and the radiographic tumor response as well as the clinical outcome with changes in ECOG (Eastern Cooperative Oncology Group) performance status and pain severity. RESULTS: The first 3 patients were treated with a lower activity of 3.7 GBq in cycle 1. Due to a favorable safety profile the activity was increased to 7.4 GBq in 19 subsequent patients who completed a total of 40 cycles. With the higher activity no grade 3/4 toxicities were observed. The main nonhematological and hematological grade 1/2 toxicities were dry mouth in 7 patients (37%), anemia in 6 (32%) and thrombopenia in 5 (25%). The proportion of patients who achieved a maximum prostate specific antigen decrease of 30% or greater, 50% or greater and 90% or greater was 56%, 33% and 11%, respectively. Combined assessment of bone and soft tissue metastases showed complete remission in 5% of patients, stable disease in 63% and progressive disease in 32%. ECOG performance status improved or was stable in 74% of patients. Of men with bone pain 58% achieved complete resolution or reduced pain. CONCLUSIONS: Radioligand therapy with (177)Lu-PSMA-I&T appears to be safe and active in heavily pretreated patients with metastatic castration resistant prostate cancer. PMID- 26964919 TI - Assessing the application and downstream effects of pulsed mode ultrasound as a pre-treatment for alum coagulation. AB - The application of pulsed mode ultrasound (PMU) as a pre-treatment for alum coagulation was investigated at various alum dosages and pH levels. The effects of the treatments on turbidity and dissolved organic carbon (DOC) removal and residual Al were evaluated. Response surface methodology (RSM) was utilized to optimize the operating conditions of the applied treatments. The results showed that PMU pre-treatment increased turbidity and DOC removal percentages from maximum of 96.6% and 43% to 98.8% and 52%, respectively. It also helped decrease the minimum residual Al from 0.100 to 0.094 ppm. The multiple response optimization was carried out using the desirability function. A desirability value of >0.97 estimated respective turbidity removal, DOC removal and Al residual of 89.24%, 45.66% and ~ 0.1 ppm for coagulation (control) and 90.61%, >55% and ~ 0 for coagulation preceded by PMU. These figures were validated via confirmatory experiments. PMU pre-treatment increased total coliform removal from 80% to >98% and decreased trihalomethane formation potential (THMFP) from 250 to 200 ppb CH3Cl. Additionally, PMU application prior to coagulation improved the settleability of sludge due to the degassing effects. The results of this study confirms that PMU pre-treatment can significantly improve coagulation performance. PMID- 26964920 TI - Effects of ultrasound and ultrasound assisted alkaline pretreatments on the enzymolysis and structural characteristics of rice protein. AB - The objectives of this study were to investigate the effects of multi-frequency energy-gathered ultrasound (MFEGU) and MFEGU assisted alkaline pretreatments on the enzymolysis and the mechanism of two pretreatments accelerating the rice protein (RP) proteolysis process. The results showed that MFEGU and MFEGU assisted alkaline pretreatments improved significantly (P<0.05) the degree of hydrolysis (DH) and the protein elution amount of RP. Furthermore under the same DH conditions, ultrasound and ultrasound assisted alkaline pretreatments were more save the enzymolysis time than the unpretreatment. The changes in UV-vis spectra, fluorescence emission spectra indicated unfolding and destruction of RP by MFEGU and MFEGU assisted alkaline pretreatments. The circular dichroism analysis showed that both pretreatments decreased alpha-helix but increased beta sheet and random coil of RP. Amino acid composition revealed that MFEGU and MFEGU assisted alkaline pretreatments could increase the protein elution amount and the ratio of hydrophobic amino acids. Atomic force microscopy (AFM) indicated that both pretreatments destroyed the microstructures and reduced the particle size of RP. Therefore, MFEGU and MFEGU assisted alkaline pretreatments are beneficial to improving the degree of hydrolysis due to its sonochemistry effect on the molecular conformation as well as on the microstructure of protein. PMID- 26964922 TI - Ultrasonication assisted and surfactant mediated synergistic approach for synthesis of calcium sulfate nano-dendrites. AB - Calcium sulfate (CaSO4) nano-dendrimers were fabricated successfully via ultrasonic irradiation method using calcium chloride [CaCl2] and ammonium per sulfate [(NH4)2SO4] as precursors in aqueous solution by using cetyl trimethyl ammonium bromide (CTAB) as chemical surfactants. Diffusion-induced branching growth mechanism (DIBGM), influenced with the action of head-group and hydrocarbon chain effect of cationic surfactants, was the backbone in the formation of CaSO4 nano-dendrites. Fourier Transform Infra-red Spectroscopy (FTIR), X-Ray powder Diffraction (XRD), Atomic Emission Spectroscopy (AES), Selected Area Electron Diffraction (SAED), Field-Emission Scanning Electron Microscopy (FE-SEM), Energy-Dispersive Spectroscopy (EDS), Dynamic Light Spectroscopy (DLS) and BET surface area analyzer were used to characterize the products. Results obtained were compared with conventional stirring method that proved the superiority of sonication method to obtain well-crystalline nanostructures. Also, surfactant concentration, sonication frequency and time were noticed as the critical factors to generate such absolute morphologies at nano-crystalline size. PMID- 26964921 TI - Formulation of saponin stabilized nanoemulsion by ultrasonic method and its role to protect the degradation of quercitin from UV light. AB - The objective of the present study was to prepare quercitin (QT) loaded o/w nanoemulsion using food grade surfactants (saponin and tween 80). The prepared nanoemulsion) was stable up to 30 days. The average particle size of the nanoemulsion was 52 +/- 10 nm. The formation of saponin stabilized nanoemulsion was confirmed by transmission electron microscopy. Quercitin (QT) trapped nanoemulsion showed higher stability on exposure to UV light (254 nm) as compared to water/ethanol system. The degradation rate was found to decrease from 9 +/- 1%, 11 +/- 1% at pH 7.4, 8.0 respectively as compared to 42 +/- 2% in water/ethanol system. Attempt was also made to study the interaction of QT with two different bile salts (sodium cholate and sodium taurocholate). The free radical scavenging activity of DPPH quercitin and curcumin was compared in NEm media. The obtained IC50 value of quercitin, curcumin and ascorbic acid are 28.88 +/- 1, 45.53 +/- 2 and 51.51 +/- 2 MUM respectively. The values of binding constant for sodium cholate (NaC) and sodium taurocholate (NaTC) are 2.66 * 10(5) and 2.72 * 10(4) M(-1) respectively. Sodium cholate (NaC) was found to show strong interaction towards quercitin (QT) due to more electron density on oxygen atom of carboxylate ion. PMID- 26964923 TI - Sonochemical procedures; the main synthetic method for synthesis of coinage metal ion supramolecular polymer nano structures. AB - During the last two decades, supramolecular polymers have received great attention and the number of their synthesized compounds is still growing. Although people have long been interested in their crystalline network form it was only until 2005 that the first examples of nano- or microscale coordination polymers particles be demonstrated. This review tries to give an overview of all nano supramolecular compounds which were reported from coinage metal ions, their attributed synthetic procedures and to investigate the relation between the dimensions of coinage metal ions (Cu, Ag and Au) coordination and supramolecular polymers with their nano-structural morphologies and dimensions. Eleven compounds (from twenty compounds) with nano-structure morphology were prepared by sonochemical process and Ag(I) coordination and supramolecular polymer nano structures can be easily prepared by sonochemical procedures. PMID- 26964924 TI - Sonochemical degradation of ethyl paraben in environmental samples: Statistically important parameters determining kinetics, by-products and pathways. AB - The sonochemical degradation of ethyl paraben (EP), a representative of the parabens family, was investigated. Experiments were conducted at constant ultrasound frequency of 20 kHz and liquid bulk temperature of 30 degrees C in the following range of experimental conditions: EP concentration 250-1250 MUg/L, ultrasound (US) density 20-60 W/L, reaction time up to 120 min, initial pH 3-8 and sodium persulfate 0-100mg/L, either in ultrapure water or secondary treated wastewater. A factorial design methodology was adopted to elucidate the statistically important effects and their interactions and a full empirical model comprising seventeen terms was originally developed. Omitting several terms of lower significance, a reduced model that can reliably simulate the process was finally proposed; this includes EP concentration, reaction time, power density and initial pH, as well as the interactions (EP concentration)*(US density), (EP concentration)*(pHo) and (EP concentration)*(time). Experiments at an increased EP concentration of 3.5mg/L were also performed to identify degradation by products. LC-TOF-MS analysis revealed that EP sonochemical degradation occurs through dealkylation of the ethyl chain to form methyl paraben, while successive hydroxylation of the aromatic ring yields 4-hydroxybenzoic, 2,4-dihydroxybenzoic and 3,4-dihydroxybenzoic acids. By-products are less toxic to bacterium V. fischeri than the parent compound. PMID- 26964925 TI - Optimization of ultrasound induced emulsification on the formulation of palm olein based nanoemulsions for the incorporation of antioxidant beta-D-glucan polysaccharides. AB - Polysaccharides of beta-D-glucan configuration have well-known antioxidant activity against reactive free radicals generated from the oxidation of metabolic processes. In this study, beta-D-glucan-polysaccharides extracted from Ganoderma lucidum were incorporated in palm olein based nanoemulsions which act as carrier systems to enhance the delivery and bioactivity of these polysaccharides and could be potentially useful for skin care applications. Initially response surface statistical design (Central Composite Design--CCD) was subjected to optimize the formulation variables of oil-in-water (O/W) nanoemulsions induced by ultrasound. The optimal formulation variables as predicted by CCD resulted in considerably improving the physical characteristics of ultrasonically formulated nanoemulsions by minimizing their droplet size, polydispersity index and viscosity. Moreover, the beta-D-glucan-loaded nanoemulsions exhibited good stability over 90 days under different storage conditions (4 degrees C and 25 degrees C). The studies using palm olein based beta-D-glucan-loaded nanoemulsion generated using ultrasound confirm higher antioxidant activity as compared to free beta-D-glucan. PMID- 26964927 TI - High yield synthesis of Ni-BTC metal-organic framework with ultrasonic irradiation: Role of polar aprotic DMF solvent. AB - Nickel based porous solid was synthesized with 20 kHz ultrasonic irradiation. The reaction of Ni(II) nitrate hexahydrate with 1,3,5-benzene tricarboxylic acid in N,N-Dimethylformamide (DMF) as the sole solvent under ultrasonic radiation produced porous Ni-BTC MOF. Choice of correct solvent for the ultrasonic treatment was proven important. The effect of varying ultrasonic powers (40%, 60% and 80% of 750 W) along with different temperature conditions (50 degrees C, 60 degrees C, 70 degrees C and 80 degrees C) influenced the respective yield. A very high yield of 88% Ni-BTC MOF was obtained from 80% ultrasonic power at 60 degrees C. BET surface areas of the MOF crystals measured by N2 gas adsorption isotherms were in the range of 960-1000 m(2)/g. PMID- 26964926 TI - Enzymolysis kinetics and structural characteristics of rice protein with energy gathered ultrasound and ultrasound assisted alkali pretreatments. AB - This research investigated the structural characteristics and enzymolysis kinetics of rice protein which was pretreated by energy-gathered ultrasound and ultrasound assisted alkali. The structural characteristics of rice protein before and after the pretreatment were performed with surface hydrophobicity and Fourier transform infrared (FTIR). There was an increase in the intensity of fluorescence spectrum and changes in functional groups after the pretreatment on rice protein compared with the control (without ultrasound and ultrasound assisted alkali processed), thus significantly enhancing efficiency of the enzymatic hydrolysis. A simplified kinetic equation for the enzymolysis model with the impeded reaction of enzyme was deduced to successfully describe the enzymatic hydrolysis of rice protein by different pretreatments. The initial observed rate constants (Kin,0) as well as ineffective coefficients (kimp) were proposed and obtained based on the experimental observation. The results showed that the parameter of kin,0 increased after ultrasound and ultrasound assisted alkali pretreatments, which proved the effects of the pretreatments on the substrate enhancing the enzymolysis process and had relation to the structure changes of the pretreatments on the substrate. Furthermore, the applicability of the simplified model was demonstrated by the enzymatic hydrolysis process for other materials. PMID- 26964928 TI - One-pot sonochemical synthesis of 1,3-thiazolidin-4-ones using nano-CdZr4(PO4)6 as a robust heterogeneous catalyst. AB - An efficient three-component synthesis of 1,3-thiazolidin-4-ones is described by one-pot condensation of aldehydes, aniline and thioglycolic acid with nano CdZr4(PO4)6 as a robust heterogeneous catalyst under ultrasonic irradiation. Use of simple and readily available starting materials, experimental simplicity, applying the sonochemical methodology as an efficient method and innocuous means of activation in synthetic chemistry are some advantages of this protocol. PMID- 26964929 TI - Effect of non-acoustic parameters on heterogeneous sonoporation mediated by single-pulse ultrasound and microbubbles. AB - Sonoporation-transient plasma membrane perforation elicited by the interaction of ultrasound waves with microbubbles--has shown great potential for drug delivery and gene therapy. However, the heterogeneity of sonoporation introduces complexities and challenges in the realization of controllable and predictable drug delivery. The aim of this investigation was to understand how non-acoustic parameters (bubble related and bubble-cell interaction parameters) affect sonoporation. Using a customized ultrasound-exposure and fluorescence-imaging platform, we observed sonoporation dynamics at the single-cell level and quantified exogenous molecular uptake levels to characterize the degree of sonoporation. Sonovue microbubbles were introduced to passively regulate microbubble-to-cell distance and number, and bubble size. 1 MHz ultrasound with 10-cycle pulse duration and 0.6 MPa peak negative pressure were applied to trigger the inertial collapse of microbubbles. Our data revealed the impact of non-acoustic parameters on the heterogeneity of sonoporation. (i) The localized collapse of relatively small bubbles (diameter, D<5.5 MUm) led to predictable sonoporation, the degree of which depended on the bubble-to-cell distance (d). No sonoporation was observed when d/D>1, whereas reversible sonoporation occurred when d/D<1. (ii) Large bubbles (D>5.5 MUm) exhibited translational movement over large distances, resulting in unpredictable sonoporation. Translation towards the cell surface led to variable reversible sonoporation or irreversible sonoporation, and translation away from the cell caused either no or reversible sonoporation. (iii) The number of bubbles correlated positively with the degree of sonoporation when D<5.5 MUm and d/D<1. Localized collapse of two to three bubbles mainly resulted in reversible sonoporation, whereas irreversible sonoporation was more likely following the collapse of four or more bubbles. These findings offer useful insight into the relationship between non-acoustic parameters and the degree of sonoporation. PMID- 26964930 TI - Modification of nanosized natural montmorillonite for ultrasound-enhanced adsorption of Acid Red 17. AB - This work aims to modify montmorillonite (MMT) via dodecyltrimethylammonium bromide (DTMA) and investigate its ability in ultrasound (US) assisted decolorization of a polluted solution. BET surface area of MMT was increased from 19.76 to 42.57 m(2)/g and basal spacing of MMT structural layers was increased from 1.13 to 1.69 nm by DTMA modification. The application of DTMA-modified MMT (DTMA-MMT) and US for the decolorization of Acid Red 17 (AR17) showed that US could improve the ability of DTMA-MMT on decolorization of AR17 solution due to simultaneous adsorption and sonocatalysis. The ability of US assisted DTMA-MMT was slightly decreased with pH, the initial dye concentration and the presence of inorganic anions. PMID- 26964931 TI - Sonochemical synthesis of a new nano-sized cerium(III) supramolecular compound; Precursor for nanoceria. AB - Using a sonochemical method, nanoparticles of a new Ce(III) supramolecular compound, (NAMH(+))2[Ce4(pydc)6(pydcH)2(H2O)8].8H2O (1), (H2pydc=2,6 pyridinedicarboxylic acid, NAM=nicotinamide), have been synthesized. Compound 1 was characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), FT-IR spectroscopy and elemental analyses, and its structure was determined by X-ray crystallography. It has been revealed that its structure consists of tetra-nuclear building units that extend to a 3D supramolecular network via non-covalent interactions mainly hydrogen bonding. The thermal stability of complex 1 both for its crystals and nanostructures has been studied by the thermal gravimetric (TG) method and compared with each other. The role of ultrasound irradiation power and the concentration of initial reactants on the size and morphology of the nano-structured complex 1, has been investigated. Ceria nanoparticles were obtained upon the calcination of complex 1 at 800 degrees C under atmospheric air. Furthermore, the fluorescent properties of complex 1 at room temperature were studied. PMID- 26964932 TI - Syntheses and structural characterization of two new nanostructured Bi(III) supramolecular polymers via sonochemical method. AB - Two new bismuth(III) coordination supramolecular polymers, {[Bi2(Hbpp)(bpp)(MU I)2I6](Hbpp).MeOH}n (1) and [Bi(Hbpp)(Br4)] (2), (bpp=1,3-di(pyridin-4 yl)propane) were prepared and were structurally characterized by single crystal X ray diffraction. Single crystalline one-dimensional materials were prepared using a heat gradient applied a solution of the reagents using the branched tube method. The structural determination by single crystal X-ray crystallography shows that compounds 1 and 2 form monoclinic polymers with symmetry space group P21 in the solid state. These new nanostructured Bi(III) supramolecular compounds, {[Bi2(Hbpp)(bpp)(MU-I)2I6](Hbpp).MeOH} (1) and [Bi(Hbpp)(Br4)] (2), were also synthesized by sonochemical method. The nanostructures were characterized by Field Emission-scanning electron microscopy (FE-SEM), powder X ray diffraction (PXRD) and IR spectroscopy. PMID- 26964933 TI - Intensification of degradation of methomyl (carbamate group pesticide) by using the combination of ultrasonic cavitation and process intensifying additives. AB - In the present work, the degradation of methomyl has been carried out by using the ultrasound cavitation (US) and its combination with H2O2, Fenton and photo Fenton process. The study of effect of operating pH and ultrasound power density has indicated that maximum extent of degradation of 28.57% could be obtained at the optimal pH of 2.5 and power density of 0.155 W/mL. Application of US in combination with H2O2, Fenton and photo-Fenton process has further accelerated the rate of degradation of methomyl with complete degradation of methomyl in 27 min, 18 min and 9 min respectively. Mineralization study has proved that a combination of US and photo-Fenton process is the most effective process with maximum extent of mineralization of 78.8%. Comparison of energy efficiency and cost effectiveness of various processes has indicated that the electrical cost of 79892.34Rs./m(3) for ultrasonic degradation of methomyl has drastically reduced to 2277.00Rs./m(3), 1518.00Rs./m(3) and 807.58Rs./m(3) by using US in combination with H2O2, Fenton and photo-Fenton process respectively. The cost analysis has also indicated that the combination of US and photo-Fenton process is the most energy efficient and cost effective process. PMID- 26964935 TI - Cavitation erosion mechanism of titanium alloy radiation rods in aluminum melt. AB - Ultrasound radiation rods play a key role in introducing ultrasonic to the grain refinement of large-size cast aluminum ingots (with diameter over 800 mm), but the severe cavitation corrosion of radiation rods limit the wide application of ultrasonic in the metallurgy field. In this paper, the cavitation erosion of Ti alloy radiation rod (TARR) in the semi-continuous direct-chill casting of 7050 Al alloy was investigated using a 20 kHz ultrasonic vibrator. The macro/micro characterization of Ti alloy was performed using an optical digital microscopy and a scanning electron microscopy, respectively. The results indicated that the cavitation erosion and the chemical reaction play different roles throughout different corrosion periods. Meanwhile, the relationship between mass-loss and time during cavitation erosion was measured and analyzed. According to the rate of mass-loss to time, the whole cavitation erosion process was divided into four individual periods and the mechanism in each period was studied accordingly. PMID- 26964934 TI - Comparison of ultrasonic-assisted and regular leaching of germanium from by product of zinc metallurgy. AB - A major source of germanium recovery and also the source of this research is the by-product of lead and zinc metallurgical process. The primary purpose of the research is to investigate the effects of ultrasonic assisted and regular methods on the leaching yield of germanium from roasted slag containing germanium. In the study, the HCl-CaCl2 mixed solution is adopted as the reacting system and the Ca(ClO)2 used as the oxidant. Through six single factor (leaching time, temperature, amount of Ca(ClO)2, acid concentration, concentration of CaCl2 solution, ultrasonic power) experiments and the comparison of the two methods, it is found the optimum collective of germanium for ultrasonic-assisted method is obtained at temperature 80 degrees C for a leaching duration of 40 min. The optimum concentration for hydrochloric acid, CaCl2 and oxidizing agent are identified to be 3.5 mol/L, 150 g/L and 58.33 g/L, respectively. In addition, 700 W is the best ultrasonic power and an over-high power is adverse in the leaching process. Under the optimum condition, the recovery of germanium could reach up to 92.7%. While, the optimum leaching condition for regular leaching method is same to ultrasonic-assisted method, except regular method consume 100 min and the leaching rate of Ge 88.35% is lower about 4.35%. All in all, the experiment manifests that the leaching time can be reduced by as much as 60% and the leaching rate of Ge can be increased by 3-5% with the application of ultrasonic tool, which is mainly thanks to the mechanical action of ultrasonic. PMID- 26964936 TI - Effect of sonication frequency on the disruption of algae. AB - In this study, the efficiency of ultrasonic disruption of Chaetoceros gracilis, Chaetoceros calcitrans, and Nannochloropsis sp. was investigated by applying ultrasonic waves of 0.02, 0.4, 1.0, 2.2, 3.3, and 4.3 MHz to algal suspensions. The results showed that reduction in the number of algae was frequency dependent and that the highest efficiency was achieved at 2.2, 3.3, and 4.3MHz for C. gracilis, C. calcitrans, and Nannochloropsis sp., respectively. A review of the literature suggested that cavitation, rather than direct effects of ultrasonication, are required for ultrasonic algae disruption, and that chemical effects are likely not the main mechanism for algal cell disruption. The mechanical resonance frequencies estimated by a shell model, taking into account elastic properties, demonstrated that suitable disruption frequencies for each alga were associated with the cell's mechanical properties. Taken together, we consider here that physical effects of ultrasonication were responsible for algae disruption. PMID- 26964937 TI - Precise spatial control of cavitation erosion in a vessel phantom by using an ultrasonic standing wave. AB - In atherosclerotic inducement in animal models, the conventionally used balloon injury is invasive, produces excessive vessel injuries at unpredictable locations and is inconvenient in arterioles. Fortunately, cavitation erosion, which plays an important role in therapeutic ultrasound in blood vessels, has the potential to induce atherosclerosis noninvasively at predictable sites. In this study, precise spatial control of cavitation erosion for superficial lesions in a vessel phantom was realised by using an ultrasonic standing wave (USW) with the participation of cavitation nuclei and medium-intensity ultrasound pulses. The superficial vessel erosions were restricted between adjacent pressure nodes, which were 0.87 mm apart in the USW field of 1 MHz. The erosion positions could be shifted along the vessel by nodal modulation under a submillimetre-scale accuracy without moving the ultrasound transducers. Moreover, the cavitation erosion of the proximal or distal wall could be determined by the types of cavitation nuclei and their corresponding cavitation pulses, i.e., phase-change microbubbles with cavitation pulses of 5 MHz and SonoVue microbubbles with cavitation pulses of 1 MHz. Effects of acoustic parameters of the cavitation pulses on the cavitation erosions were investigated. The flow conditions in the experiments were considered and discussed. Compared to only using travelling waves, the proposed method in this paper improves the controllability of the cavitation erosion and reduces the erosion depth, providing a more suitable approach for vessel endothelial injury while avoiding haemorrhage. PMID- 26964938 TI - Sono-synthesis and characterization of bimetallic Ni-Co/Al2O3-MgO nanocatalyst: Effects of metal content on catalytic properties and activity for hydrogen production via CO2 reforming of CH4. AB - Sono-dispersion of Ni, Co and Ni-Co over Al2O3-MgO with Al/Mg ratio of 1.5 was prepared and tested for dry reforming of methane. The samples were characterized by XRD, FESEM, PSD, EDX, TEM, BET and FTIR analyses. In order to assess the effect of ultrasound irradiation, Ni-Co/Al2O3-MgO with Co content of 8% prepared via sonochemistry and impregnation methods. The sono-synthesized sample showed better textural properties and higher activity than that of impregnated one. Comparison of XRD patterns indicated that the NiO peaks became broader by increasing Co content over the support. The FESEM images displayed the particles are small and well-dispersed as a result of sonochemistry method. Also, EDX analysis demonstrated better dispersion of Ni and Co as a result of sonochemistry method in confirmation of XRD analysis. The sono-synthesized Ni-Co/Al2O3-MgO as a superior nanocatalyst with Co content of 3% illustrates much higher conversions (97.5% and 99% for CH4 and CO2 at 850 degrees C), yields (94% and 96% for H2 and CO at 850 degrees C) and 0.97 of H2/CO molar ratio in all samples using an equimolar feed ratio at 850 degrees C. During the 1200 min stability test, H2/CO molar ratio remained constant for the superior nanocatalyst. PMID- 26964939 TI - Eco-friendly processing in enzymatic xylooligosaccharides production from corncob: Influence of pretreatment with sonocatalytic-synergistic Fenton reaction and its antioxidant potentials. AB - Delignification can be considered as a feasible process to pretreat lignocellulosic biomass in xylooligosaccharides production after the performance and efficiency has been improved through a few modifications. This study compared various pretreatment strategies such as Fenton, sonocatalytic, and sonocatalytic synergistic Fenton employed on corncob in order to expose lignin content and saccharides to enhance the xylooligosaccharides yield by enzymatic hydrolysis. The dissolution of lignin and xylooligosaccharides production of corncob was enhanced by ultrasound assisted TiO2 and Fenton reaction. The corncob pretreated with a sonocatalytic-synergistic Fenton reaction gave the highest release of the lignin concentration level (1.03 g/L), dissolution level (80.25%), and xylooligosaccharides content (46.45 mg/g substrate). A two-step pretreatment processes consisting of the alkali treatment (pretreatment) and sonocatalytic synergistic Fenton process (posttreatment) illustrated that subsequent enzymatic hydrolysis could be enhanced considerably. The release of the lignin concentration and xylooligosaccharides content were 33.20 g/L and 174.81 mg/g substrate, respectively. The antioxidant potential of xylooligosaccharides showed significant differences regarding the amount of xylooligosaccharides and the phenolic compounds produced. PMID- 26964940 TI - Sono-advanced Fenton decolorization of azo dye Orange G: Analysis of synergistic effect and mechanisms. AB - In this study, a successful decolorization of Orange G was achieved by means of coupling zero valent iron (ZVI), H2O2 and ultrasound (US) under acidic pH conditions. The synergistic effect and characterization of potential roles of the factors including ZVI, tert-Butanol as radical scavenger, dissolved ferrous ions and H2O2 generated from sonication were evaluated in this sono-advanced Fenton process (SAFP) system. A clear synergy was evident in terms of decolorization rate and the TOC removal as the input of US enhanced the activity of the Fe(0)/H2O2 system. The results suggested that the ZVI was potential replacement for the Fe(2+) ion. This remarkable activity was attributed to the capacity of Fe(2+) formed and reduction of sonic-dissolved Fe(2+) concentration by the formation of {Fe.Fe(2+)}. The modification of the condition of H2O2 addition such as the dosage and input method showed significant variations in terms of decolorization rate. This result indicated that the optimal external addition of H2O2 and input method is a limited factor of decolorization rate due to its comparatively insufficient generated by ultrasound. PMID- 26964941 TI - Ultrasound-assisted fabrication of a new nano-rods 3D copper(II)-organic coordination supramolecular compound. AB - High-energy ultrasound irradiation has been used for the synthesis of a new copper(II) coordination supramolecular compound, [Cu2(MU-O2CCH3)2(MU OOCCH3)(phen)2](BF4) (1), ("phen" is 1,10-phenanthroline) with nano-rods morphology. The new nano-structure was characterized by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), FT-IR spectroscopy and elemental analyses. Compound 1 was structurally characterized by single crystal X ray diffraction. The utilization of high intensity ultrasound has found as a facile, environmentally friendly, and versatile synthetic tool for the supramolecular coordination compounds. PMID- 26964942 TI - Effect of platinum nanoparticles on cell death induced by ultrasound in human lymphoma U937 cells. AB - In this study, we report on the potential use of platinum nanoparticles (Pt-NPs), a superoxide dismutase (SOD)/catalase mimetic antioxidant, in combination with 1MHz ultrasound (US) at an intensity of 0.4 W/cm(2), 10% duty factor, 100 Hz PRF, for 2 min. Apoptosis induction was assessed by DNA fragmentation assay, cell cycle analysis and Annexin V-FITC/PI staining. Cell killing was confirmed by cell counting and microscopic examination. The mitochondrial and Ca(2+)-dependent pathways were investigated. Caspase-8 expression and autophagy-related proteins were detected by spectrophotometry and western blot analysis, respectively. Intracellular reactive oxygen species (ROS) elevation was detected by flow cytometry, while extracellular free radical formation was assessed by electron paramagnetic resonance spin trapping spectrometry. The results showed that Pt-NPs exerted differential effects depending on their internalization. Pt-NPs functioned as potent free radical scavengers when added immediately before sonication while pre-treatment with Pt-NPs suppressed the induction of apoptosis as well as autophagy (AP), and resulted in enhanced cell killing. Dead cells displayed the features of pyknosis. The exact mode of cell death is still unclear. In conclusion, the results indicate that US-induced AP may contribute to cell survival post sonication. To our knowledge this is the first study to discuss autophagy as a pro-survival pathway in the context of US. The combination of Pt-NPs and US might be effective in cancer eradication. PMID- 26964944 TI - Effects of ultrasonic agitation and surfactant additive on surface roughness of Si (111) crystal plane in alkaline KOH solution. AB - In the silicon wet etching process, the "pseudo-mask" formed by the hydrogen bubbles generated during the etching process is the reason causing high surface roughness and poor surface quality. Based upon the ultrasonic mechanical effect and wettability enhanced by isopropyl alcohol (IPA), ultrasonic agitation and IPA were used to improve surface quality of Si (111) crystal plane during silicon wet etching process. The surface roughness Rq is smaller than 15 nm when using ultrasonic agitation and Rq is smaller than 7 nm when using IPA. When the range of IPA concentration (mass fraction, wt%) is 5-20%, the ultrasonic frequency is 100 kHz and the ultrasound intensity is 30-50 W/L, the surface roughness Rq is smaller than 2 nm when combining ultrasonic agitation and IPA. The surface roughness Rq is equal to 1 nm when the mass fraction of IPA, ultrasound intensity and the ultrasonic frequency is 20%, 50 W and 100 kHz respectively. The experimental results indicated that the combination of ultrasonic agitation and IPA could obtain a lower surface roughness of Si (111) crystal plane in silicon wet etching process. PMID- 26964943 TI - Ultrasonic semi-solid coating soldering 6061 aluminum alloys with Sn-Pb-Zn alloys. AB - In this paper, 6061 aluminum alloys were soldered without a flux by the ultrasonic semi-solid coating soldering at a low temperature. According to the analyses, it could be obtained that the following results. The effect of ultrasound on the coating which promoted processes of metallurgical reaction between the components of the solder and 6061 aluminum alloys due to the thermal effect. Al2Zn3 was obtained near the interface. When the solder was in semi-solid state, the connection was completed. Ultimately, the interlayer mainly composed of three kinds of microstructure zones: alpha-Pb solid solution phases, beta-Sn phases and Sn-Pb eutectic phases. The strength of the joints was improved significantly with the minimum shear strength approaching 101MPa. PMID- 26964945 TI - Irradiation of ultrasound to 5-methylbenzotriazole in aqueous phase: Degradation kinetics and mechanisms. AB - Ultrasonic irradiation (640 kHz) leads to the effective degradation of 5-methyl benzotriazole (5-MBT) in O2 saturated aqueous solution. Up to 97% of 5-MBT is eliminated within 2h of treatment. Upon extended treatment of 6h, UV absorbance of the n->pi(*) and pi->pi(*) transitions associated with aromatic and conjugated systems are completely removed, indicating complete destruction of the aromatic system in 5-MBT. The decomposition of 5-MBT follows pseudo-first order kinetics and the observed decomposition rate dropped significantly in the presence of tertiary butyl alcohol. Detailed product studies were performed employing a negative mode ESI LC-MS. Twenty eight intermediate products were detected during ultrasonic mediated degradation of 5-MBT. Reaction pathways are proposed based on the structures of products assigned to observed 28 masses from LC-MS and commonly accepted degradation pathways observed by thermal and hydroxyl radical mediated pathways often associated with ultrasonic treatment. PMID- 26964946 TI - Ultrasound processing to enhance drying of cashew apple bagasse puree: Influence on antioxidant properties and in vitro bioaccessibility of bioactive compounds. AB - The present study has evaluated the effects of power ultrasound pre-treatment on air-drying and bioactive compounds of cashew apple bagasse. The sonication induced the disruption of cashew bagasse parenchyma, which resulted in lower resistance to water diffusion, less hysteresis, and increased rehydration rate. The processing did not affect the lignocellulose fibers or the sclerenchyma cells. For sonicated samples, water activity reached values below 0.4, after 2h of drying, which is appropriate to prevent bacterial and fungi growth. The sorption isotherms of cashew apple bagasse presented sigmoid-shape for all samples and followed the type II according to BET classification. Sonicated cashew apple bagasse showed higher antioxidant activity, higher total phenolic compounds (TPC) and higher vitamin C content when compared to the non-sonicated sample. The increase in TPC and vitamin C contributed to the product antioxidant activity. A slight reduction on Vitamin C bioaccessibility was observed, but the TPC bioaccessibility has increased. Sonication reduced the quality loss of conventional drying treatments improving the quality of the dried product. PMID- 26964947 TI - Sonocatalytic removal of naproxen by synthesized zinc oxide nanoparticles on montmorillonite. AB - ZnO/MMT nanocomposite as sonocatalyst was prepared by immobilizing synthesized ZnO on the montmorillonite surface. The characteristics of as-prepared nanocomposite were studied by scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM) and X-ray diffraction (XRD) techniques. The synthesized samples were used as a catalyst for sonocatalytic degradation of naproxen. ZnO/MMT catalyst in the presence of ultrasound irradiation was more effective compared to pure ZnO nanoparticles and MMT particles in the sonocatalysis of naproxen. The effect of different operational parameters on the sonocatalytic degradation of naproxen including initial drug concentration, sonocatalyst dosage, solution pH, ultrasonic power and the presence of organic and inorganic scavengers were evaluated. It was found that the presence of the scavengers suppressed the sonocatalytic degradation efficiency. The reusability of the nanocomposite was examined in several consecutive runs, and the degradation efficiency decreased only 2% after 5 repeated runs. The main intermediates of naproxen degradation were determined by gas chromatography-mass spectrometry (GC-Mass). PMID- 26964948 TI - Ultrasound mediation for one-pot sonosynthesis and deposition of magnetite nanoparticles on cotton/polyester fabric as a novel magnetic, photocatalytic, sonocatalytic, antibacterial and antifungal textile. AB - A magnetic cotton/polyester fabric with photocatalytic, sonocatalytic, antibacterial and antifungal activities was successfully prepared through in-situ sonosynthesis method under ultrasound irradiation. The process involved the oxidation of Fe(2+) to Fe(3+) via hydroxyl radicals generated through bubbles collapse in ultrasonic bath. The treated samples were analyzed by X-ray diffraction, field emission scanning electron microscopy, energy dispersive X-ray spectroscopy and vibrating sample magnetometry. Photocatalytic and sonocatalytic activities of magnetite treated fabrics were also evaluated toward Reactive Blue 2 decoloration under sunlight and ultrasound irradiation. Central composite design based on response surface methodology was applied to study the influence of iron precursor, pH and surfactant concentration to obtain appropriate amount for the best magnetism. Findings suggested the potential of one-pot sonochemical method to synthesize and fabricate Fe3O4 nanoparticles on cotton/polyester fabric possessing appropriate saturation magnetization, 95% antibacterial efficiency against Staphylococcus aureus and 99% antifungal effect against Candida albicans, 87% and 70% dye photocatalytic and sonocatalytic decoloration along with enhanced mechanical properties using only one iron rich precursor at low temperature. PMID- 26964949 TI - Surface topography, nano-mechanics and secondary structure of wheat gluten pretreated by alternate dual-frequency ultrasound and the correlation to enzymolysis. AB - The effects of alternate dual-frequency ultrasound (ADFU) pretreatment on the degree of hydrolysis (DH) of wheat gluten (WG) and angiotensin I-converting enzyme (ACE) inhibitory activity were investigated in this research. The surface topography, nano-mechanics and secondary structure of WG were also determined using atomic force microscope (AFM) and circular dichroism (CD). The correlations of ACE inhibitory activity and DH with surface topography, nano-mechanics and secondary structure of WG were determined using Pearson's correlation analysis. The results showed that with an increase in either pretreatment duration or power, the ACE inhibitory activity of the hydrolysate also increases, reaching maximum at 10 min and 150 W/L, respectively, and then decreases thereafter. Similarly, AFM analysis showed that as the pretreatment duration or power increases, the surface roughness also increase and again a decrease occurs thereafter. As the pretreatment duration or power increased, the Young's modulus and adhesion of WG also increased and then declined. Young's modulus and adhesions average values were compared with ACE inhibitory activity reversely. The result of the CD spectra analysis exhibited losses in the relative percentage of alpha-helix of WG. Pearson's correlation analysis showed that the average values of Young's modulus and the relative percentage of alpha-helix correlated with ACE inhibitory activity of the hydrolysates linearly and significantly (P<0.05); the relative percentage of beta-sheet correlated linearly with DH of WG significantly (P<0.05). In conclusion, ADFU pretreatment is an efficient method in proteolysis due to its physical and chemical effect on the Young's modulus, alpha-helix and beta-sheet of WG. PMID- 26964950 TI - High frequency ultrasound as a selective advanced oxidation process to remove penicillinic antibiotics and eliminate its antimicrobial activity from water. AB - This work studies the sonochemical degradation of a penicillinic antibiotic (oxacillin) in simulated pharmaceutical wastewater. High frequency ultrasound was applied to water containing the antibiotic combined with mannitol or calcium carbonate. In the presence of additives, oxacillin was efficiently removed through sonochemical action. For comparative purposes, the photo-Fenton, TiO2 photocatalysis and electrochemical oxidation processes were also tested. Therefore, the evolution of the antibiotic and its associated antimicrobial activity (AA) were monitored. A high inhibition was found for the other three oxidation processes in the elimination of the antimicrobial activity caused by the additives; while for the ultrasonic treatment, a negligible effect was observed. The sonochemical process was able to completely degrade the antibiotic, generating solutions without AA. In fact, the elimination of antimicrobial activity showed an excellent performance adjusted to exponential kinetic-type decay. The main sonogenerated organic by-products were determined by means of HPLC-MS. Four intermediaries were identified and they have modified the penicillinic structure, which is the moiety responsible for the antimicrobial activity. Additionally, the possible oxacillin sonodegradation mechanism was proposed based on the evolution of the by-products and their chemical structure. Furthermore, the high-frequency ultrasound action over 120 min readily removed oxacillin and eliminated its antimicrobial activity. However, the pollutant was not mineralized even after a long period of ultrasonic irradiation (360 min). Interestingly, the previously sonicated water containing oxacillin and both additives was completely mineralized using non-adapted microorganisms from a municipal wastewater treatment plant. These results show that the sonochemical treatment transformed the initial pollutant into substances that are biotreatable with a typical aerobic biological system. PMID- 26964951 TI - Effect of ultrasound on the supercritical CO2 extraction of bioactive compounds from dedo de moca pepper (Capsicum baccatum L. var. pendulum). AB - Extracts with bioactive compounds were obtained from the red pepper variety "dedo de moca" (Capsicum baccatum L. var. pendulum) through supercritical fluid extraction with carbon dioxide assisted by ultrasound (SFE-US). The process was tested at pressures of 15, 20 and 25 MPa; temperatures of 40, 50 and 60 degrees C, and ultrasonic powers of 200, 400 and 600 W applied during 40, 60 and 80 min of extraction. The CO2 mass flow rate was fixed at 1.7569 * 10(-4) kg/s. Global yield, phenolic content, antioxidant capacity and capsaicinoid concentration were evaluated in the extracts. The application of ultrasound raised the global extraction yield of SFE up to 45%. The phenolic content of the extract increased with the application of higher ultrasound power and radiation time. The capsaicinoid yield was also enhanced with ultrasound up to 12%. However, the antioxidant capacity did not increase with the ultrasound application. The BET based model and the broken and intact cell model fitted well to the kinetic SFE curves. The BET-based model with three adjustable parameters resulted in the best fits to the experimental data. Field emission scanning electron microscopy (FESEM) images showed that SFE disturbed the vegetable matrix, releasing particles from the inner region of the plant cells to their surface. When the ultrasound was applied this effect was more pronounced. On the other hand, cracks, fissures or any sign of rupture were not identified on the sample surface. PMID- 26964952 TI - Copper NPs decorated titania: A novel synthesis by high energy US with a study of the photocatalytic activity under visible light. AB - The most important drawback of the use of TiO2 as photocatalyst is its lack of activity under visible light. To overcome this problem, the surface modification of commercial micro-sized TiO2 by means of high-energy ultrasound (US), employing CuCl2 as precursor molecule to obtain both metallic copper as well as copper oxides species at the TiO2 surface, is here. We have prepared samples with different copper content, in order to evaluate its impact on the photocatalytic performances of the semiconductor, and studied in particular the photodegradation in the gas phase of some volatile organic molecules (VOCs), namely acetone and acetaldehyde. We used a LED lamp in order to have only the contribution of the visible wavelengths to the TiO2 activation (typical LED lights have no emission in the UV region). We employed several techniques (i.e., HR-TEM, XRD, FT-IR and UV-Vis) in order to characterize the prepared samples, thus evidencing different sample morphologies as a function of the various copper content, with a coherent correlation between them and the photocatalytic results. Firstly, we demonstrated the possibility to use US to modify the TiO2, even when it is commercial and micro-sized as well; secondly, by avoiding completely the UV irradiation, we confirmed that pure TiO2 is not activated by visible light. On the other hand, we showed that copper metal and metal oxides nanoparticles strongly and positively affect its photocatalytic activity. PMID- 26964953 TI - High intensity ultrasound modified ovalbumin: Structure, interface and gelation properties. AB - Influence of high intensity ultrasound (HIUS) on the structure and properties of ovalbumin (OVA) were investigated. It was found that the subunits and secondary structure of OVA did not change significantly with HIUS treatment from the electrophoretic patterns and circular dichroism (CD) spectrum. The amount of free sulfhydryl groups increased and intrinsic fluorescence spectra analysis indicated changes in the tertiary structure and partial unfold of OVA after sonication increased. Compared with the untreated OVA, HIUS treatment increased the emulsifying activity and foaming ability, and decreased interface tension (oil water and air-water interface), which due to the increased surface hydrophobicity and decreased the surface net charge in OVA, while the emulsifying and foaming stability had no remarkable differences. The increased particle size may be attributed to formation of protein aggregates. Moreover, the gelation temperatures of HIUS-treated samples were higher than the untreated OVA according to the temperature sweep model rheology, and this effect was consistent with the increased in surface hydrophobicity for ultrasound treated OVA. These changes in functional properties of OVA would promote its application in food industry. PMID- 26964954 TI - Power ultrasound as a pretreatment to convective drying of mulberry (Morus alba L.) leaves: Impact on drying kinetics and selected quality properties. AB - The effect of ultrasound pretreatment prior to convective drying on drying kinetics and selected quality properties of mulberry leaves was investigated in this study. Ultrasound pretreatment was carried out at 25.2-117.6 W/L for 5-15 min in a continuous mode. After sonication, mulberry leaves were dried in a hot air convective dryer at 60 degrees C. The results revealed that ultrasound pretreatment not only affected the weight of mulberry leaves, it also enhanced the convective drying kinetics and reduced total energy consumption. The drying kinetics was modeled using a diffusion model considering external resistance and effective diffusion coefficient De and mass transfer coefficient hm were identified. Both De and hm during convective drying increased with the increase of acoustic energy density (AED) and ultrasound duration. However, De and hm increased slowly at high AED levels. Furthermore, ultrasound pretreatment had a more profound influence on internal mass transfer resistance than on external mass transfer resistance during drying according to Sherwood numbers. Regarding the quality properties, the color, antioxidant activity and contents of several bioactive compounds of dried mulberry leaves pretreated by ultrasound at 63.0 W/L for 10 min were similar to that of mulberry leaves without any pretreatments. Overall, ultrasound pretreatment is effective to shorten the subsequent drying time of mulberry leaves without damaging the quality of final product. PMID- 26964955 TI - Ultrasound induced green solvent extraction of oil from oleaginous seeds. AB - Ultrasound-assisted extraction of rapeseed oil was investigated and compared with conventional extraction for energy efficiency, throughput time, extraction yield, cleanness, processing cost and product quality. A multivariate study enabled us to define optimal parameters (7.7 W/cm(2) for ultrasonic power intensity, 40 degrees C for processing temperature, and a solid/liquid ratio of 1/15) for ultrasound-assisted extraction of oil from oilseeds to maximize lipid yield while reducing solvent consumption and extraction time using response surface methodology (RSM) with a three-variable central composite design (CCD). A significant difference in oil quality was noted under the conditions of the initial ultrasound extraction, which was later avoided using ultrasound in the absence of oxygen. Three concepts of multistage cross-current extraction were investigated and compared: conventional multistage maceration, ultrasound assisted maceration and a combination, to assess the positive impact of using ultrasound on the seed oil extraction process. The study concludes that ultrasound-assisted extraction of oil is likely to reduce both economic and ecological impacts of the process in the fat and oil industry. PMID- 26964956 TI - A possible general mechanism for ultrasound-assisted extraction (UAE) suggested from the results of UAE of chlorogenic acid from Cynara scolymus L. (artichoke) leaves. AB - The use of ultrasound-assisted extraction (UAE) for the extraction of chlorogenic acid (CA) from Cynara scolymus L., (artichoke) leaves using 80% methanol at room temperature over 15 min gave a significant increase in yield (up to a 50%) compared with maceration at room temperature and close to that obtained by boiling over the same time period. A note of caution is introduced when comparing UAE with Soxhlet extraction because, in the latter case, the liquid entering the Soxhlet extractor is more concentrated in methanol (nearly 100%) that the solvent in the reservoir (80% methanol) due to fractionation during distillation. The mechanism of UAE is discussed in terms of the effects of cavitation on the swelling index, solvent diffusion and the removal of a stagnant layer of solvent surrounding the plant material. PMID- 26964957 TI - Effect of ultrasonic pretreatment on emulsion polymerization of styrene. AB - This study investigated the effect of pretreatment of ultrasonic irradiation on emulsion polymerization of styrene to propose a process intensification method which gives high conversion, high reaction rate, and high energy efficiency. The solution containing styrene monomer was irradiated by a horn mounted on the ultrasonic transducer with the diameter of 5mm diameter and the frequency of 28 kHz before starting polymerization. The pretreatment of ultrasound irradiation as short as 1 min drastically improved monomer dispersion and increased reaction rate even under the agitation condition with low rotational speed of impeller. Furthermore, the ultrasonic pretreatment resulted in higher monomer concentration in polymer particles and produced larger polymer particles than conventional polymerization without ultrasonic pretreatment. PMID- 26964958 TI - Synthesis of zeolite A from coal fly ash using ultrasonic treatment--A replacement for fusion step. AB - The synthesis of zeolites from fly ash has become an increasingly promising remedy to the crisis of coal fly ash production and disposal in South Africa. In recent studies, South African fly ash was proven to be a suitable feedstock for the synthesis of essential industrially used zeolite A. However, the process involves a costly energy intensive step whereby fly ash is fused at high temperatures, which may make the process economically unattractive on a large scale. The aim of this study is to investigate the possibility of replacing high temperature fusion with less energy intensive sonochemical treatment for the synthesis of zeolite A. Sonochemical treatment was first thought possible due to the violent cavitation caused by high intensity sonication. The results of the study showed that fusion can be replaced by 10 min of high intensity sonication. The incorporation of sonication also consequently reduced the crystallization temperature of the process making it possible to synthesize a pure phase zeolite A at lower temperatures and reduced times. This study effectively developed a novel process to replace the energy intensive fusion step with a short, easy and inexpensive treatment. Scale up of this synthesis approach may proffer a promising alternative option to the anticipated energy demand of the synthesis of fly ash-based zeolite with fusion method. PMID- 26964960 TI - Synchrotron quantification of ultrasound cavitation and bubble dynamics in Al 10Cu melts. AB - Knowledge of the kinetics of gas bubble formation and evolution under cavitation conditions in molten alloys is important for the control casting defects such as porosity and dissolved hydrogen. Using in situ synchrotron X-ray radiography, we studied the dynamic behaviour of ultrasonic cavitation gas bubbles in a molten Al 10 wt%Cu alloy. The size distribution, average radius and growth rate of cavitation gas bubbles were quantified under an acoustic intensity of 800 W/cm(2) and a maximum acoustic pressure of 4.5 MPa (45 atm). Bubbles exhibited a log normal size distribution with an average radius of 15.3 +/- 0.5 MUm. Under applied sonication conditions the growth rate of bubble radius, R(t), followed a power law with a form of R(t)=alphat(beta), and alpha=0.0021 &beta=0.89. The observed tendencies were discussed in relation to bubble growth mechanisms of Al alloy melts. PMID- 26964959 TI - Ultrasonic dyeing of cellulose nanofibers. AB - Textile dyeing assisted by ultrasonic energy has attained a greater interest in recent years. We report ultrasonic dyeing of nanofibers for the very first time. We chose cellulose nanofibers and dyed with two reactive dyes, CI reactive black 5 and CI reactive red 195. The cellulose nanofibers were prepared by electrospinning of cellulose acetate (CA) followed by deacetylation. The FTIR results confirmed complete conversion of CA into cellulose nanofibers. Dyeing parameters optimized were dyeing temperature, dyeing time and dye concentrations for each class of the dye used. Results revealed that the ultrasonic dyeing produced higher color yield (K/S values) than the conventional dyeing. The color fastness test results depicted good dye fixation. SEM analysis evidenced that ultrasonic energy during dyeing do not affect surface morphology of nanofibers. The results conclude successful dyeing of cellulose nanofibers using ultrasonic energy with better color yield and color fastness results than conventional dyeing. PMID- 26964961 TI - Hydrodynamic cavitation as a novel approach for pretreatment of oily wastewater for anaerobic co-digestion with waste activated sludge. AB - Application of hydrodynamic cavitation (HC) was investigated with the objective of biogas production enhancement from co-digestion of oily wastewater (OWW) and waste activated sludge (WAS). Initially, the effect of HC on the OWW was evaluated in terms of energy consumption and turbidity increase. Then, several mixtures of OWW (with and without HC pretreatment) and WAS with the same concentration of total volatile solid were prepared as a substrate for co digestion. Following, several batch co-digestion trials were conducted. To compare the biogas production, a number of digestion trials were also conducted with a mono substrate (OWW or WAS alone). The best operating condition of HC was achieved in the shortest retention time (7.5 min) with the application of 3mm diameter orifice and maximum pump rotational speed. Biogas production from all co digestion reactors was higher than the WAS mono substrate reactors. Moreover, biogas production had a direct relationship with OWW ratio and no major inhibition was observed in any of the reactors. The biogas production was also enhanced by HC pretreatment and almost all of the reactors with HC pretreatment had higher reaction rates than the reactors without pretreatment. PMID- 26964962 TI - Intensified depolymerization of aqueous polyacrylamide solution using combined processes based on hydrodynamic cavitation, ozone, ultraviolet light and hydrogen peroxide. AB - The present work deals with intensification of depolymerization of polyacrylamide (PAM) solution using hydrodynamic cavitation (HC) reactors based on a combination with hydrogen peroxide (H2O2), ozone (O3) and ultraviolet (UV) irradiation. Effect of inlet pressure in hydrodynamic cavitation reactor and power dissipation in the case of UV irradiation on the extent of viscosity reduction has been investigated. The combined approaches such as HC+UV, HC+O3, HC+H2O2, UV+H2O2 and UV+O3 have been subsequently investigated and found to be more efficient as compared to individual approaches. For the approach based on HC+UV+H2O2, the extent of viscosity reduction under the optimized conditions of HC (3 bar inlet pressure)+UV (8 W power)+H2O2 (0.2% loading) was 97.27% in 180 min whereas individual operations of HC (3 bar inlet pressure) and UV (8 W power) resulted in about 35.38% and 40.83% intrinsic viscosity reduction in 180 min respectively. In the case of HC (3 bar inlet pressure)+UV (8 W power)+ozone (400 mg/h flow rate) approach, the extent of viscosity reduction was 89.06% whereas individual processes of only ozone (400 mg/h flow rate), ozone (400 mg/h flow rate)+HC (3 bar inlet pressure) and ozone (400 mg/h flow rate)+UV (8 W power) resulted in lower extent of viscosity reduction as 50.34%, 60.65% and 75.31% respectively. The chemical structure of the treated PAM by all approaches was also characterized using FTIR (Fourier transform infrared) spectra and it was established that no significant chemical structure changes were obtained during the treatment. Overall, it can be said that the combination of HC+UV+H2O2 is an efficient approach for the depolymerization of PAM solution. PMID- 26964963 TI - Ultrasonically assisted hydrothermal synthesis of activated carbon-HKUST-1-MOF hybrid for efficient simultaneous ultrasound-assisted removal of ternary organic dyes and antibacterial investigation: Taguchi optimization. AB - Activated carbon (AC) composite with HKUST-1 metal organic framework (AC-HKUST-1 MOF) was prepared by ultrasonically assisted hydrothermal method and characterized by FTIR, SEM and XRD analysis and laterally was applied for the simultaneous ultrasound-assisted removal of crystal violet (CV), disulfine blue (DSB) and quinoline yellow (QY) dyes in their ternary solution. In addition, this material, was screened in vitro for their antibacterial actively against Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PAO1) bacteria. In dyes removal process, the effects of important variables such as initial concentration of dyes, adsorbent mass, pH and sonication time on adsorption process optimized by Taguchi approach. Optimum values of 4, 0.02 g, 4 min, 10 mg L(-1) were obtained for pH, AC-HKUST-1 MOF mass, sonication time and the concentration of each dye, respectively. At the optimized condition, the removal percentages of CV, DSB and QY were found to be 99.76%, 91.10%, and 90.75%, respectively, with desirability of 0.989. Kinetics of adsorption processes follow pseudo-second-order model. The Langmuir model as best method with high applicability for representation of experimental data, while maximum mono layer adsorption capacity for CV, DSB and QY on AC-HKUST-1 estimated to be 133.33, 129.87 and 65.37 mg g(-1) which significantly were higher than HKUST-1 as sole material with Qm to equate 59.45, 57.14 and 38.80 mg g(-1), respectively. PMID- 26964965 TI - Depolymerization of microcrystalline cellulose by the combination of ultrasound and Fenton reagent. AB - In this study, the combined use of Fenton reagent and ultrasound to the pretreatment of microcrystalline cellulose (MCC) for subsequent enzyme hydrolysis was investigated. The morphological analysis showed that the aspect ratio of MCC was greatly reduced after pretreatment. The X-ray diffraction (XRD) and degree of polymerization (DP) analyses showed that Fenton reagent was more efficient in decreasing the crystallinity of MCC while ultrasound was more efficient in decreasing the DP of MCC. The combination of Fenton reaction and ultrasound, which produced the lowest crystallinity (84.8 +/- 0.2%) and DP (124.7 +/- 0.6) of MCC and the highest yield of reducing sugar (22.9 +/- 0.3 g/100 g), provides a promising pretreatment process for MCC depolymerization. PMID- 26964966 TI - Ultrasonically-enhanced mechanochemical synthesis of CaAl-layered double hydroxides intercalated by a variety of inorganic anions. AB - CaAl-layered double hydroxides (CaAl-LDHs) were synthesised with various interlayer anions (CO3(2-), F(-), Cl(-), Br(-) and I(-)) by mechanochemical pre treatment followed by ultrasonic irradiation in aqueous media. The parameters of the syntheses (duration of pre-milling and sonication, quality of the aqueous media, temperature) were altered in order to optimise the procedure and to understand the formation of LDH and other secondary products. The products were characterised by X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The optimisation resulted in close-to-phase-pure CaAl-LDHs, not only with carbonate and chloride interlayer anions, but the hard-to-intercalate bromide and iodide as well. PMID- 26964964 TI - Scavenging dissolved oxygen via acoustic droplet vaporization. AB - Acoustic droplet vaporization (ADV) of perfluorocarbon emulsions has been explored for diagnostic and therapeutic applications. Previous studies have demonstrated that vaporization of a liquid droplet results in a gas microbubble with a diameter 5-6 times larger than the initial droplet diameter. The expansion factor can increase to a factor of 10 in gassy fluids as a result of air diffusing from the surrounding fluid into the microbubble. This study investigates the potential of this process to serve as an ultrasound-mediated gas scavenging technology. Perfluoropentane droplets diluted in phosphate-buffered saline (PBS) were insonified by a 2 MHz transducer at peak rarefactional pressures lower than and greater than the ADV pressure amplitude threshold in an in vitro flow phantom. The change in dissolved oxygen (DO) of the PBS before and after ADV was measured. A numerical model of gas scavenging, based on conservation of mass and equal partial pressures of gases at equilibrium, was developed. At insonation pressures exceeding the ADV threshold, the DO of air saturated PBS decreased with increasing insonation pressures, dropping as low as 25% of air saturation within 20s. The decrease in DO of the PBS during ADV was dependent on the volumetric size distribution of the droplets and the fraction of droplets transitioned during ultrasound exposure. Numerically predicted changes in DO from the model agreed with the experimentally measured DO, indicating that concentration gradients can explain this phenomenon. Using computationally modified droplet size distributions that would be suitable for in vivo applications, the DO of the PBS was found to decrease with increasing concentrations. This study demonstrates that ADV can significantly decrease the DO in an aqueous fluid, which may have direct therapeutic applications and should be considered for ADV-based diagnostic or therapeutic applications. PMID- 26964967 TI - Preparation of metal-ceramic composites by sonochemical synthesis of metallic nano-particles and in-situ decoration on ceramic powders. AB - Copper and nickel nanoparticles were synthesized using reducing agents in the presence of direct high energy ultra-sonication. The metallic nanoparticles were decorated on various ceramic substrates (e.g. alpha-Al2O3, and TiO2) leading to metal reinforced ceramics with up to 45% metallic content. Different parameters, such as the amount of precursor material or the substrate, as well as the intensity of ultrasound were examined, in order to evaluate the percentage of final metallic decoration on the composite materials. All products were characterized by means of Inductively Coupled Plasma Spectroscopy in order to investigate the loading with metallic particles. X-ray Diffraction and Scanning Electron Microscopy were also used for further sample characterization. Selected samples were examined using Transmission Electron Microscopy, while finally, some of the powders synthesized, were densified by means of Spark Plasma Sintering, followed by a SEM/EDX examination and an estimation of their porosity. PMID- 26964968 TI - Ultrasound-assisted synthesis of magnesium hydroxide nanoparticles from magnesium. AB - Acoustic cavitation in water provides special kinetic and thermodynamic conditions for chemical synthesis and nanostructuring of solids. Using cavitation phenomenon, we obtained magnesium hydroxide from pure magnesium. This approach allows magnesium hydroxide to be synthesized without the requirement of any additives and non-aqueous solvents. Variation of sonochemical parameters enabled a total transformation of the metal to nanosized brucite with distinct morphology. Special attention is given to the obtaining of platelet-shaped, nanometric and de-agglomerated powders. The products of the synthesis were characterized by transmission electron microscopy (TEM), electron diffraction (ED), scanning electron microscopy (SEM) and X-ray diffraction (XRD). PMID- 26964969 TI - Effect of oil extraction assisted by ultrasound on the physicochemical properties and fatty acid profile of pumpkin seed oil (Cucurbita pepo). AB - The effects of amplitude and time of ultrasound-assisted extraction on the physicochemical properties and the fatty acid profile of pumpkin seed oil (Cucurbita pepo) were evaluated. Ultrasound time (5-30 min) and the response variables amplitude (25-100%), extraction yield, efficiency, oxidative stability in terms of the free fatty acids (FFA) of the plant design comprising two independent experiments variables, peroxide (PV), p-anisidine (AV), totox value (TV) and the fatty acid profile were evaluated. The results were analyzed by multiple linear regression. The time and amplitude showed significant differences (P<0.05) for all variables. The highest yield of extraction was achieved at 5 min and amplitude of 62.5% (62%). However, the optimal ultrasound-assisted extraction conditions were as follows: ultrasound time of 26.34 min and amplitude of 89.02%. All extracts showed low FFA (2.75-4.93% oleic acid), PV (1.67-4.68 meq/kg), AV (1.94-3.69) and TV (6.25-12.55) values. The main fatty acids in all the extracts were oleic and linoleic acid. Therefore, ultrasound-assisted oil extraction had increased performance and reduced extraction time without affecting the oil quality. PMID- 26964970 TI - Sinoporphyrin sodium triggered sono-photodynamic effects on breast cancer both in vitro and in vivo. AB - Sono-photodynamic therapy (SPDT) is a promising anti-cancer strategy. Briefly, SPDT combines ultrasound and light to activate sensitizers that produce mechanical, sonochemical and photochemical activities. Sinoporphyrin sodium (DVDMS) is a newly identified sensitizer that shows great potential in both sonodynamic therapy (SDT) and photodynamic therapy (PDT). In this study, we primarily evaluated the combined effects of SDT and PDT by using DVDMS on breast cancer both in vitro and in vivo. In vitro, DVDMS-SPDT elicits much serious cytotoxicity compared with either SDT or PDT alone by MTT and colony formation assays. 2',7'-Dichlorodihydrofluo-rescein-diacetate (DCFH-DA) and dihydroethidium (DHE) staining revealed that intracellular reactive oxygen species (ROS) were significantly increased in groups given combined therapy. Terephthalic acid (TA) method and FD500-uptake assay reflected that cavitational effects and cell membrane permeability changes after ultrasound irradiation were also involved in the enhancement of combination therapy. In vivo, DVDMS-SPDT markedly inhibits the tumor volume and tumor weight growth. Hematoxylin-eosin staining and immunohistochemistry analysis show DVDMS-SPDT greatly suppressed tumor proliferation. Further, DVDMS-SPDT significantly inhibits tumor lung metastasis in the highly metastatic 4T1 mouse xenograft model, which is consistent well with the in vitro findings evaluated by transwell assay. Moreover, DVDMS-SPDT did not produces obvious effect on body weight and major organs in 4T1 xenograft model. The results suggest that by combination SDT and PDT, the sensitizer DVDMS would produce much better therapeutic effects, and DVDMS-SPDT may be a potential strategy against highly metastatic breast cancer. PMID- 26964971 TI - Anticancer activity of an ultrasonic nanoemulsion formulation of Nigella sativa L. essential oil on human breast cancer cells. AB - Nigella sativa L. (NS) is a plant renowned in traditional holistic medicine systems for almost 1400 years because of its remarkable antioxidant, antimicrobial, anti-inflammatory and anti-cancer properties. The essential oil of N. sativa, in particular, possesses these significant biological properties. However, N. sativa essential oil has many insoluble constituents with properties that have not been fully explored. Nanoemulsion-based insoluble formulations are a widely used carrier system for lipophilic materials. In the present study, we used ultrasonic emulsification, polysorbate 80 and water to formulate a highly stable N. sativa essential oil nanoemulsion (NSEO-NE). To optimize the NSEO-NE preparation, we changed the surfactant concentration, the oil-surfactant mixing ratio and the emulsification time. The droplet size distribution and morphology of the prepared NE was analyzed using dynamic light scattering and scanning electron microscopy, respectively. The droplet size of the NSEO-NE was approximately 20-50 nm in diameter. The anticancer properties of the NE preparation were studied using a modified methyl-thiazolyl-diphenyl tetrazolium bromide (MTT) assay as well as cellular uptake and nuclear morphological analyses. The NSEO-NE significantly reduced the viability of Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. The nucleo-cytoplasmic morphological features of NSEO-NE-treated cells included cell membrane blebbing, cytoplasmic vacuolation, marginalization of chromatin, and fragmentation of the nucleus. The results clearly indicate that NSEO-NE induced apoptosis in MCF-7 cells. These findings support the potential application of NSEO-NE in breast cancer therapy, and also merit future translational research. PMID- 26964972 TI - Mechanism of sonochemical reduction of permanganate to manganese dioxide in aqueous alcohol solutions: Reactivities of reducing species formed by alcohol sonolysis. AB - The sonochemical reduction of MnO4(-) to MnO2 in aqueous solutions was investigated as a function of alcohol concentration under Ar. The rate of MnO4(-) reduction initially decreased with increasing alcohol concentration, and then increased when the alcohol concentration was increased further. The concentrations at which the reduction rates were minimum depended on the hydrophobic properties of the added alcohols under ultrasonic irradiation. At low concentrations, the alcohols acted as OH radical scavengers; at high concentrations, they acted as reductant precursors: Rab, formed by abstraction reactions of the alcohols with sonochemically formed OH radicals or H atoms, and Rpy, formed by alcohol pyrolysis under ultrasonic irradiation. The results suggest that the reactivity order of the sonochemically formed reducing species with MnO4(-) at pH 7-9 is the sum of H2O2 and H>Rpy>Rab. The peak wavelengths of MnO2 colloidal solutions formed at high 1-butanol concentrations shifted to shorter wavelengths, suggesting the formation of small particles at high 1 butanol concentrations. The rates of sonochemical reduction of MnO2 to Mn(2+) in the presence of 1-butanol were slower than that in the absence of 1-butanol, because the sonochemical formation of H2O2 and H, which act as reductants, was suppressed by 1-butanol in aqueous solutions. PMID- 26964973 TI - Influence of dissolved gases on sonochemistry and sonoluminescence in a flow reactor. AB - In the present work, the influence of gas addition is investigated on both sonoluminescence (SL) and radical formation at 47 and 248 kHz. The frequencies chosen in this study generate two distinct bubble types, allowing to generalize the conclusions for other ultrasonic reactors. In this case, 47 kHz provides transient bubbles, while stable ones dominate at 248 kHz. For both bubble types, the hydroxyl radical and SL yield under gas addition followed the sequence: Ar>Air>N2>>CO2. A comprehensive interpretation is given for these results, based on a combination of thermal gas properties, chemical reactions occurring within the cavitation bubble, and the amount of bubbles. Furthermore, in the cases where argon, air and nitrogen were bubbled, a reasonable correlation existed between the OH-radical yield and the SL signal, being most pronounced under stable cavitation at 248 kHz. Presuming that SL and OH originate from different bubble populations, the results indicate that both populations respond similarly to a change in acoustic power and dissolved gas. Consequently, in the presence of non volatile pollutants that do not quench SL, sonoluminescence can be used as an online tool to qualitatively monitor radical formation. PMID- 26964974 TI - The effect of low frequency ultrasound on the production and properties of nanocrystalline cellulose suspensions and films. AB - Suspension of nanocrystalline cellulose (NCC) produced from bleached cotton by controlled sulphuric acid hydrolysis was treated with low frequency ultrasound at 20 kHz and 60% amplitude for 0, 1, 2, 5 and 10 min and the effects of sonication on the properties of both the cellulose nanocrystals and their aqueous suspensions were investigated. Furthermore, a series of nanocellulose films were manufactured from the suspensions that were sonicated for different periods of time and tested. Laser diffraction analysis and transmission electron microscopy proved that sonication not only disintegrated the large NCC aggregates (Dv50 14.7 MUm) to individual nanowhiskers with an average length and width of 171 +/- 57 and 17 +/- 4 nm, respectively, but also degraded the nanocrystals and yielded shorter and thinner particles (118 +/- 45 and 13 +/- 3 nm, respectively) at 10 min sonication. The ultrasound-assisted disintegration to nano-sized cellulose whiskers decreased the optical haze of suspensions from 98.4% to 52.8% with increasing time from 0 to 10 min, respectively. Sonication of the suspensions significantly contributed to the preparation of films with low haze (high transparency) and excellent tensile properties. With the increasing duration of sonication, the haze decreased and the tensile strength rose gradually. Irrespectively of sonication, however, all films had an outstanding oxygen transmission rate in a range of 5.5-6.9 cm(3)/m(2)day, and a poor thermal stability. PMID- 26964975 TI - Shadow-casted ultrathin surface coatings of titanium and titanium/silicon oxide sol particles via ultrasound-assisted deposition. AB - Ultrasound-assisted deposition (USAD) of sol nanoparticles enables the formation of uniform and inherently stable thin films. However, the technique still suffers in coating hard substrates and the use of fast-reacting sol-gel precursors still remains challenging. Here, we report on the deposition of ultrathin titanium and titanium/silicon hybrid oxide coatings using hydroxylated silicon wafers as a model hard substrate. We use acetic acid as the catalyst which also suppresses the reactivity of titanium tetraisopropoxide while increasing the reactivity of tetraethyl orthosilicate through chemical modifications. Taking the advantage of this peculiar behavior, we successfully prepared titanium and titanium/silicon hybrid oxide coatings by USAD. Varying the amount of acetic acid in the reaction media, we managed to modulate thickness and surface roughness of the coatings in nanoscale. Field-emission scanning electron microscopy and atomic force microscopy studies showed the formation of conformal coatings having nanoroughness. Quantitative chemical state maps obtained by x-ray photoelectron spectroscopy (XPS) suggested the formation of ultrathin (<10nm) coatings and thickness measurements by rotating analyzer ellipsometry supported this observation. For the first time, XPS chemical maps revealed the transport effect of ultrasonic waves since coatings were directly cast on rectangular substrates as circular shadows of the horn with clear thickness gradient from the center to the edges. In addition to the progress made in coating hard substrates, employing fast-reacting precursors and achieving hybrid coatings; this report provides the first visual evidence on previously suggested "acceleration and smashing" mechanism as the main driving force of USAD. PMID- 26964976 TI - Combining COMSOL modeling with acoustic pressure maps to design sono-reactors. AB - Scaled-up and economically viable sonochemical systems are critical for increased use of ultrasound in environmental and chemical processing applications. In this study, computational simulations and acoustic pressure maps were used to design a larger-scale sono-reactor containing a multi-stepped ultrasonic horn. Simulations in COMSOL Multiphysics showed ultrasonic waves emitted from the horn neck and tip, generating multiple regions of high acoustic pressure. The volume of these regions surrounding the horn neck were larger compared with those below the horn tip. The simulated acoustic field was verified by acoustic pressure contour maps generated from hydrophone measurements in a plexiglass box filled with water. These acoustic pressure contour maps revealed an asymmetric and discrete distribution of acoustic pressure due to acoustic cavitation, wave interaction, and water movement by ultrasonic irradiation. The acoustic pressure contour maps were consistent with simulation results in terms of the effective scale of cavitation zones (~ 10 cm and <5 cm above and below horn tip, respectively). With the mapped acoustic field and identified cavitation location, a cylindrically shaped sono-reactor with a conical bottom was designed to evaluate the treatment capacity (~ 5 L) for the multi-stepped horn using COMSOL simulations. In this study, verification of simulation results with experiments demonstrates that coupling of COMSOL simulations with hydrophone measurements is a simple, effective and reliable scientific method to evaluate reactor designs of ultrasonic systems. PMID- 26964977 TI - Efficient sonochemical degradation of perfluorooctanoic acid using periodate. AB - A rapid and efficient treatment method, using periodate (PI) for sonochemical oxidation of persistent and bioaccumulative perfluorooctanoic acid (PFOA) was developed. With an addition of 45 mM PI, 96.5% of PFOA was decomposed with a defluorination efficiency of 95.7% after 120 min of ultrasound (US). The removals of PFOA were augmented with an increase in PI doses. In all the PI+US experimental runs, decomposition efficiencies were essentially similar to those of defluorination, indicating that PFOA was decomposed and mineralized into fluoride ions. Lower solution pHs resulted in an increase in decomposition and defluorination efficiencies of PFOA due to acid-catalyzation. Dissolved oxygen increased the amount of IO4 radicals produced, which consumed the more effective IO3 radicals. Consequently, presence of oxygen inhibited the destruction of PFOA. The PFOA degradation rates with different gases sparging are in the following order: nitrogen>air>oxygen. Effects of anions follow the Hofmeister effects on PFOA degradation (i.e., Br(-)>none ? Cl(-)>SO4(2)(-)). Br(-) could react with OH to yield radical anion Br2(-) that enhances the PFOA degradation. A reaction pathway was also proposed to describe the PI oxidation of PFOA under US irradiation. PMID- 26964979 TI - Enhancement of mass transfer by ultrasound: Application to adsorbent regeneration and food drying/dehydration. AB - The physical mechanisms of heat and mass transfer enhancement by ultrasound have been identified by people. Basically, the effect of 'cavitation' induced by ultrasound is the main reason for the enhancement of heat and mass transfer in a liquid environment, and the acoustic streaming and vibration are the main reasons for that in a gaseous environment. The adsorbent regeneration and food drying/dehydration are typical heat and mass transfer process, and the intensification of the two processes by ultrasound is of complete feasibility. This paper makes an overview on recent studies regarding applications of power ultrasound to adsorbent regeneration and food drying/dehydration. The concerned adsorbents include desiccant materials (typically like silica gel) for air dehumidification and other ones (typically active carbon and polymeric resin) for water treatment. The applications of ultrasound in the regeneration of these adsorbents have been proved to be energy saving. The concerned foods are mostly fruits and vegetables. Although the ultrasonic treatment may cause food degradation or nutrient loss, it can greatly reduce the food processing time and decrease drying temperature. From the literature, it can be seen that the ultrasonic conditions (i.e., acoustic frequency and power levels) are always focused on during the study of ultrasonic applications. The increasing number of relevant studies argues that ultrasound is a very promising technology applied to the adsorbent regeneration and food drying/dehydration. PMID- 26964978 TI - Ultrasound enhances lipase-catalyzed synthesis of poly (ethylene glutarate). AB - The present work explores the best conditions for the enzymatic synthesis of poly (ethylene glutarate) for the first time. The start-up materials are the liquids; diethyl glutarate and ethylene glycol diacetate, without the need of addition of extra solvent. The reactions are catalyzed by lipase B from Candida antarctica immobilized on glycidyl methacrylate-ter-divinylbenzene-ter-ethylene glycol dimethacrylate at 40 degrees C during 18h in water bath with mechanical stirring or 1h in ultrasonic bath followed by 6h in vacuum in both the cases for evaporation of ethyl acetate. The application of ultrasound significantly intensified the polyesterification reaction with reduction of the processing time from 24h to 7h. The same degree of polymerization was obtained for the same enzyme loading in less time of reaction when using the ultrasound treatment. The degree of polymerization for long-term polyesterification was improved approximately 8-fold due to the presence of sonication during the reaction. The highest degree of polymerization achieved was 31, with a monomer conversion of 96.77%. The ultrasound treatment demonstrated to be an effective green approach to intensify the polyesterification reaction with enhanced initial kinetics and high degree of polymerization. PMID- 26964980 TI - Purification of serratiopeptidase from Serratia marcescens NRRL B 23112 using ultrasound assisted three phase partitioning. AB - The ultrasound assisted three phase partitioning (UATPP) is a novel bioseparation method for separation and purification of biomolecules. In the present work, UATPP was investigated for the first time for purification of serratiopeptidase from Serratia marcescens NRRL B 23112. Effect of various process parameters such as ammonium sulphate saturation, t-butanol to crude extract ratio, pH, ultrasonic frequency, ultrasonic intensity, duty cycle and irradiation time were evaluated and optimized. The optimized conditions were found to be as follows: ammonium sulphate saturation 30% (w/v), pH 7.0, t-butanol to crude ratio 1:1 (v/v), ultrasound frequency 25 kHz, ultrasound intensity 0.05 W/cm(2), duty cycle 20% and irradiation time 5 min. The maximum purity and recovery obtained from UATPP was 9.4-fold and 96% respectively as compared to the three phase partitioning (TPP) (4.2-fo ld and 83%). Also the process time for UATPP was significantly reduced to 5 min from 1h as compared to TPP. The results indicate that, UATPP is an efficient technique for the purification of serratiopeptidase with maximum purity, recovery and reduced processing time. PMID- 26964981 TI - Effect of high intensity ultrasound on the fermentation profile of Lactobacillus sakei in a meat model system. AB - The objective of this study was to investigate the efficacy of high intensity ultrasound on the fermentation profile of Lactobacillus sakei in a meat model system. Ultrasound power level (0-68.5 W) and sonication time (0-9 min) at 20 degrees C were assessed against the growth of L. sakei using a Microplate reader over a period of 24h. The L. sakei growth data showed a good fit with the Gompertz model (R(2)>0.90; SE<0.042). Second order polynomial models demonstrated the effect of ultrasonic power and sonication time on the specific growth rate (SGR, MU, h(-1)) and lag phase (lambda, h). A higher SGR and a shorter lag phase were observed at low power (2.99 W for 5 min) compared to control. Conversely, a decrease (p<0.05) in SGR with an increase in lag phase was observed with an increase in ultrasonic power level. Cell-free extracts obtained after 24h fermentation of ultrasound treated samples showed antimicrobial activity against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Salmonella typhimurium at lower concentrations compared to control. No significant difference (p<0.05) among treatments was observed for lactic acid content after a 24h fermentation period. This study showed that both stimulation and retardation of L. sakei is possible, depending on the ultrasonic power and sonication time employed. Hence, fermentation process involving probiotics to develop functional food products can be tailored by selection of ultrasound processing parameters. PMID- 26964982 TI - Ultrasonic enhancement of the simultaneous removal of quaternary toxic organic dyes by CuO nanoparticles loaded on activated carbon: Central composite design, kinetic and isotherm study. AB - Copper oxide nanoparticles loaded on activated carbon (CuO-NPs-AC) were prepared and fully analyzed and characterized with FE-SEM, XRD and FT-IR. Subsequently, this novel material was used for simultaneous ultrasound-assisted adsorption of brilliant green (BG), auramine O (AO), methylene blue (MB) and eosin yellow (EY) dyes. Problems regard to dyes spectra overlap in quaternary solution of this dyes were omitted by derivative spectrophotometric method. The best pH in quaternary system was studied by using one at a time method to achieved maximum dyes removal percentage. Subsequently, sonication time, adsorbent dosage and initial dyes concentrations influence on dyes removal was optimized by central composite design (CCD) combined with desirability function approach (DFA). Desirability score of 0.978 show optimum conditions set at sonication time (4.2 min), adsorbent mass (0.029 g), initial dyes concentration (4.5 mg L(-1)). Under this optimum condition the removal percentage for MB, AO, EY and BG dyes 97.58, 94.66, 96.22 and 94.93, respectively. The adsorption rate well fitted by pseudo second order while adsorption capacity according to the Langmuir model as best equilibrium isotherm model for BG, MB, AO and EY was 20.48, 21.26, 22.34 and 21.29 mg g(-1), respectively. PMID- 26964983 TI - Effects of high-energy ultrasound on the functional properties of proteins. AB - In recent years, high-energy ultrasound has been used as an alternative to improve the functional properties of various proteins, such as from milk, eggs, soy and poultry. The benefits of implementing this technology depend on the inherent characteristics of the protein source and the intensity and amplitude of the ultrasound, as well as on the pH, temperature, ionic strength, time, and all of the variables that have an effect on the physicochemical properties of proteins. Therefore, it is necessary to establish the optimal conditions for each type of food. The use of ultrasound is a promising technique in food technology with a low impact on the environment, and it has thus become known as a green technology. Therefore, this review focuses on the application of high-energy ultrasound to food; its effects on the functional properties of proteins; and how different conditions such as the frequency, time, amplitude, temperature, and protein concentration affect the functional properties. PMID- 26964984 TI - Synergistic effect of ultrasonic cavitation erosion and corrosion of WC-CoCr and FeCrSiBMn coatings prepared by HVOF spraying. AB - The high-velocity oxygen-fuel (HVOF) spraying process was used to fabricate conventional WC-10Co-4Cr coatings and FeCrSiBMn amorphous/nanocrystalline coatings. The synergistic effect of cavitation erosion and corrosion of both coatings was investigated. The results showed that the WC-10Co-4Cr coating had better cavitation erosion-corrosion resistance than the FeCrSiBMn coating in 3.5 wt.% NaCl solution. After eroded for 30 h, the volume loss rate of the WC-10Co 4Cr coating was about 2/5 that of the FeCrSiBMn coating. In the total cumulative volume loss rate under cavitation erosion-corrosion condition, the pure cavitation erosion played a key role for both coatings, and the total contribution of pure corrosion and erosion-induced corrosion of the WC-10Co-4Cr coating was larger than that of the FeCrSiBMn coating. Mechanical effect was the main factor for cavitation erosion-corrosion behavior of both coatings. PMID- 26964985 TI - Numerical 3D flow simulation of ultrasonic horns with attached cavitation structures and assessment of flow aggressiveness and cavitation erosion sensitive wall zones. AB - As a contribution to a better understanding of cavitation erosion mechanisms, a compressible inviscid finite volume flow solver with barotropic homogeneous liquid-vapor mixture cavitation model is applied to ultrasonic horn set-ups with and without stationary specimen, that exhibit attached cavitation at the horn tip. Void collapses and shock waves, which are closely related to cavitation erosion, are resolved. The computational results are compared to hydrophone, shadowgraphy and erosion test data. At the horn tip, vapor volume and topology, subharmonic oscillation frequency as well as the amplitude of propagating pressure waves are in good agreement with experimental data. For the evaluation of flow aggressiveness and the assessment of erosion sensitive wall zones, statistical analyses of wall loads and of the multiplicity of distinct collapses in wall-adjacent flow regions are applied to the horn tip and the stationary specimen. An a posteriori projection of load collectives, i.e. cumulative collapse rate vs. collapse pressure, onto a reference grid eliminates the grid dependency effectively for attached cavitation at the horn tip, whereas a significant grid dependency remains at the stationary specimen. The load collectives show an exponential decrease towards higher collapse pressures. Erosion sensitive wall zones are well predicted for both, horn tip and stationary specimen, and load profiles are in good qualitative agreement with measured topography profiles of eroded duplex stainless steel samples after long-term runs. For the considered amplitude and gap width according to ASTM G32-10 standard, the analysis of load collectives reveals that the distinctive erosive ring shape at the horn tip can be attributed to frequent breakdown and re development of a small portion of the tip-attached cavity. This partial breakdown of the attached cavity repeats at each driving cycle and is associated with relatively moderate collapse peak pressures, whereas the stationary specimen is rather unfrequently stressed at the end of each subharmonic oscillation cycle by the violent collapse of the complete cavity. PMID- 26964986 TI - Transglutaminase-induced gelation properties of soy protein isolate and wheat gluten mixtures with high intensity ultrasonic pretreatment. AB - Soy protein isolate (SPI) and wheat gluten (WG) are widely used in commercial food applications in Asia for their nutritional value and functional properties. However, individually each exhibits poor gelation. In this study, we examined the microbial transglutaminase (MTGase)-induced gelation properties of SPI and WG mixtures with high intensity ultrasonic pretreatment. Ultrasonic treatment reduced the particle size of SPI/WG molecules, which led to improvements in surface hydrophobicity (Ho) and free sulfhydryl (SH) group content. However, MTGase crosslinking facilitated the formation of disulfide bonds, markedly decreasing the content of free SH groups. Ultrasonic treatment improved the gel strength, water holding capacity, and storage modulus and resulted in denser and more homogeneous networks of MTGase-induced SPI/WG gels. In addition, ultrasonic treatment changed the secondary structure of the gel samples as determined by Fourier transform infrared spectroscopic analysis, with a reduction in alpha helices and beta-turns and an increase in beta-sheets and random coils. Thus, ultrasound is useful in facilitating the gelation properties of MTGase-induced SPI/WG gels and might expand their utilization in the food protein gelation industry. PMID- 26964987 TI - Effect of low frequency ultrasound on the surface properties of natural aluminosilicates. AB - Structural and surface properties of different natural aluminosilicates (layered, chain and framework structural types) exposed of 20 kHz ultrasound irradiation (0 120 min) in aqueous and 35 wt%. aqueous H2O2 dispersions were studied by X-ray diffraction (XRD), dynamic light scattering (DLS), nitrogen adsorption desorption, thermal analysis, and Fourier transform infrared spectroscopy (FTIR) techniques. It was confirmed that sonication caused slight changes in the structure of investigated minerals whereas their textural properties were significantly affected. The aqueous dispersions of montmorillonite (Mt), clinoptilolite (Zlt), glauconite (Glt) and palygorskite (Pal) were represented by several particles size fractions according to DLS-study. Ultrasound irradiation produced a decrease of the average particle diameter by 4-6 times in water and by 1.3-5 times in H2O2 dispersions except for Pal, which underwent strong agglomeration. A significant increase of total pore volume and pore diameter was observed for Glt sonicated in H2O2 dispersions whereas for Pal mainly micropore volume sharply increased in both aqueous and H2O2 dispersions. PMID- 26964988 TI - Positional stability and radial dynamics of sonoluminescent bubbles under bi harmonic driving: Effect of the high-frequency component and its relative phase. AB - The use of bi-frequency driving in sonoluminescence has proved to be an effective way to avoid the spatial instability (pseudo-orbits) developed by bubbles in systems with high viscous liquids like sulfuric or phosphoric acids. In this work, we present extensive experimental and numerical evidence in order to assess the effect of the high frequency component (PAc(HF)) of a bi-harmonic acoustic pressure field on the dynamic of sonoluminescent bubbles in an aqueous solution of sulfuric acid. The present study is mainly focused on the role of the harmonic frequency (Nf0) and the relative phase between the two frequency components (phib) of the acoustic field on the spatial, positional and diffusive stability of the bubbles. The results presented in this work were analyzed by means of three different approaches. First, we discussed some qualitative considerations about the changes observed in the radial dynamics, and the stability of similar bubbles under distinct bi-harmonic drivings. Later, we have investigated, through a series of numerical simulations, how the use of high frequency harmonic components of different order N, affects the positional stability of the SL bubbles. Furthermore, the influence of phib in their radius temporal evolution is systematically explored for harmonics ranging from the second to the fifteenth harmonic (N=2-15). Finally, a multivariate analysis based on the covariance method is performed to study the dependences among the parameters characterizing the SL bubble. Both experimental and numerical results indicate that the impact of PAc(HF) on the positional instability and the radial dynamics turns to be progressively negligible as the order of the high frequency harmonic component grows (i.e. N ? 1), however its effectiveness on the reduction of the spatial instability remains unaltered or even improved. PMID- 26964989 TI - Ultrasonic-assisted synthesis of flavones by oxidative cyclization of 2' hydroxychalcones using iodine monochloride. AB - This paper presents an efficient methodology for the synthesis of flavones via the oxidative cyclization of 2'-hydroxychalcones in the presence of iodine monochloride with DMSO under ultrasound irradiation. Ultrasonic irradiation enhances the cyclization reaction and leads to reduced reaction time at lower reaction temperatures while generating flavones with high yields. PMID- 26964990 TI - A two-dimensional nonlinear model for the generation of stable cavitation bubbles. AB - Bubbles appear by acoustic cavitation in a liquid when rarefaction pressures attain a specific threshold value in a liquid. Once they are created, the stable cavitation bubbles oscillate nonlinearly and affect the ultrasonic field. Here we present a model developed for the study of bubble generation in a liquid contained in a two-dimensional cavity in which a standing ultrasonic field is established. The model considers dissipation and dispersion due to the bubbles. It also assumes that both the ultrasonic field and the bubble oscillations are nonlinear. The numerical experiments predict where the bubbles are generated from a population of nuclei distributed in the liquid and show how they affect the ultrasonic field. PMID- 26964991 TI - Dendritic cells generated from peripheral blood monocytes (Mo-DCs) and stimulated with laryngeal cancer cell lysates are not good enough in stimulating anti-tumor immunity. PMID- 26964993 TI - To characterize the incidence of airway misplacement of nasogastric tubes in anesthetized intubated patients by using a manometer technique. AB - This study characterized the incidence of airway misplacement of nasogastric (NG) tubes in surgical patients, and the benefit of using a manometer to discriminate gastric placement from airway placement of NG tubes. Subjects included adult patients scheduled for abdominal surgery. After tracheal intubation, a 16 Fr. NG tube was inserted blindly through the nostril, and its position was assessed using the auscultation (10-ml air insufflation) or manometer (attached to NG tubes) techniques. Briefly, a biphasic pressure change synchronous with airway pressure during mechanical ventilation indicated airway misplacement. The presence of a notable pressure change while compressing the epigastric area indicated a gastric placement. A surgeon made the final confirmation of NG tube placement within the stomach using manual palpation of the tube immediately after laparotomy. The first-attempt success rate was 82.7 % in 104 patients. There were 29 misplacements of 130 attempted insertions (oral cavity, n = 23; trachea, n = 3; distal esophagus, n = 3). The incidence of airway misplacement was 2.9 % (3 of 104 cases). For confirmation of gastric placement, the auscultation technique had a sensitivity of 100.0 % and a specificity of 79.3 %. In contrast, the manometer technique had a sensitivity of 100.0 % and a specificity of 100.0 % in the discrimination of gastric placement from airway placement of NG tubes. Airway misplacement of NG tubes is not uncommon in surgical patients, and the manometer technique may be a reliable and safe method to discriminate gastric placement from airway placement of NG tubes. PMID- 26964994 TI - [The aim of stimulating discussions on preclinical intubation has been reached]. PMID- 26964992 TI - Utility of stroke volume variation measured using non-invasive bioreactance as a predictor of fluid responsiveness in the prone position. AB - The aim of this prospective study was to evaluate the usefulness of stroke volume variation (SVV) derived from NICOM(r) to predict fluid responsiveness in the prone position. Forty adult patients undergoing spinal surgery in the prone position were included in this study. We measured SVV from NICOM(r) (SVVNICOM) and FloTracTM/VigileoTM systems (SVVVigileo), and pulse pressure variation (PPV) using automatic (PPVauto) and manual (PPVmanual) calculations at four time points including supine and prone positions, and before and after fluid loading of 6 ml kg-1 colloid solution. Fluid responsiveness was defined as an increase in the cardiac index from VigileoTM of >=12 %. There were 19 responders and 21 non responders. Prone positioning induced a significant decrease in SVVNICOM, SVVVigileo, PPVauto, and PPVmanual. However, all of these parameters successfully predicted fluid responsiveness in the prone position with area under the receiver operator characteristic curves for SVVNICOM, SVVVigileo, PPVauto, and PPVmanual of 0.78 [95 % confidence interval (CI) 0.62-0.90, P = 0.0001], 0.79 (95 % CI 0.63 0.90, P = 0.0001), 0.76 (95 % CI 0.6-0.88, P = 0.0006), and 0.84 (95 % CI 0.69 0.94, P < 0.0001), respectively. The optimal cut-off values were 12 % for SVVNICOM, SVVVigileo, and PPVauto, and 10 % for PPVmanual. SVV from NICOM(r) successfully predicts fluid responsiveness during surgery in the prone position. This totally non-invasive technique for assessing individual functional intravenous volume status would be useful in a wide range of surgeries performed in the prone position. PMID- 26964995 TI - Phase Ib/II study of elisidepsin in metastatic or advanced gastroesophageal cancer (IMAGE trial). AB - PURPOSE: To determine the recommended dose and antitumor activity of single-agent elisidepsin as a 24-h intravenous (i.v.) infusion fortnightly [biweekly, d1 and 15 every 4 weeks (q4wk); Arm A, dose-intensity strategy] or as a 3-h i.v. infusion weekly (d1, 8, 15 and 22 q4wk; Arm B, dose-density strategy) in adult patients with unresectable, locally advanced or metastatic pretreated esophageal, gastroesophageal junction and gastric cancer. METHODS: Patients were randomized to one of two elisidepsin dosing schedules. Phase Ib starting doses were 8.0 mg flat dose (FD) in Arm A and 3.0 mg FD in Arm B. Phase II subsequently explored antitumor activity of both dosing schedules at the respective recommended doses. RESULTS: Forty-four patients received elisidepsin: 12 in stage Ib and 32 in stage II. The recommended doses were defined as 10 mg FD (Arm A) and 3.75 mg FD (Arm B). Both schedules were well tolerated. Most adverse events were mild or moderate, reversible and predictable with no meaningful differences between schedules. The pharmacokinetic profiles of both schedules were similar to those reported previously in patients with solid tumors treated with a comparable dose. An interim analysis found tumor control in one patient receiving elisidepsin fortnightly, and in none given elisidepsin weekly; patient accrual was therefore discontinued due to lack of efficacy. CONCLUSIONS: Both schedules at the recommended doses presented an acceptable safety profile, but lack of response means that we do not recommend further evaluation of single-agent elisidepsin as chemotherapy for unresectable, locally advanced or metastatic gastroesophageal cancer. PMID- 26964997 TI - A Pilot Study of an Acceptance-Based Behavioral Intervention for Weight Regain After Bariatric Surgery. AB - BACKGROUND: Tens of thousands of bariatric surgery patients each year experience sub-optimal weight loss, significant regain, or both. Weight regain can contribute to a worsening of weight-related co-morbidities, and for some, leads to secondary surgical procedures. Poor weight outcomes have been associated with decreased compliance to the recommended postoperative diet. Decreased compliance may be partially due to a lack of psychological skills necessary to engage in healthy eating behaviors over the long term, especially as the effects of surgery (on appetite, hunger, and desire for food) decrease. Many behavioral interventions do not sufficiently address these challenges and often have limited effectiveness. The study aimed to evaluate the feasibility, acceptability, and preliminary effectiveness of a novel 10-week acceptance-based behavioral intervention to stop postoperative weight regain. METHODS: A sample of bariatric surgery patients (n = 11) who regained at least 10 % of their maximum lost postoperative weight was recruited. All participants received the intervention, which emphasized psychological skills thought to be integral to successful weight control post-surgery. RESULTS: The intervention was shown to be feasible and acceptable, with 72 % retention and high mean rating (4.25 out of 5.00) of program satisfaction among completers. Weight regain was stopped, and even reversed, with a mean total body weight loss of 3.58 +/- 3.02 % throughout the 10 week intervention. There were also significant improvements in eating-related and acceptance-related variables. CONCLUSIONS: These findings provide initial support for the use of a psychological acceptance-based intervention for weight regain in bariatric surgery patients. PMID- 26964996 TI - Gut Wall Metabolism. Application of Pre-Clinical Models for the Prediction of Human Drug Absorption and First-Pass Elimination. AB - Quantifying the multiple processes which control and modulate the extent of oral bioavailability for drug candidates is critical to accurate projection of human pharmacokinetics (PK). Understanding how gut wall metabolism and hepatic elimination factor into first-pass clearance of drugs has improved enormously. Typically, the cytochrome P450s, uridine 5'-diphosphate-glucuronosyltransferases and sulfotransferases, are the main enzyme classes responsible for drug metabolism. Knowledge of the isoforms functionally expressed within organs of first-pass clearance, their anatomical topology (e.g. zonal distribution), protein homology and relative abundances and how these differ across species is important for building models of human metabolic extraction. The focus of this manuscript is to explore the parameters influencing bioavailability and to consider how well these are predicted in human from animal models or from in vitro to in vivo extrapolation. A unique retrospective analysis of three AstraZeneca molecules progressed to first in human PK studies is used to highlight the impact that species differences in gut wall metabolism can have on predicted human PK. Compared to the liver, pharmaceutical research has further to go in terms of adopting a common approach for characterisation and quantitative prediction of intestinal metabolism. A broad strategy is needed to integrate assessment of intestinal metabolism in the context of typical DMPK activities ongoing within drug discovery programmes up until candidate drug nomination. PMID- 26964998 TI - The development of large-cell carcinoma in the wall of a giant bulla complicated by hemorrhage. AB - There were a few reports of patients with lung cancer developing at the wall of giant bullae complicated with hemorrhage. A 40-year-old male with complaints of hemoptysis was referred to our hospital, and a solitary pulmonary mass was pointed out on his chest roentgenogram. Computed tomography (CT) demonstrated a well-circumscribed solid mass measuring 7.0 * 6.5 * 6.0 cm in the right upper lobe of the lung. At the chest CT 1 year before, only a giant bulla without mass was found. From the interval change of CT findings with his clinical course, the mass was suspected as acute hemorrhage in the giant bulla. A right upper lobectomy of the lung was performed to control his hemoptysis. The surgical specimen showed the giant bulla filled with blood clot, and a partial wall of the bulla was irregularly thickened. Pathological examination revealed that the thickened wall was composed of large-cell carcinoma. In patients with bullous diseases complicated with hemorrhage, we should be aware of a possibility of developing lung cancer in the bullae. PMID- 26964999 TI - Acute and long-term effect of percutaneous coronary intervention on serially measured oxidative, inflammatory, and coagulation biomarkers in patients with stable angina. AB - To derive insights into the temporal changes in oxidative, inflammatory and coagulation biomarkers in patients with stable angina undergoing percutaneous coronary intervention (PCI). PCI is associated with a variety of biochemical and mechanical stresses to the vessel wall. Oxidized phospholipids are present on plasminogen (OxPL-PLG) and potentiate fibrinolysis in vitro. We recently showed that OxPL-PLG increase following acute myocardial infarction, suggesting that they are involved in atherothrombosis. Plasma samples were collected before, immediately after, 6 and 24 h, 3 and 7 days, and 1, 3, and 6 months after PCI in 125 patients with stable angina undergoing uncomplicated PCI. Plasminogen levels, OxPL-PLG, and an array of 16 oxidative, inflammatory and coagulation biomarkers were measured with established assays. OxPL-PLG and plasminogen declined significantly immediately post-PCI, rebounded to baseline, peaked at 3 days and slowly returned to baseline by 6 months (p < 0.0001 by ANOVA). The temporal trends to maximal peak in biomarkers were as follows: immediately post PCI: OxPL apoB and lipoprotein (a); Day 1-the inflammatory biomarker IL-6; Day 3-CRP and coagulation biomarkers OxPL-PLG, plasminogen and tissue plasminogen activity; Day 3 to 7-plasminogen activator inhibitor activity, and complement factor H binding to malondialdehyde-LDL and MDA-LDL IgG; Day 7-30 MDA-LDL IgM, CuOxLDL IgM, and ApoB-IC IgM and IgG; >30 days uPA activity, uPA antigen, CuOxLDL IgG and peptide mimotope to MDA-LDL. Most of the biomarkers trended to baseline by 6 months. PCI results in a specific, temporal sequence of changes in plasma biomarkers. These observations provide insights into the effects of iatrogenic barotrauma and plaque disruption during PCI and suggest avenues of investigation to explain complications of PCI and development of targeted therapies to enhance procedural success. PMID- 26965000 TI - Routes for virtually guided endoscopic liver resection of subdiaphragmatic liver tumors. AB - PURPOSE: Laparoscopic and thoracoscopic/laparoscopic hepatectomy is a safe procedure that has potential advantages over open surgery. However, deeply positioned liver tumors require expert laparoscopic and thoracoscopic/laparoscopic hepatectomy techniques. Using simulated preoperative three-dimensional virtual endoscopy (P3DVE) guidance, we demonstrate herein that a thoracoscopic approach (TA), thoracoscopic-laparoscopic approach (TLA), and laparoscopic approach (LA) are all feasible and safe routes for performing pure laparoscopic and thoracoscopic/laparoscopic resection of liver tumors located in the 4a, 7, and 8 liver subdiaphragmatic areas. METHODS: Thirty-eight patients underwent laparoscopic and thoracoscopic/laparoscopic partial liver resection (TA 13 cases, TLA two cases, and LA 23 cases) of the subdiaphragmatic area at Showa University Hospital. All surgical approaches were preoperatively determined based on preoperative 3D virtual endoscopic simulation (P3DVES) visualization and findings using the image processing software SYNAPSE VINCENT((r)). RESULTS: Laparoscopic and thoracoscopic/laparoscopic liver resection was successfully performed for all cases under P3DVE instruction. The mean operative times using TA, TLA, and LA approaches were 193, 185, and 190 min, respectively. Mean blood loss during TA, TLA, and LA was 179, 138, and 73 g, respectively. No patients required conversion to open surgery, and there were no deaths, although there were three cases of Clavien-Dindo grade I in TA along with three cases of grade I and one case of grade II in LA. CONCLUSIONS: TA, TLA, and LA routes performed under P3DVE instruction are feasible and safe to perform for pure laparoscopic and thoracoscopic/laparoscopic liver resection in selected patients with lesions located in the hepatic subdiaphragmatic area. PMID- 26965001 TI - Quantifying Differences Between Native and Introduced Species. AB - Introduced species have historically been presumed to be evolutionarily novel and 'different' from native species. Recent studies question these assumptions, however, as the traits and factors promoting successful introduced and native species can be similar. We advocate a novel statistical framework utilizing quantifiable metrics of evolutionary and ecological differences among species to test whether different forces govern the success of native versus introduced species. In two case studies, we show that native and introduced species appear to follow the same 'rules' for becoming abundant. We propose that incorporating quantitative differences in traits and evolutionary history among species might largely account for many perceived effects of geographic origin, leading to more rigorous and general tests of the factors promoting organism success. PMID- 26965002 TI - Three-dimensional transesophageal echocardiography in the prevention of transcatheter aortic valve implantation-related stroke: Another brick in the wall? PMID- 26965003 TI - A novel doxorubicin loaded folic acid conjugated PAMAM modified with borneol, a nature dual-functional product of reducing PAMAM toxicity and boosting BBB penetration. AB - Effective targeting drug delivery system for glioma treatment is still greatly challenged by the existence of the blood-brain barrier (BBB) and the intracranial overspreading of anti-tumor drug. Herein, we presented a dual-functional glioma targeting delivery of doxorubicin based on the PAMAM G5 dendrimer, modified with folic acid (FA) to target tumor cell, also borneol (BO), a well known safe material derived from traditional Chinese medicine, to facilitate the BBB permeability and reduce the toxicity of naked PAMAM. The intracranial transportation and glioma targeting ability were evaluated on the BBB model and C6 glioma cells in vitro. Also, pharmacokinetics and biodistribution were studied on C6 glioma-bearing rats in vivo. It indeed reduced the cytotoxicity of PAMAM against both HBMEC and C6 cells by coupling BO on the surface, while efficiently boosted BBB permeability with the improvement of transportation ratio by 2 folds to the BO-unmodified conjugates. Furthermore, conjugated FA increased total uptake amount by C6 cells leading to strong inhibition with the 3-fold lower IC50 value than FA-unmodified DOX conjugate. In comparison with DOX solution, FA-BO PAMAM/DOX exhibited significantly prolonged half-life time and increased area under the curve and improved DOX accumulation in brain tumor. The tumor growth inhibition, in vivo, was significantly increased up to 57.4%. The median survival time of xenograft rats after administering FA-BO-PAMAM/DOX (28days) was significantly prolonged compared to free DOX (18days, P<0.05) or other controls. In conclusion, this strategy of novel targeting nanocarrier provides a promising method to increase the drug accumulation in the tumor site for therapy of glioma. PMID- 26965004 TI - The molecular assembly of the ionic liquid/aliphatic carboxylic acid/aliphatic amine as effective and safety transdermal permeation enhancers. AB - In spite of numerous advantages, transdermal drug delivery systems are unfeasible for most drugs because of the barrier effect of the stratum corneum. Ionic liquids were recently used to enhance transdermal drug delivery by improving drug solubility. In the present study, safe and effective ionic liquids for transdermal absorption were obtained as salts generated by a neutralization reaction between highly biocompatible aliphatic carboxylic acids (octanoic acid or isostearic acid) and aliphatic amines (diisopropanolamine or triisopropanolamine) (Medrx Co., Ltd., 2009). The mechanism of skin permeability enhancement by ionic liquids was investigated by hydrophilic phenol red and hydrophobic tulobuterol. Further, the skin permeation enhancing effect was remarkably superior in the acid excess state rather than the neutralization state. Infrared absorption spectrum analysis confirmed that ionic liquids/aliphatic carboxylic acid/aliphatic amine are coexisting at all mixing states. In the acid excess state, ionic liquids interact with aliphatic carboxylic acids via hydrogen bonds. Thus, the skin permeation enhancing effect is not caused by the ionic liquid alone. The "liquid salt mixture," referred to as a complex of ingredients coexisting with ionic liquids, forms a molecular assembly incorporating hydrophilic drug. This molecular assembly was considered an effective and safety enhancer of transdermal drug permeation. PMID- 26965005 TI - Tips and tricks for ORIF of displaced femoral neck fractures in the young adult patient. AB - Femoral neck fractures in the young adult are a less common, but potentially functionally significant injury commonly occurring after high-energy trauma. The management goals of these injuries are the maintenance of a native hip joint absent avascular necrosis and nonunion. The primary determinant to this end is an anatomic reduction in displaced fractures with stable fixation. In this paper, the authors provide a set of technical tips and tricks to aid orthopedic surgeons in the surgical management of these injuries while reviewing the most recent literature available to inform clinical decision making. The paper includes the recommendations of the authors from the Denver Health Orthopaedic Trauma Service. PMID- 26965006 TI - Radiologist, obstetric patient, and emergency department provider survey: radiologist-patient interaction in the emergency department setting. AB - The aim of this study was to evaluate the feasibility and acceptance of a model of direct interaction between radiologist and patients in the emergency department (ED) setting. The study population was comprised of pregnant patients accrued in a non-consecutive prospective manner from June 2014 to September 2015, who had an obstetrical ultrasound performed in the radiology department of an inner-city tertiary care hospital at the request of the ED. The feasibility and approval of direct communication between radiologist and patient were evaluated by means of a questionnaire presented by an independent observer to the ED provider, patient, and radiologist. The exam enrolled 54 patients. Ultrasound (US) exam results were divided into (31) normal live intrauterine gestation (group 1), (7) abnormal failed intrauterine gestation or ectopic pregnancy (group 2), and (16) indeterminate pregnancies that could not be placed in the former categories and may require a follow-up exam (group 3). Forty-five (83 %) ED providers approved of the radiologist's direct communication with patients. Fifty (93 %) patients stated a better understanding of the radiologist's role in their care after than before the interaction. The radiologists found the interaction with patients to be positive in 52 (96 %) cases. Direct communication between radiologist and patient yielded a good acceptance by the radiologist, ED provider, and patient. More importantly, after the encounter, the vast majority of patients reported a better understanding of the radiologist's role in their care. PMID- 26965007 TI - Thoracic venous injuries: an imaging and management overview. AB - Thoracic venous injuries are predominantly attributed to traumatic and iatrogenic causes. Gunshot wounds and knife stabbings make up the vast majority of penetrating trauma whereas motor vehicle collisions are the leading cause of blunt trauma to the chest. Iatrogenic injuries, mostly from central venous catheter complications are being described in growing detail. Although these injuries are rare, they pose a diagnostic challenge as their clinical presentation does not substantially differ from that of arterial injury. Furthermore, the highly lethal nature of some of these injuries provides limited literature for review and probably underestimates their true incidence. The widespread use of multi-detector computed tomography (MDCT) has increased the detection rate of these lesions in hemodynamically stable patients that survive the initial traumatic event. In this article, we will discuss and illustrate various causes of injury to each vein and their supporting CT findings while briefly discussing management. The available literature will be reviewed for penetrating, blunt, and iatrogenic injuries to the vena cava, innominate, subclavian, axillary, azygos, and pulmonary veins. PMID- 26965009 TI - Haemostatic property of cyanoacrylate in pedicled flaps. AB - We present a technique that can, in principle, be applied to any pedicled flap that is routinely used for reconstructions of the forehead. In our experience, cyanoacrylate glue applied to the pedicle before the flap is inserted decreases postoperative bleeding and wound exudate. PMID- 26965008 TI - Single nucleotide polymorphisms linked to mitochondrial uncoupling protein genes UCP2 and UCP3 affect mitochondrial metabolism and healthy aging in female nonagenarians. AB - Energy expenditure decreases with age, but in the oldest-old, energy demand for maintenance of body functions increases with declining health. Uncoupling proteins have profound impact on mitochondrial metabolic processes; therefore, we focused attention on mitochondrial uncoupling protein genes. Alongside resting metabolic rate (RMR), two SNPs in the promoter region of UCP2 were associated with healthy aging. These SNPs mark potential binding sites for several transcription factors; thus, they may affect expression of the gene. A third SNP in the 3'-UTR of UCP3 interacted with RMR. This UCP3 SNP is known to impact UCP3 expression in tissue culture cells, and it has been associated with body weight and mitochondrial energy metabolism. The significant main effects of the UCP2 SNPs and the interaction effect of the UCP3 SNP were also observed after controlling for fat-free mass (FFM) and physical-activity related energy consumption. The association of UCP2/3 with healthy aging was not found in males. Thus, our study provides evidence that the genetic risk factors for healthy aging differ in males and females, as expected from the differences in the phenotypes associated with healthy aging between the two sexes. It also has implications for how mitochondrial function changes during aging. PMID- 26965010 TI - Letter in reply to Letter to the Editor concerning our paper entitled: Atrophy of anterior digastric muscle detected during ultrasound of the neck - a prospective clinical study. PMID- 26965011 TI - The effect of UV-filters on the viability of neuroblastoma (SH-SY5Y) cell line. AB - Topical application of cosmetic products, containing ultraviolet filters (UV filters) are recommended as a protection against sunburns and in order to reduce the risk of skin cancer. However, some UV filters can be absorbed through skin and by consuming contaminated food. Among the chemical UV filters, benzophenone-3 (BP-3), 3-(4-methylbenzylidene)camphor (4-MBC) and 2-ethylhexyl-4 methoxycinnamate (OMC) are absorbed through the skin to the greatest extent. So far, these lipophilic compounds were demonstrated to influence the gonadal and thyroid hormone function, but their effect on central nervous system cells has not been investigated, yet. In the present study, we investigated the effect of some UV filters on cell viability and caspase-3 activity in SH-SY5Y cells. It has been found that benzophenone-2 (BP-2), BP-3, 4-methylbenzophenone (4-MBP) and OMC present in the culture medium for 72h in high concentration (10(-5) and 10(-4)M) and 4-MBC only 10(-4)M produced a significant cytotoxic effect, as determined both by the MTT reduction test and LDH release assay. In contrast to necrotic changes, all tested UV filters increased caspase-3 activity in much lower concentrations (from 10(-8) to 10(-7)M). Proapoptotic properties of the test compounds were positively verified by Hoechst staining. The obtained results indicated that UV filters adversely affected the viability of nerve cells, most likely by enhancing the process of apoptosis. The most potent effect was exerted by BP-3 and 4-MBC and at concentrations that may be reached in vivo. Since human exposure to UV filters is significant these compound should be taken into consideration as one of the possible factors involved in pathogenesis of neurodegenerative diseases. PMID- 26965013 TI - Myopic traction maculopathy. PMID- 26965012 TI - Intravitreal anti-vascular endothelial growth factor combined with half-fluence photodynamic therapy for choroidal neovascularization in chronic central serous chorioretinopathy. AB - PurposeTo evaluate the results of indocyanine green angiography (ICGA)-guided verteporfin photodynamic therapy (PDT) with half-fluence rate combined with intravitreal application of anti-VEGF in treating choroidal neovascularization (CNV) in chronic central serous chorioretinopathy (CSCR).Patients and methodsIn this retrospective cohort study 17 consecutive patients with secondary CNV due to chronic CSCR had their diagnosis verified with fluorescein angiography (FA) and ICGA at baseline. All eyes received either intravitreal ranibizumab (IVR) or bevacizumab (IVB). On the consecutive day following the initial IVR/IVB treatment, ICGA-guided verteporfin (6 mg/m(2)) PDT with half-fluence rate (25 J/cm(2)) was performed on every patient. IVR or IVB was rescheduled on a pro re nata regimen. Main outcome measures were changes in visual acuity (VA) according to the ETDRS letter score and changes in the central foveal thickness (CFT).ResultsBest-corrected VA at baseline was 65.6 letters (+/-6.7; n=17) according to the ETDRS letter score. At 12 months, mean ETDRS letter score improved to 71.2 letters (P=0.34). CFT was 309 MUm and decreased to 216 MUm at month 12 control (P=0.0004). Nine eyes (52.9%) received additional treatment with IVR/IVB due to recurrence of subretinal fluid, with an overall mean number of IVR/IVB treatment of 1.8+/-3.6 per patient with no systemic side effects during 12 months' follow-up.ConclusionsIVR or IVB combined with ICGA-guided half-fluence PDT with verteporfin is effective in treating CNV in chronic CSCR, with choroidal hyperpermeability in ICGA, resulting in stable vision and significant reduction of CFT. PMID- 26965014 TI - Reply to 'Comments on Long-term outcomes of phakic patients with diabetic macular oedema treated with intravitreal fluocinolone acetonide (FAc) implants'. PMID- 26965015 TI - Comments on 'Long-term outcomes of phakic patients with diabetic macular oedema treated with intravitreal fluocinolone acetonide (FAc) implants'. PMID- 26965017 TI - Treatment trials for diabetic macular oedema. PMID- 26965016 TI - Prevalence and associated factors of myopia among primary and middle school-aged students: a school-based study in Guangzhou. AB - PurposeTo estimate the prevalence of myopia among primary and middle school-aged students in Guangzhou and to explore the potentially contributing factors to myopia.MethodsThis cross-sectional study was based on a sample of students in grades 1-6 and grades 7-9. Data were collected from refractive error measurements and a structured questionnaire.ResultsA total of 3055 participants were involved in this analysis, and the overall prevalence of myopia was 47.4% (95% confidence interval (CI)= 45.6-49.2%). The prevalence of myopia in students increased along with the growth of grade level; the prevalence of myopia in students in grade 1 was only 0.2%, as it increased to 38.8% in students in grade 3, and the rate was the highest (68.4%) in students in grade 9. Girls were at a higher risk of myopia than boys (adjusted odds ratio=1.22, 95% CI=1.04-1.44). Both male and female students whose distance of reading was longer than 25 cm were less likely to have myopia and who have one or two myopic parents were at a higher risk of myopia. In addition, reading for pleasure more than 2 h per day (adjusted odds ratio=1.84, 95% CI=1.09-3.12) was only positively associated with myopia in boys and spending time watching television per week was only positively associated with myopia in girls.ConclusionMyopia in students is a significant public health problem in Guangzhou. Female gender, higher grade, longer time spent for near work, shorter distance of near work, and parental myopia were shown to be associated with the increasing risk of myopia in children. PMID- 26965018 TI - Predicting macular hole closure with ocriplasmin based on spectral domain optical coherence tomography. AB - PurposeTo assess the preoperative features of patients with idiopathic macular hole (IMH) and vitreomacular adhesion (VMA) treated with ocriplasmin (OCP) that can predict successful closure.MethodData were prospectively collected on all patients with IMH treated with OCP in three British ophthalmic centres. Several preoperative variables were recorded including the IMH base diameter (BD), minimum linear diameter (MLD), and VMA width measured on spectral domain optical coherence tomography. Several other IMH indices were derived including a 'width factor', defined as the BD minus the MLD in MUm. The occurrence of VMA release and hole closure were used as the main outcome measures.ResultsThirty-three patients in total with IMH were treated with OCP. Two patients developed rhegmatogenous retinal detachment and were excluded. The mean age of the remaining 31 patients was 71 years, and 71% were female. VMA release occurred in 19 of the 31 (61%) patients and macular hole closure in 11 (35%). Width factor was the most predictive feature for closure on multivariate analysis. The deviance R(2) was 67% (P<0.001). An IMH with a width factor of <60 MUm had a 95% certainty of closure, whereas if >290 MUm then there was less than a 5% chance of closure. Neither VMA width nor MLD alone was associated with VMA release or closure.ConclusionsPatients with macular holes where the BD was close in size to the MLD had an improved probability of closure than holes with wider base configurations. PMID- 26965019 TI - Comparison of Characteristics of Patients aged <=45 Years Versus >45 Years With ST-Elevation Myocardial Infarction (from the AIDA STEMI CMR Substudy). AB - It is unknown whether the occurrence of ST-elevation myocardial infarction (STEMI) at a younger age is associated with differences in myocardial damage compared with older patients. We aimed to compare the infarct characteristics (area at risk [AAR], myocardial salvage index [MSI], infarct size [IS], microvascular obstruction [MVO]) and clinical outcome in patients aged <=45 years and >45 years. We analyzed 795 patients with STEMI treated with primary percutaneous coronary intervention. All patients completed 12-month follow-up for the assessment of major adverse cardiac events (MACE). Left ventricular ejection fraction, AAR, MSI, IS, and MVO were determined by cardiac magnetic resonance imaging. Seventy-eight patients (9.8%) were aged 45 years or younger. Young patients were more likely to be male (p = 0.01), to be current smokers (p <0.001), and to have a family history of coronary artery disease (p = 0.05). Contrary, they had significantly lower prevalence of hypertension (p <0.001), diabetes (p <0.01), and 3-vessel disease (p <0.01). There were no significant differences in left ventricular ejection fraction (p = 0.36), AAR (p = 0.30), MSI (p = 0.34), IS (p = 0.29), or MVO (p = 0.58) between both groups. MACE rate was significantly lower in patients aged <=45 years compared with patients aged >45 years (1.3% vs 7.5%, p = 0.04). After multivariate adjustment for clinical risk factors and cardiac magnetic resonance findings, age remained an independent predictor of MACE (hazard ratio 1.04, 95% CI 1.01 to 1.07, p = 0.03). In conclusion, infarct characteristics are not dependent on age in patients undergoing primary percutaneous coronary intervention for STEMI. PMID- 26965021 TI - Integration of mental and physical health care: from aspiration to practice. PMID- 26965020 TI - Evaluation of risk communication in a mammography patient decision aid. AB - OBJECTIVES: We characterized patients' comprehension, memory, and impressions of risk communication messages in a patient decision aid (PtDA), Mammopad, and clarified perceived importance of numeric risk information in medical decision making. METHODS: Participants were 75 women in their forties with average risk factors for breast cancer. We used mixed methods, comprising a risk estimation problem administered within a pretest-posttest design, and semi-structured qualitative interviews with a subsample of 21 women. RESULTS: Participants' positive predictive value estimates of screening mammography improved after using Mammopad. Although risk information was only briefly memorable, through content analysis, we identified themes describing why participants value quantitative risk information, and obstacles to understanding. We describe ways the most complicated graphic was incompletely comprehended. CONCLUSIONS: Comprehension of risk information following Mammopad use could be improved. Patients valued receiving numeric statistical information, particularly in pictograph format. Obstacles to understanding risk information, including potential for confusion between statistics, should be identified and mitigated in PtDA design. PRACTICE IMPLICATIONS: Using simple pictographs accompanied by text, PtDAs may enhance a shared decision-making discussion. PtDA designers and providers should be aware of benefits and limitations of graphical risk presentations. Incorporating comprehension checks could help identify and correct misapprehensions of graphically presented statistics. PMID- 26965023 TI - Docetaxel prodrug liposomes for tumor therapy: characterization, in vitro and in vivo evaluation. AB - There is a strong desire to develop docetaxel (DTX) formulation with good therapeutic effectiveness in view of serious adverse reactions of the commercial formulation of DTX (Taxotere(r)). In this study, a redox-responsive DTX-vitamin E prodrug was successfully formulated into liposomes with the drug loading of 4.14% +/- 0.10%. Compared with DTX liposomes, the DTX prodrug liposomes (DPLs) showed good stability for 30-d shelf life and during dilution with different media. In vitro antitumor activity of DPLs on human prostatic carcinoma PC-3 cells and human lung cancer A549 cells was evaluated using cytotoxicity and apoptosis assays. In spite of a decrease in in vitro antitumor activity, the in vivo pharmacokinetic study reveals that DPLs exhibit significantly longer DTX plasma half-life (t1/2, 1.38-fold) and higher bioavailability (AUC0-t, 14.49-fold) compared with DTX liposomes. The antitumor activity of DPLs to the A549 tumor xenograft model showed selective accumulation in tumor tissue, significant inhibition the growth of the tumors and a much lower toxicity as seen in body weight loss, compared with DTX-Solution. Taken together, the results showed that DPLs is a promising strategy for DTX antitumor delivery. PMID- 26965022 TI - Matrix Extension Study: Validation of the Compact Dry CF Method for Enumeration of Total Coliform Bacteria in Selected Foods. AB - The Compact Dry "Nissui" CF method, Performance Tested Method(SM) 110401, was originally certified for enumeration of coliform bacteria by the AOAC Research Institute Performance Tested Methods(SM) program for raw meat products. Compact Dry CF is a ready-to-use dry media sheet, containing a cold-soluble gelling agent, a chromogenic medium, and selective agents, which are rehydrated by adding 1 mL of diluted sample. Coliform bacteria produce blue/blue-green colonies on the Compact Dry CF, allowing a coliform colony count to be determined in the sample after 24 +/- 2 h incubation. A validation study was organized by Campden BRI (formerly Campden and Chorleywood Food Research Association Technology, Ltd), Chipping Campden, United Kingdom, to extend the method's claim to include cooked chicken, fresh bagged prewashed shredded iceberg lettuce, frozen fish, milk powder, and pasteurized 2% milk. Campden BRI collected single-laboratory data for cooked chicken, lettuce, frozen fish, and milk powder, whereas a multilaboratory study was conducted on pasteurized milk. Thirteen laboratories participated in the interlaboratory study. The Compact Dry CF method was compared to ISO 4832:2006 "Microbiology of food and animal feeding stuffs-Horizontal method for the enumeration of coliforms-Colony-count technique," the current version at the time this study was conducted. Each matrix was evaluated at either four or five contamination levels of coliform bacteria (including an uncontaminated level). After logarithmic transformation of counts at each level, the data for pasteurized whole milk were analyzed for sr, sR, RSDr, and RSDR. Regression analysis was also performed and r(2) was reported. Mean difference between methods with 95% confidence interval (CI) was calculated. A log10 range of -0.5 to 0.5 for the CI was used as the acceptance criterion to establish significant statistical difference between methods. In the single-laboratory evaluation (for cooked chicken, lettuce, frozen fish, and milk powder), sr and RSDr values were analyzed and r(2) was reported. Statistical differences were indicated between the Compact Dry CF and ISO 4832 methods in two of five contamination levels tested for lettuce, and in the low contamination levels for cooked chicken, frozen fish, and dry milk powder. For the low levels of cooked chicken, frozen fish, and milk powder, only a few colonies were recovered for each method, and thus not a true indication of the methods' performance. In most cases, mean differences between the Compact Dry CF and ISO 4832 methods were small (<0.5 log10), with CIs within the acceptance criterion. The sr and RSDr values were similar for both methods, and r(2) values were >0.94 for all matrixes. In the multilaboratory study, no statistical differences were indicated between methods. The sr, RSDr, sR, and RSDr values were similar for each method and even slightly smaller for the Compact Dry CF. The r(2) value was 0.99. The Compact Dry CF method offers comparable results to ISO 4832 in a space saving, easy-to-use format. PMID- 26965024 TI - The Insulin:Glucagon Ratio and the Choice of Glucose-Lowering Drugs. AB - The influence of alpha and beta cells, through glucagon and insulin, on energy metabolism is well known. The insulin:glucagon ratio (IGR) is a frequently discussed entity in the medical literature. However, in recent years, focus has shifted to other pathways and markers of health and disease. This communication revisits the insulin:glucagon bipolar axis and describes the significance of the IGR. It reviews the effects of various glucose-lowering drugs on this ratio, and hypothesizes that the ratio can be used to predict the appropriate choice of drugs for managing diabetes. Drugs which increase the IGR may be beneficial in insulinopenic conditions, while those which decrease IGR may be of help in the setting of hyperinsulinemia or insulin resistance. PMID- 26965025 TI - National community pharmacy NHS influenza vaccination service in Wales: a primary care mixed methods study. AB - BACKGROUND: Influenza is a significant cause of morbidity and excess mortality, yet vaccine coverage in the UK remains below target. Community pharmacies are increasingly being promoted as an alternative to vaccination by GPs. AIM: To explore and verify the factors that influence the relative performance of pharmacies providing NHS influenza vaccinations. DESIGN AND SETTING: A mixed methods study utilising qualitative, semi-structured interviews and quantitative analysis of predictors of vaccination numbers in community pharmacies in Wales. METHOD: Interviews were conducted with 16 pharmacists who participated in the Welsh national pharmacy influenza service in 2013-2014. A purposive sampling strategy was used. Qualitative findings were analysed using framework analysis. Potential predictors of vaccination numbers were identified from interviews and a literature review, and included in a multivariable regression model. RESULTS: The contribution of community pharmacies towards vaccination in Wales is small. Findings suggest that community pharmacies reach younger at-risk individuals, in whom vaccine uptake is low, in greater proportion than influenza vaccination programmes as a whole. Extended opening hours and urban locations were positively associated with the number of vaccinations given, although pharmacists reported that workload, vaccine costs, unforeseen delays, lack of public awareness, and GPs' views of the service limited their contribution. Pharmacists, aware of the potential for conflict with GPs, moderated their behaviour to mitigate such risk. CONCLUSION: Before community pharmacies take greater responsibility for delivering healthcare services, obstacles including increasing pharmacist capacity, vaccine procurement, health service delays, managing GP-pharmacy relationships, and improving public awareness must be overcome. PMID- 26965026 TI - Safety of community-based minor surgery performed by GPs: an audit in different settings. AB - BACKGROUND: Minor surgery is a well-established part of family practice, but its safety and cost-effectiveness have been called into question. AIM: To audit the performance of GP minor surgeons in three different settings. DESIGN AND SETTING: A community-based surgery audit of GP minor surgery cases and outcomes from three settings: GPs who carried out minor surgery in their practice funded as enhanced (primary care) services (ESGPs); GPs with a special interest (GPwSIs) who worked independently within a healthcare organisation; and GPs working under acute trust governance (Model 2 GPs). METHOD: An audit form was completed by volunteer GP minor surgeons. Data were collected about areas of interest and aggregated data tables produced. Percentages were calculated with 95% confidence intervals (CIs) and significant differences across the three groups of GPs tested using the chi(2) test. RESULTS: A total of 6138 procedures were conducted, with 41% (2498; 95% CI = 39.5 to 41.9) of GP minor surgery procedures being on the head/face. Nearly all of the samples from a procedure that were expected to be sent to histology were sent (5344; 88.8%; 95% CI = 88.0 to 89.6). Malignant diagnosis was correct in 69% (33; 95% CI = 54.2 to 79.2) of cases for ESGPs, 93% (293; 95% CI = 90.1 to 95.5) for GPwSIs, and 91% (282; 95% CI = 87.2 to 93.6) for Model 2 GPs. Incomplete excision was significantly more frequent for ESGPs (17%; 9; 95% CI = 7.5 to 28.3, P<0.001). Complication rates were very low across all practitioners. CONCLUSION: GP minor surgery is safe and prompt. GPs working within a managed framework performed better. Consideration needs to be given on how better to support less well-supervised GPs. PMID- 26965027 TI - Interpreting multisource feedback: online study of consensus and variation among GP appraisers. AB - BACKGROUND: GPs collect multisource feedback (MSF) about their professional practice and discuss it at appraisal. Appraisers use such information to identify concerns about a doctor's performance, and to guide the doctor's professional development plan (PDP). AIM: To investigate whether GP appraisers detect variation in doctors' MSF results, and the degree of consensus in appraisers' interpretations of this information. DESIGN AND SETTING: Online study of GP appraisers in north-east England. METHOD: GP appraisers were invited to review eight anonymised doctors' MSF reports, which represented different patterns of scores on the UK General Medical Council's Patient and Colleague Questionnaires. Participants provided a structured assessment of each doctor's report, and recommended actions for their PDP. Appraiser ratings of each report were summarised descriptively. An 'agreement score' was calculated for each appraiser to determine whether their assessments were more lenient than those of other participants. RESULTS: At least one report was assessed by 101/146 appraisers (69%). The pattern of appraisers' ratings suggested that they could detect variation in GPs' MSF results, and recommend reasonable actions for the doctors' PDP. Increasing appraiser age was associated with more favourable interpretations of MSF results. CONCLUSION: Although preliminary, the finding of broad consensus among GP appraisers in their assessment of MSF reports should be reassuring for GPs, appraisers, and employing organisations. However, if older appraisers are more lenient than younger appraisers in their interpretation of MSF and in the actions they suggest to their appraisees as a result, organisations need to consider what steps could be taken to address such differences. PMID- 26965028 TI - A 5-year follow-up study of users of benzodiazepine: starting with diazepam versus oxazepam. AB - BACKGROUND: Drug dependency may develop during long-term benzodiazepine use, indicated, for example, by dose escalation. The first benzodiazepine chosen may affect the risk of dose escalation. AIM: To detect possible differences in benzodiazepine use between new users of diazepam and oxazepam over time. DESIGN AND SETTING: This 5-year prescription database study included 19 747 new benzodiazepine users, inhabitants of Norway, aged 30-60 years, with first redemption for diazepam or oxazepam. METHOD: Individuals starting on diazepam versus oxazepam were analysed by logistic regression with sex, age, other drug redemptions, prescriber's specialty, household income, education level, type of work, and vocational rehabilitation support as background variables. Time to reach a daily average intake of >=1 defined daily doses (DDD) over a 3-month period was analysed using a Cox proportional hazard regression model. RESULTS: New users of oxazepam had a higher risk for dose escalation compared with new users of diazepam. This was true even when accounting for differences in sociodemographic status and previous drug use (hazard ratio [HR] 1.33, 95% confidence interval = 1.17 to 1.51). CONCLUSION: Most doctors prescribed, according to recommendations, oxazepam to individuals they may have regarded as prone to and at risk of dependency. However, these individuals were at higher risk for dose escalation even when accounting for differences in sociodemographic status and previous drug use. Differences between the two user groups could be explained by different preferences for starting drug, DDD for oxazepam being possibly too low, and some unaccounted differences in illness. PMID- 26965029 TI - Investigating the public's use of Scotland's primary care telephone advice service (NHS 24): a population-based cross-sectional study. AB - BACKGROUND: There has been no comprehensive examination of the public's understanding of, and attitudes towards, NHS 24. AIM: To investigate the public's use of NHS 24 and explore their understanding of, and beliefs about, the service. DESIGN AND SETTING: Population-based cross-sectional study of adults in Scotland. METHOD: Quantitative data were collected by self-completion postal questionnaire and qualitative data by follow-up telephone interviews. RESULTS: A corrected response rate of 34.1% (n = 1190) was obtained. More than half (51.0%, n = 601) of responders had used NHS 24. Callers were more likely to be female, have at least one child, and be aged 25-34 years. Most calls (92.4%, n = 549) were made out of hours, and 54.6% (n = 327) were made on behalf of someone else. The main reason for calling was to get advice about a new symptom (69.0%, n = 414). A total of 38.6% (n = 219) of users contacted another health professional following their call, mostly on NHS 24 advice (71.7%, n = 157). Over 80.0% (n = 449) of callers were satisfied with the service and 93.9% (n = 539) would use it again.Only 8.4% (n = 78) of responders had used the NHS 24 website and 4.6% (n = 53) the NHS inform service. The main reasons for non-use were not needing the service, a preference to see their own GP, and not knowing the telephone number. NHS 24 was mainly viewed as an out-of-hours alternative to the GP. It was not considered an appropriate service for minor symptoms. The main facilitator to use was convenience, whereas the main barrier to use was not knowing how and when to use the service. CONCLUSION: Although most people who used NHS 24 were satisfied, others were unclear about how and when to use the service. Further education about the full range of services that NHS 24 offers should be considered. PMID- 26965030 TI - The relationship between prior antimicrobial prescription and meningitis: a case control study. AB - BACKGROUND: Recent research into the role of the human microbiome in maintaining health has identified the potentially harmful impact of antimicrobials. AIM: The association with bacterial and viral meningitis following antimicrobial prescription during the previous year was investigated to determine whether antimicrobials have a deleterious effect on the nasopharyngeal microbiome. DESIGN AND SETTING: A case-control study (1:4 cases to controls) was conducted examining the rate of previous antimicrobial exposure in cases of meningitis and in a matched control group. Data from a UK primary care clinical database were analysed using conditional logistic regression. RESULTS: A total of 7346 cases of meningitis were identified, 3307 (45%) viral, 1812 (25%) bacterial, and 2227 (30%) unspecified. The risks of viral (adjusted odds ratio [AOR] 2.45; 95% confidence interval [CI] = 2.24 to 2.68) or bacterial (AOR 1.98; 95% CI = 1.71 to 2.30) meningitis were both increased following antimicrobial prescription in the preceding year. Patients who received >=4 antimicrobial prescriptions in the preceding year were at significantly increased risk of all types of meningitis (AOR 2.85; 95% CI = 2.44 to 3.34), bacterial meningitis (AOR 3.06; 95% CI = 2.26 to 4.15) and viral meningitis (AOR 3.23; 95% CI = 2.55 to 4.08) compared to their matched controls. CONCLUSION: There was an increased risk of meningitis following antimicrobial prescription in the previous year. It is possible that this increase was due to an effect of antimicrobials on the microbiome or reflected an increased general susceptibility to infections in these patients. PMID- 26965032 TI - Experiences of Children With Gay Fathers. AB - An online survey was distributed via snowball sampling and resulted in responses from 61 gay fathers raising children in 2 states. Fathers reported on the barriers they experienced and the pathways they took to becoming parents. They reported also on experiences of stigma directed at them and their children, especially from family members, friends, and people in religious institutions. Despite these difficulties they reported that they engaged actively in parenting activities and that their child(ren)'s well-being was consistent with national samples. PMID- 26965033 TI - Non-Radiological Method for Fabrication of a Screw-Channel Drilling Guide in Cement-Retained Implant Restorations Using Intraoral Digital Scanning and Imaging Superimposition: A Clinical Report. AB - The difficulty of retrieving the abutment screw is a major disadvantage of cement retained implant restorations. Conventional methods for locating the screw-access hole are based largely on radiography or manual labor, which limits accuracy and clinical feasibility. This clinical report describes a non-radiological method for fabricating an accurate drilling guide for location of the screw channel using intraoral optical scanning, 3D superimposition, and computer-aided design and computer-aided manufacturing (CAD/CAM) technologies. The present technique not only improves the guide fabrication process and the accuracy of screw-channel drilling, but also has wide indications for implant restorations. PMID- 26965031 TI - Predicting antibiotic prescription after symptomatic treatment for urinary tract infection: development of a model using data from an RCT in general practice. AB - BACKGROUND: Uncomplicated urinary tract infection (UTI) is often treated with antibiotics, resulting in increasing resistance levels. A randomised controlled trial showed that two-thirds of females with UTI treated symptomatically recovered without subsequent antibiotic treatment. AIM: To investigate whether there are differences between females with a UTI who were subsequently prescribed antibiotics and those who recovered with symptomatic treatment only, and to develop a model to predict those who can safely and effectively be treated symptomatically. DESIGN AND SETTING: This is a subgroup analysis of females assigned to ibuprofen in a UTI trial in general practices. METHOD: Multiple logistic regression analysis was used to select variables for a prediction model, The discriminative value of the model was estimated by the area under the receiver operator curve (AUC) and the effects of different thresholds were calculated within the model predicting antibiotic prescription and need for follow-up visits. RESULTS: Of the 235 females in the ibuprofen group, 79 were subsequently prescribed antibiotics within 28 days of follow-up. The final model included five predictors: urgency/frequency, impaired daily activities, and positive dipstick test results for erythrocytes, leucocytes, and nitrite. The AUC was 0.73 (95% CI = 0.67 to 0.80). A reasonable threshold for antibiotic initiation would result in 58% of females presenting with UTI being treated with antibiotics. Of the remaining females, only 6% would return to the practice because of symptomatic treatment failure. CONCLUSION: The present model revealed moderately good accuracy and could be the basis for a decision aid for GPs and females to find the treatment option that fits best. PMID- 26965034 TI - Computerised cognitive training in acquired brain injury: A systematic review of outcomes using the International Classification of Functioning (ICF). AB - Computerised cognitive training (CCT) is an increasingly popular intervention for people experiencing cognitive symptoms. This systematic review evaluated the evidence for CCT in adults with acquired brain injury (ABI), focusing on how outcome measures used reflect efficacy across components of the International Classification of Functioning, Disability and Health. Database searches were conducted of studies investigating CCT to treat cognitive symptoms in adult ABI. Scientific quality was rated using the PEDro-P and RoBiNT Scales. Ninety-six studies met the criteria. Most studies examined outcomes using measures of mental functions (93/96, 97%); fewer studies included measures of activities/participation (41/96, 43%) or body structures (8/96, 8%). Only 14 studies (15%) provided Level 1 evidence (randomised controlled trials with a PEDro-P score >= 6/10), with these studies suggesting strong evidence for CCT improving processing speed in multiple sclerosis (MS) and moderate evidence for improving memory in MS and brain tumour populations. There is a large body of research examining the efficacy of CCT, but relatively few Level 1 studies and evidence is largely limited to body function outcomes. The routine use of outcome measures of activities/participation would provide more meaningful evidence for the efficacy of CCT. The use of body structure outcome measures (e.g., neuroimaging) is a newly emerging area, with potential to increase understanding of mechanisms of action for CCT. PMID- 26965035 TI - WHO strengthens Zika travel advice to pregnant women. PMID- 26965036 TI - Photosensitizer-Conjugated Hyaluronic Acid-Shielded Polydopamine Nanoparticles for Targeted Photomediated Tumor Therapy. AB - Photodynamic therapy (PDT) is a widely used clinical option for tumor therapy. However, the clinical utilization of conventional small-molecule photosensitizers (PSs) for PDT has been limited by their low selectivity for disease sites, and undesirable photoactivation. To overcome these limitations, we demonstrated a tumor-specific and photoactivity-controllable nanoparticle photomedicine based on a combination of PS-biomacromolecule conjugates and polydopamine nanoparticles (PD-NP) for an effective tumor therapy. This novel photomedicine consisted of a PD-NP core and a PS-conjugated hyaluronic acid (PS-HA) shell. The PD-NP and the PS-HA play roles as a quencher for PSs and a cancer targeting moiety, respectively. The synthesized PS-HA-shielded PD-NPs (PHPD-NPs) had a relatively narrow size distribution (approximately 130 nm) with uniform spherical shapes. In response to cancer-specific intracellular enzymes (e.g., hyaluronidase), the PHPD NPs exhibited an excellent singlet oxygen generation capacity for PDT. Furthermore, an efficient photothermal conversion ability for photothermal therapy (PTT) was also shown in the PHPD-NPs system. These properties provide superior therapeutic efficacy against cancer cells. In mice tumor model, the photoactive restorative effects of the PHPD-NPs were much higher in cancer microenvironments compared to that in the normal tissue. As a result, the PHPD NPs showed a significant antitumor activity in in vivo mice tumor model. The nanoparticle photomedicine design is a novel strategy for effective tumor therapy. PMID- 26965037 TI - UHPLC/ESI-MS/MS Determination of 187 Pesticides in Wine. AB - This paper presents an ultra HPLC/electrospray ionization-tandem MS method to determine pesticides in wine. We adopted the quick, easy, cheap, effective, rugged, and safe (QuEChERs) method for extraction and used core-shell column to achieve ultra-HPLC to develop and validate a simple and fast method to analyze 187 pesticide residues in red and white wine samples. Pesticide residues were extracted from wine samples using QuEChERS. Ultra HPLC/electrospray ionization tandem MS quantification was achieved using matrix-matched standard calibration curves with isotopically labeled standards or a chemical analogue as internal standards with an analytical range from 5.0 to 500.0 MUg/L. The method performance characteristics that included overall recovery, intermediate precision, and measurement uncertainty were evaluated according to a nested experimental design. Generally, 98.4% (in red wine) and 96.8% (in white wine) of the pesticides had recoveries between 71 and 120%; 98.9% (in red wine) and 99.5% (in white wine) of the pesticides had the intermediate precision <=20%; and 99.5% (in red wine) and 98.4% (in white wine) of the pesticides had measurement uncertainty <=50%. PMID- 26965038 TI - Measuring implementation strength: lessons from the evaluation of public health strategies in low- and middle-income settings. AB - Evaluation of strategies to ensure evidence-based, low-cost interventions reach those in need is critical. One approach is to measure the strength, or intensity, with which packages of interventions are delivered, in order to explore the association between implementation strength and public health gains. A recent systematic review suggested methodological guidance was needed. We described the approaches used in three examples of measures of implementation strength in evaluation. These addressed important public health topics with a substantial disease burden in low-and middle-income countries; they involved large-scale implementation; and featured evaluation designs without comparison areas. Strengths and weaknesses of the approaches were discussed. In the evaluation of Ethiopia's Health Extension Programme, implementation strength scoring for each kebele (ward) was based on aggregated data from interviews with mothers of children aged 12-23 months, reflecting their reports of contact with four elements of the programme. An evaluation of the Avahan HIV prevention programme in India used the cumulative amount of Avahan funding per HIV-infected person spent each year in each district. In these cases, a single measure was developed and the association with hypothesised programme outcomes presented. In the evaluation of the Affordable Medicines Facility-malaria, several implementation strength measures were developed based on the duration of activity of the programme and the level of implementation of supporting interventions. Measuring the strength of programme implementation and assessing its association with outcomes is a promising approach to strengthen pragmatic impact evaluation. Five key aspects of developing an implementation strength measure are to: (a) develop a logic model; (b) identify aspects of implementation to be assessed; (c) design and implement data collection from a range of data sources; (d) decide whether and how to combine data into a single measure; and, (e) plan whether and how to use the measure(s) in outcome analysis. PMID- 26965039 TI - Methylglyoxal, A Metabolite Increased in Diabetes is Associated with Insulin Resistance, Vascular Dysfunction and Neuropathies. AB - BACKGROUND: Diabetes mellitus (DM) is a pandemic metabolic disease characterized by a chronically elevated blood glucose concentration (hyperglycemia) due to insulin dysfunction. Approximately 50% of diabetics show diabetes complications by the time they are diagnosed. Vascular dysfunction, nephropathy and neuropathic pain are common diabetes complications. Chronic hyperglycemia contributes to reactive oxygen species (ROS) generation such as methylglyoxal (MGO). METHODS: Peer reviewed research papers were studied through bibliographic databases searching focused on review questions and inclusion/exclusion criteria. The reviewed papers were appraised according to the searching focus. The characteristics of screened papers were described, and a deductive qualitative content analysis methodology was applied to the included studies using a conceptual framework to yield this comprehensive systematic review. RESULTS: Sixty-six papers were included in this review. Eleven papers related methylglyoxal generation to carbohydrates metabolism, ten papers related lipid metabolism to methylglyoxal and 5 papers showed the proteolytic pathways that contribute to methylglyoxal generation. Methylglyoxal metabolism was derived from 7 papers. Descriptive figure 1 was drawn to explain methylglyoxal sources and how diabetes increases methylglyoxal generation. Furthermore, twenty-six papers related methylglyoxal to diabetes complications from which 9 papers showed methylglyoxal ability to induce insulin dysfunction, an effect which was described in schematic figure 2. Additionally, fifteen papers revealed methylglyoxal contribution to vascular dysfunction and 3 papers showed methylglyoxal to cause neuropathic pain. Methylglyoxal-induced vascular dysfunction was drawn in a comprehensive figure 3. This review correlated methylglyoxal with diabetes and diabetes complications which were summarised in table 1. CONCLUSION: The findings of this review suggesting methylglyoxal as an essential therapeutic target for managing diabetes in the future. PMID- 26965040 TI - The effectiveness of implementation in Indigenous Australian healthcare: an overview of literature reviews. AB - BACKGROUND: Effective implementation can maximise the beneficial impacts of health services. It is therefore important to review implementation in the context of Indigenous populations, who suffer some of the greatest disadvantage within developed countries. This paper analyses Aboriginal and Torres Strait Islander (hereafter Indigenous) Australian health implementation reviews to examine the research question: What is the effectiveness of implementation, as reported in the Indigenous Australian health implementation literature? METHODS: Eight databases were systematically searched to find reviews of Indigenous Australian health services and/or programs where implementation was the focus. Search terms included Aborigin* OR Indigen* OR Torres AND health AND service OR program* OR intervention AND implementation (or like terms) AND Australia AND review. Review findings were analysed through the lens of the PARiHS framework which theorises that successful implementation occurs through the interplay of evidence, context and facilitation. The review followed Cochrane methods but was not registered. RESULTS: Six reviews were found; these encompassed 107 studies that considered health service/program implementation. Included studies described many health services implemented across Australia as not underpinned by rigorous impact evaluation; nevertheless implementers tended to prefer evidence-based interventions. Effective implementation was supported by clearly defined management systems, employment of Indigenous health workers as leaders, community control, partnerships, tailoring for diverse places and settings; and active facilitation methods. Short-term funding meant most studies focused on implementation in one site through pilot initiatives. Only two mentioned cost effectiveness. Indigenous Australian studies incorporated two elements not included in the PARiHS reference guide: the value of community control and equity of service provision across sites. CONCLUSIONS: Comparison of the Indigenous Australian review findings against the PARiHS reference guide elements suggested a fledgling but growing state of Indigenous implementation research, and considerable scope to improve the effectiveness of implementation. Further research is required to explore Indigenous people's understandings of what is important in healthcare implementation; particularly in relation to the value of community control and equity issues. PMID- 26965046 TI - Appraising the uptake and use of recommendations for a common outcome data set for clinical trials: a case study in fall injury prevention. AB - BACKGROUND: Many researchers and professional bodies are seeking consensus for core outcomes for clinical trials. The Prevention of Falls Network Europe (ProFaNE) developed a common outcome data set for fall injury prevention trials 10 years ago. This study assesses the impact of these recommendations. METHODS: A systematic search (up to 16 January 2015) was performed using Web of Science, Scopus and PubMed for articles citing the ProFaNE recommendations. Randomised trials on fall prevention in older people were selected for further analysis. Data were extracted on study characteristics and adherence to the key domains recommended by the ProFaNE consensus: falls, fall injury, physical activity, psychological consequences and health-related quality of life. Details of non recommended outcome measures used were also recorded. RESULTS: The ProFaNE recommendations were cited in a total of 464 published articles, of which 34 were randomised trials on fall prevention in older people. Only one study (3 %) reported on all core domains. Most of the trials reported on falls (n = 32/34, 94 %) as a core outcome measure. Most of the recommendations within the falls domain were well-followed. Around half of the trials reported on fall-related injury (n = 16/34, 47 %). However, none reported the number of radiologically confirmed peripheral fracture events, which is the recommended outcome measure for injury. The other key domains (quality of life, physical activity and psychological consequences) were less frequently reported on, with a lack of consistency in the outcome measures used. CONCLUSIONS: The ProFaNE recommendations had a limited effect on standardising the reporting of outcomes in randomised trials on fall injury prevention in older people during the search period. Authors of consensus guidelines should consider maximising buy-in by including a diversity of geographic areas and academic disciplines at the development stage and using a solid dissemination strategy. PMID- 26965041 TI - Protective role of free and quercetin-loaded nanoemulsion against damage induced by intracerebral haemorrhage in rats. AB - Intracerebral haemorrhage (ICH) is a worldwide public health problem. Experimental studies have shown that oxidative stress plays an important role in the pathogenesis of ICH and could represent a target for its treatment. However, the blood-brain barrier is an obstacle to be overcome, as it hampers the administration of compounds to the central nervous system. In this study, we compared the effects of a quercetin-loaded nanoemulsion (QU-N) with the free form of the drug (QU-SP) in a collagenase-induced ICH rat model. Quercetin (QU) is a polyphenol that has an antioxidant effect in vitro, but due to its high lipophilicity, it has low bioavailability in vivo. In this study, animals submitted or not to ICH were treated with a single intraperitoneal QU dose (free or nanoemulsion) of 30 mg kg(-1). Motor assessment was evaluated by the open field, foot fault and beam walking behavioural tests. 72 h after surgery the haematoma size was evaluated and biochemical measurements were performed. Animals treated with QU-N had a significant improvement in the beam walking and open field tests. Also, QU-N was able to reduce the size of the haematoma, preserving the activity of glutathione S-transferase (GST), increasing GSH content, and the total antioxidant capacity. QU-SP recovered locomotor activity and increased the GSH content and the total antioxidant capacity. Thus, it can be observed that QU presented antioxidant activity in both formulations, but the incorporation into nanoemulsions increased its antioxidant effect, which was reflected in the improvement of the motor skills and in the haematoma size decrement. These results suggest that the nanoemulsion containing QU developed in this study could be promising for future studies on treatments for ICH. PMID- 26965047 TI - A proteome analysis of freezing tolerance in red clover (Trifolium pratense L.). AB - BACKGROUND: Improvement of freezing tolerance of red clover (Trifolium pratense L.) would increase its persistence under cold climate. In this study, we assessed the freezing tolerance and compared the proteome composition of non-acclimated and cold-acclimated plants of two initial cultivars of red clover: Endure (E-TF0) and Christie (C-TF0) and of populations issued from these cultivars after three (TF3) and four (TF4) cycles of phenotypic recurrent selection for superior freezing tolerance. Through this approach, we wanted to identify proteins that are associated with the improvement of freezing tolerance in red clover. RESULTS: Freezing tolerance expressed as the lethal temperature for 50 % of the plants (LT50) increased markedly from approximately -2 to -16 degrees C following cold acclimation. Recurrent selection allowed a significant 2 to 3 degrees C increase of the LT50 after four cycles of recurrent selection. Two-dimensional difference gel electrophoresis (2D-DIGE) was used to study variations in protein abundance. Principal component analysis based on 2D-DIGE revealed that the largest variability in the protein data set was attributable to the cold acclimation treatment and that the two genetic backgrounds had differential protein composition in the acclimated state only. Vegetative storage proteins (VSP), which are essential nitrogen reserves for plant regrowth, and dehydrins were among the most striking changes in proteome composition of cold acclimated crowns of red clovers. A subset of proteins varied in abundance in response to selection including a dehydrin that increased in abundance in TF3 and TF4 populations as compared to TF0 in the Endure background. CONCLUSION: Recurrent selection performed indoor is an effective approach to improve the freezing tolerance of red clover. Significant improvement of freezing tolerance by recurrent selection was associated with differential accumulation of a small number of cold-regulated proteins that may play an important role in the determination of the level of freezing tolerance. PMID- 26965048 TI - Nutritional status of children <5 years of age who have a working mother: an epidemiological perspective of diarrhoeal children in urban Bangladesh. AB - OBJECTIVE: The present analysis aimed to observe nutritional impacts among children <5 years of age by mother's engagement in paid employment. DESIGN: Between 1996 and 2012, 21 443 children <5 years of age with diarrhoea attended the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka Hospital. They were enrolled in the hospital-based Diarrhoeal Disease Surveillance System and their relevant information was extracted from the electronic database. SETTING: The icddr,b, Bangladesh. SUBJECTS: The analytic sample was 19 597 children aged <5 years who had a mother aged <=35 years with or without engagement in paid employment. RESULTS: Eleven per cent of the mothers (n 2051) were currently engaged in paid employment on behalf of the family. Univariate analysis showed that children with mothers engaged in paid employment had a 1.14 times higher risk of being undernourished, a 1.20 times of higher risk of being stunted, a 1.21 times higher risk of being wasted and a 1.31 times higher risk of being underweight (risk ratios) than were children with mothers not likewise engaged. Multivariate analysis showed that such associations remained significant for stunting (1.08; 95 % CI 1.00, 1.16), wasting (1.15; 95 % CI 1.06, 1.25) and underweight (1.09; 95 % CI 1.02, 1.17) after controlling for covariates. CONCLUSIONS: Mothers' engagement in income-generating employment was associated with undernutrition in children <5 years of age in urban Bangladesh. PMID- 26965050 TI - Case report of Salmonella cross-contamination in a food laboratory. AB - BACKGROUND: This paper describes a case of Salmonella cross-contamination in a food laboratory. In 2012, chocolate bars shipped from Belgium to the USA were prevented from entering the USA because a Salmonella Rissen strain had been isolated from one of the chocolate bars in a Belgian food laboratory. However, a retrospective study of the Salmonella isolates sent from the laboratory to the Belgian National Reference Laboratory for Salmonella revealed that 7 weeks prior, a Salmonella Rissen strain has been isolated from fish meal in the same food laboratory. The chocolate bars were not expected to be contaminated with Salmonella because the ingredients all tested negative during the production process. Furthermore, because Salmonella Rissen is only rarely isolated from food, it was hypothesized that the two Salmonella Rissen isolates belonged to the same strain and that the second isolation event in this laboratory was caused by cross-contamination. To confirm this hypothesis, both Salmonella Rissen isolates were fingerprinted using different molecular techniques. To evaluate the discriminatory power of the techniques used, 11 other Salmonella Rissen isolates from different origins were included in the comparison. Pulsed-field gel electrophoresis, repetitive element palindromic PCR and three random amplified polymorphic DNA PCR assays were used. RESULTS: Repetitive element palindromic PCR and random amplified polymorphic DNA PCR assays were insufficiently discriminatory, whereas pulsed-field gel electrophoresis using the combination of two restriction enzymes showed sufficient discrimination to confirm the hypothesis. CONCLUSIONS: Although cross-contamination in food laboratories are rarely reported, cross-contamination can always occur. Laboratories should therefore always be aware of the possibility of cross-contamination, especially when enrichment is used in the microbiological analysis. Furthermore, it is advised that results showing isolates of the same serotype isolated in a short time frame from unrelated food products should be interpreted carefully and should be confirmed with additional strain typing. PMID- 26965051 TI - Micro-RNAs in abdominal aortic aneurysms: insights from animal models and relevance to human disease. AB - Abdominal aortic aneurysm (AAA) is a major health concern and may be associated with high rates of mortality linked to acute complications. Diagnosis and treatment are, respectively, based on imaging and surgical techniques. Drug-based therapies are still mostly ineffective, which highlight a real unmet need. Major pathophysiological mechanisms leading to aneurysm formation involve inflammatory processes, degradation of the extracellular matrix, and loss of smooth muscle cells. However, the precise cellular and molecular pathways are still poorly understood. Recently, microRNAs have emerged as major intracellular players in a wide range of biological processes, and their stability in extracellular medium within microvesicles has led to propose them as mediators of intercellular crosstalk and as potential biomarkers and therapeutic targets in a variety of disease settings. To date, several studies have been performed to address the involvement of micro-RNAs (miRs) in aneurysm formation and complications. Here, we discuss the roles and implications of miRs in animal models and their relevance to human AAA. PMID- 26965049 TI - Expression of F-actin-capping protein subunit beta, CAPZB, is associated with cell growth and motility in epithelioid sarcoma. AB - BACKGROUND: A previous proteomics study demonstrated the overexpression of F actin capping protein subunit beta (CAPZB) in tissue specimens of epithelioid sarcoma (EpiS). The aim of the present study was to elucidate the function of CAPZB in EpiS. METHODS: Cellular functional assays were performed in two EpiS cell lines using CAPZB siRNAs. In addition, comparative protein expression analyses using Isobaric Tags for Relative and Absolute Quantitation (i-TRAQ) method were performed to identify the specific proteins whose expression was dysregulated by CAPZB, and analysed the data with the Ingenuity Pathways Analysis (IPA) system using the obtained protein profiles to clarify the functional pathway networks associated with the oncogenic function of CAPZB in EpiS. Additionally, we performed functional assays of the INI1 protein using INI1 overexpressing EpiS cells. RESULTS: All 15 EpiS cases showed an immunohistochemical expression of CAPZB, and two EpiS cell lines exhibited a strong CAPZB expression. Silencing of CAPZB inhibited the growth, invasion and migration of the EpiS cells. Analysis of protein profiles using the IPA system suggested that SWI/SNF chromatin-remodeling complexes including INI1 may function as a possible upstream regulator of CAPZB. Furthermore, silencing of CAPZB resulted in a decreased expression of INI1 proteins in the INI1-positive EpiS cells, whereas the induction of INI1 in the INI1-deficient EpiS cells resulted in an increased CAPZB mRNA expression. CONCLUSIONS: CAPZB is involved in tumor progression in cases of EpiS, irrespective of the INI1 expression, and may be a potential therapeutic target. The paradoxical relationship between the tumor suppressor INI1 and the oncoprotein CAPZB in the pathogenesis of EpiS remains to be clarified. PMID- 26965052 TI - Stabilization of the bicontinuous cubic phase in siloxane-terminated mesogens, 1,2-bis[4'-(n-(oligodimethylsiloxyl)alkoxy)benzoyl]hydrazine. AB - The introduction of oligodimethyl siloxane segments at the termini of the alkyl tails has been employed to stabilize the bicontinuous cubic (Cub(bi)) phase of a chain-core-chain type molecule having a 1,2-bis(benzoyl)hydrazine central core with two chains attached at the 4' position of each benzoyl moiety. In this study, three silylated molecules, bis-C10Si2, bis-C10Si3, and C10Si2-C8C=C, were synthesized, where "CnSim" represents the number of carbon and silicon atoms in the chain and "bis" indicates the two chains being the same, whereas the last one is asymmetric with respect to the core. The phase behaviors were examined by using polarized optical microscopy, differential scanning calorimetry, and X-ray diffraction techniques. All three compounds form Cub(bi) phases and their syntheses were compared including their parent compound bis-C18. It was clearly revealed that the introduction of oligodimethyl siloxane segments effectively suppresses the crystallization at low temperatures, and as a result stabilizes the Cub(bi) phases, in an extreme case down to room temperature. The semi quantitative analyses in terms of lattice constant and three-dimensional electron density map help us to better understand the self-assembly process in the Cub(bi) phases. The study also revealed that the introduction of oligodimethyl siloxane segments is not only an alternative for the hydrocarbon segment but also is able to provide a versatile design strategy for obtaining stable Cub(bi) phases. PMID- 26965053 TI - Complex coacervation of supercharged proteins with polyelectrolytes. AB - Complexation of proteins with polyelectrolytes or block copolymers can lead to phase separation to generate a coacervate phase or self-assembly of coacervate core micelles. However, many proteins do not coacervate at conditions near neutral pH and physiological ionic strength. Here, protein supercharging is used to systematically explore the effect of protein charge on the complex coacervation with polycations. Four model proteins were anionically supercharged to varying degrees as quantified by mass spectrometry. Proteins phase separated with strong polycations when the ratio of negatively charged residues to positively charged residues on the protein (alpha) was greater than 1.1-1.2. Efficient partitioning of the protein into the coacervate phase required larger alpha (1.5-2.0). The preferred charge ratio for coacervation was shifted away from charge symmetry for three of the four model proteins and indicated an excess of positive charge in the coacervate phase. The composition of protein and polymer in the coacervate phase was determined using fluorescently labeled components, revealing that several of the coacervates likely have both induced charging and a macromolecular charge imbalance. The model proteins were also encapsulated in complex coacervate core micelles and micelles formed when the protein charge ratio alpha was greater than 1.3-1.4. Small angle neutron scattering and transmission electron microscopy showed that the micelles were spherical. The stability of the coacervate phase in both the bulk and micelles improved to increased ionic strength as the net charge on the protein increased. The micelles were also stable to dehydration and elevated temperatures. PMID- 26965055 TI - Hot electron induced NIR detection in CdS films. AB - We report the use of random Au nanoislands to enhance the absorption of CdS photodetectors at wavelengths beyond its intrinsic absorption properties from visible to NIR spectrum enabling a high performance visible-NIR photodetector. The temperature dependent annealing method was employed to form random sized Au nanoparticles on CdS films. The hot electron induced NIR photo-detection shows high responsivity of ~780 mA/W for an area of ~57 MUm(2). The simulated optical response (absorption and responsivity) of Au nanoislands integrated in CdS films confirms the strong dependence of NIR sensitivity on the size and shape of Au nanoislands. The demonstration of plasmon enhanced IR sensitivity along with the cost-effective device fabrication method using CdS film enables the possibility of economical light harvesting applications which can be implemented in future technological applications. PMID- 26965054 TI - A metabarcoding framework for facilitated survey of endolithic phototrophs with tufA. AB - BACKGROUND: In spite of their ecological importance as primary producers and microbioeroders of marine calcium carbonate (CaCO3) substrata, endolithic phototrophs spanning both prokaryotic (the cyanobacteria) and eukaryotic algae lack established molecular resources for their facilitated survey with high throughput sequencing. Here, the development of a metabarcoding framework for the elongation factor EF-Ttu (tufA) was tested on four Illumina-sequenced marine CaCO3 microfloras for the characterization of their endolithic phototrophs, especially the abundant bioeroding Ostreobium spp. (Ulvophyceae). The framework consists of novel tufA degenerate primers and a comprehensive database enabling Operational Taxonomic Unit (OTU) identification at multiple taxonomic ranks with percent identity thresholds determined herein. RESULTS: The newly established tufA database comprises 4057 non-redundant sequences (from 1339 eukaryotic and prokaryotic phototrophs, and 2718 prokaryotic heterotrophs) including 27 classes in 10 phyla of phototrophic diversity summarized from data mining on GenBank((r)), our barcoding of >150 clones produced from coral reef microfloras, and >300 eukaryotic phototrophs (>230 Ulvophyceae including >100 'Ostreobium' spp., and >70 Florideophyceae, Phaeophyceae and miscellaneous taxa). Illumina metabarcoding with the newly designed primers resulted in 802 robust OTUs including 618 phototrophs and 184 heterotrophs (77 and 23% of OTUs, respectively). Phototrophic OTUs belonged to 14 classes of phototrophs found in seven phyla, and represented ~98% of all reads. The phylogenetic profiles of coral reef microfloras showed few OTUs in large abundance (proportion of reads) for the Chlorophyta (Ulvophyceae, i.e. Ostreobium and Phaeophila), the Rhodophyta (Florideophyceae) and Haptophyta (Coccolithophyceae), and a large diversity (richness) of OTUs in lower abundance for the Cyanophyta (Cyanophyceae) and the Ochrophyta (the diatoms, 'Bacillariophyta'). The bioerosive 'Ostreobium' spp. represented four families in a large clade of subordinal divergence, i.e. the Ostreobidineae, and a fifth, phylogenetically remote family in the suborder Halimedineae (provisionally assigned as the 'Pseudostreobiaceae'). Together they harbor 85-95 delimited cryptic species of endolithic microsiphons. CONCLUSIONS: The novel degenerate primers allowed for amplification of endolithic phototrophs across a wide phylogenetic breadth as well as their recovery in very large proportions of reads (overall 98%) and diversity (overall 77% of OTUs). The established companion tufA database and determined identity thresholds allow for OTU identification at multiple taxonomic ranks to facilitate the monitoring of phototrophic assemblages via metabarcoding, especially endolithic communities rich in bioeroding Ulvophyceae, such as those harboring 'Ostreobium' spp., Phaeophila spp. and associated algal diversity. PMID- 26965056 TI - Epidemiology and risk of juvenile idiopathic arthritis among children with allergic diseases: a nationwide population-based study. AB - BACKGROUND: Epidemiological research reveals that the incidence of allergic diseases and that of autoimmune diseases have been increasing in parallel, raising an interest in a potential link between the two disorders. However, the relationship between Th2-mediated allergic disease and Th1-mediated juvenile idiopathic arthritis (JIA) remains unclear. This population-based case-control study was aimed at investigating the development of childhood-onset allergic diseases and the subsequent risks of JIA. METHODS: We included 329 children with JIA diagnosed between 2000 and 2008, and 1316 age- and sex-matched controls. The odds ratios of developing JIA were calculated to determine an association with preexisting allergic diseases. RESULTS: The incidence rate of JIA in Taiwan between 2000 and 2008 was 1.33 cases per 100,000 children/year according to the International League of Associations for Rheumatology (ILAR) criteria. The children with a single allergic disease had an increased risk of JIA, with adjusted odds ratios of developing JIA of 1.44 for allergic conjunctivitis (95 % confidence interval [CI], 1.07-1.95), 1.50 for allergic rhinitis (1.15-1.96), and 1.44 for asthma (1.00-2.10). The adjusted odds ratios increased with the number of concurrent allergic diseases from 1.50 (95 % CI, 1.12-2.01) for those with only one allergic disease to 1.72 (1.24-2.38) for those with at least two allergic diseases. The adjusted odds ratios of those with at least two allergic diseases increased to 1.84 (95 % CI, 1.19-2.86) for boys and 2.54 (1.42-4.54) for those older than 12 years. The children who made two or more medical visits for associated allergic diseases per year had an increased risk of JIA. CONCLUSION: Children with onset of allergic diseases were at increased risk of developing JIA. The increased risk was associated with the cumulative effect of concurrent allergic diseases and frequency of seeking medical care. Further study to investigate the role of Th2-mediated allergic diseases that contribute to the development of Th1-mediated JIA is warranted. PMID- 26965058 TI - Hierarchical TiO2 spheres as highly efficient polysulfide host for lithium-sulfur batteries. AB - Hierarchical TiO2 micron spheres assembled by nano-plates were prepared through a facile hydrothermal route. Chemical tuning of the TiO2 through hydrogen reduction (H-TiO2) is shown to increase oxygen-vacancy density and thereby modifies the electronic properties. H-TiO2 spheres with a polar surface serve as the surface bound intermediates for strong polysulfides binding. Under the restricting and recapturing effect, the sulfur cathode could deliver a high reversible capacity of 928.1 mA h g(-1) after 50 charge-discharge cycles at a current density of 200 mA g(-1). The H-TiO2 additive developed here is practical for restricting and recapturing the polysulfide from the electrolyte. PMID- 26965057 TI - Structural basis for selective recognition of acyl chains by the membrane associated acyltransferase PatA. AB - The biosynthesis of phospholipids and glycolipids are critical pathways for virtually all cell membranes. PatA is an essential membrane associated acyltransferase involved in the biosynthesis of mycobacterial phosphatidyl-myo inositol mannosides (PIMs). The enzyme transfers a palmitoyl moiety from palmitoyl-CoA to the 6-position of the mannose ring linked to 2-position of inositol in PIM1/PIM2. We report here the crystal structures of PatA from Mycobacterium smegmatis in the presence of its naturally occurring acyl donor palmitate and a nonhydrolyzable palmitoyl-CoA analog. The structures reveal an alpha/beta architecture, with the acyl chain deeply buried into a hydrophobic pocket that runs perpendicular to a long groove where the active site is located. Enzyme catalysis is mediated by an unprecedented charge relay system, which markedly diverges from the canonical HX4D motif. Our studies establish the mechanistic basis of substrate/membrane recognition and catalysis for an important family of acyltransferases, providing exciting possibilities for inhibitor design. PMID- 26965060 TI - [Molecular Classification and Personalized Treatment of Gliomas]. PMID- 26965059 TI - Newborn screening for sickling and other haemoglobin disorders using tandem mass spectrometry: A pilot study of methodology in laboratories in England. AB - OBJECTIVE: To determine (i) if electrospray mass spectrometry-mass spectrometry with the SpOtOn Diagnostics Ltd reagent kit for sickle cell screening could be integrated into the English newborn screening programme, under routine screening conditions, and provide mass spectrometry-mass spectrometry results which match existing methods, and (ii) if common action values could be set for all manufacturers in the study, for all assessed haemoglobins, to indicate which samples require further investigation. METHODS: Anonymised residual blood spots were analysed using the SpOtOn reagent kit as per manufacturer's instructions, in parallel with existing techniques at four laboratories. Mass spectrometry-mass spectrometry instrumentation at Laboratories A and B was AB Sciex (Warrington, UK) AP4000, and at Laboratories C and D, Waters Micromass (Manchester, UK), Xevo TQMS and Premier, respectively. RESULTS: There were 23,898 results accepted from the four laboratories. Excellent specificity at 100% sensitivity was observed for haemoglobin S, haemoglobin C, haemoglobin E and haemoglobin OArab. A common action value was not possible for Hb C, but action values were set by manufacturer. The two haemoglobin DPunjab cases at Laboratory D were not detected using the common action value. Conversely, false-positive results with haemoglobin DPunjab were a problem at the remaining three laboratories. CONCLUSIONS: This multicentre study demonstrates that it is possible to implement mass spectrometry-mass spectrometry into an established screening programme while maintaining consistency with existing methods for haemoglobinopathy screening. However, one of the instruments investigated cannot be recommended for use with this application. PMID- 26965061 TI - [Establishment of Endoscopic Spinal Neurosurgery and its Current Status]. AB - Percutaneous endoscopic lumbar discectomy(PELD)has been used as a standard surgical technique for lumbar disc herniation at the Southern TOHOKU Healthcare Group since its introduction in 2009. We present our clinical experiences with PELD for 6 years and discuss the decision-making process for its surgical indication with a review of the pertinent literature. PELD can be performed under both local anesthesia and general anesthesia, and requires only a stab wound for surgery and 3 days of hospitalization. Our surgical results showed generally satisfactory outcomes; however, a salvage surgery was required for 10 of the 96 patients(10.4%)because of early recurrence, insufficient removal of the transligamentous disc fragment, and coexistent canal stenosis. Surgery was discontinued because of unbearable intraoperative pain in one patient each undergoing transforaminal approach and extraforaminal approach under local anesthesia. Although our experience is limited, PELD is considered a promising minimally invasive surgery for lumbar disc herniation. It is generally indicated for patients who are young, sports oriented, or extremely busy. Recurrent disc herniation after microdiscectomy, high risk for general anesthesia, and emergency are considered ideal indications for this technique. Since PELD is a newer technique with a high learning curve, further study, continuous training, and education are required before its widespread implementation. Careful selection of patients is crucial to achieve satisfactory surgical results. PMID- 26965062 TI - [Posterior Reversible Encephalopathy Syndrome Associated with Cancer Therapy]. AB - Posterior reversible encephalopathy syndrome(PRES)is a subacute neurological syndrome typically manifesting with headache, cortical blindness, and seizures. This syndrome is associated with risk factors such as malignant hypertension, eclampsia, and renal failure. Numerous case reports depict its occurrence in cancer patients. The direct causal mechanisms of PRES in cancer patients have not yet been identified. Cytotoxic chemotherapy may cause direct endothelial damage, which would impact the blood brain barrier. Angiogenesis inhibitors also cause elevation in blood pressure;this is significant, because PRES onset may be solely related to hypertension. An increased number of case reports involving new molecular targeted agent suggests that incidence of PRES as an oncological emergency may increase in the future. PMID- 26965063 TI - [Two Surgical Techniques for Metastatic Brain Tumors:Minimum Resection and Removal with Safety Margin]. AB - Successful resection of cerebral metastases is based on good basic neurosurgical techniques, in conjunction with technologies for tumor localization. A clear understanding about the border zone pathology of metastatic lesions leads to two different techniques for safe and effective tumor removal. There is no capsule or pseudocapsule around the metastatic brain tumors. The border zone is widely heterogeneous, especially in lesions after stereotactic irradiation. Resection can be performed in a circumferential and en bloc fashion with sufficient safety margin of the normal brain in non-eloquent area. However, enucleation should be done without surrounding brain damage in and near eloquent areas. PMID- 26965064 TI - [Successful Stent-Assisted Coil Embolization of Fusiform Aneurysm in P2 Segment of Posterior Cerebral Artery:A Case Report]. AB - We report a case of a fusiform aneurysm in the P2 segment of the posterior cerebral artery treated with stent-assisted coil embolization. A 44-year-old woman presented with an unruptured fusiform aneurysm in the left posterior cerebral artery. Stent-assisted coil embolization was performed using a "down-the barrel" view to preserve the parent artery. The postoperative course was uneventful, and MRI showed no evidence of cerebral infarct. The patient was discharged 12 days after surgery, with no neurological deficit. Complete occlusion of the aneurysm and patency of the parent artery were observed on MR angiography at a 3-months follow up. Stent-assisted coil embolization can therefore be an effective alternative to parent artery occlusion in P2 segment fusiform aneurysms of the posterior cerebral artery. PMID- 26965065 TI - [Anterior Communicating Artery Dissection Presenting with Subarachnoid Hemorrhage and Cerebral Infarction]. AB - We describe the case of subarachnoid hemorrhage and cerebral infarction that developed simultaneously and was caused by suspected dissection of the anterior communicating artery. A 65-year-old woman presented with sudden onset of headache and nausea. Head computed tomography(CT)and magnetic resonance imaging revealed subarachnoid hemorrhage in the interhemispheric fissure and a spotty ischemic lesion in the right frontal cortex. Both, CT angiography and angiography with arterial catheterization showed an aneurysmal dilatation of the anterior communicating artery. A repeated CT angiography nine days later demonstrated enlargement of the aneurysmal dilatation. The patient underwent craniotomy under general anesthesia. Under the microscope, a thick hematoma was seen infero dorsally from the anterior communicating artery. Two fenestrations of the anterior communicating artery were identified. After removal of the hematoma, a fusiform dilatation of the anterior communicating artery with a firm and reddish wall was confirmed. The lesion was coated with a teflon sponge and fibrin glue. The patient's postoperative course was uneventful. A follow-up CT angiography two months after surgery revealed shrinkage of the lesion, when compared with preoperative images. PMID- 26965066 TI - [Apixaban-Related Convexal Subarachnoid Hemorrhage:A Case Report]. AB - The risk of anticoagulant-associated intracranial hemorrhage(ICH)is relatively low in patients treated with non-vitamin K antagonist oral anticoagulants(NOAC). The anticoagulant-associated ICH comprises mainly intraparenchimal hemorrhage. Subdural hematoma and subarachnoid hemorrhage(SAH)are rare complications after treatment with NOAC, trauma being the most common cause for these two types of ICH. We report a case of non-traumatic convexal SAH(cSAH)associated with Apixavan. A 68-year-old man with repeated history of cerebral embolism with cardiogenic cause presented with weakness of the lower limbs. Magnetic resonance imaging revealed infarctions, and treatment with apixaban(5 mg twice per day)was administered. Three days later, SAH in the right superior frontal sulcus was discovered incidentally on computed tomography(CT). NOAC-associated SAH is a rare manifestation. Cerebral amyloid angiopathy(CAA)is the most common cause of cSAH in the elderly, and cSAH is supposed to be a warning sign of cerebral hemorrhage in CAA. Patients with CAA started on NOAC require careful monitoring. PMID- 26965067 TI - [Update Knowledge for Brain Tumors(5)Neuronal and Mixed Neuronal-Glial Tumors]. PMID- 26965068 TI - Asymmetric Desymmetrization of 1,3-Diketones via Intramolecular Benzoin Reaction. AB - A general method for the asymmetric desymmetrization of 1,3-diketone substrates via chiral N-heterocyclic carbene catalyzed intramolecular benzoin reactions was developed. Five- and six-membered cyclic ketones bearing two contiguous fully substituted stereocenters were generated with excellent diastereoselectivities and moderate to excellent enantioselectivities. PMID- 26965069 TI - Dynamic channel adjustments in the Jingjiang Reach of the Middle Yangtze River. AB - Significant channel adjustments have occurred in the Jingjiang Reach of the Middle Yangtze River, because of the operation of the Three Gorges Project (TGP). The Jingjiang Reach is selected as the study area, covering the Upper Jingjiang Reach (UJR) and Lower Jingjiang Reach (LJR). The reach-scale bankfull channel dimensions in the study reach were calculated annually from 2002 to 2013 by means of a reach-averaged approach and surveyed post-flood profiles at 171 sections. We find from the calculated results that: the reach-scale bankfull widths changed slightly in the UJR and LJR, with the corresponding depths increasing by 1.6 m and 1.0 m; the channel adjustments occurred mainly with respect to bankfull depth because of the construction of large-scale bank revetment works, although there were significant bank erosion processes in local regions without the bank protection engineering. The reach-scale bankfull dimensions in the UJR and LJR generally responded to the previous five-year average fluvial erosion intensity during flood seasons, with higher correlations being obtained for the depth and cross-sectional area. It is concluded that these dynamic adjustments of the channel geometry are a direct result of recent human activities such as the TGP operation. PMID- 26965071 TI - Immunological risk assessment: The key to individualized immunosuppression after kidney transplantation. AB - The wide range of immunosuppressive therapies and protocols permits tailored planning of the initial regimen according to the immunological risk status of individual patients. Pre-transplant risk assessment can include many factors, but there is no clear consensus on which parameters to take into account, and their relative importance. In general younger patients are known to be at higher risk for acute rejection, compounded by higher rates of non-adherence in adolescents. Donor age and recipient gender do not appear to exert a meaningful effect on risk of rejection per se, but black recipient ethnicity remains a well-established risk factor even under modern immunosuppression regimens. Little difference in risk is now observed between deceased- and living-donor recipients. Immunological risk assessment has developed substantially in recent years. Cross-match testing with cytotoxic analysis has long been supplemented by flow cytometry, but development of solid-phase single-bead antigen testing of solubilized human leukocyte antigens (HLA) to detect donor-specific antibodies (DSA) permits a far more nuanced stratification of immunological risk status, including the different classes and intensities of HLA antibodies Class I and/or II, including HLA-DSA. Immunologic risk evaluation is now often based on a combination of these tests, but other assessments are becoming more widely introduced, such as measurement of non-HLA antibodies against angiotensin type 1 (AT1) receptors or T-cell ELISPOT assay of alloantigen-specific donor. Targeted densensitization protocols can improve immunological risk, notably for DSA-positive patients with negative cytotoxicity and flow cross-match. HLA mismatch remains an important and undisputed risk factor for rejection. Delayed graft function also increases the risk of subsequent acute rejection, and the early regimen can be modified in such cases. Overall, there is a shift towards planning the immunosuppressive regimen based on pre-transplant immunology testing although certain conventional risk factors retain their importance. PMID- 26965070 TI - Transcriptome analysis reveals differentially expressed genes associated with germ cell and gonad development in the Southern bluefin tuna (Thunnus maccoyii). AB - BACKGROUND: Controlling and managing the breeding of bluefin tuna (Thunnus spp.) in captivity is an imperative step towards obtaining a sustainable supply of these fish in aquaculture production systems. Germ cell transplantation (GCT) is an innovative technology for the production of inter-species surrogates, by transplanting undifferentiated germ cells derived from a donor species into larvae of a host species. The transplanted surrogates will then grow and mature to produce donor-derived seed, thus providing a simpler alternative to maintaining large-bodied broodstock such as the bluefin tuna. Implementation of GCT for new species requires the development of molecular tools to follow the fate of the transplanted germ cells. These tools are based on key reproductive and germ cell-specific genes. RNA-Sequencing (RNA-Seq) provides a rapid, cost effective method for high throughput gene identification in non-model species. This study utilized RNA-Seq to identify key genes expressed in the gonads of Southern bluefin tuna (Thunnus maccoyii, SBT) and their specific expression patterns in male and female gonad cells. RESULTS: Key genes involved in the reproductive molecular pathway and specifically, germ cell development in gonads, were identified using analysis of RNA-Seq transcriptomes of male and female SBT gonad cells. Expression profiles of transcripts from ovary and testis cells were compared, as well as testis germ cell-enriched fraction prepared with Percoll gradient, as used in GCT studies. Ovary cells demonstrated over-expression of genes related to stem cell maintenance, while in testis cells, transcripts encoding for reproduction-associated receptors, sex steroids and hormone synthesis and signaling genes were over-expressed. Within the testis cells, the Percoll-enriched fraction showed over-expression of genes that are related to post-meiosis germ cell populations. CONCLUSIONS: Gonad development and germ cell related genes were identified from SBT gonads and their expression patterns in ovary and testis cells were determined. These expression patterns correlate with the reproductive developmental stage of the sampled fish. The majority of the genes described in this study were sequenced for the first time in T. maccoyii. The wealth of SBT gonadal and germ cell-related gene sequences made publicly available by this study provides an extensive resource for further GCT and reproductive molecular biology studies of this commercially valuable fish. PMID- 26965073 TI - High speed direct imaging of thin metal film ablation by movie-mode dynamic transmission electron microscopy. AB - Obliteration of matter by pulsed laser beams is not only prevalent in science fiction movies, but finds numerous technological applications ranging from additive manufacturing over machining of micro- and nanostructured features to health care. Pulse lengths ranging from femtoseconds to nanoseconds are utilized at varying laser beam energies and pulse lengths, and enable the removal of nanometric volumes of material. While the mechanisms for removal of material by laser irradiation, i.e., laser ablation, are well understood on the micrometer length scale, it was previously impossible to directly observe obliteration processes on smaller scales due to experimental limitations for the combination of nanometer spatial and nanosecond temporal resolution. Here, we report the direct observation of metal thin film ablation from a solid substrate through dynamic transmission electron microscopy. Quantitative analysis reveals liquid phase dewetting of the thin-film, followed by hydrodynamic sputtering of nano- to submicron sized metal droplets. We discovered unexpected fracturing of the substrate due to evolving thermal stresses. This study confirms that hydrodynamic sputtering remains a valid mechanism for droplet expulsion on the nanoscale, while irradiation induced stress fields represent limit laser processing of nanostructured materials. Our results allow for improved safety during laser ablation in manufacturing and medical applications. PMID- 26965074 TI - Dental pain and associated factors in Brazilian preschoolers. AB - OBJECTIVE: To describe the prevalence of dental pain in Brazilian preschoolers, as well as its associated factors, considering a representative sample of that population group in Brazil. METHODS: Cross-sectional study that used the analytical data of the national oral health survey (SB Brazil) carried out in 2010. A representative sample of Brazilian preschoolers aged 5 years was considered. Interviews were carried out (answered by parents/tutors), as well as clinical examinations in children. Descriptive, bivariate and multivariate analyzes were performed, described in odds ratios and 95% confidence interval (OR/95%CI). RESULTS: 7,280 preschoolers were included. Of these, 1520 (21.1%) had had dental pain in the last 6 months. The chance of the occurrence of dental pain was higher among those who used dental services (1.51 / 1.02 to 2.23), with tooth decay (3.08 / 2.08 to 4.56), that realized the need for dental treatment (3.96 / 2.48 to 6.34), whose parents reported dissatisfaction by children with their teeth and mouth (1.47 / 1.04 to 2.10) and those who reported impact of oral problems on quality of life (5.76 / 3.90 to 8.49). CONCLUSIONS: The prevalence of dental pain among Brazilian preschool children was relatively high, being associated with the use of dental services and the normative and subjective oral health status. PMID- 26965072 TI - Identification of OCTN2 variants and their association with phenotypes of Crohn's disease in a Korean population. AB - Crohn's disease (CD) is a chronic inflammatory bowel disease and a genetic variant in the OCTN2, g.-207G > C is significantly associated with CD susceptibility. This study was aimed to identify novel OCTN2 functional promoter variants and their roles in transcriptional regulation using various in vitro assays. In addition, we investigated the association between OCTN2 genotypes and CD through genetic analysis using DNA samples from 193 patients with CD and 281 healthy controls. Among the three major promoter haplotypes of OCTN2 identified, one haplotype, H3, showed a significant decrease in promoter activity: two polymorphisms in H3 were associated with a significant reduction in promoter activity. In particular, we found that the reduced transcriptional activity of those two polymorphisms results from a reduction in the binding affinity of the activators, NF-E2 and YY1, to the OCTN2 promoter. The functional haplotype of the OCTN2 promoter was associated with clinical course of CD such as the disease behavior and need for surgery. However, genetic variants or haplotypes of OCTN2 did not affect the susceptibility to CD. Our results suggest that a common promoter haplotype of OCTN2 regulates the transcriptional rate of OCTN2 and influences the clinical course of CD. PMID- 26965075 TI - The impact of varicella vaccination on varicella-related hospitalization rates: global data review. AB - OBJECTIVE: to describe the impact of varicella vaccination on varicella-related hospitalization rates in countries that implemented universal vaccination against the disease. DATA SOURCE: we identified countries that implemented universal vaccination against varicella at the http://apps.who.int/immunization_monitoring/globalsummary/schedules site of the World Health Organization and selected articles in Pubmed describing the changes (pre/post-vaccination) in the varicella-related hospitalization rates in these countries, using the Keywords "varicella", "vaccination/vaccine" and "children" (or) "hospitalization". Publications in English published between January 1995 and May 2015 were included. DATA SYNTHESIS: 24 countries with universal vaccination against varicella and 28 articles describing the impact of the vaccine on varicella-associated hospitalizations rates in seven countries were identified. The US had 81.4% -99.2% reduction in hospitalization rates in children younger than four years after 6-14 years after the onset of universal vaccination (1995), with vaccination coverage of 90%; Uruguay: 94% decrease (children aged 1-4 years) in six years, vaccination coverage of 90%; Canada: 93% decrease (age 1-4 years) in 10 years, coverage of 93%; Germany: 62.4% decrease (age 1-4 years) in 8 years, coverage of 78.2%; Australia: 76.8% decrease (age 1-4 years) in 5 years, coverage of 90%; Spain: 83.5% decrease (age <5 years) in four years, coverage of 77.2% and Italy 69.7% -73.8% decrease (general population), coverage of 60%-95%. CONCLUSIONS: The publications showed variations in the percentage of decrease in varicella-related hospitalization rates after universal vaccination in the assessed countries; the results probably depend on the time since the implementation of universal vaccination, differences in the studied age group, hospital admission criteria, vaccination coverage and strategy, which does not allow direct comparison between data. PMID- 26965077 TI - Genetics: Common co-deletion isn't a silent passenger. PMID- 26965079 TI - Rehabilitation of severely worn teeth: A systematic review. AB - OBJECTIVES: The aim of this systematic review was to evaluate the treatment performance/longevity of dental materials/techniques indicated to restore teeth with severe wear. MATERIALS AND METHODS: A systematic literature search was conducted to select retrospective studies (cohort and case series) and prospective studies that evaluated or compared techniques/materials to restore teeth with severe wear. A search was conducted in Medline (via Pubmed - June 2015) with no limits for publication year or language to identify clinical studies. Two reviewers independently selected studies, extracted data and assessed the risk of bias of randomized controlled trials included. The annual failure rate (AFR%) of restorations was calculated for each study. RESULTS: A total of 511 articles were found and 23 studies were eligible for full-text analysis; hand search included 7 more papers. From the 30 studies, 12 were eligible for the review. Most of these studies presented good performance of the restorations in teeth with severe wear. AFR ranged from 0.4% (microhybrid) to 26.3% (microfilled) for direct resin composite, 0% to 14.9% for indirect resin composite and 2.7% for porcelain veneers. CONCLUSION: There is no strong evidence to suggest that any material is better than another. Direct or indirect materials may be feasible options to restore severely worn teeth. PMID- 26965078 TI - Comparison of inhibition kinetics of several organophosphates, including some nerve agent surrogates, using human erythrocyte and rat and mouse brain acetylcholinesterase. AB - Because testing of nerve agents is limited to only authorized facilities, our laboratory developed several surrogates that resemble nerve agents because they phosphylate the acetylcholinesterase (AChE) with the same moiety as the actual nerve agents. The inhibition kinetic parameters were determined for AChE by surrogates of cyclosarin (NCMP), sarin (NIMP, PIMP and TIMP) and VX (NEMP and TEMP) and other organophosphorus compounds derived from insecticides. All compounds were tested with rat brain and a subset was tested with mouse brain and purified human erythrocyte AChE. Within the compounds tested on all AChE sources, chlorpyrifos-oxon had the highest molecular rate constant followed by NCMP and NEMP. This was followed by NIMP then paraoxon and DFP with rat and mouse brain AChE but DFP was a more potent inhibitor than NIMP and paraoxon with human AChE. With the additional compounds tested only in rat brain, TEMP was slightly less potent than NEMP but more potent than PIMP which was more potent than NIMP. Methyl paraoxon was slightly less potent than paraoxon but more potent than TIMP which was more potent than DFP. Overall, this study validates that the pattern of inhibitory potencies of our surrogates is comparable to the pattern of inhibitory potencies of actual nerve agents (i.e., cyclosarin>VX>sarin), and that these are more potent than insecticidal organophosphates. PMID- 26965080 TI - Probiotics for managing caries and periodontitis: Systematic review and meta analysis. AB - OBJECTIVES: Probiotics might be beneficial to prevent or treat caries, gingivitis or periodontitis. We aimed to appraise trials assessing probiotics for managing caries and periodontal disease. DATA: We included randomized controlled trials comparing the efficacy of probiotics versus (placebo) control with regards to Streptococcus mutans [SM], lactobacilli [LB], periodontal pathogens numbers, gingivitis, oral hygiene, caries incidence/experience increment, or periodontitis. Meta-analysis and trial-sequential-analysis were performed. SOURCES: Three electronic databases (Medline, Embase, Central) were screened. STUDY SELECTION: 50 studies (3247 participants) were included. Studies were mainly performed in children and used lactobacilli (45); bifidobacteria (12) or other genus (3). Probiotics significantly increased the chance of reducing SM (OR: 2.20, 95% CI: 1.23/3.92) or LB (OR: 2.84; 1.34/6.03)<10(4)CFU/ml. Such reduction was confirmed for SM counts (standardized mean differences: -1.18, 95% CI: -1.64/-0.72), but not LB (SMD: 0.33; 0.15/0.52). For periodontal pathogens, no significant difference was found. Probiotics significantly reduced bleeding-on probing (SMD: -1.15; -1.68/-0.62) and gingival index (SMD: -0.86; -1.52/-0.20), but not plaque index (SMD: -0.34; -0.89/0.21). Caries incidence was not significantly reduced (OR: 0.60; 0.35/1.04), neither was caries experience (SMD: 0.26; -0.55/0.03) or CAL (SMD: -0.46; -0.84/0.08). In contrast, probing-pocket depths (SMD: -0.86; -1.55/-0.17) were significantly reduced. Data was quantitatively insufficient for conclusive findings, and risk of bias was high. CONCLUSION: Current evidence is insufficient for recommending probiotics for managing dental caries, but supportive towards managing gingivitis or periodontitis. Future studies should only record bacterial numbers alongside accepted disease markers or indicators. CLINICAL SIGNIFICANCE: Probiotic therapy could be used for managing periodontal diseases. For caries, further studies should ascertain both efficacy and safety. PMID- 26965082 TI - Understanding the Subjective Experience of Medication Adherence for Older Urban African Americans With Type 2 Diabetes and a History of Illicit Drug Addiction. AB - OBJECTIVE: African Americans experience high rates of type 2 diabetes mellitus (T2D). Self-management strategies, such as medication adherence, are key to mitigating negative T2D outcomes. This article addresses a gap in the literature by examining the intersections of drug abuse histories and medication adherence among urban, older African Americans with T2D. METHOD: In-depth interview data were collected as part of a larger ethnographic study examining the subjective experience of T2D among urban older adults. Two representative focal cases were selected and thematic analysis performed to illustrate how former illicit drug addicts perceive prescription medication usage. RESULTS: Narratives reveal that participants are displeased about having to take prescription drugs and are making lifestyle changes to reduce medication usage and maintain sobriety. DISCUSSION: Previous drug abuse not only complicates medication adherence but is also a significant part of how older African Americans who are former drug users frame their understanding of T2D more broadly. PMID- 26965081 TI - Arthritis and Risk of Cognitive and Functional Impairment in Older Mexican Adults. AB - OBJECTIVE: This study investigated the risk of cognitive and functional impairment in older Mexicans diagnosed with arthritis. Participants included 2,681 Mexicans, aged >=60 years, enrolled in the Mexican Health and Aging Study cohort. METHOD: Participants were categorized into arthritis and no arthritis exposure groups. Primary outcome included participants categorized into "cognitively impaired" or "cognitively normal" groups. Secondary outcomes included participants categorized into Normal, Functionally Impaired only, Cognitively Impaired only, or Dementia (both cognitively and functionally impaired) groups. Multivariable logistic and multinomial regression models were used to assess the relationships. RESULTS: Overall, 16% or 7% were diagnosed with cognitive impairment or dementia. Compared with older Mexicans without arthritis, those who were diagnosed with arthritis had significantly increased risk of functional impairment (adjusted odds ratio [OR] 1.82, 95% confidence interval [CI] = [1.45, 2.29]), but not of dementia. CONCLUSION: Arthritis is associated with increased risk of functional impairment, but not with dementia after 11 years in older Mexicans. PMID- 26965084 TI - Animal models of head and neck squamous cell carcinoma. AB - Head and neck squamous cell carcinoma (HNSCC) is the most common oral cancer worldwide. Local bone invasion into the maxilla or mandible and metastasis to regional lymph nodes often result in a poor prognosis, decreased quality of life and shortened survival time for HNSCC patients. Poor response to treatment and clinical outcomes are the major concerns in this aggressive cancer. Multiple animal models have been developed to replicate spontaneous HNSCC and investigate genetic alterations and novel therapeutic targets. This review provides an overview of HNSCC as well as the traditional animal models used in HNSCC preclinical research. The value and challenges of each in vivo model are discussed. Similarity between HNSCC in humans and cats and the possibility of using spontaneous feline oral squamous cell carcinoma (FOSCC) as a model for HNSCC in translational research are highlighted. PMID- 26965085 TI - Survey of animal shelter managers regarding shelter veterinary medical services. AB - Veterinary services are increasingly used in animal shelters, and shelter medicine is an emerging veterinary specialty. However, little is known about working relationships between animal shelters and veterinarians. The aims of this survey were to characterize working relationships that shelter personnel have and want with veterinarians, identify opinions that shelter managers have regarding the veterinarians they work with, and determine areas for relationship growth between veterinarians and shelter managers. An electronic survey was distributed to 1373 managers of North American animal shelters; 536 (39.0%) responded. Almost all shelters had some veterinary relationship, and most had regular relationships with veterinarians. The proportion of shelters that used local clinics (73.9%) was significantly higher than the proportion that retained on-site paid veterinarians (48.5%). The proportion of respondents who did not have but wanted a paid on-site veterinarian (42%) was significantly higher than the proportion of respondents who did not use local clinics but wanted to (7.9%). These data suggest shelter managers valued veterinary relationships, and wished to expand on site veterinary services. Almost all shelters in this study provided some veterinary care, and all respondents identified at least one common infectious disease, which, for most, had a substantial negative impact on shelter successes. Respondents indicated that the most important roles and greatest expertise of veterinarians were related to surgery, diagnosis and treatment of individual animals. Education of both veterinarians and shelter managers may help ensure that shelters benefit from the full range of services veterinarians can provide, including expertise in disease prevention and animal behavior. PMID- 26965083 TI - Measuring Physical Capacity. AB - OBJECTIVE: The objective of this study was to develop and assess a composite measure of physical capacity using self-report and physical performance items. METHOD: Item response theory (IRT) is used to evaluate measurement properties of self-report and performance items and to develop a composite measure for 7,609 participants in the National Health and Aging Trends Study. RESULTS: Self-reports distinguish differences at the lower end of physical capacity but not at mid-to high levels. Performance-based measures discriminate across a fuller spectrum. An IRT-based composite score, drawing on both, provides increased measurement precision across the physical capacity spectrum and detects age group differences if either self-report or performance does so-suggesting it is better suited for studying age-related changes than either measure alone. DISCUSSION: Self-report and performance measures have different strengths on the physical capacity spectrum. IRT provides a means of combining these different measurement approaches for analyses of physical capacity across a broad range of functioning in later life. PMID- 26965086 TI - Bovine papillomatosis: First detection of bovine papillomavirus types 6, 7, 8, 10 and 12 in Italian cattle herds. AB - Limited information about the distribution of different bovine papillomavirus (BPV) types in Italy is available; therefore, this study aimed to investigate the presence of BPVs in bovine lesions in the Emilia Romagna region. Sixty-four proliferative lesions were collected between december 2011 and december 2014, and subsequently analysed by qualitative PCR with genus- and type-specific primer pairs, as well as rolling circle amplification (RCA). The results demonstrated, for the first time in Italy, the presence of BPV 6, 7, 8, 10 and 12 and also types previously described elsewhere. In addition, the high prevalence of viral co-infections in this sample set provides new information about viral tropism. PMID- 26965076 TI - Vaccines for established cancer: overcoming the challenges posed by immune evasion. AB - Therapeutic vaccines preferentially stimulate T cells against tumour-specific epitopes that are created by DNA mutations or oncogenic viruses. In the setting of premalignant disease, carcinoma in situ or minimal residual disease, therapeutic vaccination can be clinically successful as monotherapy; however, in established cancers, therapeutic vaccines will require co-treatments to overcome immune evasion and to become fully effective. In this Review, we discuss the progress that has been made in overcoming immune evasion controlled by tumour cell-intrinsic factors and the tumour microenvironment. We summarize how therapeutic benefit can be maximized in patients with established cancers by improving vaccine design and by using vaccines to increase the effects of standard chemotherapies, to establish and/or maintain tumour-specific T cells that are re-energized by checkpoint blockade and other therapies, and to sustain the antitumour response of adoptively transferred T cells. PMID- 26965087 TI - The role of tyrosine kinase inhibitor "Lapatinib" in pulmonary hypertension. AB - INTRODUCTION: Pulmonary Arterial Hypertension (PAH) and cancer share growth factor and protein kinase signaling pathways that result in smooth muscle cell proliferation and vasculopathy. There is little known about the impact of Lapatinib on the pulmonary vasculature. After reporting a case of Lapatinib induced PAH we investigated the association of Lapatinib with the development of PAH in our institution. METHODS: We reviewed charts for all patients treated with Lapatinib at our institution between 2008 and 2013. Patients who had undergone 2D echocardiogram both prior to and after treatment were included in the analysis. Increase in Pulmonary artery systolic pressure (PASP) was assessed. Patients were also evaluated in terms of risk factors for non-Group 1 PAH. RESULTS: A total of 27 patients were found to have 2-D echo done before and after starting treatment with Lapatinib. Six patients were found to have significant increase in their PASP after starting treatment. Right heart catheterization before and after stopping the medication was available in three patient, confirming the diagnosis of PAH with complete resolution after stopping the medication. The median pre treatment and post treatment PASP in those 6 patients was 29 mmHg and 65.5 mmHg respectively (N = 6; p = 0.027). CONCLUSION: Lapatinib might be associated with the development of PAH. PASP should be evaluated in patients who become short of breath while on treatment, and stopping the drug in cases where no other reasons are identified could be associated with reversibility of the elevated pulmonary artery pressure. PMID- 26965088 TI - Inspiratory loading and limb blood flow in COPD: The modulating effects of resting lung hyperinflation. AB - Inspiratory resistive loading (IRL) may have deleterious cardiocirculatory effects leading to poor peripheral perfusion in severely-hyperinflated patients with COPD. Nineteen patients (13 severely-hyperinflated with inspiratory capacity/total lung capacity ratio<=0.28) underwent calf blood flow (CBF) measurements by venous occlusion plethysmography at rest and during IRL at 60% maximal inspiratory pressure. Severely-hyperinflated patients had lower resting CBF and greater calf vascular resistance (CVR) than moderately-hyperinflated patients (p<0.05). All severely-hyperinflated patients had markedly reduced CBF (p=0.01). Opposite to our main hypothesis, however, IRL did not further reduce CBF in these patients (p>0.05). Conversely, it significantly decreased CBF and increased CVR in moderately-hyperinflated patients; in fact, end-trial CBF and CVR did not differ between the groups (p>0.05). In conclusion, marked impairments in resting appendicular blood flow in severely-hyperinflated patients with COPD were seen only after acute IRL in less hyperinflated patients. These findings set the stage for studies investigating the effects of lung deflation on peripheral hemodynamics in patients with severe hyperinflation. PMID- 26965089 TI - Selenium and zinc protect brain mitochondrial antioxidants and electron transport chain enzymes following postnatal protein malnutrition. AB - AIMS: Selenium (Se) and zinc (Zn) are trace elements required for optimal brain functions. Thus, the role of Se and Zn against protein malnutrition induced oxidative stress on mitochondrial antioxidants and electron transport chain (ETC) enzymes from rats' brain were investigated. MAIN METHODS: Normal protein (NP) and low protein (LP) rats were fed with diets containing 16% and 5% casein respectively for a period of 10weeks. Then the rats were supplemented with Se and Zn at a concentration of 0.15mgL(-1) and 227mgL(-1) in drinking water for 3weeks after which the rats were sacrificed. KEY FINDINGS: The results obtained from the study showed significant (p<0.05) increase in lipid peroxidation (LPO), ROS production, oxidized glutathione (GSSG) levels and mitochondrial swelling and significant (p<0.05) reductions in catalase (CAT) and Mn-superoxide dismutase (Mn SOD) activities, glutathione (GSH) levels, GSH/GSSG ratio and MTT reduction as a result of LP ingestion. The activities of mitochondrial ETC enzymes were also significantly inhibited in both the cortex and cerebellum of LP-fed rats. Supplementation with either Se or Zn restored the alterations in all the parameters. SIGNIFICANCE: The study showed that Se and Zn might be beneficial in protecting mitochondrial antioxidants and ETC enzymes against protein malnutrition induced oxidative stress. PMID- 26965090 TI - Regional assessment of persistent organic pollutants in resident mussels from New Jersey and New York estuaries following Hurricane Sandy. AB - Resident mussels are effective indicators of ecosystem health and have been utilized in national assessment and monitoring studies for over two decades. Mussels were chosen because contaminant concentrations in their tissues respond to changes in ambient environmental levels, accumulation occurs with little metabolic transformation and a substantial amount of historic data were available. Mussels were collected from 10 previously studied locations approximately a year after Hurricane Sandy. Regionally, concentrations of polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs) decreased significantly, while concentrations of organochlorine pesticides (OCPs) remained unchanged, and polybrominated diphenyl ethers (PBDEs) increased compared to historic concentrations. Although concentrations of PCBs, OCPs and PAHs were at or near record low concentrations, long-term trends did not change after Hurricane Sandy. To effectively measure storm-induced impacts it is necessary to understand the factors influencing changes in mussel body burdens and have a long term monitoring network and an ability to mobilize post event. PMID- 26965091 TI - Response of free-living marine nematodes to the southern Yellow Sea Cold Water Mass. AB - The Yellow Sea Cold Water Mass is a remarkable seasonal hydrographic event in the bottom water of the Yellow Sea. In order to reveal the response of free-living marine nematodes to this event, community structure and biodiversity indices of nematodes were studied in June and November 2013. The dominant species were Dorylaimopsis rabalaisi, Spilophorella sp., Daptonema sp., Sabatieria sp. and Parasphaerolaimus sp. In terms of trophic structure, epigrowth feeders were the most dominant group. Correlation analysis showed that Shannon-Wiener diversity index had significantly negative correlation with sediment silt-clay percentage, organic matter content and water content. Results of BIOENV indicated that sediment phaeophorbide content, water content, bottom water salinity and temperature were the most important factors related to nematode community. In conclusion, community structure and biodiversity indices of nematodes were consistent in the two sampling seasons. PMID- 26965092 TI - Metabolic performance of the coral reef fish Siganus guttatus exposed to combinations of water borne diesel, an anionic surfactant and elevated temperature in Indonesia. AB - Jakarta Bay in Indonesia and its offshore island chain, the Thousand Islands, are facing extreme pollution. Surfactants and diesel-borne compounds from sewage and bilge water discharges are common pollutants. However, knowledge of their effects on reef fish physiology is scarce. This study investigated combined and single effects of a) the water accommodated fraction of diesel (WAF-D, determined by ?EPA polycyclic aromatic hydrocarbons (PAHs)) and b) the surfactant linear alkylbenzene sulfonate (LAS) on metabolic performance of the coral reef fish Siganus guttatus. Responses to combinations of each pollutant with elevated temperature (+3 degrees C) were determined. Short-term exposure to WAF-D led to a significant decrease in standard metabolic rates, while LAS led to an increase. During combined exposure, metabolic depression was observed. Effects of pollutants were not amplified by elevated temperature. This study highlights the need to reduce import of these pollutants and to avoid negative long-term effects on fish health. PMID- 26965094 TI - No App for That! PMID- 26965093 TI - The influence of sediment particle size on the properties of adsorbed dissolved organic matter in the Yangtze Estuary and its interactions with As/Sb. AB - The characteristics of dissolved organic matter (DOM) extracted from sediments with four particle sizes (<25, 63-25, 200-63 and >200MUm) in the Yangtze Estuary were compared. The differences in their binding capacities for individual fluorescent components with As/Sb were studied using fluorescence-quenching titrations combined with excitation-emission matrix (EEM) spectra. The results indicated that the particle size influenced the quality and quantity of extracted DOM. With increasing particle size, the extracted DOM content, value of UV280 and acidic functional group content of the DOM decreased. Three protein-like components (C2, C3 and C4) and one humic-like component (C1) were identified using the parallel factor analysis (PARAFAC) model. Wherein, protein-like material dominated in DOM on different particle-size fractions and possessed a stronger complex capacity with As/Sb. A significant positive correlation between the complexation capacity of extracted DOM from samples, as well as with the acidic functional group content, was observed. PMID- 26965095 TI - What Makes a Competent Nutrition Educator? PMID- 26965096 TI - Adolescent Attitudes and Beliefs Regarding Caffeine and the Consumption of Caffeinated Beverages. AB - OBJECTIVES: To explore adolescents' attitudes and beliefs toward the consumption of caffeinated beverages and factors influencing their caffeinated beverage choice and consumption patterns. DESIGN: Twenty focus groups were conducted with grades 9 to 12 secondary school students. SETTING: Two secondary schools in London, Ontario, Canada. PARTICIPANTS: This study included 166 adolescents, 42% of whom were male and 72% of whom were in grades 9 and 10. PHENOMENON OF INTEREST: Adolescent views regarding caffeine and caffeinated beverages. ANALYSIS: Three researchers independently conducted inductive content analysis on the data using the principles of the immersion-crystallization method. RESULTS: Awareness levels regarding types of caffeinated beverages and their negative health effects were high in adolescents whereas awareness of other aspects of caffeine itself and recommended consumption levels were low. Adolescents also identified reasons for caffeine use, including providing energy, taste, accessibility, and image enhancement. Influences for caffeine use most noted by participants included parental role modeling, media and advertising, and social norms. CONCLUSIONS AND IMPLICATIONS: Further education is needed to correct the misconceptions adolescents have regarding certain aspects of caffeine. By gaining a deeper understanding of adolescents' caffeine use, effective educational strategies may be developed to reduce its use and mitigate potential harms. PMID- 26965098 TI - Healthy Lifestyle Fitness Camp: A Summer Approach to Prevent Obesity in Low Income Youth. AB - OBJECTIVE: To examine the effect of participation in a summer camp focused on nutrition and fitness among low-income youth. METHODS: In 2011-2012, overweight and obese youth (n = 126) from Fresno, CA participated in a free 6-week summer program, Healthy Lifestyle Fitness Camp (HLFC), which included 3 h/wk of nutrition education provided by University of California CalFresh and 3 hours of daily physical activity through Fresno Parks and Recreation. The researchers used repeated-measures ANOVA to examine changes in weight, waist circumference, and waist-to-height ratio (WHtR) between HLFC and the comparison group (n = 29). RESULTS: Significant pre-post WHtR reductions were observed in HLFC: 0.64 to 0.61 (P < .001). In addition, WHtR reductions were maintained in HLFC 2 months afterward whereas an increase occurred in the comparison group (P < .007). CONCLUSIONS AND IMPLICATIONS: Understanding the impact of nutrition- and fitness themed summer camps during unstructured months of summer is integral to obesity prevention among low-income youth. PMID- 26965097 TI - Knowledge of Recommended Calorie Intake and Influence of Calories on Food Selection Among Canadians. AB - OBJECTIVE: To examine knowledge of recommended daily calorie intake, use of calorie information, and sociodemographic correlates between knowledge and use. DESIGN: Population-based, random digit-dialed phone surveys. PARTICIPANTS: Canadian adults (n = 1,543) surveyed between October and December, 2012. MAIN OUTCOME MEASURES: Knowledge of recommended calorie intake and use of calorie information when purchasing food. ANALYSIS: Regression models, adjusting for sociodemographics and diet-related measures. RESULTS: Overall, 24% of participants correctly stated their recommended daily calorie intake; the majority (63%) underestimated it, whereas few (4%) overestimated it. Females, younger participants, those with a higher income and more education, and those who consumed fruits and vegetables at least 5 times daily were significantly more likely to state recommended intake correctly. Most respondents (82%) reported considering calories when selecting foods. Respondents considered calories more often if they were female, had a higher income and more education, perceived themselves to be overweight, were actively trying to control their weight, reported a healthier diet, or consumed fruits and vegetables at least 5 times daily. CONCLUSIONS AND IMPLICATIONS: Although most Canadians reported using calorie information to guide their food choices, few knew their daily recommended calorie intake. To promote healthy weights, policy initiatives, including education regarding daily calorie intake and changes to the Nutrition Facts table, may help consumers make better choices about food. PMID- 26965099 TI - There Are Thousands of Apps for That: Navigating Mobile Technology for Nutrition Education and Behavior. AB - Mobile health (mHealth) is an emerging field devoted to the use of mobile and wireless devices to affect health outcomes, health care services, and health research. Despite great promise, little research has examined its effectiveness. It is the authors' view that the full potential of mHealth has yet to be realized in research and practice. This Perspective article explores when and for whom mHealth approaches are effective, strengths and limitations of commercially and academically generated apps, research design considerations, and public-private partnerships. These topics have implications for researchers and practitioners who wish to advance the science and practice of mHealth. PMID- 26965100 TI - Past, Present, and Future of eHealth and mHealth Research to Improve Physical Activity and Dietary Behaviors. AB - Because physical inactivity and unhealthy diets are highly prevalent, there is a need for cost-effective interventions that can reach large populations. Electronic health (eHealth) and mobile health (mHealth) solutions have shown promising outcomes and have expanded rapidly in the past decade. The purpose of this report is to provide an overview of the state of the evidence for the use of eHealth and mHealth in improving physical activity and nutrition behaviors in general and special populations. The role of theory in eHealth and mHealth interventions is addressed, as are methodological issues. Key recommendations for future research in the field of eHealth and mHealth are provided. PMID- 26965101 TI - Community Engagement in Youth Violence Prevention: Crafting Methods to Context. AB - The purpose of the Youth Violence Prevention Centers (YVPC) Program at the Centers for Disease Control and Prevention is to reduce youth violence in defined high-risk communities through the implementation and evaluation of comprehensive, evidence based prevention strategies. Within this common framework, each YVPC varies in its structure and methods, however all engage communities in multiple ways. We explore aspects of community engagement employed by three centers that operate in very different contexts: a rural county in North Carolina; a suburban area of Denver, Colorado; and an urban setting in Flint, Michigan. While previous research has addressed theories supporting community involvement in youth violence prevention, there has been less attention to the implementation challenges of achieving and sustaining participation. In three case examples, we describe the foci and methods for community engagement in diverse YVPC sites and detail the barriers and facilitating factors that have influenced implementation. Just as intervention programs may need to be adapted in order to meet the needs of specific populations, methods of community engagement must be tailored to the context in which they occur. We discuss case examples of community engagement in areas with varying geographies, histories, and racial and ethnic compositions. Each setting presents distinct challenges and opportunities for conducting collaborative violence prevention initiatives and for adapting engagement methods to diverse communities. Although approaches may vary depending upon local contexts, there are certain principles that appear to be common across cultures and geography: trust, transparency, communication, commitment. We also discuss the importance of flexibility in community engagement efforts. PMID- 26965102 TI - Outcomes, Data, and Indicators of Violence at the Community Level. AB - Youth violence is a major problem in the United States. It remains the third leading cause of death among youth between the ages of 10 and 24 years and the leading cause of death in Blacks between 10 and 24 years of age. In its effort to prevent youth violence, the Center for Disease Control and Prevention funds six Youth Violence Prevention Centers (YVPCs) to design, implement and evaluate community-based youth violence prevention programs. These Centers rely on surveillance data to monitor youth violence and evaluate the impact of their interventions. In public health, surveillance entails a systematic collection and analysis of data, typically within defined populations. In the case of youth violence, surveillance data may include archival records from medical examiners, death certificates, hospital discharges, emergency room visits, ambulance pickups, juvenile justice system intakes, police incident reports, and school disciplinary incidents and actions. This article illustrates the process the YVPCs used for collecting and utilizing youth violence surveillance data. Specifically, we will describe available surveillance data sources, describe community-level outcomes, illustrate effective utilization of the data, and discuss the benefits and limitations of each data source. Public health professionals should utilize local surveillance data to monitor and describe youth violence in the community. Further, the data can be used to evaluate the impact of interventions in improving community-level outcomes. PMID- 26965103 TI - Editorial overview: Cell regulation: Amazingly sophisticated regulatory processes in bacteria! PMID- 26965108 TI - Zika virus: a flavivirus caused pandemics in Latin America. PMID- 26965104 TI - Sinomenine down-regulates TLR4/TRAF6 expression and attenuates lipopolysaccharide induced osteoclastogenesis and osteolysis. AB - Sinomenine (SIN) is an anti-inflammatory and anti-arthritic alkaloid derived from Sinomenioum acutum. Effects of SIN on lipopolysaccharide (LPS)-induced osteolysis have not been reported. Here, we found that SIN reduced LPS-induced erosion of skull bones in C57BL/6 mice significantly. LPS can induce bone-absorbing osteoclast formation independent of RANKL in pre-osteoclastic RAW264.7 cells in vitro. Here, SIN suppressed LPS-induced osteoclast formation and osteoclast survival in RAW264.7 cells. Expression of osteoclastic-specific marker genes was also inhibited by SIN during osteoclast differentiation and osteoclast survival stimulated with LPS. SIN showed much stronger inhibitory effects on expression of Fra-1 and MMP-9 mRNA in osteoclast differentiation rather than osteoclast survival. SIN dramatically inhibited LPS-induced TNF-alpha production in vitro and in vivo. Further signaling studies revealed that SIN suppressed the activation and relative gene expression of three notable nuclear factors (NF kappaB, AP-1, NFAT), reduced intracellular levels of Ca(2+), and down-regulated phosphorylation of MAPK p38 (but not JNK) in LPS-induced osteoclastogenesis. Focusing on upstream signals after LPS stimulation, SIN decreased expression of TLR4 and TRAF6 during osteoclast differentiation, and reduced expression of TLR4 (but not TRAF6) in osteoclast survival. These data suggest that SIN might be a potential agent for the treatment of osteolysis caused by Gram-negative bacteria infection or inflammation due to its inhibition of osteoclastogenesis through reduction of TLR4/TRAF6 expression and downstream signal transduction. PMID- 26965105 TI - Engagement in a National Naloxone Programme among people who inject drugs. AB - BACKGROUND: Availability of the opioid antagonist naloxone for lay administration has grown substantially since first proposed in 1996. Gaps remain, though, in our understanding of how people who inject drugs (PWID) engage with naloxone programmes over time. AIMS: This paper aimed to address three specific evidence gaps: the extent of naloxone supply to PWID; supply-source (community or prisons); and the carriage of naloxone among PWID. MATERIALS AND METHODS: Analysis of Scotland's Needle Exchange Surveillance Initiative (NESI) responses in 2011-2012 and 2013-2014 was undertaken with a specific focus on the extent of Scotland's naloxone supply to PWID; including by source (community or prisons); and on the carriage of naloxone. Differences in responses between the two surveys were measured using Chi-square tests together with 95% confidence intervals for rate-differences over time. RESULTS: The proportion of NESI participants who reported that they had been prescribed naloxone within the last year increased significantly from 8% (175/2146; 95% CI: 7-9%) in 2011-2012 to 32% (745/2331; 95% CI: 30% to 34%) in 2013-2014. In contrast, the proportion of NESI participants who carried naloxone with them on the day they were interviewed decreased significantly from 16% (27/169; 95% CI: 10% to 22%) in 2011-2012 to 5% (39/741; 95% CI: 4% to 7%) in 2013-2014. CONCLUSIONS: The supply of naloxone to PWID has increased significantly since the introduction of a National Naloxone Programme in Scotland in January 2011. In contrast, naloxone carriage is low and decreased between the two NESI surveys; this area requires further investigation. PMID- 26965109 TI - The host immune response in respiratory virus infection: balancing virus clearance and immunopathology. AB - The respiratory tract is constantly exposed to the external environment, and therefore, must be equipped to respond to and eliminate pathogens. Viral clearance and resolution of infection requires a complex, multi-faceted response initiated by resident respiratory tract cells and innate immune cells and ultimately resolved by adaptive immune cells. Although an effective immune response to eliminate viral pathogens is essential, a prolonged or exaggerated response can damage the respiratory tract. Immune-mediated pulmonary damage is manifested clinically in a variety of ways depending on location and extent of injury. Thus, the antiviral immune response represents a balancing act between the elimination of virus and immune-mediated pulmonary injury. In this review, we highlight major components of the host response to acute viral infection and their role in contributing to mitigating respiratory damage. We also briefly describe common clinical manifestations of respiratory viral infection and morphological correlates. The continuing threat posed by pandemic influenza as well as the emergence of novel respiratory viruses also capable of producing severe acute lung injury such as SARS-CoV, MERS-CoV, and enterovirus D68, highlights the need for an understanding of the immune mechanisms that contribute to virus elimination and immune-mediated injury. PMID- 26965111 TI - Obese patients with endometrial cancer: is the robotic approach a challenge or a new era of safer and more cost-effective management of such patients? PMID- 26965112 TI - Optogenetics: Basic Concepts and Their Development. AB - The discovery of light-gated ion channels and their application to controlling neural activities have had a transformative impact on the field of neuroscience. In recent years, the concept of using light-activated proteins to control biological processes has greatly diversified into other fields, driven by the natural diversity of photoreceptors and decades of knowledge obtained from their biophysical characterization. In this chapter, we will briefly discuss the origin and development of optogenetics and highlight the basic concepts that make it such a powerful technology. We will review how these enabling concepts have developed over the past decade, and discuss future perspectives. PMID- 26965113 TI - Natural Resources for Optogenetic Tools. AB - Photoreceptors are found in all kingdoms of life and mediate crucial responses to environmental challenges. Nature has evolved various types of photoresponsive protein structures with different chromophores and signaling concepts for their given purpose. The abundance of these signaling proteins as found nowadays by (meta-)genomic screens enriched the palette of optogenetic tools significantly. In addition, molecular insights into signal transduction mechanisms and design principles from biophysical studies and from structural and mechanistic comparison of homologous proteins opened seemingly unlimited possibilities for customizing the naturally occurring proteins for a given optogenetic task. Here, a brief overview on the photoreceptor concepts already established as optogenetic tools in natural or engineered form, their photochemistry and their signaling/design principles is given. Finally, so far not regarded photosensitive modules and protein architectures with potential for optogenetic application are described. PMID- 26965115 TI - Reversible Photoregulation of Gene Expression and Translation. AB - Several methods for controlling gene expression by light illumination have been reported. Most of these methods control transcription by regulating the interaction between DNA and transcription factors. The use of a photolabile protecting compound (cage compound) is another promising approach for controlling gene expression, although typically in an irreversible manner. We here describe a new approach for reversibly controlling translation using a photoresponsive 8 styryl cap (8ST-cap) that can be reversibly isomerized by illumination with light of a specific wavelength. PMID- 26965114 TI - Algal Photobiology: A Rich Source of Unusual Light Sensitive Proteins for Synthetic Biology and Optogenetics. AB - The light absorption system in eukaryotic (micro)algae includes highly sensitive photoreceptors, which change their conformation in response to different light qualities on a subsecond time scale and induce physiological and behavioral responses. Some of the light sensitive modules are already in use to engineer and design photoswitchable tools for control of cellular and physiological activities in living organisms with various degrees of complexity. Thus, identification of new light sensitive modules will not only extend the source material for the generation of optogenetic tools but also foster the development of new light based strategies in cell signaling research. Apart from searching for new proteins with suitable light-sensitive modules, smaller variants of existing light-sensitive modules would be helpful to simplify the construction of hybrid genes and facilitate the generation of mutated and chimerized modules. Advances in genome and transcriptome sequencing as well as functional analysis of photoreceptors and their interaction partners will help to discover new light sensitive modules. PMID- 26965110 TI - Type 2 innate lymphoid cells: at the cross-roads in allergic asthma. AB - Allergic asthma is a chronic inflammatory disease of the lower airways that affects millions of people worldwide. Allergic asthma is a T helper 2 cell (Th2) mediated disease, in which Th2 cytokines interleukin (IL)-4, IL-5, and IL-13 are closely associated with the symptoms. IL-4 is needed by B cells to switch toward an IgE response, IL-5 recruits and activates eosinophils while IL-13 increases mucus production. The identification of type 2 innate lymphoid cells (ILC2), which are able to rapidly produce large amounts of IL-5 and IL-13 in response to epithelial derived cytokines, implicated a new key player besides Th2 cells. ILCs constitute a family of innate lymphocytes distinct from T and B cells. ILC2s are located in various epithelial compartments in mice and human, including the lung. The recent finding of increased numbers of ILC2s in the airways of severe asthma patients prompts further research to clarify their immunological function. Murine studies have shown that ILC2s are an early innate source of IL-5 and IL-13 after allergen exposure, which induce airway eosinophilic infiltration, mucus hyperproduction, and airway hyperresponsiveness but not allergen-specific IgE production. ILC2s contribute to the initiation as well as to the maintenance of the adaptive type 2 immune response. Here, we review the recent progress on our understanding of the role of ILC2s in the immunopathology of allergic asthma, in particular by studies using murine models which have elucidated fundamental mechanisms by which ILC2s act. PMID- 26965116 TI - Controlling Protein Activity and Degradation Using Blue Light. AB - Regulation of protein stability is a fundamental process in eukaryotic cells and pivotal to, e.g., cell cycle progression, faithful chromosome segregation, or protein quality control. Synthetic regulation of protein stability requires conditional degradation sequences (degrons) that induce a stability switch upon a specific signal. Fusion to a selected target protein permits to influence virtually every process in a cell. Light as signal is advantageous due to its precise applicability in time, space, quality, and quantity. Light control of protein stability was achieved by fusing the LOV2 photoreceptor domain of Arabidopsis thaliana phototropin1 with a synthetic degron (cODC1) derived from the carboxy-terminal degron of ornithine decarboxylase to obtain the photosensitive degron (psd) module. The psd module can be attached to the carboxy terminus of target proteins that are localized to the cytosol or nucleus to obtain light control over their stability. Blue light induces structural changes in the LOV2 domain, which in turn lead to activation of the degron and thus proteasomal degradation of the whole fusion protein. Variants of the psd module with diverse characteristics are useful to fine-tune the stability of a selected target at permissive (darkness) and restrictive conditions (blue light). PMID- 26965117 TI - Photo Control of Protein Function Using Photoactive Yellow Protein. AB - Photoswitchable proteins are becoming increasingly common tools for manipulating cellular processes with high spatial and temporal precision. Photoactive yellow protein (PYP) is a small, water-soluble protein that undergoes a blue light induced change in conformation. It can serve as a scaffold for designing new tools to manipulate biological processes, but with respect to other protein scaffolds it presents some technical challenges. Here, we present practical information on how to overcome these, including how to synthesize the PYP chromophore, how to express and purify PYP, and how to screen for desired activity. PMID- 26965118 TI - A Fluorometric Activity Assay for Light-Regulated Cyclic-Nucleotide-Monophosphate Actuators. AB - As a transformative approach in neuroscience and cell biology, optogenetics grants control over manifold cellular events with unprecedented spatiotemporal definition, reversibility, and noninvasiveness. Sensory photoreceptors serve as genetically encoded, light-regulated actuators and hence embody the cornerstone of optogenetics. To expand the scope of optogenetics, ever more naturally occurring photoreceptors are being characterized, and synthetic photoreceptors with customized, light-regulated function are being engineered. Perturbational control over intracellular cyclic-nucleotide-monophosphate (cNMP) levels is achieved via sensory photoreceptors that catalyze the making and breaking of these second messengers in response to light. To facilitate discovery, engineering and quantitative characterization of such light-regulated cNMP actuators, we have developed an efficient fluorometric assay. Both the formation and the hydrolysis of cNMPs are accompanied by proton release which can be quantified with the fluorescent pH indicator 2',7'-bis-(2-carboxyethyl)-5-(and-6) carboxyfluorescein (BCECF). This assay equally applies to nucleotide cyclases, e.g., blue-light-activated bPAC, and to cNMP phosphodiesterases, e.g., red-light activated LAPD. Key benefits include potential for parallelization and automation, as well as suitability for both purified enzymes and crude cell lysates. The BCECF assay hence stands to accelerate discovery and characterization of light-regulated actuators of cNMP metabolism. PMID- 26965119 TI - Optogenetic Control of Pancreatic Islets. AB - In light of the emerging diabetes epidemic, new experimental approaches in islet research are needed to elucidate the mechanisms behind pancreatic islet dysfunction and to facilitate the development of more effective therapies. Optogenetics has created numerous new experimental tools enabling us to gain insights into processes little was known about before. The spatial and temporal precision that it can achieve is also attractive for studying the cells of the pancreatic islet and we set out to explore the possibilities of this technology for our purposes. We here describe how to use the islets of an "optogenetic beta cell" mouse line in islet batch incubations and Ca(2+) imaging experiments. This protocol enables light-induced insulin release and provides an all-optical solution to control and measure intracellular Ca(2+) levels in pancreatic beta cells. The technique is easy to set up and provides a useful tool for controlling the activity of distinct islet cell populations. PMID- 26965121 TI - Enhancing Channelrhodopsins: An Overview. AB - After the discovery of Channelrhodopsin, a light-gated ion channel, only a few people saw the diverse range of applications for such a protein. Now, more than 10 years later Channelrhodopsins have become widely accepted as the ultimate tool to control the membrane potential of excitable cells via illumination. The demand for more application-specific Channelrhodopsin variants started a race between protein engineers to design improved variants. Even though many engineered variants have undisputable advantages compared to wild-type variants, many users are alienated by the tremendous amount of new variants and their perplexing names. Here, we review new variants whose efficacy has already been proven in neurophysiological experiments, or variants which are likely to extend the optogenetic toolbox. Variants are described based on their mechanistic and operational properties in terms of expression, kinetics, ion selectivity, and wavelength responsivity. PMID- 26965120 TI - Optogenetics in Plants: Red/Far-Red Light Control of Gene Expression. AB - Optogenetic tools to control gene expression have many advantages over the classical chemically inducible systems, overcoming intrinsic limitations of chemical inducers such as solubility, diffusion, and cell toxicity. They offer an unmatched spatiotemporal resolution and permit quantitative and noninvasive control of the gene expression. Here we describe a protocol of a synthetic light inducible system for the targeted control of gene expression in plants based on the plant photoreceptor phytochrome B and one of its interacting factors (PIF6). The synthetic toggle switch system is in the ON state when plant protoplasts are illuminated with red light (660 nm) and can be returned to the OFF state by subsequent illumination with far-red light (760 nm). In this protocol, the implementation of a red light-inducible expression system in plants using Light Emitting Diode (LED) illumination boxes is described, including the isolation and transient transformation of plant protoplasts from Arabidopsis thaliana and Nicotiana tabacum. PMID- 26965122 TI - Optogenetics in Drosophila Neuroscience. AB - Optogenetic techniques enable one to target specific neurons with light-sensitive proteins, e.g., ion channels, ion pumps, or enzymes, and to manipulate their physiological state through illumination. Such artificial interference with selected elements of complex neuronal circuits can help to determine causal relationships between neuronal activity and the effect on the functioning of neuronal circuits controlling animal behavior. The advantages of optogenetics can best be exploited in genetically tractable animals whose nervous systems are, on the one hand, small enough in terms of cell numbers and to a certain degree stereotypically organized, such that distinct and identifiable neurons can be targeted reproducibly. On the other hand, the neuronal circuitry and the behavioral repertoire should be complex enough to enable one to address interesting questions. The fruit fly Drosophila melanogaster is a favorable model organism in this regard. However, the application of optogenetic tools to depolarize or hyperpolarize neurons through light-induced ionic currents has been difficult in adult flies. Only recently, several variants of Channelrhodopsin-2 (ChR2) have been introduced that provide sufficient light sensitivity, expression, and stability to depolarize central brain neurons efficiently in adult Drosophila. Here, we focus on the version currently providing highest photostimulation efficiency, ChR2-XXL. We exemplify the use of this optogenetic tool by applying it to a widely used aversive olfactory learning paradigm. Optogenetic activation of a population of dopamine-releasing neurons mimics the reinforcing properties of a punitive electric shock typically used as an unconditioned stimulus. In temporal coincidence with an odor stimulus this artificially induced neuronal activity causes learning of the odor signal, thereby creating a light-induced memory. PMID- 26965123 TI - Optogenetic Control of Mammalian Ion Channels with Chemical Photoswitches. AB - In neurons, ligand-gated ion channels decode the chemical signal of neurotransmitters into an electric response, resulting in a transient excitation or inhibition. Neurotransmitters act on multiple receptor types and subtypes, with spatially and temporally precise patterns. Hence, understanding the neural function of a given receptor requires methods for its targeted, rapid activation/inactivation in defined brain regions. To address this, we have developed a versatile optochemical genetic strategy, which allows the reversible control of defined receptor subtypes in designated cell types, with millisecond and micrometer precision. In this chapter, we describe the engineering of light activated and -inhibited neuronal nicotinic acetylcholine receptors, as well as their characterization and use in cultured cells. PMID- 26965124 TI - Optogenetic Modulation of Locomotor Activity on Free-Behaving Rats. AB - The technology of optogenetics provides a new method to modulate neural activity with spatial specificity and millisecond-temporal scale. This nonelectrical modulation method also gives chance for simultaneous electrophysiological recording during stimulations. Here, we describe our locomotor activity modulation on free-behaving rats using optogenetic techniques. The target sites of the rat brain were dorsal periaqueductal gray (dPAG) and ventral tegmental area (VTA) for the modulation of defensive and reward behaviors, respectively. PMID- 26965125 TI - Combined Optogenetic and Chemogenetic Control of Neurons. AB - Optogenetics provides an array of elements for specific biophysical control, while designer chemogenetic receptors provide a minimally invasive method to control circuits in vivo by peripheral injection. We developed a strategy for selective regulation of activity in specific cells that integrates opto- and chemogenetic approaches, and thus allows manipulation of neuronal activity over a range of spatial and temporal scales in the same experimental animal. Light sensing molecules (opsins) are activated by biologically produced light through luciferases upon peripheral injection of a small molecule substrate. Such luminescent opsins, luminopsins, allow conventional fiber optic use of optogenetic sensors, while at the same time providing chemogenetic access to the same sensors. We describe applications of this approach in cultured neurons in vitro, in brain slices ex vivo, and in awake and anesthetized animals in vivo. PMID- 26965126 TI - Intracranial Injection of an Optogenetics Viral Vector Followed by Optical Cannula Implantation for Neural Stimulation in Rat Brain Cortex. AB - Optogenetics is rapidly gaining acceptance as a preferred method to study specific neuronal cell types using light. Optogenetic neuromodulation requires the introduction of a cell-specific viral vector encoding for a light activating ion channel or ion pump and the utilization of a system to deliver light stimulation to brain. Here, we describe a two-part methodology starting with a procedure to inject an optogenetic AAV virus into rat cortex followed by a second procedure to surgically implant an optical cannula for light delivery to the deeper cortical layers. PMID- 26965127 TI - An Optimized Calcium-Phosphate Transfection Method for Characterizing Genetically Encoded Tools in Primary Neurons. AB - In order to characterize genetically encoded tools under the most relevant conditions, the constructs need to be expressed in the cell type in which they will be used. This is a major hurdle in developing optogenetic tools for neuronal cells, due to the difficulty of gene transfer to these cells. Several protocols have been developed for transfecting neurons, focusing on improved transfection efficiency. However, obtaining healthy cells is as important. We monitored transfected cell health by measuring electrophysiological parameters, and used them as a guideline to optimize transfection. Here we describe an optimized transfection protocol that achieves reasonably high efficiency (10-20 %) with no discernable impact on cell health, as characterized by electrophysiology. PMID- 26965128 TI - Optogenetic Approaches for Mesoscopic Brain Mapping. AB - Recent advances in identifying genetically unique neuronal proteins has revolutionized the study of brain circuitry. Researchers are now able to insert specific light-sensitive proteins (opsins) into a wide range of specific cell types via viral injections or by breeding transgenic mice. These opsins enable the activation, inhibition, or modulation of neuronal activity with millisecond control within distinct brain regions defined by genetic markers. Here we present a useful guide to implement this technique into any lab. We first review the materials needed and practical considerations and provide in-depth instructions for acute surgeries in mice. We conclude with all-optical mapping techniques for simultaneous recording and manipulation of population activity of many neurons in vivo by combining arbitrary point optogenetic stimulation and regional voltage sensitive dye imaging. It is our intent to make these methods available to anyone wishing to use them. PMID- 26965129 TI - Optogenetic Tools for Confined Stimulation in Deep Brain Structures. AB - Optogenetics has emerged in the past decade as a technique to modulate brain activity with cell-type specificity and with high temporal resolution. Among the challenges associated with this technique is the difficulty to target a spatially restricted neuron population. Indeed, light absorption and scattering in biological tissues make it difficult to illuminate a minute volume, especially in the deep brain, without the use of optical fibers to guide light. This work describes the design and the in vivo application of a side-firing optical fiber adequate for delivering light to specific regions within a brain subcortical structure. PMID- 26965130 TI - Remote Patterning of Transgene Expression Using Near Infrared-Responsive Plasmonic Hydrogels. AB - The development of noninvasive technologies for remote control of gene expression has received increased attention for their therapeutic potential in clinical scenarios, including cancer, neurological disorders, immunology, tissue engineering, as well as developmental biology research. Near-infrared (NIR) light is a suitable source of energy that can be employed to pattern transgene expression in plasmonic cell constructs. Gold nanoparticles tailored to exhibit a plasmon surface band absorption peaking at NIR wavelengths within the so called tissue optical window (TOW) can be used as fillers in fibrin-based hydrogels. These biocompatible composites can be loaded with cells harboring heat-inducible gene switches. NIR laser irradiation of the resulting plasmonic cell constructs causes the local conversion of NIR photon energy into heat, achieving spatially restricted patterns of transgene expression that faithfully match the illuminated areas of the hydrogels. In combination with cells genetically engineered to harbor gene switches activated by heat and dependent on a small-molecule regulator (SMR), NIR-responsive hydrogels allow reliable and safe control of the spatiotemporal availability of therapeutic biomolecules in target tissues. PMID- 26965131 TI - Optogenetic Light Crafting Tools for the Control of Cardiac Arrhythmias. AB - The control of spatiotemporal dynamics in biological systems is a fundamental problem in nonlinear sciences and has important applications in engineering and medicine. Optogenetic tools combined with advanced optical technologies provide unique opportunities to develop and validate novel approaches to control spatiotemporal complexity in neuronal and cardiac systems. Understanding of the mechanisms and instabilities underlying the onset, perpetuation, and control of cardiac arrhythmias will enable the development and translation of novel therapeutic approaches. Here we describe in detail the preparation and optical mapping of transgenic channelrhodopsin-2 (ChR2) mouse hearts, cardiac cell cultures, and the optical setup for photostimulation using digital light processing. PMID- 26965133 TI - Optogenetic Engineering of Atrial Cardiomyocytes. AB - Optogenetics is emerging in the cardiology field as a new strategy to explore biological functions through the use of light-sensitive proteins and dedicated light sources. For example, this technology allows modification of the electrophysiological properties of cardiac muscle cells with superb spatiotemporal resolution and quantitative control. In this chapter, the optogenetic modification of atrial cardiomyocytes (aCMCs) from 2-day-old Wistar rats using lentiviral vector (LV) technology and the subsequent activation of the light-sensitive proteins (i.e., ion channels) through light-emitting diodes (LEDs) are described. PMID- 26965132 TI - Inscribing Optical Excitability to Non-Excitable Cardiac Cells: Viral Delivery of Optogenetic Tools in Primary Cardiac Fibroblasts. AB - We describe in detail a method to introduce optogenetic actuation tools, a mutant version of channelrhodopsin-2, ChR2(H134R), and archaerhodopsin (ArchT), into primary cardiac fibroblasts (cFB) in vitro by adenoviral infection to yield quick, robust, and consistent expression. Instructions on adjusting infection parameters such as the multiplicity of infection and virus incubation duration are provided to generalize the method for different lab settings or cell types. Specific conditions are discussed to create hybrid co-cultures of the optogenetically modified cFB and non-transformed cardiomyocytes to obtain light sensitive excitable cardiac syncytium, including stencil-patterned cell growth. We also describe an all-optical framework for the functional testing of responsiveness of these opsins in cFB. The presented methodology provides cell specific tools for the mechanistic investigation of the functional bioelectric contribution of different non-excitable cells in the heart and their electrical coupling to cardiomyocytes under different conditions. PMID- 26965134 TI - A Multichannel Recording System with Optical Stimulation for Closed-Loop Optogenetic Experiments. AB - Selective perturbation of the activity of specific cell types in the brain tissue is essential in understanding the function of neuronal circuits involved in cognition and behavior and might also provide therapeutic neuromodulation strategies. Such selective neuronal addressing can be achieved through the optical activation of light-sensitive proteins called opsins that are expressed in specific cell populations through genetic methods-hence the name "optogenetics." In optogenetic experiments, the electrical activity of the targeted cell populations is optically triggered and monitored using arrays of microelectrodes. In closed-loop studies, the optical stimulation parameters are adjusted based on the recorded activity, ideally in real time. Here we describe the basic tools and the protocols allowing closed-loop optogenic experiments in vivo. PMID- 26965135 TI - Optogenetic Control of Fibroblast Growth Factor Receptor Signaling. AB - FGFR1 is a member of the fibroblast growth factor family, which controls diverse cellular functions such as cell proliferation, migration, and differentiation. OptoFGFR1, an optogenetic method to modulate the FGFR signaling pathway with light by utilizing PHR domain of cryptochrome2 and cytoplasmic region of FGFR1, enabled light-guided activation of FGFR to study its effects on downstream signaling pathway and during diverse biological processes such as cell migration. Here, we describe about optogenetic and microscopic methods to spatiotemporally manipulate FGFR signaling in a single cell or group of cells using confocal microscope and LED array. PMID- 26965136 TI - Protein Inactivation by Optogenetic Trapping in Living Cells. AB - Optogenetic modules that use genetically encoded elements to control protein function in response to light allow for precise spatiotemporal modulation of signaling pathways. As one of optical approaches, LARIAT (Light-Activated Reversible Inhibition by Assembled Trap) is a unique light-inducible inhibition system that reversibly sequesters target proteins into clusters, generated by multimeric proteins and a blue light-induced heterodimerization module. Here we present a method based on LARIAT for optical inhibition of targets in living mammalian cells. In the protocol, we focus on the inhibition of proteins that modulate cytoskeleton and cell cycle, and describe how to transfect, conduct a photo-stimulation, and analyze the data. PMID- 26965137 TI - Optogenetic Manipulation of Selective Neural Activity in Free-Moving Drosophila Adults. AB - Activating selected neurons elicits specific behaviors in Drosophila adults. By combining optogenetics and laser-tracking techniques, we have recently developed an automated laser-tracking and optogenetic manipulation system (ALTOMS) for studying how brain circuits orchestrate complex behaviors. The established ALTOMS can independently target three lasers (473-nm blue laser, 593.5-nm yellow laser, and 1064-nm infrared laser) on any specified body part of two freely moving flies. Triggering light-sensitive proteins in real time, the blue laser and yellow laser can respectively activate and inhibit target neurons in artificial transgenic flies. Since infrared light is invisible to flies, we use the 1064-nm laser as an aversive stimulus in operant learning without perturbing visual inputs. Herein, we provide a detailed protocol for the construction of ALTOMS and optogenetic manipulation of target neurons in Drosophila adults during social interactions. PMID- 26965138 TI - Guidelines for Photoreceptor Engineering. AB - Sensory photoreceptors underpin optogenetics by mediating the noninvasive and reversible perturbation of living cells by light with unprecedented temporal and spatial resolution. Spurred by seminal optogenetic applications of natural photoreceptors, the engineering of photoreceptors has recently garnered wide interest and has led to the construction of a broad palette of novel light regulated actuators. Photoreceptors are modularly built of photosensors that receive light signals, and of effectors that carry out specific cellular functions. These modules have to be precisely connected to allow efficient communication, such that light stimuli are relayed from photosensor to effector. The engineering of photoreceptors benefits from a thorough understanding of the underlying signaling mechanisms. This chapter gives a brief overview of key characteristics and signal-transduction mechanisms of sensory photoreceptors. Adaptation of these concepts in photoreceptor engineering has enabled the generation of novel optogenetic tools that greatly transcend the repertoire of natural photoreceptors. PMID- 26965139 TI - [Not Available]. PMID- 26965140 TI - Reply to the letter by Ali Kagan Coskun et al.: The effects of oxidative stress following ischemia-reperfusion injury. PMID- 26965141 TI - Nicotinic receptor involvement in regulation of functions of mouse neutrophils from inflammatory site. AB - Participation of nicotinic acetylcholine receptors (nAChRs) in functioning of polymorphonuclear neutrophils (PMNs) isolated from inflammatory site of mice and expression of different nAChR subunits were studied. Nicotine and acetylcholine (ACh) modified respiratory burst induced by a chemotactic peptide N-formyl-MLF in neutrophils of male (but not female) mice. Antagonists of nAChRs alpha-cobratoxin (alphaCTX), alpha-conotoxins MII and [A10L]PnIA at concentrations of 0.01-5MUM, 0.2MUM and 1MUM, respectively, eliminated nAChR agonist effects. ACh also affected adhesion of PMNs, this effect was also prevented by alphaCTX (100nM) and MII (1nM). Neutrophils of female mice after chronic nicotine consumption acquired sensitivity to nAChR agonists. Changes of free intracellular Ca(2+) concentration in neutrophils under the action of nAChR ligands were analyzed. In cells with no Ca(2+) oscillations and relatively low resting level of intracellular Ca(2+), nicotine triggered Ca(2+)-spikes, the lag of the response shortened with increasing nicotine concentration. A nicotinic antagonist caramiphen strongly decreased the effect of nicotine. RT-PCR analysis revealed mRNAs of alpha2, alpha3, alpha4, alpha5, alpha6, alpha7, alpha9, beta2, beta3, and beta4 nAChR subunits. Specific binding of [(125)I]-alpha-bungarotoxin was demonstrated. Thus in view of the effects and binding characteristics the results obtained suggest a regulatory role of alpha7, alpha3beta2 or alpha6* nAChR types in specific functions of PMNs. PMID- 26965142 TI - Investigating how the attributes of self-associated drug complexes influence the passive transport of molecules through biological membranes. AB - Relatively little is known about how drug self-association influences absorption into the human body. This study presented two hydrophobic membranes with a series of solutions containing different types of tetracaine aggregates with the aim of understanding how the attributes of supramolecular aggregate formation influenced passive membrane transport. The data showed that aqueous solutions of the unprotonated form of tetracaine displayed a significantly higher (p<0.05) passive membrane transport compared to solutions with mixtures of the unprotonated and protonated drug microspecies (e.g. transport through the skin was 0.96+/ 0.31MUgcm(-2)min(-1) and 1.59+/-0.26MUgcm(-2)min(-1) respectively). However, despite an enhanced rate of drug transport and a better membrane partitioning the unionised molecules showed a significantly longer (p<0.05) lag time to membrane penetration compared solutions rich in the ionised microspecies. Analytical characterisation of the solutions applied to the apical surface of the membranes in the transport studies showed that larger tetracaine aggregates with smaller surface charge gave rise to the longer lag times. These large aggregates demonstrated more extensive intermolecular bonding and therefore, it was suggest that it was the enhanced propensity of the unionised species to form tightly bound drug aggregates that caused the delay in the membrane penetration. PMID- 26965143 TI - Constitutive Activation of DNA Damage Checkpoint Signaling Contributes to Mutant p53 Accumulation via Modulation of p53 Ubiquitination. AB - Many mutant p53 proteins exhibit an abnormally long half-life and overall increased abundance compared with wild-type p53 in tumors, contributing to mutant p53's gain-of-function oncogenic properties. Here, a novel mechanism is revealed for the maintenance of mutant p53 abundance in cancer that is dependent on DNA damage checkpoint activation. High-level mutant p53 expression in lung cancer cells was associated with preferential p53 monoubiquitination versus polyubiquitination, suggesting a role for the ubiquitin/proteasome system in regulation of mutant p53 abundance in cancer cells. Interestingly, mutant p53 ubiquitination status was regulated by ataxia-telangectasia mutated (ATM) activation and downstream phosphorylation of mutant p53 (serine 15), both in resting and in genotoxin-treated lung cancer cells. Specifically, either inhibition of ATM with caffeine or mutation of p53 (serine 15 to alanine) restored MDM2-dependent polyubiquitination of otherwise monoubiquitinated mutant p53. Caffeine treatment rescued MDM2-dependent proteasome degradation of mutant p53 in cells exhibiting active DNA damage signaling, and ATM knockdown phenocopied the caffeine effect. Importantly, in cells analyzed individually by flow cytometry, p53 levels were highest in cells exhibiting the greatest levels of DNA damage response, and interference with DNA damage signaling preferentially decreased the relative percentage of cells in a population with the highest levels of mutant p53. These data demonstrate that active DNA damage signaling contributes to high levels of mutant p53 via modulation of ubiquitin/proteasome activity toward p53. IMPLICATION: The ability of DNA damage checkpoint signaling to mediate accumulation of mutant p53 suggests that targeting this signaling pathway may provide therapeutic gain. Mol Cancer Res; 14(5); 423-36. (c)2016 AACR. PMID- 26965146 TI - Contribution of K(+) channels to endothelium-derived hypolarization-induced renal vasodilation in rats in vivo and in vitro. AB - We investigated the mechanisms behind the endothelial-derived hyperpolarization (EDH)-induced renal vasodilation in vivo and in vitro in rats. We assessed the role of Ca(2+)-activated K(+) channels and whether K(+) released from the endothelial cells activates inward rectifier K(+) (Kir) channels and/or the Na(+)/K(+)-ATPase. Also, involvement of renal myoendothelial gap junctions was evaluated in vitro. Isometric tension in rat renal interlobar arteries was measured using a wire myograph. Renal blood flow was measured in isoflurane anesthetized rats. The EDH response was defined as the ACh-induced vasodilation assessed after inhibition of nitric oxide synthase and cyclooxygenase using L NAME and indomethacin, respectively. After inhibition of small conductance Ca(2+) activated K(+) channels (SKCa) and intermediate conductance Ca(2+)-activated K(+) channels (IKCa) (by apamin and TRAM-34, respectively), the EDH response in vitro was strongly attenuated whereas the EDH response in vivo was not significantly reduced. Inhibition of Kir channels and Na(+)/K(+)-ATPases (by ouabain and Ba(2+), respectively) significantly attenuated renal vasorelaxation in vitro but did not affect the response in vivo. Inhibition of gap junctions in vitro using carbenoxolone or 18alpha-glycyrrhetinic acid significantly reduced the endothelial-derived hyperpolarization-induced vasorelaxation. We conclude that SKCa and IKCa channels are important for EDH-induced renal vasorelaxation in vitro. Activation of Kir channels and Na(+)/K(+)-ATPases plays a significant role in the renal vascular EDH response in vitro but not in vivo. The renal EDH response in vivo is complex and may consist of several overlapping mechanisms some of which remain obscure. PMID- 26965148 TI - Endocannabinoids and endocannabinoid-related mediators: Targets, metabolism and role in neurological disorders. AB - The endocannabinoid system (ECS) is composed of two G protein-coupled receptors (GPCRs), the cannabinoid CB1 and CB2 receptors, and the two main endogenous lipid ligands of such receptors (also known as the "endocannabinoids"), anandamide and 2-arachidonoyl-glycerol. The ECS is a pleiotropic signalling system involved in all aspects of mammalian physiology and pathology, and for this reason it represents a potential target for the design and development of new therapeutic drugs. However, the endocannabinoids as well as some of their congeners also interact with a much wider range of receptors, including members of the Transient Receptor Potential (TRP) channels, Peroxisome Proliferator-Activated Receptors (PPARs), and other GPCRs. Indeed, following the discovery of the endocannabinoids, endocannabinoid-related lipid mediators, which often share the same metabolic pathways of the endocannabinoids, have also been identified or rediscovered. In this review article, we discuss the role of endocannabinoids and related lipids during physiological functions, as well as their involvement in some of the most common neurological disorders. PMID- 26965145 TI - Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance. AB - The transcription factor AP-1 is downstream of growth factor (GF) receptors (GFRs) and stress-related kinases, both of which are implicated in breast cancer endocrine resistance. Previously, we have suggested that acquired endocrine resistance is associated with increased activity of AP-1 in an in vivo model. In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo AP-1 blockade enhanced the antiproliferative effect of endocrine treatments in vitro, accelerated xenograft tumor response to tamoxifen and estrogen deprivation in vivo, promoted complete regression of tumors, and delayed the onset of tamoxifen resistance. Induction of DN-cJun after the development of tamoxifen resistance resulted in dramatic tumor shrinkage, accompanied by reduced proliferation and increased apoptosis. These data suggest that AP-1 is a key determinant of endocrine resistance by mediating a global shift in the ER transcriptional program. IMPLICATIONS: AP-1 represents a viable therapeutic target to overcome endocrine resistance. Mol Cancer Res; 14(5); 470-81. (c)2016 AACR. PMID- 26965147 TI - The adenosine A2B receptor is involved in anion secretion in human pancreatic duct Capan-1 epithelial cells. AB - Adenosine modulates a wide variety of biological processes via adenosine receptors. In the exocrine pancreas, adenosine regulates transepithelial anion secretion in duct cells and is considered to play a role in acini-to-duct signaling. To identify the functional adenosine receptors and Cl(-) channels important for anion secretion, we herein performed experiments on Capan-1, a human pancreatic duct cell line, using open-circuit Ussing chamber and gramicidin perforated patch-clamp techniques. The luminal addition of adenosine increased the negative transepithelial potential difference (V te) in Capan-1 monolayers with a half-maximal effective concentration value of approximately 10 MUM, which corresponded to the value obtained on whole-cell Cl(-) currents in Capan-1 single cells. The effects of adenosine on V te, an equivalent short-circuit current (I sc), and whole-cell Cl(-) currents were inhibited by CFTRinh-172, a cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel inhibitor. The adenosine A2B receptor agonist, BAY 60-6583, increased I sc and whole-cell Cl(-) currents through CFTR Cl(-) channels, whereas the A2A receptor agonist, CGS 21680, had negligible effects. The A2B receptor antagonist, PSB 603, inhibited the response of I sc to adenosine. Immunohistochemical analysis showed that the A2A and A2B receptors colocalized with Ezrin in the luminal membranes of Capan-1 monolayers and in rat pancreatic ducts. Adenosine elicited the whole-cell Cl(-) currents in guinea pig duct cells. These results demonstrate that luminal adenosine regulates anion secretion by activating CFTR Cl(-) channels via adenosine A2B receptors on the luminal membranes of Capan-1 cells. The present study endorses that purinergic signaling is important in the regulation of pancreatic secretion. PMID- 26965150 TI - High expression of growth factor receptor-bound protein 14 predicts poor prognosis for colorectal cancer patients. AB - OBJECTS: To explore the roles of growth factor receptor-bound protein 14 (GRB14) in colorectal cancer (CRC) and its correlation with clinicopathological characteristics and prognosis of CRC patients. RESULTS: GRB14 was localized in the cytoplasm of CRC and benign glandular epithelium cells, showing higher levels in CRC tissues compared with normal colon samples (P < 0.001). High GRB14 was associated with a high pathological grade (P = 0.045), advanced clinical stage (P = 0.018), enhanced tumor invasion (P < 0.001) and lymph node metastasis (P = 0.028). The cancer genome atlas (TCGA) mRNA sequence data showed that GRB14 was upregulated in CRC at an advanced clinical stage (P = 0.011) with enhanced tumor invasion (P < 0.001) and lymph node metastasis (P = 0.014). Kaplan-Meier survival curves revealed that CRC patients with high GRB14 levels had a shorter survival compared with those showing low GRB14 expression (P = 0.007). High GRB14 expression was an independent prognostic factor for CRC patients (HR 2.847, 95 %CI 1.058-7.659; P = 0.038). CONCLUSIONS: GRB14 may be an important cancer promoter that enhances CRC progression. Upregulated GRB14 levels may predict a poor clinical outcome in CRC patients. PMID- 26965149 TI - The role of the gastrointestinal tract and microbiota on uremic toxins and chronic kidney disease development. AB - It is well-established that uremic toxins are positively correlated with the risk of developing chronic kidney disease and cardiovascular disease. In addition, emerging data suggest that gut bacteria exert an influence over both the production of uremic toxins and the development of chronic kidney disease. As such, modifying the gut microbiota may have the potential as a treatment for chronic kidney disease. This is supported by data that suggest that rescuing microbiota dysbiosis may: reduce uremic toxin production; prevent toxins and pathogens from crossing the intestinal barrier; and, reduce gastrointestinal tract transit time allowing nutrients to reach the microbiota in the distal portion of the gastrointestinal tract. Despite emerging literature, the gut kidney axis has yet to be fully explored. A special focus should be placed on examining clinically translatable strategies that might encourage improvements to the microbiome, thereby potentially reducing the risk of the development of chronic kidney disease. This review aims to present an overview of literature linking changes to the gastrointestinal tract with microbiota dysbiosis and the development and progression of chronic kidney disease. PMID- 26965151 TI - Sus scrofa matrix attachment region enhances expression of the PiggyBac system transfected into HEK293T cells. AB - OBJECTIVES: To determine the effects of the Sus scrofa matrix attachment region (SusMAR) on transgene expression in HEK293T cells. RESULTS: Three expression vectors with the MAR at different sites in the PiggyBac (PB) transposon vector backbone were compared: two MARs flanking the beta-galactosidase (beta-gal) expression cassette, and one at the upstream or downstream site. Bos taurus MAR (BosMAR) and a beta-gal expression cassette without MARs were the positive and negative controls, respectively. Compared to the control, beta-gal activity of all SusMAR and BosMAR vectors was significantly improved in the presence of PB transposase (PBase). However, only the downstream SusMAR and upstream BosMAR vectors showed increased expression in the absence of PBase. Expression was significantly increased in all vectors with the PBase group compared to those without the PBase group. Gene copy numbers were not increased compared to the negative control. CONCLUSIONS: SusMAR enhanced recombinant gene expression levels and stability in HEK293T cells, was not increase transgene copy number. These results could facilitate the development of vectors for stable production of therapeutic proteins. PMID- 26965152 TI - Exocrine Pancreatic Insufficiency after Roux-en-Y gastric bypass. AB - BACKGROUND: Gastric resection, short bowel syndrome, and diabetes mellitus are risk factors for development of exocrine pancreatic insufficiency (EPI). Reasons are multifactorial and not completely elucidated. OBJECTIVES: To determine the prevalence of EPI after distal (dRYGB) and proximal Roux-en-Y gastric bypass (pRYGB) and to assess the influence of respective limb lengths. SETTING: University hospital, Switzerland. METHODS: The study comprised 188 consecutive patients who underwent primary dRYGB (common channel<120 cm, biliopancreatic limb 80-100 cm) or pRYGB (alimentary limb = 155 cm, biliopancreatic limb 40-75 cm) and who were followed-up for at least 2 years. Patients with a history of gastrointestinal or hepatobiliary resection (except for cholecystectomy), postoperative pregnancy, and any revision of RYGB (gastric pouch, limb lengths) were excluded. EPI was defined by clinical symptoms in combination with fecal pancreatic elastase-1<200 MUg/g stool or fecal pancreatic elastase-1>200 and<500 MUg/g stool and positive dechallenge-rechallenge test with pancreatic enzyme replacement therapy. RESULTS: Mean follow-up was 52.2 months (range 24-120). Seventy-nine patients (42%) underwent dRYGB, and 109 (58%) underwent pRYGB. Of those, 59 (31%) patients were diagnosed with EPI after a mean 12.5+/-16.3 months. There was a significant difference between dRYGB and pRYGB groups in initial body mass index (dRYGB 47.1+/-8.1 kg/m(2) versus pRYGB 42.7+/-6.1 kg/m(2); P<.01), patients in Obesity Surgery Mortality Risk Score group C (13% versus 3%; P = .02), and prevalence of EPI (48% versus 19%; P<.01). Neither overall small bowel length nor absolute or relative limb lengths were influencing factors on EPI after dRYGB. CONCLUSION: Prevalence of EPI after dRYGB (48%) and pRYGB (19%) is of clinical importance. There was no significant difference in absolute or relative limb lengths between EPI and non-EPI groups after dRYGB. PMID- 26965153 TI - beta-cell pancreatic dysfunction plays a role in hyperglycemic peaks observed after gastric bypass surgery of obese patients. AB - BACKGROUND: Early and intense hyperglycemic peaks are observed after Roux-en-Y gastric bypass (RYGB). OBJECTIVES: The aim of this observational study was to compare the beta-cell pancreatic function of patients with (PEAK) and without hyperglycemic peaks (NOPEAK). SETTING: Referral bariatric surgery center. METHODS: Insulin secretion rate, clearance, and sensitivity and beta-cell and rate sensitivities were computed after a 75-g oral glucose tolerance test in 42 patients who underwent RYGB. RESULTS: PEAK patients (n = 18; 30-min glycemia>10.4 mmol/L) did not differ from NOPEAK patients (n = 24) in their presurgery or weight loss characteristics. PEAK patients had significantly higher plasma concentrations of glucose and C-peptide than did NOPEAK patients, whereas insulin and glucagon-like peptide-1 concentrations did not differ. The insulin secretion rate and whole-body insulin clearance (208%) were significantly greater, but insulin sensitivity was significantly less (48%) in PEAK patients. Insulin secretion normalized to plasma glucose was significantly lower in PEAK patients, and the disposition index was reduced (35% to 41% of the values in NOPEAK patients). CONCLUSION: We conclude that RYGB reveals a series of dysfunctions leading to hyperglycemia in a subset of patients. In PEAK patients, an insufficient adaptation of beta-cell function to glycemia, an increased insulin clearance, and a decreased insulin sensitivity cumulated to contribute to hyperglycemic peaks. PMID- 26965154 TI - Bariatric Surgery: The Rise and Fall of Bile Acids. PMID- 26965155 TI - Use of noninvasive markers to predict advanced fibrosis/cirrhosis in severe obesity. AB - BACKGROUND: Nonalcoholic steatohepatitis is observed in 25%-55% of patients with severe obesity and in 2%-12% with bridging fibrosis or cirrhosis. There is currently no noninvasive test for the diagnosis of severe liver fibrosis before bariatric surgery. OBJECTIVES: To determine the best noninvasive test for predicting advanced liver disease in patients with severe obesity. SETTING: University tertiary care hospital, Brazil. METHODS: A cross-sectional retrospective study was conducted with 699 patients with severe obesity undergoing bariatric surgery: 568 without a biopsy (nonbiopsy cohort) and 131 patients who had undergone an intraoperative liver biopsy. The tissues were subjected to histologic diagnosis (Brunt criteria) and classified as advanced fibrosis (stages 3 and 4) or no significant fibrosis (absence of nonalcoholic steatohepatitis and stages 1 or 2). The following predictive indices of cirrhosis were calculated in all patients: aspartate aminotransferase/alanine aminotransferase ratio (AAR), age-platelet (AP) index, aminotransferase-to platelet ratio index (APRI), cirrhosis discriminant score (CDS), and hepatitis C antiviral long-term treatment against cirrhosis (HALT-C). The cutoff values, sensitivity, specificity, and areas under the receiver operating characteristic curves (AUROCs) were calculated for patients with biopsies. RESULTS: The AUROC of the AAR, AP, APRI, CDS, and HALT-C model for predicting advanced fibrosis or cirrhosis were, respectively, .522, .88, .99, .905, and .921. The calculated cutoff values, sensitivity, and specificity, respectively, were as follows: AAR: .94, .7, .45; AP 5, .7, .93; APRI .44, 1.0, .97; CDS 6, .7, .97; and HALT-C: .76, 1.0, .77. CONCLUSION: APRI index was the best predictor of advanced liver disease in patients with severe obesity. PMID- 26965156 TI - The effect of sleeve gastrectomy on extraesophageal reflux disease. AB - BACKGROUND: Sleeve gastrectomy (SG) has been linked to increased rates of postoperative gastroesophageal reflux. OBJECTIVE: The aim of this study was to evaluate whether SG is also linked to increased pulmonary extraesophageal reflux disease in a rodent model, based on histologic inflammatory distal airway changes. SETTING: University hospital. METHODS: Wistar rats (Charles River Institute, Wilmington, MA) were fed a high fat diet (HFD) for 4 months. They were divided into HFD only (n = 25) and SG+HFD (n = 19) groups and euthanized at 12 weeks, and the trachea and lungs were harvested en bloc then preserved for analysis by a blinded board-certified pathologist. RESULTS: Rats who underwent SG were significantly less likely to show postmortem distal airway changes (4.0% versus 31.0%, P = .03), had a lower average chronic aspiration pneumonitis grade (.73 versus 1.57, P = .006), and had a lower total lung injury score (1.19 versus 2.28, P = .005). Alveolar hemorrhage was also less common in the SG+HFD group (37.5% versus 80.0%, P = .006). CONCLUSION: SG is associated with increased incidence of normal lung histology on postmortem examination, less evidence of chronic aspiration pneumonitis and alveolar hemorrhage, and decreased total lung injury score in a rodent model. SG appears to have a protective effect on the pulmonary system. This suggests that SG does not exacerbate extraesophageal reflux effects on the pulmonary epithelium. PMID- 26965159 TI - Additive effects of Artemisia capillaris extract and scopoletin on the relaxation of penile corpus cavernosum smooth muscle. PMID- 26965158 TI - Preoperative predictors of adherence to dietary and physical activity recommendations and weight loss one year after surgery. AB - BACKGROUND: Weight loss and weight loss maintenance vary considerably between patients after bariatric surgery. Postoperative weight gain has partially been explained by lack of adherence to postoperative dietary and physical activity recommendations. However, little is known about factors related to postoperative adherence. OBJECTIVES: The aim of this study was to examine psychological, behavioral, and demographic predictors of adherence to behavior recommendations and weight loss 1 year after bariatric surgery. SETTING: Oslo University Hospital. METHODS: In a prospective cohort study, 230 patients who underwent Roux en-Y gastric bypass were recruited from Oslo University hospital from 2011 to 2013. They completed a comprehensive questionnaire before and 1 year after surgery. Weight was measured preoperatively, on the day of surgery, and 1-year postoperatively. RESULTS: Mean body mass index was 44.9 kg/m(2) (standard deviation [SD] = 6.0) preoperatively and 30.6 kg/m(2) (SD = 5.2) 1 year after surgery. Patients lost on average 29.2 % (SD = 8.2) of their initial weight. Predictors of dietary adherence were years with dieting experience, readiness to limit food intake, and night eating tendency. Preoperative physical activity and planning predicted postoperative physical activity whereas predictors of weight loss were higher frequency of snacking preoperatively, greater past weight loss, and lower age. CONCLUSION: Several preoperative psychological predictors were related to postoperative adherence to dietary and physical activity recommendations but were not associated with weight loss. Interventions targeting psychological factors facilitating behavior change during the initial postoperative phase are recommended as this might improve long-term outcomes. PMID- 26965157 TI - One or two steps for laparoscopic conversion of failed adjustable gastric banding to sleeve gastrectomy: a nationwide French study on 3357 morbidly obese patients. AB - BACKGROUND: Adjustable gastric banding (AGB) has been a very common bariatric procedure, but long-term AGB related complications have led to an increased number of second procedures. Sleeve gastrectomy (SG) is one option and can be done as a 1- or 2-step procedure. OBJECTIVES: To compare the 1-step and 2-step approachs of conversion of AGB to SG with respect to postoperative mortality and morbidity. SETTING: Nationwide study, France. METHODS: All morbidly obese patients who underwent AGB followed by SG in France between 2007 and 2012 were included. Multivariate analyses were conducted using the French National Health Service Database data to ascertain predictive factors for 90-day postoperative mortality and morbidity. RESULTS: There were 2061 and 1296 patients in the 1-step and 2-step conversion groups, respectively. The readmission rate was 22.8% and 16.5% in the 1- and 2-step groups, respectively (P<.001). More patients required an intensive care unit stay in the 1-step group (11.7 % versus 6.7%; P<.001). The 90-day mortality was .1%, with no difference between the 2 groups (1% versus .08%). The complication rate was 14.7% (1-step 15.9% versus 2-step 12.7%; P = .009). The timing of AGB removal (P = .02), patient age 50-60 years (P = .004), hypertension (P = .01), surgical approach (P = .002), and hospital status (P = .015) were significantly associated with the complication rate. CONCLUSION: This study indicates that the 2-step conversion of failed AGB to SG results in a significantly reduced rate of postoperative staple line leaks, gastric tube stricture, respiratory complication, and need for intensive care unit stay. PMID- 26965160 TI - Factors predicting outcomes of penile rehabilitation with udenafil 50 mg following radical prostatectomy. PMID- 26965161 TI - Hand pains in women and men in early rheumatoid arthritis, a one year follow-up after diagnosis. The Swedish TIRA project. AB - Purpose This research analysed general pain intensity, hand pain at rest and hand pain during activity in women and men in early rheumatoid arhtritis (RA). Method Out of the 454 patients that were recruited into the Swedish early RA project "TIRA" the 373 patients (67% women) that remained at 12 months follow-up are reported here. Disease activity 28 joint score (DAS-28), disability (Health Assessment Questionnaire = HAQ) and pain (VAS) were recorded at inclusion and after 3 (M3), 6 (M6) and 12 (M12) months. General pain, hand pain during rest, hand pain during test of grip force as assessed by GrippitTM, prescribed disease modifying anti-inflammatory drugs (DMARDs) and hand dominance were recorded. Results DAS-28 and HAQ scores were high at inclusion and improved thereafter in both women and men. There were no significant differences between sexes at inclusion but women had higher DAS-28 and HAQ at all follow-ups. Women were more often prescribed DMARDs than were men. In both women and men all pain types were significantly lower at follow-up compared to at inclusion and women reported higher pain than men at follow-ups. The pain types differed significantly from each other at inclusion into TIRA, general pain was highest and hand pain during rest was lowest. There were no significant differences in hand pain related to hand dominance or between right and left hands. Conclusions Disease activity, disability and pain were high at inclusion and reduced over the first year. Despite more DMARDs prescribed in women than in men, women were more affected than were men. General pain was highest and not surprisingly hand pain during active grip testing was higher than hand pain during rest that was lowest in both sexes. Although our cohort was well controlled, it was evident that hand pain remains a problem. This has implications for rehabilitation and suggests potential ongoing activity limitations that should continue to receive attention from a multi-professional team. Implications for Rehabilitation General pain and hand pain remain a problem in RA despite today's early intervention and effective disease control with new era biologics. The extent of hand pain evidenced in our work gives a more detailed and comprehensive account of pain status. Higher hand pain during active grip testing than that during rest indicates a potential relationship to ongoing activity limitation. Hand pain assessment can help guiding multi-professional interventions directed to reduce hand pain and thereby probably reduce activity limitations. PMID- 26965162 TI - Differential Mobility Spectrometry-Hydrogen Deuterium Exchange (DMS-HDX) as a Probe of Protein Conformation in Solution. AB - Differential mobility spectrometry (DMS) is an ion mobility technique that has been adopted chiefly as a pre-filter for small- to medium-sized analytes (<1 000 Da). With the exception of a handful of studies that employ an analogue of DMS field asymmetric waveform ion mobility spectroscopy (FAIMS)-the application of DMS to intact biomacromolecules remains largely unexplored. In this work, we employ DMS combined with gas-phase hydrogen deuterium exchange (DMS-HDX) to probe the gas-phase conformations generated from proteins that were initially folded, partially-folded, and unfolded in solution. Our findings indicate that proteins with distinct structural features in solution exhibit unique deuterium uptake profiles as function of their optimal transmission through the DMS. Ultimately we propose that DMS-HDX can, if properly implemented, provide rapid measurements of liquid-phase protein structural stability that could be of use in biopharmaceuticals development. Graphical Abstract ?. PMID- 26965163 TI - Multifunctional Guide for Implant Placement, Impressions, and an Occlusal Index for Fixed Complete Dentures. AB - This article proposes an approach to simplify the steps and reduce fabrication time for fixed implant-supported complete dentures. A multifunctional guide can function as a surgical template during implant placement and provides a framework for the definitive impression and occlusal registration. It therefore enables immediate or early loading of dental implants in full-arch rehabilitations. PMID- 26965166 TI - Can a total knee arthroplasty be both rotationally unconstrained and anteroposteriorly stabilised? A pulsed fluoroscopic investigation. AB - OBJECTIVES: Throughout the 20th Century, it has been postulated that the knee moves on the basis of a four-bar link mechanism composed of the cruciate ligaments, the femur and the tibia. As a consequence, the femur has been thought to roll back with flexion, and total knee arthroplasty (TKA) prostheses have been designed on this basis. Recent work, however, has proposed that at a position of between 0 degrees and 120 degrees the medial femoral condyle does not move anteroposteriorly whereas the lateral femoral condyle tends, but is not obliged, to roll back - a combination of movements which equates to tibial internal/ femoral external rotation with flexion. The aim of this paper was to assess if the articular geometry of the GMK Sphere TKA could recreate the natural knee movements in situ/in vivo. METHODS: The pattern of knee movement was studied in 15 patients (six male: nine female; one male with bilateral TKAs) with 16 GMK Sphere implants, at a mean age of 66 years (53 to 76) with a mean BMI of 30 kg/m(2) (20 to 35). The motions of all 16 knees were observed using pulsed fluoroscopy during a number of weight-bearing and non-weight-bearing static and dynamic activities. RESULTS: During maximally flexed kneeling and lunging activities, the mean tibial internal rotation was 8 degrees (standard deviation (sd) 6). At a mean 112 degrees flexion (sd 16) during lunging, the medial and lateral condyles were a mean of 2 mm (sd 3) and 8 mm (sd 4) posterior to a transverse line passing through the centre of the medial tibial concavity. With a mean flexion of 117 degrees (sd 14) during kneeling, the medial and lateral condyles were a mean of 1 mm (sd 4) anterior and 6 mm (sd 4) posterior to the same line. During dynamic stair and pivoting activities, there was a mean anteroposterior translation of 0 mm to 2 mm of the medial femoral condyle. Backward lateral condylar translation occurred and was linearly related to tibial rotation. CONCLUSION: The GMK Sphere TKA in our study group shows movements similar in pattern, although reduced in magnitude, to those in recent reports relating to normal knees during several activities. Specifically, little or no translation of the medial femoral condyle was observed during flexion, but there was posterior roll-back of the lateral femoral condyle, equating to tibiofemoral rotation. We conclude that the GMK Sphere is anteroposteriorly stable medially and permits rotation about the medial compartment.Cite this article: Professor G. Scott. Can a total knee arthroplasty be both rotationally unconstrained and anteroposteriorly stabilised?: A pulsed fluoroscopic investigation. Bone Joint Res 2016;5:80-86. DOI: 10.1302/2046-3758.53.2000621. PMID- 26965167 TI - Responsiveness and ceiling effects of the Forgotten Joint Score-12 following total hip arthroplasty. AB - OBJECTIVES: To assess the responsiveness and ceiling/floor effects of the Forgotten Joint Score -12 and to compare these with that of the more widely used Oxford Hip Score (OHS) in patients six and 12 months after primary total hip arthroplasty. METHODS: We prospectively collected data at six and 12 months following total hip arthroplasty from 193 patients undergoing surgery at a single centre. Ceiling effects are outlined with frequencies for patients obtaining the lowest or highest possible score. Change over time from six months to 12 months post-surgery is reported as effect size (Cohen's d). RESULTS: The mean OHS improved from 40.3 (sd 7.9) at six months to 41.9 (sd 7.2) at 12 months. The mean FJS-12 improved from 56.8 (sd 30.1) at six months to 62.1 (sd 29.0) at 12 months. At six months, 15.5% of patients reached the best possible score (48 points) on the OHS and 8.3% obtained the best score (100 points) on the FJS-12. At 12 months, this percentage increased to 20.8% for the OHS and to 10.4% for the FJS 12. In terms of the effect size (Cohen's d), the change was d = 0.10 for the OHS and d = 0.17 for the FJS-12. CONCLUSIONS: The FJS-12 is more responsive to change between six and 12 months following total hip arthroplasty than is the OHS, with the measured ceiling effect for the OHS twice that of the FJS-12. The difference in effect size of change results in substantial differences in required sample size if aiming to detect change between these two time points. This has important implications for powering clinical trials with patient-reported measures as the primary outcome.Cite this article: Dr D. F. Hamilton. Responsiveness and ceiling effects of the Forgotten Joint Score-12 following total hip arthroplasty. Bone Joint Res 2016;5:87-91. DOI: 10.1302/2046-3758.53.2000480. PMID- 26965165 TI - Diet and exercise in uterine cancer survivors (DEUS pilot) - piloting a healthy eating and physical activity program: study protocol for a randomized controlled trial. AB - BACKGROUND: Endometrial cancer survivors comprise a high-risk group for obesity related comorbidities. Healthy eating and physical activity can lead to better health and well-being, but this population may experience difficulties adopting healthy lifestyle practices. Personalised behaviour change programmes that are feasible, acceptable and cost-effective are needed. The aim of this trial is to pilot a manualised programme about healthy eating and physical activity. METHODS/DESIGN: This is a phase II, individually randomized, parallel, controlled, two-site, pilot clinical trial. Adult endometrial cancer survivors (n = 64) who have been diagnosed with endometrial cancer within the previous 3 years and are not on active treatment will be invited to participate. Participants will be assigned in a 1:1 ratio through minimisation to either an 8-week, group-based, behaviour-change programme with weekly 90-min sessions about healthy eating and physical activity or usual care. The intervention will focus on self-monitoring, goal setting and self-rewards. Follow-up assessments will be conducted at 8 and 24 weeks from the baseline assessment. Primary feasibility outcomes will include rates of recruitment, adherence, and retention. DISCUSSION: The study results will inform the development of a definitive randomised controlled trial to test if the programme can improve the health and quality of life of this population. It will also provide guidance on costing the intervention and the health care resource use in this population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02433080, 20 April 2015. PMID- 26965164 TI - A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20. AB - Congenital heart defects involving left-sided lesions (LSLs) are relatively common birth defects with substantial morbidity and mortality. Previous studies have suggested a high heritability with a complex genetic architecture, such that only a few LSL loci have been identified. We performed a genome-wide case-control association study to address the role of common variants using a discovery cohort of 778 cases and 2756 controls. We identified a genome-wide significant association mapping to a 200 kb region on chromosome 20q11 [P= 1.72 * 10-8 for rs3746446; imputed Single Nucleotide Polymorphism (SNP) rs6088703 P= 3.01 * 10-9, odds ratio (OR)= 1.6 for both]. This result was supported by transmission disequilibrium analyses using a subset of 541 case families (lowest P in region= 4.51 * 10-5, OR= 1.5). Replication in a cohort of 367 LSL cases and 5159 controls showed nominal association (P= 0.03 for rs3746446) resulting in P= 9.49 * 10-9 for rs3746446 upon meta-analysis of the combined cohorts. In addition, a group of seven SNPs on chromosome 1q21.3 met threshold for suggestive association (lowest P= 9.35 * 10-7 for rs12045807). Both regions include genes involved in cardiac development-MYH7B/miR499A on chromosome 20 and CTSK, CTSS and ARNT on chromosome 1. Genome-wide heritability analysis using case-control genotyped SNPs suggested that the mean heritability of LSLs attributable to common variants is moderately high ([Formula: see text] range= 0.26-0.34) and consistent with previous assertions. These results provide evidence for the role of common variation in LSLs, proffer new genes as potential biological candidates, and give further insight to the complex genetic architecture of congenital heart disease. PMID- 26965168 TI - Plasma glutamine levels in patients after non-elective or elective ICU admission: an observational study. AB - BACKGROUND: A low plasma glutamine level at the time of acute admission to the intensive care unit (ICU) is an independent predictor of an unfavourable outcome in critically ill patients. The primary objective of this study was to determine whether there are differences in plasma glutamine levels upon non-elective or elective ICU admission. The secondary objective was to compare glutamine levels over time, and to determine correlations between glutamine levels and the severity of illness and presence of infection in ICU patients. METHODS: We performed a single-centre observational study in a closed-format, 22-bed, mixed ICU. Plasma glutamine levels were measured at admission and every morning at 6.00 a.m. during the ICU stay. We aimed to include at least 80 patients per group. The study was approved by the local Medical Ethics Committee. RESULTS: In 88 patients after elective surgery, the median plasma glutamine level at admission was significantly higher compared with that in 90 non-elective patients (0.43 mmol/l [0.33-0.55 mmol/l] versus 0.25 mmol/l [0.09-0.37 mmol/l], P = 0.001). During the ICU stay, plasma glutamine levels remained significantly higher in elective patients than in non-elective patients. There was a significant correlation between the APACHE IV score and glutamine levels (R = 0.52, P < 0.001). Moreover, backward linear regression analysis showed that this correlation was independently associated with the APACHE IV score and the presence of infection, but not with the type of admission. CONCLUSIONS: Plasma glutamine levels are significantly lower after non-elective admission compared with elective admission to the ICU. A considerable amount of elective and non-elective patients have decreased plasma glutamine levels, but this is not independently associated with the type of admission. In contrast to previous studies, we found that plasma glutamine levels were determined by the severity of illness and the presence of an infection. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02310035. PMID- 26965169 TI - Transcutaneous bilirubin monitoring predicts unexplained late-onset hemolysis in a very low birthweight infant. AB - BACKGROUND: In term infants, transcutaneous bilirubin (TcB) monitoring can be used to predict hemolytic hyperbilirubinemia. However, it is not clear whether the technique can also be used to predict unexplained late-onset hemolysis in very low birthweight (VLBW) infants. CASE PRESENTATION: The case was an infant with a birthweight of 1154 g who developed unexplained late-onset hemolysis at 8 days of age. The hyperbilirubinemia rapidly worsened, and therefore both phototherapy and exchange transfusion were performed. TcB levels were measured using the JM-105 jaundice meter and found to have increased by >3 mg/dL since before the onset, demonstrating for the first time that the device clearly detects changes in hemolytic rate. CONCLUSIONS: Although TcB levels did not correspond directly with total serum bilirubin levels in VLBW infants, the two values exhibited parallel changes in this case. Therefore, serial TcB monitoring may be useful in the early prediction of unexplained late-onset hemolysis in VLBW infants. PMID- 26965170 TI - Immunohistochemical expression of glucose transporter 1 in keratin-producing odontogenic cysts. AB - BACKGROUND: Keratin-producing odontogenic cysts (KPOCs) are a group of cystic lesions that are often aggressive, with high rates of recurrence and multifocality. KPOCs included orthokeratinised odontogenic cyst (OOC) and parakeratotic odontogenic cysts, which are now considered true tumours denominated keratocystic odontogenic tumours (KCOTs). GLUT1 is a protein transporter that is involved in the active uptake of glucose across cell membranes and that is overexpressed in tumours in close correlation with the proliferation rate and positron emission tomography (PET) imaging results. METHODS: A series of 58 keratin-producing odontogenic cysts was evaluated histologically and immunohistochemically in terms of GLUT1 expression. Different data were correlated using the beta regression model in relation to histological type and immunohistochemical expression of GLUT1, which was quantified using two different morphological methods. RESULTS: KPOC cases comprised 12 OOCs and 46 KCOTs, the latter corresponding to 6 syndromic and 40 sporadic KCOTs. GLUT1 expression was very low in OOC cases compared with KCOT cases, with statistical significant differences when quantification was considered. Different GLUT1 localisation patterns were revealed by immunostaining, with the parabasal cells showing higher reactivity in KCOTs. However, among KCOTs cases, GLUT1 expression was unable to establish differences between syndromic and sporadic cases. CONCLUSIONS: GLUT1 expression differentiated between OOC and KCOT cases, with significantly higher expression in KCOTs, but did not differentiate between syndromic and sporadic KCOT cases. However, given the structural characteristics of KCOTs, we hypothesised that PET imaging methodology is probably not a useful diagnostic tool for KCOTs. Further studies of GLUT1 expression and PET examination in KCOT series are needed to confirm this last hypothesis. PMID- 26965171 TI - Species composition, activity patterns and blood meal analysis of sand fly populations (Diptera: Psychodidae) in the metropolitan region of Thessaloniki, an endemic focus of canine leishmaniasis. AB - Species composition, activity patterns and blood meal analysis of sand fly populations were investigated in the metropolitan region of Thessaloniki, North Greece from May to October 2011. Sampling was conducted weekly in 3 different environments (animal facilities, open fields, residential areas) along the outskirts of the city in areas of increased canine leishmania transmission. Six sand fly species (Phlebotomus perfiliewi, Phlebotomus tobbi, Phlebotomus simici, Plebotomus papatasi, Sergentomya minuta and Sergentomya dentata) were identified using both classical and molecular techniques. DNA barcodes were characterized for the first time for two (P. simici and S. dentata) of the six recorded species. Phylogenetic analysis based on the COI gene sequences confirmed the grouping of P. tobbi, P. perniciosus and P. perfiliewi (subgenus Larrousius) and the monophyly of P. simici (subgenus Adlerius). By far the most prevalent species was P. perfiliewi, followed by P. simici and P. tobbi. The largest populations of sand flies were collected from animal facilities, followed by residential areas and open agricultural fields. Peak activity of sand flies overall occurred mid August to mid-September and then declined sharply in October. Blood meal analysis showed that P. perfiliewi and P. simici feed preferentially on humans (88% & 95%, respectively) but also feed on chickens and goats. When designing a control strategy to alleviate sand fly nuisance in the region of Thessaloniki the following conclusions can be reached from this study: a) August and September are high risk months due to increased sand fly activity levels, b) animal facilities within or adjacent to urban settlements are high risk areas and may act as a maintenance and amplification foci for the vector as well as the parasite, and c) the abundance, ubiquity and feeding behavior of P. perfiliewi and P. simici establishes them as potentially important vectors of Leishmania in the region. PMID- 26965172 TI - Inhibition of Setaria cervi protein tyrosine phosphatases by Phenylarsine oxide: A proteomic and biochemical study. AB - Phenylarsine oxide (PAO), a specific protein tyrosine phosphatase (PTP) inhibitor significantly decreased the motility and viability of Setaria cervi ultimately leading to its death. The PTP activity present in the cytosolic and detergent soluble fractions as well as on surface of these parasites was significantly inhibited by PAO. A marked alteration in protein spots abundance after proteomic analysis showed 14 down-regulated and 9 upregulated spots in the treated parasites as compared to the control. The PTP inhibition led to increase in the cytosolic and mitochondrial calpain activity in these parasites. PAO also blocked the ATP generation in the parasite depicted by reduced activity of phosphoglycerate kinase and expression of enolase. An increased ROS level, induced lipid peroxidation/protein carbonyl formation and decreased activity of different antioxidant enzymes like thioredoxin reductase, glutathione reductase and glutathione transferases was also observed in the PAO treated parasites. PAO, thus disturbs the overall homeostasis of the filarial parasite by inhibiting PTPs. Thereby suggesting that these molecules could be used as a good chemotherapeutic target for lymphatic filariasis. PMID- 26965174 TI - Integrated Cognitive Behavioral Intervention Reduces Intimate Partner Violence Among Alcohol Dependent Men, and Improves Mental Health Outcomes in their Spouses: A Clinic Based Randomized Controlled Trial from South India. AB - BACKGROUND AND AIM: Alcohol abuse has been associated with intimate partner violence (IPV). The current study examined the effectiveness of an integrated cognitive-behavioral intervention (ICBI) in reducing intimate partner violence (IPV) perpetration among alcohol dependent men, and improving mental health outcomes among their wives and children. METHODS: One hundred seventy-seven alcohol dependent male inpatients who screened positive for IPV perpetration in the last 6 months were randomly assigned to receive ICBI which addressed both the alcohol use and IPV (n=88), or TAU (TAU: treatment as usual) (n=89). The ICBI sessions were attended by the patients alone. All patients and their spouses were followed up over 3 months following discharge from the treatment centre. RESULTS: Compared to TAU participants in the ICBI group reported significantly lower IPV perpetration, and their wives scored significantly lower on depression, anxiety, and stress levels at 3-month follow up. Alcohol consumption in the men and emotional and behavioral problems in their children were not significantly different between the groups, from baseline to follow up. CONCLUSIONS: Findings demonstrate the feasibility and effectiveness of an ICBI which addressed both the IPV and alcohol use in a coordinated manner in a vulnerable sample. PMID- 26965175 TI - Acute liver failure due to primary amyloidosis in a nephrotic syndrome: a swiftly progressive course. AB - AL amyloidosis is a clonal plasma cell proliferative disorder characterised by extracellular tissue deposits of insoluble fibrils derived from kappa or lambda immunoglobulin light chains. The most common organs affected by AL amyloidosis are the kidney, presenting with nephrotic syndrome and/or progressive renal dysfunction, and the heart, with restrictive cardiomyopathy. Hepatic deposition of fibrils occurs in half the cases but the liver is rarely the predominantly affected organ. The most common presentation of hepatic amyloidosis is hepatomegaly with elevated alkaline phosphatase. Acute liver failure with cholestasis and jaundice is a rare complication, with a prevalence of approximately 5%, and is usually associated with a worse prognosis. We report a case of a 39-year-old man admitted to our nephrology department with an unusual presentation of primary amyloidosis with nephrotic syndrome and acute liver failure, complicated by obstructive cholestasis resulting in death 2 months after diagnosis. PMID- 26965178 TI - Effect of Calcium beta-Hydroxy-beta-Methylbutyrate (CaHMB), Vitamin D, and Protein Supplementation on Postoperative Immobilization in Malnourished Older Adult Patients With Hip Fracture: A Randomized Controlled Study. AB - BACKGROUND: Nutrition support in orthopedic patients with malnutrition shortens the immobilization period. The efficacy of calcium beta-hydroxy-beta methylbutyrate (CaHMB), vitamin D, and protein intake on bone structure is studied and well known; however, there is no evidence supporting the effect of combined use in orthopedic conditions. We investigated the effects of CaHMB, vitamin D, and protein supplementation on wound healing, immobilization period, muscle strength, and laboratory parameters. MATERIALS AND METHODS: This randomized controlled study included 75 older female patients with a hip fracture admitted to orthopedic clinics. The control group received standard postoperative nutrition. The study group received an enteral product containing 3 g CaHMB, 1000 IU vitamin D, and 36 g protein, in addition to standard postoperative nutrition. Anthropometric, laboratory, wound-healing, immobilization period, and muscle strength assessments were evaluated preoperatively and on postoperative days 15 and 30. RESULTS: Wound-healing period was significantly shorter in the CaHMB/vitamin D/protein group than in the control group ( P < .05). The number of patients in the CaHMB/vitamin D/protein group who were mobile on days 15 and 30 (81.3%) was significantly higher than patients in the control group, who were mobile on days 15 and 30 (26.7%) ( P = .001). Muscle strength on day 30 was significantly higher in the CaHMB/vitamin D/protein group vs the control group. CONCLUSION: Nutrition of elderly patients with a CaHMB/vitamin D/protein combination led to acceleration of wound healing, shortening of immobilization period, and increased muscle strength without changing body mass index. It also reduced dependence to bed and related complications after an orthopedic operation. PMID- 26965176 TI - Adiponectin improves NF-kappaB-mediated inflammation and abates atherosclerosis progression in apolipoprotein E-deficient mice. AB - BACKGROUND: Atherosclerosis is a common pathological basis of cardiovascular disease. Adiponectin (APN) has been shown to have an anti-atherosclerosis effect, and the underlying mechanisms, however, are largely unknown. Nuclear factor kappaB (NF-kappaB) has also been regarded as a proatherogenic factor, mainly because of its regulation of a variety of the proinflammatory genes linked to atherosclerosis. It was hypothesized that the inhibitory effects of adiponectin on the atherosclerosis is through the inhibition of NF-kappaB signaling pathway. METHODS: We injected adenovirus of Ad-eGFP virus (control group) or the same amount of Ad-APN-eGFP virus (APN group) in ApoE(-/-) mice tail-intravenously. Blood samples and aorta were executed at 0 day, 4, and 8 week of high-fat diet feeding. Histopathological changes of aortic arch root were detected. Levels of TC, TG, HDL-C, LDL-C were measured. Adiponectin and Matrix metalloproteinases-9 (MMP-9) concentration were detected by enzyme-linked immunosorbent assay. Gene and protein levels of adiponectin, eNOS, IL-6, MCP-1,VCAM-1, and other inflammatory factors were determined. Adiponectin, NF-kappaB p65 in aortic arch root were determined by immunofluorescence and western blot. RESULTS: Transduction of Ad-APN inhibited the formation of atherosclerotic plaque in aorta when compared with control group. The lesion formation in aortic arch root was inhibited significantly (P < 0.01). Lesion lumen ratio decreased significantly (P < 0.001). The expression of adiponectin attenuated the increases of serum TC (P < 0.001), TG (P < 0.001), and LDL-C (P < 0.001) induced by the high-fat diet, and the increase in body weight (P < 0.05). As increasing serum adiponectin, the levels of MMP-9 were significantly decreased (P < 0.05). The exogenous adiponectin increased the gene expression of the anti-inflammatory factors eNOS (P < 0.05) and IL-10 (P < 0.001), and reduced the gene expression of inflammatory factors tumor necrosis factor-alpha (TNF-alpha) (P < 0.001), IL-6 (P < 0.001), VCAM-1 (P < 0.05), respectively. Adiponectin effectively inhibited the activation of NF-kappaB pathway and the expression of NF-kappaB nuclear protein p65. CONCLUSIONS: Adiponectin may protect the aorta from atherosclerotic injury by reducing inflammation. The molecular mechanism may involve inhibited the expression of downstream components of NF-kappaB and its transcription factors. PMID- 26965173 TI - Familial autoimmunity in the Childhood Arthritis and Rheumatology Research Alliance registry. AB - BACKGROUND: Clinically distinct autoimmune phenotypes share genetic susceptibility factors. We investigated the prevalence of familial autoimmunity among subjects with juvenile idiopathic arthritis (JIA), childhood systemic lupus erythematosus (cSLE) and juvenile dermatomyositis (JDM) in the CARRA Registry, the largest multicenter observational Registry for pediatric rheumatic disease. METHODS: Children with JIA, cSLE and JDM enrolled in the CARRA Registry between May 2010 and May 2012 were investigated for differences in proportion of subjects who had first-degree relatives (FDR) with autoimmunity. If a significant difference was detected, pairwise comparisons, adjusted for multiple comparisons, were made. RESULTS: There were 4677 JIA, 639 cSLE and 440 JDM subjects. The proportion of subjects having FDR with any autoimmune disease in the JDM group (20.5 %) was less compared to subjects with JIA (31.8 %, p < 0.001) or SLE (31.9 %; p < 0.001). Significantly greater proportion of JIA cases had FDR with inflammatory arthritis (13 %) compared to cSLE (9.2 %, p = 0.007) or JDM (4.3 %, p <0.001). Significantly greater proportion of cSLE cases had FDR with SLE (11.1 % vs. 1.7 % for JIA and 1.1 % for JDM p < 0.001) or type-I diabetes (7.4 % for cSLE vs. 3.1 % for JIA and 3.0 % for JDM p < 0.001). CONCLUSION: Higher proportions of subjects with JIA and cSLE have FDR with autoimmunity compared to those of JDM. Relatives of cSLE cases had an increased prevalence of SLE, and relatives of JIA cases were enriched for inflammatory arthropathies demonstrating distinct patterns of familial autoimmunity among these phenotypes. PMID- 26965181 TI - Polarization induced Z2 and Chern topological phases in a periodically driving field. AB - Z2 and Chern topological phases such as newly discovered quantum spin Hall and original quantum Hall states hardly both co-exist in a single material due to their contradictory requirement on the time-reversal symmetry (TRS). We show that although the TRS is broken in systems with a periodically driving field, an effective TRS can still be defined provided the ac-field is linearly polarized or certain other conditions are satisfied. The controllable TRS provides us a route to manipulate contradictory phases by tuning the polarization. To demonstrate the idea, we consider a tight-binding model that is relevant to several monolayered materials as a benchmark system. Our calculation shows not only topological Z2 to Chern phase transition occurs but rich Chern phases are also observed. In addition, we also discussed the realization of our proposal in real materials, such as spin-orbit coupled graphene and crystal Bismuth. This opens the possibility of manipulating various topological phases in a single material and can be a promising approach to engineer new electronic states of matter. PMID- 26965182 TI - Furfural Determination with Disposable Polymer Films and Smartphone-Based Colorimetry for Beer Freshness Assessment. AB - We have developed disposable color-changing polymeric films for quantification of furfural-a freshness indicator-in beer using a smartphone-based reader. The films are prepared by radical polymerization of 4-vinylaniline, as a furfural-sensitive indicator monomer, 2-hydroxymethyl methacrylate as a comonomer, and ethylene dimethyl methacrylate (EDMA) as a cross-linker. The sensing mechanism is based on the Stenhouse reaction in which aniline and furfural react in acidic media with the generation of a deep red cyanine derivative, absorbing at 537 nm, which is visible to the naked eye. The colorimetric response has been monitored using either a portable fiber-optic spectrophotometer or the built-in camera of a smartphone. Under the optimized conditions, a linear response to furfural in beer was obtained in the 39 to 500 MUg L(-1) range, with a detection limit of 12 MUg L(-1), thus improving the performance of other well-established colorimetric or chromatographic methods. The novel films are highly selective to furfural, and no cross-reactivity has been observed from other volatile compounds generated during beer aging. A smartphone application (app), developed for Android platforms, measures the RGB color coordinates of the sensing membranes after exposure to the analyte. Following data processing, the signals are converted into concentration values by preloaded calibration curves. The method has been applied to determination of furfural in pale lager beers with different storage times at room temperature. A linear correlation (r > 0.995) between the storage time and the furfural concentration in the samples has been confirmed; our results have been validated by HPLC with diode-array detection. PMID- 26965180 TI - Averting the Legacy of Kidney Disease--Focus on Childhood. PMID- 26965179 TI - Role of autophagy-related protein expression in patients with rectal cancer treated with neoadjuvant chemoradiotherapy. AB - BACKGROUND: Autophagy, a cellular degradation process, has complex roles in tumourigenesis and resistance to cancer treatment in humans. The aim of this study was to explore the expression levels of autophagy-related proteins in patients with rectal cancer and evaluate their clinical role in the neoadjuvant chemoradiotherapy setting. METHODS: All specimens evaluated were obtained from 101 patients with colorectal cancer who had undergone neoadjuvant chemoradiotherapy and curative surgery. The primary outcomes measured were the expression levels of two autophagy-related proteins (microtubule-associated protein 1 light chain 3 beta (LC3beta) and beclin-1) by immunohistochemistry and their association with clinicopathological parameters and patient survival. RESULTS: Among the 101 patients, the frequency of high expression of beclin-1 was 31.7% (32/101) and that of LC3beta was 46.5% (47/101). A pathologic complete response was inversely associated with LC3beta expression (P = 0.003) and alterations in the expression of autophagy-related proteins (P = 0.046). In the multivariate analysis, however, autophagy-related protein expression did not show prognostic significance for relapse-free survival or overall survival. CONCLUSIONS: High expression of autophagy-related proteins shows a strong negative association with the efficacy of neoadjuvant chemoradiotherapy in patients with rectal cancer. Autophagy has clear implications as a therapeutic target with which to improve the efficacy of neoadjuvant chemoradiotherapy. PMID- 26965183 TI - Monofunctional Platinum (PtII) Compounds - Shifting the Paradigm in Designing New Pt-based Anticancer Agents. AB - Platinum (Pt)-based anticancer drugs, exemplified by cisplatin, are key components in combination chemotherapy. However, their effective use is hindered by toxicity and emergence of drug resistance. They bind to DNA and mainly form the Pt-GG diadduct, subsequently leading to apoptosis to mediate cell death. On the other hand, the Pt drug -proteins and -metabolites interactions, which involve the reaction between Pt and sulfur sites located in protein side chains and important bionucleophiles (e.g., glutathione), are responsible for the toxicity and drug resistance problem. Therefore, carefully designed coordinating ligands may provide the means of fine tuning the electronic environment around the core Pt atom and allow the resulting Pt compounds to bind with the DNA in a different manner. This may produce alternative cell death mechanisms in cancer cells, thereby circumventing Pt resistance. This article reviewed the recent development in monofunctional Pt complexes and their prospects in becoming a new generation of anticancer drugs. PMID- 26965184 TI - Immunoproteasome-Selective Inhibitors: A Promising Strategy to Treat Hematologic Malignancies, Autoimmune and Inflammatory Diseases. AB - The immunoproteasome is predominantly expressed in monocytes and lymphocytes and is responsible for the generation of antigenic peptides for cell-mediated immunity. Upon the exposure of inflammatory cytokines IFN-gamma and TNF-alpha, constitutive subunits can be replaced by the synthesis of the immuno-core particles beta1i, beta2i and beta5i. Recent studies demonstrated that the immunoproteasome function is not only limited to MHC class I presentation, but it is also implicated in a number of pathological disorders including hematological malignancies, inflammatory and autoimmune diseases. At present the commercially available proteasome inhibitors Bortezomib and Carfilzomib, which have been validated in multiple myeloma and other diseases, appear to target both the constitutive and immunoproteasomes indiscriminately. This lack of specificity may, in part, explain some of the side effects of these agents. In contrast, by selectively targeting the immunoproteasome, it may be possible to keep the antimyeloma and antilymphoma efficacy unchanged and, at the same time, to increase the therapeutic index. The aim of this review article is to discuss the most promising immunoproteasome core particle-selective inhibitors which have been developed in the recent years, with a particular attention to their structural features, mechanism of action and therapeutic application. PMID- 26965185 TI - Enhancing the electroluminescence efficiency of Si NC/SiO2 superlattice-based light-emitting diodes through hydrogen ion beam treatment. AB - This paper presents a novel method for enhancing the electroluminescence (EL) efficiency of ten-period silicon-rich oxide (SRO)/SiO2 superlattice-based light emitting diodes (LEDs). A hydrogen ion beam (HIB) was used to irradiate each SRO layer of the superlattices to increase the interfacial roughness on the nanoscale and the density of the Si nanocrystals (Si NCs). Fowler-Nordheim (F-N) tunneling was the major mechanism for injecting the carriers into the Si NCs. The barrier height of the F-N tunneling was lowered by forming a nano-roughened interface and the nonradiative Pb centers were passivated through the HIB treatment. Additionally, the reflectance of the LEDs was lowered because of the nano roughened interface. These factors considerably increased the slope efficiency of EL and the maximum output power of the LEDs. The lighting efficiency increased by an order of magnitude, and the turn-on voltage decreased considerably. This study established an efficient approach for obtaining bright Si NC/SiO2 superlattice based LEDs. PMID- 26965186 TI - Effect of adsorbants on in vitro biohydrogenation of 22:6n-3 by mixed cultures of rumen microorganisms. AB - Studies on microbial biohydrogenation of fatty acids in the rumen are of importance as this process lowers the availability of nutritionally beneficial unsaturated fatty acids for incorporation into meat and milk but also might result in the accumulation of biologically active intermediates. The impact was studied of adsorption of 22:6n-3 (DHA) to particulate material on its disappearance during 24 h in vitro batch incubations with rumen inoculum. Four adsorbants were used in two doses (1 and 5 mg/ml of mucin, gum arabic, bentonite or silicic acid). In addition, the distribution of 22:6n-3 in the pellet and supernatant of diluted rumen fluid was measured. Bentonite and silicic acid did not alter the distribution of 22:6n-3 between pellet and supernatant nor increased the disappearance of 22:6n-3 during the incubation. Both mucin and gum arabic increased the recovery of 22:6n-3 in the supernatant, indicating that these compounds lowered the adsorption of the fatty acid to ruminal particles. This was associated with an increased disappearance of 22:6n-3, when initial 22:6n-3 was 0.06 or 0.10 mg/ml, and an increased formation of 22:0, when initial 22:6n-3 was 0.02 mg/ml, during the 24 h batch culture experiment. Addition of gum arabic to pure cultures of Butyrivibrio fibrisolvens or Butyrivibrio proteoclasticus did not negate the inhibitory effect of 22:6n-3 on growth. As both mucin and gum arabic provide fermentable substrate for ruminal bacteria, an additional experiment was performed in which mucin and gum arabic were replaced by equal amounts of starch, cellulose or xylan. No differences in disappearance of 22:6n-3 were observed, suggesting that the stimulatory effect of mucin and gum arabic on disappearance of 22:6n-3 most probably is not due to provision of an alternative site of adsorption but related to stimulation of bacterial growth. A relatively high proportion of 22:6n-3 can be reduced to 22:0 provided the initial concentration is low. PMID- 26965187 TI - Copper-Catalyzed Enantioselective Hetero-Diels-Alder Reaction of Danishefsky's Diene with Glyoxals. AB - The highly enantioselective hetero-Diels-Alder reaction of Danishefsky's diene with glyoxals was developed by virtue of a readily accessible chiral copper catalyst. This efficient transformation provided a facile and scalable access to a wide range of biologically active dihydropyrones with a high level of enantioselectivities. Moreover, the substrate scope of this reaction could be extended to isatins with this catalytic system. More importantly, the mechanism involved in this reaction was proposed on the basis of the unambiguous structures of intermediates. PMID- 26965193 TI - The origin of the enhanced performance of nitrogen-doped MoS2 in lithium ion batteries. AB - MoS2 with a similar layered structure to graphene has been widely applied in various areas including lithium ion batteries. However, low conductivity, capacity fading and poor rate performance are still the main challenges for MoS2 anode materials. In this work, for the first time, we prepared nitrogen-doped MoS2 (N-MoS2) nanosheets through a simple two-step method involving the preparation of MoS2 with defects by the hydrothermal method, followed by sintering in a NH3 atmosphere. Our electrochemical characterizations and density functional theory calculations demonstrated that nitrogen doping could enhance the electron conductivity and showed higher specific capacity than pristine MoS2 as anode materials of lithium ion batteries, which can be attributed to the faster transportation of electrons and ions because of nitrogen doping. This work helps us understand the origin of the enhanced performance of N-doped MoS2 in lithium ion batteries. PMID- 26965192 TI - A New Acyl-homoserine Lactone Molecule Generated by Nitrobacter winogradskyi. AB - It is crucial to reveal the regulatory mechanism of nitrification to understand nitrogen conversion in agricultural systems and wastewater treatment. In this study, the nwiI gene of Nitrobacter winogradskyi was confirmed to be a homoserine lactone synthase by heterologous expression in Escherichia coli that synthesized several acyl-homoserine lactone signals with 7 to 11 carbon acyl groups. A novel signal, 7, 8-trans-N-(decanoyl) homoserine lactone (C10:1-HSL), was identified in both N. winogradskyi and the recombined E. coli. Furthermore, this novel signal also triggered variances in the nitrification rate and the level of transcripts for the genes involved in the nitrification process. These results indicate that quorum sensing may have a potential role in regulating nitrogen metabolism. PMID- 26965188 TI - alphav Integrins combine with LC3 and atg5 to regulate Toll-like receptor signalling in B cells. AB - Integrin signalling triggers cytoskeletal rearrangements, including endocytosis and exocytosis of integrins and other membrane proteins. In addition to recycling integrins, this trafficking can also regulate intracellular signalling pathways. Here we describe a role for alphav integrins in regulating Toll-like receptor (TLR) signalling by modulating intracellular trafficking. We show that deletion of alphav or beta3 causes increased B-cell responses to TLR stimulation in vitro, and alphav-conditional knockout mice have elevated antibody responses to TLR ligand-associated antigens. alphav regulates TLR signalling by promoting recruitment of the autophagy component LC3 (microtubule-associated proteins 1 light chain 3) to TLR-containing endosomes, which is essential for progression from NF-kappaB to IRF signalling, and ultimately for traffic to lysosomes where signalling is terminated. Disruption of LC3 recruitment leads to prolonged NF kappaB signalling and increased B-cell proliferation and antibody production. This work identifies a previously unrecognized role for alphav and the autophagy components LC3 and atg5 in regulating TLR signalling and B-cell immunity. PMID- 26965194 TI - Quantification of long cane usage characteristics with the constant contact technique. AB - While a number of Electronic Travel Aids (ETAs) have been developed over the past decades, the conventional long cane remains the most widely utilized navigation tool for people with visual impairments. Understanding the characteristics of long cane usage is crucial for the development and acceptance of ETAs. Using optical tracking, cameras and inertial measurement units, we investigated grasp type, cane orientation and sweeping characteristics of the long cane with the constant contact technique. The mean cane tilt angle, sweeping angle, and grip rotation deviation were measured. Grasp type varied among subjects, but was maintained throughout the experiments, with thumb and index finger in contact with the cane handle over 90% of the time. We found large inter-subject differences in sweeping range and frequency, while the sweeping frequency showed low intra-subject variability. These findings give insights into long cane usage characteristics and provide critical information for the development of effective ETAs. PMID- 26965195 TI - General Strategy for Broadband Coherent Perfect Absorption and Multi-wavelength All-optical Switching Based on Epsilon-Near-Zero Multilayer Films. AB - We propose a general, easy-to-implement scheme for broadband coherent perfect absorption (CPA) using epsilon-near-zero (ENZ) multilayer films. Specifically, we employ indium tin oxide (ITO) as a tunable ENZ material, and theoretically investigate CPA in the near-infrared region. We first derive general CPA conditions using the scattering matrix and the admittance matching methods. Then, by combining these two methods, we extract analytic expressions for all relevant parameters for CPA. Based on this theoretical framework, we proceed to study ENZ CPA in a single layer ITO film and apply it to all-optical switching. Finally, using an ITO multilayer of different ENZ wavelengths, we implement broadband ENZ CPA structures and investigate multi-wavelength all-optical switching in the technologically important telecommunication window. In our design, the admittance matching diagram was employed to graphically extract not only the structural parameters (the film thicknesses and incident angles), but also the input beam parameters (the irradiance ratio and phase difference between two input beams). We find that the multi-wavelength all-optical switching in our broadband ENZ CPA system can be fully controlled by the phase difference between two input beams. The simple but general design principles and analyses in this work can be widely used in various thin-film devices. PMID- 26965197 TI - Generation of a stable supramolecular hydrogen evolving photocatalyst by alteration of the catalytic center. AB - A new dyad consisting of a Ru(II) chromophore, a tetrapyridophenazine bridging ligand and a Rh(Cp*)Cl catalytic center, [Ru(tbbpy)2(tpphz)Rh(Cp*)Cl]Cl(PF6)2, acts as durable photocatalyst for hydrogen production from water. Catalytic activity is observed for more than 650 hours. Electrochemical investigations reveal that up to two electrons can be transferred to the catalytic center by a thermodynamically favorable intramolecular process, which has so far not been reported for similar tpphz based supramolecular photocatalysts. Additionally, mercury poisoning tests indicate that the new dyad works as a homogeneous photocatalyst. PMID- 26965196 TI - State Scope of Practice Laws, Nurse-Midwifery Workforce, and Childbirth Procedures and Outcomes. AB - BACKGROUND: Despite research indicating that health, cost, and quality of care outcomes in midwife-led maternity care are comparable with and in some case preferable to those for patients with physician-led care, midwifery plays a more important role in some U.S. states than in others. However, this variability is not well-understood. OBJECTIVES: This study estimates the association between state scope of practice laws related to the autonomy of midwifery practice with the certified nurse-midwifery (CNM) workforce, access to midwife-attended births, and childbirth-related procedures and outcomes. METHODS: Using multivariate regression models, we analyzed Natality Detail File data from births occurring from 2009 to 2011. Each state was classified regarding autonomous midwifery practice (not requiring supervision or contractual agreements) based on Lexis legal search. RESULTS: States with autonomous practice laws had an average of 4.85 CNMs per 1,000 births, compared with 2.17 in states where CNM practice is subject to collaborative agreement. In states with autonomous CNM practice, women had higher odds of having a CNM-attended birth (adjusted odds ratio [AOR], 1.59; p = .004), compared with women in states where midwifery is subject to collaborative agreement. In addition, women in states with autonomous practice had lower odds of cesarean delivery (AOR, 0.87; p = .016), preterm birth (AOR, 0.87; p < .001), and low birth weight (AOR, 0.89; p = .001), compared with women in states without such practice. CONCLUSIONS: States with regulations that support autonomous midwifery practice have a larger nurse-midwifery workforce, and a greater proportion of CNM-attended births. Correlations between autonomous practice laws and better birth outcomes suggest future policy efforts to enhance access to midwifery services may be beneficial to pregnancy outcomes and infant health. PMID- 26965198 TI - In vitro and in vivo evaluation of drug-eluting microspheres designed for transarterial chemoembolization therapy. AB - Poly(D,L-lactic acid) biodegradable microspheres, loaded with the drugs cisplatin and/or sorafenib tosylate, were prepared, characterized and studied. Degradation of the microspheres, and release of cisplatin and/or sorafenib tosylate from them, were investigated in detail. Incubation of the drug-carrying microspheres in phosphate buffered saline (pH=7.4) revealed slow degradation. Nevertheless, significant release of cisplatin and sorafenib tosylate from microspheres loaded with both drugs was apparent in vitro; this can be attributed to their porous structure. Supernatants from microspheres loaded with both drugs showed strong toxic effects on cells (i.e. endothelial cells, fibroblast cells and Renca tumor cells) and potent anti-angiogenic effect in the matrigel endothelial tube assay. In vivo anti-tumor effects of the microspheres were also observed, in a Renca tumor mouse model. The poly(D,L-lactic acid) microspheres containing both cisplatin and sorafenib tosylate revealed highest therapeutic efficacy, probably demonstrating that combined local administration of cisplatin and sorafenib tosylate synergistically inhibits tumor growth in situ. In conclusion, this study demonstrates the applicability of biodegradable poly(D,L-lactic acid) microspheres loaded with cisplatin and sorafenib tosylate for local drug delivery as well as the potential of these microspheres for future use in transarterial chemoembolization. PMID- 26965199 TI - Mucoadhesive polymers: Synthesis and in vitro characterization of thiolated poly(vinyl alcohol). AB - The aim of this study was to synthesize thiolated poly(vinyl alcohol) (PVA) and to evaluate its mucoadhesive properties. Thiourea and 3-mercaptopropionic acid were utilized in order to obtain thiolated PVAs, namely, TPVA1 and TPVA2, respectively. TPVA1 and TPVA2 displayed 130.44 +/- 14.99 and 958.35 +/- 155.27 MUmol immobilized thiol groups per gram polymer, respectively, which were then evaluated regarding reactivity of thiol groups, swelling behavior and mucoadhesive properties. Both thiolated PVAs exhibited the highest reactivity at pH 8.0 whereas more than 95% of free thiol groups were preserved at pH 5.0. Thiolation of PVA decelerated water uptake and prolonged disintegration time of test discs compared to unmodified PVA. Contact time of TPVA1- and TPVA2-based test discs on porcine intestinal mucosa was 3.2- and 15.8-fold prolonged, respectively, in comparison to non-thiolated PVA as measured by rotating cylinder method. According to tensile studies on mucosa, the total work of adhesion (TWA) and the maximum detachment force (MDF) were increased when compared to PVA. Furthermore, thiolated PVAs preserved higher percentage of viable cells compared to unmodified PVA within 24h as evaluated by MTT assay. Accordingly, thiolated PVA represents a novel excipient that can likely improve the mucoadhesive properties of various pharmaceutical formulations. PMID- 26965200 TI - Dispersibility of lactose fines as compared to API in dry powders for inhalation. AB - This work investigates the dispersion performance of fine lactose particles as function of processing time, and compares it to the API, using Beclomethasone Dipropionate (BDP) as model API. The total load of fine particles is kept constant in the formulations while the proportions of API and lactose fines are varied. Fine particle assessment demonstrates that the lactose fines have higher dispersibility than the API. For standard formulations, processing time has a limited effect on the Fine Particle Fraction (FPF). For formulations containing magnesium stearate (MgSt), FPF of BDP is heavily influenced by processing time, with an initial increase, followed by a decrease at longer mixing times. An equation modeling the observed behavior is presented. Surprisingly, the dispersibility of the lactose fines present in the same formulation remains unaffected by mixing time. Magnesium analysis demonstrates that MgSt is transferred to the fine particles during the mixing process, thus lubrication both BDP and lactose fines, which leads to an increased FPF. Dry particle sizing of the formulations reveals a loss of fine particles at longer mixing times. Incorporation of fine particles into the carrier surfaces is believed to be behind this, and is hence a mechanism of importance as regards the dispersion performance of dry powders for inhalation. PMID- 26965201 TI - Three-dimensional printing of continuous-fiber composites by in-nozzle impregnation. AB - We have developed a method for the three-dimensional (3D) printing of continuous fiber-reinforced thermoplastics based on fused-deposition modeling. The technique enables direct 3D fabrication without the use of molds and may become the standard next-generation composite fabrication methodology. A thermoplastic filament and continuous fibers were separately supplied to the 3D printer and the fibers were impregnated with the filament within the heated nozzle of the printer immediately before printing. Polylactic acid was used as the matrix while carbon fibers, or twisted yarns of natural jute fibers, were used as the reinforcements. The thermoplastics reinforced with unidirectional jute fibers were examples of plant-sourced composites; those reinforced with unidirectional carbon fiber showed mechanical properties superior to those of both the jute-reinforced and unreinforced thermoplastics. Continuous fiber reinforcement improved the tensile strength of the printed composites relative to the values shown by conventional 3D-printed polymer-based composites. PMID- 26965203 TI - Development of immuno-oncology drugs - from CTLA4 to PD1 to the next generations. AB - Since the regulatory approval of ipilimumab in 2011, the field of cancer immunotherapy has been experiencing a renaissance. This success is based on progress in both preclinical and clinical science, including the development of new methods of investigation. Immuno-oncology has become a sub-specialty within oncology owing to its unique science and its potential for substantial and long term clinical benefit. Immunotherapy agents do not directly attack the tumour but instead mobilize the immune system - this can be achieved through various approaches that utilize adaptive or innate immunity. Therefore, immuno-oncology drug development encompasses a broad range of agents, including antibodies, peptides, proteins, small molecules, adjuvants, cytokines, oncolytic viruses, bi specific molecules and cellular therapies. This Perspective summarizes the recent history of cancer immunotherapy, including the factors that led to its success, provides an overview of novel drug-development considerations, summarizes three generations of immunotherapies that have been developed since 2011 and, thus, illustrates the breadth of opportunities these new generations of immunotherapies represent. PMID- 26965205 TI - Reply to Letter: The importance of comorbidity and illness severity scores in cardiac arrest research. PMID- 26965202 TI - Emerging applications of metabolomics in drug discovery and precision medicine. AB - Metabolomics is an emerging 'omics' science involving the comprehensive characterization of metabolites and metabolism in biological systems. Recent advances in metabolomics technologies are leading to a growing number of mainstream biomedical applications. In particular, metabolomics is increasingly being used to diagnose disease, understand disease mechanisms, identify novel drug targets, customize drug treatments and monitor therapeutic outcomes. This Review discusses some of the latest technological advances in metabolomics, focusing on the application of metabolomics towards uncovering the underlying causes of complex diseases (such as atherosclerosis, cancer and diabetes), the growing role of metabolomics in drug discovery and its potential effect on precision medicine. PMID- 26965206 TI - SOFA score to assess the severity of the post-cardiac arrest syndrome. AB - AIM OF THE STUDY: The aim of the study was to assess the prognostic impact of organ failures at ICU admission after out-of-hospital cardiac arrest (CA) according to the SOFA score. METHODS: We performed a retrospective analysis of a prospective cohort of all adult patients admitted to a 15-bed medical ICU in a university-affiliated hospital after an out-of-hospital CA. In addition to demographic and clinical data, initial illness severity was measured using the SOFA score. Outcomes (mortality and neurological prognosis) were also collected at day 28 and one year. RESULTS: A total of 304 patients (age: 66+/-16 years, male: 55%) were admitted for post-CA management. An initial nonshockable cardiac rhythm was recorded in 274 (90%) cases. At admission, SOFA score averaged 9.8+/ 3.1 for the entire cohort (8.1+/-3.3 for day 28 survivors versus 10.1+/-3.1 for non-survivors, p<0.001). At day 1, SOFA remained significantly (p<0.001) higher in nonsurvivors (9.8+/-3.8) when compared to survivors (6.5+/-4.1). Death occurred in 269 (88%) and 275 (90%) patients within the 28-day and one-year period, respectively. Neurological outcome at one year was favorable (CPC score 1 2) in 23patients (8%). Multivariate analysis identified the SOFA score at admission as independently associated with mortality at day28 (OR per point of SOFA score 1.17; 95% CI 1.01-1.35; p=0.03). CONCLUSIONS: In the present study, early organ failures, as assessed by the SOFA score at ICU admission, were independently associated with day 28 mortality. SOFA score may help clinicians objectively evaluate the severity of the post-CA syndrome. PMID- 26965208 TI - Reactive oxygen species and calcium signals in skeletal muscle: A crosstalk involved in both normal signaling and disease. AB - Reactive Oxygen Species (ROS) have been profusely studied as agents of potential damage to living cells and they have been related to a number of pathological processes. Increasing evidence points to a more positive role of ROS in cell signaling and the detailed mechanism that regulates the precise amount of ROS needed for cell functioning without the deleterious effects of excess ROS still needs to be resolved in detail. In skeletal muscle the main source of ROS during normal functioning appears to be NADPH oxidase 2 (NOX2), which is activated by electrical stimuli (or exercise) through a cascade of events that include ATP release through pannexin1 channels. NOX2 is a protein complex that assembles in the T-tubule membrane before activation and ROS production by NOX2 appears to be important for muscle adaptation through gene expression and mitochondrial biogenesis as well as for improving glucose transport after insulin action. Excess ROS production (or diminished antioxidant defenses) plays a role in a number of pathological processes in skeletal muscle. Together with increased reactive nitrogen species, an increase in ROS appears to have a deleterious role in a model of Duchenne muscular dystrophy as well as muscle wasting in other diseases such as aging sarcopenia and cancer cachexia. In addition, ROS is involved in obesity and muscle insulin resistance, both of which are causally related to type 2 diabetes. A detailed description of the fine-tuning of ROS (including all sources of ROS) in skeletal muscle in health and disease will significantly contribute to our knowledge of both muscle adaptation and muscle related pathologies. PMID- 26965207 TI - An implantable compound-releasing capsule triggered on demand by ultrasound. AB - Implantable devices have a large potential to improve human health, but they are often made of biofouling materials that necessitate special coatings, rely on electrical connections for external communication, and require a continuous power source. This paper demonstrates an alternative platform, which we call iTAG (implantable thermally actuated gel), where an implanted capsule can be wirelessly controlled by ultrasound to trigger the release of compounds. We constructed a millimeter-sized capsule containing a co-polymer gel (NiPAAm-co AAm) that contracts above body temperature (i.e. at 45 degrees C) to release compounds through an opening. This gel-containing capsule is biocompatible and free of toxic electronic or battery components. An ultrasound hardware, with a focused ultrasound (FUS) transducer and a co-axial A-mode imaging transducer, was used to image the capsule (to monitor in real time its position, temperature, and effectiveness of dose delivery), as well as to trigger a rapid local rise in temperature, contraction of gel, and release of compounds in vitro and in vivo. The combination of this gel-based capsule and compact ultrasound hardware can serve as a platform for triggering local release of compounds, including potentially in deep tissue, to achieve tailored personalized therapy. PMID- 26965209 TI - Early white matter involvement in an infant carrying a novel mutation in ACOX1. AB - We describe the clinical findings and MRI features observed in a child who presented a two-step disease course: he was hypotonic at birth and soon afterwards developed seizures, which were partially responsive to treatment; he subsequently showed developmental delay and a progressive neurological deterioration with the onset of severe seizures at around three years of age. Head MRI at age 20 days was unremarkable, whereas at 25 months it showed bilateral hyperintensity of the deep cerebellar nuclei; five months later, the signal hyperintensity was also present in the cerebellar white matter and ventral pontine fibre tracts. Molecular analysis revealed a novel ACOX1 mutation, predicting a largely truncated protein. The white matter involvement, which followed an ascending trajectory from cerebellar and brainstem structures to the cerebral hemispheres, seemed to originate from the perinuclear white matter of the deep cerebellar nuclei. PMID- 26965210 TI - Ammonia modification for flotation separation of polycarbonate and polystyrene waste plastics. AB - A promising method, ammonia modification, was developed for flotation separation of polycarbonate (PC) and polystyrene (PS) waste plastics. Ammonia modification has little effect on flotation behavior of PS, while it changes significantly that of PC. The PC recovery in the floated product drops from 100% to 3.17% when modification time is 13min and then rises to 100% after longer modification. The mechanism of ammonia modification was studied by contact angle, and Fourier transform infrared (FT-IR) and X-ray photoelectron spectroscopy (XPS) measurements. Contact angle of PC indicates the decline of PC recovery in the floated product is ascribed to an increase in surface wettability. FT-IR and XPS spectra suggest that ammonia modification causes chemical reactions occurred on PC surface. Flotation behavior of ammonia-modified PC and PS was investigated with respect to flotation time, frother concentration and particle sizes. Flotation separation of PC and PS waste plastics was conducted based on the flotation behavior of single plastic. PC and PS mixtures with different particle sizes are separated efficiently, implying that the technology possesses superior applicability to particle sizes of plastics. The purity of PS and PC is up to 99.53% and 98.21%, respectively, and the recovery of PS and PC is larger than 92.06%. A reliable, cheap and effective process is proposed for separation of PC and PS waste plastics. PMID- 26965211 TI - Recovery of energy and nutrient resources from cattle paunch waste using temperature phased anaerobic digestion. AB - Cattle paunch is comprised of partially digested cattle feed, containing mainly grass and grain and is a major waste produced at cattle slaughterhouses contributing 20-30% of organic matter and 40-50% of P waste produced on-site. In this work, Temperature Phased Anaerobic Digestion (TPAD) and struvite crystallization processes were developed at pilot-scale to recover methane energy and nutrients from paunch solid waste. The TPAD plant achieved a maximum sustainable organic loading rate of 1-1.5kgCODm(-3)day(-1) using a feed solids concentration of approximately 3%; this loading rate was limited by plant engineering and not the biology of the process. Organic solids destruction (60%) and methane production (230LCH4kg(-1) VSfed) achieved in the plant were similar to levels predicted from laboratory biochemical methane potential (BMP) testing. Model based analysis identified no significant difference in batch laboratory parameters vs pilot-scale continuous parameters, and no change in speed or extent of degradation. However the TPAD process did result in a degree of process intensification with a high level of solids destruction at an average treatment time of 21days. Results from the pilot plant show that an integrated process enabled resource recovery at 7.8GJ/dry tonne paunch, 1.8kgP/dry tonne paunch and 1.0kgN/dry tonne paunch. PMID- 26965204 TI - Convertible visceral fat as a therapeutic target to curb obesity. AB - New therapeutic and preventative strategies are needed to address the growing obesity epidemic. In animal models, brown adipose tissue activation and the associated heat produced contribute to countering obesity and the accompanying metabolic abnormalities. Adult humans also have functional brown fat. Here, we present and discuss the concepts of murine and human white adipose tissue plasticity and the transdifferentiation of white adipocytes into brown adipocytes. Human visceral adipocytes - which are crucial contributors to the burden of obesity and its complications - are particularly susceptible to such transdifferentiation. Therefore, we propose that this process should be a focus of anti-obesity research. Approved drugs that have browning properties as well as future drugs that target molecular pathways involved in white-to-brown visceral adipocyte transdifferentiation may provide new avenues for obesity therapy. PMID- 26965212 TI - Production of nitrate-rich compost from the solid fraction of dairy manure by a lab-scale composting system. AB - In the present study, we developed an efficient composting process for the solid fraction of dairy manure (SFDM) using lab-scale systems. We first evaluated the factors affecting the SFDM composting process using different thermophilic phase durations (TPD, 6 or 3days) and aeration rates (AR, 0.4 or 0.2 lmin(-1)kg(-1) total solid (TS)). Results indicated that a similar volatile total solid (VTS) degradation efficiency (approximately 60%) was achieved with a TPD of 6 or 3days and an AR of 0.4 l min(-1) kg(-1)-TS (hereafter called higher AR), and a TPD of 3days resulted in less N loss caused by ammonia stripping. N loss was least when AR was decreased to 0.2 l min(-1) kg(-1)-TS (hereafter called lower AR) during the SFDM composting process. However, moisture content (MC) in the composting pile increased at the lower AR because of water production by VTS degradation and less water volatilization. Reduced oxygen availability caused by excess water led to lower VTS degradation efficiency and inhibition of nitrification. Adding sawdust to adjust the C/N ratio and decrease the MC improved nitrification during the composing processes; however, the addition of increasing amounts of sawdust decreased NO3(-) concentration in matured compost. When an improved composting reactor with a condensate removal and collection system was used for the SFDM composting process, the MC of the composting pile was significantly reduced, and nitrification was detected 10-14days earlier. This was attributed to the activity of ammonia-oxidizing bacteria (AOB). Highly matured compost could be generated within 40-50days. The VTS degradation efficiency reached 62.0% and the final N content, NO3(-) concentration, and germination index (GI) at the end of the composting process were 3.3%, 15.5*10(3)mg kg(-1)-TS, and 112.1%, respectively. PMID- 26965213 TI - Effect of phosphoric acid as a catalyst on the hydrothermal pretreatment and acidogenic fermentation of food waste. AB - The hydrothermal method was applied to food waste (FW) pretreatment with phosphoric acid as a catalyst. The content of soluble substances such as protein and carbohydrate in the FW increased after the hydrothermal pretreatment with phosphoric acid addition (?5%). The SCOD approached approximately 29.0g/L in 5% phosphoric acid group, which is almost 65% more than the original FW. The hydrothermal condition was 160 degrees C for 10min, which means that at least 40% of energy and 60% of reaction time were saved to achieve the expected pretreatment effect. Subsequent fermentation tests showed that the optimal dosage of phosphoric acid was 3% with a VFA yield of 0.763g/gVSremoval, but the increase in salinity caused by phosphoric acid could adversely affect the acidogenesis. With an increase in the quantity of phosphoric acid, among the VFAs, the percentage of propionic acid decreased and that of butyric acid increased. The PCR-DGGE analysis indicated that the microbial diversity could decrease with excessive phosphoric acid, which resulted in a low VFA yield. PMID- 26965214 TI - An environmental benign process for cobalt and lithium recovery from spent lithium-ion batteries by mechanochemical approach. AB - In the current study, an environmental benign process namely mechanochemical approach was developed for cobalt and lithium recovery from spent lithium-ion batteries (LIBs). The main merit of the process was that neither corrosive acid nor strong oxidant was applied. In the proposed process, lithium cobalt oxide (obtained from spent LIBs) was firstly co-grinded with various additives in a hermetic ball milling system, then Co and Li could be easily recovered by a water leaching procedure. It was found that EDTA was the most suitable co-grinding reagent, and 98% of Co and 99% of Li were respectively recovered under optimum conditions: LiCoO2 to EDTA mass ratio 1:4, milling time 4h, rotary speed 600r/min and ball-to-powder mass ratio 80:1, respectively. Mechanisms study implied that lone pair electrons provided by two nitrogen atoms and four hydroxyl oxygen atoms of EDTA could enter the empty orbit of Co and Li by solid-solid reaction, thus forming stable and water-soluble metal chelates Li-EDTA and Co-EDTA. Moreover, the separation of Co and Li could be achieved through a chemical precipitation approach. This study provides a high efficiency and environmentally friendly process for Co and Li recovery from spent LIBs. PMID- 26965215 TI - Salter-Harris type II metacarpal and metatarsal fracture in three foals. Treatment by minimally-invasive lag screw osteosynthesis combined with external coaptation. AB - OBJECTIVES: To describe minimally-invasive lag screw osteosynthesis combined with external coaptation for the treatment of Salter-Harris type II third metacarpal and third metatarsal bone fractures. METHODS: Three foals aged two weeks to four months with a Salter-Harris type II third metacarpal or third metatarsal fracture. Surgery was carried out under general anaesthesia in lateral recumbency. After fracture reduction, the metaphyseal fragment was stabilized with two cortical screws placed in lag fashion under fluoroscopic control. A cast was applied for at least two weeks. RESULTS: All foals had a good outcome with complete fracture healing and return to complete soundness without any angular limb deformity. All foals had moderate transient digital hyperextension after cast removal. CLINICAL SIGNIFICANCE: Internal fixation of Salter-Harris type II third metacarpal or third metatarsal fractures with two cortical screws in lag fashion, combined with external coaptation provided good stabilization and preserved the longitudinal growth potential of the injured physis. PMID- 26965216 TI - Matrix Extension Study: Validation of the Compact Dry EC Method for Enumeration of Escherichia coli and non-E. coli Coliform Bacteria in Selected Foods. AB - The Compact Dry "Nissui" EC method, originally certified by the AOAC Research Institute Performance Test Method(SM) program for enumeration of Escherichia coli and non-E. coli coliforms in raw meat products (Performance Tested Method(SM) 110402), has undergone an evaluation to extend the method's claim to cooked chicken, prewashed bagged shredded iceberg lettuce, frozen cod filets, instant nonfat dry milk powder, and pasteurized milk (2% fat). Compact Dry EC is a ready to-use dry media sheet containing a cold-soluble gelling agent, selective agents, and a chromogenic medium, which are rehydrated by adding 1 mL diluted sample. E. coli form blue/blue-purple colonies, whereas other coliform bacteria form red/pink colonies. Users can obtain an E. coli count (blue/blue-purple colonies only) and a total coliform count (red/pink plus blue/blue-purple colonies) after 24 +/- 2 h of incubation at 37 +/- 1 degrees C. The matrix extension study was organized by Campden BRI (formerly Campden and Chorleywood Food Research Association Technology, Ltd), Chipping Campden, United Kingdom. Method comparison data for cooked chicken, prewashed bagged shredded iceberg lettuce, frozen cod filets, and instant nonfat dry milk powder were collected in a single-laboratory evaluation by Campden BRI. A multilaboratory study was conducted on pasteurized milk (2% fat), with 13 laboratories participating. The Compact Dry EC method was compared to ISO 16649-2:2001 "Microbiology of food and animal feeding stuffs Horizontal method for the enumeration of beta-glucuronidase-positive Escherichia coli-Part 2: Colony-count technique at 44 degrees C using 5-bromo-4-chloro-3 indolyl beta-D-glucuronide" and to ISO 4832:2006 "Microbiology of food and animal feeding stuffs-Horizontal method for the enumeration of coliforms-Colony-count technique," the current standards at the time of this study. Each matrix was evaluated separately for E. coli and non-E. coli coliforms at each contamination level (including an uncontaminated level). In the single-laboratory evaluation (cooked chicken, prewashed bagged shredded iceberg lettuce, frozen cod filets, and instant nonfat dry milk powder), colony counts were logarithmically transformed, and then the data were analyzed at each level for sr, RSDr, and mean difference between methods with 95% confidence intervals (CIs). A CI outside a range of -0.5 to 0.5 on the log10 mean difference between methods was used as the criterion to establish a significant statistical difference. In the multilaboratory study on pasteurized milk, after logarithmic transformation, the data were analyzed for sR and RSDR in addition to sr, RSDr, and mean difference with 95% CIs. Regression analysis was performed on all matrixes and reported as r(2). In the single-laboratory evaluation, statistical differences were indicated between the Compact Dry EC and ISO 16649-2 methods for the enumeration of E. coli in two of five contamination levels tested for lettuce, and in the low contamination level for cooked chicken. For the cooked chicken and lettuce at the low level, only a few colonies were recovered for each method, and thus not a true indication of the methods' performance. For the high contamination level of lettuce, counts varied within the sets of five replicates more than 10-fold for each method, which may have contributed to the significant difference. Statistical differences were also indicated between the Compact Dry EC and ISO 4832 methods for the enumeration of coliforms in two of five contamination levels tested for lettuce, two of five contamination levels of milk powder, and in the low contamination level for frozen fish. For the lowest levels of frozen fish and milk powder, only a few colonies were recovered for each method. For the lettuce and the other level of milk powder, counts varied within the sets of five replicates more than 10-fold for each method, which may have contributed to the significant differences indicated in the those contamination levels. In most cases, mean differences between the Compact Dry EC and International Organization of Standardization (ISO) methods were well below 0.5 log10, and the CIs were within the acceptance criterion (-0.5 to 0.5). The sr and RSDr values were similar for both methods, and r(2) values were >0.92 for all comparisons. In the multilaboratory study, no statistical differences were indicated between the methods. The sr, RSDr, sR, and RSDr values were similar for each method and even slightly smaller in most cases for the Compact Dry EC. The r(2) value was 0.97 in comparison to ISO 16649-2, and 0.99 in comparison to ISO 4832. The Compact Dry EC offers comparable results to the ISO standard plating methods in a space saving, easy-to-use format. PMID- 26965217 TI - Orexin A induces bidirectional modulation of synaptic plasticity: Inhibiting long term potentiation and preventing depotentiation. AB - The orexin system consists of two peptides, orexin A and B and two receptors, OX1R and OX2R. It is implicated in learning and memory regulation while controversy remains on its role in modulating hippocampal synaptic plasticity in vivo and in vitro. Here, we investigated effects of orexin A on two forms of synaptic plasticity, long-term potentiation (LTP) and depotentiation of field excitatory postsynaptic potentials (fEPSPs), at the Schaffer Collateral-CA1 synapse of mouse hippocampal slices. Orexin A (?30 nM) attenuated LTP induced by theta burst stimulation (TBS) in a manner antagonized by an OX1R (SB-334867), but not OX2R (EMPA), antagonist. Conversely, at 1 pM, co-application of orexin A prevented the induction of depotentiation induced by low frequency stimulation (LFS), i.e. restoring LTP. This re-potentiation effect of sub-nanomolar orexin A occurred at LFS of 1 Hz, but not 2 Hz, and with LTP induced by either TBS or tetanic stimulation. It was significantly antagonized by SB-334867, EMPA and TCS 1102, selective OX1R, OX2R and dual OXR antagonists, respectively, and prevented by D609, SQ22536 and H89, inhibitors of phospholipase C (PLC), adenylyl cyclase (AC) and protein kinase A (PKA), respectively. LFS-induced depotentiation was antagonized by blockers of NMDA, A1-adenosine and type 1/5 metabotropic glutamate (mGlu1/5) receptors, respectively. However, orexin A (1 pM) did not affect chemical-induced depotentiation by agonists of these receptors. These results suggest that orexin A bidirectionally modulates hippocampal CA1 synaptic plasticity, inhibiting LTP via OX1Rs at moderate concentrations while inducing re potentiation via OX1Rs and OX2Rs, possibly through PLC and AC-PKA signaling at sub-nanomolar concentrations. PMID- 26965218 TI - Endovanilloid control of pain modulation by the rostroventromedial medulla in an animal model of diabetic neuropathy. AB - The involvement of transient receptor vanilloid type-1 (TRPV1) channels in pain modulation by the brain remains understudied. The rostroventromedial medulla (RVM) plays a key role in conveying to the spinal cord pain modulatory influences triggered in higher brain centres, with co-existence of inhibitory (antinociceptive) and facilitatory (pronociceptive) effects. In spite of some reports of TRPV1 expression in the RVM, it remains unknown if endovanilloid signalling plays a direct role in local pain modulation. Here we used a model of diabetic neuropathy, the streptozotocin (STZ)-diabetic rat, to study the role of endovanilloid signalling in RVM-mediated pain modulation during chronic pain. Four weeks after diabetes induction, the levels of TRPV1 mRNA and fatty acid amide hydrolase (FAAH), a crucial enzyme for endovanilloid catabolism, in the RVM of STZ-diabetic rats were higher than control. The RVM of STZ-diabetic rats presented decreased levels of several TRPV1 endogenous ligands, namely anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). Administration of capsaicin (a TRPV1 agonist) into the RVM decreased nociceptive behavioural responses in the inflammatory phase of the formalin test (phase 2). These findings suggest that diabetic neuropathy induces plastic changes of RVM endovanilloid signalling, indicating that TRPV1 may be a putative target for pain modulation in this chronic pain condition. PMID- 26965220 TI - [Chronic ischaemic heart disease in the elderly]. AB - It is the aim of this manuscript to take into account the peculiarities and specific characteristics of elderly patients with chronic ischaemic heart disease from a multidisciplinary perspective, with the participation of the Spanish Society of Cardiology (sections of Geriatric Cardiology and Ischaemic Heart Disease/Acute Cardiovascular Care), the Spanish Society of Internal Medicine, the Spanish Society of Primary Care Physicians and the Spanish Society of Geriatrics and Gerontology. This consensus document shows that in order to adequately address these elderly patients a comprehensive assessment is needed, which includes comorbidity, frailty, functional status, polypharmacy and drug interactions. We conclude that in most patients medical treatment is the best option and that this treatment must take into account the above factors and the biological changes associated with aging. PMID- 26965219 TI - Venlafaxine treatment after endothelin-1-induced cortical stroke modulates growth factor expression and reduces tissue damage in rats. AB - Neuromodulators, such as antidepressants, may contribute to neuroprotection by modulating growth factor expression to exert anti-inflammatory effects and to support neuronal plasticity after stroke. Our objective was to study whether early treatment with venlafaxine, a serotonin-norepinephrine reuptake inhibitor, modulates growth factor expression and positively contributes to reducing the volume of infarcted brain tissue resulting in increased functional recovery. We studied the expression of BDNF, FGF2 and TGF-beta1 by examining their mRNA and protein levels and cellular distribution using quantitative confocal microscopy at 5 days after venlafaxine treatment in control and infarcted brains. Venlafaxine treatment did not change the expression of these growth factors in sham rats. In infarcted rats, BDNF mRNA and protein levels were reduced, while the mRNA and protein levels of FGF2 and TGF-beta1 were increased. Venlafaxine treatment potentiated all of the changes that were induced by cortical stroke alone. In particular, increased levels of FGF2 and TGF-beta1 were observed in astrocytes at 5 days after stroke induction, and these increases were correlated with decreased astrogliosis (measured by GFAP) and increased synaptophysin immunostaining at twenty-one days after stroke in venlafaxine-treated rats. Finally, we show that venlafaxine reduced infarct volume after stroke resulting in increased functional recovery, which was measured using ladder rung motor tests, at 21 days after stroke. Our results indicate that the early oral administration of venlafaxine positively contributes to neuroprotection during the acute and late events that follow stroke. PMID- 26965221 TI - Estimating the extent and economic impact of under and overdiagnosis of chronic obstructive pulmonary disease in primary care. AB - The aim of the present study was to estimate the frequency of under- and over diagnosis as well as overtreatment and their impact on the financial burden of inhaled drugs for stable chronic obstructive pulmonary disease (COPD). We examined 3200 subjects (65.5% males) of the general population (>40 year old, current or former smokers, and asthma patients were excluded) during a 3-year period. All participants gave detailed medical history, underwent spirometry, and their current and past inhaled medications were registered through the national electronic prescription system. We diagnosed 342 subjects (10.7%) with COPD of whom 180 (52.6%) had no prior medical diagnosis. Overdiagnosis was the case for 306 subjects (9.6%) of whom 35.1% were treated with inhaled drugs during the last year. We calculated that 55.4% of the current cost for inhaled drugs is wasted to overtreatment and overdiagnosis. If there was adherence to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines both for the diagnosis and treatment it would be a net profit of 36,059? annually, which would be increased to 116,017? if we had excluded underdiagnosed patients. Under- and over-diagnosis of COPD as well as non-adherence to GOLD guidelines for treatment are common problems in the primary care setting that increase significantly the economic burden of inhaled medications. PMID- 26965222 TI - Chronic respiratory diseases and quality of life in elderly nursing home residents. AB - Few studies have assessed the quality of life (QOL) related to chronic respiratory diseases in the elderly. In the framework of the geriatric study on the health effects of air quality in elderly care centers (GERIA) study, a questionnaire was completed by elderly subjects from 53 selected nursing homes. It included various sections in order to assess respiratory complaints, QOL (World Health Organization QOL (WHOQOL)-BREF), and the cognitive and depression status. The outcome variables were the presence of a score lower than 50 (<50) in each of the WHOQOL-BREF domains (physical health, psychological health, social relationships, and environmental health). Chronic bronchitis, frequent cough, current wheezing, asthma, and allergic rhinitis were considered as potential risk factors. The surveyed sample was (n = 887) 79% female, with a mean age of 84 years (SD: 7 years). In the multivariable analysis, a score of <50 in the physical domain was associated with wheezing in the previous 12 months (odds ratio (OR): 2.03, confidence interval (CI): 1.25-3.31) and asthma (OR: 1.95, CI: 1.12-3.38). The psychological domain was related with a frequent cough (OR: 1.43, CI: 0.95-2.91). A score of <50 in the environmental domain was associated with chronic bronchitis (OR: 2.89, CI: 1.34-6.23) and emphysema (OR: 3.89, CI: 1.27 11.88). In view of these findings, the presence of respiratory diseases seems to be an important risk factor for a low QOL among elderly nursing home residents. PMID- 26965224 TI - Axonal transport along retinal ganglion cells is grossly intact during reduced function post-injury. AB - It has been established that beyond middle age, mice are slower to recover inner retinal function following an acute intraocular pressure (IOP) injury. While 3 month old animals exhibit near-complete recovery 1 week following injury, 12 and 18 month old animals demonstrate prolonged inner retinal dysfunction. In this study we aim to determine whether age-related differences in functional recovery of the inner retina are due to differences in retinal ganglion cell (RGC) axonal transport. C57BL/6J mice at 3 (n = 8) and 18 months (n = 8) of age were used. At day 0, right eyes were cannulated and the IOP was maintained at 50 mmHg for 30 min. At day 5, mice received bilateral intravitreal injections of choleratoxin subunit B (CTB) conjugated to Alexafluor 488. At day 7, mice were euthanized and tissue was collected. Axonal transport of CTB was quantified in retinas and superior colliculi (SC) using fluorescent microscopy. In response to IOP elevation, the overall degree of axonal transport was comparable between young and old mice. Furthermore, no differences in axonal transport were detected between control eyes and injured in mice at any age. In conclusion, impaired recovery of inner retinal function 1 week following acute IOP injury in old mice is not associated with changes in active axonal transport in RGCs at this time. PMID- 26965223 TI - Traditional and emerging indicators of cardiovascular risk in chronic obstructive pulmonary disease. AB - With the increased cardiovascular (CV) morbidity and mortality in subjects with chronic obstructive pulmonary disease (COPD), there is a priority to identify those patients at increased risk of cardiovascular disease. Stable patients with COPD (n = 185) and controls with a smoking history (n = 106) underwent aortic pulse wave velocity (PWV), blood pressure (BP) and skin autofluorescence (AF) at clinical stability. Blood was sent for fasting lipids, soluble receptor for advanced glycation end products (sRAGE) and CV risk prediction scores were calculated. More patients (18%) had a self-reported history of CV disease than controls (8%), p = 0.02, whilst diabetes was similar (14% and 10%), p = 0.44. Mean (SD) skin AF was greater in patients: 3.1 (0.5) AU than controls 2.8 (0.6) AU, p < 0.001. Aortic PWV was greater in patients: 10.2 (2.3) m/s than controls: 9.6 (2.0) m/s, p = 0.02 despite similar BP. The CV risk prediction scores did not differentiate between patients and controls nor were the individual components of the scores different. The sRAGE levels were not statistically different. We present different indicators of CV risk alongside each other in well-defined subjects with and without COPD. Two non-invasive biomarkers associated with future CV burden: skin AF and aortic PWV are both significantly greater in patients with COPD compared to the controls. The traditional CV prediction scores used in the general population were not statistically different. We provide new data to suggest that alternative approaches for optimal CV risk detection should be employed in COPD management. PMID- 26965227 TI - Autopsy/necropsy, diagnosis/detection . . . what's in a word? PMID- 26965228 TI - Validation according to OIE criteria of a monoclonal, recombinant p26-based, serologic competitive enzyme-linked immunosorbent assay as screening method in surveillance programs for the detection of Equine infectious anemia virus antibodies. AB - The Italian National Reference Center for equine infectious anemia (CRAIE; Rome, Italy) developed and validated a monoclonal, recombinant p26-based competitive enzyme-linked immunosorbent assay (cELISA) for the detection of EIA virus antibodies employing the 2010 criteria of the World Organization for Animal Health (OIE). The following parameters were evaluated: cutoff values, repeatability, reproducibility, concordance, analytical sensitivity (Se), absolute analytical specificity (Sp), and diagnostic Se and Sp. Positive and negative predictive values were also defined in relation to the estimated prevalence. When the cELISA was used as a screening test for 96,468 samples in the Italian EIA surveillance program, 17% more EIA cases were detected than by the agar gel immunodiffusion test, and the apparent diagnostic Sp estimated from these samples was 99.8%, which was more than the diagnostic Sp (80.2%) estimated from validation. The high Se and Sp of the cELISA confirm its fit for purpose as a screening test. PMID- 26965229 TI - Rapid diagnosis of hypoglycin A intoxication in atypical myopathy of horses. AB - Hypoglycin A (2-amino-3-(2-methylidenecyclopropyl)propanoic acid) is the plant toxin shown to cause atypical myopathy in horses. It is converted in vivo to methylenecyclopropyl acetic acid, which is transformed to a coenzyme A ester that subsequently blocks beta oxidation of fatty acids. Methylenecyclopropyl acetic acid is also conjugated with carnitine and glycine. Acute atypical myopathy may be diagnosed by quantifying the conjugates of methylenecyclopropyl acetic acid plus a selection of acyl conjugates in urine and serum. We describe a new mass spectrometric method for sample volumes of <0.5 mL. Samples were extracted with methanol containing 5 different internal standards. Extracts were analyzed by ultra-high-performance liquid chromatography-tandem mass spectrometry focusing on 11 metabolites. The total preparation time for a series of 20 samples was 100 min. Instrument run time was 14 min per sample. For the quantification of carnitine and glycine conjugates of methylenecyclopropyl acetic acid in urine, the coefficients of variation for intraday quantification were 2.9% and 3.0%, respectively. The respective values for interday were 9.3% and 8.0%. Methylenecyclopropyl acetyl carnitine was detected as high as 1.18 umol/L in serum (median: 0.46 umol/L) and 1.98 mmol/mol creatinine in urine (median: 0.79 mmol/mol creatinine) of diseased horses, while the glycine derivative accumulated up to 1.97 mmol/mol creatinine in urine but was undetectable in most serum samples. In serum samples from horses with atypical myopathy, the intraday coefficients of variation for C4-C8 carnitines and glycines were <=4.5%. Measured concentrations exceeded those in healthy horses by ~10 to 1,400 times. PMID- 26965230 TI - Pathology of Haemonchus contortus in New World camelids in the southeastern United States: a retrospective review. AB - Most small ruminant farms in tropical climates are plagued by Haemonchus contortus, a hematophagous, abomasal parasite. Heavy burdens of this parasite can cause anemia, hypoproteinemia, weight loss, and mortality in susceptible animals. Haemonchus contortus is becoming a major health concern in New World camelids as well, namely llamas (Llama glama) and alpacas (Vicugna pacos), yet little research has been conducted regarding its prevalence or pathology in these species. Herein, we present a retrospective review of llamas and alpacas that were admitted to The University of Georgia Veterinary Teaching Hospital and Athens Diagnostic Laboratory between the years 2002 and 2013. Antemortem fecal egg count (FEC) estimates performed on 30 alpacas were negatively correlated with hematocrit, hemoglobin, and red blood cell count. Total protein was not significantly correlated with FEC. On postmortem examination, 55 of 198 camelids, including 2 from the aforementioned antemortem review, were infected with H. contortus, with llamas (42.6%) having a significantly higher infection rate than alpacas (22.2%). In 15.7% of the total cases, the parasite was the major cause of death. Common gross lesions included peritoneal, thoracic, and pericardial effusions, visceral pallor, subcutaneous edema, and serous atrophy of fat. Histologic lesions included centrilobular hepatic necrosis, hepatic atrophy, lymphoplasmacytic inflammation of the mucosa of the third gastric compartment (C3), extramedullary hematopoiesis in both the liver and spleen, and the presence of nematodes in C3. Our study emphasizes the importance of H. contortus diagnosis and herd monitoring in New World camelids, particularly llamas. PMID- 26965225 TI - Are viruses alive? The replicator paradigm sheds decisive light on an old but misguided question. AB - The question whether or not "viruses are alive" has caused considerable debate over many years. Yet, the question is effectively without substance because the answer depends entirely on the definition of life or the state of "being alive" that is bound to be arbitrary. In contrast, the status of viruses among biological entities is readily defined within the replicator paradigm. All biological replicators form a continuum along the selfishness-cooperativity axis, from the completely selfish to fully cooperative forms. Within this range, typical, lytic viruses represent the selfish extreme whereas temperate viruses and various mobile elements occupy positions closer to the middle of the range. Selfish replicators not only belong to the biological realm but are intrinsic to any evolving system of replicators. No such system can evolve without the emergence of parasites, and moreover, parasites drive the evolution of biological complexity at multiple levels. The history of life is a story of parasite-host coevolution that includes both the incessant arms race and various forms of cooperation. All organisms are communities of interacting, coevolving replicators of different classes. A complete theory of replicator coevolution remains to be developed, but it appears likely that not only the differentiation between selfish and cooperative replicators but the emergence of the entire range of replication strategies, from selfish to cooperative, is intrinsic to biological evolution. PMID- 26965231 TI - Optimized methods for total nucleic acid extraction and quantification of the bat white-nose syndrome fungus, Pseudogymnoascus destructans, from swab and environmental samples. AB - The continued spread of white-nose syndrome and its impacts on hibernating bat populations across North America has prompted nationwide surveillance efforts and the need for high-throughput, noninvasive diagnostic tools. Quantitative real time polymerase chain reaction (qPCR) analysis has been increasingly used for detection of the causative fungus, Pseudogymnoascus destructans, in both bat- and environment-associated samples and provides a tool for quantification of fungal DNA useful for research and monitoring purposes. However, precise quantification of nucleic acid from P. destructans is dependent on effective and standardized methods for extracting nucleic acid from various relevant sample types. We describe optimized methodologies for extracting fungal nucleic acids from sediment, guano, and swab-based samples using commercial kits together with a combination of chemical, enzymatic, and mechanical modifications. Additionally, we define modifications to a previously published intergenic spacer-based qPCR test for P. destructans to refine quantification capabilities of this assay. PMID- 26965232 TI - Herd outbreak of bovine tuberculosis illustrates that route of infection correlates with anatomic distribution of lesions in cattle and cats. AB - An outbreak of bovine tuberculosis (TB) in a Michigan dairy herd resulted in quarantine, depopulation, pathology, and epidemiologic investigations. This herd, compared to other TB-infected herds in Michigan, was unusual in the long-term feeding of waste milk to its replacement calves. The herd had 80 cattle with positive results on caudal fold test or gamma interferon testing, which were reclassified as suspects because the herd had never been known to be tuberculous previously. Autopsy revealed striking variation in the anatomic distribution of gross anatomic lesions, microscopic lesions, and culture-positive lymph nodes between the adult cattle, the calves, and the domestic cats present on the farm. Adult cattle had lesions and culture-positive lymph nodes predominantly within the thoracic lymph nodes, whereas cats had 50% of their lesions and culture positive lymph nodes in their abdomens, and 50% of positive calves had culture positive lymph nodes in their abdomens. This difference in anatomic distribution correlated with the likely routes of infection, which are believed to be by direct airborne transmission in adult cattle and indirect ingestion of contaminated milk in both calves and cats. Although TB literature over the past 100-plus years states that the route of infection may manifest itself in differences in lesion anatomic distribution, our team has been working with TB for over 20 years, and we have never encountered such striking variation between different groups of animals on the same farm. PMID- 26965233 TI - Comparison of agar dilution and antibiotic gradient strip test with broth microdilution for susceptibility testing of swine Brachyspira species. AB - Production-limiting diseases in swine caused by Brachyspira are characterized by mucohemorrhagic diarrhea (B. hyodysenteriae and "B. hampsonii") or mild colitis (B. pilosicoli), while B. murdochii is often isolated from healthy pigs. Emergence of novel pathogenic Brachyspira species and strains with reduced susceptibility to commonly used antimicrobials has reinforced the need for standardized susceptibility testing. Two methods are currently used for Brachyspira susceptibility testing: agar dilution (AD) and broth microdilution (BMD). However, these tests have primarily been used for B. hyodysenteriae and rarely for B. pilosicoli. Information on the use of commercial susceptibility testing products such as antibiotic gradient strips is lacking. Our main objective was to validate and compare the susceptibility results, measured as the minimum inhibitory concentration (MIC), of 6 antimicrobials for 4 Brachyspira species (B. hyodysenteriae, "B. hampsonii", B. pilosicoli, and B. murdochii) by BMD and AD (tiamulin, valnemulin, lincomycin, tylosin, and carbadox) or antibiotic gradient strip (doxycycline) methods. In general, the results of a high percentage of all 4 Brachyspira species differed by +/-1 log2 dilution or less by BMD and AD for tiamulin, valnemulin, lincomycin, and tylosin, and by BMD and antibiotic gradient strip for doxycycline. The carbadox MICs obtained by BMD were 1-5 doubling dilutions different than those obtained by AD. BMD for Brachyspira was quicker to perform with less ambiguous interpretation of results when compared with AD and antibiotic gradient strip methods, and the results confirm the utility of BMD in routine diagnostics. PMID- 26965234 TI - Fatal pyogranulomatous myocarditis in 10 Boxer puppies. AB - Over a period of 5 years, 10 pure-bred Boxer puppies, 9-16 weeks old, were presented with a history of sudden death and were diagnosed with pyogranulomatous myocarditis. The myocarditis was characterized by a mixed infiltrate composed predominantly of neutrophils and macrophages. In our retrospective study, original case records and archived materials were examined. All dogs were positive for Borrelia burgdorferi on immunohistochemistry (IHC). There was no evidence of infectious agents in formalin-fixed, paraffin-embedded (FFPE) heart tissue sections stained with hematoxylin and eosin, Ziehl-Neelsen, Gram, Grocott methenamine silver, Warthin-Starry, Von Kossa, and Steiner-Chapman stains. IHC for Chlamydia sp., Toxoplasma gondii, Neospora caninum, West Nile virus, and canine parvovirus also yielded a negative result in all dogs. Polymerase chain reaction testing for vector-borne pathogens on heart tissue from 9 of the dogs (1 frozen and 8 FFPE samples) yielded positive results for 1 dog with B. burgdorferi as well as Anaplasma phagocytophilum in another dog. Subsequently, 2 additional cases were found in a French Bulldog and a French Bulldog-Beagle mix that had identical morphology, test results, age, and seasonality to these 10 Boxer dogs. The similarities in the seasonality, signalment of the affected dogs, and the gross and microscopic lesions suggest a common etiology. Positive IHC and morphologic similarities to human Lyme carditis indicate that B. burgdorferi is likely the agent involved. An additional consideration for these cases is the possibility of a breed-specific autoimmune myocarditis or potential predisposition for cardiopathogenic agents in young Boxers. PMID- 26965235 TI - Failed detection of Bovine viral diarrhea virus 2 subgenotype a (BVDV-2a) by direct fluorescent antibody test on tissue samples due to reduced reactivity of field isolates to raw anti-BVDV antibody. AB - Bovine viral diarrhea virus 1 (BVDV-1) is associated with mild or subclinical infections, whereas BVDV-2 is frequently implicated in outbreaks of severe thrombocytopenia and acute fatal disease. In the present study, the carcass of a beef breed cow and tissue samples of a beef calf were received for laboratory diagnosis. Both animals exhibited severe clinical signs compatible with thrombocytopenia or hemorrhagic syndrome. Direct fluorescent antibody test (DFAT) failed to detect BVDV antigen in the tissue specimens of both cases. However, immunohistochemistry (IHC) revealed the presence of BVDV antigen in oral and esophageal mucosa and Peyer patches of the beef breed cow. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) detected BVDV-2 in selected tissues of both animals. Subsequently, BVDV was isolated from both cases and subjected to genetic and serologic characterizations. Mutations in the 5' untranslated genomic region (5'-UTR) primer and probe binding sites and the E2 gene were associated with reduced efficiency of an established real-time RT-PCR assay and amino acid alterations in the E2 glycoprotein, respectively. Both viral isolates were classified by real-time RT-PCR and phylogenetic analysis as BVDV-2 subgenotype a. Unlike BVDV reference strains Singer and 125c, the isolates cross reacted with anti-BVDV-1 and anti-BVDV-2 reference sera, indicating antigenic variations in field isolates. The isolates also showed reduced reactivity to porcine anti-BVDV antiserum (the raw serum used to produce BVDV DFA conjugate). In summary, data from the present investigation indicated that genetic and antigenic variations affected the performance of detection assays, especially DFAT, highlighting the need for regular evaluation and modification of BVDV tests. PMID- 26965236 TI - Evaluation of cytospin precision in low cellularity canine cerebrospinal fluid. AB - The cell count and differential of cerebrospinal fluid (CSF) cytologic examination classify CSF as inflammatory or not. The cytospin cell yield is related to cell count, but to our knowledge a relationship has not been characterized and cytospin precision is undocumented in any species. The objective of our study was to calculate intra-assay precision of cellular yield and differential on cytocentrifuged canine CSF, determine the factors that may affect precision, and predict the number of cytospins necessary to confirm mild neutrophilic pleocytosis. Ten concurrent replicate cytospins were created from nonhemorrhagic CSF, obtained from 60 dogs in other terminal studies, with either a manual or calibrated pipetting technique. Up to 500 cells per cytospin were counted and classified on each slide. Coefficient of variation (CV), multiple regression, and probabilities were calculated for relationships between cell yield and independent factors including technique, total nucleated cell count, cell differential, and total protein. Manual and calibrated pipetting had similar CVs (average 31%) for total cell yield, but the calibrated technique had fewer foamy macrophages. CV for neutrophil percentage among low cellularity samples with any neutrophils was 146%. Probability based on linear regression showed that 1 cytospin is sufficient to identify samples with >3% neutrophils. Occasional neutrophils, eosinophils, mitotic figures, phagocytic cells, and ependymal cells were seen in many low cellularity canine CSF samples. Canine CSF cytospin cell yield and differential evaluations are imprecise. Calibrated rather than manual pipetting is recommended. PMID- 26965237 TI - Histological and immunohistochemical features of histiocytic sarcoma in four domestic ferrets (Mustela putorius furo). AB - Four cases of histiocytic sarcoma in domestic ferrets (Mustela putorius furo) are described in the present study. Tumor samples obtained from the abdominal viscera, including the spleen, were submitted for histologic examination. Microscopically, poorly demarcated masses contained numerous round- to pleomorphic-shaped cells with coarsely vacuolated and eosinophilic cytoplasm. Bizarre, binucleated tumor cells and multinucleated giant tumor cells with low phagocytic activity were commonly observed. Immunohistochemically, tumor cells in all of the cases were positive for vimentin, human leukocyte antigen-DR, ionized calcium-binding adapter molecule-1, and lysozyme, but some of them lacked cluster of differentiation (CD)163 or CD208 expression. The survival time after surgical resection was 9 days to 5 months. Histiocytic sarcoma in the ferret is a rare, but highly aggressive, tumor commonly found in the spleen. PMID- 26965238 TI - Seroprevalence of Trypanosoma evansi infection in capybaras (Hydrochoerus hydrochaeris) from a nonendemic area in Brazil. AB - In South America, capybaras (Hydrochoerus hydrochaeris) as well as coatis (Nasua nasua) are the reservoir hosts of Trypanosoma evansi. Capybaras from a T. evansi nonendemic area in the State of Sao Paulo, southeastern Brazil, were culled because of an ongoing outbreak of Brazilian spotted fever; serum samples from these capybaras were tested for antibodies to T. evansi. Of the 172 sera tested, 17 (9.9%) were seropositive by card agglutination test, with antibody titers of 1:8-1:128; 14 (8.1%) of these 17 seropositive sera were also seropositive by indirect fluorescent antibody test, with antibody titers of 1:16-1:256. Both serologic techniques proved to be efficient, with similar results for detection of antibodies to T. evansi in capybaras from a nonendemic area in Brazil. PMID- 26965239 TI - Mycoplasma hyopneumoniae genetic variability within a swine operation. AB - The objective of our study was to characterize the Mycoplasma hyopneumoniae genetic diversity within a swine operation comingling weaned pigs. Bronchial swabs and tracheal aspirates were collected from 3 nursery-to-finish farms. During the finishing production stages, samples were obtained from mortalities and from live coughing pigs in rooms where mortality was not observed. A total of 105 samples were examined by a M. hyopneumoniae real-time polymerase chain reaction and subjected to genetic typing using a multilocus variable number tandem repeat analysis (MLVA) assay. The MLVA was used to identify genetic variants based on the number of repeats in 2 variable number tandem repeats loci, namely P97 and P146, thought to mediate adherence of M. hyopneumoniae to swine cilia. Four distinguishable M. hyopneumoniae variants were identified: MVLA variants 9-15, 11-21, 9-21, and 7-15. Variant 9-15 was the most prevalent, observed in 79% of rooms, and detected on all 3 farms. Variant 11-21 was present in 37% of the rooms on 2 of the 3 farms. Only one 9-21 variant was identified in 1 farm, and all samples of variant 7-15 were recovered from another farm. Based on the low prevalence and limited geographic distribution of the last 2 variants, it is hypothesized that they might be the result of in-situ recombination. All variants detected in this investigation appeared to belong to 3 clusters. Overall, a limited number of variants and clusters were identified in a system that comingles pigs from different sources, suggesting limited M. hyopneumoniae genetic variation within commercial swine production environments. PMID- 26965240 TI - Diagnostic value of serum procalcitonin, neopterin, and gamma interferon in neonatal calves with septicemic colibacillosis. AB - The objective of our study was to compare the serum concentrations of procalcitonin (PCT), neopterin, tumor necrosis factor alpha (TNF-alpha), prostaglandin E2, malondialdehyde, interleukin 8, and gamma interferon (IFN gamma) in neonatal calves with septicemic colibacillosis (n = 15) with healthy controls (n = 15). Septicemic colibacillosis was diagnosed based on clinical signs and the isolation of Escherichia coli from heparinized blood in clinically suspected cases. PCT, neopterin, TNF-alpha (p < 0.05), and IFN-gamma concentrations in calves with septicemic colibacillosis were significantly higher than in the healthy controls (p < 0.01). Serum PCT concentrations were ~4 times higher in the calves with septicemic colibacillosis than in the healthy calves, suggesting that PCT could be a useful marker of septicemic colibacillosis in neonatal calves. PMID- 26965241 TI - Chlamydia pecorum: fetal and placental lesions in sporadic caprine abortion. AB - Chlamydial abortion in small ruminants is usually associated with Chlamydia abortus infection. Although Chlamydia pecorum has been detected in aborted ruminants and epidemiological data suggests that C. pecorum is abortigenic in these species, published descriptions of lesions in fetuses are lacking. This work describes fetoplacental lesions in a caprine abortion with C. pecorum infection, and further supports the abortigenic role of C. pecorum in ruminants. A 16-month-old Boer goat aborted twin fetuses at ~130 days of gestation. Both fetuses (A and B) and the placenta of fetus A were submitted for postmortem examination and diagnostic workup. At autopsy, the fetuses had moderate anasarca, intermuscular edema in the hindquarters (A), and brachygnathia and palatoschisis (B). In the placenta, the cotyledons were covered by yellow fibrinosuppurative exudate that extended into the adjacent intercotyledonary areas. Histologically, there was severe suppurative and necrotizing placentitis with vasculitis (arteriolitis) and thrombosis, multifocal lymphohistiocytic and neutrophilic hepatitis (A), and fibrinosuppurative enteritis in both fetuses. Chlamydia antigen was detected in the placenta by the direct fluorescent antibody test and in fetal intestines by immunohistochemistry. Nested polymerase chain reaction of DNA extracted from formalin-fixed, paraffin-embedded sections of placenta and intestine amplified 400 bp of the Chlamydia 16S rRNA gene that was sequenced and found to be 99% identical to C. pecorum by BLAST analysis. Other known abortigenic infectious agents were ruled out by specific testing. It is concluded that C. pecorum infection is associated with fetoplacental lesions and sporadic abortion in goats. PMID- 26965243 TI - Perception Abilities of L1 Cypriot Greek Listeners - Types of Errors Involving Plosive Consonants in L2 English. AB - This paper investigates the difficulties adult second language (L2) users of English encounter with plosive consonants in the L2. It presents the results of a task examining the acquisition of plosive voicing contrasts by college students with Cypriot Greek (CG) linguistic background. The task focused on the types of errors involving plosive consonants indicating that performance was significantly better in the voiceless plosive category. Participants were able to perceive voiced plosives but they treated such instances as a /nasal + voiced plosive/ sequence. Therefore, the question raised concerns different phonological contrasts realised through similar phonetic cues. The patterns observed suggested that this gap between phonetic cues and phonological contrast might explain why CG users have difficulties perceiving voiced English plosives. In this context, voice onset time (VOT) differences between the L1 and L2 are of crucial importance. In English, voiced plosives are characterised by short lag VOT while their voiceless counterparts fall within the long lag VOT continuum. The same phonetic contrast is used in CG to differentiate between single and geminate voiceless plosives. The results are discussed in relation to the frameworks of second language phonology and speech perception suggesting that the difficulties faced by the L2 listeners support the operation of a phonetic-phonological challenge. PMID- 26965242 TI - Delay of late-venous phase cortical vein filling in acute ischemic stroke patients: Associations with collateral status. AB - Evaluation of the venous system may be useful in stroke prognostication and patient selection for acute intervention strategies. We report a novel phenomenon, delayed-late venous phase cortical vein filling, observed on dynamic computed tomography angiography obtained using multidetector computed tomography scanner, in acute ischemic stroke patients. The aim of this study was to examine the frequency of delayed-late venous phase cortical vein filling and assess its association to baseline collateral status. Dynamic computed tomography angiography images of acute ischemic stroke patients, being assessed for reperfusion therapy, were prospectively studied. Delayed-late venous phase cortical vein filling was defined by late venous phase opacification of cortical veins despite contrast clearance from contralateral cortical veins on dynamic computed tomography angiography. Time to peak of maximum arterial enhancement was recorded. A total of 117 patients (mean age = 70.6 +/- 13.3 years; males = 48%) with hemispheric ischemic stroke who underwent acute dynamic computed tomography angiography were included in the study. Overall, 56 (48%) demonstrated delayed late venous phase cortical vein filling. Poor collateralization (OR = 13.50; 95% CI = (4.2, 43); p <= 0.0001) and longer time to peak of maximum arterial enhancement (OR = 3.2; 95% CI = (1.96, 5.3); p <= 0.0001) were positively associated with delayed-late venous phase cortical vein filling. Delayed-late venous phase cortical vein filling was independently associated with poor baseline collateral status (75% vs. 15%, p <= 0.0001; OR = 14.38; 95% CI = (4.33, 47.8); p <= 0.0001). Delayed-late venous phase cortical vein filling is frequently seen in patients with acute ischemic stroke and is associated with poor baseline collateralization. PMID- 26965244 TI - Cell-autonomous programming of rat adipose tissue insulin signalling proteins by maternal nutrition. AB - AIMS/HYPOTHESIS: Individuals with a low birthweight have an increased risk of developing type 2 diabetes mellitus in adulthood. This is associated with peripheral insulin resistance. Here, we aimed to determine whether changes in insulin signalling proteins in white adipose tissue (WAT) can be detected prior to the onset of impaired glucose tolerance, determine whether these changes are cell-autonomous and identify the underlying mechanisms involved. METHODS: Fourteen-month-old male rat offspring born to dams fed a standard protein (20%) diet or a low (8%) protein diet throughout gestation and lactation were studied. Fat distribution and adipocyte size were determined. Protein content and mRNA expression of key insulin signalling molecules were analysed in epididymal WAT and in pre-adipocytes that had undergone in vitro differentiation. RESULTS: The offspring of low protein fed dams (LP offspring) had reduced visceral WAT mass, altered fat distribution and a higher percentage of small adipocytes in epididymal WAT. This was associated with reduced levels of IRS1, PI3K p110beta, Akt1 and PKCzeta proteins and of phospho-Akt Ser473. Corresponding mRNA transcript levels were unchanged. Similarly, in vitro differentiated adipocytes from LP offspring showed reduced protein levels of IRbeta, IRS1, PI3K p85alpha and p110beta subunits, and Akt1. Levels of Akt Ser473 and IRS1 Tyr612 phosphorylation were reduced, while IRS1 Ser307 phosphorylation was increased. CONCLUSIONS/INTERPRETATION: Maternal protein restriction during gestation and lactation changes the distribution and morphology of WAT and reduces the levels of key insulin signalling proteins in the male offspring. This phenotype is retained in in vitro differentiated adipocytes, suggesting that programming occurs via cell-autonomous mechanism(s). PMID- 26965245 TI - Trends in Gastrointestinal Cancer Mortality Rate in Hungary. AB - The aim of this study was to investigate the annual death trends for gastrointestinal cancer in Hungary between 1963 and 2012. Data on the numbers of cancer deaths were obtained from the published nationwide population register. Numbers of deaths from esophageal, gastric and colorectal cancer were available during the study period. However, the mortality data for hepatic, pancreatic and gallbladder cancer have been published only since 1979. Joinpoint regression was applied to investigate the annual trends in the rates of cancer mortality. The annual mortality rates of gastric and gallbladder cancer decreased throughout the study period. Furthermore, declines in mortality from esophageal and hepatic cancers have been observed since 1998 and 1995, respectively. However, the rates of colorectal and pancreatic cancer mortality have been increasing in the past few years. Nevertheless, the mortality rates of colorectal and pancreatic cancers have increased in males aged 40-59 years during the study period. Moreover, significantly higher risks of gastrointestinal cancer-related deaths have been observed in males as compared with females except for death related to cancer of the gallbladder. The presented data suggest that the Hungarian mortality rates are particularly high. The detection of gastrointestinal cancers at an early stage would significantly improves the outcome of these malignancies. PMID- 26965246 TI - Oxidative Stress, DNA, Cell Cycle/Cell Cycle Associated Proteins and Multidrug Resistance Proteins: Targets of Human Amniotic Membrane in Hepatocellular Carcinoma. AB - The anticancer effects of human amniotic membrane (hAM) have been studied over the last decade. However, the action mechanisms responsible for these effects are not fully understood until now. Previously results reported by our team proved that hAM is able to induce cytotoxicity and cell death in hepatocellular carcinoma (HCC), a worldwide high incident and mortal cancer. Therefore, this experimental study aimed to investigate the cellular targets of hAM protein extracts (hAMPE) in HCC through in vitro studies. Our results showed that hAMPE is able to modify oxidative stress environment in all HCC cell lines, as well as its cell cycle. hAMPE differently targets deoxyribonucleic acid (DNA), P21, P53, beta-catenin and multidrug resistance (MDR) proteins in HCC cell lines. In conclusion, hAMPE has several targets in HCC, being clear that the success of this treatment depends of a personalized therapy based on the biological and genetic characteristics of the tumor. PMID- 26965249 TI - Oropharyngeal NK/T-cell lymphoma presenting with bilateral uveitis. PMID- 26965247 TI - Surface deformation and shear flow in ligand mediated cell adhesion. AB - We present a unified, multiscale model to study the attachment/detachment dynamics of two deforming, charged, near spherical cells, coated with binding ligands and subject to a slow, homogeneous shear flow in a viscous, ionic fluid medium. The binding ligands on the surface of the cells experience both attractive and repulsive forces in an ionic medium and exhibit finite resistance to rotation via bond tilting. The microscale drag forces and couples describing the fluid flow inside the small separation gap between the cells, are calculated using a combination of methods in lubrication theory and previously published numerical results. For a selected range of material and fluid parameters, a hysteretic transition of the sticking probability curves (i.e., the function [Formula: see text]) between the adhesion phase (when [Formula: see text]) and the fragmentation phase (when [Formula: see text]) is attributed to a nonlinear relation between the total nanoscale binding forces and the separation gap between the cells. We show that adhesion is favoured in highly ionic fluids, increased deformability of the cells, elastic binders and a higher fluid shear rate (until a critical threshold value of shear rate is reached). Within a selected range of critical shear rates, the continuation of the limit points (i.e., the turning points where the slope of [Formula: see text] changes sign) predict a bistable region, indicating an abrupt switching between the adhesion and the fragmentation regimes. Although, bistability in the adhesion fragmentation phase diagram of two deformable, charged cells immersed in an ionic aqueous environment has been identified by some in vitro experiments, but until now, has not been quantified theoretically. PMID- 26965248 TI - [Early phase multimodality imaging in unilateral acute idiopathic maculopathy]. PMID- 26965250 TI - Insights into the Freiburg Anatomical Institute during National Socialism, 1933 1945. AB - The Anatomical Institute at the Albert-Ludwigs-Universitat Freiburg is among the anatomical departments for which a comprehensive account of its history during National Socialism (NS) is still missing. Previous investigations (such as in: Grun et al., 2002) have revealed the political activities of some anatomists, but, in the absence of relevant body-registers, a more comprehensive examination of the anatomical body procurement has not been attempted. The inspection of records in university and municipal archives allows insight into the activities in the institute within the historical context. The Freiburg Institute shared the experience of the impact of NS politics with other German anatomies. Four anatomists were dismissed because of NS racial discrimination, and chairman von Mollendorf left for political reasons. His successor Nauck's appointment was politically motivated, as he was a staunch Nazi. His colleagues were also members of NS political organizations. Body procurement was controversial between the public and the anatomists in Freiburg prior to and following the Third Reich, and much of the anatomists' efforts focused on the improvement of the body supply. In 1935, and, again during the war, the number of bodies was sufficient for anatomical education. Among the traditional sources of body procurement were increasing numbers of NS victims. Forty-four of them can be identified, among them 21 forced laborers and their children who died of so-called natural causes, and 22 men who had been executed at Stuttgart prison on April 6, 1943. While the victims' names have been ascertained, their biographies still need restoration to ensure an appropriate commemoration. PMID- 26965251 TI - Uncoupling EPA and DHA in Fish Nutrition: Dietary Demand is Limited in Atlantic Salmon and Effectively Met by DHA Alone. AB - Due to the scarcity of marine fish oil resources, the aquaculture industry is developing more efficient strategies for the utilization of dietary omega-3 long chain polyunsaturated fatty acids (n-3 LC-PUFA). A better understanding of how fish utilize EPA and DHA, typically provided by fish oil, is needed. However, EPA and DHA have different physiological functions, may be metabolized and incorporated into tissues differently, and may vary in terms of their importance in meeting the fatty acid requirements of fish. To address these questions, Atlantic salmon were fed experimental diets containing, as the sole added dietary lipid source, fish oil (positive control), tallow (negative control), or tallow supplemented with EPA, DHA, or both fatty acids to ~50 or 100% of their respective levels in the positive control diet. Following 14 weeks of feeding, the negative control diet yielded optimum growth performance. Though surprising, these results support the notion that Atlantic salmon requirements for n-3 LC PUFA are quite low. EPA was largely beta-oxidized and inefficiently deposited in tissues, and increasing dietary levels were associated with potential negative effects on growth. Conversely, DHA was completely spared from catabolism and very efficiently deposited into flesh. EPA bioconversion to DHA was largely influenced by substrate availability, with the presence of preformed DHA having little inhibitory effect. These results clearly indicate EPA and DHA are metabolized differently by Atlantic salmon, and suggest that the n-3 LC-PUFA dietary requirements of Atlantic salmon may be lower than reported and different, if originating primarily from EPA or DHA. PMID- 26965252 TI - Characterization of RNA-Protein Interactions: Lessons from Two RNA-Binding Proteins, SRSF1 and SRSF2. AB - SR proteins are a class of RNA-binding proteins whose RNA-binding ability is required for both constitutive and alternative splicing. While members of the SR protein family were once thought to have redundant functions, in-depth biochemical analysis of their RNA-binding abilities has revealed distinct binding profiles for each SR protein, that often lead to either synergistic or antagonistic functions. SR protein family members SRSF1 and SRSF2 are two of the most highly studied RNA-binding proteins. Here we examine the various methods used to differentiate SRSF1 and SRSF2 RNA-binding ability. We discuss the benefits and type of information that can be determined using each method. PMID- 26965253 TI - Identification of mRNA-Interacting Factors by MS2-TRAP (MS2-Tagged RNA Affinity Purification). AB - Posttranscriptional gene expression is governed by the interaction of mRNAs with vast families of RNA-binding proteins (RBPs) and noncoding (nc)RNAs. RBPs and ncRNAs jointly influence all aspects of posttranscriptional metabolism, including pre-mRNA splicing and maturation, mRNA transport, editing, stability, and translation. Given the impact of mRNA-interacting molecules on gene expression, there is great interest in identifying mRNA-binding factors comprehensively. Here, we provide a detailed protocol to tag mRNAs with MS2 hairpins and then affinity-purify trans-binding factors (RBPs, ncRNAs) associated with the MS2 tagged mRNA. This method, termed MS2-TRAP, permits the systematic characterization of ribonucleoprotein (RNP) complexes formed on a given mRNA of interest. We describe how to prepare the mRNA-MS2 expression vector, purify the MS2-tagged RNP complexes, and detect bound RNAs and RBPs, as well as variations of this methodology to address related questions of RNP biology. PMID- 26965254 TI - Biotin-Streptavidin Affinity Purification of RNA-Protein Complexes Assembled In Vitro. AB - RNA-protein complexes are essential for the function of different RNAs, yet purification of specific RNA-protein complexes can be complicated and is a major obstacle in understanding the mechanism of regulatory RNAs. Here we present a protocol to purify RNA-protein complexes assembled in vitro based on biotin streptavidin affinity. In vitro transcribed RNA is labeled with (32)P and biotin, ribonucleoprotein particles or RNPs are assembled by incubation of RNA in nuclear extract and fractionated using gel filtration, and RNP fractions are pooled for biotin-streptavidin affinity purification. The amount of RNA-protein complexes purified following this protocol is sufficient for mass spectrometry. PMID- 26965255 TI - Detecting RNA-Protein Interaction Using End-Labeled Biotinylated RNA Oligonucleotides and Immunoblotting. AB - RNA-protein interaction can be detected by RNA pull-down and immunoblotting methods. Here, we describe a method to detect RNA-protein interaction using RNA pull down and to identify the proteins that are pulled-down by the RNA using immunoblotting. In this protocol, RNAs with specific sequences are biotinylated and immobilized onto Streptavidin beads, which are then used to pull down interacting proteins from cellular extracts. The presence of a specific protein is subsequently verified by SDS- polyacrylamide gel electrophoresis and immunoblotting with antibodies. Interactions between the SMN RNA and the PSF protein and between the caspase-2 RNA and the SRSF3 protein (SRp20) in nuclear extract prepared from HeLa cells are illustrated as examples. PMID- 26965256 TI - Purification of RNA-Protein Splicing Complexes Using a Tagged Protein from In Vitro Splicing Reaction Mixture. AB - In eukaryotes, pre-mRNA splicing is an essential step for gene expression. Splicing reactions have been well investigated by using in vitro splicing reactions with extracts prepared from cultured cells. Here, we describe protocols for the preparation of splicing-competent extracts from cells expressing a tagged spliceosomal protein. The whole-cell extracts are able to splice exogenously added pre-mRNA and the RNA-protein complex formed in the in vitro splicing reaction can be purified by immunoprecipitation using antibodies against the peptide tag on the splicing protein. The method described here to prepare splicing-active extracts from whole cells is particularly useful when studying pre-mRNA splicing in various cell types, and the expression of a tagged spliceosomal protein allows one to purify and analyze the RNA-protein complexes by simple immunoprecipitation. PMID- 26965257 TI - Loading of Argonaute Protein with Small Duplex RNA in Cellular Extracts. AB - Argonaute (Ago) proteins are the minimum core proteins required for executing RNA interference (RNAi) mechanisms of gene regulation. For Ago proteins to regulate gene expression through RNAi they must be loaded, or "programmed," with a single strand of small RNA. Natural small RNAs are typically double-stranded duplexes that require additional factors for efficient and specific loading into Ago proteins. Here, a protocol is described for investigating RNAi programming through loading of human Ago2 using radiolabeled small interfering RNA (siRNA) and HeLa cell extracts. This protocol provides an Ago loading assay to study RNAi programming when starting with crude or partially purified cell extracts. The Ago loading assay should prove useful for studying other Ago proteins using a variety of mammalian cell extracts. PMID- 26965258 TI - In Vitro Analysis of Ribonucleoprotein Complex Remodeling and Disassembly. AB - Ribonucleoprotein (RNP) complexes play essential roles in gene expression. Their assembly and disassembly control the fate of mRNA molecules. Here, we describe a method that examines the remodeling and disassembly of RNPs. One unique aspect of this method is that the RNA-binding proteins (RBPs) of interest are produced in HeLa cells with or without the desired modification and the RNP is assembled in cellular extracts with synthetic RNA oligonucleotides. We use this method to investigate how ubiquitination of an RBP affects its ability to bind its RNA target. PMID- 26965259 TI - Single-Turnover Kinetics of Methyl Transfer to tRNA by Methyltransferases. AB - Methyl transfer from S-adenosyl methionine (abbreviated as AdoMet) to biologically active molecules such as mRNAs and tRNAs is one of the most fundamental and widespread reactions in nature, occurring in all three domains of life. The measurement of kinetic constants of AdoMet-dependent methyl transfer is therefore important for understanding the reaction mechanism in the context of biology. When kinetic constants of methyl transfer are measured in steady state over multiple rounds of turnover, the meaning of these constants is difficult to define and is often limited by non-chemical steps of the reaction, such as product release after each turnover. Here, the measurement of kinetic constants of methyl transfer by tRNA methyltransferases in rapid equilibrium binding condition for one methyl transfer is described. The advantage of such a measurement is that the meaning of kinetic constants can be directly assigned to the steps associated with the chemistry of methyl transfer, including the substrate binding affinity to the methyltransferase, the pre-chemistry re arrangement of the active site, and the chemical step of methyl transfer. An additional advantage is that kinetic constants measured for one methyl transfer can be correlated with structural information of the methyltransferase to gain direct insight into its reaction mechanism. PMID- 26965260 TI - Purification and Functional Reconstitution of Box H/ACA Ribonucleoprotein Particles. AB - Pseudouridylation is the most abundant and widespread RNA modification, and it plays an important role in modulating the structure and function of RNA. In eukaryotes and archaea, RNA pseudouridylation is catalyzed largely by box H/ACA ribonucleoproteins (RNPs), a distinct group of RNA-protein complexes each consisting of a unique RNA and four common proteins. The RNA component of the complex serves as a guide that base-pairs with its substrate RNA and specifies the target uridine to be modified. In order to systematically study the function and mechanism of pseudouridylation, it is desirable to have a reconstitution system in which biochemically purified/reconstituted box H/ACA RNPs are capable of introducing pseudouridines into an RNA at any target site. Here, we describe a method for the reconstitution of functional box H/ACA RNPs using designer box H/ACA guide RNAs, which in principle can be adopted to reconstitute other RNA protein complexes as well. PMID- 26965261 TI - Northwestern Blot Analysis: Detecting RNA-Protein Interaction After Gel Separation of Protein Mixture. AB - Northwestern assays detect a direct binding of a given RNA molecule to a protein immobilized on a nitrocellulose membrane. Here, we describe protocols to prepare (32)P-labeled RNA probes and to use them to assay for RNA-protein interactions after partially purified protein preparations are resolved on denaturing SDS polyacrylamide gels. The method can unambiguously determine whether the protein of interest can directly and independently bind RNA even in the presence of contaminating bacterial proteins or degradation products that at times may hinder interpretation of results obtained from gel mobility shift or RNP immunoprecipitation assays. PMID- 26965262 TI - Measuring mRNA Translation by Polysome Profiling. AB - Determination of mRNA translation rates is essential to understanding the regulatory pathways governing eukaryotic gene expression. In this chapter, we present a transcriptome-wide method to assess translation by association of mRNAs with polysomes on sucrose density gradients. After sedimentation, the fractions are spiked with a control RNA mixture and the RNA content is measured by high throughput sequencing. Normalization to the spike-ins provides a global quantitative view on the translational status of cellular mRNAs, with the ability to measure changes and identify active and silent subpopulations of each. PMID- 26965263 TI - Genome-Wide Profiling of RNA-Protein Interactions Using CLIP-Seq. AB - UV crosslinking immunoprecipitation (CLIP) is an increasingly popular technique to study protein-RNA interactions in tissues and cells. Whole cells or tissues are ultraviolet irradiated to generate a covalent bond between RNA and proteins that are in close contact. After partial RNase digestion, antibodies specific to an RNA binding protein (RBP) or a protein-epitope tag is then used to immunoprecipitate the protein-RNA complexes. After stringent washing and gel separation the RBP-RNA complex is excised. The RBP is protease digested to allow purification of the bound RNA. Reverse transcription of the RNA followed by high throughput sequencing of the cDNA library is now often used to identify protein bound RNA on a genome-wide scale. UV irradiation can result in cDNA truncations and/or mutations at the crosslink sites, which complicates the alignment of the sequencing library to the reference genome and the identification of the crosslinking sites. Meanwhile, one or more amino acids of a crosslinked RBP can remain attached to its bound RNA due to incomplete digestion of the protein. As a result, reverse transcriptase may not read through the crosslink sites, and produce cDNA ending at the crosslinked nucleotide. This is harnessed by one variant of CLIP methods to identify crosslinking sites at a nucleotide resolution. This method, individual nucleotide resolution CLIP (iCLIP) circularizes cDNA to capture the truncated cDNA and also increases the efficiency of ligating sequencing adapters to the library. Here, we describe the detailed procedure of iCLIP. PMID- 26965264 TI - Identification of Endogenous mRNA-Binding Proteins in Yeast Using Crosslinking and PolyA Enrichment. AB - The maturation, localization, stability, and translation of messenger RNAs (mRNAs) are regulated by a wide variety of mRNA-binding proteins. Identification of the complete set of mRNA-binding proteins is a key step in understanding the regulation of gene expression. Herein, we describe a method for identifying yeast mRNA-binding proteins in a systematic manner using UV crosslinking, purification of polyA(+) mRNAs under denaturing conditions, and mass spectrometry to identify covalently bound proteins. PMID- 26965265 TI - Ribo-Proteomics Approach to Profile RNA-Protein and Protein-Protein Interaction Networks. AB - Characterizing protein-protein and protein-RNA interaction networks is a fundamental step to understanding the function of an RNA-binding protein. In many cases, these interactions are transient and highly dynamic. Therefore, capturing stable as well as transient interactions in living cells for the identification of protein-binding partners and the mapping of RNA-binding sequences is key to a successful establishment of the molecular interaction network. In this chapter, we will describe a method for capturing the molecular interactions in living cells using formaldehyde as a crosslinker and enriching a specific RNA-protein complex from cell extracts followed by mass spectrometry and Next-Gen sequencing analyses. PMID- 26965266 TI - Detection of Protein-Protein Interaction Within an RNA-Protein Complex Via Unnatural-Amino-Acid-Mediated Photochemical Crosslinking. AB - Although DExD/H-box proteins are known to unwind RNA duplexes and modulate RNA structures in vitro, it is highly plausible that, in vivo, some may function to remodel RNA-protein complexes. Precisely how the latter is achieved remains a mystery. We investigated this critical issue by using yeast Prp28p, an evolutionarily conserved DExD/H-box splicing factor, as a model system. To probe how Prp28p interacts with spliceosome, we strategically placed p-benzoyl phenylalanine (BPA), a photoactivatable unnatural amino acid, along the body of Prp28p in vivo. Extracts prepared from these engineered strains were then used to assemble in vitro splicing reactions for BPA-mediated protein-protein crosslinkings. This enabled us, for the first time, to "capture" Prp28p in action. This approach may be applicable to studying the roles of other DExD/H-box proteins functioning in diverse RNA-related pathways, as well as to investigating protein-protein contacts within an RNA-protein complex. PMID- 26965267 TI - Evolution of Cell-Type-Specific RNA Aptamers Via Live Cell-Based SELEX. AB - Live cell-based SELEX (Systematic Evolution of Ligand EXponential enrichment) is a promising approach for identifying aptamers that can selectively bind to a cell surface antigen or a particular target cell population. In particular, it offers a facile selection strategy for some special cell-surface proteins that are original glycosylated or heavily post-translationally modified, and are unavailable in their native/active conformation after in vitro expression and purification. In this chapter, we describe evolution of cell-type-specific RNA aptamers targeting the human CCR5 by combining the live cell-based SELEX strategy with high-throughput sequencing (HTS) and bioinformatics analysis. PMID- 26965268 TI - mCarts: Genome-Wide Prediction of Clustered Sequence Motifs as Binding Sites for RNA-Binding Proteins. AB - RNA-binding proteins (RBPs) are critical components of post-transcriptional gene expression regulation. However, their binding sites have until recently been difficult to determine due to the apparent low specificity of RBPs for their target transcripts and the lack of high-throughput assays for analyzing binding sites genome wide. Here we present a bioinformatics method for predicting RBP binding motif sites on a genome-wide scale that leverages motif conservation, RNA secondary structure, and the tendency of RBP binding sites to cluster together. A probabilistic model is learned from bona fide binding sites determined by CLIP and applied genome wide to generate high specificity binding site predictions. PMID- 26965269 TI - Design of RNA-Binding Proteins: Manipulate Alternative Splicing in Human Cells with Artificial Splicing Factors. AB - The majority of human genes undergo alternative splicing to produce multiple isoforms with distinct functions. The dysregulations of alternative splicing have been found to be closely associated with various human diseases; thus new approaches to modulate disease-associated splicing events will provide great therapeutic potentials. Here we report protocols for constructing novel artificial splicing factors that can be designed to specifically modulate alternative splicing of target genes. By following the method outlined in this protocol, it is possible to design and generate artificial splicing factors with diverse activities in regulating different types of alternative splicing. The artificial splicing factors can be used to change splicing of either minigenes or endogenous genes in cultured human cells, providing a new strategy to study the regulation of alternative splicing and function of alternatively spliced products. PMID- 26965270 TI - Informational Suppression to Probe RNA:RNA Interactions in the Context of Ribonucleoproteins: U1 and 5' Splice-Site Base-Pairing. AB - Informational suppression is a method to map specific RNA:RNA interactions by taking advantage of the rules of base complementarity. First, a predicted Watson Crick base pair is broken by single-nucleotide substitution which disrupts the RNA's structure and/or function. Second, the base pair is restored by mutating the opposing nucleotide, thereby rescuing structure and/or function. This method applies to RNP:RNA interactions such as 5' splice-site (5'ss) base-pairing to the 5' end of U1 small nuclear RNA as part of a small nuclear RNP. Our protocol aims to determine the 5'ss:U1 base-pairing register for natural 5'ss, because for distinct 5'ss sequences the nucleotides on each strand can be aligned differently. This methodology includes cloning of a wild-type splicing minigene and introduction of 5'ss variants by PCR mutagenesis. A U1-expression plasmid is mutated to construct "suppressor U1" snRNAs with restored base-pairing to mutant 5'ss in different registers. Cells are transfected with combinations of minigenes and suppressor U1s, and the splicing patterns are analyzed by reverse transcription and semiquantitative PCR, followed by gel electrophoresis. The identity of suppressor U1s that rescue splicing for specific mutations indicates the register used in that 5'ss. We also provide tips to adapt this protocol to other minigenes or registers. PMID- 26965271 TI - Analysis of Alternative Pre-RNA Splicing in the Mouse Retina Using a Fluorescent Reporter. AB - In vivo alternative splicing is controlled in a tissue and cell type specific manner. Often individual cellular components of complex tissues will express different splicing programs. Thus, when studying splicing in multicellular organisms it is critical to determine the exon inclusion levels in individual cells positioned in the context of their native tissue or organ. Here we describe how a fluorescent splicing reporter in combination with in vivo electroporation can be used to visualize alternative splicing in individual cells within mature tissues. In a test case we show how the splicing of a photoreceptor specific exon can be visualized within the mouse retina. The retina was chosen as an example of a complex tissue that is fragile and whose cells cannot be studied in culture. With minor modifications to the injection and electroporation procedure, the protocol we outline can be applied to other tissues and organs. PMID- 26965272 TI - Prior colorectal surgery for endometriosis-associated infertility improves ICSI IVF outcomes: results from two expert centres. AB - OBJECTIVE(S): To assess fertility outcomes after ICSI-IVF in infertile women having undergone prior complete surgical removal of colorectal endometriosis. STUDY DESIGN: Prospective longitudinal cohort study in two referral French centres including 60 infertile women who underwent ICSI-IVF after complete surgical removal of colorectal endometriosis, from January 2005 to May 2014. Women underwent either conservative colorectal surgery (i.e., rectal shaving or full thickness disc excision, n=18) or segmental colorectal resection (n=42). Clinical pregnancies were defined by the presence of a gestational sac on vaginal ultrasound examination from the fifth week. The overall pregnancy rate was calculated. The Kaplan-Meier method was used to estimate the cumulative pregnancy rate (CPR). Comparisons of CPR were made using the log-rank test to detect determinant factors. RESULTS: The median number of ICSI-IVF cycles per patient was one (range: 1-4). Of the 60 women, 36 became pregnant (i.e., overall pregnancy rate=60%). The CPR was 41.7% after one ICSI-IVF cycle, 65% after two ICSI-IVF cycles and 78.1% after three ICSI-IVF cycles. A decreased CPR was observed for women who required segmental colorectal resection compared to those who underwent rectal shaving or full thickness disc excision (p=0.04). A trend for a decreased CPR was observed for women who received a first ICSI-IVF cycle more than 18 months following surgery (p=0.07). Among the nine women with prior ICSI-IVF failure, five (55.5%) became pregnant after surgery. CONCLUSION(S): Colorectal surgery for endometriosis completed by ICSI-IVF is a good option for women with proven infertility, even if prior ICSI-IVF had failed. PMID- 26965273 TI - Start-up of sequencing batch reactor with Thiosphaera pantotropha for treatment of high-strength nitrogenous wastewater and sludge characterization. AB - Biological treatment of high-strength nitrogenous wastewater is challenging due to low growth rate of autotrophic nitrifiers. This study reports bioaugmentation of Thiosphaera pantotropha capable of simultaneously performing heterotrophic nitrification and aerobic denitrification (SND) in sequencing batch reactors (SBRs). SBRs fed with 1:1 organic-nitrogen (N) and NH4+-N were started up with activated sludge and T. pantotropha by gradual increase in N concentration. Sludge bulking problems initially observed could be overcome through improved aeration and mixing and change in carbon source. N removal decreased with increase in initial nitrogen concentration, and only 50-60 % removal could be achieved at the highest N concentration of 1000 mg L-1 at 12-h cycle time. SND accounted for 28 % nitrogen loss. Reducing the settling time to 5-10 min and addition of divalent metal ions gradually improved the settling characteristics of sludge. Sludge aggregates of 0.05-0.2 mm diameter, much smaller than typical aerobic granules, were formed and progressive increase in settling velocity, specific gravity, Ca2+, Mg2+, protein, and polysaccharides was observed over time. Granulation facilitated total nitrogen (TN) removal at a constant rate over the entire 12-h cycle and thus increased TN removal up to 70 %. Concentrations of NO2--N and NO3--N were consistently low indicating effective denitrification. Nitrogen removal was possibly limited by urea hydrolysis/nitrification. Presence of T. pantotropha in the SBRs was confirmed through biochemical tests and 16S rDNA analysis. PMID- 26965274 TI - Prenatal low-level mercury exposure and infant neurodevelopment at 12 months in rural northern China. AB - Although MeHg is a confirmed neurotoxin at sufficiently high dosages, the effect of prenatal low-level Hg exposure on infant neurodevelopment is still unknown. Four hundred ten mother-infant pairs were recruited in rural northern China from September 2010 to September 2012. We investigated maternal diet during pregnancy, collected maternal and umbilical blood samples, and tested infant neurodevelopment using Gesell developmental schedules (GDS) at the age of 1 year old. The geometric means (GM) of Hg exposure in maternal and umbilical blood were 0.72 and 1.2 MUg/L, respectively. Positive associations between Hg levels and the frequency of total fish consumption were found (Spearman's correlation, r = 0.09 for maternal Hg, r = 0.14 for umbilical Hg, p < 0.01). After adjusting for confounding factors, we found a log-unit increase in umbilical blood Hg levels was associated with a 4.22-point (95 % confidence interval (95 %CI) 0.77 to 7.67) increase in the adaptive domain and a 4.06-point (95 %CI 0.51 to 7.62) increase in the social domain. No significant association has been found between other domains and Hg levels in our study. In further analysis, we noticed the positive correlation between the developmental quotient (DQ) scores of the adaptive domain and frequencies of total fish consumption (p = 0.04). Our results failed to indicate the adverse effects between prenatal Hg exposure and infant neurodevelopment. However, given the low-level Hg exposure and its predominant source, the potential positive associations in our study may be attributed to the beneficial nutrients of fish consumption. PMID- 26965275 TI - Subtype analysis of Giardia duodenalis isolates from municipal and domestic raw wastewaters in Iran. AB - A total of 54 raw wastewater samples collected from three urban treatment plants and two slaughterhouses in Tehran, Iran, were assessed for the presence of the Giardia cysts using immunofluorescence with monoclonal antibodies. To characterize the cysts at the molecular level, the three genetic loci were amplified and sequenced. The assemblages A (37.5 %) and E (58.3 %) were detected in livestock wastewater samples. Assemblage A, which is composed of only G. duodenalis genotype, was detected in 100 % of urban wastewater samples. The subassemblages A2, A3, A-I, A-II, and E3 were identified with beta-giardin, triose phosphate isomerase, and glutamate dehydrogenase genes. This study is the first to report on G. duodenalis genotypes in aquatic environmental samples in Iran. PMID- 26965277 TI - Effects of gravel on infiltration, runoff, and sediment yield in landslide deposit slope in Wenchuan earthquake area, China. AB - Amounts of landslide deposits were triggered by the Wenchuan earthquake with magnitude 8.0 on May 12, 2008. The landslide deposits were composed of soil and rock fragments, which play important roles in hydrological and erosion processes in the steep slope of landslide deposits. The mixtures of soil and gravels are common in the top layers of landslide deposits, and its processes are obviously different with the soil without gravels. Based on the data of field investigation, a series of simulated scouring flow experiments with four proportion of gravel (0, 25, 33.3, and 50 %) and three scouring flow rates (4, 8, 12 L/min) under two steep slopes (67.5, 72.7 %) were conducted sequentially to know the effects of proportion of gravel on infiltration capacity, runoff generation, and sediment production in the steep slope of landslide deposit. Results indicated that gravel had promoted or reduced effects on infiltration capacity which could affect further the cumulative runoff volume and cumulative sediment mass increase or decrease. The cumulative infiltration volume in 25 % proportion of gravel was less than those in 0, 33.3, and 50 % proportion of gravel. The cumulative runoff volume was in an order of 25 > 0 > 33.3 > 50 % while cumulative sediment mass ranked as 25 > 33.3 > 0 > 50 % with different proportions of gravel. A significant power relationship was found between scouring time and cumulative runoff volume as well as cumulative sediment mass. The relationship between average soil and water loss rate and proportion of gravel was able to express by quadratic function, with a high degree of reliability. The results have important implications for soil and water conservation and modeling in landslide deposit but also provide useful information for the similar conditions. PMID- 26965276 TI - Bioanalytical and instrumental screening of the uptake of sediment-borne, dioxin like compounds in roach (Rutilus rutilus). AB - To examine the uptake of dioxin-like compounds (DLCs), common roaches (Rutilus rutilus) were exposed for 28 days to differently contaminated sediments from two major European rivers in a purpose-built facility. Dietary transfer of DLCs was investigated by exposing fish to sediments inoculated or non-inoculated with black worms (Lumbriculus variegatus). Dioxin-like polychlorinated biphenyls (DL PCBs), polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), measured via high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS) in sediments and whole fish, were used to calculate toxicity equivalent quotients (TEQs). TEQs were compared with biological toxicity equivalent quotients (BEQs) determined via the 7-ethoxyresorufin-O-deethylase (EROD) assay, performed with mammalian (H4IIE) and fish (RTL-W1) liver cell lines. TEQs and BEQs indicated an uptake of sediment-borne DLCs by roach, which was independent of sediment contamination levels, but rather reflected sediment specific characteristics. For most sediment treatments, DLC uptake did not increase with time. Highest congener-specific uptake (DL-PCB 123) was 10-fold compared to control. Exposure to worm-inoculated sediment of highest overall DLC contamination caused a 2-fold (TEQ and H4IIE BEQ) greater uptake of DLCs by fish compared to the respective non-inoculated treatment. H4IIE cells showed the greatest sensitivity (0.37 +/- 0.25 pM TCDD) and the strongest correlation with TEQs (r (2) = 0.79), hence, they seem to be best suited for DLC screening of sediments and biota, amended by compound-specific instrumental analysis if required. PMID- 26965278 TI - Differential toxicity of Al2O3 particles on Gram-positive and Gram-negative sediment bacterial isolates from freshwater. AB - The current study was aimed to explore the differential effects on Gram-positive and Gram-negative freshwater sediment bacterial isolates upon exposure to nano particles and bulk particles of Al2O3 at low concentrations (0.25, 0.5, and 1 mg/L). The Gram-negative Pseudomonas aeruginosa was more susceptible to both the nano-forms and bulk forms than the Gram-positive Bacillus altitudinis. The generation of reactive oxygen species (ROS) and release of lipopolysaccharide due to membrane damage were dependent on the dose of nano-Al2O3. The Fourier transform infrared spectroscopy (FT-IR) studies confirmed the attachment of nano Al2O3 on bacterial cells, which may lead to subsequent changes in the cell membrane composition and integrity. Internalization of nano-Al2O3 was estimated to be more for P. aeruginosa than for B. altitudinis cells. As a role of defense mechanism, the biofilm formation and production of extracellular polymeric substances (EPSs; polysaccharide and protein) were increased with respect to the concentration of toxicant. Nano-Al2O3 was estimated to cause more DNA damage than the bulk particles in both Gram-positive and Gram-negative bacterial strains. PMID- 26965279 TI - Conductometric measurement of the changes in humic substances caused by ozone oxidation. AB - Humic substances (HS), a broad category of organic compounds and a major constituent of soil, are responsible for serious problems during water purification processes. In particular, HS react with chlorine during disinfection processes to produce a variety of organochlorine compounds such as trihalomethanes (THMs), which are potentially carcinogenic to humans. The use of ozone as a disinfection method represents a potential solution to this problem; however, HS that are not completely oxidized may form by-products more reactive than the original molecules. The structural changes of HS during oxidation with ozone were evaluated through a replicated 2(2) design, where concentrations of 5 and 30 mg/L of two commercial HS (Aldrich and Fluka) were ozonized over different time intervals (0, 10, and 20 min). The ozone-treated HS were titrated with acid and base solutions, and the shifts of the slopes were then analyzed and finally related to the ionic alterations of the HS. The Aldrich HS (AHS) showed only protonated functional groups; the Fluka HS (FHS) showed only ionized groups; and in both cases, the amount of functional groups increased with increasing ozonation. For AHS and FHA, respectively, the maximum ozone exposure time (20 min) and the highest concentration of HS (30 mg/L) produced the greatest reductions in total organic carbon (TOC) (39 and 34 %), UV254 (50 and 60.8 %), and color (16.4 and 19.6 %). As for aromaticity, AHS showed removals of 39.6 % (from a starting concentration of 5 mg/L) and 17.2 % (from a starting concentration of 30 mg/L). FHS showed the opposite effect, with removals of 33.3 % (starting at 5 mg/L) and 40.1 % (starting at 30 mg/L). In this study, the structural changes of HS submitted to ozonation were inferred in a relatively quick and easy way by using a conductometric titration, thus demonstrating the applicability of the technique. PMID- 26965281 TI - Geochemical modeling and assessment of leaching from carbonated municipal solid waste incinerator (MSWI) fly ash. AB - Municipal solid waste incinerator (MSWI) fly ashes are characterized by high calcium oxide (CaO) content. Carbon dioxide (CO2) adsorption by MSWI fly ash was discussed based on thermogravimetry (TG)/differential thermal analysis (DTA), minerology analysis, and adapting the Stenoir equation. TG/DTA analysis showed that the weight gain of the fly ash below 440 degrees C was as high as 5.70 %. An adapted Stenoir equation for MSWI fly ash was discussed. The chloride in MSWI fly ash has a major impact on CO2 adsorption by MSWI fly ash or air pollution control (APC) residues. Geochemical modeling of the critical trace elements copper (Cu), cadmium (Cd), zinc (Zn), lead (Pb), and antimony (Sb) before and after carbonation was performed using a thermodynamic equilibrium model for solubility and a surface complexation model for metal sorption. Leaching of critical trace elements was generally found to be strongly dependent on the degree of carbonation attained, and their solubility appeared to be controlled by several minerals. Adsorption on ferrum (Fe) and aluminum (Al) colloids was also responsible for removal of the trace elements Cd, Pb, and Sb. We used Hakanson's potential ecological risk index (HPERI) to evaluate the risk of trace element leaching in general. The results demonstrate that the ecological risk showed a V shaped dependency on pH; the optimum pH of the carbonated fly ash was found to be 10.3-11, resulting from the optimum carbonation (liquid-to-solid (L/S) ratio = 0.25, carbonation duration = ~30-48 h). The dataset and modeling results presented here provide a contribution to assessing the leaching behavior of MSWI fly ash under a wide range of conditions. PMID- 26965282 TI - vox homeobox gene: a novel regulator of midbrain-hindbrain boundary development in medaka fish? AB - The midbrain-hindbrain boundary (MHB) is one of the key organizing centers of the vertebrate central nervous system (CNS). Its patterning is governed by a well described gene regulatory network (GRN) involving several transcription factors, namely, pax, gbx, en, and otx, together with signaling molecules of the Wnt and Fgf families. Here, we describe the onset of these markers in Oryzias latipes (medaka) early brain development in comparison to previously known zebrafish expression patterns. Moreover, we show for the first time that vox, a member of the vent gene family, is expressed in the developing neural tube similarly to CNS markers. Overexpression of vox leads to profound changes in the gene expression patterns of individual components of MHB-specific GRN, most notably of fgf8, a crucial organizer molecule of MHB. Our data suggest that genes from the vent family, in addition to their crucial role in body axis formation, may play a role in regionalization of vertebrate CNS. PMID- 26965283 TI - Relative DNA content in diploid, polyploid, and multiploid species of Paspalum (Poaceae) with relation to reproductive mode and taxonomy. AB - It is generally accepted that polyploids have downsized basic genomes rather than additive values with respect to their related diploids. Changes in genome size have been reported in correlation with several biological characteristics. About 75 % of around 350 species recognized for Paspalum (Poaceae) are polyploid and most polyploids are apomictic. Multiploid species are common with most of them bearing sexual diploid and apomictic tetraploid or other ploidy levels. DNA content in the embryo and the endosperm was measured by flow cytometry in a seed by-seed analysis of 47 species including 77 different entities. The relative DNA content of the embryo informed the genome size of the accession while the embryo:endosperm ratio of DNA content revealed its reproductive mode. The genome sizes (2C-value) varied from 0.5 to 6.5 pg and for 29 species were measured for the first time. Flow cytometry provided new information on the reproductive mode for 12 species and one botanical variety and supplied new data for 10 species concerning cytotypes reported for the first time. There was no significant difference between the mean basic genome sizes (1Cx-values) of 32 sexual and 45 apomictic entities. Seventeen entities were diploid and 60 were polyploids with different degrees. There were no clear patterns of changes in 1Cx-values due to polyploidy or reproductive systems, and the existing variations are in concordance with subgeneric taxonomical grouping. PMID- 26965280 TI - A review of toxicity and mechanisms of individual and mixtures of heavy metals in the environment. AB - The rational for the study was to review the literature on the toxicity and corresponding mechanisms associated with lead (Pb), mercury (Hg), cadmium (Cd), and arsenic (As), individually and as mixtures, in the environment. Heavy metals are ubiquitous and generally persist in the environment, enabling them to biomagnify in the food chain. Living systems most often interact with a cocktail of heavy metals in the environment. Heavy metal exposure to biological systems may lead to oxidation stress which may induce DNA damage, protein modification, lipid peroxidation, and others. In this review, the major mechanism associated with toxicities of individual metals was the generation of reactive oxygen species (ROS). Additionally, toxicities were expressed through depletion of glutathione and bonding to sulfhydryl groups of proteins. Interestingly, a metal like Pb becomes toxic to organisms through the depletion of antioxidants while Cd indirectly generates ROS by its ability to replace iron and copper. ROS generated through exposure to arsenic were associated with many modes of action, and heavy metal mixtures were found to have varied effects on organisms. Many models based on concentration addition (CA) and independent action (IA) have been introduced to help predict toxicities and mechanisms associated with metal mixtures. An integrated model which combines CA and IA was further proposed for evaluating toxicities of non-interactive mixtures. In cases where there are molecular interactions, the toxicogenomic approach was used to predict toxicities. The high throughput toxicogenomics combines studies in genetics, genome-scale expression, cell and tissue expression, metabolite profiling, and bioinformatics. PMID- 26965284 TI - MIM regulates the trafficking of bone marrow cells via modulating surface expression of CXCR4. AB - Missing in metastasis (MIM) is abundantly expressed in hematopoietic cells. Here we characterized the impact of MIM deficiency on murine bone marrow (BM) cells. Although MIM(-/-) cells proliferated similarly to wild type (WT), they exhibited stronger response to chemokine stromal-derived factor 1 (SDF-1), increase in surface expression of CXCR4, impaired CXCR4 internalization and constitutive activation of Rac, Cdc42 and p38. Transplantation of MIM(-/-) BM cells into lethally irradiated mice showed enhanced homing to BM, which was abolished when mice were pretreated with a p38 antagonist. Interestingly, MIM(-/-) BM cells, including hematopoietic stem and progenitor cells (HSPCs), showed two- to fivefold increase in mobilization into the peripheral blood upon treatment with AMD3100. In vitro, MIM(-/-) leukocytes were susceptible to AMD3100 and maintained increased response to AMD3100 for mobilization even after transfer into WT mice. MIM(-/-) mice had also a higher level of SDF-1 in the circulation. Our data highlighted an unprecedented role of MIM in the homeostasis of BM cells, including HSPCs, through modulation of the CXCR4/SDF-1 axis and interactions of BM leukocytes with their microenvironments. PMID- 26965285 TI - Targeting the PI3K/Akt pathway in murine MDS/MPN driven by hyperactive Ras. AB - Chronic and juvenile myelomonocytic leukemias (CMML and JMML) are myelodysplastic/myeloproliferative neoplasia (MDS/MPN) overlap syndromes that respond poorly to conventional treatments. Aberrant Ras activation because of NRAS, KRAS, PTPN11, CBL and NF1 mutations is common in CMML and JMML. However, no mechanism-based treatments currently exist for cancers with any of these mutations. An alternative therapeutic strategy involves targeting Ras-regulated effector pathways that are aberrantly activated in CMML and JMML, which include the Raf/MEK/ERK and phosphoinositide-3'-OH kinase (PI3K)/Akt cascades. Mx1-Cre, Kras(D12) and Mx1-Cre, Nf1(flox/)(-) mice accurately model many aspects of CMML and JMML. Treating Mx1-Cre, Kras(D12) mice with GDC-0941 (also referred to as pictilisib), an orally bioavailable inhibitor of class I PI3K isoforms, reduced leukocytosis, anemia and splenomegaly while extending survival. However, GDC-0941 treatment attenuated activation of both PI3K/Akt and Raf/MEK/ERK pathways in primary hematopoietic cells, suggesting it could be acting through suppression of Raf/MEK/ERK signals. To interrogate the importance of the PI3K/Akt pathway specifically, we treated mice with the allosteric Akt inhibitor MK-2206. This compound had no effect on Raf/MEK/ERK signaling, yet it also induced robust hematologic responses in Kras and Nf1 mice with MPN. These data support investigating PI3K/Akt pathway inhibitors as a therapeutic strategy in JMML and CMML patients. PMID- 26965287 TI - Does the medical treatment for prolactinoma remain the standard of care? PMID- 26965286 TI - A novel gene expression signature for bone metastasis in breast carcinomas. AB - Metastatic cancer remains the leading cause of death for patients with breast cancer. To understand the mechanisms underlying the development of distant metastases to specific sites is therefore important and of potential clinical value. From 157 primary breast tumours of the patients with known metastatic disease, gene expression profiling data were generated and correlated to metastatic behaviour including site-specific metastasis, metastasis pattern and survival outcomes. We analysed gene expression signatures specifically associated with the development of bone metastases. As a validation cohort, we used a published dataset of 376 breast carcinomas for which gene expression data and site-specific metastasis information were available. 80.5 % of luminal-type tumours developed bone metastasis as opposed to 41.7 % of basal and 55.6 % of HER2-like tumours. A novel 15-gene signature identified 82.4 % of the tumours with bone metastasis, 85.2 % of the tumours which had bone metastasis as first site of metastasis and 100 % of the ones with bone metastasis only (p 9.99e-09), in the training set. In the independent dataset, 81.2 % of the positive tested tumours had known metastatic disease to the bone (p 4.28e-10). This 15-gene signature showed much better correlation with the development of bone metastases than previously identified signatures and was predictive in both ER-positive as well as in ER-negative tumours. Multivariate analyses revealed that together with the molecular subtype, our 15-gene expression signature was significantly correlated to bone metastasis status (p <0.001, 95 % CI 3.86-48.02 in the training set; p 0.001, 95 % CI 1.54-5.00 in the independent set). The 15 genes, APOPEC3B, ATL2, BBS1, C6orf61, C6orf167, MMS22L, KCNS1, MFAP3L, NIP7, NUP155, PALM2, PH-4, PGD5, SFT2D2 and STEAP3, encoded mainly membrane-bound molecules with molecular function of protein binding. The expression levels of the up regulated genes (NAT1, BBS1 and PH-4) were also found to be correlated to epithelial to mesenchymal transition status of the tumour. We have identified a novel 15-gene expression signature associated with the development of bone metastases in breast cancer patients. This bone metastasis signature is the first to be identified using a supervised classification approach in a large series of patients and will help forward research in this area towards clinical applications. PMID- 26965288 TI - Linoleic acid-derived lipid mediators increase in a female-dominated subphenotype of COPD. AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality; however, the role of inflammatory mediators in its pathobiology remains unclear. The aim of this study was to investigate the influence of gender in COPD on lipid mediator levels.Bronchoalveolar lavage fluid (BALF) and serum were obtained from healthy never-smokers, smokers and COPD patients (Global Initiative for Chronic Obstructive Lung Disease stage I-II/A-B) (n=114). 94 lipid mediators derived from the cytochrome-P450, lipoxygenase, and cyclooxygenase pathways were analysed by liquid chromatography-mass spectrometry.Multivariate modelling identified a 9 lipid panel in BALF that classified female smokers with COPD from healthy female smokers (p=6*10(-6)). No differences were observed for the corresponding male population (p=1.0). These findings were replicated in an independent cohort with 92% accuracy (p=0.005). The strongest drivers were the cytochrome P450-derived epoxide products of linoleic acid (leukotoxins) and their corresponding soluble epoxide hydrolase (sEH)-derived products (leukotoxin-diols). These species correlated with lung function (r=0.87; p=0.0009) and mRNA levels of enzymes putatively involved in their biosynthesis (r=0.96; p=0.003). Leukotoxin levels correlated with goblet cell abundance (r=0.72; p=0.028).These findings suggest a mechanism by which goblet cell-associated cytochrome-P450 and sEH activity produce elevated leukotoxin-diol levels, which play a putative role in the clinical manifestations of COPD in a female-dominated disease sub-phenotype. PMID- 26965289 TI - Low yield of screening asylum seekers from countries with a tuberculosis incidence of <50 per 100 000 population. PMID- 26965291 TI - Follow-up of pulmonary right-to-left shunt in hereditary haemorrhagic telangiectasia. AB - Pulmonary arteriovenous malformations (PAVMs) are associated with severe neurological complications in hereditary haemorrhagic telangiectasia (HHT). Transthoracic contrast echocardiography (TTCE) is recommended for screening of pulmonary right-to-left shunts (RLS). Although growth of PAVMs is shown in two small studies, no studies on follow-up with TTCE exist.All HHT patients underwent a second TTCE 5 years after initial screening. Patients with a history of PAVM embolisation were excluded. Pulmonary RLS grade on TTCE after 5 years was compared to the grade at screening.200 patients (53.5% female, mean+/-sd age at screening 44.7+/-14.1 years) were included. Increase in RLS grade occurred in 36 (18%) patients, of whom six (17%) underwent embolisation. The change in grade between screening and follow-up was not more than one grade. Of patients with nontreatable pulmonary RLS at screening (n=113), 14 (12.4%) underwent embolisation. In patients without pulmonary RLS at initial screening (n=87), no treatable PAVMs developed during follow-up.Within 5 years, no treatable PAVMs developed in HHT patients without pulmonary RLS at initial screening. Increase in pulmonary RLS grade occurred in 18% of patients, and never increased by more than one grade. Of patients with nontreatable pulmonary RLS at initial screening, 12% underwent embolisation. PMID- 26965290 TI - Effectiveness and safety of meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB. AB - No large study has ever evaluated the efficacy, safety and tolerability of meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to evaluate the therapeutic contribution, effectiveness, safety and tolerability profile of meropenem/clavulanate added to a background regimen when treating MDR- and XDR-TB cases.Patients treated with a meropenem/clavulanate-containing regimen (n=96) showed a greater drug resistance profile than those exposed to a meropenem/clavulanate-sparing regimen (n=168): in the former group XDR-TB was more frequent (49% versus 6.0%, p<0.0001) and the median (interquartile range (IQR)) number of antibiotic resistances was higher (8 (6-9)versus 5 (4-6)). Patients were treated with a meropenem/clavulanate-containing regimen for a median (IQR) of 85 (49-156) days.No statistically significant differences were observed in the overall MDR-TB cohort and in the subgroups with and without the XDR-TB patients; in particular, sputum smear and culture conversion rates were similar in XDR-TB patients exposed to meropenem/clavulanate-containing regimens (88.0% versus 100.0%, p=1.00 and 88.0% versus 100.0%, p=1.00, respectively). Only six cases reported adverse events attributable to meropenem/clavulanate (four of them then restarting treatment).The nondifferent outcomes and bacteriological conversion rate observed in cases who were more severe than controls might imply that meropenem/clavulanate could be active in treating MDR- and XDR-TB cases. PMID- 26965292 TI - Resting pulmonary artery pressure of 21-24 mmHg predicts abnormal exercise haemodynamics. AB - A resting mean pulmonary artery pressure (mPAP) of 21-24 mmHg is above the upper limit of normal but does not reach criteria for the diagnosis of pulmonary hypertension (PH). We sought to determine whether an mPAP of 21-24 mmHg is associated with an increased risk of developing an abnormal pulmonary vascular response during exercise.Consecutive patients (n=290) with resting mPAP <25 mmHg who underwent invasive exercise haemodynamics were analysed. Risk factors for pulmonary vascular disease or left heart disease were present in 63.4% and 43.8% of subjects. An abnormal pulmonary vascular response (or exercise PH) was defined by mPAP >30 mmHg and total pulmonary vascular resistance >3 WU at maximal exercise.Exercise PH occurred in 74 (86.0%) out of 86 versus 96 (47.1%) out of 204 in the mPAP of 21-24 mmHg and mPAP <21 mmHg groups, respectively (OR 6.9, 95% CI: 3.6-13.6; p<0.0001). Patients with mPAP of 21-24 mmHg had lower 6-min walk distance (p=0.002) and higher New York Heart Association functional class status (p=0.03). Decreasing levels of mPAP were associated with a lower prevalence of exercise PH, which occurred in 60.3%, 38.7% and 7.7% of patients with mPAP of 17 20, 13-16 and <13 mmHg, respectively.In an at-risk population, a resting mPAP between 21-24 mmHg is closely associated with exercise PH together with worse functional capacity. PMID- 26965293 TI - In-hospital mortality following lung cancer resection: nationwide administrative database. AB - Our aim was to determine the effect of a national strategy for quality improvement in cancer management (the "Plan Cancer") according to time period and to assess the influence of type and volume of hospital activity on in-hospital mortality (IHM) within a large national cohort of patients operated on for lung cancer.From January 2005 to December 2013, 76 235 patients were included in the French Administrative Database. Patient characteristics, hospital volume of activity and hospital type were analysed over three periods: 2005-2007, 2008-2010 and 2011-2013.Global crude IHM was 3.9%: 4.3% during 2005-2007, 4% during 2008 2010 and 3.5% during 2011-2013 (p<0.01). 296, 259 and 209 centres performed pulmonary resections in 2005-2007, 2008-2010 and 2011-2013, respectively (p<0.01). The risk of death was higher in centres performing <13 resections per year than in centres performing >43 resections per year (adjusted (a)OR 1.48, 95% CI 1.197-1.834). The risk of death was lower in the period 2011-2013 than in the period 2008-2010 (aOR 0.841, 95% CI 0.764-0.926). Adjustment variables (age, sex, Charlson score and type of resection) were significantly linked to IHM, whereas the type of hospital was not.The French national strategy for quality improvement seems to have induced a significant decrease in IHM. PMID- 26965295 TI - Enhanced monocyte migration to CXCR3 and CCR5 chemokines in COPD. AB - Chronic obstructive pulmonary disease (COPD) patients exhibit chronic inflammation, both in the lung parenchyma and the airways, which is characterised by an increased infiltration of macrophages and T-lymphocytes, particularly CD8+ cells. Both cell types can express chemokine (C-X-C motif) receptor (CXCR)3 and C C chemokine receptor 5 and the relevant chemokines for these receptors are elevated in COPD. The aim of this study was to compare chemotactic responses of lymphocytes and monocytes of nonsmokers, smokers and COPD patients towards CXCR3 ligands and chemokine (C-C motif) ligand (CCL)5. Migration of peripheral blood mononuclear cells, monocytes and lymphocytes from nonsmokers, smokers and COPD patients toward CXCR3 chemokines and CCL5 was analysed using chemotaxis assays. There was increased migration of peripheral blood mononuclear cells from COPD patients towards all chemokines studied when compared with nonsmokers and smokers. Both lymphocytes and monocytes contributed to this enhanced response, which was not explained by increased receptor expression. However, isolated lymphocytes failed to migrate and isolated monocytes from COPD patients lost their enhanced migratory capacity. Both monocytes and lymphocytes cooperate to enhance migration towards CXCR3 chemokines and CCL5. This may contribute to increased numbers of macrophages and T-cells in the lungs of COPD patients, and inhibition of recruitment using selective antagonists might be a treatment to reduce the inflammatory response in COPD. PMID- 26965296 TI - FG-3019 anti-connective tissue growth factor monoclonal antibody: results of an open-label clinical trial in idiopathic pulmonary fibrosis. AB - FG-3019 is a fully human monoclonal antibody that interferes with the action of connective tissue growth factor, a central mediator in the pathogenesis of fibrosis.This open-label phase 2 trial evaluated the safety and efficacy of two doses of FG-3019 administered by intravenous infusion every 3 weeks for 45 weeks in patients with idiopathic pulmonary fibrosis (IPF). Subjects had a diagnosis of IPF within the prior 5 years defined by either usual interstitial pneumonia (UIP) pattern on a recent high-resolution computed tomography (HRCT) scan, or a possible UIP pattern on HRCT scan and a recent surgical lung biopsy showing UIP pattern. Pulmonary function tests were performed every 12 weeks, and changes in the extent of pulmonary fibrosis were measured by quantitative HRCT scans performed at baseline and every 24 weeks.FG-3019 was safe and well-tolerated in IPF patients participating in the study. Changes in fibrosis were correlated with changes in pulmonary function.Further investigation of FG-3019 in IPF with a placebo-controlled clinical trial is warranted and is underway. PMID- 26965294 TI - The independent role of prenatal and postnatal exposure to active and passive smoking on the development of early wheeze in children. AB - Maternal smoking during pregnancy increases childhood asthma risk, but health effects in children of nonsmoking mothers passively exposed to tobacco smoke during pregnancy are unclear. We examined the association of maternal passive smoking during pregnancy and wheeze in children aged <=2 years.Individual data of 27 993 mother-child pairs from 15 European birth cohorts were combined in pooled analyses taking into consideration potential confounders.Children with maternal exposure to passive smoking during pregnancy and no other smoking exposure were more likely to develop wheeze up to the age of 2 years (OR 1.11, 95% CI 1.03 1.20) compared with unexposed children. Risk of wheeze was further increased by children's postnatal passive smoke exposure in addition to their mothers' passive exposure during pregnancy (OR 1.29, 95% CI 1.19-1.40) and highest in children with both sources of passive exposure and mothers who smoked actively during pregnancy (OR 1.73, 95% CI 1.59-1.88). Risk of wheeze associated with tobacco smoke exposure was higher in children with an allergic versus nonallergic family history.Maternal passive smoking exposure during pregnancy is an independent risk factor for wheeze in children up to the age of 2 years. Pregnant females should avoid active and passive exposure to tobacco smoke for the benefit of their children's health. PMID- 26965297 TI - Serum pentraxin 3 as a possible marker for mature cystic teratomas. AB - Pentraxin 3 (PTX3) is an inflammatory mediator that is released by a wide range of tissues and cells. Elevated PTX3 levels may represent a useful diagnostic and/or prognostic marker for a number of diseases. The purpose of this study was to investigate serum PTX3 levels in benign gynecological conditions including mature cystic teratomas (MCTs), endometriomas, and uterine leiomyomas. Serum PTX3 levels of the MCT group were found to be significantly higher compared to those of the other groups, including healthy controls (p = 0.001), although carbohydrate antigen 19-9 (CA19-9) did not exhibit a significant difference. Serum PTX3 levels of the MCT, but not the endometrioma group, were also found to have significantly decreased post-operatively (mean +/- standard deviation, 4.98 +/- 2.10 to 3.61 +/- 1.53 ng/mL). Immunohistochemical analyses demonstrated positive staining for PTX3 protein in the sebaceous glands, epidermal tissues, and hair roots of MCT specimens. PTX3 is expressed by MCTs and is associated with increased serum concentrations compared to healthy controls and patients with either endometriomas or uterine leiomyomas. We conclude that serum PTX3 levels could be used as a potential diagnostic marker for MCTs, especially helpful in differentiating them from endometriomas with elevated expression of CA19-9. PMID- 26965298 TI - The Impact of Core/Veneer Thickness Ratio and Cyclic Loading on Fracture Resistance of Lithium Disilicate Crown. PMID- 26965300 TI - Pancreas Transplantation: Past, Present, Future. AB - Diabetes is the pandemic disease of the modern era, with 10% of these patients having type 1 diabetes mellitus. Despite the prevalence, morbidities, and associated financial burden, treatment options have not changed since the introduction of injectable insulin. To date, over 40,000 pancreas transplants have been performed globally. It remains the only known method for restoring glycemic control and thus curing type 1 diabetes mellitus. The aim of this review is to bring pancreatic transplantation out of the specialist realm, informing practitioners about this important procedure, so that they feel better equipped to refer suitable patients for transplantation and manage, counsel, and support when encountering them within their own specialty. This study was a narrative review conducted in October 2015, with OVID interface searching EMBASE and MEDLINE databases, using Timeframe: Inception to October 2015. Articles were assessed for clinical relevance and most up-to-date content, with articles written in English as the only inclusion criterion. Other sources used included conference proceedings/presentations and unpublished data from our institution (Oxford Transplant Centre). Pancreatic transplantation is growing and has quickly become the gold standard of care for patients with type 1 diabetes mellitus and renal failure. Significant improvements in quality of life and life expectancy make pancreatic transplant a viable and economically feasible intervention. It remains the most effective method of establishing and maintaining euglycemia, halting and potentially reversing complications associated with diabetes. PMID- 26965301 TI - Can Benefit Corporations Redeem the Pharmaceutical Industry? PMID- 26965299 TI - Cognitive reserve and neuropsychological functioning in older HIV-infected people. AB - Progress in treatments has led to HIV+ patients getting older. Age and HIV are risk factors for neurocognitive impairment (NCI). We explored the role of cognitive reserve (CR) on cognition in a group of virologically suppressed older HIV+ people. We performed a multicenter study, consecutively enrolling asymptomatic HIV+ subjects >=60 years old during routine outpatient visits. A comprehensive neuropsychological battery was administered. Raw test scores were adjusted based on Italian normative data and transformed into z-scores; NCI was defined according to Frascati criteria. All participants underwent the Brief Intelligence Test (TIB) and the Cognitive Reserve Index (CRI) questionnaire as proxies for CR. Relationships between TIB, CRI, and NCI were investigated by logistic or linear regression analyses. Sixty patients (85 % males, median age 66, median education 12, 10 % HCV co-infected, 25 % with past acquired immunodeficiency syndrome (AIDS)-defining events, median CD4 cells count 581 cells/MUL, median nadir CD4 cells count 109 cells/MUL) were enrolled. Twenty-four patients (40 %) showed Asymptomatic Neurocognitive Impairment. At logistic regression analysis, only CRI (OR 0.94; 95 % CI 0.91-0.97; P = 0.001) and TIB (OR 0.80; 95 % CI 0.71-0.90; P < 0.001) were associated with a lower risk of NCI. Higher CRI and TIB were significantly correlated with a better performance (composite z-score) both globally and at individual cognitive domains. Our findings highlight the role of CR over clinical variables in maintaining cognitive integrity in a virologically suppressed older HIV-infected population. A lifestyle characterized by experiences of mental stimulation may help to cope aging and HIV-related neurodegeneration. PMID- 26965302 TI - Appropriateness: A Key to Enabling the Use of Genomics in Clinical Practice? PMID- 26965303 TI - Extra-abdominal desmoid fibromatosis: A review of management, current guidance and unanswered questions. AB - Extra abdominal desmoid fibromatosis is a complex condition with many recognised treatments including active observation, hormonal therapy, chemotherapy, radiotherapy and surgical resection. There is large variation in the natural history of individual desmoid tumours, with some cases progressing aggressively and others regressing spontaneously when observed alone. This combined with an absence of accurate clinical predictors of a desmoid tumour's behaviour has led to difficulties in identifying which patients would benefit most from aggressive treatment, and which could be adequately managed with a policy of active observation alone. This review explores the aetiology and common presentation of extra-abdominal desmoid fibromatosis including the condition's histopathological, clinical and radiological characteristics. The current evidence for potential predictors of desmoid tumour behaviour is also reviewed, along with the indications and evidence for the multitude of treatments available. We also summarise the published guidelines that are currently available for oncologists and surgeons managing extra-abdominal desmoid fibromatosis, and highlight some of the unanswered questions that need to be addressed to optimise the management of this condition. PMID- 26965304 TI - HIPEC and nephrotoxicity: A cisplatin induced effect? PMID- 26965305 TI - Patterns and outcomes of breast reconstruction in older women - A systematic review of the literature. AB - PURPOSE: Older age is associated with lower rates of breast reconstruction (BR) for women requiring mastectomy. The purpose was to assess the available evidence on uptake, outcome and quality of life (QoL) after BR in older women. METHODS: A systematic literature review was performed via Medline, Embase and Cochrane databases using the search terms breast reconstruction, breast cancer, and mastectomy. Eligible studies reported rates of BR, rates of different reconstructive techniques, complication rates, and/or patient reported outcome measures (PROMs) of BR in women aged 60 years or older undergoing mastectomy for ductal carcinoma in situ or invasive carcinoma. RESULTS: A total of 42 eligible studies were included, with 32 of these reporting BR rates, 10 reporting rates of different reconstructive techniques, 10 reporting rates of complications, and four reporting PROMs. The studies reported 24,746 cases of BR in 407,570 mastectomy patients aged 60 years or older from 1987 to 2012. Implant based BR was more common than autologous techniques. Mostly, complication rates were not higher in older women, and QoL outcomes were similar to younger women. CONCLUSIONS: This review confirms that BR rates are lower in older women despite recent studies demonstrating its efficacy. The perception among some surgeons and women requiring mastectomy that the potential risks of BR in older women outweigh the benefits needs to be revisited. Education of consumers and surgeons along with public advocacy for offering BR to all clinically eligible women are the most promising means of changing practice. PMID- 26965306 TI - Erratum to: 'Recruitment challenges in clinical research including cancer patients and their caregivers. A randomized controlled trial study and lessons learned'. PMID- 26965307 TI - Collaborating in the context of co-location: a grounded theory study. AB - BACKGROUND: Most individuals with mental health concerns seek care from their primary care provider, who may lack comfort, knowledge, and time to provide care. Interprofessional collaboration between providers improves access to primary mental health services and increases primary care providers' comfort offering these services. Building and sustaining interprofessional relationships is foundational to collaborative practice in primary care settings. However, little is known about the relationship building process within these collaborative relationships. The purpose of this grounded theory study was to gain a theoretical understanding of the interprofessional collaborative relationship building process to guide health care providers and leaders as they integrate mental health services into primary care settings. METHODS: Forty primary and mental health care providers completed a demographic questionnaire and participated in either an individual or group interview. Interviews were audio recorded and transcribed verbatim. Transcripts were reviewed several times and then individually coded. Codes were reviewed and similar codes were collapsed to form categories using using constant comparison. All codes and categories were discussed amongst the researchers and the final categories and core category was agreed upon using constant comparison and consensus. RESULTS: A four-stage developmental interprofessional collaborative relationship-building model explained the emergent core category of Collaboration in the Context of Co location. The four stages included 1) Looking for Help, 2) Initiating Co location, 3) Fitting-in, and 4) Growing Reciprocity. A patient-focus and communication strategies were essential processes throughout the interprofessional collaborative relationship-building process. CONCLUSIONS: Building interprofessional collaborative relationships amongst health care providers are essential to delivering mental health services in primary care settings. This developmental model describes the process of how these relationships are co-created and supported by the health care region. Furthermore, the model emphasizes that all providers must develop and sustain a patient-focus and communication strategies that are flexible. Applying this model, health care providers can guide the creation and sustainability of primary care interprofessional collaborative relationships. Moreover, this model may guide health care leaders and policy makers as they initiate interprofessional collaborative practice in other health care settings. PMID- 26965308 TI - Correction of severe columella and tip retraction in silicone implanted Asian short noses. AB - BACKGROUND: Silicone Implants and other alloplastic materials are frequently used in rhinoplasty to augment Asian short noses. However, nasal deformities as a result of implant-related infections are increasing in incidence. The resulting tissue scarrings hinder the application of traditional techniques of lengthening short noses. The following paper presents a technique to correct severe postoperative retractions of the tip and columella caused by silicone implants. METHODS: We present a retrospective case study of two Asian patients with recurrent acute infections, secondary to silicone dorsum implants, leading to chronic inflammation of the tip and columella. The treatment consisted of implant removal and the immediate nasal reconstruction by combining uni- or bilateral gingivobuccal flaps along with L-shaped costal cartilage grafting. To evaluate the surgical results, various anthropometric measurements, particularly the nasal length (NL) and nasal tip projection (NTP) of pre- and postoperative profile photographs, were analyzed. RESULTS: Successful nasal lengthening and correction of columellar retraction were achieved. In case I, postoperative NTP and NL increased by 34.7% and 21.1%, respectively. In case II, NL and NTP increased by 23.8% and 10.6%, respectively. However, case II presented necrosis of the distal extremity of one gingivobuccal flap without rib graft resorption, which later healed by secondary intention. CONCLUSION: Pronounced columellar retraction in severe short noses can be successfully managed with a combination of gingivobuccal flaps along with L-shaped costal cartilage grafting. The use of autologous materials decreases the risk of long-term extrusion through the tip. The gingivobuccal flap provides vascularity to the exposed rib cartilage on the columella and prevents its resorption. PMID- 26965309 TI - Context, mechanisms and outcomes in end of life care for people with advanced dementia. AB - BACKGROUND: The majority of people with dementia in the UK die in care homes. The quality of end of life care in these environments is often suboptimal. The aim of the present study was to explore the context, mechanisms and outcomes for providing good palliative care to people with advanced dementia residing in UK care homes from the perspective of health and social care providers. METHOD: The design of the study was qualitative which involved purposive sampling of health care professionals to undertake interactive interviews within a realist framework. Interviews were completed between September 2012 and October 2013 and were thematically analysed and then conceptualised according to context, mechanisms and outcomes. The settings were private care homes and services provided by the National Health Service including memory clinics, mental health and commissioning services in London, United Kingdom. The participants included 14 health and social care professionals including health care assistants, care home managers, commissioners for older adults' services and nursing staff. RESULTS: Good palliative care for people with advanced dementia is underpinned by the prioritisation of psychosocial and spiritual care, developing relationships with family carers, addressing physical needs including symptom management and continuous, integrated care provided by a multidisciplinary team. Contextual factors that detract from good end of life care included: an emphasis on financial efficiency over person-centred care; a complex health and social care system, societal and family attitudes towards staff; staff training and experience, governance and bureaucratisation; complexity of dementia; advance care planning and staff characteristics. Mechanisms that influence the quality of end of life care include: level of health care professionals' confidence, family uncertainty about end of life care, resources for improving end of life care and supporting families, and uncertainty about whether dementia specific palliative care is required. CONCLUSIONS: Contextual factors regarding the care home environment may be obdurate and tend to negatively impact on the quality of end of life dementia care. Local level mechanisms may be more amenable to improvement. However, systemic changes to the care home environment are necessary to promote consistent, equitable and sustainable high quality end of life dementia care across the UK care home sector. PMID- 26965311 TI - Reply: Methodological considerations in measuring different AMH splice forms using ELISA: validity of proAMH ELISA. PMID- 26965312 TI - Methodological considerations in measuring different AMH cleavage forms using ELISA: validity of proAMH ELISA. PMID- 26965310 TI - Role of docosahexaenoic acid in the modulation of glial cells in Alzheimer's disease. AB - Docosahexaenoic acid (DHA) is an omega-3 (omega-3) long-chain polyunsaturated fatty acid (LCPUFA) relevant for brain function. It has largely been explored as a potential candidate to treat Alzheimer's disease (AD). Clinical evidence favors a role for DHA in the improvement of cognition in very early stages of the AD. In response to stress or damage, DHA generates oxygenated derivatives called docosanoids that can activate the peroxisome proliferator-activated receptor gamma (PPARgamma). In conjunction with activated retinoid X receptors (RXR), PPARgamma modulates inflammation, cell survival, and lipid metabolism. As an early event in AD, inflammation is associated with an excess of amyloid beta peptide (Abeta) that contributes to neural insult. Glial cells are recognized to be actively involved during AD, and their dysfunction is associated with the early appearance of this pathology. These cells give support to neurons, remove amyloid beta peptides from the brain, and modulate inflammation. Since DHA can modulate glial cell activity, the present work reviews the evidence about this modulation as well as the effect of docosanoids on neuroinflammation and in some AD models. The evidence supports PPARgamma as a preferred target for gene modulation. The effective use of DHA and/or its derivatives in a subgroup of people at risk of developing AD is discussed. PMID- 26965315 TI - LINE-1 hypomethylation and mutational status in cutaneous melanomas. AB - Epigenetic dysregulation is an important emerging hallmark of cutaneous melanoma development. The global loss of DNA methylation in gene-poor regions and transposable DNA elements of cancer cells contributes to increased genomic instability. Long interspersed element-1 (LINE-1) sequences are the most abundant repetitive sequence of the genome and can be evaluated as a surrogate marker of the global level of DNA methylation. In this work, LINE-1 methylation levels were evaluated in cutaneous melanomas and normal melanocyte primary cell cultures to investigate their possible association with both distinct clinicopathological characteristics and tumor mutational profile. A set of driver mutations frequently identified in cutaneous melanoma was assessed by sequencing (actionable mutations in BRAF, NRAS, and KIT genes, and mutations affecting the TER T promoter) or multiplex ligation-dependent probe amplification (MLPA) (CDKN2A deletions). Pyrosequencing was performed to investigate the methylation level of LINE-1 and CDKN2A promoter sequences. The qualitative analysis showed a trend toward an association between LINE-1 hypomethylation and CDKN2A inactivation (p=0.05). In a quantitative approach, primary tumors, mainly the thicker ones (>4 mm), exhibited a trend toward LINE-1 hypomethylation when compared with control melanocytes. To date, this is the first study reporting in cutaneous melanomas a possible link between the dysregulation of LINE-1 methylation and the presence of driver mutations. PMID- 26965316 TI - Simple, Robust, and Plasticizer-Free Iodide-Selective Sensor Based on Copolymerized Triazole-Based Ionic Liquid. AB - Novel solid-contact iodide-selective electrodes based on covalently attached 1,2,3 triazole ionic liquid (IL) were prepared and investigated in this study. Triazole-based IL moieties were synthesized using click chemistry and were further copolymerized with lauryl methacrylate via a simple one-step free radical polymerization to produce a "self-plasticized" copolymer. The mechanical properties of the copolymer are suitable for the fabrication of plasticizer-free ion-selective membrane electrodes. We demonstrate that covalently attached IL moieties provide adequate functionality to the ion-selective membrane, thus achieving a very simple, one-component sensing membrane. We also demonstrate that the presence of iodide as the counterion in the triazole moiety has direct influence on the membrane's functionality. Potentiometric experiments revealed that each electrode displays high selectivity toward iodide anions over a number of inorganic anions. Moreover, the inherent presence of the iodide in the membrane reduces the need for conditioning. The nonconditioned electrodes show strikingly similar response characteristics compared to the conditioned ones. The electrodes exhibited a near Nernstian behavior with a slope of -56.1 mV per decade across a large concentration range with lower detection limits found at approximately 6.3 * 10(-8) M or 8 ppb. These all-solid-state sensors were utilized for the selective potentiometric determination of iodide ions in artificial urine samples in the nanomolar concentration range. PMID- 26965313 TI - Granulosa cell and oocyte mitochondrial abnormalities in a mouse model of fragile X primary ovarian insufficiency. AB - STUDY HYPOTHESIS: We hypothesized that the mitochondria of granulosa cells (GC) and/or oocytes might be abnormal in a mouse model of fragile X premutation (FXPM). STUDY FINDING: Mice heterozygous and homozygous for the FXPM have increased death (atresia) of large ovarian follicles, fewer corpora lutea with a gene dosage effect manifesting in decreased litter size(s). Furthermore, granulosa cells (GC) and oocytes of FXPM mice have decreased mitochondrial content, structurally abnormal mitochondria, and reduced expression of critical mitochondrial genes. Because this mouse allele produces the mutant Fragile X mental retardation 1 (Fmr1) transcript and reduced levels of wild-type (WT) Fmr1 protein (FMRP), but does not produce a Repeat Associated Non-ATG Translation (RAN)-translation product, our data lend support to the idea that Fmr1 mRNA with large numbers of CGG-repeats is intrinsically deleterious in the ovary. WHAT IS KNOWN ALREADY: Mitochondrial dysfunction has been detected in somatic cells of human and mouse FX PM carriers and mitochondria are essential for oogenesis and ovarian follicle development, FX-associated primary ovarian insufficiency (FXPOI) is seen in women with FXPM alleles. These alleles have 55-200 CGG repeats in the 5' UTR of an X-linked gene known as FMR1. The molecular basis of the pathology seen in this disorder is unclear but is thought to involve either some deleterious consequence of overexpression of RNA with long CGG-repeat tracts or of the generation of a repeat-associated non-AUG translation (RAN translation) product that is toxic. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Analysis of ovarian function in a knock-in FXPM mouse model carrying 130 CGG repeats was performed as follows on WT, PM/+, and PM/PM genotypes. Histomorphometric assessment of follicle and corpora lutea numbers in ovaries from 8-month-old mice was executed, along with litter size analysis. Mitochondrial DNA copy number was quantified in oocytes and GC using quantitative PCR, and cumulus granulosa mitochondrial content was measured by flow cytometric analysis after staining of cells with Mitotracker dye. Transmission electron micrographs were prepared of GC within small growing follicles and mitochondrial architecture was compared. Quantitative RT-PCR analysis of key genes involved in mitochondrial structure and recycling was performed. MAIN RESULTS AND THE ROLE OF CHANCE: A defect was found in follicle survival at the large antral stage in PM/+ and PM/PM mice. Litter size was significantly decreased in PM/PM mice, and corpora lutea were significantly reduced in mice of both mutant genotypes. Mitochondrial DNA copy number was significantly decreased in GC and metaphase II eggs in mutants. Flow cytometric analysis revealed that PM/+ and PM/PM animals lack the cumulus GC that harbor the greatest mitochondrial content as found in wild-type animals. Electron microscopic evaluation of GC of small growing follicles revealed mitochondrial structural abnormalities, including disorganized and vacuolar cristae. Finally, aberrant mitochondrial gene expression was detected. Mitofusin 2 (Mfn2) and Optic atrophy 1 (Opa1), genes involved in mitochondrial fusion and structure, respectively, were significantly decreased in whole ovaries of both mutant genotypes. Mitochondrial fission factor 1 (Mff1) was significantly decreased in PM/+ and PM/PM GC and eggs compared with wild-type controls. LIMITATIONS, REASONS FOR CAUTION: Data from the mouse model used for these studies should be viewed with some caution when considering parallels to the human FXPOI condition. WIDER IMPLICATIONS OF THE FINDINGS: Our data lend support to the idea that Fmr1 mRNA with large numbers of CGG-repeats is intrinsically deleterious in the ovary. FXPM disease states, including FXPOI, may share mitochondrial dysfunction as a common underlying mechanism. LARGE SCALE DATA: Not applicable. STUDY FUNDING AND COMPETING INTERESTS: Studies were supported by NIH R21 071873 (J.J./G.H), The Albert McKern Fund for Perinatal Research (J.J.), NIH Intramural Funds (K.U.), and a TUBITAK Research Fellowship Award (B.U.). No conflict(s) of interest or competing interest(s) are noted. PMID- 26965314 TI - Gene polymorphisms associated with non-alcoholic fatty liver disease and coronary artery disease: a concise review. AB - Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease which represents a wide spectrum of hepatic damage. Several studies have reported that NAFLD is a strong independent risk factor for coronary artery disease (CAD). And patients with NAFLD are at higher risk and suggested undergoperiodic cardiovascular risk assessment. Cardiovascular disease (CVD) is responsible for the main cause of death in patients with NAFLD, and is mostly influenced by genetic factors. Both NAFLD and CAD are heterogeneous disease. Common pathways involved in the pathogenesis of NAFLD and CAD includes insulin resistance (IR), atherogenic dyslipidemia, subclinical inflammation, oxidative stress, etc. Genomic characteristics of these two diseases have been widely studied, further research about the association of these two diseases draws attention. The gene polymorphisms of adiponectin-encoding gene (ADIPOQ), leptin receptor (LEPR), apolipoprotein C3 (APOC3), peroxisome proliferator-activated receptors (PPAR), sterol regulatory elementbinding proteins (SREBP), transmembrane 6 superfamily member 2 (TM6SF2), microsomal triglyceride transfer protein (MTTP), tumor necrosis factors-alpha (TNF-alpha) and manganese superoxide dismutase (MnSOD) have been reported to be related to NAFLD and CAD. In this review, we aimed to provide an overview of recent insights into the genetic basis of NAFLD and CAD. PMID- 26965317 TI - Effect of timing of umbilical cord clamping on anaemia at 8 and 12 months and later neurodevelopment in late pre-term and term infants; a facility-based, randomized-controlled trial in Nepal. AB - BACKGROUND: Delayed cord clamping at birth has shown to benefit neonates with increased placental transfusion leading to higher haemoglobin concentrations, additional iron stores and less anaemia later in infancy, higher red blood cell flow to vital organs and better cardiopulmonary adaptation. As iron deficiency in infants even without anaemia has been associated with impaired development, delayed cord clamping seems to benefit full term infants also in regions with a relatively low prevalence of iron deficiency anaemia. In Nepal, there is a high anaemia prevalence among children between 6 and 17 months (72-78 %). The objective of the proposed study is to evaluate the effects of delayed and early cord clamping on anaemia (and haemoglobin level) at 8 and 12 months, ferritin at 8 and 12 months, bilirubin at 2-3 days, admission to Neonatal Intensive Care Unit (NICU) or special care nursery, and development at 12 and 18-24 months of age. METHODS/DESIGN: A randomized, controlled trial comparing delayed and early cord clamping will be implemented at Paropakar Maternity and Women's Hospital in Kathmandu, Nepal. Pregnant woman of gestational age 34-41 weeks who deliver vaginally will be included in the study. The interventions will consist of delayed clamping of the umbilical cord (>=180 s after delivery) or early clamping of the umbilical cord (<=60 s). At 8 and 12 months of age, infant's iron status and developmental milestones will be measured. DISCUSSION: This trial is important to perform because, although strong indications for the beneficial effect of delayed cord clamping on anaemia at 8 to 12 months of age exist, it has not yet been evaluated by a randomized trial in this setting. The proposed study will analyse both outcome as well as safety effects. Additionally, the results may not only contribute to practice in Nepal, but also to the global community, in particular to other low-income countries with a high prevalence of iron deficiency anaemia. TRIAL REGISTRATION: Clinical trial.gov NCT02222805 . Registered August 19 2014. PMID- 26965319 TI - Enhancing the ballistic thermal transport of silicene through smooth interface coupling. AB - We have performed nonequilibrium molecular dynamics calculations on the length (L) dependence of thermal conductivity (Kappa) of silicene both supported on and sandwiched between the smooth surfaces, i.e. h-BN, at room temperature. We find that Kappa of silicene follows a power law Kappa [proportional] L(beta), with beta increasing from about 0.3-0.4 under the effect of interface coupling, showing an enhancement of the ballistic thermal transport of silicene. We also find that beta can be further increased to about 0.6 by increasing the interface coupling strength for the silicene sandwiched between h-BN. The increase of beta for the supported case is found to come from the variation of the flexural acoustic (ZA) phonon mode and the first optical phonon mode induced by the substrate, whereas the unusual increase of beta for the sandwiched case is attributed to the increment of velocities of all three acoustic phonon modes. These findings provide an interesting route for manipulating the ballistic energy flow in nanomaterials. PMID- 26965321 TI - Experimental phase determination of the structure factor from Kossel line profile. AB - Kossel lines are formed when radiation from point x-ray sources inside a single crystal are diffracted by the crystal itself. In principle, Kossel line patterns contain full information on the crystalline structure: phase and magnitude of the structure factors. The phase is coded into the profile of the lines. Although this was known for a long time, experimental realization has not been presented. In this work we demonstrate experimentally that phases can be directly determined from the profile of the Kossel lines. These measurements are interesting not only theoretically, but they would facilitate structure solution of samples within extreme conditions, such as high pressure, high and low temperatures, high magnetic fields and extremely short times. The parallel measurement of many diffraction lines on a stationary sample will allow a more efficient use of the new generation of x-ray sources the X-ray free electron lasers (XFELs). PMID- 26965320 TI - IL-17-producing gammadelta T cells enhance bone regeneration. AB - Immune responses are crucial not only for host defence against pathogens but also for tissue maintenance and repair after injury. Lymphocytes are involved in the healing process after tissue injury, including bone fracture and muscle damage. However, the specific immune cell subsets and mediators of healing are not entirely clear. Here we show that gammadelta T cells produce IL-17A, which promotes bone formation and facilitates bone fracture healing. Repair is impaired in IL-17A-deficient mice due to a defect in osteoblastic bone formation. IL-17A accelerates bone formation by stimulating the proliferation and osteoblastic differentiation of mesenchymal progenitor cells. This study identifies a novel role for IL-17-producing gammadelta T cells in skeletal tissue regeneration. PMID- 26965318 TI - Elevated on-treatment levels of serum IFN-gamma is associated with treatment failure of peginterferon plus ribavirin therapy for chronic hepatitis C. AB - Chronic hepatitis C virus (HCV) infection had been associated with cytokine imbalance. Cytokine dynamics in response to peginterferon/ribavirin therapy have an impact on the treatment efficacy for HCV patients. Ninety-two treatment-naive chronic hepatitis C patients were treated with 24 or 48 weeks of peginterferon/ribavirin therapy according to their viral genotypes. Sustained virologic response (SVR) is defined as undetectable HCV RNA throughout a 24-week post-treatment follow-up period. Dynamic serum levels of the following cytokines: (1) Th1-mediated cytokines: IFN-gamma, interleukin-2, and TNF-alpha; (2)Th2 mediated cytokines: interleukin-4, interleukin-5, interleukin-6, and interleukin 10 and (3)immuno-modulatory cytokines: interleukin-1beta, interleukin-8, and interleukin-12 were determined by Fluorescent Bead immunoassay. Serial dynamic cytokine expression demonstrated that not only elevated IFN-gamma concentrations at specific time points but also the total IFN-gamma amount was strongly linked to non-response in peginterferon/ribavirin therapy. IFN-gamma levels could serve as an independent predictor for SVR analyzed by multivariate logistic regression test. The accuracy of discriminating responders from non-responders was acceptable when IFN-gamma cut-off levels were set at 180, 120, and 40 pg/ml at the 4th week, 12th week, and end-of-treatment of therapy, respectively. Elevated on-treatment IFN-gamma concentration was significantly associated with treatment failure among interleukin-28B rs8099917TT carriers and those patients failed to achieve rapid virologic response. PMID- 26965322 TI - Detection of methotrexate in a flow system using electrochemical impedance spectroscopy and multivariate data analysis. AB - Methotrexate (MTX), a common pharmaceutical drug in cancer therapy and treatment of rheumatic diseases, is known to cause severe adverse side effects at high dose. As the side effect may be life threatening, there is an urgent need for a continuous, bed-side monitoring of the nominal MTX serum level in a patient while the chemical is being administered. This article describes a detection of MTX using a flow system that consists two modified gold electrodes. Interaction of MTX with the antibodies fixed on the electrode surface is detected by electrochemical impedance spectroscopy and evaluated using singular value decomposition (SVD). The key finding of this work is that the change in the electrode capacitance is found to be quantitative with respect to the concentration of MTX. Moreover a calibration curve constructed using the principal component regression method has a linear range of six orders of magnitude and a detection limit of 1.65 * 10(-10) M. PMID- 26965323 TI - A review on continuous-flow microfluidic PCR in droplets: Advances, challenges and future. AB - Significant advances have been made in developing microfluidic polymerase chain reaction (PCR) devices in the last two decades. More recently, microfluidic microdroplet technology has been exploited to perform PCR in droplets because of its unique features. For example, it can prevent crossover contamination and PCR inhibition, is suitable for single-cell and single-molecule analyses, and has the potential for system integration and automation. This review will therefore focus on recent developments on droplet-based continuous-flow microfluidic PCR, and the major research challenges. This paper will also discuss a new way of on-chip flow control and a rational design simulation tool, which are required to underpin fully integrated and automated droplet-based microfluidic systems. We will conclude with a scientific speculation of future autonomous scientific discoveries enabled by microfluidic microdroplet technologies. PMID- 26965324 TI - Chemometric methods in data processing of mass spectrometry-based metabolomics: A review. AB - This review focuses on recent and potential advances in chemometric methods in relation to data processing in metabolomics, especially for data generated from mass spectrometric techniques. Metabolomics is gradually being regarded a valuable and promising biotechnology rather than an ambitious advancement. Herein, we outline significant developments in metabolomics, especially in the combination with modern chemical analysis techniques, and dedicated statistical, and chemometric data analytical strategies. Advanced skills in the preprocessing of raw data, identification of metabolites, variable selection, and modeling are illustrated. We believe that insights from these developments will help narrow the gap between the original dataset and current biological knowledge. We also discuss the limitations and perspectives of extracting information from high throughput datasets. PMID- 26965325 TI - Extension of least squares spectral resolution algorithm to high-resolution lipidomics data. AB - Lipidomics, which focuses on the global study of molecular lipids in biological systems, has been driven tremendously by technical advances in mass spectrometry (MS) instrumentation, particularly high-resolution MS. This requires powerful computational tools that handle the high-throughput lipidomics data analysis. To address this issue, a novel computational tool has been developed for the analysis of high-resolution MS data, including the data pretreatment, visualization, automated identification, deconvolution and quantification of lipid species. The algorithm features the customized generation of a lipid compound library and mass spectral library, which covers the major lipid classes such as glycerolipids, glycerophospholipids and sphingolipids. Next, the algorithm performs least squares resolution of spectra and chromatograms based on the theoretical isotope distribution of molecular ions, which enables automated identification and quantification of molecular lipid species. Currently, this methodology supports analysis of both high and low resolution MS as well as liquid chromatography-MS (LC-MS) lipidomics data. The flexibility of the methodology allows it to be expanded to support more lipid classes and more data interpretation functions, making it a promising tool in lipidomic data analysis. PMID- 26965326 TI - Direct analysis of palladium in active pharmaceutical ingredients by anodic stripping voltammetry. AB - Anodic stripping voltammetry, a classical electroanalytical method has been optimized to analyze trace Pd(II) in active pharmaceutical ingredient matrices. The electroanalytical approach with an unmodified glassy carbon electrode was performed in both aqueous and 95% DMSO/5% water (95/5 DMSO/H2O) solutions, without pretreatment such as acid digestion or dry ashing to remove the organics. Limits of detection (LODs) in the presence of caffeine and ketoprofen were determined to be 11 and 9.6 MUg g(-1), with a relative standard deviation (RSD) of 5.7% and 2.3%, respectively. This method is simple, highly reproducible, sensitive, and robust. The instrumentation has the potential to be portable and the obviation of sample pretreatment makes it an ideal approach for determining lost catalytic metals in pharmaceutical-related industries. Furthermore, the simultaneous detection of Pd(II) with Cd(II) and Pb(II) in the low MUg L(-1) range indicates that this system is capable of simultaneous multi-analyte analysis in a variety of matrices. PMID- 26965327 TI - Non-invasive determination of glucose directly in raw fruits using a continuous flow system based on microdialysis sampling and amperometric detection at an integrated enzymatic biosensor. AB - A non-destructive, rapid and simple to use sensing method for direct determination of glucose in non-processed fruits is described. The strategy involved on-line microdialysis sampling coupled with a continuous flow system with amperometric detection at an enzymatic biosensor. Apart from direct determination of glucose in fruit juices and blended fruits, this work describes for the first time the successful application of an enzymatic biosensor-based electrochemical approach to the non-invasive determination of glucose in raw fruits. The methodology correlates, through previous calibration set-up, the amperometric signal generated from glucose in non-processed fruits with its content in % (w/w). The comparison of the obtained results using the proposed approach in different fruits with those provided by other method involving the same commercial biosensor as amperometric detector in stirred solutions pointed out that there were no significant differences. Moreover, in comparison with other available methodologies, this microdialysis-coupled continuous flow system amperometric biosensor-based procedure features straightforward sample preparation, low cost, reduced assay time (sampling rate of 7 h(-1)) and ease of automation. PMID- 26965328 TI - Matrix molecularly imprinted mesoporous sol-gel sorbent for efficient solid-phase extraction of chloramphenicol from milk. AB - Highly selective and efficient chloramphenicol imprinted sol-gel silica based inorganic polymeric sorbent (sol-gel MIP) was synthesized via matrix imprinting approach for the extraction of chloramphenicol in milk. Chloramphenicol was used as the template molecule, 3-aminopropyltriethoxysilane (3-APTES) and triethoxyphenylsilane (TEPS) as the functional precursors, tetramethyl orthosilicate (TMOS) as the cross-linker, isopropanol as the solvent/porogen, and HCl as the sol-gel catalyst. Non-imprinted sol-gel polymer (sol-gel NIP) was synthesized under identical conditions in absence of template molecules for comparison purpose. Both synthesized materials were characterized by Scanning Electron Microscopy (SEM), Fourier Transform Infrared Spectroscopy (FT-IR) and nitrogen adsorption porosimetry, which unambiguously confirmed their significant structural and morphological differences. The synthesized MIP and NIP materials were evaluated as sorbents for molecularly imprinted solid phase extraction (MISPE) of chloramphenicol in milk. The effect of critical extraction parameters (flow rate, elution solvent, sample and eluent volume, selectivity coefficient, retention capacity) was studied in terms of retention and desorption of chloramphenicol. Competition and cross reactivity tests have proved that sol-gel MIP sorbent possesses significantly higher specific retention and enrichment capacity for chloramphenicol compared to its non-imprinted analogue. The maximum imprinting factor (IF) was found as 9.7, whereas the highest adsorption capacity of chloramphenicol by sol-gel MIP was 23 mg/g. The sol-gel MIP was found to be adequately selective towards chloramphenicol to provide the necessary minimum required performance limit (MRPL) of 0.3 MUg/kg set forth by European Commission after analysis by LC-MS even without requiring time consuming solvent evaporation and sample reconstitution step, often considered as an integral part in solid phase extraction work-flow. Intra and inter-assay RSD values were less than 13% and accuracy expressed as relative recovery ranged from 85 to 106%. PMID- 26965329 TI - Interfacial reaction using particle-immobilized reagents in a fluidized reactor. Determination of glycerol in biodiesel. AB - A novel fluidized beads strategy for utilization of particle-immobilized reagents in flow analysis was developed in this study. The performance of the suggested strategy was demonstrated by the determination of glycerol in biodiesel. This analytical task was used as a proof-of-concept example. The method is based on on line extraction of glycerol from biodiesel into aqueous stationary phase of extraction-chromatographic column, followed by elution and spectrophotometric determination in the form of copper glycerate formed in a fluidized reactor of stepwise injection system. The floating of cation exchange resin Dowex((r)) 50WX4, saturated with Cu(II) ions in liquid phase, was accomplished by air bubbling. The linear range was from 100 to 1000 mg kg(-1), and the limit of detection, calculated as 3s of a blank test (n = 5), was found to be 30 mg kg( 1). The method was successfully applied to the analysis of biodiesel and biodiesel-blend (B 20) samples. PMID- 26965330 TI - Target and suspect screening of psychoactive substances in sewage-based samples by UHPLC-QTOF. AB - The quantification of illicit drug and pharmaceutical residues in sewage has been shown to be a valuable tool that complements existing approaches in monitoring the patterns and trends of drug use. The present work delineates the development of a novel analytical tool and dynamic workflow for the analysis of a wide range of substances in sewage-based samples. The validated method can simultaneously quantify 51 target psychoactive substances and pharmaceuticals in sewage-based samples using an off-line automated solid phase extraction (SPE-DEX) method, using Oasis HLB disks, followed by ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UHPLC-QTOF) in MS(e). Quantification and matrix effect corrections were overcome with the use of 25 isotopic labeled internal standards (ILIS). Recoveries were generally greater than 60% and the limits of quantification were in the low nanogram-per-liter range (0.4-187 ng L(-1)). The emergence of new psychoactive substances (NPS) on the drug scene poses a specific analytical challenge since their market is highly dynamic with new compounds continuously entering the market. Suspect screening using high-resolution mass spectrometry (HRMS) simultaneously allowed the unequivocal identification of NPS based on a mass accuracy criteria of 5 ppm (of the molecular ion and at least two fragments) and retention time (2.5% tolerance) using the UNIFI screening platform. Applying MS(e) data against a suspect screening database of over 1000 drugs and metabolites, this method becomes a broad and reliable tool to detect and confirm NPS occurrence. This was demonstrated through the HRMS analysis of three different sewage-based sample types; influent wastewater, passive sampler extracts and pooled urine samples resulting in the concurrent quantification of known psychoactive substances and the identification of NPS and pharmaceuticals. PMID- 26965331 TI - Expanding the analytical toolbox for identity testing of pharmaceutical ingredients: Spectroscopic screening of dextrose using portable Raman and near infrared spectrometers. AB - In the pharmaceutical industry, dextrose is used as an active ingredient in parenteral solutions and as an inactive ingredient (excipient) in tablets and capsules. In order to address the need for more sophisticated analytical techniques, we report our efforts to develop enhanced identification methods to screen pharmaceutical ingredients at risk for adulteration or substitution using field-deployable spectroscopic screening. In this paper, we report our results for a study designed to evaluate the performance of field-deployable Raman and near infrared (NIR) methods to identify dextrose samples. We report a comparison of the sensitivity of the spectroscopic screening methods against current compendial identification tests that rely largely on a colorimetric assay. Our findings indicate that NIR and Raman spectroscopy are both able to distinguish dextrose by hydration state and from other sugar substitutes with 100% accuracy for all methods tested including spectral correlation based library methods, principal component analysis and classification methods. PMID- 26965332 TI - Speciation of water soluble iron in size segregated airborne particulate matter using LED based liquid waveguide with a novel dispersive absorption spectroscopic measurement technique. AB - In this study, we present the development and evaluation of a dispersive absorption spectroscopic technique for trace level soluble ferrous detection. The technique makes use of the broadband absorption spectra of the ferrous-ferrozine complex with a novel spectral fitting algorithm to determine soluble ferrous concentrations in samples and achieves much improved measurement precision compared to conventional methods. The developed method was evaluated by both model simulations and experimental investigations. The results demonstrated the robustness of the method against the spectral fluctuation, wavelength drift and electronic noise, while achieving excellent linearity (R(2) > 0.999) and low detection limit (0.06 MUg L(-1)) for soluble ferrous detection. The developed method was also used for the speciation of soluble iron in size segregated atmospheric aerosols. The measurement was carried out during Spring and Summer in typical urban environment in Hong Kong. The measured total iron concentrations are in good agreement compared to conventional Inductively Coupled Plasma - Optical Emission Spectroscopy (ICP-OES) measurements. Investigation on ambient particulate matter samples shows the size dependent characteristic of iron speciation in the atmosphere with a more active role of fine particles in transforming between ferrous and ferric. The method demonstrated in this study provides a cost and time effective approach for the speciation of iron in ambient aerosols. PMID- 26965333 TI - Three-dimensional printed knotted reactors enabling highly sensitive differentiation of silver nanoparticles and ions in aqueous environmental samples. AB - Whether silver nanoparticles (AgNPs) persist or release silver ions (Ag(+)) when discharged into a natural environment has remained an unresolved issue. In this study, we employed a low-cost stereolithographic three-dimensional printing (3DP) technology to fabricate the angle-defined knotted reactors (KRs) to construct a simple differentiation scheme for quantitative assessment of Ag(+) ions and AgNPs in municipal wastewater samples. We chose xanthan/phosphate-buffered saline as a dispersion medium for in situ stabilization of the two silver species, while also facilitating their extraction from complicated wastewater matrices. After method optimization, we measured extraction efficiencies of 54.5 and 32.3% for retaining Ag(+) ions and AgNPs, respectively, in the printed KR (768-turn), with detection limits (DLs) of 0.86 and 0.52 ng L(-1) when determining Ag(+) ions and AgNPs, respectively (sample run at pH 11 without a rinse solution), and 0.86 ng L(-1) when determining Ag(+) ions alone (sample run at pH 12 with a 1.5-mL rinse solution). The proposed scheme is tolerant of the wastewater matrix and provides more reliable differentiation between Ag(+)/AgNPs than does a conventional filtration method. The concept and applicability of adopting 3DP technology to renew traditional KR devices were evidently proven by means of these significantly improved analytical performance. Our analytical data suggested that the concentrations of Ag(+) ions and AgNPs in the tested industrial wastewater sample were both higher than those in domestic wastewater, implying that industrial activity might be a main source of environmental silver species, rather than domestic discharge from AgNP-containing products. PMID- 26965335 TI - A theoretical study of dispersion-to-aggregation of nanoparticles in adsorbing polymers using molecular dynamics simulations. AB - The properties of polymer-nanoparticle (NP) mixtures significantly depend on the dispersion of the NPs. Using molecular dynamics simulations, we demonstrate that, in the presence of polymer-NP attraction, the dispersion of NPs in semidilute and concentrated polymers can be stabilized by increasing the polymer concentration. A lower polymer concentration facilitates the aggregation of NPs bridged by polymer chains, as well as a further increase of the polymer-NP attraction. Evaluating the binding of NPs through shared polymer segments in an adsorption blob, we derive a linear relationship between the polymer concentration and the polymer-NP attraction at the phase boundary between dispersed and aggregated NPs. Our theoretical findings are directly relevant for understanding and controlling many self-assembly processes that use either dispersion or aggregation of NPs to yield the desired materials. PMID- 26965334 TI - Simultaneous screening for lipophilic and hydrophilic toxins in marine harmful algae using a serially coupled reversed-phase and hydrophilic interaction liquid chromatography separation system with high-resolution mass spectrometry. AB - The presence of toxins in harmful algal blooms (HABs) poses considerable concerns because of their potential adverse effects on ecological environments and human health. When marine HABs occur, efficient screening and identification of toxins in different kinds of HAB algae remains a challenge. In this study, the applicability of serial coupling of reversed-phase liquid chromatography (RPLC) and hydrophilic interaction chromatography (HILIC) combined with high resolution mass spectrometry (HR-MS) for the simultaneous screening and identification of various kinds of known lipophilic and hydrophilic toxins in HAB algae was investigated for the first time. Ultrasound-assisted extraction (UAE) was explored to extract both lipophilic and hydrophilic toxins in algae simultaneously. As in most cases, toxin standards were not available; therefore, an identification procedure based on accurate mass data and chromatographic behavior was proposed. According to this procedure, eight known lipophilic toxins and 11 hydrophilic toxins were successfully detected in a single injection, and the proposed method was validated. Satisfactory sensitivity, repeatability (RSD <14.87%) and recovery (89.4-105.8%) of the method were achieved. A major advantage of the proposed method is that it can almost detect members of all eight groups of marine algal toxins in a single run. Using this method, several known toxins in different marine toxigenic algae including Alexandrium tamarense, Alexandrium minutum and Prorocentrum lima were successfully observed and identified. This work demonstrates that RPLC/HILIC-HR-MS combined with an accurate mass list of known marine algal toxins may be used as a powerful tool for screening of different classes of known toxins in marine harmful algae. PMID- 26965336 TI - Iodine-catalyzed Sulfonylation of Arylacetylenic Acids and Arylacetylenes with Sodium Sulfinates: Synthesis of Arylacetylenic Sulfones. AB - A highly efficient and generally applicable iodine-catalyzed reaction of arylacetylenic acids and arylacetylenes with sodium sulfinates for the synthesis of arylacetylenic sulfones was developed. The methodology has the advantages of a metal-free strategy, easy to handle reagents, functional group tolerance, a wide range of arylacetylenic acids and arylacetylenes, and easy access to arylacetylenic sulfones. PMID- 26965338 TI - US workers without paid sick leave are more likely to forgo care, study finds. PMID- 26965340 TI - Sleep regulation: physiological models and hypotheses. AB - The elucidation of sleep regulation is not an easy task. On one side, there is a multitude of solid yet disparate data, on the other side, the topic is tempting for engaging in wild speculation, particularly with respect to the functions of sleep. Models may exert a moderating influence by mediating between the two extremes. However, also they navigate between the risk of banality in reformulating the obvious, and the peril of fancy in losing touch with empirical reality. PMID- 26965337 TI - Validation of indicators used to assess unconsciousness in veal calves at slaughter. AB - European legislation states that after stunning regular checks should be performed to guarantee animals are unconscious between the end of the stunning process and death. When animals are killed without prior stunning these checks should be performed before the animal is released from restraint. The validity of certain indicators used to assess unconsciousness under different stunning and slaughter conditions is under debate. The aim of this study was to validate the absence of threat-, withdrawal-, corneal- and eyelid reflex as indicators to assess unconsciousness in calves subjected to different stunning and slaughter methods. Calves (201+/-22 kg) were randomly assigned to one of the following four treatments: (1) Captive bolt stunning followed by neck cut in an inverted position (n=25); (2) Non-stunned slaughter in an upright position (n=7); (3) Non stunned slaughter in an inverted position (180 degrees rotation) (n=25); (4) Non stunned slaughter in an upright position followed by captive bolt stunning 40 s after the neck cut (n=25). Each calf was equipped with non-invasive electroencephalogram (EEG) electrodes before the slaughter procedure. All reflexes were verified once before the slaughter procedure. At the beginning of the procedure (T=0 s) calves were stunned (treatment 1) or neck cut in an upright position (treatment 2, 4) or inverted position (treatment 3). Calves of treatment 4 were captive bolt stunned 34+/-8 s after the neck cut. Reflexes were assessed every 20 s from T=15 s for all treatments until all reflex tests resulted in a negative response three times in a row and a flat line EEG was observed. In addition, reflexes were assessed 5 s after captive bolt stunning in calves of treatments 1 and 4. Visual assessment of changes in the amplitude and frequency of EEG traces was used to determine loss of consciousness. Timing of loss of consciousness was related to timing of loss of reflexes. After captive bolt stunning, absence of threat-, withdrawal-, corneal- and eyelid reflex indicated unconsciousness as determined by EEG recordings. After non-stunned slaughter, both threat- and withdrawal reflex were on average lost before calves were unconscious based on EEG recordings. The eyelid- and corneal reflex were on average lost after calves had lost consciousness based on EEG recordings and appeared to be distinctly conservative indicators of unconsciousness in non stunned slaughtered calves since they were observed until 76+/-50 and 85+/-45 s (mean+/-SD), respectively, after EEG-based loss of consciousness. PMID- 26965341 TI - Circadian tuning of motivation. A little organ of yesterday? AB - The analysis of motivational systems underlying temporal organisation in animal behaviour has relied primarily on two conceptual functional frameworks: Homeostasis and biological clocks. Homeostasis is one of the most general and influential concepts in physiology. Walter Cannon introduced homeostasis as a universal regulatory principle which animals employ to maintain constancy of their 'internal milieu' in the face of challenges and perturbations from the external environment. Cannon spoke of "The Wisdom of the Body", the collective of responses designed to defend the ideal internal state against those perturbations. PMID- 26965342 TI - Circadian regulation of sleep propensity, sleep structure and alertness: A symphony of paradoxes. AB - The adult human typically exhibits a monophasic sleep-wake cycle, i.e., remains awake and alert for approximately 16 hours and then sleeps for 8 hours. Recent experiments have provided new insights in the role of the endogenous circadian pacemaker in this consolidation of sleep and wakefulness. Sleep deprivation studies had shown previously that sleepiness and alertness are co-determined by a process which keeps track of the history of sleep and wakefulness and the circadian pacemaker, which keeps track of time. During every day life and during sleep deprivation both processes change simultaneously and their relative contribution to alertness and sleep propensity cannot be assessed under these conditions. PMID- 26965344 TI - An interpersonal view on depression. AB - Cognitive and behavioural processes may constitute a risk for onset and persistence of depression. People who become depressed frequently show enduring negative cognitions which predispose them to depression. In addition, interpersonal processes are supposed to contribute to the etiology and maintenance of depression. Depression-prone persons are presumed to display deficient or problematic social behaviours that elicit negative reactions in others, finally resulting in withdrawal by family and friends. About 60% of human communication is non-verbal. An ethological approach may therefore contribute to reveal behavioural and cognitive vulnerability factors for depression onset or persistence. Various studies support this presumption: High levels of patients' observed behaviour indicating involvement in the interaction between depressives and clinicians at admission are related with persistence of depression. PMID- 26965343 TI - Social stress in rats: An animal model of depression? AB - Our current understanding of the physiological mechanisms underlying depressive disorders is not only based on behavioral, neuroendocrine and pharmacological studies in depressed humans, but also on experimental studies in a wide variety of animal models of depression. Ideally, the two approaches should operate in close interaction, each providing additional information to the other approach. However, in practice the animal model approach seems to be rather independent from the human studies. In a critical evaluation of the available animal models of depression, Willner concluded that none of the models fulfilled the criteria of a sufficient face, construct and predictive validity. Although this evaluation was made ten years ago, we feel that the situation has improved very little since that time. Most animal models fail to sufficiently mimic both the etiology and the symptomatology of human depressive disorders. With respect to the etiology, stress and major life events are generally considered to be an important factor in the development of depression. Most of the animal models however use stressors which bear little or no relationship to the biology of the species, i.e. to the situations an animal may meet in its everyday life in a natural habitat. Moreover, these models do not pay attention to the temporal dynamics of the disease. In humans, the disease is characterized by its gradual onset, which is often preceded by symptoms of anxiety. Moreover, a relatively large number of patients suffers from recurrent episodes of depression, which tend to occur with decreasing intervals and increasing duration and severity. If we want to improve our knowledge of the causal mechanisms of depression, animal models which allow an experimental analysis of the temporal dynamics of the disease are essential. PMID- 26965345 TI - Functional brain imaging, sleep, and sleep deprivation: contributions to the "overarousal" hypothesis of depression. AB - In 1975 van den Burg and van den Hoofdakker hypothesized that depressed patients might be 'overaroused.' This suggestion is consistent not only with their seminal observations on the antidepressant effects of total sleep deprivation in depression, but with the short, fragmented, and shallow sleep of depressed patients, lowered arousal thresholds, hyperactivity of the hypothalamus-pituitary adrenal (HPA) axis, and elevated core body temperature commonly found in some patients during the sleep period. PMID- 26965347 TI - Spectral analysis of the sleep EEG of depressed patients before and after total sleep deprivation. AB - Sleep electroencephalography in depressed patients reveals many signs of disrupted sleep, like long sleep latency, frequent awakenings, reduced amounts of time spent in the sleep stages 3 and 4, and early morning wakefulness. Upon total deprivation of sleep for one night, many patients experience an unexpected alleviation of their depression, which usually lasts until the subsequent sleep period. Attempts have been made to explain these changes of mood to result from induced changes in sleep physiological mechanisms. Such attempts can roughly be categorized in two classes. One class of hypotheses concerns proposed disturbances in circadian sleep control (i.e. the timing of sleep is inappropriately controlled), the other class concerns postulated disrupted homeostatic sleep control (i.e. the intensity of sleep is inappropriately controlled). For both types of theoretical approaches data have been published which are consistent with the hypotheses as well as data which are not. PMID- 26965346 TI - Response of human melatonin secretion to changes in nightlength (scotoperiod): Implications for seasonal affective disorder and other psychiatric illnesses. AB - Many of the dramatic seasonal changes that occur in animals are triggered by changes in the length of night. Changes in the duration of melatonin secretion, which usually occurs exclusively at night and therefore lasts longer in winter than in summer, often act as a chemical transducer of the effects of seasonal changes in night-length on animals' behavior and physiology. Cells in sites that regulate seasonal behaviors, such as those associated with breeding, appear to possess melatonin receptors and interval timing mechanisms that enable them to detect melatonin and measure the duration of the nightly interval when it is present. These sites then trigger changes that are appropriate for the season that is indexed by the measured length of the interval. PMID- 26965349 TI - Treatment indications for light therapy. AB - Light therapy (LT) has become increasingly popular in various countries around the world in the last decade. For instance, according to a recent survey carried out in Germany in 1992, 13% (n = 56) of all German psychiatric hospitals (n = 422) used LT for different treatment indications and another 8% indicated their interest to do so. Among university facilities LT is even more popular, with a percentage of 57%. Although the most frequently used treatment indication for LT is seasonal affective disorder (SAD) or its subsyndromal form (S-SAD) it is apparent that other forms of depression e.g. non-seasonal forms, either acute or chronic are also a target for this new treatment modality. There is a number of studies supporting the use of LT for SAD (for review), however there are just a few studies for non-seasonal depression or for the other treatment indications (for review). PMID- 26965348 TI - Circadian rhythms and sleep regulation in seasonal affective disorder. AB - Seasonal affective disorder (SAD) is characterised by recurrent episodes in autumn and winter of depression, hypersomnia, augmented appetite with carbohydrate craving, and weight gain, and can be successfully treated with bright light. Circadian rhythm hypotheses (summarized in) have stimulated research into the pathophysiology of SAD, postulating that: 1.The illness is a consequence of delayed phase position, 2.It is correlated with diminished circadian amplitude, or 3.It results from changes in the nocturnal duration between dusk and dawn e.g. of low core body temperature or melatonin secretion. Light is considered to act directly on the circadian pacemaker ('Process C') and not on sleep dependent processes ('Process S'). Thus successful treatment of SAD must act via mechanisms within known retinohypothalamic pathways. Conversely, emergence of SAD symptoms may reflect inappropriate neurobiological response to decreasing daylength. PMID- 26965350 TI - The prevalence of seasonal affective disorder (SAD) in The Netherlands. AB - Since the description of SAD the prevalence of this disorder has been of particular interest. The more so, because early studies, indicated the correctness of the on theoretical grounds - expected interaction between latitude and prevalence rate of SAD. More eleborate prevalence studies, mainly in the USA indeed showed a positive correlation between prevalence rate and latitude. In Europe, only few studies have appeared. Although the results of most of these studies are preliminary and research-methods and criteria vary across studies, tentative conclusions are that the prevalence rates in Europe are considerably lower than in the USA, but that there is a similar trend in the direction of an increase of prevalence at higher latitudes.8"10 In the present study, the prevalence of SAD in the Netherlands is investigated. PMID- 26965351 TI - Treating depression with sleep deprivation and consecutive sleep phase advance therapy. AB - The common treatment modalities for depression, i.e. pharmacotherapy and psychotherapy have the significant disadvantage of at least a three- to four-week time lag between initiation of treatment and amelioration of mood. Total sleep deprivation (TSD) in contrast, leads to an immediate antidepressant effect in 60% of the patients. However, it has gained only little clinical relevance as usually the improvement is only transient and almost regularly reversed by the next nights of sleep. A procedure preserving the antidepressive effect of sleep deprivation would therefore be of high clinical relevance. PMID- 26965352 TI - The clinical relevance of treatment with antidepressants. AB - Oince the discovery in the late 1950's of imipramine (Tofranil(r)), the first tricyclic antidepressant (TCA), and iproniazid, the first monoamine oxidase inhibitor (MAOI), many other TCAs and MAOIs, now being considered the classical antidepressants, have become available. Their effectiveness has been shown in numerous studies, although according to nowadays standards well designed studies (placebo-controlled, defined diagnostic groups, the use of standardized rating scales) with these compounds are relatively scarce. From the early 1980's the so called modern antidepressants have been introduced: the selective serotonin re uptake inhibitors (SSRIs), the reversible selective monoamine oxidase-A inhibitors (RIMAs) and a variety of other compounds. All these drugs have been registered after their effectiveness had been shown in well designed, placebo controlled studies. In defining the efficacy of antidepressants, registration authorities consider two aspects important: statistical evidence and clinical relevance. PMID- 26965353 TI - Biological theories of depressions: premisses - and progress? AB - Although less undisputed in biological psychiatry than formerly, there are basically still two premisses which underly most hypotheses in biological depression research. These are deeply rooted in the medical way of thinking and have guided the construction of DSM-III. The first is that depressive symptoms and complaints cluster in one or more discrete syndromes, and the second is that these correspond to separate nosological entities, characterized by specific biological derangements and pathogenetic processes. Below a number of issues are raised which cast doubts on the validity of these premisses and on the progress made in pinpointing the derangements looked for. PMID- 26965354 TI - A longitudinal study of sleep deprivation responses in depression; The variability is highly related to diurnal mood variability. AB - Unequivocal results demonstrating a causal relationship between a disturbance in circadian rhythms and depression have not yet been reported (reviews). However, acute mood changes, such as the antidepressive effect of sleep deprivation, diurnal variations of mood and their interrelationship, are commonly put forward as evidence of the importance of circadian dysregulations in affective disorders. The purpose of the present study is to obtain more insight in the mechanisms underlying these mood changes. The results will be discussed in the context of a recently postulated non-chronobiological explanation. Earlier studies have suggested that the relationship between diurnal variation of mood and the response to total sleep deprivation (TSD) is clear and unambiguous: improvement of mood during the day prior to TSD (a positive diurnal variation) is followed by a positive response (mood improvement) to TSD, while no improvement or deterioration of mood during the day prior to TSD (a negative diurnal variation) may result in no, or even a negative, TSD response (for references see Van den Hoofdakker). However, these conclusions were based on the results from cross sectional studies, comparing single TSD effects across individuals. Comparison of sleep deprivation effects within individuals, however, revealed that the course of mood during the day prior to TSD is irrelevant for the TSD response. Accordingly, a favourable response to TSD appeared to be related to the patient's propensity to show diurnal mood variations per se, irrespective of their direction. PMID- 26965355 TI - The timing of light therapy and response assessment in winter depression. AB - Since Rosenthal et al published their first study about the effects of light treatment on mood in patients suffering from winter depression, many research centres have become interested in the study and treatment of seasonal affective disorders (SAD), one of them being the department of Biological Psychiatry in Groningen. In 1987, we started the first experiments under the inspiring direction of Prof. Rudi van den Hoofdakker and hundreds of patients have participated in various investigations ever since. PMID- 26965356 TI - Attunement of non-verbal behaviour between depressed patients and a psychiatrist at admission is related to persistence of depression. AB - According to interpersonal theories on depression, the type of interaction between depression-prone subjects and their social environment plays a causal role in the development and course of depression (e.g. Coyne et al.). So far, interpersonal theories have been tackled mostly by psychometrical methods. However, non-verbal behaviour plays an important role in human social interactions. It is assumed that 60-65% of human communication is non-verbal. Ethological observations have shown that non-verbal interpersonal behaviour of depressed subjects, as assessed prior to treatment, is related to treatment response or subsequent course of depression. These results are in line with an interpersonal approach of depression. PMID- 26965357 TI - Lithium treatment in affective disorders: The significance of strongly elevated erythrocyte choline levels. AB - In manic-depressive patients treated with lithium salts the transport of choline over the erythrocyte membrane is strongly inhibited, resulting in dramatically increased erythrocyte choline levels (for review see ref. 1). Whether or not there is a relationship between this effect and treatment response is not clear. Data on this issue are scarce possibly because the measurement of treatment response in lithium prophylaxis is very difficult and time consuming. Also the effect on erythrocyte choline is specific for lithium and not for manic depressive illness. We will address here the question of a possible relation between erythrocyte choline and clinical effects of lithium. PMID- 26965358 TI - The rat hippocampus as a target for prolonged stress: Biochemical and behavioral effects. AB - The probability that an individual will suffer from a major depressive episode is often considered to be influenced by risk factors such as gender, premature parental loss, exposure to pathogenic parental rearing, personality, a history of traumatic events, a previous history of major depression, low social support, recent stressful life events and difficulties and predisposing genetic influences. Although several studies suffer from methodological limitations, major depression (endogenous depression) is regarded as a multifactorial disorder and understanding its etiology requires the rigorous integration of several risk factors. PMID- 26965359 TI - Microwave synthesis of branched silver nanowires and their use as fillers for high thermal conductivity polymer composites. AB - We report a rapid synthesis approach to obtain branched Ag nanowires by microwave stimulated polyvinylpyrrolidone-directed polyol-reduction of silver nitrate. Microwave exposure results in micrometer-long nanowires passivated with polyvinylpyrrolidone. Cooling the reaction mixture by interrupting microwave exposure promotes nanocrystal nucleation at low-surfactant coverage sites. The nascent nuclei grow into nanowire branches upon further microwave exposure. Dispersions of low fractions of the branched nanowires in polydimethylsiloxane yield up to 60% higher thermal conductivity than that obtained using unbranched nanowire fillers. Our findings should be useful for realizing nanocomposites with tailored thermal transport properties for applications. PMID- 26965361 TI - National Trends and Outcomes of Transjugular Intrahepatic Portosystemic Shunt Creation Using the Nationwide Inpatient Sample. AB - PURPOSE: To elucidate trends in transjugular intrahepatic portosystemic shunt (TIPS) use and outcomes over the course of a decade, including predictors of inpatient mortality and extended length of hospital stay. MATERIALS AND METHODS: The Nationwide Inpatient Sample was interrogated for the most recent 10 years available: 2003-2012. TIPS procedures and associated diagnoses were identified via International Classification of Diseases (version 9) codes, with the latter categorized into primary diagnoses in a hierarchy of disease severity. Linear regression analysis was used to determine trends of TIPS use and outcomes over time. Independent predictors of mortality and extended length of stay were determined by logistic regression. RESULTS: A total of 55,145 TIPS procedures were captured during the study period. Annual procedural volume did not change significantly (5,979 in 2003, 5,880 in 2012). The majority of TIPSs were created for ascites and/or varices (84%). Inpatient mortality (12.5% in 2003, 10.6% in 2012; P < .05) decreased but varied considerably by diagnosis (from 3.7% to 59.3%), with a disparity between bleeding and nonbleeding varices (18.7% vs 3.8%; P < .01). Multivariate predictors of mortality (P < .001 for all) included primary diagnoses (bleeding varices, hepatorenal and abdominal compartment syndromes), patient characteristics (age > 80 y, black race), and sequelae of advanced cirrhosis (comorbid hepatocellular carcinoma, spontaneous bacterial peritonitis, encephalopathy, and coagulopathy). CONCLUSIONS: National TIPS inpatient mortality has decreased since 2003 while procedural volume has not changed. Postprocedural outcome is a function of patient demographic and socioeconomic factors and associated diagnoses. Independent predictors of poor outcome identified in this large national population study may aid clinicians in better assessing preprocedural risk. PMID- 26965360 TI - Preservation of ancestral Cretaceous microflora recovered from a hypersaline oil reservoir. AB - Microbiology of a hypersaline oil reservoir located in Central Africa was investigated with molecular and culture methods applied to preserved core samples. Here we show that the community structure was partially acquired during sedimentation, as many prokaryotic 16S rRNA gene sequences retrieved from the extracted DNA are phylogenetically related to actual Archaea inhabiting surface evaporitic environments, similar to the Cretaceous sediment paleoenvironment. Results are discussed in term of microorganisms and/or DNA preservation in such hypersaline and Mg-rich solutions. High salt concentrations together with anaerobic conditions could have preserved microbial/molecular diversity originating from the ancient sediment basin wherein organic matter was deposited. PMID- 26965362 TI - Therapeutic Application of Percutaneous Peritoneovenous (Denver) Shunt in Treating Chylous Ascites in Cancer Patients. AB - PURPOSE: To evaluate the safety and efficacy of percutaneous peritoneovenous shunt (PPVS) placement in treating intractable chylous ascites (CA) in patients with cancer. MATERIALS AND METHODS: Data from 28 patients with refractory CA treated with PPVS from April 2001 to June 2015 were reviewed. Demographic characteristics, technical success, efficacy, laboratory values, and complications were recorded. Univariate and multivariate logistic regression analysis was performed. RESULTS: Technical success was 100%, and ascites resolved or symptoms were relieved in 92.3% (26 of 28) of patients. In 13 (46%) patients with urologic malignancies, whose ascites had resulted from retroperitoneal lymph node dissection, the ascites resolved, resulting in shunt removal within 128 days +/- 84. The shunt provided palliation of symptoms in 13 of the remaining 15 patients (87%) for a mean duration of 198 days +/- 214. Serum albumin levels increased significantly (21.4%) after PPVS placement from a mean of 2.98 g/dL +/- 0.64 before the procedure to 3.62 g/dL +/- 0.83 (P < .001). The complication rate was 37%, including shunt malfunction/occlusion (22%), venous thrombosis (7%), and subclinical disseminated intravascular coagulopathy (DIC) (7%). Smaller venous limb size (11.5 F) and the presence of peritoneal tumor were associated with a higher rate of shunt malfunction (P < .05). No patient developed overt DIC. CONCLUSIONS: PPVS can safely and effectively treat CA in patients with cancer, resulting in significant improvement in serum albumin in addition to palliation of symptoms. PMID- 26965364 TI - The importance of a border: Medical, veterinary, and wild food ethnobotany of the Hutsuls living on the Romanian and Ukrainian sides of Bukovina. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Recent studies have shown that groups sharing the same or very similar environments, but with diverse cultural backgrounds (e.g. different ethnos and/or religion) have considerably different knowledge of folk (medicinal) plant uses. Yet, it is not clear to what extent various factors (such as culture, economy, isolation, and especially social and political situations) contribute to such differences in the utilization of the same natural resources. AIM OF THE STUDY: This paper addresses the effect of border created in 1940 and subsequent separation of a single ethnic group on changes in their folk use of medicinal and wild food plants. The Hutsuls of Bukovina had been homogenous for centuries, but were separated in 1940 as a result of the formation of state borders between Romania and the former Soviet Union (now Ukraine). The aim of the study is to analyse if the belonging to this different states for 75 years have induced different changes in local plant use within communities that share a common historical legacy and environment. MATERIALS AND METHODS: In depth semi structured interviews were conducted with 42 people in May 2015. Collected data were analysed, and comparisons were made between the data gathered on the two sides of the border for different use categories: medicinal, wild food and veterinary plants, as well as other remedies. Recently collected data were also compared with historical data obtained for the region, medicinal plant folk uses in Romania and medicinal plant uses of The State Pharmacopeia of the Soviet Union. RESULTS: Divergences in current medicinal plant use are much greater than in the use of wild food plants. The majority of the wild food taxa, including those used for making recreational teas, are also used for medicinal purposes and hence contribute to the food-medicine continuum, representing emergency foods in the past and serving as memory markers for possible future food shortages. Compared with the historical data, considerable changes have occurred within specific medicinal applications and less in the taxa used. The influence of the Soviet State Pharmacopeia on present ethnomedicine on the Ukrainian side is minimal. CONCLUSIONS: Hutsul herbal ethnomedicine on the Ukrainian side of the border has continued to evolve (the abandonment of some uses and the adoption of others), whereas on the Romanian side it has undergone significant erosion with a proportionally smaller adoption of new uses and the leaving behind of possibly more "traditional" uses than on the Ukrainian side. In sum, current ethnomedicinal practices of Hutsuls living on both sides of the border are more extensive than those reported in historical sources. Yet the unknown sampling method employed to collect the historical data and possible skipping of "ordinary" uses by folklorists and ethnographers does not allow for definitive conclusions to be drawn. Cross-cultural and cross-border ethnobotany represents one of the most powerful means for addressing the issue of change and variability of medicinal plant uses and heritage, and further studies in other areas of Eastern Europe and beyond need to address the trajectory proposed by the present study. PMID- 26965363 TI - Health related quality of life and return to work after minor extremity injuries: A longitudinal study comparing upper versus lower extremity injuries. AB - PURPOSE: To investigate the impact on health related quality of life (HRQL) during the first year after minor extremity injury and to determine whether there is a difference in recovery patterns and return to work between upper extremity injuries (UEI) and lower extremity injuries (LEI). METHOD: A total of 181 adults' age 18 years or older randomly selected from patients admitted to an emergency department with minor injuries were studied. HRQL was measured using the Functional Status Questionnaire (FSQ) at 1-2 weeks, 3, 6, and 12-months post injury. Pre-injury FSQ scores were measured retrospectively at admission. A quasi least square (QLS) model was constructed to examine differences of FSQ scores at each measuring point for UEI and LEI. RESULTS: Fractures of the knee/lower leg (25%) were the most frequently injured body area. Slips or falls (57%) and traffic-related events (22%) were the most common injury causes. The mean ISS was 4.2 (SD 0.86). Both groups had significant declines in the FSQ scores physical and social functioning at 1-2 weeks after injury. Patients with UEI made larger improvements in the first 3 months post-injury versus patients with LEI whose improvements extended over the first 6 months. None of the groups reached the pre injury FSQ scores during the first post-injury year except in the subscale work performance where UEI exceeded the pre-injury scores. At 12 months post-injury, significant lower FSQ scores remained in the LEI group compared to the UEI group in intermediate activities of daily living (p=0.036, d 0.4) and work performance (p=0.004, d 0.7). The return to work at 3 months and 12 months were 76% and 88% for UEI and 58% and 77% for LEI. No significant differences were found between groups in the FSQ scale mental health and social interaction. CONCLUSIONS: LEI had the highest impact on HRQL and return to work during the first year which exceeded the consequences of UEI. These findings contribute to the information about the consequences of injury in order to give sufficient prognostic information to patients and different stakeholders. Future investigations should aim to investigate specific minor extremity injuries and identify factors that facilitate recovery and return to work. PMID- 26965365 TI - Anti-inflammatory and antioxidant activities of aqueous extract of Cecropia glaziovii leaves. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cecropia glaziovii Sneth leaves extract is widely used as a traditional folk medicine in Brazil, especially for the treatment of diabetes, and as an antihypertensive and antiinflammatory agent. AIM OF THE STUDY: To investigate the anti-inflammatory and antioxidant properties of crude aqueous extract (CAE) of C. glaziovii leaves. MATERIALS AND METHODS: The in vivo anti-inflammatory and antioxidant effect of the CAE (10-300mg/kg, intragastrically) was investigated in the animal model of pleurisy. The cell migration, proinflammatory cytokines (TNF-alpha, IL-1beta and IL-6), nitrite/nitrate concentration, myeloperoxidase (MPO) activity, oxidative damage in lipids and proteins, lactate dehydrogenase (LDH) activity and total protein content were also analyzed. Furthermore, the in vitro antioxidant activity of CAE was evaluated by the inhibition of formation of thiobarbituric acid reactive substances (TBARS), induced by free radical generators (H2O2, FeSO4 and AAPH) on a lipid-rich substrate. Hence, the chemical characterizarion of CAE by HPLC was therefore performed. The results showed that the inflammatory process caused by the administration of carragenin (Cg) into the pleural cavity resulted in a substantial increase in inflammatory parameters and oxidative damage. These levels seems to be reversed after CAE treatment in animals with similar results to Dexamethasone (Dex) treatment. Further, the CAE was effective in reducing proinflammatory cytokines, cell infiltrate, MPO activity, nitrite/nitrate concentration, LDH activity, and total protein levels with concomitant attenuation of all parameters associated with oxidative damage induced by Cg. Finally, the CAE presented in vitro antioxidant activity induced by free radical generators at all the concentrations investigated. HPLC analysis confirmed the presence of chlorogenic acid and C-glycosylflavonoids (isoorientin and isovitexin) as the major compounds of the CAE. CONCLUSION: CAE of C. glaziovii exerts significant antiinflammatory and antioxidant activities and this effect can be attributed, at least in part, to the presence of chlorogenic acid and the C-glycosylflavonoids. PMID- 26965366 TI - Metabolomics study on the toxicity of Annona squamosa by ultraperformance liquid chromatography high-definition mass spectrometry coupled with pattern recognition approach and metabolic pathways analysis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Annona squamosa Linn (Annonaceae) is a commonly used and effective traditional Chinese medicine (TCM) especially in the South China. The seeds of Annona squamosa Linn (SAS) have been used as a folk remedy to treat "malignant sores" (cancer) in South of China, but they also have high toxicity on human body. AIM OF THE STUDY: To discover the potential biomarkers in the mice caused by SAS. MATERIALS AND METHODS: We made metabonomics studies on the toxicity of SAS by ultraperformance liquid-chromatography high-definition mass spectrometry coupled with pattern recognition approach and metabolic pathways analysis. RESULTS: The significant difference in metabolic profiles and changes of metabolite biomarkers between the Control group and SAS group were well observed. 11 positive ions and 9 negative ions (P<0.05) were indicated based on UFLC-QTOF-HDMS. The metabolic pathways of SAS group are discussed according to the identified endogenous metabolites, and eight metabolic pathways are identified using Kyoto Encyclopedia of Genes and Genomes (KEGG). CONCLUSIONS: The present study demonstrates that metabonomics analysis could greatly facilitate and provide useful information for the further comprehensive understanding of the pharmacological activity and potential toxicity of SAS in the progress of them being designed to a new anti-tumor medicine. PMID- 26965367 TI - Loss of Bmi1 causes anomalies in retinal development and degeneration of cone photoreceptors. AB - Retinal development occurs through the sequential but overlapping generation of six types of neuronal cells and one glial cell type. Of these, rod and cone photoreceptors represent the functional unit of light detection and phototransduction and are frequently affected in retinal degenerative diseases. During mouse development, the Polycomb group protein Bmi1 is expressed in immature retinal progenitors and differentiated retinal neurons, including cones. We show here that Bmi1 is required to prevent post natal degeneration of cone photoreceptors and bipolar neurons and that inactivation of Chk2 or p53 could improve but not overcome cone degeneration in Bmi1(-/-) mice. The retinal phenotype of Bmi1(-/-) mice was also characterized by loss of heterochromatin, activation of tandem repeats, oxidative stress and Rip3-associated necroptosis. In the human retina, BMI1 was preferentially expressed in cones at heterochromatic foci. BMI1 inactivation in human embryonic stem cells was compatible with retinal induction but impaired cone terminal differentiation. Despite this developmental arrest, BMI1-deficient cones recapitulated several anomalies observed in Bmi1(-/-) photoreceptors, such as loss of heterochromatin, activation of tandem repeats and induction of p53, revealing partly conserved biological functions between mouse and man. PMID- 26965369 TI - A quantitative analysis of growth control in the Drosophila eye disc. AB - The size and shape of organs is species specific, and even in species in which organ size is strongly influenced by environmental cues, such as nutrition or temperature, it follows defined rules. Therefore, mechanisms must exist to ensure a tight control of organ size within a given species, while being flexible enough to allow for the evolution of different organ sizes in different species. We combined computational modeling and quantitative measurements to analyze growth control in the Drosophila eye disc. We find that the area growth rate declines inversely proportional to the increasing total eye disc area. We identify two growth laws that are consistent with the growth data and that would explain the extraordinary robustness and evolutionary plasticity of the growth process and thus of the final adult eye size. These two growth laws correspond to very different control mechanisms and we discuss how each of these laws constrains the set of candidate biological mechanisms for growth control in the Drosophila eye disc. PMID- 26965368 TI - Retinoid signaling controls spermatogonial differentiation by regulating expression of replication-dependent core histone genes. AB - Retinoic acid (RA) signaling is crucial for spermatogonial differentiation, which is a key step for spermatogenesis. We explored the mechanisms underlying spermatogonial differentiation by targeting expression of a dominant-negative mutant of retinoic acid receptor alpha (RARalpha) specifically to the germ cells of transgenic mice to subvert the activity of endogenous receptors. Here we show that: (1) inhibition of retinoid signaling in germ cells completely blocked spermatogonial differentiation identical to vitamin A-deficient (VAD) mice; (2) the blockage of spermatogonial differentiation by impaired retinoid signaling resulted from an arrest of entry of the undifferentiated spermatogonia into S phase; and (3) retinoid signaling regulated spermatogonial differentiation through controlling expression of its direct target genes, including replication dependent core histone genes. Taken together, our results demonstrate that the action of retinoid signaling on spermatogonial differentiation in vivo is direct through the spermatogonia itself, and provide the first evidence that this is mediated by regulation of expression of replication-dependent core histone genes. PMID- 26965370 TI - Spinal motor neurons are regenerated after mechanical lesion and genetic ablation in larval zebrafish. AB - In adult zebrafish, relatively quiescent progenitor cells show lesion-induced generation of motor neurons. Developmental motor neuron generation from the spinal motor neuron progenitor domain (pMN) sharply declines at 48 hours post fertilisation (hpf). After that, mostly oligodendrocytes are generated from the same domain. We demonstrate here that within 48 h of a spinal lesion or specific genetic ablation of motor neurons at 72 hpf, the pMN domain reverts to motor neuron generation at the expense of oligodendrogenesis. By contrast, generation of dorsal Pax2-positive interneurons was not altered. Larval motor neuron regeneration can be boosted by dopaminergic drugs, similar to adult regeneration. We use larval lesions to show that pharmacological suppression of the cellular response of the innate immune system inhibits motor neuron regeneration. Hence, we have established a rapid larval regeneration paradigm. Either mechanical lesions or motor neuron ablation is sufficient to reveal a high degree of developmental flexibility of pMN progenitor cells. In addition, we show an important influence of the immune system on motor neuron regeneration from these progenitor cells. PMID- 26965371 TI - Centrosomal protein CP110 controls maturation of the mother centriole during cilia biogenesis. AB - Defects in cilia centrosomal genes cause pleiotropic clinical phenotypes, collectively called ciliopathies. Cilia biogenesis is initiated by the interaction of positive and negative regulators. Centriolar coiled coil protein 110 (CP110) caps the distal end of the mother centriole and is known to act as a suppressor to control the timing of ciliogenesis. Here, we demonstrate that CP110 promotes cilia formation in vivo, in contrast to findings in cultured cells. Cp110(-/-) mice die shortly after birth owing to organogenesis defects as in ciliopathies. Shh signaling is impaired in null embryos and primary cilia are reduced in multiple tissues. We show that CP110 is required for anchoring of basal bodies to the membrane during cilia formation. CP110 loss resulted in an abnormal distribution of core components of subdistal appendages (SDAs) and of recycling endosomes, which may be associated with premature extension of axonemal microtubules. Our data implicate CP110 in SDA assembly and ciliary vesicle docking, two requisite early steps in cilia formation. We suggest that CP110 has unique context-dependent functions, acting as both a suppressor and a promoter of ciliogenesis. PMID- 26965372 TI - Single-stranded DNA binding proteins are required for LIM complexes to induce transcriptionally active chromatin and specify spinal neuronal identities. AB - LIM homeodomain factors regulate the development of many cell types. However, transcriptional coactivators that mediate their developmental function remain poorly defined. To address these, we examined how two related NLI-dependent LIM complexes, which govern the development of spinal motor neurons and V2a interneurons, activate the transcription in the embryonic spinal cord. We found that single-stranded DNA-binding proteins are recruited to these LIM complexes via NLI, and enhance their transcriptional activation potential. Ssdp1 and Ssdp2 (Ssdp1/2) are highly expressed in the neural tube and promote motor neuron differentiation in the embryonic spinal cord and P19 stem cells. Inhibition of Ssdp1/2 activity in mouse and chick embryos suppresses the generation of motor neurons and V2a interneurons. Furthermore, Ssdp1/2 recruit histone-modifying enzymes to the motor neuron-specifying LIM complex and trigger acetylation and lysine 4 trimethylation of histone H3, which are well-established chromatin marks for active transcription. Our results suggest that Ssdp1/2 function as crucial transcriptional coactivators for LIM complexes to specify spinal neuronal identities during development. PMID- 26965373 TI - Restricting calcium currents is required for correct fiber type specification in skeletal muscle. AB - Skeletal muscle excitation-contraction (EC) coupling is independent of calcium influx. In fact, alternative splicing of the voltage-gated calcium channel CaV1.1 actively suppresses calcium currents in mature muscle. Whether this is necessary for normal development and function of muscle is not known. However, splicing defects that cause aberrant expression of the calcium-conducting developmental CaV1.1e splice variant correlate with muscle weakness in myotonic dystrophy. Here, we deleted CaV1.1 (Cacna1s) exon 29 in mice. These mice displayed normal overall motor performance, although grip force and voluntary running were reduced. Continued expression of the developmental CaV1.1e splice variant in adult mice caused increased calcium influx during EC coupling, altered calcium homeostasis, and spontaneous calcium sparklets in isolated muscle fibers. Contractile force was reduced and endurance enhanced. Key regulators of fiber type specification were dysregulated and the fiber type composition was shifted toward slower fibers. However, oxidative enzyme activity and mitochondrial content declined. These findings indicate that limiting calcium influx during skeletal muscle EC coupling is important for the secondary function of the calcium signal in the activity-dependent regulation of fiber type composition and to prevent muscle disease. PMID- 26965376 TI - Erratum. PMID- 26965374 TI - aura (mid1ip1l) regulates the cytoskeleton at the zebrafish egg-to-embryo transition. AB - Embryos from females homozygous for a recessive maternal-effect mutation in the gene aura exhibit defects including reduced cortical integrity, defective cortical granule (CG) release upon egg activation, failure to complete cytokinesis, and abnormal cell wound healing. We show that the cytokinesis defects are associated with aberrant cytoskeletal reorganization during furrow maturation, including abnormal F-actin enrichment and microtubule reorganization. Cortical F-actin prior to furrow formation fails to exhibit a normal transition into F-actin-rich arcs, and drug inhibition is consistent with aura function promoting F-actin polymerization and/or stabilization. In mutants, components of exocytic and endocytic vesicles, such as Vamp2, Clathrin and Dynamin, are sequestered in unreleased CGs, indicating a need for CG recycling in the normal redistribution of these factors. However, the exocytic targeting factor Rab11 is recruited to the furrow plane normally at the tip of bundling microtubules, suggesting an alternative anchoring mechanism independent of membrane recycling. A positional cloning approach indicates that the mutation in aura is associated with a truncation of Mid1 interacting protein 1 like (Mid1ip1l), previously identified as an interactor of the X-linked Opitz G/BBB syndrome gene product Mid1. A Cas9/CRISPR-induced mutant allele in mid1ip1l fails to complement the originally isolated aura maternal-effect mutation, confirming gene assignment. Mid1ip1l protein localizes to cortical F-actin aggregates, consistent with a direct role in cytoskeletal regulation. Our studies indicate that maternally provided aura (mid1ip1l) acts during the reorganization of the cytoskeleton at the egg-to-embryo transition and highlight the importance of cytoskeletal dynamics and membrane recycling during this developmental period. PMID- 26965375 TI - Clinical and subclinical endometritis induced alterations in bovine endometrial transcriptome and miRNome profile. AB - BACKGROUND: Clinical and subclinical endometritis are known to affect the fertility of dairy cows by inducing uterine inflammation. We hypothesized that clinical or subclinical endometritis could affect the fertility of cows by disturbing the molecular milieu of the uterine environment. Here we aimed to investigate the endometrial molecular signatures and pathways affected by clinical and subclinical endometritis. For this, Holstein Frisian cows at 42-60 days postpartum were classified as healthy (HE), subclinical endometritis (SE) or clinical endometritis (CE) based on veterinary clinical examination of the animals and histological evaluation the corresponding endometrial biopsies. Endometrial transcriptome and miRNome profile changes and associated molecular pathways induced by subclinical or clinical endometritis were then investigated using GeneChip(r) Bovine Genome Array and Exiqon microRNA PCR Human Panel arrays, respectively. The results were further validated in vitro using endometrial stromal and epithelial cells challenged with subclinical and clinical doses of lipopolysaccharide (LPS). RESULT: Transcriptome profile analysis revealed altered expression level of 203 genes in CE compared to HE animals. Of these, 92 genes including PTHLH, INHBA, DAPL1 and SERPINA1 were significantly upregulated, whereas the expression level of 111 genes including MAOB, CXCR4, HSD11B and, BOLA, were significantly downregulated in CE compared to the HE animal group. However, in SE group, the expression patterns of only 28 genes were found to be significantly altered, of which 26 genes including PTHLH, INHBA, DAPL1, MAOB, CXCR4 and TGIF1 were common to the CE group. Gene annotation analysis indicated the immune system processes; G-protein coupled receptor signaling pathway and chemotaxis to be among the affected functions in endometritis animal groups. In addition, miRNA expression analysis indicated the dysregulation of 35 miRNAs including miR-608, miR-526b* and miR-1265 in CE animals and 102 miRNAs including let-7 family (let-7a, let-7c, let-7d, let-7d*, let-7e, let-7f, let-7i) in SE animals. Interestingly, 14 miRNAs including let-7e, miR-92b, miR-337-3p, let-7f and miR-145 were affected in both SE and CE animal groups. Further in vitro analysis of selected differentially expressed genes and miRNAs in endometrial stroma and epithelial cells challenged with SE and CE doses of LPS showed similar results to that of the array data generated using samples collected from SE and CE animals. CONCLUSION: The results of this study unraveled endometrial transcriptome and miRNome profile alterations in cows affected by subclinical or clinical endometritis which may have a significant effect on the uterine homeostasis and uterine receptivity. PMID- 26965377 TI - Unique glycosignature for intervertebral disc and articular cartilage cells and tissues in immaturity and maturity. AB - In this study, on/off markers for intervertebral disc (IVD) and articular cartilage (AC) cells (chondrocytes) and distinct glycoprofiles of cell and tissue types were identified from immaturity to maturity. Three and eleven month-old ovine IVD and AC tissues were histochemically profiled with a panel of lectins and antibodies. Relationships between tissue and cell types were analysed by hierarchical clustering. Chondroitin sulfate (CS) composition of annulus fibrosus (AF), nucleus pulposus (NP) and AC tissues was determined by HPLC analysis. Clear on/off cell type markers were identified, which enabled the discrimination of chondrocytes, AF and NP cells. AF and NP cells were distinguishable using MAA, SNA-I, SBA and WFA lectins, which bound to both NP cells and chondrocytes but not AF cells. Chondrocytes were distinguished from NP and AF cells with a specific binding of LTA and PNA lectins to chondrocytes. Each tissue showed a unique CS composition with a distinct switch in sulfation pattern in AF and NP tissues upon disc maturity while cartilage maintained the same sulfation pattern over time. In conclusion, distinct glycoprofiles for cell and tissue-types across age groups were identified in addition to altered CS composition and sulfation patterns for tissue types upon maturity. PMID- 26965378 TI - A genetic and molecular update on adrenocortical causes of Cushing syndrome. AB - Primary adrenal Cushing syndrome is the result of cortisol hypersecretion mainly by adenomas and, rarely, by bilateral micronodular or macronodular adrenocortical hyperplasia. cAMP-dependent protein kinase A (PKA) signalling is the major activator of cortisol secretion in the adrenal cortex. Many adenomas and hyperplasias associated with primary hypercortisolism carry somatic or germline mutations in genes that encode constituents of the cAMP-PKA pathway. In this Review, we discuss Cushing syndrome and its linkage to dysregulated cAMP-PKA signalling, with a focus on genetic findings in the past few years. In addition, we discuss the presence of germline inactivating mutations in ARMC5 in patients with primary bilateral macronodular adrenocortical hyperplasia. This finding has implications for genetic counselling of affected patients; hitherto, most patients with this form of adrenal hyperplasia and Cushing syndrome were thought to have a sporadic and not a familial disorder. PMID- 26965379 TI - Thyroid cancer: Incidence trends in the USA. PMID- 26965380 TI - Obesity: Variations in adipose tissue fibrosis. PMID- 26965381 TI - Diabetes: Metformin linked to vitamin B12 deficiency. PMID- 26965382 TI - Neuroendocrinology: New regulator of leptin signalling. PMID- 26965383 TI - Epigenetics: Don't stress dad - it's bad for your kids' health. PMID- 26965384 TI - PCOS: Benefits of brown adipose tissue transplantation. PMID- 26965385 TI - Site-specific recombinases: molecular machines for the Genetic Revolution. AB - The fields of molecular genetics, biotechnology and synthetic biology are demanding ever more sophisticated molecular tools for programmed precise modification of cell genomic DNA and other DNA sequences. This review presents the current state of knowledge and development of one important group of DNA modifying enzymes, the site-specific recombinases (SSRs). SSRs are Nature's 'molecular machines' for cut-and-paste editing of DNA molecules by inserting, deleting or inverting precisely defined DNA segments. We survey the SSRs that have been put to use, and the types of applications for which they are suitable. We also discuss problems associated with uses of SSRs, how these problems can be minimized, and how recombinases are being re-engineered for improved performance and novel applications. PMID- 26965386 TI - Enhanced translation initiation factor 4G levels correlate with production levels of monoclonal antibodies in recombinant CHO cell lines. AB - Using cells to manufacture protein-based therapeutics or biopharmaceuticals is a rapidly expanding industrial activity. Chinese hamster ovary (CHO) cells are the most frequently used mammalian host-expression system for the manufacture of biopharmaceuticals. Over the past ~30 years academic and industrial researchers have studied cell expression characteristics with aims to improve product yield, quality, scalability and reproducibility. Although many steps in the gene expression and secretion pathways have been optimized, little attention has been paid to optimizing protein synthesis factors and regulators during this process. A new study in Biochemical Journal by Mead et al., provides a first systematic study of several protein synthesis factors and finds that the expression level of eIF4G1 correlates with the level of recombinant protein expressed in cultures. Optimizing levels and activities of protein synthesis factors may help to enhance recombinant protein expression of biopharmaceuticals. PMID- 26965388 TI - Hibernation-like neuroprotection in stroke by attenuating brain metabolic dysfunction. AB - Many mammalian species naturally undergo hibernation, a process that is associated with drastic changes in metabolism and systemic physiology. Their ability to retain an undamaged central nervous system during severely reduced cerebral blood flow has been studied for possible therapeutic application in human ischemic stroke. By inducing a less extreme 'hibernation-like' state, it has been hypothesized that similar neuroprotective effects reduce ischemia mediated tissue damage in stroke patients. This manuscript includes reviews and evaluations of: (1) true hibernation, (2) hibernation-like state and its neuroprotective characteristics, (3) the preclinical and clinical methods for induction of artificial hibernation (i.e., therapeutic hypothermia, phenothiazine drugs, and ethanol), and (4) the mechanisms by which cerebral ischemia leads to tissue damage and how the above-mentioned induction methods function to inhibit those processes. PMID- 26965390 TI - [CO2 laser treatment of fibrofolliculomas and cutaneous tumors in Birt-Hogg-Dube syndrome]. PMID- 26965389 TI - Determination of cyanidin 3-glucoside in rat brain, liver and kidneys by UPLC/MS MS and its application to a short-term pharmacokinetic study. AB - Anthocyanins exert neuroprotection in various in vitro and in vivo experimental models. However, no details regarding their brain-related pharmacokinetics are so far available to support claims about their direct neuronal bioactivity as well as to design proper formulations of anthocyanin-based products. To gather this missing piece of knowledge, we intravenously administered a bolus of 668 nmol cyanidin 3-glucoside (C3G) in anaesthetized Wistar rats and shortly after (15 s to 20 min) we collected blood, brain, liver, kidneys and urine samples. Extracts thereof were analysed for C3G and its expected metabolites using UPLC/MS-MS. The data enabled to calculate a set of pharmacokinetics parameters. The main finding was the distinctive, rapid distribution of C3G in the brain, with an apparently constant plasma/brain ratio in the physiologically relevant plasma concentration range (19-355 nM). This is the first report that accurately determines the distribution pattern of C3G in the brain, paving the way to the rational design of future tests of neuroprotection by C3G in animal models and humans. PMID- 26965391 TI - Human Blastocystis subtyping with subtype-specific primers developed from unique sequences of the SSU rRNA gene. AB - The genus Blastocystis is one of the most genetically diverse parasites. Blastocystis isolates from humans and animals have been classified into subtypes (STs) based on the phylogeny of the small subunit rRNA gene (SSU rDNA). Although human Blastocystis isolates are limited to STs 1-9, the identification of all 9 STs remains challenging due to the lack of specific primers for several STs. The sequencing of partial SSU rDNA is therefore essential for the identification of several STs. In this study, we developed 9 sets of PCR primers to detect each of the 9 kinds of ST in humans. When these ST-specific primer pairs were examined reference Blastocystis for the 9 STs, all 9 amplified only the target ST even in a DNA mixture of all 9 STs. The specificities of the 9 primer sets were tested against several intestinal parasites and fungi found in human stool samples. No amplification with these common human intestinal eukaryotes was observed using the primer pairs for 8 STs, while the ST5 primer set gave only faint bands with some parasites. Since genomic DNA levels of these parasites extracted from Blastocystis-positive cultures are expected to be markedly lower than the pure or highly concentrated DNA samples tested, the cross-amplifications with these organisms are unlikely to be detected when DNA samples are extracted from Blastocystis-positive cultures. The PCR conditions for all 9 primer sets were the same, hence a one-step analysis by PCR amplification, followed by electrophoresis has potential as a simple tool for the subtyping of human Blastocystis isolates. PMID- 26965392 TI - Editorial overview: Energy biotechnology. PMID- 26965393 TI - What is your diagnosis? Acute non-weight bearing pelvic limb lameness in a dog. Question and answer. PMID- 26965387 TI - Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders. AB - Epilepsy is a common central nervous system (CNS) disease characterized by recurrent transient neurological events occurring due to abnormally excessive or synchronous neuronal activity in the brain. The CNS is affected by systemic acid base disorders, and epileptic seizures are sensitive indicators of underlying imbalances in cellular pH regulation. Na(+)/H(+) exchangers (NHEs) are a family of membrane transporter proteins actively involved in regulating intracellular and organellar pH by extruding H(+) in exchange for Na(+) influx. Altering NHE function significantly influences neuronal excitability and plays a role in epilepsy. This review gives an overview of pH regulatory mechanisms in the brain with a special focus on the NHE family and the relationship between epilepsy and dysfunction of NHE isoforms. We first discuss how cells translocate acids and bases across the membrane and establish pH homeostasis as a result of the concerted effort of enzymes and ion transporters. We focus on the specific roles of the NHE family by detailing how the loss of NHE1 in two NHE mutant mice results in enhanced neuronal excitability in these animals. Furthermore, we highlight new findings on the link between mutations of NHE6 and NHE9 and developmental brain disorders including epilepsy, autism, and attention deficit hyperactivity disorder (ADHD). These studies demonstrate the importance of NHE proteins in maintaining H(+) homeostasis and their intricate roles in the regulation of neuronal function. A better understanding of the mechanisms underlying NHE1, 6, and 9 dysfunctions in epilepsy formation may advance the development of new epilepsy treatment strategies. PMID- 26965395 TI - Preparation of copper-containing bioactive glass/eggshell membrane nanocomposites for improving angiogenesis, antibacterial activity and wound healing. AB - Effectively stimulating angiogenesis and avoiding wound infection are great challenges in wound care management. Designing new healing dressings with requisite angiogenic capacity and antibacterial performance is of particular significance. In order to achieve this aim, we prepared a copper (Cu)-containing bioactive glass nanocoating (40-50nm) with uniform nanostructure on natural eggshell membrane (Cu-BG/ESM) by the pulsed laser deposition (PLD) technique. The surface physicochemical properties including hydrophilicity and hardness of ESM were significantly improved after depositing Cu-BG nanocoatings. Meanwhile, 5Cu BG/ESM films containing 5mol% Cu stimulated proangiogenesis by improving vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1alpha protein secretion as well as angiogenesis-related gene expression (VEGF, HIF 1alpha, VEGF receptor 2 (KDR) and endothelial nitric oxide (eNos)) of human umbilical vein endothelial cells (HUVECs). When used to treat full-thickness skin defects in mice, 5Cu-BG/ESM films enhanced the healing quality as confirmed by the significantly improved angiogenesis (as indicated by CD31 expression) and formation of continuous and uniform epidermis layer in vivo. Furthermore, 5Cu BG/ESM films could maintain a sustained release of Cu(2+) ions and distinctly inhibited the viability of bacteria (Escherichia coli). The results indicate that Cu(2+) ions released from Cu-BG/ESM nanocomposite films play an important role for improving both angiogenesis and antibacterial activity and the prepared nanocomposite films combined Cu-containing BG nanocoatings with ESM are a promising biomaterial for wound healing application. STATEMENT OF SIGNIFICANCE: Designing new healing dressings with requisite angiogenic capacity and antibacterial performance is of particular significance in wound care management. In our study, we successfully prepared copper-containing bioactive glass/eggshell membrane (Cu-BG/ESM) nanocomposites with uniform bioactive glass nanocoatings by using pulsed laser deposition (PLD) technology. Due to the deposited Cu-BG nanocoatings on the surface of ESM, Cu-BG/ESM nanocomposites possessed significantly improved physicochemical and biological properties, including surface hydrophilicity, hardness, antibacterial ability, angiogenesis rate in vitro and wound healing quality in vivo as compared to pure ESM and BG/ESM films. Our study showed that prepared nanocoatings on Cu-BG/ESM nanocomposites offer a beneficial carrier for sustained release of Cu(2+) ions which played a key role for improving both angiogenesis and antibacterial activity. The prepared nanocomposites combined Cu-containing BG nanocoatings with ESM are a promising biomaterial for wound healing application. PMID- 26965394 TI - Assessment of a polyelectrolyte multilayer film coating loaded with BMP-2 on titanium and PEEK implants in the rabbit femoral condyle. AB - The aim of this study was to evaluate the osseointegration of titanium implants (Ti-6Al-4V, noted here TA6V) and poly(etheretherketone) PEEK implants induced by a BMP-2-delivering surface coating made of polyelectrolyte multilayer films. The in vitro bioactivity of the polyelectrolyte film-coated implants was assessed using the alkaline phosphatase assay. BMP-2-coated TA6V and PEEK implants with a total dose of 9.3MUg of BMP-2 were inserted into the femoral condyles of New Zealand white rabbits and compared to uncoated implants. Rabbits were sacrificed 4 and 8weeks after implantation. Histomorphometric analyses on TA6V and PEEK implants and microcomputed tomography on PEEK implants revealed that the bone-to implant contact and bone area around the implants were significantly lower for the BMP-2-coated implants than for the bare implants. This was confirmed by scanning electron microscopy imaging. This difference was more pronounced at 4weeks in comparison to the 8-week time point. However, bone growth inside the hexagonal upper hollow cavity of the screws was higher in the case of the BMP-2 coated implants. Overall, this study shows that a high dose of BMP-2 leads to localized and temporary bone impairment, and that the dose of BMP-2 delivered at the surface of an implant needs to be carefully optimized. STATEMENT OF SIGNIFICANCE: The presentation of growth factors from material surfaces currently presents significant challenges in academia, clinics and industry. Applying osteoinductive factors to different types of implants, made of metals or polymers, may improve bone repair in difficult situations. Here, we show the effects of an osteoinductive coating made of polyelectrolyte multilayer films on two widely used materials, titanium TA6V alloys and PEEK implants, which were implanted in the rabbit femoral condyle. We show that a too high dose of BMP-2 delivered from the screw surface has a negative short-term effect on bone regeneration in close vicinity of the screw surface. In contrast, bone formation was increased at early times in the empty spaces around the screw. These results highlight the need for future dose-dependence studies on bone formation in response to osteoinductive coatings. PMID- 26965397 TI - Newly-acquired words are more phonologically robust in verbal short-term memory when they have associated semantic representations. AB - Verbal short-term memory (STM) is a crucial cognitive function central to language learning, comprehension and reasoning, yet the processes that underlie this capacity are not fully understood. In particular, although STM primarily draws on a phonological code, interactions between long-term phonological and semantic representations might help to stabilise the phonological trace for words ("semantic binding hypothesis"). This idea was first proposed to explain the frequent phoneme recombination errors made by patients with semantic dementia when recalling words that are no longer fully understood. However, converging evidence in support of semantic binding is scant: it is unusual for studies of healthy participants to examine serial recall at the phoneme level and also it is difficult to separate the contribution of phonological-lexical knowledge from effects of word meaning. We used a new method to disentangle these influences in healthy individuals by training new 'words' with or without associated semantic information. We examined phonological coherence in immediate serial recall (ISR), both immediately and the day after training. Trained items were more likely to be recalled than novel nonwords, confirming the importance of phonological-lexical knowledge, and items with semantic associations were also produced more accurately than those with no meaning, at both time points. For semantically trained items, there were fewer phoneme ordering and identity errors, and consequently more complete target items were produced in both correct and incorrect list positions. These data show that lexical-semantic knowledge improves the robustness of verbal STM at the sub-item level, even when the effect of phonological familiarity is taken into account. PMID- 26965396 TI - Salt-responsive polyzwitterionic materials for surface regeneration between switchable fouling and antifouling properties. AB - Development of smart regenerative surface is a highly challenging but important task for many scientific and industrial applications. Specifically, very limited research efforts were made for surface regeneration between bio-adhesion and antifouling properties, because bioadhesion and antifouling are the two highly desirable but completely opposite properties of materials. Herein, we developed salt-responsive polymer brushes of poly(3-(1-(4-vinylbenzyl)-1H-imidazol-3-ium-3 yl) propane-1-sulfonate) (polyVBIPS), which can be switched reversibly and repeatedly between protein capture/release and surface wettability in a controllable manner. PolyVBIPS brush has demonstrated its switching ability to resist both protein adsorption from 100% blood plasma/serum and bacterial attachment in multiple cycles. PolyVBIPS brush also exhibits reversible surface wettability from ~40 degrees to 25 degrees between in PBS and in 1M NaCl solutions in multiple cycles. Overall, the salt-responsive behaviors of polyVBIPS brushes can be interpreted by the "anti-polyelectrolyte effect", i.e. polyVBIPS brushes adopt a collapsed chain conformation at low ionic strengths to achieve surface adhesive, but an extended chain conformation at high ionic strength to realize antifouling properties. We expect that polyVBIPS will provide a simple, robust, and promising system for the fabrication of smart surfaces with biocompatible, reliable, and regenerative properties. STATEMENT OF SIGNIFICANCE: Unlike many materials with "one-time switching" capability for surface regeneration, we developed a new regenerative surface of zwitterionic polymer brush, which exhibits a reversible salt-induced switching property between a biomolecule-adhesive state and a biomolecule repellent state in complex media for multiple cycles. PolyVBIPS is easily synthesized and can be straightforward coated on the surface, which provides a simple, robust, and promising system for the fabrication of smart surfaces with biocompatible, reliable, regenerative properties. PMID- 26965398 TI - Do temporary workers have a higher risk of occupational injury than permanent employees? PMID- 26965399 TI - RBC invasion and invasion-inhibition assays using free merozoites isolated after cold treatment of Babesia bovis in vitro culture. AB - Babesia bovis is an apicomplexan hemoprotozoan that can invade bovine red blood cells (RBCs), where it multiplies asexually. RBC invasion assays using free viable merozoites are now routinely used to understand the invasion mechanism of B. bovis, and to evaluate the efficacy of chemicals and antibodies that potentially inhibit RBC invasion by the parasite. The application of high-voltage pulses (high-voltage electroporation), a commonly used method to isolate free merozoites from infected RBCs, reduces the viability of the merozoites. Recently, a cold treatment of B. bovis in vitro culture was found to induce an effective release of merozoites from the infected RBCs. In the present study, we incubated in vitro cultures of B. bovis in an ice bath to liberate merozoites from infected RBCs and then evaluated the isolated merozoites in RBC invasion and invasion inhibitions assays. The viability of the purified merozoites (72.4%) was significantly higher than that of merozoites isolated with high-voltage electroporation (48.5%). The viable merozoites prepared with the cold treatment also invaded uninfected bovine RBCs at a higher rate (0.572%) than did merozoites prepared with high-voltage electroporation (0.251%). The invasion-blocking capacities of heparin, a polyclonal rabbit antibody directed against recombinant B. bovis rhoptry associated protein 1, and B. bovis-infected bovine serum were successfully demonstrated in an RBC invasion assay with the live merozoites prepared with the cold treatment, suggesting that the targets of these inhibitors were intact in the merozoites. These findings indicate that the cold treatment technique is a useful tool for the isolation of free, viable, invasion-competent B. bovis merozoites, which can be effectively used for RBC invasion and invasion inhibition assays in Babesia research. PMID- 26965401 TI - Matrix Extension Study: Validation of the Compact Dry TC Method for Enumeration of Total Aerobic Bacteria in Selected Foods. AB - A validation study was conducted to extend the matrix claim for the Nissui Compact Dry Total Count (TC), Performance Tested Method(s)(SM) (PTM) Certification No. 010404, to cooked chicken, lettuce, frozen fish, milk powder, and pasteurized whole milk. The method was originally certified by the AOAC Research Institute Performance Tested Method(s)(SM) Program for raw meat products. The Compact Dry TC is a ready-to-use dry media sheet that is rehydrated by adding 1 mL of diluted sample. A total aerobic colony count can be determined in the sample following 48 h of incubation. Matrix extension studies were conducted by Campden BRI (formerly Campden and Chorleywood Food Research Association Technology Limited), Chipping Campden, UK. Single-laboratory data were collected for cooked chicken, lettuce, frozen fish, and milk powder, whereas a multilaboratory study was conducted on pasteurized milk. Fourteen laboratories participated in the collaborative study. The Compact Dry TC was tested at two time points, 48 +/- 3 h and 72 +/- 3 h and compared with the current International Organization for Standardization (ISO) method at the time of the study, ISO 4833:2003 (this standard is withdrawn and has been replaced by: ISO 4833-1:2013 and ISO 4833-2:2013), Microbiology of food and animal feeding stuffs Horizontal method for the enumeration of microorganisms-Colony-count technique at 30 degrees C. The data were logarithmically transformed and evaluated for repeatability (plus reproducibility for pasteurized milk), RSD of repeatability (plus RSD of reproducibility for milk), r(2), and mean difference between methods with 95% confidence interval (CI). A CI outside of (-0.5 to 0.5) on the log10 mean difference was used as the criterion to establish significant statistical difference between methods. No significant differences were found between the Compact Dry TC 48 and 72 h time points, with the exception of one contamination level of cooked chicken and one contamination level of dry milk powder. Mean differences were small at these levels (<0.5 log10), but the upper CIs were above 0.5. Statistical differences were indicated between the Compact Dry TC and ISO 4833 in two of five contamination levels tested each for lettuce and frozen fish. In each case, mean differences were >0.5 log10, and the total aerobic colony count was higher for the ISO method. In most cases, mean differences between the Compact Dry and ISO methods were small (<0.5 log10) with CIs within the acceptance criterion. Repeatability, reproducibility, and RSD were similar for both methods, and r(2) values were >0.97 for all matrixes. The Compact Dry TC, at 48 h, offers the advantage of a shorter time to results than ISO 4833 in an easy to-use format. PMID- 26965400 TI - Exploration of fluorescence-based real-time loop-mediated isothermal amplification (LAMP) assay for detection of Isospora suis oocysts. AB - Isospora suis is an intestinal protozoan parasite in pigs. The 2-3 weeks old piglets are most often infected by I. suis because their immune system is not fully developed. The infection exhibits clinical features such as diarrhea and dehydration and seriously affects the economic interests of farmers. The traditional method of identifying I. suis relies on the detection of fecal oocysts, which depends heavily on the accumulation of experience. Thus, missed detection, and false alarms often occur during detection. With the development of molecular-based detection methods, development of a simple, convenient and more sensitive method for the detection of I. suis is an urgent need. In this study, based on the 18S rRNA gene sequence, a fluorescence -based real-time loop mediated isothermal amplification (LAMP) assay was established for the detection of I. suis. The results showed that the assay is highly specific and sensitive, with a detection limit of 2.74 * 10(2) copies/MUL recombinant plasmid of I. suis, corresponding to 1 fg/MUL plasmid when converted to DNA concentration. The sensitivity is about 100 times higher than conventional PCR. Additionally, DNA extracted from a certain number of oocysts was used for detection, and it showed that the LAMP assay had a detection limit of 5 oocysts, lower than that of 13 oocysts of conventional PCR. The established LAMP assay overcomes the shortage of the traditional microscopy-based method, and provides a valuable way for molecular detection of I. suis. PMID- 26965402 TI - Sex estimation based on scapula analysis in a Japanese population using multidetector computed tomography. AB - Accurate sex estimation based on measurements of dimorphic dimensions in human unknown remains is important as the first step toward making individual identification. The purpose of this study was to assess the sexual dimorphism of the scapula and to quantify the accuracy of sex estimation in a contemporary Japanese forensic sample using scapular measurements based on three-dimensional (3D) computed tomographic (CT) images. A total of 218 cadavers (109 males, 109 females) that underwent postmortem CT and subsequent forensic autopsy were used. Ten scapular measurements were performed on 3D CT reconstructed images that extracted only bone data, and were analyzed using descriptive statistics and discriminant function analyses (DFA). All measurements were dimorphic in terms of sex differences. Univariate DFA provided sex classification accuracy rates of 75.7-91.3%. Stepwise DFA yielded sex prediction accuracy rates of 93.1-94.5%. In conclusion, the scapular measurements using 3D CT images of a contemporary Japanese population may be useful for the estimation of skeletal sex in the field of forensic anthropology. PMID- 26965403 TI - Alexander of Tralles and the first portrayal of a placebo by illusion in the 6th century AD. PMID- 26965404 TI - Landfill site selection using geographic information system and analytical hierarchy process: A case study Al-Hillah Qadhaa, Babylon, Iraq. AB - Al-Hillah Qadhaa is located in the central part of Iraq. It covers an area of 908 km(2) with a total population of 856,804 inhabitants. This Qadhaa is the capital of Babylon Governorate. Presently, no landfill site exists in that area based on scientific site selection criteria. For this reason, an attempt has been carried out to find the best locations for landfills. A total of 15 variables were considered in this process (groundwater depth, rivers, soil types, agricultural land use, land use, elevation, slope, gas pipelines, oil pipelines, power lines, roads, railways, urban centres, villages and archaeological sites) using a geographic information system. In addition, an analytical hierarchy process was used to identify the weight for each variable. Two suitable candidate landfill sites were determined that fulfil the requirements with an area of 9.153 km(2) and 8.204 km(2) These sites can accommodate solid waste till 2030. PMID- 26965405 TI - Cyclist's nodule: no smooth ride. AB - A fit and active amateur cyclist was referred by his general practitioner to a surgical oncology outpatient clinic with a slowly-growing perineal mass. Following clinical examination, the patient underwent imaging and biopsy at a tertiary soft tissue tumour centre, which diagnosed perineal nodular induration: a rare, benign tumour caused by repetitive trauma associated with 'saddle sports' such as cycling or horse riding. It is important to consider soft tissue tumours in patients who present with 'lumps and bumps'; they can occur anywhere in the body including the groin or perineum, where it is sometimes referred to as a 'third' or 'accessory' testicle in men. Although unusual, the case emphasises the importance of rapid specialist referral from primary care, and consideration of a patient's occupation and hobbies when formulating diagnoses. PMID- 26965407 TI - Idiopathic female pseudohermaphroditism with urethral duplication and female hypospadias. AB - Female hypospadias is a rare anomaly of the female urethra where it opens on the anterior vaginal wall anywhere between the introitus and the fornix. It is often associated with other genitourinary anomalies such as Cloacal malformation, female pseudohermaphroditism, nonneurogenic neurogenic bladder and urethral duplication. Idiopathic female pseudohermaphroditism is extremely rare, and most cases occur secondary to adrenogenital syndrome or maternal androgen exposure. We report a unique case of a 1-year and 4-month-old girl who presented with ambiguous genitalia and renal failure secondary to a non-neurogenic neurogenic bladder. On further evaluation, she was found to have urethral duplication with a hypospadiac female urethra. She initially underwent a vesicostomy and was further planned to undergo an appendicular Mitrofanoff at an older age. The mainstay of treatment in these cases includes relief of bladder outlet obstruction and recovery of renal function by adequate urinary drainage. Clitoral reduction, if cosmetically warranted, may be planned at puberty. PMID- 26965406 TI - Intrauterine device infection causing concomitant streptococcal toxic shock syndrome and pelvic abscess with Actinomyces odontolyticus bacteraemia. AB - Intrauterine devices (IUDs) are rarely associated with serious infections. We report an unusual concomitant infection of group A Streptococcus (GAS) causing toxic shock syndrome and pelvic abscess with Actinomyces odontolyticus associated with an IUD in a healthy 50-year-old patient. The IUD was subsequently removed and the patient recovered on the appropriate antibiotics. This case highlights the importance of clinicians' high index of suspicion of an IUD infection and prompt removal of the infected foreign body to obtain source control. PMID- 26965408 TI - Uncommon condition mimicking non-resolving pneumonia and malignancy on radiography that improves dramatically with a course of steroids. AB - A 58-year-old man was seen in a specialist respiratory clinic, with non-resolving pneumonia. Various investigations including CT scan, bronchoscopy and CT-guided biopsy were carried out for suspected malignancy but they could not find any evidence of neoplasia or anything else of significance. The lung mass that persisted for years later resolved with a course of steroids, at which point further investigations for alternative differential diagnoses suggested a surprising conclusion. PMID- 26965409 TI - Bilateral adrenal haemorrhage: a cause of haemodynamic collapse in heparin induced thrombocytopaenia. AB - Heparin-induced thrombocytopaenia (HIT) is a life-threatening complication of exposure to heparin. It is mediated by autoantibodies to platelet factor-4 causing platelet activation, destruction and thrombosis. Given their rich arterial supply and a single central vein, the adrenal glands are particularly susceptible to congestive haemorrhage following venous thrombosis. We report a case of bilateral adrenal haemorrhage (BAH) associated with HIT following prophylactic use of unfractionated heparin for venous thromboembolism causing adrenal insufficiency. BAH is a life-threatening paradoxical complication associated with HIT, a prothrombotic state. The resulting adrenal insufficiency can lead to haemodynamic collapse if unrecognised. Early diagnosis, in the wake of vague symptoms, and prompt treatment primarily aimed at repletion of glucocorticoids and close monitoring of enlarging haemorrhage is of utmost importance. Likewise, early identification of HIT is important to prevent potential complications including adrenal haemorrhage. PMID- 26965410 TI - Hidradenitis suppurativa (HS): An unrecognized paradoxical effect of biologic agents (BA) used in chronic inflammatory diseases. AB - BACKGROUND: Paradoxical hidradenitis suppurativa (HS) induced by biologic agents (BA) is scarcely reported. OBJECTIVE: We sought to describe the clinical characteristics and outcome of patients developing paradoxical HS under BA. METHODS: This was a multicenter nationwide retrospective study asking physicians to report all cases of HS, confirmed by a dermatologist, occurring during treatment of an inflammatory disease by a BA. RESULTS: We included 25 patients (15 inflammatory rheumatism, 9 Crohn's disease, 1 psoriasis) treated by 5 BA (adalimumab = 12, infliximab = 6, etanercept = 4, rituximab = 2, tocilizumab = 1). Median duration of BA exposure before HS onset was 12 (range 1-120) months. Patients were mostly Hurley stage I (n = 13) or II (n = 11). Simultaneously to HS or within 1 year, 11 patients developed additional inflammatory diseases, including paradoxical reactions (psoriasis = 9, Crohn's disease = 3, alopecia areata = 1, erythema elevatum diutinum = 1). Complete improvement of HS was more frequently obtained after BA discontinuation or switch (n = 6/10, 60%) rather than maintenance (n = 1/14, 7%). Reintroducing the same BA resulted in HS relapse in 3 of 3 patients. LIMITATIONS: Retrospective nature and lack of complete follow up for some patients are limitations. CONCLUSION: HS is a rare paradoxical adverse effect of BA, but fortuitous association cannot be excluded in some cases. We observed a trend toward better outcome when the BA was discontinued or switched. PMID- 26965412 TI - Robotic vesico-vaginal fistula repair with no omental flap interposition. AB - INTRODUCTION AND HYPOTHESIS: A vesico-vaginal fistula (VVF) is a fistulous tract that connects bladder and vagina, causing urine leakage via the vagina. In the developed world, iatrogenic postoperative VVF is the most common case. Classically, when treating a VVF via the abdominal route, an abdominal flap is mobilized and interposed between the bladder and the vagina. METHODS: In our video, we describe a robotic VVF repair technique with no omental flap interpositioning for a vaginal vault-located fistula. RESULTS: Duration of surgery was 95 min, estimated blood loss was <50 ml. The postoperative course was uneventful. At the 6-month follow-up, which included clinical and cystographic examinations, the patient had not experienced any recurrence. CONCLUSION: In our opinion, a two-layered suturing technique using two semi-continuous sutures for vaginal closure and perpendicular interrupted stitches for bladder closure does not require omental flap mobilization, reducing operating time and possible complications related to accidental peritoneal injuries. PMID- 26965411 TI - Pelvic floor dysfunction in female Sjogren's syndrome: an 8-year audit. AB - INTRODUCTION AND HYPOTHESIS: The classic triad of dry eyes, mouth and vagina is known to most gynaecologists as pathognomonic of Sjogren's syndrome, but rheumatologists seldom consider vaginal symptoms. Our hypothesis was that women with Sjogren's syndrome would have an increased likelihood of postoperative voiding dysfunction, severe vaginal stenosis or poor response to anticholinergics compared with the general urogynaecology patient. METHODS: All patients with Sjogren's syndrome were prospectively recorded from July 2007 to June 2015. Presenting complaint, pelvic examination findings, previous/subsequent pelvic surgery, voiding dysfunction and response to anticholinergics were noted. The denominator, all new urogynaecology patients, was prospectively recorded. RESULTS: Fifteen patients were identified over 8 years (0.5 % of 2794 new presentations). Of the seven patients who had previously undergone surgery elsewhere, all had demonstrable pelvic tissue fibrosis; five had such severe fibrosis that no speculum could be passed. Anticholinergic medications were completely intolerable in 10/11 (91 %) women, and severe postoperative voiding dysfunction occurred in 6/9 (67 %) women. Only 2/15 (13 %) women were unaffected by fibrosis, postoperative voiding dysfunction or intolerance to anticholinergics. CONCLUSIONS: This audit demonstrates a substantial risk of vaginal stenosis, postoperative voiding dysfunction or severe intolerance to anticholinergics in women with Sjogren's syndrome. PMID- 26965413 TI - Telomerase repeat amplification protocol (TRAP) activity upon recombinant expression and purification of human telomerase in a bacterial system. AB - Telomerase biogenesis is a highly regulated process that solves the DNA end replication problem. Recombinant expression has so far been accomplished only within a eukaryotic background. Towards structural and functional analyses, we developed bacterial expression of human telomerase. Positive activity by the telomerase repeat amplification protocol (TRAP) was identified in cell extracts of Escherichia coli expressing a sequence-optimized hTERT gene, the full-length hTR RNA with a self-splicing hepatitis delta virus ribozyme, and the human heat shock complex of Hsp90, Hsp70, p60/Hop, Hsp40, and p23. The Hsp90 inhibitor geldanamycin did not affect post-assembly TRAP activity. By various purification methods, TRAP activity was also obtained upon expression of only hTERT and hTR. hTERT was confirmed by tandem mass spectrometry in a ~120 kDa SDS-PAGE fragment from a TRAP-positive purification fraction. TRAP activity was also supported by hTR constructs lacking the box H/ACA small nucleolar RNA domain. End-point TRAP indicated expression levels within 3-fold of that from HeLa carcinoma cells, which is several orders of magnitude below detection by the direct assay. These results represent the first report of TRAP activity from a bacterium and provide a facile system for the investigation of assembly factors and anti-cancer therapeutics independently of a eukaryotic setting. PMID- 26965414 TI - Purification and characterization of recombinant supersweet protein thaumatin II from tomato fruit. AB - Thaumatin, a supersweet protein from the African plant katemfe (Thaumatococcus daniellii Benth.), is a promising zero-calorie sweetener for use in the food and pharmaceutical industries. Due to limited natural sources of thaumatin, its production using transgenic plants is an advantageous alternative. We report a simple protocol for purification of recombinant thaumatin II from transgenic tomato. Thaumatin was extracted from ripe tomato fruit in a low-salt buffer and purified on an SP-Sephacryl column. Recombinant thaumatin yield averaged 50 mg/kg fresh fruit. MALDI-MS analysis showed correct processing of thaumatin in tomato plants. The recombinant thaumatin was indistinguishable from the native protein in a taste test. The purified tomato-derived thaumatin had an intrinsic sweetness with a threshold value in taste tests of around 50 nM. These results demonstrate the potential of an expression system based on transgenic tomato plants for production of recombinant thaumatin for the food and pharmaceutical industries. PMID- 26965415 TI - Different apoptotic effects of saxifragifolin C in human breast cancer cells. AB - Breast cancer is currently the most common form of cancer affecting women. Recent studies have reported that triterpenoid saponins isolated from Androsace umbellata exhibit anti-proliferative effects in several types of cancer cells. However, the cytotoxic effect of saxifragifolin C (Saxi C) on breast cancer cells remains unclear. The purpose of this study is to evaluate the in vitro anti-tumor activity of Saxi C in human breast cancer cells. Our data indicated that MDA-MB 231 cells were more sensitive than MCF-7 cells to Saxi C treatment. In addition, Saxi C inhibited cell survival through the induction of reactive oxygen species and the caspase-dependent pathway in the MDA-MB-231 cells, whereas MCF-7 cells treated with Saxi C underwent the apoptotic cell death in a caspase-independent manner. Although Saxi C treatment resulted in the induction of activation of MAPKs in both types of human breast cancer cells, p38 MAPK and JNK, but not ERK1/2, appeared to be involved in Saxi C-induced apoptosis. Moreover, ERalpha overexpressing MDA-MB-231 cells remained alive, whereas the survival of shERalpha transfected MCF-7 cells decreased. Taken together, Saxi C induced apoptosis in MCF-7 cells and MDA-MB-231 cells via different regulatory mechanisms, and ERalpha status might be essential for regulating Saxi C-induced apoptosis in breast cancer cells. Thus, Saxi C is a potential chemotherapeutic agent in breast cancer. PMID- 26965416 TI - Why don't patients take their analgesics? A meta-ethnography assessing the perceptions of medication adherence in patients with osteoarthritis. AB - Whilst analgesics and medications have demonstrated efficacy for people with osteoarthritis, their effectiveness is dependent on adherence. This has previously been reported as particularly low in this population. The purpose of this meta-ethnography was to explore possible perceptions for this. A systematic review of published and unpublished literature was undertaken. All qualitative studies assessing the attitudes or perceptions of people with osteoarthritis towards medication adherence were eligible. Study quality was assessed using the Critical Appraisal Skills Programme qualitative tool. Analysis was undertaken using a meta-ethnography approach, distilling to a third-order construct and developing a line of argument. From 881 citations, five studies met the eligibility criteria. The meta-ethnography generated a model where medication adherence for people with osteoarthritis is perceived as a balance between the willingness and preference to take medications with the alterative being toleration of symptoms. Motivators to influence this 'balance' may fluctuate and change over time but include: severity of symptoms, education and understanding of osteoarthritis and current medications, or general health which may raise issues for poly-pharmacy as other medications are added or substituted into the patient's formulary. Medicine adherence in people with osteoarthritis is complex, involving motivators which will fluctuate in impact on individuals at different points along the disease progression. Awareness of each motivator may better inform clinicians as to what education, support or change in prescription practice should be adopted to ensure that medicine adherence is individualised to better promote long-term behaviour change. PMID- 26965418 TI - Massive ascites in a canakinumab resistant case with MVA leading to bone marrow transplantation. PMID- 26965417 TI - Incidence and risk factors of fractures in patients with rheumatoid arthritis: an Asian prospective cohort study. AB - Rheumatoid arthritis (RA) patients have high risk for osteoporosis and fracture. We aimed to identify the incidence rate and risk factors of fractures in Asian RA patients. A total of 3557 RA patients in the KORean Observational study Network for Arthritis (KORONA) were included and observed over a mean follow-up of 18 months. A fracture was assessed as total, major, or minor fractures; major fracture was defined as a vertebral or hip fracture, and the other fractures were classified as minor fractures. The standardized incidence ratio (SIR) of fracture in RA patients was calculated compared with general population, and possible risk factors for fractures were explored using multivariable logistic regression analyses. A total of 194 patients with 215 fractures were observed, and the SIR of the total fracture in RA patients was 2.2 [95 % confidence interval (CI) 1.9 2.6]. The SIRs of major and minor fractures were 1.5 (CI 1.1-2.0) and 3.0 (CI 2.5 3.7), respectively. Advanced age [odds ratio (OR) 1.03, CI 1.02-1.05, p < 0.01] and having history of prior fracture (OR 2.17, CI 1.54-3.08, p < 0.01) were risk factors for total fractures. In addition, higher HAQ increased fracture risk (OR 2.02, CI 1.05-3.89, p = 0.04), whereas the use of bisphosphonate showed protective effect for future fractures (OR 0.34, CI 0.14-0.87, p = 0.02) in patients with osteoporosis. RA patients had a 2.2-fold increased risk of fractures as compared with general population. In Asian RA patients, advanced age and history of prior fracture were the most important risk factors for new fractures. PMID- 26965419 TI - The interferon-inducible protein p205 acts as an activator in osteoblast differentiation of mouse BMSCs. AB - p205, an interferon-inducible protein, is induced in the course of osteogenesis in mouse bone marrow stromal cells (BMSCs). Knocking down p205 markedly impairs whereas overexpressing p205 enhances the osteoblast differentiation of BMSCs, as revealed by the altered expression of osteogenic genes, the change of ALP activity and the ARS-stained mineral nodules. The positive role of p205 in BMSC osteogenesis is probably due, at least in part, to the association of it with Id proteins. Further investigation indicated that p205 may disturb the formation of Runx2/Ids complex and free more Runx2 to induce the differentiation process. Taken together, our findings demonstrated for the first time that p205 functions as an activator in osteoblast differentiation. PMID- 26965420 TI - Novel dengue virus inhibitor 4-HPR activates ATF4 independent of protein kinase R like Endoplasmic Reticulum Kinase and elevates levels of eIF2alpha phosphorylation in virus infected cells. AB - Infections by dengue virus (DENV) are increasing worldwide, with an urgent need for effective anti-DENV agents. We recently identified N-(4-hydroxyphenyl) retinamide (4-HPR), an anti-DENV agent effective against all 4 serotypes of DENV in cell culture, and in a lethal mouse model for DENV infection (Fraser et al., 2014b). Although identified as an inhibitor of DENV non-structural protein 5 (NS5) recognition by host nuclear import proteins, the precise impact and mode of action of 4-HPR in effecting DENV clearance remains to be defined. Significantly, concurrent with decreased viral RNA and infectious DENV in 4-HPR-treated cells, we previously observed specific up-regulation of transcripts representing the Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) arm of the unfolded protein response (UPR) pathway upon 4-HPR addition. Here we pursue these findings in detail, examining the role of specific PERK pathway components in DENV clearance. We demonstrate that 4-HPR-induced nuclear localization of Activating Transcription Factor 4 (ATF4), a pathway component downstream from PERK, occurs in a PERK-independent manner, implying activation instead occurs through Integrated Stress Response (ISR) kinases. Significantly, ATF4 does not appear to be required for the antiviral activity of 4-HPR, suggesting transcriptional events induced by ATF4 do not drive the 4-HPR-induced antiviral state. Instead, we demonstrate that 4-HPR induces phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha), a target of ISR kinases which controls translation attenuation, and confirm the importance of phosphorylated-eIF2alpha in DENV infection using guanabenz, a specific inhibitor of eIF2alpha dephosphorylation. This study provides the first detailed insight into the cellular effects modulated by 4-HPR in DENV-infected cells, critical to progressing 4-HPR towards the clinic. PMID- 26965421 TI - Management of deep vein thrombosis and pulmonary embolism (venous thromboembolism) during pregnancy. AB - PURPOSE: The risk of venous thromboembolism (VTE) is high during pregnancy. Although most patients with VTE are safely treated via medications, the optimal treatment for massive pulmonary embolism remains controversial. To evaluate the safety and efficacy of VTE management during pregnancy, we report our single center experience of treating VTE in pregnant women. METHODS: Case records were retrospectively reviewed from seven patients who underwent treatment for venous thromboembolism between 2002 and 2014. RESULTS: Mean gestational time was 28 +/- 6.2 weeks. Four patients with deep vein thrombosis were treated medically, and they all had vaginal delivery at full term without hemorrhagic complication. Three patients with massive pulmonary embolism underwent surgical embolectomy. Two of these three patients underwent cesarean delivery at 28 and 29 weeks respectively. There was no maternal death, but one fetal death occurred during surgical embolectomy. CONCLUSION: VTE during pregnant women is safely managed by anticoagulant therapy. Massive pulmonary embolism during pregnancy can be managed safely by surgical embolectomy using cardiopulmonary bypass, but the rate of fetal loss remains high. PMID- 26965422 TI - English Language Abilities and Unmet Needs in Community Mental Health Services: a Cross-Sectional Study. PMID- 26965424 TI - Three-dimensional Micro-culture System for Tooth Tissue Engineering. AB - The arrangement of cells within a tissue plays an essential role in organogenesis, including tooth development. Progress is being made to regenerate teeth by reassociating dissociated embryonic dental cells and implanting them in vivo. In the present study, we tested the hanging drop method to study mixed epithelial-mesenchymal cell reorganization in a liquid instead of semisolid medium to see whether it could lead to tooth histogenesis and organogenesis. This method allowed the control of the proportion and number of cells to be used, and the forming microtissues showed homogeneous size. The liquid environment favored cell migrations as compared with collagen gels. Three protocols were compared. The one that sequentially combined the hanging drop and semisolid medium cultures prior to in vivo implantation gave the best results. Indeed, after implantation, teeth developed, showing a well-formed crown, mineralization of dentin and enamel, and the initiation of root formation. Vascularization and the cellular heterogeneity in the mesenchyme were similar to what was observed in developing molars. Finally, after coimplantation with a trigeminal ganglion, the dental mesenchyme, including the odontoblast layer, became innervated. The real advantage of this technique is the small number of cells required to make a tooth. This experimental model can be employed to study the development, physiology, metabolism, or toxicology in forming teeth and test other cell sources. PMID- 26965423 TI - The Emotional Brain as a Predictor and Amplifier of Chronic Pain. AB - Human neuroimaging studies and complementary animal experiments now identify the gross elements of the brain involved in the chronification of pain. We briefly review these advances in relation to somatic and orofacial persistent pain conditions. First, we emphasize the importance of reverse translational research for understanding chronic pain-that is, the power of deriving hypotheses directly from human brain imaging of clinical conditions that can be invasively and mechanistically studied in animal models. We then review recent findings demonstrating the importance of the emotional brain (i.e., the corticolimbic system) in the modulation of acute pain and in the prediction and amplification of chronic pain, contrasting this evidence with recent findings regarding the role of central sensitization in pain chronification, especially for orofacial pain. We next elaborate on the corticolimbic circuitry and underlying mechanisms that determine the transition to chronic pain. Given this knowledge, we advance a new mechanistic definition of chronic pain and discuss the clinical implications of this new definition as well as novel therapeutic potentials suggested by these advances. PMID- 26965425 TI - New host records of Haemaphysalis leporispalustris (Acari: Ixodidae) on birds in Brazil. AB - Birds are an important component of the life histories and bioecology of a number of tick species and of some tick associated pathogens. An examination of the data concerning bird/tick associations in the Neotropics, showed that the tick Haemaphysalis leporispalustrisis (Packard, 1869) was rarely recorded infesting birds. The current study reports parasitism by H. leporispalustris in wild birds collected from Atlantic rain forest environments in the states of Rio de Janeiro (4LL) and Minas Gerais (17LL, 1NN), Brazil. All ticks were identified morphologically to the genus level; total DNA was extracted from each Haemaphysalis tick and examined by PCR and nucleotide sequencing of fragments of the eukaryotic genes encoding 16S rRNA and 12S rRNA. The bird species Arremon semitorquatus, Corythopis delalandi, Fluvicola nengeta, Troglodytes musculus, and Volatinia jacarina were recorded as hosts for H. leporispalustris for the first time in South America, and Turdus rufiventris represented a new record for Brazil. PMID- 26965426 TI - Detection of Balamuthia mandrillaris DNA in the storage case of contact lenses in Germany. AB - Acanthamoeba spp. are frequently the etiological agents of a severe form of sight threatening keratitis, called Acanthamoeba keratitis. The contact lens storage solution of a patient with keratitis of unknown genesis was screened using our diagnostic tools to detect potentially pathogenic free-living amoebae (FLA). Culture methods and a triplex quantitative real-time polymerase chain reaction (qPCR) targeting Acanthamoeba spp., Naegleria fowleri, and Balamuthia mandrillaris were used in context of this routine screening. While no amoebae were detected by culture, qPCR specifically detected DNA of B. mandrillaris. This FLA is known as the etiological agent of a fatal form of encephalitis in humans and other mammals, Balamuthia amoebic encephalitis (BAE). A fragment of the 18S rDNA gene was amplified from the sample and showed 99 % sequence identity to B. mandrillaris sequences from GenBank. To the best of our knowledge, this is the first report of B. mandrillaris found in association with contact lenses. Although no viable amoeba was obtained by culturing efforts, the verification of B. mandrillaris DNA in the contact lens storage solution demonstrates how easily this pathogen might come into close contact with humans. PMID- 26965427 TI - Application of DNA barcoding for identifying forensically relevant Diptera from northern Thailand. AB - In recent decades, forensic entomology has become a useful tool in criminal investigations all over the world. Species-specific identification of flies plays an important role in this field and is obligatory for accurate calculation of the post-mortem interval. However, not all important colonizers of a corpse can be identified by common morphological keys. Due to similar morphology and the lack of keys for some taxa, especially for immature stages, DNA barcoding has become more popular during the last recent years. This development is particularly important for countries like Thailand, in which forensic entomology is a newly developing research area and which faces several challenges such as a high biodiversity of fly species. The most commonly used barcoding region in forensic entomology, the mitochondrial cytochrome oxidase subunit 1 (coI) gene, as well as a 1000-bp-long region of the 28S nuclear rRNA gene, was used to analyze and establish the molecular barcodes of 13 different species of flies of forensic relevance in northern Thailand. PMID- 26965428 TI - Improving freeze-tolerance of baker's yeast through seamless gene deletion of NTH1 and PUT1. AB - Baker's yeast strains with freeze-tolerance are highly desirable to maintain high leavening ability after freezing. Enhanced intracellular concentration of trehalose and proline in yeast is linked with freeze-tolerance. In this study, we constructed baker's yeast with enhanced freeze-tolerance by simultaneous deletion of the neutral trehalase-encoded gene NTH1 and the proline oxidase-encoded gene PUT1. We first used the two-step integration-based seamless gene deletion method to separately delete NTH1 and PUT1 in haploid yeast. Subsequently, through two rounds of hybridization and sporulation-based allelic exchange and colony PCR mediated tetrad analysis, we obtained strains with restored URA3 and deletion of NTH1 and/or PUT1. The resulting strain showed higher cell survival and dough leavening ability after freezing compared to the wild-type strain due to enhanced accumulation of trehalose and/or proline. Moreover, mutant with simultaneous deletion of NTH1 and PUT1 exhibits the highest relative dough-leavening ability after freezing compared to mutants with single-gene deletion perhaps due to elevated levels of both trehalose and proline. These results verified that it is applicable to construct frozen dough baker's yeast using the method proposed in this paper. PMID- 26965429 TI - e-Therapy to reduce emotional distress in women undergoing assisted reproductive technology (ART): a feasibility randomized controlled trial. AB - STUDY QUESTION: Is it feasible to evaluate a personalized e-therapy program (Internet based) for women during fertility treatment aimed to reduce the chance of having clinically relevant symptoms of anxiety and/or depression after unsuccessful assisted reproductive technology (ART) treatment within a randomized controlled trial (RCT)? STUDY ANSWER: The evaluation of a personalized e-therapy program is feasible, reflected by good acceptability and integration within current guidelines, but adjustments to the e-therapy program and study design of the RCT have to be made to enhance demand, practicality and efficacy. WHAT IS KNOWN ALREADY: Internet-based interventions are promising in reducing psychological distress, especially when treatment is personalized to specific risk profiles of patients. However in fertility care, the beneficial effects of personalized e-therapy on psychological distress and its implementation in daily clinical care still have to be evaluated. STUDY DESIGN, SIZE, DURATION: To evaluate the feasibility of a personalized e-therapy program, we conducted a two arm, parallel group, single-blind feasibility randomized controlled trial with a 1:1 allocation. Feasibility was assessed in terms of demand, acceptability, practicality, implementation, integration and limited efficacy. Women were included between 1 February 2011 and 1 June 2013. Women in the control group received care as usual, whereas women in the intervention group received in addition to their usual care access to a personalized e-therapy program. Women were monitored until 3 months after the start of their first ART cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: In a university hospital in the Netherlands women who were screened as at risk for emotional adjustment problems and intended to start their first ART cycle were invited, and of them 120 were randomized. Of these women, 48% in the intervention group were compliant to the intervention. Outcome measures associated with the feasibility to analyse this e therapy program within an RCT were assessed. MAIN RESULTS AND THE ROLE OF CHANCE: It is feasible to evaluate a personalized e-therapy program within an RCT. The acceptability was good, as was the integration within current clinical guidelines and care. However, the demand reflected by a participation rate of 44% was low, since most women declined participation because they felt no need for support at that moment. The practicality of the intervention was moderate illustrated by a relatively high dropout rate (30%) due to practical concerns. The intervention was effective, shown by a reduction in the percentage women having clinically relevant symptoms of anxiety and/or depression in the compliant intervention group compared with the control group 3 months after the first ART cycle; risk difference of 24% (95% CI: 2-46%; ITALIC! P = 0.03). LIMITATIONS, REASONS FOR CAUTION: The large non-participation rate (56%) needs further evaluation. This also could have influenced results on limited efficacy. Barriers for participation could be assessed more in-depth. Moreover, ~30% dropped out. This percentage is comparable with other e-health studies. Finally, this is a single centre study. Generalizability could be enlarged by a multi-centre approach. WIDER IMPLICATIONS OF THE FINDINGS: In clinical fertility care, personalizing an e-therapy program to the patients' risk profile is promising and feasible. However, in future studies, we recommend modification of the study protocol by for example offering the intervention to the preferred moment in the treatment process. Moreover, adjustment of the study protocol tailored to the found barriers and facilitators is needed. When performing a multi-centre consecutive RCT to assess the effectiveness of personalized e-therapy in fertility care, the findings of this study, for example concerning the preferred timing or reasons for non-participation, could be helpful. STUDY FUNDING/COMPETING INTERESTS: NutsOhra (Study Number 0702-94) funded this study with an unrestricted grant. There were no competing interests. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT 01283607. TRIAL REGISTRATION DATE: 21 January 2011. DATE OF FIRST PATIENT'S ENROLMENT: February, 2011. PMID- 26965430 TI - Overexpression of chloride channel-3 is associated with the increased migration and invasion ability of ectopic endometrial cells from patients with endometriosis. AB - STUDY QUESTION: Is chloride channel-3 (ClC-3) involved in regulating the biological behavior of endometrial stromal cells (ESCs)? SUMMARY ANSWER: ClC-3 promotes endometriotic cell migration and invasion. WHAT IS KNOWN ALREADY: ClC-3 plays a significant role in the migration and invasion of various kinds of cells. STUDY DESIGN, SIZE, DURATION: An ITALIC! in vitro investigation of the effect of ClC-3 on the migration and invasion of ectopic ESCs from patients with endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: The ectopic and eutopic endometrial samples from 43 female patients with endometriosis and the endometrial samples from 39 non-endometriotic female patients were collected. Primary cells from these samples were isolated and cultured. Real-time RT-PCR, immunohistochemistry and western blot were used to detect the expression of ClC-3 and matrix metalloproteinase 9 (MMP-9). Small interfering RNA (siRNA) technology was employed to knock down ClC-3 expression. The migration and invasion ability of ESCs was measured by the transwell assay with uncoated or Matrigel-coated membranes. MAIN RESULTS AND THE ROLE OF CHANCE: The expression of ClC-3 mRNA and proteins was significantly up-regulated in the ectopic tissues from endometriotic patients, while that in the eutopic endometrial tissues of the same patients did not significantly differ from that in non-endometriotic patients. The migration and invasion ability and MMP-9 expression was increased in the ESCs from ectopic endometrial tissues. The knockdown of ClC-3 expression by ClC-3 siRNA inhibited ESC migration and invasion and attenuated the expression of MMP-9. ClC-3 expression level was well-correlated to the clinical characteristics and symptoms of endometriosis patients, including infertility, dysmenorrhea, chronic pelvic pain, dyspareunia and diameter of endometriosis lesion. LIMITATIONS, REASONS FOR CAUTION: Further studies are needed to examine the regulatory mechanism of estrogen on ClC-3 expression of ESCs. WIDER IMPLICATIONS OF THE FINDINGS: ClC-3 is involved in the migration and invasion processes of ESCs and can regulate MMP 9 expression. Up-regulation of ClC-3 expression may contribute to endometriosis development by regulating MMP-9 expression. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the National Natural Science Foundation of China (81173064, 81272223, 81273539), the Ministry of Education of China (20124401110009), the Natural Science Foundation of Guangdong Province (S2011010001589) and the Science and Technology Programs of Guangdong (2013B051000059), Guangzhou (2013J500015) and Dongguan (2011108102006). The authors have no conflict of interest. PMID- 26965431 TI - Infertile women below the age of 40 have similar anti-Mullerian hormone levels and antral follicle count compared with women of the same age with no history of infertility. AB - STUDY QUESTION: Do infertile patients below the age of 40 years have a lower ovarian reserve, estimated by anti-Mullerian hormone (AMH) and total antral follicle count (AFC), than women of the same age with no history of infertility? SUMMARY ANSWER: Serum AMH and AFC were not lower in infertile patients aged 20-39 years compared with a control group of the same age with no history of infertility. WHAT IS KNOWN ALREADY?: The management of patients with a low ovarian reserve and a poor response to controlled ovarian stimulation (COS) remains a challenge in assisted reproductive technologies (ART). Both AMH levels and AFC reflect the ovarian reserve and are valuable predictors of the ovarian response to exogenous gonadotrophins. However, there is a large inter-individual variation in the age-related depletion of the ovarian reserve and a broad variability in the levels of AMH and AFC compatible with conception. Women with an early depletion of the ovarian reserve may experience infertility as a consequence of postponement of childbearing. Thus, low ovarian reserve is considered to be overrepresented among infertile patients. STUDY DESIGN, SIZE, DURATION: A prospective cohort study including 382 women with a male partner referred to fertility treatment at Rigshospitalet, Copenhagen, Denmark during 2011-2013 compared with a control group of 350 non-users of hormonal contraception with no history of infertility recruited during 2008-2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Included patients and controls were aged 20-39 years. Women with polycystic ovary syndrome were excluded. On Cycle Days 2-5, AFC and ovarian volume were measured by transvaginal sonography, and serum levels of AMH, FSH and LH were assessed. MAIN RESULTS AND THE ROLE OF CHANCE: Infertile patients had similar AMH levels (11%, 95% confidence interval (CI): -1;24%) and AFC (1%, 95% CI: -7;8%) compared with controls with no history of infertility in an age-adjusted linear regression analysis. The prevalence of very low AMH levels (<5 pmol/l) was similar in the two cohorts (age-adjusted odds ratio: 0.9, 95% CI: 0.5;1.7). The findings persisted after adjustment for smoking status, body mass index, gestational age at birth, previous conception and chronic disease in addition to age. LIMITATIONS, REASON FOR CAUTION: The comparison of ovarian reserve parameters in women recruited at different time intervals could be a reason for caution. However, all women were examined at the same centre using the same sonographic algorithm and AMH immunoassay. WIDER IMPLICATIONS OF THE FINDINGS: This study indicates that the frequent observation of patients with a poor response to COS in ART may not be due to an overrepresentation of women with an early depletion of the ovarian reserve but rather a result of the expected age-related decline in fertility. STUDY FUNDING/COMPETING INTERESTS: The study received funding from MSD and the Interregional European Union (EU) projects 'ReproSund' and 'ReproHigh'. The authors have no conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 26965433 TI - Shared risk aversion in spontaneous and induced abortion. AB - STUDY QUESTION: Does the incidence of spontaneous abortion correlate positively over conception cohorts with the incidence of non-clinically indicated induced abortion as predicted by shared risk aversion? SUMMARY ANSWER: We find that the number of spontaneous and non-clinically indicated induced abortions correlates in conception cohorts, suggesting that risk aversion affects both the conscious and non-conscious mechanisms that control parturition. WHAT IS KNOWN ALREADY: Much literature speculates that natural selection conserved risk aversion because the trait enhanced Darwinian fitness. Risk aversion, moreover, supposedly influences all decisions including those that individuals can and cannot report making. We argue that these circumstances, if real, would manifest in conscious and non-conscious decisions to invest in prospective offspring, and therefore affect incidence of induced and spontaneous abortion over time. STUDY DESIGN, SIZE, DURATION: Using data from Denmark, we test the hypothesis that monthly conception cohorts yielding unexpectedly many non-clinically indicated induced abortions also yield unexpectedly many spontaneous abortions. The 180 month test period (January 1995 through December 2009), yielded 1 351 800 gestations including 156 780 spontaneous as well as 233 280 induced abortions 9100 of which were clinically indicated. PARTICIPANTS/MATERIALS, SETTING, METHODS: We use Box Jenkins transfer functions to adjust the incidence of spontaneous and non clinically indicated induced abortions for autocorrelation (including seasonality), cohort size, and fetal as well as gestational anomalies over the 180-month test period. We use cross-correlation to test our hypothesized association. MAIN RESULTS AND THE ROLE OF CHANCE: We find a positive association between spontaneous and non-clinically indicated induced abortions. This suggests, consistent with our theory, that mothers of conception cohorts that yielded more spontaneous abortions than expected opted more frequently than expected for non-clinically indicated induced abortion. LIMITATIONS, REASONS FOR CAUTION: Limitations of our work include that even the world's best registration system will not capture all spontaneous abortions and that results may not generalize beyond Denmark. WIDER IMPLICATIONS OF THE FINDINGS: Our findings imply that abortion, intentional or 'spontaneous,' follows from a woman's estimate, made consciously or otherwise, of the costs and benefits of extending gestation given characteristics of the prospective offspring, likely environmental circumstances at birth, and maternal resources. STUDY FUNDING/COMPETING INTERESTS: The Robert Wood Johnson Health and Society Scholars Program funded the research described in this manuscript. None of the authors has any conflict of interest to declare. PMID- 26965432 TI - Transplantation of adipose-derived stem cells combined with collagen scaffolds restores ovarian function in a rat model of premature ovarian insufficiency. AB - STUDY QUESTION: Does the transplantation of adipose-derived stem cells (ADSCs) on soluble collagen scaffolds (collagen/ADSCs) have better therapeutic effect than transplantation of ADSCs alone, to treat premature ovarian insufficiency (POI) in a rat model induced by Tripterygium Glycosides (TG)? SUMMARY ANSWER: The transplantation of collagen/ADSCs increased the short-term retention of ADSCs in ovaries and contributed to long-term restoration of ovarian function, as well as the fertility of rats with TG-induced ovarian damage. WHAT IS KNOWN ALREADY: About 50% of young women in China, who have been treated with TG, have subsequently developed ovarian insufficiency. Rats exhibit similar symptoms to these patients when given an equivalent dose of TG. Transplantation of ADSCs improves ovarian function impaired by chemotherapy in rodent models. STUDY DESIGN, SIZE, DURATION: After the administration of TG, 54 POI model rats were randomly assigned to 4 groups: phosphate buffered saline (PBS) ( ITALIC! n = 14), collagen ( ITALIC! n = 11), ADSCs ( ITALIC! n = 16) and collagen/ADSCs ( ITALIC! n = 13). Seventeen normal rats were assigned as control group. The retention of ADSCs in ovaries was confirmed immediately or at 3, 7, 14 and 28 days after transplantation ( ITALIC! n = 9). Four weeks after transplantation, ovarian function was evaluated from estrous cycle, estradiol level, the follicle number, granulosa cell proliferation and a fertility test. PARTICIPANTS/MATERIALS, SETTING, METHODS: To establish the POI model, rats were administered 60 mg TG/kg/day intragastrically for 50 days. The estrous cycles were assessed by vaginal smear. The concentration of plasma estradiol in diestrus stage was measured using a radioimmunoassay kit. Disordered estrous cycles and low serum estradiol levels indicated the successful establishment of the POI model. Four types of suspensions (PBS, collagen, ADSCs and collagen/ADSCs) were transplanted directly into the core of the ovaries. The short-term retention of ADSCs in ovaries was evaluated by small-animal positron emission tomography images immediately after transplantation of (18)F-Fluorodeoxyglucose ((18)F-FDG) labeled ADSCs. The long-term retention of ADSCs in ovaries was observed by immunohistochemistry after transplantation of green fluorescent protein (GFP) labeled ADSCs. Serial sections of ovaries were prepared for histological analysis, follicle counting, and immunohistochemistry for Ki67 and Cleaved Caspase-3. For the assessment of fertility, rats were mated with proven fertile male rats for 10 days. MAIN RESULTS AND THE ROLE OF CHANCE: The (18)F-FDG signal decreased more slowly in ovaries injected with collagen/ADSCs than in ovaries with injected with ADSCs alone. Significantly more GFP-positive cells were observed in ovaries injected with collagen/GFP-ADSCs than in ovaries injected with GFP-ADSCs alone up to 14 days after the injection. However, in both groups very few GFP-positive cells were present at 4 weeks after transplantation. The collagen/ADSCs and ADSCs groups both showed better estrous cycle recovery than the PBS and collagen groups. The estradiol (E2) level in the collagen/ADSCs group was significantly increased compared with that of the PBS group ( ITALIC! P < 0.05). The number of antral follicles in the collagen/ADSCs group and the ADSCs group significantly increased compared with the PBS group ( ITALIC! P < 0.05). The granulosa cell proliferation in the collagen/ADSCs group was better than in the PBS group ( ITALIC! P < 0.01). The mating rates of the collagen/ADSCs group (88.9%) and the ADSCs group (90.9%) were higher than that of PBS group (60%, ITALIC! P < 0.05). The pregnancy rates of the collagen/ADSCs group (77.8%) and the ADSCs group (72.7%) were higher than the PBS group (50%, ITALIC! P < 0.05). LIMITATIONS, REASONS FOR CAUTION: We chose ADSCs for their accessibility, convenience and safety. We did not use other cells or materials for POI treatments to show that the collagen/ADSCs are the most promising materials. WIDER IMPLICATIONS OF THE FINDINGS: Soluble collagen scaffolds may be useful in stem cells transplantation therapy for POI. STUDY FUNDING/COMPETING INTERESTS: This work is supported by grants from the 'Strategic Priority Research Program' of the Chinese Academy of Sciences (XDA01030000); Maternal-Fetal Medicine from Jiangsu Province Health Department of China (XK2011027); Clinical Center of Obstetric, Gynecologic and Genetic Diseases, Nanjing Health Department of Jiangsu Province, China; Fundamental Research Funds for the Central Universities (20620140652). The authors declare no competing financial interests. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 26965434 TI - Increased rate of spontaneous miscarriages in endometriosis-affected women. AB - STUDY QUESTION: Were spontaneous miscarriages more frequent in women with histologically proven endometriosis when compared with endometriosis-free controls? SUMMARY ANSWER: Endometriosis-affected women display a significantly higher rate of previous spontaneous miscarriages than endometriosis-free controls. WHAT IS KNOWN ALREADY: The association between endometriosis and miscarriages has long been debated without reaching a consensus. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective cohort study comparing exposed women (endometriosis) and control (without endometriosis) regarding the incidence of miscarriages. All study participants underwent surgery for benign gynaecological conditions in a tertiary-care university hospital between January 2004 and March 2013. After thorough surgical examination of the abdominopelvic cavity, 870 women with histologically proven endometriosis were allocated to the endometriosis group and 981 unaffected women to the control group. Only previously pregnant women were finally included for the study analysis: 284 women in the endometriosis group and 466 in the control group. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were collected preoperatively using a structured questionnaire. Among women with at least one pregnancy before the surgery, the type and number of the different previous first trimester pregnancies outcomes were studied. Previous history of miscarriage was studied according to the existence of previous infertility history and the disease severity (revised American Fertility Society and surgical classification). MAIN RESULTS AND THE ROLE OF CHANCE: Four hundred and seventy-eight pregnancies in endometriosis affected women and 964 pregnancies in controls were analysed. The previous miscarriage rate was significantly higher in women with endometriosis compared with the controls (139/478 [29] versus 187/964 [19%], respectively; ITALIC! P < 0.001). After a subgroup analysis, the miscarriage rates of women with endometriosis and the controls were, respectively: 20 versus 12% ( ITALIC! P = 0.003) among women without a previous history of infertility and 53 versus 30% ( ITALIC! P < 0.001) for women with a previous history of infertility. After using a random-effects Poisson regression and adjusting for confounding factors, we found a significantly increased incidence rate ratio (IRR) for miscarriages in women with endometriosis (adjusted IRR: 1.70, 95% confidence interval: 1.34 2.16). LIMITATIONS, REASONS FOR CAUTION: There is a possible selection bias due to the specificity of the study design which included only surgical patients. In the control group, certain of the surgical gynaecological conditions, such as fibroids, ovarian cysts or tubal pathologies, might be associated with higher spontaneous miscarriage rates. In the endometriosis group, asymptomatic women were less likely to be referred for surgery and might therefore be underrepresented. WIDER IMPLICATIONS OF THE FINDINGS: This study opens the doors to future, more mechanistic studies to establish the exact link between endometriosis and spontaneous miscarriage rates. STUDY FUNDING/COMPETING INTERESTS: No external funding was used for this study. The authors have no conflicts of interest to declare. PMID- 26965435 TI - Growth trajectories of the human embryonic head and periconceptional maternal conditions. AB - STUDY QUESTION: Can growth trajectories of the human embryonic head be created using 3D ultrasound (3D-US) and virtual reality (VR) technology, and be associated with second trimester fetal head size and periconceptional maternal conditions? SUMMARY ANSWER: Serial first trimester head circumference (HC) and head volume (HV) measurements were used to create reliable growth trajectories of the embryonic head, which were significantly associated with fetal head size and periconceptional maternal smoking, age and ITALIC! in vitro fertilization (IVF)/intra-cytoplasmic sperm injection (ICSI) treatment. WHAT IS KNOWN ALREADY: Fetal growth is influenced by periconceptional maternal conditions. STUDY DESIGN, SIZE, DURATION: We selected 149 singleton pregnancies with a live born non malformed fetus from the Rotterdam periconception cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Bi-parietal diameter and occipital frontal diameter to calculate HC, HV and crown-rump length (CRL) were measured weekly between 9 + 0 and 12 + 6 weeks gestational age (GA) using 3D-US and VR. Fetal HC was obtained from second trimester structural anomaly scans. Growth trajectories of the embryonic head were created with general additive models and linear mixed models were used to estimate associations with maternal periconceptional conditions as a function of GA and CRL, respectively. MAIN RESULTS: A total of 303 3D-US images of 149 pregnancies were eligible for embryonic head measurements (intra-class correlation coefficients >0.99). Associations were found between embryonic HC and fetal HC ( ITALIC! rho = 0.617, ITALIC! P < 0.001) and between embryonic HV and fetal HC ( ITALIC! rho = 0.660, ITALIC! P < 0.001) in ITALIC! Z-scores. Maternal periconceptional smoking was associated with decreased, and maternal age and IVF/ICSI treatment with increased growth trajectories of the embryonic head measured by HC and HV (All ITALIC! P < 0.05). LIMITATIONS, REASONS FOR CAUTION: The consequences of the small effect sizes for neurodevelopmental outcome need further investigation. As the study population consists largely of tertiary hospital patients, external validity should be studied in the general population. WIDER IMPLICATIONS OF THE FINDINGS: Assessment of growth trajectories of the embryonic head may be of benefit in future early antenatal care. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Department of Obstetrics and Gynaecology, Erasmus MC University Medical Centre and Sophia Foundation for Medical Research, Rotterdam, The Netherlands (SSWO grant number 644). No competing interests are declared. PMID- 26965436 TI - Metagenomic analysis demonstrates the diversity of the fecal virome in asymptomatic pigs in East Africa. AB - Pigs harbor a variety of viruses that are closely related to human viruses and are suspected to have zoonotic potential. Little is known about the presence of viruses in smallholder farms where pigs are in close contact with humans and wildlife. This study provides insight into viral communities and the prevalence and characteristics of enteric viral co-infections in smallholder pigs in East Africa. Sequence-independent amplification and high-throughput sequencing were applied to the metagenomics analysis of viruses in feces collected from asymptomatic pigs. A total of 47,213 de novo-assembled contigs were constructed and compared with sequences from the GenBank database. Blastx search results revealed that 1039 contigs (>200 nt) were related to viral sequences in the GenBank database. Of the 1039 contigs, 612 were not assigned to any viral taxa because they had little similarity to known viral genomic or protein sequences, while 427 contigs had a high level of sequence similarity to known viruses and were assigned to viral taxa. The most frequent contigs related to mammalian viruses resembling members of the viral genera Astrovirus, Rotavirus, Bocavirus, Circovirus, and Kobuvirus. Other less abundant contigs were related to members of the genera Sapelovirus, Pasivirus, Posavirus, Teschovirus and Picobirnavirus. This is the first report on the diversity of the fecal virome of pig populations in East Africa. The findings of the present study help to elucidate the etiology of diarrheal diseases in pigs and identify potential zoonotic and emerging viruses in the region. Further investigations are required to compare the incidence of these viruses in healthy and diseased pigs in order to better elucidate their pathogenic role. PMID- 26965437 TI - Cognitive costs of motor planning do not differ between pointing and grasping in a sequential task. AB - Neurophysiologic studies have shown differences in brain activation between pointing and grasping movements. We asked whether these two movement types would differ in their cognitive costs of motor planning. To this end, we designed a sequential, continuous posture selection task, suitable to investigate pointing and grasping movements to identical target locations. Participants had to open a column of drawers or point to a column of targets in ascending and descending progression. The global hand pro/supination at the moment of drawer/target contact was measured. The size of the motor hysteresis effect, i.e., the persistence to a former posture, was used as a proxy for the cognitive cost of motor planning. A larger hysteresis effect equals higher cognitive cost. Both motor tasks had similar costs of motor planning, but a larger range of motion was found for the grasping movements. PMID- 26965438 TI - Podokinetic circular vection: characteristics and interaction with optokinetic circular vection. AB - Stabilising horizontal body orientation in space without sight on a rotating platform by holding to a stationary structure and circular 'treadmill' stepping in the opposite direction can elicit an illusion of self-turning in space (Bles and Kapteyn in Agressologie 18:325-328, 1977). Because this illusion is analogous to the well-known illusion of optokinetic circular vection (oCV), we call it 'podokinetic circular vection' (pCV) here. Previous studies using eccentric stepping on a path tangential to the rotation found that pCV was always contraversive relative to platform rotation. In contrast, when our subjects stepped at the centre of rotation about their vertical axis, we observed an inverted, ipsiversive pCV as a reproducible trait in many of our subjects. This ipCV occurred at the same latency as the pCV of subjects reporting the actually expected contraversive direction, but had lower gain. In contrast to pCV, the nystagmus accompanying circular treadmill stepping had the same direction in all individuals (slow phase in the direction of platform motion). The direction of an individual's pCV predicted the characteristics of the CV resulting from combined opto- and podokinetic stimulation (circular treadmill stepping while viewing a pattern rotating together with the platform): in individuals with contraversive pCV, latency shortened and both gain and felt naturalness increased in comparison with pure oCV, whereas the opposite (longer latency, reduced gain and naturalness) occurred in individuals with ipCV. Taken together, the reproducibility of ipCV, the constant direction of nystagmus and the fact that pCV direction predicts the outcome of combined stimulation suggest that ipCV is an individual trait of many subjects during compensatory stepping at the centre of rotation. A hypothetical model is presented of how ipCV possibly could arise. PMID- 26965439 TI - Clinical predictors of cardiac magnetic resonance late gadolinium enhancement in patients with atrial fibrillation. AB - Aims: This study aims to examine the association of clinical co-morbidities with the presence of left atrial (LA) late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR). Previous studies have established the severity of LA LGE to be associated with atrial fibrillation (AF) recurrence following AF ablation. We sought to determine whether baseline clinical characteristics were associated with LGE extent among patients presenting for an initial AF ablation. Methods and results: The cohort consisted of 179 consecutive patients with no prior cardiac ablation procedures who underwent pre-procedure LGE-CMR. The extent of LA LGE for each patient was calculated using the image intensity ratio, normalized to the mean blood pool intensity, corresponding to a bipolar voltage <=0.3 mV. The association of LGE extent with baseline clinical characteristics was examined using non-parametric and multivariable models. The mean age of the cohort was 60.9 +/- 9.6 years and 128 (72%) were male. In total, 56 (31%) patients had persistent AF. The mean LA volume was 118.4 +/- 41.6 mL, and the mean LA LGE extent was 14.1 +/- 10.4%. There was no association with any clinical variables with LGE extent by quartiles in the multivariable model. Extent of LGE as a continuous variable was positively, but weakly associated with LA volume in a multivariable model adjusting for age, body mass index, AF persistence, and left ventricular ejection fraction (1.5% scar/mL, P = 0.038). Conclusion: In a cohort of patients presenting for initial AF ablation, the presence of pre ablation LA LGE extent was weakly, but positively associated with increasing LA volume. PMID- 26965440 TI - Age, not therapy intensity, determines outcomes of adults with acute myeloid leukemia. PMID- 26965441 TI - The impact of a concurrent motor task on auditory and visual temporal discrimination tasks. AB - Previous studies have shown the presence of an interference effect on temporal perception when participants are required to simultaneously execute a nontemporal task. Such interference likely has an attentional source. In the present work, a temporal discrimination task was performed alone or together with a self-paced finger-tapping task used as concurrent, nontemporal task. Temporal durations were presented in either the visual or the auditory modality, and two standard durations (500 and 1,500 ms) were used. For each experimental condition, the participant's threshold was estimated and analyzed. The mean Weber fraction was higher in the visual than in the auditory modality, but only for the subsecond duration, and it was higher with the 500-ms than with the 1,500-ms standard duration. Interestingly, the Weber fraction was significantly higher in the dual task condition, but only in the visual modality. The results suggest that the processing of time in the auditory modality is likely automatic, but not in the visual modality. PMID- 26965442 TI - Molecular characterization of human Cryptosporidium spp. isolates after an unusual increase in late summer 2012. AB - BACKGROUND: During the late summer 2012, a number of medical microbiological laboratories (MMLs) reported an unusual increase in cases of cryptosporidiosis, a gastrointestinal infection caused by the protozoan parasites Cryptosporidium spp. Prompted by this signal, the National Institute of Public Health and the Environment (RIVM) started an epidemiological investigation into possible causes. Simultaneously, samples diagnosed at MMLs were sent to RIVM for genotyping, aiming to further identify the possible source of the increase. METHODS: Genotyping was performed by sequencing a fragment of the GP60 gene. Additional genotyping was performed on a subset of samples using six microsatellite markers. Population genetic analysis was performed using BEAST. RESULTS: The majority of the samples were typed as C. hominis, and a single GP60 genotype (IbA10G2) largely predominated. Genotyping microsatellite markers further supported the circulation of a single genetic type. Population genetic analysis with genotypes found in previous years is inconsistent with a decrease in effective population size. CONCLUSIONS: The conclusion of this finding is that the rise reflects more an overall increase and not a common source outbreak. PMID- 26965443 TI - Symptoms as the main problem: a cross- sectional study of patient experience in primary care. AB - BACKGROUND: Symptoms are common in primary care. Besides providing thorough assessment of possible severe disease, the general practitioner (GP) must ensure good health care to all patients, irrespective of diagnoses. We aimed to explore patient satisfaction with the provided care and how well expectations in patients were met when no diagnosis was made during the consultation. METHOD: Cross sectional study based on a questionnaire survey conducted in 2008-2009 among 377 GPs and their patients in the Central Denmark Region. A total of 2286 patients completed a questionnaire after the consultation (response rate: 54 %). The questionnaire included four satisfaction items from the EUROPEP instrument and a question about unmet expectations. For each patient, the GP answered a one-page registration form including information about the main problem in the consultation, chronic disorders and assessment of prognosis. Statistical analyses were adjusted for patient characteristics and GP clustering. RESULTS: A higher proportion of patients reported illness worry (20 vs. 17 %, p-value: 0.005), unmet expectations (17 vs. 13 %, p-value: 0.019) and dissatisfaction with their GP after the consultation when no diagnosis was made. Dissatisfaction was primarily related to the medical examination (adjusted OR 1.30; 95 % CI: 1.06 1.60) and GP explanations (adjusted OR 1.40; 95 % CI: 1.14-1.71). Exploratory analyses revealed an association between dissatisfaction with examination and the GP assessment that symptoms were unrelated to biomedical disease. This association was found both in patients with 'symptoms only' and patients given a specific diagnosis. CONCLUSION: GPs are challenged by patients presenting symptoms that do not fit the patterns of biomedical diagnoses. The current study demonstrates more illness worry, unmet expectations and dissatisfaction with the consultation in these patients compared to patients receiving a diagnosis. This trend is true for all patients assessed as having 'symptoms only' at the end of a consultation and not only for the minority group with 'medically unexplained symptoms'. As primary care is the frontline of the health-care system, symptoms are managed as the main problem in almost one in three consultations. It is about time that we take the same professional approach to symptoms as we have done for years to biomedical disease. PMID- 26965445 TI - How can the audiogram be more useful? AB - The Canadian Hearing and Auditory Research Translation (CHART) group is a newly formed taskforce to develop collaborative research initiatives. Initial discussions centered on diagnostic improvements for middle ear disease, auditory neuropathy spectrum disorder, tinnitus and presbycusis. Central to these discussions was the widely held view that the standard audiogram and its interpretation is inadequate to for describing many forms of hearing problems that we now recognize. This letter is designed to create awareness and to seek feedback from hearing healthcare professionals on their experience regarding the adequacy (or otherwise) of the audiogram in its present form. PMID- 26965446 TI - The impact and optimal indication of non-curative gastric resection for stage IV advanced gastric cancer diagnosed during surgery: 10 years of experience at a single institute. AB - BACKGROUND: The survival benefit of non-curative gastric resection for patients with stage IV gastric cancer is still unclear. METHODS: Of the patients who underwent open abdominal surgery that was preoperatively intended to be a radical excision procedure for gastric cancer, 72 were diagnosed with stage IV during the operation. At this institution, non-curative gastric resection is performed whenever possible. RESULTS: Non-curative gastric resection was performed in 44 of the 72 patients. According to the survival analysis, the median survival times in the gastric resection and no-resection groups were 1.9 and 0.9 years, respectively (log-rank test, p = 0.014). Based on the multivariate analysis, we selected gastric resection (hazard ratio [HR] = 0.309; 95% confidence interval [CI] = 0.152-0.615) and postoperative chemotherapy (HR = 0.136; 95% CI = 0.056 0.353) as independent factors associated with overall survival (OS). In the subgroup analyses of OS, the factors that were associated with gastric resection having no survival benefit were the existence of distant lymph node or liver metastasis (p = 0.527) and the lack of postoperative chemotherapy (p = 0.589). CONCLUSIONS: For patients who have distant lymph node or liver metastasis and those who will not undergo postoperative chemotherapy, non-curative gastric resection has no survival benefit. PMID- 26965444 TI - The organelle of differentiation in embryos: the cell state splitter. AB - The cell state splitter is a membraneless organelle at the apical end of each epithelial cell in a developing embryo. It consists of a microfilament ring and an intermediate filament ring subtending a microtubule mat. The microtubules and microfilament ring are in mechanical opposition as in a tensegrity structure. The cell state splitter is bistable, perturbations causing it to contract or expand radially. The intermediate filament ring provides metastability against small perturbations. Once this snap-through organelle is triggered, it initiates signal transduction to the nucleus, which changes gene expression in one of two readied manners, causing its cell to undergo a step of determination and subsequent differentiation. The cell state splitter also triggers the cell state splitters of adjacent cells to respond, resulting in a differentiation wave. Embryogenesis may be represented then as a bifurcating differentiation tree, each edge representing one cell type. In combination with the differentiation waves they propagate, cell state splitters explain the spatiotemporal course of differentiation in the developing embryo. This review is excerpted from and elaborates on "Embryogenesis Explained" (World Scientific Publishing, Singapore, 2016). PMID- 26965448 TI - Antiarrhythmic Action of Flecainide in Polymorphic Ventricular Arrhythmias Caused by a Gain-of-Function Mutation in the Nav 1.5 Sodium Channel. AB - BACKGROUND: The cardiac sodium channel Nav 1.5, encoded by the gene SCN5A, is associated with a wide spectrum of hereditary arrhythmias. The gain-of-function mutation p.I141V in SCN5A was identified in a large multigenerational family with exercise-induced polymorphic ventricular arrhythmias. The purpose of this study was to evaluate the molecular and clinical effects of flecainide administration on patients with this syndrome. METHODS: Eleven p.I141V carriers who exhibited frequent multiformic premature ventricular complexes (PVCs) during exercise were subjected to exercise stress tests, both before and after intravenous infusion of 2 mg/kg flecainide. The in vitro effects of flecainide were evaluated using the patch-clamp technique with HEK293 cells expressing the Nav 1.5 channel. RESULTS: The flecainide treatment significantly reduced the frequency of PVCs during and after exercise. Next, the sensitivity of the p.I141V mutant channel to flecainide was compared to that of the wild type channel. Perfusion of flecainide inhibited the peak and window currents in both groups. CONCLUSION: The clinical investigations of the affected patients, as well as the molecular and pharmacological characterization of the SCN5A p.I141V mutation, provide new evidence supporting the association of this mutation with exercise-induced polymorphic ventricular arrhythmias. These data also demonstrate that flecainide may serve as an effective treatment for the defect in Nav 1.5 that leads to an increased sodium window current. PMID- 26965450 TI - Be an Expert: Take Action with Evidence-Based Practice. PMID- 26965449 TI - Skewed risk perceptions in pregnant women: the case of influenza vaccination. AB - BACKGROUND: Pregnant women and their newborns have an increased risk of developing severe influenza and influenza-related complications. In Germany, seasonal influenza vaccination is recommended for pregnant women since 2010. However, little is known about pregnant women's vaccination-related knowledge and attitudes, as well as their risk perceptions. This study therefore assessed pregnant women's vaccination-related knowledge, risk perceptions related to influenza disease and influenza vaccination during pregnancy, and aimed to identify determinants of influenza vaccination uptake during pregnancy in Germany. METHODS: Between 2012 and 2014, a nationwide web-based prospective cohort study with follow-up interviews was conducted in initially pregnant women who gave birth over the study period. Control groups were set up in a cross sectional fashion during the follow-up interviews. Women who participated in both, the baseline interview before giving birth and in the 1st interview after giving birth were included in the analysis. Univariate and multiple logistic regression were used to identify associations between influenza vaccination uptake and sociodemographic characteristics as well as items assessing attitude and knowledge. RESULTS: In total, 838 women were included in the analyses. Pregnant women had a positive attitude towards vaccination in general, but only modest vaccination knowledge. Overall, 10.9 % of women were vaccinated against seasonal influenza during pregnancy. While pregnant women perceived classical childhood diseases to be more risky than the respective vaccinations, this relation reversed for influenza: The risk of vaccination was perceived higher than the risk of the disease. These two types of risk perceptions independently determined influenza vaccination uptake-higher perception of disease risk and lower perceptions of vaccination-related risks increased uptake. Additionally, knowledge about the vaccination recommendation for pregnant women and a positive gynaecologist's attitude towards vaccination during pregnancy influenced the uptake significantly. CONCLUSIONS: Influenza vaccination uptake in pregnant women is low in Germany. Tailored communication strategies for pregnant women should focus especially on changing the perceptions of personal risks regarding influenza and influenza vaccination during pregnancy. Gynaecologists should be made aware about their crucial role in supporting vaccination decision-making of pregnant women and the need to provide relevant information to counteract misconceptions. PMID- 26965447 TI - The placental membrane microbiome is altered among subjects with spontaneous preterm birth with and without chorioamnionitis. AB - BACKGROUND: Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality and is not uncommonly associated with chorioamnionitis. We recently have demonstrated that the placenta harbors a unique microbiome with similar flora to the oral community. We also have shown an association of these placental microbiota with PTB, history of antenatal infection, and excess maternal weight gain. On the basis of these previous observations, we hypothesized that the placental membranes would retain a microbiome community that would vary in association with preterm birth and chorioamnionitis. OBJECTIVE: In the current study, we aimed to examine the differences in the placental membrane microbiome in association with PTB in both the presence and absence of chorioamnionitis and/or funisitis using state-of-the-science whole-genome shotgun metagenomics. STUDY DESIGN: This was a cross-sectional analysis with 6 nested spontaneous birth cohorts (n = 9-15 subjects/cohort): Term gestations without chorioamnionitis, term with chorioamnionitis, preterm without chorioamnionitis, preterm with mild chorioamnionitis, preterm with severe chorioamnionitis, and preterm with chorioamnionitis and funisitis. Histologic analysis was performed with Redline's criteria, and inflammatory cytokines were analyzed in the cord blood. DNA from placental membranes was extracted from sterile swabs collected at delivery, and whole-genome shotgun sequencing was performed on the Illumina HiSeq platform. Filtered microbial DNA sequences were annotated and analyzed with MG-RAST (ie, Metagenomic Rapid Annotations using Subsystems Technology) and R. RESULTS: Subjects were assigned to cohorts on the basis of gestational age at delivery and independent scoring of histologic chorioamnionitis. We found that preterm subjects with severe chorioamnionitis and funisitis had increases in cord blood inflammatory cytokines. Of interest, although the placental membrane microbiome was altered in association with severity of histologic chorioamnionitis (permutational multivariate analysis of variance P = .005), there was no observable impact with either betamethasone or antibiotic treatment. In preterm subjects with chorioamnionitis, we found a high abundance of both urogenital and oral commensal bacteria. These alterations in the microbiome were accompanied by significant variation (P < .05) in microbial metabolic pathways important in the glucose-fed pentose phosphate pathway (term subjects), or glycerophopholipid metabolism, and the biosynthesis of the siderophore group nonribosomal peptides (preterm subjects). CONCLUSION: Consistent with ours and others previous findings, women who experienced spontaneous PTB harbor placental microbiota that further differed by severity of chorioamnionitis. Integrative metagenomic analysis revealed significant variation in distinct bacterial metabolic pathways, which we speculate may contribute to risk of preterm birth with and without severe chorioamnionitis. PMID- 26965453 TI - Analysis of the effect of LRP-1 silencing on the invasive potential of cancer cells by nanomechanical probing and adhesion force measurements using atomic force microscopy. AB - Low-density lipoprotein receptor-related protein 1 (LRP-1) can internalize proteases involved in cancer progression and is thus considered a promising therapeutic target. However, it has been demonstrated that LRP-1 is also able to regulate the endocytosis of membrane-anchored proteins. Thus, strategies that target LRP-1 to modulate proteolysis could also affect adhesion and cytoskeleton dynamics. Here, we investigated the effect of LRP-1 silencing on parameters reflecting cancer cells' invasiveness by atomic force microscopy (AFM). The results show that LRP-1 silencing induces changes in the cells' adhesion behavior, particularly the dynamics of cell attachment. Clear alterations in morphology, such as more pronounced stress fibers and increased spreading, leading to increased area and circularity, were also observed. The determination of the cells' mechanical properties by AFM showed that these differences are correlated with an increase in Young's modulus. Moreover, the measurements show an overall decrease in cell motility and modifications of directional persistence. An overall increase in the adhesion force between the LRP-1-silenced cells and a gelatin-coated bead was also observed. Ultimately, our AFM-based force spectroscopy data, recorded using an antibody directed against the beta1 integrin subunit, provide evidence that LRP-1 silencing modifies the rupture force distribution. Together, our results show that techniques traditionally used for the investigation of cancer cells can be coupled with AFM to gain access to complementary phenotypic parameters that can help discriminate between specific phenotypes associated with different degrees of invasiveness. PMID- 26965454 TI - Advances in the Simulation of Protein Aggregation at the Atomistic Scale. AB - Protein aggregation into highly structured amyloid fibrils is associated with various diseases including Alzheimer's disease, Parkinson's disease, and type II diabetes. Amyloids can also have normal biological functions and, in the future, could be used as the basis for novel nanoscale materials. However, a full understanding of the physicochemical forces that drive protein aggregation is still lacking. Such understanding is crucial for the development of drugs that can effectively inhibit aberrant amyloid aggregation and for the directed design of functional amyloids. Atomistic simulations can help understand protein aggregation. In particular, atomistic simulations can be used to study the initial formation of toxic oligomers which are hard to characterize experimentally and to understand the difference in aggregation behavior between different amyloidogenic peptides. Here, we review the latest atomistic simulations of protein aggregation, concentrating on amyloidogenic protein fragments, and provide an outlook for the future in this field. PMID- 26965451 TI - Novel MET/TIE2/VEGFR2 inhibitor altiratinib inhibits tumor growth and invasiveness in bevacizumab-resistant glioblastoma mouse models. AB - BACKGROUND: Glioblastoma highly expresses the proto-oncogene MET in the setting of resistance to bevacizumab. MET engagement by hepatocyte growth factor (HGF) results in receptor dimerization and autophosphorylation mediating tumor growth, invasion, and metastasis. Evasive revascularization and the recruitment of TIE2 expressing macrophages (TEMs) are also triggered by anti-VEGF therapy. METHODS: We investigated the activity of altiratinib (a novel balanced inhibitor of MET/TIE2/VEGFR2) against human glioblastoma stem cell lines in vitro and in vivo using xenograft mouse models. The biological activity of altiratinib was assessed in vitro by testing the expression of HGF-stimulated MET phosphorylation as well as cell viability after altiratinib treatment. Tumor volume, stem cell and mesenchymal marker levels, microvessel density, and TIE2-expressing monocyte infiltration were evaluated in vivo following treatment with a control, bevacizumab alone, bevacizumab combined with altiratinib, or altiratinib alone. RESULTS: In vitro, HGF-stimulated MET phosphorylation was completely suppressed by altiratinib in GSC17 and GSC267, and altiratinib markedly inhibited cell viability in several glioblastoma stem cell lines. More importantly, in multiple xenograft mouse models, altiratinib combined with bevacizumab dramatically reduced tumor volume, invasiveness, mesenchymal marker expression, microvessel density, and TIE2-expressing monocyte infiltration compared with bevacizumab alone. Furthermore, in the GSC17 xenograft model, altiratinib combined with bevacizumab significantly prolonged survival compared with bevacizumab alone. CONCLUSIONS: Together, these data suggest that altiratinib may suppress tumor growth, invasiveness, angiogenesis, and myeloid cell infiltration in glioblastoma. Thus, altiratinib administered alone or in combination with bevacizumab may overcome resistance to bevacizumab and prolong survival in patients with glioblastoma. PMID- 26965452 TI - Aminopeptidase P Mediated Targeting for Breast Tissue Specific Conjugate Delivery. AB - Cytotoxic chemotherapies are used to treat breast cancer, but are limited by systemic toxicity. The key to addressing this important issue is the development of a nontoxic, tissue selective, and molecular specific delivery system. In order to potentially increase the therapeutic index of clinical reagents, we designed an Aminopeptidase P (APaseP) targeting tissue-specific construct conjugated to a homing peptide for selective binding to human breast-derived cancer cells. Homing peptides are short amino acid sequences derived from phage display libraries that have the unique property of localizing to specific organs. Our molecular construct allows for tissue-specific drug delivery, by binding to APaseP in the vascular endothelium. The breast homing peptide evaluated in our studies is a cyclic nine-amino-acid peptide with the sequence CPGPEGAGC, referred to as PEGA. We show by confocal microscopy that the PEGA peptide and similar peptide conjugates distribute to human breast tissue xenograft specifically and evaluate the interaction with the membrane-bound proline-specific APaseP (KD = 723 +/- 3 nM) by binding studies. To achieve intracellular breast cancer cell delivery, the incorporation of the Tat sequence, a cell-penetrating motif derived from HIV, was conjugated with the fluorescently labeled PEGA peptide sequence. Ultimately, tissue specific peptides and their conjugates can enhance drug delivery and treatment by their ability to discriminate between tissue types. Tissue specific conjugates as we have designed may be valuable tools for drug delivery and visualization, including the potential to treat breast cancer, while simultaneously minimizing systemic toxicity. PMID- 26965455 TI - Polyomavirus infections and its clinical relevance in cancer patients: A Prospective Study. AB - BK and JC polyomaviruses (PyV) have been demonstrated to be associated with the pathogenesis of various human cancers. We aimed to investigate the impact of BK and JC polyomavirus infections on several clinical parameters in different human cancers. A total of 150 cancer patients were included in the study (51 patients with solid tumors, 48 patients with lymphomas and 51 patients with leukemias). Amplification of PyV DNA was performed using a semi-nested version of Polymerase chain reaction targeting the T genomic region of PyV. The polyomavirus load was determined using real-time PCR assay. The clinical data were collected. Polyomavirus DNA could be detected in 84 (56%) of 150 of all cancerous patients. The solid tumors had the lowest proportion of JCV (6 (11.8%) of 51), whereas had the highest proportion of JCV (200copies/MUl). JCV was more frequent among NHL patients (30%) and absent in HL patients (0%). During follow-up, PyV positivity decreased significantly (p=0.004) in lymphoma patients (n=28). Although PyV positivity decreased significantly from 39% to 7% in 28 of 48 lymphoma patients after treatment, it significantly persisted in leukemic patients after treatment (from 22% to 38%). JC was more frequent among leukemic patients with leukopenia. The presence of JC polyomavirus was more frequent among leukemic patients without any significant impact on their overall survival. PMID- 26965457 TI - Improved ductility of Cu64Zr36 metallic glass/Cu nanocomposites via phase and grain boundaries. AB - We investigate tensile deformation of metallic glass/crystalline interpenetrating phase nanocomposites as regards the effects of specific area of amorphous/crystalline phase interfaces, and grain boundaries. As an illustrative case, large-scale molecular dynamics simulations are performed on Cu64Zr36 metallic glass/Cu nanocomposites with different specific interface areas and grain boundary characteristics. Plastic deformation is achieved via shear bands, shear transformation zones, and crystal plasticity. Three-dimensional amorphous/crystalline interfaces serve as effective barriers to the propagation of shear transformation zones and shear bands if formed, diffuse strain localizations, and give rise to improved ductility. Ductility increases with increasing specific interface area. In addition, introducing grain boundaries into the second phase facilitates crystal plasticity, which helps reduce or eliminate mature shear bands in the glass matrix. PMID- 26965456 TI - Rutin attenuates intestinal toxicity induced by Methotrexate linked with anti oxidative and anti-inflammatory effects. AB - BACKGROUND: Methotrexate (MTX) is recognized as an anti-metabolite in cancer chemotherapy and is associated with various toxicities assigned to inflammation and oxidative stress. Rutin has been reported to have significant anti inflammatory, antioxidant along with antiulcer properties. The present study was undertaken to corroborate the effect of rutin against MTX induced intestinal toxicity in experimental animals. METHOD: Six groups of rats (n = 6) were dosed with normal saline (3 ml/kg,i.p.); MTX (2.5 mg/kg,i.p.); rutin (50 and 100 mg/kg,i.p.); rutin + MTX (50 mg/kg + 2.5 mg/kg,i.p.); rutin + MTX (100 mg/kg + 2.5 mg/kg,i.p.) for seven consecutive days and sacrificed on eighth day. The intestinal contents were scrutinized physiologically (pH, total acidity, free acidity, CMDI), biochemically (TBARS, protein carbonyl, SOD, catalase and GSH) and for immunoregulatory cytokines (IL-2, IL-4 and IL-10). RESULTS AND DISCUSSION: The administration of rutin demonstrated significant protection against intestinal lesions damaged by MTX. The treatment with rutin elicited noticeable inhibition of free acidity (26.20%), total acidity (22.05%) and CMDI (1.16%) in the experimental animals similar to control. In MTX treated toxic group, the levels of oxidative markers and immunoregulatory cytokines significantly increased in comparison to control, which was subsequently restored after rutin treatment. Rutin also demonstrated 75.63, 81.00 and 80.43% inhibition of cyclooxygenase-1 and 2, and 15-lipoxygenase respectively. CONCLUSION: The positive modulation of MTX toxicity could be attributed to the free radical scavenging and anti-inflammatory (dual inhibition of arachidonic acid pathways) potential of rutin. PMID- 26965459 TI - Ring formation in the quasi-two-dimensional system of the patchy magnetic spheres. AB - Fabricating new functional materials has always been at the center of colloidal science, and how to form circular rings is a meaningful challenge due to their special electronic, magnetic and optical properties. Magnetic colloidal spheres can self-assemble into rings, but these rings have an uncontrollable length and shape and also have to coexist with chains and defected clusters. To make the most of magnetic spheres being able to self-assemble into rings, a patch is added to the surface of the sphere to form a chiral link between particles. The structural transition in the system of patchy magnetic spheres is studied using the Monte Carlo simulation. When the patch angle is in the interval 60 degrees to 75 degrees , rings become the dominant structure if the strength of patchy interaction exceeds a particular threshold and the shape of these rings is close to the circle. With an increase in the patch angle, the threshold of patchy interaction decreases and the average length of the circular ring increases approximately from 5 to 8.5. PMID- 26965458 TI - A high-throughput peptidomic strategy to decipher the molecular diversity of cyclic cysteine-rich peptides. AB - Cyclotides are plant cyclic cysteine-rich peptides (CRPs). The cyclic nature is reported to be gene-determined with a precursor containing a cyclization competent domain which contains an essential C-terminal Asn/Asp (Asx) processing signal recognized by a cyclase. Linear forms of cyclotides are rare and are likely uncyclizable because they lack this essential C-terminal Asx signal (uncyclotide). Here we show that in the cyclotide-producing plant Clitoria ternatea, both cyclic and acyclic products, collectively named cliotides, can be bioprocessed from the same cyclization-competent precursor. Using an improved peptidomic strategy coupled with the novel Asx-specific endopeptidase butelase 2 to linearize cliotides at a biosynthetic ligation site for transcriptomic analysis, we characterized 272 cliotides derived from 38 genes. Several types of post-translational modifications of the processed cyclotides were observed, including deamidation, oxidation, hydroxylation, dehydration, glycosylation, methylation, and truncation. Taken together, our results suggest that cyclotide biosynthesis involves 'fuzzy' processing of precursors into both cyclic and linear forms as well as post-translational modifications to achieve molecular diversity, which is a commonly found trait of natural product biosynthesis. PMID- 26965461 TI - Reply. PMID- 26965462 TI - Cooling Catheters for Selective Brain Hypothermia. PMID- 26965460 TI - Association between secondary thrombocytosis and viral respiratory tract infections in children. AB - Secondary thrombocytosis (ST) is frequently observed in children with a variety of clinical conditions. The leading cause of ST is respiratory tract infection (RTI) in children. Nasopharyngeal aspirate samples were collected and assessed for common respiratory viruses. The relationships between virus infections and secondary thrombocytosis were analyzed retrospectively. The blood platelet count and the presence of respiratory viruses were determined for 3156 RTI patients, and 817 (25.9%) cases with platelet >=500 * 10(9)/L were considered as the thrombocytosis group. Compared with the normal group, the detection rates of respiratory syncytial virus (RSV) and human rhinovirus (HRV) were significantly higher in the thrombocytosis group (P = 0.017 and 0.042, respectively). HRV single infection was a risk factor associated with thrombocytosis [odds ratio (OR) = 1.560, 95% confidence interval (CI) = 1.108-2.197]. Furthermore, ST was more likely to occur in younger patients who had clinical manifestations of wheezing and dyspnea and who had been diagnosed with bronchiolitis. Furthermore, the course of disease lasted longer in these patients. ST is associated with viral respiratory tract infections, especially RSV and HRV infections. HRV single infection is a risk factor associated with thrombocytosis. PMID- 26965463 TI - White Matter Diffusion Changes during the First Year of Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: Natalizumab treatment strongly affects relapsing remitting multiple sclerosis, possibly by restraining white matter damage. This study investigated changes in white matter diffusivity in patients with relapsing remitting multiple sclerosis during their first year of natalizumab treatment by using diffusion tensor imaging. MATERIALS AND METHODS: The study included patients with relapsing-remitting multiple sclerosis initiating natalizumab at baseline (n = 22), patients with relapsing-remitting multiple sclerosis continuing interferon-beta or glatiramer acetate (n = 17), and healthy controls (n = 12). Diffusion tensor imaging parameters were analyzed at baseline and month 12. We measured the extent and severity of white matter damage with diffusion tensor imaging parameters such as fractional anisotropy, comparing the patient groups with healthy controls at both time points. RESULTS: The extent and severity of white matter damage were reduced significantly in the natalizumab group with time (fractional anisotropy-based extent, 56.8% to 47.2%; severity, z = -0.67 to -0.59; P = .02); this reduction was not observed in the interferon beta/glatiramer acetate group (extent, 41.4% to 39.1%, and severity, z = -0.64 to -0.67; P = .94). Cognitive performance did not change with time in the patient groups but did correlate with the severity of damage (r = 0.53, P = < .001). CONCLUSIONS: In patients with relapsing-remitting multiple sclerosis starting natalizumab treatment, the extent and severity of white matter damage were reduced significantly in the first year of treatment. These findings may aid in explaining the large observed clinical effect of natalizumab in relapsing remitting multiple sclerosis. PMID- 26965464 TI - Quantitative Susceptibility Mapping in Cerebral Cavernous Malformations: Clinical Correlations. AB - BACKGROUND AND PURPOSE: Quantitative susceptibility mapping has been shown to assess iron content in cerebral cavernous malformations. In this study, our aim was to correlate lesional iron deposition assessed by quantitative susceptibility mapping with clinical and disease features in patients with cerebral cavernous malformations. MATERIALS AND METHODS: Patients underwent routine clinical scans in addition to quantitative susceptibility mapping on 3T systems. Data from 105 patients met the inclusion criteria. Cerebral cavernous malformation lesions identified on susceptibility maps were cross-verified by T2-weighted images and differentiated on the basis of prior overt hemorrhage. Mean susceptibility per cerebral cavernous malformation lesion (chilesion) was measured to correlate with lesion volume, age at scanning, and hemorrhagic history. Temporal rates of change in chilesion were evaluated in 33 patients. RESULTS: Average chilesion per patient was positively correlated with patient age at scanning (P < .05, 4.1% change with each decade of life). Cerebral cavernous malformation lesions with prior overt hemorrhages exhibited higher chilesion than those without (P < .05). Changes in chilesion during 3- to 15-month follow-up were small in patients without new hemorrhage between the 2 scans (bias = -0.0003; 95% CI, -0.06-0.06). CONCLUSIONS: The study revealed a positive correlation between mean quantitative susceptibility mapping signal and patient age in cerebral cavernous malformation lesions, higher mean quantitative susceptibility mapping signal in hemorrhagic lesions, and minimum longitudinal quantitative susceptibility mapping signal change in clinically stable lesions. Quantitative susceptibility mapping has the potential to be a novel imaging biomarker supplementing conventional imaging in cerebral cavernous malformations. The clinical significance of such measures merits further study. PMID- 26965465 TI - Evaluating Permeability Surface-Area Product as a Measure of Blood-Brain Barrier Permeability in a Murine Model. AB - BACKGROUND AND PURPOSE: Permeability surface-area product has been suggested as a marker for BBB permeability with potential applications in clinical care and research. However, few studies have demonstrated its correlation with actual quantitative measurements of BBB permeability. Our aim was to demonstrate the correlation of quantitative permeability surface-area product and BBB permeability in a murine model by histologic confirmation. MATERIALS AND METHODS: Coronal MR imaging was performed on mice treated with mannitol (n = 6) for disruption of the BBB and controls treated with saline (n = 5). Permeability surface-area product was determined by ROI placement and was compared between saline- and mannitol-treated mice. Correlation was made with contrast-enhancement measurements and immunohistologic-stained sections of tripeptidyl peptidase-1 distribution in mice treated with mannitol and saline followed by injection of a viral vector containing the CLN2 gene, which directs production of tripeptidyl peptidase-1. RESULTS: Significantly increased permeability surface-area product was seen in mannitol- compared with saline-treated mice in the whole brain (P = .008), MCA territory (P = .014), and mixed vascular territories (P = .008). These findings were compared with contrast-enhancement measurements of BBB permeability and were correlated with immunohistologic-stained sections demonstrating BBB permeability to a large vector. CONCLUSIONS: Permeability surface-area product is increased in situations with known disruptions of the BBB, as evidenced by immunologic staining of large-vector passage through the BBB and concordance with contrast-enhancement measurements in a murine model. Quantitative permeability surface-area product has potential as an imaging marker of BBB permeability. PMID- 26965467 TI - Endovascular Management of Tandem Occlusion Stroke Related to Internal Carotid Artery Dissection Using a Distal to Proximal Approach: Insight from the RECOST Study. AB - BACKGROUND AND PURPOSE: Internal carotid artery dissection is a common cause of stroke in young adults. It may be responsible for tandem occlusion defined by a cervical steno-occlusive carotid wall hematoma associated with an intracranial large-vessel stroke. Intravenous thrombolysis is associated with a poor clinical outcome in these cases, and endovascular treatment has not been specifically evaluated to date. Our aim was to evaluate endovascular treatment technical and clinical efficiency in this specific occlusion topography, in comparison with treatment of isolated anterior circulation stroke. MATERIALS AND METHODS: As part of our ongoing prospective stroke data base started in August 2009 (Prognostic Factors Related to Clinical Outcome Following Thrombectomy in Ischemic Stroke [RECOST] Study), we analyzed all carotid artery dissection tandem occlusion strokes and isolated anterior circulation occlusions. All patients were selected for endovascular treatment according to clinical-radiologic mismatch, NIHSS >= 7 and DWI-ASPECTS >=5, within 6 hours after onset. For carotid artery dissection, the revascularization procedure consisted first of distal recanalization by a stent retriever in the intracranial vessel. Following assessment of the circle of Willis, internal carotid artery stent placement was only performed in case of insufficiency. Carotid artery dissection treatment efficacy, safety, and clinical outcome were compared with the results of the isolated anterior circulation occlusion cohort. RESULTS: Two hundred fifty-eight patients with an anterior circulation stroke were analyzed, including 57 with tandem occlusions (22%); among them, 20 were carotid artery dissection-related occlusions (7.6%). The median age of patients with tandem occlusions with internal carotid dissection was 52.45 versus 66.85 years for isolated anterior circulation occlusion (P < .05); the mean initial NIHSS score was 17.53 +/- 4.11 versus 17.55 +/- 4.8 (P = .983). The median DWI-ASPECTS was 6.05 versus 6.64 (P = .098), and the average time from onset to puncture was 4.38 for tandem occlusions versus 4.53 hours in isolated anterior circulation occlusion (P = .704). Complication rates and symptomatic intracranial hemorrhage were comparable in both groups (5% versus 3%, P = .49). The duration of the procedure was significantly prolonged in case of tandem occlusion (80.69 versus 65.45 minutes, P = .030). Fourteen patients with carotid artery dissection (70%) had a 3-month mRS of <= 2, without a significant difference from patients with an isolated anterior circulation occlusion (44%, P = .2). Only 5 carotid artery dissections (25%) necessitated cervical stent placement. No early ipsilateral stroke recurrence was recorded, despite the absence of stent placement in 15 patients (75%) with carotid artery dissection. CONCLUSIONS: Mechanical endovascular treatment of carotid artery dissection tandem occlusions is safe and effective compared with isolated anterior circulation occlusion stroke therapy. Hence, a more conservative approach with stent placement only in cases of circle of Willis insufficiency may be a reliable and safe strategy. PMID- 26965466 TI - Performance of CT ASPECTS and Collateral Score in Risk Stratification: Can Target Perfusion Profiles Be Predicted without Perfusion Imaging? AB - BACKGROUND AND PURPOSE: Endovascular trials suggest that revascularization benefits a subset of acute ischemic stroke patients with large-artery occlusion and small-core infarct volumes. The objective of our study was to identify thresholds of noncontrast CT-ASPECTS and collateral scores on CT angiography that best predict ischemic core volume thresholds quantified by CT perfusion among patients with acute ischemic stroke. MATERIALS AND METHODS: Fifty-four patients with acute ischemic stroke (<12 hours) and MCA/intracranial ICA occlusion underwent NCCT/CTP during their initial evaluation. CTP analysis was performed on a user-independent platform (RApid processing of PerfusIon and Diffusion), computing core infarct (defined as CBF of <30% normal). A target mismatch profile consisting of infarction core of <=50 mL was selected to define candidates with acute ischemic stroke likely to benefit from revascularization. RESULTS: NCCT ASPECTS of >=9 with a CTA collateral score of 3 had 100% specificity for identifying patients with a CBF core volume of <=50 mL. NCCT-ASPECTS of <=6 had 100% specificity for identifying patients with a CBF core volume of >50 mL. In our cohort, 44 (81%) patients had an NCCT-ASPECTS of >=9, a CTA collateral score of 3, or an NCCT-ASPECTS of <=6. CONCLUSIONS: Using an NCCT-ASPECTS of >=9 or a CTA collateral score of 3 best predicts CBF core volume infarct of <=50 mL, while an NCCT-ASPECTS of <=6 best predicts a CBF core volume infarct of >50 mL. Together these thresholds suggest that a specific population of patients with acute ischemic stroke not meeting such profiles may benefit most from CTP imaging to determine candidacy for revascularization. PMID- 26965468 TI - Fate of Coiled Aneurysms with Minor Recanalization at 6 Months: Rate of Progression to Further Recanalization and Related Risk Factors. AB - BACKGROUND AND PURPOSE: Minor recanalization in coiled aneurysms may remain stable with time or may progress to major recanalization. Our aim was to monitor the aneurysms displaying minor recanalization in imaging studies at 6 months, gauging major recanalization rates and related risk factors through extended follow-up. MATERIALS AND METHODS: Sixty-five aneurysms (in 65 patients) showing minor recanalization in follow-up imaging at 6 months were reviewed retrospectively. Medical records and radiologic data accruing during extended monitoring (mean, 24.8 +/- 8.2 months) were assessed. Univariate and multivariate analyses were conducted to identify risk factors for progression from minor-to major recanalization. RESULTS: Progression to major recanalization was observed in 24 (36.9%) of the initially qualifying aneurysms during a follow-up of 112.5 aneurysm-years, for an annual rate of 17.84% per aneurysm-year. Progression was determined chronologically as follows: 14 (58.3%) at 6 months, 8 (33.3%) at 18 months, and 2 (8.4%) at 30 months. Stent deployment significantly decreased the occurrence of major recanalization (OR = 0.22, P = .03), whereas antiplatelet therapy (OR = 0.82, P = .75), posterior location (OR = 0.24, P = .20), and second coiling for recanalized aneurysms (OR = 0.96, P = .96) were unrelated. CONCLUSIONS: Our analysis determined a 36.9% rate of major recanalization during a follow-up of 112.5 aneurysm-years in coiled aneurysms showing minor recanalization at 6 months. Stent deployment alone conferred a protective effect, preventing further recanalization without additional treatment. Given the fair probability of late major recanalization, aneurysms showing minor recanalization at 6 months should be monitored diligently, particularly in the absence of stent placement. PMID- 26965469 TI - Stroke Presentation of Acute Type A Aortic Dissection with 100% Perfusion Weighted Imaging-Diffusion-Weighted Imaging Mismatch: A Call for Urgent Action. AB - BACKGROUND AND PURPOSE: Acute stroke in the setting of acute type A aortic dissection is not rare and may contraindicate immediate surgery. Evaluating irreversible brain damage is critical in this setting and magnetic resonance imaging is a key determinant in the decision of selecting surgical over medical treatment for these patients. SUMMARY OF CASES: We report herein 2 cases assessed at a tertiary care center for acute stroke. The initial diagnosis workup revealed cerebral hemispheric severe hypoperfusion without any brain infarction. The absence of ischemic lesions prompted surgical repair, despite the severity of clinical symptoms. Both patients demonstrated complete neurological recovery and neuroimaging showed no persistent sequel. CONCLUSION: Acute type A aortic dissection is an important differential diagnosis in the causative workup for stroke. Brain hypoperfusion alone should not be a contraindication for urgent surgical treatment, regardless of initial clinical neurological severity. PMID- 26965470 TI - Occurrence of Obstructive Sleep Apnea Syndrome in Patients with Transient Ischemic Attack. AB - BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a sleep breathing disorder with episodes of upper airway obstructions. Patients with cardiovascular diseases such as myocardial infarction and stroke show a high prevalence of OSAS. Several studies focus on stroke and not on transient ischemic attack (TIA), suggesting it could be a symptom after stroke. We analyzed the occurrence of OSAS in high-risk patients with TIA. METHODS: There were 555 patients suspected for TIA by the general practitioner who were referred to our TIA daycare clinic. They were screened for OSAS using 3 screening factors: snoring (yes/no), body mass index greater than or equal to 30, and Epworth Sleepiness Score greater than 10. When 2 out of 3 were positive, patients received a polysomnography. An apnea-hypopnea index (AHI) of 5-15 is defined as mild OSAS, AHI 15-30 as moderate OSAS, and AHI greater than 30 as severe OSAS. RESULTS: Seventy-seven patients received a polysomnography. Twenty-five patients had a diagnosis of TIA and 18 had a diagnosis of cerebral ischemia, whereas 34 had other diagnoses. Twenty of the 25 (80%) TIA patients had OSAS, compared to 16 of the 34 (47%) patients without a vascular diagnosis (P = .010). When excluding patients with a cardiovascular history, we found 15 of the 20 patients with OSAS, compared to 14 out of 30 patients (P = .047). CONCLUSIONS: There is a significant higher occurrence of OSAS in TIA patients compared to patients without a vascular diagnosis, even after excluding patients with a history of cardiovascular events. PMID- 26965471 TI - Effect of bone inhomogeneity on tibiofemoral contact mechanics during physiological loading. AB - It is not known how inhomogeneous mechanical properties of bone affect contact mechanics and cartilage response during physiological loading of the knee joint. In this study, a finite element model of a cadaver knee joint was constructed based on quantitative computed tomography (QCT). The mechanical properties of bone were altered and their effect on tibiofemoral contact mechanics and cartilage stresses, strains and pore pressures were evaluated during the first 20% of stance. For this purpose, models with rigid, homogeneous and inhomogeneous bones were created. When bone was modeled to be rigid, the resulting contact pressures were substantially higher in the medial side of the joint, as compared to the non-rigid bones. Similar changes were revealed also in stresses, strains and pore pressures throughout the cartilage depth at the cartilage-cartilage contact area. Furthermore, the mechanical response of medial tibial cartilage was found to be highly dependent on the bone properties. When Young's modulus in the model with homogeneous bone was 5GPa, cartilage mechanical response approached to that of the model with inhomogeneous bone. Finally, when the apparent bone mineral densities were decreased globally in the inhomogeneous bone, stresses, strains and pore pressures were decreased at all layers of medial tibial cartilage. Similar changes were observed also in cartilage-cartilage contact area of the lateral compartment but with a lesser extent. These results indicate that during physiological loading Young's modulus of bone has a substantial influence on cartilage stresses and strains, especially in the medial compartment. PMID- 26965472 TI - A numerical framework for the mechanical analysis of dual-layer stents in intracranial aneurysm treatment. AB - Dual-layer stents and multi-layer stents represent a new paradigm in endovascular interventions. Multi-layer stents match different stent designs in order to offer auxiliary functions. For example, dual-layer stents used in the endovascular treatment of intracranial aneurysms, like the FRED(TM) (MicroVention, CA) stent, combine a densely braided inner metallic mesh with a loosely braided outer mesh. The inner layer is designed to divert blood flow, whereas the outer one ensures microvessels branching out of the main artery remain patent. In this work, the implemented finite element (FE) analysis identifies the key aspects of dual-stent mechanics. In particular, dual-layer stents used in the treatment of intracranial aneurysms require the ability to conform to very narrow passages in their closed configuration, while at the same time they have to provide support and stability once deployed. This study developed a numerical framework for the analysis of dual-layer stents for endovascular intracranial aneurysm treatment. Our results were validated against analytical methods. For the designs considered, we observed that foreshortening was in average 37.5%+/-2.5%, and that doubling the number of wires in the outer stent increased bending moment by 23%, while halving the number of wires of the inner stent reduced von Mises stress by 2.3%. This framework can be extended to the design optimization of multi-layer stents used in other endovascular treatments. PMID- 26965473 TI - Type 1 diabetes in adults: supporting self management. PMID- 26965474 TI - Effects of sodium fluoride on immune response in murine macrophages. AB - Excessive fluoride intake may be harmful for health, producing dental and skeletal fluorosis, and effects upon neurobehavioral development. Studies in animals have revealed effects upon the gastrointestinal, renal and reproductive systems. Some of the disorders may be a consequence of immune system alterations. In this study, an in vitro evaluation is made of fluoride immunotoxicity using the RAW 264.7 murine macrophage line over a broad range of concentrations (2.5 75mg/L). The results show that the highest fluoride concentrations used (50 75mg/L) reduce the macrophage population in part as a consequence of the generation of reactive oxygen and/or nitrogen species and consequent redox imbalance, which in turn is accompanied by lipid peroxidation. A decrease in the expression of the antiinflammatory cytokine Il10 is observed from the lowest concentrations (5mg/L). High concentrations (50mg/L) in turn produce a significant increase in the proinflammatory cytokines Il6 and Mip2 from 4h of exposure. In addition, cell phagocytic capacity is seen to decrease at concentrations of >=20mg/L. These data indicate that fluoride, at high concentrations, may affect macrophages and thus immune system function - particularly with regard to the inflammation autoregulatory processes, in which macrophages play a key role. PMID- 26965475 TI - A three-dimensional actuated origami-inspired transformable metamaterial with multiple degrees of freedom. AB - Reconfigurable devices, whose shape can be drastically altered, are central to expandable shelters, deployable space structures, reversible encapsulation systems and medical tools and robots. All these applications require structures whose shape can be actively controlled, both for deployment and to conform to the surrounding environment. While most current reconfigurable designs are application specific, here we present a mechanical metamaterial with tunable shape, volume and stiffness. Our approach exploits a simple modular origami-like design consisting of rigid faces and hinges, which are connected to form a periodic structure consisting of extruded cubes. We show both analytically and experimentally that the transformable metamaterial has three degrees of freedom, which can be actively deformed into numerous specific shapes through embedded actuation. The proposed metamaterial can be used to realize transformable structures with arbitrary architectures, highlighting a robust strategy for the design of reconfigurable devices over a wide range of length scales. PMID- 26965477 TI - Are personalised treatments of adult depression finally within reach? PMID- 26965476 TI - A randomized-control trial for the teachers' diploma programme on psychosocial care, support and protection in Zambian government primary schools. AB - Orphaned and vulnerable children (OVC) experience poverty, stigma, and abuse resulting in poor physical, emotional, and psychological outcomes. The Teachers' Diploma Programme on Psychosocial Care, Support, and Protection is a child centered 15-month long-distance learning program focused on providing teachers with the knowledge and skills to enhance their school environments, foster psychosocial support, and facilitate school-community relationships. A randomized controlled trial was implemented in 2013-2014. Both teachers (n=325) and students (n=1378) were assessed at baseline and 15-months post-intervention from randomly assigned primary schools in Lusaka and Eastern Provinces, Zambia. Multilevel linear mixed models (MLM) indicate positive significant changes for intervention teachers on outcomes related to self-care, teaching resources, safety, social support, and gender equity. Positive outcomes for intervention students related to future orientation, respect, support, safety, sexual abuse, and bullying. Outcomes support the hypothesis that teachers and students benefit from a program designed to enhance teachers' psychosocial skills and knowledge. PMID- 26965479 TI - A Simple Geotracer Compositional Correlation Analysis Reveals Oil Charge and Migration Pathways. AB - A novel approach, based on geotracer compositional correlation analysis is reported, which reveals the oil charge sequence and migration pathways for five oil fields in Saudi Arabia. The geotracers utilised are carbazoles, a family of neutral pyrrolic nitrogen compounds known to occur naturally in crude oils. The approach is based on the concept that closely related fields, with respect to filling sequence, will show a higher carbazole compositional correlation, than those fields that are less related. That is, carbazole compositional correlation coefficients can quantify the charge and filling relationships among different fields. Consequently, oil migration pathways can be defined based on the established filling relationships. The compositional correlation coefficients of isomers of C1 and C2 carbazoles, and benzo[a]carbazole for all different combination pairs of the five fields were found to vary extremely widely (0.28 to 0.94). A wide range of compositional correlation coefficients allows adequate differentiation of separate filling relationships. Based on the established filling relationships, three distinct migration pathways were inferred, with each apparently being charged from a different part of a common source kitchen. The recognition of these charge and migration pathways will greatly aid the search for new accumulations. PMID- 26965478 TI - Human limbal mesenchymal stem cells express ABCB5 and can grow on amniotic membrane. AB - AIM: To isolate and characterize limbal mesenchymal stem cells (LMSCs) from human corneoscleral rings. MATERIALS & METHODS: Cells were isolated from corneoscleral rings and cultured in a mesenchymal stem cell (MSC)-selective media and examined for differentiation, phenotyping and characterization. RESULTS: LMSCs were capable of trilineage differentiation, adhered to tissue culture plastic, expressed HLA class I and cell surface antigens associated with human MSC while having no/low expression of HLA class II and negative hematopoietic lineage markers. They were capable for CXCL12-mediated cellular migration. LMSCs adhered, proliferated on amniotic membrane and expressed the common putative limbal stem cell markers. CONCLUSION: Limbal-derived MSC exhibited plasticity, could maintain limbal markers expression and demonstrated viable growth on amniotic membrane. PMID- 26965480 TI - Melatonine en stemmingsstoornissen. AB - Melatonin is a hormone secreted by the pineal gland mainly during the night. The discovery that this melatonin secretion decreases under the influence of bright light, gave rise to the use of light therapy in some affective disorders. The literature on the relationship between melatonin secretion and mood is reviewed concerning seasonal affective disorder, non-seasonal affective disorder and premenstrual syndrome. Light therapy could reduce an abnormal high melatonin secretion back to normal proportions. None of the affective disorders, however, is accompanied by an unusual high melatonin level. Nevertheless, light therapy as well as other therapies that suppress melatonin have a therapeutic effect. This is not the case with the administration of melatonin. Mood is not affected by extra melatonin in seasonal affective disorder but it is in both other affective disorders. Melatonin plays a part in the pathogenesis of the affective disorders but it is not yet clear which one. PMID- 26965481 TI - Pharmacotherapeutical treatment of personality disorders. AB - Since some years it has become evident that objective disturbances can be found in patients suffering from personality disorders. Research findings from earlier date already demonstrated low levels of 5-hydroxyindoleacetic acid in the cerebrospinal fluid, especially in patients with personality disorders, under exclusion of depressive features. Furthermore, data have been collected on the correlation between a hyposerotonergic state and disturbances in aggression and impulse control in a variety of syndromes such as automutilation, bulimia nervosa, suicide attempts and various states of drug abuse. However, psychopharmacological research in personality disorders is rare and to date mainly patients with borderline and schizotypical personality disorders have been studied. It is quite remarkable for this area to find more review articles than original contributions based on the results of clinical trials. A great variety of recommendations for pharmacotherapy in these patients exists in literature, among which treatment with carbamazepine, lithium, low-dose neuroleptics, tricyclic antidepressants and serotonin uptake inhibitors. In this article we will analyze the research methodology and the results of clinical trials forming the base for pharmacotherapeutic treatment recommendations. Only the results of well-controlled studies will be reviewed. PMID- 26965482 TI - Risperidone in the treatment of psychosis; a concise review. AB - Risperidone (Risperdal(r)) is a recently developed antipsychotic drug with the combination of serotonin-5HT2A-and dopamine-D2-antagonism (SDA). In patients with schizophrenia, risperidone reduces positive symptoms at least equally effective as haloperidol, however, risperidone has a reduced propensity for the induction of extrapyramidal symptoms. In addition, available evidence indicates that risperidone may be an effective treatment for negative symptoms. The optimum daily dose range is between 4 and 8 mgfor most patients. In this review article, risperidone is compared with some other (classical and atypical) neuroleptics. In addition, the pharmacological and pharmacokinetic properties of risperidone are reviewed. PMID- 26965483 TI - Psychological and neurophysiological dysfunctioning during wakefulness in narcolepsy. AB - Memory complaints and altered states of consciousness with automatic behaviour of narcoleptic patients indicate cognitive dysfunctioning. Although more problems arise while performing attention tasks than memory tasks, the neuropsychological test inquiry doesn't indicate one particular neuropsychological function as consistently impaired. They often perform well because they compensate impaired wakefulness by an increased willingness to respond. Neurophysiological research indicates that the sometimes occurring cognitive dysfunction is associated with a waxing and waning between wakefulness and sleep. The increased psychopathology is partly a reflection of, partly a reaction to the symptoms. The impact of hypersomnia on psychosocial functioning is more important than that of epilepsy in epileptics. In severe cases smoking and driving should better be dissuaded. PMID- 26965485 TI - Increased anticipatory contingent negative variation in posttraumatic stress disorder. AB - Altered anticipation processes are implicated across various clinical samples, but few studies focused on the posttraumatic stress disorder (PTSD). We measured contingent negative variation (CNV) in a choice reaction paradigm among 58 survivors of the Wenchuan earthquake, including 28 individuals who were diagnosed with PTSD and 30 without PTSD. Compared to the non-PTSD group, the PTSD group had significantly larger CNV amplitude. On the behavioral level, although the reaction times were comparable between groups, the PTSD group committed more errors than the non-PTSD group. Furthermore, the total PTSD symptom severity score as well as the re-experiencing symptom score were positively related to CNV amplitude. These results suggested that individuals with PTSD might be more alerted to and anticipate more to upcoming events in their environment, yet still have degraded performance in response to the stimulus. PMID- 26965488 TI - Editorial: Signal Transduction, Targeted Therapy and Cancer: From Bench to Clinics. PMID- 26965487 TI - Cement plug technique for the management of disc-associated cervical spondylopathy in 52 Dobermann Pinscher dogs. AB - OBJECTIVES: To report the radiographic and clinical outcome of an intervertebral bone cement plug technique for the management of disc-associated cervical spondylopathy in Dobermann Pinscher dogs. METHODS: Retrospective study of 52 Dobermann Pinscher dogs. RESULTS: A variable degree of cement plug subsidence with loss of vertebral distraction was evident in all dogs (n = 40) that were radiographed >6 weeks postoperatively. In no case was there definitive evidence of vertebral body fusion. Eight dogs had a sudden deterioration in neurological status, cervical hyperaesthesia, or both between three days and 12 weeks following surgery that was considered to be implant-associated; six of these dogs were euthanatized. Following surgery, 43/52 dogs were considered to be neurologically normal or to have improved, however, nine of 43 subsequently deteriorated due to adjacent segment disease. At the long-term follow-up, 34 dogs were considered to be neurologically normal or to have improved. Twenty-nine dogs were dead by the end of the study period. CLINICAL SIGNIFICANCE: Intervertebral bone cement plug surgery results in an initial improvement in clinical signs in the majority of Dobermann Pinschers with disc-associated cervical spondylopathy. However, it fails to maintain vertebral distraction or achieve vertebral body fusion, and is associated with acute implant complications, additional cervical disc protrusions or mortality in a significant proportion of cases. PMID- 26965486 TI - Wax and cutin mutants of Arabidopsis: Quantitative characterization of the cuticular transport barrier in relation to chemical composition. AB - Using (14)C-labeled epoxiconazole as a tracer, cuticular permeability of Arabidopsis thaliana leaves was quantitatively measured in order to compare different wax and cutin mutants (wax2, cut1, cer5, att1, bdg, shn3 and shn1) to the corresponding wild types (Col-0 and Ws). Mutants were characterized by decreases or increases in wax and/or cutin amounts. Permeances [ms(-1)] of Arabidopsis cuticles either increased in the mutants compared to wild type or were not affected. Thus, genetic changes in wax and cutin biosynthesis in some of the investigated Arabidopsis mutants obviously impaired the coordinated cutin and wax deposition at the outer leaf epidermal cell wall. As a consequence, barrier properties of cuticles were significantly decreased. However, increasing cutin and wax amounts by genetic modifications, did not automatically lead to improved cuticular barrier properties. As an alternative approach to the radioactive transport assay, changes in chlorophyll fluorescence were monitored after foliar application of metribuzine, an herbicide inhibiting electron transport in chloroplasts. Since both, half-times of photosynthesis inhibition as well as times of complete inhibition, in fact correlated with (14)C-epoxiconazole permeances, different rates of decline of photosynthetic yield between mutants and wild type must be a function of foliar uptake of the herbicide across the cuticle. Thus, monitoring changes in chlorophyll fluorescence, instead of conducting radioactive transport assays, represents an easy-to-handle and fast alternative evaluating cuticular barrier properties of different genotypes. This article is part of a Special Issue entitled: Plant Lipid Biology edited by Kent D. Chapman and Ivo Feussner. PMID- 26965484 TI - Illness progression in chronic fatigue syndrome: a shifting immune baseline. AB - BACKGROUND: Validation of biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) across data sets has proven disappointing. As immune signature may be affected by many factors, our objective was to explore the shift in discriminatory cytokines across ME/CFS subjects separated by duration of illness. METHODS: Cytokine expression collected at rest across multiple studies for female ME/CFS subjects (i) 18 years or younger, ill for 2 years or less (n = 18), (ii) 18-50 years of age, ill for 7 years (n = 22), and (iii) age 50 years or older (n = 28), ill for 11 years on average. Control subjects were matched for age and body mass index (BMI). Data describing the levels of 16 cytokines using a chemiluminescent assay was used to support the identification of separate linear classification models for each subgroup. In order to isolate the effects of duration of illness alone, cytokines that changed significantly with age in the healthy control subjects were excluded a priori. RESULTS: Optimal selection of cytokines in each group resulted in subsets of IL-1alpha, 6, 8, 15 and TNFalpha. Common to any 2 of 3 groups were IL-1alpha, 6 and 8. Setting these 3 markers as a triple screen and adjusting their contribution according to illness duration sub groups produced ME/CFS classification accuracies of 75-88 %. The contribution of IL-1alpha, higher in recently ill adolescent ME/CFS subjects was progressively less important with duration. While high levels of IL-8 screened positive for ME/CFS in the recently afflicted, the opposite was true for subjects ill for more than 2 years. Similarly, while low levels of IL-6 suggested early ME/CFS, the reverse was true in subjects over 18 years of age ill for more than 2 years. CONCLUSIONS: These preliminary results suggest that IL-1alpha, 6 and 8 adjusted for illness duration may serve as robust biomarkers, independent of age, in screening for ME/CFS. PMID- 26965489 TI - Electrocardiographic and Cardiac Autonomic Indices - Implications of Sex-Specific Risk Stratification in Women After Acute Myocardial Infarction. AB - BACKGROUND: The debate on whether sex-specific predictive models improve risk stratification after myocardial infarction is ongoing. METHODS: This review summarises the current clinical knowledge on sex-specific differences in post infarction risk stratification parameters. Particular focus is given to electrocardiographic risk factors and indices of cardiac autonomic status. RESULTS: Differences in the underlying pathophysiology between men and women are known. However, clinical findings often lead to uncertain conclusions for a number of risk predictors including, among others, resting heart rate, heart rate variability, heart rate turbulence, QT interval duration, and QRS-T angle. The review links recent findings in prognostic parameters with successful approaches in sex-specific non-invasive risk stratification. CONCLUSION: Disparities are described in the current clinical opinions on the relevance of investigated parameters in women and possible directions for further research in the field are given. PMID- 26965490 TI - Barriers to Risk Stratification Accuracy in Ischemic Heart Disease in Women: The Role of Non-Obstructive Coronary Artery Disease. AB - BACKGROUND: A substantial part of literature has been centered on sex differences in the clinical aspects of ischemic heart disease (IHD). Many reports have documented differences in the presentation and risk profile between women and men. Such differences drive sex-related inequalities in the referral and treatment of IHD. Yet data are insufficient to clarify the reasons for such disparities. The objective of this review is to analyze the main gender differences regarding symptoms, diagnosis, and risk stratification of coronary heart disease in order to identify "gaps" in existing literature that need to be addressed in future research efforts. METHODS: We searched English-language studies on MEDLINE and the Cochrane Database of Systematic Reviews from the database start dates to January 2016. Evidence synthesis was based on cohort studies, registry data, and clinical trial data. RESULTS: Women do not often participate in clinical studies. In a number of articles, authors have questioned how the "white male" came to be the prototype of the human research subject. Consequently although many reports continue to describe differential treatment based on patients' sex, the extent to which such inequalities are due to true sex differences in pathophysiology or whether they reflects inaccuracy in risk stratification is unclear. CONCLUSION: Today, even the best database is incapable in and of itself of supplying answers to the question of whether women are being treated less compared with men by the medical community. PMID- 26965491 TI - Polypharmacological Properties and Therapeutic Potential of beta-Caryophyllene: A Dietary Phytocannabinoid of Pharmaceutical Promise. AB - BACKGROUND: beta-Caryophyllene (BCP) is a natural bicyclic sesquiterpene abundantly found in essential oils from various spices, fruits and medicinal as well as ornamental plants. It is approved by United States Food and Drug Administration and European agencies as food additive, taste enhancer and flavoring agent and termed as a phytocannabinoid. METHODS: All the available literature on BCP and its synonyms were collected through different literature databases. RESULTS: BCP was found to elicit a full agonist action on cannabinoid type 2 (CB2) receptors, a G-protein coupled receptor representing important therapeutic target in several diseases. Activation of CB2 receptors notably appeared devoid of psychotropic adverse effect of cannabinoids contrary to the CB1 receptors. In addition, it activates peroxisome proliferated activator receptors (PPARs) isoforms; PPAR-alpha &-gamma and inhibits pathways triggered by the activation of toll like receptor complex; CD14/TLR4/MD2, reduce immuneinflammatory processes and exhibit synergy with u-opioid receptor dependent pathways. Additionally, it found as potent antagonist of homomeric nicotinic acetylcholine receptors (alpha7-nAChRs) and devoid of effects mediated by serotonergic and GABAergic receptors. It also modulates numerous molecular targets by altering their gene expression, signaling pathways or through direct interaction. Various pharmacological activities such as cardioprotective, hepatoprotective, gastroprotective, neuroprotective, nephroprotective, antioxidant, anti-inflammatory, antimicrobial and immune-modulator have been reported in experimental studies. It has shown potent therapeutic promise in neuropathic pain, neurodegenerative and metabolic diseases. CONCLUSION: The present review provides a comprehensive insight of pharmacological and therapeutic potential of BCP, its molecular mechanism and signaling pathways in different pathological conditions. The review also examines the possibility of its further development as a novel candidate for various pathologies considering the polypharmacological and multifaceted therapeutic properties potential along with favorable oral bioavailability, lipophilicity and physicochemical properties. PMID- 26965492 TI - Orange juice consumption and its effect on blood lipid profile and indices of the metabolic syndrome; a randomised, controlled trial in an at-risk population. AB - Data from epidemiological and in vitro studies suggest that orange juice (OJ) may have a positive impact on lipid metabolism. However, there have been reports in the media claiming detrimental consequences of 100% juice consumption, including weight-gain and adverse effects on insulin sensitivity and blood lipid profile. The effect of daily OJ consumption was assessed using a randomised, placebo controlled, single-blinded, parallel group design. Thirty-six overweight, but otherwise healthy men (40-60 years; 27-35 kg m(-2)) with elevated fasting serum cholesterol (5-7 mmol l(-1)), were recruited from the general UK population. None were using nutritional strategies or medication to lower their cholesterol, nor were regular consumers of citrus products. Assessment of BMI, HOMA-IR, and circulating lipid (total cholesterol, low-density lipoprotein, high-density lipoprotein, non-esterified fatty acids, triacylglycerol, apolipoprotein-A1 and apolipoprotein-B) concentrations, was made when fasted before (V1) and after a 12 week intervention (V2), during which participants consumed 250 ml per d of OJ or an energy and sugars-matched orange-flavoured drink (control). The two groups were matched at V1 with respect to all parameters described above. Although triacylglycerol concentration was similar between the groups at both visits, a trend for the change in this variable to differ between groups was observed (P = 0.060), with those in control exhibiting a significant increase in triacylglycerol at V2, compared with V1. In OJ, those with the highest initial triacylglycerol concentration showed the greatest reduction at V2 (R(2) = 0.579; P < 0.001), whereas there was no correlation between these variables in controls (R(2) = 0.023; P = 0.548). Twelve weeks consumption of 250 ml per d of OJ did not adversely affect insulin sensitivity, circulating lipids or body weight. PMID- 26965493 TI - DTDP-rhamnosyl transferase RfbF, is a newfound receptor-related regulatory protein for phage phiYe-F10 specific for Yersinia enterocolitica serotype O:3. AB - Bacteriophages and their hosts are continuously engaged in evolutionary competition. Here we isolated a lytic phage phiYe-F10 specific for Yersinia enterocolitica serotype O:3. We firstly described the phage receptor was regulated by DTDP-rhamnosyl transferase RfbF, encoded within the rfb cluster that was responsible for the biosynthesis of the O antigens. The deletion of DTDP rhamnosyl transferase RfbF of wild type O:3 strain caused failure in phiYe-F10 adsorption; however, the mutation strain retained agglutination with O:3 antiserum; and complementation of its mutant converted its sensitivity to phiYe F10. Therefore, DTDP-rhamnosyl transferase RfbF was responsible for the phage infection but did not affect recognition of Y. enterocolitica O:3 antiserum. Further, the deletions in the putative O-antigen biosynthesis protein precursor and outer membrane protein had no effect on sensitivity to phiYe-F10 infection. However, adsorption of phages onto mutant HNF10-DeltaO-antigen took longer time than onto the WT, suggesting that deletion of the putative O-antigen biosynthesis protein precursor reduced the infection efficiency. PMID- 26965495 TI - Radiographic Severity of Arthritis Affects Functional Outcome in Total Ankle Replacement (TAR). AB - BACKGROUND: It has been previously demonstrated that radiographic severity of arthritis predicts outcome following knee replacement. In certain circumstances, patients may undergo arthroplasty without severe radiographic disease. An example may be the patient with significant chondral damage unsuccessfully treated with arthroscopy. This patient may proceed to joint replacement when their radiographs would not normally merit such intervention. We investigated whether these findings were also applicable to total ankle replacements (TARs). METHODS: We retrospectively reviewed a single-surgeon, single-implant series of 178 TARs in 170 patients. Of them, 124 patients who took part in the hospital joint registry with a minimum 2-year follow-up were included for this study. The radiographic severity of arthritis was graded using the Kellgren-Lawrence classification. Preoperative weight-bearing radiographs were reviewed for severity of arthritis by 2 blinded observers: the first author and an independent colleague from the radiology department. Patients were grouped into 4 subgroups based on degree of severity of radiographic grading for arthritis-A, B, C, and D (for grades 1, 2, 3, and 4 grades, respectively). Data collected included Foot and Ankle Outcome Score (FAOS; pain, function, and stiffness), MOS 36-item Short-Form Health Survey (SF-36) scores, and patient satisfaction scores collected prospectively and at 1 and 2 years postoperation. RESULTS: Groups were similar in terms of demographic data (P > .1) and preoperative FAOS scores (P > .89) for pain, function and stiffness. Group D had the biggest improvement in all domains of FAOS. This reached significance in each domain when compared to group C. No significant differences were demonstrated in SF-36 scores. Overall, 91.1% of patients in group D were satisfied at 2 years, compared with 50.0% of patients in groups A, B, and C (P < .001). In addition, 93.9% of patients in group D felt that their quality of life had been improved by the surgery, compared to 47% of patients with groups A, B, and C (P < .001). Further, 77.3% of patients from group D said they would have the operation again, vs only 52.2% of patients with grade III or less (P = .014). Patients who were "very satisfied" or "somewhat satisfied" postoperatively had an average Kellgren-Lawrence (KL) grade of 3.9 preoperatively. In contrast the "very dissatisfied" and "somewhat dissatisfied" patients had an average KL grade of 2.9 (P < .05). CONCLUSION: Although this study does not explain all of the dissatisfaction in TAR, radiologic severity is an important factor that surgeons must consider when planning how best to treat their patients. There may be a different pathophysiology in this patient group that is not well served by arthroplasty. LEVEL OF EVIDENCE: Level III, retrospective comparative series. PMID- 26965496 TI - Characterization of chemical-induced sterile inflammation in vitro: application of the model compound ketoconazole in a human hepatic co-culture system. AB - Liver injury as a result of a sterile inflammation is closely linked to the activation of immune cells, including macrophages, by damaged hepatocytes. This interaction between immune cells and hepatocytes is as yet not considered in any of the in vitro test systems applied during the generation of new drugs. Here, we established and characterized a novel in vitro co-culture model with two human cell lines, HepG2 and differentiated THP-1. Ketoconazole, an antifungal drug known for its hepatotoxicity, was used as a model compound in the testing of the co-culture. Single cultures of HepG2 and THP-1 cells were studied as controls. Different metabolism patterns of ketoconazole were observed for the single and co culture incubations as well as for the different cell types. The main metabolite N-deacetyl ketoconazole was found in cell pellets, but not in supernatants of cell cultures. Global proteome analysis showed that the NRF2-mediated stress response and the CXCL8 (IL-8) pathway were induced by ketoconazole treatment under co-culture conditions. The upregulation and ketoconazole-induced secretion of several pro-inflammatory cytokines, including CXCL8, TNF-alpha and CCL3, was observed in the co-culture system only, but not in single cell cultures. Taking together, we provide evidence that the co-culture model applied might be suitable to serve as tool for the prediction of chemical-induced sterile inflammation in liver tissue in vivo. PMID- 26965497 TI - The wrong end of the telescope: neuromuscular mimics of movement disorders (and vice versa). AB - The rapid advances in modern neurology have led to increased specialisation in clinical practice. Being an expert in a neurology subspecialty offers advantages for diagnosing and managing specific disorders. However, specialisation also risks tunnel vision: interpreting symptoms and signs within one's own framework of reference, while ignoring differential diagnostic options from other subspecialties. This is particularly relevant when the patient's presentation potentially belongs to different neurological subspecialties. We illustrate this challenge by highlighting a series of clinical features that partially overlap between two common subspecialties: movement disorders and neuromuscular disorders. An overlap in clinical presentation is not rare, and includes, for example, involuntary eyelid closure (which could be active eye closure due to blepharospasm, or ptosis due to weakness). Other overlapping features include abnormal postures, involuntary movements and gait changes. We describe two of these overlapping features in more detail and emphasise the possible consequences of 'looking through the wrong end of the telescope' in such patients, as this may lead to a wrong differential diagnosis, unnecessary investigations and a delayed treatment start. PMID- 26965494 TI - Neurochemical modulation involved in the beneficial effect of liraglutide, GLP-1 agonist on PTZ kindling epilepsy-induced comorbidities in mice. AB - Epilepsy is a neurological disorder which occurs due to excessive firing of excitatory neurons in specific region of brain and associated with cognitive impairment and depression. GLP-1 has been reported to maintain hyperexcitability of neurons. Therefore, this study was designed to investigate the neuroprotective effect of liraglutide, GLP-1 analogue in PTZ kindling epilepsy-induced comorbidities and neurochemical alteration in mice. Male albino mice were administered PTZ (35 mg/kg) on every alternate day up to 29th days and challenge test was performed on 33rd day. From 1st day liraglutide (75 and 150 ug/kg) and diazepam (3 mg/kg) were administered up to 33rd day, 30 min prior to PTZ treatment. On 30th day animals were trained on elevated plus maze and passive shock avoidance paradigm and retention was recorded on 31st and 33rd day. On 32nd day tail suspension test was performed. Animals were sacrificed on 34th day for biochemical (LPO, GSH, and nitrite) and neurotransmitters (GABA, glutamate, DA, NE, 5-HT and their metabolites) estimation. Chronic treatment with PTZ developed generalized tonic-clonic seizures, reduced cognitive skills, increased oxidative stress and alteration in the level of neurotransmitters. Pre-treatment with liraglutide (75 and 150 MUg/kg) significantly prevented the seizure severity, restored behavioural activity, oxidative defence enzymes, and altered level of neurochemicals in mice brain. The protective effect of liraglutide is attributed to restoration of altered level of GABA, glutamate, DA, NE, and 5-HT by the up regulation of GLP-1Rs in mice brain. PMID- 26965498 TI - Trapped without a diagnosis: Tumour necrosis factor receptor-associated periodic syndrome (TRAPS). AB - Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant condition caused by mutations in the TNFRSF1A gene. It is characterised by recurrent episodes of myalgia, followed by prolonged fever, migratory rashes, headache, serositis, arthralgia, abdominal pain and periorbital oedema. We describe a 49-year-old man with a self-limiting episode of paraparesis who reported recurrent bouts of abdominal symptoms and headaches since childhood. He had a persistent inflammatory response with night sweats and weight loss. We diagnosed TRAPS 2 years after having identified a TNFRSF1A gene mutation. His symptoms and inflammatory response resolved dramatically with the interleukin-1 receptor antagonist anakinra. PMID- 26965499 TI - Adherence to Cancer Prevention Guidelines and Cancer Risk in Low-Income and African American Populations. AB - BACKGROUND: The American Cancer Society (ACS) publishes behavioral guidelines for cancer prevention, including standards on body weight, physical activity, nutrition, alcohol, and tobacco use. The impact of these guidelines has been rarely studied in low-income and African American populations. METHODS: The study included 61,098 racially diverse, mainly low-income adults who participated in the Southern Community Cohort Study and were followed for a median of 6 years. Cox models were used to estimate HRs for cancer incidence associated with behaviors and with an ACS physical activity/nutrition 0-to-4 compliance score indicating the number of body weight, physical activity, healthy eating, and alcohol guidelines met. RESULTS: During the study period, 2,240 incident cancers were identified. Significantly lower cancer incidence was found among never smokers and non/moderate alcohol drinkers, but not among those meeting guidelines for obesity, physical activity, and diet. The ACS compliance score was inversely associated with cancer risk among the 25,509 participants without baseline chronic disease. HRs for cancer incidence among those without baseline chronic diseases and who met one, two, three, or four guidelines versus zero guidelines were 0.93 (95% confidence intervals, 0.71-1.21), 0.85 (0.65-1.12), 0.70 (0.51 0.97), and 0.55 (0.31-0.99), respectively. Associations were consistent in analyses stratified by sex, race, household income, and smoking status. CONCLUSIONS: Meeting the ACS smoking and body weight/physical activity/dietary/alcohol guidelines for cancer prevention is associated with reductions in cancer incidence in low-income and African American populations. IMPACT: This study provides strong evidence supporting lifestyle modification to lower cancer incidence in these underserved populations. Cancer Epidemiol Biomarkers Prev; 25(5); 846-53. (c)2016 AACR. PMID- 26965500 TI - Surgical treatment of neglected congenital idiopathic talipes equinovarus after walking age in Eritrea: an Italo-Eritrean cooperation. AB - An Italian team of orthopaedic surgeons joined Eritrean colleagues to perform a clinical study in ambulating children affected by neglected idiopathic congenital talipes equinovarus (clubfoot). This study reports the surgical strategy as well as clinical outcomes, early complications and relapse at a mid-term follow-up. Four expeditions of 7 days were organized between 2012 and 2015 from Italy to the Halibet Hospital of Asmara in Eritrea. In each expedition were included two experienced surgeons, two assistants and one anaesthesiologist. During these expeditions, a total of 468 patients were evaluated together with Eritrean colleagues and 45 cases of neglected talipes equinovarus in ambulating children were diagnosed and selected for surgery. Follow-up range was 1-3 years. During the four expeditions, the Eritrean team of orthopaedic surgeons learned to manage most cases of neglected talipes equinovarus. No major complications were reported. Sixteen feet were considered excellent, 25 good and four poor. No overcorrections were observed. Neglected congenital talipes equinovarus is the result of delayed treatment of congenital deformity in developing countries, and its treatment often requires extensive surgery. Collaboration with foreign expert surgeons may help local doctors to learn how to treat this disease. The current study demonstrates that surgical expeditions in developing countries, when organized in collaboration with local doctors, help to manage on site this severe deformity. PMID- 26965502 TI - Repeat fine-needle aspiration can be performed at 6 months or more after initial atypia of undetermined significance or follicular lesion of undetermined significance results for thyroid nodules 10 mm or larger. AB - OBJECTIVES: To investigate whether repeat ultrasound-guided fine-needle aspiration (US-FNA) in initial atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) results could be performed 6 months after or more. METHODS: A total of 221 AUS/FLUS >=10 mm with any follow-up were grouped according to the first follow-up interval at less than 6 months (group 1, n = 87) and 6 months or more (group 2, n = 134). Clinical features, final assessment of ultrasound (US) or the Thyroid Imaging Reporting and Data System (TIRADS), tumour size, extrathyroidal extension and lymph node metastasis in malignancies were compared. RESULTS: Thirty-four (15.4 %) were malignant. Age, gender, size, final assessment, TIRADS and malignancy rate were not significantly different between the two groups (p = 0.660, 0.691, 0.502, 0.237, 0.819 and 0.420). Tumour size, extrathyroidal extension and lymph node metastasis were not significantly different between the two malignancy groups (p = 0.770, 0.611 and 0.068). Two of 10 nodules with increased size were malignancies found at 7.1 and 25.0 months. None of 33 nodules (14.9 %) with decreased size at a median 10 months were malignant. CONCLUSIONS: Repeat US-FNA performed on nodules >=10 mm at 6 months or more after initial AUS/FLUS results can reduce unnecessary repeat US FNAs without progression of malignancy. KEY POINTS: * Follow-up intervals of AUS/FLUS did not affect the malignancy rate * Tumour stage was not different according to the follow-up intervals * None of the nodules with decreased size were malignant * Repeat US-FNA can be performed at >=6 months after initial AUS/FLUS. PMID- 26965501 TI - Survival evaluation of the patients with diabetic major lower-extremity amputations. AB - PURPOSE: The purpose of this study was to evaluate the survival after major lower limb amputation, at a level either below (BKA) or above (AKA) the knee, in diabetic patients. METHODS: A total of 140 diabetic patients who underwent major lower-limb amputation during the period of 2001-2011 were enrolled in the study. The patients were grouped as below-knee and above-knee amputations. The differences in survival by age, gender, amputation level and revision surgery were investigated. The clinical follow-up periods and the results of the patients with major lower-limb amputation were retrospectively assessed. RESULTS: The mean follow-up period was 24.87 months (range 0.06-120 months). The mortality rate of series was 32.8 % for 1 year and 70 % for 5 years. One-year mortality rate was 24.6 % and 5-year mortality rate was 66.3 % in below-knee group, 1-year mortality rate was 43.3 % and 5-year mortality rate was 83.3 % in above-knee group. The difference between mortality rates of these groups was significant (p: 0.019). There was no statistically significant difference according to age and gender (p: 0.543 and 0.568). The previous minor amputations were found to have no effect on mortality (p: 0.471). CONCLUSION: Routine utilization of diabetes follow-up, screening and treatment programs with a multidisciplinary approach might be mandatory to handle early multisystem involvement-prevent major amputation, and increase survival rate in diabetic patients. LEVEL OF EVIDENCE: Retrospective cohort study, Level III. PMID- 26965503 TI - Multidetector CT of pancreatic ductal adenocarcinoma: Effect of tube voltage and iodine load on tumour conspicuity and image quality. AB - OBJECTIVES: To compare a low-tube-voltage with or without high-iodine-load multidetector CT (MDCT) protocol with a normal-tube-voltage, normal-iodine-load (standard) protocol in patients with pancreatic ductal adenocarcinoma (PDAC) with respect to tumour conspicuity and image quality. METHODS: Thirty consecutive patients (mean age: 66 years, men/women: 14/16) preoperatively underwent triple phase 64-channel MDCT examinations twice according to: (i) 120-kV standard protocol (PS; 0.75 g iodine (I)/kg body weight, n = 30) and (ii) 80-kV protocol A (PA; 0.75 g I/kg, n = 14) or protocol B (PB; 1 g I/kg, n = 16). Two independent readers evaluated tumour delineation and image quality blindly for all protocols. A third reader estimated the pancreas-to-tumour contrast-to-noise ratio (CNR). Statistical analysis was performed with the Chi-square test. RESULTS: Tumour delineation was significantly better in PB and PA compared with PS (P = 0.02). The evaluation of image quality was similar for the three protocols (all, P > 0.05). The highest CNR was observed with PB and was significantly better compared to PA (P = 0.02) and PS (P = 0.0002). CONCLUSION: In patients with PDAC, a low tube-voltage, high-iodine-load protocol improves tumour delineation and CNR leading to higher tumour conspicuity compared to standard protocol MDCT. KEY POINTS: * Low-tube-voltage high-iodine-load MDCT improves pancreatic cancer conspicuity compared to a standard protocol. * The pancreas-to-tumour attenuation difference increases significantly by reducing the tube voltage. * The radiation exposure dose decreases by reducing the tube voltage. PMID- 26965506 TI - Erratum to: Genome-wide analysis and expression patterns of ZF-HD transcription factors under different developmental tissues and abiotic stresses in Chinese cabbage. PMID- 26965505 TI - Differentiation of human mesenchymal stromal cells cultured on collagen sponges for cartilage repair. AB - AIM: The aim of this study was to evaluate proliferation and chondrogenic differentiation of human bone-marrow mesenchymal stromal cells (hBMSCs) cultured on collagen biomaterials. MATERIALS AND METHODS: hBMSCs were seeded on five different collagen (Col) sponges: C1C2 (types I and II Col), C1C2HS (types I and II Col plus heparan sulphate (HS)), C1C2CHS (types I and II Col plus chondroitin sulphate (CHS)), C1-OLH3 (type I Col plus low molecular weight heparin) and C1CHS (type I Col plus CHS). The resulting constructs were analyzed by histological and immunohistochemical staining, molecular biology and electron microscopy. Col released into culture media was measured by a dye-binding method Results: hBMSCs on biomaterials C1C2, C1C2HS and C1C2CHS had more capacity to attach, proliferate and synthesize Col II and proteoglycans in the extracellular matrix (ECM) than on C1-OLH3 and C1CHS. The presence of aggrecan was detected only at the gene level. Total Col liberated by the cells in the supernatants in all scaffold cultures was detected. The level of Col I in the ECM was lower in C1-OLH3 and that of Col II was highest in C1C2 and C1C2HS. Electron microscopy showed differently shaped cells, from rounded to flattened, in all constructs. Col fibers in bundles were observed in C1C2CHS by transmission electron microscopy. CONCLUSIONS: The results show that Col I and Col II (C1C2, C1C2HS and C1C2CHS) biomaterials allowed cell proliferation and chondrogenic-like differentiation of hBMSCs at an early stage. Constructs cultured on C1C2HS and C1C2CHS showed better cartilage-like phenotype than the other ones. PMID- 26965507 TI - Telomere length change plateaus at 4 years of age in Latino children: associations with baseline length and maternal change. AB - Telomeres are the protective complexes at the end of chromosomes, required for genomic stability. Little is known about predictors of attrition in young children or the relationship between parental and child patterns of telomere change. Telomere length was assessed twice over one year, at 4 and at 5 years of age, in Latino preschool children (n = 77) and their mothers (n = 70) in whole blood leukocytes. Maternal and child rates of attrition during the same time period were compared in 70 mother-child pairs. More children showed lengthened telomeres over one year compared to their mothers and very few children showed attrition (2.6 %). Approximately 31 % of children and 16 % of mothers displayed lengthening over one year while 66 % of children showed maintenance in contrast with 74 % of mothers. The strongest predictor for child telomere length change was child's baseline telomere length (r = -0.61, p < 0.01). Maternal rate of change was associated with child rate of change (r = 0.33, p < 0.01). After controlling for child baseline telomere length, the relationship between child and maternal rate of change trended towards significance (Coeff = 0.20, 95 % CI 0.03 to 0.43; p = 0.08). We found primarily maintenance and lengthening from 4 to 5 years of age in children, with minimal telomere attrition, indicating that most of the telomere loss happens in the first 4 years, plateauing by age 4. Lastly, we found close to 10 % of the variance in rate of change in children shared by mothers. While some of this shared variance is genetic, there are likely environmental factors that need to be further identified that impact rate of telomere length change. PMID- 26965508 TI - High-resolution genetic linkage mapping, high-temperature tolerance and growth related quantitative trait locus (QTL) identification in Marsupenaeus japonicus. AB - The Kuruma prawn, Marsupenaeus japonicus, is one of the most promising marine invertebrates in the industry in Asia, Europe and Australia. However, the increasing global temperatures result in considerable economic losses in M. japonicus farming. In the present study, to select genetically improved animals for the sustainable development of the Kuruma prawn industry, a high-resolution genetic linkage map and quantitative trait locus (QTL) identification were performed using the RAD technology. The maternal map contained 5849 SNP markers and spanned 3127.23 cM, with an average marker interval of 0.535 cM. Instead, the paternal map contained 3927 SNP markers and spanned 3326.19 cM, with an average marker interval of 0.847 cM. The consensus map contained 9289 SNP markers and spanned 3610.90 cM, with an average marker interval of 0.388 cM and coverage of 99.06 % of the genome. The markers were grouped into 41 linkage groups in the maps. Significantly, negative correlation was detected between high-temperature tolerance (UTT) and body weight (BW). The QTL mapping revealed 129 significant QTL loci for UTT and four significant QTL loci for BW at the genome-wide significance threshold. Among these QTLs, 129 overlapped with linked SNPs, and the remaining four were located in regions between contiguous SNPs. They explained the total phenotypic variance ranging from 8.9 to 12.4 %. Because of a significantly negative correlation between growth and high-temperature tolerance, we demonstrate that this high-resolution linkage map and QTLs would be useful for further marker-assisted selection in the genetic improvement of M. japonicus. PMID- 26965504 TI - Combining standardized uptake value of FDG-PET and apparent diffusion coefficient of DW-MRI improves risk stratification in head and neck squamous cell carcinoma. AB - OBJECTIVES: To assess the independent prognostic value of standardized uptake value (SUV) and apparent diffusion coefficient (ADC), separately and combined, in order to evaluate if the combination of these two variables allows further prognostic stratification of patients with head and neck squamous cell carcinomas (HNSCC). METHODS: Pretreatment SUV and ADC were calculated in 57 patients with HNSCC. Mean follow-up was 21.3 months. Semiquantitative analysis of primary tumours was performed using SUVmaxT/B, ADCmean, ADCmin and ADCmax. The prognostic value of SUVmaxT/B, ADCmean, ADCmin and ADCmax in predicting disease-free survival (DFS) was evaluated with log-rank test and Cox regression models. RESULTS: Patients with SUVmaxT/B >=5.75 had an overall worse prognosis (p = 0.003). After adjusting for lymph node status and diameter, SUVmaxT/B and ADCmin were both significant predictors of DFS with hazard ratio (HR) = 10.37 (95 % CI 1.22-87.95) and 3.26 (95 % CI 1.20-8.85) for SUVmaxT/B >=5.75 and ADCmin >=0.58 * 10-3 mm2/s, respectively. When the analysis was restricted to subjects with SUVmaxT/B >=5.75, high ADCmin significantly predicted a worse prognosis, with adjusted HR = 3.11 (95 % CI 1.13-8.55). CONCLUSIONS: The combination of SUVmaxT/B and ADCmin improves the prognostic role of the two separate parameters; patients with high SUVmaxT/B and high ADCmin are associated with a poor prognosis. KEY POINTS: * High SUV maxT/B is a poor prognostic factor in HNSCC * High ADC min is a poor prognostic factor in HNSCC * In patients with high SUV maxT/B , high ADC min identified those with worse prognosis. PMID- 26965509 TI - Reproducibility and regional variations of an improved gagCEST protocol for the in vivo evaluation of knee cartilage at 7 T. AB - OBJECTIVE: The objective was to establish a gagCEST protocol that would enable robust and reproducible assessment of the glycosaminoglycan (GAG) content in knee cartilage at 7 T within a clinically feasible measurement time. MATERIALS AND METHODS: Ten young healthy volunteers (mean age 26 years, range 24-28, five males, five females) were examined on a 7 T MR system. Informed consent was obtained from all individual participants prior to enrollment into the study. Each volunteer was measured twice for reproducibility assessment. The examined knee was immobilized using a custom-made fixation device. For the gagCEST measurement, a prototype segmented 3-D RF-spoiled gradient-echo sequence with an improved saturation scheme employing adiabatic pulses was used in a scan time of 19 min. The asymmetry of the Z-spectra (MTRasym) in selected regions of interest in knee cartilage was calculated. Differences in MTRasym between different regions were evaluated using ANOVA and the Bonferroni corrected post hoc test. RESULTS: The improvement of the saturation scheme reduced the influence of field inhomogeneities, resulted in more uniform saturation, and allowed for good reproducibility in a reasonable measurement time (19 min), as demonstrated by an intraclass correlation coefficient of 0.77. Improved fixation helped to reduce motion artifacts. Whereas similar MTRasym values were found for weight-bearing and non-weight-bearing femoral cartilage, lower values were observed in the trochlear groove (p = 0.028), patellar (p = 0.015) and tibial cartilage (p < 0.001) when compared to non-weight-bearing femoral cartilage. CONCLUSION: Reasonable reproducibility and sensitivity to regional differences in GAG content suggests that the improved gagCEST protocol might be useful for assessing the biochemical changes in articular cartilage that are associated with early stages of cartilage degeneration. PMID- 26965511 TI - Amide proton transfer (APT) magnetic resonance imaging of prostate cancer: comparison with Gleason scores. AB - OBJECTIVE: To evaluate the utility of amide proton transfer (APT) imaging in estimating the Gleason score (GS) of prostate cancer (Pca). MATERIALS AND METHODS: Sixty-six biopsy-proven cancers were categorized into four groups according to the GS: GS-6 (3 + 3); GS-7 (3 + 4/4 + 3); GS-8 (4 + 4) and GS-9 (4 + 5/5 + 4). APT signal intensities (APT SIs) and apparent diffusion coefficient (ADC) values of each GS group were compared by one-way analysis of variance with Tukey's HSD post hoc test. RESULTS: The mean and standard deviation of the APT SIs (%) and ADC values (*10(-3) mm(2)/s) were as follows: GS-6, 2.48 +/- 0.59 and 1.16 +/- 0.26; GS-7, 5.17 +/- 0.66 and 0.92 +/- 0.18; GS-8, 2.56 +/- 0.85 and 0.86 +/- 0.17; GS-9, 1.96 +/- 0.75 and 0.85 +/- 0.18, respectively. The APT SI of the GS-7 group was highest, and there were significant differences between the GS 6 and GS-7 groups and the GS-7 and GS-9 groups (p < 0.05). The ADC value of the GS-6 group was significantly higher than each value of the GS-7, GS-8, and GS-9 groups (p < 0.05), but no significant differences were obtained among the GS-7, GS-8, and GS-9 groups. CONCLUSION: The mean APT SI in Pca with a GS of 7 was higher than that for the other GS groups. PMID- 26965510 TI - Endoluminal high-resolution MR imaging protocol for colon walls analysis in a mouse model of colitis. AB - OBJECTIVE: An endoluminal magnetic resonance (MR) imaging protocol including the design of an endoluminal coil (EC) was defined for high-spatial-resolution MR imaging of mice gastrointestinal walls at 4.7 T. MATERIALS AND METHODS: A receive only radiofrequency single-loop coil was developed for mice colon wall imaging. Combined with a specific protocol, the prototype was first characterized in vitro on phantoms and on vegetables. Signal-to-noise ratio (SNR) profiles were compared with a quadrature volume birdcage coil (QVBC). Endoluminal MR imaging protocol combined with the EC was assessed in vivo on mice. RESULTS: The SNR measured close to the coil is significantly higher (10 times and up to 3 mm of the EC center) than the SNR measured with the QVBC. The gain in SNR can be used to reduce the in-plane pixel size up to 39 * 39 um(2) (234 um slice thickness) without time penalty. The different colon wall layers can only be distinguished on images acquired with the EC. CONCLUSION: Dedicated EC provides suitable images for the assessment of mice colon wall layers. This proof of concept provides gains in spatial resolution and leads to adequate protocols for the assessment of human colorectal cancer, and can now be used as a new imaging tool for a better understanding of the pathology. PMID- 26965513 TI - Surgery for prosthetic valve endocarditis: associations between morbidity, mortality and costs. AB - OBJECTIVES: Surgery for prosthetic valve endocarditis (PVE) is associated with significant morbidity and mortality as well as with increased resource utilization and costs. For risk and cost reduction, an understanding of contributing factors and interrelations is essential. METHODS: Out of 1080 heart valve procedures performed between January 2010 and December 2012, 41 patients underwent surgery for PVE. Complete economic data were available for 30 of them (study cohort). The patients' mean age was 64 +/- 12 years (range 37-79 years), and 73% were men. The clinical course was reviewed and morbidity, mortality and costs as well as associations between them were analysed. The cost matrix for each individual patient was obtained from the Institute for the Hospital Remuneration System (InEK GmbH, Germany). The median follow-up was 2.6 years [interquartile range (IQR) 3.7 years; 100% complete]. RESULTS: Preoperative status was critical (EuroSCORE II >20%) in 43% of patients. Staphylococci were the most common infecting micro-organisms (27%). The operative mortality rate (<=30 days) was 17%. At 1 year, the overall survival rate was 71 +/- 9%. At least one disease- or surgery-related complication affected 21 patients (early morbidity 70%), >1 complication affected 12 patients (40%). There was neither a recurrence of endocarditis, nor was a reoperation required. The mean total hospital costs were 42.6 +/- 37.4 Thousand Euro (T?), median 25.7 T?, IQR 28.4 T? and >100 T? in 10% of cases. Intensive care unit/intermediate care (ICU/IMC) and operation accounted for 40.4 +/- 18.6 and 25.7 +/- 12.1% of costs, respectively. There was a significant correlation (Pearson's sample correlation coefficient) between total costs and duration of hospital stay (r = 0.83, P < 0.001) and between ICU/IMC costs and duration of ICU/IMC stay (r = 0.97, P < 0.001). The median daily hospital costs were 1.8 T?/day, but >2.4 T?/day in 25% of patients (upper quartile). The following pattern of associations was identified (P < 0.05). Early mortality was related to preoperative morbidity and postoperative renal failure. Early morbidity was associated with preoperative morbidity and urgency. Total costs were mainly explained by preoperative morbidity, postoperative morbidity and urgency. High EuroSCORE II, complex surgery, need for mechanical circulatory support as well as postoperative mortality and morbidity increased daily costs. CONCLUSIONS: The timely diagnosis and treatment of these patients must be a priority, as preoperative morbidity is the major contributor towards mortality, morbidity and costs after surgery for PVE. PMID- 26965512 TI - Improving the clinical potential of ultra-high field fMRI using a model-free analysis method based on response consistency. AB - OBJECTIVE: To develop an analysis method that is sensitive to non-model-conform responses often encountered in ultra-high field presurgical planning fMRI. Using the consistency of time courses over a number of experiment repetitions, it should exclude low quality runs and generate activation maps that reflect the reliability of responses. MATERIALS AND METHODS: 7 T fMRI data were acquired from six healthy volunteers: three performing purely motor tasks and three a visuomotor task. These were analysed with the proposed approach (UNBIASED) and the GLM. RESULTS: UNBIASED results were generally less affected by false positive results than the GLM. Runs that were identified as being of low quality were confirmed to contain little or no activation. In two cases, regions were identified as activated in UNBIASED but not GLM results. Signal changes in these areas were time-locked to the task, but were delayed or transient. CONCLUSION: UNBIASED is shown to be a reliable means of identifying consistent task-related signal changes regardless of response timing. In presurgical planning, UNBIASED could be used to rapidly generate reliable maps of the consistency with which eloquent brain regions are activated without recourse to task timing and despite modified hemodynamics. PMID- 26965515 TI - Addendum to Abstracts presented at the 14th International Congress on Amino Acids, Peptides and Proteins. PMID- 26965514 TI - A clinically relevant pharmacokinetic interaction between cyclosporine and imatinib. AB - PURPOSE: Cyclosporine A (CsA) and imatinib are both CYP3A4 and P-glycoprotein substrates. Concomitant use after hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (ALL) may therefore result in a pharmacokinetic interaction. Although case reports and a recent small study in children indeed suggested there is a relevant pharmacokinetic interaction, a larger study in adults is lacking. In this study, we assessed the presence and extent of this interaction in patients with CML or Ph+ ALL undergoing HSCT. METHODS: From a large database containing data of all patients receiving HSCT in our center between 2005 and 2015, we selected 16 patients using this drug combination. The average dose-corrected CsA concentration was calculated before and after initiation of imatinib. RESULTS: The average dose-corrected CsA concentration increased during imatinib use in all patients, on average by 94 % (p < 0.001). Based on measured drug concentrations, the CsA dosage needed to be reduced, on average, by 27 % after initiation of imatinib (p = 0.004). CONCLUSIONS: Imatinib significantly increases CsA concentrations in HSCT patients, putting these patients at increased risk of CsA toxicity. We recommend intensive monitoring of CsA concentrations after initiation of imatinib; a pre-emptive CsA dose reduction of 25 % might be considered. PMID- 26965517 TI - Core Fucosylation on T Cells, Required for Activation of T-Cell Receptor Signaling and Induction of Colitis in Mice, Is Increased in Patients With Inflammatory Bowel Disease. AB - BACKGROUND & AIMS: Attachment of a fucose molecule to the innermost N-glycan in a glycoprotein (core fucosylation) regulates the activity of many growth factor receptors and adhesion molecules. The process is catalyzed by alpha1-6 fucosyltransferase (FUT8) and required for immune regulation, but it is not clear whether this process is dysregulated during disease pathogenesis. We investigated whether core fucosylation regulates T-cell activation and induction of colitis in mice, and is altered in patients with inflammatory bowel disease (IBD). METHODS: Biopsy samples were collected from inflamed and noninflamed regions of intestine from patients (8 with Crohn's disease, 4 with ulcerative colitis, and 4 without IBD [controls]) at Osaka University Hospital. Colitis was induced in FUT8 deficient (Fut8(-/-)) mice and Fut8(+/+) littermates by administration of trinitrobenzene sulfonic acid. Intestinal tissues were collected and analyzed histologically. Immune cells were collected and analyzed by lectin flow cytometry, immunofluorescence, and reverse-transcription polymerase chain reaction, as well as for production of cytokines and levels of T-cell receptor (TCR) in lipid raft fractions. T-cell function was analyzed by intraperitoneal injection of CD4(+)CD62L(+) naive T cells into RAG2-deficient mice. RESULTS: Levels of core fucosylation were increased on T cells from mice with colitis, compared with mice without colitis, as well as on inflamed mucosa from patients with IBD, compared with their noninflamed tissues or tissues from control patients. Fut8(-/-) mice developed less-severe colitis than Fut8(+/+) mice, and T cells from Fut8(-/-) mice produced lower levels of T-helper 1 and 2 cytokines. Adoptive transfer of Fut8(-/-) T cells to RAG2-deficient mice reduced the severity of colitis. Compared with CD4(+) T cells from Fut8(+/+) mice, those from Fut8(-/-) mice expressed similar levels of TCR and CD28, but these proteins did not contain core fucosylation. TCR complexes formed on CD4(+) T cells from Fut8( /-) mice did not signal properly after activation and were not transported to lipid rafts. CONCLUSIONS: Core fucosylation of the TCR is required for T-cell signaling and production of inflammatory cytokines and induction of colitis in mice. Levels of TCR core fucosylation are increased on T cells from intestinal tissues of patients with IBD; this process might be blocked as a therapeutic strategy. PMID- 26965518 TI - Reversible normalisation of serum TSH levels in patients with autoimmune atrophic gastritis who received L-T4 in tablet form after switching to an oral liquid formulation: a case series. AB - BACKGROUND: L-thyroxine (L-T4) malabsorption is a potential concern in patients with autoimmune atrophic gastritis. METHODS: We evaluated five patients with autoimmune gastritis, who showed high serum thyrotropin (TSH) levels (in the hypothyroid range) while in therapy with L-T4 in tablet. All patients were switched to receive an oral L-T4 liquid formulation maintaining the same dosage. RESULTS: In all patients who received L-T4 in tablet form after switching to an oral liquid formulation with the same L-T4 dosage, TSH circulating levels were normalized. In four patients who were switched back again to receive L-T4 in tablets, maintaining the dosage, TSH levels worsened again reaching levels in the hypothyroid range. CONCLUSIONS: The fact that the change from tablets to liquid oral formulation normalised serum TSH levels, and that switching back to tablets caused thyrotropin levels to worsen, leads us to believe that absorption of L-T4 is greater with oral liquid formulations in these patients. These results suggest that the L-T4 oral liquid formulation could circumvent the pH alteration resulting from atrophic gastritis. PMID- 26965519 TI - A model for preemptive maintenance of medical linear accelerators-predictive maintenance. AB - BACKGROUND: Unscheduled accelerator downtime can negatively impact the quality of life of patients during their struggle against cancer. Currently digital data accumulated in the accelerator system is not being exploited in a systematic manner to assist in more efficient deployment of service engineering resources. The purpose of this study is to develop an effective process for detecting unexpected deviations in accelerator system operating parameters and/or performance that predicts component failure or system dysfunction and allows maintenance to be performed prior to the actuation of interlocks. METHODS: The proposed predictive maintenance (PdM) model is as follows: 1) deliver a daily quality assurance (QA) treatment; 2) automatically transfer and interrogate the resulting log files; 3) once baselines are established, subject daily operating and performance values to statistical process control (SPC) analysis; 4) determine if any alarms have been triggered; and 5) alert facility and system service engineers. A robust volumetric modulated arc QA treatment is delivered to establish mean operating values and perform continuous sampling and monitoring using SPC methodology. Chart limits are calculated using a hybrid technique that includes the use of the standard SPC 3sigma limits and an empirical factor based on the parameter/system specification. RESULTS: There are 7 accelerators currently under active surveillance. Currently 45 parameters plus each MLC leaf (120) are analyzed using Individual and Moving Range (I/MR) charts. The initial warning and alarm rule is as follows: warning (2 out of 3 consecutive values >= 2sigma hybrid) and alarm (2 out of 3 consecutive values or 3 out of 5 consecutive values >= 3sigma hybrid). A customized graphical user interface provides a means to review the SPC charts for each parameter and a visual color code to alert the reviewer of parameter status. Forty-five synthetic errors/changes were introduced to test the effectiveness of our initial chart limits. Forty-three of the forty five errors (95.6 %) were detected in either the I or MR chart for each of the subsystems monitored. CONCLUSION: Our PdM model shows promise in providing a means for reducing unscheduled downtime. Long term monitoring will be required to establish the effectiveness of the model. PMID- 26965520 TI - Obituary: A Remembrance of Robert S. Siffert MD (1918-2015). PMID- 26965522 TI - Uncovering the mystery of Ebola virus entry: Lock and key. PMID- 26965521 TI - An exceptional fossil skull from South America and the origins of the archosauriform radiation. AB - Birds, dinosaurs, crocodilians, pterosaurs and their close relatives form the highly diverse clade Archosauriformes. Archosauriforms have a deep evolutionary history, originating in the late Permian, prior to the end-Permian mass extinction, and radiating in the Triassic to dominate Mesozoic ecosystems. However, the origins of this clade and its extraordinarily successful body plan remain obscure. Here, we describe an exceptionally preserved fossil skull from the Lower Triassic of Brazil, representing a new species, Teyujagua paradoxa, transitional in morphology between archosauriforms and more primitive reptiles. This skull reveals for the first time the mosaic assembly of key features of the archosauriform skull, including the antorbital and mandibular fenestrae, serrated teeth, and closed lower temporal bar. Phylogenetic analysis recovers Teyujagua as the sister taxon to Archosauriformes, and is congruent with a two-phase model of early archosauriform evolution, in response to two mass extinctions occurring at the end of the Guadalupian and the Permian. PMID- 26965523 TI - Establishing guidelines for CAR-T cells: challenges and considerations. AB - T cells, genetically modified by chimeric antigen receptors (CAR-T), are endowed with specificity to a desired antigen and are cytotoxic to cells expressing the targeted antigen. CAR-T-based cancer immunotherapy is a promising therapy for curing hematological malignancy, such as acute lymphoid leukemia, and is promising for extending their efficacy to defeat solid tumors. To date, dozens of different CAR-T cells have been evaluated in clinical trials to treat tumors; this necessitates the establishment of guidelines for the production and application of CAR-T cells. However, it is challenging to standardize CAR-T cancer therapy because it involves a combination of gene therapy and cell therapy. In this review, we compare the existing guidelines for CAR-T cells and discuss the challenges and considerations for establishing guidance for CAR-T based cancer immunotherapy. PMID- 26965524 TI - Emerging roles of NudC family: from molecular regulation to clinical implications. AB - Nuclear distribution gene C (NudC) was first found in Aspergillus nidulans as an upstream regulator of NudF, whose mammalian homolog is Lissencephaly 1 (Lis1). NudC is conserved from fungi to mammals. Vertebrate NudC has three homologs: NudC, NudC-like protein (NudCL), and NudC-like protein 2 (NudCL2). All members of the NudC family share a conserved p23 domain, which possesses chaperone activity both in conjunction with and independently of heat shock protein 90 (Hsp90). Our group and the others found that NudC homologs were involved in cell cycle regulation by stabilizing the components of the LIS1/dynein complex. Additionally, NudC plays important roles in cell migration, ciliogenesis, thrombopoiesis, and the inflammatory response. It has been reported that NudCL is essential for the stability of the dynein intermediate chain and ciliogenesis via its interaction with the dynein 2 complex. Our data showed that NudCL2 regulates the LIS1/dynein pathway by stabilizing LIS1 with Hsp90 chaperone. The fourth distantly related member of the NudC family, CML66, a tumor-associated antigen in human leukemia, contains a p23 domain and appears to promote oncogenesis by regulating the IGF-1R-MAPK signaling pathway. In this review, we summarize our current knowledge of the NudC family and highlight its potential clinical relevance. PMID- 26965516 TI - Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk. AB - BACKGROUND & AIMS: Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. METHODS: This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. RESULTS: We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 * 10(-8) to 1.24 * 10(-12): 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P < .05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. CONCLUSIONS: We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis. PMID- 26965526 TI - Making time for mindfulness. AB - OBJECTIVE: Digital mental wellbeing interventions are increasingly being used by the general public as well as within clinical treatment. Among these, mindfulness and meditation programs delivered through mobile device applications are gaining popularity. However, little is known about how people use and experience such applications and what are the enabling factors and barriers to effective use. To address this gap, the study reported here sought to understand how users adopt and experience a popular mobile-based mindfulness intervention. METHODS: A qualitative semi-structured interview study was carried out with 16 participants aged 25-38 (M=32.5) using the commercially popular mindfulness application Headspace for 30-40days. All participants were employed and living in a large UK city. The study design and interview schedule were informed by an autoethnography carried out by the first author for thirty days before the main study began. Results were interpreted in terms of the Reasoned Action Approach to understand behaviour change. RESULTS: The core concern of users was fitting the application into their busy lives. Use was also influenced by patterns in daily routines, on going reflections about the consequences of using the app, perceived self efficacy, emotion and mood states, personal relationships and social norms. Enabling factors for use included positive attitudes towards mindfulness and use of the app, realistic expectations and positive social influences. Barriers to use were found to be busy lifestyles, lack of routine, strong negative emotions and negative perceptions of mindfulness. CONCLUSIONS: Mobile wellbeing interventions should be designed with consideration of people's beliefs, affective states and lifestyles, and should be flexible to meet the needs of different users. Designers should incorporate features in the design of applications that manage expectations about use and that support users to fit app use into a busy lifestyle. The Reasoned Action Approach was found to be a useful theory to inform future research and design of persuasive mental wellbeing technologies. PMID- 26965525 TI - Hurdles of CAR-T cell-based cancer immunotherapy directed against solid tumors. AB - Recent reports on the impressive efficacy of chimeric antigen receptor (CAR) modified T cells against hematologic malignancies have inspired oncologists to extend these efforts for the treatment of solid tumors. Clinical trials of CAR-T based cancer immunotherapy for solid tumors showed that the efficacies are not as remarkable as in the case of hematologic malignancies. There are several challenges that researchers must face when treating solid cancers with CAR-T cells, these include choosing an ideal target, promoting efficient trafficking and infiltration, overcoming the immunosuppressive microenvironment, and avoiding associated toxicity. In this review, we discuss the obstacles imposed by solid tumors on CAR-T cell-based immunotherapy and strategies adopted to improve the therapeutic potential of this approach. Continued investigations are necessary to improve therapeutic outcomes and decrease the adverse effects of CAR-T cell therapy in patients with solid malignancies in the future. PMID- 26965528 TI - Reconstruction of Congenital Nose, Cleft Primary Palate, and Lip Disorders. AB - Clefts of the primary palate in the dog are uncommon, and their repair can be challenging. The aims of this article are to provide information regarding pathogenesis and convey practical information for the repair of these defects. PMID- 26965527 TI - Cortisol response to acute stress in asthma: Moderation by depressive mood. AB - Both individuals with asthma and depression show signs of a dysregulated hypothalamus-pituitary-adrenal axis. However, little is known about the cortisol response to stress in the context of co-occurring asthma and depressive mood. Thirty-nine individuals with asthma and 41 healthy controls underwent a combined speech and mental arithmetic stressor. During the course of the laboratory session, salivary cortisol was collected 5 times, with 1 sample at 0min before the stressor and 4 samples at 0, 15, 30 and 45min after the stressor. Depressive mood in the past week was assessed with the Hospital Anxiety and Depression Scale at the beginning of the session. Depressive symptoms moderated cortisol response to the acute stressor, but only among asthmatic patients. Higher depressive mood was associated with a significant increase in cortisol, whereas low depressive mood was associated with no cortisol response. In healthy participants, depressive mood had no substantial effect on cortisol response to the stressor. These findings suggest that depressive mood and chronic inflammatory diseases such as asthma can interact to augment cortisol response to stress. PMID- 26965529 TI - Risk of Age-related Macular Degeneration 4 to 5 Years after Cataract Surgery. PMID- 26965531 TI - [Innovation in healthcare processes and patient safety using clinical simulation]. AB - OBJECTIVE: Many excellent ideas are never implemented or generalised by healthcare organisations. There are two related paradigms: thinking that individuals primarily change through accumulating knowledge, and believing that the dissemination of that knowledge within the organisation is the key element to facilitate change. As an alternative, a description and evaluation of a simulation-based inter-professional team training program conducted in a Regional Health Service to promote and facilitate change is presented. MATERIAL AND METHODS: The Department of Continuing Education completed the needs assessment using the proposals presented by clinical units and management. Skills and behaviors that could be learned using simulation were selected, and all personnel from the units participating were included. Experiential learning principles based on clinical simulation and debriefing, were used for the instructional design. The Kirkpatrick model was used to evaluate the program. RESULTS: Objectives included: a) decision-making and teamwork skills training in high prevalence diseases with a high rate of preventable complications; b) care processes reorganisation to improve efficiency, while maintaining patient safety; and, c) implementation of new complex techniques with a long learning curve, and high preventable complications rate. Thirty clinical units organised 39 training programs in the 3 public hospitals, and primary care of the Regional Health Service during 2013-2014. Over 1,559 healthcare professionals participated, including nursing assistants, nurses and physicians. CONCLUSION: Simulation in healthcare to train inter-professional teams can promote and facilitate change in patient care, and organisational re-engineering. PMID- 26965530 TI - Serum fibroblast growth factor 23, serum iron and bone mineral density in premenopausal women. AB - Fibroblast growth factor 23 (FGF23) circulates as active protein and inactive fragments. Low iron status increases FGF23 gene expression, and iron deficiency is common. We hypothesized that in healthy premenopausal women, serum iron influences C-terminal and intact FGF23 concentrations, and that iron and FGF23 associate with bone mineral density (BMD). Serum iron, iron binding capacity, percent iron saturation, phosphorus, and other biochemistries were measured in stored fasting samples from healthy premenopausal white (n=1898) and black women (n=994), age 20-55years. Serum C-terminal and intact FGF23 were measured in a subset (1631 white and 296 black women). BMD was measured at the lumbar spine and femur neck. Serum phosphorus, calcium, alkaline phosphatase and creatinine were lower in white women than black women (p<0.001). Serum iron (p<0.0001) and intact FGF23 (p<0.01) were higher in white women. C-terminal FGF23 did not differ between races. Phosphorus correlated with intact FGF23 (white women, r=0.120, p<0.0001; black women r=0.163, p<0.01). However, phosphorus correlated with C terminal FGF23 only in black women (r=0.157, p<0.01). Intact FGF23 did not correlate with iron. C-terminal FGF23 correlated inversely with iron (white women r=-0.134, p<0.0001; black women r=-0.188, p<0.01), having a steeper slope at iron <50mcg/dl than >=50mcg/dl. Longitudinal changes in iron predicted changes in C terminal FGF23. Spine BMD correlated with iron negatively (r=-0.076, p<0.01) in white women; femur neck BMD correlated with iron negatively (r=-0.119, p<0.0001) in black women. Both relationships were eliminated in weight-adjusted models. BMD did not correlate with FGF23. Serum iron did not relate to intact FGF23, but was inversely related to C-terminal FGF23. Intact FGF23 correlated with serum phosphorus. In weight-adjusted models, BMD was not related to intact FGF23, C terminal FGF23 or iron. The influence of iron on FGF23 gene expression is not important in determining bone density in healthy premenopausal women. PMID- 26965533 TI - Commercial Use of MVR: What Have We Learned and What Do We Need to Know? PMID- 26965532 TI - Initial Experience With Commercial Transcatheter Mitral Valve Repair in the United States. AB - BACKGROUND: Transcatheter mitral valve (MV) repair with the MitraClip received approval in 2013 for the treatment of prohibitive-risk patients with primary mitral regurgitation (MR). OBJECTIVES: The aim of this study was to report the initial U.S. commercial experience with transcatheter MV repair. METHODS: Data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry on patients commercially treated with this percutaneous mitral valve repair device were analyzed. RESULTS: Of 564 patients (56% men, median age 83 years), severe symptoms were present in 473 (86.0%). The median Society of Thoracic Surgeons Predicted Risk of Mortality scores for MV repair and replacement were 7.9% (interquartile range: 4.7% to 12.2%) and 10.0% (interquartile range: 6.3% to 14.5%), respectively. Frailty was noted in 323 patients (57.3%). Transcatheter MV repair was performed for degenerative disease, present in 90.8% of patients. Overall, MR was reduced to grade <=2 in 93.0%. In hospital mortality was 2.3%; 30-day mortality was 5.8%. Other 30-day events were stroke (1.8%), bleeding (2.6%), and device-related complications (1.4%). The median length of stay was 3 days (interquartile range: 1 to 6 days), with 84.0% patients discharged home. Overall, procedure success occurred in 90.6%. Variables associated with reduction in MR were end-diastolic dimension, MR severity, clip location, and case volume. CONCLUSIONS: In this study of the initial commercial U.S. experience, it was found that procedural success was achieved in approximately 91% of patients, and the majority of patients were discharged home with moderate or less MR. These data support the effectiveness of this therapy in appropriately selected high-risk patients in a commercial setting. Further study is required to determine the long-term impact of transcatheter MV repair in this patient population. PMID- 26965534 TI - Platelet Inhibition With Ticagrelor 60 mg Versus 90 mg Twice Daily in the PEGASUS TIMI 54 Trial. AB - BACKGROUND: The PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54) trial studied 2 doses of ticagrelor, 90 mg twice a day (bid) and 60 mg bid, for long-term prevention of ischemic events in patients with prior myocardial infarction. Both doses similarly reduced the rate of ischemic events versus placebo. The pharmacokinetics and pharmacodynamics of ticagrelor 60 mg bid have not been studied. OBJECTIVES: In this study, the authors sought to study the pharmacokinetics and pharmacodynamics for ticagrelor 60 mg compared with 90 mg bid. METHODS: A total of 180 patients who received >4 weeks of study medication had blood sampling in the morning pre-maintenance dose and again 2 h post-dose. All patients received aspirin. Plasma levels of ticagrelor and its active metabolite AR-C124910XX were determined. P2Y12 inhibition was assessed by the VerifyNow P2Y12 assay (Accumetrics, Inc., San Diego, California) (P2Y12 reaction units [PRU]), light transmittance aggregometry (adenosine diphosphate 5 and 20 MUmol/l and arachidonic acid), and vasodilator-stimulated phosphoprotein phosphorylation assays. VerifyNow Aspirin assays and serum thromboxane B2 measurements were performed. RESULTS: Mean pre- and post-dose plasma levels of ticagrelor were 35% and 38% lower, respectively, with 60 mg versus 90 mg. Both doses achieved high levels of platelet inhibition pre- and post-dose, with numerically slightly more variability with 60 mg: mean (SD) pre-dose PRU values were 59 +/- 63 and 47 +/- 43 for ticagrelor 60 and 90 mg, respectively (p = 0.34). High platelet reactivity, determined as PRU >208, was rare with the 60-mg pre-dose and was absent post-dose. Platelet reactivity pre- and post-dose, as measured by light transmittance aggregometry or vasodilator-stimulated phosphoprotein assays, was numerically but not significantly lower with 90 mg than with 60 mg. Aspirin response was not affected by either dose. CONCLUSIONS: Ticagrelor 60 mg bid achieved high levels of peak and trough platelet inhibition in nearly all patients, similar to that with 90 mg bid, helping to explain the efficacy of the lower ticagrelor dose in PEGASUS-TIMI 54. PMID- 26965535 TI - The Yin and Yang of Long-Term Dual Antiplatelet Therapy. PMID- 26965537 TI - Microvascular (Dys)Function and Clinical Outcome in Stable Coronary Disease. PMID- 26965536 TI - Coronary Flow Reserve and Microcirculatory Resistance in Patients With Intermediate Coronary Stenosis. AB - BACKGROUND: The prognostic impact of microvascular status in patients with high fractional flow reserve (FFR) is not clear. OBJECTIVES: The goal of this study was to investigate the implications of coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) in patients who underwent FFR measurement. METHODS: Patients with high FFR (>0.80) were grouped according to CFR (<=2) and IMR (>=23 U) levels: group A, high CFR with low IMR; group B, high CFR with high IMR; group C, low CFR with low IMR; and group D, low CFR with high IMR. Patient oriented composite outcome (POCO) of any death, myocardial infarction, and revascularization was assessed. The median follow-up was 658 days (interquartile range: 503.8 to 1,139.3 days). RESULTS: A total of 313 patients (663 vessels) were assessed with FFR, CFR, and IMR. Correlation (r = 0.201; p < 0.001) and categorical agreement (kappa value = 0.178; p < 0.001) between FFR and CFR were modest. Low CFR was associated with higher POCO than high CFR (p = 0.034). There were no significant differences in clinical and angiographic characteristics among groups. Patients with high IMR with low CFR had the highest POCO (p = 0.002). Overt microvascular disease (p = 0.008), multivessel disease (p = 0.033), and diabetes mellitus (p = 0.033) were independent predictors of POCO. Inclusion of a physiological index significantly improved the discriminant function of a predictive model (relative integrated discrimination improvement 0.467 [p = 0.037]; category-free net reclassification index 0.648 [p = 0.007]). CONCLUSIONS: CFR and IMR improved the risk stratification of patients with high FFR. Low CFR with high IMR was associated with poor prognosis. (Clinical, Physiological and Prognostic Implication of Microvascular Status; NCT02186093). PMID- 26965539 TI - Influence of Chronic Renal Failure on Cardiac Structure. PMID- 26965538 TI - Echocardiography Criteria for Structural Heart Disease in Patients With End-Stage Renal Disease Initiating Hemodialysis. AB - BACKGROUND: Cardiovascular disease among hemodialysis (HD) patients is linked to poor outcomes. The Acute Dialysis Quality Initiative Workgroup proposed echocardiographic (ECHO) criteria for structural heart disease (SHD) in dialysis patients. The association of SHD with important patient outcomes is not well defined. OBJECTIVES: This study sought to determine prevalence of ECHO-determined SHD and its association with survival among incident HD patients. METHODS: We analyzed patients who began chronic HD from 2001 to 2013 who underwent ECHO <=1 month prior to or <=3 months following initiation of HD (n = 654). RESULTS: Mean patient age was 66 +/- 16 years, and 60% of patients were male. ECHO findings that met 1 or more and >=3 of the new criteria were discovered in 87% and 54% of patients, respectively. Over a median of 2.4 years, 415 patients died: 108 (26%) died within 6 months. Five-year mortality was 62%. Age- and sex-adjusted structural heart disease variables associated with death were left ventricular ejection fraction (LVEF) <=45% (hazard ratio [HR]: 1.48; confidence interval [CI]: 1.20 to 1.83) and right ventricular (RV) systolic dysfunction (HR: 1.68; CI: 1.35 to 2.07). An additive of higher death risk included LVEF <=45% and RV systolic dysfunction rather than neither (HR: 2.04; CI: 1.57 to 2.67; p = 0.53 for test for interaction). Following adjustment for age, sex, race, diabetic kidney disease, and dialysis access, RV dysfunction was independently associated with death (HR: 1.66; CI 1.34 to 2.06; p < 0.001). CONCLUSIONS: SHD was common in our HD study population, and RV systolic dysfunction independently predicted mortality. PMID- 26965541 TI - Cardiologists Are Accountable to Determine the Need for ICD Therapy After Myocardial Infarction. PMID- 26965540 TI - Predicting Persistent Left Ventricular Dysfunction Following Myocardial Infarction: The PREDICTS Study. AB - BACKGROUND: Persistent severe left ventricular (LV) systolic dysfunction after myocardial infarction (MI) is associated with increased mortality and is a class I indication for implantation of a cardioverter-defibrillator. OBJECTIVES: This study developed models and assessed independent predictors of LV recovery to >35% and >=50% after 90-day follow-up in patients presenting with acute MI and severe LV dysfunction. METHODS: Our multicenter prospective observational study enrolled participants with ejection fraction (EF) of <=35% at the time of MI (n = 231). Predictors for EF recovery to >35% and >=50% were identified after multivariate modeling and validated in a separate cohort (n = 236). RESULTS: In the PREDICTS (PREDiction of ICd Treatment Study) study, 43% of patients had persistent EF <=35%, 31% had an EF of 36% to 49%, and 26% had an EF >=50%. The model that best predicted recovery of EF to >35% included EF at presentation, length of stay, prior MI, lateral wall motion abnormality at presentation, and peak troponin. The model that best predicted recovery of EF to >=50% included EF at presentation, peak troponin, prior MI, and presentation with ventricular fibrillation or cardiac arrest. After predictors were transformed into point scores, the lowest point scores predicted a 9% and 4% probability of EF recovery to >35% and >=50%, respectively, whereas profiles with the highest point scores predicted an 87% and 49% probability of EF recovery to >35% and >=50%, respectively. CONCLUSIONS: In patients with severe systolic dysfunction following acute MI with an EF <=35%, 57% had EF recovery to >35%. A model using clinical variables present at the time of MI can help predict EF recovery. PMID- 26965543 TI - Pharmacometabolomics Meets Genetics: A "Natural" Clinical Trial of Statin Effects. PMID- 26965544 TI - Long Noncoding RNAs: From Clinical Genetics to Therapeutic Targets? AB - Recent studies suggest that the majority of the human genome is transcribed, but only about 2% accounts for protein-coding exons. Long noncoding RNAs (lncRNAs) constitute a heterogenic class of RNAs that includes, for example, intergenic lncRNAs, antisense transcripts, and enhancer RNAs. Moreover, alternative splicing can lead to the formation of circular RNAs. In support of putative functions, GWAS for cardiovascular diseases have shown predictive single-nucleotide polymorphisms in lncRNAs, such as the 9p21 susceptibility locus that encodes the lncRNA antisense noncoding RNA in the INK4 locus (ANRIL). Many lncRNAs are regulated during disease. For example, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and myocardial infarction-associated transcript (MIAT) were shown to affect endothelial cell functions and diabetic retinopathy, whereas lincRNA-p21 controls neointima formation. In the heart, several lncRNAs were shown to act as microRNA sponges and to control ischemia-reperfusion injury or act as epigenetic regulators. In this review, the authors summarize the current understanding of lncRNA functions and their role as biomarkers in cardiovascular diseases. PMID- 26965545 TI - Fasting or Nonfasting Lipid Measurements: It Depends on the Question. AB - In the 2013 American College of Cardiology (ACC)/American Heart Association Guideline (AHA) on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, low-density lipoprotein cholesterol treatment thresholds have been replaced with a focus on global risk. In this context, we re examine the need for fasting lipid measurements in various clinical scenarios including estimating initial risk for atherosclerotic cardiovascular disease in a primary prevention patient; screening for familial lipid disorders in a patient with a strong family history of premature atherosclerotic cardiovascular disease or genetic dyslipidemia; clarifying a diagnosis of metabolic syndrome so it can be used to make lifestyle counseling more effective; assessing residual risk in a treated patient; diagnosing and treating patients with suspected hypertriglyceridemic pancreatitis; or diagnosing hypertriglyceridemia in patients who require therapy for other conditions that may further elevate triglycerides. Posing a specific question can aid the clinician in understanding when fasting lipids are needed and when nonfasting lipids are adequate. PMID- 26965542 TI - Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase. AB - BACKGROUND: Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. OBJECTIVES: This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. METHODS: Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. RESULTS: Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R(2) = 0.94, slope 1.00 +/- 0.03). CONCLUSIONS: Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms. PMID- 26965546 TI - Seven Deadly Sins of Health Care: Part II. PMID- 26965547 TI - Rehospitalization Is a Major Determinant of Inpatient Care Costs in Adult Congenital Heart Disease. PMID- 26965548 TI - Thoracic Endovascular Aortic Repair for Type B Aortic Dissection: Analysis Among Acute, Subacute, and Chronic Patients. PMID- 26965549 TI - Benefit of Exercise in Atrial Fibrillation: Diastolic Function Matters! PMID- 26965550 TI - Reply: Benefit of Exercise in Atrial Fibrillation: Diastolic Function Matters! PMID- 26965551 TI - Mechanisms of Late and Very Late Bioresorbable Vascular Scaffold Thrombosis: Is it Only About Flow? PMID- 26965552 TI - Reply: Mechanisms of Late and Very Late Bioresorbable Vascular Scaffold Thrombosis: Is it Only About Flow? PMID- 26965553 TI - Are viscoelastic tests essential in polytrauma patient resuscitation? PMID- 26965554 TI - Clinical practice guideline on thromboprophylaxis and management of anticoagulant and antiplatelet drugs in neurosurgical and neurocritical patients. PMID- 26965555 TI - Ultrasound-guided transthecal digital block. PMID- 26965556 TI - Bone cement implantation syndrome: A case report. PMID- 26965557 TI - The molecular organization of the beta-sheet region in Corneous beta-proteins (beta-keratins) of sauropsids explains its stability and polymerization into filaments. AB - The hard corneous material of avian and reptilian scales, claws, beak and feathers is mainly derived from the presence of proteins formerly known as beta keratins but now termed Corneous beta-proteins of sauropsids to distinguish them from keratins, which are members of the intermediate filament protein family. The modeling of the conserved 34 amino acid residues long central beta-sheet region of Corneous beta-proteins using an ab initio protein folding and structure prediction algorithm indicates that this region is formed by four antiparallel beta-sheets. Molecular dynamic simulations and Molecular Mechanics/Poisson Boltzmann Surface Area (MM-PBSA) analysis showed that the disposition of polar and apolar amino acids within the beta-region gives rise to an amphipathic core whose stability is further increased, especially in an aqueous environment, by the association into a dimer due to apolar interactions and specific amino-acid interactions. The dimers in turn polymerize into a 3nm thick linear beta-filament due to van der Waals and hydrogen-bond interactions. It is suggested that once this nuclear core of anti-parallel sheets evolved in the genome of a reptilian ancestor of the extant reptiles and birds about 300 millions years ago, new properties emerged in the corneous material forming scales, claws, beaks and feathers in these amniotes based on the tendency of these unique corneous proteins to form stable filaments different from keratin intermediate filaments or sterical structures formed by other corneous proteins so far known. PMID- 26965558 TI - Structural analysis of Gossypium hirsutum fibers grown under greenhouse and hydroponic conditions. AB - Cotton is the one of the world's most important crops. Like any other crop, cotton growth/development and fiber quality is highly dependent on environmental factors. Increasing global weather instability has been negatively impacting its economy. Cotton is a crop that exerts an intensive pressure over natural resources (land and water) and demands an overuse of pesticides. Thus, the search for alternative cotton culture methods that are pesticide-free (biocotton) and enable customized standard fiber quality should be encouraged. Here we describe a culture of Gossypium hirsutum ("Upland" Cotton) utilizing a greenhouse and hydroponics in which the fibers are morphological similar to conventional cultures and structurally fit into the classical two-phase cellulose I model with 4.19nm crystalline domains surrounded by amorphous regions. These fibers exhibit a single crystalline form of cellulose I-Ibeta, monoclinic unit cell. Fiber quality bulk analysis shows an improved length, strength, whiteness when compared with soil-based cultures. Finally, we show that our fibers can be spun, used for production of non-woven fabrics and indigo-vat stained demonstrating its potential in industrial and commercial applications. PMID- 26965559 TI - The Expression of Inflammatory Mediators in Bladder Pain Syndrome. AB - BACKGROUND: Bladder pain syndrome (BPS) pathology is poorly understood. Treatment strategies are empirical, with limited efficacy, and affected patients have diminished quality of life. OBJECTIVE: We examined the hypothesis that inflammatory mediators within the bladder contribute to BPS pathology. DESIGN, SETTING, AND PARTICIPANTS: Fifteen women with BPS and 15 women with stress urinary incontinence without bladder pain were recruited from Cork University Maternity Hospital from October 2011 to October 2012. During cystoscopy, 5-mm bladder biopsies were taken and processed for gene expression analysis. The effect of the identified genes was tested in laboratory animals. OUTCOME MEASURES AND STATISTICAL ANALYSIS: We studied the expression of 96 inflammation-related genes in diseased and healthy bladders. We measured the correlation between genes and patient clinical profiles using the Pearson correlation coefficient. RESULTS AND LIMITATIONS: Analysis revealed 15 differentially expressed genes, confirmed in a replication study. FGF7 and CCL21 correlated significantly with clinical outcomes. Intravesical CCL21 instillation in rats caused increased bladder excitability and increased c-fos activity in spinal cord neurons. CCL21 atypical receptor knockout mice showed significantly more c-fos upon bladder stimulation with CCL21 than wild-type littermates. There was no change in FGF7-treated animals. The variability in patient samples presented as the main limitation. We used principal component analysis to identify similarities within the patient group. CONCLUSIONS: Our study identified two biologically relevant inflammatory mediators in BPS and demonstrated an increase in nociceptive signalling with CCL21. Manipulation of this ligand is a potential new therapeutic strategy for BPS. PATIENT SUMMARY: We compared gene expression in bladder biopsies of patients with bladder pain syndrome (BPS) and controls without pain and identified two genes that were increased in BPS patients and correlated with clinical profiles. We tested the effect of these genes in laboratory animals, confirming their role in bladder pain. Manipulating these genes in BPS is a potential treatment strategy. PMID- 26965560 TI - Efficacy and Safety of Mirabegron Add-on Therapy to Solifenacin in Incontinent Overactive Bladder Patients with an Inadequate Response to Initial 4-Week Solifenacin Monotherapy: A Randomised Double-blind Multicentre Phase 3B Study (BESIDE). AB - BACKGROUND: Incontinence has a greater detrimental effect on quality of life than other symptoms of overactive bladder (OAB) and is often difficult to treat with antimuscarinic monotherapy. OBJECTIVE: To evaluate the efficacy and the safety and tolerability of combination (solifenacin 5mg and mirabegron 50mg) versus solifenacin 5 or 10mg in OAB patients remaining incontinent after 4 wk of solifenacin 5mg. DESIGN, SETTING, AND PARTICIPANTS: OAB patients remaining incontinent despite daily solifenacin 5mg during 4-wk single-blind run-in were randomised 1:1:1 to double-blind daily combination or solifenacin 5 or 10mg for 12 wk. Patients receiving the combination were initiated on mirabegron 25mg increasing to 50mg after week 4. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was a change from baseline to end of treatment (EOT) in the mean number of incontinence episodes per 24h (stratified rank analysis of covariance [ANCOVA]). Key secondary end points were a change from baseline to EOT in the mean number of micturitions per 24h (ANCOVA) and number of incontinence episodes noted in a 3-d diary at EOT (mixed-effects Poisson regression). A trial (BESIDE) comparing combination treatment (solifenacin plus mirabegron) with one treatment alone (solifenacin) tested the superiority of combination versus solifenacin 5mg, noninferiority (and potential superiority) of combination versus solifenacin 10mg (key secondary end points), and the safety and tolerability of combination therapy versus solifenacin monotherapy. RESULTS AND LIMITATIONS: A total of 2174 patients were randomised to combination (n=727), solifenacin 5mg (n=728), or solifenacin 10mg (n=719). At EOT, combination was superior to solifenacin 5mg, with significant improvements in daily incontinence (p=0.001), daily micturitions (p<0.001), and incontinence noted in a 3-d diary (p=0.014). Combination was noninferior to solifenacin 10mg for key secondary end points and superior to solifenacin 10mg for improving daily micturitions. All treatments were well tolerated. CONCLUSIONS: Adding mirabegron 50mg to solifenacin 5mg further improved OAB symptoms versus solifenacin 5 or 10mg, and it was well tolerated in OAB patients remaining incontinent after initial solifenacin 5mg. PATIENT SUMMARY: In this 12-wk study, overactive bladder patients who remained incontinent despite initial solifenacin 5mg treatment received additional treatment with mirabegron 50mg. Combining mirabegron 50mg with solifenacin 5mg was superior to solifenacin 5mg alone in improving symptoms of incontinence and frequent urination, and it was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov NCT01908829. PMID- 26965563 TI - What counts as 'ethics education'? PMID- 26965561 TI - Prostate-specific Antigen Decline After 4 Weeks of Treatment with Abiraterone Acetate and Overall Survival in Patients with Metastatic Castration-resistant Prostate Cancer. AB - BACKGROUND: The availability of multiple new treatments for metastatic castration resistant prostate cancer (mCRPC) mandates earlier treatment switches in the absence of a response. A decline in prostate-specific antigen (PSA) is widely used to monitor treatment response, but is not validated as an intermediate endpoint for overall survival (OS). OBJECTIVE: To evaluate the association between early PSA decline and OS following abiraterone acetate (AA) treatment. DESIGN, SETTING, AND PARTICIPANTS: We identified mCRPC patients treated with AA before or after docetaxel at the Royal Marsden NHS Foundation Trust between 2006 and 2014. Early PSA decline was defined as a 30% decrease in PSA at 4 wk relative to baseline, and early PSA rise as a 25% increase. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Association with OS was analyzed using multivariate Cox regression and log-rank analyses. Spearman's rho correlation coefficient (r) was calculated to evaluate the association between PSA changes at 4 wk and 12 wk. RESULTS AND LIMITATIONS: There were 274 patients eligible for this analysis. A 30% PSA decline at 4 wk was associated with longer OS (25.8 vs 15.1 mo; hazard ratio [HR] 0.47, p<0.001), and a 25% PSA rise at 4 wk with shorter OS (15.1 vs 23.8 mo; HR 1.7, p=0.001) in both univariate and multivariable models. The percentage PSA decline at 4 wk was significantly correlated with the percentage PSA change at 12 wk (r=0.82; p<0.001). Patients achieving a 30% PSA decline at 4 wk were 11.7 times more likely to achieve a 50% PSA decrease at 12 wk (sensitivity 90.9%, specificity 79.4%). Limitations include the retrospective design of this analysis. CONCLUSIONS: Patients not achieving 30% PSA decline after 4 wk of AA have a lower likelihood of achieving PSA response at 12 wk and significantly inferior OS. Prospective multicentre validation studies are needed to confirm these findings. PATIENT SUMMARY: Prostate-specific antigen (PSA) is commonly used to evaluate response to treatment in metastatic castration resistant prostate cancer. Expert recommendations discourage reliance on PSA changes earlier than 12 wk after treatment initiation. Our data suggest that early PSA changes are associated with survival in patients receiving abiraterone acetate. PMID- 26965562 TI - Low Incidence of Corticosteroid-associated Adverse Events on Long-term Exposure to Low-dose Prednisone Given with Abiraterone Acetate to Patients with Metastatic Castration-resistant Prostate Cancer. AB - BACKGROUND: Abiraterone acetate (AA) is the prodrug of abiraterone, which inhibits CYP17A1 and testosterone synthesis and prolongs the survival of patients with metastatic castration-resistant prostate cancer (mCRPC). AA plus prednisone (P) (AA+P) is approved for the treatment of patients with mCRPC. OBJECTIVE: To investigate whether long-term use of low-dose P with or without AA leads to corticosteroid-associated adverse events (CA-AEs) in mCRPC patients. DESIGN, SETTING, AND PARTICIPANTS: The study included 2267 patients in COU-AA-301 and COU AA-302. We used an inclusive Standardized MedDRA Queries-oriented approach to identify 112 preferred terms for known CA-AEs, and assessed the incidence of CA AEs during 3-mo exposure intervals and across all P exposure levels. INTERVENTION: All 2267 patients received 5mg of P twice daily, and 1333/2267 received AA (1g) plus P. RESULTS AND LIMITATIONS: The CA-AE incidence after any P exposure was 25%, 26%, and 23% for any grade, and 5%, 5%, and 4% for grade >=3 CA AEs for all patients and the AA+P and P alone groups, respectively. The most common any-grade CA-AEs were hyperglycemia (7.4%, 7.8%, and 6.9% for all patients, AA+P, and P alone, respectively) and weight increase (4.3%, 3.9%, and 4.8%, respectively). When assessed by duration of exposure (3-mo intervals up to >=30 mo), no discernable trend was observed for CA-AEs, including hyperglycemia and weight increase. The investigator-reported study discontinuation rate due to CA-AEs was 11/2267 (0.5%), and one patient had a CA-AE resulting in death. CONCLUSIONS: Low-dose P given with or without AA is associated with low overall incidence of CA-AEs. The frequency of CA-AEs remained low with increased duration of exposure to P. PATIENT SUMMARY: We assessed adverse events in patients with metastatic castration-resistant prostate cancer during long-term treatment with a low dose of a corticosteroid. We found that long-term treatment with this low dose corticosteroid is safe and tolerable. PMID- 26965566 TI - The activation and blockage of CRF type 2 receptors of the medial amygdala alter elevated T-maze inhibitory avoidance, an anxiety-related response. AB - Previous results show that the activation of CRF type 1 (CRFR1) receptors of the medial amygdala (MeA) induces anxiogenic-like effects. The present study investigates the role played by medial amygdala CRF type 2 receptors (CRFR2) in the modulation of anxiety and panic-related responses. Male Wistar rats were administered into the MeA with the CRFR2 agonist urocortin 2 (0.5 e 1.0MUg/0.2MUl, experiment 1) or with the CRFR2 antagonist astressin 2-B (60ng/0.2MUl, experiment 2) and 10min later tested in the elevated T-maze (ETM) for inhibitory avoidance and escape measurements. In clinical terms, these responses have been respectively related to generalized anxiety and panic disorder. In a third experiment, the effects of the combined treatment with urocortin 2 (1.0MUg/0.2MUl) and a sub-effective dose of astressin 2-B (30ng/0.2MUl) were also investigated. All animals were tested in an open field, immediately after the ETM, for locomotor activity assessment. Results showed that urocortin 2, in the highest dose administered (1.0MUg/0.2MUl), facilitated ETM avoidance, an anxiogenic-like effect. Astressin 2-B, also in the highest dose (60ng/0.2MUl), significantly decreased avoidance latencies, an anxiolytic-like effect. The lower dose of astressin 2-B (30ng/0.2MUl) did not induce anxiolytic like effects but was able to counteract the anxiogenic-like effects of urocortin 2. None of the compounds administered altered escape responses or locomotor activity measurements. These results suggest that CRFR2 in the medial amygdala, as CRFR1, selectively modulate an anxiety-related response. PMID- 26965567 TI - Anthocyanin effects on microglia M1/M2 phenotype: Consequence on neuronal fractalkine expression. AB - Microglia mediate multiple aspects of neuroinflammation, including cytotoxicity, repair, regeneration, and immunosuppression due to their ability to acquire diverse activation states, or phenotypes. Modulation of microglial phenotype or microglia-neuron crosstalk can be an appealing neurotherapeutic strategy. Anthocyanins are a class of flavonoids found e.g., in berries that has been attracting interest due to its neuroprotective potential. However, there are no data clarifying the impact of anthocyanins on microglial phenotype or on microglia-neuron crosstalk (CX3CR1/CX3CL1). N9 microglia cell line was treated with 1MUM cyanidin (Cy), cyanidin-3-glucose (Cy3glc) and a methylated form of cyanidin-3-glucose (Met-Cy3glc) in basal conditions and with LPS/IL-4 stimulation. SH-SY5Y cell line was treated with the conditioned medium of microglia and with the anthocyanins alone. At basal conditions, microglia treatment with anthocyanins for 24h induced a less pro-inflammatory profile. Decreased TNF-alpha mRNA expression was induced either by Cy and Met-Cy3glc. LPS markedly increase IL-6 mRNA expression, which was lowered by Cy3glc. IL-1beta LPS induced expression was reverted by Cy. Cy increased CX3CL1 mRNA expression in SH SY5Y comparing either with control or LPS. Anthocyanins and metabolites were not able to shift microglia to an M2 strict phenotype however they did interact with microglia biology. There was an attenuation of M1 phenotype and increase of neuronal expression of CX3CL1 mRNA. Understanding how flavonoids modulate microglia-neuron crosstalk can open new directions for future nutritional interventions. PMID- 26965568 TI - Routine handling methods affect behaviour of three-spined sticklebacks in a novel test of anxiety. AB - Fish are increasingly popular subjects in behavioural and neurobiological research. It is therefore important that they are housed and handled appropriately to ensure good welfare and reliable scientific findings, and that species-appropriate behavioural tests (e.g. of cognitive/affective states) are developed. Routine handling of captive animals may cause physiological stress responses that lead to anxiety-like states (e.g. increased perception of danger). In fish, these may be particularly pronounced when handling during tank-to-tank transfer involves removal from water into air. Here we develop and use a new combined scototaxis (preference for dark over light areas) and novel-tank-diving test, alongside conventional open-field and novel-object tests, to measure the effects of transferring three-spined sticklebacks (Gasterosteus aculeatus) between tanks using a box or net (in and out of water respectively). Preference tests for dark over light areas confirmed the presence of scototaxis in this species. Open-field and novel-object tests failed to detect any significant differences between net and box-handled fish. However, the combined diving and scototaxis detected consistent differences between the treatments. Net-handled fish spent less time on the dark side of the tank, less time in the bottom third, and kept a greater distance from the 'safe' bottom dark area than box-handled fish. Possible explanations for this reduction in anxiety-like behaviour in net handled fish are discussed. The combined diving and scototaxis test may be a sensitive and taxon-appropriate method for measuring anxiety-like states in fish. PMID- 26965569 TI - Age and gender-related differences in a spatial memory task in humans. AB - Cognitive skills decline with age. Our ability to keep oriented in our surrounding environment was demonstrated to be influenced by factors like age and gender. Introduction of virtual reality based tasks improved assessment of spatial memory in humans. In this study, spatial orientation was assessed in a virtual memory task in order to determine the effect of aging and gender on navigational skills. Subjects from 45 to 74 years of age were organized in three groups (45-54, 55-64, 65-74 years old). Two levels of difficulty were considered. Results showed that males outperformed females in 65-74 years-old group. In addition to this, females showed a more noticeable poor performance in spatial memory than males, since memory differences appeared between all age groups. On the other hand, 65-74 year-old males showed an impaired performance in comparison with 45-54 year-old group. These results support that spatial memory becomes less accurate as we age and gender is an important factor influencing spatial orientation skills. PMID- 26965570 TI - The misfolded pro-inflammatory protein S100A9 disrupts memory via neurochemical remodelling instigating an Alzheimer's disease-like cognitive deficit. AB - Memory deficits may develop from a variety of neuropathologies including Alzheimer's disease dementia. During neurodegenerative conditions there are contributory factors such as neuroinflammation and amyloidogenesis involved in memory impairment. In the present study, dual properties of S100A9 protein as a pro-inflammatory and amyloidogenic agent were explored in the passive avoidance memory task along with neurochemical assays in the prefrontal cortex and hippocampus of aged mice. S100A9 oligomers and fibrils were generated in vitro and verified by AFM, Thioflavin T and A11 antibody binding. Native S100A9 as well as S100A9 oligomers and fibrils or their combination were administered intranasally over 14 days followed by behavioral and neurochemical analysis. Both oligomers and fibrils evoked amnestic activity which correlated with disrupted prefrontal cortical and hippocampal dopaminergic neurochemistry. The oligomer fibril combination produced similar but weaker neurochemistry to the fibrils administered alone but without passive avoidance amnesia. Native S100A9 did not modify memory task performance even though it generated a general and consistent decrease in monoamine levels (DA, 5-HT and NA) and increased metabolic marker ratios of DA and 5-HT turnover (DOPAC/DA, HVA/DA and 5-HIAA) in the prefrontal cortex. These results provide insight into a novel pathogenetic mechanism underlying amnesia in a fear-aggravated memory task based on amyloidogenesis of a pro-inflammatory factor leading to disrupted brain neurochemistry in the aged brain. The data further suggests that amyloid species of S100A9 create deleterious effects principally on the dopaminergic system and this novel finding might be potentially exploited during dementia management through a neuroprotective strategy. PMID- 26965571 TI - The role of the medial prefrontal cortex in updating reward value and avoiding perseveration. AB - The medial prefrontal cortex (mPFC) plays a major role in goal-directed behaviours, but it is unclear whether it plays a role in breaking away from a high-value reward in order to explore for better options. To address this question, we designed a novel 3-arm Bandit Task in which rats were required to choose one of three potential reward arms, each of which was associated with a different amount of food reward and time-out punishment. After a variable number of choice trials the reward locations were shuffled and animals had to disengage from the now devalued arm and explore the other options in order to optimise payout. Lesion and control groups' behaviours on the task were then analysed by fitting data with a reinforcement learning model. As expected, lesioned animals obtained less reward overall due to an inability to flexibly adapt their behaviours after a change in reward location. However, modelling results showed that lesioned animals were no more likely to explore than control animals. We also discovered that all animals showed a strong preference for certain maze arms, at the expense of reward. This tendency was exacerbated in the lesioned animals, with the strongest effects seen in a subset of animals with damage to dorsal mPFC. The results confirm a role for mPFC in goal-directed behaviours but suggest that rats rely on other areas to resolve the explore-exploit dilemma. PMID- 26965573 TI - Altered social cognition in male BDNF heterozygous mice and following chronic methamphetamine exposure. AB - Growing clinical evidence suggests that persistent psychosis which occurs in methamphetamine users is closely related to schizophrenia. However, preclinical studies in animal models have focussed on psychosis-related behaviours following methamphetamine, and less work has been done to assess endophenotypes relevant to other deficits observed in schizophrenia. Altered social behaviour is a feature of both the negative symptoms and cognitive deficits in schizophrenia, and significantly impacts patient functioning. We recently found that brain-derived neurotrophic factor (BDNF) heterozygous mice show disrupted sensitization to methamphetamine, supporting other work suggesting an important role of this neurotrophin in the pathophysiology of psychosis and the neuronal response to stimulant drugs. In the current study, we assessed social and cognitive behaviours in methamphetamine-treated BDNF heterozygous mice and wildtype littermate controls. Following chronic methamphetamine exposure male wildtype mice showed a 50% reduction in social novelty preference. Vehicle-treated male BDNF heterozygous mice showed a similar impairment in social novelty preference, with a trend for no further disruption by methamphetamine exposure. Female mice were unaffected in this task, and no groups showed any changes in sociability or short-term spatial memory. These findings suggest that chronic methamphetamine alters behaviour relevant to disruption of social cognition in schizophrenia, supporting other studies which demonstrate a close resemblance between persistent methamphetamine psychosis and schizophrenia. Together these findings suggest that dynamic regulation of BDNF signalling is necessary to mediate the effects of methamphetamine on behaviours relevant to schizophrenia. PMID- 26965572 TI - Predator-scent stress, ethanol consumption and the opioid system in an animal model of PTSD. AB - Emerging literature points to stress exposure as a potential contributor to the development of alcohol abuse, but animal models have yielded inconsistent results. Converging experimental data indicate that the endogenous opioid system modulates alcohol consumption and stress regulation. The aim of the present study is to examine the interplay between stress exposure, behavioral stress responses, ethanol (EtOH) consumption and the endogenous opioid system in an animal model of posttraumatic stress disorder. Rats were exposed to stress and then tested in a two-bottle free choice (TBC) assay or in a conditioned place preference paradigm. In some experiments, the endogenous opioid system was pharmacologically manipulated prior to stress exposure. The behavioral outcomes of stress exposure were assessed in an elevated plus-maze, with the acoustic startle response, and by monitoring the freezing response to trauma reminder. Immunoreactivity of phosphorylated opioid receptors in hippocampal subregions was also measured. Stress significantly increased the consumption of EtOH in the TBC assay. The severity of the behavioral response to stress was associated with EtOH consumption, cue-triggered freezing response to a trauma reminder, and endogenous levels of phosphorylated opioid receptors in the hippocampus. Pharmacologically manipulating the endogenous opioid system prior to stress exposure attenuated trauma cue-triggered freezing responses and blocked predator scent stress-induced potentiation of EtOH consumption. These data demonstrate a stress-induced potentiation of EtOH self-administration and reveal a clear association between individual patterns of the behavioral response to stress and alcohol preference, while indicating a role for the endogenous opioid system in the neurobiological response to stress. PMID- 26965574 TI - Diagnosis and treatment of hyponatraemia in neurosurgical patients. AB - Hyponatraemia is the most common electrolyte imbalance in neurosurgical patients. Acute hyponatraemia is particularly common in neurosurgical patients after any type of brain insult, including brain tumours and their treatment, pituitary surgery, subarachnoid haemorrhage or traumatic brain injury. Acute hyponatraemia is an emergency condition, as it leads to cerebral oedema due to passive osmotic movement of water from the hypotonic plasma to the relatively hypertonic brain which ultimately is the cause of the symptoms associated with hyponatraemia. These include decreased level of consciousness, seizures, non-cardiogenic pulmonary oedema or transtentorial brain herniation. Prompt treatment is mandatory to prevent such complications, minimize permanent brain damage and therefore permit rapid recovery after brain insult. The infusion of 3% hypertonic saline is the treatment of choice with different rates of administration based on the severity of symptoms and the rate of drop in plasma sodium concentration. The pathophysiology of hyponatraemia in neurotrauma is multifactorial; although the syndrome of inappropriate antidiuresis (SIADH) and central adrenal insufficiency are the commonest causes encountered. Fluid restriction has historically been the classical treatment for SIADH, although it is relatively contraindicated in some neurosurgical patients such as those with subarachnoid haemorrhage. Furthermore, many cases admitted have acute onset hyponatraemia, who require hypertonic saline infusion. The recently developed vasopressin receptor 2 antagonist class of drug is a promising and effective tool but more evidence is needed in neurosurgical patients. Central adrenal insufficiency may also cause acute hyponatraemia in neurosurgical patients; this responds clinically and biochemically to hydrocortisone. The rare cerebral salt wasting syndrome is treated with large volume normal saline infusion. In this review, we summarize the current evidence based on the clinical presentation, causes and treatment of different types of hyponatraemia in neurosurgical patients. PMID- 26965575 TI - Isolation of broad-specificity domain antibody from phage library for development of pyrethroid immunoassay. AB - An antibody to phenoxybenzoic acid (PBA), the conserved chemical region of pyrethroids, was developed using a domain antibody (DAB) library to enable pyrethroid detection in agricultural products. The DAB library, constructed without animal immunization and based on a human VH framework, displayed repertoires on filamentous bacteriophage. After four rounds of panning, we obtained five domain antibodies that are capable of binding to PBA. Antibody A3 has strong identification capability to cypermethrin, beta-cypermethrin, and fenvalerate. The antibody A3 was used to develop an enzyme-linked immunosorbent assay (ELISA). The IC50 values were 2.586, 1.814, and 2.251 MUg/ml for cypermethrin, beta-cypermethrin, and fenvalerate, respectively. The assay shows weak competition with flucythrinate but shows no competition with fenpropathrin, deltamethrin, and permethrin. The developed ELISA process was successfully applied to fortified Chinese cabbage samples, with the recoveries of cypermethrin, beta-cypermethrin, and fenvalerate ranging from 84.4 to 112.3%. We developed an immunoassay to detect pyrethroids depending on the domain antibody library, which overcomes the limitation of requiring protein antigen to immunize animals raising antibody. PMID- 26965576 TI - Transtympanic balloon dilatation of the eustachian tube: systematic review. AB - OBJECTIVE: To investigate the evidence for balloon dilatation of the eustachian tube using a transtympanic approach. METHODS: A systematic search of several databases was conducted (using the search terms 'dilation' or 'dilatation', and 'balloon' and 'eustachian tube'). Only studies that used a transtympanic approach for the procedure were included. These studies were then assessed for risk of bias. RESULTS: Three studies were included. Each of these studies was a limited case series, with two performed on human subjects and one on human cadavers. Results of safety and efficacy are conflicting. There is a high risk of bias overall. CONCLUSION: At present, there is a very narrow evidence base for transtympanic balloon dilatation of the eustachian tube. There are a number of advantages and disadvantages of the technique. Previously identified and theoretical safety concerns will need to be addressed thoroughly in future studies prior to wider clinical use. PMID- 26965577 TI - Measuring Ochratoxin A Concentrations in Coffee Beverages with Immunoaffinity Columns and Ultra-Performance Liquid Chromatography/Tandem Mass Spectrometry. AB - This study developed and validated a method for measuring concentrations of ochratoxin A (OTA) in coffee beverages, not coffee beans. The new method involved extraction using immunoaffinity columns and ultra-performance LC (UPLC)-MS/MS using isotope-dilution techniques. The combination of a fused-core column and UPLC significantly shortened chromatographic time to 3 min compared to reported UPLC methods. The method was sensitive, with an LOD and LOQ of 0.52 and 1.73 pg/mL, respectively. Quantitative intraday (n = 4) and interday (n = 4) biases and RSD were both below 15%. The OTA levels in 40 samples of freshly brewed coffee from chain stores, 24 samples of canned ready-to-drink coffee, and 6 beverages made from instant coffee granules ranged from 1.60 to 93.2 pg/mL (90% positive), 6.00 to 131 pg/mL (100% positive), and 21.8 to 59.0 pg/mL (100% positive), respectively. Based on published tolerable daily intake, men and women in Taiwan should consume no more than 6.3 and 5.1 fifteen gram packages of instant coffee per day, respectively. Specific suggestions were not made for brewed coffee and canned coffee because of their large variation in OTA concentrations. This study should be more relevant to actual human exposure than those studying OTA in green, roasted, and ground coffee beans alone. PMID- 26965578 TI - Clinical, radiological, and pathological features of 33 adult unilateral thalamic gliomas. AB - BACKGROUND: Unilateral adult thalamic gliomas are rarely reported. In this study, the authors aimed to analyze the clinical, radiological, and pathological features of adult primary unilateral thalamus gliomas (UTGs). METHODS: Clinical data of 33 UTGs in adults who underwent surgical treatment between 2005 and 2014 at the Beijing Tiantan Hospital were collected and retrospectively studied. Follow-up evaluation was performed. RESULTS: This study included 21 males and 12 females with a mean age of 43.1 years. The most common symptoms were headache (75.8%, 25/33 patients) and motor deficits (42.4%, 14/33 patients). Radiological results showed that enhancement was common (90.9%, 30/33 patients) and included cystic appearances in 9 cases (27.3%). All patients underwent maximal safe tumor resection. Gross total resection (GTR) was achieved in 19 cases, subtotal resection (>=80%) in 9 cases, and partial resection (<80%) in 5 cases. Molecular pathology results were available in 15 cases. After surgery, 25 patients received postoperative adjuvant therapy based on the remaining pathology. The median follow-up period of all 33 patients with UTGs was 17 months (1 week~49 months). Twenty-four patients experienced tumor recurrence. The 1-year and 2-year progression-free survival (PFS) rates were 49.0 and 10.2%, respectively. The 1 year and 2-year overall survival (OS) rates were 68.1 and 25.9%, respectively. Survival analyses revealed that several predictive factors were correlated with better prognosis, among which, GTR and tumor with cystic appearances were significantly associated with a longer survival. CONCLUSIONS: Adult UTGs displayed a wide spectrum of clinical features. GTR can be achieved in adult UTGs with acceptable complications and conferred a better prognosis. Tumor with cystic appearance may indicate better prognosis. More patients and longer follow-up periods are needed to further elucidate the biological features of adult UTGs. PMID- 26965579 TI - High prevalence of TERT promoter mutations in primary squamous cell carcinoma of the urinary bladder. AB - TERT promoter mutations (TERT-mut) are detectable in the majority of urothelial carcinomas. The detection of TERT-mut in urine is under investigation as a potential urine-based molecular-screening assay for bladder cancer. A small but significant number of bladder carcinomas are pure squamous cell carcinoma. We sought to assess the incidence of TERT-mut in squamous cell carcinoma of the urinary bladder. A retrospective search of the institutional pathology archives yielded 15 cystectomy specimens performed for squamous cell carcinoma (2000 2014). Histologic slides were reviewed by a senior urologic pathologist to confirm the diagnosis and select a representative formalin-fixed paraffin embedded tissue block for mutational analysis. All cases yielded adequate material for DNA analysis. Sequencing for TERT-mut was performed using previously described SafeSeq technique. We detected TERT-mut in 12/15 (80%) of bladder squamous cell carcinomas. TERT promoter mutations, commonly found in conventional urothelial carcinoma, are also highly prevalent in urinary bladder squamous cell carcinoma suggesting a common tumorigenesis and potential utility as a molecular urine-based-screening assay. PMID- 26965580 TI - Post-ablation lymphocytic esophagitis in Barrett esophagus with high grade dysplasia or intramucosal carcinoma. AB - In patients who have undergone ablation therapy for treatment of Barrett's esophagus with dysplasia, histologic features of eosinophilic esophagitis, but not lymphocytic esophagitis, have been described. We evaluated for histologic evidence of eosinophilic esophagitis and lymphocytic esophagitis and correlated with endoscopic findings in this population. A single-institution Barrett's esophagus registry was searched for patients who had received radiofrequency ablation, cryotherapy, or both for treatment of Barrett's esophagus with dysplasia. Clinical and endoscopic data were collected and biopsies were reviewed for inflammation and reactive changes at three time points: pre-intervention, first surveillance after ablation therapy, and most recent surveillance. Of the 173 patients initially identified, 102 met the inclusion criteria. Intraepithelial eosinophils were increased at first surveillance (60%, P=0.096) and last surveillance (69%, P=0.048) compared with pre-intervention (50%), although histologic evidence of post-ablation eosinophilic esophagitis was not significant. Prevalence of lymphocytic esophagitis was significantly higher at first surveillance (17%, P=0.02) and at last surveillance (43%, P<0.001), compared with pre-intervention (7%). Smoking, hyperlipidemia, and cryotherapy were identified as independent risk factors for developing histologic lymphocytic esophagitis. This is the first report that histologic evidence of lymphocytic esophagitis increased over time in patients undergoing ablation for Barrett's esophagus with dysplasia. Though the pathophysiology of lymphocytic esophagitis remains unknown, patients in our study with a history of smoking, hyperlipidemia, or cryotherapy were more likely to develop post-ablation lymphocytic esophagitis. PMID- 26965581 TI - Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment. AB - Medullary carcinoma of the colon is a unique histologic subtype of microsatellite unstable colorectal carcinoma but little is known regarding its tumor immunoregulatory microenvironment. The aims of this study were to characterize the immune environment of medullary carcinoma and compare it with other microsatellite unstable and microsatellite stable colorectal carcinomas. An initial gene expression microarray analysis of six cases of medullary carcinoma was used to detect potentially differentially expressed genes. We extended this analysis utilizing genomic data from the Cancer Genome Atlas to compare eight cases of medullary carcinoma with other microsatellite unstable and stable carcinomas. Finally, we evaluated expression of key immune pathway proteins and lymphocyte subsets via immunohistochemistry of a large group of medullary carcinomas (n=105) and compared these findings with three other groups: poorly differentiated, microsatellite unstable well-differentiated and microsatellite stable well-differentiated carcinomas. Microarray and the Cancer Genome Atlas data analysis identified significant upregulation of several immunoregulatory genes induced by IFNgamma including IDO-1, WARS (tRNA(trp)), GBP1, GBP4, GBP5, PDCD1 (PD-1), and CD274 (PD-L1) in medullary carcinoma compared with other microsatellite unstable and microsatellite stable tumors. By immunohistochemistry, IDO-1 was expressed in 64% of medullary carcinomas compared with 19% (9/47) of poorly differentiated carcinomas, 14% (3/22) of microsatellite unstable, and 7% (2/30) of the microsatellite stable well-differentiated carcinomas (P<0.0001). tRNA(trp) was overexpressed in 81% (84/104) of medullary carcinomas, 19% (9/47) of poorly differentiated, 32% (7/22) of microsatellite unstable, and 3% (1/30) of microsatellite stable well-differentiated carcinomas (P<0.0001). Medullary carcinoma had higher mean CD8+ and PD-L1+ tumor infiltrating lymphocytes compared with all other groups (P<0.0001). This study demonstrates overexpression of several immunoregulatory genes in microsatellite unstable colorectal carcinomas and that expression of these genes and proteins is more prevalent in the medullary carcinoma subtype, which may be of use both diagnostically and therapeutically. PMID- 26965582 TI - Expression profiling of small intestinal neuroendocrine tumors identifies subgroups with clinical relevance, prognostic markers and therapeutic targets. AB - We wanted to define the transcriptome of small intestinal neuroendocrine tumors in order to identify clinically relevant subgroups of tumors, prognostic markers and novel targets for treatment. Genome-wide expression profiling was conducted on tumor biopsies from 33 patients with well-differentiated neuroendocrine tumors of the distal ileum and metastatic disease at the time of diagnosis. Unsupervised hierarchical clustering analysis identified three groups of tumors. The largest group, comprising half of the tumors, was characterized by longer patient survival and higher expression of neuroendocrine markers, including SSTR2. Tumors with higher grade (G2/3) or gain of chromosome 14 were associated with shorter patient survival and increased expression of cell cycle-promoting genes. Pathway analysis predicted the prostaglandin E receptor 2 (PTGER2) as the most significantly activated regulator in tumors of higher grade, whereas Forkhead box M1 (FOXM1) was the most significantly activated regulator in tumors with gain of chromosome 14. Druggable genes identified from expression profiles included clinically proven SSTR2 and also novel targets, for example, receptor tyrosine kinases (RET, FGFR1/3, PDGFRB and FLT1), epigenetic regulators, molecular chaperones and signal transduction molecules. Evaluation of candidate drug targets on neuroendocrine tumors cells (GOT1) showed significant inhibition of tumor cell growth after treatment with tyrosine kinase inhibitors or inhibitors of HDAC, HSP90 and AKT. In conclusion, we have defined the transcriptome of small intestinal neuroendocrine tumors and identified novel subgroups with clinical relevance. We found specific gene expression patterns associated with tumor grade and chromosomal alterations. Our data also suggest novel prognostic biomarkers and therapies for these patients. PMID- 26965584 TI - The influence of birth weight amongst 33-35 weeks gestational age (wGA) infants on the risk of respiratory syncytial virus (RSV) hospitalisation: a pooled analysis. AB - OBJECTIVE: To investigate the association between birth weight and respiratory syncytial virus (RSV) hospitalisation during the first year of life in 33 degrees -356 weeks' gestational age (wGA) infants. STUDY DESIGN: Pooled analysis of data (n = 1218) from Spain, Germany, France and Italy. RESULT: RSV hospitalised infants overall had a significantly higher birth weight than non-hospitalised infants (2.24 versus 2.14 kg; p < 0.001) for both males (2.25 versus 2.18 kg; p = 0.049) and females (2.22 versus 2.11 kg, p = 0.007). The effect was significant only in 34 wGA infants (33 wGA: hospitalised 1.95 kg versus non-hospitalised 1.95 kg, p = 0.976; 34 wGA: 2.26 versus 2.14 kg, p = 0.007; 35 wGA: 2.37 versus 2.29 kg, p = 0.070), particularly female 34 wGA infants (female: 2.24 versus 2.08 kg, p = 0.019; male: 2.27 versus 2.20, p = 0.191). Birth weight was shown to be an independent risk factor for RSV hospitalisation. CONCLUSIONS: In 33-35 wGA infants, a higher birth weight appeared independently associated with an increased risk of RSV hospitalisation. PMID- 26965583 TI - Characterization of a variant of t(14;18) negative nodal diffuse follicular lymphoma with CD23 expression, 1p36/TNFRSF14 abnormalities, and STAT6 mutations. AB - A predominantly diffuse growth pattern and CD23 co-expression are uncommon findings in nodal follicular lymphoma and can create diagnostic challenges. A single case series in 2009 (Katzenberger et al) proposed a unique morphologic variant of nodal follicular lymphoma, characterized by a predominantly diffuse architecture, lack of the t(14;18) IGH/BCL2 translocation, presence of 1p36 deletion, frequent inguinal lymph node involvement, CD23 co-expression, and low clinical stage. Other studies on CD23+ follicular lymphoma, while associating inguinal location, have not specifically described this architecture. In addition, no follow-up studies have correlated the histopathologic and cytogenetic/molecular features of these cases, and they remain a diagnostic problem. We identified 11 cases of diffuse, CD23+ follicular lymphoma with histopathologic features similar to those described by Katzenberger et al. Along with pertinent clinical information, we detail their histopathology, IGH/BCL2 translocation status, lymphoma-associated chromosomal gains/losses, and assessment of mutations in 220 lymphoma-associated genes by massively parallel sequencing. All cases showed a diffuse growth pattern around well- to ill-defined residual germinal centers, uniform CD23 expression, mixed centrocytic/centroblastic cytology, and expression of at least one germinal center marker. Ten of 11 involved inguinal lymph nodes, 5 solely. By fluorescence in situ hybridization analysis, the vast majority lacked IGH/BCL2 translocation (9/11). Deletion of 1p36 was observed in five cases and included TNFRSF14. Of the six cases lacking 1p36 deletion, TNFRSF14 mutations were identified in three, highlighting the strong association of 1p36/TNFRSF14 abnormalities with this follicular lymphoma variant. In addition, 9 of the 11 cases tested (82%) had STAT6 mutations and nuclear P-STAT6 expression was detectable in the mutated cases by immunohistochemistry. The proportion of STAT6 mutations is higher than recently reported in conventional follicular lymphoma (11%). These findings lend support for a clinicopathologic variant of t(14;18) negative nodal follicular lymphoma and suggests importance of the interleukin (IL)-4/JAK/STAT6 pathway in this variant. PMID- 26965585 TI - Petroclival Meningioma: Patient's Outcomes Can Be Improved by Being Flexible When Choosing the Surgical Approach. PMID- 26965587 TI - Patterns of lymphatic spread and the management of eyelid carcinomas. AB - OBJECTIVE: Eyelid carcinomas are rare, and the management strategy of regional lymph node metastasis linked to eyelid carcinomas has not been standardized to date. The aim of the present study was to analyze the patterns of regional metastasis and to assess the optimal extent of surgical treatment for lymph node metastasis of eyelid carcinoma. METHODS: This study was a retrospective review of patient data from a single institution. From a series of 268 eyelid carcinomas, we selected the 21 patients with lymph node metastasis, and we analyzed the patterns of lymphatic spread, approach to treatment and outcomes. RESULTS: The most common histological type of eyelid carcinoma with regional metastasis was sebaceous carcinoma (17/21, 81.0%). Submandibular area metastases were seen only in the patients with the primary tumor originating in the medial half of the eyelid, but parotid area metastases were seen in both the patients whose tumors had a medial-half origin and those with a lateral-half origin. Although 11 of the 16 patients with parotid-area metastases underwent a tumorectomy or superficial parotidectomy (which resulted in four cases of recurrence in the parotid area), none of the five patients who underwent a total parotidectomy developed parotid area recurrence. The incidence of regional recurrence of the patients who received adjuvant radiotherapy (14.3%) was lower than that of the patients without adjuvant radiotherapy (57.1%). CONCLUSION: Continued surveillance and optimal management of regional lymph node metastases are important for the control and survival of eyelid carcinomas. PMID- 26965589 TI - Patient-Reported Metal Allergy: A Risk Factor for Poor Outcomes After Total Joint Arthroplasty? AB - BACKGROUND: Metal sensitivity after total joint arthroplasty has been of increased concern, but the impact of a patient-reported metal allergy on clinical outcomes has not been investigated. The purpose of this study was to report the incidence and impact of patient-reported metal allergy after total knee arthroplasty (TKA) and total hip arthroplasty (THA). METHODS: This was a retrospective, institutional review board-approved investigation of patients undergoing a primary, elective total joint arthroplasty between 2009 and 2011. All patients completed a preoperative questionnaire asking about drug and environmental allergies. In January 2010, a specific question was added regarding the presence of a metal allergy. University of California at Los Angeles Activity, Short Form 12 (SF-12), Modified Harris Hip, and Knee Society scores were collected preoperatively and at most recent follow-up. Overall cohorts of metal allergy and nonmetal allergy patients were compared, and a 1:2 matching analysis was also performed. RESULTS: Nine hundred six primary THAs and 589 primary TKAs were included. The incidence of patient-reported metal allergy was 1.7% before January 2010 and 4.0% after (overall 2.3% of THAs and 4.1% of TKAs); 97.8% of metal allergy patients were female. After TKA, postoperative Knee Society Function, Symptoms, Satisfaction, and Expectation scores were all decreased in the metal allergy cohort (P < .001-.002). After THA, metal allergy patients had a decreased postoperative SF-12 Mental Component Score and less incremental improvement in their SF-12 Mental Component Score vs the nonmetal allergy cohort (P < .0001 and P = .001, respectively). CONCLUSION: Patient reported metal allergy is associated with decreased functional outcomes after TKA and decreased mental health scores after THA. PMID- 26965588 TI - miR-30 family promotes migratory and invasive abilities in CD133(+) pancreatic cancer stem-like cells. AB - Pancreatic cancer is a deadly disease with a poor prognosis. Recently, miRNAs have been reported to be abnormally expressed in several cancers and play a role in cancer development and progression. However, the role of miRNA in cancer stem cells remains unclear. Therefore, our aim was to investigate the role of miRNA in the CD133(+) pancreatic cancer cell line Capan-1M9 because CD133 is a putative marker of pancreatic cancer stem cells. Using miRNA microarray, we found that the expression level of the miR-30 family decreased in CD133 genetic knockdown shCD133 Capan-1M9 cells. We focused on miR-30a, -30b, and -30c in the miR-30 family and created pancreatic cancer cell sublines, each transfected with these miRNAs. High expression of miR-30a, -30b, or -30c had no effect on cell proliferation and sphere forming. In contrast, these sublines were resistant to gemcitabine, which is a standard anticancer drug for pancreatic cancer, and in addition, promoted migration and invasion. Moreover, mesenchymal markers were up regulated by these miRNAs, suggesting that mesenchymal phenotype is associated with an increase in migration and invasion. Thus, our study demonstrated that high expression of the miR-30 family modulated by CD133 promotes migratory and invasive abilities in CD133(+) pancreatic cancer cells. These findings suggest that targeted therapies to the miR-30 family contribute to the development of novel therapies for CD133(+) pancreatic cancer stem cells. PMID- 26965591 TI - Cover stories: Making the cover for the Forensics special issue. PMID- 26965590 TI - Prevalence of bovine trypanosomosis in Ethiopia: a meta-analysis. AB - BACKGROUND: Trypanosomosis is a haemoprotozoan disease, mostly transmitted by the tsetse fly (Glossina spp.), it causes severe disease in humans and animals in Sub Saharan Africa (SSA). The disease results in loss of livestock and agricultural productivity with severe socio-economic impacts. In Ethiopia, bovine trypanosomosis is widely distributed in western and south-western parts of the country. It is estimated that some 10 to 14 million heads of cattle in Ethiopia are exposed to the risk of trypanosomosis. METHODS: This study describes the prevalence of bovine trypanosomosis in Ethiopia through a meta-analysis. A comprehensive search was conducted on PubMed and non-PubMed indexed articles were also incorporated based on expert suggestion. Eligible studies were selected by using inclusion and exclusion criteria. Pooled prevalence was estimated by random effect model. Publication bias and the variation in prevalence estimates attributed to heterogeneity were also assessed. RESULTS: Twenty-four studies with relevant prevalence data were identified and included in the analysis. The apparent prevalence of bovine trypanosomosis varied from 1.38 to 17.15 %. The pooled estimate of bovine trypanosomosis prevalence across studies for the entire period was 8.12 % (95 % CI: 6.88; 9.35), ranging from 10.27 % (95 % CI: 7.34; 13.20) in the late 1990s and early 2000s, to 6.81 % (95 % CI: 5.00; 8.62) after 2010. Sub-analysis by region revealed wide variations in prevalence. The highest estimated regional prevalence was 13.30 % (95 % CI: 7.73; 18.88) in Benishangul Gumuz Regional state. A high degree of heterogeneity was observed in most pooled estimates and even after sub-group analysis. The visual inspection of the funnel plot and the Egger's regression asymmetry coefficient [b = 2.18] (95 % CI = 1.09, 5.46; p > 0.05) did not suggest the presence of publication bias. T. congolense and T. vivax were reported to be the predominant causative agents. From the total positive animals, 45.5 and 44.3 % of the infections are accounted to T. congolense and T. vivax, respectively. CONCLUSIONS: The meta-analysis showed a significant reduction in prevalence of bovine trypanosomosis in recent years, but the reduction is not to the lowest necessary level. Since T. vivax is reported to be one of the most important trypanosome species involved, efforts should also be made to control the mechanical transmission by biting flies. PMID- 26965592 TI - Tackling toxics. PMID- 26965593 TI - PREview of new products. PMID- 26965595 TI - PLANETARY SCIENCE. Mars orbiter to sniff for methane. PMID- 26965596 TI - INFECTIOUS DISEASE. Evidence grows for Zika virus as pregnancy danger. PMID- 26965597 TI - GRAVITATIONAL WAVES. In search of spacetime megawaves. PMID- 26965598 TI - LIPID BIOLOGY. Why high 'good cholesterol' can be bad news. PMID- 26965599 TI - ITALY. Plans for new research hub get critical reception. PMID- 26965600 TI - Evidence on trial. PMID- 26965601 TI - Sizing up the evidence. PMID- 26965602 TI - When DNA is lying. PMID- 26965603 TI - How hair can reveal a history. PMID- 26965605 TI - Who dropped the bomb? PMID- 26965604 TI - A trail of microbes. PMID- 26965606 TI - Whose voice is that? PMID- 26965607 TI - Clues from the ashes. PMID- 26965608 TI - The microbial death clock. PMID- 26965609 TI - The Bitcoin busts. PMID- 26965610 TI - MARINE GOVERNANCE. Ending hide and seek at sea. PMID- 26965611 TI - MICROBIOLOGY. The invisible dimension of fungal diversity. PMID- 26965612 TI - QUANTUM OPTICS. The time is right for multiphoton entangled states. PMID- 26965613 TI - AUTISM. Unraveling a pathway to autism. PMID- 26965614 TI - MICROBIOLOGY. Feeding on plastic. PMID- 26965615 TI - PHYSICS. To see the world in a grain of spins. PMID- 26965616 TI - Streamlining China's protected areas. PMID- 26965617 TI - Social cost of carbon: Global duty. PMID- 26965618 TI - Reforming China's science awards. PMID- 26965619 TI - Comment on "Math at home adds up to achievement in school". AB - Berkowitz et al. (Reports, 9 October 2015, p. 196) described a randomized field experiment testing whether a math app designed to increase parent-child interaction could also bring academic benefits. A reanalysis of the data suggests that this well-designed trial failed to find strong evidence for the efficacy of the intervention. In particular, there was no significant effect of the intervention on math performance. PMID- 26965620 TI - Response to Comment on "Math at home adds up to achievement in school". AB - Frank presents an alternative interpretation of our data, yet reports largely similar results to those in our original Report. A critical difference centers on how to interpret and test interaction effects. Frank finds no mistakes in our analyses. We stand by our original conclusions of meaningful effects of the Bedtime Learning Together (BLT) math app on children's math achievement. PMID- 26965622 TI - Wavelike charge density fluctuations and van der Waals interactions at the nanoscale. AB - Recent experiments on noncovalent interactions at the nanoscale have challenged the basic assumptions of commonly used particle- or fragment-based models for describing van der Waals (vdW) or dispersion forces. We demonstrate that a qualitatively correct description of the vdW interactions between polarizable nanostructures over a wide range of finite distances can only be attained by accounting for the wavelike nature of charge density fluctuations. By considering a diverse set of materials and biological systems with markedly different dimensionalities, topologies, and polarizabilities, we find a visible enhancement in the nonlocality of the charge density response in the range of 10 to 20 nanometers. These collective wavelike fluctuations are responsible for the emergence of nontrivial modifications of the power laws that govern noncovalent interactions at the nanoscale. PMID- 26965623 TI - Generation of multiphoton entangled quantum states by means of integrated frequency combs. AB - Complex optical photon states with entanglement shared among several modes are critical to improving our fundamental understanding of quantum mechanics and have applications for quantum information processing, imaging, and microscopy. We demonstrate that optical integrated Kerr frequency combs can be used to generate several bi- and multiphoton entangled qubits, with direct applications for quantum communication and computation. Our method is compatible with contemporary fiber and quantum memory infrastructures and with chip-scale semiconductor technology, enabling compact, low-cost, and scalable implementations. The exploitation of integrated Kerr frequency combs, with their ability to generate multiple, customizable, and complex quantum states, can provide a scalable, practical, and compact platform for quantum technologies. PMID- 26965624 TI - Simple universal models capture all classical spin physics. AB - Spin models are used in many studies of complex systems because they exhibit rich macroscopic behavior despite their microscopic simplicity. Here, we prove that all the physics of every classical spin model is reproduced in the low-energy sector of certain "universal models," with at most polynomial overhead. This holds for classical models with discrete or continuous degrees of freedom. We prove necessary and sufficient conditions for a spin model to be universal and show that one of the simplest and most widely studied spin models, the two dimensional Ising model with fields, is universal. Our results may facilitate physical simulations of Hamiltonians with complex interactions. PMID- 26965625 TI - Quasiparticle interference of the Fermi arcs and surface-bulk connectivity of a Weyl semimetal. AB - Weyl semimetals host topologically protected surface states, with arced Fermi surface contours that are predicted to propagate through the bulk when their momentum matches that of the surface projections of the bulk's Weyl nodes. We used spectroscopic mapping with a scanning tunneling microscope to visualize quasiparticle scattering and interference at the surface of the Weyl semimetal TaAs. Our measurements reveal 10 different scattering wave vectors, which can be understood and precisely reproduced with a theory that takes into account the shape, spin texture, and momentum-dependent propagation of the Fermi arc surface states into the bulk. Our findings provide evidence that Weyl nodes act as sinks for electron transport on the surface of these materials. PMID- 26965626 TI - Accelerated crystallization of zeolites via hydroxyl free radicals. AB - In the hydrothermal crystallization of zeolites from basic media, hydroxide ions (OH(-)) catalyze the depolymerization of the aluminosilicate gel by breaking the Si,Al-O-Si,Al bonds and catalyze the polymerization of the aluminosilicate anions around the hydrated cation species by remaking the Si,Al-O-Si,Al bonds. We report that hydroxyl free radicals (*OH) are involved in the zeolite crystallization under hydrothermal conditions. The crystallization processes of zeolites-such as Na-A, Na-X, NaZ-21, and silicalite-1-can be accelerated with hydroxyl free radicals generated by ultraviolet irradiation or Fenton's reagent. PMID- 26965630 TI - The water watchdog. PMID- 26965629 TI - Measurement of gene regulation in individual cells reveals rapid switching between promoter states. AB - In vivo mapping of transcription-factor binding to the transcriptional output of the regulated gene is hindered by probabilistic promoter occupancy, the presence of multiple gene copies, and cell-to-cell variability. We demonstrate how to overcome these obstacles in the lysogeny maintenance promoter of bacteriophage lambda, P(RM). We simultaneously measured the concentration of the lambda repressor CI and the number of messenger RNAs (mRNAs) from P(RM) in individual Escherichia coli cells, and used a theoretical model to identify the stochastic activity corresponding to different CI binding configurations. We found that switching between promoter configurations is faster than mRNA lifetime and that individual gene copies within the same cell act independently. The simultaneous quantification of transcription factor and promoter activity, followed by stochastic theoretical analysis, provides a tool that can be applied to other genetic circuits. PMID- 26965627 TI - A bacterium that degrades and assimilates poly(ethylene terephthalate). AB - Poly(ethylene terephthalate) (PET) is used extensively worldwide in plastic products, and its accumulation in the environment has become a global concern. Because the ability to enzymatically degrade PET has been thought to be limited to a few fungal species, biodegradation is not yet a viable remediation or recycling strategy. By screening natural microbial communities exposed to PET in the environment, we isolated a novel bacterium, Ideonella sakaiensis 201-F6, that is able to use PET as its major energy and carbon source. When grown on PET, this strain produces two enzymes capable of hydrolyzing PET and the reaction intermediate, mono(2-hydroxyethyl) terephthalic acid. Both enzymes are required to enzymatically convert PET efficiently into its two environmentally benign monomers, terephthalic acid and ethylene glycol. PMID- 26965628 TI - Schedule-dependent interaction between anticancer treatments. AB - The oncogene MDMX is overexpressed in many cancers, leading to suppression of the tumor suppressor p53. Inhibitors of the oncogene product MDMX therefore might help reactivate p53 and enhance the efficacy of DNA-damaging drugs. However, we currently lack a quantitative understanding of how MDMX inhibition affects the p53 signaling pathway and cell sensitivity to DNA damage. Live cell imaging showed that MDMX depletion triggered two distinct phases of p53 accumulation in single cells: an initial postmitotic pulse, followed by low-amplitude oscillations. The response to DNA damage was sharply different in these two phases; in the first phase, MDMX depletion was synergistic with DNA damage in causing cell death, whereas in the second phase, depletion of MDMX inhibited cell death. Thus a quantitative understanding of signal dynamics and cellular states is important for designing an optimal schedule of dual-drug administration. PMID- 26965621 TI - Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. AB - Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant). PMID- 26965631 TI - Architecture of the type IVa pilus machine. AB - Type IVa pili are filamentous cell surface structures observed in many bacteria. They pull cells forward by extending, adhering to surfaces, and then retracting. We used cryo-electron tomography of intact Myxococcus xanthus cells to visualize type IVa pili and the protein machine that assembles and retracts them (the type IVa pilus machine, or T4PM) in situ, in both the piliated and nonpiliated states, at a resolution of 3 to 4 nanometers. We found that T4PM comprises an outer membrane pore, four interconnected ring structures in the periplasm and cytoplasm, a cytoplasmic disc and dome, and a periplasmic stem. By systematically imaging mutants lacking defined T4PM proteins or with individual proteins fused to tags, we mapped the locations of all 10 T4PM core components and the minor pilins, thereby providing insights into pilus assembly, structure, and function. PMID- 26965632 TI - PKC-delta activation in neutrophils promotes fungal clearance. AB - The C-type lectin receptor dectin-1 and the integrin Mac-1 have key roles in controlling fungal infection. Here, we demonstrate that dectin-1- and Mac-1 induced activation of protein kinase Cdelta in neutrophils, independent of the Card9 adaptor, is required for reactive oxygen species production and for intracellular killing upon Candida albicans uptake. Protein kinase Cdelta was also required for zymosan-induced cytokine generation in neutrophils. In macrophages, protein kinase Cdelta deficiency prevented fungi-induced reactive oxygen species generation but had no effect on activation of TGF-beta-activated kinase-1, an effector of Card9, or nuclear factor kappaB activation, nor did it affect phagolysosomal maturation, autophagy, or intracellular C. albicans killing. In vivo, protein kinase Cdelta-deficient mice were highly susceptible to C. albicans and Aspergillus fumigatus infection, which was partially rescued with adoptively transferred wild-type neutrophils. Thus, protein kinase Cdelta activation downstream of dectin-1 and Mac-1 has an important role in neutrophil, but not macrophage, functions required for host defense against fungal pathogens. PMID- 26965634 TI - Interleukin-7 promotes human regulatory T cell development at the CD4+CD8+ double positive thymocyte stage. AB - Although mature human FOXP3(+) regulatory T cells are CD127 (IL-7Ralpha) negative, CD4(+)CD8(+) FOXP3(+) thymocytes express relatively high levels of CD127 and are responsive to IL-7. However, the role of IL-7 in human regulatory T cell development is poorly known. We show that at the CD4(+)CD8(+) stage, FOXP3(+) thymocytes are highly susceptible to apoptosis, and IL-7 selectively rescues them from death, leading to an increased frequency of FOXP3(+) cells. IL 7 also promotes the development of regulatory T cell phenotype by inducing up regulation of FOXP3(+) and CTLA-4 expression. In contrast, IL-7 does not enhance proliferation of FOXP3(+)thymocytes or induce demethylation of FOXP3(+) regulatory T cell-specific demethylated region. After the CD4(+)CD8(+) stage, the FOXP3(+) thymocytes down-regulate CD127 expression but despite very low levels of CD127, remain responsive to IL-7. These results suggest that IL-7 affects human regulatory T cell development in the thymus by at least 2 distinct mechanisms: suppression of apoptosis and up-regulation of FOXP3(+) expression. PMID- 26965633 TI - CD63 is tightly associated with intracellular, secretory events chaperoning piecemeal degranulation and compound exocytosis in human eosinophils. AB - Eosinophil activation leads to secretion of presynthesized, granule-stored mediators that determine the course of allergic, inflammatory, and immunoregulatory responses. CD63, a member of the transmembrane-4 glycoprotein superfamily (tetraspanins) and present on the limiting membranes of eosinophil specific (secretory) granules, is considered a potential surface marker for eosinophil degranulation. However, the intracellular secretory trafficking of CD63 in eosinophils and other leukocytes is not understood. Here, we provide a comprehensive investigation of CD63 trafficking at high resolution within human eosinophils stimulated with inflammatory stimuli, CCL11 and tumor necrosis factor alpha, which induce distinctly differing secretory processes in eosinophils: piecemeal degranulation and compound exocytosis, respectively. By using different transmission electron microscopy approaches, including an immunonanogold technique, for enhanced detection of CD63 at subcellular compartments, we identified a major intracellular pool of CD63 that is directly linked to eosinophil degranulation events. Transmission electron microscopy quantitative analyses demonstrated that, in response to stimulation, CD63 is concentrated within granules undergoing secretion by piecemeal degranulation or compound exocytosis and that CD63 tracks with the movements of vesicles and granules in the cytoplasm. Although CD63 was observed at the cell surface after stimulation, immunonanogold electron microscopy revealed that a strong CD63 pool remains in the cytoplasm. It is remarkable that CCL11 and tumor necrosis factor alpha triggered increased formation of CD63(+) large vesiculotubular carriers (eosinophil sombrero vesicles), which fused with granules in the process of secretion, likely acting in the intracellular translocation of CD63. Altogether, we identified active, intracellular CD63 trafficking connected to eosinophil granule-derived secretory pathways. This is important for understanding the complex secretory activities of eosinophils underlying immune responses. PMID- 26965636 TI - Long noncoding RNAs as regulators of Toll-like receptor signaling and innate immunity. AB - Sensing of microbial pathogens and endogenous "alarmins" by macrophages and dendritic cells is reliant on pattern recognition receptors, including membrane associated TLRs, cytosolic nucleotide-binding and oligomerization domain leucine rich repeat-containing receptors, retinoic acid-inducible gene I-like receptors, and absent in melanoma 2-like receptors. Engagement of TLRs elicits signaling pathways that activate inflammatory genes whose expression is regulated by chromatin-modifying complexes and transcription factors. Long noncoding RNAs have emerged as new regulators of inflammatory mediators in the immune system. They are expressed in macrophages, dendritic cells, neutrophils, NK cells, and T- and B-lymphocytes and are involved in immune cell differentiation and activation. Long noncoding RNAs act via repression or activation of transcription factors, modulation of stability of mRNA and microRNA, regulation of ribosome entry and translation of mRNAs, and controlling components of the epigenetic machinery. In this review, we focus on recent advances in deciphering the mechanisms by which long noncoding RNAs regulate TLR-driven responses in macrophages and dendritic cells and discuss the involvement of long noncoding RNAs in endotoxin tolerance, autoimmune, and inflammatory diseases. The dissection of the role of long noncoding RNAs will improve our understanding of the mechanisms of regulation of inflammation and may provide new targets for therapeutic intervention. PMID- 26965637 TI - Proteolytic processing of human serum albumin generates EPI-X4, an endogenous antagonist of CXCR4. AB - The chemokine receptor CXCR4 is an important G protein-coupled receptor. Signaling via CXCL12 regulates a number of important biologic processes, including immune responses, organogenesis, or hematopoiesis. Dysregulation of CXCR4 signaling is associated with a variety of diseases, such as cancer development and metastasis, immunodeficiencies, or chronic inflammation. Here, we review our findings on endogenous peptide inhibitor of CXCR4 as a novel antagonist of CXCR4. This peptide is a 16-residue fragment of human serum albumin and was isolated as an inhibitor of CXCR4-tropic human immunodeficiency virus type 1 from a blood-derived peptide library. Endogenous peptide inhibitor of CXCR4 binds the second extracellular loop of CXCR4, thereby preventing engagement of CXCL12 and antagonizing the receptor. Consequently, endogenous peptide inhibitor of CXCR4 inhibits CXCL12-mediated migration of CXCR4-expressing cells in vitro, mobilizes hematopoietic stem cells, and suppresses inflammatory responses in vivo. We discuss the generation of endogenous peptide inhibitor of CXCR4, its relevance as biomarker for disease, and its role in human immunodeficiency virus/acquired immunodeficiency syndrome pathogenesis and cancer. Furthermore, we discuss why optimized endogenous peptide inhibitor of CXCR4 derivatives might have advantages over other CXCR4 antagonists. PMID- 26965635 TI - Frontline Science: Splenic progenitors aid in maintaining high neutrophil numbers at sites of sterile chronic inflammation. AB - Neutrophils are constantly generated from hematopoietic stem and progenitor cells in the bone marrow to maintain high numbers in circulation. A considerable number of neutrophils and their progenitors have been shown to be present in the spleen too; however, their exact role in this organ remains unclear. Herein, we sought to study the function of splenic neutrophils and their progenitors using a mouse model for sterile, peritoneal inflammation. In this microcapsule device implantation model, we show chronic neutrophil presence at implant sites, with recruitment from circulation as the primary mechanism for their prevalence in the peritoneal exudate. Furthermore, we demonstrate that progenitor populations in the spleen play a key role in maintaining elevated neutrophil numbers. Our results provide new insight into the role for splenic neutrophils and their progenitors and establish a model to study neutrophil function during sterile inflammation. PMID- 26965638 TI - Reduced TNF-alpha response in preterm neonates is associated with impaired nonclassic monocyte function. AB - Premature infants are highly susceptible to severe bacterial infections. The impaired infection control related to the functional immaturity of the neonatal innate immune system is an important cause of infection. Different monocyte subpopulations have been described and functionally characterized. However, data from preterm infants are scarce. We analyzed constitutive monocyte TLR2, TLR4, CD163, and HLA-DR expression in preterm cord blood. We further investigated activation of the signaling proteins ERK1/2 and NF-kappaB in monocyte subpopulations after ex vivo stimulation with the bacterial TLR agonists LPS and lipoteichoic acid. The functional outcome of the stimulation was determined by the intracellular production of TNF. Furthermore, the phagocytic activity was measured via flow cytometry. TLR4 and HLA-DR showed a gestational age-dependent increase. However, activation of ERK1/2 and NF-kappaB was impaired in neonatal monocyte subpopulations after stimulation with TLR agonists. Accordingly, intracellular TNF was diminished in preterm monocytes, especially in nonclassic monocytes. Premature monocytes showed high phagocytic activity, with significantly lower acidification of the phagosome. The reduced functional response of nonclassic monocytes of preterm neonates appears to be part of the diminished early immune response to bacterial cell wall components and is likely to contribute to their susceptibility to bacterial infection. PMID- 26965641 TI - Spectra-selective PbS quantum dot infrared photodetectors. AB - Traditional photoconductive photodetectors (PDs) commonly respond to higher energy photons compared with the bandgaps of PD active materials. Different from the wide detection spectra of traditional PDs, the present reported PbS quantum dot (QD) PDs can detect the spectra-selective light source. Spectra-selective PDs (ss-PDs) of perovskite/QDs and QD/QDs were respectively implemented by integrating two functional layers. The top layer (facing the light) was utilized to filter the non-target spectra and the bottom layer was used for detection. The response spectrum wavelength and the range of ss-PDs can be conveniently tailored by tuning the QD size. The obtained selectivity factor and normalized detectivity ratio from target and non-target illumination can reach at least 10. A narrow detection range with a full width at half maximum (FWHM) ~100 nm was applied by typical QD/QD based ss-PDs. The prototype ss-PDs were successfully applied in identifying an unknown light source. The convenient tuning and identification capabilities of the present QD based ss-PDs may provide a versatile route to obtain highly spectrum-selective PDs in order to meet the demands for special fields. PMID- 26965640 TI - NMRmix: A Tool for the Optimization of Compound Mixtures in 1D (1)H NMR Ligand Affinity Screens. AB - NMR ligand affinity screening is a powerful technique that is routinely used in drug discovery or functional genomics to directly detect protein-ligand binding events. Binding events can be identified by monitoring differences in the 1D (1)H NMR spectrum of a compound with and without protein. Although a single NMR spectrum can be collected within a short period (2-10 min per sample), one-by-one screening of a protein against a library of hundreds or thousands of compounds requires a large amount of spectrometer time and a large quantity of protein. Therefore, compounds are usually evaluated in mixtures ranging in size from 3 to 20 compounds to improve the efficiency of these screens in both time and material. Ideally, the NMR signals from individual compounds in the mixture should not overlap so that spectral changes can be associated with a particular compound. We have developed a software tool, NMRmix, to assist in creating ideal mixtures from a large panel of compounds with known chemical shifts. Input to NMRmix consists of an (1)H NMR peak list for each compound, a user-defined overlap threshold, and additional user-defined parameters if default settings are not used. NMRmix utilizes a simulated annealing algorithm to optimize the composition of the mixtures to minimize spectral peak overlaps so that each compound in the mixture is represented by a maximum number of nonoverlapping chemical shifts. A built-in graphical user interface simplifies data import and visual evaluation of the results. PMID- 26965639 TI - A restaurant-based intervention to promote sales of healthy children's menu items: the Kids' Choice Restaurant Program cluster randomized trial. AB - BACKGROUND: Away-from-home eating is an important dietary behavior with implications on diet quality. Thus, it is an important behavior to target to prevent and control childhood obesity and other chronic health conditions. Numerous studies have been conducted to improve children's dietary intake at home, in early care and education, and in schools; however, few studies have sought to modify the restaurant food environment for children. This study adds to this body of research by describing the development and launch of an innovative intervention to promote sales of healthy children's menu items in independent restaurants in Southern California, United States. METHODS: This is a cluster randomized trial with eight pair-matched restaurants in San Diego, California. Restaurants were randomized to a menu-only versus menu-plus intervention condition. The menu-only intervention condition involves manager/owner collaboration on the addition of pre-determined healthy children's menu items and kitchen manager/owner collaboration to prepare and plate these items and train kitchen staff. The menu-plus intervention condition involves more extensive manager/owner collaboration and kitchen staff training to select, prepare, and plate new healthy children's menu items, and a healthy children's menu campaign that includes marketing materials and server training to promote the items. The primary outcome is sales of healthy children's menu items over an 18-week period. In addition, dining parties consisting of adults with children under 18 years of age are being observed unobtrusively while ordering and then interviewed throughout the 18-week study period to determine the impact of the intervention on ordering behaviors. Manager/owner interviews and restaurant audits provide additional evidence of impact on customers, employees, and the restaurant environment. Our process evaluation assesses dose delivered, dose received, and intervention fidelity. DISCUSSION: Successful recruitment of the restaurants has been completed, providing evidence that the restaurant industry is open to working on the public health challenge of childhood obesity. Determining whether a restaurant intervention can promote sales of healthy children's menu items will provide evidence for how to create environments that support the healthy choices needed to prevent and control obesity. Despite these strengths, collection of sales data that will allow comprehensive analysis of intervention effects remains a challenge. TRIAL REGISTRATION: NCT02511938. PMID- 26965642 TI - Uptake Mechanisms of Eu(III) on Hydroxyapatite: A Potential Permeable Reactive Barrier Backfill Material for Trapping Trivalent Minor Actinides. AB - The permeable reactive barrier (PRB) technique has attracted an increasing level of attention for the in situ remediation of contaminated groundwater. In this study, the macroscopic uptake behaviors and microscopic speciation of Eu(III) on hydroxyapatite (HAP) were investigated by a combination of theoretical modeling, batch experiments, powder X-ray diffraction (PXRD) fitting, and X-ray absorption spectroscopy (XAS). The underlying removal mechanisms were identified to further assess the application potential of HAP as an effective PRB backfill material. The macroscopic analysis revealed that nearly all dissolved Eu(III) in solution was removed at pH 6.5 within an extremely short reaction time of 5 min. In addition, the thermodynamic calculations, desorption experiments, and PXRD and XAS analyses definitely confirmed the formation of the EuPO4.H2O(s) phase during the process of uptake of dissolved Eu(III) by HAP via the dissolution precipitation mechanism. A detailed comparison of the present experimental findings and related HAP-metal systems suggests that the relative contribution of precipitation to the total Eu(III) removal increases as the P:Eu ratio decreases. The dosage of HAP-based PRB for the remediation of groundwater polluted by Eu(III) and analogous trivalent actinides [e.g., Am(III) and Cm(III)] should be strictly controlled depending on the dissolved Eu(III) concentration to obtain an optimal P:M (M represents Eu, Am, or Cm) ratio and treatment efficiency. PMID- 26965644 TI - Are quantum spin Hall edge modes more resilient to disorder, sample geometry and inelastic scattering than quantum Hall edge modes? AB - On the surface of 2D topological insulators, 1D quantum spin Hall (QSH) edge modes occur with Dirac-like dispersion. Unlike quantum Hall (QH) edge modes, which occur at high magnetic fields in 2D electron gases, the occurrence of QSH edge modes is due to spin-orbit scattering in the bulk of the material. These QSH edge modes are spin-dependent, and chiral-opposite spins move in opposing directions. Electronic spin has a larger decoherence and relaxation time than charge. In view of this, it is expected that QSH edge modes will be more robust to disorder and inelastic scattering than QH edge modes, which are charge dependent and spin-unpolarized. However, we notice no such advantage accrues in QSH edge modes when subjected to the same degree of contact disorder and/or inelastic scattering in similar setups as QH edge modes. In fact we observe that QSH edge modes are more susceptible to inelastic scattering and contact disorder than QH edge modes. Furthermore, while a single disordered contact has no effect on QH edge modes, it leads to a finite charge Hall current in the case of QSH edge modes, and thus a vanishing of the pure QSH effect. For more than a single disordered contact while QH states continue to remain immune to disorder, QSH edge modes become more susceptible--the Hall resistance for the QSH effect changes sign with increasing disorder. In the case of many disordered contacts with inelastic scattering included, while quantization of Hall edge modes holds, for QSH edge modes a finite charge Hall current still flows. For QSH edge modes in the inelastic scattering regime we distinguish between two cases: with spin flip and without spin-flip scattering. Finally, while asymmetry in sample geometry can have a deleterious effect in the QSH case, it has no impact in the QH case. PMID- 26965643 TI - The Wnt/beta-catenin signaling/Id2 cascade mediates the effects of hypoxia on the hierarchy of colorectal-cancer stem cells. AB - Hypoxia, a feature common to most solid tumors, is known to regulate many aspects of tumorigenesis. Recently, it was suggested that hypoxia increased the size of the cancer stem-cell (CSC) subpopulations and promoted the acquisition of a CSC like phenotype. However, candidate hypoxia-regulated mediators specifically relevant to the stemness-related functions of colorectal CSCs have not been examined in detail. In the present study, we showed that hypoxia specifically promoted the self-renewal potential of CSCs. Through various in vitro studies, we found that hypoxia-induced Wnt/beta-catenin signaling increased the occurrence of CSC-like phenotypes and the level of Id2 expression in colorectal-cancer cells. Importantly, the levels of hypoxia-induced CSC-sphere formation and Id2 expression were successfully attenuated by treatment with a Wnt/beta-catenin signaling inhibitor. We further demonstrated, for the first time, that the degree of hypoxia-induced CSC-sphere formation (CD44(+) subpopulation) in vitro and of tumor metastasis/dissemination in vivo were markedly suppressed by knocking down Id2 expression. Taken together, these data suggested that Wnt/beta-catenin signaling mediated the hypoxia-induced self-renewal potential of colorectal cancer CSCs through reactivating Id2 expression. PMID- 26965645 TI - Lumbar Morel-Lavallee lesion: Case report and review of the literature. AB - The Morel-Lavallee lesion (MLL) is a rarely reported closed degloving injury, in which shearing forces have lead to break off subcutaneous tissues from the underlying fascia. Lumbar MLL have been rarely reported to date, explaining that patients are frequently misdiagnosed. While patients could be treated conservatively or with non-invasive procedures, delayed diagnosis may require open surgery for its cure. Indeed, untreated lesions can cause pain, infection or growing subcutaneous mass that can be confused with a soft tissue tumor. We report the clinical and radiological features of a 45-year old man with voluminous lumbar MLL initially misdiagnosed. We also reviewed the relevant English literature to summarize the diagnostic tools and the main therapeutic options. PMID- 26965646 TI - A Case of Neuro-Behcet's Disease Presenting with Central Neurogenic Hyperventilation. AB - BACKGROUND: Behcet's disease is a chronic inflammatory disorder usually characterized by the triad of oral ulcers, genital ulcers, and uveitis. Central to the pathogenesis of Behcet's disease is an autoimmune vasculitis. Neurological involvement, so called "Neuro-Behcet's disease", occurs in 10-20% of patients, usually from a meningoencephalitis or venous thrombosis. CASE REPORT: We report the case of a 46-year-old patient with Neuro-Behcet's disease who presented with central neurogenic hyperventilation as a result of brainstem involvement from venulitis. CONCLUSIONS: To the best of our knowledge, central neurogenic hyperventilation has not previously been described in a patient with Neuro Behcet's disease. PMID- 26965648 TI - The tapeworm's elusive antero-posterior polarity. AB - Because of their sessile lifestyle and the lack of the sensory and feeding structures usually associated with the cephalic end, fixing the antero-posterior (AP) polarity of tapeworms is somewhat equivocal and has been a matter of century long debates. Koziol et al. offer the first molecular evidence finally fixing the scolex as the animal's anterior pole. PMID- 26965647 TI - Evolution of conditional cooperation under multilevel selection. AB - We study the emergence of conditional cooperation in the presence of both intra group and inter-group selection. Individuals play public goods games within their groups using conditional strategies, which are represented as piecewise linear response functions. Accordingly, groups engage in conflicts with a certain probability. In contrast to previous studies, we consider continuous contribution levels and a rich set of conditional strategies, allowing for a wide range of possible interactions between strategies. We find that the existence of conditional strategies enables the stabilization of cooperation even under strong intra-group selection. The strategy that eventually dominates in the population has two key properties: (i) It is unexploitable with strong intra-group selection; (ii) It can achieve full contribution to outperform other strategies in the inter-group selection. The success of this strategy is robust to initial conditions as well as changes to important parameters. We also investigate the influence of different factors on cooperation levels, including group conflicts, group size, and migration rate. Their effect on cooperation can be attributed to and explained by their influence on the relative strength of intra-group and inter-group selection. PMID- 26965650 TI - Determination of 1-naphthol and 2-naphthol from environmental waters by magnetic solid phase extraction with Fe@MgAl-layered double hydroxides nanoparticles as the adsorbents prior to high performance liquid chromatography. AB - Magnetic Fe@MgAl-layered double hydroxides (MgAl-LDHs) composite was firstly synthesized by coating MgAl-layered double hydroxides on the surface of the dispersed nanoscale zero valent irons with co-precipitation method and characterized by transmission electron microscopy and X-ray diffraction techniques. The synthesized Fe@MgAl-LDHs nanoparticles were investigated for magnetic solid phase extraction (MSPE) of 1-naphthol and 2-naphthol from the water samples. The elutent containing 1-naphthol and 2-naphthol was analyzed by high performance liquid chromatography with variable wavelength detection (HPLC UV). Under optimal conditions, there is good linear relationship between the concentration and the peak area in the range of 0.5-200 MUgL(-1) with the correlation coefficients (r(2)) above 0.998 for 1-naphthol and 2-naphthol. The limits of detection were 0.22 MUgL(-1) and 0.19 MUgL(-1) for 1-naphthol and 2 naphthol, respectively, and precisions were both below 2.5% (n=6). The real water analysis demonstrated that the spiked recoveries were in the range of 79.2-80.9% (n=3). All these results indicated that the developed MSPE-HPLC-UV method was proved to be an efficient tool for the analysis of naphthols. PMID- 26965649 TI - Hydrophilic interaction liquid chromatography-tandem mass spectrometry methylphosponic and alkyl methylphosphonic acids determination in environmental samples after pre-column derivatization with p-bromophenacyl bromide. AB - Once exposed to the environment organophosphate nerve agents readily degrade by rapid hydrolysis to the corresponding alkyl methylphosphonic acids which do not exist in nature. These alkyl methylphosphonic acids are finally slowly hydrolyzed to methylphosphonic acid. Methylphosphonic acid is the most stable hydrolysis product of organophosphate nerve agents, persisting in environment for a long time. A highly sensitive method of methylphosphonic acid and alkyl methylphosphonic acids detection in dust and ground mixed samples has been developed and validated. The fact that alkyl methylphosphonic acids unlike methylphosphonic acid did not react with p-bromophenacyl bromide under chosen conditions was discovered. This allowed simultaneous chromatographic separation and mass spectrometric detection of derivatized methylphosphonic acid and underivatized alkyl methylphosphonic acids using HILIC-MS/MS method. Very simple sample pretreatment with high recoveries for each analyte was developed. Methylphosphonic acid pre-column derivate and alkyl methylphosphonic acids were detected using tandem mass spectrometry with electrospray ionization after hydrophilic interaction liquid chromatography separation. The developed approach allows achieving ultra-low detection limits: 200 pg mL(-1) for methylphosphonic acid, 70 pg mL(-1) for ethyl methylphosphonic acid, 8 pg mL(-1) for i-propyl methylphosphonic acid, 8 pg mL(-1) for i-butyl methylphosphonic acid, 5 pg mL(-1) for pinacolyl methylphosphonic acid in the extracts of dust and ground mixed samples. This approach was successfully applied to the dust and ground mixed samples from decommissioned plant for the production of chemical weapons. PMID- 26965652 TI - Antibody-induced neutrophil depletion prior to the onset of pneumococcal meningitis influences long-term neurological complications in mice. AB - During pneumococcal meningitis, clearance of bacteria by recruited neutrophils is crucial for host protection. However, these innate immune mechanisms are often insufficient and treatment with antibiotics is necessary to prevent death. Despite this antibiotic treatment, approximately half of all survivors suffer lifelong neurological problems. There is growing evidence indicating the harmful effects of neutrophils on CNS integrity. Therefore, the present study investigated the roles of neutrophils in the acute inflammatory response and the resulting long-term neuropsychological effects in murine pneumococcal meningitis. Long-term behavioural and cognitive functions in mice were measured using an automated IntelliCage system. Neutrophil depletion with antibody 1A8 as adjunctive therapy was shown to remarkably impair survival in meningitic C57BL/6J mice despite antibiotic (ceftriaxone) treatment. This was accompanied by increased bacterial load in the cerebrospinal fluid (CSF) and an increase in IL 1beta, but decrease in TNF, within the CSF at 20h after bacterial inoculation. In the longer term, the surviving neutrophil-depleted post-meningitic (PM) mice displayed reduced diurnal hypolocomotion compared to PM mice treated with an isotype antibody. However, they showed nocturnal hyperactivity, and greater learning impairment in a patrolling task that is believed to depend upon an intact hippocampus. The data thus demonstrate two important mechanisms: 1. Neutrophil extravasation into the CNS during pneumococcal meningitis influences the pro-inflammatory response and is central to control of the bacterial load, an increase in which may lead to death. 2. Neutrophil-mediated changes in the acute inflammatory response modulate the neuropsychological sequelae in mice that survive pneumococcal meningitis. PMID- 26965653 TI - Indoleamine-2,3-dioxygenase mediates neurobehavioral alterations induced by an intracerebroventricular injection of amyloid-beta1-42 peptide in mice. AB - Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by a progressive cognitive decline along with various neuropsychiatric symptoms, including depression and anxiety. Increasing evidence has been proposed the activation of the tryptophan-degrading indoleamine-2,3-dyoxigenase (IDO), the rate-limiting enzyme of kynurerine pathway (KP), as a pathogenic factor of amyloid-beta (Abeta)-related inflammation in AD. In the current study, the effects of an intracerebroventricular (i.c.v.) injection of Abeta1-42 peptide (400pmol/mice; 3MUl/site) on the regulation of KP biomarkers (IDO activity, tryptophan and kynurerine levels) and the impact of Abeta1-42 on neurotrophic factors levels were investigated as potential mechanisms linking neuroinflammation to cognitive/emotional disturbances in mice. Our results demonstrated that Abeta1-42 induced memory impairment in the object recognition test. Abeta1-42 also induced emotional alterations, such as depressive and anxiety-like behaviors, as evaluated in the tail suspension and elevated-plus maze tests, respectively. We observed an increase in levels of proinflammatory cytokines in the Abeta1-42-treated mice, which led to an increase in IDO activity in the prefrontal cortex (PFC) and the hippocampus (HC). The IDO activation subsequently increased kynurerine production and the kynurenine/tryptophan ratio and decreased the levels of neurotrophic factors in the PFC and HC, which contributed to Abeta-associated behavioral disturbances. The inhibition of IDO activation by IDO inhibitor 1-methyltryptophan (1-MT), prevented the development of behavioral and neurochemical alterations. These data demonstrate that brain IDO activation plays a key role in mediating the memory and emotional disturbances in an experimental model based on Abeta-induced neuroinflammation. PMID- 26965658 TI - Carry-over effect between diet and physical activity: the bottom-up and top-down hypotheses of hierarchical self-efficacy. AB - Healthy diet and physical activity have consistently been found to be positively correlated; however, most health behavior theories are focused on regulation of changes in single, rather than multiple, behaviors. Thus, this study explored the mechanism of the carry-over effect between diet and physical activity by conducting a longitudinal study with 706 participants to test the bottom-up and top-down hypotheses of hierarchical self-efficacy (SE). At Time 1 (baseline) and Time 3 (4 weeks after baseline), dietary behavior, physical activity, and self efficacies of these behaviors (at the contextual level) were measured, while at Time 2 (2 weeks after baseline), general SE (at the general level) was assessed. Mediation analysis and structural equation models supported both the bottom-up and top-down hypotheses for different levels of self-efficacies, suggesting that hierarchical SE is an important factor underlying the carry-over mechanism between diet and physical activity. PMID- 26965651 TI - CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. AB - The low-density lipoprotein receptor (LDLR) plays a pivotal role in clearing atherogenic circulating low-density lipoprotein (LDL) cholesterol. Here we show that the COMMD/CCDC22/CCDC93 (CCC) and the Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) complexes are both crucial for endosomal sorting of LDLR and for its function. We find that patients with X-linked intellectual disability caused by mutations in CCDC22 are hypercholesterolaemic, and that COMMD1 deficient dogs and liver-specific Commd1 knockout mice have elevated plasma LDL cholesterol levels. Furthermore, Commd1 depletion results in mislocalization of LDLR, accompanied by decreased LDL uptake. Increased total plasma cholesterol levels are also seen in hepatic COMMD9-deficient mice. Inactivation of the CCC associated WASH complex causes LDLR mislocalization, increased lysosomal degradation of LDLR and impaired LDL uptake. Furthermore, a mutation in the WASH component KIAA0196 (strumpellin) is associated with hypercholesterolaemia in humans. Altogether, this study provides valuable insights into the mechanisms regulating cholesterol homeostasis and LDLR trafficking. PMID- 26965660 TI - [Hydrocephalus complicating sarcoidosis in a patient with a meningocele]. PMID- 26965661 TI - Autism and autistic-like disorders: the hypothalamic-pituita-ry-adrenal system as a model for research. AB - In this article an overview is given of the differential diagnosis of autism and autistic-like disorders. The diagnosis of the so-called 'Multiple Complex Developmental Disorders' (MCDD) as a distinct entity is discussed in relation to autism and schizophrenia. Biological research and the relevance of results until recently are discussed. Finally, the importance of the hypothalamic-pituitary adrenal system (HPA system) as a model for research is proposed. Research on the flexibility of this system may contribute in understanding the ways of stress processing in disorders like autism, MCDD and schizophrenia. PMID- 26965659 TI - Human adipose-derived stem cells promote vascularization of collagen-based scaffolds transplanted into nude mice. AB - AIM: After in vivo implantation of cell-loaded devices, only the cells close to the capillaries can obtain nutrients to maintain their functions. It is known that factors secreted by stem cells, rather than stem cells themselves, are fundamental to guarantee new vascularization in the area of implant. MATERIALS & METHODS: To investigate this possibility, we have grafted mice with Bilayer and Flowable Integra((r)) scaffolds, loaded or not with human adipose-derived stem cells. RESULTS: Our results support the therapeutic potential of human adipose derived stem cells to induce new vascular networks of engineered organs and tissues. CONCLUSION: This finding suggests that our approach can help to form new vascular networks that allow sufficient vascularization of engineered organs and tissues in cases of difficult wound healing due to ischemic conditions. PMID- 26965662 TI - The immune system mediates blood-brain barrier damage; possible implications for pathophysiology of neuropsychiatric illnesses. AB - In this investigation the effects of immune activation on the brain are characterized. In order to study this, we used a model for chronic immune activation, the myocardial infarction, and intravenous injections with the pro inflammatory cytokine Tumour Necrosis Factor alpha (TNF-alpha). The incentive for this study is the observation that myocardial infarction is accompanied by behavioural and neuronal abnormalities. The effects of myocardial infarction on the brain and its functioning are widespread. In order to examine the mechanism through which this interaction occurs, a group of rats underwent an experimentally induced myocardial infarction whereafter immunohistochemistry was performed on slices of the brain. This experiment revealed regional serum protein extravasation, pointing to leakage of the blood-brain barrier. This process occurred in certain cortical, subcortical and hindbrain areas in discrete patches. The leakage was co-localized with the expression of the immune activation marker ICAM-1. A second group of rats was therefore injected with TNF alpha, a major pro-inflammatory cytokine, to assess the involvement of the immune system in the effects shown. This procedure rendered the same results. It is concluded that myocardial infarction may interfere with the integrity of the blood-brain barrier and possibly with brain functioning through activation of the immune system. The relevance for pathophysiological processes is discussed. PMID- 26965663 TI - Cholesterol and psyche. AB - This paper reviews the relationship between cholesterol and psychological functioning. Possibly a relationship exists between the lowering of cholesterol, low serum cholesterol concentration and mood and/or impulse control disorders. This might be associated with a disregulated cerebral serotonin metabolism. These hypotheses are based on (meta-analyses of) epidemiologic research investigating the lowering of cholesterol. One of the findings was an increased mortality due to suicide, homicide and accidents. Much is still unknown about the matters mentioned above. However, recommendations for research and clinical psychiatric practice are formulated. PMID- 26965664 TI - Biology of personality disorders. AB - Since the introduction of international psychiatric classification systems, systematic diagnostic methods have become available for personality disorders. Recent developments in the dimensional diagnostic approach of personality disorders have yielded relationships between this type of disorders and neurobiological processes including both monoaminergic and stress-hormonal systems. It is hypothesized that the pathogenesis of borderline personality disorders is related to an enhanced serotonergic tone in septo-hippocampal structures. Preliminary clinical data are suggestive for potential therapeutic effects of serotonin-modulating compounds in borderline personality disorders. PMID- 26965666 TI - Social prescribing could help alleviate pressure on GPs. PMID- 26965665 TI - Relative stability of network states in Boolean network models of gene regulation in development. AB - Progress in cell type reprogramming has revived the interest in Waddington's concept of the epigenetic landscape. Recently researchers developed the quasi potential theory to represent the Waddington's landscape. The Quasi-potential U(x), derived from interactions in the gene regulatory network (GRN) of a cell, quantifies the relative stability of network states, which determine the effort required for state transitions in a multi-stable dynamical system. However, quasi potential landscapes, originally developed for continuous systems, are not suitable for discrete-valued networks which are important tools to study complex systems. In this paper, we provide a framework to quantify the landscape for discrete Boolean networks (BNs). We apply our framework to study pancreas cell differentiation where an ensemble of BN models is considered based on the structure of a minimal GRN for pancreas development. We impose biologically motivated structural constraints (corresponding to specific type of Boolean functions) and dynamical constraints (corresponding to stable attractor states) to limit the space of BN models for pancreas development. In addition, we enforce a novel functional constraint corresponding to the relative ordering of attractor states in BN models to restrict the space of BN models to the biological relevant class. We find that BNs with canalyzing/sign-compatible Boolean functions best capture the dynamics of pancreas cell differentiation. This framework can also determine the genes' influence on cell state transitions, and thus can facilitate the rational design of cell reprogramming protocols. PMID- 26965667 TI - Deleterious effects of tributyltin on porcine vascular stem cells physiology. AB - The vascular functional and structural integrity is essential for the maintenance of the whole organism and it has been demonstrated that different types of vascular progenitor cells resident in the vessel wall play an important role in this process. The purpose of the present research was to observe the effect of tributyltin (TBT), a risk factor for vascular disorders, on porcine Aortic Vascular Precursor Cells (pAVPCs) in term of cytotoxicity, gene expression profile, functionality and differentiation potential. We have demonstrated that pAVPCs morphology deeply changed following TBT treatment. After 48h a cytotoxic effect has been detected and Annexin binding assay demonstrated that TBT induced apoptosis. The transcriptional profile of characteristic pericyte markers has been altered: TBT 10nM substantially induced alpha-SMA, while, TBT 500nM determined a significant reduction of all pericyte markers. IL-6 protein detected in the medium of pAVPCs treated with TBT at both doses studied and with a dose response. TBT has interfered with normal pAVPC functionality preventing their ability to support a capillary-like network. In addition TBT has determined an increase of pAVPC adipogenic differentiation. In conclusion in the present paper we have demonstrated that TBT alters the vascular stem cells in terms of structure, functionality and differentiating capability, therefore effects of TBT in blood should be deeply explored to understand the potential vascular risk associated with the alteration of vascular stem cell physiology. PMID- 26965668 TI - Reorganisation of a mesophilic biogas microbiome as response to a stepwise increase of ammonium nitrogen induced by poultry manure supply. AB - An anaerobic digestion experiment was investigated to evaluate the impact of increasing amounts of ammonium nitrogen due to poultry manure addition on the reactor performance, especially on the microbiome response. The microbial community structure was assessed by using a 16S rRNA gene approach, which was further correlated with the prevalent environmental conditions by using statistical analyses. The addition of 50% poultry manure led to a process disturbance indicated by a high VFA content (almost 10 g(HAc-Eq) L(-1)) in combination with elevated concentrations of ammonium nitrogen (5.9 g NH4(+)-N kg(FM)(-1)) and free ammonia (0.5 g NH3 kg(FM)(-1)). Simultaneously the microbiome, changed from a Bacteroidetes-dominated to a Clostridiales-dominated community accompanied by a shift from the acetoclastic to the hydrogenotrophic pathway. The "new" microbial community was functional redundant as the overall process rates were similar to the former one. A further increase of poultry manure resulted in a complete process failure. PMID- 26965669 TI - Determination of Gibbs energies of formation in aqueous solution using chemical engineering tools. AB - Standard Gibbs energies of formation are of primary importance in the field of biothermodynamics. In the absence of any directly measured values, thermodynamic calculations are required to determine the missing data. For several biochemical species, this study shows that the knowledge of the standard Gibbs energy of formation of the pure compounds (in the gaseous, solid or liquid states) enables to determine the corresponding standard Gibbs energies of formation in aqueous solutions. To do so, using chemical engineering tools (thermodynamic tables and a model enabling to predict activity coefficients, solvation Gibbs energies and pKa data), it becomes possible to determine the partial chemical potential of neutral and charged components in real metabolic conditions, even in concentrated mixtures. PMID- 26965670 TI - Converting paper mill sludge into neutral lipids by oleaginous yeast Cryptococcus vishniaccii for biodiesel production. AB - Paper mill sludge (PMS) was assessed as cheap renewable lignocellulosic biomass for lipid production by the oleaginous yeast Cryptococcus vishniaccii (MTCC 232). The sonicated paper mill sludge extract (PMSE) exhibited enhanced lipid yield and lipid content 7.8+/-0.57g/l, 53.40% in comparison to 5.5+/-0.8g/l, 40.44% glucose synthetic medium, respectively. The accumulated triglycerides (TAG) inside the lipid droplets (LDs) were converted to biodiesel by transesterification and thoroughly characterized using GC-MS technique. The fatty acid methyl ester (FAME) profile obtained reveals elevated content of oleic acid followed by palmitic acid, linoleic acid and stearic acid with improved oxidative stability related to biodiesel quality. PMID- 26965671 TI - Alzheimer disease: Meta-analysis finds high reversion rate from MCI to normal cognition. PMID- 26965672 TI - Dementia: Cerebellar atrophy has disease-specific patterns. PMID- 26965675 TI - Management and monitoring of hyperthyroid cats: a survey of Australian veterinarians. AB - Objectives This study sought to evaluate how Australian veterinarians approach management and monitoring of feline hyperthyroidism and compare these results with a similar survey recently performed in the UK. Methods An invitation to complete an online survey was sent to veterinarians in all states and territories of Australia. The survey comprised questions relating to management of hyperthyroidism, use of antithyroid drugs vs radioiodine treatment vs surgical thyroidectomy, in addition to demographic information for respondents. Results A total of 546 clinicians completed the survey. The most commonly preferred treatments for long-term management of feline hyperthyroidism were antithyroid medications (305/546; 56%) and radioiodine (210/546; 38%), with substantially more respondents selecting radioiodine when cost was removed as a consideration (425/546; 78%). However, most respondents had treated or referred few cases for radioiodine (median 2). Most veterinarians (500/546; 92%) used antithyroid medications either long term or prior to definitive treatment of hyperthyroidism. For medical management, 45% (244/546) of veterinarians used twice-daily carbimazole. Half of respondents (274/546) aimed to maintain the total thyroxine concentration anywhere within the laboratory reference interval in hyperthyroid cats without chronic kidney disease. Blood pressure monitoring was uncommon. Surgical thyroidectomy was rarely performed. Conclusions and relevance Radioiodine was more frequently preferred by Australian veterinarians compared with those in the UK, likely associated with greater availability, reduced cost and shorter hospitalisation times in this jurisdiction, although antithyroid medications were the most frequently used treatment modality. Barriers remain to its utilisation, however, including perceived cost, misconceptions with regard to expected success rate and accessibility. Recent changes to recommendations on the management and monitoring of hyperthyroid cats do not appear to have been widely adopted by veterinarians at this time. PMID- 26965676 TI - Confirmatory field study for the evaluation of ciclosporin at a target dose of 7.0 mg/kg (3.2 mg/lb) in the control of feline hypersensitivity dermatitis. AB - Objectives This study was designed to confirm the efficacy and tolerability of a daily dose of 7.0 mg/kg (3.2 mg/lb) ciclosporin (CsA) in the treatment of feline hypersensitivity dermatitis (HD), as this includes some of the most frequently suspected skin diseases in cats and recent publications have reported the successful use of CsA in the treatment of feline HD. Methods In total, 217 cats with feline HD were treated daily for 42 days with a target dose of 7 mg/kg CsA (n = 144) or a placebo control (n = 73) administered either in the food or directly in the mouth following feeding. Clinical and dermatological evaluations were conducted on days 0, 21 and 42, or study exit. Safety was evaluated through physical examinations, clinical pathology and the monitoring of adverse events (AEs). Results Administration of CsA at 7.0 mg/kg produced a significant improvement in the total lesion score ( P <0.0001). The average reduction from visit 1 to visit 3 was 65.1% in the CsA group (9.2% for the placebo). In addition, owners assessed 78.3% of the cases in the CsA group as a success. Statistically significant recoveries were also seen in extent of lesions, investigator assessment of overall improvement, and mean improvement in both the investigators' and owners' assessment of pruritus. Mild gastrointestinal disorders were the most common AEs but did not require cessation of therapy. Conclusions and relevance Results confirm that 7.0 mg/kg CsA dosed daily in food or orally for up to 6 weeks is effective and well tolerated by cats with feline HD. PMID- 26965677 TI - Clinical, pathological, immunohistochemical and molecular characterization of feline chronic gingivostomatitis. AB - Veronica Machado Rolim, Saulo Petinatti Pavarini, Fabricio Souza Campos, Viviam Pignone, Claudia Faraco, Marcelo de Souza Muccillo, Paulo Michel Roehe, Fernanda Viera Amorim da Costa, and David Driemeier J Feline Med Surg. Epub ahead of print 8 February 2016. DOI: 10.1177/1098612X16628578. PMID- 26965679 TI - [Erratum to "Risk factors of increased abortions in dairy herds - a statistical analysis"]. PMID- 26965673 TI - Seizures and gliomas--towards a single therapeutic approach. AB - Epilepsy often develops in patients with glioma, and the two conditions share common pathogenic mechanisms. Altered expression of glutamate transporters, including the cystine-glutamate transporter (xCT) system, increases concentrations of extracellular glutamate, which contribute to epileptic discharge, tumour proliferation and peripheral excitotoxicity. Furthermore, mutation of the isocitrate dehydrogenase 1 gene in low-grade gliomas causes production of D-2-hydroxyglutarate, a steric analogue of glutamate. Dysregulation of intracellular chloride promotes glioma cell mitosis and migration, and gamma aminobutyric acid (GABA) signalling suppresses proliferation. In neurons, however, chloride accumulation leads to aberrant depolarization on GABA receptor activation, thereby promoting epileptic activity. The molecular target of rapamycin (mTOR) pathway and epigenetic abnormalities are also involved in the development of tumours and seizures. Antitumour therapy can contribute to seizure control, and antiepileptic drugs might have beneficial effects on tumours. Symptomatic treatment with antiepileptic drugs carries risks of adverse effects and drug interactions. In this Review, we discuss the potential for single therapeutic agents, such as the xCT blocker sulfasalazine, the chloride regulator bumetanide, and the histone deacetylase inhibitor valproic acid, to manage both gliomas and associated epilepsy. We also provide guidance on the evidence-based use of antiepileptic drugs in brain tumours. The development of solo therapies to treat both aspects of gliomas promises to yield more-effective treatment with fewer risks of toxicity and drug interactions. PMID- 26965680 TI - Degenerative Changes in the Knee 2 Years After Anterior Cruciate Ligament Rupture and Related Risk Factors: A Prospective Observational Follow-up Study. AB - BACKGROUND: Anterior cruciate ligament (ACL) rupture is a well-known risk factor for development of knee osteoarthritis. Early identification of those patients at risk and early identification of the process of ACL rupture leading to osteoarthritis may aid in preventing the onset or progression of osteoarthritis. PURPOSE: To identify early degenerative changes as assessed on magnetic resonance imaging (MRI) after 2-year follow-up in patients with a recent ACL rupture and to evaluate which determinants are related to these changes. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Included in this study were 154 adults aged between 18 and 45 years with acute ACL rupture diagnosed by physical examination and MRI, without previous knee trauma or surgery, and without osteoarthritic changes on radiographs. A total of 143 patients completed the 2-year follow-up, and the results in this study apply to these 143 patients. All patients were treated according to the Dutch guideline on ACL injury. Of the 143 patients, 50 patients were treated nonoperatively during the 2-year follow-up period. Main outcome was early degenerative changes assessed on MRI defined as progression of cartilage defects and osteophytes in tibiofemoral and patellofemoral compartments. Patient characteristics, activity level, functional instability, treatment type, and trauma-related variables were evaluated as determinants. RESULTS: The median time between MRI at baseline and MRI at 2-year follow-up was 25.9 months (interquartile range, 24.7-26.9 months). Progression of cartilage defects in the medial and lateral tibiofemoral compartments was present in 12% and 27% of patients, and progression of osteophytes in tibiofemoral and patellofemoral compartments was present in 10% and 8% of patients, respectively. The following determinants were positively significantly associated with early degenerative changes: male sex (odds ratio [OR], 4.43; 95% CI, 1.43-13.66; P = .010), cartilage defect in the medial tibiofemoral compartment at baseline (OR, 3.66; 95% CI, 1.04-12.95; P = .044), presence of bone marrow lesions in the medial tibiofemoral compartment 1 year after trauma (OR, 5.19; 95% CI, 1.56 17.25; P = .007), joint effusion 1 year after trauma (OR, 4.19; 95% CI, 1.05 16.72; P = .042), and presence of meniscal tears (OR, 6.37; 95% CI, 1.94-20.88; P = .002). When the patients were categorized into 3 treatment groups (nonoperative, reconstruction <6 months after ACL rupture, and reconstruction >=6 months after ACL rupture), there was no significant relationship between the treatment options and the development of early degenerative changes. CONCLUSION: Two years after ACL rupture, early degenerative changes were assessed on MRI. Concomitant medial cartilage defect and meniscal injury, male sex, persistent bone marrow lesions in the medial tibiofemoral compartment, and joint effusion are risk factors for degenerative changes. PMID- 26965678 TI - The virulence factor ychO has a pleiotropic action in an Avian Pathogenic Escherichia coli (APEC) strain. AB - BACKGROUND: Avian pathogenic Escherichia coli strains cause extraintestinal diseases in birds, leading to substantial economic losses to the poultry industry worldwide. Bacteria that invade cells can overcome the host humoral immune response, resulting in a higher pathogenicity potential. Invasins are members of a large family of outer membrane proteins that allow pathogen invasion into host cells by interacting with specific receptors on the cell surface. RESULTS: An in silico analysis of the genome of a septicemic APEC strain (SEPT362) demonstrated the presence of a putative invasin homologous to the ychO gene from E. coli str. K-12 substr. MG1655. In vitro and in vivo assays comparing a mutant strain carrying a null mutation of this gene, a complemented strain, and its counterpart wild-type strain showed that ychO plays a role in the pathogenicity of APEC strain SEPT362. In vitro assays demonstrated that the mutant strain exhibited significant decreases in bacterial adhesiveness and invasiveness in chicken cells and biofilm formation. In vivo assay indicated a decrease in pathogenicity of the mutant strain. Moreover, transcriptome analysis demonstrated that the ychO deletion affected the expression of 426 genes. Among the altered genes, 93.66% were downregulated in the mutant, including membrane proteins and metabolism genes. CONCLUSION: The results led us to propose that gene ychO contributes to the pathogenicity of APEC strain SEPT362 influencing, in a pleiotropic manner, many biological characteristics, such as adhesion and invasion of in vitro cultured cells, biofilm formation and motility, which could be due to the possible membrane location of this protein. All of these results suggest that the absence of gene ychO would influence the virulence of the APEC strain herein studied. PMID- 26965674 TI - HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. AB - In the past two decades, several advancements have improved the care of HIV infected individuals. Most importantly, the development and deployment of combination antiretroviral therapy (CART) has resulted in a dramatic decline in the rate of deaths from AIDS, so that people living with HIV today have nearly normal life expectancies if treated with CART. The term HIV-associated neurocognitive disorder (HAND) has been used to describe the spectrum of neurocognitive dysfunction associated with HIV infection. HIV can enter the CNS during early stages of infection, and persistent CNS HIV infection and inflammation probably contribute to the development of HAND. The brain can subsequently serve as a sanctuary for ongoing HIV replication, even when systemic viral suppression has been achieved. HAND can remain in patients treated with CART, and its effects on survival, quality of life and everyday functioning make it an important unresolved issue. In this Review, we describe the epidemiology of HAND, the evolving concepts of its neuropathogenesis, novel insights from animal models, and new approaches to treatment. We also discuss how inflammation is sustained in chronic HIV infection. Moreover, we suggest that adjunctive therapies--treatments targeting CNS inflammation and other metabolic processes, including glutamate homeostasis, lipid and energy metabolism--are needed to reverse or improve HAND-related neurological dysfunction. PMID- 26965681 TI - Autologous Bone Plug Supplemented With Autologous Chondrocyte Implantation in Osteochondral Defects of the Knee. AB - BACKGROUND: Structural and functional outcome of bone graft with first- or second generation autologous chondrocyte implantation (ACI) in treating cartilage and subchondral bone defect has not been reported previously. PURPOSE: To evaluate the outcome of simultaneous transplantation of an autologous bone plug with first or second-generation ACI for restoration of concomitant subchondral bone and full-thickness cartilage defect in the femoral condyle of the knee. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Seventeen patients (mean +/- SD age, 27 +/- 7 years; range, 17-40 years)-12 with osteochondritis dissecans (International Cartilage Repair Society [ICRS] grades 3 and 4) and 5 with an isolated osteochondral defect (ICRS grade 4)-had the defect reconstructed with implantation of a unicortical autologous bone graft combined with ACI (the OsPlug technique). Functional outcome was assessed with Lysholm scores obtained preoperatively and at 1 and 5 years postoperatively. The repair site was evaluated with the Oswestry Arthroscopy Score (OAS), MOCART score (magnetic resonance observation of cartilage repair tissue), and ICRS II histology score. Formation of a subchondral lamina and lateral integration of the bone grafts were evaluated from magnetic resonance imaging scans. RESULTS: The mean defect size was 4.5 +/- 2.6 cm(2) (range, 1-9 cm(2)), and the mean depth was 11.3 +/- 5 mm (range, 5-18 mm). The preoperative Lysholm score improved from 45 (interquartile range [IQR], 24; range, 16-79) to 77 (IQR, 28; range, 41-100) at 1 year (P = .001) and 70 (IQR, 35; range, 33-91) at 5 years (P = .009). The mean OAS of the repair site was 6.2 (range, 0-9) at a mean of 1.3 years. The mean MOCART score was 61 +/- 22 (range, 20-85) at 2.6 +/- 1.8 years. Histology demonstrated generally good integration of the repair cartilage with the underlying bone. Poor lateral integration of the bone graft, as assessed on magnetic resonance imaging scan, and a low OAS were significantly associated with a poor Lysholm score and failure. A total of 3 patients had treatment failure, with 1 requiring total knee replacement at 5 years (Lysholm score of 33 at failure) and the other 2 requiring further surgical intervention because of persistent symptoms at 2 and 4 years, respectively (both had Lysholm score of 45 at failure). The Lysholm score in these patients before failure were still noted to be higher than at the preoperative level. CONCLUSION: The OsPlug technique shows significant improvement of functional outcome for up to 5 years in patients with high-grade osteochondritis dissecans or osteochondral defect. This is the first report describing association of bone graft integration with functional outcome after such a procedure. It also demonstrates histologic evidence of integration of the repair cartilage with the underlying bone graft. PMID- 26965682 TI - Vulnerability and resilience: a critical nexus. AB - Not all forms of human fragility or vulnerability are unavoidable. Sometimes we knowingly and intentionally impose conditions of vulnerability on others; and sometimes we knowingly and intentionally enter into and assume conditions of vulnerability for ourselves (for example, when we decide to trust or forgive, enter into intimate relationships with others, become a parent, become a subject of medical or psychotherapeutic treatment, and the like). In this article, I propose a presently overlooked basis on which one might evaluate whether the imposition or assumption of vulnerability is acceptable, and on which one might ground a significant class of vulnerability-related obligations. Distinct from existing accounts of the importance of promoting autonomy in conditions of vulnerability, this article offers a preliminary exploration of the nature, role, and importance of resilience promotion, its relationship to autonomy promotion, and its prospects for improving human wellbeing in autonomy inhibiting conditions. PMID- 26965683 TI - Inhibition of inflammatory signaling pathways in 3T3-L1 adipocytes by apolipoprotein A-I. AB - Activation of inflammatory signaling pathways links obesity with metabolic disorders. TLR4-mediated activation of MAPKs and NF-kappaB are 2 such pathways implicated in obesity-induced inflammation. Apolipoprotein A-I (apoA-I) exerts anti-inflammatory effects on adipocytes by effluxing cholesterol from the cells via the ATP binding cassette transporter A1 (ABCA1). It is not known if these effects involve inhibition of inflammatory signaling pathways by apoA-I. This study asks if apoA-I inhibits activation of MAPKs and NF-kappaB in mouse 3T3-L1 adipocytes and whether this inhibition is ABCA1 dependent. Incubation of differentiated 3T3-L1 adipocytes with apoA-I decreased cell surface expression of TLR4 by 16 +/- 2% and synthesis of the TLR4 adaptor protein, myeloid differentiation primary response 88, by 24 +/- 4% in an ABCA1-dependent manner. ApoA-I also inhibited downstream activation of MAPKs, such as ERK, p38MAPK, and JNK, as well as expression of proinflammatory adipokines in bacterial LPS stimulated 3T3-L1 adipocytes in an ABCA1-dependent manner. ApoA-I, by contrast, suppressed nuclear localization of the p65 subunit of NF-kappaB by 30 +/- 3% in LPS-stimulated 3T3-L1 adipocytes in an ABCA1-independent manner. In conclusion, apoA-I inhibits TLR4-mediated inflammatory signaling pathways in adipocytes by preventing MAPK and NF-kappaB activation.-Sultana, A., Cochran, B. J., Tabet, F., Patel, M., Cuesta Torres, L., Barter, P. J., Rye, K.-A. Inhibition of inflammatory signaling pathways in 3T3-L1 adipocytes by apolipoprotein A-I. PMID- 26965685 TI - Lipoxin A4 augments host defense in sepsis and reduces Pseudomonas aeruginosa virulence through quorum sensing inhibition. AB - Bacterial infections can quickly turn into sepsis, with its attendant clinical sequelae of inflammation, tissue injury, and organ failure. Paradoxically, sustained inflammation in sepsis may lead to immune suppression, because of which the host is unable to clear the existing infection. Use of agents that suppress the inflammatory response may accelerate host immune suppression, whereas use of traditional antibiotics does not significantly affect inflammation. In this study, we investigated whether lipoxin A4 (LXA4), a specialized, proresolution lipid mediator, could increase neutrophil phagocytic activity as well as reduce bacterial virulence. Using the mouse cecal ligation and puncture (CLP) model of sepsis, the administration of LXA4 (7 MUg/kg i.v.) 1 h after surgery increased neutrophil phagocytic ability and Fcgamma receptor I (CD64) expression. Ex vivo studies have confirmed that the direct addition of LXA4 to CLP neutrophils increased phagocytic ability but not CD64 expression. LXA4 did not affect neutrophils taken from control mice in which CD64 expression was minimal. Taken together with in vivo data, these results suggest that LXA4 directly augments CD64-mediated neutrophil phagocytic ability but does not directly increase neutrophil CD64 expression. Bacterial communication and virulence is regulated by quorum sensing inducers. In Pseudomonas aeruginosa, virulence is induced with release of various virulence factors, by N-3-oxododecanolyl homoserine lactone binding to the quorum sensing receptor, LasR. We show that LXA4 is an inhibitor of LasR in P. aeruginosa and that it decreases the release of pyocyanin exotoxin. These results suggest that LXA4 has the novel dual properties of increasing host defense and decreasing pathogen virulence by inhibiting quorum sensing.-Wu, B., Capilato, J., Pham, M. P., Walker, J., Spur, B., Rodriguez, A., Perez, L. J., Yin, K. Lipoxin A4 augments host defense in sepsis and reduces Pseudomonas aeruginosa virulence through quorum sensing inhibition. PMID- 26965686 TI - Other Proteins Involved in Parkinson's Disease and Related Disorders. AB - In order to explain the molecular causes of Parkinson's Disease (PD) it is important to understand the effect that mutations described as causative of the disease have at the functional level. In this special issue, several authors have been reviewing the effects in PD and other parkinsonisms of mutations described in LRRK2, alpha-synuclein, PINK1-Parkin-DJ-1, UCHL1, ATP13A2, GBA, VPS35, FBOX7 and HTRA2. In this review, we compile the knowledge about other proteins with a more general role in neurodegenerative diseases (MAPT) or for which less data is available due to its recent discovery (EIF4G1, DNAJC13), the lack of structural or functional data (as for PLA2G6 or DNAJC6), or even their doubtful association with the disease (as for GIGYF2, SYNJ1 and SPR). Also the cellular pathways involved in this disease are reviewed, with the goal of having an overview of the effects on the proteins and its possible role in the disease. This knowledge could also serve as the basis for designing tools that may potentially be used as a treatment for the disease, such as inhibitory or activating molecules, as well as other involved in regulating the half-life of the proteins involved. PMID- 26965684 TI - 12-HETER1/GPR31, a high-affinity 12(S)-hydroxyeicosatetraenoic acid receptor, is significantly up-regulated in prostate cancer and plays a critical role in prostate cancer progression. AB - Previously we identified and deorphaned G-protein-coupled receptor 31 (GPR31) as the high-affinity 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] receptor (12 HETER1). Here we have determined its distribution in prostate cancer tissue and its role in prostate tumorigenesis using in vitro and in vivo assays. Data-mining studies strongly suggest that 12-HETER1 expression positively correlates with the aggressiveness and progression of prostate tumors. This was corroborated with real-time PCR analysis of human prostate tumor tissue arrays that revealed the expression of 12-HETER1 positively correlates with the clinical stages of prostate cancers and Gleason scores. Immunohistochemistry analysis also proved that the expression of 12-HETER1 is positively correlated with the grades of prostate cancer. Knockdown of 12-HETER1 in prostate cancer cells markedly reduced colony formation and inhibited tumor growth in animals. To discover the regulatory factors, 5 candidate 12-HETER1 promoter cis elements were assayed as luciferase reporter fusions in Chinese hamster ovary (CHO) cells, where the putative cis element required for gene regulation was mapped 2 kb upstream of the 12-HETER1 transcriptional start site. The data implicate 12-HETER1 in a critical new role in the regulation of prostate cancer progression and offer a novel alternative target for therapeutic intervention.-Honn, K. V., Guo, Y., Cai, Y., Lee, M.-J., Dyson, G., Zhang, W., Tucker, S. C. 12-HETER1/GPR31, a high-affinity 12(S)-hydroxyeicosatetraenoic acid receptor, is significantly up-regulated in prostate cancer and plays a critical role in prostate cancer progression. PMID- 26965688 TI - LRRK2 and Parkinson's Disease: From Lack of Structure to Gain of Function. AB - Mutations in LRRK2 comprise the most common cause for familial Parkinson's disease (PD), and variations increase risk for sporadic disease, implicating LRRK2 in the entire disease spectrum. LRRK2 is a large protein harbouring both GTPase and kinase domains which display measurable catalytic activity. Most pathogenic mutations increase the kinase activity, with increased activity being cytotoxic under certain conditions. These findings have spurred great interest in drug development approaches, and various specific LRRK2 kinase inhibitors have been developed. However, LRRK2 is a largely ubiquitously expressed protein, and inhibiting its function in some non-neuronal tissues has raised safety liability issues for kinase inhibitor approaches. Therefore, understanding the cellular and cell type-specific role(s) of LRRK2 has become of paramount importance. This review will highlight current knowledge on the precise biochemical activities of normal and pathogenic LRRK2, and highlight the most common proposed cellular roles so as to gain a better understanding of the cell type-specific effects of LRRK2 modulators. PMID- 26965689 TI - Hereditary Parkinsonism-Associated Genetic Variations in PARK9 Locus Lead to Functional Impairment of ATPase Type 13A2. AB - Kufor-Rakeb syndrome (KRS) is an autosomal recessive form of Parkinson's disease (PD) with juvenile onset of parkinsonism, often accompanied by extra clinical features such as supranuclear gaze palsy, dementia and generalised brain atrophy. Mutations in ATP13A2, associated with the PARK9 locus (chromosome 1p36) have been identified in KRS patients. ATP13A2 encodes a lysosomal P5B-type ATPase which has functional domains similar to other P-type ATPases which mainly transport cations. Consistently, recent studies suggest that human ATP13A2 may preferably regulate Zn2+, while ATP13A2 from other species have different substrate selectivity. Until now, fourteen mutations in ATP13A2 have been associated with KRS, while other mutations have been reported in association with neuronal ceroid lipofuscinosis (NCL) and early-onset PD. Experimentally, these disease- associated ATP13A2 mutations have been shown to confer loss-of-function to the protein by disrupting its protein structure and function to varying degrees, ranging from impairment in ATPase function to total loss of protein, confirming their pathogenicity. Loss of functional ATP13A2 has been shown to induce Zn2+ dyshomeostasis. Disturbances in Zn2+ homeostasis impair mitochondrial and lysosomal function which leads to loss of mitochondrial bioenergetic capacity and accumulation of lysosomal substrates such as alpha-synuclein and lipofuscin. Additionally, ATP13A2 appears to be involved in alpha-synuclein externalisation through its Zn2+-regulating activity. In this review, we will discuss all the reported KRS/NCL-associated ATP13A2 mutations along with several PD-associated mutations which have been experimentally assessed, in respect to their impact on the protein structure and function of ATP13A2. PMID- 26965690 TI - Structure and Function of Fbxo7/PARK15 in Parkinson's Disease. AB - Fbxo7/PARK15 has well-defined roles, acting as part of a Skp1-Cul1-F box protein (SCF)- type E3 ubiquitin ligase and also having SCF-independent activities. Mutations within FBXO7 have been found to cause an early-onset Parkinson's disease, and these are found within or near to its functional domains, including its F-box domain (FBD), its proline rich region (PRR), and its ubiquitinlike domain (Ubl). We highlight recent advances in our understanding of Fbxo7 function in Parkinson's disease, with respect to these mutations and where they occur in the Fbxo7 protein. We hypothesize that many of Fbxo7 functions contribute to its role in PD pathogenesis. PMID- 26965691 TI - Retromer's Role in Endosomal Trafficking and Impaired Function in Neurodegenerative Diseases. AB - The retromer complex is a highly conserved membrane trafficking assembly composed of three proteins - Vps26, Vps29 and Vps35 - that were identified over a decade ago in Saccharomyces cerevisiae (S. cerevisiae). Initially, mammalian retromer was shown to sort transmembrane proteins from the endosome to the trans-Golgi network (TGN), though recent work has identified a critical role for retromer in multiple trafficking pathways, including recycling to the plasma membrane and regulation of cell polarity. In recent years, genetic, cellular, pharmacological and animal model studies have identified retromer and its interacting proteins as being linked to familial forms of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD). Here, this commentary will summarize recently identified point mutations in retromer linked to PD, and explore the molecular functions of retromer that may be relevant to disease progression. PMID- 26965687 TI - The Effects of Variants in the Parkin, PINK1, and DJ-1 Genes along with Evidence for their Pathogenicity. AB - Early onset Parkinson's disease can be caused by variants in the PINK1, Parkin, and DJ-1 genes. Since their initial discoveries, hundreds of variants have been found in these genes that are associated with a Parkinsonian phenotype. This review will briefly discuss the functions of the protein products of the three genes, then focus on the effects that disease associated variants have on these functions. We will also discuss how experimental findings can help decide whether individual variants are pathogenic or not. PMID- 26965692 TI - Involvement of Gaucher Disease Mutations in Parkinson Disease. AB - Gaucher disease is an autosomal recessive lysosomal storage disorder, caused by mutations in the GBA gene. The frequency of Gaucher disease patients and heterozygote carriers that developed Parkinson disease has been found to be above that of the control population. This fact suggests that mutations in the GBA gene can be involved in Parkison's etiology. Analysis of large cohorts of patients with Parkinson disease has shown that there are significantly more cases bearing GBA mutations than those found among healthy individuals. Functional studies have proven an interaction between alpha-synuclein and GBA, the levels of which presented an inverse correlation. Mutant GBA proteins cause increases in alpha synuclein levels, while an inhibition of GBA by alpha-synuclein has been also demonstrated. Saposin C, a coactivator of GBA, has been shown to protect GBA from this inhibition. Among the GBA variants associated with Parkinson disease, E326K seems to be one of the most prevalent. Interestingly, it is involved in Gaucher disease only when it forms part of a double-mutant allele, usually with the L444P mutation. Structural analyses have revealed that both residues (E326 and L444) interact with Saposin C and, probably, also with alpha-synuclein. This could explain the antagonistic role of these two proteins in relation to GBA. PMID- 26965693 TI - Pathogenic Role of Serine Protease HtrA2/Omi in Neurodegenerative Diseases. AB - High-temperature-requirement A2 (HtrA2)/Omi/PARK13 is a serine protease with extensive homology to the Escherichia coli HtrAs that are required for bacterial survival at high temperatures. The HtrA2 protein is a key modulator of mitochondrial molecular quality control but under stressful conditions it is released into the cytosol, where it promotes cell death by various pathways, including caspase-dependent pathway and ER stress-mediated apoptosis. Recently, the HtrA2 protein has received great attention for its potential role in neurodegeneration. Here, we review the current knowledge and pathophysiological functions of the HtrA2 protein in neurodegenerative disorders such as Parkinson's and Alzheimer's disease. PMID- 26965696 TI - Erratum to: Collagens VI and XII form complexes mediating osteoblast interactions during osteogenesis. PMID- 26965695 TI - Importance of additional temporary pin fixation combined coracoclavicular augmentation using a suture button device for acute acromioclavicular joint dislocation. AB - INTRODUCTION: We evaluated the outcomes of coracoclavicular (CC) augmentation using a suture button device with additional temporary pin fixation for acute acromioclavicular (AC) joint dislocation. MATERIALS AND METHODS: Thirty-six consecutive cases who underwent CC augmentation using TightRopeTM (Arthrex, Naples, FL, USA) were included. We temporarily fixed trans-articular pins in the first 10 cases (TA group) and a trans-spine pin in the next 26 cases (TS group). The radiological and clinical outcomes were evaluated at minimum 2 years postoperatively. RESULTS: The mean follow-up period was 56.7 months (range, 24-84 months). At the final follow-up evaluation, reduction status showed anatomical reduction in 25 cases (69.4 %), slight loss of reduction in seven cases (19.4 %), partial loss of reduction in two cases (5.6 %), and total loss of reduction in two cases (5.6 %). The mean ASES score, UCLA score, and subjective shoulder value were 92.3, 32.9, and 91.6 %, respectively. There were no significant differences between the two groups with respect to the outcomes. Intraoperative complications occurred in three cases (8.3 %) including two cases of failed reduction and one case of technical failure of the implant. Postoperative complications occurred in three cases (8.3 %) including one case of pin tract infection and distal clavicle fracture at the clavicle-hole, one case of reduction loss by severe subsidence of the clavicular button, and one case of shoulder stiffness. CONCLUSIONS: CC augmentation using a suture button device with temporary pin fixation yielded satisfactory radiological and clinical outcomes. These results support that temporary pin fixation for the AC joint may help to protect the AC reduction in the early phase of healing and rigid scar formation when performing CC fixation using a suture button device. LEVEL OF EVIDENCE: Level-IV, Retrospective Case Series, Treatment Study. PMID- 26965694 TI - Once-Monthly Continuous Erythropoietin Receptor Activator (C.E.R.A.) in Patients with Hemodialysis-Dependent Chronic Kidney Disease: Pooled Data from Phase III Trials. AB - INTRODUCTION: Erythropoiesis-stimulating agents and iron are commonly used in patients with chronic kidney disease with the aim of correcting anemia and maintaining stable hemoglobin levels. We analyzed pooled data from 13 studies with similar designs included in the Umbrella Continuous Erythropoietin Receptor Activator (C.E.R.A.) program to investigate the effects of continuous erythropoiesis receptor activator in clinically relevant subgroups of patients with chronic kidney disease and to determine whether the efficacy and safety outcomes demonstrated in the overall chronic kidney disease population are maintained in specific subgroups. METHODS: Data from 13 Phase III trials set up with similar design were retrospectively pooled for this analysis. Patients with chronic kidney disease who had previously been receiving epoetin or darbepoetin were switched to continuous erythropoiesis receptor activator once-monthly after a 4- to 8-week screening period. Patients entered a 16-week continuous erythropoiesis receptor activator dose-titration period followed by an 8-week evaluation period. In total, 2060 patients were included in the analysis. Subgroups were defined based on: hemoglobin target range [lower (10.0-12.0 g/dL)/upper (10.5-13.0 g/dL)], gender (female/male), age (<65/>=65), baseline N terminal pro-B-type natriuretic peptide levels (<5000/>=5000), cardiovascular risk factors (diabetes/cardiac/vascular/none). RESULTS: Across all subgroups analyzed, switching from shorter-acting erythropoiesis-stimulating agents to continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin concentrations in a high proportion of patients (78%), with only moderate hemoglobin fluctuations and a low number of dose changes. The safety profile across subgroups was as expected based on pre-existing risk factors; observed increases in adverse events were attributable to underlying risk factors rather than study drug. CONCLUSIONS: This retrospective analysis of 13 trials showed that continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin levels across a number of clinically relevant patient subgroups, including those with higher inherent cardiovascular risk. The safety profile was consistent with that previously established in the chronic kidney disease population. CLINICALTRIALS. GOV IDENTIFIERS: NCT00413894/NCT00545571/NCT00517413/NCT00560404/NCT00882713/NCT00550680/NCT005763 3/NCT00660023/NCT00717821/NCT00642850/NCT00605293/NCT00661505/NCT00699348. FUNDING: F. Hoffmann-La Roche Ltd, Basel, Switzerland. PMID- 26965697 TI - Prostate Health Index and %p2PSA Predict Aggressive Prostate Cancer Pathology in Chinese Patients Undergoing Radical Prostatectomy. AB - PURPOSE: To investigate the performance of prostate health index (PHI) and percentage prostate-specific antigen (PSA) isoform [-2]proPSA (%p2PSA) in predicting pathologic outcomes at radical prostatectomy (RP) in a Chinese population. METHODS: We performed a prospective study of 135 prostate cancer patients with RP. The accuracy of preoperative %p2PSA (= p2PSA/free PSA) and PHI [= (p2PSA/free PSA) * ?PSA] in predicting pathologic outcomes of RP including pT3 disease, pathologic Gleason score (pGS) >=7, Gleason score (GS) upgrade at RP, tumor volume >0.5 ml, and Epstein criteria for significant tumor were calculated using multivariate analyses and area under the curve. The base model in multivariate analysis included age, PSA, abnormal digital rectal examination, and biopsy GS. RESULTS: PHI was significantly higher in patients with pT3 or pGS >= 7 (p < 0.001), pT3 disease (p = 0.001), pGS >= 7 (p < 0.001), GS upgrade (p < 0.001), tumor volume >0.5 ml (p < 0.001), and Epstein criteria for significant tumor (p = 0.001). %p2PSA was also significantly higher in all the above outcomes. The risk of pT3 or pGS >= 7 was 16.1 % for PHI < 35 and 60.8 % for PHI > 35 (sensitivity 84.2 %, specificity of 60.3 %), and the risk of tumor volume >0.5 ml was 25.5 % for PHI < 35 and 72.6 % for PHI > 35 (sensitivity 79.1 %, specificity 67.2 %). In multivariate analysis, adding %p2PSA or PHI to the base model significantly improved the accuracy (area under the curve) in predicting pT3 or pGS >= 7 (by 7.2-7.9 %), tumor volume >0.5 ml (by 10.3-12.8 %), and Epstein criteria for significant tumor (by 13.9-15.9 %). Net clinical benefit was observed in decision curve analyses for prediction of both tumor volume >0.5 ml, and pT3 or pGS >= 7. CONCLUSIONS: Both PHI and %p2PSA predict aggressive and significant pathologies in RP in Chinese men. This enabled identification of nonaggressive cancers for better counseling on active surveillance or treatment. PMID- 26965698 TI - Complications After Percutaneous Pedicle Screw Fixation for the Treatment of Unstable Spinal Metastases. AB - BACKGROUND: Complications after surgical stabilization for the treatment of unstable spinal metastases are common. Less invasive surgical (LIS) procedures are potentially associated with a lower risk of complications; however, little is known regarding the complications after LIS procedures for the treatment of spinal metastases. Our primary objective was to determine the characteristics and rate of complications after percutaneous pedicle screw fixation (PPSF) for the treatment of mechanically unstable spinal metastases. The secondary objective was to identify factors associated with the occurrence of complications and survival. METHODS: A retrospective multicenter cohort study of patients who underwent PPSF between 2009 and 2014 for the treatment of unstable spinal metastases was performed. Patient data pertaining to demographics, diagnosis, treatment, neurologic function, complications, and survival were collected. RESULTS: A total of 101 patients were identified, 45 men (45 %) and 56 women (55 %) with a mean age of 60.3 +/- 11.2 years. The median operating time was 122 (range 57-325) minutes with a median blood loss of 100 ml (based on 41 subjects). Eighty-eight patients (87 %) ambulated within the first 3 days after surgery. An overall median survival of 11.0 (range 0-70) months was observed, with 79 % of the patients alive at 3 months after treatment. Eighteen patients experienced a total of 30 complications; nonsurgical complications were the most commonly encountered. Prolonged operating time was independently associated with an increased risk of complications. CONCLUSIONS: A complication rate of 18 % was found after PPSF for unstable spinal metastases. Potential advantages of less invasive treatment are limited blood loss and high early ambulation rate. PMID- 26965699 TI - Interobserver Agreement Between Pathologists Assessing Tumor-Infiltrating Lymphocytes (TILs) in Breast Cancer Using Methodology Proposed by the International TILs Working Group. AB - BACKGROUND: The presence of tumor-infiltrating lymphocytes (TILs) in breast tumors is prognostic and predictive, suggesting that TILs may be an important biomarker. Recently, an international TILs working group formulated consensus recommendations for TIL evaluation. The current study was performed to determine interobserver agreement using that methodology. METHODS: Tumor-infiltrating lymphocytes were assessed on a single hematoxylin and eosin (H&E)-stained slide obtained from the core biopsy of 75 triple-negative breast cancers. Four pathologists independently reviewed each slide and evaluated stromal TILs (sTILs) and intratumoral TIL (iTILs). The kappa statistic was used to estimate interobserver agreement for identification of sTILs, and the intraclass correlation coefficient (ICC) was used to estimate the agreement among observers for iTILs. Cases with poor agreement were reviewed to identify pathologic factors that may contribute to the lack of agreement. RESULTS: The kappa statistic for sTIL evaluation was 0.57 (standard error, 0.04). For iTILs, the ICC calculated to determine internal consistency within raters was 0.65 (95 % confidence interval [CI] 0.56-0.74; p < 0.0001), and the ICC calculated to determine agreement among raters was 0.62 (95 % CI 0.50-0.72; p < 0.0001). In 10 cases (13 %), there was not agreement between three of four pathologists. The pathologic features contributing to difficulty in TIL enumeration included marked individual tumor cell necrosis or apoptosis, the presence of reactive plasma cells mimicking tumor cells, plasmatoid tumor cells, and accurate quantification of TILs in specimens with focal areas of heavy immune infiltrate. CONCLUSION: Acceptable agreement in TIL enumeration was observed, suggesting that the proposed methodology can be used to facilitate the use of TILs as a biomarker in research and clinical trial settings. PMID- 26965700 TI - Patterns of Referral for Adjuvant Chemotherapy for Stage II and III Colon Cancer: A Population-Based Study. AB - PURPOSE: Reasons for variable utilization of adjuvant chemotherapy (ACT) for colon cancer have not been well described. We report medical oncology (MO) referral patterns and subsequent use of ACT. METHODS: Treatment records were linked to the population-based Ontario Cancer Registry to describe MO referral and ACT use among 5289 patients with stage II-III colon cancer treated in 2002 2008. Modified Poisson regression was used to analyze factors associated with MO referral and ACT use. Multilevel modeling was used to explore the proportion of variation in practice attributable to providers. RESULTS: There was wide geographic variation in MO referral rates for stage II (range 37-80 %, p < 0.001) and stage III disease (range 77-98 %, p < 0.001). Use of ACT among referred patients varied across regions for stage II (range 12-49 %, p < 0.001) but not stage III (range 67-79 %, p = 0.353). For both stages, younger patients (p < 0.001) with less comorbidity (p < 0.010) were more likely to be referred to MO and treated with ACT. Applying the fitted regression model to nonreferred stage III patients suggests that 38 % had >50 % probability of having ACT if they had seen a MO. Among stage III patients, 15 % percent of the variance in MO referral rate and 6 % of the variance in ACT utilization rate is attributable to the surgeon and MO respectively. CONCLUSIONS: A substantial proportion of non referred patients with stage III colon cancer may have been offered ACT if they had seen MO. A small proportion of variance in referral rate and ACT treatment is attributable to providers. PMID- 26965701 TI - Mixed Adeno-neuroendocrine Carcinoma: An Aggressive Clinical Entity. AB - BACKGROUND: Mixed adeno-neuroendocrine carcinoma (MANEC) is a rare pathologic diagnosis recently defined by the World Health Organization in 2010. Due to poor understanding of MANEC as a clinical entity, there is significant variation in the management of these patients. The purpose of our study was to characterize MANEC to develop evidence-based treatment strategies. METHODS: The Ohio State University patient database was queried for the diagnosis of MANEC and 46 patients were identified. For comparison, the database also was queried for goblet cell carcinoid (GCC) of the appendix, signet ring cell carcinoma, and carcinoid/neuroendocrine tumor of the appendix. Charts were then retrospectively reviewed for clinicopathologic characteristics, patient treatment, and survival data. RESULTS: The mean age of diagnosis of MANEC was 54 years. Eighty-seven percent of MANEC arose from the appendix, with 28 % of patients undergoing appendectomy and 35 % undergoing right hemicolectomy as their index operation. Immunohistochemical staining was positive for chromogranin (82 %), synaptophysin (97 %), and CD56 (67 %). Sixty-seven percent of patients presented with stage IV disease and 41 % had nodal metastases. Overall survival was 4.1 years, which was statistically significantly different (p <= 0.05) compared with carcinoid tumors (13.4 years), GCC (15.4 years), and signet ring carcinoma (2.2 years). CONCLUSIONS: MANEC is a more aggressive clinical entity than both GCC of the appendix and carcinoid/neuroendocrine tumors of the appendix. Based on these findings, we recommend patients with MANEC tumors undergo aggressive multidisciplinary cancer management and close surveillance. PMID- 26965702 TI - Perineural Invasion and Lymphovascular Invasion are Associated with Increased Risk of Biochemical Recurrence in Patients Undergoing Radical Prostatectomy. AB - PURPOSE: This study was designed to determine whether perineural invasion (PNI) and lymphovascular invasion (LVI) are independent predictors for biochemical recurrence (BCR) of prostate cancer (PCa) following radical prostatectomy (RP) in the Asian population. METHODS: The study population comprised 2394 PCa patients undergoing RP at our institution in Korea. After excluding 360 patients, we compared the baseline characteristics between the groups according to the presence of PNI or LVI and estimated BCR-free survival using the Kaplan-Meier survival. Multivariate Cox regression model was adopted to identify significant predictive factors of BCR following RP. RESULTS: Among 2034 patients, PNI and LVI were detected in 69.3 and 12.4 % patients, respectively. Patients with PNI or LVI had higher rates of advanced biopsy and pathological Gleason score (>=7), and higher proportions of advanced clinical and pathological T stage >=3, extraprostatic extension, seminal vesicle invasion, and surgical margin positivity. Notably, BCR-free survival was lower in patients with PNI or LVI compared with that in patients without these markers and lower in patients with both markers compared with that in other populations of patients. Moreover, PNI (hazard ratio [HR] = 2.11) and LVI (HR = 1.57) were significant predictors of BCR. The presence of the two markers was associated with a higher risk of BCR (HR = 4.60) compared with the presence of either marker alone (HR = 3.47). CONCLUSIONS: PNI and LVI are adverse pathologic parameters and independent predictors for BCR, and the concurrent presence of PNI and LVI resulted in poorer outcomes for BCR in PCa patients who underwent RP. PMID- 26965703 TI - Effect of two commercial herbicides on life history traits of a human disease vector, Aedes aegypti, in the laboratory setting. AB - Some mosquito species utilize the small niches of water that are abundant in farmland habitats. These niches are susceptible to effects from agricultural pesticides, many of which are applied aerially over large tracts of land. One principal form of weed control in agricultural systems involves the development of herbicide-tolerant crops. The impact of sub-agricultural levels of these herbicides on mosquito survival and life-history traits of resulting adults have not been determined. The aim of this study was to test the effect of two commercial herbicides (Beyond and Roundup) on the survivorship, eclosion time, and body mass of Aedes aegypti. First instar A. aegypti larvae were exposed to varying concentrations (270, 550 and 820 MUg/m(2) of glyphosate and 0.74, 1.49, 2.24 MUL imazamox/m(2)), all treatments being below recommended application rates, of commercial herbicides in a controlled environment and resulting adult mosquitoes were collected and weighed. Exposure to Roundup had a significant negative effect on A. aegypti survivorship at medium and high sub-agricultural application concentrations, and negatively affected adult eclosion time at the highest concentration. However, exposure to low concentrations of Beyond significantly increased A. aegypti survivorship, although adult female mass was decreased at medium sub-agricultural concentrations. These results demonstrate that low concentrations of two different herbicides, which can occur in rural larval habitats as a result of spray drift, can affect the same species of mosquito in both positive and negative ways depending on the herbicide applied. The effects of commercial herbicides on mosquito populations could have an important effect on disease transmission within agricultural settings, where these and other herbicides are extensively applied to reduce weed growth. PMID- 26965704 TI - Prolonged effects of in-hive monoterpenoids on the honey bee Apis mellifera. AB - Honey bees are exposed in their environment to contaminants but also to biological stressors such as Varroa destructor that can weaken the colony. Preparations containing monoterpenoids that are essential oil components, can be introduced into hives to control Varroa. The long-term sublethal effects of monoterpenoids used as miticides have been poorly investigated. Analysis of behavior of free-moving bees in the laboratory is useful to evaluate the impact of chemical stressors on their cognitive functions such as vision function. Here, the walking behavior was quantified under a 200-lux light intensity. Weeks and months after introduction of the miticide (74 % thymol) into the hives, decreases of phototaxis was observed with both summer and winter bees. Curiously, in spring, bees collected in treated hives were less attracted by light in the morning than control bees. The survival of bees collected in spring was increased by treatment. After a 1-year period of observation, the colony losses were identical in treated and non-treated groups. Colony loss started earlier in the non-treated group. In public opinion, natural substances as essential oils are safer and more environmentally friendly. We demonstrated that a monoterpenoid based treatment affects bee responses to light. The latter results have notable implications regarding the evaluation of miticides in beekeeping. PMID- 26965705 TI - Factors Affecting Length of Postoperative Hospitalization for Pediatric Cardiac Operations in a Large North American Registry (1982-2007). AB - Surgical treatment of congenital heart disease represents a major cause of pediatric hospitalization and healthcare resource use. Larger centers may provide more efficient care with resulting shorter length of postoperative hospitalization (LOH). Data from 46 centers over 25 years were used to evaluate whether surgical volume was an important determinant of LOH using a competing risk regression strategy that concurrently accounted for deaths, transfers, and discharges with some time interactions. Earlier discharge was more likely for infants and older children compared to neonates [subhazard ratios at postoperative day 6 of 1.64 (99 % confidence interval (CI) 1.57, 1.72) and 2.67 (99 % CI 2.53, 2.80), respectively], but less likely for patients undergoing operations in Risk Adjustment for Congenital Heart Surgery categories 2, 3, 4, and 5/6 compared to category 1 [subhazard ratios at postoperative day 6 of 0.66 (99 % CI 0.64, 0.68), 0.34 (95 % CI 0.33, 0.35), 0.28 (99 % CI 0.27, 0.30), and 0.10 (99 % CI 0.09, 0.11), respectively]. There was no difference by sex [non time-dependent subhazard ratio 1.019 (99 % CI 0.995, 1.040)]. For every 100 operation increase in center annual surgical volume, the non-time-dependent subhazard for discharge was 1.035 (99 % CI 1.006, 1.064) times greater, and center-specific exponentiated random effects ranged from 0.70 to 1.42 with a variance of 0.023. The conditional discharge rate increased with increasing age and later era. No sex-specific difference was found. Centers performing more operations discharged patients sooner than lower volume centers, but this difference appears to be too small to be of clinical significance. Interestingly, unmeasured institutional characteristics estimated by the center random effects were variable, suggesting that these played an important role in LOH and merit further investigation. PMID- 26965706 TI - Inulin and fructooligosaccharide affect in vitro calcium uptake and absorption from calcium-enriched gluten-free bread. AB - Compromised intestinal calcium absorption affecting a deterioration of bone state is a sign of coeliac disease. Experimental calcium-fortified gluten-free bread (GFB) of improved calcium bioavailability could increase calcium content in the diets of coeliac disease patients, allowing them to obtain the amount of calcium they need for therapeutic use. Prebiotics, including inulin-type fructans (IFs) have a beneficial effect on calcium bioavailability. In the present study, the in vitro model composed of the intestinal-like Caco-2 cells and the human intestinal bacteria (Lactobacillus, Enterococcus and Enterobacteriaceae) were used to analyse the effect of inulin and fructooligosaccharide (FOS) of different chain lengths, on calcium uptake and absorption from experimental GFB. Analysed IFs, especially short-chain FOS, significantly (p < 0.05) increased cellular calcium uptake from GFB digest and stimulated the intestinal bacteria applied in the cultures to the intensive synthesis of organic acids. In particular, the concentration of butyric, valeric and lactic acids increased significantly. Similarly, in the calcium absorption experiment, IFs increased the cellular calcium retention but concomitantly reduced its content in basolateral filtrates. The results obtained suggest that the applied IFs affected differentially calcium uptake and absorption from the experimental calcium-enriched GFB, therefore a further study is needed to assess whether these observations made in vitro contribute to IF effects on calcium absorption from experimental GFB in vivo. PMID- 26965707 TI - Prenatal predictors of postpartum depression and postpartum depressive symptoms in Mexican mothers: a longitudinal study. AB - Prospective studies on the predictors of postpartum depression (PPD) in Latin America are scarce, which is a matter of importance, since the significance of PPD risk factors may vary according to the level of development of a country, the types of measurement and the time periods assessed. This study identifies the prenatal predictors for PPD (diagnostic interview) and postpartum depressive symptoms (PPDS) (self-report scale) in Mexican mothers at 6 weeks and 6 months postpartum. Two hundred and ten women were interviewed using the Structured Clinical Interview (SCID-I), Patient Health Questionnaire (PHQ-9) and various risk factor scales. Univariate logistic regressions showed that social support, marital satisfaction, life events, a history of psychopathology, anxiety symptoms, depressive symptoms, the traditional female role, previous miscarriages/termination of pregnancy and unplanned/unwanted pregnancy were significant predictors for both PPD and PPDS at both assessment times in the postpartum. Education, age, marital status, income, occupation, parity, C-section and resilience were significant for only one of the measurements and/or at just one assessment time. General findings replicate a high- and low-income country observed psychosocial risk profile and confirm a sociodemographic and obstetric profile of vulnerability that is more prevalent in resource-constrained countries. PPD constitutes a high burden for new mothers, particularly for those living in low-middle-income countries who face social disadvantages (such as low educational attainment and income). PMID- 26965708 TI - The effect of Wazzup Mama?! An antenatal intervention to prevent or reduce maternal distress in pregnancy. AB - We evaluated the effect of the intervention WazzUp Mama?! on antenatal maternal distress in a non-randomized pre-post study including healthy women in 17 Dutch midwifery practices. The control group (n = 215) received antenatal care-as usual. The experimental group (n = 218) received the intervention. Data were collected at the first and third trimester of pregnancy. Maternal distress (MD) was measured with the Edinburgh Depression Scale (EDS), State-Trait Anxiety Inventory (STAI), and Pregnancy-Related Anxiety Questionnaire (PRAQ). We used multivariate repeated-measure analysis to examine the across time changes and ANCOVA was used to examine the differences between the two groups. In the control group, mean EDS, STAI, and MD scores significantly increased from first to third trimester of pregnancy, mean PRAQ scores increased, but not significantly, the proportion of scores above cut-off level of EDS, STAI, and PRAQ significantly increased from first to third trimester, and the proportion of MD scores above cut-off level increased, but not significantly. Within the experimental group, the mean STAI, PRAQ, and MD scores significantly decreased from first to third trimester, the EDS mean scores decreased but not significantly, proportions of scores above cut-off level for PRAQ and MD significantly decreased from first to third trimester of pregnancy, the proportions of EDS and STAI scores above cut off level decreased but not significantly. There was a moderate significant positive effect of WazzUP Mama?! on the MD scores (F(1.43) = 27.05, p < 0.001, d = 0.5). The results provide support for the effectiveness of the intervention WazzUp Mama?! PMID- 26965709 TI - Causation by Diesel Exhaust Particles of Endothelial Dysfunctions in Cytotoxicity, Pro-inflammation, Permeability, and Apoptosis Induced by ROS Generation. AB - Epidemiological studies suggest that an increase of diesel exhaust particles (DEP) in ambient air corresponds to an increase in hospital-recorded myocardial infarctions within 48 h after exposure. Among the many theories to explain this data are endothelial dysfunction and translocation of DEP into vasculature. The mechanisms for such DEP-induced vascular permeability remain unknown. One of the major mechanisms underlying the effects of DEP is suggested to be oxidative stress. Experiments have shown that DEP induce the generation of reactive oxygen species (ROS), such as superoxide anion and H2O2 in the HUVEC tube cells. Transcription factor Nrf2 is translocated to the cell nucleus, where it activates transcription of the antioxidative enzyme HO-1 and sequentially induces the release of vascular permeability factor VEGF-A. Furthermore, a recent study shows that DEP-induced intracellular ROS may cause the release of pro-inflammatory TNF alpha and IL-6, which may induce endothelial permeability as well by promoting VEGF-A secretion independently of HO-1 activation. These results demonstrated that the adherens junction molecule, VE-cadherin, becomes redistributed from the membrane at cell-cell borders to the cytoplasm in response to DEP, separating the plasma membranes of adjacent cells. DEP were occasionally found in endothelial cell cytoplasm and in tube lumen. In addition, the induced ROS is cytotoxic to the endothelial tube-like HUVEC. Acute DEP exposure stimulates ATP depletion, followed by depolarization of their actin cytoskeleton, which sequentially inhibits PI3K/Akt activity and induces endothelial apoptosis. Nevertheless, high dose DEP augments tube cell apoptosis up to 70 % but disrupts the p53 negative regulator Mdm2. In summary, exposure to DEP affects parameters influencing vasculature permeability and viability, i.e., oxidative stress and its upregulated antioxidative and pro-inflammatory responses, which sequentially induce vascular permeability factor, VEGF-A release and disrupt cell-cell junction integrity. While exposure to a low dose of DEP actin triggers cytoskeleton depolarization, reduces PI3K/Akt activity, and induces a p53/Mdm2 feedback loop, a high dose causes apoptosis by depleting Mdm2. Addition of ROS scavenger N-acetyl cysteine suppresses DEP-induced oxidative stress efficiently and reduces subsequent damages by increasing endogenous glutathione. PMID- 26965710 TI - Potential impact of the implementation of multiple-criteria decision analysis (MCDA) on the Polish pricing and reimbursement process of orphan drugs. AB - BACKGROUND: The objective of this study was to assess the potential impact of the implementation of multiple-criteria decision analysis (MCDA) on the Polish pricing and reimbursement (P&R) process with regard to orphan drugs. METHODS: A four step approach was designed. Firstly, a systematic literature review was conducted to select the MCDA criteria. Secondly, a database of orphan drugs was established. Thirdly, health technology appraisals (HTA recommendations) were categorized and an MCDA appraisal was conducted. Finally, a comparison of HTA and MCDA outcomes was carried out. An MCDA outcome was considered positive if more than 50% of the maximum number of points was reached (base case). In the sensitivity analysis, 25% and 75% thresholds were tested as well. RESULTS: Out of 2242 publications, 23 full-text articles were included. The final MCDA tool consisted of ten criteria. In total, 27 distinctive drug-indication pairs regarding 21 drugs were used for the study. Six negative and 21 positive HTA recommendations were issued. In the base case, there were 19 positive MCDA outcomes. Of the 27 cases, there were 12 disagreements between the HTA and MCDA outcomes, the majority of which related to positive HTA guidance for negative MCDA outcomes. All drug-indication pairs with negative HTA recommendations were appraised positively in the MCDA framework. Economic details were available for 12 cases, of which there were 9 positive MCDA outcomes. Amongst the 12 drug indication pairs, two were negatively appraised in the HTA process, with positive MCDA guidance, and two were appraised in the opposite direction. CONCLUSIONS: An MCDA approach may lead to different P&R outcomes compared to a standard HTA process. On the one hand, enrichment of the list of decision making criteria means further scrutiny of a given health technology and as such increases the odds of a negative P&R outcome. On the other hand, it may uncover additional values and as such increase the odds of positive P&R outcomes. PMID- 26965711 TI - Analytical solution for time-dependent potentials in a fiber stimulated by an external electrode. AB - This study provides an analytical solution for time-dependent potentials in a 3D cylindrical fiber stimulated by an extracellular point electrode. The membrane is passive and represented by surface resistance and surface capacitance. Separation of variables solution expresses intracellular and extracellular potentials as sums involving modified Bessel functions; the coefficients ([Formula: see text] and [Formula: see text]) depend on time. In contrast to previous analytical solutions, where [Formula: see text] and [Formula: see text] had to be determined numerically, here [Formula: see text] and [Formula: see text] are given by explicit formulas that resemble the formulas for potentials in a fiber stimulated by a transverse electric field. The comparison of the 3D analytical solution with the 1D cable model shows that the cable model approximates transmembrane potential with the error below 5 % when the distance between the electrode and the fiber is 0.2-4 mm and when the stimulus is longer than 3.3 ms. For stimuli between 0.43 and 3.3 ms, the range of fiber-electrode distances with error below 5 % shrinks, and it disappears completely for stimuli shorter than 0.43 ms. Thus, our study shows that the applicability of the 1D cable model may be more limited than previously considered. PMID- 26965712 TI - Immunonutrition suppresses acute inflammatory responses through modulation of resolvin E1 in patients undergoing major hepatobiliary resection. AB - BACKGROUND: Although several studies have reported the effects of immunonutrition on clinical outcomes, detailed mechanisms of immunonutrition after an operation are still unclear. It was recently reported that resolvin E1, a novel lipid mediator generated from eicosapentaenoic acid (EPA), activates factors that reduce inflammation. This randomized clinical trial was designed to investigate not only the effect of immunonutrition on postoperative complications but also the participation of resolvin E1 on anti-inflammatory effects of immunonutrition in patients undergoing major hepatobiliary resection. METHODS: Forty patients who underwent major hepatobiliary resection were divided into 2 groups. Twenty patients received oral supplementation enriched with EPA, arginine, and nucleotides before the operation (group IN). Twenty patients (control group) received no artificial nutrition before the operation (group C). RESULTS: The rate of infectious complications and severity of complications in group IN was significantly lower than in group C (P < .05). Immediately after the operation, plasma resolvin E1 levels were significantly higher in group IN than in group C (P < .05), and plasma interleukin-6 levels were significantly lower in group IN than in group C (P < .05). Preoperative serum EPA levels correlated with plasma resolvin E1 levels immediately after the operation. Plasma resolvin E1 levels correlated with plasma interleukin-6 levels immediately after the operation. CONCLUSION: Preoperative immunonutrition reduced inflammatory responses and protected against the aggravation of postoperative complications in patients undergoing major hepatobiliary resection. Resolvin E1 may play a key role in the resolution of acute inflammation when immunonutrition is supplemented with EPA. (ClinicalTrials.gov Identifier: NCT01256047.). PMID- 26965713 TI - Localized surface plasmon resonances dominated giant lateral photovoltaic effect observed in ZnO/Ag/Si nanostructure. AB - We report substantially enlarged lateral photovoltaic effect (LPE) in the ZnO/Ag/Si nanostructures. The maximum LPE sensitivity (55.05 mv/mm) obtained in this structure is about seven times larger than that observed in the control sample (7.88 mv/mm) of ZnO/Si. We attribute this phenomenon to the strong localized surface plasmon resonances (LSPRs) induced by nano Ag semicontinuous films. Quite different from the traditional LPE in PN junction type structures, in which light-generated carriers contributed to LPE merely depends on direct excitation of light in semiconductor, this work firstly demonstrates that, by introducing a super thin metal Ag in the interface between two different kinds of semiconductors, the nanoscale Ag embedded in the interface will produce strong resonance of localized field, causing extra intraband excitation, interband excitation and an enhanced direct excitation. As a consequence, these LSPRs dominated contributions harvest much more carriers, giving rise to a greatly enhanced LPE. In particular, this LSPRs-driven mechanism constitutes a sharp contrast to the traditional LPE operation mechanism. This work suggests a brand new LSPRs approach for tailoring LPE-based devices and also opens avenues of research within current photoelectric sensors area. PMID- 26965714 TI - Metabolic syndrome in people with a psychotic illness: is cannabis protective? AB - BACKGROUND: Rates of the metabolic syndrome in people with psychotic illness are high. Emerging evidence suggests that cannabis use may have a positive impact on cardiometabolic risk factors in the general population, but little is known about its impact for people with psychotic illness. Our aim was to investigate whether the rate of the metabolic syndrome in people with psychotic illness was associated with frequency of cannabis use. METHOD: The 2010 Australian psychosis survey used a two-phase design to randomly select a nationally representative sample of 1825 adults with psychotic illness for interview and physical assessment. This study is based on 1813 participants who provided data on cannabis use. Multiple logistic regression was used to model the influence of frequency of cannabis use on the metabolic syndrome, adjusting for potential covariates including antipsychotic medication use, smoking, alcohol use and cognitive function. RESULTS: One-third (33.0%) of participants had used cannabis in the past year. The proportion of non-users, occasional users and frequent users with the metabolic syndrome was 63.0, 51.7 and 43.5%, respectively (p < 0.001). In unadjusted analyses, both occasional use and frequent cannabis use were associated with significantly lower odds of the metabolic syndrome. In the adjusted analyses, the association between the metabolic syndrome and frequent cannabis use remained significant [odds ratio = 0.56, 95% confidence interval (CI) 0.39-0.80], but not the association with occasional use (odds ratio = 0.75, 95% CI 0.49-1.13). CONCLUSIONS: While cannabis use may be detrimental for mental health, these data suggest that it may also have a cardiometabolic protective effect. Further investigation is required to understand the mechanism underlying this paradoxical finding. PMID- 26965715 TI - Increased enhancement of the liver adjacent to the gallbladder seen with contrast ultrasound: comparison between acute cholecystitis and non-cholecystitis. AB - BACKGROUND: This study was performed to evaluate the ability of contrast-enhanced ultrasonography (CEUS) with time-intensity curve analysis to demonstrate an increased enhancement of the liver parenchyma adjacent to the inflamed gallbladder, as seen on contrast-enhanced computed tomography. METHODS: The Ethics Committee of our institution approved the study protocol (Kawasaki Medical School, registration number 1277). From April to November 2013, 11 consecutive patients with acute cholecystitis and 16 patients without cholecystitis consented to CEUS (SonazoidTM) and were enrolled in this study. The gallbladder and liver were scanned by one gastroenterologist using harmonic imaging with a low mechanical index. The raw imaging data were stored. Another physician, blinded to all clinical information, constructed the time-intensity curve. The major axis of the region of interest (ROI) was set in segment 5 (pericholecystic area), and the control ROI in segment 8 at the same depth. The intensity ratio (IR) was defined as the peak intensity of segment 5 divided by the simultaneous value of segment 8. The characteristics of the patient with and without acute cholecystitis were compared. The correlation between the IR and the presence of acute cholecystitis was analyzed using binomial logistic regression analysis. A receiver operating characteristic (ROC) curve analysis was performed as well. RESULTS: The IR was significantly higher in the group with than without acute cholecystitis (p = 0.006). The IR correlated significantly with the presence of acute gallbladder inflammation (p = 0.043). The area under the ROC curve was estimated as 0.852 (95% confidence interval, 0.709-0.995). A cut-off value of 2.72 had a sensitivity of 81.8% and a specificity of 81.3%. CONCLUSIONS: The IR obtained by CEUS with time-intensity curve analysis generally demonstrated increased enhancement of the liver parenchyma adjacent to the inflamed gallbladder. PMID- 26965716 TI - Dissection of a non-bifurcating cervical carotid artery. AB - A non-bifurcating cervical carotid artery is a rare anomaly in the population. Radiologic diagnosis of pathologies seen together with this anomaly can be challenging. Despite not being diagnostic all the time, digital subtraction angiography is accepted as the gold standard method for the diagnosis of dissection. We present a case of a non-bifurcating cervical carotid artery and concomitant dissection, which presented to the hospital with trauma and ischemic findings. PMID- 26965717 TI - Variability of Insulin Requirements Over 12 Weeks of Closed-Loop Insulin Delivery in Adults With Type 1 Diabetes. AB - OBJECTIVE: To quantify variability of insulin requirements during closed-loop insulin delivery. RESEARCH DESIGN AND METHODS: We retrospectively analyzed overnight, daytime, and total daily insulin amounts delivered during a multicenter closed-loop trial involving 32 adults with type 1 diabetes. Participants applied hybrid day-and-night closed-loop insulin delivery under free living home conditions over 12 weeks. The coefficient of variation was adopted to measure variability of insulin requirements in individual subjects. RESULTS: Data were analyzed from 1,918 nights, 1,883 daytime periods and 1,564 total days characterized by closed-loop use over 85% of time. Variability of overnight insulin requirements (mean [SD] coefficient of variation 31% [4]) was nearly twice as high as variability of total daily requirements (17% [3], P < 0.001) and was also higher than variability of daytime insulin requirements (22% [4], P < 0.001). CONCLUSIONS: Overnight insulin requirements were significantly more variable than daytime and total daily amounts. This may explain why some people with type 1 diabetes report frustrating variability in morning glycemia. PMID- 26965718 TI - Racial and Ethnic Disparities in Diabetes Care and Impact of Vendor-Based Disease Management Programs. AB - OBJECTIVE: We examined the existence of disparities in receipt of appropriate diabetes care among California's fee-for-service Medicaid beneficiaries and the effectiveness of a telephonic-based disease management program delivered by a disease management vendor on the reduction of racial/ethnic disparities in diabetes care. RESEARCH DESIGN AND METHODS: We conducted an intervention-control cohort study to test the effectiveness of a 3-year-long disease management program delivered to Medicaid fee-for-service beneficiaries aged 22 to 75 with a diagnosis of diabetes in Los Angeles and Alameda counties. The outcome measures were the receipt of at least one hemoglobin A1c (HbA1c) test, LDL cholesterol test, and retinal examination each year. We used generalized estimating equations models with logit link to analyze the claims data for a cohort of beneficiaries in two intervention counties (n = 2,933) and eight control counties (n = 2,988) from September 2005 through August 2010. RESULTS: Racial/ethnic disparities existed in the receipt of all three types of testing in the intervention counties before the program. African Americans (0.66; 95% CI 0.62-0.70) and Latinos (0.77; 95% CI 0.74-0.80) had lower rates of receipt for HbA1c testing than whites (0.83; 95% CI 0.81-0.85) in the intervention counties. After the intervention, the disparity among African Americans and Latinos compared with whites persisted in the intervention counties. For Asian Americans and Pacific Islanders, the disparity in testing rates decreased. We did not find similar disparities in the control counties. CONCLUSIONS: This disease management program was not effective in reducing racial/ethnic disparities in diabetes care in the most racially/ethnically diverse counties in California. PMID- 26965719 TI - Variations in Diabetes Prevalence in Low-, Middle-, and High-Income Countries: Results From the Prospective Urban and Rural Epidemiological Study. AB - OBJECTIVE: The goal of this study was to assess whether diabetes prevalence varies by countries at different economic levels and whether this can be explained by known risk factors. RESEARCH DESIGN AND METHODS: The prevalence of diabetes, defined as self-reported or fasting glycemia >=7 mmol/L, was documented in 119,666 adults from three high-income (HIC), seven upper-middle-income (UMIC), four lower-middle-income (LMIC), and four low-income (LIC) countries. Relationships between diabetes and its risk factors within these country groupings were assessed using multivariable analyses. RESULTS: Age- and sex adjusted diabetes prevalences were highest in the poorer countries and lowest in the wealthiest countries (LIC 12.3%, UMIC 11.1%, LMIC 8.7%, and HIC 6.6%; P < 0.0001). In the overall population, diabetes risk was higher with a 5-year increase in age (odds ratio 1.29 [95% CI 1.28-1.31]), male sex (1.19 [1.13 1.25]), urban residency (1.24 [1.11-1.38]), low versus high education level (1.10 [1.02-1.19]), low versus high physical activity (1.28 [1.20-1.38]), family history of diabetes (3.15 [3.00-3.31]), higher waist-to-hip ratio (highest vs. lowest quartile; 3.63 [3.33-3.96]), and BMI (>=35 vs. <25 kg/m(2); 2.76 [2.52 3.03]). The relationship between diabetes prevalence and both BMI and family history of diabetes differed in higher- versus lower-income country groups (P for interaction < 0.0001). After adjustment for all risk factors and ethnicity, diabetes prevalences continued to show a gradient (LIC 14.0%, LMIC 10.1%, UMIC 10.9%, and HIC 5.6%). CONCLUSIONS: Conventional risk factors do not fully account for the higher prevalence of diabetes in LIC countries. These findings suggest that other factors are responsible for the higher prevalence of diabetes in LIC countries. PMID- 26965721 TI - Prognostic factors in the patients with T2N0M0 colorectal cancer. AB - BACKGROUND: The 5-year survival rate of the patients with stage I colorectal cancer is about 90%; therefore, adjuvant therapy has not been recommended after radical resection; however, about 16-26% of T2N0M0 patients will be dead at 5 years despite radical curative resection. It indicated that there is a defined group of patients who are at high risk for relapse or metastasis despite radical operation. This study aimed to find the patients with T2N0M0 colorectal cancer at high risk for relapse or metastasis. METHODS: From January 1993 to December 2014, 812 patients with histologically confirmed stage T2N0M0 primary colorectal cancer treated by radical surgery with complete clinical follow-up data were eligible for this study. The medical records of all patients were collected and were retrospectively analyzed. Survival rates were calculated using Kaplan-Meier method, and survival cures were compared using the log-rank test. Cox proportional hazards model was used to analyze the significant factors defined in univariate test. RESULTS: The 5-year and 10-year overall survival rates were 81.9 and 67.7%, respectively. Male gender, old age, lymphovascular permeation, perineural invasion, and poor differentiation were associated with low cancer specific survival rates in Kaplan-Meier analysis. Multivariate analyses revealed old age, lymphovascular permeation, perineural invasion, and poor differentiation as significant independent factors predicting worse prognosis (P < 0.05). CONCLUSIONS: Old age, lymphovascular permeation, perineural invasion, and poor differentiation are risk factors for the worse prognostic patients with T2N0M0 colorectal patients who would potential benefit from more aggressive therapy. PMID- 26965722 TI - The influence of epidural blockade on gut permeability in patients undergoing open surgical repair of abdominal aortic aneurysm. AB - BACKGROUND: Abdominal aortic clamping during aneurysm repair may cause a decrease in splanchnic blood flow and deterioration of gut barrier integrity. Epidural blocks have beneficial effects on vital organs during abdominal surgery, but sparse data are available on the influence on gut permeability during open aortic surgery. The aim of this study was to verify the hypothesis that epidural blocks may have beneficial effects on intestine permeability changes. METHODS: Seventy individuals undergoing elective open abdominal aortic aneurysm repair were randomly assigned to receive either balanced anaesthesia (continuous epidural and general anaesthesia, group E&G) or only general anaesthesia (group G). For group E&G, an epidural catheter was inserted into the epidural space before the induction of general anaesthesia. Ropivacaine was used for intraoperative and postoperative blocks. For both groups general anaesthesia was maintained with sevoflurane. For group G, analgesia was provided with remifentanil. The assessments of gut function were based on measurements of the absorption and percentages of urinary excretion of four sugars (m 3-O-methyl-D-glucose, D xylose, L-rhamnose and lactulose) and the lactulose/rhamnose (L/R) ratio. RESULTS: No intergroup differences were observed for sugar recovery or L/R ratio. Significant decreases in 3-O-methyl-D-glucose, D-xylose, and L-rhamnose recoveries were revealed in both examined groups when comparing the results obtained at 12 and 24 hours following the administration of anaesthesia. The rate of blood pressure decrease was significantly higher in group E&G. CONCLUSIONS: Aortic clamping during open abdominal aortic repair led to unfavorable changes in intestinal permeability. Epidural block did not attenuate this deterioration. PMID- 26965723 TI - An urgent call for infectious diseases specialists. PMID- 26965720 TI - Metabolic Syndrome Components Are Associated With Symptomatic Polyneuropathy Independent of Glycemic Status. AB - OBJECTIVE: Previous studies demonstrate that the metabolic syndrome is associated with distal symmetric polyneuropathy (DSP). We aimed to determine the magnitude of this effect and the precise components involved. RESEARCH DESIGN AND METHODS: We determined the symptomatic DSP prevalence in the Health, Aging, and Body Composition (Health ABC) study (prospective cohort study, with subjects aged 70 79 years at baseline), stratified by glycemic status (glucose tolerance test) and the number of additional metabolic syndrome components (updated National Cholesterol Education Program/Adult Treatment Panel III definition). DSP was defined as neuropathic symptoms (questionnaire) plus at least one of three confirmatory tests (heavy monofilament, peroneal conduction velocity, and vibration threshold). Multivariable logistic and linear regression evaluated the association of metabolic syndrome components with DSP in cross-sectional and longitudinal analyses. RESULTS: Of 2,382 participants with neuropathy measures (mean age 73.5 +/- 2.9 years, 38.2% black, 51.7% women), 21.0% had diabetes, 29.9% prediabetes, 52.8% metabolic syndrome, and 11.1% DSP. Stratified by glycemic status, DSP prevalence increased as the number of metabolic syndrome components increased (P = 0.03). Diabetes (cross-sectional model, odds ratio [OR] 1.65 [95% CI 1.18-2.31]) and baseline hemoglobin A1C (longitudinal model, OR 1.42 [95% CI 1.15-1.75]) were the only metabolic syndrome measures significantly associated with DSP. Waist circumference and HDL were significantly associated with multiple secondary neuropathy outcomes. CONCLUSIONS: Independent of glycemic status, symptomatic DSP is more common in those with additional metabolic syndrome components. However, the issue of which metabolic syndrome components drive this association, in addition to hyperglycemia, remains unclear. Larger waist circumference and low HDL may be associated with DSP, but larger studies with more precise metabolic measures are needed. PMID- 26965724 TI - [Tramadol associated with increased risk of hypoglycaemia]. PMID- 26965725 TI - Congenital varicella syndrome: A systematic review. AB - Varicella-zoster virus (VZV) is a teratogen that can cross the placenta and cause the congenital varicella syndrome (CVS), which is characterised by multi-system anomalies. There have been 130 reported cases of CVS from 1947 to 2013. The estimated incidence of CVS was 0.59% and 0.84% for women infected with VZV during the entire pregnancy and for those infected the first 20 weeks of pregnancy, respectively. Nine cases were reported at 21-27 weeks of gestation and one case was identified at 36 weeks. Herpes zoster caused CVS in two cases. Regarding treatment, varicella zoster immunoglobulin treatment, irrespective of gestational age, should be considered in addition to antiviral drugs for women who have been exposed to or infected with virus. PMID- 26965726 TI - Mixed regiospecificity compromises alkene synthesis by a cytochrome P450 peroxygenase from Methylobacterium populi. AB - Intensive interest has focused on enzymes that are capable of synthesizing hydrocarbons, alkenes and alkanes, for sustainable fuel production. A recently described cytochrome P450 (OleTJE) from the CYP152 family catalyzes an unusual carbon-carbon scission reaction, transforming Cn fatty acids to Cn-1 1-alkenes. Here, we show that a second CYP152, CYP-MP from Methylobacterium populi ATCC BAA 705, also catalyzes oxidative substrate decarboxylation. Alkene production is accompanied with the production of fatty alcohol products, underscoring the mechanistic similarity of the decarboxylation reaction with canonical P450 monooxygenation chemistry. The branchpoint of these two chemistries, and regiospecificity of oxidation products, is strongly chain length dependent, suggesting an importance of substrate coordination for regulating alkene production. PMID- 26965727 TI - Prenatal low-dose methylmercury exposure impairs neurite outgrowth and synaptic protein expression and suppresses TrkA pathway activity and eEF1A1 expression in the rat cerebellum. AB - Methylmercury (MeHg) is a highly neurotoxic environmental chemical that can cause developmental impairments. Human fetuses and neonates are particularly susceptible to MeHg toxicity; however, the mechanisms governing its effects in the developing brain are unclear. In the present study, we investigated the effects of prenatal and lactational MeHg exposure on the developing cerebellum in rats. We demonstrated that exposure to 5ppm MeHg decreased postnatal expression of pre- and postsynaptic proteins, suggesting an impairment in synaptic development. MeHg exposure also reduced neurite outgrowth, as shown by a decrease in the expression of the neurite marker neurofilament H. These changes were not observed in rats exposed to 1ppm MeHg. In order to define the underlying mechanism, we investigated the effects of MeHg exposure on the tropomyosin receptor kinase (Trk) A pathway, which plays important roles in neuronal differentiation and synapse formation. We demonstrated suppression of the TrkA pathway on gestation day 20 in rats exposed to 5ppm MeHg. In addition, down regulation of eukaryotic elongation factor 1A1 (eEF1A1) was observed on postnatal day 1. eEF1A1 knockdown in differentiating PC12 cells impaired neurite outgrowth and synaptic protein expression, similar to the results of MeHg exposure in the cerebellum. These results suggest that suppression of the TrkA pathway and subsequent decreases in eEF1A1 expression induced by prenatal exposure to MeHg may lead to reduced neurite outgrowth and synaptic protein expression in the developing cerebellum. PMID- 26965728 TI - Fluid dynamic lateral slicing of high tensile strength carbon nanotubes. AB - Lateral slicing of micron length carbon nanotubes (CNTs) is effective on laser irradiation of the materials suspended within dynamic liquid thin films in a microfluidic vortex fluidic device (VFD). The method produces sliced CNTs with minimal defects in the absence of any chemical stabilizers, having broad length distributions centred at ca 190, 160 nm and 171 nm for single, double and multi walled CNTs respectively, as established using atomic force microscopy and supported by small angle neutron scattering solution data. Molecular dynamics simulations on a bent single walled carbon nanotube (SWCNT) with a radius of curvature of order 10 nm results in tearing across the tube upon heating, highlighting the role of shear forces which bend the tube forming strained bonds which are ruptured by the laser irradiation. CNT slicing occurs with the VFD operating in both the confined mode for a finite volume of liquid and continuous flow for scalability purposes. PMID- 26965730 TI - Diagnosing Cardiac Allograft Vasculopathy: Focusing on the Little Things... PMID- 26965729 TI - Myocardial Perfusion Reserve and Strain-Encoded CMR for Evaluation of Cardiac Allograft Microvasculopathy. AB - OBJECTIVES: This study sought to evaluate myocardial perfusion reserve index (MPRI) and diastolic strain rate, both assessed by cardiac magnetic resonance (CMR) as a noninvasive tool for the detection of microvasculopathy. BACKGROUND: Long-term survival of cardiac allograft recipients is limited primarily by cancer and cardiac allograft vasculopathy (CAV). Besides epicardial CAV, diagnosed by coronary angiography, stenotic microvasculopathy was found to be an additional independent risk factor for survival after heart transplantation. METHODS: Sixty three consecutive heart transplant recipients who underwent CMR, coronary angiography, and myocardial biopsy were enrolled. Stenotic vasculopathy in microvessels was considered in myocardial biopsies by immunohistochemistry and CAV was graded during coronary angiography according to International Society of Heart and Lung Transplantation criteria. In addition, by CMR microvasculopathy was assessed by myocardial perfusion reserve during pharmacologic hyperemia with adenosine and strain-encoded magnetic resonance using a modified spatial modulation of magnetization tagging pulse sequence in all patients. RESULTS: Decreasing MPRI and diastolic strain rates were observed in patients with decreasing microvessel luminal radius to wall thickness ratio and decreasing capillary density (r = 0.45 and r = 0.61 for MPRI and r = 0.50 and r = 0.38 for diastolic strain rate, respectively; p < 0.005 for all). Using multivariable analysis, both MPRI and diastolic strain rate were robust predictors of stenotic microvasculopathy, independent of age, organ age, and CAV by International Society of Heart and Lung Transplantation criteria (hazard ratio: 0.07, p = 0.006 for MPRI; hazard ratio: 0.91, p = 0.002 for diastolic strain rate). Patients without stenotic microvasculopathy in the presence of no or mild CAV (n = 36) exhibited significantly higher median survival free of events, compared with patients with stenotic microvasculopathy in the presence of no or mild CAV (n = 18; p = 0.04 by log rank). CONCLUSIONS: CMR represents a valuable noninvasive diagnostic tool, which may be used for the early detection of transplant microvasculopathy before the manifestation of CAV during surveillance coronary angiographic procedures. PMID- 26965731 TI - Evidence Base for Quality Control Activities in Cardiovascular Imaging. AB - Quality control is pervasive in most modern business, but, surprisingly, is in its infancy in medicine in general-and cardiovascular imaging in particular. The increasing awareness of the cost of cardiovascular imaging, matched by a desire to show benefits from imaging to patient outcome, suggests that this deficiency should be reassessed. Demonstration of improved quality has been proposed to require a focus on several domains: laboratory organization, patient selection, image acquisition, image interpretation, and results communication. Improvement in these steps will require adoption of a variety of interventions, including laboratory accreditation, appropriate use criteria, and continuous quality control and enhancements in reporting, but the evidence base for the benefit of interventions on these steps has been sparse. The purpose of this review is to evaluate the current status and future goals of developing the evidence base for these processes in cardiovascular imaging. PMID- 26965732 TI - MR Imaging of Coronary Arteries and Plaques. AB - Cardiac magnetic resonance offers the promise of radiation-free imaging of the coronary arteries, providing information with respect to luminal stenosis, plaque burden, high-risk plaque characteristics, and disease activity. In combination, this would provide a comprehensive, individualized assessment of coronary atherosclerosis that could be used to improve patient risk stratification and to guide treatment. However, the technical challenges involved with delivering upon this promise are considerable, requiring sophisticated approaches to both data acquisition and post-processing. In this review, we describe the current status of this technology, its capabilities, its limitations, and what will be required in the future to translate this technology into routine clinical practice. PMID- 26965733 TI - Nonatherosclerotic Coronary Artery Narrowing. PMID- 26965734 TI - How to Distinguish Between Myocarditis and Sarcoidosis Based on CMR Imaging. PMID- 26965735 TI - The Authors Reply. PMID- 26965736 TI - CT Coronary Angiography in Kidney Transplantation Candidates. PMID- 26965737 TI - The Authors Reply. PMID- 26965738 TI - Coronary Artery Calcium Scanning: Past, Present, and Future. PMID- 26965739 TI - The Author Replies. PMID- 26965740 TI - Imaging and the Valley of Death: Developing the Evidence Base for the Use of Imaging in Follow-Up. PMID- 26965741 TI - Extraction of esophageal foreign body with burrowing technique. PMID- 26965742 TI - Whole genome sequence of Pantoea ananatis R100, an antagonistic bacterium isolated from rice seed. AB - Pantoea ananatis is a group of bacteria, which was first reported as plant pathogen. Recently, several papers also described its biocontrol ability. In 2003, P. ananatis R100, which showed strong antagonism against several plant pathogens, was isolated from rice seeds. In this study, whole genome sequence of this strain was determined by SMRT Cell technology. The total genome size of R100 is 4,857,861bp with 4659 coding genes (CDS), 82 tRNAs and 22 rRNAs. The genome sequence of R100 may shed a light on the research of antagonism P. ananatis. PMID- 26965743 TI - Atlas of select poisonous plants and mushrooms. PMID- 26965744 TI - Has deinstitutionalization affected inpatient suicide? Psychiatric inpatient suicide rates between 1990 and 2013 in Israel. AB - OBJECTIVE: To examine variations in rates of inpatient suicide and clinical risk factors for this phenomenon. METHOD: The National Israeli Psychiatric Hospitalization Case Registry was used to study inpatient suicide. Clinical risk factors for inpatient suicide were examined in a nested case control design. RESULTS: Between 1990 and 2013 there were 326 inpatient suicides, at an average of one inpatient suicide per 1614 admissions. A significant decline in rates of suicide per admission over time (p<0.001) was associated with a reduced number of beds (p<0.001) and a decline in nationwide suicide rates (p=0.001). Clinical risk factors for inpatient suicide were: affective disorders (OR=5.95), schizoaffective disorder (OR=5.27), schizophrenia (OR=3.82), previous suicide attempts (OR=2.59), involuntary hospitalization (OR=1.67), and more previous hospitalizations (OR=1.16,). A multivariate model with sensitivity of 27.3% and specificity of 95.3% for inpatient suicide, showed a positive predictive value of 0.4%. CONCLUSIONS: The absolute number and rates of inpatient suicide per admission have decreased over time, probably due to the decreased number of beds lowering total time at risk. Patients with affective and psychotic disorders and with previous suicide attempts have the greatest risk of inpatient suicide. However, clinical characteristics do not enable identification of patients who are at risk for suicide. PMID- 26965748 TI - Cloning, characterization and mRNA expression of interleukin-6 in blunt snout bream (Megalobrama amblycephala). AB - In the present study, the interleukin-6 gene (IL-6) cDNA in blunt snout bream (Megalobrama amblycephala) was identified and its expression profiles under ammonia stress and bacterial challenge were investigated. The IL-6 sequence consisted of 1045 bp, including a 696 bp ORF which translated into a 232 amino acid (AA) protein. The protein contained a putative signal peptide of 24 AA in length. IL-6 expression analysis showed that the it is differentially expressed in various tissues under normal conditions and the highest IL-6 level was observed in the intestine tissue, followed by the liver, and then in the gills. Under ammonia stress, the IL-6 mRNA level both in spleens and intestine increased significantly (P < 0.05), with the maximum levels attained at 6 h, 12 h (72, 10 fold, respectively). Thereafter, they all significantly decreased (P < 0.01) and returned to the basal value within 48 h. Whereas, in livers it slightly decreased at 3 h firstly (0.5-fold), and then significantly (P < 0.05) increased with the maximum level attained 12 h (3-fold). Further expression analysis showed that the mRNA level of IL-6 in spleens, intestine and livers of blunt snout bream all increased significantly (P < 0.05), with maximum values attained at 6 h, 3 h, 6 h (10, 6, 18-fold, respectively) after Aeromonas hydrophila (A. hydrophila) injection, and then decreased to the basal value within 24 h which suggested that IL-6 was involved in the immune response to A. hydrophila. The cloning and expression analysis of the IL-6 provide theoretical basis to further study the mechanism of anti-adverseness and expression characteristics under stress conditions in blunt snout bream. PMID- 26965746 TI - Paratransgenesis to control malaria vectors: a semi-field pilot study. AB - BACKGROUND: Malaria still remains a serious health burden in developing countries, causing more than 1 million deaths annually. Given the lack of an effective vaccine against its major etiological agent, Plasmodium falciparum, and the growing resistance of this parasite to the currently available drugs repertoire and of Anopheles mosquitoes to insecticides, the development of innovative control measures is an imperative to reduce malaria transmission. Paratransgenesis, the modification of symbiotic organisms to deliver anti pathogen effector molecules, represents a novel strategy against Plasmodium development in mosquito vectors, showing the potential to reduce parasite development. However, the field application of laboratory-based evidence of paratransgenesis imposes the use of more realistic confined semi-field environments. METHODS: Large cages were used to evaluate the ability of bacteria of the genus Asaia expressing green fluorescent protein (Asaia (gfp)), to diffuse in Anopheles stephensi and Anopheles gambiae target mosquito populations. Asaia (gfp) was introduced in large cages through the release of paratransgenic males or by sugar feeding stations. Recombinant bacteria transmission was directly detected by fluorescent microscopy, and further assessed by molecular analysis. RESULTS: Here we show the first known trial in semi-field condition on paratransgenic anophelines. Modified bacteria were able to spread at high rate in different populations of An. stephensi and An. gambiae, dominant malaria vectors, exploring horizontal ways and successfully colonising mosquito midguts. Moreover, in An. gambiae, vertical and trans-stadial diffusion mechanisms were demonstrated. CONCLUSIONS: Our results demonstrate the considerable ability of modified Asaia to colonise different populations of malaria vectors, including pecies where its association is not primary, in large environments. The data support the potential to employ transgenic Asaia as a tool for malaria control, disclosing promising perspective for its field application with suitable effector molecules. PMID- 26965750 TI - From the Editor. PMID- 26965749 TI - Effects of melatonin injection or green-wavelength LED light on the antioxidant system in goldfish (Carassius auratus) during thermal stress. AB - We tested the mitigating effects of melatonin injections or irradiation from green-wavelength light-emitting diodes (LEDs) on goldfish (Carassius auratus) exposed to thermal stress (high water temperature, 30 degrees C). The effects of the two treatments were assessed by measuring the expression and activity levels of the antioxidant enzymes, superoxide dismutase and catalase, plasma hydrogen peroxide, lipid hydroperoxide, and lysozyme. In addition, a comet assay was conducted to confirm that high water temperature damaged nuclear DNA. The expression and activity of the antioxidant enzymes, plasma hydrogen peroxide, and lipid hydroperoxide were significantly higher after exposure to high temperature and were significantly lower in fish that received melatonin or LED light than in those that received no mitigating treatment. Plasma lysozyme was significantly lower after exposure to high temperature and was significantly higher after exposure to melatonin or LED light. The comet assay revealed that thermal stress caused a great deal of damage to nuclear DNA; however, treatment with melatonin or green-wavelength LED light prevented a significant portion of this damage from occurring. These results indicate that, although high temperatures induce oxidative stress and reduce immune system strength in goldfish, both melatonin and green-wavelength LED light inhibit oxidative stress and boost the immune system. LED treatment increased the antioxidant and immune system activity more significantly than did melatonin treatment. PMID- 26965745 TI - Hyperactivity of caudate, parahippocampal, and prefrontal regions during working memory in never-medicated persons at clinical high-risk for psychosis. AB - BACKGROUND: Deficits in working memory (WM) are a core feature of schizophrenia (SZ) and other psychotic disorders. We examined brain activity during WM in persons at clinical high risk (CHR) for psychosis. METHODS: Thirty-seven CHR and 34 healthy control participants underwent functional MRI (fMRI) on a 3.0T scanner while performing an N-back WM task. The sample included a sub-sample of CHR participants who had no lifetime history of treatment with psychotropic medications (n=11). Data were analyzed using SPM8 (2-back>0-back contrast). Pearson correlations between brain activity, symptoms, and WM performance were examined. RESULTS: The total CHR group and medication-naive CHR sub-sample were comparable to controls in most demographic features and in N-back WM performance, but had significantly lower IQ. Relative to controls, medication-naive CHR showed hyperactivity in the left parahippocampus (PHP) and the left caudate during performance of the N-back WM task. Relative to medication-exposed CHR, medication naive CHR exhibited hyperactivity in the left caudate and the right dorsolateral prefrontal cortex (DLPFC). DLPFC activity was significantly negatively correlated with WM performance. PHP, caudate and DLPFC activity correlated strongly with symptoms, but results did not withstand FDR-correction for multiple comparisons. When all CHR participants were combined (regardless of medication status), only trend-level PHP hyperactivity was observed in CHR relative to controls. CONCLUSIONS: Medication-naive CHR exhibit hyperactivity in regions that subserve WM. These regions are implicated in studies of schizophrenia and risk for psychosis. Results emphasize the importance of medication status in the interpretation of task - induced brain activity. PMID- 26965751 TI - Derivation of a measure of systolic blood pressure mutability: a novel information theory-based metric from ambulatory blood pressure tests. AB - We provide ambulatory blood pressure (BP) exams with tools based on information theory to quantify fluctuations thus increasing the capture of dynamic test components. Data from 515 ambulatory 24-hour BP exams were considered. Average age was 54 years, 54% were women, and 53% were under BP treatment. The average systolic pressure (SP) was 127 +/- 8 mm Hg. A data compressor (wlzip) designed to recognize meaningful information is invoked to measure mutability which is a form of dynamical variability. For patients with the same average SP, different mutability values are obtained which reflects the differences in dynamical variability. In unadjusted linear regression models, mutability had low association with the mean systolic BP (R(2) = 0.056; P < .000001) but larger association with the SP deviation (R(2) = 0.761; P < .001). Wlzip allows detecting levels of variability in SP that could be hazardous. This new indicator can be easily added to the 24-hour BP monitors improving information toward diagnosis. PMID- 26965752 TI - Integrating acute malnutrition interventions into national health systems: lessons from Niger. AB - BACKGROUND: Since 2007, integrated care of acute malnutrition has been promoted in Niger, a country affected by high burden of disease. This policy change aimed at strengthening capacity and ownership to manage the condition. Integration was neither defined nor planned but assumed to have been achieved. This paper studied the level and progress of integration of acute malnutrition interventions into key health system functions. METHODS: The qualitative study method involved literature searches on acute malnutrition interventions for children under 5 in low-income countries to develop a matrix of integration. Integration indicators defined three levels of integration of acute malnutrition interventions into health system functions-full, partial or none. Indicators of health services and health status were added to describe health system improvements. Data from qualitative and quantitative studies conducted in Niger between 2007 and 2013 were used to measure the indicators for the years under study. RESULTS: Results showed a mosaic of integration levels across key health system functions. Four indicators showed full integration, 22 showed partial integration and three showed no integration. Two-thirds of system functions showed progress in assimilating acute malnutrition interventions, while six persistently stagnated over time. There was variation within and across health system domains, with governance and health information functions scoring highest and financing lowest. Steady improvements were noted in geographic coverage, access and under-5 mortality risk. CONCLUSIONS: This study provided useful information to inform policy makers and guide strategic planning to improve integration of acute malnutrition interventions in Niger. The proposed method of assessing the extent of integration and monitoring progress may be adapted and used in Niger and other low-income countries that are integrating or intending to integrate acute malnutrition interventions. PMID- 26965753 TI - Pre-steady-state kinetic studies of redox reactions catalysed by Bacillus subtilis ferredoxin-NADP(+) oxidoreductase with NADP(+)/NADPH and ferredoxin. AB - Ferredoxin-NADP(+) oxidoreductase ([EC1.18.1.2], FNR) from Bacillus subtilis (BsFNR) is a homodimeric flavoprotein sharing structural homology with bacterial NADPH-thioredoxin reductase. Pre-steady-state kinetics of the reactions of BsFNR with NADP(+), NADPH, NADPD (deuterated form) and B. subtilis ferredoxin (BsFd) using stopped-flow spectrophotometry were studied. Mixing BsFNR with NADP(+) and NADPH yielded two types of charge-transfer (CT) complexes, oxidized FNR (FNR(ox)) NADPH and reduced FNR (FNR(red))-NADP(+), both having CT absorption bands centered at approximately 600n m. After mixing BsFNR(ox) with about a 10-fold molar excess of NADPH (forward reaction), BsFNR was almost completely reduced at equilibrium. When BsFNR(red) was mixed with NADP(+), the amount of BsFNR(ox) increased with increasing NADP(+) concentration, but BsFNR(red) remained as the major species at equilibrium even with about 50-fold molar excess NADP(+). In both directions, the hydride-transfer was the rate-determining step, where the forward direction rate constant (~500 s(-1)) was much higher than the reverse one (<10 s(-1)). Mixing BsFd(red) with BsFNR(ox) induced rapid formation of a neutral semiquinone form. This process was almost completed within 1 ms. Subsequently the neutral semiquinone form was reduced to the hydroquinone form with an apparent rate constant of 50 to 70 s(-1) at 10 degrees C, which increased as BsFd(red) increased from 40 to 120 MUM. The reduction rate of BsFNR(ox) by BsFd(red) was markedly decreased by premixing BsFNR(ox) with BsFd(ox), indicating that the dissociation of BsFd(ox) from BsFNR(sq) is rate-limiting in the reaction. The characteristics of the BsFNR reactions with NADP(+)/NADPH were compared with those of other types of FNRs. PMID- 26965754 TI - Recent advancements in ion concentration polarization. AB - In this minireview, we discuss advancements in ion concentration polarization (ICP)-based preconcentration, separation, desalination, and dielectrophoresis that have been made over the past three years. ICP as a means of controlling the distribution of the ions and electric field in a microfluidic device has rapidly expanded its areas of application. Recent advancements have focused on the development of ion-permselective materials with tunable dimensions and surface chemistry, adaptation to paper microfluidics, higher-throughput device geometries, and coupling ICP with other separation (isotachophoresis and dielectrophoresis) and fluidic (valve and droplet microfluidic) strategies. These studies have made great strides toward solving real-world problems such as low cost and rapid analysis, accessible desalination technology, and single-cell research tools. PMID- 26965755 TI - Eosinophilic pneumonia: Daptomycin-induced lung complication. PMID- 26965756 TI - Health benefits of legumes and pulses with a focus on Australian sweet lupins. AB - BACKGROUND AND OBJECTIVES: The 68th United Nations General Assembly declared 2016 the International Year of Pulses. Therefore it is timely to review the current evidence of the benefits of legumes for human health with a focus on Australian sweet lupins. METHODS AND STUDY DESIGN: Medline, Pubmed, Cochrane library were searched to identify cross-sectional/epidemiological studies, randomised controlled trials (RCTs) and systematic reviews. RESULTS: The strongest evidence appears to be for links between eating legumes and reduced risk of colorectal cancer as well as eating soy foods and reduced LDL cholesterol. However, epidemiological studies and RCTs suggest that replacing several meat-based meals a week with legumes can have a positive impact on longevity, diabetes, cardiovascular disease and weight management, potentially via favourable effects on the gut microbiome. Sweet lupins are unique among legumes with one of the highest combined amounts of digestible plant protein (38%) and dietary fibre (30%). Unlike other legumes, their low amount of anti-nutritional factors negates the need for soaking/cooking and they can therefore be eaten uncooked. Sweet lupins may lower blood pressure, improve blood lipids and insulin sensitivity and favourably alter the gut microbiome. There is growing interest in pulses, especially sweet lupins, as ingredients to improve the nutritional value of baked goods (particularly gluten free) and to create novel products to replace meat. CONCLUSION: Legumes form part of most traditional diets. They, including sweet lupins, can play a useful role in health maintenance. PMID- 26965757 TI - Rapid estimation of the energy content of composite foods: the application of the Calorie AnswerTM. AB - The estimation of calories in foods is central in the maintenance of body weight and energy regulation. Conventional laboratory analysis using bomb calorimetry to determine calorie content is expensive and time-consuming. There is a need to explore alternative techniques for calorie estimation that requires less processing and resources. The potential of using near infrared spectroscopy for calorie measurements with Calorie AnswerTM was evaluated in this study. The caloric content of 105 different foods was measured, and compared against values reported on nutrition labels. The average percentage relative standard deviation for triplicate measurements was 1.7% for all foods. The percentage difference between stated and measured calories was modest, at 4.0% for all foods. Stated and measured calorie contents were significantly and highly correlated (R2=0.98, p<0.001). The use of near infrared spectroscopy, using Calorie AnswerTM, is a rapid, reproducible and cost-effective way of measuring calorie content in a diverse range of foods. Its application in many parts of Asia Pacific and other emerging nations will generate much needed information on the calorie content of complex foods consumed by people living in these regions. PMID- 26965758 TI - Dialysis Malnutrition and Malnutrition Inflammation Scores: screening tools for prediction of dialysis-related protein-energy wasting in Malaysia. AB - BACKGROUND AND OBJECTIVES: Malnutrition is highly prevalent in Malaysian dialysis patients and there is a need for a valid screening tool for early identification and management. This cross-sectional study aims to examine the sensitivity of the Dialysis Malnutrition Score (DMS) and Malnutrition Inflammation Score (MIS) tools in predicting protein-energy wasting (PEW) among Malaysian dialysis patients. METHODS AND STUDY DESIGN: A total of 155 haemodialysis (HD) and 90 peritoneal dialysis (PD) patients were screened for risk of malnutrition using DMS and MIS and comparisons were made with established guidelines by International Society of Renal Nutrition and Metabolism (ISRNM) for PEW. RESULTS: MIS cut-off score of >=5 indicated presence of malnutrition in all patients. A total of 59% of HD and 83% of PD patients had PEW by ISRNM criteria. Based on DMS, 73% of HD and 71% of PD patients exhibited moderate malnutrition, whilst using MIS, 88% and 90%, respectively were malnourished. DMS and MIS correlated significantly in HD (r2=0.552, p<0.001) and PD (r2=0.466, p<0.001) patients. DMS and MIS had higher sensitivity values in PD (81% and 82%, respectively) compared to HD (59% and 60%, respectively) patients. CONCLUSIONS: The MIS cut-off scores for malnutrition classification were established (score >=5) for use amongst Malaysian dialysis patients. Both DMS and MIS are valid tools to be used for nutrition screening of dialysis patients especially those undergoing peritoneal dialysis. The DMS may be a more practical and simpler tool to be utilized in the Malaysian dialysis settings as it does not require laboratory markers. PMID- 26965759 TI - Conventional MRI for diagnosis of subacute combined degeneration (SCD) of the spinal cord due to vitamin B-12 deficiency. AB - Subacute combined degeneration of the spinal cord (SCD) is often found in vitamin B-12 deficiency and typically shows hyperintensity on T2-weighted images of the lateral and posterior columns. The purpose of the study was to evaluate the use of conventional magnetic resonance examination in diagnosing SCD. Thirty-six patients were clinically confirmed and retrospectively analyzed; conventional spine MRIs were available for all patients and eight of them had contrast enhancement MRIs. 19 out of 36 patients showed abnormal signal intensity on T2 weighted images with a sensitivity of 52.8%, among which 18 in the posterior aspect of the spinal cord and 1 in the anterior horn of the thoracic spinal cord The spinal cord abnormalities were seen at the cervical spine in 12 patients (33.3%) and at the thoracic spine in the other 7 patients (19.4%). Axial T2 weighted images showed symmetric linear T2-hyperintensity as an "inverted V" at the cervical spinal cord in 5 patients, which has been reported as a typical sign of SCD. For patients with thoracic spinal cord abnormalities, the bilateral paired nodular T2-hyperintensity looked like "binoculars" at the thoracic spinal cord. Only one out of the eight patients showed slight enhancement after injection with contrast agent. All the 36 patients reported clinical improvement after appropriate vitamin B-12 treatment. The two follow-up spine MRIs showed a decreased extent of the lesion. Therefore, conventional MRI is useful in the diagnosis and management of SCD caused by vitamin B-12 deficiency. PMID- 26965761 TI - Early enteral nutrition in neonates with partial gastrectomy: a multi-center study. AB - BACKGROUND AND OBJECTIVES: Compared with total parenteral nutrition (TPN), enteral nutrition is more suitable for patients post-operatively. Our aim was to determine the safety and feasibility of early enteral nutrition (EEN) using a jejunum feeding tube in neonates after undergoing a partial gastrectomy. METHODS AND STUDY DESIGN: This was a retrospective review of 46 patients who underwent partial gastrectomies for gastric perforation in our hospital. These patients were categorized into two groups (EEN group [n=24 patients], a jejunal feeding tube was inserted during surgery; and a control group [n=22 patients], a jejunal feeding tube was not placed). Differences in operative time, time to first defecation post-operatively, time to first oral feeding post-operatively, length of hospital stay post-operatively, nutrition indices, and post-operative complications (died due to septic shock, cholestasis, pneumonia, abdominal distension, and diarrhea) were reviewed. RESULTS: There were no significant differences in the operative time and the time to first oral feeding post operatively between the two groups; however, the time to first defecation post operatively in the EEN group and the hospital length of stay post-operatively for the EEN group were significantly shorter than the control group. The levels of albumin, retinol binding protein, and prealbumin were not significantly different between the two groups pre-operatively and 14 days postoperatively. The incidence of cholestasis and abdominal distention in the EEN group was significantly lower than the control group. CONCLUSION: EEN using a jejunal feeding tube in neonates who have undergone a partial gastrectomy for gastric perforation is safe, easy, and has fewer complications than TPN. PMID- 26965760 TI - Daily salt intake estimated by overnight urine collections indicates a high cardiovascular disease risk in Thailand. AB - This cross-sectional study (February 2012 to March 2013) was conducted to estimate daily salt intake and basic characteristics among 793 community-dwelling participants at high risk of cardiovascular disease (Framingham risk score >15%), who had visited diabetes or hypertension clinics at health centres in the Muang district, Chiang Rai, Thailand. We performed descriptive analysis of baseline data and used an automated analyser to estimate the average of 24-hour salt intake estimated from 3 days overnight urine collection. Participants were divided into two groups based on median estimated daily salt intake. Mean age and proportion of males were 65.2 years and 37.6% in the higher salt intake group (>=10.0 g/day, n=362), and 67.5 years and 42.7% in the lower salt intake group (<10.0 g/day, n=431), respectively (p=0.01, p<0.01). The higher salt intake group comprised more patients with a family history of hypertension, antihypertensive drug use, less ideal body mass index (18.5-24.9), higher exercise frequency (>=2 times weekly) and lower awareness of high salt intake. Among higher salt intake participants, those with lower awareness of high salt intake were younger and more often had a family history of hypertension, relative to those with more awareness. Our data indicated that families often share lifestyles involving high salt intake, and discrepancies between actual salt intake and awareness of high salt intake may represent a need for salt reduction intervention aiming at family level. Awareness of actual salt intake should be improved for each family. PMID- 26965762 TI - Amino acid dosing in parenteral nutrition for very low birth weight preterm neonates: an outcome assessment. AB - This study aimed to investigate the effects of parenteral nutrition (PN) administration of amino acids (AA) on physical changes among very low birth weight infants in a local hospital setting in Malaysia. A retrospective study was carried out at a hospital in Malaysia. Records of neonates prescribed PN in the neonatal unit in 2012 were screened for eligibility. A total of 199 premature neonates received PN support in the year 2012 and, of these, 100 fulfilled the inclusion criteria. The median value of AA intake on the first day of PN was 2.00 (<28 weeks group); 1.00 (28-31 weeks group) and 0.75 (>31 weeks group). Neonates in the <28 weeks group were more likely to receive AA at an earlier time and higher initial dose compared with the other age groups. The study also found that there was no statistically significant difference in the dose of AA on the first day of PN administration and that the significant variations in nutritional parameters among the subjects did not lead to differences in physical outcomes. This study identified that when PN is provided in the local hospital setting, it is likely that the current nutritional practices are inadequate to achieve the standard growth recommendations. Our findings call for a need to optimize AA and calorie intake since growth restriction is a morbidity which will affect the infants' growth and development. Current prescriptions for PN in this hospital need to be reviewed in order to improve patient outcomes. PMID- 26965763 TI - Folic acid fortified milk increases blood folate to concentrations associated with a very low risk of neural tube defects in Singaporean women of childbearing age. AB - BACKGROUND AND OBJECTIVES: Folic acid (400 MUg/d) taken during the periconceptional period reduces neural tube defect (NTD) risk by >75%. Achieving red cell folate (RCF) or plasma folate (PF) >905 nmol/L and >35 nmol/L, respectively, has been associated with a low risk of NTDs. We determined whether daily consumption of folic acid fortified milk increases blood folate concentrations to levels associated with a low risk of NTDs in Singaporean women of childbearing age. METHODS AND STUDY DESIGN: In this double-blind placebo controlled trial, 70 non-pregnant women (21-35 y) were randomly assigned to receive fortified milk (FM) powder providing 400 MUg folic acid per day or unfortified placebo milk (PM) powder for 12 weeks. Blood samples were collected at baseline and at 6 and 12 weeks. RESULTS: At 12 weeks, mean (95% CI) RCF and PF concentrations were 376 (240, 512) and 39 (26, 51) nmol/L higher in the FM group compared with the PM group (p<0.001). Of the women receiving FM, 71% (n=25) and 86% (n=30) achieved a RCF and PF associated with a very low risk of NTDs, respectively. CONCLUSION: Folic acid fortified milk increased blood folate concentrations in women of childbearing age to levels associated with a reduced risk of an NTD-affected pregnancy. PMID- 26965764 TI - Correction of hypovitaminosis D does not improve the metabolic syndrome risk profile in a Chinese population: a randomized controlled trial for 1 year. AB - BACKGROUND AND OBJECTIVES: Vitamin D deficiency is associated with a variety of chronic metabolic diseases. In vitro and animal studies suggest that vitamin D may play a crucial role in obesity and related metabolic disorders. Limited evidence regarding vitamin D deficiency exists within the Chinese population. The aims of the present study were to assess whether supplementation with vitamin D would improve metabolic indices in a middle-aged urban Chinese population. METHODS AND STUDY DESIGN: We designed a randomized placebo controlled trial involving 126 metabolic syndrome sufferers with vitamin D deficiency, allocated to receive either a daily oral tablet contain 700 IU vitamin D or a matching placebo. Metabolic indices including body mass index, plasma glucose, lipid profile and other parameters were measured in subjects who completed a 12 months intervention trial. RESULTS: There were significantly higher serum 25(OH)D and lower serum parathyroid hormone in vitamin D treatment group after the 12 months intervention, but no significant effect was observed for the metabolic variables which included body mass index, blood pressure, blood glucose and lipids in both treatment and control groups. CONCLUSIONS: Correction of hypovitaminosis D did not improve the metabolic syndrome in this urban Chinese cohort. Further studies are warranted in order to elucidate the cause-effect relation between vitamin D status, obesity and related metabolic disorders. PMID- 26965765 TI - A randomised trial of the feasibility of a low carbohydrate diet vs standard carbohydrate counting in adults with type 1 diabetes taking body weight into account. AB - BACKGROUND AND OBJECTIVES: To determine the effect of a low carbohydrate diet and standard carbohydrate counting on glycaemic control, glucose excursions and daily insulin use compared with standard carbohydrate counting in participants with type 1 diabetes. METHODS AND STUDY DESIGN: Participants (n=10) with type 1 diabetes using a basal; bolus insulin regimen, who attended a secondary care clinic, were randomly allocated (1:1) to either a standard carbohydrate counting course or the same course with added information on following a carbohydrate restricted diet (75 g per day). Participants attended visits at baseline and 12 weeks for measurements of weight, height, blood pressure, HbA1c, lipid profile and creatinine. They also completed a 3-day food diary and had 3 days of continuous subcutaneous glucose monitoring. RESULTS: The carbohydrate restricted group had significant reductions in HbA1c (63 to 55 mmol/mol (8.9-8.2%), p<0.05) and daily insulin use (64.4 to 44.2 units/day, p<0.05) and non-significant reductions in body weight (83.2 to 78.0 kg). There were no changes in blood pressure, creatinine or lipid profile and all outcomes in the carbohydrate counting group were unchanged. There was no change in glycaemic variability as measured by the mean amplitude of glycaemic excursion in either group. CONCLUSIONS: A low carbohydrate diet is a feasible option for people with type 1 diabetes, and may be of benefit in reducing insulin doses and improving glycaemic control, particularly for those wishing to lose weight. PMID- 26965766 TI - Effect of food service form on eating rate: meal served in a separated form might lower eating rate. AB - In this study, we investigated the association between food form (mixed vs separated) and eating rate. The experiment used a within-subjects design (n=29, young healthy women with normal weight). Test meals (white rice and side dishes) with the same content and volume were served at lunch in a mixed or separated form. The form in which the food was served had significant effects on consumption volume and eating rate; subjects ate significantly more (p<0.05) when a test meal was served as a mixed form (285 g, 575 kcal) compared to a separated form (244 g, 492 kcal). Moreover, subjects also ate significantly faster (p<0.05) when the test meal was served as a mixed form (22.4 g/min) as compared to a separated form (16.2 g/min). Despite consuming more when the test meal was served as a mixed form than when served as a separated form, the subjects did not feel significantly fuller. In conclusion, we confirmed that meals served in a separated form might lower the eating rate and, moreover, slower eating might be associated with less energy intake, without compromising satiety. PMID- 26965768 TI - Differential dietary habits among 570 young underweight Japanese women with and without a desire for thinness: a comparison with normal weight counterparts. AB - The strong social pressure for thinness in Japanese society has produced a dramatic increase in underweight (body mass index: <18.5 kg/m2) among young women. Being underweight is associated with several negative health outcomes, including nutritional deficiency, osteoporosis, and unfavourable pregnancy outcomes. However, evidence which would help deal with this problem from a public health perspective is scarce. Here, we aimed to identify the dietary characteristics of underweight female university students, particularly those with a desire for thinness. Data on dietary habits and other lifestyle variables, including the desire for thinness, were obtained through a self-administered questionnaire survey conducted at 54 academic institutions in Japan, from which we selected 3634 female students for analysis. The subjects were divided into three groups of normal weight (84.3%), and underweight with (6.4%) or without (9.3%) a desire for thinness. After adjusting for potential confounders, the underweight subjects with a desire for thinness consumed less cereal and rice, whereas those without a desire for thinness consumed more cereal and rice than the normal weight subjects. In addition, those without a desire for thinness consumed less confectionaries, including candies and ice cream, and less fats and oils than the normal weight subjects. These results suggest that dietary habits differ between underweight women with and without a desire for thinness. Although both groups require nutritional education to maintain appropriate body weight, underweight women with a desire for thinness require particular attention to improve recognition of their constitution and dietary habits. PMID- 26965767 TI - Plasma isoflavones in Malaysian men according to vegetarianism and by age. AB - Epidemiological studies indicate lower prevalences of breast and prostate cancers and cardiovascular disease in Southeast Asia where vegetarianism is popular and diets are traditionally high in phytoestrogens. This study assessed plasma isoflavones in vegetarian and non-vegetarian Malaysian men according to age. Daidzein, genistein, equol (a daidzein metabolite), formononetin, biochanin A, estrone, estradiol and testosterone were measured by validated liquid chromatography tandem mass spectrometry (LCMSMS). Plasma isoflavone and sex hormone concentrations were measured in 225 subjects according to age (18-34, 35 44 and 45-67 years old). In all age groups, vegetarians had a higher concentration of circulating isoflavones compared with non-vegetarians especially in the 45-67 year age group where all isoflavones except equol, were significantly higher in vegetarians compared with omnivores. By contrast, the 18 34 year group had a significantly higher concentration of daidzein in vegetarians and significantly higher testosterone and estrone concentrations compared with non-vegetarians. In this age group there were weak correlations between estrone, estradiol and testosterone with some of the isoflavones. This human study provides the first Malaysian data for the phytoestrogen status of vegetarian and nonvegetarian men. PMID- 26965769 TI - Measurements and profiles of body weight misperceptions among Taiwanese teenagers: a national survey. AB - Children and adolescents tend to lose weight, which may be associated with misperceptions of weight. Previous studies have emphasized establishing correlations between eating disorders and an overestimated perception of body weight, but few studies have focused on an underestimated perception of body weight. The objective of this study was to explore the relationship between misperceptions of body weight and weight-related risk factors, such as eating disorders, inactivity, and unhealthy behaviors, among overweight children who underestimated their body weight. We conducted a cross-sectional, descriptive study between December 1, 2006 and February 15, 2007. A total of 29,313 children and adolescents studying in grades 4-12 were enrolled in this nationwide, cross sectional survey, and they were asked to complete questionnaires. A multivariate logistic regression using maximum likelihood estimates was used. The prevalence of body weight misperception was 43.2% (26.4% overestimation and 16.8% underestimation). Factors associated with the underestimated perception of weight among overweight children were parental obesity, dietary control for weight loss, breakfast consumption, self-induced vomiting as a weight control strategy, fried food consumption, engaging in vigorous physical activities, and sleeping for >8 hours per day (odds ratios=0.86, 0.42, 0.88, 1.37, 1.13, 1.11, and 1.17, respectively). In conclusion, the early establishment of an accurate perception of body weight may mitigate unhealthy behaviors. PMID- 26965770 TI - Survey of contemporary feeding practices in critically ill children in the Asia Pacific and the Middle East. AB - BACKGROUND AND OBJECTIVES: Nutrition is a fundamental component of care of critically ill children. Determining variation in nutritional practices within paediatric intensive care units (PICUs) allows for review and improvement of nutrition practices. METHODS AND STUDY DESIGN: The aim was to survey the nutrition practices and perspectives of paediatric intensivists and dieticians in Asia-Pacific and the Middle East. A questionnaire was developed to collect data on (1) the respondent's and institution's characteristics, (2) nutritional assessments and nutrient delivery practices, and (3) the perceived importance and barriers to optimal enteral feeding in the PICU. RESULTS: We analysed 47 responses from 35 centres in 18 different countries. Dedicated dietetic services were only present in 13 (37%) centres and regular nutrition assessments were conducted in only 12 (34%) centres. In centres with dedicated dieticians, we found greater use of carbohydrate, fat additives and special formulas. Two thirds [31 (66%)] of respondents used total fluids to estimate energy requirements. Only 11 (31%) centres utilized feeding protocols. These centres had higher use of small bowel feeding, acid suppressants, laxatives and gastric residual volume thresholds. When dealing with feed intolerance, they were also more likely to start a motility agent. There was also a lack of consensus on when feeding should start and the use of adjuncts. CONCLUSIONS: Nutrition practices and barriers are unique in Asia-Pacific and the Middle East and strongly reflect a lack of dietetic services. Future effort should focus on developing a uniform approach on nutrition practices to drive paediatric critical care nutrition research in these regions. PMID- 26965771 TI - Insulin resistance, body composition, and fat distribution in obese children with nonalcoholic fatty liver disease. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the influence of body composition, especially distribution of body fat, and insulin resistance on nonalcoholic fatty liver disease (NAFLD) in obese children. METHODS AND STUDY DESIGN: One hundred obese children (66 boys, 34 girls) with (n=60) and without NAFLD (n=40) were assessed. Anthropometry, laboratory tests, abdominal ultrasonography, and dual energy x-ray absorption metry (DXA) were evaluated in all subjects. RESULTS: Subject age and measurements of liver enzymes, gamma- glutamyl transpeptidase (gammaGT), uric acid, high-density lipoprotein cholesterol, and insulin resistance were significantly different between the non NAFLD group and NAFLD group. Body fat and trunk fat percentage were significantly different between the two groups (p<0.001 and p=0.003), whereas extremity fat percentage was not (p=0.683). Insulin resistance correlated significantly with body fat and trunk fat percentages, age, liver enzymes, gammaGT, and uric acid in obese children. Multiple logistic regression analysis indicated that insulin resistance and trunk fat percentage significantly affected the development of NAFLD in obese children. CONCLUSIONS: Body fat, especially abdominal fat, influences the development of insulin resistance and subsequent NAFLD in obese children. Therefore, body composition measurement using DXA, in conjunction with biochemical tests, may be beneficial in evaluating obese children with NAFLD. PMID- 26965772 TI - Influence of proximities to food establishments on body mass index among children in China. AB - BACKGROUND AND OBJECTIVES: Over the past two decades, food environment has changed, and the obesity and overweight rates have increased dramatically in China. Previous studies have suggested an association between food environment and obesity, while most studies were based on the data from developed countries, and few were conducted in developing countries. METHODS AND STUDY DESIGN: The current study evaluated the influence of food establishments (distance to and types of grocery store, free market, restaurant, and food stall) on body mass index (BMI) in 348 children aged 6-17 years, surveyed in the 2009 and 2011 China Health and Nutrition Survey in nine provinces. Food establishments were assessed using geographic information system (GIS) data. Weight and height of children were directly measured. RESULTS: Our longitudinal analysis suggested boys in the 2nd quartile of the proximity to the nearest grocery store had higher BMI (by 1.6 kg/m2, 95% CI, 0.07 to 3.24) as compared to those in the 1st quartile, while girls in higher quartiles had lower BMI (-1.78 kg/m2, 95% CI: -3.38 to - 0.18, 2nd quartile; -1.62 kg/m2, 95%: -3.22 to -0.01, 3rd quartile) as compared to those in the 1st quartile. Boys and girls in the 2nd quartile of the proximity to the nearest Chinese restaurant had lower BMI (-1.69 kg/m2, 95% CI: - 3.27 to 0.12; -1.76 kg/m2, 95% CI: -3.26, -0.27, respectively) as compared to those in the 1st quartile. CONCLUSIONS: Food environment may affect children's BMI in China, while the association is inconsistent with previous studies. Further research is needed. PMID- 26965773 TI - Salt intake and iodine status of women in Samoa. AB - The objective of this study was to determine iodine nutrition status and whether iodine status differs across salt intake levels among a sample of women aged 18 45 years living in Samoa. A cross-sectional survey was completed and 24-hr urine samples were collected and assessed for iodine (n=152) and salt excretion (n=119). The median urinary iodine concentration (UIC) among the women was 88 MUg/L (Interquartile range (IQR)=54-121 MUg/L). 62% of the women had a UIC <100 MUg/L. The crude estimated mean 24-hr urinary salt excretion was 6.6 (standard deviation 3.2) g/day. More than two-thirds (66%) of the women exceeded the World Health Organization recommended maximum level of 5 g/day. No association was found between median UIC and salt excretion (81 MUg/L iodine where urinary salt excretion >=5 g/day versus 76 MUg/L where urinary salt excretion <5 g/day; p=0.4). Iodine nutrition appears to be insufficient in this population and may be indicative of iodine deficiency disorders in Samoan women. A collaborative approach in monitoring iodine status and salt intake will strengthen both programs and greatly inform the level of iodine fortification required to ensure optimal iodine intake as population salt reduction programs take effect. PMID- 26965774 TI - Distribution of iron status among urban Chinese women. AB - BACKGROUND AND OBJECTIVES: To assess the distribution of serum ferritin, serum soluble transferrin receptor and body iron among girls and women by age and anaemia. METHODS AND STUDY DESIGN: Serum ferritin, serum soluble transferrin receptor and high sensitive C-reactive protein of 1625 and 1372 women in general and anaemic were measured in the National Health and Nutrition Survey commenced in 2010. RESULTS: The distributions of serum ferritin, serum soluble transferrin receptor and body iron for 6-11-y, 12-17-y, 18-44-y, 45-59-y and >=60-y subgroups were significantly different. Both in population-representative women and those anaemic, the iron status of 18-44-y women was the lowest and that of 12-17-y girls the second lowest. The iron status of anaemic women was lower than that in representative women at ages 12-17 y, 18-44 y, 45-59 y and >=60 y. CONCLUSION: Iron status in women of different ages and anaemic had different distributions, but consistently lower than that of population-representative women. The observed iron status of Chinese urban women supports program planning for iron nutrition promotion in women. Iron status information is also needed for men and to understand the pathogenesis which may be related to intake or loss. PMID- 26965776 TI - Factors associated with irregular breakfast consumption among high school students in a Japanese community. AB - BACKGROUND AND OBJECTIVES: This study evaluated the associations between the characteristics of high school students and irregular breakfast consumption and explored the association with knowledge regarding diet and dietary education in a community in Japan. METHODS AND STUDY DESIGN: A cross-sectional survey using a self-administered questionnaire was conducted in 2007 among all the high school students in the second grade in Imari, Saga. Data for 318 male and 292 female students were analyzed. Irregular breakfast consumption was defined as consuming breakfast three times or less in a week. The associations between the characteristics of students and irregular breakfast consumption were assessed using logistic regression with adjustments for sex and school. RESULTS: Among male students, a strong association between the consumption of juice or pop and irregular breakfast consumption was observed (OR comparing ">=2 servings" vs "rarely"=8.97, 95% CI=2.99-26.9). The associations with wake times and bed times were strong among male students, and the association with regular bowel movements was strong among female students. Students who had knowledge of regional agricultural and livestock products were more likely to consume breakfast regularly, and this association was significant among female students (OR=2.89, 95% CI=1.23-6.82). Significant associations were also observed with the consumption of snacks, and traditional greeting before meals. CONCLUSIONS: Several characteristics, including specific knowledge, were associated with the irregular consumption of breakfast. The results are of interest to policy makers, nutrition specialists, and educators working to enhance regular breakfast consumption among students. PMID- 26965775 TI - Self-reported health problems related to traditional dietary practices in postpartum women from urban, suburban and rural areas of Hubei province, China: the 'zuo yuezi'. AB - BACKGROUND AND OBJECTIVES: We aimed to investigate the prevalence of maternal health problems in the postpartum period and their association with traditional Chinese postpartum diets and behaviours in three selected regions in Hubei province, China. METHODS AND STUDY DESIGN: A cross-sectional study was conducted in urban, suburban and rural areas. A total of 2100 women who had given birth to full-term single infants in the past two years were enrolled. Their postpartum diet, personal behaviours, and health problems were surveyed by trained interviewers. RESULTS: During the puerperium women consumed plentiful eggs, fish, poultry and meats; however, fruit, vegetable and milk consumption were limited. A high prevalence of health problems potentially related to pregnancy and the puerperium were found. At least one such problem was reported by 59.3% of women. The putative postpartum problems were backaches (29.6%), arthralgia or leg clonus (12.7%), breast problems (19.6%), constipation (18.7%), haemorrhoids (11.7%), dizziness or headaches (14.8%), anaemia (10.0%). Multiple logistic regression analysis showed that leafy vegetable intake and frequent recipe change in the puerperium were positively associated with less anal diseases. Bathing or hair washing did not increase the risk of maternal infection as belief would have suggested. However, bathing was a risk factor for backache or arthralgia, and tooth brushing was a risk factor for bleeding gums. Excessive housework was a risk factor for anal diseases and disordered uterine involution. CONCLUSION: Postpartum maternal health problems were prevalent in Hubei province. These were in part associated with postpartum traditional Chinese diets and behaviours. PMID- 26965777 TI - Excessive screen viewing time by adolescents and body fatness in a developing country: Vietnam. AB - BACKGROUND AND OBJECTIVES: Screen time among youth has been increasingly recognized as a public health problem because of its link with obesity. This has been demonstrated in many studies conducted in developed countries but few studies have addressed the problem in developing countries, despite an increase literature about the emergence of obesity and a greater access to screen devices in a country like Vietnam. Our study aimed at assessing screen time and its relationship with BMI in adolescents of Ho Chi Minh City (HCMC), Vietnam. METHODS AND STUDY DESIGN: In a cross-sectional study of 2024 junior high school students aged 11-14 of HCMC, students were measured for BMI and questioned on time spent watching television/Video/DVD or using computer for fun. High users were defined as time >=2 h/d. International Obesity Task Force BMI cutoffs were used to define overweight and obesity. RESULTS: Adolescents spent 2.2 h/d in screen time, with higher values for boys than girls (p<0.001). 53.8% of the respondents were high users. Time spent using computers for fun increased with age, and with the household wealthy index. The overall prevalence of overweight and obesity was 21.1%. Using multiple logistic regression, overweight and obesity was higher in boys (adjusted OR=2.66, 95% CI: [2.06; 3.44], p<0.001) and in children aged 11-12 who had a screen time >=2 h/d (adjusted OR=1.48, 95% CI: [1.09; 1.99], p<0.02). CONCLUSIONS: In HCMC, a majority of adolescents spent >=2 h/d on screen time. High screen time is associated with an increased prevalence of overweight and obesity in young adolescents. Public health intervention programs are needed to reduce screen time among youth. PMID- 26965778 TI - Alcoholic beverage preferences and associated drinking patterns by socioeconomic status among high-school drinkers in three metropolises of China. AB - To examine the association between socioeconomic status (SES) and adolescent alcoholic beverage preferences and the associated drinking patterns in China. The study used cross-sectional data collected from 136 junior or senior high schools, using a self-administered questionnaire. A total number of 7,075 subjects of drinking students were selected from three metropolises (Beijing, Shanghai, and Guangzhou) via a two-stage stratified sampling method. Among the adolescent drinkers, 87.8% (95% CI: 86.5-89.0) reported that they drunk alcohol during the past years preceding the study, while 42.4% (95% CI: 40.4-44.4) of the subjects stated that they had drunk alcohol during the past 30 days. There were gradual increases in the usual quantity (>1 Standard Drink, SD) of alcoholic beverages with increasing SES, with highest rates reported by the high-level SES. Beer and grape wine were the most widely consumed alcoholic beverage, regardless of SES. Our findings suggest that high-level SES students have an increasing prevalence of drinking behaviour. Their confirmation by future studies which extend the sampling regions is required to further the prevention of adolescent alcohol abuse in China. PMID- 26965779 TI - Validity of a food frequency questionnaire in a population with high alcohol consumption in Japan. AB - BACKGROUND AND OBJECTIVES: Alcohol consumption has a relatively large impact on energy intake in drinkers, and several studies reported different dietary habits from non-drinkers. However, few studies have investigated the influence of alcohol consumption on the validity of the Food Frequency Questionnaire (FFQ). To investigate its influence, we conducted a validity test in a population with high alcohol consumption. METHODS AND STUDY DESIGN: The study subjects were 66 residents living on an island in the south-western part of Japan. We conducted the FFQ and 12-day-weighed dietary records (12d-WDRs) in each 3 day of each 4 season. We calculated Pearson correlation coefficients (CCs) and agreement rates according to quartile classification after adjusting for energy. RESULTS: The intake energy (kcal) estimated from 12d-WDRs and FFQ was 1,641 and 1,534 in women, and 2,093 and 1,979 in men, respectively. The cumulative percentage contribution of the alcohol energy was 6.7% in men. De-attenuated, log transformed Pearson's median CCs between the nutrients quantified with the 12d WDRs and FFQ were 0.51 in women and 0.38 in men. The CCs for carbohydrate and saturated fatty acids intake of men were lower than those in the previous Tokai study using the same FFQ. The findings in agreement rates were consistent with the Tokai study. CONCLUSION: This study suggested that the FFQ can be used for epidemiological studies using categorical comparisons in this population, although the underestimation of carbohydrates and other nutrients in the FFQ should be taken into consideration. PMID- 26965780 TI - Novel dietary intake assessment in populations with poor literacy. AB - BACKGROUND AND OBJECTIVES: Cultural and/or environmental barriers make the assessment of dietary intake in rural populations challenging. We aimed to assess the accuracy of a meal recall questionnaire, adapted for use with impoverished South Indian populations living in rural areas. METHODS AND STUDY DESIGN: Dietary data collected by recall versus weighed meals were compared. Data were obtained from 45 adults aged 19-85 years, living in rural Andhra Pradesh, who were recruited by convenience sampling. Weighed meal records (WMRs) were conducted in the household by a researcher aided by a trained field worker. The following day, field workers conducted a recall interview with the same participant. Eight life size photographs of portions of South Indian foods were created to aid each participant's recall and a database of nutrients was developed to calculate nutrient intake. Pearson correlations were used to assess the strength of associations between intake of energy and nutrients calculated from meal recalls versus WMRs. Least products regression was conducted to examine fixed and proportional bias. Bland-Altman plots were constructed to measure systematic or differential bias. RESULTS: Significant correlations were observed between estimates for energy and nutrients obtained by the two methods (r2=0.19-0.67, p<0.001). No systematic bias was detected by Bland-Altman plots. Recall method underestimated the intake of protein and fat in a manner proportional to the level of intake. CONCLUSIONS: Our culturally adapted meal recall questionnaire provides an accurate measure for assessment of the intake of energy, macronutrients and some micronutrients in rural Indian populations. PMID- 26965781 TI - Melanocortin-4 receptor rs17782313 polymorphisms are associated with serum triglycerides in older Chinese women. AB - BACKGROUND AND OBJECTIVES: MC4R (melanocortin-4 receptor) gene polymorphisms have been associated with serum triglycerides (TG) in Caucasians and Japanese, but no reports are available Chinese. The purpose of this study was to find whether there was an association of rs17782313 polymorphisms at the MC4R gene with serum TG in elderly Chinese. METHODS AND STUDY DESIGN: 2,012 over 40 years participated in a cross-sectional study in which their body mass index (BMI), TG, high density lipoprotein-cholesterol (HDL-C), and MC4R rs17782313 polymorphisms were determined. RESULTS: For women, carriers of the T/T genotype had significantly lower serum TG than those with C/C genotype (p=0.006). Carriers of the C/C genotype of this polymorphisms exhibited significantly lower fasting HDL-C levels compared with T/T and T/C genotypes (p=0.025), and increased glycosylated hemoglobin (HbA1c) (p=0.043), but no change in blood pressure. Higher serum TG in carriers of the C/C genotype of MC4R gene remained stable after adjustment for age, smoking, drinking, BMI, waist circumference (WC) and three or more components of the metabolic syndrome (MS) by multivariable linear regression (p=0.01) in women. The carriers of the C/C genotype of MC4R gene showed significantly greater odds ratio for TG than T/C and T/T genotypes, even when adjusted for age, smoking, drinking, BMI and WC in women. CONCLUSIONS: The rs17782313 C/C genotype is associated with higher TG levels in older Chinese women. PMID- 26965782 TI - Combining routine markers improves the accuracy of transient elastography for hepatitis B cirrhosis detection. AB - BACKGROUND AND AIM: Vibration Controlled Transient Elastography (VCTE) is a non invasive test for liver fibrosis and cirrhosis but may be inaccurate in some patients, especially in those with chronic hepatitis B. This study aims at improving the accuracy of VCTE in cirrhosis detection by combining ultrasound and routine blood parameters. METHODS: Hepatitis B patients with liver biopsies samples >=20mm underwent VCTE, ultrasound and blood tests, and were divided into training set (n=170) and validation set (n=75). RESULTS: An algorithm consisting of VCTE, international normalization ratio (INR), ultrasonic hepatic vessel and platelet count (CIR-4) and a VCTE-based cirrhosis six-index score (CIR-6) comprised VCTE, INR, platelet, albumin, ultrasonic hepatic vessel and liver parenchyma were derived. In training set, area under receiver operating characteristics curve of CIR-6 and CIR-4 to detect cirrhosis was 0.946 and 0.945, respectively, which was superior to that of VCTE 0.907. CIR-4 could save more liver biopsies. In validation set, CIR-6 detected cirrhosis with accuracy similar to that in training set. However, the sensitivity of CIR-4 and VCTE in validation set lowered to 0.538 and 0.846, respectively. CONCLUSIONS: Combining routine markers improve the accuracy of VCTE for cirrhosis detection in hepatitis B patients. CIR-6 may be more valuable. PMID- 26965783 TI - Risk of pancreatic malignancy and mortality in branch-duct IPMNs undergoing surveillance: A systematic review and meta-analysis. AB - BACKGROUND: Safety of non-operative management for low-risk branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) is debated. AIM: To perform a systematic review/meta-analysis to determine their risk of developing pancreatic malignancy and of pancreatic malignancy-related deaths. METHODS: A MEDLINE search was performed and methodology was based on PRISMA statement. Incidence rates of overall pancreatic malignancy, malignant BD-IPMN, IPMN-distinct PDAC, and of pancreatic malignancy-related death rates were calculated by dividing the total number of events by the total number of person-years (pyrs) of follow-up. Heterogeneity was determined by I(2) statistic. RESULTS: 20 studies including 2177 patients were included. Mean follow-up ranged from 29.3 to 76.7 months. Overall, 82 patients (3.7%) developed a pancreatic malignancy with a pooled estimate rate of 0.007/pyrs (I(2)=32.8%). The pooled estimate rate of malignant IPMN was 0.004/pyrs (I(2)=40.8%), and the pooled estimate rate of distinct PDAC 0.002/pyrs (I(2)=0%). The rate of death due to pancreatic malignancy during follow-up was 0.9%, with an overall pooled estimate rate of death of 0.002/pyrs (I(2)=0%). CONCLUSION: Non-operative management of low-risk BD-IPMN is safe, with a very low risk of malignant transformation of IPMN and of distinct PDAC. The rate of pancreatic malignancy-related mortality is low, particularly when compared with the mortality of pancreatic surgery. PMID- 26965784 TI - Appendiceal diverticulosis incidentally detected by computed tomographic colonography. PMID- 26965785 TI - Drug-eluting beads versus conventional chemoembolization for the treatment of unresectable hepatocellular carcinoma: A meta-analysis. AB - BACKGROUND: Despite the promising results of earlier studies, a clear superiority of drug-eluting beads transarterial chemoembolization over conventional chemoembolization in unresectable hepatocellular carcinoma patients has not been established yet. AIMS: To evaluate the efficacy and safety of the two treatments in unresectable hepatocellular carcinoma patients. METHODS: Computerized bibliographic search on the main databases was performed. One-year, two-year, three-year survival rates were analyzed. Hazard ratios from Kaplan-Meier curves were extracted in order to perform an unbiased comparison of survival estimates. Objective response and severe adverse event rate were analyzed too. RESULTS: Four randomized-controlled trials and 8 observational studies with 1449 patients were included in the meta-analysis. Non-significant trends in favor of drug-eluting beads chemoembolization were observed as for 1-year (odds ratio: 0.76, 0.48-1.21, p=0.25), 2-year (odds ratio: 0.68, 0.42-1.12, p=0.13) and 3-year survival (odds ratio: 0.57, 0.32-1.01, p=0.06). Meta-analysis of plotted hazard ratios confirmed this trend (hazard ratio: 0.86, 0.71-1.03, p=0.10). Pooled data of objective response showed no significant difference between the two treatments (odds ratio: 1.21, 0.69-2.12, p=0.51). No statistically significant difference in adverse events was registered (odds ratio: 0.85, 0.60-1.20, p=0.36). CONCLUSIONS: Our results stand for a non-superiority of drug-eluting beads chemoembolization with respect to conventional chemoembolization in hepatocarcinoma patients. PMID- 26965787 TI - Genetic diversity, acaricide resistance status and evolutionary potential of a Rhipicephalus microplus population from a disease-controlled cattle farming area in South Africa. AB - The Southern cattle tick, Rhipicephalus microplus is a hematophagous ectoparasite of great veterinary and economic importance. Along with its adaptability, reproductive success and vectoring capacity, R. microplus has been reported to develop resistance to the major chemical classes of acaricides currently in use. In South Africa, the Mnisi community in the Mpumalanga region offers a unique opportunity to study the adaptive potential of R. microplus. The aims of this study therefore included characterising acaricide resistance and determining the level and pattern of genetic diversity for R. microplus in this region from one primary population consisting of 12 communal dip-stations. The level of acaricide resistance was evaluated using single nucleotide polymorphisms (SNPs) in genes that contribute to acaricide insensitivity. Additionally, the ribosomal internal transcribed spacer 2 (ITS2) gene fragments of collected individuals were sequenced and a haplotype network was constructed. A high prevalence of alleles attributed to resistance against formamidines (amitraz) in the octopamine/tyramine (OCT/Tyr) receptor (frequency of 0.55) and pyrethroids in the carboxylesterase (frequency of 0.81) genes were observed. Overall, the sampled tick population was homozygous resistant to pyrethroid-based acaricides in the voltage-gated sodium channel (VGS) gene. A total of 11 haplotypes were identified in the Mnisi R. microplus population from ITS2 analysis with no clear population structure. From these allele frequencies it appears that formamidine resistance in the Mnisi community is on the rise, as the R. microplus populations is acquiring or generating these resistance alleles. Apart from rearing multi resistant ticks to commonly used acaricides in this community these ticks may pose future problems to its surrounding areas. PMID- 26965786 TI - Kbeta Valence to Core X-ray Emission Studies of Cu(I) Binding Proteins with Mixed Methionine - Histidine Coordination. Relevance to the Reactivity of the M- and H sites of Peptidylglycine Monooxygenase. AB - Biological systems use copper as a redox center in many metalloproteins, where the role of the metal is to cycle between its +1 and +2 oxidation states. This chemistry requires the redox potential to be in a range that can stabilize both Cu(I) and Cu(II) states and often involves protein-derived ligand sets involving mixed histidine-methionine coordination that balance the preferences of both oxidation states. Transport proteins, on the other hand, utilize copper in the Cu(I) state and often contain sites comprised predominately of the cuprophilic residue methionine. The electronic factors that allow enzymes and transporters to balance their redox requirements are complex and are often elusive due to the dearth of spectroscopic probes of the Cu(I) state. Here we present the novel application of X-ray emission spectroscopy to copper proteins via a study of a series of mixed His-Met copper sites where the ligand set varies in a systematic way between the His3 and Met3 limits. The sites are derived from the wild-type peptidylglycine monooxygenase (PHM), two single-site variants which replicate each of its two copper sites (CuM-site and CuH-site), and the transporters CusF and CusB. Clear differences are observed in the Kbeta2,5 region at the Met3 and His3 limits. CusB (Met3) has a distinct peak at 8978.4 eV with a broad shoulder at 8975.6 eV, whereas CuH (His3) has two well-resolved features: a more intense feature at 8974.8 eV and a second at 8977.2 eV. The mixed coordination sphere CusF (Met2His) and the PHM CuM variant (Met1His2) have very similar spectra consisting of two features at 8975.2 and 8977.8 eV. An analysis of DFT calculated spectra indicate that the intensity of the higher energy peak near 8978 eV is mediated by mixing of ligand-based orbitals into the Cu d(10) manifold, with S from Met providing more intensity by facilitating increased Cu p-d mixing. Furthermore, reaction of WT PHM with CO (an oxygen analogue) produced the M site CO complex, which showed a unique XES spectrum that could be computationally reproduced by including interactions between Cu(I) and the CO ligand. The study suggests that the valence-to-core (VtC) region can not only serve as a probe of ligand speciation but also offer insight into the coordination geometry, in a fashion similar to XAS pre-edges, and may be sufficiently sensitive to the coordination of exogenous ligands to be useful in the study of reaction mechanisms. PMID- 26965789 TI - Phonon Scattering Dynamics of Thermophoretic Motion in Carbon Nanotube Oscillators. AB - Using phonon wave packet molecular dynamics simulations, we find that anomalous longitudinal acoustic (LA) mode phonon scattering in low to moderate energy ranges is responsible for initiating thermophoretic motion in carbon nanotube oscillators. The repeated scattering of a single mode LA phonon wave packet near the ends of the inner nanotube provides a net unbalanced force that, if large enough, initiates thermophoresis. By applying a coherent phonon pulse on the outer tube, which generalizes the single mode phonon wave packet, we are able to achieve thermophoresis in a carbon nanotube oscillator. We also find the nature of the unbalanced force on end-atoms to be qualitatively similar to that under an imposed thermal gradient. The thermodiffusion coefficient obtained for a range of thermal gradients and core lengths suggest that LA phonon scattering is the dominant mechanism for thermophoresis in longer cores, whereas for shorter cores, it is the highly diffusive mechanism that provides the effective force. PMID- 26965788 TI - Absence of serological evidence of Rickettsia spp., Bartonella spp., Ehrlichia spp. and Coxiella burnetii infections in American Samoa. AB - Little is known about the epidemiology of zoonotic diseases in American Samoa (Pacific). A review of literature did not identify any published information on human Rickettsia spp., Bartonella spp., Ehrlichia spp. or Coxiella burnetii infections in this country. To determine the presence of these diseases, we conducted a serosurvey of American Samoans. The presence of immunoglobulin G antibodies against Rickettsia felis, Rickettsia typhi, Rickettsia conorii, C. burnetii, Bartonella henselae, Bartonella quintana, and Ehrlichia chaffeensis was evaluated by indirect immunofluorescence assay in sera from 197 American Samoan adults. None of the samples had antibodies at a significant level against Rickettsia spp., Bartonella spp., Ehrlichia spp. or C. burnetii (seroprevalence 0%; one-tailed 95% CI 0-1.86%). We cannot conclude that these pathogens are absent in American Samoa but, if present, their prevalence is probably very low. Q fever has been reported worldwide except in New Zealand and French Polynesia; these new data suggest that the prevalence of Q fever is likely to be very low in the Pacific Islands. PMID- 26965790 TI - Abrupt climate shift in the Western Mediterranean Sea. AB - One century of oceanographic measurements has evidenced gradual increases in temperature and salinity of western Mediterranean water masses, even though the vertical stratification has basically remained unchanged. Starting in 2005, the basic structure of the intermediate and deep layers abruptly changed. We report here evidence of reinforced thermohaline variability in the deep western basin with significant dense water formation events producing large amounts of warmer, saltier and denser water masses than ever before. We provide a detailed chronological order to these changes, giving an overview of the new water masses and following their route from the central basin interior to the east (toward the Tyrrhenian) and toward the Atlantic Ocean. As a consequence of this climate shift, new deep waters outflowing through Gibraltar will impact the North Atlantic in terms of salt and heat input. In addition, modifications in the Mediterranean abyssal ecosystems and biogeochemical cycles are to be expected. PMID- 26965791 TI - Comparison of Prednisolone, Etoricoxib, and Indomethacin in Treatment of Acute Gouty Arthritis: An Open-Label, Randomized, Controlled Trial. AB - BACKGROUND: At present there are several kinds of medicine for treating acute gout arthritis (AGA). This study compared the efficacy and safety of prednisolone, etoricoxib, and indomethacin in the treatment of AGA. MATERIAL/METHODS: This was an open-label, randomized, active-comparator study in patients with AGA. Patients were randomized to 4 days of prednisolone 35 mg qd, etoricoxib 120 mg qd, or indomethacin 50 mg tid. The primary efficacy endpoint was the reduction of self-assessed pain in the index joint from baseline. Secondary endpoints included changes in physician's assessment of tenderness, erythema, swelling, and joint activity; patient assessment of response to therapy; and safety. RESULTS: We analyzed 113 patients. Baseline demographics were comparable among treatment groups. Oral prednisolone, etoricoxib, and indomethacin were similarly effective in improving pain, tenderness, and joint activity over 4 days. For inflammation, oral prednisolone, etoricoxib, and indomethacin were similarly effective in reducing erythema, but prednisolone might be more effective in reducing swelling than indomethacin. The patient response to therapy was similar in the 3 groups. There were more total adverse events with indomethacin compared with the other 2 drugs. CONCLUSIONS: Efficacy was comparable among prednisolone, etoricoxib, and indomethacin for the treatment of AGA. Prednisolone might be more effective in reducing inflammation and it had a better safety profile. PMID- 26965792 TI - Vaginal Fibroblastic Cells from Women with Pelvic Organ Prolapse Produce Matrices with Increased Stiffness and Collagen Content. AB - Pelvic organ prolapse (POP) is characterised by the weakening of the pelvic floor support tissues, and often by subsequent prolapse of the bladder outside the body, i.e. cystocele. The bladder is kept in place by the anterior vaginal wall which consists of a dense extracellular matrix rich in collagen content that is maintained and remodelled by fibroblastic cells, i.e. fibroblasts and myofibroblasts. Since altered matrix production influences tissue quality, and myofibroblasts are involved in normal and pathological soft tissue repair processes, we evaluated matrix production of cells derived from pre- and post menopausal POP and non-POP control anterior vaginal wall tissues. Results showed that cells from postmenopausal POP women deposited matrices with high percentage of collagen fibres with less anisotropic orientation and increased stiffness than those produced by controls. There was a transient increase in myofibroblastic phenotype that was lost after the peak of tissue remodelling. In conclusion, affected fibroblasts from postmenopausal prolapsed tissues produced altered matrices in vitro compared to controls. Such aberrant altered matrix production does not appear to be a consequence of abnormal phenotypical changes towards the myofibroblastic lineage. PMID- 26965793 TI - A Rapid Method for the Analysis of Paralytic Shellfish Toxins Utilizing Standard Pressure HPLC: Refinement of AOAC 2005.06. AB - Superficially porous column technologies have previously been shown to provide faster chromatographic analysis of toxin oxidation products when analyzing shellfish for paralytic shellfish toxins. While sub 3 MUm fused core columns have facilitated enhanced method performance, including significantly lower analysis times and lower LOD, they were also found to last for only a few hundred injections before pressure increases rendered them unusable with standard HPLC. Recently 5 MUm superficially porous columns have become commercially available. In this study, a 5 MUm fused core column was used to develop a fast chromatographic method for the analysis of paralytic shellfish toxins, with performance characteristics and column lifetime being assessed. The 5 MUm column was found to be able to perform approximately 3000 injections without significant increases in back pressure or reduction in performance. Data generated using the column were found to be equivalent to that determined using current HPLC column technologies for both screening and quantitation methods. Furthermore, an increase in sensitivity for all toxins tested under the routine monitoring program for British waters was observed and the overall run time of the analysis halved. Overall, the 5 MUm fused core column provided a significant increase in sample throughput, a reduction in mobile phase consumption, and an increase in method sensitivity. PMID- 26965795 TI - Prognostic significance of glycemic variability after cardiac surgery. AB - INTRODUCTION: The prognostic significance of acute glycemic variability (GV) after cardiac surgery is not known. This study was therefore planned to analyze the independent prognostic value of GV after cardiac surgery. MATERIALS AND METHODS: This is a single center prospective observational study in 870 consecutive cardiac surgery patients over a 3-month period at a tertiary care institute in India. RESULTS: In linear regression analysis, GV was a significant predictor of length of stay in intensive care unit (LOS-ICU) (beta 0.102, p=0.007) and rise in creatinine after surgery (beta 0.229, p<0.001). Mean POC-BG was a significant positive predictor of length of stay in hospital (LOS-hospital) (beta 0.1, p=0.004). In multivariable logistic regression analysis, GV predicted prolonged LOS-ICU (p=0.006, OR 1.016) and acute kidney injury (p<0.001, OR 1.034). CONCLUSION: This study showed that GV, as measured by standard deviation, was a predictor of LOS-ICU, rise in creatinine and AKI after cardiac surgery. GV is therefore a new dimension in postoperative glycemic management in cardiac surgery patients, which needs to be explored. PMID- 26965797 TI - Tomographic Measurement of Gutters and Analysis of the Conformability of Stent Grafts in the Octopus Technique for Endovascular Thoracoabdominal Aneurysm Repair. AB - BACKGROUND: The Octopus technique is an off-label and off-the-shelf strategy used as an option in the management of some specific and selected cases of thoracoabdominal aortic aneurysms (TAAA). We sought to compare 2 different methods of measurements on computed tomography (CT) slices and to evaluate the accommodation and conformability, before and after ballooning, of the components used in the Octopus technique. METHODS: The CT gutter analysis between the 3 stent grafts within the short docking limb of the Excluder((r)) was made using Viabahns((r)) of 8, 7, and 6 mm in diameter. Each of the 10 possible combinations underwent a CT established protocol. The best axial image of the docking limb was submitted for an evaluation by 2 independent analysts, using 2 different methods. We also performed a postballooning evaluation, and the same CT protocol was used. RESULTS: There was no significant difference between the formats of measurement type "A" and type "B." Furthermore, there was no significant difference between the measurements made by the independent analysts. The tomography analyses demonstrated that the combination of stent grafts (Viabahn) of 8 and 7 mm diameter, inside the short docking limb of the bifurcated endoprosthesis, had the best possible relationship between the diameters used. These combinations showed better conformability and juxtaposition, with smaller areas of gutters and theoretically less possibility of endoleak. In addition, we found that postimplant balloon dilatation impaired the conformability and juxtaposition of the stent grafts (Viabahn) in the optimum combinations. CONCLUSIONS: In this analysis, we demonstrated a feasible, reliable, and reproducible form of CT measurement of the gutters in the Octopus technique for endovascular repair of TAAAs. Based on these measurements, there is a preferable combination of Viabahn sizes to be used in the Octopus technique and that postdilatation impairs the conformability and juxtaposition. PMID- 26965794 TI - Causative pathogens and antibiotic resistance in diabetic foot infections: A prospective multi-center study. AB - AIM: Clinical practice guidelines for the management of diabetic foot infections developed by the Infectious Diseases Society of America (IDSA) are commonly used worldwide. The issue of whether or not these guidelines need to be adjusted for local circumstances, however, has seldom been assessed in large prospective trials. METHODS: The Turk-DAY trial was a prospective, multi-center study in which infectious disease specialists from centers across Turkey were invited to participate (NCT02026830). RESULTS: A total of 35 centers throughout Turkey enrolled patients in the trial. Overall, investigators collected a total of 522 specimens from infected diabetic foot wounds for culture from 447 individual patients. Among all isolates, 36.4% were gram-positive organisms, with Staphylococcus aureus the most common among these (11.4%). Gram-negative organisms constituted 60.2% of all the isolates, and the most commonly isolated gram-negative was Escherichia coli (15%). The sensitivity rates of the isolated species were remarkably low for several antimicrobials used in the mild infection group. CONCLUSIONS: Based on our findings, several of the antimicrobials frequently used for empirical treatment, including some also recommended in the IDSA guidelines, would not be optimal for treating diabetic foot infections in Turkey. Although the IDSA guideline recommendations may be helpful to guide empiric antimicrobial therapy of DFIs, they should be adjusted to local conditions. PMID- 26965796 TI - Anti-apolipoprotein A-1 autoantibodies as risk biomarker for cardiovascular diseases in type 2 diabetes mellitus. AB - OBJECTIVE: Anti-Apolipoprotein A-1 autoantibodies (anti-ApoA-1 IgG) represent an emerging prognostic cardiovascular marker in patients with myocardial infarction or autoimmune diseases associated with high thrombotic events. The aim of this work is to investigate the incidence of anti-apoA-1 autoantibodies in type 2 diabetes (T2DM) patients with and without CVD and to study potential association with disease risk and its effect on plasma lipid parameters. METHODS: Qualitative determination of anti-apoA-1 IgG was assayed in sera from 302 subjects classified into T2DM patients (n=102), T2DM+CVD (n=112) and healthy controls (n=88). RESULTS: The incidence of anti-apoA-1 IgG was significantly higher among CVD patients (35.7%) than T2DM patients (8.8%) or control subjects (6.1%), p<0.0001. A significant association with CVD was identified (p<0.0001) and subjects who were positive for anti-apoA-1 IgG were at 8.5 times increased risk to develop CVD when compared to controls. Diabetic patients who were positive for the antibodies showed 5.7 times increased CVD risk. ROC analysis indicated anti-apoA-1 IgG as a risk biomarker for CVD in T2DM patients with an AUC value of 0.76, sensitivity of 35.7% and specificity of 91.2%. Studying the effect on lipid parameters, anti apoA-1 IgG associated with significantly higher serum concentrations of TC and non-HDL-C in all groups and with higher concentrations of LDL-C in diabetic patients and higher TC/HDL-C ratio in CVD patients. CONCLUSION: Our results indicate that anti-apoA-1 IgG is a cardiovascular risk biomarker in T2DM patients. PMID- 26965799 TI - Mycotic Abdominal Aortic Aneurysm Secondary to Septic Embolism of a Thoracic Aorta Graft Infection. AB - Mycotic aneurysms account for 1% of abdominal aortic aneurysms. There are very few cases published that describe the formation of mycotic aneurysms after septic embolism due to graft infection. We present the first case to our knowledge to be described in the literature of a mycotic aneurysm caused by septic embolism derived from a thoracic aorta graft infection, treated with conventional surgery leading to a successful outcome and evolution. PMID- 26965798 TI - Infantile Renovascular Hypertension with Failure to Thrive. AB - Severe hypertension in infancy is a rare cause of failure to thrive. The successful surgical management of this disease in an infant having refractory renovascular hypertension and growth failure is reported. PMID- 26965800 TI - A Case of Primary Aortoenteric Fistula: Review of Therapeutic Challenges. AB - BACKGROUNDS: Primary aortoenteric fistula (PAEF) is a lethal cause of gastrointestinal bleeding. They mainly originate from eroding abdominal aortic aneurysms into the intestinal wall. Other known causes involve malignancies, infection, corpora aliena, or radiation therapy. Traditional treatment consists of resection of the fistula and extra-anatomic reconstruction. In situ repair and endovascular stenting have offered new therapeutic options in managing this complex entity. CASE REPORT: A 79-year-old woman presented with a PAEF. She was known with a 3.9-cm abdominal aortic aneurysm and polymyalgia rheumatica. The initial treatment consisted of endovascular stenting. Several months later, she presented with persistent inflammation of the aortic endoprosthesis. The prosthesis and inflammatory tissue were resected, and in situ reconstruction with autologous superficial femoral vein and omentoplasty was performed. Two years later, she remains well with no evidence for infection or bleeding. CONCLUSIONS: Polymyalgia rheumatica might induce an AEF as in this patient no other provoking factors were retained. The different therapeutic options all have their advantages and disadvantages. In line with this case, we suggest an individualized approach for AEFs. In case of precarious hemodynamical state or life expectancy, endovascular treatment is indicated. Afterward, the possibility and/or necessity of open repair should be discussed. For stable patients with respectable life expectancy in situ repair with autologuous vein or rifampicin soaked prosthesis (adjusted to comorbidities) might be most appropriate. Extra anatomic reconstruction still remains a valuable alternative in older patients and in the presence of any other local factors hampering in situ reconstruction. PMID- 26965801 TI - Outcomes after External Iliac and Femoral Vascular Injuries. AB - BACKGROUND: Vascular injuries occurring at the junction of the trunk and lower extremity are uncommon yet challenging because of their location and potential for associated truncal injuries. The purpose of this study was to examine and compare outcomes among patients sustaining external iliac and femoral vascular injuries. METHODS: We performed a 13-year retrospective analysis of our level 1 trauma center database to identify and compare patients with external iliac and femoral vessel injuries. Multiple logistic regression analysis was performed to identify independent predictors for mortality. RESULTS: During the study period, 135 patients with a median (interquartile range [IQR]) age of 25 (20-35) years were identified with external iliac (n = 29) and femoral vascular injuries (n = 106). The majority were male (85.9%) with a penetrating mechanism (84.5%), and the median (IQR) Injury Severity Score (ISS) was 16 (11-26). The overall mortality rate was 14.1%. In comparison with patients with femoral vascular injuries, patients with external iliac injuries presented with higher ISS (25 vs. 16, P < 0.001), lower Glasgow Coma Scale (14 vs. 15, P = 0.001) and had a higher incidence of mortality (41.4% vs. 6.6%, P < 0.001) and disability (13.8% vs. 1%, P = 0.007). Shunts were used in only 7 patients (5.2%). Stepwise logistic regression consistently identified external iliac injury (odds ratio, 15.6; 95% confidence interval, 1.72-141, P = 0.014 in best-fitted model) as independently associated with mortality. CONCLUSIONS: In comparison with femoral vascular injuries, external iliac vascular injuries are associated with higher blood loss, more intense resuscitation, higher disability and mortality in patients sustaining junctional groin injuries. Early recognition and application of damage control techniques and resuscitative practices may result in improved outcomes. PMID- 26965802 TI - Carotid Endarterectomy or Stenting in Octogenarians in a Monocentric Experience. AB - BACKGROUND: Carotid artery stenting (CAS) has emerged as an alternative to carotid endarterectomy (CEA) in patients at high risk for complications from surgery. The very elderly (>=80-year-old) are 1 subgroup of patients identified as being at increased risk for carotid surgery. However, there is concern that the very elderly are also at increased risk for complications of CAS. A stroke and death rate of 12% were reported in very elderly patients during the roll-in phase of Carotid Revascularization Endarterectomy versus Stent Trial. We are reporting on a clinical series of CAS and CEA with independent neurologic assessment in the very elderly. The aim of this article is to evaluate early and mild-term results obtained in the treatment of the carotid artery stenosis in symptomatic and asymptomatic octogenarians, comparing the data of CEA and CAS in academic hospital. METHODS: Between 2002 and 2013, a consecutive series of 129 CAS and 45 CEA patients (>=80-year-old) were treated in our academic hospital, a center with extensive carotid revascularization experience. Independent neurologic assessment was performed before and after procedures. Exclusion criteria were cerebral hemorrhage diagnosed within 6 months, cerebral tumors and dementia. Hostile aortic arches were nevertheless treated with alternative approaches like cervical or radial access. All the procedures have been performed by the senior authors. RESULTS: The average age was 86.9 years. Most patients were male (56%), and the target lesion carotid stenosis was asymptomatic in 80% of patients. No significant differences were obtained regarding gender, symptoms, risk factors or comorbidities, and evident CT lesions among the 2 groups of different treatments. Embolic protection devices were used in all cases with the CAS procedure. The overall 30-day incidence of stroke and death was 2.3% (3 of 129) in CAS group and 4.4% (2 of 45) in CEA group. CONCLUSIONS: Exclusion of high risk patients from CAS, based on age alone, seems to be unjustified. Octogenarians are not at increased risk of periprocedural adverse events after CAS compared with younger patients. The key to obtain satisfactory results is CAS to be performed by an experienced team able to use not only standard filter protected CAS but also familiar with all the other types of access and protection techniques. PMID- 26965803 TI - The Addition of Ultrasound Arterial Examination to Upper Extremity Vein Mapping before Hemodialysis Access. AB - BACKGROUND: Routine upper extremity vein mapping by ultrasound (Ven-US) is recommended by current National Kidney Foundation/Kidney Disease Outcomes Quality Initiative guidelines before arteriovenous fistula (AVF) creation. However, the impact of concomitant arterial US (Art-US) examination is not clear. METHODS: The Ven-US protocol at our institution was modified to include Art-US starting January 2013. Therefore, retrospective review of patients who received Ven-US with Art-US between January 2013 and July 2014 was performed. The Art-US component included distal brachial and radial artery diameters, level of brachial bifurcation, and Doppler Allen's test. A plan for hemodialysis (HD) access was proposed by 2 attending vascular surgeons (VS1 and VS2) and based on a set of criteria for fistula creation (CFC) using Ven-US findings alone. The Art-US findings were subsequently reviewed, and the plan was changed based on either vascular surgeon judgment (VS1 and VS2) or predetermined arterial anatomic criteria (CFC). RESULTS: In total, 163 patients (326 arms) were included. The mean age was 53 years, most patients were male (60%), and most were HD dependent at the time of US evaluation (67%). The initial plan based on Ven-US was: 17-19% radiocephalic (RC) AVF, 33-48% brachiocephalic AVF, 20-27% brachiobasilic AVF, and 14-23% grafts. The Art-US revealed 159 radial arteries (49%) with diameter <2 mm, 16 brachial arteries (5%) with high bifurcation, 93 (29%) incomplete palmar arches, and 7 arms (2%) with arterial waveform blunting. Review of Art-US findings resulted in an overall change to the operative plan from 4% to 12% of patients. Those with an initially planned RC AVF were more likely to have a change in operative approach (21-57%) compared with all other types of planned access (1-3%, P < 0.001). CONCLUSIONS: Preoperative Art-US may significantly change the operative plan, particularly when planning a RC AVF, and should be performed before HD access surgery at the wrist. PMID- 26965805 TI - Axillary Artery Injury Associated with Proximal Humeral Fractures: Review of Long Term Vascular, Orthopedic, and Neurologic Outcomes. AB - BACKGROUND: Fracture and dislocation of the proximal humerus is common. It is associated with a number of vascular, neurologic, and orthopedic complications; these include brachial plexopathy and avascular necrosis (AVN) of the humeral head. These complications are rare but can potentially cause severe disability to patients; however, they remain poorly described in the literature. To describe vascular, orthopedic, and neurologic outcomes after axillary artery repair, in patients with proximal humeral fractures or dislocations. METHODS: We conducted a retrospective review of patients admitted to 2 tertiary trauma centers in Victoria, Australia, with fracture or dislocation of the proximal humerus and associated axillary artery injury. Patients were selected according to guidelines for trauma call or alert and the presence of high-risk mechanism of injury. Data on vascular, orthopedic, and neurologic complications were collected. RESULTS: Twenty-one patients were identified. Injury to the first part of the axillary artery was noted in 11 patients (52%). Brachial plexus exploration was performed in 17 patients (81%). Four patients (19%) underwent nerve repair. Long-term neurologic recovery was universally poor. Major orthopedic complications included AVN of the humeral head, delayed union, and the need for prosthesis or arthrodesis. Eleven patients (52%) received upper limb fasciotomy. Five patients (24%) underwent delayed secondary upper limb amputation. CONCLUSIONS: There was an unusually high rate of injuries to the first part of the axillary artery. Close clinical observation is recommended for such patients. AVN of the humeral head and brachial plexopathy remain significant and debilitating complications. PMID- 26965804 TI - Postintervention Patency: A Comparison of Stenting versus Patch Angioplasty for Dysfunctional Hemodialysis Access Sites. AB - BACKGROUND: Arteriovenous access dysfunction is commonly caused by venous outflow stenosis, leading to thrombosis of the conduit. Given that there are limited lifetime hemodialysis access sites, the preservation of existing sites through novel means is of high priority. This study compares the efficacy of balloon angioplasty and stent placement to surgical patch angioplasty for upper arm (brachium) thrombosed or dysfunctional hemodialysis access sites in a group of patients at a single institution. METHODS: Using the operating room log and electronic medical record system, we retrospectively examined the outcomes of 52 consecutive patients (3 were lost to follow-up), who had either stent placement (34 patients) or patch angioplasty (15 patients) for hemodialysis access salvage to calculate postintervention patency. RESULTS: Initial postinterventional patency (PIP1) for patch angioplasty compared with stent placement was not statistically significant at any time during a mean 6-month follow-up (60% vs. 67.65% at 1 month, 33.33% vs. 41.18% at 3 months, and 13.33% vs. 17.65% at 6 months, respectively; P = 0.75). Patency after secondary reintervention (PIP2) was longer for patients who had stent placement as the initial intervention (n = 15) than patients who had patch angioplasty (n = 5; 100% vs. 80% at 1 month, 66.68% vs. 80% at 3 months, and 46.67% vs. 40% at 6 months, respectively), but again there was no statistically significant difference between the 2 groups (P = 0.84). At last, the initial PIP1 of arteriovenous fistula (AVF) and arteriovenous graft (AVG) salvaged before occlusion was significantly different from that of occluded access sites (40% vs. 10% at 6 months, P = 0.024). CONCLUSIONS: Our data suggest that AVF had a longer postinterventional primary patency than AVG though the difference did not reach statistical significance. Stents extended PIP1 for the thrombosed or failing arteriovenous access longer than patch angioplasty, but the difference was not statistically significant. Patency is longer if intervention is made before graft thrombosis. Our data also indicate better prolongation of patency with a second reintervention (PIP2) if the first intervention was a stent placement. Patch angioplasty appears to be a less attractive alternative for correction of venous outflow stenosis given the more invasive and occasionally technically difficult procedure. PMID- 26965807 TI - Lead, Follow, or Get out of the Way-How Bold Young Surgeons Brought Vascular Surgery into Clinical Practice from the Korean War Battlefield. AB - The maturation of vascular surgery into widespread clinical practice was accelerated by events that took place in Korea during the conflict of 1950-1953. Early research and anecdotal clinical trials were just then resulting in publication of cases of the successful vascular repairs and replacements. Noncrushing vascular clamps were being developed and limited manufacture begun. The stage was set for a major advance in the treatment of arterial injury, just as war commenced in Korea, which provided a clinical laboratory. When the war on the Korean Peninsula erupted in June 1950, the policy of the Army Medical department was to ligate all arterial injuries unless a simple transverse or end to-end anastomosis could be performed, and repair was "contrary to policy and orders." Despite pressure and threats of "courts martial for vascular repairs" from the senior military medicine leaders-clinical experiments in arterial repair were carried out at Mobile Army Surgical Hospital facilities at battlefield locations across Korea. The young surgeons, mostly draftees and reservists, resisted rigid doctrine and orders to desist, and in the face of threatened punishment, were committed to do the right thing, and ultimately went on to change military medicine and vascular surgery. The "on-the-job" training in vascular surgery that was carried out in Korea by military surgeons who demonstrated substantially higher limb salvage rates energized the field from the battlefield laboratory. Many wounded soldiers had limbs saved by the new techniques in vascular repair pioneered by surgeons in the Korean War, and countless thousands who entered civilian hospitals for emergency vascular surgery in subsequent years also ultimately benefited from their work. PMID- 26965806 TI - Outcomes of the Endovascular Treatment for the Supra-Aortic Trunks Occlusive Disease: A 14-Year Monocentric Experience. AB - BACKGROUND: Endovascular treatment of proximal supra-aortic trunks (SAT) has become a safe and reliable alternative to conventional open surgery, with a lower morbimortality rate and good short- and middle-term patency rates. The aim of our study was to assess the long-term results of endovascular treatment of proximal lesions of the SAT (brachiocephalic trunk, common carotid artery, and subclavian artery) and identify predictive risk factors of restenosis. METHODS: From 1999 to 2013, 67 consecutive stenotic lesions of the proximal SAT were treated by angioplasty (13.4%) or stenting (86.6%) in 63 patients with a mean age of 65.5 years (40-87). Procedures were performed under general (69%), local (24%), or locoregional (7%) anesthesia, with percutaneous puncture (47.8%) or open access (52.2%). Patients were followed up for 3, 6, and 12 months, and then every year with clinical examination, Doppler ultrasound and if required an angio-CT scan. RESULTS: The technical success rate was 98.5%. There was no postoperative death or strokes. One myocardial infarction occurred at day 2. There were 2 access complications: a nonsurgical hematoma after brachial access and a brachial thrombosis postpuncture. The mean follow-up was 4.5 years (2-163 months). The primary- and assisted-patency rates were 90.1%, 86.4%, 77.9% and 93.3%, 91.4%, 82.9% at 1, 2, and 5 years, respectively. Eleven restenosis (16.4%) occurred at 28.5 months (3, 0-112, 0) of follow-up. Four of them required an endovascular repair and 3 required a surgical one. The restenosis rate was 17.5% in the stented group on average at 30.2 months of follow-up (range, 3.0-112.0) and 10% in the group of patients with angioplasty alone at 8 months of follow-up, without significant statistically difference (P = 0.9). No predictive risk factor of restenosis was statistically identified. CONCLUSIONS: The endovascular treatment of proximal stenosis of SAT is a safe, reliable, and efficient technique with a low morbidity and mortality. The long-term results are good, but restenosis can occur. Long-term follow-up should be performed to detect and treat restenosis. PMID- 26965809 TI - Direct Cervical Carotid Angioplasty with Flow Reversal: A Single-Center Report from the Roadster Trial. AB - BACKGROUND: Carotid stent and/or angioplasty (CAS) via the transfemoral route with distal protection carries twice the risk of stroke and/or death when compared with carotid endarterectomy (CEA) in multiple randomized trials. Potential causes for this include disadvantaged aortic arch anatomy and the need to traverse the lesion to place a distal protection device. This report describes the technique and our experience with direct CAS using flow reversal for embolic protection. METHODS: University of California at Los Angeles (UCLA) division of Vascular and Endovascular surgery was a participant in the multi-institutional Roadster Trial of high-risk patients. We are reporting on our experience with 8 patients who met high-risk criteria. Using a small supraclavicular cutdown, the Michi sheath from Silk Road Medical was inserted into the common carotid artery. This provides a working channel for internal CAS as well as a side port to reverse and divert blood flow to the femoral vein, for embolic protection. All patients qualified as medically high risk because of a combination of factors including advanced age, smoking history, hypertension, diabetes, coronary artery disease, or hostile neck anatomy. RESULTS: All 8 patients had 3 or more risk factors including age >75 years (6 of 8), smoking (6 of 8), hypertension (7 of 8), overt coronary artery disease (4 of 8), diabetes (2 of 8), and chronic obstructive pulmonary disease (1 of 8). All stenoses were in the 80-99% category, and all were asymptomatic. All patients tolerated temporary clamping with flow reversal with no electroencephalogram changes. There were no deaths, strokes, transient ischemic attacks, or myocardial infarctions. All patients were discharged on the first postoperative day. Follow-up ranged from 7 to 21 months. One patient developed in-stent restenosis (asymptomatic). CONCLUSIONS: Direct CAS with flow reversal appears to be a safe, less invasive alternative to CEA. PMID- 26965808 TI - Predictors of Severity in Diabetic Foot Infections. AB - BACKGROUND: Diabetic foot infections (DFIs) constitute a large burden of the morbidity of diabetes, with more than 70,000 lower-extremity amputations (LEA) performed annually in the United States. A necrotizing infection signifies the most severe form of infection and is a key factor in the decision to proceed to LEA for source control. Key clinical and laboratory variables can assist in the identification of necrotizing infections; however, the effect of diabetes on these variables is unknown. Given the increased level and complexity of metabolic derangements in diabetic patients, we sought to examine characteristics predictive of necrotizing infection in patients with DFI who underwent LEA. METHODS: We performed a single-institutional retrospective analysis of diabetic patients who underwent a LEA for DFIs over an 18-month period. Patients with necrotizing infection on final pathology were compared with patients without this pathologic finding. Multivariate analysis was performed to identify independent predictors of necrotizing infection. RESULTS: Of 183 patients, 57 (31%) had evidence of necrotizing infections. Factors associated with necrotizing infection on univariate analysis were the presence of bullae (11% vs. 2%; odds ratio [OR] = 4.8, P = 0.03), a higher mean admission white blood cell count (WBC; 15 vs. 12, P = 0.002), a lower mean absolute sodium (132 vs. 134, P = 0.01), a higher hemoglobin A1C (11.3 vs. 10.3, P = 0.05), hyperglycemia (289 vs. 248, P = 0.04), elevated C-reactive protein (20 vs. 11, P = 0.02), and the presence of Pseudomonas aeruginosa on final tissue culture (12.3 vs. 1.6, P = 0.004). These patients were taken to surgery more rapidly (22.5 vs. 31 hr, P = 0.04), and they had a longer postoperative stay (7 vs. 4 days, P = 0.02). On multivariate analysis, an elevated WBC was predictive of necrotizing infection (OR = 1.1, P = 0.01), whereas alcohol use was found to be protective (OR = 0.3, P = 0.04). CONCLUSIONS: Clinical and laboratory variables known to be associated with necrotizing infections among the general population appear to be predictive of disease severity among patients undergoing amputation for DFIs. Identification of these abnormalities preoperatively may allow for improved operative planning, shared decision making, and resource management. Prospective validation of these findings is potentially warranted. PMID- 26965810 TI - Smoking, Periodontitis, and Buerger Disease. PMID- 26965811 TI - Comment on Clinical Features and Therapeutic Options for Isolated Visceral Artery Dissection. PMID- 26965812 TI - Recognition and Surgical Techniques for Management of Nonrecurrent Laryngeal Nerve during Carotid Endarterectomy. AB - The presence of a nonrecurrent laryngeal nerve (NRLN) during carotid endarterectomy (CEA) may significantly limit the exposure of the surgical field during this operation. Although its reported incidence is rare, NRLN typically overlies the carotid bifurcation and failure to recognize this anatomic variation increases the risk of NRLN injury. A retrospective chart review of all patients who underwent CEA for hemodynamically significant extracranial carotid stenosis between January 2005 and December 2014 was performed. All patients with NRLN encountered intraoperatively were identified. Clinical outcomes, surgical techniques, and complications were reviewed and reported. Four left-sided NRLN were identified and 4 were right sided. No cranial nerve deficits or injuries occurred after CEA in patients where NRLN was encountered. Two distinct surgical techniques were used to manage patients with NRLN and they are discussed in detail. PMID- 26965813 TI - A National Survey on Teaching and Assessing Technical Proficiency in Vascular Surgery in Canada. AB - BACKGROUND: This survey aims to explore trainees' perspectives on how Canadian vascular surgery training programs are using simulation in teaching and assessing technical skills through a cross-sectional national survey. METHODS: A 10-min online questionnaire was sent to Program Directors of Canada's Royal College of Physicians and Surgeons' of Canada approved training programs in vascular surgery. This survey was distributed among residents and fellows who were studying in the 2013-2014 academic year. RESULTS: Twenty-eight (58%) of the 48 Canadian vascular surgery trainees completed the survey. A total of 68% of the respondents were part of the 0 + 5 integrated vascular surgery training program. The use of simulation in the assessment of technical skills at the beginning of training was reported by only 3 (11%) respondents, whereas 43% reported that simulation was used in their programs in the assessment of technical skills at some time during their training. Training programs most often provided simulation as a method of teaching and learning endovascular abdominal aortic or thoracic aneurysm repair (64%). Furthermore, 96% of trainees reported the most common resource to learn and enhance technical skills was dialog with vascular surgery staff. CONCLUSIONS: Surveyed vascular surgery trainees in Canada report that simulation is rarely used as a tool to assess baseline technical skills at the beginning of training. Less than half of surveyed trainees in vascular surgery programs in Canada report that simulation is being used for skills acquisition. Currently, in Canadian training programs, simulation is most commonly used to teach endovascular skills. PMID- 26965814 TI - Vascular Trauma Operative Experience is Inadequate in General Surgery Programs. AB - BACKGROUND: Vascular injuries may be challenging, particularly for surgeons who have not received formal vascular surgery fellowship training. Lack of experience and improper technique can result in significant complications. The objective of this study was to examine changes in resident experience with operative vascular trauma over time. METHODS: A retrospective review was performed using Accreditation Council for Graduate Medical Education (ACGME) case logs of general surgery residents graduating between 2004 and 2014 at 2 academic, university affiliated institutions associated with level 1 trauma centers. The primary outcome was number of reported vascular trauma operations, stratified by year of graduation and institution. RESULTS: A total of 112 residents graduated in the study period with a median 7 (interquartile range 4.5-13.5) vascular trauma cases per resident. Fasciotomy and exposure and/or repair of peripheral vessels constituted the bulk of the operative volume. Linear regression showed no significant trend in cases with respect to year of graduation (P = 0.266). Residents from program A (n = 53) reported a significantly higher number of vascular trauma cases when compared with program B (n = 59): 12.0 vs. 5.0 cases, respectively (P < 0.001). CONCLUSIONS: Level 1 trauma center verification does not guarantee sufficient exposure to vascular trauma. The operative exposure in program B is reflective of the national average of 4.0 cases per resident as reported by the ACGME, and this trend is unlikely to change in the near future. Fellowship training may be critical for surgeons who plan to work in a trauma setting, particularly in areas lacking vascular surgeons. PMID- 26965815 TI - Post-Thoracic Endovascular Aortic Repair Complicated with Mycotic Aneurysm Rupture, Repaired by Redo Thoracic Endovascular Aortic Repair. AB - Mycotic aneurysms although rare can be devastating. We encountered a dialysis patient with rapidly expanding distal aortic arch aneurysm who underwent axilloaxillary bypass and thoracic endovascular aortic repair (TEVAR). Three months later, he suffered mycotic aneurysm rupture for which redo TEVAR was performed. Antibiotic therapy was discontinued 16 weeks after the second operation, and renal transplantation was performed 6 months later. Dialysis was discontinued in the patient without infection recurrence. PMID- 26965816 TI - Endovascular Aortoiliac Aneurysm Repair with Fenestrated Stent Graft and Iliac Side Branch Using Image Fusion without Iodinated Contrast Medium. AB - BACKGROUND: The endovascular aneurysm repair (EVAR) is becoming the preferred method to treat an aortic aneurysm with its better short-term postoperative mortality and morbidity rates in comparison with the open repair. A main drawback of this method is the need to use a nephrotoxic iodinated contrast medium to visualize the aorta and its side branches. CASE REPORT: An 83-year-old man with an asymptomatic infrarenal aortic aneurysm of a 51-mm diameter accompanied by a 42-mm aneurysm of the left common iliac artery was treated with combined fenestrated EVAR (FEVAR) and iliac side branch stent graft (ISBG) under guidance of image fusion (IF) without the intraoperative use of iodinated contrast agent. CONCLUSIONS: Complex EVAR (FEVAR and ISBG) using computed tomography angiography IF is feasible and together with the use of CO2 angiography may help to abstain from need to nephrotoxic contrast medium. PMID- 26965817 TI - Transthoracic Median Arcuate Ligament Release and Mesenteric Revascularization. AB - Surgical revascularization for chronic or acute mesenteric ischemia is often technically challenging. In many instances, because of the presence of hostile abdominal conditions or the lack of adequate intra-abdominal arterial inflow sources, alternative surgical approaches that avoid the abdomen and use a more proximal source of arterial inflow are necessary. In these situations, a bypass from the descending or ascending thoracic aorta to the mesenteric vessels may be the only viable option. However, the standard thoracoabdominal approach for mesenteric revascularization carries an extensive surgical insult, and in some situations, this approach does not obviate hostile abdominal pathology. We here describe a transthoracic surgical technique that allows antegrade celiac and mesenteric revascularization without a thoracoabdominal incision. This approach facilitates the easy transection of the median arcuate ligament of the diaphragm and, when needed, resection of the celiac autonomic ganglia. The transthoracic mesenteric revascularization is less invasive than a thoracoabdominal approach, whereas allowing a similar antegrade, short bypass to the mesenteric vessels from the descending thoracic aorta equal to that done through a thoracoabdominal exposure. This procedure provides a superb approach for the treatment of median arcuate ligament syndrome, and an excellent alternative for mesenteric revascularization when avoidance of the abdomen is advisable. PMID- 26965818 TI - Coronary Artery Bypass Grafting Combined with Open Versus Endovascular Abdominal Aortic Aneurysm Repair. PMID- 26965819 TI - Dialysis Access Surgery: Does Anesthesia Type Affect Maturation and Complication Rates? AB - BACKGROUND: Creation of an arteriovenous fistula (AVF) is the preferred method of establishing long-term dialysis access. There are multiple anesthetic techniques used for patients undergoing this surgery including general endotracheal intubation, laryngeal mask airway, regional anesthesia with nerve blocks, and monitored anesthesia care with local infiltration. It is unclear what effect the method of anesthesia has on AVF creation success rate. It is our objective to determine if anesthesia type affects success of these surgeries defined by complication and maturation rates. METHODS: A retrospective review was performed in a single institution, single surgeon study of 253 patients who underwent AVF creation between January 2003 and December 2010. Patients were cross analyzed between 3 anesthesia types (General Endotracheal Intubation, Laryngeal Mask Airway and Local Infiltration with Monitored Anesthesia Care) and AVF creation surgeries (radiocephalic, brachiocephalic, and basilic vein transposition). No patients had regional anesthesia performed. Demographic data including comorbidities and risk factors were stratified among all categories. Analysis of variance, chi-squared testing, and Fisher's exact P testing was performed across all anesthesia types and specific operations and measured according to success of fistula maturation and complication rates (including death within 30 days, myocardial infarction within 30 days, respiratory insufficiency, venous hypertension, wound infections, neuropathy, and vascular steal syndrome). RESULTS: There were no significant differences in maturation rate in terms of all 3 anesthesia types for radiocephalic (P = 0.191), brachiocephalic (P = 0.191), and basilic vein transposition surgeries (P = 0.305). In addition, there were no differences in complication rates between the surgeries and the 3 types of anesthesia (P = 0.557). CONCLUSIONS: Our study shows that despite anesthesia type, outcomes in terms of maturation and complication rate are not statistically different in AVF creation surgeries. The use of monitored anesthesia care with local anesthesia may improve operative efficiency in terms of time in the operating room and in the recovery unit and therefore may be the preferred method of anesthesia. This recommendation may also parallel the preference to avoid general anesthesia in a patient population with more medical comorbidities. It is our conclusion that dialysis access surgery should therefore be performed under local anesthesia with monitored anesthesia care. PMID- 26965820 TI - Blunt Thoracic Aortic Injury in Case of a 15-Year-Old Boy: Difficulties and Possibilities of the Endovascular Approach. AB - BACKGROUND: Blunt thoracic aortic injuries (BTAIs) are rare but life threatening. Most BTAI are caused by high-energy trauma. Among children with blunt trauma, the incidence of BTAI is below 1 percent. The present case deals with covered thoracic aortic rupture of a 15-year-old boy. Emphasizing the value and the difficulties of endovascular surgery in children is the motivation for this case report. CASE REPORT: We are presenting the case of a 15-year-old boy, who suffered multiple traumata after accident. Beneath multiple fractures and a liver laceration, a thoracic aortic rupture with pseudoaneurysm of the aortic wall was diagnosed. Owing to the comorbidities, an endovascular therapy in combination with a transposition of the left subclavian artery to the common carotid artery was performed. The chronological line-up of the events and the endovascular treatment as well as the in-hospital follow-up are described. DISCUSSION: Injury induced BTAI in pubescent children rarely occurs. Only few cases can be found in literature, none of which were associated with the presented pattern of injury. CONCLUSIONS: The optimal treatment for childhood BTAI is a case-by-case decision. We critically discuss the value of endovascular therapy in the present case. PMID- 26965821 TI - Oral Anticoagulant Therapy and Endovascular Procedures. PMID- 26965822 TI - GIA-Aneurysmorrhaphy and Dermal Detachment: A Novel Technique to Repair Arteriovenous Fistula Aneurysms. AB - This report describes a simplified technique for management of aneurysmal arteriovenous fistulas along with results of initial clinical experience in 12 patients. Various techniques have been described which seek to repair the arteriovenous fistula and lengthen its duration of use. Here, we introduce the GIA-aneurysmorrhaphy and dermal detachment (GADD) procedure, a novel technique which requires minimal dissection to decompress tension on the overlying skin. Transverse incisions were made proximally and distally to the aneurysmal segment, which was then bluntly dissected along its length on either side. A GIA stapler is then fired along the longitudinal axis, narrowing the lumen of the fistula and separating the aneurysm from the skin. After the operation, the arteriovenous fistulae were used continuously until death (1 patient for 12 months), until thrombosis (1 patient for 13 months), or continue to be in use (9 patients, mean patency 18 months). One patient underwent conversion to open aneurysmorrhaphy due to intraoperative fistula occlusion. Five patients resumed hemodialysis immediately, while the remaining resumed hemodialysis within 3 months. The most common complication was cellulitis (3 patients). The GADD procedure as described in this report offers an effective and low-risk option for the management of venous aneurysms with threatened skin in hemodialysis patients. PMID- 26965823 TI - Distal Radial Artery Embolization: An Alternative Approach towards Access Preservation and Limb Salvage in Radiocephalic Arteriovenous Fistulae Complicated by Steal Syndrome. AB - The incidence of radiocephalic arteriovenous fistulae complicated by ischemic steal syndrome is low; however, its sequelae can be quite devastating. Traditional management includes open ligation of the distal radial artery. This series details 4 cases of successful embolization of the distal radial artery for flow interruption to treat ischemic steal syndrome and salvage functional dialysis access. For radiocephalic arteriovenous fistulae complicated by steal syndrome, distal radial artery endovascular coil embolization is a valuable treatment strategy. PMID- 26965824 TI - Catheter-Directed Thrombolysis for Massive Pulmonary Embolism Resulting from Thrombosis in a Duplicated Inferior Vena Cava: A Case Report. AB - Pulmonary embolism (PE) associated with duplicated inferior vena cava (IVC) is rare, and there are no reports of this condition treated with catheter-directed thrombolysis. We present the case of a 54-year-old man who developed massive PE caused by thrombi in a duplicated IVC that detached during transcatheter angiography. After implantation of a retrievable filter in the common IVC, the patient underwent catheter-directed thrombolysis. He was asymptomatic at discharge, with complete resolution of thrombosis and successful retrieval of the filter. The patient had an uneventful 9-month follow-up with no further complications. PMID- 26965825 TI - Applicability of Zenith p-branch Standard Fenestrated Endograft in Our Series. AB - BACKGROUND: In the endovascular treatment of abdominal aortic aneurysm (AAA) with short or absent infrarenal neck, the delay in the availability of fenestrated device and its high cost, have led to the manufacture of standardized models. Another option is the endografts with stents in parallel; however, regulated criteria for their use and long-term studies are lacking. The aim of this study was to assessed whether the AAA treated with fenestrated device or stents in parallel in our department, complied with the characteristics for the placement of the new endograft p-branch((r)). Furthermore, the differences between the p branch and the implanted prosthesis were analyzed. METHODS: Single-center and descriptive study of 41 aneurysms treated consecutively from 2008 to 2015. The anatomic characteristics analyzed were: relative distances between the visceral arteries, time position, diameter in the sealing area and number of fenestrations, and its compatibility with the p-branch. RESULTS: The anatomic compatibility rate with the p-branch options was 73.2% (30 cases). Of the 11 incompatible cases, 6 were due to misalignment of the visceral branches, 2 due to the aortic neck diameter being greater, another because the femoral access was inappropriate, and 2 more due to the fenestration configuration. Of the 30 cases in which compatibility existed, in 12 (40%) the configuration used coincided with the p-branch. In 13 cases, the number of fenestrations was higher than those actually used, with 23 fenestrations carried out and 39 hypothetical fenestrations with the new endograft. In the 5 remaining cases, a fenestration for the celiac trunk was necessary to achieve an adequate seal. CONCLUSIONS: The p-branch could meet the needs of three-quarters of the aortic anatomies of our series, with favorable expectations on cost and waiting time. However, in most cases either a higher number of fenestrations are needed for visceral arteries or the proximal seal was shorter than would be ideal. PMID- 26965826 TI - Tg6F ameliorates the increase in oxidized phospholipids in the jejunum of mice fed unsaturated LysoPC or WD. AB - Mouse chow supplemented with lysophosphatidylcholine with oleic acid at sn-1 and a hydroxyl group at sn-2 (LysoPC 18:1) increased LysoPC 18:1 in tissue of the jejunum of LDL receptor (LDLR)-null mice by 8.9 +/- 1.7-fold compared with chow alone. Western diet (WD) contained dramatically less phosphatidylcholine 18:1 or LysoPC 18:1 compared with chow, but feeding WD increased LysoPC 18:1 in the jejunum by 7.5 +/- 1.4-fold compared with chow. Feeding LysoPC 18:1 or feeding WD increased oxidized phospholipids in the jejunum by 5.2 +/- 3.0-fold or 8.6 +/- 2.2-fold, respectively, in LDLR-null mice (P < 0.0004), and 2.6 +/- 1.5-fold or 2.4 +/- 0.92-fold, respectively, in WT C57BL/6J mice (P < 0.0001). Adding 0.06% by weight of a concentrate of transgenic tomatoes expressing the 6F peptide (Tg6F) decreased LysoPC 18:1 in the jejunum of LDLR-null mice on both diets (P < 0.0001), and prevented the increase in oxidized phospholipids in the jejunum in LDLR-null and WT mice on both diets (P < 0.008). Tg6F decreased inflammatory cells in the villi of the jejunum, decreased dyslipidemia, and decreased systemic inflammation in LDLR-null and WT mice on both diets. We conclude that Tg6F reduces diet-induced inflammation by reducing the content of unsaturated LysoPC and oxidized phospholipids in the jejunum of mice. PMID- 26965832 TI - New Labdane diterpenes from Hedychium yunnanense with cytotoxicity and inhibitory effects on nitric oxide production. AB - Two new labdane diterpenes, hedychenoids A (1) and B (2), were isolated from the rhizomes of Hedychium yunnanense, together with four known ones hedychenone (3), forrestin A (4), villosin (5) and calcaratarin C (6). Their structures were determined on the basis of NMR (1D and 2D) and mass spectroscopic analysis. Compounds 2, 3 and 5 exhibited cytotoxicity against SGC-7901 with IC50 values of 14.88 +/- 0.52, 7.08 +/- 0.21 and 7.76 +/- 0.21 MUg/ml, 3 and 5 against HeLa with IC50 values of 9.76 +/- 0.48 and 13.24 +/- 0.63 MUg/ml, respectively. Compounds 2, 5 showed inhibitory effects against nitric oxide production in LPS and IFN gamma-induced RAW 264.7 murine macrophages with IC50 values of 6.57 +/- 0.88 and 5.99 +/- 1.20 MUg/ml, respectively. PMID- 26965833 TI - CRISPR: taking the shortcut to a healthy genome editing enterprise. PMID- 26965835 TI - Unexplained somatic complaints in relation to paroxysmal EEG phenomena and localised abnormalities in the electroencephalogram. AB - A positive significant relationship (p<0,01) is found between a psychiatric judgement on autonomic nervous system complaints and a "blind" neurological judgement on paroxysmal EEG phenomena. CLASSIFICATION: Somatization Disorder (DSM III-R; IV 300.81). Diagnoses: nervous functional complaints, hyperventilation syndrome, Da Costa's disease (irritable heart syndrome, neurocirculatory asthenia) and irritable bowel syndrome. A positive significant relationship (p<0,001) is found between a diagnosis of "Da Costa's disease" and a "blind" neurological judgement on PEF. A positive significant relationship (p<0,001) is found between a psychiatric judgement on neurasthenia (atypical headache and atypical tiredness) classified as dysthymia DSM-IH-R 300.40 and a neurological judgement on localised (cortical) abnormalities by "blind" EEG evaluation. No medication in the last half year. Logistic regression analysis (n=116) revealed that sex and age are of no importance. No medication in the last half year before EEG registration. PMID- 26965836 TI - Antidepressive interventions: on state and vulnerability of the brain. AB - An attempt is made to relate drug and non-drug antidepressive interventions to brain processes. In the present context two concepts are proposed: vulnerability towards depressogenic factors and depression as a state of the brain. Accordingly, it is assumed that the current antidepressants make the brain less vulnerable by inhibiting monoaminergic neurons and by reducing the number or efficacy of their postsynaptic receptors. In contrast, electroconvulsive therapie and sleep-deprivation affect primarily the state of the brain and can produce spectacular (but often short lasting) improvements. It is proposed that the combination of the two aspects may lead to fast and lasting antidepressive effects. PMID- 26965837 TI - Nightmares in psychiatry. AB - Nightmares are frightening dreams awakening the dreamer. In psychiatry they are often considered as an indication of psychopathology or even as a feature of schizophrenia. Assumptions are made that nightmares occur more often in psychiatric patients than in the normal population and that they are accompanied by an elevated anxiety level in the daytime. From a psychophysiological point of view nightmares possibly are derailed attemps of problem solving, of overcoming frightening experiences. In this review the importance of nightmares as symptom in psychiatry is assessed. It appears that they are no indication of an elevated anxiety level in the day-time or of psychopathology in general, and they are no criterium for the diagnosis of schizophrenia either. PMID- 26965827 TI - The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model. AB - Dysregulated expression of miR-219, a brain-specific microRNA, has been observed in neurodevelopmental disorders, such as schizophrenia (SCZ). However, its role in normal mammalian neural stem cells (NSCs) and in SCZ pathogenesis remains unknown. We show here that the nuclear receptor TLX, an essential regulator of NSC proliferation and self-renewal, inhibits miR-219 processing. miR-219 suppresses mouse NSC proliferation downstream of TLX. Moreover, we demonstrate upregulation of miR-219 and downregulation of TLX expression in NSCs derived from SCZ patient iPSCs and DISC1-mutant isogenic iPSCs. SCZ NSCs exhibit reduced cell proliferation. Overexpression of TLX or inhibition of miR-219 action rescues the proliferative defect in SCZ NSCs. Therefore, this study uncovers an important role for TLX and miR-219 in both normal neurodevelopment and in SCZ patient iPSC derived NSCs. Moreover, this study reveals an unexpected role for TLX in regulating microRNA processing, independent of its well-characterized role in transcriptional regulation. PMID- 26965834 TI - Oral chondroitin sulfate and prebiotics for the treatment of canine Inflammatory Bowel Disease: a randomized, controlled clinical trial. AB - BACKGROUND: Canine inflammatory bowel disease (IBD) is a chronic enteropathy of unknown etiology, although microbiome dysbiosis, genetic susceptibility, and dietary and/or environmental factors are hypothesized to be involved in its pathogenesis. Since some of the current therapies are associated with severe side effects, novel therapeutic modalities are needed. A new oral supplement for long term management of canine IBD containing chondroitin sulfate (CS) and prebiotics (resistant starch, beta-glucans and mannaoligosaccharides) was developed to target intestinal inflammation and oxidative stress, and restore normobiosis, without exhibiting any side effects. This double-blinded, randomized, placebo controlled trial in dogs with IBD aims to evaluate the effects of 180 days administration of this supplement together with a hydrolyzed diet on clinical signs, intestinal histology, gut microbiota, and serum biomarkers of inflammation and oxidative stress. RESULTS: Twenty-seven client-owned biopsy-confirmed IBD dogs were included in the study, switched to the same hydrolyzed diet and classified into one of two groups: supplement and placebo. Initially, there were no significant differences between groups (p > 0.05) for any of the studied parameters. Final data analysis (supplement: n = 9; placebo: n = 10) showed a significant decrease in canine IBD activity index (CIBDAI) score in both groups after treatment (p < 0.001). After treatment, a significant decrease (1.53-fold; p < 0.01) in histologic score was seen only in the supplement group. When groups were compared, the supplement group showed significantly higher serum cholesterol (p < 0.05) and paraoxonase-1 (PON1) levels after 60 days of treatment (p < 0.01), and the placebo group showed significantly reduced serum total antioxidant capacity (TAC) levels after 120 days (p < 0.05). No significant differences were found between groups at any time point for CIBDAI, WSAVA histologic score and fecal microbiota evaluated by PCR-restriction fragment length polymorphism (PCR RFLP). No side effects were reported in any group. CONCLUSIONS: The combined administration of the supplement with hydrolyzed diet over 180 days was safe and induced improvements in selected serum biomarkers, possibly suggesting a reduction in disease activity. This study was likely underpowered, therefore larger studies are warranted in order to demonstrate a supplemental effect to dietary treatment of this supplement on intestinal histology and CIBDAI. PMID- 26965838 TI - Pharmacological treatment strategies in mood, panic and obsessive compulsive disorders. AB - Since the introduction of the monoamine oxydase inhibitors and the first tricyclic antidepressant (TCA) imipramine in the late fifties, the treatment of depressive disorders has been changed dramatically. Althought a great variety of antidepressants such as TCA's, selective serotoninte-re-uptake inhibitors (SSRI's) mianserin, trazodone, mirtazapine, moclobemide and venlafaxine has become available, the exact mode of action is not revealed as yet, and classification should be done according to the interference of antidepressants with central monoaminergic processes. As to the potential of causing interactions, special attention has to be given to the SSRI's because of their interference with the CYP450 isozyme system. Therapeutic monotoring is recommended for the TCA's. The choiseforan antidepressant should be based on various factors like symptomatology and severity of the depression, potential interactions and somatic and/or psychiatric comorbidity. Extensive clinical research has demonstrated that TCA's are the most effective for major depression with melancholia (vital depression) and depressive disorders in the elderly. PMID- 26965839 TI - Establishment of a lectotype for the species Plesiochelys langii Rutimeyer, 1873. AB - Background. In a recent paper, we proposed a lectotype for the species Plesiochelys langii Rutimeyer, 1873. However, we failed to register this publication in ZooBank as required by the International Commission on Zoological Nomenclature (ICZN) for electronic publication. Although our conclusions remain unchanged, this particular nomenclatural act cannot be considered as published under ICZN regulations. Results. The present work fulfills the requirements of the ICZN for a lectotype designation and has been registered in ZooBank. PMID- 26965841 TI - In this issue of Occupational Medicine. PMID- 26965840 TI - In vitro bioassay investigations of the endocrine disrupting potential of steviol glycosides and their metabolite steviol, components of the natural sweetener Stevia. AB - The food industry is moving towards the use of natural sweeteners such as those produced by Stevia rebaudiana due to the number of health and safety concerns surrounding artificial sweeteners. Despite the fact that these sweeteners are natural; they cannot be assumed safe. Steviol glycosides have a steroidal structure and therefore may have the potential to act as an endocrine disruptor in the body. Reporter gene assays (RGAs), H295R steroidogenesis assay and Ca(2+) fluorimetry based assays using human sperm cells have been used to assess the endocrine disrupting potential of two steviol glycosides: stevioside and rebaudioside A, and their metabolite steviol. A decrease in transcriptional activity of the progestagen receptor was seen following treatment with 25,000 ng/ml steviol in the presence of progesterone (157 ng/ml) resulting in a 31% decrease in progestagen response (p=<0.01). At the level of steroidogenesis, the metabolite steviol (500-25,000 ng/ml) increased progesterone production significantly by 2.3 fold when exposed to 10,000 ng/ml (p=<0.05) and 5 fold when exposed to 25,000 ng/ml (p=<0.001). Additionally, steviol was found to induce an agonistic response on CatSper, a progesterone receptor of sperm, causing a rapid influx of Ca(2+). The response was fully inhibited using a specific CatSper inhibitor. These findings highlight the potential for steviol to act as a potential endocrine disruptor. PMID- 26965842 TI - Analysis of Biopsies From Duodenal Bulbs of All Endoscopy Patients Increases Detection of Abnormalities but has a Minimal Effect on Diagnosis of Celiac Disease. AB - BACKGROUND & AIMS: In patients with positive results from serologic tests for celiac disease, analysis of tissues samples from the duodenal bulb, in addition to those from other parts of the small bowel, might increase the diagnostic yield. However, biopsies are not routinely collected from the duodenal bulb because of concerns that villous atrophy detected there could be caused by other disorders (Brunner glands or peptic duodenitis, gastric metaplasia, shorter villi, or lymphoid follicles). We investigated whether analysis of biopsies from duodenal bulbs of all patients undergoing endoscopy (a population with a low probability for celiac disease) increases diagnoses of celiac disease. METHODS: We performed a retrospective analysis of data from 679 patients (63% female; mean age, 50 years) from whom duodenal bulb and small bowel biopsies were collected during endoscopy at 3 Mayo Clinic sites, from January 1, 2011 through December 31, 2011. Records were reviewed for age, sex, pathology findings, serology test results (HLA DQ2 or DQ), indications for biopsy analyses, and adherence to a gluten-free diet. Patients with celiac disease were identified on the basis of increased intraepithelial lymphocytosis, with or without villous atrophy and crypt hyperplasia, and results from serology tests. Findings from duodenal bulbs were compared with diagnoses using the Fisher exact test. RESULTS: Of all patients undergoing endoscopy, 16 patients (2%) were found to have celiac disease. Analysis of the duodenal bulb biopsies identified 1 patient (0.1%) with celiac disease limited to this region. Of 399 patients whose celiac serology was not known before endoscopic examination, only 2 patients had histologic changes consistent with celiac disease but not limited to duodenal bulb. Abnormal duodenal histology was detected in 265 patients (39%), most commonly in the bulb (n = 241; P < .0001). Of abnormal bulb histologies, chronic peptic duodenitis was most common (observed in 114 patients, 47%). In patients with a normal distal duodenum (n = 576), the duodenal bulb had abnormal histology in 162 (28%). CONCLUSIONS: In a low pretest probability cohort, separate sampling of the duodenal bulb had minimal effect on celiac disease detection. Abnormal histologic findings are more commonly detected in the duodenal bulb; although they do not seem to impair identification of celiac disease, their clinical implications are unclear. PMID- 26965844 TI - A Rare Cause of Acute Abdomen. PMID- 26965843 TI - Total Pancreatectomy With Islet Autotransplantation Improves Quality of Life in Patients With Refractory Recurrent Acute Pancreatitis. AB - BACKGROUND & AIMS: Therapeutic options are limited for patients with recurrent acute pancreatitis who have intractable symptoms despite maximal endoscopic and medical treatment, but equivocal or no morphologic or functional evidence of chronic pancreatitis. We performed a prospective observational cohort study to determine the efficacy of total pancreatectomy with islet autotransplantation (TPIAT) for these patients. METHODS: We collected data from all patients undergoing TPIAT at the University of Minnesota from 2007 through 2013; 49 patients (42 female; mean age, 32.8 +/- 7.8 years) had a diagnosis of recurrent acute pancreatitis not provoked by intervention, with negative or equivocal findings from nondiagnostic imaging or pancreatic function tests for chronic pancreatitis, and intractable pain between episodes. Data on insulin use, narcotic requirements, pain scores, and health-related quality of life were collected before TPIAT; 3 months, 6 months, and 1 year afterward; and then yearly. RESULTS: All 49 patients studied required narcotics before TPIAT (45 daily users and 4 intermittent users); 2 had insulin-treated diabetes. At 1 year after TPIAT, 22 out of 48 patients (46%) reported no use of narcotic pain medications (P < .001 vs baseline). Health-related quality of life score, measured by the physical and mental component summary score, increased by approximately 1 standard deviation from the population mean (P < .001 for the physical component summary; P = .019 for the mental component summary). At 1 year after TPIAT, 21 out of 48 patients (45%) were insulin independent; their mean percent glycosylated hemoglobin A1c at 1 year after TPIAT was 6.0% +/- 0.9% (5.2% +/- 0.6% pre-TPIAT). CONCLUSIONS: Patients with recurrent acute pancreatitis but lacking clear chronic pancreatitis benefit from TPIAT, with outcomes similar to those previously described for patients with chronic pancreatitis (improved quality of life and reduced narcotic use). For these patients who have otherwise limited surgical treatment options, TPIAT can be considered when medical and endoscopic therapies have failed. PMID- 26965845 TI - Heritability and Genome-Wide Association Analyses of Intracranial Carotid Artery Calcification: The Rotterdam Study. AB - BACKGROUND AND PURPOSE: Intracranial carotid artery calcification (ICAC) is one of the most important risk factors for stroke. Although several environmental risk factors for ICAC have been identified, its genetic background remains unclear. METHODS: Between 2003 and 2006, 2034 participants from the prospective population-based Rotterdam study (mean age: 69.6+/-6.8 years; 51.7% female) underwent computed tomography to quantify vascular calcification in the intracranial internal carotid artery. Blood samples were drawn for genotyping. Genotypes of the participants were imputed to the 1000 Genomes reference panel to generate genetic relationship matrices for the estimation of the heritability of ICAC volume. Adjustments were made for age and sex. Subsequently, genome-wide association analyses were performed to identify specific variants. RESULTS: The age- and sex-adjusted heritability (h(2)) of ICAC was 47% [standard error (SE): 19%; P=0.009]. Genome-wide association analyses identified a variant on chromosome 9p21.3 (rs1537372; N=2034; P=4.75*10(-9)) and 1 variant on chromosome 11p11.2 (rs11038042, N=2034; P=3.27*10(-8)) that were significantly associated with ICAC volume. Rs1537372 replicated in an independent sample of 716 stroke patients (Pcombined=1.38*10(-10)). CONCLUSIONS: ICAC volume is a heritable trait, which is partly explained by common genetic variation. We identified specific genetic variants associated with ICAC, which given the importance of ICAC in stroke risk, needs replication in larger-scale studies to further elucidate its genetic basis. PMID- 26965848 TI - Response to Letter Regarding Article, "Damage to the Left Precentral Gyrus Is Associated With Apraxia of Speech in Acute Stroke". PMID- 26965846 TI - Effects of Arterial Stiffness on Brain Integrity in Young Adults From the Framingham Heart Study. AB - BACKGROUND AND PURPOSE: Previous work from the Framingham Heart Study suggests that brain changes because of arterial aging may begin in young adulthood and that such changes precede cognitive deficits. The objective of this study was to determine the association of arterial stiffness with measures of white matter and gray matter (GM) integrity in young adults. METHODS: One thousand nine hundred three participants from the Framingham Heart Study Third Generation (mean age, 46+/-8.7 years) had complete tonometry measurements and brain magnetic resonance imaging (T1-weighted and diffusion tensor imaging). Tonometry measures included carotid-femoral pulse wave velocity, augmentation index, carotid-brachial pressure amplification, and central pulse pressure. Fractional anisotropy and GM density images were computed from diffusion tensor imaging and T1 images. Registration to a common anatomic template enabled voxel-based linear regressions relating measures of fractional anisotropy and GM to tonometry measures, adjusting for relevant covariables. RESULTS: Higher carotid-femoral pulse wave velocity was associated with lower regional fractional anisotropy, including the corpus callosum and the corona radiata (8.7 and 8.6 cc, respectively, P<0.001), as well as lower GM density in the thalamus region (0.9 cc, P<0.001). Analyses did not reveal significant associations between other tonometry measures and fractional anisotropy or GM. CONCLUSIONS: Among young healthy adults, higher aortic stiffness was associated with measures of reduced white matter and GM integrity in areas implicated in cognitive decline and Alzheimer's disease. Greater aortic stiffness may result in subclinical vascular brain injury at ages much younger than previously described. PMID- 26965849 TI - Perfusion Computed Tomography for the Evaluation of Acute Ischemic Stroke: Strengths and Pitfalls. PMID- 26965847 TI - Astrocyte-Derived Pentraxin 3 Supports Blood-Brain Barrier Integrity Under Acute Phase of Stroke. AB - BACKGROUND AND PURPOSE: Pentraxin 3 (PTX3) is released on inflammatory responses in many organs. However, roles of PTX3 in brain are still mostly unknown. Here we asked whether and how PTX3 contributes to blood-brain barrier dysfunction during the acute phase of ischemic stroke. METHODS: In vivo, spontaneously hypertensive rats were subjected to focal cerebral ischemia by transient middle cerebral artery occlusion. At day 3, brains were analyzed to evaluate the cellular origin of PTX3 expression. Correlations with blood-brain barrier breakdown were assessed by IgG staining. In vitro, rat primary astrocytes and rat brain endothelial RBE.4 cells were cultured to study the role of astrocyte-derived PTX3 on vascular endothelial growth factor-mediated endothelial permeability. RESULTS: During the acute phase of stroke, reactive astrocytes in the peri-infarct area expressed PTX3. There was negative correlation between gradients of IgG leakage and PTX3 positive astrocytes. Cell culture experiments showed that astrocyte-conditioned media increased levels of tight junction proteins and reduced endothelial permeability under normal conditions. Removing PTX3 from astrocyte-conditioned media by immunoprecipitation increased endothelial permeability. PTX3 strongly bound vascular endothelial growth factor in vitro and was able to decrease vascular endothelial growth factor-induced endothelial permeability. CONCLUSIONS: Astrocytes in peri-infarct areas upregulate PTX3, which may support blood-brain barrier integrity by regulating vascular endothelial growth factor-related mechanisms. This response in astrocytes may comprise a compensatory mechanism for maintaining blood-brain barrier function after ischemic stroke. PMID- 26965850 TI - Letter by Terao et al Regarding Article, "Damage to the Left Precentral Gyrus Is Associated With Apraxia of Speech in Acute Stroke". PMID- 26965851 TI - Apolipoprotein B-100 Antibody Interaction With Atherosclerotic Plaque Inflammation and Repair Processes. AB - BACKGROUND AND PURPOSE: Treatment with IgG against the malondialdehyde (MDA) modified apolipoprotein B-100 epitope p45 reduces atherosclerosis in experimental models. This study investigated the association between p45 IgG autoantibodies and plaque inflammation in subjects with advanced cardiovascular disease. METHODS: Native and MDA-p45 IgG levels were analyzed by ELISA in 349 carotid endarterectomy patients. In a subcohort of 195 subjects, endarterectomy samples were analyzed by immunohistochemistry and ELISA to determine plaque constituents and inflammation. Peripheral blood mononuclear cells were isolated from healthy donors. RESULTS: Patients with preoperative events of neurological ischemia had lower levels of native p45 IgG. Low levels of MDA-p45 IgG were associated with increased risk of postoperative cardiovascular death during a mean follow-up of 54 months. High plasma levels of native p45 IgG were associated with increased plaque content of collagen and smooth muscle cell growth factors, as well as with lower levels of proinflammatory cytokines. Exposure of peripheral blood mononuclear cells from healthy donors to recombinant MDA-p45 IgG in presence of oxidized low-density lipoprotein reduced the expression of tumor necrosis factor alpha and stimulated release of smooth muscle cell growth factors. CONCLUSIONS: This study confirms previous experimental findings of anti-inflammatory properties of apolipoprotein B-100 p45 antibodies and provides the first clinical evidence of associations between p45 IgG autoantibody levels and atherosclerotic plaque inflammation, plaque repair as well as prevalent and incident cardiovascular events in carotid endarterectomy patients. These findings suggest the possibility that treatment with anti-p45 antibodies may have beneficial effects in advanced cardiovascular disease. PMID- 26965852 TI - Cracking the Role of Cocaine in Stroke. PMID- 26965853 TI - Cocaine Use and Risk of Ischemic Stroke in Young Adults. AB - BACKGROUND AND PURPOSE: Although case reports have long identified a temporal association between cocaine use and ischemic stroke (IS), few epidemiological studies have examined the association of cocaine use with IS in young adults, by timing, route, and frequency of use. METHODS: A population-based case-control study design with 1090 cases and 1154 controls was used to investigate the relationship of cocaine use and young-onset IS. Stroke cases were between the ages of 15 and 49 years. Logistic regression analysis was used to evaluate the association between cocaine use and IS with and without adjustment for potential confounders. RESULTS: Ever use of cocaine was not associated with stroke with 28% of cases and 26% of controls reporting ever use. In contrast, acute cocaine use in the previous 24 hours was strongly associated with increased risk of stroke (age-sex-race adjusted odds ratio, 6.4; 95% confidence interval, 2.2-18.6). Among acute users, the smoking route had an adjusted odds ratio of 7.9 (95% confidence interval, 1.8-35.0), whereas the inhalation route had an adjusted odds ratio of 3.5 (95% confidence interval, 0.7-16.9). After additional adjustment for current alcohol, smoking use, and hypertension, the odds ratio for acute cocaine use by any route was 5.7 (95% confidence interval, 1.7-19.7). Of the 26 patients with cocaine use within 24 hours of their stroke, 14 reported use within 6 hours of their event. CONCLUSIONS: Our data are consistent with a causal association between acute cocaine use and risk of early-onset IS. PMID- 26965854 TI - Isoindolinone compounds active as Kv1.5 blockers identified using a multicomponent reaction approach. AB - A series of isoindolinone compounds have been developed showing good in vitro potency on the Kv1.5 ion channel. By modification of two side chains on the isoindolinone scaffold, metabolically stable compounds with good in vivo PK profile could be obtained leaving the core structure unsubstituted. In this way, low microsomal intrinsic clearance (CLint) could be achieved despite a relatively high logD. The compounds were synthesized using the Ugi reaction, in some cases followed by Suzuki and Diels-Alder reactions, giving a diverse set of compounds in a small number of reaction steps. PMID- 26965856 TI - Development of potential broad spectrum antimicrobials using C2-symmetric 9 fluorenone alkyl amine. AB - DNA-dependent RNA primase is essential for de novo primer synthesis during DNA replication in all living organisms. Bacterial DnaG primase is an attractive target for inhibition because it is essential, low in copy number and structurally distinct from eukaryotic and archaeal primases. DnaG primase is sensitive to known inhibitors including suramin and doxorubicin. Recently, tilorone was discovered by high throughput screening to be an inhibitor of Bacillus anthracis primase DnaG but it failed to reduce the growth of B. anthracis in vitro. In this study we determined that tilorone also inhibited DnaG primase from Staphylococcus aureus. C2-Symmetric fluorenone-based compounds, similar to tilorone chemical structure were synthesized and tested to identify potential lead compounds that inhibit bacterial growth in B. anthracis, MRSA and Burkholderia thailandensis. These compounds were evaluated by determining the minimum inhibitory concentration (MIC) against several different bacterial species which demonstrated 17.5 and 16 MUg/ml MIC profiles. Importantly, some of the fluorenone-based compounds with a long carbon chain showed a relatively low MIC against B. anthracis, S. aureus, MRSA, Francisella tularensis, and B. thailandensis, suggesting it may be a promising lead compound. PMID- 26965855 TI - Synthesis and in vitro anticancer evaluation of some 4,6-diamino-1,3,5-triazine-2 carbohydrazides as Rad6 ubiquitin conjugating enzyme inhibitors. AB - Series of 4-amino-6-(arylamino)-1,3,5-triazine-2-carbohydrazides (3a-e) and N' phenyl-4,6-bis(arylamino)-1,3,5-triazine-2-carbohydrazides (6a-e), for ease of readership, we will abbreviate our compound names as 'new triazines', have been synthesized, based on the previously reported Rad6B-inhibitory diamino triazinylmethyl benzoate anticancer agents TZ9 and 4-amino-N'-phenyl-6 (arylamino)-1,3,5-triazine-2-carbohydrazides. Synthesis of the target compounds was readily accomplished in two steps from either bis-aryl/aryl biguanides via reaction of phenylhydrazine or hydrazinehydrate with key 4-amino-6 bis(arylamino)/(arylamino)-1,3,5-triazine-2-carboxylate intermediates. These new triazine derivatives were evaluated for their abilities to inhibit Rad6B ubiquitin conjugation and in vitro anticancer activity against several human cancer cell lines: ovarian (OV90 and A2780), lung (H1299 and A549), breast (MCF-7 and MDA-MB231) and colon (HT29) cancer cells by MTS assays. All the 10 new triazines exhibited superior Rad6B inhibitory activities in comparison to selective Rad6 inhibitor TZ9 that was reported previously. Similarly, new triazines also showed better IC50 values in survival assays of various tumor cell lines. Particularly, new triazines 6a-c, exhibited lower IC50 (3.3-22 MUM) values compared to TZ9. PMID- 26965857 TI - New antimalarial norterpene cyclic peroxides from Xisha Islands sponge Diacarnus megaspinorhabdosa. AB - Four new norterpene cyclic peroxides (1-4), together with three known norterpene cyclic peroxides were isolated from the Xisha Islands Sponge Diacarnus megaspinorhabdosa. Their structures were elucidated on the basis of spectroscopic analyses and comparison with the related model compounds. The compounds (1-7) were evaluated for the inhibitory activity against the malaria parasite Plasmodium falciparum, all of them showed significant antimalarial activity with IC50 values in the range of 1.6-8.6 MUM. PMID- 26965858 TI - Development of a selective activity-based probe for glycosylated LIPA. AB - Loss of LIPA activity leads to diseases such as Wolman's Disease and Cholesterol Ester Storage Disease. While it is possible to measure defects in LIPA protein levels, it is difficult to directly measure LIPA activity in cells. In order to measure LIPA activity directly we developed a LIPA specific activity based probe. LIPA is heavily glycosylated although it is unclear how glycosylation affects LIPA activity or function. Our probe is specific for a glycosylated form of LIPA in cells, although it labels purified LIPA regardless of glycosylation. PMID- 26965859 TI - New isosteroidal alkaloids with tracheal relaxant effect from the bulbs of Fritillaria pallidiflora Schrenk. AB - Four new isosteroidal alkaloids, yibeinones A-D (1-4), along with four known ones, imperialine-3beta-d-glucoside (5), imperialine (6), imperialine beta-N oxide (7), and dongbeinine (8), were isolated from the bulbs of Fritillaria pallidiflora. Their structures were confirmed on the basis of extensive spectroscopic analysis or comparison with the data in the literatures (known compounds). Compounds 2, 3, 4, and 6 showed an apparent concentration-dependant relaxation of isolated tracheal preparation, amongst 3 and 6 exhibited significant effects with pA2 values of 6.19 +/- 0.02 and 8.41 +/- 0.10, and EC50 values of 0.65 +/- 0.02 MUmol L(-1) and 4.40 +/- 0.90 nmol L(-1), respectively. PMID- 26965860 TI - Insights into the substrate specificity of the MutT pyrophosphohydrolase using structural analogues of 8-oxo-2'-deoxyguanosine nucleotide. AB - The bacterial repair enzyme MutT hydrolyzes the damaged nucleotide OdGTP (the 5' triphosphate derivative of 8-oxo-2'-deoxyguanosine; OdG), which is a known mutagen and has been linked to antibacterial action. Previous work has indicated important roles for the C8-oxygen, N7-hydrogen, and C2-exocyclic amine during OdGTP recognition by MutT. In order to gain a more nuanced understanding of the contribution of these three sites to the overall activity of MutT, we determined the reaction parameters for dGTP, OdGTP, and nine of their analogues using steady state kinetics. Our results indicate that overall high reaction efficiencies can be achieved despite altering any one of these sites. However, altering two or more sites leads to a significant decrease in efficiency. The data also suggest that, similar to another bacterial OdG repair enzyme, MutM, a specific carbonyl in the enzyme can not only promote activity by forming an active site hydrogen bond with the N7-hydrogen of OdGTP, but can also hinder activity through electrostatic repulsion with the N7-lone pair of dGTP. PMID- 26965861 TI - D-Amino acid oxidase inhibitors based on the 5-hydroxy-1,2,4-triazin-6(1H)-one scaffold. AB - A series of 3-substituted 5-hydroxy-1,2,4-triazin-6(1H)-one derivatives were designed and synthesized as a new class of d-amino acid oxidase (DAAO) inhibitors. Some of the newly synthesized derivatives showed potent inhibitory activity against human DAAO with IC50 values in the nanomolar range. Among them, 6-hydroxy-3-phenethyl-1,2,4-triazin-5(2H)-one 6b and 3-((6-fluoronaphthalen-2 yl)methylthio)-6-hydroxy-1,2,4-triazin-5(2H)-one 6m were found to be metabolically stable in mouse liver microsomes. In addition, compound 6b was found to be orally available in mice and able to enhance plasma d-serine levels following its co-administration with d-serine compared to the oral administration of d-serine alone. PMID- 26965862 TI - 7-Substituted umbelliferone derivatives as androgen receptor antagonists for the potential treatment of prostate and breast cancer. AB - The clinically used androgen receptor (AR) antagonists (bicalutamide, flutamide and nilutamide) bind with low affinity to AR and can induce escape mechanisms. Furthermore, under AR gene amplification or mutation conditions they demonstrate agonist activity and fail to inhibit AR, causing relapse into castration resistant prostate cancer (CRPC). Discovery of new scaffolds distinct from the 4 cyano/nitro-3-(trifluoromethyl)phenyl group common to currently used antiandrogens is urgently needed to avoid cross-resistance with these compounds. In this study, a series of twenty-nine 7-substituted umbelliferone derivatives was prepared and their antiproliferative activities were evaluated. The most active compound 7a demonstrated submicromolar inhibitory activity in the human prostate cancer cell line (22Rv1); IC50=0.93 MUM which represents a 50 fold improvement over the clinical antiandrogen bicalutamide (IC50=46 MUM) and a more than 30 fold improvement over enzalutamide (IC50=32 MUM). Interestingly, this compound showed even better activity against the human breast cancer cell line (MCF-7); IC50=0.47 MUM. Molecular modelling studies provided a plausible theoretical explanation for our findings. PMID- 26965863 TI - Synthesis, characterization, antimicrobial and biofilm inhibitory studies of new esterquats. AB - Novel esterquats (monoesterquats and diesterquats) were synthesized from 11-bromo undecanoic acid (11-BUA) and different alkyl amines. The prepared compounds were characterized by FT-IR, (1)H NMR, (13)C NMR and mass spectral analysis. 11-BUA was converted into methyl 11-bromo undecanoate which was further converted into amine ester (amine monoester and diester) by reacting with different aliphatic amines (hexyl, dodecyl, octadecyl, dioctyl and dicyclohexyl amine). Finally, the obtained amine esters were converted into esterquats (monoesterquat and diesterquat) by reacting with methyl iodide followed by ion exchange to afford chloride counter ion esterquats (5a-h). The synthesized esterquat products were studied for their antimicrobial and biofilm inhibitory activities. Among all the compounds, amine ester 3a and esterquat 5d showed potent antimicrobial activity towards pathogenic Gram-positive bacterial strains with minimum inhibitory concentration (MIC) values in the range of 3.9-15.6 MUg mL(-1) and 1.9-7.8 MUg mL(-1), respectively. The esterquat 5d also showed promising antifungal activity against Candida albicans MTCC 3017, Candida albicans MTCC 4748 and Candida aaseri MTCC 1962 strains with MIC value of 7.8 MUg mL(-1) which was identical to standard Miconazole. The compounds which exhibited antimicrobial activity were also effective in anti-biofilm activity and it was found that compound 5d exhibited excellent biofilm inhibitory activity with IC50 value of 0.9 MUg mL(-1) against Staphylococcus aureus MLS16 MTCC 2940. PMID- 26965864 TI - Novel Imbricatolic acid derivatives as protein tyrosine phosphatase-1B inhibitors: Design, synthesis, biological evaluation and molecular docking. AB - Protein tyrosine phosphatase (PTP-1B) antagonizes insulin signaling and is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To find potential PTP-1B inhibitors, derivatives of Imbricatolic acid (1) have been synthesized by introducing various nitrogenous functionalities at C-15 and C-19 positions. They were evaluated for PTP-1B enzyme inhibition activity. Compounds 3, 6, 14, and 15 exhibited promising PTP-1B inhibitory activity at 10 MUM concentrations with IC50 6.3, 6.8, 7.0 and 7.8 values, respectively. Structure activity relationship and molecular docking studies of these derivatives demonstrated that the integrity of the polar substituents were important for significant PTP-1B inhibitory activity. The Imbricatolic acid and active derivatives in this study might represent a starting point for development of new potential PTP-1B inhibitors. PMID- 26965866 TI - Regioselective and stereoselective route to N2-beta-tetrazolyl unnatural nucleosides via SN2 reaction at the anomeric center of Hoffer's chlorosugar. AB - We are reporting a regioselective and stereoselective route to N2-beta-tetrazolyl aromatic donor/acceptor unnatural nucleosides as new class of possible DNA base analogs. The SN2 substitution reaction at the anomeric center of Hoffer's chlorosugar with various 5-substituted aromatic tetrazoles in THF in presence of K2CO3 proceeds with regioselectivity at N2-tetrazoles and stereoselectivity at alpha-chlorosugar with very good yield. The stereoelectronic and steric effects play a crucial role for the observed outcome which is also supported from a theoretical (DFT) study. The methodology is simple, eco-compatible and the tetrazolyl unnatural nucleosides might find applications in decorating DNA for various biotechnological and DNA based material science applications. PMID- 26965865 TI - Exploring the purine core of 3'-C-ethynyladenosine (EAdo) in search of novel nucleoside therapeutics. AB - A series of new nucleoside analogues based on a C-3 branched ethynyl sugar derivative as present in 3'-C-ethynylcytidine (ECyd) and -adenosine (EAdo), combined with modified purine bases was synthetized and evaluated against a broad array of viruses and tumour cell lines. The pronounced cytostatic activity of EAdo was confirmed. EAdo and its 2,6-diaminopurine analogue showed inhibitory activity against vaccinia virus (EC50: 0.31 and 51 MUM, respectively). Derivative 10 on the other hand was found active against varicella zoster virus (EC50: 4.68 MUM). PMID- 26965867 TI - Design, synthesis and docking studies of novel dipeptidyl boronic acid proteasome inhibitors constructed from alphaalpha- and alphabeta-amino acids. AB - A series of novel dipeptidyl boronic acid proteasome inhibitors constructed from alphaalpha- and alphabeta-amino acids were designed and synthesized. Their structures were elucidated by (1)H NMR, (13)C NMR, LC-MS and HRMS. These compounds were evaluated for their beta5 subunit inhibitory activities of human proteasome. The results showed that dipeptidyl boronic acid inhibitors composed of alphaalpha-amino acids were as active as bortezomib. Interestingly, the activities of those derived from alphabeta-amino acids lost completely. Of all the inhibitors, compound 22 (IC50=4.82 nM) was the most potent for the inhibition of proteasome activity. Compound 22 was also the most active against three MM cell lines with IC50 values less than 5 nM in inhibiting cell growth assays. Molecular docking studies displayed that 22 fitted very well in the beta5 subunit active pocket of proteasome. PMID- 26965868 TI - ACEMg Diet Supplement Modifies Progression of Hereditary Deafness. AB - Dietary supplements consisting of beta-carotene (precursor to vitamin A), vitamins C and E and the mineral magnesium (ACEMg) can be beneficial for reducing hearing loss due to aminoglycosides and overstimulation. This regimen also slowed progression of deafness for a boy with GJB2 (CONNEXIN 26) mutations. To assess the potential for treating GJB2 and other forms of hereditary hearing loss with ACEMg, we tested the influence of ACEMg on the cochlea and hearing of mouse models for two human mutations: GJB2, the leading cause of childhood deafness, and DIAPH3, a cause of auditory neuropathy. One group of mice modeling GJB2 (Gjb2 CKO) received ACEMg diet starting shortly after they were weaned (4 weeks) until 16 weeks of age. Another group of Gjb2-CKO mice received ACEMg in utero and after weaning. The ACEMg diet was given to mice modeling DIAPH3 (Diap3-Tg) after weaning (4 weeks) until 12 weeks of age. Control groups received food pellets without the ACEMg supplement. Hearing thresholds measured by auditory brainstem response were significantly better for Gjb2-CKO mice fed ACEMg than for the control diet group. In contrast, Diap3-Tg mice displayed worse thresholds than controls. These results indicate that ACEMg supplementation can influence the progression of genetic hearing loss. PMID- 26965869 TI - Men who have sex with men in Great Britain: comparing methods and estimates from probability and convenience sample surveys. AB - OBJECTIVE: To examine sociodemographic and behavioural differences between men who have sex with men (MSM) participating in recent UK convenience surveys and a national probability sample survey. METHODS: We compared 148 MSM aged 18-64 years interviewed for Britain's third National Survey of Sexual Attitudes and Lifestyles (Natsal-3) undertaken in 2010-2012, with men in the same age range participating in contemporaneous convenience surveys of MSM: 15 500 British resident men in the European MSM Internet Survey (EMIS); 797 in the London Gay Men's Sexual Health Survey; and 1234 in Scotland's Gay Men's Sexual Health Survey. Analyses compared men reporting at least one male sexual partner (past year) on similarly worded questions and multivariable analyses accounted for sociodemographic differences between the surveys. RESULTS: MSM in convenience surveys were younger and better educated than MSM in Natsal-3, and a larger proportion identified as gay (85%-95% vs 62%). Partner numbers were higher and same-sex anal sex more common in convenience surveys. Unprotected anal intercourse was more commonly reported in EMIS. Compared with Natsal-3, MSM in convenience surveys were more likely to report gonorrhoea diagnoses and HIV testing (both past year). Differences between the samples were reduced when restricting analysis to gay-identifying MSM. CONCLUSIONS: National probability surveys better reflect the population of MSM but are limited by their smaller samples of MSM. Convenience surveys recruit larger samples of MSM but tend to over-represent MSM identifying as gay and reporting more sexual risk behaviours. Because both sampling strategies have strengths and weaknesses, methods are needed to triangulate data from probability and convenience surveys. PMID- 26965871 TI - [Gentamicin pharmacokinetics in term newborn: ?Is it necessary to systematically monitor plasmatic levels?]. AB - BACKGROUND: Gentamicin is indicated as empiric treatment for neonatal sepsis. Plasmatic levels dosification of gentamicin is a common practice. The relationship between peak plasma concentration (Cmax) with minimum inhibitory concentration (MIC) (Cmax/MIC) is the parameter that best predicts treatment efficacy. AIM: To determine pharmacokinetics of gentamicin in term newborn infants. METHODS: Term newborn infants receiving gentamicin, without critical illness in which plasmatic levels of gentamicin was performed were included. Elimination clearance (Cl) elimination half-life (t1/2) and volume of distribution (Vd) were calculated. In each case the value of Cmax/MIC parameter was calculated, considering a MIC value of 1 MUg/mL for Escherichia coli. RESULTS: Thirteen newborns were included. The mean PK values were Cl: 0.26 mL/hour, Vd: 0.54 L/kg and t1/2: 6.8 h. Cmax/MIC was > 8 in 6 newborns. CONCLUSIONS: Pharmacokinetic parameters of gentamicin are predictable in term newborn infants. With gentamicin doses normally used Cmax/MIC values reached 8 in 6 newborns. It is necessary to review the usefulness of plasma drug monitoring and gentamicin dosage in this group of newborns. PMID- 26965870 TI - A fruitful alliance: the synergy between Atopobium vaginae and Gardnerella vaginalis in bacterial vaginosis-associated biofilm. AB - OBJECTIVES: Bacterial vaginosis (BV) is characterised by a change in the microbial composition of the vagina. The BV-associated organisms outnumber the health-associated Lactobacillus species and form a polymicrobial biofilm on the vaginal epithelium, possibly explaining the difficulties with antibiotic treatment. A better understanding of vaginal biofilm with emphasis on Atopobium vaginae and Gardnerella vaginalis may contribute to a better diagnosis and treatment of BV. METHODS: To this purpose, we evaluated the association between the presence of both bacteria by fluorescence in situ hybridisation (FISH) and BV by Nugent scoring in 463 vaginal slides of 120 participants participating in a clinical trial in Rwanda. RESULTS: A bacterial biofilm was detected in half of the samples using a universal bacterial probe. The biofilm contained A. vaginae in 54.1% and G. vaginalis in 82.0% of the samples. A. vaginae was accompanied by G. vaginalis in 99.5% of samples. The odds of having a Nugent score above 4 were increased for samples with dispersed G. vaginalis and/or A. vaginae present (OR 4.5; CI 2 to 10.3). The probability of having a high Nugent score was even higher when a combination of adherent G. vaginalis and dispersed A. vaginae was visualised (OR 75.6; CI 13.3 to 429.5) and highest when both bacteria were part of the biofilm (OR 119; CI 39.9 to 360.8). CONCLUSIONS: Our study, although not comprehensive at studying the polymicrobial biofilm in BV, provided a strong indication towards the importance of A. vaginae and the symbiosis of A. vaginae and G. vaginalis in this biofilm. TRIAL REGISTRATION NUMBER: NCT01796613. PMID- 26965872 TI - [Geographic distribution of Kawasaki disease throughout Chile]. AB - BACKGROUND: Incidence of Kawasaki disease (KD) in Chile is rising, however the distribution of cases throughout Chile is unknown. OBJECTIVE: To describe the epidemiology of KD in Chile between years 2001 and 2011, and study the geographic distribution of KD cases throughout the country. METHODS: We reviewed national hospital discharge databases for KD cases (ICD10 code M30.3) in children < 18 years. KD admission rates per 100,000 children < 5 years were calculated for every commune, health district and region, as a proxy of KD incidence. RESULTS: 1,404 KD cases were registered with a national KD incidence rate of 8.7. KD incidence rate increased significantly from 5.9 in 2001-2003 to 10.4 in 2009-2011 (p < 0.001). Regions IX (Araucania), Metropolitan and VI (O'Higgins) had the highest KD incidence (12.4, 11.1 and 10.5 respectively), and regions III (Atacama), II (Antofagasta) and XII (Magallanes), had the lowest incidence (0.8, 3.9 and 4, respectively). The Eastern Metropolitan Health District, the population with the highest socioeconomic status in Chile, had the highest KD incidence rate (19.8) and concentrated 23.9% of the country's hospital discharges for KD. CONCLUSION: KD incidence in Chile is heterogeneous, with concentration of caseloads in the central regions and especially in the Eastern Metropolitan Health District. Geographic variations of KD in Chile could be associated with real differences in incidence or with disparities in diagnostic opportunity, and access to specialists and tertiary healthcare centers. PMID- 26965873 TI - [Stethoscope or staphyloscope?: Potential vector in nosocomial infections]. AB - Healthcare-associated infections (HCAI) are a problem worldwide. In our country, the estimated incidence of HCAI is 70,000 per year. This results in an increase in the average length of hospital stay by 10 days per patient, an estimated annual cost of US $ 70 million and an overstay of 700 thousand bed days a year. For over 30 years stethoscopes have been considered as potential HCAI vectors, since pathogens like methicillin-resistant Staphylococcus aureus and vancomycin resistant Enterococcus strains adhere and colonize them. These organisms can be transmitted between patients if the instruments are not sanitized. Several studies conclude that disinfecting the stethoscope with isopropyl alcohol eliminates up to 99% of bacteria. Simple, economic measures such as implementation of guidelines for stethoscope disinfection are a clear opportunity for preventing infections. PMID- 26965875 TI - [Knowledge and attitudes of the parents in relation to the vaccination of their children]. AB - INTRODUCTION: Vaccination, a health action that has allowed to decrease mortality and to eradicate many diseases, may be at risk as a result of misinformation of parents and campaigns led by movements against vaccines. OBJECTIVE: To describe and analyze the knowledge and attitudes of parents of newborns and children of 2 and more months of age against the application of vaccines. METHOD: Exploratory study performed by application of a questionnaire to parents attending the UC CHRISTUS health network. RESULTS: Knowledge and attitude of parents of newborns is rated as very good. 32.5% think that the vaccines can cause damage or claim not to know and have wrong knowledge; vaccination is considered a measure in favor of their childrens' health, but manifest that scarce information does not allow to make right decisions and suspect economic interests behind them. The parents of older children have no precise knowledge of the existing calendar, nor of the name of vaccines. They think that the existing information does not allow them to be sure of the real benefits, with some of them even feeling forced to vaccinate their children. DISCUSSION: It is urgent to educate and answer questions about the importance and safety of vaccines and to perform studies at a national level. PMID- 26965874 TI - [Usefulness of conventional polymerase chain reaction for the detection of Mycoplasma hominis, Ureaplasma spp. and Trichomonas vaginalis in female outpatient's genital samples]. AB - INTRODUCTION: Trichomonas vaginalis, Mycoplasma hominis and Ureaplasma spp. are microorganisms responsible for genitourinary and pregnancy pathologies. Nucleic acid amplification methods have shown several advantages, but have not been widely studied for the detection of these microorganisms. AIM: To implement a conventional polymerase chain reaction (PCR) for the detection of the microorganisms and to compare its results versus the methods currently used at our laboratory. MATERIAL AND METHODS: 91 available samples were processed by PCR, culture (M. hominis y Ureaplasma spp.) and wet mount (T vaginalis). Results were compared and statistically analyzed by kappa agreement test. RESULTS: 85, 80 and 87 samples resulted in agreement for the detection of M. hominis, Ureaplasma spp. y T. vaginalis, respectively. For M. hominis and Ureaplasma spp., agreement was substantial, whereas for T. vaginalis it was moderate, however, for the latter, PCR detected more cases than wet mount. CONCLUSION: We recommend the implementation of PCR for detection of T. vaginalis whereas culture kit is still a useful method for the other microorganisms. PMID- 26965876 TI - [Characteristics associated with pre travel medical consultation in tourists visiting Cuzco, Peru]. AB - BACKGROUND: International tourism is increasing. Preventive Medicine remains important, especially the Pre-Travel Consultation (PTC). OBJECTIVE: To determinate, the characteristics of tourists associated with PTC in tourists at Cuzco, Peru. METHODS: A cross-sectional, analytical study, a secondary analysis of data from a database generated by survey of foreign tourists who visited Cuzco, in the waiting room of the airport was performed. The main variable was to have had a PTC at the tourist's country of residence, the area of residence was categorized according to health/risk of acquiring infectious diseases as traveler's diarrhea during their stay. These and other variables were analyzed and statistical association with generalized linear models were done. RESULTS: Of the 1827 tourists, 875 (48%) were men, with a median age of 33 years (range 18-88 years); 42% had a PTC. In the multivariate analysis, it was found that a PTC lower frequency was associated with male gender (aPR: 0.84; 95% CI: 0.75-0.94), and a higher frequency was associated with have born (aPR: 1.77; 95% CI: 1.39 2.27) and reside in an area of low risk of acquiring infectious diseases (aPR: 1.95; 95% CI: 1.26-3.00), adjusted for the history of a disease. CONCLUSIONS: Sex, region of birth and residence of tourists (as risk of acquiring infectious diseases) are associated with having a PTC. These findings may serve the health and government attending tourists who come to our country. PMID- 26965877 TI - [Modulation of apoptosis by cytomegalovirus, from the perspective of the central nervous system]. AB - Apoptosis is one of the most effective mechanisms against the spread of pathogens such as viruses. However, viruses have developed measures to counter the protective role of apoptosis in infected cells. Cytomegalovirus (CMV) represents the major cause of congenital infection worldwide triggering important damage in the developing central nervous system (CNS). Several mechanisms of apoptosis prevention during CMV infection have been described, among them, viral proteins and RNAs are capable of prevent apoptosis by the intrinsic and extrinsic pathways as well as the one mediated by stress in the endoplasmic reticulum. Nevertheless, the CMV pro-apoptotic effect remains enigmatic and it has been suggested as a bystander effect in non-infected cells. This review summarizes the mechanisms by which CMV modulates the signaling pathways involved in apoptosis. It also includes a brief description of the permissiveness of the CNS to CMV infection and the generated cell death after infection, which may relate to the observed damage during a congenital infection. PMID- 26965879 TI - [Neosartorya fischeri (Wehmer) Malloch & Cain]. PMID- 26965878 TI - [Is it time to vaccine pregnant woman against pertussis?]. AB - Pertussis may cause death in neonates and very young infants. In these ages pertussis vaccine has not been administered yet or infants haven't received enough doses of vaccine to protect them. Cocoon strategy have been implemented in several countries and has limited efficacy because of low coverage among households. In vaccinated pregnant women transplacental transfer of pertussis antibodies starts at 32-34 weeks of pregnancy. United Kingdom, The United States of America and afterward other countries in Europe and America have adopted this strategy. Recent British research about security and effectiveness of pertussis vaccination in pregnant women to reduce pertussis incidence and fatality cases in neonate and very young infants infant support this strategy despite the fact that controlled studies about the efficacy and security in mothers and neonates have not been published. Several studies still not published or in progress are trying to answer these two questions and to evaluate possible interference between transplacentaly transferred pertussis antibodies and infants immune response to routine vaccines. Recently WHO has recommended pertussis vaccination during pregnancy in countries where neonatal pertussis is a public health problem. Nowadays, Chilean experts discuss if pertussis vaccination of pregnant women must be adopted in our country. PMID- 26965880 TI - [The research-study of pneumococci transformation in the laboratory, and the rise of bacterial genetics and molecular biology]. AB - The virulence of pneumococci for mice depends on the production of a polysaccharide-capsule, which encloses the bacteria and protects it against phagocytosis. Capsulated pneumococci yield smooth, brilliant colonies designated S, but mutant strains arise frequently which have lost the capacity to sinthetise the capsule, are avirulent and rough designated R. F. Griffith discovery of bacterial "transformation" in 1928, is a landmark in the history of genetics, because hereditary determinants could be transferred from one bacteria to another, and laid the foundation for the subsequent recognition of deoxyribonucleic acid (DNA) as the hereditary material. A systematic analysis of the chemical nature of the "transforming principle", by O. T. Avery and his colleagues during next 10 years, culminated in a formidable weight of evidence that it possessed all properties of DNA. In 1953, J. D. Watson and F. H. C Crick by a brilliant synthesis, fitted the chemical X-ray diffraction data together into a symmetrical double-helix structure, which possessed the inherent properties of genetic material, and carries the information necessary to direct all biochemical-cellular activities and self-replications. This paper describes de early rise and development of bacterial genetics and molecular biology. PMID- 26965881 TI - [Acute generalized exanthematous pustulosis associated with Mycoplasma pneumoniae infection: a case report]. AB - Acute generalized exanthematous pustulosis is an uncommon skin eruption, characterized by fever and the rapid onset of disseminated, non-follicular, sterile pustules, over an erythematous skin background. It is usually classified as a severe cutaneous adverse drug reaction, whose most relevant triggers are antibiotics and anticonvulsants. However, viral and bacterial infections have also rarely been associated with this dermatosis. We report the case of a patient, who developed lesions of acute generalized exanthematous pustulosis as an extrapulmonary manifestation of Mycoplasma pneumoniae infection. PMID- 26965882 TI - [Endocarditis and arthritis caused by extended spectrum beta-lactamase-producing non-Typhi Salmonella]. AB - We present the case of a patient with endocarditis and arthritis caused by extended spectrum beta-lactamase producing non-Typhi Salmonella, with incomplete response (defined as persistence of Salmonella in joint fluid) to initial instituted treatment (trimethoprim-sulfamethoxazole) and posterior recovery with ertapenem. The disease was associated with implantable central venous catheter infection. Five percent of patients with non-Typhi Salmonella gastroenteritis develop bacteremia. Infective endocarditis and joint infection has been reported in 1,4% and less than 1% of cases, respectively. PMID- 26965883 TI - [Aspergillus fumigatus mediastinitis in an immunocompetent pediatric patient after heart surgery]. AB - Postsurgical aspergillosis occurs primarily in immunocompetent patients whose main predisposing factor is the loss of skin and mucosal integrity during surgery. Local infection tends to be destructive and refractory to treatment and relapses are common. It is important to consider aspergillosis in the differential diagnosis of slowly progressive and destructive surgical site infections with negative bacterial cultures. We present the case of a child who developed Aspergillus fumigatus mediastinitis months after heart surgery. PMID- 26965884 TI - [Fatal pneumococcal meningitis due to serotype 19 A: A preventable case?]. AB - Invasive pneumococcal disease (IPD) remains as an important cause of morbidity in the world and in our country, while in Chile the incidence has decreased after the incorporation of the 10 valent pneumococcal conjugate vaccine, in the routine infant inmunization schedule (EPI). One of the expected effects of the program after vaccination with 10-valent pneumococcal vaccine is the likely replacement serotype phenomenon that means the presence of ENI caused by serotypes not included in the vaccine. In this context, we present the case of a child with pneumococcal meningitis caused by serotype 19 A of fatal course. The occurrence of ENI in a later stage of pneumococcal vaccine incorporation in Chile reinforces the importance of active surveillance, in order to know in detail the impact of vaccination, distribution of circulating serotypes and their correlation with the different clinical disease and their severity. PMID- 26965885 TI - [Pasteurella canis hemorragic sepsis and empyema]. AB - We report the case of a 56-year-old female patient, with a three-day history of hematemesis, melena, abdominal wall hematoma and epistaxis associated with thrombocytopenia and anemia. Idiopathic thrombocytopenic purpura was diagnosed and she was treated with dexamethasone for four days. The patient developed acute respiratory failure with signs of systemic inflammatory response. Blood and pleural fluid cultures grew Pasteurella canis. This is the first case, to our knowledge, of P. canis empyema associated with hemorrhagic septicemia without epidemiological background and the third case of septicemia caused by P. canis reported in the literature. PMID- 26965886 TI - [Filmarray GI TM panel for detection of enteric pathogens in stool samples: preliminary experience]. AB - INTRODUCTION: Gastrointestinal infections remain a major public health problem worldwide and its etiologic diagnosis is one of the main challenges. In molecular diagnostic techniques recently developed, the Filmarray GI(r) panel allows detection of 23 pathogens (14 bacteria, virus 5 and 4 parasites) within an hour. OBJECTIVE: To describe the experience of Filmarray GI(r) panel in the Molecular Biology Laboratory of Clinica Las Condes. METHOD: A cross-sectional observational study that includes the results of 305 stool samples tested by Filmarray GI(r) panel was performed. RESULTS: Of the 305 tests requested 99 (32.5%) were negative and 206 were positive (67.5%). Of the positive samples, in 107 samples (51.9%) one pathogen was detected and in 99 samples (48.1%) more than one pathogen was found. CONCLUSIONS: Describe the experience of using FilmArray GI(r) panel in stool specimens, which highlights the large number of positive samples for a microorganism and co-detection of enteric pathogens. PMID- 26965887 TI - [Simplified protocol for Carba NP test for enhanced detection of carbapenemase producers directly from bacterial cultures]. PMID- 26965888 TI - [Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg?]. PMID- 26965889 TI - [Esparganosis cerebral]. PMID- 26965890 TI - [Chilean consensus of prevention, diagnosis and treatment of Clostridium difficile-associated diarrhea]. AB - BACKGROUND: Clostridium dijfficile-associated diarrhea (CDAD) has become very important due to the increase in its incidence, severity, recurrence and the associated economic burden. Having a national consensus guideline is essential to improve its management. OBJECTIVE: To build a multidisciplinary and evidence based consensus in prevention, diagnosis and treatment of CDAD. METHODS: We convened a panel of experts in the field of infectious diseases, gastroenterology, evidence-based medicine and consensus methodology. The panel conducted a structured review of published literature in CDAD evaluating evidence levels and recommendation degree according to the methodology proposed by the GRADE working-group. A modified three-round Delphi technique was used to reach a consensus among the experts. RESULTS: A group of 16 experts was established, 12 of them answered 18 clinically relevant questions. The levels of agreement achieved by the panel of 16 experts were 79% in the first round and 100% in the second and third round. The main consensus recommendations in prevention are: restricting the use of proton-pump inhibitors, primary prophylaxis with probiotics in antibiotics users, education of health personnel, isolation for patients hospitalized with CDAD, and cleaning the rooms exposed to C. difficile with products based in chlorine or hydrogen peroxide. In the diagnosis: use of biology molecular-based techniques is preferred and if not available, glutamate dehydrogenase-based algorithms may be recommended. With regard to treatment: the use of oral metronidazole in mild-moderate CDAD and oral vancomycin in severe CDAD are recommended. Treat the first recurrence with the same antibiotics according to severity. In the case of second and subsequent recurrences consider prolonged therapy with vancomycin, rifaximin or fecal microbiota transplant. CONCLUSION: The first Chilean consensus on prevention, diagnosis and treatment of CDAD is presented, which is a major step in improving national standards in the management of this disease. PMID- 26965891 TI - Matrix-assisted laser desorption ionization time-of-flight mass spectrometry for rapid identification of mold and yeast cultures of Penicillium marneffei. AB - BACKGROUND: Penicillium marneffei is the most important thermal dimorphic fungus causing systemic mycosis in HIV-infected and other immunocompromised patients in Southeast Asia. However, laboratory diagnosis of penicilliosis, which relies on microscopic morphology and mycelial-to-yeast conversion, is time-consuming and expertise-dependent, thus delaying diagnosis and treatment. Although matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) is useful for identification of various medically important fungi, its performance for identification of P. marneffei is less clear. RESULTS: We evaluated the performance of the Bruker MALDI-TOF MS system for identification of mold and yeast cultures of 59 clinical strains and the type strain of P. marneffei using the direct transfer method, with results compared to four phylogenetically closely related species, P. brevi-compactum, P. chrysogenum, Talaromyces aurantiacus and T. stipitatus. Using the Bruker original database combined with BDAL v4.0.0.1 and Filamentous Fungi Library 1.0, MALDI-TOF MS failed to identify the 60 P. marneffei strains grown in mold and yeast phase (identified as P. funiculosum and P. purpurogenum with scores <1.7 respectively). However, when the combined database was expanded with inclusion of spectra from 21 P. marneffei strains in mold and/or yeast phase, all the remaining 39 P. marneffei strains grown in mold or phase were correctly identified to the species level with score >2.0. The MS spectra of P. marneffei exhibited significant difference to those of P. brevi-compactum, P. chrysogenum, T. aurantiacus and T. stipitatus. However, MALDI-TOF MS failed to identify these four fungi to the species level using the combined database with or without spectra from P. marneffei. CONCLUSIONS: MALDI-TOF MS is useful for rapid identification of both yeast and mold cultures of P. marneffei and differentiation from related species. However, accurate identification to the species level requires database expansion using P. marneffei strains. PMID- 26965892 TI - Pig fatness in relation to FASN and INSIG2 genes polymorphism and their transcript level. AB - Fat content and fatty acid (FA) profile influence meat quality in pigs. These parameters are important for consumers due to their preferences for healthy, high quality meat. The aim of this study was searching for polymorphisms and transcript levels of two positional and functional candidate genes, FASN and INSIG2, encoding proteins which take part in lipid metabolism. The molecular findings were analyzed in relation to fatness traits. Pigs of four commercial breeds were included: Polish Landrace (PL), Polish Large White (PLW), Duroc and Pietrain. DNA sequencing, 5'RACE technique and real time PCR and association analysis were applied. In total, 20 polymorphisms in 5'-flanking, 5'UTR and 3'UTR regions of FASN (12 novel polymorphisms) and INSIG2 (seven novel ones and one known) genes were found. Association study with fatness traits (PL n = 225, PLW n = 179) revealed that four polymorphisms (c.-2908G>A, c.-2335C>T, c.*42_43insCCCCA and c.*264A>G) of the FASN gene were associated with back fat thickness in PL and PLW. Since the polymorphisms were identified in regulatory sequences of the both genes also their transcript levels were studied in PLW (n = 23), PL (n = 22), Pietrain (n = 17) and Duroc (n = 23). The INSIG2 transcript level was positively correlated with monounsaturated FA contents in the longissimus thoracis et lumborum muscle. Several correlations were also found between three polymorphisms (c.*264A>G and c.-2335C>T in FASN, and c.-5527C>G in INSIG2) and the FA content. Our study showed that the FASN gene is a promising marker for subcutaneous fat tissue accumulation, while INSIG2 is a promising marker for FA composition. PMID- 26965894 TI - The binding landscape of plasmepsin V and the implications for flap dynamics. AB - Plasmepsin V belongs to the plasmepsin family of aspartic proteases. PlmV is unique compared to other plasmepsins, as this membrane bound aspartic protease resides in the endoplasmic reticulum and is responsible for the cleavage of PEXEL tagged proteins destined for export outside of the host red blood cell. Plasmepsin V is highly conserved throughout the Plasmodium species, and is essential to the survival of the parasite. Recently, two potent inhibitors of Plmv have been identified, WEHI-916 and WEHI-842. Of these inhibitors, WEHI-842 has a higher binding affinity for P. vivax PlmV, and a crystal structure of PlmV in complex with WEHI-842 has recently been resolved (). The structure of PlmV is unique compared to other plasmepsins; it is stabilised internally by seven disulfide bonds, a NAP1 insert/fold is associated with the movement of the flap covering the active site and a highly conserved helix-turn-helix is situated towards the C-terminus. Flap motion and dynamics play an important role in enzyme selectivity and function. To better understand the impact of ligand binding on the flap dynamics, molecular dynamic simulations and post-dynamic analysis were employed in the present study on PlmV in complex with WEHI-842. Previously defined parameters, which accurately accounted for the opening and closing of the active site, were used to assess the conformational changes induced in the absence and presence of WEHI-842. From the simulations it can be seen that inhibitor binding significantly reduces the flexibility and mobility of not only the flap and flexible loop but areas outside of the active site. Ligand binding leads to the formation of a more stable compact structure. This being said, there is a possibility of reducing the flexibility even further with potentially more lethal effects on the plasmodium parasite. We believe that results presented herein would assist researchers in the discovery of potent PlmV inhibitors as potential antimalarial therapies. PMID- 26965893 TI - Adjunctive use of systematic retinal thickness map analysis to monitor disease activity in punctate inner choroidopathy. AB - A challenge in the management of 'white dot syndromes' is the lack of sensitive objective measures of disease activity. Retinal thickness maps from spectral domain optical coherence tomography (SD-OCT) inform treatment decisions in other retinal conditions such as age-related macular degeneration and diabetic maculopathy. In this report, we demonstrate their value in providing quantitative monitoring of a patient with punctate inner choroidopathy (PIC). Retinal thickness maps referenced against a baseline scan reliably detected focal areas of increased macular volume in active PIC lesions during symptomatic episodes, highlighting these as 'hot spots' that could be quantified, providing an objective basis for treatment decisions. PMID- 26965895 TI - Getting into hot water: sick guppies frequent warmer thermal conditions. AB - Ectotherms depend on the environmental temperature for thermoregulation and exploit thermal regimes that optimise physiological functioning. They may also frequent warmer conditions to up-regulate their immune response against parasite infection and/or impede parasite development. This adaptive response, known as 'behavioural fever', has been documented in various taxa including insects, reptiles and fish, but only in response to endoparasite infections. Here, a choice chamber experiment was used to investigate the thermal preferences of a tropical freshwater fish, the Trinidadian guppy (Poecilia reticulata), when infected with a common helminth ectoparasite Gyrodactylus turnbulli, in female only and mixed-sex shoals. The temperature tolerance of G. turnbulli was also investigated by monitoring parasite population trajectories on guppies maintained at a continuous 18, 24 or 32 degrees C. Regardless of shoal composition, infected fish frequented the 32 degrees C choice chamber more often than when uninfected, significantly increasing their mean temperature preference. Parasites maintained continuously at 32 degrees C decreased to extinction within 3 days, whereas mean parasite abundance increased on hosts incubated at 18 and 24 degrees C. We show for the first time that gyrodactylid-infected fish have a preference for warmer waters and speculate that sick fish exploit the upper thermal tolerances of their parasites to self medicate. PMID- 26965896 TI - The experience of gasless endoscopic-assisted thyroidectomy via the anterior chest approach for Graves' disease. AB - The aim of this study was to evaluate the safety, feasibility, effectiveness, and cosmesis of a gasless endoscopic-assisted thyroidectomy via the anterior chest in patients with Graves' disease. We retrospectively reviewed 38 patients with Graves' disease treated with thyroidectomy from November 2007 to June 2015. We analyzed clinical characteristics of patients, type of operation, operative indications, operative duration, length of postoperative hospital stay, and postoperative complications. The thyroidectomies were classified as total thyroidectomy (n = 12) or near-total thyroidectomy with a remnant of <1 g (n = 26). Surgical indications were recurrence after antithyroid drugs (ATDs) and unwillingness to undergo radioiodine therapy (n = 27), local compressive symptoms (n = 2), adverse drug reactions to ATDs (n = 5), and patient's preference (n = 4). Mean resection weight was 71.7 +/- 16.2 g (range 44-109 g), mean operative duration 87.7 +/- 17.3 min (range 66-136 min), intraoperative blood loss 70.6 +/- 11.3 mL (range 43-92 mL), and drainage was 42.0 +/- 8.5 mL (range 20-62 mL). Temporary postoperative recurrent laryngeal nerve palsy and temporary hypoparathyroidism occurred in 3 cases (7.89 %) each. Mean hospital stay was 2.5 +/- 0.3 days (range 2-4 days). There was no recurrence of hyperthyroidism over the follow-up period of for 68.1 +/- 5.6 months (range 6-89 months). All patients were satisfied with their cosmetic results. Gasless endoscopic-assisted thyroidectomy via the anterior chest approach for Graves' disease is a safe, feasible, and effective and provides an excellent cosmetic outcome procedure. It is a valid option in appropriately selected patients. PMID- 26965897 TI - Silent sinus syndrome an acquired condition and the essential role of otorhinolaryngologist consultation: a retrospective study. AB - The silent sinus syndrome (SSS) is a rare clinical entity characterized by painless spontaneous enophthalmos, hypoglobus, and facial deformities secondary to chronic maxillary sinus atelectasis. The aim of this study was to present an SSS diagnostic feature and evaluate the relationship between nasal septum deviation and maxillary sinus volume. A retrospective chart review of the clinical characteristics of 20 patients diagnosed with SSS between January 2013 and July 2014 were analyzed by the Department of Otorhinolaryngology of University Hospital Complex of Santiago de Compostela. 14 patients were females and six males. The mean age was 43 years (range 28-67 years). The right maxillary sinus was involved in 12 patients and the left maxillary sinus in eight patients. There was no statistical difference between gender and the presence of SSS. Maxillary sinus sizes were significantly smaller on the same side as the deviation (p < 0.01). 14 patients were treated with functional endoscopic sinus surgery (FESS) with maxillary antrostomy. We concluded that patients with SSS usually present with facial asymmetry, and the best approach to document and show all facial asymmetries for these patients are the frontal and craneo-caudal photographs. The present study demonstrates that, in adult patients, SSS generally presents a septal deviation to the affected maxillary sinus. We recommend performing a paranasal sinus CT scan when the patient has a deviated nasal septum, retraction of the malar eminence (evidenced from the viewpoint cranio-caudal facial) and hypoglobus. FESS performing postero-anterior uncinectomy and enlargement of the maxillary ostium is recommended to restore sinus pressure and prevent progression of the enophthalmos, hypoglobus and facial deformities. PMID- 26965899 TI - Comment on "Synergistic co-digestion of solid-organic-waste and municipal-sewage sludge: 1 plus 1 equals more than 2 in terms of biogas production and solids reduction" [Water Research 87, 416-423]. AB - Co-digestion of organic waste and sewage sludge enhances biogas production and reduces the mass of remaining solids. This phenomenon of enhanced organic matter decomposition by adding labile substrate is known from other habitats like soils and sediments where it is called priming effect. It is thus suggested to adopt the term priming effect also in environmental biotechnology, and in particular for biomethanisation of wastewater sludges by the addition of energy-rich co substrates. PMID- 26965898 TI - In vitro modeling of endothelial interaction with macrophages and pericytes demonstrates Notch signaling function in the vascular microenvironment. AB - Angiogenesis is regulated by complex interactions between endothelial cells and support cells of the vascular microenvironment, such as tissue myeloid cells and vascular mural cells. Multicellular interactions during angiogenesis are difficult to study in animals and challenging in a reductive setting. We incorporated stromal cells into an established bead-based capillary sprouting assay to develop assays that faithfully reproduce major steps of vessel sprouting and maturation. We observed that macrophages enhance angiogenesis, increasing the number and length of endothelial sprouts, a property we have dubbed "angiotrophism." We found that polarizing macrophages toward a pro-inflammatory profile further increased their angiotrophic stimulation of vessel sprouting, and this increase was dependent on macrophage Notch signaling. To study endothelial/pericyte interactions, we added vascular pericytes directly to the bead-bound endothelial monolayer. These pericytes formed close associations with the endothelial sprouts, causing increased sprout number and vessel caliber. We found that Jagged1 expression and Notch signaling are essential for the growth of both endothelial cells and pericytes and may function in their interaction. We observed that combining endothelial cells with both macrophages and pericytes in the same sprouting assay has multiplicative effects on sprouting. These results significantly improve bead-capillary sprouting assays and provide an enhanced method for modeling interactions between the endothelium and the vascular microenvironment. Achieving this in a reductive in vitro setting represents a significant step toward a better understanding of the cellular elements that contribute to the formation of mature vasculature. PMID- 26965900 TI - The use of cell phone and insight into its potential human health impacts. AB - The rapid evolution of mobile phone technology has raised public concern about its possible association with adverse health effects. Given the huge number of mobile phone users at present days, even simple adverse health effects could have major implications. This article reviews the present knowledge concerning the health effects stemming from the use of cellular phones by emphasizing adverse biological effects, epidemiological issues, and indirect health effects. A line of epidemiological evidence suggests that there is no concrete association between mobile phone radiation and cancer. The evidence regarding the occurrence of cancer due to exposure to the radio frequency energy of mobile phones is nonetheless conflicting. Consequently, long-term research in this field is necessary to account for the vital issue of this scientific research to the public in a meaningful way. PMID- 26965901 TI - Ancestral Exposure to Stress Generates New Behavioral Traits and a Functional Hemispheric Dominance Shift. AB - In a continuously stressful environment, the effects of recurrent prenatal stress (PS) accumulate across generations and generate new behavioral traits in the absence of genetic variation. Here, we investigated if PS or multigenerational PS across 4 generations differentially affect behavioral traits, laterality, and hemispheric dominance in male and female rats. Using skilled reaching and skilled walking tasks, 3 findings support the formation of new behavioral traits and shifted laterality by multigenerational stress. First, while PS in the F1 generation did not alter paw preference, multigenerational stress in the F4 generation shifted paw preference to favor left-handedness only in males. Second, multigenerational stress impaired skilled reaching and skilled walking movement abilities in males, while improving these abilities in females beyond the levels of controls. Third, the shift toward left-handedness in multigenerationally stressed males was accompanied by increased dendritic complexity and greater spine density in the right parietal cortex. Thus, cumulative multigenerational stress generates sexually dimorphic left-handedness and dominance shift toward the right hemisphere in males. These findings explain the origins of apparently heritable behavioral traits and handedness in the absence of DNA sequence variations while proposing epigenetic mechanisms. PMID- 26965902 TI - Post-Inhibitory Rebound Spikes in Rat Medial Entorhinal Layer II/III Principal Cells: In Vivo, In Vitro, and Computational Modeling Characterization. AB - Medial entorhinal cortex Layer-II stellate cells (mEC-LII-SCs) primarily interact via inhibitory interneurons. This suggests the presence of alternative mechanisms other than excitatory synaptic inputs for triggering action potentials (APs) in stellate cells during spatial navigation. Our intracellular recordings show that the hyperpolarization-activated cation current (Ih) allows post-inhibitory rebound spikes (PIRS) in mEC-LII-SCs. In vivo, strong inhibitory-post-synaptic potentials immediately preceded most APs shortening their delay and enhancing excitability. In vitro experiments showed that inhibition initiated spikes more effectively than excitation and that more dorsal mEC-LII-SCs produced faster and more synchronous spikes. In contrast, PIRS in Layer-II/III pyramidal cells were harder to evoke, voltage-independent, and slower in dorsal mEC. In computational simulations, mEC-LII-SCs morphology and Ih homeostatically regulated the dorso ventral differences in PIRS timing and most dendrites generated PIRS with a narrow range of stimulus amplitudes. These results suggest inhibitory inputs could mediate the emergence of grid cell firing in a neuronal network. PMID- 26965904 TI - Evidence of Stereoscopic Surface Disambiguation in the Responses of V1 Neurons. AB - For the important task of binocular depth perception from complex natural-image stimuli, the neurophysiological basis for disambiguating multiple matches between the eyes across similar features has remained a long-standing problem. Recurrent interactions among binocular disparity-tuned neurons in the primary visual cortex (V1) could play a role in stereoscopic computations by altering responses to favor the most likely depth interpretation for a given image pair. Psychophysical research has shown that binocular disparity stimuli displayed in 1 region of the visual field can be extrapolated into neighboring regions that contain ambiguous depth information. We tested whether neurons in macaque V1 interact in a similar manner and found that unambiguous binocular disparity stimuli displayed in the surrounding visual fields of disparity-selective V1 neurons indeed modified their responses when either bistable stereoscopic or uniform featureless stimuli were presented within their receptive field centers. The delayed timing of the response behavior compared with the timing of classical surround suppression and multiple control experiments suggests that these modulations are carried out by slower disparity-specific recurrent connections among V1 neurons. These results provide explicit evidence that the spatial interactions that are predicted by cooperative algorithms play an important role in solving the stereo correspondence problem. PMID- 26965903 TI - Area-Specific Features of Pyramidal Neurons-a Comparative Study in Mouse and Rhesus Monkey. AB - A principal challenge of systems neuroscience is to understand the unique characteristics of cortical neurons and circuits that enable area- and species specific sensory encoding, motor function, cognition, and behavior. To address this issue, we compared properties of layer 3 pyramidal neurons in 2 cortical areas that span a broad range of cortical function-primary sensory (V1), to cognitive (frontal)-in the mouse and the rhesus monkey. Hierarchical clustering and discriminant analyses of 15 physiological and 25 morphological variables revealed 2 fundamental principles. First, V1 and frontal neurons are remarkably similar with regard to nearly every property in the mouse, while the opposite is true in the monkey, with V1 and frontal neurons exhibiting significant differences in nearly every property assessed. Second, neurons within visual and frontal areas differ significantly between the mouse and the monkey. Neurons in mouse and monkey V1 are the same size, but differ in nearly every other way; mouse frontal cortical neurons are smaller than those in the monkey and also differ substantially with regard to most other properties. These findings have broad implications for understanding the differential contributions of heterogeneous neuronal types in construction of cortical microcircuitry in diverse brain areas and species. PMID- 26965905 TI - Pain-Related Suppression of Beta Oscillations Facilitates Voluntary Movement. AB - Increased beta oscillations over sensorimotor cortex are antikinetic. Motor- and pain-related processes separately suppress beta oscillations over sensorimotor cortex leading to the prediction that ongoing pain should facilitate movement. In the current study, we used a paradigm in which voluntary movements were executed during an ongoing pain-eliciting stimulus to test the hypothesis that a pain related suppression of beta oscillations would facilitate the initiation of a subsequent voluntary movement. Using kinematic measures, electromyography, and high-density electroencephalography, we demonstrate that ongoing pain leads to shorter reaction times without affecting the kinematics or accuracy of movement. Reaction time was positively correlated with beta power prior to movement in contralateral premotor areas. Our findings corroborate the view that beta-band oscillations are antikinetic and provide new evidence that pain primes the motor system for action. Our observations provide the first evidence that a pain related suppression of beta oscillations over contralateral premotor areas leads to shorter reaction times for voluntary movement. PMID- 26965908 TI - Raising a Red Flag on Dating Violence: Evaluation of a Low-Resource, College Based Bystander Behavior Intervention Program. AB - Encouraging bystanders to intervene safely and effectively in situations that could escalate to violence-known as bystander behavior programs-is a growing yet largely untested strategy to prevent dating violence. Using a quasi-experimental design, we evaluate a low-resource, low-intensity intervention aimed at preventing dating violence among college students. The integrated behavioral model (IBM) was used to guide the evaluation. We also assess which IBM variables were most strongly associated with bystander behaviors. Participants were drawn from two Virginia colleges that predominantly train females in the health profession sciences. The intervention group ( n = 329) participated in a university-wide bystander behavior intervention consisting of a 30-min presentation on dating violence at new-student orientation and a week-long "red flag" social marketing campaign on campus to raise awareness of dating violence. Controlling for changes at the comparison university, results showed an increase in bystander behaviors, such as encouraging a friend who may be in an abusive relationship to get help, after the intervention and adjusting for potential confounders (increase of 1.41 bystander behaviors, p = .04). However, no significant changes were found for bystander intentions, self-efficacy, social norms, or attitudes related to dating violence from pre- to post-intervention. Self-efficacy had a direct relationship with bystander behaviors. Results suggest that low-resource interventions have a modest effect on increasing bystander behaviors. However, higher resource interventions likely are needed for a larger impact, especially among students who already demonstrate strong baseline intentions to intervene and prevent dating violence. PMID- 26965906 TI - The Right Dorsal Premotor Mosaic: Organization, Functions, and Connectivity. AB - The right dorsal premotor cortex (PMd) of humans has been reported to be involved in a broad range of motor and cognitive functions. We explored the basis of this behavioral heterogeneity by performing a connectivity-based parcellation using meta-analytic approach applied to PMd coactivations. We compared our connectivity based parcellation results with parcellations obtained through resting-state functional connectivity and probabilistic diffusion tractography. Functional connectivity profiles and behavioral decoding of the resulting PMd subregions allowed characterizing their respective behavior profile. These procedures divided the right PMd into 5 distinct subregions that formed a cognitive-motor gradient along a rostro-caudal axis. In particular, we found 1) a rostral subregion functionally connected with prefrontal cortex, which likely supports high-level cognitive processes, such as working memory, 2) a central subregion showing a mixed behavioral profile and functional connectivity to parietal regions of the dorsal attention network, and 3) a caudal subregion closely integrated with the motor system. Additionally, we found 4) a dorsal subregion, preferentially related to hand movements and connected to both cognitive and motor regions, and 5) a ventral subregion, whose functional profile fits the concept of an eye movement-related field. In conclusion, right PMd may be considered as a functional mosaic formed by 5 subregions. PMID- 26965907 TI - Behavioral Resilience and Sensitivity to Locally Restricted Cortical Migration Deficits Induced by In Utero Knockdown of Disabled-1 in the Adult Rat. AB - Irregular neuronal migration plays a causal role in mental illnesses such as schizophrenia and autism, but the very nature of the migration deficits necessary to evoke adult behavioral changes is unknown. Here, we used in utero electroporation (IUE) in rats to induce a locally restricted, cortical migration deficit by knockdown of disabled-1 (Dab1), an intracellular converging point of the reelin pathway. After birth, selection of successfully electroporated rats by detection of in vivo bioluminescence of a simultaneously electroporated luciferase gene correlated to and was thus predictive to the number of electroporated neurons in postmortem histochemistry at 6 months of age. Rat neurons silenced for Dab1 did not migrate properly and their number surprisingly decreased after E22. Behavioral tests at adult ages (P180) revealed increased sensitivity to amphetamine as well as decreased habituation, but no deficits in memory tasks or motor functions. The data suggest that even subtle migration deficits involving only ten-thousands of cortical neurons during neurodevelopment can lead to lasting behavioral and neuronal changes into adulthood in some very specific behavioral domains. On the other hand, the lack of effects on various memory-related tasks may indicate resilience and plasticity of cognitive functions critical for survival under these specific conditions. PMID- 26965909 TI - Erratum to: Utility of ultrasound in noninvasive preoperative workup of neonatal brachial plexus palsy. PMID- 26965911 TI - In silico assessment of primers for eDNA studies using PrimerTree and application to characterize the biodiversity surrounding the Cuyahoga River. AB - Analysis of environmental DNA (eDNA) enables the detection of species of interest from water and soil samples, typically using species-specific PCR. Here, we describe a method to characterize the biodiversity of a given environment by amplifying eDNA using primer pairs targeting a wide range of taxa and high throughput sequencing for species identification. We tested this approach on 91 water samples of 40 mL collected along the Cuyahoga River (Ohio, USA). We amplified eDNA using 12 primer pairs targeting mammals, fish, amphibians, birds, bryophytes, arthropods, copepods, plants and several microorganism taxa and sequenced all PCR products simultaneously by high-throughput sequencing. Overall, we identified DNA sequences from 15 species of fish, 17 species of mammals, 8 species of birds, 15 species of arthropods, one turtle and one salamander. Interestingly, in addition to aquatic and semi-aquatic animals, we identified DNA from terrestrial species that live near the Cuyahoga River. We also identified DNA from one Asian carp species invasive to the Great Lakes but that had not been previously reported in the Cuyahoga River. Our study shows that analysis of eDNA extracted from small water samples using wide-range PCR amplification combined with high-throughput sequencing can provide a broad perspective on biological diversity. PMID- 26965910 TI - Sclerotic bone lesions at abdominal magnetic resonance imaging in children with tuberous sclerosis complex. AB - BACKGROUND: Sclerotic bone lesions are often seen on chest CT in adults with tuberous sclerosis complex. OBJECTIVE: To characterize bone lesions at abdominal MRI in children with tuberous sclerosis complex. MATERIALS AND METHODS: This retrospective review included 70 children with tuberous sclerosis complex who had undergone abdominal MRI for renal imaging. An additional longitudinal study was performed in 50 children who had had two or more MRI scans. Abdominal CT (eight children) and radiographs (three children) were reviewed and compared with MRI. RESULTS: A total of 173 sclerotic bone lesions were detected in 51/70 children (73%; 95% confidence interval: 0.61-0.82) chiefly affecting vertebral pedicles. New lesions appeared in 20 children and growth of previous sclerotic bone lesions was documented in 14 children. Sclerotic bone lesions were more frequent in girls and in children with more extensive renal involvement. CONCLUSION: Sclerotic bone lesions are commonly detected by abdominal MRI in children with tuberous sclerosis complex. They usually affect posterior vertebral elements and their number and size increase with age. As current recommendations for tuberous sclerosis complex surveillance include renal MR performed in childhood, recognition of these lesions is useful. PMID- 26965912 TI - The degree of urinary hypercortisolism is not correlated with the severity of cushing's syndrome. AB - Cushing syndrome (CS) is characterized by increased morbidity and mortality compared to the general population. However, there are patients who have more clinical aggressive forms than others. Aim of the study is to evaluate whether the degree of hypercortisolism, defined by the number of times urinary free cortisol (UFC) levels exceed the upper limit of the normal range (ULN), is related to the worsening of phenotypic features, as well as metabolic and cardiovascular parameters, in a cohort of CS patients. A cross-sectional study was conducted on 192 patients with active CS, consecutively presenting at the outpatients' clinic of the University Hospitals of Ancona, Naples, and Palermo. Patients were grouped into mild (UFC not exceeding twice the ULN), moderate (2-5 times the ULN), and severe (more than 5 times the ULN) hypercortisolism. Thirty seven patients (19.3 %) had mild, 115 (59.8 %) moderate, and 40 (20.9 %) severe hypercortisolism. A significant trend of increase among the three groups was demonstrated for 8-, 16-, and 24-h serum cortisol levels (p < 0.001) and serum cortisol after low dose of dexamethasone suppression test (p = 0.001). No significant trend of increase was found regarding phenotype and comorbidities. The degree of hypercortisolism by itself does not appear to be a sufficient parameter to express the severity of CS. Therefore, estimating the severity of CS according to biochemical parameters remains a challenge, while the clinical phenotype and the associated comorbidities might be more useful to assessing the severity of the CS. PMID- 26965913 TI - Development of an algorithm to predict serum vitamin D levels using a simple questionnaire based on sunlight exposure. AB - Sun exposure is the main determinant of vitamin D production. The aim of this study was to develop an algorithm to assess individual vitamin D status, independently of serum 25(OHD) measurement, using a simple questionnaire, mostly relying upon sunlight exposure, which might help select subjects requiring serum 25(OHD) measurement. Six hundred and twenty adult subjects living in a mountain village in Southern Italy, located at 954 m above the sea level and at a latitude of 40 degrees 50'11"76N, were asked to fill the questionnaire in two different periods of the year: August 2010 and March 2011. Seven predictors were considered: month of investigation, age, sex, BMI, average daily sunlight exposure, beach holidays in the past 12 months, and frequency of going outdoors. The statistical model assumes four classes of serum 25(OHD) concentrations: <=10, 10-19.9, 20-29.9, and >=30 ng/ml. The algorithm was developed using a two-step procedure. In Step 1, the linear regression equation was defined in 385 randomly selected subjects. In Step 2, the predictive ability of the regression model was tested in the remaining 235 subjects. Seasonality, daily sunlight exposure and beach holidays in the past 12 months accounted for 27.9, 13.5, and 6.4 % of the explained variance in predicting vitamin D status, respectively. The algorithm performed extremely well: 212 of 235 (90.2 %) subjects were assigned to the correct vitamin D status. In conclusion, our pilot study demonstrates that an algorithm to estimate the vitamin D status can be developed using a simple questionnaire based on sunlight exposure. PMID- 26965914 TI - Differential immunohistochemical expression profiles of perlecan-binding growth factors in epithelial dysplasia, carcinoma in situ, and squamous cell carcinoma of the oral mucosa. AB - The intercellular deposit of perlecan, a basement-membrane type heparan sulfate proteoglycan, is considered to function as a growth factor reservoir and is enhanced in oral epithelial dysplasia and carcinoma in situ (CIS). However, it remains unknown which types of growth factors function in these perlecan-enriched epithelial conditions. The aim of this study was to determine immunohistochemically which growth factors were associated with perlecan in normal oral epithelia and in different epithelial lesions from dysplasia and CIS to squamous cell carcinoma (SCC). Eighty-one surgical tissue specimens of oral SCC containing different precancerous stages, along with ten of normal mucosa, were examined by immunohistochemistry for growth factors. In normal epithelia, perlecan and growth factors were not definitely expressed. In epithelial dysplasia, VEGF, SHH, KGF, Flt-1, and Flk-1were localized in the lower half of rete ridges (in concordance with perlecan, 33-100%), in which Ki-67 positive cells were densely packed. In CIS, perlecan and those growth factors/receptors were more strongly expressed in the cell proliferating zone (63-100%). In SCC, perlecan and KGF disappeared from carcinoma cells but emerged in the stromal space (65-100%), while VEGF, SHH, and VEGF receptors remained positive in SCC cells (0%). Immunofluorescence showed that the four growth factors were shown to be produced by three oral SCC cell lines and that their signals were partially overlapped with perlecan signals. The results indicate that perlecan and its binding growth factors are differentially expressed and function in specific manners before (dysplasia/CIS) and after (SCC) invasion of dysplasia/carcinoma cells. PMID- 26965916 TI - 12 year follow up of enzyme-replacement therapy in two siblings with attenuated mucopolysaccharidosis I: the important role of early treatment. AB - BACKGROUND: Mucopolysaccharidosis type I is an autosomal recessive disorder caused by deficiency of alpha-L-iduronidase and characterized by a progressive course with multisystem involvement. Clinically, Mucopolysaccharidosis type I is classified into two forms: severe (Hurler syndrome), which presents in infancy and is characterized by rapid progressive neurological involvement and attenuated (Hurler/Scheie and Scheie syndromes), which presents with slower progression and absent to mild nervous system involvement. The specific treatment for attenuated Mucopolysaccharidosis type I consists of enzyme-replacement therapy with laronidase (human recombinant alpha-L-iduronidase, Aldurazyme). We present here the clinical and laboratory results in an 12-year-old patient affected by the attenuated form of Mucopolysaccharidosis type I treated by enzyme-replacement therapy from the age of 5 months, compared with his 17 year old affected sister, who started therapy at 5 years of age. CASE PRESENTATION: Clinical evaluation of these siblings shows that initiation of therapy prior of the onset of clinically detectable disease resulted in considerable improvement in outcome in the young sibling. After 12 years of enzyme-replacement therapy, facial appearance, linear growth rate, and liver and spleen volumes were normal; moreover, the degree of joint disease, vertebral, and cardiac valvular involvement were only minimal compared with those of his sister. CONCLUSION: This study demonstrates that early diagnosis and early initiation of enzyme-replacement therapy substantially modify the natural history of the attenuated form of Mucopolysaccharidosis type I. PMID- 26965915 TI - Romidepsin for the treatment of relapsed/refractory peripheral T cell lymphoma: prolonged stable disease provides clinical benefits for patients in the pivotal trial. AB - BACKGROUND: Achievement of durable responses in patients with relapsed/refractory peripheral T cell lymphoma (PTCL) is challenging with current therapies, and there are few data regarding the potential benefits of continuing treatment in patients with the best response of stable disease (SD). Histone deacetylase inhibitors are a novel class of drugs with activity in T cell malignancies. Romidepsin was approved by the US Food and Drug Administration for the treatment of relapsed/refractory PTCL based on a pivotal trial demonstrating an objective response rate of 25% (33/130), including 15% with confirmed/unconfirmed complete response and a median duration of response of 28 months. Our objective was to further study the clinical benefits of romidepsin in patients that had the best response of SD. METHODS: Patients with PTCL relapsed/refractory to >=1 prior therapy were treated with the approved dose of 14 mg/m(2) romidepsin on days 1, 8, and 15 of six 28-day cycles; patients with SD or response after cycle 6 were allowed to continue on study until progression. By protocol amendment, patients treated for >=12 cycles could receive maintenance dosing twice per cycle; after cycle 24, dosing could be further reduced to once per cycle in those who had received maintenance dosing for >=6 months. RESULTS: Of the 32 patients (25%) with the best response of SD, 22 had SD for >=90 days (SD90; cycle 4 response assessment). The longest SD was >3 years in a patient who received maintenance dosing of 14 mg/m(2) on days 1 and 15 beginning in cycle 13. Patients with the best response of SD90 or partial response achieved similar overall and progression-free survival. Prolonged dosing of romidepsin was well tolerated. CONCLUSIONS: We concluded that patients who achieve SD may consider continuing treatment because the clinical benefits of romidepsin may extend beyond objective responses. TRIAL REGISTRATION: NCT00426764. PMID- 26965917 TI - Transarterial embolization of hypervascular tumors using trisacryl gelatin microspheres (Embosphere): a prospective multicenter clinical trial in Japan. AB - PURPOSE: To evaluate the feasibility and safety of transarterial embolization (TAE) using trisacryl gelatin microspheres (TGMs) for hypervascular tumors. MATERIALS AND METHODS: This was a prospective multicenter clinical trial involving five institutions. TAE using TGMs was performed for hypervascular tumors in various locations. The primary endpoint was the technical success. The secondary endpoints included catheter accessibility, preservation of the feeding arteries, local tumor response based on the Response Evaluation Criteria in Cancer of the Liver (RECICL) and adverse events related to TAE based on the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Twenty three patients with liver tumors (n = 9), uterine fibroids (n = 3) and other tumors (n = 11) were enrolled. The technical success rate was 95.7 % (22 of 23 patients). Catheter accessibility and preservation of the feeding arteries were obtained in all 55 target vessels (100 %). Local tumor response rates were 46.7 and 55.8 % at 4 and 12 weeks, respectively. Eighteen (78.3 %) patients developed 53 symptomatic events including grade ?3 events: hypertension 21.7 %, pain 8.7 %, vomiting 4.3 % and anorexia 4.3 %, all related to postembolization syndromes. CONCLUSION: TAE using TGMs was technically feasible and safe for devascularization of hypervascular tumors. PMID- 26965918 TI - Rosenthal MC, Pisciotta AV, Komninos ZD, Goldenberg H, Dameshek W. The auto immune hemolytic anemia of malignant lymphocytic disease. Blood. 1955;10(3):197 227. PMID- 26965919 TI - Mutant calreticulin: when a chaperone becomes intrusive. AB - In this issue of Blood, Marty et al, Chachoua et al, and Araki et al report results of studies unraveling the molecular pathogenesis of CALR-mutant myeloproliferative neoplasms (MPNs). Together, these 3 reports define a novel disease paradigm, whereby a mutant chaperone constitutively activates receptor signaling through an abnormal interaction with the thrombopoietin (TPO) receptor (MPL). PMID- 26965920 TI - Prothrombotic lipoprotein patterns in stroke. AB - The importance of research focused on the final events of atherothrombosis cannot be overestimated. Platelet hyperreactivity leading to thrombosis is the main reason for mortality and morbidity in patients with cardiovascular disease and stroke, which together remain a leading cause of death in developed countries. In this issue of Blood, Shen et al1 establish another functional link between proatherogenic lipoproteins and platelet-mediated thrombus formation with a specific focus on stroke. In their model, the initiating component is L5, the electronegative subfraction of low-density lipoproteins (LDLs), which was shown to be substantially elevated in patients with ischemic stroke. L5 was shown to activate platelets via its receptor, lectin-like oxidized LDL receptor-1 (LOX-1), and alphabeta amyloid peptide, which together contribute to platelet hyperreactivity and stroke complications. PMID- 26965921 TI - Platelet VIII pack evades immune detection. AB - In this issue of Blood, Chen et al demonstrate that platelets expressing factor VIII (FVIII) shield FVIII from immune detection. In the naive FVIII null hemophilia A (HA) mouse, platelet-derived VIII prevents both a primary and memory anti-FVIII immune response, and together with total body irradiation, suppresses anti-FVIII immune response. PMID- 26965922 TI - Allogeneic CAR19 cells clear ALL. AB - Chimeric antigen receptor T cells redirected to CD19 (chimeric antigen receptor [CAR19]) show great promise in the clinic to treat refractory CD19+ acute lymphoblastic leukemia (ALL). However, production of autologous CAR19 cells from these patients can be difficult as patients frequently have T-cell dysfunction, due to disease and/or treatment-related effects. In this issue of Blood, Jacoby et al1 addressed this by exploring whether allogeneic donor CAR19 cells could be used to treat ALL-bearing mice using a minor mismatch bone marrow transplant model. PMID- 26965923 TI - Does father-child conflict mediate the association between fathers' postnatal depressive symptoms and children's adjustment problems at 7 years old? AB - BACKGROUND: Paternal depressive symptoms are associated with children's emotional and behavioural problems, which may be mediated by negative parenting. But there is no research on the influence of paternal depressive symptoms on children's emotion regulation and limited literature investigating fathers' parenting as a mediator in the pathway between paternal depressive symptoms and children's externalizing and internalizing problems. We aimed to investigate the mediating role of father-child conflict (at 3 years) in the association between postnatal paternal depressive symptoms (at 9 months) and children's emotional and behavioural problems (at 7 years) (aim 1). We also examined whether mediation pathways were more pronounced for boys or for girls (aim 2). METHOD: Secondary data analysis was conducted on the Millennium Cohort Study, when children were 9 months, 3 years and 7 years old (n = 3520). Main study variables were measured by self-report questionnaires. Fathers completed the Rutter Scale (depressive symptoms) and the Parent-Child Relationship Questionnaire (father-child conflict), while mothers completed the Strengths and Difficulties Questionnaire and the Social Behaviour Questionnaire (child emotional and behavioural problems, emotion regulation). We used structural equation modelling to estimate direct, indirect and total effects of paternal depressive symptoms on child outcomes, mediated by father-child conflict whilst adjusting for relevant covariates (maternal depressive symptoms, child temperament, marital conflict, and socio economic factors such as poverty indicator and fathers' education level). Multi group and interaction analysis was then conducted to determine the differential effect by gender of the association between paternal depressive symptoms on child outcomes via father-child conflict. RESULTS: Father-child conflict mediated the association between paternal depressive symptoms and emotion regulation problems [standardized indirect effect (SIE) 95% confidence interval (CI) -0.03 to -0.01, p < 0.001; standardized total effect (STE) 95% CI -0.05 to -0.01, p < 0.05] (aim 1). Father-child conflict mediated a larger proportion of the effect in boys (SIE 95% CI -0.03 to -0.01, p < 0.001; STE 95% CI -0.05 to 0.00, p = 0.063) than it did in girls (SIE 95% CI -0.02 to -0.01, p < 0.001; STE 95% CI -0.04 to 0.01, p = 0.216) (aim 2). CONCLUSIONS: Father-child conflict may mediate the association between postnatal paternal depressive symptoms and children's emotion regulation problems. Paternal depressive symptoms and father-child conflict resolution may be potential targets in preventative interventions. PMID- 26965924 TI - Enjoy your heart-beets. The role of dietary inorganic nitrate in cardiovascular health. PMID- 26965925 TI - Changes in flow-mediated dilatation in patients with femoropopliteal occlusion receiving conservative and invasive treatment. AB - BACKGROUND: Although the beneficial effect of revascularisation on reduction of local clinical ischaemic symptoms has been well established, its effect on systemic vascular endothelial function has not been fully explained yet. AIM: To determine changes in endothelium-dependent flow-mediated dilatation in patients with unilateral femoropopliteal occlusion receiving medical and surgical treatment. METHODS: Seventy-nine patients with symptomatic atherosclerotic ischaemia of lower extremities, treated with endovascular procedures, with femoropopliteal graft, or receiving conservative treatment (21-day controlled treadmill training) were enrolled in the study. Ankle brachial pressure index (ABPI), skin blood flow on the feet, and flow-mediated dilatation (FMD) of brachial arteries were measured in each patient at baseline and after 90 days of follow-up. RESULTS: The ABPI, vasomotion in the myogenic frequency band, and FMD increased significantly in surgical patients. In patients after femoropopliteal bypass a significant increase of vasomotion in the endothelial frequency band was also observed. In patients receiving conservative treatment (treadmill training), vasomotion in the myogenic frequency band increased whereas the FMD remained unchanged. CONCLUSIONS: It seems that surgical treatment may contribute to reducing the risk of cardiovascular complications in patients with advanced peripheral artery disease, as a result of improving the systemic vascular endothelial function. Limiting treatment to just treadmill training increases pain-free walking distance but does not improve systemic vascular endothelial function. PMID- 26965926 TI - Expression and partial biochemical characterization of a recombinant serine protease from Bothrops pauloensis snake venom. AB - Snake venom serine proteases (SVSPs) are enzymes capable of interfering at several points of hemostasis. Some serine proteases present thrombin-like activity, which makes them targets for the development of therapeutics agents in the treatment of many hemostatic disorders. In this study, a recombinant thrombin like serine protease, denominated rBpSP-II, was obtained from cDNA of the Bothrops pauloensis venom gland and was characterized enzymatically and biochemically. The enzyme rBpSP-II showed clotting activity on bovine plasma and proteolytic activity on fibrinogen, cleaving exclusively the Aalpha chain. The evaluation of rBpSP-II activity on chromogenic substrates demonstrated thrombin like activity of the enzyme due to its capacity to hydrolyze the thrombin substrate. These characteristics make rBpSP-II an attractive molecule for additional studies. Further research is needed to verify whether rBpSP-II can serve as a template for the synthesis of therapeutic agents to treat hemostatic disorders. PMID- 26965927 TI - Establishment of a cone photoreceptor transplantation platform based on a novel cone-GFP reporter mouse line. AB - We report successful retinal cone enrichment and transplantation using a novel cone-GFP reporter mouse line. Using the putative cone photoreceptor-enriched transcript Coiled-Coil Domain Containing 136 (Ccdc136) GFP-trapped allele, we monitored developmental reporter expression, facilitated the enrichment of cones, and evaluated transplanted GFP-labeled cones in wildtype and retinal degeneration mutant retinas. GFP reporter and endogenous Ccdc136 transcripts exhibit overlapping temporal and spatial expression patterns, both initiated in cone precursors of the embryonic retina and persisting to the adult stage in S and S/M opsin(+) cones as well as rod bipolar cells. The trapped allele does not affect cone function or survival in the adult mutant retina. When comparing the integration of GFP(+) embryonic cones and postnatal Nrl(-/-) 'cods' into retinas of adult wildtype and blind mice, both cell types integrated and exhibited a degree of morphological maturation that was dependent on donor age. These results demonstrate the amenability of the adult retina to cone transplantation using a novel transgenic resource that can advance therapeutic cone transplantation in models of age-related macular degeneration. PMID- 26965930 TI - Cancer Moonshot 2020: a new march of clinical and translational medicine. PMID- 26965929 TI - Localization of tamoxifen in human breast cancer tumors by MALDI mass spectrometry imaging. AB - BACKGROUND: Tamoxifen is used in endocrine treatment of breast cancer to inhibit estrogen signaling. A set of stratified ER-positive and ER-negative tumor sections was subjected to manual deposition of tamoxifen solution in order to investigate its spatial distribution upon exposure to interaction within thin tissue sections. METHODS: The localization of tamoxifen in tumor sections was assessed by matrix assisted laser deposition/ionization mass spectrometry imaging. The images of extracted ion maps were analyzed for comparison of signal intensity distributions. RESULTS: The precursor ion of tamoxifen (m/z 372.233) displayed heterogeneous signal intensity distributions in histological compartments of tumor tissue sections. The levels of tamoxifen in tumor cells compared with stroma were higher in ER-positive tissues, whereas ER-negative tissue sections showed lower signal intensities in tumor cells. CONCLUSIONS: The experimental model was successfully applied on frozen tumor samples allowing for differentiation between ER groups based on distribution of tamoxifen. PMID- 26965928 TI - The potential of deferasirox as a novel therapeutic modality in gastric cancer. AB - BACKGROUND: Iron is a crucial element for cell proliferation, growth, and metabolism. However, excess iron and altered iron metabolism are both associated with tumor initiation and tumor growth. Deferasirox is an oral iron chelator. Although some studies have indicated that deferasirox is a promising candidate for anti-cancer therapies, its effectiveness against gastric cancer has not yet been determined. This study was conducted to determine whether deferasirox exerts anti-tumor effects in gastric cancer cell lines and whether deferasirox and cisplatin act synergistically. METHODS: Four human gastric cancer cell lines (AGS, MKN-28, SNU-484, and SNU-638) were treated with various concentrations of deferasirox to determine the IC50 for each cell line. The effects of deferasirox on the cell cycle were evaluated by flow cytometry, and the effects of deferasirox on iron metabolism, the cell cycle, and apoptosis were assessed by Western blotting. To determine whether deferasirox enhances the effect of cisplatin, AGS cells were cultured in the presence and absence of cisplatin. RESULTS: Deferasirox inhibited the proliferation of all gastric cancer cell lines as assessed by MTT assays. Since the IC50 of deferasirox was the lowest (below 10 MUM) in AGS cells, subsequent experiments were performed in this line. Deferasirox upregulated transferrin receptor 1 expression and decreased ferroportin expression. Moreover, deferasirox induced G1 arrest; upregulated p21, p27, and p53 expression; and downregulated cyclin D1, cyclin B, and CDK4 expression. Furthermore, deferasirox induced apoptosis, upregulated N-myc downstream regulated gene 1 (NDRG1), and downregulated p-mTOR and c-myc expression. It was also found to act synergistically with cisplatin. CONCLUSIONS: Our results suggest that deferasirox may exert anti-tumor effects in the context of gastric cancer. Deferasirox affects a number of different pathways and molecules; for instance, deferasirox upregulates NDRG1 expression, inhibits the cell cycle, downregulates mTOR and c-myc expression, and induces apoptosis. In addition, deferasirox appears to potentiate the anti-cancer effects of cisplatin. Although the efficacy of deferasirox remains to be tested in future studies, the results presented here indicate that deferasirox is a promising novel anti-cancer therapeutic agent. PMID- 26965931 TI - Cardiovascular Magnetic Resonance Imaging for Structural and Valvular Heart Disease Interventions. AB - The field of percutaneous interventions for the treatment of structural and valvular heart diseases has been expanding rapidly in the last 5 years. Noninvasive cardiac imaging has been a critical part of the planning, procedural guidance, and follow-up of these procedures. Although echocardiography and cardiovascular computed tomography are the most commonly used and studied imaging techniques in this field today, advances in cardiovascular magnetic resonance imaging continue to provide important contributions in the comprehensive assessment and management of these patients. In this comprehensive paper, we will review and demonstrate how cardiovascular magnetic resonance imaging can be used to assist in diagnosis, treatment planning, and follow-up of patients who are being considered for and/or who have undergone interventions for structural and valvular heart diseases. PMID- 26965933 TI - Can't Bare It Any Longer. PMID- 26965932 TI - Is Bare-Metal Stent Implantation Still Justifiable in High Bleeding Risk Patients Undergoing Percutaneous Coronary Intervention?: A Pre-Specified Analysis From the ZEUS Trial. AB - OBJECTIVES: This study sought to investigate the ischemic and bleeding outcomes of patients fulfilling high bleeding risk (HBR) criteria who were randomized to zotarolimus-eluting Endeavor Sprint stent (E-ZES) or bare-metal stent (BMS) implantation followed by an abbreviated dual antiplatelet therapy (DAPT) duration for stable or unstable coronary artery disease. BACKGROUND: DES instead of BMS use remains controversial in HBR patients, in whom long-term DAPT poses safety concerns. METHODS: The ZEUS (Zotarolimus-Eluting Endeavor Sprint Stent in Uncertain DES Candidates) is a multinational, randomized single-blinded trial that randomized among others, in a stratified manner, 828 patients fulfilling pre defined clinical or biochemical HBR criteria-including advanced age, indication to oral anticoagulants or other pro-hemorrhagic medications, history of bleeding and known anemia-to receive E-ZES or BMS followed by a protocol-mandated 30-day DAPT regimen. The primary endpoint of the study was the 12-month major adverse cardiovascular event rate, consisting of death, myocardial infarction, or target vessel revascularization. RESULTS: Compared with patients without, those with 1 or more HBR criteria had worse outcomes, owing to higher ischemic and bleeding risks. Among HBR patients, major adverse cardiovascular events occurred in 22.6% of the E-ZES and 29% of the BMS patients (hazard ratio: 0.75; 95% confidence interval: 0.57 to 0.98; p = 0.033), driven by lower myocardial infarction (3.5% vs. 10.4%; p < 0.001) and target vessel revascularization (5.9% vs. 11.4%; p = 0.005) rates in the E-ZES arm. The composite of definite or probable stent thrombosis was significantly reduced in E-ZES recipients, whereas bleeding events did not differ between stent groups. CONCLUSIONS: Among HBR patients with stable or unstable coronary artery disease, E-ZES implantation provides superior efficacy and safety as compared with conventional BMS. (Zotarolimus-Eluting Endeavor Sprint Stent in Uncertain DES Candidates [ZEUS]; NCT01385319). PMID- 26965934 TI - The Dilemma of Selecting Patients for Bioresorbable Vascular Scaffolds in Our Daily Routine: Neither Too Much Nor Too Little! PMID- 26965935 TI - Long-Term Outcome of Alcohol Septal Ablation for Obstructive Hypertrophic Cardiomyopathy in the Young and the Elderly. AB - OBJECTIVES: The aim of this study was to compare outcomes of alcohol septal ablation (ASA) in young and elderly patients with obstructive hypertrophic cardiomyopathy (HCM). BACKGROUND: The American College of Cardiology Foundation/American Heart Association guidelines reserve ASA for elderly patients and patients with serious comorbidities. Information on long-term age-specific outcomes after ASA is scarce. METHODS: This cohort study included 217 HCM patients (age 54 +/- 12 years) who underwent ASA because of symptomatic left ventricular outflow tract obstruction. Patients were divided into young (age <=55 years) and elderly (age >55 years) groups and matched by age in a 1:1 fashion to nonobstructive HCM patients. RESULTS: Atrioventricular block following ASA was more common in elderly patients (43% vs. 21%; p = 0.001), resulting in pacemaker implantation in 13% and 5%, respectively (p = 0.06). Residual left ventricular outflow tract gradient, post-procedural New York Heart Association functional class, and necessity for additional septal reduction therapy was comparable between age groups. During a follow-up of 7.6 +/- 4.6 years, 54 patients died. The 5- and 10-year survival following ASA was 95% and 90% in patients age <=55 years and 93% and 82% in patients age >55 years, which was comparable to their control groups. The annual adverse arrhythmic event rate following ASA was 0.7%/year in young patients and 1.4%/year in elderly patients, which was comparable to their control groups. CONCLUSIONS: ASA is similarly effective for reduction of symptoms in young and elderly patients; however, younger patients have a lower risk of procedure-related atrioventricular conduction disturbances. The long-term mortality rate and risk of adverse arrhythmic events following ASA are low, both in young and elderly patients, and are comparable to age-matched nonobstructive HCM patients. PMID- 26965936 TI - Patient Selection for Alcohol Septal Ablation: Does Age Matter? PMID- 26965937 TI - Transcarotid Transcatheter Aortic Valve Replacement: Feasibility and Safety. AB - OBJECTIVES: The purpose of this study was to assess the feasibility and safety of transcarotid transcatheter aortic valve replacement (TAVR). BACKGROUND: Many candidates for TAVR have challenging vascular anatomy that precludes transfemoral access. Transcarotid arterial access may be an option for such patients. METHODS: The French Transcarotid TAVR Registry is a voluntary database that prospectively collected patient demographics, procedural characteristics, and clinical outcomes among patients undergoing transcarotid TAVR. Outcomes are reported according to the updated Valve Academic Research Consortium criteria. RESULTS: Among 96 patients undergoing transcarotid TAVR at 3 French sites (2009 to 2013), the mean age and Society of Thoracic Surgeons predicted risk of mortality were 79.4 +/- 9.2 years and 7.1 +/- 4.1%, respectively. Successful carotid artery access was achieved in all patients. The Medtronic CoreValve (Medtronic, Inc., Minneapolis, Minnesota) (n = 89; 92.7%) and Edwards SAPIEN valves (Edwards Lifesciences, Irvine, California) (n = 7; 7.3%) were used. Procedural complications included: valve embolization (3.1%), requirement for a second valve (3.1%), and tamponade (4.2%). There were no major bleeds or major vascular complications related to the access site. There were 3 (3.1%) procedural deaths and 6 (6.3%) deaths at 30 days. The 1-year mortality rate was 16.7%. There were 3 (3.1%) cases of Valve Academic Research Consortium-defined in-hospital stroke (n = 0) or transient ischemic attack (TIA) (n = 3). None of these patients achieved the criteria for stroke and none manifested new ischemic lesions on cerebral computed tomography or magnetic resonance imaging. At 30 days, a further 3 TIAs were observed, giving an overall stroke/TIA rate of 6.3%. CONCLUSIONS: Transcarotid vascular access for TAVR is feasible and is associated with encouraging short- and medium-term clinical outcomes. Prospective studies are required to ascertain if transcarotid TAVR yields equivalent results to other nonfemoral vascular access routes. PMID- 26965938 TI - How Many Roads Lead to Rome? PMID- 26965939 TI - Public Reporting of Mortality After PCI in Cardiac Arrest and Cardiogenic Shock: An Opinion From the Interventional Council and the Board of Governors of the American College of Cardiology. PMID- 26965940 TI - Novel 3-Dimensional Vessel and Scaffold Reconstruction Methodology for the Assessment of Strut-Level Wall Shear Stress After Deployment of Bioresorbable Vascular Scaffolds From the ABSORB III Imaging Substudy. PMID- 26965941 TI - A Remedy to the Paradoxical Increase of Femoral Access Complications: A Full Switch to the Radial Route for Cardiac Catheterization. PMID- 26965942 TI - Reply: A Remedy to the Paradoxical Increase of Femoral Access Complications: A Full Switch to the Radial Route for Cardiac Catheterization. PMID- 26965943 TI - DCB and Dissections: In Search of a Good Balance Between Enthusiasm and Scientific Strictness. PMID- 26965944 TI - Mathematics and Cardiovascular Interventions: Role of the Finite Element Modeling in Clinical Decision Making. PMID- 26965945 TI - Patient-Specific Computer Modeling to Predict Aortic Regurgitation After Transcatheter Aortic Valve Replacement. PMID- 26965946 TI - Response to a Differing Perspective: The Real Issues Related to Public Reporting Around Percutaneous Coronary Intervention. PMID- 26965947 TI - Chenodeoxycholic acid reduces feed intake and modulates the expression of hypothalamic neuropeptides and hepatic lipogenic genes in broiler chickens. AB - Bile acids have recently become an emerging research hot spot in mammals due to their roles as metabolic regulators and molecular signatures controlling whole body metabolic homeostasis. Such effects are still unknown in avian (non mammalian) species. We, therefore, undertook this study to determine the effect of chenodeoxycholic acid (CDCA) on growth performance and on the expression of hypothalamic neuropeptides and hepatic lipogenic genes in broiler chickens. Chickens fed with diet-containing 0.1% or 0.5% CDCA for two weeks exhibited a significant and a dose dependent reduction of feed intake and body weight compared to the control (standard diet). These changes were accompanied with a significant decrease in plasma glucose levels at d10 and d15 post-treatment. At molecular levels, CDCA treatment significantly up-regulated the expression of feeding-related hypothalamic neuropeptides (NPY, AgRP, ORX, CRH, Ghrl, and MC1R) and down-regulated the hypothalamic expression of SOCS3. CDCA treatment also decreased the mRNA levels of key hepatic lipogenic genes (FAS, ACCalpha, ME, ATPcl, and SCD-1) and their related transcription factors SREBP-1/2 and PPARalpha. In addition, CDCA reduced the hepatic expression of FXR and the adipokine, visfatin, and adiponectin genes compared to the control. Together, our data provide evidence that CDCA alters growth performances in broilers and modulates the expression of hypothalamic neuropeptides and hepatic lipogenic and adipocytokine genes. PMID- 26965948 TI - Effect of Letrozole, a selective aromatase inhibitor, on testicular activities in adult mice: Both in vivo and in vitro study. AB - The aim of present study was to evaluate the significance of estradiol (E2) in testicular activities and to find out the mechanism by which E2 regulates spermatogenesis in mice. To achieve this, both in vivo and in vitro effect of Letrozole on testis of adult mice was investigated. Letrozole-induced changes in testicular histology, cell proliferation (proliferating cell nuclear antigen; PCNA), cell survival (B cell lymphoma factor-2; Bcl2), apoptotic (cysteine aspartic proteases; caspase-3), steroidogenic (side chain cleavage; SCC, 3beta hydroxy steroid dehydrogenase enzyme; 3beta HSD, steroidogenic acute regulatory protein; StAR, aromatase and luteinizing hormone receptor; LH-R) markers, glucose level, and rate of expression of glucose transporter (GLUT) 8 and insulin receptor (IR) proteins in the testis along with changes in serum E2 and testosterone (T) levels were evaluated. Letrozole acts on testis and caused significant decrease in E2 synthesis, but increase in testosterone level and showed regressive changes in the spermatogenesis. Letrozole-induced changes in various testicular markers were compared with the changes in serum E2 level. The correlation study showed that decreased circulating E2 level may be responsible for decreased insulin receptor (IR) level in the testis. The decreased effects of insulin inhibited the glucose transport in the testis by suppressing GLUT8. The decreased level of testicular glucose may produce less lactate as energy support to developing germ cells consequently resulting in decreased cell proliferation and cell survival, but increased apoptosis. Thus, Letrozole suppresses spermatogenesis by reducing insulin sensitivity and glucose transport in the testis, but significantly increased testosterone level by promoting gonadotrophin release by decreased E2. PMID- 26965949 TI - Wound-healing ability is conserved during periods of chronic stress and costly life history events in a wild-caught bird. AB - Chronic stress, potentially through the actions of corticosterone, is thought to directly impair the function of immune cells. However, chronic stress may also have an indirect effect by influencing allocation of energy, ultimately shifting resources away from the immune system. If so, the effects of chronic stress on immune responses may be greater during energetically-costly life history events. To test whether the effects of chronic stress on immune responses differ during expensive life history events we measured wound healing rate in molting and non molting European starlings (Sturnus vulgaris) exposed to control or chronic stress conditions. To determine whether corticosterone correlated with wound healing rates before starting chronic stress, we measured baseline and stress induced corticosterone and two estimates of corticosterone release and regulation, negative feedback (using dexamethasone injection), and maximal capacity of the adrenals to secrete corticosterone (using adrenocorticotropin hormone [ACTH] injection). After 8days of exposure to chronic stress, we wounded both control and chronically stressed birds and monitored healing daily. We monitored nighttime heart rate, which strongly correlates with energy expenditure, and body mass throughout the study. Measures of corticosterone did not differ with molt status. Contrary to work on lizards and small mammals, all birds, regardless of stress or molt status, fully-healed wounds at similar rates. Although chronic stress did not influence healing rates, individuals with low baseline corticosterone or strong negative feedback had faster healing rates than individuals with high baseline corticosterone or weak negative feedback. In addition, wound healing does appear to be linked to energy expenditure and body mass. Non-molting, chronically stressed birds decreased nighttime heart rate during healing, but this pattern did not exist in molting birds. Additionally, birds of heavier body mass at the start of the experiment healed wounds more rapidly than lighter birds. Finally, chronically stressed birds lost body mass at the start of chronic stress, but after wounding all birds regardless of stress or molt status started gaining weight, which continued for the remainder of the study. Increased body mass could suggest compensatory feeding to offset energetic or resource demands (e.g., proteins) of wound healing. Although chronic stress did not inhibit healing, our data suggest that corticosterone may play an important role in mediating healing processes and that molt could influence energy saving tactics during periods of chronic stress. Although the experiment was designed to test allostasis, interpretation of data through reactive scope appears to be a better fit. PMID- 26965950 TI - In-vitro and in-vivo biological activity of recombinant yellowtail kingfish (Seriola lalandi) follicle stimulating hormone. AB - Biologically active recombinant yellowtail kingfish follicle stimulating hormone (rytkFsh) was produced in yeast Pichia pastoris and its biological activity was demonstrated by both in-vitro and in-vivo bioassays. Incubation of ovarian and testicular fragments with the recombinant hormone stimulated E2 and 11-KT secretion, respectively. In-vivo trial in immature female YTK resulted in a significant increase of plasma E2 levels and development of oocytes. In males at the early stages of puberty, advancement of spermatogenesis was observed, however plasma 11-KT levels were reduced when administered with rytkFsh. PMID- 26965952 TI - Prolactin is related to individual differences in parental behavior and reproductive success in a biparental passerine, the zebra finch (Taeniopygia guttata). AB - Variation in parental care can lead to important fitness consequences. The endocrine system is known to regulate physiological and behavioral reproductive traits that are important contributors to lifetime reproductive success. However, the hormonal basis of variation in avian parental care is still not well understood. Plasma prolactin (PRL) concentrations are generally high during post hatch parental care in birds, and may be a candidate mechanism that regulates variation in parental care and other reproductive success outcomes. Here we analyze the relationship between PRL, parental behavior (chick brooding and feeding) and reproductive success outcomes (clutch size, number of chicks hatched, and chick survival) for the first time in the zebra finch (Taeniopygia guttata). Birds were given cabergoline, a dopamine agonist traditionally used to lower prolactin in mammals, or vehicle in their food. Cabergoline had no effect on prolactin concentrations, but across both groups we found that PRL is positively correlated with parental behavior, number of chicks hatched, and chick survival, but not clutch size. Results from this study will inform hypotheses and predictions for future manipulation studies which test for a causal role for PRL in parental traits. PMID- 26965951 TI - Expression of stress hormones AVP and CRH in the hypothalamus of Mus musculus following water and food deprivation. AB - Neurohypophyseal hormone, arginine vasopressin (AVP), in addition to acting as antidiuretic hormone is also considered to be stress hormone like hypothalamic corticotropin-releasing hormone (CRH). Present study was designed to investigate the relative response of these stress hormones during water and food deprivation. In this study, male laboratory mice of Swiss strain were divided in 5 groups, control - provided water and food ad libitum, two experimental groups water deprived for 2 and 4days respectively (WD2 and WD4) and another two groups food deprived for 2 and 4days respectively (FD2 and FD4). Results indicate an increased expression of AVP mRNA as well as peptide in the hypothalamus of WD2 mice and the expression was further upregulated after 4days of water deprivation but the expression of CRH remained unchanged compare to their respective controls. On the other hand no change was observed in the expression of hypothalamic AVP mRNA while AVP peptide increased significantly in FD2 and FD4 mice compare to control. Further, the expression of CRH mRNA although increased in hypothalamus of both FD2 and FD4 mice, the immunofluorescent staining shows decreased expression of CRH in PVN of food deprived mice. Based on these findings it is concluded that since during osmotic stress only AVP expression is upregulated but during metabolic stress i.e. food deprivation transcription and translation of both the stress hormones are differentially regulated. Further, it is suggested that role of AVP and CRH may be stress specific. PMID- 26965953 TI - Effects of the fish spawning inducer ovaprim on vasotocin receptor gene expression in brain and ovary of the catfish Heteropneustes fossilis with a note on differential transcript expression in ovarian follicles. AB - Ovaprim (OVP), a commercial formulation of a salmon GnRH analogue and the dopamine receptor-2 blocker domperidone, is a successful spawning inducer for fish breeding. It induces a preovulatory surge in LH, which stimulates the synthesis of a maturation-inducing steroid (MIS, 17,20beta-dihydroxy-4-pregnen-3 one) that initiates germinal vesicle breakdown (GVBD) and ovulation. Coincidently, the OVP treatment also stimulates vasotocin (VT) secretion in the brain and ovary of the catfish Heteropneustes fossilis that also stimulates the synthesis of the MIS. VT mediates its effect through V1- and V2-type receptors. In the present study in the catfish, we report that OVP stimulates the expression of VT receptor genes v1a1, v1a2 and v2a in the brain and ovary. A single intraperitoneal administration of OVP (0.5MUL/g body weight) or incubation of post-vitellogenic ovarian follicles with 5MUL/mL OVP, for 0, 4, 8, 12, 16, and 24h stimulated ovulation and GVBD, respectively, in a time-dependent manner. The OVP treatment in vivo stimulated brain VT receptor transcript levels 4h onwards. The peak expression was noticed at 12h (v1a1), 8 and 12h (v1a2), and 8, 12 and 16h (v2a), coinciding with FOM and ovulation. The VT receptor genes are expressed in the ovarian follicles compartmentally; both v1a1 and v1a2 are expressed in the isolated follicular layer (theca and granulosa) but absent in denuded oocytes. V2a is expressed in the denuded oocytes and not in the follicular layer. The OVP injection stimulated the v1a1 and v1a2 expression from 4h onwards in both intact follicle and isolated follicular layer, the peak expression was observed at 16h. The v2a expression was up-regulated in both intact follicles and denuded oocytes at 4h (denuded oocytes) or 8h (intact follicle) onwards with the peak expression at 12h and 16h (denuded oocytes) or at 16h (intact follicles). Under in vitro conditions, the OVP incubations elicited similar pattern of changes with the peak stimulation at 16h for all the genes. In conclusion, the VT receptor genes are differentially expressed in the ovarian follicles and OVP induced periovulatory stimulation of the VT receptor genes, coinciding with FOM and ovulation. PMID- 26965954 TI - Prediction of Scylla olivacea (Crustacea; Brachyura) peptide hormones using publicly accessible transcriptome shotgun assembly (TSA) sequences. AB - The aquaculture of crabs from the genus Scylla is of increasing economic importance for many Southeast Asian countries. Expansion of Scylla farming has led to increased efforts to understand the physiology and behavior of these crabs, and as such, there are growing molecular resources for them. Here, publicly accessible Scylla olivacea transcriptomic data were mined for putative peptide-encoding transcripts; the proteins deduced from the identified sequences were then used to predict the structures of mature peptide hormones. Forty-nine pre/preprohormone-encoding transcripts were identified, allowing for the prediction of 187 distinct mature peptides. The identified peptides included isoforms of adipokinetic hormone-corazonin-like peptide, allatostatin A, allatostatin B, allatostatin C, bursicon beta, CCHamide, corazonin, crustacean cardioactive peptide, crustacean hyperglycemic hormone/molt-inhibiting hormone, diuretic hormone 31, eclosion hormone, FMRFamide-like peptide, HIGSLYRamide, insulin-like peptide, intocin, leucokinin, myosuppressin, neuroparsin, neuropeptide F, orcokinin, pigment dispersing hormone, pyrokinin, red pigment concentrating hormone, RYamide, short neuropeptide F, SIFamide and tachykinin related peptide, all well-known neuropeptide families. Surprisingly, the tissue used to generate the transcriptome mined here is reported to be testis. Whether or not the testis samples had neural contamination is unknown. However, if the peptides are truly produced by this reproductive organ, it could have far reaching consequences for the study of crustacean endocrinology, particularly in the area of reproductive control. Regardless, this peptidome is the largest thus far predicted for any brachyuran (true crab) species, and will serve as a foundation for future studies of peptidergic control in members of the commercially important genus Scylla. PMID- 26965955 TI - Immune-endocrine crosstalk during pregnancy. AB - The success of pregnancy depends mostly on a synchronized immune-endocrine crosstalk at the maternal-fetal interface. Hormones are important in terms of maintaining the suitable environment and sufficient nutrition for the developing fetus. They also play a major role during the process of parturition and lactation. Maternal immunomodulation is important for the tolerance of semiallogeneic fetus. This is achieved in concert with a variety of endocrine stimulation. Estrogen, progesterone, and Human Chorionic Gonadotropin play a major role in immune modulation during pregnancy. Hormones modulate B cells, dendritic cells, uterine natural killer cells, macrophages, neutrophils to adopt fetal friendly immune phenotypes. Recently the use of hormones in assisted reproductive technology has been found to improve the pregnancy outcome. The present review focuses on the pregnancy-related hormones, their role in immunomodulation for successful pregnancy outcome. This also shed light on the immune-endocrine crosstalk at maternal-fetal interface during pregnancy. PMID- 26965957 TI - Development of edge-activated liposomes for siRNA delivery to human basal epidermis for melanoma therapy. AB - Delivery of macromolecules such as siRNA into cells that reside in the basal epidermis of the skin is a major challenge due to the transport barriers that need to be overcome. siRNAs have potential therapeutic applications in various dermatological diseases such as psoriasis, atopic dermatitis, and cancer. Unfortunately, a low permeability of siRNA through the stratum corneum and epidermis has significantly limited its use for topical application. The objective of this study was to develop a topical siRNA delivery system that can permeate through the stratum corneum and viable epidermis and efficiently deposit therapeutic levels of siRNA to the basal epidermis/upper dermis where melanoma cells reside. To achieve this objective, a series of liposome compositions that contained various concentrations of edge activator in their structures were prepared and then complexed with siRNA at different ratios to generate a small library of liposome-siRNA complexes (lipoplexes) with different physicochemical properties. In this study we used melanoma as a disease model. Through use of quantitative imaging analysis, we identified the necessary design parameters for effective permeation of lipoplexes through the skin layers and deposition at the upper dermis. The ability of the formulated lipoplexes to internalize into melanoma cells, knockdown the expression of the BRAF protein and induce cell death in melanoma cells was studied by fluorescent microscopy, in-cell immunofluorescence assay and WST-1 cell proliferation assay. By providing direct quantitative and qualitative microscopy evidence, the results of this study demonstrate for the first time that the passive delivery of an edge-activated liposomal formulation can effectively carry siRNA through the stratum corneum and deposit it at the lower epidermis/upper dermis. PMID- 26965958 TI - Statistical analysis of differences in turnover times among operating theatres. PMID- 26965956 TI - Seeing is believing, PLGA microsphere degradation revealed in PLGA microsphere/PVA hydrogel composites. AB - The aim of this study was to understand the polymer degradation and drug release mechanism from PLGA microspheres embedded in a PVA hydrogel. Two types of microspheres were prepared with different molecular weight PLGA polymers (approximately 25 and 7 kDa) to achieve different drug release profiles, with a 9 day lag phase and without a lag phase, respectively. The kinetics of water uptake into the microspheres coincided with the drug release profiles for both formulations. For the 25 kDa microspheres, minimal water uptake was observed in the early part of the lag phase followed by substantial water uptake at the later stages and in the drug release phase. For the 7 kDa microspheres, water uptake occurred simultaneously with drug release. Water uptake was approximately 2-3 times that of the initial microsphere weight for both formulations. The internal structure of the PLGA microspheres was evaluated using low temperature scanning electron microscopy (cryo-SEM). Burst drug release occurred followed by pore forming from the exterior to the core of both microspheres. A well-defined hydrogel/microsphere interface was observed. For the 25 kDa microspheres, internal pore formation and swelling occurred before the second drug release phase. The surface layer of the microspheres remained intact whereas swelling, and degradation of the core continued throughout the drug release period. In addition, microsphere swelling reduced glucose transport through the coatings in PBS media and this was considered to be a as a consequence of the increased thickness of the coatings. The combination of the swelling and microdialysis results provides a fresh understanding on the competing processes affecting molecular transport of bioanalytes (i.e. glucose) through these composite coatings during prolonged exposure in PBS. PMID- 26965959 TI - Response to: 'Statistical analysis of differences in turnover times among operating theatres' by Dexter. PMID- 26965960 TI - An Intestinal Inflammasome - The ILC3-Cytokine Tango. AB - The inflammasome is a key regulator of immune responses in the gut. Two recent studies in the journal Cell demonstrate that epithelial inflammasome activation and IL-18 secretion can control intestinal homeostasis or induce autoinflammation. ILC3 cells are triggered to secrete IL-22, regulating IL-18 expression in epithelial cells, in turn modulating homeostasis and inflammation. PMID- 26965961 TI - 'Mitotherapy' for Heart Failure. AB - Abnormalities in mitochondrial dynamics along with those for the molecular mediators involved are presently being viewed with increased interest in the field of cardiovascular disease. Recent research highlights OPA1, a dynamin-like GTPase mediating mitochondrial fusion, as well as the 'mitoproteases' OMA1 and YME1L, as potential therapeutic targets against heart failure. PMID- 26965962 TI - Zika virus infection-the next wave after dengue? AB - Zika virus was initially discovered in east Africa about 70 years ago and remained a neglected arboviral disease in Africa and Southeast Asia. The virus first came into the limelight in 2007 when it caused an outbreak in Micronesia. In the ensuing decade, it spread widely in other Pacific islands, after which its incursion into Brazil in 2015 led to a widespread epidemic in Latin America. In most infected patients the disease is relatively benign. Serious complications include Guillain-Barre syndrome and congenital infection which may lead to microcephaly and maculopathy. Aedes mosquitoes are the main vectors, in particular, Ae. aegypti. Ae. albopictus is another potential vector. Since the competent mosquito vectors are highly prevalent in most tropical and subtropical countries, introduction of the virus to these areas could readily result in endemic transmission of the disease. The priorities of control include reinforcing education of travellers to and residents of endemic areas, preventing further local transmission by vectors, and an integrated vector management programme. The container habitats of Ae. aegypti and Ae. albopictus means engagement of the community and citizens is of utmost importance to the success of vector control. PMID- 26965963 TI - The Problem of Treating Unexplained Chronic Cough. PMID- 26965964 TI - Use of Parenteral Prostanoids: Important Insights for CHEST Physicians. PMID- 26965965 TI - Don't Wait for COPD to Treat Tobacco Use. PMID- 26965966 TI - Giants in Chest Medicine: Leonardo M. Fabbri, MD. PMID- 26965967 TI - POINT: Does the United States Need More Intensivist Physicians? Yes. PMID- 26965968 TI - COUNTERPOINT: Does the United States Need More Intensivist Physicians? No. PMID- 26965969 TI - Rebuttal From Dr Davidson. PMID- 26965970 TI - Rebuttal From Dr Rubenfeld. PMID- 26965975 TI - A Cancer That Went Up in Smoke: Pulmonary Reaction to e-Cigarettes Imitating Metastatic Cancer. AB - e-Cigarettes have gained worldwide popularity as a substitute for smoking, but concern has been raised regarding the long-term effects associated with their use. We report a case of a 45-year-old female consumer of e-cigarettes who presented with 4 months of abdominal pain and fever. Initial imaging discovered multiple pulmonary nodules and liver lesions suspicious of widespread metastases; however, an extensive evaluation found no evidence of malignancy. Results of a lung biopsy revealed an area with multinucleated giant cells suggestive of a foreign body reaction to a lipophilic material. Upon cessation of e-cigarette use (known as vaping), the lung nodules disappeared, and the liver lesions regressed. Our case report suggests that vaping can induce an inflammatory reaction mimicking metastatic cancer. PMID- 26965976 TI - Severe Pulmonary Arterial Hypertension in Patients Treated for Hepatitis C With Sofosbuvir. AB - Development of direct-acting antiviral agents against hepatitis C virus (HCV) has changed the management of chronic HCV infection. We report three cases of newly diagnosed or exacerbated pulmonary arterial hypertension (PAH) in patients treated with sofosbuvir. All patients had PAH-associated comorbidities (HIV coinfection in two, portal hypertension in one) and one was already being treated for PAH. At admission, all patients presented with syncope, World Health Organization functional class IV, right-sided heart failure, and extremely severe hemodynamic parameters. After specific PAH therapy, the clinical and hemodynamic properties for all patients were improved. Severity and acuteness of PAH, as well as chronology, could suggest a causal link between HCV treatment and PAH onset. We hypothesize that suppression of HCV replication promotes a decrease in vasodilatory inflammatory mediators leading to worsening of underlying PAH. The current report suggests that sofosbuvir-based therapy may be associated with severe PAH. PMID- 26965977 TI - A 33-Year-Old Man With a History of Intravenous Drug Use and Fevers. PMID- 26965978 TI - A 38-Year-Old Woman With an Osteolytic Rib Lesion. AB - A 38-year-old black woman with a medical history significant for hypertension and depression presented to the emergency department with a 2-week history of lower back pain. This visit was her second in 1 week with the same symptoms, after attaining minimal pain relief with cyclobenzaprine. PMID- 26965979 TI - A 45-Year-Old Woman With 3 Weeks of Cough and Night Sweats. AB - A 45-year-old woman who received a renal transplant 7 years prior presented with a 3-week history of low-grade fever, night sweats, and a dry cough with scant sputum production. Additionally, she reported generalized weakness and increased fatigability. She denied hemoptysis or weight loss, and there had been no change in medication or foreign travel. She had no history of latent tuberculosis or sick contacts. She had recently relocated to Baton Rouge, Louisiana. She was sexually active with her boyfriend who worked as a prison guard. She also reported that she was briefly incarcerated 7 years ago shortly after her renal transplantation. Her immunosuppression consisted of tacrolimus, mycophenolate, and prednisone. PMID- 26965980 TI - A 26-Year-Old Woman With a Small Right Lung and a Right-Sided Heart. AB - A 26-year-old woman presented with abnormal findings on a chest radiograph. She had no significant history other than a fever 4 months prior to presentation that had resolved without a definite cause identified. She denied cough, shortness of breath, chest pain, history of smoking, environmental exposures, or prior pregnancies. She remained physically active. PMID- 26965981 TI - Antibodies to infliximab in Remicade-treated rheumatic patients show identical reactivity towards biosimilars. AB - OBJECTIVES: The aim of this study was to determine whether antibodies to infliximab (IFX) in Remicade-treated patients cross-react with the biosimilar CT P13. METHODS: 250 consecutive patients with rheumatic diseases under Remicade and 77 controls were retrospectively selected for the study. Anti-IFX antibodies at drug through levels were measured in parallel with three different bridging ELISA assays: Promonitor-ANTI-IFX kit, which uses Remicade to detect antibodies, and two more assays that use either Inflectra or Remsima with the same format. Correlation and association between each assay was studied. RESULTS: 50.4% of patients were tested positive with Promonitor-ANTI-IFX. All were antibodies to IFX (ATI)-positive when either Inflectra or Remsima assays were used. In all comparisons positive and negative percentage agreements were 100%, and correlation coefficients were >=0.995. No differences between rheumatoid arthritis and spondyloarthritis, or between concomitant immunosuppressives, were observed. CONCLUSIONS: Anti-IFX antibodies of Remicade-treated patients cross react with either Inflectra or Remsima. Although additional epitopes may be present in the biosimilar, results suggest that epitopes influencing the immune response to IFX are also present in the biosimilar. Antibody-positive patients treated with Remicade should not be switched to the biosimilar, since antibodies will interact with the new drug and potentially lead to loss of response. This finding supports the utility for therapeutic drug monitoring before a switching strategy is considered. PMID- 26965982 TI - Should 2016 Criteria for Macrophage Activation Syndrome be applied in children with Kawasaki disease, as well as with systemic-onset juvenile idiopathic arthritis? PMID- 26965983 TI - Low dose of fish oil in osteoarthritis: low effect? PMID- 26965984 TI - Three routes to crypsis: Stasis, convergence, and parallelism in the Mastigias species complex (Scyphozoa, Rhizostomeae). AB - Evolutionary inference can be complicated by morphological crypsis, particularly in open marine systems that may rapidly dissipate signals of evolutionary processes. These complications may be alleviated by studying systems with simpler histories and clearer boundaries, such as marine lakes-small bodies of seawater entirely surrounded by land. As an example, we consider the jellyfish Mastigias spp. which occurs in two ecotypes, one in marine lakes and one in coastal oceanic habitats, throughout the Indo-West Pacific (IWP). We tested three evolutionary hypotheses to explain the current distribution of the ecotypes: (H1) the ecotypes originated from an ancient divergence; (H2) the lake ecotype was derived recently from the ocean ecotype during a single divergence event; and (H3) the lake ecotype was derived from multiple, recent, independent, divergences. We collected specimens from 21 locations throughout the IWP, reconstructed multilocus phylogenetic and intraspecific relationships, and measured variation in up to 40 morphological characters. The species tree reveals three reciprocally monophyletic regional clades, two of which contain ocean and lake ecotypes, suggesting repeated, independent evolution of coastal ancestors into marine lake ecotypes, consistent with H3; hypothesis testing and an intraspecific haplotype network analysis of samples from Palau reaffirms this result. Phylogenetic character mapping strongly correlates morphology to environment rather than lineage (r=0.7512, p<0.00001). Considering also the deeper relationships among regional clades, morphological similarity in Mastigias spp. clearly results from three separate patterns of evolution: morphological stasis in ocean medusae, convergence of lake morphology across distinct species and parallelism between lake morphologies within species. That three evolutionary routes each result in crypsis illustrates the challenges of interpreting evolutionary processes from patterns of biogeography and diversity in the seas. Identifying cryptic species is only the first step in understanding these processes; an equally important second step is exploring and understanding the processes and patterns that create crypsis. PMID- 26965985 TI - Glycyrrhizin Protects against Acetaminophen-Induced Acute Liver Injury via Alleviating Tumor Necrosis Factor alpha-Mediated Apoptosis. AB - Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in Western countries. Glycyrrhizin (GL), a potent hepatoprotective constituent extracted from the traditional Chinese medicine liquorice, has potential clinical use in treating APAP-induced liver failure. The present study determined the hepatoprotective effects and underlying mechanisms of action of GL and its active metabolite glycyrrhetinic acid (GA). Various administration routes and pharmacokinetics-pharmacodynamics analyses were used to differentiate the effects of GL and GA on APAP toxicity in mice. Mice deficient in cytochrome P450 2E1 enzyme (CYP2E1) or receptor interacting protein 3 (RIPK3) and their relative wild-type littermates were subjected to histologic and biochemical analyses to determine the potential mechanisms. Hepatocyte death mediated by tumor necrosis factoralpha(TNFalpha)/caspase was analyzed by use of human liver-derived LO2 cells. The pharmacokinetics-pharmacodynamics analysis using various administration routes revealed that GL but not GA potently attenuated APAP induced liver injury. The protective effect of GL was found only with intraperitoneal and intravenous administration and not with gastric administration. CYP2E1-mediated metabolic activation and RIPK3-mediated necroptosis were unrelated to GL's protective effect. However, GL inhibited hepatocyte apoptosis via interference with TNFalpha-induced apoptotic hepatocyte death. These results demonstrate that GL rapidly attenuates APAP-induced liver injury by directly inhibiting TNFalpha-induced hepatocyte apoptosis. The protective effect against APAP-induced liver toxicity by GL in mice suggests the therapeutic potential of GL for the treatment of APAP overdose. PMID- 26965986 TI - CYP2D6 Is Inducible by Endogenous and Exogenous Corticosteroids. AB - Although cytochrome P450 (CYP) 2D6 has been widely considered to be noninducible on the basis of human hepatocyte studies, in vivo data suggests that it is inducible by endo- and xenobiotics. Therefore, we investigated if the experimental conditions routinely used in human hepatocyte studies may be a confounding factor in the lack of in vitro induction of CYP2D6. Sandwich cultured human hepatocytes (SCHH) were preincubated with or without dexamethasone (100 nM) for 72 hours before incubation with 1MUM endogenous (cortisol or corticosterone) or exogenous (dexamethasone or prednisolone) corticosteroids. At 72 hours, CYP2D6 mRNA, protein, and activity were quantified by real-time quantitative polymerase chain reaction, quantitative proteomics, and formation of dextrorphan from dextromethorphan, respectively. In the absence of supplemental dexamethasone, CYP2D6 activity, mRNA, and protein were significantly and robustly (>10-fold) induced by all four corticosteroids. However, this CYP2D6 induction was abolished in cells preincubated with supplemental dexamethasone. These data show, for the first time, that CYP2D6 is inducible in vitro but the routine presence of 100 nM dexamethasone in the culture medium masks this induction. Our cortisol data are in agreement with the clinical observation that CYP2D6 is inducible during the third trimester of pregnancy when the plasma concentrations of cortisol increase to ~1MUM. These findings, if confirmed in vivo, have implications for predicting CYP2D6-mediated drug-drug interactions and call for re-evaluation of regulatory guidelines on screening for CYP2D6 induction by xenobiotics. Our findings also suggest that cortisol may be a causative factor in the in vivo induction of CYP2D6 during pregnancy. PMID- 26965987 TI - The ionization properties of cardiolipin and its variants in model bilayers. AB - The anionic phospholipid cardiolipin has an unusual dimeric structure with a two phosphate headgroup and four acyl chains. Cardiolipin is present in energy transducing membranes that maintain electrochemical gradients, including most bacterial plasma membranes and the mitochondrial inner membrane, where it mediates respiratory complex assembly and activation, among many other roles. Dysfunctional biogenesis of cardiolipin is implicated in the pathogenesis of several diseases including Barth syndrome. Because cardiolipin is a dominant anionic lipid in energy-conserving membranes, its headgroup is a major contributor to surface charge density and the bilayer electrostatic profile. However, the proton dissociation behavior of its headgroup remains controversial. In one model, the pKa values of the phosphates differ by several units and the headgroup exists as a monoanion at physiological pH. In another model, both phosphates ionize as strong acids with low pKa values and the headgroup exists in dianionic form at physiological pH. Using independent electrokinetic and spectroscopic approaches, coupled with analysis using Gouy-Chapman-Stern formalism, we have analyzed the ionization properties of cardiolipin within biologically relevant lipid bilayer model systems. We show that both phosphates of the cardiolipin headgroup show strong ionization behavior with low pKa values. Moreover, cardiolipin variants lacking structural features proposed to be required to maintain disparate pKa values--namely the secondary hydroxyl on the central glycerol or a full complement of four acyl chains--were shown to have ionization behavior identical to intact cardiolipin. Hence, these results indicate that within the physiological pH range, the cardiolipin headgroup is fully ionized as a dianion. We discuss the implications of these results with respect to the role of cardiolipin in defining membrane surface potential, activating respiratory complexes, and modulating membrane curvature. PMID- 26965988 TI - Antimicrobial peptides: Cell Membrane and Microbial Surface Interactions. PMID- 26965989 TI - Impact of environmental factors on the emergence, transmission and distribution of Toxoplasma gondii. AB - Toxoplasma gondii is an obligate intracellular protozoan that poses a great threat to human health and economic well-being worldwide. The effects of environmental factors such as changing climate and human activities on the ecology of this protozoan are being discovered. Accumulated evidence shows that changes of these environmental factors can exert influence on the occurrence, transmission and distribution of T. gondii. This article reviews studies from different geographical regions with varying climates, social cultures and animal welfare standards. It aims to illustrate how these environmental factors work, highlighting their importance in influencing the ecology of T. gondii, as well as providing clues which may contribute to preventing transmission of this important zoonotic pathogen. PMID- 26965990 TI - Long-Term Condition Self-Management Support in Online Communities: A Meta Synthesis of Qualitative Papers. AB - BACKGROUND: Recent years have seen an exponential increase in people with long term conditions using the Internet for information and support. Prior research has examined support for long-term condition self-management through the provision of illness, everyday, and emotional work in the context of traditional offline communities. However, less is known about how communities hosted in digital spaces contribute through the creation of social ties and the mobilization of an online illness "workforce." OBJECTIVE: The aim was to understand the negotiation of long-term condition illness work in patient online communities and how such work may assist the self-management of long-term conditions in daily life. METHODS: A systematic search of qualitative papers was undertaken using various online databases for articles published since 2004. A total of 21 papers met the inclusion criteria of using qualitative methods and examined the use of peer-led online communities for those with a long-term condition. A qualitative meta-synthesis was undertaken and the review followed a line of argument synthesis. RESULTS: The main themes identified in relation to the negotiation of self-management support were (1) redressing offline experiential information and knowledge deficits, (2) the influence of modeling and learning behaviors from others on self-management, (3) engagement that validates illness and negates offline frustrations, (4) tie formation and community building, (5) narrative expression and cathartic release, and (6) dissociative anonymity and invisibility. These translated into a line of argument synthesis in which four network mechanisms for self-management support in patient online communities were identified. These were (1) collective knowledge and identification through lived experience; (2) support, information, and engagement through readily accessible gifting relationships; (3) sociability that extends beyond illness; and (4) online disinhibition as a facilitator in the negotiation of self-management support. CONCLUSIONS: Social ties forged in online spaces provide the basis for performing relevant self-management work that can improve an individual's illness experience, tackling aspects of self-management that are particularly difficult to meet offline. Membership in online groups can provide those living with a long-term condition with ready access to a self-management support illness workforce and illness and emotional support. The substitutability of offline illness work may be particularly important to those whose access to support offline is either limited or absent. Furthermore, such resources require little negotiation online because information and support is seemingly gifted to the community by its members. PMID- 26965991 TI - [Para-infectious seizures: A retrospective multicentre study]. AB - INTRODUCTION: Para-infectious seizures are afebrile seizures that are associated with mild infections, and occur in children with no pre-existing neurological illness. They are still little known in our environment. METHODS: A multicentre retrospective study was conducted that included patients with normal psychomotor development and had presented with one or more seizures in the context of a mild afebrile infection. RESULTS: A total of 38 patients (47% male, 53% female) were included in the study over a period of three years (2012-2015). The mean age was 2.1 years. A previous history of febrile seizures was found in 7.9% of them. Mean number of seizures per patient was 2.2, with 57.9% of them being tonic-clonic seizures. The mean duration of seizures was 3.2minutes. An EEG was performed during admission in 73.7% of cases. Lumbar punctures were performed in 34.2% of cases. All were normal. Neuroimaging tests were carried out in 36.9% of cases. Brain MRI was the imaging test performed in most cases (21.1%), with no any pathological findings. The most frequent infection found was acute gastroenteritis (68%), followed by upper respiratory tract infection (32%). Almost two-thirds (63.2%) of patients did not require anticonvulsant medication. Rectal diazepam was the most frequently used drug in emergencies. Intravenous medication was required by 28.9% of patients due to repeated seizures. The most frequently used drug in the non-emergency setting was valproic acid. Anticonvulsant treatment was continued after discharge in 16% of patients. Para infectious seizures was the diagnosis in 76.3% of cases when discharged. CONCLUSIONS: Knowledge of para-infectious seizures, their clinical diagnosis and benign course is crucial, as this would avoid further testing and unnecessary treatments. PMID- 26965992 TI - Opioid use after total hip arthroplasty surgery is associated with revision surgery. AB - BACKGROUND: Pain is an indication for total hip arthroplasty (THA) and it should be resolved post-surgery. Because patients' pain is typically treated pharmacologically we tested whether opioid use can be used as a surrogate for patient-reported pain and as an indicator for early surgical failure. Specifically, we evaluated whether the amount of opioids taken within the year after THA was associated with one and five years risk of revision surgery. METHODS: A cohort of 9943 THAs (01/2001-12/2012) was evaluated. Post-operative opioid use was the exposure of interest and cumulative daily oral morphine equivalent (OME) amounts were calculated. Total OMEs/90-day periods were categorised into quartiles. Revisions within one and five years were the outcomes of interest. RESULTS: Of the THAs, 2.0 % (N = 200) were revised within one year and 4.2 % (N = 413) within five years. After adjustments for gender, age, surgical indication, co-morbidities, and other analgesics, revision was associated with amount of OMEs in the second quarter after THA (days 91-180 after discharge). Patients on medium-high amounts of OME (400-1119 mg) had higher risk of one (hazard ratio (HR) = 2.22, 95 % CI 1.08-4.56) and five year (HR = 1.66, 95 % CI 1.08-2.56) revision than a patient not taking opioids. During the same period, patients taking the highest amounts of OMEs (>=1120 mg) had a 2.64 (95 % CI 1.03-6.74) times higher risk of one year and a 2.11 (95 % CI 1.13-3.96) times higher risk of five year revision. CONCLUSIONS: Opioid use 91-180 days post surgery is associated with higher risk of revision surgery and therefore is an early and useful indicator for surgical failure. PMID- 26965993 TI - The endocannabinoid system: A novel player in human placentation. AB - Cannabis sativa is the most consumed illegal drug around the world. Its consumption during pregnancy is associated with gestational complications, particularly with fetal growth restriction. Endocannabinoids (eCBs) are lipid molecules that act by activating the G-protein coupled cannabinoid receptors, which are also target of the phytocannabinoid Delta(9)-tetrahydrocannabinol (THC). The endocannabinoid system (ECS) participates in distinct biological processes, including pain, inflammation, neuroprotection, and several reproductive events. In addition, an abnormal expression of ECS is associated with infertility and miscarriages. This manuscript will review and discuss the expression of ECS in normal and pathological human placentas, and the role of eCBs and THC in trophoblast proliferation, apoptosis, differentiation, and function. The current evidence points towards a role of ECS in human placentation, shedding light on the contribution of the eCBs in the coordination of human placentation, and in the cellular mechanisms underlying the deleterious effects of cannabis consumption during pregnancy. PMID- 26965994 TI - Multiplex Dipstick Technologies for Rapid and Simultaneous Screening of Analytes of Importance in Agri-Food-Nutrition and Health Care: A Review. AB - Dipstick test kits are being widely used for the rapid screening of a range of antigens or toxins in food, agriculture, and health care. They provide specific results on-site within 10 min with suitable accuracy and are, therefore, cost effective. Multiplex dipsticks also provide the opportunity for simultaneous detection of multiple antigens in the target sample without using expensive instrumentation, minimizing the cost of analysis as well as the duration of assay. Because of these benefits, dipstick kits are widely being used in the simultaneous detection of several antigens/toxins in large number of samples and in high-throughput manner. This review focuses on the current status of developed multiplex strips and its working principles and future direction of the technology in the agriculture, food, nutrition, and health care sectors. PMID- 26965995 TI - Skewing of peritoneal resident macrophages toward M1-like is involved in enhancement of inflammatory responses induced by secondary necrotic neutrophils in aged mice. AB - Secondary necrotic cells, which are generated if apoptotic cells are incompletely cleared, induce severe inflammatory responses involving MIP-2 production and subsequent neutrophil infiltration. Recently, we showed that the phagocytic capacity of peritoneal resident macrophages from wild type (WT) aged mice as well as SMP30(-/-) mice fed a VC-limited diet as to secondary necrotic cells was reduced as compared with that in young mice, and that the inflammatory responses induced were stronger than those in young mice, presumably because of the delay in removal of secondary necrotic cells in aged mice. In this study, we investigated why MIP-2 production was increased in aged mice upon injection of secondary necrotic cells and why the phagocytic capacity of peritoneal resident macrophages from aged mice was reduced. When cocultured with secondary necrotic cells, the peritoneal resident macrophages from both types of aged mice significantly produced MIP-2 even in the absence of IFN-gamma, whereas MIP-2 production by macrophages from WT young mice required IFN-gamma. The peritoneal resident macrophages from both types of aged mice expressed CD40, a M1 macrophage marker, as in the case of M1 macrophages, which were obtained by treatment of macrophages from WT young mice with IFN-gamma and LPS. Furthermore, M1 macrophages exhibited less phagocytic capacity as to secondary necrotic cells than non-treated macrophages. These results suggest that the phenotype of peritoneal resident macrophages is skewed toward M1-like in aged mice and that such skewing toward M1-like is involved in enhancement of inflammatory responses induced by secondary necrotic neutrophils in aged mice. PMID- 26965996 TI - Prostate-derived ets factor represses tumorigenesis and modulates epithelial-to mesenchymal transition in bladder carcinoma cells. AB - Prostate-derived Ets (E-twenty six) factor (PDEF), an epithelium-specific member of the Ets family of transcription factors, has been shown to play a role in suppressing the development of many epithelium-derived cancers such as prostate and breast cancer. It is not clear, however, whether PDEF is involved in the development or progression of bladder cancer. In a comparison between normal urothelium and bladder tumor tissue, we identified significant decreases of PDEF in the tumor tissue. Further, the immunohistochemistry assays indicated a significantly higher immunostaining of PDEF in low-grade bladder tumors. Additionally, the highly differentiated transitional-cell bladder carcinoma RT-4 cells expressed significantly more PDEF levels than the bladder carcinoma HT1376 and the T24 cells. Ectopic overexpression of PDEF attenuated proliferation, invasion, and tumorigenesis of bladder carcinoma cells in vitro and in vivo. PDEF enhanced the expression levels of mammary serine protease inhibitor (MASPIN), N myc downstream regulated gene 1 (NDRG1), KAI1, and B-cell translocation gene 2 (BTG2). PDEF modulated epithelial-mesenchymal-transition (EMT) by upregulating E cadherin expression and downregulating the expression of N-cadherin, SNAIL, SLUG, and vimentin, leading to lower migration and invasion abilities of bladder carcinoma cells. Filamentous actin (F-actin) polarization and remodeling were observed in PDEF-knockdown RT-4 cells. Our results suggest that PDEF gene expression is associated with the extent of bladder neoplasia and PDEF modulated the expressions of EMT-related genes. The induction of BTG2, NDRG1, MASPIN, and KAI1 gene expressions by PDEF may explain the inhibitory functions of PDEF on the proliferation, invasion, and tumorigenesis in bladder carcinoma cells. PMID- 26965997 TI - High-throughput "Omics" technologies: New tools for the study of triple-negative breast cancer. AB - Triple negative breast cancer (TNBC) represents about 15% to 20% of all breast cancers and is typically associated with poorer outcome than other breast cancer subtypes. The heterogeneity of this breast cancer subtype and present lack of clinically established targeted therapies further complicates treatment of patients. The treatment of TNBC emphasizes enhancing health care and developing personalized medicine. To respond to this need, the researchers have turned their attention to a different approach to scientific enquiry: the era of "big biology" and the integrative study of biological systems, also called "Omics" technologies. The term omics comprises different fields of molecular studies and characterizes a global view on biological molecules such as DNA, RNA, proteins, and metabolites. Combined "omics" approach offers a major tool for the understanding of a challenging cancer model, TNBC. This review discusses the different discoveries made using omics technologies concerning the molecular mechanisms underlying TNBC phenotypic heterogeneity, and their potential transfer to clinical applications. PMID- 26965998 TI - Jak-STAT3 pathway triggers DICER1 for proteasomal degradation by ubiquitin ligase complex of CUL4A(DCAF1) to promote colon cancer development. AB - Chronic intestinal inflammation is closely associated with colon cancer development and STAT3 seems to take center stage in bridging chronic inflammation to colon cancer progress. Here, we discovered that DICER1 was significantly downregulated in response to IL-6 or LPS stimulation and identified a novel mechanism for DICER1 downregulation via proteasomal degradation by ubiquitin ligase complex of CUL4A(DCAF1) in colon cancer cells. Meanwhile, PI3K-AKT signaling pathway phosphorylated DICER1 and contributed to its proteasomal degradation. The regulation of DICER1 by CUL4A(DCAF1) affected cell growth and apoptosis which is controlled by IL-6 activated Jak-STAT3 pathway. Intervention of CUL4A(DCAF1) ubiquitin ligase complex led to fluctuation in expression levels of DICER1 and microRNAs, and thus affected tumor growth in a mouse xenograft model. A panel of microRNAs that were downregulated by IL-6 stimulation was rescued by siRNA-CUL4A, and their predicated functions are involved in regulation of cell proliferation, apoptosis and motility. Furthermore, clinical specimen analysis revealed that decreased DICER1 expression was negatively correlated with STAT3 activation and cancer progression in human colon cancers. DICER1 and p STAT3 expression levels correlated with 5-year overall survival of colon cancer patients. Consequently, this study proposes that inflammation-induced Jak-STAT3 signaling leads to colon cancer development through proteasomal degradation of DICER1 by ubiquitin ligase complex of CUL4A(DCAF1), which suggests a novel therapeutic opportunity for colon cancer. PMID- 26965999 TI - Long non-coding RNA: A newly deciphered "code" in prostate cancer. AB - As one of the most frequently diagnosed cancers in males, the development and progression of prostate cancer remains an open area of research. The role of lncRNAs in prostate cancer is an emerging field of study. In this review, we summarize what is currently known about lncRNAs in prostate cancer while focusing on a few key lncRNAs. PCA3 was the first lncRNA identified in prostate cancer and has been shown to be expressed in a majority of prostate cancer cases. It may act in both an androgen dependent and independent fashion and has clinical utility as a biomarker. Other lncRNAs are known to interact directly with the androgen receptor pathway including PlncRNA-1, HOTAIR, PRNCR1 and PCGEM1. Additionally, lncRNAs have been shown to interfere with tumor suppressors, DNA break repair, transcription and alternate RNA splicing. While only in its infancy, an understanding of the role of lncRNAs in prostate cancer development should present ample opportunities for the discovery of new cancer biomarkers and therapeutic targets. PMID- 26966002 TI - Atrial electrograms improve the accuracy of tachycardia interpretation from ICD and pacemaker recordings: The RATE Registry. AB - BACKGROUND: Tachycardia diagnoses from implantable device recordings ultimately depend on the analysis of captured electrograms (EGMs). The degree to which atrial EGMs improve tachycardia discrimination, dependent on the level of expertise of the medical professional involved, remains uncertain. OBJECTIVE: The purpose of this article was to determine whether atrial EGM recordings improve tachycardia discrimination and whether this improvement, if any, varies for professionals with different levels of training. METHODS: Expert-adjudicated supraventricular tachycardia (SVT) and ventricular tachycardia (VT) dual-chamber EGMs (DEGMs) from the Registry of Atrial Tachycardia and Atrial Fibrillation Episodes in the Cardiac Rhythm Management Device Population were provided to electrophysiology specialists, electrophysiology fellows (EPF), and nurse practitioners or physician assistants (NPPA). Each participant diagnosed 112 EGM episodes presented in random sequence (61 VTs and 51 SVTs) and independently categorized each as "SVT," "VT," or "uncertain" in 2 stages. First, participants analyzed ventricular EGMs (VEGMs) alone (atrial channel covered). Second, the tracings were randomized and reanalyzed with atrial EGMs exposed. The diagnostic accuracy of VEGMs alone vs DEGMs was assessed for each group. RESULTS: For all 3 groups, diagnostic accuracy improved significantly (>20% for VTs and >15% for SVTs; P < .01 for all) when DEGMs were provided. Electrophysiology specialists diagnosed VTs more accurately than did EPF and NPPA (VEGM: 73.1%+/-7.6% vs 58.7%+/-15.5% and 56.1%+/-14.1%; P < .01; DEGM: 98.0%+/-2.7% vs 90.8%+/-16.0% and 80.3%+/-7.4%; P < .01). EPF diagnosed VTs more accurately than did NPPA only when DEGMs were provided. There was no significant intergroup difference in SVT diagnoses. CONCLUSION: DEGMs are superior to VEGMs alone for tachycardia discrimination at all levels of expertise. The level of training affects diagnostic accuracy with and without atrial EGMs. PMID- 26966000 TI - CGCG clinical practice guidelines for the management of adult diffuse gliomas. AB - The Chinese Glioma Cooperative Group (CGCG) Guideline Panel for adult diffuse gliomas provided recommendations for diagnostic and therapeutic procedures. The Panel covered all fields of expertise in neuro-oncology, i.e. neurosurgeons, neurologists, neuropathologists, neuroradiologists, radiation and medical oncologists and clinical trial experts. The task made clearer and more transparent choices about outcomes considered most relevant through searching the references considered most relevant and evaluating their value. The scientific evidence of papers collected from the literature was evaluated and graded based on the Oxford Centre for Evidence-based Medicine Levels of Evidence and recommendations were given accordingly. The recommendations will provide a framework and assurance for the strategy of diagnostic and therapeutic measures to reduce complications from unnecessary treatment and cost. The guideline should serve as an application for all professionals involved in the management of patients with adult diffuse glioma and also as a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in China. PMID- 26966001 TI - Expression quantitative trait analysis reveals fine germline transcript regulation in mouse lung tumors. AB - Gene expression modulates cellular functions in both physiologic and pathologic conditions. Herein, we carried out a genetic linkage study on the transcriptome of lung tumors induced by urethane in an (A/J x C57BL/6)F4 intercross population, whose individual lung tumor multiplicity (Nlung) is linked to the genotype at the Pulmonary adenoma susceptibility 1 (Pas1) locus. We found that expression levels of 1179 and 1579 genes are modulated by an expression quantitative trait locus (eQTL) in cis and in trans, respectively (LOD score > 5). Of note, the genomic area surrounding and including the Pas1 locus regulated 14 genes in cis and 857 genes in trans. In lung tumors of the same (A/J x C57BL/6)F4 mice, we found 1124 genes whose transcript levels associated with Nlung (FDR < 0.001). The expression levels of about a third of these genes (n = 401) were regulated by the genotype at the Pas1 locus. Pathway analysis of the sets of genes associated with Nlung and regulated by Pas1 revealed a set of 14 recurrently represented genes that are components or targets of the Ras-Erk and Pi3k-Akt signaling pathways. Altogether our results illustrate the architecture of germline control of gene expression in mouse lung cancer: they highlight the importance of Pas1 as a tumor-modifier locus, attribute to it a novel role as a major regulator of transcription in lung tumor nodules and strengthen the candidacy of the Kras gene as the effector of this locus. PMID- 26966004 TI - RE: Serum vit D levels and response to molecular subtypes in breast cancer. PMID- 26966003 TI - Exposure to urban PM1 in rats: development of bronchial inflammation and airway hyperresponsiveness. AB - BACKGROUND: Several epidemiological and laboratory studies have evidenced the fact that atmospheric particulate matter (PM) increases the risk of respiratory morbidity. It is well known that the smallest fraction of PM (PM1 - particulate matter having a diameter below 1 MUm) penetrates the deepest into the airways. The ratio of the different size fractions in PM is highly variable, but in industrial areas PM1 can be significant. Despite these facts, the health effects of PM1 have been poorly investigated and air quality standards are based on PM10 and PM2.5 (PM having diameters below 10 MUm and 2.5 MUm, respectively) concentrations. Therefore, this study aimed at determining whether exposure to ambient PM1 at a near alert threshold level for PM10 has respiratory consequences in rats. METHODS: Rats were either exposed for 6 weeks to 100 MUg/m(3) (alert threshold level for PM10 in Hungary) urban submicron aerosol, or were kept in room air. End-expiratory lung volume, airway resistance (Raw) and respiratory tissue mechanics were measured. Respiratory mechanics were measured under baseline conditions and following intravenous methacholine challenges to characterize the development of airway hyperresponsiveness (AH). Bronchoalveolar lavage fluid (BALF) was analyzed and lung histology was performed. RESULTS: No significant differences were detected in lung volume and mechanical parameters at baseline. However, the exposed rats exhibited significantly greater MCh-induced responses in Raw, demonstrating the progression of AH. The associated bronchial inflammation was evidenced by the accumulation of inflammatory cells in BALF and by lung histology. CONCLUSIONS: Our findings suggest that exposure to concentrated ambient PM1 (mass concentration at the threshold level for PM10) leads to the development of mild respiratory symptoms in healthy adult rats, which may suggest a need for the reconsideration of threshold limits for airborne PM1. PMID- 26966005 TI - Estimating the Effect of Competition on Trait Evolution Using Maximum Likelihood Inference. AB - Many classical ecological and evolutionary theoretical frameworks posit that competition between species is an important selective force. For example, in adaptive radiations, resource competition between evolving lineages plays a role in driving phenotypic diversification and exploration of novel ecological space. Nevertheless, current models of trait evolution fit to phylogenies and comparative data sets are not designed to incorporate the effect of competition. The most advanced models in this direction are diversity-dependent models where evolutionary rates depend on lineage diversity. However, these models still treat changes in traits in one branch as independent of the value of traits on other branches, thus ignoring the effect of species similarity on trait evolution. Here, we consider a model where the evolutionary dynamics of traits involved in interspecific interactions are influenced by species similarity in trait values and where we can specify which lineages are in sympatry. We develop a maximum likelihood based approach to fit this model to combined phylogenetic and phenotypic data. Using simulations, we demonstrate that the approach accurately estimates the simulated parameter values across a broad range of parameter space. Additionally, we develop tools for specifying the biogeographic context in which trait evolution occurs. In order to compare models, we also apply these biogeographic methods to specify which lineages interact sympatrically for two diversity-dependent models. Finally, we fit these various models to morphological data from a classical adaptive radiation (Greater Antillean Anolis lizards). We show that models that account for competition and geography perform better than other models. The matching competition model is an important new tool for studying the influence of interspecific interactions, in particular competition, on phenotypic evolution. More generally, it constitutes a step toward a better integration of interspecific interactions in many ecological and evolutionary processes. PMID- 26966007 TI - Challenges in Fusarium, a Trans-Kingdom Pathogen. AB - Fusarium species are emerging human pathogens, next to being plant pathogens. Problems with Fusarium are in their diagnostics and in their difficult treatment, but also in what are actual Fusarium species or rather Fusarium-like species. In this issue Guevara-Suarez et al. (Mycopathologia. doi: 10.1007/s11046-016-9983-9 , 2016) characterized 89 isolates of Fusarium from Colombia showing especially lineages within the Fusarium solani and oxysporum species complexes to be responsible for onychomycosis. PMID- 26966006 TI - Changes of diet and dominant intestinal microbes in farmland frogs. AB - BACKGROUND: Agricultural activities inevitably result in anthropogenic interference with natural habitats. The diet and the gut microbiota of farmland wildlife can be altered due to the changes in food webs within agricultural ecosystems. In this work, we compared the diet and intestinal microbiota of the frog Fejervarya limnocharis in natural and farmland habitats in order to understand how custom farming affects the health of in vivo microbial ecosystems. RESULTS: The occurrence, abundance, and the numbers of prey categories of stomach content were significantly different between the frogs inhabiting natural and farmland habitats. In addition, differences in the abundance, species richness, and alpha-diversity of intestinal microbial communities were also statistically significant. The microbial composition, and particularly the composition of dominant microbes living in intestines, indicated that the land use practices might be one of factors affecting the gut microbial community composition. Although the first three dominant microbial phyla Bacteroidetes, Firmicutes, and Proteobacteria found in the intestines of frogs were classified as generalists among habitats, the most dominant gut bacterial phylum Bacteroidetes in natural environments was replaced by the microbial phylum Firmicutes in farmland frogs. Increased intestinal microbial richness of the farmland frogs, which is mostly contributed by numerous microbial species of Proteobacteria, Actinobacteria, Acidobacteria, and Planctomycetes, not only reflects the possible shifts in microbial community composition through the alteration of external ecosystem, but also indicates the higher risk of invasion by disease-related microbes. CONCLUSIONS: This study indicates that anthropogenic activities, such as the custom farming, have not only affected the food resources of frogs, but also influenced the health and in vivo microbial ecosystem of wildlife. PMID- 26966008 TI - Ketamine Affects the Neurogenesis of the Hippocampal Dentate Gyrus in 7-Day-Old Rats. AB - Ketamine has been reported to cause neonatal neurotoxicity via a neuronal apoptosis mechanism; however, no in vivo research has reported whether ketamine could affect postnatal neurogenesis in the hippocampal dentate gyrus (DG). A growing number of experiments suggest that postnatal hippocampal neurogenesis is the foundation of maintaining normal hippocampus function into adulthood. Therefore, this study investigated the effect of ketamine on hippocampal neurogenesis. Male Sprague-Dawley rats were divided into two groups: the control group (equal volume of normal saline), and the ketamine-anesthesia group (40 mg/kg ketamine in four injections at 1 h intervals). The S-phase marker 5 bromodeoxyuridine (BrdU) was administered after ketamine exposure to postnatal day 7 (PND-7) rats, and the neurogenesis in the hippocampal DG was assessed using single- or double-immunofluorescence staining. The expression of GFAP in the hippocampal DG was measured by western blot analysis. Spatial reference memory was tested by Morris water maze at 2 months after PND-7 rats exposed to ketamine treatment. The present results showed that neonatal ketamine exposure significantly inhibited neural stem cell (NSC) proliferation, decreased astrocytic differentiation, and markedly enhanced neuronal differentiation. The disruptive effect of ketamine on the proliferation and differentiation of NSCs lasted at least 1 week and disappeared by 2 weeks after ketamine exposure. Moreover, the migration of newborn neurons in the granule cell layer and the growth of astrocytes in the hippocampal DG were inhibited by ketamine on PND-37 and PND-44. Finally, ketamine caused a deficit in hippocampal-dependent spatial reference memory tasks at 2 months old. Our results suggested that ketamine may interfere with hippocampal neurogenesis and long-term neurocognitive function in PND-7 rats. These findings may provide a new perspective to explain the adult neurocognitive dysfunction induced by neonatal ketamine exposure. PMID- 26966009 TI - L-DOPA Reverses the Increased Free Amino Acids Tissue Levels Induced by Dopamine Depletion and Rises GABA and Tyrosine in the Striatum. AB - Perturbations in the cerebral levels of various amino acids are associated with neurological disorders, and previous studies have suggested that such alterations have a role in the motor and non-motor symptoms of Parkinson's disease. However, the direct effects of chronic L-DOPA treatment, that produces dyskinesia, on neural tissue amino acid concentrations have not been explored in detail. To evaluate whether striatal amino acid concentrations are altered in peak dose dyskinesia, 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian mice were treated chronically with L-DOPA and tissue amino acid concentrations were assessed by HPLC analysis. These experiments revealed that neither 6-OHDA nor L DOPA treatment are able to alter glutamate in the striatum. However, glutamine increases after 6-OHDA and returns back to normal levels with L-DOPA treatment, suggesting increased striatal glutamatergic transmission with lack of dopamine. In addition, glycine and taurine levels are increased following dopamine denervation and restored to normal levels by L-DOPA. Interestingly, dyskinetic animals showed increased levels of GABA and tyrosine, while aspartate striatal tissue levels are not altered. Overall, our results indicate that chronic L-DOPA treatment, besides normalizing the altered levels of some amino acids after 6 OHDA, robustly increases striatal GABA and tyrosine levels which may in turn contribute to the development of L-DOPA-induced dyskinesia. PMID- 26966011 TI - Enhancing ethanol production from cellulosic sugars using Scheffersomyces (Pichia) stipitis. AB - Studies were performed on the effect of CaCO3 and CaCl2 supplementation to fermentation medium for ethanol production from xylose, glucose, or their mixtures using Scheffersomyces (Pichia) stipitis. Both of these chemicals were found to improve maximum ethanol concentration and ethanol productivity. Use of xylose alone resulted in the production of 20.68 +/- 0.44 g L(-1) ethanol with a productivity of 0.17 +/- 0.00 g L(-1) h(-1), while xylose plus 3 g L(-1) CaCO3 resulted in the production of 24.68 +/- 0.75 g L(-1) ethanol with a productivity of 0.21 +/- 0.01 g L(-1) h(-1). Use of xylose plus glucose in combination with 3 g L(-1) CaCO3 resulted in the production of 47.37 +/- 0.55 g L(-1) ethanol (aerobic culture), thus resulting in an ethanol productivity of 0.39 +/- 0.00 g L(-1) h(-1). These values are 229 % of that achieved in xylose medium. Supplementation of xylose and glucose medium with 0.40 g L(-1) CaCl2 resulted in the production of 44.84 +/- 0.28 g L(-1) ethanol with a productivity of 0.37 +/- 0.02 g L(-1) h(-1). Use of glucose plus 3 g L(-1) CaCO3 resulted in the production of 57.39 +/- 1.41 g L(-1) ethanol under micro-aerophilic conditions. These results indicate that supplementation of cellulosic sugars in the fermentation medium with CaCO3 and CaCl2 would improve economics of ethanol production from agricultural residues. PMID- 26966010 TI - Overexpressed Down Syndrome Cell Adhesion Molecule (DSCAM) Deregulates P21 Activated Kinase (PAK) Activity in an In Vitro Neuronal Model of Down Syndrome: Consequences on Cell Process Formation and Extension. AB - In humans, Down syndrome (DS) is caused by the presence of an extra copy of autosome 21. The most striking finding in DS patients is intellectual disability and the onset of Alzheimer's disease (AD)-like neuropathology in adulthood. Gene overdose is most likely to underlie both developmental impairments, as well as altered neuronal function in DS. Lately, the disruption of cellular signaling and regulatory pathways has been implicated in DS pathophysiology, and many of such pathways may represent common targets for diverse DS-related genes, which could in turn represent attractive therapeutical targets. In this regard, one DS related gene Down Syndrome Cell Adhesion Molecule (DSCAM), has important functions in neuronal proliferation, maturation, and synaptogenesis. p21 associated kinases (PAKs) appear as a most interesting possibility for study, as DSCAM is known to regulate the PAKs pathway. Hence, in DS, overexpressed DSCAM could deregulate PAKs activity and affect signaling pathways that regulate synaptic plasticity such as dendritic spine dynamics and axon guidance and growth. In the present work, we used an immortalized cell line derived from the cerebral cortex of an animal model of DS such as the trisomy 16 (Ts16) fetal mouse (named CTb), and a similar cell line established from a normal littermate (named CNh), to study the effect of DSCAM in the PAKs pathway. The present study shows that DSCAM is overexpressed in CTb cells by approximately twofold, compared to CNh cells. Congruently, PAK1, as well as its downstream effectors LIMK and cofilin, stay phosphorylated for longer periods after DSCAM activation in the CTb cells, leading to an altered actin dynamics, expressed as an increased basal F/G ratio and reduced neurite growth, in the trisomic condition. The present work presents the correlation between DSCAM gene overexpression and a dysregulation of the PAK pathway, resulting in altered morphological parameters of neuronal plasticity in the trisomic cell line, namely decreased number and length of processes. PMID- 26966013 TI - Correlates of Awareness of and Willingness to Use Pre-exposure Prophylaxis (PrEP) in Gay, Bisexual, and Other Men Who Have Sex with Men Who Use Geosocial Networking Smartphone Applications in New York City. AB - Geosocial-networking smartphone applications are commonly used by gay, bisexual, and other men who have sex with men (MSM) to meet sexual partners. The purpose of the current study was to evaluate awareness of and willingness to use pre exposure prophylaxis (PrEP) among MSM who use geosocial-networking smartphone applications residing in New York City. Recruitment utilizing broadcast advertisements on a popular smartphone application for MSM yielded a sample of 152 HIV-uninfected MSM. Multivariable models were used to assess demographic and behavioral correlates of awareness of and willingness to use PrEP. Most participants (85.5 %) had heard about PrEP but few (9.2 %) reported current use. Unwillingness to use PrEP was associated with concerns about side effects (PR = 0.303; 95 % CI 0.130, 0.708; p = 0.006). Given that more than half (57.6 %) of participants were willing to use PrEP, future research is needed to elucidate both individual and structural barriers to PrEP use among MSM. PMID- 26966012 TI - Hot executive control and response to a stimulant in a double-blind randomized trial in children with ADHD. AB - Attention deficit hyperactivity disorder (ADHD) is thought to involve an executive inhibitory control (IC) deficit, yet it is not clear if this is a general deficit affecting both cold and hot EC, and if methylphenidate (MPH) affects both systems in treated children. We explored this by using a Stroop-like task in children with ADHD as compared to controls, containing different types of emotional stimuli (six levels), and we investigated the role of intervention with MPH on IC as compared to placebo. Children with ADHD and controls (N = 40; 7-13 years old) were tested with a hot and cold Stroop-like task. This was followed by a double-blind placebo-controlled crossover trial of the effect of MPH on these skills. Children with ADHD showed a specific difficulty inhibiting their responses, particularly to hot, angry and frustration-inducing stimuli. Further, treatment with MPH was effective in reducing errors toward frustration-inducing stimuli as compared to placebo (p < .05, eta 2 = .347), particularly with repeated exposure to the stimuli. Results indicate that children with ADHD experience executive control difficulties, particularly in hot negative emotional contexts. These emotion regulation difficulties are amenable to stimulant intervention. PMID- 26966015 TI - Race, APOL1 Risk, and eGFR Decline in the General Population. AB - The APOL1 high-risk genotype, present in approximately 13% of blacks in the United States, is a risk factor for kidney function decline in populations with CKD. It is unknown whether genetic screening is indicated in the general population. We evaluated the prognosis of APOL1 high-risk status in participants in the population-based Atherosclerosis Risk in Communities (ARIC) study, including associations with eGFR decline, variability in eGFR decline, and related adverse health events (AKI, ESRD, hypertension, diabetes, cardiovascular disease, pre-ESRD and total hospitalization rate, and mortality). Among 15,140 ARIC participants followed from 1987-1989 (baseline) to 2011-2013, 75.3% were white, 21.5% were black/APOL1 low-risk, and 3.2% were black/APOL1 high-risk. In a demographic-adjusted analysis, blacks had a higher risk for all assessed adverse health events; however, in analyses adjusted for comorbid conditions and socioeconomic status, blacks had a higher risk for hypertension, diabetes, and ESRD only. Among blacks, the APOL1 high-risk genotype associated only with higher risk of ESRD in a fully adjusted analysis. Black race and APOL1 high-risk status were associated with faster eGFR decline (P<0.001 for each). However, we detected substantial overlap among the groups: median (10th-90th percentile) unadjusted eGFR decline was 1.5 (1.0-2.2) ml/min per 1.73 m(2) per year for whites, 2.1 (1.4 3.1) ml/min per 1.73 m(2) per year for blacks with APOL1 low-risk status, and 2.3 (1.5-3.5) ml/min per 1.73 m(2) per year for blacks with APOL1 high-risk status. The high variability in eGFR decline among blacks with and without the APOL1 high risk genotype suggests that population-based screening is not yet justified. PMID- 26966014 TI - Somatic Mutations Modulate Autoantibodies against Galactose-Deficient IgA1 in IgA Nephropathy. AB - Autoantibodies against galactose-deficient IgA1 drive formation of pathogenic immune complexes in IgA nephropathy. IgG autoantibodies against galactose deficient IgA1 in patients with IgA nephropathy have a specific amino-acid sequence, Y1CS3, in the complementarity-determining region 3 of the heavy chain variable region compared with a Y1CA3 sequence in similar isotype-matched IgG from healthy controls. We previously found that the S3 residue is critical for binding galactose-deficient IgA1. To determine whether this difference is due to a rare germline sequence, we amplified and sequenced the corresponding germline variable region genes from peripheral blood mononuclear cells of seven patients with IgA nephropathy and six healthy controls from whom we had cloned single-cell lines secreting monoclonal IgG specific for galactose-deficient IgA1. Sanger DNA sequencing revealed that complementarity-determining region 3 in the variable region of the germline genes encoded the Y1C(A/V)3 amino-acid sequence. Thus, the A/V>S substitution in the complementarity-determining region 3 of anti-galactose deficient-IgA1 autoantibodies of the patients with IgA nephropathy is not a rare germline gene variant. Modeling analyses indicated that the S3 hydroxyl group spans the complementarity-determining region 3 loop stem, stabilizing the adjacent beta-sheet and stem structure, important features for effective binding to galactose-deficient IgA1. Understanding processes leading to production of the autoantibodies may offer new approaches to treat IgA nephropathy. PMID- 26966017 TI - Mechanists Must be Holists Too! Perspectives from Circadian Biology. AB - The pursuit of mechanistic explanations in biology has produced a great deal of knowledge about the parts, operations, and organization of mechanisms taken to be responsible for biological phenomena. Holist critics have often raised important criticisms of proposed mechanistic explanations, but until recently holists have not had alternative research strategies through which to advance explanations. This paper argues both that the results of mechanistic strategies has forced mechanists to confront ways in which whole systems affect their components and that new representational and modeling strategies are providing tools for understanding these effects of whole systems upon components. Drawing from research on the mechanism responsible for circadian rhythms in mammals, I develop two examples in which mechanistic analysis is being integrated into a more holist perspective: research revealing intercellular integration of circadian mechanisms with those involved in cell metabolism and research revealing that stable?rhythms are dependent on how individual cells in the suprachiasmatic nucleus synchronize with each other to generate regular rhythms. Tools such as network diagramming and computational modeling are providing means to integrate mechanistic models into accounts of whole systems. PMID- 26966019 TI - Mozambique's Debt and the International Monetary Fund's Influence on Poverty, Education, and Health. AB - For nearly 30 years, Mozambique has been facing austerity measures regulated by the IMF. These austerity measures, grounded in macroeconomic policies, were supposed to lift Mozambique out of poverty, and improve its healthcare and education systems. By taking an in-depth look at the major etiologies of Mozambique's debt and the conditions which forced the country to accept austerity measures-despite their protests-prior to receiving IMF funding, this paper examines how IMF policies over the past 30 years have affected poverty, health, and the education system. The results of these policies have contributed to Mozambique's enduring classification as one of the poorest countries in the world. Aside from economic outcomes, Mozambique also has abysmal health and education systems, with one of the lowest life expectancies in Sub-Saharan Africa. It is time to re-evaluate how the current IMF macroeconomic policies negatively affect, health, education and the socioeconomic status of those who live in abject poverty. As short term macroeconomic policies of PARPA have been ineffective at reducing poverty, promoting education and improving health, the IMF should consider using longer term macroeconomic policies which invest in rather than limit-public services such as health and education. PMID- 26966016 TI - The Uromodulin Gene Locus Shows Evidence of Pathogen Adaptation through Human Evolution. AB - Common variants in the UMOD gene encoding uromodulin, associated with risk of hypertension and CKD in the general population, increase UMOD expression and urinary excretion of uromodulin, causing salt-sensitive hypertension and renal lesions. To determine the effect of selective pressure on variant frequency, we investigated the allelic frequency of the lead UMOD variant rs4293393 in 156 human populations, in eight ancient human genomes, and in primate genomes. The T allele of rs4293393, associated with CKD risk, has high frequency in most modern populations and was the one detected in primate genomes. In contrast, we identified only the derived, C allele in Denisovan and Neanderthal genomes. The distribution of the UMOD ancestral allele did not follow the ancestral susceptibility model observed for variants associated with salt-sensitive hypertension. Instead, the global frequencies of the UMOD alleles significantly correlated with pathogen diversity (bacteria, helminths) and prevalence of antibiotic-resistant urinary tract infections (UTIs). The inverse correlation found between urinary levels of uromodulin and markers of UTIs in the general population substantiates the link between UMOD variants and protection against UTIs. These data strongly suggest that the UMOD ancestral allele, driving higher urinary excretion of uromodulin, has been kept at a high frequency because of its protective effect against UTIs. PMID- 26966018 TI - Prognostic value of the DNMTs mRNA expression and genetic polymorphisms on the clinical outcome in oral cancer patients. AB - OBJECTIVES: Although the importance of the epigenetic changes in tumors, including oral squamous cell carcinomas (OSCCs), is now becoming apparent, the mechanisms that trigger or cause aberrant DNA methylation in cancer are still unrevealed. DNA methylation is regulated by a family of enzymes, DNA methyltransferases (DNMTs). DNMT gene expression analysis, as well as genetic polymorphisms, has not been previously evaluated in OSCC. MATERIALS AND METHODS: In 65 OSCC patients, SYBR Green real-time PCR method was assessed for relative quantification of DNMT1, DNMT3A, and DNMT3B mRNAs, normalized to TATA-binding protein (TBP) mRNA. The expression levels of all three genes were dichotomized as high or low, with a twofold change of normalized mRNA expression used as the cutoff value. Polymorphisms in DNMT1 (rs2228612) and DNMT3B (rs406193) were analyzed in 99 OSCCs by TaqMan SNPs genotyping assays. RESULTS: DNMT1, DNMT3A, and DNMT3B were overexpressed in 36.9, 26, and 23 % of the OSCC patients, respectively. DNMT1 overexpression was significantly associated with the overall survival, p = 0.029, and relapse-free survival of OSCC patients, p = 0.003. Patients with DNMT1 overexpression, as an independent prognostic factor, had a 2.385 times higher risk to relapse than those with lower expression. The DNMT1 A201G gene polymorphism was associated with a reduced overall survival in OSCC patients, p = 0.036. CONCLUSIONS: Our results suggest that DNMT1 could play an important role in modulating OSCC patient survival. CLINICAL RELEVANCE: DNMT gene expression could be a potential prognostic marker that might lead to an improvement in diagnosis, prognosis, and prospective use of epigenetic-targeted therapy of OSCC. PMID- 26966021 TI - Strike at the heart of the stroke. PMID- 26966020 TI - Late survival and heart failure after transcatheter aortic valve implantation. AB - BACKGROUND: Short-term survival in patients undergoing transcatheter aortic valve implantation is favorable. Our aim was to evaluate late survival and composite clinical endpoints specified by the Valve Academic Research Consortium-2, including rehospitalization for congestive heart failure. METHODS: Between January 2008 and April 2014, 166 consecutive patients with severe symptomatic aortic stenosis underwent 168 transcatheter aortic valve implantation procedures at our facility. This cohort was compared with propensity score-matched aortic valve replacement patients. Event rates were estimated by the Kaplan-Meier method and compared using the log-rank test. Cox regression analysis was performed to determine predictors of outcome. RESULTS: Although 30-day mortality rates following both procedures were similar (4.2% and 4.8%; p = 0.81), significant differences were seen in corresponding rates of survival (51.7% +/- 5.8% vs. 72.3% +/- 4.3%; p < 0.001) and cumulative rehospitalization for congestive heart failure (41.3% +/- 7.2% vs. 23% +/- 4.3%; p = 0.006). New York Heart Association functional class IV preoperative status was an independent risk factor for rehospitalization due to congestive heart failure (p = 0.015). CONCLUSIONS: This study confirms the merit of transcatheter aortic valve implantation in high-risk patients with aortic stenosis, although late survival proved inferior to that of aortic valve replacement in propensity score-matched subjects. Early safety was excellent for both treatment groups, however, patients undergoing transcatheter aortic valve implantation had a higher incidence of rehospitalization for congestive heart failure and myocardial infarction during follow-up. Patients with severe congestive heart failure should be carefully monitored and aggressively treated to improve outcomes. PMID- 26966022 TI - Intracranial Pressure Monitoring in Acute Liver Failure: Institutional Case Series. AB - Acute liver failure (ALF) has been associated with cerebral edema and elevated intracranial pressure (ICP), which may be managed utilizing an ICP monitor. The most feared complication of placement is catastrophic intracranial hemorrhage in the setting of severe coagulopathy. Previous studies reported hemorrhage rates between 3.8-22 % among various devices, with epidural catheters having lower hemorrhage rates and precision relative to subdural bolts and intraparenchymal catheters. We sought to identify institutional hemorrhagic rates of ICP monitoring in ALF and its associated factors in a modern series guided by protocol implantation. Patient records treated for ALF with ICP monitoring at Mayo Clinic in Rochester, MN from 1995 to 2014 were reviewed. Protocalized since 1995, epidural (EP) ICP monitors were first used followed by intraparenchymal (IP) for stage III-IV hepatic encephalopathy. The following variables and outcomes were collected: patient demographics, ICPs and treatment methods, laboratory data, imaging studies, number of days for ICP monitoring, radiographic and symptomatic hemorrhage rates, orthotopic liver transplantation rates, and death. A total of 20 ICP monitors were placed for ALF, 7 EP, and 13 IP. International normalized ratio (INR) at placement of an EP monitor was 2.4 (1.7 3.2) with maximum of 2.7 (2.0-3.6) over the following 2.3 (1-3) days. Mean EP ICP at placement was 36.3 (11-55) and maximum of 43.1 (20-70) mm Hg. INR at placement of an IP monitor was 1.3 (<0.8-3.0) with maximum value of 2.9 (1.6-5.4) over the following 4.2 (2-6) days. Mean IP ICP at placement was 9.9 (2-19) and maximum was 39.8 (11-100) mm Hg. There was one asymptomatic hemorrhage in the EP group (14.3 % hemorrhage rate) and two hemorrhages in the IP group (hemorrhage rate was 15.4 %), both of which were fatal. Overall mortality rate in the EP group was 71.4 % (5/7) with two patients receiving transplantation, and one death in the transplant group. Overall mortality in the IP group was 38.5 % (5/13) with nine liver transplantations; three of the transplanted patients died, including one of the fatal hemorrhages due to monitor placement. Intracranial hypertension is common in patients with ALF with severe hepatic encephalopathy. Monitored patients in both groups experienced elevations of ICP in the setting of intermittent coagulopathy. Severity of coagulopathy did not influence hemorrhage rate. Yet, hemorrhages related to IP monitoring can be catastrophic and may add to the overall mortality. PMID- 26966024 TI - Interplay between pathway-specific and global regulation of the fumonisin gene cluster in the rice pathogen Fusarium fujikuroi. AB - The rice pathogenic fungus Fusarium fujikuroi is known to produce a large variety of secondary metabolites. Besides the gibberellins, causing the bakanae effect in infected rice seedlings, the fungus produces several mycotoxins and pigments. Among the 47 putative secondary metabolite gene clusters identified in the genome of F. fujikuroi, the fumonisin gene cluster (FUM) shows very high homology to the FUM cluster of the main fumonisin producer Fusarium verticillioides, a pathogen of maize. Despite the high level of cluster gene conservation, total fumonisin FB1 and FB2 levels (FBx) produced by F. fujikuroi were only 1-10 % compared to F. verticillioides under inducing conditions. Nitrogen repression was found to be relevant for wild-type strains of both species. However, addition of germinated maize kernels activated the FBx production only in F. verticillioides, reflecting the different host specificity of both wild-type strains. Over-expression of the pathway-specific transcription factor Fum21 in F. fujikuroi strongly activated the FUM cluster genes leading to 1000-fold elevated FBx levels. To gain further insights into the nitrogen metabolite repression of FBx biosynthesis, we studied the impact of the global nitrogen regulators AreA and AreB and demonstrated that both GATA-type transcription factors are essential for full activation of the FUM gene cluster. Loss of one of them obstructs the pathway-specific transcription factor Fum21 to fully activate expression of FUM cluster genes. PMID- 26966023 TI - Meta-analysis of executive functioning in ecstasy/polydrug users. AB - Ecstasy/3,4-methylenedioxymethamphetamine (MDMA) use is proposed to cause damage to serotonergic (5-HT) axons in humans. Therefore, users should show deficits in cognitive processes that rely on serotonin-rich, prefrontal areas of the brain. However, there is inconsistency in findings to support this hypothesis. The aim of the current study was to examine deficits in executive functioning in ecstasy users compared with controls using meta-analysis. We identified k = 39 studies, contributing 89 effect sizes, investigating executive functioning in ecstasy users and polydrug-using controls. We compared function-specific task performance in 1221 current ecstasy users and 1242 drug-using controls, from tasks tapping the executive functions - updating, switching, inhibition and access to long-term memory. The significant main effect demonstrated overall executive dysfunction in ecstasy users [standardized mean difference (SMD) = -0.18, 95% confidence interval (CI) -0.26 to -0.11, Z = 5.05, p < 0.001, I 2 = 82%], with a significant subgroup effect (chi 2 = 22.06, degrees of freedom = 3, p < 0.001, I 2 = 86.4%) demonstrating differential effects across executive functions. Ecstasy users showed significant performance deficits in access (SMD = -0.33, 95% CI -0.46 to 0.19, Z = 4.72, p < 0.001, I 2 = 74%), switching (SMD = -0.19, 95% CI -0.36 to 0.02, Z = 2.16, p < 0.05, I 2 = 85%) and updating (SMD = -0.26, 95% CI -0.37 to 0.15, Z = 4.49, p < 0.001, I 2 = 82%). No differences were observed in inhibitory control. We conclude that this is the most comprehensive analysis of executive function in ecstasy users to date and provides a behavioural correlate of potential serotonergic neurotoxicity. PMID- 26966025 TI - Aspergilloma in atypical localisation in severe asthma patient - case report. AB - Pulmonary aspergillosis is a condition caused by the fungi Aspergillus. The form of disease depends on the immunological condition of the host organism and other concomitant illnesses that influence the pulmonary tissue. Asthmatic patients, in particular with the severe form of disease, who require the use of systemic glucocorticoids, are predisposed to develop allergic bronchopulmonary aspergillosis. Development of aspergilloma in the lung is preceded by the formation of pathological cavity in the course of another illness. The study reports a case of a severe asthma patient who developed aspergilloma in atypical localisation, without the presence of predisposing anatomical changes and illnesses. PMID- 26966026 TI - Acromegaly and associated tumours: what should gastroenterologists know? AB - Acromegaly is a clinical syndrome caused by the excessive production of growth hormone. It is associated with high morbidity and significantly increased mortality, mainly due to cardiovascular and respiratory complications, and cancer. Mortality is reduced to that of the general population following successful treatment, in other words, when insulin-like growth factor (IGF-I) and growth hormone values return to normal levels. Not all tumours associated with this syndrome benefit from cost-effective early diagnosis programmes. An in-depth knowledge on the part of clinicians of the morbidity and mortality associated with acromegaly, allowing them in many cases to anticipate the expected clinical course of the disease, is the best therapeutic and follow-up strategy in these patients. PMID- 26966027 TI - First-in-human, open-label dose-escalation and dose-expansion study of the safety, pharmacokinetics, and antitumor effects of an oral ALK inhibitor ASP3026 in patients with advanced solid tumors. AB - BACKGROUND: ASP3026 is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has potent in vitro activity against crizotinib-resistant ALK positive tumors. This open-label, multicenter, first-in-human phase I study ( NCT01284192 ) assessed the safety, pharmacokinetic profile, and antitumor activity of ASP3026. METHODS: Advanced solid tumor patients received oral ASP3026 in 3 + 3 dose-escalation cohorts at doses of 25-800 mg once daily in 28-day cycles. The endpoints were to identify the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the pharmacokinetic profile of ASP3026. A phase Ib expansion cohort enrolled patients with metastatic, crizotinib-resistant ALK-positive solid tumors at the RP2D, and response was evaluated by RECIST 1.1. RESULTS: The dose-escalation cohort enrolled 33 patients, including three crizotinib-resistant, ALK-positive patients, and the dose-expansion cohort enrolled another 13 crizotinib-resistant, ALK-positive non-small cell lung cancer (NSCLC) patients. ASP3026 demonstrated both linear pharmacokinetics and dose proportional exposure for area under the plasma concentration-time curve and maximum concentration observed with a median terminal half-life of 35 h, supporting the daily dosing. Grade 3 rash and elevated transaminase concentrations were dose-limiting toxicities observed at 800 mg; hence, 525 mg daily was the MTD and RP2D. The most common treatment-related adverse events were nausea (38%), fatigue (35%), and vomiting (35 %). Among the 16 patients with crizotinib-resistant ALK-positive tumors (15 NSCLC, 1 neuroblastoma), eight patients achieved partial response (overall response rate 50%; 95% confidence interval 25-75%) and seven patients (44%) achieved stable disease. CONCLUSIONS: ASP3026 was well tolerated and had therapeutic activity in patients with crizotinib-resistant ALK-positive advanced tumors. TRIAL REGISTRATION: ClinTrials.gov: NCT01284192. PMID- 26966028 TI - Robotic-Assisted Versus Laparoscopic Colectomy Results in Increased Operative Time Without Improved Perioperative Outcomes. AB - BACKGROUND: Interest in robotic technology is burgeoning within the field of colorectal surgery. However, benefits of robotic-assisted colectomy (RAC) compared with laparoscopic colectomy (LC) remain ambiguous. STUDY DESIGN: Patients who underwent minimally invasive colectomy during 2012-2013 were identified from the National Surgical Quality Improvement Program (NSQIP) database. Short-term perioperative outcomes were compared between 1:1 propensity matched groups. A subset analysis was performed among patients who underwent segmental resections. RESULTS: Among the 15,976 patients included, 498 (3.1 %) colectomies were performed with robotic assistance. After matching for demographic, clinical, and treatment characteristics, there were no differences between RAC and LC in complications such as wound infection, urinary tract infection, cardiopulmonary or thromboembolic events, renal insufficiency, anastomotic leaks, transfusions, readmissions, or 30-day mortality (all p > 0.05). However, operative time was markedly higher for RAC (196 vs. 166 min, p < 0.001). Among segmental resections, operative time remained significantly longer for RAC (190 vs. 153 min, p < 0.001) without differences in perioperative outcomes (all p > 0.05). CONCLUSION: In this early experience, RAC resulted in similar perioperative outcomes when compared to LC but was associated with longer operative time. Given the focus on value-based healthcare, utilizing RAC in straightforward colectomies may not be financially justifiable at this stage of adoption. PMID- 26966030 TI - [How to assess the neutral position of the fetus for the crown-rump length measurement at the nuchal translucency scan]. AB - OBJECTIVES: The objective of this study was to establish a simple and reproducible method for the assessment of the fetal head position when measuring crown-rump length (CRL) at the nuchal translucency scan. METHODS: Two observers conducted a retrospective analysis of a consecutive series of 570 images of CRL collected by the French College of Fetal Echography (CFEF) national practice assessment program for the first-trimester scan. The images were deemed hyper flexed if no fluid was visible between the chin and the chest of the fetus. The images were deemed hyper-extended if the angle between the palate and the CRL line was 90 degrees or more. The images were deemed neutral if no hyper extension nor hyper-flexion was observed. RESULTS: The proportion of agreement for a non-neutral position of the fetal head was 91.3% (kappa=0.80, 95% CI [0.75 to 0.86]). Images with a non-neutral position corresponded to poor CRL quality images according to the CFEF score (relative risk=4.2, 95% CI [2.9 to 6.1] for one observer and 4.9, 95% CI [3.3 to 7.2] for the other observer). Proportions of agreement for the hyper-flexion and for the hyper-extension were 94.6% (kappa=0.80, 95% CI [0.72 to 0.87]) and 96.8% (kappa=0.81, 95% CI [0.72 to 0.90]), respectively. No additional lines were drawn on the ultrasound images during the evaluation process. CONCLUSIONS: The proposed method for evaluating the extent to which the fetal head has a non-neutral position at measurement of the CRL appears both simple and reproducible. PMID- 26966029 TI - ALAIN01--Alemtuzumab in autoimmune inflammatory neurodegeneration: mechanisms of action and neuroprotective potential. AB - BACKGROUND: Alemtuzumab (Lemtrada(r)) is a newly approved therapeutic agent for relapsing-remitting multiple sclerosis (RRMS). In previous phase II and III clinical trials, alemtuzumab has proven superior efficacy to subcutaneous interferon beta-1a concerning relapse rate and disability progression with unprecedented durability and long-lasting freedom of disease activity. The humanized monoclonal antibody targets CD52, leading to a rapid and long-lasting depletion, especially of B and T cells. Arising from hematopoietic precursor cells a fundamental reprogramming of the immune system restores tolerogenic networks effectively suppressing autoimmune inflammatory responses in the central nervous system (CNS). Despite its favourable effects alemtuzumab holds a severe risk of side effects with secondary autoimmunity being the most considerable. Markers for risk stratification and treatment response improving patient selection and therapy guidance are a big unmet need for MS patients and health care providers. METHODS/DESIGN: This is a mono center, single arm, explorative phase IV study including 15 patients with highly active RRMS designed for 3 years. Patients will be studied by a high-resolution analysis comprising a repertoire of various immunological assays for the detection of immune cells and their function in peripheral blood as well as the cerebrospinal fluid (CSF). These assays encompass a number of experiments investigating immune cell subset composition, activation status, cytokine secretion, migratory capacity, potential neuroprotective properties and cytolytic activity complemented by instrument based diagnostics like MRI scans, evoked potentials and optical coherence tomography (OCT). DISCUSSION: Our study represents the first in-depth and longitudinal functional analysis of key immunological parameters in the periphery and the CNS compartment underlying the fundamental effects of alemtuzumab in MS patients. By combining clinical, experimental and MRI data our study will provide a deeper understanding of alemtuzumab's mechanisms of action (MOA) potentially identifying immune signatures associated with treatment response or the development of secondary autoimmunity. After validation in larger cohorts this might help to improve efficacy and safety of alemtuzumab therapy in RRMS patients. TRIAL REGISTRATION: NCT02419378 (clinicaltrials.gov), registered 31 March 2015. PMID- 26966031 TI - Prenatal diagnosis of bilateral multicystic dysplastic kidney in three siblings. PMID- 26966032 TI - [A male breast cancer differential diagnosis: Calcific epithelioma of Malherbe or Pilomatrixoma]. PMID- 26966033 TI - [Acquired caustic vagina stenosis: Surgical outcomes of 21 cases]. AB - OBJECTIVE: To document epidemiology, causes, anatomical varieties and surgical management outcomes of caustic acquired vagina stenosis. METHODOLOGY: Retrospective study of 21 patients involved from 1996 to 2012 at the department of obstetrics and gynecology of Yopougon's teaching hospital in Abidjan, Cote d'Ivoire. Vaginal stenosis due to genital malformation, vaginal irradiation of pelvic tumours, repair of bladder and vaginal fistulae or intersexual disorders were excluded. RESULTS: The prevalence was 0.14/1000 admissions, mean age was 32.1 years, mean gravidity was 1.76 and mean parity was 1.1. Vaginal stenosis seat and extent were variable and 100 % had a caustic origin by use of traditional medicine vaginal pessaire. Of the patients, 95.2 % underwent surgical treatment followed by several dilations sessions with glass dilators. Successful surgical outcome allowing coitus was achieved in 47.6 % of cases with 52.4 % failure. CONCLUSION: Acquired caustic vagina stenosis are frequently occurring and are a public health problem related to ignorance. Health education and establishment of expert centers with exchange of experiences in West Africa should be able to improve surgical outcomes. PMID- 26966034 TI - [Thyroid function for infertile women during ovarian hyperstimulation as part of IVF]. AB - OBJECTIVES: Optimal thyroid function is necessary for an effective fertility. Many authors have suggested that thyroid function has an impact on IVF outcome. Conversely, IVF has been suggested to induce changes in thyroid function. The aim of this study was to determine the nature and the timing of alterations in thyroid function, throughout controlled ovarian hyperstimulation, from the beginning of therapy to the day of triggering ovulation. And make a clarification of the current recommendations of the thyroid function during hormonal stimulation. METHODS: Subjects were recruited from March 2013 to July 2013 at the Hospital of the University of Reims. The studied population consisted of 50 infertile patients who had undergone IVF/ICSI cycles. Thyroid axis exploration was realized before therapy and at every hormonal dosage during ovarian monitorage. RESULTS: Prematuary fluctuations were observed without impact on pregnancy rate. We could detect potential hypothyroid women thanks to this dosage and define a connection between pregnancy rate and TSH with a threshold closer to 1mUI/L than 2,5mUI/L defined by the endocrine society. CONCLUSIONS: The link between thyroid function, forecast of conception and pregnancy is well documented. Currently, there is no recommendation on the rate of TSH targets for the patients in medical assisted procreation. PMID- 26966035 TI - [Misleading diagnosis of hyperprolactinemia in women]. AB - Prolactin is a major hormone, involved in gonadotroph axis regulation. Hyperprolactinemia induces gonadotropin deficiency and therefore hypogonadotropic hypogonadism. It should be suspected in front of menstrual cycle abnormalities, infertility and/or galactorrhea. If drugs and/or PRL adenoma represent the vast majority of causes of hyperprolactinemia, other etiologies and misleading diagnosis of hyperprolactinemia should be searched for. After eliminating a pregnancy, in women of childbearing age, the first step is to interpret the result of hyperprolactinemia, according to the assay technique used. Indeed, the major active form of prolactin is the 23kDA non-glycosylated prolactin. However, some assays interfere with macroprolactinemia, an inactive form of prolactin, including glycosylated prolactin bound to an IgG immunoglobulin. Its presence in the serum is misleading as it may induce increased levels of prolactin, usually below 100 ng/mL. The diagnosis of macroprolactinemia has major issues as pituitary MRI does not need to be performed. Furthermore, neither treatment nor follow-up of patients with macroprolactinemia are necessary. It should be suspected in the presence of normal menstrual cycles. Drugs inducing hyperprolactinemia usually raise prolactin levels below 100 ng/mL. If prolactin level is higher than 250 ng/mL, the main diagnosis is pituitary macro-adenoma. If prolactin ranges between 100 and 250 ng/mL, it is usually related to a micro adenoma or a necrotic macro-adenoma. A mixed PRL/GH should always be suspected. If prolactin level is below 150 ng/mL, in the presence of a large hypothalamic pituitary tumor, the major diagnosis is hyperprolactinemia due to pituitary disconnection. Ectopic secretions of prolactin remain very rare. A new etiology of hyperprolactinemia is loss of function mutation of prolactin receptor. PMID- 26966036 TI - [Contribution of a virtual hysteroscopic simulator in the learning of hysteroscopic myoma resection]. AB - OBJECTIVES: Uterine myomas are a frequent pathology affecting 20% of women of reproductive age. Myomas induce abnormal uterine bleeding, pelvic pain and increase the risk of infertility and obstetrical complications. Symptomatic sub mucosal myomas are classically treated by hysteroscopic resection. Simulation is a method of education and training. It could improve quality and security of cares. The aim of this study is to assess the interest of a hysteroscopic simulator for the resection of myoma by novice surgeons. METHODS: Twenty medical students were recruited, in a prospective study, in august 2014. The virtual reality simulator VirtaMed HystSimTM (VirtaMed AG, Zurich, Switzerland) was used to perform the hysteroscopic training. All students received a short demonstration of myoma resection. The practice consists of a submucous myoma type 0 resection. The procedure and the evaluation were performed before and after a specific training in hysteroscopic resection of sixty minutes long. The main outcome criteria were time for the resection before and after training. The second criteria were fluid quantity used, number of contact between optic and uterine cavity and uterine perforation. RESULTS: Twenty students aged from 22 to 24 years were included. The time for the procedure was significantly reduced after training (170s versus 335s, P<0.01). There is the same for fluid quantity used (335 mL versus 717mL, P<0.01) and the number of contact between optic and uterine cavity (0.2 contact versus 3, P=0.012). No perforation occurred in the simulation. CONCLUSION: The results suggest that hysteroscopic simulator enhances and facilitates hysteroscopic resection for novice surgeons. PMID- 26966037 TI - [Uterine volume and vaginal hysterectomy: Interest and limits of uterine morcellation]. AB - Abdominal hysterectomy remains the preferred approach for large uteri or in case of narrow vaginal access. However, the traditional morcellation techniques allow safe and efficient extraction when choosing the vaginal route. Uterine volume reductive techniques do not increase perioperative morbidity thus complications do not seem to be linked to uterine size. There are numerous advantages of the vaginal route in comparison with laparotomy, such as aesthetic benefits, decreased postoperative pain, reduced hospital stay and recovery as well as decreased perioperative morbidity. Compared to laparoscopy, surgical outcomes and blood loss of the vaginal approach of a large uterus seem to be similar. Nevertheless, laparoscopic hysterectomy is associated with longer operative time and significant increase in hospital cost. Hence, a thorough knowledge and mastery of uterine morcellation techniques are essential when performing vaginal hysterectomy for large uteri or when the vagina is narrow. They must therefore continue to be taught, spread and regularly used in order to stretch the indications for vaginal hysterectomy in favour of an abdominal approach. PMID- 26966038 TI - Current Status of Lymph Node Imaging in Bladder and Prostate Cancer. AB - The bladder and the prostate have a multitude of primary lymphatic landing sites, making the sentinel node concept inapplicable in patients with bladder or prostate cancer. However, some imaging techniques may be helpful in guiding surgeons for the removal of suspicious nodes that would not have been resected in a standardized template. Despite the multitude of new imaging techniques available today, a meticulous histologic workup of lymph nodes retrieved by an extended pelvic lymph node dissection still has the highest accuracy for detection of lymph node metastases in bladder or prostate cancer. PMID- 26966039 TI - Evaluation and Impact of Workflow Interruptions During Robot-assisted Surgery. AB - OBJECTIVE: To analyze and categorize causes for interruptions during robot assisted surgery. METHODS: We analyzed 10 robot-assisted prostatectomies that were performed by 3 surgeons from October 2014 to June 2015. Interruptions to surgery were defined in terms of duration, stage of surgery, personnel involved, reasons, and impact of the interruption on the surgical workflow. RESULTS: The main reasons for interruptions included the following: console surgeons switching (29%); preparation of the surgical equipment, such as cleaning or changing the camera (29%) or an instrument (27%); or when a suture, stapler, or clip was needed (12%). The most common interruption duration was 10-29 seconds (47.6%), and the least common interruption duration was greater than 90 seconds (3.6%). Additionally, about 14% of the interruptions were considered avoidable, whereas the remaining 86% of interruptions were necessary for surgery. CONCLUSION: By identifying and analyzing interruptions, we can develop evidence-based strategies to improve operating room efficiency, lower costs, and advance patient safety. PMID- 26966040 TI - Reply by the Authors. PMID- 26966041 TI - Reply by the Authors. PMID- 26966042 TI - Re: Han et al: The Prevalence and Association of Varicoceles on Male Patients With Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms (Urology 2016;90:97-100). PMID- 26966044 TI - Re: Han et al: The Prevalence and Association of Varicoceles on Male Patients With Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms (Urology 2016;90:97-100). PMID- 26966043 TI - Diagnostic Value of Guided Biopsies: Fusion and Cognitive-registration Magnetic Resonance Imaging Versus Conventional Ultrasound Biopsy of the Prostate. AB - OBJECTIVE: To better assess the increased utilization of multiparametric magnetic resonance imaging (mpMRI) and fusion biopsy of the prostate, we compared prostate cancer detection rates among (a) men undergoing MR-ultrasound (US) fusion biopsy, (b) mpMRI cognitive-registration biopsy, and (c) conventional transrectal US guided biopsy for the detection of prostate cancer. MATERIALS AND METHODS: We present a retrospective review of consecutive patients undergoing mpMRI of the prostate with subsequent prostate biopsy from October 2013 to September 2015. Lesions concerning for prostate cancer visualized on mpMRI were targeted with cognitive-registration or MR-US fusion biopsies. A cohort of men undergoing conventional prostate biopsy was utilized for comparison. Rates of cancer detection were compared among the 3 cohorts. RESULTS: A total of 231 patients underwent mpMRI-targeted biopsy (81 fusion, 150 cognitive). There was no difference in prostate specific antigen, mpMRI-defined Prostate Imaging Reporting and Data System score or number of lesions, or history of prostate cancer among the cohorts. The overall detection rate of cancer was significantly higher in the fusion cohort (48.1%) compared with both the cognitive (34.6% P = .04) and conventional (32.0%, P = .03) cohorts. Cancer detection rates were comparable in the MRI-cognitive and transrectal prostate US biopsy groups (34.6% vs 32%). MR fusion detected significantly more Gleason >=7 cancer (61.5 vs 37.5%, P = .04) and significantly less Gleason 6 cancer (38.5 vs 62.5%, P = .04) compared with conventional biopsy. CONCLUSION: Targeted biopsy of the prostate using MR-US fusion increased the cancer detection rate compared with both cognitive registration and conventional biopsy and was associated with detection of higher grade cancer compared with conventional biopsy. PMID- 26966046 TI - Intramedullary nailing has sufficient durability for metastatic femoral fractures. AB - BACKGROUND: Surgical treatment options of femoral metastases include intramedullary nailing (IMN) and endoprosthetic reconstruction (EPR). Previous studies have demonstrated functional and oncological advantages of EPR over IMN. The purpose of this study was to (1) report the durability of IMN and (2) establish the indication of IMN for femoral metastases. METHODS: In 2003-2013, among 186 surgically treated femoral metastasis cases, we retrospectively reviewed 80 consecutive IMN cases in 75 patients, including 14 pathological and 66 impending fractures. For the decision of surgical procedure (IMN, EPR, or plating), the following factors are considered: (1) fracture pattern (impending or pathological fracture), (2) Mirels' score (>=8 or <8), (3) fracture site (femoral head, neck, intertrochanter, subtrochanter, diaphysis, or distal), (4) number of metastases (solitary or multiple), and (5) patient's estimated prognosis. Patient demographics, postoperative survival, implant survival, and early postoperative mortality were reviewed. RESULTS: The patients were 37 males and 38 females, with a mean age of 60.1 (20-84) years. Average follow-up period was 11.4 (1-77) months. The most common fracture site was the subtrochanter (46/80), followed by the diaphysis (26/80) and the intertrochanter (8/80). The most common primary tumor was lung cancer (24/80, 32%), followed by breast cancer (24%) and melanoma (15%). With the exception of six cases, all patients underwent postoperative radiotherapy to the affected whole femur. The postoperative patient survival was 14.2 and 8.4% at 2 and 3 years from surgery, respectively, while the implant survival rate remained 94.0% at both 2 and 3 years. Three out of 46 subtrochanteric cases required revision surgeries because of proximal breakage of implant 4-50 months after initial surgery for femoral metastases, but all were replaced by mega-prosthesis and did not need further operation until their death. Early postoperative fatal complications were observed in three patients, all of which were pulmonary dysfunction. CONCLUSIONS: The performance of IMN in this study was satisfactory although a large portion of sub- and intertrochanter metastases were included. Broader indication including these parts should be considered, for IMN has advantages such as lower cost and less invasiveness and even an implant failure can be revised by mega-prosthetic reconstruction. PMID- 26966047 TI - Update on hepatitis E virology: Implications for clinical practice. AB - Hepatitis E virus (HEV) is a positive-strand RNA virus transmitted by the fecal oral route. The 7.2kb genome encodes three open reading frames (ORF) which are translated into (i) the ORF1 polyprotein, representing the viral replicase, (ii) the ORF2 protein, corresponding to the viral capsid, and (iii) the ORF3 protein, a small protein involved in particle secretion. Although HEV is a non-enveloped virus in bile and feces, it circulates in the bloodstream wrapped in cellular membranes. HEV genotypes 1 and 2 infect only humans and cause mainly waterborne outbreaks. HEV genotypes 3 and 4 are widely represented in the animal kingdom and are transmitted as a zoonosis mainly via contaminated meat. HEV infection is usually self-limited but may persist and cause chronic hepatitis in immunocompromised patients. Reduction of immunosuppressive treatment or antiviral therapy with ribavirin have proven effective in most patients with chronic hepatitis E but therapy failures have been reported. Alternative treatment options are needed, therefore. Infection with HEV may also cause a number of extrahepatic manifestations, especially neurologic complications. Progress in the understanding of the biology of HEV should contribute to improved control and treatment of HEV infection. PMID- 26966049 TI - Intra-cycle variation of the uterine cavity indentation assessed with three dimensional ultrasound in natural and stimulated cycles. AB - The recent ESHRE-ESGE classification for female genital anomalies attempts to promote objectivity in diagnosis of normal and septate uteri. The aim of this study was to ascertain whether the uterine cavity indentation - the characteristic feature of septate uteri - varies significantly throughout the cycle. Seventy consecutive women underwent three-dimensional ultrasound twice: 35 during the proliferative and luteal phase of a natural cycle, and 35 during the first and final day of a stimulated cycle. Endometrial thickness, interostial distance, cavity indentation and percentage of cavity indentation were all assessed in accordance with the ESHRE-ESGE consensus on diagnosis of female genital anomalies. Overall, throughout both cycles, there was a significant increase in endometrial thickness (from 4.6 mm to 10.2 mm; P < 0.001) and interostial distance (from 30.1 mm to 35.1 mm; P < 0.001), which was associated with a significant reduction in the percentage of cavity indentation (from 30.3% to 15.0%; P < 0.001). Between the first and second assessment, 3/70 (4.3%) patients had a change in diagnosis from septate to normal uterus, although this did not reach statistical significance. This observation of a significant intra cycle variation of the uterine cavity indentation has important implications for both clinical practice and research. PMID- 26966048 TI - Pharmacotherapy for Dravet Syndrome. AB - Dravet syndrome (DS) is an intractable pediatric epilepsy syndrome, starting in early childhood. This disorder typically manifests with febrile status epilepticus, and progresses to a multifocal epilepsy with febrile and non-febrile seizures with encephalopathy. Most cases are due to a mutation in the SCN1A gene. This article reviews treatments for DS, with an emphasis on pharmacotherapy. While many medications are used in treating the seizures associated with DS, these patients typically have medically refractory epilepsy, and polytherapy is often required. First-line agents include valproate and clobazam, although there are supportive data for topiramate, levetiracetam, stiripentol and the ketogenic diet. Other agents such as fenfluramine are promising therapies for Dravet syndrome. Sodium channel-blocking anticonvulsants such as carbamazepine and lamotrigine are generally contraindicated in this syndrome. Nonpharmacologic therapies (such as neurostimulation or surgery) are understudied in DS. Because DS is a global encephalopathy, pharmacologic treatment of non-epileptic manifestations of the disease is often necessary. Attention-deficit hyperactivity disorder is often encountered in patients with DS, and psychostimulants can be helpful for this indication. Other psychoactive drugs are less studied in this context. Extrapyramidal and gait disorders are often encountered in DS as well. While DS is a severe epileptic encephalopathy with a high (up to 15 %) mortality rate in childhood, careful pharmacologic management can improve these patients' clinical picture and quality of life. PMID- 26966050 TI - Annexin A5 haplotype M2 is not a risk factor for recurrent spontaneous abortion in Northern Europe: is there sufficient evidence? AB - The M2 haplotype of the annexin A5 gene is a well-recognized predisposition factor for recurrent spontaneous abortion (RSA). A recent publication by Nagirnaja et al. (2015) in PLoS One discusses the risk role of the M2 haplotype for RSA in cases compared with controls of North European extraction and arrives at a negative result. As a number of previous and fairly recent studies have supported the proposed involvement of the M2 haplotype in the cause of idiopathic RSA, this commentary aims to highlight problematic issues in the above publication. It is the opinion of the authors that the study by Nagirnaja et al. (2015) does not generate adequate proof of the absence of RSA risk, attributable to carriage of the M2 haplotype. PMID- 26966045 TI - Comparative genomics analysis of mononuclear phagocyte subsets confirms homology between lymphoid tissue-resident and dermal XCR1(+) DCs in mouse and human and distinguishes them from Langerhans cells. AB - Dendritic cells (DC) are mononuclear phagocytes which exhibit a branching (dendritic) morphology and excel at naive T cell activation. DC encompass several subsets initially identified by their expression of cell surface molecules and later shown to possess distinct functions. DC subset differentiation is orchestrated by transcription factors, growth factors and cytokines. Identifying DC subsets is challenging as very few cell surface molecules are uniquely expressed on any one of these cell populations. There is no standard consensus to identify mononuclear phagocyte subsets; varying antigens are employed depending on the tissue and animal species studied and between laboratories. This has led to confusion in how to accurately define and classify DCs across tissues and between species. Here we report a comparative genomics strategy that enables universal definition of DC and other mononuclear phagocyte subsets across species. We performed a meta-analysis of several public datasets of human and mouse mononuclear phagocyte subsets isolated from blood, spleen, skin or cutaneous lymph nodes, including by using a novel and user friendly software, BubbleGUM, which generates and integrates gene signatures for high throughput gene set enrichment analysis. This analysis demonstrates the equivalence between human and mouse skin XCR1(+) DCs, and between mouse and human Langerhans cells. PMID- 26966051 TI - Ultrastructural features of the differentiating thyroid primordium in the sand lizard (Lacerta agilis L.) from the differentiation of the cellular cords to the formation of the follicular lumen. AB - The differentiation of the thyroid primordium of lacertilian species is poorly understood. The present study reports on the ultrastructural analysis of the developing thyroid primordium in the sand lizard (Lacerta agilis) during the early stages of differentiation. The early thyroid primordium of sand lizard embryos was composed of cellular cords that contained single cells with a giant lipid droplet, which were eliminated by specific autophagy (lipophagy). The follicular lumens at the periphery of the primordium differentiated even before the division of the cellular cords. When the single cells within the cords started to die through paraptosis, the adjacent cells started to polarise and junctional complexes began to form around them. After polarisation and clearing up after the formation of the lumens, the cellular cords divided into definitive follicles. The cellular cords in the central part of the primordium started to differentiate later than those at the periphery. The cellular cords divided into presumptive follicles first and only later differentiated into definitive follicles. During this process, a population of centrally located cells was removed through apoptosis to form the lumen. Although the follicular lumen in sand lizard embryos is differentiated by cavitation similar to that in the grass snake, there were very important differences during the early stages of the differentiation of the cellular cords and the formation of the thyroid follicles. PMID- 26966052 TI - Targeting Comorbidities in Elderly Patients With Heart Failure: The OPTIMIZE HFPEF Trial. PMID- 26966053 TI - Household survey analysis of the impact of comprehensive strategies to improve the expanded programme on immunisation at the county level in western China, 2006 2010. AB - OBJECTIVE: To evaluate interventions to improve routine vaccination coverage and caregiver knowledge in China's remote west, where routine immunisation is relatively weak. DESIGN: Prospective pre-post (2006-2010) evaluation in project counties; retrospective comparison based on 2004 administrative data at baseline and surveyed post-intervention (2010) data in selected non-project counties. SETTING: Four project counties and one non-project county in each of four provinces. PARTICIPANTS: 3390 children in project counties at baseline, and 3299 in project and 830 in non-project counties post-intervention; and 3279 caregivers at baseline, and 3389 in project and 830 in non-project counties post intervention. INTERVENTION: Multicomponent inexpensive knowledge-strengthening and service-strengthening and innovative, multisectoral engagement. DATA COLLECTION: Standard 30-cluster household surveys of vaccine coverage and caregiver interviews pre-intervention and post-intervention in each project county. Similar surveys in one non-project county selected by local authorities in each province post-intervention. Administrative data on vaccination coverage in non-project counties at baseline. PRIMARY OUTCOME MEASURES: Changes in vaccine coverage between baseline and project completion (2010); comparative caregiver knowledge in all counties in 2010. ANALYSIS: Crude (chi(2)) analysis of changes and differences in vaccination coverage and related knowledge. Multiple logistic regression to assess associations with timely coverage. RESULTS: Timely coverage of four routine vaccines increased by 21% (p<0.001) and hepatitis B (HepB) birth dose by 35% (p<0.001) over baseline in project counties. Comparison with non project counties revealed secular improvement in most provinces, except new vaccine coverage was mostly higher in project counties. Ethnicity, province, birthplace, vaccination site, dual-parental out-migration and parental knowledge had significant associations with coverage. Knowledge increased for all variables but one in project counties (highest p<0.05) and was substantially higher than in non-project counties (p<0.01). CONCLUSIONS: Comprehensive but inexpensive strategies improved vaccination coverage and caretaker knowledge in western China. Establishing multisectoral leadership, involving the education sector and including immunisation in public-sector performance standards, are affordable and effective interventions. PMID- 26966054 TI - Prevalence of alcohol and drug use in injured British Columbia drivers. AB - OBJECTIVES: Determine the prevalence of drug use in injured drivers and identify associated demographic factors and crash characteristics. DESIGN: Prospective cross-sectional study. SETTING: Seven trauma centres in British Columbia, Canada (2010-2012). PARTICIPANTS: Automobile drivers who had blood obtained within 6 h of a crash. MAIN OUTCOME MEASURES: We analysed blood for cannabis, alcohol and other impairing drugs using liquid chromatography/mass spectrometry (LCMS). RESULTS: 1097 drivers met inclusion criteria. 60% were aged 20-50 years, 63.2% were male and 29.0% were admitted to hospital. We found alcohol in 17.8% (15.6% to 20.1%) of drivers. Cannabis was the second most common recreational drug: cannabis metabolites were present in 12.6% (10.7% to 14.7%) of drivers and we detected Delta-9-tetrahydrocannabinol (Delta-9-THC) in 7.3% (5.9% to 9.0%), indicating recent use. Males and drivers aged under 30 years were most likely to use cannabis. We detected cocaine in 2.8% (2.0% to 4.0%) of drivers and amphetamines in 1.2% (0.7% to 2.0%). We also found medications including benzodiazepines (4.0% (2.9% to 5.3%)), antidepressants (6.5% (5.2% to 8.1%)) and diphenhydramine (4.7% (3.5% to 6.2%)). Drivers aged over 50 years and those requiring hospital admission were most likely to have used medications. Overall, 40.1% (37.2% to 43.0%) of drivers tested positive for alcohol or at least one impairing drug and 12.7% (10.7% to 14.7%) tested positive for more than one substance. CONCLUSIONS: Alcohol, cannabis and a broad range of other impairing drugs are commonly detected in injured drivers. Alcohol is well known to cause crashes, but further research is needed to determine the impact of other drug use, including drug-alcohol and drug-drug combinations, on crash risk. In particular, more work is needed to understand the role of medications in causing crashes to guide driver education programmes and improve public safety. PMID- 26966055 TI - Determinants of postnatal depression in Sudanese women at 3 months postpartum: a cross-sectional study. AB - OBJECTIVES: Maternal mental health is a neglected issue in Sudanese healthcare. The aim of this study was to explore the factors associated with postnatal depression (PND) at 3 months postpartum in a sample of Sudanese women in Khartoum state. SETTING: Recruitment was from two major public antenatal care (ANC) clinics in two maternity teaching hospitals in Khartoum state. The study participants were recruited during their pregnancy and were followed up and screened for PND at 3 months postpartum using the Edinburgh Postnatal Depression Scale (EPDS). PARTICIPANTS: A sample of 300 pregnant Sudanese women in their second or third trimester was included in the study. The inclusion criteria were Sudanese nationality, pregnancy in the second or third trimester and satisfactory contact information. OUTCOME MEASURES: PND was assessed using the EPDS at a cut off score of >= 12. Maternal and sociodemographic factors of interest were illustrated in a directed acyclic graph (DAG) to identify which variables to adjust for in multivariate analyses and to show their type of effect on PND. A forward logistic regression model was built to assess the factors that are independently associated with PND. RESULTS: History of violence increased the odds of PND sevenfold, OR=7.4 (95% CI 1.9 to 27.6). Older age of mothers decreased the odds of PND by almost 20%, OR=0.82 (95% CI 0.73 to 0.92). Exclusive breast feeding and regular prenatal vitamins during pregnancy are associated with an 80% decrease in odds of PND, OR=0.2 (95% CI 0.06 to 0.70) and 0.17 (95% CI 0.06 to 0.5), respectively. CONCLUSIONS: Factors associated with PND in this study are comparable to factors from other developing countries, although findings should be judged with caution owing to the high number of women who refused recruitment into the study. PMID- 26966056 TI - What factors are important for deprescribing in Australian long-term care facilities? Perspectives of residents and health professionals. AB - OBJECTIVES: Polypharmacy and multimorbidity are common in long-term care facilities (LTCFs). Reducing polypharmacy may reduce adverse events and maintain quality of life. Deprescribing refers to reducing medications after consideration of therapeutic goals, benefits and risks, and medical ethics. The objective was to use nominal group technique (NGT) to generate then rank factors that general medical practitioners (GPs), nurses, pharmacists and residents or their representatives perceive are most important when deciding whether or not to deprescribe medications. DESIGN: Qualitative research using NGT. SETTING: Participants were invited if they worked with, or resided in LTCFs across metropolitan and regional South Australia. PARTICIPANTS: 11 residents/representatives, 19 GPs, 12 nurses and 14 pharmacists participated across six separate groups. METHODS: Individual groups of GPs, nurses, pharmacists and residents/representatives were convened. Using NGT each group ranked factors perceived to be most important when deciding whether or not to deprescribe. Then, using NGT, the prioritised factors from individual groups were discussed and prioritised by a multidisciplinary metropolitan and regional group comprised of resident representatives, GPs, nurses and pharmacists. RESULTS: No two groups had the same priorities. GPs ranked 'evidence for deprescribing' and 'communication with family/resident' as most important factors. Nurses ranked 'GP receptivity to deprescribing' and 'nurses ability to advocate for residents' as most important. Pharmacists ranked 'clinical appropriateness of therapy' and 'identifying residents' goals of care' as most important. Residents ranked 'wellbeing of the resident' and 'continuity of nursing staff' as most important. The multidisciplinary groups ranked 'adequacy of medical and medication history' and 'identifying residents' goals of care' as most important. CONCLUSIONS: While each group prioritised different factors, common and contrasting factors emerged. Future deprescribing interventions need to consider the similarities and differences within the range of factors prioritised by residents and health professionals. PMID- 26966057 TI - Health service utilisation for anogenital warts in Ontario, Canada prior to the human papillomavirus (HPV) vaccine programme introduction: a retrospective longitudinal population-based study. AB - OBJECTIVE: Trends in occurrence of anogenital warts (AGWs) can provide early evidence of human papillomavirus (HPV) vaccination programme impact on preventing HPV infection and HPV-induced lesions. The objective of this study was to provide a baseline of AGW epidemiology in Ontario prior to the introduction of the publicly-funded school-based HPV vaccination programme in September 2007. SETTING AND PARTICIPANTS: As a retrospective longitudinal population-based study, we used health administrative data as a proxy to estimate incident AGWs and total health service utilisation (HSU) for AGWs for all Ontario residents 15 years and older with valid health cards between 1 April 2003 and 31 March 2007. OUTCOME MEASURES: The outcome of interest was AGW healthcare utilisation identified using the International Classification of Diseases, 10th revision (ICD-10) diagnostic code for AGWs, as well as an algorithm for identifying AGW physician office visits in a database with a unique system of diagnostic and procedural codes. An AGW case was considered incident if preceded by 12 months without HSU for AGWs. Time trends by age group and sex were analysed. RESULTS: Between fiscal years 2003 and 2006, we identified 123,247 health service visits for AGWs by 51,436 Ontario residents 15 years and older. Incident AGWs peaked in females and males in the 21 23 year age group, at 3.74 per 1000 and 2.81 per 1000, respectively. HSU for AGWs peaked in females and males within the 21-23 year age group, at 9.34 per 1000 and 7.22 per 1000, respectively. CONCLUSIONS: To the best of our knowledge, this is the first population-based study of AGW incidence and HSU in Ontario. The sex and age distribution of individuals with incident and prevalent AGWs in Ontario was similar to that of other provinces before HPV vaccine programme implementation in Canada. PMID- 26966059 TI - Pregnancy history and current use of contraception among women of reproductive age in Burundi, Kenya, Rwanda, Tanzania and Uganda: analysis of demographic and health survey data. AB - OBJECTIVE: To examine the relationship between pregnancy history and the use of contraception among women of reproductive age (15-49 years) in East Africa. METHODS: Demographic and Health Surveys data from Burundi (2010), Kenya (2008 2009), Rwanda (2010), Tanzania (2010) and Uganda (2011) were used in the analysis. Logistic regression was used to determine the effects of women's pregnancy history on their use of contraception. SETTING: Burundi, Kenya, Rwanda, Tanzania and Uganda. PARTICIPANTS: 3226, 2377, 4396, 3250 and 2596 women of reproductive age (15-49 years) from Burundi, Kenya, Rwanda, Tanzania and Uganda, respectively, were included in the analysis. RESULTS: Women who had experienced a mistimed pregnancy were more likely to use a modern contraceptive method during their most recent sexual encounter in Kenya, Rwanda, Burundi and Uganda. Other significant correlates of women's contraceptive use were: desire for more children, parity, household wealth, maternal education and access information through radio. In-country regional differences on use of modern contraceptive methods were noted across five East African countries. CONCLUSIONS: Women's birth histories were significantly associated with their decision to adopt a modern contraceptive method. This highlights the importance of considering women's birth histories, especially women with mistimed births, in the promotion of contraceptive use in East Africa. Variations as a result of place of residency, educational attainment, access to family planning information and products, and wealth ought to be addressed in efforts to increase use of modern contraceptive methods in the East African region. PMID- 26966058 TI - Study protocol for a single-blind, placebo-controlled randomised trial of Tianjiu effects in patients with intradialytic hypotension. AB - INTRODUCTION: Intradialytic hypotension (IDH) is the most frequent complication of haemodialysis (HD) and may contribute to cardiovascular events and high mortality. The aetiology of IDH is multifactorial; therefore, it remains a challenging problem in the management of patients with HD. Since the application of Tianjiu at specific points can influence haemodynamics, we hypothesise that Tianjiu therapy at the traditionally used meridian points will reduce the severity of hypotension in patients who undergo HD. METHODS/ANALYSIS: In this clinical trial, eligible patients with IDH will be divided randomly and equally into a Tianjiu group and a control group for 4 weeks. In the Tianjiu group, the patients will have Tianjiu applied at three points (conception vessel 4, and bilateral kidney 1) during each HD session. In the control group, patients will have clay patches applied in the same way as those in the Tianjiu treatment group. Both groups will be followed up for 2 weeks. The primary outcome measure will be the percentage of target ultrafiltration achieved, defined as the actual ultrafiltration volume divided by the target ultrafiltration volume. Secondary outcome measures, including frequency of IDH episodes and number of nursing interventions during HD sessions, predialysis and postdialysis blood pressure (BP), patient's participative assessment of the degree of fatigue after dialysis (scale from 0, not at all, to 10, extremely), and recovery time from fatigue after dialysis will be recorded at the 0th and 4th weeks. ETHICS/DISSEMINATION: This trial has undergone ethical scrutiny and been approved by the ethics review board of Chang Gung Memorial Hospital (Permission number: 102-4749A3 and 104 3156C). The pre-results of this trial will help to determine whether Tianjiu is an effective and safe treatment for IDH, and, if so, whether it is a therapeutic effect rather than a placebo effect. TRIAL REGISTRATION NUMBER: NCT02210377; Pre results. PMID- 26966060 TI - Past speculations of the future: a review of the methods used for forecasting emerging health technologies. AB - OBJECTIVES: Forecasting can support rational decision-making around the introduction and use of emerging health technologies and prevent investment in technologies that have limited long-term potential. However, forecasting methods need to be credible. We performed a systematic search to identify the methods used in forecasting studies to predict future health technologies within a 3-20 year timeframe. Identification and retrospective assessment of such methods potentially offer a route to more reliable prediction. DESIGN: Systematic search of the literature to identify studies reported on methods of forecasting in healthcare. PARTICIPANTS: People are not needed in this study. DATA SOURCES: The authors searched MEDLINE, EMBASE, PsychINFO and grey literature sources, and included articles published in English that reported their methods and a list of identified technologies. MAIN OUTCOME MEASURE: Studies reporting methods used to predict future health technologies within a 3-20-year timeframe with an identified list of individual healthcare technologies. Commercially sponsored reviews, long-term futurology studies (with over 20-year timeframes) and speculative editorials were excluded. RESULTS: 15 studies met our inclusion criteria. Our results showed that the majority of studies (13/15) consulted experts either alone or in combination with other methods such as literature searching. Only 2 studies used more complex forecasting tools such as scenario building. CONCLUSIONS: The methodological fundamentals of formal 3-20-year prediction are consistent but vary in details. Further research needs to be conducted to ascertain if the predictions made were accurate and whether accuracy varies by the methods used or by the types of technologies identified. PMID- 26966061 TI - Cross-sectional survey of Good Samaritan behaviour by physicians in North Carolina. AB - OBJECTIVE: To assess the responses of physicians to providing emergency medical assistance outside of routine clinical care. We assessed the percentage who reported previous Good Samaritan behaviour, their responses to hypothetical situations, their comfort providing specific interventions and the most likely reason they would not intervene. SETTING: Physicians residing in North Carolina. PARTICIPANTS: Convenience sample of 1000 licensed physicians. INTERVENTION: Mailed survey. DESIGN: Cross-sectional study conducted May 2015 to September 2015. MAIN OUTCOME AND MEASURES: Willingness of physicians to act as Good Samaritans as determined by the last opportunity to intervene in an out-of-office emergency. RESULTS: The adjusted response rate was 26.1% (253/970 delivered). 4 out of 5 physicians reported previous opportunities to act as Good Samaritans. Approximately, 93% reported acting as a Good Samaritan during their last opportunity. There were no differences in this outcome between sexes, practice setting, specialty type or experience level. Doctors with greater perceived knowledge of Good Samaritan law were more likely to have intervened during a recent opportunity (p=0.02). The most commonly cited reason for potentially not intervening was that another health provider had taken charge. CONCLUSIONS: We found the frequency of Good Samaritan behaviour among physicians to be much higher than reported in previous studies. Greater helping behaviour was exhibited by those who expressed more familiarity with Good Samaritan law. These findings suggest that physicians may respond to legal protections. PMID- 26966062 TI - Does family-centred neonatal discharge planning reduce healthcare usage? A before and after study in South West England. AB - OBJECTIVE: To implement parent-oriented discharge planning (Train-to-Home) for preterm infants in neonatal care. DESIGN: Before and after study, investigating the effects of the intervention during two 11-month periods before and after implementation. SETTING: Four local neonatal units (LNUs) in South West England. PARTICIPANTS: Infants without major anomalies born at 27-33 weeks' gestation admitted to participating units, and their parents. TRAIN-TO-HOME INTERVENTION: A family-centred discharge package to increase parents' involvement and understanding of their baby's needs, comprising a train graphic and supporting care pathways to facilitate parents' understanding of their baby's progress and physiological maturation, combined with improved estimation of the likely discharge date. MAIN OUTCOME MEASURES: Perceived Maternal Parenting Self-Efficacy (PMP S-E) scores, infant length of stay (LOS) and healthcare utilisation for 8 weeks following discharge. RESULTS: Parents reported that the Train-to-Home improved understanding of their baby's progress and their preparedness for discharge. Despite a lack of change in PMP S-E scores with the intervention, the number of post-discharge visits to emergency departments (EDs) fell from 31 to 20 (p<0.05), with a significant reduction in associated healthcare costs (L3400 to L2200; p<0.05) after discharge. In both study phases, over 50% of infants went home more than 3 weeks before their estimated date of delivery (EDD), though no reduction in LOS occurred. CONCLUSIONS: Despite the lack of measurable effect on the parental self-efficacy scores, the reduction in ED attendances and associated costs supports the potential value of this approach. PMID- 26966063 TI - Biodiversity and biogeography of rhizobia associated with common bean (Phaseolus vulgaris L.) in Shaanxi Province. AB - The biodiversity and biogeography of rhizobia associated with bean in Shaanxi Province were investigated. A total of 194 bacterial isolates from bean nodules collected from 13 sampling sites were characterized based on phylogenetic analyses of the 16S rRNA gene, the housekeeping genes recA, glnII and atpD, and the symbiotic genes nodC and nifH. Fifteen genospecies belonging to the genera Rhizobium, Agrobacterium, Ensifer, Bradyrhizobium and Ochrobactrum were defined among the isolates, with Rhizobium sp. II, Agrobacterium sp. II, E. fredii and R. phaseoli being the dominant groups. Four symbiotic gene lineages corresponding to Rhizobium sp. I, Rhizobium sp. II, R. phaseoli and B. liaoningense were detected in the nodC and nifH sequence analyses, indicating different origins for the symbiotic genes and their co-evolution with the chromosome of the bacteria. Moreover, the Ensifer isolates harbored symbiotic genes closely related to bean nodulating Pararhizobium giardinii, indicating possible lateral gene transfer from Rhizobium to Ensifer. Correlation of rhizobial community composition with moisture, temperature, intercropping, soil features and nutrients were detected. All the results demonstrated a great diversity of bean rhizobia in Shaanxi that might be due to the adaptable evolution of the bean-nodulating rhizobia subjected to the diverse ecological conditions in the area. PMID- 26966064 TI - Transforming growth factor-beta1 induces cell cycle arrest by activating atypical cyclin-dependent kinase 5 through up-regulation of Smad3-dependent p35 expression in human MCF10A mammary epithelial cells. AB - Cyclin-dependent kinases (Cdks) play important roles in control of cell division. Cdk5 is an atypical member of Cdk family with non-cyclin-like regulatory subunit, p35, but its role in cell cycle progression is still unclear. In the present study, we investigated the role of Cdk5/p35 on transforming growth factor-beta1 (TGF-beta1)-induced cell cycle arrest. In human MCF10A mammary epithelial cells, TGF-beta1 induced cell cycle arrest at G1 phase and increased p27KIP1 expression. Interestingly, pretreatment with roscovitine, an inhibitor of Cdk5, or transfection with small interfering (si) RNAs specific to Cdk5 and p35 significantly attenuated the TGF-beta1-induced p27KIP1 expression and cell cycle arrest. TGF-beta1 increased Cdk5 activity via up-regulation of p35 gene at transcriptional level, and these effects were abolished by transfection with Smad3 siRNA or infection of adenovirus carrying Smad3 mutant at the C-tail (3SA). Chromatin immunoprecipitation assay further revealed that wild type Smad3, but not mutant Smad3 (3SA), binds to the region of the p35 promoter region (-1000- 755) in a TGF-beta1-dependent manner. These results for the first time demonstrate a role of Cdk5/p35 in the regulation of cell cycle progression modulated by TGF-beta1. PMID- 26966065 TI - Phospholamban degradation is induced by phosphorylation-mediated ubiquitination and inhibited by interaction with cardiac type Sarco(endo)plasmic reticulum Ca(2+)-ATPase. AB - Phospholamban (PLN) regulates cardiac type sarco (endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) via Ser(16)-phosphorylation. During heart failure, PLN expression is downregulated with SERCA2a; however, the mechanism of its regulation is not fully understood. Phosphorylation triggers protein degradation and because PLN phosphorylation is upregulated in failing hearts, we examined whether PLN is degraded by Ser(16)-phosphorylation. Cells overexpressing PLN exhibited its degradation post isoproterenol (Iso), forskolin, or 3-isobutyl-1 methylxanthine (IBMX) addition. Moreover, this degradation was inhibited by a cAMP-dependent protein kinase (PKA) inhibitor--H89. Co-immunoprecipitation revealed that Lys(3) of PLN was oligo-ubiquitinated when ubiquitin was overexpressed, and was degraded by Iso treatment. However, when co-expressed with SERCA2a, oligo-ubiquitinated PLN at Lys(3) was not degraded by Iso treatment. In failing hearts from 16 week-old TgPLN(R9C) mice, oligo-ubiquitinated PLN levels increased and PLN expression was downregulated. Furthermore, SERCA2a mRNA levels in TgPLN(R9C) mice hearts were lower than that in wild type mice; however, PLN mRNA levels showed no changes. In another heart failure model, MG132 treatment reversed PLN degradation. These data suggest that PLN is, at least partially, oligo-ubiquitinated at Lys(3) and degraded through Ser(16)-phosphorylation mediated poly-ubiquitination during heart failure. PMID- 26966066 TI - PEDF and PEDF-derived peptide 44mer inhibit oxygen-glucose deprivation-induced oxidative stress through upregulating PPARgamma via PEDF-R in H9c2 cells. AB - Pigment epithelial-derived factor (PEDF) is a glycoprotein with broad biological activities including inhibiting oxygen-glucose deprivation(OGD)-induced cardiomyocytes apoptosis through its anti-oxidative properties. PEDF derived peptide-44mer shows similar cytoprotective effect to PEDF. However, the molecular mechanisms mediating cardiomyocytes apoptosis have not been fully established. Here we found that PEDF and 44mer decreased the content of ROS. This content was abolished by either PEDF-R small interfering RNA (siRNA) or PPARgamma antagonist. The level of Lysophosphatidic acid (LPA) and phospholipase A2 (PLA2) was observed as drawn from the ELISA assays. PEDF and 44mer sequentially induced PPARgamma expression was observed both in qPCR and Western blot assays. The level of LPA and PLA2 and PPARgamma expression increased by PEDF and 44mer was significantly attenuated by PEDF-R siRNA. However, PEDF and 44mer inhibited the H9c2 cells and cultured neonatal rat myocardial cells apoptosis rate. On the other hand, TUNEL assay and cleavage of procaspase-3 showed that PEDF-R siRNA or PPARgamma antagonist increased the apoptosis again. We conclude that under OGD condition, PEDF and 44mer reduce H9c2 cells apoptosis and inhibit OGD-induced oxidative stress via its receptor PEDF-R and the PPARgamma signaling pathway. PMID- 26966068 TI - HMGA2 promotes adipogenesis by activating C/EBPbeta-mediated expression of PPARgamma. AB - Adipogenesis is orchestrated by a highly ordered network of transcription factors including peroxisome-proliferator activated receptor-gamma (PPARgamma) and CCAAT enhancer binding protein (C/EBP) family proteins. High mobility group protein AT hook 2 (HMGA2), an architectural transcription factor, has been reported to play an essential role in preadipocyte proliferation, and its overexpression has been implicated in obesity in mice and humans. However, the direct role of HMGA2 in regulating the gene expression program during adipogenesis is not known. Here, we demonstrate that HMGA2 is required for C/EBPbeta-mediated expression of PPARgamma, and thus promotes adipogenic differentiation. We observed a transient but marked increase of Hmga2 transcript at an early phase of differentiation of mouse 3T3-L1 preadipocytes. Importantly, Hmga2 knockdown greatly impaired adipocyte formation, while its overexpression promoted the formation of mature adipocytes. We found that HMGA2 colocalized with C/EBPbeta in the nucleus and was required for the recruitment of C/EBPbeta to its binding element at the Ppargamma2 promoter. Accordingly, HMGA2 and C/EBPbeta cooperatively enhanced the Ppargamma2 promoter activity. Our results indicate that HMGA2 is an essential constituent of the adipogenic transcription factor network, and thus its function may be affected during the course of obesity. PMID- 26966067 TI - MiR-30e suppresses proliferation of hepatoma cells via targeting prolyl 4 hydroxylase subunit alpha-1 (P4HA1) mRNA. AB - Aberrant microRNA expression has been shown to be characteristic of many cancers. It has been reported that the expression levels of miR-30e are decreased in liver cancer tissues. However, the role of miR-30e in hepatocellular carcinoma remains poorly understood. In the present study, we investigated the significance of miR 30e in hepatocarcinogenesis. Bioinformatics analysis reveals a putative target site of miR-30e in the 3'-untranslated region (3'UTR) of prolyl 4-hydroxylase subunit alpha-1 (P4HA1) mRNA. Moreover, luciferase reporter gene assays verified that miR-30e directly targeted 3'UTR of P4HA1 mRNA. Then, we demonstrated that miR-30e was able to reduce the expression of P4HA1 at the levels of mRNA and protein using reverse transcription-polymerase chain reaction and Western blot analysis. Enforced expression of miR-30e suppressed proliferation of HepG2 cells by 5-ethynyl-2-deoxyuridine (EdU) assay and reduced colony formation of these cells by colony formation analysis. Conversely, anti-miR-30e enhanced the proliferation of hepatoma cells in vitro. Interestingly, the ectopic expression of P4HA1 could efficiently rescue the inhibition of cell proliferation mediated by miR-30e in HepG2 cells. Meanwhile, silencing of P4HA1 abolished the anti-miR 30e-induced proliferation of cells. Clinically, quantitative real-time PCR showed that miR-30e was down-regulated in liver tumor tissues relative to their peritumor tissues. The expression levels of miR-30e were negatively correlated to those of P4HA1 mRNA in clinical liver tumor tissues. Thus, we conclude that miR 30e suppresses proliferation of hepatoma cells through targeting P4HA1 mRNA. Our finding provides new insights into the mechanism of hepatocarcinogenesis. PMID- 26966069 TI - Proteomic insight into the effects of the Salmonella ubiquitin ligase SlrP on host cells. AB - The virulence of the human and animal pathogen Salmonella enterica serovar Typhimurium is dependent on two type III secretion systems. These systems translocate proteins called effectors into eukaryotic host cells. SlrP is a Salmonella type III secretion effector with ubiquitin ligase activity. Here, we used two complementary proteomic approaches, two-dimensional gel electrophoresis and iTRAQ (isobaric tags for relative and absolute quantification) to study the consequences of the presence of SlrP in human epithelial cells. We identified 37 proteins that were differentially expressed in HeLa cells expressing slrP compared to control cells. Microarray analysis revealed that more than a half of differentially expressed proteins did not show changes in the transcriptome, suggesting post-transcriptional regulation. A gene ontology overrepresentation test carried out on the differentially expressed proteins revealed enrichment of ontology terms related to several types of junctions mediating adhesion in epithelial cells. Consistently, slrP-transfected cells showed defects in migration and adhesion. Our results suggest that the modification of cell-cell interaction ability of the host could be one of the final consequences of the action of SlrP during an infection. PMID- 26966071 TI - Modeling of drug-mediated CYP3A4 induction by using human iPS cell-derived enterocyte-like cells. AB - Many drugs have potential to induce the expression of drug-metabolizing enzymes, particularly cytochrome P450 3A4 (CYP3A4), in small intestinal enterocytes. Therefore, a model that can accurately evaluate drug-mediated CYP3A4 induction is urgently needed. In this study, we overlaid Matrigel on the human induced pluripotent stem cells-derived enterocyte-like cells (hiPS-ELCs) to generate the mature hiPS-ELCs that could be applied to drug-mediated CYP3A4 induction test. By overlaying Matrigel in the maturation process of enterocyte-like cells, the gene expression levels of intestinal markers (VILLIN, sucrase-isomaltase, intestine specific homeobox, caudal type homeobox 2, and intestinal fatty acid-binding protein) were enhanced suggesting that the enterocyte-like cells were maturated by Matrigel overlay. The percentage of VILLIN-positive cells in the hiPS-ELCs found to be approximately 55.6%. To examine the CYP3A4 induction potential, the hiPS-ELCs were treated with various drugs. Treatment with dexamethasone, phenobarbital, rifampicin, or 1alpha,25-dihydroxyvitamin D3 resulted in 5.8-fold, 13.4-fold, 9.8-fold, or 95.0-fold induction of CYP3A4 expression relative to that in the untreated controls, respectively. These results suggest that our hiPS-ELCs would be a useful model for CYP3A4 induction test. PMID- 26966070 TI - Regulation of aryl hydrocarbon receptor-mediated transcription in human retinal pigmented epithelial cells. AB - The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with pleiotropic effects in normal physiology or vascular development, xenobiotic metabolism, and cancer. A previous study has reported that BRG1, a component of the SWI/SNF complex, is a coactivator for AHR and is recruited to the promoter region of the CYP1A1 gene in mouse hepatocytes. Recent data suggest that AHR is also expressed in human retinal pigment epithelial cells (ARPE-19), which play a crucial role in retinal physiology and the visual cycle. Multiple studies have shown that the AHR plays an important role in the pathogenesis of retinal diseases including age-related macular degeneration. However, the mechanism of AHR transcriptional activation in retinal pigment cells has not been reported. Here, we demonstrate that the AHR signaling pathway is active in ARPE-19 cells, as in hepatocytes, but with different target gene specificity. We also found that chromatin remodeling by the BRG1-containing SWI/SNF complex is required for the AHR-mediated expression of target genes in ARPE-19 cells. We identified a novel enhancer region (-12 kb) of the CYP1A1 gene in ARPE-19 cells, to which both AHR and BRG1 are recruited in a ligand-dependent manner. BRG1 is associated with the AHR in ARPE-19 cells, and the C-terminal activation domain of the AHR directly interacts with BRG1. Furthermore, depletion of BRG1 caused a reduction in chromatin accessibility at the CYP1A1 enhancer. These results suggest that ARPE 19 cells possess an AHR-mediated transcription pathway with different target gene specificity, and that BRG1 is required for AHR-mediated transcription in ARPE-19 cells. PMID- 26966073 TI - The ratio of intracellular CRY proteins determines the clock period length. AB - Although a deficiency in CRY1 or CRY2 correlates with a shorter or longer circadian period, the regulation of CRY proteins in the circadian period has not been well studied. In this study, we found that both CRY1 and CRY2 were able to rescue oscillation in CRY null cells and that they displayed different periods. Furthermore, we demonstrated that protein nuclear import rates, not protein stability, regulate the period-length at the cellular level. Co-transfection of CRY1 and CRY2 in various ratios in the same cells gives rise to the predicted period length in a dose-dependent manner. Given the distinct characteristics of the C-terminal tails of the CRY1 and CRY2 proteins, our study addresses a long standing hypothesis that the ratio of these two CRY molecules affects the clock period. PMID- 26966072 TI - Rac1-PAK2 pathway is essential for zebrafish heart regeneration. AB - P-21 activated kinases, or PAKs, are serine-threonine kinases that play important roles in diverse heart functions include heart development, cardiovascular development and function in a range of models; however, the mechanisms by which PAKs mediate heart regeneration are unknown. Here, we demonstrate that PAK2 and PAK4 expression is induced in cardiomyocytes and vessels, respectively, following zebrafish heart injury. Inhibition of PAK2 and PAK4 using a specific small molecule inhibitor impedes cardiomyocyte proliferation/dedifferentiation and cardiovascular regeneration, respectively. Cdc42 is specifically expressed in the ventricle and may function upstream of PAK2 but not PAK4 under normal conditions and that cardiomyocyte proliferentation during heart regeneration relies on Rac1 mediated activation of Pak2. Our results indicate that PAKs play a key role in heart regeneration. PMID- 26966074 TI - Targeting of the BLT2 in chronic myeloid leukemia inhibits leukemia stem/progenitor cell function. AB - Imatinib, a tyrosine kinase inhibitor (TKI) has significantly improved clinical outcome for chronic myeloid leukemia (CML) patients. However, patients develop resistance when the disease progresses to the blast phase (BP) and the mechanisms are not well understood. Here we show that BCR-ABL activates BLT2 in hematopoietic stem/progenitor cells to promote leukemogenesis and this involves the p53 signaling pathway. Compared to normal bone marrow (NBM), the mRNA and protein levels of BLT2 are significantly increased in BP-CML CD34(+) stem/progenitor cells. This is correlated with increasing BCR-ABL expression. In contrast, knockdown of BCR-ABL or inhibition of its tyrosine kinase activity decreases Blt2 protein level. BLT2 inhibition induces apoptosis, inhibits proliferation, colony formation and self-renewal capacity of CD34(+) cells from TKI-resistant BP-CML patients. Importantly, the inhibitory effects of BCR-ABL TKI on CML stem/progenitor cells are further enhanced upon combination with BLT2 inhibition. We further show that BLT2 activation selectively suppresses p53 but not Wnt or BMP-mediated luciferase activity and transcription. Our results demonstrate that BLT2 is a novel pathway activated by BCR-ABL and critically involved in the resistance of BP-CML CD34(+) stem/progenitors to TKIs treatment. Our findings suggest that BLT2 and p53 can serve as therapeutic targets for CML treatment. PMID- 26966076 TI - In vivo characterization of the integration and vascularization of a silk-derived surgical scaffold. AB - BACKGROUND: The application of acellular matrices, biomaterials, and polymeric scaffolds in reconstructive surgery facilitates postsurgical tissue remodeling and is increasingly used clinically in order to improve tissue healing and implant coverage. This study presents an in vivo investigation of the integration of the knitted, silk-derived surgical scaffold, SERI((r)) with regard to angiogenesis and wound healing. METHODS: SERI((r)) Surgical Scaffold was implanted into a full-thickness skin defect in male C57BL/6J mice (n = 45) via the dorsal skinfold chamber (DSC). Skin tissue samples were collected for histology on days 2, 5, 7, 10, 14, and 21 (n = 5 per time point) post implantation. Immunohistochemistry was performed for various angiogenic and inflammatory markers, as well as collagen deposition (CD31, VEGF, CD3, CD45, Desmin, and Sirius red). Vascular corrosion casting was used to assess the neovasculature within the silk and was visualized with scanning electron microscopy. RESULTS: We observed both early and late stages of inflammation during the healing process characterized by the infiltration of regenerating tissue by different subsets of leukocytes. Histological analysis displayed capillary-containing granulation tissue with full scaffold integration. In addition, collagen deposition within the scaffold and full skin defect was significantly increased over time. Qualitative analysis of the regenerated vasculature through corrosion casting and scanning electron microscopy revealed a complex, angiogenic network of capillaries originating from the wound bed. CONCLUSIONS: Based on these findings, SERI((r)) displays the potential to be a promising resorbable bioengineered material for use in reconstructive surgery. PMID- 26966075 TI - Family history in breast cancer in Sao Luis, Maranhao, Brazil. AB - BACKGROUND: Familial cancer includes some types of cancer aggregation without a well-defined inheritance pattern. Cancer genetics is an essential component of clinical practice in oncology. In Brazil, breast cancer is the leading cause of death in women. In Maranhao, studies on genetic predisposition are necessary to investigate the incidence and mortality rates. The aim of this study was to investigate familial cancer among relatives of women who died of breast cancer in Sao Luis, Brazil, constructing a pedigree to identify families with a hereditary predisposition, an important step in the early diagnosis of malignant tumors. METHODS: The city of Sao Luis is located on the Island of Maranhao, northeastern Brazil, with a population of 997,098 inhabitants mainly comprising blacks and mulattoes, including descendants of runaway slaves from the Amazon region itself. Data for pedigree construction were obtained from the records of 54 patients seen at the Aldenora Bello Institute of Oncology, Sao Luis, between 2000 and 2007, as well as by interview with relatives of the patients. RESULTS: The mean patient age at diagnosis was 39.5 years. Most women were mulattoes (36/54, 66.6%). A history of cancer was observed in 18 families, with 16 families possessing cases of cancer among first-degree relatives and five among second-degree relatives. CONCLUSION: A concentration of cancer cases was found in families of patients diagnosed until the age of 40, a finding demonstrating the importance of a family history prior to genetic counseling. PMID- 26966077 TI - The reverse abdominal reduction and the 'waistcoating' procedure for the correction of the fixated Pfannenstiel incision. AB - The principles of a standard abdominal reduction are well understood; this technique has been used for many years. However, a reverse abdominal reduction may be considered in some cases, for example, continued weight loss, and thus skin redundancy on the upper abdomen in patients who have already undergone abdominal reduction and upper abdomen improvement in patients requiring a mastopexy or breast reduction simultaneously. Reverse abdominal reduction is rarely mentioned in the medical literature, but it can prove successful; although the scar across the lower sternum has often been considered to be unsatisfactory, often it does not prove to be so. Thus, this procedure can be proven to be successful in suitable cases. Secondly, the Pfannenstiel incision, if not satisfactorily repaired in the first instance, can become fixated to the abdominal wall; this fixation along with the inevitable migration of skin and fat at its cephalic edge causes a rather displeasing contour defect when wearing tight-fitting swimwear. The principle of the waistcoating procedure is essentially to chamfer the fat cephalically; this procedure is employed for removing the Pfannenstiel scar from the abdominal wall. The principle is simple and effective and can be applied in cases with fixated scars. These two aforementioned principles are not commonly used, but they can prove particularly effective in suitable cases. We illustrate the principles. PMID- 26966078 TI - Understanding Online Health Groups for Depression: Social Network and Linguistic Perspectives. AB - BACKGROUND: Mental health problems have become increasingly prevalent in the past decade. With the advance of Web 2.0 technologies, social media present a novel platform for Web users to form online health groups. Members of online health groups discuss health-related issues and mutually help one another by anonymously revealing their mental conditions, sharing personal experiences, exchanging health information, and providing suggestions and support. The conversations in online health groups contain valuable information to facilitate the understanding of their mutual help behaviors and their mental health problems. OBJECTIVE: We aimed to characterize the conversations in a major online health group for major depressive disorder (MDD) patients in a popular Chinese social media platform. In particular, we intended to explain how Web users discuss depression-related issues from the perspective of the social networks and linguistic patterns revealed by the members' conversations. METHODS: Social network analysis and linguistic analysis were employed to characterize the social structure and linguistic patterns, respectively. Furthermore, we integrated both perspectives to exploit the hidden relations between them. RESULTS: We found an intensive use of self-focus words and negative affect words. In general, group members used a higher proportion of negative affect words than positive affect words. The social network of the MDD group for depression possessed small-world and scale-free properties, with a much higher reciprocity ratio and clustering coefficient value as compared to the networks of other social media platforms and classic network models. We observed a number of interesting relationships, either strong correlations or convergent trends, between the topological properties and linguistic properties of the MDD group members. CONCLUSIONS: (1) The MDD group members have the characteristics of self-preoccupation and negative thought content, according to Beck's cognitive theory of depression; (2) the social structure of the MDD group is much stickier than those of other social media groups, indicating the tendency of mutual communications and efficient spread of information in the MDD group; and (3) the linguistic patterns of MDD members are associated with their topological positions in the social network. PMID- 26966079 TI - Comparative Outcomes of Resident vs Attending Performed Surgery: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To determine whether outcomes are different when surgery is performed by resident or attending surgeons, and which variables may affect outcomes. DESIGN: MEDLINE, EMBASE, and the Cochrane Library were searched from inception to May 2014 alongside the bibliographies of all included or relevant studies. Any study comparing outcomes from surgery performed by resident vs attending surgeons was eligible for inclusion. The main outcome measures were surgical complications (classified by Clavien-Dindo grade), death, operative time, and length of stay. Data were extracted independently by 2 authors and analyzed using the random effects model. RESULTS: The final analysis included 182 eligible studies that enrolled 141 555 patients. Resident performed surgery took longer by 10.2 minutes (95% confidence interval (CI): 8.38-11.95), and had more Clavien-Dindo grade 1 (rate ratio = 1.14, 95% CI: 1.02-1.29) and grade 3a complications (rate ratio = 1.22, 95% CI: 1.04-1.44). Resident performed surgery resulted in fewer deaths (risk ratio = 0.83, 95% CI: 0.70-0.999) with a shorter length of stay of -0.49 days (95% CI: -0.77 to -0.21). Significant heterogeneity was present in 7 of 10 outcomes, which persisted during multiple subgroup analyses. CONCLUSIONS: Resident performed surgery appears to be safe in carefully selected patients. The significant amount of heterogeneity present in the study outcomes prevents generalizability of these results to specific clinical contexts. PMID- 26966080 TI - The Surgery Fellow's Education Workshop: A Pilot Study to Determine the Feasibility of Training Senior Learners to Teach in the Operating Room. AB - BACKGROUND: In 2013, we developed an education workshop to enhance the teaching skills of surgical fellows. We sought to investigate the feasibility of the monthly educational workshop format and its effect on participant teaching skills. STUDY DESIGN: Surgical and medical education faculty created a broadly applicable curriculum developed from evidence-based teaching principles, delivered across 8 monthly 90-minute weekday sessions. Workshop feasibility and effect were assessed using evaluations, attendance records, and a variety of self reported surveys. Each session was associated with a specified education action plan to be completed between sessions. RESULTS: A total of 13 fellows intended to participate. More than 60% attendance was achieved in 7 of 8 sessions. In all, 11 of 13 fellows were engaged (actual attendance or excused absence) across 75% or more of the sessions. Mean participant satisfaction scores ranged from 4.0 to 4.9 on a 5 point Likert scale across 87.5% of sessions. Postworkshop surveys showed increased understanding of the following: (1) knowledge gaps related to education; (2) the role of education for academic surgeons; (3) educational tools to improve teaching performance; and (4) perceived knowledge and attitudes about teaching in the operating room. An action plan was performed in 43% of cases; the most common reason for nonparticipation was lack of time (38%). CONCLUSIONS: Our pilot supports the feasibility of an educational workshop series to enhance fellow's educational skills in the area of intraoperative teaching. Participant engagement and satisfaction were high in this self-selected group of initial trainees. Sessions were effective, resulting in a thoughtful self-assessment of teaching skills. PMID- 26966081 TI - Operative Experience vs. Competence: A Curriculum Concordance and Learning Curve Analysis. AB - OBJECTIVE: Certification of completion of training in general surgery requires proof of competence of index operations by means of 3, level-4 consultant validated procedural-based assessments. The aim of this study was to examine the relationship between index operative experience and competence. DESIGN: Higher surgical trainee procedural-based assessments were compared with e-logbooks to determine the relationship between index operative experience and achievement of a third level 4 competence (L4C) related to the indicative procedures of emergency laparotomy (EL, target 100), Hartmann procedure (5), appendicectomy (80), segmental colectomy (20), laparoscopic cholecystectomy (50), and inguinal hernia (80). SETTING: All trainees are from a single UK Deanery. PARTICIPANTS: Consecutive 69 national training number higher surgical trainees were appointed to a single UK Deanery between 2007 and 2014. RESULTS: EL L4C was achieved at a median of 76 (15-136) cases, Hartmann procedure L4C at 17 (7-27) cases (p = 0.009 vs. EL), appendicectomy L4C at 107 (20-206) cases, segmental colectomy L4C at 52 (15-131) cases, laparoscopic cholecystectomy L4C at 72 (40-197) cases, and inguinal hernia L4C at 64 (17-132) cases. CONCLUSIONS: The learning curve and caseload required to demonstrate L4C related to specific procedure varied over 4 fold, from 0.76 to 3.4 times the national indicative target number guidance. Certification of completion of training operative logbook number targets should be reconsidered to better reflect the competencies demanded by the curriculum. PMID- 26966082 TI - Assessment of Surgical Competence: Development and Validation of Rating Scales Used for Laparoscopic Supracervical Hysterectomy. AB - OBJECTIVE: To develop a procedure-specific rating scale for laparoscopic supracervical hysterectomy (LSH), and to compare the construct validity and reliability with a general rating scale in laparoscopic surgery, global operative assessment of laparoscopic skills (GOALS). DESIGN: Prospective interobserver study. In collaboration with an expert group, we developed the procedure-specific rating scale, competence assessment tool for laparoscopic supracervical hysterectomy (CAT-LSH). LSH was performed by gynecologists with different levels of surgical competence levels (13 procedures were performed by inexperienced trainees, 13 by intermediate experienced, and 15 by laparoscopic experts). All procedures were video-recorded. Surgical performance was evaluated in all procedures using both CAT-LSH and GOALS by the surgical assistant, as well as by 2 blinded observers evaluating the video recordings. SETTING: University teaching hospital. PARTICIPANTS: Laparoscopic experts, consultants and gynecological registrars from the Department of Gynecology. RESULTS: There were significant differences between the 3 proficiency groups in both the rating scales. Mean GOALS score evaluated by the operating assistant and the 2 observers were for inexperienced surgeons 16.4 vs. 13.6 (p < 0.01), for surgeons with intermediate experienced 22.6 vs. 19.5 (p < 0.05) and for expert surgeons 26.1 vs. 22.4 (p < 0.01), respectively. Corresponding results for the CAT-LSH scores were 41.0/34.6 (p < 0.01), 49.2/43.1 (p < 0.01), and 58.7/51.1 (p < 0.01), respectively. The interrater reliability measured by the interclass correlation coefficient between the surgical assistant and the 2 blinded observers for GOALS and CAT-LSH were 0.71 and 0.75, respectively. CONCLUSIONS: The GOALS and CAT-LSH appear to have construct validity and high interrater reliability. Assessment of surgical competence during LSH is feasible in daily practice with objective rating scales like CAT-LSH and GOALS. PMID- 26966083 TI - An Assessment of the Industry-Faculty Surgeon Relationship Within Colon and Rectum Surgical Training Programs. AB - INTRODUCTION: Industry funding of surgical training programs poses a potential conflict of interest. With the recent implementation of the Sunshine Act, industry funding can be more accurately determined. OBJECTIVE: To determine the financial relationship between faculty surgeons within colon and rectal fellowship programs and industry. DESIGN: Review of industry funding based on the first reporting period (August-December, 2013) using the Centers for Medicare and Medicaid Services online database. SETTING: ACGME certified colon and rectum surgical fellowship programs. PARTICIPANTS: Overall, 343 Faculty surgeons from 55 colon and rectum surgical fellowship programs were identified using the American Board of Colon and Rectum Surgery website. There was complete identification of faculty surgeons in 47 (85.5%) programs, partially complete identification (i.e., >80%) in 6 (10.9%) programs, and inadequate identification of faculty in 2 (3.6%) programs. MAIN OUTCOME: Industry funding as defined by the Sunshine Act included general payments (honorariums, consulting fees, food and beverage, and travel), research payments, and amount invested. RESULTS: In all, 69.1% of program directors and 59.4% of other faculty received at least one payment during the reporting period (Delta9.7%, 95% CI: -4.4% to 23.8%, p = 0.18). Program directors received higher amounts of funding than other faculty ($7072.90 vs. $2,819.29, Delta$4,253.61, 95% CI: $1132-$7375, p = 0.008). Overall, 49 of 53 (93%) programs had surgeons receive funding, with a median of 3.5 surgeons receiving funding per program. A total of 65 companies made payments to surgeons, with 80.1% of the funding categorized as general payments, 16.2% as investments, and 3.7% as research payments. CONCLUSIONS: Industry funding was common. This financial relationship poses a potential conflict of interest in training fellows for future practice. PMID- 26966084 TI - Examination of the Acute Abdomen in Children. AB - The history and physical examination (H&P) on a child with an acute abdomen is an opportunity to build a solid relationship with the child and parents. Building confidence and trust under fraught circumstances requires a genuine affection for children, and sympathy for the anxiety of the parents. Arrival of a surgeon is a signal that the illness is serious and not likely to respond to the usual remedies. The surgeon therefore must have a gentle, unhurried approach. Obtaining the history should be non-directive and allow both parent and child to describe the entire timeline of the illness without interruption. The physical examination should be done without hurting the child, first observing how the child moves about in bed and undresses, then having the child control palpation by holding the examiner's hand and pulling it away should undue pain be elicited. Even though a diagnosis and a plan for surgery may already have been made, exiting the exam room after the H&P to review lab and radiological images gives the family time to regroup information. The diagnosis and decision for operation require simple and direct explanations that communicate patience, have a tone of reassurance, and affirm repeatedly that parents understand what is being said. The message is that surgery is a shared decision, and safety and the child's wellbeing always foremost. To the child three points have to be paramount: They won't feel pain during or after the procedure; after the operation they will feel better; and they won't be alone. The goal is to build a trusting relationship so that the child has some calm in departing to the operating room and the parents willingly see them leave. PMID- 26966086 TI - The effect of venous anatomy on the morphology of multiple sclerosis lesions: a susceptibility-weighted imaging study. AB - AIM: To investigate the cause of morphology in non-ovoid multiple sclerosis (MS) lesions lacking a radial course and typical shape. MATERIALS AND METHODS: Non ovoid atypical lesions without perpendicular extensions to the ventricle were investigated in 95 MS patients by retrospective examination of T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. The relationship between the morphology of these atypical lesions detected in 38 patients and central vein anatomy was examined using susceptibility-weighted imaging (SWI). RESULTS: A central venous structure was observed in 107 (65.6%) of 163 atypical lesions in 38 patients. The distribution of atypical lesions grouped by their shape was as follows: (1) V- or Y-shaped lesions (n=27, 48.6%) were observed where veins bifurcated; (2) crescent-shaped lesions (n=9, 8.4%) were observed where veins formed an arc; (3) patchy lesions comprised 48.6% (n=52) of the atypical lesions and involved multiple medullary veins or medullary veins showing a "caput medusae" distribution; (4) ovoid lesions with a non-radial course (n=19, 17.7%) were generally observed where medullary veins converged to form internal cerebral vein branches. CONCLUSION: Unlike typical MS plaques, non-ovoid atypical lesions make the differential diagnosis of MS challenging. Demonstration of the relationship between venous anatomy and lesion morphology in atypical lesions using SWI will aid in the differential diagnosis. PMID- 26966085 TI - Using self-drilling screws in volar plate osteosynthesis for distal radius fractures: a feasibility study. AB - BACKGROUND: Symptomatic extensor tendon irritation is a frequent complication in volar plate osteosynthesis of distal radius fractures. It is typically caused by dorsal screw protrusion and overdrilling of the dorsal cortex. The use of self drilling locking screws (SDLS) could overcome both causes. The practical applicability of SDLS depends on two prerequisites: (1) the feasibility of preoperative distal screw length determination, and (2) sufficient primary biomechanical stability of SDLS compared to standard locking screws (SLS). METHODS: We first assessed the feasibility of preoperative screw length determination (1): Distal radius width, depth and distal screw lengths were measured in 38 human radii. Correlations between distal radius width and depth were assessed, a cluster analysis (Ward's method and squared Euclidean distance) for distal radius width conducted, and intra-cluster screw lengths analyzed (ANOVA). The biomechanical performance of SDLS (2) was assessed by comparison to SLS in a distal radius fracture model (AO-23 A3). 75 % distal screw length was chosen for both groups to simulate a worst-case scenario. Uniaxial compression tests were conducted to measure stiffness, elastic limit, maximum force and residual tilt. Statistics comprised of independent sample t-tests and a Bonferroni correction (p < 0.0125). RESULTS: (1) Distal radius width and depth showed a high correlation (R (2) = 0.79; p < 0.001). Three distal radius width clusters could be identified: small <34 mm; medium 34-36.9 mm; large >36.9 mm. ANOVA and Tukey post-hoc analysis revealed significantly different volar-dorsal depths (p < 0.05) for nearly all screws. (2) To assess biomechanical stability nine specimens were tested each; no significant differences were found between the SDLS and SLS groups. CONCLUSIONS: This feasibility study demonstrates that (1) distal radius width can be used as a predictor for distal screw length and (2) that SDLS provides mechanical stability equivalent to SLS. These results highlight the feasibility of applying SDLS screws in volar plate osteosynthesis at least in extraarticular fractures. PMID- 26966087 TI - Evaluation of different types of inferior vena cava cannulae placement by transesophageal echocardiography and its impact on hepatic dysfunction. AB - BACKGROUND: Postoperative hepatic dysfunction may occur in an otherwise uncomplicated open heart surgery. One of the reasons is malpositioning of the inferior vena cava (IVC) cannula in the hepatic vein (HV) or beyond. A straight cannula is considered more likely to be malpositioned compared to the angled cannula and a malpositioned cannula can lead to hepatic dysfunction. METHODS: In this prospective study, forty adult patients undergoing atrial septal defect repair were randomized into two groups as: straight cannula group (n=20) and angled cannula group (n=20). The cannula position was assessed by transesophageal echocardiography (TEE) (hepatic vein view). Alanine aminotransferase levels (ALT) and bilirubin levels were measured immediately, at 6 hours and on day 1, day 2 and day 7 after surgery as a marker of hepatic injury. RESULTS: TEE localization of the IVC cannula was achieved in all patients except one. Visualization was good in 85% of patients. A cannula in the HV or beyond the HV in the IVC was considered malpositioned. The number of cases of cannula malposition was 10 (50%) and 4 (20%) in the straight and angled cannula groups, respectively. The pattern of change in serum bilirubin and liver enzymes levels in the postoperative period was similar in both the groups (p>0.05). The mean distance between the right atrium (RA) - inferior vena cava (IVC) junction to the hepatic vein was 1.94+/ 0.56 cm and the mean diameters of the IVC and HV were 1.95+/-0.5 and 1.31+/-0.33 cm, respectively. CONCLUSION: TEE can be used to monitor IVC cannula position. A higher frequency of cannula malposition was observed with the straight cannula compared to the angled cannula, but was not found to be associated with hepatic dysfunction. PMID- 26966088 TI - Aryl hydrocarbon receptor-dependent enrichment of a megakaryocytic precursor with a high potential to produce proplatelets. AB - The mechanisms regulating megakaryopoiesis and platelet production (thrombopoiesis) are still incompletely understood. Identification of a progenitor with enhanced thrombopoietic capacity would be useful to decipher these mechanisms and to improve our capacity to produce platelets in vitro. Differentiation of peripheral blood CD34(+) cells in the presence of bone marrow human mesenchymal stromal cells (MSCs) enhanced the production of proplatelet bearing megakaryocytes (MKs) and platelet-like elements. This was accompanied by enrichment in a MK precursor population exhibiting an intermediate level of CD41 positivity while maintaining its expression of CD34. Following sorting and subculture with MSCs, this CD34(+)CD41(low) population was able to efficiently generate proplatelet-bearing MKs and platelet-like particles. Similarly, StemRegenin 1 (SR1), an antagonist of the aryl hydrocarbon receptor (AhR) transcription factor known to maintain CD34 expression of progenitor cells, led to an enriched CD34(+)CD41(low) fraction and to an increased capacity to generate proplatelet-producing MKs and platelet-like elements ultrastructurally and functionally similar to circulating platelets. The effect of MSCs, like that of SR1, appeared to be mediated by an AhR-dependent mechanism because both culture conditions resulted in repression of its downstream effector CYP1B1. This newly described isolation of a precursor exhibiting strong MK potential could be exploited to study normal and abnormal thrombopoiesis and for in vitro platelet production. PMID- 26966092 TI - On the electronic measurement of pain intensity: Can we use different pain intensity scales interchangeably? AB - The objective of this work was to study the agreement between four pain intensity scales when administered electronically: the Numerical Rating Scale-11, the Faces Pain Scale-Revised, the Visual Analogue Scale and the Coloured Analogue Scale. In all, 180 schoolchildren between 12 and 19 years old participated in the study. They had to report the maximum intensity of their most frequent pain using the electronic versions of the four scales. Agreement was calculated using the Bland Altman method. Results show that the electronic versions of Numerical Rating Scale-11, Coloured Analogue Scale and Visual Analogue Scale can be used interchangeably. PMID- 26966090 TI - An autonomous CEBPA enhancer specific for myeloid-lineage priming and neutrophilic differentiation. AB - Neutrophilic differentiation is dependent on CCAAT enhancer-binding protein alpha (C/EBPalpha), a transcription factor expressed in multiple organs including the bone marrow. Using functional genomic technologies in combination with clustered regularly-interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 genome editing and in vivo mouse modeling, we show that CEBPA is located in a 170-kb topological-associated domain that contains 14 potential enhancers. Of these, 1 enhancer located +42 kb from CEBPA is active and engages with the CEBPA promoter in myeloid cells only. Germ line deletion of the homologous enhancer in mice in vivo reduces Cebpa levels exclusively in hematopoietic stem cells (HSCs) and myeloid-primed progenitor cells leading to severe defects in the granulocytic lineage, without affecting any other Cebpa-expressing organ studied. The enhancer deleted progenitor cells lose their myeloid transcription program and are blocked in differentiation. Deletion of the enhancer also causes loss of HSC maintenance. We conclude that a single +42-kb enhancer is essential for CEBPA expression in myeloid cells only. PMID- 26966094 TI - Work environment and quality improvement in healthcare. PMID- 26966091 TI - Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting. AB - The spectrum of somatic alterations in hematologic malignancies includes substitutions, insertions/deletions (indels), copy number alterations (CNAs), and a wide range of gene fusions; no current clinically available single assay captures the different types of alterations. We developed a novel next-generation sequencing-based assay to identify all classes of genomic alterations using archived formalin-fixed paraffin-embedded blood and bone marrow samples with high accuracy in a clinically relevant time frame, which is performed in our Clinical Laboratory Improvement Amendments-certified College of American Pathologists accredited laboratory. Targeted capture of DNA/RNA and next-generation sequencing reliably identifies substitutions, indels, CNAs, and gene fusions, with similar accuracy to lower-throughput assays that focus on specific genes and types of genomic alterations. Profiling of 3696 samples identified recurrent somatic alterations that impact diagnosis, prognosis, and therapy selection. This comprehensive genomic profiling approach has proved effective in detecting all types of genomic alterations, including fusion transcripts, which increases the ability to identify clinically relevant genomic alterations with therapeutic relevance. PMID- 26966093 TI - Evaluation of novel inducible promoter/repressor systems for recombinant protein expression in Lactobacillus plantarum. AB - BACKGROUND: Engineering lactic acid bacteria (LAB) is of growing importance for food and feed industry as well as for in vivo vaccination or the production of recombinant proteins in food grade organisms. Often, expression of a transgene is only desired at a certain time point or period, e.g. to minimize the metabolic burden for the host cell or to control the expression time span. For this purpose, inducible expression systems are preferred, though cost and availability of the inducing agent must be feasible. We selected the plasmid free strain Lactobacillus plantarum 3NSH for testing and characterization of novel inducible promoters/repressor systems. Their feasibility in recombinant protein production was evaluated. Expression of the reporter protein mCherry was monitored with the BioLector((r)) micro-fermentation system. RESULTS: Reporter gene mCherry expression was compared under the control of different promoter/repressor systems: PlacA (an endogenous promoter/repressor system derived from L. plantarum 3NSH), PxylA (a promoter/repressor system derived from Bacillus megaterium DSMZ 319) and PlacSynth (synthetic promoter and codon-optimized repressor gene based on the Escherichia coli lac operon). We observed that PlacA was inducible solely by lactose, but not by non-metabolizable allolactose analoga. PxylA was inducible by xylose, yet showed basal expression under non-induced conditions. Growth on galactose (as compared to exponential growth phase on glucose) reduced basal mCherry expression at non-induced conditions. PlacSynth was inducible with TMG (methyl beta-D-thiogalactopyranoside) and IPTG (isopropyl beta-D-1 thiogalactopyranoside), but also showed basal expression without inducer. The promoter PlacSynth was used for establishment of a dual plasmid expression system, based on T7 RNA polymerase driven expression in L. plantarum. Comparative Western blot supported BioLector((r)) micro-fermentation measurements. Conclusively, overall expression levels were moderate (compared to a constitutive promoter). CONCLUSIONS: We evaluated different inducible promoters, as well as an orthologous expression system, for controlled gene expression in L. plantarum. Furthermore, here we provide proof of concept for a T7 RNA polymerase based expression system for L. plantarum. Thereby we expanded the molecular toolbox for an industrial relevant and generally regarded as safe (GRAS) strain. PMID- 26966089 TI - Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. AB - The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders. PMID- 26966097 TI - Erratum to: Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases. PMID- 26966095 TI - A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy. AB - Disulfiram, a generic alcohol aversion drug, has promising preclinical activity against glioblastoma (GBM). This phase I study aims to evaluate its safety, maximum tolerated dose (MTD), pharmacodynamic effect, and preliminary efficacy when combined with adjuvant temozolomide in GBM patients after standard chemoradiotherapy. Patients received disulfiram 500-1000 mg once daily, in combination with 150-200 mg/m(2) temozolomide. A modified 3 + 3 dose-escalation design was used to determine the MTD. The pharmacodynamic effect of proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cells. The MTD was determined based on the dose-limiting toxicities (DLTs) within the first month of therapy. Twelve patients were enrolled to two dose levels: 500 and 1000 mg. Two DLTs of grade 3 delirium occurred after 15 days of administration at 1000 mg per day. Other possible grade 2-3 DSF-related toxicities included fatigue, ataxia, dizziness, and peripheral neuropathy. The toxicities were self-limiting or resolved after discontinuing DSF. The MTD was determined to be 500 mg per day. Limited proteasome inhibition was observed at week 4 and showed an increased trend with escalated disulfiram. Median progression-free survival with 500 mg of DSF was 5.4 months from the start of disulfiram and 8.1 months from the start of chemoradiotherapy. Disulfiram can be safely combined with temozolomide but can cause reversible neurological toxicities. The MTD of disulfiram with adjuvant temozolomide appears to produce limited proteasome inhibition on peripheral blood cells. PMID- 26966096 TI - Pre-treatment factors associated with detecting additional brain metastases at stereotactic radiosurgery. AB - The number of brain metastases identified on diagnostic magnetic resonance imaging (MRI) is a key factor in consideration of stereotactic radiosurgery (SRS). However, additional lesions are often detected on high-resolution SRS planning MRI. We investigated pre-treatment clinical characteristics that are associated with finding additional metastases at SRS. Patients treated with SRS for brain metastases between the years of 2009-2014 comprised the study cohort. All patients underwent frame-fixed, 1 mm thick MRI on the day of SRS. Patient, tumor, and treatment characteristics were analyzed for an association with increase in number of metastases identified on SRS-planning MRI. 289 consecutive SRS cases were analyzed. 725 metastases were identified on pre-treatment MRI and 1062 metastases were identified on SRS-planning MRI. An increase in the number of metastases occurred in 34 % of the cases. On univariate analysis, more than four metastases and the diameter of the largest lesion were significantly associated with an increase in number of metastases on SRS-planning MRI. When stratified by the diameter of the largest lesion into <2, 2-3, or >=3 cm, additional metastases were identified in 37, 29, and 18 %, respectively. While this increase in the number of metastases is largely due to the difference in imaging technique, the number and size of the metastases were also associated with finding additional lesions. These clinical factors may be considered when determining treatment options for brain metastases. PMID- 26966098 TI - A novel method for pair-matching using three-dimensional digital models of bone: mesh-to-mesh value comparison. AB - The commingling of human remains often hinders forensic/physical anthropologists during the identification process, as there are limited methods to accurately sort these remains. This study investigates a new method for pair-matching, a common individualization technique, which uses digital three-dimensional models of bone: mesh-to-mesh value comparison (MVC). The MVC method digitally compares the entire three-dimensional geometry of two bones at once to produce a single value to indicate their similarity. Two different versions of this method, one manual and the other automated, were created and then tested for how well they accurately pair-matched humeri. Each version was assessed using sensitivity and specificity. The manual mesh-to-mesh value comparison method was 100 % sensitive and 100 % specific. The automated mesh-to-mesh value comparison method was 95 % sensitive and 60 % specific. Our results indicate that the mesh-to-mesh value comparison method overall is a powerful new tool for accurately pair-matching commingled skeletal elements, although the automated version still needs improvement. PMID- 26966099 TI - Codeine-spiked beer in a date rape case? AB - A case of suspected drug-facilitated sexual assault, involving codeine and acetaminophen, possibly mixed in beer, was recently addressed at the Norwegian Institute of Public Health. To examine the case, a small study was performed, spiking beer with preparations containing codeine and acetaminophen and observing the concentrations, appearance, and taste of the solutions. The study revealed the majority of the preparations to be quickly soluble in beer, achieving high concentrations, but at the expense of strong taste and drastic visible changes in the beer. PMID- 26966100 TI - Social deprivation and the rate of emergency medical admission for older persons. AB - BACKGROUND: Deprivation Status increases the annual admission incidence of emergency medical admissions; the extent to which deprivation influences the admission of older persons is less well known. AIM: To examine whether deprivation within a hospital catchment area influences emergency medical admissions for the elderly population. DESIGN: The relationship between Deprivation Status, Dependency Ratio (population proportion of non-working age (<15 or >=65 years) and age for all emergency admissions (82 368 episodes of 44 628 patients), over a 13-year period, were examined and ranked by quintile. METHODS: Univariate and multi-variable risk estimates (incidence rate ratios) were calculated, using truncated Poisson regression. RESULTS: The Dependency Ratio and the Deprivation index independently predicted the annual incidence rate of medical emergencies; however, when calculated for older persons, the corresponding incidence rate ratios showed a falling trend with increasing Deprivation Status-Q2 0.51 (95% confidence interval [CI]: 0.50, 0.52), Q3 0.59 (95% CI: 0.58, 0.60), Q4 0.51 (95% CI: 0.50, 0.52) and Q5 0.37 (95% CI: 0.36, 0.38). Thus, with increasing Deprivation Status, the proportion of total admission from the >=65-year cohort fell substantially. CONCLUSION: The admission incidence rate for emergency medical patients is strongly influenced by the catchment area Deprivation Status. However, because of its greater impact on the younger population, increasing deprivation alters the ratio of younger to older persons as a proportion of total emergency admissions. PMID- 26966101 TI - Emphysematous osteomyelitis of spine. PMID- 26966102 TI - Qualitative effects of omalizumab on concomitant IgE-mediated disease in a severe asthmatic population: a real life observational study. AB - INTRODUCTION: Omalizumab is a recombinant humanized monoclonal antibody (anti IgE) licensed for use in GINA 5 asthma or for chronic idiopathic urticaria. Many patients with asthma have concomitant allergic diseases such as dermatitis and sinusitis. IgE is also implicated in allergic-bronchopulmonary disease (ABPA). In addition, extreme sensitivity to allergen can prevent the initiation of allergen immunotherapy. AIM: The aim of this study was to assess the efficacy of omalizumab on symptoms of concomitant non asthmatic IgE-mediated allergic disease in a population of severe GINA 5 in a real life observational setting. DESIGN: This study is a retrospective, observational study assessing patients reported allergic, non-asthmatic symptom response to omalizumab treatment. METHODS: Fifty six severe asthmatics treated with omalizumab were studied. Thirty-seven patients had concomitant rhino-sinusitis, 13 had dermatitis and 4 ABPA. Subjects were asked to grade the improvement in their symptom scores on an analogue scale from 0 (no response) to 10 (excellent response). RESULTS: Mean improvement from baseline was 5 and 1.8 in patients with allergic rhino-sinusitis and dermatitis, respectively. Mean improvement from baseline in respiratory symptoms in patients with ABPA was 4.0. CONCLUSIONS: The results from our study suggest that omalizumab may have a role in allergic disease outside of its current license. PMID- 26966103 TI - Behavioral Rehearsal for Analogue Fidelity: Feasibility in a State-Funded Children's Mental Health Initiative. AB - A substantial number of evidence-based treatments (EBTs) are available, but are delivered infrequently in public mental health. To improve the quality of care, some states and systems have focused on EBT training; however, these efforts have rarely included objective measurement of clinician fidelity because of feasibility issues. The primary goal of the current study was evaluating the feasibility of the behavioral rehearsal (BR) method to assess "analogue fidelity" in a children's mental health quality improvement initiative. Results indicated low-but representative-clinician participation. Participants demonstrated greatest improvement at post-training with maintenance or decreases at 6-months (post-consultation). Implications for future use of BR are discussed. PMID- 26966105 TI - Urinary tract infections in intensive care unit patients - a single-centre, 3 year observational study according to the INICC project. AB - BACKGROUND: Urinary tract infections (UTI) in patients with urinary catheters could be a serious complication of hospitalisation in the intensive care unit (ICU). METHODS: A prospective study (01.01.2012-31.12.2014) was conducted in the 20-bed ICU of the University Hospital in Wroclaw, Poland. The frequency (density, incidence) and aetiology of UTI as well as prophylactic method compliance were estimated in patients of the ICU according to the INICC project. RESULTS: Among 1261 ICU patients, urinary tract infections were diagnosed in 91 (7%). The incidence index was 7.25/100 admissions to the ICU. CA-UTI constituted 36% of the device-associated, healthcare-associated infections (n = 255). A urinary catheter was used in 92.21 +/- 4.51% of patients during 14,006 patient-days and 12,917 urinarycatheter- days. The density of CA-UTI/1000 catheter-days was 6.44, 6.84, 7.16 during the years 2012, 2013, and 2014, respectively. The main pathogens of CA-UTI were Enterococcus spp. (22%), Acinetobacter baumannii (20%), Klebsiella pneumoniae (18%), Pseudomonas aeruginosa (13%), and Candida spp. (13%). Only in four elements of the "Urinary Catheter Bundle" was 100% compliance noted. CONCLUSIONS: In the observed period of time, the incidence of CA-UTI was higher than in the INICC (2014) report and the NHSN/CDC (2012) report. Analysis of compliance with a "Urinary Catheter Bundle" to prevent UTI shows low implementation of preventative methods with the INICC protocol. PMID- 26966104 TI - Acute angle-closure glaucoma in a highly myopic patient secondary to Weill Marchesani syndrome: histopathologic lens features. AB - The authors describe a case of acute angle-closure glaucoma in a highly myopic patient secondary to Weill-Marchesani syndrome (WMS) and histopathologic features of his lens. A 37-year-old male patient visited our clinic for ocular pain with elevated intraocular pressure (19/57 mmHg). The slit-lamp examination showed an inferiorly subluxated lens in the right eye, and anterior dislocated microspherophakia with corneolenticular contact in the left eye. The physical examination showed brachydactyly and relatively short stature. To control the IOP and to improve visual acuity, lens extraction, anterior vitrectomy, and scleral sutured IOL implantation surgery were performed. To the best of our knowledge, this is the first histopathologic report of bilateral lens in a Korean patient with WMS. The pathologic specimens showed epithelial cell changes, hyaloid degeneration, and subcapsular cortical fiber changes. The authors attributed these changes to physical and mechanical factors because the lens is highly mobile and often comes in contact with the iris. PMID- 26966106 TI - Etomidate, but not thiopental, decreases serum cortisol concentration in morbidly obese patients. A randomized controlled trial. AB - BACKGROUND: The effect of etomidate administration on the adrenal cortex in obese patients is still unclear. The objective of the study was to determine the influence of a single dose of etomidate on cortisol secretion in the morbidly obese. METHODS: 127 healthy patients were enrolled into the study. Data from 82 patients scheduled for elective laparoscopic surgery were analyzed. 62 of them were morbidly obese, while 20 had normal body mass. The participants were divided equally into etomidate and thiopental groups, depending on the kind of intravenous anaesthetic used for the induction of anaesthesia. Each patient's serum cortisol concentration was measured five times: on the day before surgery (sample A), two hours after the induction of anaesthesia (sample B), after a short tetracosactide test (sample C), 24 hours after the induction of anaesthesia (sample D), and after a second short stimulation test (sample E). RESULTS: The mean cortisol concentration in obese patients in the etomidate group was lower two hours after the induction of anaesthesia (sample B, P < 0.001), and 30 minutes after the first tetracosactide test (sample C, P < 0.001) compared to obese patients in the thiopental group. There were no differences between the groups in sample A (P = 0.833), D (P = 0.614) and E (P = 0.769). We found no changes in haemodynamic parameters between both groups. CONCLUSIONS: Etomidate decreased serum cortisol concentration and decreased reactivity to tetracosactide both in morbidly obese and in normal weight patients. This effect was reversible within 24 hours. PMID- 26966107 TI - A comparison of subhypnotic doses of propofol and midazolam during spinal anaesthesia for elective Caesarean section. AB - BACKGROUND: This study compared two types of sedation in pregnant women receiving subarachnoid anaesthesia for elective Caesarean section. METHODS: This prospective randomised study included 56 women. Patients were sedated with propofol (PROP group, n = 27) or midazolam (MID group, n = 29) via intravenous infusion after extraction of the foetus. The following parameters were assessed at five-minute intervals: degree of sedation, heart rate, arterial pressure, ECG recording and arterial haemoglobin oxygen saturation. Moreover, we recorded drug doses, changes in infusion rates to ensure a desirable degree of sedation and adverse side effects. The maternal recall of delivery and satisfaction with sedation were also evaluated. RESULTS: The incidence of increased sedative infusion rates was higher in the PROP group (59.3% vs. 37.9%). In contrast, decreased infusion rates were observed in the MID group (41.4% vs. 29.6%). After the initial dose, a desirable level of sedation was easier to obtain in the PROP group (77.7% vs. 55.1%), whereas excessive sedation was noted more frequently in the MID group (34.5% vs. 11.5%). The deepest degree of sedation was found in 2 PROP patients and 1 MID patient. In the PROP group, excessive sedation was rapidly alleviated by reducing the infusion rate. In the MID group, excessive sedation was observed throughout the examination, despite reduced infusion rates. No significant intergroup differences were found for desired sedation levels. The mean heart rate and arterial pressure were lower in the PROP group. In the MID group, only 5% of patients developed an elevated systolic RR. No ECG alterations were observed in any patient. A haemoglobin oxygen saturation level below 92% was found in 1 patient from each group. Logorrhoea was characteristic in the PROP group (44.4%). The incidence of nausea and vomiting were higher in the MID group. Other side effects (e.g., headache, backache, erythema and chills) were observed in a subset of patients from both groups. In the MID group, birth recall was significantly lower (82.8% vs. 96.3%). Full satisfaction with sedation was declared by 89.6% of MID patients and 92.6% of PROP patients. CONCLUSIONS: Midazolam and propofol induce effective and safe sedation in patients receiving subarachnoid anaesthesia for Caesarean section. Propofol appears to be more useful for Caesarean section sedation when compared with midazolam because of its shorter action, antiemetic effects and better maternal recall of foetal delivery. PMID- 26966108 TI - Single strip lesions radiofrequency denervation for treatment of sacroiliac joint pain: two years' results. AB - BACKGROUND: Sacroiliac joint pain can be managed by intra-articular injections or radiofrequency of its innervation. Single strip lesions radiofrequency denervation is a new system. The objective of this study was to present one of the first utilizations of this innovative technique. METHODS: 60 patients who met the diagnostic criteria for sacroiliac joint syndrome were enrolled in the study. In total, 102 single strip lesions radiofrequency denervations were performed. Pain intensity was measured with the Oswestry low back pain disability questionnaire and the Oswestry Disability Index whose scores were assessed at 1, 3, 6 and 12 months after the procedure. RESULTS: 91.8 % of the 102 radiofrequency treatments resulted in a reduction of more than 50% pain intensity relief at 1 month, 81.6% at 3 months and 59.16% at 6 months. In 35.7% of cases, the relief was continuative up to 1 year. No relief was observed in 12.24% of cases. The ODI scores improved significantly 1 month after the procedure, compared with the baseline scores. The ODI scores after 6 months improved very clearly compared with the baseline scores and with the 3-month scores. CONCLUSIONS: Single strip lesions radiofrequency denervation using the Simplicity III probe is a potential modality for intermediate term relief for patients with sacroiliac pain. PMID- 26966109 TI - Tissue oximetry in anaesthesia and intensive care. AB - Conventional monitoring during surgery and intensive care is not sufficiently sensitive to detect acute changes in vital organs perfusion, while its good quality is critical for maintaining their function. Disturbed vital organ perfusion may lead to the development of postoperative complications, including neurological sequel and renal failure. Near-infra-red spectroscopy (NIRS) represents one of up-to-date techniques of patient monitoring which is commonly used for the assessment of brain oximetry in thoracic aorta surgery, and - increasingly more often -in open-heart surgery. Algorithms for maintaining adequate brain saturation may result in a decrease of neurological complications and cognitive dysfunction following cardiac surgery. The assessment of kidney and visceral perfusion with tissue oximetry is gaining increasing interest during pediatric cardiac surgery. Attempts at decreasing complications by the use of brain oximetry during carotid endarterectomy, as well as thoracic and abdominal surgery demonstrated conflicting results. In recent years NIRS technique was proposed as a tool for muscle perfusion assessment under short term ischemia and reperfusion, referred to as vascular occlusion test (VOT). This monitoring extension allows for the identification of early disturbances in tissue perfusion. Results of recent studies utilizing VOT suggest that the muscle saturation decrease rate is reduced in septic shock patients, while decreased speed of saturation recovery on reperfusion is related to disturbed microcirculation. Being non-invasive and feasible technique, NIRS offers an improvement of preoperative risk assessment in cardiac surgery and promises more comprehensive intraoperative and ICU patient monitoring allowing for better outcome. PMID- 26966110 TI - Anaesthetic perioperative management according to the ERAS protocol. AB - After many years of experience in surgery, a series of recommendations have been created by a group of European specialists to improve the quality of perioperative care and maximize postoperative outcomes. Early mobilization and oral feeding, preoperative oral intake of carbohydrate-rich fluids, proper fluid and pain management, intensive postoperative nausea and vomiting prophylaxis, and antimicrobial and thromboembolism prophylaxis are the interventions that may decrease surgery-induced metabolic stress and facilitate the return of bowel function and early discharge. The Enhanced Recovery After Surgery (ERAS) Society is the group that focuses on these perioperative issues. This paper aims to summarize the role of anaesthesiologists in the implementation of the ERAS protocol. PMID- 26966111 TI - Comparison of the C-Mac video laryngoscope with the McGrath Series 5 video laryngoscope concerning an extremely difficult airway. PMID- 26966112 TI - Commentary to "Remifentanil for labour pain relief". PMID- 26966113 TI - In reply to the commentary to Commentary to "Remifentanil for labour pain relief". PMID- 26966114 TI - Cut-off point for switching from non- -invasive ventilation to intubation in severe ARDS. Still a spectrum of greys and whites. PMID- 26966115 TI - Cut-off point for switching from non- -invasive ventilation to intubation in severe ARDS. Fifty shades of grey? PMID- 26966116 TI - The role of Argentine Federation of Associations of Anaesthesia, Analgesia and Reanimation. PMID- 26966117 TI - Snaring swans: intraoperative knotting of pulmonary artery catheters. PMID- 26966118 TI - Successful surgery for refractory seizures associated with bilateral schizencephaly: two case reports and literature review. AB - Schizencephaly is a rare malformation of cortical development resulting from cell migration defects that occur unilaterally or bilaterally. The type of the schizencephalic cleft can be open lip or closed lip. Patients suffering from refractory seizures secondary to schizencephaly should be considered for surgical treatment. In this paper, we retrospectively analyzed two patients with confirmed schizencephaly and intractable seizures. The evaluation methods included a medical history assessment, a neurological examination and magnetic resonance imaging (MRI). Continuous intracranial video-electroencephalogram (vEEG) monitoring with surface electrodes and deep electrodes was evaluated to confirm the epileptogenic zones associated with the schizencephalic lesions. Cortical electrical stimulation was performed to evaluate the neurophysiology of the relevant brain regions. Epileptic focus resection was performed close to the schizencephalic cleft according to the results of intracranial EEG and stimulation while preserving neurological functions. MRI revealed bilateral open lip schizencephaly in one patient and closed lip schizencephaly in the other patient. The epileptogenic zones were localized close to the schizencephalic clefts. The seizure outcome was Engel's class Ia in both patients at 1-year follow-up. No significant neurological deficits were found, and their activities of daily life were significantly improved. We conclude that abnormal cortex near the schizencephalic clefts may display an extrinsic epileptogenicity. Accurate localization of the epileptogenic zones using intracranial EEG and electrical stimulation can lead to a seizure-free outcome in patients with refractory epilepsy associated with schizencephaly. PMID- 26966120 TI - What role for ?vortioxetine? AB - ?Vortioxetine (Brintellix-Lundbeck) is licensed for treating adults with major depressive episodes.(1) It acts on the serotonin system and is described as having a 'novel multimodal mechanism of action'.(2) The company claims that it is the first antidepressant in the EU to include an effect on certain aspects of cognitive function in patients with depression in its Summary of Product Characteristics.(3) The National Institute for Health and Care Excellence has recommended it as an option for patients whose current episode has responded inadequately to two antidepressants. Here we consider the evidence for vortioxetine and its place in treating major depression in adults. PMID- 26966119 TI - A proof-of-concept, randomized controlled trial of DAR-0100A, a dopamine-1 receptor agonist, for cognitive enhancement in schizophrenia. AB - BACKGROUND: Evidence from preclinical and human studies indicates the presence of reduced dopamine-1 receptor (D1R) signaling in the cortex, where D1Rs predominate, in patients with schizophrenia (SCZ), which may contribute to their cognitive deficits. Furthermore, studies in nonhuman primates (NHP) have suggested that intermittent administration of low doses of D1R agonists produce long-lasting reversals in cognitive deficits. The purpose of this trial was to test whether a similar design, involving subacute intermittent administration of low doses of a full, selective agonist at D1Rs, DAR-0100A, would improve cognitive deficits in SCZ. METHODS: We randomized 49 clinically stable individuals with SCZ to three weeks of intermittent treatment with 0.5 mg or 15 mg of DAR-0100A, or placebo (normal saline). Functional magnetic resonance imaging (fMRI) BOLD was used to evaluate the effects of drug administration on brain activity during a working memory (WM) task. Effects on cognition were also assessed using the MATRICS and the N-back task as primary endpoints. The CogState battery was used as a secondary endpoint. RESULTS: There were no observed treatment effects on either the BOLD fMRI signal during WM tasks or the WM domains of the MATRICS. Moderate improvement was detected on the CogState battery and on the attention domain of the MATRICS. CONCLUSION: These results suggest that low doses of D1 agonists that do not result in measureable occupancy of the D1R do not reliably improve cognition in SCZ, unlike the observations in NHP. As this drug is limited by its pharmacokinetic profile, better D1R agonists that can achieve adequate levels of D1R occupancy are needed to test the efficacy of this mechanism for cognitive enhancement in SCZ. PMID- 26966121 TI - QT interval and drug therapy. AB - The QT interval is an important component of the electrocardiogram, which when prolonged can predict the risk of developing the potentially fatal cardiac arrhythmia, torsades de pointes. There is growing understanding of the genetics associated with cardiac arrhythmias and an increasing number of drugs that can prolong the QT interval. Consequently, assessment of the effect of drugs on the QT interval has become a significant aspect of drug development, regulatory assessment and clinical care. Here, we review the QT interval and the risks associated with drug-induced prolongation of the QT interval. PMID- 26966123 TI - Capsule Commentary on Boissy et al., Communication Skills Training for Physicians Improves Patient Experiences. PMID- 26966122 TI - (18)F-DOPA: the versatile radiopharmaceutical. PMID- 26966124 TI - Capsule Commentary on Melzer et al., Predictors of Pharmacotherapy for Tobacco Use among Veterans Admitted for COPD: The Role of Disparities and Tobacco Control Processes. PMID- 26966125 TI - Cost Effectiveness of Protease Inhibitor Monotherapy Versus Standard Triple Therapy in the Long-Term Management of HIV Patients: Analysis Using Evidence from the PIVOT Trial. AB - BACKGROUND: Protease inhibitor (PI) monotherapy can maintain virological suppression in the majority of patients once it has been established on triple therapy and may also have the potential for substantial cost savings arising from the use of fewer drugs. However, the cost effectiveness of PI monotherapy has yet to be demonstrated. OBJECTIVES: In this study we examine the cost effectiveness of PI monotherapy with prompt return to combination therapy in the event of viral load rebound compared with ongoing triple therapy (OT) in patients with suppressed viral load on combination antiretroviral therapy (ART) in the UK. METHODS: The analysis used data from the PIVOT trial in which HIV-positive adults with suppressed viral load for >=24 weeks on combination ART were randomised to maintain OT or to a strategy of PI monotherapy with prompt return to combination therapy if viral load rebounded. A cost-effectiveness analysis including long term modelling was conducted. Main outcomes included UK National Health Service (NHS) costs and quality-adjusted life-years (QALYs) with comparative results presented as incremental cost-effectiveness ratios. RESULTS: PI monotherapy was cost saving as a result of large savings in ART drug costs while being no less effective in terms of QALYs in the within-trial analysis and marginally less effective with lifetime modelling. In the base-case analysis over 3 years, the incremental total cost per patient was -L6424.11 (95 % confidence interval 7418.84 to -5429.38) and incremental QALYs were 0.0051 (95 % CI -0.0479 to 0.0582), resulting in PI monotherapy 'dominating' OT. Multiple scenario analyses found that PI monotherapy was cost saving with no marked differences in QALYs. Modelling of lifetime costs and QALYs showed that PI monotherapy was associated with significant cost savings and was marginally less effective; PI monotherapy was cost effective at accepted cost-effectiveness thresholds in all but one scenario analysis. CONCLUSIONS: Under most assumptions, PI monotherapy appears to be a cost-effective treatment strategy compared with OT for HIV-infected patients who have achieved sustained virological suppression. PMID- 26966126 TI - Effect of Outflow Tract Contributions to 82Rb-PET Global Myocardial Blood Flow Computations. AB - Algorithms are able to compute myocardial blood flow (MBF) from dynamic PET data for each of the 17 left ventricular segments, with global MBF obtained by averaging segmental values. This study was undertaken to compare MBFs with and without the basal-septal segments. METHODS: Data were examined retrospectively for 196 patients who underwent rest and regadenoson-stress (82)Rb PET/CT scanning for evaluation of known or suspected coronary artery disease. MBF data were acquired in gated list mode and rebinned to isolate the first-pass dynamic portion. Coronary vascular resistance (CVR) was computed as mean arterial pressure divided by MBF. MBF inhomogeneity was computed as the ratio of SD to mean MBF. Relative perfusion scores were obtained using (82)Rb-specific normal limits applied to polar maps of myocardial perfusion generated from myocardial equilibrium portions of PET data. MBF and CVRs from 17 and 14 segments were compared. RESULTS: Mean MBFs were lower for 17- than 14-segment means for rest (0.78 +/- 0.50 vs. 0.85 +/- 0.54 mL/g/min, paired t test P < 0.0001) and stress (1.50 +/- 0.88 vs. 1.67 +/- 0.96 mL/g/min, P < 0.0001). Bland-Altman plots of MBF differences versus means exhibited nonzero intercept (-0.04 +/- 0.01, P = 0.0004) and significant correlation (r = -0.64, P < 0.0001), with slopes significantly different from 0.0 (-7.2% +/- 0.6% and -8.3% +/- 0.7% for rest and stress MBF; P < 0.0001). Seventeen-segment CVRs were higher than 14-segment CVRs for rest (159 +/- 86 vs. 147 +/- 81 mm Hg/mL/g/min, paired t test P < 0.0001) and stress CVR (85 +/- 52 vs. 76 +/- 48 mm Hg/mL/g/min, P < 0.0001). MBF inhomogeneity correlated significantly (P < 0.0001) with summed perfusion scores, but values correlated significantly more strongly for 14- than 17-segment values for rest (r = 0.67 vs. r = 0.52, P = 0.02) and stress (r = 0.69 vs. r = 0.47, P = 0.001). When basal segments were included in MBF determinations, perfusion inhomogeneity was greater both for rest (39% +/- 10% vs. 31% +/- 10%, P < 0.0001) and for stress (42% +/- 12% vs. 32% +/- 11%, P < 0.0001). CONCLUSION: Averaging 17 versus 14 segments leads to systematically 7%-8% lower MBF calculations, higher CVRs, and greater computed inhomogeneity. Consideration should be given to excluding basal-septal segments from standard global MBF determination. PMID- 26966127 TI - Incidental Detection of Follicular Thyroid Carcinoma in 68Ga-PSMA PET/CT Imaging. AB - Prostate-specific membrane antigen (PSMA) is a type II transmembrane protein. It has been shown to be expressed in various solid malignant neoplasms. We report a case of a prostate cancer patient who underwent (68)Ga-PSMA PET/CT imaging. There is a large thyroid nodule in the right thyroid gland, which had intense PSMA accumulation. Follicular thyroid lesions can be seen on (68)Ga-PSMA PET/CT imaging. PMID- 26966128 TI - Optimizing 18F-FDG Uptake Time Before Imaging Improves the Accuracy of PET/CT in Liver Lesions. AB - (18)F-FDG PET/CT has emerged as one of the fastest-growing imaging modalities. A shorter protocol results in a lower target-to-background ratio, which can increase the challenge of identifying mildly (18)F-FDG-avid lesions and differentiating inflammatory or physiologic activity from malignant activity. The purpose of this study was to determine the delay between radiotracer injection and imaging that optimizes target-to-background ratio while maintaining counts high enough to ensure scan sensitivity. METHODS: The study included 140 patients (66 male and 74 female; age range, 42-95 y) with suspected hepatic lesions as seen on an (18)F-FDG PET scan. SUV was determined as region-of-interest activity/(dose/total body weight). RESULTS: The mean injected dose was 610 +/- 66.6 MBq (16.5 +/-1.8 mCi), with a mean glucose level of 107 +/- 26.6 mg/dL (standardized to 90 mg/dL). The uptake time before imaging ranged from 61 to 158 min, with a mean of 108.8 +/- 24.8 min. The P values for the correlation of SUV to time were 0.004, 0.003, and 0.0001 for malignant lesions, benign lesions, and background hepatic tissue, respectively. CONCLUSION: An approximately 90-min time window from (18)F-FDG injection to PET imaging would significantly improve target to-background ratio and, thus, quantitation and visual interpretation. This benefit outweighs the minimal loss in patient throughput. PMID- 26966129 TI - Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. PMID- 26966130 TI - Comments on: Analysis of cerebrospinal fluid for xanthochromia versus modern computed tomography scanners in the diagnosis of subarachnoid haemorrhage: experience at a tertiary trauma referral centre. PMID- 26966131 TI - Subcutaneous Immunoglobulin in Refractory Juvenile Dermatomyositis. AB - Juvenile dermatomyositis (JDM) is the most common form of juvenile idiopathic inflammatory myopathy. We report a child with steroid-dependent JDM refractory to hydroxychloroquine and subcutaneous methotrexate who experienced systemic reactions to intravenous immunoglobulin and was successfully treated with subcutaneous immunoglobulin. This form of therapy has been shown to be safe, has a very low rate of adverse effects, does not require hospital admission, reduces the number of missed school days, and decreases the costs associated with treatment. PMID- 26966132 TI - Adverse Childhood Experiences and Adult Well-Being in a Low-income, Urban Cohort. AB - OBJECTIVE: This study tests the association between adverse childhood experiences (ACEs) and multidimensional well-being in early adulthood for a low-income, urban cohort, and whether a preschool preventive intervention moderates this association. METHODS: Follow-up data were analyzed for 1202 low-income, minority participants in the Chicago Longitudinal Study, a prospective investigation of the impact of early experiences on life-course well-being. Born between 1979 and 1980 in high-poverty neighborhoods, individuals retrospectively reported ACEs from birth to adolescence, except in cases of child abuse and neglect. RESULTS: Nearly two-thirds of the study sample experienced >=1 ACEs by age 18. After controlling for demographic factors and early intervention status, individuals reporting ACEs were significantly more likely to exhibit poor outcomes than those with no ACEs. Those with >=4 ACEs had significantly reduced likelihood of high school graduation (odds ratio [OR] = 0.37; P < .001), increased risk for depression (OR = 3.9; P < .001), health compromising behaviors (OR = 4.5; P < .001), juvenile arrest (OR = 3.1; P < .001), and felony charges (OR = 2.8; P < .001). They were also less likely to hold skilled jobs (OR = 0.50; P = .001) and to go further in school even for adversity measured by age 5. CONCLUSIONS: ACEs consistently predicted a diverse set of adult outcomes in a high-risk, economically disadvantaged sample. Effective and widely available preventive interventions are needed to counteract the long-term consequences of ACEs. PMID- 26966134 TI - Number of children given antidepressants is rising, study shows. PMID- 26966133 TI - A Standardized Discharge Process Decreases Length of Stay for Ventilator Dependent Children. AB - OBJECTIVE: Children who require chronic mechanical ventilation via tracheostomy are medically complex and require prolonged hospitalization, placing a heavy burden on caregivers and hospital systems. We developed an interdisciplinary Ventilator Care Program to relieve this burden, through improved communication and standardized care. We hypothesized that a standardized team approach to the discharge of tracheostomy- and ventilator-dependent children would decrease length of stay (LOS), reduce patient costs, and improve safety. METHODS: We used process mapping to standardize the discharge process for children requiring chronic ventilation. Interventions included developing education materials, a Chronic Ventilation Road Map for caregivers, utilization of the electronic medical record to track discharge readiness, team-based care coordination, and timely case management to arrange home nursing. We aimed to decrease overall and pediatric respiratory care unit LOS as the primary outcomes. We also analyzed secondary outcomes (mortality, emergency department visits, unplanned readmissions), and per-patient hospital costs during 2-year "preintervention" and "postintervention" periods (n = 18 and 30, respectively). RESULTS: Patient demographics were not different between groups. As compared with the preintervention cohort, the overall LOS decreased 42% (P = .002). Pediatric respiratory care unit LOS decreased 56% (P = .001). As a result, unplanned readmissions, emergency department visits, and mortality were not increased. Direct costs per hospitalization were decreased by an average of 43% (P = .01). CONCLUSIONS: Although LOS remained high, a standardized discharge process for chronically ventilated children by an interdisciplinary Ventilator Care Program team resulted in decreased LOS and costs without a negative impact on patient safety. PMID- 26966135 TI - Neurotoxicity and LSD treatment: a follow-up study of 151 patients in Denmark. AB - LSD was introduced in psychiatry in the 1950s. Between 1960 and 1973, nearly 400 patients were treated with LSD in Denmark. By 1964, one homicide, two suicides and four suicide attempts had been reported. In 1986 the Danish LSD Damages Law was passed after complaints by only one patient. According to the Law, all 154 applicants received financial compensation for LSD-inflicted harm. The Danish State Archives has preserved the case material of 151 of the 154 applicants. Most of the patients suffered from severe side effects of the LSD treatment many years afterwards. In particular, two-thirds of the patients had flashbacks. With the recent interest in LSD therapy, we should consider the neurotoxic potential of LSD. PMID- 26966136 TI - Epigenome-wide DNA methylation patterns associated with fatigue in primary Sjogren's syndrome. AB - OBJECTIVE: Chronic fatigue is a common, disabling and poorly understood phenomenon. Recent studies indicate that epigenetic mechanisms may be involved in the expression of fatigue, a prominent feature of primary SS (pSS). The aim of this study was to investigate whether DNA methylation profiles of whole blood are associated with fatigue in patients with pSS. METHODS: Forty-eight pSS patients with high (n = 24) or low (n = 24) fatigue as measured by a visual analogue scale were included. Genome-wide DNA methylation was investigated using the Illumina HumanMethylation450 BeadChip array. After quality control, a total of 383 358 Cytosine-phosphate-Guanine (CpG) sites remained for further analysis. Age, sex and differential cell count estimates were included as covariates in the association model. A false discovery rate-corrected P < 0.05 was considered significant, and a cut-off of 3% average difference in methylation levels between high- and low-fatigue patients was applied. RESULTS: A total of 251 differentially methylated CpG sites were associated with fatigue. The CpG site with the most pronounced hypomethylation in pSS high fatigue annotated to the SBF2-antisense RNA1 gene. The most distinct hypermethylation was observed at a CpG site annotated to the lymphotoxin alpha gene. Functional pathway analysis of genes with differently methylated CpG sites in subjects with high vs low fatigue revealed enrichment in several pathways associated with innate and adaptive immunity. CONCLUSION: Some genes involved in regulation of the immune system and in inflammation are differently methylated in pSS patients with high vs low fatigue. These findings point to functional networks that may underlie fatigue. Epigenetic changes could constitute a fatigue-regulating mechanism in pSS. PMID- 26966137 TI - Temporal plus epilepsy is a major determinant of temporal lobe surgery failures. PMID- 26966138 TI - Reply: Temporal plus epilepsy is a major determinant of temporal lobe surgery failures. PMID- 26966141 TI - Partial breast radiotherapy is as effective as standard whole breast radiotherapy, study finds. PMID- 26966140 TI - Mycobacterium bovis Cerebellar Abscess Following Treatment With Bacillus Calmette Guerin. AB - Bacillus Calmette-Guerin (BCG) is a live, attenuated strain of Mycobacterium bovis that is used to treat superficial bladder cancer. Although its use is typically associated with only mild, localized side effects, rare systemic complications can occur. Disseminated mycobacterium infections after BCG therapy have been reported in over 30 cases; however, central nervous system (CNS) infections do not commonly occur. We report a 74-year-old male who developed a M. bovis cerebellar abscess after receiving intravesical BCG infusion for bladder cancer for less than 1 year. This patient was successfully treated with antituberculosis therapy and corticosteroids. This patient case demonstrates that early-onset M bovis CNS infections can occur after BCG therapy. Patients presenting with altered mental status while on BCG therapy should be evaluated for disseminated infections. PMID- 26966139 TI - Surface errors without semantic impairment in acquired dyslexia: a voxel-based lesion-symptom mapping study. AB - Patients with surface dyslexia have disproportionate difficulty pronouncing irregularly spelled words (e.g. pint), suggesting impaired use of lexical semantic information to mediate phonological retrieval. Patients with this deficit also make characteristic 'regularization' errors, in which an irregularly spelled word is mispronounced by incorrect application of regular spelling-sound correspondences (e.g. reading plaid as 'played'), indicating over-reliance on sublexical grapheme-phoneme correspondences. We examined the neuroanatomical correlates of this specific error type in 45 patients with left hemisphere chronic stroke. Voxel-based lesion-symptom mapping showed a strong positive relationship between the rate of regularization errors and damage to the posterior half of the left middle temporal gyrus. Semantic deficits on tests of single-word comprehension were generally mild, and these deficits were not correlated with the rate of regularization errors. Furthermore, the deep occipital-temporal white matter locus associated with these mild semantic deficits was distinct from the lesion site associated with regularization errors. Thus, in contrast to patients with surface dyslexia and semantic impairment from anterior temporal lobe degeneration, surface errors in our patients were not related to a semantic deficit. We propose that these patients have an inability to link intact semantic representations with phonological representations. The data provide novel evidence for a post-semantic mechanism mediating the production of surface errors, and suggest that the posterior middle temporal gyrus may compute an intermediate representation linking semantics with phonology. PMID- 26966142 TI - Protective effects of sevoflurane in hepatic ischemia-reperfusion injury. AB - The endothelial glycocalyx plays a critical role in the regulation of vascular structure and functions. Previous studies have demonstrated that sevoflurane, a volatile anesthetic, can preserve the endothelial glycocalyx in heart tissues against ischemia-reperfusion injury. However, little is known about the effects of sevoflurane pretreatment on the vascular structure and functions of liver tissues following ischemia-reperfusion injury. To this end, female Sprague-Dawley rats (n = 28) were anesthetized either with ketamine (80-120 mg/kg, i.p.) or with one minimum alveolar concentration (MAC) sevoflurane (2% v/v). Following in vivo hepatic ischemia procedure, the liver was isolated and reperfusion was produced. During the period of reperfusion, liver reperfusion samples were collected, and the concentrations of heparan sulfate and syndecan-1 (Syn-1), and the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes, were measured. The morphology of hepatocytes and endothelial glycocalyx were then assessed by using the light and electron microscopies, respectively. Ischemia reperfusion increased the release of HS and Syn-1, and elevated the levels of ALT and AST in a time-dependent manner. However, sevoflurane pretreatment reduced the release of HS and Syn-1and attenuated the levels of ALT and AST, in a time dependent manner, as compared with ketamine pretreatment. Furthermore, sevoflurane pretreatment decreased the shedding of endothelial glycocalyx and hepatocytes necrosis. Sevoflurane pretreatment preserved the endothelial glycocalyx in the liver tissue against ischemia-reperfusion injury. The effect appears to help protect hepatocytes against ischemia-reperfusion-induced necrosis. PMID- 26966144 TI - Focus on harm reduction in fight against HIV, says report. PMID- 26966145 TI - Contrast medium enhanced susceptibility imaging signal mechanism; should we use contrast medium? AB - BACKGROUND: Intracranial lesions exhibit clear contrast enhancement in T1 weighted imaging, but the mechanism whereby contrast-enhanced susceptibility weighted imaging (CE-SWI) generates signals remains unclear. Contrast enhancement patterns cannot be reliably predicted. PURPOSE: To explore the mechanism of CE SWI contrast enhancement. MATERIAL AND METHODS: Fifty-five patients were retrospectively enrolled. All of the imaging employed a clinical 3T magnetic resonance imaging (MRI) system fitted with a 32-channel head coil. Minimum intensity projection reformatted images were evaluated. Intracranial lesions and brain parenchymal intensities were explored using SWI and CE-SWI. signal intensity rates were calculated by dividing the lesional intensity by the white matter intensity, after which the SWI and CE-SWI signal intensity rate were compared. Two observers independently performed intralesional susceptibility signal analysis. RESULTS: After contrast medium administration, malignant and extra-axial tumors exhibited obvious contrast enhancement on CE-SWI (P < 0.001 and P = 0.013, respectively). The signal intensity of white matter was significantly reduced. The signal intensity rates rose significantly in the benign, malignant, and extra-axial groups (P < 0.001). Between-radiologist agreement in terms of intralesional susceptibility signal assessment was strong (kappa = 0.8, P < 0.001). CONCLUSION: Contrast media can either reduce or increase SWI signal intensities. The dual contrast feature of CE-SWI can be useful when exploring intracranial disorders. PMID- 26966143 TI - Role of oxidative stress in the pathophysiology of Toxoplasma gondii infection. AB - Oxidative stress (OS) plays an essential role in the pathogenesis of common neurodegenerative diseases. We have previously shown that Toxoplasma gondii (T. gondii) induces high nitric oxide (NO) production, glial activation, and apoptosis that altogether cause severe neuropathology in toxoplasma encephalitis (TE). The objective of this study was to investigate the cytotoxic effect of OS and to identify a correlation between the causes of T. gondii induced neuropathology. Expression levels of glutathione reductase (GR), Cu/Zn superoxide dismutase (SOD1), neuron specific enolase (NSE), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were investigated. Results of the study revealed that the levels of GR (P <0.005) and NSE (P <0.001) expression in the brain tissue markedly increased while SOD1 activity decreased (P <0.001) in the infected group compared to the non-infected group. In addition, intense staining for 8-OHdG (P <0.05) was observed both in the nucleus and the cytoplasm of neurons and glial cells that underwent OS. These results were reasonable to suggest that T. gondii-mediated OS might play a pivotal role and a different type of role in the mechanism of neurodegeneration/neuropathology in the process of TE. The results also clearly indicated that increased levels of NO and apoptosis might contribute to OS related pathogenesis of TE. As a result, OS and expression of NSE might give an idea of the disease progress and may have a critical diagnostic significance for patients with T. gondii infection. PMID- 26966146 TI - CT-based measurement of the inner pelvic volume. AB - Background Surgery in the lesser pelvis is associated with a high complication rate as surgeons are spatially limited by solid anatomic structures and soft tissue borders. So far, only two-dimensional (2D) parameters have been used for risk stratification. Purpose To precisely measure the inner pelvic volume a computed tomography (CT)-based three-dimensional (3D) approach was established and compared to approximations by 2D parameter combinations. Material and Methods Thin-layered multi-slice CT datasets were used retrospectively for slice by slice depiction of the inner pelvic surface. The inner pelvic volume was then automatically compounded. Combinations of two to four 2D dimensions determined in 3D volume rendered reconstructions were correlated with the inner pelvic volume. Pearson's correlation coefficient and Chi square test were used for statistical calculations. Significance level was set at P < 0.05. Results In total 142 patients (91 men, 51 women) aged 64.8 +/- 10.6 years at surgery were included in the study. Mean calculated pelvic volume was 1031.13 +/- 180.06 cm3 (men, 996.57 +/- 172.43 cm3; women, 1093.34 +/- 178.39 cm3). Best approximations were obtained by combination of the 2D measurements transverse inlet and pelvic height for men (r = 0.799, P < 0.05) as well as transverse inlet, obstetric conjugate, interspinous distance and pelvic depth for women (r = 0.855, P < 0.05). Conclusion We describe a precise and reproducible CT-based method for pelvic volumetry. A less time consuming but still reliable approximation can be achieved by combination of two to four 2D dimensions. PMID- 26966147 TI - Closing PFO closure for migraine? PMID- 26966148 TI - Is takotsubo syndrome a microvascular acute coronary syndrome? Towards of a new definition. PMID- 26966149 TI - Physical activity, resting heart rate, and atrial fibrillation: the Tromso Study. AB - AIMS: The objective was to examine the association of physical activity and resting heart rate (RHR) with hospital-diagnosed atrial fibrillation (AF) in a Norwegian cohort. METHODS AND RESULTS: This prospective study included 20 484 adults (50.3% men) who participated in the third Tromso Study survey in 1986-87. At baseline, physical activity was assessed by a validated questionnaire, and RHR was objectively measured. Participants were followed from baseline through 2010 with respect to incident cases of hospital-diagnosed AF documented on an electrocardiogram. During a mean follow-up period of 20 years (409 045 person years), 750 participants (70.5% men) were diagnosed with AF. Compared with the low physical activity group, moderately active individuals had a 19% lower risk of any AF [adjusted hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.68 0.97], whereas highly active had similar risk of AF. Vigorously active individuals showed a non-significantly higher risk of AF (adjusted HR 1.37, 95% CI 0.77-2.43). Risk of AF increased with decreasing RHR (adjusted HR 0.92, 95% CI 0.86-0.98 for each 10 b.p.m. increase in RHR), and RHR < 50 b.p.m. was a risk factor for AF (P < 0.05). CONCLUSION: In this prospective cohort study, leisure time physical activity was associated with AF in a J-shaped pattern. Moderate physical activity was associated with a reduced risk of AF, whereas higher activity levels attenuated the benefits of moderate activity. Low RHR was a risk factor for AF. Our results support the hypothesis that moderate and vigorous physical activity may affect AF risk via different pathophysiological mechanisms. PMID- 26966150 TI - Differential substrate recognition by isozymes of plant protein-only Ribonuclease P. AB - Ribonuclease P (RNase P) catalyzes the cleavage of leader sequences from precursor tRNA (pre-tRNA). Typically, these enzymes are ribonucleic protein complexes that are found in all domains of life. However, a new class of RNase P has been discovered that is composed entirely of protein, termed protein-only RNase P (PRORP). To investigate the molecular determinants of PRORP substrate recognition, we measured the binding affinities and cleavage kinetics of Arabidopsis PRORP1 for varied pre-tRNA substrates. This analysis revealed that PRORP1 does not make significant contacts within the trailer or beyond N-1of the leader, indicating that this enzyme recognizes primarily the tRNA body. To determine the extent to which sequence variation within the tRNA body modulates substrate selectivity and to provide insight into the evolution and function of PRORP enzymes, we measured the reactivity of the three Arabidopsis PRORP isozymes (PRORP1-3) with four pre-tRNA substrates. A 13-fold range in catalytic efficiencies (10(4)-10(5)M(-1)s(-1)) was observed, demonstrating moderate selectivity for pre-tRNA substrates. Although PRORPs bind the different pre-tRNA species with affinities varying by as much as 100-fold, the three isozymes have similar affinities for a given pre-tRNA, suggesting similar binding modes. However, PRORP isozymes have varying degrees of cleavage fidelity, which is dependent on the pre-tRNA species and the presence of a 3'-discriminator base. This work defines molecular determinants of PRORP substrate recognition that provides insight into this new class of RNA processing enzymes. PMID- 26966152 TI - Writing an Independently Composed Sentence by Spanish-Speaking Children With and Without Poor Transcription Skills: A Writing-Level Match Design. AB - The main objective of this research was to analyze the impact of transcription skills of Spanish writers when writing an independently composed sentence within a writing-level design. The free-writing sentence task from the Early Grade Writing Assessment (Jimenez, in press) was used to examine the production, accuracy, speed, syntactic complexity, quality, and fluency of children with poor transcription skills (PTS). The results showed that there were significant differences between children with PTS and peers who had good transcription skills. The PTS group members were less accurate, slower, and less fluent or even dysfluent. Furthermore, their sentences were less complex and contained lower quality content. These results suggest that transcription skills play a crucial role in early written expression in Spanish, and poor transcription abilities hamper the acquisition and normal development of sentence composition. PMID- 26966154 TI - Five minutes with . . . Candace Imison. PMID- 26966153 TI - Error Patterns in Ordering Fractions Among At-Risk Fourth-Grade Students. AB - The three purposes of this study were to (a) describe fraction ordering errors among at-risk fourth grade students, (b) assess the effect of part-whole understanding and accuracy of fraction magnitude estimation on the probability of committing errors, and (c) examine the effect of students' ability to explain comparing problems on the probability of committing errors. Students ( N = 227) completed a nine-item ordering test. A high proportion (81%) of problems were completed incorrectly. Most (65%) errors were due to students misapplying whole number logic to fractions. Fraction-magnitude estimation skill, but not part whole understanding, significantly predicted the probability of committing this type of error. Implications for practice are discussed. PMID- 26966151 TI - Secondary structure confirmation and localization of Mg2+ ions in the mammalian CPEB3 ribozyme. AB - Most of today's knowledge of the CPEB3 ribozyme, one of the few small self cleaving ribozymes known to occur in humans, is based on comparative studies with the hepatitis delta virus (HDV) ribozyme, which is highly similar in cleavage mechanism and probably also in structure. Here we present detailed NMR studies of the CPEB3 ribozyme in order to verify the formation of the predicted nested double pseudoknot in solution. In particular, the influence of Mg(2+), the ribozyme's crucial cofactor, on the CPEB3 structure is investigated. NMR titrations, Tb(3+)-induced cleavage, as well as stoichiometry determination by hydroxyquinoline sulfonic acid fluorescence and equilibrium dialysis, are used to evaluate the number, location, and binding mode of Mg(2+)ions. Up to eight Mg(2+)ions interact site-specifically with the ribozyme, four of which are bound with high affinity. The global fold of the CPEB3 ribozyme, encompassing 80%-90% of the predicted base pairs, is formed in the presence of monovalent ions alone. Low millimolar concentrations of Mg(2+)promote a more compact fold and lead to the formation of additional structures in the core of the ribozyme, which contains the inner small pseudoknot and the active site. Several Mg(2+)binding sites, which are important for the functional fold, appear to be located in corresponding locations in the HDV and CPEB3 ribozyme, demonstrating the particular relevance of Mg(2+)for the nested double pseudoknot structure. PMID- 26966155 TI - Sjogren's syndrome complicated with Fanconi syndrome and Hashimoto's thyroiditis: Case report and literature review. AB - We report a unique case of Sjogren's syndrome complicated with Fanconi syndrome and Hashimoto's thyroiditis in a 53-year-old Chinese woman, initially found to have proteinuria, fatigue and multiple old costal fractures. Distal tubular dysfunction is the most common renal damage in Sjogren's syndrome, while Fanconi syndrome (which is caused by proximal tubular dysfunction) and Hypothyroidism are rare complications of Sjogren's syndrome. PMID- 26966156 TI - Sleep quality, daytime sleepiness and health-related quality-of-life in maintenance haemodialysis patients. AB - OBJECTIVES: To assess the relationship between sleep quality, daytime sleepiness and health-related quality-of-life (HRQoL) in Chinese patients undergoing maintenance haemodialysis (MHD). METHODS: This cross-sectional study enrolled patients undergoing MHD. Self-reported sleep quality (Pittsburgh Sleep Quality Index [PSQI]), daytime sleepiness (Epworth Sleepiness Scale [ESS]) and HRQoL (36 item Short Form [SF-36]) were recorded for all patients. RESULTS: Sixty eight patients (mean +/- SD age = 61.75 +/- 16.56 years; 43 male/25 female) who regularly received MHD were included. The prevalence of poor sleepers was 69.1% (47/68) and daytime sleepiness was 11.8% (eight of 68). Poor sleepers had a significantly lower Physical Component Scale (PCS) score, Mental Component Scale (MCS) score and total SF-36 score than good sleepers. The PSQI score correlated inversely with both the PCS and MCS scores and correlated positively with age. Independent variables associated with total SF-36 score were duration of MHD, ESS score and PSQI score. CONCLUSIONS: Poor sleep quality is a common and severe issue for MHD patients in east China. Both sleep quality and daytime sleepiness were associated with lower HRQoL scores. PMID- 26966157 TI - Brain connectivity reflects human aesthetic responses to music. AB - Humans uniquely appreciate aesthetics, experiencing pleasurable responses to complex stimuli that confer no clear intrinsic value for survival. However, substantial variability exists in the frequency and specificity of aesthetic responses. While pleasure from aesthetics is attributed to the neural circuitry for reward, what accounts for individual differences in aesthetic reward sensitivity remains unclear. Using a combination of survey data, behavioral and psychophysiological measures and diffusion tensor imaging, we found that white matter connectivity between sensory processing areas in the superior temporal gyrus and emotional and social processing areas in the insula and medial prefrontal cortex explains individual differences in reward sensitivity to music. Our findings provide the first evidence for a neural basis of individual differences in sensory access to the reward system, and suggest that social emotional communication through the auditory channel may offer an evolutionary basis for music making as an aesthetically rewarding function in humans. PMID- 26966158 TI - The Role of Attractiveness: Imaging the Interaction Between Cardiovascular and Immune System. PMID- 26966159 TI - The Current State of Nuclear Medicine Physics Training: Findings of the AAPM/SNMMI Task Force. PMID- 26966160 TI - Hepatobiliary Secretion Kinetics of Conjugated Bile Acids Measured in Pigs by 11C Cholylsarcosine PET. AB - The aim of this study was to develop a method for the quantification of hepatobiliary uptake and secretion of conjugated bile acids with PET and the (11)C-labeled conjugated bile acid analog [N-methyl-(11)C]cholylsarcosine ((11)C CSar). METHODS: Six pigs (13 experiments) underwent dynamic (11)C-CSar PET of the liver with simultaneous measurements of hepatic blood perfusion and (11)C-CSar concentrations in arterial, portal, and hepatic venous blood. In 3 pigs (7 experiments), bile was collected from a catheter in the common hepatic duct. PET data were analyzed with a 2-tissue compartmental model with calculation of rate constants for the transport of (11)C-CSar among blood, hepatocytes, and intra- and extrahepatic bile ducts. PET results were validated against invasive blood and bile measurements. RESULTS: The directly measured rate of secretion of (11)C CSar into bile was equal to the rate of removal from blood at steady state. Accordingly, hepatocytes did not accumulate bile acids but simply facilitated the transport of bile acids from blood to bile against a measured concentration gradient of 4,000. The rate constant for the secretion of (11)C-CSar from hepatocytes into bile in experiments with a catheter in the common hepatic duct was 25% of that in experiments without a catheter (P < 0.05); we interpreted this result to be mild cholestasis caused by the catheter. The catheter caused an increased backflux of (11)C-CSar from hepatocytes to blood, and hepatic blood flow was 25% higher than in experiments without the catheter. The capacity for the overall transport of (11)C-CSar from blood to bile, as quantified by intrinsic clearance, was significantly lower in experiments with the catheter than in those without the catheter (P < 0.001). PET and blood measurements correlated significantly (P < 0.05). CONCLUSION: The in vivo kinetics of hepatobiliary secretion of conjugated bile acids can now be determined by dynamic (11)C-CSar PET. PMID- 26966168 TI - Clinicians will get legal protection for owning up to mistakes. PMID- 26966161 TI - Comparison of Tumor Uptake Heterogeneity Characterization Between Static and Parametric 18F-FDG PET Images in Non-Small Cell Lung Cancer. AB - (18)F-FDG PET is well established in the field of oncology for diagnosis and staging purposes and is increasingly being used to assess therapeutic response and prognosis. Many quantitative indices can be used to characterize tumors on (18)F-FDG PET images, such as SUVmax, metabolically active tumor volume (MATV), total lesion glycolysis, and, more recently, the proposed intratumor uptake heterogeneity features. Although most PET data considered within this context concern the analysis of activity distribution using images obtained from a single static acquisition, parametric images generated from dynamic acquisitions and reflecting radiotracer kinetics may provide additional information. The purpose of this study was to quantify differences between volumetry, uptake, and heterogeneity features extracted from static and parametric PET images of non small cell lung carcinoma (NSCLC) in order to provide insight on the potential added value of parametric images. METHODS: Dynamic (18)F-FDG PET/CT was performed on 20 therapy-naive NSCLC patients for whom primary surgical resection was planned. Both static and parametric PET images were analyzed, with quantitative parameters (MATV, SUVmax, SUVmean, heterogeneity) being extracted from the segmented tumors. Differences were investigated using Spearman rank correlation and Bland-Altman analysis. RESULTS: MATV was slightly smaller on static images ( 2% +/- 7%), but the difference was not significant (P = 0.14). All derived parameters, including those characterizing tumor functional heterogeneity, correlated strongly between static and parametric images (r = 0.70-0.98, P <= 0.0006), exhibiting differences of less than +/-25%. CONCLUSION: In NSCLC primary tumors, parametric and static baseline (18)F-FDG PET images provided strongly correlated quantitative features for both standard (MATV, SUVmax, SUVmean) and heterogeneity quantification. Consequently, heterogeneity quantification on parametric images does not seem to provide significant complementary information compared with static SUV images. PMID- 26966162 TI - Relationship Between 18F-FDG PET/CT Findings and HER2 Expression in Gastric Cancer. AB - (18)F-FDG PET has been widely used in the management of malignant tumors. In gastric cancer, the status of human epidermal growth factor receptor 2 (HER2) predicts the response to anti-HER2 antibody therapy, and testing of HER2 expression is now routine in the management of gastric cancer patients. However, to date, the relationship between (18)F-FDG uptake and HER2 expression has not, to our knowledge, been investigated. In this study, we aimed to investigate whether HER2 expression is associated with (18)F-FDG uptake and whether (18)F-FDG PET/CT can be used to predict the HER2 status of gastric cancer. METHODS: A retrospective analysis was performed on 64 gastric cancer patients who had undergone (18)F-FDG PET/CT before surgical resection. Tumor SUVmax was calculated from the level of (18)F-FDG uptake. RESULTS: No significant correlation was found between SUVmax and HER2 expression in gastric cancer. However, when signet-ring cell carcinoma was excluded, SUVmax was significantly higher in the HER2-negative group than in the HER2-positive group (8.619 +/- 5.878 vs. 3.789 +/- 2.613, respectively; P = 0.021). Multivariate analysis indicated that SUVmax and tumor differentiation remained significantly associated with HER2 expression (P = 0.048 and P = 0.028, respectively). HER2 expression was predicted with an accuracy of 64.4% when an SUVmax cutoff of 6.2 was used. CONCLUSION: (18)F-FDG uptake by gastric cancer is associated with HER2 expression. (18)F-FDG PET/CT may be useful for predicting the HER2 status of gastric cancer and for determining the therapeutic strategy. PMID- 26966169 TI - Programming of Plant Leaf Senescence with Temporal and Inter-Organellar Coordination of Transcriptome in Arabidopsis. AB - Plant leaves, harvesting light energy and fixing CO2, are a major source of foods on the earth. Leaves undergo developmental and physiological shifts during their lifespan, ending with senescence and death. We characterized the key regulatory features of the leaf transcriptome during aging by analyzing total- and small-RNA transcriptomes throughout the lifespan of Arabidopsis (Arabidopsis thaliana) leaves at multidimensions, including age, RNA-type, and organelle. Intriguingly, senescing leaves showed more coordinated temporal changes in transcriptomes than growing leaves, with sophisticated regulatory networks comprising transcription factors and diverse small regulatory RNAs. The chloroplast transcriptome, but not the mitochondrial transcriptome, showed major changes during leaf aging, with a strongly shared expression pattern of nuclear transcripts encoding chloroplast targeted proteins. Thus, unlike animal aging, leaf senescence proceeds with tight temporal and distinct interorganellar coordination of various transcriptomes that would be critical for the highly regulated degeneration and nutrient recycling contributing to plant fitness and productivity. PMID- 26966170 TI - A Short Open Reading Frame Encompassing the MicroRNA173 Target Site Plays a Role in trans-Acting Small Interfering RNA Biogenesis. AB - trans-Acting small interfering RNAs (tasiRNAs) participate in the regulation of organ morphogenesis and determination of developmental timing in plants by down regulating target genes through mRNA cleavage. The production of tasiRNAs is triggered by microRNA173 (miR173) and other specific microRNA-mediated cleavage of 5'-capped and 3'-polyadenylated primary TAS transcripts (pri-TASs). Although pri-TASs are not thought to encode functional proteins, they contain multiple short open reading frames (ORFs). For example, the primary TAS2 transcript (pri TAS2) contains 11 short ORFs, and the third ORF from the 5' terminus (ORF3) encompasses the miR173 target site. Here, we show that nonsense mutations in ORF3 of pri-TAS2 upstream of the miR173 recognition site suppress tasiRNA accumulation and that ORF3 is translated in vitro. Glycerol gradient centrifugation analysis of Arabidopsis (Arabidopsis thaliana) plant extracts revealed that pri-TAS2 and its miR173-cleaved 5' and 3' fragments are fractionated together in the polysome fractions. These and previous results suggest that the 3' fragment of pri-TAS2, which is a source of tasiRNAs, forms a huge complex containing SGS3, miR173 programmed AGO1 RNA-induced silencing complex, the 5' fragment, and ribosomes. This complex overaccumulated, moderately accumulated, and did not accumulate in rdr6, sde5, and sgs3 mutants, respectively. The sgs3 sde5 and rdr6 sde5 double mutants showed phenotypes similar to those of sgs3 and sde5 single mutants, respectively, with regard to the TAS2-related RNA accumulation, suggesting that the complex is formed in an SGS3-dependent manner, somehow modified and stabilized by SDE5, and becomes competent for RDR6 action. Ribosomes in this complex likely play an important role in this process. PMID- 26966171 TI - Potato NPH3/RPT2-Like Protein StNRL1, Targeted by a Phytophthora infestans RXLR Effector, Is a Susceptibility Factor. AB - Plant pathogens deliver effectors to manipulate host processes. We know little about how fungal and oomycete effectors target host proteins to promote susceptibility, yet such knowledge is vital to understand crop disease. We show that either transient expression in Nicotiana benthamiana, or stable transgenic expression in potato (Solanum tuberosum), of the Phytophthora infestans RXLR effector Pi02860 enhances leaf colonization by the pathogen. Expression of Pi02860 also attenuates cell death triggered by the P. infestans microbe associated molecular pattern INF1, indicating that the effector suppresses pattern-triggered immunity. However, the effector does not attenuate cell death triggered by Cf4/Avr4 coexpression, showing that it does not suppress all cell death activated by cell surface receptors. Pi02860 interacts in yeast two-hybrid assays with potato NPH3/RPT2-LIKE1 (NRL1), a predicted CULLIN3-associated ubiquitin E3 ligase. Interaction of Pi02860 in planta was confirmed by coimmunoprecipitation and bimolecular fluorescence complementation assays. Virus induced gene silencing of NRL1 in N. benthamiana resulted in reduced P. infestans colonization and accelerated INF1-mediated cell death, indicating that this host protein acts as a negative regulator of immunity. Moreover, whereas NRL1 virus induced gene silencing had no effect on the ability of the P. infestans effector Avr3a to suppress INF1-mediated cell death, such suppression by Pi02860 was significantly attenuated, indicating that this activity of Pi02860 is mediated by NRL1. Transient overexpression of NRL1 resulted in the suppression of INF1 mediated cell death and enhanced P. infestans leaf colonization, demonstrating that NRL1 acts as a susceptibility factor to promote late blight disease. PMID- 26966173 TI - Thyroid nodules with indeterminate cytology: prospective comparison between 18F FDG-PET/CT, multiparametric neck ultrasonography, 99mTc-MIBI scintigraphy and histology. AB - PURPOSE: To evaluate the role of (18)F-flurodeoxiglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) in predicting malignancy of thyroid nodules with indeterminate cytology. PATIENTS AND METHODS: We analysed 87 patients who have been scheduled to undergo surgery for thyroid nodule with indeterminate cytology. All patients underwent (18)F-FDG-PET/CT, multiparametric neck ultrasonography (MPUS), and (99m)Tc-methoxyisobutylisonitrile scintigraphy ((99m)Tc-MIBI-scan). Histopathology was the standard of reference. We compared the sensitivity (SE), specificity (SP), accuracy (AC), positive (PPV) and negative predictive (NPV) values of (18)F-FDG-PET/CT with those of (99m)Tc-MIBI scan and MPUS in detecting cancer. Univariate and multivariate analyses evaluated the association between each diagnostic tool and histopathology. RESULTS: On histopathology, 69 out of 87 nodules were found to be benign and 18 to be malignant. The SE, SP, AC, PPV and NPV of (18)F-FDG-PET/CT were 94, 58, 66, 37 and 98% respectively. The SE, AC and NPV of (18)F-FDG-PET/CT were significantly higher than those of MPUS and (99m)Tc-MIBI-scan. The association of both positive (18)F-FDG-PET/CT and MPUS (FDG+/MPUS+) showed significantly lower SE (61% vs 94%) and NPV (88% vs 98%) than (18)F-FDG-PET/CT alone, but significantly higher SP (77% vs 58%). On univariate analysis, (18)F-FDG-PET/CT and the combination of FDG+/MPUS+ and of FDG+/MIBI- were all significantly associated with histopathology. On multivariate analysis, only FDG+/MIBI- was significantly associated with histopathology. CONCLUSION: The AC of (18)F-FDG-PET /CT in detecting thyroid malignancy is higher than that of (99m)Tc-MIBI-scan and MPUS. A negative (18)F-FDG-PET/CT correctly predicts benign findings on histopathology. The association of FDG+/MPS+ is significantly more specific than (18)F-FDG-PET/CT alone in identifying differentiated thyroid cancer. A positive (18)F-FDG-PET/CT is significantly associated with malignancy when qualitative (99m)Tc-MIBI-scan is rated as negative. PMID- 26966174 TI - Physical activity, sedentary behaviors and risk of gestational diabetes mellitus: a population-based cross-sectional study in Tianjin, China. AB - OBJECTIVE: Physical activity in a nonpregnant state or before pregnancy reduces the risk of type 2 diabetes and is also associated with reduced risk of gestational diabetes mellitus (GDM). However, it is uncertain whether physical activity during pregnancy reduces the risk of GDM. DESIGN AND METHODS: Using an established universal screening system in Tianjin, China, we prospectively recruited 11 450 pregnant women within the 12th gestational week from 2010 to 2012. These women underwent a 50-g 1-h glucose challenge test (GCT) at 24-28 weeks of gestation and a 75-g 2-h oral glucose tolerance test if GCT glucose >=7.8mmol/L. GDM was defined according to the International Association of Diabetes and Pregnancy Study Group's criteria. Self-reported physical activity in the last month was collected at GCT time using a validated questionnaire. RESULTS: GDM developed in 7.3% (n=840) of the women. Women with GDM were less likely to be engaged in moderate-to-high physical activity during pregnancy than those without (79.8% vs 81.6%, P=0.191). Moderate-to-high physical activity during pregnancy was associated with decreased risk of GDM (multivariable odds ratio (OR): 0.81, 95% confidence interval (CI): 0.67-0.97). Sitting at home for 2 4h per day and >4h per day were associated with significantly increased risk of GDM (multivariable OR of sitting time for 2-4h vs <2h: 1.59, 95% CI: 1.18-2.15; OR of sitting time for >4h vs <2h: 1.73, 95% CI: 1.22-2.43). CONCLUSIONS: Increased physical activity during pregnancy was associated with reduced GDM risk, whereas sedentary lifestyle was associated with increased GDM risk among Chinese pregnant women. PMID- 26966172 TI - Novel Approach for High-Throughput Metabolic Screening of Whole Plants by Stable Isotopes. AB - Here, we demonstrate whole-plant metabolic profiling by stable isotope labeling and combustion isotope-ratio mass spectrometry for precise quantification of assimilation, translocation, and molecular reallocation of (13)CO2 and (15)NH4NO3 The technology was applied to rice (Oryza sativa) plants at different growth stages. For adult plants, (13)CO2 labeling revealed enhanced carbon assimilation of the flag leaf from flowering to late grain-filling stage, linked to efficient translocation into the panicle. Simultaneous (13)CO2 and (15)NH4NO3 labeling with hydroponically grown seedlings was used to quantify the relative distribution of carbon and nitrogen. Two hours after labeling, assimilated carbon was mainly retained in the shoot (69%), whereas 7% entered the root and 24% was respired. Nitrogen, taken up via the root, was largely translocated into the shoot (85%). Salt-stressed seedlings showed decreased uptake and translocation of nitrogen (69%), whereas carbon metabolism was unaffected. Coupled to a gas chromatograph, labeling analysis provided enrichment of proteinogenic amino acids. This revealed significant protein synthesis in the panicle of adult plants, whereas protein biosynthesis in adult leaves was 8-fold lower than that in seedling shoots. Generally, amino acid enrichment was similar among biosynthetic families and allowed us to infer labeling dynamics of their precursors. On this basis, early and strong (13)C enrichment of Embden-Meyerhof-Parnas pathway and pentose phosphate pathway intermediates indicated high activity of these routes. Applied to mode-of-action analysis of herbicides, the approach showed severe disturbance in the synthesis of branched-chain amino acids upon treatment with imazapyr. The established technology displays a breakthrough for quantitative high-throughput plant metabolic phenotyping. PMID- 26966175 TI - Diabetes and risk of community-acquired Staphylococcus aureus bacteremia: a population-based case-control study. AB - OBJECTIVE: Patients with diabetes may experience higher risk of Staphylococcus aureus bacteremia (SAB) than patients without diabetes due to decreased immunity or coexisting morbidities. We investigated the risk of community-acquired (CA) SAB in persons with and without diabetes. DESIGN: Using population-based medical databases, we conducted a case-control study of all adults with first-time CA-SAB and matched population controls in Northern Denmark, 2000-2011. METHODS: Based on conditional logistic regression, we computed odds ratios (ORs) of CA-SAB according to diabetes. We further assessed whether the risk of CA-SAB differed according to various diabetes-related characteristics (e.g. duration of diabetes, glycemic control, and presence of diabetes complications). RESULTS: We identified 2638 patients with incident CA-SAB, of whom 713 (27.0%) had diabetes, and 26,379 matched population controls (2495 or 9.5% with diabetes). Individuals with diabetes had a substantially increased risk of CA-SAB compared with population controls (adjusted OR = 2.8 (95% confidence interval (CI): 2.5-3.1)). Duration of diabetes of >=10 years and poor glycemic control conferred higher risk estimates, with an adjusted OR = 2.3 (95% CI: 1.9-2.7) for diabetes with Hba1c < 7% (< 53 mmol/mol) and an adjusted OR = 5.7 (95% CI: 4.2-7.7) for diabetes with Hba1c >=9% (>=75 mmol/mol). The risk of CA-SAB was particularly high in patient with diabetes complications: adjusted OR = 5.5 (95% CI: 4.2-7.2) with presence of microvascular complications and OR = 7.0 (95% CI: 5.4-9.0) with combined macro- and microvascular complications. CONCLUSIONS: Diabetes is associated with a substantially increased risk of CA-SAB, particularly in patients with diabetes of long duration, poor glycemic control, and diabetes complications. PMID- 26966176 TI - Myelodysplastic Syndrome Revealed by Systems Immunology in a Melanoma Patient Undergoing Anti-PD-1 Therapy. AB - Antibodies aimed at blocking the interaction between programmed cell death-1 (PD 1) and its ligands have shown impressive efficacy in a variety of malignancies and are generally well tolerated. Research has focused intensely on T cells and their interaction with cells within melanoma tumors, while relatively little is understood about the systems immunology of the cells in the blood during checkpoint inhibitor therapy. Longitudinal cytomic analysis using mass cytometry can characterize all the cells in a small sample of blood and has the potential to reveal key shifts in the cellular milieu occurring during treatment. We report a case of advanced melanoma in which mass cytometry detected abnormal myeloid cells resulting from myelodysplastic syndrome (MDS) in the blood following treatment with an anti-PD-1 agent. Myeloid blasts comprised <1% of peripheral blood mononuclear cells (PBMC) 1 month after the start of treatment. Six months after starting therapy, myeloid blasts comprised 5% of PBMCs, and a bone marrow biopsy confirmed refractory anemia with excess blasts-2 (RAEB-2). Longitudinal mass cytometry immunophenotyping comprehensively characterized blast phenotype evolution and revealed elevated PD-1 expression on the surface of nonblast myeloid cells. These findings highlight the clinical significance of cytomic monitoring, indicate that the myeloid compartment should be monitored during checkpoint inhibitor therapy, and emphasize the value of systems immunology in medicine. Cancer Immunol Res; 4(6); 474-80. (c)2016 AACR. PMID- 26966177 TI - Identification of Haloferax volcanii Pilin N-Glycans with Diverse Roles in Pilus Biosynthesis, Adhesion, and Microcolony Formation. AB - N-Glycosylation is a post-translational modification common to all three domains of life. In many archaea, the oligosacharyltransferase (AglB)-dependent N glycosylation of flagellins is required for flagella assembly. However, whether N glycosylation is required for the assembly and/or function of the structurally related archaeal type IV pili is unknown. Here, we show that of six Haloferax volcanii adhesion pilins, PilA1 and PilA2, the most abundant pilins in pili of wild-type and DeltaaglB strains, are modified under planktonic conditions in an AglB-dependent manner by the same pentasaccharide detected on H. volcanii flagellins. However, unlike wild-type cells, which have surfaces decorated with discrete pili and form a dispersed layer of cells on a plastic surface, DeltaaglB cells have thick pili bundles and form microcolonies. Moreover, expressing PilA1, PilA2, or PilA6 in DeltapilA[1-6]DeltaaglB stimulates microcolony formation compared with their expression in DeltapilA[1-6]. Conversely, expressing PilA3 or PilA4 in DeltapilA[1-6] cells results in strong surface adhesion, but not microcolony formation, and neither pilin stimulates surface adhesion in DeltapilA[1-6]DeltaaglB cells. Although PilA4 assembles into pili in the DeltapilA[1-6]DeltaaglB cells, these pili are, unlike wild-type pili, curled, perhaps rendering them non-functional. To our knowledge, this is the first demonstration of a differential effect of glycosylation on pilus assembly and function of paralogous pilins. The growth of wild-type cells in low salt media, a condition that decreases AglB glycosylation, also stimulates microcolony formation and inhibits motility, supporting our hypothesis that N-glycosylation plays an important role in regulating the transition between planktonic to sessile cell states as a response to stress. PMID- 26966178 TI - Potassium and the K+/H+ Exchanger Kha1p Promote Binding of Copper to ApoFet3p Multi-copper Ferroxidase. AB - Acquisition and distribution of metal ions support a number of biological processes. Here we show that respiratory growth of and iron acquisition by the yeast Saccharomyces cerevisiae relies on potassium (K(+)) compartmentalization to the trans-Golgi network via Kha1p, a K(+)/H(+) exchanger. K(+) in the trans-Golgi network facilitates binding of copper to the Fet3p multi-copper ferroxidase. The effect of K(+) is not dependent on stable binding with Fet3p or alteration of the characteristics of the secretory pathway. The data suggest that K(+) acts as a chemical factor in Fet3p maturation, a role similar to that of cations in folding of nucleic acids. Up-regulation of KHA1 gene in response to iron limitation via iron-specific transcription factors indicates that K(+) compartmentalization is linked to cellular iron homeostasis. Our study reveals a novel functional role of K(+) in the binding of copper to apoFet3p and identifies a K(+)/H(+) exchanger at the secretory pathway as a new molecular factor associated with iron uptake in yeast. PMID- 26966180 TI - Ectodomain Shedding of Lymphatic Vessel Endothelial Hyaluronan Receptor 1 (LYVE 1) Is Induced by Vascular Endothelial Growth Factor A (VEGF-A). AB - Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), a type I transmembrane glycoprotein, is known as one of the most specific lymphatic vessel markers in the skin. In this study, we found that the ectodomain of LYVE-1 undergoes proteolytic cleavage, and this process produces soluble LYVE-1. We further identified the cleavage site for ectodomain shedding and generated an uncleavable mutant of LYVE-1. In lymphatic endothelial cells, ectodomain shedding of LYVE-1 was induced by vascular endothelial growth factor (VEGF)-A, an important factor for angiogenesis and lymphangiogenesis under pathological conditions. VEGF-A-induced LYVE-1 ectodomain shedding was mediated via the extracellular signal-regulated kinase (ERK) and a disintegrin and metalloproteinase (ADAM) 17. Wild-type LYVE-1, but not uncleavable LYVE-1, promoted migration of lymphatic endothelial cells in response to VEGF-A. Immunostaining analyses in human psoriasis skin lesions and VEGF-A transgenic mouse skin suggested that the ectodomain shedding of LYVE-1 occurred in lymphatic vessels undergoing chronic inflammation. These results indicate that the ectodomain shedding of LYVE-1 might be involved in promoting pathological lymphangiogenesis. PMID- 26966179 TI - Cathepsin S Contributes to the Pathogenesis of Muscular Dystrophy in Mice. AB - Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin protein compromises the stability of the sarcolemma membrane surrounding each muscle cell fiber, leading to membrane ruptures and leakiness that induces myofiber necrosis, a subsequent inflammatory response, and progressive tissue fibrosis with loss of functional capacity. Cathepsin S (Ctss) is a cysteine protease that is actively secreted in areas of tissue injury and ongoing inflammation, where it participates in extracellular matrix remodeling and healing. Here we show significant induction of Ctss expression and proteolytic activity following acute muscle injury or in muscle from mdx mice, a model of DMD. To examine the functional ramifications associated with greater Ctss expression, the Ctss gene was deleted in the mdx genetic background, resulting in protection from muscular dystrophy pathogenesis that included reduced myofiber turnover and histopathology, reduced fibrosis, and improved running capacity. Mechanistically, deletion of the Ctss gene in the mdx background significantly increased myofiber sarcolemmal membrane stability with greater expression and membrane localization of utrophin, integrins, and beta-dystroglycan, which anchor the membrane to the basal lamina and underlying cytoskeletal proteins. Consistent with these results, skeletal muscle-specific transgenic mice overexpressing Ctss showed increased myofiber necrosis, muscle histopathology, and a functional deficit reminiscent of muscular dystrophy. Hence, Ctss induction during muscular dystrophy is a pathologic event that partially underlies disease pathogenesis, and its inhibition might serve as a new therapeutic strategy in DMD. PMID- 26966181 TI - Deletions of Retinoblastoma 1 (Rb1) and Its Repressing Target S Phase Kinase associated protein 2 (Skp2) Are Synthetic Lethal in Mouse Embryogenesis. AB - Tumor suppressor pRb represses Skp2, a substrate-recruiting subunit of the SCF(Skp2) ubiquitin ligase. Rb1(+/-) mice incur "two-hit" pituitary tumorigenesis; Skp2(-/-);Rb1(+/-) mice do not. Rb1(-/-) embryos die on embryonic day (E) 14.5-15.5. Here, we report that Skp2(-/-);Rb1(-/-) embryos died on E11.5, establishing an organismal level synthetic lethal relationship between Rb1 and Skp2 On E10.5, Rb1(-/-) placentas showed similarly active proliferation and similarly inactive apoptosis as WT placenta, whereas Rb1(-/-) embryos showed ectopic proliferation without increased apoptosis in the brain. Combining Skp2(-/ ) did not reduce proliferation or increase apoptosis in the placentas but induced extensive apoptosis in the brain. We conditionally deleted Rb1 in neuronal lineage with Nes-Cre and reproduced the brain apoptosis in E13.5 Nes Cre;Rb1(lox/lox);Skp2(-/-) embryos, demonstrating their synthetic lethal relationship at a cell autonomous level. Nes-Cre-mediated Rb1 deletion increased expression of proliferative E2F target genes in the brains of Skp2(+/+) embryos; the increases rose higher with activation of expression of apoptotic E2F target genes in Skp2(-/-) embryos. The brain apoptosis was independent of p53 but coincident with proliferation. The highly activated expression of proliferative and apoptotic E2F target genes subsided with gradually reduced roles of Skp2 in preventing p27 protein accumulation in the brain in late gestation, allowing the embryos to reach full term with normally sized brains. These findings establish that Rb1 and Skp2 deletions are synthetic lethal and suggest how this lethal relationship might be circumvented, which could help design better therapies for pRb-deficient cancer. PMID- 26966182 TI - Crystal Structure of the LysY.LysW Complex from Thermus thermophilus. AB - Several bacteria and archaea utilize the amino group-carrier protein, LysW, for lysine biosynthesis, in which an isopeptide bond is formed between the C-terminal Glu of LysW and an amino group of alpha-aminoadipate (AAA). The resulting LysW gamma-AAA is phosphorylated by LysZ to form LysW-gamma-AAA phosphate, which is subsequently reduced to LysW-gamma-aminoadipic semialdehyde (LysW-gamma-AASA) through a reaction catalyzed by LysY. In this study, we determined the crystal structures of LysY from Thermus thermophilus HB27 (TtLysY) complexed with TtLysW gamma-AASA and TtLysW-gamma-AAA, respectively. In both structures, the globular domain of TtLysW was recognized by positively charged residues on helix alpha9 and the beta11-alpha10 loop of TtLysY through conformational changes. A mutational analysis confirmed that the interactions observed between TtLysY and TtLysW are important for the function of TtLysY. The extended LysW recognition loop and conserved arginine residue were identified as signatures to discriminate LysY from ArgC, which is involved in arginine biosynthesis. Combined with the previously determined TtLysZ.TtLysW complex structure, TtLysW may simultaneously bind TtLysZ and TtLysY. These structural insights suggest the formation of a TtLysWZY ternary complex, in which the flexible C-terminal extension of TtLysW promotes the efficient transfer of the labile intermediate from the active site of TtLysZ to that of TtLysY during the sequential reactions catalyzed by TtLysZY. PMID- 26966184 TI - The global push for institutional childbirths--in unhygienic facilities. PMID- 26966183 TI - Endo-F3 Glycosynthase Mutants Enable Chemoenzymatic Synthesis of Core-fucosylated Triantennary Complex Type Glycopeptides and Glycoproteins. AB - Chemoenzymatic synthesis is emerging as a promising approach to the synthesis of homogeneous glycopeptides and glycoproteins highly demanded for functional glycomics studies, but its generality relies on the availability of a range of enzymes with high catalytic efficiency and well defined substrate specificity. We describe in this paper the discovery of glycosynthase mutants derived from Elizabethkingia meningoseptica endoglycosidase F3 (Endo-F3) of the GH18 family, which are devoid of the inherent hydrolytic activity but are able to take glycan oxazolines for transglycosylation. Notably, the Endo-F3 D165A and D165Q mutants demonstrated high acceptorsubstrate specificity toward alpha1,6-fucosyl-GlcNAc Asn or alpha1,6-fucosyl-GlcNAc-polypeptide in transglycosylation, enabling a highly convergent synthesis of core-fucosylated, complex CD52 glycopeptide antigen. The Endo-F3 mutants were able to use both bi- and triantennary glycan oxazolines as substrates for transglycosylation, in contrast to previously reported endoglycosidases derived from Endo-S, Endo-M, Endo-D, and Endo-A mutants that could not recognize triantennary N-glycans. Using rituximab as a model system, we have further demonstrated that the Endo-F3 mutants are highly efficient for glycosylation remodeling of monoclonal antibodies to produce homogeneous intact antibody glycoforms. Interestingly, the new triantennary glycan glycoform of antibody showed much higher affinity for galectin-3 than that of the commercial antibody. The Endo-F3 mutants represent the first endoglycosidase-based glycosynthases capable of transferring triantennary complex N-glycans, which would be very useful for glycoprotein synthesis and glycosylation remodeling of antibodies. PMID- 26966186 TI - ARMS/Kidins220 and synembryn-B levels regulate NGF-mediated secretion. AB - Proper development of the nervous system requires a temporally and spatially orchestrated set of events including differentiation, synapse formation and neurotransmission. Nerve growth factor (NGF) acting through the TrkA neurotrophin receptor (also known as NTRK1) regulates many of these events. However, the molecular mechanisms responsible for NGF-regulated secretion are not completely understood. Here, we describe a new signaling pathway involving TrkA, ARMS (also known as Kidins220), synembryn-B and Rac1 in NGF-mediated secretion in PC12 cells. Whereas overexpression of ARMS blocked NGF-mediated secretion, without affecting basal secretion, a decrease in ARMS resulted in potentiation. Similar effects were observed with synembryn-B, a protein that interacts directly with ARMS. Downstream of ARMS and synembryn-B are Galphaq and Trio proteins, which modulate the activity of Rac1 in response to NGF. Expression of dominant-negative Rac1 rescued the secretion defects of cells overexpressing ARMS or synembryn-B. Thus, this neurotrophin pathway represents a new mechanism responsible for NGF regulated secretion. PMID- 26966185 TI - CEP164-null cells generated by genome editing show a ciliation defect with intact DNA repair capacity. AB - Primary cilia are microtubule structures that extend from the distal end of the mature, mother centriole. CEP164 is a component of the distal appendages carried by the mother centriole that is required for primary cilium formation. Recent data have implicated CEP164 as a ciliopathy gene and suggest that CEP164 plays some roles in the DNA damage response (DDR). We used reverse genetics to test the role of CEP164 in the DDR. We found that conditional depletion of CEP164 in chicken DT40 cells using an auxin-inducible degron led to no increase in sensitivity to DNA damage induced by ionising or ultraviolet irradiation. Disruption of CEP164 in human retinal pigmented epithelial cells blocked primary cilium formation but did not affect cellular proliferation or cellular responses to ionising or ultraviolet irradiation. Furthermore, we observed no localisation of CEP164 to the nucleus using immunofluorescence microscopy and analysis of multiple tagged forms of CEP164. Our data suggest that CEP164 is not required in the DDR. PMID- 26966188 TI - Identification of FAM3D as a new endogenous chemotaxis agonist for the formyl peptide receptors. AB - The family with sequence similarity 3 (FAM3) gene family is a cytokine-like gene family with four members FAM3A, FAM3B, FAM3C and FAM3D. In this study, we found that FAM3D strongly chemoattracted human peripheral blood neutrophils and monocytes. To identify the FAM3D receptor, we used chemotaxis, receptor internalization, Ca(2+) flux and radioligand-binding assays in FAM3D-stimulated HEK293 cells that transiently expressed formyl peptide receptor (FPR)1 or FPR2 to show that FAM3D was a high affinity ligand of these receptors, both of which were highly expressed on the surface of neutrophils, and monocytes and macrophages. After being injected into the mouse peritoneal cavity, FAM3D chemoattracted CD11b+ Ly6G+ neutrophils in a short time. In response to FAM3D stimulation, phosphorylated ERK1/2 and phosphorylated p38 MAPK family proteins were upregulated in the mouse neutrophils, and this increase was inhibited upon treatment with an inhibitor of FPR1 or FPR2. FAM3D has been reported to be constitutively expressed in the gastrointestinal tract. We found that FAM3D expression increased significantly during colitis induced by dextran sulfate sodium. Taken together, we propose that FAM3D plays a role in gastrointestinal homeostasis and inflammation through its receptors FPR1 and FPR2. PMID- 26966187 TI - E-cadherin-mediated force transduction signals regulate global cell mechanics. AB - This report elucidates an E-cadherin-based force-transduction pathway that triggers changes in cell mechanics through a mechanism requiring epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase (PI3K), and the downstream formation of new integrin adhesions. This mechanism operates in addition to local cytoskeletal remodeling triggered by conformational changes in the E-cadherin associated protein alpha-catenin, at sites of mechanical perturbation. Studies using magnetic twisting cytometry (MTC), together with traction force microscopy (TFM) and confocal imaging identified force-activated E-cadherin-specific signals that integrate cadherin force transduction, integrin activation and cell contractility. EGFR is required for the downstream activation of PI3K and myosin II-dependent cell stiffening. Our findings also demonstrated that alpha-catenin dependent cytoskeletal remodeling at perturbed E-cadherin adhesions does not require cell stiffening. These results broaden the repertoire of E-cadherin-based force transduction mechanisms, and define the force-sensitive signaling network underlying the mechano-chemical integration of spatially segregated adhesion receptors. PMID- 26966189 TI - Structure and organization of heteromeric AMPA-type glutamate receptors. AB - AMPA-type glutamate receptors (AMPARs), which are central mediators of rapid neurotransmission and synaptic plasticity, predominantly exist as heteromers of the subunits GluA1 to GluA4. Here we report the first AMPAR heteromer structures, which deviate substantially from existing GluA2 homomer structures. Crystal structures of the GluA2/3 and GluA2/4 N-terminal domains reveal a novel compact conformation with an alternating arrangement of the four subunits around a central axis. This organization is confirmed by cysteine cross-linking in full length receptors, and it permitted us to determine the structure of an intact GluA2/3 receptor by cryogenic electron microscopy. Two models in the ligand-free state, at resolutions of 8.25 and 10.3 angstroms, exhibit substantial vertical compression and close associations between domain layers, reminiscent of N-methyl D-aspartate receptors. Model 1 resembles a resting state and model 2 a desensitized state, thus providing snapshots of gating transitions in the nominal absence of ligand. Our data reveal organizational features of heteromeric AMPARs and provide a framework to decipher AMPAR architecture and signaling. PMID- 26966190 TI - A 21st-century shift from fossil-fuel to biogenic methane emissions indicated by 13CH4. AB - Between 1999 and 2006, a plateau interrupted the otherwise continuous increase of atmospheric methane concentration [CH4] since preindustrial times. Causes could be sink variability or a temporary reduction in industrial or climate-sensitive sources. We reconstructed the global history of [CH4] and its stable carbon isotopes from ice cores, archived air, and a global network of monitoring stations. A box-model analysis suggests that diminishing thermogenic emissions, probably from the fossil-fuel industry, and/or variations in the hydroxyl CH4 sink caused the [CH4] plateau. Thermogenic emissions did not resume to cause the renewed [CH4] rise after 2006, which contradicts emission inventories. Post-2006 source increases are predominantly biogenic, outside the Arctic, and arguably more consistent with agriculture than wetlands. If so, mitigating CH4 emissions must be balanced with the need for food production. PMID- 26966192 TI - CLIMATE. How Antarctica got its ice. PMID- 26966191 TI - MYC regulates the antitumor immune response through CD47 and PD-L1. AB - The MYC oncogene codes for a transcription factor that is overexpressed in many human cancers. Here we show that MYC regulates the expression of two immune checkpoint proteins on the tumor cell surface: the innate immune regulator CD47 (cluster of differentiation 47) and the adaptive immune checkpoint PD-L1 (programmed death-ligand 1). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PD-L1 messenger RNA and protein. MYC was found to bind directly to the promoters of the Cd47 and Pd-l1 genes. MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the antitumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PD-L1, the immune response was suppressed, and tumors continued to grow. Thus, MYC appears to initiate and maintain tumorigenesis, in part, through the modulation of immune regulatory molecules. PMID- 26966194 TI - An estimate of Lyme borreliosis incidence in Western Europe?. AB - Background: Lyme borreliosis (LB) is the most common zoonotic disease transmitted by ticks in the USA and Europe. This review aims to estimate the regional burden of LB in Western Europe. Data from previous publications will be used to calculate the mean incidence. The mean incidence rates will then be combined to estimate the regional burden and a population-weighted regional burden of disease based on the standardized incidence rate from the included studies and the total population at risk. Methods: Reviews and surveillance reports identified by the initial database search were assessed for eligibility first by their title and abstract and subsequently by a more detailed review of the source by two independent authors for the most recent data regarding LB. Eleven sources of incidence data were included in the review representing 17 countries in total. Incidence estimates were calculated from reported values and population data. Results: Countries in Western Europe have a large variance in the incidence rates. The highest reported incidences for LB were reported in southern Sweden with 464/100 000 and the lowest in Italy of 0.001/100 000. The unweighted mean for the included data provided an incidence rate of 56.3/100 000 persons per year, equating to ~232 125 cases in 1 year throughout the region. The calculated population-weighted average incidence rate for the regional burden of LB in Western Europe was 22.05 cases per 100 000 person-years. Conclusions: LB is a continually emerging disease and the most common zoonotic infection in Western Europe approaching endemic proportions in many European countries. The population weighted incidence rate has been estimated by this study to be 22.04/100 000 person-years. Concordant and well-conducted surveillance and disease awareness should continue to be encouraged to monitor LB, as tick numbers and activity are increasing, leading to greater risks of infection. PMID- 26966195 TI - Draft Genome Sequence of Rheinheimera sp. F8, a Biofilm-Forming Strain Which Produces Large Amounts of Extracellular DNA. AB - Rheinheimera sp. strain F8 is a biofilm-forming gammaproteobacterium that has been found to produce large amounts of filamentous extracellular DNA. Here, we announce the de novo assembly of its genome. It is estimated to be 4,464,511 bp in length, with 3,970 protein-coding sequences and 92 RNA-coding sequences. PMID- 26966193 TI - Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. AB - Heterozygous SHANK3 mutations are associated with idiopathic autism and Phelan McDermid syndrome. SHANK3 is a ubiquitously expressed scaffolding protein that is enriched in postsynaptic excitatory synapses. Here, we used engineered conditional mutations in human neurons and found that heterozygous and homozygous SHANK3 mutations severely and specifically impaired hyperpolarization-activated cation (Ih) channels. SHANK3 mutations caused alterations in neuronal morphology and synaptic connectivity; chronic pharmacological blockage of Ih channels reproduced these phenotypes, suggesting that they may be secondary to Ih-channel impairment. Moreover, mouse Shank3-deficient neurons also exhibited severe decreases in Ih currents. SHANK3 protein interacted with hyperpolarization activated cyclic nucleotide-gated channel proteins (HCN proteins) that form Ih channels, indicating that SHANK3 functions to organize HCN channels. Our data suggest that SHANK3 mutations predispose to autism, at least partially, by inducing an Ih channelopathy that may be amenable to pharmacological intervention. PMID- 26966196 TI - Genome Sequence of Elizabethkingia anophelis Strain EaAs1, Isolated from the Asian Malaria Mosquito Anopheles stephensi. AB - We sequenced the genome of a strain of the Gram-negative bacterial species Elizabethkingia anophelis, which is an important component of the Anopheles mosquito microbiome. This genome sequence will add to the list of resources used to examine host-microbe interactions in mosquitoes. PMID- 26966197 TI - Genome Sequences of Staphylococcus hominis Strains ShAs1, ShAs2, and ShAs3, Isolated from the Asian Malaria Mosquito Anopheles stephensi. AB - Staphylococcus hominis is a culturable component of the bacterial microbiome of Anopheles stephensi. Here, we present the annotated draft genome sequences of three S. hominis isolates from A. stephensi. These genomic resources will facilitate experiments to further our understanding of the role of bacteria in mosquito biology. PMID- 26966198 TI - Genome Sequence of Stenotrophomonas maltophilia Strain SmAs1, Isolated From the Asian Malaria Mosquito Anopheles stephensi. AB - An isolate of Stenotrophomonas maltophilia was cultured from the Asian malaria vector Anopheles stephensi. Here, we present the annotated draft genome sequence of this S. maltophilia strain. This genomic resource will facilitate further characterization of bacteria associated with mosquitoes. PMID- 26966199 TI - Draft Genome Sequence of Escherichia coli Strain SEC470, Isolated from a Piglet Experiencing Diarrhea. AB - Escherichia coli strain SEC470 is a diarrhea-causing strain, isolated from a piglet experiencing serious diarrhea in Jingxi Province, China. Here, we present the draft genome of this strain, which provides the genetic basis for exploring the mechanism of enterotoxigenic E. coli infections. PMID- 26966200 TI - Draft Genome Sequence of Thermodesulfovibrio aggregans TGE-P1T, an Obligately Anaerobic, Thermophilic, Sulfate-Reducing Bacterium in the Phylum Nitrospirae. AB - We report a high-quality draft genome sequence of the type strain (TGE-P1(T)) of Thermodesulfovibrio aggregans, an obligately anaerobic, thermophilic, sulfate reducing bacterium in the phylum Nitrospirae. The genome comprises 2.00 Mb in 16 contigs (3 scaffolds), has a G+C content of 34.5%, and contains 1,998 predicted protein-encoding genes. PMID- 26966201 TI - Complete Genome Sequence of Nitrosomonas ureae Strain Nm10, an Oligotrophic Group 6a Nitrosomonad. AB - The complete genome of Nitrosomonas ureae strain Nm10, a mesophilic betaproteobacterial ammonia oxidizer isolated from Mediterranean soils in Sardinia, Italy, is reported here. This genome represents a cluster 6a nitrosomonad. PMID- 26966202 TI - Draft Genome Sequence of Kocuria rhizophila RF, a Radiation-Resistant Soil Isolate. AB - Kocuria rhizophila RF, a soil isolate from Iran, is a radiation-resistant bacterium. Only a limited amount of genomic information for radiation-resistant bacteria is currently available. Here, we report the draft genome sequence of this bacterium, providing knowledge to aid in the discovery of the genomic basis of its resistance to radiation. PMID- 26966203 TI - Draft Genome Sequences of Rhodosporidium toruloides Strains ATCC 10788 and ATCC 10657 with Compatible Mating Types. AB - Rhodosporidium toruloides ATCC 10788 (haploid, A1 mating type) and ATCC 10657 (haploid, A2 mating type) were derived from the same diploid parent strain Rhodotorula glutinis ATCC 90781 and are important strains for metabolic engineering. Draft genome sequences of both strains are reported here. The current assembly of strain ATCC 10788 comprises 61 scaffolds with a total size of 20.75 Mbp and a GC content of 62.01%, while that of strain ATCC 10657 comprises 137 scaffolds with a total size of 21.49 Mbp and a GC content of 61.81%. Genome annotation predicts 7,730 and 7,800 protein encoding genes for strain ATCC 10788 and strain ATCC 10657, respectively. PMID- 26966204 TI - Draft Genome Sequences of Fungus Aspergillus calidoustus. AB - Here, we report the draft genome sequence of Aspergillus calidoustus (strain SF006504). The functional annotation of A. calidoustus predicts a relatively large number of secondary metabolite gene clusters. The presented genome sequence builds the basis for further genome mining. PMID- 26966205 TI - Draft Genome Sequence of Commercial Textile Dye-Decolorizing and -Degrading Bacillus subtilis Strain C3 Isolated in India. AB - Bacillus subtilis C3, a commercial textile dye-decolorizing and -degrading bacterium, was isolated from the common effluent treatment plant (CEPT) of the Jetpur textile dyeing and printing industrial sector situated in the district of Rajkot, Gujarat, India. Here, we present the annotated 4.18-Mb draft genome sequence of B. subtilis C3, providing information about the metabolic pathways involved in decolorization and degradation of several commercial textile azo dyes. Thus, we confirm B. subtilis C3 as a potential candidate for bioremediation of textile effluents. PMID- 26966207 TI - Complete Coding Genome Sequence of a Putative Novel Teschovirus Serotype 12 Strain. AB - Porcine teschoviruses are ubiquitous and prevalent viruses generally harmless to their hosts, the suids. Here, we report the first complete coding genome sequence of a putative new serotype of porcine teschovirus (PTV-12), strain CC25, isolated from fecal material from a healthy pig in Spain. PMID- 26966206 TI - Genome Sequences of Listeria monocytogenes Strains Responsible for Cheese- and Cooked Ham Product-Associated Swiss Listeriosis Outbreaks in 2005 and 2011. AB - The complete genome sequences of three Listeria monocytogenes serotype 1/2a strains, Lm 3136, Lm 3163, and Lm N1546, which were responsible for listeriosis outbreaks in 2005 and 2011 in Switzerland, are presented here. PMID- 26966208 TI - Draft Genome Sequence of Lactobacillus plantarum CRL1506, an Immunomodulatory Strain Isolated from Goat Milk. AB - This report describes a draft genome sequence of Lactobacillus plantarum CRL1506, a probiotic strain with immunomodulatory properties isolated from goat milk. The reads generated by a whole-genome shotgun (WGS) strategy on an Illumina MiSeq sequencer were assembled into contigs with a total size of 3,228,096 bp. The draft genome sequence of L. plantarum CRL1506 will be useful for further studies of specific genetic features of this strain and for understanding the mechanisms of its immunobiotic properties. PMID- 26966209 TI - Draft Genome Sequence of Pseudoalteromonas sp. Strain XI10 Isolated from the Brine-Seawater Interface of Erba Deep in the Red Sea. AB - Pseudoalteromonas sp. strain XI10 was isolated from the brine-seawater interface of Erba Deep in the Red Sea, Saudi Arabia. Here, we present the draft genome sequence of strain XI10, a gammaproteobacterium that synthesizes polysaccharides for biofilm formation when grown in liquid culture. PMID- 26966210 TI - Draft Genome Sequences of Three Flavobacterium psychrophilum Strains Isolated from Coldwater Disease Outbreaks at Three Production Hatcheries. AB - We report here the genome sequences of three Flavobacterium psychrophilum strains causing a bacterial coldwater disease (BCWD) outbreak, isolated from infected rainbow trout from hatcheries in Montana and South Dakota. The availability of these virulent outbreak-causing strain genome sequences will help further understand the pathogenesis of BCWD. PMID- 26966211 TI - Genome Sequences of Five Clinical Isolates of Klebsiella pneumoniae. AB - Klebsiella pneumoniae is a nosocomial pathogen of emerging importance and displays resistance to broad-spectrum antibiotics, such as carbapenems. Here, we report the genome sequences of five clinical K. pneumoniae isolates, four of which are carbapenem resistant. Carbapenem resistance is conferred by hydrolyzing class A beta-lactamases found adjacent to transposases. PMID- 26966212 TI - Genome Sequencing of Serinicoccus chungangensis Strain CD08_5 Isolated from Duodenal Mucosa of a Celiac Disease Patient. AB - For the first time, we report here the 3.5-Mb genome of Serinicoccus chungangensis strain CD08_5, isolated from duodenal mucosa from a celiac disease (CD) patient. The specific annotations obtained revealed genes associated with virulence, disease, and defense, which predict its probable role in the pathogenesis of CD. PMID- 26966213 TI - Draft Genome Sequences of Strains Representing Each of the Elizabethkingia Genomospecies Previously Determined by DNA-DNA Hybridization. AB - Draft genome sequences of Elizabethkingia meningoseptica and representatives of each of its four historically described genomospecies were sequenced here. Preliminary analysis suggests that Elizabethkingia miricola belongs to genomospecies 2, and both Elizabethkingia anophelis and Elizabethkingia endophytica are most similar to genomospecies 1. PMID- 26966214 TI - Draft Genome Sequence of Mesorhizobium sp. UFLA 01-765, a Multitolerant, Efficient Symbiont and Plant Growth-Promoting Strain Isolated from Zn-Mining Soil Using Leucaena leucocephala as a Trap Plant. AB - We report the 7.4-Mb draft genome sequence of Mesorhizobium sp. strain UFLA 01 765, a Gram-negative bacterium of the Phyllobacteriaceae isolated from Zn-mining soil in Minas Gerais, Brazil. This strain promotes plant growth, efficiently fixes N2 in symbiosis with Leucaena leucocephala on multicontaminated soil, and has potential for application in bioremediation of marginal lands. PMID- 26966215 TI - Complete Genome Sequence of Bacillus methylotrophicus Strain B25, a Potential Plant Growth-Promoting Rhizobacterium. AB - The complete genome of Bacillus methylotrophicus strain B25, isolated in Switzerland, was sequenced. Its size is 3.85 Mb, and several genes that may contribute to plant growth-promoting activities were identified in silico. PMID- 26966216 TI - Draft Genome Sequences of Two Thiomicrospira Strains Isolated from the Brine Seawater Interface of Kebrit Deep in the Red Sea. AB - Two Thiomicrospira strains, WB1 and XS5, were isolated from the Kebrit Deep brine seawater interface in the Red Sea, Saudi Arabia. Here, we present the draft genome sequences of these gammaproteobacteria, which both produce sulfuric acid from thiosulfate in culture. PMID- 26966217 TI - Whole-Genome Sequence of Bradyrhizobium elkanii Strain UASWS1015, a Highly Ammonia-Tolerant Nitrifying Bacterium. AB - Bradyrhizobium elkanii UASWS1015 was isolated from a sewage plant in Switzerland. Its genome indicates that it is fully equipped for ammonia assimilation and aromatic compound degradation, and it displays a large type IV secretion system, which characterizes plant-associated microbes. Totally deprived of toxins, it could be considered for agricultural and environmental uses. PMID- 26966219 TI - Draft Genome Sequence of Cobetia sp. UCD-24C, Isolated from Roots and Leaves of the Seagrass Zostera marina. AB - Here, we present the 4,230,758-bp draft genome for Cobetia sp. UCD-24C. This strain was isolated from Zostera marina roots collected in Woods Hole, Massachusetts, USA. PMID- 26966218 TI - Whole-Genome Sequence of Staphylococcus epidermidis Tu3298. AB - Staphylococcus epidermidis Tu3298 is a frequently used laboratory strain, known for its production of epidermin and absence of the icaABCD operon. We report the whole-genome sequence of this strain, a 2.5-kb genome containing 2,332 genes. PMID- 26966220 TI - Draft Genome Sequence of Acinetobacter bereziniae HPC229, a Carbapenem-Resistant Clinical Strain from Argentina Harboring blaNDM-1. AB - We report here the draft genome sequence of an NDM-1-producing Acinetobacter bereziniae clinical strain, HPC229. This strain harbors both plasmid and chromosomal resistance determinants toward different beta-lactams and aminoglycosides as well as several types of multidrug efflux pumps, most likely representing an adaptation strategy for survival under different environments. PMID- 26966221 TI - Genome Sequences of Two Pseudomonas syringae pv. tomato Race 1 Strains, Isolated from Tomato Fields in California. AB - Pseudomonas syringae pv. tomato race 1 strains have evolved to overcome genetic resistance in tomato. Here, we present the draft genome sequences of two race 1 P. syringae pv. tomato strains, A9 and 407, isolated from diseased tomato plants in California. PMID- 26966222 TI - Draft Genome Sequence of White Spot Syndrome Virus Isolated from Cultured Litopenaeus vannamei in Mexico. AB - The first genome sequence of a Mexican white spot syndrome virus is presented here. White spot syndrome is a shrimp pandemic virus that has devastated production in Mexico for more than 10 years. The availability of this genome will greatly aid epidemiological studies worldwide, contributing to the molecular diagnostic and disease prevention in shrimp farming. PMID- 26966224 TI - Scientific Phishing: Fact or Fiction? PMID- 26966223 TI - Genomic Sequence of the First Porcine Rotavirus Group H Strain in the United States. AB - The genomic sequence of a rotavirus group H was identified in the intestine of a diarrheal pig in the United States, designated RVH/Pig-wt/USA/MN9.65/2008/GxP[x]. PMID- 26966225 TI - Suppurative appendicitis presenting as acute scrotum confounded by a testicular appendage. AB - Patients presenting with testicular pain and swelling mandate an urgent urology review and scrotal exploration to prevent testicle loss due to torsion. Other pathology masquerading as torsion is extremely rare but can occur. We present one such case. A 14-year-old male presented with a 1-day history of right testicular swelling and tenderness. He was apyrexial and denied any other symptoms. Blood tests demonstrated raised inflammatory markers. He had lower left-sided abdominal tenderness with a swollen, erythematous right hemiscrotum. During an urgent scrotal exploration for testicular torsion, a purulent hydrocele with a patent process vaginalis was noted, but no torsion. Post-operative abdominal pain mandated a general surgical review and subsequent appendicectomy. The patient made a full recovery. Acute suppurative appendicitis presenting as a urological emergency is extremely rare. To make a correct diagnosis and prevent multiple surgeries, a joint urological and general surgical assessment with a high index of suspicion is required. PMID- 26966226 TI - Balancing Safety and Efficacy of Epidermal Growth Factor Receptor Inhibitors in Patients With Squamous Cell Carcinoma of the Head and Neck. PMID- 26966227 TI - Expression of Concern. PMID- 26966228 TI - Attention Alters Perceived Attractiveness. AB - Can attention alter the impression of a face? Previous studies showed that attention modulates the appearance of lower-level visual features. For instance, attention can make a simple stimulus appear to have higher contrast than it actually does. We tested whether attention can also alter the perception of a higher-order property-namely, facial attractiveness. We asked participants to judge the relative attractiveness of two faces after summoning their attention to one of the faces using a briefly presented visual cue. Across trials, participants judged the attended face to be more attractive than the same face when it was unattended. This effect was not due to decision or response biases, but rather was due to changes in perceptual processing of the faces. These results show that attention alters perceived facial attractiveness, and broadly demonstrate that attention can influence higher-level perception and may affect people's initial impressions of one another. PMID- 26966229 TI - Stable biomarker for plastic microglia. PMID- 26966230 TI - Cardiac myosin-binding protein C: A protein once at loose ends finds its regulatory groove. PMID- 26966231 TI - Cytochrome c folds through foldon-dependent native-like intermediates in an ordered pathway. AB - Previous hydrogen exchange (HX) studies of the spontaneous reversible unfolding of Cytochrome c (Cyt c) under native conditions have led to the following conclusions. Native Cyt c (104 residues) is composed of five cooperative folding units, called foldons. The high-energy landscape is dominated by an energy ladder of partially folded forms that differ from each other by one cooperative foldon unit. The reversible equilibrium unfolding of native Cyt c steps up through these intermediate forms to the unfolded state in an energy-ordered sequence, one foldon unit at a time. To more directly study Cyt c intermediates and pathways during normal energetically downhill kinetic folding, the present work used HX pulse labeling analyzed by a fragment separation-mass spectrometry method. The results show that 95% or more of the Cyt c population folds by stepping down through the same set of foldon-dependent pathway intermediates as in energetically uphill equilibrium unfolding. These results add to growing evidence that proteins fold through a classical pathway sequence of native-like intermediates rather than through a vast number of undefinable intermediates and pathways. The present results also emphasize the condition-dependent nature of kinetic barriers, which, with less informative experimental methods (fluorescence, etc.), are often confused with variability in intermediates and pathways. PMID- 26966232 TI - Identifying genetic modulators of the connectivity between transcription factors and their transcriptional targets. AB - Regulation of gene expression by transcription factors (TFs) is highly dependent on genetic background and interactions with cofactors. Identifying specific context factors is a major challenge that requires new approaches. Here we show that exploiting natural variation is a potent strategy for probing functional interactions within gene regulatory networks. We developed an algorithm to identify genetic polymorphisms that modulate the regulatory connectivity between specific transcription factors and their target genes in vivo. As a proof of principle, we mapped connectivity quantitative trait loci (cQTLs) using parallel genotype and gene expression data for segregants from a cross between two strains of the yeast Saccharomyces cerevisiae We identified a nonsynonymous mutation in the DIG2 gene as a cQTL for the transcription factor Ste12p and confirmed this prediction empirically. We also identified three polymorphisms in TAF13 as putative modulators of regulation by Gcn4p. Our method has potential for revealing how genetic differences among individuals influence gene regulatory networks in any organism for which gene expression and genotype data are available along with information on binding preferences for transcription factors. PMID- 26966233 TI - Unfolded protein response regulates yeast small GTPase Arl1p activation at late Golgi via phosphorylation of Arf GEF Syt1p. AB - ADP ribosylation factor (Arf) GTPases are key regulators of membrane traffic at the Golgi complex. In yeast, Arf guanine nucleotide-exchange factor (GEF) Syt1p activates Arf-like protein Arl1p, which was accompanied by accumulation of golgin Imh1p at late Golgi, but whether and how this function of Syt1p is regulated remains unclear. Here, we report that the inositol-requiring kinase 1 (Ire1p) mediated unfolded protein response (UPR) modulated Arl1p activation at late Golgi. Arl1p activation was dependent on both kinase and endo-RNase activities of Ire1p. Moreover, constitutively active transcription factor Hac1p restored the Golgi localization of Arl1p and Imh1p inIRE1-deleted cells. Elucidating the mechanism of Ire1p-Hac1p axis actions, we found that it regulated phosphorylation of Syt1p, which enhances Arl1p activation, recruitment of Imh1p to the Golgi, and Syt1p interaction with Arl1p. Consistent with these findings, the induction of UPR by tunicamycin treatment increases phosphorylation of Syt1p, resulting in Arl1p activation. Thus, these findings clarify how the UPR influences the roles of Syt1p, Arl1p, and Imh1p in Golgi transport. PMID- 26966234 TI - Temporally chimeric mice reveal flexibility of circadian period-setting in the suprachiasmatic nucleus. AB - The suprachiasmatic nucleus (SCN) is the master circadian clock controlling daily behavior in mammals. It consists of a heterogeneous network of neurons, in which cell-autonomous molecular feedback loops determine the period and amplitude of circadian oscillations of individual cells. In contrast, circuit-level properties of coherence, synchrony, and ensemble period are determined by intercellular signals and are embodied in a circadian wave of gene expression that progresses daily across the SCN. How cell-autonomous and circuit-level mechanisms interact in timekeeping is poorly understood. To explore this interaction, we used intersectional genetics to create temporally chimeric mice with SCN containing dopamine 1a receptor (Drd1a) cells with an intrinsic period of 24 h alongside non Drd1a cells with 20-h clocks. Recording of circadian behavior in vivo alongside cellular molecular pacemaking in SCN slices in vitro demonstrated that such chimeric circuits form robust and resilient circadian clocks. It also showed that the computation of ensemble period is nonlinear. Moreover, the chimeric circuit sustained a wave of gene expression comparable to that of nonchimeric SCN, demonstrating that this circuit-level property is independent of differences in cell-intrinsic periods. The relative dominance of 24-h Drd1a and 20-h non-Drd1a neurons in setting ensemble period could be switched by exposure to resonant or nonresonant 24-h or 20-h lighting cycles. The chimeric circuit therefore reveals unanticipated principles of circuit-level operation underlying the emergent plasticity, resilience, and robustness of the SCN clock. The spontaneous and light-driven flexibility of period observed in chimeric mice provides a new perspective on the concept of SCN pacemaker cells. PMID- 26966235 TI - Transcriptional errors and the drift barrier. PMID- 26966236 TI - Chimney stove intervention--ready for scale up? CON. PMID- 26966238 TI - Chimney stove intervention--ready for scale up? PRO. PMID- 26966237 TI - Lung function in woodsmoke-exposed Guatemalan children following a chimney stove intervention. AB - RATIONALE: Household air pollution (HAP) from solid fuel combustion is a major contributor to the global burden of disease, with considerable impact from respiratory infections in children. The impact of HAP on lung function is unknown. OBJECTIVES: The Childhood Exposure to Respirable Particulate Matter (CRECER) prospective cohort study followed Guatemalan children who participated in the Randomised Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) trial of a chimney stove intervention to determine the effect of early childhood HAP exposure on growth of lung function. METHODS: RESPIRE households with pregnant women or infant children were randomised to receive a chimney stove at the beginning or at the end of the 18-month trial. During CRECER, a subset of these children, as well as children from households with newly installed stoves, were followed with spirometry beginning at age 5. Biomass smoke exposure was measured using personal carbon monoxide tubes. Two-stage regression models were employed to analyse associations with lung function growth. MEASUREMENTS AND MAIN RESULTS: Longitudinal peak expiratory flow (PEF) and FEV1 data were available for 443 and 437 children, respectively, aged 5-8 (mean follow-up 1.3 years). Decreases in PEF growth of 173 mL/min/year (95% CI -341 to -7) and FEV1 of 44 mL/year (95% CI -91 to 4) were observed with stove installation at 18 months compared with stove installation at birth in analyses adjusted for multiple covariates. No statistically significant associations were observed between personal HAP exposure and lung function. CONCLUSIONS: A significant decrease in PEF growth and a large non-significant decrease in FEV1 growth were observed with later stove installation. Additional studies including longer follow-up and cleaner stoves or fuels are needed. PMID- 26966240 TI - Rings Reconcile Genotypic and Phenotypic Evolution within the Proteobacteria. PMID- 26966241 TI - Necrotizing Periodontal Diseases in Children: A Literature Review and Adjustment of Treatment. AB - Necrotizing ulcerative gingivitis, sometimes observed in young children, may lead to necrotizing stomatitis and noma. Therefore, its interception is a necessity and a challenge for the paediatric practitioners. First, this article aims to propose a systematic review of recent literature on the use of local antiseptic and antibiotic prescription in this particular periodontal condition. Then, a protocol is proposed to have a simple, costless and reproducible treatment on children. PMID- 26966242 TI - Perfusion Index-Bedside Diagnosis of Hemodynamically Significant Patent Ductus Arteriosus. AB - BACKGROUND: Patent ductus arteriosus (PDA) is a significant problem in preterm babies <34 weeks old. Echocardiogram (echo) is the gold standard for diagnosing PDA. Perfusion index (PI) using a pulse oximeter could aid in diagnosing a hemodynamically significant PDA (HsPDA). OBJECTIVE: To evaluate the accuracy of delta-PI (DeltaPI; pre-ductal - post-ductal PI) in diagnosing HsPDA in preterm babies <34 weeks old. DESIGN: Prospective analytical cross-sectional (observational) study. METHODS: Preterm infants <34 weeks old (n = 27) were enrolled in the study after parental consent. DeltaPI was calculated on Days 1 and 3. Babies are categorized into two groups-HsPDA and no HsPDA based on echo on Day 3. RESULTS: The mean gestational ages were 30.4 +/- 1.9 (HsPDA) and 31.7 +/- 1.6 weeks (no HsPDA), and birth weights were 1.23 +/- 0.32 kg and 1.43 +/- 0.34 kg, respectively (p > 0.05). Ten infants had HsPDA. The DeltaPI values in Groups A and B differed significantly on Days 1 and 3 (Day 1: 1.06 +/- 0.3 vs. 0.54 +/- 0.2 and Day 3: 1.11 +/- 0.15 vs. 0.57 +/- 0.3). The area under the receiver operating characteristic curve was significant for DeltaPI on Days 1 and 3. The DeltaPI > 0.85 on Day 1 and > 0.95 on Day 3 had a sensitivity and specificity of 80% and 94% and 80% and 88.2%, respectively, for diagnosing HsPDA. CONCLUSION: DeltaPI is a useful, simple parameter, which could help in the assessment of PDA in preterm babies. PMID- 26966243 TI - Plasmodium vivax Malaria Presenting with Multifocal Hemorrhagic Brain Infarcts in a School-going Child. AB - Cerebral malaria is a well-known complication of Plasmodium falciparum malaria. Over recent years, however, Plasmodium vivax also has been reported to cause cerebral malaria with or without co-infection with P. falciparum Here, we report a boy aged 10 years presenting with acute febrile encephalopathy with raised intracranial pressure to the emergency, who was later diagnosed to have P. vivax malaria. His neurological status improved gradually during 6 weeks of pediatric intensive care unit stay. We report this case to highlight the unusual radiologic findings in the patient, such as multifocal hemorrhagic infarcts in the brainstem, bilateral thalami, frontal cortex and basal ganglia, which have not been reported with P. vivax malaria. PMID- 26966239 TI - Evolutionary Insights into RNA trans-Splicing in Vertebrates. AB - Pre-RNA splicing is an essential step in generating mature mRNA. RNA trans splicing combines two separate pre-mRNA molecules to form a chimeric non-co linear RNA, which may exert a function distinct from its original molecules. Trans-spliced RNAs may encode novel proteins or serve as noncoding or regulatory RNAs. These novel RNAs not only increase the complexity of the proteome but also provide new regulatory mechanisms for gene expression. An increasing amount of evidence indicates that trans-splicing occurs frequently in both physiological and pathological processes. In addition, mRNA reprogramming based on trans splicing has been successfully applied in RNA-based therapies for human genetic diseases. Nevertheless, clarifying the extent and evolution of trans-splicing in vertebrates and developing detection methods for trans-splicing remain challenging. In this review, we summarize previous research, highlight recent advances in trans-splicing, and discuss possible splicing mechanisms and functions from an evolutionary viewpoint. PMID- 26966244 TI - Prevalence of Overweight and Obesity among Children and Adolescents in Shandong, China: Urban-Rural Disparity. AB - BACKGROUND: The pattern of urban-rural disparity in childhood obesity varies across countries. The present study examined the change trend of urban-rural disparity in childhood overweight and obesity from 1985 to 2014 in Shandong, China. METHODS: Data for this study were obtained from four cross-sectional surveys of school children carried out in 1985, 1995, 2005 and 2014 in Shandong Province, China. In this study, 39 943 students aged 7-18 years were included (14 458 in 1985, 7198 in 1995, 8568 in 2005 and 9719 in 2014). Height and weight of all subjects were measured; body mass index (BMI) was calculated from their height and weight. The BMI cutoff points recommended by the International Obesity Task Force were used to define overweight and obesity. RESULTS: The prevalence of overweight and obesity was increasing continuously both in urban and rural areas over the past 29 years (1985-2014). The prevalence of combined overweight and obesity was significantly higher in urban than in rural children and adolescents in 1985, 1995 and 2005 (p < 0.01). However, a rapid increase in the prevalence of combined overweight and obesity was observed in rural areas after 2005; as a result, the urban-rural disparity was getting narrower, and no significant urban rural disparity was observed in 2014 (p > 0.05). CONCLUSION: The change trend of urban-rural disparity should be concerned in the future; policies and interventions focused on childhood overweight and obesity should pay attention to rural areas. PMID- 26966245 TI - Nucleosome repositioning underlies dynamic gene expression. AB - Nucleosome repositioning at gene promoters is a fundamental aspect of the regulation of gene expression. However, the extent to which nucleosome repositioning is used within eukaryotic genomes is poorly understood. Here we report a comprehensive analysis of nucleosome positions as budding yeast transit through an ultradian cycle in which expression of >50% of all genes is highly synchronized. We present evidence of extensive nucleosome repositioning at thousands of gene promoters as genes are activated and repressed. During activation, nucleosomes are relocated to allow sites of general transcription factor binding and transcription initiation to become accessible. The extent of nucleosome shifting is closely related to the dynamic range of gene transcription and generally related to DNA sequence properties and use of the coactivators TFIID or SAGA. However, dynamic gene expression is not limited to SAGA-regulated promoters and is an inherent feature of most genes. While nucleosome repositioning occurs pervasively, we found that a class of genes required for growth experience acute nucleosome shifting as cells enter the cell cycle. Significantly, our data identify that the ATP-dependent chromatin-remodeling enzyme Snf2 plays a fundamental role in nucleosome repositioning and the expression of growth genes. We also reveal that nucleosome organization changes extensively in concert with phases of the cell cycle, with large, regularly spaced nucleosome arrays being established in mitosis. Collectively, our data and analysis provide a framework for understanding nucleosome dynamics in relation to fundamental DNA-dependent transactions. PMID- 26966247 TI - Integrated molecular mechanism directing nucleosome reorganization by human FACT. AB - Facilitates chromatin transcription (FACT) plays essential roles in chromatin remodeling during DNA transcription, replication, and repair. Our structural and biochemical studies of human FACT-histone interactions present precise views of nucleosome reorganization, conducted by the FACT-SPT16 (suppressor of Ty 16) Mid domain and its adjacent acidic AID segment. AID accesses the H2B N-terminal basic region exposed by partial unwrapping of the nucleosomal DNA, thereby triggering the invasion of FACT into the nucleosome. The crystal structure of the Mid domain complexed with an H3-H4 tetramer exhibits two separate contact sites; the Mid domain forms a novel intermolecular beta structure with H4. At the other site, the Mid-H2A steric collision on the H2A-docking surface of the H3-H4 tetramer within the nucleosome induces H2A-H2B displacement. This integrated mechanism results in disrupting the H3 alphaN helix, which is essential for retaining the nucleosomal DNA ends, and hence facilitates DNA stripping from histone. PMID- 26966246 TI - Differential regulation of the anti-crossover and replication fork regression activities of Mph1 by Mte1. AB - We identified Mte1 (Mph1-associated telomere maintenance protein 1) as a multifunctional regulator of Saccharomyces cerevisiae Mph1, a member of the FANCM family of DNA motor proteins important for DNA replication fork repair and crossover suppression during homologous recombination. We show that Mte1 interacts with Mph1 and DNA species that resemble a DNA replication fork and the D loop formed during recombination. Biochemically, Mte1 stimulates Mph1-mediated DNA replication fork regression and branch migration in a model substrate. Consistent with this activity, genetic analysis reveals that Mte1 functions with Mph1 and the associated MHF complex in replication fork repair. Surprisingly, Mte1 antagonizes the D-loop-dissociative activity of Mph1-MHF and exerts a procrossover role in mitotic recombination. We further show that the influence of Mte1 on Mph1 activities requires its binding to Mph1 and DNA. Thus, Mte1 differentially regulates Mph1 activities to achieve distinct outcomes in recombination and replication fork repair. PMID- 26966250 TI - Introduction to Special Issue. PMID- 26966249 TI - Current management practices and interventions prioritised as part of a nationwide mastitis control plan. AB - The objectives of this study were to report performance and management data taken from a sample of UK dairy farms that have participated in the Agriculture and Horticulture Development Board Dairy Mastitis Control Plan (DMCP) and to identify important mastitis prevention practices that are not currently widely implemented. A total of 234 UK dairy herds were included in the study from which farm management and udder health data were collected. Herds were grouped according to their mastitis epidemiology and could be classed as (i) environmental dry period (EDP) (i.e. environmental pathogen with majority of infections being acquired during the dry period), (ii) environmental lactation (EL), (iii) contagious dry period (CDP) or (iv) contagious lactation (CL). The results of this study showed that many mastitis-related management practices that are generally considered to be important were not widely performed. A better understanding of those practices not widely adopted by UK dairy farmers at present may aid practitioners in identifying and overcoming potential barriers to improved mastitis control. PMID- 26966251 TI - Will the Latino Mortality Advantage Endure? AB - Persons of Mexican origin and some other Latino groups in the United States have experienced a survival advantage compared with their non-Latino White counterparts, a pattern known as the Latino, Hispanic, or epidemiological paradox. However, high rates of obesity and diabetes among Latinos relative to Whites and continued increases in the prevalence of these conditions suggest that this advantage may soon disappear. Other phenomena, including high rates of disability in the older Latino population compared with Whites, new evidence of health declines shortly after migration to the United States, increasing environmental stressors for immigrants, and high-risk values of inflammatory markers among Latinos compared with Whites support this prediction. One powerful counterargument, however, is substantially lower smoking-attributable mortality among Latinos. Still, it is questionable as to whether smoking behavior can counteract the many forces at play that may impede Latinos from experiencing future improvements in longevity on a par with Whites. PMID- 26966252 TI - The Effect of Changes in Educational Composition on Adult Female Mortality in Brazil. AB - The last century in Brazil was witness to profound changes. Female life expectancy at birth increased from 34.6 years in 1910 to 77.26 years in 2010. At the same time, the educational composition of the population has changed dramatically. In the 1940s, only 25% of the children aged 5-14 years old were enrolled in school. Currently, nearly all children attend school. We examine the extent to which changes in the age-specific distribution of education have contributed to the decline in adult mortality among women in Brazil. Our analysis follows other applications in the literature to measure the mortality reduction that would occur if exposure to specific risk factors was changed at the counterfactual level. The effects are not trivial: Between 1960 and 2010, about 38% of the increase in life expectancy at age 30 can be attributed to changes in the educational composition of women. An additional 22% increase is expected until 2040. PMID- 26966248 TI - Mte1 interacts with Mph1 and promotes crossover recombination and telomere maintenance. AB - Mph1 is a member of the conserved FANCM family of DNA motor proteins that play key roles in genome maintenance processes underlying Fanconi anemia, a cancer predisposition syndrome in humans. Here, we identify Mte1 as a novel interactor of the Mph1 helicase in Saccharomyces cerevisiae. In vitro, Mte1 (Mph1-associated telomere maintenance protein 1) binds directly to DNA with a preference for branched molecules such as D loops and fork structures. In addition, Mte1 stimulates the helicase and fork regression activities of Mph1 while inhibiting the ability of Mph1 to dissociate recombination intermediates. Deletion of MTE1 reduces crossover recombination and suppresses the sensitivity of mph1Delta mutant cells to replication stress. Mph1 and Mte1 interdependently colocalize at DNA damage-induced foci and dysfunctional telomeres, and MTE1 deletion results in elongated telomeres. Taken together, our data indicate that Mte1 plays a role in regulation of crossover recombination, response to replication stress, and telomere maintenance. PMID- 26966254 TI - Adult Children's Education and Parents' Functional Limitations in Mexico. AB - This article asks how adult children's education influences older parents' physical health in Mexico, a context where older adults often lack access to institutional resources and rely on kin, primarily children, as a main source of support. Using logistic and negative binomial regression models and data from the first wave of the Mexican Health and Aging Study (N = 9,661), we find that parents whose children all completed high school are less likely to report any functional limitations as well as fewer limitations compared to parents with no children who completed high school. This association remains significant even after accounting for parent and offspring-level characteristics, including parents' income that accounts for children's financial transfers to parents. Future research should aim to understand the mechanisms that explain the association between adult children's education and changes to parents' health over time. PMID- 26966253 TI - Educational Gradients and Pathways of Disability Onset Among Older Mexicans. AB - INTRODUCTION: Educational disparities research is less common in developing countries. We evaluate whether educational gradients of disability onset exist in Mexico across groups (birth cohort and sex) and whether the association is unexplained or indirect via health (health behaviors, chronic conditions, and self-rated health) or economic (income, wealth, and health insurance) pathways. METHOD: Data come from the Mexican Health & Aging study. Activities of daily living are reported in 2001, 2003, and 2012 by respondents and spouses aged 50+ (N = 9,560). Groups are analyzed using logistic regression to test education disability onset associations. RESULTS: Significant education-ADL onset associations were observed across groups, and much of these associations were direct (unexplained by pathways). Indirect effects operated primarily through the health pathway. DISCUSSION: Those with less education were disadvantaged in terms of disability across birth cohorts and sex. Unexplained effects of education may suggest unobserved mediators or differential returns to resources by educational level. PMID- 26966255 TI - Household Composition and Longitudinal Health Outcomes for Older Mexican Return Migrants. AB - Mexican return migrant population is increasing, yet our knowledge about their lives after resettlement in Mexico remains fragmentary. Using 2001-2012 longitudinal data from the Mexican Health and Aging Study, we investigate difference in household composition for older migrants who returned from the United States compared to nonmigrants. Furthermore, we fit a Cox proportional hazards model to assess the relationship between household composition and health and functional trajectories of return migrants and nonmigrants. The results indicate that return migrants with long duration of U.S. stay have different household composition than nonmigrants or short-term migrants: On average, they have smaller household size, including fewer females who may be available to offer assistance to older adults. Presence of middle-age females in the household has positive effects on health and functional trajectories. We highlight implications of this research for policy makers in Mexico and the United States. PMID- 26966256 TI - Perceived Social Support Trajectories and the All-Cause Mortality Risk of Older Mexican American Women and Men. AB - Although numerous studies of non-Hispanic Whites and Blacks show that social integration and social support tend to favor longevity, it is unclear whether this general pattern extends to the Mexican American population. Building on previous research, we employed seven waves of data from the Hispanic Established Populations for the Epidemiologic Study of the Elderly to examine the association between perceived social support trajectories and the all-cause mortality risk of older Mexican Americans. Growth mixture estimates revealed three latent classes of support trajectories: high, moderate, and low. Cox regression estimates indicated that older Mexican American men in the low support trajectory tend to exhibit a higher mortality risk than their counterparts in the high support trajectory. Social support trajectories were unrelated to the mortality risk of older Mexican American women. A statistically significant interaction term confirmed that social support was more strongly associated with the mortality risk of men. PMID- 26966257 TI - Racial Disparities in Functional Limitations Among Hispanic Women in the United States. AB - This article assesses whether there are race differences in functional health among Hispanic women in the United States; ascertains whether the race differences in functional health vary by age; and examines the extent to which race differences in functional health are attributable to key dimensions of demographic, geographic, and socioeconomic heterogeneity. The analysis is based on 15 years of aggregated data from the National Health Interview Survey. Both U.S.- and foreign-born Black and other race Hispanic women display a higher level of functional limitations than their White Hispanic counterparts. There is little evidence that such health differences widen with age. U.S.-born Black Hispanic women, however, suffer from a high burden of functional limitations across the adult age range. This research speaks to the need for greater attention to racial differences in health among Hispanics and particularly so within the U.S.-born segment of this rapidly aging population. PMID- 26966260 TI - Obituary for Prof. Torsten Almen. PMID- 26966258 TI - Mitonuclear Epistasis for Development Time and Its Modification by Diet in Drosophila. AB - Mitochondrial (mtDNA) and nuclear genes have to operate in a coordinated manner to maintain organismal function, and the regulation of this homeostasis presents a substantial source of potential epistatic (G * G) interactions. How these interactions shape the fitness landscape is poorly understood. Here we developed a novel mitonuclear epistasis model, using selected strains of the Drosophila Genetic Reference Panel (DGRP) and mitochondrial genomes from within Drosophila melanogaster and D. simulans to test the hypothesis that mtDNA * nDNA interactions influence fitness. In total we built 72 genotypes (12 nuclear backgrounds * 6 mtDNA haplotypes, with 3 from each species) to dissect the relationship between genotype and phenotype. Each genotype was assayed on four food environments. We found considerable variation in several phenotypes, including development time and egg-to-adult viability, and this variation was partitioned into genetic (G), environmental (E), and higher-order (G * G, G * E, and G * G * E) components. Food type had a significant impact on development time and also modified mitonuclear epistases, evidencing a broad spectrum of G * G * E across these genotypes. Nuclear background effects were substantial, followed by mtDNA effects and their G * G interaction. The species of mtDNA haplotype had negligible effects on phenotypic variation and there was no evidence that mtDNA variation has different effects on male and female fitness traits. Our results demonstrate that mitonuclear epistases are context dependent, suggesting the selective pressure acting on mitonuclear genotypes may vary with food environment in a genotype-specific manner. PMID- 26966261 TI - 'Classic papers' in this issue of Acta Radiologica. PMID- 26966259 TI - Characterization of Chicken MMP13 Expression and Genetic Effect on Egg Production Traits of Its Promoter Polymorphisms. AB - Extracelluar matrix undergoes constant remodeling, cell-cell, and cell-matrix interactions during chicken ovarian follicle growth, which is coordinated by matrix metalloproteinases (MMPs), and their associated endogenous inhibitors (TIMPs). Transcriptome analysis revealed upregulation of MMP13 in sexually mature chicken ovaries. In this study, we found that the expression of MMP13 in chicken ovary was stably elevated from 60 d to 159 d, and was significantly higher at 159 d than at the other three developmental stages (P < 0.05). The expression of MMP13 mRNA increased from SW (small white follicles) to F5 (fifth largest follicles), then decreased to F1 (first largest follicles), and dramatically increased again in POF1 (newly postovulatory follicles) follicles (P < 0.05). The MMP13 protein was localized in stroma cells and primordial follicles of sexually immature chicken ovaries, in the theca cell layers of all sized follicles of sexually mature chicken ovaries. Furthermore, we identified a positive element (positions -1863 to -1036) controlling chicken MMP13 transcription, and, in this region, six single nucleotide polymorphisms were found and genotyped in chicken populations. In the White Recessive Rock population, hens with A(-1356)-C( 1079)/A(-1356)-C(-1079) genotype had earlier "age at first laying" than those with G(-1356)-T(-1079)/G(-1356)-T(-1079) genotype (P < 0.05), and exhibited significantly lower transcriptional activity (P < 0.01). Collectively, chicken MMP13 plays an important role in ovarian follicle growth and regression, and polymorphisms in its promoter region could be used as molecular markers for improving the trait "age at first laying" in chicken breeding. PMID- 26966262 TI - Roentgen Examination of Ileocaecal Tuberculosis with Special Reference to the so called Stierlin-Sign. PMID- 26966263 TI - A Hitherto Unknown Affection of the Patella In Children. PMID- 26966265 TI - How well does the capillary thyroid-stimulating hormone test for newborn thyroid screening predict the venous free thyroxine level? AB - OBJECTIVES: To determine, in newborn infants referred with elevated capillary thyroid-stimulating hormone (TSH), a threshold below which a frankly subnormal venous free thyroxine (fT4) level of <10 pmol/L is unlikely, so that treatment with levo-thyroxine (L-T4) might be deferred until venous thyroid function tests (TFTs) become available. SUBJECTS AND METHODS: All infants referred in Scotland since 1979 with capillary TSH elevation were studied, with particular focus on infants screened using the AutoDELFIA assay between 2002 and 2013. RESULTS: Of the 321 infants referred with capillary TSH elevation using AutoDELFIA, 35 were excluded (fT4/TSH unavailable (12), venous sample either preceding or >10 days after capillary sampling (13, 10)), leaving 286 eligible for analysis (208 definite/probable hypothyroidism, 61 transient TSH elevation, 17 of uncertain thyroid status). Capillary TSH and venous T4 were strongly correlated (Spearman's rank correlation coefficient -0.707355). The optimal capillary TSH threshold for predicting a venous fT4 of <10 pmol/L was found to be >40 mU/L (90.3% sensitivity and 65.9% specificity compared with 90.25% and 59.1% for >35 mU/L and 88.3% and 68.2% for >45 mU/L). 93 infants (32.5%) had capillary TSH <=40 mU/L at referral of whom 15 (9.7%) had venous fT4 <10 pmol/L, comprising seven with true congenital hypothyroidism, five with transient TSH elevation and three with uncertain status, two of whom died. CONCLUSION: For infants in whom capillary TSH is <=40 mU/L, it is reasonable to defer L-T4 treatment until venous TFT results are known provided that the latter become available quickly. PMID- 26966268 TI - Detection and Direction Determination of Approaching Vehicle Noises Among Older Adults. AB - We examined detection and direction determination of auditory cues from a pedestrian environment among a sample of older and younger adults. Review of relevant research suggests normal aging is associated with declines in physical, cognitive, and perceptual abilities. Relatively, few studies have examined the impact of such developmental changes on pedestrian safety among older adults, and none have examined such factors in relation to use of auditory cues. Thirty-five younger and 35 older adults completed cognitive measures and a pedestrian auditory detection task. Some results by speed were similar to past research that examined younger samples. Interactions were discovered between age and speed conditions within the auditory task. Results are discussed in the context of past research and with regard to informing future injury prevention efforts. PMID- 26966270 TI - Chiral Separation and Thermodynamic Investigation of Ezetimibe Optical Isomers on a Chiralpak IC Column. AB - A liquid chromatographic separation method of ezetimibe optical isomers on the immobilised-type Chiralpak IC chiral stationary phase, onto which cellulose tris (3,5-dichlorophenylcarbamate) was covalently grafted as a chiral selector, was developed under normal-phase conditions. The optimized chromatographic conditions were as follows: n-hexane-isopropanol-diethylamine (90:10:0.1, v/v) as mobile phase, 1.0 mL min-1 as flow rate, 256 nm as UV detection wavelength and 25 degrees C as column temperature. Several factors concerning the enantioseparation were studied, including quality and quantity of different polar organic modifiers, additives, and flow rate and column temperature. Separation and resolution in the temperature range of 15-35 degrees C was investigated. Apparent thermodynamic parameters were calculated from the Van't Hoff plots and used to explain the strength of interactions between the optical isomers and chiral selector. The validated method is simple, rapid and robust. Four ezetimibe optical isomers can be effectively separated from each other and the resolutions are 3.5, 2.7 and 2.5 successively. The method has been demonstrated to be applicable in routine quality control of Ezetimibe. PMID- 26966269 TI - Overview of ICRP Committee 3: protection in medicine. AB - Committee 3 of the International Commission on Radiological Protection (ICRP) develops recommendations and guidance for protection of patients, staff, and the public against radiation exposure when ionising radiation is used for medical diagnosis, therapy, or biomedical research. This paper presents a summary of the work that Committee 3 has accomplished over the past few years, and also describes its current work. The most recent reports published by the Commission that relate to radiological protection in medicine are 'Radiological protection in cone beam computed tomography' (Publication 129), 'Radiation dose to patients from radiopharmaceuticals: a compendium of current information related to frequently used substances' (Publication 128, in cooperation with Committee 2), 'Radiological protection in ion beam radiotherapy' (Publication 127), 'Radiological protection in paediatric diagnostic and interventional radiology' (Publication 121), 'Radiological protection in cardiology' (Publication 120), and 'Radiological protection in fluoroscopically guided procedures outside the imaging department' (Publication 117). A new report on diagnostic reference levels in medical imaging will provide specific advice for interventional radiology, digital imaging, computed tomography, nuclear medicine, paediatrics, and hybrid (multi-modality) imaging procedures, and is expected to be published in 2016. Committee 3 is also working on guidance for occupational radiological protection in brachytherapy, and on guidance on occupational protection issues in interventional procedures, paying particular attention to the 2011 Commission's recommendations on the occupational dose limit for the lens of the eye (Publication 118). Other reports in preparation deal with justification, radiological protection in therapy with radiopharmaceuticals, radiological protection in medicine as related to individual radiosusceptibility, appropriate use of effective dose (in cooperation with other Committees), and guidance for healthcare practitioners on radiological and patient protection. Committee 3 has also suggested specific priorities for research on radiological protection in medicine to the Commission. PMID- 26966266 TI - Different Patterns of Cortical Inputs to Subregions of the Primary Motor Cortex Hand Representation in Cebus apella. AB - The primary motor cortex (M1) plays an essential role in the control of hand movements in primates and is part of a complex cortical sensorimotor network involving multiple premotor and parietal areas. In a previous study in squirrel monkeys, we found that the ventral premotor cortex (PMv) projected mainly to 3 regions within the M1 forearm representation [rostro-medial (RM), rostro-lateral (RL), and caudo-lateral (CL)] with very few caudo-medial (CM) projections. These results suggest that projections from premotor areas to M1 are not uniform, but rather segregated into subregions. The goal of the present work was to study how inputs from diverse areas of the ipsilateral cortical network are organized within the M1 hand representation. In Cebus apella, different retrograde neuroanatomical tracers were injected in 4 subregions of the hand area of M1 (RM, RL, CM, and CL). We found a different pattern of input to each subregion of M1. RM receives inputs predominantly from dorsal premotor cortex, RL from PMv, CM from area 5, and CL from area 2. These results support that the M1 hand representation is composed of several subregions, each part of a unique cortical network. PMID- 26966271 TI - Development of Solid-Phase Extraction Coupled with Dispersive Liquid-Liquid Microextraction Method for the Simultaneous Determination of Three Benzodiazepines in Human Urine and Plasma. AB - A new pretreatment method termed solid-phase extraction (SPE) which is combined with dispersive liquid-liquid microextraction (SPE-DLLME) has been developed for the determination of oxazepam, alprazolam and diazepam in urine and plasma samples. The analytes were extracted from biological samples using SPE followed by DLLME. Various parameters that affect the efficiency of the two extraction techniques have been optimized. The calibration plots were linear in the range of 2.5-500 ug L(-1) for oxazepam, alprazolam and 1.0-500 ug L(-1) for diazepam with detection limits of 0.7 ug L(-1) for oxazepam, alprazolam and 0.4 ug L(-1) for diazepam in plasma sample. The results confirm the suitability of the SPE-DLLME HPLC-UV as a sensitive method for the analysis of the targeted analytes in urine and plasma samples. PMID- 26966272 TI - Development and Validation of New Ultra-High-Performance Liquid Chromatography Hybrid Quadrupole-Orbitrap Mass Spectrometry Method for Determination of Melatonin in Fruits. AB - A new reliable analytical method based on ultra-high-performance liquid chromatography coupled with hybrid quadrupole-Orbitrap mass spectrometry was developed for the analysis of melatonin (MEL) in food products. In-house validation was performed using deuterated melatonin (MEL-d4) as an internal standard to ensure method selectivity and accuracy and to evaluate the efficiency of a robust ethyl acetate extraction technique used for sample preparation. The analysis of 18 tart cherry varieties and 28 tomato varieties was performed at optimized conditions. The method was linear (R(2)> 0.99) over the concentration range of 5-200 pg/g. A very low limit of quantification (10 pg/g) was provided for both analyzed matrices. The determined average recoveries (102 and 110%) and the values of intraday repeatability (6.30 and 10.9%) for cherry and tomato matrices, respectively, indicated a good accuracy and precision. The elaborated procedure proved the absence of MEL in any of tart cherries (<10 pg/g), whereas the concentration levels in tomatoes were found to be in the range of <10-149 pg/g, where the highest concentrations were determined in "Cherry," "Cherry Red" and "Rome" tomatoes grown in the Netherlands. PMID- 26966273 TI - Protease-Activated Receptor 4 Variant p.Tyr157Cys Reduces Platelet Functional Responses and Alters Receptor Trafficking. AB - OBJECTIVE: Protease-activated receptor 4 (PAR4) is a key regulator of platelet reactivity and is encoded by F2RL3, which has abundant rare missense variants. We aimed to provide proof of principle that rare F2LR3 variants potentially affect platelet reactivity and responsiveness to PAR1 antagonist drugs and to explore underlying molecular mechanisms. APPROACH AND RESULTS: We identified 6 rare F2RL3 missense variants in 236 cardiac patients, of which the variant causing a tyrosine 157 to cysteine substitution (Y157C) was predicted computationally to have the greatest effect on PAR4 structure. Y157C platelets from 3 cases showed reduced responses to PAR4-activating peptide and to alpha-thrombin compared with controls, but no reduction in responses to PAR1-activating peptide. Pretreatment with the PAR1 antagonist vorapaxar caused lower residual alpha-thrombin responses in Y157C platelets than in controls, indicating greater platelet inhibition. HEK293 cells transfected with a PAR4 Y157C expression construct had reduced PAR4 functional responses, unchanged total PAR4 expression but reduced surface expression. PAR4 Y157C was partially retained in the endoplasmic reticulum and displayed an expression pattern consistent with defective N-glycosylation. Mutagenesis of Y322, which is the putative hydrogen bond partner of Y157, also reduced PAR4 surface expression in HEK293 cells. CONCLUSIONS: Reduced PAR4 responses associated with Y157C result from aberrant anterograde surface receptor trafficking, in part, because of disrupted intramolecular hydrogen bonding. Characterization of PAR4 Y157C establishes that rare F2RL3 variants have the potential to markedly alter platelet PAR4 reactivity particularly after exposure to therapeutic PAR1 antagonists. PMID- 26966274 TI - Functional Analysis of a Novel Genome-Wide Association Study Signal in SMAD3 That Confers Protection From Coronary Artery Disease. AB - OBJECTIVE: A recent genome-wide association study meta-analysis identified an intronic single nucleotide polymorphism in SMAD3, rs56062135C>T, the minor allele (T) which associates with protection from coronary artery disease. Relevant to atherosclerosis, SMAD3 is a key contributor to transforming growth factor-beta pathway signaling. Here, we seek to identify >=1 causal coronary artery disease associated single nucleotide polymorphisms at the SMAD3 locus and characterize mechanisms whereby the risk allele(s) contribute to coronary artery disease risk. APPROACH AND RESULTS: By genetic and epigenetic fine mapping, we identified a candidate causal single nucleotide polymorphism rs17293632C>T (D', 0.97; r(2), 0.94 with rs56062135) in intron 1 of SMAD3 with predicted functional effects. We show that the sequence encompassing rs17293632 acts as a strong enhancer in human arterial smooth muscle cells. The common allele (C) preserves an activator protein (AP)-1 site and enhancer function, whereas the protective (T) allele disrupts the AP-1 site and significantly reduces enhancer activity (P<0.001). Pharmacological inhibition of AP-1 activity upstream demonstrates that this allele-specific enhancer effect is AP-1 dependent (P<0.001). Chromatin immunoprecipitation experiments reveal binding of several AP-1 component proteins with preferential binding to the (C) allele. We show that rs17293632 is an expression quantitative trait locus for SMAD3 in blood and atherosclerotic plaque with reduced expression of SMAD3 in carriers of the protective allele. Finally, siRNA knockdown of SMAD3 in human arterial smooth muscle cells increases cell viability, consistent with an antiproliferative role. CONCLUSIONS: The coronary artery disease-associated rs17293632C>T single nucleotide polymorphism represents a novel functional cis-acting element at the SMAD3 locus. The protective (T) allele of rs17293632 disrupts a consensus AP-1 binding site in a SMAD3 intron 1 enhancer, reduces enhancer activity and SMAD3 expression, altering human arterial smooth muscle cell proliferation. PMID- 26966275 TI - Network-Based Identification and Prioritization of Key Regulators of Coronary Artery Disease Loci. AB - OBJECTIVE: Recent genome-wide association studies of coronary artery disease (CAD) have revealed 58 genome-wide significant and 148 suggestive genetic loci. However, the molecular mechanisms through which they contribute to CAD and the clinical implications of these findings remain largely unknown. We aim to retrieve gene subnetworks of the 206 CAD loci and identify and prioritize candidate regulators to better understand the biological mechanisms underlying the genetic associations. APPROACH AND RESULTS: We devised a new integrative genomics approach that incorporated (1) candidate genes from the top CAD loci, (2) the complete genetic association results from the 1000 genomes-based CAD genome-wide association studies from the Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus the Coronary Artery Disease consortium, (3) tissue-specific gene regulatory networks that depict the potential relationship and interactions between genes, and (4) tissue-specific gene expression patterns between CAD patients and controls. The networks and top-ranked regulators according to these data-driven criteria were further queried against literature, experimental evidence, and drug information to evaluate their disease relevance and potential as drug targets. Our analysis uncovered several potential novel regulators of CAD such as LUM and STAT3, which possess properties suitable as drug targets. We also revealed molecular relations and potential mechanisms through which the top CAD loci operate. Furthermore, we found that multiple CAD relevant biological processes such as extracellular matrix, inflammatory and immune pathways, complement and coagulation cascades, and lipid metabolism interact in the CAD networks. CONCLUSIONS: Our data-driven integrative genomics framework unraveled tissue-specific relations among the candidate genes of the CAD genome-wide association studies loci and prioritized novel network regulatory genes orchestrating biological processes relevant to CAD. PMID- 26966276 TI - Modulation of Kinin B2 Receptor Signaling Controls Aortic Dilatation and Rupture in the Angiotensin II-Infused Apolipoprotein E-Deficient Mouse. AB - OBJECTIVE: Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Activity of the local kallikrein-kinin system may be important in cardiovascular disease. The effect of kinin B2 receptor (B2R) agonist and antagonist peptides on experimental AAA was investigated. APPROACH AND RESULTS: AAA was induced in apolipoprotein E-deficient mice via infusion of angiotensin II (1.0 MUg/kg per minute SC). B2R agonists or antagonists were given via injection (2 mg/kg IP) every other day. The B2R agonist (B9772) promoted aortic rupture in response to angiotensin II associated with an increase in neutrophil infiltration of the aorta in comparison to controls. Mice receiving a B2R/kinin B1 receptor antagonist (B9430) were relatively protected from aortic rupture. Neutrophil depletion abrogated the ability of the B2R agonist to promote aortic rupture. Progression of angiotensin II-induced aortic dilatation was inhibited in mice receiving a B2R antagonist (B9330). Secretion of metalloproteinase-2 and -9, osteoprotegerin, and osteopontin by human AAA explant was reduced in the presence of the B2R antagonist (B9330). B2R agonist and antagonist peptides enhanced and inhibited, respectively, angiotensin II-induced neutrophil activation and aortic smooth muscle cell inflammatory phenotype. The B2R antagonist (B9330; 5 MUg) delivered directly to the aortic wall 1 week post-AAA induction with calcium phosphate in a rat model reduced aneurysm growth associated with downregulation of aortic metalloproteinase-9. CONCLUSIONS: B2R signaling promotes aortic rupture within a mouse model associated with the ability to stimulate inflammatory phenotypes of neutrophils and vascular smooth muscle cells. B2R antagonism could be a potential therapy for AAA. PMID- 26966278 TI - Diabetes Mellitus Is Associated With Reduced High-Density Lipoprotein Sphingosine 1-Phosphate Content and Impaired High-Density Lipoprotein Cardiac Cell Protection. AB - OBJECTIVE: The dyslipidemia of type 2 diabetes mellitus has multiple etiologies and impairs lipoprotein functionality, thereby increasing risk for cardiovascular disease. High-density lipoproteins (HDLs) have several beneficial effects, notably protecting the heart from myocardial ischemia. We hypothesized that glycation of HDL could compromise this cardioprotective effect. APPROACH AND RESULTS: We used in vitro (cardiomyocytes) and ex vivo (whole heart) models subjected to oxidative stress together with HDL isolated from diabetic patients and nondiabetic HDL glycated in vitro (methylglyoxal). Diabetic and in vitro glycated HDL were less effective (P<0.05) than control HDL in protecting from oxidative stress. Protection was significantly, inversely correlated with the degree of in vitro glycation (P<0.001) and the levels of hemoglobin A1c in diabetic patients (P<0.007). The ability to activate protective, intracellular survival pathways involving Akt, Stat3, and Erk1/2 was significantly reduced (P<0.05) using glycated HDL. Glycation reduced the sphingosine-1-phosphate (S1P) content of HDL, whereas the S1P concentrations of diabetic HDL were inversely correlated with hemoglobin A1c (P<0.005). The S1P contents of in vitro glycated and diabetic HDL were significantly, positively correlated (both <0.01) with cardiomyocyte survival during oxidative stress. Adding S1P to diabetic HDL increased its S1P content and restored its cardioprotective function. CONCLUSIONS: Our data demonstrate that glycation can reduce the S1P content of HDL, leading to increased cardiomyocyte cell death because of less effective activation of intracellular survival pathways. It has important implications for the functionality of HDL in diabetes mellitus because HDL-S1P has several beneficial effects on the vasculature. PMID- 26966277 TI - Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Neointimal Hyperplasia and Suppresses Macrophage Inflammation Through SGK1-AP1/NF-kappaB Pathways. AB - OBJECTIVE: Restenosis after percutaneous coronary intervention remains to be a serious medical problem. Although mineralocorticoid receptor (MR) has been implicated as a potential target for treating restenosis, the cellular and molecular mechanisms are largely unknown. This study aims to explore the functions of macrophage MR in neointimal hyperplasia and to delineate the molecular mechanisms. APPROACH AND RESULTS: Myeloid MR knockout (MMRKO) mice and controls were subjected to femoral artery injury. MMRKO reduced intima area and intima/media ratio, Ki67- and BrdU-positive vascular smooth muscle cells, expression of proinflammatory molecules, and macrophage accumulation in injured arteries. MMRKO macrophages migrated less in culture. MMRKO decreased Ki67- and BrdU-positive macrophages in injured arteries. MMRKO macrophages were less Ki67 positive in culture. Conditioned media from MMRKO macrophages induced less migration, Ki67 positivity, and proinflammatory gene expression of vascular smooth muscle cells. After lipopolysaccharide treatment, MMRKO macrophages had decreased p-cFos and p-cJun compared with control macrophages, suggesting suppressed activation of activator protein-1 (AP1). Nuclear factor-kappaB (NF kappaB) pathway was also inhibited by MMRKO, manifested by decreased p-IkappaB kinase-beta and p-IkappaBalpha, increased IkappaBalpha expression, decreased nuclear translocation of p65 and p50, as welll as decreased phosphorylation and expression of p65. Finally, overexpression of serum-and-glucocorticoid-inducible kinase-1 (SGK1) attenuated the effects of MR deficiency in macrophages. CONCLUSIONS: Selective deletion of MR in myeloid cells limits macrophage accumulation and vascular inflammation and, therefore, inhibits neointimal hyperplasia and vascular remodeling. Mechanistically, MR deficiency suppresses migration and proliferation of macrophages and leads to less vascular smooth muscle cell activation. At the molecular level, MR deficiency suppresses macrophage inflammatory response via SGK1-AP1/NF-kappaB pathways. PMID- 26966279 TI - Cholesteryl Ester Transfer Protein Inhibition With Anacetrapib Decreases Fractional Clearance Rates of High-Density Lipoprotein Apolipoprotein A-I and Plasma Cholesteryl Ester Transfer Protein. AB - OBJECTIVE: Anacetrapib (ANA), an inhibitor of cholesteryl ester transfer protein (CETP) activity, increases plasma concentrations of high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (apoA)-I, apoA-II, and CETP. The mechanisms responsible for these treatment-related increases in apolipoproteins and plasma CETP are unknown. We performed a randomized, placebo (PBO)-controlled, double-blind, fixed-sequence study to examine the effects of ANA on the metabolism of HDL apoA-I and apoA-II and plasma CETP. APPROACH AND RESULTS: Twenty-nine participants received atorvastatin (ATV) 20 mg/d plus PBO for 4 weeks, followed by ATV plus ANA 100 mg/d for 8 weeks (ATV-ANA). Ten participants received double PBO for 4 weeks followed by PBO plus ANA for 8 weeks (PBO-ANA). At the end of each treatment, we examined the kinetics of HDL apoA-I, HDL apoA II, and plasma CETP after D3-leucine administration as well as 2D gel analysis of HDL subspecies. In the combined ATV-ANA and PBO-ANA groups, ANA treatment increased plasma HDL-C (63.0%; P<0.001) and apoA-I levels (29.5%; P<0.001). These increases were associated with reductions in HDL apoA-I fractional clearance rate (18.2%; P=0.002) without changes in production rate. Although the apoA-II levels increased by 12.6% (P<0.001), we could not discern significant changes in either apoA-II fractional clearance rate or production rate. CETP levels increased 102% (P<0.001) on ANA because of a significant reduction in the fractional clearance rate of CETP (57.6%, P<0.001) with no change in CETP production rate. CONCLUSIONS: ANA treatment increases HDL apoA-I and CETP levels by decreasing the fractional clearance rate of each protein. PMID- 26966281 TI - The High-Density Lipoprotein Puzzle: Why Classic Epidemiology, Genetic Epidemiology, and Clinical Trials Conflict? AB - Classical epidemiology has established the incremental contribution of the high density lipoprotein (HDL) cholesterol measure in the assessment of atherosclerotic cardiovascular disease risk; yet, genetic epidemiology does not support a causal relationship between HDL cholesterol and the future risk of myocardial infarction. Therapeutic interventions directed toward cholesterol loading of the HDL particle have been based on epidemiological studies that have established HDL cholesterol as a biomarker of atherosclerotic cardiovascular risk. However, therapeutic interventions such as niacin, cholesteryl ester transfer protein inhibitors increase HDL cholesterol in patients treated with statins, but have repeatedly failed to reduce cardiovascular events. Statin therapy interferes with ATP-binding cassette transporter-mediated macrophage cholesterol efflux via miR33 and thus may diminish certain HDL functional properties. Unraveling the HDL puzzle will require continued technical advances in the characterization and quantification of multiple HDL subclasses and their functional properties. Key mechanistic criteria for clinical outcomes trials with HDL-based therapies include formation of HDL subclasses that improve the efficiency of macrophage cholesterol efflux and compositional changes in the proteome and lipidome of the HDL particle that are associated with improved antioxidant and anti-inflammatory properties. These measures require validation in genetic studies and clinical trials of HDL-based therapies on the background of statins. PMID- 26966280 TI - Leukocyte Calpain Deficiency Reduces Angiotensin II-Induced Inflammation and Atherosclerosis But Not Abdominal Aortic Aneurysms in Mice. AB - OBJECTIVE: Angiotensin II (AngII) infusion profoundly increases activity of calpains, calcium-dependent neutral cysteine proteases, in mice. Pharmacological inhibition of calpains attenuates AngII-induced aortic medial macrophage accumulation, atherosclerosis, and abdominal aortic aneurysm in mice. However, the precise functional contribution of leukocyte-derived calpains in AngII induced vascular pathologies has not been determined. The purpose of this study was to determine whether calpains expressed in bone marrow (BM)-derived cells contribute to AngII-induced atherosclerosis and aortic aneurysms in hypercholesterolemic mice. APPROACH AND RESULTS: To study whether leukocyte calpains contributed to AngII-induced aortic pathologies, irradiated male low density lipoprotein receptor(-/-) mice were repopulated with BM-derived cells that were either wild-type or overexpressed calpastatin, the endogenous inhibitor of calpains. Mice were fed a fat-enriched diet and infused with AngII (1000 ng/kg per minute) for 4 weeks. Overexpression of calpastatin in BM-derived cells significantly attenuated AngII-induced atherosclerotic lesion formation in aortic arches, but had no effect on aneurysm formation. Using either BM-derived cells from calpain-1-deficient mice or mice with leukocyte-specific calpain-2 deficiency generated using cre-loxP recombination technology, further studies demonstrated that independent deficiency of either calpain-1 or -2 in leukocytes modestly attenuated AngII-induced atherosclerosis. Calpastatin overexpression significantly attenuated AngII-induced inflammatory responses in macrophages and spleen. Furthermore, calpain inhibition suppressed migration and adhesion of macrophages to endothelial cells in vitro. Calpain inhibition also significantly decreased hypercholesterolemia-induced atherosclerosis in the absence of AngII. CONCLUSIONS: The present study demonstrates a pivotal role for BM-derived calpains in mediating AngII-induced atherosclerosis by influencing macrophage function. PMID- 26966282 TI - Multi-marker linkage disequilibrium mapping of quantitative trait loci. AB - Single nucleotide polymorphisms (SNPs), the most common genetic markers in genome wide association studies, are usually in linkage disequilibrium (LD) with each other within a small genomic region. Both single- and two-marker-based LD mapping methods have been developed by taking advantage of the LD structures. In this study, a more general LD mapping framework with an arbitrary number of markers has been developed to further improve LD mapping and its detection power. This method is referred as multi-marker linkage disequilibrium mapping (mmLD). For the parameter estimation, we implemented a two-phase estimation procedure: first, haplotype frequencies were estimated for known markers; then, haplotype frequencies were updated to include the unknown quantitative trait loci based on estimates from the first step. For the hypothesis testing, we proposed a novel sequential likelihood ratio test procedure, which iteratively removed haplotypes with zero frequency and subsequently determined the proper degree of freedom. To compare the proposed mmLD method with other existing mapping methods, e.g. the adjusted single-marker LD mapping and the SKAT_C, we performed extensive simulations under various scenarios. The simulation results demonstrated that the mmLD has the same or higher power than the existing methods, while maintaining the correct type I errors. We further applied the mmLD to a public data set, 'GAW17', to investigate its applicability. The result showed the good performance of mmLD. We concluded that this improved mmLD method will be useful for future genome-wide association studies and genetic association analyses. PMID- 26966283 TI - Effect of lossy compression of quality scores on variant calling. AB - Recent advancements in sequencing technology have led to a drastic reduction in genome sequencing costs. This development has generated an unprecedented amount of data that must be stored, processed, and communicated. To facilitate this effort, compression of genomic files has been proposed. Specifically, lossy compression of quality scores is emerging as a natural candidate for reducing the growing costs of storage. A main goal of performing DNA sequencing in population studies and clinical settings is to identify genetic variation. Though the field agrees that smaller files are advantageous, the cost of lossy compression, in terms of variant discovery, is unclear.Bioinformatic algorithms to identify SNPs and INDELs use base quality score information; here, we evaluate the effect of lossy compression of quality scores on SNP and INDEL detection. Specifically, we investigate how the output of the variant caller when using the original data differs from that obtained when quality scores are replaced by those generated by a lossy compressor. Using gold standard genomic datasets and simulated data, we are able to analyze how accurate the output of the variant calling is, both for the original data and that previously lossily compressed. We show that lossy compression can significantly alleviate the storage while maintaining variant calling performance comparable to that with the original data. Further, in some cases lossy compression can lead to variant calling performance that is superior to that using the original file. We envisage our findings and framework serving as a benchmark in future development and analyses of lossy genomic data compressors. PMID- 26966284 TI - GeneXpert MTB/Rif to Diagnose Tuberculous Meningitis: Perhaps the First Test but not the Last. AB - Tuberculous meningitis (TBM) is the most severe form of tuberculous with substantial mortality. In May 2015, 54 researchers from 10 countries met in Da Lat, Vietnam, to discuss advances in TBM. Among the attendees were researchers involved in pivotal studies on the use of Xpert MTB/Rif for TBM diagnosis. Attendees discussed the 2014 World Health Organization strong recommendation favoring the use of Xpert "in preference to conventional microscopy and culture as the initial diagnostic test for cerebrospinal fluid (CSF) if the sample volume is low or if additional specimens cannot be obtained to make a quick diagnosis." Attendees were concerned that the limitations of Xpert testing for TBM are not emphasized. Clear guidance is needed for the investigational pathway for TBM, including recommendations on the diagnostic package of investigations, which does not stop with Xpert testing. Second, emphasis on the large CSF volumes (ideally 8 10 mL) needed for Xpert testing is required. Guidelines should also emphasize that TBM is a medical emergency and early treatment reduces mortality. PMID- 26966285 TI - Race, disability, and grade: Social relationships in children with autism spectrum disorders. AB - Race is associated with social relationships among typically developing children; however, studies rarely examine the impact of race on social outcomes for children with autism spectrum disorder. This study examined how race (African American, Latino, Asian, or White) in conjunction with disability status (autism spectrum disorders or typically developing) and grade (grades K-2 or 3-5) affects friendships and social networks. The sample comprises 85 children with autism spectrum disorders and 85 typically developing controls matched on race, gender, age/grade, and classroom (wherever possible). Race, disability, and grade each had an independent effect on friendship nominations, and there was an interaction among the three variables. Specifically, children with autism spectrum disorders who were African American or Latino in the upper elementary grades received fewer friendship nominations than typically developing White children in the lower elementary grades. Only the presence of autism spectrum disorders was associated with social network centrality. Our results also suggested that Latino children with autism spectrum disorders in the upper elementary grades were at the highest risk of social isolation. Implications for re-conceptualizing social skills interventions are discussed. PMID- 26966287 TI - Association Between Left Atrial Stiffness Index and Atrial Fibrillation Recurrence in Patients Undergoing Left Atrial Ablation. AB - BACKGROUND: Atrial fibrillation (AF) is associated with significant abnormalities of left atrial (LA) systolic and diastolic function. This study describes a novel measure, LA stiffness index, that estimates LA diastolic function and its association with clinical outcomes of catheter ablation. METHODS AND RESULTS: A total of 219 AF patients referred for ablation (59% paroxysmal, mean CHA2DS2VASc score 1.7 +/- 1.4) were enrolled. Atrial pressure and volume loops were prepared from invasive pressure measures and cardiac magnetic resonance imaging volumetric data during sinus rhythm for all patients. An LA stiffness index was created, defined by the ratio of change in LA pressure to volume during passive filling of LA (DeltaP/DeltaV). Patients were followed prospectively. Mean LA stiffness index for AF patients was 0.6 +/- 0.5 mm Hg/mL (paroxysmal AF 0.51 +/- 0.4 and persistent AF 0.73 +/- 0.6; P < 0.001). Linear regression analysis showed a rise in the stiffness index with age, increasing at a rate of 0.02 mm Hg/mL per year (P < 0.001). The LA stiffness index was higher in patients with previous LA ablation(s) for AF (0.51 +/- 0.35 versus 0.83 +/- 0.70; P < 0.001). Forty of 160 patients had recurrence after AF ablation with a mean follow-up of 10.4 +/- 7.6 months. Patients with recurrence had higher stiffness index than those without recurrence (0.83 +/- 0.46 versus 0.40 +/- 0.22; P < 0.001). CONCLUSIONS: LA stiffness index, a novel measure to assess LA diastolic function, increases with age and is higher in persistent AF and in the setting of repeat AF ablation. Greater LA stiffness index was independently associated with recurrence of AF after LA ablation. PMID- 26966286 TI - Ablation of Persistent Atrial Fibrillation Targeting Low-Voltage Areas With Selective Activation Characteristics. AB - BACKGROUND: Complex-fractionated atrial electrograms and atrial fibrosis are associated with maintenance of persistent atrial fibrillation (AF). We hypothesized that pulmonary vein isolation (PVI) plus ablation of selective atrial low-voltage sites may be more successful than PVI only. METHODS AND RESULTS: A total of 85 consecutive patients with persistent AF underwent high density atrial voltage mapping, PVI, and ablation at low-voltage areas (LVA < 0.5 mV in AF) associated with electric activity lasting > 70% of AF cycle length on a single electrode (fractionated activity) or multiple electrodes around the circumferential mapping catheter (rotational activity) or discrete rapid local activity (group I). The procedural end point was AF termination. Arrhythmia freedom was compared with a control group (66 patients) undergoing PVI only (group II). PVI alone was performed in 23 of 85 (27%) patients of group I with low amount (< 10% of left atrial surface area) of atrial low voltage. Selective atrial ablation in addition to PVI was performed in 62 patients with termination of AF in 45 (73%) after 11 +/- 9 minutes radiofrequency delivery. AF-termination sites colocalized within LVA in 80% and at border zones in 20%. Single-procedural arrhythmia freedom at 13 months median follow-up was achieved in 59 of 85 (69%) patients in group I, which was significantly higher than the matched control group (31/66 [47%], P < 0.001). There was no significant difference in the success rate of patients in group I with a low amount of low voltage undergoing PVI only and patients requiring PVI+selective low-voltage ablation (P = 0.42). CONCLUSIONS: Ablation of sites with distinct activation characteristics within/at borderzones of LVA in addition to PVI is more effective than conventional PVI only strategy for persistent AF. PVI only seems to be sufficient to treat patients with left atrial low voltage < 10%. PMID- 26966289 TI - The Stiff Left Atrium Is to Atrial Fibrillation as the Stiff Left Ventricle Is to Diastolic Heart Failure. PMID- 26966290 TI - 2016 manifestos online. PMID- 26966291 TI - RCVS Council votes for governance reform. PMID- 26966292 TI - 'Animal health law' adopted. PMID- 26966288 TI - Long-Term Clinical Outcome of Arrhythmogenic Right Ventricular Cardiomyopathy in Individuals With a p.S358L Mutation in TMEM43 Following Implantable Cardioverter Defibrillator Therapy. AB - BACKGROUND: We previously showed a survival benefit of the implantable cardioverter defibrillator (ICD) in males with arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43. We present long-term data (median follow-up 8.5 years) after ICD for primary (PP) and secondary prophylaxis in males and females, determine whether ICD discharges for ventricular tachycardia/ventricular fibrillation were equivalent to an aborted death, and assess relevant clinical predictors. METHODS AND RESULTS: We studied 24 multiplex families segregating an autosomal dominant p.S358L mutation in TMEM43. We compared survival in 148 mutation carriers with an ICD to 148 controls matched for age, sex, disease status, and family. Of 80 male mutation carriers with ICDs (median age at implantation 31 years), 61 (76%) were for PP; of 68 females (median age at implantation 43 years), 66 (97%) were for PP. In males, irrespective of indication, survival was better in the ICD groups compared with control groups (relative risk 9.3 [95% confidence interval 3.3-26] for PP and 9.7 [95% confidence interval 3.2-29.6] for secondary prophylaxis). For PP females, the relative risk was 3.6 (95% confidence interval 1.3-9.5). ICD discharge-free survival for ventricular tachycardia/ventricular fibrillation >= 240 beats per minute was equivalent to the control survival rate. Ectopy (>= 1000 premature ventricular complexes/24 hours) was the only independent clinical predictor of ICD discharge in males, and no predictor was identified in females. CONCLUSIONS: ICD therapy is indicated for PP in postpubertal males and in females >= 30 years with the p.S358L TMEM43 mutation. ICD termination of rapid ventricular tachycardia/ventricular fibrillation can reasonably be considered an aborted death. PMID- 26966293 TI - Testing for BVD virus becomes compulsory in Northern Ireland. PMID- 26966294 TI - FSA reports further progress in reducing Campylobacter contamination. PMID- 26966295 TI - Defra to consult on tackling TB in non-bovine animals. PMID- 26966296 TI - Animal medicines body warns of the dangers of 'humanising' pets. PMID- 26966297 TI - RVC to deliver Emirati scholarship programme. PMID- 26966298 TI - Farriers present their research and hone their speaking skills. PMID- 26966299 TI - Interactive maps to help forecast the risk of nematodirosis in lambs. PMID- 26966300 TI - Bloggers aim to encourage engagement with CPD. PMID- 26966302 TI - Vets with Horsepower to head to South Africa. PMID- 26966301 TI - New masters degree in bioveterinary science. PMID- 26966303 TI - Focus on equine practice at student symposium. AB - Veterinary students with a particular interest in equine medicine and surgery gathered at Nottingham vet school recently to further their knowledge and skills in these areas. Jordan Sinclair, editor of the Journal of the Association of Veterinary Students, reports. PMID- 26966304 TI - Measuring progesterone from the milk line. PMID- 26966306 TI - Importance of ketamine. PMID- 26966305 TI - Transmission routes of African swine fever virus to domestic pigs: current knowledge and future research directions. AB - African swine fever (ASF) is a major threat to the pig industry in Europe. Since 2007, ASF outbreaks have been ongoing in the Caucasus, Eastern Europe and the Baltic countries, causing severe economic losses for many pig farmers and pork producers. In addition, the number of ASF cases in wild boar populations has dramatically increased over the past few years. Evidence supports direct contact with infectious domestic pigs and wild boars, and consumption of contaminated feed, as the main transmission routes of ASF virus (ASFV) to domestic pigs. However, significant knowledge gaps highlight the urgent need for research to investigate the dynamics of indirect transmission via the environment, the minimal infective doses for contaminated feed ingestion, the probability of effective contacts between infectious wild boars and domestic pigs, the potential for recovered animals to become carriers and a reservoir for transmission, the potential virus persistence within wild boar populations and the influence of human behaviour for the spread of ASFV. This will provide an improved scientific basis to optimise current interventions and develop new tools and strategies to reduce the risk of ASFV transmission to domestic pigs. PMID- 26966307 TI - Nematodirus lamae identified in an alpaca in the UK. PMID- 26966308 TI - Biocidal properties of copper. PMID- 26966309 TI - Help in crisis. PMID- 26966316 TI - Never a dull day as a vet working in public health. AB - Jason Aldiss entered vet school in New Zealand knowing that he didn't want to go into general practice. Despite that, after qualifying he did spend two years in large animal practice. Having taken a keen interest in the role vets can play in society, he came to the UK to become an Official Veterinarian. PMID- 26966317 TI - Second-year student diary. AB - Rosie Perrett can't believe it's nearly Easter already but is looking forward to lambing. In the meantime she has been learning pharmacology and communication skills. PMID- 26966318 TI - Genetic epidemiology of migraine and depression. AB - BACKGROUND: Migraine and major depressive disorder (commonly referred to as depression) are both common disorders with a significant impact on society. Studies in both clinical and community-based settings have demonstrated a strong relationship between migraine and depression. In addition to complicating the diagnosis, depression that is comorbid with migraine may lower treatment adherence, increase risk of medication overuse and is associated with migraine chronification, thus leading to higher direct and indirect costs and poorer health-related outcomes with increased disability. AIM: The aim of this review is to summarise the current knowledge on the genetic epidemiology of migraine and depression and the possible biological mechanisms underlying their comorbidity. METHODS: We present a narrative review reporting on the current literature. RESULTS AND CONCLUSIONS: Epidemiological findings indicate that there is a bidirectional relationship between migraine and depression, with one disorder increasing the risk for the other and vice versa, suggesting shared biological mechanisms. Twin and family studies indicate that this bidirectional relationship can be explained, at least partly, by shared underlying genetically determined disease mechanisms. Although no genes have been robustly associated with the aetiology of both migraine and depression, genes from serotonergic, dopaminergic and GABAergic systems together with variants in the MTHFR and BDNF genes remain strong candidates. PMID- 26966319 TI - Cold Water Swimming Beneficially Modulates Insulin Sensitivity in Middle-Aged Individuals. AB - We determined whether cold water swimming for six consecutive months results in adaptive changes in body composition and insulin sensitivity. Thirty healthy subjects aged 50.2 +/- 9.4 years were exposed to cold water at least twice a week. Body composition was determined and serum glucose and insulin served to calculate beta-cell function, insulin sensitivity, and resistance using HOMA2. Compared with control subjects, swimmers were overweight, and had greater percent body fat and beta cell function. Women had lower values of BMI, fat free mass, muscle mass, visceral adipose tissue level, and greater percent body fat than men. Increased insulin sensitivity and decreased insulin secretion and resistance from beginning to middle of swim season was observed in females and in lean subjects. Findings suggest that men and women differ in regard to body composition and response to repeated cold exposure. Cold water swimming may beneficially modulate insulin sensitivity in cold acclimated lean swimmers. PMID- 26966320 TI - Searching for resilience: addressing the impacts of changing disturbance regimes on forest ecosystem services. AB - 1. The provisioning of ecosystem services to society is increasingly under pressure from global change. Changing disturbance regimes are of particular concern in this context due to their high potential impact on ecosystem structure, function and composition. Resilience-based stewardship is advocated to address these changes in ecosystem management, but its operational implementation has remained challenging. 2. We review observed and expected changes in disturbance regimes and their potential impacts on provisioning, regulating, cultural and supporting ecosystem services, concentrating on temperate and boreal forests. Subsequently, we focus on resilience as a powerful concept to quantify and address these changes and their impacts, and present an approach towards its operational application using established methods from disturbance ecology. 3. We suggest using the range of variability concept - characterizing and bounding the long-term behaviour of ecosystems - to locate and delineate the basins of attraction of a system. System recovery in relation to its range of variability can be used to measure resilience of ecosystems, allowing inferences on both engineering resilience (recovery rate) and monitoring for regime shifts (directionality of recovery trajectory). 4. It is important to consider the dynamic nature of these properties in ecosystem analysis and management decision making, as both disturbance processes and mechanisms of resilience will be subject to changes in the future. Furthermore, because ecosystem services are at the interface between natural and human systems, the social dimension of resilience (social adaptive capacity and range of variability) requires consideration in responding to changing disturbance regimes in forests. 5.Synthesis and applications. Based on examples from temperate and boreal forests we synthesize principles and pathways for fostering resilience to changing disturbance regimes in ecosystem management. We conclude that future work should focus on testing and implementing these pathways in different contexts to make ecosystem services provisioning more robust to changing disturbance regimes and advance our understanding of how to cope with change and uncertainty in ecosystem management. PMID- 26966322 TI - Data sharing in public health emergencies: a call to researchers. PMID- 26966323 TI - Monitoring adolescent sexual and reproductive health. PMID- 26966325 TI - Meeting the need for surgery. AB - Surgical provision falls far short of what is needed in developing countries, but recent initiatives aim to correct this deficit. Carolyn Mahoney and Fiona Fleck report. PMID- 26966326 TI - Brazil's scientists scramble to solve the Zika puzzle. AB - The World Health Organization has declared the recent leap in the number of microcephaly cases and their suspected association with Zika virus a public health emergency of international concern. Ana Bispo tells Andreia Azevedo Soares why Brazil should have some scientific answers in coming months. PMID- 26966327 TI - Care services for elderly people with dementia in rural China: a case study. AB - OBJECTIVE: To determine the state of the health and supportive services available to elderly people with dementia - and their families - in rural Lanxi county, in the province of Zhejiang, China. METHODS: In November 2014 and January 2015, we interviewed 14 key informants on dementia care face-to-face, using a semi structured questionnaire. The informants included three rural physicians, an urban geriatrician, seven directors of institutions for the care of the elderly and three officials of the civil affairs bureau. We also completed in-depth interviews with five family caregivers of elderly people with dementia. FINDINGS: The interviewees indicated that there was a lack of specialized services designed specifically to address the needs of individuals with dementia and their family members. Non-psychiatric medical services and the available facilities for long term care appeared to be ill-equipped to manage these needs. They lacked both clinical staff and standardized, evidence-based practices for the diagnosis, care, treatment and rehabilitation of patients with dementia. As care facilities often refused to admit elderly people with dementia, families were generally forced to care for elderly relatives with dementia at home. CONCLUSION: In Lanxi county - and probably in much of rural China - more public resources are needed to support family caregivers and to improve the capacity of care facilities for the elderly to care for individuals with dementia. PMID- 26966328 TI - An assessment of GLOBOCAN methods for deriving national estimates of cancer incidence. AB - OBJECTIVE: To assess the validity of the GLOBOCAN methods for deriving national estimates of cancer incidence. METHODS: We obtained incidence and mortality data from Norway by region, year of diagnosis, cancer site, sex and 5-year age group for the period 1983-2012 from the NORDCAN database. Estimates for the year 2010 were derived using nine different methods from GLOBOCAN. These included the projection of national historical rates, the use of regional proxies and the combination of national mortality data with mortality to incidence ratios or relative survival proportions. We then compared the national estimates with recorded cancer incidence data. FINDINGS: Differences between the estimates derived using different methods varied by cancer site and sex. Methods based on projections performed better where major changes in recent trends were absent. Methods based on mortality data performed less well for cancers associated with small numbers of deaths and for cancers detectable by screening. In countries with longstanding cancer registries of high quality, regional-based, or trends based incidence estimates perform reasonably well in comparison with recorded incidence. CONCLUSION: Although the performance of the GLOBOCAN methods varies by cancer site and sex in this study, the results emphasize a need for more high quality population-based cancer registries - either regional or, where practical and feasible, national registries - to describe cancer patterns and trends for planning cancer control priorities. PMID- 26966329 TI - Nutritional quality of diet and academic performance in Chilean students. AB - OBJECTIVE: To explore associations between the nutritional quality of diet at age 16 years and academic performance in students from Santiago, Chile. METHODS: We assessed the nutritional quality of diet, using a validated food frequency questionnaire, in 395 students aged 16.8 +/- 0.5 years. Depending on the amount of saturated fat, fibre, sugar and salt in the foods, diet was categorized as unhealthy, fair or healthy. Academic performance was assessed using high school grade-point average (GPA) and tests for college admission in language and mathematics. Academic results on or above the 75th percentile in our sample were considered good academic performance. We tested associations between nutritional quality of diet and good academic performance using logistic regression models. We considered sociodemographic, educational and body-mass index (BMI) factors as potential confounders. FINDINGS: After controlling for potential confounding factors, an unhealthy diet at age 16 years was associated with reduced academic performance. Compared to participants with healthy diets, those with unhealthy diets were significantly less likely to perform well based on language tests (odds ratio, OR: 0.42; 95% confidence interval, CI: 0.18-0.98) mathematics tests (OR: 0.35; 95% CI: 0.15-0.82) or GPA (OR: 0.22; 95% CI: 0.09-0.56). CONCLUSION: In our sample, excessive consumption of energy-dense, low-fibre, high-fat foods at age 16 years was associated with reduced academic performance. PMID- 26966330 TI - Catastrophic health expenditure on acute coronary events in Asia: a prospective study. AB - OBJECTIVE: To estimate out-of-pocket costs and the incidence of catastrophic health expenditure in people admitted to hospital with acute coronary syndromes in Asia. METHODS: Participants were enrolled between June 2011 and May 2012 into this observational study in China, India, Malaysia, Republic of Korea, Singapore, Thailand and Viet Nam. Sites were required to enrol a minimum of 10 consecutive participants who had been hospitalized for an acute coronary syndrome. Catastrophic health expenditure was defined as out-of-pocket costs of initial hospitalization > 30% of annual baseline household income, and it was assessed six weeks after discharge. We assessed associations between health expenditure and age, sex, diagnosis of the index coronary event and health insurance status of the participant, using logistic regression models. FINDINGS: Of 12,922 participants, 9370 (73%) had complete data on expenditure. The mean out-of-pocket cost was 3237 United States dollars. Catastrophic health expenditure was reported by 66% (1984/3007) of those without insurance versus 52% (3296/6366) of those with health insurance (P < 0.05). The occurrence of catastrophic expenditure ranged from 80% (1055/1327) in uninsured and 56% (3212/5692) of insured participants in China, to 0% (0/41) in Malaysia. CONCLUSION: Large variation exists across Asia in catastrophic health expenditure resulting from hospitalization for acute coronary syndromes. While insurance offers some protection, substantial numbers of people with health insurance still incur financial catastrophe. PMID- 26966331 TI - Size and distribution of the global volume of surgery in 2012. AB - OBJECTIVE: To estimate global surgical volume in 2012 and compare it with estimates from 2004. METHODS: For the 194 Member States of the World Health Organization, we searched PubMed for studies and contacted key informants for reports on surgical volumes between 2005 and 2012. We obtained data on population and total health expenditure per capita for 2012 and categorized Member States as very-low, low, middle and high expenditure. Data on caesarean delivery were obtained from validated statistical reports. For Member States without recorded surgical data, we estimated volumes by multiple imputation using data on total health expenditure. We estimated caesarean deliveries as a proportion of all surgery. FINDINGS: We identified 66 Member States reporting surgical data. We estimated that 312.9 million operations (95% confidence interval, CI: 266.2 359.5) took place in 2012, an increase from the 2004 estimate of 226.4 million operations. Only 6.3% (95% CI: 1.7-22.9) and 23.1% (95% CI: 14.8-36.7) of operations took place in very-low- and low-expenditure Member States representing 36.8% (2573 million people) and 34.2% (2393 million people) of the global population of 7001 million people, respectively. Caesarean deliveries comprised 29.6% (5.8/19.6 million operations; 95% CI: 9.7-91.7) of the total surgical volume in very-low-expenditure Member States, but only 2.7% (5.1/187.0 million operations; 95% CI: 2.2-3.4) in high-expenditure Member States. CONCLUSION: Surgical volume is large and growing, with caesarean delivery comprising nearly a third of operations in most resource-poor settings. Nonetheless, there remains disparity in the provision of surgical services globally. PMID- 26966333 TI - Household air pollution and the sustainable development goals. AB - Globally, 41% of households, over 2.8 billion people, rely on solid fuels (coal and biomass) for cooking and heating. In developing countries in Asia and sub Saharan Africa where these fuels are predominantly used, women who are customarily responsible for cooking, and their young children, are most exposed to the resulting air pollution. Solid fuels are still in widespread use and it appears that intervention efforts are not keeping pace with population growth in developing countries. Here we pinpoint the challenges and identify opportunities for addressing household air pollution while mitigating global climate change and promoting the sustainable development goals. We recommend the following actions: implementation of the WHO indoor air quality guidelines on household fuel combustion; effective promotion and dissemination of improved cookstoves through formation of country alliances for clean cookstoves; expansion of liquefied petroleum gas production facilities and distribution networks; harnessing renewable energy potential; promotion of biogas production at both household and community level; ensuring improved ventilation of homes through education and enforcement of building standards; and exploiting opportunities in the health and other sectors for changing health-damaging cooking behaviour. PMID- 26966332 TI - Psychosocial effects of an Ebola outbreak at individual, community and international levels. AB - The 2013-2016 Ebola outbreak in Guinea, Liberia and Sierra Leone was the worst in history with over 28,000 cases and 11,000 deaths. Here we examine the psychosocial consequences of the epidemic. Ebola is a traumatic illness both in terms of symptom severity and mortality rates. Those affected are likely to experience psychological effects due to the traumatic course of the infection, fear of death and experience of witnessing others dying. Survivors can also experience psychosocial consequences due to feelings of shame or guilt (e.g. from transmitting infection to others) and stigmatization or blame from their communities. At the community level, a cyclical pattern of fear occurs, with a loss of trust in health services and stigma, resulting in disruptions of community interactions and community break down. Health systems in affected countries were severely disrupted and overstretched by the outbreak and their capacities were significantly reduced as almost 900 health-care workers were infected with Ebola and more than 500 died. The outbreak resulted in an increased need for health services, reduced quality of life and economic productivity and social system break down. It is essential that the global response to the outbreak considers both acute and long-term psychosocial needs of individuals and communities. Response efforts should involve communities to address psychosocial need, to rebuild health systems and trust and to limit stigma. The severity of this epidemic and its long-lasting repercussions should spur investment in and development of health systems. PMID- 26966335 TI - A new global agenda for nutrition and health: the importance of agriculture and food systems. PMID- 26966336 TI - Disability, noncommunicable disease and health information. PMID- 26966334 TI - Providing HIV-related services in China for men who have sex with men. AB - PROBLEM: In China, human immunodeficiency virus (HIV) care provided by community based organizations and the public sector are not well integrated. APPROACH: A community-based organization and experts from the Guangzhou Center for Disease Control and Prevention developed internet-based services for men who have sex with men, in Guangzhou, China. The internet services were linked to clinical services offering HIV testing and care. LOCAL SETTING: The expanding HIV epidemic among men who have sex with men is a public health problem in China. HIV control and prevention measures are implemented primarily through the public system. Only a limited number of community organizations are involved in providing HIV services. RELEVANT CHANGES: The programme integrated community and public sector HIV services including health education, online HIV risk assessment, on-site HIV counselling and testing, partner notification, psychosocial care and support, counting of CD4+ T-lymphocytes and treatment guidance. LESSONS LEARNT: The internet can facilitate HIV prevention among a subset of men who have sex with men by enhancing awareness, service uptake, retention in care and adherence to treatment. Collaboration between the public sector and the community group promoted acceptance by the target population. Task sharing by community groups can increase access of this high-risk group to available HIV-related services. PMID- 26966337 TI - Differences in coda voicing trigger changes in gestural timing: A test case from the American English diphthong /ai/. AB - We investigate the hypothesis that duration and spectral differences in vowels before voiceless versus voiced codas originate from a single source, namely the reorganization of articulatory gestures relative to one another in time. As a test case, we examine the American English diphthong /ai/, in which the acoustic manifestations of the nucleus /a/ and offglide /i/ gestures are relatively easy to identify, and we use the ratio of nucleus-to-offglide duration as an index of the temporal distance between these gestures. Experiment 1 demonstrates that, in production, the ratio is smaller before voiceless codas than before voiced codas; this effect is consistent across speakers as well as changes in speech rate and phrasal position. Experiment 2 demonstrates that, in perception, diphthongs with contextually incongruent ratios delay listeners' identification of target words containing voiceless codas, even when the other durational and spectral correlates of voicing remain intact. This, we argue, is evidence that listeners are sensitive to the gestural origins of voicing differences. Both sets of results support the idea that the voicing contrast triggers changes in timing: gestures are close to one another in time before voiceless codas, but separated from one another before voiced codas. PMID- 26966338 TI - Warmth of the Welcome: Attitudes toward Immigrants and Immigration Policy. AB - Natives' attitudes toward immigrants and immigration policy are important factors in the context of reception of immigrants since they contribute to a warm or chilly welcome, which potentially shapes immigrant and ethnic identities and inter-group relations. Public opinion polls show a recent "warming" of Americans' traditional ambivalence about immigration. Empirical research on attitudes toward immigrants and racial groups formed by recent waves of immigrants resonate with the dynamic nature of Blumer's (1958) theory of prejudice as a sense of relative group position. To better understand this dynamism, research that intentionally contrasts study sites on conflict and contact conditions and the presence of absence of symbolic politics, as well as research with different native-born racial and ethnic groups, would reveal a broader range of natives' attitude formation processes and the role they play in immigrant reception. PMID- 26966340 TI - Hydroxytyrosol Protects against Myocardial Ischemia/Reperfusion Injury through a PI3K/Akt-Dependent Mechanism. AB - OBJECTIVE: To investigate the effects and mechanisms of hydroxytyrosol (HT) during the pathogenesis of myocardial ischemia reperfusion (I/R) in rat hearts. METHODS: The rats were randomized into five groups: sham group, I/R group, HT+I/R group, HT+LY294002+I/R group, and LY+I/R group. Myocardial infarct size, markers of oxidative stress, extent of myocardial apoptosis, echocardiographically assessed cardiac function, and expression of Akt and GSK 3beta were measured in each group. RESULTS: Prereperfusion administration of HT was associated with a significantly smaller area of myocardial infarction and remarkably decreased level of myocardial apoptosis and necrosis, as evidenced by a lower apoptotic index, reduced cleaved caspase-3, and the serum activities of lactate dehydrogenase and creatinine kinase MB. Moreover, HT also attenuated the impairment of cardiac systolic function. However, cotreatment with LY294002 and HT completely abolished the above cardioprotective effects of HT. A subsequent mechanistic study revealed that the cardioprotective effects of HT during the process of I/R of the myocardium were dependent on the activation of the Akt/GSK3beta pathway. CONCLUSION: Pretreatment with HT may have antiapoptotic and cardioprotective effects against myocardial I/R injury, and these effects seem to be related to the activation of the Akt/GSK3beta pathway in the myocardium. PMID- 26966339 TI - Host genome polymorphisms and tuberculosis infection: What we have to say? AB - Several epidemiology studies suggest that host genetic factors play important roles in susceptibility, protection and progression of tuberculosis infection. Here we have reviewed the implications of some genetic polymorphisms in pathways related to tuberculosis susceptibility, severity and development. Large case control studies examining single-nucleotide polymorphisms (SNPs) in genes have been performed in tuberculosis patients in some countries. Polymorphisms in natural resistance-associated macrophage protein 1 (NRAMP1), toll-like receptor 2 (TLR2), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), interleukin-1 receptor antagonist (IL-1RA), IL-10, vitamin D receptor (VDR), dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN), monocyte chemoattractant protein-1 (MCP-1), nucleotide oligomerization binding domain 2 (NOD2), interferon-gamma (IFN-gamma), inducible nitric oxide synthase (iNOS), mannose-binding lectin (MBL) and surfactant proteins A (SP-A) have been reviewed. These genes have been variably associated with tuberculosis infection and there is strong evidence indicating that host genetic factors play critical roles in tuberculosis susceptibility, severity and development. PMID- 26966341 TI - Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment. AB - Distinct tumor microenvironment forms in each progression step of cancer and has diverse capacities to induce both adverse and beneficial consequences for tumorigenesis. It is now known that immune cells can be activated to favor tumor growth and progression, most probably influenced by the tumor microenvironment. Tumor-associated macrophages and tumor-associated neutrophils can exert protumoral functions, enhancing tumor cell invasion and metastasis, angiogenesis, and extracellular matrix remodeling, while inhibiting the antitumoral immune surveillance. Considering that neutrophils in inflammatory environments recruit macrophages and that recruited macrophages affect neutrophil functions, there may be various degrees of interaction between tumor-associated macrophages and tumor associated neutrophils. Platelets also play an important role in the recruitment and regulation of monocytic and granulocytic cells in the tumor tissues, suggesting that platelet function may be essential for generation of tumor associated macrophages and tumor-associated neutrophils. In this review, we will explore the biology of tumor-associated macrophages and tumor-associated neutrophils and their possible interactions in the tumor microenvironment. Special attention will be given to the recruitment and activation of these tumor associated cells and to the roles they play in maintenance of the tumor microenvironment and progression of tumors. PMID- 26966343 TI - A Latent Profile Analysis of Latino Parenting: The Infusion of Cultural Values on Family Conflict. AB - The purpose of the present study was to (a) examine how acculturation and social support inform Latinos' parenting behaviors, controlling for gender and education; (b) describe parenting styles among Latino immigrants while accounting for cultural elements; and (c) test how these parenting styles are associated with family conflict. A 3 step latent profile analysis with the sample (N = 489) revealed best fit with a 4 profile model (n = 410) of parenting: family parenting (n = 268, 65%), child-centered parenting (n = 68, 17%), moderate parenting (n = 60, 15%), and disciplinarian parenting (n = 14, 3%). Parents' gender, acculturation, and social support significantly predicted profile membership. Disciplinarian and moderate parenting were associated with more family conflict. Recommendations include integrating culturally based parenting practices as a critical element to family interventions to minimize conflict and promote positive youth development. PMID- 26966344 TI - Testing the Validity of a Protocol to Screen for Spiritual Struggle among Parents of Children with Cystic Fibrosis. AB - Spirituality is important to many Americans and is used to cope with adverse events. Some forms of spiritual coping are maladaptive or troubling, and are known as negative spiritual coping or spiritual struggle. These forms of spirituality are often associated with poorer physical and mental health outcomes. Thus, in clinical contexts there is a need to identify persons who may be experiencing spiritual struggle and, if indicated, offer spiritual care that may address that struggle. Twenty-two parents of children with cystic fibrosis (CF) completed semi-structured interviews and questionnaires exploring spirituality's role in their child's illness. Interviews included oral administration of a protocol to screen for spiritual struggle. The parents also completed the negative religious coping subscale of the Brief RCOPE, a commonly used measure of spiritual struggle. Descriptive statistics were obtained. The screening protocol identified 18% of the parents as potentially having spiritual struggle. Thirty-two percent had negative religious coping scores suggestive of spiritual struggle. Comparison of results with both measures found the screening protocol had good specificity (87%) but relatively low sensitivity (29%). Using either measure, indications of spiritual struggle were associated with higher levels of depressive symptoms. The screener's administration was acceptable and feasible. The low sensitivity may be due in part to differences between the focus of the screener and that of the negative religious coping subscale, which focuses on struggle with the Divine. Further work is needed to establish the best approach to screening for spiritual struggle. PMID- 26966345 TI - Acinetobacter baumannii: An Emerging and Important Pathogen. AB - OBJECTIVE: To review the clinical significance, management, and control of Acinetobacter infections. METHODS: Literature review. RESULTS: Acinetobacter infections have become a major cause of hospital-acquired infections worldwide. Acinetobacter is noted for its ability to survive for long periods on hospital surfaces and equipment, its predilection to develop resistance to multiple antibiotics, its affinity to cause serious infections in critically ill patients, and many well described outbreaks attributable to contamination of a common source. The crude ICU mortality is approximately 40%. Rigorous antibiotic stewardship and infection control measures are critical to prevent the spread of multidrug-resistant Acinetobacter infections. There is also a pressing need for new therapeutic options. CONCLUSION: Acinetobacter is an emerging pathogen of increasing significance. PMID- 26966346 TI - Introduction to the Special Issue: Advancing the State-of-the-Science in Reading Research through Modeling. AB - Reading research is increasingly a multi-disciplinary endeavor involving more complex, team-based science approaches. These approaches offer the potential of capturing the complexity of reading development, the emergence of individual differences in reading performance over time, how these differences relate to the development of reading difficulties and disability, and more fully understanding the nature of skilled reading in adults. This special issue focuses on the potential opportunities and insights that early and richly integrated advanced statistical and computational modeling approaches can provide to our foundational (and translational) understanding of reading. The issue explores how computational and statistical modeling, using both observed and simulated data, can serve as a contact point among research domains and topics, complement other data sources and critically provide analytic advantages over current approaches. PMID- 26966342 TI - Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential. AB - Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cell processes. It is produced by the phosphorylation of sphingosine by sphingosine kinases (SphKs) and exported out of cells via transporters such as spinster homolog 2 (Spns2). S1P regulates diverse physiological processes by binding to specific G protein-binding receptors, S1P receptors (S1PRs) 1-5, through a process coined as "inside-out signaling." The S1P concentration gradient between various tissues promotes S1PR1-dependent migration of T cells from secondary lymphoid organs into the lymphatic and blood circulation. S1P suppresses T cell egress from and promotes retention in inflamed peripheral tissues. S1PR1 in T and B cells as well as Spns2 in endothelial cells contributes to lymphocyte trafficking. FTY720 (Fingolimod) is a functional antagonist of S1PRs that induces systemic lymphopenia by suppression of lymphocyte egress from lymphoid organs. In this review, we summarize previous findings and new discoveries about the importance of S1P and S1PR signaling in the recruitment of immune cells and lymphocyte retention in inflamed tissues. We also discuss the role of S1P-S1PR1 axis in inflammatory diseases and wound healing. PMID- 26966347 TI - Detection of Productively Rearranged TcR-alpha V-J Sequences in TCGA Exome Files: Implications for Tumor Immunoscoring and Recovery of Antitumor T-cells. AB - Tumor immunoscoring is rapidly becoming a universal parameter of prognosis, and T cells isolated from tumor masses are used for ex vivo amplification and readministration to patients to facilitate an antitumor immune response. We recently exploited the cancer genome atlas (TCGA) RNASeq data to assess T-cell receptor (TcR) expression and, in particular, discovered strong correlations between major histocompatibility class II (MHCII) and TcR-alpha constant region expression levels. In this article, we describe the results of searching TCGA exome files for TcR-alpha V-regions, followed by searching the V-region datasets for TcR-alpha-J regions. Both primary and metastatic breast cancer sample files contained recombined TcR-alpha V-J regions, ranging in read counts from 16-39, at the higher level. Among four such V-J rearrangements, three were productive rearrangements. Rearranged TcR-alpha V-J regions were also detected in TCGA bladder cancer, -lung cancer, and -ovarian cancer datasets, as well as exome files representing bladder cancer, in Moffitt Cancer Center patients. These results suggest that a direct search of commonly available, conventional exome files for rearranged TcR segments could play a role in more sophisticated immunoscoring or in identifying particular T-cell clones and TcRs directed against tumor antigens. PMID- 26966349 TI - Review of external ocular compression: clinical applications of the ocular pressure estimator. AB - PURPOSE: The authors have previously validated an Ocular Pressure Estimator (OPE) that can estimate the intraocular pressure (IOP) during external ocular compression (EOC). The authors now apply the OPE in clinical states where EOC is clinically important. The original work is described for two periods of risk: during sleep and during the digital ocular massage (DOM) maneuver used by surgeons after trabeculectomy to keep the operation functional. Other periods of risk for external ocular compression are then reviewed. METHODS: The first protocol estimated the IOP in the dependent eye during simulated sleep. Subjects had their IOPs initially measured in an upright-seated position, immediately upon assuming a right eye dependent side sleeping position (with nothing contacting the eye), and then 5 minutes later while still in this position. While maintaining this position, the fluid filled bladder of the OPE was then placed between the subject's closed eye and a pillow during simulated sleep. The IOP was continuously estimated in this position for 5 minutes. The subjects then had the IOP measured in both eyes in an upright-seated position. The second protocol determined if a larger vertical cup-to-disc ratio was more common on the side that patients reported they preferred to sleep on. The hypothesis was that chronic asymmetric, compression induced, elevations of IOP during sleep would be associated with otherwise unexplained asymmetry of the vertical cup-to-disc ratio. The third protocol assessed the IOP during DOM. The OPE was used to characterize the IOP produced during the DOM maneuver of five glaucoma surgeons. After this, 90 mmHg was chosen as a target pressure for DOM. The surgeons were then verbally coached during three additional compressions. After a 5-minute period, the surgeons were asked to reproduce this targeted IOP during subsequent compressions. RESULTS: The mean IOP during the "sleep session" was 22+/-5 mmHg (SEM). The mean peak pressure was 40+/-11 mmHg (SEM) and the mean trough pressure was 15+/-2 mmHg (SEM). There was a 78% agreement between the eye that was reported to be dependent during sleep and the eye with the larger vertical cup-to disc ratio, for eyes with at least a 0.10 cup-to-disc ratio difference, P=0.001, n=137. The OPE estimated an average induced IOP during typical DOM of 104+/-8 mmHg (SEM), with each compression having an average range of 17+/-3 mmHg (SEM). After coaching, and a 5-minute waiting period, the average induced IOP reduced to 95+/-3 mmHg (SEM) with a reduced average range of IOP to 11+/-1 mmHg. CONCLUSION: The OPE was successfully used to estimate the IOP while subjects experienced EOC during normal sleep postures. These EOC-induced elevations of IOP were considerable, and likely contribute to significant ocular pathology, not only for glaucoma, but for retinal vascular occlusive diseases, retinal vascular leakage, and the induction of the ocular-cardiac reflex in infants, as well. The correlation of a larger vertical cup-to-disc ratio in patients with a sleep posture preference suggests a causal relationship, since patients with other conditions known to be associated with cup-to disc ratio asymmetry were excluded from this study. The OPE is a useful device to teach DOM to surgeons and patients for home use. PMID- 26966348 TI - Brain Histamine N-Methyltransferase As a Possible Target of Treatment for Methamphetamine Overdose. AB - Stereotypical behaviors induced by methamphetamine (METH) overdose are one of the overt symptoms of METH abuse, which can be easily assessed in animal models. Currently, there is no successful treatment for METH overdose. There is increasing evidence that elevated levels of brain histamine can attenuate METH induced behavioral abnormalities, which might therefore constitute a novel therapeutic treatment for METH abuse and METH overdose. In mammals, histamine N methyltransferase (HMT) is the sole enzyme responsible for degrading histamine in the brain. Metoprine, one of the most potent HMT inhibitors, can cross the blood brain barrier and increase brain histamine levels by inhibiting HMT. Consequently, this compound can be a candidate for a prototype of drugs for the treatment of METH overdose. PMID- 26966351 TI - miR-125b acts as a tumor suppressor in chondrosarcoma cells by the sensitization to doxorubicin through direct targeting the ErbB2-regulated glucose metabolism. AB - Chondrosarcoma is the second most common type of primary bone malignancy in the United States after osteosarcoma. Surgical resections of these tumors are the only effective treatment to chondrosarcoma patients due to their resistance to conventional chemo- and radiotherapy. In this study, miR-125b was found to perform its tumor-suppressor function to inhibit glucose metabolism via the direct targeting of oncogene, ErbB2. We report miR-125b was downregulated in both chondrosarcoma patient samples and cell lines. The total 20 Asian chondrosarcoma patients showed significantly downregulated miR-125b expression compared with normal tissues. Meanwhile, miR-125 was downregulated in chondrosarcoma cells and doxorubicin resistant cells. Overexpression of miR-125 enhanced the sensitivity of both parental and doxorubicin resistant cells to doxorubicin through direct targeting on the ErbB2-mediated upregulation of glycolysis in chondrosarcoma cells. Moreover, restoration of the expression of ErbB2 and glucose metabolic enzymes in miR-125 pretransfected cells recovered the susceptibility to doxorubicin. Our study will provide a novel aspect on the overcoming chemoresistance in human chondrosarcoma cells and may help in the development of therapeutic strategies for the treatments of patients. PMID- 26966352 TI - Total saponin of Dioscoreae hypoglaucae rhizoma ameliorates streptozotocin induced diabetic nephropathy. AB - BACKGROUND: Diabetic nephropathy has become the most common cause of morbidity and mortality in diabetic patients. Therefore, there is an urgent need for more effective and safer drugs for use in this condition. PURPOSE: The aims of this study were to investigate the ameliorative effects of total saponin of Dioscoreae hypoglaucae rhizoma (TSD) on diabetic nephropathy and to explore the potential underlying mechanism(s). METHODS: Rats with streptozotocin-induced diabetes were orally treated with TSD at 40, 80, and 160 mg/kg/d for 12 weeks. At the end of the treatment, blood, urine, and kidneys were collected for biochemical and histological examination. RESULTS: The results demonstrated that TSD significantly decreased the fasting blood glucose, glycosylated hemoglobin, urinary protein, serum creatinine, and blood urea nitrogen levels in diabetic rats. The results of histological examinations showed that TSD ameliorated glomerular and tubular pathological changes in diabetic rats. Furthermore, TSD significantly prevented oxidative stress and reduced the renal levels of advanced glycation end products, transforming growth factor-beta1, connective tissue growth factor, and tumor necrosis factor-alpha. CONCLUSION: This study demonstrated the renoprotective effects of TSD in experimental diabetic nephropathy via a number of different mechanisms. PMID- 26966350 TI - A clinical prognostic scoring system for resectable gastric cancer to predict survival and benefit from paclitaxel- or oxaliplatin-based adjuvant chemotherapy. AB - BACKGROUND: Gastrectomy with D2 lymphadenectomy is a standard procedure of curative resection for gastric cancer (GC). The aim of this study was to develop a simple and reliable prognostic scoring system for GC treated with D2 gastrectomy combined with adjuvant chemotherapy. METHODS: A prognostic scoring system was established based on clinical and laboratory data from 579 patients with localized GC without distant metastasis treated with D2 gastrectomy and adjuvant chemotherapy. RESULTS: From the multivariate model for overall survival (OS), five factors were selected for the scoring system: >=50% metastatic lymph node rate, positive lymphovascular invasion, pathologic TNM Stage II or III, >=5 ng/mL preoperative carcinoembryonic antigen level, and <110 g/L preoperative hemoglobin. Two models were derived using different methods. Model A identified low- and high-risk patients for OS (P<0.001), while Model B differentiated low-, intermediate-, and high-risk patients for OS (P<0.001). Stage III patients in the low-risk group had higher survival probabilities than Stage II patients. Both Model A (area under the curve [AUC]: 0.74, 95% confidence interval [CI]: 0.69 0.78) and Model B (AUC: 0.79, 95% CI: 0.72-0.83) were better predictors compared with the pathologic TNM classification (AUC: 0.62, 95% CI: 0.59-0.71, P<0.001). Adjuvant paclitaxel- or oxaliplatin-based or triple chemotherapy showed significantly better outcomes in patients classified as high risk, but not in those with low and intermediate risk. CONCLUSION: A clinical three-tier prognostic risk scoring system was established to predict OS of GC treated with D2 gastrectomy and adjuvant chemotherapy. The potential advantage of this scoring system is that it can identify high-risk patients in Stage II or III who may benefit from paclitaxel- or oxaliplatin-based regimens. Prospective studies are needed to confirm these results before they are applied clinically. PMID- 26966353 TI - Maximizing the encapsulation efficiency and the bioavailability of controlled release cetirizine microspheres using Draper-Lin small composite design. AB - This study was aimed at developing a controlled-release cetirizine hydrochloride (CTZ)-loaded polymethacrylate microsphere by optimization technique using software-based response surface methodology. The emulsion solvent evaporation method was utilized in the preparation of microspheres. Four process variables were selected, namely, Eudragit RLPO loading percentage in total polymer, the emulsifier hydrophilic lipophilic balance (HLB), the antitacking percentage, and the dispersed phase volume. The desired responses were particle size, angle of repose, production yield, encapsulation efficiency, loading capacity, initial drug release, and the time for 85% of drug release from the microspheres. Optimization was carried out by fitting the experimental data to the software program (Statgraphics Centurion XV). Moreover, 18 batches were subjected to various characterization tests required for the production of dosage form. The pharmacokinetic parameters were evaluated after the oral administration of 10 mg CTZ in both optimized formulation and commercial product on healthy human volunteers using a double-blind, randomized, cross-over design. The optimized formulation showed satisfactory yield (84.43%) and drug encapsulation efficiency (87.1%). Microspheres were of spherical shape, smooth surface, and good flowability with an average size of 142.3 MUm. The developed optimized batch of microspheres ensured 28.87% initial release after 2 hours, and the release of CTZ extended for >12 hours. In addition, the relative bioavailability of the optimized formulation was 165.5% with respect to the marketed CTZ tablets indicating a significant enhancement of CTZ bioavailability. Thus, there is an expectation to decrease the administered dose and the frequency of administration, and subsequently minimize the adverse effects that are faced by the patient during the treatment. PMID- 26966354 TI - The mechanism underlying alpinetin-mediated alleviation of pancreatitis associated lung injury through upregulating aquaporin-1. AB - Characterized by its acute onset, critical condition, poor prognosis, and high mortality rate, severe acute pancreatitis (SAP) can cause multiple organ failure at its early stage, particularly acute lung injury (ALI). The pathogenesis of ALI is diffuse alveolar damage, including an increase in pulmonary microvascular permeability, a decrease in compliance, and invasion of many inflammatory cells. Corticosteroids are the main treatment method for ALI; however, the associated high toxicity and side effects induce pain in patients. Recent studies show that the effective components in many traditional Chinese medicines can effectively inhibit inflammation with few side effects, which can decrease the complications caused by steroid consumption. Based on these observations, the main objective of the current study is to investigate the effect of alpinetin, which is a flavonoid extracted from Alpinia katsumadai Hayata, on treating lung injury induced by SAP and to explore the mechanism underlying the alpinetin-mediated decrease in the extent of ALI. In this study, we have shown through in vitro experiments that a therapeutic dose of alpinetin can promote human pulmonary microvascular endothelial cell proliferation. We have also shown via in vitro and in vivo experiments that alpinetin upregulates aquaporin-1 and, thereby, inhibits tumor necrosis factor-alpha expression as well as reduces the degree of lung injury. Overall, our study shows that alpinetin alleviates SAP-induced ALI. The likely molecular mechanism includes upregulated aquaporin expression, which inhibits tumor necrosis factor-alpha and, thus, alleviates SAP-induced ALI. PMID- 26966355 TI - Temporal arteritis with erythrocyte sedimentation rate <50 mm/h: a clinical reminder. AB - Temporal arteritis, also known as giant cell arteritis (GCA), is a systemic vasculitis that predominantly involves the temporal arteries. It is a medical emergency and should be treated promptly as it can lead to permanent loss of vision. It is very commonly associated with a raised erythrocyte sedimentation rate (ESR), usually >50 mm/h, one of the essential criteria defined by the American College of Rheumatology classification of GCA. Here, we describe the case of a 73-year-old male presenting with a 2-day history of a sudden onset of a severe left-sided headache, which had the signs and symptoms consistent with GCA but he had an ESR of only 27 mm/h. The patient was urgently treated with prednisolone 60 mg per day, and his symptoms dramatically improved within 24 hours of therapy. Temporal artery biopsy results were consistent with an inflammatory response, and withdrawal of treatment led to a relapse of the symptoms. The patient was slowly tapered off the high steroid dose and is now currently managed on a low steroid dose. We should keep a high index of suspicion for GCA in patients presenting with clinical symptoms of GCA even though the ESR is <50 mm/h as stated in the criteria for GCA diagnosis. PMID- 26966357 TI - Prevalence and pattern of torus palatinus and torus mandibularis among edentulous patients of Saudi Arabia. AB - BACKGROUND: The most remarkable exostoses of the human jaws are torus palatinus (TP) and torus mandibularis (TM). The aim of the present study was to actuate the prevalence of TP and TM in relation to age and sex among the edentulous patients of Saudi Arabia. METHODS: The present study included 847 edentulous subjects (458 men and 389 women) aged between 51 and 79 years. The subjects were examined for the existence of tori by clinical inspection and palpation. Statistical analysis was performed using SPSS for Windows version. RESULTS: Among the 847 subjects, 149 (17.59%) had either TP or TM. Sixty six (7.79%) subjects had TP, whereas 83 (9.80%) had TM. The maximum percentage (36.36%) of tori was observed in the age group of 60-69 years. The percentage of males with either tori was higher (19.0%) when compared to females (15.94%). According to shape, the occurrence of flat shaped TP (57.58%) and bilateral solitary TM (39.76%) was more common. CONCLUSION: No significant difference in the presence of tori with respect to sex and age was observed. A comparatively increased prevalence of TP and TM was however observed, and this should be taken into consideration while planning for prosthodontic and periodontal therapy in these patients. PMID- 26966358 TI - Lower cognitive function in patients with age-related macular degeneration: a meta-analysis. AB - OBJECTIVE: To investigate the cognitive impairment in patients with age-related macular degeneration (AMD). METHODS: Relevant articles were identified through a search of the following electronic databases through October 2015, without language restriction: 1) PubMed; 2) the Cochrane Library; 3) EMBASE; 4) ScienceDirect. Meta-analysis was conducted using STATA 12.0 software. Standardized mean differences with corresponding 95% confidence intervals were calculated. All of the included studies met the following four criteria: 1) the study design was a case-control or randomized controlled trial (RCT) study; 2) the study investigated cognitive function in the patient with AMD; 3) the diagnoses of AMD must be provided; 4) there were sufficient scores data to extract for evaluating cognitive function between cases and controls. The Newcastle-Ottawa Scale criteria were used to assess the methodological quality of the studies. RESULTS: Of the initial 278 literatures, only six case-control and one RCT studies met all of the inclusion criteria. A total of 794 AMD patients and 1,227 controls were included in this study. Five studies were performed with mini-mental state examination (MMSE), two studies with animal fluency, two studies with trail making test (TMT)-A and -B, one study with Mini-Cog. Results of the meta-analysis revealed lower cognitive function test scores in patients with AMD, especially with MMSE and Mini-Cog test (P<=0.001 for all). The results also showed that differences in the TMT-A (except AMD [total] vs controls) and TMT-B test had no statistical significance (P>0.01). The Newcastle-Ottawa Scale score was >=5 for all of the included studies. Based on the sensitivity analysis, no single study influenced the overall pooled estimates. CONCLUSION: This meta analysis suggests lower cognitive function test scores in patients with AMD, especially with MMSE and Mini-Cog test. The other cognitive impairment screening tests, such as animal fluency test and TMT, need more studies to assess. PMID- 26966356 TI - Oropharyngeal dysphagia in older persons - from pathophysiology to adequate intervention: a review and summary of an international expert meeting. AB - Oropharyngeal dysphagia (OD) is a highly prevalent and growing condition in the older population. Although OD may cause very severe complications, it is often not detected, explored, and treated. Older patients are frequently unaware of their swallowing dysfunction which is one of the reasons why the consequences of OD, ie, aspiration, dehydration, and malnutrition, are regularly not attributed to dysphagia. Older patients are particularly vulnerable to dysphagia because multiple age-related changes increase the risk of dysphagia. Physicians in charge of older patients should be aware that malnutrition, dehydration, and pneumonia are frequently caused by (unrecognized) dysphagia. The diagnosis is particularly difficult in the case of silent aspiration. In addition to numerous screening tools, videofluoroscopy was the traditional gold standard of diagnosing OD. Recently, the fiberoptic endoscopic evaluation of swallowing is increasingly utilized because it has several advantages. Besides making a diagnosis, fiberoptic endoscopic evaluation of swallowing is applied to evaluate the effectiveness of therapeutic maneuvers and texture modification of food and liquids. In addition to swallowing training and nutritional interventions, newer rehabilitation approaches of stimulation techniques are showing promise and may significantly impact future treatment strategies. PMID- 26966359 TI - Development of a spirometry T-score in the general population. AB - BACKGROUND AND OBJECTIVE: Spirometry values may be expressed as T-scores in standard deviation units relative to a reference in a young, normal population as an analogy to the T-score for bone mineral density. This study was performed to develop the spirometry T-score. METHODS: T-scores were calculated from lambda-mu sigma-derived Z-scores using a young, normal age reference. Three outcomes of all cause death, respiratory death, and COPD death were evaluated in 9,101 US subjects followed for 10 years; an outcome of COPD-related health care utilization (COPD utilization) was evaluated in 1,894 Korean subjects followed for 4 years. RESULTS: The probability of all-cause death appeared to remain nearly zero until -1 of forced expiratory volume in 1 second (FEV1) T-score but increased steeply where FEV1 T-score reached below -2.5. Survival curves for all cause death, respiratory death, COPD death, and COPD utilization differed significantly among the groups when stratified by FEV1 T-score (P<0.001). The adjusted hazard ratios of the FEV1 T-score for the four outcomes were 0.54 (95% confidence interval, 0.48-0.60), 0.43 (95% CI: 0.37-0.50), 0.30 (95% CI: 0.24 0.37), and 0.69 (95% CI: 0.59-0.81), respectively, adjusting for covariates (P<0.001). CONCLUSION: The spirometry T-score could predict all-cause death, respiratory death, COPD death, and COPD utilization. PMID- 26966360 TI - Self-assembled lecithin/chitosan nanoparticles for oral insulin delivery: preparation and functional evaluation. AB - PURPOSE: Here, we investigated the formation and functional properties of self assembled lecithin/chitosan nanoparticles (L/C NPs) loaded with insulin following insulin-phospholipid complex preparation, with the aim of developing a method for oral insulin delivery. METHODS: Using a modified solvent-injection method, insulin-loaded L/C NPs were obtained by combining insulin-phospholipid complexes with L/C NPs. The nanoparticle size distribution was determined by dynamic light scattering, and morphologies were analyzed by cryogenic transmission electron microscopy. Fourier transform infrared spectroscopy analysis was used to disclose the molecular mechanism of prepared insulin-loaded L/C NPs. Fast ultrafiltration and a reversed-phase high-performance liquid chromatography assay were used to separate free insulin from insulin entrapped in the L/C NPs, as well as to measure the insulin-entrapment and drug-loading efficiencies. The in vitro release profile was obtained, and in vivo hypoglycemic effects were evaluated in streptozotocin-induced diabetic rats. RESULTS: Our results indicated that insulin containing L/C NPs had a mean size of 180 nm, an insulin-entrapment efficiency of 94%, and an insulin-loading efficiency of 4.5%. Cryogenic transmission electron microscopy observations of insulin-loaded L/C NPs revealed multilamellar structures with a hollow core, encircled by several bilayers. In vitro analysis revealed that insulin release from L/C NPs depended on the L/C ratio. Insulin loaded L/C NPs orally administered to streptozotocin-induced diabetic rats exerted a significant hypoglycemic effect. The relative pharmacological bioavailability following oral administration of L/C NPs was 6.01%. CONCLUSION: With the aid of phospholipid-complexation techniques, some hydrophilic peptides, such as insulin, can be successfully entrapped into L/C NPs, which could improve oral bioavailability, time-dependent release, and therapeutic activity. PMID- 26966361 TI - Functioning in patients with major depression treated with duloxetine or a selective serotonin reuptake inhibitor in East Asia. AB - PURPOSE: To assess and compare the levels of functioning in patients with major depressive disorder treated with either duloxetine with a daily dose of <=60 mg or a selective serotonin reuptake inhibitor (SSRI) as monotherapy for up to 6 months in a naturalistic setting in East Asia. In addition, this study examined the impact of painful physical symptoms (PPS) on the effects of these treatments. PATIENTS AND METHODS: Data for this post hoc analysis were taken from a 6-month prospective observational study involving 1,549 patients with major depressive disorder without sexual dysfunction. The present analysis focused on a subgroup of patients from East Asia (n=587). Functioning was measured using the Sheehan Disability Scale (SDS). Depression severity was assessed using the 16-item Quick Inventory of Depressive Symptomatology-Self Report. PPS were rated using the modified Somatic Symptom Inventory. A mixed model with repeated measures was fitted to compare the levels of functioning between duloxetine-treated (n=227) and SSRI-treated (n=225) patients, adjusting for baseline patient characteristics. RESULTS: The mean SDS total score was similar between the two treatment cohorts (15.46 [standard deviation =6.11] in the duloxetine cohort and 16.36 [standard deviation =6.53] in the SSRI cohort, P=0.077) at baseline. Both descriptive and regression analyses confirmed improvement in functioning in both groups during follow-up, but duloxetine-treated patients achieved better functioning. At 24 weeks, the estimated mean SDS total score was 4.48 (standard error =0.80) in the duloxetine cohort, which was statistically significantly lower (ie, better functioning) than that of 6.76 (standard error =0.77) in the SSRI cohort (P<0.001). This treatment difference was more apparent in the subgroup of patients with PPS at baseline. Similar patterns were also observed for SDS subscores (work, social life, and family life). CONCLUSION: Depressed patients treated with duloxetine achieved better functioning compared to those treated with SSRIs. This treatment difference was mostly driven by patients with PPS at baseline. PMID- 26966362 TI - The investigation of factors related to suicide attempts in Southeastern Turkey. AB - BACKGROUND: Suicide is an important health problem in Turkey as it is in all regions of the world. Suicidal behavior has multiple causes, which are broadly divided into those related to proximal stressors and those due to predisposition. Suicide statistics may be associated with mental health disorders, which are among the foremost predictors of suicide attempts. More than 90% of patients who commit suicide have a diagnosable psychiatric disorder, usually a major depressive disorder. Other major risk factors for suicide attempts are history of suicide attempts in the family, stressful life events, sleep disturbances, poor income, unemployment, severity of symptoms of depression, and anxiety. Sleep is a complex phenomenon. Sleep disturbances can therefore be contributed to the emergence of suicidal behavior allowing for the possibility of predicting future suicides. METHODS: We evaluated 106 patients who were admitted after suicide attempts to the Department of Psychiatry at Dicle University Faculty of Medicine. The recruited subjects were assessed by Structured Clinical Interview for DSM-IV Axis I disorders, and the intensity of symptoms was evaluated using the Beck Anxiety Inventory, Hamilton Depression Rating Scale, and Pittsburgh Sleep Quality Index. The mean values of the subjects attempting multiple and single suicides were compared using appropriate inferential statistical tests. RESULTS: Most suicide attempts are believed to be preventable. Our results revealed that a great variety of risk factors are associated with an increased risk for multiple suicide attempts. Most of these attempts appeared to be spontaneous and impulsive rather than planned. In particular, this study highlights the importance of previous suicide attempts, history of suicide in the family, history of stressful life events in the previous 6 months, poor income, unemployment, sleep disturbances, severe hopelessness with depression, and coexisting symptoms of anxiety as risk factors. CONCLUSION: The first step in prevention of suicides is doubtlessly strong and reliable communication, due to the fact that the majority of subjects who commit suicide have had contact with a health professional during the month before the suicide. PMID- 26966363 TI - Intractable restless legs syndrome: role of prolonged-release oxycodone-naloxone. AB - Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move the legs accompanied by uncomfortable sensations that occur at night or at time of rest. Pharmacological therapy should be limited to patients who suffer from clinically relevant symptoms. Chronic RLS is usually treated with either a dopamine agonist (pramipexole, ropinirole, rotigotine) or an alpha2delta calcium-channel ligand (gabapentin, gabapentin enacarbil, pregabalin). Augmentation is the main complication of long-term dopaminergic treatment, and frequently requires a reduction of current dopaminergic dose or a switch to non-dopaminergic medications. Opioids as monotherapy or add-on treatment should be considered when alternative satisfactory regimens are unavailable and the severity of symptoms warrants it. In a recent Phase III trial, oxycodone-naloxone prolonged release (PR) demonstrated a significant and sustained effect on patients with severe RLS inadequately controlled by previous treatments. The adverse-event profile was consistent with the safety profile of opioids. The most frequent adverse events were fatigue, constipation, nausea, headache, hyperhidrosis, somnolence, dry mouth, and pruritus. Adverse events were usually mild or moderate in intensity. No cases of augmentation were reported. Oxycodone-naloxone PR is approved for the second-line symptomatic treatment of adults with severe to very severe idiopathic RLS after failure of dopaminergic treatment. Further studies are needed to evaluate if oxycodone-naloxone PR is equally efficacious as a first-line treatment. Moreover, long-term comparative studies between opioids, dopaminergic drugs and alpha2delta ligands are needed. PMID- 26966364 TI - Attitudes toward metabolic adverse events among patients with schizophrenia in Japan. AB - BACKGROUND: Metabolic syndrome is a growing concern among patients with schizophrenia because metabolic abnormalities are widely regarded as a major risk factor for cardiovascular disease and premature death. The current study assessed attitudes toward metabolic adverse events among patients with schizophrenia. METHODS: A brief questionnaire was constructed to investigate patient recognition of the following broad areas: dietary habits, lifestyle, self-monitoring, knowledge, and medical practice. Between January 2012 and June 2013, questionnaires were sent to patients associated with 520 outpatient facilities and 247 inpatient facilities belonging to the Japan Psychiatric Hospital Association. All of the participants (n=22,072; inpatients =15,170, outpatients =6,902) were diagnosed with schizophrenia based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, or the International Classification of Diseases, tenth revision. RESULTS: Approximately 55.0% (8,069/14,669) of inpatients and 44.8% of outpatients (2,978/6,649) reported that they did not exercise at all. Although 60.9% (4,116/6,760) of outpatients reported that they felt obese, only 35.6% (5,261/14,794) of inpatients felt obese. More than half of the inpatients (51.2%; 7,514/14,690) and outpatients (60.8%; 4,086/6,721) hoped to receive regular blood tests to prevent weight gain and diseases such as diabetes. CONCLUSION: Although more than half of patients hoped to prevent weight gain and diabetes, only a minority of patients were mindful of eating balanced meals and having physical exercise. Educational efforts and the promotion of the best pharmacotherapy and monitoring practices are needed for patients with schizophrenia. PMID- 26966365 TI - Development and validation of the Thai version of the 4 'A's Test for delirium screening in hospitalized elderly patients with acute medical illnesses. AB - BACKGROUND: The English version of the 4 'A's Test (4AT) is a rapid screening tool for delirium with a high sensitivity and specificity among hospitalized elderly patients. OBJECTIVE: To develop the Thai version of the 4AT (4AT-T) and assess its validity. SUBJECTS AND SETTING: A total of 97 elderly patients aged 60 years or above who were admitted to the general medical wards were included. METHODS: Both authors independently translated the English version of the 4AT into Thai and thereafter developed a single reconciled forward translation by consensus. Back translation was performed by a bilingual native English speaker and it was then reviewed to ensure its agreement with the original one. After 24 hours of admission, subjects were enrolled and clinical data collected. Definite diagnosis of delirium was made by a psychiatrist using the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text-Revision criteria and the 6-item Thai Delirium Rating Scale; the 4AT was then administered to participants by nurses within 30 minutes. A 4AT score >=4 was considered positive for delirium screening. The optimal cut-off point of the 4AT-T was identified by Youden's index. RESULTS: In all, 24 out of 97 participants met the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text-Revision criteria for delirium. At a cut-off score of 4 or greater, the 4AT-T exhibited satisfactory diagnostic performance with a sensitivity of 83.3% (95% confidence interval (CI): 62.6%-95.3%) and specificity of 86.3% (95% CI: 76.3%-93.2%). The area under the receiver operating characteristic curve was 0.92. The specified score provided maximal Youden's index, suggesting an optimal criterion value for delirium screening. CONCLUSION: The 4AT-T is a valid delirium-screening instrument for hospitalized elderly patients with acute medical illnesses. PMID- 26966366 TI - A voxel-based morphometric study of age- and sex-related changes in white matter volume in the normal aging brain. AB - OBJECTIVE: To carry out a cross-sectional study of 187 cognitively normal Chinese adults using the voxel-based morphometry (VBM) approach to delineate age-related changes in the white matter volume of regions of interest in the brain and further analyze their correlation with age. MATERIALS AND METHODS: A total of 187 cognitively normal adults were divided into the young, middle, and old age groups. Conventional magnetic resonance imaging was performed with the Achieva 3.0 T system. Structural images were processed using VBM8 and statistical parametric mapping 8. Regions of interest were obtained by WFU PickAtlas, and all realigned images were spatially normalized. RESULTS: Females showed significantly greater total white matter volume than males (t=2.36, P=0.0096, false-discovery rate [FDR] corrected). VBM demonstrated statistically significant age-related differences in white matter volume between the young age-group and the middle age group (P<0.05, FDR corrected) and between the middle age-group and the old age group (P<0.05, FDR corrected). No interaction was found between age and sex on white matter volume (P<0.05, FDR corrected). Logistic regression analysis revealed nonlinear correlation between total white matter volume and age (R (2)=0.124, P<0.001). White matter volume gradually increased before 40 years of age, peaked around 50 years of age, and rapidly declined after 60 years of age. CONCLUSION: Significant age-related differences are present in white matter volume across multiple brain regions during aging. The VBM approach may help differentiate underlying normal neurobiological aging changes of specific brain regions from neurodegenerative impairments. PMID- 26966368 TI - Effect of red yeast rice combined with antioxidants on lipid pattern, hs-CRP level, and endothelial function in moderately hypercholesterolemic subjects. AB - Our aim was to test, through a crossover, double-blind, placebo-controlled randomized clinical trial, if a short-term treatment with 10 mg monacolins combined with antioxidants could improve lipid pattern, high-sensitivity C reactive protein (hs-CRP), and endothelial function in a small cohort of moderately hypercholesterolemic subjects. Thus, 25 healthy, moderately hypercholesterolemic subjects were consecutively enrolled and, after 4 weeks of stabilization diet, were randomized to the sequence placebo followed by a washout, monacolins or monacolins followed by a washout, placebo, with each period being 4 weeks long. At each study step, a complete lipid pattern, safety parameters, hs-CRP, and endothelial function have been measured. When compared to the placebo phase, during monacolin treatment, patients experienced a more favorable percentage change in total cholesterol (TC) (TC after monacolin treatment, -18.35%; TC after placebo treatment, -5.39%), low-density lipoprotein cholesterol (LDL-C) (LDL after monacolin treatment, -22.36%; LDL after placebo treatment, -1.38%), non-high-density lipoprotein cholesterol (HDL-C) (non-HDL after monacolin treatment, -22.83%; non-HDL after placebo treatment: -7.15%), hs CRP (hs-CRP after monacolin treatment: -2.33%; hs-CRP after placebo treatment, 2.11%), and endothelial function (pulse volume displacement after monacolin treatment, 18.59%; pulse volume displacement after placebo treatment, -6.69%). No significant difference was observed with regard to triglycerides, HDL cholesterol, and safety parameters. On the basis of our data, we could demonstrate that a 10 mg monacolin nutraceutical treatment appears to safely reduce cholesterolemia, hs-CRP, and markers of vascular remodeling in moderately hypercholesterolemic subjects. These results need to be confirmed in larger patient samples and in studies with longer duration. PMID- 26966369 TI - Ethyl pyruvate protects against sepsis by regulating energy metabolism. AB - BACKGROUND: Ethyl pyruvate (EP) is a derivative of pyruvic acid that has been demonstrated to be a potential scavenger of reactive oxygen species as well as an anti-inflammatory agent. In this study, we investigated the protective effects of EP and its role in regulating the energy metabolism in the livers of cecal ligation-and-puncture-induced septic mice. METHODS: The animals were treated intraperitoneally with 0.2 mL of Ringer's lactate solution or an equivalent volume of Ringer's lactate solution containing EP immediately after cecal ligation and puncture. Each mouse in the Sham group was only subjected to a laparotomy. At 30-, 60-, 180-, and 360-minute time points, we measured the histopathological alterations of the intestines, and the plasma levels of interleukin (IL)-1beta, IL-6, IL-10, and tumor necrosis factor-alpha, and the total antioxidative capacity, malondialdehyde content, and lactate and lactate/pyruvate levels in livers. Furthermore, we detected the levels of adenosine triphosphate, total adenylate, and energy charge in the livers. RESULTS: Our results demonstrated that the administration of EP significantly improved the survival rate and reduced intestinal histological alterations. EP inhibited the plasma levels of IL-1beta, IL-6, and tumor necrosis factor-alpha and increased the IL-10 level. EP significantly inhibited the elevation of the malondialdehyde, lactate, and lactate/pyruvate levels and enhanced the total antioxidative capacity levels in the liver tissues. The downregulation of the adenosine triphosphate, total adenylate, and energy charge levels in the liver tissues was reversed in the septic mice treated with EP. CONCLUSION: The results suggest that EP administration effectively modulates the energy metabolism, which may be an important component in treatment of sepsis. PMID- 26966367 TI - Medical management of epileptic seizures: challenges and solutions. AB - Epilepsy is one of the most common neurologic illnesses. This condition afflicts 2.9 million adults and children in the US, leading to an economic impact amounting to $15.5 billion. Despite the significant burden epilepsy places on the population, it is not very well understood. As this understanding continues to evolve, it is important for clinicians to stay up to date with the latest advances to provide the best care for patients. In the last 20 years, the US Food and Drug Administration has approved 15 new antiepileptic drugs (AEDs), with many more currently in development. Other advances have been achieved in terms of diagnostic modalities like electroencephalography technology, treatment devices like vagal nerve and deep-brain stimulators, novel alternate routes of drug administration, and improvement in surgical techniques. Specific patient populations, such as the pregnant, elderly, those with HIV/AIDS, and those with psychiatric illness, present their own unique challenges, with AED side effects, drug interactions, and medical-psychiatric comorbidities adding to the conundrum. The purpose of this article is to review the latest literature guiding the management of acute epileptic seizures, focusing on the current challenges across different practice settings, and it discusses studies in various patient populations, including the pregnant, geriatric, those with HIV/AIDS, comatose, psychiatric, and "pseudoseizure" patients, and offers possible evidence-based solutions or the expert opinion of the authors. Also included is information on newer AEDs, routes of administration, and significant AED-related drug interaction tables. This review has tried to address only some of these issues that any practitioner who deals with the acute management of seizures may encounter. The document also highlights the numerous avenues for new research that would help practitioners optimize epilepsy management. PMID- 26966370 TI - Radiofrequency ablation versus resection for Barcelona clinic liver cancer very early/early stage hepatocellular carcinoma: a systematic review. AB - AIM: To compare the long-term survival outcomes of radiofrequency ablation and liver resection for single very early/early stage hepatocellular carcinoma (HCC). METHODS: The Cochrane Library (Issue 3, 2015), Embase (1974 to March 15, 2015), PubMed (1950 to March 15, 2015), Web of Science (1900 to March 15, 2015), and Chinese Biomedical Literature Database (1978 to March 15, 2015) were searched to identify relevant trials. Only trials that compared radiofrequency ablation and liver resection for single very early stage (<=2 cm) or early stage (<=3 cm) HCC according to the Barcelona clinic liver cancer (BCLC) staging system were considered for inclusion in this review. The primary outcomes that we analyzed were the 3-year and 5-year overall survival (OS) rates, and the secondary outcomes that we analyzed were the 3-year and 5-year disease-free survival (DFS) rates. Review Manager 5.3 was used to perform a cumulative meta-analysis. Possible publication bias was examined using a funnel plot. A random-effects model was applied to summarize the various outcomes. RESULTS: Six studies involving 947 patients were identified that compared radiofrequency ablation (n=528) to liver resection (n=419) for single BCLC very early HCC. In these six studies, the rates of 3-year OS, 5-year OS, 3-year DFS, and 5-year DFS were significantly lower in the radiofrequency ablation group than in the liver resection group (risk ratio [RR] =0.90, 95% confidence interval [CI]: 0.83-0.98, P=0.01; RR =0.84, 95% CI: 0.75-0.95, P=0.004; RR =0.77, 95% CI: 0.60-0.98, P=0.04; and RR =0.70, 95% CI: 0.52-0.94, P=0.02, respectively). Ten studies involving 2,501 patients were identified that compared radiofrequency ablation (n=1,476) to liver resection (n=1,025) for single BCLC early HCC. In these ten studies, the rates of 3-year OS, 5-year OS, 3-year DFS, and 5-year DFS were also significantly lower in the radiofrequency ablation group than in the liver resection group (RR =0.93, 95% CI: 0.88-0.98, P=0.003; RR =0.84, 95% CI: 0.75 0.94, P=0.002; RR =0.72, 95% CI: 0.58-0.89, P=0.002; and RR =0.47, 95% CI: 0.33 0.67, P<0.0001, respectively). CONCLUSION: The long-term survival outcomes for patients with single BCLC very early/early stage HCC appear to be superior after liver resection compared to radiofrequency ablation. PMID- 26966371 TI - Home care assistants' perspectives on detecting mental health problems and promoting mental health among community-dwelling seniors with multimorbidity. AB - INTRODUCTION: Elderly people with multiple chronic conditions, or multimorbidity, are at risk of developing poor mental health. These seniors often remain in their homes with support from home care assistants (HCAs). Mental health promotion by HCAs needs to be studied further because they may be among the first to observe changes in clients' mental health status. AIM: To describe HCAs' perspectives on detecting mental health problems and promoting mental health among homebound seniors with multimorbidity. METHODS: We applied a descriptive qualitative study design using semi-structured interviews. Content analyses were performed on five focus group interviews conducted in 2014 with 26 HCAs. RESULTS: Most HCAs stated that they were experienced in caring for clients with mental health problems such as anxiety, depression, sleep problems, and high alcohol consumption. The HCAs mentioned as causes, or risk factors, multiple chronic conditions, feelings of loneliness, and social isolation. The findings reveal that continuity of care and seniors' own thoughts and perceptions were essential to detecting mental health problems. Observation, collaboration, and social support emerged as important means of detecting mental health problems and promoting mental health. CONCLUSION: The HCAs had knowledge of risk factors, but they seemed insecure about which health professionals had the primary responsibility for mental health. They also seemed to have detected early signs of mental health problems, even though good personal knowledge of the client and continuity in home visits were crucial to do so. When it came to mental health promotion, the suggestions related to the aim of ending social isolation, decreasing feelings of loneliness, and increasing physical activity. The results indicate that the HCAs seemed dependent on supervision by district nurses and on care managers' decisions to support the needed care, to schedule assignments related to the detection of mental health problems, and to promote mental health. PMID- 26966374 TI - Primary renal carcinoid tumor: case report and review of the literature. AB - OBJECTIVE: The aim of this case report is to discuss the clinicopathological features of a patient with a primary renal carcinoid tumor. METHODS: We report on the clinical and pathological information of one case of a patient with a primary renal carcinoid tumor as well as review relative literature. RESULTS: The patient was diagnosed with a renal tumor when she received physical examination, and exhibited no positive symptoms. The diameter of tumor was 5 cm, the cross surface of the tumor was light yellow and firm, and the central part was soft with hemorrhage and necrosis. Immunohistochemical staining revealed strong and diffuse staining with synaptophysin, chromogranin A, and neuron-specific enolase. CONCLUSION: A primary renal carcinoid tumor is extremely rare. Surgical resection is a preferred therapeutic method. PMID- 26966373 TI - Inferring Orthologs: Open Questions and Perspectives. AB - With the increasing number of sequenced genomes and their comparisons, the detection of orthologs is crucial for reliable functional annotation and evolutionary analyses of genes and species. Yet, the dynamic remodeling of genome content through gain, loss, transfer of genes, and segmental and whole-genome duplication hinders reliable orthology detection. Moreover, the lack of direct functional evidence and the questionable quality of some available genome sequences and annotations present additional difficulties to assess orthology. This article reviews the existing computational methods and their potential accuracy in the high-throughput era of genome sequencing and anticipates open questions in terms of methodology, reliability, and computation. Appropriate taxon sampling together with combination of methods based on similarity, phylogeny, synteny, and evolutionary knowledge that may help detecting speciation events appears to be the most accurate strategy. This review also raises perspectives on the potential determination of orthology throughout the whole species phylogeny. PMID- 26966372 TI - Effects of Environmental Pollutants on Cellular Iron Homeostasis and Ultimate Links to Human Disease. AB - Chronic disease has increased in the past several decades, and environmental pollutants have been implicated. The magnitude and variety of diseases may indicate the malfunctioning of some basic mechanisms underlying human health. Environmental pollutants demonstrate a capability to complex iron through electronegative functional groups containing oxygen, nitrogen, or sulfur. Cellular exposure to the chemical or its metabolite may cause a loss of requisite functional iron from intracellular sites. The cell is compelled to acquire further iron critical to its survival by activation of iron-responsive proteins and increasing iron import. Iron homeostasis in the exposed cells is altered due to a new equilibrium being established between iron-requiring cells and the inappropriate chelator (the pollutant or its catabolite). Following exposure to environmental pollutants, the perturbation of functional iron homeostasis may be the mechanism leading to adverse biological effects. Understanding the mechanism may lead to intervention methods for this major public health concern. PMID- 26966375 TI - Elevated preoperative neutrophil-to-lymphocyte ratio is associated with poor prognosis in gastrointestinal stromal tumor patients. AB - PURPOSE: To investigate the prognostic relevance of preoperative peripheral neutrophil- to-lymphocyte ratio (NLR) in gastrointestinal stromal tumor (GIST) patients. MATERIALS AND METHODS: We enrolled 129 consecutive GIST patients who underwent initial curative surgical resection with or without adjuvant/palliative imatinib treatment in our study. Blood NLR was calculated as neutrophil count (number of neutrophils *10(9)/L) divided by lymphocyte count (number of lymphocytes *10(9)/L). Survival curves were constructed by using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazard regression models were performed to identify associations with outcome variable. All tests were two sided, and P<0.05 was considered statistically significant. RESULTS: The optimal cut-off value of NLR was 2.07 in the receiver operating characteristic curve analysis. The median overall survival (OS) of high NLR group was 113.0 months, whereas that of the low NLR group had not reached the median OS both in the general (P<0.001) and subgroup analyses. The elevated NLR suggested shorter OS in the high malignant potential groups (P=0.01) and the combined low and moderate groups (P=0.02). Increased NLR indicated poor OS in patients regardless of whether if received imatinib treatment or not (P=0.005, and P=0.032, respectively). High NLR indicated poor OS of patients in stage I and II disease (P=0.005) and a clear tendency that increased level of NLR is inimical to OS. CONCLUSION: Elevated NLR was detected as an independent adverse prognostic factor. Elevated preoperative NLR predicts poor clinical outcome in GIST patients and may serve as a cost-effective and broadly available independent prognostic biomarker. PMID- 26966377 TI - Interleukin-27 rs153109 polymorphism and the risk of non-small-cell lung cancer in a Chinese population. AB - Non-small-cell lung cancer (NSCLC) has a multifactorial pathogenesis, and the genetic background may be one of the critical etiologic factors. Interleukin (IL) 27, a novel member of the IL-12 family, plays a vital role in antitumor immunity. The aim of the current study was to determine the association of a single nucleotide polymorphism of the IL-27 gene with the risk of NSCLC. The genotype of the IL-27 rs153109 polymorphism was analyzed in 388 patients with NSCLC and 390 healthy controls by using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. In the patients with NSCLC, the frequencies of the GG, GA, and AA genotypes and the G and A alleles were 14.0%, 56.4%, 29.6%, 42.1%, and 57.9%, respectively. There were no significant differences in the genotype and allele distributions of the IL-27 rs153109 polymorphism between the patients with NSCLC and healthy controls (P>0.05). Furthermore, no association was determined between this polymorphism and different clinical characteristics in patients with NSCLC. Taken together, these findings suggest that the IL-27 gene may not be involved in the development of NSCLC in the Chinese population. PMID- 26966376 TI - Arsenic trioxide inhibits viability and induces apoptosis through reactivating the Wnt inhibitor secreted frizzled related protein-1 in prostate cancer cells. AB - BACKGROUND: Growing evidence suggests that arsenic trioxide (As2O3) induces apoptosis and inhibits tumor cell growth in prostate cancer (PCa), although details of the mechanism are still inconclusive. We investigated the antitumor effect of As2O3 in human PCa cell lines LNCaP and PC3 and the underlying mechanisms by focusing on the Wnt signaling pathway. METHODS: The effect of As2O3 on the viability and apoptosis of PCa cells was investigated by cholecystokinin-8 and flow cytometry. The expression of the related proteins in the Wnt signaling pathway and the downstream target genes of the Wnt signaling pathway was examined by Western blot and quantitative real-time PCR assay. The methylation status of the SFRP1 gene promoter was assessed by bisulfite sequencing. RESULTS: As2O3 inhibited the viability of PCa cells and induced apoptosis of PCa cells in a dose dependent manner. The protein level of phosphoglycogen synthase kinase-3beta was upregulated, whereas the protein level of beta-catenin and the mRNA levels of c MYC, MMP-7, and COX-2 were downregulated in a dose-dependent manner in PCa cells treated with As2O3. In addition, As2O3 upregulated the protein and mRNA levels of secreted frizzled related protein-1, and increased the demethylation of the SFRP1 gene promoter. CONCLUSION: Our results suggest that As2O3 may inhibit cell viability and induce apoptosis through reactivating the Wnt inhibitor secreted frizzled related protein-1 in both androgen-dependent and -independent human PCa. PMID- 26966378 TI - Association between three exonuclease 1 polymorphisms and cancer risks: a meta analysis. AB - To date, the results of studies exploring the relation between exonuclease 1 (Exo1) polymorphisms and cancer risks have differed. In this study, we performed a meta-analysis to investigate the effect of the three most extensively studied Exo1 polymorphisms (Pro757Leu, Glu589Lys, and Glu670Gly) on cancer susceptibility. The related studies published before August 5, 2015, were collected by searching the PubMed and EMBASE databases. We found 16 publications containing studies that were eligible for our study, including 10 studies for Pro757Leu polymorphism (4,093 cases and 3,834 controls), 12 studies for Glu589Lys polymorphism (6,479 cases and 6,550 controls), and 7 studies for Glu670Gly polymorphism (3,700 cases and 3,496 controls). Pooled odds ratios and 95% confidence intervals were used to assess the strength of the associations, and all the statistical analyses were calculated using the software program STATA version 12.0. Our results revealed that the Pro757Leu polymorphism was significantly associated with a reduced cancer risk, whereas an inverse association was found for the Glu589Lys polymorphism. Furthermore, subgroup analysis of smoking status indicated that the Glu589Lys polymorphism was significantly associated with an increased cancer risk in smokers, but not in nonsmokers. However, no evidence was found for an association between the Glu670Gly polymorphism and cancer risk. In conclusion, this meta-analysis suggests that the Pro757Leu polymorphism may provide protective effects against cancer, while the Glu589Lys polymorphism may be a risk factor for cancer. Moreover, the Glu670Gly polymorphism may have no influence on cancer susceptibility. In the future, large-scaled and well-designed studies are needed to achieve a more precise and comprehensive result. PMID- 26966379 TI - Plasma levels and diagnostic utility of VEGF, MMP-9, and TIMP-1 in the diagnosis of patients with breast cancer. AB - Vascular endothelial growth factor (VEGF), matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 may play a role in the pathogenesis of cancer disease. We investigated their levels and utility in comparison to cancer antigen (CA) 15-3 in patients with breast cancer (BC) and in relation to the control groups. The study included 100 women with BC, 50 patients with benign breast tumor, and 50 healthy women. The plasma levels of the tested parameters were determined using enzyme-linked immunosorbent assay, while CA 15-3 with chemiluminescent microparticle immunoassay. The results demonstrated significant differences in the concentration of the tested parameters and CA 15-3 between groups of patients with BC and healthy patients or patients with benign breast tumor. The plasma levels of VEGF and tissue inhibitor of metalloproteinase-1 were significantly higher in advanced tumor stages. The tested parameters were comparable to CA 15-3 values of the diagnostic sensitivity, specificity, the predictive values of positive and negative test results, and the area under the receiver-operating characteristic curve. The combined use of the tested parameters with CA 15-3 resulted in the increase in sensitivity, negative predictive value, and area under the receiver-operating characteristic curve, especially in the combination of VEGF with tumor marker (84%, 73%, 0.888, respectively). These findings suggest the usefulness of the tested parameters in the diagnosis of BC. VEGF, especially in combination with CA 15-3, showed the highest usefulness in the diagnosis of early BC. PMID- 26966380 TI - Adjuvant chemotherapy plus radiotherapy is superior to chemotherapy following surgical treatment of stage IIIA N2 non-small-cell lung cancer. AB - The use of additional radiotherapy for resected stage IIIA N2 non-small-cell lung cancer in the setting of standard adjuvant chemotherapy remains controversial. A comprehensive search (last search updated in March 2015) for relevant studies comparing patients with stage IIIA N2 non-small-cell lung cancer undergoing resection after treatment with adjuvant postoperative chemotherapy alone or adjuvant postoperative chemoradiotherapy (POCRT) was conducted. Hazard ratios (HRs) were extracted from these studies to give pooled estimates of the effects of POCRT on overall survival (OS) and disease-free survival (DFS). Six studies were included. The meta-analysis demonstrated that POCRT had a greater OS benefit than postoperative chemotherapy (HR =0.87, 95% confidence interval [CI]: 0.79 0.96, P=0.006). Unfortunately, there was no significant difference in DFS between the two groups: the combined HR for DFS was 0.91 (95% CI: 0.57-1.46, P=0.706). In a subgroup analysis of two randomized controlled trials (n=172 patients), adding radiation was of no benefit to either OS (HR =0.72, 95% CI: 0.49-1.06, P=0.094) or DFS (HR =1.45, 95% CI: 1.00-2.09, P=0.047). In summary, compared with postoperative chemotherapy, POCRT was beneficial to OS but not DFS in patients with stage IIIA N2 non-small-cell lung cancer. PMID- 26966382 TI - Short- and longer-term health-care resource utilization and costs associated with acute ischemic stroke. AB - OBJECTIVES: The mean lifetime cost of ischemic stroke is approximately $140,048 in the United States, placing stroke among the top 10 most costly conditions among Medicare beneficiaries. The objective of this study was to describe the health-care resource utilization and costs in the year following hospitalization for acute ischemic stroke (AIS). METHODS: This retrospective claims analysis quantifies utilization and costs following inpatient admission for AIS among the commercially insured and Medicare beneficiaries in the Truven Health databases. Patients who were 18 years or older and continuously enrolled for 12 months before and after an AIS event occurring (index) between January 2009 and December 2012 were identified. Patients with AIS in the year preindex were excluded. Demographic and clinical characteristics were evaluated at admission and in the preindex, respectively. Direct costs, readmissions, and inpatient length of stay (LOS) were described in the year postindex. RESULTS: The eligible populations comprised 20,314 commercially insured patients and 31,037 Medicare beneficiaries. Average all-cause costs were $61,354 and $44,929 (commercial and Medicare, respectively) in the first year after the AIS. Approximately 50%-55% of total 12 month costs were incurred between day 31 and day 365 following the incident AIS. One quarter (24.6%) of commercially insured patients and 38.8% of Medicare beneficiaries were readmitted within 30 days with 16.6% and 71.7% (commercial and Medicare, respectively) of those having a principal diagnosis of AIS. The average AIS-related readmission length of stay was nearly three times that of the initial hospitalization for both commercially insured patients (3.8 vs 10.8 days) and Medicare beneficiaries (4.0 vs 10.8 days). CONCLUSION: In addition to the substantial costs of the initial hospitalization of an AIS, these costs double within the year following this event. Given the high cost associated with AIS, new interventions reducing either the acute or longer-term burden of AIS are needed. PMID- 26966381 TI - Efficacy and safety of icotinib as first-line therapy in patients with advanced non-small-cell lung cancer. AB - BACKGROUND AND OBJECTIVE: Several clinical trials have proven that icotinib hydrochloride, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, exhibits encouraging efficacy and tolerability in patients with advanced non-small-cell lung cancer (NSCLC) who failed previous chemotherapy. This study was performed to assess the efficacy and toxicity of icotinib as first line therapy for patients with advanced pulmonary adenocarcinoma with EGFR sensitive mutation. PATIENTS AND METHODS: Thirty-five patients with advanced NSCLC with EGFR-sensitive mutation who were sequentially admitted to the First Affiliated Hospital of Xi'an Jiaotong University from March 2012 to March 2014 were enrolled into our retrospective research. All patients were administered icotinib as first-line treatment. The tumor responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). RESULTS: Among the 35 patients, the tumor objective response rate (ORR) and disease control rate were 62.9% (22/35) and 88.6% (31/35), respectively. The median progression-free survival was 11.0 months (95% confidence interval [CI]: 10.2 11.8 months), and median overall survival was 21.0 months (95% CI: 20.1-21.9 months). The most common drug-related toxicities were rashes (eleven patients) and diarrhea (nine patients), but these were generally manageable and reversible. CONCLUSION: Icotinib monotherapy is effective and tolerable as first-line treatment for patients with advanced lung adenocarcinoma with EGFR-sensitive mutation. PMID- 26966383 TI - Patient considerations in type 2 diabetes - role of combination dapagliflozin metformin XR. AB - PURPOSE: The purpose of this review article is to provide guidance to health care providers regarding the use of dapagliflozin-metformin XR (extended release) as a therapeutic option for the treatment of patients with type 2 diabetes mellitus (T2DM). METHODS: The PubMed database was searched through August 2015 to identify clinical trials and meta-analyses evaluating the use of the sodium-glucose cotransporter type 2 inhibitor dapagliflozin administered as monotherapy or in combination with metformin. RESULTS: Fourteen studies were included for this review, six of which evaluated dapagliflozin in combination with metformin, one of which evaluated dapagliflozin monotherapy, and four of which evaluated dapagliflozin as an add-on therapy to other antidiabetic agents. The combination of dapagliflozin and metformin resulted in an A1C decrease of up to 2%, weight loss of 2-3 kg, and modest systolic blood pressure decrease of 3-5 mmHg. However, long-term effects on cancer and cardiovascular health are still being investigated. Providing patients with a fixed-dose combination therapy such as dapagliflozin-metformin XR can increase medication adherence and patient satisfaction, and improve glycemic control. Dapagliflozin-metformin XR is ideal because it can be administered orally once a day, is associated with a low risk of hypoglycemia, and provides the added benefit of weight reduction and modest blood pressure lowering. CONCLUSION: The unique combined mechanism of action and favorable efficacy and safety profile of dapagliflozin-metformin XR support consideration of this fixed-dose combination as a treatment option for patients with T2DM. PMID- 26966385 TI - Emery-Dreifuss muscular dystrophy: a test case for precision medicine. AB - Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of scapulohumeroperoneal muscle weakness, joint contractures, and cardiac defects that include arrhythmias and dilated cardiomyopathy. Although there is a defining group of clinical findings, the proteins responsible and their underlying gene defects leading to EDMD are varied. A common aspect of the gene defects is their involvement in, or with, the nuclear envelope. Treatment approaches are largely based on clinical symptoms. The genetic diversity of EDMD predicts that a cure will ultimately depend upon the individual's defect at the gene level, making this an ideal candidate for a precision medicine approach. PMID- 26966386 TI - The cost-utility of treating anemia with continuous erythropoietin receptor activator or Epoetin versus routine blood transfusions among chronic hemodialysis patients. AB - OBJECTIVE: The purpose of this study was to determine the cost-utility of treating anemic dialysis patients with continuous erythropoietin receptor activator (CERA) once monthly or Epoetin Beta (EpoB) thrice weekly compared with a reference strategy of managing anemia with red blood cell transfusion (RBCT). METHODS: Cost-utility analysis study design. Decision analysis model, National health care payer, over 1 year with the publicly funded health care system. Chronic hemodialysis patients with renal anemia were included. The outcome marker of this study was the incremental cost per quality-adjusted life-year (QALY) gained (incremental cost-utility ratio [ICUR]) of CERA or EpoB relative to RBCT. RESULTS: The total cost per patient (in US$) was estimated at $2,176.37, $4,107.01, and $4,356.69 for RBCT, CERA, and EpoB, respectively. The cost-utility ratio was calculated at 4,423.52, 6,955.50, and 7,406.38 $/QALY for RBCT, CERA, and EpoB, with an ICUR of CERA and EpoB in relation to RBCT at 19,606.40 and 22,466.09 $/QALY, respectively. In sensitivity analysis, the model was most sensitive to hospitalization costs, hospital stay, and annual number of RBCT units. Also, assuming utility and survival improvement with erythropoiesis stimulating agents use resulted in a decrease in ICUR at 13,429 $/QALY for CERA and 15,331 $/QALY for EpoB. In probabilistic sensitivity analysis, the main results of our model were unchanged; CERA and EpoB were more costly and more effective than RBCT below a threshold of 19,500 $/QALY. CERA was the best option for a willingness to pay over 19,500 $/QALY. LIMITATIONS: Some model parameters were obtained from observational data, the comparator RBCT is not the standard of care. CONCLUSION: Our study suggests that managing anemia in dialysis patients with CERA or EpoB may result in better outcomes with higher overall costs. Considering different assumptions, we found substantial variability in the estimates of the cost-utility and incremental of using CERA or EpoB. PMID- 26966384 TI - In vitro study of RRS HA injectable mesotherapy/biorevitalization product on human skin fibroblasts and its clinical utilization. AB - Mesotherapy/biorevitalization with hyaluronic acid (HA) is a treatment approach currently used for skin rejuvenation. Various products with a wide range of polycomponent formulations are available on the market. Most of these formulations contain noncross-linked HA in combination with a biorevitalization cocktail, formed by various amounts of vitamins, minerals, amino acids, nucleotides, coenzymes, and antioxidants. Although ingredients are very similar among the different products, in vitro and clinical effects may vary substantially. There is a real need for better characterization of these products in terms of their action on human skin or in vitro skin models. In this study, we analyzed the effect of the RRS((r)) (Repairs, Refills, Stimulates) HA injectable medical device on human skin fibroblasts in vitro. Skin fibroblast viability and its capacity to induce the production of key extracellular matrix were evaluated in the presence of different concentrations of RRS HA injectable. Viability was evaluated through colorimetric MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay, and key extracellular matrix genes, type I collagen and elastin, were quantified by quantitative polymerase chain reaction. Results demonstrated that RRS HA injectable could promote human skin fibroblast viability (+15%) and increase fibroblast gene expression of type I collagen and elastin by 9.7-fold and 14-fold in vitro, respectively. These results demonstrate that mesotherapy/biorevitalization products can, at least in vitro, effectively modulate human skin fibroblasts. PMID- 26966387 TI - Quality of life under oxycodone/naloxone, oxycodone, or morphine treatment for chronic low back pain in routine clinical practice. AB - OBJECTIVE: To compare the quality of life of patients with moderate-to-severe chronic low back pain under treatment with the WHO-step III opioids oxycodone/naloxone, oxycodone, or morphine in routine clinical practice. STUDY DESIGN: Prospective, 12-week, randomized, open-label, blinded end-point study in 88 medical centers in Germany. PATIENTS AND METHODS: A total of 901 patients requiring around-the-clock pain treatment with a WHO-step III opioid were randomized to either morphine, oxycodone, or oxycodone/naloxone (1:1:1). Changes from baseline to week 12 in quality of life were assessed using different validated tools (EuroQoL-5 Dimensions [EQ-5D], Short Form 12 [SF-12], quality of life impairment by pain inventory [QLIP]). RESULTS: EQ-5D weighted index scores significantly improved over the 12-week treatment period under all three opioids (P<0.001) with significantly greater improvements under oxycodone/naloxone (65.2% vs 49.6% for oxycodone and 48.2% for morphine, P<0.001). The proportion of patients without EQ-5D complaints was also significantly higher under oxycodone/naloxone (P<0.001). Although quality of life ratings with the QLIP inventory showed significant improvements in all the three treatment arms, improvements were significantly higher under oxycodone/naloxone than under oxycodone and morphine (P<0.001): 90.7% of all oxycodone/naloxone patients achieved >=30% improvements in quality of life, 72.8% had >=50%, and 33.2% >=70% improvements. Similarly, both physical and mental SF-12 component scores showed significantly greater improvements under oxycodone/naloxone with both scores close to the German population norm after 12 weeks. CONCLUSION: Treatment with morphine, oxycodone, or oxycodone/naloxone under routine daily practice conditions significantly improved state of health and quality of life of patients with moderate-to-severe low back pain over a 12-week treatment period. Comparison between the treatment groups showed significantly greater improvements for oxycodone/naloxone than for the other two opioids. PMID- 26966388 TI - Not everything that can be done should be done. PMID- 26966389 TI - Autophagy Induction Protects Against 7-Oxysterol-induced Cell Death via Lysosomal Pathway and Oxidative Stress. AB - 7-Oxysterols are major toxic components in oxidized low-density lipoprotein and human atheroma lesions, which cause lysosomal membrane permeabilization (LMP) and cell death. Autophagy may function as a survival mechanism in this process. Here, we investigated whether 7-oxysterols mixed in an atheroma-relevant proportion induce autophagy, whether autophagy induction influences 7-oxysterol-mediated cell death, and the underlying mechanisms, by focusing on cellular lipid levels, oxidative stress, and LMP in 7-oxysterol-treated macrophages. We found that 7 oxysterols induced cellular lipid accumulation, autophagy dysfunction, and cell death in the form of both apoptosis and necrosis. Exposure to 7-oxysterols induced autophagic vacuole synthesis in the form of increased autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and LC3 phosphatidylethanolamine conjugate (LC3-II) and autophagic vacuole formation. This led to an accumulation of p62, indicating a reduction in autophagic vacuole degradation. Importantly, autophagy induction significantly reduced 7-oxysterol mediated cell death by diminishing LMP and oxidative stress. Moreover, autophagy induction minimized cellular lipid accumulation induced by 7-oxysterols. These findings highlight the importance of autophagy in combating cellular stress, LMP, and cell death in atherosclerosis. Therefore, activation of the autophagy pathway may be a potential therapeutic strategy for prevention of necrotic core formation in atherosclerotic lesions. PMID- 26966391 TI - Smoking Knowledge, Attitude, and Practices Among Health Care Professionals from Sulaymaniyah City/Iraq. AB - BACKGROUND: Smoking is a serious risk to health globally. Health care professionals play a key role in the prevention of smoking as they are considered a role model by patients. OBJECTIVES: The aims of this study are to evaluate smoking rate among physicians and dentists from Sulaymaniyah, Iraqi Kurdistan, Iraq, and to understand their knowledge and attitudes toward tobacco smoking. METHODS: A cross-sectional web-based survey was conducted involving physicians and dentists working in both University of Sulaimani and Sulaymaniyah Teaching Hospitals. A questionnaire created based on World Health Organization Global Health Professional Survey with slight modifications was emailed to the study participants and the responses received were analyzed. RESULTS: Incidence of smoking among physicians and dentists was 26.5%, with a significantly higher rate among male compared to female health care professionals. The mean age of starting smoking was 22.3 (+/-4.8) years. Only 7.3% of health care professionals received formal training on smoking cessation. All responders agreed that smoking is harmful to health. However, ever smokers compared to never smokers were less likely to agree that health care professionals should set a positive impact by not smoking. CONCLUSION: Smoking rate is high among physicians and dentists from Sulaymaniyah city/Iraq, and at the same time, there is a low rate of training on smoking cessation. PMID- 26966393 TI - A Unique Procedure to Identify Cell Surface Markers Through a Spherical Self Organizing Map Applied to DNA Microarray Analysis. AB - To identify cell-specific markers, we designed a DNA microarray platform with oligonucleotide probes for human membrane-anchored proteins. Human glioma cell lines were analyzed using microarray and compared with normal and fetal brain tissues. For the microarray analysis, we employed a spherical self-organizing map, which is a clustering method suitable for the conversion of multidimensional data into two-dimensional data and displays the relationship on a spherical surface. Based on the gene expression profile, the cell surface characteristics were successfully mirrored onto the spherical surface, thereby distinguishing normal brain tissue from the disease model based on the strength of gene expression. The clustered glioma-specific genes were further analyzed by polymerase chain reaction procedure and immunocytochemical staining of glioma cells. Our platform and the following procedure were successfully demonstrated to categorize the genes coding for cell surface proteins that are specific to glioma cells. Our assessment demonstrates that a spherical self-organizing map is a valuable tool for distinguishing cell surface markers and can be employed in marker discovery studies for the treatment of cancer. PMID- 26966390 TI - Epigenetic Mechanisms of the Aging Human Retina. AB - Degenerative retinal diseases, such as glaucoma, age-related macular degeneration, and diabetic retinopathy, have complex etiologies with environmental, genetic, and epigenetic contributions to disease pathology. Much effort has gone into elucidating both the genetic and the environmental risk factors for these retinal diseases. However, little is known about how these genetic and environmental risk factors bring about molecular changes that lead to pathology. Epigenetic mechanisms have received extensive attention of late for their promise of bridging the gap between environmental exposures and disease development via their influence on gene expression. Recent studies have identified epigenetic changes that associate with the incidence and/or progression of each of these retinal diseases. Therefore, these epigenetic modifications may be involved in the underlying pathological mechanisms leading to blindness. Further genome-wide epigenetic studies that incorporate well characterized tissue samples, consider challenges similar to those relevant to gene expression studies, and combine the genome-wide epigenetic data with genome wide genetic and expression data to identify additional potentially causative agents of disease are needed. Such studies will allow researchers to create much needed therapeutics to prevent and/or intervene in disease progression. Improved therapeutics will greatly enhance the quality of life and reduce the burden of disease management for millions of patients living with these potentially blinding conditions. PMID- 26966394 TI - Molecular Characterization and Bioinformatics Analysis of a Prophenoloxidase-1 (PPO1) in Plutella xylostella. AB - Phenoloxidase (PO) is an important enzyme in insect life, which is involved in important physical functions, such as defensive encapsulation and melanization of foreign organisms and wound healing. In this study, we obtained a cDNA sequence of 2838 bp with 2049 open reading frames encoding 682 amino acids. The protein sequence deduced from the cDNA has high homology with the known PPO1 sequences of other lepidopterous insects. There were three conserved regions, including the two copper-binding sites characteristic of arthropod PPOs. The whole PxPPO1 DNA was also obtained with 7202 bp when the five fragments were stitched together and the overlapping sequences were deleted. The PxPPO1 DNA consists of 11 introns and 12 exons, and the homology is 99.9% when the exons are compared with the above cDNA. Moreover, the gene expression levels were also determined by semiquantitative polymerase chain reaction (PCR), Western blotting, and real-time quantitative PCR; the results indicated that PxPPO1 transcripts in the eggs and the fourth instar larvae were more abundant, followed by the second and the third instar larvae, prepupae, and pupa. PMID- 26966395 TI - Serum and Urinary Interleukin-6 in Assessment of Renal Activity in Egyptian Patients with Systemic Lupus Erythematosus. AB - AIM OF THE WORK: This study investigates whether serum and urinary interleukin-6 (IL-6) represent an early marker of kidney involvement and assesses the difference between them and renal biopsy in lupus nephritis (LN). PATIENTS AND METHODS: A total of 60 systemic lupus erythematosus (SLE) patients were compared to 20 healthy controls. Urinary and serum IL-6 were measured in both patients and controls. In addition, renal biopsy was done prior or shortly after urine and blood sampling; the results were classified according to the International Society of Nephrology/Renal Pathology Society classification of LN by recording the activity score and chronicity score for each sample. RESULTS: There was a significant higher level of urinary IL-6 in the SLE patients with biopsy-proven LN than in those without LN and those of the control group. However, no significant difference was reported between the three groups as regards serum IL 6. A strong positive correlation was found between urinary IL-6 and renal disease activity based on the renal SLE disease activity index (SLEDAI) score with no significant correlation regarding the extra renal SLEDAI. Urinary IL-6 was positively correlated with renal biopsy results and with its activity scores but weakly correlated with the chronicity scores. CONCLUSION: Urinary IL-6 may provide a simple noninvasive potential marker of disease activity of renal involvement in adult patients with SLE. PMID- 26966392 TI - Lysophospholipid receptors LPA1-3 are not required for the inhibitory effects of LPA on mouse retinal growth cones. AB - One of the major requirements in the development of the visual system is axonal guidance of retinal ganglion cells toward correct targets in the brain. A novel class of extracellular lipid signaling molecules, lysophospholipids, may serve as potential axon guidance cues. They signal through cognate G protein-coupled receptors, at least some of which are expressed in the visual system. Here we show that in the mouse visual system, a lysophospholipid known as lysophosphatidic acid (LPA) is inhibitory to retinal neurites in vitro when delivered extracellularly, causing growth cone collapse and neurite retraction. This inhibitory effect of LPA is both active in the nanomolar range and specific compared to the related lysophospholipid, sphingosine 1-phosphate (S1P). Knockout mice lacking three of the five known LPA receptors, LPA1-3, continue to display retinal growth cone collapse and neurite retraction in response to LPA, demonstrating that these three receptors are not required for these inhibitory effects and indicating the existence of one or more functional LPA receptors expressed on mouse retinal neurites that can mediate neurite retraction. PMID- 26966396 TI - Radical Surgery for Endometriosis: Analysis of Quality of Life and Surgical Procedure. AB - OBJECTIVE: The main aim of this study is to determine the improvement in quality of life in patients who have undergone radical surgery because of severe endometriosis. PATIENTS AND METHODS: This nonrandomized interventional study (quasi experimental) was carried out between January 2009 and September 2014. A total of 46 patients with diagnosis of severe endometriosis were included. Radical surgery, including hysterectomy, was performed. Acting as their own control group, the patients were asked to fill in a validated questionnaire of quality of life [Endometriosis Health Profile-5 (EHP-5)] and a visual analog scale of pain at the moment of the preoperative visit (one month prior to surgery) and six months after the surgery. RESULTS: Radical surgery for endometriosis was performed in 46 patients at our center over the period of six years. Among the patients, 73.9% of them had undergone previous surgery for endometriosis. In 82.6% of cases, a complete laparoscopic resection was carried out. Gastrointestinal tract resection was performed in 21.7%, and urinary tract resection was necessary in 8.7%. The mean age of the patients was 38.6 years. The rate of complications was 30.4%. Six months after the surgery, all items of the EHP-5 questionnaire had a lower score, which means an improvement in all aspects of quality of life related to endometriosis. The difference obtained between the scores before and after the surgery was statistically significant. The mean visual analog scale score before the surgery was 8.5, whereas it decreased to 1.4 after the surgery (P < 0.001). CONCLUSION: Performing a radical surgery is a difficult decision to make; however, it can provide optimal results in terms of improvement of quality of life and, therefore, should be considered when conservative therapy fails. PMID- 26966398 TI - The second Current Oncology Scholar's Conference. PMID- 26966399 TI - Expression and clinical significance of insulin-like growth factor 1 in lung cancer tissues and perioperative circulation from patients with non-small-cell lung cancer. AB - OBJECTIVE: We explored the role of insulin-like growth factor 1 (igf-1) in the development of lung cancer. METHODS: We used immunohistochemistry to measure the expression of igf-1 and igf-1 receptor (igf-1r) in specimens of tissue and perioperative circulation from 80 patients with primary non-small-cell lung cancer (nsclc) and from 45 patients with benign pulmonary lesions (bpls). Correlations of those measurements with clinicopathologic characteristics and clinical follow-up were analyzed. Circulating igf-1 was measured before and after surgery in all patients. RESULTS: Compared with bpl specimens, nsclc specimens showed overexpression of igf-1and igf-1r (p < 0.001). The expression levels of igf-1 and igf-1r were significantly associated with advanced-stage disease (p = 0.034 and 0.029 respectively) and lymph node metastasis (p = 0.012 and 0.017 respectively), and expression of igf-1 correlated with tumour differentiation and tumour diameter (p = 0.011 and 0.021 respectively). Specimens positive for igf-1 or igf-1r were significantly correlated with shorter patient survival (p = 0.0012 and 0.0016 respectively). After surgery, circulating igf-1 was significantly elevated in patients with bpl (p = 0.0346) and significantly lower in patients with nsclc (p = 0.0030), especially in those with advanced-stage disease, a larger tumour size, regional lymphoid node metastasis, or lesser differentiation (p = 0.0092, 0.0051, 0.0131, and p < 0.001 respectively). CONCLUSIONS: In nsclc, igf-1 and igf-1r are upregulated, and expression of those factors is correlated with tumour progression and prognosis in nsclc patients. Radical resection of nsclc can directly influence the serum concentration of igf-1. Autocrine/paracrine igf-1 might be playing an important role in the development of lung cancer. PMID- 26966400 TI - Quebec public funding facilitates fertility preservation for male cancer patients. AB - BACKGROUND: Sperm cryopreservation remains the only clinically feasible option to preserve male fertility. The quality of counselling provided by the treating physicians and the cost of sperm cryopreservation can both influence a patient's decision about whether to preserve sperm. On 5 August 2010, the Quebec government introduced provincial coverage of assisted reproductive technologies, with sperm cryopreservation included as a covered service. The aim of the present study was to evaluate whether and how such a program affects the behaviour of cancer patients with respect to sperm cryopreservation. METHODS: We analyzed the database derived from male patients undergoing sperm cryopreservation from August 2008 to August 2012 at our centre. The retrieved data included patient age, male infertility or oncologic diagnosis, sperm quality parameters, and details about the number of visits for sperm cryopreservation. RESULTS: The number of cancer patients who cryopreserved sperm before and after the policy change did not differ significantly, but a marked increase in the number of non-cancer patients was observed. Further analysis revealed that, after implementation of the public funding program, the total number of sperm cryopreservation sessions per patient increased significantly in cancer patients but not in non-cancer patients. CONCLUSIONS: It appears that cancer patients who are willing to freeze sperm are keen to return for more sessions of sperm banking when no fees are associated with the service. Those findings suggest that cost reduction is an important factor for improving delivery of fertility preservation services to male cancer patients. PMID- 26966397 TI - A Review of Imaging Methods for Prostate Cancer Detection. AB - Imaging is playing an increasingly important role in the detection of prostate cancer (PCa). This review summarizes the key imaging modalities-multiparametric ultrasound (US), multiparametric magnetic resonance imaging (MRI), MRI-US fusion imaging, and positron emission tomography (PET) imaging-used in the diagnosis and localization of PCa. Emphasis is laid on the biological and functional characteristics of tumors that rationalize the use of a specific imaging technique. Changes to anatomical architecture of tissue can be detected by anatomical grayscale US and T2-weighted MRI. Tumors are known to progress through angiogenesis-a fact exploited by Doppler and contrast-enhanced US and dynamic contrast-enhanced MRI. The increased cellular density of tumors is targeted by elastography and diffusion-weighted MRI. PET imaging employs several different radionuclides to target the metabolic and cellular activities during tumor growth. Results from studies using these various imaging techniques are discussed and compared. PMID- 26966401 TI - Adenoid cystic carcinoma of head and neck: clinical predictors of outcome from a Canadian centre. AB - OBJECTIVES: Adenoid cystic carcinoma (acc) is often treated with surgery, with or without adjuvant radiation therapy (rt). We evaluated disease characteristics, treatments, and potentially prognostic variables in patients with acc. METHODS: Our retrospective analysis considered consecutive cases of acc presenting at a tertiary care hospital between 2000 and 2014. Factors predictive of overall survival (os) and disease-free survival (dfs) were identified by univariate analysis. RESULTS: The 60 patients analyzed had a mean age of 58 years (range: 22 88 years), with a 2:1 female:male ratio. Tumour locations included the major salivary glands (40% parotid, 17% submandibular and sublingual), the oro nasopharyngeal cavity (27%), and other locations (16%). Of the 60 patients, 35 (58%) received surgery with adjuvant rt; 12 (20%), rt only; 13 (22%), surgery only. Of 18 patients (30%) who experienced a recurrence within 5 years, 3 (5%) developed local recurrence only, and the remaining 15 (25%), distant metastasis. The 5-year os and dfs were 64.5% [95% confidence interval (ci): 45.9% to 78.1%] and 46.2% (95% ci: 29.7% to 61.2%) respectively. In patients without recurrence, 5-year os was 77% (95% ci: 52.8% to 89.9%), and in patients with recurrence, it was 42.7% (95% ci: 15.8% to 67.6%). Patients treated with rt only had a 5-year os of 9.2%. Predictors of 5-year dfs were TNM stage, T stage, nodal status, treatment received, and margin status; age, nodal status, treatment received, and margin status predicted 5-year os. CONCLUSIONS: Despite surgery and rt, one third of patients with acc experience distant recurrence. Patients whose tumours are not amenable to surgery have a poor prognosis, indicating a need for alternative approaches to improve outcomes. PMID- 26966403 TI - A Canadian perspective on the use of immunoglobulin therapy to reduce infectious complications in chronic lymphocytic leukemia. AB - Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (cll), who typically have increased susceptibility because of hypogammaglobulinemia (hgg) related to their disease and its treatment. Immunoglobulin replacement therapy (igrt) has been shown to reduce the frequency of bacterial infections and associated hospitalizations in patients with hgg or a history of infection, or both. However, use of igrt in cll is contentious. Studies examining such treatment were conducted largely before the use of newer chemoimmunotherapies, which can extend lifespan, but do not correct the hgg inherent to the disease. Thus, the utility of igrt has to be re-evaluated in the current setting. Here, we discuss the evidence for the use of igrt in cll and provide a practical approach to its use in the prevention and management of infections. PMID- 26966405 TI - Patterns of care and treatment trends for Canadian men with localized low-risk prostate cancer: an analysis of provincial cancer registry data. AB - BACKGROUND: Many prostate cancers (pcas) are indolent and, if left untreated, are unlikely to cause death or morbidity in a man's lifetime. As a result of testing for prostate-specific antigen, more such cases are being identified, leading to concerns about "overdiagnosis" and consequent overtreatment of pca. To mitigate the risks associated with overtreatment (that is, invasive therapies that might cause harm to the patient without tangible benefit), approaches such as active surveillance are now preferred for many men with low-risk localized pca (specifically, T1/2a, prostate-specific antigen <= 10 ng/mL, and Gleason score <= 6). Here, we report on patterns of care and treatment trends for men with localized low-risk pca. RESULTS: The provinces varied substantially with respect to the types of primary treatment received by men with localized low-risk pca. From 2010 to 2013, many men had no record of surgical or radiation treatment within 1 year of diagnosis-a proxy for active surveillance; the proportion ranged from 53.3% in Nova Scotia to 80.8% in New Brunswick. Among men who did receive primary treatment, the use of radical prostatectomy ranged from 12.0% in New Brunswick to 35.9% in Nova Scotia. The use of radiation therapy (external-beam radiation therapy or brachytherapy) ranged from 4.1% in Newfoundland and Labrador to 17.6% in Alberta. Treatment trends over time suggest an increase in the use of active surveillance. The proportion of men with low-risk pca and no record of surgical or radiation treatment rose to 69.9% in 2013 from 46.1% in 2010 for all provinces combined. CONCLUSIONS: The provinces varied substantially with respect to patterns of care for localized low-risk pca. Treatment trends over time suggest an increasing use of active surveillance. Those findings can further the discussion about the complex care associated with pca and identify opportunities for improvement in clinical practice. PMID- 26966406 TI - Eye-witnessing cancer-an ever-challenging experience. PMID- 26966402 TI - Targeting leukemia stem cells: which pathways drive self-renewal activity in T cell acute lymphoblastic leukemia? AB - T-Cell acute lymphoblastic leukemia (t-all) is a malignancy of white blood cells, characterized by an uncontrolled accumulation of T-cell progenitors. During leukemic progression, immature T cells grow abnormally and crowd into the bone marrow, preventing it from making normal blood cells and spilling out into the bloodstream. Recent studies suggest that only discrete cell populations that possess the ability to recreate the entire tumour might be responsible for the initiation and propagation of t-all. Those unique cells are commonly called "cancer stem cells" or, in the case of hematopoietic malignancies, "leukemia stem cells" (lscs). Like normal hematopoietic stem cells, lscs are thought to be capable of self-renewal, during which, by asymmetrical division, they give rise to an identical copy of themselves as well as to a daughter cell that is no longer capable of self-renewal activity and represents a more "differentiated" progeny. Here, we review the main pathways of self-renewal activity in lscs, focusing on their involvement in the maintenance and development of t-all. New stem cell-directed therapies and lsc-targeted agents are also discussed. PMID- 26966404 TI - Eastern Canadian Colorectal Cancer Consensus Conference 2013: emerging therapies in the treatment of pancreatic, rectal, and colorectal cancers. AB - The annual Eastern Canadian Colorectal Cancer Consensus Conference held in Montreal, Quebec, 17-19 October 2013, marked the 10-year anniversary of this meeting that is attended by leaders in medical, radiation, and surgical oncology. The goal of the attendees is to improve the care of patients affected by gastrointestinal malignancies. Topics discussed during the conference included pancreatic cancer, rectal cancer, and metastatic colorectal cancer. PMID- 26966407 TI - Relationship between HLA-DRB1 allele polymorphisms and familial aggregations of hepatocellular carcinoma. AB - OBJECTIVE: We explored the relationship between HLA-DRB1 allele polymorphisms and familial aggregation of hepatocellular carcinoma (fhcc). METHODS: Polymerase chain reaction sequence-specific primers were used to determine HLA-DRB1 genotypes for 130 members of families with 2 or more liver cancer patients and for 130 members of families without any diagnosed cancers. The genotype profiles were then compared to explore the relationship between HLA-DRB1 gene polymorphism and fhcc. RESULT: Of 11 selected alleles, the frequencies of DRB1*11 and DRB1*12 were significantly lower in the fhcc group than in no-cancer group (p < 0.05; odds ratio: 0.286; 95% confidence interval: 0.091 to 0.901; and odds ratio: 0.493; 95% confidence interval: 0.292 to 0.893). Differences in the frequencies of the other 9 alleles were not statistically significant in the two groups (p > 0.05). CONCLUSIONS: Our research suggests that if genetic factors play a role in fhcc, the deficiency in the DRB1*11 and DRB1*12 alleles might be the risk factor at work in Guangxi Zhuang Autonomous Region, P.R.C. PMID- 26966408 TI - Genetic polymorphisms of insulin-like growth factor 1 and insulin-like growth factor binding protein 3, xenoestrogen, phytoestrogen, and premenopausal breast cancer. AB - BACKGROUND: Previous studies suggest a combined effect of insulin-like growth factor 1 (igf-1) and igf binding protein 3 (igfbp-3) gene polymorphisms, xenoestrogen, and phytoestrogen on the igf-1 signalling pathway and serum concentrations in the igf system, which are associated with premenopausal breast cancer (bca) risk. METHODS: Between 2010 and 2012, our study recruited 140 premenopausal bca patients and 160 community-based premenopausal control subjects. Participants were surveyed about oral contraceptive (oc) use, dietary habits, and other bca risk factors. TaqMan assays were used to determine igf-1 rs1520220 and igfbp-3 rs2854744 genotypes. Daily intakes of energy-adjusted soy isoflavones (easis) were calculated by the residual method. Multivariate logistic regression was applied to estimate the adjusted odds ratios (ors) and 95% confidence intervals (cis) of the igf-1 rs1520220 and igfbp-3 rs2854744 genotypes, oc use, and intake of easis. Stratified analyses were performed to detect the gene-environment combined effect, and multivariate logistic regression was used to estimate interaction coefficients (iors) by the multiplicative model, with 95% cis. The delta method was used to calculate interaction coefficients by the additive model [relative excess risk of interaction (reri), attributable proportions of interaction (apis)] and 95% cis. RESULTS: The igf-1 and igfbp-3 genotypes, oc use, and easis were not found to be associated with bca risk (p > 0.05). Stratified analysis showed that the risk of bca was markedly increased in women carrying the igfbp-3C allele and using ocs compared with women either carrying the igfbp-3C allele or using ocs (or: 3.02; 95% ci: 1.04 to 8.79). The interaction coefficients ior, reri, and api were 4.89 (95% ci: 1.09 to 21.90), 2.42 (95% ci: -0.76 to 5.61), and 0.80 (95% ci: 0.46 to 1.67) respectively. CONCLUSIONS: The igfbp-3 rs2854744 polymorphism and oc use might synergistically increase premenopausal bca risk. PMID- 26966409 TI - Hepcidin and ferroportin expression in breast cancer tissue and serum and their relationship with anemia. AB - OBJECTIVE: Our correlation study investigated the relationships of the expression of hepcidin and ferroportin (fpn) in tissues and serum from breast cancer (bca) patients and the relationships of hepcidin and fpn with anemia. METHODS: We used elisa and immunohistochemistry to detect the expression of hepcidin and fpn in tissue and serum from 62 individuals with bca, and we analyzed correlations between hepcidin and fpn expression in tissue and in serum. At the same time, we evaluated the relationships between hepcidin, fpn, and anemia. RESULTS: Mean serum hepcidin was 8.18 +/- 3.75 MUg/L in bca patients with anemia and 4.53 +/- 2.07MUg/L in those without anemia, a statistically significant difference (t = 3.7090, p < 0.01). Mean serum fpn was obviously lower in the anemia group than in the non-anemia group (1.77 +/- 0.51 MUg/L vs. 2.46 +/- 0.52 MUg/L, t = 3.5115, p < 0.01). Serum hepcidin and hemoglobin were negatively correlated (r = -0.502, p < 0.01); however, serum fpn was positively correlated with hemoglobin, and serum hepcidin was negatively correlated with fpn. The rates of hepcidin and fpn expression in bca tissues were 50.0% and 61.2% respectively, but no association with anemia was observed. We also observed no relationship between expression of hepcidin and fpn in serum and in tissue. CONCLUSIONS: In bca patients, expression of hepcidin in serum was high, but expression of fpn was low, suggesting that serum hepcidin plays a major role in anemia in those patients. Expression of hepcidin and fpn in bca tissue showed no correlation with their expression in serum and no clear relationship with anemia. PMID- 26966410 TI - Effects of warm acupuncture on breast cancer-related chronic lymphedema: a randomized controlled trial. AB - BACKGROUND: Effective treatment for breast cancer-related chronic lymphedema (bcrl) remains a clinical challenge. Acupuncture and moxibustion treatments have been shown to be beneficial and safe for treating bcrl. In the present randomized controlled trial, we compared the effectiveness of combined acupuncture and moxibustion ("warm acupuncture") with that of diosmin in bcrl. METHODS: Breast cancer patients who met the inclusion and exclusion criteria (n = 30) were randomized to experimental and control groups (15 per group). On alternate days, patients in the experimental group received 30 minutes of acupuncture at 6 acupoints, with 3 of the needles each being topped by a 3-cm moxa stick. The control treatment was diosmin 900 mg 3 times daily. The control and experimental treatments were administered for 30 days. Outcome measures included arm circumferences (index of effectiveness), range of motion [rom (shoulder joint function)], quality of life, clinical safety, and adverse events. RESULTS: Measured by the index of effectiveness, bcrl improved by 51.46% in the experimental group and by 26.27% in the control group (p < 0.00001). Effects were greatest at 10 cm above the elbow and at the wrist, where the warm needling was provided. Impairments in shoulder joint rom were minimal at baseline in both treatment groups. However, the roms of rear protraction, abduction, intorsion, and extorsion in the experimental group improved significantly; they did not change in the control group. Self-reported quality of life was significantly better with warm acupuncture than with diosmin. No adverse effects were reported during the treatment period, and laboratory examinations for clinical safety fell within the normal ranges. CONCLUSIONS: Compared with diosmin, warm acupuncture treatment can effectively reduce the degree of bcrl at the specific acupoints treated and can promote quality of life. Warm acupuncture showed good clinical safety, without any adverse effects on blood or the cardiovascular system. PMID- 26966411 TI - In vitro and in vivo studies on the inhibitory effects of myocardial cell culture medium on growth of a human lung adenocarcinoma cell line, A549. AB - BACKGROUND: Although the heart is one of the body's vital organs, with an abundant blood supply, metastasis to the heart is considered rare. In a previous study, we found that the myocardial microenvironment might contain a low molecular weight natural tumour suppressor. The present study was designed to investigate the inhibitory effect of cardiac myocyte-conditioned medium (cmcm) on the growth of A549 human lung adenocarcinoma cells in vitro and in vivo. METHODS: An mtt assay was used to detect the inhibition ratio with respect to A549 proliferation. Human lung adenocarcinoma cells (A549 cell strain) were transplanted subcutaneously into nude mice to produce tumours. The xenograft tumour growth in mice was observed after selected drug administration. RESULTS: After treatment with cmcm and cisplatin (Cis), A549 cell viability significantly declined (p < 0.001). The cell viability in the cmcm and Cis groups were 53.42% +/- 3.45% and 58.45% +/- 6.39% respectively. Growth of implanted tumour cells in vivo was significantly inhibited in the cmcm group, the group treated with recombinant human adenovirus-p53, and the Cis-treated group compared with a control group. The inhibition rates were 41.44% in the cmcm group, 41.34% in the p53 group, and 64.50% in the Cis group. Lung metastasis capacity was significantly reduced in the presence of cmcm (p < 0.05). Lung metastasis inhibition rates in mice were 56.52% in the cmcm group, 47.83% in the p53 group, and 82.61% in the Cis group. With cmcm, the lives of A549-tumour-bearing mice could be significantly prolonged without any effect on weight loss. CONCLUSIONS: Use of cmcm has the effect of reducing A549 cell viability, tumour volume, and lung metastasis rate, while prolonging survival duration without severe toxicity. PMID- 26966412 TI - Dosimetric and clinical toxicity comparison of critical organ preservation with three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and RapidArc for the treatment of locally advanced cancer of the pancreatic head. AB - PURPOSE: We compared dosimetry and clinical toxicity for 3-dimensional conformal radiotherapy (3D-crt), intensity-modulated radiotherapy (imrt), and RapidArc (Varian Medical Systems, Palo Alto, CA, U.S.A.) in locally advanced pancreatic cancer (lapcc). We hypothesized that the technique with better sparing of organs at risk (oars) and better target dose distributions could lead to decreased clinical toxicity. METHODS: The study analyzed 280 patients with lapcc who had undergone radiotherapy. The dosimetry comparison was performed using 20 of those patients. Dose-volume histograms for the target volume and the oars were compared. The clinical toxicity comparison used the 280 patients who received radiation with 3D-crt, imrt, or RapidArc. RESULTS: Compared with 3D-crt, RapidArc and imrt both achieved a better conformal index, homogeneity index, V95%, and V110%. Compared with 3D-crt or imrt, RapidArc reduced the V10, V20, and mean dose to duodenum, the V20 of the right kidney, and the liver mean dose. Compared with 3D-crt, RapidArc reduced the V35, and V45 of duodenum, the mean dose to small bowel, and the V15 of right kidney. The incidences of grades 3 and 4 diarrhea (p = 0.037) and anorexia (p = 0.042) were lower with RapidArc than with 3D-crt, and the incidences of grades 3 and 4 diarrhea (p = 0.027) were lower with RapidArc than with imrt. CONCLUSIONS: Compared with 3D-crt or imrt, RapidArc showed better sparing of oars, especially duodenum, small bowel, and right kidney. Also, fewer acute grades 3 and 4 gastrointestinal toxicities were seen with RapidArc than with 3D-crt or imrt. A technique with better sparing of oars and better target dose distributions could result in decreased clinical toxicities during radiation treatment for lapcc. PMID- 26966413 TI - Cancer Evolution-Development: experience of hepatitis B virus-induced hepatocarcinogenesis. AB - Here, we present the basic concept and theoretical framework of a scientific hypothesis called Cancer Evolution-Development ("Cancer Evo-Dev"), based on our recent studies of the molecular mechanisms by which chronic infection with the hepatitis B virus induces hepatocarcinogenesis, together with related advances in that field. Several aspects central to our hypothesis are presented: ? Immune imbalance-caused by the interaction of genetic predispositions and environmental exposures such as viral infection-is responsible for the maintenance of chronic non-resolving inflammation. Non-resolving inflammation promotes the occurrence and progression of cancers, characterized by an evolutionary process of "mutation selection-adaptation" for both viruses and host cells.? Under a microenvironment of non-resolving inflammation, proinflammatory factors promote mutations in viral or host genomes by transactivation of the expression of cytidine deaminases and their analogues. Most cells with genomic mutations and mutated viruses are eliminated in the competition for survival in the inflammatory microenvironment. Only a small percentage of the mutated cells that alter their survival signal pathways and exhibit the characteristics of "stem-ness" can survive and function as cancer-initiating cells.? Cancers generally develop with properties of "backward evolution" and "retro-differentiation," indicating the indispensability of stem-like signal pathways in the evolution and development of cancers. The hypothesis of Cancer Evo-Dev not only lays the theoretical foundation for understanding the mechanisms by which inflammation promotes the development of cancers, but also plays an important role in specific prophylaxis, prediction, early diagnosis, and targeted treatment of cancers. PMID- 26966415 TI - Impact of oxaliplatin-induced neuropathy in patients with colorectal cancer: a prospective evaluation at a single institution. AB - Oxaliplatin plays a major role in the treatment of colorectal cancer (crc), but is associated with the development of neuropathies. The main objective of the present prospective study was to estimate the proportion of participants with grade 1, 2, 3, or 4 peripheral sensory neuropathies according to the U.S. National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4) among crc patients treated with oxaliplatin (adjuvant or metastatic, folfox or xelox regimens) at the Centre hospitalier universitaire de Sherbrooke. Among the 57 patients so treated between May 2012 and April 2013, about 60% reported grade 2 neuropathy, at maximum, during treatment. About 25% of patients had to stop treatment because of neuropathies. In a subset of patients contacted approximately 22 months after treatment cessation, neuropathies persisted in 70%. Oxaliplatin-induced neuropathy affects a significant number of crc patients and can influence the course of treatment and outcomes. PMID- 26966417 TI - A simple approach for eliminating spam. PMID- 26966416 TI - Synchronous rectal adenocarcinoma and splenic marginal zone lymphoma. AB - Synchronous cancers of different primary origin are rare. Here, we describe the case of a patient with concomitant diagnoses of rectal adenocarcinoma and splenic marginal zone lymphoma (smzl). A 57-year-old woman initially presented with abdominal pain. Physical examination and computed tomography demonstrated massive splenomegaly, and a complete blood count revealed microcytic anemia and lymphopenia. During the subsequent evaluation, she presented with hematochezia, melena, and constipation, which prompted gastroenterology referral. Subsequent endoscopic rectal ultrasonography revealed a T3N1 moderately differentiated rectal adenocarcinoma, with computed tomography imaging of chest, abdomen, and pelvis confirming no metastasis. Thus, the cancer was classified as clinical stage T3N1M0, stage iii. Bone marrow biopsy confirmed co-existing marginal zone lymphoma, and with the clinical presentation of massive splenomegaly, a diagnosis of smzl was made. The patient's management was individually tailored for simultaneous optimal treatment of both conditions. Concurrent treatment with neoadjuvant rituximab and 5-fluorouracil chemotherapy, with external-beam radiation therapy to the pelvis, was administered, followed by surgery consisting of en bloc splenectomy and distal pancreatectomy, and low anterior resection. The patient completed a standard course of adjuvant folfox (fluorouracil-leucovorin oxaliplatin) chemotherapy and has remained disease-free for 7 years. To our knowledge, this report is the first to specifically describe simultaneous diagnoses of locally advanced rectal cancer and smzl. We also describe the successful combined neoadjuvant treatment combination of 5-fluorouracil, rituximab, and pelvic radiation. PMID- 26966414 TI - Management of uveal melanoma: a consensus-based provincial clinical practice guideline. AB - INTRODUCTION: Survival in uveal melanoma has remained unchanged since the early 1970s. Because outcomes are highly related to the size of the tumour, timely and accurate diagnosis can increase the chance for cure. METHODS: A consensus-based guideline was developed to inform practitioners. PubMed was searched for publications related to this topic. Reference lists of key publications were hand searched. The National Guidelines Clearinghouse and individual guideline organizations were searched for relevant guidelines. Consensus discussions by a group of content experts from medical, radiation, and surgical oncology were used to formulate the recommendations. RESULTS: Eighty-four publications, including five existing guidelines, formed the evidence base. SUMMARY: Key recommendations highlight that, for uveal melanoma and its indeterminate melanocytic lesions in the uveal tract, management is complex and requires experienced specialists with training in ophthalmologic oncology. Staging examinations include serum and radiologic investigations. Large lesions are still most often treated with enucleation, and yet radiotherapy is the most common treatment for tumours that qualify. Adjuvant therapy has yet to demonstrate efficacy in reducing the risk of metastasis, and no systemic therapy clearly improves outcomes in metastatic disease. Where available, enrolment in clinical trials is encouraged for patients with metastatic disease. Highly selected patients might benefit from surgical resection of liver metastases. PMID- 26966418 TI - De-escalation of bone-targeted agents for metastatic prostate cancer. PMID- 26966419 TI - The ultra-performance liquid chromatography tandem mass spectrometry method for detection and quantification of C4NP in rat plasma and its application to pharmacokinetic studies. AB - INTRODUCTION: Combretastatins, which are excellent anticancer agents, are isolated from Combretum. A sensitive ultra-performance liquid chromatography tandem mass spectrometry method was developed and validated for the pharmacokinetic study of a combretastatin analog (C4NP) in rats. METHODS: Sample pretreatment was finished by simple protein precipitation in which methanol was added to plasma containing an internal standard (buspirone hydrochloride). Liquid chromatograph separation was accomplished on a reverse-phase Kinetex XB-C18 column [50*4.6 mm; internal diameter: 2.6 MUm (Phenomenex, Torrance, CA, U.S.A.)] with a gradient mobile phase of acetonitrile (0.05% formic acid, volume for volume) and water (0.05% formic acid) at a flow rate of 0.3 mL/min. The analytes were analyzed in the positive ion by electrospray ionization and quantified in the selective reaction monitoring mode. The entire procedure was validated following the U.S. Food and Drug Administration guidelines for bioanalytical methods validation. RESULTS: Our study investigated, for the first time, the detection and pharmacokinetic characteristics of C4NP in Sprague-Dawley rat plasma. The pharmacokinetic results suggest that C4NP is predominantly restricted to blood or extracellular fluid and is not extensively distributed to most organ tissues. In addition, C4NP can be cleared by renal filtration and active tubular secretion in Sprague-Dawley rats. Toxicokinetics of C4NP in these rats indicate that no saturation of the metabolic or excretion process occurs for C4NP, and metabolic induction and accumulation of toxic injury from multiple dosing are both absent. CONCLUSIONS: For 100 MUL of analyte, recovery plus high accuracy and reproducibility indicate that our new ultra-performance liquid chromatography tandem mass spectrometry method is a reliable and high-throughput analytical tool for the pharmacokinetic study of C4NP in rats. Those results should be useful for risk assessment. PMID- 26966420 TI - Evidence that phospholipase C is involved in the antitumour action of NSC768313, a new thieno[2,3-b]pyridine derivative. AB - BACKGROUND: The thieno[2,3-b]pyridines were discovered by virtual high throughput screening as potential inhibitors of phospholipase C (PLC) isoforms and showed potent growth inhibitory effects in National Cancer Institute's human tumour cell line panel (NCI60). The mechanism of the anti-proliferative activity of thieno[2,3-b]pyridines is explored here. OBJECTIVES: We aimed to investigate the basis for the anti-proliferative activity of these thieno[2,3-b]pyridines and to determine whether the cellular inhibition was related to their inhibition of PLC. METHODS: Four breast cancer cell lines were used to assess the anti-proliferative effects (IC50 values) of six representative thieno[2,3-b]pyridines. The most potent compound (derivative 3; NSC768313), was further studied in MDA-MB-231 cells. DNA damage was examined by gammaH2AX expression level, and cell cycle arrest by flow cytometry. Cell morphology was examined by tubulin antibody staining. The growth inhibitory effect of combination treatment with derivative 3 and paclitaxel (tubulin inhibitor), doxorubicin (topoisomerase II inhibitor) or camptothecin (topoisomerase I inhibitor) was evaluated. A preliminary mouse toxicity assay was used to evaluate the pharmacological properties. RESULTS: Addition of the thieno[2,3-b]pyridine derivative 3 to the MDA-MB-231 cells induced G2/M growth inhibition, cell cycle arrest in G2-phase, membrane blebbing and the formation of multinucleated cells. It did not induce DNA damage, mitotic arrest or changes in calcium ion flux. Combination of derivative 3 with paclitaxel showed a high degree of synergy, while combinations with doxorubicin and camptothecin showed only additive effects. A mouse pharmacokinetic study of derivative 3 showed that after intraperitoneal injection of a single does (10 mg/Kg), the Cmax was 0.087 MUmol/L and the half-life was 4.11 h. CONCLUSIONS: The results are consistent with a mechanism in which thieno[2,3-b]pyridine derivatives interact with PLC isoforms (possibly PLC-delta), which in turn affect the cellular dynamics of tubulin-beta, inducing cell cycle arrest in G2-phase. We conclude that these compounds have novelty because of their PLC target and may have utility in combination with mitotic poisons for cancer treatment. PMID- 26966422 TI - Use of Insurance Against a Small Loss as an Incentive Strategy. AB - The success of extended warranties and buyer protection plans suggests that insurance against a small loss has high decision utility. We explore whether the behavioral insight that people are highly averse to small chances of loss can be used to create a powerful incentive that has very low expected value. We compare decisions of individuals offered fixed payments for healthy choices to those offered insurance in exchange for healthy choices. We test the prediction that aversion to small losses will result in very high rates of health behavior uptake in exchange for insurance. Three hundred participants endowed with a $2 bonus randomly received one of two incentives for completing a scheduled health risk assessment: (1) an insurance guarantee against the 1% risk of losing the $2 bonus or (2) a fixed payment at the expected value of the insurance. Relative to the fixed payment condition, participants in the insurance intervention were 70% more likely to meet their health risk assessment appointment (p < 0.01). Fixed payments of $2.59 were needed for every $1 spent on insurance to achieve the same behavioral effect. Loss aversion, probability weighting, and the certainty effect may account for this result. Incentive design may benefit from utilizing an insurance paradigm. PMID- 26966421 TI - MicroRNA biogenesis and their functions in regulating stem cell potency and differentiation. AB - Stem cells are unspecialized/undifferentiated cells that exist in embryos and adult tissues or can be converted from somatic differentiated cells. Use of stem cells for tissue regeneration and tissue engineering has been a cornerstone of the regenerative medicine. Stem cells are also believed to exist in cancer tissues, namely cancer stem cells (CSCs). Growing evidence suggests that CSCs are the culprit of cancer dormancy, progression and recurrence, and thus have recently received great attention. MicroRNAs (miRNAs) are a group of short, non coding RNAs that regulate expression of a wide range of genes at a post transcriptional manner. They are emerging as key regulators of stem cell behaviors. This mini review summarizes the basic biogenesis and mode of actions of miRNAs, recent progress and discoveries of miRNAs in cellular reprogramming, stem cell differentiation and cellular communication, as well as miRNAs in CSCs. Some potential of miRNAs in future biomedical applications and research pertaining to stem cells are briefly discussed. PMID- 26966423 TI - Enzymatic saccharification and lactic acid production from banana pseudo-stem through optimized pretreatment at lowest catalyst concentration. AB - This work estimates the potential of banana pseudo-stem with high cellulosic content 42.2-63 %, for the production of fermentable sugars for lactic acid production through statistically optimized pretreatment method. To evaluate the catalyzed pretreatment efficiency of banana pseudo stem based on the enzymatic digestibility, Response Surface Methodology (RSM) was employed for the optimization of pretreatment temperature and time using lowest concentrations of H2SO4, NaOH, NaOH catalyzed Na2S and Na2SO3 that seemed to be significant variables with P<0.05. High F and R (2) values and low p-value for hydrolysis yield indicated the model predictability. The optimized condition for NaOH was determined to be conc. 1 %, temperature 130 (o)C for 2.6 hr; Na2S; conc. 1 %, temperature 130 (o)C for 2.29 hr; Na2SO3; conc. 1 %, temperature 130 (o)C for 2.41 hr and H2SO4; conc. 1 %, temperature 129.45 (o)C for 2.18 hr, produced 84.91 %, 85.23 %, 81.2 % and 76.02 % hydrolysis yield, respectively. Sulphuric acid provided 33+1 gL(-1) reducing sugars in pretreatment step along with 38+0.5 gL( 1) during enzymatic hydrolysis. Separate hydrolysis and fermentation of resulting sugars showed that the conversion of glucans into lactic acid reached 92 % of the theoretical yield of glucose. PMID- 26966424 TI - The protective effects of pomelo extract (Citrus grandis L. Osbeck) against fructose-mediated protein oxidation and glycation. AB - Chronic hyperglycemia induces non-enzymatic protein glycation, which plays an important role in the development of diabetic complications. Immense efforts have been made to determine effective antiglycation compounds from natural products. Pomelo has shown beneficial effects for human health. The objective of this study was to determine the antiglycation effect of pomelo extract against fructose mediated protein oxidation and glycation. Our results showed that the pomelo extract (0.25 - 2.00 mg/mL) significantly inhibited the overall formation of advanced glycation end products (AGEs) in a concentration-dependent manner. The pomelo extract markedly decreased the level of fructosamine, which is directly associated with reduction in formation of AGEs and N (epsilon) (carboxymethyl)lysine (CML). In addition, the pomelo extract inhibited protein oxidation through its ability to prevent the loss of thiol groups and reduced protein carbonyl formation. We characterized the active components in the pomelo extract by using high-performance liquid chromatography (HPLC), which showed that the pomelo extract contained naringin (11.90 +/- 0.21 mg/g dried extract), hesperidin (12.04 +/- 0.12 mg/g dried extract), neohesperidin (25.4 +/- 0.12 mg/g dried extract), and naringenin (9.20 +/- 0.19 mg/g dried extract). Our findings could provide a new insight into the antiglycation properties of the extract of the naturally occurring fruit pomelo for preventing AGE-mediated diabetic complications. PMID- 26966425 TI - Natural porous and nano fiber chitin structure from Gammarus argaeus (Gammaridae Crustacea). AB - Chitin and its derivatives are commercially important biopolymers due to their applications in medicine, agriculture, water treatment, cosmetics and various biotechnological areas. Since chitin and its derivatives exhibit different chemical and physical properties depending on the source and isolation method, there is a growing demand for new chitin sources other than crab and shrimp worldwide. In this study Gammarus, a Crustacea, was investigated as a novel chitin source. Gammarus, which belongs to the family Gammaridae Crustacea, lives in the bottom of aquatic ecosystems. More than 200 species are known worldwide. One of these species, G. argaeus was investigated for chitin isolation. The alpha chitin isolated from G. argaeus was characterized by using analysis techniques such as infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), X-ray diffraction (XRD) and scanning electron microscopy (SEM). All these analyses confirmed that the isolated chitin from G. argaeus was in the alpha form. Furthermore, we described that dry weight of this species contained 11-12 % chitin. SEM examination of the isolated alpha-chitin revealed that it was composed of nanofibrils (15-55 nm) and pores (about 150 nm). PMID- 26966426 TI - Association between individual ovarian dimensions with ovarian reserve indices. AB - INTRODUCTION: In some young female candidates of assisted reproductive technology (ART), ovarian response to simulative treatments is less than what is expected. More precise assessment of oocyte quality and quantity through studying ovarian dimensions can be useful for determining the dose of ovarian stimulant drugs and for preventing ART cycles cancellation. The aim of the present study is to determine the association between ovarian dimensions and ovarian reserve (OR) indices and whether ovarian dimensions can predict ovarian reserve. METHODS: In this cross-sectional study, 85 infertile women were studied. In early follicular phase, ovarian diameters (including length and width of the ovaries) were measured using transvaginal ultrasonography. Mean ovarian diameters (MOD) were calculated according to average length and width of the ovaries. A serum sample was taken from all patients to measure the level of Follicular Stimulating Hormone (FSH) and oestradiol as OR indices. RESULTS: The results of univariate analysis showed that FSH and oestradiol had a negative significant association with width, length and MOD (P < 0.01). The results of multivariate regression analysis showed that FSH and oestradiol had a negative significant association with width (betaFSH = -0.59, P = 0.001 and betaOestradiol = -0.019, P = 0.029) and MOD (betaFSH = -0.52, P = 0.003 and betaOestradiol = -0.021, P = 0.017) and had a borderline negative significant correlation with ovarian length (betaFSH = 0.49, P=0.077 and betaOestradiol = 0.022, P = 0.08) CONCLUSIONS: The results of this study revealed that despite a moderate correlation, ovarian diameters could be an applicable index for predicting OR. Using this method along with other methods may be useful in treatment with ovarian stimulants. PMID- 26966427 TI - Hematological alterations in diabetic rats - Role of adipocytokines and effect of citrus flavonoids. AB - Dysfunction in adipocytes is associated with insulin resistance and type 2 diabetes. Diabetes-associated anemia has been reported due to the increased non enzymatic glycosylation of RBC membrane proteins, which correlates with hyperglycemia. The present study was hypothesized to assess the effect of citrus flavonoids on hematological parameters and adipose tissue interleukin-6 and adiponectin in type 2 diabetic rats. Diabetes was induced by feeding rats with a high fat diet for 2 weeks followed by an intraperitoneal injection of streptozotocin. An oral dose of 50 mg/kg hesperidin or naringin was daily given for 4 weeks after diabetes induction. By the end of the experiment, blood samples were collected and were immediately used for determination of haematological parameters. Expression levels of adiponectin and interleukin-6 were assayed in adipose tissue samples. Both hesperidin and naringin significantly improved the levels of erythrocytes, leukocytes and their functional indices. Similarly, supplementation with either compound significantly ameliorated the declined adipose tissue adiponectin expression in conjunction with down-regulated interleukin-6. The findings of the present study indicated that hesperidin and naringin exert protection to diabetes-associated anemia in type 2 diabetic rats. This could be due to attenuation of proinflammatory cytokine production and stimulation of adiponectin expression. PMID- 26966428 TI - Post-operative acute kidney injury in non-suprainguinal vascular surgery patients with a pre-operative history of hypertension. AB - Hypertension is an independent predictor of acute kidney injury (AKI) in non cardiac surgery patients. There are a few published studies which report AKI following non-suprainguinal vascular procedures, but these studies have not investigated predictors of AKI, including anti-hypertensive medications and other comorbidities, in the hypertensive population alone. We sought to identify independent predictors of post-operative AKI in non-suprainguinal vascular surgery patients with a pre-operative history of hypertension. We performed univariate (chi-squared, or Fisher's exact testing) and multivariate (binary logistic regression) statistical analysis of prospectively collected data from 243 adult hypertensive patients who underwent non-suprainguinal vascular surgery (lower limb amputation or peripheral artery bypass surgery) at a tertiary hospital between 2008 and 2011 in an attempt to identify possible associations between comorbidity, acute pre-operative antihypertensive medication administration, and post-operative AKI (a post-operative increase in serum creatinine of >= 25 % above the pre-operative measurement) in these patients. The incidence of post-operative AKI in this study was 5.3 % (95 % Confidence Interval: 3.2-8.9 %). Acute pre-operative beta-blocker administration was independently associated with post-operative AKI in non-suprainguinal vascular surgery patients with a pre-operative history of hypertension (Odds Ratio: 3.24; 95 % Confidence Interval: 1.03-10.25). The acute pre-operative administration of beta-blockers should be carefully considered in non-suprainguinal vascular surgery patients with a pre-operative history of hypertension, in lieu of an increased risk of potentially poor post-operative renal outcomes. PMID- 26966429 TI - New Imaging in Gastrointestinal Tract. PMID- 26966430 TI - Synergistic Effects of Simvastatin and Irinotecan against Colon Cancer Cells with or without Irinotecan Resistance. AB - Aims. We here investigated whether the combination of simvastatin and irinotecan could induce the synergistic effect on colon cancer cells with or without resistance to irinotecan. Methods. We investigated cell proliferation assay and assessed cell death detection ELISA and caspase-3 activity assay of various concentrations of simvastatin and irinotecan to evaluate the efficacy of drug combination on colon cancer cells with or without irinotecan resistance. Results. The IC50 values of simvastatin alone and irinotecan alone were 115.4 +/- 0.14 MUM (r = 0.98) and 62.5 +/- 0.18 MUM (r = 0.98) in HT-29 cells without resistance to irinotecan. The IC50 values of these two drugs were 221.9 +/- 0.22 MUM (r = 0.98) and 195.9 +/- 0.16 MUM (r = 0.99), respectively, in HT-29 cell with resistance to irinotecan. The results of combinations of the various concentrations of two drugs showed that combined treatment with irinotecan and simvastatin more efficiently suppressed cell proliferation of HT-29 cells even with resistance to irinotecan as well as without resistance. Furthermore, the combination of simvastatin and irinotecan at 2 : 1 molar ratio showed the best synergistic interaction. Conclusion. Simvastatin could act synergistically with irinotecan to overcome irinotecan resistance of colon cancer. PMID- 26966431 TI - Extensive Use of Interventional Therapies Improves Survival in Unresectable or Recurrent Intrahepatic Cholangiocarcinoma. AB - Aim. To assess the outcomes of patients with unresectable intrahepatic cholangiocellular carcinoma (ICC) treated by a tailored therapeutic approach, combining systemic with advanced image-guided local or locoregional therapies. Materials and Methods. Treatment followed an algorithm established by a multidisciplinary GI-tumor team. Treatment options comprised ablation (RFA, CT guided brachytherapy) or locoregional techniques (TACE, radioembolization, i.a. chemotherapy). Results. Median survival was 33.1 months from time of diagnosis and 16.0 months from first therapy. UICC stage analysis showed a median survival of 15.9 months for stage I, 9 months for IIIa, 18.4 months for IIIc, and 13 months for IV. Only the number of lesions, baseline serum CEA and serum CA19-9, and objective response (RECIST) were independently associated with survival. Extrahepatic metastases had no influence. Conclusion. Patients with unresectable ICC may benefit from hepatic tumor control provided by local or locoregional therapies. Future prospective study formats should focus on supplementing systemic therapy by classes of interventions ("toolbox") rather than specific techniques, that is, local ablation leading to complete tumor destruction (such as RFA) or locoregional treatment leading to partial remission (such as radioembolization). This trial is registered with German Clinical Trials Registry (Deutsche Register Klinischer Studien), DRKS-ID: DRKS00006237. PMID- 26966432 TI - The Relationship of the Subclavius Muscle with Relevance to Venous Cannulation below the Clavicle. AB - Introduction. The catheter "pinch-off syndrome" has been described to be secondary to crimping of the catheter between the clavicle and the first rib, as well as entrapment of the catheter at the site of penetration of the subclavius muscle. The lateral insertion technique has been recommended to prevent catheter pinch-off, but it is unknown if this technique can prevent entrapment by the subclavius muscle. We undertook this study to evaluate the anatomical relationship of the subclavius muscle and the subclavian vein. Methods. Twenty eight adult cadavers were studied on both right and left sides. The adherence between the subclavian vein and subclavius muscle was subjectively assessed and the distance between the two structures was measured in mm. Results. The subclavius muscle and subclavian vein were tightly adherent in 72% of specimens, partly adherent in 14% with a mean distance of 4.5 mm and loosely connected in 14% with a mean distance of 6.1 mm. Conclusions. The anatomical relationship between the subclavius muscle and vein was very close in the majority of specimens, suggesting that the lateral insertion technique may not prevent penetration of the muscle, which may contribute to catheter pinch-off. The real time ultrasound-guided technique may prevent penetration of the subclavius muscle. PMID- 26966433 TI - Clinical Screening Tools for Sarcopenia and Its Management. AB - Sarcopenia, an age-related decline in muscle mass and function, is affecting the older population worldwide. Sarcopenia is associated with poor health outcomes, such as falls, disability, loss of independence, and mortality; however it is potentially treatable if recognized and intervened early. Over the last two decades, there has been significant expansion of research in this area. Currently there is international recognition of a need to identify the condition early for intervention and prevention of the disastrous consequences of sarcopenia if left untreated. There are currently various screening tools proposed. As yet, there is no consensus on the best tool. Effective interventions of sarcopenia include physical exercise and nutrition supplementation. This review paper examined the screening tools and interventions for sarcopenia. PMID- 26966434 TI - Protective Effect of Vitamins C and E on Depot-Medroxyprogesterone Acetate Induced Ovarian Oxidative Stress In Vivo. AB - A study was designed to investigate ameliorates effect of combined vitamins C and E able to against depot-medroxyprogesterone acetate- (DMPA-) induced ovarian oxidative stress in rat. Twenty-five female Wistar rats were divided into the following groups (n = 5 rats each): control (untreated) (C); depot medroxyprogesterone acetate (DMPA); DMPA plus green vitamin C (at dose of 0.2 mg/gram; 0.4 mg/gram; 0.8 mg/gram) and vitamin E (0.04 IU/gram). The treatment with combined vitamins C and E was performed for four weeks. Analysis of malondialdehyde (MDA) level as a marker of oxidative stress was done colorimetrically. Analysis of SOD level was done by enzyme linked immunosorbent assay (ELISA) technically. This increase in ovarium MDA was significantly (P < 0.05) attenuated by medium dose treatments of combined vitamins C and E. DMPA insignificantly decreased SOD levels compared to the untreated group. This decrease in ovarian SOD level was significantly attenuated by all doses of the combined vitamins C and E. In conclusion, DMPA induces ovarian oxidative stress. Combined vitamins C and E prohibit the increase in ovarian lipid peroxidation, at least in part by modulating of superoxide dismutase. Therefore, this may provide an antioxidant therapy for attenuating the ovarian toxicity found in the DMPA therapy. PMID- 26966435 TI - Comparison between New-Onset and Old-Diagnosed Type 2 Diabetes with Ketosis in Rural Regions of China. AB - Objectives. Type 2 diabetes (T2D) with ketosis was common because of late diagnosis and lacking adequate treatment in rural regions of China. This study aimed to provide the data of T2D with ketosis among inpatients in a south-west border city of China. Methods. Data of 371 patients of T2D with ketosis who were hospitalized between January 2011 and July 2015 in Baoshan People's Hospital, Yunnan, China, were analyzed. New-onset and old-diagnosed T2D patients presenting with ketosis were compared according to clinical characteristics, laboratory results, and chronic diabetic complications. Results. Overall, the blood glucose control was poor in our study subjects. Male predominated in both groups (male prevalence was 68% in new-onset and 64% in old-diagnosed groups). Overweight and obesity accounted for 50% in new-onset and 46% in old-diagnosed cases. Inducements of ketosis were 13.8% in new-onset and 38.7% in old-diagnosed patients. Infections were the first inducements in both groups. The prevalence of chronic complications of diabetes was common in both groups. Conclusions. More medical supports were needed for the early detection and adequate treatment of diabetes in rural areas of China. PMID- 26966437 TI - Innervation of Cochlear Hair Cells by Human Induced Pluripotent Stem Cell-Derived Neurons In Vitro. AB - Induced pluripotent stem cells (iPSCs) may serve as an autologous source of replacement neurons in the injured cochlea, if they can be successfully differentiated and reconnected with residual elements in the damaged auditory system. Here, we explored the potential of hiPSC-derived neurons to innervate early postnatal hair cells, using established in vitro assays. We compared two hiPSC lines against a well-characterized hESC line. After ten days' coculture in vitro, hiPSC-derived neural processes contacted inner and outer hair cells in whole cochlear explant cultures. Neural processes from hiPSC-derived neurons also made contact with hair cells in denervated sensory epithelia explants and expressed synapsin at these points of contact. Interestingly, hiPSC-derived neurons cocultured with hair cells at an early stage of differentiation formed synapses with a higher number of hair cells, compared to hiPSC-derived neurons cocultured at a later stage of differentiation. Notable differences in the innervation potentials of the hiPSC-derived neurons were also observed and variations existed between the hiPSC lines in their innervation efficiencies. Collectively, these data illustrate the promise of hiPSCs for auditory neuron replacement and highlight the need to develop methods to mitigate variabilities observed amongst hiPSC lines, in order to achieve reliable clinical improvements for patients. PMID- 26966436 TI - Intrahepatic Fat Content and Markers of Hepatic Fibrosis in Obese Children. AB - Aim. We evaluated both direct and indirect hepatic fibrosis markers in obese children and their relationship with intrahepatic fat (IHF) content. We also aimed to investigate the possible roles of IHF and fibrosis markers in metabolic syndrome (MS). Methods. 189 obese children were divided into simple obese (SOB), simple steatosis (SS), and nonalcoholic steatohepatitis (NASH) groups according to their IHF and blood alanine transaminase (ALT) levels. They were also scored for the MS components. IHF was assessed as a continuous variable by proton magnetic resonance spectroscopy (1H-MRS). In addition, 30 nonobese children were enrolled as controls and their direct hepatic fibrosis markers and IHF were assessed. Results. Age was related to IHF, NFS, and FIB-4. Both NFS and APRI were related to IHF more significantly than the direct markers. In the estimation of liver function impairment, indirect markers had greater AUROC than direct markers. In MS, IHF and all the fibrosis markers showed similar AUROC. Conclusions. Both direct and indirect markers played a valuable role in evaluating MS. Indirect markers were more effective in distinguishing fatty hepatitis. Age is an important factor underlying hepatic steatosis and fibrosis even in children. PMID- 26966438 TI - Mesenchymal Stromal Cells as Cell-Based Therapeutics for Wound Healing. AB - Chronic wounds are a source of substantial morbidity for patients and are a major financial burden for the healthcare system. There are no current therapies that reliably improve nonhealing wounds or reverse pathological scarring. Mesenchymal stromal cells (MSCs) are a promising source of novel cell-based therapies due to the ease of their harvest and their integral role in the native wound repair process. Recent work has addressed the problems of loss of plasticity and off target delivery through use of modern bioengineering techniques. Here we describe the applications of MSCs harvested from different sources to the wound healing process and recent advances in delivery of MSCs to targeted sites of injury. PMID- 26966439 TI - Standardizing Umbilical Cord Mesenchymal Stromal Cells for Translation to Clinical Use: Selection of GMP-Compliant Medium and a Simplified Isolation Method. AB - Umbilical cord derived mesenchymal stromal cells (UC-MSCs) are a focus for clinical translation but standardized methods for isolation and expansion are lacking. Previously we published isolation and expansion methods for UC-MSCs which presented challenges when considering good manufacturing practices (GMP) for clinical translation. Here, a new and more standardized method for isolation and expansion of UC-MSCs is described. The new method eliminates dissection of blood vessels and uses a closed-vessel dissociation following enzymatic digestion which reduces contamination risk and manipulation time. The new method produced >10 times more cells per cm of UC than our previous method. When biographical variables were compared, more UC-MSCs per gram were isolated after vaginal birth compared to Caesarian-section births, an unexpected result. UC-MSCs were expanded in medium enriched with 2%, 5%, or 10% pooled human platelet lysate (HPL) eliminating the xenogeneic serum components. When the HPL concentrations were compared, media supplemented with 10% HPL had the highest growth rate, smallest cells, and the most viable cells at passage. UC-MSCs grown in 10% HPL had surface marker expression typical of MSCs, high colony forming efficiency, and could undergo trilineage differentiation. The new protocol standardizes manufacturing of UC-MSCs and enables clinical translation. PMID- 26966441 TI - Off-label indications for bioresorbable scaffolds: "Beethoven can, but you cannot". PMID- 26966440 TI - The Use of Stem Cells to Model Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: From Basic Research to Regenerative Medicine. AB - In recent years several genes have linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as a spectrum disease; however little is known about what triggers their onset. With the ability to generate patient specific stem cell lines from somatic cells, it is possible to model disease without the need to transfect cells with exogenous DNA. These pluripotent stem cells have opened new avenues for identification of disease phenotypes and their relation to specific molecular pathways. Thus, as never before, compounds with potential applications for regenerative medicine can be specifically tailored in patient derived cultures. In this review, we discuss how patient specific induced pluripotent stem cells (iPSCs) have been used to model ALS and FTD and the most recent drug screening targets for these diseases. We also discuss how an iPSC bank would improve the quality of the available cell lines and how it would increase knowledge about the ALS/FTD disease spectrum. PMID- 26966442 TI - The role of manual aspiration thrombectomy in the management of STEMI: a TOTALly different TASTE of TAPAS. PMID- 26966443 TI - Diagnostic imaging methods applied in long-term surveillance after EVAR. Will computed tomography angiography be replaced by other methods? AB - Endovascular implantation of a stent graft in the abdominal aorta (endovascular aneurysm repair - EVAR) is a widely accepted alternative to open surgery in treatment of abdominal aortic aneurysms. Although EVAR is connected with a significant reduction in the risk of peri- and post-operative complications, it does not eliminate them totally. Long-term surveillance of post-EVAR patients is aimed at early detection of and fast reaction to a group of complications called endovascular leaks. Currently, the gold standard in leak diagnostics is computed tomography angiography (CTA). The other methods are ultrasonography, magnetic resonance (MR) angiography, intra-aneurysm sac pressure measurement, X-ray, and digital subtraction angiography (DSA). Despite many analyses based on long-term research, emphasising the high value and competitiveness of less invasive tests such as US or X-ray compared to CTA, it is still difficult for them to win the trust and acceptance of clinicians. The persisting view is that computed tomography is the test that finally resolves any inaccuracies. Consequently, a patient with a number of concurrent diseases is subject to absurdly high radiation exposure and effects of a radiocontrast agent within a short time. It is therefore logical to acknowledge that the EVAR-related risk is catching up with the open surgery risk, while the endovascular procedure is much more costly. Nevertheless, the status of CTA as the gold standard ultimately seems to be unthreatened. This paper presents a description of the diagnostic imaging tests that make it possible to detect any vascular leaks and to develop strategies for therapeutic processes. PMID- 26966444 TI - Novel device-based interventional strategies for advanced heart failure. AB - While heart failure is one of the leading causes of mortality and morbidity, our tools to provide ultimate treatment solutions are still limited. Recent developments in new devices are designed to fill this therapeutic gap. The scope of this review is to focus on two particular targets, namely (1) left ventricular geometric restoration and (2) atrial depressurization. (1) Reduction of the wall stress by shrinking the ventricular cavity has been traditionally attempted surgically. Recently, the Parachute device (CardioKinetix Inc., Menlo Park, CA, USA) has been introduced to restore ventricular geometry and cardiac mechanics. The intervention aims to partition distal dysfunctional segments that are non contributory to the ventricular mechanics and forward cardiac output. (2) Diastolic heart failure is characterized by abnormal relaxation and chamber stiffness. The main therapeutic goal achieved should be the reduction of afterload and diastolic pressure load. Recently, new catheter-based approaches were proposed to reduce left atrial pressure and ventricular decompression: the InterAtrial Shunt Device (IASDTM) (Corvia Medical Inc., Tewksbury, MA, USA) and the V-Wave Shunt (V-Wave Ltd, Or Akiva, Israel). Both are designed to create a controlled atrial septal defect in symptomatic patients with heart failure. While the assist devices are aimed at end-stage heart failure, emerging device-based percutaneous or minimal invasive techniques comprise a wide spectrum of innovative concepts that target ventricular remodeling, cardiac contractility or neuro-humoral modulation. The clinical adoption is in the early stages of the initial feasibility and safety studies, and clinical evidence needs to be gathered in appropriately designed clinical trials. PMID- 26966445 TI - Predictors of successful percutaneous coronary intervention in chronic total coronary occlusions. AB - INTRODUCTION: Percutaneous coronary intervention (PCI) of chronic total coronary occlusions (CTOs) is one of the most challenging procedures of interventional cardiology and is associated with increased risk of significant complications. However, debate continues in regard to which factors adversely influence the success rate of PCI and whether the benefits of revascularization of CTO outweigh the risks and challenges. AIM: To analyze the relationship between lesion characteristics and overall success rates as well as in-hospital outcomes after PCI for CTO. MATERIAL AND METHODS: We retrospectively examined the procedural outcomes of 173 consecutive native coronary artery CTO PCIs performed from February 2012 to March 2013 (78% men; mean age: 60.3 +/-12.1 years). RESULTS: The CTO target vessel was the right coronary artery (53.8%), circumflex (10.4%) and left anterior descending artery (35.8%), respectively. The retrograde approach was used in 13.9% of all procedures. Successful revascularization was achieved in 83.2% of patients. Major complications occurred in 13.3% of patients. In multivariate analysis, bridge collaterals, severe calcification and tortuosity as well as tandem occlusions were independent predictors of procedural failure, whereas existence of micro-channels was the only predictor of procedural success. CONCLUSIONS: Revascularization of coronary CTOs may be performed with high success and low major complication rates. Bridge collaterals, severe calcification and tortuosity, tandem/multiple occlusions and micro-channels were independent predictors of successful CTO revascularization. PMID- 26966446 TI - Three-dimensional modeling and numerical analysis of fractional flow reserve in human coronary arteries. AB - INTRODUCTION: Noninvasive fractional flow reserve (FFR) computed from CT (FFRCT) is a novel method for determining the physiologic significance of coronary artery disease (CAD). Several clinical trials have been conducted, but its diagnostic performance varied among different trials. AIM: To determine the cut-off value of FFRCT and its correlation with the gold standard used to diagnose CAD in clinical practice. MATERIAL AND METHODS: Forty patients with single vessel disease were included in our study. Computed tomography scan and coronary angiography with FFR were conducted for these patients. Three-dimensional geometric reconstruction and numerical analysis based on the computed tomographic angiogram (CTA) of coronary arteries were applied to obtain the values of FFRCT. The correlation between FFRCT and the gold standard used in clinical practice was tested. RESULTS: For FFRCT, the best cut-off value was 0.76, with the sensitivity, specificity, positive predictive value and negative predictive values of 84.6%, 92.9%, 88% and 73.3%, respectively. The area under the receiver-operator characteristics curve was 0.945 (p < 0.0001). There was a good correlation of FFRCT values with FFR values (r = 0.94, p < 0.0001), with a slight overestimation of FFRCT as compared with measured FFR (mean difference 0.01 +/-0.11, p < 0.05). For inter-observer agreement, the mean kappa value was 0.69 (0.61 to 0.78) and for intra-observer agreement the mean kappa value was 0.61 (0.50 to 0.72). CONCLUSIONS: FFRCT derived from CT of the coronary artery is a reliable non-invasive way providing reliable functional information of coronary artery stenosis. PMID- 26966447 TI - No clinical benefit from manual thrombus aspiration in patients with non-ST elevation myocardial infarction. AB - INTRODUCTION: There are scarce data on the usefulness of manual thrombectomy among patients with non-ST-elevation myocardial infarction (NSTEMI). Early positive reports were not supported by the clinical outcome in the recent TATORT NSTEMI (Thrombus Aspiration in Thrombus Containing Culprit Lesions in Non-ST Elevation Myocardial Infarction) study. AIM: To analyze the long-term outcome of NSTEMI patients treated with manual thrombectomy during percutaneous coronary intervention (PCI) in the Polish multicenter National Registry of Drug Eluting Stents (NRDES) study. MATERIAL AND METHODS: There were 13 catheterization laboratories in Poland that enrolled patients in NRDES Registry in 2010-2011. Patients with a diagnosis of NSTEMI were divided into two groups: those that were treated with manual thrombectomy for their primary PCI (T) and those who were not (NT). RESULTS: There were 923 patients diagnosed with NSTEMI in NRDES. Aspiration thrombectomy was used in 71 (7.7%) patients and the remaining 852 (92.3%) NSTEMI cases were treated without thrombectomy during the index PCI. Thrombectomy was more often used in patients with TIMI less than 1, thrombus grades 4 and 5 and older male patients. Percutaneous coronary interventions complications such as distal embolization and slow flow were more often observed in the thrombectomy subgroup. Overall mortality at 1 year was 1.69% in the T and 5.92% in the NT group (p = 0.24 and p = 0.32 after propensity score matching adjustment with p = 0.11 in the multivariate logistic regression model). CONCLUSIONS: There was no mortality benefit from thrombus aspiration in NSTEMI patients at 1-year follow up. PMID- 26966448 TI - Rise of serum troponin levels following uncomplicated elective percutaneous coronary interventions in patients without clinical and procedural signs suggestive of myocardial necrosis. AB - INTRODUCTION: The new definition of periprocedural myocardial infarction (type 4a MI) excludes patients without angina and electrocardiographic or echocardiographic changes suggestive of myocardial ischemia even though significant serum troponin elevations occur following percutaneous coronary intervention (PCI). AIM: To evaluate the incidence and predictors of serum troponin rise following elective PCI in patients without clinical and procedural signs suggestive of myocardial necrosis by using a high-sensitivite troponin assay (hsTnT). MATERIAL AND METHODS: Three hundred and four patients (mean age: 60.8 +/-8.8 years, 204 male) undergoing elective PCI were enrolled. Patients with periprocedural angina, electrocardiographic or echocardiographic signs indicating myocardial ischemia or a visible procedural complication such as dissection or side branch occlusion were excluded. Mild-moderate periprocedural myocardial injury (PMI) and severe PMI were defined as post-PCI (12 h later) elevation of serum hsTnT concentrations to the range of 14-70 ng/l and > 70 ng/l, respectively. RESULTS: The median pre-procedural hsTnT level was 9.7 ng/l (interquartile range: 7.1-12.2 ng/l). Serum hsTnT concentration elevated (p < 0.001) to 19.4 ng/l (IQR: 12.0-38.8 ng/l) 12 h after PCI. Mild-moderate PMI and severe PMI were detected in 49.3% and 12.2% of patients, respectively. Post procedural hsTnT levels were significantly higher in multivessel PCI, overlapping stenting, predilatation and postdilatation subgroups. In addition, post procedural hsTnT levels were correlated (r = 0.340; p < 0.001) with the stent lengths. CONCLUSIONS: High-sensitivite troponin measurements indicate a high incidence of PMI even though no clinical or procedural signs suggestive of myocardial ischemia exist. Multivessel PCI, overlapping stenting, predilatation, postdilatation and longer stent length are associated with PMI following elective PCI. PMID- 26966450 TI - Anomalous origin of right coronary artery from mid-left anterior descending artery leading to coronary steal phenomenon and ischemia. PMID- 26966451 TI - Noninvasive pacing during transfemoral implantation of the Edwards SAPIEN valve for tricuspid valve bioprosthesis stenosis. PMID- 26966452 TI - Endovascular thrombectomy with the AngioJet System for the treatment of intermediate-risk acute pulmonary embolism: a case report of two patients. PMID- 26966449 TI - Long-term follow-up after percutaneous closure of patent foramen ovale with Amplatzer PFO Occluder: a single center experience. AB - INTRODUCTION: Patent foramen ovale (PFO) is associated with the occurrence of cryptogenic strokes, transient neurological ischemic attacks (TIA) and migraine. Therefore despite the recent ambiguous results of prospective controlled trials, percutaneous closure of PFO is still performed in many centers. AIM: To evaluate the safety and effectiveness of percutaneous PFO closure in the prevention of recurrence of neurologic events and migraine symptoms in long-term observation. MATERIAL AND METHODS: In 70 patients (31 male, age: 38 +/-18 years) percutaneous PFO closure was successfully performed with the Amplatzer PFO Occluder. An interview in conjunction with neurological follow-up was performed in all patients to reveal recurrence of embolism such as TIA or stroke and the presence of migraine symptoms before and after the procedure. RESULTS: The mean follow-up period was 857 +/-363 days (median: 571 days). No serious complications of the procedure and no death were observed. Neurological events recurred in 5 (7.1%) patients - stroke in 1 patient, TIA in 3 patients, ocular embolism in 1 patient. All of these patients were over 40 years old or had other cardiovascular risk factors. Migraine was observed in 21 (30%) patients before the procedure and in 11 (15.7%) after the procedure (p = 0.04). CONCLUSIONS: The complication rate and recurrence of neurological events in young patients after PFO closure are low. However, careful qualification and postprocedural monitoring of the patients are necessary. Patent foramen ovale closure seems to result in attenuation of migraine symptoms. PMID- 26966453 TI - Staged interventional and surgical treatment of tetralogy of Fallot with critical stenosis of proximal aortic arch in premature hypotrophic newborn. PMID- 26966454 TI - Is there still a place for thrombectomy? PMID- 26966455 TI - The first reported aspiration thrombectomy with a guide extension mother-and child catheter in ST elevation myocardial infarction due to bacterial vegetation coronary artery embolism. PMID- 26966456 TI - Acute myocardial infarction due to coronary embolism originating from left ventricle thrombus in a patient with dilated cardiomyopathy and sinus rhythm. PMID- 26966457 TI - A case of doxazosin-induced acute coronary syndrome in a patient with myocardial bridging. PMID- 26966459 TI - Segregation in Post-Civil Rights America: Stalled Integration or End of the Segregated Century? AB - In this paper we adjudicate between competing claims of persisting segregation and rapid integration by analyzing trends in residential dissimilarity and spatial isolation for African Americans, Hispanics, and Asians living in 287 consistently defined metropolitan areas from 1970 to 2010. On average, black segregation and isolation have fallen steadily but still remain very high in many areas, particularly those areas historically characterized by hypersegregation. In contrast, Hispanic segregation has increased slightly but Hispanic isolation has risen substantially owing to rapid population growth. Asian segregation has changed little and remains moderate, and although Asian isolation has increased it remains at low levels compared with other groups. Multivariate analyses reveal that segregation and isolation are being actively produced in some areas by restrictive density zoning regimes, large and/or rising minority percentages, lagging minority socioeconomic status, and active expressions of anti-black and anti-Latino sentiment, especially in large metropolitan areas. Areas displaying these characteristics are either integrating very slowly (in the case of blacks) or becoming more segregated (in the case of Hispanics), whereas those lacking these attributes are clearly moving toward integration, often quite rapidly. PMID- 26966458 TI - Attenuation of Oxidative Stress of Erythrocytes by Plant-Derived Flavonoids, Orientin and Luteolin. AB - Erythrocytes are easy to be injured by oxidative stress in their lifespan. Although there are several chemicals such as vitamin C (VC) that would be able to reduce oxidative stress, natural herbal products still remain an interesting research area. The current study investigated the effects of two plant-derived flavonoids, orientin and luteolin, on erythrocytes and their possible mechanisms. This experiment was divided into nine groups, which were normal group, model group, VC control group, and treated groups with different doses of orientin and luteolin (10, 20, and 40 MUg/mL), respectively. Hemolysis rate was determined by spectrophotometry. Antioxidative enzyme and products were evaluated by different methods. Erythrocyte cell surface and cellular structure were observed with scanning or transmission electron microscope, respectively. Oxidative stress induced significant increase in hemolysis rate of erythrocytes. Orientin or luteolin ameliorated hemolysis of erythrocytes in oxidative stress in a dose dependent manner. Both orientin and luteolin reduced oxidative products and increased antioxidative enzyme activities. Moreover, orientin and luteolin attenuated oxidative stress induced damage of erythrocyte cell surface morphology and cellular structure. In conclusion, orientin and luteolin could protect human erythrocytes from oxidative damage by attenuating oxidative stress, protecting antioxidative enzyme activities, and preserving integrity of erythrocyte structure. PMID- 26966460 TI - Comparative analysis of volatiles difference of Yunnan sun-dried Pu-erh green tea from different tea mountains: Jingmai and Wuliang mountain by chemical fingerprint similarity combined with principal component analysis and cluster analysis. AB - BACKGROUND: Modern instrumental analysis technology can provide various chemical data and information on tea samples. Unfortunately, it remains difficult to extract the useful information. We describe the use of chemical fingerprint similarities, combined with principal component and cluster analyses, to distinguish and recognize Pu-erh green teas, which from two tea mountains, Wuliang and Jingmai, in the Pu-erh district of Yunnan province. The volatile components of all 20 Pu-erh green teas (10 Wuliang and 10 Jingmai teas) were extracted and identified by headspace solid-phase micro extraction (HS-SPME) combined with gas chromatography-mass spectrometry (GC-MS). RESULTS: Sixty-three volatiles (including alcohols, hydrocarbons, ketones, and aldehydes) were identified in the 20 Pu-erh green teas, and differences in compound compositions between them were also observed. Through fingerprint similarity, combined with principal component and cluster analyses, the 20 Pu-erh green teas were differentiated successfully based on their volatile characteristics. CONCLUSIONS: This study demonstrates that the GC-MS combined with chemical fingerprint and unsupervised pattern recognition method is suitable for the investigation of the volatile profiling and evaluating the quality and authenticity of teas related to the different origins.Graphical abstractDifferentiate Pu-erh green teas from different tea mountains by using chemical fingerprint similarity and multivariate statistical methods. PMID- 26966463 TI - A Classification Proposal for Peri-Implant Mucositis and Peri-Implantitis: A Critical Update. AB - Definitions of peri-implant mucositis and peri-implantitis vary in the literature, and no clear criteria have been established for the diagnosis and treatment of such disorders. This study proposes a classification for peri implant mucositis and peri-implantitis based on the severity of the disease, using a combination of peri-implant clinical and radiological parameters to classify severity into several stages (Stage 0A and 0B = peri-implant mucositis, and Stage I to IV = periimplantitis). Following a review of the literature on the subject and justification of the proposed peri-implant disease classification, the latter aims to facilitate professional communication and data collection for research and community health studies. PMID- 26966462 TI - Key enzymes catalyzing glycerol to 1,3-propanediol. AB - Biodiesel can replace petroleum diesel as it is produced from animal fats and vegetable oils, and it produces about 10 % (w/w) glycerol, which is a promising new industrial microbial carbon, as a major by-product. One of the most potential applications of glycerol is its biotransformation to high value chemicals such as 1,3-propanediol (1,3-PD), dihydroxyacetone (DHA), succinic acid, etc., through microbial fermentation. Glycerol dehydratase, 1,3-propanediol dehydrogenase (1,3 propanediol-oxydoreductase), and glycerol dehydrogenase, which were encoded, respectively, by dhaB, dhaT, and dhaD and with DHA kinase are encompassed by the dha regulon, are the three key enzymes in glycerol bioconversion into 1,3-PD and DHA, and these are discussed in this review article. The summary of the main research direction of these three key enzyme and methods of glycerol bioconversion into 1,3-PD and DHA indicates their potential application in future enzymatic research and industrial production, especially in biodiesel industry. PMID- 26966466 TI - Evaluating Resin-Dentin Bond by Microtensile Bond Strength Test: Effects of Various Resin Composites and Placement Techniques. AB - OBJECTIVES: This in vitro study evaluated the microtensile bond strength (MTBS) of a methacrylate-based compared to a silorane-based resin composite in Class I cavity using different placement techniques. MATERIALS AND METHODS: Class I cavities with dimension of (4 mm long, 4 mm wide, 3 mm deep) were prepared in extracted sound human molars. The teeth were randomly divided into six groups. The first three groups were filled with Filtek P90 using three methods of insertion; bulk, incremental and snow-plow, and the remaining three groups were filled with Clearfil AP-X using the same three placement techniques. After 24 hours of storage in water at 37 degrees C, the specimens were thermocycled to 1000 cycles. Specimens were prepared for MTBS testing by creating bonded beams obtained from the pulpal floor. STATISTICAL ANALYSIS USED: Statistical analyses of data were performed by two-way ANOVA/Tukey (alpha=.05). RESULTS: The experiment showed significant differences between the two resin composites with regard to filling techniques (P<0.05). The MTBS was significantly higher in each of Filtek P90 subgroup compared to Clearfil AP-X ones (P<0.05). With respect to filling technique in both resin composites, bulk insertion showed the significantly lowest MTBS (P<0.05), while no significant difference was found between the outcome of incremental and snow-plow techniques (P>0.05). CONCLUSION: Silorane-based resin composite as opposed to methacrylate based resin composite and layering placements in contrast to bulk filling method had higher microtensile bond strength. PMID- 26966464 TI - Intracanal Antibiotic Medication for Sustained Root Surface Disinfection-A Laboratory Evaluation. AB - PURPOSE: To measure the release of an antibiotic mixture of ciprofloxacin, cerfuroxim and metronidazole (TreVitaMix, TVM) through human dentine and to assess the growth inhibition of Fusobacterium nucleatum. MATERIAL AND METHODS: Twenty-four extracted human incisors were scaled and endodontically treated. Root canals were either filled with antibiotic tri-mixture (TVM) or with the carrier material alone (propylene glycol, PG) and were coronally and apically sealed with a flowable composite. Transradicular medicament release was spectrophotometrically measured at 277 nm in simulated body fluid for up to 21 days. In a second part, an agar diffusion assay (F. nucleatum) with representative TVM concentrations as determined in the first part was performed to study the growth inhibition. Samples were anaerobical incubated for 48 h and inhibition zones were measured. RESULTS: TVM was spectrophotometrically detectable in the immersion solution and released in decreasing concentrations up to 21 days (222.5 +/- 65.2 mg/ml at day 1 and 35.1 +/- 15.6 mg/ml at day 21). In addition, inhibition zones were shown in the agar diffusion assay at representative TVM concentrations. The carrier material showed no antibacterial effect. CONLUSION: TVM showed the potential to penetrate through dentine and to inhibit bacterial growth. Therefore, it might have the potential to disinfect the outer root surface in perio-endo lesions, but further research is needed to confirm these observations. PMID- 26966465 TI - Effect of Food Simulating Agents on the Hardness and Bond Strength of a Silicone Soft Liner to a Denture Base Acrylic Resin. AB - STATEMENT OF THE PROBLEM: Bonding failure between acrylic resin and soft liner material and also gradual loss of soft liner resiliency over time are two impending challenges frequently recognized with a denture base embraced with a resilient liner. Since patients drink various beverages, it is crucial to assess the influences of these beverages on physical characteristics of soft liners. PURPOSE: This in vitro study envisioned to assess the influence of food simulating agents (FSA) on the hardness of a silicone soft liner by employing a Shore A durometer test and also evaluate its bond strength to a denture base resin by using tensile bond strength test. MATERIALS AND METHODS: To test the hardness of samples, 50 rectangular samples (40 mm * 10 mm * 3 mm) were prepared from a heat-polymerized polymethyl methacrylate (Meliodent). Mollosil, a commercially available silicone resilient liner, was provided and applied on the specimens following the manufacturer's directions. In order to test tensile bond strength, 100 cylindrical specimens (30 mm * 10 mm) were fabricated. The liners were added between specimens with the thicknesses of 3 mm. The specimens were divided into 5 groups (n=10) and immersed in distilled water, heptane, citric acid, and 50% ethanol. For each test, we used 10 specimens as a baseline measurement; control group. All specimens were kept in dispersed containers at 37oC for 12 days and all solutions were changed every day. The hardness was verified using a Shore A durometer and the tensile bond strength was examined by an Instron testing machine at a cross-head speed of 5 mm/min. The records were analyzed employing one-way ANOVA, Tukey's HSD, and LSD tests. RESULTS: The mean tensile bond strength +/- standard deviation (SD) for Mollosil was as follows for each group: 3.1 +/- 0.4 (water), 1.8 +/- 0.4 (citric acid), 3.0 +/- 0.4 (heptane), 1.2 +/- 0.3 (50% ethanol), and 3.8 +/- 0.4 (control). The hardness values for each group were: 28.7 +/- 2.11 (water), 33.2 +/- 2.82 (citric acid), 39.2 +/- 4.8 (heptane), 32.3 +/- 3.56 (50% ethanol) and 22.2 +/- 2.08 (control). Mean values for hardness indicated that all of the food simulating agents significantly increased hardness of the Mollosil soft liner compared to the control group (p<0.05). The results of tensile bond strength depicted that water and FSA decreased the bond strength of the soft liner -denture base resin compared to the control group and it was statistically significant (p<0.05). CONCLUSION: The food simulating agents could influence the mechanical properties of silicone soft liners; hence, clinicians should inform their patients concerning their possible adverse effects and complications. PMID- 26966467 TI - Sinus Lift Augmentation by Using Calcium Sulphate. A Retrospective 12 Months Radiographic Evaluation Over 25 Treated Italian Patients. AB - PURPOSE: The aim of this investigation was to assess bone healing of sinus lift procedure in which the augmentation has been performed by using calcium sulphate like bone substitutes. The methods of this investigation how the use of Cone Beam Computed Tomography (CBCT) may be a valid instrument to support reconstructive surgery of the jaws. PATIENTS AND METHODOLOGY: 25 Patients presented large bone defects after tooth extractions located in the upper jaw posterior area. Vertical bone volume was assessed by CBCT examinations before and about six months after sinus lift surgery. RESULTS: Examined defects treated with sinus lift surgery and evaluated by CBCT showed a strong increasing on the bone volume at 6 months follow up control. CONCLUSION: Calcium sulphate application in sinus lift surgery represent a safe and predictable option in the place of autologous bone. Therefore the application of CBCT investigation may give the clinicians the opportunity of evaluating with high precision value, the consistence of the bone defects before the surgery. PMID- 26966468 TI - Medical Risk Assessment in Patients Referred to Dental Clinics, Mashhad, Iran (2011-2012). AB - Advances in medical and dental techniques have led to a growing aged population living with complex medical conditions. This study focuses on the detection of medically compromised dental patients by means of a validated patient administered medical risk-related history questionnaire. MATERIALS AND METHODS: We used the questionnaire EMRRH (European Risk Related Medical History) in order to study the prevalence as well as the risk assessment of past medical problems in a population who visited dental centers (dental university, dental offices and clinics) for treatment in Mashhad, Iran. RESULTS: A total number of 1,188 patients were registered, 871 of whom had a medical history that was of some interest to us. From the population with medical problems which was 30.6% of the total (N=219), 26.7% of the patients were classified as risk ASA I; 37.3% as ASA II, 16.9% as ASA III; and 19.1% as ASA IV. Among the diverse pathologies, the highest percentage was hypertension (11.6%), followed by allergies to different drugs (8.37%). CONCLUSION: It seems absolutely essential for dental practitioners to take a detailed medical history prior to any therapeutic procedure, as certain medical conditions, if unnoticed, will lead to unfavorable consequences and/or repercussions. PMID- 26966469 TI - Piezosurgery in Bone Augmentation Procedures Previous to Dental Implant Surgery: A Review of the Literature. AB - The piezosurgery has been used with increasing frequency and applicability by health professionals, especially those who deal with dental implants. The concept of piezoelectricity has emerged in the nineteenth century, but it was applied in oral surgery from 1988 by Tomaso Vercellotti. It consists of an ultrasonic device able to cut mineralized bone tissue, without injuring the adjacent soft tissue. It also has several advantages when compared to conventional techniques with drills and saws, such as the production of a precise, clean and low bleed bone cut that shows positive biological results. In dental implants surgery, it has been used for maxillary sinus lifting, removal of bone blocks, distraction osteogenesis, lateralization of the inferior alveolar nerve, split crest of alveolar ridge and even for dental implants placement. The purpose of this paper is to discuss the use of piezosurgery in bone augmentation procedures used previously to dental implants placement. PMID- 26966470 TI - A Colorimetric Interdental Probe as a Standard Method to Evaluate Interdental Efficiency of Interdental Brush. AB - The aim of this study is to evaluate the concordance between the empirical choice of interdental brushes of different diameters compared to the gold standard, the IAP CURAPROX((c)) calibrating colorimetric probe. It is carried out with the aim of facilitating the consensus development of best practices. All the subjects' interproximal spaces were evaluated using the reference technique (colorimetric probe), then after a time lapse of 1.2 +/- 0.2 hours, using the empirical clinical technique (brushes) by the same examiner. Each examiner explored 3 subjects. The order the patients were examined with the colorimetric interdental probe (CIP) was random. 446 sites were selected in the study out of 468 potential sites. The correspondence of scores between interdental bushes vs. colorimetric probe is 43.0% [95%-CI: 38.5-47.6]. In 33.41% of the 446 sites, the brush is inferior to the probe; in 23.54% of cases, the brush is superior to the probe. Among the discrepancies there is thus a tendency for the subjects to use brushes with smaller diameter than that recommended by the colorimetric probe. This review has found very high-quality evidence that colorimetric probes plus interdental brushing is more beneficial than interdental brushing alone for increase the concordance between the empirical choice of interdental brushes of different diameters compared to the gold standard. Uncertainties remain and further research is required to provide detailed data on user satisfaction. PMID- 26966471 TI - Pedunculated Hepatic Hemangioma Masquerading as a Peritoneal Tumor. A Case Report. AB - BACKGROUND: Although being classically located inside the liver parenchyma, hemangiomas may occasionally develop outside the extra-hepatic capsule, thus appearing as a pedunculated mass. CASE REPORT: We report the case of a 66-year old anal cancer female patient presenting with an asymptomatic sub-hepatic mass. Incidental diagnosis of a pedunculated hepatic hemangioma was strongly suggested by the typical imaging features on computed tomography (CT) and magnetic resonance (MR) examinations, and was confirmed by histopathological examination. CONCLUSIONS: Exophytic pedunculated growth is a rare and atypical feature of hepatic hemangioma. Thin contrast- enhanced sections and multiplanar CT and MR scan reformations helped to the final diagnosis of hemangioma, showing its origin from the liver edge. Surgical resection is mandatory to prevent threatening mass pedicle torsion. PMID- 26966473 TI - Deep Vein Thrombosis of the Left Lower Limb in a 12 Year-Old Female Child with Ulcerative Colitis - Case Report. AB - BACKGROUND: Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. CASE REPORT: This case report presents a patient with ulcerative colitis, with thrombotic complication of the left common iliac vein that occurred at the age of 11, two years after diagnosis. After a year of anticoagulation and compression therapy, although exacerbations of underlying disease occurred in the first 6 months of treatment, there was no recurrence of deep venous thrombosis, partial recanalization within affected venous system has been achieved and the patient is remission of ulcerative colitis for the last six months. CONCLUSIONS: In children, thromboembolic complications occur about 7 times less often than in adults, but increases in the case of hospitalized children. In children with IBD this complication can occur independently og disease activity even in patients with any other risk factors. PMID- 26966474 TI - Right Aortic Arch with Aplasia of the Left Brachiocephalic Trunk Presented as Systolic Blood Pressure Difference Between Upper Extremities. AB - BACKGROUND: The right aortic arch with mirror-image of branching arteries without coexisting congenital heart disease is a very rare anomaly. CASE REPORT: We report a case of the right-sided aortic arch with aplasia of the left brachiocephalic trunk in a 64-year-old women, presenting difference in systolic blood pressure between upper extremities. The history of the patient and angio-CT findings were described and visualized with images. CONCLUSIONS: The knowledge of vascular variations is important for the clinical and therapeutic aspects. PMID- 26966472 TI - Irreversible Electroporation (IRE): Standardization of Terminology and Reporting Criteria for Analysis and Comparison. AB - BACKGROUND: Irreversible electroporation (IRE) as newer ablation modality has been introduced and its clinical niche is under investigation. At present just one IRE system has been approved for clinical use and is currently commercially available (NanoKnife(r) system). In 2014, the International Working Group on Image-Guided Tumor Ablation updated the recommendation about standardization of terms and reporting criteria for image-guided tumor ablation. The IRE method is not covered in detail. But the non-thermal IRE method and the NanoKnife System differ fundamentally from established ablations techniques, especially thermal approaches, e.g. radio frequency ablation (RFA). MATERIAL/METHODS: As numerous publications on IRE with varying terminology exist so far - with numbers continuously increasing - standardized terms and reporting criteria of IRE are needed urgently. The use of standardized terminology may then allow for a better inter-study comparison of the methodology applied as well as results achieved. RESULTS: Thus, the main objective of this document is to supplement the updated recommendation for image-guided tumor ablation by outlining a standardized set of terminology for the IRE procedure with the NanoKnife Sytem as well as address essential clinical and technical informations that should be provided when reporting on IRE tumor ablation. CONCLUSIONS: We emphasize that the usage of all above recommended reporting criteria and terms can make IRE ablation reports comparable and provide treatment transparency to assess the current value of IRE and provide further development. PMID- 26966475 TI - LATENT DEMOGRAPHIC PROFILE ESTIMATION IN HARD-TO-REACH GROUPS. AB - The sampling frame in most social science surveys excludes members of certain groups, known as hard-to-reach groups. These groups, or sub-populations, may be difficult to access (the homeless, e.g.), camouflaged by stigma (individuals with HIV/AIDS), or both (commercial sex workers). Even basic demographic information about these groups is typically unknown, especially in many developing nations. We present statistical models which leverage social network structure to estimate demographic characteristics of these subpopulations using Aggregated relational data (ARD), or questions of the form "How many X's do you know?" Unlike other network-based techniques for reaching these groups, ARD require no special sampling strategy and are easily incorporated into standard surveys. ARD also do not require respondents to reveal their own group membership. We propose a Bayesian hierarchical model for estimating the demographic characteristics of hard-to-reach groups, or latent demographic profiles, using ARD. We propose two estimation techniques. First, we propose a Markov-chain Monte Carlo algorithm for existing data or cases where the full posterior distribution is of interest. For cases when new data can be collected, we propose guidelines and, based on these guidelines, propose a simple estimate motivated by a missing data approach. Using data from McCarty et al. [Human Organization60 (2001) 28-39], we estimate the age and gender profiles of six hard-to-reach groups, such as individuals who have HIV, women who were raped, and homeless persons. We also evaluate our simple estimates using simulation studies. PMID- 26966476 TI - Comparative Ab-Initio Study of Substituted Norbornadiene-Quadricyclane Compounds for Solar Thermal Storage. AB - Molecular photoswitches that are capable of storing solar energy, so-called molecular solar thermal storage systems, are interesting candidates for future renewable energy applications. In this context, substituted norbornadiene quadricyclane systems have received renewed interest due to recent advances in their synthesis. The optical, thermodynamic, and kinetic properties of these systems can vary dramatically depending on the chosen substituents. The molecular design of optimal compounds therefore requires a detailed understanding of the effect of individual substituents as well as their interplay. Here, we model absorption spectra, potential energy storage, and thermal barriers for back conversion of several substituted systems using both single-reference (density functional theory using PBE, B3LYP, CAM-B3LYP, M06, M06-2x, and M06-L functionals as well as MP2 calculations) and multireference methods (complete active space techniques). Already the diaryl substituted compound displays a strong red-shift compared to the unsubstituted system, which is shown to result from the extension of the conjugated pi-system upon substitution. Using specific donor/acceptor groups gives rise to a further albeit relatively smaller red-shift. The calculated storage energy is found to be rather insensitive to the specific substituents, although solvent effects are likely to be important and require further study. The barrier for thermal back-conversion exhibits strong multireference character and as a result is noticeably correlated with the red shift. Two possible reaction paths for the thermal back-conversion of diaryl substituted quadricyclane are identified and it is shown that among the compounds considered the path via the acceptor side is systematically favored. Finally, the present study establishes the basis for high-throughput screening of norbornadiene-quadricyclane compounds as it provides guidelines for the level of accuracy that can be expected for key properties from several different techniques. PMID- 26966477 TI - Injuries Caused by Explosion of Electronic Cigarette Devices. PMID- 26966478 TI - [Parecoxib effects in the prevention of postoperative abdominal adhesions: randomized experimental study in rats]. PMID- 26966479 TI - Retraction: Redundant Publication of the article Dental caries and oral health practices among 12 year old children in Nairobi West and Mathira West Districts, Kenya. Gladwell Gathecha et al. The Pan African Medical Journal. 2012;12:42. PMID- 26966480 TI - [A case of cervical muscle hematoma found in Antananarivo]. PMID- 26966481 TI - [Nosocomial pneumonia in ICU CHU Hassan II of Fez]. PMID- 26966483 TI - [The posterior reversible encephalopathy syndrome in a boy on peritoneal dialysis]. PMID- 26966484 TI - [Athletic pubalgia: update about a retrospective study of 128 players]. PMID- 26966482 TI - Prevalence of undiagnosed diabetes and pre-diabetes among hypertensive patients attending Kiambu district Hospital, Kenya: a cross-sectional study. AB - INTRODUCTION: Hypertension (HTN) and diabetes mellitus (DM) are two common non communicable diseases (NCDs) that are closely linked: one cannot be properly managed without attention to the other. The aim of this study was to determine the prevalence of undiagnosed diabetic and pre-diabetic states that is abnormal glucose regulation (AGR) and factors associated with it among hypertensive patients in Kiambu Hospital, Kenya. METHODS: We conducted a cross-sectional study from February 2014 to April 2014. Hypertensive patients aged >= 18 attending the out-patient medical clinic were included in the study. Pregnant and known diabetic patients were excluded. Data was collected on socio-demographics, behavior, and anthropometrics. Diabetes status was based on a Glycated Haemoglobin (HbA1C) classification of >= 6.5% for diabetes, 6.0-6.4% for pre diabetes and <= 6.0% for normal. AGR was the dependable variable and included two diabetic categories; diabetes and pre-diabetes. RESULTS: We enrolled 334 patients into the study: the mean age was 59 years (Standard deviation = 14.3). Of these patients 254 (76%) were women. Thirty two percent (107/334; 32%) were found to have AGR, with 14% (46) having un-diagnosed DM and 18%(61) with pre-diabetes. Factors associated with AGR were age >= 45 (OR = 3.23; 95% CI 1.37 >= 7.62), basal metabolic index (BMI) >= 25 Kg/m(2) (OR = 3.13; 95% CI 1.53 - 6.41), low formal education (primary/none)(OR= 2; 95%CI 1.08 - 3.56) and family history of DM (OR = 2.19; 95%CI 1.16 - 4.15). CONCLUSION: There was a high prevalence of undiagnosed AGR among hypertensive patients. This highlights the need to regularly screen for AGR among hypertensive patients as recommended by WHO. PMID- 26966485 TI - An exceptional collision tumor: gastric calcified stromal tumor and pancreatic adenocarcinoma. AB - The authors report an exceptional case of collision tumor comprised of a gastric calcified stromal tumor and a pancreatic adenocarcinoma. The pancreatic tumor was detected fortuitously on the histological exam of resection specimen. PMID- 26966486 TI - [An unusual mode of discovery of primary hyperparathyroidism: multiple fractures on brown tumors secondary to ectopic mediastinal parathyroid adenoma]. PMID- 26966487 TI - [Suspicious melanonychia revealing Laugier Hunziker syndrome]. PMID- 26966488 TI - Multiple myeloma in Nigeria: a multi-centre epidemiological and biomedical study. AB - INTRODUCTION: Myelomatosis is a malignant proliferation of plasma cells in the bone marrow, with relatively high prevalence in African populations. Variation in genetic mutations has been observed in individual patients and may be responsible for differences in disease pattern and treatment outcomes. This study described the presentations and treatment outcomes of multiple myeloma in nigerian. METHODS: The data was obtained retrospectively from the case notes of 135 patients diagnosed with multiple myeloma from eight tertiary health institutions across the six geopolitical zones of Nigeria from 2005 to 2014. Data analysis was carried out using SPSS 17.0. RESULTS: The predominant presentations were bone pain in 97 (74%), nephropathy in 47 (35.9%) and pathological fractures in 58 (44.3%). Sixty-seven percent (67%) of the patients were less than 60 years, and 35% had Bence Jones proteinuria. The overall survival beyond 6 months was 91.3%, mean duration of survival rate was 7.4 months. Majority (66.2%) were on Melphalan alone or on melphalan-containing combinations. A higher packed cell volume (PCV) and total serum protein levels at presentation were associated with increased survival, p=0.033 and 0.036, respectively. CONCLUSION: This study portrayed the importance of detail investigation on the causes of bone pain and anaemia in person's aged 40 years and above. There is a high prevalence of nephropathy in this cohort of patients which needs to be further investigated. Majority of the patients, though < 65 years of age were placed on melphalan-containing combinations, which foreclosed chances of future autologous bone marrow transplantation. PMID- 26966489 TI - New-onset diabetic ketoacidosis in a 13-months old african toddler: a case report. AB - Type 1 diabetes mellitus is very rare in infants and toddlers and is usually associated with high mortality when complicated with diabetic ketoacidosis (DKA). Toddlers in DKA are often missed in our typical African setting where there is low index of suspicion. Usually, the classical symptoms are not usually at the forefront and many infants and toddlers who develop DKA are mistreated for infections. The case of a 13-months old toddler with new-onset type 1 diabetes mellitus, complicated with DKA at diagnosis is reported in view of its rarity and elevated mortality even when diagnosed in our African setting. She was subsequently treated with intravenous insulin and was passed over to subcutaneous insulin after the eradication of ketones in urine. She continues follow-up at the out-patient children diabetes clinic at the Bafoussam Regional Hospital. PMID- 26966490 TI - Intralaryngeal thyroglossal duct cyst. PMID- 26966491 TI - [Not Available]. PMID- 26966493 TI - Phenytoin intoxication with no symptoms correlated with serum drug level: a case study. AB - In high-dose intake of phenytoin, which is used frequently to treat epilepsy, nystagmus, diplopia, nausea-vomiting, lethargy, confusion, seizure, and coma can be observed. In recent studies on phenytoin intoxication, in which seizure and coma were observed in drug levels greater than 50 ug/mL. The serum phenytoin level of a patient, who consumed approximately 100 pcs of 100 mg phenytoin tablets in an effort to commit suicide, and who had no pathological finding in her neurologic examination, was 124 ug/mL. High drug level and the absence of toxic effect (or the absence of toxic effect correlated with the drug level) indicates that cytochrome P450 is functioning, but there can be a mutation in the MDR1 gene. In our case study, we report on phenytoin intoxication in a patient having a high level of phenytoin but no symptoms correlated with serum drug level, as supported by the findings in the literature. PMID- 26966494 TI - Cutaneous onchocerciasis in Dumbu, a pastoral area in the North-West region of Cameroon: diagnostic challenge and socio-economic implications. AB - Onchocerciasis is a severe parasitic infestation caused by Onchocerca volvulus which causes disabling skin and subcutaneous tissue changes and ultimately leads to blindness. It has a huge public health impact due to its socioeconomic burden and the vast number of people it affects in developing countries. In this case, a 60 years old woman was encountered with leopard skin like changes, rashes and pruritus on the left leg; which had been managed as cutaneous mycosis for over a period of 8 years. A diagnosis of onchocerciasis was finally made after a skin snip identified onchocercal microfilariae. The above case shows that onchocerciasis is still a neglected tropical disease (NTD) in Cameroon. This emphasizes the need for more expansive outreach programs in remote areas in Cameroon, a change in health policies to ensure the eradication of this disabling disease and health promotion amongst vulnerable populations. PMID- 26966492 TI - [Prevalence, associated and predisposing factors of metabolic syndrome among people living with HIV on antiretroviral treatment in Porto Novo in 2014]. PMID- 26966495 TI - Fibrodysplasia ossificans progressiva with minor unilateral hallux anomaly in a sporadic case from Northern Tanzania with the common ACVR1c.617G>A mutation. AB - Fibrodysplasia ossificans progressiva is a rare autosomal dominantly inherited disorder of connective tissue caused by mutations in the gene encoding for ACVR1/ALK2, a bone morphogenetic protein type I receptor. It is mainly characterized by congenital malformations of the great toes and the formation of qualitatively normal bone in extra-skeletal sites leading to severe disability and eventually death. We present a sporadic case from Northern Tanzania with a minor unilateral hallux anomaly and the common ACVR1 c.617G>A mutation. PMID- 26966496 TI - [An atypical presentation of celiac disease: central retinal vein occlusion]. PMID- 26966497 TI - [Blackwater fever (BWF) of late revelation about a case at the University Hospital of Dakar]. PMID- 26966498 TI - Tuberculosis following kidney transplantation: report of paediatric case. AB - Recipients of solid organ transplantation are, because of immunosuppressive therapy, at high risk to develop opportunistic infections including tuberculosis (TB). The incidence, clinical manifestations, and optimal diagnostic tests of this disease in this population have not been adequately defined. In this paper, we report a case of 13 year-old boy who developed pulmonary tuberculosis following a second renal transplantation from a deceased donor. The described case points diagnostic difficulties of the tuberculosis disease which are due to insidious and non specific clinical presentation. Also, the treatment is delicate because interaction between immunosuppressive drugs and antituberculosis drugs. PMID- 26966500 TI - SD Bioline malaria antigen Pf (HRP-2/pLHD) for assessing efficacy of artemisinin combination therapy against Plasmodium falciparum in pediatric patients in the Democratic Republic of the Congo. AB - INTRODUCTION: The emergence of Plasmodium falciparum resistance to artemisinin combination therapy (ACT) is a worrying development. It calls for close surveillance to monitor the efficacy of the drugs. The objectives of this study were to determine the performance of SD Bioline malaria AgPf(HRP-2/pLDH) 3 band Rapid Diagnostic Test (RDT) against Giemsa-stained blood smear and evaluate the suitability of this test in assessing the therapeutic efficacy of ACT in pediatric malaria patients in the Democratic Republic of the Congo (DRC). METHODS: Five hundred and one patients with malaria symptoms were screened for P. falciparum in Kinshasa, DRC. Of the 166 patients who tested positive for P. falciparum at recruitment (day 0), 103 consented to participate in this study and were followed up and retested for P. falciparum on day 3, day 7, day 14, day 21 and day 28. RESULTS: Sensitivity and specificity of the test were significantly high on day 0 and so were their positive and negative predictive values. Higher proportions of false positive cases were observed on the HRP-2 band irrespective of patient parasite densities during the follow up but these were barely seen on the pLDH band. Some patients turned positive during follow up but pLDH readings remained consistent with blood smear readings. CONCLUSION: SD Bioline malaria AgPf(HRP-2/pLDH) RDT demonstrated high performance in DRC. Thus, the test can be employed to assess the efficacy of ACT in pediatric malaria patients and prioritize areas that require the deployment of advanced testing like polymerase chain reaction (PCR). PMID- 26966501 TI - [Gliosarcoma: rare tumor of the central nervous system--presentation of two cases]. PMID- 26966499 TI - [Effectiveness of Prevention of Mother to Child Transmission of Human Immunodeficiency Virus by the 2010 protocol of the World Health Organisation at the Medical Center St. Camille of Ouagadougou (Burkina Faso)]. PMID- 26966502 TI - Sustainable Health Development Goals (SHDG): breaking down the walls. AB - The world's governments failed to achieve the Health for All 2000 goals from the Alma Ata Declaration of 1978. Although a lot of milestones have been covered since 2000, the world's governing authorities are unlikely to achieve the current Millennium Development Goals (MDGs) which expire by the end of this year. The inability to achieve these goals may be linked to the multiplicity of health related directives and fragmentation of health systems in many countries. However, with the proposed 17 sustainability development goals, health has only one universal aim: to ensure healthy lives and promote wellbeing for all at all ages. Accomplishing this will require a focus on health systems (system thinking), commonization of services and full integration of services with total dismantling of vertical programs across the world. PMID- 26966503 TI - [Syndrome Heerfordt]. PMID- 26966504 TI - [Angiocholitis secondary to a tumor thrombus of a primitive neuroendocrine tumor of the liver]. PMID- 26966505 TI - [Tinnitus indicative of Horton disease]. PMID- 26966506 TI - [Mount Fuji sign: compressive pneumocephalus]. PMID- 26966507 TI - Protective Effect of Parsley Juice (Petroselinum crispum, Apiaceae) against Cadmium Deleterious Changes in the Developed Albino Mice Newborns (Mus musculus) Brain. AB - Parsley was used as a probe of the current experiment to prevent the behavioral, morphological and biochemical changes in the newborn brain following the administration of cadmium (Cd) to the pregnant mice. The nonanesthetized pregnant mice were given daily parsley juice (Petroselinum crispum) at doses of 20 mg/kg and 10 mg/kg. Pregnant mothers were given Cd at a dose of 30 mg/kg divided into 3 equal times. The newborns have been divided into 6 groups: Group A, mothers did not take treatment; Groups B and C, mothers were treated with low and high dose of parsley, respectively; Group D, mothers were treated only with Cd (perinatal intoxication); Groups E and F, mothers were treated with Cd doses and protected by low and high doses of parsley, respectively. Light microscopy showed that Cd induced neuronal degeneration by chromatolysis and pyknosis in the brain regions. The low dose of parsley 10 g/kg/day exhibited significant effects in neutralizing and reducing the deleterious changes due to Cd exposure during pregnancy on the behavioral activities, neurotransmitters, oxidative stress, and brain neurons morphology of the mice newborns. PMID- 26966510 TI - Energy drink consumption in Israeli youth: Public health & the perils of energetic marketing. AB - In a recently published IJHPR article, Magnezi and colleagues add to our knowledge of consumption of energy drinks (ED), and alcohol mixed with energy drinks (AmED), by exploring these patterns among public school students in Tel Aviv, Israel. Prior research on this topic is largely limited to young adults, but adolescents are clearly targets of energy drink marketing, and this age group is at well-known risk for initiating risky exposures. The survey data presented here indicate that ED exposure is widespread in high school, and often begins in middle school. Among students consuming energy drinks, AmED exposure is also high, and of particular concern. Knowledge of ED and AmED hazards does not clearly associate with reduced intake, but a suggestion that awareness of caffeine thresholds may offer some dissuasion is noteworthy. The authors propose warning labels, and education directed to both youth and their parents. A case is made here for regulation of the energetic marketing of these products to youth as well. PMID- 26966509 TI - Draft genome sequence and overview of the purple non sulfur bacterium Rhodopseudomonas palustris 42OL. AB - Rhodopseudomonas palustris strain 42OL was isolated in 1973 from a sugar refinery waste treatment pond. The strain has been prevalently used for hydrogen production processes using a wide variety of waste-derived substrates, and cultured both indoors and outdoors, either freely suspended or immobilized. R. palustris 42OL was suitable for many other applications and capable of growing in very different culturing conditions, revealing a wide metabolic versatility. The analysis of the genome sequence allowed to identify the metabolic pathways for hydrogen and poly-beta-hydroxy-butyrate production, and confirmed the ability of using a wide range of organic acids as substrates. PMID- 26966508 TI - Periodic Exposure of Keratinocytes to Cold Physical Plasma: An In Vitro Model for Redox-Related Diseases of the Skin. AB - Oxidative stress illustrates an imbalance between radical formation and removal. Frequent redox stress is critically involved in many human pathologies including cancer, psoriasis, and chronic wounds. However, reactive species pursue a dual role being involved in signaling on the one hand and oxidative damage on the other. Using a HaCaT keratinocyte cell culture model, we investigated redox regulation and inflammation to periodic, low-dose oxidative stress after two, six, eight, ten, and twelve weeks. Chronic redox stress was generated by recurrent incubation with cold physical plasma-treated cell culture medium. Using transcriptome microarray technology, we identified both acute ROS-stress responses as well as numerous adaptions after several weeks of redox challenge. We determined a differential expression (2-fold, FDR < 0.01, p < 0.05) of 260 genes that function in inflammation and redox homeostasis, such as cytokines (e.g., IL-6, IL-8, and IL-10), growth factors (e.g., CSF2, FGF, and IGF-2), and antioxidant enzymes (e.g., HMOX, NQO1, GPX, and PRDX). Apoptotic signaling was affected rather modestly, especially in p53 downstream targets (e.g., BCL2, BBC3, and GADD45). Strikingly, the cell-protective heat shock protein HSP27 was strongly upregulated (p < 0.001). These results suggested cellular adaptions to frequent redox stress and may help to better understand the inflammatory responses in redox-related diseases. PMID- 26966513 TI - EEG correlates of social interaction at distance. AB - This study investigated EEG correlates of social interaction at distance between twenty-five pairs of participants who were not connected by any traditional channels of communication. Each session involved the application of 128 stimulations separated by intervals of random duration ranging from 4 to 6 seconds. One of the pair received a one-second stimulation from a light signal produced by an arrangement of red LEDs, and a simultaneous 500 Hz sinusoidal audio signal of the same length. The other member of the pair sat in an isolated sound-proof room, such that any sensory interaction between the pair was impossible. An analysis of the Event-Related Potentials associated with sensory stimulation using traditional averaging methods showed a distinct peak at approximately 300 ms, but only in the EEG activity of subjects who were directly stimulated. However, when a new algorithm was applied to the EEG activity based on the correlation between signals from all active electrodes, a weak but robust response was also detected in the EEG activity of the passive member of the pair, particularly within 9 - 10 Hz in the Alpha range. Using the Bootstrap method and the Monte Carlo emulation, this signal was found to be statistically significant. PMID- 26966512 TI - Novel in vitro and mathematical models for the prediction of chemical toxicity. AB - The focus of much scientific and medical research is directed towards understanding the disease process and defining therapeutic intervention strategies. The scientific basis of drug safety is very complex and currently remains poorly understood, despite the fact that adverse drug reactions (ADRs) are a major health concern and a serious impediment to development of new medicines. Toxicity issues account for ~21% drug attrition during drug development and safety testing strategies require considerable animal use. Mechanistic relationships between drug plasma levels and molecular/cellular events that culminate in whole organ toxicity underpins development of novel safety assessment strategies. Current in vitro test systems are poorly predictive of toxicity of chemicals entering the systemic circulation, particularly to the liver. Such systems fall short because of (1) the physiological gap between cells currently used and human hepatocytes existing in their native state, (2) the lack of physiological integration with other cells/systems within organs, required to amplify the initial toxicological lesion into overt toxicity, (3) the inability to assess how low level cell damage induced by chemicals may develop into overt organ toxicity in a minority of patients, (4) lack of consideration of systemic effects. Reproduction of centrilobular and periportal hepatocyte phenotypes in in vitro culture is crucial for sensitive detection of cellular stress. Hepatocyte metabolism/phenotype is dependent on cell position along the liver lobule, with corresponding differences in exposure to substrate, oxygen and hormone gradients. Application of bioartificial liver (BAL) technology can encompass in vitro predictive toxicity testing with enhanced sensitivity and improved mechanistic understanding. Combining this technology with mechanistic mathematical models describing intracellular metabolism, fluid-flow, substrate, hormone and nutrient distribution provides the opportunity to design the BAL specifically to mimic the in vivo scenario. Such mathematical models enable theoretical hypothesis testing, will inform the design of in vitro experiments, and will enable both refinement and reduction of in vivo animal trials. In this way, development of novel mathematical modelling tools will help to focus and direct in vitro and in vivo research, and can be used as a framework for other areas of drug safety science. PMID- 26925227 TI - Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences. AB - High-throughput sequencing of cDNA (RNA-seq) is used extensively to characterize the transcriptome of cells. Many transcriptomic studies aim at comparing either abundance levels or the transcriptome composition between given conditions, and as a first step, the sequencing reads must be used as the basis for abundance quantification of transcriptomic features of interest, such as genes or transcripts. Various quantification approaches have been proposed, ranging from simple counting of reads that overlap given genomic regions to more complex estimation of underlying transcript abundances. In this paper, we show that gene level abundance estimates and statistical inference offer advantages over transcript-level analyses, in terms of performance and interpretability. We also illustrate that the presence of differential isoform usage can lead to inflated false discovery rates in differential gene expression analyses on simple count matrices but that this can be addressed by incorporating offsets derived from transcript-level abundance estimates. We also show that the problem is relatively minor in several real data sets. Finally, we provide an R package ( tximport) to help users integrate transcript-level abundance estimates from common quantification pipelines into count-based statistical inference engines. PMID- 26966515 TI - IL-21 Signaling in Immunity. AB - IL-21 is a type I cytokine produced by T cells and natural killer T cells that has pleiotropic actions on a wide range of immune and non-immune cell types. Since its discovery in 2000, extensive studies on the biological actions of IL-21 have been performed in vitro and in vivo. Recent reports describing patients with primary immunodeficiency caused by mutations of IL21 or IL21R have further deepened our knowledge of the role of this cytokine in host defense. Elucidation of the molecular mechanisms that mediate IL-21's actions has provided the rationale for targeting IL-21 and IL-21 downstream mediators for therapeutic purposes. The use of next-generation sequencing technology has provided further insights into the complexity of IL-21 signaling and has identified transcription factors and co-factors involved in mediating the actions of this cytokine. In this review, we discuss recent advances in the biology and signaling of IL-21 and how this knowledge can be potentially translated into clinical settings. PMID- 26966516 TI - Impact of female adult eating disorder inpatients' attitudes to compulsive exercise on outcome at discharge and follow-up. AB - BACKGROUND: The link between compulsive exercise and eating disorders is well known, but research with clinical samples has been limited. The purpose of the study was to investigate changes in attitudes towards compulsive exercise and its impact on outcome at follow-up in female adult hospitalised patients with eating disorders. METHODS: The sample consisted of 78 patients: Diagnostic distribution: anorexia nervosa 59 % (n = 46), approximately 22 % (n = 16) in bulimia nervosa, and Eating Disorder not Otherwise Specified respectively. The average follow-up period was 26 months (SD =15 months). Compulsive exercise was measured by the Exercise and Eating Disorder (EED) questionnaire. Other measures were the Eating Disorder Inventory (EDI-2), Body Attitude Test (BAT), Symptom Checklist (SCL-90), Inventory of Interpersonal Problems (IIP 64), Beck Depression Inventory (BDI), and body mass index (BMI). Outcome measures were EDI-2 and BMI (patients with admission BMI <= 18.5). Paired sample t-tests and mixed model regression analysis were conducted to investigate changes in compulsive exercise and predictors of outcome respectively. RESULTS: All measures revealed significant improvements (p < .01 - p < .001) from admission to follow-up. EED scores significantly predicted changes in EDI-2 scores and BMI (p < .01 and p < .001 respectively). Other significant predictors were BAT, SCL-90, IIP-64, BMI (p < .01-.001) (EDI-2 as outcome measure), and BAT and BDI (p < .001) (BMI as outcome measure). CONCLUSIONS: The results demonstrated significant improvements in attitudes towards compulsive exercise during treatment and follow-up. The change in compulsive exercise scores predicted the longer-term course of eating disorder symptoms and BMI. PMID- 26966517 TI - Effects of preoperative proton pump inhibitor administration on bleeding after gastric endoscopic submucosal dissection: A systematic review and meta-analysis. AB - BACKGROUND AND AIM: The efficacy of using proton pump inhibitors (PPIs) prior to gastric endoscopic submucosal dissection (ESD) to reduce gastric bleeding remains controversial. This study aimed to systematically review the literature to evaluate the efficacy of preoperative PPI use to reduce post-ESD bleeding. METHODS: PubMed, the Cochrane library, and the Igaku-Chuo-Zasshi database were searched to identify randomized trials eligible for inclusion in the systematic review. Data from four studies (406 patients) were combined to calculate a pooled risk difference (RD) for developing post-ESD bleeding. RESULTS: Compared with patients who received no premedication, the pooled RD for post-ESD bleeding in patients who received preoperavive PPI was -0.027 (95% confidence interval: 0.070-0.017, p = 0.228), without significant heterogeneity. Preoperavive PPI use significantly increased gastric pH (weighted mean difference: 1.289, 95% CI: 0.227-2.352, p = 0.0174). CONCLUSIONS: This systematic review and meta-analysis showed that premedication with PPI had no advantage for the prevention of post ESD bleeding, despite increasing gastric pH. PMID- 26966519 TI - Systematic review and meta-analysis of endoscopic submucosal dissection vs endoscopic mucosal resection for colorectal lesions. AB - BACKGROUND AND AIMS: This systematic review and meta-analysis compares the safety and effectiveness of endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) in the treatment of flat and sessile colorectal lesions >20 mm preoperatively assessed as noninvasive. METHODS: We reviewed the literature published between January 2000 and March 2014. Pooled estimates of the proportion of patients with en bloc, R0 resection, complications, recurrence, and need for further treatment were compared in a meta-analysis using fixed and random effects. RESULTS: A total of 11 studies and 4678 patients were included. The en bloc resection rate was 89.9% for ESD vs 34.9% for EMR patients (RR 1.93 p < 0.001). The R0 resection rate was 79.6% for ESD vs 36.2% for EMR patients (RR 2.01 p < 0.001). The rate of perforation was 4.9% for the ESD group and 0.9% for EMR (RR 3.19, p < 0.001), while the rate of bleeding was 1.9% for ESD and 2.9% for EMR (RR 0.68, p = 0.070). Therefore, the overall need for further surgery, including surgery for oncologic reasons and surgery for complications, was 7.8% for ESD and 3.0% for EMR (RR 2.40, p < 0.001). CONCLUSIONS: ESD achieves a higher rate of en bloc and R0 resection compared to EMR, at the cost of a higher risk of complications. This, added to an increased need for surgery for oncologic reasons for a plausible tendency to extend indication for endoscopic excision, increases the risk of further surgery after ESD. PMID- 26966518 TI - Effects of carbon dioxide insufflation in balloon-assisted enteroscopy: A systematic review and meta-analysis. AB - BACKGROUND AND AIM: The efficacy of CO2 insufflation during balloon-assisted enteroscopy remains controversial. This study aimed to perform a systematic review with meta-analysis of randomized controlled trials (RCTs) in which CO2 insufflation was compared with air insufflation in balloon-assisted enteroscopy. METHODS: PubMed, the Cochrane library, and the Igaku-Chuo-Zasshi database were searched to identify RCTs eligible for inclusion in the systematic review. Data from the eligible studies were combined to calculate the pooled odds ratios (ORs) or weighted mean differences (WMDs) with 95% confidence intervals (CIs). RESULTS: Four RCTs (461 patients) were identified. Compared with air insufflation, CO2 insufflation significantly increased intubation depth of oral enteroscopy (WMD: 55.2, 95% CI: 10.77-99.65, p = 0.015). However, there was significant heterogeneity. The intubation depth of anal enteroscopy showed no significant difference between the CO2 group and the air group. CO2 insufflation significantly reduced abdominal pain compared with air insufflation (WMD: -2.463, 95% CI: -4.452 to -0.474, p = 0.015), without significant heterogeneity. The PaCO2 or end-tidal CO2 level showed no significant difference between the CO2 group and air group. CONCLUSIONS: Compared with air insufflation, CO2 insufflation during balloon-assisted enteroscopy caused less post-procedural pain without CO2 retention. PMID- 26966521 TI - Adherence to therapy for Barrett's esophagus-associated neoplasia. AB - OBJECTIVES: Multiple endoscopic sessions may be necessary for treatment and surveillance of Barrett's esophagus (BE)-associated neoplasia. Adherence to an endoscopic therapeutic regimen is important for longitudinal management of BE. The objective of this study was to identify the factors associated with adherence to therapy for BE-associated neoplasia. METHODS: We retrospectively identified patients with BE whom were referred to a tertiary center for endoscopic mucosal resection (EMR) or radiofrequency ablation (RFA) between 2009 and 2012. Demographic and clinical data were extracted from the medical record. RESULTS: We had 69 subjects meet our inclusion criteria. Referral diagnosis was low-grade dysplasia in 9 (13%) subjects, high-grade dysplasia in 33 (48%) subjects and adenocarcinoma in 26 (38%) subjects. The majority (55%) lived more than 100 miles from the treatment center. The primary third-party payer was US Medicare for 54% of the subjects and private insurance for 36% of them; 45% of the subjects were seen in the clinic by the treating endoscopist, prior to endoscopic therapy and 71% underwent EMR as the initial treatment, while 29% underwent RFA without prior EMR. We found that 72% of subjects were adherent to therapy, including: 23 (33%) completing endoscopic therapy with documented post-treatment surveillance, 18 (26%) with ongoing endoscopic therapy, and 9 (13%) whom underwent esophagectomy. Subjects seen in gastroenterology clinical consultation were significantly more likely to demonstrate adherence than those referred for open access endoscopy (Lasso OR 2.31). CONCLUSIONS: Patients seen in a clinical consultation prior to endoscopic therapy for BE-associated neoplasia were more likely to demonstrate treatment adherence, compared to patients referred for open-access endoscopy. A clinic visit prior to therapy may define expectations regarding treatment course and increase the likelihood of patient adherence. PMID- 26966520 TI - The European Society of Gastrointestinal Endoscopy Quality Improvement Initiative: developing performance measures. AB - The European Society of Gastrointestinal Endoscopy (ESGE) and United European Gastroenterology (UEG) have a vision to create a thriving community of endoscopy services across Europe, collaborating with each other to provide high quality, safe, accurate, patient-centered and accessible endoscopic care. Whilst the boundaries of what can be achieved by advanced endoscopy are continually expanding, we believe that one of the most fundamental steps to achieving our goal is to raise the quality of everyday endoscopy. The development of robust, consensus- and evidence-based key performance measures is the first step in this vision. ESGE and UEG have identified quality of endoscopy as a major priority. This paper explains the rationale behind the ESGE Quality Improvement Initiative and describes the processes that were followed. We recommend that all units develop mechanisms for audit and feedback of endoscopist and service performance using the ESGE performance measures that will be published in future issues of this journal over the next year. We urge all endoscopists and endoscopy services to prioritize quality and to ensure that these performance measures are implemented and monitored at a local level, so that we can provide the highest possible care for our patients. PMID- 26966522 TI - Argon plasma coagulation for the endoscopic treatment of gastrointestinal tumor bleeding: A retrospective comparison with a non-treated historical cohort. AB - BACKGROUND: The endoscopic use of argon plasma coagulation (APC) to achieve hemostasis for upper gastrointestinal tumor bleeding (UGITB) has not been adequately evaluated in controlled trials. This study aimed to evaluate the efficacy of APC for the treatment of upper gastrointestinal bleeding from malignant lesions. METHODS: Between January and September 2011, all patients with UGITB underwent high-potency APC therapy (up to 70 Watts). This group was compared with a historical cohort of patients admitted between January and December 2010, when the endoscopic treatment of bleeding malignancies was not routinely performed. Patients were stratified into two categories, grouping the Eastern Cooperative Oncology Group (ECOG) performance status scale: Category I (ECOG 0-2) patients with a good clinical status and Category II (ECOG 3-4) patients with a poor clinical status. RESULTS: Our study had 25 patients with UGITB whom underwent APC treatment and 28 patients whom received no endoscopic therapy. The clinical characteristics of the groups were similar, except for endoscopic active bleeding, which was more frequently detected in APC group. We had 15 patients in the APC group whom had active bleeding, and initial hemostasis was obtained in 11 of them (73.3%). In the control group, four patients had active bleeding. There were no differences in 30-day re-bleeding (33.3% in the APC group versus 14.3% in the control group; p = 0.104) and 30-day mortality rates (20.8% in the APC group, versus 42.9% in the control group; p = 0.091). When patients were categorized according to their ECOG status, we found that APC therapy had no impact in re-bleeding and mortality rates (Group I: APC versus no endoscopic treatment: re-bleeding p = 0.412, mortality p = 0.669; Group II: APC versus no endoscopic treatment: re-bleeding p = 0.505, mortality p = 0.580). Hematemesis and site of bleeding located at the esophagus or duodenum were associated with a higher 30-day mortality. CONCLUSIONS: Endoscopic hemostasis of UGITB with APC has no significant impact on 30-day re-bleeding and mortality rates, irrespective of patient performance status. PMID- 26966523 TI - Correlation of esophageal clearance and dysphagia symptom assessment after treatment for achalasia. AB - BACKGROUND: Early relapse after treatment of achalasia occurs in 10-32 % of patients. The best method to follow up these patients is not known. Symptoms often do not correlate with esophageal clearance: some patients are oligosymptomatic despite persistent esophageal stasis/dilatation. AIM: The aim was to compare two methods of measurement of esophageal clearance (impedance manometry with barium swallow) in achalasia patients following treatment. Symptom assessment (Eckardt score/detailed dysphagia questions) was correlated with objective measurements of esophageal stasis (barium swallow and impedance manometry) in achalasia patients following treatment. METHODS: Post-treatment patients were followed up after median 38.4 months (median range 1-144 months). Symptoms were quantified using the Eckardt score and detailed dysphagia questions. Timed barium swallow quantified distal esophageal retention 0.5, 1, 3, and 5 minutes after oral contrast and impedance manometry assessed total and segmental esophageal clearance during water/viscous swallows and free drinking (200 mL). RESULTS: Thirty-two patients (7 women, age 48.3; range 20-74) completed all investigations. Bolus retention in the distal esophagus assessed by impedance correlated well with barium swallow. There were no differences in impedance and timed barium swallow parameters between patients with Eckardt score 0-2 points or >=3 points. Nine (28%) patients had an Eckardt score >=3 points and 21 (66%) had >=1 point in the detailed dysphagia questions. Patients without any dysphagia history had lower barium column height and width at 3 and 5 minutes compared to those with >=1 positive answer in the detailed dysphagia questions. Correlation between the Eckardt score and detailed dysphagia questions was moderately good (r = 0.546; p = 0.001). CONCLUSION: A detailed history of esophageal dysphagia rather than the Eckardt score is more sensitive to detect oligosymptomatic patients with disturbed esophageal clearance. Impedance manometry correlates well with the timed-barium swallow examination and represents an alternative objective assessment as it avoids radiation exposure. PMID- 26966524 TI - Simultaneous combined balloon-occluded retrograde transvenous obliteration and partial splenic embolization for gastric fundal varices. AB - BACKGROUND: We previously reported the techniques and usefulness of simultaneous combined balloon-occluded retrograde transvenous obliteration (B-RTO) and partial splenic embolization (PSE), based on the hypothesis that concomitant PSE can diminish the increase in portal venous pressure after B-RTO. OBJECTIVE: After experiencing more cases and performing longer-term follow-up, we re-evaluated the efficacy of simultaneous combined B-RTO and PSE for gastric fundal varices (GVs). METHODS: We performed B-RTO in 36 consecutive patients treated for GVs from 2005 to 2013. Twenty-three patients underwent simultaneous combined B-RTO and PSE (Group 1) and 13 underwent B-RTO monotherapy (Group 2). The outcomes were retrospectively evaluated. RESULTS: There were no significant differences in baseline characteristics between the two groups except that the splenic volumes were larger in Group 1 than 2. B-RTO was technically successful in 21 of 23 patients (91.3%) in Group 1 and in 12 of 13 patients (92.3%) in Group 2. In all patients with ruptured GVs (six in Group 1 and five in Group 2), complete hemostasis was obtained by B-RTO. Exacerbation of esophageal varices was significantly less frequent in Group 1 than 2 (p = 0.0017). CONCLUSION: Concomitant PSE with B-RTO may contribute to prevention of the exacerbation of esophageal varices after B-RTO. PMID- 26966525 TI - Long-acting somatostatin analogues provide significant beneficial effect in patients with refractory small bowel angiodysplasia: Results from a proof of concept open label mono-centre trial. AB - INTRODUCTION: Small bowel angiodysplasias account for over 50% of causes of small bowel bleeding and carry a worse prognosis than lesions located elsewhere in the gastrointestinal tract. Re-bleeding rates are high even after first-line endoscopic therapy and are associated with high levels of morbidity for affected patients. Small trials of long-acting somatostatin analogues have shown promising results but have not yet been assessed in patients with refractory small bowel disease. AIM: The purpose of this study was to assess the effect of long-acting somatostatin analogues in reducing re-bleeding rates and transfusion requirements, and improving haemoglobin levels in patients with refractory small bowel angiodysplasia. METHODS: Patients with refractory small bowel angiodysplasia were treated with 20 mg of long-acting octreotide for a minimum of three months. Response was assessed according to: rates of re-bleeding, haemoglobin levels, transfusion requirements, and side effects. RESULTS: A total of 24 patients were initially treated and 20 received at least three doses. Rates of complete, partial and non-response were 70%, 20% and 10% respectively. Average haemoglobin rates increased from 9.19 g/dl to 11.35 g/dl (p = 0.0027, 95% confidence interval (CI) -3.5 to -1.1) in the group overall and 70% remained transfusion-free after a mean treatment duration of 8.8 months. The rate of adverse events was higher than previously reported at 30%. CONCLUSION: Long acting somatostatin analogues offer a therapeutic advantage in a significant proportion of patients with small bowel angiodysplasia. With careful patient selection and close observation, a long-acting somatostatin analogue should be considered in all patients with persistent anaemia attributable to refractory disease in conjunction with other standard treatments. PMID- 26966526 TI - Prospective study of profile of hepatic osteodystrophy in patients with non choleastatic liver cirrhosis and impact of bisphosphonate supplementation. AB - BACKGROUND AND OBJECTIVES: Patients with liver cirrhosis are more prone to develop reduced bone mineral density (BMD), i.e. hepatic osteodystrophy (HOD). There are few data on the prevalence of HOD in the Indian population and its treatment. We aimed to determine the prevalence of HOD, factors associated with it and the impact of bisphosphonates on BMD in patients with liver cirrhosis. PATIENTS AND METHODS: Consecutive patients with liver cirrhosis admitted at Sir Ganga Ram Hospital, New Delhi, between August 2012 and July 2013 were enrolled. Patients with chronic kidney disease, hyperparathyroidism and those on steroids were excluded. BMD was measured by dual-energy X-ray absorptiometry (DEXA) at the lumbar spine and femoral neck. Osteopenia and osteoporosis were defined according to WHO criteria. Ibandronic acid 150 mg per day orally for six months was given to patients with osteoporosis and DEXA scan repeated. RESULTS: A total of 215 patients (males 179, 83%) with a mean age of 50.9 +/- 11 years were enrolled in this study. Prevalence of HOD was found to be 66% (142/215). On multivariate analysis BMI, TLC, total serum bilirubin and transient elastography values were found to be independently associated with HOD. All the patients with osteoporosis (n = 47) were treated with ibandronic acid as per protocol. Treated patients had significant improvement in DEXA scans after six months as compared to baseline. CONCLUSIONS: HOD was seen in two-thirds of patients with liver cirrhosis. Higher liver stiffness as determined by transient elastography is significantly associated with HOD. Severity scores of liver disease (CTP and MELD) and etiology of liver cirrhosis did not determine HOD. Ibandronic acid is a safe drug that showed significant improvement in BMD in patients with liver disease along with osteoporosis. PMID- 26966527 TI - A common genetic variant of fucosyltransferase 2 correlates with serum carcinoembryonic antigen levels and affects cancer screening in patients with primary sclerosing cholangitis. AB - BACKGROUND: Primary sclerosing cholangitis (PSC) patients are at increased risk of biliary tract cancer, and carcinoembryonic antigen (CEA) serum levels might be used for screening. OBJECTIVE: To examine cancer screening with CEA in PSC patients and analyse how serum CEA levels are affected by genetic variants of fucosyltransferase (FUT) 2 and 3. METHODS: In a retrospective cohort analysis we evaluated CEA levels in 226 PSC patients, including 19 with biliary malignancy, and investigated how FUT2 and FUT3 SNPs affected CEA levels. Receiver-operating characteristic (ROC) analysis was performed and cut-off values were determined based on Youden's index. A control cohort contained 240 patients, including 28 with biliary malignancy. RESULTS: Median CEA concentration was lower in cancer free patients (1.4 ng/mL) than in cancer patients (2.0 ng/mL, P = 0.014). ROC analysis revealed an area under the curve (AUC) of 0.671, the optimal cut-off was 3.2 ng/mL. The FUT2 variant rs601338 (G428A) correlated with CEA levels, and the effect was most prominent in a subgroup of patients genetically incapable of expressing CA19-9. The AUC improved if ROC analysis was performed separately for wild-type (AUC: 0.731) and homozygous mutant (AUC: 0.816) G428A. The influence of FUT2 on CEA was confirmed in the control cohort. CONCLUSIONS: CEA is interesting for biliary-malignancy screening in PSC patients, especially in patients who do not express CA19-9. This is the first study to show that the combined use of CEA measurement and FUT genotyping is clinically beneficial and that it might enhance the early detection of biliary malignancy in clinical practice. This approach could also be effective when screening for other common gastrointestinal malignancies. PMID- 26966528 TI - The association of endoplasmic reticulum aminopeptidase-1 (ERAP-1) with Familial Mediterranean Fever (FMF). AB - BACKGROUND: The ERAP1 gene cleaves the receptors and reduces their ability to transmit chemical signals to the cell that affect the process of inflammation and, secondly, it cleaves many types of proteins into small peptides that are recognized by the immune system. OBJECTIVE: ERAP-1 gene mutations may create a sensitivity for Familial Mediterranean Fever (FMF). METHOD: We included 15 FMF patients with the M694 (+) mutation in the study in order to exclude patients without pyrin gene mutations and create a homogeneous study group. Fifteen patients with ulcerative colitis formed the control group. RESULTS: There wasn't any case without ERAP-1 gene mutations. At least one mutation at exon 3 or exon 10 was found in all cases in both groups. There were 14 ERAP-1 gene mutations at exon 10 and 11 at exon 3 in patients with FMF. Interestingly, if there were ERAP 1 gene mutations at exon 3, a p.Arg127 Pro (c.380 G>C) mutation always existed for three FMF patients with polymorphic mutations at this exon. There were 11 ERAP-1 gene mutations at exon 10 and 12 gene mutations at exon 3 in patients with ulcerative colitis. Exon 3 mutations were usually single p.Arg127 Pro (c.380 G>C) mutations for 12 patients with ulcerative colitis as seen in the patients with FMF. The single mutation was always p.Ser453 Ser (c.1359T>C) for patients with ulcerative colitis at exon 10. CONCLUSION: There are more ERAP-1 mutations in the FMF group in comparison to the ulcerative colitis group. So, there may be a strong susceptibility to ERAP-1 gene mutations in FMF patients according to our results. However, further studies with larger study and control groups are needed. PMID- 26966529 TI - Alicaforsen, an antisense inhibitor of ICAM-1, as treatment for chronic refractory pouchitis after proctocolectomy: A case series. AB - BACKGROUND AND AIMS: The published data about the efficacy of the intercellular adhesion molecule-1 (ICAM-1) antisense oligonucleotide termed alicaforsen in inflammatory bowel disease (IBD) is rather inconsistent. This case series analyzes its efficacy in chronic refractory pouchitis, after proctocolectomy. METHODS: We performed a retrospective analysis on all patients who had received at least one dose of alicaforsen for IBD at three referral centers in Switzerland. We assessed the drug's efficacy in patients treated for chronic refractory pouchitis, by comparing the clinical and/or endoscopic disease activity at baseline with a 2-3-month follow-up visit. RESULTS: We identified 22 patients who had received at least one dose. Among them, 13 patients were being treated for chronic refractory pouchitis. These patients had a median age of 38.0 years (95% CI 21.0-69.0) and five were female (38.5%). The median time since pouch surgery was 102.5 months (95% CI 16.0-288.0), with a median pouchitis duration of 16.0 months (95% CI 4.0-216.0). At 2-3 months after therapy, clinical and endoscopic disease activity was significantly reduced (stool frequency 9.0 versus 6.0, the Pouchitis Disease Activity Index (PDAI) clinical subscore was 4.0 versus 1.0, and the endoscopic disease activity was 4.0 versus 2.0). Clinical improvement was achieved in 11 out of 13 pouchitis patients (84.6%); however, a relapse was observed in nine of these patients (81.8%). The median time from clinical improvement to relapse was 16 weeks (95% CI 9.0-23.0). CONCLUSIONS: Alicaforsen seemed to be efficacious in inducing clinical and/or endoscopic improvement in chronic refractory pouchitis and may be a promising treatment alternative in those patients; however, given the high proportion of relapse, one 6-week course of alicaforsen may not be sufficient. PMID- 26966530 TI - Feasibility study of minimal prepared hydroflush screening colonoscopy. AB - BACKGROUND: Although screening colonoscopy is effective for early detection of colorectal cancer (CRC), screening rates remain low. Multiple factors are thought to be responsible for the low rates of screening colonoscopy, but bowel preparation appears to be a key deterrent. Tolerability issues with bowel preparations may lead to poor patient compliance, inadequate colon cleansing, and reduced detection of colonic polyps. AIM: The aim of this article is to evaluate the feasibility, safety, and outcomes of minimally prepared intra-procedural hydroflush technique as an alternative to traditional bowel preparation in screening colonoscopy. DESIGN: We conducted a prospective feasibility study of intraprocedural hydroflush technique aided by water-jet pumps and a mechanical suction novel device following minimal bowel preparation for CRC screening. PATIENTS AND METHODS: Nine procedures were performed in nine healthy individuals scheduled for routine screening colonoscopy. Preparation included mild diet restriction, laxative tablets two to three days prior to the procedure and two Fleet enemas one to two hours before the colonoscopy. The cleanliness of the colon was assessed by using the Boston bowel preparation scale. Insertion and withdrawal times were recorded. RESULTS: Complete colonoscopy to the cecum was performed in all patients (100%). Mean time to the cecum was 5.78 +/- 2.68 minutes, and mean withdrawal time was 15.33 +/- 3.94 minutes. Endoscopic visualization of the entire mucosa was achieved in all cases with no colonoscopy repeated because of inadequate preparation. Four polyps have been detected and removed in three patients. Mild mucosal erosions were seen in some areas where the suction was used extensively, similar to those that can be seen during conventional colonoscopy. Mild stiffness of the shaft of the scope was noted. LIMITATIONS: This was an uncontrolled feasibility study of selected patients. CONCLUSIONS: Minimally prepared colonoscopy with the intra-procedural hydroflush technique for colorectal screening is feasible. The water exchange technology compensates for the mild stiffness of the scope. This technique might increase patients' compliance for CRC screening. PMID- 26966531 TI - Time trends in quality indicators of colonoscopy. AB - BACKGROUND: There is considerable variation in the quality of colonoscopy performance. The Norwegian quality assurance programme Gastronet registers outpatient colonoscopies performed in Norwegian endoscopy centres. The aim of Gastronet is long-term improvement of endoscopist and centre performance by annual feedback of performance data. OBJECTIVE: The objective of this article is to perform an analysis of trends of quality indicators for colonoscopy in Gastronet. METHODS: This prospective cohort study included 73,522 outpatient colonoscopies from 73 endoscopists at 25 endoscopy centres from 2003 to 2012. We used multivariate logistic regression with adjustment for relevant variables to determine annual trends of three performance indicators: caecum intubation rate, pain during the procedure, and detection rate of polyps >=5 mm. RESULTS: The proportion of severely painful colonoscopies decreased from 14.8% to 9.2% (relative risk reduction of 38%; OR = 0.92 per year in Gastronet; 95% CI 0.86 1.00; p = 0.045). Caecal intubation (OR = 0.99; 95% CI 0.94-1.04; p = 0.6) and polyp detection (OR = 1.03; 95% CI 0.99-1.07; p = 0.15) remained unchanged during the study period. CONCLUSIONS: Pain at colonoscopy showed a significant decrease during years of Gastronet participation while caecal intubation and polyp detection remained unchanged - independent of the use of sedation and/or analgesics and level of endoscopist experience. This may be due to the Gastronet audit, but effects of improved endoscopy technology cannot be excluded. PMID- 26966532 TI - Post-infectious irritable bowel syndrome (PI-IBS) after infection with Shiga-like toxin-producing Escherichia coli (STEC) O104:H4: A cohort study with prospective follow-up. AB - BACKGROUND: In May/June 2011, the new Shiga-like toxin-producing Escherichia coli (STEC) strain O104:H4 caused the severest outbreak ever recorded of hemorrhagic enterocolitis in 3842 patients in Germany. OBJECTIVES: As bacterial enterocolitis is an established risk factor of subsequent irritable bowel syndrome (IBS), we aimed to estimate prevalence and incidence of post-infectious (PI)-IBS after six and 12 months in a cohort of STEC O104:H4 patients and to prospectively identify associated somatic and psychometric risk factors. METHODS: A total of 389 patients were studied prospectively at baseline and at six and 12 months after STEC infection using STEC disease-related questionnaires and validated instruments for IBS (Rome III) and psychological factors. Frequencies and logistic regression models using multiple imputations were applied to assess predictor variables. RESULTS: Prevalence of IBS increased from 9.8% prior to STEC infection to 23.6% at six and 25.3% at 12 months after STEC infection. In patients without IBS symptoms prior to STEC infection, incidence of new IBS was 16.9%. Logistic regression models indicated higher somatization and anxiety scores as risk factors for, and mesalazine treatment during, STEC infection as the only significant protective factor against IBS. No other factor analyzed, including disease severity, showed an association. CONCLUSIONS: PI-IBS rates following this unusually severe STEC outbreak were similar to what has been observed after other infectious gastroenteritis outbreaks. Our findings suggest that mesalazine may have reduced the risk of subsequent PI-IBS. As altered mucosal immune activity is a pivotal pathogenic factor in PI-IBS, our observation of a potential protective effect of mesalazine might be explained by its known modulatory action on mucosal immunity, and may warrant further investigation. PMID- 26966534 TI - Chronic constipation and co-morbidities: A prospective population-based nested case-control study. AB - BACKGROUND: Chronic constipation (CC) is common in the community but surprisingly little is known about relevant gastro-intestinal (GI) and non-GI co-morbidities. OBJECTIVE: The purpose of this study was to assess the epidemiology of CC and in particular provide new insights into the co-morbidities linked to this condition. METHODS: In a prospective, population-based nested case-control study, a cohort of randomly selected community residents (n = 8006) were mailed a validated self report gastrointestinal symptom questionnaire. CC was defined according to Rome III criteria. Medical records of each case and control were abstracted to identify potential CC comorbidities. RESULTS: Altogether 3831 (48%) subjects returned questionnaires; 307 met criteria for CC. Age-adjusted prevalence in females was 8.7 (95% confidence interval (CI) 7.1-10.3) and 5.1 (3.6-6.7) in males, per 100 persons. CC was not associated with most GI pathology, but the odds for constipation were increased in subjects with anal surgery relative to those without (odds ratio (OR) = 3.3, 95% CI 1.2-9.1). In those with constipation vs those without, neurological diseases including Parkinson's disease (OR = 6.5, 95% CI 2.9-14.4) and multiple sclerosis (OR = 5.5, 95% CI 1.9-15.8) showed significantly increased odds for chronic constipation, adjusting for age and gender. In addition, modestly increased odds for chronic constipation in those with angina (OR = 1.4, 95% CI 1.1-1.9) and myocardial infarction (OR = 1.5, 95% CI 1.0-2.4) were observed. CONCLUSIONS: Neurological and cardiovascular diseases are linked to constipation but in the community constipation is unlikely to account for most lower GI pathology. PMID- 26966535 TI - Safety of gluten in gluten-free foods. PMID- 26966536 TI - Response to Forbes's comment. PMID- 26966537 TI - Why submit an abstract to United European Gastroenterology Week, and how to be successful with your submission? PMID- 26966533 TI - Visceral pain perception in patients with irritable bowel syndrome and healthy volunteers is affected by the MRI scanner environment. AB - BACKGROUND: The MRI scanner environment induces marked psychological effects, but specific effects on pain perception and processing are unknown and relevant to all brain imaging studies. OBJECTIVES AND METHODS: We performed visceral and somatic quantitative sensory and pain testing and studied endogenous pain modulation by heterotopic stimulation outside and inside the functional MRI scanner in 11 healthy controls and 13 patients with irritable bowel syndrome. RESULTS: Rectal pain intensity (VAS 0-100) during identical distension pressures increased from 39 (95% confidence interval: 35-42) outside the scanner to 53 (43 63) inside the scanner in irritable bowel syndrome, and from 42 (31-52) to 49 (39 58), respectively, in controls (ANOVA for scanner effect: p = 0.006, group effect: p = 0.92). The difference in rectal pain outside versus inside correlated significantly with stress (r = -0.76, p = 0.006), anxiety (r = -0.68, p = 0.02) and depression scores (r = -0.67, p = 0.02) in controls, but not in irritable bowel syndrome patients, who a priori had significantly higher stress and anxiety scores. ANOVA analysis showed trends for effect of the scanner environment and subject group on endogenous pain modulation (p = 0.09 and p = 0.1, respectively), but not on somatic pain (p > 0.3). CONCLUSION: The scanner environment significantly increased visceral, but not somatic, pain perception in irritable bowel syndrome patients and healthy controls in a protocol specifically aimed at investigating visceral pain. Psychological factors, including anxiety and stress, are the likely underlying causes, whereas classic endogenous pain modulation pathways activated by heterotopic stimulation play a lesser role. These results are highly relevant to a wide range of imaging applications and need to be taken into account in future pain research. Further controlled studies are indicated to clarify these findings. PMID- 26966538 TI - Young GI Angle: Young physicians and researchers within UEG - Perspectives and a toolbox for future development. PMID- 26966541 TI - Treatment with rituximab and brentuximab vedotin in a patient of common variable immune deficiency-associated classic Hodgkin lymphoma. AB - BACKGROUND: Patients with common variable immunodeficiency (CVID) have an increased risk of developing lymphoproliferative diseases, including non-Hodgkins lymphoma (Blood 116:1228-1234, 2010; Blood 119:1650-7, 2012). The incidence and prognosis of Hodgkin lymphoma in this population is not clear, with only a few case reports in the literature. Conventional cytotoxic chemotherapy, although highly efficacious in treating Hodgkin lymphoma in immune competent patients, is problematic in patients with CVID due to the increased risk of infectious complications (Ther Umsch 69:687-91, 2012; Pediatr Hematol Oncol 24:337-42, 2012). Rituximab and brentuximab vedotin are both targeted agents used to treat lymphomas that express CD20 and CD30, respectively. Compared to cytotoxic chemotherapy typically used in Hodgkin lymphoma, these agents are better tolerated with minimal side effects. This makes them an attractive option for treating lymphoma in patients who have significant co-morbidities, including those with immune deficiencies. Additionally, rituximab has been used safely to treat autoimmune cytopenias in patients with CVID5. However, the role of these targeted therapies in CVID-associated Hodgkin lymphoma has not been reported. CASE PRESENTATION: Here we report the case of a 25 year old female diagnosed with CVID-associated classic Hodgkin lymphoma, who achieved a complete remission following treatment with rituximab followed by brentuximab vedotin. CONCLUSIONS: We demonstrate that rituximab and brentuximab are likely safe and effective in CVID-associated Hodgkin lymphoma, providing a feasible and potentially optimal treatment option for this patient population. PMID- 26966540 TI - Circulating micrornas associated with glycemic impairment and progression in Asian Indians. AB - AIMS/HYPOTHESIS: Asian Indians have a high incidence of type 2 diabetes, but factors associated with glycemic progression in this population are not understood. MicroRNAs are emerging as important mediators of glucose homeostasis and have not been previously studied in Asian Indians. We examined microRNA (miR) expression associated with glycemic impairment and progression in Asian Indians from the San Francisco Bay Area. We studied 128 Asian Indians age 45-84 years without known cardiovascular disease and not taking diabetes medications. Oral glucose tolerance tests were performed at baseline and after 2.5 years. We quantified circulating miRs from plasma collected during the enrollment visit using a flow cytometry-based assay. RESULTS: Glycemic impairment was present in 57 % (n = 73) at baseline. MiR-191 was positively associated with glycemic impairment (odds ratio (OR) 1.7 (95 % CI 1.2, 2.4), p < 0.01). The prevalence of glycemic progression after 2.5 years was 24 % (n = 23). Six miRs were negatively associated with glycemic progression: miR-122 (OR 0.5 (0.2, 0.8), p < 0.01), miR 15a (OR 0.6 (0.4, 0.9), p < 0.01), miR-197 (OR 0.6 (0.4, 0.9), p < 0.01), miR 320a (OR 0.6 (0.4, 0.9), p < 0.01), miR-423 (OR 0.6 (0.4, 0.9), p < 0.01), and miR-486 (OR 0.5 (0.3, 0.8), p < 0.01). Further multivariate adjustment did not attenuate these results. CONCLUSIONS/INTERPRETATION: This is the first study to investigate circulating miRs associated with glycemic status among this high-risk ethnic group. Individual miRs were significantly associated with both glycemic impairment and glycemic progression. Further studies are needed to determine whether miR (s) might be useful clinical biomarkers for incident T2D in the Asian Indian population. PMID- 26966543 TI - A novel immunopathological association of IgG4-RD and vasculitis with Hashimoto's thyroiditis. AB - A 73-year-old man with Hashimoto's thyroiditis (HT) suffered from purpura on the lower legs. He was diagnosed with IgG4-related disease (IgG4-RD) with serum IgG4 elevation and dacryo-sialadenitis confirmed histologically. Serum Th2 and Treg cytokines, interleukin 7 (IL7), IL8 and Th2 chemokine levels were elevated, while skewed Th1 balance was seen in fluorescence-activated cell sorting (FACS). Therefore, preferential Th1 balance in HT appeared to be followed by IgG4-RD characterized with Th2 and Treg polarization. The commencement of steroid therapy dramatically exacerbated clinical manifestations including IgG4-RD-associated HT. The measurement of cytokine and chemokine levels as well as FACS analysis in the development of IgG4-RD seemed to be beneficial. In conclusion, an innovative association of HT, IgG4-RD and vasculitis was observed. This report also offers novel diagnostic and therapeutic approaches for IgG4-RD. LEARNING POINTS: Recently, a subtype of HT has been considered to be a thyroid manifestation of IgG4-RD, although the etiology of IgG4-RD is not established yet.Immunologically a close association between HT and vasculitis was reported.Leukocytoclastic vasculitis is a rare skin presentation of IgG4-RD.In the current case, during the course of HT, IgG4-RD and leukocytoclastic vasculitis occurred; thus, innate immunity and acquired immunity seem to be involved in the development of IgG4 RD.The measurement of cytokine and chemokines appeared to be beneficial in the development of IgG4-RD.Remarkably, effectiveness of steroid therapy for HT suggested presence of IgG4-RD-associated HT. Therefore, this report highlights the pathogenesis of IgG4-RD and proposes novel therapeutic mechanisms. Clinicians should pay attention to the development of IgG4-RD and vasculitis during long course of HT. PMID- 26966542 TI - Profiles of direct oral anticoagulants and clinical usage-dosage and dose regimen differences. AB - The availability of direct oral anticoagulants (DOACs) has caused a paradigm shift in thrombosis management. DOAC profiles do not differ greatly, though they are quite different from that of warfarin, whereas their dosage and dose regimens are not consistent. The direct thrombin inhibitor dabigatran seems to obstruct tenase by inhibiting thrombin generated in the initial phase and feedback to the amplification phase of cell-based coagulation reactions. Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) mainly inhibit factor Xa activity of the prothrombinase complex in the propagation phase. The dose regimens of these inhibitors can be classified into once (rivaroxaban, edoxaban) and twice (dabigatran, apixaban) daily. On the other hand, their plasma elimination half life times are similar, which can be explained by differences in the type of aimed anticoagulation, such as persistent (e.g., warfarin) and intermittent (e.g., low-molecular-weight heparin). Because of the differences among DOACs, an indicator is necessary to compare them. We investigated relative potency to compare dosage and intensity by calculation of conversion using a profile comprised of molecular weight, bioavailability, protein-binding rate, inhibitory constant, and dosage. We found that the relative potencies were different, with that of apixaban higher than edoxaban (60 mg) and nearly twice that of rivaroxaban. However, dabigatran could not be evaluated with this profile, likely due to its different mode of action. These results suggest that rivaroxaban and apixaban differ in regard to anticoagulation type, as the former shows persistent and the latter intermittent anticoagulation. PMID- 26966544 TI - Predictors of early attrition and successful weight loss in patients attending an obesity management program. AB - BACKGROUND: Our objective was to identify factors that are independently associated with early attrition and successful weight loss (WL) in an obesity management program. METHODS: Participants were 9,498 patients enrolled in treatment at the Wharton Weight Management Clinic for at least 6 months. Predictors of early attrition (<6 months) and successful WL (>=5 %) were analyzed using relative risk (RR) in men and women separately. Pearson's correlation was used to determine the relationship between WL and treatment time Weight loss and attrition analysis was restricted to patients who had more than two visits (n = 5415). RESULTS: Older individuals had lower early attrition (RR Range:0.74-0.92, P < 0.05) and greater WL success (RR Range:1.40-1.65, P < 0.05) than younger individuals. Males with hypertension and females with depression had greater early attrition (RR Range:1.09-1.20, P < 0.05) and lower WL success (RR Range:0.48-0.57, P < 0.05) than those without these health conditions. Males with lower education had greater early attrition (RR = 1.11[1.03-1.19]) than males with higher education, but did not differ in WL. Females who smoked had greater early attrition (RR = 1.06[1.01-1.11]) than females who did not smoke, but did not differ in WL. Ethnicity was not related to early attrition, however, females of Black and Other ethnicities had lower WL success compared to White females (RR Range:0.58-0.74, P < 0.05). After adjusting for treatment time, all above associations were no longer significant and treatment time remained as the only independent predictor of WL success (P < 0.0001). CONCLUSION: As WL is positively and independently related with treatment time, individuals at risk for early attrition may need alternative treatment options, in order to improve patient retention and improve WL success. PMID- 26966545 TI - Effectiveness analysis of an internet-based intervention for overweight adolescents: next steps for researchers and clinicians. AB - BACKGROUNDS: The development of effective strategies for the management of overweight in adolescence is a well recognized need. The current study investigates the effectiveness of an e-therapeutic platform (Next.Step) which aims to promote weight management skills and the adoption of health-promoting behaviours among overweight adolescents. METHODS: We conducted a randomized clinical trial with a sample of 80 adolescents. The control group followed the standard intervention. The experimental group was invited to access the platform during 12 weeks in addition to the standard intervention. RESULTS: Although there was no change in the primary outcomes (body mass index and percentage of fat mass), the results suggest that the program is associated with an improvement in the 'positive perspective of life' and 'benefits perceived from the intervention', which have been identified as relevant factors for an effective weight management. CONCLUSIONS: Our findings provide little support for the effectiveness of internet-based weight management programs as an add-on to the standard intervention. TRIAL REGISTRATION: NCT01904474. PMID- 26966546 TI - Readability and content analysis of lifestyle education resources for weight management in Australian general practice. AB - BACKGROUND: Weight management education is one of the key strategies to assist patients to manage their weight. Educational resources provide an important adjunct in the chain of communication between practitioners and patients. However, one in five Australian adults has low health literacy. The purpose of this study was to assess the readability and analyse the content of weight management resources. METHODS: This study is based on the analysis of 23 resources found in the waiting rooms of ten Sydney-based general practices and downloaded from two clinical software packages used at these practices. The reading grade level of these resources was calculated using the Flesch Reading Ease, Flesch-Kincaid Grade Level, Fry Readability Graph, and the Simplified Measure of Gobbledygook. Resources' content was analysed for the presence of dietary, physical activity, and behaviour change elements, as recommended by the Clinical practice guidelines for the management of overweight and obesity in adults, adolescents, and children in Australia. RESULTS: The resources' average reading grade level was for a 10(th) grader (9.5 +/- 1.8). These findings highlight that the average reading grade level was two grades higher than the recommended reading grade level for health education resources of 8th grade level or below. Seventy percent of resources contained dietary and behaviour change elements. Physical activity was included in half of the resources. Two messages were identified to be inconsistent with the guidelines and three messages had no scientific basis. CONCLUSION: A body of evidence now exists that supports the need to develop evidence-based education resources for weight management that place low demand on literacy, without compromising content accuracy. The findings from this study suggest that there is significant room for improvement in the educational resources provided in general practices. PMID- 26966547 TI - Lower response to simeprevir and sofosbuvir in HCV genotype 1 in routine practice compared with clinical trials. AB - BACKGROUND: High sustained virological response at 12 weeks after end of treatment (SVR12) with 12 weeks of simeprevir and sofosbuvir+/-ribavirin (SMV+SOF+/-RBV) has been demonstrated in hepatitis C virus genotype 1 (HCV-1) but is based on limited data. Therefore, we performed a meta-analysis of available data evaluating the effectiveness of SMV+SOF+/-RBV in HCV-1. METHODS: We performed a comprehensive literature search in June 2015 to identify randomised controlled trials (RCTs) and observational studies of HCV-1 patients treated with 12 weeks of SMV+SOF+/-RBV. Original studies with SVR12 data in >=5 HCV-1 patients were included. We excluded studies on liver transplant recipients and/or patients co-infected with HIV or hepatitis B/D. We estimated pooled effect sizes using a random-effects model and evaluated heterogeneity with Cochrane Q-test, p<=0.10 and I(2) statistic >=50%. RESULTS: Pooled SVR12 was 85.6% (CI 81.3% to 89.0%) in 1389 HCV-1 patients from 15 studies. On subgroup analysis, SVR12 was 83.9% (CI 79.4% to 87.5%) in observational studies, which was lower than 93.5% (CI 85.7% to 97.2%) in RCTs. A trend showed SVR12 was higher in mild fibrosis, 93.0% (CI 86.2% to 96.6%) compared with advanced fibrosis, 81.5% (CI 75.7% to 86.1%), OR 2.22 (CI 0.79 to 6.25, p=0.131). There was no significant difference in SVR12 rates between HCV-1a, 89.9% (CI 81.9% to 94.6%) and HCV-1b, 89.0% (CI 78.9% to 94.6%) with OR 1.35 (CI 0.75 to 2.42, p=0.322). The most common pooled side effects were: headache 15.2% (n=55/361), fatigue 12.1% (n=78/646), nausea 9.5% (n=50/527) and rash 9.3% (n=68/728). CONCLUSIONS: SMV+SOF+/-RBV is an effective regimen in HCV-1 patients. The SVR12 rate in observational studies was lower than that in RCTs, which may reflect the more diverse patient population in real-world settings. PMID- 26966548 TI - Development and validation of a lipase nasogastric tube position test. AB - BACKGROUND: Nasogastric tube position should be checked every day by either aspirate pH or chest radiography to prevent fatal misplaced feeding into the lungs. Many patients do not have acidic gastric aspirates and require daily chest radiographs. We developed and validated a lipase test that was compatible with non-acidic gastric aspirates. METHODS: We conducted evaluations of diagnostic test accuracy at a teaching hospital in development and validation stages. DEVELOPMENT: We collected gastric and lung aspirates from 34 consecutive patients. We measured pH and human gastric lipase activity in the laboratory. These data helped us develop the lipase test. Ingenza Ltd (Roslin, Scotland) created tributyrin-coated pH test paper, which human gastric lipase converted into butyric acid, thus correcting false negatives. VALIDATION: We tested nasogastric feeding tube aspirates from 36 consecutive patients with pH and lipase tests, using chest radiography or trial by use as the reference standard. RESULTS: DEVELOPMENT: We demonstrated human gastric lipase activity in the non acidic stomach aspirates. VALIDATION: The accuracy of the lipase test (sensitivity 97.2%, specificity 100%) was significantly better than pH (sensitivity 65.7%, specificity 100%, p<0.05). CONCLUSIONS: When nasogastric tube stomach aspirates were not acidic and pH was falsely negative, the lipase test showed a true positive and was significantly more accurate. PMID- 26966549 TI - Tolerability and effectiveness of sofosbuvir and simeprevir in the post transplant setting: systematic review and meta-analysis. AB - BACKGROUND: Outcome data on simeprevir and sofosbuvir (SMV+SOF) in patients with liver transplantation (LT) with hepatitis C virus genotype 1 (HCV-1) are limited with individual studies having a small sample size and limited SVR12 (sustained virological response) data. Our goal was to perform a meta-analysis to study the outcome of SMV+SOF+/-ribavirin (RBV) in recipients with LT. METHODS: In April 2015, we conducted a literature search for 'simeprevir' in MEDLINE/EMBASE and five major liver meetings. We included studies with SVR12 data in >=5 post-LT mono-infected HCV-1 patients treated with SMV+SOF+/-RBV. We used random-effects models to estimate effect sizes, and the Cochrane Q-test (p value <0.10) with I(2) (>50%) to assess study heterogeneity. RESULTS: We included nine studies with a total of 325 patients with post-LT. Studies included mostly men (59-81%). Pooled SVR12 was 88.0% (95% CI 83.4% to 91.5%). In two studies, HCV-1a patients with mild fibrosis (n=108) had an SVR12 rate of 95.0% (95% CI 82.4% to 98.7%), which was significantly higher than that of HCV-1a patients with advanced fibrosis (n=49) with an SVR12 rate of 81.7% (95% CI 69.8% to 89.5%), OR 4.2 (95% CI 1.1 to 16.1, p=0.03). The most common pooled side effects were: fatigue 21% (n=48/237), headache 9% (n=23/254), dermatological symptoms 15% (n=38/254), and gastrointestinal symptoms 6% (12/193). CONCLUSIONS: SMV+SOF+/-RBV is safe and effective in recipients with LT with HCV-1 infection. PMID- 26966550 TI - Prevalence of hepatitis B seromarkers and hepatitis C antibodies in blood donors in Basra, Iraq. AB - BACKGROUND: Transfusion-caused hepatitis remains a major problem in Iraq. Therefore, testing for hepatitis B surface antigen (HBsAg), antibodies to hepatitis B core antigen (anti-HBc) and antibodies to hepatitis C antigen (anti HCV) is a very important preventative measure. The objective of this study was to establish the prevalence of hepatitis B and C virus seromarkers among blood donors as a foundation for safe blood transfusion in Iraq. METHODS: A cross sectional observational study was conducted in the blood banks in Basra, Iraq from 1 January to 31 December 2013. Blood samples were collected and were tested for HBsAg, anti-HBc and anti-HCV using standard laboratory techniques. RESULTS: A total of 69 915 blood donors were enrolled for the study. A total of 1625 (2.3%) donors have shown serological evidence for hepatitis B virus infection; of those donors, 125 (0.2%) showed a positive test result for both anti-HBc and HBsAg while 1475 (2.1%) had positive anti-HBc results as the only positive test for HBV infection. There was no significant difference between males and females (p=0.28). The prevalence of anti-HCV was 0.1%. CONCLUSIONS: This is the first large population study of its kind in Basra, Iraq. The prevalence of hepatitis B and C among blood donors is very low in Basra. Around 2% of blood donors had anti HBc as the only serological evidence of HBV infection. Inclusion of anti-HBc in routine screening of blood donors in Iraq should be encouraged. PMID- 26966552 TI - Hyperbilirubinaemia in HIV-HCV co-infected patients on antiretroviral therapy: drug effect or liver disease severity? AB - OBJECTIVE: Hyperbilirubinaemia (HB) is common in HIV and hepatitis C virus (HIV HCV) co-infected patients and poses a unique challenge in management as it may be due to medications such as the protease inhibitors (PIs) or to hepatic dysfunction. There are no data on the relationship of HB to liver histology and PI use in this population. Clinicians caring for these patients are faced with the difficult task of determining whether increasing serum bilirubin is due to drug effects or progression of liver disease. METHODS: To address this gap in knowledge, we performed a retrospective analysis of 344 consecutive HIV-HCV co infected patients undergoing liver biopsy to identify factors associated with HB. Demographic, clinical, laboratory data were collected. Advanced fibrosis was defined as bridging fibrosis or cirrhosis. Those with hepatitis B virus, hepatic decompensation or hepatocellular carcinoma were excluded. RESULTS: The prevalence of HB (range 1.3-9.4) was 33% and more common in those on a PI (46%) than those who were not (10%; p<=0.001) and mostly in those on indinavir (40%) or atazanavir (46%). Of the patients on these PIs, HB was not associated with fibrosis grade, demographics, or other clinical variables. Conversely, in those not on a PI, HB was associated with fibrosis grade (p<=0.0001) after adjusting for other clinical and demographic variables. CONCLUSIONS: In the setting of indinavir or atazanavir use, HB is common and unrelated to underlying disease severity and the medications can be continued safely. Conversely, HB in HIV-HCV co-infected patients not on a PI is due to their underlying liver disease and suggests these patients require closer monitoring. PMID- 26966551 TI - Effectiveness of disease-specific cognitive-behavioural therapy on depression, anxiety, quality of life and the clinical course of disease in adolescents with inflammatory bowel disease: study protocol of a multicentre randomised controlled trial (HAPPY-IBD). AB - INTRODUCTION: Adolescents with inflammatory bowel disease (IBD) show a higher prevalence of depression and anxiety, compared to youth with other chronic diseases. The inflammation-depression hypothesis might explain this association, and implies that treating depression can decrease intestinal inflammation and improve disease course. The present multicentre randomised controlled trial aims to test the effectiveness of an IBD-specific cognitive-behavioural therapy (CBT) protocol in reducing symptoms of subclinical depression and anxiety, while improving quality of life and disease course in adolescents with IBD. METHODS AND ANALYSIS: Adolescents with IBD (10-20 years) from 7 hospitals undergo screening (online questionnaires) for symptoms of depression and anxiety. Those with elevated scores of depression (Child Depression Inventory (CDI) >=13 or Beck Depression Inventory (BDI) II >=14) and/or anxiety (Screen for Child Anxiety Related Disorders: boys >=26, girls >=30) receive a psychiatric interview. Patients meeting criteria for depressive/anxiety disorders are referred for psychotherapy outside the trial. Patients with elevated (subclinical) symptoms are randomly assigned to medical care-as-usual (CAU; n=50) or CAU plus IBD specific CBT (n=50). MAIN OUTCOMES: (1) reduction in depressive and/or anxiety symptoms after 3 months and (2) sustained remission for 12 months. SECONDARY OUTCOMES: quality of life, psychosocial functioning, treatment adherence. In addition, we will assess inflammatory cytokines in peripheral blood mononuclear cells and whole blood RNA expression profiles. For analysis, multilevel linear models and generalised estimating equations will be used. ETHICS AND DISSEMINATION: The Medical Ethics Committee of the Erasmus MC approved this study. If we prove that this CBT improves emotional well-being as well as disease course, implementation is recommended. TRIAL REGISTRATION NUMBER: NCT02265588. PMID- 26966553 TI - Women in HIV cure research: multilevel interventions to improve sex equity in recruitment. AB - Women are underrepresented in HIV cure research. In this paper we discuss the rationale for including women and propose multilevel strategies to improve sex equity in HIV cure research. The inadequate inclusion of women in HIV cure research is concerning for both scientific and ethical reasons. Biological responses to HIV and HIV treatment, as well as social contexts, differ between men and women, and this may affect the efficacy of curative interventions. Strategies for improving sex equity in HIV cure research include addressing eligibility criteria, adapting recruitment strategies, engaging community members early in the research process, and promoting funder policy changes. We conclude by describing the Gender, Race, and Clinical Experience (GRACE) study, which is one example of how women can be effectively recruited into HIV-related clinical trials. While HIV cure research is currently in the early stages, as it continues to develop it is important to mobilise for adequate inclusion of women. PMID- 26966554 TI - Systematic literature review of domains assessed in psoriatic arthritis to inform the update of the psoriatic arthritis core domain set. AB - The objectives of this systematic literature review (SLR) were to identify domains and outcome measures used in psoriatic arthritis (PsA) studies in the past 5 years, and to compare the measurement of the Outcome Measures in Rheumatology (OMERACT) 2006 PsA Core Domain Set in studies published in 2010-2015 vs those published in 2006-2010. We performed a systematic literature search in two databases, PubMed and Embase, to identify randomised controlled trials (RCTs) in PsA. We also identified PsA longitudinal observational studies (LOS). Three patient research partners provided input into study conception, and data collection and interpretation. We identified 41 studies representing 22 unique RCTs, 27 LOS and 12 registries. Across all studies, we identified 24 domains and 169 outcome measures. In addition to the PsA Core Domain Set (6 domains), the following domains were also assessed in more than 30% of RCTs: acute phase reactants, dactylitis, enthesitis, fatigue and work productivity. We identified a range of 1-15 outcome measures per domain with a mean (SD) of 7 (4.7) per domain. The complete PsA Core Domain Set was assessed in 59% of RCTs in 2010-2015 compared to 23.5% RCTs in 2006-2010. There has been increased measurement of the PsA Core Domain Set in RCTs and LOS in the past 5 years. Numerous additional outcomes were also measured. The PsA Core Domain Set needs an update to standardise PsA outcome assessments. This SLR will inform the development of an updated PsA Core Domain Set with patient research partner input. PMID- 26966555 TI - Carbon Fiber Biocompatibility for Implants. AB - Carbon fibers have multiple potential advantages in developing high-strength biomaterials with a density close to bone for better stress transfer and electrical properties that enhance tissue formation. As a breakthrough example in biomaterials, a 1.5 mm diameter bisphenol-epoxy/carbon-fiber-reinforced composite rod was compared for two weeks in a rat tibia model with a similar 1.5 mm diameter titanium-6-4 alloy screw manufactured to retain bone implants. Results showed that carbon-fiber-reinforced composite stimulated osseointegration inside the tibia bone marrow measured as percent bone area (PBA) to a great extent when compared to the titanium-6-4 alloy at statistically significant levels. PBA increased significantly with the carbon-fiber composite over the titanium-6-4 alloy for distances from the implant surfaces of 0.1 mm at 77.7% vs. 19.3% (p < 10-8) and 0.8 mm at 41.6% vs. 19.5% (p < 10-4), respectively. The review focuses on carbon fiber properties that increased PBA for enhanced implant osseointegration. Carbon fibers acting as polymer coated electrically conducting micro-biocircuits appear to provide a biocompatible semi-antioxidant property to remove damaging electron free radicals from the surrounding implant surface. Further, carbon fibers by removing excess electrons produced from the cellular mitochondrial electron transport chain during periods of hypoxia perhaps stimulate bone cell recruitment by free-radical chemotactic influences. In addition, well-studied bioorganic cell actin carbon fiber growth would appear to interface in close contact with the carbon-fiber-reinforced composite implant. Resulting subsequent actin carbon fiber/implant carbon fiber contacts then could help in discharging the electron biological overloads through electrochemical gradients to lower negative charges and lower concentration. PMID- 26966556 TI - Mean Platelet Volume in Patients with Nonarteritic Anterior Ischemic Optic Neuropathy. AB - Objective. We aimed to investigate the mean platelet volume (MPV) of the patients with nonarteritic anterior ischemic optic neuropathy (NAION). Methods. The medical records of 46 patients with the diagnosis of NAION and 90 control subjects were retrospectively evaluated. All participants underwent complete ocular examination including intraocular pressure (IOP) measurement. Hematocrit, MPV, hemoglobin, and platelet levels of the patients with NAION were compared with those of control subjects. Results. There was no significant difference between the groups in platelet counts (p = 0.76). NAION group had significantly higher MPV values (8.25 +/- 1.26 fL) than that of control subjects (7.64 +/- 1.01 fL) (p < 0.001). Multivariate logistic regression analysis showed that MPV is an independent predictor of NAION (odds ratio = 1.61; 95% confidence interval (CI) = 1.13-2.28; p = 0.007). The mean IOP was significantly higher in NAION group (p < 0.001). IOP was also found as an independent predictor of NAION according to the regression analysis (OR = 1.27; 95% CI = 1.08-1.48; p = 0.003). Conclusion. Our results demonstrated that the MPV values were significantly higher in NAION patients, suggesting that larger platelets may contribute to the pathogenesis of the NAION. PMID- 26966557 TI - Comparison of Two Different OCT Systems: Retina Layer Segmentation and Impact on Structure-Function Analysis in Glaucoma. AB - Purpose. To compare two different spectral-domain optical coherence tomography (OCT) systems in regard to full macular thickness (MT) and ganglion cell layer inner plexiform layer (GCIPL) measures and in regard to structure-function correlation when compared to standard automated perimetry (SAP). Methods. Seventeen primary open angle glaucoma patients and 16 controls (one eye per subject) were enrolled. MT and GCIPL thicknesses were measured by Cirrus and Spectralis OCTs. Octopus Perimeter 101 (G2 protocol) reports sensitivity in mean defect (dB). Differences between measurements were assessed with Student's t-test and Bland Altman. Diagnostic performance was also compared between each parameter calculating the areas under the operator receiver (ROC). Linear models were used to investigate structure-function association between OCT and SAP. Results. Disagreement between OCTs in both MT and GCIPL values was significant. Spectralis values were thicker than Cirrus. Average difference between OCTs was 21.64 MUm (SD 4.5) for MT and 9.8 MUm (SD 5.4) for GCIPL (p < 0.001). Patients differed significantly from controls in both OCTs, in both measurements. MT and GCIPL were negatively associated with MD (p < 0.001). Conclusions. Although OCT values were not interchangeable, both machines differentiated patients from controls with statistical significance. Structure-function analysis results were comparable, when either OCT was compared to SAP. PMID- 26966558 TI - Surgical and Functional Results of Hybrid 25-27-Gauge Vitrectomy Combined with Coaxial 2.2 mm Small Incision Cataract Surgery. AB - Purpose. To investigate outcomes after coaxial 2.2 mm small incision cataract surgery combined with hybrid 25-27-gauge vitrectomy in eyes with vitreoretinal disease and age-related cataract. Methods. A single-center, retrospective case series study of 55 subjects (55 eyes) with a mean age of 70 years who underwent combined small incision phacoemulsification, intraocular lens (IOL) implantation, and hybrid 25-27-gauge vitrectomy during the 12-month period to December 2014. Intraoperative and postoperative complications and visual results were the main outcome measures. Results. The mean follow-up period was 6 months (range: 2-18 months). Intraoperative findings were 3 retinal breaks (5.5%). No cases required corneal or scleral suture or conversion to larger-gauge vitrectomy. Postoperative complications consisted of posterior capsule opacification (12.7%), elevated intraocular pressure >30 mmHg (1.8%), and fibrin reaction (5.5%). There were no cases of hypotony (<7 mmHg), IOL decentration, or postoperative endophthalmitis. Visual acuity (mean +/- SD) improved from 0.52 +/- 0.6 logMAR preoperatively to 0.22 +/- 0.46 logMAR at final postoperative visit (P < 0.0001). Conclusion. Surgical and visual outcomes suggest hybrid 25-27-gauge vitrectomy combined with small incision phacoemulsification and IOL implantation is feasible, safe, and effective as a one-step surgical procedure for the management of vitreoretinal pathologies and concurrent cataract. PMID- 26966561 TI - Symmetric encryption algorithms using chaotic and non-chaotic generators: A review. AB - This paper summarizes the symmetric image encryption results of 27 different algorithms, which include substitution-only, permutation-only or both phases. The cores of these algorithms are based on several discrete chaotic maps (Arnold's cat map and a combination of three generalized maps), one continuous chaotic system (Lorenz) and two non-chaotic generators (fractals and chess-based algorithms). Each algorithm has been analyzed by the correlation coefficients between pixels (horizontal, vertical and diagonal), differential attack measures, Mean Square Error (MSE), entropy, sensitivity analyses and the 15 standard tests of the National Institute of Standards and Technology (NIST) SP-800-22 statistical suite. The analyzed algorithms include a set of new image encryption algorithms based on non-chaotic generators, either using substitution only (using fractals) and permutation only (chess-based) or both. Moreover, two different permutation scenarios are presented where the permutation-phase has or does not have a relationship with the input image through an ON/OFF switch. Different encryption-key lengths and complexities are provided from short to long key to persist brute-force attacks. In addition, sensitivities of those different techniques to a one bit change in the input parameters of the substitution key as well as the permutation key are assessed. Finally, a comparative discussion of this work versus many recent research with respect to the used generators, type of encryption, and analyses is presented to highlight the strengths and added contribution of this paper. PMID- 26966559 TI - Review of available studies of the neurobiology and pharmacotherapeutic management of trichotillomania. AB - Trichotillomania (TTM) is a psychiatric disorder characterized by an irresistible urge to pull out one's hair. Currently there are no FDA approved treatments for TTM, which makes it difficult for clinicians to select an appropriate therapeutic plan. The clinical studies that have been performed do not provide sufficient or consistent evidence regarding which drug classes should be administered. Unfortunately, most of the available data consist of case reports and clinical trials with limited sample size. This review provides an overview of currently available clinical literature that targets TTM. A summary of clinical trials as well as case reports is provided. The most common rating scales used for clinical assessment are also reviewed. The etiology of TTM remains unclear. Studies that examine various neuroanatomical, neurobiologic, as well as genetic factors associated with TTM are thoroughly discussed in this review. It is evident that clear understanding of TTM is crucial to provide better recognition, assessment, and treatment to patients of this disorder. Finally, despite research efforts for establishing pharmacological options for treatment, it is clear that new targets are warranted in order to ensure a clinically supported effective pharmacological approach to treat TTM. PMID- 26966560 TI - TNF-alpha -308 polymorphisms and male infertility risk: A meta-analysis and systematic review. AB - This study aimed to conduct a systematic review and meta-analysis of prospective studies discussing TNF-alpha -308 polymorphism and male infertility. This study was conformed to Preferred Reported Items for Systematic Reviews and Meta Analyses guidelines. PubMed, Embase and Scopus databases were searched to identify relevant studies by two independent reviewers. Hazard ratios were pooled using fixed-effect or random-effects models when appropriate. Q-test was performed to evaluate study heterogeneity and publication bias appraised using funnel plots. The search yielded five studies (three of Caucasians ethnicity and 2 of Asian ethnicity) comprising 2939 men (2262 infertile men and 677 fertile controls). Most of the studied cases were carried out on TNF-alpha promoter region at positions -308 G/A (four studies) where -308 C/T was dealt with in one study. Overall, significant associations between TNF-alpha -308 gene polymorphisms and idiopathic male infertility risk were observed (fixed effect: OR = 0.472, 95% CI: 0.378-0.589; P = 0.001; random effect: OR = 0.407, 95% CI: 0.211-0.785; P = 0.007) with robust findings according to sensitivity analyses. Funnel plot inspections did not give evidences of publication bias. A stratified analysis performed for ethnic groups revealed significant association in both Caucasian and Asian populations. It is concluded that there are evidences of associations between TNF-alpha -308 gene polymorphisms and male infertility risk. PMID- 26966562 TI - Chemical and biological profile of Cespitularia species: A mini review. AB - Soft corals belonging to the genus Cespitularia have been well recognized as a rich source of bioactive secondary metabolites especially diterpenoids. This review furnishes an overview of all naturally isolated compounds from Cespitularia genus as, diterpenoids, nitrogen-containing diterpenes, sesquiterpenoids and steroids as well as biological activities of these species. Cespitularia species have been studied for their anticancer, immunomodulatory, antiviral, antimicrobial, and anti-inflammatory activities. This work is the first review published on this topic. PMID- 26966563 TI - Anode optimization for miniature electronic brachytherapy X-ray sources using Monte Carlo and computational fluid dynamic codes. AB - A miniature X-ray source has been optimized for electronic brachytherapy. The cooling fluid for this device is water. Unlike the radionuclide brachytherapy sources, this source is able to operate at variable voltages and currents to match the dose with the tumor depth. First, Monte Carlo (MC) optimization was performed on the tungsten target-buffer thickness layers versus energy such that the minimum X-ray attenuation occurred. Second optimization was done on the selection of the anode shape based on the Monte Carlo in water TG-43U1 anisotropy function. This optimization was carried out to get the dose anisotropy functions closer to unity at any angle from 0 degrees to 170 degrees . Three anode shapes including cylindrical, spherical, and conical were considered. Moreover, by Computational Fluid Dynamic (CFD) code the optimal target-buffer shape and different nozzle shapes for electronic brachytherapy were evaluated. The characterization criteria of the CFD were the minimum temperature on the anode shape, cooling water, and pressure loss from inlet to outlet. The optimal anode was conical in shape with a conical nozzle. Finally, the TG-43U1 parameters of the optimal source were compared with the literature. PMID- 26966564 TI - Therapeutic efficacy of amniotic membrane stem cells and adipose tissue stem cells in rats with chemically induced ovarian failure. AB - The present study was conducted to compare between the therapeutic efficacies of human amniotic membrane-derived stem cells (hAM-MSCs) vs. adipose tissue derived stem cells (AD-MSCs) in cyclophosphamide (CTX)-induced ovarian failure in rats. Forty-eight adult female rats were included in the study; 10 rats were used as control group. Thirty-eight rats were injected with CTX to induce ovarian failure and divided into four groups: ovarian failure (IOF) (IOF group), IOF + phosphate buffer saline (PBS group), IOF + hAM-MSCs group and IOF + AD-MSCs group. Serum levels of FSH and estradiol (E2) were assessed. Histopathological examination of the ovarian tissues was performed and quantitative gene expressions of Oct-4, Stra8 and integrin beta-1 genes were conducted by quantitative real time PCR. Results showed that IOF and IOF + PBS rat groups exhibited decreased ovarian follicles, increased interstitial fibrosis with significant decrease of serum E2, significant increase serum FSH level and significant down-regulation of Stra8 and integrin beta-1. In hAM-MSCs and AD-MSCs rat groups, there were increased follicles and corpora with evident the presence of oocytes, significant increase in serum E2, significant decrease in serum FSH levels (in hAM-MSCs treated group only) and significant up-regulation of the three studied genes with higher levels in hAM-MSCs treated rats group when compared to AD-MSCs treated rats group. In Conclusion, administration of either hAM-derived MSCs or AD-MSCs exerts a significant therapeutic efficacy in chemotherapy induced ovarian insult in rats. hAM-MSCs exert higher therapeutic efficacy as compared to AD-MSCs. PMID- 26966565 TI - Acute inflammation induces immunomodulatory effects on myeloid cells associated with anti-tumor responses in a tumor mouse model. AB - Given the self nature of cancer, anti-tumor immune response is weak. As such, acute inflammation induced by microbial products can induce signals that result in initiation of an inflammatory cascade that helps activation of immune cells. We aimed to compare the nature and magnitude of acute inflammation induced by toll-like receptor ligands (TLRLs) on the tumor growth and the associated inflammatory immune responses. To induce acute inflammation in tumor-bearing host, CD1 mice were inoculated with intraperitoneal (i.p.) injection of Ehrlich ascites carcinoma (EAC) (5 * 10(5) cells/mouse), and then treated with i.p. injection on day 1, day 7 or days 1 + 7 with: (1) polyinosinic:polycytidylic (poly(I:C)) (TLR3L); (2) Poly-ICLC (clinical grade of TLR3L); (3) Bacillus Calmette Guerin (BCG) (coding for TLR9L); (4) Complete Freund's adjuvant (CFA) (coding for TLR9L); and (5) Incomplete Freund's Adjuvant (IFA). Treatment with poly(I:C), Poly-ICLC, BCG, CFA, or IFA induced anti-tumor activities as measured by 79.1%, 75.94%, 73.94%, 71.88% and 47.75% decreases, respectively in the total number of tumor cells collected 7 days after tumor challenge. Among the tested TLRLs, both poly(I:C) (TLR3L) and BCG (contain TLR9L) showed the highest anti tumor effects as reflected by the decrease in the number of EAc cells. These effects were associated with a 2-fold increase in the numbers of inflammatory cells expressing the myeloid markers CD11b(+)Ly6G(+), CD11b(+)Ly6G(-), and CD11b(+)Ly6G(-). We concluded that Provision of the proper inflammatory signal with optimally defined magnitude and duration during tumor growth can induce inflammatory immune cells with potent anti-tumor responses without vaccination. PMID- 26966566 TI - Efficient variable bandwidth filters for digital hearing aid using Farrow structure. AB - Design of a digital hearing aid requires a set of filters that gives reasonable audiogram matching for the concerned type of hearing loss. This paper proposes the use of a variable bandwidth filter, using Farrow subfilters, for this purpose. The design of the variable bandwidth filter is carried out for a set of selected bandwidths. Each of these bands is frequency shifted and provided with sufficient magnitude gain, such that, the different bands combine to give a frequency response that closely matches the audiogram. Due to the adjustable bandedges in the basic filter, this technique allows the designer to add reconfigurability to the system. This technique is simple and efficient when compared with the existing methods. Results show that lower order filters and better audiogram matching with lesser matching errors are obtained using Farrow structure. This, in turn reduces implementation complexity. The cost effectiveness of this technique also comes from the fact that, the user can reprogram the same device, once his hearing loss pattern is found to have changed in due course of time, without the need to replace it completely. PMID- 26966567 TI - Repair bond strength of dual-cured resin composite core buildup materials. AB - The reparability of dual-cured resin composite core buildup materials using a light-cured one following one week or three months storage, prior to repair was evaluated. Two different dual-cured resin composites; CosmecoreTM DC automix and ClearfilTM DC automix core buildup materials and a light-cured nanofilled resin composite; FiltekTM Z350 XT were used. Substrate specimens were prepared (n = 12/each substrate material) and stored in artificial saliva at 37 degrees C either for one week or three months. Afterward, all specimens were ground flat, etched using ScotchbondTM phosphoric acid etchant and received Single Bond Universal adhesive system according to the manufacturers' instructions. The light cured nanofilled resin composite (FiltekTM Z350 XT) was used as a repair material buildup. To determine the cohesive strength of each solid substrate material, additional specimens from each core material (n = 12) were prepared and stored for the same periods. Five sticks (0.8 +/- 0.01 mm(2)) were obtained from each specimen (30 sticks/group) for microtensile bond strength (MUTBS) testing. Modes of failure were also determined. Two-way ANOVA revealed a significant effect for the core materials but not for the storage periods or their interaction. After one week, dual-cured resin composite core buildup materials (CosmecoreTM DC and ClearfilTM DC) achieved significantly higher repair MUTBS than the light-cured nanofilled resin composite (FiltekTM Z350 XT). However, ClearfilTM DC revealed the highest value, then CosmecoreTM DC and FiltekTM Z350 XT, following storage for 3-month. Repair strength values recovered 64-86% of the cohesive strengths of solid substrate materials. The predominant mode of failure was the mixed type. Dual-cured resin composite core buildup materials revealed acceptable repair bond strength values even after 3-month storage. PMID- 26966568 TI - Numerical study for multi-strain tuberculosis (TB) model of variable-order fractional derivatives. AB - In this paper, we presented a novel multi-strain TB model of variable-order fractional derivatives, which incorporates three strains: drug-sensitive, emerging multi-drug resistant (MDR) and extensively drug-resistant (XDR), as an extension for multi-strain TB model of nonlinear ordinary differential equations which developed in 2014 by Arino and Soliman [1]. Numerical simulations for this variable-order fractional model are the main aim of this work, where the variable order fractional derivative is defined in the sense of Grunwald-Letnikov definition. Two numerical methods are presented for this model, the standard finite difference method (SFDM) and nonstandard finite difference method (NSFDM). Numerical comparison between SFDM and NSFDM is presented. It is concluded that, NSFDM preserves the positivity of the solutions and numerically stable in large regions than SFDM. PMID- 26966569 TI - Multi-agents and learning: Implications for Webusage mining. AB - Characterization of user activities is an important issue in the design and maintenance of websites. Server weblog files have abundant information about the user's current interests. This information can be mined and analyzed therefore the administrators may be able to guide the users in their browsing activity so they may obtain relevant information in a shorter span of time to obtain user satisfaction. Web-based technology facilitates the creation of personally meaningful and socially useful knowledge through supportive interactions, communication and collaboration among educators, learners and information. This paper suggests a new methodology based on learning techniques for a Web-based Multiagent-based application to discover the hidden patterns in the user's visited links. It presents a new approach that involves unsupervised, reinforcement learning, and cooperation between agents. It is utilized to discover patterns that represent the user's profiles in a sample website into specific categories of materials using significance percentages. These profiles are used to make recommendations of interesting links and categories to the user. The experimental results of the approach showed successful user pattern recognition, and cooperative learning among agents to obtain user profiles. It indicates that combining different learning algorithms is capable of improving user satisfaction indicated by the percentage of precision, recall, the progressive category weight and F 1-measure. PMID- 26966570 TI - Porous bodies of hydroxyapatite produced by a combination of the gel-casting and polymer sponge methods. AB - A combination of gel-casting and polymeric foam infiltration methods is used in this study to prepare porous bodies of hydroxyapatite (HA), to provide a better control over the microstructures of samples. These scaffolds were prepared by impregnating a body of porous polyurethane foam with slurry containing HA powder, and using a percentage of solids between 40% and 50% w/v, and three different types of monomers to provide a better performance. X-Ray Diffraction (XRD), and Fourier Transformed Infrared (FTIR) and Scanning Electron Microscopy (SEM) were employed to evaluate both the powder hydroxyapatite and the scaffolds obtained. In addition, porosity and interconnectivity measurements were taken in accordance with the international norm. Bioactivity was checked using immersion tests in Simulated Body Fluids (SBF). After the sintering process of the porous bodies, the XRD results showed peaks characteristic of a pure and crystalline HA (JCPDS 9 432) as a single phase. SEM images indicate open and interconnected pores inside the material, with pore sizes between 50 and 600 MUm. Also, SEM images demonstrate the relatively good bioactivity of the HA scaffolds after immersion in SBF. All results for the porous HA bodies suggest that these materials have great potential for use in tissue engineering. PMID- 26966572 TI - Morphological, molecular and pathological appraisal of Callitetrarhynchus gracilis plerocerci (Lacistorhynchidae) infecting Atlantic little tunny (Euthynnus alletteratus) in Southeastern Mediterranean. AB - The Atlantic little tunny, Euthynnus alletteratus, is widely distributed in temperate and tropical waters of the Atlantic Ocean, Black and Mediterranean Seas. In this study, wild-caught little tunny from Egypt, were found to be naturally infected with trypanorhyncha metacestodes, and the overall prevalence rate of infection was 38.7%. The blastocysts were either loosely attached to the mesentery of infected fish, or firmly attached and deeply embedded within the hepatic parenchyma. These encysted plerocerci are identified as Callitetrarhynchus gracilis (Trypanorhyncha, Lacistorhynchidae) based on its morphological and molecular characterization. The morphological characteristics of C. gracilis including scolex shape; the bothridia groove; the presence of frontal glands; the length of post-larval (appendix); metabasal armature; the existence of 'Chainette' and satellite hooks of different size were studied and described by Light and Scanning electron microscope. The phylogenetic analysis of lsrDNA gene of plerocerci confirmed the identification of the species to be deeply embedded in genus Callitetrarhynchus. The histopathological examination revealed severe pathological changes in the affected organs, including necrosis, inflammatory reactions, fibrosis and migratory tracts of the parasitic larvae together with marked visceral organs adhesions. To the best of our knowledge, this is the first report describing the detection of C. gracilis in little tunny collected from the Abu Qir landing site in Alexandria, Egypt. PMID- 26966573 TI - Antianemic Treatment of Cancer Patients in German Routine Practice: Data from a Prospective Cohort Study-The Tumor Anemia Registry. AB - The aim of this prospective cohort study was to assess current antianemic treatment of cancer patients in German routine practice, including diagnostics, treatments, and quality of life (QoL). 88 study sites recruited 1018 patients at the start of antianemic treatment with hemoglobin (Hb) levels <11 g/dL (females) or <12 g/dL (males). Patients were followed up for 12 weeks. 63% of the patients had inoperable solid tumors, 22% operable solid tumors, and 15% hematological malignancies. Over 85% received chemotherapy. Median age was 67 years; 48% were male. Red blood cell transfusions (RBCTx) were given to 59% of all patients and to 55% of the patients with Hb >=8 g/dL on day 1 of the observation period (day 1 treatment). Erythropoiesis-stimulating agents (ESAs) were the second most frequently applied day 1 treatment (20%), followed by intravenous (IV) iron (15%) and ESA + IV iron (6%). Only about a third of patients were tested for blood serum iron parameters at the start of treatment. Overall, more than half of the patients had long-term responses to antianemic therapy. Our data suggest that in routine practice diagnostics for treatable causes of anemia are underused. A high proportion of cancer patients receive RBCTx. It should be discussed whether thorough diagnostics and earlier intervention could decrease the need for RBCTx. This trial is registered with NCT01795690. PMID- 26966571 TI - Plant-based culture media: Efficiently support culturing rhizobacteria and correctly mirror their in-situ diversity. AB - Our previous publications and the data presented here provide evidences on the ability of plant-based culture media to optimize the cultivability of rhizobacteria and to support their recovery from plant-soil environments. Compared to the tested chemically-synthetic culture media (e.g. nutrient agar and N-deficient combined-carbon sources media), slurry homogenates, crude saps, juices and powders of cactus (Opuntia ficus-indica) and succulent plants (Aloe vera and Aloe arborescens) were rich enough to support growth of rhizobacteria. Representative isolates of Enterobacter spp., Klebsiella spp., Bacillus spp. and Azospirillum spp. exhibited good growth on agar plates of such plant-based culture media. Cell growth and biomass production in liquid batch cultures were comparable to those reported with the synthetic culture media. In addition, the tested plant-based culture media efficiently recovered populations of rhizobacteria associated to plant roots. Culturable populations of >10(6)-10(8) cfu g(-1) were recovered from the ecto- and endo-rhizospheres of tested host plants. More than 100 endophytic culture-dependent isolates were secured and subjected to morphophysiological identification. Factor and cluster analyses indicated the unique community structure, on species, genera, class and phyla levels, of the culturable population recovered with plant-based culture media, being distinct from that obtained with the chemically-synthetic culture media. Proteobacteria were the dominant (78.8%) on plant-based agar culture medium compared to only 31% on nutrient agar, while Firmicutes prevailed on nutrient agar (69%) compared to the plant-based agar culture media (18.2%). Bacteroidetes, represented by Chryseobacterium indologenes, was only reported (3%) among the culturable rhizobacteria community of the plant-based agar culture medium. PMID- 26966574 TI - The Role of Mean Platelet Volume as a Predictor of Mortality in Critically Ill Patients: A Systematic Review and Meta-Analysis. AB - Background. An increase in the mean platelet volume (MPV) has been proposed as a novel prognostic indicator in critically ill patients. Objective. We conducted a systematic review and meta-analysis to determine whether there is an association between MPV and mortality in critically ill patients. Methods. We did electronic search in Medline, Scopus, and Embase up to November 2015. Results. Eleven observational studies, involving 3724 patients, were included. The values of initial MPV in nonsurvivors and survivors were not different, with the mean difference with 95% confident interval (95% CI) being 0.17 (95% CI: -0.04, 0.38; p = 0.112). However, after small sample studies were excluded in sensitivity analysis, the pooling mean difference of MPV was 0.32 (95% CI: 0.04, 0.60; p = 0.03). In addition, the MPV was observed to be significantly higher in nonsurvivor groups after the third day of admission. On the subgroup analysis, although patient types (sepsis or mixed ICU) and study type (prospective or retrospective study) did not show any significant difference between groups, the difference of MPV was significantly difference on the unit which had mortality up to 30%. Conclusions. Initial values of MPV might not be used as a prognostic marker of mortality in critically ill patients. Subsequent values of MPV after the 3rd day and the lower mortality rate unit might be useful. However, the heterogeneity between studies is high. PMID- 26966575 TI - Parents' Experiences of Caring Responsibility for Their Adult Child with Schizophrenia. AB - As a consequence of the latest psychiatry-related reform in Sweden and its implementation, relatives and family members have taken over from the formal healthcare system significant responsibility for the care of persons with a mental disability and illness. The aim of this study was to systematically describe and analyze the experiences of parents' informal care responsibility. The questions were, what are the experiences around parents' informal care activities and responsibilities and how do parents construct and manage their caring responsibility and with what consequences? Semistructured in-depth interviews were conducted (16 hours of recorded material) with eight parents who were all members of the Interest Association for Schizophrenia (Intresseforeningen for Schizofreni (IFS)) in Sweden. A mixed hermeneutic deductive and inductive method was used for the interpretation of the material. The parents endow their informal caring responsibility with meaning of being a good, responsible, and accountable parent with respect to their social context and social relationships as well as with respect to the psychiatric care representatives. In this tense situation, parents compromise between elements of struggle, cooperation, avoidance, and adaption in their interaction with the world outside, meaning the world beyond the care provision for their child, as well as with the world inside themselves. PMID- 26966577 TI - Contribution of Cell Surface Hydrophobicity in the Resistance of Staphylococcus aureus against Antimicrobial Agents. AB - Staphylococcus aureus is found in a wide variety of habitats, including human skin, where many strains are commensals that may be clinically significant or contaminants of food. To determine the physiological characteristics of resistant strain of Staphylococcus aureus against pediocin, a class IIa bacteriocin, a resistant strain was compared with wild type in order to investigate the contribution of hydrophobicity to this resistance. Additional clumping of resistant strain relative to wild type in light microscopy was considered as an elementary evidence of resistance attainment. A delay in log phase attainment was observed in resistant strain compared to the wild type strain. A significant increase in cell surface hydrophobicity was detected for resistant strain in both hexadecane and xylene indicating the contribution of cell surface hydrophobicity as adaptive reaction against antimicrobial agents. PMID- 26966576 TI - Soluble Expression and Characterization of Biologically Active Bacillus anthracis Protective Antigen in Escherichia coli. AB - Bacillus anthracis secretory protein protective antigen (PA) is primary candidate for subunit vaccine against anthrax. Attempts to obtain large quantity of PA from Escherichia coli expression system often result in the formation of insoluble inclusion bodies. Therefore, it is always better to produce recombinant proteins in a soluble form. In the present study, we have obtained biologically active recombinant PA in small scale E. coli shake culture system using three different expression constructs. The PA gene was cloned in expression vectors bearing trc, T5, and T7 promoters and transformed into their respective E. coli hosts. The growth conditions were optimized to obtain maximum expression of PA in soluble form. The expression construct PA-pET32c in DE3-pLysS E. coli host resulted in a maximum production of soluble PA (15 mg L(-1)) compared to other combinations. Purified PA was subjected to trypsin digestion and binding assay with lethal factor to confirm the protein's functionality. Biological activity was confirmed by cytotoxicity assay on J774.1 cells. Balb/c mice were immunized with PA and the immunogenicity was tested by ELISA and toxin neutralization assay. This study highlights the expression of soluble and biologically active recombinant PA in larger quantity using simpler E. coli production platform. PMID- 26966578 TI - Lack of Association between Pulse Steroid Therapy and Bone Mineral Density in Patients with Multiple Sclerosis. AB - Multiple sclerosis (MS) has been associated with reduced bone mineral density (BMD). The purpose of this study was to determine the possible factors affecting BMD in patients with MS. We included consecutive 155 patients with MS and 90 age- and sex-matched control subjects. Patients with MS exhibited significantly lower T-scores and Z-scores in the femoral neck and trochanter compared to the controls. Ninety-four (61%) patients had reduced bone mass in either the lumbar spine or the femoral neck; of these, 64 (41.3%) had osteopenia and 30 (19.4%) had osteoporosis. The main factors affecting BMD were disability, duration of MS, and smoking. There was a negative relationship between femoral BMD and EDSS and disease duration. No association with lumbar BMD was determined. There were no correlations between BMD at any anatomic region and cumulative corticosteroid dose. BMD is significantly lower in patients with MS than in healthy controls. Reduced BMD in MS is mainly associated with disability and duration of the disease. Short courses of high dose steroid therapy did not result in an obvious negative impact on BMD in the lumbar spine and femoral neck in patients with MS. PMID- 26966579 TI - Management of Multiple Sclerosis in the Breastfeeding Mother. AB - Multiple Sclerosis (MS) is an autoimmune neurological disease characterized by inflammation of the brain and spinal cord. Relapsing-Remitting MS is characterized by acute attacks followed by remission. Treatment is aimed at halting these attacks; therapy may last for months to years. Because MS disproportionately affects females and commonly begins during the childbearing years, clinicians treat pregnant or nursing MS patients. The intent of this review is to perform an in-depth analysis into the safety of drugs used in breastfeeding women with MS. This paper is composed of several drugs used in the treatment of MS and current research regarding their safety in breastfeeding including immunomodulators, immunosuppressants, monoclonal antibodies, corticosteroids, and drugs used for symptomatic treatment. Typically, some medications are large polar molecules which often do not pass into the milk in clinically relevant amounts. For this reason, interferon beta is likely safe for the infant when given to a breastfeeding mother. However, other drugs with particularly dangerous side effects may not be recommended. While treatment options are available and some data from clinical studies does exist, there continues to be a need for investigation and ongoing review of the medications used in breastfeeding mothers. PMID- 26966580 TI - Imaging Techniques for Diagnosis of Thoracic Aortic Atherosclerosis. AB - The most severe complications after cardiac surgery are neurological complications including stroke which is often caused by emboli merging from atherosclerosis in the ascending aorta to the brain. Information about the thoracic aorta is crucial in reducing the embolization risk for both surgical open and closed chest procedures such as transaortic heart valve implantation. Several techniques are available to screen the ascending aorta, for example, transesophageal echocardiography (TEE), epiaortic ultrasound, TEE A-view method, manual palpation, computed tomography, and magnetic resonance imaging. This paper provides a description of the advantages and disadvantages of these imaging techniques. PMID- 26966581 TI - Dependence of Proximal GC Boxes and Binding Transcription Factors in the Regulation of Basal and Valproic Acid-Induced Expression of t-PA. AB - Objective. Endothelial tissue-type plasminogen activator (t-PA) release is a pivotal response to protect the circulation from occluding thrombosis. We have shown that the t-PA gene is epigenetically regulated and greatly induced by the histone deacetylase (HDAC) inhibitor valproic acid (VPA). We now investigated involvement of known t-PA promoter regulatory elements and evaluated dependence of potential interacting transcription factors/cofactors. Methods. A reporter vector with an insert, separately mutated at either the t-PA promoter CRE or GC box II or GC box III elements, was transfected into HT-1080 and HUVECs and challenged with VPA. HUVECs were targeted with siRNA against histone acetyl transferases (HAT) and selected transcription factors from the Sp/KLF family. Results. An intact VPA-response was observed with CRE mutated constructs, whereas mutation of GC boxes II and III reduced the magnitude of the induction by 54 and 79% in HT-1080 and 49 and 50% in HUVECs, respectively. An attenuated induction of t-PA mRNA was observed after Sp2, Sp4, and KLF5 depletion. KLF2 and p300 (HAT) were identified as positive regulators of basal t-PA expression and Sp4 and KLF9 as repressors. Conclusion. VPA-induced t-PA expression is dependent on the proximal GC boxes in the t-PA promoter and may involve interactions with Sp2, Sp4, and KLF5. PMID- 26966582 TI - Antibiotic-Resistant Acinetobacter baumannii Increasing Success Remains a Challenge as a Nosocomial Pathogen. AB - Antibiotic-resistant infectious bacteria currently imply a high risk and therefore constitute a strong challenge when treating patients in hospital settings. Characterization of these species and of particular strains is a priority for the establishment of diagnostic tests and preventive procedures. The relevance of Acinetobacter baumannii as a problematic microorganism in inpatient facilities, particularly intensive care units, has increased over time. This review aims to draw attention to (i) the historical emergence of carbapenem resistant Acinetobacter baumannii, (ii) the current status of surveillance needs in Latin America, and (iii) recent data suggesting that A. baumannii continues to spread and evolve in hospital settings. First, we present synopsis of the series of events leading to the discovery and precise identification of this microorganism in hospital settings. Then key events in the acquisition of antibiotic-resistant genes by this microorganism are summarized, highlighting the race between new antibiotic generation and emergence of A. baumannii resistant strains. Here we review the historical development of this species as an infectious threat, the current state of its distribution, and antibiotic resistance characteristics, and we discuss future prospects for its control. PMID- 26966583 TI - Natural Product-Derived Treatments for Attention-Deficit/Hyperactivity Disorder: Safety, Efficacy, and Therapeutic Potential of Combination Therapy. AB - Typical treatment plans for attention-deficit/hyperactivity disorder (ADHD) utilize nonpharmacological (behavioral/psychosocial) and/or pharmacological interventions. Limited accessibility to behavioral therapies and concerns over adverse effects of pharmacological treatments prompted research for alternative ADHD therapies such as natural product-derived treatments and nutritional supplements. In this study, we reviewed the herbal preparations and nutritional supplements evaluated in clinical studies as potential ADHD treatments and discussed their performance with regard to safety and efficacy in clinical trials. We also discussed some evidence suggesting that adjunct treatment of these agents (with another botanical agent or pharmacological ADHD treatments) may be a promising approach to treat ADHD. The analysis indicated mixed findings with regard to efficacy of natural product-derived ADHD interventions. Nevertheless, these treatments were considered as a "safer" approach than conventional ADHD medications. More comprehensive and appropriately controlled clinical studies are required to fully ascertain efficacy and safety of natural product-derived ADHD treatments. Studies that replicate encouraging findings on the efficacy of combining botanical agents and nutritional supplements with other natural product-derived therapies and widely used ADHD medications are also warranted. In conclusion, the risk-benefit balance of natural product-derived ADHD treatments should be carefully monitored when used as standalone treatment or when combined with other conventional ADHD treatments. PMID- 26966585 TI - Sildenafil citrate as a medical expulsive therapy for distal ureteric stones: A randomised double-blind placebo-controlled study. AB - OBJECTIVE: To study the effect of sildenafil citrate on spontaneous passage of distal ureteric stones (DUS). PATIENTS AND METHODS: This was a randomised double blinded placebo-controlled study of 100 patients with DUS. Inclusion criteria were: male, age 18-65 years, normal renal function, and a single radiopaque unilateral DUS of 5-10 mm. Patients were randomly allocated into two equal groups, one that received placebo and the other that received 50 mg sildenafil citrate once daily. Both investigators and patients were masked to the type of treatment. Patients self-administered the medication until spontaneous passage of the DUS. In patients where there was uncontrolled pain, fever, an increase in serum creatinine of >1.8 mg/dL, progressive hydronephrosis or no further progress after 4 weeks, a decision was taken for further treatment. RESULTS: In all, 47 and 49 patients were available for analysis in both the placebo and sildenafil citrate groups; respectively. Both groups were comparable for age and stone characteristics. Spontaneous expulsion occurred in 19 of 47 patients (40.4%) in the placebo group and in 33 of 49 (67.3%) in the sildenafil citrate group (P = 0.014). The mean time to stone expulsion was significantly shorter in the sildenafil citrate group (P < 0.001). A multivariable Cox proportional hazards model showed that receiving sildenafil citrate was the only independent factor that had a significant impact on stone passage with a hazard ratio of 2.7 (95% confidence interval 1.5-4.8; P < 0.001). CONCLUSION: Sildenafil citrate enhances spontaneous passage of 5-10 mm DUS. PMID- 26966584 TI - Acute Footshock Stress Induces Time-Dependent Modifications of AMPA/NMDA Protein Expression and AMPA Phosphorylation. AB - Clinical studies on patients with stress-related neuropsychiatric disorders reported functional and morphological changes in brain areas where glutamatergic transmission is predominant, including frontal and prefrontal areas. In line with this evidence, several preclinical works suggest that glutamate receptors are targets of both rapid and long-lasting effects of stress. Here we found that acute footshock- (FS-) stress, although inducing no transcriptional and RNA editing alterations of ionotropic AMPA and NMDA glutamate receptor subunits, rapidly and transiently modulates their protein expression, phosphorylation, and localization at postsynaptic spines in prefrontal and frontal cortex. In total extract, FS-stress increased the phosphorylation levels of GluA1 AMPA subunit at Ser(845) immediately after stress and of GluA2 Ser(880) 2 h after start of stress. At postsynaptic spines, stress induced a rapid decrease of GluA2 expression, together with an increase of its phosphorylation at Ser(880), suggesting internalization of GluA2 AMPA containing receptors. GluN1 and GluN2A NMDA receptor subunits were found markedly upregulated in postsynaptic spines, 2 h after start of stress. These results suggest selected time-dependent changes in glutamatergic receptor subunits induced by acute stress, which may suggest early and transient enhancement of AMPA-mediated currents, followed by a transient activation of NMDA receptors. PMID- 26966586 TI - Outcome of alpha-blockers, with or without methylprednisolone combination, in medical expulsive therapy for lower ureteric stones: A prospective randomised study. AB - OBJECTIVES: To compare the safety and efficacy of tamsulosin, alfuzosin, and their combinations with methylprednisolone, in the medical management of lower ureteric stones. PATIENTS AND METHODS: Between September 2012 and June 2014, patients diagnosed with a single lower ureteric stone of ?10 mm (longest dimension) were enrolled. Patients with urinary tract infection, severe hydronephrosis, pregnancy, hypertension, diabetes, ulcer disease, or renal insufficiency were excluded. According to the medication added to the analgesic anti-inflammatory, patients were stratified into four groups, with 53 patients in each. Group I patients received tamsulosin 0.4 mg and those in Group II received tamsulosin 0.4 mg and methylprednisolone 8 mg. Group III patients received alfuzosin 10 mg and those in Group IV received alfuzosin 10 mg and methylprednisolone 8 mg. Treatment was continued until stone expulsion or to a maximum of 2 weeks. The patients' demographics, stone criteria, and stone-free rates were calculated and analysed. RESULTS: The mean (SD) maximum stone dimension was 7.8 (1.5), 8.1 (1.3), 7.9 (1.6) and 8.0 (1.4) mm in Groups I, II, III and IV, respectively. Groups II and IV had significantly higher stone-free rates than Groups I and III (P < 0.05), whilst there were no statistically significant differences between Groups I and III or between Groups II and IV. There was no statistical difference among the four groups for the time to stone expulsion. Three patients in Group II and two patients in Group IV developed transient hyperglycaemia, which resolved after cessation of methylprednisolone. CONCLUSIONS: The combination of alfuzosin or tamsulosin with methylprednisolone seems to be effective and safe for managing lower ureteric stones of <1 cm. PMID- 26966587 TI - Silodosin vs tamsulosin in the management of distal ureteric stones: A prospective randomised study. AB - OBJECTIVES: To compare the efficacy of silodosin (8 mg) vs tamsulosin (0.4 mg), as a medical expulsive therapy, in the management of distal ureteric stones (DUS) in terms of stone clearance rate and stone expulsion time. PATIENTS AND METHODS: A prospective randomised study was conducted on 115 patients, aged 21-55 years, who had unilateral DUS of ?10 mm. Patients were divided into two groups. Group 1 received silodosin (8 mg) and Group 2 received tamsulosin (0.4 mg) daily for 1 month. The patients were followed-up by ultrasonography, plain abdominal radiograph of the kidneys, ureters and bladder, and computed tomography (in some cases). RESULTS: There was a significantly higher stone clearance rate of 83% in Group 1 vs 57% in Group 2 (P = 0.007). Group 1 also showed a significant advantage for stone expulsion time and analgesic use. Four patients, two in each group, discontinued the treatment in first few days due to side-effects (orthostatic hypotension). No severe complications were recorded during the treatment period. Retrograde ejaculation was recorded in nine and three patients in Groups 1 and 2, respectively. CONCLUSION: Our data show that silodosin is more effective than tamsulosin in the management of DUS for stone clearance rates and stone expulsion times. A multicentre study on larger scale is needed to confirm the efficacy and safety of silodosin. PMID- 26966589 TI - Antegrade JJ stenting after percutaneous renal procedures: The 'pull and push' technique. PMID- 26966588 TI - Standard versus tubeless mini-percutaneous nephrolithotomy: A randomised controlled trial. AB - OBJECTIVE: To prospectively compare the outcome of standard mini-percutaneous nephrolithotomy (SmPCNL) versus tubeless mini-percutaneous nephrolithotomy (TmPCNL) as primary treatments of renal stones. PATIENTS AND METHODS: In all, 80 patients with a solitary radio-opaque renal stone and candidates for PCNL were selected. The patients were randomly divided into two groups of 40, one group treated with SmPCNL and the other with TmPCNL. Patients and stone characters, as well as operative and postoperative data of both groups were compared and statistically analysed. RESULTS: There was no significant difference between the two groups for patient demographics and stone characteristics. There was no statistically significant difference between the two groups for the mean operative time, mean postoperative drop in haemoglobin, mean postoperative urine leakage, mean hospital stay, and stone-free rate. The mean (SD) postoperative dose of analgesia was statistically significantly higher in the SmPCNL group compared with the TmPCNL group, at 112.5 (48.03) versus 48.8 (43.5) mg, respectively. CONCLUSION: Both procedures are safe and effective for managing renal stones, without any significant difference between the two procedures; however, the postoperative analgesic requirement is significantly higher in SmPCNL. PMID- 26966590 TI - Robot-assisted ureterocalycostomy: A single centre contemporary experience in adults. AB - OBJECTIVE: To present our technique and experience of robot-assisted ureterocalycostomy (RAUC) in managing secondary pelvi-ureteric junction obstruction (PUJO) in adults. PATIENTS AND METHODS: We retrospectively reviewed all patients from our centre who underwent RAUC, between 2011 and 2015, for secondary PUJO resulting from previous surgical intervention. Six procedures in five patients, including a bilateral RAUC were performed. The median (range) patient age was 33.7 (18-41) years. The outcome variables included operative time, duration of hospital stay, and objective evidence of unimpeded drainage on urography. RESULTS: The mean (range) operating time was 172 (144-260) min and estimated blood loss was 100 (50-250) mL. There were no conversions to open or laparoscopic surgery, and no intraoperative complications. Two patients had Clavien-Dindo Grade I complications that were managed conservatively and one patient had a Grade IIIb complication, which required balloon dilatation and re stenting. After a median (range) follow-up of 11 (7-48) months, five of the six renal units had successful outcomes. CONCLUSION: The robot-assisted approach appears to be ideally suited for redo cases demanding fine dissection with meticulous suturing. In our present series of adult patients, we could safely and successfully perform RAUC with minimal morbidity. However, a larger multi institutional outcome analysis is required to substantiate the role of the robot assisted approach in performing UC. PMID- 26966591 TI - Testosterone replacement therapy improves the health-related quality of life of men diagnosed with late-onset hypogonadism. AB - OBJECTIVES: To test the hypothesis that testosterone replacement therapy (TRT) improves the long-term health-related quality of life (HRQoL) of men with late onset hypogonadism (LOH), as studies have shown that sub-physiological testosterone levels have a negative impact on psychological (e.g. mood, vitality, libido and sexual interest) and physical features (e.g. erectile function and physical strength), all of which contribute to a sense of well-being. PATIENTS AND METHODS: In all, 261 patients (mean age 58 years) diagnosed with LOH were treated with long-acting intramuscular testosterone undecanoate (TU) for up to 5 years. Health quality indicators including the International Prostate Symptom Score (IPSS), the five-item version of the International Index of Erectile Function (IIEF-5), the Aging Males' Symptoms (AMS) scale, and the percentage of patients reporting joint and muscle pain were measured at baseline and at each visit. The means were then plotted over time in parallel with mean total testosterone (TT) levels. RESULTS: Both the mean IPSS and AMS scores fell significantly within the first 3 months and the mean IIEF-5 score and TT levels increased within the first 3 months. All four parameters continued to improve over the course of the trial. The percentage of patients reporting both joint and muscle pain decreased during TRT. CONCLUSIONS: This prospective, observational and longitudinal analysis shows a clear improvement in both psychological and physical characteristics as physiological testosterone levels are reached and maintained contributing to an improvement in the HRQoL in men with diagnosed LOH. PMID- 26966592 TI - Venous thromboembolism after radical cystectomy: Experience with screening ultrasonography. AB - OBJECTIVES: To detect the incidence of immediate postoperative deep vein thrombosis (DVT) using screening lower extremity ultrasonography (US) in patients undergoing radical cystectomy (RC) and to determine the rate of symptomatic pulmonary embolism (PE) after RC and identify risk factors for venous thromboembolic (VTE) events in a RC population. PATIENTS AND METHODS: We performed a retrospective review of prospective data collected on patients who underwent RC between July 2008 and January 2012. These patients underwent screening US at 2/3 days after RC to determine the rate of asymptomatic DVT. A chart review was completed to identify those who had a symptomatic PE. Univariate and multivariable analysis was used to identify risk factors associated with DVT, PE and total VTE events. RESULTS: In all, 221 patients underwent RC and asymptomatic DVT was identified in 21 (9.5%) on screening US. Nine (4.5%) developed symptomatic PE at a median of 9 days, of which no patients had positive lower extremity US postoperatively. Increased length of hospital stay, increased estimated blood loss, and lower body mass index were linked to risk of PE, and only a previous history of DVT was associated with postoperative DVT. CONCLUSION: Patients who undergo RC are at high-risk for thromboembolic events and multimodal prophylaxis should be administered. Clinicians should be especially vigilant in those who demonstrate factors associated with higher risk for VTE events. PMID- 26966593 TI - Adult-type granulosa cell tumour of the testis: Report of a case and review of the literature. AB - Granulosa cell tumours (GCTs) can be either juvenile or adult type, and more commonly occur in the ovaries. Adult-type GCTs of the testis (AGCTT) are very rare and only 46 cases have previously been reported. We report here on a 48-year old Filipino man with a left testicular AGCTT, which measured 1.2 * 1.2 * 1.0 cm. He underwent radical orchidectomy with postoperative surveillance for 1 year, which included computed tomography with oral intravenous contrast and clinical examinations, which have been unremarkable. The previously reported AGCTTs were briefly reviewed. PMID- 26966594 TI - Holmium laser enucleation versus simple prostatectomy for treating large prostates: Results of a systematic review and meta-analysis. AB - OBJECTIVE: To compare and evaluate the safety and efficacy of holmium laser enucleation of the prostate (HoLEP) and simple prostatectomy for large prostate burdens, as discussion and debate continue about the optimal surgical intervention for this common pathology. MATERIALS AND METHODS: A systematic search was conducted for studies comparing HoLEP with simple prostatectomy [open (OP), robot-assisted, laparoscopic] using a sensitive strategy and in accordance with Cochrane collaboration guidelines. Primary parameters of interest were objective measurements including maximum urinary flow rate (Q max) and post-void residual urine volume (PVR), and subjective outcomes including International Prostate Symptom Score (IPSS) and quality of life (QoL). Secondary outcomes of interest included volume of tissue retrieved, catheterisation time, hospital stay, blood loss and serum sodium decrease. Data on baseline characteristics and complications were also collected. Where possible, comparable data were combined and meta-analysis was conducted. RESULTS: In all, 310 articles were identified and after screening abstracts (114) and full manuscripts (14), three randomised studies (263 patients) were included, which met our pre-defined inclusion criteria. All these compared HoLEP with OP. The mean transrectal ultrasonography (TRUS) volume was 113.9 mL in the HoLEP group and 119.4 mL in the OP group. There was no statistically significant difference in Q max, PVR, IPSS and QoL at 12 and 24 months between the two interventions. OP was associated with a significantly shorter operative time (P = 0.01) and greater tissue retrieved (P < 0.001). However, with HoLEP there was significantly less blood loss (P < 0.001), patients had a shorter hospital stay (P = 0.03), and were catheterised for significantly fewer hours (P = 0.01). There were no significant differences in the total number of complications recorded amongst HoLEP and OP (P = 0.80). CONCLUSION: The results of the meta-analysis have shown that HoLEP and OP possess similar overall efficacy profiles for both objective and subjective disease status outcome measures. This review shows these improvements persist to at least the 24 month follow-up point. Further randomised studies are warranted to fully determine the optimal surgical intervention for large prostate burdens. PMID- 26966596 TI - Transperineal ultrasonography in stress urinary incontinence: The significance of urethral rotation angles. AB - OBJECTIVE: To assess, using transperineal ultrasonography (TPUS), the numerical value of the rotation of the bladder neck [represented by the difference in the anterior (alpha angle) and posterior urethral angles (beta angle)] at rest and straining, in continent women and women with stress urinary incontinence (SUI), to ascertain if there are significant differences in the angles of rotation (Ralpha and Rbeta) between the groups. PATIENTS SUBJECTS AND METHODS: In all, 30 women with SUI (SUI group) and 30 continent women (control group) were included. TPUS was performed at rest and straining (Valsalva manoeuver), and the threshold value for the urethral angles (alpha and beta angles) for each group were estimated. The degree of rotation for each angle was calculated and was considered as the angle of rotation. RESULTS: Both the alpha and beta angles were significantly different between the groups at rest and straining, and there was a significant difference in the mean increment in the value of each angle. Higher values of increment (higher rotation angles) were reported in the SUI group for both the alpha and beta angles compared with those of the control group [mean (SD) Ralpha SUI group 19.43 (12.76) vs controls 10.53 (2.98) degrees ; Rbeta SUI group 28.30 (12.96) vs controls 16.33 (10.8) degrees ; P < 0.001]. CONCLUSION: Urethral rotation angles may assist in the assessment and diagnosis of patients with SUI, which may in turn reduce the need for more sophisticated urodynamic studies. PMID- 26966595 TI - Goserelin acetate before transurethral resection of moderately enlarged benign prostatic hyperplasia: Prospective randomised-controlled clinical trial. AB - OBJECTIVE: To evaluate the impact of a luteinising hormone-releasing hormone (LHRH) agonist, goserelin acetate (GA), on surgical blood loss during transurethral resection of the prostate (TURP), as well as its histopathological effect on prostatic microvessel density (MVD). PATIENTS AND METHODS: Patients who underwent TURP due to benign prostatic enlargement (60-100 mL) were randomly subdivided into two equal groups according to whether they received preoperative GA administration (3.6 mg; group A) or not (group B). Evaluation parameters were operative time, weight of resected prostatic tissue, perioperative haematocrit (HCT) changes, estimation of intraoperative blood loss, and suburethral and stromal prostatic MVD. Effects of GA on prostate weight and any possible side effects were also monitored. RESULTS: In all, 35 and 33 patients were included in groups A and B, respectively. Operative time and HCT values' changes were significantly less in group A (P < 0.05). Also, operative blood loss (both total and adjusted per weight of resected tissue) was lower in group A, at a mean (SD) of 178.13 (77.71) mL and 3.74 (1.52) mL/g vs 371.75 (91.09) mL and 8.59 (2.42) mL/g (P < 0.001). The median MVD in both suburethral [8 vs 11 vessels/high-power field (HPF)] and stromal tissues (9 vs 17 vessels/HPF) were significantly lower in group A (P < 0.001). Side-effects were minimal. CONCLUSION: A single dose of GA, a LHRH agonist, before TURP is safe and effective in reducing surgical blood loss. It significantly reduced MVD in both suburethral and stromal nodular prostatic tissues without regional discrepancy. PMID- 26966597 TI - Corrigendum to "Percutaneous nephrolithotomy for treating staghorn stones: 10 years of experience of a tertiary-care centre" [Arab J. Urol. 10 (2012) 324-329]. AB - [This corrects the article DOI: 10.1016/j.aju.2012.03.002.]. PMID- 26966598 TI - Corrigendum to "Percutaneous nephrolithotomy vs. extracorporeal shockwave lithotripsy for treating a 20-30 mm single renal pelvic stone" [Arab J. Urol. 13(3) (2015) 212-216]. AB - [This corrects the article DOI: 10.1016/j.aju.2015.04.002.]. PMID- 26966599 TI - Ischemic Left Ventricular Perforation Covered by a Thrombus in a Patient Presenting with Cerebral Ischemia: Importance of Time-Sensitive Performance and Adequate Interpretation of Bedside Transthoracic Echography. AB - If myocardial infarction remains silent, only clinical signs of complications may unveil its presence. Life-threatening complications include myocardial rupture, thrombus formation, or arterial embolization. In the presented case, a 76-year old patient was admitted with left-sided hemiparesis. In duplex sonography, a critical stenosis of the right internal carotid artery was identified and initially but retrospectively incorrectly judged as the potential cause for ischemia. During operative thromboendarterectomy, arterial embolism of the right leg occurred coincidentally, more likely pointing towards a cardioembolic origin. Percutaneous interventions remained unsuccessful and local fibrinolysis was applied. Delayed bedside echocardiography by an experienced cardiologist demonstrated a discontinuity of the normal myocardial texture of the left ventricular apex together with an echodense, partly floating structure merely attached by a thin bridge not completely sealing the myocardial defect, accompanied by pericardial effusion. The patient was immediately transferred to emergency cardiac surgery with extirpation of the thrombus, aortocoronary bypass graft placement, and aneurysmectomy. This didactic case reveals decisive structural shortcomings in patient's admission and triage processes and underlines, if performed timely and correctly, the value of transthoracic echocardiography as a noninvasive and cost-effective tool allowing immediate decision-making, which, in this case, led to the correct but almost fatally delayed diagnosis. PMID- 26966600 TI - Retained Products of Conception: An Atypical Presentation Diagnosed Immediately with Bedside Emergency Ultrasound. AB - Background. Retained products of conception is an important diagnosis to consider in patients presenting with postpartum complaints. Bedside ultrasound is a rapid, accurate, noninvasive modality to evaluate these patients. Objective. To report an atypical case of retained products of conception diagnosed with bedside ultrasound in the emergency department. Case Report. A 27-year-old female who was 1-month postpartum presented with vaginal bleeding, pelvic pain, and no fever. At the time of initial H&P, bedside ultrasound revealed echogenic material within the endometrial cavity with blood flow seen by color Doppler consistent with retained products of conception. The bedside ultrasound rapidly narrowed the differential and allowed a definitive diagnosis immediately. Ob/Gyn was consulted and dilation and curettage was performed in the operating room. Conclusions. Retained products of conception is an important diagnosis for the emergency physician to consider in at-risk patients. The sonographic findings are easily obtained and interpreted by emergency physicians. Earlier diagnosis of this disease process should lead to more focused patient evaluations and management. PMID- 26966601 TI - First Case Report of Sinusitis with Lophomonas blattarum from Iran. AB - Introduction. Lophomonas blattarum is a rare cause of bronchopulmonary and sinus infection. This paper presents a rare case of Lophomonas sinusitis. Case Presentation. The patient was a 31-year-old woman who was admitted because of a history of upper respiratory infection and sinusitis. Direct microscopic examination of the sputum and nasal discharge showed large numbers of living Lophomonas blattarum with irregular movement of flagella. The patient was successfully treated by Metronidazole 750 mg t.i.d. for 30 days. Conclusions. This is the first case report of Lophomonas blattarum sinusitis from Iran. PMID- 26966602 TI - A Case of Recurrent Rudimentary Horn Ectopic Pregnancies Managed by Methotrexate Therapy and Laparoscopic Excision of the Rudimentary Horn. AB - This report presents a case of a 31-year-old woman successfully treated medically for a noncommunicating rudimentary horn ectopic pregnancy who presented with a second, successive rudimentary horn pregnancy. Patient underwent laparoscopic excision of right rudimentary horn and right salpingectomy after failed methotrexate therapy. Given the potential for rupture and recurrence, serious efforts should be made to excise a uterine rudimentary horn. PMID- 26966603 TI - Capecitabine Induced Multifocal Leukoencephalopathy: Do We Have Always to Switch off the Chemotherapy? AB - Capecitabine is a well tolerated and safe 5-fluorouracil agent for adjuvant, neoadjuvant chemotherapy or metastatic cases. Neurological side effects require discontinuation of chemotherapy. We report this unique case of a 50-year-old female, who presented an isolated episode of dysarthria and ataxia under bevacizumab, capecitabine, and oxaliplatin treatment due to reversible multifocal leukoencephalopathy that did not recur after readministration of chemotherapy. PMID- 26966604 TI - Pseudotumor Cerebri in a Child with Idiopathic Growth Hormone Insufficiency Two Months after Initiation of Recombinant Human Growth Hormone Treatment. AB - Purpose. To report a rare case of pseudotumor cerebri (PTC) in a child two months after receiving treatment with recombinant human growth hormone (rhGH) and to emphasize the need of close collaboration between ophthalmologists and pediatric endocrinologists in monitoring children receiving rhGH. Methods. A 12-year-old boy with congenital hypothyroidism started treatment with rhGH on a dose of 1,5 mg/daily IM (4.5 IU daily). Eight weeks later, he was complaining of severe headache without any other accompanying symptoms. The child was further investigated with computed tomography scan and lumbar puncture. Results. Computed tomography scan showed normal ventricular size and lumbar puncture revealed an elevated opening pressure of 360 mm H2O. RhGH was discontinued and acetazolamide 250 mg per os twice daily was initiated. Eight weeks later, the papilledema was resolved. Conclusions. There appears to be a causal relationship between the initiation of treatment with rhGH and the development of PTC. All children receiving rhGH should have a complete ophthalmological examination if they report headache or visual disturbances shortly after the treatment. Discontinuation of rhGH and initiation of treatment with acetazolamide may be needed and regular follow-up examinations by an ophthalmologist should be recommended. PMID- 26966605 TI - Lymphomatoid Granulomatosis with Paraneoplastic Polymyositis: A Rare Malignancy with Rare Complication. AB - Lymphomatoid granulomatosis is a rare Epstein-Barr virus driven lymphoproliferative disease. It most commonly presents with symptoms of lung involvement such as cough, chest tightness, and dyspnea or constitutional symptoms of weight loss, malaise, and fever. The diagnosis is obtained by biopsy and histopathology. Here we report the case of a 31-year-old male who presented with weight loss, rash, and weakness and was diagnosed with lymphomatoid granulomatosis with paraneoplastic polymyositis. We explore the relationship of Epstein-Barr virus with inflammatory myopathy and discuss paraneoplastic inflammatory myopathy. PMID- 26966606 TI - Surgical Management and Reconstruction of Hoffman's Disease (Dissecting Cellulitis of the Scalp). AB - Dissecting cellulitis of the scalp, or Hoffman's disease, is a rare dermatologic condition characterized by recurrent pustules and sinus tract formation leading to scarring and alopecia. Medical management includes the use of corticosteroids, antibiotics, isotretinoin, and adalimumab. In cases where the disease is severe, refractory, and intractable, surgery is an option. We report two cases of Hoffman's disease, where medical management failed to achieve remission. Surgical treatment was undertaken with complete resection of the affected scalp in staged procedures with subsequent split-thickness skin grafting for reconstruction. Surgery achieved both disease remission and excellent aesthetic outcomes in both patients. PMID- 26966607 TI - Scrotal Abscess Precipitating Late Infection of a Malleable Penile Prosthesis: The Risk Never Evanesces. AB - Although infrequent, infections represent the dreadful complication of penile prosthesis implantation. The incidence substantially decreases after a few infection-free postoperative months. We report herein a case of a very late penile prosthesis infection from a fistualizing scrotal abscess in a 67-year-old man. The patient presented with a one-month history of persistent penile-base discharge from a right hemiscrotal swelling. On examination, mild penile tenderness and a discharging penoscrotal-junction sinus were noted. Microbiological wound culture was positive for Staphylococcus epidermidis. Magnetic resonance imaging revealed this multiloculated fluid collection's communication with the right corporal body. Removal of the prosthesis was performed. Pathological evaluation of the dissected fistula was suggestive of acute on top of chronic inflammatory reactions. To our knowledge, this is the first report of a scrotal abscess leading to penile prosthesis infection 15 years after an uneventful implantation. PMID- 26966608 TI - Utilization and Predictors of Electrical Cardioversion in Patients Hospitalized for Atrial Fibrillation. AB - Atrial fibrillation (AF) is a common arrhythmia in adults associated with thromboembolic complications. External electrical cardioversion (DCCV) is a safe procedure used to convert AF to normal sinus rhythm. We sought to study factors that affect utilization of DCCV in hospitalized patients with AF. The study sample was drawn from the Nationwide Inpatient Sample (NIS) of the Healthcare Cost and Utilization Project in the United States. Patients with a primary discharge diagnosis of AF that received DCCV during hospitalization in the years 2000-2010 were included. An estimated 2,810,530 patients with a primary diagnosis of AF were hospitalized between 2001 and 2010, of which 1,19,840 (4.26%) received DCCV. The likelihood of receiving DCCV was higher in patients who were males, whites, privately insured, and aged < 40 years and those with fewer comorbid conditions. Higher CHADS2 score was found to have an inverse association with DCCV use. In-hospital stroke, in-hospital mortality, length of stay, and cost for hospitalization were significantly lower for patients undergoing DCCV during AF related hospitalization. Further research is required to study the contribution of other disease and patient related factors affecting the use of this procedure as well as postprocedure outcomes. PMID- 26966609 TI - The Heavy Links between Geological Events and Vascular Plants Evolution: A Brief Outline. AB - Since the rise of photosynthesis, life has influenced terrestrial atmosphere, particularly the O2 and the CO2 content (the latter being originally more than 95%), changing the chemistry of waters, atmosphere, and soils. Billions of years after, a far offspring of these first unicellular forms conquered emerging lands, not only completely changing landscape, but also modifying geological cycles of deposition and erosion, many chemical and physical characteristics of soils and fresh waters, and, more, the cycle of various elements. So, there are no doubts that vascular plants modified geology; but it is true that also geology has affected (and, more, has driven) plant evolution. New software, PyRate, has determined vascular plant origin and diversification through a Bayesian analysis of fossil record from Silurian to today, particularly observing their origination and extinction rate. A comparison between PyRate data and geological history suggests that geological events massively influenced plant evolution and that also the rise of nonflowering seed plants and the fast diffusion of flowering plants can be explained, almost partly, with the environmental condition changes induced by geological phenomena. PMID- 26966610 TI - The Pattern of Juvenile Idiopathic Arthritis in a Single Tertiary Center in Saudi Arabia. AB - Introduction. Juvenile Idiopathic Arthritis (JIA) is the most common chronic arthritis in children. Our aim is to describe demographic, clinical, and laboratory characteristics and treatment of JIA patients followed up in Pediatric Rheumatology clinic in a tertiary center in Saudi Arabia. Methods. Medical records of all patients who are followed up between January 2007 and January 2015 were retrospectively reviewed. Data were collected about demographic, clinical, and laboratory features and treatment. Results. Total patients were 82, males were 31 (37.8%), and mean age of JIA onset was 7.1 +/- 3.6 yr. Mean follow-up duration was 2.67+/-1.6 yr. Systemic onset JIA (SoJIA) was the commonest (36.5%), followed by polyarticular in 29.2% and oligoarticular in 28%. Large and small joints are involved in 76 (92%) and 30 (36.6%), respectively. Main extra articular feature was fever in 34 (41.4%). Uveitis was diagnosed in 7 (8.5%) and in 5 (21.7%) of oligoarticular JIA. Anemia was found in 49 (59.7%), high ESR in 45 (54.8%), and leukocytosis and thrombocytosis in 33 (40.2%). Positive ANA was found in 30 (36.5%) mainly in oligoarticular subtype as 12 (52%) patients (out of 23) had this positive test. 9 patients (10.9%) required NSAIDs only, 6 patients (7.3%) required NSAIDs and intra-articular steroids only, and 19 (23%) required NSAIDs, methotrexate, steroids, and biologics. Conclusion. SoJIA is the most common JIA subtype in our study. A population based rather than a single center study will give more details about JIA characteristics in Saudi Arabia. PMID- 26966612 TI - Medicinal Effect of Nutraceutical Fruits for the Cognition and Brain Health. AB - The recent era is witnessing evaluation of medicinal and nutritional value of fruits and fruit juices for the management and prevention of brain diseases like headache stress, anxiety, hypertension, and Alzheimer's and Parkinson's diseases by the scientists and researchers worldwide. Fruits possess various chemicals such as antioxidants and polyphenols, which reduce and balance the effect of hormone in brain responsible for brain disease. Natural remedy is cheap, easily available, nontoxic, and easy to prepare and provides good mental health as compared to other remedies. The main objective of this review is to acknowledge medicinal benefits of fruits for the cognition and management of brain disease. PMID- 26966613 TI - Do Health Reforms Impact Cost Consciousness of Health Care Professionals? Results from a Nation-Wide Survey in the Balkans. AB - BACKGROUND: Serbia, as the largest market of the Western Balkans, has entered socioeconomic transition with substantial delay compared to most of Eastern Europe. Its health system reform efforts were bold during the past 15 years, but their results were inconsistent in various areas. The two waves of global recession that hit Balkan economies ultimately reflected to the financial situation of healthcare. Serious difficulties in providing accessible medical care to the citizens became a reality. A large part of the unbearable expenses actually belongs to the overt prescription of pharmaceuticals and various laboratory and imaging diagnostic procedures requested by physicians. Therefore, a broad national survey was conducted at all levels of the healthcare system hierarchy to distinguish the ability of cost containment strategies to reshape clinician's mindsets and decision-making in practice. AIMS: Assessment of healthcare professionals' judgment on economic consequences of prescribed medical interventions and evaluation of responsiveness of healthcare professionals to policy measures targeted at increasing cost-consciousness. STUDY DESIGN: Cross sectional study. METHODS: A nationwide cross-sectional survey was conducted through a hierarchy of medical facilities across diverse geographical regions before and after policy action, from January 2010 to April 2013. In the middle of the observed period, the National Health Insurance Fund (RFZO) adopted severe cost-containment measures. Independently, pharmacoeconomic guidelines targeted at prescribers were disseminated. Administration in large hospitals and community pharmacies was forced to restrict access to high budget-impact medical care. Economic Awareness of Healthcare Professionals Questionnaire-29 (EAHPQ-29), developed in Serbian language, was used in face-to-face interviews. The questionnaire documented clinician's attitudes on: Clinical-Decision-Making between-Alternative-Interventions (CDMAI), Quality-of-Health-Care (QHC), and Cost Containment-Policy (CCP). The authors randomly and anonymously recruited 2000 healthcare experts, with a total of 1487 responding; after eliminating incomplete surveys, 649 participants were considered before and 651 after policy intervention. RESULTS: Dentists (1.195+/-0.560) had a higher mean CDMAI score compared to physicians (1.017+/-0.453). The surgical group compared to the internist group had a higher total EAHPQ-29 score, CCP score and CDMAI score. Policy intervention had a statistically significant negative impact on the QHC score (F=4.958; df=1; p=0.027). There was no substantial impact of policy interventions on professional behavior and judgment with regard to the CDMAI, CCP, and total EAHPQ-29 scores. CONCLUSION: Although cost savings were forcibly imposed in practice, the effects on clinical decision-making were modest. Clinicians' perceptions of quality of medical care were explained in a less effective manner due to the severely constrained resources allocated to the providers. This pioneering effort in the Balkans exposes the inefficiency of current policies to expand clinicians' cost consciousness. PMID- 26966611 TI - Salivary and Urinary Total Antioxidant Capacity as Biomarkers of Oxidative Stress in Humans. AB - Total Antioxidant Capacity (TAC) is a biomarker often used in order to investigate oxidative stress in many pathological conditions. Saliva and urine can be collected noninvasively and represent attractive diagnostic fluids for detecting biomarkers of various pathological conditions. The reviewed case control and intervention studies that measured salivary or urinary TAC revealed that diseases, antioxidant foods, or supplements and age, gender, and lifestyle factors influenced salivary or urinary TAC. Salivary and urinary TAC were particularly affected by oral or renal status, respectively, as well as by infection; therefore these factors must be taken into account in both case control and intervention studies. Furthermore, some considerations on sample collection and normalization strategies could be made. In particular, unstimulated saliva could be the better approach to measure salivary TAC, whereas 24 h or spontaneous urine collection should be chosen on the basis of the study outcome and of the creatinine clearance. Finally, the uric acid-independent TAC could be the better approach to evaluate red-ox status of body, in particular after nutritional interventions and in diseases associated with hyperuricaemia. PMID- 26966615 TI - Criteria for Drug Reimbursement Decision-Making: An Emerging Public Health Challenge in Bulgaria. AB - BACKGROUND: During times of fiscal austerity, means of reimbursement decision making are of particular interest for public health theory and practice. Introduction of advanced health technologies, growing health expenditures and increased public scrutiny over drug reimbursement decisions have pushed governments to consider mechanisms that promote the use of effective health technologies, while constraining costs. AIMS: The study's aim was to explore the current rationale of the drug reimbursement decision-making framework in Bulgaria. Our pilot research focused on one particular component of this process the criteria used - because of the critical role that criteria are known to have in setting budgets and priorities in the field of public health. The analysis pursued two objectives: to identify important criteria relevant to drug reimbursement decision-making and to unveil relationships between theory and practice. STUDY DESIGN: Cross-sectional study. METHODS: The study was realized through a closed-ended survey on reimbursement criteria among four major public health stakeholders - medical professionals, patients, health authorities, and industry. Empirical outcomes were then cross-compared with the theoretical framework, as defined by current Bulgarian public health legislation. Analysis outlined what is done and what needs to be done in the field of public health reimbursement decision-making. RESULTS: Bulgarian public health stakeholders agreed on 15 criteria to form a tentative optimal framework for drug reimbursement decision-making. The most apparent gap between the empirically found preferences and the official legislation is the lack of consideration for the strength of evidence in reimbursement decisions. CONCLUSION: Bulgarian policy makers need to address specific gaps, such as formal consideration for strength of evidence, explicit role of efficiency criteria, and means to effectively empower patient and citizen involvement in public health decision-making. Drug reimbursement criteria have to be integrated into legitimate public health decision support tools that ensure the achievement of national public health objectives. These recommendations could be expanded to all Eastern European countries who share common public health problems. PMID- 26966616 TI - Socioeconomic Inequalities in Mental Health of Adult Population: Serbian National Health Survey. AB - BACKGROUND: The global burden of mental disorders is rising. In Serbia, anxiety is the leading cause of disability-adjusted life years. Serbia has no mental health survey at the population level. The information on prevalence of mental disorders and related socioeconomic inequalities are valuable for mental care improvement. AIMS: To explore the prevalence of mental health disorders and socioeconomic inequalities in mental health of adult Serbian population, and to explore whether age years and employment status interact with mental health in urban and rural settlements. STUDY DESIGN: Cross-sectional study. METHODS: This study is an additional analysis of Serbian Health Survey 2006 that was carried out with standardized household questionnaires at the representative sample of 7673 randomly selected households - 15563 adults. The response rate was 93%. A multivariate logistic regression modeling highlighted the predictors of the 5 item Mental Health Inventory (MHI-5), and of chronic anxiety or depression within eight independent variables (age, gender, type of settlement, marital status and self-perceived health, education, employment status and Wealth Index). The significance level in descriptive statistics, chi square analysis and bivariate and multivariate logistic regressions was set at p<0.05. RESULTS: Chronic anxiety or depression was seen in 4.9% of the respondents, and poor MHI-5 in 47% of respondents. Low education (Odds Ratios 1.32; 95% confidence intervals=1.16 1.51), unemployment (1.36; 1.18-1.56), single status (1.34; 1.23-1.45), and Wealth Index middle class (1.20; 1.08-1.32) or poor (1.33; 1.21-1.47) were significantly related with poor MHI-5. Unemployed persons in urban settlements had higher odds for poormMHI-5 than unemployed in rural areas (0.73; 0.59-0.89). Single (1.50; 1.26-1.78), unemployed (1.39; 1.07-1.80) and inactive respondents (1.42; 1.10-1.83) had a higher odds of chronic anxiety or depression than married individuals, or those with partner, and employed persons. Those with perceived good health status had lower odds for poor MHI-5, chronic anxiety or depression than those whose general health was average and poor. CONCLUSION: Almost half of the population assessed their mental health as poor and 5% had diagnosed chronic anxiety or depression. Multi-sectoral socioeconomic and female-sensitive policies should be wisely tailored to reduce mental health inequalities contributed by differences in age, education, employment, marriage and the wealth status of the adult population. PMID- 26966614 TI - Evaluation of Dual Therapy in Real Life Setting in Treatment-Naive Turkish Patients with HCV Infection: A Multicenter, Retrospective Study. AB - BACKGROUND: Before the introduction of direct-acting antivirals in the treatment of chronic hepatitis C patients, the combination of peginterferon alpha and ribavirin was the standard therapy. Observational studies that investigated sustained virological response (SVR) rates by these drugs yielded different outcomes. AIMS: The goal of the study was to demonstrate real life data concerning SVR rate achieved by peginterferon alpha plus ribavirin in patients who were treatment-naive. STUDY DESIGN: A multicenter, retrospective observational study. METHODS: The study was conducted retrospectively on 1214 treatment naive-patients, being treated with peginterferon alpha-2a or 2b plus ribavirin in respect of the current guidelines between 2005 and 2013. The patients' data were collected from 22 centers via a standard form, which has been prepared for this study. The data included demographic and clinical characteristics (gender, age, body weight, initial Hepatitis C virus RNA (HCV RNA) level, disease staging) as well as course of treatment (duration of treatment, outcomes, discontinuations and adverse events). Renal insufficiency, decompensated liver disease, history of transplantation, immunosuppressive therapy or autoimmune liver disease were exclusion criteria for the study. Treatment efficacy was assessed according to the patient's demographic characteristics, baseline viral load, genotype, and fibrosis scores. RESULTS: The mean age of the patients was 50.74 (+/-0.64) years. Most of them were infected with genotype 1 (91.8%). SVR was achieved in 761 (62.7%) patients. SVR rate was 59.1% in genotype 1, 89.4% in genotype 2, 93.8% in genotype 3, and 33.3% in genotype 4 patients. Patients with lower viral load yielded higher SVR (65.8% vs. 58.4%, p=0.09). SVR rates according to histologic severity were found to be 69.3%, 66.3%, 59.9%, 47.3%, and 45.5% in patients with fibrosis stage 0, 1, 2, 3 and 4, respectively. The predictors of SVR were male gender, genotype 2/3, age less than 45 years, low fibrosis stage, low baseline viral load and presence of early virological response. SVR rates to each peginterferon were found to be similar in genotype 1/4 although SVR rates were found to be higher for peginterferon alpha-2b in patients with genotype 2/3. The number of patients who failed to complete treatment due to adverse effects was 33 (2.7%). The number of patients failed to complete treatment due to adverse effects was 33 (2.7%). CONCLUSION: Our findings showed that the rate of SVR to dual therapy was higher in treatment-naive Turkish patients than that reported in randomized controlled trials. Also peginterferon alpha-2a and alpha-2b were found to be similar in terms of SVR in genotype 1 patients. PMID- 26966617 TI - Evaluation of a Community Health Service Center-Based Intervention Program for Managing Chronic Heart Failure. AB - BACKGROUND: Although the role of primary care for the management of patients with chronic heart failure (CHF) has been highly recommended, structural involvement of primary care in heart failure (HF) management programs is extremely limited. AIMS: To examine the feasibility and applicability of two most recommended forms of care delivery mode, home visit and telephone support, for CHF management in the setting of community health service center (CHSC). STUDY DESIGN: Prospective study. METHODS: This study was conducted in two CHSCs in Beijing, China. Care delivery was led by trained general practitioners or community nurses via home visits in one CHSC and telephone support in the other. Data regarding the change in mortality and hospitalization rate during 12 months and self-care level at 6 months were prospectively collected and compared across the intervention groups. RESULTS: A total of 329 patients were included, with 142 in the home visit group and 187 in the telephone support group. Patients in both groups had frequent visits to CHSC (8.1+/-5.9 in the home visit and 7.7+/-4.1 in the telephone support group, p=0.45) during the follow-up period. Compared to the telephone support group, patients in the home visit group showed a reduction in all-cause mortality (14.1% versus 20.3%, p=0.14), one or more hospitalizations due to any cause (33.8% versus 44.2%, p=0.12) and one or more hospitalizations due to cardiac cause (17.6% versus 24.6%, p=0.13) in the home visit group. The absolute differences were 6.2% (95% CI: 1.9%, 14.3%), 8.4% (95% CI: 2.1%, 18.9%) and 7.3% (95% CI: 1.5%, 16.1%), respectively, although the results were not statistically significant. After 6 months of intervention, patients in both groups achieved marked improvement in self-care with reference to their own baseline values. CONCLUSION: Although no statistical difference was observed between the two care delivery approaches regarding the clinical outcomes of interest, given the high participation rates, the acceptable rate of adverse events, frequent CHSC visits and patients' preferences in the current study, it was concluded that CHSC might be the optimal setting for delivering care to CHF patients in China. PMID- 26966618 TI - Isolated Diastolic Hypertension among Adults in Saudi Arabia: Prevalence, Risk Factors, Predictors and Treatment. Results of a National Survey. AB - BACKGROUND: In the past, diastolic hypertension was the main criterion for treatment, but currently, systolic pressure is the main criterion because it was thought that Isolated Diastolic Hypertension (IDH) is not associated with complications. Studies later revealed that IDH carries significant risks. Quantifying the magnitude and risk factors of IDH in the community is essential for all intervention strategies. AIMS: This study aims to determine the prevalence, risk factors, predictors, treatment modalities and lifestyle practices of IDH adult patients in the Kingdom of Saudi Arabia (KSA). STUDY DESIGN: Cross-sectional study. METHODS: A community-based cross-sectional study using STEPwise approach among adults using a multistage, stratified, cluster random sample was carried out. Data were collected using questionnaires which included socio-demographics, blood pressure, biochemical, anthropometric measurements and lifestyle practices. Statistical analysis included calculating means and standard deviations, proportions, univariate and multiple logistic regression analysis. RESULTS: Of a total 4562 subjects, 180 (3.95%) suffered from IDH, which was significantly related to age, gender, employment, smoking, diabetes mellitus, obesity and hypercholesterolemia. More than 93% were using some form of treatment, with 77.2% on prescribed drugs, 63% using diet, and 23% using exercise. Significant predictors of IDH were retirement and hypercholesterolemia. CONCLUSION: IDH is associated with some sociodemographic characteristics and co-morbidity. Given the risk of cardiovascular disease associated with IDH, the findings of this study emphasize the need for diagnosing the disease in middle-aged persons focusing on the modifiable risk factors of IDH. PMID- 26966619 TI - ST-Segment Elevation in the Right Precordial Leads in Patients with Acute Anterior Myocardial Infarction. AB - BACKGROUND: Elevation of ST segment in leads V3R/ V4R, which is commonly encountered in right ventricular myocardial infarction, may also occur in patients with anterior ST elevation myocardial infarction (STEMI). However, the clinical impact of this finding in the setting of anterior myocardial infarction is not well understood. AIMS: We aimed to investigate the prognostic value of ST segment elevation in leads V3R/V4R in patients with first acute anterior myocardial infarction. STUDY DESIGN: Prospective cohort study. METHODS: Right precordial leads V3R/V4R were recorded in 111 patients admitted with first time anterior myocardial infarction. Patients were allocated into two groups based on the presence or absence of ST elevation in leads V3R/V4R. Demographic, biochemical and echocardiographic data, as well as the angiographic information, were recorded. In-hospital and 3 month mortality, and major adverse cardiac events (MACE), death, heart failure and ventricular dysrhythmia were also compared. RESULTS: ST elevation in lead V3R or V4R was present in 72 out of 111 patients (64.9%). Involvement of the proximal part of the left anterior descending (LAD) artery was not different in the two groups (44.4% of patients with elevation vs. 53.8% of patients without elevation, p=0.22). Post-myocardial infarction complications, mortality and major adverse cardiac events were similar in the two groups. Left ventricular ejection fraction (LVEF) was significantly lower in patients with ST elevation in V3R/V4R (35 %+/-8 vs. 38 %+/-8, p=0.02). Twenty three out of 111 patients (20.7%) developed heart failure, which was similar in the two groups [16 (22.2%) of patients with ST elevation vs. 7 (17.9%) of patients without ST elevation, p=0.39]. CONCLUSION: Although ST elevation in V3R/V4R can be present in patients with left anterior descending artery occlusion, it does not seem to predict the prognosis. Lower left ventricular ejection fraction in this group may play a role in the long-term prognosis; however, this issue needs further investigation. PMID- 26966620 TI - The Relationship between Telomerase Activity and Clinicopathological Parameters in Colorectal Cancer: A Meta-Analysis. AB - BACKGROUND: Recently, accumulated research has found that the expression of telomerase activity (TA) was associated with colorectal cancer (CRC) advancement, whereas the TA prognostic effect in CRC patients is still controversial. AIMS: To investigate relationships between TA and CRC clinicopathological parameters. STUDY DESIGN: Meta-analysis study. METHODS: We searched published studies in databases, such as EMBASE, the Cochrane Library, PubMed, and Ovid databases (last search updated to October 2014) by meeting specified search criteria. The quality of the included studies was usually evaluated and a meta-analysis was implemented by Stata 12.0 software. We used an odds ratio (OR) with a 95% confidence interval (CI) to evaluate relationship strengths between TA and CRC clinicopathological parameters. RESULTS: In total, 11 studies (715 patients) were included to assess the relation between TA and metastasis-related parameters in CRC patients. The results indicate that a senior TA expression was connected with the existence of lymph node metastasis (180 patients; OR=2.85, 95% CI=1.40-5.81, p=0.004), and tumor site (522 patients; OR=2.93, 95% CI=1.29-6.67, p=0.010). However, a senior TA expression was not connected with tumor size (137 patients; OR=1.57, 95% CI=0.71-3.47, p=0.267), histological differentiation (570 patients; OR=1.28, 95% CI=0.78-2.09, p=0.332), depth of invasion (57 patients; OR=3.76, 95% CI=0.61 23.04, p=0.152), distant metastasis (123 patients; OR=1.76, 95% CI=0.54-5.74, p=0.346), and clinical stage of the cancer (543 patients; OR=1.59, 95% CI=0.74 3.38, p=0.232). CONCLUSION: This meta-analysis suggests that a positive TA was correlated with lymph node metastasis progression and tumor site of the CRC but did not correlate with other important clinicopathological parameters. TA can play a useful part in the prognosis and treatment of CRC patients, but further studies are required to confirm this. PMID- 26966621 TI - Evaluating Unscheduled Readmission to Emergency Department in the Early Period. AB - BACKGROUND: The readmission in the early period (RAEP) is defined as the admission of a patient to emergency department (ED) for the second time within 72 hours after discharge from the ED. AIMS: The aim of this study was to determine the disease, patient, doctor, and system related causes of RAEP. STUDY DESIGN: Descriptive study. METHODS: This study is a two-stage study that was conducted at Department of Emergency, Gazi University Faculty of Medicine. The causes of RAEP were defined as disease, patient, doctor, and system related causes. RESULTS: A total of 46,800 adult patients admitted to ED during the study period and 779 (1.66%) patients required RAEP. After the exclusion criteria, 429 of these patients were included the study. The most common reasons for RAEP were renal colic in 46 (10.7%) patients. It was detected that 60.4% of the causes of RAEP were related to disease, 20.0% were related to the doctor, 12.1% were related to the patient, and 7.5% were related to the hospital management system. CONCLUSION: This study revealed that there are patient-, doctor-, and system-related preventable reasons for RAEP and the patients requiring RAEP constitute the high risk group. PMID- 26966622 TI - A Diagnostic Algorithm for the Detection of Clostridium difficile-Associated Diarrhea. AB - BACKGROUND: Clostridium difficile is a common cause of hospital-acquired diarrhea, which is usually associated with previous antibiotic use. The clinical manifestations of C. difficile infection (CDI) may range from mild diarrhea to fulminant colitis. Clostridium difficile should be considered in diarrhea cases with a history of antibiotic use within the last 8 weeks (community-associated CDI) or with a hospital stay of at least 3 days, regardless of the duration of antibiotic use (hospital-acquired CDI). AIMS: This study investigated the frequency of CDI in diarrheic patients and evaluated the efficacy of the triple diagnostic algorithm that is proposed here for C. difficile detection. STUDY DESIGN: Cross-sectional study. METHODS: In this study, we compared three methods currently employed for C. difficile detection using 95 patient stool samples: an enzyme immunoassay (EIA) for toxin A/B (C. diff Toxin A+B; Diagnostic Automation Inc.; Calabasas, CA, USA), an EIA for glutamate dehydrogenase (GDH) (C. DIFF CHEK 60TM, TechLab Inc.; Blacksburg, VA, USA), and a polymerase chain reaction (PCR) based assay (GeneXpert((r)) C. difficile; Cepheid, Sunnyvale, CA, USA) that detects C. difficile toxin genes and conventional methods as well. In this study, 50.5% of the patients were male, 50 patients were outpatients, 32 were from inpatient clinics and 13 patients were from the intensive care unit. RESULTS: Of the 95 stool samples tested for GDH, 28 were positive. Six samples were positive by PCR, while nine samples were positive for toxin A/B. The hypervirulent strain NAP-1 and binary toxin was not detected. The rate of occurrence of toxigenic C. difficile was 5.1% in the samples. Cefaclor, ampicillin-sulbactam, ertapenem, and piperacillin-tazobactam were the most commonly used antibiotics by patients preceding the onset of diarrhea. Among the patients who were hospitalized in an intensive care unit for more than 7 days, 83.3% were positive for CDI by PCR screening. If the PCR test is accepted as the reference: C. difficile Toxin A/B ELISA sensitivity and specificity were 67% and 94%, respectively, and GDH sensitivity and specificity were 100% and 75%, respectively. CONCLUSION: Tests targeting C. difficile toxins are frequently applied for the purpose of diagnosing CDI in a clinical setting. However, changes in the temperature and reductant composition of the feces may affect toxin stability, potentially yielding false-negative test results. Therefore, employment of a GDH EIA, which has high sensitivity, as a screening test for the detection of toxigenic strains, may prevent false-negative results, and its adoption as part of a multistep diagnostic algorithm may increase accuracy in the diagnosis of CDIs. PMID- 26966623 TI - Prognostic Factors in Sudden Sensorineural Hearing Loss. AB - BACKGROUND: Sudden sensorineural hearing loss (SSNHL) is still a complex and challenging process which requires clinical evidence regarding its etiology, treatment and prognostic factors. Therefore, determination of prognostic factors might aid in the selection of proper treatment modality. AIMS: The aim of this study is to analyze whether there is correlation between SSNHL outcomes and (1) systemic steroid therapy, (2) time gap between onset of symptoms and initiation of therapy and (3) audiological pattern of hearing loss. STUDY DESIGN: Retrospective chart review. METHODS: Patients diagnosed at our clinic with SSNHL between May 2005 and December 2011 were reviewed. A detailed history of demographic features, side of hearing loss, previous SSNHL and/or ear surgery, recent upper respiratory tract infection, season of admission, duration of symptoms before admission and the presence of co-morbid diseases was obtained. Radiological and audiological evaluations were recorded and treatment protocol was assessed to determine whether systemic steroids were administered or not. Treatment started <=5 days was regarded as "early" and >5 days as "delayed". Initial audiological configurations were grouped as "upward sloping", "downward sloping", "flat" and "profound" hearing loss. Significant recovery was defined as thresholds improved to the same level with the unaffected ear or improved >=30 dB on average. Slight recovery was hearing improvement between 10-30dB on average. Hearing recovery less than 10 dB was accepted as unchanged. RESULTS: Among the 181 patients who met the inclusion criteria, systemic steroid was administered to 122 patients (67.4%), whereas 59 (32.6%) patients did not have steroids. It was found that steroid administration did not have any statistically significant effect in either recovered or unchanged hearing groups. Early treatment was achieved in 105 patients (58%) and 76 patients (42%) had delayed treatment. Recovery rates were no different in these two groups; however, when unchanged hearing rates were compared, it was statistically significantly lower in the early treatment group (p<0.05). When hearing outcomes were compared according to initial audiological pattern, significant recovery and unchanged hearing rates did not differ between groups; however, slight recovery rate was highest in the "flat" type audiological configuration (p<0.05). CONCLUSION: According to this patient series, oral steroid therapy does not have any influence on the outcomes of SSNHL. However, mid-frequency hearing loss of flat type and initiation of treatment earlier than 5 days from the onset of symptoms, seem to have positive prognostic effects. Further randomized controlled subject groups might contribute to determine prognostic factors of SSNHL. PMID- 26966625 TI - Beneficial Effect of Leptin on Spatial Learning and Memory in Streptozotocin Induced Diabetic Rats. AB - BACKGROUND: Diabetes mellitus is a chronic disease which may be accompanied by cognitive impairments. The expression of the obesity gene (ob) is decreased in insulin-deficient diabetic animals and increased after the administration of insulin or leptin. Plasma leptin levels are reduced in the streptozotocin (STZ) induced diabetic rats. Therefore, the deleterious effects of diabetes on memory may be due to the reduction of leptin. AIMS: Investigate the effect of subcutaneous injection of leptin on spatial learning and memory in STZ-induced diabetic rats. STUDY DESIGN: Animal experimentation. METHODS: The rats were divided into three groups: 1-control, 2- diabetic, and 3- diabetic-leptin. Diabetes was induced in groups 2 and 3 by STZ injection (55 mg/kg) intraperitoneally (i.p). The animals received leptin (0.1 mg/kg) or saline subcutaneously (s.c) for 10 days before behavioral studies. Then, they were examined in the Morris water maze over 3 blocks after 3 days of the last injection of leptin. RESULTS: The travelled path length and time spent to reach the platform significantly increased in the diabetic group (p<0.001) and decreased with leptin treatment (p<0.01 & p<0.001 respectively); also, a significant increase in path length and time was observed between the diabetic leptin group and the diabetic group (p<0.01, p<0.001, respectively) in the probe test. CONCLUSION: Leptin can exert positive effects on memory impairments in diabetic rats. PMID- 26966624 TI - The Effect of Autologous Platelet Rich Plasma in the Treatment of Achilles Tendon Ruptures: An Experimental Study on Rabbits. AB - BACKGROUND: Achilles tendon ruptures are characterized by a long recovery period, high re-rupture rate and late return to work. To overcome these difficulties and augment tendon repair, many agents have been used. AIMS: To determine the effect of autologous platelet rich plasma (PRP) in the treatment of Achilles tendon ruptures in rabbits. STUDY DESIGN: Animal experimentation. METHODS: The study included 14 New Zealand albino rabbits that were divided randomly into 2 groups, A and B, each containing seven rabbits. On day zero, all 28 Achilles tendons were tenotomized and repaired. In group A, the tendons were injected with PRP post surgery, whereas those in group B were left untreated. On day 28, the right tendons in both groups were examined histopathologically via both light and electron microscopy, and the left tendons were subjected to biomechanical testing. RESULTS: The histological and biomechanical findings in both light and electron microscopy in group A were better than those in group B, but the difference was not significant. According to Tang's scale, the mean value in Group A was 3.57, while it was 3.0 in Group B. The mean value of Group A for the length of collagen bands was 48.09 nm while the mean value of Group B was 46.58 nm (p=0.406). In biomechanical tests, although stiffness values were higher in group A, the difference between groups was not significant. In addition, maximum load values did not differ between groups A and B. CONCLUSION: PRP had no effect on the healing process 28 days post-Achilles tendon rupture. PMID- 26966627 TI - Sonographic Diagnosis of Fetal Adrenal Hemorrhage Complicating a Vein of Galen Aneurysmal Malformation. AB - BACKGROUND: The vein of Galen aneurysmal malformation (VGAM) is a rare intracranial vascular malformation which causes end-organ ischemia or venous congestion due to heart failure. Adrenal hemorrhage associated with VGAM has not been reported in the literature. We present the imaging findings of a fetal VGAM with adrenal hemorrhage. CASE REPORT: A 26 year-old primigravida woman whose fetus with VGAM and mild cardiomegaly was scanned in the 34th week. On fetal ultrasound, a hyperechoic, well-circumscribed mass in the left suprarenal region was shown. Fetal and postnatal magnetic resonance imaging confirmed the diagnosis of adrenal hemorrhage. The baby died after delivery. CONCLUSION: Adrenal hemorrhage can complicate VGAM in fetuses with severe heart failure. Evaluation of the adrenal gland in affected cases may contribute to the prenatal counseling, and postnatal management. PMID- 26966626 TI - Cochlear Implantation in Neurobrucellosis. AB - BACKGROUND: Neurobrucellosis is a disease consisting of a wide spectrum of complications such as peripheral neuropathy, cranial nerve involvement, ataxia, meningeal irritation, paraplegia, seizures, coma, and even death. The vestibulocochlear nerve seems to be the most commonly affected cranial nerve (10%). We present a patient with neurobrucellosis whose auditory perception and speech intelligibility skill performances improved after cochlear implantation. CASE REPORT: A 35 year-old woman was admitted to another hospital 2 years ago with the symptoms of headache, nausea, and altered consciousness, who was finally diagnosed with neurobrucellosis. She developed bilateral profound sensorineural hearing loss during the following 6 months. There was no benefit of using hearing aids. After successful treatment of her illness, she was found to be suitable for cochlear implantation. After the operation, her auditory perception skills improved significantly with a Categories of Auditory Performance (CAP) score of 5. According to clinical observations and her family members' statements, her Speech Intelligibility Rating (SIR) score was 3. Her speech intelligibility skills are still improving. CONCLUSION: Our case report represents the second case of hearing rehabilitation with cochlear implantation after neurobrucellosis. Cochlear implantation is a cost-effective and time-proven successful intervention in post-lingual adult patients with sensorineural hearing loss. Early timing of the surgery after appropriate treatment of meningitis helps the patient to achieve better postoperative results. PMID- 26966628 TI - Can Vemurafenib Induce Vitiligo in Metastatic Melanoma Patients? PMID- 26966629 TI - A Rare Cause of Acute Pancreatitis: Unexpected Travel of the Biliary Catheter. PMID- 26966630 TI - High Efficacy of Prednisolone in a Complicated Case of Weil Disease. PMID- 26966631 TI - Intracerebroventricular Transplantation of Cord Blood-Derived Neural Progenitors in a Child With Severe Global Brain Ischemic Injury. AB - Transplantation of neural stem/precursor cells has recently been proposed as a promising, albeit still controversial, approach to brain repair. Human umbilical cord blood could be a source of such therapeutic cells, proven beneficial in several preclinical models of stroke. Intracerebroventricular infusion of neutrally committed cord blood-derived cells allows their broad distribution in the CNS, whereas additional labeling with iron oxide nanoparticles (SPIO) enables to follow the fate of engrafted cells by MRI. A 16-month-old child at 7 months after the onset of cardiac arrest-induced global hypoxic/ischemic brain injury, resulting in a permanent vegetative state, was subjected to intracerebroventricular transplantation of the autologous neutrally committed cord blood cells. These cells obtained by 10-day culture in vitro in neurogenic conditions were tagged with SPIO nanoparticles and grafted monthly by three serial injections (12 * 10(6) cells/0.5 ml) into lateral ventricle of the brain. Neural conversion of cord blood cells and superparamagnetic labeling efficiency was confirmed by gene expression, immunocytochemistry, and phantom study. MRI examination revealed the discrete hypointense areas appearing immediately after transplantation in the vicinity of lateral ventricles wall with subsequent lowering of the signal during entire period of observation. The child was followed up for 6 months after the last transplantation and his neurological status slightly but significantly improved. No clinically significant adverse events were noted. This report indicates that intracerebroventricular transplantation of autologous, neutrally committed cord blood cells is a feasible, well tolerated, and safe procedure, at least during 6 months of our observation period. Moreover, a cell-related MRI signal persisted at a wall of lateral ventricle for more than 4 months and could be monitored in transplanted brain hemisphere. PMID- 26966632 TI - Transplant of Primary Human Hepatocytes Cocultured With Bone Marrow Stromal Cells to SCID Alb-uPA Mice. AB - Hepatocytes are vulnerable to loss of function and viability in culture. Modified culture methods have been applied to maintain their functional status. Heterotypic interactions between hepatocytes and nonparenchymal neighbors in liver milieu are thought to modulate cell differentiation. Cocultivation of hepatocyte with various cell types has been applied to mimic the hepatic environment. Bone marrow stromal cells (BMSC) are plastic cell lines capable of transforming to other cell types. In this study hepatocyte coculture with BMSCs achieved long-term function of human hepatocytes in culture for 4 weeks. In vitro functional status of human hepatocytes in BMSC coculture was compared with fibroblast coculture and collagen culture by measuring albumin, human-alpha-1 antitrypsin (hAAT), urea secretion, CYP450 activity, and staining for intracellular albumin and glycogen. After 2 weeks in culture hepatocytes were retrieved and transplanted to severe combined immunodeficiency/albumin linked urokinase type plasminogen activator (SCID Alb-uPA) mice and engraft-ment capacity was analyzed by human hepatic-specific function measured by hAAT levels in mouse serum, and Alu staining of mouse liver for human hepatocytes. Hepatocytes from BMSC coculture had significantly higher albumin, hAAT secretion, urea production, and cytochrome P450 (CYP450) activity than other culture groups. Staining confirmed the higher functional status in BMSC coculture. Transplantation of hepatocytes detached from BMSC cocultures showed significantly higher engraftment function than hepatocytes from other culture groups measured by hAAT levels in mouse serum. In conclusion, BMSC coculture has excellent potential for hepatocyte function preservation in vitro and in vivo after transplant. It is possible to use BMSC hepatocyte coculture as a supply of cell therapy in liver disease. PMID- 26966634 TI - Effects of Quantum Dot Labeling on Endothelial Progenitor Cell Function and Viability. AB - Endothelial progenitor cells (EPC) play an important role in repairing damaged endothelium. An effective imaging method for in vivo tracking of EPCs is essential for understanding EPC-based cell therapy. Fluorescent quantum dots (QDs) have attractive optical characteristics such as extreme brightness and photostability. QDs are currently being investigated as probes for stem cell labeling; however, there is concern about whether QDs can be used safely. We investigated whether quantum dot (QD) labeling would influence EPC viability and function. Rat bone marrow-derived EPCs were cultured and characterized. The cells were labeled with near-infrared-emitting, carboxyl-coated QDs (8 nM) for 24 h. QD labeling efficiency was higher than 97%. Using WST-1 assay, we showed that the viability of the QD-labeled EPCs was not different from that of the control EPCs. Moreover, QD labeling did not influence the ability of EPCs to form capillary tubes on Matrigel and to migrate. The percentage of QD-positive cells decreased with time, probably due to the rapid division of EPCs. These data suggest that the carboxyl-coated QD705 can be useful for labeling EPCs without interrupting their viability and functions. PMID- 26966633 TI - In Vivo Growing of New Cell Colonies in a Portion of Bone Marrow: Potential Use for Indirect Cell Therapy. AB - The ability of bone marrow cells (BMCs) to migrate to different organs can be used for indirect cell therapy, a procedure based on the engraftment of therapeutic cells in a different place from where they will finally move to and perform their action and which could be particularly useful for chronic illness where a persistent and long-lasting therapeutic action is required. Thus, establishing a stable colony of engineered BMCs is a requisite for the chronic provision of damaged tissues with engineered cells. Reported here is a procedure for creating such a cell colony in a portion of the bone marrow (BM). The study was performed in C57BL/6j mice and consisted of developing a focal niche in a portion of the bone marrow with focal irradiation so that it could be selectively colonized by BM cells (C57BL/6-FG-VC-GFP mice) injected in the blood stream. Both the arrival of cells coming from the nonirradiated BM (week 1 after irradiation) and the proliferation of cells in the irradiated BM (week 2) prevented the homing of injected cells in the BM niche. However, when BMCs were injected in a time window about 48 h after irradiation they migrated to the BM niche where they established a cell colony able to: 1) survive for a long period of time [the percentage of injected cells increased in the BM from day 30 postinjection (15%) to day 110 postinjection 28%)]; 2) express cell differentiation markers (90% of them were lineage committed 4 weeks after engraftment); and 3) colonize to the blood stream (with 5% and 9% of all blood cells being computed 1 and 3 months after engraftment, respectively). The intravenous injection of BMCs in combination with a previous transitory focal myeloablation is a safe and easy method for creating the long-lasting colony of modified BMCs needed for treating chronic and progressive illness with indirect cell therapy. PMID- 26966635 TI - Exercise Improves Glucose Disposal and Insulin Signaling in Pregnant Mice Fed a High Fat Diet. AB - OBJECTIVE: Physical activity has been suggested as a non-pharmacological intervention that can be used to improve glucose homeostasis in women with gestational diabetes mellitus. The purpose of this study was to determine the effects of voluntary exercise on glucose tolerance and body composition in pregnant high fat diet fed mice. METHODS: Female mice were put on a standard diet or high fat diet for two weeks. The mice were then split into 4 groups; control standard diet fed, exercise standard diet fed, control high fat diet fed, and exercise high fat diet fed. Exercise mice had voluntary access to a running wheel in their home cage one week prior to mating, during mating, and throughout pregnancy. Glucose tolerance and body composition were measured during pregnancy. Akt levels were quantified in skeletal muscle and adipose tissue isolated from saline or insulin injected pregnant dams as a marker for insulin signaling. RESULTS: Consumption of the high fat diet led to significantly increased body weight, fat mass, and impaired glucose tolerance in control mice. However, voluntary running in the high fat diet fed dams significantly reduced weight gain and fat mass and ultimately improved glucose tolerance compared to control high fat diet fed dams. Further, body weight, fat mass, and glucose disposal in exercise high fat diet dams were indistinguishable from control dams fed the standard diet. High fat diet fed exercise dams also had significantly increased insulin stimulated phosphorylated Akt expression in adipose tissue, but not skeletal muscle, compared to control dams on high fat diet. CONCLUSION: The use of voluntary exercise improves glucose homeostasis and body composition in pregnant female mice. Thus, future studies could investigate potential long-term health benefits in offspring born to obese exercising dams. PMID- 26966637 TI - Longitudinal and Cross-Sectional Analyses of Age Effects on Retinal Nerve Fiber Layer and Ganglion Cell Complex Thickness by Fourier-Domain OCT. AB - PURPOSE: We studied the effects of age and intraocular pressure (IOP) on retinal nerve fiber layer (NFL) and macular ganglion cell complex (GCC) thickness in normal eyes. METHODS: Data from subjects from the multicenter Advanced Imaging for Glaucoma Study (AIGS) were analyzed. The data included yearly visits from the normal subjects in the AIGS study. Fourier-domain optical coherence tomography (FD-OCT) was used to measure retinal NFL and macular GCC on each visit. Mixed effect models were used to evaluate the longitudinal effect of age and IOP on the NFL and GCC thickness. The measurements at baseline were used to examine the cross-sectional effects. RESULTS: The analysis included 192 eyes (92 participants) from AIGS between 2009 and 2013. The longitudinal analyses showed overall GCC thickness decreased 0.25 +/- 0.05 MUm per year (P < 0.001) while the overall NFL thickness decreased 0.14 +/- 0.07 MUm per year (P = 0.04). The cross sectional analyses showed the GCC thickness was 0.17 +/- 0.05 MUm thinner per year of baseline age (P < 0.001), while the NFL was 0.21 +/- 0.06 MUm thinner (P < 0.001). There was no significant IOP effect on either GCC or NFL from either the longitudinal or cross-sectional analysis. CONCLUSIONS: Longitudinal and cross sectional analyses provided consistent rates of approximately 0.2% per year of age-related thinning in NFL and GCC thicknesses. This is relevant in establishing criteria to detect glaucoma-related thinning (disease progression) in excess of normal aging. IOP does not seem to be a significant confounder for progression analysis. TRANSLATIONAL RELEVANCE: This study demonstrated the relevance of advanced imaging technology in diagnosing and monitoring glaucoma disease. PMID- 26966636 TI - Cardiac Ischemia Reperfusion Injury Following Instillation of 20 nm Citrate capped Nanosilver. AB - BACKGROUND: Silver nanoparticles (AgNP) have garnered much interest due to their antimicrobial properties, becoming one of the most utilized nano-scale materials. However, any potential evocable cardiovascular injury associated with exposure has not been reported to date. We have previously demonstrated expansion of myocardial infarction after intratracheal (IT) instillation of carbon-based nanomaterials. We hypothesized pulmonary exposure to Ag core AgNP induces a measureable increase in circulating cytokines, expansion of cardiac ischemia reperfusion (I/R) injury and is associated with depressed coronary constrictor and relaxation responses. Secondarily, we addressed the potential contribution of silver ion release on AgNP toxicity. METHODS: Male Sprague-Dawley rats were exposed to 200 MUl of 1 mg/ml of 20 nm citrate-capped Ag core AgNP, 0.01, 0.1, 1 mg/ml Silver Acetate (AgAc), or a citrate vehicle by intratracheal (IT) instillation. One and 7 days following IT instillation the lungs were evaluated for inflammation and the presence of silver; serum was analyzed for concentrations of selected cytokines; cardiac I/R injury and coronary artery reactivity were assessed. RESULTS: AgNP instillation resulted in modest pulmonary inflammation with detection of silver in lung tissue and alveolar macrophages, elevation of serum cytokines: G-CSF, MIP-1alpha, IL-1beta, IL-2, IL-6, IL-13, IL 10, IL-18, IL-17alpha, TNFalpha, and RANTES, expansion of I/R injury and depression of the coronary vessel reactivity at 1 day post IT compared to vehicle treated rats. Silver within lung tissue was persistent at 7 days post IT instillation and was associated with an elevation in cytokines: IL-2, IL-13, and TNFalpha and expansion of I/R injury. AgAc resulted in a concentration dependent infarct expansion and depressed vascular reactivity without marked pulmonary inflammation or serum cytokine response. CONCLUSIONS: Based on these data, IT instillation of AgNP increases circulating levels of several key cytokines, which may contribute to persistent expansion of I/R injury possibly through an impaired vascular responsiveness. PMID- 26966638 TI - Oral Mineralocorticoid-Receptor Antagonists: Real-Life Experience in Clinical Subtypes of Nonresolving Central Serous Chorioretinopathy With Chronic Epitheliopathy. AB - PURPOSE: To evaluate the efficacy and safety of oral mineralocorticoid-receptor antagonist (MRa) therapy in three clinical presentations of nonresolving central serous chorioretinopathy (CSCR) with chronic epitheliopathy. METHODS: Retrospective case series of consecutive patients with nonresolving CSCR treated with oral eplerenone or spironolactone. Treatment criteria were: persistent CSCR with subretinal fluid (SRF) lasting longer than 4 months; recurrent CSCR with SRF lasting longer than 2 months; persistent CSCR (SRF >= 4 months) with fundus autofluorescence gravitational tracks. Outcomes at 1, 3, and 6 months were: foveal SRF height, central macular thickness (CMT), subfoveal choroidal thickness (SFCT), best-corrected visual acuity (BCVA), and occurrence of side effects. RESULTS: Among 54 eyes from 42 patients (mean age: 53 years), mean foveal SRF, CMT, and SFCT decreased significantly at 1, 3, and 6 months after treatment initiation. Mean BCVA improved significantly at 6 months. In the subgroup analysis, mean foveal SRF, CMT, and SFCT decreased significantly at 3 and 6 months in the persistent and recurrent groups. In persistent cases with tracks, a significant diminution of mean CMT and SFCT was achieved at 6 months. Treatment related side effects were observed in 6 patients, prompting treatment discontinuation in one case. CONCLUSION: Response to treatment was observed in the three subgroups. In persistent CSCR with tracks the response was delayed compared with persistent and recurrent cases, suggesting that longer treatment durations would be beneficial in patients with gravitational tracks of RPE alteration. TRANSLATIONAL RELEVANCE: The clinical response to oral MRa is consistent with the involvement of the mineralocorticoid pathway in CSCR pathogenesis. PMID- 26966639 TI - Automated Retinal Image Analysis for Evaluation of Focal Hyperpigmentary Changes in Intermediate Age-Related Macular Degeneration. AB - PURPOSE: To develop and evaluate a software tool for automated detection of focal hyperpigmentary changes (FHC) in eyes with intermediate age-related macular degeneration (AMD). METHODS: Color fundus (CFP) and autofluorescence (AF) photographs of 33 eyes with FHC of 28 AMD patients (mean age 71 years) from the prospective longitudinal natural history MODIAMD-study were included. Fully automated to semiautomated registration of baseline to corresponding follow-up images was evaluated. Following the manual circumscription of individual FHC (four different readings by two readers), a machine-learning algorithm was evaluated for automatic FHC detection. RESULTS: The overall pixel distance error for the semiautomated (CFP follow-up to CFP baseline: median 5.7; CFP to AF images from the same visit: median 6.5) was larger as compared for the automated image registration (4.5 and 5.7; P < 0.001 and P < 0.001). The total number of manually circumscribed objects and the corresponding total size varied between 637 to 1163 and 520,848 pixels to 924,860 pixels, respectively. Performance of the learning algorithms showed a sensitivity of 96% at a specificity level of 98% using information from both CFP and AF images and defining small areas of FHC ("speckle appearance") as "neutral." CONCLUSIONS: FHC as a high-risk feature for progression of AMD to late stages can be automatically assessed at different time points with similar sensitivity and specificity as compared to manual outlining. Upon further development of the research prototype, this approach may be useful both in natural history and interventional large-scale studies for a more refined classification and risk assessment of eyes with intermediate AMD. TRANSLATIONAL RELEVANCE: Automated FHC detection opens the door for a more refined and detailed classification and risk assessment of eyes with intermediate AMD in both natural history and future interventional studies. PMID- 26966640 TI - Efficacy of Column Scatter Plots for Presenting Retinitis Pigmentosa Phenotypes in a Japanese Cohort. AB - PURPOSE: We evaluated the efficacy of column scatter plots to describe genotype phenotype correlations in a Japanese cohort with retinitis pigmentosa (RP). METHODS: Clinical records of 121 patients with RP with identified causative mutations were reviewed. Visual acuity, central and peripheral visual fields, electroretinography (ERG), lens status, and measurements of optical coherence tomography were evaluated according to causative genes using column scatter plots. Values for three common genes (EYS, USH2A, and RHO) were compared statistically. RESULTS: All patients with PDE6B, PRPH2, and RPGR mutations, those 55 years old or younger with RP1L1 and USH2A mutations, and those 45 years old or younger with EYS and RHO mutations retained visual acuity of at least 0.1. All patients with RPGR mutations showed at least -20 dB mean deviation. Goldmann perimeter measures of 4/6 patients with RHO mutations showed remaining peripheral visual fields. Dark-adapted 0.01 and 3.0 ERGs were extinguished for most genes. Half of the patients with RHO RP maintained cone responses in light-adapted 3.0 and 3.0 flicker ERG. All patients with PRPH2, those 55 years old or younger with USH2A and RP1L1, and those 45 years old or younger with PDE6B and EYS mutations maintained subfoveal ellipsoid zones. No differences were identified between EYS and USH2A or RHO and USH2A. CONCLUSIONS: Column scatter plots enabled comparisons of the associated severities and illustration of the ophthalmological measurements for every RP causative gene. TRANSLATIONAL RELEVANCE: Analysis of mutations in specific genes may be helpful for determining visual prognoses in the clinical setting. PMID- 26966641 TI - Normal Values for the Full Visual Field, Corrected for Age- and Reaction Time, Using Semiautomated Kinetic Testing on the Octopus 900 Perimeter. AB - PURPOSE: To determine normal values of the visual field (VF), corrected for age and reaction time (RT) for semiautomated kinetic perimetry (SKP) on the Octopus 900 perimeter, create a model describing the age-dependency of these values, and assess test-retest reliability for each isopter. METHODS: Eighty-six eyes of 86 ophthalmologically healthy subjects (age 11-79 years, 34 males, 52 females) underwent full-field kinetic perimetry with the Octopus 900 instrument. Stimulus size, luminance, velocity, meridional angle, subject age, and their interactions, were used to create a smooth multiple regression mathematical model (V/4e, III/4e, I/4e, I/3e, I/2e, I/1e, and I/1a isopters). Fourteen subjects (2 from each of 7 age groups) were evaluated on three separate sessions to assess test retest reliability of the isopters. Reaction time (RT) was tested by presenting 12 designated RT-vectors between 10 degrees and 20 degrees within the seeing areas for the III/4e isopter (stimulus velocity, 3 degrees /second). Four RT- vectors were presented at the nasal (0 degrees or 180 degrees ), superotemporal (45 degrees ), and inferior (270 degrees ) meridians. RESULTS: The model fit was excellent (r2 = 0.94). The test-retest variability was less than 5 degrees , and the median decrease in this deviation attributed to aging, per decade, for all age groups and for all stimulus sizes was 0.8 degrees . No significant learning effect was observed for any age group or isopter. CONCLUSION: Age-corrected and RT-corrected normative threshold values for full-field kinetic perimetry can be adequately described by a smooth multiple linear regression mathematical model. TRANSLATIONAL RELEVANCE: A description of the entire kinetic VF is useful for assessing a full characterization of VF sensitivity, determining function losses associated with ocular and neurologic diseases, and for providing a more comprehensive analysis of structure-function relationships. PMID- 26966642 TI - Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder. AB - Background. Schizophrenia (SZ) and bipolar disorder (BD) have both been associated with reduced microstructural white matter integrity using, as a proxy, fractional anisotropy (FA) detected using diffusion tensor imaging (DTI). Genetic susceptibility for both illnesses has also been positively correlated in recent genome-wide association studies with allele A (adenine) of single nucleotide polymorphism (SNP) rs1344706 of the ZNF804A gene. However, little is known about how the genomic linkage disequilibrium region tagged by this SNP impacts on the brain to increase risk for psychosis. This study aimed to assess the impact of this risk variant on FA in patients with SZ, in those with BD and in healthy controls. Methods. 230 individuals were genotyped for the rs1344706 SNP and underwent DTI. We used tract-based spatial statistics (TBSS) followed by an analysis of variance, with threshold-free cluster enhancement (TFCE), to assess underlying effects of genotype, diagnosis and their interaction, on FA. Results. As predicted, statistically significant reductions in FA across a widely distributed brain network (p < 0.05, TFCE-corrected) were positively associated both with a diagnosis of SZ or BD and with the double (homozygous) presence of the ZNF804A rs1344706 risk variant (A). The main effect of genotype was medium (d = 0.48 in a 44,054-voxel cluster) and the effect in the SZ group alone was large (d = 1.01 in a 51,260-voxel cluster), with no significant effects in BD or controls, in isolation. No areas under a significant diagnosis by genotype interaction were found. Discussion. We provide the first evidence in a predominantly Caucasian clinical sample, of an association between ZNF804A rs1344706 A-homozygosity and reduced FA, both irrespective of diagnosis and particularly in SZ (in overlapping brain areas). This suggests that the previously observed involvement of this genomic region in psychosis susceptibility, and in impaired functional connectivity, may be conferred through it inducing abnormalities in white matter microstructure. PMID- 26966643 TI - Samples and data accessibility in research biobanks: an explorative survey. AB - Biobanks, which contain human biological samples and/or data, provide a crucial contribution to the progress of biomedical research. However, the effective and efficient use of biobank resources depends on their accessibility. In fact, making bio-resources promptly accessible to everybody may increase the benefits for society. Furthermore, optimizing their use and ensuring their quality will promote scientific creativity and, in general, contribute to the progress of bio medical research. Although this has become a rather common belief, several laboratories are still secretive and continue to withhold samples and data. In this study, we conducted a questionnaire-based survey in order to investigate sample and data accessibility in research biobanks operating all over the world. The survey involved a total of 46 biobanks. Most of them gave permission to access their samples (95.7%) and data (85.4%), but free and unconditioned accessibility seemed not to be common practice. The analysis of the guidelines regarding the accessibility to resources of the biobanks that responded to the survey highlights three issues: (i) the request for applicants to explain what they would like to do with the resources requested; (ii) the role of funding, public or private, in the establishment of fruitful collaborations between biobanks and research labs; (iii) the request of co-authorship in order to give access to their data. These results suggest that economic and academic aspects are involved in determining the extent of sample and data sharing stored in biobanks. As a second step of this study, we investigated the reasons behind the high diversity of requirements to access biobank resources. The analysis of informative answers suggested that the different modalities of resource accessibility seem to be largely influenced by both social context and legislation of the countries where the biobanks operate. PMID- 26966644 TI - Influence of isoflurane on the diastolic pressure-flow relationship and critical occlusion pressure during arterial CABG surgery: a randomized controlled trial. AB - The effects of isoflurane on the determinants of blood flow during Coronary Artery Bypass Graft (CABG) surgery are not completely understood. This study characterized the influence of isoflurane on the diastolic Pressure-Flow (P-F) relationship and Critical Occlusion Pressure (COP) during CABG surgery. Twenty patients undergoing CABG surgery were studied. Patients were assigned to an isoflurane or control group. Hemodynamic and flow measurements during CABG surgery were performed twice (15 minutes after the discontinuation of extracorporeal circulation (T15) and again 15 minutes later (T30)). The zero flow pressure intercept (a measure of COP) was extrapolated from a linear regression analysis of the instantaneous diastolic P-F relationship. In the isoflurane group, the application of isoflurane significantly increased the slope of the diastolic P-F relationship by 215% indicating a mean reduction of Coronary Vascular Resistance (CVR) by 46%. Simultaneously, the Mean Diastolic Aortic Pressure (MDAP) decreased by 19% mainly due to a decrease in the systemic vascular resistance index by 21%. The COP, cardiac index, heart rate, Left Ventricular End-Diastolic Pressure (LVEDP) and Coronary Sinus Pressure (CSP) did not change significantly. In the control group, the parameters remained unchanged. In both groups, COP significantly exceeded the CSP and LVEDP at both time points. We conclude that short-term application of isoflurane at a sedative concentration markedly increases the slope of the instantaneous diastolic P-F relationship during CABG surgery implying a distinct decrease with CVR in patients undergoing CABG surgery. PMID- 26966645 TI - Low-frequency, low-magnitude vibrations (LFLM) enhances chondrogenic differentiation potential of human adipose derived mesenchymal stromal stem cells (hASCs). AB - The aim of this study was to evaluate if low-frequency, low-magnitude vibrations (LFLM) could enhance chondrogenic differentiation potential of human adipose derived mesenchymal stem cells (hASCs) with simultaneous inhibition of their adipogenic properties for biomedical purposes. We developed a prototype device that induces low-magnitude (0.3 g) low-frequency vibrations with the following frequencies: 25, 35 and 45 Hz. Afterwards, we used human adipose derived mesenchymal stem cell (hASCS), to investigate their cellular response to the mechanical signals. We have also evaluated hASCs morphological and proliferative activity changes in response to each frequency. Induction of chondrogenesis in hASCs, under the influence of a 35 Hz signal leads to most effective and stable cartilaginous tissue formation through highest secretion of Bone Morphogenetic Protein 2 (BMP-2), and Collagen type II, with low concentration of Collagen type I. These results correlated well with appropriate gene expression level. Simultaneously, we observed significant up-regulation of alpha3, alpha4, beta1 and beta3 integrins in chondroblast progenitor cells treated with 35 Hz vibrations, as well as Sox-9. Interestingly, we noticed that application of 35 Hz frequencies significantly inhibited adipogenesis of hASCs. The obtained results suggest that application of LFLM vibrations together with stem cell therapy might be a promising tool in cartilage regeneration. PMID- 26966646 TI - The semantic basis of taste-shape associations. AB - Previous research shows that people systematically match tastes with shapes. Here, we assess the extent to which matched taste and shape stimuli share a common semantic space and whether semantically congruent versus incongruent taste/shape associations can influence the speed with which people respond to both shapes and taste words. In Experiment 1, semantic differentiation was used to assess the semantic space of both taste words and shapes. The results suggest a common semantic space containing two principal components (seemingly, intensity and hedonics) and two principal clusters, one including round shapes and the taste word "sweet," and the other including angular shapes and the taste words "salty," "sour," and "bitter." The former cluster appears more positively valenced whilst less potent than the latter. In Experiment 2, two speeded classification tasks assessed whether congruent versus incongruent mappings of stimuli and responses (e.g., sweet with round versus sweet with angular) would influence the speed of participants' responding, to both shapes and taste words. The results revealed an overall effect of congruence with congruent trials yielding faster responses than their incongruent counterparts. These results are consistent with previous evidence suggesting a close relation (or crossmodal correspondence) between tastes and shape curvature that may derive from common semantic coding, perhaps along the intensity and hedonic dimensions. PMID- 26966647 TI - Ultra-structural changes and expression of chondrogenic and hypertrophic genes during chondrogenic differentiation of mesenchymal stromal cells in alginate beads. AB - Chondrogenic differentiation of mesenchymal stromal cells (MSCs) in the form of pellet culture and encapsulation in alginate beads has been widely used as conventional model for in vitro chondrogenesis. However, comparative characterization between differentiation, hypertrophic markers, cell adhesion molecule and ultrastructural changes during alginate and pellet culture has not been described. Hence, the present study was conducted comparing MSCs cultured in pellet and alginate beads with monolayer culture. qPCR was performed to assess the expression of chondrogenic, hypertrophic, and cell adhesion molecule genes, whereas transmission electron microscopy (TEM) was used to assess the ultrastructural changes. In addition, immunocytochemistry for Collagen type II and aggrecan and glycosaminoglycan (GAG) analysis were performed. Our results indicate that pellet and alginate bead cultures were necessary for chondrogenic differentiation of MSC. It also indicates that cultures using alginate bead demonstrated significantly higher (p < 0.05) chondrogenic but lower hypertrophic (p < 0.05) gene expressions as compared with pellet cultures. N-cadherin and N CAM1 expression were up-regulated in second and third weeks of culture and were comparable between the alginate bead and pellet culture groups, respectively. TEM images demonstrated ultrastructural changes resembling cell death in pellet cultures. Our results indicate that using alginate beads, MSCs express higher chondrogenic but lower hypertrophic gene expression. Enhanced production of extracellular matrix and cell adhesion molecules was also observed in this group. These findings suggest that alginate bead culture may serve as a superior chondrogenic model, whereas pellet culture is more appropriate as a hypertrophic model of chondrogenesis. PMID- 26966648 TI - The use and evaluation of self-regulation techniques can predict health goal attainment in adults: an explorative study. AB - Background. Self-regulation tools are not always used optimally, and implementation intention plans often lack quality. Therefore, this study explored participants' use and evaluation of self-regulation techniques and their impact on goal attainment. Methods. Data were obtained from 452 adults in a proof of concept (POC) intervention of 'MyPlan', an eHealth intervention using self regulation techniques to promote three healthy behaviours (physical activity (PA), fruit intake, or vegetable intake). Participants applied self-regulation techniques to a self-selected health behaviour, and evaluated the self-regulation techniques. The quality of implementation intentions was rated by the authors as a function of instrumentality (instrumental and non-instrumental) and specificity (non-specific and medium to highly specific). Logistic regression analyses were conducted to predict goal attainment. Results. Goal attainment was significantly predicted by the motivational value of the personal advice (OR:1.86), by the specificity of the implementation intentions (OR:3.5), by the motivational value of the action plan (OR:1.86), and by making a new action plan at follow-up (OR:4.10). Interaction-effects with behaviour showed that the specificity score of the implementation intention plans (OR:4.59), the motivational value of the personal advice (OR:2.38), selecting hindering factors and solutions(OR:2.00) and making a new action plan at follow-up (OR:7.54) were predictive of goal attainment only for fruit or vegetable intake. Also, when participants in the fruit and vegetable group made more than three plans, they were more likely to attain their goal (OR:1.73), whereas the reverse was the case in the PA group (OR:0.34). Discussion. The chance that adults reach fruit and vegetable goals can be increased by including motivating personal advice, self-formulated action plans, and instructions/strategies to make specific implementation intentions into eHealth interventions. To increase the chance that adults reach short-term PA goals, it is suggested to keep eHealth PA interventions simple and focus only on developing a few implementation intentions. However, more research is needed to identify behaviour change techniques that can increase health goal attainment at long-term. PMID- 26966650 TI - The dark cube: dark and light character profiles. AB - Background. Research addressing distinctions and similarities between people's malevolent character traits (i.e., the Dark Triad: Machiavellianism, narcissism, and psychopathy) has detected inconsistent linear associations to temperament traits. Additionally, these dark traits seem to have a common core expressed as uncooperativeness. Hence, some researchers suggest that the dark traits are best represented as one global construct (i.e., the unification argument) rather than as ternary construct (i.e., the uniqueness argument). We put forward the dark cube (cf. Cloninger's character cube) comprising eight dark profiles that can be used to compare individuals who differ in one dark character trait while holding the other two constant. Our aim was to investigate in which circumstances individuals who are high in each one of the dark character traits differ in Cloninger's "light" character traits: self-directedness, cooperativeness, and self-transcendence. We also investigated if people's dark character profiles were associated to their light character profiles. Method. A total of 997 participants recruited from Amazon's Mechanical Turk (MTurk) responded to the Short Dark Triad and the Short Character Inventory. Participants were allocated to eight different dark profiles and eight light profiles based on their scores in each of the traits and any possible combination of high and low scores. We used three-way interaction regression analyses and t-tests to investigate differences in light character traits between individuals with different dark profiles. As a second step, we compared the individuals' dark profile with her/his character profile using an exact cell-wise analysis conducted in the ROPstat software (http://www.ropstat.com). Results. Individuals who expressed high levels of Machiavellianism and those who expressed high levels of psychopathy also expressed low self-directedness and low cooperativeness. Individuals with high levels of narcissism, in contrast, scored high in self-directedness. Moreover, individuals with a profile low in the dark traits were more likely to end up with a profile high in cooperativeness. The opposite was true for those individuals with a profile high in the dark traits. The rest of the cross-comparisons revealed some of the characteristics of human personality as a non-linear complex dynamic system. Conclusions. Our study suggests that individuals who are high in Machiavellianism and psychopathy share a unified non-agentic and uncooperative character (i.e., irresponsible, low in self-control, unempathetic, unhelpful, untolerant), while individuals high in narcissism have a more unique character configuration expressed as high agency and, when the other dark traits are high, highly spiritual but uncooperative. In other words, based on differences in their associations to the light side of character, the Dark Triad seems to be a dyad rather than a triad. PMID- 26966649 TI - Monogenean anchor morphometry: systematic value, phylogenetic signal, and evolution. AB - Background. Anchors are one of the important attachment appendages for monogenean parasites. Common descent and evolutionary processes have left their mark on anchor morphometry, in the form of patterns of shape and size variation useful for systematic and evolutionary studies. When combined with morphological and molecular data, analysis of anchor morphometry can potentially answer a wide range of biological questions. Materials and Methods. We used data from anchor morphometry, body size and morphology of 13 Ligophorus (Monogenea: Ancyrocephalidae) species infecting two marine mugilid (Teleostei: Mugilidae) fish hosts: Moolgarda buchanani (Bleeker) and Liza subviridis (Valenciennes) from Malaysia. Anchor shape and size data (n = 530) were generated using methods of geometric morphometrics. We used 28S rRNA, 18S rRNA, and ITS1 sequence data to infer a maximum likelihood phylogeny. We discriminated species using principal component and cluster analysis of shape data. Adams's K mult was used to detect phylogenetic signal in anchor shape. Phylogeny-correlated size and shape changes were investigated using continuous character mapping and directional statistics, respectively. We assessed morphological constraints in anchor morphometry using phylogenetic regression of anchor shape against body size and anchor size. Anchor morphological integration was studied using partial least squares method. The association between copulatory organ morphology and anchor shape and size in phylomorphospace was used to test the Rohde-Hobbs hypothesis. We created monogeneaGM, a new R package that integrates analyses of monogenean anchor geometric morphometric data with morphological and phylogenetic data. Results. We discriminated 12 of the 13 Ligophorus species using anchor shape data. Significant phylogenetic signal was detected in anchor shape. Thus, we discovered new morphological characters based on anchor shaft shape, the length between the inner root point and the outer root point, and the length between the inner root point and the dent point. The species on M. buchanani evolved larger, more robust anchors; those on L. subviridis evolved smaller, more delicate anchors. Anchor shape and size were significantly correlated, suggesting constraints in anchor evolution. Tight integration between the root and the point compartments within anchors confirms the anchor as a single, fully integrated module. The correlation between male copulatory organ morphology and size with anchor shape was consistent with predictions from the Rohde-Hobbs hypothesis. Conclusions. Monogenean anchors are tightly integrated structures, and their shape variation correlates strongly with phylogeny, thus underscoring their value for systematic and evolutionary biology studies. Our MonogeneaGM R package provides tools for researchers to mine biological insights from geometric morphometric data of speciose monogenean genera. PMID- 26966652 TI - Comparison of three clustering approaches for detecting novel environmental microbial diversity. AB - Discovery of novel diversity in high-throughput sequencing studies is an important aspect in environmental microbial ecology. To evaluate the effects that amplicon clustering methods have on the discovery of novel diversity, we clustered an environmental marine high-throughput sequencing dataset of protist amplicons together with reference sequences from the taxonomically curated Protist Ribosomal Reference (PR(2)) database using three de novo approaches: sequence similarity networks, USEARCH, and Swarm. The potentially novel diversity uncovered by each clustering approach differed drastically in the number of operational taxonomic units (OTUs) and in the number of environmental amplicons in these novel diversity OTUs. Global pairwise alignment comparisons revealed that numerous amplicons classified as potentially novel by USEARCH and Swarm were more than 97% similar to references of PR(2). Using shortest path analyses on sequence similarity network OTUs and Swarm OTUs we found additional novel diversity within OTUs that would have gone unnoticed without further exploiting their underlying network topologies. These results demonstrate that graph theory provides powerful tools for microbial ecology and the analysis of environmental high-throughput sequencing datasets. Furthermore, sequence similarity networks were most accurate in delineating novel diversity from previously discovered diversity. PMID- 26966651 TI - Iflavirus increases its infectivity and physical stability in association with baculovirus. AB - Virus transmission and the prevalence of infection depend on multiple factors, including the interaction with other viral pathogens infecting the same host. In this study, active replication of an iflavirus, Spodoptera exigua iflavirus 1 (order Picornavirales) was observed in the offspring of insects that survived following inoculation with a pathogenic baculovirus, Spodoptera exigua multiple nucleopolyhedrovirus. Tracking the origin of the iflavirus suggested the association of this virus with the occlusion bodies of the baculovirus. Here we investigated the effect of this association on the stability and infectivity of both viruses. A reduction in baculovirus pathogenicity, without affecting its infectivity and productivity, was observed when associated with the iflavirus. In contrast, viral association increased the infectivity of the iflavirus and its resistance to ultraviolet radiation and high temperature, two of the main factors affecting virus stability in the field. In addition, electron microscopy analysis revealed the presence of particles resembling iflavirus virions inside the occlusion bodies of the baculovirus, suggesting the possible co-occlusion of both viruses. Results reported here are indicative of facultative phoresis of a virus and suggest that virus-virus interactions may be more common than currently recognized, and may be influential in the ecology of baculovirus and host populations and in consequence in the use of baculoviruses as biological insecticides. PMID- 26966653 TI - Broad-scale sampling of primary freshwater fish populations reveals the role of intrinsic traits, inter-basin connectivity, drainage area and latitude on shaping contemporary patterns of genetic diversity. AB - Background. Worldwide predictions suggest that up to 75% of the freshwater fish species occurring in rivers with reduced discharge could be extinct by 2070 due to the combined effect of climate change and water abstraction. The Mediterranean region is considered to be a hotspot of freshwater fish diversity but also one of the regions where the effects of climate change will be more severe. Iberian cyprinids are currently highly endangered, with over 68% of the species raising some level of conservation concern. Methods. During the FISHATLAS project, the Portuguese hydrographical network was extensively covered (all the 34 river basins and 47 sub-basins) in order to contribute with valuable data on the genetic diversity distribution patterns of native cyprinid species. A total of 188 populations belonging to 16 cyprinid species of Squalius, Luciobarbus, Achondrostoma, Iberochondrostoma, Anaecypris and Pseudochondrostoma were characterized, for a total of 3,678 cytochrome b gene sequences. Results. When the genetic diversity of these populations was mapped, it highlighted differences among populations from the same species and between species with identical distribution areas. Factors shaping the contemporary patterns of genetic diversity were explored and the results revealed the role of latitude, inter basin connectivity, migratory behaviour, species maximum size, species range and other species intrinsic traits in determining the genetic diversity of sampled populations. Contrastingly, drainage area and hydrological regime (permanent vs. temporary) seem to have no significant effect on genetic diversity. Species intrinsic traits, maximum size attained, inter-basin connectivity and latitude explained over 30% of the haplotype diversity variance and, generally, the levels of diversity were significantly higher for smaller sized species, from connected and southerly river basins. Discussion. Targeting multiple co-distributed species of primary freshwater fish allowed us to assess the relative role of historical versus contemporary factors affecting genetic diversity. Since different patterns were detected for species with identical distribution areas we postulate that contemporary determinants of genetic diversity (species' intrinsic traits and landscape features) must have played a more significant role than historical factors. Implications for conservation in a context of climate change and highly disturbed habitats are detailed, namely the need to focus management and conservation actions on intraspecific genetic data and to frequently conduct combined genetic and demographic surveys. PMID- 26966654 TI - Sexual behaviour and risk of sexually transmitted infections in young female healthcare students in Spain. AB - Background. Several authors have examined the risk for sexually transmitted infections (STI), but no study has yet analyzed it solely in relation with sexual behaviour in women. We analyzed the association of sexual behaviour with STI risk in female university students of healthcare sciences. Methods. We designed a cross-sectional study assessing over three months vaginal intercourse with a man. The study involved 175 female university students, without a stable partner, studying healthcare sciences in Spain. MAIN OUTCOME VARIABLE: STI risk (not always using male condoms). Secondary variables: sexual behaviour, method of orgasm, desire to increase the frequency of sexual relations, desire to have more variety in sexual relations, frequency of sexual intercourse with the partner, and age. The information was collected with an original questionnaire. A logistic regression model was used to estimate the adjusted odds ratios (ORs) in order to analyze the association between the STI risk and the study variables. Results. Of the 175 women, 52 were positive for STI risk (29.7%, 95% CI [22.9-36.5%]). Factors significantly associated with STI risk (p < 0.05) included: orgasm (not having orgasms ->OR = 7.01, 95% CI [1.49-33.00]; several methods ->OR = 0.77, 95% CI [0.31-1.90]; one single method ->OR = 1; p = 0.008) and desiring an increased frequency of sexual activities (OR = 0.27, 95% CI [0.13-0.59], p < 0.001). Conclusions. Women's desire for sexual activities and their sexual function were significant predictors of their risk for STI. Information about sexual function is an intrinsic aspect of sexual behaviour and should be taken into consideration when seeking approaches to reduce risks for STI. PMID- 26966655 TI - A systematic review of pediatric clinical trials of high dose vitamin D. AB - Background. Due to inadequate UV exposure, intake of small quantities of vitamin D is recommended to prevent musculoskeletal disease. Both basic science and observational literature strongly suggest that higher doses may benefit specific populations and have non-musculoskeletal roles. Evaluating the evidence surrounding high dose supplementation can be challenging given a relatively large and growing body of clinical trial evidence spanning time, geography, populations and dosing regimens. Study objectives were to identify and summarize the clinical trial literature, recognize areas with high quality evidence, and develop a resource database that makes the literature more immediately accessible to end users. Methods. Medline (1946 to January 2015), Embase (1974 to January 2015), and Cochrane databases (January 2015), were searched for trials. All pediatric (0 18 years) trials administering doses higher than 400 IU (<1 year) or 600 IU (>=1 year) were included. Data was extracted independently by two of the authors. An online searchable database of trials was developed containing relevant extracted information (http://www.cheori.org/en/pedvitaminddatabaseOverview). Sensitivity and utility were assessed by comparing the trials in the database with those from systematic reviews of vitamin D supplementation including children. Results. A total of 2,579 candidate papers were identified, yielding 169 trials having one or more arms meeting eligibility criteria. The publication rate has increased significantly from 1 per year (1970-1979) to 14 per year (2010-2015). Although 84% of the total trials focused on healthy children or known high risk populations (e.g., renal, prematurity), this proportion has declined in recent years due to the rise in trials evaluating populations and outcomes not directly related to the musculoskeletal actions of vitamin D (27% in 2010s). Beyond healthy children, the only pediatric populations with more than 50 participants from low risk of bias trials evaluating a clinically relevant outcome were prematurity and respiratory illness. Finally, we created and validated the online searchable database using 13 recent systematic reviews. Of the 38 high dose trials identified by the systematic review, 36 (94.7%) could be found within the database. When compared with the search strategy reported in each systematic review, use of the database reduced the number of full papers to assess for eligibility by 85.2% (+/-13.4%). Conclusion. The pediatric vitamin D field is highly active, with a significant increase in trials evaluating non-classical diseases and outcomes. Despite the large overall number there are few high quality trials of sufficient size to provide answers on clinical efficacy of high dose vitamin D. An open access online searchable data should assist end users in the rapid and comprehensive identification and evaluation of trials relevant to their population or question of interest. PMID- 26966656 TI - Head capsule stacking by caterpillars: morphology complements behaviour to provide a novel defence. AB - Herbivores employ a variety of chemical, behavioural and morphological defences to reduce mortality from natural enemies. In some caterpillars the head capsules of successive instars are retained and stacked on top of each other and it has been suggested that this could serve as a defence against natural enemies. We tested this hypothesis by comparing the survival of groups of the gumleaf skeletoniser Uraba lugens Walker caterpillars, allocated to one of three treatments: "-HC," where stacked head capsules were removed from all individuals, "+HC," where the caterpillars retained their stacked head capsules, and "mixed," where only half of the caterpillars in a group had their stacked head capsules removed. We found no difference in predation rate between the three treatments, but within the mixed treatment, caterpillars with head capsules were more than twice as likely to survive. During predator choice trials, conducted to observe how head capsule stacking acts as a defence, the predatory pentatomid bug attacked the -HC caterpillar in four out of six trials. The two attacks on +HC caterpillars took over 10 times longer because the bug would poke its rostrum through the head capsule stack, while the caterpillar used its head capsule stack to deflect the bug's rostrum. Our results support the hypothesis that the retention of moulted head capsules by U. lugens provides some protection against their natural enemies and suggest that this is because stacked head capsules can function as a false target for natural enemies as well as a weapon to fend off attackers. This represents the first demonstration of a defensive function. PMID- 26966658 TI - A comparison of clustering methods for biogeography with fossil datasets. AB - Cluster analysis is one of the most commonly used methods in palaeoecological studies, particularly in studies investigating biogeographic patterns. Although a number of different clustering methods are widely used, the approach and underlying assumptions of many of these methods are quite different. For example, methods may be hierarchical or non-hierarchical in their approaches, and may use Euclidean distance or non-Euclidean indices to cluster the data. In order to assess the effectiveness of the different clustering methods as compared to one another, a simulation was designed that could assess each method over a range of both cluster distinctiveness and sampling intensity. Additionally, a non hierarchical, non-Euclidean, iterative clustering method implemented in the R Statistical Language is described. This method, Non-Euclidean Relational Clustering (NERC), creates distinct clusters by dividing the data set in order to maximize the average similarity within each cluster, identifying clusters in which each data point is on average more similar to those within its own group than to those in any other group. While all the methods performed well with clearly differentiated and well-sampled datasets, when data are less than ideal the linkage methods perform poorly compared to non-Euclidean based k-means and the NERC method. Based on this analysis, Unweighted Pair Group Method with Arithmetic Mean and neighbor joining methods are less reliable with incomplete datasets like those found in palaeobiological analyses, and the k-means and NERC methods should be used in their place. PMID- 26966657 TI - New phiomorph rodents from the latest Eocene of Egypt, and the impact of Bayesian "clock"-based phylogenetic methods on estimates of basal hystricognath relationships and biochronology. AB - The Fayum Depression of Egypt has yielded fossils of hystricognathous rodents from multiple Eocene and Oligocene horizons that range in age from ~37 to ~30 Ma and document several phases in the early evolution of crown Hystricognathi and one of its major subclades, Phiomorpha. Here we describe two new genera and species of basal phiomorphs, Birkamys korai and Mubhammys vadumensis, based on rostra and maxillary and mandibular remains from the terminal Eocene (~34 Ma) Fayum Locality 41 (L-41). Birkamys is the smallest known Paleogene hystricognath, has very simple molars, and, like derived Oligocene-to-Recent phiomorphs (but unlike contemporaneous and older taxa) apparently retained dP(4)/4 late into life, with no evidence for P(4)/4 eruption or formation. Mubhammys is very similar in dental morphology to Birkamys, and also shows no evidence for P(4)/4 formation or eruption, but is considerably larger. Though parsimony analysis with all characters equally weighted places Birkamys and Mubhammys as sister taxa of extant Thryonomys to the exclusion of much younger relatives of that genus, all other methods (standard Bayesian inference, Bayesian "tip-dating," and parsimony analysis with scaled transitions between "fixed" and polymorphic states) place these species in more basal positions within Hystricognathi, as sister taxa of Oligocene-to-Recent phiomorphs. We also employ tip-dating as a means for estimating the ages of early hystricognath-bearing localities, many of which are not well-constrained by geological, geochronological, or biostratigraphic evidence. By simultaneously taking into account phylogeny, evolutionary rates, and uniform priors that appropriately encompass the range of possible ages for fossil localities, dating of tips in this Bayesian framework allows paleontologists to move beyond vague and assumption-laden "stage of evolution" arguments in biochronology to provide relatively rigorous age assessments of poorly-constrained faunas. This approach should become increasingly robust as estimates are combined from multiple independent analyses of distantly related clades, and is broadly applicable across the tree of life; as such it is deserving of paleontologists' close attention. Notably, in the example provided here, hystricognathous rodents from Libya and Namibia that are controversially considered to be of middle Eocene age are instead estimated to be of late Eocene and late Oligocene age, respectively. Finally, we reconstruct the evolution of first lower molar size among Paleogene African hystricognaths using a Bayesian approach; the results of this analysis reconstruct a rapid latest Eocene dwarfing event along the lineage leading to Birkamys. PMID- 26966659 TI - Identifying key conservation threats to Alpine birds through expert knowledge. AB - Alpine biodiversity is subject to a range of increasing threats, but the scarcity of data for many taxa means that it is difficult to assess the level and likely future impact of a given threat. Expert opinion can be a useful tool to address knowledge gaps in the absence of adequate data. Experts with experience in Alpine ecology were approached to rank threat levels for 69 Alpine bird species over the next 50 years for the whole European Alps in relation to ten categories: land abandonment, climate change, renewable energy, fire, forestry practices, grazing practices, hunting, leisure, mining and urbanization. There was a high degree of concordance in ranking of perceived threats among experts for most threat categories. The major overall perceived threats to Alpine birds identified through expert knowledge were land abandonment, urbanization, leisure and forestry, although other perceived threats were ranked highly for particular species groups (renewable energy and hunting for raptors, hunting for gamebirds). For groups of species defined according to their breeding habitat, open habitat species and treeline species were perceived as the most threatened. A spatial risk assessment tool based on summed scores for the whole community showed threat levels were highest for bird communities of the northern and western Alps. Development of the approaches given in this paper, including addressing biases in the selection of experts and adopting a more detailed ranking procedure, could prove useful in the future in identifying future threats, and in carrying out risk assessments based on levels of threat to the whole bird community. PMID- 26966660 TI - Bioinformatics analysis identifies several intrinsically disordered human E3 ubiquitin-protein ligases. AB - The ubiquitin-proteasome system targets misfolded proteins for degradation. Since the accumulation of such proteins is potentially harmful for the cell, their prompt removal is important. E3 ubiquitin-protein ligases mediate substrate ubiquitination by bringing together the substrate with an E2 ubiquitin conjugating enzyme, which transfers ubiquitin to the substrate. For misfolded proteins, substrate recognition is generally delegated to molecular chaperones that subsequently interact with specific E3 ligases. An important exception is San1, a yeast E3 ligase. San1 harbors extensive regions of intrinsic disorder, which provide both conformational flexibility and sites for direct recognition of misfolded targets of vastly different conformations. So far, no mammalian ortholog of San1 is known, nor is it clear whether other E3 ligases utilize disordered regions for substrate recognition. Here, we conduct a bioinformatics analysis to examine >600 human and S. cerevisiae E3 ligases to identify enzymes that are similar to San1 in terms of function and/or mechanism of substrate recognition. An initial sequence-based database search was found to detect candidates primarily based on the homology of their ordered regions, and did not capture the unique disorder patterns that encode the functional mechanism of San1. However, by searching specifically for key features of the San1 sequence, such as long regions of intrinsic disorder embedded with short stretches predicted to be suitable for substrate interaction, we identified several E3 ligases with these characteristics. Our initial analysis revealed that another remarkable trait of San1 is shared with several candidate E3 ligases: long stretches of complete lysine suppression, which in San1 limits auto ubiquitination. We encode these characteristic features into a San1 similarity score, and present a set of proteins that are plausible candidates as San1 counterparts in humans. In conclusion, our work indicates that San1 is not a unique case, and that several other yeast and human E3 ligases have sequence properties that may allow them to recognize substrates by a similar mechanism as San1. PMID- 26966661 TI - The origin of the medial circumflex femoral artery: a meta-analysis and proposal of a new classification system. AB - Background and Objectives. The medial circumflex femoral artery (MCFA) is a common branch of the deep femoral artery (DFA) responsible for supplying the femoral head and the greater trochanteric fossa. The prevalence rates of MCFA origin, its branching patterns and its distance to the mid-inguinal point (MIP) vary significantly throughout the literature. The aim of this study was to determine the true prevalence of these characteristics and to study their associated anatomical and clinical relevance. Methods. A search of the major electronic databases Pubmed, EMBASE, Scopus, ScienceDirect, Web of Science, SciELO, BIOSIS, and CNKI was performed to identify all articles reporting data on the origin of the MCFA, its branching patterns and its distance to the MIP. No data or language restriction was set. Additionally, an extensive search of the references of all relevant articles was performed. All data on origin, branching and distance to MIP was extracted and pooled into a meta-analysis using MetaXL v2.0. Results. A total of 38 (36 cadaveric and 2 imaging) studies (n = 4,351 lower limbs) were included into the meta-analysis. The pooled prevalence of the MCFA originating from the DFA was 64.6% (95% CI [58.0-71.5]), while the pooled prevalence of the MCFA originating from the CFA was 32.2% (95% CI [25.9-39.1]). The CFA-derived MCFA was found to originate as a single branch in 81.1% (95% CI [70.1-91.7]) of cases with a mean pooled distance of 50.14 mm (95% CI [42.50 57.78]) from the MIP. Conclusion. The MCFA's variability must be taken into account by surgeons, especially during orthopedic interventions in the region of the hip to prevent iatrogenic injury to the circulation of the femoral head. Based on our analysis, we present a new proposed classification system for origin of the MCFA. PMID- 26966662 TI - A hierarchical model of daily stream temperature using air-water temperature synchronization, autocorrelation, and time lags. AB - Water temperature is a primary driver of stream ecosystems and commonly forms the basis of stream classifications. Robust models of stream temperature are critical as the climate changes, but estimating daily stream temperature poses several important challenges. We developed a statistical model that accounts for many challenges that can make stream temperature estimation difficult. Our model identifies the yearly period when air and water temperature are synchronized, accommodates hysteresis, incorporates time lags, deals with missing data and autocorrelation and can include external drivers. In a small stream network, the model performed well (RMSE = 0.59 degrees C), identified a clear warming trend (0.63 degrees C decade(-1)) and a widening of the synchronized period (29 d decade(-1)). We also carefully evaluated how missing data influenced predictions. Missing data within a year had a small effect on performance (~0.05% average drop in RMSE with 10% fewer days with data). Missing all data for a year decreased performance (~0.6 degrees C jump in RMSE), but this decrease was moderated when data were available from other streams in the network. PMID- 26966663 TI - Familiarity breeds content: assessing bird species popularity with culturomics. AB - Understanding public perceptions of biodiversity is essential to ensure continued support for conservation efforts. Despite this, insights remain scarce at broader spatial scales, mostly due to a lack of adequate methods for their assessment. The emergence of new technologies with global reach and high levels of participation provide exciting new opportunities to study the public visibility of biodiversity and the factors that drive it. Here, we use a measure of internet saliency to assess the national and international visibility of species within four taxa of Brazilian birds (toucans, hummingbirds, parrots and woodpeckers), and evaluate how much of this visibility can be explained by factors associated with familiarity, aesthetic appeal and conservation interest. Our results strongly indicate that familiarity (human population within the range of a species) is the most important factor driving internet saliency within Brazil, while aesthetic appeal (body size) best explains variation in international saliency. Endemism and conservation status of a species had small, but often negative, effects on either metric of internet saliency. While further studies are needed to evaluate the relationship between internet content and the cultural visibility of different species, our results strongly indicate that internet saliency can be considered as a broad proxy of cultural interest. PMID- 26966664 TI - Global miRNA expression is temporally correlated with acute kidney injury in mice. AB - MicroRNAs (miRNAs) are negative regulators of gene expression and protein abundance. Current evidence shows an association of miRNAs with acute kidney injury (AKI) leading to substantially increased morbidity and mortality. Here, we investigated whether miRNAs are inductive regulators responsible for the pathological development of AKI. Microarray analysis was used to detect temporal changes in global miRNA expression within 48 h after AKI in mice. Results indicated that global miRNA expression gradually increased over 24 h from ischemia reperfusion injury after 24 h, and then decreased from 24 h to 48 h. A similar trend was observed for the index of tubulointerstitial injury and the level of serum creatinine, and there was a significant correlation between the level of total miRNA expression and the level of serum creatinine (p < 0.05). This expression-phenotype correlation was validated by quantitative reverse transcription PCR on individual miRNAs, including miR-18a, -134, -182, -210 and 214. Increased global miRNA expression may lead to widespread translational repression and reduced cellular activity. Furthermore, significant inflammatory cytokine release and peritubular capillary loss were observed, suggesting that the initiation of systematic destruction programs was due to AKI. Our findings provide new understanding of the dominant role of miRNAs in promoting the pathological development of AKI. PMID- 26966665 TI - An examination of clinical differences between carriers and non-carriers of chromosome 8q24 risk alleles in a New Zealand Caucasian population with prostate cancer. AB - Background. Prostate cancer makes up approximately 15% of all cancers diagnosed in men in developed nations and approximately 4% of cases in developing nations. Although it is clear that prostate cancer has a genetic component and single nucleotide polymorphisms (SNPs) can contribute to prostate cancer risk, detecting associations is difficult in multi-factorial diseases, as environmental and lifestyle factors also play a role. In this study, specific clinical characteristics, environmental factors and genetic risk factors were assessed for interaction with prostate cancer. Methods. A total of 489 prostate cancer cases and 427 healthy controls were genotyped for SNPs found on chromosome 8q24 and a genetic risk score was calculated. In addition the SNPs were tested for an association with a number of clinical and environmental factors. Results. Age and tobacco use were positively associated, whilst alcohol consumption was negatively associated with prostate cancer risk. The following SNPs found on chromosome 8q24 were statistically significantly associated with prostate cancer: rs10086908, rs16901979; rs1447295and rs4242382. No association between Gleason score and smoking status, or between Gleason score and genotype were detected. Conclusion. A genetic risk score was calculated based on the 15 SNPs tested and found to be significantly associated with prostate cancer risk. Smoking significantly contributed to the risk of developing prostate cancer, and this risk was further increased by the presence of four SNPs in the 8q24 chromosomal region. PMID- 26966666 TI - Potential contribution of fish restocking to the recovery of deteriorated coral reefs: an alternative restoration method? AB - Counteracting the worldwide trend of coral reef degeneration is a major challenge for the scientific community. A crucial management approach to minimizing stress effects on healthy reefs and helping the recovery of disturbed reefs is reef protection. However, the current rapid decline of the world's reefs suggests that protection might be insufficient as a viable stand-alone management approach for some reefs. We thus suggest that the ecological restoration of coral reefs (CRR) should be considered as a valid component of coral reef management, in addition to protection, if the applied method is economically applicable and scalable. This theoretical study examines the potential applicability and outcomes of restocking grazers as a restoration tool for coral reef recovery-a tool that has not been applied so far in reef restoration projects. We studied the effect of restocking grazing fish as a restoration method using a mathematical model of degrading reefs, and analyzed the financial outcomes of the restocking intervention. The results suggest that applying this restoration method, in addition to protection, can facilitate reef recovery. Moreover, our analysis suggests that the restocking approach almost always becomes profitable within several years. Considering the relatively low cost of this restoration approach and the feasibility of mass production of herbivorous fish, we suggest that this approach should be considered and examined as an additional viable restoration tool for coral reefs. PMID- 26966667 TI - Attitudes towards preventive tuberculosis treatment among hospital staff. AB - Background. Healthcare workers have an increased risk of latent tuberculosis infection (LTBI), but previous studies suggested that they might be reluctant to accept preventive tuberculosis (TB) treatment. We aimed to examine doctors' and nurses' experience of TB screening and to explore their attitudes towards preventive TB treatment. Methods. We conducted a survey among randomly selected healthcare workers at a tertiary hospital in Sydney, Australia, using a paper based questionnaire. Results. A total of 1,304 questionnaires were distributed and 311 (24%) responses were received. The majority of hospital staff supported preventive TB treatment in health care workers with evidence of latent TB infection (LTBI) in general (74%, 164/223) and for them personally (81%, 198/244) while 80 and 53 healthcare workers respectively had no opinion on the topic. Staff working in respiratory medicine were significantly less likely to support preventive TB treatment in health care workers in general or for them personally if they would have evidence of LTBI compared to other specialties (p = 0.001). Only 13% (14/106) of respondents with evidence of LTBI indicated that they had been offered preventive TB treatment. Twenty-one percent (64/306) of respondents indicated that they did not know the difference between active and latent TB. Among staff who had undergone testing for LTBI, only 33% (75/230) felt adequately informed about the meaning of their test results. Discussion. Hospital staff in general had positive attitudes towards preventive TB treatment, but actual treatment rates were low and perceived knowledge about LTBI was insufficient among a significant proportion of staff. The gap between high support for preventive TB treatment among staff and low treatment rates needs to be addressed. Better education on the concept of LTBI and the meaning of screening test results is required. PMID- 26966668 TI - Metamorphosis of the invasive ascidian Ciona savignyi: environmental variables and chemical exposure. AB - In this study, the effects of environmental variables on larval metamorphosis of the solitary ascidian Ciona savignyi were investigated in a laboratory setting. The progression of metamorphic changes were tracked under various temperature, photoperiod, substrate, larval density, and vessel size regimes. Metamorphosis was maximised at 18 degrees C, 12:12 h subdued light:dark, smooth polystyrene substrate, and 10 larvae mL(-1) in a twelve-well tissue culture plate. Eliminating the air-water interface by filling culture vessels to capacity further increased the proportion of metamorphosed larvae; 87 +/- 5% of larvae completed metamorphosis within 5 days compared to 45 +/- 5% in control wells. The effects of the reference antifouling compounds polygodial, portimine, oroidin, chlorothalonil, and tolylfluanid on C. savignyi were subsequently determined, highlighting (1) the sensitivity of C. savignyi metamorphosis to chemical exposure and (2) the potential to use C. savignyi larvae to screen for bioactivity in an optimised laboratory setting. The compounds were bioactive in the low ng mL(-1) to high ug mL(-1) range. Polygodial was chosen for additional investigations, where it was shown that mean reductions in the proportions of larvae reaching stage E were highly repeatable both within (repeatability = 14 +/ 9%) and between (intermediate precision = 17 +/- 3%) independent experiments. An environmental extract had no effect on the larvae but exposing larvae to both the extract and polygodial reduced potency relative to polygodial alone. This change in potency stresses the need for caution when working with complex samples, as is routinely implemented when isolating natural compounds from their biological source. Overall, the outcomes of this study highlight the sensitivity of C. savignyi metamorphosis to environmental variations and chemical exposure. PMID- 26966669 TI - Increasing land use drives changes in plant phylogenetic diversity and prevalence of specialists. AB - Increased human land use has resulted in the increased homogenization of biodiversity between sites, yet we lack sufficient indicators to predict which species decline and the consequence of their potential loss on ecosystem services. We used comparative phylogenetic analysis to (1) characterize how increasing conversion of forest and grasslands to grazing pasturelands changes plant diversity and composition; (2) examine how changes in land use relate to declines in functional trait diversity; and (3) specifically investigate how these changes in plant composition affect the prevalence of zygomorphy and the possible consequences that these changes may have on pollinator functional groups. As predicted, we found that the conversion to grazing pasturelands negatively impacted species richness and phylogenetic composition. Clades with significantly more represented taxa in grasslands (GL) were genera with a high representation of agricultural weeds, while the composition was biased towards clades of subalpine herbaceous wildflowers in Mixed Forest (MF). Changes in community composition and structure had strong effects on the prevalence of zygomorphic species likely driven by nitrogen-fixing abilities of certain clades with zygomorphic flowers (e.g., Fabaceae). Land conversion can thus have unexpected impacts on trait distributions relevant for the functioning of the community in other capacities (e.g., cascading effects to other trophic levels (i.e., pollinators). Finally, the combination of traits represented by the current composition of species in GL and MF might enhance the diagnostic value of productivity and ecosystem processes in the most eroded ecosystems. PMID- 26966670 TI - Looking upstream: enhancers of child nutritional status in post-flood rural settings. AB - Background. Child undernutrition and flooding are highly prevalent public health issues in many developing countries, yet we have little understanding of preventive strategies for effective coping in these circumstances. Education has been recently highlighted as key to reduce the societal impacts of extreme weather events under climate change, but there is a lack of studies assessing to what extent parental education may prevent post-flood child undernutrition. Methods and Materials. One year after large floods in 2008, we conducted a two stage cluster population-based survey of 6-59 months children inhabiting flooded and non-flooded communities of Jagatsinghpur district, Odisha (India), and collected anthropometric measurements on children along with child, parental and household level variables through face-to-face interviews. Using multivariate logistic regression models, we examined separately the effect of maternal and paternal education and other risk factors (mainly income, socio-demographic, and child and mother variables) on stunting and wasting in children from households inhabiting recurrently flooded communities (2006 and 2008; n = 299). As a comparison, separate analyses on children in non-flooded communities were carried out (n = 385). All analyses were adjusted by income as additional robustness check. Results. Overall, fathers with at least completed middle education (up to 14 years of age and compulsory in India) had an advantage in protecting their children from child wasting and stunting. For child stunting, the clearest result was a 100-200% lower prevalence associated with at least paternal secondary schooling (compared to no schooling) in flooded-areas. Again, only in flooded communities, an increase in per capita annual household income of 1,000 rupees was associated to a 4.7-4.9% lower prevalence of child stunting. For child wasting in flooded areas, delayed motherhood was associated to better nutritional outcomes (3.4% lower prevalence per year). In flooded communities, households dedicated to activities other than agriculture, a 50-51% lower prevalence of child wasting was estimated, suggesting farmers and fishermen as the most vulnerable livelihoods under flooding. In flooded areas, lower rank castes were at higher odds of both child wasting and stunting. Conclusions. In the short term, protracted nutritional response in the aftermath of floods should be urgently implemented and target agricultural livelihoods and low-rank castes. Education promotion and schooling up to 14 years should have positive impacts on improving children nutritional health in the long run, especially under flooding. Policies effectively helping sustainable livelihood economic development and delayed motherhood are also recommended. PMID- 26966671 TI - The pretreatment albumin to globulin ratio predicts survival in patients with natural killer/T-cell lymphoma. AB - Background. The pretreatment albumin to globulin ratio (AGR) has been reported to be a predictor of survival in several types of cancer. The aim of this study was to evaluate the prognostic impact of AGR in patients with natural killer/T-cell lymphoma (NKTCL). Methods. We retrospectively reviewed the available serum biochemistry results for 331 NKTCL patients before treatment. AGR was calculated as albumin/(total protein-albumin), and a cut-off value of 1.3 was used to define AGR as low or high. Survival analysis was used to assess the prognostic value of AGR. Results. A low AGR (<1.3) was associated with significantly more adverse clinical features, including old age, poor performance status, advanced stage, elevated lactate dehydrogenase, B symptoms, and high International Prognostic Index (IPI) and natural killer/T-cell lymphoma prognostic index (NKPI) scores. Patients with a low AGR had a significantly lower 5-year overall survival (44.5 vs. 65.2%, P < 0.001) and progression-free survival (33.1 vs. 57.4%, P < 0.001). In the multivariate analysis, a low AGR remained an independent predictor of poorer survival. Additionally, AGR distinguished patients with different outcomes in the IPI low-risk group and in the NKPI high-risk group. Discussion. Pretreatment AGR may serve as a simple and effective predictor of prognosis in patients with NKTCL. PMID- 26966672 TI - Distinguishing between enamel fluorosis and other enamel defects in permanent teeth of children. AB - Background. The inconsistent prevalence of fluorosis for a given level of fluoride in drinking water suggests developmental defects of enamel (DDEs) other than fluorosis were being misdiagnosed as fluorosis. The imprecise definition and subjective perception of fluorosis indices could result in misdiagnosis of dental fluorosis. This study was conducted to distinguish genuine fluorosis from fluorosis-resembling defects that could have adverse health-related events as a cause using Early Childhood Events Life-grid method (ECEL). Methods. A study was conducted on 400 9-year-old children from areas with high, optimal and low levels of fluoride in the drinking water of Fars province, Iran. Fluorosis cases were diagnosed on the standardized one view photographs of the anterior teeth using Dean's and TF (Thylstrup and Fejerskov) Indices by calibrated dentists. Agreements between examiners were tested. Early childhood health-related data collected retrospectively by ECEL method were matched with the position of enamel defects. Results. Using both Dean and TF indices three out of four dentists diagnosed that 31.3% (115) children had fluorosis, 58.0%, 29.1%, and 10.0% in high (2.12-2.85 ppm), optimal (0.62-1.22 ppm), and low (0.24-0.29 ppm) fluoride areas respectively (p < 0.001). After matching health-related events in the 115 (31.3%) of children diagnosed with fluorosis, 31 (8.4%) of children had fluorosis which could be matched with their adverse health-related events. This suggests that what was diagnosed as fluorosis were non-fluoride related DDEs that resemble fluorosis. Discussion. The frequently used measures of fluorosis appear to overscore fluorosis. Use of ECEL method to consider health related events relevant to DDEs could help to differentiate between genuine fluorosis and fluorosis-resembling defects. PMID- 26966673 TI - The (mis)measurement of the Dark Triad Dirty Dozen: exploitation at the core of the scale. AB - Background. The dark side of human character has been conceptualized in the Dark Triad Model: Machiavellianism, psychopathy, and narcissism. These three dark traits are often measured using single long instruments for each one of the traits. Nevertheless, there is a necessity of short and valid personality measures in psychological research. As an independent research group, we replicated the factor structure, convergent validity and item response for one of the most recent and widely used short measures to operationalize these malevolent traits, namely, Jonason's Dark Triad Dirty Dozen. We aimed to expand the understanding of what the Dirty Dozen really captures because the mixed results on construct validity in previous research. Method. We used the largest sample to date to respond to the Dirty Dozen (N = 3,698). We firstly investigated the factor structure using Confirmatory Factor Analysis and an exploratory distribution analysis of the items in the Dirty Dozen. Secondly, using a sub sample (n = 500) and correlation analyses, we investigated the Dirty Dozen dark traits convergent validity to Machiavellianism measured by the Mach-IV, psychopathy measured by Eysenck's Personality Questionnaire Revised, narcissism using the Narcissism Personality Inventory, and both neuroticism and extraversion from the Eysenck's questionnaire. Finally, besides these Classic Test Theory analyses, we analyzed the responses for each Dirty Dozen item using Item Response Theory (IRT). Results. The results confirmed previous findings of a bi-factor model fit: one latent core dark trait and three dark traits. All three Dirty Dozen traits had a striking bi-modal distribution, which might indicate unconcealed social undesirability with the items. The three Dirty Dozen traits did converge too, although not strongly, with the contiguous single Dark Triad scales (r between .41 and .49). The probabilities of filling out steps on the Dirty Dozen narcissism-items were much higher than on the Dirty Dozen items for Machiavellianism and psychopathy. Overall, the Dirty Dozen instrument delivered the most predictive value with persons with average and high Dark Triad traits (theta > -0.5). Moreover, the Dirty Dozen scale was better conceptualized as a combined Machiavellianism-psychopathy factor, not narcissism, and is well captured with item 4: 'I tend to exploit others towards my own end.' Conclusion. The Dirty Dozen showed a consistent factor structure, a relatively convergent validity similar to that found in earlier studies. Narcissism measured using the Dirty Dozen, however, did not contribute with information to the core of the Dirty Dozen construct. More importantly, the results imply that the core of the Dirty Dozen scale, a manipulative and anti-social trait, can be measured by a Single Item Dirty Dark Dyad (SIDDD). PMID- 26966674 TI - How do colonial Eurasian Griffon Vultures prevent extra-pair mating? AB - In colonial breeding species, preventive measures to reduce the risks of extra pair copulations (EPCs) should reflect the actual risk perceived by males (e.g., proximity of neighbors, intrusions into the nest) mainly during the fertile period. In colonial vultures, specific studies examining the preventive measures that minimize the risks of EPCs occurring within the competitive context of colonial breeding have not been conducted. Here we tested at Eurasian Griffon Vulture (Gyps fulvus) nesting sites the intensity of paternity assurance behavior, shown as frequency and duration of within-pair copulations (WPCs), potential mate vigilance or nest attendance, and levels of aggressivity. This was measured according to the frequency of territorial intrusions and comparison of the fertile vs. the non-fertile period. Our findings suggest that the frequency of WPCs and their duration increased significantly during the presumed fertile period, regarded as the period when Griffon pairs spent significantly more time together at their nests. In addition, low levels of territorial intrusions were observed, an aggressive response of pairs towards intruders, and a relatively high presence of pairs at the nests during the fertile period. Thus, although nesting sites are subject to low exposure to EPC attempts, the increased frequency and duration of copulations during the fertile period suggests that, under pressure from the colonial breeding system, a higher rate of copulations is the most effective preventive mechanism against relative uncertainty of paternity. PMID- 26966675 TI - A large abelisaurid (Dinosauria, Theropoda) from Morocco and comments on the Cenomanian theropods from North Africa. AB - We describe the partially preserved femur of a large-bodied theropod dinosaur from the Cenomanian "Kem Kem Compound Assemblage" (KKCA) of Morocco. The fossil is housed in the Museo Geologico e Paleontologico "Gaetano Giorgio Gemmellaro" in Palermo (Italy). The specimen is compared with the theropod fossil record from the KKCA and coeval assemblages from North Africa. The combination of a distally reclined head, a not prominent trochanteric shelf, distally placed lesser trochanter of stout, alariform shape, a stocky shaft with the fourth trochanter placed proximally, and rugose muscular insertion areas in the specimen distinguishes it from Carcharodontosaurus, Deltadromeus and Spinosaurus and supports referral to an abelisaurid. The estimated body size for the individual from which this femur was derived is comparable to Carnotaurus and Ekrixinatosaurus (up to 9 meters in length and 2 tons in body mass). This find confirms that abelisaurids had reached their largest body size in the "middle Cretaceous," and that large abelisaurids coexisted with other giant theropods in Africa. We review the taxonomic status of the theropods from the Cenomanian of North Africa, and provisionally restrict the Linnean binomina Carcharodontosaurus iguidensis and Spinosaurus aegyptiacus to the type specimens. Based on comparisons among the theropod records from the Aptian-Cenomanian of South America and Africa, a partial explanation for the so-called "Stromer's riddle" (namely, the coexistence of many large predatory dinosaurs in the "middle Cretaceous" record from North Africa) is offered in term of taphonomic artifacts among lineage records that were ecologically and environmentally non-overlapping. Although morphofunctional and stratigraphic evidence supports an ecological segregation between spinosaurids and the other lineages, the co-occurrence of abelisaurids and carcharodontosaurids, two groups showing several craniodental convergences that suggest direct resource competition, remains to be explained. PMID- 26966677 TI - Genetic structure of the threatened West-Pannonian population of Great Bustard (Otis tarda). AB - The genetic diversity, population structure and gene flow of the Great Bustards (Otis tarda) living in Austria-Slovakia-West Hungary (West-Pannonian region), one of the few populations of this globally threatened species that survives across the Palaearctic, has been assessed for the first time in this study. Fourteen recently developed microsatellite loci identified one single population in the study area, with high values of genetic diversity and gene flow between two different genetic subunits. One of these subunits (Heideboden) was recognized as a priority for conservation, as it could be crucial to maintain connectivity with the central Hungarian population and thus contribute to keeping contemporary genetic diversity. Current conservation efforts have been successful in saving this threatened population from extinction two decades ago, and should continue to guarantee its future survival. PMID- 26966676 TI - Cell cycle progression in glioblastoma cells is unaffected by pathophysiological levels of hypoxia. AB - Hypoxia is associated with the increased malignancy of a broad range of solid tumours. While very severe hypoxia has been widely shown to induce cell cycle arrest, the impact of pathophysiological hypoxia on tumour cell proliferation is poorly understood. The aim of this study was to investigate the effect of different oxygen levels on glioblastoma (GBM) cell proliferation and survival. GBM is an extremely aggressive brain tumour with a heterogeneous oxygenation pattern. The effects of a range of oxygen tensions on GBM cell lines and primary cells were assessed using flow cytometry. Results indicate that cell cycle distribution and viability are unaffected by long term exposure (24-96 h) to pathophysiological levels of oxygen (1-8% O2). Both transient cell cycle arrest and small amounts of cell death could only be detected when cells were exposed to severe hypoxia (0.1% O2). No significant changes in p21 protein expression levels were detected. These findings reinforce the importance of using physiologically relevant oxygen tensions when investigating tumour hypoxia, and help to explain how solid tumours can be both hypoxic and highly proliferative, as is the case with GBM. PMID- 26966679 TI - The effect of weight controllability beliefs on prejudice and self-efficacy. AB - An experiment was conducted to test for the presence of prejudice towards obesity and whether weight controllability beliefs information reduces this prejudice and impacts on a person's own healthy eating self-efficacy. The experiment randomly allocated 346 participants (49 males) into one of three conditions: controllable contributors toward obesity condition (e.g., information about personal control about diet and exercise); uncontrollable contributors toward obesity condition (e.g., information about genes, factors in society); and a control condition with no information given. Prejudice was present in 81% of the sample. High prejudice was predicted by low self-efficacy for exercise and weight. Weight controllability beliefs information had no significant effect on prejudice levels or exercise or healthy eating self-efficacy levels. Future research directions are discussed. PMID- 26966680 TI - Aboveground carbon in Quebec forests: stock quantification at the provincial scale and assessment of temperature, precipitation and edaphic properties effects on the potential stand-level stocking. AB - Biological carbon sequestration by forest ecosystems plays an important role in the net balance of greenhouse gases, acting as a carbon sink for anthropogenic CO2 emissions. Nevertheless, relatively little is known about the abiotic environmental factors (including climate) that control carbon storage in temperate and boreal forests and consequently, about their potential response to climate changes. From a set of more than 94,000 forest inventory plots and a large set of spatial data on forest attributes interpreted from aerial photographs, we constructed a fine-resolution map (~375 m) of the current carbon stock in aboveground live biomass in the 435,000 km(2) of managed forests in Quebec, Canada. Our analysis resulted in an area-weighted average aboveground carbon stock for productive forestland of 37.6 Mg ha(-1), which is lower than commonly reported values for similar environment. Models capable of predicting the influence of mean annual temperature, annual precipitation, and soil physical environment on maximum stand-level aboveground carbon stock (MSAC) were developed. These models were then used to project the future MSAC in response to climate change. Our results indicate that the MSAC was significantly related to both mean annual temperature and precipitation, or to the interaction of these variables, and suggest that Quebec's managed forests MSAC may increase by 20% by 2041-2070 in response to climate change. Along with changes in climate, the natural disturbance regime and forest management practices will nevertheless largely drive future carbon stock at the landscape scale. Overall, our results allow accurate accounting of carbon stock in aboveground live tree biomass of Quebec's forests, and provide a better understanding of possible feedbacks between climate change and carbon storage in temperate and boreal forests. PMID- 26966678 TI - The beneficial effects of cumulus cells and oocyte-cumulus cell gap junctions depends on oocyte maturation and fertilization methods in mice. AB - Cumulus cells are a group of closely associated granulosa cells that surround and nourish oocytes. Previous studies have shown that cumulus cells contribute to oocyte maturation and fertilization through gap junction communication. However, it is not known how this gap junction signaling affects in vivo versus in vitro maturation of oocytes, and their subsequent fertilization and embryonic development following insemination. Therefore, in our study, we performed mouse oocyte maturation and insemination using in vivo- or in vitro-matured oocyte cumulus complexes (OCCs, which retain gap junctions between the cumulus cells and the oocytes), in vitro-matured, denuded oocytes co-cultured with cumulus cells (DCs, which lack gap junctions between the cumulus cells and the oocytes), and in vitro-matured, denuded oocytes without cumulus cells (DOs). Using these models, we were able to analyze the effects of gap junction signaling on oocyte maturation, fertilization, and early embryo development. We found that gap junctions were necessary for both in vivo and in vitro oocyte maturation. In addition, for oocytes matured in vivo, the presence of cumulus cells during insemination improved fertilization and blastocyst formation, and this improvement was strengthened by gap junctions. Moreover, for oocytes matured in vitro, the presence of cumulus cells during insemination improved fertilization, but not blastocyst formation, and this improvement was independent of gap junctions. Our results demonstrate, for the first time, that the beneficial effect of gap junction signaling from cumulus cells depends on oocyte maturation and fertilization methods. PMID- 26966681 TI - Mechanism by which nuclear factor-kappa beta (NF-kB) regulates ovine fetal pulmonary vascular smooth muscle cell proliferation. AB - Platelet activating factor (PAF) modulates ovine fetal pulmonary hemodynamic. PAF acts through its receptors (PAFR) in pulmonary vascular smooth muscle cells (PVSMC) to phosphorylate and induce nuclear translocation of NF-kB p65 leading to PVSMC proliferation. However, the interaction of NF-kB p65 and PAF in the nuclear domain to effect PVSMC cell growth is not clearly defined. We used siRNA dependent translation initiation arrest to study a mechanism by which NF-kB p65 regulates PAF stimulation of PVSMC proliferation. Our hypotheses are: (a) PAF induces NF-kB p65 DNA binding and (b) NF-kB p65 siRNA attenuates PAF stimulation of PVSMC proliferation. For DNA binding, cells were fed 10 nM PAF with and without PAFR antagonists WEB 2170, CV 3988 or BN 52021 and incubated for 12 h. DNA binding was measured by specific ELISA. For NF-kB p65 siRNA effect, starved cells transfected with the siRNA were incubated for 24 h with and without 10 nM PAF. Cell proliferation was measured by DNA synthesis while expression of NF-kB p65 and PAFR protein was measured by Western blotting. In both studies, the effect of 10% FBS alone was used as the positive control. In general, PAF stimulated DNA binding which was inhibited by PAFR antagonists. siRNAs to NF-kB p65 and PAFR significantly attenuated cell proliferation compared to 10% FBS and PAF effect. Inclusion of PAF in siRNA-treated cells did not reverse inhibitory effect of NF-kB p65 siRNA on DNA synthesis. PAFR expression was inhibited in siRNA-treated cells. These data show that PAF-stimulation of PVSMC proliferation occurs via a PAFR-NF-kB p65 linked pathway. PMID- 26966682 TI - Glutaredoxin mediated redox effects of coenzyme Q10 treatment in type 1 and type 2 diabetes patients. AB - The possible beneficial effects of coenzyme Q10 (CoQ10) supplementation on disease progression and oxidant status in diabetes remains debated. In the present study, patients with type 1 and type 2 diabetes were treated with oral CoQ10, 100 mg twice daily for 12 weeks. We assessed total antioxidant capacity, intra- and extracellular levels of the redox regulating protein glutaredoxin 1 (Grx1), CoQ10, oxidized LDL-cholesterol, lipid profile and HbA1c. We have previously shown that extracellular Grx1 is increased in patients with type 2 diabetes compared to healthy subjects. In the present study, CoQ10 treatment significantly decreased serum Grx1 activity as well as total antioxidant capacity independent of type of diabetes, indicating an improvement to a less oxidized extracellular environment. The effect on serum Grx1 activity was more prominent in patients not on statin treatment. Conversely, intracellular Grx1 activity as well as mRNA levels increased independent of statin treatment. There was a significant improvement in oxidized LDL-cholesterol and lipid profile, with a tendency to improved metabolic control (HbA1c). Additionally, we describe for the first time that CoQ10 is a direct substrate for glutathione, and that Grx1 catalyzes this reaction, thus presenting a novel mechanism for CoQ10 reduction which could explain our findings of an increased intracellular Grx1. In conclusion, 12 weeks CoQ10 treatment significantly improved the extracellular redox balance and lipid profile, indicating that prolonged treatment may have beneficial effects also on clinical outcome in diabetes. PMID- 26966683 TI - Calcium vitamin D3 supplementation in clinical practice: side effect and satisfaction. AB - BACKGROUND: The objective of this study was to assess side effects and satisfaction about OsteoCalVitFort (500 mg calcium and 400 I.U. of vitamin D3) usage. METHODS: A total 186 people were participated with range age from 18 to 65 years old. Each participant received 1 pack that contains 60 OsteoCalVitFort tablet and used two tablet OsteoCalVitFort daily (1 tablet after breakfast and 1 after dinner). By a phone call, side effects and satisfaction about OsteoCalVitFort were assessed. RESULTS: The rate of constipating (8.0 %) and bloating (12.5 %) were decreased significantly after OsteoCalVitFort supplement intake (1.2 %, and 0.6 %, respectively). Similar results were observed in metallic taste in mouth, tiredness, weakness, loss of appetite, bone/muscle pain and mental/mood change after Calcium Vitamin D3 supplementation intake. Totally, 94 % of patients were satisfied about OsteoCalVitFort usage. CONCLUSION: The results of the research indicate despite the high quality of OsteoCalVitFort supplement, there are no side effects which have been seen in other supplements. PMID- 26966685 TI - Newly Emerging Parasitic Threats for Human Health: National and International Trends. PMID- 26966684 TI - PIPINO: A Software Package to Facilitate the Identification of Protein-Protein Interactions from Affinity Purification Mass Spectrometry Data. AB - The functionality of most proteins is regulated by protein-protein interactions. Hence, the comprehensive characterization of the interactome is the next milestone on the path to understand the biochemistry of the cell. A powerful method to detect protein-protein interactions is a combination of coimmunoprecipitation or affinity purification with quantitative mass spectrometry. Nevertheless, both methods tend to precipitate a high number of background proteins due to nonspecific interactions. To address this challenge the software Protein-Protein-Interaction-Optimizer (PIPINO) was developed to perform an automated data analysis, to facilitate the selection of bona fide binding partners, and to compare the dynamic of interaction networks. In this study we investigated the STAT1 interaction network and its activation dependent dynamics. Stable isotope labeling by amino acids in cell culture (SILAC) was applied to analyze the STAT1 interactome after streptavidin pull-down of biotagged STAT1 from human embryonic kidney 293T cells with and without activation. Starting from more than 2,000 captured proteins 30 potential STAT1 interaction partners were extracted. Interestingly, more than 50% of these were already reported or predicted to bind STAT1. Furthermore, 16 proteins were found to affect the binding behavior depending on STAT1 phosphorylation such as STAT3 or the importin subunits alpha 1 and alpha 6. PMID- 26966686 TI - Optimizing Human Bile Preparation for Two-Dimensional Gel Electrophoresis. AB - AIMS: Bile is an important body fluid which assists in the digestion of fat and excretion of endogenous and exogenous compounds. In the present study, an improved sample preparation for human bile was established. METHODS AND MATERIAL: The method involved acetone precipitation followed by protein extraction using commercially available 2D Clean-Up kit. The effectiveness was evaluated by 2 dimensional electrophoresis (2DE) profiling quality, including number of protein spots and spot distribution. RESULTS: The total protein of bile fluid in benign biliary disorders was 0.797 +/- 0.465 MUg/MUL. The sample preparation method using acetone precipitation first followed by 2D Clean-Up kit protein extraction resulted in better quality of 2DE gel images in terms of resolution as compared with other sample preparation methods. Using this protocol, we obtained approximately 558 protein spots on the gel images and with better protein spots presentation of haptoglobin, serum albumin, serotransferrin, and transthyretin. CONCLUSIONS: Protein samples of bile prepared using acetone precipitation followed by 2D Clean-Up kit exhibited high protein resolution and significant protein profile. This optimized protein preparation protocol can effectively concentrate bile proteins, remove abundant proteins and debris, and yield clear presentation of nonabundant proteins and its isoforms on 2-dimensional electrophoresis gel images. PMID- 26966687 TI - Development and Validation of a Questionnaire to Assess Multimorbidity in Primary Care: An Indian Experience. AB - Multimorbidity remains an underexplored domain in Indian primary care. We undertook a study to assess the prevalence, correlates, and outcomes of multimorbidity in primary care settings in India. This paper describes the process of development and validation of our data collection tool "Multimorbidity Assessment Questionnaire for Primary Care (MAQ-PC)." An iterative process comprising desk review, chart review, and expert consultations was undertaken to generate the questionnaire. The MAQ-PC contained items on chronic conditions, health care utilization, health related quality of life, disease severity, and sociodemographics. It was first tested with twelve adults for comprehensibility followed by test-retest reliability with 103 patients from four primary care practices. For interrater reliability, two interviewers separately administered the questionnaire to sixteen patients. MAQ-PC displayed strong internal consistency (Cronbach's alpha: 0.69), interrater reliability (Cohen's Kappa: 0.78 1), and test-retest reliability (ICC: 0.970-0.741). Substantial concordance between self-report and physician diagnosis (Scott Kappa: 0.59-1.0) was observed for listed chronic conditions indicating strong concurrent validity. Nearly 54% had one chronic condition and 23.3% had multimorbidity. Our findings demonstrate MAQ-PC to be a valid and reliable measure of multimorbidity in primary care practice and suggest its potential utility in multimorbidity research in India. PMID- 26966688 TI - Coxiella burnetii Seroprevalence and Risk Factors in Cattle Farmers and Farm Residents in Three Northeastern Provinces and Inner Mongolia Autonomous Region, China. AB - Little is known about Coxiella burnetii infection among cattle farmers and farm residents in China. Thus, the present study was conducted to detect the seroprevalence of C. burnetii infection and estimate associated risk factors among cattle farmers and farm residents in China. A cross-sectional study was designed, and sera of 362 people living or working on 106 cattle farms were tested for C. burnetii IgG and IgM antibodies by immunofluorescence assay. Overall C. burnetii seroprevalence was 35.6% (129/362, 95% CI: 30.70-40.57), and 112 participants had experienced a past infection and seventeen (4.7%) had experienced a relatively recent infection. In the final combined multilevel model, the following activities were significantly associated with presence of antibodies against C. burnetii: milking cattle, providing general healthcare to cattle, providing birth assistance, contact dead-born animals, urbanization, and presence of mice and/or rats in the stable. Moreover, presence of disinfection equipment was a significant protective factor. This is the first study addressing the seroprevalence and risk factors of C. burnetii infection in cattle farmers and farm residents in three northeastern provinces and Inner Mongolia Autonomous Region, China. PMID- 26966689 TI - Self-Perception of Swallowing-Related Problems in Laryngopharyngeal Reflux Patients Diagnosed with 24-Hour Oropharyngeal pH Monitoring. AB - BACKGROUND AND OBJECTIVES: Swallowing difficulty is considered one of the nonspecific symptoms that many patients with laryngopharyngeal reflux complain of. However, the relationship between laryngopharyngeal reflux and swallowing problems is not clear. The purpose of this work is to explore correlation between swallowing-related problems and laryngopharyngeal reflux (LPR) in a group of patients diagnosed with oropharyngeal pH monitoring and to study the effect of laryngopharyngeal reflux on the patients' self-perception of swallowing problems. METHODS: 44 patients complaining of reflux-related problems were included in the study. Patients underwent 24-hour oropharyngeal pH monitoring and were divided into positive and negative LPR groups based on the pH monitoring results. All patient filled out the Dysphagia Handicap Index (DHI) and Reflux Symptom Index (RSI) questionnaires. Comparison was made between the positive and negative LPR groups regarding the results of the DHI and RSI ratings. Also, correlation between DHI scores, RSI scores, and pH monitoring results was studied. RESULTS: Significant difference was reported between positive and negative LPR groups regarding DHI scores, RSI scores, and overall rating of swallowing difficulty. There was significant correlation demonstrated between DHI scores, RSI scores, and 24-hour oropharyngeal pH results. CONCLUSION: Laryngopharyngeal reflux appears to have a significant impact on patients' self-perception of swallowing problems as measured by DHI. PMID- 26966690 TI - A Prediction Model for Membrane Proteins Using Moments Based Features. AB - The most expedient unit of the human body is its cell. Encapsulated within the cell are many infinitesimal entities and molecules which are protected by a cell membrane. The proteins that are associated with this lipid based bilayer cell membrane are known as membrane proteins and are considered to play a significant role. These membrane proteins exhibit their effect in cellular activities inside and outside of the cell. According to the scientists in pharmaceutical organizations, these membrane proteins perform key task in drug interactions. In this study, a technique is presented that is based on various computationally intelligent methods used for the prediction of membrane protein without the experimental use of mass spectrometry. Statistical moments were used to extract features and furthermore a Multilayer Neural Network was trained using backpropagation for the prediction of membrane proteins. Results show that the proposed technique performs better than existing methodologies. PMID- 26966691 TI - Current Applications for the Use of Extracorporeal Carbon Dioxide Removal in Critically Ill Patients. AB - Mechanical ventilation in patients with respiratory failure has been associated with secondary lung injury, termed ventilator-induced lung injury. Extracorporeal venovenous carbon dioxide removal (ECCO2R) appears to be a feasible means to facilitate more protective mechanical ventilation or potentially avoid mechanical ventilation in select patient groups. With this expanding role of ECCO2R, we aim to describe the technology and the main indications of ECCO2R. PMID- 26966692 TI - Longitudinal Frequencies of Blood Leukocyte Subpopulations Differ between NOD and NOR Mice but Do Not Predict Diabetes in NOD Mice. AB - Immune phenotyping provides insight into disease pathogenesis and prognostic markers. Trajectories from age of 4 to 36 weeks were modeled for insulin autoantibodies and for leukocyte subpopulations in peripheral blood from female NOD (n = 58) and NOR (n = 22) mice. NOD mice had higher trajectories of insulin autoantibodies, CD4(+) and CD8(+) T lymphocytes, B lymphocytes, IgD(+)IgM(-) B lymphocytes, and NK cells and lower trajectories of CD4(+)CD25(+) T lymphocytes, IgM(+) B lymphocytes, granulocytes, and monocytes than NOR mice (all p < 0.001). Of these, only the increased IAA trajectory was observed in NOD mice that developed diabetes as compared to NOD mice that remained diabetes-free. Therefore, the profound differences in peripheral blood leukocyte proportions observed between the diabetes-prone NOD mice and the diabetes-resistant mice do not explain the variation in diabetes development within NOD mice and do not provide markers for diabetes prediction in this model. PMID- 26966694 TI - Perception of Time Since Smoking Cessation: Time in Memory Can Elapse Faster. AB - Self-reports concerning smoking behaviors are subject to different types of response bias that may severely affect the data quality. This study examined the evidence and extent of backward telescoping bias in reports on time since completely quitting smoking among former smokers. The study goals were to determine whether the extent of bias differs, on average, across subpopulations with diverse sociodemographic characteristics, prior smoking habits and duration of smoking abstinence, and across the survey administration mode (phone, in person, mixed). The sample included 1,611 subjects who responded to the 2002-2003 Tobacco Use Supplement to the Current Population Survey. Multiple regressions for subjects who quit smoking recently, some time ago, and a long time ago were fitted, where the variance was estimated via the Balanced Repeated Replications approach. The model-based estimates were used to compare the extent of response bias across diverse subpopulations of respondents. Analyses revealed a significantly smaller overall extent of response bias for respondents who were younger (p < 0.01), female (p < 0.01), Non-Hispanic White (p = 0.02), employed (p < 0.01), who were regular (rather than occasional) smokers in the past (p < 0.01), and who quit smoking recently or some time ago as opposed to a long time ago (p < 0.01); a significant overall effect of survey mode was also detected (p < 0.01). Male respondents who smoked occasionally in the past tended to provide the most disagreeing reports. The discrepancy in reports may be due to backward telescoping bias. Studies which use the national survey smoking cessation measures should be aware of not only possible forward telescoping (that has been addressed in the literature) but also backward telescoping. This will help correctly account for possible impaired perception of time elapsed since smoking cessation in former smokers. PMID- 26966693 TI - Dendritic Cells under Hypoxia: How Oxygen Shortage Affects the Linkage between Innate and Adaptive Immunity. AB - Dendritic cells (DCs) are considered as one of the main regulators of immune responses. They collect antigens, process them, and present typical antigenic structures to lymphocytes, thereby inducing an adaptive immune response. All these processes take place under conditions of oxygen shortage (hypoxia) which is often not considered in experimental settings. This review highlights how deeply hypoxia modulates human as well as mouse immature and mature dendritic cell functions. It tries to link in vitro results to actual in vivo studies and outlines how hypoxia-mediated shaping of dendritic cells affects the activation of (innate) immunity. PMID- 26966696 TI - Relationship Between Upper Respiratory Tract Influenza Test Result and Clinical Outcomes Among Critically Ill Influenza Patients. AB - Among critically ill patients with lower respiratory tract (LRT)-confirmed influenza, we retrospectively observed worse 28-day clinical outcomes in upper respiratory tract (URT)-negative versus URT-positive subjects. This finding may reflect disease progression and highlights the need for influenza testing of both URT and LRT specimens to improve diagnostic yield and possibly inform prognosis. PMID- 26966695 TI - Genital Shedding of Resistant Human Immunodeficiency Virus-1 Among Women Diagnosed With Treatment Failure by Clinical and Immunologic Monitoring. AB - Background. The accumulation of human immunodeficiency virus (HIV) resistance mutations can compromise treatment outcomes and promote transmission of drug resistant virus. We conducted a study to determine the duration and evolution of genotypic drug resistance in the female genital tract among HIV-1-infected women failing first-line therapy. Methods. Treatment failure was diagnosed based on World Health Organization (WHO) clinical or immunologic criteria, and second-line therapy was initiated. Stored plasma and genital samples were tested to determine the presence and timing of virologic failure and emergence of drug resistance. The median duration of genital shedding of genotypically resistant virus prior to regimen switch was estimated. Results. Nineteen of 184 women were diagnosed with treatment failure, of whom 12 (63.2%) had confirmed virologic failure at the switch date. All 12 women with virologic failure (viral load, 5855-1 086 500 copies/mL) had dual-class resistance in plasma. Seven of the 12 (58.3%) had genital HIV-1 RNA levels high enough to amplify (673-116 494 copies/swab), all with dual-class resistance. The median time from detection of resistance in stored samples to regimen switch was 895 days (95% confidence interval [CI], 130 1414 days) for plasma and 629 days (95% CI, 341-984 days) for genital tract secretions. Conclusions. Among women diagnosed with treatment failure using WHO clinical or immunologic criteria, over half had virologic failure confirmed in stored samples. Resistant HIV-1 RNA was shed in the genital tract at detectable levels for ~1.7 years before failure diagnosis, with steady accumulation of mutations. These findings add urgency to the ongoing scale-up of viral load testing in resource-limited settings. PMID- 26966697 TI - Systemic Cytokine Levels Do Not Predict CD4(+) T-Cell Recovery After Suppressive Combination Antiretroviral Therapy in Chronic Human Immunodeficiency Virus Infection. AB - Background. Subjects on suppressive combination antiretroviral therapy (cART) who do not achieve robust reconstitution of CD4(+) T cells face higher risk of complications and death. We studied participants in the Women's Interagency HIV Study with good (immunological responder [IR]) or poor (immunological nonresponder [INR]) CD4(+) T-cell recovery after suppressive cART (n = 50 per group) to determine whether cytokine levels or low-level viral load correlated with INR status. Methods. A baseline sample prior to viral control and 2 subsequent samples 1 and 2 years after viral control were tested. Serum levels of 30 cytokines were measured at each time point, and low-level human immunodeficiency virus (HIV) viral load and anti-HIV antibody levels were measured 2 years after viral suppression. Results. There were minimal differences in cytokine levels between IR and INR subjects. At baseline, macrophage inflammatory protein-3beta levels were higher in IR subjects; after 1 year of suppressive cART, soluble vascular endothelial growth factor-R3 levels were higher in IR subjects; and after 2 years of suppressive cART, interferon gamma-induced protein 10 levels were higher in INR subjects. Very low-level HIV viral load and anti-HIV antibody levels did not differ between IR and INR subjects. Conclusions. These results imply that targeting residual viral replication might not be the optimum therapeutic approach for INR subjects. PMID- 26966698 TI - Construction of a hybrid beta-hexosaminidase subunit capable of forming stable homodimers that hydrolyze GM2 ganglioside in vivo. AB - Tay-Sachs or Sandhoff disease result from mutations in either the evolutionarily related HEXA or HEXB genes encoding respectively, the alpha- or beta-subunits of beta-hexosaminidase A (HexA). Of the three Hex isozymes, only HexA can interact with its cofactor, the GM2 activator protein (GM2AP), and hydrolyze GM2 ganglioside. A major impediment to establishing gene or enzyme replacement therapy based on HexA is the need to synthesize both subunits. Thus, we combined the critical features of both alpha- and beta-subunits into a single hybrid u subunit that contains the alpha-subunit active site, the stable beta-subunit interface and unique areas in each subunit needed to interact with GM2AP. To facilitate intracellular analysis and the purification of the u-homodimer (HexM), CRISPR-based genome editing was used to disrupt the HEXA and HEXB genes in a Human Embryonic Kidney 293 cell line stably expressing the u-subunit. In association with GM2AP, HexM was shown to hydrolyze a fluorescent GM2 ganglioside derivative both in cellulo and in vitro. Gene transfer studies in both Tay-Sachs and Sandhoff mouse models demonstrated that HexM expression reduced brain GM2 ganglioside levels. PMID- 26966699 TI - Efficient detection of human circulating tumor cells without significant production of false-positive cells by a novel conditionally replicating adenovirus. AB - Circulating tumor cells (CTCs) are promising biomarkers in several cancers, and thus methods and apparatuses for their detection and quantification in the blood have been actively pursued. A novel CTC detection system using a green fluorescence protein (GFP)-expressing conditionally replicating adenovirus (Ad) (rAd-GFP) was recently developed; however, there is concern about the production of false-positive cells (GFP-positive normal blood cells) when using rAd-GFP, particularly at high titers. In addition, CTCs lacking or expressing low levels of coxsackievirus-adenovirus receptor (CAR) cannot be detected by rAd-GFP, because rAd-GFP is constructed based on Ad serotype 5, which recognizes CAR. In order to suppress the production of false-positive cells, sequences perfectly complementary to blood cell-specific microRNA, miR-142-3p, were incorporated into the 3'-untranslated region of the E1B and GFP genes. In addition, the fiber protein was replaced with that of Ad serotype 35, which recognizes human CD46, creating rAdF35-142T-GFP. rAdF35-142T-GFP efficiently labeled not only CAR positive tumor cells but also CAR-negative tumor cells with GFP. The numbers of false-positive cells were dramatically lower for rAdF35-142T-GFP than for rAd GFP. CTCs in the blood of cancer patients were detected by rAdF35-142T-GFP with a large reduction in false-positive cells. PMID- 26966700 TI - Development of a real-time imaging system for hypoxic cell apoptosis. AB - Hypoxic regions within the tumor form due to imbalances between cell proliferation and angiogenesis; specifically, temporary closure or a reduced flow due to abnormal vasculature. They create environments where cancer cells acquire resistance to therapies. Therefore, the development of therapeutic approaches targeting the hypoxic cells is one of the most crucial challenges for cancer regression. Screening potential candidates for effective diagnostic modalities even under a hypoxic environment would be an important first step. In this study, we describe the development of a real-time imaging system to monitor hypoxic cell apoptosis for such screening. The imaging system is composed of a cyclic luciferase (luc) gene under the control of an improved hypoxic-responsive promoter. The cyclic luc gene product works as a caspase-3 (cas-3) monitor as it gains luc activity in response to cas-3 activation. The promoter composed of six hypoxic responsible elements and the CMV IE1 core promoter drives the effective expression of the cyclic luc gene in hypoxic conditions, enhancing hypoxic cell apoptosis visualization. We also confirmed real-time imaging of hypoxic cell apoptosis in the spheroid, which shares properties with the tumor. Thus, this constructed system could be a powerful tool for the development of effective anticancer diagnostic modalities. PMID- 26966701 TI - Assessment of the Shear Bond Strength between Nanofilled Composite Bonded to Glass-ionomer Cement Using Self-etch Adhesive with Different pHs and Total-Etch Adhesive. AB - STATEMENT OF THE PROBLEM: In the sandwich technique, the undesirable bond between the composite resin and glass-ionomer cement (GIc) is one of the most important factors which lead to the failure of restoration. Total-etch and self-etch adhesives may improve the bond strength based on their pH. PURPOSE: The purpose of this study was to evaluate the shear bond strength between the nanofilled composite resin and GIc using different adhesives. MATERIALS AND METHOD: In this experimental study, 40 specimens (6*6mm) in 4 groups (n=10) were prepared in acrylic mold. Each specimen contained conventional GI ChemFil Superior with a height of 3mm, bonded to Z350 composite resin with a height measured 3mm. In order to bond the composite to the GI, the following adhesives were used, respectively: A: mild Clearfil SE Bond self-etch (pH=2), B: intermediate OptiBond self-etch (pH=1.4), C: strong Adper Prompt L-Pop (pH=1), and D: Adper Single Bond 2 total-etch (pH=7.2). The shear bond strength was measured by using universal testing machine with a crosshead speed of 1mm/min. One-way ANOVA and Tukey's test were used to analyze the data (p< 0.05). RESULTS: The shear bond strength in group A was significantly higher than group B (p= 0.002), C (p< 0.001), and D (p< 0.001). Moreover, the shear bond strength of groups A and B (self-etch) was significantly different from group D (total-etch) (p< 0.001); and C (self-etch) with D (p= 0.024). CONCLUSION: The results of this study showed that applying the mild self-etch adhesive between the composite and the GIc results in stronger shear bond strength compared to intermediate and strong self-etch adhesives. Moreover, the self-etch adhesive increased the shear bond strength between composite resin and GIc more significantly than total-etch adhesive. PMID- 26966702 TI - Evaluation of Anatomic Variations in Maxillary Sinus with the Aid of Cone Beam Computed Tomography (CBCT) in a Population in South of Iran. AB - STATEMENT OF THE PROBLEM: Anatomic variations of the maxillary sinus can be detected in cone-beam computed tomography (CBCT) and may assist to locate the posterior superior alveolar artery (PSAA) and define the maxillary sinus morphology more accurately for a more strict surgical treatment plan. PURPOSE: The study aimed to determine normal variations of the maxillary sinus with the aid of CBCT in a sample population in south of Iran. MATERIALS AND METHOD: This cross-sectional prevalence study was based on evaluation of 198 projection data of CBCT scans of some Iranian patients aged 18-45 who referred to a private oral and maxillofacial radiology center in Shiraz from 2011 to 2013. CBCT scans were taken and analyzed with NewTom VGi device and software. The anatomic variations which were evaluated in the axial images included the presence of alveolar pneumatization, anterior pneumatization, exostosis, and hypoplasia. Moreover the location and height of sinus septa, and the location of PSAA were assessed. SPSS software (version 17.0) was used to analyze the data. RESULTS: In a total of 396 examined sinuses, maxillary sinus alveolar pneumatization was the most common anatomic variation detected. Anterior pneumatization was detected in 96 sinuses (24.2%). Antral septa were found in 180 sinuses (45.4%) and were mostly located in the anterior region. Meanwhile, PSAA was mostly detected intra-osseous in 242 sinuses (65.7%). CONCLUSION: Anatomic variations of the maxillary sinus were common findings in CBCT of the maxilla. Preoperative imaging with CBCT seems to be very helpful for assessing the location of PSAA and the maxillary sinus morphology, which may be used to adjust the surgical treatment plan to yield more successful treatments. PMID- 26966703 TI - The Effects of Alkaline pH on Microleakage of Mineral Trioxide Aggregate and Calcium Enriched Mixture Apical Plugs. AB - STATEMENT OF THE PROBLEM: Alkaline pH can affect the physical and chemical properties and sealing ability of apical plug material. Calcium hydroxide is used as an intracanal medication to complete disinfection of root canals. It raises the pH of environment to alkaline value. PURPOSE: The aim of this in vitro study was to evaluate and compare the effect of alkaline pH on the sealing ability of calcium-enriched mixture (CEM) cement and mineral trioxide aggregate (MTA) apical plugs. MATERIALS AND METHOD: Seventy single-rooted human maxillary anterior teeth were randomly divided to two experimental groups for Angelus MTA and CEM cement (n=30) and two control groups (n=5). Each group was divided into two subgroups of 15 for neutral and alkaline pH, and 1 negative and 1 positive control groups of 5. The root canals were cleaned and shaped by using ProTaper rotary system (Dentsply Maillefer; Ballaigues, Switzerland) and the terminal 3mm of the roots were resected. Then, MTA and CEM cement were condensed in apical region with 3mm thickness. The samples were exposed to two environments with different pH values of 13 and 7.4. The leakage was assessed by using the fluid filtration technique at 1, 7, 14, 30 days intervals. Data were analyzed by the repeated measures MANOVA. RESULTS: There was no statistically significant difference in the rate of microleakage between neutral and alkaline pH of CEM cement and MTA (p> 0.05). The sealing ability of MTA in an alkaline pH of 13 was significantly less than CEM cement in this pH (p< 0.05). CONCLUSION: An environment with alkaline pH had no adverse effect on the sealing ability of MTA and CEM cement used as apical plugs. CEM cement had better sealing ability in alkaline pH. PMID- 26966704 TI - Evaluation of Plasma Isoprostane in Patients with Oral Lichen Planus. AB - STATEMENT OF THE PROBLEMS: Lichen planus is a chronic inflammatory disease. Free radicals and reactive oxygen species play important roles in pathogenesis of oral lichen planus (OLP). Isoprostanes show oxidative stress and are formed by free radical mediated lipid peroxidation of arachidonic acid and cell membrane phospholipids. PURPOSE: This study was conducted to evaluate the plasma level of 8-isoprostane in patients suffering from erosive and non-erosive forms of OLP. MATERIALS AND METHOD: In this case-control study, 31 patients with OLP and 30 control subjects were enrolled. Plasma samples were obtained and the level of 8 isoprostane was measured with Sandwich enzyme-linked immunosorbent assay (ELISA) in both groups. The data were analyzed by using two-sample t-test, chi-square and ANOVA tests. RESULTS: The results showed significant increase in the plasma level of 8-isoprostane in OLP group compared with the control group. The results of independent t-test revealed no significant correlation between the plasma level of isoprostane and sex, smoking, or previous treatment. CONCLUSION: Based on the findings of this study, oxidative stress was increased in patients with OLP, reflected by higher concentrations of 8-isoprostane in plasma. PMID- 26966706 TI - Normal Variations of Sphenoid Sinus and the Adjacent Structures Detected in Cone Beam Computed Tomography. AB - STATEMENT OF THE PROBLEM: The sphenoid sinus is a common target of paranasal surgery. Functional endoscopic sinus surgery is likely to endanger the anatomic variations of vital structures adjacent to the sphenoid sinus. PURPOSE: The aim of this study was to determine the variations of sphenoid sinus and the related structures by using cone-beam computed tomography (CBCT). MATERIALS AND METHOD: In this descriptive-analytic study, CBCT images of 103 patients aged above 20 years were selected (206 sides). Degree of pneumatization of sphenoid sinus, pneumatization of the anterior clinoid process, pterygoid process, protrusion of optic canal, vidian canal, and foramen rotundum, as well as prevalence of sinus septa were recorded. Examinations were performed using On-Demand software (Version 1); data were analyzed by using chi-square test. RESULTS: There was a statistically significant correlation between the pterygoid pneumatization and vidian canal protrusion (p< 0.001), and foramen rotundum protrusion (p< 0.001). The optic canal protrusion was found to be significantly associated with the anterior clinoid pneumatization and pterygoid process (p< 0.001). Statistically significant relationship was also observed between the carotid canal protrusion and pterygoid process pneumatization (p< 0.001). CONCLUSION: The anatomical variations of the sphenoid sinus tend to give rise to a complexity of symptoms and potentially serious complications. This variability necessitates a comprehensive understanding of the regional sphenoid sinus anatomy by a detailed CBCT sinus examination. PMID- 26966705 TI - The Effects of Septal Deviation, Concha Bullosa, and Their Combination on the Depth of Posterior Palatal Arch in Cone-Beam Computed Tomography. AB - STATEMENT OF THE PROBLEM: Nasal breathing is the major pattern of air intake. Changes in breathing pattern alter the posture of the head, jaws and tongue that could change pressure on the jaw and teeth and affect their growth. PURPOSE: This study aimed to investigate the relationship between septal deviations (SD) per se and in combination with concha bullosa (CB) on maxilla; particularly the depth of palatal arch. MATERIALS AND METHOD: This descriptive-comparative study was performed on 116 cone-beam computed tomography (CBCT) images. The images were categorized into four groups (n=29) as follows; group 1: SD+CB, group 2: only SD, group 3: neither SD nor CB, and group 4: only CB. In coronal images, deviated septal length (DSL), angle of deviated septal curve (DSCA), palatal arch depth (PAD), palatal interalveolar length (PIL), PAD/PIL ratio, septal vertical length (SVL), maxillopalatal arch angle (MPAA), interjugum distance (IJD), and jugum angle (JA) were measured. The data were statistically analyzed with Tukey's HSD and Chi-square tests. RESULTS: There were statistically significant differences in DSL and DSCA (p= 0.0001) among the four groups. The study groups were not statistically different regarding the IJD, JA, MPAA, PAD/PIL, PAD, PIL, and SVL. However, in group 1, PAD/PIL were significantly correlated with DSCA and DSL (p= 0.037, and p= 0.043, respectively). CONCLUSION: Based on the findings of this study, simultaneous occurrence of SD and CB influenced the depth and curve of the palatal bone. The PAD/PIL ratio was negatively correlated with the DSCA angle. This correlation was associated with a decrease in PAD, indicating that concurrent occurrence of SD and CB remarkably affected the palatal base of maxilla. PMID- 26966707 TI - Evaluation of the Association between Oral Lichen Planus and Hypothyroidism: a Retrospective Comparative Study. AB - STATEMENT OF THE PROBLEM: Oral Lichen planus (OLP) is an autoimmune mucocutaneous disease. There are some reports of thyroid diseases, especially hypothyroidism, to have association with OLP in some studies. PURPOSE: Based on the controversial results of former studies in other populations about the association of hypothyroidism and OLP, the current study aimed to evaluate this association in a sample of Iranian population. MATERIALS AND METHOD: This retrospective comparative study evaluated 523 patients with OLP referring to the Oral and Maxillofacial Department of Shiraz Dental Faculty as the test group and 523 age- and sex-matched patients as the control group. Those participants with oral lichenoid reactions and other mucosal lesions were excluded. The odds ratio (OR) with 95% confidence intervals (CI) for the association of OLP and thyroid diseases were estimated by logistic regression adjusted for the matched age and sex. RESULTS: In the test group, 74% (n=387) and in the control group 73.8% of the patients were female (n=386). In the test group, 26% (n=136) and in the control group 26.2% of the samples were male (n=137). A total of 4% of the patients in the control group (n=21) and 6.7% in the case group (n=35) had a history of hypothyroidism. The reported OR for association of thyroid disease and OLP was 1.714 (CI=0.984-2.987). CONCLUSION: The results of this study showed no significant association between hypothyroidism and OLP in comparison with the age and sex-matched control group. PMID- 26966708 TI - Histological Evaluation of Wound Healing Process after Photodynamic Therapy of Rat Oral Mucosal Ulcer. AB - STATEMENT OF THE PROBLEM: When the body defense is compromised, wounds can act as a route for entrance and colonization of microorganisms in the body. Photodynamic therapy with methylene blue is known as a promising antimicrobial modality. PURPOSE: The present study aimed to investigate the effects of this procedure on wound healing processes. MATERIALS AND METHOD: In this experimental study, 48 male Wistar rats were recruited. Experimental wounds were surgically made on their buccal mucosa. Based on the treatment modality, they were divided into 3 groups (n=16) of control (CG), laser (LG), photosensitizer+ laser (PLG) by methylene blue (MB). The treatment procedure in the two latter groups was done in days 1-4 and 6-9. After sacrificing on 2, 4, 7 and 14-day follow-ups, the microscopic grade of healing of the wounds was assigned on each interval according to histological grading criteria. RESULTS: A qualitative result was obtained that showed a healing progression in PLG at day 2 of follow-up. At day 4 of follow-up, no difference was seen in healing stage among the groups. However on day 7 of follow-up, samples of the LG showed a lower degree of healing compared with the other two groups. Likewise, on day 14 of follow- up, both PLG and LG showed lower degree of healing than CG. CONCLUSION: This study qualitatively showed that MB- mediated photodynamic therapy would have an inhibitory effect on healing process after 14 days of the wound creation. PMID- 26966709 TI - Assessment of Anti HSV-1 Activity of Aloe Vera Gel Extract: an In Vitro Study. AB - STATEMENT OF THE PROBLEM: Herpes simplex virus (HSV) infection is one of the most common and debilitating oral diseases; yet, there is no standard topical treatment to control it. The extract of Aloe vera leaves has been previously reported to have anti-inflammatory, antibacterial, and also antiviral effects. There is no data on anti-Herpes simplex virus type 1 (HSV-1) activity of Aloe vera gel. PURPOSE: This study aimed to evaluate the anti-HSV-1 activity of Aloe vera gel in Vero cell line. MATERIALS AND METHOD: In this study, gel extraction and cytotoxicity of various increasing concentrations of Aloe vera gel (0.2, 0.5, 1, 2, and 5%) was evaluated in Dulbecco's Modified Eagle Medium (DMEM) containing 2% fetal bovine serum (FBS). Having been washed with phosphate buffered saline, 50 plaque-forming units (PFU) of HSV-1 was added to each well. After 1 hour of incubation at 37 degrees C, cell monolayers in 24 well plates were exposed to different increasing concentrations of Aloe vera gel. The anti-HSV-1 activity of Aloe vera gel in different concentrations was assessed by plaque reduction assays. Data were analyzed by using One-way ANOVA. RESULTS: The cytotoxicity assay showed that Aloe vera in prearranged concentrations was cell-compatible. The inhibitory effect of various concentrations of Aloe vera was observed one hour after the Vero cell was infected with HSV-1. However, there was no significant difference between two serial concentrations (p> 0.05). One-way ANOVA also revealed no significant difference between the groups. The findings indicated a dose-dependent antiviral effect of Aloe vera. CONCLUSION: The findings showed significant inhibitory effect of 0.2-5% Aloe vera gel on HSV-1 growth in Vero cell line. Therefore, this gel could be a useful topical treatment for oral HSV-1 infections without any significant toxicity. PMID- 26966710 TI - A Comparative Evaluation of Microleakage of Two Low-Shrinkage Composites with a Conventional Resin Composite: an In Vitro Assessment. AB - STATEMENT OF THE PROBLEM: Polymerization shrinkage stress in composite restorations may lead to microleakage. Clinical methods such as using low shrinkage composites have been suggested to overcome this problem; however, there are controversies about their efficiency in decreasing the microleakage. PURPOSE: This in vitro study was conducted to compare the microleakage of two low shrinkage resin composites with a conventional one. MATERIALS AND METHOD: Fifty class V cavities of 2.5*3*2 mm (depth* length* width) were prepared in the buccal surfaces of intact bovine incisor teeth with the incisal margin on the enamel and gingival margin on the cementum. The teeth were randomly divided into 5 groups. In group 1, Clearfil APX (conventional) with SE Bond was used in 2 layers (Kuraray; Japan). In group 2, GC Kalore (low -shrinkage) with GC UniFil Bond was applied in one layer (GC Company). In group 3, the material of group 2 was applied in two layers. In group 4, FiltekP90 (low -shrinkage) with P90 System adhesive was applied in one layer (3M ESPE). In group 5, the materials of group 4 were applied in two layers. The samples were thermocycled and immersed in 0.5% fuchsin solution for 24h. The restorations were sectioned in buccolingual direction. Then they were evaluated for microleakage by using a stereomicroscope and scored as 0, 1, 2, and 3 and then Kruskal-Wallis test was used (p< 0.05). RESULTS: The groups were not significantly different regarding the microleakage in the coronal and cervical margins (p< 0.423 and p< 0.212, respectively); however, the Filtek P90 yielded the best results. In all groups, except group 5 (p= 0.018), the cervical margins had greater microleakage than the coronal margins. CONCLUSION: The results suggested that low-shrinkage resin composites may not reduce the marginal microleakage. The proper use of conventional resin composites may offer comparable clinical results. PMID- 26966711 TI - Gingival Enlargement in a Case of Variant Jones Syndrome: a Case Report. AB - Gingival enlargement can be caused by a variety of etiological factors like inflammation, drugs, and systemic diseases or can be presented as a part of a syndrome. One such syndrome is Jones Syndrome, which is associated with gingival enlargement and progressive hearing loss. We present here a case of fifteen-year old boy with gingival enlargement, hearing loss, and generalized alveolar bone loss and diagnosed as Jones syndrome. The diagnosis was made based on history, clinical, radiographic, and histopathological findings. Gingival enlargement was surgically managed using gingivectomy and no recurrence was observed. The patient showed remarkable esthetical and functional improvement. PMID- 26966712 TI - Bilateral Supernumerary Deciduous Maxillary Lateral Incisors with Fusion: Report of a Rare Case. AB - Dental anomaly in number, size and shape might be due to excessive activation of dental lamina during the morpho-differentiation stage. Fusion is one of the most unusual and rare anomalies of shape of the teeth. It frequently involves the supernumerary teeth resulting in a challenging differential diagnosis with gemination. Dental anomalies may result in different problems such as delayed eruption and crowding; thus, early diagnosis is required for effective intervention and proper in-time treatment. The case reported here is a 4-year-old girl with bilateral supernumerary primary maxillary lateral incisors associated with fusion between primary maxillary left lateral incisor and supernumerary lateral tooth. PMID- 26966713 TI - Syndromic craniosynostosis associated with microdeletion of chromosome 19p13.12 19p13.2. AB - Craniosynostosis, a condition in which the cranial sutures prematurely fuse, can lead to elevated intracranial pressure and craniofacial abnormalities in young children. Currently surgical intervention is the only therapeutic option for patients with this condition. Craniosynostosis has been associated with a variety of different gene mutations and chromosome anomalies. Here we describe three cases of partial deletion of chromosome 19p. Two of the cases present with syndromic craniosynostosis while one has metopic ridging. A review of the genes involved in the rearrangements between the three cases suggests several gene candidates for craniosynostosis. CALR and DAND5, BMP regulators involved in osteoblast differentiation, and MORG1, a mediator of osteoclast dysregulation may play a role in abnormal cranial vault development. Additionally, CACNA1A, a gene that when mutated is associated with epilepsy and CC2D1A, a gene associated with nonsyndromic mental retardation may contribute to additional phenotypic features seen in the patients we describe. In addition, these findings further support the need for genetic testing in cases of syndromic craniosynostosis. PMID- 26966714 TI - Data for iTRAQ profiling of micro-vesicular plasma specimens: In search of potential prognostic circulatory biomarkers for Lacunar infarction. AB - To discover potential prognostic biomarkers of Lacunar infarction (LACI), here we present quantitative proteomics data of plasma microvesicle-enriched fraction derived by comparative isobaric profiling of three groups of prospectively followed-up LACI patients (LACI - no adverse outcome, LACI -recurrent vascular event and LACI - cognitive decline) and a demographically matched control group. We confidently (unused prot score >3, FDR=1.1%) identified 183 proteins, 43 out of which were significantly regulated (p-value<0.05) in at least one of the three LACI groups in comparison to control group. Bioinformatics analysis and data mining revealed upregulation of brain-specific proteins including myelin basic protein, proteins of coagulation cascade (e.g., fibrinogen alpha chain, fibrinogen beta chain) and focal adhesion (e.g., integrin alpha-IIb, talin-1, and filamin-A) while albumin was downregulated in both groups of patients with adverse outcome. The data of this study are also in line with our previously published article entitled "Discovery of prognostic biomarker candidates of Lacunar infarction by quantitative proteomics of microvesicles enriched plasma" by Datta et al. (2014). The raw data had been deposited to the ProteomeXchange consortium with identifier PXD000748. PMID- 26966715 TI - Data supporting the role of electric field and electrode material on the improvement of the ageing effects in hydrogenated amorphous silicon solar cells. AB - Hydrogenated amorphous Si (a-Si:H) solar cells are strongly affected by the well known Staebler-Wronski effect. This is a worsening of solar cell performances under light soaking which results in a substantial loss of cell power conversion efficiency compared to time zero performance. It is believed not to be an extrinsic effect, but rather a basic phenomenon related to the nature of a-Si:H and to the stability and motion of H-related species in the a-Si:H lattice. This work has been designed in support of the research article entitled "Role of electric field and electrode material on the improvement of the ageing effects in hydrogenated amorphous silicon solar cells" in Solar Energy Materials & Solar Cells (Scuto et al. [1]), which discusses an electrical method based on reverse bias stress to improve the solar cell parameters, and in particular the effect of temperature, electric field intensity and illumination level as a function of the stress time. Here we provide a further set of the obtained experimental data results. PMID- 26966716 TI - Mechanical properties and drug release behavior of PCL/zein coated 45S5 bioactive glass scaffolds for bone tissue engineering application. AB - This article presents data related to the research article entitled "The effect of coating type on mechanical properties and controlled drug release of PCL/zein coated 45S5 bioactive glass scaffolds for bone tissue engineering" [1]. We provide data on mechanical properties, in vitro bioactivity and drug release of bioactive glass (BG) scaffolds coated by poly (epsilon-caprolactone) (PCL) and zein used as a controlled release device for tetracycline hydrochloride (TCH). By coating the BG scaffolds with PCL or PCL/zein blend the mechanical properties of the scaffolds were substantially improved, i.e., the compressive strength increased from 0.004+/-0.001 MPa (uncoated BG scaffolds) to 0.15+/-0.02 MPa (PCL/zein coated BG scaffolds). A dense bone-like apatite layer formed on the surface of PCL/zein coated scaffolds immersed for 14 days in simulated body fluid (SBF). The data describe control of drug release and in vitro degradation behavior of coating by engineering the concentration of zein. Thus, the developed scaffolds exhibit attractive properties for application in bone tissue engineering research. PMID- 26966717 TI - Data in support of association study of the brain-derived neurotrophic factor gene SNPs and completed suicide in the Slovenian sample. AB - This data article provides the data generated from additional analyses of a genetic association study, where 7 single nucleotide polymorphisms (SNPs) near/within the brain-derived neurotrophic factor (BDNF) gene were investigated for an association with completed suicide in Slavic population (Ropret et al., 2015) [1]. One SNP was excluded from the present analyses due to insufficient genotyping rate (rs1491850) and the remaining 6 SNPs (rs7124442, rs10767664, rs962369, rs12273363, rs908867, rs1491851) were analyzed to gain deeper insight into the possible role of these SNPs in the studied phenotype. We present data on logistic regression analyses of: (a) genotypes under four inheritance models, and (b) haplotypes using 2-, 3- and 4-adjacent SNPs sliding window procedure. In both analyses adjustments for potential confounders (age, gender and alcohol dependence syndrome status) were executed. Data may serve as a reference for comparison of the populations with either low or very high suicide rates. The raw genotyping data that could be used in case meta-analyses should be performed may be provided upon request. PMID- 26966718 TI - Handwriting Moroccan regions recognition using Tifinagh character. AB - The territorial organization of Morocco during administratives division of 2009 is based on 16 regions. In this work we will create a system of recognition of handwritten words (names of regions) using the Amazigh language is an official language by the Moroccan Royal Institute of Amazigh Culture (IRCAM) (2003a) [1] such as this language is slightly treated by researchers in pattern recognition field that is why we decided to study this language (El Kessab et al., 2013 [3]; El Kessab et al., 2014 [4]) that knowing the state make a decision to computerize the various public sectors by this language. In this context we propose a data set for handwritten Tifinagh regions composed of 1600 image (100 Image for each region). The dataset can be used in one hand to test the efficiency of the Tifinagh region recognition system in extraction of characteristics significatives and the correct identification of each region in classification phase in the other hand. PMID- 26966719 TI - Interaction of beta1-adrenoceptor with RAGE mediates cardiomyopathy via CaMKII signaling. AB - Stimulation of beta1-adrenergic receptor (beta1AR), a GPCR, and the receptor for advanced glycation end-products (RAGE), a pattern recognition receptor (PRR), have been independently implicated in the pathogenesis of cardiomyopathy caused by various etiologies, including myocardial infarction, ischemia/reperfusion injury, and metabolic stress. Here, we show that the two distinctly different receptors, beta1AR and RAGE, are mutually dependent in mediating myocardial injury and the sequelae of cardiomyopathy. Deficiency or inhibition of RAGE blocks beta1AR- and RAGE-mediated myocardial cell death and maladaptive remodeling. Ablation or blockade of beta1AR fully abolishes RAGE-induced detrimental effects. Mechanistically, RAGE and beta1AR form a complex, which in turn activates Ca2+/calmodulin-dependent kinase II (CaMKII), resulting in loss of cardiomyocytes and myocardial remodeling. These results indicate that RAGE and beta1AR not only physically crosstalk at the receptor level, but also functionally converge at the common mediator, CaMKII, highlighting a combined inhibition of RAGE and beta1AR as a more effective therapy to treat diverse cardiovascular diseases, such as myocardial infarction, ischemia/reperfusion injury, and diabetic cardiovascular complications. PMID- 26966720 TI - Journal title changes from Korean Journal of Urology to Investigative and Clinical Urology. PMID- 26966721 TI - The artificial urinary sphincter and male sling for postprostatectomy incontinence: Which patient should get which procedure? AB - Surgery is the most efficacious treatment for postprostatectomy incontinence. The ideal surgical approach depends on a variety of patient factors including history of prior incontinence surgery or radiation treatment, bladder contractility, severity of leakage, and patient expectations. Most patients choose to avoid a mechanical device, opting for the male sling over the artificial urinary sphincter. The modern male sling has continued to evolve with respect to device design and surgical technique. Various types of slings address sphincteric incompetence via different mechanisms of action. The recommended surgery, however, must be individualized to the patient based on degree of incontinence, detrusor contractility, and urethral compliance. A thorough urodynamic evaluation is indicated for the majority of patients, and the recommendation for an artificial urinary sphincter, a transobturator sling, or a quadratic sling will depend on urodynamic findings and the patient's particular preference. As advancements in this field evolve, and our understanding of the pathophysiology of incontinence and mechanisms of various devices improves, we expect to see continued evolution in device design. PMID- 26966722 TI - Current status of active surveillance in prostate cancer. AB - Active surveillance (AS) is a management strategy involving close monitoring the course of disease with the expectation to intervene if the cancer progress, in a super-selected group of low-risk prostate cancer (PCa) patients. Determining AS candidates should be based on careful individualized weighing of numerous factors: life expectancy, general health condition, disease characteristics, potential side effects of treatment, and patient preference. Several protocols have been developed to determine insignificant PCa for choosing ideal AS candidates. Results regarding disease reclassification during AS have been also reported. In an effort to enhance accuracy during selection of AS candidate, there were several reports on using magnetic resonance imaging for prediction of insignificant PCa. Currently, there is an urgent need for further clinical studies regarding the criteria for recommending AS, the criteria for reclassification on AS, and the schedule for AS. Considering the racial differences in behavior of PCa between Western and Asian populations, more stringent AS protocols for Asian patients should be established from additional, well-designed, large clinical studies. PMID- 26966723 TI - Therapeutic efficacy of nanomedicines for prostate cancer: An update. AB - Recent advances in cancer nanomedicine have attracted remarkable attention in medical sectors. Pharmacologic research on nanomedicines, including targeted cancer therapy, has increased dramatically in the past 5 years. The success stories of nanomedicines in the clinical field include the fabrication of nanomedicines that show maximum loading efficiency into carriers, maximal release kinetics, and minimum toxicity to healthy cells. Nanoparticle-mediated medicines have been developed to specifically target prostate cancer tissue by use of aptamers, antibody targeting, and sustained release of nanomedicines in a dose- and time-dependent manner. Nanomedicines have been developed for therapeutic application in combination with image-guided therapy in real time. The scope of one of these nanomedicines, Abraxane (paclitaxel), may be extended to prostate cancer therapeutic applications for better quality of patient life and longer survival. This review provides an update on the latest directions and developments in nanomedicines for prostate cancer. PMID- 26966725 TI - Chromosomal aberrations in benign prostatic hyperplasia patients. AB - PURPOSE: To investigate the chromosomal changes in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A total of 54 patients diagnosed with clinical BPH underwent transurethral prostate resection to address their primary urological problem. All patients were evaluated by use of a comprehensive medical history and rectal digital examination. The preoperative evaluation also included serum prostate-specific antigen (PSA) measurement and ultrasonographic measurement of prostate volume. Prostate cancer was detected in one patient, who was then excluded from the study. We performed conventional cytogenetic analyses of short-term cultures of 53 peripheral blood samples obtained from the BPH patients. RESULTS: The mean (+/-standard deviation) age of the 53 patients was 67.8+/-9.4 years. The mean PSA value of the patients was 5.8+/-7.0 ng/mL. The mean prostate volume was 53.6+/-22.9 mL. Chromosomal abnormalities were noted in 5 of the 53 cases (9.4%). Loss of the Y chromosome was the most frequent chromosomal abnormality and was observed in three patients (5.7%). There was no statistically significant relationship among age, PSA, prostate volume, and chromosomal changes. CONCLUSIONS: Loss of the Y chromosome was the main chromosomal abnormality found in our study. However, this coexistence did not reach a significant level. Our study concluded that loss of the Y chromosome cannot be considered relevant for the diagnosis of BPH as it is for prostate cancer. Because BPH usually occurs in aging men, loss of the Y chromosome in BPH patients may instead be related to the aging process. PMID- 26966724 TI - Korean clinical practice guideline for benign prostatic hyperplasia. AB - In 2014, the Korean Urological Association organized the Benign Prostatic Hyperplasia Guideline Developing Committee composed of experts in the field of benign prostatic hyperplasia (BPH) with the participation of the Korean Academy of Family Medicine and the Korean Continence Society to develop a Korean clinical practice guideline for BPH. The purpose of this clinical practice guideline is to provide current and comprehensive recommendations for the evaluation and treatment of BPH. The committee developed the guideline mainly by adapting existing guidelines and partially by using the de novo method. A comprehensive literature review was carried out primarily from 2009 to 2013 by using medical search engines including data from Korea. Based on the published evidence, recommendations were synthesized, and the level of evidence of the recommendations was determined by using methods adapted from the 2011 Oxford Centre for Evidence-Based Medicine. Meta-analysis was done for one key question and four recommendations. A draft guideline was reviewed by expert peer reviewers and discussed at an expert consensus meeting until final agreement was achieved. This evidence-based guideline for BPH provides recommendations to primary practitioners and urologists for the diagnosis and treatment of BPH in men older than 40 years. PMID- 26966726 TI - The establishment of KORCC (KOrean Renal Cell Carcinoma) database. AB - PURPOSE: The purpose of this article is to report establishment of the 1st Web based database (DB) system to collect renal cell carcinoma (RCC) data in Korea. MATERIALS AND METHODS: The new Web-based DB system was established to collect basic demographic and clinicopahtological characteristics of a large cohort of patients with RCC in Korea. Data from a total of 6,849 patients were collected from 8 tertiary care hospitals that agreed to participate in organizing the Korean Renal Cell Carcinoma (KORCC) study group as of 1 July 2015. Basic demographic and clinicopathological characteristics were collected. The data of patients who underwent surgical treatments were analyzed to characterize Korean RCC. RESULTS: We established the 1st Web-based DB of Korean RCC, a database comprising renal mass management cases from multiple centers in Korea. The data of 5,281 patients who underwent surgical management (mean follow-up, 32 months) were analyzed. The most common symptom was incidentally detected renal mass (76.9%). Clinical T1a was the most common (54.3%) stage and mean tumor size was 4.8+/-4.2 cm. Radical nephrectomy accounted for 62.7% of cases and an open approach was used in 50.7% and 52.2% of radical and partial nephrectomies, respectively. The 5-year overall, cancer-specific and recurrence-free survival rates were 88.1%, 92.2%, and 88.0%, respectively. CONCLUSIONS: We report the 1st establishment of a Web-based DB system to collect RCC data in Korea. This DB system will provide a solid basis for the characterization of Korean RCC. PMID- 26966727 TI - Secondary surgery for vesicoureteral reflux after failed endoscopic injection: Comparison to primary surgery. AB - PURPOSE: As endoscopic treatment for vesicoureteral reflux (VUR) has increased, secondary ureteral reimplantation (UR) after failure of endoscopic treatment has increased. We studied the clinical feature and efficacy of secondary UR after failure of endoscopic treatment compared with primary UR. MATERIALS AND METHODS: Eighty-one children who had UR for VUR were enrolled. Charts were reviewed retrospectively for age, sex, grade of VUR before surgery, operative time, hospitalization period, postoperative complication, and success rate. Primary UR (group A, n=64) was compared with secondary UR after failed endoscopic treatment (group B, n=17). In group B, telephone survey for the satisfaction of endoscopic treatment and surgery was done. RESULTS: Mean age of each group was 49.6+/-37.1 and 56.6+/-22.5 months (p=0.236). There was no significant difference between each group in sex, mean operative time, postoperative transfusion, complication rate, and success rate. As telephone survey in group B, eleven responders preferred endoscopic treatment as primary treatment of VUR because it was a simple method and no hospitalization. CONCLUSIONS: Secondary UR after failure of endoscopic treatment was similar to primary UR. Parents preferred endoscopic treatment as first line treatment for VUR in spite of the need for secondary UR after failure of endoscopic treatment. PMID- 26966730 TI - Mechanism for the photoreduction of poly(vinylpyrrolidone) to HAuCl4 and the dominating saturable absorption of Au colloids. AB - Both fabrication of Au nano-objects and the nonlinear optical properties of Au nano-objects are the focus of research. In the present work, Au nanoparticles with different mean sizes (18, 32, 42, and 70 nm) are controllably fabricated in ethanol by changing the concentration of poly(vinylpyrrolidone) (PVP) and HAuCl4, as well as the power of continuous wave UV light at 365 nm. PVP acts as both reducing and protective agent. The mechanism of photoreduction of PVP to HAuCl4 is proposed. PVP undergoes a series of chemical reactions which include the attack of the hydrogen atom on the tertiary carbon atom at the alpha-position of the nitrogen atom, production of a hydroxyl radical, and chain scission. The hydroxyl radical combines with the hydrogen atom produced through the dissociation of HAuCl4, which facilitates the decomposition of HAuCl4. The fabrication mechanism of Au nanoparticles is discussed. The nonlinear absorption of these Au nanoparticles is investigated; all of them exhibit saturable absorption, and the saturable absorption dominates the nonlinear absorption with the increase of laser energy. The dominance of saturable absorption in the nonlinear absorption is due to the stronger single-photon absorbed intraband absorption from the ground state to the first excited state in the conduction band, the weaker excited state absorption in the conduction band, and the weaker two-photon absorption from the d band to the conduction band. PMID- 26966729 TI - Ultrasound Accuracy of Liver Length Measurement with Cadaveric Specimens. AB - The liver is one of the principal organs of our body involved in over 500 physiological functions related to metabolism, digestion, immunity, and storage of nutrients, which makes it an essential organ to preserve life. Given that there are a number of approaches to measure liver length through diagnostic 2D sonography, this work aims to determine the most accurate measurement of this organ. Cadaveric specimens (n = 21) were employed to assess measurements in midclavicular line (MCL) and midaxillary line (MAL). Each measurement was calculated in anteroposterior (AP) and craniocaudal (CC) planes. In addition, in situ measurements were obtained by accessing the organ through the anterior thoracoabdominal wall. Statistical differences were detected between MCL and MAL measurements (p < 0.05), a positive correlation between MAL CC and in situ anterior measurements were noted (r = 0.97). Liver size, as assessed through in situ measurements, varied as a funtion of BMI and waist circumference (p < 0.05). It is concluded that CC measurement of the RLL in MAL from the uppermost right hemi-diaphragm to the inferior tip of the right lobe through a horizontal line parallel to the anterior liver wall is the most accurate measurement of the organ by sonography. PMID- 26966728 TI - Upregulated expression of BCL2, MCM7, and CCNE1 indicate cisplatin-resistance in the set of two human bladder cancer cell lines: T24 cisplatin sensitive and T24R2 cisplatin resistant bladder cancer cell lines. AB - PURPOSE: The mechanism of resistance to cisplatin during treatment of bladder cancer (BC) has been a subject of intense investigation in clinical research. This study aims to identify candidate genes associated with resistance to cisplatin, in order to understand the resistance mechanism of BC cells to the drug, by combining the use of microarray profiling, quantitative reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analyses. MATERIALS AND METHODS: The cisplatin sensitive human BC cell line (T24) and the cisplatin resistant BC cell line, T24R2, were used for microarray analysis to determine the differential expression of genes that are significant in cisplatin resistance. Candidate upregulated genes belonging to three well-known cancer related KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways (p53 tumor suppressor, apoptosis, and cell cycle) were selected from the microarray data. These candidate genes, differentially expressed in T24 and T24R2, were then confirmed by quantitative RT-PCR and western blot. A fold change >=2 with a p value <0.05 was considered significant. RESULTS: A total of 18 significantly upregulated genes were detected in the three selected cancer-related pathways in both microarray and RT-PCR analyses. These genes were PRKAR2A, PRKAR2B, CYCS, BCL2, BIRC3, DFFB, CASP6, CDK6, CCNE1, STEAP3, MCM7, ORC2, ORC5, ANAPC1, and ANAPC7, CDC7, CDC27, and SKP1. Western blot analyses also confirmed the upregulation of BCL2, MCM7, and CCNE1 at the protein level, indicating their crucial association with cisplatin resistance. CONCLUSIONS: The BCL2, MCM7, and CCNE1 genes might play distinctive roles in cisplatin resistance in BC. PMID- 26966731 TI - Charge retention of soft-landed phosphotungstate Keggin anions on self-assembled monolayers. AB - Soft landing of mass-selected ions onto surfaces often results in partial loss of charge that may affect the structure and reactivity of deposited species. In this study, Keggin phosphotungstate anions in two selected charge states, PW12O40(3-) (WPOM(3-)) and PW12O40(2-) (WPOM(2-)), were soft-landed onto different self assembled monolayer (SAM) surfaces and examined using in situ infrared reflection absorption spectroscopy (IRRAS) and density functional theory (DFT) calculations. Partial retention of the 3- charge was observed when WPOM(3-) was soft-landed onto the fluorinated SAM (FSAM), while the charge state distribution was dominated by the 2- charge after both WPOM(3-) and WPOM(2-) were deposited onto a hydrophilic alkylthiol SAM terminated with cationic NH3(+) functional groups (NH3(+)SAM). We found that during the course of the soft landing of WPOM(3-), the relative abundance of WPOM(3-) on FSAM decreased while that of WPOM(2-) increased. We propose that the higher stability of immobilized WPOM(2-) in comparison with WPOM(3-) makes it the preferred charge state of WPOM on both the FSAM and NH3(+)SAM. We also observe weaker binding of WPOM anions to SAMs in comparison with phosphomolybdate ions (MoPOM) reported previously (J. Phys. Chem. C, 2014, 118, 27611-27622). The weaker binding of WPOM to SAMs is attributed to the lower reactivity of WPOM reported in the literature. This study demonstrates that both the charge retention and the reactivity of deposited anionic POM clusters on surfaces are determined by the type of addenda metal atoms in the cluster. PMID- 26966732 TI - Aromatic cages B: unprecedented existence of octagonal holes in boron clusters. AB - The cage-like structures containing octagonal holes are located as the lowest lying isomers for the B. The presence of octagonal holes, which have been found for the first time, not only gives us new insight into the bonding motif, but also marks a breakthrough in the structural characteristics of boron clusters since they were never expected to be stable units for elemental clusters. These cages are composed of both delocalized sigma and pi electron systems that consequently make them aromatic and thermodynamically stable. PMID- 26966733 TI - Effects of Fe cations in ruthenium-complex multilayers fabricated by a layer-by layer method. AB - Molecular multilayers were fabricated using a Ru complex containing Fe cations on an indium tin oxide surface to control the properties of the Ru-complex multilayers such as the multilayer orientation and the electron transport. The Ru complex multilayer films containing Fe cations were thicker than those containing Zr cations, which have been used previously. The electron transport properties of the multilayers containing Fe cations were evaluated. Solid-state sandwich cell measurements showed that the Ru-complex multilayer films containing Fe cations exhibited increased electron transport with a lower transport coefficient beta of 0.01 A(-1), whereas those that contain Zr cations have beta ~ 0.07 A(-1). Thus, Fe cations are effective in obtaining thicker Ru-complex layers with increased electron transport abilities. PMID- 26966735 TI - Ionic liquid-based materials: a platform to design engineered CO2 separation membranes. AB - During the past decade, significant advances in ionic liquid-based materials for the development of CO2 separation membranes have been accomplished. This review presents a perspective on different strategies that use ionic liquid-based materials as a unique tuneable platform to design task-specific advanced materials for CO2 separation membranes. Based on compilation and analysis of the data hitherto reported, we provide a judicious assessment of the CO2 separation efficiency of different membranes, and highlight breakthroughs and key challenges in this field. In particular, configurations such as supported ionic liquid membranes, polymer/ionic liquid composite membranes, gelled ionic liquid membranes and poly(ionic liquid)-based membranes are detailed, discussed and evaluated in terms of their efficiency, which is attributed to their chemical and structural features. Finally, an integrated perspective on technology, economy and sustainability is provided. PMID- 26966734 TI - A study of temperature dependent local atomic displacements in a Ba(Fe(1 x)Co(x))2As2 superconductor. AB - We have studied the local structure of a Ba(Fe(1-x)Co(x))2As2 superconductor using temperature dependent extended X-ray absorption fine structure (EXAFS) measurements. Polarized EXAFS at the Fe K-edge on an optimally doped (x = 0.06) single crystal has permitted us to determine atomic displacements across the superconducting transition temperature (T(c)). The Fe-As bondlength hardly shows any change with temperature; however, the Fe-Fe sublattice reveals a sharp anomaly across T(c), indicated by a significant drop in mean square relative displacements, similar to the one known for cuprates and A15-type superconductors. We have also found a large atomic disorder around the substituted Co, revealed by polarized Co K-edge EXAFS measurements. The Co-Fe/Co bonds are more flexible than the Fe-Fe bonds with the As-height in Co-containing tetrahedra being larger than the one in FeAs4. The results suggest that the local Fe-Fe bondlength fluctuations and the atomic disorder in this sub-lattice should have some important role in the superconductivity of Ba(Fe(1-x)Co(x))2As2 pnictides. PMID- 26966736 TI - A stable open-shell redox active ditopic ligand. AB - Herein we describe the synthesis, structure and electronic properties of an unusual redox-active ditopic ligand with a stable open-shell configuration. This stable phenoxyl radical features intense and very low energy electronic transitions in the near infrared (NIR) part of the spectrum and is structurally set up to strongly spin couple coordinated transition metal ions in [2 * 2] grid type structures. PMID- 26966737 TI - [Not Available]. PMID- 26966738 TI - [Not Available]. PMID- 26966740 TI - [Not Available]. PMID- 26966739 TI - [Not Available]. PMID- 26966741 TI - [Not Available]. PMID- 26966742 TI - Author reply. PMID- 26966743 TI - In Memoriam Daniel Morton. PMID- 26966745 TI - [Not Available]. PMID- 26966744 TI - Group dynamics: A lab of their own. PMID- 26966747 TI - Message from the WHO Regional Director for Europe: European Member States welcome increased WHO support for refugee and migrant health. PMID- 26966746 TI - Cryoglobulinemia presenting with crystals in peripheral blood. PMID- 26966748 TI - THE ORIGIN OF THE CONCEPT OF NEUROPATHIC PAIN IN EARLY MEDIEVAL PERSIA (9TH-12TH CENTURY CE). AB - Neuropathic pain is supposed to be a post-renaissance described medical entity. Although it is often believed that John Fothergill (1712-1780) provided the first description of this condition in 1773, a review of the medieval Persian medical writings will show the fact that neuropathic pain was a medieval-originated concept. "Auojae Asab" [Nerve-originated Pain] was used as a medical term in medieval Persian medical literature for pain syndromes which etiologically originated from nerves. Physicians like Rhazes (d. 925 CE), Haly Abbas (d. 982 CE), Avicenna (d. 1037 CE), and Jorjani (d. 1137 CE) have discussed multiple aspects of nerve-originated pain including its classification, etiology, differentiating characteristics, different qualities, and pharmacologic and non pharmacologic treatments. Recognizing medieval scholars' views on nerve originated pain can lighten old historical origins of this concept. PMID- 26966749 TI - [HYPERPROLACTINEMIA AND SELECTIVE SEROTONIN REUPTAKE INHIBITORS. A NARRATIVE REVIEW OF THE LITERATURE]. AB - A large number of scientific papers have reported the relationship between the development of hyperprolactinemia and the use of psychotropic drugs, especially the role of antipsychotics which are antidopaminergic drugs. However, less information is known about the role of antidepressants in the development of hyperprolactinemia, specially the selective reuptake inhibitors (SSRIs). The prevalence of hyperprolactinemia as a pharmacological side effect of SSRIs is still unknown, despite the widespread use over the last decade. The aim of this review is to explore the relationship between hyperprolactinemia and SSRIs. PMID- 26966751 TI - [QUATERNARY PREVENTION IN MENTAL HEALTH]. PMID- 26966750 TI - [RESEARCH AMONG PSYCHIATRISTS IN TRAINING IN CIUDAD DE BUENOS AIRES]. AB - Research is a cornerstone in the training of medical doctors in any specialty, whereas it substantially contributes to good clinical practice. The aim of this study is to determine the importance of research among psychiatrists in training in Ciudad de Buenos Aires. A cross sectional descriptive study using a paper survey, which was voluntary and anonymous, was sent to psychiatrists in training in different training centers between October-November 2013. 76.6% considered research training deficient; 27.8% participated in a research project during their psychiatric training and only 21.5% presented their results at a scientific activity. 95.6% participants considered important to include research in their training. In summary, a small proportion of psychiatrists in training who participated in this study conducted research and we observed limited experience in the area, as opposed to the interest in being trained in this field. PMID- 26966752 TI - [QUATERNARY PREVENTION: AN ATTEMPT TO AVOID THE EXCESSES OF MEDICINE]. AB - Seduced by technology, biometrics, practical guidelines and the use of medication, medicine has been driven away from the subject of its care. Quaternary prevention is, among other voices around the world, trying to denounce the consequent excesses of medical practice given by this situation. There are visible excesses, such as the long list of studies being performed on patients without indication, and others, much more subtle, as excessive prevention and the continuous and progressive medicalization of life itself that are rooted in our culture and demanded by a society that requests certainty at almost any cost. Quaternary prevention proposes a series of actions leaning towards avoiding and diminishing the damage produced by health care activities, in order to protect the subject of overdiagnosis and overtreatment; offering also ethical and viable alternatives in which the balance of risks and benefits (based on the best evidences) respects the autonomy of the subject by properly informing and allowing him to decide among the best options he has; altogether in a process that contemplates a rational and equitable use of resources. In order to achieve this, reliable sources of information and a medical education not dependent on industries related to technology or pharmaceuticals, are vital; in conjuction with a medicine that restablishes the subject as its main and central interest. PMID- 26966754 TI - [THE MATTER: NO PSYCHIATRIZATION]. AB - Anxiety, sadness, worries, fears, irritability, fatigue, tedium, are situations that life confront us with. They don't qualify as psy- chiatric disorders, but nevertheless they are treated as though. We refer to the psychiatrization of daily life. The aim of this article is to prevent such psychiatrization. To support this assertion, we are going to develop different aspects tending to explain the origins of the patient's demands and the answers given by the psychiatrist. A critical reflection of our practice is proposed. PMID- 26966753 TI - [THE ART OF DOING MINIMAL HARM IN MENTAL HEALTH]. AB - There are socio-cultural and political-economic conditions that favor interventionism in mental health and iatrogenesis. However, the professional, in relationship with the patient, has the ability to reduce harm in clinical practice. This article, briefly, reviews the damage of work in mental health and arises, from the recognition of professional intellectual and personal conflicts, the foundation for a practice that causes the least harm to patients PMID- 26966755 TI - [PSYCHOTHERAPY, THE PRECIOUS GIRL IN THE HEALTH FIELD: ALWAYS USEFUL AND NEVER HARMFUL?]. AB - The present paper reviews some psychotherapy's features through the light of it's alleged supposedly invariant usefulness and incapacity to harm consultants. Differences between general health field and mental health field are discussed with the assis- tance of the concepts of necessity, supply and demand, in order to understand psychotherapeutic supply dynamics. Its use with non-diagnosed clients and the explicit decission to give assistance to people ailed with discomfort are discussed based on international studies on prevalence and efficacy of psychotherapy. Its harmfulness, underreporting by psychotherapists and specific proposals to reduce it are reviewed. Some considerations regarding psychotherapy as part of the health field are discussed. PMID- 26966756 TI - [FROM ULYSSES TO PARIS: JOURNEY TO THE MEDICALIZATION OF AGEING]. AB - In the following study we will be introducing the Paris Syndrome, taking as a departure stand the Ulises Syndrome described by Mercer Rang back in 1972. This syndrome is analyzed within the current context of medicalization that old people within Western societies are currently undergoing. We decided to present this topic by looking at the medical trajectories of four paradigmatic patients with the intention of capturing how they themselves experience this process. Through these cases, we would also like to further understand current medical practices toward the elderly. PMID- 26966757 TI - [THE OPPORTUNITY TO TRANSFORM THE MODEL OF MENTAL HEALTH CARE OF ARGENTINA TO A MODEL BASED ON SCIENTIFIC EVIDENCE BASED ON THE NATIONAL MENTAL HEALTH LAW]. AB - Mental disorders significantly contribute to the burden of disease, reduce the quality or life, and pose vast economic and social costs. Furthermore, access to treatment and treatment quality is often poor, particularly in low- and middle income countries. Indeed, WHO urged countries to develop policies and comprehensive mental health strategies. In response, Argentina promulgated a National Mental Health Law (NMHL, No. 26.657) that was regulated through the Regulatory Decree No. 603/2013 and implemented through the National Mental Health Plan (NMHP). The NMHL defines the vision, values, and principles for improving the mental health system for the country via urging that mental health care be based on scientific evidence adjusted to ethical principles. This is not new in other areas of health; however, it implies a paradigm shift for the mental health system in Argentina. Inconsistencies between the conceptual framework that raises the NMHL and operational instruments issued by the National Mental Health and Addiction Department were observed. These inconsistencies reflect the resistance to change in paradigm. PMID- 26966758 TI - [Doctoral theses at the University of Buenos Aires]. PMID- 26966760 TI - [The Magic Mountain]. PMID- 26966761 TI - PAEDIATRIC DENTISTRY--WHY CARIES?. PMID- 26966759 TI - [Pedro Alcacer (1883). ]. PMID- 26966762 TI - DEAN'S UPDATE. PMID- 26966763 TI - MEMBERSHIP UPDATE. PMID- 26966764 TI - EDUCATION UPDATE. PMID- 26966765 TI - INTERFACE BETWEEN DEMENTIA AND ORAL HEALTH. PMID- 26966766 TI - WORKING TOGETHER TO DELIVER JOINED-UP CARE FOR OUR YOUNG PATIENTS. PMID- 26966767 TI - DESIGNED TO SMILE--TACKLING CARIES IN YOUNG CHILDREN IN WALES. PMID- 26966768 TI - A CHANGE IN PRACTICE PROTOCOL: PREFORMED METAL CROWNS FOR TREATING NON-INFECTED CARIOUS PRIMARY MOLARS IN A GENERAL PRACTICE SETTING--A SERVICE EVALUATION. AB - Restoring non-infected carious primary molars can pose a challenge to the general dental practitioner. This paper aims to assess the effect on primary caries management and patient experience in a general dental practice setting, when restoring non-infected carious primary molars using a Hall preformed metal crown (PMC). PMID- 26966769 TI - EFFECTIVE CARIES PREVENTION IN A HEBRIDEAN ISLAND POPULATION. AB - BACKGROUND: The Isle of Islay has a remote-rural population. Two dentists have been responsible for the care of the majority of the school-age children for 15 years. The island affords a unique situation to measure caries prevalence in a relatively static population. AIM: This study measures the changes in the dental caries experience of five and 12-year olds exposed to a preventive-based approach to improving dental health, which included a school-based tooth-brushing programme (four to 12-year-olds). DESIGN: Data from practice-based records were collected for children aged five and 12 in the years 1999-2003 and 2012-2014. Indices including percentage of children with no obvious caries, decayed, missing or filled teeth (dmft/DMFT) and care indexes were calculated, translated into graphs and compared to Scotland's National Dental Inspection Programme (NDIP) data. RESULTS: 478 children were included in the study. The mean number in each year group for five-year-olds was 28 (SD +/- 5.65) and for 12-year-olds was 31.75 (SD +/- 8.30). The percentage of children caries-free increased from 39% to 85% (five-year-olds) and 31% to 97% (12-year-olds). DMFT decreased from 3.04 to 0.30 (five-year-olds) and 3.74 to 0.03 (12-year-olds). Figures for care index and percentage of first permanent molars fissure sealed were higher than national data averages. CONCLUSION: Caries prevalence decreased in children in Islay aged five and 12 years over the period 1999-2014. There was no control group but the differences described above can be associated with the introduction of a preventive approach, however they cannot be assumed to be causative. PMID- 26966770 TI - CHILDSMILE: THE CHlLD ORAL HEALTH IMPROVEMENT PROGRAMME IN SCOTLAND. PMID- 26966771 TI - CLUB POLICIES FOR MOUTH PROTECTORS AND DENTAL EMERGENCY COVER IN SCOTTISH RUGBY UNION (SRU) AFFILIATED JUNIOR TEAMS. AB - AIMS: To determine whether club policies exist for junior players concerning the wearing of mouth protectors during training and playing, and whether dental emergency cover is present on both training and match days at Scottish Rugby Union (SRU) affiliated junior clubs. METHOD: A self-reporting structured questionnaire, sent to all SRU affiliated clubs with junior playing members. RESULTS: Response rate was 77% (117 out of 151 clubs) showing a wide variation in policies and implementation. Exclusion was reported from training in 11% (13 out of 151) and from playing on match days in 17% (20 out of 151) of clubs if a mouth protector was not worn. The majority of clubs advocated that shop-bought protectors were satisfactory. First aiders were present at training at 86% (130 out of 151) and on match days at 95% (143 out of 151) of clubs. Fewer than 1% had a dentist and only 3% a doctor present at training. On match days fewer than 2% had a dentist and fewer than 20% a doctor present. CONCLUSION: There is a wide variation in club policies and guidelines thus allowing parents, players and club staff considerable latitude in interpretation. A significant number of youngsters will be at increased risk of dental injury. First aiders are present in a significant number of clubs during training and playing. PMID- 26966772 TI - PREFORMED METAL CROWNS FOR THE PERMANENT DENTITION. AB - Preformed metal crowns have a range of uses in paediatric dentistry in both the primary and permanent dentition. This article provides an overview of their use in permanent teeth, including teeth that have been affected by molar incisor hypomineralisation, caries, developmental defects and tooth surface loss. The indications for use are described, along with the clinical technique for placement PMID- 26966773 TI - PLACEMENT OF PREFORMED METAL CROWNS ON CARIOUS PRIMARY MOLARS BY DENTAL HYGIENE/THERAPY VOCATIONAL TRAINEES IN SCOTLAND: A SERVICE EVALUATION ASSESSING PATIENT AND PARENT SATISFACTION. AB - BACKGROUND: The utility and acceptability of preformed metal crowns (PMC) for management of carious primary molars has been established in the literature and published guidance. The role of dental hygienist and therapists (DHT) in the evolving team model in primary care has been recognised as requiring further investigation. The importance of patient and parental acceptance is acknowledged in recent healthcare research. METHOD: This study focuses on patient and parent acceptance of preformed metal crowns placed by DHTs. Prescription format is investigated and the availability of bitewing radiographs considered. Reflective assignments at the end of training gave an indication of DHTs views on increased professional autonomy and the issue of direct access. Patient and parent satisfaction following placement of PMCs by DHT vocational trainees (DHTVT) were evaluated. Data was collected in two audit rounds from 2013 to 2014 using a 'faces' scale for children and a Likert scale for parents following placement of PMCs on carious primary molars. RESULTS: 133 PMCs were placed (110 children) by 10 DHTVTs over an eight-month period. Overall, radiographs were available for 10.5% of cases. The data showed high levels of patient and parent acceptance of the use of PMCs. CONCLUSIONS: Low availability of radiographs may represent a missed diagnostic opportunity. PMC placement by DHTVTs resulted in high patient and parent satisfaction, comparable to other studies. Although caries has been declining over the last decade in Scotland, evidence shows that inequalities and a social gradient in experience of caries in children remain. There is a need for tools and strategies for the prevention, recognition, risk assessment, diagnosis, and management of caries in the primary dentition. These must be accessible, acceptable to children and their parents/carers, cost effective, affordable and applicable in the primary care general dental practice environment where most families are likely to be registered. The emerging theme of dentistry being provided in a team model with dental care professionals (DCPs) taking on an expanded role is under continuing review following the General Dental Council (GDC) announcements on 'direct access'. The Scottish Dental Hygiene and Therapy Vocational Training (DHTVT) programme is a one-year, elective, post-qualification training programme for Dental Hygiene and Therapy graduates run by NHS Education for Scotland (NES). In 2013-2014, DHTVTs were employed across six Scottish health board areas in hospital, salaried and independent settings in urban and rural locations. The elements of the programme involve a blend of clinical mentoring, web-based learning, case presentations, critical reading, reflective assignments and face-to-face theoretical and practical teaching across a number of modules. The aim of this project was to collect data to indicate patient and parental response following the placement of PMCs, collect data on the use of radiographs in children having PMCs placed and to investigate the role of dental therapists in the dental team. The data, once collated, was presented to DHTVTs to inform reflection on the management of carious primary molars and to raise awareness of issues relating to cost effectiveness of providing treatment in a primary care environment and critically appraise perceived barriers to the use of PMCs in the treatment of carious primary molars. Collated data has been presented to trainers in future cohorts to inform discussion amongst the group of trainers at induction days around dental team working, effective detection, diagnosis, risk assessment and prescription to DHTs. PMID- 26966774 TI - DENTAL CARE PROFESSIONALS AND CHILD PROTECTION: CASE SCENARIOS AND DISCUSSIONS. AB - Any concerns about paediatric patients in general dental practice can be stressful for all involved. Barriers to the reporting of concerns by dental teams are known to exist. Anything that can help ease those situations can only be beneficial. In this article we look at three scenarios that could arise which I am often asked about during teaching and training sessions on safeguarding and child protection for dental teams. They can be discussed at team meetings and training, so that if they are ever to happen for real, everyone will know exactly what to do. This article cannot be completely prescriptive as there will be local variations, but it gives general guidance on issues raised by the scenarios. If you already have a child protection policy in your practice, make sure you know what it says; and if you don't this article will point the way to further resources for developing one. PMID- 26966775 TI - WHY DO YOU NEED TO USE A CARIES RISK ASSESSMENT PROTOCOL TO PROVIDE AN EFFECTIVE CARIES PREVENTIVE REGIME? AB - BACKGROUND: Clinical guidelines recommend an individual is given a caries risk status based on analysis of defined clinical and social criteria before implementing a tailored preventive plan. AIMS: Improve documentation of caries risk assessment (CRA) in a general dental practice setting, using a systems-based approach to quality improvement methods. Investigate the impact of quality improvement efforts on subsequent design and delivery of preventive care. Identify barriers to delivery of CRA and provision of preventive care. DESIGN: Data for patients aged 0-16 years was collected over two cycles using standard audit methodology. The first cycle was a retrospective analysis (n = 400) using random sampling. The second cycle a prospective analysis (n = 513) using consecutive sampling over a 15-week period. Five staff meetings with feedback occurred between cycles. RESULTS: In cycle one, no specific CRA system was identified. CRA status was not stated widely, risk factors were not analysed and there was variation with respect to the prescription and delivery of preventive strategies. These discrepancies were demonstrable for all four participating dentists and at all ages. In cycle two, 100% recorded CRA. All risk factors were analysed and individual caries risk was correctly annotated. There was 100% compliance with the protocol for preventive plans. CONCLUSIONS: The use of CRA improved documentation of caries risk status. This has improved subsequent prescription of age specific evidence-based preventive care appropriate to the risk status of that individual. Barriers were identified to the delivery of CRA and the provision of comprehensive preventive care by the dentists and other healthcare professionals. PMID- 26966776 TI - INVESTIGATING THE MANAGEMENT OF CARIOUS PRIMARY TEETH IN GENERAL DENTAL PRACTICE: AN OVERVIEW OF THE DEVELOPMENT AND CONDUCT OF THE FICTION TRIAL. AB - The management of carious primary teeth is a challenge for patients, parents and clinicians. Most evidence supporting different management strategies originates from a specialist setting and therefore its relevance to the primary care setting is questionable. The UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) has commissioned the FiCTION (Filling Children's Teeth: Indicated Or Not?) trial; a multi-centre primary dental care randomised controlled trial (RCT) to determine the most clinically and cost- effective approach to managing caries in the primary dentition in the UK. This large trial began in 2012, is due to be completed in late 2017 and involves 72 practices and 1,124 children initially aged three to seven years with dentine caries, following randomisation to one of three caries management strategies. Clinical, radiographic, quality of life, treatment acceptability and health economics data are collected during the three-year follow up period. This article provides an overview of the development and conduct of FiCTION and discusses some approaches adopted to manage challenges and achieve the patient recruitment target. PMID- 26966777 TI - MUCH ADO ABOUT BRUSHING: PROMOTING DENTAL HEALTH IN SCHOOLS. PMID- 26966778 TI - CAREER FOCUS: EXPEDITION DENTISTRY. PMID- 26966779 TI - Microaggressions Toward Lesbian, Gay, Bisexual, Transgender, Queer, and Genderqueer People: A Review of the Literature. AB - Microaggressions are subtle forms of discrimination, often unconscious or unintentional, that communicate hostile or derogatory messages, particularly to and about members of historically marginalized social groups. While Sue's (2010a, 2010b) microaggression theory formed its foundation in studies based on racial microaggressions, the following review summarizes microaggression literature to date, as it pertains to the lesbian, gay, bisexual, transgender, queer, and genderqueer (LGBTQ) people. Searching PsycINFO and other databases between 2010 and 2015, we found 35 peer-reviewed papers or dissertations that concentrate on the negative impact microaggressions have on LGBTQ people. A comprehensive overview of the experiences of individual LGBTQ subgroups (e.g., lesbian women, gay men, bisexual people, transgender people, and genderqueer people) is included, as well as microaggressions based on intersectional identities (e.g., experiences of LGBTQ people of color). The significance of this review is that it is the only known article to comprehensively analyze the literature on LGBTQ people and microaggressions, examining the strengths and weaknesses of past literature while encouraging future areas of theory, research, and practice. PMID- 26966780 TI - Tanshinone IIA increases levels of NeuN, protein disulfide isomerase, and Na+/K+ ATPase and decreases evidence of microglial activation after cerebral ischemic injury. AB - This study was designed to clarify the neuroprotective effects of tanshinone IIA (TSA) following cerebral ischemic insult. Adult Sprague-Dawley rats were operated upon to achieve a middle cerebral artery occlusion to cause transient focal cerebral ischemia, which were then randomly divided into the sham-operated control group and cerebral ischemia/reperfusion (I/R) groups receiving a 2 h occlusion. The treatment groups received daily intraperitoneal injections of high or low doses of TSA, for 7 or 15 days. NeuN immunostaining revealed neuronal loss following I/R, which was partially prevented with subsequent TSA dosing. Protein disulfide isomerase and adenosine triphosphatase (Na(+)/K(+)-ATPase) levels were all depressed by means of I/R. TSA treatment markedly reversed the depression of all indices examined. The intensity of microglial activation, as evidenced with CD11b staining, was increased by means of cerebral artery occlusion, but this was partially reversed with subsequent TSA treatment. TSA may affect neuroprotection by way of minimizing deficits in energy metabolism and reduction of the extent of cell death within affected regions. PMID- 26966781 TI - Short-term high-altitude pre-exposure improves neurobehavioral ability. AB - This study aims to evaluate the effect of the duration of high-altitude (HA) pre exposure on human neurobehavioral parameters including mood states and cognitive performance at HA. One hundred and eleven healthy individuals (ranging in age from 18 to 35 years) were recruited to participate in this study. They were divided into two groups: a 4-day short-term HA pre-exposure group (n=57) and a 3 month long-term HA pre-exposure group (n=54). All participants lived in the area at 400 m altitude above sea level before pre-exposure to HA. They were then transported to 3700 m plateau for either a 4-day or a 3-month HA pre-exposure, and finally delivered to 4400 m plateau. On the last day of pre-exposure at 3700 m and on the 10th day at 4400 m, neurobehavioral parameters of the participants in the two groups were evaluated. At the end of pre-exposure and on the 10th day of HA exposure, participants in the short-term group had significantly lower negative mood states, better cognitive performance with higher sensorimotor, attention, and psychomotor abilities, and less acute mountain sickness in comparison with the participants in the long-term pre-exposure group. Our field study with large samples showed that in comparison with 3-month long-term pre exposure, 4-day short-term HA pre-exposure at 3700 m has a better effect in improving human neurobehavioral parameters including mood states and cognitive performance and reducing acute mountain sickness when exposed to a HA at 4400 m. PMID- 26966782 TI - Stress-responsive heme oxygenase-1 isoenzyme participates in Toll-like receptor 4 induced inflammation during brain ischemia. AB - Toll-like receptors (TLRs) are involved in the progression of ischemic brain injury and hence vascular dementia; however, the underlying mechanisms are largely unknown. Here, we have investigated the interrelationship between stress responsive heme oxygenase (HO)-1 isoenzyme and TLR4 during chronic brain hypoperfusion. The right unilateral common carotid artery occlusion was performed by ligation of the right common carotid artery in C57BL/6J mice. The brain cortex or hippocampus was removed for western blotting and confocal immunofluorescence analysis. The link between HO-1 and TLR4 was further examined by silencing TLR4 and pharmacological inhibition of HO-1 in primary cultured cortical neurons. Cognitive dysfunction and decrease in cerebral blood flow in mice were observed 4 weeks after the occlusion. Our data further show that common carotid artery occlusion induced an increase in TLR4 and HO-1 protein levels. Although the administration of CoPP (10 mg/kg), HO-1 agonist, improved the cognitive dysfunction in a mice model of occlusion, western blot analysis in primary cultured cortical neurons showed that HO-1 was upregulated after lipopolysaccharide treatment; this was partially abolished by the TLR4 siRNA interference. The flow cytometry analysis showed that pharmacological inhibition of HO-1 by ZnPP (100 MUM) further exaggerated lipopolysaccharide-induced neuronal cell death. Hence, stress-responsive HO-1 isoenzyme participates in TLR4-induced inflammation during chronic brain ischemia. The pharmacological manipulation of TLR4 or the HO-1 antioxidant defense pathway may represent a novel treatment strategy for neuronal protection in vascular dementia. PMID- 26966783 TI - Imidacloprid toxicity impairs spatial memory of echolocation bats through neural apoptosis in hippocampal CA1 and medial entorhinal cortex areas. AB - It has been reported that the decimation of honey bees was because of pesticides of imidacloprid. The imidacloprid is a wildly used neonicotinoid insecticide. However, whether imidacloprid toxicity interferes with the spatial memory of echolocation bats is still unclear. Thus, we compared the spatial memory of Formosan leaf-nosed bats, Hipposideros terasensis, before and after chronic treatment with a low dose of imidacloprid. We observed that stereotyped flight patterns of echolocation bats that received chronic imidacloprid treatment were quite different from their originally learned paths. We further found that neural apoptosis in hippocampal CA1 and medial entorhinal cortex areas of echolocation bats that received imidacloprid treatment was significantly enhanced in comparison with echolocation bats that received sham treatment. Thus, we suggest that imidacloprid toxicity may interfere with the spatial memory of echolocation bats through neural apoptosis in hippocampal CA1 and medial entorhinal cortex areas. The results provide direct evidence that pesticide toxicity causes a spatial memory disorder in echolocation bats. This implies that agricultural pesticides may pose severe threats to the survival of echolocation bats. PMID- 26966785 TI - Advances in the pharmacological treatment of Graves' orbitopathy. AB - Graves' orbitopathy has a deteriorating effect on patients' appearance and vision, thus significantly decreases their quality of life. A multidisciplinary team of endocrinologists, ophthalmologists, head and neck surgeons, nuclear medicine physicians, radiologists, and psychologists should constitute a standard health care team for those patients. It is vital that the therapy is based on an individual approach, with patients being well informed and involved in the decision-making process. Generally, traditional therapies include immunosuppression with steroids, orbital irradiation and surgical decompression. Novel treatment modalities include: biological agents, somatostatin analogs, antioxidants, methotrexate. Better insight into pathogenesis of Graves' orbitopathy is the only chance for targeted therapy development. PMID- 26966784 TI - Admission Peripheral Edema, Central Venous Pressure, and Survival in Critically Ill Patients. AB - RATIONALE: The clinical significance of peripheral edema has not been well described in critical illness. OBJECTIVES: To assess the clinical significance of peripheral edema detected on physical examination at the time of hospital admission for patients who were treated in an intensive care unit (ICU). METHODS: Using a large inception cohort of critically ill patients, we examined the association of peripheral edema, as documented on hospital admission physical examination, with hospital and 1-year survival. MEASUREMENTS AND MAIN RESULTS: Of 12,778 patients admitted to an ICU at a teaching hospital in Boston, Massachusetts, 2,338 (18%) had peripheral edema. Adjusting for severity of illness and comorbidities, including pulmonary edema, admission peripheral edema was associated with a 26% (95% confidence interval [CI] = 1.11-1.44, P < 0.001) higher risk of hospital mortality. In those patients whose peripheral edema could be graded, trace, 1+, 2+, and 3+ admission peripheral edema was associated with a 2% (95% CI = 0.80-1.31, P = 0.89), 17% (95% CI = 1.00-1.56, P = 0.05), 60% (95% CI = 1.26-2.04, P < 0.001), and 54% (95% CI = 1.04-2.29, P = 0.03) higher adjusted risk of hospital mortality, respectively, compared with patients without edema. The association was consistent across strata of patients with diabetes, congestive heart failure, sepsis, and premorbid diuretic or calcium channel blocker use. In a subset of patients with central venous pressures measurements obtained within 6 hours of ICU admission, the highest central venous pressure quartile (>13 cm H2O) was similarly associated with a 35% (95% CI = 1.05-1.75, P = 0.02) higher adjusted risk of hospital mortality compared with the lowest quartile (<=7 cm H2O). CONCLUSIONS: Peripheral edema, as detected on physical examination at the time of hospital admission, is a poor prognostic indicator in critical illness. Whether peripheral edema simply reflects underlying pathophysiology, or has an independent pathogenic role, will require further interventional studies. PMID- 26966786 TI - Identification of Kinesin-1 Cargos Using Fluorescence Microscopy. AB - Fluorescence microscopy is employed to identify Kinesin-1 cargos. Recently, the heavy chain of Kinesin-1 (KIF5B) was shown to transport the nuclear transcription factor c-MYC for proteosomal degradation in the cytoplasm. The method described here involves the study of a motorless KIF5B mutant for fluorescence microscopy. The wild-type and motorless KIF5B proteins are tagged with the fluorescent protein tdTomato. The wild-type tdTomato-KIF5B appears homogenously in the cytoplasm, while the motorless tdTomato-KIF5B mutant forms aggregates in the cytoplasm. Aggregation of the motorless KIF5B mutant induces aggregation of its cargo c-MYC in the cytoplasm. Hence, this method provides a visual means to identify the cargos of Kinesin-1. A similar strategy can be utilized to identify cargos of other motor proteins. PMID- 26966787 TI - Nationwide Distribution of Per- and Polyfluoroalkyl Substances in Outdoor Dust in Mainland China From Eastern to Western Areas. AB - From eastern to western areas, per- and polyfluoroalkyl substances (PFASs) were detected at substantial levels in the outdoor dust across mainland China. Urban samples generally showed higher levels compared with those of rural samples. Compared with neutral PFASs, ionizable PFASs (C4-C12 perfluoroalkyl carboxylic acids and C4/C8 perfluoroalkyl sulfonic acids) were more abundant, with the highest total concentration up to 1.6 * 10(2) ng/g and perfluorooctanoic acid (PFOA) being a predominant analogue. Fluorotelomer alcohols (FTOHs) and polyfluoroalkyl phosphoric acid diesters (DiPAPs) were both detected in most samples with total concentrations of 0.12-32 and 0.030-20 ng/g, respectively. Perfluorooctane sulfonamidoethanols/sulfonamides (FOSE/As) were detected at low frequencies (<30%). In addition to partitioning to organic moiety, specific adsorption onto mineral particles can be important for PFASs to bind onto outdoor dust, especially for short-chain ionizable PFASs. The eastern plain areas were characterized by a higher contribution of long-chain ionizable PFASs; whereas the western high plateau areas were characterized by the dominating contribution of short-chain analogues. The difference suggests that the long-range atmospheric transport potential of PFASs from source regions to the inland is probably limited by the increase in altitude, and different sources from adjacent regions may influence the western border area of China. PMID- 26966788 TI - Octazethrene and Its Isomer with Different Diradical Characters and Chemical Reactivity: The Role of the Bridge Structure. AB - The fundamental relationship between structure and diradical character is important for the development of open-shell diradicaloid-based materials. In this work, we synthesized two structural isomers bearing a 2,6-naphthoquinodimethane or a 1,5-naphthoquinodimethane bridge and demonstrated that their diradical characters and chemical reactivity are quite different. The mesityl-or pentafluorophenyl-substituted octazethrene derivatives OZ-M/OZ-F and their isomer OZI-M (with mesityl substituents) were synthesized via an intramolecular Friedel Crafts alkylation followed by oxidative dehydrogenation strategy from the key building blocks 4 and 11. Our detailed experimental and theoretical studies showed that both isomers have an open-shell singlet ground state with a remarkable diradical character (y0 = 0.35 and 0.34 for OZ-M and OZ-F, and y0 = 0.58 for OZI-M). Compounds OZ-M and OZ-F have good stability in an ambient environment, while OZI-M has high reactivity and can be easily oxidized to a dioxo product 15, which can be correlated to their different diradical characters. Additionally, we investigated the physical properties of OZ-M, OZ-F, and 15. PMID- 26966789 TI - Root-Shoot Signaling crosstalk involved in the shoot growth promoting action of rhizospheric humic acids. AB - Numerous studies have shown the ability of humic substances to improve plant development. This action is normally reflected in an enhancement of crop yields and quality. However, the mechanisms responsible for this action of humic substances remain rather unknown. Our studies have shown that the shoot promoting action of sedimentary humic acids is dependent of its ability to increase root hydraulic conductivity through signaling pathways related to ABA, which in turn is affected in roots by humic acids in an IAA-NO dependent way. Furthermore, these studies also indicate that the primary action of humic acids in roots might also be physical, resulting from a transient mild stress caused by humic acids associated with a fouling-cleaning cycle of wall cell pores. Finally the role of alternative signal molecules, such as ROS, and corresponding signaling pathways are also discussed and modeled in the context of the above-mentioned framework. PMID- 26966790 TI - Parent binge eating and restrictive feeding practices: Indirect effects of parent's responses to child's negative emotion. AB - OBJECTIVE: Parents' emotion regulation difficulties are related to binge eating (BE), and to responses to children's negative emotion. However, less is known about how responses to children's negative emotion are related to eating and feeding in the parenting context. We examined the degree to which BE had both direct and indirect effects on parental restrictive feeding practices, through parents' reported responses to negative emotion. METHOD: Parents of preschoolers (n=441) completed validated questionnaires about their feeding strategies, responses to children's negative emotion, and their children's eating behaviors. Height and weight were measured in children and self-reported by parents. Unsupportive (Distress, Minimizing, and Punitive), and Supportive (Emotion focused, Problem-focused, and Expressive Encouragement) responses to negative emotion were measured using the Coping with Children's Negative Emotions Scale. RESULTS: Parent's BE was correlated with Distress responses, Restriction for health, and Restriction for weight control. Controlling for confounders, BE was associated with Restriction for weight control, and Restriction for health. Model testing revealed that BE had significant direct (R(2) [SE]=.073 [.031], 95% CI [.013, .134]) and indirect effects (R(2) [SE]=.011 [.005], 95% CI [.003, .023]) on Restriction for weight control, through Distress responses, but only indirect effects on Restriction for health (R(2) [SE]=.018 [.009], 95% CI [.004, .039]). CONCLUSIONS: This study shows an association between emotion regulation and energy-intake regulation in the parenting context. Efforts to modify feeding practices may be more effective if parents' eating behaviors and their emotional responsiveness to distress are taken into account. PMID- 26966792 TI - Approaching Bulk Carrier Dynamics in Organo-Halide Perovskite Nanocrystalline Films by Surface Passivation. AB - The electronic properties of organo-halide perovskite absorbers described in the literature have been closely associated with their morphologies and processing conditions. However, the underlying origins of this dependence remain unclear. A combination of inorganic synthesis, surface chemistry, and time-resolved photoluminescence spectroscopy was used to show that charge recombination centers in organo-halide perovskites are almost exclusively localized on the surfaces of the crystals rather than in the bulk. Passivation of these surface defects causes average charge carrier lifetimes in nanocrystalline thin films to approach the bulk limit reported for single-crystal organo-halide perovskites. These findings indicate that the charge carrier lifetimes of perovskites are correlated with their thin-film processing conditions and morphologies through the influence these have on the surface chemistry of the nanocrystals. Therefore, surface passivation may provide a means to decouple the electronic properties of organo halide perovskites from their thin-film processing conditions and corresponding morphologies. PMID- 26966791 TI - The mechanism of action of tofacitinib - an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterised by infiltration of immune cells into the affected synovium, release of inflammatory cytokines and degradative mediators, and subsequent joint damage. Both innate and adaptive arms of the immune response play a role, with activation of immune cells leading to dysregulated expression of inflammatory cytokines. Cytokines work within a complex regulatory network in RA, signalling through different intracellular kinase pathways to modulate recruitment, activation and function of immune cells and other leukocytes. As our understanding of RA has advanced, intracellular signalling pathways such as Janus kinase (JAK) pathways have emerged as key hubs in the cytokine network and, therefore, important as therapeutic targets. Tofacitinib is an oral JAK inhibitor for the treatment of RA. Tofacitinib is a targeted small molecule, and an innovative advance in RA therapy, which modulates cytokines critical to the progression of immune and inflammatory responses. Herein we describe the mechanism of action of tofacitinib and the impact of JAK inhibition on the immune and inflammatory responses in RA. PMID- 26966793 TI - Neuromuscular Disease. PMID- 26966794 TI - Once again, complex care leads the way. PMID- 26966796 TI - Clinical course of growth in patients with congenital neuromuscular disease in a single multidisciplinary neuromuscular clinic. AB - OBJECTIVE: To assess the effect of nutritional interventions on growth and on respiratory status in patients with congenital myopathy (CM), congenital muscular dystrophy (CMD), and congenital myasthenic syndrome (CMS). METHODS: Retrospective cohort study based on case-note review of 18 patients affected by CM, CMD, and CMS, followed at a single pediatric neuromuscular center, between 2006 and 2014. RESULTS: Seventy-two percent of patients required placement of a gastrostomy tube for bulbar weakness or for growth failure. Of those patients, 10 had 1 year follow up anthropometric data and 6 had 2 year follow up anthropometric data. Height percentiles and z-scores were significantly improved in patients after 1 year, while weight and BMI percentiles and z-scores were not. Weight and height percentiles and z-scores were significantly improved in patients at 2 year follow up, while BMI percentiles and z-scores were not. The number of respiratory illnesses was not significantly different before or after placement of the feeding tube. Of the patients who did not have placement of a gastrostomy tube, 4 had 1 year follow up anthropometric data and 3 had 2 year follow up anthropometric data. Gastrostomy tube fed patients had significantly higher mean weight percentiles and z-scores compared to orally fed patients. There was no significant difference in height or BMI between the gastrostomy fed and orally fed groups. Individual growth curves highlight the effect of intervention on weight and height. CONCLUSIONS: This is a single multidisciplinary center experience describing the effect of nutritional interventions on growth in patients with congenital neuromuscular disorders. While the number of patients and their data in this report are limited, it highlights that the growth in this group of patients is unique but that the low weight and short stature respond to nutritional interventions with changes typically seen after 2 years of intervention. PMID- 26966795 TI - Age at onset of first signs or symptoms predicts age at loss of ambulation in Duchenne and Becker Muscular Dystrophy: Data from the MD STARnet. AB - PURPOSE: We investigated the prognostic utility of onset age at first signs and symptoms (SS) to predict onset age at loss of ambulation (LOA) for childhood onset Duchenne and Becker Muscular Dystrophies (DBMD). METHODS: Our cohort comprised male cases with DBMD ascertained by the population-based Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models for associations between onset ages of first SS and LOA. Covariates controlled for were corticosteroid use, family history of DBMD, birth year, race/ethnicity, and MD STARnet site. Onset age at first SS was considered as a continuous and as a categorical variable. RESULTS: A one-year increase in onset age at first SS was significantly associated with a 10% reduction in annual risk of LOA (HR = 0.90, CI = 0.87-0.94). Treating onset age at first SS as a categorical variable yielded a similar association (>= 5 years: referent; >= 3 to < 5 years: HR = 1.36, CI = 1.02-1.81; 18 months to < 3 years: HR = 1.72, CI = 1.31-2.26; < 18 months: HR = 1.52, CI = 1.14-2.02). CONCLUSIONS: Earlier onset age at first SS is associated with earlier onset age at LOA and may have clinical utility in differentiating childhood-onset Duchenne and Becker muscular dystrophies. PMID- 26966797 TI - Management of scoliosis in patients with Duchenne muscular dystrophy and spinal muscular atrophy: A literature review. AB - Scoliosis occurs in nearly all non-ambulatory children with spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Non-operative treatments have not been shown to be effective at preventing progression of scoliosis. Progressive scoliosis can impact the ability of patients to sit comfortably, be cosmetically unappealing, and in severe cases exacerbate pulmonary disease. The main goal of operative treatment is to improve sitting balance and prevent progression of scoliosis. Complication rates are high and there is little data on effect of operative treatment on quality of life in children with SMA and DMD. Comprehensive multi-disciplinary pre-operative evaluations are vital to reduce the risks of operative treatment. PMID- 26966798 TI - Rehabilitation issues in Charcot-Marie-Tooth disease. AB - Charcot Marie Tooth (CMT) disease is the most common hereditary sensorimotor neuropathy that has a slow onset. It presents usually in childhood, starting distally and from the lower limbs progressing to more proximal muscles. Due to the lack of curative medical treatments and the problematic outcomes of surgical intervention, rehabilitation continues to play a major role in treatment. This paper aims to summarize the rehabilitation approaches like aerobic, stretching and strengthening exercises. Orthotics is another important part of treatment that complete rehabilitative approaches. Orthotic devices that are currently being used and investigated in patients with CMT are also reviewed. The evidence shows that exercise is effective in improving strength and general fitness. Stretching is somewhat effective in maintaining range of motion. Orthotic devices are the mainstay of maintaining mobility and ambulation and upper extremity function. PMID- 26966799 TI - Physical therapy services received by individuals with spinal muscular atrophy (SMA). AB - PURPOSE: The consensus statement for standard of care in SMA recommends multidisciplinary medical care including physical therapy (PT) services. To date there are no reports regarding the implementation of these recommendations and the type of care or services received by individuals with SMA. The purpose of this study is to describe the PT services received by individuals with SMA. METHODS: Interviews were conducted with patients or their caregivers at the Pediatric Neuromuscular Clinical Research (PNCR) Network sites from October 2011 to September 2012. Questions included information about clinical status of the patient, sociodemographic profile of the patient or caregiver, and PT services received in the past year, including the setting, frequency, duration and type of PT, and therapies administered by caregivers. RESULTS: Eighty-six percent of 105 participants reported receiving PT services, some in multiple settings: 62% in the neuromuscular clinic, 38% at school, 34% at home, and 13% in an outpatient clinic. Greater frequency of PT services received was associated with younger age and inability to walk, but not SMA type. CONCLUSION: This is the first multicenter study documenting PT services received by patients with SMA. Further research is needed to better understand the impact of PT services on the natural history of SMA. PMID- 26966800 TI - Rehabilitative technology use among individuals with Duchenne/Becker muscular dystrophy. AB - PURPOSE: To document use of rehabilitative technology among individuals with Duchenne/Becker muscular dystrophy (DBMD) among sites of the Muscular Dystrophy Surveillance, Tracking, and Research network (MD STARnet). METHODS: Data from 362 caregivers who participated in the MD STARnet caregiver interview between April 2006 and March 2012 (54.7% response rate) were analyzed to assess the type, frequency and duration of use of assistive technology. RESULTS: Caregiver reports of technology use by individuals with DBMD across five MD STARnet sites in the US demonstrated significant regional differences in the proportion of individuals who had ever used night splints (36.9%-73.0%), standers (3.1%-22.2%) and scooters (10.7%-54.5%). Among individuals who used night splints 59.7% stopped using them at a mean age of 10.3 years after a mean duration of 2.9 years in spite of the current recommendation to continue using them through the non-ambulatory phase. DISCUSSION: Results of this comprehensive survey document the frequency of assistive device use by individuals with DBMD in the USA and also provides data on differences across the sites. Further research is needed to understand the reasons for and the impact of these differences on clinical outcomes and health related quality of life of individuals with DBMD. PMID- 26966801 TI - Physical activity and the use of standard and complementary therapies in Duchenne and Becker muscular dystrophies. AB - PURPOSE: To record the use and perceived benefits of mainstream allied health services, complementary therapies, nutritional supplements and structured physical activity in a paediatric population of males with Duchenne or Becker muscular dystrophy. METHOD: A questionnaire was distributed to 125 parents of males with a dystrophinopathy within a tertiary neuromuscular clinic population in Melbourne, Australia. RESULTS: Response rate to the survey was 41%. Most families (73%) reported use of allied health services: physiotherapy (65%), occupational therapy (47%), and psychology (25%). The most commonly used complementary therapy was massage (31%). Sixty-five percent of families reported using nutritional supplements. Fifty-one and 38% of families reported participation in swimming and other organised sports, respectively. Physical and psychological benefits of sporting activities were identified by families. Participation in physical activity was lowest in those transitioning to full-time wheelchair use. CONCLUSIONS: Access to allied health services by boys with dystrophinopathies is variable and inconsistent with published international standards of care. There is frequent use of complementary therapies, despite a lack of proven efficacy. Studies of the effects of such therapies would support provision of evidence-based advice to families. Continued involvement in physical activity for those boys with declining function should be supported by clinicians. PMID- 26966802 TI - Factors associated with caregiver experience in families with a child with cerebral palsy. AB - PURPOSE: Managing the stresses of parenting a child with cerebral palsy (CP) can be challenging. This study sought to identify factors that are associated with higher levels of caregiver stress. METHODS: A retrospective review of data from the Learn From Every PatientTM project conducted in an interdisciplinary CP clinic were used to compare caregiver responses on 2 subsets (financial and time/emotional) of the Assessment of Caregiver Experience in Neuromuscular Disorders (ACEND) and physical and medical characteristics of the child. RESULTS: The range of scores in both the financial and emotional subset was large. The presence of behavior problems, seizures, and severity of CP showed the strongest associations with emotional stress and accounted for 14% of the variance in scaled scores (r= 0.392, adj R2= 14.3, p< 0.01). The child's age was not significantly related to parental stress. The most highly reported areas of stress were worry about the child's pain, and the financial impact of lost wages. CONCLUSION: Caregiver experience varied widely and is associated with a range of factors among families caring for a child with CP. Further research is needed to test whether interventions to minimize the areas of greatest stress could make a meaningful difference in family functioning. PMID- 26966803 TI - Complementary therapies that do not include respiratory therapies are a very small part of the story. PMID- 26966804 TI - Authors' Response to Commentary. PMID- 26966808 TI - Solubility enhancement of dioxins and PCBs by surfactant monomers and micelles quantified with polymer depletion techniques. AB - Partitioning of super-hydrophobic organic contaminants (SHOCs) to dissolved or colloidal materials such as surfactants can alter their behaviour by enhancing apparent aqueous solubility. Relevant partition constants are, however, challenging to quantify with reasonable accuracy. Partition constants to colloidal surfactants can be measured by introducing a polymer (PDMS) as third phase with known PDMS-water partition constant in combination with the mass balance approach. We quantified partition constants of PCBs and PCDDs (log KOW 5.8-8.3) between water and sodium dodecyl sulphate monomers (KMO) and micelles (KMI). A refined, recently introduced swelling-based polymer loading technique allowed highly precise (4.5-10% RSD) and fast (<24 h) loading of SHOCs into PDMS, and due to the miniaturisation of batch systems equilibrium was reached in <5 days for KMI and <3 weeks for KMO. SHOC losses to experimental surfaces were substantial (8-26%) in monomer solutions, but had a low impact on KMO (0.10-0.16 log units). Log KMO for PCDDs (4.0-5.2) were approximately 2.6 log units lower than respective log KMI, which ranged from 5.2 to 7.0 for PCDDs and 6.6-7.5 for PCBs. The linear relationship between log KMI and log KOW was consistent with more polar and moderately hydrophobic compounds. Apparent solubility increased with increasing hydrophobicity and was highest in micelle solutions. However, this solubility enhancement was also considerable in monomer solutions, up to 200 times for OCDD. Given the pervasive presence of surfactant monomers in typical field scenarios, these data suggest that low surfactant concentrations may be effective long-term facilitators for subsurface transport of SHOCs. PMID- 26966807 TI - Molecular Dynamics of Fibrinogen Adsorption onto Graphene, but Not onto Poly(ethylene glycol) Surface, Increases Exposure of Recognition Sites That Trigger Immune Response. AB - Changes in the conformation of blood proteins due to their binding to nonbiological surfaces is the initial step in the chain of immunological reactions to foreign bodies. Despite the large number of experimental studies that have been performed on fibrinogen adsorption to nonbiological surfaces, a clear picture describing this complex process has eluded researchers to date. Developing a better understanding of the behavior of bioactive fibrinogen motifs upon their interaction with surfaces may facilitate the design of advanced materials with improved biocompatibility. This is especially important within the context of medical implants. Here we present results of explicit-solvent, all atom MD simulations of the adsorption of the fibrinogen D-domain onto a graphene surface and a poly(ethylene glycol) (PEG) surface. Our results are consistent with experimental observations that interactions with PEG do not induce significant conformational changes on immune-reactive sites present in the D domain of fibrinogen. In contrast, our results indicate that significant conformational changes induced by adsorption to graphene surfaces may occur under conditions that promote a high density of blood proteins on the surface. The structural rearrangements observed on graphene directly affect the secondary structure content of the D-domain, with consequent exposure of the recognition sites P1 (gamma190-202) and P2 (gamma377-395) and the subsite P2-C (gamma383-395) involved in immune response. Analysis of the structural parameters of the MD conformers was shown to accurately assess the biocompatibility of the modeled surfaces. PMID- 26966809 TI - On-line classification of pollutants in water using wireless portable electronic noses. AB - A portable electronic nose with database connection for on-line classification of pollutants in water is presented in this paper. It is a hand-held, lightweight and powered instrument with wireless communications capable of standalone operation. A network of similar devices can be configured for distributed measurements. It uses four resistive microsensors and headspace as sampling method for extracting the volatile compounds from glass vials. The measurement and control program has been developed in LabVIEW using the database connection toolkit to send the sensors data to a server for training and classification with Artificial Neural Networks (ANNs). The use of a server instead of the microprocessor of the e-nose increases the capacity of memory and the computing power of the classifier and allows external users to perform data classification. To address this challenge, this paper also proposes a web-based framework (based on RESTFul web services, Asynchronous JavaScript and XML and JavaScript Object Notation) that allows remote users to train ANNs and request classification values regardless user's location and the type of device used. Results show that the proposed prototype can discriminate the samples measured (Blank water, acetone, toluene, ammonia, formaldehyde, hydrogen peroxide, ethanol, benzene, dichloromethane, acetic acid, xylene and dimethylacetamide) with a 94% classification success rate. PMID- 26966810 TI - Determination of uptake, accumulation, and stress effects in corn (Zea mays L.) grown in single-wall carbon nanotube contaminated soil. AB - Single-wall carbon nanotubes (SWNTs) are projected to increase in usage across many industries. Two studies were conducted using Zea L. (corn) seeds exposed to SWNT spiked soil for 40 d. In Study 1, corn was exposed to various SWNT concentrations (0, 10, and 100 mg/kg) with different functionalities (non functionalized, OH-functionalized, or surfactant stabilized). A microwave induced heating method was used to determine SWNTs accumulated mostly in roots (0-24 MUg/g), with minimal accumulation in stems and leaves (2-10 MUg/g) with a limit of detection at 0.1 MUg/g. Uptake was not functional group dependent. In Study 2, corn was exposed to 10 mg/kg SWNTs (non-functionalized or COOH-functionalized) under optimally grown or water deficit conditions. Plant physiological stress was determined by the measurement of photosynthetic rate throughout Study 2. No significant differences were seen between control and SWNT treatments. Considering the amount of SWNTs accumulated in corn roots, further studies are needed to address the potential for SWNTs to enter root crop species (i.e., carrots), which could present a significant pathway for human dietary exposure. PMID- 26966812 TI - Relationship between antibiotic- and disinfectant-resistance profiles in bacteria harvested from tap water. AB - Chlorination is commonly used to control levels of bacteria in drinking water; however, viable bacteria may remain due to chlorine resistance. What is concerning is that surviving bacteria, due to co-selection factors, may also have increased resistance to common antibiotics. This would pose a public health risk as it could link resistant bacteria in the natural environment to human population. Here, we investigated the relationship between chlorine- and antibiotic-resistances by harvesting 148 surviving bacteria from chlorinated drinking-water systems and compared their susceptibilities against chlorine disinfectants and antibiotics. Twenty-two genera were isolated, including members of Paenibacillus, Burkholderia, Escherichia, Sphingomonas and Dermacoccus species. Weak (but significant) correlations were found between chlorine tolerance and minimum inhibitory concentrations against the antibiotics tetracycline, sulfamethoxazole and amoxicillin, but not against ciprofloxacin; this suggest that chlorine-tolerant bacteria are more likely to also be antibiotic resistant. Further, antibiotic-resistant bacteria survived longer than antibiotic-sensitive organisms when exposed to free chlorine in a contact-time assay; however, there were little differences in susceptibility when exposed to monochloramine. Irrespective of antibiotic-resistance, spore-forming bacteria had higher tolerance against disinfection compounds. The presence of chlorine resistant bacteria surviving in drinking-water systems may carry additional risk of antibiotic resistance. PMID- 26966811 TI - GIS-based multielement source analysis of dustfall in Beijing: A study of 40 major and trace elements. AB - Dust, as an important carrier of inorganic and organic pollutants, daily exposes to human without any protection. It affects our health adversely, especially its chemical elements and ions. In this research, we investigated the chemical characteristics of dustfall in Beijing, specifically in terms of 40 major and trace elements, and presented semi-quantitative evaluations of the relative local and remote contributions. In total, 58 samples were collected in Beijing and nearby cities during 2013-2014 "the winter heating period". Using multiple statistical methods and GIS techniques, we obtained the relative similarities among certain elements and identified their pollution sources (from local or nearby cities). And more interestingly, the relative contributions of nearby cities can be calculated by the Hysplit4 backward-trajectory model. In addition, the correlation analysis for the 40 elements in dust and soil indicated that traffic restricted interchange between them; the city center, with the heaviest traffic, had the most significant influence. Finally, the resulting source apportionment was examined and modified using land use data and terrain information. We hope it can provide a strong basis for the environmental protection and risk assessment. PMID- 26966813 TI - Dispersal and dilution of wastewater from an ocean outfall at Davis Station, Antarctica, and resulting environmental contamination. AB - The Antarctic Treaty permits the discharge of wastewater into Antarctic marine waters providing that conditions exist for initial dilution and rapid dispersal. We investigated the dilution and dispersal of macerated wastewater around Australia's Davis Station in East Antarctica and examined sediments for evidence of contaminants. Methods used to examine hydrodynamic conditions included current meters, dye release experiments and measurement of sewage-associated microbial markers and surfactants in the water column. We measured marine sediments for metals, nutrients, PBDEs, hydrocarbons and faecal sterols. We propose that if there is adequate dilution and dispersal there would be no significant difference in contaminant concentrations in sediments around the outfall compared to distant control sites. Currents were strongly correlated with prevailing wind conditions. Modelling indicated that diffusivity of wastewater had the greatest effect on dilution factors and that neither discharge rates nor local currents had as much effect. During summer conditions of open water, wastewater is likely to be constrained in a narrow plume close to the coast. Concentrations of sewage bacteria were high around the outfall and detected up to 1.5 km away, along with dye. There were significant differences in sediment concentrations of metals, PBDEs, hydrocarbons, nutrients and faecal sterols between sites within 2 km of the outfall and control sites. We conclude that dilution and dispersal conditions at the Davis outfall are insufficient to prevent the accumulation of contaminants in local sediments and that microbial hazards posed by wastewater are an environmental risk to local wildlife. PMID- 26966814 TI - Negative Pressure Wound Therapy With Instillation: Review of Evidence and Recommendations. AB - Negative pressure wound therapy with instillation (NPWTi) and dwell time is an adjunctive treatment modality for selected complex wounds. Because of the greater amount of research now available, a multidisciplinary expert panel comprising the fields of podiatry, plastic and general surgery, burn treatment, infectious diseases, and orthopedics was convened on July 11, 2015, to produce a summary of the data and recommendations on the use of NPWTi. The panel members each reviewed available published literature on NPWTi in the PubMed, Cochrane, and Google Scholar databases from 1 January 2012 up until 20 July 2015 using the string search term negative pressure wound therapy instillation provided by the panel moderator; there were no restrictions on the language or type of publication. Panel members discussed their experiences and worked to reach consensus on several predefined topics. NPWTi was found to be most appropriate for properly selected complex hosts or wounds such as patients with multiple comorbidities, patients with an American Society of Anesthesiology Classification >= 2, severe traumatic wounds, diabetic foot infections, and wounds complicated by invasive infection or extensive biofilm. NPWTi should not be used routinely to treat simple wounds or hosts without comorbidities.There is evidence that when NPWTi is added to standard of care in properly selected cases it provides better overall clinical outcomes than standard of care alone, even when including NPWT. Based on published evidence and panel member experience, the Panel recommends a dwell time - fluid briefly instilled into the wound and allowed to diffuse for a user specified time - of 10-20 minutes followed by 2-4 hours of negative pressure at 125 mmHg, although larger wounds may need times of up to 6 hours. Normal saline (0.9%) is the preferred solution for NPWTi, except in special situations. NPWTi with dwell time is an adjunct to other standard principles of appropriate wound assessment and treatment (e.g., debridement, pressure offloading, systemic antibiotic therapy, vascular assessment and revascularization when needed, or glycemic control). PMID- 26966816 TI - Local, national, and service component cost variations in the management of low back pain: Considerations for the clinician. AB - In the past two decades, the cost associated with managing low back pain has increased significantly. Improved consciousness of how clinicians utilize resources when managing low back pain is necessary in the current economic climate. The goal of this review is to examine the component costs associated with managing low back pain and provide practical solutions for reducing healthcare costs. This is accomplished by utilizing examples from a major metropolitan area with several major academic institutions and private health care centers. It is clear that there is considerable local and national variation in the component costs of managing low back pain, including physician visits, imaging studies, medications, and therapy services. By being well informed about these variations in one's environment, clinicians and patients alike can make strides towards reducing the financial impact of low back pain. Investigation of the cost discrepancies for services within one's community of practice is important. Improved public access to both cost and outcomes data is needed. PMID- 26966815 TI - Dissecting Electrostatic Contributions to Folding and Self-Assembly Using Designed Multicomponent Peptide Systems. AB - We investigate formation of nano- to microscale peptide fibers and sheets where assembly requires association of two distinct collagen mimetic peptides (CMPs). The multicomponent nature of these designs allows the decoupling of amino acid contributions to peptide folding versus higher-order assembly. While both arginine and lysine containing CMP sequences can favor triple-helix folding, only arginine promotes rapid supramolecular assembly in each of the three two component systems examined. Unlike lysine, the polyvalent guanidyl group of arginine is capable of both intra- and intermolecular contacts, promoting assembly. This is consistent with the supramolecular diversity of CMP morphologies observed throughout the literature. It also connects CMP self assembly with a broad range of biomolecular interaction phenomena, providing general principles for modeling and design. PMID- 26966817 TI - Three week results of transforaminal epidural steroid injection in patients with chronic unilateral low back related leg pain: The relation to MRI findings and clinical features. AB - BACKGROUND: Transforaminal epidural steroid injection (TESI) is a frequently used intervention for lumbar radicular pain. OBJECTIVE: To evaluate the value of MRI findings, neurologic assessment and the Slump test (neurodynamic test) as predictors of treatment response to TESI. METHOD: One hundred subjects (mean age 58 [SD13], 54% females) were included in this trial. The sample was stratified by location of disc herniaton, grade of nerve root compression, clinically assessed neurologic deficit and positive Slump test.Treatment response was primarily evaluated by Visual Analogue Scale for leg pain after three weeks. Predictive value for each stratum was analyzed using logistic regression after the sample was dichotomized into definite treatment response (>= 50% reduction of pain) and negative response (<= 0% reduction) to TESI (the 1-49% reduction group was excluded). RESULTS: The overall definite treatment response rate was 27%. The Slump test was the only predictor of the response to TESI (p= 0.031). The definite treatment response rates for subjects with positive and negative Slump test were 33% and 15%, respectively. CONCLUSION: In patients with chronic low back related leg pain, MRI findings and neurologic assessment results failed to predict treatment response, whereas a positive Slump test predicted the best 3 week response to TESI. PMID- 26966818 TI - Ultrasonographic evaluation of femoral cartilage thickness in patients with psoriatic arthritis. AB - BACKGROUND: Psoriatic arthritis (PsA) is a common form of arthritis that may vary from asymmetric oligoarthritis to symmetric polyarthritis and spondyloarthritis. OBJECTIVES: To evaluate femoral cartilage thickness using ultrasonography in patients with PsA. METHODS: Thirty-three patients (24 female, 9 male) with a diagnosis of PsA and 31 age-, sex- and body mass index-similar healthy subjects were enrolled in this study. Demographic and clinical characteristics of the patients were recorded, including disease duration, morning stiffness and medications. The femoral cartilage thicknesses of both knees (while held in maximum flexion) were measured with a 7-12 MHz linear probe. Three mid-point measurements were taken from both knees (at the lateral condyle, intercondylar area and medial condyle). RESULTS: Cartilage thicknesses were similar between PsA patients and healthy control subjects. However, there were significant correlations between cartilage thickness and the Maastricht Ankylosing Spondylitis Enthesitis Score, Bath AS functional index and Bath AS disease activity index scores. CONCLUSION: Femoral cartilage thickness is similar between PsA patients and healthy controls. The femoral cartilage thickness in PsA patients is associated with disease activity, functional inadequacy, and enthesopathy scores. PMID- 26966819 TI - Short term effects of kinesio taping on pain and functional disability in young females with menstrual low back pain: A randomised control trial study. AB - BACKGROUND: Menstrual low back pain (LBP) in young females can reduce daily activity and cause functional disability, while the progressive application of kinesio-taping (KT) on pain reduction and functional correction has been stated. OBJECTIVE: This study has been designed to investigate the efficacy of the lumbar vertebral column KT in young female with menstrual LBP. METHODS: Thirty-two young females with menstrual LBP participated in this crossover study and were assigned randomly in two separate groups. The first group received KT during their first menstrual cycle and No-KT in their next menstrual, while the other group had no KT during the first mentrual cycle and received KT during the next menstrual cycle. The primary outcome measurements included the visual analogue scale (VAS) of pain, Oswestry disability index and McGill pain questionnaire score which were planned to collect at the end of the third day of the menstrual cycle. RESULTS: Comparing pain and disability between two conditions, of menstrual cycle with KT and menstrual cycle without KT, revealed significant reduction in VAS (mean change = 1.7; 95%CI = 0.6 to 2.8; P= 0.005), McGill pain score (mean change = 20.1; 95%CI = 8.7 to 31.3; P= 0.001) and functional disability (mean change = 12.3; 95%CI = 7.2 to 17.5; P< 0.0001) by using KT during menstrual cycle. CONCLUSIONS: Results showed that KT may effectively reduce pain and disability. The findings may support the clinical application of kinesiotaping in young females with menstrual LBP. PMID- 26966820 TI - Spinal accessory nerve injury: A potentially missed cause of a painful, droopy shoulder. AB - BACKGROUND: Spinal accessory nerve (SAN) injury can be an overlooked cause of scapular winging and shoulder dysfunction. The most common etiology is iatrogenic injury following surgical procedures at the posterior triangle of the neck. We present three cases of isolated injury to the SAN following trauma. OBJECTIVE: To improve detection of SAN injuries through highlighting the clinical presentation, diagnosis and treatment via three cases in which the injuries were initially missed. METHODS: Clinical case series and narrative review. RESULTS: Three (3) patients were evaluated by history, physical exam and electrodiagnostic study (EMG). Clinical symptoms included, a painful, droopy shoulder and difficulties with overhead activities. Clinical signs included the observation of scapular winging, and focal atrophy of the trapezius and in some cases the sternocleidomastoid (SCM). Novel clinical signs such as the active elevation lag sign and triangle sign were also helpful clinically to highlight the SAN as the site of pathology. EMG revealed denervation and reduced motor unit recruitment in the trapezius and SCM. CONCLUSIONS: Early detection of SAN injuries can be improved through appropriate clinical suspicion, a detailed history and careful physical exam. EMG testing can help guide prognosis, direct conservative and surgical treatment, and reduce patient morbidity. PMID- 26966822 TI - Diabetic peripheral neuropathy: Correlation between nerve cross-sectional area on ultrasound and clinical features. AB - BACKGROUND AND OBJECTIVE: To evaluate the correlations of the cross-sectional area (CSA) of peripheral nerves in diabetic peripheral neuropathy (DPN) patients based on ultrasound (US) with clinical and demographic characteristics. METHODS: A DPN patient group (n= 53) and a matched healthy control group (n= 53) underwent US imaging of the sciatic, tibial and median nerves. The CSAs of these nerves were recorded, and their associations with pain intensity according to the visual analog scale (VAS) score and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale score, diabetes mellitus (DM) duration, body mass index (BMI), HbA1c level and blood glucose levels were evaluated. RESULTS: The CSAs of the examined nerves in diabetic patients were larger than those in healthy individuals (p< 0.05). No correlations were detected between the CSAs of the examined nerves and the parameters of interest (p> 0.05), including the VAS and LANSS pain scale scores (p= 0.32 and p= 0.31, respectively). CONCLUSIONS: US is a sensitive diagnostic technique for detecting DPN; however, it does not indicate disease severity. PMID- 26966821 TI - Factors influencing the evaluation and management of neuromuscular scoliosis: A review of the literature. AB - Neuromuscular scoliosis (NMS) is the second most prevalent spinal deformity (after idiopathic scoliosis) and is usually first identified during early childhood. Cerebral palsy (CP) is the most common cause of NMS, followed by Duchenne muscular dystrophy (DMD). Progressive spinal deformity causes difficulty with daily care, walking and sitting, and can lead to back and rib pain, cardiac and pulmonary complications, altered seizure thresholds, and skin compromise. Early referral to specialist spinal services and early diagnosis of NMS is essential to ensure appropriate multidisciplinary patient management. The most important goals for patients are preservation of function, facilitation of daily care, and alleviation of pain. Non-operative management includes observation or bracing for less severe and flexible deformity in young patients as a temporising measure to provide postural support. Surgical correction and stabilisation of NMS is considered for patients with a deformity >40-50 degrees , but may be performed for less severe deformity in patients with DMD. Post-operative intensive care, early mobilisation and nutritional supplementation aim to minimise the rate of post-surgical complications, which are relatively common in this patient group. However, surgical management of NMS is associated with good long-term outcomes and high satisfaction rates for patients, their relatives and carers. PMID- 26966823 TI - Evaluation of the effectiveness of home based or hospital based calisthenic exercises in patients with ankylosing spondylitis. AB - OBJECTIVE: The aim of this study is to evaluate the effects of calisthenic exercises on functionality, mobility, disaese activity, quality of life, and psychological status in patients with Ankylosing spondylitis (AS). METHODS: Prospective analysis of forty patients diagnosed with AS were randomized into two exercise groups. AS patients having diagnosis based on 1984-modified New York criteria were involved. Patients were given 8 weeks calisthenic exercise program. Outcome measures including the Bath AS Functional Index (BASFI), Bath AS Disease Activity Index (BASDAI), Bath AS Metrology Index (BASMI), AS Quality of Life Questionnaire (ASQoL), Bath AS Patient Global Score (BAS-G) Hospital Anxiety Depression Score (HADS), erythrocyte sedimentation rate (ESR) and the serum C reactive protein (CRP) levels were assessed at the baseline and at 8 weeks. RESULTS: Thirty-seven participants completed the exercise programme. After the 8 week exercise programme, the home-based exercise group showed significant improvement in ESR levels and hospital-based exercise group showed significant improvements in terms of the BASMI and HADS-A scores. CONCLUSION: Calisthenic exercises can be easily performed both at home and in hospital setting. In patients with AS, calisthenic exercises performed at the hospital may improve the mobility, and psychological status (anxiety). PMID- 26966824 TI - Pelvic floor muscle contraction and abdominal hollowing during walking can selectively activate local trunk stabilizing muscles. AB - BACKGROUND: Trunk muscle exercises are widely performed, and many studies have been performed to examine their effects on low back pains. However, the effect of trunk muscles activations during walking with pelvic floor muscle contraction (PFMC) and abdominal hollowing (AH) has not been clarified. OBJECT: To investigate whether walking with PFMC and AH is more effective for promoting local trunk muscle activation than walking without PFMC and AH. METHODS: Twenty healthy men (28.9 +/- 3.14 years, 177.2 +/- 4.25 cm, 72.1 +/- 6.39 kg, body mass index 22.78 +/- 2.38 kg/m2) were participated in this study. Surface electrodes were attached over the multifidus (MF), lumbar erector spinae (LES), thoracic erector spinae (TES), transverse abdominus-internal oblique abdominals (TrA-IO), external oblique abdominals (EO), and rectus abdominus (RA). The amplitudes of electromyographic signals were measured during a normal walking with and without PFMC and AH. RESULT: PFMC and AH while walking was found to result in significant bilateral increases in the normalized maximum voluntary contraction (MVC) of MFs and TrA-IOs (p< 0.05). Ratios of local muscle activity to global muscle activities were increased while performing PFMC and AH during normal walking. Bilateral TrA-IO/EO activity ratios were significantly increased by PFMC and AH (p< 0.05). CONCLUSION: Performance of the PFMC and AH during walking resulted in significantly more recruitment of local trunk muscles. This study suggests that PFMC and AH during normal daily walking improves activation of muscles responsible for spinal dynamic stabilization and might be useful if integrated into low back disability and pain physical rehabilitation efforts. PMID- 26966825 TI - Effect of thoracic mobilization on respiratory parameters in chronic non-specific low back pain: A randomized controlled trial. AB - BACKGROUND: Altered respiratory function has been found to be associated with back pain. Limited chest excursion in subjects with chronic low back pain (CLBP) may be due to co-contraction or bracing of erector spinae and abdominal muscles; their flexed spinal posture; and/or their compromised spinal stability resulting from dysfunctional transversus abdominis. OBJECTIVE: To check for the effects of thoracic mobilization on respiratory parameters in subjects with chronic non specific low back pain. METHODS: Sixty-two subjects (excluding 11 dropouts) with CLBP of age group 30-60 were randomly allocated to two groups. Both groups received individualized treatment for low back pain (LBP) and HEP (home exercise program) regime of breathing exercises. In addition, group 1 received Maitland's Central postero-anterior vertebral pressure for thoracic spine (T1-T8). Total treatment duration was 10 sessions in 2 weeks (5 sessions/week). RESULTS: Results showed significant improvement in respiratory parameters viz. Forced Vital Capacity (FVC), Sustained Maximal Inspiratory Pressure (SMIP) and Chest Wall Expansion (CWE) and Oswestry Disability Index (ODI) in both groups (p< 0.05) at end of 2 weeks of intervention. However, improvement was significantly more in group 1 (p < 0.05) receiving additional thoracic mobilization. CONCLUSION: Subjects with non-specific chronic low back pain with or without radiation to lower limbs when treated with thoracic central PA mobilization, in addition to LBP specific treatment and breathing exercises, show an improvement in respiratory parameters and reduction in disability. PMID- 26966826 TI - Breast size impacts spine motion and postural muscle activation. AB - BACKGROUND: While it is generally accepted that large breast sizes in females contribute to back pain and poor posture, the effects of breast size on spinal motion and muscle activation characteristics are poorly understood. OBJECTIVE: This study examined the relationship between breast size, spine motion, and trunk muscle activation. METHODS: Fifteen university-aged females, free of back pain symptoms, were tested. Breast sizes were calculated, and three-dimensional spine motion and activation from five trunk muscles bilaterally were measured during standing and trunk flexion movements. Correlations between breast size and motion and muscle activation measures were assessed. RESULTS: Head and trunk angles were strongly, negatively correlated to breast size during upright standing; thoracic angles were moderately, positively correlated to breast size during thoracic flexion movements. Trunk muscles showed positive, moderate-strength relationships with breast size during upright standing and some trunk movements. CONCLUSIONS: These findings provide a preliminary indication that increasing breast sizes are associated with altered postures and increased muscle activation in a non clinical population, and constitute a baseline for the study of females with a full range of breast sizes. Further research is required to confirm the generalizability of these findings to other sizes, in order to inform strategies for the prevention or reduction of back pain, as well as diagnosis, treatment, and rehabilitation techniques associated with breast size and back pain. PMID- 26966827 TI - Peripheral nerve injuries: Long term follow-up results of rehabilitation. AB - BACKGROUND: Peripheral nerve injury (PNI) is a common problem in the world resulting with severe disability. Etiological data is different in studies because of the study period, patient population, economic status, and workplace safety policies of the different countries. OBJECTIVE: To define epidemiological and etiological data of our patients with peripheral nerve injury and to identify factors influencing efficacy of rehabilitation methods and recovery. METHODS: Patients were compared by means of electromyography and muscle strength changes. Influence of orthotics use, disease interval and type of physical therapy (electrical stimulation or EMG biofeedback) was assessed. RESULTS: There was no significant difference between groups. But we found weak correlation between EMG and motor changes. There was no difference in EMG and motor score changes in terms of orthotics use and type of physical therapy. When the patients were grouped according to EMG changes, we found significant difference by disease interval. Disease interval was longest in patients with no change in EMG. When the patients were grouped according to motor score changes, there was no significant difference by disease interval. CONCLUSION: Etiology of the patients didn't affect long term results in peripheral nerve injury. The results of this study might help rehabilitation teams to guide their follow-up. PMID- 26966828 TI - Quality of life, depression and musculoskeletal pain experience among employed women: A controlled study. AB - OBJECTIVE: The musculoskeletal pain is one of the leading health problems among employed women. The aim of our study was to examine musculoskeletal pain, depression and quality of life (QOL) among employed women and find out the differences with unemployed women. METHODS: A hundred and fifty employed women and 151 housewives were included in our study. We used visual analog scale (VAS) for the assessment of pain, Beck Depression Inventory (BDI) for the depressive symptoms and Nottingham Health Profile (NHP) for the assessment of QOL. RESULTS: The ratio of musculoskeletal pain among employed women and unemployed women were found as 42.5% and 57.5% respectively. A mild level of depression was found among employed women whereas moderate and vigorous level of depression were found among unemployed women. There were significant differences in terms of depression and QOL parameters. When the correlations of pain, depression and QOL were analyzed, significant high positive relationships between spinal, lower extremity, upper extremity pain levels and BDI and NHP were found only in housewives. CONCLUSIONS: Lower levels of depression among employed women can give the idea that social ambience at work place, focusing at work and economic independence play a role in decreasing depression. PMID- 26966829 TI - Kinesio Taping for temporomandibular disorders: Single-blind, randomized, controlled trial of effectiveness. AB - BACKGROUND: Data regarding the effectiveness of Kinesio Taping in temporomandibular disorders (TMD) is scarce. OBJECTIVE: To determine the efficacy of Kinesio Taping (KT) in patients with TMD. METHODS: Patients with TMDs were randomized into experimental and control groups. The experimental group (n= 14) received KT in combination with counseling and jaw exercise, whilst controls (n= 14) were given the regimen of counseling and exercise alone. Jaw movements, Visual analogue scale (VAS) scores and self-reported measures (functional limitation and masticatory efficiency) were evaluated at baseline, first and sixth weeks of the treatment. Biobehavioral questionnaire was filled out at baseline and at sixth week. RESULTS: Active mouth opening improved more in the experimental group than controls (p= 0.003). In the experimental group, VAS for temporomandibular joint, masticatory efficiency and functional limitation improved significantly at the sixth week when compared to baseline (p= 0.011, p= 0.001 and p= 0.001, respectively), but not in controls. Subjective treatment efficacy was higher in the experimental group than that of controls (p= 0.000). Pain, depression and disability scores reduced significantly in the experimental group (p= 0.001, p= 0.006 and p= 0.01, respectively), but not in controls. CONCLUSION: In conclusion, KT in combination with counseling and exercise is more effective than counseling and exercise alone in TMDs. PMID- 26966830 TI - Assessment on selectivity of multi-contact cuff electrode for recording peripheral nerve signals using Fitzhugh-Nagumo model of nerve excitation. AB - BACKGROUND: Nerve cuff electrodes provide a safe technique for recording nerve signals. Defining a more realized modeling to investigate the selectivity of a cuff electrode in recording from peripheral nervous system is an interesting field of research. METHODS: A four-contact cuff electrode was modeled to evaluate selective recording from a peripheral nerve. Fitzhugh-Nagumo equations were used to model the electromagnetic fields generated by active nerves and electrodes and the ''selectivity index'' used to quantify the selective property of the cuff electrode. RESULTS: The action potentials amplitude and impulse velocity generated by Fitzhugh-Nagumo model are similar to real-life nerve measurements according to the literature. The electrical field distribution caused by the impulse propagation along a specific nerve was the maximum near the corresponding contact. Also, the selectivity was increased with increasing the distance between the active sources and the number of contacts. CONCLUSION: The results of this research showed that Fitzhugh-Nagumo equations could model the nerve excitation accurately and could be used in computer simulation for studying nervous systems. Also, using these equations indicated that multi-contact cuff electrodes could be used in recording peripheral nerve signals in order to discriminate active fascicles in a nerve bundle. PMID- 26966831 TI - A Filter-based Surface Enhanced Raman Spectroscopic Assay for Rapid Detection of Chemical Contaminants. AB - We demonstrate a method to fabricate highly sensitive surface-enhanced Raman spectroscopic (SERS) substrates using a filter syringe system that can be applied to the detection of various chemical contaminants. Silver nanoparticles (Ag NPs) are synthesized via reduction of silver nitrate by sodium citrate. Then the NPs are aggregated by sodium chloride to form nanoclusters that could be trapped in the pores of the filter membrane. A syringe is connected to the filter holder, with a filter membrane inside. By loading the nanoclusters into the syringe and passing through the membrane, the liquid goes through the membrane but not the nanoclusters, forming a SERS-active membrane. When testing the analyte, the liquid sample is loaded into the syringe and flowed through the Ag NPs coated membrane. The analyte binds and concentrates on the Ag NPs coated membrane. Then the membrane is detached from the filter holder, air dried and measured by a Raman instrument. Here we present the study of the volume effect of Ag NPs and sample on the detection sensitivity as well as the detection of 10 ppb ferbam and 1 ppm ampicillin using the developed assay. PMID- 26966832 TI - AIE-Active Tetraphenylethylene Cross-Linked N-Isopropylacrylamide Polymer: A Long Term Fluorescent Cellular Tracker. AB - There is a great demand to understand cell transplantation, migration, division, fusion, and lysis. Correspondingly, illuminant object-labeled bioprobes have been employed as long-term cellular tracers, which could provide valuable insights into detecting these biological processes. In this work, we designed and synthesized a fluorescent polymer, which was comprised of hydrophilic N isopropylacrylamide polymers as matrix and a hydrophobic tetraphenylethene (TPE) unit as AIE-active cross-linkers (DDBV). It was found that when the feed molar ratio of N-isopropylacrylamides to cross-linkers was 22:1, the produced polymers demonstrated the desirable LCST at 37.5 degrees C. And also, the temperature sensitivity of polymers could induce phase transfer within a narrow window (32-38 degrees C). Meanwhile, phase transfer was able to lead the florescent response. And thus, we concluded that two responses occur when one stimulus is input. Therefore, the new cross-linker of DDBV rendered a new performance from PNIPAm and a new chance to create new materials. Moreover, the resulted polymers demonstrated very good biocompatibility with living A549 human lung adenocarcinoma cells and L929 mouse fibroblast cells, respectively. Both of these cells retained very active viabilities in the concentration range of 7.8-125 MUL/mg of polymers. Notably, P[(NIPAm)22-(DDBV)1] (P6) could be readily internalized by living cells with a noninvasive manner. The cellular staining by the fluorescent polymer is so indelible that it enables cell tracing for at least 10 passages. PMID- 26966833 TI - A Quick and Efficient Method for the Purification of Endoderm Cells Generated from Human Embryonic Stem Cells. AB - The differentiation capabilities of pluripotent stem cells such as embryonic stem cells (ESCs) allow a potential therapeutic application for cell replacement therapies. Terminally differentiated cell types could be used for the treatment of various degenerative diseases. In vitro differentiation of these cells towards tissues of the lung, liver and pancreas requires as a first step the generation of definitive endodermal cells. This step is rate-limiting for further differentiation towards terminally matured cell types such as insulin-producing beta cells, hepatocytes or other endoderm-derived cell types. Cells that are committed towards the endoderm lineage highly express a multitude of transcription factors such as FOXA2, SOX17, HNF1B, members of the GATA family, and the surface receptor CXCR4. However, differentiation protocols are rarely 100% efficient. Here, we describe a method for the purification of a CXCR4+ cell population after differentiation into the DE by using magnetic microbeads. This purification additionally removes cells of unwanted lineages. The gentle purification method is quick and reliable and might be used to improve downstream applications and differentiations. PMID- 26966834 TI - Orally administered hyaluronan affects skin dryness and epidermal thickening in photoaged hairless mice. AB - The oral administration of hyaluronans (HAs) (molecular weight, 300k and less than 10k) to photoaged hairless mice increased the moisture content of the stratum corneum and decreased the epidermal thickness, respectively. Furthermore, orally administered HAs suppressed the low-molecular weight of HA content of the skin. This study indicates oral administered HAs may ameliorate the skin condition resulting from photoaging. PMID- 26966835 TI - Oral Fluoroquinolones, Retinal Detachments, and Claims Database Studies. PMID- 26966837 TI - Cycle helmet legislation should apply only to children, say researchers. AB - Laws to make the wearing of helmets by cyclists compulsory in the UK should apply to children only, research has concluded. PMID- 26966838 TI - England's chief nursing officer identifies her proudest achievement. AB - The newly appointed chief nursing officer (CNO) for England says that one of her proudest achievements was meeting the national four-hour operational standard for emergency care. PMID- 26966836 TI - Trabeculectomy in eyes with unsuspected retinoblastoma. AB - BACKGROUND: To report the management and clinical outcome of children with unsuspected retinoblastoma who underwent trabeculectomy surgery. METHODS: Three children who presented to us after trabeculectomy surgery were diagnosed with retinoblastoma. They were treated with enucleation of the affected eye. Histopathology of the enucleated eyeball showed tumor infiltration into the iris and the ciliary body in two cases, and massive choroidal invasion in the third case. Six cycles of adjuvant systemic chemotherapy with carboplatin, vincristine and etoposide were given. RESULTS: The follow-up ranged from 18-48 months. At last follow-up, all children were alive and well, with no local recurrence or systemic metastasis. CONCLUSIONS: The management of retinoblastoma with operated trabeculectomy is challenging due to risk of tumor dissemination. Timely intervention can result in good clinical outcome. Nevertheless, a meticulous posterior segment evaluation to rule out retinoblastoma in children presenting with buphthalmos or secondary glaucoma should always be considered. PMID- 26966839 TI - Fewer NHS nurses work in Scotland than at any time in past five years. AB - Seventy one nurses in Scotland lost their jobs between September and December last year, bringing the remaining number of nurses working in NHS Scotland to its lowest level since September 2006, the RCN has said. PMID- 26966840 TI - Cardiac arrest vest test. AB - Heart attacks could be diagnosed up to 12 hours faster if trials of a cardiac vest that presents a three-dimensional computer image of the heart succeed. PMID- 26966841 TI - Value of teamwork. AB - I recently attended a national consensus conference to take part in a debate on advanced nursing practice. PMID- 26966842 TI - Role of physical activity, physical fitness, and chronic health conditions on the physical independence of community-dwelling older adults over a 5-year period. AB - The variability in the individual characteristics and habits could help determine how older adults maintain independence. The impact of the variability in physical activity, physical fitness, body composition, and chronic health conditions (co morbidities) on the independence of older adults, especially over time, is seldom examined. This study aims to analyze quantitatively the impact of baseline values and changes in physical activity, physical fitness, body composition, and co morbidities on the physical independence of community-dwelling, older adults over a 5-year period. Data from 106 and 85 community-dwelling adults (>=60 years) were collected at baseline and after five years, respectively. Linear regression selected the main predictors of changes in physical independence as follows: the baseline physical independence (beta=0.032, R(2)=9.9%) and co-morbidities (beta= 0.191, R(2)=6.3%) and the changes in co-morbidities (beta=-0.244, R(2)=10.8%), agility (beta=-0.288, R(2)=6.7%), aerobic endurance (beta=0.007, R(2)=3.2%), and walking expenditure (beta=0.001, R(2)=5.1%) (p<0.05). In conclusion, baseline physical independence, baseline co-morbidities, and changes in co-morbidities, walking, agility, and aerobic endurance predicted physical independence over five years regardless of age and gender. Gains of up to 8.3% in physical independence were associated with improvements in these variables, which corresponds to regaining independence for performing one or two activities of daily living. PMID- 26966843 TI - Implementation and Operational Research: What Happens After a Negative Test for Tuberculosis? Evaluating Adherence to TB Diagnostic Algorithms in South African Primary Health Clinics. AB - INTRODUCTION AND BACKGROUND: Diagnostic tests for tuberculosis (TB) using sputum have suboptimal sensitivity among HIV-positive persons. We assessed health care worker adherence to TB diagnostic algorithms after negative sputum test results. METHODS: The XTEND (Xpert for TB-Evaluating a New Diagnostic) trial compared outcomes among people tested for TB in primary care clinics using Xpert MTB/RIF vs. smear microscopy as the initial test. We analyzed data from XTEND participants who were HIV positive or HIV status unknown, whose initial sputum Xpert MTB/RIF or microscopy result was negative. If chest radiography, sputum culture, or hospital referral took place, the algorithm for TB diagnosis was considered followed. Analysis of intervention (Xpert MTB/RIF) effect on algorithm adherence used methods for cluster-randomized trials with small number of clusters. RESULTS: Among 4037 XTEND participants with initial negative test results, 2155 (53%) reported being or testing HIV positive and 540 (14%) had unknown HIV status. Among 2155 HIV-positive participants [684 (32%) male, mean age 37 years (range, 18-79 years)], there was evidence of algorithm adherence among 515 (24%). Adherence was less likely among persons tested initially with Xpert MTB/RIF vs. smear [14% (142/1031) vs. 32% (364/1122), adjusted risk ratio 0.34 (95% CI: 0.17 to 0.65)] and for participants with unknown vs. positive HIV status [59/540 (11%) vs. 507/2155 (24%)]. CONCLUSIONS: We observed poorer adherence to TB diagnostic algorithms among HIV-positive persons tested initially with Xpert MTB/RIF vs. microscopy. Poor adherence to TB diagnostic algorithms and incomplete coverage of HIV testing represents a missed opportunity to diagnose TB and HIV, and may contribute to TB mortality. PMID- 26966845 TI - [In Process Citation]. PMID- 26966846 TI - [Sexual minorities: Concepts, attitudes and structure for an appropriate psychotherapeutic approach]. AB - Objective To propose a theoretical model and clinical approach to sexual minority patients who consult mental health professionalsMethods Clinicians at the McGill University Sexual Identity Center (MUSIC) who have been treating patients from various sexual minorities for more than 15 years present useful theoretical constructs of gender and sexuality as well as guidelines for the evaluation and treatment of patients consulting for discomfort or confusion surrounding their sexual orientation, their gender identity or both, based on both the current literature and their clinical experience.Results The notions of non-binary construction of gender, of social determinism of gender roles and expression, and of gender creativity are presented. Sexual orientation is divided into four most commonly used dimensions (emotional attraction, physical attraction, behaviour and identity); the fluidity of these and their potential non-concordance are described. The fact that attraction to one gender is independent of attraction to another gender is highlighted. An attitude of openness to all forms of gender expression and sexual orientation constellations is encouraged to allow the patient free exploration of the several facets of their sexuality.Various domains to explore in evaluating sexual orientation and gender as well as therapeutic avenues are proposed. Areas to enquire about include: mental, physical and social experiences of gender, eroticism and sexual fantasies towards all genders, emotional attraction towards them, sexual and romantic experiences, comfort and certainty about one's identity and about disclosing it.Psychoeducation can be used to teach about sexual diversity and to assess the risks and benefits of coming out to self, family, friends, co-workers or strangers. Cognitive strategies can be undertaken to debunk homophobic and transphobic myths which may fuel poor self-esteem. Psychodynamic approaches can be used to heal the narcissistic wounds of homophobia that may lead one to be mistrustful of authority figures or to suppress sexual feelings when emotional attachment becomes important. Some of these dynamic patterns are rooted in past reactions to parental homophobia and the compromises sexual minorities made as children in order to preserve their relationships with their parents. For youth coming out in present times, family support is crucial to well-being and can be enhanced through family therapy. In mixed orientation couples, couple therapy can help both spouses adapt to the coming out of one of the partners and find a new partnership. Group therapy is useful for many of the above issues particularly as it provides a sense of community which is often lacking in minority groups, especially when individuals and their families do not share the same minority status.Conclusion With the proposed framework and an attitude of openness to sexual diversity, clinicians should feel competent to treat sexual minority patients. PMID- 26966847 TI - [Rethinking identity]. AB - Pioneering work conducted over the past decades used to design sex, gender and sexual orientation in order to go beyond the traditional binary model. In general, professionals in the health and social services, however, are a little bit slow to take note of this paradigm shift making more space for human diversity, and much less to the marginalization or pathologizing of differences. In this article, the work of Alfred Kinsey, Sandra Bem and Anne Fausto-Sterling will be especially presented, respectively on sexual orientation, gender and sex. It will be proposed to include their contributions (and also those of their successors) in a model taking into account both the diversity and the fluidity that may be present in identities and self-expressions related to sex, gender and sexual orientation. PMID- 26966844 TI - Enzyme-Instructed Self-Assembly of Small D-Peptides as a Multiple-Step Process for Selectively Killing Cancer Cells. AB - Selective inhibition of cancer cells remains a challenge in chemotherapy. Here we report the molecular and cellular validation of enzyme-instructed self-assembly (EISA) as a multiple step process for selectively killing cancer cells that overexpress alkaline phosphatases (ALPs). We design and synthesize two kinds of D tetrapeptide containing one or two phosphotyrosine residues and with the N terminal capped by a naphthyl group. Upon enzymatic dephosphorylation, these D tetrapeptides turn into self-assembling molecules to form nanofibers in water. Incubating these D-tetrapeptides with several cancer cell lines and one normal cell line, the unphosphorylated D-tetrapeptides are innocuous to all the cell lines, the mono- and diphosphorylated D-tetrapeptides selectively inhibit the cancer cells, but not the normal cell. The monophosphorylated D-tetrapeptides exhibit more potent inhibitory activity than the diphosphorylated D-tetrapeptides do; the cancer cell lines express higher level of ALPs are more susceptible to inhibition by the phosphorylated D-tetrapeptides; the precursors of D tetrapeptides that possess higher self-assembling abilities exhibit higher inhibitory activities. These results confirm the important role of enzymatic reaction and self-assembly. Using uncompetitive inhibitors of ALPs and fluorescent D-tetrapeptides, we delineate that the enzyme catalyzed dephosphorylation and the self-assembly steps, together, result in the localization of the nanofibers of D-tetrapeptides for killing the cancer cells. We find that the cell death modality likely associates with the cell type and prove the interactions between nanofibers and the death receptors. This work illustrates a paradigm-shifting and biomimetic approach and contributes useful molecular insights for the development of spatiotemporal defined supramolecular processes/assemblies as potential anticancer therapeutics. PMID- 26966848 TI - [The association of bullying with suicide ideation, plan, and attempt among adolescents with GLB or unsure sexual identity, heterosexual identity with same sex attraction or behavior, or heterosexual identity without same-sex attraction or behavior]. AB - Context Bullying is a known risk factor for suicidality, and suicide is the second leading cause of death for adolescents. Both are increased in sexual minority youth (SMY). As SMY are comprised of youth who self-identify as gay, lesbian, bisexual (GLB) or who have same-sex attractions or behaviors, our previous finding that different subgroups have different risks for suicidality is understandable. Given that the difference was along sexual identity lines (GLB vs heterosexual SMY), the analysis of bullying data in the same subgroups was felt to be important.Objective To compare the association of bullying and suicide among heterosexual students without same-sex attractions or behaviors, heterosexual students with same-sex attractions and behaviors, and students with gay, lesbian or bisexual (GLB) or unsure sexual identities.Design The 2004 Quebec Youth Risk Behavior Survey (QYRBS) questionnaire was based on the 2001 Center for Disease Control Youth Risk Behavior Survey, and included items assessing the three dimensions of sexual orientation (identity, attraction and behavior), health risk behaviors, experiences of harassment, and suicidal ideation, plans and attempts.Methods A total of 1852 students 14-18 years of age from 14 public and private high schools in Montreal Quebec were surveyed anonymously during the 2004-2005 academic year.Main outcome measure Self reports of suicidal ideation, suicidal plan and suicide attempts in the last 12 months.Results In all, 117 students (6.3%) had a non-heterosexual identity (GLB or unsure) and 115 students (6.3%) had a heterosexual identity with same-sex attraction or behavior. Bullying occurred in 24% of heterosexual students without same-sex attraction or behavior, 32% of heterosexual students with same-sex attraction or behavior, and 48% of non heterosexually identified students. In multivariable analysis, the common risk factors of age, gender, depressed mood, drug use, fighting, physical and sexual abuse, and age of initial sexual contact were controlled. The reference group was heterosexual students without same-sex attraction or behavior and no bullying. When these students were bullied, they were more likely to have suicidal ideation (odds ratio [OR] = 2.11, 95% confidence interval [CI] = 1.52-2.92) but not suicide attempts. Non-heterosexual students with no bullying were twice as likely to have suicidal ideation (OR = 2.35, 95% CI = 1.24-4.48) and four times as likely when bullied (OR = 4.44, 95% CI = 2.26-8.72). Similarly for suicide attempts, they were not at increased risk when not bullied, but they were almost three times as likely when bullied (OR = 2.87, 95% CI = 1.43-5.78). Heterosexual students with same-sex attraction or behavior were never more likely on any of the suicide measures compared to the reference group, even when bullied.Conclusion This study was the first to show that adolescent students with a non-heterosexual identity will have a disproportionate increase in their suicide parameters when subject to harassment, but that heterosexually identified students with same-sex attraction or behavior did not have an increased risk over heterosexually identified students without same-sex attraction. This suggests that same-sex attraction and behavior on their own are not contributory to suicide risk, and that the efforts of future research as well as public health efforts may be better served by examining the interface between sexual identity and the school, family, and larger culture that surrounds the sexual minority youth. Longitudinal studies looking at the interplay between all these factors are needed. PMID- 26966849 TI - [Victimization, mental health and well-being among trans youths in the province of Quebec]. AB - Introduction Trans youths are more likely to experience negative social and parental reactions suggesting reprehension, from disapproving looks to physical violence. While victimization increases the likelihood of poor mental health outcomes, little is known about potential mediating factors between mental health and victimization. Self-esteem is one of the factors that may mediate the impact of homophobic victimization on mental health. Yet, data on trans youths are scarce.Objectives The objectives of this paper are: 1) to compare trans youths to cisgender heterosexual male and female youths regarding two different forms of victimization (victimization based on gender nonconformity and parental verbal abuse), self-esteem, and psychological distress, as well as 2) to test a path model of the impact of these two forms of victimization on self-esteem and psychological distress.Methods Data for this study are drawn from the Quebec Youths' Romantic Relationships survey. Data were collected among youth aged 14 to 22 years old recruited either in schools or online. Thirty-seven participants endorsed being trans or questioning their gender identity. They were paired to 74 cisgender heterosexual youths (37 male and 37 female) using propensity scores based on socio-demographic characteristics.Results Results showed that verbal parental abuse and victimization based on gender nonconformity were more prevalent among trans participants. Parental verbal abuse and victimization based on gender nonconformity were both directly and negatively associated with self esteem (explained variance: 36%). Sexual status explains 19.6% of the variance of parental victimization and 50.6% of the variance of victimization on the basis of gender nonconformity. A higher self-esteem was associated with decreased psychological distress (explained variance: 66.9%). Moreover, parental verbal abuse was also directly associated with higher psychological distress. Although there was no direct relationship between trans status and psychological distress and self-esteem, its total indirect effects on these two indicators of mental health and wellbeing status were significant (p-value < 0.001), suggesting that the impact of sexual status on them is mediated by the victimization.Conclusion This study showed the high vulnerability of trans youths to poor mental health and wellbeing outcomes because of the victimization they experience. The results highlight the importance of preventing victimization based on sexual-minority status and to educate people, including parents, to sexual and gender diversity. PMID- 26966850 TI - [Trans Youth and their Parents: an exploration of experiences and interventions in a trans-affirming perspective]. AB - This article explores the most recent knowledge on the experiences of trans youth and their parents. The article also explores best practices for professional who work with those families. Finally the article proposes two main principles of intervention to work with those populations, highlighting the importance of a transaffirmative perspective. In particular, it is proposed to challenge the current way of understanding gender and to appreciate the complexity of the various trajectories young people may take. Furthermore, we suggest focusing the intervention on promoting self-determination of the young person as well as to support families so they can better meet their child's needs.Objectives To provide comprehensive review of current knowledge on the experience of parenting a transgender youth, and to propose some reflections on directions for working with those families.Method Written as a theoretical paper, this article employs a systematic literature review to identify promising interventions with families who support a transgender youth.Results Because families of transgender children and youth experience difficulties both on personal and social levels, many of which are coming from social stigmatization and lack of knowledge about their experience, it is proposed that practitioners work toward interventions that not only facilitate families support, but also works toward a more just and inclusive society by broadening access to services and by challenging oppressive structures that contribute to the difficulties experiences by children, youth and their families.Conclusion The paper proposes that practitioners working with families of transgender children must be guided by an reviewed conception of gender and an understanding of the multiplicity of contexts that may affect the person's trajectory, as well as promoting self-determination and supporting families in meeting their needs. PMID- 26966852 TI - [Distinguishing normal identity formation process for sexual minorities from obsessive compulsive disorder with sexual orientation obsessions]. AB - Objectives In synthesizing a homosexual or bisexual identity, an individual may go through different stages before coming to a positive healthy identity. It is likely that there will be a period in which homosexual yearnings will be unwanted. Sometimes this distress leads the person to consult a health professional. Conversion therapy has been proven both ineffective and harmful and therefore has been ethically prohibited by all major psychiatric and psychological associations. The responsible clinician will attempt to assist the individual in his acceptance of his sexual minority. Occasionally individuals without homoeroticism consult because of distress related to sexual identity questioning which poses a different problem for clinicians especially if the situation goes unrecognized. The objective of this paper is to describe homosexual obsessive compulsive disorder (HOCD) and distinguish it clinically from the normal process of sexual minority identity formation in western culture.Methods A literature review yielded very few descriptions of homosexual OCD. A retrospective chart review of all patients seen in the last 3 years at the McGill University Sexual Identity Centre was conducted to identify all the cases of OCD. Six cases were found, 4 of which were of HOCD and are presented. Similarities between cases are highlighted.Results All cases were young men with relatively little relationship and sexual experience. Most were rather shy and had some other obsessional history in the past though often at a sub-clinical threshold. Obsessional doubt about their orientation was very distressing and did not abate over time as would normally occur with a homoerotic individual. The four patients who had an obsession of being gay despite little or no homoerotism are presented in detail. They all presented mental compulsions, avoidance and physiological monitoring. Continuous internal debate trying to prove or disprove sexual orientation was a ubiquitous mental compulsion. They all spent a majority of time monitoring their physiological reactions to members of both sexes to check for arousal. They attempted homosexual activity and were disgusted by it, yet this did not end their questioning. They avoided relationships with the opposite sex, being either too anxious to initiate, or too conflicted to maintain them. The obsession with being gay seemed like a horrific thought symptomatic of homophobia, however the level of horror was out of proportion to the patient's overall level of homonegativity suggesting that the horror came mostly from feeling like their core identity was threatened.Conclusion HOCD can present in ways similar to normal homosexual identity formation. A thorough exploration of eroticism towards both sexes as well as prior history of subclinical anxiety should help distinguish the two. Treatment of HOCD should combine education about sexuality and OCD as well as usual OCD treatments such as relaxation techniques, cognitive restructuring, mindfulness training and pharmacology. PMID- 26966853 TI - [Mental health implications of workplace discrimination against sexual and gender minorities: A literature review]. AB - Despite legislative advances in terms of workplace equality for sexual and gender minorities (SGM), available data ascertains the persistence of workplace discrimination of lesbian, gay, bisexual, and especially of transgender/transsexual employees. This article, based on an extensive literature review, explores the relationship between different types of workplace discrimination experiences and their impacts on the mental health of SGM and of different sub-populations: men who have sex with men, non-heterosexual women, lesbian and gay parents, and trans people. Furthermore, the article explores certain individual and systemic protection and risk factors that have an impact on this relationship, such as coming-out at work and organisational support. Finally, the existing literature on workplace discrimination and mental health of sexual and gender minorities highlights the importance, in the current legal and social context, of intersectional approaches and of research on homo- and trans negative microaggressions. The article ends with a discussion on the implications for practice, research, and workplace settings, as well as with several recommendations for these settings. PMID- 26966851 TI - [The role of parental support in the relationship between homophobic bullying, internalized homophobia and psychological distress among sexual-minority youths (SMY): a moderated mediation approach]. AB - Introduction Sexual-minority youths (SMY) report high rates of psychological distress such as depression, anxiety and suicidal ideation (Burton, Marshal, Chisolm, Sucato et Friedman, 2013; Williams & Chapman, 2011). Several studies confirm that the poor mental health outcomes are partly related to their high likelihood of experiencing homophobic victimization (Blais, Gervais, Boucher, Hebert & Lavoie, 2013; Taylor & Peter, 2011; Hughes, McCabe, Wilsnack, West & Boyd, 2010; Chamberland, Richard & Bernier, 2013). Whereas the development of a positive sexual minority identity is crucial for the mental health of SMY (Chamberland, Richard & Chevrier, 2011; Rosario, Schrimshaw & Hunter, 2011; Luhtanen, 2002), the victimization they experience put them at risk of internalizing societal homophobia and heterosexism (Meyer, 2003; Hatzenbuehler, 2009). It is important to identify variables that may influence the impact of distal and proximal factors that impact SMY's mental health.Objectives The objectives of this paper are 1) to document different forms of homophobic victimization experienced by SMY, according to gender and age, and 2) to test the potential moderating effect of parental support in the relationship between homophobic victimization, internalized homophobia and psychological distress.Method Data come from 228 SMY aged 14 to 22 years old recruited through online means as part of the Quebec Youth's Romantic Relationships Survey. The impact of homophobic victimization, parental support, and internalized homophobia on psychological distress is explored by a linear regression model including moderated mediation effects.Results Results show the relationship between homophobic victimization and psychological distress as well as indirect significant relationship through internalized homophobia. The moderated mediation analysis also confirms the moderating role of parental support in the relationship between homophobic victimization and psychological distress. Thus, at equal level of victimization, participants with low parental support experienced more psychological distress. However, parental support did not lessen the impact of victimization on internalized homophobia. The linear regression model explains 22.5% of the variance in psychological distress and 6.6% of the variance of internalized homophobia.Conclusion The results emphasize the importance of continuing efforts to prevent homophobic behaviors and attitudes among school staff, parents as well as employers and colleagues in the workplace. Given their key role, parents must also be educated and trained to support their gay, lesbian, bisexual or questioning children. PMID- 26966855 TI - [RaeRae and Mahu: third polynesian gender]. AB - Background On numerous islands of the Pacific, under various names, there are people considered to be neither men nor women but half-men/half-women. In French Polynesia, there is a sociological and anthropological condition called RaeRae or Mahu. A RaeRae is a man who behaves as and considers himself to be a woman. RaeRae and Mahu are good examples of culture-bound transsexuality or cross dressing. Being Mahu has a cultural meaning, recognized in the history of Polynesian society, and cannot be considered as a medical or psychiatric condition. Being RaeRae extends the transformation to possible hormone therapy and surgery; the traditional social role (education, tourism) of Mahu is retained but in some cases is influenced by prostitution and at-risk homosexuality.Bibliographic sources and method We conducted a literature search using several medical, social, and anthropological bibliographic sources (MedLine, Google Scholar, PsycINFO, DUMAS). We used the terms RaeRae, Mahu, Polynesian androphilia, and Polynesian sexuality. We found 20 articles and theses. Some articles discuss a very similar condition in Samoa (fa'afafine). In addition, Mahu seems to be a derogatory term for a male homosexual or drag queen in the Hawaiian Islands.Results and contents RaeRae and Mahu is broadly defined as men with sweetness [OK?] or women who are prisoners of men's bodies. There is evidence of their presence and social functions in ancient times. The arrival of the missionaries and Christian morality resulted in the emergence of a new moral and sexual order. RaeRae and Mahu remain present and visible today. They are integrated into local professional and cultural life and are accepted, as long as their sexuality remains unspoken and invisible, which is more difficult for RaeRae. We describe the phenomenon and its context and the sociocultural hypotheses. We retain a reference connected to tacit knowledge of Polynesian sacrificial rites: Mahu did not undergo sacrifices the victims of which had to be men. A general discussion must be envisaged concerning the DSM-5, transgender identity and stigmatization. For instance, in Hawaii, people who identify as transgender continue to suffer high rates of violence, sexual assault and discrimination. The description contributes to an investigation of the limits of considering gender as binary; rather, it is a continuum not governed by the medicalization and psychologization of a cultural feature, which is also recognizable in other cultural areas including among the Amerindians. Studying RaeRae and Mahu in Polynesia means agreeing to confront the binary concept that structures and divides the world into two categories of gender and sex, male and female, just like grammatical gender in French. Examples from other cultures include the new half in Japan, muxe or muche among the Zapotecs of Tehuantepec, woubi in Cote d'Ivoire, femminielli in Italy, ladyboys or kathoeys in Thailand, natkadaw in Myanmar, hijra in India and Pakistan, khounta in Arab Islamic culture, and in Canada and the USA, agokwa among the Ojibwa, and ikoneta in the Illinois language. Mahu, or transgendered individuals and transvestites, were in fact viewed by the ancient Hawaiians as a normal element of the old social culture that preceded missionary days and American and French military missions. Mahu were not merely tolerated; they were regarded as a legitimate and contributory part of the ancient Polynesian community. PMID- 26966854 TI - [The mental health issues among gay and lesbian elders]. AB - Most gay and lesbian elders have experienced discrimination and stigmatization related to their sexual orientation in their life trajectory. These negative experiences may have had an impact on their life course and on their mental health. Even if the majority of gay and lesbian older adults actually have and maintain good mental health, studies show that non-heterosexual people are at a greater risk of developing certain difficulties, such as anxiety, depression, suicidal thoughts and excessive consumption of alcohol and other substances. This article presents the factors that may weaken the mental health of older gay and lesbian people, such as victimization and the exposure to various forms of prejudice in their life course, the continuous management of the disclosure or dissimulation of their sexual orientation, the degree of internalized homophobia, as well as loneliness; and also presents the potential protective factors, such as building resilience, social networks and social support. This article concludes by illustrating the implications concerning the specific needs of the gay and lesbian elders. Some recommendations are also formulated with regards to recognizing the issues affecting gay and lesbian older adults as well as improving the services that are offered to them. PMID- 26966856 TI - [Adaptation and Neuroscience I: Fears, society, methodology, finality]. AB - This article is a first article in a series of two articles exploring the bidirectional links between the concept of adaptation and of neuroscience. In this first article, first of all we will see that neurosciences can be seen as ambitious and all-powerful oscillating between a reductionist and dehumanizing threat or crystallizing some control fantasies. We will then see that society adapts itself to neurosciences methodologies and incorporate some discoveries in various fields so that we can ask ourselves about the neuro-society of tomorrow. Then we will see that the methodology of neurosciences themselves is frequently challenged and requires that everyone knows the limitations and not only stick to promises. After that, we will see that the adaptation seen as the promise of a determined and finite goal may be reassuring but is most unlikely. PMID- 26966857 TI - [Systemic biopsychological perspective of basic emotions]. AB - The systemic biopsychological perspective of basic emotions is a heuristic model that allows a better understanding of how people learn to adapt to their environment through different emotions that developed gradually along neurohormonal circuit myelination from birth until about the age of twenty-one. These same emotions, acting in complementarity, will allow the individual to maintain a balance throughout his life.Five basic emotions were retained in line with the five emotions related to neuronal circuits, which are defined in the literature, and these are the five circuits described by Panksepp as follows: aggressiveness (Rage, angry), stress (Fear- surprise), developed by LeDoux, reward (Seeking-joy), developed by Tassin, empathy (Panic-sadness), developed by Decety, and consciousness (consciousness-happiness), developed by Damasio.Several studies on myelination (Kinney, 1988, Parazzini, 2002, Deoni, 2012), Miller, 2012, and Welker, 2012) provide us with a scientific platform to determine the order of development of the neurohormonal circuits underlying basic emotions.Neurohormonal circuits development begins at conception and will continue up until the age of 20-30 years. This article specifically addresses the first three years of life. It offers a systemic biopsychological perspective of basic emotions developed from the latest data in neuroscience. These informations have been integrated into a coherent whole that allows understanding the origin, the development and the functioning of basic emotions.In addition to the information output from the thalamus to the midbrain that set in motion the somatic nervous system there exist, according to Roberge (1998), two other brain information sources that are managed by the hypothalamus (the limbic system). These two information sources allow the refining of the behavioural responses and they favour the homeostasis of the organism. The first information source goes from the midbrain to the hypothalamus to activate the peripheral nervous system. The latter is divided into two: the sympathetic (norepinephrine) that accelerates the motor response and the parasympathetic (acetylcholine), which slows it down. These two systems work in tandem. As for the second release of information, it is endocrine, thus it will follow the hypothalamus-pituitary-adrenal axis to cortisol, the hypothalamus-pituitary axis to endorphin and oxytocin and the hypothalamus-pineal axis to melatonin. The different emotional behaviours result from one of these two sources of information or from a combination of these two and are then managed by the limbic system, which is in continuous connection with the neocortex.In short, no specific centre totally controls human behaviour. Control is achieved through a group of brain structures and relays, permitting adaptive behaviour and maintenance of balance by means of permanent exchanges. Anger, for instance, is a survival emotion, which allows protecting one's physical integrity. It is very useful as an immediate response in an emergency situation, but it can also be harmful if it is used extensively in all situations, giving way to conduct disorders. Thus, the other neurohormonal circuits will regulate anger.Emotions are an integral part of human behaviour. They allow the individual to constantly adapt to the physical and social environment. This approach brings a new perspective to understand how each person maintains balance to avoid the onset of clinical disorders. The understanding of neurochemical mechanisms underlying basic emotions opens up the door to several clinical applications. PMID- 26966858 TI - [In Process Citation]. AB - Objectives The Borderline Personality Disorder (BPD) is a severe psychopathology related to great personal and family distress, which aetiology goes back to childhood. Empirical data supports a certain temporal stability of personality traits from childhood to adolescence and adulthood. Several authors argue that it is possible to identify in children and adolescents personality traits that could be associated with the characteristics of BPD observed in adulthood. However, only few instruments have been developed to assess child and adolescent traits associated with BPD. This article aims to present the results of the first validity study of the French version of the Borderline Personality Features Scale for Children (BPFS-C).Method The French version of the instrument, which has been developed using translation/back-translation was administered to 262 children, aged 9 to 12 years old (M = 10.52; ET = 0.96), attending regular schools in Quebec (55.70% were girls). Forty-three bilingual children (M = 10.65, SD = 0.98; 60.50% were girls) completed the two versions of the questionnaire (English and French), on a one-week interval. In addition, 23 English-speaking children from Quebec (M = 10.42, SD = 1.12) completed the original version of the questionnaire.Results The first validity study of the French version of the instrument shows a very satisfactory internal consistency. The correlations between the English and French versions of the instrument are significant. The principal component analysis revealed a four component model that have similarities with the four subscales of the English version, but differs in the distribution of items originally belonging to the subscale Identity problems of the BPFS-C.Conclusions The results of the first validity study of the French version of the instrument are promising. However, further research is needed in order to demonstrate the temporal stability as well as the construct validity of this measure. The instrument should also be validated with children from a clinical population with a higher preponderance of biological and environmental risk factors associated with the development of BPD. Finally, it would be interesting to establish the standardized values of the instrument allowing clinicians to identify which scores can be considered normal and which may indicate a strong presence of borderline personality traits. The identification of personality traits and behaviours associated with BPD in children and adolescents could promote prospective research and increase knowledge about the aetiology, characteristics, and trajectory of BPD throughout child development. PMID- 26966859 TI - Therapeutic compositions and uses of alpha1-antitrypsin: a patent review (2012 - 2015). AB - INTRODUCTION: Identified as a circulating serine-protease inhibitor, the genetic deficiency of which predisposes to the development of lung emphysema, alpha1 antitrypsin (AAT) has recently been found to possess various anti-inflammatory and immunomodulatory activities outside the biochemical inhibition of serine proteases. AAT is presently extracted from human plasma to supply life-long infusions to patients with genetic AAT deficiency. However, its newly appreciated functions point to extended therapeutic uses; these, alongside modified production attempts, represent a novel and dynamic niche of drug repurposing, set apart from addressing lung emphysema in AAT-deficient individuals. AREAS COVERED: The review provides a comprehensive summary of patent-protected inventions in the field of novel clinical indications for AAT and innovations in AAT production. EXPERT OPINION: A molecule no longer patentable per se, presents with novel clinical applications; its mechanism still unfolding. While modified protein sequences are patentable and potentially superior, they are burdened by regulatory setbacks. Thus, recent approaches in the context of AAT appear in patents that describe combinations with other drugs, redefined clinical subclasses, and unique recombinant entities, carefully skirting saturated areas of AAT patentology. It will be fascinating to follow technologies and creative patenting as AAT navigates the trying trades of pharmaceutical industry towards an increasing lineup of unmet clinical needs. PMID- 26966860 TI - Synthesis of Poly(N-isopropylacrylamide) Janus Microhydrogels for Anisotropic Thermo-responsiveness and Organophilic/Hydrophilic Loading Capability. AB - Janus microparticles are compartmentalized particles with differing molecular structures and/or functionality on each of their two sides. Because of this unique property, Janus microparticles have been recognized as a new class of materials, thereby attracting a great deal of attention from various research fields. The versatility of these microparticles has been exemplified through their uses as building blocks for self-assembly, electrically responsive actuators, emulsifiers for painting and cosmetics, and carriers for drug delivery. This study introduces a detailed protocol that explicitly describes a synthetic method for designing novel Janus microhydrogels composed of a single base material, poly(N-isopropylacrylamide) (PNIPAAm). Janus microdroplets are firstly generated via a hydrodynamic focusing microfluidic device (HFMD) based on the separation of a supersaturated aqueous NIPAAm monomer solution and subsequently polymerized through exposure to UV irradiation. The resulting Janus microhydrogels were found to be entirely composed of the same base material, featured an easily identifiable compartmentalized morphology, and exhibited anisotropic thermo-responsiveness and organophilic/hydrophilic loading capability. We believe that the proposed method introduces a novel hydrogel platform with the potential for advanced synthesis of multi-functional Janus microhydrogels. PMID- 26966861 TI - Effects of transgene expression level per cell in mice livers on induction of transgene-specific immune responses after hydrodynamic gene transfer. AB - We previously showed that high and sustained transgene expression of antigenic proteins induced transgene-specific immune responses. In the present study, a detailed relationship between the level of transgene expression per cell and immune response after hydrodynamic gene transfer was investigated. Cypridina luciferase (cLuc), a secretory antigenic reporter protein, was selected as a model antigen, and pROSA-cLuc, a plasmid expressing cLuc, was constructed. A fixed dose (30 MUg) of pROSA-cLuc was delivered to mice by a single hydrodynamic injection or three injections at 24-h intervals because the number of cells transfected with plasmids is dependent on the number of hydrodynamic injections. Serum cLuc activity, an indicator of the total amount of cLuc transgene expression, was almost equal between these two groups. In contrast, the high-dose single injection induced higher levels of cLuc-specific humoral and cellular immune responses than the three low-dose injections. Moreover, the serum cLuc activity of the high-dose single injection group began to decline ~10 days after injection, whereas the activity remained constant in the three low-dose injection group. These results indicate that it is preferable to reduce the level of transgene expression per cell to avoid induction of the transgene-specific immune response after hydrodynamic gene transfer. PMID- 26966863 TI - Ethical Considerations When Counseling Patients With Thyroid Cancer About Surgery vs Observation-Reply. PMID- 26966862 TI - Adenovirus-mediated hAQP1 expression in irradiated mouse salivary glands causes recovery of saliva secretion by enhancing acinar cell volume decrease. AB - Head and neck irradiation (IR) during cancer treatment causes by-stander effects on the salivary glands leading to irreversible loss of saliva secretion. The mechanism underlying loss of fluid secretion is not understood and no adequate therapy is currently available. Delivery of an adenoviral vector encoding human aquaporin-1 (hAQP1) into the salivary glands of human subjects and animal models with radiation-induced salivary hypofunction leads to significant recovery of saliva secretion and symptomatic relief in subjects. To elucidate the mechanism underlying loss of salivary secretion and the basis for AdhAQP1-dependent recovery of salivary gland function we assessed submandibular gland function in control mice and mice 2 and 8 months after treatment with a single 15-Gy dose of IR (delivered to the salivary gland region). Salivary secretion and neurotransmitter-stimulated changes in acinar cell volume, an in vitro read-out for fluid secretion, were monitored. Consistent with the sustained 60% loss of fluid secretion following IR, a carbachol (CCh)-induced decrease in acinar cell volume from the glands of mice post IR was transient and attenuated as compared with that in cells from non-IR age-matched mice. The hAQP1 expression in non-IR mice induced no significant effect on salivary fluid secretion or CCh-stimulated cell volume changes, except in acinar cells from 8-month group where the initial rate of cell shrinkage was increased. Importantly, the expression of hAQP1 in the glands of mice post IR induced recovery of salivary fluid secretion and a volume decrease in acinar cells to levels similar to those in cells from non-IR mice. The initial rates of CCh-stimulated cell volume reduction in acinar cells from hAQP1-expressing glands post IR were similar to those from control cells. Altogether, the data suggest that expression of hAQP1 increases the water permeability of acinar cells, which underlies the recovery of fluid secretion in the salivary glands functionally compromised post IR. PMID- 26966864 TI - VITREORETINAL SURGERY WITH SILICONE OIL TAMPONADE IN PRIMARY UNCOMPLICATED RHEGMATOGENOUS RETINAL DETACHMENT: Clinical Outcomes and Complications. AB - BACKGROUND: To determine the anatomical and functional outcomes and possible complications after pars plana vitrectomy (PPV) with silicone oil (SO) tamponade in primary uncomplicated rhegmatogenous retinal detachments. METHODS: This is a prospective observational study. Overall, 62 consecutive patients who underwent surgical repair by PPV and SO injection for primary uncomplicated rhegmatogenous retinal detachment between January 01, 2006 and April 30, 2012 were followed. In general, PPV was chosen over scleral buckling when a significant cataract or a vitreous hemorrhage prevented adequate fundus visualization. Silicone oil was chosen over gas tamponade in patients living at 1,000 meters above the sea level, where SF6 or C3F8 tamponade could not be performed because of the risk of acute increase of intraocular pressure (IOP). One thousand centistokes SO was used in all eyes. At all visits, patients had a detailed ocular history and thorough bilateral evaluation, including best-corrected visual acuity, anterior segment examination, and IOP measurements by aplanation and fundus examination. Outcomes were assessed at 1 day, 1 week, 1 month, 3 months, 6 months, and every 6 months thereafter. Increased IOP was defined as an IOP of more than 21 mmHg. RESULTS: Anatomical success rate, final best-corrected visual acuity, IOP elevation, cataract formation, and other complications were the main outcome measures. This study included 62 eyes of 62 patients (41 men and 21 women) that underwent retinal detachment repair by PPV and SO injection. The age at the time of intervention was 57.6 +/- 10.5 years (mean +/- standard deviation; range, 34-79 years). All patients were whites. Mean follow-up was 24.5 +/- 17.3 months (range, 6-70 months). Anatomical success rate defined as retinal reattachment 6 months after SO removal was 93.5%. Final BCVA was improved in 55 eyes (88.7%), with a mean of 4 Snellen lines, unchanged in 5 (8.1%), and worse in 2 eyes (3.2%), with a mean of 3 Snellen lines. Mean duration of SO tamponade was 5.12 +/- 2.37 months (range, 2-12 months). From the 30 eyes that were still phakic after vitrectomy, 24 eyes (80.0%) underwent cataract surgery within a period of 7.37 +/- 3.00 months (range, 2-13 months). Thirty-five eyes (56.5%) had an increase in IOP during the follow-up period. Thirty-one patients had transient ocular hypertension requiring topical treatment during the immediate postoperative period (one month). Only 1 eye (2.9%) required filtrating drainage surgery for IOP control. No eyes developed optic neuropathy secondary to IOP elevation. CONCLUSION: Pars plana vitrectomy with SO injection seems to be a safe and efficient surgical approach in the treatment of primary uncomplicated rhegmatogenous retinal detachment in patients living in high altitude (>1,000 m). Also, PPV and SO injection are associated with good anatomical and functional outcomes in our series. Reattachment rates are high, and rates of proliferative vitreoretinopathy are low. Cataract formation and elevated IOP represent frequent but successfully controlled complications. PMID- 26966865 TI - INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE FOR MACULAR HOLES IN HIGH MYOPIA WITH AXIAL LENGTH >=30 mm. AB - PURPOSE: To evaluate the closure rate of macular holes in highly myopic eyes treated with the inverted internal limiting membrane flap technique. METHODS: Retrospective study in 33 consecutive patients (33 eyes) with a myopic macular hole (axial length >=30 mm) and no associated macular retinoschisis, undergoing 23-gauge pars plana vitrectomy combined with the inverted internal limiting membrane flap technique. RESULTS: Mean initial logarithm of the minimum angle of resolution best-corrected visual acuity was 0.59 (range, 0.22-1.8) (Snellen fraction, 20/80). At the 1-month postoperative control visit, the macular hole was closed in all patients. Reopening of the hole occurred in 2 patients. Visual acuity improved in 13 patients (39.4%): final mean ETDRS (Early Treatment Diabetic Retinopathy Study) improvement was +80 letters, and logarithm of the minimum angle of resolution was 0.4 (20/50). Staphyloma with macular involvement was present in all patients. Dissociated optic nerve fiber layer was observed in 25 patients (75.7%) and was absent in 2 (6.1%); in the remaining 6 patients, the layer could not be assessed. Gliosis was found in 14 patients (42.4%). CONCLUSION: Vitrectomy plus the inverted internal limiting membrane flap technique was effective for treating macular holes in eyes with axial length >=30 mm and no associated retinoschisis. PMID- 26966866 TI - CORRELATION OF OPTICAL INTENSITY ON OPTICAL COHERENCE TOMOGRAPHY AND VISUAL OUTCOME IN CENTRAL RETINAL ARTERY OCCLUSION. AB - PURPOSE: To investigate the relationship between optical coherence tomography (OCT) characteristics at baseline and visual outcome in central retinal artery occlusion (CRAO). METHODS: The medical charts and OCT images of patients with central retinal artery occlusion with follow-up for more than 90 days were reviewed. Optical intensities of inner retinal layers, outer nuclear layers, and photoreceptor/retinal pigment epithelium were measured using Image J software. Optical intensity ratio was calculated as the optical intensity of inner retinal layers divided by that of photoreceptor/retinal pigment epithelium. Retinal thickness over the nine early treatment diabetic retinopathy study regions was automatically calculated by OCT software. The relationship between best-corrected visual acuity at the last follow-up and OCT characteristics were analyzed using Spearman correlation. RESULTS: Fifteen eyes of 15 central retinal artery occlusion patients were included, with mean follow-up of 327.1 +/- 184.1 days. The final best-corrected visual acuity was mildly or moderately correlated with retinal thicknesses, and strongly correlated with the optical intensity of photoreceptor/retinal pigment epithelium (r = -0.707, P = 0.003) and optical intensity ratio (r = 0.825, P < 0.001). CONCLUSION: Optical intensity ratio on OCT is highly correlated with visual prognosis in central retinal artery occlusion. It may be a potential biomarker of retinal ischemia. PMID- 26966867 TI - RISK OF AGE-RELATED MACULAR DEGENERATION IN END-STAGE RENAL DISEASE PATIENTS RECEIVING LONG-TERM DIALYSIS. AB - PURPOSE: This study investigated the risk of age-related macular degeneration (AMD) in patients with end-stage renal disease (ESRD) receiving long-term dialysis and compared the risk between various dialysis modalities using propensity score-matching methods. METHODS: From the National Health Insurance Research Database of Taiwan, the authors identified 27,232 patients with ESRD newly diagnosed from 2000 to 2010, including 9,287 patients on peritoneal dialysis (PD) and 17,945 patients on hemodialysis (HD). A total of 108,928 controls without kidney disease were randomly selected and frequency matched by age, sex, and index year of ESRD patients. The authors established an additional HD cohort matched by propensity scores of PD patients (N = 9,256 each). All cohorts were followed up until the end of 2011 to measure the incidence of AMD. RESULTS: The incidences of AMD were 1.84, 4.03, 5.37, and 3.50 per 1,000 person years in the control, ESRD (PD and HD), PD, and HD cohorts, respectively. The hazard ratios for AMD were 1.72, 2.47, and 1.43 for the ESRD, PD, and HD cohorts, with 95% confidence intervals of 1.50 to 1.97, 2.05 to 2.98, and 1.22 to 1.68, respectively, compared with the control cohort. The patients on PD exhibited a hazard ratio of 1.74 (95% confidence interval = 1.27-2.38) for developing AMD compared with propensity score-matched patients on HD. CONCLUSION: Patients with ESRD may exhibit a higher risk of AMD than people without kidney disease. Patients on PD may be more likely to develop AMD than patients on HD. PMID- 26966868 TI - ANATOMICAL AND FUNCTIONAL OUTCOMES OF SYMPTOMATIC IDIOPATHIC VITREOMACULAR TRACTION: A Natural History Study From the Pan American Collaborative Retina Study Group. AB - PURPOSE: To describe the natural history of eyes with symptomatic idiopathic vitreomacular traction (VMT). METHODS: Retrospective multicenter study of 168 eyes with spectral-domain optical coherence tomography (SD-OCT) findings consistent with idiopathic VMT. All eyes were graded according to SD-OCT findings. Grade 1 was defined as incomplete cortical vitreous separation with foveal attachment. Grade 2 was defined as Grade 1 plus intraretinal cysts or clefts. Grade 3 was defined as Grade 2 plus a foveal detachment. All patients were followed for at least 6 months. RESULTS: There were 168 patients (51 men) with a mean age of 68.8 +/- 10.7 years. Patients were followed for a mean of 22.7 +/- 20.1 months. The mean duration of symptoms before the initial presentation was 3.65 +/- 5.42 months. At baseline, 72 eyes had Grade 1, 74 eyes had Grade 2, and 22 eyes had Grade 3 SD-OCT findings. Over the follow-up period, 36 eyes (21.4%) had spontaneous resolution of the VMT with normalization of the foveal anatomy. The mean time to resolution was 12.3 +/- 12.6 months. An unfavorable anatomical outcome occurred in 7.7% (13 of 168) of the eyes, with 6 eyes developing a lamellar macular hole and 7 eyes developing a full-thickness macular hole. This occurred at a mean of 10.3 +/- 10.7 months after the presentation. Subgroup analysis based on baseline SD-OCT grade showed that 4.1% (3 of 73) of Grade 1 eyes compared with 6.8% (5 of 74) of Grade 2 eyes, and 23.8% (5 of 21) of Grade 3 eyes developed a full-thickness macular hole or lamellar macular hole (P = 0.0109, chi-square test). In the remaining 119 eyes, at the last follow-up, 65 eyes had Grade 1, 42 eyes had Grade 2, and 12 eyes had Grade 3 VMT. On average, the best-corrected visual acuity improved from 0.40 +/- 0.35 logarithm of the minimum angle of resolution (Snellen, 20/50) at baseline to 0.35 +/- 0.36 logarithm of the minimum angle of resolution (Snellen, 20/45; P = 0.0372), and the mean central macular thickness improved from 350 +/- 132 MUm to 323 +/- 121 MUm. CONCLUSION: Spontaneous resolution of VMT occurred in 21.4% (36 of 168) of eyes after a mean follow-up of 11.4 +/- 12.6 months. An unfavorable anatomical outcome occurred in 7.7% (13 of 168) of eyes. The baseline SD-OCT grade may predict the progression to full-thickness macular hole. PMID- 26966869 TI - ELECTRONIC MEDICAL RECORD DATABASE STUDY OF VITRECTOMY AND OBSERVATION FOR VITREOMACULAR TRACTION. AB - PURPOSE: To audit the natural history of vitreomacular traction, and the risks and benefits of surgery. METHODS: Database study of 1,254 patients (1,399 eyes) with vitreomacular traction from 16 UK vitreoretinal units. RESULTS: The median age was 75 years, with 36.2% of patients diagnosed as diabetic. In 986 (70.5%) eyes managed conservatively, the median presenting logarithm of the minimum angle of resolution visual acuity of 0.30 (Snellen 20/40) was unchanged over follow-up. Of 413 eyes (29.5%) that required pars plana vitrectomy, the median preoperative visual acuity improved from 0.60 to 0.50 (20/80-20/63), 6 months to 12 months after surgery, with 33% gaining at least 0.3 units (approximately 2 Snellen lines). Vitrectomy was combined with internal limiting membrane peel in 43.8%, epiretinal membrane peel in 42.4%, gas/air tamponade in 46.2%, and cataract surgery in 27.9%. One or more intraoperative complications occurred in 12.6%; most commonly retinal breaks (8.0%), retinal trauma (1.9%), and retinal hemorrhage (1.0%). Postoperative retinal detachment occurred in 2.7% and macular hole in 2.2%. The 1, 2, and 3 year rates of postvitrectomy cataract surgery were 28.2%, 38.2%, and 42.7%, respectively. CONCLUSION: Many eyes with vitreomacular traction have stable visual acuity. Those progressing to vitrectomy have relatively modest visual acuity gains, and complications are not infrequent. PMID- 26966870 TI - Macro-microscopy: clinical surface microscopy using digital cameras. PMID- 26966871 TI - An update on heparin-induced thrombocytopenia: diagnosis and management. AB - INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is a drug-mediated, prothrombotic disorder caused by immunization against platelet factor 4 (PF4) after complex formation with heparin or other polyanions. A subset of anti PF4/heparin antibodies are capable of intravascular platelet activation by cross linking Fcgamma receptor IIA leading to platelet count decrease and/or thrombosis. HIT can be potentially associated with devastating complications such as life-threatening thrombosis making it one of the most serious adverse drug reactions. Diagnosis of HIT based on clinical information is often difficult. AREA COVERED: This review highlights the pathophysiology of HIT, emphasizing characteristic clinical features and the role of laboratory assays in the diagnosis of HIT. In addition, a summary of current therapeutic options for patients with HIT will be provided. EXPERT OPINION: A combination of clinical pretest scoring system and laboratory investigation is usually necessary to diagnose HIT. If HIT is strongly suspected, all sources of heparin must be stopped and an alternative non-heparin anticoagulant should be started to prevent new thromboembolic complications. However, heparin alternative anticoagulants bear a considerable bleeding risk, especially if given to patients with thrombocytopenia due to other reasons than HIT. A better understanding of clinical and laboratory features of HIT may help developing strategies to avoid complications induced by this serious adverse reaction against heparin. PMID- 26966872 TI - Vinclozolin alters the expression of hormonal and stress genes in the midge Chironomus riparius. AB - Vinclozolin is a fungicide used in agriculture that can reach aquatic ecosystems and affect the organisms living there. Its effects have been intensively studied in vertebrates, where it acts as an antiandrogen, but there is a lack of information about its mechanistic effects on invertebrates. In this work, we analyzed the response of genes related to the endocrine system, the stress response, and the detoxification mechanisms of Chironomus riparius fourth instar larvae after 24h and 48h exposures to 20 (69.9nM), 200 (699nM), and 2000MUg/L (6.99MUM) of Vinclozolin. Survival analysis showed that this compound has low toxicity, as it was not lethal for this organism at the concentrations used. However, this fungicide was shown to modify the transcriptional activity of the ecdysone response pathway genes EcR, E74, and Kr-h1 by increasing their mRNA levels. While no changes were observed in disembodied, a gene related with the ecdysone synthesis metabolic pathway, Cyp18A1, which is involved in the inactivation of the active form of ecdysone, was upregulated. Additionally, the expression of two genes related to other hormones, FOXO and MAPR, did not show any changes when Vinclozolin was present. The analysis of stress response genes showed significant changes in the mRNA levels of Hsp70, Hsp24, and Gp93, indicating that Vinclozolin activates the cellular stress mechanisms. Finally, the expressions of the genes Cyp4G and GstD3, which encode enzymes involved in phase I and phase II detoxification, respectively, were analyzed. It was found that their mRNA levels were altered by Vinclozolin, suggesting their involvement in the degradation of this compound. For the first time, these results show evidence that Vinclozolin can modulate gene expression, leading to possible significant endocrine alterations of the insect endocrine system. These results also offer new clues about the mode of action of this compound in invertebrates. PMID- 26966873 TI - Sublethal effects of copper sulphate compared to copper nanoparticles in rainbow trout (Oncorhynchus mykiss) at low pH: physiology and metal accumulation. AB - A few studies have investigated the interaction between copper toxicity and water pH in fishes, but little is known about the effects of acidic pH on the toxicity of copper nanoparticles (Cu-NPs). This study aimed to describe the sub-lethal toxic effects of Cu-NPs compared to CuSO4 at neutral and acidic water pH values in juvenile rainbow trout. Fish were exposed in triplicate (3 tanks/treatment) to control (no added Cu), or 20MUgl(-1) of either Cu as CuSO4 or Cu-NPs, at pH 7 and 5 in a semi-static aqueous exposure regime for up to 7 days. Acidification of the water altered the mean primary particle size (at pH 7, 60+/-2nm and pH 5, 55+/ 1nm) and dialysis experiments to measure dissolution showed an increased release of dissolved Cu from Cu-NPs at pH 5 compared to pH 7. Copper accumulation was observed in the gills of trout exposed to CuSO4 and Cu-NPs at pH 7 and 5, with a greater accumulation from the CuSO4 treatment than Cu-NPs at each pH. The liver also showed Cu accumulation with both Cu treatments at pH 7 only, whereas, the spleen and kidney did not show measurable accumulation of Cu at any of the water pH values. Exposure to acid water caused changes in the ionoregulatory physiology of control fish and also altered the observed effects of Cu exposure; at pH 5, branchial Na(+)/K(+)-ATPase activity was greater than at pH 7 and the inhibition of Na(+)/K(+)-ATPase activity caused by exposure to CuSO4 at pH 7 was also not observed. There were some changes in haematology and depletion of plasma Na(+) at pH 7 and 5 due to Cu exposure, but there were few material-type or pH effects. Overall, the data show that the accumulation of Cu is greater from CuSO4 than Cu NPs; however, understanding of the effects of low pH on bioavailability of CuSO4 may not be directly transferred to Cu-NPs without further consideration of the physico-chemical behaviour of Cu-NPs in acid water. PMID- 26966874 TI - Salinity-dependent mechanisms of copper toxicity in the galaxiid fish, Galaxias maculatus. AB - The euryhaline galaxiid fish, inanga (Galaxias maculatus) is widely spread throughout the Southern hemisphere occupying near-coastal streams that may be elevated in trace elements such as copper (Cu). Despite this, nothing is known regarding their sensitivity to Cu contamination. The mechanisms of Cu toxicity in inanga, and the ameliorating role of salinity, were investigated by acclimating fish to freshwater (FW), 50% seawater (SW), or 100% SW and exposing them to a graded series of Cu concentrations (0-200MUgL(-1)) for 48h. Mortality, whole body Cu accumulation, measures of ionoregulatory disturbance (whole body ions, sodium (Na) influx, sodium/potassium ATPase activity) and ammonia excretion were monitored. Toxicity of Cu was greatest in FW, with mortality likely resulting from impaired Na influx. In both FW and 100% SW, ammonia excretion was significantly elevated, an effect opposite to that observed in previous studies, suggesting fundamental differences in the effect of Cu in this species relative to other studied fish. Salinity was protective against Cu toxicity, and physiology seemed to play a more important role than water chemistry in this protection. Inanga are sensitive to waterborne Cu through a conserved impairment of Na ion homeostasis, but some effects of Cu exposure in this species are distinct. Based on effect concentrations, current regulatory tools and limits are likely protective of this species in New Zealand waters. PMID- 26966875 TI - Physiological effects and cellular responses of metamorphic larvae and juveniles of sea urchin exposed to ionic and nanoparticulate silver. AB - The widespread use of silver nanoparticles (AgNPs) would likely result in their discharge into wastewater and inevitable release in densely populated coastal areas. It is known that AgNPs can cause harmful effects to marine fauna, but how they affect development stages is still an open question. In order to understand in details how polymer-coated AgNPs (PAAm-AgNPs) (from 0.19 to 4.64mM as Ag) can affect critical stages of marine invertebrate development, metamorphic larvae and juveniles of sea urchins were used as biological models. Multidimensional scaling (MDS) approach based on Bray-Curtis similarity matrix with PERMANOVA showed organisms in a multivariate space undergoing through different physiological conditions as a function of time, chemical forms of silver, nominal concentrations, and presence or absence of food. Sublethal effects such as lethargy, oedema and immobility mainly characterized PAAm-AgNPs effects with juveniles and postlarvae, whereas necrosis and death arose in Ag(+) conditions in short-term tests. Chronically exposed metamorphic larvae had their morphogenic processes interrupted by PAAm-AgNPs and a high mortality rate was observed in recovery period. On the contrary, Ag(+) ions caused progressive mortality during exposure, but a quick recovery in uncontaminated seawater was observed. By means of fluorescent markers we showed that nanosilver could be transferred between consecutive stages (swimming larvae and postlarvae) and highlighted how important is food to enhance PAAm-AgNPs uptake. Using TEM we observed that unfed juveniles had nanosilver aggregates mostly restricted to their coelomic sinuses, while metamorphic larvae already had nano-contamination overspread in different tissues and blastocoel. Our main hypothesis for nanotoxicity of PAAM-AgNPs relies on the slow dissolution of nano-core over time, but in this study the effects of particulate silver form itself are also evoked. Main mechanisms governing tissular and cellular responses to nano-intoxication such as inflammatory response and detoxification based on the role of sentinel cells (peritoneal cells and coelomocytes) for general homeostasis are discussed. This paper is first to detail physiological states, main uptake routes and cellular response against polymer-coated AgNPs in developmental stages of marine invertebrate species. PMID- 26966876 TI - Decontamination of Anodized Implant Surface With Different Modalities for Peri Implantitis Treatment: Lasers and Mechanical Debridement With Citric Acid. AB - BACKGROUND: Although oral rehabilitation with dental implants is a very promising and effective procedure, peri-implantitis is an emerging concern. Surgical and non-surgical methods have been applied to treat peri-implantitis together with various implant surface decontamination methods. However, there is no consensus concerning the most effective treatment for peri-implantitis. The aim of the present study is to evaluate the effects of erbium-doped:yttrium, aluminum, and garnet (Er:YAG) laser, photodynamic therapy (PDT), and titanium bur with and without citric acid on ligature-induced peri-implantitis around an anodized implant surface. METHODS: Thirty dental implants with anodized surface (3.3 * 10 mm) were installed in the mandibles of five beagle dogs. After 3 months, peri implantitis was induced by applying cotton ligatures subgingivally. After ligature removal (baseline), the implants were divided into the following treatment groups: 1) Er:YAG laser, 2) PDT, 3) titanium bur alone, and 4) titanium bur with citric acid. Animals were sacrificed after 3 months, and clinical, radiologic, histologic, and histomorphometric evaluations were conducted for all treatment modalities. The data were analyzed using one-way analysis of variance and Tukey test. A value of P <0.05 was considered statistically significant. RESULTS: The titanium bur with citric acid group exhibited statistically significantly greater improvement in vertical bone height than the Er:YAG laser group and significantly better bone-to-implant contact than the PDT group and the bur-alone group. CONCLUSION: Within the limits of the study, the combination of mechanical and chemical treatment proved to be the most effective treatment for disinfection of the anodized implant surface. PMID- 26966881 TI - Automatic detection of rate change in large data sets with an unsupervised approach: the case of influenza viruses. AB - Influenza viruses evolve at such a high rate that vaccine recommendations need to be changed, but not quite on a regular basis. This observation suggests that the rate of evolution of these viruses is not constant through time, which begs the question as to when such rate changes occur, if they do so independently of the host in which they circulate and (or) independently of their subtype. To address these outstanding questions, we introduce a novel heuristics, Mclust*, that is based on a two-tier clustering approach in a phylogenetic context to estimate (i) absolute rates of evolution and (ii) when rate change occurs. We employ the novel approach to compare the two influenza surface proteins, hemagglutinin and neuraminidase, that circulated in avian, human, and swine hosts between 1960 and 2014 in two subtypes: H3N2 and H1N1. We show that the algorithm performs well in most conditions, accounting for phylogenetic uncertainty by means of bootstrapping and scales up to analyze very large data sets. Our results show that our approach is robust to the time-dependent artifact of rate estimation, and confirm pervasive punctuated evolution across hosts and subtypes. As such, the novel approach can potentially detect when vaccine composition needs to be updated. PMID- 26966882 TI - Surface modification of layered zirconium phosphate with PNIPAM. AB - A new method was reported to modify layered zirconium phosphate (ZrP) with thermoresponsive polymer PNIPAM (poly N-isopropylacrylamide). PNIPAM was proved to be covalently grafted onto ZrP. (60)Co gamma-rays irradiation produced peroxide groups on the surface which, upon heating, initiated free radical polymerization and subsequent attachment of PNIPAM. PMID- 26966880 TI - Evaluation of Planar-Cell-Polarity Phenotypes in Ciliopathy Mouse Mutant Cochlea. AB - In recent years, primary cilia have emerged as key regulators in development and disease by influencing numerous signaling pathways. One of the earliest signaling pathways shown to be associated with ciliary function was the non-canonical Wnt signaling pathway, also referred to as planar cell polarity (PCP) signaling. One of the best places in which to study the effects of planar cell polarity (PCP) signaling during vertebrate development is the mammalian cochlea. PCP signaling disruption in the mouse cochlea disrupts cochlear outgrowth, cellular patterning and hair cell orientation, all of which are affected by cilia dysfunction. The goal of this protocol is to describe the analysis of PCP signaling in the developing mammalian cochlea via phenotypic analysis, immunohistochemistry and scanning electron microscopy. Defects in convergence and extension are manifested as a shortening of the cochlear duct and/or changes in cellular patterning, which can be quantified following dissection from developing mouse mutants. Changes in stereociliary bundle orientation and kinocilia length or positioning can be observed and quantitated using either immunofluorescence or scanning electron microscopy (SEM). A deeper insight into the role of ciliary proteins in cellular signaling pathways and other biological phenomena is crucial for our understanding of cellular and developmental biology, as well as for the development of targeted treatment strategies. PMID- 26966883 TI - Implications of patient-borne costs associated with pediatric neurosurgical care in eastern Africa. AB - OBJECTIVE Pediatric neurosurgery can be highly cost-effective even in the developing world, but delivery of these services is hampered by resource limitations at the levels of both health care infrastructure and individual patients. Few studies have evaluated costs borne by neurosurgical patients in the developing world and their potential implications for efficient and effective delivery of care in this population. METHODS The families of 40 pediatric neurosurgery patients were surveyed in February 2015 at the AIC Kijabe Hospital in Kijabe, Kenya. Costs associated with obtaining inpatient care were assessed. RESULTS Patient families were charged an average of US $539.44 for neurosurgical services, representing 132% of their annual income. Indirect expenses (transport, food and lodging, lost wages) constituted US $79.37, representing 14.7% of the overall cost and 19.5% of their annual income. CONCLUSIONS Expansion of pediatric neurosurgical services throughout the developing world necessitates increased attention to seemingly insignificant expenses that are absorbed by patients and their families. Even when all direct costs are covered at the institutional or national level, without additional assistance, some patients may be too poor to obtain even "free" neurosurgical care. PMID- 26966884 TI - The Preventable Shunt Revision Rate: a potential quality metric for pediatric shunt surgery. AB - OBJECTIVE Shunt surgery consumes a large amount of pediatric neurosurgical health care resources. Although many studies have sought to identify risk factors for shunt failure, there is no consensus within the literature on variables that are predictive or protective. In this era of "quality outcome measures," some authors have proposed various metrics to assess quality outcomes for shunt surgery. In this paper, the Preventable Shunt Revision Rate (PSRR) is proposed as a novel quality metric. METHODS An institutional shunt database was queried to identify all shunt surgeries performed from January 1, 2010, to December 31, 2014, at Le Bonheur Children's Hospital. Patients' records were reviewed for 90 days following each "index" shunt surgery to identify those patients who required a return to the operating room. Clinical, demographic, and radiological factors were reviewed for each index operation, and each failure was analyzed for potentially preventable causes. RESULTS During the study period, there were 927 de novo or revision shunt operations in 525 patients. A return to the operating room occurred 202 times within 90 days of shunt surgery in 927 index surgeries (21.8%). In 67 cases (33% of failures), the revision surgery was due to potentially preventable causes, defined as inaccurate proximal or distal catheter placement, infection, or inadequately secured or assembled shunt apparatus. Comparing cases in which failure was due to preventable causes and those in which it was due to nonpreventable causes showed that in cases in which failure was due to preventable causes, the patients were significantly younger (median 3.1 vs 6.7 years, p = 0.01) and the failure was more likely to occur within 30 days of the index surgery (80.6% vs 64.4% of cases, p = 0.02). The most common causes of preventable shunt failure were inaccurate proximal catheter placement (33 [49.3%] of 67 cases) and infection (28 [41.8%] of 67 cases). No variables were found to be predictive of preventable shunt failure with multivariate logistic regression. CONCLUSIONS With economic and governmental pressures to identify and implement "quality measures" for shunt surgery, pediatric neurosurgeons and hospital administrators must be careful to avoid linking all shunt revisions with "poor" or less-than-optimal quality care. To date, many of the purported risk factors for shunt failure and causes of shunt revision surgery are beyond the influence and control of the surgeon. We propose the PSRR as a specific, meaningful, measurable, and-hopefully-modifiable quality metric for shunt surgery in children. PMID- 26966885 TI - En bloc resection of a C-1 lateral mass osteosarcoma: technical note. AB - Osteosarcoma is an aggressive primary bone tumor. It is currently treated with multimodality therapy including en bloc resection, which has been demonstrated to confer a survival benefit over intralesional resection. The authors present the case of an 8-year-old girl with a C-1 lateral mass osteosarcoma, which was treated with a 4-stage en bloc resection and spinal reconstruction. While technically complex, the feasibility of en bloc resection for spinal osteosarcoma should be explored in the pediatric population. PMID- 26966886 TI - Something Old, New, Borrowed, Blue: Anthracenedione Agents for Treatment of Multiple Sclerosis. AB - OBJECTIVE: This study aimed to present anthracenedione agents that have been used to treat multiple sclerosis (MS), problems related to their use, and knowledge gained from our experiences using these agents to develop more efficacious drugs with fewer adverse effects. METHODS: We review preclinical and clinical data during the development mitoxantrone, an anthracycline, for the treatment of MS; benefits and potential risks; and strategies to reduce complications of anthracyclines. RESULTS: Mitoxantrone had unacceptable and greater-than anticipated toxicity for use in a chronic disease such as MS. Adverse effects included cardiotoxicity, treatment-associated leukemia, and amenorrhea. Toxicity was identified primarily in retrospect. Structurally related compounds include pixantrone (BBR2278) and BBR3378. Pixantrone is in clinical development in oncology. BBR3378 prevents the development of autoimmunity and experimental autoimmune encephalomyelitis and blocks experimental autoimmune encephalomyelitis even when given after the onset of autoimmunity. CONCLUSIONS: There remains a need for effective MS treatment, particularly for nonrelapsing forms of MS. Mitoxantrone was the first nonbiologic drug approved by the Food and Drug Administration for use in MS. Chromophore modification of anthracenedione agents yielded a novel class of DNA binding agents (aza-anthracenediones such as pixantrone and aza-anthrapyrazoles such as BBR3378) with the potential for less cardiotoxicity compared with mitoxantrone. There is a need for long-term observation for delayed toxicity among humans enrolled in pixantrone trials. Preclinical toxicity studies for delayed toxicities in rodents and other models are warranted before consideration of derivatives of anthracenediones, aza anthrazenediones, or aza-anthrapyrazoles for use in human MS clinical trials. PMID- 26966887 TI - Treating Schizophrenia With the Diuretic Bumetanide: A Case Report. AB - Administration of the diuretic and NKCC1 chloride cotransporter antagonist bumetanide reduces the severity of autism spectrum disorders in children, and this effect is mediated by a reduction of the elevated intracellular chloride concentrations and a reinforcement of GABAergic inhibition (Lemonnier et al Transl Psychiatry. 2012;2:e202; Tyzio et al Science. 2014;343:675-679). Here, we report that this treatment also reduces the severity of symptoms in an adolescent with schizophrenia. Long-term treatment reduced hallucinations significantly, suggesting that this treatment may also be useful to treat schizophrenia. Further clinical trials and experimental studies are warranted to test this hypothesis. PMID- 26966889 TI - New developments in flavivirus drug discovery. AB - INTRODUCTION: Flaviviruses are major causes of infectious disease. The vast global, social and economic impact due to morbidity and mortality associated with diseases caused by these viruses urgently demands effective therapeutic interventions. There is currently no specific antiviral therapy available for the effective clinical treatment of infections by any of the flaviviridae. Development of more effective vaccines and antiviral agents for the prevention and treatment of most flavivirus infections remains a clear public health priority in the 21st century. AREAS COVERED: This review describes some of the recent discoveries in the field of flavivirus inhibitor development, with a particular focus on targeting viral proteins. Emphasis is placed on the advances published during the 2012-2015 period. EXPERT OPINION: The field of drug discovery targeting viral proteins has progressed slowly in recent years. New information, particularly on structures, location and mechanisms of action of established protein targets have been reported. There have also been studies on repurposing known drugs as templates for targeting flavivirus proteins and these hits could be promising templates for developing new more potent inhibitors. Further research should be conducted to improve in vitro assays that better reflect the conditions found in cellular environments. PMID- 26966888 TI - Alternating Magnetic Field-Responsive Hybrid Gelatin Microgels for Controlled Drug Release. AB - Magnetically-responsive nano/micro-engineered biomaterials that enable a tightly controlled, on-demand drug delivery have been developed as new types of smart soft devices for biomedical applications. Although a number of magnetically responsive drug delivery systems have demonstrated efficacies through either in vitro proof of concept studies or in vivo preclinical applications, their use in clinical settings is still limited by their insufficient biocompatibility or biodegradability. Additionally, many of the existing platforms rely on sophisticated techniques for their fabrications. We recently demonstrated the fabrication of biodegradable, gelatin-based thermo-responsive microgel by physically entrapping poly(N-isopropylacrylamide-co-acrylamide) chains as a minor component within a three-dimensional gelatin network. In this study, we present a facile method to fabricate a biodegradable drug release platform that enables a magneto-thermally triggered drug release. This was achieved by incorporating superparamagnetic iron oxide nanoparticles and thermo-responsive polymers within gelatin-based colloidal microgels, in conjunction with an alternating magnetic field application system. PMID- 26966890 TI - Risk of occupational exposure to asbestos, silicon and arsenic on pulmonary disorders: Understanding the genetic-epigenetic interplay and future prospects. AB - BACKGROUND: Epidemiological studies suggest strong association of lung disorders with occupational exposure to asbestos, silicon and arsenic. The chronic occupational exposure primarily through inhalation results in adverse outcome on the respiratory tract which may also be fatal. Although several mechanisms have attributed towards these diseases; the molecular pathogenesis is still unknown. OBJECTIVE: In this review, we investigated the plausible molecular mechanism based on current research that may identify the genetic and epigenetic susceptibility of respiratory disorders upon such occupational exposures in humans. METHODS: We considered genetic variants and epigenetic alterations associated with pulmonary exposure hazards leading to asbestosis, silicosis and arsenicosis. Our review is stringently based on the literatures available through peer-reviewed articles mostly published in the last 10 years. Relevant search were conducted using keywords like "occupational lung disorders" along with "asbestos", "silicon" and "arsenic". RESULTS: Till September 2015, pubmed search yielded approximately 780 articles relating to asbestos exposure; 240 articles for silicon exposure and 60 articles for arsenic exposure. Extensive screening for genetic and epigenetic factors identified certain genes and related pathways that are important to determine the susceptibility of an individual towards such occupational exposure. CONCLUSION: The link between genotype and phenotype and its association with disease susceptibility is very complex in nature due to several factors like person's environment, lifestyle and nutritional status. The epigenome is dynamic as well as reversible and can be reshaped further by certain dietary components throughout its life. In the present review, we have addressed the role of molecular pathogenesis of occupational lung diseases based on the genetic variability and epigenetic alterations and also attempted to highlight the promising aspect of dietary interventions to counter toxic outcomes upon occupational exposure to asbestos, silicon or arsenic. PMID- 26966891 TI - Nrf2 silencing to inhibit proteolytic defense induced by hyperthermia in HT22 cells. AB - Nrf2 pathway has been known to be protective against cancer progression however recent studies have revealed that the antioxidant activity of Nrf2 contributes to chemotherapy resistance. For many years, hyperthermia has been used as an additional therapy to increase the efficiency of chemotherapy and radiotherapy. Besides the positive effects of hyperthermia during treatment procedure, thermotolerance has been found to develop against heat treatment. Although the involved molecular mechanisms have not been fully clarified, heat shock proteins (HSP) and proteasome activity are known to be involved in the acquisition of thermotolerance. The aim of this study was to investigate the potential beneficial effects of combining hyperthermia with Nrf2 silencing to inhibit molecular mechanisms leading to induction of defense mechanisms in transcription level. Following heat treatment of HT22 cells, HSP70 and the proteasome levels and as well as proteasome activity were found to be elevated in the nucleus. Our results demonstrated that Nrf2 silencing reduced defense mechanisms against heat treatment both in antioxidant and proteolytic manner and Nrf2 may be a potential target for therapeutic approach in order to improve the beneficial effects of hyperthermia in cancer therapy. PMID- 26966892 TI - Role of heme Oxygenase-1 in low dose Radioadaptive response. AB - Radioadaptive response (RAR) is an important phenomenon induced by low dose radiation. However, the molecular mechanism of RAR is obscure. In this study, we focused on the possible role of heme oxygenase 1 (HO-1) in RAR. Consistent with previous studies, priming dose of X-ray radiation (1-10cGy) induced significant RAR in normal human skin fibroblasts (AG 1522 cells). Transcription and translation of HO-1 was up-regulated more than two fold by a priming dose of radiation (5cGy). Zinc protoporphyrin IX, a specific competitive inhibitor of HO 1, efficiently inhibited RAR whereas hemin, an inducer of HO-1, could mimic priming dose of X-rays to induce RAR. Knocking down of HO-1 by transfection of HO 1 siRNA significantly attenuated RAR. Furthermore, the expression of HO-1 gene was modulated by the nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which translocated from cytoplasm to nucleus after priming dose radiation and enhance the antioxidant level of cells. PMID- 26966894 TI - Glucose-induced abnormal egg-laying rate in Caenorhabditis elegans. AB - High glucose reduced the egg-laying rate of the nematode Caenorhabditis elegans and was dependent on serotonergic signaling. Antidiabetic drugs of the biguanide and thiazolidine classes ameliorated the detrimental effect of glucose on egg laying rate, suggesting the possibility that this quick and easy assay system may be applicable to whole-animal screening for novel antidiabetic drugs, at least, of these classes. PMID- 26966893 TI - The MLN4924 inhibitor exerts a neuroprotective effect against oxidative stress injury via Nrf2 protein accumulation. AB - It was explored the cytoprotective and antioxidant effect of MLN4924, a specific inhibitor of Nedd8-activating enzyme (NAE), against hydrogen peroxide (H2O2) induced damage in cerebellar granule neurons (CGNs). Primary cultures of CGNs were exposed to H2O2 after preincubation with MLN4924. The compounds were removed, and CGNs were incubated in culture medium for 24h in order to determine cell viability by 3-[4,5-dimethylthiazol-2-yl)]-2,5-diphenyl-tetrazolium bromide (MTT) and fluorescein diacetate (FDA) assays. It was demonstrated that MLN4924 remarkably attenuated H2O2-induced cell damage. Meanwhile reactive oxygen species (ROS) production was evaluated with the fluorescent probe dihydroethidium (DHE). Interestingly H2O2-induced ROS production was inhibited by pretreatment with MLN4924. MLN4924 treatment in CGNs resulted in nuclear factor E2-related factor 2 (Nrf2) protein accumulation. Intriguingly this effect was observed in the cytosolic and nuclear compartments of the CGNs. The cytoprotective effect of MLN4924 was associated with its ability to diminish ROS production induced by H2O2 and the accumulation of Nrf2 protein levels in the cytoplasm and nucleus of the CGNs. PMID- 26966895 TI - Simultaneous determination of selected tyrosine kinase inhibitors with corticosteroids and antiemetics in rat plasma by solid phase extraction and ultra performance liquid chromatography-tandem mass spectrometry: Application to pharmacokinetic interaction studies. AB - A sensitive and selective ultra-performance liquid chromatography-tandem mass spectrometry method has been developed and validated for the simultaneous analysis of selected tyrosine kinase inhibitors (TKIs)(gefitinib GEF, erlotinib ERL), corticosteroids (dexamethasone DEX, prednisolone PRED), and the antiemetic ondansetron (OND) in rat plasma samples. After the addition of domperidone (DOM) as internal standard (IS), spiked plasma samples were prepared using the solid phase extraction (SPE) C 18 cartridges. Chromatographic separation was performed on a Waters BEH C18 column with an isocratic elution using a mobile phase composed of acetonitrile and water, each with 0.1% formic acid, (80: 20, v/v), at a flow rate of 0.2 mL/min. Quantitation of the analytes was performed using the multiple reaction monitoring (MRM) mode with the positive ionization mode at m/z 447.25>128.08 (GEF), m/z 394.20>278.04 (ERL), m/z 393.30>147.04 (DEX), m/z 361.29>147.02 (PRED), m/z 294.18>170.16 (OND), and m/z 426.26>175.07 (DOM). The method was validated over the concentration range of 0.025-100 (GEF, ERL, OND) and 0.05-100 ng/mL plasma (PRED, DEX) with very low lower limit of quantification of 0.025 (GEF, ERL, OND) and 0.05 ng/mL (DEX, PRED). The intra- and inter-day precision (RSD%) evaluated at four different concentration levels were within the acceptable limits (<15%). The method provided good extraction recovery of all analytes from rat plasma (Er% from -14.05 to -1.08). The validated method was successfully applied to the pharmacokinetic studies following the oral administration of selected combinations of the studied drugs. This study can be readily applied in therapeutic drug monitoring (TDM) in patients receiving these drug combinations as well as investigation of possible drug interactions between TKIs and DEX/PRED/OND. PMID- 26966896 TI - Development of complementary HPLC-DAD/APCI MS methods for chemical characterization of pharmaceutical packaging materials. AB - The chemical characterization of plastics for pharmaceutical packaging has been subject to ever increasing regulatory scrutiny, the reasons for which being: a) plastic additives and degradation products can be extremely hazardous to the patients' health (especially patients on chronic therapy) and b) they offer no therapeutic or formulatory benefit whatsoever. The last decade has seen the issuing of several books, monographs and guidelines dealing with extractables and leachables, however the amount of scientific work done so far is still fairly small (the majority of it performed by only a few research groups), with only a small number of methods published in the literature. This work focuses on developing a set of two complementary HPLC-DAD/APCI MS methods for simultaneous separation, detection, identification and quantification of a wide variety of packaging additives and degradants, the second method specifically targeting a group of compounds known as polymeric hindered amine light stabilizers (HALS), which are known to be notoriously difficult to separate and analyze with standard analytical techniques. The methods are capable of detecting plastic additives present in low ppb concentrations, from samples extracted in solvents with various polarities and pH values. Both methods were developed and optimized using system suitability mixtures comprised of 9 additives commonly encountered in plastic materials, and their practical applicability tested on a variety of extracts from low-density polyethylene (LDPE) and polypropylene (PP), where several additives were successfully separated, detected and identified. PMID- 26966897 TI - Metabonomic study of the fruits of Alpinia oxyphylla as an effective treatment for chronic renal injury in rats. AB - Alpinia oxyphylla (Zingiberaceae) is a well-known medicinal plant. Its fruit ("Yi Zhi-Ren" in Chinese) is used as an anti-diuretic and traditionally used for the treatment of enuresis and reduce urination. Chronic kidney disease (CKD) is a disease with the characteristic of the slowly loss of kidney function and has a prevalence of up to 7-10% in adults. Recent advances in its etiology and pathogenesis are providing more speculative hypotheses focused on integral systems. Using a UPLC-QTOF-MS/MS-based metabolomic platform, we explored the changes of metabolic profiling in plasma/urine simultaneously between chronic kidney disease (CKD) induced from adenine excess and the protective effects of A. oxyphylla extract (AOE). The total twenty-one metabolites (twelve in urine and nine in plasma), up-regulated or down-regulated, were identified and contributed to CKD progress. Among these biomarkers, agmatine, CAMP, 7-methylguanine, hippuric acid, indoxyl sulfate, asparagines, kynurenic acid and p-cresol sulfate were restored back to the control-like level after the treatment of AOE (p<0.05 or 0.01), These findings may be promising to yield a valuable insight into the pathophysiology of CKD and serve as characteristics to explain the mechanisms of AOE. PMID- 26966898 TI - Simultaneous determination of shikimic acid, salicylic acid and jasmonic acid in wild and transgenic Nicotiana langsdorffii plants exposed to abiotic stresses. AB - The presence and relative concentration of phytohormones may be regarded as a good indicator of an organism's physiological state. The integration of the rolC gene from Agrobacterium rhizogenes and of the rat glucocorticoid receptor (gr) in Nicotiana langsdorffii Weinmann plants has shown to determine various physiological and metabolic effects. The analysis of wild and transgenic N. langsdorffii plants, exposed to different abiotic stresses (high temperature, water deficit, and high chromium concentrations) was conducted, in order to investigate the metabolic effects of the inserted genes in response to the applied stresses. The development of a new analytical procedure was necessary, in order to assure the simultaneous determination of analytes and to obtain an adequately low limit of quantification. For the first time, a sensitive HPLC-HRMS quantitative method for the simultaneous determination of salicylic acid, jasmonic acid and shikimic acid was developed and validated. The method was applied to 80 plant samples, permitting the evaluation of plant stress responses and highlighting some metabolic mechanisms. Salicylic, jasmonic and shikimic acids proved to be suitable for the comprehension of plant stress responses. Chemical and heat stresses showed to induce the highest changes in plant hormonal status, differently affecting plant response. The potential of each genetic modification toward the applied stresses was marked and particularly the resistance of the gr modified plants was evidenced. This work provides new information in the study of N. langsdorffii and transgenic organisms, which could be useful for the further application of these transgenes. PMID- 26966899 TI - Transcriptomics of tomato plants infected with TYLCSV or expressing the central TYLCSV Rep protein domain uncover changes impacting pathogen response and senescence. AB - To establish a successful infection viruses need to overcome plant innate immune responses and redirect host gene expression for their multiplication and diffusion. Tomato yellow leaf curl Sardinia virus (TYLCSV) is a geminivirus, which causes significant economic losses in tomato. The multifunctional replication associated geminivirus protein (Rep) has an important role during viral infection. In particular, the Rep central domain spanning from aa 120 to 180 is known to interact with viral and host factors. In this study, we used long serial analysis of gene expression to analyse the transcriptional profiles of transgenic tomato plants expressing the first 210 amino acids of TYLCSV Rep (Rep210) and TYLCSV-infected wild-type tomato plants (Wt-Ty). Also, we compared these profiles with those of transgenic Rep130 tomatoes. Comparison of Wt-Ty and Rep210 libraries with the wild-type one identified 118 and 203 differentially expressed genes (DEGs), respectively. Importantly, 55% of Wt-Ty DEGs were in common with Rep210, and no ones showed opposite expression. Conversely, a negligible overlap was found between Rep130 DEGs and Wt-Ty and Rep210 ones. TYLCSV- and Rep210-repressed genes, but not induced ones, overlapped with the leaf senescence process. Interestingly, TYLCSV upregulates expression of genes involved in the negative regulation of programmed cell death (PCD), several of which were also regulated by the abscisic acid. Rep210 upregulated genes related to defence response, immune system processes and negative regulation of PCD. Collectively, our results support a model in which the Rep central domain has a pivotal role in redirecting host plant gene expression. PMID- 26966900 TI - Accurate and Phenol Free DNA Sexing of Day 30 Porcine Embryos by PCR. AB - Research into prenatal programming in the pig has shown that the sex of the developing embryo or fetus can influence the developmental outcome. Therefore, the ability to determine an embryo's sex is necessary in many experiments particularly regarding early development. The present protocol demonstrates an inexpensive, rapid and non-toxic preparation of pig genomic DNA for use with PCR. Day 30 embryos must be humanely collected according to the guidelines established by Institutional Animal Policy and Welfare Committees for the present protocol. The preparation of the whole embryo for this PCR based sexing technique simply involves grinding the frozen embryo to a fine powder using a pre-chilled mortar and pestle. PCR-quality DNA is released from a small amount of embryo powder by applying a hot incubation in an alkaline lysis reagent. Next, the DNA solution is mixed with neutralization buffer and used directly for PCR. Two primer pairs are generated to detect specific sex determining region of the Y- chromosome (SRY) and ZFX region of the X- chromosome with high accuracy and specificity. The same protocol can be applied to other elongated embryos (Day 10 to Day 14) earlier than Day 30. Also, this protocol can be carried with 96-welled plates when screening a large number of embryos, making it feasible for automation and high throughput sex typing. PMID- 26966901 TI - Are MUPs a Toxic Waste Disposal System? AB - Male house mice produce large quantities of major urinary proteins (MUPs), which function to bind and transport volatile pheromones, though they may also function as scavengers that bind and excrete toxic compounds ('toxic waste hypothesis'). In this study, we demonstrate the presence of an industrial chemical, 2,4-di-tert butylphenol (DTBP), in the urine of wild-derived house mice (Mus musculus musculus). Addition of guanidine hydrochloride to male and female urine resulted in an increased release of DTBP. This increase was only observed in the high molecular weight fractions (HMWF; > 3 kDa) separated from male or female urine, suggesting that the increased release of DTBP was likely due to the denaturation of MUPs and the subsequent release of MUP-bound DTBP. Furthermore, when DTBP was added to a HMWF isolated from male urine, an increase in 2-sec-butyl-4,5 dihydrothiazole (SBT), the major ligand of MUPs and a male-specific pheromone, was observed, indicating that DTBP was bound to MUPs and displaced SBT. These results suggest that DTBP is a MUP ligand. Moreover, we found evidence for competitive ligand binding between DTBP and SBT, suggesting that males potentially face a tradeoff between eliminating toxic wastes versus transporting pheromones. Our findings support the hypothesis that MUPs bind and eliminate toxic wastes, which may provide the most important fitness benefits of excreting large quantities of these proteins. PMID- 26966902 TI - First Molecular Characterization of Leishmania Species Causing Visceral Leishmaniasis among Children in Yemen. AB - Visceral leishmaniasis (VL) is a debilitating, often fatal disease caused by Leishmania donovani complex; however, it is a neglected tropical disease. L. donovani complex comprises two closely related species, L. donovani that is mostly anthroponotic and L. infantum that is zoonotic. Differentiation between these two species is critical due to the differences in their epidemiology and pathology. However, they cannot be differentiated morphologically, and their speciation using isoenzyme-based methods poses a difficult task and may be unreliable. Molecular characterization is now the most reliable method to differentiate between them and to determine their phylogenetic relationships. The present study aims to characterize Leishmania species isolated from bone marrows of Yemeni pediatric patients using sequence analysis of the ribosomal internal transcribed spacer-1 (ITS1) gene. Out of 41 isolates from Giemsa-stained bone marrow smears, 25 isolates were successfully amplified by nested polymerase chain reaction and sequenced in both directions. Phylogenetic analysis using neighbor joining method placed all study isolates in one cluster with L. donovani complex (99% bootstrap). The analysis of ITS1 for microsatellite repeat numbers identified L. infantum in 11 isolates and L. donovani in 14 isolates. These data suggest the possibility of both anthroponotic and zoonotic transmission of VL causing Leishmania species in Yemen. Exploring the possible animal reservoir hosts is therefore needed for effective control to be achieved. PMID- 26966904 TI - Production of Tetraploid Gynogenetic Loach Using Diploid Eggs of Natural Tetraploid Loach, Misgurnus anguillicaudatus, Fertilized with UV-Irradiated Sperm of Megalobrama amblycephala without Treatments for Chromosome Doubling. AB - The gynogenesis phenomenon in nature mainly appears in the reproduction of fish and invertebrates. So far, gynogenesis has been successfully induced in many fish species with the aid of some physical or chemical methods for chromosome doubling. However, few fish can produce gynogenetic progenies, genetically identical or similar to the somatic cells of the mothers, without a treatment for the doubling of chromosomes, which may be related to apomixis, premeiotic endoreduplication, or premeiotic endomitosis. At present, no studies are available about fish with normal ovarian structures producing gynogenetic progenies that could spontaneously double their chromosomes. According to the analyses of flow cytometry, chromosome number, and microsatellites, we found that, with the use of UV-irradiated sperm of blunt snout bream Megalobrama amblycephala, tetraploid loach Misgurnus anguillicaudatus produced tetraploid gynogenetic progenies without any treatments for the doubling of chromosomes. To determine the genetic relationships of gynogenetic progenies and their maternal parent, microsatellite genotyping was conducted. The results indicated that the reason for spontaneous chromosome duplication in gynogenetic progenies may be cytokinesis or inhibition of the extrusion of the second polar body. This is the first report on fish with normal ovarian structures that can produce gynogenetic progenies which spontaneously double their chromosomes and which are genetically identical or similar to the somatic cells of the mothers. PMID- 26966905 TI - Correction: The Impact of a One-Dose versus Two-Dose Oral Cholera Vaccine Regimen in Outbreak Settings: A Modeling Study. PMID- 26966903 TI - Comorbidities of Psoriasis - Exploring the Links by Network Approach. AB - Increasing epidemiological studies in patients with psoriasis report the frequent occurrence of one or more associated disorders. Psoriasis is associated with multiple comorbidities including autoimmune disease, neurological disorders, cardiometabolic diseases and inflammatory-bowel disease. An integrated system biology approach is utilized to decipher the molecular alliance of psoriasis with its comorbidities. An unbiased integrative network medicine methodology is adopted for the investigation of diseasome, biological process and pathways of five most common psoriasis associated comorbidities. A significant overlap was observed between genes acting in similar direction in psoriasis and its comorbidities proving the mandatory occurrence of either one of its comorbidities. The biological processes involved in inflammatory response and cell signaling formed a common basis between psoriasis and its associated comorbidities. The pathway analysis revealed the presence of few common pathways such as angiogenesis and few uncommon pathways which includes CCKR signaling map and gonadotrophin-realising hormone receptor pathway overlapping in all the comorbidities. The work shed light on few common genes and pathways that were previously overlooked. These fruitful targets may serve as a starting point for diagnosis and/or treatment of psoriasis comorbidities. The current research provides an evidence for the existence of shared component hypothesis between psoriasis and its comorbidities. PMID- 26966906 TI - Hepatitis C Virus E1 and E2 Proteins Used as Separate Immunogens Induce Neutralizing Antibodies with Additive Properties. AB - Various strategies involving the use of hepatitis C virus (HCV) E1 and E2 envelope glycoproteins as immunogens have been developed for prophylactic vaccination against HCV. However, the ideal mode of processing and presenting these immunogens for effective vaccination has yet to be determined. We used our recently described vaccine candidate based on full-length HCV E1 or E2 glycoproteins fused to the heterologous hepatitis B virus S envelope protein to compare the use of the E1 and E2 proteins as separate immunogens with their use as the E1E2 heterodimer, in terms of immunogenetic potential and the capacity to induce neutralizing antibodies. The specific anti-E1 and anti-E2 antibody responses induced in animals immunized with vaccine particles harboring the heterodimer were profoundly impaired with respect to those in animals immunized with particles harboring E1 and E2 separately. Moreover, the anti-E1 and anti-E2 antibodies had additive neutralizing properties that increase the cross neutralization of heterologous strains of various HCV genotypes, highlighting the importance of including both E1 and E2 in the vaccine for an effective vaccination strategy. Our study has important implications for the optimization of HCV vaccination strategies based on HCV envelope proteins, regardless of the platform used to present these proteins to the immune system. PMID- 26966907 TI - A Gain-Of-Function Mutation in the Plcg2 Gene Protects Mice from Helicobacter felis-Induced Gastric MALT Lymphoma. AB - Gastric mucosa-associated lymphoid tissue (MALT) lymphomas develop from a chronic Helicobacter infection. Phospholipase C gamma 2 (PLCG2) is important for B-cell survival and proliferation. We used BALB/c mice with a gain-of-function mutation in the Plcg2 gene (Ali5) to analyze its role in the development of gastric MALT lymphoma. Heterozygous BALB/c Plcg2Ali5/+ and wildtype (WT) mice were infected with Helicobacter felis (H. felis) and observed up to 16 months for development of gastric MALT lymphomas. In contrast to our initial hypothesis, Plcg2Ali5/+ mice developed MALT lymphomas less frequently than their WT littermates after long-term infection of 16 months. Infected Plcg2Ali5/+ mice showed downregulation of proinflammatory cytokines and decreased H. felis-specific IgG1 and IgG2a antibody responses. These results suggested a blunted immune response of Plcg2Ali5/+ mice towards H. felis infection. Intriguingly, Plcg2Ali5/+ mice harboured higher numbers of CD73 expressing regulatory T cells (Tregs), possibly responsible for impaired immune response towards Helicobacter infection. We suggest that Plcg2Ali5/+ mice may be protected from developing gastric MALT lymphomas as a result of elevated Treg numbers, reduced response to H. felis and decrease of proinflammatory cytokines. PMID- 26966908 TI - A Continuous Correlated Beta Process Model for Genetic Ancestry in Admixed Populations. AB - Admixture and recombination create populations and genomes with genetic ancestry from multiple source populations. Analyses of genetic ancestry in admixed populations are relevant for trait and disease mapping, studies of speciation, and conservation efforts. Consequently, many methods have been developed to infer genome-average ancestry and to deconvolute ancestry into continuous local ancestry blocks or tracts within individuals. Current methods for local ancestry inference perform well when admixture occurred recently or hybridization is ongoing, or when admixture occurred in the distant past such that local ancestry blocks have fixed in the admixed population. However, methods to infer local ancestry frequencies in isolated admixed populations still segregating for ancestry do not exist. In the current paper, I develop and test a continuous correlated beta process model to fill this analytical gap. The method explicitly models autocorrelations in ancestry frequencies at the population-level and uses discriminant analysis of SNP windows to take advantage of ancestry blocks within individuals. Analyses of simulated data sets show that the method is generally accurate such that ancestry frequency estimates exhibited low root-mean-square error and were highly correlated with the true values, particularly when large (+/-10 or +/-20) SNP windows were used. Along these lines, the proposed method outperformed post hoc inference of ancestry frequencies from a traditional hidden Markov model (i.e., the linkage model in structure), particularly when admixture occurred more distantly in the past with little on-going gene flow or was followed by natural selection. The reliability and utility of the method was further assessed by analyzing genetic ancestry in an admixed human population (Uyghur) and three populations from a hybrid zone between Mus domesticus and M. musculus. Considerable variation in ancestry frequencies was detected within and among chromosomes in the Uyghur, with a large region of excess French ancestry harboring a gene with a known disease association. Similar variation was detected in the mouse hybrid zone, with notable constancy in regions of excess ancestry among admixed populations. By filling what has been an analytical gap, the proposed method should be a useful tool for many biologists. A computer program (popanc), written in C++, has been developed based on the proposed method and is available on-line at http://sourceforge.net/projects/popanc/. PMID- 26966910 TI - Correction: A Conserved Interaction between a C-Terminal Motif in Norovirus VPg and the HEAT-1 Domain of eIF4G Is Essential for Translation Initiation. PMID- 26966909 TI - Motor Demands Constrain Cognitive Rule Structures. AB - Study of human executive function focuses on our ability to represent cognitive rules independently of stimulus or response modality. However, recent findings suggest that executive functions cannot be modularized separately from perceptual and motor systems, and that they instead scaffold on top of motor action selection. Here we investigate whether patterns of motor demands influence how participants choose to implement abstract rule structures. In a learning task that requires integrating two stimulus dimensions for determining appropriate responses, subjects typically structure the problem hierarchically, using one dimension to cue the task-set and the other to cue the response given the task set. However, the choice of which dimension to use at each level can be arbitrary. We hypothesized that the specific structure subjects adopt would be constrained by the motor patterns afforded within each rule. Across four independent data-sets, we show that subjects create rule structures that afford motor clustering, preferring structures in which adjacent motor actions are valid within each task-set. In a fifth data-set using instructed rules, this bias was strong enough to counteract the well-known task switch-cost when instructions were incongruent with motor clustering. Computational simulations confirm that observed biases can be explained by leveraging overlap in cortical motor representations to improve outcome prediction and hence infer the structure to be learned. These results highlight the importance of sensorimotor constraints in abstract rule formation and shed light on why humans have strong biases to invent structure even when it does not exist. PMID- 26966912 TI - Rhinosinusal Inflammation and High Mobility Group Box 1 Protein: A New Target for Therapy. AB - BACKGROUND/AIMS: High mobility group box 1 (HMGB1) is a protein belonging to the class of damage-associated molecular pattern molecules, which activates innate immunity and powerful inflammatory factors. The aim of this review is to show the importance of HMGB1 in the pathogenesis of nasal inflammatory diseases and to suggest that inhibition of HMGB1 may be an innovative therapeutic target. METHODS: We used immunohistochemistry to study whether HMGB1 increases in chronic rhinosinusitis with nasal polyps and whether its expression is associated with eosinophils and inflammatory cytokines. Using primary cultures of human nasal epithelial cells, we localised lipopolysaccharide-induced active translocation and release of HMGB1 by immunofluorescence assay and Western blot. RESULTS: Patients with severe symptoms have the highest HMGB1 serum levels. Glycyrrhetic acid inhibits the chemotactic and mitogenic function of HMGB1, binding to the hydrophobic residues that delimit the pockets in box A and B. CONCLUSIONS: Chronic inflammatory diseases of the nose and paranasal sinuses are increasingly prevalent and are a financial burden for society. HMGB1 has been shown to play a role in several inflammatory diseases of otolaryngological interest. The inhibition of HMGB1 may be an innovative therapeutic target for patients with chronic upper airway inflammatory diseases having nasal obstruction as a major symptom. PMID- 26966911 TI - Safety Evaluation of Neo Transgenic Pigs by Studying Changes in Gut Microbiota Using High-Throughput Sequencing Technology. AB - The neo (neomycin phosphotransferase) gene is widely used as a selection marker in the production of genetically engineered animals and plants. Recent attention has been focused on safety concerns regarding neo transgene expression. In this study, neo transgenic and non-transgenic piglets were randomly assigned into Group A and Group B to evaluate effects of neo transgene by studying changes in gut microbiota using high-throughput sequencing. Group A pigs were fed a standard diet supplemented with antibiotic neomycin; Group B pigs were fed a standard diet. We examined horizontal transfer of exogenous neo gene using multiplex PCR; and investigated if the presence of secreted NPT II (neo expression product) in the intestine could lead to some protection against neomycin in transgenic pigs by monitoring different patterns of changes in gut microbiota in Group A animals. The unintended effects of neo transgene on gut microbiota were studied in Group B animals. Horizontal gene transfer was not detected in gut microbiota of any transgenic pigs. In Group A, a significant difference was observed between transgenic pigs and non-transgenic pigs in pattern of changes in Proteobacteria populations in fecal samples during and post neomycin feeding. In Group B, there were significant differences in the relative abundance of phyla Firmicutes, Bacteroidetes and Proteobacteria, and genera Lactobacillus and Escherichia Shigella-Hafnia between transgenic pigs and non-transgenic pigs. We speculate that the secretion of NPT II from transgenic tissues/cells into gut microbiota results in the inhibition of neomycin activity and the different patterns of changes in bacterial populations. Furthermore, the neo gene also leads to unintended effects on gut microbiota in transgenic pigs that were fed with basic diet (not supplemented with neomycin). Thus, our data in this study caution that wide use of the neo transgene in genetically engineered animals should be carefully considered and fully assessed. PMID- 26966915 TI - Electronic Structures of the [Fe(N2)(SiP(iPr)3)](+1/0/-1) Electron Transfer Series: A Counterintuitive Correlation between Isomer Shifts and Oxidation States. AB - The electronic structure analysis of the low-spin iron(II/I/0) complexes [Fe(N2)(SiP(iPr)3)](+/0/-) (SiP(iPr)3 = [Si(o-C6H4P(i)Pr2)3](-)) recently published by J. Peters et al. (Nature Chem. 2010, 2, 558-565) reveals that the redox processes stringing this electron transfer series are best viewed as metal centered reductions, i.e. Fe(II)N2(0) -> Fe(I)N2(0) -> Fe(0)N2(0). Superficially, the interpretation seems to be incompatible with the Mossbauer measurement, because the observed isomer shifts are more negative for the lower oxidation states, whereas typically iron-based reduction tends to increase the isomer shift. To rationalize the experimental findings, we analyzed the contributions from the 1s to 4s orbitals to the charge density at the Mossbauer nucleus and found that the positive correlation between the isomer shift and the oxidation state results from an unusual shrinking of the Fe-N2 bond upon reduction due to enhanced N2 to Fe pi-backbonding. The other effects of reduction arising from shielding of the nuclear potential, decreasing covalency, and changes in the 4s population would induce the usual negative correlation. The structure distortion dictates the radial distribution of the 4s orbital and the charge density at the nucleus such that a virtually linear relationship between the isomer shift and the Fe-N2 distance could be identified for this series. PMID- 26966913 TI - Heavy Metal Exposure Influences Double Strand Break DNA Repair Outcomes. AB - Heavy metals such as cadmium, arsenic and nickel are classified as carcinogens. Although the precise mechanism of carcinogenesis is undefined, heavy metal exposure can contribute to genetic damage by inducing double strand breaks (DSBs) as well as inhibiting critical proteins from different DNA repair pathways. Here we take advantage of two previously published culture assay systems developed to address mechanistic aspects of DNA repair to evaluate the effects of heavy metal exposures on competing DNA repair outcomes. Our results demonstrate that exposure to heavy metals significantly alters how cells repair double strand breaks. The effects observed are both specific to the particular metal and dose dependent. Low doses of NiCl2 favored resolution of DSBs through homologous recombination (HR) and single strand annealing (SSA), which were inhibited by higher NiCl2 doses. In contrast, cells exposed to arsenic trioxide preferentially repaired using the "error prone" non-homologous end joining (alt-NHEJ) while inhibiting repair by HR. In addition, we determined that low doses of nickel and cadmium contributed to an increase in mutagenic recombination-mediated by Alu elements, the most numerous family of repetitive elements in humans. Sequence verification confirmed that the majority of the genetic deletions were the result of Alu mediated non-allelic recombination events that predominantly arose from repair by SSA. All heavy metals showed a shift in the outcomes of alt-NHEJ repair with a significant increase of non-templated sequence insertions at the DSB repair site. Our data suggest that exposure to heavy metals will alter the choice of DNA repair pathway changing the genetic outcome of DSBs repair. PMID- 26966914 TI - Neoglycoenzyme-Gated Mesoporous Silica Nanoparticles: Toward the Design of Nanodevices for Pulsatile Programmed Sequential Delivery. AB - We report herein the design of a stimulus-programmed pulsatile delivery system for sequential cargo release based on the use of a lactose-modified esterase as a capping agent in phenylboronic acid functionalized mesoporous silica nanoparticles. The dual-release mechanism was based on the distinct stability of the cyclic boronic acid esters formed with lactose residues and the long naturally occurring glycosylation chains in the modified neoglycoenzyme. Cargo delivery in succession was achieved using glucose and ethyl butyrate as triggers. PMID- 26966917 TI - FormylBODIPYs: Privileged Building Blocks for Multicomponent Reactions. The Case of the Passerini Reaction. AB - Eleven formyl-containing BODIPY dyes were prepared by means of either the Liebeskind-Srogl cross-coupling reaction or the Vilsmeier reaction. These dyes were used as components in the Passerini reaction to give highly substituted BODIPY dyes. A joined spectroscopic and theoretical characterization of the synthesized compounds was conducted to unravel the impact of the structural rigidity/flexibility on the photophysical signatures. These dyes were tested as fluorescent trackers for phagocytosis. Additionally, they proved to be useful to stain different blood cells with an intense and stable signal at a very low exposure time. PMID- 26966916 TI - Three-dimensional Alginate-bead Culture of Human Pituitary Adenoma Cells. AB - A three-dimensional culture method is described in which primary pituitary adenoma cells are grown in alginate beads. Alginate is a polymer derived from brown sea algae. Briefly, the tumor tissue is cut into small pieces and submitted to an enzymatic digestion with collagenase and trypsin. Next, a cell suspension is obtained. The tumor cell suspension is mixed with 1.2% sodium alginate and dropped into a CaCl2 solution, and the alginate/cell suspension is gelled on contact with the CaCl2 to form spherical beads. The cells embedded in the alginate beads are supplied with nutrients provided by the culture media enriched with 20% FBS. Three-dimensional culture in alginate beads maintains the viability of adenoma cells for long periods of time, up to four months. Moreover, the cells can be liberated from the alginate by washing the beads with sodium citrate and seeded on glass coverslips for further immunocytochemical analyses. The use of a cell culture model allows for the fixation and visualization of the actin cytoskeleton with minimal disorganization. In summary, alginate beads provide a reliable culture system for the maintenance of pituitary adenoma cells. PMID- 26966918 TI - Computer Simulation Study of Graphene Oxide Supercapacitors: Charge Screening Mechanism. AB - Graphene oxide supercapacitors in the parallel plate configuration are studied via molecular dynamics (MD) simulations. The full range of electrode oxidation from 0 to 100% is examined by oxidizing the graphene surface with hydroxyl groups. Two different electrolytes, 1-ethyl-3-methylimidazolium tetrafluoroborate (EMI(+)BF4(-)) as an ionic liquid and its 1.3 M solution in acetonitrile as an organic electrolyte, are considered. While the area-specific capacitance tends to decrease with increasing electrode oxidation for both electrolytes, its details show interesting differences between the organic electrolyte and ionic liquid, including the extent of decrease. For detailed insight into these differences, the screening mechanisms of electrode charges by electrolytes and their variations with electrode oxidation are analyzed with special attention paid to the aspects shared by and the contrasts between the organic electrolyte and ionic liquid. PMID- 26966920 TI - Accelerating Ab Initio Path Integral Simulations via Imaginary Multiple Timestepping. AB - This work investigates the use of multiple-timestep schemes in imaginary time for computationally efficient ab initio equilibrium path integral simulations of quantum molecular motion. In the simplest formulation, only every n(th) path integral replica is computed at the target level of electronic structure theory, whereas the remaining low-level replicas still account for nuclear motion quantum effects with a more computationally economical theory. Motivated by recent developments for multiple-timestep techniques in real-time classical molecular dynamics, both 1-electron (atomic-orbital basis set) and 2-electron (electron correlation) truncations are shown to be effective. Structural distributions and thermodynamic averages are tested for representative analytic potentials and ab initio molecular examples. Target quantum chemistry methods include density functional theory and second-order Moller-Plesset perturbation theory, although any level of theory is formally amenable to this framework. For a standard two level splitting, computational speedups of 1.6-4.0x are observed when using a 4 fold reduction in time slices; an 8-fold reduction is feasible in some cases. Multitiered options further reduce computational requirements and suggest that quantum mechanical motion could potentially be obtained at a cost not significantly different from the cost of classical simulations. PMID- 26966921 TI - Wrong-level spinal surgery - 'never' again? PMID- 26966919 TI - Efficacy and prognostic factors of treatment retention with intravenous abatacept for rheumatoid arthritis: 24-month results from an international, prospective, real-world study. AB - OBJECTIVES: To evaluate retention of abatacept over 24 months in patients with rheumatoid arthritis (RA) in routine clinical practice across Europe and Canada. METHODS: ACTION (AbataCepT In rOutiNe clinical practice) was a prospective, observational, multicentre study of adult patients with moderate-to-severe RA who, at their physician's discretion, initiated treatment with intravenous abatacept. Enrolment occurred from May 2008 to December 2010, with up to 30 months of follow-up. The primary endpoint was the abatacept retention rate over 24 months. Crude abatacept retention rate was estimated using the Kaplan-Meier method. Prognostic factors of abatacept retention in patients with >=1 prior biologic failure were derived from a Cox proportional hazards regression model, accounting for clustered data. RESULTS: A total of 1137 patients were enrolled (1573 patient-years on abatacept); most (89.2%) had experienced prior biologic failure. The overall crude abatacept retention rate at 24 months was 54.4% (95% confidence interval: 51.3, 57.4). Positivity for both rheumatoid factor and anti cyclic citrullinated antibody, previous exposure to one or no anti-tumour necrosis factor agents, and cardiovascular comorbidity were prognostic of higher abatacept retention. Erythrocyte sedimentation rate >=51 mm/hour and introduction of corticosteroid use at abatacept initiation were predictors of lower abatacept retention. Abatacept retention varied according to country. Abatacept was well tolerated without any unexpected safety signals. CONCLUSIONS: In a real-world setting, intravenous abatacept treatment retention was more than 50% at 24 months. The identification of prognostic factors of abatacept retention could support individualised biologic treatment strategies in patients with moderate-to severe RA. PMID- 26966922 TI - Microalbuminuria in Patients with Obstructive Sleep Apnea-Chronic Obstructive Pulmonary Disease Overlap Syndrome. AB - RATIONALE: Microalbuminuria is said to reflect systemic vascular damage and endothelial dysfunction and is an established indicator of cardiovascular morbidity and mortality. Patients with obstructive sleep apnea (OSA)-chronic obstructive pulmonary disease (COPD) overlap syndrome have worse survival than those with OSA or COPD alone. OBJECTIVES: This study evaluated the association between overlap syndrome and microalbuminuria. METHODS: Data on patients in whom OSA was suspected and who underwent polysomnography between January 2010 and December 2012 were reviewed. Microalbuminuria was defined as an albumin creatinine ratio between 20 and 299 mg/g in men and between 30 and 299 mg/g in women. MEASUREMENTS AND MAIN RESULTS: Of 740 consecutive patients, 344 were analyzed. Sixty-four were control participants, 248 had OSA only, 4 had COPD only, and 28 had OSA-COPD overlap syndrome. Prevalence of microalbuminuria significantly increased in the order of control, OSA, and overlap syndrome groups (3.1, 12.9, and 32.1%, respectively; P = 0.0006). After adjusting for age and sex, multivariate logistic regression analysis demonstrated a significant association of overlap syndrome with microalbuminuria compared with OSA (odds ratio, 2.61; 95% confidence interval, 1.02-6.38; P = 0.047), but after adjusting for other confounding factors, the difference in the association did not reach significance (odds ratio, 2.54; 95% confidence interval, 0.93-6.72; P = 0.070). Of 63 patients reevaluated after 3 months of continuous positive airway pressure therapy, the logarithm of the albumin-creatinine ratio in 36 patients with good compliance significantly decreased, but there was no difference in patients with poor compliance. CONCLUSIONS: OSA-COPD overlap syndrome was more prevalent than OSA alone in patients with microalbuminuria, but the difference might be mediated by conventional risk factors rather than the addition of COPD itself. PMID- 26966924 TI - Addressing challenges for sustainable healthcare in Central and Eastern Europe. AB - All European countries face increasing challenges in the provision of equitable and comprehensive healthcare for their citizens in view of a number of factors. These include changing demographics and the continual launch of new premium priced medicines. The challenges are even more difficult among Central and Eastern European healthcare systems. Consequently, there is a need for countries to learn from each other to help address some of these challenges and to maintain sustainable systems. This was the basis of the 2-day conference, The Fifth International Conference: Challenges for Efficient Healthcare in Central and Eastern Europe, 9-10 October 2015, Belgrade, Serbia. PMID- 26966923 TI - New roles for the GLUTAMATE RECEPTOR-LIKE 3.3, 3.5, and 3.6 genes as on/off switches of wound-induced systemic electrical signals. AB - Wounding induces systemic potentials in Arabidopsis thaliana that can be abolished by concomitant suppression of the GLUTAMATE RECEPTOR-LIKE GLR3.3 and GLR3.6 genes. However, the roles of specific GLR channels to these potentials remain unclear. Here I applied the Electrical Penetration Graph (EPG) to study the contribution of three GLR channels to wound-induced, systemically propagated electrical potentials in Arabidopsis thaliana. In contrast to recordings made with conventional rigs for whole-plant electrophysiology, the EPG allows for the unambiguous distinction of the phloem-propagated action potential (AP) from the electrical activity outside of the phloem. The data reported here suggest that: (a) the transmission of wound-induced, phloem-propagated AP to neighbor leaves, requires expression of GLR3.3 or GLR3.6, whereas GLR3.5 prevents its transmission to non-neighbor leaves; (b) the generation of wound-induced electrical signals outside the phloem network depends on GLR3.6 expression; and (c) wound-induced systemic potentials initiated in the shoot are transmitted to the root in the adult plant, which suggests a role for these electrical signals in coordinating the plant defenses in the shoot and in the root. Here, I propose a model for wound-induced systemic electrical signals at the molecular, cellular and anatomical level. In this model, GLR3.3 and GLR3.6 function as on switches for the propagation of wound-induced potentials beyond the wounded leaf, while GLR3.5 functions as an off switch that prevents the propagation of wound-induced electrical potentials to distal, non-neighbor leaves. PMID- 26966925 TI - Influence of a bonding agent on the bond strength between a dental Co-Cr alloy and nine different veneering porcelains. AB - Adequate bonding between dental veneering porcelains and non-precious metal alloys is a main factor for the long-term functionality of porcelain fused to metal restorations. Although a huge number of veneering porcelains are on the market, only few studies have reported about the role of bonding agents for the bond strength at their respective interface to cobalt-chromium (Co-Cr). The aim of this study was to compare the influence of a metal-ceramic bonding agent for Co-Cr alloys on the bond strength of metal-ceramic systems. The bond strength test was done according to ISO 9693 with additional detection of the first acoustic crack initiated signal while testing. The bonding agent had only minor effects on the bond strength of the different Co-Cr/ceramic systems. Only three of the nine studied systems showed statistically significant differences (p<0.05) upon applying the bonding agent. Scanning electron microscopy (SEM) showed cracks predominantly caused by adhesive failure. Based on this study, Co-Cr alloys veneered with porcelains with and without a bonding agent exceeded the minimum bond strength of 25 MPa required according to ISO 9693. However, if bond strength values based on acoustic signals were calculated, values below the threshold of 25 MPa could be observed. Such findings are important for failures caused by the occurrence of early cracks. PMID- 26966926 TI - Preparation of anticoagulant polyvinylidene fluoride hollow fiber hemodialysis membranes. AB - In this study, polyvinylidene fluoride (PVDF) hollow fiber membranes (HFMs) were modified by coating with polyvinyl alcohol (PVA) and chitosan. The influences of PVA and chitosan amount on PVDF membrane mechanical and separation performance were investigated. The results showed that the modified PVDF membranes had better mechanical and separation performance when the amount of PVA and chitosan was 20 mg/m2. At the same time, the biocompatibility of PVDF membranes was also investigated. Compared with virgin PVDF membranes, the modified PVDF membranes showed better anticoagulation, hydrophilicity, less bovine serum albumin (BSA) adsorption, and lower hemolytic ratio. The anticoagulation behavior of modified PVDF membranes coating with PVA had been obviously improved. Prothrombin time (PT) and activated partial thromboplastin time (APTT) of the modified PVDF membrane are 44.8 s and 72.5 s while the PT and APTT of virgin PVDF membrane are 15.6 s and 37.3 s. The advancing water contact angle (WCA) and BSA adsorption of the modified PVDF membrane coating with PVA are 24 degrees and 23 mg/m2 while virgin PVDF membrane is 52 degrees and 49 mg/m2. However, further biocompatibility evaluation is needed to obtain a more comprehensive conclusion. PMID- 26966927 TI - Cost effectiveness of universal umbilical cord blood gas and lactate analysis in a tertiary level maternity unit. AB - OBJECTIVE: There is an increasing body of literature supporting universal umbilical cord blood gas analysis (UCBGA) into all maternity units. A significant impediment to UCBGA's introduction is the perceived expense of the introduction and associated ongoing costs. Consequently, this study set out to conduct the first cost-effectiveness analysis of introducing universal UCBGA. METHODS: Analysis was based on 42,100 consecutive deliveries >=23 weeks of gestation at a single tertiary obstetric unit. Within 4 years of UCBGA's introduction there was a 45% reduction in term special care nursery (SCN) admissions >2499 g. Incurred costs included initial and ongoing costs associated with universal UCBGA. Averted costs were based on local diagnosis-related grouping costs for reduction in term SCN admissions. Incremental cost-effectiveness ratio (ICER) and sensitivity analysis results were reported. RESULTS: Under the base-case scenario, the adoption of universal UCBGA was less costly and more effective than selective UCBGA over 4 years and resulted in saving of AU$641,532 while adverting 376 SCN admissions. Sensitivity analysis showed that UCBGA was cost-effective in 51.8%, 83.3%, 99.6% and 100% of simulations in years 1, 2, 3 and 4. These conclusions were not sensitive to wide, clinically possible variations in parameter values for neonatal intensive care unit and SCN admissions, magnitude of averted SCN admissions, cumulative delivery numbers, and SCN admission costs. CONCLUSIONS: Universal UCBGA is associated with significant initial and ongoing costs; however, potential averted costs (due to reduced SCN admissions) exceed incurred costs in most scenarios. PMID- 26966928 TI - Postural instability and falls in Parkinson's disease. AB - Postural instability (PI) is one of the most debilitating motor symptoms of Parkinson's disease (PD), as it is associated with an increased risk of falls and subsequent medical complications (e.g. fractures), fear of falling, decreased mobility, self-restricted physical activity, social isolation, and decreased quality of life. The pathophysiological mechanisms underlying PI in PD remain elusive. This short review provides a critical summary of the literature on PI in PD, covering the clinical features, the neural and cognitive substrates, and the effects of dopaminergic medications and deep brain stimulation. The delayed effect of dopaminergic medication combined with the success of extrastriatal deep brain stimulation suggests that PI involves neurotransmitter systems other than dopamine and brain regions extending beyond the basal ganglia, further challenging the traditional view of PD as a predominantly single-system neurodegenerative disease. PMID- 26966929 TI - Molecular mechanisms mediating the beneficial metabolic effects of [Arg4]tigerinin-1R in mice with diet-induced obesity and insulin resistance. AB - The frog skin host-defense peptide tigerinin-1R stimulates insulin release in vitro and improves glucose tolerance and insulin sensitivity in animal models of type 2 diabetes. This study extends these observations by investigating the molecular mechanisms of action underlying the beneficial metabolic effects of the analogue [Arg4]tigerinin-1R in mice with diet-induced obesity, glucose intolerance and insulin resistance. The study also investigates the electrophysiological effects of the peptide on KATP and L-type Ca2+ channels in BRIN-BD11 clonal beta cells. Non-fasting plasma glucose and glucagon concentrations were significantly (p<0.05) decreased and plasma insulin increased by twice daily treatment with [Arg4]tigerinin-1R (75 nmol/kg body weight) for 28 days. Oral and intraperitoneal glucose tolerance were significantly (p<0.05) improved accompanied by enhanced secretion and action of insulin. The peptide blocked KATP channels and, consistent with this, improved beta cell responses of isolated islets to a range of secretagogues. Peptide administration resulted in up-regulation of key functional genes in islets involved insulin secretion (Abcc8, Kcnj11, Cacna1c and Slc2a2) and in skeletal muscle involved with insulin action (Insr, Irs1, Pdk1, Pik3ca, and Slc2a4). These observations encourage further development of tigerinin-1R analogues for the treatment of patients with type 2 diabetes. PMID- 26966930 TI - Seasonal variations in plasma free metanephrine concentrations are not evident in the West of Ireland. PMID- 26966932 TI - Theranos phenomenon--part 3. PMID- 26966931 TI - Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. AB - Kounis syndrome has been established as a hypersensitivity coronary disorder induced by various conditions, drugs, environmental exposures, foods and coronary stents. Allergic, hypersensitivity, anaphylactic and anaphylactoid reactions are associated with this syndrome. Vasospastic allergic angina, allergic myocardial infarction and stent thrombosis with occluding thrombus infiltrated by eosinophils and/or mast cells constitute are the three reported, so far, variants of this syndrome. Apart from coronary arteries, it affects the cerebral and mesenteric arteries. Its manifestations are broadening and its etiology is continuously increasing. Kounis syndrome is a ubiquitous disease which represents a magnificent natural paradigm and nature's own experiment in a final trigger pathway implicated in cases of coronary artery spasm and plaque rupture. Kounis syndrome seems to be not a rare disease but an infrequently diagnosed clinical entity which has revealed that the same mediators released from the same inflammatory cells are also present and in acute coronary events of non allergic etiology. These cells are not only present in the culprit region before plaque erosion or rupture but they release their contents just before an actual coronary event. Therefore, awareness of etiology, epidemiology, pathogenesis and clinical manifestations seems to be important for its prognosis, diagnosis, treatment, prevention. PMID- 26966933 TI - Hormones and endometrial carcinogenesis. AB - Endometrial cancer (EC) is the commonest gynaecological cancer in the Western World with an alarmingly increasing incidence related to longevity and obesity. Ovarian hormones regulate normal human endometrial cell proliferation, regeneration and function therefore are implicated in endometrial carcinogenesis directly or via influencing other hormones and metabolic pathways. Although the role of unopposed oestrogen in the pathogenesis of EC has received considerable attention, the emerging role of other hormones in this process, such as androgens and gonadotropin-releasing hormones (GnRH) is less well recognised. This review aims to consolidate the current knowledge of the involvement of the three main endogenous ovarian hormones (oestrogens, progesterone and androgens) as well as the other hormones in endometrial carcinogenesis, to identify important avenues for future research. PMID- 26966934 TI - Manipulating Magnetism at Organic/Ferromagnetic Interfaces by Molecule-Induced Surface Reconstruction. AB - Fullerenes have several advantages as potential materials for organic spintronics. Through a theoretical first-principles study, we report that fullerene C60 adsorption can induce a magnetic reconstruction in a Ni(111) surface and expose the merits of the reconstructed C60/Ni(111) spinterface for molecular spintronics applications. Surface reconstruction drastically modifies the magnetic properties at both sides of the C60/Ni interface. Three outstanding properties of the reconstructed structure are revealed, which originate from reconstruction enhanced spin-split pi-d coupling between C60 and Ni(111): (1) the C60 spin polarization and conductance around the Fermi level are enhanced simultaneously, which can be important for read-head sensor miniaturization; (2) localized spin-polarized states appear in C60 with a spin-filter functionality; and (3) magnetocrystalline anisotropic energy and exchange coupling in the outermost Ni layer are reduced enormously. Surface reconstruction can be realized simply by controlling the annealing temperature in experiments. PMID- 26966936 TI - Post-Treatments for Multifunctional Property Enhancement of Carbon Nanotube Fibers from the Floating Catalyst Method. AB - We investigated the effects of the synthesis conditions and condensation processes on the chemical compositions and multifunctional performance of the directly spun carbon nanotube (CNT) fibers. On the basis of the optimized synthesis conditions, a two-step post-treatment technique which involved acidification and epoxy infiltration was also developed to further enhance their mechanical and electrical properties. As a result, their tensile strength and Young's modulus increased remarkably by 177% and 325%, respectively, while their electrical conductivity also reached 8235 S/cm. This work may provide a general strategy for the postprocessing optimization of the directly spun CNT fibers. The treated CNT fibers with superior properties are promising for a wide range of applications, such as structural reinforcements and lightweight electric cables. PMID- 26966935 TI - Determination of Photoreceptor Cell Spectral Sensitivity in an Insect Model from In Vivo Intracellular Recordings. AB - Intracellular recording is a powerful technique used to determine how a single cell may respond to a given stimulus. In vision research, intracellular recording has historically been a common technique used to study sensitivities of individual photoreceptor cells to different light stimuli that is still being used today. However, there remains a dearth of detailed methodology in the literature for researchers wishing to replicate intracellular recording experiments in the eye. Here we present the insect as a model for examining eye physiology more generally. Insect photoreceptor cells are located near the surface of the eye and are therefore easy to reach, and many of the mechanisms involved in vision are conserved across animal phyla. We describe the basic procedure for in vivo intracellular recording of photoreceptor cells in the eye of a butterfly, with the goal of making this technique more accessible to researchers with little prior experience in electrophysiology. We introduce the basic equipment needed, how to prepare a live butterfly for recording, how to insert a glass microelectrode into a single cell, and finally the recording procedure itself. We also explain the basic analysis of raw response data for determining spectral sensitivity of individual cell types. Although our protocol focuses on determining spectral sensitivity, other stimuli (e.g., polarized light) and variations of the method are applicable to this setup. PMID- 26966937 TI - Highly Sensitive Assay for Measurement of Arenavirus-cell Attachment. AB - Arenaviruses are a family of enveloped RNA viruses that cause severe human disease. The first step in the arenavirus life cycle is attachment of viral particles to host cells. While virus-cell attachment can be measured through the use of virions labeled with biotin, radioactive isotopes, or fluorescent dyes, these approaches typically require high multiplicities of infection (MOI) to enable detection of bound virus. We describe a quantitative (q)RT-PCR-based assay that measures Junin virus strain Candid 1 attachment via quantitation of virion packaged viral genomic RNA. This assay has several advantages including its extreme sensitivity and ability to measure attachment over a large dynamic range of MOIs without the need to purify or label input virus. Importantly, this approach can be easily tailored for use with other viruses through the use of virus-specific qRT-PCR reagents. Further, this assay can be modified to permit measurement of particle endocytosis and genome uncoating. In conclusion, we describe a simple, yet robust assay for highly sensitive measurement of arenavirus-cell attachment. PMID- 26966938 TI - Accelerated Removal of Fe-Antisite Defects while Nanosizing Hydrothermal LiFePO4 with Ca(2). AB - Based on neutron powder diffraction (NPD) and high angle annular dark field scanning transmission electron microscopy (HAADF-STEM), we show that calcium ions help eliminate the Fe-antisite defects by controlling the nucleation and evolution of the LiFePO4 particles during their hydrothermal synthesis. This Ca regulated formation of LiFePO4 particles has an overwhelming impact on the removal of their iron antisite defects during the subsequent carbon-coating step since (i) almost all the Fe-antisite defects aggregate at the surface of the LiFePO4 crystal when the crystals are small enough and (ii) the concomitant increase of the surface area, which further exposes the Fe-antisite defects. Our results not only justify a low-cost, efficient and reliable hydrothermal synthesis method for LiFePO4 but also provide a promising alternative viewpoint on the mechanism controlling the nanosizing of LiFePO4, which leads to improved electrochemical performances. PMID- 26966939 TI - A Lactobacillus mutant capable of accumulating long-chain polyphosphates that enhance intestinal barrier function. AB - Inorganic polyphosphate (polyP) was previously identified as a probiotic-derived substance that enhances intestinal barrier function. PolyP-accumulating bacteria are expected to have beneficial effects on the human gastrointestinal tract. In this study, we selected Lactobacillus paracasei JCM 1163 as a strain with the potential to accumulate polyP, because among the probiotic bacteria stored in our laboratory, it had the largest amount of polyP. The chain length of polyP accumulated in L. paracasei JCM 1163 was approximately 700 phosphate (Pi) residues. L. paracasei JCM 1163 accumulated polyP when Pi was added to Pi-starved cells. We further improved the ability of L. paracasei JCM 1163 to accumulate polyP by nitrosoguanidine mutagenesis. The mutant accumulated polyP at a level of 1500 nmol/mg protein-approximately 190 times that of the wild-type strain. PolyP extracted from the L. paracasei JCM 1163 significantly suppressed the oxidant induced intestinal permeability in mouse small intestine. In conclusion, we have succeeded in breeding the polyP-accumulating Lactobacillus mutant that is expected to enhance intestinal barrier function. PMID- 26966940 TI - Management of Postpartum Diastasis of the Pubic Symphysis. AB - Conservative management is typically recommended for postpartum diastasis of the pubic symphysis, despite significant functional disability and chronic pain associated with this condition. With a reported incidence of 1:500, the authors describe diagnosis and management controversies with an additional review of relevant literature related to the management of this orthopedic condition. The case is of a 27-year-old woman diagnosed with 5.5-cm diastasis of the pubic symphysis after spontaneous vaginal delivery of a 5 lb 5 oz infant. She underwent early orthopedic surgical correction via open reduction and internal fixation. The patient achieved pain-free ambulation within 3 months of surgery, and returned to full activity at 6 months. Postpartum diastasis of the pubic symphysis is typically treated conservatively; however, the authors illustrate that early orthopedic consultation and intervention at diastasis greater than 5 cm may improve recovery and functional outcome. PMID- 26966941 TI - Prospective, Longitudinal Evaluation of Gender Differences After Total Hip Arthroplasty. AB - Temporal trends in survivorship, patient-reported outcomes, and activity levels following total hip arthroplasty were compared between 61 men and 127 women. Overall implant survivorship was excellent for both genders. Similar functional improvements were found between men and women out until 5 years. Some gender differences were observed: men had a faster time to functional recovery and higher preoperative Short-Form 12-item survey mental component scores, whereas women had a significant improvement in Short-Form 12-item survey mental component scores. Increased understanding of these differences by patients and surgeons, combined with gender-based interventions, may further advance outcomes for these patients. PMID- 26966943 TI - Repair of Chronic Tibialis Anterior Tendon Ruptures. AB - This article presents a novel technique for repair of chronic tibialis anterior tendon ruptures. All chronic tibialis anterior tendon ruptures reviewed were treated with this technique. Patients with chronic tibialis anterior tendon ruptures presenting to the authors' institution from 2006 to 2012 had preoperative and postoperative Foot and Ankle Ability Measure scores. The average follow-up time was 2.1 years. The average Foot and Ankle Ability Measure score was 66.1% preoperatively and 87.1% postoperatively (P=.002). This technique offers theoretical improved strength and may help avoid the need for tendon graft often required by other techniques. PMID- 26966942 TI - Effect of Different Distal Fixation Augmentation Methods on the Pullout Strength of Fassier-Duval Telescoping Rods. AB - Antegrade telescoping rods have been introduced for use in pediatric patients with osteogenesis imperfecta (OI) to decrease the incidence of long-bone fractures and to correct and prevent deformities. Recent studies have documented failures of telescoping intramedullary rods due to inadequate distal fixation. The purpose of this study was to evaluate the pullout strength of distal fixation of the telescoping rod with and without synthetic calcium phosphate or polymethylmethacrylate (PMMA) augmentation. Four sets of 6 telescoping distal fixation rods were fixed according to standard insertion technique into an open cell rigid-foam synthetic bone block simulating OI bone. The groups tested were as follows: control (no augmentation), 0.75 mL of PMMA-augmented, 0.75 mL of PMMA rescued (stripped distal fixation, then resecured after PMMA augmentation), and 0.75 mL of bioabsorbable-calcium phosphate (CP)-augmented. All rods were tested to failure. The peak load was recorded. Average pullout strengths were as follows: control, 20+/-6.6 N; PMMA, 125+/-16.8 N; PMMA-rescued, 137+/-11.9 N; bioabsorbable-CP, 81+/-10.3 N. All augmented groups had significantly higher pullout strength compared with the control (P<.001). The PMMA and PMMA-rescued groups failed at the PMMA/bone interface, whereas the bioabsorbable-CP group failed at the cement/rod interface. All augmented constructs improved pullout strength by at least 400% compared with the control. Bioabsorbable cement may be less detrimental to the physis if pullout still occurs despite augmentation due to its mode of failure. This study provides biomechanical evidence to support the further in vivo investigation of either PMMA or bioabsorbable cement augmentation to improve pullout strength of distal telescoping rod fixation. PMID- 26966944 TI - Total Hip Arthroplasty Complicated by a Gluteal Hematoma Resulting in Acute Foot Drop. AB - Total hip arthroplasty is a prevalent orthopedic intervention in the United States. Massive postoperative hematomas are a rare albeit serious complication of the procedure. Sequelae of these hematomas can include lower extremity paralysis from compression of the sciatic nerve. A 66-year-old woman taking aspirin and clopidogrel for coronary stents presented with a complete foot drop, paresthesias, and lower extremity pain 10 days after a total hip arthroplasty. The patient was initially seen by a neurology service at another hospital and thought to have lateral recess stenosis. At the authors' center, magnetic resonance imaging of the lumbar spine failed to show lateral recess stenosis. Urgent pelvic computed tomography showed a large hematoma and raised suspicion of sciatic nerve compression. Hip magnetic resonance imaging showed a right gluteal hematoma compressing the sciatic nerve. The patient was then taken to the operating room for the clot to be evacuated and was later referred for rehabilitation. Massive hematomas after total hip arthroplasty are an important consideration in the differential diagnosis of nontraumatic acute foot drop. Prompt diagnosis may correlate with improved neurological outcome and help reduce overall morbidity. PMID- 26966945 TI - Painful Intramuscular Lipoma of the Infraspinatus: Unusual Location and Presentation. AB - Intramuscular lipomas are considered a rare type of benign lipomas. They are usually located deeper and are less palpable than subcutaneous lipomas. A painful presentation with no palpable mass will make clinical diagnosis difficult; in these cases, further imaging should be considered. Only a small number of cases of intramuscular lipomas present with pain; these are located in the supraspinatus and deltoid muscles. To the authors' knowledge, there have been no previous reports of painful intramuscular lipomas involving the infraspinatus muscle. This article describes a case of intramuscular lipoma uniquely located in the infraspinatus muscle and presenting with shoulder pain. A 49-year-old woman presented with 2 months of left shoulder pain. There was no history of preceding trauma. Pain was aggravated by lying on the left shoulder and by the hand behind the back similar to Crass position. On the physical examination, her shoulder joint range of motion was slightly decreased. Simple radiography showed no significant abnormality, but ultrasonography revealed a hyperechogenic mass within the infraspinatus muscle. There was focal tenderness over the mass, but definite palpation of the mass was not possible. Magnetic resonance imaging revealed a well-circumscribed, homogeneous lesion measuring 43 * 28 * 16 mm within the infraspinatus muscle, leading to a diagnosis of intramuscular lipoma. Her pain was not improved with medication, suprascapular nerve block, and steroid injections. Finally, surgical intervention was done and intramuscular lipoma was confirmed by specimen. After excision, her shoulder pain was improved and resolved. PMID- 26966947 TI - Taliban victim responds well to treatment after trauma centre transfer. AB - Fifteen-year-old Malala Yousufzai, shot in the head last month by religious fundamentalists, continues to respond well to treatment, according to staff at Queen Elizabeth Hospital Birmingham. PMID- 26966948 TI - Younger patients miss out on temperature and blood monitoring. AB - Emergency care staff are failing to monitor the temperatures and blood pressures of younger patients who have low levels of consciousness, audit results show. PMID- 26966949 TI - Homeless people are dying in middle age, according to research. AB - The average age of death among homeless people is 30 years earlier than that of the general population, according to a study published last month. PMID- 26966950 TI - Trauma centre status. AB - In March, the hospital in which I work, Queen Elizabeth Hospital Birmingham (QEHB), was designated a major trauma centre and is equipped to treat some of the most seriously injured patients in the West Midlands. PMID- 26966946 TI - Molecular Occupancy of Nanodot Arrays. AB - Single-molecule nanodot arrays, in which a biomolecule of choice (protein, nucleic acid, etc.) is bound to a metallic nanoparticle on a solid substrate, are becoming an increasingly important tool in the study of biomolecular and cellular interactions. We have developed an on-chip measurement protocol to monitor and control the molecular occupancy of nanodots. Arrays of widely spaced nanodots and nanodot clusters were fabricated on glass surfaces by nanolithography and functionalized with fluorescently labeled proteins. The molecular occupancy was determined by monitoring individual fluorophore bleaching events, while accounting for fluorescence quenching effects. We found that the occupancy can be interpreted as a packing problem, and depends on nanodot size and binding ligand concentration, where the latter is easily adjusted to compensate the flexibility of dimension control in nanofabrication. The results are scalable with nanodot cluster size, extending to large area close packed arrays. As an example, the nanoarray platform was used to probe the geometric requirement of T-cell activation at the single-molecule level. PMID- 26966951 TI - The Liver Segmental Volume Ratio for Noninvasive Detection of Cirrhosis: Comparison With Established Linear and Volumetric Measures. AB - OBJECTIVE: The aim of this study was to compare the liver segmental volume ratio (LSVR), a novel volumetric computed tomography measurement, with established linear measurements for differentiating normal from cirrhotic livers. METHODS: Hepatic volumes were measured using semiautomated software (Liver Analysis Application, Philips IntelliSpace Portal) on contrast-enhanced abdominal computed tomography scans in 312 adults, including 108 patients with end-stage liver disease (mean age, 55 years; 63 men/45 women) and 204 healthy controls (potential renal donors; mean age, 46 years; 82 men/122 women). The LSVR was defined as the volume ratio of Couinaud segments I to III to segments IV to VIII. Linear measures included the caudate-to-right lobe ratio and maximal splenic dimension. RESULTS: Differences in LSVR between cirrhotics and controls were highly significant (P < 0.0001; mean, 0.55 +/- 0.29 versus 0.27 +/- 0.07; receiver operating characteristic [ROC] area under the curve [AUC], 0.916). Linear caudate to-right lobe ratio differences were not statistically significant between the 2 cohorts (P = 0.051; ROC AUC, 0.567). Total liver volume was ineffective for discrimination (ROC AUC, 0.598). An LSVR threshold of 0.35 or greater had a sensitivity and specificity for cirrhosis of 81.5% and 88.7%, respectively. CONCLUSIONS: Regional hepatic volume changes, as reflected by the LSVR, are more effective than standard linear measures or total liver volume for differentiating cirrhotic from normal livers. PMID- 26966952 TI - Usefulness of the Short-Echo Time Cube Sequence at 3-T Magnetic Resonance Cholangiopancreatography: Prospective Comparison With the Conventional 3 Dimensional Fast Spin-Echo Sequence. AB - OBJECTIVES: We evaluated prospectively the clinical use of the short-echo time (TE) Cube sequence for magnetic resonance cholangiopancreatography (MRCP) at 3 T. METHODS: Using a 3-T unit, we subjected 41 consecutive patients to short-TE Cube MRCP and conventional 3-dimensional fast spin-echo (3D-FSE) MRCP. Two radiologists independently rated the image quality and the visibility of the right and left hepatic, cystic, common bile, and main pancreatic ducts and the gallbladder on a 4-point scale. The averaged visual scores by 2 readers for the image quality were calculated, and the artifacts were evaluated in cases with relatively lower (<3) score. The signal-to-noise ratio, contrast-to-noise ratio, and acquisition time were evaluated by quantitative analysis. RESULTS: The visual scores of the common bile duct (P < 0.05), cystic duct (P < 0.01), and gallbladder (P < 0.01) were significantly higher for Cube than 3D-FSE MRCP. Signal-to-noise ratio was also significantly higher for Cube than 3D-FSE MRCP (P < 0.01). There was no significant difference in the image acquisition time (352.1 +/- 93.0 vs 314.1 +/- 126.2 seconds, P = 0.059). Four cases on 3D-FSE MRCP and 2 cases on Cube MRCP have relatively lower image quality; however, the difference was not significant (P = 0.18). CONCLUSIONS: The visibility of biliary structures is significantly better on short-TE Cube MRCP than conventional 3D-FSE MRCP images at a clinically acceptable acquisition time. PMID- 26966953 TI - Where Does Diffuse Large B-Cell Lymphoma Relapse? AB - OBJECTIVE: This study aimed to investigate the anatomic pattern of disease spread at first disease relapse compared with baseline in diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: All patients who were newly diagnosed as having DLBCL between January 2004 and June 2014 who initially achieved complete remission but who eventually developed relapsed disease during follow-up were retrospectively identified. Available histological and imaging data were used to determine which nodal regions and extranodal locations were involved at relapse. RESULTS: A total of 21 patients with relapsed DLBCL were included, of whom 8 (38.1%) presented with disease relapse at previously involved sites only, 7 (33.3%) presented with disease relapse at both previously involved and new sites, and 6 (28.6%) presented with disease relapse at new sites only. A total of 57 nodal stations and 34 extranodal locations were involved in all 21 relapsed DLBCL patients. Of these 57 involved nodal regions, 47 (82.5%) were also involved at baseline, whereas 10 (17.5%) were not involved at baseline. Of the 34 involved extranodal locations, 17 (50.0%) were also involved at baseline, whereas 17 (50.0%) were not involved at baseline. CONCLUSIONS: Relapsed DLBCL generally tends to affect previously involved sites, although close to one third of patients seem to have disease recurrence exclusively in previously uninvolved sites. The great majority of involved nodal stations at relapse are also involved at baseline, whereas only one half of involved extranodal locations at relapse are involved at baseline. PMID- 26966954 TI - Correlation Between Magnetic Resonance Imaging-Based Evaluation of Extramural Vascular Invasion and Prognostic Parameters of T3 Stage Rectal Cancer. AB - PURPOSE: The aim of this study was to analyze the correlation between magnetic resonance imaging-based extramural vascular invasion (EMVI) and the prognostic clinical and histological parameters of stage T3 rectal cancers. METHODS: Eighty six patients with T3 stage rectal cancer who received surgical resection without neoadjuvant therapy were included. Magnetic resonance imaging-based EMVI scores were determined. Correlations between the scores and pretreatment carcinoembryonic antigen levels, tumor differentiation grade, nodal stage, and vascular endothelial growth factor expression were analyzed using Spearman rank coefficient analysis. RESULTS: Magnetic resonance imaging-based EMVI scores were statistically different (P = 0.001) between histological nodal stages (N0 vs N1 vs N2). Correlations were found between magnetic resonance imaging-based EMVI scores and tumor histological grade (rs = 0.227, P = 0.035), histological nodal stage (rs = 0.524, P < 0.001), and vascular endothelial growth factor expression (rs = 0.422; P = 0.016). CONCLUSIONS: Magnetic resonance imaging-based EMVI score is correlated with prognostic parameters of T3 stage rectal cancers and has the potential to become an imaging biomarker of tumor aggressiveness. Magnetic resonance imaging-based EMVI may be useful in helping the multidisciplinary team to stratify T3 rectal cancer patients for neoadjuvant therapies. PMID- 26966955 TI - Preoperative Fluorine 18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for Prediction of Microvascular Invasion in Small Hepatocellular Carcinoma. AB - OBJECTIVES: This study aimed to assess the value of preoperative fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET CT) for predicting microvascular invasion (MVI) in small hepatocellular carcinoma (HCC). METHODS: We retrospectively examined 60 patients who received F-FDG PET-CT prior to hepatic resection for small HCC (<=30 mm) with subsequent MVI confirmation by histopathology. The associations between PET-positive status and tumor factors were assessed. Furthermore, independent predictors for MVI and diagnostic utility of each MVI predictor were assessed. RESULTS: Multivariate analysis revealed the presence of MVI as an independent predictor of PET-positive status (P = 0.023). Maximum standardized uptake value (SUVmax) of 3.2 or greater (P = 0.017) and lens culinaris agglutinin a-reactive alpha-fetoprotein (AFP-L3) 19% or greater (P = 0.010) were independent predictors of MVI. Areas under the receiver operating characteristic curves for SUVmax of 3.2 or greater, AFP-L3 19% or greater, and both factors combined for predicting MVI were 0.712 (0.493 0.932), 0.755 (0.563-0.947), and 0.856 (0.721-0.991), respectively. The sensitivity and specificity for predicting MVI were 77.8% and 74.5% for SUVmax of 3.2 or greater, 66.7% and 84.3% for AFP-L3 19% or greater, and 88.9% and 82.4% for the combination. CONCLUSIONS: F-FDG PET-CT and AFP-L3 may be useful for predicting MVI in small HCC, and the combination of the 2 factors provided reliable assessment for selection of suitable hepatic resection and liver transplantation candidates. PMID- 26966957 TI - Is Playing in the Pit Really the Pits?: Pain, Strength, Music Performance Anxiety, and Workplace Satisfaction in Professional Musicians in Stage, Pit, and Combined Stage/Pit Orchestras. AB - INTRODUCTION: Typically, Australian orchestral musicians perform on stage, in an orchestra pit, or in a combination of both workplaces. This study explored a range of physical and mental health indicators in musicians who played in these different orchestra types to ascertain whether orchestra environment was a risk factor affecting musician wellbeing. METHODS: Participants comprised 380 full time orchestral musicians from the eight major state orchestras in Australia comprised of two dedicated pit orchestras, three stage-only symphonic orchestras, and three mixed stage/pit orchestras. Participants completed a physical assessment and a range of self-report measures assessing performance-related musculoskeletal disorders (PRMD), physical characteristics including strength and perceived exertion, and psychological health, including music performance anxiety (MPA), workplace satisfaction, and bullying. RESULTS: Physical characteristics and performance-related musculoskeletal profiles were similar for most factors on the detailed survey completed by orchestra members. The exceptions were that pit musicians demonstrated greater shoulder and elbow strength, while mixed-workload orchestra musicians had greater flexibility Significantly more exertion was reported by pit musicians when rehearsing and performing. Stage/pit musicians reported less physical exertion when performing in the pit compared with performing on stage. Severity of MPA was significantly greater in pit musicians than mixed orchestra musicians. Pit musicians also reported more frequent bullying and lower job satisfaction compared with stage musicians. DISCUSSION: There were few differences in the objective physical measures between musicians in the different orchestra types. However, pit musicians appear more psychologically vulnerable and less satisfied with their work than musicians from the other two orchestra types. The physical and psychological characteristics of musicians who perform in different orchestra types have not been adequately theorized or studied. We offer some preliminary thoughts that may account for the observed differences. PMID- 26966958 TI - Occupational Diseases of Professional Orchestra Musicians from Northern Portugal: A Descriptive Study. AB - BACKGROUND: Owing to repetitive movements and a very stressful and competitive lifestyle, musicians are a group that may be prone to suffer from occupational diseases. According to the literature, musicians are affected mainly by two types of occupational diseases: music performance anxiety (MPA) and playing-related musculoskeletal disorders (PRMDs). The aim of this study was to describe the prevalence of the most common complaints affecting musicians in the three professional orchestras from northern Portugal. METHODS: Professional orchestra musicians (n=112) from the three main professional orchestras from northern Portugal were individually interviewed about their physical and psychological complaints. RESULTS: Results indicated that 94% of musicians interviewed self reported at least one working-related problem. PRMDs were the most common conditions, affecting 84.8% of musicians. The most affected areas were the shoulder and the cervical and lumbar regions. MPA was reported by 13.2% of musicians. CONCLUSION: The present work covers about 50% of all Portuguese professional orchestra musicians. It raises awareness of the importance of focusing on the high prevalence of professional diseases among musicians. PMID- 26966956 TI - Highly Branched Pentasaccharide-Bearing Amphiphiles for Membrane Protein Studies. AB - Detergents are essential tools for membrane protein manipulation. Micelles formed by detergent molecules have the ability to encapsulate the hydrophobic domains of membrane proteins. The resulting protein-detergent complexes (PDCs) are compatible with the polar environments of aqueous media, making structural and functional analysis feasible. Although a number of novel agents have been developed to overcome the limitations of conventional detergents, most have traditional head groups such as glucoside or maltoside. In this study, we introduce a class of amphiphiles, the PSA/Es with a novel highly branched pentasaccharide hydrophilic group. The PSA/Es conferred markedly increased stability to a diverse range of membrane proteins compared to conventional detergents, indicating a positive role for the new hydrophilic group in maintaining the native protein integrity. In addition, PDCs formed by PSA/Es were smaller and more suitable for electron microscopic analysis than those formed by DDM, indicating that the new agents have significant potential for the structure function studies of membrane proteins. PMID- 26966959 TI - Injuries Among Italian DanceSport Athletes: A Questionnaire Survey. AB - During training and competition, athletic dancers perform complex artistic movements that can lead to stress on the musculoskeletal system, making them subject to high risk of injury. The purpose of this study was to evaluate the prevalence, location, and nature of musculoskeletal injuries among dancesport athletes and to identify potential risk factors for injury. This cross-sectional study was performed at several national dancesport meetings in Italy. All 168 dancesport athletes who participated at the meetings were invited to complete a questionnaire related to injuries they may have suffered during the previous year; other information collected included demographic data (age, sex, height, weight), dance participation (discipline, categories), training (training duration, years since starting to dance), and injury (location, etiology). Of the 168 dancers, 153 completed the questionnaire. Of the 102 injuries reported, 73 athletes (47.7%) reported at least 1 injury. The locations of the injuries were the lower limbs (n=75, 73.5%), upper limbs (8, 7.8%), and spine (19, 18.7%). Significant differences were found in the injury location (p<0.01) as well as the nature of the injury (p<0.01). No significant differences were found between injured and non-injured athletes in demographic data, dance participation, and training variables (p>0.05). The results indicate that about half of the dancers reported at least 1 injury, with these being located particularly in the lower limbs and predominantly strain and sprain injuries. To reduce the prevalence of injuries, a prevention program may be indicated, with future research needed to identify appropriate strategies to prevent injuries. PMID- 26966960 TI - Subjective and Objective Analyses of Voice Improvement After Phonosurgery in Professional Voice Users. AB - OBJECTIVES: To evaluate voice improvement after phonosurgery by subjective and objective voice analysis. DESIGN: Prospective observational analytic group study. METHODS: This study was conducted from January 2012 to December 2013. Two hundred forty professional voice users (patients), classified as Koufman level I or II with benign vocal fold lesions, were divided in two groups. Patients in group 1 had a diagnosis of superficial vocal fold lesions, and patients in group 2 had deep lesions on the vocal folds. All patients completed the Vocal Performance Questionnaire (VPQ) and underwent acoustic voice tests using the Praat program. Subjective and objective voice analyses were performed before phonosurgery and at 1, 2, and 3 months after phonosurgery. A control group of 100 volunteers was created and underwent the same voice metrics that were applied to the patients. RESULTS: Jitter, shimmer, harmonic-to-noise ratio, and VPQ scores significantly differentiated patients with vocal fold lesions from individuals in the control group. All of the analyzed parameters improved significantly after phonosurgery. Additionally, patients with superficial vocal fold lesions achieved normal voice parameters 1 month after surgery, and patients with deep lesions achieved normal voice parameters 3 months after surgery. CONCLUSIONS: Analysis of vocal parameters using the VPQ and acoustic tests revealed voice improvement after phonosurgery for both patient groups. PMID- 26966961 TI - Bone Mineral Density in Elite DanceSport Athletes. AB - This study compared bone mineral density (BMD) variables of female and male elite dancesport athletes with untrained control subjects of the same gender. Sixty-six elite dancesport athletes (M 33, F 33) and 64 untrained controls (M 34, F 31) participated in this study. Elite dancesport athletes were dancing couples competing at the international level. Whole-body bone mineral content and whole body, forearm, lumbar-spine, and femoral-neck BMD, as well as whole-body fat mass and fat free mass, were measured by dual-energy X-ray absorptiometry. There were no differences (p>0.05) in height and body mass between dancers and controls of the same gender, but percent body fat was lower (p<0.05) in dancers of both genders than in untrained controls. Elite dancesport athletes had significantly higher femoral-neck BMD, and male dancers also higher whole-body BMD values when compared with controls of the same gender. All other measured bone mineral values did not differ between the groups of the same gender. In addition, training experience was positively correlated with whole-body BMD (r=0.27; p<0.05) in dancesport athletes. Based on this study, it can be concluded that elite dancesport athletes have higher BMD values at the weight-bearing site (femoral neck BMD), while other measured areas and whole-body bone mineral values do not differ from the corresponding values of healthy sedentary controls of the same gender. According to our results, low BMD is not an issue for elite female dancesport athletes, despite their lower percent body fat values. PMID- 26966962 TI - Hearing Health in College Instrumental Musicians and Prevention of Hearing Loss. AB - OBJECTIVE: College musicians exhibit greater declines in hearing than the general population and are at particular risk because they rehearse and perform daily in loud environments. Also, they engage in use of personal listening devices which increases the amount of "exposure" time. Despite increased risk, many do not use hearing protection devices (HPD). The purpose of this study was to (1) to identify the present level of education about hearing health, (2) identify the perceived advantages and disadvantages of using HPD, and (3) evaluate results among different musical instrument groups. METHODS: A mixed-methods group design was used including both quantitative and qualitative instruments. SPSS was used to generate descriptive statistics, and non-parametric statistical analysis was performed on quantitative data. NVivo software was used to evaluate qualitative responses. RESULTS: Of the 90 college instrumental music students who participated, 12% reported a history of hearing loss, and over one-third reported tinnitus. Seventy-seven percent of participants had never received any training about hearing health and only a small percentage of students used HPD. The most cited reason for lack of protection use was its negative impact on sound quality. However, group differences were noted between brass, woodwind, and percussion musicians in terms of HPD uptake. CONCLUSION: Improving the type of information disseminated to college musicians may reduce the risk of ear-related deficits. Noise dosage information, HPD information, and prevention education grounded in theories like the Health Belief Model may increase awareness and promote greater use of HPDs in this population. PMID- 26966963 TI - Life Expectancy and Cause of Death in Popular Musicians: Is the Popular Musician Lifestyle the Road to Ruin? AB - Does a combination of lifestyle pressures and personality, as reflected in genre, lead to the early death of popular musicians? We explored overall mortality, cause of death, and changes in patterns of death over time and by music genre membership in popular musicians who died between 1950 and 2014. The death records of 13,195 popular musicians were coded for age and year of death, cause of death, gender, and music genre. Musician death statistics were compared with age-matched deaths in the US population using actuarial methods. Although the common perception is of a glamorous, free-wheeling lifestyle for this occupational group, the figures tell a very different story. Results showed that popular musicians have shortened life expectancy compared with comparable general populations. Results showed excess mortality from violent deaths (suicide, homicide, accidental death, including vehicular deaths and drug overdoses) and liver disease for each age group studied compared with population mortality patterns. These excess deaths were highest for the under-25-year age group and reduced chronologically thereafter. Overall mortality rates were twice as high compared with the population when averaged over the whole age range. Mortality impacts differed by music genre. In particular, excess suicides and liver-related disease were observed in country, metal, and rock musicians; excess homicides were observed in 6 of the 14 genres, in particular hip hop and rap musicians. For accidental death, actual deaths significantly exceeded expected deaths for country, folk, jazz, metal, pop, punk, and rock. PMID- 26966964 TI - Brain Activation During Singing: "Clef de Sol Activation" Is the "Concert" of the Human Brain. AB - Humans are the most complex singers in nature, and the human voice is thought by many to be the most beautiful musical instrument. Aside from spoken language, singing represents a second mode of acoustic communication in humans. The purpose of this review article is to explore the functional anatomy of the "singing" brain. Methodologically, the existing literature regarding activation of the human brain during singing was carefully reviewed, with emphasis on the anatomic localization of such activation. Relevant human studies are mainly neuroimaging studies, namely functional magnetic resonance imaging and positron emission tomography studies. Singing necessitates activation of several cortical, subcortical, cerebellar, and brainstem areas, served and coordinated by multiple neural networks. Functionally vital cortical areas of the frontal, parietal, and temporal lobes bilaterally participate in the brain's activation process during singing, confirming the latter's role in human communication. Perisylvian cortical activity of the right hemisphere seems to be the most crucial component of this activation. This also explains why aphasic patients due to left hemispheric lesions are able to sing but not speak the same words. The term clef de sol activation is proposed for this crucial perisylvian cortical activation due to the clef de sol shape of the topographical distribution of these cortical areas around the sylvian fissure. Further research is needed to explore the connectivity and sequence of how the human brain activates to sing. PMID- 26966965 TI - Raynaud's Phenomenon in a Slap Bass Player: A Case Report. AB - OBJECTIVE: Secondary Raynaud's phenomenon is a frequent condition related to occupational exposure to local vibration but has not been described in musicians. This study aims to describe cold-induced blanching of the right second and (in particular) third digits in a 67-year-old double bass player following decades of cumulative repetitive blunt trauma to the fingers from slapping the strings. METHODS: A physical examination was undertaken and systolic blood pressure measured before and after cold provocation. RESULTS: At 10 deg C the brachial systolic blood pressure was 156 mm Hg while blood pressure was immeasurable at the finger level, corresponding to a finger/brachial index of 0% of the second and third fingers. CONCLUSION: This is the first reported case of objectively verified, playing-related Raynaud's phenomenon in a musician. PMID- 26966966 TI - Risk Factors for Musculoskeletal Disorders in Musicians. PMID- 26966968 TI - Reporting mental health problems of undocumented migrants in Greece: A qualitative exploration. AB - BACKGROUND: Mental health problems are highly prevalent amongst undocumented migrants (UMs), and often part of their consultations with general practitioners (GPs). Little empirical data are available of how GPs and UMs engage around mental health in Greece, a country with a lack of balance between primary and secondary care and limited healthcare provisions for UMs. OBJECTIVES: To acquire insight in the barriers and levers in the provision of mental healthcare for UMs by GPs in Greece. METHODS: This was a qualitative study using semi-structured interviews with 12 GPs in Crete, Greece with clinical expertise in the care of UMs. All interviews were audio-taped and transcribed verbatim and were analysed using thematic content analysis. RESULTS: Greek GPs recognized many mental health problems in UMs and identified the barriers that prevented them from discussing these problems and delivering appropriate care: growing societal resistance towards UMs, budget cuts in healthcare, administrative obstacles and lack of support from the healthcare system. To overcome these barriers, Greek GPs provided UMs with free access to care and psychotropic drugs free of charge, and referred to other primary care professionals rather than to mental healthcare institutions. CONCLUSION: Greek GPs experienced substantial barriers in the provision of mental healthcare to UMs and political, economic and organizational factors played a major role. PMID- 26966969 TI - Research and Development of High-performance Explosives. AB - Developmental testing of high explosives for military applications involves small scale formulation, safety testing, and finally detonation performance tests to verify theoretical calculations. small-scale For newly developed formulations, the process begins with small-scale mixes, thermal testing, and impact and friction sensitivity. Only then do subsequent larger scale formulations proceed to detonation testing, which will be covered in this paper. Recent advances in characterization techniques have led to unparalleled precision in the characterization of early-time evolution of detonations. The new technique of photo-Doppler velocimetry (PDV) for the measurement of detonation pressure and velocity will be shared and compared with traditional fiber-optic detonation velocity and plate-dent calculation of detonation pressure. In particular, the role of aluminum in explosive formulations will be discussed. Recent developments led to the development of explosive formulations that result in reaction of aluminum very early in the detonation product expansion. This enhanced reaction leads to changes in the detonation velocity and pressure due to reaction of the aluminum with oxygen in the expanding gas products. PMID- 26966970 TI - Cognitive Patient Education for Low Back Pain in Primary Care: A Cluster Randomized Controlled Trial and Cost-Effectiveness Analysis. AB - STUDY DESIGN: A pragmatic cluster randomized controlled trial in primary care. OBJECTIVE: The aim of this study was to estimate the clinical effectiveness and cost-effectiveness of a cognitive-based education program on patients with subacute or chronic low back pain (LBP) in primary care, compared to usual treatment, provided by general practitioners (GP) and physiotherapists (PT). SUMMARY OF BACKGROUND DATA: Patient education has been reported to have a favorable effect on patients with chronic musculoskeletal disorders. In this study, an "Explain Pain" model was adapted to fit into an ordinary clinical setting in Norwegian primary care. METHODS: Sixteen GPs and 20 PTs participated in the study and a total of 216 patients were recruited. The GPs and PTs were randomly assigned to provide either a cognitive patient education or usual treatment. All patients in both groups were provided with four consultations of 30 min with their provider during the study. In the intervention group the patients were educated according to a specific manual written for the purpose of this study. RESULTS: Eighty-one percent responded at 4-week, and 68% at the 12 month follow-up. There was a substantial improvement in function, pain, and sick leave in both groups. After 4 weeks the intervention group scored 0.51 RMDQ points lower than the control group (Beta -0.506 [95% CI -1.76-0.75]). After 12 months the intervention group scored 0.66 RMDQ points higher than the control group (Beta 0.66 [95% CI -0.56-1.88]). There was no significant difference in QALYs in the two treatment groups; the estimated difference was 0.005 (-0.016 0.027) in favor of the intervention. CONCLUSION: This study showed no clinical or health economic benefits as a result of adding a cognitive education program to usual treatment for patients with subacute and chronic LBP. Potential weaknesses such as a long recruiting period and potentially low compliance with the cognitive intervention warrant a careful interpretation of the results. PMID- 26966971 TI - Comparison of 1-Level Versus 2-Level Anterior Cervical Discectomy and Fusion: Clinical and Radiographic Follow-Up at 60 Months. AB - STUDY DESIGN: This study represents a posthoc analysis of data collected from 2 control arms of a prospective, randomized study. OBJECTIVE: The purpose of this study was to compare results of patients undergoing 1- versus 2-level anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: For single level ACDF, reported outcomes have generally been good; however, results for 2 levels have been less consistent. METHODS: This 60-month follow-up study was based on data from the prospective Food and Drug Administration regulated Mobi-C artificial disc trial. Serving as the control, ACDF was performed at 1 level in 81 patients and 2 levels in 105 patients. Study selection criteria, fusion technique, and outcome measures were identical, with the only exception being the number of levels that were pathological and operated. RESULTS: Neck Disability Index (NDI) scores, visual analog scales assessing neck and arm pain, and SF-12 scores improved significantly in both groups. Significant differences were observed between groups on NDI and SF-12 PCS scores through 60 months. Fusion rates were 93.3% in the 1-level group and 86.1% in the 2-level (60 months, not significantly different). Adjacent segment degeneration occurred in 54.7% of patients at the superior level and 44.7% at the inferior segment in the 1-level group and 70.8%, and 55.0% respectively in 2-level patients (trend at superior level; 0.05 < P < 0.10). Subsequent index level surgery was performed in 11.1% of single-level patients versus 16.2% of the 2-level group (not significantly different). CONCLUSION: One- and 2-level ACDF groups improved significantly and maintained improvement throughout 60 month follow-up. When comparing groups, outcomes were often similar, though the 1-level group demonstrated higher fusion rates at 6 and 12 months, greater improvement in NDI scores from 18 to 60-month follow-up, and greater improvement in SF-12 PCS from 12 to 60 months. PMID- 26966973 TI - National Trends in the Surgical Management of Adult Lumbar Isthmic Spondylolisthesis: 1998 to 2011. AB - STUDY DESIGN: A retrospective review. OBJECTIVE: Isthmic spondylolisthesis (ISY) is a common orthopedic condition. Our objective was to identify trends in the surgical management of adult ISY in the United States and to evaluate trends in the surgical techniques utilized. SUMMARY OF BACKGROUND DATA: Various surgical approaches have been described for ISY but preferred trends are not known. METHODS: Using the Nationwide Inpatient Sample (NIS), 47,132 adult patients (>= 18 years) with ISY undergoing lumbar spine fusion from 1998 to 2011 were identified. Our primary outcome of interest was the national trend in use of anterior (ASF), posterior (PSF), posterior with interbody (P/TLIF), and combined anterior-posterior fusion (A/PSF) surgeries for ISY patients. Poisson regression, modified Wald's test, and linear and logistic regression analysis with P < 0.05 were used for statistical analysis. RESULTS: The annual rate of fusion surgeries for ISY increased 4.33 times-from 28.31 surgeries in 1998 to 122.69 surgeries per million US adults per year in 2011. Over the study period, annual rates of ASFs increased 2.65 times (P < 0.001), PSFs increased 1.03 times (P = 0.24), P/TLIFs increased 4.33 times (P < 0.001), and A/PSF increased 2.93 times (P < 0.001). In 2010 to 2011, the complication rate was significantly higher for A/PSF (18.86%, P < 0.001). PSFs had a higher complication rate of 3.61% and P/TLIFs (2.58%). The risk of complications was lower for females, elective admissions, and in hospitals in the South. Mean hospitalization charges adjusted to 2011 dollars were significantly higher for A/PSF ($157,560; 95% CI [95% confidence interval]: 14,480-170,360; P < .001), followed by P/TLIFs ($103,700; 95% CI: 9840-109,030) and PSFs had lower mean hospitalization charges ($87,420; 95% CI: 8210-92,770). CONCLUSION: Use of fusion for ISY has significantly increased and interbody fusion has become the most preferred approach over the study period. Hospital charges and complications were highest for combined anterior-posterior fusions. PMID- 26966972 TI - Exploration of the Intraoperative Motor Evoked Potential. AB - STUDY DESIGN: Prospective study. OBJECTIVE: The objectives of the study was to (1) seek a relation between motor evoked potential (MEP) and corresponding cervical cord function in cervical compression myelopathy (CCM) and (2) explore a high-sensitive MEP range that can predict the intraoperative monitoring change ahead in cervical spine surgery. SUMMARY OF BACKGROUND DATA: There have been lots of controversies concerning the application of transcranial MEP in cervical spine surgery. METHODS: We prospectively investigate 86 consecutive patients with CCM who underwent posterior laminoplasty or laminectomy from December 2012 to September 2014. The 18-point modified Japanese Orthopedic Association (mJOA) score and intraoperative MEP were used for neurological and electrophysiological assessment. Statistical correlation analysis and curve fitting were used to definite the relationship between MEP and corresponding cervical cord function. And a novel concept of high-sensitive MEP range was firstly addressed for predicting the intraoperative monitoring change ahead in CCM. RESULTS: Our results showed that the preoperative mJOA score of lower extremity presented a significant correlation with MEP parameters in CCM, and the correlation was expressed in an exponential relationship. The monitoring change in CCM often appeared at a high-sensitive MEP range (amplitude <159 MUV or latency >36.1 ms). In addition, the high-sensitive MEP ranges not only included MEP degeneration but also a larger number of MEP improvement cases. CONCLUSION: Intraoperative MEP may imply an exponential correlation with the corresponding cervical cord function in CCM. And we first characterize a high-sensitive MEP range which may indicate high risk for the impending monitoring change during cervical cord decompression and we must watch more closely. PMID- 26966974 TI - Implant Failure of Titanium Versus Cobalt-Chromium Growing Rods in Early-onset Scoliosis. AB - STUDY DESIGN: Retrospective case series of one institute database. OBJECTIVE: To investigate the differences in the metallic strength of rods used for implant failure in the dual growing rod technique and evaluate clinical outcomes. SUMMARY OF BACKGROUND DATA: The dual growing rod technique in which implanted rods extend with the growth of the spine is a useful treatment for early onset scoliosis. However, many complications, particularly those associated with rods, exist. Especially, the implant failure of growing rod focused on metallic strength is unknown. METHODS: Thirteen patients (42 lengthening surgeries) who underwent surgery by this technique at our hospital from 2007 were divided into a titanium rod plus titanium connector group (T group, n = 4, 26 lengthening surgeries) and cobalt-chromium rod plus titanium connection group (C group, n = 9, 16 lengthening surgeries). The incidence of implant failure and the site of fracture were retrospectively investigated. RESULTS: Implant failure occurred in three patients in the T group, because of rod fracture in two patients and connector fracture in one. In the C group, implant failure occurred in six patients, because of rod fracture in one patient and connector fracture in seven. Fracture occurred twice in two patients. The rod fracture rate decreased with the use of cobalt-chromium rods but the rate of connector fracture increased. We performed a stress distribution analysis using the finite element method to clarify the mechanisms underlying implant failure in both groups. Regardless of the rod type, the greater load was placed on the distal rod. However, differences in the metallic strength caused the rod to fracture when titanium rods were used and connectors (weak metallic strength) to fracture when cobalt-chromium rods were used. CONCLUSION: Rod fractures occurred more commonly with titanium rods and connector fractures with cobalt-chromium rods. PMID- 26966975 TI - Variation in Costs of Spinal Implants in United States Academic Medical Centers. AB - STUDY DESIGN: Retrospective study of benchmarking database. OBJECTIVE: To evaluate the variability in direct costs of spinal implants across various academic medical centers, determining variability between and within specific manufacturers, and to measure the relationship between purchasing volume and price. SUMMARY OF BACKGROUND DATA: Spinal implants are a significant component of the cost of surgery. There is an absence of transparency of how much various medical centers in the United States pay for implants because of the use of nondisclosure agreements as part of price negotiations. Transparency of information on costs and awareness of costs by physicians will be useful in managing costs in a value-based health care economy. METHODS: Purchasing records of 45 academic medical centers over a 12-month period were examined. Purchasing volume and unit pricing for pedicle screws (PS), anterior cervical plates (ACP), and transforaminal lumbar interbody fusion (TLIF) cages were collected for 6 manufacturers. Overall variation in implant costs across centers and for each manufacturer was determined as was the relationship between purchasing volume and unit price. RESULTS: We found variation in implant costs between medical centers, and between manufacturers for PS, ACP and TLIF similar to joint replacement implants. Regression analysis showed that for each 10-fold increase in purchasing volume, the unit price decreased by $126 for PS, $242 for ACP, and $789 for TLIF. CONCLUSION: There was variation in implant costs between medical centers and manufacturers of implants, with a small negative relationship between purchasing volume and cost. Transparency in cost negotiation, surgeon awareness of costs and alignment between surgeon and hospital goals may help decrease the cost of spinal implants, and the cost of care for patients undergoing instrumented fusions. PMID- 26966976 TI - Development of a Competence-Based Spine Surgery Fellowship Curriculum Set of Learning Objectives in Canada. AB - STUDY DESIGN: Modified-Delphi expert consensus method. OBJECTIVE: The aim of this study was to develop competence-based spine fellowship curricula as a set of learning goals through expert consensus methodology in order to provide an educational tool for surgical educators and trainees. Secondarily, we aimed to determine potential differences among specialties in their rating of learning objectives to defined curriculum documents. SUMMARY OF BACKGROUND DATA: There has been recent interest in competence-based education in the training of future surgeons. Current spine fellowships often work on a preceptor-based model, and recent studies have demonstrated that graduating spine fellows may not necessarily be exposed to key cognitive and procedural competencies throughout their training that are expected of a practicing spine surgeon. METHODS: A consensus group of 32 spine surgeons from across Canada was assembled. A modified Delphi approach refined an initial fellowship-level curriculum set of learning objectives (108 cognitive and 84 procedural competencies obtained from open sources). A consensus threshold of 70% was chosen with up to 5 rounds of blinded voting performed. Members were asked to ratify objectives into either a general comprehensive or focused/advanced curriculum. RESULTS: Twenty-eight of 32 consultants (88%) responded and participated in voting rounds. Seventy-eight (72%) cognitive and 63 (75%) procedural competency objectives reached 70% consensus in the first round. This increased to 82 cognitive and 73 procedural objectives by round 4. The final curriculum document evolved to include a general comprehensive curriculum (91 cognitive and 53 procedural objectives), a focused/advanced curriculum (22 procedural objectives), and a pediatrics curriculum (22 cognitive and 9 procedural objectives). CONCLUSION: Through a consensus-building approach, the study authors have developed a competence-based curriculum set of learning objectives anticipated to be of educational value to spine surgery fellowship educators and trainees. To our knowledge, this is one of the first nationally based efforts of its kind that is also anticipated to be of interest by international colleagues. PMID- 26966977 TI - Rate of Unsuspected Malignancy in Patients With Vertebral Compression Fracture Undergoing Percutaneous Vertebroplasty. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To determine the malignancy rate and histology in bone biopsies obtained during PVP for VCF. SUMMARY OF BACKGROUND DATA: Osteoporotic vertebral compression fractures (VCF) affect approximately 20% of postmenopausal women and can lead to long-term disability. Percutaneous vertebroplasty (PVP) is a minimally invasive procedure, primarily used in patients with severe pain after VCF. Even with a thorough clinical examination, magnetic resonance imaging (MRI) scans, and blood samples, some fractures maybe caused by an underlying malignant disease. METHODS: 144 consecutive patients underwent PVP for painful VCF, at the Center for Spine Surgery and Research, Middelfart Hospital. All patients had bone biopsies obtained during the PVP, and these biopsies were sent to the Department for Pathology at Vejle Sygehus for histologic diagnosis. RESULTS: About 144 patients were included in this study. The majority of the biopsy specimens (137, 95.1%) were acceptable for histological diagnosis. One hundred and twenty nine (89.6%) biopsies showed no signs of malignancy. Seven (4.9 %) were positive for malignancy. One biopsy was positive for MGUS. Seven (4.9 %) of the biopsies were unsuitable for histologic diagnosis. CONCLUSION: Our study shows an incidence of unsuspected malignancy in biopsies during PVP of 4.9%. Conservative treatment with analgesics and brace can potentially delay diagnosis and treatment of underlying malignant disease. We recommend biopsy during PVP as a standard procedure, to insure not to overlook any underlying malignancy despite the MRI-scan, blood analysis, and clinical examination being inconspicuous. PMID- 26966978 TI - Retraction. Prospective, randomized, controlled trial of silicate-substituted calcium phosphate versus rhBMP-2 in a minimally invasive transforaminal lumbar interbody fusion. Spine (Phila Pa 1976) 2014. 39(3): 185-191. Nandyala, Sreeharsha V.; Marquez-Lara, Alejandro; Fineberg, Steven J.; Pelton, Miguel; Singh, Kern. PMID- 26966979 TI - Dopamine D1 Receptor Agonist A-68930 Inhibits NLRP3 Inflammasome Activation, Controls Inflammation, and Alleviates Histopathology in a Rat Model of Spinal Cord Injury. AB - STUDY DESIGN: A randomized experimental study. OBJECTIVE: The aim of this study was to investigate the therapeutic efficacy and molecular mechanisms of dopamine D1 receptor agonist A-68930 in spinal cord injury (SCI) rats. SUMMARY OF BACKGROUND DATA: The inflammation induced by SCI includes maturation and secretion of pro-inflammatory cytokines interleukin (IL)-1beta and IL-18 mediated by nucleotide-binding domain -like receptor protein 3 (NLRP3) inflammasome. Dopamine D1 receptor agonist A-68930 has been reported to exert neuroprotective effect via suppressing NLRP3 inflammasome activation in some central nervous injury models. However, whether A-68930 can exert nueroprotection in rat SCI models through inhibition of NLRP3 inflammasome activation has yet to be investigated. METHODS: Eighty female Sprague-Dawley rats were randomly divided into 4 groups: sham group, SCI group, SCI + Vehicle (Veh) group, SCI + A-68930 group. The influences of A-68930 on the proinflammatory cytokines levels, histological changes, and locomotion scale were estimated. RESULTS: SCI significantly promoted NLRP3 inflammasome activation and increased proinflammatory cytokines productions in SCI group as compared with sham group. A 68930 administration significantly inhibited NLRP3 inflammasome activation and reduced inflammatory cytokines levels. Moreover, A-68930 administration attenuated histopathology and promoted locomotion recovery. CONCLUSION: A-68930 can attenuate tissue damage and improve neurological function recovery, and the mechanism may be related to the inhibition of NLRP3 inflammasome activation. PMID- 26966980 TI - Primary Epidural Lumbar Ewing Sarcoma: Case Report and Review of the Literature. AB - STUDY DESIGN: Case report. OBJECTIVE: We present a case of isolated primary epidural lumbar Ewing sarcoma and review the current literature on the standard management. We also propose laminoplasty as safe procedure in this patient population that can provide good stabilization in young people. SUMMARY OF BACKGROUND DATA: Primary epidural Ewing's sarcoma is a very rare entity. The best generally accepted treatment option in sarcomas is to achieve a gross total resection with safe margins followed by local radiotherapy and chemotherapy. A total resection with safe margins is a great challenge in neurosurgical patients. METHODS: We present a previously healthy 17-year-old girl who complained of right sciatica with an epidural lumbar mass at L3-L4. She underwent complete resection of the tumor and a laminoplasty, which, in our experience, is a good way to preserve stability. RESULTS: At surgery, an isolated and noninvasive lesion was identified. Histopathological confirmation of Ewing sarcoma was obtained by immunohistochemical study and EWSR1 gene rearrangement detection. Treatment with 6 months of chemotherapy resulted in no further identifiable lesions by PET and MRI imaging at 4 years postsurgery. The laminoplasty has remained stable. CONCLUSION: Primary epidural Ewing sarcoma is extremely rare. The detection of the EWSR1 gene rearrangement can help to diagnose these tumors. The decision on how to treat these patients is difficult and can hardly be based on data from the current literature because of the small number of patients. The laminoplasty procedure can be safely performed in the setting of sarcoma of the epidural space. PMID- 26966981 TI - Anticholinergics: theoretical and clinical overview. AB - INTRODUCTION: Anticholinergics are a class of medicines that block the neurotransmitter, acetylcholine, in the brain and peripheral tissues. Medicines with anticholinergic activity are widely prescribed for and used by older people for various medical conditions. One-third to one-half of the medicines commonly prescribed for older people have anticholinergic activity. Several studies have reported anticholinergic burden to be a predictor of cognitive and functional impairments in older people. AREAS COVERED: This article exemplifies the theoretical and clinical aspects of medicines with anticholinergic activity, including pharmacology (definition of medicines that possess anticholinergic activity, antimuscarinic receptors, therapeutic and adverse effects), epidemiology, measures and effects of cumulative anticholinergic burden in older adults, and clinical recommendations. In addition, the gaps in the literature have been identified for future research. EXPERT OPINION: Many medicines that are commonly prescribed to older people have a degree of anticholinergic activity that can contribute to anticholinergic burden. Anticholinergic burden, measured in several ways that consider number, dose and/or degree of anticholinergic activity of medicines, has shown to be a predictor of adverse health and functional outcomes. The anticholinergic burden on older people should be minimised by avoiding, reducing dose and deprescribing medicines with anticholinergic activity where clinically possible. PMID- 26966982 TI - Teaching Tip: Developing an Intercollegiate Twitter Forum to Improve Student Exam Study and Digital Professionalism. AB - #VetFinals has been developed as a novel online Twitter teaching event designed to support intercollegiate veterinary teaching using social media. Previous studies in other fields have suggested that Twitter use within universities may have benefits for undergraduate education. This "teaching tip" paper describes a project using Twitter to host online exam study sessions. The project has been a highly successful collaborative effort between the Royal Veterinary College and Nottingham Veterinary School in the UK. Over 4 years, the #VetFinals project has developed into a long-term, self-sustaining enterprise. This initiative provides a semi-structured means for student exam preparation with direct real-time input from a faculty member. It also creates a network of peers both horizontally across institutions and vertically throughout year groups. Based on similar initiatives in other disciplines, an anticipated outcome of this project was to contribute to student online professionalism. This could help address the veterinary community's recently highlighted problems with professional conduct and appropriate use of social media. Analysis of the success of this endeavor will be available in a future publication. PMID- 26966983 TI - The Impact of a Group Communication Course on Veterinary Medical Students' Perceptions of Communication Competence and Communication Apprehension. AB - This paper explores the impact of a group communication course on veterinary medical students' perceptions of communication competence and communication anxiety. Students enrolled in the Group Communication in Veterinary Medicine course completed the Personal Report of Communication Apprehension and the Communicative Competence Scale at the beginning (Time 1) and end (Time 2) of the semester. Results show that first-year veterinary students' self-perceptions of communication competence increased and their self-reported levels of communication apprehension decreased across multiple contexts from Time 1 to Time 2. This research provides support for experiential communication training fostering skill development and confidence. PMID- 26966984 TI - Novel Card Games for Learning Radiographic Image Quality and Urologic Imaging in Veterinary Medicine. AB - Second-year veterinary students are often challenged by concepts in veterinary radiology, including the fundamentals of image quality and generation of differential lists. Four card games were developed to provide veterinary students with a supplemental means of learning about radiographic image quality and differential diagnoses in urogenital imaging. Students played these games and completed assessments of their subject knowledge before and after playing. The hypothesis was that playing each game would improve students' understanding of the topic area. For each game, students who played the game performed better on the post-test than students who did not play that game (all p<.01). For three of the four games, students who played each respective game demonstrated significant improvement in scores between the pre-test and the post-test (p<.002). The majority of students expressed that the games were both helpful and enjoyable. Educationally focused games can help students learn classroom and laboratory material. However, game design is important, as the game using the most passive learning process also demonstrated the weakest results. In addition, based on participants' comments, the games were very useful in improving student engagement in the learning process. Thus, use of games in the classroom and laboratory setting seems to benefit the learning process. PMID- 26966985 TI - Evaluation of a Communication Skills Training Program for Companion-Animal Veterinarians: A Pilot Study Using RIAS Coding. AB - Effective veterinarian communication skills training and the related key outcomes provided the impetus for this study. We implemented a pre-experimental pre test/post-test single-group design with a sample of 13 veterinarians and their 71 clients to evaluate the effects of a 6.5-hour communication skills intervention for veterinarians. Consultations were audiotaped and analyzed with the Roter Interaction Analysis System (RIAS). Clients completed the Consultation and Relational Care Measure, a global satisfaction scale, a Parent Medical Interview Satisfaction Scale, and the Adherence Intent measure. Veterinarians completed a communication confidence measure and a workshop satisfaction scale. Contrary to expectation, neither veterinarian communication skills nor their confidence improved post-training. Despite client satisfaction and perceptions of veterinarians' relational communication skills not increasing, clients nevertheless reported an increased intent to adhere to veterinarian recommendations. This result is important because client adherence is critical to managing and enhancing the health and well-being of animals. The results of the study suggest that while the workshop was highly regarded, either the duration of the training or practice opportunities were insufficient or a booster session was required to increase veterinarian confidence and integration of new skills. Future research should utilize a randomized control study design to investigate the appropriate intervention with which to achieve change in veterinarian communication skills. Such change could translate to more effective interactions in veterinarians' daily lives. PMID- 26966986 TI - Structural integrity of frontostriatal connections predicts longitudinal changes in self-esteem. AB - Diverse neurological and psychiatric conditions are marked by a diminished sense of positive self-regard, and reductions in self-esteem are associated with risk for these disorders. Recent evidence has shown that the connectivity of frontostriatal circuitry reflects individual differences in self-esteem. However, it remains an open question as to whether the integrity of these connections can predict self-esteem changes over larger timescales. Using diffusion magnetic resonance imaging and probabilistic tractography, we demonstrate that the integrity of white matter pathways linking the medial prefrontal cortex to the ventral striatum predicts changes in self-esteem 8 months after initial scanning in a sample of 30 young adults. Individuals with greater integrity of this pathway during the scanning session at Time 1 showed increased levels of self esteem at follow-up, whereas individuals with lower integrity showed stifled or decreased levels of self-esteem. These results provide evidence that frontostriatal white matter integrity predicts the trajectory of self-esteem development in early adulthood, which may contribute to blunted levels of positive self-regard seen in multiple psychiatric conditions, including depression and anxiety. PMID- 26966987 TI - Deacetylation Assays to Unravel the Interplay between Sirtuins (SIRT2) and Specific Protein-substrates. AB - Acetylation has emerged as an important post-translational modification (PTM) regulating a plethora of cellular processes and functions. This is further supported by recent findings in high-resolution mass spectrometry based proteomics showing that many new proteins and sites within these proteins can be acetylated. However the identity of the enzymes regulating these proteins and sites is often unknown. Among these enzymes, sirtuins, which belong to the class III histone lysine deacetylases, have attracted great interest as enzymes regulating the acetylome under different physiological or pathophysiological conditions. Here we describe methods to link SIRT2, the cytoplasmic sirtuin, with its substrates including both in vitro and in vivo deacetylation assays. These assays can be applied in studies focused on other members of the sirtuin family to unravel the specific role of sirtuins and are necessary in order to establish the regulatory interplay of specific deacetylases with their substrates as a first step to better understand the role of protein acetylation. Furthermore, such assays can be used to distinguish functional acetylation sites on a protein from what may be non-regulatory acetylated lysines, as well as to examine the interplay between a deacetylase and its substrate in a physiological context. PMID- 26966988 TI - Characterization and abiotic stress-responsive expression analysis of SGT1 genes in Brassica oleracea. AB - SGT1 genes are involved in enhancing plant responses to various biotic and abiotic stresses. Brassica oleracea is known to contain two types of SGT1 genes, namely suppressor of G2 allele of SKP1 and suppressor of GCR2. In this study, through systematic analysis, four putative SGT1 genes were identified and characterized in B. oleracea. In phylogenetic analysis, the genes clearly formed separate groups, namely BolSGT1a, BolSGT1b (both suppressor of G2 allele of SKP1 types), and BolSGT1 (suppressor of GCR2). Functional domain analysis and organ specific expression patterns suggested possible roles for BolSGT1 genes during stress conditions. BolSGT1 genes showed significant changes in expression in response to heat, cold, drought, salt, or ABA treatment. Interaction network analysis supported the expression analysis, and showed that the BolSGT1a and BolSGT1b genes are strongly associated with co-regulators during stress conditions. However, the BolSGT1 gene did not show any strong association. Hence, BolSGT1 might be a stress resistance-related gene that functions without a co regulator. Our results show that BolSGT1 genes are potential target genes to improve B. oleracea resistance to abiotic stresses such as heat, cold, and salt. PMID- 26966989 TI - In Vitro Mean Red Blood Cell Volume Change Induced by Diode Pump Solid State Low Level Laser of 405 nm. AB - OBJECTIVE: This study was conducted to investigate the effects of low-level laser (LLL) doses on human red blood cell volume. The effects of exposure to a diode pump solid state (DPSS) (lambda = 405 nm) laser were observed. BACKGROUND DATA: The response of human blood to LLL irradiation gives important information about the mechanism of interaction of laser light with living organisms. Materials and methods Blood samples were collected into ethylenediaminetetraacetic acid (EDTA) containing tubes, and each sample was divided into two equal aliquots, one to serve as control and the other for irradiation. The aliquot was subjected to laser irradiation for 20, 30, 40, or 50 min at a fixed power density of 0.03 W/cm(2). Mean cell volume (MCV) and red blood cell (RBC) counts were measured immediately after irradiation using a computerized hemtoanalyzer. RESULTS: Significant decrease in RBC volume (p < 0.05, p < 0.0001, p < 0.0001, and p < 0.05, respectively) was induced with variation in laser doses.The highest response was observed with an exposure time of 40 min. This result was reproduced in RBCs suspended in a buffered NaCl solution. In contrast to this finding, laser induced RBC volume change was completely abolished by suspending RBCs in a solution containing a higher concentration of EDTA. CONCLUSIONS: It was suggested that LLL can reduce RBC volume possibly because of the increased free intracellular Ca(+2) concentrations, which activate Ca(+2)-dependent K(+) channels with consequent K(+) ion efflux and cell shrinkage. PMID- 26966993 TI - Identification of a Human Toll-Like Receptor (TLR) 8-Specific Agonist and a Functional Pan-TLR Inhibitor in 2-Aminoimidazoles. AB - Activation of human toll-like receptor-8 (TLR8), expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells, evokes a distinct cytokine profile which favors the development of Type 1 helper T cells. Part structures of the 2-aminobenzimidazole scaffold were examined with a view to identifying structural requisites corresponding to the smallest possible fragment of the benzimidazole core that would allow for retention of TLR8-agonistic activity. TLR8-specific agonistic activity was retained in 1-pentyl-4-phenyl-1H imidazol-2-amine. The crystal structure of this compound bound to the TLR8 ectodomain displayed binding interactions that are common to other TLR8 agonists. This compound showed markedly attenuated proinflammatory properties in ex vivo human blood models. SAR studies revealed that 4-(2-(benzyloxy)phenyl)-1-pentyl-1H imidazol-2-amine inhibited TLR signaling in a variety of TLR reporter cell lines, as well as in pharmacologically relevant human blood model systems. A kinase screen of this compound showed relative specificity for calmodulin kinases. PMID- 26966994 TI - 'Struggling to be the alpha': sources of tension and intimate partner violence in same-sex relationships between men. AB - In countries such as the USA, gay and bisexual men experience high rates of intimate partner violence. However, little is known about the factors that contribute to this form of violence. In this study, we examine gay and bisexual men's perceptions of sources of tension in same-sex male relationships and how these may contribute to intimate partner violence. We conducted seven focus-group discussions with 64 gay and bisexual men in Atlanta, GA. Focus groups examined men's reactions to the short-form revised Conflicts Tactics Scale to determine if each item was considered to be intimate partner violence if it were to occur among gay and bisexual men. Analysts completed a thematic analysis, using elements of grounded theory. The sources of tension that men identified included: gender role conflict, dyadic inequalities (e.g. differences in income, age, education), differences in 'outness' about sexual identity, substance use, jealousy and external homophobic violence. Results suggest that intimate partner violence interventions for gay and bisexual men should address behavioural factors, while also focusing on structural interventions. Interventions that aim to reduce homophobic stigma and redefine male gender roles may help to address some of the tension that contributes to intimate partner violence in same-sex male relationships. PMID- 26966996 TI - Advances in immobilized artificial membrane (IAM) chromatography for novel drug discovery. AB - INTRODUCTION: The development of immobilized artificial membrane (IAM) chromatography has unfolded new perspectives for the use of chromatographic techniques in drug discovery, combining simulation of the environment of cell membranes with rapid measurements. AREAS COVERED: The present review describes the characteristics of phosphatidylcholine-based stationary phases and analyses the molecular factors governing IAM retention in comparison to n-octanol-water and liposomes partitioning systems as well as to reversed phase chromatography. Other biomimetic stationary phases are also briefly discussed. The potential of IAM chromatography to model permeability through the main physiological barriers and drug membrane interactions is outlined. Further applications to calculate complex pharmacokinetic properties, related to tissue binding, and to screen drug candidates for phospholipidosis, as well as to estimate cell accumulation/retention are surveyed. EXPERT OPINION: The ambivalent nature of IAM chromatography, as a border case between passive diffusion and binding, defines its multiple potential applications. However, despite its successful performance in many permeability and drug-membrane interactions studies, IAM chromatography is still used as a supportive and not a stand-alone technique. Further studies looking at IAM chromatography in different biological processes are still required if this technique is to have a more focused and consistent application in drug discovery. PMID- 26966995 TI - In Situ Characterization of Hydrated Proteins in Water by SALVI and ToF-SIMS. AB - This work demonstrates in situ characterization of protein biomolecules in the aqueous solution using the System for Analysis at the Liquid Vacuum Interface (SALVI) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). The fibronectin protein film was immobilized on the silicon nitride (SiN) membrane that forms the SALVI detection area. During ToF-SIMS analysis, three modes of analysis were conducted including high spatial resolution mass spectrometry, two dimensional (2D) imaging, and depth profiling. Mass spectra were acquired in both positive and negative modes. Deionized water was also analyzed as a reference sample. Our results show that the fibronectin film in water has more distinct and stronger water cluster peaks compared to water alone. Characteristic peaks of amino acid fragments are also observable in the hydrated protein ToF-SIMS spectra. These results illustrate that protein molecule adsorption on a surface can be studied dynamically using SALVI and ToF-SIMS in the liquid environment for the first time. PMID- 26966997 TI - Effects of C-xylopyranoside derivative on epithelial regeneration in an in vitro 3D oral mucosa model. AB - Identifying substandard tissue-engineered oral mucosa grafts with a poor epithelium before clinical use is critical to ensure quality assurance/control in regenerative medicine, leading to success of grafting. This study investigated the effects of one of the C-xylopyranoside derivatives, beta-D-xylopyranoside-n propane-2-one (XPP), on oral epithelial regeneration. Using a three-dimensional oral mucosa model, we analyzed changes of the epithelial structure, glycosaminoglycan (GAG) synthesis, the expression levels of basement membrane zone markers, and substrates of Akt/mTOR signaling. Compared with the control, 2 mM XPP treatment increased the mean and minimal epithelial thickness, and reduced the variation of epithelial thickness. It also stimulated expressions of decorin and syndecan-1 with change of GAG amount and/or composition, and enhanced the expressions of integrin alpha6, CD44, and Akt/mTOR signaling substrates. These findings suggest that XPP supplementation contributes to consistent epithelial regeneration. Moreover, upregulation of those markers may play a role in increasing the quality of the oral mucosal epithelium. PMID- 26966998 TI - Detailed investigation of ROS arisen from chlorophyll a/Chitosan based-biofilm. AB - The aim of this work is to study the nature of reactive oxygen species, ROS, arisen from Chitosan/2-HP-beta-Cyclodextrin/Chlorophyll a (CH/CD/Chla) blended biofilm under a photodynamic activity. Suitable molecules, called primary acceptors, able to react selectively with ROS, in turn generated by the photosensitizer (PS), herein Chla, are used to attempt this purpose. The changes of the absorption and the emission spectra of these acceptors after the irradiation of aqueous solution containing the active biofilm have provided the specific nature of ROS and thus the main pathway of reaction followed by PS, in our condition. The (1)O2 formation was unveiled using Uric Acid (UA) and 9,10 diphenilanthracene (DPA). On the other hand, 2,7- dichlorofluorescin and Ferricytochrome c (Cyt-c) were used to detect the formation of hydrogen peroxide and superoxide radical anion, respectively. Results suggest that among the possible pathways of reaction, namely Type I and Type II, potentially followed by PSs, in our condition the hybrid biofilm CH/CD/Chla follows mainly Type II mechanism with the formation of (1)O2. However, the latter is involved in subsequent pathway of reaction involving Chla inducing, in addition, the formation of O2(-) and H2O2. PMID- 26966999 TI - Effective delivery of immunosuppressive drug molecules by silica coated iron oxide nanoparticles. AB - Iron oxide nanoparticles have been used in a wide range of biomedical applications, including drug delivery, molecular imaging, and cellular imaging. Various surface modifications have been applied to the particles to stabilize their surface and to give them a moiety for anchoring tags and/or drug molecules. Conventional methods of delivering immunosuppressant drugs often require a high dose of drugs to ensure therapeutic effects, but this can lead to toxic side effects. In this study, we used silica-coated iron oxide nanoparticles (IOSs) for a drug delivery application in which the nanoparticles carry the minimum amount of drug required to be effective to the target cells. IOSs could be loaded with water-insoluble immunosuppressive drug molecules (MPA: mycophenolic acid) and be used as a contrast agent for MRI. We characterized the IOSs for their physicochemical properties and found their average hydrodynamic diameter and core size to be 40.5nm and 5nm, respectively. Following the introduction of MPA-loaded IOSs (IOS/M), we evaluated the secretion dynamics of cytokines from peripheral blood mononuclear cells stimulated with phytohemagglutinin (PHA). The results showed that IOS/M effectively inhibited the secretion of the cytokines interleukin-2 and tumor necrosis factor alpha, with a minimal concentration of MPA. In conclusion, IOS/M may have potential applications in both efficient drug delivery and MRI. PMID- 26967000 TI - Glycoside hydrolase family 13 alpha-glucosidases encoded by Bifidobacterium breve UCC2003; A comparative analysis of function, structure and phylogeny. AB - Bifidobacterium breve is a noted inhabitant and one of the first colonizers of the human gastro intestinal tract (GIT). The ability of this bacterium to persist in the GIT is reflected by the abundance of carbohydrate-active enzymes that are encoded by its genome. One such family of enzymes is represented by the alpha glucosidases, of which three, Agl1, Agl2 and MelD, have previously been identified and characterized in the prototype B. breve strain UCC2003. In this report, we describe an additional B. breve UCC2003-encoded alpha-glucosidase, along with a B. breve UCC2003-encoded alpha-glucosidase-like protein, designated here as Agl3 and Agl4, respectively, which together with the three previously described enzymes belong to glycoside hydrolase (GH) family 13. Agl3 was shown to exhibit hydrolytic specificity towards the alpha-(1->6) linkage present in palatinose; the alpha-(1->3) linkage present in turanose; the alpha-(1->4) linkages found in maltotriose and maltose; and to a lesser degree, the alpha-(1 >2) linkage found in sucrose and kojibiose; and the alpha-(1->5) linkage found in leucrose. Surprisingly, based on the substrates analyzed, Agl4 did not exhibit biologically relevant alpha-glucosidic activity. With the presence of four functionally active GH13 alpha-glucosidases, B. breve UCC2003 is capable of hydrolyzing all alpha-glucosidic linkages that can be expected in glycan substrates in the lower GIT. This abundance of alpha-glucosidases provides B. breve UCC2003 with an adaptive ability and metabolic versatility befitting the transient nature of growth substrates in the GIT. PMID- 26967002 TI - Effects of transport distance, lairage time and stunning efficiency on cortisol, glucose, HSPA1A and how they relate with meat quality in cattle. AB - This study determined the effects of distance travelled, lairage duration and number of stunning shots on the plasma levels of bovine heat shock protein 70 (HSPA1A), cortisol (CORT) and glucose (GLU) and their relationship with beef quality. There were positive correlations among HSPA1A, GLU, CORT, a*, b* and the HUE angle. Animals that were stunned more than once had the highest HSPA1A (13.61+/-2.874ng/ml) and CORT (109.36+/-8.373nmol/L) levels. Animals that travelled for 200<400km had lower HSPA1A expression (8.29+/-2.026ng/ml) than those that were transported for 400<800km (12.11+/-2.548ng/ml) and <200km (17.32+/-2.362ng/ml). Lairage duration affected (P<0.05) the expression of HSPA1A, GLU and CORT levels. Animals stunned more than once had elevated CORT and HSPA1A levels. HSPA1A, CORT and GLU were related to beef quality. Stunning of animals more than once increased the levels of blood CORT and HSPA1A. PMID- 26967001 TI - Experimental Approaches to Study Mitochondrial Localization and Function of a Nuclear Cell Cycle Kinase, Cdk1. AB - Although mitochondria possess their own transcriptional machinery, merely 1% of mitochondrial proteins are synthesized inside the organelle. The nuclear-encoded proteins are transported into mitochondria guided by their mitochondria targeting sequences (MTS); however, a majority of mitochondrial localized proteins lack an identifiable MTS. Nevertheless, the fact that MTS can instruct proteins to go into the mitochondria provides a valuable tool for studying mitochondrial functions of normally nuclear and/or cytoplasmic proteins. We have recently identified the cell cycle kinase CyclinB1/Cdk1 complex in the mitochondria. To specifically study the mitochondrial functions of this complex, mitochondrial overexpression and knock-down of this complex without interfering with its nuclear or cytoplasmic functions were essential. By tagging CyclinB1/Cdk1 with MTS, we were able to achieve mitochondrial overexpression of this complex to study its mitochondrial targets as well as functions. Via tagging dominant negative Cdk1 with MTS, inhibition of Cdk1 activity was accomplished particularly in the mitochondria. Potential mitochondrial targets of CyclinB1/Cdk1 complex were identified using a gel-based proteomics approach. Unlike traditional 2D gel analysis, we employed 2-dimensional difference gel electrophoresis (2D-DIGE) technology followed by phosphoprotein staining to fluorescently label differentially phosphorylated proteins in mitochondrial Cdk1 expressing cells. Identification of phosphoprotein spots that were altered in wild type versus dominant negative Cdk1 bearing mitochondria revealed the identity of mitochondrial targets of Cdk1. Finally, to determine the effect of CyclinB1/Cdk1 mitochondrial localization in cell cycle progression, a cell proliferation assay using a synthetic thymidine analogue EdU (5-ethynyl-2'-deoxyuridine) was used to monitor the cells as they go through the cell cycle and replicate their DNA. Altogether, we demonstrated a variety of approaches available to study mitochondrial localization and activity of a cell cycle kinase. These are advanced, yet easy to follow methods that will be beneficial to many cell biology researchers. PMID- 26967003 TI - Early signaling, synthesis, transport and metabolism of ureides. AB - The symbiosis between alpha nitrogen (N2)-fixing Proteobacteria (family Rhizobiaceae) and legumes belonging to the Fabaceae (a single phylogenetic group comprising three subfamilies: Caesalpinioideae, Mimosoideae and Papilionoideae) results in the formation of a novel root structure called a nodule, where atmospheric N2 is fixed into NH3(+). In the determinate type of nodules harbored by Rhizobium-nodulated Fabaceae species, newly synthesized NH3(+) is finally converted into allantoin (C4H6N4O3) and allantoic acid (C4H8N4O4) (ureides) through complex pathways involving at least 20 different enzymes that act synchronously in two types of nodule cells with contrasting ultrastructure, including the tree nodule cell organelles. Newly synthesized ureides are loaded into the network of nodule-root xylem vessels and transported to aerial organs by the transpirational water current. Once inside the leaves, ureides undergo an enzymatically driven reverse process to yield NH4(+) that is used for growth. This supports the role of ureides as key nitrogen (N)-compounds for the growth and yield of legumes nodulated by Rhizobium that grow in soils with a low N content. Thus, a concrete understanding of the mechanisms underlying ureide biogenesis and catabolism in legumes may help agrobiologists to achieve greater agricultural discoveries. In this review we focus on the transmembranal and transorganellar symplastic and apoplastic movement of N-precursors within the nodules, as well as on the occurrence, localization and properties of enzymes and genes involved in the biogenesis and catabolism of ureides. The synthesis and transport of ureides are not unique events in Rhizobium-nodulated N2-fixing legumes. Thus, a brief description of the synthesis and catabolism of ureides in non-legumes was included for comparison. The establishment of the symbiosis, nodule organogenesis and the plant's control of nodule number, synthesis and translocation of ureides via feed-back inhibition mechanisms are also reviewed. PMID- 26967004 TI - Growth of Arabidopsis thaliana and Eutrema salsugineum in a closed growing system designed for quantification of plant water use. AB - The identification of genetic determinants for water-use efficiency (WUE) and their incorporation into crop plants is critical as world water resources are predicted to become less stable over the coming decades. However, quantification of WUE in small model species such as Arabidopsis is difficult because of low plant water loss relative to root zone evaporation. Furthermore, measurements of long-term WUE are labor-intensive and time-consuming. A novel high-throughput closed-container growing system for measuring plant WUE is described. The system eliminates nearly all water loss from the media and does not require irrigation throughout the duration of a typical experiment. Using the model species Arabidopsis thaliana and Eutrema salsugineum, it was confirmed that under growth chamber conditions, this system: (1) eliminates the need for irrigation for as much as 30 days with media water content remaining above 80% full capacity; (2) allows for quantification of WUE in plants with a leaf area as small as ca. 20 cm(2); (3) does not inhibit plant growth; and (4) does not alter media conditions outside of an acceptable range for these species. The growing system provides an efficient high-throughput system for quantifying plant water loss and WUE. PMID- 26967005 TI - Association Between Oral Fluoroquinolone Use and Retinal Detachment. AB - IMPORTANCE: Several studies have focused on the current use of oral fluoroquinolones and the risk for retinal detachment (RD), but the existence of this association is under debate. Given the widespread fluoroquinolone use, investigation of this association is essential. OBJECTIVE: To assess the association between oral fluoroquinolone use and the risk for RD, including the rhegmatogenous and exudative types. DESIGN, SETTING, AND PARTICIPANTS: This case crossover study included 27,540 adults with RD from French health care databases from July 1, 2010, through December 31, 2013. Patients with a history of RD or retinal break, endophthalmitis, intravitreal injection, choroidal retinal vitreal biopsy, and human immunodeficiency virus infection or those hospitalized within 6 months of RD were excluded. The risk period of primary interest was current use, defined as exposure to fluoroquinolones within 10 days immediately before RD surgery, according to previous findings. Oral fluoroquinolone use was assumed to start on the day the prescription was dispensed. MAIN OUTCOMES AND MEASURES: Exposure to fluoroquinolones during the risk period (1-10 days) compared with the control period (61-180 days). The association was also assessed regarding use in the recent (11-30 days) and past (31-60 days) intermediate risk period, type of fluoroquinolone, and type of RD. RESULTS: Of the 27,540 eligible patients (57% men; mean [SD] age, 61.5 [13.6] years), 663 patients with RD were exposed to fluoroquinolones during the observation period, corresponding to 80 cases exposed during the 10-day risk period (<=10 days before RD) and 583 cases exposed during the control period (61-180 days). We found a significant increased risk for RD during the 10-day period after the dispensing of oral fluoroquinolones, with an adjusted odds ratio of 1.46 (95% CI, 1.15-1.87). The risk was significantly increased for rhegmatogenous and exudative RD, with adjusted odds ratios of 1.41 (95% CI, 1.04-1.92) and 2.57 (95% CI, 1.46-4.53), respectively. Recent and past use of fluoroquinolones were not associated with a higher risk for RD, with adjusted odds ratios of 0.94 (95% CI, 0.78-1.14) and 1.06 (95% CI, 0.91-1.24), respectively. CONCLUSIONS AND RELEVANCE: Current oral fluoroquinolone use was associated with an increased risk for RD, including the rhegmatogenous and exudative types. These findings, along with the available literature, suggest an association between fluoroquinolone use and the risk for RD. The nature of this association should be further investigated in future studies. PMID- 26967006 TI - Luteolin rescues pentylenetetrazole-induced cognitive impairment in epileptic rats by reducing oxidative stress and activating PKA/CREB/BDNF signaling. AB - Most antiepileptic drugs (AEDs) interfere with cognitive function, and there is therefore an urgent need for AEDs that are effective but do not have this side effect. Various studies have reported the antiinflammatory and cytoprotective properties of the natural flavonoid luteolin (LU); however, none has examined systematically its antiseizure potential. The current study investigated the effects of LU on pentylenetetrazole (PTZ)-induced cognitive impairment in rats and the underlying mechanisms. Seizures were induced in rats by daily injection of PTZ for 36 days. Two other groups were pretreated with LU (50 or 100 mg/kg/day by oral administration) 30 min prior to PTZ administration. Seizure severity was scored, and cognitive function was tested in the Morris water maze. Neuronal damage, mitochondrial generation of reactive oxygen species, oxidative stress, phosphoactivation of the protein kinase A (PKA)-cyclic AMP response element binding protein (CREB) pathway, and brain-derived neurotrophic factor (BDNF) expression were measured in the hippocampus. Pretreatment with LU suppressed seizure induction, duration, and severity following PTZ injection, reversed cognitive impairment, reduced neuronal and oxidative stress damage, and increased phosphoactivation of PKA and CREB as well as BDNF expression. These results indicate that LU should be further investigated as a treatment for epilepsy. PMID- 26967008 TI - Investigation of Postoperative Oral Fluid Intake as a Predictor of Postoperative Emergency Department Visits After Pediatric Tonsillectomy. AB - IMPORTANCE: This study contributes novel data on the association between oral fluid intake before discharge and adverse outcomes following tonsillectomy in pediatric patients. These data contribute to evidence-based, safe, and cost effective decision making regarding discharge. OBJECTIVE: To determine whether the quantity of oral fluid intake before discharge is associated with adverse outcomes following tonsillectomy in pediatric patients. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort analysis was conducted using the electronic medical records of 1183 pediatric patients undergoing tonsillectomy between September 24, 2012, and June 5, 2015, at a tertiary care academic medical center. Exclusion criteria included age 18 years or older, overnight admission, and missing data on fluid intake. The final cohort comprised 473 patients. Data analysis was conducted from July 8 to August 23, 2015. EXPOSURES: All patients underwent tonsillectomy by 1 of 7 attending surgeons at our institution. All patients were given intravenous fluids and analgesia in the postanesthesia care unit before being admitted to the pediatric inpatient floor for monitoring before discharge. MAIN OUTCOMES AND MEASURES: The primary outcome measured was presentation to the emergency department within 2 weeks after tonsillectomy with a related complication. We also recorded hospital readmissions and returns to the operating room for related complications. The primary diagnosis was noted for each complication. RESULTS: Among 473 patients (235 male; mean [SD] age, 7.2 [3.5] years), oral fluid intake after tonsillectomy ranged from 0.7 to 66.7 mL/kg, with a mean (SD) intake of 18.2 (10.8) mL/kg. Mean (SD) time to discharge was 6.96 (1.91) hours (range, 1.68-14.25 hours). Overall, 31 patients (6.6%) presented to the emergency department for a related complication after tonsillectomy. No correlation was found between oral fluid intake after tonsillectomy and presentation to the emergency department (odds ratio, 1.03; 95% CI, 0.98-1.08; P = .29). CONCLUSIONS AND RELEVANCE: This study suggests that oral fluid intake before discharge is not predictive of presentation to the emergency department after tonsillectomy within the ranges studied and at this institution. Therefore, discharge criteria based strictly on thresholds for oral fluid intake may be unnecessary. Further study at multiple institutions using a wider range of fluid intake volumes or a large-scale randomized clinical trial is needed before conclusions can be generalized. PMID- 26967007 TI - Point-of-use water disinfection using ultraviolet and visible light-emitting diodes. AB - Improvements in point-of-use (POU) drinking water disinfection technologies for remote and regional communities are urgently needed. Conceptually, UV-C light emitting diodes (LEDs) overcome many drawbacks of low-pressure mercury tube based UV devices, and UV-A or visible light LEDs also show potential. To realistically evaluate the promise of LED disinfection, our study assessed the performance of a model 1.3 L reactor, similar in size to solar disinfection bottles. In all, 12 different commercial or semi-commercial LED arrays (270-740 nm) were compared for their ability to inactivate Escherichia coli K12 ATCC W3110 and Enterococcus faecalis ATCC 19433 over 6h. Five log10 and greater reductions were consistently achieved using the 270, 365, 385 and 405 nm arrays. The output of the 310 nm array was insufficient for useful disinfection while 430 and 455 nm performance was marginal (~ 4.2 and 2.3-log10s E. coli and E. faecalis over the 6h). No significant disinfection was observed with the 525, 590, 623, 660 and 740 nm arrays. Delays in log-phase inactivation of E. coli were observed, particularly with UV-A wavelengths. The radiation doses required for >3-log10 reduction of E. coli and E. faecalis differed by 10 fold at 270 nm but only 1.5-2.5 fold at 365 455 nm. Action spectra, consistent with the literature, were observed with both indicators. The design process revealed cost and technical constraints pertaining to LED electrical efficiency, availability and lifetime. We concluded that POU LED disinfection using existing LED technology is already technically possible. UV-C LEDs offer speed and energy demand advantages, while UV-A/violet units are safer. Both approaches still require further costing and engineering development. Our study provides data needed for such work. PMID- 26967010 TI - Coloration in different areas of facial skin is a cue to health: The role of cheek redness and periorbital luminance in health perception. AB - Looking healthy is a desirable trait, and facial skin color is a predictor of perceived health. However, skin conditions that cause dissatisfaction with appearance are specific to particular facial areas. We investigated whether color variation in facial skin is related to perceived health. Study 1 defined three areas based on color differences between faces perceived as healthy or unhealthy: the forehead, periorbital areas, and the cheeks. Periorbital luminance and cheek redness predicted perceived health, as did global skin yellowness. In Study 2, increased luminance and redness caused faces to be perceived as healthier, but only when the increase was in the periorbital and cheek areas, respectively. Manipulating each area separately in Study 3 revealed cheek redness and periorbital luminance equally increased perceived health, with low periorbital luminance more negatively affecting perceptions. These findings show that color variation in facial skin is a cue for health perception in female faces. PMID- 26967011 TI - Corrections to: Attention allocation before antisaccades. PMID- 26967009 TI - Influenza vaccine with adjuvant on disease activity in psoriatic arthritis patients under anti-TNF-alpha therapy. AB - OBJECTIVES: To evaluate the effects on disease activity of seasonal influenza vaccination with adjuvant in psoriatic arthritis (PsA) patients in stable disease activity on anti-TNF-alpha drugs as compared to not vaccinated PsA patients adequately matched. METHODS: An observational study was conducted on a cohort of PsA patients in stable disease activity who underwent administration of an adjuvanted vaccine for seasonal influenza. Cases (Group 1) were matched for age, sex, disease activity and therapy with not vaccinated PsA patients (Group 2). Analysis included patients data before vaccination (T0), and one month (T1) and three months (T3) after administration of the vaccination for Group 1 and at correspondent intervals for Group 2. Assessment of disease activity parameters was performed at each visit. RESULTS: Twenty-five vaccinated and 25 not vaccinated patients were included in the study. As a first approach, we analysed the data within groups. At T1, as compared to baseline, the group of vaccinated patients had a statistically significant increase in TJC (tender joint count) and ESR (erythrocyte sedimentation rate). At T3, a statistically significant difference from baseline characteristics was found only for the TJC. In Group 2, all the observed variables showed no significant differences when comparing baseline to T1 and T3. Analysis of the data between groups at T1, Group 1, as compared to Group 2, showed a significant increase of TJC, ESR, HAQ (Health Assessment Questionnaire), PtGA (patient global assessment) and PhGA (physician global assessment). These findings were also confirmed when comparing the two groups at T3 for ESR and PtGA, while they were not confirmed for TJC, HAQ and PhGA. CONCLUSIONS: Influenza vaccination is clinically efficacious in PsA patients under anti-TNF-alpha therapy, but it could trigger a short-lasting exacerbation of the disease. PMID- 26967012 TI - Where are you looking? Pseudogaze in afterimages. AB - How do we know where we are looking? A frequent assumption is that the subjective experience of our direction of gaze is assigned to the location in the world that falls on our fovea. However, we find that observers can shift their subjective direction of gaze among different nonfoveal points in an afterimage. Observers were asked to look directly at different corners of a diamond-shaped afterimage. When the requested corner was 3.5 degrees in the periphery, the observer often reported that the image moved away in the direction of the attempted gaze shift. However, when the corner was at 1.75 degrees eccentricity, most reported successfully fixating at the point. Eye-tracking data revealed systematic drift during the subjective fixations on peripheral locations. For example, when observers reported looking directly at a point above the fovea, their eyes were often drifting steadily upwards. We then asked observers to make a saccade from a subjectively fixated, nonfoveal point to another point in the afterimage, 7 degrees directly below their fovea. The observers consistently reported making appropriately diagonal saccades, but the eye movement traces only occasionally followed the perceived oblique direction. These results suggest that the perceived direction of gaze can be assigned flexibly to an attended point near the fovea. This may be how the visual world acquires its stability during fixation of an object, despite the drifts and microsaccades that are normal characteristics of visual fixation. PMID- 26967013 TI - Visual continuity across saccades is influenced by expectations. AB - As we make saccades, the image on each retina is displaced, yet our visual perception is uninterrupted. This is commonly referred to as transsaccadic perceptual stability, but such a description is inadequate. Some visual objects are stable (e.g., rocks) and should be perceived as such across saccades, but other objects may move at any time (e.g., birds). Stability is probabilistic in natural scenes. Here we extend the common notion of transsaccadic visual stability to a more general, ecologically based hypothesis of transsaccadic visual continuity in which postsaccadic percepts of objects depend on expectations about their probability of movement. Subjects made a saccade to a target and reported whether it seemed displaced after the saccade. Targets had varying probabilities of movement (ranging from 0.1-0.9) that corresponded to their color (spectrum from blue to red). Performance was compared before and after subjects were told about the color-probability pairings ("uninformed" vs. "informed" conditions). Analyses focused on signal detection and psychometric threshold measures. We found that in the uninformed condition, performance was similar across color-probability pairings, but in the informed condition, response biases varied with probability of movement, and movement-detection sensitivities were higher for rarely moving targets. We conclude that subjects incorporate priors about object movement into their judgments of visual continuity across saccades. PMID- 26967014 TI - Object attributes combine additively in visual search. AB - We perceive objects as containing a variety of attributes: local features, relations between features, internal details, and global properties. But we know little about how they combine. Here, we report a remarkably simple additive rule that governs how these diverse object attributes combine in vision. The perceived dissimilarity between two objects was accurately explained as a sum of (a) spatially tuned local contour-matching processes modulated by part decomposition; (b) differences in internal details, such as texture; (c) differences in emergent attributes, such as symmetry; and (d) differences in global properties, such as orientation or overall configuration of parts. Our results elucidate an enduring question in object vision by showing that the whole object is not a sum of its parts but a sum of its many attributes. PMID- 26967015 TI - Learning and inference using complex generative models in a spatial localization task. AB - A large body of research has established that, under relatively simple task conditions, human observers integrate uncertain sensory information with learned prior knowledge in an approximately Bayes-optimal manner. However, in many natural tasks, observers must perform this sensory-plus-prior integration when the underlying generative model of the environment consists of multiple causes. Here we ask if the Bayes-optimal integration seen with simple tasks also applies to such natural tasks when the generative model is more complex, or whether observers rely instead on a less efficient set of heuristics that approximate ideal performance. Participants localized a "hidden" target whose position on a touch screen was sampled from a location-contingent bimodal generative model with different variances around each mode. Over repeated exposure to this task, participants learned the a priori locations of the target (i.e., the bimodal generative model), and integrated this learned knowledge with uncertain sensory information on a trial-by-trial basis in a manner consistent with the predictions of Bayes-optimal behavior. In particular, participants rapidly learned the locations of the two modes of the generative model, but the relative variances of the modes were learned much more slowly. Taken together, our results suggest that human performance in a more complex localization task, which requires the integration of sensory information with learned knowledge of a bimodal generative model, is consistent with the predictions of Bayes-optimal behavior, but involves a much longer time-course than in simpler tasks. PMID- 26967016 TI - MoS2-Titanium Contact Interface Reactions. AB - The formation of the Ti-MoS2 interface, which is heavily utilized in nanoelectronic device research, is studied by X-ray photoelectron spectroscopy. It is found that, if deposition under high vacuum (~1 * 10(-6) mbar) as opposed to ultrahigh vacuum (~1 * 10(-9) mbar) conditions are used, TiO2 forms at the interface rather than Ti. The high vacuum deposition results in an interface free of any detectable reaction between the semiconductor and the deposited contact. In contrast, when metallic titanium is successfully deposited by carrying out depositions in ultrahigh vacuum, the titanium reacts with MoS2 forming Ti(x)S(y) and metallic Mo at the interface. These results have far reaching implications as many prior studies assuming Ti contacts may have actually used TiO2 due to the nature of the deposition tools used. PMID- 26967017 TI - Inclusion for People with Developmental Disabilities: Measuring an Elusive Construct. AB - The philosophy of inclusion for people with intellectual and developmental disabilities (IDD) has evolved over the last 50 years. Over time, inclusion research has shifted from a focus on deinstitutionalization to understanding the extent to which individuals with IDD are meaningfully involved in the community and social relationships. Yet, there has been no agreed on way to measure inclusion. Many different measurement and data collection techniques have been used in the literature. This study proposes a brief measure of inclusion that can be used with family members and on survey instruments. PMID- 26967019 TI - Solvent Effects on Electronic Excitations of an Organic Chromophore. AB - In this work we study the solvatochromic shift of a selected low-energy excited state of alizarin in water by using a linear-scaling implementation of large scale time-dependent density functional theory (TDDFT). While alizarin, a small organic dye, is chosen as a simple example of solute-solvent interactions, the findings presented here have wider ramifications for the realistic modeling of dyes, paints, and pigment-protein complexes. We find that about 380 molecules of explicit water need to be considered in order to yield an accurate representation of the solute-solvent interaction and a reliable solvatochromic shift. By using a novel method of constraining the TDDFT excitation vector, we confirm that the origin of the slow convergence of the solvatochromic shift with system size is due to two different effects. The first factor is a strong redshift of the excitation due to an explicit delocalization of a small fraction of the electron and the hole from the alizarin onto the water, which is mainly confined to within a distance of 7 A from the alizarin molecule. The second factor can be identified as long-range electrostatic influences of water molecules beyond the 7 A region on the ground-state properties of alizarin. We also show that these electrostatic influences are not well reproduced by a QM/MM model, suggesting that full QM studies of relatively large systems may be necessary in order to obtain reliable results. PMID- 26967020 TI - Unveiling the Role of Hot Charge-Transfer States in Molecular Aggregates via Nonadiabatic Dynamics. AB - Exciton dynamics governs energy transfer and charge generation in organic functional materials. We investigate high-energy nonadiabatic excited-state dynamics for a bithiophene dimer to describe time-dependent excitonic effects in molecular aggregates. We show that the lowest excited states are populated on the subpicosecond time scale. These states are localized and unproductive in terms of charge separation. Productive high-energy charge-transfer (CT) states are populated within 50 fs during exciton deactivation, but they are short-lived (~100 fs) and quickly transfer their population to lower states. Our simulations offer molecular-level insights into ultrafast photoinduced charge separation potentially triggered by hot CT states in solid-state organic materials. Design rules are suggested to increase hot exciton lifetimes, favoring the population of CT states as gateways for direct charge generation. These rules may boost the CT quantum yield by depleting unproductive recombination channels. PMID- 26967018 TI - A game of tag: MAPS catches up on RNA interactomes. AB - In the last few decades, small regulatory RNA (sRNA) molecules emerged as key regulators in every kingdom of life. Resolving the full targetome of sRNAs has however remained a challenge. To address this, we used an in vivo tagging MS2 affinity purification protocol coupled with RNA sequencing technology, namely MAPS, to assemble full bacterial small RNAs targetomes. The impressive potential of MAPS has been supported by a number of reports. Here, we concisely overview RNA-tagging history that preceded the development of the MAPS assay and expose the range of possible uses of this technology. PMID- 26967021 TI - Calix[3]carbazole: One-Step Synthesis and Host-Guest Binding. AB - The one-step synthetic strategy for the preparation of the hitherto unknown calix[3]carbazole from readily available starting materials is described. Calix[3]carbazole is obtained in 20% yield, and it could selectively bind the N(C2H5)4(+) cation (tetraethylammonium, TEA) via cation-pi interactions. The experimental and modeling results indicate that calix[3]carbazole possesses a larger pi-cavity as well as a better chromophoric property than the traditional phenol-based macrocycles, and thus is capable of binding to and optically responding to the relatively large guest TEA. PMID- 26967022 TI - Advantages and disadvantages of discrete-event simulation for health economic analyses. PMID- 26967023 TI - Interactive Online Module Failed to Improve Sustained Knowledge of the Maryland Medical Orders for Life-Sustaining Treatment Form. AB - RATIONALE: Legal documents similar to the Maryland Medical Orders for Life Sustaining Treatment (MOLST) form requiring physician endorsement are increasingly used by critically ill patients. OBJECTIVES: To evaluate whether an interactive, online training module on completion and interpretation of the MOLST form leads to a sustained increase in knowledge among house staff. METHODS: Pre/post survey of 329 house staff at Johns Hopkins Hospital who admit and discharge patients between June 2014 and July 2015. House staff were encouraged to complete a voluntary, interactive, online educational module on completing and interpreting MOLST forms. Participants received $25 for accessing the module and $10 for completing each survey. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the change in the number of questions answered correctly on the post- versus presurvey comparing house staff who viewed the module for at least 20 minutes with house staff who never viewed or never completed the module. Overall, 329 (69%) house staff completed the knowledge assessment survey both before and after the module was available, and 201 (61%) of these house staff completed the voluntary module. The median score on the presurvey conducted in July and August of 2014 was 14 out of 21 (interquartile range [IQR] 12, 16). The median (IQR) score on the postsurvey conducted in May and June of 2015 was 15 out of 21 (13, 17). The median (IQR) change in score among those who spent at least 20 minutes completing the module was 1 question (-1, 3), and among those who never viewed or never completed the module it was also 1 (IQR -1, 2). The postsurvey was completed a median (IQR) of 59 (52, 62) days after viewing the module. After adjusting for years of postgraduate clinical training, self-reported baseline experience completing MOLST forms, and self-reported responsibility for discharging patients, viewing the module for at least 20 minutes was associated with a nonsignificant increase in score of 0.41 questions (95% confidence interval, -0.25, 1.06; P = 0.23). CONCLUSIONS: An interactive, online educational module had no effect on trainee knowledge of completing and interpreting MOLST forms approximately 2 months after completion. Information conveyed via online modules alone may have minimal sustained impact on house staff knowledge. PMID- 26967024 TI - Convertible resistive switching characteristics between memory switching and threshold switching in a single ferritin-based memristor. AB - A bio-memristor fabricated with ferritin exhibits novel resistive switching characteristics wherein memory switching and threshold switching are made steadily coexistent and inter-convertible through controlling the magnitude of compliance current presets. PMID- 26967027 TI - Association between postures and work-related musculoskeletal discomforts (WRMD) among beverage bottling workers. AB - BACKGROUND: Bottling tasks postures may increase risk for developing work related musculoskeletal discomforts (WRMDs). Postural evaluation with epidemiological investigation for possible association may be appropriate for planning ergonomic programs. OBJECTIVE: To evaluate working postures and investigate associations between postural risks and prevalence of WRMDs among beverage bottling workers. METHOD: 301 beverage bottling company workers (8 work-stations) participated in this survey. They were required to complete a modified standard Nordic questionnaire, and their working postures examined utilizing Rapid Entire Body Assessment (REBA). RESULTS: Postural risks ratings were high (8- 10) to very high (11- 15). Shoulder was the most commonly reported body part with WRMDs except at the carbonating workstations where Neck, Upper and Lower back discomforts were the most common (60.0%). The compounding workstations recorded the highest prevalence of WRMDs in all body regions except shoulder and wrist. There was a significant association between working posture and occurrence of WRMDs in at least one body part. Similarly, working posture was significantly associated with WRMDs at Neck, Upper back and Wrist. CONCLUSIONS: Working postures may be exposing beverage bottling workers to significant risk of developing WRMDs in at least one body part, more specifically, Shoulder, Neck, Upper back and Wrist. Intervention aimed at reducing postural risks is necessary. PMID- 26967028 TI - Best practice intervention for post-traumatic stress disorder among transit workers. AB - BACKGROUND: Transportation industry workers are at high risk for exposure to traumatic incidents in the workplace. A considerable number of those exposed to such incidents will develop post-traumatic stress disorder (PTSD) symptoms, which leads to high rates of absenteeism and are costly to the public transit corporation and workplace safety compensation insurance. OBJECTIVE: To determine whether the newly implemented Best Practice Intervention (BPI) provides superior outcomeswhen compared with Treatment-as-Usual (TAU) interventions in improving workers' rates of return to work (RTW), decreasing duration of time lost from work and overall reduction in severity of PTSD symptoms 6 months after exposure. METHODS: A sequential mixed methods approach was used with qualitative analysis followed by a pre-post intervention design. Sixty-two participants were recruited to the (TAU) phase of the study and 79 to the (BPI) phase. RESULTS: Significant differences were observed between the TAU and BPI groups in number of lost work days (TAU: 20 days vs. BPI: 52 days, p = 0.02). PTSD symptoms decreased with time (MPPS score: 51.3 vs. 24.35; p < 0.001). One-fifth of the participants (21 %) did not return to work by the end of the 6 months follow-up period. CONCLUSIONS: The study demonstrated the value of workplace interventions in improving awareness of psychological symptoms after exposure to a traumatic incident and the value of screening for PTSD symptoms. PMID- 26967029 TI - Facilitators and barriers to doing workplace mental health research: Case study of acute psychological trauma in a public transit system. AB - The Acute Psychological Trauma (APT) Study was a collaboration between an acute care hospital, a specialized multidisciplinary program designed to meet the mental health needs of injured workers, and a large urban public transit system. The overall purpose was to evaluate a Best Practices Intervention (BPI) for employees affected by acute psychological trauma compared to a Treatment as Usual (TAU) group. The specific purpose is to discuss facilitators and barriers that were recognized in implementing and carrying out mental health research in a workplace setting. Over the course of the APT study, a joint implementation committee was responsible for day-to-day study operations and made regular observations on the facilitators and barriers that arose throughout the study. The facilitators to this study included the longstanding relationships among the partners, increased recognition for the need of mental health research in the workplace, and the existence of a community advisory committee. The significant barriers to doing this study of mental health research in the workplace included differences in organizational culture, inconsistent union support, co interventions, and stigma. Researchers and funding agencies need to be flexible and provide additional resources in order to overcome the barriers that can exist doing workplace mental health research. PMID- 26967026 TI - Assessment of the Mitigative Capacity of Dietary Zinc on PCB126 Hepatotoxicity and the Contribution of Zinc to Toxicity. AB - Hepatic levels of the essential micronutrient, zinc, are diminished by several hepatotoxicants, and the dietary supplementation of zinc has proven protective in those cases. 3,3',4,4',5-Pentachlorobiphenyl (PCB126), a liver toxicant, alters hepatic nutrient homeostasis and lowers hepatic zinc levels. The current study was designed to determine the mitigative potential of dietary zinc in the toxicity associated with PCB126 and the role of zinc in that toxicity. Male Sprague-Dawley rats were divided into three dietary groups and fed diets deficient in zinc (7 ppm Zn), adequate in zinc (30 ppm Zn), and supplemented in zinc (300 ppm). The animals were maintained for 3 weeks on these diets, then given a single IP injection of vehicle or 1 or 5 MUmol/kg PCB126. After 2 weeks, the animals were euthanized. Dietary zinc increased the level of ROS, the activity of CuZnSOD, and the expression of metallothionein but decreased the levels of hepatic manganese. PCB126 exposed rats exhibited classic signs of exposure, including hepatomegaly, increased hepatic lipids, increased ROS and CYP induction. Liver histology suggests some mild ameliorative properties of both zinc deficiency and zinc supplementation. Other metrics of toxicity (relative liver and thymus weights, hepatic lipids, and hepatic ROS) did not support this trend. Interestingly, the zinc supplemented high dose PCB126 group had mildly improved histology and less efficacious induction of investigated genes than did the low dose PCB126 group. Overall, decreases in zinc caused by PCB126 likely contribute little to the ongoing toxicity, and the mitigative/preventive capacity of zinc against PCB126 exposure seems limited. PMID- 26967030 TI - Hiring people with disabilities: A scoping review. AB - BACKGROUND: Many people with disabilities continue to encounter challenges trying to secure employment. OBJECTIVE: The purpose of this study was to synthesize existent knowledge about the hiring process for people with disabilities and explore research priorities from the perspective of key stakeholders. METHODS: A scoping review of the literature related to hiring processes and practices as they relate to people with disabilities was undertaken. As part of the scoping review, seven key informant consultations were conducted in order to gain further insight into the key issues identified by those most involved in the hiring process for people with disabilities. RESULTS: Findings from the literature and consultations revolve around seven inter-related topics: 1) regulationsversus practice, 2) stigma, 3) disclosure, 4) accommodations, 5) relationship building and use of disability organizations,6) information and support to employers, and 7) hiring practices that invite people with disabilities. CONCLUSIONS: Although barriers to employment for people with disabilities have been examined in the literature, there remains a paucity of literature examining and evaluating strategies to improve hiring practices and employment opportunities for people with disabilities. Future research must occur in consultation with key stakeholders including employers, people with disabilities, and employment support workers. PMID- 26967031 TI - Firefighters' cardiovascular health and fitness: An observation of adaptations that occur during firefighter training academies. AB - BACKGROUND: Firefighters' cardiovascular fitness remains a foremost concern among fire departments and organizations, yet very little research has been conducted to examine the cardiovascular fitness adaptations that occur during firefighter training academies. OBJECTIVE: To describe the cardiovascular adaptations observed among firefighter recruits during firefighter training academies using measures of estimated maximal oxygen uptake (VO2max) and heart rate recovery (DeltaHR). METHODS: Firefighter recruits (n = 41) enrolled in a 16-week firefighter training academy completed a 5-minute step test during the first, eighth, and sixteenth week of training. Repeated measures analysis of variance (RM ANOVA) calculations were conducted to determine changes in estimated VO2max and DeltaHR. RESULTS: Results of the RM ANOVA calculations revealed that mean estimated VO2max and mean DeltaHR differed significantly between time points: F(2, 80) = 75.525, p < 0.001, and F(2, 80) = 4.368, p = 0.016, respectively. No significant changes were observed in mean estimated VO2max and mean DeltaHR beyond the eighth week of training. No significant relationship was identified between estimated VO2max and DeltaHR. CONCLUSIONS: Although firefighter recruits' estimated VO2max and DeltaHR change significantly over the course of the firefighter training academy, the measures may not be equal predictors of cardiovascular fitness. PMID- 26967032 TI - An examination of retention factors among registered nurses in Northeastern Ontario, Canada: Nurses intent to stay in their current position. AB - BACKGROUND: The purpose of the study was to examine factors related to the retention of registered nurses in northeastern Ontario, Canada. OBJECTIVE/METHOD: A cross-sectional survey of registered nurses working in northeastern Ontario, Canada was conducted. Logistic regression analyses were used to consider intent to stay in current employment in relation to the following: 1) demographic factors, and 2) occupation and career satisfaction factors. RESULTS: A total of 459 (29.8% response rate) questionnaires were completed. The adjusted odds logistic regression analysis of RNs who intended to remain in their current position for the next five years, demonstrated that respondents in the 46 to 56 age group (OR: 2.65; 95% CI: 1.50 to 4.69), the importance of staff development in the organization (OR: 3.04; 95% CI: 1.13 to 8.13) northeastern Ontario lifestyle (OR: 2.61; 95% CI: 1.55 to 4.40), working in nursing for 14 to 22.5 years (OR: 2.55; 95% CI: 1.10 to 5.93), and working between 0 to 1 hour of overtime per week (OR: 1.20; 95% CI: 1.20 to 4.64) were significant factors in staying in their current position for the next five years. CONCLUSIONS: This study shows that a further understanding of the work environment could assist with developing retention for rural nurses. Furthermore, employers may use such information to ameliorate the working conditions of nurses, while researchers may use such evidence to develop interventions that are applicable to improving the working conditions of nurses. PMID- 26967033 TI - Validity and reliability of Persian version of the Specific Nordic questionnaire in Iranian industrial workers. AB - BACKGROUND: Nordic is one of the most popular questionnaires for evaluating Work related Musculoskeletal Disorders (WMSDs), but no studies have been reported on the reliability and validity of this questionnaire in Iran. OBJECTIVE: The aim of this study was translation, cross-cultural adaptation and validation of the Persian version of the Specific Nordic questionnaire (SNQ), and evaluation of the reliability of this questionnaire for the assessment of WMSDs in Iranian industrial workers. METHODS: The SNQ was completed by 122 Iranian industrial workers with lumbar or knee musculoskeletal disorders to assess the reliability and construct validity. The validity was assessed by knee injury and Osteoarthritis Outcome Score (KOOS) and Oswestry Disability Index (ODI) questionnaires. Reliability was assessed by a test-retest procedure for 60 patients with 7-days interval. RESULTS: There was significant positive correlation between KSNQ and KOOS pain (r = 0.71, p < 0.05) and the KSNQ and KOOS QOL (r = 0.72, p < 0.05). There was High Pearson correlation between LSNQ and ODI (r = 0.77, p < 0.05). Both lumbar and knee SNQ had a high Kappa coefficient correlation (0.83-1 for KSNQ and 0.63-1 for LSNQ). CONCLUSIONS: The Persian version of the SNQ is a reliable and valid instrument to be used for the assessment of WMSDs in Iranian industrial workers. PMID- 26967035 TI - Feeling well by being together: Study of Swedish auditors. AB - BACKGROUND: As guardians of the public interest, auditors represent a unique occupational group. The group that has shown to experience high level of stress and overload is often being associated with environmentally imposed responsibility as well as organizationally imposed performance demands. It is the latter aspects, represented by the concept of organizational culture, that is being highlighted in this paper and its relationship to auditor's well-being OBJECTIVES: The paper aims to explore organizational culture as an antecedent of auditors' well-being, which is assumed to have important consequences for the quality of auditors' work. METHODS: This study is based on a survey of 207 Swedish auditors. Using established and validated instruments measuring aspects of organizational culture and personal well-being, the study employed correlations and multiple regression analysis in testing the relationship between the two. RESULTS: The results of the study suggest that an increasing degree of collectivistic organizational culture has a positive relationship with three aspects of well-being: Job satisfaction, life balance and life satisfaction. CONCLUSIONS: This study is the first attempt to explore well-being of auditors and its antecedents represented by organizational culture. Contrary to the expectation that auditors take an individualistic approach to their work, this study establishes that auditors feel best in a work environment characterized by a collectivist organizational culture. PMID- 26967034 TI - The Bahasa Melayu version of Cornell Musculoskeletal Discomfort Questionnaire (CMDQ): Reliability and validity study in Malaysia. AB - BACKGROUND: The Cornell Musculoskeletal Discomfort Questionnaire (CMDQ) was developed to assess the level of musculoskeletal discomfort among office workers related to their ergonomic situation. OBJECTIVE: The primary objective of this initial study is to analyze the validity and dependability of the Malay translation of the Cornell Musculoskeletal Discomfort Questionnaire. METHODS: The questionnaire was self-administered two times, with an interval of two weeks in order to evaluate the accuracy of the original findings with a retest. The study involved 115 participants. RESULTS: The range of Cronbach Alpha coefficient showed a considerable consistency of the items for each sub-scale (Cronbach's a > 0.95). The range of Kappa coefficients was between (ICC = 0.690-0.949, p < 0.001), (ICC = 0.801-0.979, p < 0.001) and (ICC = 0.778-0.944, p < 0.001) for frequency, severity and interference scales. CONCLUSIONS: This research, introduced the Malay-language version of the CMDQ (CMDQ-M) as the first formal validation of the CMDQ, and confirmed a high reliability and validity for the evaluation of musculoskeletal discomfort among the study population. PMID- 26967036 TI - Organizational identification moderates the impact of organizational justice on job satisfaction. AB - BACKGROUND: Few studies concern the moderator effect of organizational identification between organizational justice and job satisfaction. OBJECTIVE: This study aimed to examine the trilateral relationship among organizational identification, organizational justice and job satisfaction, especially focus on the moderator effect of organizational identification. METHODS: 354 staffs completed the measures of organizational justice, organizational identification and job satisfaction. RESULTS: Hierarchical regression analysis showed that organizational identification moderated the association between organizational justice and job satisfaction. When staffs reported a low level of organizational identification, those with high organizational justice reported higher scores in job satisfaction than those with low organizational justice. However, the impact of organizational justice on job satisfaction was not significant in high organizational identification group. CONCLUSIONS: Organizational identification can significantly moderate the impact of organizational justice on job satisfaction. The significance and limitations of the results are discussed. PMID- 26967037 TI - Perceived safety management practices in the logistics sector. AB - BACKGROUND: Malaysia's progress on logistics has been slowed to keep pace with its growth in trade. The Government has been pressing companies to improve the safety of their activities in order to reduce society's loss due to occupational accidents and illnesses. Occupational safety and health is a crucial part of a workplace because every worker has to take care of his/her own safety and health. The main occupational safety and health (OSH) national policy in Malaysia is the enactment of the Occupational Safety and Health Act (OSHA) 1994. Only those companies which have excellent health and safety care have good quality and productive employees. This study investigated safety management practices in the logistics sector. OBJECTIVES: The present study is concerned with the human factors to safety in the logistics industry. The authors examined the perceived safety management practices of workers in the logistics sector. The purpose was to identify the perception of safety management practices of Malaysian logistics personnel. METHODS: Survey questionnaires were distributed to assess logistics personnel about management commitment. The quantitative method using the availability sampling method was applied. The data gathered from the survey were analysed using SPSS software. The responses to the survey were rated according to the Likert scale type, with '1' indicating strongly disagree and '5' indicating strongly agree. One hundred and three employees of logistics functions completed the survey. RESULTS: The highest mean scores were found for fire apparatus, prioritisation of safety, and safety policy. CONCLUSIONS: The results from this study also emphasise the importance of the management's commitment in enhancing workplace safety. Specifically, companies should maintain good relations between the employer and the employee to help reduce workplace injuries. PMID- 26967039 TI - From the Editor. PMID- 26967038 TI - Exploration of the associations of touch-screen tablet computer usage and musculoskeletal discomfort. AB - BACKGROUND: Tablet users may be at high risk of developing physical discomfort because of their usage behaviors and tablet design. OBJECTIVE: Investigate the usage of tablets, variations in head and neck posture associated with different tablet tilt angles, and the association of tablet use with users' musculoskeletal discomfort. METHODS: A survey of users' subjective perceptions conducted by questionnaire and measurements of users' postures by a 3D Motion analysis system was used to explore the effects of tablet use. RESULTS: The questionnaire results indicated that over half of the participants reported physical discomfort after using tablets, with the most prevalent discomfort in the neck and shoulders, and more intensity of discomfort for the back although only few participants experienced it. Chi-squared tests indicated that significantly more participants who tended to use tablet computers to play games reported having musculoskeletal discomfort after using a tablet. In addition, preferences for tablet tilt angles varied across tasks (reading and game playing). The results from the 3D motion analysis revealed that head and neck flexion angles were significantly reduced when the tablets were positioned at relatively steep tilt angles. Neck flexion angle was significantly higher in game playing. CONCLUSIONS: These data add information regarding to the usage of tablet and its associations with physical discomfort (significantly more participants who tended to use tablet computers to play games reported having musculoskeletal discomfort after using a tablet). Steep tilt angles (such as 60 degrees ) may cause tablet users to decrease their head and neck flexion angles, which could lead to a more neutral, effortless, and ergonomically correct posture. Maintaining proper neck posture during active activities such as game playing is recommended to avoid neck discomfort. PMID- 26967041 TI - Work ability index among healthcare personnel in a university hospital in Tehran, Iran. AB - BACKGOUND: Work ability is an important issue from a social point of view, as it is essential for workers health and welfare. OBJECTIVE: This study aimed to determine work ability among healthcare personnel and to investigate its relationship with demographic and lifestyle-related factors. METHODS: Data were collected using the Work Ability Index (WAI) questionnaire among 517 personnel of a hospital in Tehran, Iran. RSULTS: Findings showed a mean WAI of 40.3 (+/-5.2) for the study population. Work ability was significantly lower in the older personnel and higher for men. A significant correlation was observed between BMI and exercise activity and WAI score. Moreover, employees with experience of less than five years had significant higher work ability than those with 16-20 years of service. CONCLUSIONS: Considering the young study population, it seems the mean WAI is not as desirable. The use of lifestyle promoting programs, besides workplace interventions, can be an effective strategy to increase work ability among healthcare workers. PMID- 26967040 TI - A practical tool to improve outcomes in Work Injury Management. AB - BACKGROUND: Psychosocial factors have the greatest influence on work rehabilitation outcomes yet effective and efficient systems to manage these factors are not widely utilized in Work Injury Management. OBJECTIVE: To report on the development and validation of a comprehensive assessment tool with practical utility in identifying and measuring the biopsychosocial factors which are barriers to return to work and community. METHODS: Literature search identified many instruments designed to identify the presence of psychosocial factors impacting recovery and return to work following musculoskeletal injury. This research aimed to match assessment with intervention. In clinical practice over a 5 year period, this led to development of a composite questionnaire, the Abilita Rehabilitation Index, which was trialed with 43 adults participating in Occupational Rehabilitation. The validation data are based on the results of 957 case records of Occupational Rehabilitation participants. RESULTS: Examination of Cronbach coefficient alpha of the instrument indicates strong internal consistency (0.90) and factor analysis supports satisfactory construct validity of the domains (subscales) with factor loading scores ranging from 0.73 to 0.90. CONCLUSION: There is evidence that the proprietary Abilita Rehabilitation Index is a valid and reliable instrument to identify and measure the influence of psychosocial factors impacting an individual's recovery and return to work. Automated reports generated from this tool provide an evidence-based resource to identify risk and support rehabilitation planning in Work Injury Management. PMID- 26967042 TI - A comparison of carpal tunnel syndrome between digital and paper textbook users in elementary schools. AB - BACKGROUND: There are advantages to using digital textbooks, but also health concerns yet to be evaluated. OBJECTIVE: This study examines the use of digital textbooks' effects on carpal tunnel, considered one of the potential health risks in students using digital textbooks. METHODS: Data were obtained from 43 elementary school students in the sixth grade, selected from two groups who had used digital and paper textbooks, respectively. To assess carpal tunnel function, this study performed median motor nerve and median sensory nerve conduction studies. RESULTS: There were no statistically significant differences between the groups, indicating that there were no functional differences related to carpal tunnel syndrome between the groups. CONCLUSION: Usage of digital textbook is expanding nationwide in the Republic of Korea. There is no short-term risk of carpal tunnel syndrome in this population of elementary school students. PMID- 26967043 TI - Ergonomics evaluation of user-hand tool interaction. AB - BACKGROUND: An in-depth evaluation of user hand tool interaction aids to derive strenuous areas for redesigning. OBJECTIVE: In this paper, we examined user perception about the hand tool features and derived features that exert an influence on human system. This nature of study aids to reduce the risk and enhance the comfort. METHODS: Workers from six occupational groups participated in the study. Ergonomic checkpoints pertaining tool features and a general health questionnaire that included musculoskeletal discomforts, stress symptoms and general health complaints were administered to check user's interaction with hand tools. RESULTS: Risk estimates identified varied factors such as weight of tool, improperly designed handle and sharp edges associated with workers risk to pain in upper extremities, anxiety and injury. The workers' response indicated that handle redesign and protection against sharp-edged tools are crucial for improving comfort. CONCLUSION: The study aims to provide an approach to examine the characteristics of tools for redesign and increase user's comfort and safety. PMID- 26967044 TI - A Robust Luminescent Tb(III)-MOF with Lewis Basic Pyridyl Sites for the Highly Sensitive Detection of Metal Ions and Small Molecules. AB - A new luminescent terbium-metal-organic framework [Tb3(L)2(HCOO)(H2O)5].DMF.4H2O (1) (H4L = 4,4'-(pyridine-3,5-diyl)diisophthalic acid) has been successfully assembled by Tb(3+) ions and an undeveloped pyridyl-tetracarboxylate. Compound 1 exhibits a 3D porous (3,8)-connected (4.5(2))2(4(2).5(12).6(6).7(5).8(3)) topological framework with fascinating 1D open hydrophilic channels decorated by uncoordinated Lewis basic pyridyl nitrogen atoms. In particular, the Tb-MOF (1) can detect Cu(2+) ions with high selectivity and sensitivity, and its luminescence is nearly entirely quenched in N,N-dimethylformamide (DMF) solution and biological system. In addition, 1 still has high detection for the trace content of nitromethane with 70 ppm, which suggests that 1 is a promising example of dual functional materials with sensing copper ions and nitromethane. PMID- 26967045 TI - Measuring Cardiac Autonomic Nervous System (ANS) Activity in Toddlers - Resting and Developmental Challenges. AB - The autonomic nervous system (ANS) consists of two branches, the parasympathetic and sympathetic nervous systems, and controls the function of internal organs (e.g., heart rate, respiration, digestion) and responds to everyday and adverse experiences (1). ANS measures in children have been found to be related to behavior problems, emotion regulation, and health (2-7). Therefore, understanding the factors that affect ANS development during early childhood is important. Both branches of the ANS affect young children's cardiovascular responses to stimuli and have been measured noninvasively, via external monitoring equipment, using valid and reliable measures of physiological change (8-11). However, there are few studies of very young children with simultaneous measures of the parasympathetic and sympathetic nervous systems, which limits understanding of the integrated functioning of the two systems. In addition, the majority of existing studies of young children report on infants' resting ANS measures or their reactivity to commonly used mother-child interaction paradigms, and less is known about ANS reactivity to other challenging conditions. We present a study design and standardized protocol for a non-invasive and rapid assessment of cardiac autonomic control in 18 month old children. We describe methods for continuous monitoring of the parasympathetic and sympathetic branches of the ANS under resting and challenge conditions during a home or laboratory visit and provide descriptive findings from our sample of 140 ethnically diverse toddlers using validated equipment and scoring software. Results revealed that this protocol can produce a range of physiological responses to both resting and developmentally challenging conditions, as indicated by changes in heart rate and indices of parasympathetic and sympathetic activity. Individuals demonstrated variability in resting levels, responses to challenges, and challenge reactivity, which provides additional evidence that this protocol is useful for the examination of ANS individual differences for toddlers. PMID- 26967046 TI - Capillary-based Centrifugal Microfluidic Device for Size-controllable Formation of Monodisperse Microdroplets. AB - Here, we demonstrate a simple method for the rapid production of size controllable, monodisperse, W/O microdroplets using a capillary-based centrifugal microfluidic device. W/O microdroplets have recently been used in powerful methods that enable miniaturized chemical experiments. Therefore, developing a versatile method to yield monodisperse W/O microdroplets is needed. We have developed a method for generating monodisperse W/O microdroplets based on a capillary-based centrifugal axisymmetric co-flowing microfluidic device. We succeeded in controlling the size of microdroplets by adjusting the capillary orifice. Our method requires equipment that is easier-to-use than with other microfluidic techniques, requires only a small volume (0.1-1 ul) of sample solution for encapsulation, and enables the production of hundreds of thousands number of W/O microdroplets per second. We expect this method will assist biological studies that require precious biological samples by conserving the volume of the samples for rapid quantitative analysis biochemical and biological studies. PMID- 26967047 TI - Anisotropic Nanoantenna-Based Magnetoplasmonic Crystals for Highly Enhanced and Tunable Magneto-Optical Activity. AB - We present a novel concept of a magnetically tunable plasmonic crystal based on the excitation of Fano lattice surface modes in periodic arrays of magnetic and optically anisotropic nanoantennas. We show how coherent diffractive far-field coupling between elliptical nickel nanoantennas is governed by the two in-plane, orthogonal and spectrally detuned plasmonic responses of the individual building block, one directly induced by the incident radiation and the other induced by the application of an external magnetic field. The consequent excitation of magnetic field-induced Fano lattice surface modes leads to highly tunable and amplified magneto-optical effects as compared to a continuous film or metasurfaces made of disordered noninteracting magnetoplasmonic anisotropic nanoantennas. The concepts presented here can be exploited to design novel magnetoplasmonic sensors based on coupled localized plasmonic resonances, and nanoscale metamaterials for precise control and magnetically driven tunability of light polarization states. PMID- 26967048 TI - Ivabradine for the treatment of chronic heart failure. AB - Several studies have underlined the beneficial effects of a lower heart rate on mortality in patients with chronic heart failure and reduced ejection fraction. In clinical practice, achieving a heart rate <=70 bpm with beta-blockers is not always possible. In this context, the more recent guidelines added ivabradine to the management of those patients if heart rate remains >=70 bpm in sinus rhythm and symptoms persist despite treatment with an evidence-based or maximum tolerated dose of a beta-blocker, an angiotensin converting enzyme inhibitor or angiotensin-receptor blocker, and a mineralocorticoid receptor antagonist. Ivabradine is a well-tolerated, safe and effective treatment option with the objective to improve prognosis, left ventricular structure and function, exercise tolerance and quality of life. Accordingly, the following article will evaluate the benefits of a combination of the currently recommended pharmacological therapy in chronic heart failure with the selective heart rate reducing agent ivabradine. PMID- 26967049 TI - A rank-based transcriptional signature for predicting relapse risk of stage II colorectal cancer identified with proper data sources. AB - The irreproducibility problem seriously hinders the studies on transcriptional signatures for predicting relapse risk of early stage colorectal cancer (CRC) patients. Through reviewing recently published 34 literatures for the development of CRC prognostic signatures based on gene expression profiles, we revealed a surprising phenomenon that 33 of these studies analyzed CRC samples with and without adjuvant chemotherapy together in the training and/or validation datasets. This data misuse problem could be partially attributed to the unclear and incomplete data annotation in public data sources. Furthermore, all the signatures proposed by these studies were based on risk scores summarized from gene expression levels, which are sensitive to experimental batch effects and risk compositions of the samples analyzed together. To avoid the above-mentioned problems, we carefully selected three qualified large datasets to develop and validate a signature consisting of three pairs of genes. The within-sample relative expression orderings of these gene pairs could robustly predict relapse risk of stage II CRC samples assessed in different laboratories. The transcriptional and functional analyses provided clear evidence that the high risk patients predicted by the proposed signature represent patients with micro metastases. PMID- 26967050 TI - Oral isoflavone supplementation on endometrial thickness: a meta-analysis of randomized placebo-controlled trials. AB - BACKGROUND: Isoflavone from soy and other plants modulate hormonal effects in women, and the hormone disorder might result in different caners including endometrial cancer. However, it's effect on the risk of endometrial cancer is still inconclusive. We aimed to assess the effects of isoflavone on endometrial thickness, a risk factor of endometrial cancer in peri- and post-menopausal women. METHODS: A meta-analysis of randomized controlled trials was conducted to evaluate the effect of oral isoflavone supplementation on endometrial thickness in peri- and post-menopausal women. Electronic searches were performed on the PubMed, Embase, the Cochrane Library, web of science, CINAHL, and WHO ICTRP to August 1st, 2015. Reviews and reference lists of relevant articles were also searched to identify more studies. Summary estimates of standard mean differences (SMD's) and 95%CIs were obtained with random-effects models. Heterogeneity was evaluated with meta-regression and stratified analyses. RESULTS: A total of 23 trials were included in the current analysis. The overall results did not show significant change of endometrial thickness after oral isoflavone supplementation (23 studies, 2167subjects; SMD:-0.05; 95%CI:-0.23, 0.13; P=0.60). Stratified analysis suggested that a daily dose of more than 54mg could decrease the endometrial thickness for 0.26mm (10 trials, 984subjects; SMD:-0.26; 95%CI:-0.45, -0.07; P=0.007). Furthermore, isoflavone supplementation significantly decrease the endometrial thickness for 0.23mm in North American studies (7 trials, 726 subjects; SMD:-0.23; 95%CI:-0.44, -0.01; P=0.04), but it suggested an increase for 0.23mm in Asian studies (3 trials, 224 subjects; SMD: 0.23; 95%CI:-0.04, 0.50; P=0.10). CONCLUSIONS: Oral isoflavone supplementation might have different effects in different populations and at different daily doses. Multiple-centre, larger, and long-term trials are deserved to further evaluate its effect. PMID- 26967051 TI - Lipidome in colorectal cancer. AB - Colorectal cancer (CRC) is the second leading cause of cancer-related deaths. Understanding its pathophysiology is essential for developing efficient strategies to treat this disease. Lipidome, the sum of total lipids, related enzymes, receptors and signaling pathways, plays crucial roles in multiple cellular processes, such as metabolism, energy storage, proliferation and apoptosis. Dysregulation of lipid metabolism and function contributes to the development of CRC, and can be used towards the evaluation of prognosis. The strategies targeting lipidome have been applied in clinical trails and showed promising results. Here we discuss recent advances in abnormal lipid metabolism in CRC, the mechanisms by which the lipidome regulates tumorigenesis and tumor progression, and suggest potential therapeutic targets for clinical trials. PMID- 26967052 TI - PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. AB - Glioblastoma multiform (GBM) is the most common malignant glioma of all the brain tumors and currently effective treatment options are still lacking. GBM is frequently accompanied with overexpression and/or mutation of epidermal growth factor receptor (EGFR), which subsequently leads to activation of many downstream signal pathways such as phosphatidylinositol 3-kinase (PI3K)/Akt/rapamycin sensitive mTOR-complex (mTOR) pathway. Here we explored the reason why inhibition of the pathway may serve as a compelling therapeutic target for the disease, and provided an update data of EFGR and PI3K/Akt/mTOR inhibitors in clinical trials. PMID- 26967054 TI - Comparative analysis of human and mouse transcriptomes of Th17 cell priming. AB - Uncontrolled Th17 cell activity is associated with cancer and autoimmune and inflammatory diseases. To validate the potential relevance of mouse models of targeting the Th17 pathway in human diseases we used RNA sequencing to compare the expression of coding and non-coding transcripts during the priming of Th17 cell differentiation in both human and mouse. In addition to already known targets, several transcripts not previously linked to Th17 cell polarization were found in both species. Moreover, a considerable number of human-specific long non coding RNAs were identified that responded to cytokines stimulating Th17 cell differentiation. We integrated our transcriptomics data with known disease associated polymorphisms and show that conserved regulation pinpoints genes that are relevant to Th17 cell-mediated human diseases and that can be modelled in mouse. Substantial differences observed in non-coding transcriptomes between the two species as well as increased overlap between Th17 cell-specific gene expression and disease-associated polymorphisms underline the need of parallel analysis of human and mouse models. Comprehensive analysis of genes regulated during Th17 cell priming and their classification to conserved and non-conserved between human and mouse facilitates translational research, pointing out which candidate targets identified in human are worth studying by using in vivo mouse models. PMID- 26967053 TI - Long-range and short-range tumor-stroma networks synergistically contribute to tumor-associated epilepsy. AB - Epileptic seizures are frequently caused by brain tumors. Traditional anti epileptic treatments do not acquire satisfactory responses. Preoperative and postoperative seizures seriously influence the quality of life of patients. Thus, tumor-associated epilepsy (TAE) is an important subject of the current research. The delineation of the etiology of epileptogenesis in patients with primary brain tumor may help to find the novel and effective drug targets for treating this disease. In this review, we describe the current status of treatment of TAE. More importantly, we focus on the factors that are involved in the functional connectivity between tumors and stromal cells. We propose that there exist two modes, namely, long-range and short-range modes, which likely trigger neuronal hyperexcitation and subsequent epileptic seizures. The long-range mode is referred to as factors released by tumors including glutamate and GABA, binding to the corresponding receptor on the cellular membrane and causing neuronal hyperactivity, while the short-range mode is considered to involve direct intracellular communication between tumor cells and stromas. Gap junctions and tunneling nanotube network are involved in cellular interconnections. Future investigations focused on those two modes may find a potential novel therapeutic target for treating TAE. PMID- 26967055 TI - Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia. AB - Both preclinical and clinical investigations suggest that Notch signalling is critical for the development of many cancers and for their response to chemotherapy. We previously showed that Notch inhibition abrogates stromal induced chemoresistance in lymphoid neoplasms. However, the role of Notch in acute myeloid leukemia (AML) and its contribution to the crosstalk between leukemia cells and bone marrow stromal cells remain controversial. Thus, we evaluated the role of the Notch pathway in the proliferation, survival and chemoresistance of AML cells in co-culture with bone marrow mesenchymal stromal cells expanded from both healthy donors (hBM-MSCs) and AML patients (hBM-MSCs*). As compared to hBM-MSCs, hBM-MSCs* showed higher level of Notch1, Jagged1 as well as the main Notch target gene HES1. Notably, hBM-MSCs* induced expression and activation of Notch signalling in AML cells, supporting AML proliferation and being more efficientin inducing AML chemoresistance than hBM-MSCs*. Pharmacological inhibition of Notch using combinations of Notch receptor-blocking antibodies or gamma-secretase inhibitors (GSIs), in presence of chemotherapeutic agents, significant lowered the supportive effect of hBM-MSCs and hBM-MSCs* towards AML cells, by activating apoptotic cascade and reducing protein level of STAT3, AKT and NF-kappaB.These results suggest that Notch signalling inhibition, by overcoming the stromal-mediated promotion of chemoresistance,may represent a potential therapeutic targetnot only for lymphoid neoplasms, but also for AML. PMID- 26967056 TI - MicroRNAs mediated regulation of MAPK signaling pathways in chronic myeloid leukemia. AB - Chronic myeloid leukemia (CML) is a severe problem throughout the world and requires identification of novel targets for its treatment. This multifactorial disease accounts for about 15% of the all diagnosed leukemia cases. Mitogen activated protein kinase (MAPK) signaling pathway is crucial for the cell survival and its dysregulation is being implicated in various types of cancers. In here, we have discussed the potential role of various miRNAs that are found involved in regulating the proteins cascades of MAPK signaling pathway associated with CML. An emphasis has been paid to summarize the influence of various miRNAs in elevating or suppressing the expression level of significant proteins such as miR-203, miR-196a, miR-196b, miR-30a, miR-29b, miR-138 in BCR-ABL tyrosine kinase; miR-126, miR-221, miR-128, miR-15a, miR-188-5p, miR-17 in CRK family proteins; miR-155, miR-181a with SOS proteins; miR-155, miR-19a, with KRAS proteins; miR-19a with RAF1 protein; and miR-17, miR-19a, miR-17-92 cluster with MAPK/ERK proteins. In light of ever-increasing importance and ever-widening regulatory roles of miRNAs in cells, we have reviewed the recent progress in the field of miRNAs and have tried to suggest them as controlling targets for various protein cascades of MAPK signaling pathway. An understanding of the supervisory mechanism of MAPK by miRNAs might provide novel targets for treating CML. PMID- 26967057 TI - A chemical screen for medulloblastoma identifies quercetin as a putative radiosensitizer. AB - Treatment of medulloblastoma in children fails in approximately 30% of patients, and is often accompanied by severe late sequelae. Therefore, more effective drugs are needed that spare normal tissue and diminish long-term side effects. Since radiotherapy plays a pivotal role in the treatment of medulloblastoma, we set out to identify novel drugs that could potentiate the effect of ionizing radiation.Thereto, a small molecule library, consisting of 960 chemical compounds, was screened for its ability to sensitize towards irradiation. This small molecule screen identified the flavonoid quercetin as a novel radiosensitizer for the medulloblastoma cell lines DAOY, D283-med, and, to a lesser extent, D458-med at low micromolar concentrations and irradiation doses used in fractionated radiation schemes. Quercetin did not affect the proliferation of neural precursor cells or normal human fibroblasts. Importantly, in vivo experiments confirmed the radiosensitizing properties of quercetin. Administration of this flavonoid at the time of irradiation significantly prolonged survival in orthotopically xenografted mice. Together, these findings indicate that quercetin is a potent radiosensitizer for medulloblastoma cells that may be a promising lead for the treatment of medulloblastoma in patients. PMID- 26967058 TI - Pantoprazole, an FDA-approved proton-pump inhibitor, suppresses colorectal cancer growth by targeting T-cell-originated protein kinase. AB - T-cell-originated protein kinase (TOPK) is highly expressed in several cancer cells and promotes tumorigenesis and progression, and therefore, it is an important target for drug treatment of tumor. Pantoprazole (PPZ) was identified to be a TOPK inhibitor from FDA-approved drug database by structure based virtual ligand screening. Herein, the data indicated that pantoprazole inhibited TOPK activities by directly binding with TOPK in vitro and in vivo. Ex vivo studies showed that pantoprazole inhibited TOPK activities in JB6 Cl41 cells and HCT 116 colorectal cancer cells. Moreover, knockdown of TOPK in HCT 116 cells decreased their sensitivities to pantoprazole. Results of an in vivo study demonstrated that i.p. injection of pantoprazole in HCT 116 colon tumor-bearing mice effectively suppressed cancer growth. The TOPK downstream signaling molecule phospho-histone H3 in tumor tissues was also decreased after pantoprazole treatment. In short, pantoprazole can suppress growth of colorectal cancer cells as a TOPK inhibitor both in vitro and in vivo. PMID- 26967059 TI - Hypoxia-inducible factor 1 alpha is required for the tumourigenic and aggressive phenotype associated with Rab25 expression in ovarian cancer. AB - The small GTPase Rab25 has been functionally linked to tumour progression and aggressiveness in ovarian cancer and promotes invasion in three-dimensional environments. This type of migration has been shown to require the expression of the hypoxia-inducible factor 1 alpha (HIF-1alpha). In this report we demonstrate that Rab25 regulates HIF-1alpha protein expression in an oxygen independent manner in a panel of cancer cell lines. Regulation of HIF-1alpha protein expression by Rab25 did not require transcriptional upregulation, but was dependent on de novo protein synthesis through the Erbb2/ERK1/2 and p70S6K/mTOR pathways. Rab25 expression induced HIF-1 transcriptional activity, increased cisplatin resistance, and conferred intraperitoneal growth to the A2780 cell line in immunocompromised mice. Targeting HIF1 activity by silencing HIF-1beta re sensitised cells to cisplatin in vitro and reduced tumour formation of A2780 Rab25 expressing cells in vivo in a mouse ovarian peritoneal carcinomatosis model. Similar effects on cisplatin resistance in vitro and intraperitoneal tumourigenesis in vivo were obtained after HIF1b knockdown in the ovarian cancer cell line SKOV3, which expresses endogenous Rab25 and HIF-1alpha at atmospheric oxygen concentrations. Our results suggest that Rab25 tumourigenic potential and chemoresistance relies on HIF1 activity in aggressive and metastatic ovarian cancer. Targeting HIF-1 activity may potentially be effective either alone or in combination with standard chemotherapy for aggressive metastatic ovarian cancer. PMID- 26967060 TI - Cancer-associated S100P protein binds and inactivates p53, permits therapy induced senescence and supports chemoresistance. AB - S100P belongs to the S100 family of calcium-binding proteins regulating diverse cellular processes. Certain S100 family members (S100A4 and S100B) are associated with cancer and used as biomarkers of metastatic phenotype. Also S100P is abnormally expressed in tumors and implicated in migration-invasion, survival, and response to therapy. Here we show that S100P binds the tumor suppressor protein p53 as well as its negative regulator HDM2, and that this interaction perturbs the p53-HDM2 binding and increases the p53 level. Paradoxically, the S100P-induced p53 is unable to activate its transcriptional targets hdm2, p21WAF, and bax following the DNA damage. This appears to be related to reduced phosphorylation of serine residues in both N-terminal and C-terminal regions of the p53 molecule. Furthermore, the S100P expression results in lower levels of pro-apoptotic proteins, in reduced cell death response to cytotoxic treatments, followed by stimulation of therapy-induced senescence and increased clonogenic survival. Conversely, the S100P silencing suppresses the ability of cancer cells to survive the DNA damage and form colonies. Thus, we propose that the oncogenic role of S100P involves binding and inactivation of p53, which leads to aberrant DNA damage responses linked with senescence and escape to proliferation. Thereby, the S100P protein may contribute to the outgrowth of aggressive tumor cells resistant to cytotoxic therapy and promote cancer progression. PMID- 26967061 TI - Electronic Structure of the Dark Surface of the Weak Topological Insulator Bi14Rh3I9. AB - Compound Bi14Rh3I9 consists of ionic stacks of intermetallic [(Bi4Rh)3I](2+) and insulating [Bi2I8](2-) layers and has been identified to be a weak topological insulator. Scanning tunneling microscopy revealed the robust edge states at all step edges of the cationic layer as a topological fingerprint. However, these edge states are found 0.25 eV below the Fermi level, which is an obstacle for transport experiments. Here, we address this obstacle by comparing results of density functional slab calculations with scanning tunneling spectroscopy and angle-resolved photoemission spectroscopy. We show that the n-type doping of the intermetallic layer is intrinsically caused by the polar surface and is well screened toward the bulk. In contrast, the anionic "spacer" layer shows a gap at the Fermi level, both on the surface and in the bulk; that is, it is not surface doped due to iodine desorption. The well-screened surface dipole implies that a buried edge state, probably already below a single spacer layer, is located at the Fermi level. Consequently, a multilayer step covered by a spacer layer could provide access to the transport properties of the topological edge states. In addition, we find a lateral electronic modulation of the topologically nontrivial surface layer, which is traced back to the coupling with the underlying zigzag chain structure of the spacer layer. PMID- 26967062 TI - Risk factors for persistent disease in papillary thyroid carcinoma with lymph node metastasis. AB - PURPOSE: It is known that the presence of neck lymph node (LN) metastasis is correlated with persistent disease in papillary thyroid carcinoma (PTC) patients. After appropriate therapy, most patients become disease free, whereas some may still have persistent disease. The present study aimed to determine the potential variables affecting the clinical course of the disease and persistent disease patterns in PTC patients with LN metastasis. MATERIALS AND METHODS: The study group included consecutive PTC patients with LN metastasis. Clinicopathological characteristics and persistent disease pattern during the follow-up period were examined to identify risk factors for persistent disease using univariate and multivariate analyses. RESULTS: At the end of a median follow-up of 84 months, 90 (69%) patients became disease free and 40 (31%) patients had persistent disease. Univariate analysis showed that male sex, older age at initial diagnose (>=45 years), larger tumor size (>4 cm), presence of lateral cervical LN metastasis, extrathyroidal invasion, and higher number of metastatic LN (>=10) were significant predictors for persistent disease. Multivariate analysis showed that extrathyroidal involvement, presence of lateral cervical LN metastasis, and older age at initial diagnosis (>=45 years) were independent predictors for persistent disease. CONCLUSION: Despite the presence of LN involvement, most patients may become disease free with therapy. Patients with extrathyroidal invasion, lateral cervical LN involvement, and those at least 45 years old at initial diagnosis are more likely to have persistent disease. However, disease control can be achieved with close clinical follow-up and therapy. PMID- 26967063 TI - Toward 3D Printing of Medical Implants: Reduced Lateral Droplet Spreading of Silicone Rubber under Intense IR Curing. AB - The direct fabrication of silicone-rubber-based individually shaped active neural implants requires high-speed-curing systems in order to prevent extensive spreading of the viscous silicone rubber materials during vulcanization. Therefore, an infrared-laser-based test setup was developed to cure the silicone rubber materials rapidly and to evaluate the resulting spreading in relation to its initial viscosity, the absorbed infrared radiation, and the surface tensions of the fabrication bed's material. Different low-adhesion materials (polyimide, Parylene-C, polytetrafluoroethylene, and fluorinated ethylenepropylene) were used as bed materials to reduce the spreading of the silicone rubber materials by means of their well-known weak surface tensions. Further, O2-plasma treatment was performed on the bed materials to reduce the surface tensions. To calculate the absorbed radiation, the emittance of the laser was measured, and the absorptances of the materials were investigated with Fourier transform infrared spectroscopy in attenuated total reflection mode. A minimum silicone rubber spreading of 3.24% was achieved after 2 s curing time, indicating the potential usability of the presented high-speed-curing process for the direct fabrication of thermal-curing silicone rubbers. PMID- 26967064 TI - Sex differences in cardiovascular demands of refereeing during international basketball competition. AB - OBJECTIVES: The aim of this study was to investigate the impact of sex on cardiovascular responses of referees during elite international basketball competition. METHODS: Twenty-seven elite referees (9 female; 18 male) officiated a random sample of 18 matches during the final round of the 2013 Women's Eurobasket Championship. Continuous recordings of referees' heart rate (HR) during matches were obtained and analyzed for average HR, relative exercise intensity (% maximum HR, HRmax) and proportion of time spent within different exercise-intensity categories. RESULTS: During the championship, the average match HR was >150 bpm and approximated an exercise intensity of >85% HRmax for referees. Female referees exhibited lower average match HR (156.8 +/- 10.2 vs. 163.6 +/- 11.6 bpm, p<0.05) and exercise intensity (86.2 +/- 5.5 vs. 89.5 +/- 6.0% HRmax, p<0.05) compared to male referees. Referees spent most (>70%) of each match at a HR intensity of 70-89% HRmax with females experiencing more match time within the 55-69% HRmax category compared to males. Average HR and exercise intensity was greatest for all referees during the early part of the match (Quarter 1) that declined over the match. CONCLUSION: This study has demonstrated that sex significantly influences cardiovascular responses for elite basketball referees with lower responses for females potentially reflective of different movement patterns. Reductions in cardiovascular response noted during matches for all referees may reflect alterations in metabolism, match activities or induction of fatigue that should be considered in the development and training of elite referees for optimal match performance. PMID- 26967065 TI - Immunofluorescence Analysis of Endogenous and Exogenous Centromere-kinetochore Proteins. AB - "Centromeres" and "kinetochores" refer to the site where chromosomes associate with the spindle during cell division. Direct visualization of centromere kinetochore proteins during the cell cycle remains a fundamental tool in investigating the mechanism(s) of these proteins. Advanced imaging methods in fluorescence microscopy provide remarkable resolution of centromere-kinetochore components and allow direct observation of specific molecular components of the centromeres and kinetochores. In addition, methods of indirect immunofluorescent (IIF) staining using specific antibodies are crucial to these observations. However, despite numerous reports about IIF protocols, few discussed in detail problems of specific centromere-kinetochore proteins.(1-4) Here we report optimized protocols to stain endogenous centromere-kinetochore proteins in human cells by using paraformaldehyde fixation and IIF staining. Furthermore, we report protocols to detect Flag-tagged exogenous CENP-A proteins in human cells subjected to acetone or methanol fixation. These methods are useful in detecting and quantifying endogenous centromere-kinetochore proteins and Flag-tagged CENP-A proteins, including those in human cells. PMID- 26967067 TI - Comparison of Nasal Septum and Ear Cartilage as a Graft for Lower Eyelid Reconstruction. AB - In lower eyelid reconstruction, several types of grafts from the nasal septum, ear cartilage, buccal mucosa, and hard palate mucosa have been used for an inner layer of the lower eyelid, but there have been no studies comparing these grafts. The authors retrospectively reviewed our cases of lower eyelid reconstruction, and compared chondromucosal grafts from the nasal septum (N = 8) and ear cartilage grafts (N = 10) for an inner layer of the lower eyelid. The authors observed no significant difference in operative time, blood loss, or length of hospital stay between the "nasal septum" and "ear cartilage" groups. The final results were aesthetically and functionally satisfactory in both groups. In the nasal septum group, 1 patient suffered from perforation of the nasal septum and another patient suffered from nasal bleeding postoperatively. There were no donor site complications in the ear cartilage group. These findings indicate that both a chondromucosal graft from the nasal septum and an ear cartilage graft are good grafts for an inner layer of the lower eyelid. Regarding the donor site, however, an ear cartilage graft has the advantage of a lower complication rate. PMID- 26967066 TI - Surgical Optimization of Motor Recovery in Face Transplantation. AB - BACKGROUND: Face transplantation (FT) has emerged as a viable option for treating devastating facial injuries. Most reported outcomes have demonstrated satisfactory motor and sensory restoration despite differences in technique. The authors have developed an algorithm of facial nerve management in these challenging patients. Our principles of management are illustrated by 2 specific patients. METHODS: A retrospective analysis of prospectively collected data on 2 full face transplants was performed. Both patients required nerve grafting during full FT. Patient 1 due to short donor facial nerve stumps and patient 2 due to intraoperative soft tissue swelling. Patient 2 required a nerve transfer 11 months after full FT due to impaired motor recovery opposite the side of nerve grafting. Follow-up examinations consisting of manual muscle testing and Sunnybrook Facial Grading System 6 to 42 months after full FT with selected video examinations were critically reviewed. RESULTS: Patient 1 had symmetrical motor recovery with gradual improvements noted throughout. At 6 months, Patient 2 had asymmetrically improving motor function. After nerve transfer, the patient showed gradual improvement in motor recovery, symmetry, and tone. Videos for each patient demonstrate the evolution of the patients' ability to smile from 6 to 42 months. DISCUSSION: The authors describe their assessment of motor recovery and management of facial nerve reconstruction as it pertains to FT. Finally, the authors illustrate the principles of nerve transfer are applicable to FT recipients. PMID- 26967068 TI - Treatment Efficacy of the Transsylvian Approach Versus the Transtemporal Cortex Approach to Evacuate Basal Ganglia Hematoma Under a Microscope. AB - This study aimed to evaluate the clinical efficacy of the transsylvian approach versus the transtemporal cortex approach to evacuate basal ganglia hemorrhage under a microscope. The relevant literature was collected from PubMed, Embase, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature database, and China National Knowledge Infrastructure databases. The meta analysis was conducted by Stata 12.0 software. Seven studies were included in the meta-analysis. There were 659 patients, including 329 patients who were treated by the transsylvian approach and 330 patients who were treated by the transtemporal cortex approach. There were significant advantages in the transsylvian approach group, including a high clearance rate of hematoma (OR = 2.361; 95% CI: 1.443-3.861) and a better postoperative recovery (OR = 2.248; 95% CI: 1.598-3.160). A better postoperative recovery could also be found in patients with a history of hypertension (OR = 2.063; 95% CI: 1.429-2.980) and patients whose volume of hematoma ranged from 25 to 60 mL (OR = 2.275; 95% CI: 1.466 3.529). The authors conclude that there are significant advantages to the transsylvian approach, such as a high clearance rate of hematoma and a good postoperative recovery. These advantages should be taken into account when devising appropriate therapeutic strategies for patients with basal ganglia hematoma. PMID- 26967069 TI - Acellular Dermal Graft in Secondary Cleft Lip Deficiencies: Assessment of Results With a Reproducible Quantitative Technique. AB - PURPOSE: Considering the little evidence around acellular dermal graft application in secondary lip reshaping, this study is aimed to quantitatively examine the effect of acellular dermal graft in combination with Z-plasty technique in secondary defects of cleft lip. METHODS: In this clinical investigation, patients with secondary unilateral cleft lip deformity were selected. Standard photographs were prepared for each patient. Subsequent to scar revision, submucosal tunneling and Z-plasty, implantable human acellular dermal graft was placed and fixed in submucosal pocket. Quantitative parameters included angle of symmetry , dimension of symmetry (DS), defect height (DH), parallel lines, and lip thickness were measured presurgically and 1 year after treatment. Pre and post-operative pictures were compared and the changes were documented according to the criteria. P value less than 0.05 were considered as significant. RESULTS: Eighteen patients were included in this study. The difference of "DS" between normal side and cleft side was 3.1 +/- 1.5 mm presurgically and 1.1 +/- 1.8 mm postsurgically. The change was significant (P value < 0.05). The difference between pretreatment and posttreatment measures of "DS", "DH", and "Lip Thickness" were 2.75 +/- 4.55, 3.43 +/- 4.82, and 2.66 +/- 3.04 mm, respectively. The results were significant (P value<0.05). CONCLUSIONS: Based on the results, acellular dermal graft in combination with Z-plasty was able to improve lip deformity in patients with secondary defects of cleft lip. Further studies are recommended regarding the application of this technique in patients with bilateral cleft lip and severe "DH." PMID- 26967070 TI - Comparing the Effect of Nonactivated Platelet-Rich Plasma, Activated Platelet Rich Plasma, and Bone Morphogenetic Protein-2 on Calvarial Bone Regeneration. AB - Although platelet-rich plasma (PRP) is widely used to enhance bone graft survival, the effect of PRP itself on bone regeneration is unclear. Because activated PRP releases many growth factors in a bolus, there are controversies regarding the effect of activation of the PRP on bone regeneration. Thus, we studied the effect of activated versus nonactivated PRP on bone regeneration and compared the effect with that of recombinant human bone morphogenetic protein-2 (rhBMP-2) in a critical-sized cranial defect model. Forty New Zealand white rabbits were randomly divided into 4 groups. Defect sizing 15 * 15 mm(2) was created on the cranium of each rabbit, and then a collagen sponge soaked with normal saline, rhBMP-2, nonactivated PRP, or PRP activated with CaCl2 solution was immediately placed on the defect. After 16 weeks, using three-dimensional computed tomography and digital photography, the volume and new bone surface area were measured. The newly created bone was histologically analyzed. The experimental groups showed a significantly increased volume and surface area of new bone compared with the control group (P < 0.05), but no significant differences were found among the experimental groups. Histologic examination in the experimental groups showed newly created bone that had emerged in the center as well as the margin of the defect. Overall, these results indicate that PRP enhanced bony regeneration regardless of activation with an effect that was comparable to that of rhBMP-2. Thus, PRP has therapeutic effects on bone regeneration and may replace rhBMP-2, which is costly. PMID- 26967071 TI - The Auricular Cartilage in 197 Secondary and Tertiary Rhinoplasties. AB - BACKGROUND: The purpose of this study was to describe and evaluate the efficacy of the use of auricular cartilage to treat aesthetic and functional deformities of patients who underwent secondary rhinoplasty o tertiary. METHODS: From July 2005 to July 2014, 197 patients (144 women and 53 men) underwent rhinoplasty with the use of cartilage grafts. A total of 137 patients (70%) underwent secondary rhinoplasty, 60 patients (30%) underwent tertiary rhinoplasty. Patients in whom the Cottle maneuver was positive (108 patients, 55%) underwent a rhinomanometry test and responded to a simple questionnaire that reported on their nasal patency. Patients were evaluated at 6, 12, 24 months after surgery. RESULTS: The results of this study revealed an effective correction of aesthetic deformities of patients and a significant improvement in airway patency in 108 patients with respiratory obstruction. No major complication was observed. CONCLUSIONS: The use of auricular cartilage graft is efficacy to solve aesthetic and functional remnants after an incorrect procedure, or primary or secondary. PMID- 26967072 TI - Epidemiological Profile of Facial Fractures and Their Relationship With Clinical Epidemiological Variables. AB - The objective of this study was to identify the epidemiological profile of facial fractures and to associate with clinical-epidemiological variables. An epidemiological survey was conducted in which data retrieved from the records of patients with facial fractures were analyzed. Pearson chi(2) test, Student t test, one-way analysis of variance, Bonferroni post-hoc test, and logistic regression were used for statistical analysis, adopting a level of significance of 5%. The sample consisted of 718 patients ranging in age from 21 to 30 years (56.4%), including 480 (66.9%) men. Traffic accidents were the main etiological agent (62.7%) and the nasal bones were the most affected (41.8%). An association was observed between age and etiology (P < 0.001), fractured bone (P < 0.001), type of treatment (P < 0.001), hospital length of stay (P < 0.001), and complications (P = 0.001). Patients with traffic accident [odds ratio (OR) = 3.08, P < 0.001] and fall (OR = 2.50, P = 0.049) as etiology had more risk of complications. The type of fractured bone was associated with etiology (P < 0.001), type of treatment (P < 0.001), hospital length of stay (P < 0.001), and complications (maxilla--OR = 1.90, P = 0.004). In conclusion, facial fractures predominantly affect men aged 21 to 30 years. Traffic accidents are the main etiology and the nasal bone is the site most affected. It was observed that the older the patient, the greater the susceptibility to falls, surgical treatment, hospital stay, and complications. Patients with maxillary or mandibular fractures remain hospitalized for longer periods of time. Fractures by traffic accident and fall had more risk of complications. The risk of complications was also higher in patients with maxilla fracture. PMID- 26967073 TI - Cephalometric Assessment of Upper Airway Effects on Craniofacial Morphology. AB - To investigate craniofacial growth deformities in children with upper airway obstruction, this controlled study was performed. Cephalometry is used as a screening test for anatomic abnormalities in patients with obstructive sleep apnea syndrome. Therefore, the current work selected this method to investigate the effect of upper airway obstruction on craniofacial morphology.Patients with upper airway obstruction (104) were compared with 71 controls. Patients with upper airway compromise had mandibular hypoplasia, mandibular retrognathism, and higher hard palates in comparison with controls with no history of airway obstruction. The difference was higher in the older age group.Airway obstruction has significant correlation craniofacial morphology. Our findings support the idea of early assessment and thorough management of mouth breathing in children. PMID- 26967074 TI - Brows Asymmetry Correction With the Direct Approach: Myth or Reality? AB - OBJECTIVES: The current article is aimed to test the effectiveness of direct and indirect brow lifting to correct brows asymmetry. METHODS: Fifty patients treated with direct brow lift between January of 2011 and January of 2013 were investigated. All patients were men and treated under local anesthesia. In all patients, the brow lifting was associated with an upper blepharoplasty. The amount of brow elevation produced was assessed by comparison of the preoperative and at 1-year postoperative vertical distances between the superior eyebrow hairline and the interpupillary line at midpupil and at lateral and medial canthus. Paired sample t-test was used to investigate brow lifting amelioration after 1 year. The differences in measurements between the 2 sides were plotted to evaluate the degree of symmetry between 2 sides. In addition, a comparison was performed; a series of 45 patients treated with temporal (ie, indirect) approach. RESULTS AND CONCLUSIONS: The paired sample test demonstrated that direct brow lifting is a proper surgical technique to correct brow asymmetry. Also temporal (ie, indirect) approach is able to ameliorate brow asymmetry but direct technique provide better results. The direct brow lifting is a reliable, reproducible and safe surgical procedure, provides excellent and long-lasting results, and is very efficacious in brows asymmetry correction. PMID- 26967076 TI - The Efficacy and Safety of Tranexamic Acid in Cranio-Maxillofacial and Plastic Surgery. AB - The antifibrinolytic drug tranexamic acid (TXA) is effective in reducing blood loss and transfusion requirements in other fields of elective surgery and its use is emerging in a number of plastic surgical subspecialties. This systematic review and meta-analysis evaluates the current evidence for the efficacy and safety of TXA in craniomaxillofacial, head and neck, breast, aesthetic, burns, and reconstructive microsurgery. We searched PubMed, EMBASE, Medline, The Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials for randomized controlled trials of TXA in plastic surgery. Studies were analyzed using standard methodology. A total of 7965 records were screened, of which 14 met the inclusion criteria. Seven were suitable for meta analysis. In craniofacial surgery, TXA was associated with a mean reduction in blood loss of 18.2 mL/kg (P = 0.00001) and a mean reduction in blood transfusion of 8.7 mL/kg (P = 0.0001). In orthognathic surgery, TXA was associated with a mean reduction in blood loss of 156 mL (P = 0.001). Tranexamic acid may also have a role in reducing drainage output volumes in oncological breast excision and lymph node dissection of the neck. Level-1 evidence for efficacy in aesthetic surgery, burns, and reconstructive microsurgery is lacking. Although no reported complications were attributable to TXA, there remain no phase IV trials published. Level-1 evidence supports the use of TXA in craniofacial and orthognathic surgery. There exists an unmet need for studies in areas, including burns, aesthetic surgery, and reconstructive microsurgery. Phase IV trials in areas of proven efficacy are also required. PMID- 26967075 TI - Real Time Navigation-Assisted Orbital Wall Reconstruction in Blowout Fractures. AB - BACKGROUND: Limitation in performing restoration of orbital structures is the narrow, deep, and dark surgical field, which makes it difficult to view the operative site directly. To avoid perioperative complications from this limitation, the authors have evaluated the usefulness of computer-assisted navigation techniques in surgical treatment of blowout fracture. METHODS: Total 37 patients (14 medial orbital wall fractures and 23 inferior orbital wall fractures) with facial deformities had surgical treatment under the guide of navigation system between September 2012 and January 2015. RESULTS: All 37 patients were treated successfully and safely with navigation-assisted surgery without any complications, including diplopia, retrobulbar hematoma, globe injury, implant migration, and blindness. CONCLUSIONS: Blowout fracture can be treated safely under guidance of a surgical navigation system. In orbital surgery, navigation-assisted technology could give rise to improvements in the functional and aesthetic outcome and checking the position of the instruments on the surgical site in real time, without injuring important anatomic structures. PMID- 26967077 TI - Risk Factors for Life-Threatening Complications of Maxillofacial Space Infection. AB - The purpose of this study was to review the clinical features of maxillofacial space infection (MSI), and to identify the potential risk factors predisposing to life-threatening complications. A retrospective review of the medical charts of patients with MSI treated at Peking University School and Hospital of Stomatology from August 2008 to September 2013 was conducted. A total of 127 patients [75 men (59.1%) and 52 women (40.9%); mean age, 45.39 +/- 21.18 years, with a range of 1 85 years] formed the study cohort. The most common cause of MSI was odontogenic infection (57.5%). The most common space involved was the submandibular space. All patients were treated by antibiotics as well as surgical incision and drainage. Sixteen patients developed life-threatening complications, and the dominant complication was respiratory obstruction. Multivariate logistic regression analysis revealed the percentage of neutrophils (NEUT%) upon hospital admission >= 85.0% to be associated with life-threatening complications (P < 0.05). Even though adequate antibiotic therapy and incision and drainage of abscess were given, MSI patients with NEUT% upon hospital admission >= 85.0% carry a higher risk of life-threatening complications. In these patients, an aggressive treatment strategy is mandatory. PMID- 26967079 TI - Improvement of the Marginal Reflex Distance-1 in Blepharoptosis Surgeries. AB - The aim of this study was to predict the improvement of the marginal reflex distance (MRD1) in each blepharoptosis surgery.In PubMed and Scopus, the search terms 1. (blepharoptosis) AND 2. (surgery) AND 3. (levator OR outcome OR MRD OR function OR ptosis amount) were used and 1268 titles were found. Among them 28 papers were analyzed: Aponeurotic surgery (A-group, 8), Muller muscle resection (M-group, 10), Levator resection (L-group, 4), and Frontalis suspension (F-group, 6).The preop-MRD1 was greatest in L-group (1.7 +/- 1.0 mm) followed by the A group (1.3 +/- 0.5 mm) and the M-group (1.3 +/- 0.5 mm). The F-group had the lowest (-0.4 +/- 0.7 mm). Age was oldest in the M-group (58.6 +/- 11.9 years) followed by the A-group (42.4 +/- 18.9 years) and the F-group (27.2 +/- 17.9 years). The L-group was the youngest (18.9 +/- 11.5 years). The mean improved amount of MRD1 (DeltaL) was 2.15 +/- 0.90 mm. The DeltaL was different among the four operative methods. The F-group was greatest (2.4 +/- 1.5 mm) followed by the A-group (2.3 +/- 0.5 mm) and the M-group (2.0 +/- 0.6 mm). The L-group had the least improved amount of MRD1 (1.8 +/- 0.8 mm). There were significant differences between the groups (P < 0.05), except between the F-group and the A group (P = 0.284). The mean follow-up period was 8.1 +/- 7.0 months. In the 3 groups except A-group, the DeltaL decreased in follow-up periods, with different degree of decrement. Only in A-group, DeltaL increased slightly in follow-up periods. We think this is due to relatively well preserved levator function and short follow-up period (5.4 +/- 3.3 months) of A-group patients.The results of this review can be used in choosing blepharoptosis correction methods. PMID- 26967078 TI - Assessment of Patient Satisfaction With Evaluation Methods in Open Technique Septorhinoplasty. AB - The aim of this study was to measure the postoperative satisfaction of patients who underwent open technique septorhinoplasty (SRP) using Nasal Obstruction Symptoms Evaluation (NOSE), Rhinoplasty Outcomes Evaluation (ROE) and visual analog scale (VAS), and to assess the reliability and usability of these forms in the outcome of SRP.Forty-five patients who underwent primary open technique SRP were included in the study. The levels of patient satisfaction were assessed before the surgery and in the long-term using NOSE, ROE, and VAS.Nasal Obstruction Symptoms Evaluation scores were found to be decreased significantly after surgery, whereas ROE scores were increased postoperatively (P < 0.01). Patients' either functional (VAS) and aesthetic (VAS) increased significantly in the long-term after surgery (P < 0.01). There were no statistically significant differences between preoperative and postoperative measurements of NOSE, ROE, functional VAS, and aesthetic VAS by sex (P > 0.05).There was a statistically significant positive relationship between ROE difference before and after surgery, and functional VAS difference (r = 0.544, P = 0.001).There was a positive correlation between pre-postoperative ROE difference, and aesthetic VAS difference (r = 0.766, P = 0.001). The relationship between the pre-postoperative NOSE score difference and functional VAS difference was found to be significantly negative (r = -0.833, P = 0.001). The relationship between pre-postoperative NOSE difference and aesthetic VAS difference was also significantly negative (r = 0.475, P = 0.001). There was a significant negative correlation between ROE difference between before and after surgery, and NOSE difference (r = -0.640, P = 0.00).The disease-specific quality of life assessment forms used to evaluate patient esthetic and functional satisfaction correlate significantly with nasal obstruction and ROE. PMID- 26967080 TI - Prevention of Recurrence in the Surgical Correction of Cryptotia Using Local Flaps With a Cartilage Wedge Graft. AB - Cryptotia attributable to deficient posterior skin coverage frequently recurs. Because local flaps cover only the posterior aspects of the defective upper auricular cartilage and lack functional support to resist collapse of the helix, especially if severe helical cartilage anomalies are present, additional support is required to prevent the postoperative recurrence of this anomaly. The authors present cases of cryptotia treated using local flaps including a Z-plasty or formation of a trefoil flap with an additional cartilage wedge graft on the cephaloauricular sulcus to enhance projection of the helix. The combination of a graft with a local flap using a large Z-plasty or trefoil flap efficiently corrects the cryptotia, and is associated with minimal visible scarring and few complications, including recurrence. PMID- 26967081 TI - Otoplasty Outcomes With Different Suture Materials in a Rabbit Model. AB - Otoplasty is a commonly performed procedure to correct prominent ears. Many different otoplasty techniques have been described but there is no gold standard technique. As well, many different suture materials are used in otoplasty but studies directly comparing different sutures materials are lacking. An otoplasty outcome study with Nylon and Mersilene (2 of the most commonly used sutures in otoplasty) sutures was conducted using a rabbit model. Each rabbit ear was randomized to receive a Mustarde-type horizontal mattress suture with either 4-0 clear Nylon (N = 12 ears) or 4-0 Mersilene sutures (N = 12 ears). Two weeks after surgery, the auricular bend angle was measured with a finger goniometer and histologic analysis with hematoxylin and eosin staining was performed on the rabbit auricular cartilage. Overall, there was no significant difference in the mean bend angle between the 2 groups (Nylon: 135.8 degrees , SD = 22.7 degrees and Mersilene: 143.2 degrees , SD = 19.7 degrees ; P = 0.559). Also, no qualitative difference was observed on histologic analysis between the 2 suture groups. In the current rabbit model study, both Nylon and Mersilene sutures performed well and no significant differences were noted. PMID- 26967082 TI - Primary Abbe Flap for Median Cleft Lip Deformity: New Trends on an Old Concept. AB - OBJECTIVE: The authors present our experience using primary Abbe flaps for median cleft lip. METHODS: The records of 9 patients who underwent primary Abbe flaps were reviewed for indications, operative details, and complications. Flap design is discussed, including the "W" method to facilitate columellar reconstruction. Maxillomandibular fixation was not used. RESULTS: From 2004 to 2015, 9 patients with median cleft lip received primary Abbe flaps. Mean age was 10.2 +/- 6.2 months. Lobar holoprosencephaly was confirmed by imaging in 5 of the 9 patients. Operative time averaged 70 +/- 22 minutes. Flap division was performed at a mean of 3.6 +/- 0.9 weeks. Patients were followed for a mean of 45 +/- 49 months. No flaps were lost to vascular compromise and no dehiscences or infections were noted after initial repair. Five patients required prolonged intubation ranging from 4 to 7 days and 3 required transition to gastric feedings postoperatively. One patient with holoprosencephaly expired for reasons independent of surgery. Four patients have undergone 5 lip revisions to date. CONCLUSIONS: Patients with holoprosencephaly-spectrum disorder and median cleft lip have more favorable prognoses today. The Abbe flap may be safely and advantageously used for the primary repair of median cleft lip with extreme prolabial tissue deficiency. PMID- 26967087 TI - Scalp Dermatofibrosarcoma Protuberans: A Potential Diagnostic Pitfall. PMID- 26967083 TI - A Three-dimensional Analysis of Zygomatic Symmetry in Normal, Uninjured Faces. AB - Current approaches to facial reconstruction are based on the assumption of facial symmetry, though this has yet to be established in the literature. Through quantitative and qualitative analysis, symmetry of normal, male faces is examined here using the zygomatic complex as a bellwether for the rest of the facial skeleton. Three-dimensional models reconstructed from the computed tomography scans of 30 adult male patients displaying normal facial skeletal anatomy were analyzed. Seven zygomatic landmarks were identified on all craniofacial models, and asymmetry scores were calculated based on the average deviation distance upon reflection of 1 hemiface across the midfacial plane. Deviation maps were then generated for each zygomatic pair to enable visualization of the asymmetry. All landmarks displayed a slight (<3 mm) deviation from perfect symmetry, and analysis of zygomatic form asymmetry revealed an average of 0.4 mm of surface deviation between hemifaces. The presence of such slight asymmetries in the zygoma warrants further investigation as to the clinical relevance of such skeletal asymmetries from both an esthetic and biomechanical consideration to provide insight as to the proper approach to zygomatic restoration in cases of zygomatic fracture. PMID- 26967088 TI - Endoscopic Sinus Surgery in Sinus-Oral Pathology. PMID- 26967089 TI - Comment on the Effect of Nasal Septal Deviation on Frontal and Maxillary Sinus Volumes and Development of Sinusitis. PMID- 26967090 TI - Early Descriptions of the Forehead Muscle and Traumatic Blepharoptosis: Historical Vignette. PMID- 26967091 TI - Dumbbell-Shaped Recurrent Skin Cancer in the Temple Area. PMID- 26967092 TI - Allergic Contact Dermatitis After Bone-anchored Hearing Aid Surgery. PMID- 26967093 TI - Cleft Le Fort I Osteotomy: A Video Presentation. AB - In this video, we present a single piece Le Fort I osteotomy with bone graft in a patient with a unilateral cleft lip and palate. Maxillary osteotomies in the cleft patient can be challenging because of the presence of scar, palatal or alveolar fistulae, compromised teeth, and vascularization of the segments. The video demonstrates our current approach and technique. The authors particularly want to highlight aspects of the approach, such as the incision, exposure, osteotomies, mobilization, splints, and plating. The associated manuscript discusses the depicted video as well as the blood supply to the maxilla, and postoperative patient care. PMID- 26967094 TI - Alveolar Bone, Upper Lip and Columellar Reconstruction With Composite Abbe Flap. AB - Bilateral cleft lip and palate repair usually requires secondary corrective intentions. Abbe flap is a useful option and has many modifications for revision surgeries of cleft lip nose deformities. Study evaluated a 23-year-old woman for secondary cleft lip nose correction. The authors performed a composite Abbe flap, which included mental bone for repairing the upper lip harmony, maintaining the columellar elongation and bridging central alveolar bone cleft. No complications were observed and aesthetic and functional improvement was maintained. Presented new modification of Abbe flap maintains not only upper lip relaxation (additional skin soft tissue replacement) and columellar lengthening (extended designed flap) but also alveolar cleft reconstruction (vascularized mental bone) by a composite flap. Also, this modification prevents additional surgeries for alveolar cleft repair in cleft lip nose patients. PMID- 26967095 TI - Mandibular Condyle Reimplantation and Free Bone Grafting: Considerations to Increase Its Efficacy. AB - BACKGROUND: Mandibulectomy and disarticulation, resection of the lesion, and subsequent reimplantation of the condyle is a method to manage benign mandibular intraosseous lesions, involving the ramus but not extending to the mandibular condyle. OBJECTIVE: This article presents some considerations to increase the efficacy of this method. METHOD AND MATERIAL: Archived files of the patients that this method had been used for mandibular reconstruction were reevaluated. Patients were recalled and favorable and unfavorable results in reconstruction of the mandible with this technique were evaluated. RESULT: Intact large segment of the condyle is necessary for success of this procedure. CONCLUSIONS: Inferior alveolar nerve anastomosis, coronoidectomy, concomitant free bone grafting with adequate width, and attention to the intraoral soft tissue incision design will decrease unfavorable outcomes. PMID- 26967096 TI - Chyle Leak Following Neck Dissection: Could Radiotherapy Be Considered a Management Option? AB - Chyle leak after neck dissection is a relatively rare complication in head and neck cancer scenario.This review summarizes the basic knowledge of chyle leak underlying the potential benefit induced by low-dose radiation therapy and may serve as basis for future studies, necessary to optimize chyle leak management in head and neck cancer patients. PMID- 26967097 TI - Our Treatment Approaches in Severe Maxillofacial Injuries Occurring After Failed Suicide Attempts Using Long-Barreled Guns. AB - Maxillofacial traumas with long-barreled guns may sometimes cause catastrophic results by means of smashing in facial structures. In these patients, reconstruction strategies of both fragmented/lost soft and hard tissues still remain controversial. In their clinic, the authors treated 5 patients with severely injured face after failed suicide attempt between 2008 and 2013. In this study, the authors aimed to present their clinical experiences on these severely injured maxillofacial gunshot traumas and offer a treatment algorithm to gain a result as possible as satisfactory in terms of functionality and appearance. PMID- 26967098 TI - Trancutaneous Versus Intraoral Approach to Isolated Zygomatic Arch Fractures: A Comparison of Two Techniques. AB - Zygomatic arch fractures are caused by a vector force orthogonal to the bone segment that causes the collapse of the arch through depression of the bone fragments. Reduction of isolated zygomatic arch fractures are usually only of esthetic interest, with the exception of those cases where the fracture causes an impingement with the underlying mandibular coronoid process, causing limitation of mandibular movements. Reduction is usually performed with an extraoral approach, more rarely through a transoral approach. In this article, authors compare the traditional transcutaneous technique with the intraoral approach in 2 groups for a total number of 42 patients.For what concerns the correct alignment of the fragments, the 2 techniques have shown being equivalent. Although the intraoral approach has shown being a faster surgical procedure leaving no visible incision, allowing faster recovering and reduced postoperative pain. PMID- 26967099 TI - Schwannoma With Cystic Changes in the Pterygomandibular Space. AB - Schwannomas are tumors that arise from Schwann cells. Although schwannomas can occur almost anywhere in the body where nerve cells are present, they rarely occur in the head and neck region, including the oral and maxillofacial region. Cystic changes in schwannomas are extremely rare. This report is on a case of schwannoma with cystic changes that occurred in the pterygomandibular space.A 46 year-old woman presented with a complaint of limited mouth opening and pain on the left side of the mandible for 3 months. On panoramic radiography, radiolucency was seen on the left mandibular ramus. On enhanced computed tomography, a 4 * 3 cm cystic mass was found along the inner side of the left mandibular ramus area. Magnetic resonance imaging showed a multiseptated, well demarcated cystic lesion on the inner side of the mandibular ramus on the left side. Under general anesthesia, the tumor was excised. The final diagnosis was schwannoma with cystic changes. Lower lip hypoesthesia occurred postoperatively. At the 1-year postoperative follow-up, maximum mouth opening was increased to 44 mm, and lip hypoesthesia was improved. PMID- 26967100 TI - Treatment of Maxillary Glandular Odontogenic Cyst Involving the Same Place of Previously Treated Traumatic Bone Cyst. AB - Glandular odontogenic cyst is a rare developmental odontogenic cysts of the jaws having an aggressive behavior. The most common site of occurrence is the anterior mandible, and it is widely seen in middle-aged people. It is suggested that trauma could be a precipitating factor for its occurrence. This article presents the diagnosis and treatment of a case of glandular odontogenic cyst at anterior maxilla that occurred at the same localization of a traumatic bone cyst, 5 years after its management. PMID- 26967101 TI - Forehead Mass Removal by Endoscopic Approach. AB - Patients with forehead mass have a cosmetic problem because the forehead is an important first impression. Conventional skin approach results in visible scar even though surgeons designed the incision along the relaxed skin tension line1. Since Onishi introduced the technique for endoscopic approach in 1995, endoscopic surgery has become rapidly popular in the field of plastic surgery. Endoscopic approach to the forehead mass by small incision on the scalp behind hair line is big advantageous for leaving less ugly scar on the forehead. All procedures need to be identified under the endoscopic visualization. When it was completed, the mass was pulled out. The authors also used the osteotome or rasp when it was the osteoma. The forehead and scalp were applied compressive dressing to prevent hematoma and swelling for 2 days. The cosmesis was excellent because they have no visible scar on the forehead. Endoscopic approaching technique is getting popular and commonly used during the cosmetic surgery because it has many advantages. This method also, however, has difficulties to remove large-sized mass and to perform caudal dissection, and for increased operative times. Furthermore, there are complication of incomplete removal, hematoma, and swelling. The proper candidate is the patient with smooth forehead, with a mobile and soft mass, with a propensity for keloid formation, or hypertrophic scarring. Endoscopic technique is not only advantageous but also disadvantageous. That is why surgeon's selection is more important. PMID- 26967102 TI - Scuba Diving After Extensive Head and Neck Reconstructive Surgery: Is it Possible? PMID- 26967103 TI - Pharmacological treatment for Buerger's disease. AB - BACKGROUND: Buerger's disease (thromboangiitis obliterans) is a non atherosclerotic, segmental inflammatory pathology that most commonly affects the small and medium sized arteries, veins, and nerves in the upper and lower extremities. The etiology is unknown, but involves hereditary susceptibility, tobacco exposure, immune and coagulation responses. In many cases, there is no possibility of revascularization to improve the condition. Pharmacological treatment is an option for patients with severe complications, such as ischaemic ulcers or rest pain. OBJECTIVES: To assess the effectiveness of any pharmacological agent (intravenous or oral) compared with placebo or any other pharmacological agent in patients with Buerger's disease. SEARCH METHODS: The Cochrane Vascular Trials Search Co-ordinator searched their Specialised Register (last searched in April 2015) and the Cochrane Register of Studies (Issue 3, 2015). The review authors searched trial registers and the European grey literature; screened reference lists of relevant studies, and contacted study authors and major pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials (RCTs) involving pharmacological agents used in the treatment of Buerger's disease. DATA COLLECTION AND ANALYSIS: Two review authors, independently assessed the studies, extracted data and performed data analysis. MAIN RESULTS: Five randomised controlled trials (total 602 participants) compared prostacyclin analogue with placebo, aspirin, or a prostaglandin analogue, and folic acid with placebo. No studies assessed other pharmacological agents such as cilostazol, clopidogrel and pentoxifylline or compared oral versus intravenous prostanoid.Compared with aspirin, intravenous prostacyclin analogue iloprost improved ulcer healing (risk ratio (RR) 2.65; 95% confidence interval (CI) 1.15 to 6.11; 98 participants; one study; moderate quality evidence), and helped to eradicate rest pain after 28 days (RR 2.28; 95% CI 1.48 to 3.52; 133 participants; one study; moderate quality evidence), although amputation rates were similar six months after treatment (RR 0.32; 95% CI 0.09 to 1.15; 95 participants; one study; moderate quality evidence). When comparing prostacyclin (iloprost and clinprost) with prostaglandin (alprostadil) analogues, ulcer healing was similar (RR 1.13; 95% CI 0.76 to 1.69; 89 participants; two studies; I2 = 0%; very low quality evidence), as was the eradication of rest pain after 28 days (RR 1.57; 95% CI 0.72 to 3.44; 38 participants; one study; low quality evidence), while amputation rates were not measured. Compared with placebo, the effects of oral prostacyclin analogue iloprost were similar for: healing ischaemic ulcers (iloprost 200 mcg: RR 1.11; 95% CI 0.54 to 2.29; 133 participants; one study; moderate quality evidence, and iloprost 400 mcg: RR 0.90; 95% CI 0.42 to 1.93; 135 participants; one study; moderate quality evidence), eradication of rest pain after eight weeks (iloprost 200 mcg: RR 1.14; 95% CI 0.79 to 1.63; 207 participants; one study; moderate quality evidence, and iloprost 400 mcg: RR 1.11; 95% CI 0.77 to 1.59; 201 participants; one study; moderate quality evidence), and amputation rates after six months (iloprost 200 mcg: RR 0.54; 95% CI 0.19 to 1.56; 209 participants; one study, and iloprost 400 mcg: RR 0.42; 95% CI 0.13 to 1.31; 213 participants; one study). When comparing folic acid with placebo in patients with Buerger's disease and hyperhomocysteinaemia, pain scores were similar, there were no new cases of amputation in either group, and ulcer healing was not assessed (very low quality evidence).Treatment side effects such as headaches, flushing or nausea were not associated with treatment interruptions or more serious consequences. Outcomes such as amputation-free survival, walking distance or pain-free walking distance, and ankle brachial index were not assessed by any study.Overall, the quality of the evidence was very low to moderate, with few studies, small numbers of participants, variation in severity of disease of participants between studies and missing information regarding for example baseline tobacco exposure. AUTHORS' CONCLUSIONS: Moderate quality evidence suggests that intravenous iloprost (prostacyclin analogue) is more effective than aspirin for eradicating rest pain and healing ischaemic ulcers in Buerger's disease, but oral iloprost is not more effective than placebo. Verylow and low quality evidence suggests there is no difference between prostacyclin (iloprost and clinprost) and the prostaglandin analogue alprostadil for healing ulcers and relieving pain respectively in severe Buerger's disease. Very-low quality evidence suggests there is no difference in pain scores and amputation rates between folic acid and placebo, in people with Buerger's disease and hyperhomocysteinaemia. High quality trials assessing the effectiveness of pharmacological agents (intravenous or oral) in people with Buerger's disease are needed. PMID- 26967104 TI - The nutritional value of narrow-leafed lupine (Lupinus angustifolius) for fattening pigs. AB - The aim of this study was to determine the nutrient digestibility of seeds of four varieties of narrow-leafed lupines (Lupinus angustifolius) and the possibility of soya bean meal (SBM) substitution by lupine seeds alone and in combination with rapeseed meal (RSM) in the diets of pigs. The seeds of the lupine varieties Kalif, Sonet, Zeus and Boruta were analysed. The apparent total tract digestibility (ATTD) was determined on 50 cross-bred pigs using the difference method with titanium dioxide as a marker. The substitution of SBM by lupine seeds alone (at 0 - 100%) was tested on 60 pigs (20-105 kg body weight (BW)) and by a combination of lupine seeds and RSM on 180 fattening pigs (35-80 kg BW). The chemical composition of lupine seeds differed considerably, especially in terms of crude protein and mineral content. All seeds contained less than 0.05% alkaloids and 9.3% oligosaccharides in dry matter. The ATTD of protein ranged from 70% to 74%, those of ether extract from 36% to 55% and those of gross energy from 77% to 84%. The entire replacement of SBM by lupine seeds (var. Sonet) did not have a negative effect on the performance of grower and fattener pigs. The substitution of SBM by a combination of lupines and RSM reduced the performance of growing and finishing pigs significantly. PMID- 26967106 TI - Factors Predicting the Need for Retreatment After Laser Refractive Surgery. AB - PURPOSE: To identify the potential risk factors that increase the likelihood of requiring retreatment after refractive surgery. METHODS: This retrospective study included patients who underwent laser in situ keratomileusis or photorefractive keratectomy between January 2005 and December 2012 at the Care-Vision Laser Centers, Tel-Aviv, Israel. Patients were divided into 2 groups according to whether they underwent additional refractive surgery (retreatment) during the study period. RESULTS: Overall, 41,504 eyes (n = 21,313) were included in the final analysis of this study. Throughout the study period, there was a significant reduction in the 2-year annual retreatment rates with a decline from 4.52% for primary surgeries done in 2005 to 0.18% for surgeries performed in 2012 (quadratic R = 0.96, P < 0.001). The retreatment group had significantly higher preoperative age, maximum keratometric power, sphere, cylinder, and better best corrected visual acuity. They were more likely to have preoperative hyperopia, photorefractive keratectomy as opposed to laser in situ keratomileusis, intraoperative higher humidity conditions and lower temperature, and higher ablation depths. Significant differences in retreatment rates were found between the 5 high-volume surgeons (>1500 procedures performed) ranging from 0.48 to 3.14% (P < 0.0001). Multiple logistic regression analysis demonstrated that age, astigmatism, hyperopia, temperature, and surgeon's experience all significantly affected the need for retreatment. CONCLUSIONS: The following factors significantly increase the need for refractive retreatment: older preoperative age, higher degrees of astigmatism, hyperopia, colder operating room temperature, and less surgeon experience. Some of these factors may be incorporated into nomograms to reduce future retreatment rates. PMID- 26967105 TI - Engineering microbial consortia for controllable outputs. AB - Much research has been invested into engineering microorganisms to perform desired biotransformations; nonetheless, these efforts frequently fall short of expected results due to the unforeseen effects of biofeedback regulation and functional incompatibility. In nature, metabolic function is compartmentalized into diverse organisms assembled into robust consortia, in which the division of labor is thought to lead to increased community efficiency and productivity. Here we consider whether and how consortia can be designed to perform bioprocesses of interest beyond the metabolic flexibility limitations of a single organism. Advances in post-genomic analysis of microbial consortia and application of high resolution global measurements now offer the promise of systems-level understanding of how microbial consortia adapt to changes in environmental variables and inputs of carbon and energy. We argue that, when combined with appropriate modeling frameworks, systems-level knowledge can markedly improve our ability to predict the fate and functioning of consortia. Here we articulate our collective perspective on the current and future state of microbial community engineering and control while placing specific emphasis on ecological principles that promote control over community function and emergent properties. PMID- 26967108 TI - In Vitro Corneal Tomography of Donor Cornea Using Anterior Segment OCT. AB - PURPOSE: The aim of this study was to establish a tomographic screening method for revealing potential pathologies in corneal donors before keratoplasty so they may be excluded as candidates for corneal transplantation. METHODS: Donor corneal tomographies were measured in a viewing chamber filled with preservation medium and with the use of a clinical optical coherence tomography (OCT) device. Custom written software was developed to extract corneal surfaces from the raw data, which were analyzed in the central and peripheral regions. An adaptive nonlinear edge-enhancement algorithm was used to observe scars within the corneal volume. The thickness distribution map was analyzed to detect keratoconus and corneas with extreme topographic irregularities. Measurements were repeated 5 times to assess reproducibility. RESULTS: Eight corneas were investigated: 6 randomly selected intact donors, unsuitable for implantation because of low endothelial cell densities, and 2 keratoconus corneas, excised from patients during corneal transplantation. A major thickness abnormality was detected in one of the intact donor corneas, so it was excluded from further analysis. The keratoconus corneas were clearly evident in optical coherence tomography cross-sectional images, and similarly, they could easily be identified by analyzing the thickness map. Overall, the measurements were reliable and had a Cronbach's alpha coefficient greater than 0.8. CONCLUSIONS: Donor corneal examination using sterile viewing chambers was found to be suitable as a pre-keratoplasty advanced screening routine. A proof of concept was demonstrated, which could identify both irregular corneas and those affected by keratoconus. PMID- 26967107 TI - Long-Term Topical Ganciclovir and Corticosteroids Preserve Corneal Endothelial Function in Cytomegalovirus Corneal Endotheliitis. AB - PURPOSE: To report the long-term outcomes of topical ganciclovir (GCV) and corticosteroids as a maintenance therapy for cytomegalovirus (CMV) corneal endotheliitis. METHODS: This retrospective study included 10 eyes of 9 patients diagnosed with CMV corneal endotheliitis with a minimum 1-year follow-up at a tertiary referral hospital between 2008 and 2014. CMV corneal endotheliitis was defined by corneal edema associated with typical keratic precipitates (KPs) and a positive CMV polymerase chain reaction from aqueous humor taps. Patients receiving long-term topical 0.5% GCV and topical corticosteroids without discontinuation were included. The final corneal condition and endothelial cell density (ECD) were reported. RESULTS: The mean age was 45.6 +/- 11.7 years. The mean follow-up duration was 48 +/- 25 months. All patients exhibited typical coin shaped and/or linear KPs. A significant resolution of corneal edema and decreased KPs were achieved within 1 month in all patients after initiating topical 0.5% GCV every 2 hours and topical corticosteroids twice a day. The dose frequency was gradually tapered to GCV 4 times and corticosteroids once or twice a day as a maintenance therapy. All 10 eyes had a clear graft or corneas at the end of this study. The mean ECD was 1630 +/- 699 cells per millimeter square before treatment and 1776 +/- 834 cells per millimeter square at the end of the study period. CONCLUSIONS: Topical 0.5% GCV and corticosteroids as a maintenance regimen without interruption effectively preserved long-term corneal endothelial function. PMID- 26967109 TI - Association of Birth Parameters With Corneal Thickness in Prematurely Born and Full-Term School-Aged Children. AB - PURPOSE: The objective of this study was to investigate and compare corneal thicknesses of prematurely born and full-term early school-aged children, who were grouped into birth weight categories according to gestational age. METHODS: This cross-sectional study included 136 school-aged white children. They were grouped as premature (born before 37 weeks of gestation) and full term (born at or after 37 weeks of gestation). These 2 groups were further divided into birth weight groups according to gestational age as small, appropriate, and large for gestational age. Central corneal thickness (CCT) was measured by ultrasound pachymetry. The intraocular pressures of both groups were measured by a Goldmann applanation tonometer. RESULTS: The study included right eyes of 136 children. There were 53 girls and 83 boys whose mean age was 6.5 +/- 0.9 years (range: 5-8 yrs). Mean pachymetry of the small for gestational age group (526.8 +/- 37.9 MUm) in prematurely born children was significantly lower than that of appropriate for gestational age (554.6 +/- 34.2 MUm) (P = 0.039, mean difference 27.8, 95% confidence interval, 1.1-54.5). When prematurely born and full-term children are compared, the mean pachymetric values of the term children (574.5 +/- 37.8 MUm) were found to be significantly higher than those of the prematurely born children (545.4 +/- 35.6 MUm) (P <= 0.001). CONCLUSIONS: Birth parameters affect CCT in early school-aged children. Prematurely born, small for gestational age children have lesser CCT. This should be kept in mind at their follow-ups. PMID- 26967110 TI - Efficacy of Intraductal Meibomian Gland Probing on Tear Function in Patients With Obstructive Meibomian Gland Dysfunction. AB - PURPOSE: To assess the efficacy and safety of intraductal meibomian gland probing in patients with obstructive meibomian gland dysfunction who experienced little improvement with eyelid warming, massage, or artificial tears. METHODS: Forty nine patients with obstructive meibomian gland dysfunction were randomly divided into 2 groups: intraductal meibomian gland probing with 0.1% fluorometholone (group I), and 0.1% fluorometholone alone (group II). Subjective symptom scores and objective signs, including lid margin abnormalities, meibum quality and expressibility, meibomian gland dropout, fluorescein staining, tear break-up time (TBUT), and Schirmer I test results, were recorded before treatment and after 1 day, 1 week, and 1 month posttreatment. RESULTS: Clinical subjective symptoms and objective signs including meibum grade, TBUT, lid margin abnormalities, and fluorescein staining demonstrated significant improvements in both groups after treatment over time (all P < 0.05), and group I was better than group II 1 month after treatment in meibum grade (6.1 +/- 3.3 vs. 10.4 +/- 4.9, respectively; P < 0.001), lid margin abnormalities (0.8 +/- 0.1 vs. 1.3 +/- 0.3, respectively; P < 0.001), and TBUT (8.2 +/- 2.1 vs. 7.0 +/- 3.0, respectively; P = 0.0293). Before applying any medications, 76% of patients obtained immediate symptom relief 1 day after probing. However, the Schirmer I test results and meibomian gland dropout were insignificant pre- and posttreatment in either group (P > 0.1, respectively). CONCLUSIONS: Intraductal meibomian gland probing demonstrated significant efficacy in symptom relief and tear film stabilization. Probing helped release accumulated meibum and could help increase the accessibility of diseased meibomian glands to topical corticosteroids. PMID- 26967111 TI - Instrument to Enhance Visualization of Descemet Membrane During Graft Preparation for DMEK Surgery. AB - PURPOSE: Descemet membrane (DM) endothelial keratoplasty has improved outcomes of corneal transplantation in patients with corneal endothelial disease. However, the procedure has been criticized for jeopardizing donor tissue during graft preparation. Standardization of this procedure may provide a way toward minimizing tissue loss. For this purpose, we propose the use of a novel tool. METHODS: Computerized numerical control milling was used to create a blunt instrument, which was used to remove endothelial cells within a defined area in the periphery of donor corneas. Trypan blue was used to stain denuded DM. Graft preparation was continued as per our standard protocol. Transmission electron microscopy was performed on the treated area, and endothelial cell counts were obtained. RESULTS: Use of the modified procedure resulted in delineation of a peripheral band of denuded DM, which readily stained with trypan blue. This provided increased visibility of DM during subsequent steps. Transmission electron microscopy confirmed that no structural deficits of DM were induced. Mean endothelial cell loss (+/-SD) at 24 hours after preparation was 63 (+/-130) cells per square millimeter in the group prepared with the use of the new instrument (n = 7), versus 116 (+/-107) cells per square millimeter in the group prepared without the new instrument (n = 7; P = 0.45). CONCLUSIONS: The device presented here enhances visualization of DM during creation of the peripheral margin for subsequent lifting of the margin and stripping of the graft. This may increase success rates and shorten preparation times and learning periods for DM preparation. DM ultrastructure and endothelial cells were not negatively affected. PMID- 26967112 TI - In Vitro Study of the Deturgescence Ability of Cultivated Human Corneal Endothelial Cells. AB - PURPOSE: To evaluate the efficiency of cultivated human corneal endothelial cells (HCECs) to dehydrate the cornea, using models of the posterior cornea, composed of artificial collagen mass (to represent corneal stroma) and equine collagen membranes (to represent Descemet membrane). METHODS: HCECs were isolated from donor corneal rings and cultivated at 37 degrees C in 5% CO2 and 95% humidified air. The study design included 4 different sets of models: in set 1, the HCECs were placed directly on the collagen mass complex; in set 2, HCECs were placed on a thin equine collagen membrane and laid over the collagen mass; in set 3, HCECs were placed on a thick equine collagen membrane laid over the collagen mass; and in set 4 (the control group), the hydrophilic collagen mass was left alone to interact with the nutritional medium. The minimum thickness of each sample was measured with optical coherence tomography directly before placement of cells and after exposure to the nutritional fluid for 48 hours. RESULTS: After 2 days of exposure to the nutritional medium, the percentage decreases in thickness in "posterior cornea" models were 66% for set 1, 57% for set 2, and 13% set 3. In the control set, measurement of thickness after 2 days of exposure was not possible because of excessive fluid absorption. CONCLUSIONS: This in vitro study of HCECs showed that the dehydrating ability of HCECs is adversely affected by increased thickness of the artificial (Descemet) membrane. Further studies with similar models would aid better understanding of corneal diseases. PMID- 26967113 TI - Differential Changes in Intraocular Pressure and Corneal Manifestations in Individuals With Viral Endotheliitis After Keratoplasty. AB - PURPOSE: To investigate the clinical characteristics of viral endotheliitis after keratoplasty, we evaluated clinical parameters in individuals with anterior chamber inflammation after keratoplasty classified according to the absence or presence of DNA from various viruses in aqueous humor. METHODS: A total of 29 eyes of 27 subjects with anterior chamber inflammation after keratoplasty were enrolled in the study. The subjects were classified into the herpes simplex virus (HSV) group (7 patients, 8 eyes), cytomegalovirus (CMV) group (6 patients, 6 eyes), varicella zoster virus group (2 patients, 2 eyes), and nonviral group (12 patients, 13 eyes) on the basis of detection of viral DNA in aqueous humor. The interval between keratoplasty and the onset of inflammation, changes in intraocular pressure (IOP), and corneal manifestations of inflammation were retrospectively reviewed. RESULTS: Sixteen of the 29 eyes developed anterior chamber inflammation within 2 years after keratoplasty. IOP during active inflammation was significantly increased in the HSV and CMV groups compared with preinflammation values, and the increased IOP was significantly ameliorated in association with resolution of inflammation. Linear-type keratoprecipitates were frequently detected in the HSV (5 of 8 eyes), CMV (3 of 6 eyes), and nonviral (6 of 13 eyes) groups. Corneal edema was also commonly observed in the HSV (7 of 8 eyes) and nonviral (13 of 13 eyes) groups. CONCLUSIONS: Changes in IOP and corneal manifestations may provide a basis for differentiation of viral endotheliitis from allograft rejection and among viral pathogens in individuals with anterior chamber inflammation after keratoplasty, and they may thus allow initiation of appropriate treatment before viral DNA is identified. PMID- 26967115 TI - Searching for novel ATF4 target genes in human hepatoma cells by microarray analysis. AB - Activating transcription factor 4 (ATF4) is a transcription factor with an important biological activity. ATF4 is induced by various stresses, such as endoplasmic reticulum stress, through the phosphorylation of eukaryotic translation initiation factor 2alpha. ATF4 is also involved in lipid metabolism. In the present study, we performed a microarray experiment to identify new ATF4 target genes, particularly those involved in lipid metabolism, and identified C12orf39, CSTA, and CALCB as novel ATF4 target genes. An amino acid response element (AARE) as an ATF4-binding site is present in the promoter regions of these genes. In a detailed analysis using luciferase assay, we showed that ATF4 activated C12orf39 promoter activity and that this activation was diminished by deletion or mutation of the AARE sequence in the promoter region. Our results suggest that C12orf39, CSTA, and CALCB are novel ATF4 target genes and that C12orf39 promoter activity is activated by ATF4 through AARE. PMID- 26967116 TI - Negative Studies in Cancer Research: Why the Negativity? PMID- 26967119 TI - Minced Tissue in Compressed Collagen: A Cell-containing Biotransplant for Single staged Reconstructive Repair. AB - Conventional techniques for cell expansion and transplantation of autologous cells for tissue engineering purposes can take place in specially equipped human cell culture facilities. These methods include isolation of cells in single cell suspension and several laborious and time-consuming events before transplantation back to the patient. Previous studies suggest that the body itself could be used as a bioreactor for cell expansion and regeneration of tissue in order to minimize ex vivo manipulations of tissues and cells before transplanting to the patient. The aim of this study was to demonstrate a method for tissue harvesting, isolation of continuous epithelium, mincing of the epithelium into small pieces and incorporating them into a three-layered biomaterial. The three-layered biomaterial then served as a delivery vehicle, to allow surgical handling, exchange of nutrition across the transplant, and a controlled degradation. The biomaterial consisted of two outer layers of collagen and a core of a mechanically stable and slowly degradable polymer. The minced epithelium was incorporated into one of the collagen layers before transplantation. By mincing the epithelial tissue into small pieces, the pieces could be spread and thereby the propagation of cells was stimulated. After the initial take of the transplants, cell expansion and reorganization would take place and extracellular matrix mature to allow ingrowth of capillaries and nerves and further maturation of the extracellular matrix. The technique minimizes ex vivo manipulations and allow cell harvesting, preparation of autograft, and transplantation to the patient as a simple one-stage intervention. In the future, tissue expansion could be initiated around a 3D mold inside the body itself, according to the specific needs of the patient. Additionally, the technique could be performed in an ordinary surgical setting without the need for sophisticated cell culturing facilities. PMID- 26967120 TI - Sulfur Isotopic Fractionation of Carbonyl Sulfide during Degradation by Soil Bacteria. AB - We performed laboratory incubation experiments on the degradation of gaseous phase carbonyl sulfide (OCS) by soil bacteria to determine its sulfur isotopic fractionation constants ((34)epsilon). Incubation experiments were conducted using strains belonging to the genera Mycobacterium, Williamsia, and Cupriavidus isolated from natural soil environments. The (34)epsilon values determined were 3.67 +/- 0.330/00, -3.99 +/- 0.190/00, -3.57 +/- 0.220/00, and -3.56 +/- 0.230/00 for Mycobacterium spp. strains THI401, THI402, THI404, and THI405; -3.74 +/- 0.290/00 for Williamsia sp. strain THI410; and -2.09 +/- 0.070/00 and -2.38 +/- 0.350/00 for Cupriavidus spp. strains THI414 and THI415. Although OCS degradation rates divided by cell numbers (cell-specific activity) were different among strains of the same genus, the (34)epsilon values for same genus showed no significant differences. Even though the numbers of bacterial species examined were limited, our results suggest that (34)epsilon values for OCS bacterial degradation depend not on cell-specific activities, but on genus-level biological differences, suggesting that (34)epsilon values are dependent on enzymatic and/or membrane properties. Taking our (34)epsilon values as representative for bacterial OCS degradation, the expected atmospheric changes in delta(34)S values of OCS range from 0.50/00 to 0.90/00, based on previously reported decreases in OCS concentrations at Mt. Fuji, Japan. Consequently, tropospheric observation of delta(34)S values for OCS coupled with (34)epsilon values for OCS bacterial degradation can potentially be used to investigate soil as an OCS sink. PMID- 26967114 TI - Enantiodivergent Fluorination of Allylic Alcohols: Data Set Design Reveals Structural Interplay between Achiral Directing Group and Chiral Anion. AB - Enantioselectivity values represent relative rate measurements that are sensitive to the structural features of the substrates and catalysts interacting to produce them. Therefore, well-designed enantioselectivity data sets are information rich and can provide key insights regarding specific molecular interactions. However, if the mechanism for enantioselection varies throughout a data set, these values cannot be easily compared. This premise, which is the crux of free energy relationships, exposes a challenging issue of identifying mechanistic breaks within multivariate correlations. Herein, we describe an approach to addressing this problem in the context of a chiral phosphoric acid catalyzed fluorination of allylic alcohols using aryl boronic acids as transient directing groups. By designing a data set in which both the phosphoric and boronic acid structures were systematically varied, key enantioselectivity outliers were identified and analyzed. A mechanistic study was executed to reveal the structural origins of these outliers, which was consistent with the presence of several mechanistic regimes within the data set. While 2- and 4-substituted aryl boronic acids favored the (R)-enantiomer with most of the studied catalysts, meta-alkoxy substituted aryl boronic acids resulted in the (S)-enantiomer when used in combination with certain (R)-phosphoric acids. We propose that this selectivity reversal is the result of a lone pair-pi interaction between the substrate ligated boronic acid and the phosphate. On the basis of this proposal, a catalyst system was identified, capable of producing either enantiomer in high enantioselectivity (77% (R)-2 to 92% (S)-2) using the same chiral catalyst by subtly changing the structure of the achiral boronic acid. PMID- 26967121 TI - Acquired lymphangiectasia (lymphangioma circumscriptum) of the vulva: Clinicopathologic study of 11 patients from a single institution and 67 from the literature. AB - BACKGROUND: Acquired lymphangiectasia of the vulva (ALV) is a rare condition thought to be secondary to pelvic lymphatic obstruction. Although benign, this entity often occurs after previous malignancy and can be confused with conditions such as genital warts. We sought to clarify the clinicopathologic features of ALV by studying affected patients from our institution and from the existing literature. METHODS: We reviewed retrospectively the clinical and histopathologic characteristics of patients with ALV from our institution and performed an extensive literature search to identify all published cases of ALV. RESULTS: Eleven patients with ALV were identified from our institution. Three patients had Crohn disease, three had malignancies involving the pelvic region (rectal adenocarcinoma, cervical carcinoma, endometrial carcinoma), and three (two with pelvic malignancy) had previous radiation therapy. One patient had Proteus syndrome. Of 67 distinct cases of ALV identified in the literature, 41 (61%) had a history of malignancy. CONCLUSIONS: In any acquired or clinically unusual lymphatic process in the skin and soft tissues, a lesion or obstructive process of the draining lymphatics should be investigated. PMID- 26967122 TI - Prevalence and Location of Neuropathic Pain in Lumbar Spinal Disorders: Analysis of 1804 Consecutive Patients With Primary Lower Back Pain. AB - STUDY DESIGN: A cross-sectional study of 1804 consecutive patients. OBJECTIVE: The aim of this study was to investigate the prevalence of pathological pain and its distribution features in patients with chronic lumbar spinal disorders. SUMMARY OF BACKGROUND DATA: Clinical spinal disorders can involve pathological neuropathic pain (NeP) as well as physiological nociceptive pain (NocP), as they have varied pathology, including spinal cord injury, stenosis, and compression. A study conducted by the Japanese Society for Spine Surgery and Related Research (JSSR) has determined a prevalence of 29.4% for NeP in patients with lumbar spinal disorder. However, the data did not include information on pain location. METHODS: Patients aged 20 to 79 years with chronic lower back pain (>=3 months, visual analog scale score >=30) were recruited from 137 JSSR-related institutions. Patient data included an NeP screening questionnaire score and pain location (lower back, buttock, and legs). The association between the pain pathology and its location was analyzed statistically using the unpaired t test and Chi-square test followed by Fisher test. P < 0.05 was considered significant. RESULTS: Low back pain subjects showed 31.9% of NeP prevalence, and the pain distribution showed [NocP(%)/NeP(%)] low back pain only cases: 44/22, while low back pain with leg pain cases showed a prevalence of 56/78. This indicates that low back pain alone can significantly induce NocP rather than NeP (P < 0.01). Buttock pain was revealed to significantly induce both lower back pain and leg pain with NeP properties (P < 0.01). Leg pain was revealed to be predominantly neuropathic, especially when it included peripheral pain (P < 0.01). CONCLUSION: Low back pain with no buttock pain induces NocP rather than NeP. Buttock pain is significantly associated with NeP prevalence whether or not leg pain exists. Leg pain can increase the prevalence of NeP, especially when it contains a peripheral element. LEVEL OF EVIDENCE: 3. PMID- 26967123 TI - Hospital Readmission Within 2 Years Following Adult Thoracolumbar Spinal Deformity Surgery: Prevalence, Predictors, and Effect on Patient-derived Outcome Measures. AB - STUDY DESIGN: A retrospective review of prospective multicenter database. OBJECTIVE: The aim of this study was to identify factors influencing readmission, reoperation, and the impact on health-related quality of life outcomes (HRQoLs) in adult spinal deformity (ASD) surgery. SUMMARY OF BACKGROUND DATA: Many ASD patients experience complications requiring readmission. It is important to identify baseline/operative factors leading to rehospitalizations and reoperation, which may impact outcomes. METHODS: INCLUSION CRITERIA: ASD surgical patients (age >18 yrs, major coronal Cobb >=20 degrees , sagittal vertical axis >=5 cm, pelvic tilt >=25 degrees , and/or thoracic kyphosis >60 degrees ) with complete baseline, 1-, and 2-year follow-up. Patients were grouped on the basis of readmission occurrence (yes/no) and type [medical (no reoperation) vs. surgical (revision surgery)]. Readmissions caused by infections requiring surgical treatment (e.g., deep infections) were considered reoperations. Univariate and multivariate analyses determined readmission and reoperation predictors. Repeated measures mixed models evaluated readmission impact on HRQoLs at 1 and 2 years. RESULTS: Three hundred thirty-four patients were included: 76 (22.8%) readmissions, involving 65 (85.5% of 76) reoperations (surgical readmission) and 11 (14.5% of 76) medical readmissions. The most common surgical readmission indication (n = 65) was implant complications (36.9%; rod breakage n = 13); the most common medical readmission indication was infection (36.4%, n = 4), treated with antibiotics. Noninfectious medical readmission (n = 7) included pleural effusion, deep vein thrombosis (DVT), intraoperative blood loss, neurologic, and unspecified. Readmission predictors: increased number of major peri-operative complications [odds ratio (OR) 5.13, P = 0.014], infection presence (OR 25.02, P = 0.001), implant complications (OR 6.12, P < 0.001), and radiographic complications (DJK, proximal junctional kyphosis, pseudoarthrosis, sagittal/coronal imbalance) (OR 16.94, P < 0.001). HRQoL analysis revealed overall improvement of the full cohort (P < 0.01), though the 76 readmitted improved less overall and at each time point P < 0.001) except in 6-week MCS (P = 0.14). CONCLUSION: Major peri-operative, implant, radiographic, and infection complications during index were associated with increased readmission odds. Implant complications most frequently caused surgical readmissions. Readmitted patients improved in outcome scores, although less compared with the nonreadmitted cohort, yet displayed reduced 6-week SF-36 Mental Component Summary. LEVEL OF EVIDENCE: 3. PMID- 26967125 TI - Intraspinal Pathology Associated With Pediatric Scoliosis: A Ten-year Review Analyzing the Effect of Neurosurgery on Scoliosis Curve Progression. AB - STUDY DESIGN: This was a retrospective study of patients with Chiari I (CM I) and Chiari II (CM II) malformations, tethered cord syndrome, and syringomyelia examining the effect of neurosurgery on scoliosis. OBJECTIVE: The aim of this study was to determine the factors affecting spinal deformity progression in patients with diseases of the neural axis following neurosurgical management. SUMMARY OF BACKGROUND DATA: There have been attempts to explain which factors influence the spinal deformity in diseases of the neural axis with varying results. Debate still exists as to the effectiveness of neurosurgery in curve stabilization. METHODS: The medical records for patients treated over the past 10 years were reviewed. The spinal deformity surgical group consisted of patients who received surgery or progressed to surgical range (50 degrees ) and the nonsurgical group those who did not undergo fusion. RESULTS: Fifteen patients (eight females and seven males) with scoliosis who underwent neurosurgical intervention were identified. Ten had tethered cord, six CM II, four CM I, and 11 syrinx. Average age at the time of neurosurgery was 7 +/- 4 years (range 0.7-14 yrs). Following neurosurgery, no patients experienced improvement in their curves (defined as >10 degrees decrease in Cobb angle), eight patients experienced stabilization (<10 degrees decrease), and seven experienced worsening (>10 degrees increase). The group that went on to spinal deformity surgery possessed larger curves before neurosurgery (mean 42 degrees , range 20 degrees -63 degrees ) than the nonsurgical group (19 degrees , range 15 degrees -26 degrees ; P = 0.004). CM II patients had the greatest magnitude of curve progression, mean of 49 degrees , compared with patients with CM I (6 degrees ) or tether cord without CM I or II (11 degrees , P = 0.01). CONCLUSION: Neurosurgical intervention may prevent curve progression in patients with scoliosis and Cobb angles < 30 degrees if they do not have a complex CM II malformation. Patients with CM II are at a higher risk of curve progression and undergoing spinal fusion than patients with CM I, tethered cord syndrome, or syringomyelia. LEVEL OF EVIDENCE: 4. PMID- 26967124 TI - Risk Factors for 30-Day Unplanned Readmission and Major Perioperative Complications After Spine Fusion Surgery in Adults: A Review of the National Surgical Quality Improvement Program Database. AB - STUDY DESIGN: Retrospective review of a prospective cohort. OBJECTIVE: The aim of the study was to determine the patient characteristics and surgical procedure factors related to increased rates of 30-day unplanned readmission and major perioperative complications after spinal fusion surgery, and the association between unplanned readmission and major complications. SUMMARY OF BACKGROUND DATA: Reducing unplanned readmissions can reduce the cost of healthcare. Payers are implementing penalties for 30-day readmissions after discharge. There is limited data regarding the current rates and risk factors for unplanned readmission and major complications related to spinal fusion surgery. METHODS: Spine fusion patients were identified using the 2012 and 2013 American College of Surgeons National Surgical Quality Improvement Program Participant User File. Rates of readmissions within 30 days after spine fusion surgery were calculated using the person-years method. Cox proportional hazards models were used to assess the independent associations of spine surgical procedure types, diagnoses, patient profiles, and major perioperative complications with unplanned related readmissions. Independent risk factors for major complications were assessed by multivariable logistic regression. RESULTS: Of the 18,602 identified patients, there was a 5.2% overall major perioperative complication rate. There was a rate of 4.4% per 30 person-days for unplanned readmissions related to index surgery. Independent risk factors for both readmissions and major perioperative complications included combined anterior and posterior surgery, diagnosis of solitary tumor, older age, and higher American Society of Anesthesiologists class. Patients with deep/organ surgical site infection carried higher risk of having unplanned readmission, followed by pulmonary embolism, acute renal failure, and stroke/cerebral vascular accident with neurological deficit. CONCLUSION: This study provides benchmark rates of 30-day readmission based on diagnosis and procedure codes from a high-quality database for adult spinal fusion patients and showed increased rates of 30-day unplanned readmission and major perioperative complications for patients with specific risk factors. Targeted preoperative planning on modifiable risk factors with proportional reimbursement may promote higher-quality healthcare. LEVEL OF EVIDENCE: 3. PMID- 26967126 TI - Safety and tolerability of antipsychotic co-treatment in patients with schizophrenia: results from a systematic review and meta-analysis of randomized controlled trials. AB - INTRODUCTION: Antipsychotic co-treatment is common in schizophrenia, despite lacking evidence for its efficacy and safety. Areas: We conducted a systematic search of PubMed/PsycInfo/CJN/WangFan/CBM without language restrictions from database inception until 05/25/2015 for randomized trials comparing antipsychotic monotherapy with antipsychotic co-treatment in >=20 adults with schizophrenia reporting meta-analyzable adverse events (AEs) data. Meta-analyzing 67 studies (n=4,861, duration=10.3+/-5.2 weeks), antipsychotic co-treatment was similar to monotherapy regarding intolerability-related discontinuation (risk ratio (RR)=0.84, 95% confidence interval (CI)=0.53-1.33, p=0.455). While incidence of >=1 AE was lower with antipsychotic co-treatment (RR=0.77, 95%CI=0.66-0.90, p=0.001), these results were solely driven by open-label and efficacy-focused studies. Adjunctive D2-antagonists lead to less nausea (RR=0.220, 95%CI=0.06 0.87, p=0.030) and insomnia (RR=0.26, 95%CI=0.08-0.86, p=0.028), but higher prolactin (SMD=2.20, 95%CI=0.43-3.96, p=0.015). Conversely, adjunctive partial D2 agonists (aripiprazole=100%) resulted in lower electrocardiogram abnormalities (RR=0.43, 95%CI=0.25-0.73, p=0.002), constipation (RR=0.45, 95%CI=0.25-0.79, p=0.006), drooling/hypersalivation (RR=0.14, 95%CI=0.07-0.29, p<0.001), prolactin (SMD=-1.77, 95%CI=-2.38, -1.15, p<0.001), total and LDL-cholesterol (SMD=-0.33, 95%CI=-0.55, -0.11, p=0.003; SMD=-0.33, 95%CI=-0.54, -0.10, p=0.004). EXPERT OPINION: No double-blind evidence for altered AE burden associated with antipsychotic co-treatment was found. However, AEs were insufficiently and incompletely reported and follow-up duration was modest. Adjunctive partial D2 agonists might be beneficial for counteracting several AEs. High-quality, long term studies that comprehensively assess AEs are needed. PMID- 26967127 TI - Canine Distemper Virus in Wild Felids of Costa Rica. AB - Several highly infectious diseases can be transmitted through feces and cause elevated mortality among carnivore species. One such infectious agent, canine distemper virus (CDV; Paramyxoviridae: Morbillivirus), has been reported to affect wild carnivores, among them several felid species. We screened free ranging and captive wild carnivores in Costa Rica for CDV. Between 2006 and 2012, we collected 306 fecal samples from 70 jaguars (Panther onca), 71 ocelots ( Leopardus pardalis ), five jaguarundis (Puma yaguaroundi), 105 pumas ( Puma concolor ), five margays ( Leopardus wiedii ), 23 coyotes ( Canis latrans ), and 27 undetermined Leopardus spp. We found CDV in six individuals: one captive jaguarundi (rescued in 2009), three free-ranging ocelots (samples collected in 2012), and two free-ranging pumas (samples collected in 2007). Phylogenetic analyses were performed using sequences of the phosphoprotein (P) gene. We provide evidence of CDV in wild carnivores in Costa Rica and sequence data from a Costa Rican CDV isolate, adding to the very few sequence data available for CDV isolates from wild Central American carnivores. PMID- 26967128 TI - RANAVIRUS CAUSES MASS DIE-OFFS OF ALPINE AMPHIBIANS IN THE SOUTHWESTERN ALPS, FRANCE. AB - Pathogenic fungi and viruses cause mortality outbreaks in wild amphibians worldwide. In the summer of 2012, dead tadpoles and adults of the European common frog Rana temporaria were reported in alpine lakes in the southwestern Alps (Mercantour National Park, France). A preliminary investigation using molecular diagnostic techniques identified a Ranavirus as the potential pathogenic agent. Three mortality events were recorded in the park, and samples were collected. The amphibian chytrid fungus Batrachochytrium dendrobatidis was not detected in any of the dead adult and juvenile frogs sampled (n=16) whereas all specimens were positive for a Ranavirus. The genome sequence of this Ranavirus was identical to previously published sequences of the common midwife toad virus (CMTV), a Ranavirus that has been associated with amphibian mortalities throughout Europe. We cultured virus from the organs of the dead common frogs and infecting adult male common frogs collected in another alpine region where no frog mortality had been observed. The experimentally infected frogs suffered 100% mortality (n=10). The alpine die-off is the first CMTV outbreak associated with mass mortality in wild amphibians in France. We describe the lesions observed and summarize amphibian populations affected by Ranaviruses in Europe. In addition, we discuss the ecologic specificities of mountain amphibians that may contribute to increasing their risk of exposure to and transmission of Ranaviruses. PMID- 26967129 TI - AN EPIZOOTIC OF EMERGING NOVEL AVIAN POX IN CARRION CROWS (CORVUS CORONE) AND LARGE-BILLED CROWS (CORVUS MACRORHYNCHOS) IN JAPAN. AB - In 2006-10, an epizootic of emerging avian pox occurred in Carrion Crows ( Corvus corone ) and Large-billed Crows ( Corvus macrorhynchos ), leading to mortality of juvenile crows in Hokkaido, the northernmost island of Japan. We diagnosed 27 crows with proliferative skin lesions (19 carcasses and eight biopsied cases [one in zoo captivity]) as avian pox clinically, histopathologically by detection of Avipoxvirus-specific 4b core protein (P4b) gene, and epidemiologically. The fatal cases demonstrated intensively severe infection and aggressive lesions with secondary bacterial infection. Since the first identification of avian pox in Sapporo, Japan, in 2006, the frequency of mortality events has increased, peaking in 2007-08. Mortalities have subsequently occurred in other areas, suggesting disease expansion. In Sapporo, prevalence of avian pox evaluated by field censuses during 2007-12 was 17.6% (6.6-27.2%), peaked during 2007-08 and 2008-09, and then decreased. All diseased crows were juveniles, except for one adult. The number of crows assembling in the winter roosts had been stable for >10 yr; however, it declined in 2007-08, decreased by about 50% in 2008-09, and recovered to the previous level in 2009-10, correlated with the avian pox outbreak. Thus, avian pox probably contributed to the unusual crow population decline. All P4b sequences detected in six specimens in Sapporo were identical and different from any previously reported sequences. The sequence detected in the zoo-kept crow was distinct from any reported clades, and interspecies transmission was suspected. This report demonstrates an emerging novel avian pox in the Japanese avifauna and in global populations of Carrion Crows and Large-billed Crows. Longitudinal monitoring is needed to evaluate its impact on the crow population. PMID- 26967131 TI - GEOGRAPHIC DISTRIBUTION AND MOLECULAR DIVERSITY OF BARTONELLA SPP. INFECTIONS IN MOOSE (ALCES ALCES) IN FINLAND. AB - Moose, Alces alces (Artiodactyla: Cervidae) in Finland are heavily infested with deer keds, Lipoptena cervi (Diptera: Hippoboschidae). The deer ked, which carries species of the genus Bartonella, has been proposed as a vector for the transmission of bartonellae to animals and humans. Previously, bartonella DNA was found in deer keds as well as in moose blood collected in Finland. We investigated the prevalence and molecular diversity of Bartonella spp. infection from blood samples collected from free-ranging moose. Given that the deer ked is not present in northernmost Finland, we also investigated whether there were geographic differences in the prevalence of bartonella infection in moose. The overall prevalence of bartonella infection was 72.9% (108/148). Geographically, the prevalence was highest in the south (90.6%) and lowest in the north (55.9%). At least two species of bartonellae were identified by multilocus sequence analysis. Based on logistic regression analysis, there was no significant association between bartonella infection and either age or sex; however, moose from outside the deer ked zone were significantly less likely to be infected (P<0.015) than were moose hunted within the deer ked zone. PMID- 26967130 TI - DIAGNOSIS AND THERAPY OF LIVER FLUKE (FASCIOLOIDES MAGNA) INFECTION IN FALLOW DEER (DAMA DAMA) IN SERBIA. AB - Giant liver fluke ( Fascioloides magna ) infection is an important health problem of cervids in southeastern Europe. We measured the prevalence and intensity of infection with F. magna in a fenced area near the Danube River in the South Backa District of Serbia. Parasitologic, pathomorphologic, and histopathologic examinations were conducted from November 2007 to February 2008, beginning with a population of 127 adult fallow deer ( Dama dama ). After a positive diagnosis, therapy with triclabendazole-medicated corn was applied. Deer were treated at four baiting stations, using medicated feed providing triclabendazole at an estimated dose of 10-14 mg/kg of body weight per deer. Treatment lasted for 7 d in early February 2008 and an additional 7 d 2 wk later. For the complete success of pharmacotherapy it was necessary to prevent any contact of deer with the snail intermediate host ( Galba truncatula ). Intervention in the habitat, removing grass and low vegetation, and draining ponds reduces the possibility of contact. Six months after the treatment, livers of hunted deer were reddish, with fibrous tracks; pigmentation and cysts in the parenchyma were surrounded by a fibrous capsule and their fecal samples contained no eggs of F. magna . Over the following years, livers of hunted deer were negative, and the last control cull in March 2015 confirmed complete absence of infection. We reconfirmed the presence of giant liver flukes in fallow deer in Serbia, apparently the result of natural spread across the Danube from Hungary and Croatia. We also report that the treatment of deer with triclabendazole-medicated corn is an effective method for administration of therapeutic doses of drug in semicaptive deer. Interventions in the environment are necessary to prevent recontact of deer with habitats used by the snail intermediate host, and enable the success of the therapy. PMID- 26967133 TI - ECO-EPIZOOTIOLOGIC STUDY OF FRANCISELLA TULARENSIS, THE AGENT OF TULAREMIA, IN QUEBEC WILDLIFE. AB - In Canada, Francisella tularensis , the zoonotic bacterial agent of tularemia, affects mostly snowshoe hares ( Lepus americanus ), muskrats ( Ondatra zibethicus ), and beavers ( Castor canadensis ). Despite numerous studies, the ecologic cycle and natural reservoirs of F. tularensis are not clearly defined. We conducted a cross-sectional study to estimate the prevalence of F. tularensis in snowshoe hares, muskrats, and coyotes ( Canis latrans ) in four regions of Quebec, Canada, and to describe the risk of infection in relation to host and environmental characteristics at three spatial scales. Between October 2012 and April 2013, trappers captured 345 snowshoe hares, 411 muskrats, and 385 coyotes. Blood samples were tested by microagglutination tests, and DNA extracts of liver, kidney, lung, and spleen of snowshoe hares and muskrats were tested by real-time PCR to detect past and active infection to F. tularensis , respectively. Individual host characteristics, including body condition, age, and sex, were evaluated as risk factors of infection, along with ecologic characteristics of the location of capture extracted from geographic databases. Prevalences of antibody to F. tularensis and 95% confidence intervals were 2.9% (1.4-5.1%) in coyotes, 0.6% (0.1-2.1%) in hares, and 0% (0.0-0.9%) in muskrats. Francisella tularensis DNA was not detected by real-time PCR in the pools of four organs from muskrats and hares, but F. tularensis type AI was detected during testing of the individual organs of two antibody-positive hares. Exact logistic regression analyses showed that age was a significant predictor of antibody detection in coyotes, as were the proportion of forest and the proportion of area considered as suitable habitat for hares in the environment around the location of capture of the coyotes. Our results suggest a terrestrial cycle of F. tularensis in the regions studied. PMID- 26967132 TI - PREVALENCE AND PATHOLOGIC FEATURES OF CHLAMYDIA PECORUM INFECTIONS IN SOUTH AUSTRALIAN KOALAS (PHASCOLARCTOS CINEREUS). AB - Chlamydia pecorum infection is highly prevalent in many koala ( Phascolarctos cinereus ) populations in the eastern states of Australia, causing ocular and urogenital tract disease. In contrast, the current prevalence of chlamydiosis in South Australian (SA) koalas is largely unknown, with few reports of clinical cases. We examined 65 SA rescued wild koalas at necropsy and collected ocular and urogenital swabs for the detection of C. pecorum by PCR. We detected C. pecorum in ocular or urogenital swabs from 57 koalas (88%), and 34 koalas were positive at both ocular and urogenital sites. Clinically overt chlamydial disease was present in only 12 (21%) positive koalas. Gross lesions were often externally inapparent as they affected the urogenital tract (n=5), and 24 infected koalas had microscopically evident lesions only. Lesions were predominantly mild and included conjunctivitis, cystitis, and urethritis. Reproductive tract disease was infrequently observed. We detected C. pecorum in 16 (28%) koalas with no evidence of chlamydial disease, suggesting the presence of subclinical carriers in this population. Based on these findings, chlamydiosis has a higher occurrence in SA koala populations than previously thought, but is most often mild and does not always result in overt clinical disease; inapparent and subclinical infections appear common. Further studies of the prevalence in wild-caught SA koalas are needed along with research into the host and bacterial factors that may influence disease outcome in these animals. PMID- 26967134 TI - OCCURRENCE OF LUNGWORMS IN EUROPEAN WILDCATS (FELIS SILVESTRIS SILVESTRIS) OF CENTRAL ITALY. AB - The increasing focus on infections in domestic cats ( Felis catus ) has raised questions about lungworm distribution in wild hosts. To enhance knowledge of the occurrence of lungworms in enzootic regions of central Italy, we examined the carcasses of 16 European wildcats ( Felis silvestris silvestris). Adult nematodes, feces, respiratory flushings, and pulmonary tissues were collected at necropsy and then microscopically and genetically analyzed. Fourteen wildcats had single or mixed lungworm species. Aelurostrongylus abstrusus was the most common parasite retrieved, followed by Troglostrongylus brevior. In addition, three specimens of Angiostrongylus chabaudi were found in the pulmonary arteries of one wildcat. Histologically, the most common lesions were a mild-to-severe chronic catarrhal bronchitis and a chronic interstitial pneumonia with smooth muscle hypertrophy, associated with T. brevior and A. abstrusus , respectively. These results demonstrate that the European wildcats may harbor several species of lungworms that may impair their health and welfare. Also, F. s. silvestris is a potential reservoir for respiratory nematodes in domestic cats. PMID- 26967136 TI - PATHOGENIC LEPTOSPIRA SEROVARS IN FREE-LIVING SEA LIONS IN THE GULF OF CALIFORNIA AND ALONG THE BAJA CALIFORNIA COAST OF MEXICO. AB - The California sea lion ( Zalophus californianus ), a permanent inhabitant of the Gulf of California in Mexico, is susceptible to pathogenic Leptospira spp. infection, which can result in hepatic and renal damage and may lead to renal failure and death. During summer 2013, we used the microscopic agglutination test (MAT) to investigate the prevalence of anti-Leptospira antibodies in blood of clinically healthy sea lion pups from seven rookery islands on the Pacific Coast of Baja California (Pacific Ocean) and in the Gulf of California. We also used PCR to examine blood for Leptospira DNA. Isolation of Leptospira in liquid media was unsuccessful. We found higher antibody prevalence in sea lions from the rookery islands in the gulf than in those from the Pacific Coast. Antibodies against 11 serovars were identified in the Gulf of California population; the most frequent reactions were against serovars Bataviae (90%), Pyrogenes (86%), Wolffi (86%), Celledoni (71%), and Pomona (65%). In the Pacific Ocean population, MAT was positive against eight serovars, where Wolffi (88%), Pomona (75%), and Bataviae (70%) were the most frequent. Serum samples agglutinated with more than one Leptospira serovar. The maximum titer was 3,200. Each island had a different serology profile, and islands combined showed a distinct profile for each region. We detected pathogenic Leptospira DNA in 63% of blood samples, but we found no saprophytic Leptospira. Positive PCR results were obtained in blood samples with high and low MAT titers. Together, these two methods enhance the diagnosis and interpretation of sea lion leptospirosis. Our results may be related to human activities or the presence of other reservoirs with which sea lions interact, and they may also be related to sea lion stranding. PMID- 26967135 TI - EFFECT OF DIFFERENT ECOSYSTEMS AND MANAGEMENT PRACTICES ON TOXOPLASMA GONDII AND NEOSPORA CANINUM INFECTIONS IN WILD RUMINANTS IN SPAIN. AB - Toxoplasma gondii and Neospora caninum are two major abortifacient protozoans in domestic small ruminants and cattle, respectively, and they also parasitize a wide range of wildlife. Numerous serosurveys have been conducted in wild ruminants worldwide. However, the potential effect of different ecosystems and management practices on these infections has not been investigated. We studied the prevalence of antibodies to T. gondii and N. caninum in wild ruminants between 2007 and 2012 from four national wildlife reserves: three open space reserves in northwest Spain (Ancares, Mampodre, and Riano) and a fenced reserve in central Spain (Quintos de Mora). Sera from roe deer ( Capreolus capreolus ) and chamois ( Rupicapra rupicapra ) were collected in Ancares (roe deer), Mampodre (both species), and Riano (both species), whereas red deer ( Cervus elaphus ) sera were collected only in Quintos de Mora. The results of immunofluorescence antibody tests showed a T. gondii antibody prevalence significantly higher in red deer (13%; 17/131) than in roe deer (2%; 5/228) and chamois (4%; 6/149) (P<0.05, Fisher's exact test). Moreover, N. caninum -specific antibodies were only detected in 1% of animals (2/131 red deer, 2/228 roe deer, and 2/149 chamois). Management measures were implemented in the Quintos de Mora reserve and T. gondii antibody prevalence in red deer decreased from 13% to 2% after 5 yr. In contrast, N. caninum antibody prevalences were very low (<2%) over the years. The results suggest a low frequency of sylvatic life cycles in the hunting reservations studied, so interconnection between sylvatic and domestic life cycles is unlikely. Regardless, a sustainable exploitation of natural resources in wildlife reserves may help to reduce the prevalence of T. gondii infection. PMID- 26967137 TI - THE HIGH COST OF MOTHERHOOD: END-LACTATION SYNDROME IN SOUTHERN SEA OTTERS (ENHYDRA LUTRIS NEREIS) ON THE CENTRAL CALIFORNIA COAST, USA. AB - Sea otters ( Enhydra lutris ) have exceptionally high energetic requirements, which nearly double during lactation and pup care. Thus, females are extremely vulnerable to caloric insufficiency. Despite a number of compensatory strategies, the metabolic challenge of reproduction culminates in numerous maternal deaths annually. Massive depletion of energy reserves results in a case presentation that we define as end-lactation syndrome (ELS), characterized by moderate to severe emaciation not attributable to a concurrent, independent disease process in females dying during late pup care or postweaning. We compiled detailed data for 108 adult female southern sea otters ( Enhydra lutris nereis) examined postmortem that stranded in California, US, 2005-12, and assessed pathology, reproductive status, and the location and timing of stranding. We introduce simple, grossly apparent, standardized physical criteria to assess reproductive stage for female sea otters. We also describe ELS, examine associated risk factors, and highlight female life history strategies that likely optimize reproduction and survival. Our data suggest that females can reset both the timing and energetic demands of reproduction through fetal loss, pup abandonment, or early weaning as part of specific physiologic checkpoints during each reproductive cycle. Females appear to preload nutritionally during delayed implantation and gestation to increase fitness and reproductive success. We found that ELS was a major cause of death, affecting 56% of enrolled adult females. Peak ELS prevalence occurred in late spring, possibly reflecting the population trend toward fall/winter pupping. Increasing age and number of pregnancies were associated with a higher risk of ELS. Although the proportion of ELS females was highest in areas with dense sea otter populations, cases were recovered throughout the range, suggesting that death from ELS is associated with, but not solely caused by, population resource limitation. PMID- 26967138 TI - TOXOPLASMA GONDII ANTIBODY PREVALENCE AND TWO NEW GENOTYPES OF THE PARASITE IN ENDANGERED HAWAIIAN GEESE (NENE: BRANTA SANDVICENSIS). AB - Toxoplasma gondii is a protozoan parasite transmitted by domestic cats ( Felis catus ) that has historically caused mortality in native Hawaiian birds. To estimate how widespread exposure to the parasite is in nene (Hawaiian Geese, Branta sandvicensis), we did a serologic survey for T. gondii antibody and genetically characterized parasite DNA from the tissues of dead birds that had confirmed infections by immunohistochemistry. Of 94 geese sampled, prevalence on the island of Kauai, Maui, and Molokai was 21% (n=42), 23% (n=31), and 48% (n=21), respectively. Two new T. gondii genotypes (ToxoDB #261 and #262) were identified by PCR-restriction fragment length polymorphism from four geese, and these appeared segregated geographically. Exposure to T. gondii in wild nene is widespread and, while the parasite is not a major cause of death, it could have sublethal or behavioral effects. How to translate such information to implement effective ways to manage feral cats in Hawaii poses challenges. PMID- 26967139 TI - THE STRUCTURE AND SEASONALITY OF BAYLISASCARIS PROCYONIS POPULATIONS IN RACCOONS (PROCYON LOTOR). AB - Baylisascaris procyonis , the raccoon ( Procyon lotor ) ascarid, is a common roundworm parasite of raccoons that is also a well-recognized zoonotic pathogen, and a cause for conservation concern. The transmission dynamics of B. procyonis differ with host population attributes, season, and landscape. We examined how the parasite's population attributes change with season, parasite population structure, and host demographics. We examined 1,050 raccoon gastrointestinal tracts collected from 1996 to 2012. Of the 1,050 raccoons necropsied, 382 (36%) were infected with at least one B. procyonis (x-=15.8 [95% confidence interval=13.39-18.26]; median=7; range 1-199 worms/host), and populations were overdispersed. There was a seasonal change in prevalence with a peak in October/November. Worm burdens decreased approximately 28% per month from January to June and increased approximately 31% per month from June to December. The sex structure of B. procyonis populations was female-biased (56% female). Host demographics did not impact parasite population attributes. This study provides evidence that B. procyonis populations exhibit a yearly cycle of loss and recruitment that may impact the transmission dynamics of the parasite. PMID- 26967140 TI - HEMATOLOGY IN AN EASTERN MASSASAUGA (SISTRURUS CATENATUS) POPULATION AND THE EMERGENCE OF OPHIDIOMYCES IN ILLINOIS, USA. AB - Disease events are threatening wildlife populations across North America. Specifically, mortality events due to Ophidiomyces (snake fungal disease; SFD) have been observed recently in snakes in Illinois, US. We investigated the health of a population of eastern massasaugas ( Sistrurus catenatus ) in south-central Illinois using 1) a meta-analysis of hematologic findings from 2004, 2011, 2013, and 2014; 2) a determination of the prevalence of SFD in snakes examined in 2013 and 2014; and 3) the examination of 184 museum specimens collected from 1999-2013 for signs and presence of SFD. For the meta-analysis and prevalence of SFD, hematologic analytes were reduced to three principle components that explained 67.5% of the cumulative variance. There were significant differences among one principle component (total white blood cell counts, monocytes, lymphocytes, and basophils) across years when it was highest in 2004 and 2014. The top general linear model explaining the difference in principle components included the main effects of year and stage, body condition index (BCI), and the interaction between stage and BCI. The prevalence of SFD was 18% (n=7) in 2013 and 24% (n=11) in 2014, and no hematologic analytes were associated with SFD. In museum specimens, Ophidiomyces DNA was first detected from an individual collected in 2000. Studies such as these, integrating multiple modalities of health, can elucidate the epidemiology of diseases that may pose conservation threats. PMID- 26967141 TI - THIAFENTANIL-AZAPERONE-XYLAZINE AND CARFENTANIL-XYLAZINE IMMOBILIZATIONS OF FREE RANGING CARIBOU (RANGIFER TARANDUS GRANTI) IN ALASKA, USA. AB - Carfentanil-xylazine (CX) has been the primary drug combination used for immobilizing free-ranging ungulates in Alaska, US since 1986. We investigated the efficacy of a potential new drug of choice, thiafentanil (Investigational New Animal Drug A-3080). Captive trials indicated that thiafentanil-azaperone medetomidine could provide good levels of immobilization. However, field trials conducted in October 2013 on free-ranging caribou ( Rangifer tarandus granti) calves showed the combination too potent, causing three respiratory arrests and one mortality. The protocol was revised to thiafentanil-azaperone-xylazine (TAX), with good results. The induction time was not significantly different between the two combinations. However, the recovery time was significantly shorter for the TAX group than for the CX group. A physiologic evaluation was performed on 12 animals immobilized on CX and 15 animals on TAX. Arterial blood was collected after induction and again after 10 min of intranasal oxygen supplements (1 L/min). Both groups had significant increases in partial pressure of arterial oxygen after oxygen treatment. There was a concurrent significant increase in partial pressure of arterial carbon dioxide in both groups. Rectal temperature increased significantly in both groups during the downtime, which is consistent with other studies of potent opioids in ungulates. On the basis of our results, we found TAX to be a potential alternative for the current CX protocol for immobilizing free-ranging caribou calves via helicopter darting. PMID- 26967142 TI - EUCOLEUS BOEHMI INFECTION IN THE NASAL CONCHAE AND PARANASAL SINUSES OF RED FOX (VULPES VULPES) ON PRINCE EDWARD ISLAND, CANADA. AB - Eucoleus boehmi (Nematoda: Capillariidae) occurs in the nasal conchae and paranasal sinuses of wild and domestic canids. We surveyed the red fox ( Vulpes vulpes ) on Prince Edward Island, Canada, for E. boehmi infection and characterized the associated histopathology. Nasal capillarid infections were detected based on histologic examination of three coronal sections of the nasal cavity and by centrifugal flotation examination (CFE) of rectal feces. Capillarids were detected in histologic sections in 28 of 36 (78%) foxes; detection occurred most frequently in the caudal section (28 foxes) and least in the rostral section (10 foxes). Adult worm morphology was typical for capillarids (stichosome esophagus, bacillary bands, bipolar plugged eggs); E. boehmi eggs were specifically identified based on the characteristic pitted shell wall surface. Adult worms were detected in histologic sections in all 28 and E. boehmi eggs in 21 of the positive foxes. No eggs of Eucoleus aerophilus were observed in any of the sections. Affected foxes had an eosinophilic and lymphoplasmacytic rhinitis with goblet cell hyperplasia. Eggs of E. aerophilus were detected on CFE in 20 of 36 (56%) foxes; 19 of the histologically positive foxes were coinfected with E. aerophilus. Eggs of E. boehmi were detected on CFE in 26 of 36 (72%) foxes and were consistent in size and morphology with those described from wild canids, but they differed from those reported from cases of infection in dogs. Prevalence based on identification of eggs on histologic section or CFE indicated 27 of 36 (75%) red foxes examined were infected with E. boehmi. PMID- 26967144 TI - Correlation of Doxorubicin Delivery and Tumor Necrosis after Drug-eluting Bead Transarterial Chemoembolization of Rabbit VX2 Liver Tumors. AB - Purpose To quantify the correlation between doxorubicin (DOX) delivery and tumor necrosis after drug-eluting bead (DEB) transarterial chemoembolization (TACE). Materials and Methods In this animal care committee-approved study, New Zealand white rabbit VX2 liver tumors were treated transarterially with DOX-loaded 70-150 MUm DEBs in five treatment groups with varying drug doses: sham (saline), 0 mg, 12.5 mg, 25 mg, and 37.5 mg. DEB TACE was followed by 3- and 7-day sacrifice, tumor harvest, and sectioning. Drug delivery was assessed by using fluorescence imaging, and tumor necrosis was quantified by means of histologic analysis. Statistical correlation of DOX delivery and tumor necrosis was performed by using the Spearman rank correlation coefficient (rho). Results Thirty-six VX2 tumors (median diameter, 1.3 cm) in 20 rabbits (median weight, 2.8 kg) underwent successful DEB TACE. Treatment groups included eight, seven, eight, five, and eight tumors of similar size (P > .05). Tumors showed progressively greater DOX extent (sham, 0%; 0 mg, 0%; 12.5 mg, 3%; 25 mg, 20%; and 37.5 mg, 27%) and intensity (sham, 0.4; 0 mg, 1.9; 12.5 mg, 8.5; 25 mg, 9.6; and 37.5 mg, 18.3) and higher median percentage necrosis (sham, 68%; 0 mg, 64%; 12.5 mg, 76%; 25 mg, 78%; and 37.5 mg, 83%) across DOX treatment groups. Correlation of DOX extent (rho = 0.975, P = .005) and intensity (rho = 0.900, P = .037) with percentage tumor necrosis was statistically significant. Conclusion Incremental increases in DOX correlate with greater necrosis in rabbit VX2 liver tumors after DEB TACE. This result indicates an essential role for chemotherapy-induced cytotoxicity in TACE effectiveness and supports the use of chemotherapeutic drugs in transarterial therapy. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 26967145 TI - Three-dimensional Biomimetic Technology: Novel Biorubber Creates Defined Micro- and Macro-scale Architectures in Collagen Hydrogels. AB - Tissue scaffolds play a crucial role in the tissue regeneration process. The ideal scaffold must fulfill several requirements such as having proper composition, targeted modulus, and well-defined architectural features. Biomaterials that recapitulate the intrinsic architecture of in vivo tissue are vital for studying diseases as well as to facilitate the regeneration of lost and malformed soft tissue. A novel biofabrication technique was developed which combines state of the art imaging, three-dimensional (3D) printing, and selective enzymatic activity to create a new generation of biomaterials for research and clinical application. The developed material, Bovine Serum Albumin rubber, is reaction injected into a mold that upholds specific geometrical features. This sacrificial material allows the adequate transfer of architectural features to a natural scaffold material. The prototype consists of a 3D collagen scaffold with 4 and 3 mm channels that represent a branched architecture. This paper emphasizes the use of this biofabrication technique for the generation of natural constructs. This protocol utilizes a computer-aided software (CAD) to manufacture a solid mold which will be reaction injected with BSA rubber followed by the enzymatic digestion of the rubber, leaving its architectural features within the scaffold material. PMID- 26967143 TI - Fibrofatty Changes: Incidence at Cardiac MR Imaging in Patients with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. AB - Purpose To determine the incidence of ventricular fatty replacement and late gadolinium enhancement (LGE) at cardiac magnetic resonance (MR) imaging in patients with arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy (ARVD/C) and the relationship of these findings to disease severity. Materials and Methods This was a retrospective institutional review board-approved HIPAA compliant study. All subjects provided written informed consent. Seventy-six patients with ARVD/C were enrolled from 2002 to 2012. Quantitative and qualitative cardiac MR imaging analyses of the RV and the left ventricle (LV) were performed to determine cardiac MR imaging-specific Task Force Criteria (TFC) and non-TFC features (ARVD/C-type pattern of fatty infiltration and/or nonischemic pattern LGE). Patients were separated into four groups on the basis of cardiac MR imaging TFC: (a) patients with major cardiac MR imaging criteria, (b) patients with minor criteria, (c) patients with partial criteria, and (d) patients with no criterion. Continuous variables were compared by using the independent Student t test and analysis of variance. Categoric variables were compared by using the Fisher exact test. Results Of 76 patients (mean age, 34.2 years +/- 14 [standard deviation]; 51.3% men), 42 met major cardiac MR imaging criteria, seven met minor criteria, seven met partial criteria, and 20 met no criterion. Most probands (36 [80.0%] of 45) met major or minor cardiac MR imaging criteria. Only 13 (41.9%) of 31 family members met any cardiac MR imaging criterion. The most common non-TFC MR imaging features were RV fatty infiltration (28.9%) and LV LGE (35.5%). Non-TFC cardiac MR imaging features were seen in 88.1% of subjects with major criteria, in 28.6% of those with minor criteria, in 71.4% of those with partial criteria, and in 10.0% of those with no criteria. Conclusion In this large cohort of patients with ARVD/C, non-TFC findings of ventricular fatty infiltration and LGE were frequent and were most often found in those who met major cardiac MR imaging criteria and in probands. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 26967146 TI - Genome scan for nonadditive heterotic trait loci reveals mainly underdominant effects in Saccharomyces cerevisiae. AB - The overdominant model of heterosis explains the superior phenotype of hybrids by synergistic allelic interaction within heterozygous loci. To map such genetic variation in yeast, we used a population doubling time dataset of Saccharomyces cerevisiae 16 * 16 diallel and searched for major contributing heterotic trait loci (HTL). Heterosis was observed for the majority of hybrids, as they surpassed their best parent growth rate. However, most of the local heterozygous loci identified by genome scan were surprisingly underdominant, i.e., reduced growth. We speculated that in these loci adverse effects on growth resulted from incompatible allelic interactions. To test this assumption, we eliminated these allelic interactions by creating hybrids with local hemizygosity for the underdominant HTLs, as well as for control random loci. Growth of hybrids was indeed elevated for most hemizygous to HTL genes but not for control genes, hence validating the results of our genome scan. Assessing the consequences of local heterozygosity by reciprocal hemizygosity and allele replacement assays revealed the influence of genetic background on the underdominant effects of HTLs. Overall, this genome-wide study on a multi-parental hybrid population provides a strong argument against single gene overdominance as a major contributor to heterosis, and favors the dominance complementation model. PMID- 26967152 TI - Total Synthesis of Laspartomycin C and Characterization of Its Antibacterial Mechanism of Action. AB - Laspartomycin C is a lipopeptide antibiotic with activity against a range of Gram positive bacteria including drug-resistant pathogens. We report the first total synthesis of laspartomycin C as well as a series of structural variants. Laspartomycin C was found to specifically bind undecaprenyl phosphate (C55-P) and inhibit formation of the bacterial cell wall precursor lipid II. While several clinically used antibiotics target the lipid II pathway, there are no approved drugs that act on its C55-P precursor. PMID- 26967151 TI - What can structured professional judgement tools contribute to management of neurobehavioural disability? Predictive validity of the Short-Term Assessment of Risk and Treatability (START) in acquired brain injury. AB - Aggression is a frequently cited outcome of acquired brain injury (ABI). Paradoxically, evidence suggests that ABI clinicians underestimate the risk of violence, and aggression in neurobehavioural services appears more frequent than in forensic/secure psychiatric settings. Risk assessment tools are endemic in the latter and highly beneficial in managing harm. However, none has been validated for ABI. This study examines the predictive validity of ABI violence using one established tool, the Short-Term Assessment of Risk and Treatability (START). It is argued that successful management of aggression in neurobehavioural rehabilitation is partly attributable to ongoing programme calibration following regular review of measures conceptualised for ABI. The predictive ability of START and ABI measures was determined through correlational, receiver operating characteristic and hierarchical multiple regression analyses, using 4559 aggression recordings concerning 76 patients over 4 weeks. The START risk of violence was classed "low" for 50% of the sample and "high" for 13.7%. Significant relationships between individual measures and aggression were evident. However, multivariate analysis confirmed that the best fitting model comprised ABI measures of neurobehavioural disability and functional abilities: START data did not increase explained variance. ABI risk prediction may benefit from development of specific tools. However, these should be conceptualised for ABI to incorporate the diverse range of variables underpinning neurobehavioural disability. PMID- 26967147 TI - Interactions between intestinal pathogens, enteropathy and malnutrition in developing countries. AB - PURPOSE OF REVIEW: This review focuses on recent data highlighting the interactions between intestinal pathogens, enteropathy and malnutrition in developing countries, which drive morbidity and mortality and hinder the long term developmental potential of children. RECENT FINDINGS: Diarrhoea remains the second commonest cause of death in children below 5 years, and malnutrition underlies 45% of all child deaths. Even in the absence of diarrhoea, subclinical pathogen carriage and enteropathy are almost universal in developing countries. Here, we review recent studies addressing the causes and consequences of diarrhoea; emerging data on environmental influences that govern postnatal development of the gut and microbiota; current concepts of environmental enteric dysfunction; and recent intervention trials in the field. We highlight the interactions between these processes, whereby intestinal pathogens drive a cycle of gut damage, malabsorption, chronic inflammation and failed mucosal regeneration, leading to malnutrition and susceptibility to further enteric infections. SUMMARY: Efforts to improve child survival and long-term developmental potential need to address the overlapping and interacting effects of diarrhoea, enteropathy and malnutrition. Recent insights from human and animal studies suggest potential targets for intervention. PMID- 26967153 TI - Light-responsive in situ forming injectable implants for effective drug delivery to the posterior segment of the eye. AB - INTRODUCTION: Frequent intravitreal injections are currently the preferred treatment method for diseases affecting the posterior segment of the eye. However, these repeated injections have been associated with pain, risk of infection, hemorrhages, retinal detachment and high treatment costs. To overcome these limitations, light-responsive in situ forming injectable implants (ISFIs) may emerge as novel systems providing site-specific controlled drug delivery to the retinal tissues with great accuracy, safety, minimal invasiveness and high cost efficiency. AREA COVERED: Complex ocular barriers, routes for drug delivery, types of injectable implants, ocular application of light and benefits of light responsive systems are discussed with regards to challenges and strategies employed for effective drug delivery to the posterior segment of the eye. In particular, we have highlighted photoresponsive moieties, photopolymerization mechanisms and different development strategies with their limitations as well as recent advancements in the field. EXPERT OPINION: Biodegradable light-responsive ISFIs are promising drug delivery systems that have shown a high degree of biocompatibility with sustained drug release in a number of applications. However, their use in intravitreal drug delivery is still in the very early stages. Issues related to the biocompatibility of the photoinitiator and the elimination of photo-degraded by-products from the ocular tissues need careful consideration, not only from a chemistry standpoint, but also from a biological perspective to improve the suitability of these systems for clinical applications. PMID- 26967154 TI - Characterization of HIV Transmission in South-East Austria. AB - To gain deeper insight into the epidemiology of HIV-1 transmission in South-East Austria we performed a retrospective analysis of 259 HIV-1 partial pol sequences obtained from unique individuals newly diagnosed with HIV infection in South-East Austria from 2008 through 2014. After quality filtering, putative transmission linkages were inferred when two sequences were <=1.5% genetically different. Multiple linkages were resolved into putative transmission clusters. Further phylogenetic analyses were performed using BEAST v1.8.1. Finally, we investigated putative links between the 259 sequences from South-East Austria and all publicly available HIV polymerase sequences in the Los Alamos National Laboratory HIV sequence database. We found that 45.6% (118/259) of the sampled sequences were genetically linked with at least one other sequence from South-East Austria forming putative transmission clusters. Clustering individuals were more likely to be men who have sex with men (MSM; p<0.001), infected with subtype B (p<0.001) or subtype F (p = 0.02). Among clustered males who reported only heterosexual (HSX) sex as an HIV risk, 47% clustered closely with MSM (either as pairs or within larger MSM clusters). One hundred and seven of the 259 sequences (41.3%) from South-East Austria had at least one putative inferred linkage with sequences from a total of 69 other countries. In conclusion, analysis of HIV-1 sequences from newly diagnosed individuals residing in South-East Austria revealed a high degree of national and international clustering mainly within MSM. Interestingly, we found that a high number of heterosexual males clustered within MSM networks, suggesting either linkage between risk groups or misrepresentation of sexual risk behaviors by subjects. PMID- 26967156 TI - An ethanol extract of Ramulus mori improves blood circulation by inhibiting platelet aggregation. AB - Inappropriate platelet aggregation can cause blood coagulation and thrombosis. In this study, the effect of an ethanol extract of Ramulus mori (ERM) on blood circulation was investigated. The antithrombotic activity of ERM on rat carotid arterial thrombosis was evaluated in vivo, and the effect of ERM on platelet aggregation and blood coagulation time was evaluated ex vivo. To evaluate the safety of ERM, its cytotoxicity to platelets and its effect on tail bleeding time were assessed; ERM was not toxic to rat platelets and did not prolong bleeding time. Moreover, administering ERM to rats had a significant preventive effect on carotid arterial thrombosis in vivo, and significantly inhibited adenosine diphosphate- and collagen-induced platelet aggregation ex vivo, whereas it did not prolong coagulation periods, such as prothrombin time and activated partial thromboplastin time. The results suggest that ERM is effective in improving blood circulation via antiplatelet activity rather than anticoagulation activity. PMID- 26967155 TI - Pharmacological Modulation of Hemodynamics in Adult Zebrafish In Vivo. AB - INTRODUCTION: Hemodynamic parameters in zebrafish receive increasing attention because of their important role in cardiovascular processes such as atherosclerosis, hematopoiesis, sprouting and intussusceptive angiogenesis. To study underlying mechanisms, the precise modulation of parameters like blood flow velocity or shear stress is centrally important. Questions related to blood flow have been addressed in the past in either embryonic or ex vivo-zebrafish models but little information is available for adult animals. Here we describe a pharmacological approach to modulate cardiac and hemodynamic parameters in adult zebrafish in vivo. MATERIALS AND METHODS: Adult zebrafish were paralyzed and orally perfused with salt water. The drugs isoprenaline and sodium nitroprusside were directly applied with the perfusate, thus closely resembling the preferred method for drug delivery in zebrafish, namely within the water. Drug effects on the heart and on blood flow in the submental vein were studied using electrocardiograms, in vivo-microscopy and mathematical flow simulations. RESULTS: Under control conditions, heart rate, blood flow velocity and shear stress varied less than +/- 5%. Maximal chronotropic effects of isoprenaline were achieved at a concentration of 50 MUmol/L, where it increased the heart rate by 22.6 +/- 1.3% (n = 4; p < 0.0001). Blood flow velocity and shear stress in the submental vein were not significantly increased. Sodium nitroprusside at 1 mmol/L did not alter the heart rate but increased blood flow velocity by 110.46 +/- 19.64% (p = 0.01) and shear stress by 117.96 +/- 23.65% (n = 9; p = 0.03). DISCUSSION: In this study, we demonstrate that cardiac and hemodynamic parameters in adult zebrafish can be efficiently modulated by isoprenaline and sodium nitroprusside. Together with the suitability of the zebrafish for in vivo microscopy and genetic modifications, the methodology described permits studying biological processes that are dependent on hemodynamic alterations. PMID- 26967158 TI - Multicentre Double-Blind Placebo-Controlled Food Challenge Study in Children Sensitised to Cashew Nut. AB - BACKGROUND: Few studies with a limited number of patients have provided indications that cashew-allergic patients may experience severe allergic reactions to minimal amounts of cashew nut. The objectives of this multicentre study were to assess the clinical relevance of cashew nut sensitisation, to study the clinical reaction patterns in double-blind placebo-controlled food challenge tests and to establish the amount of cashew nuts that can elicit an allergic reaction. METHODS AND FINDINGS: A total of 179 children were included (median age 9.0 years; range 2-17 years) with cashew nut sensitisation and a clinical history of reactions to cashew nuts or unknown exposure. Sensitised children who could tolerate cashew nuts were excluded. The study included three clinical visits and a telephone consultation. During the first visit, the medical history was evaluated, physical examinations were conducted, blood samples were drawn and skin prick tests were performed. The children underwent a double-blind placebo controlled food challenge test with cashew nut during the second and third visits. The study showed that 137 (76.5%) of the sensitised children suspected of allergy to cashew nut had a positive double-blind placebo-controlled food challenge test, with 46% (63) manifesting subjective symptoms to the lowest dose of 1 mg cashew nut protein and 11% (15) developing objective symptoms to the lowest dose. Children most frequently had gastro-intestinal symptoms, followed by oral allergy and skin symptoms. A total of 36% (49/137) of the children experienced an anaphylactic reaction and 6% (8/137) of the children were treated with epinephrine. CONCLUSION: This prospective study demonstrated a strikingly high percentage of clinical reactions to cashew nut in this third line population. Severe allergic reactions, including anaphylaxis requiring epinephrine, were observed. These reactions were to minimal amounts of cashew nut, demonstrated the high potency of this allergens. TRIAL REGISTRATION: www.ncbi.nlm.nih.gov/pubmed NTR3572. PMID- 26967157 TI - Factors Associated with Correct and Consistent Insecticide Treated Curtain Use in Iquitos, Peru. AB - Dengue is an arthropod-borne virus of great public health importance, and control of its mosquito vectors is currently the only available method for prevention. Previous research has suggested that insecticide treated curtains (ITCs) can lower dengue vector infestations in houses. This observational study investigated individual and household-level socio-demographic factors associated with correct and consistent use of ITCs in Iquitos, Peru. A baseline knowledge, attitudes, and practices (KAP) survey was administered to 1,333 study participants, and ITCs were then distributed to 593 households as part of a cluster-randomized trial. Follow up KAP surveys and ITC-monitoring checklists were conducted at 9, 18, and 27 months post-ITC distribution. At 9 months post-distribution, almost 70% of ITCs were hanging properly (e.g. hanging fully extended or tied up), particularly those hung on walls compared to other locations. Proper ITC hanging dropped at 18 months to 45.7%. The odds of hanging ITCs correctly and consistently were significantly greater among those participants who were housewives, knew three or more correct symptoms of dengue and at least one correct treatment for dengue, knew a relative or close friend who had had dengue, had children sleeping under a mosquito net, or perceived a change in the amount of mosquitoes in the home. Additionally, the odds of recommending ITCs in the future were significantly greater among those who perceived a change in the amount of mosquitoes in the home (e.g. perceived the ITCs to be effective). Despite various challenges associated with the sustained effectiveness of the selected ITCs, almost half of the ITCs were still hanging at 18 months, suggesting a feasible vector control strategy for sustained community use. PMID- 26967159 TI - The Silk Road Health Project: How Mobility and Migration Status Influence HIV Risks among Male Migrant Workers in Central Asia. AB - OBJECTIVES: We examined whether mobility, migrant status, and risk environments are associated with sexually transmitted infections (STIs) and HIV risk behaviors (e.g. sex trading, multiple partners, and unprotected sex). METHODS: We used Respondent Driven Sampling (RDS) to recruit external male migrant market vendors from Kyrgyzstan, Uzbekistan, and Tajikistan as well internal migrant and non migrant market vendors from Kazakhstan. We conducted multivariate logistic regressions to examine the effects of mobility combined with the interaction between mobility and migration status on STIs and sexual risk behaviors, when controlling for risk environment characteristics. RESULTS: Mobility was associated with increased risk for biologically-confirmed STIs, sex trading, and unprotected sex among non-migrants, but not among internal or external migrants. Condom use rates were low among all three groups, particularly external migrants. Risk environment factors of low-income status, debt, homelessness, and limited access to medical care were associated with unprotected sex among external migrants. CONCLUSION: Study findings underscore the role mobility and risk environments play in shaping HIV/STI risks. They highlight the need to consider mobility in the context of migration status and other risk environment factors in developing effective prevention strategies for this population. PMID- 26967160 TI - Reference-Free Assessment of Speech Intelligibility Using Bispectrum of an Auditory Neurogram. AB - Sensorineural hearing loss occurs due to damage to the inner and outer hair cells of the peripheral auditory system. Hearing loss can cause decreases in audibility, dynamic range, frequency and temporal resolution of the auditory system, and all of these effects are known to affect speech intelligibility. In this study, a new reference-free speech intelligibility metric is proposed using 2-D neurograms constructed from the output of a computational model of the auditory periphery. The responses of the auditory-nerve fibers with a wide range of characteristic frequencies were simulated to construct neurograms. The features of the neurograms were extracted using third-order statistics referred to as bispectrum. The phase coupling of neurogram bispectrum provides a unique insight for the presence (or deficit) of supra-threshold nonlinearities beyond audibility for listeners with normal hearing (or hearing loss). The speech intelligibility scores predicted by the proposed method were compared to the behavioral scores for listeners with normal hearing and hearing loss both in quiet and under noisy background conditions. The results were also compared to the performance of some existing methods. The predicted results showed a good fit with a small error suggesting that the subjective scores can be estimated reliably using the proposed neural-response-based metric. The proposed metric also had a wide dynamic range, and the predicted scores were well-separated as a function of hearing loss. The proposed metric successfully captures the effects of hearing loss and supra-threshold nonlinearities on speech intelligibility. This metric could be applied to evaluate the performance of various speech processing algorithms designed for hearing aids and cochlear implants. PMID- 26967161 TI - A Lymph Node Staging System for Gastric Cancer: A Hybrid Type Based on Topographic and Numeric Systems. AB - Although changing a lymph node staging system from an anatomically based system to a numerically based system in gastric cancer offers better prognostic performance, several problems can arise: it does not offer information on the anatomical extent of disease and cannot represent the extent of lymph node dissection. The purpose of this study was to discover an alternative lymph node staging system for gastric cancer. Data from 6025 patients who underwent gastrectomy for primary gastric cancer between January 2000 and December 2010 were reviewed. The lymph node groups were reclassified into lesser-curvature, greater-curvature, and extra-perigastric groups. Presence of any metastatic lymph node in one group was considered positive. Lymph node groups were further stratified into four (new N0-new N3) according to the number of positive lymph node groups. Survival outcomes with this new N staging were compared with those of the current TNM system. For validation, two centers in Japan (large center, n = 3443; medium center, n = 560) were invited. Even among the same pN stages, the more advanced new N stage showed worse prognosis, indicating that the anatomical extent of metastatic lymph nodes is important. The prognostic performance of the new staging system was as good as that of the current TNM system for overall advanced gastric cancer as well as lymph node-positive gastric cancer (Harrell C index was 0.799, 0.726, and 0.703 in current TNM and 0.799, 0.727, and 0.703 in new TNM stage). Validation sets supported these outcomes. The new N staging system demonstrated prognostic performance equal to that of the current TNM system and could thus be used as an alternative. PMID- 26967162 TI - Effect of Metformin Use on Survival in Resectable Pancreatic Cancer: A Single Institution Experience and Review of the Literature. AB - Observational studies have demonstrated that metformin use in diabetic patients is associated with reduced cancer incidence and mortality. Here, we aimed to determine whether metformin use was associated with improved survival in patients with resected pancreatic cancer. All patients with diabetes who underwent resection for pancreatic adenocarcinoma between 12/1/1986 and 4/30/2013 at our institution were categorized by metformin use. Survival analysis was done using the Kaplan-Meier method, with log-rank test and Cox proportional hazards multivariable regression models. For analyses of our data and the only other published study, we used Meta-Analysis version 2.2. We identified 44 pancreatic cancer patients with diabetes who underwent resection of the primary tumor (19 with ongoing metformin use, 25 never used metformin). There were no significant differences in major clinical and demographic characteristics between metformin and non-metformin users. Metformin users had a better median survival than nonusers, but the difference was not statistically significant (35.3 versus 20.2 months; P = 0.3875). The estimated 2-, 3-, and 5-year survival rates for non metformin users were 42%, 28%, and 14%, respectively. Metformin users fared better with corresponding rates of 68%, 34%, and 34%, respectively. In our literature review, which included 111 patients from the two studies (46 metformin users and 65 non-users), overall hazard ratio was 0.668 (95% CI 0.397-1.125), with P = 0.129. Metformin use was associated with improved survival outcomes in patients with resected pancreatic cancer, but the difference was not statistically significant. The potential benefit of metformin should be investigated in adequately powered prospective studies. PMID- 26967164 TI - Tranexamic acid-associated seizures: A meta-analysis. AB - PURPOSE: To investigate the incidence rate of tranexamic acid (TXA)-associated seizures. METHODS: Two electronic databases (Medline and Embase) were searched. We looked for additional studies in the references of all identified publications. The cutoff day was 2015 Dec 06. Two authors independently reviewed the titles and abstracts of the publications identified firstly. Odds ratio (OR) and 95% confidence interval (CI) were used to compare discontinuous variables. RESULTS: Ten studies enrolling 26,079 patients with TXA exposure and 7395 patients with non-TXA exposure were included. The cumulative incidence rate of TXA-associated seizures is 2.7%. The odds ratio of seizure is 5.39 (95%CI: 3.29 8.85; I(2)=0%; P<0.001) in patients with TXA exposure vs patients with non-TXA exposure. The incidence rate of TXA-associated seizures increased when the dose levels increased. CONCLUSION: The risk of seizure increased in patients with TXA exposure and the incidence rate of TXA-associated seizures increased when the dose levels increased. PMID- 26967163 TI - H3 Histone Tail Conformation within the Nucleosome and the Impact of K14 Acetylation Studied Using Enhanced Sampling Simulation. AB - Acetylation of lysine residues in histone tails is associated with gene transcription. Because histone tails are structurally flexible and intrinsically disordered, it is difficult to experimentally determine the tail conformations and the impact of acetylation. In this work, we performed simulations to sample H3 tail conformations with and without acetylation. The results show that irrespective of the presence or absence of the acetylation, the H3 tail remains in contact with the DNA and assumes an alpha-helix structure in some regions. Acetylation slightly weakened the interaction between the tail and DNA and enhanced alpha-helix formation, resulting in a more compact tail conformation. We inferred that this compaction induces unwrapping and exposure of the linker DNA, enabling DNA-binding proteins (e.g., transcription factors) to bind to their target sequences. In addition, our simulation also showed that acetylated lysine was more often exposed to the solvent, which is consistent with the fact that acetylation functions as a post-translational modification recognition site marker. PMID- 26967165 TI - Motivations for Intravaginal Product Use among a Cohort of Women in Los Angeles. AB - OBJECTIVE: Intravaginal practices-including behaviors such as intravaginal cleansing and insertion of products-have been linked to a number of adverse reproductive health outcomes, including increased risk for bacterial vaginosis, sexually transmitted infections, and HIV. Currently, little is known about the motivations for intravaginal practices among women in the United States. The objective of this study was to identify and describe motivations for intravaginal washing and intravaginal insertion of products among women of differing ages and racial/ethnic groups. METHODS: Between 2008 and 2010, we enrolled a convenience sample of sexually active women aged 18-65 years living in Los Angeles recruited through community education and outreach activities in HIV/AIDS service organizations, women's health clinics, community-based organizations, and HIV testing sites. At the enrollment visit, women completed a self-administered, computer-assisted questionnaire covering demographics, sexual behaviors, intravaginal practices, and motivations for intravaginal practices over the past month and past year. RESULTS: We enrolled 141 women; 34% of participants were Caucasian, 40% African American, and 26% Latina. Peri-sexual intravaginal washing was common in all groups, whether to clean up after sex (70%) or to prepare for sex (54%). African American women were more likely to report learning to wash intravaginally from their mothers compared to Latina or Caucasian women (70% vs. 49%, P = 0.04). Sixty-one percent of African American women reported using a douching device over the past year compared to 41% of Latina and 40% of Caucasian women (p = 0.02). Younger women were more likely to report that their male partners wanted them to wash intravaginally than older women (77% vs. 24%, P<0.01), and more likely to report the removal of odors as a motive than older women (65% vs. 40%, P = 0.04). The most commonly used intravaginal products included sexual lubricants, petroleum jelly, body lotions, oils, and wet wipes. Use of these products varied by race, and motives given included increasing lubrication, preparing for sex, smelling good, and preventing sexually transmitted infections. CONCLUSION: Women's intravaginal practices and motivations for these practices differ across race and age. Motivations for use also vary by type of intravaginal product used. Given that some intravaginal practices have been shown to be harmful, interventions, programs and counseling messages to encourage less harmful practices are needed, and should consider underlying motivations that influence women's vaginal practices. Practitioners may use these results to better support women in achieving vaginal health. PMID- 26967166 TI - Transposons, Genome Size, and Evolutionary Insights in Animals. AB - The relationship between genome size and the percentage of transposons in 161 animal species evidenced that variations in genome size are linked to the amplification or the contraction of transposable elements. The activity of transposable elements could represent a response to environmental stressors. Indeed, although with different trends in protostomes and deuterostomes, comprehensive changes in genome size were recorded in concomitance with particular periods of evolutionary history or adaptations to specific environments. During evolution, genome size and the presence of transposable elements have influenced structural and functional parameters of genomes and cells. Changes of these parameters have had an impact on morphological and functional characteristics of the organism on which natural selection directly acts. Therefore, the current situation represents a balance between insertion and amplification of transposons and the mechanisms responsible for their deletion or for decreasing their activity. Among the latter, methylation and the silencing action of small RNAs likely represent the most frequent mechanisms. PMID- 26967167 TI - Er:Yag Laser Treatment of Simple Snorers in an Outpatient Setting. AB - OBJECTIVE: Snoring occurs as a result of soft tissue vibration caused by a partial upper airway collapse during sleep. This study evaluated the effectiveness and potential adverse side effects associated with the use of a nonsurgical, erbium-doped yttrium aluminum garnet (Er:YAG) laser treatment for patients with snoring conditions. MATERIALS AND METHODS: In total, 33 patients with different degrees of snoring were analyzed retrospectively. All patients received three NightLaseTM Er:YAG laser treatments. Results were measured using a follow-up questionnaire and then statistically analyzed. Any effects that occurred during the first year after treatment (i.e., short-term effects) were followed up with interviews. RESULTS: Laser treatment effectively reduced patients' snoring and achieved a 65% satisfaction rate after three treatments. The greatest improvement and satisfaction were experienced by patients aged >=50 years. Patients reported additional benefits from this treatment including easier breathing, higher alertness, and increased focus. CONCLUSION: Nonsurgical Er:YAG laser treatment is an effective and minimally invasive procedure to reduce patient snoring and other sleep-disordered breathing symptoms. Patients reported minimal disadvantages including minor discomfort and a low risk of side effects. PMID- 26967168 TI - Photoinduced formation of threadlike micelles from mixtures of a cationic surfactant and a stilbene amphiphile. AB - This study examined the influence of ultraviolet (UV) irradiation on aqueous surfactant solutions containing an anionic stilbene derivative (sodium [4-[(E)-2 (4-butylphenyl)ethenyl]phenoxy]acetate; C4StilNa) as a photoresponsive skeleton. Prior to UV irradiation, an aqueous solution of cetyltrimethylammonium bromide (CTAB) and C4StilNa was a low-viscosity fluid forming spheroidal micelles. Exposure of the low-viscosity fluid to UV light resulted in the formation of threadlike micelles and an increase in the viscosity of the aqueous CTAB/C4StilNa solution. (1)H nuclear magnetic resonance spectroscopy indicated that the photochemically induced isomerization and dimerization reactions of C4StilNa molecules had occurred in the aggregates due to UV irradiation. Overall, the structural transformation of the stilbene groups in the C4StilNa molecules with the photochemical reactions leads to an increase in the critical packing parameter and consequently a photoinduced transition of spheroidal micelles to threadlike micelles. PMID- 26967170 TI - Course of Glaucomatous Visual Field Loss Across the Entire Perimetric Range. AB - Importance: Identifying the course of glaucomatous visual field (VF) loss that progresses from normal to perimetric blindness is important for treatment and prognostication. Objective: To model the process of glaucomatous VF decay over the entire perimetric range from normal to perimetric blindness. Design, Setting, and Participants: A post hoc, retrospective analysis was performed using data from the Advanced Glaucoma Intervention Study and the UCLA (University of California, Los Angeles) Jules Stein Eye Institute Glaucoma Division. Patients with open-angle glaucoma and VFs obtained from reliable examinations (defined as <30% fixation losses, <30% false-positive rates, and <30% false-negative rates) were recruited. All tests were performed with standard automated perimetry and a 24-2 test pattern. Linear, exponential, and sigmoid regression models were used to assess the pattern of threshold sensitivity deterioration at each VF location as a function of time. Visual field locations of interest included those with a mean of the initial 2 sensitivities of 26 dB or greater and a less than 10-dB mean of the final 2 sensitivities. Root mean squared error (RMSE) was used to evaluate goodness of fit for each regression model. The error was defined as the difference between the sensitivities modeled by the function and the observed sensitivities. The Advanced Glaucoma Intervention Study was conducted from 1998 to 2006; the present post hoc analysis was conducted from March 1, 2014, to March 1, 2015. Main Outcomes and Measures: The RMSE of the residuals (fitted minus observed values) for the 3 regression models was used to evaluate goodness of fit. Results: A total of 798 eyes from 583 patients (mean [SD] age, 64.7 [10.7] years; 301 [51.6%] women) who had more than 6 years of follow-up and underwent more than 10 VF examinations were included in this analysis. Mean (SD) follow-up time was 8.7 (2.2) years, and each eye had a mean of 15.2 (4.9) VF tests. For the VF locations with an initial sensitivity of 26 dB or greater and final sensitivity of less than 10 dB (309 locations), the sigmoid best-fit regression model had the lowest RMSE in 248 (80.3%) of the locations, the exponential function in 39 (12.6%), and the linear function in 22 (7.1%). The means (SDs) of RMSE were sigmoid, 4.1 (1.9); exponential, 6.0 (1.5); and linear 5.8 (1.6). Conclusions and Relevance: Pointwise sigmoid regression had a better ability to fit perimetric decay into a subset of locations that traverse the entire range of perimetric measurements from near normal to near perimetric blindness compared with linear and exponential functions. These results support the concept that the measured behavior of glaucomatous VF loss to perimetric blindness is nonlinear and that its course of deterioration may change with the course of disease. PMID- 26967169 TI - Construction and Systematical Symmetric Studies of a Series of Supramolecular Clusters with Binary or Ternary Ammonium Triphenylacetates. AB - Functions of clusters in nano or sub-nano scale significantly depend on not only kinds of their components but also arrangements, or symmetry, of their components. Therefore, the arrangements in the clusters have been precisely characterized, especially for metal complexes. Contrary to this, characterizations of molecular arrangements in supramolecular clusters composed of organic molecules are limited to a few cases. This is because construction of the supramolecular clusters, especially obtaining a series of the supramolecular clusters, is difficult due to low stability of non-covalent bonds compare to covalent bonds. From this viewpoint, utilization of organic salts is one of the most useful strategies. A series of the supramolecules could be constructed by combinations of a specific organic molecule with various counter ions. Especially, primary ammonium carboxylates are suitable as typical examples of supramolecules because various kinds of carboxylic acids and primary amines are commercially available, and it is easy to change their combinations. Previously, it was demonstrated that primary ammonium triphenylacetates using various kinds of primary amines specifically construct supramolecular clusters, which are composed of four ammoniums and four triphenylacetates assembled by charge assisted hydrogen bonds, in crystals obtained from non-polar solvents. This study demonstrates an application of the specific construction of the supramolecular clusters as a strategy to conduct systematical symmetric study for clarification of correlations between molecular arrangements in supramolecules and kinds and numbers of their components. In the same way with binary salts composed of triphenylacetates and one kind of primary ammoniums, ternary organic salts composed of triphenylacetates and two kinds of ammoniums construct the supramolecular clusters, affording a series of the supramolecular clusters with various kinds and numbers of the components. PMID- 26967171 TI - Depression-Specific Outcomes After Treatment of Chronic Rhinosinusitis. AB - IMPORTANCE: Depression is frequently undiagnosed in patients with chronic rhinosinusitis (CRS) and affects quality of life, productivity, and health care use. OBJECTIVE: To examine depression-specific outcomes after medical or surgical treatment of CRS. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional, prospective study of patients with refractory CRS treated at tertiary academic rhinology centers was performed from March 1, 2011, to November 1, 2015. Data analysis was performed from October 1, 2015, to November 1, 2015. INTERVENTIONS: Patients self-selected to undergo continued medical management or endoscopic sinus surgery for refractory CRS. MAIN OUTCOMES AND MEASURES: Patients completed the 22-item Sinonasal Outcome Test (SNOT22), Rhinosinusitis Disability Index (RSDI), Pittsburgh Sleep Quality Index (PSQI), and missed productivity and medication use questionnaires before and at least 6 months after treatment. Computed tomography and endoscopy scoring were performed with reviewers masked to patient-reported data. Depression-specific outcomes were recorded using the 2 item Patient Health Questionnaire (PHQ2). RESULTS: Baseline data were available on 685 patients, with 167 (24.4%) having depression according to the PHQ2 scores. The mean (SD) age of the patients was 50.5 (15.0) years, and 332 (48.4%) were male. Revision surgery status was the only baseline factor associated with depression (53.9% vs 38.0%, P < .001). Patients with depression had worse baseline SNOT22 (mean, 64.5 vs 47.6), PSQI (mean, 12.8 vs 8.4), productivity (mean, 22.8 vs 5.2 days missed), and medication use scores for oral antibiotics (mean, 23.8 vs 14.8) and oral corticosteroids (mean, 17.8 vs 9.9) (P < .001 for all). Medical and surgical treatments had similar outcomes for patients with depression with mean improvement in the PHQ2 scores from 3.96 to 1.91 (P < .001), and 110 of 167 patients (65.9%) categorized as having depression at baseline were categorized as not having depression after treatment. Improvements in the PHQ2 scores were associated with improvements in the SNOT22, PSQI, oral antibiotic use, and productivity scores (P <= .001 for all). CONCLUSIONS AND RELEVANCE: Depression is a common comorbidity in patients with CRS and affects numerous quality-of-life and health care outcomes. There are few objective baseline factors to aid physicians in identifying depression in patients with CRS. Medical and surgical treatments for CRS improve depression and related clinical outcomes. PMID- 26967172 TI - The role of the illusion in the construction of erotic desire: narratives from heterosexual men who have occasional sex with transgender women. AB - Little is known about men's sexual desire for and erotic attraction to male-to female transgender women. To better understand how erotic desire is constructed, this study examined the narratives of a sample of heterosexual men who had had an occasional sexual encounter with a transgender woman. Open-ended qualitative interviews were conducted with 16 heterosexual men who reported at least one sexual encounter with a transgender woman in the previous 12 months. Using principles of Grounded Theory, three themes emerged: (1) the erotic desire that transpired from a transgender woman's construction of her femininity, (2) the sexual act that dictated the specific navigation of a transgender woman's penis and (3) the sexual dissonance that resulted from being a heterosexually identified man having sex with a partner who had a penis. These themes reflected how the participants defined and negotiated their sexual encounters, both psychologically through their understanding of sex with a transgender woman with a penis, and physically through the navigation of specific sex acts. The role of the 'illusion' was central to the meaning and construction of erotic desire. These narratives provided another framework for continuing discourse on the complexity of erotic desire. PMID- 26967175 TI - Pathologic Abnormalities Behind Ductal Carcinoma In Situ Terminology. PMID- 26967176 TI - Treatment and Long-Term Risks for Patients With a Diagnosis of Ductal Carcinoma In Situ. PMID- 26967177 TI - Treatment and Long-Term Risks for Patients With a Diagnosis of Ductal Carcinoma In Situ-Reply. PMID- 26967178 TI - Treatment and Long-term Risks for Patients With a Diagnosis of Ductal Carcinoma In Situ. PMID- 26967179 TI - Effects of Standard Treatments for Ductal Carcinoma In Situ-Making Informed Choices. PMID- 26967180 TI - Treatment and Long-Term Risks for Patients With a Diagnosis of Ductal Carcinoma In Situ. PMID- 26967181 TI - Treatment Recommendations for Patients With a Diagnosis of Ductal Carcinoma In Situ. PMID- 26967182 TI - Treatment and Long-Term Risks for Patients With a Diagnosis of Ductal Carcinoma In Situ. PMID- 26967183 TI - Treatment and Long-Term Risks for Patients With a Diagnosis of Ductal Carcinoma In Situ. PMID- 26967184 TI - Treatment and Long-Term Risks for Patients With a Diagnosis of Ductal Carcinoma In Situ. PMID- 26967186 TI - Perspectives in Oncology Drug Pricing. PMID- 26967185 TI - Treatment and Long-Term Risks for Patients With a Diagnosis of Ductal Carcinoma In Situ-Reply. PMID- 26967187 TI - Perspectives in Oncology Drug Pricing. PMID- 26967188 TI - Perspectives in Oncology Drug Pricing. PMID- 26967189 TI - Perspectives in Oncology Drug Pricing-Reply. PMID- 26967190 TI - 340B Drug Pricing Program Reform. PMID- 26967191 TI - 340B Drug Pricing Program Reform-Reply. PMID- 26967192 TI - Co-intercalation of Mg(2+) and Na(+) in Na(0.69)Fe2(CN)6 as a High-Voltage Cathode for Magnesium Batteries. AB - Thanks to the advantages of low cost and good safety, magnesium metal batteries get the limelight as substituent for lithium ion batteries. However, the energy density of state-of-the-art magnesium batteries is not high enough because of their low operating potential; thus, it is necessary to improve the energy density by developing new high-voltage cathode materials. In this study, nanosized Berlin green Fe2(CN)6 and Prussian blue Na(0.69)Fe2(CN)6 are compared as high-voltage cathode materials for magnesium batteries. Interestingly, while Mg(2+) ions cannot be intercalated in Fe2(CN)6, Na(0.69)Fe2(CN)6 shows reversible intercalation and deintercalation of Mg(2+) ions, although they have the same crystal structure except for the presence of Na(+) ions. This phenomenon is attributed to the fact that Mg(2+) ions are more stable in Na(+)-containing Na(0.69)Fe2(CN)6 than in Na(+)-free Fe2(CN)6, indicating Na(+) ions in Na(0.69)Fe2(CN)6 plays a crucial role in stabilizing Mg(2+) ions. Na(0.69)Fe2(CN)6 delivers reversible capacity of approximately 70 mA h g(-1) at 3.0 V vs Mg/Mg(2+) and shows stable cycle performance over 35 cycles. Therefore, Prussian blue analogues are promising structures for high-voltage cathode materials in Mg batteries. Furthermore, this co-intercalation effect suggests new avenues for the development of cathode materials in hybrid magnesium batteries that use both Mg(2+) and Na(+) ions as charge carriers. PMID- 26967193 TI - To anticoagulate or not to anticoagulate vascular thrombosis in Behcet's syndrome: an enduring question. PMID- 26967194 TI - PR3 antibodies: not always an immunological emergency. PMID- 26967195 TI - Global Liver Proteome Analysis Using iTRAQ Reveals AMPK-mTOR-Autophagy Signaling Is Altered by Intrauterine Growth Restriction in Newborn Piglets. AB - Intrauterine growth restriction (IUGR) impairs fetal growth and development, perturbs nutrient metabolism, and increases the risk of developing diseases in postnatal life. However, the underlying mechanisms by which IUGR affects fetal liver development and metabolism remain incompletely understood. Here, we applied a high-throughput proteomics approach and biochemical analysis to investigate the impact of IUGR on the liver of newborn piglets. As a result, we identified 78 differentially expressed proteins in the three biological replicates, including 31 significantly up-regulated proteins and 47 significantly down-regulated proteins. Among them, a majority of differentially expressed proteins were related to nutrient metabolism and mitochondrial function. Additionally, many significantly down-regulated proteins participated in the mTOR signaling pathway and the phagosome maturation signaling pathway. Further analysis suggested that glucose concentration and hepatic glycogen storage were both reduced in IUGR newborn piglets, which may contribute to AMPK activation and mTORC1 inhibition. However, AMPK activation and mTORC1 inhibition failed to induce autophagy in the liver of IUGR neonatal pigs. A possible reason is that PP2Ac, a potential candidate in autophagy regulation, is significantly down-regulated in the liver of IUGR newborn piglets. These findings may provide implications for preventing and treating IUGR in human beings and domestic animals. PMID- 26967196 TI - Association diastolic function by echo and infarct size by magnetic resonance imaging after STEMI. AB - OBJECTIVES: Left ventricular (LV) diastolic dysfunction is a predictor of increased morbidity and mortality; however, little is known about diastolic function and the degree of myocardial damage after myocardial infarction (MI). The aim was to assess the association between diastolic dysfunction by echocardiography and myocardial salvage assessed with cardiac magnetic resonance (CMR) imaging in patients with ST-segment elevation MI (STEMI). DESIGN: In a prospective study, echocardiography and CMR were performed in STEMI patients in the early post-MI phase assessing diastolic dysfunction according to E/A and E/e'average and area at risk, and after three months with measurement of final infarct size and salvage index. Linear regression analyses were performed testing the association of diastolic dysfunction with area at risk, final infarct size and salvage index. RESULTS: A total of 193 patients (61 +/- 11 years) were included. Median system delay (first medical contact to primary PCI) was 185 min, 123 patients (63%) had TIMI 0/1 flow before intervention and 85 (46%) sustained an anterior MI. In 74 patients (38%), diastolic function was normal. The presence of diastolic dysfunction was associated with larger area at risk of median 6.6% (p < 0.001), larger final infarct size of 4.5% (p < 0.001), and lower salvage index of -5.9% (p = 0.02) compared with patients with normal diastolic function. CONCLUSION: Diastolic dysfunction in the early phase after STEMI is associated with more extensive myocardial damage and significantly poorer myocardial salvage after three months, and the presence of diastolic dysfunction acutely after STEMI may therefore be used as a marker of worse myocardial outcome. PMID- 26967197 TI - En Face Detection of Nitric Oxide and Superoxide in Endothelial Layer of Intact Arteries. AB - Endothelium-derived nitric oxide (NO) produced from endothelial NO-synthase (eNOS) is one of the most important vasoprotective molecules in cardiovascular physiology. Dysfunctional eNOS such as uncoupling of eNOS leads to decrease in NO bioavailability and increase in superoxide anion (O2(.-)) production, and in turn promotes cardiovascular diseases. Therefore, appropriate measurement of NO and O2(.-) levels in the endothelial cells are pivotal for research on cardiovascular diseases and complications. Because of the extremely labile nature of NO and O2(. ), it is difficult to measure NO and O2(.-) directly in a blood vessel. Numerous methods have been developed to measure NO and O2(.-) production. It is, however, either insensitive, or non-specific, or technically demanding and requires special equipment. Here we describe an adaption of the fluorescence dye method for en face simultaneous detection and visualization of intracellular NO and O2(. ) using the cell permeable diaminofluorescein-2 diacetate (DAF-2DA) and dihydroethidium (DHE), respectively, in intact aortas of an obesity mouse model induced by high-fat-diet feeding. We could demonstrate decreased intracellular NO and enhanced O2(.-) levels in the freshly isolated intact aortas of obesity mouse as compared to the control lean mouse. We demonstrate that this method is an easy technique for direct detection and visualization of NO and O2(.-) in the intact blood vessels and can be widely applied for investigation of endothelial (dys)function under (physio)pathological conditions. PMID- 26967198 TI - Solvatochromic Shifts in UV-Vis Absorption Spectra: The Challenging Case of 4 Nitropyridine N-Oxide. AB - 4-Nitropyridine N-oxide is a well-known molecular probe for which the experimental UV/vis absorption spectrum has been measured in a large number of solvents. Previous measurements and their analyses suggest a dominant role of the solvent hydrogen-bond donation (HBD) capability in the solvatochromic shifts measured for the absorption spectra. Herein, we analyze these solvatochromic effects using a series of complementary approaches, including empirical solvent parameters, high-level calculation of the excited-state dipole and polarizability, several flavors of the polarizable continuum model, as well as dynamics using an effective fragment potential (EFP) description of the solvent molecules. First, applying a recently proposed set of solvent parameters, we show the importance of dispersion interactions for non-HBD solvents. This statement confronts advanced coupled-cluster and multireference calculations of dipole moments and polarizabilities of both the ground and excited states in gas phase. We further address the pros and cons of implicit solvent models combined to time dependent density functional theory (TD-DFT) in describing the solvents effects for all (HBD and non-HBD) media, the simplest linear-response approach turning out to be the most adequate. Finally, we show that the explicit TD-DFT/EFP2 models work correctly for HBD molecules and allow for restoration of the main experimental trends. PMID- 26967199 TI - Experimental Inferential Structure Determination of Ensembles for Intrinsically Disordered Proteins. AB - We develop a Bayesian approach to determine the most probable structural ensemble model from candidate structures for intrinsically disordered proteins (IDPs) that takes full advantage of NMR chemical shifts and J-coupling data, their known errors and variances, and the quality of the theoretical back-calculation from structure to experimental observables. Our approach differs from previous formulations in the optimization of experimental and back-calculation nuisance parameters that are treated as random variables with known distributions, as opposed to structural or ensemble weight optimization or use of a reference ensemble. The resulting experimental inferential structure determination (EISD) method is size extensive with O(N) scaling, with N = number of structures, that allows for the rapid ranking of large ensemble data comprising tens of thousands of conformations. We apply the EISD approach on singular folded proteins and a corresponding set of ~25 000 misfolded states to illustrate the problems that can arise using Boltzmann weighted priors. We then apply the EISD method to rank IDP ensembles most consistent with the NMR data and show that the primary error for ranking or creating good IDP ensembles resides in the poor back-calculation from structure to simulated experimental observable. We show that a reduction by a factor of 3 in the uncertainty of the back-calculation error can improve the discrimination among qualitatively different IDP ensembles for the amyloid-beta peptide. PMID- 26967200 TI - Pandemic influenza vaccine & narcolepsy: simulations on the potential impact of bias. AB - Several studies have identified an association between Pandemrix(TM), an AS03 adjuvanted pandemic influenza A(H1N1) vaccine, and narcolepsy, a rare and under diagnosed sleep disorder with a median onset-to-diagnosis interval of ten years. This paper reviews potential sources of bias in published studies and aims to provide, through simulation, methodological recommendations for assessment of vaccine safety signals. Our simulation study showed that in the absence of an association between the vaccine and the outcome, presence of detection bias and differential exposure misclassification could account for elevated risk estimates. These may play a major role, particularly in alert situations when observation times are limited and the disease has a long latency period. Estimates from the case-control design were less inflated than those from the cohort design when these biases were present. Overall, these simulations provide useful insights for the design and interpretation of future studies. PMID- 26967201 TI - The Search for Extraterrestrial Intelligence in Earth's Solar Transit Zone. AB - Over the past few years, astronomers have detected thousands of planets and candidate planets by observing their periodic transits in front of their host stars. A related method, called transit spectroscopy, might soon allow studies of the chemical imprints of life in extrasolar planetary atmospheres. Here, we address the reciprocal question, namely, from where is Earth detectable by extrasolar observers using similar methods. We explore Earth's transit zone (ETZ), the projection of a band around Earth's ecliptic onto the celestial plane, where observers can detect Earth transits across the Sun. ETZ is between 0.520 degrees and 0.537 degrees wide due to the noncircular Earth orbit. The restricted Earth transit zone (rETZ), where Earth transits the Sun less than 0.5 solar radii from its center, is about 0.262 degrees wide. We first compile a target list of 45 K and 37 G dwarf stars inside the rETZ and within 1 kpc (about 3260 light-years) using the Hipparcos catalogue. We then greatly enlarge the number of potential targets by constructing an analytic galactic disk model and find that about 10(5) K and G dwarf stars should reside within the rETZ. The ongoing Gaia space mission can potentially discover all G dwarfs among them (several 10(4)) within the next 5 years. Many more potentially habitable planets orbit dim, unknown M stars in ETZ and other stars that traversed ETZ thousands of years ago. If any of these planets host intelligent observers, they could have identified Earth as a habitable, or even as a living, world long ago, and we could be receiving their broadcasts today. The K2 mission, the Allen Telescope Array, the upcoming Square Kilometer Array, or the Green Bank Telescope might detect such deliberate extraterrestrial messages. Ultimately, ETZ would be an ideal region to be monitored by the Breakthrough Listen Initiatives, an upcoming survey that will constitute the most comprehensive search for extraterrestrial intelligence so far. PMID- 26967202 TI - Fibrous polyaniline@manganese oxide nanocomposites as supercapacitor electrode materials and cathode catalysts for improved power production in microbial fuel cells. AB - Fibrous Pani-MnO2 nanocomposite were prepared using a one-step and scalable in situ chemical oxidative polymerization method. The formation, structural and morphological properties were investigated using a range of characterization techniques. The electrochemical capacitive behavior of the fibrous Pani-MnO2 nanocomposite was examined by cyclic voltammetry and galvanostatic charge discharge measurements using a three-electrode experimental setup in an aqueous electrolyte. The fibrous Pani-MnO2 nanocomposite achieved high capacitance (525 F g(-1) at a current density of 2 A g(-1)) and excellent cycling stability of 76.9% after 1000 cycles at 10 A g(-1). Furthermore, the microbial fuel cell constructed with the fibrous Pani-MnO2 cathode catalyst showed an improved power density of 0.0588 W m(-2), which was higher than that of pure Pani and carbon paper, respectively. The improved electrochemical supercapacitive performance and cathode catalyst performance in microbial fuel cells were attributed mainly to the synergistic effect of Pani and MnO2 in fibrous Pani-MnO2, which provides high surface area for the electrode/electrolyte contact as well as electronic conductive channels and exhibits pseudocapacitance behavior. PMID- 26967203 TI - Free Energies of Ion Binding in the Bacterial CLC-ec1 Chloride Transporter with Implications for the Transport Mechanism and Selectivity. AB - The chloride channel/transporter family of proteins facilitates anion transport across biological membranes. There is extensive physiological and bioinformatic evidence that the channels and transporters are closely related. Each monomer of a homodimeric CLC transport protein contains a narrow selectivity filter. Investigating the ion binding properties inside the filter is crucial for understanding key mechanistic states during ion transit. Here computer simulations are used to explore the free energies of Cl(-) ions in the binding sites of the wild-type CLC-ec1 transporter and its mutant E148A. Specifically, a local molecular field theory approach for free energy calculations is exploited to compute the absolute free energies in water and in the protein binding sites. The calculations indicate a close synergy between anion binding and protonation of the external glutamate gate. Electrostatic differences between the bacterial CLC-ec1 and eukaryotic CmCLC transporters revealed by these and other simulations help to rationalize the observed differing structures in the pore region. In addition, quantum chemical calculations on the F(-), Cl(-), and Br(-) ions in the central binding site are used to examine ion selectivity. The calculations show a significant extent of charge transfer from the ion to the nearby residues. The computed free energies, in conjunction with experimental measurements, place constraints on proposed mechanisms for the transport cycle. PMID- 26967204 TI - Peptide-Mediated Specific Immobilization of Catalytically Active Cytochrome P450 BM3 Variant. AB - Cytochrome P450 BM3 (CYP102A1) from Bacillus megaterium is an interesting target for biotechnological applications, because of its vast substrate variety combined with high P450 monooxygenase activity. The low stability in vitro could be overcome by immobilization on surfaces. Here we describe a novel method for immobilization on metal surfaces by using selectively binding peptides. A P450 BM3 triple mutant (3M-P450BM3: A74G, F87V, L188Q) was purified as protein thioester and ligated to indium tin oxide or gold binding peptides (BP) named HighSP-BP and Cys-BP, respectively. The ligation products were characterized by Western Blot and tryptic digestion combined with mass spectrometry, and displayed high affinity binding on the depicted surfaces. Next, we could demonstrate by benzyloxyresorufin O-dealkylation assay (BROD assay) that the activity of immobilized ligation products is higher than for the soluble form. The study provides a new tool for selective modification and immobilization of P450 variants. PMID- 26967205 TI - Electrochemical Zinc-Ion Intercalation Properties and Crystal Structures of ZnMo6S8 and Zn2Mo6S8 Chevrel Phases in Aqueous Electrolytes. AB - The crystal structures and electrochemical properties of ZnxMo6S8 Chevrel phases (x = 1, 2) prepared via electrochemical Zn(2+)-ion intercalation into the Mo6S8 host material, in an aqueous electrolyte, were characterized. Mo6S8 [trigonal, R3, a = 9.1910(6) A, c = 10.8785(10) A, Z = 3] was first prepared via the chemical extraction of Cu ions from Cu2Mo6S8, which was synthesized via a solid state reaction for 24 h at 1000 degrees C. The electrochemical zinc-ion insertion into Mo6S8 occurred stepwise, and two separate potential regions were depicted in the cyclic voltammogram (CV) and galvanostatic profile. ZnMo6S8 first formed from Mo6S8 in the higher-voltage region around 0.45-0.50 V in the CV, through a pseudo two-phase reaction. The inserted zinc ions occupied the interstitial sites in cavities surrounded by sulfur atoms (Zn1 sites). A significant number of the inserted zinc ions were trapped in these Zn1 sites, giving rise to the first-cycle irreversible capacity of ~46 mAh g(-1) out of the discharge capacity of 134 mAh g(-1) at a rate of 0.05 C. In the lower-voltage region, further insertion occurred to form Zn2Mo6S8 at around 0.35 V in the CV, also involving a two-phase reaction. The electrochemical insertion and extraction into the Zn2 sites appeared to be relatively reversible and fast. The crystal structures of Mo6S8, ZnMo6S8, and Zn2Mo6S8 were refined using X-ray Rietveld refinement techniques, while the new structure of Zn2Mo6S8 was determined for the first time in this study using the technique of structure determination from powder X-ray diffraction data. With the zinc ions inserted into Mo6S8 forming Zn2Mo6S8, the cell volume and a parameter increased by 5.3% and 5.9%, respectively, but the c parameter decreased by 6.0%. The average Mo-Mo distance in the Mo6 cluster decreased from 2.81 to 2.62 A. PMID- 26967206 TI - Two Phase 2 Multiple Ascending-Dose Studies of Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate Alzheimer's Disease. AB - Vanutide cridificar (ACC-001), an immunotherapeutic vaccine, is a potentially disease-modifying therapy that aims to reduce brain amyloid-beta (Abeta) plaques in patients with Alzheimer's disease (AD). ACC-001 was evaluated in two phase 2a, multicenter, randomized, third party-unblinded, placebo-controlled, multiple ascending-dose studies of ACC-001 (3MUg, 10MUg, 30MUg) with and without QS-21 adjuvant that enrolled patients with mild-to-moderate AD (n = 245). Patients were treated with up to five doses of study vaccine or placebo and followed for safety and tolerability (primary objective) and anti-Abeta IgG immunogenicity (secondary objective) up to 12 months after the last vaccination. Exploratory assessments included cognitive/functional measures, brain magnetic resonance imaging (MRI) volumetry, and pharmacodynamic markers in plasma and cerebrospinal fluid (CSF). The most frequent treatment-emergent adverse events (>=10%) were local injection reactions and headache. Amyloid-related imaging abnormalities with vasogenic edema occurred in two (0.8%) patients (ACC-001 30MUg + QS-21; ACC-001 10MUg). ACC 001 + QS-21 elicited consistently higher peak and sustained anti-Abeta IgG titers compared with ACC-001 alone. Plasma Abetax-40 was significantly higher in all ACC 001 + QS-21 groups versus placebo (weeks 16-56), with no evidence of dose response. Exploratory cognitive evaluations, volumetric brain MRI, and CSF biomarkers did not show differences or trends between treatment groups and placebo. ACC-001 with or without QS-21 adjuvant has an acceptable safety profile in patients with mild-to-moderate AD. PMID- 26967208 TI - Chronic Obstructive Pulmonary Disease as a Risk Factor for Cognitive Dysfunction: A Meta-Analysis of Current Studies. AB - Cognitive dysfunction has been shown to be associated with many risk factors, such as smoking, diabetes, and body mass index. Chronic obstructive pulmonary disease (COPD), a common disease within the elderly population, has also been found to be related to cognitive decline. However, whether COPD is a risk factor of cognitive dysfunction is not well established. The purpose of this meta analysis is to investigate the role COPD plays in cognitive dysfunction. PubMed, Cochrane library and Web of Science databases were searched. Three cohort studies and eleven cross-sectional studies were found to be eligible. According to our results, COPD patients had a higher risk of cognitive dysfunction than controls (OR [odds ratio]: 1.72; 95% CI, 1.12-2.65; p = 0.01). The exacerbation of COPD was strongly correlated with cognitive decline. COPD patients performed worse than controls on the Mini- Mental State Examination test, but the results were not statistically significant (OR: -0.79; 95% CI, [-1.78, 0.19]; p = 0.11). Thus, more attention should be given to the occurrence of cognitive decline in COPD patients. The prevention and control of COPD exacerbation are critical. PMID- 26967207 TI - Nutritional Status is Associated with Faster Cognitive Decline and Worse Functional Impairment in the Progression of Dementia: The Cache County Dementia Progression Study1. AB - Nutritional status may be a modifiable factor in the progression of dementia. We examined the association of nutritional status and rate of cognitive and functional decline in a U.S. population-based sample. Study design was an observational longitudinal study with annual follow-ups up to 6 years of 292 persons with dementia (72% Alzheimer's disease, 56% female) in Cache County, UT using the Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-sb), and modified Mini Nutritional Assessment (mMNA). mMNA scores declined by approximately 0.50 points/year, suggesting increasing risk for malnutrition. Lower mMNA score predicted faster rate of decline on the MMSE at earlier follow up times, but slower decline at later follow-up times, whereas higher mMNA scores had the opposite pattern (mMNA by time beta= 0.22, p = 0.017; mMNA by time2 beta= -0.04, p = 0.04). Lower mMNA score was associated with greater impairment on the CDR-sb over the course of dementia (beta= 0.35, p < 0.001). Assessment of malnutrition may be useful in predicting rates of progression in dementia and may provide a target for clinical intervention. PMID- 26967209 TI - Spatial Navigation in Preclinical Alzheimer's Disease. AB - Although several previous studies have demonstrated navigational deficits in early-stage symptomatic Alzheimer's disease (AD), navigational abilities in preclinical AD have not been examined. The present investigation examined the effects of preclinical AD and early-stage symptomatic AD on spatial navigation performance. Performance on tasks of wayfinding and route learning in a virtual reality environment were examined. Comparisons were made across the following three groups: Clinically normal without preclinical AD (n = 42), clinically normal with preclinical AD (n = 13), and early-stage symptomatic AD (n = 16) groups. Preclinical AD was defined based on cerebrospinal fluid Abeta42 levels below 500 pg/ml. Preclinical AD was associated with deficits in the use of a wayfinding strategy, but not a route learning strategy. Moreover, post-hoc analyses indicated that wayfinding performance had moderate sensitivity and specificity. Results also confirmed early-stage symptomatic AD-related deficits in the use of both wayfinding and route learning strategies. The results of this study suggest that aspects of spatial navigation may be particularly sensitive at detecting the earliest cognitive deficits of AD. PMID- 26967212 TI - Diversity of Cognitive Phenotypes Associated with C9ORF72 Hexanucleotide Expansion. AB - For diagnostic purposes, we screened for the C9ORF72 mutation in a) 162 FTLD cases, and b) 145 cases with other diagnoses but with some frontotemporal features or manifestations previously reported in C9 carriers. Ten cases (onset 50 to 75 years) harbored the expansion: seven had FTLD syndromes (4.3% of total, 11% of familial cases), and three (2%) had a different diagnosis. All positive cases had family history of dementia, psychiatric disease, or ALS, but only 20% of families with mixed FTLD/ALS phenotypes carried the expansion. Language impairment was the most common symptom, followed by behavioral changes, memory deficits, and parkinsonism. C9ORF72 mutation has a low frequency in our dementia series and very diverse clinical manifestations. PMID- 26967210 TI - Comparison of Different Matrices as Potential Quality Control Samples for Neurochemical Dementia Diagnostics. AB - BACKGROUND: Assay-vendor independent quality control (QC) samples for neurochemical dementia diagnostics (NDD) biomarkers are so far commercially unavailable. This requires that NDD laboratories prepare their own QC samples, for example by pooling leftover cerebrospinal fluid (CSF) samples. OBJECTIVE: To prepare and test alternative matrices for QC samples that could facilitate intra- and inter-laboratory QC of the NDD biomarkers. METHODS: Three matrices were validated in this study: (A) human pooled CSF, (B) Abeta peptides spiked into human prediluted plasma, and (C) Abeta peptides spiked into solution of bovine serum albumin in phosphate-buffered saline. All matrices were tested also after supplementation with an antibacterial agent (sodium azide). We analyzed short- and long-term stability of the biomarkers with ELISA and chemiluminescence (Fujirebio Europe, MSD, IBL International), and performed an inter-laboratory variability study. RESULTS: NDD biomarkers turned out to be stable in almost all samples stored at the tested conditions for up to 14 days as well as in samples stored deep-frozen (at - 80 degrees C) for up to one year. Sodium azide did not influence biomarker stability. Inter-center variability of the samples sent at room temperature (pooled CSF, freeze-dried CSF, and four artificial matrices) was comparable to the results obtained on deep-frozen samples in other large-scale projects. CONCLUSION: Our results suggest that it is possible to replace self made, CSF-based QC samples with large-scale volumes of QC materials prepared with artificial peptides and matrices. This would greatly facilitate intra- and inter laboratory QC schedules for NDD measurements. PMID- 26967213 TI - Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer's Disease. AB - BACKGROUND: The earliest stage of preclinical Alzheimer's disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-beta (Abeta42). However, covariance in longitudinal dynamic change of Abeta42 and tau in incipient preclinical AD is poorly understood. OBJECTIVE: To examine dynamic interrelationships between Abeta42 and tau in preclinical AD. METHODS: We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Abeta42 levels in CSF, CI were classified into three groups: 1) Abeta42 stable with normal levels of Abeta42 over time (n = 15); 2) Abeta42 declining with normal Abeta42 levels at baseline but showing decline over time (n = 14); and 3) Abeta42 levels consistently abnormal (n = 18). RESULTS: In the Abeta42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Abeta42 and p-tau confirmed that both trajectories were anti-correlated (rho = -0.60; p = 0.02). Regression analysis showed that Abeta42 slope (decreasing Abeta42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Abeta42 and p-tau slopes (p < 0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p tau. CONCLUSIONS: The evolution of Abeta42 and p-tau CSF biomarkers in CI subjects follows an anti-correlated trajectory, i.e., as Abeta42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Abeta42 and p-tau thus may be evident in very early stages of preclinical AD. PMID- 26967211 TI - The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview. AB - BACKGROUND: Vascular health factors frequently co-occur with Alzheimer's disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities. OBJECTIVE: To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics. METHODS: From September 2012 to November 2014, 335 participants age 60- 92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73+/-8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72+/-7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection. RESULTS: As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values < 0.001), were more likely to be APOEE4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower Abeta42 (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants. CONCLUSION: Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline. PMID- 26967216 TI - Music and Memory in Alzheimer's Disease and The Potential Underlying Mechanisms. AB - With population aging and a projected exponential expansion of persons diagnosed with Alzheimer's disease (AD), the development of treatment and prevention programs has become a fervent area of research and discovery. A growing body of evidence suggests that music exposure can enhance memory and emotional function in persons with AD. However, there is a paucity of research that aims to identify specific underlying neural mechanisms associated with music's beneficial effects in this particular population. As such, this paper reviews existing anecdotal and empirical evidence related to the enhancing effects of music exposure on cognitive function and further provides a discussion on the potential underlying mechanisms that may explain music's beneficial effect. Specifically, this paper will outline the potential role of the dopaminergic system, the autonomic nervous system, and the default network in explaining how music may enhance memory function in persons with AD. PMID- 26967214 TI - Efficacy and Safety of ABT-126 in Subjects with Mild-to-Moderate Alzheimer's Disease on Stable Doses of Acetylcholinesterase Inhibitors: A Randomized, Double Blind, Placebo-Controlled Study. AB - BACKGROUND: ABT-126 is a potent, selective alpha7 nicotinic acetylcholine receptor agonist with putative procognitive effects as a monotherapy in treating Alzheimer's disease (AD). OBJECTIVE: This randomized, double-blind, placebo controlled multicenter study (NCT01549834) investigated the efficacy and safety of ABT-126 in subjects with mild-to-moderate AD who were taking stable doses of acetylcholinesterase inhibitors (AChEIs). METHODS: Subjects received 25 mg ABT 126 (n = 143), 75 mg ABT-126 (n = 145), or placebo (n = 146) once daily for 24 weeks. Subjects who completed the 24-week double-blind study were eligible to enroll in a 28-week open-label extension study (NCT01690195) and received 75 mg ABT-126 daily. The primary efficacy endpoint was the change from baseline to week 24 in the 11-item total score of the Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog). RESULTS: Neither dose of ABT-126 demonstrated significant improvement compared with placebo in the primary efficacy endpoint. However, 25 mg ABT-126 demonstrated significant improvement compared with placebo in ADAS-Cog scores at week 4 (least squares mean difference, -1.21; standard error, 0.51; p < 0.010, one-sided); 75 mg ABT-126 did not demonstrate significant improvements in ADAS-Cog scores compared with placebo at any time point. A treatment effect was not observed for any secondary efficacy measures of cognition, function, or global improvement. ABT-126 was generally well tolerated; the most common adverse events were agitation, constipation, diarrhea, fall, and headache. CONCLUSIONS: Overall, the efficacy profile of ABT-126 did not warrant further development as add-on therapy to AChEIs to treat mild-to-moderate AD. PMID- 26967217 TI - A Qualitative Impairment in Face Perception in Alzheimer's Disease: Evidence from a Reduced Face Inversion Effect. AB - Prevalent face recognition difficulties in Alzheimer's disease (AD) have typically been attributed to the underlying episodic and semantic memory impairment. The aim of the current study was to determine if AD patients are also impaired at the perceptual level for faces, more specifically at extracting a visual representation of an individual face. To address this question, we investigated the matching of simultaneously presented individual faces and of other nonface familiar shapes (cars), at both upright and inverted orientation, in a group of mild AD patients and in a group of healthy older controls matched for age and education. AD patients showed a reduced inversion effect (i.e., larger performance for upright than inverted stimuli) for faces, but not for cars, both in terms of error rates and response times. While healthy participants showed a much larger decrease in performance for faces than for cars with inversion, the inversion effect did not differ significantly for faces and cars in AD. This abnormal inversion effect for faces was observed in a large subset of individual patients with AD. These results suggest that AD patients have deficits in higher-level visual processes, more specifically at perceiving individual faces, a function that relies on holistic representations specific to upright face stimuli. These deficits, combined with their memory impairment, may contribute to the difficulties in recognizing familiar people that are often reported in patients suffering from the disease and by their caregivers. PMID- 26967218 TI - Association of Frontotemporal Dementia GWAS Loci with Late-Onset Alzheimer's Disease in a Northern Han Chinese Population. AB - BACKGROUND: Both Alzheimer's disease (AD) and frontotemporal dementia (FTD) are a class of neurodegenerative diseases. Strong similarities in cerebrospinal fluid biomarker, imaging markers, and disease progression profiles suggest that some or most of the pathophysiology is shared between AD and FTD. A recent large genome wide association study reported several single nucleotide polymorphisms (SNPs) at the RAB38, RAB38/CTSC, HLA-DRA/HLA-DRB5, and BTNL2 in association with FTD. OBJECTIVE: To explore whether these SNPs are associated with AD risk. METHODS: We conducted a case-control study to investigate the association of FTD-associated loci in 2338 Han Chinese subjects. RESULTS: We observed significant differences in genotype distributions of rs302668 (pc = 0.025), rs9268877 (pc = 0.025), rs9268856 (p < 0.001), and rs1980493 (pc = 0.045) between cases and controls. The SNPs rs16913634 for RAB38/CTSC was unrelated to LOAD risk (p = 0.088). CONCLUSION: The SNPs rs302668 in RAB38, rs9268877 and rs9268856 polymorphism in HLA-DRA/HLA-DRB5, and rs1980493 polymorphism in BTNL2 might play a role in the susceptibility to late-onset AD in the Han Chinese population. PMID- 26967215 TI - Unraveling Alzheimer's: Making Sense of the Relationship between Diabetes and Alzheimer's Disease1. AB - Numerous studies have documented a strong association between diabetes and Alzheimer's disease (AD). The nature of the relationship, however, has remained a puzzle, in part because of seemingly incongruent findings. For example, some studies have concluded that insulin deficiency is primarily at fault, suggesting that intranasal insulin or inhibiting the insulin-degrading enzyme (IDE) could be beneficial. Other research has concluded that hyperinsulinemia is to blame, which implies that intranasal insulin or the inhibition of IDE would exacerbate the disease. Such antithetical conclusions pose a serious obstacle to making progress on treatments. However, careful integration of multiple strands of research, with attention to the methods used in different studies, makes it possible to disentangle the research on AD. This integration suggests that there is an important relationship between insulin, IDE, and AD that yields multiple pathways to AD depending on the where deficiency or excess in the cycle occurs. I review evidence for each of these pathways here. The results suggest that avoiding excess insulin, and supporting robust IDE levels, could be important ways of preventing and lessening the impact of AD. I also describe what further tests need to be conducted to verify the arguments made in the paper, and their implications for treating AD. PMID- 26967219 TI - Maintenance of Cognitive Performance and Mood for Individuals with Alzheimer's Disease Following Consumption of a Nutraceutical Formulation: A One-Year, Open Label Study. AB - Nutritional interventions have shown varied efficacy on cognitive performance during Alzheimer's disease (AD). Twenty-four individuals diagnosed with AD received a nutraceutical formulation (NF: folate, alpha-tocopherol, B12, S adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) under open-label conditions (ClinicalTrials.gov NCT01320527). Primary outcome was cognitive performance. Secondary outcomes were behavioral and psychological symptoms of dementia (BPSD) and activities of daily living. Participants maintained their baseline cognitive performance and BPSD over 12 months. These findings are consistent with improvement in cognitive performance and BPSD in prior placebo controlled studies with NF, and contrast with the routine decline for participants receiving placebo. PMID- 26967220 TI - PDE5 Exists in Human Neurons and is a Viable Therapeutic Target for Neurologic Disease. AB - Phosphodiesterase 5 (PDE5) is a critical component of the cGMP-PKG axis of cellular signaling in neurons, and inhibition of PDE5 has been shown to be therapeutic in a wide range of neurologic conditions in animal models. However, enthusiasm for PDE5 inhibitors in humans is limited by data suggesting that PDE5 may not exist in human neurons. Here, we first show that past attempts to quantify PDE5 mRNA were flawed due to the use of incorrect primers, and that when correct primers are used, PDE5 mRNA is detectable in human brain tissue. We then show that PDE5 protein exists in human brain by western blot and ELISA. Most importantly, we performed immunohistochemistry and demonstrate that PDE5 is present in human neurons. We hope that this work will trigger a renewed interest in the development of PDE5 inhibitors for neurologic disease. PMID- 26967222 TI - Efficacy and Safety of Sustained Release Donepezil High Dose versus Immediate Release Donepezil Standard Dose in Japanese Patients with Severe Alzheimer's Disease: A Randomized, Double-Blind Trial. AB - BACKGROUND: Donepezil is an established treatment for mild, moderate, and severe Alzheimer's disease (AD). An international study demonstrated superior efficacy of sustained release (SR) 23 mg/day donepezil over immediate release (IR) 10 mg/day donepezil for cognitive function, but not global function in moderate-to severe AD. OBJECTIVE: To demonstrate the superiority of SR 23 mg/day donepezil over IR 10 mg/day donepezil in Japanese patients with severe AD (SAD). METHODS: In this multicenter, randomized, double-blind, parallel-group study, Japanese outpatients with SAD were randomly assigned to continue IR 10 mg/day or switch to SR 23 mg/day for 24 weeks. Endpoints included the Severe Impairment Battery (SIB), Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus), and safety. RESULTS: Overall, 166 and 185 patients were randomized to receive IR 10 mg/day and SR 23 mg/day, respectively. SR 23 mg/day was not statistically superior to IR 10 mg/day by SIB (least squares mean difference [LSMD]: 0.0; 95% confidence interval [CI]: -1.7, 1.8; p = 0.981) or CIBIC-plus (LSMD: 0.2; 95% CI: 0.0, 0.4; p = 0.080). Common adverse events in the SR 23 mg group were decreased appetite, vomiting, diarrhea, and contusion. Safety findings were consistent with known safety profiles of donepezil. CONCLUSION: SR 23 mg/day donepezil was not superior to IR 10 mg/day donepezil regarding the efficacy endpoints for Japanese SAD. Considering that a 10 mg/day dose is approved for SAD in Japan, the present findings suggest that IR 10 mg/day donepezil is the optimal dosage for Japanese patients with SAD. PMID- 26967221 TI - Activation of p53 in Down Syndrome and in the Ts65Dn Mouse Brain is Associated with a Pro-Apoptotic Phenotype. AB - Down syndrome (DS) is the most common genetic cause of intellectual disability, resulting from trisomy of chromosome 21. The main feature of DS neuropathology includes early onset of Alzheimer's disease (AD), with deposition of senile plaques and tangles. We hypothesized that apoptosis may be activated in the presence of AD neuropathology in DS, thus we measured proteins associated with upstream and downstream pathways of p53 in the frontal cortex from DS cases with and without AD pathology and from Ts65Dn mice, at different ages. We observed increased acetylation and phosphorylation of p53, coupled to reduced MDM2/p53 complex level and lower levels of SIRT1. Activation of p53 was associated with a number of targets (BAX, PARP1, caspase-3, p21, heat shock proteins, and PGC1alpha) that were modulated in both DS and DS/AD compared with age-matched controls. In particular, the most relevant changes (increased p-p53 and acetyl p53 and reduced formation of MDM2/p53 complex) were found to be modified only in the presence of AD pathology in DS. In addition, a similar pattern of alterations in the p53 pathway was found in Ts65Dn mice. These results suggest that p53 may integrate different signals, which can result in a pro-apoptotic-phenotype contributing to AD neuropathology in people with DS. PMID- 26967223 TI - Salidroside, a Bioactive Compound of Rhodiola Rosea, Ameliorates Memory and Emotional Behavior in Adult Mice. AB - Rhodiola Rosea (R. Rosea) is a plant used in traditional popular medicine to enhance cognition and physical performance. R. Rosea medicinal properties have been related to its capability to act as an adaptogen, i.e., a substance able to increase the organism's resistance to a variety of chemical, biological, and physical stressors in a non-specific way. These adaptogen properties have been mainly attributed to the glycoside salidroside, one of the bioactive compounds present in the standardized extracts of R. Rosea. Here, we aimed to investigate whether a single dose of salidroside is able to affect memory and emotional behavior in wild type adult mice. We performed fear conditioning to assess cued and contextual memory, elevated plus maze and open field to evaluate anxiety, and tail suspension test to evaluate depression. Our results showed that a single i.p. administration of salidroside was able to enhance fear memory and exerted an anxiolytic and antidepressant effect. These data confirmed the adaptogenic effect of R. Rosea bioactive compounds in animal models and suggest that salidroside might represent an interesting pharmacological tool to ameliorate cognition and counteract mood disorders. PMID- 26967225 TI - Formal Psychiatric Disorders are not Overrepresented in Behavioral Variant Frontotemporal Dementia. AB - While psychiatric misdiagnosis is well-known in behavioral variant frontotemporal dementia (bvFTD), a systematic evaluation of standardized criteria for psychiatric disorders in bvFTD is still missing. Our aim was to define frequency and character of DSM-IV psychiatric disorders among patients with probable and definite bvFTD compared to possible bvFTD, other neurodegenerative diseases, and psychiatric diagnoses, using MINI-International Neuropsychiatric Interview. We additionally compared psychiatric prodromes between these groups. Subjects were participants of the late-onset frontal lobe (LOF) study, a longitudinal multicenter study. In each patient, after baseline diagnostic procedure, a neurologist and geriatric psychiatrist made a joint clinical diagnosis. Independently, a structured diagnostic interview according to DSM-IV and ICD-10 criteria (MINI-Plus) was performed by a trained professional blinded to clinical diagnosis. Out of 91 patients, 23 with probable and definite bvFTD, 3 with possible bvFTD, 25 with a non bvFTD neurodegenerative disease, and 40 with a clinical psychiatric diagnosis were included. Overall frequency of formal current and past psychiatric disorders in probable and definite bvFTD (21.7% current, 8.7% past) did not differ from other neurodegenerative diseases (12.0% current, 16.0% past) or possible bvFTD (66.7% current, 66.7% past), but was less than in patients with a clinical psychiatric diagnosis (57.5% current, 62.5% past; p < 0.01). In probable and definite bvFTD unipolar mood disorders were most common. Formally diagnosed psychiatric disorders are not overrepresented in probable bvFTD, suggesting that psychiatric misdiagnosis in bvFTD can be reduced by strictly applying diagnostic criteria. In suspected bvFTD close collaboration between neurologists and psychiatrists will advance diagnostics and subsequent treatment. PMID- 26967224 TI - Incidence and Duration of Cumulative Bisphosphonate Use among Community-Dwelling Persons with or without Alzheimer's Disease. AB - We studied the incidence and duration of cumulative bisphosphonate use among older Finnish women and men with or without Alzheimer's disease (AD). The MEDALZ 2005 cohort is a nationwide sample of all persons with clinically diagnosed AD on 31 December 2005 and their age-, gender-, and region of residence-matched control persons without AD. Information on bisphosphonate use by persons with an AD diagnosis and their controls without AD during 2002-2009 was obtained from the prescription register database containing reimbursed medications. A total of 6,041 (11.8%) persons used bisphosphonates during the 8-year follow-up. Bisphosphonates were more commonly used among persons without AD (n = 3121, 12.3%) than among persons with AD (n = 2,920, 11.2%) (p = 0.001). The median duration of bisphosphonate use was 743 days (IQR). Among persons with AD, the median duration of use was 777 days (IQR) and among persons without AD, 701 days (IQR) (p = 0.011). People without AD more often used bisphosphonate combination preparations including vitamin D than did people with AD (p < 0.0001). Bisphosphonate use was more common among people without AD who had comorbidities, asthma/COPD, or rheumatoid arthritis compared with users with AD. Short-term users were more likely to be male, at least 80 years old, and not having AD. Although the incidence of bisphosphonate use was slightly higher among persons without AD, the cumulative duration of bisphosphonate use was longer in persons with AD. Short-term use was associated with male gender, older age, and not having AD. PMID- 26967226 TI - Metformin Facilitates Amyloid-beta Generation by beta- and gamma-Secretases via Autophagy Activation. AB - The evidence of strong pathological associations between type 2 diabetes and Alzheimer's disease (AD) has increased in recent years. Contrary to suggestions that anti-diabetes drugs may have potential for treating AD, we demonstrate here that the insulin sensitizing anti-diabetes drug metformin (Glucophage(r)) increased the generation of amyloid-beta (Abeta), one of the major pathological hallmarks of AD, by promoting beta- and gamma-secretase-mediated cleavage of amyloid-beta protein precursor (AbetaPP) in SH-SY5Y cells. In addition, we show that metformin caused autophagosome accumulation in Tg6799 AD model mice. Extremely high gamma-secretase activity was also detected in autophagic vacuoles, apparently a novel site of Abeta peptide generation. Together, these data suggest that metformin-induced accumulation of autophagosomes resulted in increased gamma secretase activity and Abeta generation. Additional experiments indicated that metformin increased phosphorylation of AMP-activated protein kinase, which activates autophagy by suppressing mammalian target of rapamycin (mTOR). The suppression of mTOR then induces the abnormal accumulation of autophagosomes. We conclude that metformin, an anti-diabetes drug, may exacerbate AD pathogenesis by promoting amyloidogenic AbetaPP processing in autophagosomes. PMID- 26967227 TI - Longitudinal Relationships between Caloric Expenditure and Gray Matter in the Cardiovascular Health Study. AB - BACKGROUND: Physical activity (PA) can be neuroprotective and reduce the risk for Alzheimer's disease (AD). In assessing physical activity, caloric expenditure is a proxy marker reflecting the sum total of multiple physical activity types conducted by an individual. OBJECTIVE: To assess caloric expenditure, as a proxy marker of PA, as a predictive measure of gray matter (GM) volumes in the normal and cognitively impaired elderly persons. METHODS: All subjects in this study were recruited from the Institutional Review Board approved Cardiovascular Health Study (CHS), a multisite population-based longitudinal study in persons aged 65 and older. We analyzed a sub-sample of CHS participants 876 subjects (mean age 78.3, 57.5% F, 42.5% M) who had i) energy output assessed as kilocalories (kcal) per week using the standardized Minnesota Leisure-Time Activities questionnaire, ii) cognitive assessments for clinical classification of normal cognition, mild cognitive impairment (MCI), and AD, and iii) volumetric MR imaging of the brain. Voxel-based morphometry modeled the relationship between kcal/week and GM volumes while accounting for standard covariates including head size, age, sex, white matter hyperintensity lesions, MCI or AD status, and site. Multiple comparisons were controlled using a False Discovery Rate of 5 percent. RESULTS: Higher energy output, from a variety of physical activity types, was associated with larger GM volumes in frontal, temporal, and parietal lobes, as well as hippocampus, thalamus, and basal ganglia. High levels of caloric expenditure moderated neurodegeneration-associated volume loss in the precuneus, posterior cingulate, and cerebellar vermis. CONCLUSION: Increasing energy output from a variety of physical activities is related to larger gray matter volumes in the elderly, regardless of cognitive status. PMID- 26967228 TI - Less Daily Computer Use is Related to Smaller Hippocampal Volumes in Cognitively Intact Elderly. AB - BACKGROUND: Computer use is becoming a common activity in the daily life of older individuals and declines over time in those with mild cognitive impairment (MCI). The relationship between daily computer use (DCU) and imaging markers of neurodegeneration is unknown. OBJECTIVE: The objective of this study was to examine the relationship between average DCU and volumetric markers of neurodegeneration on brain MRI. METHODS: Cognitively intact volunteers enrolled in the Intelligent Systems for Assessing Aging Change study underwent MRI. Total in-home computer use per day was calculated using mouse movement detection and averaged over a one-month period surrounding the MRI. Spearman's rank order correlation (univariate analysis) and linear regression models (multivariate analysis) examined hippocampal, gray matter (GM), white matter hyperintensity (WMH), and ventricular cerebral spinal fluid (vCSF) volumes in relation to DCU. A voxel-based morphometry analysis identified relationships between regional GM density and DCU. RESULTS: Twenty-seven cognitively intact participants used their computer for 51.3 minutes per day on average. Less DCU was associated with smaller hippocampal volumes (r = 0.48, p = 0.01), but not total GM, WMH, or vCSF volumes. After adjusting for age, education, and gender, less DCU remained associated with smaller hippocampal volume (p = 0.01). Voxel-wise analysis demonstrated that less daily computer use was associated with decreased GM density in the bilateral hippocampi and temporal lobes. CONCLUSIONS: Less daily computer use is associated with smaller brain volume in regions that are integral to memory function and known to be involved early with Alzheimer's pathology and conversion to dementia. Continuous monitoring of daily computer use may detect signs of preclinical neurodegeneration in older individuals at risk for dementia. PMID- 26967230 TI - Quantitative Analysis of Protein Expression to Study Lineage Specification in Mouse Preimplantation Embryos. AB - This protocol presents a method to perform quantitative, single-cell in situ analyses of protein expression to study lineage specification in mouse preimplantation embryos. The procedures necessary for embryo collection, immunofluorescence, imaging on a confocal microscope, and image segmentation and analysis are described. This method allows quantitation of the expression of multiple nuclear markers and the spatial (XYZ) coordinates of all cells in the embryo. It takes advantage of MINS, an image segmentation software tool specifically developed for the analysis of confocal images of preimplantation embryos and embryonic stem cell (ESC) colonies. MINS carries out unsupervised nuclear segmentation across the X, Y and Z dimensions, and produces information on cell position in three-dimensional space, as well as nuclear fluorescence levels for all channels with minimal user input. While this protocol has been optimized for the analysis of images of preimplantation stage mouse embryos, it can easily be adapted to the analysis of any other samples exhibiting a good signal-to-noise ratio and where high nuclear density poses a hurdle to image segmentation (e.g., expression analysis of embryonic stem cell (ESC) colonies, differentiating cells in culture, embryos of other species or stages, etc.). PMID- 26967231 TI - Fluorescence Time-lapse Imaging of the Complete S. venezuelae Life Cycle Using a Microfluidic Device. AB - Live-cell imaging of biological processes at the single cell level has been instrumental to our current understanding of the subcellular organization of bacterial cells. However, the application of time-lapse microscopy to study the cell biological processes underpinning development in the sporulating filamentous bacteria Streptomyces has been hampered by technical difficulties. Here we present a protocol to overcome these limitations by growing the new model species, Streptomyces venezuelae, in a commercially available microfluidic device which is connected to an inverted fluorescence widefield microscope. Unlike the classical model species, Streptomyces coelicolor, S. venezuelae sporulates in liquid, allowing the application of microfluidic growth chambers to cultivate and microscopically monitor the cellular development and differentiation of S. venezuelae over long time periods. In addition to monitoring morphological changes, the spatio-temporal distribution of fluorescently labeled target proteins can also be visualized by time-lapse microscopy. Moreover, the microfluidic platform offers the experimental flexibility to exchange the culture medium, which is used in the detailed protocol to stimulate sporulation of S. venezuelae in the microfluidic chamber. Images of the entire S. venezuelae life cycle are acquired at specific intervals and processed in the open-source software Fiji to produce movies of the recorded time-series. PMID- 26967232 TI - [Significance of alanine aminotransferase screening in blood donors for risk reduction of hepatitis B and C transmission by haemotherapy]. AB - BACKGROUND: The goal of the retrospective observatory cross-sectional study was to evaluate the benefit of alanine aminotransferase screening of blood donors in prevention of hepatitis B and C transmission by haemotherapy in context of actual screening methods. METHODS: Donations with elevated ALT more than the defined limit (ALT men 80 IU/l, women 64 IU/l, spectrophotometric UV test, KUADRO(TM), BPC BioSed Srt, Castelnuovo di Porto Roma, Italy) and/or reactivity any of the hepatitis screening parameters HBsAg, anti-HBc, anti-HCV (chemiluminescence method, ARCHITECT i2000(TM), Illinois, USA) were evaluated. Donors were confirmatory retested. They were classified into groups with common biological properties according to their final virological status and statistically evaluated in programs Graph Pad Prism 6.05 and Microsoft Excel 2003. RESULTS: From a total of 61 214 donations elevated ALT was found in 420 (0.69 %), active HBV in 25 (0.04 %), active HCV infection in 5 (0.01 %) blood donors. Coincidental elevation of ALT and active HBV infection occured in 1 donor (0.002 %), as well as HCV (0.002 %). Levels of ALT were higher in the group with elevated ALT without active HBV or HCV infection than in groups with active HCV and HCV infection (p < 0.05). Occurence of blood donor in seronegative anti-HCV window was not observed. Elevated ALT was low specific (69.14 %) and senzitive (6.45 %) for active hepatitis. We did not prove positive correlation of ALT and S/CO (signal-to-cut-off) anti-HBc (Spearman r = -0,565, p < 0.0001), ALT and S/CO anti HCV (Spearman r = -0.1046, p = 0.0022), in ALT and S/CO HBsAg the result was not statistically significant (Spearman r = -0.00968, p = 0.77). Positive but statistically insignificant correlation ALT and S/CO anti-HCV occured in the group of 5 blood donors with active HCV infection (Spearman r = 0.4, p = 0.51). Screening scheme for HCV infection testing anti-HCV + ALT was per one donation by ? 0.18 more expensive than the scheme anti-HCV + HCV RNA due to amount of waisted donations with ALT elevation (825 TU, ? 41 388.89). CONCLUSION: Elevation of ALT in blood donors was not pathognomonic for hepatitis B and C infection. Screening of HCV consisting of anti-HCV + HCV RNA (nucleic acid testing method, COBAS AmpliScreen HCV 2.0(TM), ROCHE Diagnostics, Hague Road, Indianapolis, USA) is more cost-effective than the scheme anti-HCV + ALT. PMID- 26967233 TI - ["3P (Patient-Pulse-Prognosis) in heart failure" survey: focus on heart rate]. AB - BACKGROUND: The data on heart rate in chronic heart failure in the real-world practice in Slovakia are not sufficiently known. The objective of the "3P (Patient-Pulse-Prognosis) in heart failure" survey was to collect epidemiological data with particular emphasis on heart rate control in sinus rhythm. METHODS: The survey was performed by 162 cardiologists and internists. Outpatients or clinically stable hospitalized patients diagnosed with chronic heart failure were included in the survey. No exclusion criteria for patients enrollment were used. A total of 4738 patients were prospectively included. RESULTS: 93.6% of patients with heart failure were taking beta-blockers. At least 50% of the target dose according to ESC had 48.1% of patients receiving beta-blockers. Heart rate >= 70 bpm was present in 55.3% of all patients and in 48.1% of patients with sinus rhythm. Out of the total unselected study population we identified 28.0% of patients with symptomatic heart failure (NYHA class II-IV), sinus rhythm, and suboptimal heart rate >= 70 bpm. The prevalence of heart rate >= 70 bpm was significantly higher in patients with beta-blocker dose < 50% of the target dose according to ESC compared with patients receiving >= 50% of the target dose (58.0% vs 52.4%, p < 0.001). Heart rate >= 70 bpm was significantly more common in patients with history of hospitalization for heart failure compared with patients who have not been hospitalized (56.8% vs 53.7%, p < 0.05). The physicians planned up-titration of the dose only in 20.2% of patients treated with beta-blockers. CONCLUSIONS: Despite extensive beta-blockers therapy we found suboptimal heart rate control in chronic heart failure. Patients on lower doses of beta-blockers (< 50 % of the target dose according to ESC) and patients with history of hospitalization for heart failure were noted to be in significantly higher risk of unsatisfactory heart rate. The proportion of patients with intended up-titration of the beta-blocker dose was low. Therefore it is necessary to reduce heart rate by alternative or complementary pharmacotherapy. PMID- 26967229 TI - Microbes and Alzheimer's Disease. PMID- 26967234 TI - [Changes in the prognosis and treatment of Waldenstrom macroglobulinemia. Literature overview and own experience]. AB - Waldenstrom macroglobulinemia is defined by the presence of monoclonal immunoglobulin IgM type (M-IgM) and evidence of lymphoplasmacytic bone marrow infiltration. The disease has an indolent course, the treatment is only initiated when the disease has begun to damage its carrier. The following symptoms are regarded as proven indications for initiating therapy: B symptoms, symptomatic lymphadenopathy, splenomegaly, anemia with hemoglobin below 100 g / l or thrombocytopenia < 100 * 10(9)/l, caused by lymphoplasmacytic bone marrow infiltration. Frequent indications for initiating treatment include clinical evidence of hyperviscosity or cryoglobulinemia. M-IgM tends to have a character of autoantibody reaching up to 50 %, which may harm the organism, and therefore any proven damage to the organism by an autoimmune activity of M-IgM is also an indication for treatment. The text includes an overview of rare and very rare types of damage to the organism by M-IgM autoimmune activity. A combination of rituximab, cyclophosphamide and dexamethasone (RCD) is recommended for the initial treatment, possibly extended to R-CHOP regimen (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone). In our cohort of 43 patients the therapy involving a combination of R-CHOP achieved 3 (8.1 %) complete remissions and 31 (83.8 %) partial remissions. The remission in 75 % of the patients lasted more than 3 years. In case of recurrence after > 2 years, the same therapy can be used, in case of a relapse within a shorter period of time different treatment schedules are recommended. High-dose chemotherapy with an autologous transplant of stem cells obtained from peripheral blood is only recommended after the first recurrence for people under 65 years of age without contraindications. The text analyses the benefits of the new drugs for the treatment of Waldenstrom macroglobulinemia (bendamustine, thalidomide, lenalidomide, ibrutinib and high-dose chemotherapy). PMID- 26967235 TI - [Gene mutations connected to Waldenstom macroglobulinemia]. AB - Waldenstom macroglobulinemia (WM) is a rare lymphoproliferative disorder, currently classified as a monoclonal gammopathy, with incidence rate of 3 per million. The disease is characterized by presence of clonal B lymphocytes in the bone marrow and by presence of monoclonal immunoglobulin IgM in serum. It is mostly an indolent disorder, with median overall survival 6 years. Molecular pathogenesis of WM remains unclear, but deletion of 6q and 13q, trisomy of chromosomes 4 and 8 seem to be typical. Mutations of MYD88(L265P) and CXCR4(WHIM) are very common for WM and affect growth and survival of malignant cells. This work is aimed at the current knowledge of chromosomal aberrations and gene mutations connected to the pathophysiology of WM. PMID- 26967236 TI - [The SPRINT Research. A Randomized Trial of Intensive versus Standard Blood Pressure Control]. AB - BACKGROUND: The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain. METHODS: We randomly assigned 9 361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. RESULTS: At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive treatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65 % per year vs 2.19 % per year; hazard ratio with intensive treatment, 0.75; 95% confidence interval (CI) 0.64 to 0.89; p < 0.001). All causes mortality was also significantly lower in the intensive-treatment group (hazard ratio, 0.73; 95% CI 0.60 to 0.90; p = 0.003). Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive-treatment group than in the standard-treatment group. CONCLUSIONS: Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group. Funded by the National Institutes of Health. PMID- 26967237 TI - [Rare diagnostics of infective endocarditis after kidney transplantation]. AB - INTRODUCTION: Infective endocarditis in a patient after kidney transplantation is a serious infective complication which increases the risk of loss of the graft and also the mortality of patients. The most important predisposing factor is the immunosuppressive therapy - mainly induction immunosuppression.Material and case description: 250 patients underwent kidney transplantation throughout the period of 12 years in the Transplant Center Martin. This set of patients included 5 patients (2 %) after heart valve replacement. We present the case of a patient after kidney transplantation with development of endocarditis of the bioprosthesis of the aortic valve one month after successful kidney transplantation. Diagnostics of endocarditis by standard procedures (examination by transthoracic echocardiogram, transesophageal echocardiography, hemocultures) was unsuccessful. We rarely diagnosed endocarditis only by PET-CT examination with a consequent change of the antibiotic treatment and successful managing of this post-transplant complication. CONCLUSION: Endocarditis after kidney transplantation is a serious complication which significantly worsens the mortality of patients. The risk of development of infective endocarditis after transplantation is also increased by induction, mainly by antithymocyte globulin. Diagnostics only by PET-CT examination is rare; however, in this case it fundamentally changed the approach to the patient and led to a successful treatment. PMID- 26967238 TI - [A rare case of mobile atherosclerotic plaque with a high embolic potential in the femoral artery]. AB - Atherosclerosis is a diffuse disease which may lead to the development of unstable atherosclerotic plaque. Its rupture can result in acute ischemic event. The atherosclerotic plaques with a mobile component are typical presentations of such instability and patients with these plaques are at high risk of acute ischemic events. In the current literature, substantial data regarding the mobile atherosclerotic plaques in carotid arteries and thoracic aorta is published. However there are almost no data concerning the mobile plaques in the peripheral arteries of the lower limbs. We present a rare case of a patient with generalized atherosclerosis, in whom an asymptomatic mobile atherosclerotic plaque in the common femoral artery with a high embolic potential was diagnosed. This plaque was successfully removed by femoral endarterectomy. On the basis of this case, we review the possibilities and limitations of the current imaging methods in detection of mobile plaques in the peripheral arteries. Moreover optimal therapeutic approaches in such patients are discussed. PMID- 26967239 TI - [Dangerous cucumbers - Leylls syndrome]. AB - Leylls syndrome (syndrome of toxic epidermal necrolysis) is a rare disease, firstly described by Scottish doctor of medicine Allan Lyell in 1956. It is characterized by huge skin and mucosa necrolysis, which affects at least 30 % of body surface, and systemic symptoms. According to the frequency of the occurrence it is an extremely rare condition, with an incidence of 0.5-2 cases per million residents per year. Leylls syndrome is considered as a toxoallergic reaction, triggered mostly by some medication and it is associated with a very high mortality rate (in the literature reported between 30 to 90 %). Adequate and timely local and systemic treatment at the Intensive Care Unit or at the specialized clinic can improve the overall poor prognosis of the patients. In our case report we describe a very rare case of the Lyells syndrome after exposure to the antifungal organosulfur compound, which is widely used by the homegardners and farmers. PMID- 26967240 TI - [Toxic epidermal necrolysis]. AB - Toxic epidermal necrolysis is a rare, acute and life-threatening disorder manifested by extensive separation of the epidermis and mucosal surfaces. It is a serious adverse response to administered drugs, mostly antibiotics, anticonvulsants or NSAIDs. First described by Scottish dermatologist Alan Lyell in 1956, it is also known as Lyells syndrome. Mortality of the disease is high, therefore its early diagnosis is crucial and immediate initiation of appropriate patient care necessary. It is a rare disease with a very low incidence and serious prognosis, which is a considerable hindrance to undertaking large randomized clinical studies. It is therefore difficult to evaluate the effectiveness of various therapeutic options. As the most promising so far appears the administration of intravenous immunoglobulins, apparently reaching improvement in the clinical condition of the patient, with a good tolerances and minimal side adverse effects. New experimental techniques endeavour to seek a way to the therapy through targeted influencing of granulysin as the major cytotoxic mediator. PMID- 26967241 TI - Neutrophil lymphocyte ratio in peripheral vascular disease: a review. AB - Peripheral vascular disease (PVD) carries a significant morbidity and mortality. The role of inflammatory markers in cardiovascular medicine has been extensively studied. Neutrophil Lymphocyte ratio (NLR) is a novel biomarker which has been proposed as a marker of cardiovascular disease. We review the association of NLR with PVD. NLR has been shown to be an independent predictor of early and midterm amputation in patients with acute limb ischemia after embolectomy. A recent risk stratification model including NLR has emerged as a predictor of mortality and/or major amputation in critical limb ischemia. NLR appears to be an independent predictor of severity of PVD based on TransAtlantic Inter-Society Consensus classification, which classifies PVD based on the nature of the lesion and its anatomic distribution. A review of a large cohort of patients who had major vascular surgery, an NLR > 5 was found to be an independent predictor of mortality. In patients with intermediate carotid artery disease, NLR of 2.6 was found to be an independent variable for symptomatic carotid artery disease. It is a good predictor of early death in acute pulmonary embolism. NLR is inexpensive and readily available and appears to have a major role in peripheral vascular disease. PMID- 26967242 TI - High expression of Zinc-finger protein X-linked promotes tumor growth and predicts a poor outcome for stage II/III colorectal cancer patients. AB - Zinc-finger protein X-linked (ZFX) was recently identified as a novel oncoprotein in several human malignancies. In this study, we examined the correlation between ZFX expression and the clinical characteristics of stage II/III CRC patients, as well as the molecular mechanism by which ZFX apparently contributes to CRC tumor progression. Using immunohistochemistry, we detected expression of ZFX in CRC tissues collected from stage II/III patients and determined that its expression correlated with tumor differentiation and stage. Survival analysis indicated that patients with high ZFX expression had poorer overall and disease-free survival. ZFX knockdown in SW620 and SW480 CRC cells significantly inhibited cell proliferation and colony formation, enhanced apoptosis and induced cell cycle arrest. It also enhanced the sensitivity of CRC cells to 5-Fu. In a xenograft model, ZFX knockdown suppressed in vivo CRC tumor growth. Microarray analysis revealed the primary target of ZFX to be DUSP5. Whereas ZFX knockdown increased DUSP5 expression, DUSP5 knockdown rescued ZFX-mediated cell proliferation in ZFX knockdown cells. These findings demonstrate that ZFX promotes CRC progression by suppressing DUSP5 expression and suggest that ZFX is a novel prognostic biomarker and potentially useful therapeutic target in stage II/III CRC patients. PMID- 26967244 TI - Systematic meta-analyses of gene-specific genetic association studies in prostate cancer. AB - In the past twenty-five years, over 700 case-control association studies on the risk of prostate cancer have been published worldwide, but their results were largely inconsistent. To facilitate following and explaining these findings, we performed a systematic meta-analysis using allelic contrasts for gene-specific SNVs from at least three independent population-based case-control studies, which were published in the field of prostate cancer between August 1, 1990 and August 1, 2015. Across 66 meta-analyses, a total of 20 genetic variants involving 584,100 subjects in 19 different genes (KLK3, IGFBP3, ESR1, SOD2, CAT, CYP1B1, VDR, RFX6, HNF1B, SRD5A2, FGFR4, LEP, HOXB13, FAS, FOXP4, SLC22A3, LMTK2, EHBP1 and MSMB) exhibited significant association with prostate cancer. The average summary OR was 1.33 (ranging from: 1.016-3.788) for risk alleles and 0.838 (ranging from: 0.757-0.896) for protective alleles. Of these positive variants, FOXP4 rs1983891, LMTK2 rs6465657 and RFX6 rs339331 had not been previously meta analyzed. Further analyses with sufficient power design and investigations of the potential biological roles of these genetic variants in prostate cancer should be conducted. PMID- 26967243 TI - Specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 are non-oncogene addiction genes in cancer cells. AB - Specificity protein (Sp) transcription factor (TF) Sp1 is overexpressed in multiple tumors and is a negative prognostic factor for patient survival. Sp1 and also Sp3 and Sp4 are highly expressed in cancer cells and in this study, we have used results of RNA interference (RNAi) to show that the three TFs individually play a role in the growth, survival and migration/invasion of breast, kidney, pancreatic, lung and colon cancer cell lines. Moreover, tumor growth in athymic nude mice bearing L3.6pL pancreatic cancer cells as xenografts were significantly decreased in cells depleted for Sp1, Sp3 and Sp4 (combined) or Sp1 alone. Ingenuity Pathway Analysis (IPA) of changes in gene expression in Panc1 pancreatic cancer cells after individual knockdown of Sp1, Sp3 and Sp4 demonstrates that these TFs regulate genes and pathways that correlated with the functional responses observed after knockdown but also some genes and pathways that inversely correlated with the functional responses. However, causal IPA analysis which integrates all pathway-dependent changes in all genes strongly predicted that Sp1-, Sp3- and Sp4-regulated genes were associated with the pro oncogenic activity. These functional and genomic results coupled with overexpression of Sp transcription factors in tumor vs. non-tumor tissues and decreased Sp1 expression with age indicate that Sp1, Sp3 and Sp4 are non-oncogene addiction (NOA) genes and are attractive drug targets for individual and combined cancer chemotherapies. PMID- 26967245 TI - Exploring the role of sphingolipid machinery during the epithelial to mesenchymal transition program using an integrative approach. AB - The epithelial to mesenchymal transition (EMT) program is activated in epithelial cancer cells and facilitates their ability to metastasize based on enhanced migratory, proliferative, anti-apoptotic, and pluripotent capacities. Given the fundamental impact of sphingolipid machinery to each individual process, the sphingolipid-related mechanisms might be considered among the most prominent drivers/players of EMT; yet, there is still limited knowledge. Given the complexity of the interconnected sphingolipid system, which includes distinct sphingolipid mediators, their synthesizing enzymes, receptors and transporters, we herein apply an integrative approach for assessment of the sphingolipid associated mechanisms underlying EMT program. We created the sphingolipid-/EMT relevant 41-gene/23-gene signatures which were applied to denote transcriptional events in a lung cancer cell-based EMT model. Based on defined 35-gene sphingolipid/EMT-attributed signature of regulated genes, we show close associations between EMT markers, genes comprising the sphingolipid network at multiple levels and encoding sphingosine 1-phosphate (S1P)-/ceramide-metabolizing enzymes, S1P and lysophosphatidic acid (LPA) receptors and S1P transporters, pluripotency genes and inflammation-related molecules, and demonstrate the underlying biological pathways and regulators. Mass spectrometry-based sphingolipid analysis revealed an EMT-attributed shift towards increased S1P and LPA accompanied by reduced ceramide levels. Notably, using transcriptomics data across various cell-based perturbations and neoplastic tissues (24193 arrays), we identified the sphingolipid/EMT signature primarily in lung adenocarcinoma tissues; besides, bladder, colorectal and prostate cancers were among the top ranked. The findings also highlight novel regulatory associations between influenza virus and the sphingolipid/EMT-associated mechanisms. In sum, data propose the multidimensional contribution of sphingolipid machinery to pathological EMT and may yield new biomarkers and therapeutic targets. PMID- 26967248 TI - CWP232228 targets liver cancer stem cells through Wnt/beta-catenin signaling: a novel therapeutic approach for liver cancer treatment. AB - Liver cancer stem cells (CSCs) are resistant to conventional chemotherapy and radiation, which may destroy tumor masses, but not all liver CSCs contribute to tumor initiation, metastasis, and relapse. In the present study, we showed that liver CSCs with elevated Wnt/beta-catenin signaling possess much greater self renewal and clonogenic potential. We further documented that the increased clonogenic potential of liver CSCs is highly associated with changes in Wnt/beta catenin signaling and that Wnt/beta-catenin signaling activity is positively correlated with CD133 expression and aldehyde dehydrogenase (ALDH) enzymatic activity. Notably, the small molecule inhibitor CWP232228, which antagonizes the binding of beta-catenin to TCF in the nucleus, inhibits Wnt/beta-catenin signaling and depletes CD133+/ALDH+ liver CSCs, thus ultimately diminishing the self-renewal capacity of CSCs and decreasing tumorigenicity in vitro and in vivo. Taken together, our findings suggest that CWP232228 acts as a candidate therapeutic agent for liver cancer by preferentially targeting liver CSCs. PMID- 26967247 TI - miR-155 regulates the proliferation and invasion of clear cell renal cell carcinoma cells by targeting E2F2. AB - MicroRNAs (miRNAs) have emerged as critical modulators of carcinogenesis and tumor progression. In the present work, we sought to identify the biological function of miR-155 as well as its underlying mechanism in clear cell renal cell carcinoma (ccRCC). We examined the expression of miR-155 in clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-155 both in vitro and in vivo. The results of this analysis indicated that miR-155 activity was significantly upregulated in ccRCC tissues compared with the corresponding normal tissues. miR-155 was associated with ccRCC aggressiveness in both cell lines and clinical specimens, and a specific and inverse correlation between miR-155 and E2F2 expression was found in human ccRCC samples. Overexpression of miR-155 in 786-O cells decreased E2F2 expression while reduction of miR-155 by anti-miR-155 in ACHN cells elevated E2F2 expression. Re expression of E2F2 in 786-O cells repressed the cell migration/invasion abilities elevated by miR-155, whereas knockdown of E2F2 in ACHN cells restored these cellular functions hampered by the miR-155 inhibitor. Using Western blot and luciferase reporter assays, we determined that E2F2 was a direct target of miR 155. Taken together, the in vitro and in vivo results demonstrate that miR-155 functions as a tumor-promoting miRNA by targeting E2F2 in ccRCC. PMID- 26967246 TI - The clinical value of aberrant epigenetic changes of DNA damage repair genes in human cancer. AB - The stability and integrity of the human genome are maintained by the DNA damage repair (DDR) system. Unrepaired DNA damage is a major source of potentially mutagenic lesions that drive carcinogenesis. In addition to gene mutation, DNA methylation occurs more frequently in DDR genes in human cancer. Thus, DNA methylation may play more important roles in DNA damage repair genes to drive carcinogenesis. Aberrant methylation patterns in DNA damage repair genes may serve as predictive, diagnostic, prognostic and chemosensitive markers of human cancer. MGMT methylation is a marker for poor prognosis in human glioma, while, MGMT methylation is a sensitive marker of glioma cells to alkylating agents. Aberrant epigenetic changes in DNA damage repair genes may serve as therapeutic targets. Treatment of MLH1-methylated colon cancer cell lines with the demethylating agent 5'-aza-2'-deoxycytidine induces the expression of MLH1 and sensitizes cancer cells to 5-fluorouracil. Synthetic lethality is a more exciting approach in patients with DDR defects. PARP inhibitors are the most effective anticancer reagents in BRCA-deficient cancer cells. PMID- 26967249 TI - Age-related changes in the transcriptome of antibody-secreting cells. AB - We analyzed age-related defects in B cell populations from young and aged mice. Microarray analysis of bone marrow resident antibody secreting cells (ASCs) showed significant changes upon aging, affecting multiple genes, pathways and functions including those that play a role in immune regulation, humoral immune responses, chromatin structure and assembly, cell metabolism and the endoplasmic reticulum (ER) stress response. Further analysis showed upon aging defects in energy production through glucose catabolism with reduced oxidative phosphorylation. In addition aged B cells had increased levels of reactive oxygen species (ROS), which was linked to enhanced expression of the co-inhibitor programmed cell death (PD)-1. PMID- 26967250 TI - Acetylation and deacetylation of Cdc25A constitutes a novel mechanism for modulating Cdc25A functions with implications for cancer. AB - The dual specificity phosphatase Cdc25A is a key regulator of the cell cycle that promotes cell cycle progression by dephosphorylating and activating cyclin dependent kinases. In response to genotoxicants, Cdc25A undergoes posttranslational modifications which contribute to its proteasome-mediated degradation and consequent cell cycle checkpoint arrest. The most thoroughly studied Cdc25A modification is phosphorylation. We now provide the first evidence that Cdc25A can be acetylated and that it directly interacts with the ARD1 acetyltransferase which acetylates Cdc25A both biochemically and in cultured cells. When acetylated, Cdc25A has an extended half-life. We have also identified the class IV histone deacetylase, HDAC11, as a Cdc25A deacetylase. We further show that DNA damage, such as exposure to methyl methanesulfonate (MMS), etoposide or arsenic, increases Cdc25A acetylation. Importantly, this acetylation modulates Cdc25A phosphatase activity and its function as a cell cycle regulator, and may reflect a cellular response to DNA damage. Since Cdc25A, ARD1, and HDAC11 are frequently dysregulated in multiple types of cancer, our findings may provide insight into a novel mechanism in carcinogenesis. PMID- 26967252 TI - Metabolomics profiling in plasma samples from glioma patients correlates with tumor phenotypes. AB - BACKGROUND: Tumor-based molecular biomarkers have redefined in the classification gliomas. However, the association of systemic metabolomics with glioma phenotype has not been explored yet. METHODS: In this study, we conducted two-step (discovery and validation) metabolomic profiling in plasma samples from 87 glioma patients. The metabolomics data were tested for correlation with glioma grade (high vs low), glioblastoma (GBM) versus malignant gliomas, and IDH mutation status. RESULTS: Five metabolites, namely uracil, arginine, lactate, cystamine, and ornithine, significantly differed between high- and low-grade glioma patients in both the discovery and validation cohorts. When the discovery and validation cohorts were combined, we identified 29 significant metabolites with 18 remaining significant after adjusting for multiple comparisons. Those 18 significant metabolites separated high- from low-grade glioma patients with 91.1% accuracy. In the pathway analysis, a total of 18 significantly metabolic pathways were identified. Similarly, we identified 2 and 6 metabolites that significantly differed between GBM and non-GBM, and IDH mutation positive and negative patients after multiple comparison adjusting. Those 6 significant metabolites separated IDH1 mutation positive from negative glioma patients with 94.4% accuracy. Three pathways were identified to be associated with IDH mutation status. Within arginine and proline metabolism, levels of intermediate metabolites in creatine pathway were all significantly lower in IDH mutation positive than in negative patients, suggesting an increased activity of creatine pathway in IDH mutation positive tumors. CONCLUSION: Our findings identified metabolites and metabolic pathways that differentiated tumor phenotypes. These may be useful as host biomarker candidates to further help glioma molecular classification. PMID- 26967251 TI - The antinociceptive effects of ferulic acid on neuropathic pain: involvement of descending monoaminergic system and opioid receptors. AB - Neuropathic pain can be considered as a form of chronic stress that may share common neuropathological mechanism between pain and stress-related depression and respond to similar treatment. Ferulic acid (FA) is a major active component of angelica sinensis and has been reported to exert antidepressant-like effects; however, it remains unknown whether FA ameliorate chronic constriction injury (CCI)-induced neuropathic pain and the involvement of descending monoaminergic system and opioid receptors. Chronic treatment with FA (20, 40 and 80 mg/kg) ameliorated mechanical allodynia and thermal hyperalgesia in von Frey hair and hot plate tasks, accompanied by increasing spinal noradrenaline (NA) and serotonin (5-HT) levels. Subsequent study suggested that treatment of CCI animals with 40 and 80 mg/kg FA also inhibited spinal MAO-A levels. FA's effects on mechanical allodynia or thermal hyperalgesiawas blocked by 6-hydroxydopamine (6 OHDA) or p-chlorophenylalanine (PCPA) via pharmacological depletion of spinal noradrenaline or serotonin. Moreover, the anti-allodynic action of FA on mechanical stimuli was prevented by pre-treatment with beta2-adrenoceptor antagonist ICI 118,551, or by the delta-opioid receptor antagonist naltrindole. While the anti-hyperalgesia on thermal stimuli induced by FA was blocked by pre treatment with 5-HT1A receptor antagonist WAY-100635, or with the irreversible mu opioid receptor antagonist beta-funaltrexamine. These results suggest that the effect of FA on neuropathic pain is potentially mediated via amelioration of the descending monoaminergic system that coupled with spinal beta2- and 5-HT1A receptors and the downstream delta- and mu-opioid receptors differentially. PMID- 26967253 TI - Nomograms to estimate long-term overall survival and breast cancer-specific survival of patients with luminal breast cancer. AB - Luminal breast cancer constitutes a group of highly heterogeneous diseases with a sustained high risk of late recurrence. We aimed to develop comprehensive and practical nomograms to better estimate the long-term survival of luminal breast cancer.Patients with luminal breast cancer diagnosed between 1990 and 2006 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into the training (n = 87,867) and validation (n = 88,215) cohorts. The cumulative incidence function (CIF) and a competing-risks model were used to estimate the probability of breast cancer-specific survival (BCSS) and death from other causes. We integrated significant prognostic factors to build nomograms and subjected the nomograms to bootstrap internal validation and to external validation.We screened 176,082 luminal breast cancer cases. The 5- and 10-year probabilities of overall death were 0.089 and 0.202, respectively. The 5- and 10-year probabilities of breast cancer-specific mortality (BCSM) were 0.053 and 0.112, respectively. Nine independent prognostic factors for both OS and BCSS were integrated to construct the nomograms. The calibration curves for the probabilities of 5- and 10-year OS and BCSS showed excellent agreement between the nomogram prediction and actual observation. The C-indexes of the nomograms were high in both internal validation (0.732 for OS and 0.800 for BCSS) and external validation (0.731 for OS and 0.794 for BCSS).We established nomograms that accurately predict OS and BCSS for patients with luminal breast cancer. The nomograms can identify patients with higher risk of late overall mortality and BCSM, helping physicians in facilitating individualized treatment. PMID- 26967255 TI - Word Recognition Variability With Cochlear Implants: The Degradation of Phonemic Sensitivity. AB - OBJECTIVE: Cochlear implants (CIs) do not automatically restore speech recognition for postlingually deafened adults. Average word recognition remains at 60%, and enormous variability exists. Understanding speech requires knowledge of phonemic codes, the basic sound units of language. Hearing loss may result in degeneration of these long-term mental representations (i.e., "phonemic sensitivity"), and CI use may not adequately restore those representations. This investigation examined whether phonemic sensitivity is degraded for CI users, and whether this degradation results in poorer word recognition. STUDY DESIGN: Thirty adults with CIs and 20 normal-hearing controls underwent testing. METHODS: Participants were assessed for word recognition in quiet, along with tasks of phonemic sensitivity using an audiovisual format to maximize recognition: initial consonant choice (ICC), in which they selected the word with the same starting sound as a target word, final consonant choice (FCC), in which they selected the word with the same ending sound, and backwards words, in which they repeated phonemes comprising words in backwards order. RESULTS: Phonemic sensitivity was poorer for CI users than for normal-hearing controls for ICC and FCC. For CI users, ICC and FCC predicted 25% and 40% of variance in word recognition, respectively. Longer duration of CI use did not lead to greater restoration in phonemic sensitivity. CONCLUSION: Even for adults who presumably had developed refined phonemic representations, hearing loss can degrade those representations, which results in poorer word recognition. Cochlear implants do not adequately restore those representations. Findings suggest the need for rehabilitative efforts to improve CI users' phonemic sensitivity. PMID- 26967254 TI - Increased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging. AB - The blood-brain barrier (BBB) is partially disrupted in brain tumors. Despite the gaps in the BBB, there is an inadequate amount of pharmacological agents delivered into the brain. Thus, the low delivery efficiency renders many of these agents ineffective in treating brain cancer. In this report, we proposed an "autocatalytic" approach for increasing the transport of nanoparticles into the brain. In this strategy, a small number of nanoparticles enter into the brain via transcytosis or through the BBB gaps. After penetrating the BBB, the nanoparticles release BBB modulators, which enables more nanoparticles to be transported, creating a positive feedback loop for increased delivery. Specifically, we demonstrated that these autocatalytic brain tumor-targeting poly(amine-co-ester) terpolymer nanoparticles (ABTT NPs) can readily cross the BBB and preferentially accumulate in brain tumors at a concentration of 4.3- and 94.0-fold greater than that in the liver and in brain regions without tumors, respectively. We further demonstrated that ABTT NPs were capable of mediating brain cancer gene therapy and chemotherapy. Our results suggest ABTT NPs can prime the brain to increase the systemic delivery of therapeutics for treating brain malignancies. PMID- 26967256 TI - Biological measures to minimize the risk of radiotherapy-associated second cancer: A research perspective. AB - Purpose Second cancers are among the most serious sequelae for cancer survivors who receive radiotherapy. This article aims to review current knowledge regarding how the risk of radiotherapy-associated second cancer can be minimized by biological measures and to discuss relevant research needs. Results The risk of second cancer can be reduced not only by physical measures to decrease the radiation dose to normal tissues but also by biological means that interfere with the critical determinants of radiation-induced carcinogenesis. Requirements for such biological means include the targeting of tumor types relevant to radiotherapy-associated risk, concrete safety and efficacy evidence and feasibility and minimal invasiveness. Mechanistic insights into the process of radiation carcinogenesis provide rational approaches to minimize the risk. Five mechanism-based strategies are proposed herein based on the current state of knowledge. Epidemiological studies on the joint effects of radiation and lifestyle or other factors can provide evidence for factors that modify radiation associated risks if deliberately controlled. Conclusions Mechanistic and epidemiological evidence indicates that it is possible to develop interventional measures to minimize the second cancer risk associated with radiotherapy. Research is needed regarding the critical determinants of radiation-induced carcinogenesis available for intervention and joint effects of radiation and controllable factors. PMID- 26967257 TI - Encapsulating Cytochrome c in Silica Aerogel Nanoarchitectures without Metal Nanoparticles while Retaining Gas-phase Bioactivity. AB - Applications such as sensors, batteries, and fuel cells have been improved through the use of highly porous aerogels when functional compounds are encapsulated within the aerogels. However, few reports on encapsulating proteins within sol-gels that are processed to form aerogels exist. A procedure for encapsulating cytochrome c (cyt. c) in silica (SiO2) sol-gels that are supercritically processed to form bioaerogels with gas-phase activity for nitric oxide (NO) is presented. Cyt. c is added to a mixed silica sol under controlled protein concentration and buffer strength conditions. The sol mixture is then gelled and the liquid filling the gel pores is replaced through a series of solvent exchanges with liquid carbon dioxide. The carbon dioxide is brought to its critical point and vented off to form dry aerogels with cyt. c encapsulated inside. These bioaerogels are characterized with UV-visible spectroscopy and circular dichroism spectroscopy and can be used to detect the presence of gas phase nitric oxide. The success of this procedure depends on regulating the cyt. c concentration and the buffer concentration and does not require other components such as metal nanoparticles. It may be possible to encapsulate other proteins using a similar approach making this procedure important for potential future bioanalytical device development. PMID- 26967258 TI - Incidence and Management of Glaucoma in Vogt Koyanagi Harada Disease. AB - PURPOSE: To analyse the prevalence, incidence, and risk factors of glaucoma in Vogt Koyanagi Harada (VKH) disease and study the changes in visual acuity and intraocular pressure (IOP) with treatment. MATERIALS AND METHODS: Retrospective chart analysis of 448 eyes of 224 patients of Indian origin diagnosed with VKH disease from January 1990 to December 2013, who had a minimum follow-up of 3 months was performed. RESULTS: Seventy-one eyes (15.8%) developed sustained elevation in IOP. The prevalence of glaucoma at presentation was 15.8% and the cumulative incidence of glaucoma was 11.7%. The mechanisms of glaucoma were open angle glaucoma in 46 eyes, (64.8%), angle closure in 21 eyes (29.6%), and of combined mechanisms in the remainder (4 eyes, 5.6%). Acute angle-closure crisis developed in 9 eyes (12.6%). Uveal effusion (odds ratio 9.47; confidence interval, 4.08-20.03) and increased number of recurrences (odds ratio 1.31; confidence interval, 1.13-1.53) were found to be significant risk factors for the development of glaucoma. Successful control of IOP was achieved in 64% at 12 months using medical/ laser treatment for glaucoma and was 50 % at 12 months following surgical management. CONCLUSIONS: Glaucoma is a frequent complication of uveitis in VKH disease. Presence of uveal effusion and increased number of recurrences of inflammation are significant risk factors. PMID- 26967259 TI - Interventions for preventing delirium in hospitalised non-ICU patients. AB - BACKGROUND: Delirium is a common mental disorder, which is distressing and has serious adverse outcomes in hospitalised patients. Prevention of delirium is desirable from the perspective of patients and carers, and healthcare providers. It is currently unclear, however, whether interventions for preventing delirium are effective. OBJECTIVES: To assess the effectiveness of interventions for preventing delirium in hospitalised non-Intensive Care Unit (ICU) patients. SEARCH METHODS: We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 4 December 2015 for all randomised studies on preventing delirium. We also searched MEDLINE (Ovid SP), EMBASE (Ovid SP), PsycINFO (Ovid SP), Central (The Cochrane Library), CINAHL (EBSCOhost), LILACS (BIREME), Web of Science core collection (ISI Web of Science), ClinicalTrials.gov and the WHO meta register of trials, ICTRP. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of single and multi- component non-pharmacological and pharmacological interventions for preventing delirium in hospitalised non-ICU patients. DATA COLLECTION AND ANALYSIS: Two review authors examined titles and abstracts of citations identified by the search for eligibility and extracted data independently, with any disagreements settled by consensus. The primary outcome was incidence of delirium; secondary outcomes included duration and severity of delirium, institutional care at discharge, quality of life and healthcare costs. We used risk ratios (RRs) as measures of treatment effect for dichotomous outcomes; and between group mean differences and standard deviations for continuous outcomes. MAIN RESULTS: We included 39 trials that recruited 16,082 participants, assessing 22 different interventions or comparisons. Fourteen trials were placebo-controlled, 15 evaluated a delirium prevention intervention against usual care, and 10 compared two different interventions. Thirty-two studies were conducted in patients undergoing surgery, the majority in orthopaedic settings. Seven studies were conducted in general medical or geriatric medicine settings.We found multi component interventions reduced the incidence of delirium compared to usual care (RR 0.69, 95% CI 0.59 to 0.81; seven studies; 1950 participants; moderate-quality evidence). Effect sizes were similar in medical (RR 0.63, 95% CI 0.43 to 0.92; four studies; 1365 participants) and surgical settings (RR 0.71, 95% CI 0.59 to 0.85; three studies; 585 participants). In the subgroup of patients with pre existing dementia, the effect of multi-component interventions remains uncertain (RR 0.90, 95% CI 0.59 to 1.36; one study, 50 participants; low-quality evidence).There is no clear evidence that cholinesterase inhibitors are effective in preventing delirium compared to placebo (RR 0.68, 95% CI, 0.17 to 2.62; two studies, 113 participants; very low-quality evidence).Three trials provide no clear evidence of an effect of antipsychotic medications as a group on the incidence of delirium (RR 0.73, 95% CI, 0.33 to 1.59; 916 participants; very low quality evidence). In a pre-planned subgroup analysis there was no evidence for effectiveness of a typical antipsychotic (haloperidol) (RR 1.05, 95% CI 0.69 to 1.60; two studies; 516 participants, low-quality evidence). However, delirium incidence was lower (RR 0.36, 95% CI 0.24 to 0.52; one study; 400 participants, moderate-quality evidence) for patients treated with an atypical antipsychotic (olanzapine) compared to placebo (moderate-quality evidence).There is no clear evidence that melatonin or melatonin agonists reduce delirium incidence compared to placebo (RR 0.41, 95% CI 0.09 to 1.89; three studies, 529 participants; low quality evidence).There is moderate-quality evidence that Bispectral Index (BIS) guided anaesthesia reduces the incidence of delirium compared to BIS-blinded anaesthesia or clinical judgement (RR 0.71, 95% CI 0.60 to 0.85; two studies; 2057 participants).It is not possible to generate robust evidence statements for a range of additional pharmacological and anaesthetic interventions due to small numbers of trials, of variable methodological quality. AUTHORS' CONCLUSIONS: There is strong evidence supporting multi-component interventions to prevent delirium in hospitalised patients. There is no clear evidence that cholinesterase inhibitors, antipsychotic medication or melatonin reduce the incidence of delirium. Using the Bispectral Index to monitor and control depth of anaesthesia reduces the incidence of postoperative delirium. The role of drugs and other anaesthetic techniques to prevent delirium remains uncertain. PMID- 26967260 TI - The Scientific Impact of Positive and Negative Phase 3 Cancer Clinical Trials. AB - IMPORTANCE: Positive phase 3 cancer clinical trials are widely hailed, while trials with negative results are often interpreted as scientific failures. We hypothesized that these interpretations would be reflected in the scientific literature. OBJECTIVE: To compare the scientific impact of positive vs negative phase 3 cancer clinical treatment trials. DESIGN, SETTING, AND PARTICIPANTS: We examined the phase 3 trial history of SWOG, a national cancer clinical trials consortium, over a 30-year period (1985-2014). Scientific impact was assessed according to multiple publication and citation outcomes. Citation data were obtained using Google Scholar. Citation counts were compared using generalized estimating equations for Poisson regression. Any trial that was formally evaluated for the randomized treatment comparison was included for analysis of publication and citation outcomes. Trials were categorized as positive if they achieved a statistically significant result in favor of the new experimental treatment for the protocol-specified primary end point. Trials were categorized as negative if they achieved a statistically significant result in favor of standard therapy or a null result with no statistically significant benefit for either the experimental or standard therapy. MAIN OUTCOMES AND MEASURES: Impact factors for the journals publishing the primary trial results, and the number of citations for the primary trial articles and all secondary articles associated with the trials. RESULTS: Ninety-four studies enrolling n = 46 424 patients were analyzed. Twenty-eight percent of trials were positive (26 of 94). The primary publications from positive trials were published in journals with higher mean (SD) 2-year impact factors (28 [19] vs 18 [13]; P = .007) and were cited twice as often as negative trials (mean per year, 43 vs 21; relative risk, 2.0; 95% CI, 1.1-3.9; P = .03). However, the number of citations from all primary and secondary articles did not significantly differ between positive and negative trials (mean per year, 55 vs 45; relative risk, 1.2; 95% CI, 0.7-2.3; P = .53). CONCLUSIONS AND RELEVANCE: The scientific impact of the primary articles from positive phase 3 randomized cancer clinical trials was twice as great as for negative trials. But when all of the articles associated with the trials were considered, the scientific impact between positive and negative trials was similar. Positive trials indicate clinical advances, but negative trials also have a sizeable scientific impact by generating important scientific observations and new hypotheses and by showing what new treatments should not be used. PMID- 26967261 TI - Profiling and Spatial Variation Analysis of Persistent Organic Pollutants in South African Delphinids. AB - The continuous disposal of persistent organic pollutants (POPs) in South Africa (SA) warrants concern about their detrimental effects on humans and wildlife. We surveyed six dolphin species (n = 90) incidentally captured in shark net installations or stranded off the SA east and south coast from 2005 to 2009 to study the POP exposure. Sousa plumbea, an inshore and estuarine species, was found to be the most contaminated by total POPs (21 100 ng g(-1) lw) of all the dolphins off SA, followed by Tursiops aduncus (19 800 ng g(-1) lw), Lagenodelphis hosei (13 600 ng g(-1) lw), and Delphinus capensis (5500 ng g(-1) lw), whereas POP levels in the offshore or pelagic delphinids were much lower. In all delphinids, dominant pollutants were dichlorodiphenyltrichloroethanes (DDTs), which represented more than 60% of the total concentration of total POPs, followed by polychlorinated biphenyls (PCBs, 30%). Concentrations of DDTs in S. plumbea and T. aduncus off SA were among the highest levels reported in delphinids globally. Approximately half of the adult T. aduncus had PCB concentrations above the effect threshold for impairment of immune functions. The concentrations of Mirex and Dieldrin in SA delphinids were higher than those found in species from other regions of the Southern Hemisphere. PMID- 26967263 TI - New technologies in tumor ablation. AB - PURPOSE OF REVIEW: The application of ablative modalities for small renal masses continues to increase. In addition, multiple technologies continue to be studied for the treatment of these renal masses. This review focuses on new and emerging technologies so that the clinician can become more familiar with these modalities as they become available in clinical practice. RECENT FINDINGS: Radiofrequency ablation (RFA) and cryoablation (cryo) continue to be the most often used ablative modalities for the treatment of small renal masses. In addition, they are the most thoroughly studied modalities leading to a set of well defined variables predicting successful ablation. Microwave ablation (MWA) and irreversible electroporation are newer modalities that offer theoretical advantages to RFA and cryo, although each differs in the specific advantage provided. Multiple animal studies have been performed with each modality; however, in both cases, the optimal device settings are not well defined. For MWA in particular, there are a significant number of systems available and within each system, there are an array of variables that can be modified, which influences the ablation zone size and shape. Other emerging technologies include stereotactic body radiation and high-intensity focused ultrasound, although each has limited data supporting their efficacy to date. SUMMARY: Ablation technology continues to multiply and evolve. Newer technologies such as MWA and irreversible electroporation are promising as they offer theoretical advantages to RFA and cryo. However, both require further studies to identify the optimal tumor characteristics and device settings leading to successful ablation. PMID- 26967262 TI - Fluorescence Monitoring of the Oxidative Repair of DNA Alkylation Damage by ALKBH3, a Prostate Cancer Marker. AB - The 2-oxoglutarate-dependent iron enzyme ALKBH3 is an antitumor target and a potential diagnostic marker for several tumor types, including prostate cancer. However, there is at present no simple way to measure this enzyme's activity. Here we describe a fluorogenic probe design (MAQ) that is directly responsive to ALKBH3 repair activity. It makes use of the fluorescence-quenching properties of 1-methyladenine; removal of the alkyl group results in a >10-fold light-up signal. The probe is specific for ALKBH3 over its related homologue ALKBH2 and can be used to identify and measure the effectiveness of enzyme inhibitors. Measurements of the enzyme substrate parameters show that MAQ displays Km and kcat values essentially the same as those of the native substrate. Finally, we show that the probe functions efficiently in cells, allowing imaging and quantitation of ALKBH3 activity by microscopy and flow cytometry. We expect that MAQ probes will be broadly useful in the study of the basic biology of ALKBH3 and in clinical cancer applications as well. PMID- 26967264 TI - Innovations in surgical stone disease. AB - PURPOSE OF REVIEW: Urinary stone disease is a condition characterized by a rich history of surgical innovation. Herein, we review the new ideas, devices and methods that are the cornerstones of contemporary surgical innovation in stone disease, specifically flexible ureteroscopy and percutaneous nephrolithotomy. RECENT FINDINGS: The new ideas being applied to flexible ureteroscopy include extending the boundaries of surgical indications and eliminating the need for intraoperative fluoroscopy. Device advancements include disposable ureteroscopes and flexi semirigid ureteroscopes. Robotic flexible ureteroscopy, the use of magnets and mobile technology applications represent progress in methods of performing flexible ureteroscopy. Three-dimensional computed tomography and printing technology are enhancing percutaneous renal access. Novel image-guided access techniques are improving the accuracy of percutaneous surgery particularly for complex cases. SUMMARY: New ideas, devices and methods are continuing to reshape the landscape of surgical stone treatment and in so doing not only have the potential to improve surgical outcomes but also to cultivate further scientific and technological advancements in this area. PMID- 26967265 TI - Nocturia in women. AB - PURPOSE OF REVIEW: Nocturia in women is a notable health concern, associated with significant morbidity and decreases in health-related quality of life. It is implicated in daytime somnolence and poor sleep quality, and has been found to negatively impact household activities, work, exercise, and sexual activity. This review is intended to relay new information regarding the prevalence, cause, risk factors, ramifications, and treatment options for nocturia in women as it gains traction as a clinical entity in and of itself. RECENT FINDINGS: New literature exposes the prevalence and burden of nocturia among young, healthy nulliparous women; reveals its presence in women without daytime symptoms; suggests its relationship with abnormal bowel function; and supports its association with obesity, cardiac burden and poor sleep. The link between nocturia and menopause has been challenged, and recent nomenclature describing the genitourinary symptoms of menopause excludes it from the list. Desmopressin and tamsulosin trials in women have demonstrated safety and efficacy in limiting nocturia frequency and severity, as well as in improving sleep parameters. SUMMARY: Nocturia is an impactful health issue at risk of being missed, especially in younger female patients. Open dialogue, purposeful questioning, and screening surveys can help elicit this symptom in women who are embarrassed or who accredit it to normal aging and therefore do not seek medical attention. In light of a growing geriatric population, nocturia is a clinical entity of increasing importance as it can be a clue to underlying systemic disorder or it can be an isolated symptom with significant clinical implications if left unaddressed. PMID- 26967266 TI - Chloroquine-induced subacute paranoid-like disorder as a complication of dermatological treatment. PMID- 26967268 TI - Characterization of an RNA receptor motif that recognizes a GCGA tetraloop. AB - Tertiary interactions between a new RNA motif and RNA tetraloops were analyzed to determine whether this new motif shows preference for a GCGA tetraloop. In the structural context of a ligase ribozyme, this motif discriminated GCGA loop from 3 other tetraloops. The affinity between the GCGA loop and its receptor is strong enough to carry out the ribozyme activity. PMID- 26967267 TI - Will novel oral formulations change the management of inflammatory bowel disease? AB - INTRODUCTION: The traditional management of inflammatory bowel disease (IBD) with sulphasalazine/5-aminosalicylic acid, glucocorticoids and immunomodulators (i.e., thiopurines and methotrexate) was nearly two decades ago extended with intravenously or subcutaneously administered biologics (i.e., tumor necrosis factor inhibitors and later gut-selective integrin antagonists). However, recently, orally administered treatments with simple, well-characterized, and stable structures consisting of either small molecules or anti-sense therapy have been devised. AREAS COVERED: This review discusses the current approaches with promising new oral drugs with distinct modes of action, including: the Janus kinase inhibitors (i.e., tofacitinib, filgotinib and peficitinib); the immunomodulatory drug (laquinimod); a small alpha4 antagonist (AJM300); agonists for sphingosine-phosphate receptors (i.e., ozanimod, APD334, and amiselimod), as well as anti-sense therapy (mongersen) targeting SMAD7, drugs which directly target intracellular pathways of relevance for intestinal inflammation. EXPERT OPINION: A new avenue using easily administered oral therapies for the management of IBD is being introduced. While their place in the clinical armamentarium remains to be proven, it is likely that many of these drugs will find their place in the treatment algorithm of IBD in the next few years. Thus, we will face times in which IBD therapy will be based on significantly more tablets than prescribed today. PMID- 26967270 TI - Communication In and Of Biology. PMID- 26967269 TI - Performing Permanent Distal Middle Cerebral with Common Carotid Artery Occlusion in Aged Rats to Study Cortical Ischemia with Sustained Disability. AB - Stroke typically occurs in elderly people with a range of comorbidities including carotid (or other arterial) atherosclerosis, high blood pressure, obesity and diabetes. Accordingly, when evaluating therapies for stroke in animals, it is important to select a model with excellent face validity. Ischemic stroke accounts for 80% of all strokes, and the majority of these occur in the territory of the middle cerebral artery (MCA), often inducing infarcts that affect the sensorimotor cortex, causing persistent plegia or paresis on the contralateral side of the body. We demonstrate in this video a method for producing ischemic stroke in elderly rats, which causes sustained sensorimotor disability and substantial cortical infarcts. Specifically, we induce permanent distal middle cerebral artery occlusion (MCAO) in elderly female rats by using diathermy forceps to occlude a short segment of this artery. The carotid artery on the ipsilateral side to the lesion was then permanently occluded and the contralateral carotid artery was transiently occluded for 60 min. We measure the infarct size using structural T2-weighted magnetic resonance imaging (MRI) at 24 hr and 8 weeks after stroke. In this study, the mean infarct volume was 4.5% +/- 2.0% (standard deviation) of the ipsilateral hemisphere at 24 hr (corrected for brain swelling using Gerriet's equation, n = 5). This model is feasible and clinically relevant as it permits the induction of sustained sensorimotor deficits, which is important for the elucidation of pathophysiological mechanisms and novel treatments. PMID- 26967272 TI - Spreading Knowledge and Wonder. PMID- 26967273 TI - When Biology Doesn't Add Up. AB - Physical models are increasingly used to inform our understanding of biology. Where such models still run into limits was the question that Cell's Robert Kruger posed to Julie Theriot, K.C. Huang, and Mark Goulian. Annotated excerpts from this conversation are presented below, and the full conversation is available with the article online. PMID- 26967274 TI - All You Need Is Mentorship. PMID- 26967275 TI - Staying Afloat in the Rising Tide of Science. AB - New York Times columnist and science writer Carl Zimmer discusses the challenges of effectively communicating with the public about science. PMID- 26967276 TI - You, Me, and We: Biolabs for the 21st Century. AB - Twenty-first century biomedical research is advantaged by institutional infrastructures that foster a collaborative, multidisciplinary approach. A few critical elements in the design of labs, research buildings, or campus can make interaction easier while preserving privacy and comfort for the individual researcher. PMID- 26967277 TI - Communication in Drug Development: "Translating" Scientific Discovery. AB - The discovery and development of new medicines that promote human health and potentially extend natural life remains a remarkably challenging endeavor. In this Commentary, we identify key elements of communication required to successfully translate promising biological findings to novel approved drug therapies and discuss the attendant challenges and opportunities. PMID- 26967278 TI - Reverse Engineering Human Pathophysiology with Organs-on-Chips. AB - While studies of cultured cells have led to new insights into biological control, greater understanding of human pathophysiology requires the development of experimental systems that permit analysis of intercellular communications and tissue-tissue interactions in a more relevant organ context. Human organs-on chips offer a potentially powerful new approach to confront this long-standing problem. PMID- 26967282 TI - Passive Noise Filtering by Cellular Compartmentalization. AB - Chemical reactions contain an inherent element of randomness, which presents itself as noise that interferes with cellular processes and communication. Here we discuss the ability of the spatial partitioning of molecular systems to filter and, thus, remove noise, while preserving regulated and predictable differences between single living cells. In contrast to active noise filtering by network motifs, cellular compartmentalization is highly effective and easily scales to numerous systems without requiring a substantial usage of cellular energy. We will use passive noise filtering by the eukaryotic cell nucleus as an example of how this increases predictability of transcriptional output, with possible implications for the evolution of complex multicellularity. PMID- 26967280 TI - Movement: How the Brain Communicates with the World. AB - Voluntary movement is a result of signals transmitted through a communication channel that links the internal world in our minds to the physical world around us. Intention can be considered the desire to effect change on our environment, and this is contained in the signals from the brain, passed through the nervous system to converge on muscles that generate displacements and forces on our surroundings. The resulting changes in the world act to generate sensations that feed back to the nervous system, closing the control loop. This Perspective discusses the experimental and theoretical underpinnings of current models of movement generation and the way they are modulated by external information. Movement systems embody intentionality and prediction, two factors that are propelling a revolution in engineering. Development of movement models that include the complexities of the external world may allow a better understanding of the neuronal populations regulating these processes, as well as the development of solutions for autonomous vehicles and robots, and neural prostheses for those who are motor impaired. PMID- 26967279 TI - The 3D Genome as Moderator of Chromosomal Communication. AB - Proper expression of genes requires communication with their regulatory elements that can be located elsewhere along the chromosome. The physics of chromatin fibers imposes a range of constraints on such communication. The molecular and biophysical mechanisms by which chromosomal communication is established, or prevented, have become a topic of intense study, and important roles for the spatial organization of chromosomes are being discovered. Here we present a view of the interphase 3D genome characterized by extensive physical compartmentalization and insulation on the one hand and facilitated long-range interactions on the other. We propose the existence of topological machines dedicated to set up and to exploit a 3D genome organization to both promote and censor communication along and between chromosomes. PMID- 26967281 TI - Communication in Neural Circuits: Tools, Opportunities, and Challenges. AB - Communication, the effective delivery of information, is fundamental to life across all scales and species. Nervous systems (by necessity) may be most specifically adapted among biological tissues for high rate and complexity of information transmitted, and thus, the properties of neural tissue and principles of its organization into circuits may illuminate capabilities and limitations of biological communication. Here, we consider recent developments in tools for studying neural circuits with particular attention to defining neuronal cell types by input and output information streams--i.e., by how they communicate. Complementing approaches that define cell types by virtue of genetic promoter/enhancer properties, this communication-based approach to defining cell types operationally by input/output (I/O) relationships links structure and function, resolves difficulties associated with single-genetic-feature definitions, leverages technology for observing and testing significance of precisely these I/O relationships in intact brains, and maps onto processes through which behavior may be adapted during development, experience, and evolution. PMID- 26967285 TI - Engineering Cellular Metabolism. AB - Metabolic engineering is the science of rewiring the metabolism of cells to enhance production of native metabolites or to endow cells with the ability to produce new products. The potential applications of such efforts are wide ranging, including the generation of fuels, chemicals, foods, feeds, and pharmaceuticals. However, making cells into efficient factories is challenging because cells have evolved robust metabolic networks with hard-wired, tightly regulated lines of communication between molecular pathways that resist efforts to divert resources. Here, we will review the current status and challenges of metabolic engineering and will discuss how new technologies can enable metabolic engineering to be scaled up to the industrial level, either by cutting off the lines of control for endogenous metabolism or by infiltrating the system with disruptive, heterologous pathways that overcome cellular regulation. PMID- 26967283 TI - The Nuclear Pore Complex as a Flexible and Dynamic Gate. AB - Nuclear pore complexes (NPCs) perforate the nuclear envelope and serve as the primary transport gates for molecular exchange between nucleus and cytoplasm. Stripping the megadalton complex down to its most essential organizational elements, one can divide the NPC into scaffold components and the disordered elements attached to them that generate a selective barrier between compartments. These structural elements exhibit flexibility, which may hold a clue in understanding NPC assembly and function. Here we review the current status of NPC research with a focus on the functional implications of its structural and compositional heterogeneity. PMID- 26967284 TI - The Dark Side of Cell Signaling: Positive Roles for Negative Regulators. AB - Cell signaling is dominated by analyzing positive responses to stimuli. Signal activation is balanced by negative regulators that are generally considered to terminate signaling. Rather than exerting only negative effects, however, many such regulators play important roles in enhancing cell-signaling control. Considering responses downstream of selected cell-surface receptors, we discuss how receptor internalization affects signaling specificity and how rapid kinase/phosphatase and GTP/GDP cycles increase responsiveness and allow kinetic proofreading in receptor signaling. We highlight the blurring of distinctions between positive and negative signals, recasting signal termination as the response to a switch-like transition into a new cellular state. PMID- 26967288 TI - Communication by Extracellular Vesicles: Where We Are and Where We Need to Go. AB - In multicellular organisms, distant cells can exchange information by sending out signals composed of single molecules or, as increasingly exemplified in the literature, via complex packets stuffed with a selection of proteins, lipids, and nucleic acids, called extracellular vesicles (EVs; also known as exosomes and microvesicles, among other names). This Review covers some of the most striking functions described for EV secretion but also presents the limitations on our knowledge of their physiological roles. While there are initial indications that EV-mediated pathways operate in vivo, the actual nature of the EVs involved in these effects still needs to be clarified. Here, we focus on the context of tumor cells and their microenvironment, but similar results and challenges apply to all patho/physiological systems in which EV-mediated communication is proposed to take place. PMID- 26967286 TI - Hallmarks of Tissue-Resident Lymphocytes. AB - Although they are classically viewed as continuously recirculating through the lymphoid organs and blood, lymphocytes also establish residency in non-lymphoid tissues, most prominently at barrier sites, including the mucosal surfaces and skin. These specialized tissue-resident lymphocyte subsets span the innate adaptive continuum and include innate lymphoid cells (ILCs), unconventional T cells (e.g., NKT, MAIT, gammadelta T cells, and CD8alphaalpha(+) IELs), and tissue-resident memory T (T(RM)) cells. Although these diverse cell types differ in the particulars of their biology, they nonetheless exhibit important shared features, including a role in the preservation of tissue integrity and function during homeostasis, infection, and non-infectious perturbations. In this Review, we discuss the hallmarks of tissue-resident innate, innate-like, and adaptive lymphocytes, as well as their potential functions in non-lymphoid organs. PMID- 26967287 TI - Hardwiring Stem Cell Communication through Tissue Structure. AB - Adult stem cells across diverse organs self-renew and differentiate to maintain tissue homeostasis. How stem cells receive input to preserve tissue structure and function largely relies on their communication with surrounding cellular and non cellular elements. As such, how tissues are organized and patterned not only reflects organ function, but also inherently hardwires networks of communication between stem cells and their environment to direct tissue homeostasis and injury repair. This review highlights how different methods of stem cell communication reflect the unique organization and function of diverse tissues. PMID- 26967289 TI - The Basis of Oncoimmunology. AB - Cancer heterogeneity, a hallmark enabling clonal survival and therapy resistance, is shaped by active immune responses. Antigen-specific T cells can control cancer, as revealed clinically by immunotherapeutics such as adoptive T-cell transfer and checkpoint blockade. The host immune system is thus a powerful tool that, if better harnessed, could significantly enhance the efficacy of cytotoxic therapy and improve outcomes for cancer sufferers. To realize this vision, however, a number of research frontiers must be tackled. These include developing strategies for neutralizing tumor-promoting inflammation, broadening T-cell repertoires (via vaccination), and elucidating the mechanisms by which immune cells organize tumor microenvironments to regulate T-cell activity. Such efforts will pave the way for identifying new targets for combination therapies that overcome resistance to current treatments and promote long-term cancer control. PMID- 26967290 TI - Bone and Muscle Endocrine Functions: Unexpected Paradigms of Inter-organ Communication. AB - Most physiological functions originate with the communication between organs. Mouse genetics has revived this holistic view of physiology through the identification of inter-organ communications that are unanticipated, functionally important, and would have been difficult to uncover otherwise. This Review highlights this point by showing how two tissues usually not seen as endocrine ones, bone and striated muscles, influence several physiological processes in a significant manner. PMID- 26967293 TI - Ecology and Evolution of Communication in Social Insects. AB - Insect life strategies comprise all levels of sociality from solitary to eusocial, in which individuals form persistent groups and divide labor. With increasing social complexity, the need to communicate a greater diversity of messages arose to coordinate division of labor, group cohesion, and concerted actions. Here we summarize the knowledge on prominent messages in social insects that inform about reproduction, group membership, resource locations, and threats and discuss potential evolutionary trajectories of each message in the context of social complexity. PMID- 26967295 TI - SnapShot: Timescales in Cell Biology. PMID- 26967292 TI - Insights into the Neural and Genetic Basis of Vocal Communication. AB - The use of vocalizations to communicate information and elaborate social bonds is an adaptation seen in many vertebrate species. Human speech is an extreme version of this pervasive form of communication. Unlike the vocalizations exhibited by the majority of land vertebrates, speech is a learned behavior requiring early sensory exposure and auditory feedback for its development and maintenance. Studies in humans and a small number of other species have provided insights into the neural and genetic basis for learned vocal communication and are helping to delineate the roles of brain circuits across the cortex, basal ganglia, and cerebellum in generating vocal behaviors. This Review provides an outline of the current knowledge about these circuits and the genes implicated in vocal communication, as well as a perspective on future research directions in this field. PMID- 26967291 TI - Information Integration and Communication in Plant Growth Regulation. AB - Plants are equipped with the capacity to respond to a large number of diverse signals, both internal ones and those emanating from the environment, that are critical to their survival and adaption as sessile organisms. These signals need to be integrated through highly structured intracellular networks to ensure coherent cellular responses, and in addition, spatiotemporal actions of hormones and peptides both orchestrate local cell differentiation and coordinate growth and physiology over long distances. Further, signal interactions and signaling outputs vary significantly with developmental context. This review discusses our current understanding of the integrated intracellular and intercellular signaling networks that control plant growth. PMID- 26967296 TI - Screening for Asymptomatic Gonorrhea and Chlamydia in the Pediatric Emergency Department. AB - BACKGROUND: Because adolescents rely heavily on emergency services for health care, a pediatric emergency department (PED) visit may be their only opportunity for sexually transmitted infection (STI) screening. The primary objectives of this study were to determine the proportion of Neisseria gonorrheae (GC) and Chlamydia trachomatis (CT) infections in asymptomatic PED adolescents and patient perceived barriers to STI screening. METHODS: A convenience sample of patients aged 14 to 21 years presenting to an urban PED with nongenitourinary complaints was offered screening for GC and CT. Regardless of declining or accepting screening, all were asked to complete a questionnaire designed to identify barriers to screening. RESULTS: Sixty-eight percent of those approached participated (n = 719). Those who agreed to STI screening were more likely to be nonwhite (61.4% vs. 38.6%, P = 0.001) and publically insured (63.3%) versus privately insured (29.3%) or no insurance (7.58%). Four hundred three (56%) participants provided urine samples, and of those, 40 (9.9%) were positive for an STI. Controlling for other demographics, race was a significant predictor, with the odds of testing positive for nonwhite participants 5.90 times that of white participants. Patients who refused testing were more likely to report not engaging in sexual activity (54.3% vs. 42.4%, P = 0.009) and less likely to perceive that they were at risk for STIs. CONCLUSIONS: There are high proportions of GC and CT among asymptomatic adolescents visiting an academic urban PED. A universal PED STI screening program may be an important component of STI reduction initiatives, especially among adolescents who do not perceive that they are at risk and may not receive testing elsewhere. PMID- 26967294 TI - Signaling in Host-Associated Microbial Communities. AB - Human-associated microbiota form and stabilize communities based on interspecies interactions. We review how these microbe-microbe and microbe-host interactions are communicated to shape communities over a human's lifespan, including periods of health and disease. Modeling and dissecting signaling in host-associated communities is crucial to understand their function and will open the door to therapies that prevent or correct microbial community dysfunction to promote health and treat disease. PMID- 26967298 TI - Public Housing Relocations and Partnership Dynamics in Areas With High Prevalences of Sexually Transmitted Infections. AB - BACKGROUND: We investigated the implications of one structural intervention- public housing relocations--for partnership dynamics among individuals living areas with high sexually transmitted infection (STI) prevalence. High-prevalence areas fuel STI endemicity and are perpetuated by spatially assortative partnerships. METHODS: We analyzed 7 waves of data from a cohort of black adults (n = 172) relocating from 7 public housing complexes in Atlanta, Georgia. At each wave, data on whether participants' sexual partners lived in the neighborhood were gathered via survey. Participant addresses were geocoded to census tracts, and measures of tract-level STI prevalence, socioeconomic conditions, and other attributes were created for each wave. "High-prevalence tracts" were tracts in the highest quartile of STI prevalence in Georgia. Descriptive statistics and hierarchical generalized linear models examined trajectories of spatially assortative partnerships and identified predictors of assortativity among participants in high-prevalence tracts. RESULTS: All 7 tracts containing public housing complexes at baseline were high-prevalence tracts; most participants relocated to high-prevalence tracts. Spatially assortative partnerships had a U shaped distribution: the mean percent of partners living in participants' neighborhoods at baseline was 54%; this mean declined to 28% at wave 2 and was 45% at wave 7. Participants who experienced greater postrelocation improvements in tract-level socioeconomic conditions had a lower odds of having spatially assortative partnerships (adjusted odds ratio, 1.55; 95% confidence interval [95% CI], 1.06-2.26). CONCLUSIONS: Public housing relocation initiatives may disrupt high-prevalence areas if residents experience significant postrelocation gains in tract-level socioeconomic conditions. PMID- 26967297 TI - Influence of Detection Method and Study Area Scale on Syphilis Cluster Identification in North Carolina. AB - BACKGROUND: Identifying geographical clusters of sexually transmitted infections can aid in targeting prevention and control efforts. However, detectable clusters can vary between detection methods because of different underlying assumptions. Furthermore, because disease burden is not geographically homogenous, the reference population is sensitive to the study area scale, affecting cluster outcomes. We investigated the influence of cluster detection method and geographical scale on syphilis cluster detection in Mecklenburg County, North Carolina. METHODS: We analyzed primary and secondary syphilis cases reported in North Carolina (2003-2010). Primary and secondary syphilis incidence rates were estimated using census tract-level population estimates. We used 2 cluster detection methods: local Moran's I using an areal adjacency matrix and Kulldorff's spatial scan statistic using a variable size moving circular window. We evaluated 3 study area scales: North Carolina, Piedmont region, and Mecklenburg County. We focused our investigation on Mecklenburg, an urban county with historically high syphilis rates. RESULTS: Syphilis clusters detected using local Moran's I and Kulldorff's scan statistic overlapped but varied in size and composition. Because we reduced the scale to a high-incidence urban area, the reference syphilis rate increased, leading to the identification of smaller clusters with higher incidence. Cluster demographic characteristics differed when the study area was reduced to a high-incidence urban county. CONCLUSIONS: Our results underscore the importance of selecting the correct scale for analysis to more precisely identify areas with high disease burden. A more complete understanding of high-burden cluster location can inform resource allocation for geographically targeted sexually transmitted infection interventions. PMID- 26967299 TI - Race is Associated With Sexual Behaviors and Modifies the Effect of Age on Human Papillomavirus Serostatus Among Perimenopausal Women. AB - BACKGROUND: Human papillomavirus (HPV) causes oropharyngeal and cervical cancers. Oropharyngeal cancer primarily affects whites, but cervical cancer is more common among blacks. Reasons for this distinct epidemiology are unclear. METHODS: Serum was collected from women aged 35 to 60 years in the HPV in Perimenopause cohort and evaluated for antibodies to 8 HPV types. Demographic and behavioral data were collected by telephone questionnaire. Associations between sexual behaviors, race, age, HPV serostatus, and strength of serologic response to HPV were evaluated. RESULTS: There were 781 women in this analysis, including 620 white (79%) and 161 (21%) black women. Whites were less likely to report 5+ vaginal sex partners (prevalence ratio [PR], 0.86; 95% confidence interval [CI], 0.77-0.97), but more likely to report 5+ oral sex partners (PR, 2.38; 95% CI, 1.62-3.49) compared with blacks. Seropositivity to most individual HPV types and at least 3 types was significantly lower in whites than in blacks (PR, 0.62; 95% CI, 0.47 0.80). Human papillomavirus seropositivity was independently associated with younger age among blacks, but with sexual exposures among whites. Furthermore, strength of serologic response to most HPV types significantly decreased with older age among blacks, but not among whites. CONCLUSIONS: Racial differences in immune markers of HPV exposure and the epidemiology of HPV-related cancers may be linked to differences in patterns of sexual behaviors. PMID- 26967300 TI - Significant Reduction in the Incidence of Genital Warts in Young Men 5 Years into the Danish Human Papillomavirus Vaccination Program for Girls and Women. AB - BACKGROUND: Denmark introduced the quadrivalent human papillomavirus vaccine into the vaccination program for 12- to 15-year-old girls in 2008 to 2009. In 2012, the program was supplemented with a catch-up program for women aged up to 27 years. We evaluated the effectiveness of the Danish vaccination program on the nationwide incidence of genital warts (GWs), after the second catch-up by including information on both hospital treatments and on self-administered treatment with podophyllotoxin. Genital wart incidence was investigated in both sexes; however, the main focus was on potential herd protection of men. METHODS: Incident cases of GWs were identified from the Danish National Patient Register and through redemptions of prescription for podophyllotoxin in the Danish National Prescription Registry in 2006 to 2013. Age-specific incidence rates (IRs) were assessed, and estimated annual percentage change (EAPC) was calculated by Poisson regression. RESULTS: Genital wart incidence was either stable or increased in both sexes in 2006 to 2008. After introduction of the vaccination program, GW incidence decreased significantly in women aged 12 to 35 years and men aged 12 to 29 years, with rapid decrease among 16- to 17-year-olds (IRwomen, from 1071 to 58 per 100,000 person-years [EAPC, -55.1%; 95% confidence interval, 58.7 to-51.2]; IRmen, from 365 to 77 per 100,000 person-years [EAPC, -36.6%; 95% confidence interval, -40.5 to -32.5] in 2008-2013). CONCLUSIONS: We found a significantly decreasing incidence of GWs in women up to 35 years of age after the start of the human papillomavirus vaccination program. A similar pattern was observed for men aged 12 to 29 years, indicating substantial herd protection. PMID- 26967303 TI - The Prevalence of Syphilis from the Early HIV Period is Correlated With Peak HIV Prevalence at a Country Level. AB - BACKGROUND: Could we have predicted national peak HIV based on syphilis prevalence in the 1990s? Earlier studies have shown positive correlations between various sexually transmitted infections at different population levels. In this article, we test the hypothesis that there was a residual variation in the national prevalence rates of syphilis and that these rates could predict subsequent peak HIV prevalence rates. METHODS: This analysis uses linear regression to evaluate the country-level relationship between antenatal syphilis prevalence (1990-1999) and peak HIV prevalence. Antenatal syphilis data were taken from an Institute for Health Metrics and Evaluation database on the prevalence of syphilis in low-risk populations. Peak HIV prevalence was calculated based on data taken from the Global Health Observatory Data Repository of the World Health Organization. RESULTS: A moderately strong association is found for the 76 countries with data available (R = 0.53, P < 0.001). The association was weakened but remained significantly positive when we adjusted for the type of syphilis testing used. CONCLUSIONS: Syphilis prevalence in the 1990s predicted approximately 53% of the variation in peak HIV prevalence. Populations with generalized HIV epidemics had a higher prevalence of syphilis in the pre-HIV period. This finding provides additional rationale to carefully monitor sexual behavior, sexual networks, and sexually transmitted infection incidence in these populations. PMID- 26967301 TI - Prevalence of Anal High-Risk Human Papillomavirus Infections Among HIV-Positive and HIV-Negative Men Who Have Sex With Men in Nigeria. AB - BACKGROUND: Prevalence estimates of anal high-risk human papillomavirus (HR-HPV) are needed in sub-Saharan Africa where HIV is endemic. This study evaluated anal HR-HPV in Nigeria among HIV-positive and HIV-negative men who have sex with men (MSM) for future immunization recommendations. METHODS: We conducted a cross sectional study to compare the prevalence of anal HR-HPV infections between 64 HIV-negative and 90 HIV-positive MSM. Multivariate Poisson regression analyses were used to examine demographic and behavioral risk factors associated with any HR-HPV infections. RESULTS: The median age of the 154 participants was 25 years (interquartile range, 22-28 years; range, 16-38 years), and the median age at initiation of anal sex with another man was 16 years (interquartile range, 13-18 years; range, 7-29 years). The prevalence of anal HR-HPV was higher among HIV positive than HIV-negative MSM (91.1% vs. 40.6%, P < 0.001). In the multivariate analysis, HIV infection (adjusted prevalence ratio [aPR], 2.02; 95% confidence interval [CI], 1.49-2.72), 10 years or more since anal sexual debut (aPR, 1.26; 95% CI, 1.07-1.49), and concurrent relationships with men (aPR, 1.32; 95% CI, 1.04-1.67) were associated with increased anal HR-HPV prevalence. CONCLUSIONS: Anal HR-HPV infection is high for young Nigerian MSM, and rates are amplified in those coinfected with HIV. Providing universal coverage as well as catch-up immunization for young MSM may be an effective anal cancer prevention strategy in Nigeria. PMID- 26967302 TI - HIV Incidence Among Men Who Have Sex With Men After Diagnosis With Sexually Transmitted Infections. AB - BACKGROUND: Men who have sex with men (MSM) are at high risk for acquiring HIV infection after diagnosis with other sexually transmitted infections (STIs). Identifying the STIs associated with the greatest risk of subsequent HIV infection could help target prevention interventions, particularly preexposure prophylaxis (PrEP). METHODS: Using matched HIV and STI surveillance data from Washington State from January 1, 2007, to June 30, 2013, we calculated the incidence of new HIV diagnoses after different STI diagnoses among MSM. Men entered observation at the time of their first STI diagnosis during the study period and exited at HIV diagnosis or June 30, 2013. Cox proportional hazards regression was used to conduct a global comparison of rates. RESULTS: From January 1, 2007, to June 30, 2013, 6577 HIV-negative MSM were diagnosed as having 10,080 bacterial STIs at 8371 unique time points and followed for 17,419 person years. Two hundred eighty (4.3%) men were subsequently diagnosed as having HIV infection for an overall incidence of 1.6 per 100 person-years (95% confidence interval, 1.4-1.8). The estimated incidence of HIV diagnoses among all MSM in the state was 0.4 per 100 person-years. Men who have sex with men were at the greatest risk for HIV diagnosis after being diagnosed as having rectal gonorrhea (HIV incidence, 4.1 per 100 person-years), followed by early syphilis (2.8), urethral gonorrhea (1.6), rectal chlamydial infection (1.6), pharyngeal gonorrhea (1.1), late syphilis (1.0), and urethral chlamydial infection (0.6; P < 0.0001 overall). CONCLUSIONS: Men who have sex with men diagnosed as having rectal gonorrhea and early syphilis were at the greatest risk for being diagnosed as having HIV infection after STI diagnosis. These men should be prioritized for more intensive prevention interventions, including PrEP. PMID- 26967304 TI - A Case of Persistent and Possibly Treatment Resistant Pharyngeal Gonorrhea. AB - An HIV-negative man with pharyngeal gonorrhea had a positive test-of-cure (nucleic acid amplification test) result 7 days after treatment with ceftriaxone/azithromycin. Neisseria gonorrhoeae Multi-Antigen Sequencing Type 1407 and mosaic pen A (XXXIV) gene were identified in the test-of-cure specimen, and culture was negative. Retreatment with ceftriaxone 500 mg intramuscularly plus azithromycin 2 g orally yielded a negative test-of-cure result. PMID- 26967305 TI - The Change in Insurance Status Among Patients Seeking Care at Chicago Sexually Transmitted Disease Clinics After Affordable Care Act Implementation. AB - There was a 13% increase in the number of insured patients in Chicago sexually transmitted disease clinics 1 year after Affordable Care Act implementation. Major disparities in being insured persisted among those at higher risk for sexually transmitted diseases. ABSTRACT: There was a 13% increase in the number of insured patients in Chicago sexually transmitted disease clinics 1 year after Affordable Care Act implementation. Insured patients were more likely to report having access to preventive (65% vs. 36%, P < 0.01) and sick care (72% vs. 44%, P < 0.01). Major disparities in being insured persisted among men, those aged 26 to 45 years, and racial minorities. PMID- 26967306 TI - Public Health-Seattle & King County and Washington State Department of Health Preexposure Prophylaxis Implementation Guidelines, 2015. PMID- 26967307 TI - An Opportunity Too Good to Miss: Implementing Human Immunodeficiency Virus Preexposure Prophylaxis in Sexually Transmitted Diseases Clinics. PMID- 26967309 TI - Reference values for the incremental shuttle walk test in patients with cardiovascular disease entering exercise-based cardiac rehabilitation. AB - The incremental shuttle walk test (ISWT) is used to assess functional capacity of patients entering cardiac rehabilitation. Factors such as age and sex account for a proportion of the variance in test performance in healthy individuals but there are no reference values for patients with cardiovascular disease. The aim of this study was to produce reference values for the ISWT. Participants were n = 548 patients referred to outpatient cardiac rehabilitation who underwent a clinical examination and performed the ISWT. We used regression to identify predictors of performance and produced centile values using the generalised additive model for location, scale and shape model. Men walked significantly further than women (395 +/- 165 vs. 269 +/- 118 m; t = 9.5, P < 0.001) so data were analysed separately by sex. Age (years) was the strongest predictor of performance in men (beta = 5.9; 95% CI: -7.1 to -4.6 m) and women (beta = -4.8; 95% CI: -6.3 to 3.3). Centile curves demonstrated a broadly linear decrease in expected ISWT values in males (25-85 years) and a more curvilinear trend in females. Patients entering cardiac rehabilitation present with highly heterogeneous ISWT values. Much of the variance in performance can be explained by patients' age and sex. Comparing absolute values with age-and sex-specific reference values may aid interpretation of ISWT performance during initial patient assessment at entry to cardiac rehabilitation. PMID- 26967311 TI - The force output of handle and pedal in different bicycle-riding postures. AB - The purpose of this study was to analyse the force output of handle and pedal as well as the electromyography (EMG) of lower extremity in different cycling postures. Bilateral pedalling asymmetry indices of force and EMG were also determined in this study. Twelve healthy cyclists were recruited for this study and tested for force output and EMG during steady state cycling adopting different pedalling and handle bar postures. The standing posture increased the maximal stepping torque (posture 1: 204.2 +/- 47.0 Nm; posture 2: 212.5 +/- 46.1 Nm; posture 3: 561.5 +/- 143.0 Nm; posture 4: 585.5 +/- 139.1 Nm), stepping work (posture 1: 655.2 +/- 134.6 Nm; posture 2: 673.2 +/- 116.3 Nm; posture 3: 1852.3 +/- 394.4 Nm; posture 4: 1911.3 +/- 432.9 Nm), and handle force (posture 1: 16.6 +/- 3.6 N; posture 2: 16.4 +/- 3.6 N; posture 3: 26.5 +/- 8.2 N; posture 4: 41.4 +/- 11.1 N), as well as muscle activation (posture 1: 13.6-25.1%; posture 2: 13.0 23.9%; posture 3: 23.6-61.8%; posture 4: 22.5-65.8%) in the erector spine, rectus femoris, tibialis anterior, and soleus. However, neither a sitting nor a standing riding posture affected the hamstring. The riding asymmetry was detected between the right and left legs only in sitting conditions. When a cyclist changes posture from sitting to standing, the upper and lower extremities are forced to produce more force output because of the shift in body weight. These findings suggest that cyclists can switch between sitting and standing postures during competition to increase cycling efficiency in different situations. Furthermore, coaches and trainers can modify sitting and standing durations to moderate cycling intensity, without concerning unbalanced muscle development. PMID- 26967312 TI - Free energy landscapes of sodium ions bound to DMPC-cholesterol membrane surfaces at infinite dilution. AB - Exploring the free energy landscapes of metal cations on phospholipid membrane surfaces is important for the understanding of chemical and biological processes in cellular environments. Using metadynamics simulations we have performed systematic free energy calculations of sodium cations bound to DMPC phospholipid membranes with cholesterol concentration varying between 0% (cholesterol-free) and 50% (cholesterol-rich) at infinite dilution. The resulting free energy landscapes reveal the competition between binding of sodium to water and to lipid head groups. Moreover, the binding competitiveness of lipid head groups is diminished by cholesterol contents. As cholesterol concentration increases, the ionic affinity to membranes decreases. When cholesterol concentration is greater than 30%, the ionic binding is significantly reduced, which coincides with the phase transition point of DMPC-cholesterol membranes from a liquid-disordered phase to a liquid-ordered phase. We have also evaluated the contributions of different lipid head groups to the binding free energy separately. The DMPC's carbonyl group is the most favorable binding site for sodium, followed by DMPC's phosphate group and then the hydroxyl group of cholesterol. PMID- 26967308 TI - The DNA methylation profile of activated human natural killer cells. AB - Natural killer (NK) cells are now recognized to exhibit characteristics akin to cells of the adaptive immune system. The generation of adaptive memory is linked to epigenetic reprogramming including alterations in DNA methylation. The study herein found reproducible genome wide DNA methylation changes associated with human NK cell activation. Activation led predominately to CpG hypomethylation (81% of significant loci). Bioinformatics analysis confirmed that non-coding and gene-associated differentially methylated sites (DMS) are enriched for immune related functions (i.e., immune cell activation). Known DNA methylation-regulated immune loci were also identified in activated NK cells (e.g., TNFA, LTA, IL13, CSF2). Twenty-one loci were designated high priority and further investigated as potential markers of NK activation. BHLHE40 was identified as a viable candidate for which a droplet digital PCR assay for demethylation was developed. The assay revealed high demethylation in activated NK cells and low demethylation in naive NK, T- and B-cells. We conclude the NK cell methylome is plastic with potential for remodeling. The differentially methylated region signature of activated NKs revealed similarities with T cell activation, but also provided unique biomarker candidates of NK activation, which could be useful in epigenome-wide association studies to interrogate the role of NK subtypes in global methylation changes associated with exposures and/or disease states. PMID- 26967310 TI - CN-GELFrEE - Clear Native Gel-eluted Liquid Fraction Entrapment Electrophoresis. AB - Protein complexes perform an array of crucial cellular functions. Elucidating their non-covalent interactions and dynamics is paramount for understanding the role of complexes in biological systems. While the direct characterization of biomolecular assemblies has become increasingly important in recent years, native fractionation techniques that are compatible with downstream analysis techniques, including mass spectrometry, are necessary to further expand these studies. Nevertheless, the field lacks a high-throughput, wide-range, high-recovery separation method for native protein assemblies. Here, we present clear native gel-eluted liquid fraction entrapment electrophoresis (CN-GELFrEE), which is a novel separation modality for non-covalent protein assemblies. CN-GELFrEE separation performance was demonstrated by fractionating complexes extracted from mouse heart. Fractions were collected over 2 hr and displayed discrete bands ranging from ~30 to 500 kDa. A consistent pattern of increasing molecular weight bandwidths was observed, each ranging ~100 kDa. Further, subsequent reanalysis of native fractions via SDS-PAGE showed molecular-weight shifts consistent with the denaturation of protein complexes. Therefore, CN-GELFrEE was proved to offer the ability to perform high-resolution and high-recovery native separations on protein complexes from a large molecular weight range, providing fractions that are compatible with downstream protein analyses. PMID- 26967314 TI - The role of social media in schizophrenia: evaluating risks, benefits, and potential. AB - PURPOSE OF REVIEW: Patients with schizophrenia suffer from numerous social problems often because of negative symptoms of the illness and impairments in social cognition. Social media and social networks now offer a novel tool to engage and help patients navigate and potentially improve social functioning. In this review, we aim to explore how impaired neural networks in schizophrenia impair social functioning, examine the evidence base for social networks and social media to help in the role, consider the evidence for current risks and benefits of use, and discuss the future of social media and social networks for schizophrenia. RECENT FINDINGS: Patients with schizophrenia are increasingly connected to and engaged with social media. There is strong evidence that they own, use, and accept digital tools like smartphones and already use social media services like Facebook at high rates, especially among those who are younger. Less is known about the clinical risks and benefits of social media use in schizophrenia, although there are increasingly more social networking platforms being designed specifically for those with mental illness. SUMMARY: Social media tools have the potential to offer a plethora of new services to patients with schizophrenia, although the clinical evidence base for such is still nascent. It is important to ensure that both clinicians and patients are aware of and educated about the risks of using social media. Going forward, it is likely that social media will have an expanding role in care, with social media offering new pathways to address negative symptoms and impairments in social cognition in schizophrenia. PMID- 26967313 TI - How long should antipsychotic treatment be continued after a single episode of schizophrenia? AB - PURPOSE OF REVIEW: In this article, recent publications addressing the pros and cons of antipsychotic maintenance treatment are reviewed and some recommendations formulated. RECENT FINDINGS: On one hand, relapse rates are extremely high when antipsychotic treatment is discontinued, even after a single episode of psychosis; there are no reliable predictors of relapse; and there are serious psychosocial and biological consequences of relapse. On the other hand, in addition to the well recognised side-effect burden of antipsychotics, a few recent publications suggest an association between greater exposure to antipsychotic treatment and poorer long-term outcome. SUMMARY: There is more evidence in favour of maintaining patients on antipsychotics than on stopping them. There is an urgent need for more and better research before the question of duration of maintenance after a single episode of schizophrenia can be answered with confidence. Until such studies have been conducted, clinicians should prioritize relapse prevention, particularly in the early years of illness, by encouraging indefinite, continuous antipsychotic treatment, and avoid unnecessary side-effects by using the lowest possible effective dose and selecting the best tolerated antipsychotic. PMID- 26967319 TI - Redirecting adenovirus tropism by genetic, chemical, and mechanical modification of the adenovirus surface for cancer gene therapy. AB - INTRODUCTION: Despite remarkable advancements, clinical evaluations of adenovirus (Ad)-mediated cancer gene therapies have highlighted the need for improved delivery and targeting. AREA COVERED: Genetic modification of Ad capsid proteins has been extensively attempted. Although genetic modification enhances the therapeutic potential of Ad, it is difficult to successfully incorporate extraneous moieties into the capsid and the engineering process is laborious. Recently, chemical modification of the Ad surface with nanomaterials and targeting moieties has been found to enhance Ad internalization into the target by both passive and active mechanisms. Alternatively, external stimulus-mediated targeting can result in selective accumulation of Ad in the tumor and prevent dissemination of Ad into surrounding nontarget tissues. In the present review, we discuss various genetic, chemical, and mechanical engineering strategies for overcoming the challenges that hinder the therapeutic efficacy of Ad-based approaches. EXPERT OPINION: Surface modification of Ad by genetic, chemical, or mechanical engineering strategies enables Ad to overcome the shortcomings of conventional Ad and enhances delivery efficiency through distinct and unique mechanisms that unmodified Ad cannot mimic. However, although the therapeutic potential of Ad-mediated gene therapy has been enhanced by various surface modification strategies, each strategy still possesses innate limitations that must be addressed, requiring innovative ideas and designs. PMID- 26967318 TI - Effect of alpha-Methyl versus alpha-Hydrogen Substitution on Brain Availability and Tumor Imaging Properties of Heptanoic [F-18]Fluoroalkyl Amino Acids for Positron Emission Tomography (PET). AB - Two [(18)F]fluoroalkyl substituted amino acids differing only by the presence or absence of a methyl group on the alpha-carbon, (S)-2-amino-7-[(18)F]fluoro-2 methylheptanoic acid ((S)-[(18)F]FAMHep, (S)-[(18)F]14) and (S)-2-amino-7 [(18)F]fluoroheptanoic acid ((S)-[(18)F]FAHep, (S)-[(18)F]15), were developed for brain tumor imaging and compared to the well-established system L amino acid tracer, O-(2-[(18)F]fluoroethyl)-l-tyrosine ([(18)F]FET), in the delayed brain tumor (DBT) mouse model of high-grade glioma. Cell uptake, biodistribution, and PET/CT imaging studies showed differences in amino acid transport of these tracer by DBT cells. Recognition of (S)-[(18)F]15 but not (S)-[(18)F]14 by system L amino acid transporters led to approximately 8-10-fold higher uptake of the alpha hydrogen substituted analogue (S)-[(18)F]15 in normal brain. (S)-[(18)F]15 had imaging properties similar to those of (S)-[(18)F]FET in the DBT tumor model while (S)-[(18)F]14 afforded higher tumor to brain ratios due to much lower uptake by normal brain. These results have important implications for the future development of alpha-alkyl and alpha,alpha-dialkyl substituted amino acids for brain tumor imaging. PMID- 26967320 TI - Altered Cerebellar White Matter Integrity in Patients with Mild Traumatic Brain Injury in the Acute Stage. AB - BACKGROUND AND PURPOSE: Imaging studies of traumatic brain injury demonstrate that the cerebellum is often affected. We aim to examine fractional anisotropy alteration in acute-phase mild traumatic brain injury patients in cerebellum related white matter tracts. MATERIALS AND METHODS: This prospective study included 47 mild traumatic brain injury patients in the acute stage and 37 controls. MR imaging and neurocognitive tests were performed in patients within 7 days of injury. White matter integrity was examined by using diffusion tensor imaging. We used three approaches, tract-based spatial statistics, graphical model-based multivariate analysis, and region-of-interest analysis, to detect altered cerebellar white matter integrity in mild traumatic brain injury patients. RESULTS: Results from three analysis methods were in accordance with each other, and suggested fractional anisotropy in the middle cerebellar peduncle and the pontine crossing tract was changed in the acute-phase mild traumatic brain injury patients, relative to controls (adjusted p-value < 0.05). Higher fractional anisotropy in the middle cerebellar peduncle was associated with worse performance in the fluid cognition composite (r = -0.289, p-value = 0.037). CONCLUSION: Altered cerebellar fractional anisotropy in acute-phase mild traumatic brain injury patients is localized in specific regions and statistically associated with cognitive deficits detectable on neurocognitive testing. PMID- 26967322 TI - Purification and characterization of 2S albumin from Nelumbo nucifera. AB - The 2S albumins are a group of seed storage proteins that have recently attracted considerable attention in the field of allergen science due to their allergenic potential. A new 2S albumin from seeds of Nelumbo nucifera (Nn-2S alb) was purified to electrophoretic homogeneity by the combination of ammonium sulfate fractionation, gel filtration, and ion exchange chromatography. The protein has a molecular mass of about 12 kDa estimated by SDS-PAGE, in good agreement with 12.5 +/- 0.01 kDa determined by ESI-MS. Circular dichroism data showed that protein contained about 66% alpha-helices as estimated by K2D3, indicating that the protein was predominantly helical. The sedimentation coefficient (s degrees 20,w) of the predicted model was 1.72 +/- 0.21 S. The predicted 3-dimensional structure of the Nn-2S alb revealed that the protein has a region of 12 amino acids which largely corresponds to the conserved immuno-dominant epitope of 2S allergens. PMID- 26967321 TI - Impact of Cytochrome P450 2D6 Function on the Chiral Blood Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine (MDMA) and Its Phase I and II Metabolites in Humans. AB - 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) metabolism is known to be stereoselective, with preference for S-stereoisomers. Its major metabolic step involves CYP2D6-catalyzed demethylenation to 3,4-dihydroxymethamphetamine (DHMA), followed by methylation and conjugation. Alterations in CYP2D6 genotype and/or phenotype have been associated with higher toxicity. Therefore, the impact of CYP2D6 function on the plasma pharmacokinetics of MDMA and its phase I and II metabolites was tested by comparing extensive metabolizers (EMs), intermediate metabolizers (IMs), and EMs that were pretreated with bupropion as a metabolic inhibitor in a controlled MDMA administration study. Blood plasma samples were collected from 16 healthy participants (13 EMs and three IMs) up to 24 h after MDMA administration in a double-blind, placebo-controlled, four-period, cross over design, with subjects receiving 1 week placebo or bupropion pretreatment followed by a single placebo or MDMA (125 mg) dose. Bupropion pretreatment increased the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC24) of R-MDMA (9% and 25%, respectively) and S-MDMA (16% and 38%, respectively). Bupropion reduced the Cmax and AUC24 of the CYP2D6-dependently formed metabolite stereoisomers of DHMA 3 sulfate, DHMA 4-sulfate, and 4-hydroxy-3-methoxymethamphetamine (HMMA sulfate and HMMA glucuronide) by approximately 40%. The changes that were observed in IMs were generally comparable to bupropion-pretreated EMs. Although changes in stereoselectivity based on CYP2D6 activity were observed, these likely have low clinical relevance. Bupropion and hydroxybupropion stereoisomer pharmacokinetics were unaltered by MDMA co-administration. The present data might aid further interpretations of toxicity based on CYP2D6-dependent MDMA metabolism. PMID- 26967323 TI - Correction: Seeing Touches Early in Life. PMID- 26967324 TI - Generation and Characterization of a Human/Mouse Chimeric GD2-Mimicking Anti Idiotype Antibody Ganglidiximab for Active Immunotherapy against Neuroblastoma. AB - Vaccination with proteins mimicking GD2 that is highly expressed on neuroblastoma (NB) cells is a promising strategy in treatment of NB, a pediatric malignancy with poor prognosis. We previously showed efficacy of ganglidiomab in vivo, a murine anti-idiotype (anti-Id) IgG1. In order to tailor immune responses to variable regions, we generated a new human/mouse chimeric anti-Id antibody (Ab) ganglidiximab by replacing murine constant fragments with corresponding human IgG1 regions. DNA sequences encoding for variable regions of heavy (VH) and light chains (VL) were synthesized by RT-PCR from total RNA of ganglidiomab-producing hybridoma cells and further ligated into mammalian expression plasmids with coding sequences for constant regions of human IgG1 heavy and light chains, respectively. We established a stable production cell line using Chinese hamster ovarian (CHO) cells co-transfected with two expression plasmids driving the expression of either ganglidiximab heavy or light chain. After purification from supernatants, anti-idiotypic characteristics of ganglidiximab were demonstrated. Binding of ganglidiximab to anti-GD2 Abs of the 14.18 family as well as to NK 92tr cells expressing a GD2-specific chimeric antigen receptor (scFv(ch14.18) zeta) was shown using standard ELISA and flow cytometry analysis, respectively. Ganglidiximab binding affinities to anti-GD2 Abs were further determined by surface plasmon resonance technique. Moreover, binding of anti-GD2 Abs to the nominal antigen GD2 as well as GD2-specific Ab-mediated cytotoxicity (ADCC, CDC) was competitively inhibited by ganglidiximab. Finally, ganglidiximab was successfully used as a protein vaccine in vivo to induce a GD2-specific humoral immune response. In summary, we report generation and characterization of a new human/mouse chimeric anti-Id Ab ganglidiximab for active immunotherapy against NB. This Ab may be useful to tailor immune responses to the paratope regions mimicking GD2 overexpressed in NB. PMID- 26967325 TI - Shared Decision-Making in Oncology - A Qualitative Analysis of Healthcare Providers' Views on Current Practice. AB - BACKGROUND: Despite an increased awareness of shared decision-making (SDM) and its prominent position on the health policy agenda, its implementation in routine care remains a challenge in Germany. In order to overcome this challenge, it is important to understand healthcare providers' views regarding SDM and to take their perspectives and opinions into account in the development of an implementation program. The present study aimed at exploring a) the attitudes of different healthcare providers regarding SDM in oncology and b) their experiences with treatment decisions in daily practice. MATERIAL AND METHODS: A qualitative study was conducted using focus groups and individual interviews with different healthcare providers at the University Cancer Center Hamburg, Germany. Focus groups and interviews were audio-recorded, transcribed and analyzed using conventional content analysis and descriptive statistics. RESULTS: N = 4 focus groups with a total of N = 25 participants and N = 17 individual interviews were conducted. Attitudes regarding SDM varied greatly between the different participants, especially concerning the definition of SDM, the attitude towards the degree of patient involvement in decision-making and assumptions about when SDM should take place. Experiences on how treatment decisions are currently made varied. Negative experiences included time and structural constraints, and a lack of (multidisciplinary) communication. Positive experiences comprised informed patients, involvement of relatives and a good physician-patient relationship. CONCLUSION: The results show that German healthcare providers in oncology have a range of attitudes that currently function as barriers towards the implementation of SDM. Also, their experiences on how decision-making is currently done reveal difficulties in actively involving patients in decision-making processes. It will be crucial to take these attitudes and experiences seriously and to subsequently disentangle existing misconceptions in future implementation programs. PMID- 26967326 TI - MiRComb: An R Package to Analyse miRNA-mRNA Interactions. Examples across Five Digestive Cancers. AB - MicroRNAs (miRNAs) are small RNAs that regulate the expression of target mRNAs by specific binding on the mRNA 3'UTR and promoting mRNA degradation in the majority of cases. It is often of interest to know the specific targets of a miRNA in order to study them in a particular disease context. In that sense, some databases have been designed to predict potential miRNA-mRNA interactions based on hybridization sequences. However, one of the main limitations is that these databases have too many false positives and do not take into account disease specific interactions. We have developed an R package (miRComb) able to combine miRNA and mRNA expression data with hybridization information, in order to find potential miRNA-mRNA targets that are more reliable to occur in a specific physiological or disease context. This article summarizes the pipeline and the main outputs of this package by using as example TCGA data from five gastrointestinal cancers (colon cancer, rectal cancer, liver cancer, stomach cancer and esophageal cancer). The obtained results can be used to develop a huge number of testable hypotheses by other authors. Globally, we show that the miRComb package is a useful tool to deal with miRNA and mRNA expression data, that helps to filter the high amount of miRNA-mRNA interactions obtained from the pre-existing miRNA target prediction databases and it presents the results in a standardised way (pdf report). Moreover, an integrative analysis of the miRComb miRNA-mRNA interactions from the five digestive cancers is presented. Therefore, miRComb is a very useful tool to start understanding miRNA gene regulation in a specific context. The package can be downloaded in http://mircomb.sourceforge.net. PMID- 26967327 TI - Overview of Current Treatment Options and Investigational Targeted Therapies for Locally Advanced Squamous Cell Carcinoma of the Head and Neck. AB - Patients with squamous cell carcinoma of the head and neck (SCCHN) typically present with locally advanced (LA) stage III or IV disease and are treated with combined-modality therapy with chemotherapy, radiotherapy, and surgery (if resectable). These aggressive, upfront treatment measures are often associated with substantial morbidity, and about half the patients develop locoregional or distant recurrences. Thus, new therapeutic strategies are needed that offer similar efficacy benefits with less toxicity. Current research is focused on selectively targeting signaling pathways involved in the proliferation and malignant transformation of SCCHN cells and the tumor microenvironment. For example, the ErbB receptor pathway has been implicated in the development and progression of SCCHN, and several agents targeting this pathway and downstream effectors are in various phases of clinical investigation. Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), is the only currently approved targeted therapy for the treatment of LA SCCHN. Additional agents targeting EGFR and other ErbB family members, including monoclonal antibodies (eg, panitumumab, nimotuzumab) and small-molecule tyrosine kinase inhibitors (eg, erlotinib, afatinib, lapatinib) are being studied in LA SCCHN with varying results. Other treatment strategies for LA SCCHN include targeting downstream effectors of signaling and resistance mechanisms to EGFR inhibitors (eg, mammalian target of rapamycin, Src family, and Aurora kinase family). Data from ongoing and future clinical trials will continue to refine current treatment paradigms for LA SCCHN and provide new therapeutic options and potential predictive biomarkers to improve patient efficacy and safety and abrogate resistance. PMID- 26967329 TI - Age Bias in Time From Diagnosis Comparisons of Prostate Cancer Treatment. AB - OBJECTIVES: Observational studies of prostate cancer treatment have demonstrated a major survival benefit with prostatectomy; randomized trials have been less certain in this regard. This discrepancy is hypothesized to be due to the use survival calculations based on time from diagnosis (TFD), which can bias toward better survival for younger cohorts. Attained age is an alternative timescale that can mitigate this effect. A Surveillance, Epidemiology and End Results comparison of prostatectomy, radiotherapy (XRT), and conservative management for localized prostatic cancer was conducted to compare these 2 timescales. METHODS: Kaplan-Meier analysis was used to contrast overall survival based on TFD and attained age from 279,064 prostate cancer cases. Proportional hazards models were constructed and baseline hazard functions estimated. RESULTS: The prostatectomy cohort averaged 9 to 12 years younger than the radiotherapy or conservative management cohorts, and the baseline hazard depended more strongly upon age than TFD. Survival calculations based on TFD demonstrated a major benefit with prostatectomy compared with XRT and conservative management, consistent with prior observational studies. Calculations based on attained age, however, demonstrated lesser differences between treatment cohorts and were more consistent with published randomized trials. CONCLUSIONS: The survival benefit apparent to prostatectomy in conventional observational cohort studies could reflect an age-related bias attributable to their use of TFD analysis. Care is warranted in the choice of timescale in observational analysis if large age differences exist between treatment cohorts. Randomized controlled trials remain the most reliable means to compare prostate cancer treatments. PMID- 26967328 TI - EGFR Exon 19 Deletion is Associated With Favorable Overall Survival After First line Gefitinib Therapy in Advanced Non-Small Cell Lung Cancer Patients. AB - OBJECTIVES: Exon 19 deletion and L858R mutation in exon 21 of the epidermal growth factor receptor (EGFR) are both common mutations that predict a good response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). However, the existence of clinically significant difference in sensitivity to EGFR tyrosine kinase inhibitors among different EGFR mutation subtypes is still a matter of debate. MATERIALS AND METHODS: The outcome of 60 EGFR mutation-positive advanced NSCLC patients who received first-line gefitinib therapy (250 mg/d) was retrospectively analyzed according to EGFR mutation subtypes. RESULTS: The median progression-free survival (PFS) and overall survival (OS) after the initiation of gefitinib therapy for all patients was 11 and 26 months, respectively. Univariate analysis showed that patients with exon 19 deletion (n=28) had significantly longer median PFS (20 vs. 8 mo, P=0.004) and OS (36 vs. 22 mo, P=0.001) compared with those with L858R mutation (n=25) and uncommon or dual mutations (n=7). Multivariate analysis revealed that exon 19 deletion (P=0.007) was an independent prognostic factor of favorable PFS, with an independent association with poor PFS of male sex (P=0.049). Exon 19 deletion was also independently associated with favorable OS (P<0.0001), whereas male sex (P=0.004) and primary metastatic disease (P=0.032) were independent prognostic factors of poor OS. CONCLUSIONS: The EGFR exon 19 deletion was associated with favorable PFS and OS in patients receiving first-line gefitinib treatment. The EGFR mutation subtype should be considered when making treatment decision or designing clinical trials for chemotherapy-naive, EGFR mutation-positive advanced NSCLC patients. PMID- 26967330 TI - Correction: Using Linkage Analysis to Detect Gene-Gene Interactions. 2. Improved Reliability and Extension to More-Complex Models. PMID- 26967331 TI - Effect of Two or Six Doses 800 mg of Albendazole Every Two Months on Loa loa Microfilaraemia: A Double Blind, Randomized, Placebo-Controlled Trial. AB - BACKGROUND: Loiasis is a parasitic infection endemic in the African rain forest caused by the filarial nematode Loa loa. Loiasis can be co-endemic with onchocerciasis and/or lymphatic filariasis. Ivermectin, the drug used in the control of these diseases, can induce serious adverse reactions in patients with high L loa microfilaraemia (LLM). A drug is needed which can lower LLM below the level that represents a risk so that ivermectin mass treatment to support onchocerciasis and lymphatic filariasis elimination can be implemented safely. METHODOLOGY: Sixty men and women from a loiasis endemic area in Cameroon were randomized after stratification by screening LLM (<= 30000, 30001-50000, >50000) to three treatment arms: two doses albendazole followed by 4 doses matching placebo (n = 20), six doses albendazole (n = 20) albendazole or 6 doses matching placebo (n = 20) administered every two months. LLM was measured before each treatment and 14, 18, 21 and 24 months after the first treatment. Monitoring for adverse events occurred three and seven days as well as 2 months after each treatment. PRINCIPAL FINDINGS: None of the adverse events recorded were considered treatment related. The percentages of participants with >= 50% decrease in LLM from pre-treatment for >= 4 months were 53%, 17% and 11% in the 6 dose, 2-dose and placebo treatment arms, respectively. The difference between the 6-dose and the placebo arm was significant (p = 0.01). The percentages of participants with LLM < 8100 mf/ml for >= 4 months were 21%, 11% and 0% in the 6 dose, 2-dose and placebo treatment arms, respectively. CONCLUSIONS/ SIGNIFICANCE: The 6-dose regimen reduced LLM significantly, but the reduction was insufficient to eliminate the risk of severe and/or serious adverse reactions during ivermectin mass drug administration in loiasis co-endemic areas. PMID- 26967333 TI - Catalytic conversion of xylose and corn stalk into furfural over carbon solid acid catalyst in gamma-valerolactone. AB - A novel carbon solid acid catalyst was synthesized by the sulfonation of carbonaceous material which was prepared by carbonization of sucrose using 4-BDS as a sulfonating agent. TEM, N2 adsorption-desorption, elemental analysis, XPS and FT-IR were used to characterize the catalyst. Then, the catalyst was applied for the conversion of xylose and corn stalk into furfural in GVL. The influence of the reaction time, temperature and dosage of catalyst on xylose dehydration were also investigated. The Bronsted acid catalyst exhibited high activity in the dehydration of xylose, with a high furfural yield of 78.5% at 170 degrees C in 30min. What's more, a 60.6% furfural yield from corn stalk was achieved in 100min at 200 degrees C. The recyclability of the sulfonated carbon catalyst was perfect, and it could be reused for 5times without the loss of furfural yields. PMID- 26967332 TI - Dynamic Modelling Reveals 'Hotspots' on the Pathway to Enzyme-Substrate Complex Formation. AB - Dihydrodipicolinate synthase (DHDPS) catalyzes the first committed step in the diaminopimelate pathway of bacteria, yielding amino acids required for cell wall and protein biosyntheses. The essentiality of the enzyme to bacteria, coupled with its absence in humans, validates DHDPS as an antibacterial drug target. Conventional drug design efforts have thus far been unsuccessful in identifying potent DHDPS inhibitors. Here, we make use of contemporary molecular dynamics simulation and Markov state models to explore the interactions between DHDPS from the human pathogen Staphylococcus aureus and its cognate substrate, pyruvate. Our simulations recover the crystallographic DHDPS-pyruvate complex without a priori knowledge of the final bound structure. The highly conserved residue Arg140 was found to have a pivotal role in coordinating the entry of pyruvate into the active site from bulk solvent, consistent with previous kinetic reports, indicating an indirect role for the residue in DHDPS catalysis. A metastable binding intermediate characterized by multiple points of intermolecular interaction between pyruvate and key DHDPS residue Arg140 was found to be a highly conserved feature of the binding trajectory when comparing alternative binding pathways. By means of umbrella sampling we show that these binding intermediates are thermodynamically metastable, consistent with both the available experimental data and the substrate binding model presented in this study. Our results provide insight into an important enzyme-substrate interaction in atomistic detail that offers the potential to be exploited for the discovery of more effective DHDPS inhibitors and, in a broader sense, dynamic protein-drug interactions. PMID- 26967334 TI - A novel stepwise pretreatment on corn stalk by alkali deacetylation and liquid hot water for enhancing enzymatic hydrolysis and energy utilization efficiency. AB - A novel stepwise pretreatment on corn stalk (CS) by alkali deacetylation combined with liquid hot water (LHW) was investigated to enhance enzymatic hydrolysis. After deacetylated treatment, strength of alkali deacetylation of CS was from 1.79% to 91.34% which was subsequently pretreated by LHW with severity from 3.27 to 4.27. It was found that higher strength of alkali deacetylation could reduce both the degradation of hemicellulose and inhibitors formation in liquid hot water pretreatment (LHWP). Enzymatic hydrolysis efficiency was confirmed to be affected by LHW pretreatment severity (PS) and strength of alkali treatment. This combined pretreatment of alkali deacetylation and LHW could not only increase glucose yield, but also enhance energy utilization efficiency. The maximum enzymatic hydrolysis of 87.55%+/-3.64 with the ratio of glucose yield to energy input at 50.39gglucosekJ(-1) was obtained when strength of alkali deacetylation at 84.96% with PS at 3.97 were used. PMID- 26967335 TI - Nitrification cessation and recovery in an aerated saturated vertical subsurface flow treatment wetland: Field studies and microscale biofilm modeling. AB - In aerated treatment wetlands, oxygen availability is not a limiting factor in sustaining a high level of nitrification in wastewater treatment. In the case of an air blower failure, nitrification would cease, potentially causing adverse effects to the nitrifying bacteria. A field trial was completed investigating nitrification loss when aeration is switched off, and the system recovery rate after the aeration is switched back on. Loss of dissolved oxygen was observed to be more rapid than loss of nitrification. Nitrate was observed in the effluent long after the aeration was switched off (48h+). A complementary modeling study predicted nitrate diffusion out of biofilm over a 48h period. After two weeks of no aeration in the established system, nitrification recovered within two days, whereas nitrification establishment in a new system was previously observed to require 20-45days. These results suggest that once established resident nitrifying microbial communities are quite robust. PMID- 26967336 TI - Increase in the carbohydrate content of the microalgae Spirulina in culture by nutrient starvation and the addition of residues of whey protein concentrate. AB - Non-renewable sources that will end with time are the largest part of world energy consumption, which emphasizes the necessity to develop renewable sources of energy. This necessity has created opportunities for the use of microalgae as a biofuel. The use of microalgae as a feedstock source for bioethanol production requires high yields of both biomass and carbohydrates. With mixotrophic cultures, wastewater can be used to culture algae. The aim of the study was to increase the carbohydrate content in the microalgae Spirulina with the additions of residues from the ultra and nanofiltration of whey protein. The nutrient deficit in the Zarrouk medium diluted to 20% and the addition of 2.5% of both residue types led to high carbohydrate productivity (60 mg L(-1) d(-1)). With these culture conditions, the increase in carbohydrate production in Spirulina indicated that the conditions were appropriate for use with microalgae as a feedstock in the production of bioethanol. PMID- 26967337 TI - Study on pyrolysis characteristics of lignocellulosic biomass impregnated with ammonia source. AB - The current study presents the pyrolysis characteristics of rice husk impregnated with different kinds of ammonia source (ammonium acetate, urea, ammonium sulfate and ammonium dihydrogen phosphate) in a fixed bed reactor. The introduction of ammonia source in pyrolysis process achieved the conversation from carbonyl compounds to nitrogenous heterocyclic compounds. The liquid product of urea impregnated biomass has higher content of nitrogenous heterocyclic compounds (8.35%) and phenols (30.4%). For ammonium sulfate and ammonium dihydrogen phosphate-impregnated biomass, the quantity of compounds in liquid products reduces remarkably, and the gas products are rich in CO and H2. All the solid products of pyrolysis have great potential application in biochar-based fertilizer and activated carbon for their high N content. PMID- 26967338 TI - Potential enhancement of direct interspecies electron transfer for syntrophic metabolism of propionate and butyrate with biochar in up-flow anaerobic sludge blanket reactors. AB - Promoting direct interspecies electron transfer (DIET) to enhance syntrophic metabolism may be a strategy for accelerating the conversion of organic wastes to methane, but microorganisms capable of metabolizing propionate and butyrate via DIET under methanogenic conditions have yet to be identified. In an attempt to establish methanogenic communities metabolizing propionate or butyrate with DIET, enrichments were initiated with up-flow anaerobic sludge blanket (UASB), similar to those that were previously reported to support communities that metabolized ethanol with DIET that relied on direct biological electrical connections. In the absence of any amendments, microbial communities enriched were dominated by microorganisms closely related to pure cultures that are known to metabolize propionate or butyrate to acetate with production of H2. When biochar was added to the reactors there was a substantial enrichment on the biochar surface of 16S rRNA gene sequences closely related to Geobacter and Methanosaeta species known to participate in DIET. PMID- 26967339 TI - Synergetic and inhibition effects in carbon dioxide gasification of blends of coals and biomass fuels of Indian origin. AB - The present study investigates the enhancement of CO2 gasification reactivity of coals due to the presence of catalytic elements in biomass such as K2O, CaO, Na2O and MgO. Co-gasification of three Indian coal chars with two biomass chars has been studied using isothermal thermogravimetric analysis (TGA) in CO2 environment at 900, 1000 and 1100 degrees C. The conversion profiles have been used to establish synergetic or inhibitory effect on coal char reactivity by the presence of catalytic elements in biomass char by comparing the 90% conversion time with and without biomass. It is concluded that both biomasses exhibit synergistic behavior when blended with the three coals with casuarina being more synergetic than empty fruit bunch. Some inhibitory effect has been noted for the high ash coal at the highest temperature with higher 90% conversion time for the blend over pure coal, presumably due to diffusional control of the conversion rate. PMID- 26967340 TI - Lipase coated clusters of iron oxide nanoparticles for biodiesel synthesis in a solvent free medium. AB - Methyl or ethyl esters of long chain fatty acids are called biodiesel. Biodiesel is synthesized by the alcoholysis of oils/fats. In this work, lipase from Thermomyces lanuginosus was precipitated over the clusters of Fe3O4 nanoparticles. This biocatalyst preparation was used for obtaining biodiesel from soybean oil. After optimization of both immobilization conditions and process parameters, complete conversion to biodiesel was obtained in 3h and on lowering the enzyme amount, as little as 1.7U of lipase gave 96% conversion in 7h. The solvent free media with oil:ethanol (w/w) of 1:4 and 40 degrees C with 2% (w/w) water along with 20% (w/w) silica (for facilitating acyl migration) were employed for reaching this high % of conversion. The biocatalyst design enables one to use a rather small amount of lipase. This should help in switching over to a biobased production of biodiesel. PMID- 26967342 TI - Diagnostic accuracy of 3D-transvaginal ultrasound in detecting uterine cavity abnormalities in infertile patients as compared with hysteroscopy. AB - OBJECTIVE: To assess diagnostic accuracy of 3D transvaginal ultrasound (3D-TVS) compared with hysteroscopy in detecting uterine cavity abnormalities in infertile women. STUDY DESIGN: This prospective observational cross-sectional study was conducted during the July 2013 to December 2013 study period. Sixty-nine women with infertility were enrolled. In the mid to late follicular phase of each subject's menstrual cycle, 3D transvaginal ultrasound and hysteroscopy were performed on the same day in each patient. Hysteroscopy is widely considered to be the gold standard method for investigation of the uterine cavity. Uterine cavity characteristics and abnormalities were recorded. Diagnostic accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratios were evaluated. RESULTS: Hysteroscopy was successfully performed in all subjects. Hysteroscopy diagnosed pathological findings in 22 of 69 cases (31.8%). There were 18 endometrial polyps, 3 submucous myomas, and 1 septate uterus. Three-dimensional transvaginal ultrasound in comparison with hysteroscopy had 84.1% diagnostic accuracy, 68.2% sensitivity, 91.5% specificity, 79% positive predictive value, and 86% negative predictive value. The positive and negative likelihood ratios were 8.01 and 0.3, respectively. 3D-TVS successfully detected every case of submucous myoma and uterine anomaly. For detection of endometrial polyps, 3D-TVS had 61.1% sensitivity, 91.5% specificity, and 83.1% diagnostic accuracy. CONCLUSION: 3D-TVS demonstrated 84.1% diagnostic accuracy for detecting uterine cavity abnormalities in infertile women. A significant percentage of infertile patients had evidence of uterine cavity pathology. Hysteroscopy is, therefore, recommended for accurate detection and diagnosis of uterine cavity lesion. PMID- 26967341 TI - Clinical practice guidelines from the French College of Gynecologists and Obstetricians (CNGOF): benign breast tumors - short text. AB - Screening with breast ultrasound in combination with mammography is needed to investigate a clinical breast mass (Grade B), colored single-pore breast nipple discharge (Grade C), or mastitis (Grade C). The BI-RADS system is recommended for describing and classifying abnormal breast imaging findings. For a breast abscess, a percutaneous biopsy is recommended in the case of a mass or persistent symptoms (Grade C). For mastalgia, when breast imaging is normal, no MRI or breast biopsy is recommended (Grade C). Percutaneous biopsy is recommended for a BI-RADS category 4-5 mass (Grade B). For persistent erythematous nipple or atypical eczema lesions, a nipple biopsy is recommended (Grade C). For distortion and asymmetry, a vacuum core-needle biopsy is recommended due to the risk of underestimation by simple core-needle biopsy (Grade C). For BI-RADS category 4-5 microcalcifications without any ultrasound signal, a minimum 11-G vacuum core needle biopsy is recommended (Grade B). In the absence of microcalcifications on radiography cores additional samples are recommended (Grade B). For atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, flat epithelial atypia, radial scar and mucocele with atypia, surgical excision is commonly recommended (Grade C). Expectant management is feasible after multidisciplinary consensus. For these lesions, when excision margins are not clear, no new excision is recommended except for LCIS characterized as pleomorphic or with necrosis (Grade C). For grade 1 phyllodes tumor, surgical resection with clear margins is recommended. For grade 2 phyllodes tumor, 10mm margins are recommended (Grade C). For papillary breast lesions without atypia, complete disappearance of the radiological signal is recommended (Grade C). For papillary breast lesions with atypia, complete surgical excision is recommended (Grade C). PMID- 26967343 TI - Predictors for failure of vacuum-assisted vaginal delivery: a case-control study. AB - OBJECTIVE: To identify potential predictors for failed vacuum-assisted delivery. STUDY DESIGN: Retrospective case-control study conducted in two perinatal centers in the Netherlands. Cases were women who underwent a failed vacuum-assisted delivery between 1997 and 2011. A failed vacuum extraction was defined as a delivery that was started as vacuum extraction but was converted to a cesarean section because of failure to progress. As controls we studied two successful vacuum extractions that were performed before the failed one. We used multivariable logistic regression to assess the risk for failed vacuum extraction. RESULTS: Between 1997 and 2011, 6734 trials of vacuum extraction were performed of which 309 failed (4.6%). These 309 cases were compared to the data of 618 women who underwent a successful vacuum extraction. Predictors for failed vacuum-assisted vaginal delivery were increasing gestational age (OR 1.2 per week), maternal height (OR 0.97 per cm), previous vaginal birth as compared to nulliparae (OR 0.32), estimated fetal weight >=3750g as compared to <3250g (OR 5.7), epidural analgesia (OR 3.0), augmentation (OR 1.4), failure to progress as indication for trial of vacuum delivery (OR 1.7), station of descent of the fetal head (OR 0.31 per station more descended), and occiput posterior position (OR 2.6). The area under the receiver-operating characteristic curve of a prediction model integrating these indicators was 0.83. CONCLUSION: Failed vacuum extraction can be predicted accurately using both ante- and intrapartum characteristics. There is a strong need for prospective studies on the subject. PMID- 26967344 TI - Prevalence and trends of pelvic floor disorders in late pregnancy and after delivery in a cohort of Israeli women using the PFDI-20. AB - OBJECTIVE: To investigate the prevalence of pelvic floor disorders (PFD) in a cohort of Israeli women at late pregnancy and three months postpartum, to define changes in PFD rates and to evaluate various obstetrical factors that may correlate with these changes. METHODS: A prospective longitudinal cohort study was conducted between March and July 2014. The PFDI-20 questionnaire (validated in the Hebrew language) was used to evaluate pelvic floor distress symptoms 24h and 3 months after delivery (representing the third trimester and post-partum period, respectively). Patients with a preterm delivery (<36 completed weeks of gestation), delivery of a stillbirth, non-fluency in Hebrew and patients with inability to complete the questionnaire due to a communication problem were excluded from the study. In addition to the PFDI results demographic and clinical data were collected from the patients' medical records. Routine statistical methods were used to interpret the results. RESULTS: During the study period 117 women answered the first questionnaire and only 37 had filled the second questionnaire. The most prevalent item group reported in the third trimester was the urinary distress symptoms. Urinary frequency was the most common with 65% of patients reporting this symptom. At the post-partum period the most prevalent item group reported was the colorectal and anal distress with 31.5% of patients reporting increased straining efforts. There was a mixed trend in the changes noted between the two questionnaires. While some items improved in the puerperium as compared with late pregnancy others have worsened. In a multivariable analysis the only statistically significant finding was that at the post-partum follow-up, stress urinary incontinence was significantly associated with spontaneous perineal tears at delivery. Other obstetrical parameters including episiotomy and birth weight were not found to be significantly associated with any of the PFD items. CONCLUSION: We have demonstrated that PFD is prevalent both in late pregnancy and in the puerperium. There are mixed trends of spontaneous recovery following childbirth. A significant association between perineal tears and SUI 3 months after delivery was noted. PMID- 26967345 TI - Systematic classification of uterine cervical elongation in patients with pelvic organ prolapse. AB - OBJECTIVE: To define and classify cervical elongation, to compare uterine measurements after prolapse hysterectomy with a non-prolapse control group, and to associate stage of prolapse and degree of cervical elongation. STUDY DESIGN: This was a single-centre retrospective case-control study conducted at the University Hospital, Urogynaecological Unit, with a certified urogynaecological surgeon. Data were collected from patients with and without pelvic organ prolapse (POP) who underwent laparoscopically assisted vaginal hysterectomy. Post hysterectomy uterine cervical elongation was examined using the corpus/cervix ratio (CCR), calculated from measurements taken on photographs. Cervical elongation was classified as physiological (grade 0, CCR>1.5) grade I (CCR>1 and <=1.5) grade II (CCR>0.5 and <=1), and grade III (CCR<=0.5). RESULTS: Cervical elongation was detected in 288/295 (97.6%) patients in the prolapse group (grade I, 44/288 [15.2%]; grade II, 212 [73.6%]; grade III, 32 [11.1%]). Mean CCR was greater among those with stage II/III than among those with stage IV prolapse (1.0+/-0.4 vs. 0.8+/-0.2; p<0.001). Grades of cervical elongation and prolapse stages were associated (p<0.001). Grade I cervical elongation was detected in 26/69 (37.6%), grade II in 5/69, and grade III in 0/69 patients of the control group. Cervical elongation was found more often in the prolapse group compared to the control group (p<0.001). Mean total uterine length did not differ between the prolapse and control groups (8.0+/-1.6 vs. 8.2+/-1.3cm), but mean calculated cervical length was greater in the prolapse group than in the control group (4.4+/-1.1 vs. 3.1+0.8cm; p<0.001). CONCLUSIONS: Uterine cervical elongation is found in patients undergoing hysterectomy for pelvic organ prolapse. Cervical elongation grades and prolapse stages are correlated. Defining uterine cervical elongation based on corpus/cervix ratio with grades I-III could be a valuable basic tool for further research. PMID- 26967346 TI - The value of Anti-Mullerian hormone in low and extremely low ovarian reserve in relation to live birth after in vitro fertilization. AB - OBJECTIVE: To determine the relation of Anti-Mullerian hormone (AMH) with live birth after in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) in women with (extremely) low ovarian reserve. STUDY DESIGN: This study was a retrospective cohort study in a Dutch tertiary fertility clinic. Between January 2009 and March 2012, AMH levels were measured in infertile women when >=36 years of age or when showing clinical signs of diminished ovarian reserve, before they underwent IVF or ICSI treatment. Ultimately, 156 women with (extremely) low ovarian reserve were included and evaluated for cumulative live birth rates. Of each woman, only one treatment cycle was analyzed, either the one in which she became pregnant or her first treatment cycle if she did not reach pregnancy. The relation between AMH and live birth was evaluated with multivariable logistic regression analysis. A ROC curve was composed to evaluate the discriminative value of AMH in relation to live birth after IVF/ICSI. RESULTS: Thirty-three out of 156 women (21.2%) gave live birth. Live birth was significantly lower in women with AMH <=0.1ng/ml (4/37 women; 10.8%) or AMH >0.1 0.4ng/ml (7/42 women; 16.7%), compared to women with AMH >0.4-1.05ng/ml (22/77 women; 28.6%), p<0.001. Multivariable logistic regression revealed an association between the severity of low ovarian reserve and live birth (per 0.1ng/ml increase in AMH value, Odds ratio 1.21; 95% CI 1.07-1.36). CONCLUSIONS: The level of AMH is related to live birth after IVF/ICSI in women with (extremely) low ovarian reserve. The live birth rate in women with AMH >0.4ng/ml was significantly higher than in women with AMH <=0.4ng/ml. AMH could serve as a tool in the pre-treatment counseling for pregnancy and live birth chances in women with (extremely) low ovarian reserve. PMID- 26967348 TI - Syntax in Spanish-speaking children with Williams syndrome. AB - The syntactic skills of Spanish-speaking children with Williams syndrome (WS) were assessed in different areas (phrase structure, recursion, and bound anaphora). Children were compared to typically-developing peers matched either in chronological age (CA-TD) or in verbal age (VA-TD). In all tasks children with WS performed significantly worse than CA-TD children, but similarly to VA-TD children. However, significant differences were observed in specific domains, particularly regarding sentences with cross-serial dependencies. At the same time, children with WS were less sensitive to syntactic constraints and exhibited a poorer knowledge of some functional words (specifically, of nonreflexive pronouns). A processing bottleneck or a computational constraint may account for this outcome. PMID- 26967349 TI - Childhood body mass index and risk of schizophrenia in relation to childhood age, sex and age of first contact with schizophrenia. AB - Childhood leanness is associated with an increased risk of schizophrenia, but the effects of gender, age at anthropometric measurements and age at first diagnosis on this relationship are unclear. The present study aimed at elucidating these associations. METHODS: Population-based cohort study with childhood anthropometric measures obtained annually from the age of 7 to 13 years in 253,353 Danes born 1930-1976 and followed to 31 December 2010. During this period, 4936 were registered with schizophrenia. The associations of childhood BMI with risk of schizophrenia were estimated with Cox regression models. RESULTS: Childhood BMI was significantly inversely associated with risk of schizophrenia, however with different patterns among boys and girls. In boys, childhood BMI had an inverse non-linear association with schizophrenia risk dependent on age at diagnosis; in particular, a surprisingly strong association was found between leanness and later onset of schizophrenia. In girls, the risk of schizophrenia decreased linearly with increasing BMI z-score (HR: 0.93; 95% CI: 0.88-0.98). In both boys and girls, birth weight was inversely associated with later risk. In girls, but not in boys, birth weight appeared to significantly modify the associations; there was a somewhat stronger inverse association in the lowest birth weight category. CONCLUSION: Birth weight as well as childhood BMI at ages 7 through 13 years is associated with risk of schizophrenia in both genders, but with a particular high risk of late-onset in lean boys irrespective of birth weight, and in lean girls with low birth weight. If replicated, these observations may inform preventive efforts build on schizophrenia trajectories rooted in early life. PMID- 26967347 TI - Expanding the Role of FurA as Essential Global Regulator in Cyanobacteria. AB - In the nitrogen-fixing heterocyst-forming cyanobacterium Anabaena sp. PCC 7120, the ferric uptake regulator FurA plays a global regulatory role. Failures to eliminate wild-type copies of furA gene from the polyploid genome suggest essential functions. In the present study, we developed a selectively regulated furA expression system by the replacement of furA promoter in the Anabaena sp. chromosomes with the Co2+/Zn2+ inducible coaT promoter from Synechocystis sp. PCC 6803. By removing Co2+ and Zn2+ from the medium and shutting off furA expression, we showed that FurA was absolutely required for cyanobacterial growth. RNA-seq based comparative transcriptome analyses of the furA-turning off strain and its parental wild-type in conjunction with subsequent electrophoretic mobility shift assays and semi-quantitative RT-PCR were carried out in order to identify direct transcriptional targets and unravel new biological roles of FurA. The results of such approaches led us to identify 15 novel direct iron-dependent transcriptional targets belonging to different functional categories including detoxification and defences against oxidative stress, phycobilisome degradation, chlorophyll catabolism and programmed cell death, light sensing and response, heterocyst differentiation, exopolysaccharide biosynthesis, among others. Our analyses evidence novel interactions in the complex regulatory network orchestrated by FurA in cyanobacteria. PMID- 26967350 TI - Quantifying Fish Swimming Behavior in Response to Acute Exposure of Aqueous Copper Using Computer Assisted Video and Digital Image Analysis. AB - Behavioral responses of aquatic organisms to environmental contaminants can be precursors of other effects such as survival, growth, or reproduction. However, these responses may be subtle, and measurement can be challenging. Using juvenile white sturgeon (Acipenser transmontanus) with copper exposures, this paper illustrates techniques used for quantifying behavioral responses using computer assisted video and digital image analysis. In previous studies severe impairments in swimming behavior were observed among early life stage white sturgeon during acute and chronic exposures to copper. Sturgeon behavior was rapidly impaired and to the extent that survival in the field would be jeopardized, as fish would be swept downstream, or readily captured by predators. The objectives of this investigation were to illustrate protocols to quantify swimming activity during a series of acute copper exposures to determine time to effect during early lifestage development, and to understand the significance of these responses relative to survival of these vulnerable early lifestage fish. With mortality being on a time continuum, determining when copper first affects swimming ability helps us to understand the implications for population level effects. The techniques used are readily adaptable to experimental designs with other organisms and stressors. PMID- 26967351 TI - Tactic response of bacteria to zero-valent iron nanoparticles. AB - The microbial assessment of pollutant toxicity rarely includes behavioral responses. In this study, we investigated the tactic response of Pseudomonas putida G7, a representative of soil bacterium, towards engineered zero-valent iron nanoparticles (nZVIs), as a new end-point assessment of toxicity. The study integrated the characterization of size distribution and charge of nZVIs and tactic reaction response by means of inverted capillary assay and computer assisted motion analysis of motility behavior. Iron nanoparticles (diameter <= 100 nm) were prepared in the absence of oxygen to prevent aggregation, and then exposed in aerobic conditions. We first demonstrate that iron nanoparticles can elicit a negative tactic response in bacteria at low but environmentally relevant, sub-lethal concentrations (1-10 MUg/L). Cells were repelled by nZVIs in the concentration gradients created inside the capillaries, and a significant increase in turning events, characteristic of negative taxis, was detected under exposure to nZVIs. These tactic responses were not detectable after sustained exposure of the nanoparticles to oxygen. This new behavioral assessment may be prospected for the design of sensitive bioassays for nanomaterial toxicity. PMID- 26967352 TI - A century long sedimentary record of anthropogenic lead (Pb), Pb isotopes and other trace metals in Singapore. AB - Reconstructing the history of metal deposition in Singapore lake sediments contributes to understanding the anthropogenic and natural metal deposition in the data-sparse Southeast Asia. To this end, we present a sedimentary record of Pb, Pb isotopes and eleven other metals (Ag, As, Ba, Cd, Co, Cr, Cu, Ni, Tl, U and Zn) from a well-dated sediment core collected near the depocenter of MacRitchie Reservoir in central Singapore. Before the 1900s, the sedimentary Pb concentration was less than 2 mg/kg for both soil and sediment, with a corresponding (206)Pb/(207)Pb of ~1.20. The Pb concentration increased to 55 mg/kg in the 1990s, and correspondingly the (206)Pb/(207)Pb decreased to less than 1.14. The (206)Pb/(207)Pb in the core top sediment is concordant with the (206)Pb/(207)Pb signal of aerosols in Singapore and other Southeast Asian cities, suggesting that Pb in the reservoir sediment was mainly from atmospheric deposition. Using the Pb concentration in the topmost layer of sediment, the estimated atmospheric Pb flux in Singapore today is ~1.6 * 10(-2) g/m(2) yr. The concentrations of eleven other metals preserved in the sediment were also determined. A principal component analysis showed that most of the metals exhibit an increasing trend towards 1990s with a local concentration peak in the mid 20(th) century. PMID- 26967354 TI - Potential Importance of Ozone in the Association Between Outdoor Air Pollution and Dry Eye Disease in South Korea. AB - Importance: Air pollution is an important public health concern and the ocular surface is continuously exposed to pollutants in outdoor air. Ocular surface abnormalities related to air pollution are thought to be a subtype of dry eye disease (DED). However, to date, there is no large-scale study evaluating an association between air pollution and DED that includes multiple air pollutants. Objective: To investigate associations between outdoor air pollution and DED in a Korean population. Design, Setting, and Participants: A population-based cross sectional study using data on 16 824 participants in the fifth Korea National Health and Nutrition Examination Survey was conducted from January 1, 2010, to December 31, 2012. Data analysis was conducted from September 1 to 30, 2015. Dry eye disease was defined as previously diagnosed by an ophthalmologist or the presence of frequent ocular pain and discomfort. Outdoor air pollution measurements (mean annual humidity, particulate matter with aerodynamic diameter <10 um [PM10], ozone, and nitrogen dioxide levels) were collected from 283 national monitoring stations in South Korea. Main Outcomes and Measures: Associations of multiple air pollutants with DED were assessed from multivariable logistic regression analyses. Sociodemographic factors and previously known factors associated with DED were applied as covariates (model 1 controlled for sociodemographic factors and model 2 controlled for sociodemographic, behavioral, and clinical factors). Results: Among 16 824 participants (7104 men and 9720 women), higher ozone levels and lower humidity levels were significantly associated with symptoms and diagnosis of DED. In model 1, an increase in ozone levels of 0.003 ppm was significantly associated with symptoms and diagnosis of DED (symptoms: odds ratio [OR], 1.16; 95% CI, 1.02-1.30; P = .04; diagnosis: OR, 1.21; 95% CI, 1.05-1.40; P = .008), while a 5% increase in humidity levels was significantly associated with decreased symptoms and diagnoses of DED (symptoms: OR, 0.87; 95% CI, 0.77-0.98; P = .03; diagnosis: OR, 0.86; 95% CI, 0.76-0.97; P = .01). In model 2, an increase in ozone levels of 0.003 ppm was significantly associated with symptoms and diagnosis of DED (symptoms: OR, 1.17; 95% CI, 1.02 1.34; P = .03; diagnosis: OR, 1.27; 95 CI, 1.09-1.48; P = .002), while a 5% increase in humidity levels was significantly associated with decreased symptoms and diagnoses of DED (symptoms: OR, 0.88; 95% CI, 0.78-0.98; P = .045; diagnosis: OR, 0.86; 95% CI, 0.76-0.97; P = .02). In model 2, an increase in nitrogen dioxide of 0.003 ppm (OR, 1.12; 95% CI, 1.02-1.23 P = .02) was also associated with diagnosis of DED. Levels of sulfur dioxide and PM10 were not associated with symptoms or diagnosis of DED in model 1 or model 2 (P > .05 for each). Conclusions and Relevance: Higher ozone levels and lower humidity levels were associated with DED in the Korean population, while PM10 level was not associated with DED. PMID- 26967353 TI - Cross-sectional association between exposure to particulate matter and inflammatory markers in the Japanese general population: NIPPON DATA2010. AB - A suggestive mechanism behind the association between particulate matter and cardiovascular disease is inflammatory response. Earlier population-based studies investigating the association between particulate matter and inflammatory biological markers, in particular C-reactive protein (CRP), showed inconsistent results. In addition, evidence from the Asian population, in which CRP levels are typically lower than those observed in Western populations, was sparse. We examined the cross-sectional association between short- and long-term exposure to particulate matter and inflammatory markers, including high-sensitivity CRP (hs CRP) and white blood cell (WBC) count, in a representative population of Japanese community dwellers (NIPPON DATA2010). We analysed data from 2360 participants (1002 men and 1358 women), aged 20 years or older, who resided in 300 randomly selected districts (222 public health centre areas) throughout Japan. We used background concentrations of suspended particulate matter (SPM, defined as particles with a 100% cut-off level at 10 MUm aerodynamic diameter) and co pollutants within the public health centre area. A logistic regression model was applied to estimate odds ratios (ORs) of elevated hs-CRP (> 0.3 mg/dl) or WBC (> 9000/MUl). Since smoking is an important confounding factor, we firstly included this in the models, and additionally conducted the analyses after excluding current smokers. The one-month average concentration of SPM was positively associated with hs-CRP (OR per 10 MUg/m(3) increase in SPM = 1.42, 95% confidence interval = 1.00-2.04), and high exposure to SPM on the day of blood draw was associated with increased WBC count, after excluding current smokers (OR = 1.13, 1.01-1.28). Similar association patterns were observed for ozone. In conclusion, exposure to particulate matter was associated with inflammatory markers in the general Japanese population. Systemic inflammation may play a role in the link between particulate matter and cardiovascular disease. PMID- 26967355 TI - Accuracy of Ultrasonography-Guided Fine-Needle Aspiration in Detecting Persistent Nodal Disease After Chemoradiotherapy. AB - IMPORTANCE: Few patients with persistent adenopathy following chemoradiotherapy (CRT) for head and neck squamous cell carcinoma harbor viable disease. Improved selectivity for surgical salvage is needed to prevent unnecessary salvage neck dissection. OBJECTIVE: To determine whether ultrasonography-guided fine-needle aspiration (FNA) can be used to identify viable cancer cells in the lymph nodes of patients with persistent radiographic adenopathy following CRT. DESIGN, SETTING, AND PARTICIPANTS: A pilot study included patients undergoing preoperative ultrasonography-guided FNA of lymph nodes considered suspicious on radiography prior to planned neck dissection at a quaternary care facility from February 28, 2011, to March 18, 2013. Data analysis was performed from April 28 to December 24, 2013. Patients treated for head and neck squamous cell carcinoma with CRT who were determined to have persistent neck disease on a 6-week posttreatment computed tomographic scan of the neck and scheduled for salvage neck dissection were considered candidates for this pilot study. All patients enrolled in the study underwent ultrasonography-guided FNA of the suspicious lymph nodes within 2 weeks of the planned neck dissection. The cytopathologist reading the samples was blinded to the patient's identity. EXPOSURES: Fine-needle aspiration with a 23- to 25-gauge needle following CRT. MAIN OUTCOMES AND MEASURES: The accuracy of ultrasonography-guided FNA cytologic results was compared with the standard of surgical pathologic examination of neck dissection specimens. RESULTS: Fourteen patients (11 [79%] men; mean [SD] age, 57.8 [11.2] years) were enrolled in this pilot study; data were collected on 17 lymph nodes. Among these 14 patients with incomplete radiographic clinical response, 17 lymph node aspirations were performed. Ultrasonography-guided FNA identified squamous cell carcinoma in the aspirates of 4 (80%) of the 5 nodes with squamous cell carcinoma identified on pathologic testing and confirmed the absence of disease in the remaining 12 (71%) lymph nodes. The statistical analysis of these results revealed a sensitivity of 80%; specificity, 100%; positive predictive value, 100%; and negative predictive value, 92.3%. The diagnostic accuracy of ultrasonography-guided FNA at detecting residual persistent cancer was 88%. CONCLUSIONS AND RELEVANCE: This pilot study suggests that ultrasonography-guided FNA may be a feasible ancillary diagnostic imaging tool to imaging to assess patients with radiographic persistent disease prior to consideration of salvage neck dissection. PMID- 26967356 TI - In situ impact assessment of wastewater effluents by integrating multi-level biomarker responses in the pale chub (Zacco platypus). AB - The integration of biomarker responses ranging from the molecular to the individual level is of great interest for measuring the toxic effects of hazardous chemicals or effluent mixtures on aquatic organisms. This study evaluated the effects of wastewater treatment plant (WWTP) effluents on the freshwater pale chub Zacco platypus by using multi-level biomarker responses at molecular [mRNA expression of catalase (CAT), superoxide dismutase (SOD), glutathione S-transferase (GST), and metallothionein (MT)], biochemical (enzyme activities of CAT, SOD, GST, and concentration of MT), and physiological [condition factor (CF) and liver somatic index (LSI)] levels. The mRNA expression levels of GST and MT in Z. platypus from a site downstream of a WWTP significantly increased by 2.2- and 4.5-fold (p<0.05) when compared with those from an upstream site. However, the enzyme activities of CAT, SOD, and GST in fish from the downstream site significantly decreased by 43%, 98%, and 13%, respectively (p<0.05), except for an increase in MT concentration (41%). In addition, a significant increase in LSI (46%) was observed in Z. platypus from the downstream site (p<0.05). Concentrations of Cu, Zn, Cd, and Pb in the liver of Z. platypus were higher (530%, 353%, 800%, and 2,200%, respectively) in fish from a downstream site than in fish from an upstream location, and several multi level biomarker responses were significantly correlated with the accumulated metals in Z. platypus (p<0.05). Integrated biomarker responses at molecular, biochemical, and physiological levels (multi-level IBR) were much higher (about 4 fold) at the downstream site than at the upstream site. This study suggests that the multi-level IBR approach is very useful for quantifying in situ adverse effects of WWTP effluents. PMID- 26967357 TI - The stigmatisation of pregnancy: societal influences on pregnant women's physical activity Behaviour. AB - Many women going through the major life transition of pregnancy experience decreases in physical activity behaviour, which may compromise maternal and infant health and wellbeing. Although research suggests that the social environment plays a large role in influencing women's physical activity behaviour, little is known about the association between societal attitudes and physical activity behaviour during the course of pregnancy. Through a qualitative longitudinal study, we explored women's physical activity experiences throughout pregnancy and how these were formed, supported and/or opposed by their social environment. This research included telephone interviews with 30 pregnant participants, recruited via a regional public hospital. Using a feminist standpoint analysis incorporating modern dialectics, three major tensions were identified, reflecting dominant societal discourses around physical activity and pregnancy: (1) engaging in physical activity and keeping the baby safe, (2) engaging in physical activity and obtaining social approval and (3) listening to oneself and to others. These findings present previously unrecognised opportunities for developing tailored and effective physical activity interventions among pregnant women. PMID- 26967358 TI - Soft-Etching Copper and Silver Electrodes for Significant Device Performance Improvement toward Facile, Cost-Effective, Bottom-Contacted, Organic Field-Effect Transistors. AB - Poor charge injection and transport at the electrode/semiconductor contacts has been so far a severe performance hurdle for bottom-contact bottom-gate (BCBG) organic field-effect transistors (OFETs). Here, we have developed a simple, economic, and effective method to improve the carrier injection efficiency and obtained high-performance devices with low cost and widely used source/drain (S/D) electrodes (Ag/Cu). Through the simple electrode etching process, the work function of the electrodes is more aligned with the semiconductors, which reduces the energy barrier and facilitates the charge injection. Besides, the formation of the thinned electrode edge with desirable micro/nanostructures not only leads to the enlarged contact side area beneficial for the carrier injection but also is in favor of the molecular self-organization for continuous crystal growth at the contact/active channel interface, which is better for the charge injection and transport. These effects give rise to the great reduction of contact resistance and the amazing improvement of the low-cost bottom-contact configuration OFETs performance. PMID- 26967359 TI - Providing Hearing Aids to Infants and Young Children. PMID- 26967360 TI - Pediatric Audiology in North America: Current Clinical Practice and How It Relates to the American Academy of Audiology Pediatric Amplification Guideline. AB - BACKGROUND: There is broad consensus that screening and diagnosis of permanent hearing loss in children must be embedded within a comprehensive, evidence-based, family-centered intervention program. Clinical practice guidelines (CPGs) for pediatric hearing assessment and hearing aid verification aim to reduce variability in practice and increase the use of effective evidence-based diagnostic and treatment options so that optimal outcomes may be achieved. To be of value, guidelines must be translated and implemented into practice and ongoing monitoring of their use in practice should occur. PURPOSE: This paper provides the results of two studies that aim to examine current pediatric audiology and amplification practice in North America. RESEARCH DESIGN: A concurrent embedded mixed methods design was used. STUDY SAMPLE: An electronic survey was distributed to North American audiologists who delivered pediatric audiology services with 350 audiologists participating in study 1 and 63 audiologists participating in study 2. DATA COLLECTION AND ANALYSIS: A quantitative approach was the predominant method of data collection. Respondents were prompted to provide additional qualitative text and detail regarding their quantitative response choice. This qualitative text was used during the analysis phase and combined with quantitative results to assist understanding of respondents' knowledge, skills, and barriers/facilitators to implement best practice in pediatric amplification. RESULTS: Approximately 70% of audiologists reported using best practice protocols for pediatric hearing aid fitting. Despite widespread knowledge and increased use of CPGs over the last 18 yrs, results of these studies show that variation in practice patterns continue to exist. Several examples of implementation challenges are discussed with recommendations provided. CONCLUSIONS: In order for audiologists working with children who are deaf or hard of hearing and their families to achieve the principles of family centered early intervention, practice guidelines must continue to be developed, disseminated, and translated as they have a positive impact on the services provided. Researchers and clinical audiologists who deliver services must continue to collaborate to understand the "how" and "why" of implementing guidelines into practice and to identify the barriers/facilitators encountered in trying to do so. PMID- 26967361 TI - Prescribing and Verifying Hearing Aids Applying the American Academy of Audiology Pediatric Amplification Guideline: Protocols and Outcomes from the Ontario Infant Hearing Program. AB - BACKGROUND: Guidelines and protocols for pediatric hearing aid fitting are necessary to meet the goals of Early Hearing Detection and Intervention (EHDI) programs. The American Academy of Audiology published an update to their Pediatric Amplification Guideline in 2013. Ontario's Infant Hearing Program (IHP) offers specific protocols that aim to fulfill recommended guidelines. It has recently been updated to align with the American Academy of Audiology Guideline and other evidence. PURPOSE: A summary of the updates to the Ontario IHP's Amplification Protocol is described. In addition, data illustrating hearing related outcomes of the program are offered. RESEARCH DESIGN: The updated Ontario protocol is based on evidence, wherever possible. Where research is not yet available, clinical decision support has been described in a systematic way. Outcomes of the Ontario IHP were obtained through a longitudinal clinical observation study. STUDY SAMPLE: One hundred and fifteen children with hearing loss, who wore hearing aids, were included in the outcome analyses (mean = 28.6 mo; range = 1.3-115.3 mo). Hearing losses ranged from mild to profound, unilateral or bilateral sensorineural (pure-tone average = 52.3 dB HL). They were recruited from four IHP clinics within Ontario. Children with complexities in addition to hearing loss were included. INTERVENTION: The children were fitted with hearing aids following Ontario's Amplification Protocol. DATA COLLECTION AND ANALYSES: During routine clinical appointments, IHP Audiologists administered questionnaires to the parents of their pediatric patients using a systematic outcome measurement protocol (University of Western Ontario Pediatric Audiological Monitoring Protocol). Hearing aid fitting details (e.g., speech intelligibility index) were also gathered to describe the quality of the hearing aid fittings in relation to the functional outcomes. Regression analyses were conducted to characterize scores on the questionnaires and the impact of important variables. Children with complexities were analyzed separately from those who were typically developing. RESULTS: Important updates to Ontario's Amplification Protocol offer new details about candidacy considerations as well as technical updates. Outcomes from the IHP reveal protocol elements can be executed clinically and when they are, typically developing children who wear hearing aids are meeting auditory development and performance milestones. CONCLUSIONS: Updates to Ontario's Amplification Protocol are necessary to support the evolution of EHDI programs and the evidence which sustains them. With advances in technology and additional research, pediatric hearing aid fitting will continue to progress and support systematic measurement of outcomes for children who wear hearing aids. The application of state-of-the-art hearing aid fitting practices to the pediatric population within EHDI programs supports good outcomes for infants and children with hearing loss. PMID- 26967362 TI - Children with Auditory Neuropathy Spectrum Disorder Fitted with Hearing Aids Applying the American Academy of Audiology Pediatric Amplification Guideline: Current Practice and Outcomes. AB - BACKGROUND: Up to 15% of children with permanent hearing loss (HL) have auditory neuropathy spectrum disorder (ANSD), which involves normal outer hair cell function and disordered afferent neural activity in the auditory nerve or brainstem. Given the varying presentations of ANSD in children, there is a need for more evidence-based research on appropriate clinical interventions for this population. PURPOSE: This study compared the speech production, speech perception, and language outcomes of children with ANSD, who are hard of hearing, to children with similar degrees of mild-to-moderately severe sensorineural hearing loss (SNHL), all of whom were fitted with bilateral hearing aids (HAs) based on the American Academy of Audiology pediatric amplification guidelines. RESEARCH DESIGN: Speech perception and communication outcomes data were gathered in a prospective accelerated longitudinal design, with entry into the study between six mo and seven yr of age. Three sites were involved in participant recruitment: Boys Town National Research Hospital, the University of North Carolina at Chapel Hill, and the University of Iowa. STUDY SAMPLE: The sample consisted of 12 children with ANSD and 22 children with SNHL. The groups were matched based on better-ear pure-tone average, better-ear aided speech intelligibility index, gender, maternal education level, and newborn hearing screening result (i.e., pass or refer). DATA COLLECTION AND ANALYSIS: Children and their families participated in an initial baseline visit, followed by visits twice a year for children <2 yr of age and once a yr for children >2 yr of age. Paired-sample t-tests were used to compare children with ANSD to children with SNHL. RESULTS: Paired t-tests indicated no significant differences between the ANSD and SNHL groups on language and articulation measures. Children with ANSD displayed functional speech perception skills in quiet. Although the number of participants was too small to conduct statistical analyses for speech perception testing, there appeared to be a trend in which the ANSD group performed more poorly in background noise with HAs, compared to the SNHL group. CONCLUSIONS: The American Academy of Audiology Pediatric Amplification Guidelines recommend that children with ANSD receive an HA trial if their behavioral thresholds are sufficiently high enough to impede speech perception at conversational levels. For children with ANSD in the mild-to-severe HL range, the current results support this recommendation, as children with ANSD can achieve functional outcomes similar to peers with SNHL. PMID- 26967363 TI - Fitting Frequency-Lowering Signal Processing Applying the American Academy of Audiology Pediatric Amplification Guideline: Updates and Protocols. AB - BACKGROUND: Although guidelines for fitting hearing aids for children are well developed and have strong basis in evidence, specific protocols for fitting and verifying technologies can supplement such guidelines. One such technology is frequency-lowering signal processing. Children require access to a broad bandwidth of speech to detect and use all phonemes including female /s/. When access through conventional amplification is not possible, the use of frequency lowering signal processing may be considered as a means to overcome limitations. Fitting and verification protocols are needed to better define candidacy determination and options for assessing and fine tuning frequency-lowering signal processing for individuals. PURPOSE: This work aims to (1) describe a set of calibrated phonemes that can be used to characterize the variation in different brands of frequency-lowering processors in hearing aids and the verification with these signals and (2) determine whether verification with these signal are predictive of perceptual changes associated with changes in the strength of frequency-lowering signal processing. Finally, we aimed to develop a fitting protocol for use in pediatric clinical practice. STUDY SAMPLE: Study 1 used a sample of six hearing aids spanning four types of frequency lowering algorithms for an electroacoustic evaluation. Study 2 included 21 adults who had hearing loss (mean age 66 yr). DATA COLLECTION AND ANALYSIS: Simulated fricatives were designed to mimic the level and frequency shape of female fricatives extracted from two sources of speech. These signals were used to verify the frequency lowering effects of four distinct types of frequency-lowering signal processors available in commercial hearing aids, and verification measures were compared to extracted fricatives made in a reference system. In a second study, the simulated fricatives were used within a probe microphone measurement system to verify a wide range of frequency compression settings in a commercial hearing aid, and 27 adult listeners were tested at each setting. The relation between the hearing aid verification measures and the listener's ability to detect and discriminate between fricatives was examined. RESULTS: Verification measures made with the simulated fricatives agreed to within 4 dB, on average, and tended to mimic the frequency response shape of fricatives presented in a running speech context. Some processors showed a greater aided response level for fricatives in running speech than fricatives presented in isolation. Results with listeners indicated that verified settings that provided a positive sensation level of /s/ and that maximized the frequency difference between /s/ and /?/ tended to have the best performance. CONCLUSIONS: Frequency-lowering signal processors have measureable effects on the high-frequency fricative content of speech, particularly female /s/. It is possible to measure these effects either with a simple strategy that presents an isolated simulated fricative and measures the aided frequency response or with a more complex system that extracts fricatives from running speech. For some processors, a more accurate result may be achieved with a running speech system. In listeners, the aided frequency location and sensation level of fricatives may be helpful in predicting whether a specific hearing aid fitting, with or without frequency-lowering, will support access to the fricatives of speech. PMID- 26967364 TI - Fitting Noise Management Signal Processing Applying the American Academy of Audiology Pediatric Amplification Guideline: Verification Protocols. AB - BACKGROUND: Although guidelines for fitting hearing aids for children are well developed and have strong basis in evidence, specific protocols for fitting and verifying some technologies are not always available. One such technology is noise management in children's hearing aids. Children are frequently in high level and/or noisy environments, and many options for noise management exist in modern hearing aids. Verification protocols are needed to define specific test signals and levels for use in clinical practice. PURPOSE: This work aims to (1) describe the variation in different brands of noise reduction processors in hearing aids and the verification of these processors and (2) determine whether these differences are perceived by 13 children who have hearing loss. Finally, we aimed to develop a verification protocol for use in pediatric clinical practice. STUDY SAMPLE: A set of hearing aids was tested using both clinically available test systems and a reference system, so that the impacts of noise reduction signal processing in hearing aids could be characterized for speech in a variety of background noises. A second set of hearing aids was tested across a range of audiograms and across two clinical verification systems to characterize the variance in clinical verification measurements. Finally, a set of hearing aid recordings that varied by type of noise reduction was rated for sound quality by children with hearing loss. RESULTS: Significant variation across makes and models of hearing aids was observed in both the speed of noise reduction activation and the magnitude of noise reduction. Reference measures indicate that noise-only testing may overestimate noise reduction magnitude compared to speech in-noise testing. Variation across clinical test signals was also observed, indicating that some test signals may be more successful than others for characterization of hearing aid noise reduction. Children provided different sound quality ratings across hearing aids, and for one hearing aid rated the sound quality as higher with the noise reduction system activated. CONCLUSIONS: Implications for clinical verification systems may be that greater standardization and the use of speech-in-noise test signals may improve the quality and consistency of noise reduction verification cross clinics. A suggested clinical protocol for verification of noise management in children's hearing aids is suggested. PMID- 26967365 TI - Stability of Audiometric Thresholds for Children with Hearing Aids Applying the American Academy of Audiology Pediatric Amplification Guideline: Implications for Safety. AB - BACKGROUND: Children who wear hearing aids may be at risk for further damage to their hearing from overamplification. Previous research on amplification-induced hearing loss has included children using linear amplification or simulations of predicted threshold shifts based on nonlinear amplification formulae. A relationship between threshold shifts and the use of nonlinear hearing aids in children has not been empirically verified. PURPOSE: The purpose of the study was to compare predicted threshold shifts from amplification to longitudinal behavioral thresholds in a large group of children who wear hearing aids to determine the likelihood of amplification-induced hearing loss. RESEARCH DESIGN: An accelerated longitudinal design was used to collect behavioral threshold and amplification data prospectively. STUDY SAMPLE: Two-hundred and thirteen children with mild-to-profound hearing loss who wore hearing aids were included in the analysis. DATA COLLECTION AND ANALYSIS: Behavioral audiometric thresholds, hearing aid outputs, and hearing aid use data were collected for each participant across four study visits. Individual ear- and frequency-specific safety limits were derived based on the Modified Power Law to determine the level at which increased amplification could result in permanent threshold shifts. Behavioral thresholds were used to estimate which children would be above the safety limit at 500, 1000, 2000, and 4000 Hz using thresholds in dB HL and then in dB SPL in the ear canal. Changes in thresholds across visits were compared for children who were above and below the safety limits. RESULTS: Behavioral thresholds decreased across study visits for all children, regardless of whether their amplification was above the safety limits. The magnitude of threshold change across time corresponded with changes in ear canal acoustics as measured by the real-ear-to coupler difference. CONCLUSIONS: Predictions of threshold changes due to amplification for children with hearing loss did not correspond with observed changes in threshold over across 2-4 yr of monitoring amplification. Use of dB HL thresholds and predictions of hearing aid output to set the safety limit resulted in a larger number of children being classified as above the safety limit than when safety limits were based on dB SPL thresholds and measured hearing aid output. Children above the safety limit for the dB SPL criteria tended to be fit above prescriptive targets. Additional research should seek to explain how the Modified Power Law predictions of threshold shift overestimated risk for children who wear hearing aids. PMID- 26967366 TI - Using the Real-Ear-to-Coupler Difference within the American Academy of Audiology Pediatric Amplification Guideline: Protocols for Applying and Predicting Earmold RECDs. AB - BACKGROUND: Real-ear-to-coupler difference (RECD) measurements are used for the purposes of estimating degree and configuration of hearing loss (in dB SPL ear canal) and predicting hearing aid output from coupler-based measures. Accurate measurements of hearing threshold, derivation of hearing aid fitting targets, and predictions of hearing aid output in the ear canal assume consistent matching of RECD coupling procedure (i.e., foam tip or earmold) with that used during assessment and in verification of the hearing aid fitting. When there is a mismatch between these coupling procedures, errors are introduced. PURPOSE: The goal of this study was to quantify the systematic difference in measured RECD values obtained when using a foam tip versus an earmold with various tube lengths. Assuming that systematic errors exist, the second goal was to investigate the use of a foam tip to earmold correction for the purposes of improving fitting accuracy when mismatched RECD coupling conditions occur (e.g., foam tip at assessment, earmold at verification). STUDY SAMPLE: Eighteen adults and 17 children (age range: 3-127 mo) participated in this study. DATA COLLECTION AND ANALYSIS: Data were obtained using simulated ears of various volumes and earmold tubing lengths and from patients using their own earmolds. Derived RECD values based on simulated ear measurements were compared with RECD values obtained for adult and pediatric ears for foam tip and earmold coupling. RESULTS: Results indicate that differences between foam tip and earmold RECDs are consistent across test ears for adults and children which support the development of a correction between foam tip and earmold couplings for RECDs that can be applied across individuals. CONCLUSIONS: The foam tip to earmold correction values developed in this study can be used to provide improved estimations of earmold RECDs. This may support better accuracy in acoustic transforms related to transforming thresholds and/or hearing aid coupler responses to ear canal sound pressure level for the purposes of fitting behind-the-ear hearing aids. PMID- 26967367 TI - Incense Burning during Pregnancy and Birth Weight and Head Circumference among Term Births: The Taiwan Birth Cohort Study. AB - BACKGROUND: Incense burning for rituals or religious purposes is an important tradition in many countries. However, incense smoke contains particulate matter and gas products such as carbon monoxide, sulfur, and nitrogen dioxide, which are potentially harmful to health. OBJECTIVES: We analyzed the relationship between prenatal incense burning and birth weight and head circumference at birth using the Taiwan Birth Cohort Study. We also analyzed whether the associations varied by sex and along the distribution of birth outcomes. METHODS: We performed ordinary least squares (OLS) and quantile regressions analysis on a sample of 15,773 term births (> 37 gestational weeks; 8,216 boys and 7,557 girls) in Taiwan in 2005. The associations were estimated separately for boys and girls as well as for the population as a whole. We controlled extensively for factors that may be correlated with incense burning and birth weight and head circumference, such as parental religion, demographics, and health characteristics, as well as pregnancy related variables. RESULTS: Findings from fully adjusted OLS regressions indicated that exposure to incense was associated with lower birth weight in boys (-18 g; 95% CI: -36, -0.94) but not girls (1 g; 95% CI: -17, 19; interaction p value = 0.31). Associations with head circumference were negative for boys (-0.95 mm; 95% CI: -1.8, -0.16) and girls (-0.71 mm; 95% CI: -1.5, 0.11; interaction p values = 0.73). Quantile regression results suggested that the negative associations were larger among the lower quantiles of birth outcomes. CONCLUSIONS: OLS regressions showed that prenatal incense burning was associated with lower birth weight for boys and smaller head circumference for boys and girls. The associations were more pronounced among the lower quantiles of birth outcomes. Further research is necessary to confirm whether incense burning has differential effects by sex. CITATION: Chen LY, Ho C. 2016. Incense burning during pregnancy and birth weight and head circumference among term births: The Taiwan Birth Cohort Study. Environ Health Perspect 124:1487-1492; http://dx.doi.org/10.1289/ehp.1509922. PMID- 26967368 TI - Evaluation of the Alere i Influenza A&B assay for rapid identification of influenza A and influenza B viruses. AB - The Alere i Influenza A&B assay is a novel isothermal nucleic acid amplification assay capable of detecting and differentiating influenza A and B viruses in approximately 15 min with minimal hands-on time. This study was conducted in order to assess the performance of the Alere i Influenza A&B assay compared to molecular techniques, considered to be gold standard methods, to evaluate the results. A total of 119 nasopharyngeal swabs collected from inpatients with influenza-like illness were included in the study using both archived and prospectively collected samples from adults and children. Prospectively collected samples were also compared to the Alere BinaxNOW(r) Influenza A & B Card. The overall sensitivity for detection of influenza A and B viruses compared to those of molecular techniques were 65.96 % and 53.33 % respectively, while the specificity was 98.51 % and 95.96 %. Compared to the Alere BinaxNOW(r) Influenza A & B Card, the Alere i assay is considerably more sensitive for detection of influenza A and B viruses, although both tests demonstrated excellent specificity for diagnosis of influenza viruses. PMID- 26967370 TI - Isolation, Characterization and Functional Examination of the Gingival Immune Cell Network. AB - Immune cell networks in tissues play a vital role in mediating local immunity and maintaining tissue homeostasis, yet little is known of the resident immune cell populations in the oral mucosa and gingiva. We have established a technique for the isolation and study of immune cells from murine gingival tissues, an area of constant microbial exposure and a vulnerable site to a common inflammatory disease, periodontitis. Our protocol allows for a detailed phenotypic characterization of the immune cell populations resident in the gingiva, even at steady state. Our procedure also yields sufficient cells with high viability for use in functional studies, such as the assessment of cytokine secretion ex vivo. This combination of phenotypic and functional characterization of the gingival immune cell network should aid towards investigating the mechanisms involved in oral immunity and periodontal homeostasis, but will also advance our understanding of the mechanisms involved in local immunopathology. PMID- 26967371 TI - Role of Enzyme Flexibility in Ligand Access and Egress to Active Site: Bias Exchange Metadynamics Study of 1,3,7-Trimethyluric Acid in Cytochrome P450 3A4. AB - Although the majority of enzymes have buried active sites, very little is known about the energetics and mechanisms associated with substrate and product channeling in and out. Gaining direct information about these processes is a challenging task both for experimental and theoretical techniques. Here, we present a methodology that enables following of a ligand during its passage to the active site of cytochrome P450 (CYP) 3A4 and mapping of the free energy associated with this process. The technique is based on a combination of a bioinformatics tool for identifying access channels and bias-exchange metadynamics and provides converged free energies in good agreement with experimental data. In addition, it identifies the energetically preferred escape routes, limiting steps, and amino acids residues lining the channel. The approach was applied to mapping of a complex channel network in a complex environment, i.e., CYP3A4 attached to a lipid bilayer mimicking an endoplasmic reticulum membrane. The results provided direct information about the energetics and conformational changes associated with the ligand channeling. The methodology can easily be adapted to study channeling through other flexible biomacromolecular channels. PMID- 26967369 TI - Research Resource: Real-Time Analysis of Somatostatin and Dopamine Receptor Signaling in Pituitary Cells Using a Fluorescence-Based Membrane Potential Assay. AB - Stable somatostatin analogues and dopamine receptor agonists are the mainstay for the pharmacological treatment of functional pituitary adenomas; however, only a few cellular assays have been developed to detect receptor activation of novel compounds without disrupting cells to obtain the second messenger content. Here, we adapted a novel fluorescence-based membrane potential assay to characterize receptor signaling in a time-dependent manner. This minimally invasive technique provides a robust and reliable read-out for ligand-induced receptor activation in permanent and primary pituitary cells. The mouse corticotropic cell line AtT-20 endogenously expresses both the somatostatin receptors 2 (sst2) and 5 (sst5). Exposure of wild-type AtT-20 cells to the sst2- and sst5-selective agonists BIM 23120 and BIM-23268, respectively, promoted a pertussis toxin- and tertiapin-Q sensitive reduction in fluorescent signal intensity, which is indicative of activation of G protein-coupled inwardly rectifying potassium (GIRK) channels. After heterologous expression, sst1, sst3, and sst4 receptors also coupled to GIRK channels in AtT-20 cells. Similar activation of GIRK channels by dopamine required overexpression of dopamine D2 receptors (D2Rs). Interestingly, the presence of D2Rs in AtT-20 cells strongly facilitated GIRK channel activation elicited by the sst2-D2 chimeric ligand BIM-23A760, suggesting a synergistic action of sst2 and D2Rs. Furthermore, stable somatostatin analogues produced strong responses in primary pituitary cultures from wild-type mice; however, in cultures from sst2 receptor-deficient mice, only pasireotide and somatoprim, but not octreotide, induced a reduction in fluorescent signal intensity, suggesting that octreotide mediates its pharmacological action primarily via the sst2 receptor. PMID- 26967373 TI - Beyond vertical and horizontal programs: a diagonal approach to building national immunization programs through measles elimination. PMID- 26967372 TI - Design and Synthesis of New Circularly Polarized Thermally Activated Delayed Fluorescence Emitters. AB - This work describes the first thermally activated delayed fluorescence material enabling circularly polarized light emission through chiral perturbation. These new molecular architectures obtained through a scalable one-pot sequential synthetic procedure at room temperature (83% yield) display high quantum yield (up to 74%) and circularly polarized luminescence with an absolute luminescence dissymmetry factor, |glum|, of 1.3 * 10(-3). These chiral molecules have been used as an emissive dopant in an organic light emitting diode exhibiting external quantum efficiency as high as 9.1%. PMID- 26967376 TI - Negligible Isotopic Effect on Dissociation of Hydrogen Bonds. AB - Isotopic effects on the formation and dissociation kinetics of hydrogen bonds are studied in real time with ultrafast chemical exchange spectroscopy. The dissociation time of hydrogen bond between phenol-OH and p-xylene (or mesitylene) is found to be identical to that between phenol-OD and p-xylene (or mesitylene) in the same solvents. The experimental results demonstrate that the isotope substitution (D for H) has negligible effects on the hydrogen bond kinetics. DFT calculations show that the isotope substitution does not significantly change the frequencies of vibrational modes that may be along the hydrogen bond formation and dissociation coordinate. The zero point energy differences of these modes between hydrogen bonds with OH and OD are too small to affect the activation energy of the hydrogen bond dissociation in a detectible way at room temperature. PMID- 26967375 TI - Optimized Rhodamine B labeled mesoporous silica nanoparticles as fluorescent scaffolds for the immobilization of photosensitizers: a theranostic platform for optical imaging and photodynamic therapy. AB - A highly efficient bifunctional mesoporous silica nanodevice coupling optical imaging with photodynamic therapy (PDT) was successfully prepared by using Rhodamine B as a contrast agent and verteporfin as a photosensitizer. The precise localization and high dispersion of the contrast agent in the nanoparticles is the key point to get higher fluorescence quantum yields with respect to the fluorophore in solution. To obtain this information photoluminescence spectroscopy coupled with fluorescence lifetime measurements was used, due to its high sensitivity. The bifunctional nanodevice showed good performances both in terms of quantum yield of the anchored Rhodamine B (Phi(RhB) = 0.55) and the singlet oxygen delivery efficiency for PDT applications. PMID- 26967374 TI - Using Balance Tests to Discriminate Between Participants With a Recent Index Lateral Ankle Sprain and Healthy Control Participants: A Cross-Sectional Study. AB - CONTEXT: The first step to identifying factors that increase the risk of recurrent ankle sprains is to identify impairments after a first sprain and compare performance with individuals who have never sustained a sprain. Few researchers have restricted recruitment to a homogeneous group of patients with first sprains, thereby introducing the potential for confounding. OBJECTIVE: To identify impairments that differ in participants with a recent index lateral ankle sprain versus participants with no history of ankle sprain. DESIGN: Cross sectional study. PATIENTS OR OTHER PARTICIPANTS: We recruited a sample of convenience from May 2010 to April 2013 that included 70 volunteers (age = 27.4 +/- 8.3 years, height = 168.7 +/- 9.5 cm, mass = 65.0 +/- 12.5 kg) serving as controls and 30 volunteers (age = 31.1 +/- 13.3 years, height = 168.3 +/- 9.1 cm, mass = 67.3 +/- 13.7 kg) with index ankle sprains. MAIN OUTCOME MEASURE(S): We collected demographic and physical performance variables, including ankle-joint range of motion, balance (time to balance after perturbation, Star Excursion Balance Test, foot lifts during single-legged stance, demi-pointe balance test), proprioception, motor planning, inversion-eversion peak power, and timed stair tests. Discriminant analysis was conducted to determine the relationship between explanatory variables and sprain status. Sequential discriminant analysis was performed to identify the most relevant variables that explained the greatest variance. RESULTS: The average time since the sprain was 3.5 +/- 1.5 months. The model, including all variables, correctly predicted a sprain status of 77% (n = 23) of the sprain group and 80% (n = 56) of the control group and explained 40% of the variance between groups ([Formula: see text] = 42.16, P = .03). Backward stepwise discriminant analysis revealed associations between sprain status and only 2 tests: Star Excursion Balance Test in the anterior direction and foot lifts during single-legged stance ([Formula: see text] = 15.2, P = .001). These 2 tests explained 15% of the between-groups variance and correctly predicted group membership of 63% (n = 19) of the sprain group and 69% (n = 48) of the control group. CONCLUSIONS: Balance impairments were associated with a recent first ankle sprain, but proprioception, motor control, power, and function were not. PMID- 26967379 TI - Solid-State and Solution Metallophilic Aggregation of a Cationic [Pt(NCN)L](+) Cyclometalated Complex. AB - The noncovalent intermolecular interactions (pi-pi stacking, metallophilic bonding) of the cyclometalated complexes [Pt(NCN)L](+)X(-) (NCN = dipyridylbenzene, L = pyridine (1), acetonitrile (2)) are determined by the steric properties of the ancillary ligands L in the solid state and in solution, while the nature of the counterion X(-) (X(-) = PF6(-), ClO4(-), CF3SO3(-)) affects the molecular arrangement of 2.X in the crystal medium. According to the variable-temperature X-ray diffraction measurements, the extensive Pt...Pt interactions and pi-stacking in 2.X are significantly temperature-dependent. The variable concentration (1)H and diffusion coefficients NMR measurements reveal that 2.X exists in the monomeric form in dilute solutions at 298 K, while upon increase in concentration [Pt(NCN)(NCMe)](+) cations undergo the formation of the ground-state oligomeric aggregates with an average aggregation number of ~3. The photoluminescent characteristics of 1 and 2.X are largely determined by the intermolecular aggregation. For the discrete molecules the emission properties are assigned to metal perturbed IL charge transfer mixed with some MLCT contribution. In the case of oligomers 2.X the luminescence is significantly red shifted with respect to 1 and originates mainly from the (3)MMLCT excited states. The emission energies depend on the structural arrangement in the crystal and on the complex concentration in solution, variation of which allows for the modulation of the emission color from greenish to deep red. In the solid state the lability of the ligands L leads to vapor-induced reversible transformation 1 <-> 2 that is accompanied by the molecular reorganization and, consequently, dramatic change of the photophysical properties. Time-dependent density functional theory calculations adequately support the models proposed for the rationalization of the experimental observations. PMID- 26967377 TI - (1,3;1,4)-beta-Glucan Biosynthesis by the CSLF6 Enzyme: Position and Flexibility of Catalytic Residues Influence Product Fine Structure. AB - Cellulose synthase-like F6 (CslF6) genes encode polysaccharide synthases responsible for (1,3;1,4)-beta-glucan biosynthesis in cereal grains. However, it is not clear how both (1,3)- and (1,4)-linkages are incorporated into a single polysaccharide chain and how the frequency and arrangement of the two linkage types that define the fine structure of the polysaccharide are controlled. Through transient expression in Nicotiana benthamiana leaves, two CSLF6 orthologs from different cereal species were shown to mediate the synthesis of (1,3;1,4) beta-glucans with very different fine structures. Chimeric cDNA constructs with interchanged sections of the barley and sorghum CslF6 genes were developed to identify regions of the synthase enzyme responsible for these differences. A single amino acid residue upstream of the TED motif in the catalytic region was shown to dramatically change the fine structure of the polysaccharide produced. The structural basis of this effect can be rationalized by reference to a homology model of the enzyme and appears to be related to the position and flexibility of the TED motif in the active site of the enzyme. The region and amino acid residue identified provide opportunities to manipulate the solubility of (1,3;1,4)-beta-glucan in grains and vegetative tissues of the grasses and, in particular, to enhance the solubility of dietary fibers that are beneficial to human health. PMID- 26967380 TI - Isolation and Flow Cytometric Analysis of Immune Cells from the Ischemic Mouse Brain. AB - Ischemic stroke initiates a robust inflammatory response that starts in the intravascular compartment and involves rapid activation of brain resident cells. A key mechanism of this inflammatory response is the migration of circulating immune cells to the ischemic brain facilitated by chemokine release and increased endothelial adhesion molecule expression. Brain-invading leukocytes are well known contributing to early-stage secondary ischemic injury, but their significance for the termination of inflammation and later brain repair has only recently been noticed. Here, a simple protocol for the efficient isolation of immune cells from the ischemic mouse brain is provided. After transcardial perfusion, brain hemispheres are dissected and mechanically dissociated. Enzymatic digestion with Liberase is followed by density gradient (such as Percoll) centrifugation to remove myelin and cell debris. One major advantage of this protocol is the single-layer density gradient procedure which does not require time-consuming preparation of gradients and can be reliably performed. The approach yields highly reproducible cell counts per brain hemisphere and allows for measuring several flow cytometry panels in one biological replicate. Phenotypic characterization and quantification of brain-invading leukocytes after experimental stroke may contribute to a better understanding of their multifaceted roles in ischemic injury and repair. PMID- 26967382 TI - The adaptive immune system in atopic dermatitis and implications on therapy. AB - In atopic dermatitis (AD), the skin inflammation is believed to occur due to a misdirected immune reaction against harmless antigens on the one hand, and to a disturbed skin barrier on the other. In recent years, vast efforts have been made to investigate the relevance and details of the immune response to allergens. Clinically, it was demonstrated for the first time that aeroallergen exposure leads to worsening of AD symptoms. An overexpression of Th2 cytokines has been observed in acute and subacute lesions of AD. The clinical impact of the key Th2 cytokines IL-4 and IL-13 on atopic dermatitis has recently been shown in clinical studies with dupilumab, a monoclonal antibody which blocks the IL-4/IL-13 receptor. In vitro data indicate, however, that the T cell response is not solely Th2-polarized but may lead to heterogeneous cytokine production involving IFN gamma and IL-17 in an allergen-dependent manner. Classical thymus-derived Foxp3 T cells have interestingly been detected in elevated numbers in the circulation of AD patients. Therapeutic approaches with allergen specific immunotherapy aim to induce regulatory T cells of the Tr1 type. The strikingly altered microbiome of AD skin with diminished diversity of bacteria on lesional skin but increases of S. aureus colonization and the sensitization against microbial allergens and homologue self-proteins deserve special attention. For the treatment of itch symptoms, which still represent a challenge in daily practice, promising data have been published on the relevance of the H(histamine)4-receptor and on mediators such as IL-31, TSLP. PMID- 26967381 TI - Human Vastus Lateralis Skeletal Muscle Biopsy Using the Weil-Blakesley Conchotome. AB - Percutaneous muscle biopsy using the Weil-Blakesley conchotome is well established in both clinical and research practice. It is a safe, effective and well tolerated technique. The Weil-Blakesley conchotome has a sharp biting tip with a 4 - 6 mm wide hollow. It is inserted through a 5 - 10 mm skin incision and can be maneuvered for controlled tissue penetration. The tip is opened and closed within the tissue and then rotated through 90 -180 degrees to cut the muscle. The amount of muscle obtained following repeated sampling can vary from 20 mg to 290 mg which can be processed for both histology and molecular studies. The wound needs to be kept dry and vigorous physical activity kept to a minimum for approximately 72 hr although normal levels of activity can restart immediately following the procedure. This procedure is safe and effective when close attention is paid to the selection of subjects, full asepsis and post procedure care. Both right and left vastus lateralis are suitable for biopsy dependent on participant preference. PMID- 26967383 TI - Nitrilase 1 modulates lung tumor progression in vitro and in vivo. AB - Uncovering novel growth modulators for non-small cell lung cancer (NSCLC) may lead to new therapies for these patients. Previous studies suggest Nit1 suppresses chemically induced carcinogenesis of the foregut in a mouse model. In this study we aimed to determine the role of Nit1 in a transgenic mouse lung cancer model driven by a G12D Kras mutation. Nit1 knockout mice (Nit1-/-) were crossed with KrasG12D/+ mice to investigate whether a G12D Kras mutation and Nit1 inactivation interact to promote or inhibit the development of NSCLC. We found that lung tumorigenesis was suppressed in the Nit1-null background (Nit1-/ :KrasG12D/+). Micro-CT scans and gross tumor measurements demonstrated a 5-fold reduction in total tumor volumes compared to Nit1+/+KrasG12D/+ (p<0.01). Furthermore, we found that Nit1 is highly expressed in human lung cancer tissues and cell lines and use of siRNA against Nit1 decreased overall cell survival of lung cancer cells in culture. In addition, cisplatin response was enhanced in human lung cancer cells when Nit1 was knocked down and Nit1-/-:KrasG12D/+ tumors showed increased sensitivity to cisplatin in vivo. Together, our data indicate that Nit1 may play a supportive role in the modulation of lung tumorigenesis and represent a novel target for NSCLCs treatment. PMID- 26967384 TI - Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma. AB - Tumor cells co-express vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) that interact each other to support a self-sustainable cell growth. So far, this autocrine VEGF loop is not reported in human intrahepatic cholangiocarcinoma (ICC). Apatinib is a highly selective VEGFR2 inhibitor, but its effects on ICC have not been investigated. In this study, we reported that VEGF and phosphorylated VEGFR2 were expressed at a significantly high level in ICC patient tissues (P<0.05). In vitro, treating ICC cell lines RBE and SSP25 with recombinant human VEGF (rhVEGF) induced phosphorylation of VEGFR1 (pVEGFR1) and VEGFR2 (pVEGFR2); however, only the VEGFR2 played a role in the anti apoptotic cell growth through activating a PI3K-AKT-mTOR anti-apoptotic signaling pathway which generated more VEGF to enter this autocrine loop. Apatinib inhibited the anti-apoptosis induced by VEGF signaling, and promoted cell death in vitro. In addition, Apatinib treatment delayed xenograft tumor growth in vivo. In conclusion, the autocrine VEGF/VEGFR2 signaling promotes ICC cell survival. Apatinib inhibits anti-apoptotic cell growth through suppressing the autocrine VEGF signaling, supporting a potential role for using Apatinib in the treatment of ICC. PMID- 26967385 TI - Exogenous hepatitis B virus envelope proteins induce endoplasmic reticulum stress: involvement of cannabinoid axis in liver cancer cells. AB - HBV represents the most common chronic viral infection and major cause of hepatocellular carcinoma (HCC), although its exact role in liver tumorigenesis is unclear. Massive storage of the small (SHBs), middle (MHBs) and large surface (LHBs) HBV envelope proteins leads to cell stress and sustained inflammatory responses. Cannabinoid (CB) system is involved in the pathogenesis of liver diseases, stimulating acute and chronic inflammation, liver damage and fibrogenesis; it triggers endoplasmic reticulum (ER) stress response. The aim of our work was to investigate the activation of ER stress pathway after ectopic HBV envelope proteins expression, in liver cancer cells, and the role exerted by CB receptors. PCR, immunofluorescence and western blotting showed that exogenous LHBs and MHBs induce a clear ER stress response in Huh-7 cells expressing CB1 receptor. Up-regulation of the chaperone BiP/GRP78 (Binding Immunoglobulin Protein/Glucose-Regulated Protein 78) and of the transcription factor CHOP/GADD153 (C/EBP Homologous Protein/Growth Arrest and DNA Damage inducible gene 153), phosphorylation of PERK (PKR-like ER Kinase) and eIF2alpha (Eukaryotic Initiation Factor 2alpha) and splicing of XBP1 (X-box binding protein 1) was observed. CB1-/- HepG2 cells did not show any ER stress activation. Inhibition of CB1 receptor counteracted BiP expression in transfected Huh-7 and in HBV+ PLC/PRF/5 cells; whereas no effect was observed in HBV- HLF cells. These results suggest that HBV envelope proteins are able to induce the ER stress pathway. CB1 expression is directly correlated with ER stress function. Further investigations are needed to clarify the involvement of cannabinoid in HCC progression after HBV infection. PMID- 26967386 TI - The association of six polymorphisms of five genes involved in three steps of nucleotide excision repair pathways with hepatocellular cancer risk. AB - BACKGROUND: Hundreds of single nucleotide polymorphisms (SNPs) of the genes encoding nucleotide excision repair (NER) proteins are involved in every step of the DNA recognition-unwinding-incision process, which may affect cancer risk. However, only a limited number of studies have examined the association of NER SNPs with hepatocellular cancer (HCC) risk. RESULTS: In screening stage, single locus analysis showed that six SNPs in five genes were associated with HCC risk, including three risk SNPs (XPA rs10817938, XPC rs1870134 and ERCC2 rs238417) and three protective SNPs (ERCC1 rs2298881 and rs3212961, and ERCC5 rs873601). In verification stage, only XPC rs1870134 was verified to be associated with HCC risk (P = 4.7 * 10-4). Furthermore, multivariate logistic regression and MDR analysis consistently revealed a gene-gene interaction among ERCC1 rs2298881 and XPC rs1870134 SNPs associated with HCC risk (Pinteraction = 0.023). When analyzing the effect of the positive SNP on the mRNA expression, we found XPC rs1870134 GG genotype which was associated with an increased HCC risk showed lower XPC mRNA expression. METHODS: This study designed as "screening verification" experiments and included a total of 1472 participants (570 HCC patients vs. 902 controls). We explored 39 SNPs in eight genes involved in NER Pathways, including XPA, XPC, DDB2, ERCC3, ERCC2, ERCC1, ERCC4 and ERCC5, using Sequenom MassARRAY and KASPar platform. Eighty-six cases of HCC and the neighboring noncancerous tissues were subjected to the measurement of mRNA expression level of the promising gene. CONCLUSIONS: XPC promoter rs1870134 SNP and SNP-SNP interaction were associated with HCC risk. PMID- 26967387 TI - MiR-148a functions to suppress metastasis and serves as a prognostic indicator in triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) presents a major challenge in the clinic due to its lack of reliable prognostic markers and targeted therapies. Accumulating evidence strongly supports the notion that microRNAs (miRNAs) are involved in tumorigenesis and could serve as biomarkers for diagnostic purposes. To identify miRNAs that functionally suppress metastasis of TNBC, we employed a concerted approach with selecting miRNAs that display differential expression profiles from bioinformatic analyses of breast cancer patient databases and validating top candidates with functional assays using breast cancer cell lines and mouse models. We have found that miR-148a exhibits properties as a tumor suppressor as its expression is inversely correlated with the ability of both human and mouse breast cancer cells to colonize the lung in mouse xenograft tumor models. Mechanistically, miR-148a appears to suppress the extravasation process of cancer cells, likely by targeting two genes WNT1 and NRP1 in a cell non-autonomous manner. Importantly, lower expression of miR-148a is detected in higher-grade tumor samples and correlated with increased likelihood to develop metastases and poor prognosis in subsets of breast cancer patients, particularly those with TNBC. Thus, miR-148a is functionally defined as a suppressor of breast cancer metastasis and may serve as a prognostic biomarker for this disease. PMID- 26967388 TI - Antibody-based targeting of alternatively spliced tissue factor: a new approach to impede the primary growth and spread of pancreatic ductal adenocarcinoma. AB - Alternatively spliced Tissue Factor (asTF) is a secreted form of Tissue Factor (TF), the trigger of blood coagulation whose expression levels are heightened in several forms of solid cancer, including pancreatic ductal adenocarcinoma (PDAC). asTF binds to beta1 integrins on PDAC cells, whereby it promotes tumor growth, metastatic spread, and monocyte recruitment to the stroma. In this study, we determined if targeting asTF in PDAC would significantly impact tumor progression. We here report that a novel inhibitory anti-asTF monoclonal antibody curtails experimental PDAC progression. Moreover, we show that tumor-derived asTF is able to promote PDAC primary growth and spread during early as well as later stages of the disease. This raises the likelihood that asTF may comprise a viable target in early- and late-stage PDAC. In addition, we show that TF expressed by host cells plays a significant role in PDAC spread. Together, our data demonstrate that targeting asTF in PDAC is a novel strategy to stem PDAC progression and spread. PMID- 26967389 TI - Genetic variants of lncRNA HOTAIR contribute to the risk of osteosarcoma. AB - Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents and young adults. However, the essential mechanisms underlying osteosarcomagenesis remain obscure. The HOTAIR, a well-known long noncoding RNA (lncRNA), is involved in pathogenesis and progress of multiple tumors. To reveal the potential role of lncRNA HOTAIR in OS carcinogenesis, we conducted a two stage, case-control study among Chinese population with 900 OS cases and 900 controls to evaluated associations of its genetic variants with OS risk. We found that C allele of rs7958904 was associated with a significantly decreased OS risk when compared with G allele (OR: 0.77; 95% CI: 0.67-0.90; P = 6.77*10-4). Functional analyses on HOTAIR Expression showed that the expression level of HOTAIR in OS tissues was significantly higher than that in corresponding normal tissues, and subjects with the rs7958904 CC genotype had significantly lower HOTAIR RNA levels than those of other genotypes. This should be the first study to examine the association between HOTAIR variants and OS risk. PMID- 26967390 TI - Granulocyte-like myeloid derived suppressor cells (G-MDSC) are increased in multiple myeloma and are driven by dysfunctional mesenchymal stem cells (MSC). AB - Granulocytic-Myeloid-derived suppressor cells (G-MDSC) are increased in Multiple Myeloma (MM) patients but the mechanisms of G-MDSC generation are still unknown. There are many evidences of the role of mesenchymal stem cells (MSC) in promoting MM cell growth, survival and drug-resistance. We here used a specific experimental model in vitro to evaluate the ability of MSC to induce G-MDSC. We found that although MSC derived from healthy donors (HD), MGUS and MM were able to generate the same amount of MDSC, only MM-MSC-educated G-MDSC exhibited suppressive ability. In addition, in comparison with MSC derived from HD, MM-MSC produce higher amount of immune-modulatory factors that could be involved in MDSC induction. Compared to G-MDSC obtained from co-culture models with MSC from healthy subjects, both MGUS and MM-MSC-educated G-MDSC showed increase of immune modulatory factors. However, only MM-MSC educated G-MDSC 1) up-regulated immune suppressive factors as ARG1 and TNFalpha, 2) expressed higher levels of PROK2, important in angiogenesis and inflammatory process, and 3) showed ability to digest bone matrix.Our data demonstrate that MM-MSC are functionally different from healthy subjects and MGUS-MSC, supporting an evolving concept regarding the contribution of MM-MSC to tumor development and progression. PMID- 26967392 TI - RalA, a GTPase targeted by miR-181a, promotes transformation and progression by activating the Ras-related signaling pathway in chronic myelogenous leukemia. AB - BCR/ABL is a well-known activator of multiple signaling pathways. RalA, a Ras downstream signaling molecule and a small GTPase, plays an important role in Bcr Abl-induced leukemogenesis but the exact mechanism remains elusive. Here, we show that RalA GTPase activity is commonly high in chronic myelogenous leukemia (CML) cell lines and patient samples. Overexpression of RalA results in malignant transformation and progression, and induces resistance to imatinib (IM) in BaF3 and K562 cell lines. RalA reduced survival and led to IM resistance in a xenografted mouse model. Ablation of RalA by either siRNA or miR-181a, a RalA targeting microRNA, attenuated the malignant phenotypes in K562 cells. RBC8, a selective Ral inhibitor, enhanced the inhibitory effects of IM in K562, KCL22 and BaF3-P210 cells. Interestingly, the phospho-specific protein microarray assay revealed that multiple phosphorylation signal proteins were decreased by RalA inhibition, including SAPK, JNK, SRC, VEGFR2, P38 MAPK, c-Kit, JunB, and Keratin18. Among them, P38 MAPK and SAPK/JNK are Ras downstream signaling kinases. Taken together, RalA GTPase might be an important oncogene activating the Ras-related signaling pathway in CML. PMID- 26967391 TI - Tenascin-C serum levels and its prognostic power in non-small cell lung cancer. AB - BACKGROUND: Tenascin-C is overexpressed in the stroma of most solid malignancies and may function as a diagnostic tumor marker. This study was conducted to evaluate the potential significance of Tenascin-C as a predictive marker for tumor progression in the sera of non-small cell lung cancer (NSCLC) patients. RESULTS: Serum concentration of Tenascin-C is significantly elevated in NSCLC patients compared to healthy controls (p=0.013). The sensitivity of Tenascin-C in detecting NSCLC was 74% at a specificity of 57%. Elevated Tenascin-C serum values are associated with larger tumor size and lymph node involvement (p=0.022 and p=0.036, respectively). The Kaplan-Meyer-curves showed a significant association of Tenascin-C with the patient's overall survival (p=0.004), but not with the recurrence-free survival (p=0.328). METHODS: We quantified Tenascin-C in the sera of 103 NSCLC patients and 76 healthy blood donors by enzyme-linked immune absorbance assay tests. Prognostic significance was determined by area under the curve analysis and Youden-index. The results were correlated with clinical, histopathological, and patient survival data (Chi-square test, Kaplan-Meier analysis, log-rank test, multivariate Cox-regression analysis). CONCLUSION: Although significantly elevated in patients with NSCLC, the sensitivity and specificity of the Tenascin-C serum quantification test was low. However, although failing to be an independent prognosticator in multivariate analysis, the results implicate Tenascin-C as a predictive prognostic marker for NSCLC patients. The data must be further validated in future prospective trials with larger patient cohorts. PMID- 26967393 TI - Loss of SOCS3 in myeloid cells prolongs survival in a syngeneic model of glioma. AB - In glioma, microglia and macrophages are the largest population of tumor infiltrating cells, referred to as glioma associated macrophages (GAMs). Herein, we sought to determine the role of Suppressor of Cytokine Signaling 3 (SOCS3), a negative regulator of Signal Transducer and Activator of Transcription 3 (STAT3), in GAM functionality in glioma. We utilized a conditional model in which SOCS3 deletion is restricted to the myeloid cell population. We found that SOCS3 deficient bone marrow-derived macrophages display enhanced and prolonged expression of pro-inflammatory M1 cytokines when exposed to glioma tumor cell conditioned medium in vitro. Moreover, we found that deletion of SOCS3 in the myeloid cell population delays intracranial tumor growth and increases survival of mice bearing orthotopic glioma tumors in vivo. Although intracranial tumors from mice with SOCS3-deficient myeloid cells appear histologically similar to control mice, we observed that loss of SOCS3 in myeloid cells results in decreased M2 polarized macrophage infiltration in the tumors. Furthermore, loss of SOCS3 in myeloid cells results in increased CD8+ T-cell and decreased regulatory T-cell infiltration in the tumors. These findings demonstrate a beneficial effect of M1 polarized macrophages on suppressing glioma tumor growth, and highlight the importance of immune cells in the tumor microenvironment. PMID- 26967396 TI - Editorial Reminders. PMID- 26967397 TI - Mode Dependency of Quantum Decoherence Studied via an Aharonov-Bohm Interferometer. AB - We investigate the dependence of decoherence on the mode number M in a multiple mode Aharonov-Bohm (AB) interferometer. The design of the AB interferometer allows us to precisely determine M by the additivity rule of ballistic conductors; meanwhile, the decoherence rate is simultaneously deduced by the variance of the AB oscillation amplitude. The AB amplitude decreases and fluctuates with depopulating M. Moreover, the normalized amplitude exhibits a maximum at a specific M (~9). Data analysis reveals that the charge-fluctuation induced dephasing, which depends on the geometry and the charge relaxation resistance of the system, could play an essential role in the decoherence process. Our results suggest that the phase coherence, in principle, can be optimized using a deliberated design and pave one of the ways toward the engineering of quantum coherence. PMID- 26967394 TI - EVI1 promotes cell proliferation in HBx-induced hepatocarcinogenesis as a critical transcription factor regulating lncRNAs. AB - The involvement of the hepatitis B virus X (HBx) protein in epigenetic modifications during hepatocarcinogenesis has been previously characterized. Long noncoding RNAs (lncRNAs), a kind of epigenetic regulator molecules, have also been shown to play crucial roles in HBx-related hepatocellular carcinoma (HCC). In this study, we analyzed the key transcription factors of aberrantly expressed lncRNAs in the livers of HBx transgenic mice by bioinformatics prediction, and found that ecotropic viral integration site 1 (Evi1) was a potential main transcription regulator. Further investigation showed that EVI1 was positively correlated to HBx expression and was frequently up-regulated in HBV-related HCC tissues. The forced expression of HBx in liver cell lines resulted in a significant increase of the expression of EVI1. Furthermore, suppression of EVI1 expression decreased the proliferation of HCC cells overexpressing HBx in vitro and in vivo. CONCLUSION: Our findings suggest that EVI1 is frequently up regulated and regulates a cluster of lncRNAs in HBV-related hepatocellular carcinoma (HCC). These findings highlight a novel mechanism for HBx-induced hepatocarcinogenesis through transcription factor EVI1 and its target lncRNAs, and provide a potential new approach to predict the functions of lncRNAs. PMID- 26967395 TI - Dephosphorylation and mitochondrial translocation of cofilin sensitizes human leukemia cells to cerulenin-induced apoptosis via the ROCK1/Akt/JNK signaling pathway. AB - In this study, we determined that cerulenin, a natural product inhibitor of fatty acid synthase, induces mitochondrial injury and apoptosis in human leukemia cells through the mitochondrial translocation of cofilin. Only dephosphorylated cofilin could translocate to mitochondria during cerulenin-induced apoptosis. Disruption of the ROCK1/Akt/JNK signaling pathway plays a critical role in the cerulenin mediated dephosphorylation and mitochondrial translocation of cofilin and apoptosis. In vivo studies demonstrated that cerulenin-mediated inhibition of tumor growth in a mouse xenograft model of leukemia was associated with mitochondrial translocation of cofilin and apoptosis. These data are consistent with a hierarchical model in which induction of apoptosis by cerulenin primarily results from activation of ROCK1, inactivation of Akt, and activation of JNK. This leads to the dephosphorylation and mitochondrial translocation of cofilin and culminates with cytochrome c release, caspase activation, and apoptosis. Our study has revealed a novel role of cofilin in the regulation of mitochondrial injury and apoptosis and suggests that cerulenin is a potential drug for the treatment of leukemia. PMID- 26967398 TI - Converting Nonclassicality into Entanglement. AB - Quantum mechanics exhibits a wide range of nonclassical features, of which entanglement in multipartite systems takes a central place. In several specific settings, it is well known that nonclassicality (e.g., squeezing, spin squeezing, coherence) can be converted into entanglement. In this work, we present a general framework, based on superposition, for structurally connecting and converting nonclassicality to entanglement. In addition to capturing the previously known results, this framework also allows us to uncover new entanglement convertibility theorems in two broad scenarios, one which is discrete and one which is continuous. In the discrete setting, the classical states can be any finite linearly independent set. For the continuous setting, the pertinent classical states are "symmetric coherent states," connected with symmetric representations of the group SU(K). These results generalize and link convertibility properties from the resource theory of coherence, spin coherent states, and optical coherent states, while also revealing important connections between local and nonlocal pictures of nonclassicality. PMID- 26967399 TI - Thermodynamics of Weakly Measured Quantum Systems. AB - We consider continuously monitored quantum systems and introduce definitions of work and heat along individual quantum trajectories that are valid for coherent superposition of energy eigenstates. We use these quantities to extend the first and second laws of stochastic thermodynamics to the quantum domain. We illustrate our results with the case of a weakly measured driven two-level system and show how to distinguish between quantum work and heat contributions. We finally employ quantum feedback control to suppress detector backaction and determine the work statistics. PMID- 26967400 TI - Efficient Quantum Compression for Ensembles of Identically Prepared Mixed States. AB - We present one-shot compression protocols that optimally encode ensembles of N identically prepared mixed states into O(logN) qubits. In contrast to the case of pure-state ensembles, we find that the number of encoding qubits drops down discontinuously as soon as a nonzero error is tolerated and the spectrum of the states is known with sufficient precision. For qubit ensembles, this feature leads to a 25% saving of memory space. Our compression protocols can be implemented efficiently on a quantum computer. PMID- 26967401 TI - Parallel Transport Quantum Logic Gates with Trapped Ions. AB - We demonstrate single-qubit operations by transporting a beryllium ion with a controlled velocity through a stationary laser beam. We use these to perform coherent sequences of quantum operations, and to perform parallel quantum logic gates on two ions in different processing zones of a multiplexed ion trap chip using a single recycled laser beam. For the latter, we demonstrate individually addressed single-qubit gates by local control of the speed of each ion. The fidelities we observe are consistent with operations performed using standard methods involving static ions and pulsed laser fields. This work therefore provides a path to scalable ion trap quantum computing with reduced requirements on the optical control complexity. PMID- 26967402 TI - Rapid Adiabatic Preparation of Injective Projected Entangled Pair States and Gibbs States. AB - We propose a quantum algorithm for many-body state preparation. It is especially suited for injective projected entangled pair states and thermal states of local commuting Hamiltonians on a lattice. We show that for a uniform gap and sufficiently smooth paths, an adiabatic runtime and circuit depth of O(polylogN) can be achieved for O(N) spins. This is an almost exponential improvement over previous bounds. The total number of elementary gates scales as O(NpolylogN). This is also faster than the best known upper bound of O(N^{2}) on the mixing times of Monte Carlo Markov chain algorithms for sampling classical systems in thermal equilibrium. PMID- 26967404 TI - X-ray Echo Spectroscopy. AB - X-ray echo spectroscopy, a counterpart of neutron spin echo, is being introduced here to overcome limitations in spectral resolution and weak signals of the traditional inelastic x-ray scattering (IXS) probes. An image of a pointlike x ray source is defocused by a dispersing system comprised of asymmetrically cut specially arranged Bragg diffracting crystals. The defocused image is refocused into a point (echo) in a time-reversal dispersing system. If the defocused beam is inelastically scattered from a sample, the echo signal acquires a spatial distribution, which is a map of the inelastic scattering spectrum. The spectral resolution of the echo spectroscopy does not rely on the monochromaticity of the x rays, ensuring strong signals along with a very high spectral resolution. Particular schemes of x-ray echo spectrometers for 0.1-0.02 meV ultrahigh resolution IXS applications (resolving power >10^{8}) with broadband ?5-13 meV dispersing systems are introduced featuring more than 10^{3} signal enhancement. The technique is general, applicable in different photon frequency domains. PMID- 26967403 TI - Universality in the Dynamics of Second-Order Phase Transitions. AB - When traversing a symmetry-breaking second-order phase transition at a finite rate, topological defects form whose number dependence on the quench rate is given by simple power laws. We propose a general approach for the derivation of such scaling laws that is based on the analytical transformation of the associated equations of motion to a universal form rather than employing plausible physical arguments. We demonstrate the power of this approach by deriving the scaling of the number of topological defects in both homogeneous and nonhomogeneous settings. The general nature and extensions of this approach are discussed. PMID- 26967405 TI - Neutrino Cloud Instabilities Just above the Neutrino Sphere of a Supernova. AB - Most treatments of neutrino flavor evolution, above a surface of the last scattering, take identical angular distributions on this surface for the different initial (unmixed) flavors, and for particles and antiparticles. Differences in these distributions must be present, as a result of the species dependent scattering cross sections lower in the star. These lead to a new set of nonlinear equations, unstable even at the initial surface with respect to perturbations that break all-over spherical symmetry. There could be important consequences for explosion dynamics as well as for the neutrino pulse in the outer regions. PMID- 26967406 TI - Cosmic Explosions, Life in the Universe, and the Cosmological Constant. AB - Gamma-ray bursts (GRBs) are copious sources of gamma rays whose interaction with a planetary atmosphere can pose a threat to complex life. Using recent determinations of their rate and probability of causing massive extinction, we explore what types of universes are most likely to harbor advanced forms of life. We use cosmological N-body simulations to determine at what time and for what value of the cosmological constant (Lambda) the chances of life being unaffected by cosmic explosions are maximized. Life survival to GRBs favors Lambda-dominated universes. Within a cold dark matter model with a cosmological constant, the likelihood of life survival to GRBs is governed by the value of Lambda and the age of the Universe. We find that we seem to live in a favorable point in this parameter space that minimizes the exposure to cosmic explosions, yet maximizes the number of main sequence (hydrogen-burning) stars around which advanced life forms can exist. PMID- 26967408 TI - Quantum Phase Transition between a Topological and a Trivial Semimetal from Holography. AB - We present a holographic model of a topological Weyl semimetal. A key ingredient is a time-reversal breaking parameter and a mass deformation. Upon varying the ratio of mass to time-reversal breaking parameter the model undergoes a quantum phase transition from a topologically nontrivial semimetal to a trivial one. The topological nontrivial semimetal is characterized by the presence of an anomalous Hall effect. The results can be interpreted in terms of the holographic renormalization group (RG) flow leading to restoration of time reversal at the end point of the RG flow in the trivial phase. PMID- 26967407 TI - Exact Bremsstrahlung Function in N=2 Superconformal Field Theories. AB - We propose an exact formula for the energy radiated by an accelerating quark in N=2 superconformal theories in four dimensions. This formula reproduces the known bremsstrahlung function for N=4 theories and provides a prediction for all the perturbative and instanton corrections in N=2 theories. We perform a perturbative check of our proposal up to three loops. PMID- 26967409 TI - Perturbed Lepton-Specific Two-Higgs-Doublet Model Facing Experimental Hints for Physics beyond the Standard Model. AB - BABAR, Belle, and LHCb Collaborations report evidence for new physics in B >Dtaunu and B->D^{*}taunu of approximately 3.8sigma. There is also the long lasting discrepancy of about 3sigma in the anomalous magnetic moment of the muon, and the branching ratio for tau->MUnunu is 1.8sigma (2.4sigma) above the standard model expectation using the HFAG (PDG) values. Furthermore, CMS Collaboration finds hints for a nonzero decay rate of h->MUtau. Interestingly, all these observations can be explained by introducing new scalars. In this Letter we consider these processes within a lepton-specific two-Higgs doublet model (i.e., of type X) with additional nonstandard Yukawa couplings. It is found that one can accommodate tau->MUnunu with modified Higgs-tau couplings. The anomalous magnetic moment of the muon can be explained if the additional neutral CP-even Higgs boson H is light (below 100 GeV). Also R(D) and R(D^{*}) can be easily explained by additional t-c-Higgs couplings. Combining these t-c couplings with a light H the decay rate for t->Hc can be in a testable range for the LHC. Effects in h->MUtau are also possible, but in this case a simultaneous explanation of the anomalous magnetic moment of the muon is difficult due to the unavoidable tau->MUgamma decay. PMID- 26967410 TI - Measurement of Electron Neutrino Quasielastic and Quasielasticlike Scattering on Hydrocarbon at ?E_{nu}?=3.6 GeV. AB - The first direct measurement of electron neutrino quasielastic and quasielasticlike scattering on hydrocarbon in the few-GeV region of incident neutrino energy has been carried out using the MINERvA detector in the NuMI beam at Fermilab. The flux-integrated differential cross sections in the electron production angle, electron energy, and Q^{2} are presented. The ratio of the quasielastic, flux-integrated differential cross section in Q^{2} for nu_{e} with that of similarly selected nu_{MU}-induced events from the same exposure is used to probe assumptions that underpin conventional treatments of charged-current nu_{e} interactions used by long-baseline neutrino oscillation experiments. The data are found to be consistent with lepton universality and are well described by the predictions of the neutrino event generator GENIE. PMID- 26967413 TI - High-Precision Differential Predictions for Top-Quark Pairs at the LHC. AB - We present the first complete next-to-next-to-leading order (NNLO) QCD predictions for differential distributions in the top-quark pair production process at the LHC. Our results are derived from a fully differential partonic Monte Carlo calculation with stable top quarks which involves no approximations beyond the fixed-order truncation of the perturbation series. The NNLO corrections improve the agreement between existing LHC measurements [V. Khachatryan et al. (CMS Collaboration), Eur. Phys. J. C 75, 542 (2015)] and standard model predictions for the top-quark transverse momentum distribution, thus helping alleviate one long-standing discrepancy. The shape of the top-quark pair invariant mass distribution turns out to be stable with respect to radiative corrections beyond NLO which increases the value of this observable as a place to search for physics beyond the standard model. The results presented here provide essential input for parton distribution function fits, implementation of higher order effects in Monte Carlo generators, as well as top-quark mass and strong coupling determination. PMID- 26967414 TI - Hamiltonian Effective Field Theory Study of the N^{*}(1535) Resonance in Lattice QCD. AB - Drawing on experimental data for baryon resonances, Hamiltonian effective field theory (HEFT) is used to predict the positions of the finite-volume energy levels to be observed in lattice QCD simulations of the lowest-lying J^{P}=1/2^{-} nucleon excitation. In the initial analysis, the phenomenological parameters of the Hamiltonian model are constrained by experiment and the finite-volume eigenstate energies are a prediction of the model. The agreement between HEFT predictions and lattice QCD results obtained on volumes with spatial lengths of 2 and 3 fm is excellent. These lattice results also admit a more conventional analysis where the low-energy coefficients are constrained by lattice QCD results, enabling a determination of resonance properties from lattice QCD itself. Finally, the role and importance of various components of the Hamiltonian model are examined. PMID- 26967415 TI - Subradiance in a Large Cloud of Cold Atoms. AB - Since Dicke's seminal paper on coherence in spontaneous radiation by atomic ensembles, superradiance has been extensively studied. Subradiance, on the contrary, has remained elusive, mainly because subradiant states are weakly coupled to the environment and are very sensitive to nonradiative decoherence processes. Here, we report the experimental observation of subradiance in an extended and dilute cold-atom sample containing a large number of particles. We use a far detuned laser to avoid multiple scattering and observe the temporal decay after a sudden switch-off of the laser beam. After the fast decay of most of the fluorescence, we detect a very slow decay, with time constants as long as 100 times the natural lifetime of the excited state of individual atoms. This subradiant time constant scales linearly with the cooperativity parameter, corresponding to the on-resonance optical depth of the sample, and is independent of the laser detuning, as expected from a coupled-dipole model. PMID- 26967416 TI - Temporal Structure of Attosecond Pulses from Laser-Driven Coherent Synchrotron Emission. AB - The microscopic dynamics of laser-driven coherent synchrotron emission transmitted through thin foils are investigated using particle-in-cell simulations. For normal incidence interactions, we identify the formation of two distinct electron nanobunches from which emission takes place each half-cycle of the driving laser pulse. These emissions are separated temporally by 130 as and are dominant in different frequency ranges, which is a direct consequence of the distinct characteristics of each electron nanobunch. This may be exploited through spectral filtering to isolate these emissions, generating electromagnetic pulses of duration ~70 as. PMID- 26967417 TI - Photon Thermal Hall Effect. AB - A near-field thermal Hall effect (i.e., Righi-Leduc effect) in networks of magneto-optical particles placed in a constant magnetic field is predicted. This many-body effect is related to a symmetry breaking in the system induced by the magnetic field, which gives rise to preferential channels for the heat transport by near-field interaction thanks to the particle's anisotropy tuning. PMID- 26967418 TI - Stellarator Turbulence: Subdominant Eigenmodes and Quasilinear Modeling. AB - Owing to complex geometry, gyrokinetic simulations in stellarator geometry produce large numbers of subdominant unstable and stable, near-orthogonal eigenmodes. Here, results based on the full eigenmode spectrum in stellarator geometry are presented for the first time. In the nonlinear state of a low magnetic-shear ion-temperature-gradient-driven case, a multitude of these modes are active and imprint the system. Turbulent frequency spectra are broadband as a consequence, in addition to a nonlinear, narrow signature at electron frequencies. It is shown that successful quasilinear, mixing-length transport modeling is possible in stellarators, where it is essential to account for all subdominant unstable modes. PMID- 26967420 TI - Strongly Emitting Surfaces Unable to Float below Plasma Potential. AB - An important unresolved question in plasma physics concerns the effect of strong electron emission on plasma-surface interactions. Previous papers reported solutions with negative and positive floating potentials relative to the plasma edge. The two models give very different predictions for particle and energy balance. Here we show that the positive potential state is the only possible equilibrium in general. Even if a negative floating potential existed at t=0, the ionization collisions near the surface will force a transition to the positive floating potential state. This transition is demonstrated with a new simulation code. PMID- 26967419 TI - Microengineering Laser Plasma Interactions at Relativistic Intensities. AB - We report on the first successful proof-of-principle experiment to manipulate laser-matter interactions on microscales using highly ordered Si microwire arrays. The interaction of a high-contrast short-pulse laser with a flat target via periodic Si microwires yields a substantial enhancement in both the total and cutoff energies of the produced electron beam. The self-generated electric and magnetic fields behave as an electromagnetic lens that confines and guides electrons between the microwires as they acquire relativistic energies via direct laser acceleration. PMID- 26967421 TI - Synchronized Ion Acceleration by Ultraintense Slow Light. AB - An effective scheme of synchronized laser-triggered ion acceleration and the corresponding theoretical model are proposed for a slow light pulse of relativistic intensity, which penetrates into a near-critical-density plasma, strongly slows, and then increases its group velocity during propagation within a target. The 3D particle-in-cell simulations confirm this concept for proton acceleration by a femtosecond petawatt-class laser pulse experiencing relativistic self-focusing, quantify the characteristics of the generated protons, and demonstrate a significant increase of their energy compared with the proton energy generated from optimized ultrathin solid dense foils. PMID- 26967422 TI - Stable Core Symmetries and Confined Textures for a Vortex Line in a Spinor Bose Einstein Condensate. AB - We show how a singly quantized vortex can exhibit energetically stable defect cores with different symmetries in an atomic spin-1 polar Bose-Einstein condensate, and how a stable topologically nontrivial Skyrmion texture of lower dimensionality can be confined inside the core. The core isotropy and the stability of the confined texture are sensitive to Zeeman level shifts. The observed structures have analogies, respectively, in pressure-dependent symmetries of superfluid liquid ^{3}He vortices and in the models of superconducting cosmic strings. PMID- 26967423 TI - Mechanical Yield in Amorphous Solids: A First-Order Phase Transition. AB - Amorphous solids yield at a critical value of the strain (in strain-controlled experiments); for larger strains, the average stress can no longer increase-the system displays an elastoplastic steady state. A long-standing riddle in the materials community is what the difference is between the microscopic states of the material before and after yield. Explanations in the literature are material specific, but the universality of the phenomenon begs a universal answer. We argue here that there is no fundamental difference in the states of matter before and after yield, but the yield is a bona fide first-order phase transition between a highly restricted set of possible configurations residing in a small region of phase space to a vastly rich set of configurations which include many marginally stable ones. To show this, we employ an order parameter of universal applicability, independent of the microscopic interactions, that is successful in quantifying the transition in an unambiguous manner. PMID- 26967424 TI - Elasticity in Amorphous Solids: Nonlinear or Piecewise Linear? AB - Quasistatic strain-controlled measurements of stress versus strain curves in macroscopic amorphous solids result in a nonlinear-looking curve that ends up either in mechanical collapse or in a steady state with fluctuations around a mean stress that remains constant with increasing strain. It is therefore very tempting to fit a nonlinear expansion of the stress in powers of the strain. We argue here that at low temperatures the meaning of such an expansion needs to be reconsidered. We point out the enormous difference between quenched and annealed averages of the stress versus strain curves and propose that a useful description of the mechanical response is given by a stress (or strain) -dependent shear modulus for which a theoretical evaluation exists. The elastic response is piecewise linear rather than nonlinear. PMID- 26967425 TI - Short-Time Beta Relaxation in Glass-Forming Liquids Is Cooperative in Nature. AB - Temporal relaxation of density fluctuations in supercooled liquids near the glass transition occurs in multiple steps. Using molecular dynamics simulations for three model glass-forming liquids, we show that the short-time beta relaxation is cooperative in nature. Using finite-size scaling analysis, we extract a growing length scale associated with beta relaxation from the observed dependence of the beta relaxation time on the system size. We find, in qualitative agreement with the prediction of the inhomogeneous mode coupling theory, that the temperature dependence of this length scale is the same as that of the length scale that describes the spatial heterogeneity of local dynamics in the long-time alpha relaxation regime. PMID- 26967426 TI - Enhanced Configurational Entropy in High-Density Nanoconfined Bilayer Ice. AB - A novel kind of crystal order in high-density nanoconfined bilayer ice is proposed from molecular dynamics and density-functional theory simulations. A first-order transition is observed between a low-temperature proton-ordered solid and a high-temperature proton-disordered solid. The latter is shown to possess crystalline order for the oxygen positions, arranged on a close-packed triangular lattice with AA stacking. Uniquely among the ice phases, the triangular bilayer is characterized by two levels of disorder (for the bonding network and for the protons) which results in a configurational entropy twice that of bulk ice. PMID- 26967427 TI - Correlations between In Situ Conductivity and Uniform-Height Epitaxial Morphology in Pb/Si(111)-(7*7). AB - The growth of Pb on Si(111)-(7*7) at temperatures from 72 to 201 K has been investigated using in situ electrical resistivity measurements and scanning tunneling microscopy. For temperatures T>140 K the specific resistivity rho(theta) versus coverage theta shows an unusual "hump," instead of the expected monotonic decrease with theta. This novel result correlates well with the formation of uniform height eight-layer Pb islands and the superdiffusive motion of the wetting layer, despite the low temperatures. A model of the film resistivity as two resistors in series, the amorphous wetting layer and the crystalline islands, explains quantitatively the resistivity dependence on theta. PMID- 26967428 TI - Clustering of Oxygen Vacancies at CeO2(111): Critical Role of Hydroxyls. AB - By performing density functional theory calculations corrected by an on site Coulomb interaction, we find that the defects at the CeO_{2}(111) surface observed by the scanning tunneling microscopy (STM) measurements of Esch et al. [Science 309, 752 (2005)] are not mere oxygen vacancies or fluorine impurities as suggested by Kullgren et al. [Phys. Rev. Lett. 112, 156102 (2014)], but actually the hydroxyl-vacancy combined species. Specifically, we show that hydroxyls play a critical role in the formation and propagation of oxygen vacancy clusters (VCs). In the presence of neighboring hydroxyls, the thermodynamically unstable VCs can be significantly stabilized, and the behaviors of oxygen vacancies become largely consistent with the STM observations. In addition to the clarification of the long term controversy on the surface defect structures of CeO_{2}(111), the "hydroxyl-vacancy model" proposed in this work emphasizes the coexistence of hydroxyls and oxygen vacancies, especially VCs, which is important for understanding the catalytic and other physicochemical properties of reducible metal oxides. PMID- 26967429 TI - Using Nonequilibrium Dynamics to Probe Competing Orders in a Mott-Peierls System. AB - Competition between ordered phases, and their associated phase transitions, are significant in the study of strongly correlated systems. Here, we examine one aspect, the nonequilibrium dynamics of a photoexcited Mott-Peierls system, using an effective Peierls-Hubbard model and exact diagonalization. Near a transition where spin and charge become strongly intertwined, we observe antiphase dynamics and a coupling-strength-dependent suppression or enhancement in the static structure factors. The renormalized bosonic excitations coupled to a particular photoexcited electron can be extracted, which provides an approach for characterizing the underlying bosonic modes. The results from this analysis for different electronic momenta show an uneven softening due to a stronger coupling near k_{F}. This behavior reflects the strong link between the fermionic momenta, the coupling vertices, and ultimately, the bosonic susceptibilities when multiple phases compete for the ground state of the system. PMID- 26967430 TI - Calculation of Electrochemical Energy Levels in Water Using the Random Phase Approximation and a Double Hybrid Functional. AB - Understanding charge transfer at electrochemical interfaces requires consistent treatment of electronic energy levels in solids and in water at the same level of the electronic structure theory. Using density-functional-theory-based molecular dynamics and thermodynamic integration, the free energy levels of six redox couples in water are calculated at the level of the random phase approximation and a double hybrid density functional. The redox levels, together with the water band positions, are aligned against a computational standard hydrogen electrode, allowing for critical analysis of errors compared to the experiment. It is encouraging that both methods offer a good description of the electronic structures of the solutes and water, showing promise for a full treatment of electrochemical interfaces. PMID- 26967431 TI - Mott Quantum Criticality in the Anisotropic 2D Hubbard Model. AB - We present evidence for Mott quantum criticality in an anisotropic two dimensional system of coupled Hubbard chains at half-filling. In this scenario emerging from variational cluster approximation and cluster dynamical mean-field theory, the interchain hopping t_{?} acts as a control parameter driving the second-order critical end point T_{c} of the metal-insulator transition down to zero at t_{?}^{c}/t?0.2. Below t_{?}^{c}, the volume of the hole and electron Fermi pockets of a compensated metal vanishes continuously at the Mott transition. Above t_{?}^{c}, the volume reduction of the pockets is cut off by a first-order transition. We discuss the relevance of our findings to a putative quantum critical point in layered organic conductors, whose location remains elusive so far. PMID- 26967432 TI - Shubnikov-de Haas Oscillations of High-Mobility Holes in Monolayer and Bilayer WSe_{2}: Landau Level Degeneracy, Effective Mass, and Negative Compressibility. AB - We study the magnetotransport properties of high-mobility holes in monolayer and bilayer WSe_{2}, which display well defined Shubnikov-de Haas (SdH) oscillations, and quantum Hall states in high magnetic fields. In both mono- and bilayer WSe_{2}, the SdH oscillations and the quantum Hall states occur predominantly at even filling factors, evincing a twofold Landau level degeneracy. The Fourier transform analysis of the SdH oscillations in bilayer WSe_{2} reveals the presence of two subbands localized in the top or the bottom layer, as well as negative compressibility. From the temperature dependence of the SdH oscillations we determine a hole effective mass of 0.45m_{0} for both mono- and bilayer WSe_{2}. PMID- 26967433 TI - Effects of Dephasing on Spin Lifetime in Ballistic Spin-Orbit Materials. AB - We theoretically investigate spin dynamics in spin-orbit-coupled materials. In the ballistic limit, the spin lifetime is dictated by dephasing that arises from energy broadening plus a nonuniform spin precession. For the case of clean graphene, we find a strong anisotropy with spin lifetimes that can be short even for modest energy scales, on the order of a few ns. These results offer deeper insight into the nature of spin dynamics in graphene, and are also applicable to the investigation of other systems where spin-orbit coupling plays an important role. PMID- 26967434 TI - Topological Protection from Random Rashba Spin-Orbit Backscattering: Ballistic Transport in a Helical Luttinger Liquid. AB - The combination of Rashba spin-orbit coupling and potential disorder induces a random current operator for the edge states of a 2D topological insulator. We prove that charge transport through such an edge is ballistic at any temperature, with or without Luttinger liquid interactions. The solution exploits a mapping to a spin 1/2 in a time-dependent field that preserves the projection along one randomly undulating component (integrable dynamics). Our result is exact and rules out random Rashba backscattering as a source of temperature-dependent transport, absent integrability-breaking terms. PMID- 26967411 TI - Observation of the Singly Cabibbo-Suppressed Decay D^{+}->omegapi^{+} and Evidence for D^{0}->omegapi^{0}. AB - Based on 2.93 fb^{-1} e^{+}e^{-} collision data taken at center-of-mass energy of 3.773 GeV by the BESIII detector, we report searches for the singly Cabibbo suppressed decays D^{+}->omegapi^{+} and D^{0}->omegapi^{0}. A double tag technique is used to measure the absolute branching fractions B(D^{+} >omegapi^{+})=(2.79+/-0.57+/-0.16)*10^{-4} and B(D^{0}->omegapi^{0})=(1.17+/ 0.34+/-0.07)*10^{-4}, with statistical significances of 5.5sigma and 4.1sigma, where the first and second uncertainties are statistical and systematic, respectively. PMID- 26967435 TI - Tunable Hybrid Qubit in a GaAs Double Quantum Dot. AB - We experimentally demonstrate a tunable hybrid qubit in a five-electron GaAs double quantum dot. The qubit is encoded in the (1,4) charge regime of the double dot and can be manipulated completely electrically. More importantly, dot anharmonicity leads to quasiparallel energy levels and a new anticrossing, which help preserve quantum coherence of the qubit and yield a useful working point. We have performed Larmor precession and Ramsey fringe experiments near the new working point and find that the qubit decoherence time is significantly improved over a charge qubit. This work shows a new way to encode a semiconductor qubit that is controllable and coherent. PMID- 26967412 TI - Evidence for Simultaneous Production of J/psi and Upsilon Mesons. AB - We report evidence for the simultaneous production of J/psi and Upsilon mesons in 8.1 fb^{-1} of data collected at sqrt[s]=1.96 TeV by the D0 experiment at the Fermilab pp[over -] Tevatron Collider. Events with these characteristics are expected to be produced predominantly by gluon-gluon interactions. In this analysis, we extract the effective cross section characterizing the initial parton spatial distribution, sigma_{eff}=2.2+/-0.7(stat)+/-0.9(syst) mb. PMID- 26967437 TI - Non-Zhang-Rice Singlet Character of the First Ionization State of T-CuO. AB - We argue that tetragonal CuO (T-CuO) has the potential to finally settle long standing modeling issues for cuprate physics. We compare the one-hole quasiparticle (qp) dispersion of T-CuO to that of cuprates, in the framework of the strongly correlated (U_{dd}->infinity) limit of the three-band Emery model. Unlike in CuO_{2}, magnetic frustration in T-CuO breaks the C_{4} rotational symmetry and leads to strong deviations from the Zhang-Rice singlet picture in parts of the reciprocal space. Our results are consistent with angle-resolved photoemission spectroscopy data but in sharp contradiction to those of a one-band model previously suggested for them. These differences identify T-CuO as an ideal material to test a variety of scenarios proposed for explaining cuprate phenomenology. PMID- 26967438 TI - Colossal Seebeck Coefficient of Hopping Electrons in (TMTSF)_{2} PF_{6}. AB - We report on a study of the Seebeck coefficient and resistivity in the quasi-one dimensional conductor (TMTSF)_{2} PF_{6} extended deep into the spin-density-wave state. The metal-insulator transition at T_{SDW}=12 K leads to a reduction in carrier concentration by 7 orders of magnitude. Below 1 K, charge transport displays the behavior known as variable range hopping. Until now, the Seebeck response of electrons in this regime has barely been explored and is even less understood. We find that, in this system, residual carriers, hopping from one trap to another, generate a Seebeck coefficient as large as 400 k_{B}/e. The results provide the first solid evidence for a long-standing prediction according to which hopping electrons in the presence of the Coulomb interaction can generate a sizable Seebeck coefficient in the zero-temperature limit. PMID- 26967436 TI - Bulk Topological Proximity Effect. AB - Existing proximity effects stem from systems with a local order parameter, such as a local magnetic moment or a local superconducting pairing amplitude. Here, we demonstrate that despite lacking a local order parameter, topological phases also may give rise to a proximity effect of a distinctively inverted nature. We focus on a general construction in which a topological phase is extensively coupled to a second system, and we argue that, in many cases, the inverse topological order will be induced on the second system. To support our arguments, we rigorously establish this "bulk topological proximity effect" for all gapped free-fermion topological phases and representative integrable models of interacting topological phases. We present a terrace construction which illustrates the phenomenological consequences of this proximity effect. Finally, we discuss generalizations beyond our framework, including how intrinsic topological order may also exhibit this effect. PMID- 26967439 TI - Static and Dynamical Properties of the Spin-1/2 Equilateral Triangular-Lattice Antiferromagnet Ba_{3}CoSb_{2}O_{9}. AB - We present single-crystal neutron scattering measurements of the spin-1/2 equilateral triangular-lattice antiferromagnet Ba_{3}CoSb_{2}O_{9}. Besides confirming that the Co^{2+} magnetic moments lie in the ab plane for zero magnetic field and then determining all the exchange parameters of the minimal quasi-2D spin Hamiltonian, we provide conclusive experimental evidence of magnon decay through observation of intrinsic line broadening. Through detailed comparisons with the linear and nonlinear spin-wave theories, we also point out that the large-S approximation, which is conventionally employed to predict magnon decay in noncollinear magnets, is inadequate to explain our experimental observation. Thus, our results call for a new theoretical framework for describing excitation spectra in low-dimensional frustrated magnets under strong quantum effects. PMID- 26967440 TI - Anomalous Magnetothermopower in a Metallic Frustrated Antiferromagnet. AB - We report the temperature T and magnetic field H dependence of the thermopower S of an itinerant triangular antiferromagnet PdCrO_{2} in high magnetic fields up to 32 T. In the paramagnetic phase, the zero-field thermopower is positive with a value typical of good metals with a high carrier density. In marked contrast to typical metals, however, S decreases rapidly with increasing magnetic field, approaching zero at the maximum field scale for T>70 K. We argue here that this profound change in the thermoelectric response derives from the strong interaction of the 4d correlated electrons of the Pd ions with the short-range spin correlations of the Cr^{3+} spins that persist beyond the Neel ordering temperature due to the combined effects of geometrical frustration and low dimensionality. PMID- 26967441 TI - Ultralow-Frequency Collective Compression Mode and Strong Interlayer Coupling in Multilayer Black Phosphorus. AB - The recent renaissance of black phosphorus (BP) as a two-dimensional (2D) layered material has generated tremendous interest, but its unique structural characters underlying many of its outstanding properties still need elucidation. Here we report Raman measurements that reveal an ultralow-frequency collective compression mode (CCM) in BP, which is unprecedented among similar 2D layered materials. This novel CCM indicates an unusually strong interlayer coupling, and this result is quantitatively supported by a phonon frequency analysis and first principles calculations. Moreover, the CCM and another branch of low-frequency Raman modes shift sensitively with changing number of layers, allowing an accurate determination of the thickness up to tens of atomic layers, which is considerably higher than previously achieved by using high-frequency Raman modes. These findings offer fundamental insights and practical tools for further exploration of BP as a highly promising new 2D semiconductor. PMID- 26967443 TI - Divergence of Voronoi Cell Anisotropy Vector: A Threshold-Free Characterization of Local Structure in Amorphous Materials. AB - Characterizing structural inhomogeneity is an essential step in understanding the mechanical response of amorphous materials. We introduce a threshold-free measure based on the field of vectors pointing from the center of each particle to the centroid of the Voronoi cell in which the particle resides. These vectors tend to point in toward regions of high free volume and away from regions of low free volume, reminiscent of sinks and sources in a vector field. We compute the local divergence of these vectors, where positive values correspond to overpacked regions and negative values identify underpacked regions within the material. Distributions of this divergence are nearly Gaussian with zero mean, allowing for structural characterization using only the moments of the distribution. We explore how the standard deviation and skewness vary with the packing fraction for simulations of bidisperse systems and find a kink in these moments that coincides with the jamming transition. PMID- 26967442 TI - Two-Dimensional Correlation of Isotropic and Directional Diffusion Using NMR. AB - Diffusion nuclear magnetic resonance (NMR) is a powerful technique for studying porous media, but yields ambiguous results when the sample comprises multiple regions with different pore sizes, shapes, and orientations. Inspired by solid state NMR techniques for correlating isotropic and anisotropic chemical shifts, we propose a diffusion NMR method to resolve said ambiguity. Numerical data inversion relies on sparse representation of the data in a basis of radial and axial diffusivities. Experiments are performed on a composite sample with a cell suspension and a liquid crystal. PMID- 26967444 TI - New X-Ray Tomography Method Based on the 3D Radon Transform Compatible with Anisotropic Sources. AB - In this work, we propose a novel computed tomography (CT) approach for three dimensional (3D) object reconstruction, based on a generalized tomographic geometry with two-dimensional angular sampling (two angular degrees of freedom). The reconstruction is based on the 3D Radon transform and is compatible with anisotropic beam conditions. This allows isotropic 3D imaging with a source, which can be extended along one direction for increased flux, while high resolution is achieved by a small source size only in the orthogonal direction. This novel scheme for analytical CT is demonstrated by numerical simulations and proof-of-concept experiments. In this way high resolution and coherence along a single direction determines the reconstruction quality of the entire 3D data set, opening up, for example, new opportunities to achieve nanoscale resolution and/or phase contrast with low brilliance sources such as laboratory x-ray or neutron sources. PMID- 26967445 TI - Transient Cooperative Processes in Dewetting Polymer Melts. AB - We compare the high velocity dewetting behavior, at elevated temperatures, of atactic polystyrene (aPS) and isotactic polystyrene (iPS) films, with the zero shear bulk viscosity (eta_{bulk}) of aPS being approximately ten times larger than iPS. As expected, for aPS the apparent viscosity of the films (eta_{f}) derived from high-shear dewetting is less than eta_{bulk}, displaying a shear thinning behavior. Surprisingly, for iPS films, eta_{f} is always larger than eta_{bulk}, even at about 50 degrees C above the melting point, with eta_{f}/eta_{bulk} following an Arrhenius behavior. The corresponding activation energy of ~160+/-10 kJ/mol for iPS films suggests a cooperative motion of segments which are aligned and agglomerated by fast dewetting. PMID- 26967446 TI - Erratum: Fully Device-Independent Quantum Key Distribution [Phys. Rev. Lett. 113, 140501 (2014)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.113.140501. PMID- 26967447 TI - Erratum: Impact of Tensor Force on beta Decay of Magic and Semimagic Nuclei [Phys. Rev. Lett. 110, 122501 (2013)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.110.122501. PMID- 26967448 TI - Erratum: Self-Diffusion in Amorphous Silicon [Phys. Rev. Lett. 116, 025901 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.116.025901. PMID- 26967449 TI - Erratum: Symmetry-Dependent Exciton-Phonon Coupling in 2D and Bulk MoS_{2} Observed by Resonance Raman Scattering [Phys. Rev. Lett. 114, 136403 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.114.136403. PMID- 26967450 TI - The Time to Clearance of Peripheral Blood Blasts Predicts Complete Remission and Survival in Chinese Adults with Acute Myeloid Leukemia. AB - The value of clearance of peripheral blood blasts (PBB) as a predictor of outcomes in acute myeloid leukemia (AML) is controversial. To investigate the prognostic significance of the time to clearance of PBB after induction in Chinese patients with AML, a retrospective analysis of 146 patients with newly diagnosed AML at Shanghai Ruijin Hospital was performed. Patients were categorized into early blast clearance (EBC; <=5 days) and delayed blast clearance (DBC; >5 days) groups based on a receiver operating characteristic analysis. Complete remission (CR) after induction chemotherapy was related to the time to clearance of PBB (p < 0.001). Relapse-free survival (RFS; p = 0.003) and overall survival (p < 0.001) were longer in the EBC group. Multivariate analysis demonstrated that the time to clearance of PBB and cytogenetic risk independently predicted CR and RFS. Early clearance of PBB after induction chemotherapy can be a significant predictor of survival outcomes in AML patients. PMID- 26967451 TI - Clinical Profile, Etiology, and Treatment of Chronic Pancreatitis in North American Women: Analysis of a Large Multicenter Cohort. AB - OBJECTIVE: Historically, chronic pancreatitis (CP) was considered a disease of alcoholic males, but recent data suggest its etiology to be complex. To better understand CP in women, we compared data on women and men with CP in a large, prospectively ascertained multicenter US cohort. METHODS: Patients with CP enrolled in the NAPS2 Continuation and Validation study were studied. Information on demographics, etiology, risk factors, phenotype, and treatment(s) used was obtained from detailed questionnaires completed by the patients and physicians. RESULTS: Of 521 cases, 45% were women. Women were significantly (P < 0.05) less likely to have alcohol etiology (30% vs 58.5%) and more likely to have nonalcoholic etiologies (idiopathic, 32% vs 18%; obstructive, 12% vs 2.4%; genetic, 12.8% vs 7.3%). Demographics, pain experience, morphologic findings, exocrine and endocrine insufficiency, CP-related disability, and use of medical therapies were mostly similar in both sexes. Sphincterotomy (biliary, 33% vs 24%; pancreatic, 38% vs 28%; P < 0.05) was performed more frequently in women, whereas cyst/pseudocyst operations were more common in men (6.6 vs 2.6%, P = 0.02). CONCLUSIONS: Most CP cases in women are from nonalcoholic etiologies. In contrast to many other chronic diseases, clinical phenotype of CP is determined by the disease and is independent of sex. PMID- 26967452 TI - Stromal Fibrosis and Expression of Matricellular Proteins Correlate With Histological Grade of Intraductal Papillary Mucinous Neoplasm of the Pancreas. AB - OBJECTIVE: The aim of the study was to clarify the correlation between the microenvironmental factors and histological grade in intraductal papillary mucinous neoplasm (IPMN). METHODS: We investigated 65 IPMNs resected at Yamagata University Hospital between 2000 and 2011, and all cases were categorized to low inter (including low- and intermediate-grade dysplasia) and high-inv (including high-grade dysplasia and IPMN with an associated invasive carcinoma) groups. We compared between the 2 groups pathologically with regard to fibrosis and the expression of alpha-smooth muscle actin (alpha-SMA), periostin, and galectin-1 in the periductal stroma of IPMN. RESULTS: There were 41 low-inter and 24 high-inv. The subtype was categorized as 22 main duct type (MD-IPMN) and 43 branch duct type (BD-IPMN). The degree of fibrosis and the expression of alpha-SMA, periostin, and galectin-1 were significantly higher in high-inv than in low-inter within BD-IPMNs. Multivariate logistic regression analysis indicated that high expression of alpha-SMA (odds ratio, 13.802; 95% confidence interval, 1.108 171.893; P = 0.0414) was a significant independent related factor of high-inv in BD-IPMN. CONCLUSIONS: Stromal fibrosis and expression of alpha-SMA, periostin, and galectin-1 are more marked in high-inv than in low-inter within BD-IPMNs, and they could become new markers for determining the indications for surgery in BD IPMN. PMID- 26967454 TI - Smaller Width of the Pancreatic Duct During Secretin-Enhanced Magnetic Resonance Cholangiopancreatography in Pancreatic-Sufficient Cystic Fibrosis Patients. AB - OBJECTIVES: New tools are needed in cystic fibrosis (CF) diagnostics in pancreatic-sufficient CF (PS-CF) patients. Secretin-enhanced magnetic resonance cholangiopancreatography (SE-MRCP) allows for improved assessment of the width of the pancreatic duct. METHODS: Sixteen PS-CF patients and 17 healthy volunteers underwent SE-MRCP. The width of the pancreatic duct in the head, the body, and the tail of the pancreas was measured at the baseline and 1, 2, 3, 5, and 10 minutes after secretin administration. RESULTS: The width of the pancreatic duct in the head of the pancreas did not differ between the groups at the baseline; after 10 minutes of secretin stimulation, it was smaller in PS-CF patients (median, 1.4 mm [first-third quartile, 1.3-2.0] vs 2.2 mm [1.7-2.4], P = 0.008). The area under the curve for discrimination between the 2 groups using this parameter was 0.77 (95% confidence interval, 0.60-0.93). CONCLUSIONS: The SE-MRCP identified differences in the width of the pancreatic duct between PS-CF and healthy volunteers. Further improvements of the method are needed to augment its clinical utility. PMID- 26967453 TI - Prognostic Significance of MUC-1 in Circulating Tumor Cells in Patients With Metastatic Pancreatic Adenocarcinoma. AB - OBJECTIVES: Development of targeted therapies for pancreatic cancer could be enhanced by a reliable method for noninvasive tumor cell assessment. In this pilot study, we isolated and phenotypically characterized circulating tumor cells (CTCs) from patients with metastatic pancreatic cancer and explored their relationship to clinical outcome. METHODS: Peripheral blood from 50 patients was collected at treatment initiation and first disease evaluation for CTC enumeration and phenotyping by CellSearch(r) system. Expression of human mucin 1 (MUC-1) was performed. RESULTS: Forty-eight and 37 patients had evaluable samples at baseline and first disease evaluation, respectively. The cohort was 62% male, with a median age of 63 years. At least 1 CTC per 7.5 mL was detected in 23 patients (48%) pretreatment and 11 patients (30%) at first disease evaluation. No difference was seen in overall survival between patients with 1 or more CTCs versus no CTC at baseline (P = 0.14). Patients with MUC-1 expressing CTC (n = 10) had shorter median overall survival compared with those with MUC-1 negative CTC (n = 13; 2.7 vs 9.6 m; P = 0.044). CONCLUSIONS: Circulating tumor cell enumeration and phenotypic characterization from metastatic pancreatic cancer patients are feasible. No correlation was found between CTC isolation and survival. However, the presence of MUC-1 expressing CTC demonstrated a trend toward inferior survival. PMID- 26967455 TI - Duct Diameter and Size of Stones Predict Successful Extracorporeal Shock Wave Lithotripsy and Endoscopic Clearance in Patients With Chronic Pancreatitis and Pancreaticolithiasis. AB - OBJECTIVES: The need for endoscopic therapy before extracorporeal shock wave lithotripsy (SWL) to facilitate pancreatic duct stone removal is unclear. Predictive factors associated with successful fragmentation and subsequent complete duct clearance are variable. We hypothesize pancreatic duct strictures and large stones, but not pre-SWL endotherapy, correlate with successful fragmentation and complete duct clearance. METHODS: A retrospective cohort study of patients with pancreaticolithiasis who underwent SWL and endoscopic retrograde cholangiopancreatography between January 2009 and June 2014 was evaluated. RESULTS: Thirty-seven patients were treated. Technical success (TS) of fragmentation was achieved in 22 patients (60%). Technical success was associated with fewer stones and SWL sessions and smaller stone and duct size. By multivariate logistic regression, only duct dilation was associated with TS. Endoscopic success of complete duct clearance was achieved in 29 patients (80%). Endoscopic success was more frequent with stones 12 mm or less and with successful TS. By multivariate logistic regression, stones greater than 12 mm were associated with endoscopic failure. CONCLUSIONS: Pre-SWL endotherapy does not affect stone fragmentation. Patients with a dilated duct (>8 mm) and pancreatic stones 12 mm or greater were associated with unsuccessful TS and endoscopic success, respectively, and may benefit from early referral for surgical decompression. PMID- 26967456 TI - Heterogeneity of KRAS Mutations in Pancreatic Ductal Adenocarcinoma. AB - OBJECTIVES: Activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are the most common and frequent changes observed in pancreatic cancer. This study aimed to determine the frequency and extent of intratumoral and metastatic lymph node KRAS mutation heterogeneity of resected pancreatic ductal adenocarcinoma. METHODS: Tumor tissues macrodissected from tumor centers, invasion fronts (n = 97), and lymph nodes (n = 11) were subjected to DNA extraction and mutation analysis of KRAS codons 12 and 13 by pyrosequencing. RESULTS: Activating mutations in codon 12 of KRAS were detected in 90 (92.8%) tumor centers. No mutations were detected in KRAS codon 13 in any patient. After a comparison of tumor centers and invasion fronts, intratumoral heterogeneity of KRAS was observed only in 4 (4.1%) cases. Additional invasion front tumor analysis revealed the same mutation status consistent with each tumor center. No heterogeneity was observed between primary tumors and metastatic lymph nodes. CONCLUSIONS: Intratumoral heterogeneity of the KRAS mutational status is rare in pancreatic ductal adenocarcinoma. In addition, no KRAS heterogeneity between primary tumors and metastatic lymph nodes was detected in this study. This finding is consistent with the hypothesis that oncogenic activation of KRAS is the first driver mutation in pancreatic cancer. PMID- 26967457 TI - Comparison of effectiveness of 1,064-nm Nd:YAG laser and Nd:YAG laser-IPL combination treatments in hand skin rejuvenation. AB - OBJECTIVE: Evaluation of the efficacy and side effects of neodymium-doped yttrium aluminum garnet (Nd:YAG) laser and Nd:YAG laser-intense pulsed light (IPL) combination treatments in photorejuvenations of skin of the hand, and determining their impacts on patient satisfaction. MATERIALS AND METHODS: Thirty-five female patients with signs of photoaging on the skin of their hands were included in the study. Three sessions of IPL and four sessions of Nd:YAG laser treatment were applied to the right hand in total with 2-week intervals between each session, whereas six sessions of Nd:YAG laser treatment were applied to the left hand of patients with 2-week intervals between each session. RESULTS: The patients' ages ranged between 31 and 78, and mean age was 60.77 +/- 9.48. While there was no difference in pigment distribution, fine wrinkles, coarse wrinkles, and global scores between the right and left hand prior to treatment (p > 0.05), average pigment tone score was higher in the right hand with a statistically significant difference (p < 0.05). There was greater improvement in scores of pigment distribution, fine wrinkles, sallowness, pigment tone parameters, and global score on the right hand compared to left hand, which was statistically significant (p <0.001). CONCLUSION: In rejuvenation of photoaged dorsal skin of the hand, IPL-Nd:YAG laser combination treatment surpasses Nd:YAG laser treatment. PMID- 26967458 TI - Survival and SOS response induction in ultraviolet B irradiated Escherichia coli cells with defective repair mechanisms. AB - Purpose In this paper, the contribution of different genes involved in DNA repair for both survival and SOS induction in Escherichia coli mutants exposed to ultraviolet B radiation (UVB, [wavelength range 280-315 nm]) was evaluated. Materials and methods E. coli strains defective in uvrA, oxyR, recO, recN, recJ, exoX, recB, recD or xonA genes were used to determine cell survival. All strains also had the genetic sulA::lacZ fusion, which allowed for the quantification of SOS induction through the SOS Chromotest. Results Five gene products were particularly important for survival, as follows: UvrA > RecB > RecO > RecJ > XonA. Strains defective in uvrA and recJ genes showed elevated SOS induction compared with the wild type, which remained stable for up to 240 min after UVB irradiation. In addition, E. coli strains carrying the recO or recN mutation showed no SOS induction. Conclusions The nucleotide excision and DNA recombination pathways were equally used to repair UVB-induced DNA damage in E. coli cells. The sulA gene was not turned off in strains defective in UvrA and RecJ. RecO protein was essential for processing DNA damage prior to SOS induction. In this study, the roles of DNA repair proteins and their contributions to the mechanisms that induce SOS genes in E. coli are proposed. PMID- 26967459 TI - Effects of Acupuncture in Anesthesia for Craniotomy: A Meta-Analysis. AB - BACKGROUND: Acupuncture treatment has been used in China for >2500 years, and at present it is used worldwide as a form of analgesia in patients with acute and chronic pain. Furthermore, acupuncture is regularly used not only as a single anesthetic technique but also as a supplement or in addition to general anesthesia (GA). OBJECTIVES: The aim of this systematic review and meta-analysis was to assess the level of evidence for the clinical use of acupuncture in addition to GA in patients undergoing craniotomy. DESIGN: This is a systematic review of randomized controlled trials with meta-analyses. DATA SOURCES: The literature search (PubMed, Cochrane Library, and Web of Science) yielded 56 citations, published between 1972 and March 01, 2015. No systematic review or meta-analyses on this topic matched our search criteria. Each article of any language was assessed and rated for the methodological quality of the studies, using the recommendation of the Oxford Centre for Evidence Based Medicine. Ten prospective randomized controlled clinical trials with a total of 700 patients were included. ELIGIBILITY CRITERIA: Included in the meta-analysis were studies that involved any craniotomy under GA compared with a combination of GA and acupuncture. Exclusion criteria were no acupuncture during surgery, no GA during surgery, only postoperative data available, animal studies, and low grade of evidence. RESULTS: The use of acupuncture significantly reduced the amount of volatile anesthetics during surgery (P<0.001) and led to faster extubation time (P=0.001) and postoperative patient recovery (P=0.003). In addition, significantly reduced blood levels of the brain tissue injury marker S100beta 48 hours after operation (P=0.001) and occurrence of postoperative nausea and vomiting (P=0.017) were observed. No patient studied suffered from awareness. CONCLUSIONS: The analysis suggests that the complementary use of acupuncture for craniotomy has additional analgesic effects, reduces the needed amount of volatile anesthetic, reduces the onset of postoperative nausea and vomiting, and might have protective effects on brain tissue. Our findings may stimulate future randomized controlled trials to provide definitive recommendations. PMID- 26967460 TI - The Fate of Fat Grafts in Different Recipient Areas: Subcutaneous Plane, Fat Pad, and Muscle. AB - BACKGROUND: Although fat is transplanted into several layers, including subcutaneous, fat, and muscle layers, there is little (clinical) scientific basis for these procedures. OBJECTIVE: To determine the optimal recipient layer for fat transplantation. MATERIALS AND METHODS: Fat harvested from inguinal fat pads of green fluorescent protein (GFP) mice was grafted into the subcutaneous and intramuscular planes and the fat pads of C57 mice. Specimens collected after 1, 4, 8, 12, and 16 weeks were stained with hematoxylin and eosin to determine angiogenesis and fibrosis in the grafts. The survival rate of donor adipose tissue was determined by measuring GFP expression. RESULTS: Fat was retained longer in fat pads than in subcutaneous layers of recipient mice and longer in subcutaneous than in intramuscular layers. Angiogenesis and vascularized connective tissue were greater in intramuscular than in subcutaneous or fat grafts. Neovascularization, however, was similar in fat pads and subcutaneous grafts. Survival rate was higher for intramuscularly injected fat than subcutaneously and fat pad injected fat. CONCLUSION: Fat pad injection showed the highest graft retention rate, indicating that fat pads maybe the optimal area for fat transplantation. The increased blood supply to muscle suggests that intramuscular injection maybe optimal when there is little movement. PMID- 26967461 TI - Commentary on a Randomized Placebo-Controlled, Double-Blind, Half-Head Study to Assess the Efficacy of Platelet-Rich Plasma on the Treatment of Androgenetic Alopecia. PMID- 26967463 TI - Amyloid-beta and alpha-Synuclein Decrease the Level of Metal-Catalyzed Reactive Oxygen Species by Radical Scavenging and Redox Silencing. AB - The formation of reactive oxygen species (ROS) is linked to the pathogenesis of neurodegenerative diseases. Here we have investigated the effect of soluble and aggregated amyloid-beta (Abeta) and alpha-synuclein (alphaS), associated with Alzheimer's and Parkinson's diseases, respectively, on the Cu(2+)-catalyzed formation of ROS in vitro in the presence of a biological reductant. We find that the levels of ROS, and the rate by which ROS is generated, are significantly reduced when Cu(2+) is bound to Abeta or alphaS, particularly when they are in their oligomeric or fibrillar forms. This effect is attributed to a combination of radical scavenging and redox silencing mechanisms. Our findings suggest that the increase in ROS associated with the accumulation of aggregated Abeta or alphaS does not result from a particularly ROS-active form of these peptides, but rather from either a local increase of Cu(2+) and other ROS-active metal ions in the aggregates or as a downstream consequence of the formation of the pathological amyloid structures. PMID- 26967464 TI - Feeder-free Derivation of Melanocytes from Human Pluripotent Stem Cells. AB - Human pluripotent stem cells (hPSCs) represent a platform to study human development in vitro under both normal and disease conditions. Researchers can direct the differentiation of hPSCs into the cell type of interest by manipulating the culture conditions to recapitulate signals seen during development. One such cell type is the melanocyte, a pigment-producing cell of neural crest (NC) origin responsible for protecting the skin against UV irradiation. This protocol presents an extension of a currently available in vitro Neural Crest differentiation protocol from hPSCs to further differentiate NC into fully pigmented melanocytes. Melanocyte precursors can be enriched from the Neural Crest protocol via a timed exposure to activators of WNT, BMP, and EDN3 signaling under dual-SMAD-inhibition conditions. The resultant melanocyte precursors are then purified and matured into fully pigmented melanocytes by culture in a selective medium. The resultant melanocytes are fully pigmented and stain appropriately for proteins characteristic of mature melanocytes. PMID- 26967466 TI - Olaparib for the treatment of epithelial ovarian cancer. AB - INTRODUCTION: Despite recent advances in the management of epithelial ovarian cancer, overall survival rates remain poor, and there is a pressing need to develop novel therapeutic agents and maintenance strategies to improve outcomes for women with this disease. Olaparib, a potent oral poly(ADP-ribose) polymerase (PARP) inhibitor, has demonstrated antitumor activity in women with ovarian cancer, associated with homologous recombination deficiency. AREAS COVERED: This review outlines the rationale for PARP inhibitor therapy in ovarian cancer and summarizes the efficacy and tolerability data for olaparib to date. Ongoing phase III clinical trials of olaparib in ovarian cancer will be discussed. EXPERT OPINION: There are a number of issues regarding the optimal use of olaparib in ovarian cancer, including the identification of a homologous recombination deficiency signature to predict treatment response, establishment of the optimal treatment setting (maintenance or relapsed disease), and evaluation of cost effectiveness. Finally, the long term consequences of PARP inhibitors, including the risk of myelodysplasia and acute myeloid leukemia need to be quantified in ongoing large phase III clinical trials. PMID- 26967465 TI - Effect of Low-Magnitude, High-Frequency Mechanical Stimulation on BMD Among Young Childhood Cancer Survivors: A Randomized Clinical Trial. AB - IMPORTANCE: Bone accrual during youth is critical to establish sufficient strength for lifelong skeletal health. Children with cancer may develop low bone mineral density (BMD) any time before or after diagnosis. OBJECTIVE: To evaluate the ability of low-magnitude, high-frequency mechanical stimulation to enhance BMD among childhood cancer survivors. DESIGN, SETTING, AND PARTICIPANTS: Double blind randomized clinical trial conducted at St Jude Children's Research Hospital from June 1, 2010, to January 22, 2013, using cancer survivors, ages 7 to 17 years, who were previously treated at St Jude Children's Research Hospital, were in remission, and at least 5 years from diagnosis, with whole-body or lumbar spine BMD z scores of -1.0 or lower. Participants were randomized (stratified by sex and Tanner stage) to either a placebo device or low-magnitude, high-frequency mechanical stimulation device, which was used at home. INTERVENTIONS: Placebo or low-magnitude, high-frequency mechanical stimulation (0.3 g; 32-37 Hz) for 2 sessions lasting 10 minutes each, 7 days per week for 1 year. All participants were prescribed daily cholecalciferol (vitamin D) and calcium. MAIN OUTCOMES AND MEASURES: Changes in areal and volumetric BMD and bone biomarkers were compared by analysis of variance, adjusted for strata. RESULTS: Of the 65 participants, 32 were randomized to the intervention group (mean [SD] age was 13.6 [3.7] years, 18 [56.2%] were male, and 27 [84.4%] were white), and 33 were randomized to the placebo group (mean [SD] age was 13.6 [2.9] years, 17 [51.5%] were male, and 26 [78.8%] were white). Forty-eight participants completed the trial, 22 in the intervention group and 26 in the placebo group with median adherence of 70.1% for intervention and 63.7% for placebo groups. With intention-to-treat analysis, mean (SD) whole-body BMD z score by dual x-ray absorptiometry improved by 0.25 (0.78) in the intervention (n = 22), but decreased by -0.19 (0.79) in the placebo group (n = 26, P = .05). Circulating osteocalcin at 12 months correlated with change in total body BMD (r = 0.35, P = .02). Tibial trabecular bone among participants completing 70% or more of the prescribed sessions increased by a mean of 11.2% (95% CI, 5.2 to 17.2%) compared with those completing less than 70% who decreased by a mean of -1.3% (95% CI, -7.3 to 4.7%; P = .02). Change in circulating receptor activator of nuclear factor kappa-B ligand was higher in the intervention than in the placebo group (0.06 [0.16] vs -0.04 [0.17] pmol/L) (P = .04). CONCLUSIONS AND RELEVANCE: Pediatric cancer survivors with low BMD may benefit from low-magnitude, high-frequency mechanical stimulation as a novel and safe intervention to optimize peak bone mass during youth, alone or in conjunction with other therapies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01010230. PMID- 26967467 TI - Water Uptake and Hygroscopic Growth of Organosulfate Aerosol. AB - Organosulfates (OS) are important components of secondary organic aerosol (SOA) that have been identified in numerous field studies. This class of compounds within SOA can potentially affect aerosol physicochemical properties such as hygroscopicity because of their polar and hydrophilic nature as well as their low volatility. Currently, there is a dearth of information on how aerosol particles that contain OS interact with water vapor in the atmosphere. Herein we report a laboratory investigation on the hygroscopic properties of a structurally diverse set of OS salts at varying relative humidity (RH) using a Hygroscopicity-Tandem Differential Mobility Analyzer (H-TDMA). The OS studied include the potassium salts of glycolic acid sulfate, hydroxyacetone sulfate, 4-hydroxy-2,3-epoxybutane sulfate, and 2-butenediol sulfate and the sodium salts of benzyl sulfate, methyl sulfate, ethyl sulfate, and propyl sulfate. In addition, mixtures of OS and sodium chloride were also studied. The results showed gradual deliquescence of these aerosol particles characterized by continuous uptake and evaporation of water in both hydration and dehydration processes for the OS, while the mixture showed prompt deliquescence and effloresce transitions, albeit at a lower relative humidity relative to pure sodium chloride. Hygroscopic growth of these OS at 85% RH were also fit to parameterized functional forms. This new information provided here has important implications about the atmospheric lifetime, light scattering properties, and the role of OS in cloud formation. Moreover, results of these studies can ultimately serve as a basis for the development and evaluation of thermodynamic models for these compounds in order to consider their impact on the atmosphere. PMID- 26967469 TI - Synthesis of 5'-Aldehyde Oligonucleotide. AB - Synthesis of oligonucleotide ending with an aldehyde functional group at their 5' end (5'-AON) is possible for both DNA (5'-AODN) and RNA (5'-AORN) series irrespectively of the nature of the last nucleobase. The 5'-alcohol of on-support ODN is mildly oxidized under Moffat conditions. Transient protection of the resulting aldehyde by N,N'-diphenylethylenediamine derivatives allows cleavage, deprotection, and RP-HPLC purification of the protected 5'-AON. Finally, 5'-AON is deprotected by usual acetic acid treatment. In the aggregates, 5'-AON can be now synthesized and purified as routinely as non-modified ODNs, following procedures similar to the well-known "DMT-On" strategy. PMID- 26967468 TI - Synthesis of S-Adenosyl-L-Methionine Analogs with Extended Transferable Groups for Methyltransferase-Directed Labeling of DNA and RNA. AB - S-Adenosyl-L-methionine (AdoMet) is a ubiquitous methyl donor for a variety of biological methylation reactions catalyzed by methyltransferases (MTases). AdoMet analogs with extended propargylic chains replacing the sulfonium-bound methyl group can serve as surrogate cofactors for many DNA and RNA MTases enabling covalent deposition of these linear chains to their cognate targets sites in DNA or RNA. Here we describe synthetic procedures for the preparation of two representative examples of AdoMet analogs with a transferable hex-2-ynyl group carrying a terminal azide or amine functionality. Our approach is based on direct chemoselective alkylation of S-adenosyl-L-homocysteine at sulfur with corresponding nosylates under acidic conditions. We also describe synthetic routes to 6-substituted hex-2-yn-1-ols and their conversion to the corresponding nosylates. Using these protocols, synthetic AdoMet analogs can be prepared within 1 to 2 weeks. PMID- 26967470 TI - A case of scarring alopecia with Kikuchi-Fujimoto disease. PMID- 26967471 TI - The regulatory mechanism underlying light-inducible production of carotenoids in nonphototrophic bacteria. AB - Light is a ubiquitous environmental factor serving as an energy source and external stimulus. Here, I review the conserved molecular mechanism of light inducible production of carotenoids in three nonphototrophic bacteria: Streptomyces coelicolor A3(2), Thermus thermophilus HB27, and Bacillus megaterium QM B1551. A MerR family transcriptional regulator, LitR, commonly plays a central role in their light-inducible carotenoid production. Genetic and biochemical studies on LitR proteins revealed a conserved function: LitR in complex with adenosyl B12 (AdoB12) has a light-sensitive DNA-binding activity and thus suppresses the expression of the Crt biosynthesis gene cluster. The in vitro DNA binding and transcription assays showed that the LitR-AdoB12 complex serves as a repressor allowing transcription initiation by RNA polymerase in response to illumination. The existence of novel light-inducible genes and the unique role of the megaplasmid were revealed by the transcriptomic analysis of T. thermophilus. The findings suggest that LitR is a general regulator responsible for the light inducible carotenoid production in the phylogenetically divergent nonphototrophic bacteria, and that LitR performs diverse physiological functions in bacteria. PMID- 26967472 TI - Assessment of Cocaine-induced Behavioral Sensitization and Conditioned Place Preference in Mice. AB - It is thought that rewarding experiences with drugs create strong contextual associations and encourage repeated intake. In turn, repeated exposures to drugs of abuse make lasting alterations in the brain function of vulnerable individuals, and these persistent alterations likely serve to maintain the maladaptive drug seeking and taking behaviors characteristic of addiction/dependence(2). In rodents, reward experience and contextual associations are frequently measured using the conditioned place preference assay, or CPP, wherein preference for a previously drug-paired context is measured. Behavioral sensitization, on the other hand, is an increase in a drug induced behavior that develops progressively over repeated exposures. Since sensitized behaviors can often be measured after several months of drug abstinence, depending on the dose and length of initial exposure, they are considered observable correlates of lasting drug-induced plasticity. Researchers have found these assays useful in determining the neurobiological substrates mediating aspects of addiction as well as assessing the potential of different interventions in disrupting these behaviors. This manuscript describes basic, effective protocols for mouse CPP and locomotor behavioral sensitization to cocaine. PMID- 26967474 TI - Gorab Is Required for Dermal Condensate Cells to Respond to Hedgehog Signals during Hair Follicle Morphogenesis. AB - GORAB is a golgin that localizes predominantly at the Golgi apparatus and physically interacts with small guanosine triphosphatases. GORAB is ubiquitously expressed in mammalian tissues, including the skin. However, the biological function of this golgin in skin is unknown. Here, we report that disrupting the expression of the Gorab gene in mice results in hair follicle morphogenesis defects that were characterized by impaired follicular keratinocyte differentiation. This hair follicle phenotype was associated with markedly suppressed hedgehog (Hh) signaling pathway in dermal condensates in vivo. Gorab deficient dermal mesenchymal cells also displayed a significantly reduced capability to respond to Hh pathway activation in vitro. Furthermore, we found that the formation of the primary cilium, a cellular organelle that is essential for the Hh pathway, was impaired in mutant dermal condensate cells, suggesting that Gorab may be required for the Hh pathway through facilitating the formation of primary cilia. Thus, data obtained from this study provided insight into the biological functions of Gorab during embryonic morphogenesis of the skin in which Hh signaling and primary cilia exert important functions. PMID- 26967475 TI - Tamibarotene Ameliorates Bleomycin-Induced Dermal Fibrosis by Modulating Phenotypes of Fibroblasts, Endothelial Cells, and Immune Cells. AB - Tamibarotene (Am80) is a synthetic retinoid that modulates the pathologic processes of various autoimmune and inflammatory diseases and their animal models. We here investigated the therapeutic potential of Am80 against systemic sclerosis using its animal models. Am80 significantly attenuated dermal and hypodermal fibrosis in bleomycin (BLM)-treated mice and tight skin 1 mice, respectively. Consistently, Am80 significantly suppressed the expression of various molecules related to tissue fibrosis, including transforming growth factor-beta1, connective tissue growth factor, IL-4, IL-10, IL-13, IL-17A, tumor necrosis factor-alpha, IFN-gamma, and monocyte chemotactic protein 1 in the lesional skin of BLM-treated mice. Furthermore, Am80 decreased the proportion of effector T cells, while increasing that of naive T cells among CD4+ T cells in the draining lymph nodes of BLM-treated mice. Moreover, a series of BLM-induced pathologic events, including endothelial-to-mesenchymal transition; ICAM-1 expression in endothelial cells; the infiltration of macrophages, mast cells, and lymphocytes; and M2 macrophage differentiation, were attenuated by Am80. Importantly, Am80 directly reversed the profibrotic phenotype of transforming growth factor-beta1-treated dermal fibroblasts, suppressed ICAM-1 expression in endothelial cells, and promoted M1 macrophage differentiation in vitro. Collectively, Am80 inhibits the development of experimental dermal fibrosis by reversing the profibrotic phenotype of various cell types and would be a candidate for therapeutic drugs against dermal fibrosis of systemic sclerosis. PMID- 26967476 TI - Integrin-Linked Kinase Is Indispensable for Keratinocyte Differentiation and Epidermal Barrier Function. AB - A functional permeability barrier is essential to prevent the passage of water and electrolytes, macromolecules, and pathogens through the epidermis. This is accomplished in terminally differentiated keratinocytes through formation of a cornified envelope and the assembly of tight intercellular junctions. Integrin linked kinase (ILK) is a scaffold protein essential for hair follicle morphogenesis and epidermal attachment to the basement membrane. However, the biological functions of ILK in differentiated keratinocytes remain poorly understood. Furthermore, whether ILK is implicated in keratinocyte differentiation and intercellular junction formation has remained an unresolved issue. Here we describe a pivotal role for ILK in keratinocyte differentiation responses to increased extracellular Ca(2+), regulation of adherens and tight junction assembly, and the formation of an outside-in permeability barrier toward macromolecules. In the absence of ILK, the calcium sensing receptor, E-cadherin, and ZO-1 fail to translocate to the cell membrane, through mechanisms that involve abnormalities in microtubules and in RhoA activation. In situ, ILK deficient epidermis exhibits reduced tight junction formation and increased outside-in permeability to a dextran tracer, indicating reduced barrier properties toward macromolecules. Therefore, ILK is an essential component of keratinocyte differentiation programs that contribute to epidermal integrity and the establishment of its barrier properties. PMID- 26967477 TI - Palmoplantar Keratoderma in Slurp2-Deficient Mice. AB - SLURP1, a member of the lymphocyte antigen 6 protein family, is secreted by suprabasal keratinocytes. Mutations in SLURP1 cause a palmoplantar keratoderma (PPK) known as mal de Meleda. SLURP2, another secreted lymphocyte antigen 6 protein, is encoded by a gene located ?20 kb downstream from SLURP1. SLURP2 is produced by suprabasal keratinocytes. To investigate the importance of SLURP2, we first examined Slurp2 knockout mice in which exon 2-3 sequences had been replaced with lacZ and neo cassettes. Slurp2(-/-) mice exhibited hyperkeratosis on the volar surface of the paws (i.e., palmoplantar keratoderma), increased keratinocyte proliferation, and an accumulation of lipid droplets in the stratum corneum. They also exhibited reduced body weight and hind limb clasping. These phenotypes are similar to those of Slurp1(-/-) mice. To solidify a link between Slurp2 deficiency and palmoplantar keratoderma and to be confident that the disease phenotypes in Slurp2(-/-) mice were not secondary to the effects of the lacZ and neo cassettes on Slurp1 expression, we created a new line of Slurp2 knockout mice (Slurp2X(-/-)) in which Slurp2 was inactivated with a simple nonsense mutation. Slurp2X(-/-) mice exhibited the same disease phenotypes. Thus, Slurp2 deficiency and Slurp1 deficiencies cause the same disease phenotypes. PMID- 26967478 TI - MIG6 Is MEK Regulated and Affects EGF-Induced Migration in Mutant NRAS Melanoma. AB - Activating mutations in neuroblastoma RAS viral oncogene homolog (NRAS) are frequent driver events in cutaneous melanoma. NRAS is a guanosine triphosphate binding protein whose most well-characterized downstream effector is RAF, leading to activation of mitogen-activated protein kinase (MEK)-extracellular signal regulated protein kinase 1/2 signaling. Although there are no Food and Drug Administration-approved targeted therapies for melanoma patients with a primary mutation in NRAS, one form of targeted therapy that has been explored is MEK inhibition. In clinical trials, MEK inhibitors have shown disappointing efficacy in mutant NRAS patients, the reasons for which are unclear. To explore the effects of MEK inhibitors in mutant NRAS melanoma, we used a high-throughput reverse-phase protein array platform to identify signaling alterations. Reverse phase protein array analysis of phospho-proteomic changes in mutant NRAS melanoma in response to trametinib indicated a compensatory increase in v-akt murine thymoma viral oncogene homolog signaling and decreased expression of mitogen inducible gene 6 (MIG6), a negative regulator of epidermal growth factor receptor/v-erb-b2 erythroblastic leukemia viral oncogene homolog receptors. MIG6 expression did not alter the growth or survival properties of mutant NRAS melanoma cells. Rather, we identified a role for MIG6 as a negative regulator of epidermal growth factor-induced signaling and cell migration and invasion. In MEK inhibited cells, further depletion of MIG6 increased migration and invasion, whereas MIG6 expression decreased these properties. Therefore, a decrease in MIG6 may promote the migration and invasiveness of MEK-inhibited mutant NRAS melanoma, especially in response to epidermal growth factor stimulation. PMID- 26967479 TI - Synchronized Targeting of Notch and ERBB Signaling Suppresses Melanoma Tumor Growth through Inhibition of Notch1 and ERBB3. AB - Despite significant advances in melanoma therapy, melanoma remains the deadliest form of skin cancer, with a 5-year survival rate of only 15%. Thus, novel treatments are required to address this disease. Notch and ERBB are evolutionarily conserved signaling cascades required for the maintenance of melanocyte precursors. We show that active Notch1 (Notch1(NIC)) and active (phosphorylated) ERBB3 and ERBB2 correlate significantly and are similarly expressed in both mutated and wild-type BRAF melanomas, suggesting these receptors are co-reactivated in melanoma to promote survival. Whereas blocking either pathway triggers modest effects, combining a ?-secretase inhibitor to block Notch activation and a tyrosine kinase inhibitor to inhibit ERBB3/2 elicits synergistic effects, reducing cell viability by 90% and hampering melanoma tumor growth. Specific inhibition of Notch1 and ERBB3 mimics these results, suggesting these are the critical factors triggering melanoma tumor expansion. Notch and ERBB inhibition blunts AKT and NF?B signaling. Constitutive expression of NF?B partially rescues cell death. Blockade of both Notch and ERBB signaling inhibits the slow cycling JARID1B-positive cell population, which is critical for long term maintenance of melanoma growth. We propose that blocking these pathways is an effective approach to treatment of melanoma patients regardless of whether they carry mutated or wild-type BRAF. PMID- 26967480 TI - Symptomatic Improvement in Human Papillomavirus-Induced Epithelial Neoplasia by Specific Targeting of the CXCR4 Chemokine Receptor. AB - Human papillomavirus (HPV) infection is estimated to be the causal agent in 5% of all human cancers and is the leading cause of genital warts, which is the most common sexually transmitted viral disease. Currently, there are no medications to treat HPV infection, and therapeutic strategies primarily target HPV-related cancer rather than viral infection. HPV infection has severe effects on patients who display selective susceptibility to the virus in the context of primary immunodeficiencies, such as the warts, hypogammaglobulinemia, infections, and myelokathexis syndrome, which is caused by dysfunctions of CXCR4, the receptor for the CXCL12 chemokine. In this study we showed in a transgenic mouse model of HPV-induced epidermal neoplasia the beneficial effects of Cxcl12/Cxcr4 pathway blockade with the selective CXCR4 antagonist AMD3100. Daily treatment with AMD3100 for 28 days potently reduced the abnormal ear epidermal thickening in all mice. This effect was associated with reductions in keratinocyte hyperproliferation and immune cell infiltration, both of which are linked to neoplastic progression. Moreover, we observed the abnormal coordinate expression of Cxcl12 and p16INK4a (a surrogate marker of HPV-induced cancers) in dysplastic epidermal keratinocytes, which was inhibited by AMD3100 treatment. These results provide strong evidence for the therapeutic potential of CXCL12/CXCR4 pathway blockade in HPV-induced pathogenesis. PMID- 26967481 TI - Delayed Healing of Sickle Cell Ulcers Is due to Impaired Angiogenesis and CXCL12 Secretion in Skin Wounds. AB - Leg ulcers are a major complication of sickle cell disease that occur in 2.5-40% of patients. Leg ulcers are responsible for frequent complications because they are often long-lasting and are highly resistant to therapy. Although their occurrence is associated with hyperhemolysis, the mechanisms underlying sickle cell ulcers remain poorly understood. In this study, we show that skin wound healing is severely altered in old SAD sickle cell mice but is normal in young animals, consistent with reports in humans. Alterations of wound healing were associated with impaired blood and lymphatic angiogenesis in the wound beds and poor endothelial progenitor cell mobilization from the bone marrow. CXCL12 secretion by keratinocytes and inflammatory cells was low in the wounds of SAD mice. Local therapy with endothelial progenitor cells or recombinant CXCL12 injections restored wound angiogenesis and rescued the healing defect together with mobilization of circulating endothelial progenitor cells. To our knowledge, this is a previously unreported study of the cellular and molecular mechanisms of sickle cell ulcers in a murine model that provides promising therapeutic perspectives for clinical trials. PMID- 26967482 TI - Generation of a Functional Non-Shedding Collagen XVII Mouse Model: Relevance of Collagen XVII Shedding in Wound Healing. AB - Collagen XVII is a hemidesmosomal anchorage molecule of basal keratinocytes that promotes stable epidermal-dermal adhesion. One unique feature of collagen XVII is that its collagenous ectodomain is constitutively released from the cell surface by a disintegrin and metalloproteinases (ADAMs) through cleavage within its juxtamembranous linker domain. The responsivity of shedding to environmental stimuli and the high stability of the released ectodomain in several tissues suggests functions in cell detachment during epidermal morphogenesis, differentiation, and regeneration, but its physiologic relevance remained elusive. To investigate this, we generated knock-in mice, which express a functional non-sheddable collagen XVII mutant, with a 41 amino acid deletion in the linker domain spanning all ADAM cleavage sites. These mice showed no macroscopic phenotypic changes, were fertile, and had a normal lifespan. Prevention of collagen XVII shedding interfered neither with skin development nor with epidermal adhesion and differentiation. However, it led to faster wound closure due to accelerated re-epithelialization at the wound edges where shedding of wild-type collagen XVII was strongly induced. Taken together, we have successfully generated a functional non-shedding collagen XVII mouse model, which represents a powerful tool to investigate the pathophysiologic relevance of ectodomain shedding during wound regeneration and cancer invasion. PMID- 26967483 TI - Thy-1/beta3 Integrin Interaction-Induced Apoptosis of Dermal Fibroblasts Is Mediated by Up-Regulation of FasL Expression. PMID- 26967486 TI - Combined Benefits of a PAR2 Inhibitor and Stratum Corneum Acidification for Murine Atopic Dermatitis. PMID- 26967484 TI - The HLA Alleles B*0801 and DRB1*0301 Are Associated with Dermatitis Herpetiformis in a Chinese Population. PMID- 26967487 TI - Melanoma-Directed Activation of Apoptosis Using a Bispecific Antibody Directed at MCSP and TRAIL Receptor-2/Death Receptor-5. PMID- 26967489 TI - Retraction: X. Ma et al. Hybrid Endovascular Repair in Aortic Arch Pathologies: A Retrospective Study. Int. J. Mol. Sci. 2010, 11, 4687-4696. AB - We have been made aware that the figures and experimental data reported in the title paper [1] are duplicated in another publication by P. Bergeron [2]. [...]. PMID- 26967485 TI - Distinct Histologic Subtypes and Risk Factors for Early Onset Basal Cell Carcinoma: A Population-Based Case Control Study from New Hampshire. PMID- 26967488 TI - Regulation of Plant Mineral Nutrition: Transport, Sensing and Signaling. AB - Limitation in crop yield productivity significantly contributes to the pressing problem of food security and malnutrition worldwide. [...]. PMID- 26967490 TI - The influence of golf shaft stiffness on grip and clubhead kinematics. AB - The purpose of this study was to investigate the influence of shaft stiffness on grip and clubhead kinematics. Two driver shafts with disparate levels of stiffness, but very similar inertial properties, were tested by 33 golfers representing a range of abilities. Shaft deflection data as well as grip and clubhead kinematics were collected from 14 swings, with each shaft, for each golfer using an optical motion capture system. The more flexible shaft (R-Flex) demonstrated a higher contribution to clubhead speed from shaft deflection dynamics (P < .001), but was also associated with significantly less grip angular velocity at impact (P = .001), resulting in no significant difference in clubhead speed (P = .14). However, at the individual level, half of the participants demonstrated a significant difference in clubhead speed between shafts. The more flexible shaft was also associated with significantly different magnitudes of head rotation relative to the grip. More specifically, both bend loft (P < .001) and bend lie (P < .001) were greater for the R-Flex shaft, while bend close (P = .017) was greater for the stiffer (X-Flex) shaft. However, changes in grip orientation resulted in no significant differences in face orientation, between the shafts, at impact. PMID- 26967491 TI - Multifunctional Hybrid Fe2O3-Au Nanoparticles for Efficient Plasmonic Heating. AB - One of the most widely used methods for manufacturing colloidal gold nanospherical particles involves the reduction of chloroauric acid (HAuCl4) to neutral gold Au(0) by reducing agents, such as sodium citrate or sodium borohydride. The extension of this method to decorate iron oxide or similar nanoparticles with gold nanoparticles to create multifunctional hybrid Fe2O3-Au nanoparticles is straightforward. This approach yields fairly good control over Au nanoparticle dimensions and loading onto Fe2O3. Additionally, the Au metal size, shape, and loading can easily be tuned by changing experimental parameters (e.g., reactant concentrations, reducing agents, surfactants, etc.). An advantage of this procedure is that the reaction can be done in air or water, and, in principle, is amenable to scaling up. The use of such optically tunable Fe2O3-Au nanoparticles for hyperthermia studies is an attractive option as it capitalizes on plasmonic heating of gold nanoparticles tuned to absorb light strongly in the VIS-NIR region. In addition to its plasmonic effects, nanoscale Au provides a unique surface for interesting chemistries and catalysis. The Fe2O3 material provides additional functionality due to its magnetic property. For example, an external magnetic field could be used to collect and recycle the hybrid Fe2O3-Au nanoparticles after a catalytic experiment, or alternatively, the magnetic Fe2O3 can be used for hyperthermia studies through magnetic heat induction. The photothermal experiment described in this report measures bulk temperature change and nanoparticle solution mass loss as functions of time using infrared thermocouples and a balance, respectively. The ease of sample preparation and the use of readily available equipment are distinct advantages of this technique. A caveat is that these photothermal measurements assess the bulk solution temperature and not the surface of the nanoparticle where the heat is transduced and the temperature is likely to be higher. PMID- 26967492 TI - Does oral buffered sodium supplementation reduce nausea and vomiting during an ultramarathon? AB - This work examines whether nausea or vomiting during an ultramarathon are due to a fluid or electrolyte imbalance, and if these symptoms can be reduced through the use of buffered sodium supplements. Starters (n = 376) of a 161.3-km ultramarathon underwent body weight measurements, 74.5% completed a post-race questionnaire, and 53.0% also underwent a post-race blood draw. The incidence of nausea or vomiting progressively increased during the race, and affected 60% of runners overall. Weight change and rate of sodium intake in supplements or in buffered sodium supplements did not differ between those with and without nausea or vomiting. Post-race serum sodium concentration also did not differ between those with and without symptoms in the last race segment. We conclude that weight change, the rate of sodium intake in supplements or in buffered sodium supplements, and serum sodium concentration are not related to symptoms of nausea or vomiting during a 161-km ultramarathon. PMID- 26967494 TI - Genome-wide association studies in migraine: current state and route to follow. AB - PURPOSE OF REVIEW: Genome-wide association studies (GWAS) have revealed over a dozen genetic factors robustly associated with the common forms of migraine. The identification of these factors, the implicated biological mechanisms, and whether they are of use in basic research and clinic practice will be discussed. RECENT FINDINGS: Several GWAS have been performed in recent years. New approaches are being tested to identify how information of genetic susceptibility factors can be used in research and the clinic. Still, we are only at the beginning of understanding how the genetic factors may be involved in migraine pathophysiology. SUMMARY: The identification of genetic factors that confer risk for the common forms of migraine by GWAS has given insight into the genetic underpinning of migraine pathophysiology. Still, the interpretation of the findings of GWAS is not straightforward. Various strategies are being tested to investigate which pathophysiological mechanisms are involved, how they can be studied, and what this means for clinical diagnosis, and even care. PMID- 26967493 TI - The Role of Adherence and Retreatment in De Novo Emergence of MDR-TB. AB - Treatment failure after therapy of pulmonary tuberculosis (TB) infections is an important challenge, especially when it coincides with de novo emergence of multi drug-resistant TB (MDR-TB). We seek to explore possible causes why MDR-TB has been found to occur much more often in patients with a history of previous treatment. We develop a mathematical model of the replication of Mycobacterium tuberculosis within a patient reflecting the compartments of macrophages, granulomas, and open cavities as well as parameterizing the effects of drugs on the pathogen dynamics in these compartments. We use this model to study the influence of patient adherence to therapy and of common retreatment regimens on treatment outcome. As expected, the simulations show that treatment success increases with increasing adherence. However, treatment occasionally fails even under perfect adherence due to interpatient variability in pharmacological parameters. The risk of generating MDR de novo is highest between 40% and 80% adherence. Importantly, our simulations highlight the double-edged effect of retreatment: On the one hand, the recommended retreatment regimen increases the overall success rate compared to re-treating with the initial regimen. On the other hand, it increases the probability to accumulate more resistant genotypes. We conclude that treatment adherence is a key factor for a positive outcome, and that screening for resistant strains is advisable after treatment failure or relapse. PMID- 26967508 TI - Improving drug delivery technology for treating neurodegenerative diseases. AB - INTRODUCTION: Neurodegenerative diseases (NDs) represent intricate challenges for efficient uptake and transport of drugs to the brain mainly due to the restrictive blood-brain barrier (BBB). NDs are characterized by the loss of neuronal subtypes as sporadic and/or familial and several mechanisms of neurodegeneration have been identified. AREAS COVERED: This review attempts to recap, organize and concisely evaluate the advanced drug delivery systems designed for treating common NDs. It highlights key research gaps and opinionates on new neurotherapies to overcome the BBB as an addition to the current treatments of countering oxidative stress, inflammation and apoptotic mechanisms. EXPERT OPINION: Current treatments do not fully address the biological, drug and therapeutic factors faced. This has led to the development of vogue treatments such as nose-to-brain technologies, bio-engineered systems, fusion protein chaperones, stem cells, gene therapy, use of natural compounds, neuroprotectants and even vaccines. However, failure of these treatments is mainly due to the BBB and non-specific delivery in the brain. In order to increase neuroavailability various advanced drug delivery systems provide promising alternatives that are able to augment the treatment of Alzheimer's disease and Parkinson's disease. However, much work is still required in this field beyond the preclinical testing phase. PMID- 26967507 TI - Structure Property Relationships of Carboxylic Acid Isosteres. AB - The replacement of a carboxylic acid with a surrogate structure, or (bio) isostere, is a classical strategy in medicinal chemistry. The general underlying principle is that by maintaining the features of the carboxylic acid critical for biological activity, but appropriately modifying the physicochemical properties, improved analogs may result. In this context, a systematic assessment of the physicochemical properties of carboxylic acid isosteres would be desirable to enable more informed decisions of potential replacements to be used for analog design. Herein we report the structure-property relationships (SPR) of 35 phenylpropionic acid derivatives, in which the carboxylic acid moiety is replaced with a series of known isosteres. The data set generated provides an assessment of the relative impact on the physicochemical properties that these replacements may have compared to the carboxylic acid analog. As such, this study presents a framework for how to rationally apply isosteric replacements of the carboxylic acid functional group. PMID- 26967510 TI - The Recognition of Mental Illness, Schizophrenia Identification, and Help-Seeking from Friends in Late Adolescence. AB - OBJECTIVE: The recognition of mental illness without anticipating stigma might encourage adolescents' help-seeking behavior. We aimed to identify the relationship between mental illness identification and adolescents' intention to seek help if faced with mental illness. METHOD: We examined the relationships between help-seeking intentions and recognition of mental illness (RMI) without correctly identifying the disease name, as well as correct labelling of schizophrenia (LSC) using a vignette about a person with schizophrenia in a cross sectional survey of 9,484 Japanese high-school students aged 15-18 years. RESULTS: When compared with adolescents who were unable to recognize the mental illness (UMI) in the vignette, those in the RMI group reported they were significantly more likely to seek help from friends (odds ratio [OR] = 1.29; 95% confidence interval [CI] = 1.17-1.41; P < 0.001) and expressed an increased likelihood to seek help from professionals (all P < .05). Those in the LSC group reported they were significantly less likely to exhibit help-seeking behavior (OR = 0.77, 95% CI = 0.65-0.92, P = 0.003) and expressed an increased likelihood of help-seeking from health professionals than the UMI group (all P < .05). CONCLUSION: The ability to recognize mental illness without identifying the disease may increase help-seeking from friends, while the ability to identify the disease as schizophrenia might decrease late adolescents' help-seeking. To promote help-seeking behavior among adolescents, improving their ability to recognize mental illness generally is recommended. PMID- 26967511 TI - High pressure Raman spectra of monoglycine nitrate single crystal. AB - Single crystal of monoglycine nitrate has been studied by Raman spectroscopy under high pressures up to 5.5 GPa. The results show changes in lattice modes in the pressure ranges of 1.1-1.6 GPa and 4.0-4.6 GPa. The first change occurs with appearance of bands related to the lattice modes as well as discontinuity in the slope of dOmega/dP of these modes. Moreover, bands associated with the skeleton of glycine suggest that the molecule undergoes conformational modifications. The appearance of a strong band at 55 cm(-1) point to a second phase transition associated with the lattice modes, while the internal modes remain unchanged. These anomalies are probably due to rearrangement of hydrogen bonds. Additionally, decompression to ambient pressure shows that the phase transitions are reversible. Finally, the results show that the nitrate anions play an important role on the stability of the monoglycine nitrate crystal. PMID- 26967512 TI - A selective fluorescent 'turn-on' sensor for recognition of Zn(2+) in aqueous media. AB - A new rhodamine-based fluorescent probe 'RhAP' was synthesized and successfully characterized using FT-IR, (13)C NMR and (1)H NMR spectroscopies, LC-MS/MS spectrometry and elemental analysis. The RhAP, a colorless and non-fluorescent compound, showed a selective fluorescent response and colorimetric change for Zn(2+) in HEPES buffer (10mM, EtOH:water, 2:1, v/v, pH7.2). Upon the addition of two equivalents of Zn(2+) to a solution of RhAP, a nearly 35-fold enhancement of the fluorescence intensity, with an emission maximum at 578 nm, was observed in comparison to the sensor alone under the same experimental conditions. The complex formation between RhAP and Zn(2+) was found to have a 1:1 ratio based on calculations obtained from Job's plot and the mole ratio plot methods. The results showed that RhAP can be used as an effective fluorescent probe for selective detecting of Zn(2+) in an aqueous medium. PMID- 26967509 TI - Alcohol Consumption-Related Metabolites in Relation to Colorectal Cancer and Adenoma: Two Case-Control Studies Using Serum Biomarkers. AB - Alcohol is a known carcinogen that may be associated with colorectal cancer. However, most epidemiologic studies assess alcoholic beverage consumption using self-reported data, leading to potential exposure misclassification. Biomarkers of alcohol consumption may provide an alternative, complementary approach that reduces misclassification and incorporates individual differences in alcohol metabolism. Therefore, we evaluated the relationship between previously identified alcohol consumption-related metabolites and colorectal cancer and adenoma using serum metabolomics data from two studies. Data on colorectal cancer were obtained from a nested case-control study of 502 US adults (252 cases, 250 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Data on colorectal adenoma were obtained from a case-control study of 197 US adults (120 cases, 77 controls) from the Navy Colon Adenoma Study. Unconditional multivariable logistic regression models were fit to calculate odds ratios (OR) and 95% confidence intervals (CI) for eight alcohol consumption related metabolites identified in a previous analysis: ethyl glucuronide; 4 androstene-3beta,17beta-diol disulfate 1; 5-alpha-androstan-3beta,17beta-diol disulfate; 16-hydroxypalmitate; bilirubin (E,Z or Z,E); cyclo (-leu-pro); dihomo linoleate (20:2n6); and palmitoleate (16:1n7). We found no clear association between these alcohol consumption-related metabolites and either endpoint. However, we did observe an inverse association between cyclo (-leu-pro) and colorectal adenoma that was only observed in the highest metabolite quantile (OR 4th vs. 1st Quantile = 0.30, 95% CI: 0.12-0.78; P-trend = 0.047), but no association for colorectal cancer. In conclusion, there were no adverse associations between alcohol consumption-related metabolites and colorectal cancer or adenoma. PMID- 26967513 TI - Green synthesis of silver nanoparticles using Terminalia cuneata and its catalytic action in reduction of direct yellow-12 dye. AB - Facile green synthesis of silver nanoparticles (AgNPs) using aqueous bark extract of Terminalia cuneata has been reported in this article. The effects of concentration of the extract, reaction time and pH were studied by UV-Vis spectroscopy. Appearance of yellow color with lambdamax around ~420 nm suggested the formation of AgNPs. The stable AgNPs were further characterized by Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), dynamic light scattering (DLS) with zeta potential and high resolution transmission electron microscopy (HR-TEM) with energy dispersive X-ray spectroscopy (EDS) analysis. The synthesized AgNPs were in the size range of 25-50 nm with a distorted spherical shape identified from HR-TEM analysis. The catalytic activity of AgNPs on the reduction of direct yellow-12 using NaBH4 was analyzed using a UV-Vis spectrophotometer. This study showed the efficacy of biogenic AgNPs in catalyzing the reduction of direct yellow-12. PMID- 26967514 TI - NIR emission studies and dielectric properties of Er(3+)-doped multicomponent tellurite glasses. AB - Multicomponent tellurite glasses containing altered concentrations of Er2O3 (ranging from 0 to 1 mol%) were prepared by the standard melt quenching technique. Investigations through energy dispersive X-ray spectroscopy (EDS), Raman scattering spectroscopy, Fourier transform infrared (FTIR) spectroscopy, near-infrared (NIR) emission studies and dielectric measurement techniques were done to probe their compositional, structural, spectroscopic and dielectric characteristics. The broad emission together with the high values of the effective linewidth (~63 nm), stimulated emission cross-section (9.67 * 10(-21) cm(2)) and lifetime (2.56 ms) of (4)I13/2 level for 0.5 mol% of Er(3+) makes these glasses attractive for broadband amplifiers. From the measured capacitance and dissipation factor, the relative permittivity, dielectric loss and the conductivity were computed; which furnish the dielectric nature of the multicomponent tellurite glasses that depend on the applied frequency. Assuming the ideal Debye behavior as substantiated by Cole-Cole plot, an examination of the real and imaginary parts of impedance was performed. The power-law and Cole Cole parameters were resolved for all the glass samples. From the assessment of the emission analysis and dielectric properties of the glass samples, it was obvious that the Er(3+) ion concentration had played a vital role in tuning the optical and dielectric properties and the 0.5 mol% of Er(3+) -doped glass was confirmed as the optimum composition. PMID- 26967515 TI - A systematic evaluation of the safety and toxicity of fingolimod for its potential use in the treatment of acute myeloid leukaemia. AB - Treatment of acute myeloid leukaemia (AML) is challenging and emerging treatment options include protein phosphatase 2A (PP2A) activators. Fingolimod is a known PP2A activator that inhibits multiple signalling pathways and has been used extensively in patients with multiple sclerosis and other indications. The initial positive results of PP2A activators in vitro and mouse models of AML are promising; however, its safety for use in AML has not been assessed. From human studies of fingolimod in other indications, it is possible to evaluate whether the safety and toxicity profile of the PP2A activators will allow their use in treating AML. A literature review was carried out to assess safety before the commencement of Phase I trials of the PP2A activator Fingolimod in AML. From human studies of fingolimod in other indications, it is possible to evaluate whether the safety and toxicity profile of the PP2A activators will allow their use in treating AML. A systematic review of published literature in Medline, EMBASE and the Cochrane Library of critical reviews was carried out. International standards for the design and reporting of search strategies were followed. Search terms and medical subject headings used in trials involving PP2A activators as well as a specific search were performed for 'adverse events', 'serious adverse events', 'delays in treatment', ' side effects' and 'toxicity' for primary objectives. Database searches were limited to papers published in the last 12 years and available in English. The search yielded 677 articles. A total of 69 journal articles were identified as relevant and included 30 clinical trials, 24 review articles and 15 case reports. The most frequently reported adverse events were nausea, diarrhoea, fatigue, back pain, influenza viral infections, nasopharyngitis and bronchitis. Specific safety concerns include monitoring of the heart rate and conduction at commencement of treatment as cardiotoxicity has been reported. There is little evidence to suggest specific bone marrow toxicity. Lymophopenia is a desired effect in the management of multiple sclerosis, but may have implications in patients with acute leukaemia as it may potentially increase susceptibility to viral infections such as influenza. Fingolimod is a potential treatment option for AML with an acceptable risk to benefit ratio, given its lack of bone marrow toxicity and the relatively low rate of serious side effects. As most patients with AML are elderly, specific monitoring for cardiac toxicity as well as infection would be required. PMID- 26967516 TI - Involvement of an SRF-MADS protein McmA in regulation of extracellular enzyme production and asexual/sexual development in Aspergillus nidulans. AB - SRF-MADS proteins are transcription factors conserved among eukaryotes that regulate a variety of cellular functions; however, their physiological roles are still not well understood in filamentous fungi. Effects of a mutation in mcmA gene that encodes the sole SRF-MADS protein in the fungus Aspergillus nidulans were examined by RNA sequencing. Sequencing data revealed that expression levels of cellulase genes were significantly decreased by the mutation as reported previously. However, expression levels of various hemicellulolytic enzyme genes, several extracellular protease genes, the nosA and rosA genes involved in sexual development, and AN4394 encoding an ortholog of EcdR involved in Aspergillus oryzae conidiation, were also significantly decreased by the mutation. As expected from the RNA sequencing data, the mcmA mutant had reduced protease production, cleistothecial development, and conidiation. This is the first report describing the involvement of SRF-MADS proteins in protease production in fungi, and asexual and sexual development in Aspergillus. PMID- 26967517 TI - Opt-Out Panel Testing for HIV, Hepatitis B and Hepatitis C in an Urban Emergency Department: A Pilot Study. AB - OBJECTIVES: Studies suggest 2 per 1000 people in Dublin are living with HIV, the level above which universal screening is advised. We aimed to assess the feasibility and acceptability of a universal opt-out HIV, Hepatitis B and Hepatitis C testing programme for Emergency Department patients and to describe the incidence and prevalence of blood-borne viruses in this population. METHODS: An opt-out ED blood borne virus screening programme was piloted from March 2014 to January 2015. Patients undergoing blood sampling during routine clinical care were offered HIV 1&2 antibody/antigen assay, HBV surface antigen and HCV antibody tests. Linkage to care where necessary was co-ordinated by the study team. New diagnosis and prevalence rates were defined as the new cases per 1000 tested and number of positive tests per 1000 tested respectively. RESULTS: Over 45 weeks of testing, of 10,000 patient visits, 8,839 individual patient samples were available for analysis following removal of duplicates. A sustained target uptake of >50% was obtained after week 3. 97(1.09%), 44(0.49%) and 447(5.05%) HIV, Hepatitis B and Hepatitis C tests were positive respectively. Of these, 7(0.08%), 20(0.22%) and 58(0.66%) were new diagnoses of HIV, Hepatitis B and Hepatitis C respectively. The new diagnosis rate for HIV, Hepatitis B and Hepatitis C was 0.8, 2.26 and 6.5 per 1000 and study prevalence for HIV, Hepatitis B and Hepatitis C was 11.0, 5.0 and 50.5 per 1000 respectively. CONCLUSIONS: Opt-out blood borne viral screening was feasible and acceptable in an inner-city ED. Blood borne viral infections were prevalent in this population and newly diagnosed cases were diagnosed and linked to care. These results suggest widespread blood borne viral testing in differing clinical locations with differing population demographic risks may be warranted. PMID- 26967518 TI - Naringin Reduces Hyperglycemia-Induced Cardiac Fibrosis by Relieving Oxidative Stress. AB - INTRODUCTION: Hyperglycemia promotes myocardial fibrotic lesions through upregulation of PKC and p38 in response to redox changes. The effects of naringin on hyperglycemia-induced myocardial fibrotic changes and its putative effects on PKC-beta and p38 protein expression in type 1 rat model of diabetes are hereby investigated. METHODS: Male Sprague-Dawley rats were divided into six groups I VI. Groups I and II, were orally treated with distilled water {3.0 ml/kg body weight (BW)} and naringin (50 mg/kg BW), respectively. Groups III, IV, V and VI were rendered diabetic by a single intraperitoneal injection of streptozotocin (60 mg/kg, BW) and were similarly treated with subcutaneous insulin (8.0 I.U/kg BW, twice daily), naringin (50 mg/kg BW), distilled water (3.0 ml/Kg BW) and ramipril (3.0 mg/kg/BW), respectively. The animals were sacrificed after 56 days by halothane overdose; blood and heart samples removed for further analysis. RESULTS: The untreated diabetic rats exhibited significantly increased oxidative stress, NADPH oxidase activity, increased cardiac fibrosis, PKC-beta and p38 mitogen activated protein kinase expression compared to controls. Naringin treatment significantly ameliorated these changes in diabetic rats compared to the untreated diabetic controls. CONCLUSIONS: Naringin's amelioration of myocardial fibrosis by modulating p38 and PKC-beta protein expression possibly through its known antioxidant actions and may therefore be useful in retarding the progression of fibrosis in a diabetic heart. PMID- 26967519 TI - Is It Possible to Detect Activated Brown Adipose Tissue in Humans Using Single Time-Point Infrared Thermography under Thermoneutral Conditions? Impact of BMI and Subcutaneous Adipose Tissue Thickness. AB - PURPOSE: To evaluate the feasibility to detect activated brown adipose tissue (BAT) using single-time-point infrared thermography of the supraclavicular skin region under thermoneutral conditions. To this end, infrared thermography was compared with 18-F-FDG PET, the current reference standard for the detection of activated BAT. METHODS: 120 patients were enrolled in this study. After exclusion of 18 patients, 102 patients (44 female, 58 male, mean age 58+/-17 years) were included for final analysis. All patients underwent a clinically indicated 18F FDG-PET/CT examination. Immediately prior to tracer injection skin temperatures of the supraclavicular, presternal and jugular regions were measured using spatially resolved infrared thermography at room temperature. The presence of activated BAT was determined in PET by typical FDG uptake within the supraclavicular adipose tissue compartments. Local thickness of supraclavicular subcutaneous adipose tissue (SCAT) was measured on CT. Measured skin temperatures were statistically correlated with the presence of activated BAT and anthropometric data. RESULTS: Activated BAT was detected in 9 of 102 patients (8.8%). Local skin temperature of the supraclavicular region was significantly higher in individuals with active BAT compared to individuals without active BAT. However, after statistical correction for the influence of BMI, no predictive value of activated BAT on skin temperature of the supraclavicular region could be observed. Supraclavicular skin temperature was significantly negatively correlated with supraclavicular SCAT thickness. CONCLUSION: We conclude that supraclavicular SCAT thickness influences supraclavicular skin temperature and thus makes a specific detection of activated BAT using single-time-point thermography difficult. Further studies are necessary to evaluate the possibility of BAT detection using alternative thermographic methods, e.g. dynamic thermography or MR-based thermometry taking into account BMI as a confounding factor. PMID- 26967521 TI - Hypocrellin B and paclitaxel-encapsulated hyaluronic acid-ceramide nanoparticles for targeted photodynamic therapy in lung cancer. AB - To increase the therapeutic efficacy of photodynamic therapy (PDT) in treating lung cancer, we developed both photosensitizer and anticancer drug encapsulated hyaluronic acid-ceramide nanoparticles. Based on our previous study, a co delivery system of photosensitizers and anticancer agents greatly improves the therapeutic effect of PDT. Furthermore, hyaluronic acid-ceramide-based nanoparticles are ideal targeting carriers for lung cancer. In vitro phototoxicity in A549 (human lung adenocarcinoma) cells and in vivo antitumor efficacy in A549 tumor-bearing mice treated with hypocrellin B (HB)-loaded nanoparticles (HB-NPs) or hypocrellin B and paclitaxel loaded nanoparticles (HB-P NPs) were evaluated. Cell viability assay, microscopic analysis and FACS analysis were performed for the in vitro studies and HB-P-NPs showed enhanced phototoxicity compared with HB-NPs. In the animal study, the tumor volume change and the histological analysis was studied and the anticancer efficacy improved in the order of free HBA, p.E713K) in the KIAA0196 gene in a Japanese patient with SPG8. To date, only 10 mutations in the KIAA0196 gene have been reported in the world. We describe the clinical and genetic findings in our patient with SPG8, which is a rare dominant hereditary spastic paraplegia. Notably, our patient showed mild upper limb ataxia, which is a relatively atypical symptom of SPG8. Thus, our patient showed a wide clinical spectrum of SPG8. PMID- 26967523 TI - Correction: Spatial and Temporal Examination of Bivalve Communities in Several Estuaries of Southern California and Northern Baja California, MX. PMID- 26967520 TI - Chicken TREM-B1, an Inhibitory Ig-Like Receptor Expressed on Chicken Thrombocytes. AB - Triggering receptors expressed on myeloid cells (TREM) form a multigene family of immunoregulatory Ig-like receptors and play important roles in the regulation of innate and adaptive immunity. In chickens, three members of the TREM family have been identified on chromosome 26. One of them is TREM-B1 which possesses two V set Ig-domains, an uncharged transmembrane region and a long cytoplasmic tail with one ITSM and two ITIMs indicating an inhibitory function. We generated specific monoclonal antibodies by immunizing a Balb/c mouse with a TREM-B1-FLAG transfected BWZ.36 cell line and tested the hybridoma supernatants on TREM-B1 FLAG transfected 2D8 cells. We obtained two different antibodies specific for TREM-B1, mab 7E8 (mouse IgG1) and mab 1E9 (mouse IgG2a) which were used for cell surface staining. Single and double staining of different tissues, including whole blood preparations, revealed expression on thrombocytes. Next we investigated the biochemical properties of TREM-B1 by using the specific mab 1E9 for immunoprecipitation of either lysates of surface biotinylated peripheral blood cells or stably transfected 2D8 cells. Staining with streptavidin coupled horse radish peroxidase revealed a glycosylated monomeric protein of about 50 kDa. Furthermore we used the stably transfected 2D8 cell line for analyzing the cytoplasmic tyrosine based signaling motifs. After pervanadate treatment, we detected phosphorylation of the tyrosine residues and subsequent recruitment of the tyrosine specific protein phosphatase SHP-2, indicating an inhibitory potential for TREM-B1. We also showed the inhibitory effect of TREM-B1 in chicken thrombocytes using a CD107 degranulation assay. Crosslinking of TREM-B1 on activated primary thrombocytes resulted in decreased CD107 surface expression of about 50-70%. PMID- 26967524 TI - Dengue in Java, Indonesia: Relevance of Mosquito Indices as Risk Predictors. AB - BACKGROUND: No vaccine is currently available for dengue virus (DENV), therefore control programmes usually focus on managing mosquito vector populations. Entomological surveys provide the most common means of characterising vector populations and predicting the risk of local dengue virus transmission. Despite Indonesia being a country strongly affected by DENV, only limited information is available on the local factors affecting DENV transmission and the suitability of available survey methods for assessing risk. METHODOLOGY/PRINCIPAL FINDINGS: We conducted entomological surveys in the Banyumas Regency (Central Java) where dengue cases occur on an annual basis. Four villages were sampled during the dry and rainy seasons: two villages where dengue was endemic, one where dengue cases occurred sporadically and one which was dengue-free. In addition to data for conventional larvae indices, we collected data on pupae indices, and collected adult mosquitoes for species identification in order to determine mosquito species composition and population density. Traditionally used larval indices (House indices, Container indices and Breteau indices) were found to be inadequate as indicators for DENV transmission risk. In contrast, species composition of adult mosquitoes revealed that competent vector species were dominant in dengue endemic and sporadic villages. CONCLUSIONS/SIGNIFICANCE: Our data suggested that the utility of traditional larvae indices, which continue to be used in many dengue endemic countries, should be re-evaluated locally. The results highlight the need for validation of risk indicators and control strategies across DENV affected areas here and perhaps elsewhere in SE Asia. PMID- 26967526 TI - "Anyone Know What Species This Is?" - Twitter Conversations as Embryonic Citizen Science Communities. AB - Social media like blogs, micro-blogs or social networks are increasingly being investigated and employed to detect and predict trends for not only social and physical phenomena, but also to capture environmental information. Here we argue that opportunistic biodiversity observations published through Twitter represent one promising and until now unexplored example of such data mining. As we elaborate, it can contribute to real-time information to traditional ecological monitoring programmes including those sourced via citizen science activities. Using Twitter data collected for a generic assessment of social media data in ecological monitoring we investigated a sample of what we denote biodiversity observations with species determination requests (N = 191). These entail images posted as messages on the micro-blog service Twitter. As we show, these frequently trigger conversations leading to taxonomic determinations of those observations. All analysed Tweets were posted with species determination requests, which generated replies for 64% of Tweets, 86% of those contained at least one suggested determination, of which 76% were assessed as correct. All posted observations included or linked to images with the overall image quality categorised as satisfactory or better for 81% of the sample and leading to taxonomic determinations at the species level in 71% of provided determinations. We claim that the original message authors and conversation participants can be viewed as implicit or embryonic citizen science communities which have to offer valuable contributions both as an opportunistic data source in ecological monitoring as well as potential active contributors to citizen science programmes. PMID- 26967525 TI - Incomplete Lineage Sorting and Hybridization Statistics for Large-Scale Retroposon Insertion Data. AB - Ancient retroposon insertions can be used as virtually homoplasy-free markers to reconstruct the phylogenetic history of species. Inherited, orthologous insertions in related species offer reliable signals of a common origin of the given species. One prerequisite for such a phylogenetically informative insertion is that the inserted element was fixed in the ancestral population before speciation; if not, polymorphically inserted elements may lead to random distributions of presence/absence states during speciation and possibly to apparently conflicting reconstructions of their ancestry. Fortunately, such misleading fixed cases are relatively rare but nevertheless, need to be considered. Here, we present novel, comprehensive statistical models applicable for (1) analyzing any pattern of rare genomic changes, (2) testing and differentiating conflicting phylogenetic reconstructions based on rare genomic changes caused by incomplete lineage sorting or/and ancestral hybridization, and (3) differentiating between search strategies involving genome information from one or several lineages. When the new statistics are applied, in non-conflicting cases a minimum of three elements present in both of two species and absent in a third group are considered significant support (p<0.05) for the branching of the third from the other two, if all three of the given species are screened equally for genome or experimental data. Five elements are necessary for significant support (p<0.05) if a diagnostic locus derived from only one of three species is screened, and no conflicting markers are detected. Most potentially conflicting patterns can be evaluated for their significance and ancestral hybridization can be distinguished from incomplete lineage sorting by considering symmetric or asymmetric distribution of rare genomic changes among possible tree configurations. Additionally, we provide an R-application to make the new KKSC insertion significance test available for the scientific community at http://retrogenomics.uni-muenster.de:3838/KKSC_significance_test/. PMID- 26967528 TI - Patient Databases and Clinical Registries in Facial Plastic Surgery Research Looking at Outcomes Data on a Broader Scale. PMID- 26967527 TI - Orthotopic Hind Limb Transplantation in the Mouse. AB - In vivo animal model systems, and in particular mouse models, have evolved into powerful and versatile scientific tools indispensable to basic and translational research in the field of transplantation medicine. A vast array of reagents is available exclusively in this setting, including mono- and polyclonal antibodies for both diagnostic and interventional applications. In addition, a vast number of genotyped, inbred, transgenic, and knock out strains allow detailed investigation of the individual contributions of humoral and cellular components to the complex interplay of an immune response and make the mouse the gold standard for immunological research. Vascularized Composite Allotransplantation (VCA) delineates a novel field of transplantation using allografts to replace "like with like" in patients suffering traumatic or congenital tissue loss. This surgical methodological protocol shows the use of a non-suture cuff technique for super-microvascular anastomosis in an orthotopic mouse hind limb transplantation model. The model specifically allows for comparison between established paradigms in solid organ transplantation with a novel form of transplants consisting of various different tissue components. Uniquely, this model allows for the transplantation of a viable vascularized bone marrow compartment and niche that have the potential to exert a beneficial effect on the balance of immune acceptance and rejection. This technique provides a tool to investigate alloantigen recognition and allograft rejection and acceptance, as well as enables the pursuit of functional nerve regeneration studies to further advance this novel field of transplantation. PMID- 26967529 TI - Driving through the Great Recession: Why does motor vehicle fatality decrease when the economy slows down? AB - The relationship between short-term macroeconomic growth and temporary mortality increases remains strongest for motor vehicle (MV) crashes. In this paper, I investigate the mechanisms that explain falling MV fatality rates during the recent Great Recession. Using U.S. state-level panel data from 2003 to 2013, I first estimate the relationship between unemployment and MV fatality rate and then decompose it into risk and exposure factors for different types of MV crashes. Results reveal a significant 2.9 percent decrease in MV fatality rate for each percentage point increase in unemployment rate. This relationship is almost entirely explained by changes in the risk of driving rather than exposure to the amount of driving and is particularly robust for crashes involving large commercial trucks, multiple vehicles, and speeding cars. These findings provide evidence suggesting traffic patterns directly related to economic activity lead to higher risk of MV fatality rates when the economy improves. PMID- 26967530 TI - Effects of Metabolic Programming on Juvenile Play Behavior and Gene Expression in the Prefrontal Cortex of Rats. AB - Early developmental processes, such as metabolic programming, can provide cues to an organism, which allow it to make modifications that are predicted to be beneficial for survival. Similarly, social play has a multifaceted role in promoting survival and fitness of animals. Play is a complex behavior that is greatly influenced by motivational and reward circuits, as well as the energy reserves and metabolism of an organism. This study examined the association between metabolic programming and juvenile play behavior in an effort to further elucidate insight into the consequences that early adaptions have on developmental trajectories. The study also examined changes in expression of four genes (Drd2, IGF1, Opa1, and OxyR) in the prefrontal cortex known to play significant roles in reward, bioenergetics, and social-emotional functioning. Using four distinct variations in developmental programming (high-fat diet, caloric restriction, exercise, or high-fat diet combined with exercise), we found that dietary programming (high-fat diet vs. caloric restriction) had the greatest impact on play behavior and gene expression. However, exercise also induced changes in both measures. This study demonstrates that metabolic programming can alter neural circuits and bioenergetics involved in play behavior, thus providing new insights into mechanisms that allow programming to influence the evolutionary success of an organism. PMID- 26967531 TI - Microvesicle-associated tissue factor procoagulant activity for the preoperative diagnosis of ovarian cancer. AB - BACKGROUND: Tissue factor (TF) is involved in tumor growth and metastasis and contributes to venous thromboembolism (VTE) in cancer, including gynecological malignancies. The diagnostic value of microvesicle-associated TF procoagulant activity (MV TF PCA) in women with suspected ovarian cancer, however, has not been studied. OBJECTIVE: To evaluate MV TF PCA as a diagnostic tool in women with an ovarian mass of unknown etiology and as a predictive biomarker for perioperative VTE. METHODS: Plasma MVs were isolated by high-speed centrifugation and analyzed for TF-specific PCA by single-stage clotting assay. In addition, plasma TF antigen and soluble P-selectin (sCD62P) were measured by ELISA. RESULTS: D-Dimer, MV TF PCA, and sCD62P, but not the tumor marker, CA-125, significantly differentiated patients with malignant (n=40) from those with benign tumors (n=15) and healthy controls (n=34). In cancer patients, only D Dimer and CA-125 correlated with the FIGO stage. An abnormal D-dimer had the highest sensitivity for the diagnosis of cancer, while MV TF PCA above the ROC curve-derived cut-off value of 182U/mL had the highest specificity. By multivariate logistic regression analysis, addition of MV TF PCA conferred diagnostic benefit to the single variables, CA-125 (p=0.052) and D-dimer (p=0.019). Perioperative VTE occurred in 16% of cancer patients and was associated with an advanced FIGO stage, but not MV TF PCA. There was no difference in plasma TF antigen levels between study groups. CONCLUSIONS: MV TF PCA, but not plasma TF antigen, may provide valuable additional information for the diagnostic work-up of women with suspected ovarian cancer. PMID- 26967532 TI - Standardization of a well-controlled in vivo mouse model of thrombus formation induced by mechanical injury. AB - OBJECTIVE: Vascular plug formation by mechanical injury that exposes abundant extracellular matrix is an ideal model to mimic thrombus formation. The objective of this study was to standardize our previously established in vivo mouse model of thrombus formation induced by mechanical injury. RESULTS: The mechanical injury was exerted by pinching the abdominal aorta with hemostatic forceps for either 15 (moderate injury) or 60 (severe injury) seconds. Thrombus formation was monitored for 20min in real time using a fluorescent microscope coupled to a CCD camera. In the moderate injury, thrombus formation peaked at approximately 1min after injury and resolved within 3min, with the mean AUC (area under the curve) of 165.2+/-17.29mm(2), whereas a larger thrombus was observed upon the severe injury, with the mean AUC of 600.5+/-37.77mm(2). Using scanning electron microscopy and HE staining, a complete deformation of the endothelium in the moderate injury model and the exposure of the media in the severe injury model were observed. The model was also evaluate for its application on the effects of antithrombotic drugs targeting GP IIb-IIIa (eptifibatide), ADP receptor P2Y1 (MRS2500) and P2Y12 (clopidogrel), and thrombin (hirudin) on thrombus formation. CONCLUSIONS: We have improved a vascular injury model with optimal reproducibility and feasibility that allows evaluating the effect of anti thrombotic drugs on thrombus formation in vivo. PMID- 26967533 TI - Staphylococcus aureus Induces Shedding of IL-1RII in Monocytes and Neutrophils. AB - Interleukin 1 (IL-1) beta is a critical cytokine that orchestrates host defenses against Staphylococcus aureus and is crucial for the eradication of bacteria. The production and action of IL-1beta are regulated by multiple control pathways. Among them, IL-1RII (the type II IL-1 receptor) acts as a decoy receptor and has been shown to regulate the biological effects of IL-1beta. High levels of soluble IL-1RII are present in septic patients; however, the stimuli that regulate the expression and release of IL-1RII in pathological conditions are incompletely elucidated. In the present study, we demonstrated the ability of S. aureus and protein A to induce IL-1RII shedding in myeloid cells. The positive modulation of IL-1RII expression and cleavage was associated with the failure to detect IL 1beta in response to S. aureus both in vitro and in vivo, suggesting that the soluble form of the receptor could be masking the availability of IL-1beta. The absence of detectable IL-1beta was associated with low levels of inflammatory cytokines and chemokines known to be regulated by IL-1beta and with increased bacterial persistence. Modulation of decoy receptors during systemic S. aureus infection is proposed as a new strategy used by this bacterium to evade the immune response. PMID- 26967534 TI - Parent Perception of Newborn Hearing Screening: Results of a US National Survey. AB - IMPORTANCE: An unacceptably high number of children who do not pass universal newborn hearing screening (UNHS) are lost to follow-up. OBJECTIVES: To provide insight into parent recall of UNHS. DESIGN, SETTING, AND PARTICIPANTS: In this nationally representative cross-sectional survey, 2144 US parent households were surveyed in May 2012 using the Knowledge Panel. Responses of parents whose children were born before vs after UNHS implementation were compared. MAIN OUTCOMES AND MEASURES: Outcome measures included recall of hearing screen at birth, hearing screen results, and recommendations for follow-up. All outcome measures were based on parent recall and report. Descriptive statistics and multiple logistic regression analyses were used. RESULTS: The study participants included 1539 parent households and 605 nonparent households. Of the 1539 parent households surveyed, the mean age of the parents was 38.8 years (range, 18-88 years), the mean age of the children was 10.2 years (range, 0-17 years), and the mean age of children with hearing loss was 12.1 years (range, 0-17 years). A total of 1539 parents (55.8%) were women. Only 62.9% of parents (unweighted n = 950) recalled a newborn hearing screen, and among those children with risk indicators for hearing loss (n = 587), only 68.6% (unweighted n = 385) recalled a hearing screen. Higher parent educational level (odds ratio [OR], 2.27; 95% CI, 1.17-4.41, for some college and OR, 2.41; 95% CI, 1.22-4.78, for a bachelor's degree; P = .03), younger age of the child (OR, 1.16; 95% CI, 1.11-1.23; P < .001), and the presence of any risk indicator for hearing loss (OR, 1.5; 95% CI, 1.13-2.13; P = .007) were associated with parent recall of hearing screen. Reported pass rates were higher than expected. Parent recall of follow-up recommendations was not always consistent with guidelines. CONCLUSIONS AND RELEVANCE: Although this study is inherently limited by recall bias, the findings indicate a lack of parent awareness of UNHS. Changes in the system of reporting UNHS results are necessary to improve parent recall of screen results and improve follow-up for children who do not pass the screen. PMID- 26967535 TI - Carbon dioxide and methane fluxes from feeding and no-feeding mariculture ponds. AB - The CO2 and CH4 fluxes at the water-air interface were measured in shrimp (Marsupenaeus japonicus) monoculture ponds (S) with feed supply and shrimp-sea cucumber (Apostichopus japonicus) polyculture ponds (SS) without feed supply. During farming seasons of the whole year, cumulated CO2-C fluxes were -5.69 g m( 2) (S) and 11.23 g m(-2) (SS), respectively. The cumulated CO2 emissions from S and SS did not differ significantly. The cumulated CH4-C emissions from S (0.57 g m(-2)) were significantly higher than those from SS (0.068 g m(-2)). S absorbed C from the atmosphere with a mean absorption rate of -5.12 g m(-2), whereas SS emitted C to the atmosphere with a mean emission rate of 11.30 g m(-2). Over 20 year horizon, the compressive global warming potentials (cGWPs) were 33.55 (S) and 47.71 (SS), respectively, indicating both feeding and no-feeding mariculture ponds could promote global warming. PMID- 26967536 TI - Near roadway air pollution across a spatially extensive road and cycling network. AB - This study investigates the variability in near-road concentrations of ultra-fine particles (UFP). Our results are based on a mobile data collection campaign conducted in 2012 in Montreal, Canada using instrumented bicycles and covering approximately 475 km of unique roadways. The spatial extent of the data collected included a diverse array of roads and land use patterns. Average concentrations of UFP per roadway segment varied greatly across the study area (1411-192,340 particles/cm(3)) as well as across the different visits to the same segment. Mixed effects linear regression models were estimated for UFP (R(2) = 43.80%), incorporating a wide range of predictors including land-use, built environment, road characteristics, and meteorology. Temperature and wind speed had a large negative effect on near-road concentrations of UFP. Both the day of the week and time of day had a significant effect with Tuesdays and afternoon periods positively associated with UFP. Since UFP are largely associated with traffic emissions and considering the wide spatial extent of our data collection campaign, it was impossible to collect traffic volume data. For this purpose, we used simulated data for traffic volumes and speeds across the region and observed a positive effect for volumes and negative effect for speed. Finally, proximity to truck routes was also associated with higher UFP concentrations. PMID- 26967537 TI - Effects of non-steroidal anti-inflammatory drugs on cyanobacteria and algae in laboratory strains and in natural algal assemblages. AB - In recent years measurable concentrations of non-steroidal anti-inflammatory drugs (NSAIDs) have been shown in the aquatic environment as a result of increasing human consumption. Effects of five frequently used non-steroidal anti inflammatory drugs (diclofenac, diflunisal, ibuprofen, mefenamic acid and piroxicam in 0.1 mg ml(-1) concentration) in batch cultures of cyanobacteria (Synechococcus elongatus, Microcystis aeruginosa, Cylindrospermopsis raciborskii), and eukaryotic algae (Desmodesmus communis, Haematococcus pluvialis, Cryptomonas ovata) were studied. Furthermore, the effects of the same concentrations of NSAIDs were investigated in natural algal assemblages in microcosms. According to the changes of chlorophyll-a content, unicellular cyanobacteria seemed to be more tolerant to NSAIDs than eukaryotic algae in laboratory experiments. Growth of eukaryotic algae was reduced by all drugs, the cryptomonad C. ovata was the most sensitive to NSAIDs, while the flagellated green alga H. pluvialis was more sensitive than the non-motile green alga D. communis. NSAID treatments had weaker impact in the natural assemblages dominated by cyanobacteria than in the ones dominated by eukaryotic algae, confirming the results of laboratory experiments. Diversity and number of functional groups did not change notably in cyanobacteria dominated assemblages, while they decreased significantly in eukaryotic algae dominated ones compared to controls. The results highlight that cyanobacteria (especially unicellular ones) are less sensitive to the studied, mostly hardly degradable NSAIDs, which suggest that their accumulation in water bodies may contribute to the expansion of cyanobacterial mass productions in appropriate environmental circumstances by pushing back eukaryotic algae. Thus, these contaminants require special attention during wastewater treatment and monitoring of surface waters. PMID- 26967538 TI - 'When you visit a man you should prepare yourself': male community care worker approaches to working with men living with HIV in Cape Town, South Africa. AB - Caring is typically constructed as a feminised practice, resulting in women shouldering the burden of care-related work. Health-seeking behaviours are also constructed as feminine and men have poorer health outcomes globally. Employing men as carers may not only improve the health of the men they assist but also be transformative with regards to gendered constructions of caring. Using semi structured interviews and observational home visits, this study explored the techniques that community care workers employ when working with male clients. The empirical analysis draws on the perspectives of eight care workers and three of their male clients from the Cape Town area. Interviews reveal how care workers and clients perform and negotiate masculinities as they navigate hegemonic masculine norms that require men to act tough, suppress emotions and deny weakness and sickness. Both parties bump up against ideals of what it means to be a man as they strive to provide care and receive support. Community care workers avoid rupturing client performances of hegemonic masculinities which inhibit confession and support. To do this, they use techniques of indirectly broaching sensitive subjects, acting in a friendly way and being clear about the intention of their work. PMID- 26967539 TI - Stripe-like Clay Nanotubes Patterns in Glass Capillary Tubes for Capture of Tumor Cells. AB - Here, we used capillary tubes to evaporate an aqueous dispersion of halloysite nanotubes (HNTs) in a controlled manner to prepare a patterned surface with ordered alignment of the nanotubes . Sodium polystyrenesulfonate (PSS) was added to improve the surface charges of the tubes. An increased negative charge of HNTs is realized by PSS coating (from -26.1 mV to -52.2 mV). When the HNTs aqueous dispersion concentration is higher than 10%, liquid crystal phenomenon of the dispersion is found. A typical shear flow behavior and decreased viscosity upon shear is found when HNTs dispersions with concentrations higher than 10%. Upon drying the HNTs aqueous dispersion in capillary tubes, a regular pattern is formed in the wall of the tube. The width and spacing of the bands increase with HNTs dispersion concentration and decrease with the drying temperature for a given initial concentration. Morphology results show that an ordered alignment of HNTs is found especially for the sample of 10%. The patterned surface can be used as a model for preparing PDMS molding with regular micro-/nanostructure. Also, the HNTs rough surfaces can provide much higher tumor cell capture efficiency compared to blank glass surfaces. The HNTs ordered surfaces provide promising application for biomedical areas such as biosensors. PMID- 26967540 TI - Presence of mcr-1-positive Enterobacteriaceae in retail chicken meat but not in humans in the Netherlands since 2009. AB - Recently, the plasmid-mediated colistin resistance gene mcr-1 was found in Enterobacteriaceae from humans, pigs and retail meat in China. Several reports have documented global presence of the gene in Enterobacteriaceae from humans, food animals and food since. We screened several well-characterised strain collections of Enterobacteriaceae, obtained from retail chicken meat and hospitalised patients in the Netherlands between 2009 and 2015, for presence of colistin resistance and the mcr-1 gene. A total of 2,471 Enterobacteriaceae isolates, from surveys in retail chicken meat (196 isolates), prevalence surveys in hospitalised patients (1,247 isolates), clinical cultures (813 isolates) and outbreaks in healthcare settings (215 isolates), were analysed. The mcr-1 gene was identified in three (1.5%) of 196 extended-spectrum beta-lactamase (ESBL) producing Escherichia coli isolates from retail chicken meat samples in 2009 and 2014. Two isolates were obtained from the same batch of meat samples, most likely representing contamination from a common source. No mcr-1-positive isolates were identified among 2,275 human isolates tested. All mcr-1-positive isolates were colistin-resistant (minimum inhibitory concentration (MIC) > 2 mg/L). Our findings indicate that mcr-1-based colistin-resistance currently poses no threat to healthcare in the Netherlands. They indicate however that continued monitoring of colistin resistance and its underlying mechanisms in humans, livestock and food is needed. PMID- 26967541 TI - Evaluation of SAMe-TT2R2 score and other clinical factors influencing the quality of anticoagulation therapy in non-valvular atrial fibrillation: a nationwide study in Spain. AB - OBJECTIVE: To assess the major clinical factors affecting the quality of anticoagulation and evaluate the predictive value of the SAMe-TT2R2 score to identify patients who will achieve a high average time in therapeutic range (T.T.R.) with vitamin K antagonist (V.K.A.) treatment. RESEARCH DESIGN AND METHODS: This observational, cross-sectional, retrospective and nationwide multicenter study included 1524 patients from the primary care setting with non valvular atrial fibrillation receiving V.K.A. (>=12 months). We performed a bivariate analysis to identify factors individually associated with the T.T.R. and a multiple regression analysis to identify the independent predictive factors. For the validation of the SAMe-TT2R2 score, the receiver operating characteristic (R.O.C.) curve was calculated and the Hosmer-Lemeshow test was used to test calibration. RESULTS: A total of 94.8% of patients received acenocumarol (4.8% warfarin). A progressive decrease in mean T.T.R. was found when the SAMe-TT2R2 score increased from 0 points (72.1 +/- 17.1%) to 4 points (64.1 +/- 23.2%), p < 0.001. Other risk scores (CHADS2 and CHA2DS2-VASc, HAS BLED) were also associated with the mean T.T.R. We found a significant association between low T.T.R. and the following clinical factors: female sex, three or more comorbidities, amiodarone treatment, dietary habits, bleeding history and the intake of >=7 tablets per day besides V.K.A. (p < 0.01). Regarding SAMe-TT2R2 score validation, the R.O.C. curve showed significant capability, although not high, of discriminating good anticoagulation control (T.T.R. >=65%) with an area under the curve of 0.562 (95% C.I. 0.533-0.592, p < 0.001) which increased, remaining modest, to 0.594 (95% C.I. 0.564-0.624, p < 0.001) when the factors not included in SAMe-TT2R2 score were added. CONCLUSION: In this cohort, the SAMe-TT2R2 score had a significant, although modest, ability to assess the likelihood of good international normalized ration (I.N.R.) control, and its predictive value might slightly improve by adding other simple clinical factors. Further research is needed to refine the predictive scales. PMID- 26967542 TI - Optimizing Solute-Solute Interactions in the GLYCAM06 and CHARMM36 Carbohydrate Force Fields Using Osmotic Pressure Measurements. AB - GLYCAM06 and CHARMM36 are successful force fields for modeling carbohydrates. To correct recently identified deficiencies with both force fields, we adjusted intersolute nonbonded parameters to reproduce the experimental osmotic coefficient of glucose at 1 M. The modified parameters improve behavior of glucose and sucrose up to 4 M and improve modeling of a dextran 55-mer. While the modified parameters may not be applicable to all carbohydrates, they highlight the use of osmotic simulations to optimize force fields. PMID- 26967544 TI - Three-dimensional Particle Tracking Velocimetry for Turbulence Applications: Case of a Jet Flow. AB - 3D-PTV is a quantitative flow measurement technique that aims to track the Lagrangian paths of a set of particles in three dimensions using stereoscopic recording of image sequences. The basic components, features, constraints and optimization tips of a 3D-PTV topology consisting of a high-speed camera with a four-view splitter are described and discussed in this article. The technique is applied to the intermediate flow field (5 A. PMID- 26967568 TI - Structure and Function of the Kidney in Septic Shock. A Prospective Controlled Experimental Study. AB - RATIONALE: It is unclear how septic shock causes acute kidney injury (AKI) and whether this is associated with histological change. OBJECTIVES: We aimed to determine the nature and extent of changes in renal structure and function over time in an ovine model of septic shock. METHODS: Fifteen sheep were instrumented with a renal artery flow probe and renal vein cannula. Ten were given intravenous Escherichia coli to induce septic shock, and five acted as controls. Animals were mechanically ventilated for 48 hours, while receiving protocol-guided parenteral fluids and a norepinephrine infusion to maintain mean arterial pressure. Renal biopsies were taken every 24 hours or whenever animals were oliguric for 2 hours. A renal pathologist, blinded to tissue source, systematically quantified histological appearance by light and electron microscopy for 31 prespecified structural changes. MEASUREMENTS AND MAIN RESULTS: Sheep given E. coli developed septic shock, oliguria, increased serum creatinine, and reduced creatinine clearance (AKI), but there were no changes over time in renal blood flow between groups (P > 0.30) or over time within groups (P > 0.50). Renal oxygen consumption increased only in nonseptic animals (P = 0.01), but there was no between-group difference in renal lactate flux (P > 0.50). There was little structural disturbance in all biopsies and, although some cellular appearances changed over time, the only difference between septic and nonseptic animals was mesangial expansion on electron microscopy. CONCLUSIONS: In an intensive care-supported model of gram-negative septic shock, early AKI was not associated with changes in renal blood flow, oxygen delivery, or histological appearance. Other mechanisms must contribute to septic AKI. PMID- 26967567 TI - Inhibition of miR301 enhances Akt-mediated cell proliferation by accumulation of PTEN in nucleus and its effects on cell-cycle regulatory proteins. AB - Micro-RNAs (miRs) represent an innovative class of genes that act as regulators of gene expression. Recently, the aberrant expression of several miRs has been associated with different types of cancers. In this study, we show that miR301 inhibition influences PI3K-Akt pathway activity. Akt overexpression in MCF7 and MDAMB468 cells caused downregulation of miR301 expression. This effect was confirmed by co-transfection of miR301-modulators in the presence of Akt. Cells overexpressing miR301-inhibitor and Akt, exhibited increased migration and proliferation. Experimental results also confirmed PI3K, PTEN and FoxF2 as regulatory targets for miR301. Furthermore, Akt expression in conjunction with miR301-inhibitor increased nuclear accumulation of PTEN, thus preventing it from downregulating the PI3K-signalling. In summary, our data emphasize the importance of miR301 inhibition on PI3K-Akt pathway-mediated cellular functions. Hence, it opens new avenues for the development of new anti-cancer agents preferentially targeting PI3K-Akt pathway. PMID- 26967569 TI - Theory and Modeling of Asymmetric Catalytic Reactions. AB - Modern density functional theory and powerful contemporary computers have made it possible to explore complex reactions of value in organic synthesis. We describe recent explorations of mechanisms and origins of stereoselectivities with density functional theory calculations. The specific functionals and basis sets that are routinely used in computational studies of stereoselectivities of organic and organometallic reactions in our group are described, followed by our recent studies that uncovered the origins of stereocontrol in reactions catalyzed by (1) vicinal diamines, including cinchona alkaloid-derived primary amines, (2) vicinal amidophosphines, and (3) organo-transition-metal complexes. Two common cyclic models account for the stereoselectivity of aldol reactions of metal enolates (Zimmerman-Traxler) or those catalyzed by the organocatalyst proline (Houk-List). Three other models were derived from computational studies described in this Account. Cinchona alkaloid-derived primary amines and other vicinal diamines are venerable asymmetric organocatalysts. For alpha-fluorinations and a variety of aldol reactions, vicinal diamines form enamines at one terminal amine and activate electrophilically with NH(+) or NF(+) at the other. We found that the stereocontrolling transition states are cyclic and that their conformational preferences are responsible for the observed stereoselectivity. In fluorinations, the chair seven-membered cyclic transition states is highly favored, just as the Zimmerman-Traxler chair six-membered aldol transition state controls stereoselectivity. In aldol reactions with vicinal diamine catalysts, the crown transition states are favored, both in the prototype and in an experimental example, shown in the graphic. We found that low-energy conformations of cyclic transition states occur and control stereoselectivities in these reactions. Another class of bifunctional organocatalysts, the vicinal amidophosphines, catalyzes the (3 + 2) annulation reaction of allenes with activated olefins. Stereocontrol here is due to an intermolecular hydrogen bond that activates the electrophilic partner in this reaction. We have also studied complex organometallic catalysts. Krische's ruthenium-catalyzed asymmetric hydrohydroxyalkylation of butadiene involves two chiral ligands at Ru, a chiral diphosphine and a chiral phosphate. The size of this combination strains the limits of modern computations with over 160 atoms, multiple significant steps, and a variety of ligand coordinations and conformations possible. We found that carbon-carbon bond formation occurs via a chair Zimmerman-Traxler-type transition structure and that a formyl CH...O hydrogen bond from aldehyde CH to phosphate oxygen, as well as steric interactions of the two chiral ligands, control the stereoselectivity. PMID- 26967571 TI - Combination of microneedling and 10% trichloroacetic acid peels in the management of infraorbital dark circles. AB - BACKGROUND: Dark circles (DC), seen in the periorbital area, are defined as bilateral, round, homogeneous pigmented macules whose aetiology is thought to be multifactorial. Available treatments include bleaching creams, topical retinoic acid, chemical peels, lasers, autologous fat transplantation, injectable fillers and surgery (blepharoplasty). OBJECTIVE: To evaluate the efficacy and safety of a combination of microneedling and 10% trichloroacetic acid (TCA) peels in the treatment of DC. MATERIALS AND METHODS: Thirteen female patients with mild to severe infraorbital DC were included in the study. The patients were aged between 21 and 61 years. They were treated with Automatic Microneedle Therapy System Handhold and topical application of 10% TCA solution to each infraorbital area for five minutes. The effect was photo-documented and a Patient and Physician Global Assessment was evaluated. Safety was assessed by evaluating early and delayed adverse events. RESULTS: Almost all patients showed significant aesthetic improvement. Both Physician and Patient Global Assessment rated a fair, good or excellent response in 92.3%. The procedure was well tolerated. Mild discomfort, transient erythema and oedema were quite common during or immediately after the procedure. The patients were followed up regularly every month for four months, and no recurrence was recorded. CONCLUSION: Microneedling and 10% TCA constitute an innovative combination treatment for DC with encouraging results and minor side effects. PMID- 26967570 TI - Val/Val glutathione-S-transferase P1 polymorphism predicts nonresponders in psoriasis patients treated with fumaric acid esters. AB - Fumaric acid esters (FAE) are beneficial in the treatment of psoriasis. However, about a third of psoriasis patients do not respond to FAE. We aimed to determine whether glutathione-S-transferase (GST) M1 and GSTP1 polymorphisms are associated with treatment outcome in psoriasis patients treated with FAE. We studied 84 psoriasis patients who were treated with FAE for 3 months. FAE nonresponders were defined as having psoriasis area and severity improvement index less than 50% after 3-month therapy. GSTM1 genotyping for gene deletion and GSTP1 exon 5 105 Ile->Val polymorphisms were assessed using a high-resolution melting analysis. A dropout rate of 23.8% (20/84) was found; 25% (16/64) were FAE nonresponders. We observed 42 (84/50%) patients with G 9STM1*0 homozygous alleles and 42 (84/50%) patients with one or two active GSTM1 alleles. The Ile/Ile GSTP1 genotype was observed in 37 (84/44%), the Ile/Val GSTP1 genotype in 38 (84/45.2%) patients and the Val/Val GSTP1 genotype in nine (84/10.7%) patients. There was no significant (P>0.05) association between the GST genotypes assessed and the frequency FAE responder status, except for the Val/Val GSTP1 polymorphism, which was a significant (overall model fit; P=0.0012) predictor for nonresponders with an odds ratio of 43.4 (95% confidence interval: 4.2-511.1). The coefficient of regression was 3.9, with a SE of 1.2 as assessed by logistic regression analysis (P=0.0017). The Val/Val GSTP1 polymorphism predicts nonresponders in FAE treatment of psoriasis patients and may therefore serve as a biomarker that enables a laboratory-based pretreatment selection of patients. PMID- 26967572 TI - Conversion of 3,3,3-Trisubstituted Prop-1-ynes with tert-Butylhydrazine into 3,3,3-Trisubstituted Propionitriles Catalyzed by TpRh(C2H4)2/P(2-furyl)3. AB - The combination of TpRh(C2H4)2 (Tp = tris(pyrazol-1-yl)borate) and P(2-furyl)3 catalyzes the reaction of tertiary alkyl-substituted alkynes with tert butylhydrazine, leading to the formation of 3,3,3-trisubstituted propionitrile derivatives. This reaction system is applicable to 1,1-disubstituted propargyl alcohols and amines to afford the corresponding beta-cyanohydrins and beta-amino nitriles, respectively. The catalytic cycle involves the formation of a vinylidenerhodium complex as a key intermediate. PMID- 26967573 TI - Autophagic flux in glioblastoma cells. AB - To establish metabolic context for radiation sensitivity by measuring autophagic flux in two different glioblastoma (GBM) cell lines. Clonogenic survival curve analysis of U87 or U251 cells exposed to gamma radiation, fast neutrons, a mixed energy neutron beam (METNB) or Auger electrons from a gadolinium neutron capture (GdNC) reaction suggested other factors, beyond a defective DNA damage response, contribute to cell death of U251 cells. Altered tumor metabolism (autophagy) was hypothesized as a factor in U251 cells' clonogenic response. Each of the four different radiation modalities induced an increase in the number of autophagosomes in both U87 and U251 cells. Changes in the number of autophagosomes can be explained by either induction of autophagy or alterations in autophagic flux so autophagic flux was assayed by p62 immunoblotting or in engineered GBM cells that stably express an autophagy marker protein, LC3B-eGFP mCherry. Perturbations in later stages of autophagy in U251 cells corresponded with radiation sensitivity of U251 cells irradiated with 10 Gy gamma rays. Establishment of altered autophagic flux is a useful biomarker for metabolic stress and provided metabolic context for radiation sensitization to 10 Gy gamma rays. These results provide strong evidence for the usefulness of managing tumor cell metabolism as a tool for the enhancement of radiation therapy. PMID- 26967574 TI - Systemic Amyloidosis and Extraocular Muscle Deposition. AB - Isolated amyloid deposition in an extraocular muscle is a rare event but can be a presenting feature of systemic amyloidosis. A 67-year-old woman with an acquired exotropia and hypertropia was found to have unilateral diffuse extraocular muscle enlargement on magnetic resonance imaging. Owing to the progressive nature of her strabismus and the negative laboratory testing for thyroid disease, she underwent an extraocular muscle biopsy that revealed amyloid deposition. Further workup demonstrated a monoclonal gammopathy consistent with systemic amyloidosis. This case demonstrates the need to consider amyloidosis in the differential diagnosis of patients presenting with an atypical acquired strabismus. We review other reports of isolated amyloid deposition in extraocular muscles and its association with systemic amyloidosis, emphasizing the importance of the ophthalmologist in the early recognition of this disease to prevent irreversible, life-threatening end organ damage. PMID- 26967576 TI - Disaster preparedness and response improvement: comparison of the 2010 Haiti earthquake-related diagnoses with baseline medical data. AB - OBJECTIVES: Disaster medicine research generally lacks control groups. This study aims to describe categories of diagnoses encountered by the Belgian First Aid and Support Team after the 2010 Haiti earthquake and extract earthquake-related changes from comparison with comparable baseline data. The hypothesis is that besides earthquake-related trauma, medical problems emerge soon, questioning an appropriate composition of Foreign Medical Teams and Interagency Emergency Health Kits. METHODS: Using a descriptive cohort study design, diagnoses of patients presenting to the Belgian field hospital were prospectively registered during 4 weeks after the earthquake and compared with those recorded similarly by Medecins Sans Frontieres in the same area and time span in previous and later years. RESULTS: Of 7000 triaged postearthquake patients, 3500 were admitted, of whom 2795 were included and analysed. In the fortnight after the earthquake, 90% suffered from injury. In the following fortnight, medical diseases emerged, particularly respiratory (23%) and digestive (14%). More than 53% developed infections within 3 weeks after the event. Medecins Sans Frontieres registered 6407 patients in 2009; 6033 in 2011; and 7300 in 2012. A comparison indicates that postearthquake patients suffered significantly less from violence, but more from wounds, respiratory, digestive and ophthalmological diseases. CONCLUSION: This is the first comparison of postearthquake diagnoses with baseline data. Within 2 weeks after the acute phase of an earthquake, respiratory, digestive and ophthalmological problems will emerge to the prejudice of trauma. This fact should be anticipated when composing Foreign Medical Teams and Interagency Emergency Health Kits to be sent to the disaster site. PMID- 26967578 TI - Enantioselective Synthesis of Chiral Piperidines via the Stepwise Dearomatization/Borylation of Pyridines. AB - We have developed a novel approach for the synthesis of enantioenriched 3-boryl tetrahydropyridines via the Cu(I)-catalyzed regio-, diastereo-, and enantioselective protoborylation of 1,2-dihydropyridines, which were obtained by the partial reduction of the pyridine derivatives. This dearomatization/enantioselective borylation stepwise strategy provides facile access to chiral piperidines together with the stereospecific transformation of a stereogenic C-B bond from readily available starting materials. Furthermore, the utility of this method is demonstrated for the concise synthesis of the antidepressant drug (-)-paroxetine. A theoretical study of the reaction mechanism is also described. PMID- 26967579 TI - Association between Urinary Sodium Excretion and Bone Health in Male and Female Adults. AB - BACKGROUND: High salt intake is a well-known risk factor for osteoporosis, but the association between bone mass and urinary sodium excretion has not been studied as yet. This study investigates the hypothesis that urinary sodium excretion is negatively associated with bone mass and the risk of osteoporosis. METHODS: This cross-sectional study was performed using data from the Korea National Health and Nutrition Examination Survey, 2008-2011. Participants (n = 16,279) were divided into age groups; men were categorized as younger than 50 years of age or 50 years or greater, women were categorized as pre- or post menopausal. RESULTS: Multivariate linear regression analysis showed that urinary sodium excretion was negatively associated with bone mineral content (BMC) and bone mineral density (BMD) in premenopausal and postmenopausal women. Sodium excretion was negatively associated with BMC and BMD of the lumbar spine in women with normal bone health, osteopenia and osteoporosis, but there was no association in men. Increased sodium excretion was significantly associated with risk for osteoporosis/osteopenia in premenopausal women. CONCLUSIONS: This study demonstrates that urinary sodium excretion is negatively associated with bone health, suggesting that high salt intake could be a possible risk factor for osteoporosis in Korean women, but not in men. PMID- 26967580 TI - Intraluminal Drug Delivery to the Mouse Arteriovenous Fistula Endothelium. AB - Delivery of therapeutic agents to enhance arteriovenous fistula (AVF) maturation can be administered either via intraluminal or external routes. The simple murine AVF model was combined with intraluminal administration of drug solution to the venous endothelium at the same time as fistula creation. Technical aspects of this model are discussed. Under general anesthesia, an abdominal incision is made and the aorta and inferior vena cava (IVC) are exposed. The infra-renal aorta and IVC are dissected for clamping. After proximal and distal clamping, the puncture site is exposed and a 25 G needle is used to puncture both walls of the aorta and into the IVC. Immediately after the puncture, a reporter gene-expressing viral vector was infused in the IVC via the same needle, followed by 15 min of incubation. The intraluminal administration method enabled more robust viral gene delivery to the venous endothelium compared to administration by the external route. This novel method of delivery will facilitate studies that explore the role of the endothelium in AVF maturation and enable intraluminal drug delivery at the time of surgical operation. PMID- 26967581 TI - Effects of Narrow Networks on Access to High-Quality Cancer Care. PMID- 26967582 TI - Erlotinib for the treatment of brain metastases in non-small cell lung cancer. AB - INTRODUCTION: Brain metastases (BM) are a common and lethal complication of non small cell lung cancer (NSCLC) with up to 40% experiencing this complication. The use of erlotinib, a small molecule epidermal growth factor receptor (EGFR) inhibitor, holds promise in this somewhat refractory cohort of patients, and has become the subject of active clinical investigation. AREAS COVERED: This review covers the preclinical and clinical studies of erlotonib as it relates to its use in the treatment of NSCLC patients with BM. A literature search in part utilized the PubMed database up through Dec 2015. EXPERT OPINION: Preclinical and retrospective data for erlotinib provide evidence of CNS penetration, and objective responses in the setting of BM from EGFR mutated NSCLC. Phase I and II data have demonstrated the feasibility of concomitant delivery of erlotinib and WBRT in the treatment of BM from NSCLC. Phase II/III data however, from non-EGFR mutation enriched populations, have demonstrated no benefit in progression free or overall survival with the addition of erlotinib to metastasis directed radiotherapy. Currently the utilization of erlotinib with WBRT or SRS is therefore investigational and may be a reasonable option in erlotinib naive, EGFR mutated patients with refractory BM. PMID- 26967583 TI - A Techno-Economic Assessment of Hybrid Cooling Systems for Coal- and Natural-Gas Fired Power Plants with and without Carbon Capture and Storage. AB - Advanced cooling systems can be deployed to enhance the resilience of thermoelectric power generation systems. This study developed and applied a new power plant modeling option for a hybrid cooling system at coal- or natural-gas fired power plants with and without amine-based carbon capture and storage (CCS) systems. The results of the plant-level analyses show that the performance and cost of hybrid cooling systems are affected by a range of environmental, technical, and economic parameters. In general, when hot periods last the entire summer, the wet unit of a hybrid cooling system needs to share about 30% of the total plant cooling load in order to minimize the overall system cost. CCS deployment can lead to a significant increase in the water use of hybrid cooling systems, depending on the level of CO2 capture. Compared to wet cooling systems, widespread applications of hybrid cooling systems can substantially reduce water use in the electric power sector with only a moderate increase in the plant-level cost of electricity generation. PMID- 26967584 TI - Morphoeic basal cell carcinoma with ring-form ulceration. PMID- 26967585 TI - Identification of candidate genes in atopic dermatitis based on bioinformatic methods. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic or relapsing inflammatory disorder of the skin that frequently precedes asthma and allergic disorders. This study aimed to identify candidate genes related to AD using bioinformatic methods. METHODS: The microarray data of GSE32924, including 12 nonlesional AD (ANL) and 13 lesional AD (AL) skin samples obtained from 14 patients with AD as well as eight other normal human skin samples, was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened in ANL and AL skin samples compared with normal controls, followed by gene ontology (GO) and pathway enrichment analyses. Furthermore, the selected overlapping DEGs were analyzed to identify co-expressed genes, and a co expression network was established. GeneCodis database was selected for functional annotation of the differentially co-expressed genes and a regulatory network was constructed. RESULTS: Compared with normal controls, 438 DEGs were identified in ANL skin samples and were mainly enriched in two pathways and the GO terms associated with epidermis development. Besides, 779 DEGs were identified in AL skin samples and were mainly enriched in four pathways and GO terms associated with immune response. Stimulated by retinoic acid 13 (STRA13), presenilin enhancer gamma secretase subunit (PSENEN), and nucleosome assembly protein 1-like 2 (NAP1L2) were significantly enriched by integration analysis of the co-expression and regulatory network. CONCLUSION: Genes STRA13, PSENEN, and NAP1L2 were presumed to play critical roles in AD and they may serve as potential targets for the treatment of AD. PMID- 26967586 TI - Production of Double-stranded DNA Ministrings. AB - We constructed linear covalently closed (LCC) DNA minivectors as a non-viral gene delivery vector alternative produced via a simple platform in vivo. DNA ministrings possess a heightened safety profile and also efficiently deliver DNA cargo to targeted cells. Conventional DNA vectors carry undesirable prokaryotic sequences, including antibiotic resistance genes, CpG motifs, and bacterial origins of replication, which may lead to the stimulation of host immunological responses. The bioavailability of conventional DNA vectors is also compromised due to their larger molecular size. Their circular nature may also impart chromosomal integration, leading to insertional mutagenesis. Bacterial sequences are excised from DNA minivectors, leaving only the gene of interest (GOI) and necessary eukaryotic expression elements. Our LCC DNA minivectors, or DNA ministrings, are devoid of immunogenic bacterial sequences; therefore improving their bioavailability and GOI expression. In the event of vector integration into the chromosome, the LCC DNA ministring will lethally disrupt the host chromosome, thereby removing the potentially dangerous mutant from the proliferating cell population. Consequently, DNA ministrings offer the benefits of 'minicircle' DNA while eliminating the potential for undesirable vector integration events. In comparison to conventional plasmids and their isogenic circular covalently closed (CCC) counterparts, DNA ministrings demonstrate superior bioavailability, transfection efficiency, and cytoplasmic kinetics - they thus require lower amounts of cationic surfactants for effective transfection of target cells. We have constructed a one-step inducible in vivo system for the production of DNA ministrings in Escherichia coli that is simple to use, rapid, and scalable. PMID- 26967587 TI - Naringin lauroyl ester inhibits lipopolysaccharide-induced activation of nuclear factor kappaB signaling in macrophages. AB - Naringin (Nar) has antioxidant and anti-inflammatory properties. It was recently reported that enzymatic modification of Nar enhanced its functions. Here, we acylated Nar with fatty acids of different sizes (C2-C18) using immobilized lipase from Rhizomucor miehei and investigated the anti-inflammatory effects of these molecules. Treatment of murine macrophage RAW264.7 cells with Nar alkyl esters inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production, with Nar lauroyl ester (Nar-C12) showing the strongest effect. Furthermore, Nar C12 suppressed the LPS-induced expression of inducible NO synthase by blocking the phosphorylation of inhibitor of nuclear factor (NF)-kappaB-alpha as well as the nuclear translocation of NF-kappaB subunit p65 in macrophage cells. Analysis of Nar-C12 uptake in macrophage cells revealed that Nar-C12 ester bond was partially degraded in the cell membrane and free Nar was translocated to the cytosol. These results indicate that Nar released from Nar-C12 exerts anti inflammatory effects by suppressing NF-kappaB signaling pathway. PMID- 26967588 TI - Epidemiology of Uveitis in a Tertiary Eye Center in Myanmar. AB - PURPOSE: To identify the characteristics of uveitis in a tertiary eye center in Myanmar. METHODS: A retrospective study was undertaken to obtain the characteristics of uveitis in a tertiary eye center in Myanmar from September 2013 to September 2014, using a standard clinical protocol and tailored laboratory investigations. RESULTS: A total of 139 patients were included in this epidemiologic study; 71 (51.1%) men and 68 (48.9%) women. The mean age of onset was 36.3 +/- 15.5 years. Infectious uveitis constituted 76/139 (54.7%) cases and non-infectious etiologies accounted for 63/139 (45.3%) cases. The most common non infectious etiologies were idiopathic, followed by HLA-B27-associated anterior uveitis and multifocal choroiditis with panuveitis, while tuberculosis was the most common infectious etiology. CONCLUSIONS: Tuberculosis was the most frequent cause of uveitis among the infectious group of patients in this tertiary eye center as a result of endemic disease in Myanmar. PMID- 26967590 TI - Shared mental models and intra-team psychophysiological patterns: a test of the juggling paradigm. AB - We explored implicit coordination mechanisms underlying the conceptual notion of "shared mental models" (SMM) through physiological (i.e., breathing and heart rates) and affective-cognitive (i.e., arousal, pleasantness, attention, self efficacy, other's efficacy) monitoring of two professional jugglers performing a real-time interactive task of increasing difficulty. There were two experimental conditions: "individual" (i.e., solo task) and "interactive" (i.e., two jugglers established a cooperative interaction by juggling sets of balls with each other). In both conditions, there were two task difficulties: "easy" and "hard." Descriptive analyses revealed that engaging in a dyadic cooperative motor task (interactive condition) required greater physiological effort (Median Cohen's d = 2.13) than performing a solo motor task (individual condition) of similar difficulty. Our results indicated a strong positive correlation between the jugglers' heart rate for the easy (r = .87) and hard tasks (r = .77). The relationship between the jugglers' breathing rate was significant for the easy task (r = .73) but non-significant for the hard task. The findings are interpreted based on research on SMM and Theory of Mind. Practitioners should advance the notion of "shared-regulation" in the context of team coordination through the use of biofeedback training. PMID- 26967589 TI - Expectations impact short-term memory through changes in connectivity between attention- and task-related brain regions. AB - Over the recent years, neuroimaging studies have investigated the neural mechanisms underlying the influence of expectations on perception. However, it seems equally reasonable to assume that expectations impact cognitive functions. Here we used fMRI to explore the role of expectations on task performance and its underlying neural mechanisms. 43 healthy participants were randomly assigned to two groups. Using verbal instructions, group 1 was led to believe that pain enhances task performance while group 2 was instructed that pain hampers their performance. All participants performed a Rapid-Serial-Visual-Presentation (RSVP) Task (target detection and short-term memory component) with or without concomitant painful heat stimulation during 3T fMRI scanning. As hypothesized, short-term memory performance showed an interaction between painful stimulation and expectation. Positive expectations induced stronger neural activation in the right inferior parietal cortex (IPC) during painful stimulation than negative expectation. Moreover, IPC displayed differential functional coupling with the left inferior occipital cortex under pain as a function of expectancy. Our data show that an individual's expectation can influence cognitive performance in a visual short-term memory task which is associated with activity and connectivity changes in brain areas implicated in attentional processing and task performance. PMID- 26967591 TI - Comparison between the effects of 18- and 23-mmHg elastic stockings on leg volume and fatigue in golfers. AB - BACKGROUND: The aim of this study was to determine the differences in the effect of 18- versus 23-mmHg hosiery as for leg volume and fatigue control. METHODS: Forty golf players (M: N.=29, F: N.=11; mean age 48+/-11 years) were randomized for a 18-hole competition without hosiery (N.=10), with 18-mmHg graduated stockings (N.=10) and with 23-mmHg graduated stockings (N.=20, half of which footless and half footed). An echo-color-Doppler scanning excluded vascular pathologies. Limb volume was assessed by water plethysmography. The perceived fatigue was assessed by a questionnaire. RESULTS: The use of no hosiery led to a 5% increase in leg volume (P<0.0001). In the 18-mmHg group, a non-significant 1% volume reduction was observed. In the 23-mmHg group, leg volume significantly decreased by 4% both with footless and footed stockings. A significant fatigue reduction was perceived only in the 23-mmHg group. CONCLUSIONS: A leg volume increase was reported along an 18-hole competition. In the 18- and 23-mmHg groups, only the latter demonstrated a significant reduction in leg volume and perceived fatigue. PMID- 26967594 TI - Thyroid function and IVF outcome: when to investigate and when to intervene? AB - PURPOSE OF REVIEW: To summarize the evidence regarding the need to assess thyroid function in women undergoing ovarian stimulation as well as the need to intervene when thyroid function is suboptimal. RECENT FINDINGS: There is now evidence that ovarian stimulation can influence thyroid function not only via hyperestrogenism but also directly, since thyroid-related receptors are present in human granulosa cells and in the endometrium. Prospective and retrospective observational studies, as well as a few clinical trials, have been conducted in an effort to clarify the association between ovarian stimulation and thyroid function with controversial results. SUMMARY: The need of thyroid function screening with thyroid stimulating hormone (TSH) in infertile women attempting pregnancy is recognized by many international societies. Since TSH is a simple, cheap screening tool and levothyroxine (LT4) supplementation is an easy to apply, cheap and well tolerated intervention, universal thyroid screening in women undergoing IVF represents a reasonable policy. In case of subclinical hypothyroidism, when TSH exceeds the threshold of 4.0 or 4.5 MUIU/ml before IVF, LT4 replacement should be administered, while the same intervention might also be justified for women with TSH concentration more than 2.5 MUIU/ml before IVF. PMID- 26967593 TI - Testing principle working mechanisms of the health action process approach for subjective physical age groups. AB - This study investigated differences in social-cognitive predictors and self regulatory planning, as proposed by the health action process approach (HAPA), across three different subjective physical age groups for physical activity. With a cross-sectional design, 521 participants across the chronological age span from 25 to 86 years (M = 48.79; SD = 12.66) were separated into three groups: those who feel physically younger than they are in terms of chronological age, the same perceived and chronological age, and feeling physically older compared to their chronological age. Participants were assessed regarding their perceived vulnerability, outcome expectancies, general intentions, planning, self-efficacy, and stages of physical activity (non-intenders, intenders, and actors). Data were analysed via mean comparison and multigroup structural equation modelling. Mean differences for all but one construct were eminent in all groups, generally showing that those feeling physically younger also report better social-cognitive predictors of physical activity (e.g. lower perceived vulnerability) in comparison to those who feel the same age or older. The model showed that basic working mechanisms of the HAPA can be applied to all groups. With that, the results provide for the first time evidence that principle working mechanism of the HAPA can be applied to all subjective physical age groups. These may be used to tailor health promoting interventions according to participants' needs as a more suitable proxy than chronological age. PMID- 26967595 TI - Adjusting the thermoelectric properties of copper(I) oxide-graphite-polymer pastes and the applications of such flexible composites. AB - We present a facile alternative to other well known strategies for synthesizing flexible thermoelectric materials. Instead of printing thin active layers on flexible substrates or doping conductive polymers, we produce thermoelectric pastes, using a mixture of graphite, copper(I) oxide and polychlorotrifluoroethene. The Seebeck coefficient of the investigated pastes varies between 10 and 600 MUV K(-1), while the electrical conductivity spans over an even wider range of 10(-4) to 10(2) S m(-1). Here, the influence of phenomena such as percolation on the electrical transport is revealed. The resulting power factor reaches 5.69 * 10(-4) +/- 0.70 * 10(-4) MUW m(-1) K(-2) for the graphite polymer paste, with an unexpected minimum at a graphite molar fraction of approximately 0.4. The values are comparable to those of the powder mixtures, which are slightly higher, but less precisely tunable. Such compounds are further evaluated for practical applications. The graphite-polymer paste is used to exemplify, how a flexible thermoelectric sensor can be easily manufactured, step by step. Our results represent a proof of principle, that thermoelectric pastes are viable alternatives to current solutions. A further expansion of the scope for the composites can be achieved by using high performance thermoelectric materials and conductive polymers. PMID- 26967592 TI - In Vivo Quantitative Assessment of Myocardial Structure, Function, Perfusion and Viability Using Cardiac Micro-computed Tomography. AB - The use of Micro-Computed Tomography (MicroCT) for in vivo studies of small animals as models of human disease has risen tremendously due to the fact that MicroCT provides quantitative high-resolution three-dimensional (3D) anatomical data non-destructively and longitudinally. Most importantly, with the development of a novel preclinical iodinated contrast agent called eXIA160, functional and metabolic assessment of the heart became possible. However, prior to the advent of commercial MicroCT scanners equipped with X-ray flat-panel detector technology and easy-to-use cardio-respiratory gating, preclinical studies of cardiovascular disease (CVD) in small animals required a MicroCT technologist with advanced skills, and thus were impractical for widespread implementation. The goal of this work is to provide a practical guide to the use of the high-speed Quantum FX MicroCT system for comprehensive determination of myocardial global and regional function along with assessment of myocardial perfusion, metabolism and viability in healthy mice and in a cardiac ischemia mouse model induced by permanent occlusion of the left anterior descending coronary artery (LAD). PMID- 26967624 TI - Simulation and Theory of Antibody Binding to Crowded Antigen-Covered Surfaces. AB - In this paper we introduce a fully flexible coarse-grained model of immunoglobulin G (IgG) antibodies parametrized directly on cryo-EM data and simulate the binding dynamics of many IgGs to antigens adsorbed on a surface at increasing densities. Moreover, we work out a theoretical model that allows to explain all the features observed in the simulations. Our combined computational and theoretical framework is in excellent agreement with surface-plasmon resonance data and allows us to establish a number of important results. (i) Internal flexibility is key to maximize bivalent binding, flexible IgGs being able to explore the surface with their second arm in search for an available hapten. This is made clear by the strongly reduced ability to bind with both arms displayed by artificial IgGs designed to rigidly keep a prescribed shape. (ii) The large size of IgGs is instrumental to keep neighboring molecules at a certain distance (surface repulsion), which essentially makes antigens within reach of the second Fab always unoccupied on average. (iii) One needs to account independently for the thermodynamic and geometric factors that regulate the binding equilibrium. The key geometrical parameters, besides excluded-volume repulsion, describe the screening of free haptens by neighboring bound antibodies. We prove that the thermodynamic parameters govern the low-antigen concentration regime, while the surface screening and repulsion only affect the binding at high hapten densities. Importantly, we prove that screening effects are concealed in relative measures, such as the fraction of bivalently bound antibodies. Overall, our model provides a valuable, accurate theoretical paradigm beyond existing frameworks to interpret experimental profiles of antibodies binding to multi-valent surfaces of different sorts in many contexts. PMID- 26967625 TI - Additional Insights into the Obtusallene Family: Components of Laurencia marilzae. AB - The obtusallenes are a significant subset of C15-halogenated acetogenins that incorporate 12-membered cyclic ethers. We have recently reported the isolation from Laurencia marilzae of 12-epoxyobtusallene IV (1) and its related alpha,beta unsaturated carboxylate ester (2), both of special biogenetic relevance. Here we describe the final step of our study, the isolation of three new analogues (3-5), among these, the first bromopropargylic derivative (3) of this class of macrocyclic C15-acetogenins. The structures were elucidated by analysis of NMR and X-ray data. 12-Epoxyobtusallene IV (1), its new isomer 4, and known obtusallene IV (6) were evaluated for their apoptosis-inducing activities in a human hepatocarcinoma cell line. PMID- 26967626 TI - Truncation, modification, and optimization of MIG6(segment 2) peptide to target lung cancer-related EGFR. AB - Human epidermal growth factor receptor (EGFR) plays a central role in the pathological progression and metastasis of lung cancer; the development and clinical application of therapeutic agents that target the receptor provide important insights for new lung cancer therapies. The tumor-suppressor protein MIG6 is a negative regulator of EGFR, which can bind at the activation interface of asymmetric dimer of EGFR kinase domains to disrupt dimerization and then inactivate the kinase (Zhang X. et al. Nature 2007, 450: 741-744). The protein adopts two separated segments, i.e. MIG6(segment 1) and MIG6(segment 2), to directly interact with EGFR. Here, computational modeling and analysis of the intermolecular interaction between EGFR kinase domain and MIG6(segment 2) peptide revealed that the peptide is folded into a two-stranded beta-sheet composed of beta-strand 1 and beta-strand 2; only the beta-strand 2 can directly interact with EGFR activation loop, while leaving beta-strand 1 apart from the kinase. A C terminal island within the beta-strand 2 is primarily responsible for peptide binding, which was truncated from the MIG6(segment 2) and exhibited weak affinity to EGFR kinase domain. Structural and energetic analysis suggested that phosphorylation at residues Tyr394 and Tyr395 of truncated peptide can considerably improve EGFR affinity, and mutation of other residues can further optimize the peptide binding capability. Subsequently, three derivative versions of the truncated peptide, including phosphorylated and dephosphorylated peptides as well as a double-point mutant were synthesized and purified, and their affinities to the recombinant protein of human EGFR kinase domain were determined by fluorescence anisotropy titration. As expected theoretically, the dephosphorylated peptide has no observable binding to the kinase, and phosphorylation and mutation can confer low and moderate affinities to the peptide, respectively, suggesting a good consistence between the computational analysis and experimental assay. PMID- 26967627 TI - Practice Guidelines for Operative Performance Assessments. AB - OBJECTIVE: To provide recommended practice guidelines for assessing single operative performances and for combining results of operative performance assessments into estimates of overall operative performance ability. SUMMARY BACKGROUND DATA: Operative performance is one defining characteristic of surgeons. Assessment of operative performance is needed to provide feedback with learning benefits to surgical residents in training and to assist in making progress decisions for residents. Operative performance assessment has been a focus of investigation over the past 20 years. This review is designed to integrate findings of this research into a set of recommended operative performance practices. METHODS: Literature from surgery and from other pertinent research areas (psychology, education, business) was reviewed looking for evidence to inform practice guideline development. Guidelines were created along with a conceptual and scientific foundation for each guideline. RESULTS: Ten guidelines are provided for assessing individual operative performances and 10 are provided for combing data from individual operative performances into overall judgments of operative performance ability. CONCLUSIONS: The practice guidelines organize available information to be immediately useful to program directors, to support surgical training, and to provide a conceptual framework upon which to build as the base of pertinent knowledge expands through future research and development efforts. PMID- 26967629 TI - Percutaneous Microwave Ablation Liver Partition and Portal Vein Embolization for Rapid Liver Regeneration: A Minimally Invasive First Step of ALPPS for Hepatocellular Carcinoma. PMID- 26967637 TI - Screening of dietary antioxidants against mitochondria-mediated oxidative stress by visualization of intracellular redox state. AB - Mitochondrial impairment and the resulting generation of reactive oxygen species (ROS) have been associated with aging and its related pathological conditions. Recently, dietary antioxidants have gained significant attention as potential preventive and therapeutic agents against ROS-generated aging and pathological conditions. We previously demonstrated that food-derived antioxidants prevented intracellular oxidative stress under proteasome inhibition conditions, which was attributed to mitochondrial dysfunction and ROS generation, followed by cell death. Here, we further screened dietary antioxidants for their activity as redox modulators by visualization of the redox state using Redoxfluor, a fluorescent protein redox probe. Direct alleviation of ROS by antioxidants, but not induction of antioxidative enzymes, prevented mitochondria-mediated intracellular oxidation. The effective antioxidants scavenged mitochondrial ROS and suppressed cell death. Our study indicates that redox visualization under mitochondria mediated oxidative stress is useful for screening potential antioxidants to counteract mitochondrial dysfunction, which has been implicated in aging and the pathogenesis of aging-related diseases. PMID- 26967638 TI - Ginger hexane extract suppresses RANKL-induced osteoclast differentiation. AB - Osteoporosis is a debilitating disease caused by decreased bone density. Compounds with anti-osteoclastic activity, such as bisphosphonates, may help in the prevention and treatment of osteoporosis. Herein, we determined the inhibitory effects of ginger hexane extract (GHE) on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis in RAW264.7 cells. The results showed that GHE (1) suppressed osteoclast differentiation and the formation of actin rings; (2) inhibited the expression of Nfatc1, a master transcriptional factor for osteoclast differentiation, in a dose-dependent manner (10-20 MUg/mL); and (3) inhibited other osteoclastogenesis-related genes, such as Oscar, Dc-stamp, Trap, and Mmp9. These findings suggest that GHE may be used to prevent and treat osteoporosis by inhibiting osteoclast differentiation. PMID- 26967639 TI - Erratum. PMID- 26967640 TI - Cannabinoids Regulate Bcl-2 and Cyclin D2 Expression in Pancreatic beta Cells. AB - Recent reports have shown that cannabinoid 1 receptors (CB1Rs) are expressed in pancreatic beta cells, where they induce cell death and cell cycle arrest by directly inhibiting insulin receptor activation. Here, we report that CB1Rs regulate the expression of the anti-apoptotic protein Bcl-2 and cell cycle regulator cyclin D2 in pancreatic beta cells. Treatment of MIN6 and betaTC6 cells with a synthetic CB1R agonist, WIN55,212-2, led to a decrease in the expression of Bcl-2 and cyclin D2, in turn inducing cell cycle arrest in G0/G1 phase and caspase-3-dependent apoptosis. Additionally, genetic deletion and pharmacological blockade of CB1Rs after injury in mice led to increased levels of Bcl-2 and cyclin D2 in pancreatic beta cells. These findings provide evidence for the involvement of Bcl-2 and cyclin D2 mediated by CB1Rs in the regulation of beta cell survival and growth, and will serve as a basis for developing new therapeutic interventions to enhance beta-cell function and growth in diabetes. PMID- 26967641 TI - Pericardial- Rather than Intramyocardial Fat Is Independently Associated with Left Ventricular Systolic Heart Function in Metabolically Healthy Humans. AB - BACKGROUND: Obesity is a major risk factor to develop heart failure, in part due to possible lipotoxic effects of increased intramyocardial (MYCL) and/or local or paracrine effects of pericardial (PERI) lipid accumulation. Recent evidence suggests that MYCL is highly dynamic and might rather be a surrogate marker for disturbed energy metabolism than the underlying cause of cardiac dysfunction. On the other hand, PERI might contribute directly by mechanic and paracrine effects. Therefore, we hypothesized that PERI rather than MYCL is associated with myocardial function. METHODS: To avoid potential confounding of metabolic disease 31 metabolically healthy subjects (age: 29+/-10yrs; BMI: 23+/-3kg/m2) were investigated using 1H-magnetic resonance spectroscopy and imaging. MYCL and PERI, as well as systolic and diastolic left ventricular heart function were assessed. Additionally, anthropometric data and parameters of glucose and lipid metabolism were analyzed. Correlation analysis was performed using Pearson's correlation coefficient. Linear regression model was used to show individual effects of PERI and MYCL on myocardial functional parameters. RESULTS: Correlation analysis with parameters of systolic heart function revealed significant associations for PERI (Stroke Volume (SV): R = -0.513 p = 0.001; CardiacIndex (CI): R = -0.442 p = 0.014), but not for MYCL (SV: R = -0.233; p = 0.207; CI: R = -0.130; p = 0.484). No significant correlations were found for E/A ratio as a parameter of diastolic heart function. In multiple regression analysis CI was negatively predicted by PERI, whereas no impact of MYCL was observed in direct comparison. CONCLUSIONS: Cardiac fat depots impact left ventricular heart function in a metabolically healthy population. Direct comparison of different lipid stores revealed that PERI is a more important predictor than MYCL for altered myocardial function. PMID- 26967643 TI - Surface Reconstruction from Parallel Curves with Application to Parietal Bone Fracture Reconstruction. AB - Maxillofacial trauma are common, secondary to road traffic accident, sports injury, falls and require sophisticated radiological imaging to precisely diagnose. A direct surgical reconstruction is complex and require clinical expertise. Bio-modelling helps in reconstructing surface model from 2D contours. In this manuscript we have constructed the 3D surface using 2D Computerized Tomography (CT) scan contours. The fracture part of the cranial vault are reconstructed using GC1 rational cubic Ball curve with three free parameters, later the 2D contours are flipped into 3D with equidistant z component. The constructed surface is represented by contours blending interpolant. At the end of this manuscript a case report of parietal bone fracture is also illustrated by employing this method with a Graphical User Interface (GUI) illustration. PMID- 26967642 TI - Insulin-Like Growth Factor 1 (IGF-1) in Parkinson's Disease: Potential as Trait-, Progression- and Prediction Marker and Confounding Factors. AB - INTRODUCTION: Biomarkers indicating trait, progression and prediction of pathology and symptoms in Parkinson's disease (PD) often lack specificity or reliability. Investigating biomarker variance between individuals and over time and the effect of confounding factors is essential for the evaluation of biomarkers in PD, such as insulin-like growth factor 1 (IGF-1). MATERIALS AND METHODS: IGF-1 serum levels were investigated in up to 8 biannual visits in 37 PD patients and 22 healthy controls (HC) in the longitudinal MODEP study. IGF-1 baseline levels and annual changes in IGF-1 were compared between PD patients and HC while accounting for baseline disease duration (19 early stage: <=3.5 years; 18 moderate stage: >4 years), age, sex, body mass index (BMI) and common medical factors putatively modulating IGF-1. In addition, associations of baseline IGF-1 with annual changes of motor, cognitive and depressive symptoms and medication dose were investigated. RESULTS: PD patients in moderate (130+/-26 ng/mL; p = .004), but not early stages (115+/-19, p>.1), showed significantly increased baseline IGF-1 levels compared with HC (106+/-24 ng/mL; p = .017). Age had a significant negative correlation with IGF-1 levels in HC (r = -.47, p = .028) and no correlation in PD patients (r = -.06, p>.1). BMI was negatively correlated in the overall group (r = -.28, p = .034). The annual changes in IGF-1 did not differ significantly between groups and were not correlated with disease duration. Baseline IGF-1 levels were not associated with annual changes of clinical parameters. DISCUSSION: Elevated IGF-1 in serum might differentiate between patients in moderate PD stages and HC. However, the value of serum IGF-1 as a trait-, progression- and prediction marker in PD is limited as IGF-1 showed large inter- and intraindividual variability and may be modulated by several confounders. PMID- 26967644 TI - Severe Community-Acquired Pneumonia Caused by Human Adenovirus in Immunocompetent Adults: A Multicenter Case Series. AB - BACKGROUND: Severe community-acquired pneumonia (CAP) caused by human adenovirus (HAdV), especially HAdV type 55 (HAdV-55) in immunocompetent adults has raised increasing concerns. Clinical knowledge of severe CAP and acute respiratory distress syndrome induced by HAdV-55 is still limited, though the pathogen has been fully characterized by whole-genome sequencing. METHODS: We conducted a multicentre retrospective review of all consecutive patients with severe CAP caused by HAdV in immunocompetent adults admitted to the Emergency Department Intensive Care Unit of two hospitals in Northern China between February 2012 and April 2014. Clinical, laboratory, radiological characteristics, treatments and outcomes of these patients were collected and analyzed. RESULTS: A total of 15 consecutive severe CAP patients with laboratory-confirmed adenovirus infections were included. The median age was 30 years and all cases were identified during the winter and spring seasons. HAdV-55 was the most frequently (11/15) detected HAdV type. Persistent high fever, cough and rapid progression of dyspnea were typically reported in these patients. Significantly increased pneumonia severity index (PSI), respiratory rate, and lower PaO2/FiO2, hypersensitive CRP were reported in non-survivors compared to survivors (P = 0.013, 0.022, 0.019 and 0.026, respectively). The rapid development of bilateral consolidations within 10 days after illness onset were the most common radiographic finding, usually accompanied by adjacent ground glass opacities and pleural effusions. Total mortality was 26.7% in this study. Corticosteroids were prescribed to 14 patients in this report, but the utilization rate between survivors and non-survivors was not significant. CONCLUSIONS: HAdV and the HAdV-55 sub-type play an important role among viral pneumonia pathogens in hospitalized immunocompetent adults in Northern China. HAdV should be tested in severe CAP patients with negative bacterial cultures and a lack of response to antibiotic treatment, even if radiologic imaging and clinical presentation initially suggest bacterial pneumonia. PMID- 26967646 TI - Improvements of the cyclone separator performance by down-comer tubes. AB - Enhancement of fine particle (PM2.5) separation is important for cyclone separators to reduce any extra purification process required at the outlet. Therefore, the present experimental research was performed to explore the performance of cyclone separators modified with down-comer tubes at solid loading rates from 0 to 8.0 g/m(3) with a 10 m/s inlet velocity. The study proved the effectiveness of down-comer tubes in reducing the particle re-entrainment and increasing the finer separation with acceptable pressure drops, which was pronounced at low solid loading conditions. The experimental results were compared with theories of Smolik and Muschelknautz. Theories were acceptable for certain ranges, and theory breakdown was mainly due to the neglect of particle agglomeration, re-entrainment and the reduction of swirling energy, as well as the increase of wall friction due to presence of particles. PMID- 26967645 TI - Re-Infection Outcomes Following One- And Two-Stage Surgical Revision of Infected Knee Prosthesis: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Periprosthetic joint infection (PJI) is a serious complication of total knee arthroplasty. Two-stage revision is the most widely used technique and considered as the most effective for treating periprosthetic knee infection. The one-stage revision strategy is an emerging alternative option, however, its performance in comparison to the two-stage strategy is unclear. We therefore sought to ask if there was a difference in re-infection rates and other clinical outcomes when comparing the one-stage to the two-stage revision strategy. OBJECTIVE: Our first objective was to compare re-infection (new and recurrent infections) rates for one- and two-stage revision surgery for periprosthetic knee infection. Our second objective was to compare between the two revision strategies, clinical outcomes as measured by postoperative Knee Society Knee score, Knee Society Function score, Hospital for Special Surgery knee score, WOMAC score, and range of motion. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, EMBASE, Web of Science, Cochrane Library, reference lists of relevant studies to August 2015, and correspondence with investigators. STUDY SELECTION: Longitudinal (prospective or retrospective cohort) studies conducted in generally unselected patients with periprosthetic knee infection treated exclusively by one- or two-stage revision and with re-infection outcomes reported within two years of revision surgery. No clinical trials comparing both revision strategies were identified. REVIEW METHODS: Two independent investigators extracted data and discrepancies were resolved by consensus with a third investigator. Re-infection rates from 10 one-stage studies (423 participants) and 108 two-stage studies (5,129 participants) were meta-analysed using random-effect models after arcsine transformation. RESULTS: The rate (95% confidence intervals) of re-infection was 7.6% (3.4-13.1) in one-stage studies. The corresponding re infection rate for two-stage revision was 8.8% (7.2-10.6). In subgroup analyses, re-infection rates remained generally similar for several study-level and clinically relevant characteristics. Postoperative clinical outcomes of knee scores and range of motion were similar for both revision strategies. LIMITATIONS: Potential bias owing to the limited number of one-stage revision studies and inability to explore heterogeneity in greater detail. CONCLUSIONS: Available evidence from aggregate published data suggest the one-stage revision strategy may be as effective as the two-stage revision strategy in treating infected knee prostheses in generally unselected patients. Further investigation is warranted. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2015: CRD42015017327. PMID- 26967649 TI - Disentangling the relationship between tumor genetic programs and immune responsiveness. AB - Correlative studies in humans have demonstrated that an active immune microenvironment characterized by the presence of a T-helper 1 immune response typifies a tumor phenotype associated with better outcome and increased responsiveness to immune manipulation. This phenotype also signifies the counter activation of immune-regulatory mechanisms. Variables modulating the development of an effective anti-tumor immune response are increasingly scrutinized as potential therapeutic targets. Genetic alterations of cancer cells that functionally influence intratumoral immune response include mutational load, specific mutations of genes involved in oncogenic pathways and copy number aberrations involving chemokine and cytokine genes. Inhibiting oncogenic pathways that prevent the development of the immune-favorable cancer phenotype may complement modern immunotherapeutic approaches. PMID- 26967647 TI - Nanoparticle delivery of miR-223 to attenuate macrophage fusion. AB - The foreign body response (FBR) begins with injury acquired during implantation of a biomaterial (BM) and is detrimental due to the eventual encapsulation of the implant. Fusion of macrophages to form foreign body giant cells (FBGC), a hallmark of the FBR, is the consequence of a multistep mechanism induced by interleukin (IL)-4 that includes the acquisition of a fusion competent state and subsequent cytoskeletal rearrangements. However, the precise mechanism, regulation, and interplay among molecular mediators to generate FBGCs are insufficiently understood. Seeking novel mediators of fusion that might be regulated at the post-transcriptional level, we examined the role of microRNAs (miRs) in this process. A miR microarray was screened and identified miR-223 as a negative regulator of macrophage fusion. In addition, transfection of primary macrophages with a mir-223 mimic attenuated IL-4-induced fusion. Furthermore, miR 223 KO mice and mir-223 deficient cells displayed increased fusion in vivo and in vitro, respectively. Finally, we developed a method for in vivo delivery of miR 223 mimic utilizing PLGA nanoparticles, which inhibited FBGC formation in a biomaterial implant model. Our results identify miR-223 as a negative regulator of fusion and demonstrate miR-223 mimic-loaded nanoparticles as a therapeutic inhibitor of macrophage fusion. PMID- 26967650 TI - Facile Preparation of Internally Self-assembled Lipid Particles Stabilized by Carbon Nanotubes. AB - We present a facile method to prepare nanostructured lipid particles stabilized by carbon nanotubes (CNTs). Single-walled (pristine) and multi-walled (functionalized) CNTs are used as stabilizers to produce Pickering type oil-in water (O/W) emulsions. Lipids namely, Dimodan U and Phytantriol are used as emulsifiers, which in excess water self-assemble into the bicontinuous cubic Pn3m phase. This highly viscous phase is fragmented into smaller particles using a probe ultrasonicator in presence of conventional surfactant stabilizers or CNTs as done here. Initially, the CNTs (powder form) are dispersed in water followed by further ultrasonication with the molten lipid to form the final emulsion. During this process the CNTs get coated with lipid molecules, which in turn are presumed to surround the lipid droplets to form a particulate emulsion that is stable for months. The average size of CNT-stabilized nanostructured lipid particles is in the submicron range, which compares well with the particles stabilized using conventional surfactants. Small angle X-ray scattering data confirms the retention of the original Pn3m cubic phase in the CNT-stabilized lipid dispersions as compared to the pure lipid phase (bulk state). Blue shift and lowering of the intensities in characteristic G and G' bands of CNTs observed in Raman spectroscopy characterize the interaction between CNT surface and lipid molecules. These results suggest that the interactions between the CNTs and lipids are responsible for their mutual stabilization in aqueous solutions. As the concentrations of CNTs employed for stabilization are very low and lipid molecules are able to functionalize the CNTs, the toxicity of CNTs is expected to be insignificant while their biocompatibility is greatly enhanced. Hence the present approach finds a great potential in various biomedical applications, for instance, for developing hybrid nanocarrier systems for the delivery of multiple functional molecules as in combination therapy or polytherapy. PMID- 26967651 TI - Revision Rates and Risk Factors of 175 842 Patients Undergoing Septorhinoplasty. AB - IMPORTANCE: Estimates of the rate of revision septorhinoplasty and the risk factors associated with revision are unknown because the current published literature is limited to small, retrospective, single-surgeon studies with limited follow-up time. OBJECTIVES: To determine the rate of revision for septorhinoplasty surgery and to determine the risk factors associated with revision. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort analysis of 175 842 patients undergoing septorhinoplasty between January 1, 2005, and December 31, 2009, from the Healthcare Cost and Utilization Project's State Inpatient Databases, State Ambulatory Surgery and Services Databases, and State Emergency Department Databases from California, Florida, and New York. Revisit information for these patients was then collected from the 3 databases between January 1, 2005, and December 31, 2012, with a minimal follow-up time of 3 years; and study analysis done January 1, 2005, to December 31, 2012. MAIN OUTCOMES AND MEASURES: Revision surgery after an index septorhinoplasty was the main outcome measure, and the rate of revision was calculated within subgroups of patients based on different demographic and clinical characteristics. A multivariable model was then used to determine independent risk factors for the performance of revision surgery. RESULTS: The study cohort comprised 175 842 participants who underwent septorhinoplasty procedures; mean (SD) age was 41.0 (15.3) years, and 57.0% were male. The overall revision rate for any septorhinoplasty procedure was 3.3% (5775 of 175 842) (99% CI, 3.2%-3.4%). After separating the patients into primary septorhinoplasty and secondary septorhinoplasty groups, the primary group had an overall revision rate of 3.1% (5389 of 172 324), while the secondary group had an overall revision rate of 11.0% (386 of 3518). Patient characteristics associated with an increased rate of revision include younger age (5.9% [633 of 10 727]), female sex (3.8% [2536 of 67 397]), a history of anxiety (3.9% [168 of 4350]) or autoimmune disease (4.4% [57 of 1286]), and surgery for cosmetic (7.9% [340 of 4289]) or congenital nasal deformities (8.9% [208 of 2334]). CONCLUSIONS AND RELEVANCE: The study results, derived from a large cohort of patients with long follow-up time, suggest that the rate of revision septorhinoplasty is low, but certain patient characteristics are associated with higher revision rates. These data provide valuable preoperative counseling information for patients and physicians. This study also provides robust data for third-party payers or government agencies in an era in which physician performance metrics require valid risk adjustment before being used for reimbursement and quality initiatives. LEVEL OF EVIDENCE: 3. PMID- 26967648 TI - Matrix metalloproteinase-13 mediated degradation of hyaluronic acid-based matrices orchestrates stem cell engraftment through vascular integration. AB - A critical design parameter for the function of synthetic extracellular matrices is to synchronize the gradual cell-mediated degradation of the matrix with the endogenous secretion of natural extracellular matrix (ECM) (e.g., creeping substitution). In hyaluronic acid (HyA)-based hydrogel matrices, we have investigated the effects of peptide crosslinkers with different matrix metalloproteinases (MMP) sensitivities on network degradation and neovascularization in vivo. The HyA hydrogel matrices consisted of cell adhesive peptides, heparin for both the presentation of exogenous and sequestration of endogenously synthesized growth factors, and MMP cleavable peptide linkages (i.e., QPQGLAK, GPLGMHGK, and GPLGLSLGK). Sca1(+)/CD45(-)/CD34(+)/CD44(+) cardiac progenitor cells (CPCs) cultured in the matrices with the slowly degradable QPQGLAK hydrogels supported the highest production of MMP-2, MMP-9, MMP-13, VEGF165, and a range of angiogenesis related proteins. Hydrogels with QPQGLAK crosslinks supported prolonged retention of these proteins via heparin within the matrix, stimulating rapid vascular development, and anastomosis with the host vasculature when implanted in the murine hindlimb. PMID- 26967653 TI - Correction: Antenna Mechanism of Length Control of Actin Cables. PMID- 26967652 TI - Correction: Isolation of a Stable Subpopulation of Mobilized Dental Pulp Stem Cells (MDPSCs) with High Proliferation, Migration, and Regeneration Potential Is Independent of Age. PMID- 26967654 TI - Preparing for and Executing a Randomised Controlled Trial of Podoconiosis Treatment in Northern Ethiopia: The Utility of Rapid Ethical Assessment. AB - BACKGROUND: Community-based randomized controlled trials are often complex pieces of research with significant challenges around the approach to the community, information provision, and decision-making, all of which are fundamental to the informed consent process. We conducted a rapid ethical assessment to guide the preparation for and conduct of a randomized controlled trial of podoconiosis treatment in northern Ethiopia. METHODS: A qualitative study was carried out in Aneded woreda, East Gojjam Zone, Amhara Regional State from August to September, 2013. A total of 14 In-depth Interviews (IDIs) with researchers, experts, and leaders, and 8 Focus Group Discussions (FGDs) involving 80 participants (people of both gender, with and without podoconiosis), were conducted. Interviews were carried out in Amharic. Data analysis was started alongside collection. Final data analysis used a thematic approach based on themes identified a priori and those that emerged during the analysis. RESULTS: Respondents made a range of specific suggestions, including that sensitisation meetings were called by woreda or kebele leaders or the police; that Health Extension Workers were asked to accompany the research team to patients' houses; that detailed trial information was explained by someone with deep local knowledge; that analogies from agriculture and local social organisations be used to explain randomisation; that participants in the 'delayed' intervention arm be given small incentives to continue in the trial; and that key community members be asked to quell rumours arising in the course of the trial. CONCLUSION: Many of these recommendations were incorporated into the preparatory phases of the trial, or were used during the course of the trial itself. This demonstrates the utility of rapid ethical assessment preceding a complex piece of research in a relatively research-naive setting. PMID- 26967655 TI - Weighting of Criteria for Disease Prioritization Using Conjoint Analysis and Based on Health Professional and Student Opinion. AB - Disease prioritization exercises have been used by several organizations to inform surveillance and control measures. Though most methodologies for disease prioritization are based on expert opinion, it is becoming more common to include different stakeholders in the prioritization exercise. This study was performed to compare the weighting of disease criteria, and the consequent prioritization of zoonoses, by both health professionals and students in Switzerland using a Conjoint Analysis questionnaire. The health professionals comprised public health and food safety experts, cantonal physicians and cantonal veterinarians, while the student group comprised first-year veterinary and agronomy students. Eight criteria were selected for this prioritization based on expert elicitation and literature review. These criteria, described on a 3-tiered scale, were evaluated through a choice-based Conjoint Analysis questionnaire with 25 choice tasks. Questionnaire results were analyzed to obtain importance scores (for each criterion) and mean utility values (for each criterion level), and the latter were then used to rank 16 zoonoses. While the most important criterion for both groups was "Severity of the disease in humans", the second ranked criteria by the health professionals and students were "Economy" and "Treatment in humans", respectively. Regarding the criterion "Control and Prevention", health professionals tended to prioritize a disease when the control and preventive measures were described to be 95% effective, while students prioritized a disease if there were almost no control and preventive measures available. Bovine Spongiform Encephalopathy was the top-ranked disease by both groups. Health professionals and students agreed on the weighting of certain criteria such as "Severity" and "Treatment of disease in humans", but disagreed on others such as "Economy" or "Control and Prevention". Nonetheless, the overall disease ranking lists were similar, and these may be taken into consideration when making future decisions regarding resource allocation for disease control and prevention in Switzerland. PMID- 26967656 TI - Utility of Diagnostic Molecular Markers for Evaluation of Indeterminate Thyroid Nodules. PMID- 26967657 TI - Understanding the relationship of land uses and water quality in Twenty First Century: A review. AB - Rising food, housing and energy demand of increasing population creates an immense pressure on water resources, especially on water quality. The water quality around the globe is degrading primarily due to intense agricultural activities associated with rapid urbanization. This study attributes to cause of water quality problem, indices to measure water quality, methods to identify proper explanatory variables to water quality and it's processing to capture the special effect, and finally modeling of water quality using identified explanatory variables to provide insights. This would help policymakers and watershed managers to take necessary steps to protect water quality for the future as well as current generation. Finally, some knowledge gaps are also discussed which need to be addressed in the future studies. PMID- 26967658 TI - Erratum. PMID- 26967659 TI - Activity-Regulated Cytoskeleton-Associated Protein Dysfunction May Contribute to Memory Disorder and Earlier Detection of Autism Spectrum Disorders. AB - OBJECTIVE: To explore a possible role for activity-regulated cytoskeleton associated (Arc/Arg3.1) protein in the clinical identification of children with autism. SUBJECTS AND METHODS: The plasma levels of Arc/Arg3.1 in 62 boys with autism and 32 healthy boys were measured using an enzyme-linked immunosorbent assay (ELISA). The Childhood Autism Rating Scale (CARS) was used to assess the severity of autism as defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). The Mann-Whitney U test was used for comparisons between children with autism and healthy children. The Spearman r correlation coefficient (r) was used to determine the relationship between the CARS scores among patients with autism and different variables. RESULTS: The mean plasma level of Arc/Arg3.1 protein in autism was 1.689 +/- 0.917 pg/ml, significantly higher than that of healthy controls, i.e. 0.792 +/- 1.056 pg/ml (p < 0.001). No significant relationship was found between plasma levels of Arc/Arg3.1 protein and CARS scores (r = -0.06; p > 0.05) or age (r = -0.27; p > 0.05). CONCLUSIONS: The mean plasma level of Arc/Arg3.1 protein was higher in children with autism than in controls, suggesting that Arc/Arg3.1 could be a potential early blood biomarker for diagnosis of autism. PMID- 26967660 TI - When paradigms collide at the road rail interface: evaluation of a sociotechnical systems theory design toolkit for cognitive work analysis. AB - The Cognitive Work Analysis Design Toolkit (CWA-DT) is a recently developed approach that provides guidance and tools to assist in applying the outputs of CWA to design processes to incorporate the values and principles of sociotechnical systems theory. In this paper, the CWA-DT is evaluated based on an application to improve safety at rail level crossings. The evaluation considered the extent to which the CWA-DT met pre-defined methodological criteria and aligned with sociotechnical values and principles. Both process and outcome measures were taken based on the ratings of workshop participants and human factors experts. Overall, workshop participants were positive about the process and indicated that it met the methodological criteria and sociotechnical values. However, expert ratings suggested that the CWA-DT achieved only limited success in producing RLX designs that fully aligned with the sociotechnical approach. Discussion about the appropriateness of the sociotechnical approach in a public safety context is provided. Practitioner Summary: Human factors and ergonomics practitioners need evidence of the effectiveness of methods. A design toolkit for cognitive work analysis, incorporating values and principles from sociotechnical systems theory, was applied to create innovative designs for rail level crossings. Evaluation results based on the application are provided and discussed. PMID- 26967662 TI - Spectroscopic Investigation of Plasma-Fluorinated Monolayer Graphene and Application for Gas Sensing. AB - Large-area monolayer fluorinated graphene (FG) is synthesized by a controllable SF6 plasma treatment. The functional groups of FG are elucidated by various spectroscopies, including Raman spectroscopy, X-ray photoemission spectroscopy (XPS), and near edge X-ray absorption fine structure (NEXAFS) spectroscopy. Raman results suggest that the defects are introduced into the monolayer graphene during the fluorination process. The fluorine content can be varied by the plasma treatment and can reach the maximum (~24.6 atom % F) under 20 s of plasma treatment as examined by XPS measurement. The angle-dependent NEXAFS results reveal that the fluorine atoms interact with the graphene matrix to form covalent C-F bonds, which are perpendicular to the basal plane of FG. FG is applied as a gas-sensing material and owns much better performance for ammonia detection compared to pristine graphene. On the basis of our density functional theory simulation results, the fast response/recovery behavior and high sensitivity of the FG gas sensor are attributed to enhanced physical absorption due to the C-F covalent bonds on the surface of FG. PMID- 26967661 TI - The measles outbreak in Bulgaria, 2009-2011: An epidemiological assessment and lessons learnt. AB - Measles re-emerged in a nationwide outbreak in Bulgaria from 2009 to 2011 despite reported high vaccination coverage at national level. This followed an eight-year period since the last indigenous cases of measles were detected. The Bulgarian National Centre of Infectious and Parasitic Diseases collated measles surveillance data for 2009-2011. We analysed data for age group, sex, ethnicity, diagnosis confirmation, vaccination, hospitalisation, disease complications, and death and describe the outbreak control measures taken. The outbreak started in April 2009 following an importation of measles virus and affected 24,364 persons, predominantly Roma. Most cases (73%) were among children < 15 years old. Vaccination status was available for 52% (n = 12,630) of cases. Of children 1-14 years old, 22% (n = 1,769) were unvaccinated and 70% (n = 5,518) had received one dose of a measles-containing vaccine. Twenty-four measles-related deaths were reported. The Roma ethnic group was particularly susceptible to measles. The magnitude of the outbreak resulted primarily from the accumulation of susceptible children over time. This outbreak serves as a reminder that both high vaccination coverage and closing of immunity gaps across all sections of the population are crucial to reach the goal of measles elimination. PMID- 26967663 TI - A microscale multi-functional metal-organic framework as a fluorescence chemosensor for Fe(III), Al(III) and 2-hydroxy-1-naphthaldehyde. AB - A microscale metal-organic framework [Eu(atpt)1.5(phen)(H2O)]n (H2atpt=2 aminoterephthalic acid, phen=1,10-phenanthroline) (Eu-MOF) was synthesized and characterized by elemental analysis, luminescence spectrum, powder X-ray diffraction, dynamic light scattering and scanning electron microscope. The fluorescence response of Eu-MOF to metal ions and aldehydes showed that Eu-MOF is highly selective to Fe(III), Al(III) and 2-hydroxy-1-naphthaldehyde (2-OH-NA). Eu MOF could be utilized as a multi-functional fluorescence chemosensor for Fe(III), Al(III) and 2-hydroxy-1-naphthaldehyde (2-OH-NA). The detection limit of Fe(III), Al(III) and 2-OH-NA was 45, 10 and 36MUM, respectively. The corresponding sensing mechanisms were explored. PMID- 26967664 TI - Instability of Liquids in Flexible Fiber Brushes under Applied Pressure. AB - We theoretically predict the stability of liquid in a model brush made of flexible fibers for cases in which liquid is supplied from an ink reservoir. The volume of the liquid in the brush increases with increasing applied pressure by the reservoir, and the liquid shows instability at a critical pressure. When the fibers are shorter than a critical length, the end of the brush opens continuously with increasing applied pressure. The volume of the liquid that hangs from the open end of the brush increases with increasing applied pressure, and the liquid drops from the brush at the critical pressure, where the weight of the liquid becomes larger than the surface tension. In contrast, when the fibers are longer than the critical length, the end of the brush opens discontinuously to the maximal extent at the critical pressure. The discontinuous unbuckling is driven by the instability arising from the fact that the bending stiffness of the water surface, which bends together with the flexible fibers, decreases as the end of the brush opens, and it is thus a unique feature of brushes of flexible fibers. PMID- 26967665 TI - How to appoint a new chief nurse, win friends and influence people. AB - OUR CHIEF nurse for England, Sarah Mullally, has announced her intention to leave the NHS and the search is on for her replacement. Speculation on who it will be is rife; this is an opportune moment therefore to reflect on the ideal qualities of the new chief nursing officer (CNO) for England. PMID- 26967666 TI - Microneedle arrays delivery of the conventional vaccines based on nonvirulent viruses. AB - Recently, microneedle arrays (MAs) have been developed for painless inoculation of vaccines and possess many prominent advantages, including convenience for inoculation, and exact delivery of vaccine to the exact epidermal and dermal or mucosal compartments which teem with antigen-presenting cells (APCs). Among different types of MAs, while the micro-environmental stimulus-responsive MAs represent one of the developmental trends in the field, the MAs combined with the conventional vaccines that are based on nonvirulent viruses, such as live attenuated or whole inactivated viruses, and antigen-encoding DNA viral vectors, have developed rapidly into the advanced stages, with certain products already on clinical trials. The pre- and clinical research outcomes showed that the painless MA delivery of the conventional vaccines through mammalian skin or mucosa can not only elicit robust systemic and even mucosal immunity to pathogens but also, in certain circumstances, redirect the immune response toward a specific Th1 pathway, resulting in cytotoxic T lymphocytes (CTL) to erase the cell-hidden pathogens, thanks to the robust adjuvant function of MAs exerted through damaging the contacted cells to release dangerous signals. This paper focuses on reviewing the latest research and advancements in MA delivery of the conventional vaccines that are based on nonvirulent viruses, underlining MA enhancement of the overall vaccine performance and the most advanced MA vaccine products that are relatively close to markets. PMID- 26967667 TI - Correction to Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study. PMID- 26967668 TI - Immunostaining Phospho-epitopes in Ciliated Organs of Whole Mount Zebrafish Embryos. AB - The rapid proliferation of cells, the tissue-specific expression of genes and the emergence of signaling networks characterize early embryonic development of all vertebrates. The kinetics and location of signals - even within single cells - in the developing embryo complements the identification of important developmental genes. Immunostaining techniques are described that have been shown to define the kinetics of intracellular and whole animal signals in structures as small as primary cilia. The techniques for fixing, imaging and processing images using a laser-scanning confocal compound microscope can be completed in as few as 36 hr. Zebrafish (Danio rerio) is a desirable organism for investigators who seek to conduct studies in a vertebrate species that is affordable and relevant to human disease. Genetic knockouts or knockdowns must be confirmed by the loss of the actual protein product. Such confirmation of protein loss can be achieved using the techniques described here. Clues into signaling pathways can also be deciphered by using antibodies that are reactive with proteins that have been post-translationally modified by phosphorylation. Preserving and optimizing the phosphorylated state of an epitope is therefore critical to this determination and is accomplished by this protocol. This study describes techniques to fix embryos during the first 72 hr of development and co-localize a variety of relevant epitopes with cilia in the Kupffer's Vesicle (KV), the kidney and the inner ear. These techniques are straightforward, do not require dissection and can be completed in a relatively short period of time. Projecting confocal image stacks into a single image is a useful means of presenting these data. PMID- 26967669 TI - Primary ciliary dyskinesia and associated sensory ciliopathies. AB - Primary ciliary dyskinesia (PCD) is a genetic disease of motile cilia, which belongs to a group of disorders resulting from dysfunction of cilia, collectively known as ciliopathies. Insights into the genetics and phenotypes of PCD have grown over the last decade, in part propagated by the discovery of a number of novel cilia-related genes. These genes encode proteins that segregate into structural axonemal, regulatory, as well as cytoplasmic assembly proteins. Our understanding of primary (sensory) cilia has also expanded, and an ever-growing list of diverse conditions has been linked to defective function and signaling of the sensory cilium. Recent multicenter clinical and genetic studies have uncovered the heterogeneity of motile and sensory ciliopathies, and in some cases, the overlap between these conditions. Here, we will describe the genetics and pathophysiology of ciliopathies in children, focusing on PCD, review emerging genotype-phenotype relationships, and diagnostic tools available for the clinician. PMID- 26967671 TI - Characterization of 2,3,6,7,10,11-hexahydroxytriphenylene and its effects on cell viability in human cancer cell lines. AB - We synthesized 2,3,6,7,10,11-hexahydroxytriphenylene (HHTP), characterized it by electrochemistry, spectroelectrochemistry, and electron paramagnetic resonance techniques, and evaluated its cytotoxicity to human cancer cell lines. The results revealed that HHTP has accessible higher-oxidation states, especially the tris-semiquinone monoradical. This species is stable and is formed after being stored for months. HHTP exhibited cytotoxic effects on 5 human cancer cell lines, including glioma and lung cancer cells. The cytotoxic effect was evaluated based on the decrease in cell viability, increases in the percentage of cells with fragmented DNA, and elevated numbers of annexin V-PI-positive cells after HHTP treatment. PMID- 26967672 TI - Sulfidization of Organic Freshwater Flocs from a Minerotrophic Peatland: Speciation Changes of Iron, Sulfur, and Arsenic. AB - Iron-rich organic flocs are frequently observed in surface waters of wetlands and show a high affinity for trace metal(loid)s. Under low-flow stream conditions, flocs may settle, become buried, and eventually be subjected to reducing conditions facilitating trace metal(loid) release. In this study, we reacted freshwater flocs (704-1280 mg As/kg) from a minerotrophic peatland (Gola di Lago, Switzerland) with sulfide (5.2 mM, S(-II)spike/Fe = 0.75-1.62 mol/mol) at neutral pH and studied the speciation changes of Fe, S, and As at 25 +/- 1 degrees C over 1 week through a combination of synchrotron X-ray techniques and wet chemical analyses. Sulfidization of floc ferrihydrite and nanocrystalline lepidocrocite caused the rapid formation of mackinawite (52-81% of Fesolid at day 7) as well as solid-phase associated S(0) and polysulfides. Ferrihydrite was preferentially reduced over lepidocrocite, although neoformation of lepidocrocite from ferrihydrite could not be excluded. Sulfide-reacted flocs contained primarily arsenate (47-72%) which preferentially adsorbed to Fe(III) (oxyhydr)oxides, despite abundant mackinawite precipitation. At higher S( II)spike/Fe molar ratios (>=1.0), the formation of an orpiment-like phase accounted for up to 35% of solid-phase As. Despite Fe and As sulfide precipitation and the presence of residual Fe(III)-(oxyhydr)oxides, mobilization of As was recorded in all samples (Asaq = 0.45-7.0 MUM at 7 days). Aqueous As speciation analyses documented the formation of thioarsenates contributing up to 33% of Asaq. Our findings show that freshwater flocs from the Gola di Lago peatland may become a source of As under sulfate-reducing conditions and emphasize the pivotal role Fe-rich organic freshwater flocs play in trace metal(loid) cycling in S-rich wetlands characterized by oscillating redox conditions. PMID- 26967673 TI - Effects of single atom doping on the ultrafast electron dynamics of M1Au24(SR)18 (M = Pd, Pt) nanoclusters. AB - Atomically precise, doped metal clusters are receiving wide research interest due to their synergistic properties dependent on the metal composition. To understand the electronic properties of doped clusters, it is highly desirable to probe the excited state behavior. Here, we report the ultrafast relaxation dynamics of doped M1@Au24(SR)18 (M = Pd, Pt; R = CH2CH2Ph) clusters using femtosecond visible and near infrared transient absorption spectroscopy. Three relaxation components are identified for both mono-doped clusters: (1) sub-picosecond relaxation within the M1Au12 core states; (2) core to shell relaxation in a few picoseconds; and (3) relaxation back to the ground state in more than one nanosecond. Despite similar relaxation pathways for the two doped nanoclusters, the coupling between the metal core and surface ligands is accelerated by over 30% in the case of the Pt dopant compared with the Pd dopant. Compared to Pd doping, the case of Pt doping leads to much more drastic changes in the steady state and transient absorption of the clusters, which indicates that the 5d orbitals of the Pt atom are more strongly mixed with Au 5d and 6s orbitals than the 4d orbitals of the Pd dopant. These results demonstrate that a single foreign atom can lead to entirely different excited state spectral features of the whole cluster compared to the parent Au25(SR)18 cluster. The detailed excited state dynamics of atomically precise Pd/Pt doped gold clusters help further understand their properties and benefit the development of energy-related applications. PMID- 26967670 TI - Associations between Blood and Urine Arsenic Concentrations and Global Levels of Post-Translational Histone Modifications in Bangladeshi Men and Women. AB - BACKGROUND: Exposure to inorganic arsenic is associated with numerous adverse health outcomes, with susceptibility differing by sex. Although evidence from in vitro studies suggests that arsenic alters post-translational histone modifications (PTHMs), evidence in humans is limited. OBJECTIVES: The objectives were to determine: a) if arsenic exposure is associated with global (percent) levels of PTHMs H3K36me2, H3K36me3, and H3K79me2 in a sex-dependent manner, and b) if %PTHMs are stable when arsenic exposure is reduced. METHODS: We examined associations between arsenic, measured in blood and urine, and %PTHMs in peripheral blood mononuclear cells from 317 participants enrolled in the Bangladesh Folic Acid and Creatine Trial (FACT). We also examined the stability of %PTHMs after the use of arsenic-removal water filters (n = 60). RESULTS: Associations between natural log-transformed (ln) urinary arsenic, adjusted for creatinine (uAsCr), and %H3K36me2 differed significantly between men and women (p = 0.01). ln(uAsCr) was positively associated with %H3K36me2 in men [beta = 0.12; 95% confidence interval (CI): 0.01, 0.23, p = 0.03] but was negatively associated with %H3K36me2 in women (beta = -0.05; 95% CI: -0.12, 0.02, p = 0.19). The patterns of associations with blood arsenic were similar. On average, water filter use was also associated with reductions in %H3K36me2 (p < 0.01), but this did not differ significantly by sex. Arsenic was not significantly associated with %H3K36me3 or %H3K79me2 in men or women. CONCLUSIONS: Arsenic exposure was associated with %H3K36me2 in a sex-specific manner but was not associated with %H3K36me3 or %H3K79me2. Additional studies are needed to assess changes in %H3K36me2 after arsenic removal. CITATION: Howe CG, Liu X, Hall MN, Slavkovich V, Ilievski V, Parvez F, Siddique AB, Shahriar H, Uddin MN, Islam T, Graziano JH, Costa M, Gamble MV. 2016. Associations between blood and urine arsenic concentrations and global levels of post-translational histone modifications in Bangladeshi men and women. Environ Health Perspect 124:1234-1240; http://dx.doi.org/10.1289/ehp.1510412. PMID- 26967674 TI - Enterococcus faecalis Ebp pili are important for cell-cell aggregation and intraspecies gene transfer. AB - Enterococcus faecalis is an opportunistic pathogen that ranks among the leading causes of biofilm-associated infections. We previously demonstrated that the endocarditis- and biofilm-associated pili (Ebp) of E. faecalis play a major role in biofilm formation, adherence to abiotic surfaces and experimental infections. In this study, derivatives of E. faecalis strain OG1 were engineered to further characterize functions of Ebp pili. Loss of pili resulted in a 36-fold decrease in the number of closely associated cells when OG1RFDeltaebpABC was mixed with OG1SSpDeltaebpABC, compared with mixing the Ebp+ parental strains. In addition, using the Ebp+ parental strains as donor and recipient, we found a statistically significant increase (280-360 %, P < 0.05) in the frequency of plasmid transfer versus using Ebp- mutants in the conjugation experiments. These results demonstrate a previously unrecognized role of Ebp pili, namely, as important contributors to microscale cell aggregation and horizontal spread of genetic material. PMID- 26967675 TI - Direct-acting antiviral treatment in adults infected with hepatitis C virus: Reactivation of hepatitis B virus coinfection as a further challenge. AB - Use of direct-acting antiviral drugs (DAAs) greatly improves management of adults infected with hepatitis C virus (HCV) whether patients are treatment-naive or unsuccessfully pre-treated. Several inhibitors of viral nonstructural proteins (NS3/4A protease, NS5A and NS5B polymerase) allow a rapid HCV clearance and increase rates of sustained virological response. Both the EASL and AASLD guidelines have recently published up-to-date recommendations for their use, addressing each HCV genotype and particular situations. However, management of patients coinfected with hepatitis B virus (HBV) has been developed by these guidelines with reference to cases of HBV reactivation reported during previous anti-HCV regimens containing interferon known active against both HBV and HCV. In the setting of the interferon-free HCV therapies with DAAs only, the possibility of HBV reactivation during treatment of hepatitis C is raised due to viral interferences in HCV/HBV coinfected persons. Herein, we report a case of early HBV reactivation during DAAs-based anti-HCV treatment (ledipasvir/sofosbuvir) in a patient having a resolved HBV infection and chronically infected with HCV genotype 4 and HIV. Moreover, we review similar recent cases of HBV reactivation in patients infected with HBV and HCV genotype 1 during treatment of hepatitis C by regimen incorporating other combination of DAAs (sofosbuvir/simeprevir or daclatasvir/asunaprevir). Due to the potential risk of early HBV reactivation in HCV/HBV-coinfected patients during interferon-free DAAs-based HCV therapies, altogether these cases highlight the necessity to closely monitor HBV coinfection, regardless its stage (chronic, occult, resolved), whatever HCV genotype or class of DAAs used. PMID- 26967677 TI - Development of an Alpha-synuclein Based Rat Model for Parkinson's Disease via Stereotactic Injection of a Recombinant Adeno-associated Viral Vector. AB - In order to study the molecular pathways of Parkinson's disease (PD) and to develop novel therapeutic strategies, scientific investigators rely on animal models. The identification of PD-associated genes has led to the development of genetic PD models. Most transgenic alpha-SYN mouse models develop gradual alpha SYN pathology but fail to display clear dopaminergic cell loss and dopamine dependent behavioral deficits. This hurdle was overcome by direct targeting of the substantia nigra with viral vectors overexpressing PD-associated genes. Local gene delivery using viral vectors provides an attractive way to express transgenes in the central nervous system. Specific brain regions can be targeted (e.g. the substantia nigra), expression can be induced in the adult setting and high expression levels can be achieved. Further, different vector systems based on various viruses can be used. The protocol outlines all crucial steps to perform a viral vector injection in the substantia nigra of the rat to develop a viral vector-based alpha-synuclein animal model for Parkinson's disease. PMID- 26967679 TI - Neurological manifestations in ANCA-associated vasculitis - assessment and treatment. PMID- 26967678 TI - Construction of Defined Human Engineered Cardiac Tissues to Study Mechanisms of Cardiac Cell Therapy. AB - Human cardiac tissue engineering can fundamentally impact therapeutic discovery through the development of new species-specific screening systems that replicate the biofidelity of three-dimensional native human myocardium, while also enabling a controlled level of biological complexity, and allowing non-destructive longitudinal monitoring of tissue contractile function. Initially, human engineered cardiac tissues (hECT) were created using the entire cell population obtained from directed differentiation of human pluripotent stem cells, which typically yielded less than 50% cardiomyocytes. However, to create reliable predictive models of human myocardium, and to elucidate mechanisms of heterocellular interaction, it is essential to accurately control the biological composition in engineered tissues. To address this limitation, we utilize live cell sorting for the cardiac surface marker SIRPalpha and the fibroblast marker CD90 to create tissues containing a 3:1 ratio of these cell types, respectively, that are then mixed together and added to a collagen-based matrix solution. Resulting hECTs are, thus, completely defined in both their cellular and extracellular matrix composition. Here we describe the construction of defined hECTs as a model system to understand mechanisms of cell-cell interactions in cell therapies, using an example of human bone marrow-derived mesenchymal stem cells (hMSC) that are currently being used in human clinical trials. The defined tissue composition is imperative to understand how the hMSCs may be interacting with the endogenous cardiac cell types to enhance tissue function. A bioreactor system is also described that simultaneously cultures six hECTs in parallel, permitting more efficient use of the cells after sorting. PMID- 26967680 TI - A model for the pore size distribution in random and isotropic mixtures of cylindrical fibres and circular disks. AB - A model for the distribution of pore sizes in systems of randomly distributed cylindrical fibers and circular disks is developed that derives from simple excluded-volume considerations. The dimensions of the particles with finite hard cores are mapped onto those of a hypothetical system of fully penetrable objects in a manner that preserves the overall core-occupied volume fraction and specific surface area. This mapping enables us to obtain estimates for the pore size distribution, and for the first and second moments of the pore sizes, as functions of the particle volume fraction and mixture composition in terms of closed-form, analytical expressions. PMID- 26967682 TI - MU-Nitrido Diiron Macrocyclic Platform: Particular Structure for Particular Catalysis. AB - The ultimate objective of bioinspired catalysis is the development of efficient and clean chemical processes. Cytochrome P450 and soluble methane monooxygenase enzymes efficiently catalyze many challenging reactions. Extensive research has been performed to mimic their exciting chemistry, aiming to create efficient chemical catalysts for functionalization of strong C-H bonds. Two current biomimetic approaches are based on (i) mononuclear metal porphyrin-like complexes and (ii) iron and diiron non-heme complexes. However, biomimetic catalysts capable of oxidizing CH4 are still to be created. In the search for powerful oxidizing catalysts, we have recently proposed a new bioinspired strategy using N bridged diiron phthalocyanine and porphyrin complexes. This platform is particularly suitable for stabilization of Fe(IV)Fe(IV) complexes and can be useful to generate high-valent oxidizing active species. Indeed, the possibility of charge delocalization on two iron centers, two macrocyclic ligands, and the nitrogen bridge makes possible the activation of H2O2 and peracids. The ultrahigh valent diiron-oxo species (L)Fe(IV)-N-Fe(IV)(L(+*))?O (L = porphyrin or phthalocyanine) have been prepared at low temperatures and characterized by cryospray MS, UV-vis, EPR, and Mossbauer techniques. The highly electrophilic (L)Fe(IV)-N-Fe(IV)(L(+*))?O species exhibit remarkable reactivity. In this Account, we describe the catalytic applications of MU-nitrido diiron complexes in the oxidation of methane and benzene, in the transformation of aromatic C-F bonds under oxidative conditions, in oxidative dechlorination, and in the formation of C-C bonds. Importantly, all of these reactions can be performed under mild and clean conditions with high conversions and turnover numbers. MU-Nitrido diiron species retain their binuclear structure during catalysis and show the same mechanistic features (e.g., (18)O labeling, formation of benzene epoxide, and NIH shift in aromatic oxidation) as the enzymes operating via high-valent iron-oxo species. MU-Nitrido diiron complexes can react with perfluorinated aromatics under oxidative conditions, while the strongest oxidizing enzymes cannot. Advanced spectroscopic, labeling, and reactivity studies have confirmed the involvement of high-valent diiron-oxo species in these catalytic reactions. Computational studies have shed light on the origin of the remarkable catalytic properties, distinguishing the Fe-N-Fe scaffold from Fe-C-Fe and Fe-O-Fe analogues. X-ray absorption and emission spectroscopies assisted with DFT calculations allow deeper insight into the electronic structure of these particular complexes. Besides the novel chemistry involved, iron phthalocyanines are cheap and readily available in bulk quantities, suggesting high application potential. A variety of macrocyclic ligands can be used in combination with different transition metals to accommodate M-N-M platform and to tune their electronic and catalytic properties. The structural simplicity and flexibility of MU-nitrido dimers make them promising catalysts for many challenging reactions. PMID- 26967683 TI - Bone Pain in a 4-year-old Boy with Chronic Granulomatous Disease and History of Aspergillus pneumonia. PMID- 26967684 TI - The Jarisch-Herxheimer Reaction and Brucellosis. PMID- 26967681 TI - Desipramine Increases Genioglossus Activity and Reduces Upper Airway Collapsibility during Non-REM Sleep in Healthy Subjects. AB - RATIONALE: Obstructive sleep apnea is a state-dependent disease. One of the key factors that triggers upper airway collapse is decreased pharyngeal dilator muscle activity during sleep. To date, there have not been effective methods to reverse pharyngeal hypotonia pharmacologically in sleeping humans. OBJECTIVES: We tested the hypothesis that administration of desipramine 200 mg prevents the state-related reduction in genioglossus activity that occurs during sleep and thereby decreases pharyngeal collapsibility. METHODS: We conducted a placebo controlled, double-blind, crossover trial with 10 healthy participants. Participants received active treatment or placebo in randomized order 2 hours before sleep in the physiology laboratory. MEASUREMENTS AND MAIN RESULTS: Genioglossus activity during wakefulness and sleep, genioglossus muscle responsiveness to negative epiglottic pressure, and upper airway collapsibility during passive and active conditions were compared between on- and off-drug states. Desipramine abolished the normal reduction of genioglossus activity from wakefulness to non-REM sleep that occurred on the placebo night. Specifically, tonic (median, 96% [86-120] vs. 75% [50-92] wakefulness; P = 0.01) but not phasic genioglossus activity was higher with desipramine compared with placebo. Upper airway collapsibility was also reduced with desipramine compared with placebo ( 10.0 cm H2O [-15.2 to -5.8] vs. -8.1 cm H2O [-10.4 to -6.3]; P = 0.037). CONCLUSIONS: Desipramine reduces the state-related drop in tonic genioglossus muscle activity that occurs from wakefulness to non-REM sleep and reduces airway collapsibility. These data provide a rationale for a new pharmacologic therapy for obstructive sleep apnea. Clinical trial registered with www.clinicaltrials.gov (NCT02428478). PMID- 26967685 TI - Pertussis in a Portuguese Pediatric Tertiary Care Hospital. PMID- 26967686 TI - Klebsiella pneumoniae Bacteremia Complicating Adenovirus Gastroenteritis. PMID- 26967687 TI - Unexplained Anemia in a Young Infant Due to Congenital Malaria. PMID- 26967689 TI - Synthesis of 2-Aminoquinazolinones via Carbonylative Coupling of ortho Iodoanilines and Cyanamide. AB - Herein, we describe a convenient and efficient synthesis of 2-aminoquinazolin 4(3H)-ones and N1-substituted 2-aminoquinazolin-4(1H)-ones by a domino carbonylation/cyclization process. The reaction proceeds via carbonylative coupling of readily available ortho-iodoanilines with cyanamide followed by in situ ring closure of an N-cyanobenzamide intermediate. The products were easily isolated by precipitation in moderate to excellent yields for a wide range of substrates, making this a highly attractive method for the synthesis of 2 aminoquinazolinones. PMID- 26967691 TI - Serum Amino Acid Profiles in Childhood Predict Triglyceride Level in Adulthood: A 7-Year Longitudinal Study in Girls. AB - CONTEXT: Branched-chain and aromatic amino acids are associated with high risk of developing dyslipidemia and type II diabetes in adults. OBJECTIVE: This study aimed to examine whether serum amino acid profiles associate with triglyceride concentrations during pubertal growth and predict hypertriglyceridemia in early adulthood. DESIGN: This was a 7.5-year longitudinal study. SETTING: The study was conducted at the Health Science Laboratory, University of Jyvaskyla. PARTICIPANTS: A total of 396 nondiabetic Finnish girls aged 11.2 +/- 0.8 years at the baseline participated in the study. MAIN OUTCOME MEASURES: Body composition was assessed by dual-energy x-ray absorptiometry; serum concentrations of glucose, insulin, and triglyceride by enzymatic photometric methods; and amino acids by nuclear magnetic resonance spectroscopy. RESULTS: Serum leucine and isoleucine correlated significantly with future triglyceride, independent of baseline triglyceride level (P < .05 for all). In early adulthood (at the age of 18 years), these amino acids were significantly associated with hypertriglyceridemia, whereas fat mass and homeostasis model assessment of insulin resistance were not. Leucine was the strongest determinant discriminating subjects with hypertriglyceridemia from those with normal triglyceride level (area under the curve, 0.822; 95% confidence interval, 0.740-0.903; P = .000001). CONCLUSIONS: Serum leucine and isoleucine were associated with future serum triglyceride levels in girls during pubertal growth and predicted hypertriglyceridemia in early adulthood. Therefore, these amino acid indices may serve as biomarkers to identify individuals at high risk for developing hypertriglyceridemia and cardiovascular disease later in life. Further studies are needed to elucidate the role these amino acids play in the lipid metabolism. PMID- 26967690 TI - Aromatase Inhibition Reduces Insulin Sensitivity in Healthy Men. AB - CONTEXT: Deficiency of aromatase, the enzyme that catalyzes the conversion of androgens to estrogens, is associated with insulin resistance in humans and mice. OBJECTIVE: We hypothesized that pharmacological aromatase inhibition results in peripheral insulin resistance in humans. DESIGN: This was a double-blind, randomized, controlled, crossover study. SETTING: The study was conducted at a clinical research facility. PARTICIPANTS: Seventeen healthy male volunteers (18 50 y) participated in the study. INTERVENTION: The intervention included oral anastrozole (1 mg daily) and placebo, each for 6 weeks with a 2-week washout period. MAIN OUTCOME MEASURE: Glucose disposal and rates of lipolysis were measured during a stepwise hyperinsulinemic euglycemic clamp. Data are mean (SEM). RESULTS: Anastrozole therapy resulted in significant estradiol suppression (59.9 +/- 3.6 vs 102.0 +/- 5.7 pmol/L, P = < .001) and a more modest elevation of total T (25.8 +/- 1.2 vs 21.4 +/- 0.7 nmol/L, P = .003). Glucose infusion rate, during the low-dose insulin infusion, was lower after anastrozole administration (12.16 +/- 1.33 vs 14.15 +/- 1.55 MUmol/kg.min, P = .024). No differences in hepatic glucose production or rate of lipolysis were observed. CONCLUSION: Aromatase inhibition reduces insulin sensitivity, with respect to peripheral glucose disposal, in healthy men. Local generation and action of estradiol, at the level of skeletal muscle, is likely to be an important determinant of insulin sensitivity. PMID- 26967692 TI - Plasma Apelin Concentrations in Patients With Polyuria-Polydipsia Syndrome. AB - CONTEXT: Apelin and arginine vasopressin are antagonists in the regulation of body fluid and osmotic homeostasis. There are no data about apelin levels in patients with polyuria-polydipsia syndrome (PPS). OBJECTIVE: To investigate plasma apelin levels and plasma apelin to copeptin ratios in patients with PPS and healthy volunteers using copeptin as a surrogate marker for arginine vasopressin. DESIGN, PARTICIPANTS, AND SETTING: We included 41 patients with PPS in this post hoc analysis of a prospective study performed in tertiary care hospitals in Switzerland and Germany and 113 healthy volunteers as a control group. OUTCOME MEASURES: Plasma apelin and copeptin levels were measured in 15 patients with complete central diabetes insipidus (DI), seven patients with complete nephrogenic DI, 19 patients with primary polydipsia (PP), and 113 healthy volunteers. RESULTS: Plasma apelin levels were highest in patients with complete nephrogenic DI (413 pmol/L; interquartile range, 332-504 pmol/L; P = .01) and lower in patients with PP (190 [172-215] pmol/L; P < .001) or complete central DI (209 [174-241] pmol/L; P = .02) as compared to healthy volunteers (254 [225-311] pmol/L). Plasma apelin to copeptin ratio in patients with PP (53 [38 92] pmol/pmol; P > .9) was similar to healthy volunteers (57 [37-102] pmol/pmol). In contrast, the apelin to copeptin ratio was higher in patients with complete central DI (89 [73-135] pmol/pmol; P = .02) and lower in patients with complete nephrogenic DI (7 [6-10] pmol/pmol; P < .001) compared to healthy volunteers. CONCLUSION: In PP, normal plasma apelin to copeptin ratio attests a normal water homeostasis. In contrast, in patients with central or nephrogenic DI, the increased or decreased apelin to copeptin ratio, respectively, reflects a disturbed osmotic and body fluid homeostasis. PMID- 26967693 TI - Reinvitation to screening colonoscopy: a randomized-controlled trial of reminding letter and invitation to educational meeting on attendance in nonresponders to initial invitation to screening colonoscopy (REINVITE). AB - OBJECTIVES: The response rate to initial invitation to population-based primary screening colonoscopy within the NordICC trial (NCT 00883792) in Poland is around 50%. The aim of this study was to compare the effect of a reinvitation letter and invitation to an educational intervention on participation in screening colonoscopy in nonresponders to initial invitation. METHODS: Within the NordICC trial framework, individuals living in the region of Warsaw, who were drawn from Population Registries and assigned randomly to the screening group, received an invitation letter and a reminder with a prespecified screening colonoscopy appointment date. One thousand individuals, aged 55 to 64 years, who did not respond to both the invitation and the reminding letter were assigned randomly in a 1:1 ratio to the reinvitation group (REI) and the educational meeting group (MEET). The REI group was sent a reinvitation letter and reminder 6 and 3 weeks before the new colonoscopy appointment date, respectively. The MEET group was sent an invitation 6 weeks before an educational meeting date. Outcome measures were participation in screening colonoscopy within 6 months and response rate within 3 months from the date of reinvitation or invitation to an educational meeting. RESULTS: The response rate and the participation rate in colonoscopy were statistically significantly higher in the REI group compared with the MEET group (16.5 vs. 4.3%; P<0.001 and 5.2 vs. 2.1%; P=0.008, respectively). CONCLUSION: A simple reinvitation letter results in a higher response rate and participation rate to screening colonoscopy than invitation to tailored educational meeting in nonresponders to previous invitations. (NCT01183156). PMID- 26967695 TI - The heterogeneity of headache patients who self-medicate: a cluster analysis approach. AB - Patients with headache often self-treat their condition with over-the-counter analgesics. However, overuse of analgesics can cause medication-overuse headache. The present study aimed to identify subgroups of individuals with headache who self-medicate, as this could be helpful to tailor intervention strategies for prevention of medication-overuse headache. Patients (n = 1021) were recruited from 202 community pharmacies and completed a self-administered questionnaire. A hierarchical cluster analysis was used to group patients as a function of sociodemographics, pain, disability, and medication use for pain. Three patient clusters were identified. Cluster 1 (n = 498, 48.8%) consisted of relatively young individuals, and most of them suffered from migraine. They reported the least number of other pain complaints and the lowest prevalence of medication overuse (MO; 16%). Cluster 2 (n = 301, 29.5%) included older persons with mainly non-migraine headache, a low disability, and on average pain in 2 other locations. Prevalence of MO was 40%. Cluster 3 (n = 222, 21.7%) mostly consisted of patients with migraine who also report pain in many other locations. These patients reported a high disability and a severe limitation of activities. They also showed the highest rates of MO (73%). PMID- 26967694 TI - Agonist-dependence of functional properties for common nonsynonymous variants of human transient receptor potential vanilloid 1. AB - Transient receptor potential vanilloid 1 (TRPV1) is a polymodal receptor activated by capsaicin, heat, and acid, which plays critical roles in thermosensation and pain. In addition, TRPV1 also contributes to multiple pathophysiological states in respiratory, cardiovascular, metabolic, and renal systems. These contributions are further supported by evidence that variations in the human TRPV1 (hTRPV1) gene are associated with various physiological and pathological phenotypes. However, it is not well understood how the variations in hTRPV1 affect channel functions. In this study, we examined functional consequences of amino acid variations of hTRPV1 induced by 5 nonsynonymous single nucleotide polymorphisms (SNPs) that most commonly exist in the human population. Using electrophysiological assays in HEK293 cells, we examined 9 parameters: activation, Ca permeation, and desensitization after activation by capsaicin, acid, and heat. Our results demonstrated that the 5 SNPs differentially affected functional properties of hTRPV1 in an agonist-dependent manner. Based upon the directionality of change of each phenotype and cumulative changes in each SNP, we classified the 5 SNPs into 3 presumptive functional categories: gain of function (hTRPV1 Q85R, P91S, and T469I), loss of function (I585V), and mixed (M315I). These results reveal a spectrum of functional variation among common hTRPV1 polymorphisms in humans and may aid mechanistic interpretation of phenotypes associated with nonsynonymous hTRPV1 SNPs under pathophysiological conditions. PMID- 26967697 TI - Effect of dietary supplementation with inulin and/or benzoic acid on the incidence and severity of post-weaning diarrhoea in weaner pigs after experimental challenge with enterotoxigenic Escherichia coli. AB - The purpose of this study was to evaluate the effects of feeding pigs with inulin and/or benzoic acid on post-weaning diarrhoea (PWD), indices of fermentation in the gastrointestinal tract, and production in pigs experimentally infected with an enterotoxigenic strain of Escherichia coli (ETEC). Forty-eight entire male pigs (Large White*Landrace) aged 21 +/- 3 days of age and weighing 4.97 +/- 0.08 kg (mean +/- SE) were used in a 2*2 factorial experiment, with the respective factors being inulin (0 versus 8%) and benzoic acid (0 vs. 0.5%). Feeding inulin supplemented diets improved (p = 0.022) the faecal consistency (FC) and reduced (p = 0.001) the incidence of PWD; however, the use of benzoic acid had no effects on PWD or faecal ETEC shedding. Wet faeces (a higher FC score) were associated with increased faecal ETEC shedding (R(2) = 0.394, p = 0.001). Inulin reduced the total concentrations of short chain fatty acids (p = 0.029) in the proximal colon. The total concentration of lactic acid was increased by inulin in the caecum (p = 0.007) and proximal colon (p = 0.002). Feeding inulin or benzoic acid had no effects on production after weaning. PMID- 26967698 TI - Effect of xylanase on apparent ileal and total tract digestibility of nutrients and energy of rye in young pigs. AB - A digestibility experiment was carried out on weanling piglets to study the effect of an enzyme complex with predominant xylanase activity on apparent ileal (AID) and apparent total tract digestibility of nutrients and energy. The enzyme was supplemented at four levels (0, 50, 100 and 200 mg/kg) to a diet containing 96% rye. There were significant effects of the added enzyme on AID of dry matter, organic matter and crude fibre, and on apparent total tract digestibility of dry matter, organic matter and energy. However, the improvements in the digestibility were rather small. Except for galactose, there was a significant response in AID of all non-starch polysaccharide constituents to enzyme supplementation, the greatest effect being found at 100 mg/kg. The improvement in AID of arabinose + xylose (685%) was much higher than that of the remaining sugars (110%). AID of galactose was negative in all dietary treatments, presumably due to its high concentration in endogenous secretions. There was a significant response in AID of the sum of essential and total amino acids to the increased level of the enzyme. It is concluded that the enzyme complex is efficient in degrading dietary fibre components, thus improving the digestibility of organic matter, amino acids and energy. PMID- 26967699 TI - Effect of dietary phytate and phytase on proteolytic digestion and growth regulation of broilers. AB - This study was designed to investigate the effect of dietary phytate and phytase on proteolytic digestion and growth signalling in the gastrointestinal tract of broilers. Diets containing phytate phosphorus (2.2 or 4.4 g/kg) with phytase dose rates of 0, 500, or 1,000 FTU/kg were fed to 504 female Cobb chicks for three weeks. Diets containing high phytate reduced the activity of pepsin and trypsin, whereas the inclusion of microbial phytase increased the activity of pepsin, H(+)K(+)-ATPase, trypsin and alanyl aminopeptidase. In the intestine, phytate upregulated the mRNA expression of somatostatin, and down-regulated the mRNA expressions of ghrelin and target of rapamycin (TOR). Phytase down regulated the somatostatin gene, and upregulated the genes of ghrelin, TOR, p70 S6 kinase (S6K) and methionyl aminopeptidase. Significant interactions between phytate and phytase on the mRNA expressions of ghrelin, somatostatin and S6K in the jejunum were detected. The results suggest that dietary phytate and phytase can influence the gastrointestinal endocrine and exocrine systems, as well as the peripherally regulatory network of growth in broilers. PMID- 26967696 TI - (S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology. AB - Chronic pain affects the life of millions of people. Current treatments have deleterious side effects. We have advanced a strategy for targeting protein interactions which regulate the N-type voltage-gated calcium (CaV2.2) channel as an alternative to direct channel block. Peptides uncoupling CaV2.2 interactions with the axonal collapsin response mediator protein 2 (CRMP2) were antinociceptive without effects on memory, depression, and reward/addiction. A search for small molecules that could recapitulate uncoupling of the CaV2.2-CRMP2 interaction identified (S)-lacosamide [(S)-LCM], the inactive enantiomer of the Food and Drug Administration-approved antiepileptic drug (R)-lacosamide [(R)-LCM, Vimpat]. We show that (S)-LCM, but not (R)-LCM, inhibits CRMP2 phosphorylation by cyclin dependent kinase 5, a step necessary for driving CaV2.2 activity, in sensory neurons. (S)-lacosamide inhibited depolarization-induced Ca influx with a low micromolar IC50. Voltage-clamp electrophysiology experiments demonstrated a commensurate reduction in Ca currents in sensory neurons after an acute application of (S)-LCM. Using constellation pharmacology, a recently described high content phenotypic screening platform for functional fingerprinting of neurons that uses subtype-selective pharmacological agents to elucidate cell specific combinations (constellations) of key signaling proteins that define specific cell types, we investigated if (S)-LCM preferentially acts on certain types of neurons. (S)-lacosamide decreased the dorsal root ganglion neurons responding to mustard oil, and increased the number of cells responding to menthol. Finally, (S)-LCM reversed thermal hypersensitivity and mechanical allodynia in a model of postoperative pain, and 2 models of neuropathic pain. Thus, using (S)-LCM to inhibit CRMP2 phosphorylation is a novel and efficient strategy to treat pain, which works by targeting specific sensory neuron populations. PMID- 26967700 TI - A simplified management of the in situ evaluation of feedstuffs in ruminants: Application to the study of the digestive availability of protein and amino acids corrected for the ruminal microbial contamination. AB - The ruminal effective degradability (RED) and intestinal effective digestibility (IED) for dry matter, crude protein (CP) and amino acids (AA) were estimated by a simplified in situ method using pooled samples from rumen-incubated residues, which represented the ruminal outflow of undegraded feed. The effect of microbial contamination in the rumen was corrected using (15)N infusion techniques. Studies were carried out for soybean meal (SBM), barley grain (BG) and lucerne hay (LH) in three wethers cannulated in the rumen and the duodenum. Uncorrected values of RED for CP obtained either by mathematical integration or our simplified method were similar in all feeds. Microbial N in the pooled samples of SBM, BG and LH were 2%, 11% and 24% of total N, respectively. However, intestinal incubation eliminated this microbial charge by 100%, 99% and 88%, respectively. With microbial corrections, RED showed an increase, and IED showed a decrease, except for SBM. With this correction, intestinal digested CP was reduced by 2% in SBM, 13% in BG and 34% in LH. Corrected IED of AA was relatively similar in SBM (97 99%). However, large variations were observed in BG (74-93%) and in LH (10-88%). Digestion in the rumen and intestine changed the essential AA pattern. Overall, our results support that AA digestion is affected by the characteristics of their radicals and their contents in plant cell wall proteins. The accurate estimation of feed metabolisable AA or protein requires effective measures that are corrected by ruminal microbial contamination. The proposed in situ method largely simplifies these tasks and allows a more complete and less expensive feed evaluation. PMID- 26967701 TI - Effect of zeolite A on rumen fermentation and phosphorus metabolism in dairy cows. AB - The aim of the present study was to determine the effect of zeolite A on several physiological parameters and on mineral metabolism in the rumino-intestinal-tract of cows. Eight double fistulated (rumen and proximal duodenum) cows were fed maize silage, grass silage and concentrate. Zeolite A was added to the ration over a period of three weeks at 0, 10 and 20 g/kg dry matter (DM). The daily feed amounts were adjusted to the current performance and varied between 3.9 and 15.5 kg/d. Rumen fluid, duodenal chyme and faeces were sampled to characterise the nutrient digestibility. Blood samples were taken to analyse the concentration of inorganic phosphate. Zeolite A supplementation led to a significantly reduced ruminal DM digestibility and fermentation of organic matter. The molar proportion of acetate in the rumen increased, and propionate as well as valerate decreased significantly after zeolite A supplementation. The concentration of the total fatty acids and ruminal pH were not affected. No effect on faecal digestion of DM, organic matter nor on calcium and magnesium digestion was observed. Otherwise the phosphorus (P) concentration in rumen fluid correlated negatively with the mean zeolite A intake (r (2) = 0.75; p = 0.0003). Further, the faecal excretion of P increased significantly for cows with the highest zeolite A dosage (36.9 g P/d) compared to the control group (29.9 g P/d). The lower digestibility of P resulted in a significantly decreased concentration of inorganic P in serum from a basal value of 2.05-1.16 mmol/l six days after starting zeolite A supplementation. The zeolite A treated cows showed a significantly higher Al concentration already in rumen fluid (14.31 and 13.84 mmol/l) compared to the control cows (6.33 mmol/l). The Al flow in the duodenum was also higher for zeolite A treated cows. PMID- 26967702 TI - Determination of titanium dioxide supplements in different matrices using two methods involving photometer and inductively coupled plasma optical emission spectrometer measurements. AB - Titanium dioxide (TiO2) is a viable marker in digestibility studies using different animal species. The photometrical analysis is based on an intense orange colour following the addition of hydrogen peroxide to an acid solution. The measurement using inductively coupled plasma optical emission spectrometry (ICP-OES) is a method for analysing more than one element from the same sample preparation. The present study was conducted to investigate whether an established ICP-OES element analysis following acid-based hydrolysis is appropriate for titanium analysis. Defined amounts of TiO2 were added to samples obtained in studies with cows, pigs and turkeys and recoveries were determined. It was shown that supplemented TiO2 can be determined in samples of feeds, faeces or excreta, and digesta using a method based on photometric or ICP-OES measurement. The differences between the true and measured titanium concentrations indicate that using the ICP-OES method leads to a higher accuracy of determination. PMID- 26967705 TI - Bilateral Visual Disturbances in a Young Woman. PMID- 26967706 TI - An update on the treatment of osteoarthritis in obese patients. PMID- 26967704 TI - Intra-tracheal Administration of Haemophilus influenzae in Mouse Models to Study Airway Inflammation. AB - Here, we describe a detailed procedure to efficiently and directly deliver Haemophilus influenzae into the lower respiratory tracts of mice. We demonstrate the procedure for preparing H. influenzae inoculum, intra-tracheal instillation of H. influenzae into the lung, collection of broncho-alveolar lavage fluid (BALF), analysis of immune cells in the BALF, and RNA isolation for differential gene expression analysis. This procedure can be used to study the lung inflammatory response to any bacteria, virus or fungi. Direct tracheal instillation is mostly preferred over intranasal or aerosol inhalation procedures because it more efficiently delivers the bacterial inoculum into the lower respiratory tract with less ambiguity. PMID- 26967703 TI - Structurally Diverse Diazafluorene-Ligated Palladium(II) Complexes and Their Implications for Aerobic Oxidation Reactions. AB - 4,5-Diazafluoren-9-one (DAF) has been identified as a highly effective ligand in a number of Pd-catalyzed oxidation reactions, but the mechanistic basis for its utility has not been elucidated. Here, we present the complex coordination chemistry of DAF and palladium(II) carboxylate salts. Multiple complexes among an equilibrating mixture of species have been characterized by (1)H and (15)N NMR spectroscopy and X-ray crystallography. These complexes include monomeric and dimeric Pd(II) species, with monodentate (kappa(1)), bidentate (kappa(2)), and bridging (MU:kappa(1):kappa(1)) DAF coordination modes. Titration studies of DAF and Pd(OAc)2 reveal the formation of two dimeric DAF/Pd(OAc)2 complexes at low [DAF] and four monomeric species at higher [DAF]. The dimeric complexes feature two bridging acetate ligands together with either a bridging or nonbridging (kappa(1)) DAF ligand coordinated to each Pd(II) center. The monomeric structures consist of three isomeric Pd(kappa(1)-DAF)2(OAc)2 complexes, together with Pd(kappa(2)-DAF)(OAc)2 in which the DAF exhibits a traditional bidentate coordination mode. Replacing DAF with the structurally related, but more-electron rich derivative 9,9-dimethyl-4,5-diazafluorene (Me2DAF) simplifies the equilibrium mixture to two complexes: a dimeric species in which the Me2DAF bridges the two Pd centers and a monomeric species with a traditional kappa(2) Me2DAF coordination mode. The use of DAF in combination with other carboxylate ligands (CF3CO2(-) or tBuCO2(-)) also results in a simplified collection of equilibrating Pd(II)-DAF complexes. Collectively, the results highlight the ability of DAF to equilibrate rapidly among multiple coordination modes, and provide valuable insights into the utility of DAF as a ligand in Pd-catalyzed oxidation reactions. PMID- 26967708 TI - Demyelination and neurodegeneration in multiple sclerosis: The role of hypoxia. PMID- 26967707 TI - Generation of Nanoparticles from Friction between Railway Brake Disks and Pads. AB - In this study, we measured the size distribution of particles ranging in size from 5.6 to 560 nm that were emitted between brake disks and pads under various braking conditions to observe and analyze changes to the resulting particle size distribution over braking time. A peak of 178-275 nm (200 nm peak) was observed in all braking conditions. However, the generation of spherical particles of a 10 nm range was observed only when the disk speed and brake force were above certain levels and intensified only when speed and brake force further increased. The total number concentration of ultrafine particles (no larger than 0.1 MUm; PM0.1) generated was found to correlate with disk speed and brake force. Thus, the generation of nanoparticles resulting from disk speed and brake force was attributable primarily to increases in the contact surface temperature. The critical temperature for the generation of nanoparticles of a 10 nm range was found to be about 70 degrees C, which is the average temperature between the surface and the inside of the disk. If the speed or brake force was higher, that is, the temperature of the contact surface reached a certain level, evaporation and condensation took place. Vapor then left the friction surface, met with the air, and quickly cooled to form nanoparticles through nucleation. When the newly generated particles became highly concentrated, they grew through coagulation to form agglomerates or the vapor condensed directly onto the surface of existing particles of about 200 nm (formed by mechanical friction). PMID- 26967709 TI - Sweet's syndrome: a retrospective study of 90 cases from a tertiary care center. AB - BACKGROUND: Sweet's syndrome (SS) is a neutrophilic dermatosis characterized by the abrupt onset of cutaneous, systemic and histopathological alterations in response to different stimuli. OBJECTIVES: The aim of this study was to assess the epidemioclinical, histological, and therapeutic features and outcomes of SS. METHODS: A retrospective study of all patients diagnosed with SS over a 20-year period (1993-2012) was conducted. Data were analyzed using a level of significance of 5%. RESULTS: Ninety patients (mean age: 46.5 years) fulfilled the inclusion criteria. The ratio of women to men was 5. Significant associations emerged between dermohypodermic nodes and location on the lower limbs (P = 0.042), and vesiculobullous lesions and location on the legs (P = 0.030), dorsum of the hand (P = 0.015), and forearms (P = 0.003), and paraneoplastic forms (P = 0.012). The upper extremities were involved in the majority of patients (83.3%). Correlations were found between edema of the superficial dermis and vesiculobullous lesions and between leukocytoclastic vasculitis and atypical targetoid lesions. Sweet's syndrome was associated with cytomegalovirus infection (n = 1), inflammatory bowel disease (n = 4), neoplasm (n = 6), and pregnancy (n = 3). First-line treatment consisted of colchicine. CONCLUSIONS: To the best of the present authors' knowledge, this is the largest series of SS to be reported. Clinical presentations are similar to those described in the literature. Colchicine was efficient and facilitates the reduced use of corticosteroids. The association between SS and neoplasms should be considered in the context of vesiculobullous lesions. PMID- 26967710 TI - Differentiation of the SH-SY5Y Human Neuroblastoma Cell Line. AB - Having appropriate in vivo and in vitro systems that provide translational models for human disease is an integral aspect of research in neurobiology and the neurosciences. Traditional in vitro experimental models used in neurobiology include primary neuronal cultures from rats and mice, neuroblastoma cell lines including rat B35 and mouse Neuro-2A cells, rat PC12 cells, and short-term slice cultures. While many researchers rely on these models, they lack a human component and observed experimental effects could be exclusive to the respective species and may not occur identically in humans. Additionally, although these cells are neurons, they may have unstable karyotypes, making their use problematic for studies of gene expression and reproducible studies of cell signaling. It is therefore important to develop more consistent models of human neurological disease. The following procedure describes an easy-to-follow, reproducible method to obtain homogenous and viable human neuronal cultures, by differentiating the chromosomally stable human neuroblastoma cell line, SH-SY5Y. This method integrates several previously described methods(1-4) and is based on sequential removal of serum from media. The timeline includes gradual serum starvation, with introduction of extracellular matrix proteins and neurotrophic factors. This allows neurons to differentiate, while epithelial cells are selected against, resulting in a homogeneous neuronal culture. Representative results demonstrate the successful differentiation of SH-SY5Y neuroblastoma cells from an initial epithelial-like cell phenotype into a more expansive and branched neuronal phenotype. This protocol offers a reliable way to generate homogeneous populations of neuronal cultures that can be used for subsequent biochemical and molecular analyses, which provides researchers with a more accurate translational model of human infection and disease. PMID- 26967711 TI - Protein extracts from cultured cells contain nonspecific serum albumin. AB - Serum is an important component of cell culture media. The present study demonstrates contamination of intracellular protein extract by bovine serum albumin from the culture media and illustrates how this contamination can cause the misinterpretation of western blot results. Preliminary experiments can prevent the misinterpretation of some experimental results, and optimization of the washing process may enable specific protein detection. PMID- 26967712 TI - Comparison of the Visual Capabilities of an Amphibious and an Aquatic Goby That Inhabit Tidal Mudflats. AB - The mudskipper Periophthalmus modestus and the yellowfin goby Acanthogobius flavimanus are gobiid teleosts that both inhabit the intertidal mudflats in estuaries. While P. modestus has an amphibious lifestyle and forages on the exposed mudflat during low tide, the aquatic A. flavimanus can be found at the same mudflat at high tide. This study primarily aimed to elucidate the differential adaptations of these organisms to their respective habitats by comparing visual capacities and motor control in orienting behavior during prey capture. Analyses of retinal ganglion cell topography demonstrated that both species possess an area in the dorsotemporal region of the retina, indicating high acuity in the lower frontal visual field. Additionally, P. modestus has a minor area in the nasal portion of the retina near the optic disc. The horizontally extended specialized area in P. modestus possibly reflects the need for optimized horizontal sight on the exposed mudflat. Behavioral experiments to determine postural and eye direction control when orienting toward the object of interest revealed that these species direct their visual axes to the target situated below eye level just before a rapid approach toward it. A characteristic feature of the orienting behavior of P. modestus was that they aimed at the target by using the specialized retinal area by rotating the eye and lifting the head before jumping to attack the target located above eye level. This behavior could be an adaptation to a terrestrial feeding habitat in which buoyancy is irrelevant. This study provides insights into the adaptive mechanisms of gobiid species and the evolutionary changes enabling them to forage on land. PMID- 26967713 TI - Young patients with hematologic and lymphatic malignancies have an increased risk of hip and knee arthroplasty. AB - Background Skeletal complications such as osteonecrosis (ON) are potential adverse events in patients treated for cancer, especially in those treated for hematologic and lymphatic malignancies (HLMs). ON may damage the hip or knee joints and may lead to arthrosis requiring total joint arthroplasty (TJA). The aim of this study was to address the risk of TJA in patients with cancer, especially those treated for HLM, in a nationwide population-based setting. Material and methods All patients who had undergone TJA after cancer diagnosis between the years 2000 and 2012 were identified by linking the Arthroplasty Register and the Cancer Registry. Standardized incidence ratios (SIRs) of TJAs were calculated to assess whether patients with any cancer, but especially HLM, have increased risk for TJA when compared with the general population. Results In patients with HLM or other cancer, the overall SIRs were similar compared with the general population. However, in HLM patients under 50 years of age, the SIR was 7.6, and in patients under 35 years of age, it was 45.5. The corresponding SIRs in patients with other cancers were 3.6 and 6.6, respectively. The highest SIRs, including all age groups, were among patients with acute lymphoblastic leukemia (SIR = 4.5) and acute myeloid leukemia (SIR = 1.9). Discussion HLMs imply an increased risk for TJA compared with the general population. The risk is especially high in patients younger than 50 years, regardless of the type of HLM. Young patients with HLM, as well as their healthcare providers, should be aware of the highly increased risk of skeletal complications requiring TJA. PMID- 26967715 TI - Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward. AB - The growing worldwide prevalence of overnutrition and underexertion threatens the gains that we have made against atherosclerotic cardiovascular disease and other maladies. Chronic overnutrition causes the atherometabolic syndrome, which is a cluster of seemingly unrelated health problems characterized by increased abdominal girth and body-mass index, high fasting and postprandial concentrations of cholesterol- and triglyceride-rich apoB-lipoproteins (C-TRLs), low plasma HDL levels, impaired regulation of plasma glucose concentrations, hypertension, and a significant risk of developing overt type 2 diabetes mellitus (T2DM). In addition, individuals with this syndrome exhibit fatty liver, hypercoagulability, sympathetic overactivity, a gradually rising set-point for body adiposity, a substantially increased risk of atherosclerotic cardiovascular morbidity and mortality, and--crucially--hyperinsulinemia. Many lines of evidence indicate that each component of the atherometabolic syndrome arises, or is worsened by, pathway selective insulin resistance and responsiveness (SEIRR). Individuals with SEIRR require compensatory hyperinsulinemia to control plasma glucose levels. The result is overdrive of those pathways that remain insulin-responsive, particularly ERK activation and hepatic de-novo lipogenesis (DNL), while carbohydrate regulation deteriorates. The effects are easily summarized: if hyperinsulinemia does something bad in a tissue or organ, that effect remains responsive in the atherometabolic syndrome and T2DM; and if hyperinsulinemia might do something good, that effect becomes resistant. It is a deadly imbalance in insulin action. From the standpoint of human health, it is the worst possible combination of effects. In this review, we discuss the origins of the atherometabolic syndrome in our historically unprecedented environment that only recently has become full of poorly satiating calories and incessant enticements to sit. Data are examined that indicate the magnitude of daily caloric imbalance that causes obesity. We also cover key aspects of healthy, balanced insulin action in liver, endothelium, brain, and elsewhere. Recent insights into the molecular basis and pathophysiologic harm from SEIRR in these organs are discussed. Importantly, a newly discovered oxide transport chain functions as the master regulator of the balance amongst different limbs of the insulin signaling cascade. This oxide transport chain--abbreviated 'NSAPP' after its five major proteins--fails to function properly during chronic overnutrition, resulting in this harmful pattern of SEIRR. We also review the origins of widespread, chronic overnutrition. Despite its apparent complexity, one factor stands out. A sophisticated junk food industry, aided by subsidies from willing governments, has devoted years of careful effort to promote overeating through the creation of a new class of food and drink that is low- or no-cost to the consumer, convenient, savory, calorically dense, yet weakly satiating. It is past time for the rest of us to overcome these foes of good health and solve this man-made epidemic. PMID- 26967716 TI - The influence of hand positions on biomechanical injury risk factors at the wrist joint during the round-off skills in female gymnastics. AB - The aim of this study was to examine the biomechanical injury risk factors at the wrist, including joint kinetics, kinematics and stiffness in the first and second contact limb for parallel and T-shape round-off (RO) techniques. Seven international-level female gymnasts performed 10 trials of the RO to back handspring with parallel and T-shape hand positions. Synchronised kinematic (3D motion analysis system; 247 Hz) and kinetic (two force plates; 1235 Hz) data were collected for each trial. A two-way repeated measure analysis of variance (ANOVA) assessed differences in the kinematic and kinetic parameters between the techniques for each contact limb. The main findings highlighted that in both the RO techniques, the second contact limb wrist joint is exposed to higher mechanical loads than the first contact limb demonstrated by increased axial compression force and loading rate. In the parallel technique, the second contact limb wrist joint is exposed to higher axial compression load. Differences between wrist joint kinetics highlight that the T-shape technique may potentially lead to reducing these bio-physical loads and consequently protect the second contact limb wrist joint from overload and biological failure. Highlighting the biomechanical risk factors facilitates the process of technique selection making more objective and safe. PMID- 26967714 TI - Comparison of newly developed anti-bone morphogenetic protein 4 llama-derived antibodies with commercially available BMP4 inhibitors. AB - Due to improved understanding of the role of bone morphogenetic protein 4 (BMP4) in an increasing number of diseases, the development of selective inhibitors of BMP4 is an attractive therapeutic option. The currently available BMP4 inhibitors are not suitable as therapeutics because of their low specificity and low effectiveness. Here, we compared newly generated anti-BMP4 llama-derived antibodies (VHHs) with 3 different types of commercially available BMP4 inhibitors, natural antagonists, small molecule BMPR inhibitors and conventional anti-BMP4 monoclonal antibodies. We found that the anti-BMP4 VHHs were as effective as the natural antagonist or small molecule inhibitors, but had higher specificity. We also showed that commercial anti-BMP4 antibodies were inferior in terms of both specificity and effectiveness. These findings might result from the fact that the VHHs C4C4 and C8C8 target a small region within the BMPR1 epitope of BMP4, whereas the commercial antibodies target other areas of the BMP4 molecule. Our results show that the newly developed anti-BMP4 VHHs are promising antibodies with better specificity and effectivity for inhibition of BMP4, making them an attractive tool for research and for therapeutic applications. PMID- 26967717 TI - Ultrasound guided mini-invasive tailored approach and intraoperative neurophysiological monitoring: a synergistic strategy for the removal of tumors near the motor cortex. A preliminary experience. AB - BACKGROUND: The aim of this paper was to evaluate the synergic strategy comprising intraoperative neurophysiological monitoring and ultrasound sonography in terms of clinical motor scores and extent of resection. METHODS: Patients harboring tumors in close relationship with the motor cortex were operated on with image-guided mini-invasive approach and multimodal neurophysiological monitoring. The peculiarity is the partial exposure of the motor cortex and the limited electrophysiological mapping used to search for negative spots. Multimodal neurophysiological monitoring comprised the electrocortical stimulation, somatosensory evoked potentials, motor evoked potentials and subcortical stimulation. Ultrasound sonography guided the tumor removal. The post op clinical motor scores and the extent of resection were assessed. RESULTS: Twelve patients were operated on with the combined approach and were further analyzed. Six had high grade gliomas, 1 anaplastic astrocytoma, 1 oligodendroglioma, 1 pilocytic astrocytoma and three had metastasis. One out of 12 had a worsening of the motor scores at the last follow-up. The mean extent of resection was 90% ranging from 60% to 100%, but in 9 out of 12 patients, it reached or exceeded 90%. CONCLUSIONS: The synergic strategy comprising intraoperative multimodal neurophysiological monitoring and the ultrasound sonography is feasible in all surgeries. Data are promising in terms of both clinical motor scores and extent of resection. This strategy represents an alternative approach to the treatment of supratentorial tumors, although further studies are necessary to confirm the long-term efficacy of this procedure. PMID- 26967718 TI - Zebrafish as a Model to Assess the Teratogenic Potential of Nitrite. AB - High nitrate levels in the environment may result in congenital defects or miscarriages in humans. Presumably, this is due to the conversion of nitrate to nitrite by gut and salivary bacteria. However, in other mammalian studies, high nitrite levels do not cause birth defects, although they can lead to poor reproductive outcomes. Thus, the teratogenic potential of nitrite is not clear. It would be useful to have a vertebrate model system to easily assess teratogenic effects of nitrite or any other chemical of interest. Here, we demonstrate the utility of zebrafish (Danio rerio) to screen compounds for toxicity and embryonic defects. Zebrafish embryos are fertilized externally and have rapid development, making them a good model for teratogenic studies. We show that increasing the time of exposure to nitrite negatively affects survival. Increasing the concentration of nitrite also adversely affects survival, whereas nitrate does not. For embryos that survive nitrite exposure, various defects can occur, including pericardial and yolk sac edema, swim bladder noninflation, and craniofacial malformation. Our results indicate that the zebrafish is a convenient system for studying the teratogenic potential of nitrite. This approach can easily be adapted to test other chemicals for their effects on early vertebrate development. PMID- 26967719 TI - Assessing performance, stability, and cleat comfort/support in collegiate club soccer players using prophylactic ankle taping and bracing. AB - Soccer athletes at all levels of play are keenly aware of their equipment needs including cleat wear, and want to be protected from injury but without impeding on-field performance. Ankle injury is a common disorder that is prevalent in the sport of soccer and recent improvements in ankle prophylaxis interventions have proven effective. The aim of this study was to determine if the use of elastic taping or a neoprene sleeve alters performance, stability, and cleat comfort/support in soccer players compared to wearing a soccer cleat without any external support. Twenty male collegiate club soccer players were recruited and randomly assigned to the three conditions (untaped control, taped, neoprene sleeve). Performance testing and comfort/support assessment for each condition took place in one on-field test session, while stability testing was completed during a separate laboratory session. The only significant finding was improved inversion/eversion stability in both the tape and sleeve conditions as compared to the cleated condition. The addition of tape or a sleeve did not have an adverse effect on performance or comfort during functional and stability testing, and should therefore be considered as a method to decrease ankle injuries in soccer athletes as external supports provide increased stability in inversion/eversion range of motion. PMID- 26967720 TI - Prostate-specific membrane antigen positron emission tomography in prostate cancer: a step toward personalized medicine. AB - PURPOSE OF REVIEW: Increasing attention is being given to personalized medicine in oncology, where therapies are tailored to the particular characteristics of the individual cancer patient. In recent years, there has been greater focus on prostate-specific membrane antigen (PSMA) in prostate cancer (PCa) as a target for imaging and therapy with radionuclides. This review highlights the recent advancements in PSMA positron emission tomography (PET) in PCa during the past year. RECENT FINDINGS: Several reports on PSMA PET/computed tomography (CT) in PCa patients are demonstrating promising results, especially for detection of biochemical recurrence. F-PSMA PET/CT may be superior to Ga-PSMA PET/CT. The detection rate of PSMA PET is influenced by prostate-specific antigen level. PSMA PET/CT may have a higher detection rate than choline PET/CT. Only a few reports have been published on PSMA PET/magnetic resonance imaging (MRI), and this modality remains to be elucidated further. SUMMARY: Molecular imaging with PSMA PET is paving the way for personalized medicine in PCa. However, large prospective clinical studies are needed to further evaluate the role of PSMA PET/CT and PET/MRI in the clinical workflow of PCa. PSMA is an excellent target for imaging and therapy with radionuclides, and the 'image and treat' strategy has the potential to become a milestone in the management of PCa patients. PMID- 26967730 TI - Causal Inference for Spatial Constancy across Saccades. AB - Our ability to interact with the environment hinges on creating a stable visual world despite the continuous changes in retinal input. To achieve visual stability, the brain must distinguish the retinal image shifts caused by eye movements and shifts due to movements of the visual scene. This process appears not to be flawless: during saccades, we often fail to detect whether visual objects remain stable or move, which is called saccadic suppression of displacement (SSD). How does the brain evaluate the memorized information of the presaccadic scene and the actual visual feedback of the postsaccadic visual scene in the computations for visual stability? Using a SSD task, we test how participants localize the presaccadic position of the fixation target, the saccade target or a peripheral non-foveated target that was displaced parallel or orthogonal during a horizontal saccade, and subsequently viewed for three different durations. Results showed different localization errors of the three targets, depending on the viewing time of the postsaccadic stimulus and its spatial separation from the presaccadic location. We modeled the data through a Bayesian causal inference mechanism, in which at the trial level an optimal mixing of two possible strategies, integration vs. separation of the presaccadic memory and the postsaccadic sensory signals, is applied. Fits of this model generally outperformed other plausible decision strategies for producing SSD. Our findings suggest that humans exploit a Bayesian inference process with two causal structures to mediate visual stability. PMID- 26967731 TI - Valencene from the Rhizomes of Cyperus rotundus Inhibits Skin Photoaging-Related Ion Channels and UV-Induced Melanogenesis in B16F10 Melanoma Cells. AB - Ultraviolet (UV) radiation deeply penetrates skin and causes inflammation and pigmentary changes and triggers immune responses. Furthermore, accumulating evidence suggests that calcium ion channels, such as TRPV1 and ORAI1, mediate diverse dermatological processes including melanogenesis, skin wrinkling, and inflammation. The rhizomes of Cyperus rotundus have been used to treat inflammatory diseases including dermatitis. However, their effects on UV-induced photoaging-related ion channels remain unknown. Therefore, this study was undertaken to evaluate the antagonistic effects of C. rotundus extract and their constituents on TRPV1 and ORAI1 channels. Electrophysiological analysis revealed that valencene (1) isolated from the hexane fraction potently inhibited capsaicin induced TRPV1 and ORAI1 currents at 90 MUM (69 +/- 15% and 97 +/- 2% at -60 and 120 mV, respectively). The inhibitory effect of 1 on cytoplasmic Ca(2+) concentrations in response to ORAI1 activation (85 +/- 2% at 50 MUM) was also confirmed. Furthermore, 1 concentration-dependently decreased the melanin content after UVB irradiation in murine B16F10 melanoma cells by 82.66 +/- 2.14% at 15 MUg/mL. These results suggest that C. rotundus rhizomes have potential therapeutic effects on UV-induced photoaging and indicate that the therapeutic and cosmetic applications of 1 are worth further investigation. PMID- 26967732 TI - How Effective Is Help on the Doorstep? A Longitudinal Evaluation of Community Based Organisation Support. AB - Community-based responses have a lengthy history. The ravages of HIV on family functioning has included a widespread community response. Although much funding has been invested in front line community-based organisations (CBO), there was no equal investment in evaluations. This study was set up to compare children aged 9 13 years old, randomly sampled from two South African provinces, who had not received CBO support over time (YC) with a group of similarly aged children who were CBO attenders (CCC). YC baseline refusal rate was 2.5% and retention rate was 97%. CCC baseline refusal rate was 0.7% and retention rate was 86.5%. 1848 children were included-446 CBO attenders compared to 1402 9-13 year olds drawn from a random sample of high-HIV prevalence areas. Data were gathered at baseline and 12-15 months follow-up. Standardised measures recorded demographics, violence and abuse, mental health, social and educational factors. Multivariate regression analyses revealed that children attending CBOs had lower odds of experiencing weekly domestic conflict between adults in their home (OR 0.17; 95% CI 0.09, 0.32), domestic violence (OR 0.22; 95% CI 0.08, 0.62), or abuse (OR 0.11; 95% CI 0.05, 0.25) at follow-up compared to participants without CBO contact. CBO attenders had lower odds of suicidal ideation (OR 0.41; 95% CI 0.18, 0.91), fewer depressive symptoms (B = -0.40; 95% CI -0.62, -0.17), less perceived stigma (B = 0.37; 95% CI -0.57, -0.18), fewer peer problems (B = -1.08; 95% CI -1.29, -0.86) and fewer conduct problems (B = -0.77; 95% CI -0.95, -0.60) at follow-up. In addition, CBO contact was associated with more prosocial behaviours at follow-up (B = 1.40; 95% CI 1.13, 1.67). No associations were observed between CBO contact and parental praise or post-traumatic symptoms. These results suggest that CBO exposure is associated with behavioural and mental health benefits for children over time. More severe psychopathology was not affected by attendance and may need more specialised input. PMID- 26967733 TI - The Expression of Bone Morphogenetic Protein 2 and Matrix Metalloproteinase 2 through Retinoic Acid Receptor Beta Induced by All-Trans Retinoic Acid in Cultured ARPE-19 Cells. AB - PURPOSE: All-trans retinoic acid (ATRA) plays an important role in ocular development. Previous studies found that retinoic acid could influence the metabolism of scleral remodeling by promoting retinal pigment epithelium (RPE) cells to secrete secondary signaling factors. The purpose of this study was to investigate whether retinoic acid affected secretion of bone morphogenetic protein 2 (BMP-2) and matrix metalloproteinase 2 (MMP-2) and to explore the signaling pathway of retinoic acid in cultured acute retinal pigment epithelial 19 (ARPE-19) cells. METHODS: The effects of ATRA (concentrations from 10-9 to 10 5 mol/l) on the expression of retinoic acid receptors (RARs) in ARPE-19 cells were examined at the mRNA and protein levels using reverse transcription polymerase chain reaction (RT-PCR) and western blot assay, respectively. The effects of treating ARPE-19 cells with ATRA concentrations ranging from 10-9 to 10-5 mol/l for 24 h and 48 h or with 10-6mol/l ATRA at different times ranging from 6h to 72h were assessed using real-time quantitative PCR (qPCR) and enzyme linked immunosorbent assay (ELISA). The contribution of RARbeta-induced activation of ARPE-19 cells was confirmed using LE135, an antagonist of RARbeta. RESULTS: RARbeta mRNA levels significantly increased in the ARPE-19 cells treated with ATRA for 24h and 48h. These increases in RARbeta mRNA levels were dose dependent (at concentrations of 10-9 to 10-5 mol/l) with a maximum effect observed at 10-6 mol/l. There were no significant changes in the mRNA levels of RARalpha and RARgamma. Western blot assay revealed that RARbeta protein levels were increased significantly in a time-dependent manner in ARPE-19 cells treated with 10-6 mol/l ATRA from 12 h to 72 h, with a marked increase observed at 24 h and 48 h. The upregulation of RARbeta and the ATRA-induced secretion in ARPE-19 cells could be inhibited by the RARbeta antagonist LE135. CONCLUSION: ATRA induced upregulation of RARbeta in ARPE-19 cells and stimulated these cells to secrete BMP-2 and MMP-2. PMID- 26967735 TI - Rb and p53 Liver Functions Are Essential for Xenobiotic Metabolism and Tumor Suppression. AB - The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver for metabolizing therapeutic drugs or toxins. We demonstrate that Rb and p53 cooperate to metabolize the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). DDC is metabolized mainly by cytochrome P450 (Cyp)3a enzymes resulting in inhibition of heme synthesis and accumulation of protoporphyrin, an intermediate of heme pathway. Protoporphyrin accumulation causes bile injury and ductular reaction. We show that loss of Rb and p53 resulted in reduced Cyp3a expression decreased accumulation of protoporphyrin and consequently less ductular reaction in livers of mice fed with DDC for 3 weeks. These findings provide strong evidence that synergistic functions of Rb and p53 are essential for metabolism of DDC. Because Rb and p53 functions are frequently disabled in liver diseases, our results suggest that liver patients might have altered ability to remove toxins or properly metabolize therapeutic drugs. Strikingly the reduced biliary injury towards the oxidative stress inducer DCC was accompanied by enhanced hepatocellular injury and formation of HCCs in Rb and p53 deficient livers. The increase in hepatocellular injury might be related to reduce protoporphyrin accumulation, because protoporphrin is well known for its anti-oxidative activity. Furthermore our results indicate that Rb and p53 not only function as tumor suppressors in response to carcinogenic injury, but also in response to non carcinogenic injury such as DDC. PMID- 26967734 TI - Generation of Antigen Microarrays to Screen for Autoantibodies in Heart Failure and Heart Transplantation. AB - Autoantibodies directed against endogenous proteins including contractile proteins and endothelial antigens are frequently detected in patients with heart failure and after heart transplantation. There is evidence that these autoantibodies contribute to cardiac dysfunction and correlate with clinical outcomes. Currently, autoantibodies are detected in patient sera using individual ELISA assays (one for each antigen). Thus, screening for many individual autoantibodies is laborious and consumes a large amount of patient sample. To better capture the broad-scale antibody reactivities that occur in heart failure and post-transplant, we developed a custom antigen microarray technique that can simultaneously measure IgM and IgG reactivities against 64 unique antigens using just five microliters of patient serum. We first demonstrated that our antigen microarray technique displayed enhanced sensitivity to detect autoantibodies compared to the traditional ELISA method. We then piloted this technique using two sets of samples that were obtained at our institution. In the first retrospective study, we profiled pre-transplant sera from 24 heart failure patients who subsequently received heart transplants. We identified 8 antibody reactivities that were higher in patients who developed cellular rejection (2 or more episodes of grade 2R rejection in first year after transplant as defined by revised criteria from the International Society for Heart and Lung Transplantation) compared with those who did have not have rejection episodes. In a second retrospective study with 31 patients, we identified 7 IgM reactivities that were higher in heart transplant recipients who developed antibody-mediated rejection (AMR) compared with control recipients, and in time course studies, these reactivities appeared prior to overt graft dysfunction. In conclusion, we demonstrated that the autoantibody microarray technique outperforms traditional ELISAs as it uses less patient sample, has increased sensitivity, and can detect autoantibodies in a multiplex fashion. Furthermore, our results suggest that this autoantibody array technology may help to identify patients at risk of rejection following heart transplantation and identify heart transplant recipients with AMR. PMID- 26967737 TI - Improving Image Quality of Bronchial Arteries with Virtual Monochromatic Spectral CT Images. AB - OBJECTIVE: To evaluate the clinical value of using monochromatic images in spectral CT pulmonary angiography to improve image quality of bronchial arteries. METHODS: We retrospectively analyzed the chest CT images of 38 patients who underwent contrast-enhanced spectral CT. These images included a set of 140kVp polychromatic images and the default 70keV monochromatic images. Using the standard Gemstone Spectral Imaging (GSI) viewer on an advanced workstation (AW4.6,GE Healthcare), an optimal energy level (in keV) for obtaining the best contrast-to-noise ratio (CNR) for the artery could be automatically obtained. The signal-to-noise ratio (SNR), CNR and objective image quality score (1-5) for these 3 image sets (140kVp, 70keV and optimal energy level) were obtained and, statistically compared. The image quality score consistency between the two observers was also evaluated using Kappa test. RESULTS: The optimal energy levels for obtaining the best CNR were 62.58+/-2.74keV.SNR and CNR from the 140kVp polychromatic, 70keV and optimal keV monochromatic images were (16.44+/-5.85, 13.24+/-5.52), (20.79+/-7.45, 16.69+/-6.27) and (24.9+/-9.91, 20.53+/-8.46), respectively. The corresponding subjective image quality scores were 1.97+/-0.82, 3.24+/-0.75, and 4.47+/-0.60. SNR, CNR and subjective scores had significant difference among groups (all p<0.001). The optimal keV monochromatic images were superior to the 70keV monochromatic and 140kVp polychromatic images, and there was high agreement between the two observers on image quality score (kappa>0.80). CONCLUSIONS: Virtual monochromatic images at approximately 63keV in dual-energy spectral CT pulmonary angiography yielded the best CNR and highest diagnostic confidence for imaging bronchial arteries. PMID- 26967738 TI - Correction: Exploiting MEK Inhibitor-Mediated Activation of ERalpha for Therapeutic Intervention in ER-Positive Ovarian Carcinoma. PMID- 26967736 TI - Initial Results from the Survey of Organizational Research Climates (SOuRCe) in the U.S. Department of Veterans Affairs Healthcare System. AB - BACKGROUND: In service to its core mission of improving the health and well-being of veterans, Veterans Affairs (VA) leadership is committed to supporting research best practices in the VA. Recognizing that the behavior of researchers is influenced by the organizational climates in which they work, efforts to assess the integrity of research climates and share such information with research leadership in VA may be one way to support research best practices. The Survey of Organizational Research Climate (SOuRCe) is the first validated survey instrument specifically designed to assess the organizational climate of research integrity in academic research organizations. The current study reports on an initiative to use the SOuRCe in VA facilities to characterize the organizational research climates and pilot test the effectiveness of using SOuRCe data as a reporting and feedback intervention tool. METHODS: We administered the SOuRCe using a cross sectional, online survey, with mailed follow-up to non-responders, of research engaged employees in the research services of a random selection of 42 VA facilities (e.g., Hospitals/Stations) believed to employ 20 or more research staff. We attained a 51% participation rate, yielding more than 5,200 usable surveys. RESULTS: We found a general consistency in organizational research climates across a variety of sub-groups in this random sample of research services in the VA. We also observed similar SOuRCe scale score means, relative rankings of these scales and their internal reliability, in this VA-based sample as we have previously documented in more traditional academic research settings. Results also showed more substantial variability in research climate scores within than between facilities in the VA research service as reflected in meaningful subgroup differences. These findings suggest that the SOuRCe is suitable as an instrument for assessing the research integrity climates in VA and that the tool has similar patterns of results that have been observed in more traditional academic research settings. CONCLUSIONS: The local and specific nature of organizational climates in VA research services, as reflected in variability across sub-groups within individual facilities, has important policy implications. Global, "one-size-fits-all" type initiatives are not likely to yield as much benefit as efforts targeted to specific organizational units or sub groups and tailored to the specific strengths and weaknesses documented in those locations. PMID- 26967739 TI - Correction: Inferring Neuronal Dynamics from Calcium Imaging Data Using Biophysical Models and Bayesian Inference. PMID- 26967740 TI - Screening of the Open Source Malaria Box Reveals an Early Lead Compound for the Treatment of Alveolar Echinococcosis. AB - The metacestode (larval) stage of the tapeworm Echinococcus multilocularis causes alveolar echinococcosis (AE), a very severe and in many cases incurable disease. To date, benzimidazoles such as albendazole and mebendazole are the only approved chemotherapeutical treatment options. Benzimidazoles inhibit metacestode proliferation, but do not act parasiticidal. Thus, benzimidazoles have to be taken a lifelong, can cause adverse side effects such as hepatotoxicity, and are ineffective in some patients. We here describe a newly developed screening cascade for the evaluation of the in vitro efficacy of new compounds that includes assessment of parasiticidal activity. The Malaria Box from Medicines for Malaria Venture (MMV), comprised of 400 commercially available chemicals that show in vitro activity against Plasmodium falciparum, was repurposed. Primary screening was carried out at 10 MUM by employing the previously described PGI assay, and resulted in the identification of 24 compounds that caused physical damage in metacestodes. Seven out of these 24 drugs were also active at 1 MUM. Dose-response assays revealed that only 2 compounds, namely MMV665807 and MMV665794, exhibited an EC50 value below 5 MUM. Assessments using human foreskin fibroblasts and Reuber rat hepatoma cells showed that the salicylanilide MMV665807 was less toxic for these two mammalian cell lines than for metacestodes. The parasiticidal activity of MMV665807 was then confirmed using isolated germinal layer cell cultures as well as metacestode vesicles by employing viability assays, and its effect on metacestodes was morphologically evaluated by electron microscopy. However, both oral and intraperitoneal application of MMV665807 to mice experimentally infected with E. multilocularis metacestodes did not result in any reduction of the parasite load. PMID- 26967743 TI - A review of antidepressant-induced urinary hesitancy: a focus on levomilnacipran ER including two case presentations(5633). AB - INTRODUCTION: Levomilnacipran ER was recently FDA approved as Fetzima(r) for the treatment of MDD. Urinary hesitancy can be an adverse event associated with levomilnacipran treatment. AREAS COVERED: This manuscript details the longitudinal course of levomilnacipran-induced urinary hesitancy in 2 cases that were in a pivotal clinical trial, examining possible predisposing factors and treatment issues. This manuscript also reviews the literature comparing urinary hesitancy associated with levomilnacipran versus other antidepressants. Antidepressants that are potent norepinephrine reuptake inhibitors like levomilnacipran, may have increased rates of associated urinary hesitancy. The latter can cause significant discomfort and a compromised quality of life. Occasionally, it can progress to urinary retention necessitating an emergency medical intervention. EXPERT OPINION: All patients being treated with antidepressants should be carefully monitored for this side effect. Discontinuation of treatment or reduction of the dose of antidepressant frequently relieves urinary hesitancy; alternatively, treatment with an alpha1A antagonist, e.g., tamsulosin may relieve antidepressant-induced urinary hesitancy within hours to days; such strategies allow for continued antidepressant treatment without urinary hesitancy recurring. Thus, with appropriate clinical care, the benefits using levomilnacipran outweigh its risks. PMID- 26967744 TI - Measurement of the Patient Experience: Clarifying Facts, Myths, and Approaches. PMID- 26967741 TI - Asparaginase Potentiates Glucocorticoid-Induced Osteonecrosis in a Mouse Model. AB - Osteonecrosis is a common dose-limiting toxicity of glucocorticoids. Data from clinical trials suggest that other medications can increase the risk of glucocorticoid-induced osteonecrosis. Here we utilized a mouse model to study the effect of asparaginase treatment on dexamethasone-induced osteonecrosis. Mice receiving asparaginase along with dexamethasone had a higher rate of osteonecrosis than those receiving only dexamethasone after 6 weeks of treatment (44% vs. 10%, P = 0.006). Similarly, epiphyseal arteriopathy, which we have shown to be an initiating event for osteonecrosis, was observed in 58% of mice receiving asparaginase and dexamethasone compared to 17% of mice receiving dexamethasone only (P = 0.007). As in the clinic, greater exposure to asparaginase was associated with greater plasma exposure to dexamethasone (P = 0.0001). This model also recapitulated other clinical risk factors for osteonecrosis, including age at start of treatment, and association with the systemic exposure to dexamethasone (P = 0.027) and asparaginase (P = 0.036). We conclude that asparaginase can potentiate the osteonecrotic effect of glucocorticoids. PMID- 26967742 TI - Gastroprotective effect of 2-mercaptoethane sulfonate against acute gastric mucosal damage induced by ethanol. AB - Gastric mucosal damage induced by ethanol is a serious medical problem. Recent evidences suggest that reactive oxygen species and inflammatory mediators play a key role in the destruction of gastric mucosa. The present study was aimed to evaluate the potential beneficial effect of MESNA (2-mercaptoethane sulfonate) against ethanol-induced gastric mucosal damage in mice. The animals were orally pretreated with vehicle or MESNA and then treated with acidified ethanol to induce gastric mucosal damage. One hour after ethanol ingestion mice were euthanized and stomach samples were collected for biochemical analysis. Macroscopic and histopathological evaluation of gastric mucosa showed that pretreatment with MESNA attenuated gastric lesions induced by ethanol. Administration of MESNA significantly increased glutathione content and superoxide dismutase and catalase activity in the gastric tissues. In addition, MESNA markedly reduced ethanol-induced lipid peroxidation, myeloperoxidase activity, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and monocyte chemotactic protein-1 levels. These findings suggest that the thiol-containing compound MESNA is able to decrease alcohol-induced oxidative stress and inflammation in the gastric tissue. It seems that MESNA may have a protective effect against ethanol-induced gastric mucosal damage. PMID- 26967745 TI - A Rapidly Enlarging Forehead Mass in a Young Retinoblastoma Survivor. PMID- 26967747 TI - Age, Gender, Comorbidity, and the MDS-UPDRS: Results from a Population-Based Study. AB - BACKGROUND: Understanding sources of variation in International Parkinson and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores is essential for planning clinical trials in Parkinson's disease and interpreting studies of mild parkinsonian signs. METHODS: We describe the characteristics of the MDS-UPDRS in a population-based sample of individuals without parkinsonism. Multiple linear regression and Spearman's rank correlation coefficients were used to examine potential associations. RESULTS: Among 194 consecutive individuals without parkinsonism, the mean total MDS-UPDRS score was 12.5 (SD 9.8). Sixty-nine percent (134/193) had motor examination (Part III) scores of 2 or more, 16% (30/194) had scores of 10 or more. Female sex, arthritis or spondylosis, diabetes mellitus, and essential tremor were found to be associated with statistically significant increases in MDS-UPDRS Part III scores. For every 10-year increase in age, the Part III score was greater on average by 2.2 (1.5-2.8). CONCLUSIONS: Elevated MDS-UPDRS scores are common in the general population. The overall burden of motor signs of parkinsonism is especially high in older age groups, in women, and in those with particular comorbidities. Whether this represents evidence of a subclinical neurodegenerative process or the effect of comorbid conditions requires further examination. PMID- 26967746 TI - High-Resolution Quantitative Immunogold Analysis of Membrane Receptors at Retinal Ribbon Synapses. AB - Retinal ganglion cells (RGCs) receive excitatory glutamatergic input from bipolar cells. Synaptic excitation of RGCs is mediated postsynaptically by NMDA receptors (NMDARs) and AMPA receptors (AMPARs). Physiological data have indicated that glutamate receptors at RGCs are expressed not only in postsynaptic but also in perisynaptic or extrasynaptic membrane compartments. However, precise anatomical locations for glutamate receptors at RGC synapses have not been determined. Although a high-resolution quantitative analysis of glutamate receptors at central synapses is widely employed, this approach has had only limited success in the retina. We developed a postembedding immunogold method for analysis of membrane receptors, making it possible to estimate the number, density and variability of these receptors at retinal ribbon synapses. Here we describe the tools, reagents, and the practical steps that are needed for: 1) successful preparation of retinal fixation, 2) freeze-substitution, 3) postembedding immunogold electron microscope (EM) immunocytochemistry and, 4) quantitative visualization of glutamate receptors at ribbon synapses. PMID- 26967751 TI - Unilateral Choroidal Macrovessel. PMID- 26967752 TI - Overestimation of Intraocular Pressure by Goldmann Applanation Tonometry Without Astigmatic Correction. PMID- 26967753 TI - Familial Retinal Arteriolar Tortuosity. PMID- 26967754 TI - Direct Visualization of a New Choroidal Vessel on Spectral-Domain Optical Coherence Tomography. PMID- 26967756 TI - Influence of Interface Structure on Magnetic Proximity Effect in Pt/Y3Fe5O12 Heterostructures. AB - The influence of interface structure on the magnetic proximity effect (MPE) in Pt/Y3Fe5O12 (YIG) bilayered heterostructures is studied by first-principles calculations based on the density functional theory (DFT). When Pt atoms are in close proximity with Y or Fe ions at the interface, Pt-Y and Pt-Fe bonds are observed. The crystalline orientations and interface termination layers of the YIG strongly modify both the strength and the length of the Pt-Fe bonding and thereby influence the magnetic properties of the Pt. Point defects including tetrahedral Fe, octahedral Fe, and Y vacancies are introduced at the Pt/YIG interface to quantitatively evaluate the influence on the MPE from individual atoms. For the Pt(100)/YIG(100) structure, the interface tetrahedral Fe vacancies can significantly reduce or even completely diminish the magnetic moments in the Pt. In a stark contrast, the octahedral Fe vacancies slightly enhance the Pt magnetism, and the nonmagnetic Y vacancies cause little influences to the Pt magnetism. These results indicate that the strength of the MPE at the Pt/YIG interface strongly depends on the interface structure. This dependence originated from the direct exchange interaction between the Fe 3d and Pt 5d electrons via electronic state hybridization as well as the electron exchange coupling between the Pt atoms. PMID- 26967755 TI - The peroxisome as a cell signaling organelle. AB - Peroxisomes participate in lipid metabolism, and are a major source of ROS in the cell. Their importance in cellular energy balance and redox homeostasis is well established, as is the need to maintain peroxisome homeostasis to prevent pathologies associated with too few, or too many, of these organelles. How cells regulate peroxisome number has remained somewhat elusive. Recently, the tumor suppressors ATM and TSC, which regulate mTORC1 signaling, have been localized to peroxisomes. When activated by peroxisomal ROS, ATM signals to TSC to repress mTORC1 signaling and increase autophagic flux in cells, and also phosphorylates the peroxisomal protein PEX 5 to target peroxisomes for selective autophagy (pexophagy), providing a mechanism for regulation of peroxisomal homeostasis using ROS as a rheostat. PMID- 26967757 TI - Continuity of phenomenology and (in)consistency of content of meaningful autobiographical memories. AB - Phenomenology is a critical component of autobiographical memory retrieval; it reflects both (a) memory-specific features and (b) stable individual differences. Few studies have tested phenomenology longitudinally. The present work examined the continuity of memory phenomenology in a sample of Italians adults (N=105) over a 4-week period. Participants retrieved two 'key' personal memories, a Turning Point and an Early Childhood Memory, rated the phenomenology of each memory, and completed measures of personality, psychological distress and subjective well-being. Phenomenological ratings were moderately stable over time (median correlation >.40), regardless of memory content. Personality traits, psychological distress and well-being were associated with phenomenology cross sectionally and with changes in phenomenology over time. These results suggest that how individuals re-experience their most important personal memories is relatively consistent over time and shaped by both trait and state aspects of psychological functioning. PMID- 26967758 TI - Zika virus detection in urine from patients with Guillain-Barre syndrome on Martinique, January 2016. AB - We report two cases of Guillain-Barre syndrome who had concomitant Zika virus viruria. This viruria persisted for longer than 15 days after symptom onset. The cases occurred on Martinique in January 2016, at the beginning of the Zika virus outbreak. Awareness of this possible neurological complication of ZikV infection is needed. PMID- 26967759 TI - Half-life extended biotherapeutics. AB - INTRODUCTION: Many of the biotherapeutics approved or under development suffer from a short half-life necessitating frequent applications in order to maintain a therapeutic concentration over an extended period of time. The implementation of half-life extension strategies allows the generation of long-lasting therapeutics with improved pharmacokinetic and pharmacodynamic properties. AREAS COVERED: This review gives an overview of the different half-life extension strategies developed over the past years and their application to generate next-generation biotherapeutics. It focuses on srategies already used in approved drugs and drugs that are in clinical development. These strategies include those aimed at increasing the hydrodynamic radius of the biotherapeutic and strategies which further implement recycling by the neonatal Fc receptor (FcRn). EXPERT OPINION: Half-life extension strategies have become an integral part of development for many biotherapeutics. A diverse set of these strategies is available for the fine tuning of half-life and adaption to the intended treatment modality and disease. Currently, half-life extension is dominated by strategies utilizing albumin binding or fusion, fusion to an immunoglobulin Fc? region and PEGylation. However, a variety of alternative strategies, such as fusion of flexible polypeptide chains as PEG mimetic substitute, have reached advanced stages and offer further alternatives for half-life extension. PMID- 26967761 TI - Antibiotic treatment for nontuberculous mycobacterial lung disease. AB - Pulmonary infections are the most frequent diseases caused by nontuberculous mycobacteria (NTM). Common causative organisms of pulmonary infection are slowly growing mycobacteria including Mycobacterium avium complex and Mycobacterium kansasii, and rapidly growing mycobacteria including Mycobacterium abscessus complex. Clinical concern has been raised over the increasing incidence of NTM lung disease combined with the poor treatment outcomes of these chronic infectious diseases. Since treatment guidelines of the American Thoracic Society/Infectious Disease Society of America were published in 2007 there have been continuous efforts to improve the outcomes of NTM lung disease, albeit slowly and with limitations. Here, we focus on recent advances in the antibiotic treatment of NTM lung disease. PMID- 26967760 TI - Preparation of Rat Oligodendrocyte Progenitor Cultures and Quantification of Oligodendrogenesis Using Dual-infrared Fluorescence Scanning. AB - Efficient oligodendrogenesis is the therapeutic goal of a number of areas of research including spinal cord injury, neonatal hypoxia, and demyelinating diseases such as multiple sclerosis and transverse myelitis. Myelination is required to not only facilitate rapid impulse propagation within the central nervous system, but also to provide trophic support to underlying axons. Oligodendrocyte progenitor cells (OPCs) can be studied in vitro to help identify factors that may promote or inhibit oligodendrocyte differentiation. To date, many of the methods available to evaluate this process have either required large numbers of cells, thus limiting the number of conditions that can be investigated at any one time, or labor-intensive methods of quantification. Herein, we describe a protocol for the isolation of large numbers of highly pure OPCs together with a fast and reliable method to determine oligodendrogenesis from multiple conditions simultaneously. OPCs are isolated from P5-P7 neonatal rat cortices and grown in vitro for three days prior to differentiation. Four days after differentiation, oligodendrogenesis is evaluated using a dual-infrared fluorescence-scanning assay to determine expression of the myelin protein. PMID- 26967762 TI - Molecular characterization of lysR-lysXE, gcdR-gcdHG and amaR-amaAB operons for lysine export and catabolism: a comprehensive lysine catabolic network in Pseudomonas aeruginosa PAO1. AB - Among multiple interconnected pathways for l-Lysine catabolism in pseudomonads, it has been reported that Pseudomonas aeruginosa PAO1 employs the decarboxylase and the transaminase pathways. However, up until now, knowledge of several genes involved in operation and regulation of these pathways was still missing. Transcriptome analyses coupled with promoter activity measurements and growth phenotype analyses led us to identify new members in l-Lys and d-Lys catabolism and regulation, including gcdR-gcdHG for glutarate utilization, dpkA, amaR-amaAB and PA2035 for d-Lys catabolism, lysR-lysXE for putative l-Lys efflux and lysP for putative l-Lys uptake. The gcdHG operon encodes an acyl-CoA transferase (gcdG) and glutaryl-CoA dehydrogenase (gcdH) and is under the control of the transcriptional activator GcdR. Growth on l-Lys was enhanced in the mutants of lysX and lysE, supporting the operation of l-Lys efflux. The transcriptional activator LysR is responsible for l-Lys specific induction of lysXE and the PA4181-82 operon of unknown function. The putative operator sites of GcdR and LysR were deduced from serial deletions and comparative genomic sequence analyses, and the formation of nucleoprotein complexes was demonstrated with purified His-tagged GcdR and LysR. The amaAB operon encodes two enzymes to convert pipecolate to 2-aminoadipate. Induction of the amaAB operon by l-Lys, d Lys and pipecolate requires a functional AmaR, supporting convergence of Lys catabolic pathways to pipecolate. Growth on pipecolate was retarded in the gcdG and gcdH mutants, suggesting the importance of glutarate in pipecolate and 2 aminoadipate utilization. Furthermore, this study indicated links in the control of interconnected networks of lysine and arginine catabolism in P. aeruginosa. PMID- 26967763 TI - Synthesis and orthogonal functionalization of oxazolo[5',4':4,5]pyrano[2,3 b]pyridine by intra- and intermolecular Pd-catalyzed direct C-H bond heteroarylation. AB - The construction and subsequent orthogonal functionalization of a hitherto unknown oxazolo[5',4':4,5]pyrano[2,3-b]pyridine are reported. A palladium catalyzed direct C-H bond functionalization methodology was used to build the tricyclic scaffold as well as to achieve the subsequent C-H bond functionalization at the C-2 position of the oxazole unit with various (hetero)aryl iodides. Remarkably, selective C-H construction and functionalization procedures preserve the chorine atom on the pyridine moiety offering a late-stage substitution site to progress drug design. PMID- 26967764 TI - Development of a cytokine-secreting-based assay for the identification, sorting and transcriptomic analysis of polyfunctional human T cells. AB - Polyfunctional T cells that simultaneously produce the cytokines IFN-gamma, IL-2 and TNF have been correlated with better clinical outcomes in various diseases. To date, cytokine polyfunctionality within T cells has been exclusively studied by intracellular cytokine staining coupled with flow cytometric analysis. Thus, further downstream interrogation of polyfunctional T cell characteristics such as transcriptomic analysis has not been possible. Here, we report the use of a flow cytometric method based on cytokine secretion assay technology to detect and isolate, for the first time, viable human polyfunctional T cells directly from in vitro stimulated whole blood samples. We demonstrate the successful application of this method to sort polyfunctional T cells obtained from human volunteers, which can be then used for downstream applications such as transcriptomic analysis using RT-qPCR. This assay will facilitate in-depth investigations of T cells with distinct cytokine polyfunctionality, including defining their molecular profile and understanding the mechanisms regulating their generation and function. PMID- 26967765 TI - Evaluation of insulin resistance and plasma levels for visfatin and resistin in obese and non-obese patients with polycystic ovary syndrome. AB - This study was designed to evaluate insulin resistance and plasma levels of visfatin and resistin in obese and non-obese patients with polycystic ovary syndrome (PCOS). A total of 37 premenopausal PCOS patients with (n = 18, mean (SD) age: 27.5 (5.7 years) or without obesity (n = 19, mean (SD) age: 23.7 (3.1) years) and healthy volunteers (n = 18, mean (SD) age:29.8 (4.1) years) were included in this study. Data on clinical characteristics, glycemic parameters and lipid parameters were recorded for each subject as were plasma visfatin and resistin levels. Mean (SD) HOMA-IR values were significantly higher in obese PCOS patients (3.4 (1.7)) compared with non-obese PCOS patients (2.0 (1.2), p<0.01) and controls (1.6 (0.8), p<0.01). No significant difference was noted between study groups in terms of plasma resistin (ng/mL) or visfatin (ng/mL) levels. There was no correlation between serum plasma visfatin (r = 0.127, p = 0.407) and resistin (r = -0.096, p = 0.544) levels and HOMA-IR. In conclusion, our findings revealed increased likelihood of metabolic and dyslipidemic manifestations in obese compared to non-obese PCOS patients, while no significant difference was noted in visfatin and resistin levels among PCOS patients in terms of co-morbid obesity and in comparison to controls. PMID- 26967766 TI - Brief, cooperative peer-instruction sessions during lectures enhance student recall and comprehension. AB - OBJECTIVE: The objective of this study was to evaluate the academic impact of cooperative peer instruction during lecture pauses in an immunology/endocrinology course. METHODS: Third-quarter students participated across iterations of the course. Each class offered 20 lectures of 50 minutes each. Classes were divided into a peer-instruction group incorporating cooperative peer instruction and a control group receiving traditional lectures. Peer-instruction group lectures were divided into 2-3 short presentations followed by a multiple-choice question (MCQ). Students recorded an initial answer and then had 1 minute to discuss answers with group peers. Following this, students could submit a revised answer. The control group received the same lecture material, but without MCQs or peer discussions. Final-exam scores were compared across study groups. A mixed-design analysis of covariance was used to analyze the data. RESULTS: There was a statistically significant main effect for the peer-instruction activity (F(1, 93) = 6.573, p = .012, r = .257), with recall scores higher for MCQs asked after peer instruction activities than for those asked before peer instruction. Final-exam scores at the end of term were greater in the peer-instruction group than the control group (F(1, 193) = 9.264, p = .003, r = .214; question type, F(1, 193) = 26.671, p = .000, r = .348). CONCLUSION: Lectures with peer-instruction pauses increase student recall and comprehension compared with traditional lectures. PMID- 26967768 TI - Palliative care outcome measures in COPD patients: a conceptual review. AB - In chronic obstructive pulmonary disease (COPD), palliative care is appropriate in very advanced stages based on recognition of its need when conventional therapy is no longer able to control symptoms, disease morbidity, or to improve/maintain an acceptable quality of life. Palliative care aims to improve quality of life, or, if applied specifically at the end-of-life, to ensure comfortable care. In COPD palliative care effectiveness of interventions should be quantified with outcome measures able to better capture the holistic nature of approaches and not only the specific features of disease. These should include: physical outcomes, psychological outcomes, social outcomes, spiritual outcomes. Such measures are discussed in this review along with arguments supporting their use. PMID- 26967767 TI - Imaging Serotonergic Fibers in the Mouse Spinal Cord Using the CLARITY/CUBIC Technique. AB - Long descending fibers to the spinal cord are essential for locomotion, pain perception, and other behaviors. The fiber termination pattern in the spinal cord of the majority of these fiber systems have not been thoroughly investigated in any species. Serotonergic fibers, which project to the spinal cord, have been studied in rats and opossums on histological sections and their functional significance has been deduced based on their fiber termination pattern in the spinal cord. With the development of CLARITY and CUBIC techniques, it is possible to investigate this fiber system and its distribution in the spinal cord, which is likely to reveal previously unknown features of serotonergic supraspinal pathways. Here, we provide a detailed protocol for imaging the serotonergic fibers in the mouse spinal cord using the combined CLARITY and CUBIC techniques. The method involves perfusion of a mouse with a hydrogel solution and clarification of the tissue with a combination of clearing reagents. Spinal cord tissue was cleared in just under two weeks, and the subsequent immunofluorescent staining against serotonin was completed in less than ten days. With a multi photon fluorescent microscope, the tissue was scanned and a 3D image was reconstructed using Osirix software. PMID- 26967769 TI - Preparation of Thermoresponsive Nanostructured Surfaces for Tissue Engineering. AB - Thermoresponsive poly(N-isopropylacrylamide) (PIPAAm)-immobilized surfaces for controlling cell adhesion and detachment were fabricated by the Langmuir-Schaefer method. Amphiphilic block copolymers composed of polystyrene and PIPAAm (St IPAAms) were synthesized by reversible addition-fragmentation chain transfer (RAFT) radical polymerization. A chloroform solution of St-IPAAm molecules was gently dropped into a Langmuir-trough apparatus, and both barriers of the apparatus were moved horizontally to compress the film to regulate its density. Then, the St-IPAAm Langmuir film was horizontally transferred onto a hydrophobically modified glass substrate by a surface-fixed device. Atomic force microscopy images clearly revealed nanoscale sea-island structures on the surface. The strength, rate, and quality of cell adhesion and detachment on the prepared surface were modulated by changes in temperature across the lower critical solution temperature range of PIPAAm molecules. In addition, a two dimensional cell structure (cell sheet) was successfully recovered on the optimized surfaces. These unique PIPAAm surfaces may be useful for controlling the strength of cell adhesion and detachment. PMID- 26967773 TI - Letter to the Editor: Methodological advances in randomized trials. PMID- 26967774 TI - A prospective time-series quality improvement trial of a standardized analgesia protocol to reduce postoperative pain among neurosurgery patients. AB - OBJECTIVE The inclusion of the pain management domain in the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey now ties patients' perceptions of pain and analgesia to financial reimbursement for inpatient stays. Therefore, the authors wanted to determine if a quality improvement initiative centered on a standardized analgesia protocol could significantly reduce postoperative pain among neurosurgery patients. METHODS The authors implemented a 10-month, prospective, interrupted time-series trial of a quality improvement initiative. The intervention consisted of a multimodal, interdepartmental, standardized analgesia protocol with process improvements from preadmission to discharge. All neurosurgical-floor patients participated in the quality improvement intervention, with data collected on a systematically randomly sampled subset of 96 patients for detailed analysis. Patient-reported numeric rating scale pain on the first postoperative day (POD) served as the primary outcome. RESULTS Implementation of the analgesia protocol resulted in improved preoperative and postoperative documentation of pain (p < 0.001) and improved use of multimodal analgesia, including use of NSAIDs (p < 0.009) and gabapentin (p < 0.027). This intervention also correlated with a 32% reduction in reported pain on the 1st POD for all neurosurgical patients (mean pain scale scores 4.31 vs 2.94; p = 0.000) and a 43% reduction among spinal surgery patients (mean pain scale scores 5.45 vs 3.10; p = 0.036). After controlling for covariates, implementation of the protocol was a significant predictor of lowered postoperative pain (p = 0.05) on the 1st POD. This reduction in pain correlated with protocol compliance (p = 0.028), and a significant decrease in the monthly number of naloxone doses suggests improved safety (mean dose +/- SD 1.5 +/- 1.0 vs 0.33 +/- 0.5; p = 0.04). Furthermore, a significant and persistent reduction in the pain management component of the HCAHPS scores suggests a durability of results extending beyond the life of the study (72.1% vs 82.0%; p = 0.033). CONCLUSIONS The implementation of a standardized analgesia protocol can significantly reduce postoperative pain among neurosurgical patients while increasing safety. Given the current climate of patient-centered outcomes, this study has broad implications for the continuum of care model proposed in the Affordable Care Act. Clinical trial registration no.: NCT01693588 ( clincaltrials.gov ). PMID- 26967775 TI - Aneurysm growth and de novo aneurysms during aneurysm surveillance. AB - OBJECTIVE Many low-risk unruptured intracranial aneurysms (UIAs) are followed for growth with surveillance imaging. Growth of UIAs likely increases the risk of rupture. The incidence and risk factors of UIA growth or de novo aneurysm formation require further research. The authors retrospectively identify risk factors and annual risk for UIA growth or de novo aneurysm formation in an aneurysm surveillance protocol. METHODS Over an 11.5-year period, the authors recommended surveillance imaging to 192 patients with 234 UIAs. The incidence of UIA growth and de novo aneurysm formation was assessed. With logistic regression, risk factors for UIA growth or de novo aneurysm formation and patient compliance with the surveillance protocol was assessed. RESULTS During 621 patient-years of follow-up, the incidence of aneurysm growth or de novo aneurysm formation was 5.0%/patient-year. At the 6-month examination, 5.2% of patients had aneurysm growth and 4.3% of aneurysms had grown. Four de novo aneurysms formed (0.64%/patient-year). Over 793 aneurysm-years of follow-up, the annual risk of aneurysm growth was 3.7%. Only initial aneurysm size predicted aneurysm growth (UIA < 5 mm = 1.6% vs UIA >= 5 mm = 8.7%, p = 0.002). Patients with growing UIAs were more likely to also have de novo aneurysms (p = 0.01). Patient compliance with this protocol was 65%, with younger age predictive of better compliance (p = 0.01). CONCLUSIONS Observation of low-risk UIAs with surveillance imaging can be implemented safely with good adherence. Aneurysm size is the only predictor of future growth. More frequent (semiannual) surveillance imaging for newly diagnosed UIAs and UIAs >= 5 mm is warranted. PMID- 26967776 TI - Increased risk of delayed cerebral ischemia in subarachnoid hemorrhage patients with additional intracerebral hematoma. AB - OBJECTIVE Delayed cerebral ischemia (DCI) has a major impact on the outcome of patients suffering from aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to assess the influence of an additional intracerebral hematoma (ICH) on the occurrence of DCI. METHODS The authors conducted a single-center retrospective analysis of cases of SAH involving patients treated between 2006 and 2011. Patients who died or were transferred to another institution within 10 days after SAH without the occurrence of DCI were excluded from the analysis. RESULTS Additional ICH was present in 123 (24.4%) of 504 included patients (66.7% female). ICH was classified as frontal in 72 patients, temporal in 24, and perisylvian in 27. DCI occurred in 183 patients (36.3%). A total of 59 (32.2%) of these 183 patients presented with additional ICH, compared with 64 (19.9%) of the 321 without DCI (p = 0.002). In addition, DCI was detected significantly more frequently in patients with higher World Federation of Neurosurgical Societies (WFNS) grades. The authors compared the original and modified Fisher Scales with respect to the occurrence of DCI. The modified Fisher Scale (mFS) was superior to the original Fisher Scale (oFS) in predicting DCI. Furthermore, they suggest a new classification based on the mFS, which demonstrates the impact of additional ICH on the occurrence of DCI. After the different scales were corrected for age, sex, WFNS score, and aneurysm site, the oFS no longer was predictive for the occurrence of DCI, while the new scale demonstrated a superior capacity for prediction as compared with the mFS. CONCLUSIONS Additional ICH was associated with an increased risk of DCI in this study. Furthermore, adding the presence or absence of ICH to the mFS improved the identification of patients at the highest risk for the development of DCI. Thus, a simple adjustment of the mFS might help to identify patients at high risk for DCI. PMID- 26967777 TI - Incidence and predictors of dural venous sinus pressure gradient in idiopathic intracranial hypertension and non-idiopathic intracranial hypertension headache patients: results from 164 cerebral venograms. AB - OBJECTIVE Cerebral venous pressure gradient (CVPG) from dural venous sinus stenosis is implicated in headache syndromes such as idiopathic intracranial hypertension (IIH). The incidence of CVPG in headache patients has not been reported. METHODS The authors reviewed all cerebral venograms with manometry performed for headache between January 2008 and May 2015. Patient demographics, headache etiology, intracranial pressure (ICP) measurements, and radiographic and manometric results were recorded. CVPG was defined as a difference >= 8 mm Hg by venographic manometry. RESULTS One hundred sixty-four venograms were performed in 155 patients. There were no procedural complications. Ninety-six procedures (58.5%) were for patients with IIH. The overall incidence of CVPG was 25.6% (42 of 164 procedures): 35.4% (34 of 96 procedures) in IIH patients and 11.8% (8 of 68 procedures) in non-IIH patients. Sixty procedures (36.6%) were performed in patients with preexisting shunts. Seventy-seven patients (49.7%) had procedures preceded by an ICP measurement within 4 weeks of venography, and in 66 (85.7%) of these patients, the ICP had been found to be elevated. CVPG was seen in 8.3% (n = 5) of the procedures in the 60 patients with a preexisting shunt and in 0% (n = 0) of the 11 procedures in the 77 patients with normal ICP (p < 0.001 for both). Noninvasive imaging (MR venography, CT venography) was assessed prior to venography in 112 (68.3%) of 164 cases, and dural venous sinus abnormalities were demonstrated in 73 (65.2%) of these cases; there was a trend toward CVPG (p = 0.07). Multivariate analysis demonstrated an increased likelihood of CVPG in patients with IIH (OR 4.97, 95% CI 1.71-14.47) and a decreased likelihood in patients with a preexisting shunt (OR 0.09, 95% CI 0.02-0.44). CONCLUSIONS CVPG is uncommon in IIH patients, rare in those with preexisting shunts, and absent in those with normal ICP. PMID- 26967778 TI - Editorial: Health care reform and the uninsured: lessons from Massachusetts. PMID- 26967779 TI - Cortical spreading depression occurs during elective neurosurgical procedures. AB - OBJECTIVE Cortical spreading depression (CSD) has been observed with relatively high frequency in the period following human brain injury, including traumatic brain injury and ischemic/hemorrhagic stroke. These events are characterized by loss of ionic gradients through massive cellular depolarization, neuronal dysfunction (depression of electrocorticographic [ECoG] activity) and slow spread (2-5 mm/min) across the cortical surface. Previous data obtained in animals have suggested that even in the absence of underlying injury, neurosurgical manipulation can induce CSD and could potentially be a modifiable factor in neurosurgical injury. The authors report their initial experience with direct intraoperative ECoG monitoring for CSD. METHODS The authors prospectively enrolled patients undergoing elective craniotomy for supratentorial lesions in cases in which the surgical procedure was expected to last > 2 hours. These patients were monitored for CSD from the time of dural opening through the time of dural closure, using a standard 1 * 6 platinum electrode coupled with an AC or full-spectrum DC amplifier. The data were processed using standard techniques to evaluate for slow potential changes coupled with suppression of high-frequency ECoG propagating across the electrodes. Data were compared with CSD validated in previous intensive care unit (ICU) studies, to evaluate recording conditions most likely to permit CSD detection, and identify likely events during the course of neurosurgical procedures using standard criteria. RESULTS Eleven patients underwent ECoG monitoring during elective neurosurgical procedures. During the periods of monitoring, 2 definite CSDs were observed to occur in 1 patient and 8 suspicious events were detected in 4 patients. In other patients, either no events were observed or artifact limited interpretation of the data. The DC coupled amplifier system represented an improvement in stability of data compared with AC-coupled systems. Compared with more widely used postoperative ICU monitoring, there were additional challenges with artifact from saturation during bipolar cautery as well as additional noise peaks detected. CONCLUSIONS CSD can occur during elective neurosurgical procedures even in brain regions distant from the immediate operative site. ECoG monitoring with a DC-coupled full-spectrum amplifier seemed to provide the most stable signal despite significant challenges to the operating room environment. CSD may be responsible for some cases of secondary surgical injury. Though further studies on outcome related to the occurrence of these events is needed, efforts to decrease the occurrence of CSD by modification of anesthetic regimen may represent a novel target for study to increase the safety of neurosurgical procedures. PMID- 26967780 TI - Motor areas of the frontal cortex in patients with motor eloquent brain lesions. AB - OBJECTIVE Because of its huge clinical potential, the importance of premotor areas for motor function itself and plastic reshaping due to tumors or ischemic brain lesions has received increased attention. Thus, in this study the authors used navigated transcranial magnetic stimulation (nTMS) to investigate whether tumorous brain lesions induce a change in motor cortex localization in the human brain. METHODS Between 2010 and 2013, nTMS motor mapping was performed in a prospective cohort of 100 patients with brain tumors in or adjacent to the rolandic cortex. Spatial data analysis was performed by normalization of the individual motor maps and creation of overlays according to tumor location. Analysis of motor evoked potential (MEP) latencies was performed regarding mean overall latencies and potentially polysynaptic latencies, defined as latencies longer than 1 SD above the mean value. Hemispheric dominance, lesion location, and motor-function deficits were also considered. RESULTS Graphical analysis showed that motor areas were not restricted to the precentral gyrus. Instead, they spread widely in the anterior-posterior direction. An analysis of MEP latency showed that mean MEP latencies were shortest in the precentral gyrus and longest in the superior and middle frontal gyri. The percentage of latencies longer than 1 SD differed widely across gyri. The dominant hemisphere showed a greater number of longer latencies than the nondominant hemisphere (p < 0.0001). Moreover, tumor location-dependent changes in distribution of polysynaptic latencies were observed (p = 0.0002). Motor-function deficit did not show any statistically significant effect. CONCLUSIONS The distribution of primary and polysynaptic motor areas changes in patients with brain tumors and highly depends on tumor location. Thus, these data should be considered for resection planning. PMID- 26967782 TI - Editorial: Acute stress impacts psychomotor performance. PMID- 26967783 TI - Racial disparities in the diagnosis and management of trigeminal neuralgia. AB - OBJECTIVE A number of studies have documented inequalities in care and outcomes for a variety of clinical conditions. The authors sought to identify racial and socioeconomic disparities in the diagnosis and treatment of trigeminal neuralgia (TN), as well as the potential underlying reasons for those disparities, which could serve as areas of focus for future quality improvement initiatives. METHODS The medical records of patients with an ICD-9 code of 350.1, signifying a diagnosis of TN, at the Henry Ford Medical Group (HFMG) in the period from 2006 to 2012 were searched, and clinical and socioeconomic data were retrospectively reviewed. Analyses were conducted to assess potential racial differences in subspecialty referral patterns and the specific type of treatment modality undertaken for patients with TN. RESULTS The authors identified 652 patients eligible for analysis. Compared with white patients, black patients were less likely to undergo percutaneous ablative procedures, stereotactic radiosurgery, or microvascular decompression (p < 0.001). However, there was no difference in the likelihood of blacks and whites undergoing a procedure once they had seen a neurosurgeon (67% vs 70%, respectively; p = 0.712). Blacks and whites were equally likely to be seen by a neurologist or neurosurgeon if they were initially seen in either the emergency room (38% vs 37%, p = 0.879) or internal medicine (48% vs 50%, p = 0.806). Among patients diagnosed (268 patients) after the 2008 publication of the European Federation of Neurological Societies and the American Academy of Neurology guidelines for medical therapy for TN, fewer than 50% were on medications sanctioned by the guidelines, and there were no statistically significant racial disparities between white and black patients (p = 0.060). CONCLUSIONS According to data from a large database from one of the nation's largest comprehensive health care systems, there were significant racial disparities in the likelihood of a patient undergoing a procedure for TN. This appeared to stem from outside HFMG from a difference in referral patterns to the neurologists and neurosurgeons. PMID- 26967781 TI - Natural history of colloid cysts of the third ventricle. AB - OBJECTIVE Colloid cysts are rare, histologically benign lesions that may result in obstructive hydrocephalus and death. Understanding the natural history of colloid cysts has been challenging given their low incidence and the small number of cases in most reported series. This has complicated efforts to establish reliable prognostic factors and surgical indications, particularly for asymptomatic patients with incidental lesions. Risk factors for obstructive hydrocephalus in the setting of colloid cysts remain poorly defined, and there are no grading scales on which to develop standard management strategies. METHODS The authors performed a single-center retrospective review of all cases of colloid cysts of the third ventricle treated over nearly 2 decades at Washington University. Univariate analysis was used to identify clinical, imaging, and anatomical factors associated with 2 outcome variables: symptomatic clinical status and presentation with obstructive hydrocephalus. A risk-prediction model was defined using bootstrapped logistic regression. Predictive factors were then combined into a simple 5-point clinical scale referred to as the Colloid Cyst Risk Score (CCRS), and this was evaluated with receiver-operator characteristics. RESULTS The study included 163 colloid cysts, more than half of which were discovered incidentally. More than half of the incidental cysts (58%) were followed with surveillance neuroimaging (mean follow-up 5.1 years). Five patients with incidental cysts (8.8%) progressed and underwent resection. No patient with an incidental, asymptomatic colloid cyst experienced acute obstructive hydrocephalus or sudden neurological deterioration in the absence of antecedent trauma. Nearly half (46.2%) of symptomatic patients presented with hydrocephalus. Eight patients (12.3%) presented acutely, and there were 2 deaths due to obstructive hydrocephalus and herniation. The authors identified several factors that were strongly correlated with the 2 outcome variables and defined third ventricle risk zones where colloid cysts can cause obstructive hydrocephalus. No patient with a lesion outside these risk zones presented with obstructive hydrocephalus. The CCRS had significant predictive capacity for symptomatic clinical status (area under the curve [AUC] 0.917) and obstructive hydrocephalus (AUC 0.845). A CCRS >= 4 was significantly associated with obstructive hydrocephalus (p < 0.0001, RR 19.4). CONCLUSIONS Patients with incidentally discovered colloid cysts can experience both lesion enlargement and symptom progression or less commonly, contraction and symptom regression. Incidental lesions rarely cause acute obstructive hydrocephalus or sudden neurological deterioration in the absence of antecedent trauma. Nearly one-half of patients with symptomatic colloid cysts present with obstructive hydrocephalus, which has an associated 3.1% risk of death. The CCRS is a simple 5-point clinical tool that can be used to identify symptomatic lesions and stratify the risk of obstructive hydrocephalus. External validation of the CCRS will be necessary before objective surgical indications can be established. Surgical intervention should be considered for all patients with CCRS >= 4, as they represent the high-risk subgroup. PMID- 26967784 TI - Impact of the 2006 Massachusetts health care insurance reform on neurosurgical procedures and patient insurance status. AB - OBJECTIVE The Massachusetts health care insurance reform law passed in 2006 has many similarities to the federal Affordable Care Act (ACA). To address concerns that the ACA might negatively impact case volume and reimbursement for physicians, the authors analyzed trends in the number of neurosurgical procedures by type and patient insurance status in Massachusetts before and after the implementation of the state's health care insurance reform. The results can provide insight into the future of neurosurgery in the American health care system. METHODS The authors analyzed data from the Massachusetts State Inpatient Database on patients who underwent neurosurgical procedures in Massachusetts from 2001 through 2012. These data included patients' insurance status (insured or uninsured) and the numbers of procedures performed classified by neurosurgical procedural codes of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Each neurosurgical procedure was grouped into 1 of 4 categories based on ICD-9-CM codes: 1) tumor, 2) other cranial/vascular, 3) shunts, and 4) spine. Comparisons were performed of the numbers of procedures performed and uninsured patients, before and after the implementation of the reform law. Data from the state of New York were used as a control. All data were controlled for population differences. RESULTS After 2008, there were declines in the numbers of uninsured patients who underwent neurosurgical procedures in Massachusetts in all 4 categories. The number of procedures performed for tumor and spine were unchanged, whereas other cranial/vascular procedures increased. Shunt procedures decreased after implementation of the reform law but exhibited a similar trend to the control group. In New York, the number of spine surgeries increased, as did the percentage of procedures performed on uninsured patients. Other cranial/vascular procedures decreased. CONCLUSIONS After the Massachusetts health care insurance reform, the number of uninsured individuals undergoing neurosurgical procedures significantly decreased for all categories, but more importantly, the total number of surgeries performed did not change dramatically. To the extent that trends in Massachusetts can predict the overall US experience, we can expect that some aspects of reimbursement may be positively impacted by the ACA. Neurosurgeons, who often treat patients with urgent conditions, may be affected differently than other specialists. PMID- 26967785 TI - Snare technique for the remodeling of the redundant arachnoid pouch to prevent cerebrospinal fluid rhinorrhea and hematoma collection during transsphenoidal surgery for suprasellar-extended pituitary tumors. AB - OBJECTIVE Transsphenoidal surgery (TSS) is considered a most effective treatment for pituitary tumors with huge suprasellar extension. However, the chance of developing CSF leakage is relatively high, because tearing of the arachnoid membrane is common and there could be multiple tear points during the dissection of suprasellar tumors from the overlying arachnoid membrane. If there are multiple leaking points in the arachnoid membrane packing methods such as using fat or multilayered fascia graft may not be sufficient to seal off the leaking points. Moreover, the packing material may not provide sufficient tamponade to stop bleeding, and thus generates postoperative hematoma formation in the tumor resection cavity. To prevent these complications, the authors have developed a new technique for remodeling the redundant arachnoid pouch (the so-called snare technique) to reconstruct the diaphragm, seal off the CSF leak points completely, and reduce the dead space in the tumor resection cavity. METHODS In 9 patients with huge macroadenomas (> 2.5 cm in diameter) with suprasellar extension, the snare technique was used to remodel the arachnoid pouch after tumor removal via standard TSS between July 2009 and August 2014. Complications were investigated, including postoperative CSF rhinorrhea, postoperative hematoma collection, and visual compromise. RESULTS During the resection of the tumor, CSF leakage was encountered in 8 cases, all of which were sealed off using the snare technique. In 1 case without intraoperative CSF leakage, the snare technique was also applied after intentional puncturing of the arachnoid membrane to reduce the volume and tension of the arachnoid pouch. None of the 9 patients experienced postoperative CSF rhinorrhea. Lumbar CSF drainage was not required in any case. Magnetic resonance imaging studies performed 24 hours after surgery revealed a remarkable reduction in the height of the diaphragm in all cases. Visual deficits improved in all patients immediately after surgery. CONCLUSIONS Remodeling of the arachnoid pouch using the snare technique is simple and effective for completely sealing off the CSF leak point and preventing hematoma collection in the tumor resection cavity after TSS for huge pituitary tumors with suprasellar extension. PMID- 26967786 TI - Exclusive endoscopic transcanal transpromontorial approach: a new perspective for internal auditory canal vestibular schwannoma treatment. AB - OBJECTIVE The aim of this study was to describe the first case series in which an exclusive endoscopic transcanal transpromontorial approach (EETTA) was used to treat small vestibular schwannomas (VSs) and meningiomas of the internal auditory canal (IAC). METHODS The authors performed a retrospective review of patients who had undergone surgery using an EETTA to the IAC at 2 university tertiary care referral centers during the period from November 2011 to January 2015. RESULTS Ten patients underwent surgery via an EETTA for the treatment of VS in the IAC at the University Hospital of Modena or the University Hospital of Verona. The patients had Koos Grade I or II tumors and American Academy of Otolaryngology Head and Neck Surgery (AAO-HNS) Class D hearing status preoperatively. Gross total resection was achieved in all patients. No major complications such as cerebrospinal fluid leakage or hemorrhage were reported. In 7 of 10 (70%) patients, facial nerve function was normal immediately after surgery (Rough Grading System [RGS] Grade I). Two patients presented with a transitory facial palsy immediately after surgery (RGS Grade II-III) but experienced complete recovery during the follow-up period. The mean follow-up was 10 months. CONCLUSIONS The EETTA proved to be successful for the removal of VS or meningioma involving the cochlea, fundus, and IAC, with possible lower complication rates and less invasive procedures than those for traditional microscopic approaches. The potential for the extensive and routine use of this approach in lateral and posterior skull base surgery will depend on the development of technology and surgical refinements and on the diffusion of skull base endoscopic skills among the otolaryngological and neurosurgical communities. PMID- 26967787 TI - Impact of acute stress on psychomotor bimanual performance during a simulated tumor resection task. AB - OBJECTIVE Severe bleeding during neurosurgical operations can result in acute stress affecting the bimanual psychomotor performance of the operator, leading to surgical error and an adverse patient outcome. Objective methods to assess the influence of acute stress on neurosurgical bimanual psychomotor performance have not been developed. Virtual reality simulators, such as NeuroTouch, allow the testing of acute stress on psychomotor performance in risk-free environments. Thus, the purpose of this study was to explore the impact of a simulated stressful virtual reality tumor resection scenario by utilizing NeuroTouch to answer 2 questions: 1) What is the impact of acute stress on bimanual psychomotor performance during the resection of simulated tumors? 2) Does acute stress influence bimanual psychomotor performance immediately following the stressful episode? METHODS Study participants included 6 neurosurgeons, 6 senior and 6 junior neurosurgical residents, and 6 medical students. Participants resected a total of 6 simulated tumors, 1 of which (Tumor 4) involved uncontrollable "intraoperative" bleeding resulting in simulated cardiac arrest and thus providing the acute stress scenario. Tier 1 metrics included extent of blood loss, percentage of tumor resected, and "normal" brain tissue volume removed. Tier 2 metrics included simulated suction device (sucker) and ultrasonic aspirator total tip path length, as well as the sum and maximum forces applied in using these instruments. Advanced Tier 2 metrics included efficiency index, coordination index, ultrasonic aspirator path length index, and ultrasonic aspirator bimanual forces ratio. All metrics were assessed before, during, and after the stressful scenario. RESULTS The stress scenario caused expected significant increases in blood loss in all participant groups. Extent of tumor resected and brain volume removed decreased in the junior resident and medical student groups. Sucker total tip path length increased in the neurosurgeon group, whereas sucker forces increased in the senior resident group. Psychomotor performance on advanced Tier 2 metrics was altered during the stress scenario in all participant groups. Performance on all advanced Tier 2 metrics returned to pre-stress levels in the post-stress scenario tumor resections. CONCLUSIONS Results demonstrated that acute stress initiated by simulated severe intraoperative bleeding significantly decreases bimanual psychomotor performance during the acute stressful episode. The simulated intraoperative bleeding event had no significant influence on the advanced Tier 2 metrics monitored during the immediate post-stress operative performance. PMID- 26967788 TI - Bioinformatic analyses reveal a distinct Notch activation induced by STAT3 phosphorylation in the mesenchymal subtype of glioblastoma. AB - OBJECTIVE Glioblastoma (GBM) is the most common and lethal type of malignant glioma. The Cancer Genome Atlas divides the gene expression-based classification of GBM into classical, mesenchymal, neural, and proneural subtypes, which is important for understanding GBM etiology and for designing effective personalized therapy. Signal transducer and activator of transcription 3 (STAT3), a critical transcriptional activator in tumorigenesis, is persistently phosphorylated and associated with an unfavorable prognosis in GBM. Although a set of specific targets has been identified, there have been no systematic analyses of STAT3 signaling based on GBM subtype. METHODS This study compared STAT3-associated messenger RNA, protein, and microRNA expression profiles across different subtypes of GBM. RESULTS The analyses revealed a prominent role for STAT3 in the mesenchymal but not in other GBM subtypes, which can be reliably used to classify patients with mesenchymal GBM into 2 groups according to phosphorylated STAT3 expression level. Differentially expressed genes suggest an association between Notch and STAT3 signaling in the mesenchymal subtype. Their association was validated in the U87 cell, a malignant glioma cell line annotated as mesenchymal subtype. Specific associated proteins and microRNAs further profile the STAT3 signaling among GBM subtypes. CONCLUSIONS These findings suggest a prominent role for STAT3 signaling in mesenchymal GBM and highlight the importance of identifying signaling pathways that contribute to specific cancer subtypes. PMID- 26967789 TI - Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD): a scoring system for moyamoya severity based on multimodal hemodynamic imaging. AB - OBJECTIVE Quantification of the severity of vasculopathy and its impact on parenchymal hemodynamics is a necessary prerequisite for informing management decisions and evaluating intervention response in patients with moyamoya. The authors performed digital subtraction angiography and noninvasive structural and hemodynamic MRI, and they outline a new classification system for patients with moyamoya that they have named Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD). METHODS Healthy control volunteers (n = 11; age 46 +/- 12 years [mean +/- SD]) and patients (n = 25; 42 +/- 13.5 years) with angiographically confirmed moyamoya provided informed consent and underwent structural (T1-weighted, T2-weighted, FLAIR, MR angiography) and hemodynamic (T2* and cerebral blood flow-weighted) 3-T MRI. Cerebrovascular reactivity (CVR) in the internal carotid artery territory was assessed using susceptibility-weighted MRI during a hypercapnic stimulus. Only hemispheres without prior revascularization were assessed. Each hemisphere was considered symptomatic if localizing signs were present on neurological examination and/or there was a history of transient ischemic attack with symptoms referable to that hemisphere. The PIRAMD factor weighting versus symptomatology was optimized using binary logistic regression and receiver operating characteristic curve analysis with bootstrapping. The PIRAMD finding was scored from 0 to 10. For each hemisphere, 1 point was assigned for prior infarct, 3 points for reduced CVR, 3 points for a modified Suzuki Score >= Grade II, and 3 points for flow impairment in >= 2 of 7 predefined vascular territories. Hemispheres were divided into 3 severity grades based on total PIRAMD score, as follows: Grade 1, 0-5 points; Grade 2, 6-9 points; and Grade 3, 10 points. RESULTS In 28 of 46 (60.9%) hemispheres the findings met clinical symptomatic criteria. With decreased CVR, the odds ratio of having a symptomatic hemisphere was 13 (95% CI 1.1-22.6, p = 0.002). The area under the curve for individual PIRAMD factors was 0.67-0.72, and for the PIRAMD grade it was 0.845. There were 0/8 (0%), 10/18 (55.6%), and 18/20 (90%) symptomatic PIRAMD Grade 1, 2, and 3 hemispheres, respectively. CONCLUSIONS A scoring system for total impairment is proposed that uses noninvasive MRI parameters. This scoring system correlates with symptomatology and may provide a measure of hemodynamic severity in moyamoya, which could be used for guiding management decisions and evaluating intervention response. PMID- 26967791 TI - Sulfonyl Azides as Precursors in Ligand-Free Palladium-Catalyzed Synthesis of Sulfonyl Carbamates and Sulfonyl Ureas and Synthesis of Sulfonamides. AB - An efficient synthesis of sulfonyl carbamates and sulfonyl ureas from sulfonyl azides employing a palladium-catalyzed carbonylation protocol has been developed. Using a two-chamber system, sulfonyl azides, PdCl2, and CO gas, released ex situ from Mo(CO)6, were assembled to generate sulfonyl isocyanates in situ, and alcohols and aryl amines were exploited as nucleophiles to afford a broad range of sulfonyl carbamates and sulfonyl ureas. A protocol for the direct formation of substituted sulfonamides from sulfonyl azides and amines via nucleophilic substitution was also developed. PMID- 26967790 TI - De Novo DQ Donor-Specific Antibodies Are Associated with Chronic Lung Allograft Dysfunction after Lung Transplantation. AB - RATIONALE: Despite increasing evidence about the role of donor-specific human leukocyte antigen (HLA) antibodies in transplant outcomes, the incidence and impact of de novo donor-specific antibodies (dnDSA) after lung transplantation remains unclear. OBJECTIVES: To describe the incidence, characteristics, and impact of dnDSA after lung transplantation. METHODS: We investigated a single center cohort of 340 lung transplant recipients undergoing transplant during 2008 to 2011. All patients underwent HLA-antibody testing quarterly pretransplant and at regular intervals over the first 24 months after transplant. The patients received modified immunosuppression depending on their pretransplant sensitization status. Risk factors for dnDSA development, as well as the associations of dnDSA with patient survival and chronic lung allograft dysfunction (CLAD), were determined using multivariable analysis. MEASUREMENTS AND MAIN RESULTS: The cumulative incidence of dnDSA was 47% at a median of 86 days (range, 44-185 d) after lung transplantation. Seventy-six percent of recipients with dnDSA had DQ-DSA. Male sex and the use of ex vivo lung perfusion were associated with an increased risk of dnDSA, whereas increased HLA-DQB1 matching was protective. DQ-dnDSA preceded or coincided with the diagnosis of CLAD in all cases. Developing dnDSA (vs. no dnDSA) was associated with a twofold increased risk of CLAD (hazard ratio, 2.04; 95% confidence interval, 1.13-3.69). This association appeared to be driven by the development of DQ-dnDSA. CONCLUSIONS: dnDSA are common after lung transplantation, with the majority being DQ DSA. DQ-dnDSA are associated with an increased risk of CLAD. Strategies to prevent or treat DQ-dnDSA may improve outcomes for lung transplant recipients. PMID- 26967792 TI - Low thermal conductivity and improved thermoelectric performance of nanocrystalline silicon germanium films by sputtering. AB - Si x Ge1-x alloys are well-known thermoelectric materials with a high figure of merit at high temperatures. In this work, metal-induced crystallization (MIC) has been used to grow Si0.8Ge0.2 films that present improved thermoelectric performance (zT = 5.6 * 10(-4) at room temperature)--according to previously reported values on films--with a relatively large power factor (sigma . S (2) = 16 MUW . m(-1) . K(-2)). More importantly, a reduction in the thermal conductivity at room temperature (kappa = 1.13 +/- 0.12 W . m(-1) . K(-1)) compared to other Si-Ge films (~3 W . m(-1) . K(-1)) has been found. Whereas the usual crystallization of amorphous SiGe (a-SiGe) is achieved at high temperatures and for long times, which triggers dopant loss, MIC reduces the crystallization temperature and the heating time. The associated dopant loss is thus avoided, resulting in a nanostructuration of the film. Using this method, we obtained Si0.8Ge0.2 films (grown by DC plasma sputtering) with appropriate compositional and structural properties. Different thermal treatments were tested in situ (by heating the sample inside the deposition chamber) and ex situ (annealed in an external furnace with controlled conditions). From the studies of the films by: x ray diffraction (XRD), synchrotron radiation grazing incidence x-ray diffraction (SR-GIXRD), micro Raman, scanning electron microscopy (SEM), x-ray photoemission spectroscopy (XPS), Hall effect, Seebeck coefficient, electrical and thermal conductivity measurements, we observed that the in situ films at 500 degrees C presented the best zT values with no gold contamination. PMID- 26967793 TI - The Breaking and Mending of meso-Tetraarylporphyrins: Transmuting the Pyrrolic Building Blocks. AB - Naturally occurring porphyrins and hydroporphyrins vary with respect to their ring substituents and oxidation states, but their tetrapyrrolic frameworks remain fully preserved across all kingdoms of life; there are no naturally occurring porphyrin-like macrocycles known that contain nonpyrrolic building blocks. However, the study of porphyrin analogues in which one or two pyrroles were replaced with nonpyrrolic building blocks might shed light on the correlation between structural modulation and ground and excited state optical properties of the "pigments of life", unlocking their mechanisms of function. Also, porphyrinoids with strong absorbance and emission spectra in the NIR are sought after in technical (e.g., light-harvesting) and biomedical (e.g., imaging and photochemotherapy) applications. These porphyrin analogues, the so-called pyrrole modified porphyrins (PMPs), are synthetically accessible using total syntheses. Alternatively-and most handily-they can also be formed by conversion of synthetic porphyrins. Guided by older reports of the fortuitous modifications of porphyrins into PMPs, our research program generalized the so-dubbed "Breaking and Mending of Porphyrins" approach toward PMPs. This method to convert a pyrrole in meso tetraarylporphyrins to a nonpyrrolic building block with high precision relies on a number of distinct steps. Step 1: The porphyrin is functionalized in a way that activates one or two peripheral double bonds toward breakage; in all cases surveyed here, this step is an osmium tetroxide-mediated dihydroxylation to generate dihydroxychlorin and tetrahydroxybacteriochlorins. Step 2: The activated, dihydroxylated beta,beta'-bond is "broken". Step 3: The functional groups resulting from the ring-cleavage reactions are utilized in subsequent "mending" steps to form the PMPs, that themselves may be subject to further modifications, Step 4. Thus, PMPs in which a pyrrole was degraded to an imine linkage, contracted to a four-membered ring, or expanded by oxygen, sulfur, carbon, or nitrogen atoms to form six-membered building blocks have become accessible. This approach also allowed the replacement of a single beta-carbon atom by a nitrogen or oxygen atom. Depending on the ring size, conformation, conformational flexibility, the oxidation state of the pyrrole replacements, or the presence of substituents that pi-extend the chromophores, the PMPs possess porphyrin- or hydroporphyrin-like optical spectra, or they show altogether unique electronic properties. Some PMP classes allow the fine-tuning of their absorption range; others exhibit panchromatic absorption spectra from the UV to the NIR. Several PMPs take up persistent chiral helimeric conformations that could be resolved. This Account summarizes the scopes of the "Breaking and Mending" methodology with a special focus on laying out the structural diversity of PMPs accessible from meso-tetraarylporphyrins and highlighting their optical properties, with the aim of encouraging their further study and application. PMID- 26967794 TI - Influence of an Enterococcus faecium probiotic on the development of Peyer's patches B cells in piglets. AB - To study the interactions between a probiotic bacterium and the host's immune system, we undertook a feeding trial with Enterococcus faecium SF68 (NCIMB 10415). Starting at an age of 1 day, piglets received a daily oral dose of the probiotic bacteria. Immune cells were isolated from the blood and the distal continuous Peyer's patch (PP) of the piglets. While the percentage of B cells in the distal continuous PP was not influenced by the probiotic treatment, an elevated expression of CD1 on Peyer's patch B cells was observed after probiotic treatment. Furthermore, the fraction of CD4-CD8+ cells was decreased in this organ. In blood lymphocyte fractions of the probiotic-treated piglets, the proportion of CD16-positive cells was also diminished, whereas the portion of gammadelta T cells and CD4-positive T cells increased. The data indicate that early administration of the probiotic Enterococcus faecium can modulate the composition of blood lymphocyte populations in piglets. PMID- 26967795 TI - Standardised ileal crude protein and amino acid digestibilities in protein supplements for piglets. AB - Standardised ileal digestibilities (SID) of crude protein and amino acids (AA) originating from 24 different feed ingredients, including 11 feed ingredients produced from soybeans, seven by-products of starch processing, four whey products and two fish meals, were determined in piglets by means of the difference method. For the indispensable AA, the highest SID values were obtained in three out of four whey proteins (SID >=90% for most indispensable AA), one out of two fish meals (SID >=86%), soy protein concentrate, hydrolysed soy protein isolate (SID >=86% for most indispensable AA), and by-products of starch processing (SID >=84% for most indispensable AA). The lowest SID values were obtained in extruded soybeans and microbially fermented soy protein (SID <=78% for most indispensable AA), whereas the SID values for high-protein soybean meal were intermediate (SID 80-89% for indispensable AA except for Thr). The SID values in the three enzymatically fermented soy proteins (SID 80-94% for most indispensable AA) were similar to those in high-protein soybean meal and soy protein concentrate. The results of the present study indicate that SID values of AA in feed ingredients for piglets differ considerably from those reported for grower-finisher pigs, thus there may be a need for separate feed tables for piglets. PMID- 26967796 TI - Identification of cobalamin and cobalamin analogues along the gastrointestinal tract of dairy cows. AB - Cobalamin analogues in samples of rumen fluid, duodenal and ileal digesta and faeces of lactating dairy cows collected during the course of two nutritional studies were identified using a recently developed liquid chromatography-mass spectrometry method in order to determine if changes in diet composition could alter their proportions. Only cobalamin and cobinamine were detected in feedstuffs; six supplementary analogues were detected in the gastrointestinal tract content. The proportion of analogues produced by the gastrointestinal microflora was higher than the vitamin itself. The mode of conservation of forage had no effect on the proportion of analogues in rumen fluid, duodenal digesta and faeces, whereas increasing metabolisable protein supply raised the proportion of analogues reaching the duodenum (p = 0.008). The proportion of analogues was higher in ileal than duodenal digesta, this observation probably indicates a preferential absorption of cobalamin in the small intestine. The present results showed that changes in diet composition could alter cobalamin synthesis in rumen. PMID- 26967797 TI - Manipulation of ruminal fermentation and methane production by dietary saponins and tannins from mangosteen peel and soapberry fruit. AB - Four fistulated Holstein Friesian heifers were used in a 4 * 4 Latin square design with a 2 * 2 factorial arrangement. The main factors were two roughage-to concentrate ratios (R:C, 70:30 and 30:70) and two supplementation levels of soapberry fruit-mangosteen peel (SM) pellets (0 and 4% tannins-saponins of total diets). Rice straw was used as a roughage source. The diet was fed ad libitum as a total mixed ration. SM pellets contained crude tannins and saponins at 12.1 and 15.7% of DM, respectively. It was found that at R:C 30:70 the DM intake and the digestibility of DM, CP and NDF were increased (p < 0.05), while SM pellet supplementation reduced the DM digestibility (p < 0.05). Ruminal pH was decreased at R:C 30:70. Total VFA and propionate was increased at high concentrate level and after SM pellet supplementation (p < 0.05); simultaneously, the acetate concentration and the acetate-to-propionate ratios were decreased (p < 0.05). Methane production was decreased at R:C 30:70 and additionally when SM pellets were supplemented (p < 0.05). This was in agreement with the percentage of methanogens in total ruminal DNA. Furthermore, the number of fungal zoospores were reduced at a higher concentrate proportion (R:C 30:70) and by SM-pellet supplementation (p < 0.05). Protozoal populations were diminished when SM pellets were supplemented (p < 0.05). In this study, it was shown that the roughage-to concentrate ratio, as well as the supplementation of SM pellets containing condensed tannins and saponins, caused changes in ruminal microorganisms and their fermentation end-products. PMID- 26967798 TI - The effect of the source of nitrogen supplementation on nitrogen balance, rates of plasma leucine turnover, protein synthesis and degradation in sheep. AB - Combined experiments of the isotope dilution method of [1-(13)C]leucine, open circuit calorimetry and nitrogen (N) balance test were used to determine the effect of the source of N supplementation on N balance, whole body protein synthesis (WBPS) and degradation (WBPD) in sheep. The experiment was performed in a replicated 3 * 3 Latin square design. The control diet consisted of timothy hay, ground maize and soybean meal. The urea diet was the control diet supplemented with 1.5% urea. The SBM diet contained the same N and metabolisable energy as the urea diet, which was reached by changing ground maize and soybean meal weights of the control diet. Nitrogen retention was greater (p < 0.05) for the urea diet than the control and SBM diets. Plasma urea concentrations were highest for the SBM diet, followed by the urea diet, and the control diet was lowest. The WBPS and WBPD did not differ between diets, but were numerically lower for the urea and SBM diets. These results suggest that in sheep, urea supplementation influenced N retention without clear changes in WBPS and WBPD. PMID- 26967799 TI - In vivo (rat) and in vitro (Caco-2 cells) absorption of amino acids from legume protein isolates as compared to lactalbumin or casein. AB - The amino acid absorption from legume protein isolates (from chickpeas, CPI; and lupins, LPI) was studied in in vivo and in vitro experiments in comparison to animal proteins (casein and lactalbumin). In the in vivo experiment on rats, the diets were isoenergetic and isonitrogen (per kg diet 15.5 MJ digestible energy and 150 g protein, respectively). At 150 min after feeding, the concentration of free amino acids in arterial and portal blood plasma of rats fed legume proteins was significantly different (p < 0.05) from rats fed animal protein (lactalbumin). In arterial plasma the concentration for Met, Leu, Trp and Lys in rats fed legume proteins was lower than lactalbumin controls and for Val and Cys higher; in portal plasma, the concentration of free Met, Leu, Trp and Lys was lower, and the concentration of Cys was higher in rats fed legume proteins than in rats fed lactalbumin. The cumulative (total mM at 195 min after ingestion) and net absorption (% of ingested amounts) of Met, Leu, Trp and Lys were higher (p < 0.01) for rats fed lactalbumin as compared to those fed legume protein isolates or casein. In the in vitro study (Caco-2 cell monolayers), after 2 h incubation the transport values of all the individual amino acids in CPI and LPI, except for Glu, Val and Ile, were lower (p < 0.01) than for casein or lactalbumin. The results indicate that amino acids from chickpea and lupin protein isolates are absorbed at slower rates than those from animal proteins, which might explain the lower nutritional utilisation of legume storage proteins as compared with lactalbumin or casein. PMID- 26967801 TI - Carotid Artery Stenosis: Anesthetic Considerations for Open and Endovascular Management. PMID- 26967802 TI - Anesthesia for the Endovascular Management of Aortic Disease. PMID- 26967804 TI - Open Abdominal Aortic Surgery: Principles and Anesthetic Considerations. PMID- 26967803 TI - Anesthetic Management of Open Thoracoabdominal Aortic Aneurysm Repair. PMID- 26967805 TI - Phantom Limb Pain: A Review. PMID- 26967807 TI - Preface. PMID- 26967800 TI - Preoperative Cardiac Evaluation and Management of the Patient Undergoing Major Vascular Surgery. PMID- 26967808 TI - Pressure-induced conformational switch of an interfacial protein. AB - A special class of proteins adopts an inactive conformation in aqueous solution and activates at an interface (such as the surface of lipid droplet) by switching their conformations. Lipase, an essential enzyme for breaking down lipids, serves as a model system for studying such interfacial proteins. The underlying conformational switch of lipase induced by solvent condition is achieved through changing the status of the gated substrate-access channel. Interestingly, a lipase was also reported to exhibit pressure activation, which indicates it is drastically active at high hydrostatic pressure. To unravel the molecular mechanism of this unusual phenomenon, we examined the structural changes induced by high hydrostatic pressures (up to 1500 MPa) using molecular dynamics simulations. By monitoring the width of the access channel, we found that the protein undergoes a conformational transition and opens the access channel at high pressures (>100 MPa). Particularly, a disordered amphiphilic alpha5 region of the protein becomes ordered at high pressure. This positive correlation between the channel opening and alpha5 ordering is consistent with the early findings of the gating motion in the presence of a water-oil interface. Statistical analysis of the ensemble of conformations also reveals the essential collective motions of the protein and how these motions contribute to gating. Arguments are presented as to why heightened sensitivity to high-pressure perturbation can be a general feature of switchable interfacial proteins. Further mutations are also suggested to validate our observations. Proteins 2016; 84:820 827. (c) 2016 Wiley Periodicals, Inc. PMID- 26967809 TI - Reaching a consensus on scoring instruments for infantile hemangioma: are we there yet? PMID- 26967811 TI - Error in Byline. PMID- 26967810 TI - X-ray Crystallographic Structures of a Trimer, Dodecamer, and Annular Pore Formed by an Abeta17-36 beta-Hairpin. AB - High-resolution structures of oligomers formed by the beta-amyloid peptide Abeta are needed to understand the molecular basis of Alzheimer's disease and develop therapies. This paper presents the X-ray crystallographic structures of oligomers formed by a 20-residue peptide segment derived from Abeta. The development of a peptide in which Abeta17-36 is stabilized as a beta-hairpin is described, and the X-ray crystallographic structures of oligomers it forms are reported. Two covalent constraints act in tandem to stabilize the Abeta17-36 peptide in a hairpin conformation: a delta-linked ornithine turn connecting positions 17 and 36 to create a macrocycle and an intramolecular disulfide linkage between positions 24 and 29. An N-methyl group at position 33 blocks uncontrolled aggregation. The peptide readily crystallizes as a folded beta-hairpin, which assembles hierarchically in the crystal lattice. Three beta-hairpin monomers assemble to form a triangular trimer, four trimers assemble in a tetrahedral arrangement to form a dodecamer, and five dodecamers pack together to form an annular pore. This hierarchical assembly provides a model, in which full-length Abeta transitions from an unfolded monomer to a folded beta-hairpin, which assembles to form oligomers that further pack to form an annular pore. This model may provide a better understanding of the molecular basis of Alzheimer's disease at atomic resolution. PMID- 26967813 TI - Incidence and Diagnosis of Pertussis in South African Children Hospitalized With Lower Respiratory Tract Infection. AB - BACKGROUND: The incidence of pertussis in children in low- and middle-income countries is poorly described. This study aimed to prospectively investigate the incidence of pertussis in South African children hospitalized with lower respiratory tract infection (LRTI). METHODS: Children hospitalized with LRTI in Cape Town, South Africa were enrolled over 1 year. Clinical data were collected. A nasopharyngeal (NP) swab and induced sputum (IS) were taken, and polymerase chain reaction specific for Bordetella pertussis (IS481+/hIS1001-) and Bordetella parapertussis (IS1001+) was performed. RESULTS: A total of 460 children with median age 8 [interquartile range (IQR), 4-18] months were studied. B. pertussis was detected in 17 (3.7%) while total Bordetella spp. were identified on 23 (5.0 %) of 460 NP. Adding IS testing increased the identification of B. pertussis to 32 of 460 cases (7.0%; 95% confidence interval, 4.8%-9.7%); P = 0.028 and total Bordetella to 41 of 460 (8.9%; 95% confidence interval, 4-10%); P = 0.020. Shorter duration of symptoms [median 2 (IQR, 2-3) days versus 5 (IQR, 3-7) days; P = 0.0008] was associated with detection of B. pertussis on IS versus NP. B. pertussis was detected in 15.8% (n=3/19) of HIV-infected children, 10.9% (n = 10/92) of HIV exposed uninfected and 5.4% (n = 19/349) of HIV-unexposed uninfected children. Risk of B. pertussis decreased with each additional dose of diphtheria, tetanus and acellular pertussis vaccine [0 doses = 17.9%; 1 dose = 7.0%; 2 doses = 6.9%; and >3 doses = 6.2%]. CONCLUSIONS: Pertussis is common in South African children hospitalized with LRTI particularly if HIV exposed or infected but decreases sequentially with vaccination doses. Polymerase chain reaction on IS specimen provides confirmation earlier than NP while increasing overall diagnostic yield. PMID- 26967812 TI - Learning and Memory in Children and Adolescents With Perinatal HIV Infection and Perinatal HIV Exposure. AB - BACKGROUND: Learning and memory in youth with perinatally acquired HIV (PHIV) are poorly understood, despite their importance for academic, healthcare and daily functioning. METHODS: PHIV (n = 173) and perinatally HIV-exposed but uninfected (PHEU, n = 85) participants (aged 9-19 years) in a substudy of the Pediatric HIV/AIDS Cohort Study completed age-standardized tests of verbal and visual learning and delayed memory. Linear regression models implemented via generalized estimating equations were used to compare memory measures in PHEU participants versus PHIV youth with and without Centers for Disease Control and Prevention class C diagnosis (PHIV-C, n = 45 and PHIV-non-C, n = 128, respectively), adjusting for sociodemographic covariates. RESULTS: Participants (mean age = 14.10 years) were 54% female, 75% Black and 18% Hispanic. Although unadjusted analyses showed significantly lower visual recognition memory and verbal delayed recall for PHIV-C compared with PHEU participants and lower verbal learning for PHIV-C and non-C groups compared with PHEU, differences persisted only for visual recognition memory after adjusting for sociodemographic covariates. For PHIV youth, current CD4% <25 was associated with poorer verbal learning, and older age at peak viral load was associated with poorer verbal delayed recall and design memory. CONCLUSIONS: Youth with PHIV, particularly those with Centers for Disease Control and Prevention class C diagnosis, showed poorer performance on some measures of learning and memory compared with PHEU. Although group differences in verbal memory were largely attributable to sociodemographic characteristics, associations of class C diagnosis with poorer visual recognition memory and of current CD4% with poorer verbal learning suggest subtle effects of HIV on learning and memory in youth with PHIV. PMID- 26967814 TI - Acute Scedosporium apiospermum Endobronchial Infection in Cystic Fibrosis. AB - Fungi are known pathogens in cystic fibrosis patients. A boy with cystic fibrosis boy presented with acute respiratory distress. Bronchoscopy showed airways obstruction by mucus plugs and bronchial casts. Scedosporium apiospermum was identified as the only pathogen. Bronchoalveolar lavage successfully resolved the acute obstruction. Plastic bronchitis is a new clinical picture of acute Scedosporium endobronchial colonization in cystic fibrosis patients. PMID- 26967816 TI - SIKD Is On the Road. PMID- 26967815 TI - Trends in Infectious Disease Hospitalizations in US Children, 2000 to 2012. AB - BACKGROUND: Although infectious diseases (IDs) remain a major public health problem in US children, there have been no recent efforts to examine comprehensively the change in epidemiology of ID hospitalizations. METHODS: A serial cross-sectional analysis using the Kids' Inpatient Database 2000, 2003, 2006, 2009, and 2012. We identified children <=19 years of age with a primary diagnosis of IDs. Outcomes were national rate of ID hospitalizations, in-hospital mortality, length-of-stay and hospitalization-related direct costs. Negative binomial and multivariable logistic models were constructed to test the change in hospitalization rate and in-hospital mortality, respectively. RESULTS: We identified 3,691,672 weighted hospitalizations for IDs, accounting for 24.5% of all pediatric hospitalizations. From 2000 to 2012, the rate of overall ID hospitalizations decreased from 91.0 to 75.8 per 10,000 US children (P < 0.001). The most frequently listed ID subgroup was lower respiratory infections (42.8% of all ID hospitalizations in 2012). Although the hospitalization rate for most ID subgroups decreased, the hospitalization rate for skin infections significantly increased (67.6% increase; P < 0.001). The multivariable model demonstrated a significant decline in in-hospital mortality (odds ratio for comparison of 2012 with 2000, 0.63; 95% confidence interval, 0.51-0.79). From 2000 to 2012, there was no significant change in the median length-of-stay (2 days in 2000 to 2 days in 2012; Ptrend = 0.33). The median direct cost for ID hospitalization increased from $3452 in 2003 to $3784 in 2012 (P = 0.007), with the nationwide direct cost of $4.4 billion in 2012. CONCLUSIONS: We found a statistically significant decline in overall ID hospitalization rate among US children from 2000 to 2012, whereas skin infections statistically significantly increased. In addition, the median direct cost per ID hospitalization increased by 10% during the study period. PMID- 26967817 TI - Thiamine synthesis regulates the fermentation mechanisms in the fungus Aspergillus nidulans. AB - Thiamine pyrophosphate (TPP) is a critical cofactor and its biosynthesis is under the control of TPP availability. Here we disrupted a predicted thiA gene of the fungus Aspergillus nidulans and demonstrated that it is essential for synthesizing cellular thiamine. The thiamine riboswitch is a post-transcriptional mechanism for TPP to repress gene expression and it is located on A. nidulans thiA pre-messenger RNA. The thiA riboswitch was not fully derepressed under thiamine-limited conditions, and fully derepressed under environmental stressors. Upon exposure to hypoxic stress, the fungus accumulated more ThiA and NmtA proteins, and more thiamine than under aerobic conditions. The thiA gene was required for the fungus to upregulate hypoxic branched-chain amino acids and ethanol fermentation that involve enzymes containing TPP. These findings indicate that hypoxia modulates thiA expression through the thiamine riboswitch, and alters cellular fermentation mechanisms by regulating the activity of the TPP enzymes. PMID- 26967818 TI - Occurrence and prognostic significance of cytogenetic evolution in patients with multiple myeloma. AB - Cytogenetic evaluation at the time of diagnosis is essential for risk stratification in multiple myeloma, however little is known about the occurrence and prognostic significance of cytogenetic evolution during follow-up. We studied 989 patients with multiple myeloma, including 304 patients with at least two cytogenetic evaluations. Multivariable-adjusted regression models were used to assess the associations between the parameters of interest and cytogenetic evolution as well as overall survival. The prognostic significance of baseline cytogenetic abnormalities was most pronounced at the time of diagnosis and attenuated over time. In the patients with serial cytogenetic evaluations, the presence of t(11;14) at the time of diagnosis was associated with decreased odds of cytogenetic evolution during follow-up (odds ratio (OR)=0.22, 95% confidence interval (CI)=0.09-0.56, P=0.001), while the presence of at least one trisomy or tetrasomy was associated with increased odds (OR=2.96, 95% CI=1.37-6.42, P=0.006). The development of additional abnormalities during the 3 years following diagnosis was associated with increased subsequent mortality (hazard ratio=3.31, 95% CI=1.73-6.30, P<0.001). These findings emphasize the importance of the underlying clonal disease process for risk assessment and suggest that selected patients may benefit from repeated risk stratification. PMID- 26967820 TI - Loss in MCL-1 function sensitizes non-Hodgkin's lymphoma cell lines to the BCL-2 selective inhibitor venetoclax (ABT-199). PMID- 26967819 TI - Development of highly aggressive mantle cell lymphoma after sofosbuvir treatment of hepatitis C. PMID- 26967822 TI - Imetelstat therapy in refractory anemia with ring sideroblasts with or without thrombocytosis. PMID- 26967821 TI - Lenalidomide treatment and prognostic markers in relapsed or refractory chronic lymphocytic leukemia: data from the prospective, multicenter phase-II CLL-009 trial. AB - Efficacy of lenalidomide was investigated in 103 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) treated on the prospective, multicenter randomized phase-II CLL-009 trial. Interphase cytogenetic and mutational analyses identified TP53 mutations, unmutated IGHV, or del(17p) in 36/96 (37.5%), 68/88 (77.3%) or 22/92 (23.9%) patients. The overall response rate (ORR) was 40.4% (42/104). ORRs were similar irrespective of TP53 mutation (36.1% (13/36) vs 43.3% (26/60) for patients with vs without mutation) or IGHV mutation status (45.0% (9/20) vs 39.1% (27/68)); however, patients with del(17p) had lower ORRs than those without del(17p) (21.7% (5/22) vs 47.1% (33/70); P=0.049). No significant differences in progression-free survival and overall survival (OS) were observed when comparing subgroups defined by the presence or absence of high-risk genetic characteristics. In multivariate analyses, only multiple prior therapies (?3 lines) significantly impacted outcomes (median OS: 21.2 months vs not reached; P=0.019). This analysis indicates that lenalidomide is active in patients with relapsed/refractory CLL with unfavorable genetic profiles, including TP53 inactivation or unmutated IGHV. (ClinicalTrials.gov identifier: NCT00963105). PMID- 26967823 TI - Biopsy-Induced Duodenal Hematoma Is Not an Infrequent Complication Favored by Bone Marrow Transplantation. AB - OBJECTIVES: Intraduodenal hematoma (IDH) is an uncommon complication of endoscopic duodenal biopsy that can cause severe obstruction of the digestive, biliary, or pancreatic tracts. We aimed to analyze the risk factors and outcomes of biopsy-induced IDH in our series. METHODS: Between 2010 and 2014, a retrospective chart review was conducted for all children younger than 18 years of age treated for IDH. We collected their data in our tertiary pediatric center and compared them to those of controls matched for age, sex, and pathology. RESULTS: Among 2705 upper nontherapeutic endoscopies and 1163 duodenal biopsies, 7 IDH occurred in 6 children suspected of developing graft-versus-host disease (GVHD) after bone marrow transplantation (BMT) and in 1 patient with Noonan syndrome. The IDH prevalence was significantly higher after BMT compared to children who did not undergo grafting (7% vs 0.1%; P = 7.9 * 10; odds ratio = 82). After a median delay of 48 hours, patients developed intestinal obstruction with abdominal pain and vomiting. The diagnosis was confirmed by using ultrasonography or computed tomography scans. Acute pancreatitis was determined in 3 out of 7 patients. Conservative treatment allowed complete resolution in all patients. CONCLUSIONS: IDH is not an infrequent complication of endoscopic duodenal biopsy, especially in patients who undergo BMT. Endoscopists should be especially careful during the duodenal biopsy procedure in these patients. With no early perforation due to post-biopsy IDH reported, the prognosis is good and conservative management generally leads to resolution of the symptoms in 2 to 3 weeks. PMID- 26967824 TI - Pediatric Acute-on-Chronic Liver Failure in a Specialized Liver Unit: Prevalence, Profile, Outcome, and Predictive Factors. AB - OBJECTIVES: The aim of the study was to assess the prevalence, profile, outcome, and predictive factors of pediatric acute-on-chronic liver failure (ACLF). METHODS: All children 3 months to 18 years satisfying the Asia Pacific Association for the Study of Liver Diseases definition of ACLF were included. Data were both extracted from records (January 2011 to December 2014) and prospectively collected (January to October 2015). Successful outcome was defined as survival with native liver at 90 days, whereas poor outcome included those who died or received liver transplantation. RESULTS: Of the 499 children with chronic liver disease (CLD), 56 (11.2%) presented as ACLF, with a mean age of 9.35 (+/ 4.39) years. Wilson disease and autoimmune hepatitis were the commonest underlying CLDs accounting for 24 (42.8%) and 18 (32.1%) cases, respectively. The most frequent events precipitating ACLF were a flare up of the underlying disease in 27 (48.2%) and acute viral hepatitis in 17 (30%). Poor outcome occurred in 22 (39.3%) children: 17 (30.4%) died and 5 (8.9%) received liver transplantation. Poor outcome was associated with grades 3 to 4 hepatic encephalopathy, bilirubin >=17.5, international normalized ratio >=3.5, and presence of 2 or more organ failures. On multivariate analysis, a Chronic Liver Failure-Sequential Organ Failure Assessment score >=10 best predicted mortality (odds ratio 20.45, 95% confidence interval 3.9-106.7). CONCLUSIONS: ACLF is present in 11.2% of childhood CLD, with a 90-day native liver survival of 61%. A Chronic Liver Failure-Sequential Organ Failure Assessment score of >=10 best predicts mortality at day 90. PMID- 26967825 TI - Free Amino Acids in Human Milk and Associations With Maternal Anthropometry and Infant Growth. AB - OBJECTIVES: Free glutamic acid has an appetite-regulating effect and studies with infant formula have suggested that free amino acids (FAA), especially glutamic acid, can downregulate intake. The content of glutamic acid and glutamine is high in breast milk but varies considerably between mothers. The aim was to investigate whether maternal anthropometry was associated with the content of the FAA glutamic acid or glutamine in breast milk and whether there was a negative association between these FAA and current size or early infant growth in fully breastfed infants. METHODS: From a subgroup of 78 mothers, of which 50 were fully breast feeding, from the Odense Child Cohort breast milk samples were collected 4 months after birth and analyzed for FAA. Information regarding breastfeeding status and infant weight and length was also recorded. RESULTS: There was a large variation in the concentration of the FAAs between mothers. Glutamic acid was positively correlated with mother's prepregnancy weight and height (P <= 0.028), but not body mass index. There was no negative correlation between the 2 FAA and infant weight or body mass index. Infant length at 4 months was, however, positively associated with glutamine, (P = 0.013) but the correlation was attenuated when controlling for birth length (P = 0.089). CONCLUSIONS: The hypothesis that a high content of glutamic acid and glutamine in breast milk could downregulate milk intake to a degree affecting early growth could not be confirmed. Maternal factors associated with the level of these FAA in milk and the potential effect on the infant should be investigated further. PMID- 26967826 TI - Spatially and Temporally Resolved Analysis of Environmental Trade-Offs in Electricity Generation. AB - The US power sector is a leading contributor of emissions that affect air quality and climate. It also requires a lot of water for cooling thermoelectric power plants. Although these impacts affect ecosystems and human health unevenly in space and time, there has been very little quantification of these environmental trade-offs on decision-relevant scales. This work quantifies hourly water consumption, emissions (i.e., carbon dioxide, nitrogen oxides, and sulfur oxides), and marginal heat rates for 252 electricity generating units (EGUs) in the Electric Reliability Council of Texas (ERCOT) region in 2011 using a unit commitment and dispatch model (UC&D). Annual, seasonal, and daily variations, as well as spatial variability are assessed. When normalized over the grid, hourly average emissions and water consumption intensities (i.e., output per MWh) are found to be highest when electricity demand is the lowest, as baseload EGUs tend to be the most water and emissions intensive. Results suggest that a large fraction of emissions and water consumption are caused by a small number of power plants, mainly baseload coal-fired generators. Replacing 8-10 existing power plants with modern natural gas combined cycle units would result in reductions of 19-29%, 51-55%, 60-62%, and 13-27% in CO2 emissions, NOx emissions, SOx emissions, and water consumption, respectively, across the ERCOT region for two different conversion scenarios. PMID- 26967827 TI - Hypersensitivity of Arabidopsis TAXIMIN1 overexpression lines to light stress is correlated with decreased sinapoyl malate abundance and countered by the antibiotic cefotaxime. AB - Peptide signaling in plants is involved in regulating development, (1,2) ensuring cross pollination through initiation of self-incompatibility (4) and assisting with recognition of beneficial (nitrogen fixing bacteria (5)) or unfavorable organisms (pathogens (6) or herbivores (7)). Peptides function to help plants to respond to a changing environment and improve their chances of survival. Constitutive expression of the gene encoding a novel cysteine rich peptide TAXIMIN1 (TAX1) resulted in fusion of lateral organs and in abnormal fruit morphology. TAX1 signaling functions independently from transcription factors known to play a role in this process such as LATERAL ORGAN FUSION1 (LOF1). Here, we report that the TAX1 promoter is not induced by the LOF1 transcription factor and that the TAX1 peptide neither interferes with transcriptional activation by LOF1.1 or transcriptional repression by LOF1.2. Furthermore, we found that TAX1 overexpressing lines were hypersensitive to continuous light, which may be reflected by a decreased accumulation of the UV-B protecting compound sinapoyl malate. Finally, adding the antibiotic cefotaxime to the medium surprisingly countered the light hypersensitivity phenotype of TAX1 overexpressing seedlings. PMID- 26967828 TI - Synthesis and Reaction Chemistry of Nanosize Monosodium Titanate. AB - This paper describes the synthesis and peroxide-modification of nanosize monosodium titanate (nMST), along with an ion-exchange reaction to load the material with Au(III) ions. The synthesis method was derived from a sol-gel process used to produce micron-sized monosodium titanate (MST), with several key modifications, including altering reagent concentrations, omitting a particle seed step, and introducing a non-ionic surfactant to facilitate control of particle formation and growth. The resultant nMST material exhibits spherical shaped particle morphology with a monodisperse distribution of particle diameters in the range from 100 to 150 nm. The nMST material was found to have a Brunauer Emmett-Teller (BET) surface area of 285 m(2)g(-1), which is more than an order of magnitude higher than the micron-sized MST. The isoelectric point of the nMST measured 3.34 pH units, which is a pH unit lower than that measured for the micron-size MST. The nMST material was found to serve as an effective ion exchanger under weakly acidic conditions for the preparation of an Au(III) exchange nanotitanate. In addition, the formation of the corresponding peroxotitanate was demonstrated by reaction of the nMST with hydrogen peroxide. PMID- 26967829 TI - Mean arterial pressure target in patients with septic shock. AB - In patients with septic shock, a mean arterial pressure higher than 65 mmHg is recommended by the Surviving Sepsis Campaign Guidelines. However, a precise mean arterial pressure target has not been delineated. The aim of this paper was to review the physiological rationale and clinical evidence for increasing mean arterial pressure in septic shock. A mean arterial pressure level lower than renal autoregulatory threshold may lead to renal dysfunction. However, adjusting macrocirculation objectives in particular after the early phase of septic shock may not correct established microcirculation impairments. Moreover, sympathetic over-stimulation due to high doses of vasopressor (needed to achieve high mean arterial pressure targets) may be associated with numerous harmful effects. Observational and small short term interventional studies did not provide a definitive answer to this question but suggested that a high mean arterial pressure (around 75-85 mmHg) may prevent acute kidney injury in some patients. The SEPSISPAM Trial, a large prospective, randomized, controlled study, compared the targets of High (i.e. 80 to 85 mm Hg) versus Low (i.e. 65 to 70 mm Hg) mean arterial pressure in patients with septic shock. The mortality was not different in the two groups. However in patients with chronic hypertension, there were significantly less renal failure in the high mean arterial pressure group than the low mean arterial pressure group. PMID- 26967830 TI - Mid-regional pro-adrenomedullin as prognostic biomarker in septic shock. AB - BACKGROUND: The aim was to ascertain the prognostic value of mid-regional pro adrenomedullin (MR-proADM), measured within 24 hours from the onset of septic shock (SS). METHODS: We performed a prospective, observational study on all patients admitted to our hospital's Intensive Care Unit with SS over a one year period from January to December 2011 to examine the outcomes in 100 consecutive SS cases. Demographic data and severity score (APACHEII and SOFA) were recorded. MR-proADM, C-reactive protein and procalcitonin were measured within the first 24 hours from SS onset. The outcome variable studied was 28-day mortality. Data were evaluated with non-parametric statistics bivariant and multivariate analyses for survival analysis. RESULTS: In patients who died within 28 days (36%), MR-proADM, Lactate, APACHE II as well as SOFA were significantly higher compared with survivors. MR-proADM showed the best association with 28-day mortality, as well as a prognostic value (logrank test: P=0.0012). Statistical significance was also seen in the Cox regression analysis (P=0.0004) for all patients with a Relative Risk of 1.26 times that of the baseline for each mmol/L of increase in MR-proADM. CONCLUSIONS: In our study MR-proADM levels measured on admission correlates with 28-day mortality in patients with septic shock. PMID- 26967831 TI - A comparison of QTc intervals following laryngoscopic intubation and i-gel insertion during propofol-sevoflurane anesthesia. AB - BACKGROUND: Laryngoscopic intubation and supraglottic airway device insertion can prolong the corrected QT (QTc) interval during anaesthetic induction even in healthy patients. No prior study has compared the effect of laryngoscopic intubation and supraglottic airway device, i-gel, insertion on the QTc interval change. METHODS: Patients were randomised to either the intubation group (N.=25) or the i-gel group (N.=25) before induction. The QT interval was sequentially measured in lead II following a standard anaesthetic technique for induction using propofol and sevoflurane. Four sequential QT values were applied to the Bazett's formula to correct for the effect of heart rate on the QT interval, and then averaged. The peak QTc interval, the duration of QTc prolongation >20 ms compared to the QTc value immediately before intubation or i-gel insertion and the incidence of the QTc intervals >500 ms were measured. RESULTS: The peak QTc interval was lower in i-gel group (458.4+/-24.3 ms) than in intubation group (488.6+/-32.6 ms) (P=0.001). The duration of QTc prolongation >20 ms compared to the QTc values at immediately before intubation or i-gel insertion was significantly longer in the intubation group (136.5+/-104.5 s) than that of the i gel group (56.9+/-56.5 s) (P=0.031). The number of patients with QTc interval >500 ms was significantly lower in the i-gel group (4%) than in the intubation group (48%). CONCLUSIONS: The insertion of the i-gel produces less QTc interval change than laryngoscopic intubation. The i-gel may be advantageous to patients who are at risk of QTc prolongation, high blood pressure and tachycardia. PMID- 26967833 TI - Blood brain barrier as a target for traumatic brain injury therapy. PMID- 26967832 TI - Chronic cervical radicular pain: time to tackle a new horizon. PMID- 26967834 TI - Novel mutations in the L visual pigment gene found in Japanese men with protan color-vision defect having a normal order L/M gene array. PMID- 26967835 TI - Isolation and Culture of Adult Zebrafish Brain-derived Neurospheres. AB - The zebrafish is a highly relevant model organism for understanding the cellular and molecular mechanisms involved in neurogenesis and brain regeneration in vertebrates. However, an in-depth analysis of the molecular mechanisms underlying zebrafish adult neurogenesis has been limited due to the lack of a reliable protocol for isolating and culturing neural adult stem/progenitor cells. Here we provide a reproducible method to examine adult neurogenesis using a neurosphere assay derived from zebrafish whole brain or from the telencephalon, tectum and cerebellum regions of the adult zebrafish brain. The protocol involves, first the microdissection of zebrafish adult brain, then single cell dissociation and isolation of self-renewing multipotent neural stem/progenitor cells. The entire procedure takes eight days. Additionally, we describe how to manipulate gene expression in zebrafish neurospheres, which will be particularly useful to test the role of specific signaling pathways during adult neural stem/progenitor cell proliferation and differentiation in zebrafish. PMID- 26967836 TI - The cognitive and neural basis of developmental prosopagnosia. AB - Developmental prosopagnosia (DP) is a severe impairment of visual face recognition in the absence of any apparent brain damage. The factors responsible for DP have not yet been fully identified. This article provides a selective review of recent studies investigating cognitive and neural processes that may contribute to the face recognition deficits in DP, focusing primarily on event related brain potential (ERP) measures of face perception and recognition. Studies that measured the face-sensitive N170 component as a marker of perceptual face processing have shown that the perceptual discrimination between faces and non-face objects is intact in DP. Other N170 studies suggest that faces are not represented in the typical fashion in DP. Individuals with DP appear to have specific difficulties in processing spatial and contrast deviations from canonical upright visual-perceptual face templates. The rapid detection of emotional facial expressions appears to be unaffected in DP. ERP studies of the activation of visual memory for individual faces and of the explicit identification of particular individuals have revealed differences between DPs and controls in the timing of these processes and in the links between visual face memory and explicit face recognition. These observations suggest that the speed and efficiency of information propagation through the cortical face network is altered in DP. The nature of the perceptual impairments in DP suggests that atypical visual experience with the eye region of faces over development may be an important contributing factor to DP. PMID- 26967837 TI - Analysis of anticipation by 3D motion capturing - a new method presented in karate kumite. AB - Anticipation is an important performance factor in karate kumite. A new approach analysing anticipation in realistic combat situations by motion capturing with a high temporal resolution is presented. The advantage of this approach is that both karate athletes interacting sports specific can be recorded synchronously; thus, the presented method has the potential to analyse visual information pickup due to coordination pattern of interaction between real athletes. The aim is to demonstrate the usability of the current method for anticipation research and to investigate if the distance between two athletes and their attacking technique play a role in the reaction of the defending athlete. Furthermore, relevant cues lying within each attacking technique and little individual differences are shown. Four male karate athletes took part in this study. Logistic regression indicated that both factors (distance * attacking technique) play a significant role in reaction. However, a correlation between these factors shows that only the attacking technique is a good predictor for reaction. Results show that the attacking technique jabbing punch (jap. Kizami-Zuki) was easier to anticipate than the attacking techniques reverse punch (jap. Gyaku-Zuki) and the round kick (jap. Mawashi-Geri). PMID- 26967838 TI - Editorial introduction. PMID- 26967839 TI - Current state of abdominal wall transplantation. AB - PURPOSE OF REVIEW: Primary closure of the abdominal wall remains one of the early challenges of intestinal transplantation. Our aim is to review the role of abdominal wall transplantation in achieving tension-free closure of the abdomen. RECENT FINDINGS: In total, 38 full-thickness vascularized abdominal wall transplants, six partial-thickness vascularized and 17 partial-thickness nonvascularized rectus facia grafts have been reported worldwide. Different techniques have been described. The most popular choice seems to be the full thickness vascularized abdominal wall allograft, where the anastomosis is performed either in a micro- or macrovascular fashion. Temporary 'remote' revascularisation of the allograft has been performed in some cases onto the recipient's forearm vessels when there is a long anticipated cold ischaemia time (>5 h). Preliminary data suggest that the abdominal wall skin rejection might be an early predictor of intestinal rejection. Vascularized and nonvascularized rectus fascia may be effective when there is inadequate healthy muscle/fascia but sufficient skin cover. SUMMARY: Several centres have already proved the technical and immunologic feasibility of partial or full-thickness abdominal wall transplantation. It is an effective option to achieve primary abdominal closure following intestinal transplantation and in its full-thickness form, it may be useful for monitoring rejection in visceral organs. PMID- 26967840 TI - A chance to recognise caring for the carers. PMID- 26967841 TI - Leaked safe staffing guideline from NICE 'appears to be watered down'. PMID- 26967842 TI - Last chance to enter RCNi Nurse Awards 2016. PMID- 26967844 TI - Call for Ebola aid effort delayed. PMID- 26967843 TI - Staff should train in diabetes care to make up for specialist shortfall. PMID- 26967845 TI - RCN queries why word 'nursing' is axed from metric. PMID- 26967847 TI - Postgraduate courses 'will collapse' if bursaries end. PMID- 26967846 TI - 'Pishy pants' remark leads to apology. PMID- 26967848 TI - Stonewall honour for its 'star' trust. PMID- 26967849 TI - Pay threshold could price migrants out of UK nursing. PMID- 26967851 TI - Support from other services key to better discharge in dementia care. PMID- 26967852 TI - Soap fiction 'reveals truth' of perinatal care. PMID- 26967853 TI - A cap of 1% on pay means nurses will feel the squeeze even more. PMID- 26967859 TI - Continence. PMID- 26967860 TI - Ease the path from acute to community. AB - NICE offers guidelines on how to ensure patients have the social support they need to leave hospital in a timely way. Its new guidance acknowledges the patient's 'journey' often begins with emergency admission, and emphasises the dedicated role of the discharge co-ordinator. Despite pressures, nurses can lead improvements. PMID- 26967861 TI - A caring approach for people in crisis. AB - Jane Murphy is nurse lead for Operation Emblem, in which mental health nurses work with police to reduce arrests of people in crisis. The project has improved police understanding of mental health and access to care. Ms Murphy was runner-up in the 2015 Nursing Standard Nurse Awards mental health category. PMID- 26967862 TI - The many benefits of 'always events'. AB - Simple changes that make a huge difference to patients are being implemented through the Always Events programme. Staff at a Lancashire pilot site use Always Events to support patients' care transitions and communicate more clearly. The aim is to provide an exceptional patient experience. PMID- 26967873 TI - Born to Move NHS app. PMID- 26967875 TI - Would doctors display solidarity if nurses decided to strike? PMID- 26967876 TI - We must challenge any company that claims to tackle dementia. PMID- 26967877 TI - Nursing associates should not replace registered nurses. PMID- 26967878 TI - Pressure-relieving mattresses should be provided in a timely way. PMID- 26967879 TI - Looking to the past provides inspiration for the future. PMID- 26967880 TI - Correction. PMID- 26967884 TI - How to monitor blood glucose. PMID- 26967885 TI - Standards to support learning and assessment in practice. AB - This is the first article in a series of 11 that will offer guidance to new and existing mentors and practice teachers to enable them to develop in their role and help them to gather a portfolio of evidence that meets the Nursing and Midwifery Council's Standards to Support Learning and Assessment in Practice (SSLAP). This article provides background to the development of the standards and outlines the SSLAP, including the four main stages of the framework, the eight domains and outcomes, and the five principles required for the roles of mentor, sign-off mentor and practice teacher. The requirements for maintaining the mentor and practice teacher roles are explored. PMID- 26967886 TI - Promoting effective education for children with eczema. AB - Patient and parent education for children with eczema should follow a consistent approach, guided by an established framework that combines aspects of nursing, education and cognitive psychology. Using the framework enables nurses to understand how to use and develop their skills when providing education about the management of eczema in children, and enables patients and parents to understand and develop the skills required to manage a chronic condition such as eczema. This framework is transferable to the adult context. PMID- 26967887 TI - Rounding. PMID- 26967888 TI - Prepare to impress. PMID- 26967889 TI - Moving in the right direction. PMID- 26967891 TI - Cause for concern. PMID- 26967892 TI - Myritonines A-C, Alkaloids from Myrioneuron tonkinensis Based on a Novel Hexacyclic Skeleton. AB - Myritonines A-C (1-3), three new alkaloids bearing an unprecedented heterohexacyclic skeleton, were isolated from Myrioneuron tonkinensis. Their structures were determined by a combination of spectroscopic data and single crystal X-ray diffraction analysis. Compound 3 represents the first Myrioneuron alkaloid featuring a unique trans-decahydroquinoline motif and was also found to possess a rare cyano functionality. Compounds 1 and 2 showed inhibition against the hepatitis C virus in vitro. PMID- 26967893 TI - Distinguishing Antimicrobial Models with Different Resistance Mechanisms via Population Pharmacodynamic Modeling. AB - Semi-mechanistic pharmacokinetic-pharmacodynamic (PK-PD) modeling is increasingly used for antimicrobial drug development and optimization of dosage regimens, but systematic simulation-estimation studies to distinguish between competing PD models are lacking. This study compared the ability of static and dynamic in vitro infection models to distinguish between models with different resistance mechanisms and support accurate and precise parameter estimation. Monte Carlo simulations (MCS) were performed for models with one susceptible bacterial population without (M1) or with a resting stage (M2), a one population model with adaptive resistance (M5), models with pre-existing susceptible and resistant populations without (M3) or with (M4) inter-conversion, and a model with two pre existing populations with adaptive resistance (M6). For each model, 200 datasets of the total bacterial population were simulated over 24h using static antibiotic concentrations (256-fold concentration range) or over 48h under dynamic conditions (dosing every 12h; elimination half-life: 1h). Twelve-hundred random datasets (each containing 20 curves for static or four curves for dynamic conditions) were generated by bootstrapping. Each dataset was estimated by all six models via population PD modeling to compare bias and precision. For M1 and M3, most parameter estimates were unbiased (<10%) and had good imprecision (<30%). However, parameters for adaptive resistance and inter-conversion for M2, M4, M5 and M6 had poor bias and large imprecision under static and dynamic conditions. For datasets that only contained viable counts of the total population, common statistical criteria and diagnostic plots did not support sound identification of the true resistance mechanism. Therefore, it seems advisable to quantify resistant bacteria and characterize their MICs and resistance mechanisms to support extended simulations and translate from in vitro experiments to animal infection models and ultimately patients. PMID- 26967894 TI - Correction: Premature Termination of MexR Leads to Overexpression of MexAB-OprM Efflux Pump in Pseudomonas aeruginosa in a Tertiary Referral Hospital in India. PMID- 26967896 TI - Minimum Effective Doses of Succinylcholine and Rocuronium During Electroconvulsive Therapy: A Prospective, Randomized, Crossover Trial. AB - BACKGROUND: Neuromuscular blockade is required to control excessive muscle contractions during electroconvulsive therapy (ECT). In a crossover, assessor blinded, prospective randomized study, we studied the minimum effective dose (MED) of succinylcholine and rocuronium for ECT. The MED was the lowest dose to provide a predefined qualitative measure of acceptable control of muscle strength during induced convulsions. METHODS: Succinylcholine (0.8 mg kg) or rocuronium (0.4 mg kg) was randomly administered in 227 ECT sessions to 45 patients. The dose was incrementally increased or decreased by 10% based on 2 psychiatrists' (blinded to treatment) assessment of "acceptable" or "not acceptable" control of evoked muscle contractions (sufficient versus insufficient or excessive paralysis). The neuromuscular transmission was monitored quantitatively until full recovery. RESULTS: In our study, the MEDs of succinylcholine and rocuronium to produce acceptable ECT conditions in 50% of patients (MED50ECT) were 0.85 mg kg (95% confidence interval [CI], 0.77-0.94) and 0.41 mg kg (95% CI, 0.36-0.46) and in 90% of patients (MED90ECT) were 1.06 mg kg (95% CI, 1.0-1.27) and 0.57 mg kg (95% CI, 0.5-0.6), respectively. Nadir twitch height for acceptable muscle activity was 0% (0-4) and 4% (0-30; P < 0.001), respectively, and the time to recovery of the neuromuscular transmission was 9.7 +/- 3.5 and 19.5 +/- 5.7 minutes, respectively. CONCLUSIONS: A twitch suppression of >90% is needed for control of motor contractions during ECT. The initial ECT dose of succinylcholine should be selected based on each patient's preprocedural condition, ranging between 0.77 and 1.27 mg kg to produce acceptable muscle blockade in 50% to 90% of patients. Rocuronium-neostigmine combination is a safe alternative if appropriately dosed (0.36-0.6 mg kg) and monitored. PMID- 26967895 TI - MicroRNAs hsa-miR-99b, hsa-miR-330, hsa-miR-126 and hsa-miR-30c: Potential Diagnostic Biomarkers in Natural Killer (NK) Cells of Patients with Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME). AB - BACKGROUND: Chronic Fatigue Syndrome (CFS/ME) is a complex multisystem disease of unknown aetiology which causes debilitating symptoms in up to 1% of the global population. Although a large cohort of genes have been shown to exhibit altered expression in CFS/ME patients, it is currently unknown whether microRNA (miRNA) molecules which regulate gene translation contribute to disease pathogenesis. We hypothesized that changes in microRNA expression in patient leukocytes contribute to CFS/ME pathology, and may therefore represent useful diagnostic biomarkers that can be detected in the peripheral blood of CFS/ME patients. METHODS: miRNA expression in peripheral blood mononuclear cells (PBMC) from CFS/ME patients and healthy controls was analysed using the Ambion Bioarray V1. miRNA demonstrating differential expression were validated by qRT-PCR and then replicated in fractionated blood leukocyte subsets from an independent patient cohort. The CFS/ME associated miRNA identified by these experiments were then transfected into primary NK cells and gene expression analyses conducted to identify their gene targets. RESULTS: Microarray analysis identified differential expression of 34 miRNA, all of which were up-regulated. Four of the 34 miRNA had confirmed expression changes by qRT-PCR. Fractionating PBMC samples by cell type from an independent patient cohort identified changes in miRNA expression in NK-cells, B cells and monocytes with the most significant abnormalities occurring in NK cells. Transfecting primary NK cells with hsa-miR-99b or hsa-miR-330-3p, resulted in gene expression changes consistent with NK cell activation but diminished cytotoxicity, suggesting that defective NK cell function contributes to CFS/ME pathology. CONCLUSION: This study demonstrates altered microRNA expression in the peripheral blood mononuclear cells of CFS/ME patients, which are potential diagnostic biomarkers. The greatest degree of miRNA deregulation was identified in NK cells with targets consistent with cellular activation and altered effector function. PMID- 26967899 TI - PepeSearch: Semantic Data for the Masses. AB - With the emergence of the Web of Data, there is a need of tools for searching and exploring the growing amount of semantic data. Unfortunately, such tools are scarce and typically require knowledge of SPARQL/RDF. We propose here PepeSearch, a portable tool for searching semantic datasets devised for mainstream users. PepeSearch offers a multi-class search form automatically constructed from a SPARQL endpoint. We have tested PepeSearch with 15 participants searching a Linked Open Data version of the Norwegian Register of Business Enterprises for non-trivial challenges. Retrieval performance was encouragingly high and usability ratings were also very positive, thus suggesting that PepeSearch is effective for searching semantic datasets by mainstream users. We also assessed its portability by configuring PepeSearch to query other SPARQL endpoints. PMID- 26967898 TI - Liver Transcriptome Analysis of the Large Yellow Croaker (Larimichthys crocea) during Fasting by Using RNA-Seq. AB - The large yellow croaker (Larimichthys crocea) is an economically important fish species in Chinese mariculture industry. To understand the molecular basis underlying the response to fasting, Illumina HiSeqTM 2000 was used to analyze the liver transcriptome of fasting large yellow croakers. A total of 54,933,550 clean reads were obtained and assembled into 110,364 contigs. Annotation to the NCBI database identified a total of 38,728 unigenes, of which 19,654 were classified into Gene Ontology and 22,683 were found in Kyoto Encyclopedia of Genes and Genomes (KEGG). Comparative analysis of the expression profiles between fasting fish and normal-feeding fish identified a total of 7,623 differentially expressed genes (P < 0.05), including 2,500 upregulated genes and 5,123 downregulated genes. Dramatic differences were observed in the genes involved in metabolic pathways such as fat digestion and absorption, citrate cycle, and glycolysis/gluconeogenesis, and the similar results were also found in the transcriptome of skeletal muscle. Further qPCR analysis confirmed that the genes encoding the factors involved in those pathways significantly changed in terms of expression levels. The results of the present study provide insights into the molecular mechanisms underlying the metabolic response of the large yellow croaker to fasting as well as identified areas that require further investigation. PMID- 26967900 TI - How Fast Is Your Body Motion? Determining a Sufficient Frame Rate for an Optical Motion Tracking System Using Passive Markers. AB - This paper addresses how to determine a sufficient frame (sampling) rate for an optical motion tracking system using passive reflective markers. When using passive markers for the optical motion tracking, avoiding identity confusion between the markers becomes a problem as the speed of motion increases, necessitating a higher frame rate to avoid a failure of the motion tracking caused by marker confusions and/or dropouts. Initially, one might believe that the Nyquist-Shannon sampling rate estimated from the assumed maximal temporal variation of a motion (i.e. a sampling rate at least twice that of the maximum motion frequency) could be the complete solution to the problem. However, this paper shows that also the spatial distance between the markers should be taken into account in determining the suitable frame rate of an optical motion tracking with passive markers. In this paper, a frame rate criterion for the optical tracking using passive markers is theoretically derived and also experimentally verified using a high-quality optical motion tracking system. Both the theoretical and the experimental results showed that the minimum frame rate is proportional to the ratio between the maximum speed of the motion and the minimum spacing between markers, and may also be predicted precisely if the proportional constant is known in advance. The inverse of the proportional constant is here defined as the tracking efficiency constant and it can be easily determined with some test measurements. Moreover, this newly defined constant can provide a new way of evaluating the tracking algorithm performance of an optical tracking system. PMID- 26967897 TI - Metabolomic Characterizations of Liver Injury Caused by Acute Arsenic Toxicity in Zebrafish. AB - Arsenic is one of the most common metalloid contaminants in groundwater and it has both acute and chronic toxicity affecting multiple organs. Details of the mechanism of arsenic toxicity are still lacking and profile studies at metabolic level are very limited. Using gas chromatography coupled with mass spectroscopy (GC/MS), we first generated metabolomic profiles from the livers of arsenic treated zebrafish and identified 34 significantly altered metabolite peaks as potential markers, including four prominent ones: cholic acid, glycylglycine, glycine and hypotaurine. Combined results from GC/MS, histological examination and pathway analyses suggested a series of alterations, including apoptosis, glycogenolysis, changes in amino acid metabolism and fatty acid composition, accumulation of bile acids and fats, and disturbance in glycolysis related energy metabolism. The alterations in glycolysis partially resemble Warburg effect commonly observed in many cancer cells. However, cellular damages were not reflected in two conventional liver function tests performed, Bilirubin assay and alanine aminotransferase (ALT) assay, probably because the short arsenate exposure was insufficient to induce detectable damage. This study demonstrated that metabolic changes could reflect mild liver impairments induced by arsenic exposure, which underscored their potential in reporting early liver injury. PMID- 26967901 TI - TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection. AB - While T cell immunity initially limits Mycobacterium tuberculosis infection, why T cell immunity fails to sterilize the infection and allows recrudescence is not clear. One hypothesis is that T cell exhaustion impairs immunity and is detrimental to the outcome of M. tuberculosis infection. Here we provide functional evidence for the development T cell exhaustion during chronic TB. Second, we evaluate the role of the inhibitory receptor T cell immunoglobulin and mucin domain-containing-3 (TIM3) during chronic M. tuberculosis infection. We find that TIM3 expressing T cells accumulate during chronic infection, co-express other inhibitory receptors including PD1, produce less IL-2 and TNF but more IL 10, and are functionally exhausted. Finally, we show that TIM3 blockade restores T cell function and improves bacterial control, particularly in chronically infected susceptible mice. These data show that T cell immunity is suboptimal during chronic M. tuberculosis infection due to T cell exhaustion. Moreover, in chronically infected mice, treatment with anti-TIM3 mAb is an effective therapeutic strategy against tuberculosis. PMID- 26967903 TI - A recurrent solitary fibrous tumor of the thigh with malignant transformation: A case report. AB - INTRODUCTION: We describe an unusual case of a uniformly high-grade malignant solitary fibrous tumor (SFT) of the thigh with recurrence after wide resection in a 31-year-old man. PRESENTATION OF CASE: Our current case showed a long-term benign course before the operation, although the subcutaneous tumor was larger than 10cm at presentation. The SFT was diagnosed by needle biopsy, and wide resection was performed. Histological findings showed proliferation of capillaries surrounded by masses of spindle-shaped cells without any cytologic atypia, and the percentage of MIB-1-positive nuclei was 2.1%. However, a rapidly enlarging recurrent tumor was observed 11 months after the operation. A second wide resection for the recurrent tumor was performed. Histologically, the tumor cells uniformly displayed significant cytologic atypia and pleomorphism, and had 40-50 mitoses per 10 high-power fields. The proportion of MIB-1-positive nuclei was 48%. Consequently, the tumor was diagnosed as a SFT with malignant transformation. DISCUSSION: The malignant transformation described in past studies showed high-grade areas within benign, low-grade, or intermediate-grade SFTs. Therefore, in contrast to our case, uniformly high-grade malignant histological findings at recurrence were not described. CONCLUSION: Even if a tumor is non-malignant during the clinical course, as confirmed by tissue biopsy, the possibility of tumor progression to high-grade sarcoma at recurrence should be considered, and the treatment strategy should be determined carefully. PMID- 26967902 TI - Treating chronic lymphocytic leukemia with obinutuzumab: safety and efficacy considerations. AB - INTRODUCTION: Obinutuzumab is a novel glycoengineered type II anti-CD20 monoclonal antibody (MoAb) with a higher affinity for CD20 epitope. It was approved by the United States Food and Drug Administration (FDA) in November 2013 for use in combination with chlorambucil for previously untreated chronic lymphocytic leukemia (CLL). AREAS COVERED: This article evaluates the safety of obinutuzumab in CLL patients, also addressing pharmacokinetics/pharmacodynamics (PK/PD), clinical use and efficacy. Moreover, a comparison with other anti-CD20 MoAb is performed. The principal available studies on obinutuzumab are reviewed, focusing on CLL. A PubMed literature search (August 2002 to September 2015) was conducted using the terms obinutuzumab, GA101, anti-CD20 antibody, and CLL. EXPERT OPINION: Obinutuzumab, a third-generation anti-CD20 MoAb, is a safe and effective treatment for elderly patients who are un-fit for fludarabine-based regimen. Its use, proven in the CLL11 study and the results of many ongoing trials evaluating other obinutuzumab-based regimen can lead obinutuzumab to be a candidate to replace rituximab as the first-line treatment option. PMID- 26967904 TI - A Laryngeal Lesion. Laryngeal actinomycosis. PMID- 26967907 TI - Correction: Epidemiology of Leptospirosis in Africa: A Systematic Review of a Neglected Zoonosis and a Paradigm for 'One Health' in Africa. PMID- 26967906 TI - Dissolution Dynamic Nuclear Polarization Instrumentation for Real-time Enzymatic Reaction Rate Measurements by NMR. AB - The main limitation of NMR-based investigations is low sensitivity. This prompts for long acquisition times, thus preventing real-time NMR measurements of metabolic transformations. Hyperpolarization via dissolution DNP circumvents part of the sensitivity issues thanks to the large out-of-equilibrium nuclear magnetization stemming from the electron-to-nucleus spin polarization transfer. The high NMR signal obtained can be used to monitor chemical reactions in real time. The downside of hyperpolarized NMR resides in the limited time window available for signal acquisition, which is usually on the order of the nuclear spin longitudinal relaxation time constant, T1, or, in favorable cases, on the order of the relaxation time constant associated with the singlet-state of coupled nuclei, TLLS. Cellular uptake of endogenous molecules and metabolic rates can provide essential information on tumor development and drug response. Numerous previous hyperpolarized NMR studies have demonstrated the relevancy of pyruvate as a metabolic substrate for monitoring enzymatic activity in vivo. This work provides a detailed description of the experimental setup and methods required for the study of enzymatic reactions, in particular the pyruvate-to lactate conversion rate in presence of lactate dehydrogenase (LDH), by hyperpolarized NMR. PMID- 26967905 TI - Novel NEK8 Mutations Cause Severe Syndromic Renal Cystic Dysplasia through YAP Dysregulation. AB - Ciliopathies are a group of genetic multi-systemic disorders related to dysfunction of the primary cilium, a sensory organelle present at the cell surface that regulates key signaling pathways during development and tissue homeostasis. In order to identify novel genes whose mutations would cause severe developmental ciliopathies, >500 patients/fetuses were analyzed by a targeted high throughput sequencing approach allowing exome sequencing of >1200 ciliary genes. NEK8/NPHP9 mutations were identified in five cases with severe overlapping phenotypes including renal cystic dysplasia/hypodysplasia, situs inversus, cardiopathy with hypertrophic septum and bile duct paucity. These cases highlight a genotype-phenotype correlation, with missense and nonsense mutations associated with hypodysplasia and enlarged cystic organs, respectively. Functional analyses of NEK8 mutations in patient fibroblasts and mIMCD3 cells showed that these mutations differentially affect ciliogenesis, proliferation/apoptosis/DNA damage response, as well as epithelial morphogenesis. Notably, missense mutations exacerbated some of the defects due to NEK8 loss of function, highlighting their likely gain-of-function effect. We also showed that NEK8 missense and loss-of function mutations differentially affect the regulation of the main Hippo signaling effector, YAP, as well as the expression of its target genes in patient fibroblasts and renal cells. YAP imbalance was also observed in enlarged spheroids of Nek8-invalidated renal epithelial cells grown in 3D culture, as well as in cystic kidneys of Jck mice. Moreover, co-injection of nek8 MO with WT or mutated NEK8-GFP RNA in zebrafish embryos led to shortened dorsally curved body axis, similar to embryos injected with human YAP RNA. Finally, treatment with Verteporfin, an inhibitor of YAP transcriptional activity, partially rescued the 3D spheroid defects of Nek8-invalidated cells and the abnormalities of NEK8 overexpressing zebrafish embryos. Altogether, our study demonstrates that NEK8 human mutations cause major organ developmental defects due to altered ciliogenesis and cell differentiation/proliferation through deregulation of the Hippo pathway. PMID- 26967908 TI - Use of Malachite Green-Loop Mediated Isothermal Amplification for Detection of Plasmodium spp. Parasites. AB - Malaria elimination efforts are hampered by the lack of sensitive tools to detect infections with low-level parasitemia, usually below the threshold of standard diagnostic methods, microscopy and rapid diagnostic tests. Isothermal nucleic acid amplification assays such as the loop-mediated isothermal amplification (LAMP), are well suited for field use as they do not require thermal cyclers to run the test. However, the use of specialized equipment, as described by many groups, reduces the versatility of the LAMP technique as a simple tool for use in endemic countries. In this study, the use of the malachite green (MG) dye, as a visual endpoint readout, together with a simple mini heat block was evaluated for the detection of malaria parasites. The assay was performed for 1 hour at 63 degrees C and the results scored by 3 independent human readers. The limit of detection of the assay was determined using well-quantified Plasmodium spp. infected reference samples and its utility in testing clinical samples was determined using 190 pre-treatment specimens submitted for reference diagnosis of imported malaria in the United States. Use of a simplified boil and spin methods of DNA extraction from whole blood and filter paper was also investigated. We demonstrate the accurate and sensitive detection of malaria parasites using this assay with a detection limit ranging between 1-8 parasites/MUL, supporting its applicability for the detection of infections with low parasite burden. This assay is compatible with the use of a simple boil and spin sample preparation method from both whole blood and filter papers without a loss of sensitivity. The MG-LAMP assay described here has great potential to extend the reach of molecular tools to settings where they are needed. PMID- 26967909 TI - Occurrence and removal of organic micropollutants: An overview of the watch list of EU Decision 2015/495. AB - Although there are no legal discharge limits for micropollutants into the environment, some regulations have been published in the last few years. Recently, a watch list of substances for European Union-wide monitoring was reported in the Decision 2015/495/EU of 20 March 2015. Besides the substances previously recommended to be included by the Directive 39/2013/EU, namely two pharmaceuticals (diclofenac and the synthetic hormone 17-alpha-ethinylestradiol (EE2)) and a natural hormone (17-beta-estradiol (E2)), the first watch list of 10 substances/groups of substances also refers three macrolide antibiotics (azithromycin, clarithromycin and erythromycin), other natural hormone (estrone (E1)), some pesticides (methiocarb, oxadiazon, imidacloprid, thiacloprid, thiamethoxam, clothianidin, acetamiprid and triallate), a UV filter (2-ethylhexyl 4-methoxycinnamate) and an antioxidant (2,6-di-tert-butyl-4-methylphenol) commonly used as food additive. Since little is known about the removal of most of the substances included in the Decision 2015/495/EU, particularly regarding realistic concentrations in aqueous environmental samples, this review aims to: (i) overview the European policy in the water field; (ii) briefly describe the most commonly used conventional and advanced treatment processes to remove micropollutants; (iii) summarize the relevant data published in the last decade, regarding occurrence and removal in aqueous matrices of the 10 substances/groups of substances that were recently included in the first watch list for European Union monitoring (Decision 2015/495/EU); and (iv) highlight the lack of reports concerning some substances of the watch list, the study of un-spiked aquatic matrices and the assessment of transformation by-products. PMID- 26967910 TI - Long-Term Neurodevelopmental Outcome after Doxapram for Apnea of Prematurity. AB - BACKGROUND: Doxapram has been advocated as a treatment for persistent apnea of prematurity (AOP). OBJECTIVE: To evaluate the effect of doxapram on long-term neurodevelopmental outcome in preterm infants as its safety still needs to be established. METHODS: From a retrospective cohort of preterm infants with a gestational age (GA) <30 weeks and/or a birth weight <1,250 g, born between 2000 and 2010, infants treated with doxapram (n = 142) and a nontreated control group were selected (n = 284). Patient characteristics and clinical and neurodevelopmental outcome data at 24 months' corrected age were collected. Neurodevelopmental delay (ND) was defined as having a Mental or Psychomotor Developmental Index (MDI/PDI) <-1 standard deviation (SD), cerebral palsy, or a hearing or visual impairment. Odds ratios (OR) were calculated using multiple logistic regression analyses adjusting for potential confounders. RESULTS: Infants treated with doxapram had a lower GA compared to controls. The number of infants with a MDI or PDI <-1 SD was not different between the groups. The risk of the combined outcome death or ND was significantly lower in the doxapram group after adjusting for confounding factors (OR = 0.54, 95% CI: 0.37, 0.78). Doxapram treated infants had a higher risk of bronchopulmonary dysplasia and patent ductus arteriosus, but a lower risk of spontaneous intestinal perforation. All other morbidities were not different between the groups. CONCLUSIONS: This study suggests that doxapram is not associated with an increased risk of ND. These findings need to be confirmed or refuted by a large, well-designed, placebo controlled randomized trial. PMID- 26967912 TI - Primus-Eugen Mullis, November 1954 - January 2016. PMID- 26967911 TI - Psychometric validation of measures of alcohol expectancies, retrospective subjective response, and positive drinking consequences for use with adolescents. AB - The Anticipated Effects of Alcohol Scale (AEAS), the Subjective Effects of Alcohol Scale, and the Positive Drinking Consequences Questionnaire (PDCQ) are psychometrically sound measures of alcohol expectancies (expectancies), subjective response to alcohol, and positive drinking consequences, respectively, for use with adults. Prior research using these measures suggests that expectancies, subjective response, and positive drinking consequences are related yet distinct determinants of drinking. The current study presents psychometric evaluations of these measures for use with adolescents including confirmatory factor analyses (CFA) of the previously identified latent structures, internal consistency, and test-criterion relationships. Legally, alcohol cannot be administered to adolescents, so we assessed retrospective subjective response (during the first drinking episode ever [SEAS First] and the most recent drinking episode [SEAS Recent]). The sample comprised 248 Connecticut high school students (53.6% male; mean age 16.50 [1.19] years; 71.4% White) who completed an anonymous survey. CFA confirmed the latent factor structures for each measure. The AEAS, SEAS First, SEAS Recent and the PDCQ were internally consistent (mean alpha AEAS=0.83; SEAS First=0.88; SEAS Recent=0.89, PDCQ=0.87). AEAS subscales evidenced moderate overlap with corresponding SEAS First subscales (mean=0.36) and SEAS Recent subscales (mean=0.46) and modest overlap with the PDCQ (mean=0.17). Expectancies, subjective response, and positive drinking consequences also accounted for significant variance in monthly drinking, lifetime maximum number of drinks consumed, and alcohol-related problems. In sum, the AEAS, the retrospective SEAS, and the PDCQ are psychometrically sound measures for use with adolescents. PMID- 26967913 TI - Effective seed-assisted synthesis of gold nanoparticles anchored nitrogen-doped graphene for electrochemical detection of glucose and dopamine. AB - A novel gold nanoparticle-anchored nitrogen-doped graphene (AuNP/NG) nanohybrid was synthesized through a seed-assisted growth method, as an effective electrocatalyst for glucose and dopamine detection. The AuNP/NG nanohybrids exhibited high sensitivity and selectivity toward glucose and dopamine sensing applications. The as-synthesized nanohybrids exhibited excellent catalytic activity toward glucose, with a linear response throughout the concentration range from 40MUM to 16.1mM, a detection limit of 12MUM, and a short response time (~ 10s). It also exhibited an excellent response toward DA, with a wide detection range from 30nM to 48MUM, a low detection limit of 10nM, and a short response time (~ 8s). Furthermore, it also showed long-term stability and high selectivity for the target analytes. These results imply that such nanohybrids show a great potential for electrochemical biosensing application. PMID- 26967914 TI - Plasmid-mediated colistin resistance (mcr-1 gene): three months later, the story unfolds. PMID- 26967915 TI - Novel drug discovery for Chagas disease. AB - INTRODUCTION: Chagas disease is a chronic infection associated with long-term morbidity. Increased funding and advocacy for drug discovery for neglected diseases have prompted the introduction of several important technological advances, and Chagas disease is among the neglected conditions that has mostly benefited from technological developments. A number of screening campaigns, and the development of new and improved in vitro and in vivo assays, has led to advances in the field of drug discovery. AREAS COVERED: This review highlights the major advances in Chagas disease drug screening, and how these are being used not only to discover novel chemical entities and drug candidates, but also increase our knowledge about the disease and the parasite. Different methodologies used for compound screening and prioritization are discussed, as well as novel techniques for the investigation of these targets. The molecular mechanism of action is also discussed. EXPERT OPINION: Technological advances have been executed with scientific rigour for the development of new in vitro cell-based assays and in vivo animal models, to bring about novel and better drugs for Chagas disease, as well as to increase our understanding of what are the necessary properties for a compound to be successful in the clinic. The gained knowledge, combined with new exciting approaches toward target deconvolution, will help identifying new targets for Chagas disease chemotherapy in the future. PMID- 26967916 TI - Socioeconomic and lifestyle factors as risks for suicidal behavior among Korean adults. AB - BACKGROUND: Preventing suicide has become a major public health priority in Korea. The aim of this study was to evaluate the associated factors of suicidal ideation (SI(1)) and attempt (SA(2)) among Korean adults. METHODS: The data were collected from the Korea National Health and Nutrition Examination Surveys (KNHANES), a nationally representative sample recruited using a multi-stage clustered probability design. The association of putative risk factors focused on nutrition and health behaviors which were evaluated using multiple logistic regression analyses after adjusting for confounding factors. Survey sample weights were used for all analysis. RESULTS: The 12-month prevalence of SI and SA in Korea was 15.0% and 0.85%, respectively. Female, previously married status, lower education and lower household income were associated with SI and SA. In particular, the effect of age on SI presented a reverse pattern based on gender; there was a positive association for men and a negative association for women. Additionally, drinking, smoking, physical activity above moderate intensity and eating fewer meals were associated with SA in women, whereas regular exercise was protective against SI in men. LIMITATIONS: The data were collected using a cross sectional survey, embedding possible bias. CONCLUSIONS: Higher prevalence of SI and SA among women was associated with smoking, drinking, avoiding regular exercise and insufficiency of food. Lower prevalence of SI was observed in men who engaged in physical activity while men with insufficient food showed a higher prevalence of SI and SA. PMID- 26967917 TI - Major depression in hospitalized Argentine general medical patients: Prevalence and risk factors. AB - BACKGROUND: Depression is not uncommon among medically hospitalized patients, though reported prevalence has varied widely, often in samples involving elderly patients with particular illnesses. Accordingly, we evaluated risk of major depression in three metropolitan general hospitals in Buenos Aires, in subjects with a range of medical disorders and ages, comparing several standard screening methods to expert clinical examinations. METHODS: Consecutively hospitalized general medical patients were evaluated over a six-months. Excluded were subjects under age 18 and those unable to participate in assessments because of illness, medication, sensory or speech impairment, or lack of language fluency, or scored <25 on the Mini Mental State Examination (MMSE). Consenting participants were examined for DSM-IV-TR major depression by psychiatrists guided by MINI examinations, compared with other standard screening methods. Risk factors were assessed by preliminary bivariate analyses followed by multivariate logistic regression modeling. RESULTS: Overall prevalence of major depression in 257 subjects was 27% by psychiatric examination. The rate was most similar (25%) with the Hospital Anxiety & Depression Scale (HADS), and much higher with the Beck Depression Inventory-II (BDI, 44%) and Patient Health Questionnaire (PHQ, 56%). Factors associated independently with depression by multivariate modeling included: prior psychotropic-drug treatment, female sex, more children, and heavy smoking. Depression was associated most with neoplastic, urological, and infectious disorders, least with pulmonary, neurological, and hematologic conditions. LIMITATIONS: Modest numbers limited power to test for associations of depression with specific medical conditions. CONCLUSIONS: Major depression was identified in over one-quarter of Argentine, general medical inpatients, with marked differences among screening methods. Several risk factors were identified. The findings encourage assertive identification of depression in hospitalized medical patients using valid, reliable, and cost-effective means of improving their care. PMID- 26967920 TI - Topical composition for treating diabetic cataracts: a patent evaluation (WO2015026380A1). AB - Diabetes mellitus is a major threat to global public health that requires long term medical attention. In view of the potentially devastating effects of diabetes on ocular health, it highlights the urgent need of therapeutic drugs for the prevention and treatment of the diabetic complications. The patent described in this evaluation (WO2015026380A1) claimed a topical composition for treating diabetic cataracts both in animals and human beings. The composition containing a therapeutic amount of the 2R-methyl sorbinil, one of aldose reductase inhibitors, delivered to the dog's eye can exert a preventive, inhibitory, or prophylactic effect on diabetic cataracts in a statistically significant portion of the population being studied. Thus methods and strategies using new formulations of known inhibitors are promising for future use in the treatment of diabetic complications. PMID- 26967919 TI - Heterotopic Renal Autotransplantation in a Porcine Model: A Step-by-Step Protocol. AB - Kidney transplantation is the treatment of choice for patients suffering from end stage renal disease. It offers better life expectancy and higher quality of life when compared to dialysis. Although the last few decades have seen major improvements in patient outcomes following kidney transplantation, the increasing shortage of available organs represents a severe problem worldwide. To expand the donor pool, marginal kidney grafts recovered from extended criteria donors (ECD) or donated after circulatory death (DCD) are now accepted for transplantation. To further improve the postoperative outcome of these marginal grafts, research must focus on new therapeutic approaches such as alternative preservation techniques, immunomodulation, gene transfer, and stem cell administration. Experimental studies in animal models are the final step before newly developed techniques can be translated into clinical practice. Porcine kidney transplantation is an excellent model of human transplantation and allows investigation of novel approaches. The major advantage of the porcine model is its anatomical and physiological similarity to the human body, which facilitates the rapid translation of new findings to clinical trials. This article offers a surgical step-by-step protocol for an autotransplantation model and highlights key factors to ensure experimental success. Adequate pre- and postoperative housing, attentive anesthesia, and consistent surgical techniques result in favorable postoperative outcomes. Resection of the contralateral native kidney provides the opportunity to assess post-transplant graft function. The placement of venous and urinary catheters and the use of metabolic cages allow further detailed evaluation. For long-term follow-up studies and investigation of alternative graft preservation techniques, autotransplantation models are superior to allotransplantation models, as they avoid the confounding bias posed by rejection and immunosuppressive medication. PMID- 26967918 TI - Val66Met BDNF polymorphism as a vulnerability factor for inflammation-associated depressive symptoms in women with breast cancer. AB - BACKGROUND: Inflammation contributes to the development of depression in a subset of individuals, but risk factors that render certain individuals particularly vulnerable to inflammation-associated depression are undetermined. Drawing from animal studies showing that reduced neuroplasticity mediates effects of inflammation on depression, we hypothesized that individuals genetically predisposed to lower levels of neuroplasticity would be more susceptible to inflammation-associated depression. The current study examined whether the Met allele of the BDNF Val66met polymorphism, which predisposes individuals to reduced levels of brain-derived neurotrophic factor (BDNF), a protein vital for neuroplasticity, moderates the association between inflammation and depressive symptoms. METHODS: Our sample was 112 women with early-stage breast cancer who had recently completed cancer treatment, which can activate inflammation. Participants provided blood for genotyping and assessment of circulating inflammatory markers, and completed a questionnaire assessing depressive symptoms, including somatic, affective, and cognitive dimensions. RESULTS: There was a significant interaction between C-reactive protein (CRP) and the BDNF Val66met polymorphism in predicting cognitive depressive symptoms (p=.004), such that higher CRP was related to more cognitive depressive symptoms among Met allele carriers, but not among Val/Val homozygotes. Post-hoc longitudinal analyses suggested that, for Met carriers, higher CRP at baseline predicted higher cognitive depressive symptoms across a one-year follow-up period (p<.001). CONCLUSION: The BDNF Met allele may be a risk factor for inflammation-associated cognitive depressive symptoms among breast cancer survivors. Women with breast cancer who carry this genotype may benefit from early identification and treatment. LIMITATION: BDNF genotype is an indirect measure of BDNF protein levels. PMID- 26967922 TI - Regular physical activity is associated with lower levels of ESSPRI and other favourable patient-reported outcomes in patients with primary Sjogren's syndrome. PMID- 26967921 TI - Local and Sustained Activity of Doxycycline Delivered with Layer-by-Layer Microcapsules. AB - Achieving localized delivery of small molecule drugs has the potential to increase efficacy and reduce off target and side effects associated with systemic distribution. Herein, we explore the potential use of layer-by-layer (LbL) assembled microcapsules for the delivery of doxycycline. Absorbance of doxycycline onto core dextran sulfate of preassembled microcapsules provides an efficient method to load both synthetic and biodegradable microcapsules with the drug. Application of an outer layer lipid coat enhances the sustained in vitro release of doxycycline from both microcapsule types. To monitor doxycycline delivery in a biological system, C2C12 mouse myoblasts are engineered to express EGFP under the control of the optimized components of the tetracycline regulated gene expression system. Microcapsules are not toxic to these cells, and upon delivery to the cells, EGFP is more efficiently induced in those cells that contain engulfed microcapsules and monitored EGFP expression clearly demonstrates that synthetic microcapsules with a DPPC coat are the most efficient for sustain intracellular delivery. Doxycycline released from microcapsules also displayed sustained activity in an antimicrobial growth inhibition assay compared with doxycycline solution. This study reveals the potential for LbL microcapsules in small molecule drug delivery and their feasible use for achieving prolonged doxycycline activity. PMID- 26967923 TI - Phenolic Compounds from Fermented Berry Beverages Modulated Gene and Protein Expression To Increase Insulin Secretion from Pancreatic beta-Cells in Vitro. AB - Berries are a rich source of bioactive phenolic compounds that are able to bind and inhibit the enzyme dipeptidyl peptidase-IV (DPP-IV), a current target for type-2 diabetes therapy. The objectives were to determine the role of berry phenolic compounds to modulate incretin-cleaving DPP-IV and its substrate glucagon-like peptide-1 (GLP-1), insulin secretion from pancreatic beta-cells, and genes and proteins involved in the insulin secretion pathway using cell culture. Anthocyanins (ANC) from 50% blueberry-50% blackberry (Blu-Bla) and 100% blackberry (Bla) fermented beverages at 50 MUM cyanidin-3-glucoside equivalents increased (p < 0.05) glucose-stimulated insulin secretion from pancreatic beta cells (iNS-1E) both when applied directly and following simulated absorption through Caco-2 cells (by 233 and 100 MUIU insulin/mL, respectively). ANC 50%Blu Bla and ANC 100%Bla upregulated the gene for incretin hormone GLP-1 (fold-change 3.0 +/- 1.4 and 2.0 +/- 0.3, respectively) and genes in the insulin secretory pathway including insulin-like growth factor 1 receptor (iGF1R, 2.3 +/- 0.6 and 1.6 +/- 0.3, respectively), and increased (p < 0.05) the protein expression of insulin-like growth factor 2 (IGF-II), insulin-like growth factor binding proteins (IGFBP-2 and 3), and vascular endothelial growth factor (VEGF) in iNS-1E cells. Taken together, anthocyanins, predominantly delphinidin-3-arabinoside, from fermented berry beverages have the potential to modulate DPP-IV and its substrate GLP-1, to increase insulin secretion, and to upregulate expression of mRNA of insulin-receptor associated genes and proteins in pancreatic beta-cells. PMID- 26967924 TI - Automation of Mode Locking in a Nonlinear Polarization Rotation Fiber Laser through Output Polarization Measurements. AB - When a laser is mode-locked, it emits a train of ultra-short pulses at a repetition rate determined by the laser cavity length. This article outlines a new and inexpensive procedure to force mode locking in a pre-adjusted nonlinear polarization rotation fiber laser. This procedure is based on the detection of a sudden change in the output polarization state when mode locking occurs. This change is used to command the alignment of the intra-cavity polarization controller in order to find mode-locking conditions. More specifically, the value of the first Stokes parameter varies when the angle of the polarization controller is swept and, moreover, it undergoes an abrupt variation when the laser enters the mode-locked state. Monitoring this abrupt variation provides a practical easy-to-detect signal that can be used to command the alignment of the polarization controller and drive the laser towards mode locking. This monitoring is achieved by feeding a small portion of the signal to a polarization analyzer measuring the first Stokes parameter. A sudden change in the read out of this parameter from the analyzer will occur when the laser enters the mode-locked state. At this moment, the required angle of the polarization controller is kept fixed. The alignment is completed. This procedure provides an alternate way to existing automating procedures that use equipment such as an optical spectrum analyzer, an RF spectrum analyzer, a photodiode connected to an electronic pulse counter or a nonlinear detecting scheme based on two-photon absorption or second harmonic generation. It is suitable for lasers mode locked by nonlinear polarization rotation. It is relatively easy to implement, it requires inexpensive means, especially at a wavelength of 1550 nm, and it lowers the production and operation costs incurred in comparison to the above-mentioned techniques. PMID- 26967925 TI - [Vaccination in the elderly]. PMID- 26967926 TI - [Immunosenescence: a review]. AB - Immunosenescence is a progressive deterioration of the immune system with ageing. A multifactorial condition, including multimorbidities and environmental factors in the elderly, increases the frailty risks. Some infection and nutritional factors contribute to the onset of decline of response to infection. The epithelial barrier is the front line against infection. The renewal capacity of hematopoietic stem cells is reduced and provide in turn decrease of immune cells like lymphocytes, antigen-presenting dendritic cells, and phagocytes. The cellular immunity decreases considering the low cytotoxicity of natural killer. The impairment of dendritic cells alters both non-adaptive and humoral immunities. The reduction of antibody producing B-cells alters humoral production and the diversity of immunoglobulins and their affinity. Somme evidence suggests that retained function of both innate and acquired immunity in the elderly is correlated with health status. CMV might play a part in the process of immunosenescence. CMV status is included in the immune risk profile. Some factors like nutritional status and inflammatory biomarkers should be added to define a immune risk profile in the elderly. PMID- 26967927 TI - [Zoster and postherpetic neuralgia: vaccine prevention is available]. AB - Herpes zoster (HZ) infection is a common condition in the elderly. Immunosuppression involving cellular immunity favors its occurrence. The pain is the most frequent complications of HZ. It occurs in about 30% of people aged over 70 years. The virological diagnosis of typical HZ is not useful, and the diagnosis is mainly based on clinical data. Skin care is essential to limit cutaneous damage. Antiviral drugs will reduce the risk of post-herpetic neuralgia, if they are early prescribed within 72 hours after the rash onset. Analgesia is essential and should be conducted in relation evolution. Vaccination is the most effective way to prevent the occurrence of HZ complications in the elderly, in particular post-herpetic neuralgia. PMID- 26967928 TI - [Immunization schedule in the elderly]. AB - Elderly people are more likely to develop severe infections diseases. Given the significant increase in the number of the elderly population, reducing the risk of infection by vaccination is a major preventive approach. The immunization schedule for 2014 in France yields, for the first time, vaccination recommendations for patients over 65 years. Tetanus-Diphtheria-Poliomyelitis vaccination is recommended to be given at the age of 65 years and then every 10 years, together with the pertussis vaccine to protect infants less than 6 months. Recommendation for vaccinations against seasonal influenza in autumn is maintained by the High Council for Public Health, which estimates that the population benefit persists despite the lower individual effectiveness in the elderly. The pneumococcal vaccine is recommended only in high-risk populations, and only once after the age 65. Zoster vaccine is recommended between 65 and 74, and the first year of its availability, can be proposed to elderly patients between 75 and 79 years. Vaccination in the elderly must be enhanced, and information about its advantages should be disseminated. PMID- 26967929 TI - Hydrologic Controls on Nitrogen Cycling Processes and Functional Gene Abundance in Sediments of a Groundwater Flow-Through Lake. AB - The fate and transport of inorganic nitrogen (N) is a critically important issue for human and aquatic ecosystem health because discharging N-contaminated groundwater can foul drinking water and cause algal blooms. Factors controlling N processing were examined in sediments at three sites with contrasting hydrologic regimes at a lake on Cape Cod, MA. These factors included water chemistry, seepage rates and direction of groundwater flow, and the abundance and potential rates of activity of N-cycling microbial communities. Genes coding for denitrification, anaerobic ammonium oxidation (anammox), and nitrification were identified at all sites regardless of flow direction or groundwater dissolved oxygen concentrations. Flow direction was, however, a controlling factor in the potential for N-attenuation via denitrification in the sediments. Potential rates of denitrification varied from 6 to 4500 pmol N/g/h from the inflow to the outflow side of the lake, owing to fundamental differences in the supply of labile organic matter. The results of laboratory incubations suggested that when anoxia and limiting labile organic matter prevailed, the potential existed for concomitant anammox and denitrification. Where oxic lake water was downwelling, potential rates of nitrification at shallow depths were substantial (1640 pmol N/g/h). Rates of anammox, denitrification, and nitrification may be linked to rates of organic N-mineralization, serving to increase N-mobility and transport downgradient. PMID- 26967932 TI - 'Learning tool' launched to help staff check their emergency services. AB - Emergency care staff are being urged to adopt a 'learning tool' to support urgent care services launched by the Royal College of General Practitioners (RCGP). PMID- 26967933 TI - Triage, assessment and In brief streaming defined in expert policy document. AB - Emergency care experts have published a position statement to clarify the merits of triage, initial assessment and streaming. PMID- 26967931 TI - Research yields new stroke treatment. AB - Clinical researchers are developing a new drug that is expected to limit the effects of heart attack and stroke. PMID- 26967930 TI - Review and comparison of methodologies for indirect comparison of clinical trial results: an illustration with ranibizumab and aflibercept. AB - AIM: To review and compare methods for indirect comparison of aflibercept and ranibizumab in patients with diabetic macular edema. METHODS: Post stratification, inverse probability weighting based on simulated data, weight optimization, and regression model techniques were used to compare pooled individual patient-level data from the RESTORE and RESPOND (ranibizumab 0.5 mg as needed after 3 initial monthly doses) studies with summary-level data from the VIVID and VISTA (aflibercept 2.0 mg every 8 weeks after 5 initial monthly doses, 2q8) studies. The impact of adjusting for up to two baseline characteristics was assessed. RESULTS: All methods provided similar results. After adjustment for baseline best-corrected visual acuity and central retinal thickness, no statistically significant difference in average gain in baseline best-corrected visual acuity from baseline at month 12 was found between ranibizumab 0.5 mg and aflibercept 2q8. CONCLUSIONS: Weight optimization and regression methods are useful options to adjust for more than one baseline characteristic. PMID- 26967934 TI - More children under 11 attending hospital after violent injuries. AB - The number of people treated in hospital after violent injuries fell in England and Wales last year, a study has revealed. PMID- 26967935 TI - Defend the NHS. AB - As the new financial year starts, NHS staff will know that austerity measures have been put in place or are being planned while healthcare services undergo great change. PMID- 26967936 TI - Hierarchical Porous Nickel Cobaltate Nanoneedle Arrays as Flexible Carbon Protected Cathodes for High-Performance Lithium-Oxygen Batteries. AB - Rechargeable lithium-oxygen (Li-O2) batteries are consequently considered to be an attractive energy storage technology because of the high theoretical energy densities. Here, an effective binder-free cathode with high capacity for Li-O2 batteries, needle-like mesoporous NiCo2O4 nanowire arrays uniformly coated on the flexible carbon textile have been in situ fabricated via a facile hydrothermal process followed by low temperature calcination. Because of the material and structural features, the needle-like NiCo2O4 nanowire arrays (NCONWAs) served as a binder-free cathode exhibits high specific capacity (4221 mAh g(-1)), excellent rate capability, and outstanding cycling stability (200 cycles). This cathode based on nonprecious mesoporous metal oxides nanowire arrays has large open spaces and high surface area, providing numerous catalytically active sites and effective transmission pathways for lithium ion and oxygen, and promises the abundant Li2O2 storage. The fast electron transport by directly anchoring on the substrate ensures fast electrochemical reaction process involved with the every nanowire. Furthermore, a bendable Li-O2 battery assembled by using the flexible NCONWAs as the cathode, can be able to light an LED and shows good rate capability and cyclic stability. PMID- 26967938 TI - Tissue Characterization after a New Disaggregation Method for Skin Micro-Grafts Generation. AB - Several new methods have been developed in the field of biotechnology to obtain autologous cellular suspensions during surgery, in order to provide one step treatments for acute and chronic skin lesions. Moreover, the management of chronic but also acute wounds resulting from trauma, diabetes, infections and other causes, remains challenging. In this study we describe a new method to create autologous micro-grafts from cutaneous tissue of a single patient and their clinical application. Moreover, in vitro biological characterization of cutaneous tissue derived from skin, de-epidermized dermis (Ded) and dermis of multi-organ and/or multi-tissue donors was also performed. All tissues were disaggregated by this new protocol, allowing us to obtain viable micro-grafts. In particular, we reported that this innovative protocol is able to create bio complexes composed by autologous micro-grafts and collagen sponges ready to be applied on skin lesions. The clinical application of autologous bio-complexes on a leg lesion was also reported, showing an improvement of both re-epitalization process and softness of the lesion. Additionally, our in vitro model showed that cell viability after mechanical disaggregation with this system is maintained over time for up to seven (7) days of culture. We also observed, by flow cytometry analysis, that the pool of cells obtained from disaggregation is composed of several cell types, including mesenchymal stem cells, that exert a key role in the processes of tissue regeneration and repair, for their high regenerative potential. Finally, we demonstrated in vitro that this procedure maintains the sterility of micro-grafts when cultured in Agar dishes. In summary, we conclude that this new regenerative approach can be a promising tool for clinicians to obtain in one step viable, sterile and ready to use micro-grafts that can be applied alone or in combination with most common biological scaffolds. PMID- 26967937 TI - Subthalamic Nucleus Deep Brain Stimulation May Reduce Medication Costs in Early Stage Parkinson's Disease. AB - BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is well-known to reduce medication burden in advanced stage Parkinson's disease (PD). Preliminary data from a prospective, single blind, controlled pilot trial demonstrated that early stage PD subjects treated with STN-DBS also required less medication than those treated with optimal drug therapy (ODT). OBJECTIVE: The purpose of this study was to analyze medication cost and utilization from the pilot trial of DBS in early stage PD and to project 10 year medication costs. METHODS: Medication data collected at each visit were used to calculate medication costs. Medications were converted to levodopa equivalent daily dose, categorized by medication class, and compared. Medication costs were projected to advanced stage PD, the time when a typical patient may be offered DBS. RESULTS: Medication costs increased 72% in the ODT group and decreased 16% in the DBS+ODT group from baseline to 24 months. This cost difference translates into a cumulative savings for the DBS+ODT group of $7,150 over the study period. Projected medication cost savings over 10 years reach $64,590. Additionally, DBS+ODT subjects were 80% less likely to require polypharmacy compared with ODT subjects at 24 months (p < 0.05; OR = 0.2; 95% CI: 0.04-0.97). CONCLUSIONS: STN-DBS in early PD reduced medication cost over the two-year study period. DBS may offer substantial long term reduction in medication cost by maintaining a simplified, low dose medication regimen. Further study is needed to confirm these findings, and the FDA has approved a pivotal, multicenter clinical trial evaluating STN-DBS in early PD. PMID- 26967942 TI - Learning Warps Object Representations in the Ventral Temporal Cortex. AB - The human ventral temporal cortex (VTC) plays a critical role in object recognition. Although it is well established that visual experience shapes VTC object representations, the impact of semantic and contextual learning is unclear. In this study, we tracked changes in representations of novel visual objects that emerged after learning meaningful information about each object. Over multiple training sessions, participants learned to associate semantic features (e.g., "made of wood," "floats") and spatial contextual associations (e.g., "found in gardens") with novel objects. fMRI was used to examine VTC activity for objects before and after learning. Multivariate pattern similarity analyses revealed that, after learning, VTC activity patterns carried information about the learned contextual associations of the objects, such that objects with contextual associations exhibited higher pattern similarity after learning. Furthermore, these learning-induced increases in pattern information about contextual associations were correlated with reductions in pattern information about the object's visual features. In a second experiment, we validated that these contextual effects translated to real-life objects. Our findings demonstrate that visual object representations in VTC are shaped by the knowledge we have about objects and show that object representations can flexibly adapt as a consequence of learning with the changes related to the specific kind of newly acquired information. PMID- 26967943 TI - Top-Down Activation of Spatiotopic Sensory Codes in Perceptual and Working Memory Search. AB - A critical requirement of an efficient cognitive system is the selection and prioritization of relevant information. This occurs when selecting specific items from our sensory inputs, which then receive preferential status at subsequent levels of processing. Many everyday tasks also require us to select internal representations, such as a relevant item from memory. We show that both of these types of search are underpinned by the spatiotopic activation of sensory codes, using both fMRI and MEG data. When individuals searched for perceived and remembered targets, the MEG data highlighted a sensor level electrophysiological effect that reflects the contralateral organization of the visual system-namely, the N2pc. The fMRI data were used to identify a network of frontoparietal areas common to both types of search, as well as the early visual areas activated by the search display. We then combined fMRI and MEG data to explore the temporal dynamics of functional connections between the frontoparietal network and the early visual areas. Searching for a target item resulted in significantly enhanced phase-phase coupling between the frontoparietal network and the visual areas contralateral to the perceived or remembered location of that target. This enhancement of spatially specific phase-phase coupling occurred before the N2pc effect and was significantly associated with it on a trial-by-trial basis. The combination of these two imaging modalities suggests that perceptual and working memory search are underpinned by the synchronization of a frontoparietal network and the relevant sensory cortices. PMID- 26967945 TI - "How Did I Make It?": Uncertainty about Own Motor Performance after Inhibition of the Premotor Cortex. AB - Optimal motor performance requires the monitoring of sensorimotor input to ensure that the motor output matches current intentions. The brain is thought to be equipped with a "comparator" system, which monitors and detects the congruence between intended and actual movement; results of such a comparison can reach awareness. This study explored in healthy participants whether the cathodal transcranial direct current stimulation (tDCS) of the right premotor cortex (PM) and right posterior parietal cortex (PPC) can disrupt performance monitoring in a skilled motor task. Before and after tDCS, participants underwent a two-digit sequence motor task; in post-tDCS session, single-pulse TMS (sTMS) was applied to the right motor cortex, contralateral to the performing hand, with the aim of interfering with motor execution. Then, participants rated on a five-item questionnaire their performance at the motor task. Cathodal tDCS of PM (but not sham or PPC tDCS) impaired the participants' ability to evaluate their motor performance reliably, making them unconfident about their judgments. Congruently with the worsened motor performance induced by sTMS, participants reported to have committed more errors after sham and PPC tDCS; such a correlation was not significant after PM tDCS. In line with current computational and neuropsychological models of motor control and awareness, the present results show that a mechanism in the PM monitors and compares intended versus actual movements, evaluating their congruence. Cathodal tDCS of the PM impairs the activity of such a "comparator," disrupting self-confidence about own motor performance. PMID- 26967944 TI - Addiction History Associates with the Propensity to Form Habits. AB - Learned habitual responses to environmental stimuli allow efficient interaction with the environment, freeing cognitive resources for more demanding tasks. However, when the outcome of such actions is no longer a desired goal, established stimulus-response (S-R) associations or habits must be overcome. Among people with substance use disorders (SUDs), difficulty in overcoming habitual responses to stimuli associated with their addiction in favor of new, goal-directed behaviors contributes to relapse. Animal models of habit learning demonstrate that chronic self-administration of drugs of abuse promotes habitual responding beyond the domain of compulsive drug seeking. However, whether a similar propensity toward domain-general habitual responding occurs in humans with SUDs has remained unclear. To address this question, we used a visuomotor S R learning and relearning task, the Hidden Association between Images Task, which employs abstract visual stimuli and manual responses. This task allows us to measure new S-R association learning and well-learned S-R association execution and includes a response contingency change manipulation to quantify the degree to which responding is habit-based, rather than goal-directed. We find that people with SUDs learn new S-R associations as well as healthy control participants do. Moreover, people with an SUD history slightly outperform controls in S-R execution. In contrast, people with SUDs are specifically impaired in overcoming well-learned S-R associations; those with SUDs make a significantly greater proportion of perseverative errors during well-learned S-R replacement, indicating the more habitual nature of their responses. Thus, with equivalent training and practice, people with SUDs appear to show enhanced domain-general habit formation. PMID- 26967946 TI - Transient Distraction and Attentional Control during a Sustained Selective Attention Task. AB - Distracting stimuli in the environment can pull our attention away from our goal directed tasks. fMRI studies have implicated regions in right frontal cortex as being particularly important for processing distractors [e.g., de Fockert, J. W., & Theeuwes, J. Role of frontal cortex in attentional capture by singleton distractors. Brain and Cognition, 80, 367-373, 2012; Demeter, E., Hernandez Garcia, L., Sarter, M., & Lustig, C. Challenges to attention: A continuous arterial spin labeling (ASL) study of the effects of distraction on sustained attention. Neuroimage, 54, 1518-1529, 2011]. Less is known, however, about the timing and sequence of how right frontal or other brain regions respond selectively to distractors and how distractors impinge upon the cascade of processes related to detecting and processing behaviorally relevant target stimuli. Here we used EEG and ERPs to investigate the neural consequences of a perceptually salient but task-irrelevant distractor on the detection of rare target stimuli embedded in a rapid, serial visual presentation (RSVP) stream. We found that distractors that occur during the presentation of a target interfere behaviorally with detection of those targets, reflected by reduced detection rates, and that these missed targets show a reduced amplitude of the long latency, detection-related P3 component. We also found that distractors elicited a right-lateralized frontal negativity beginning at 100 msec, whose amplitude negatively correlated across participants with their distraction-related behavioral impairment. Finally, we also quantified the instantaneous amplitude of the steady-state visual evoked potentials elicited by the RSVP stream and found that the occurrence of a distractor resulted in a transient amplitude decrement of the steady-state visual evoked potential, presumably reflecting the pull of attention away from the RSVP stream when distracting stimuli occur in the environment. PMID- 26967947 TI - Cue-related Temporal Factors Modulate Movement-related Beta Oscillatory Activity in the Human Motor Circuit. AB - In humans, there is a strong beta (15-30 Hz) event-related desynchronization (ERD) that begins before movement, which has been tentatively linked to motor planning operations. The dynamics of this response are strongly modulated by whether a pending movement is cued and the inherent parameters of the cue. However, previous studies have focused on the information content of cues and not on parameters such as the timing of the cue relative to other events. Variations in such timing are critical, as they directly impact the amount of time that participants have to plan pending movements. In this study, participants performed finger-tapping sequences during magnetoencephalography, and we manipulated the amount of time (i.e., "long" vs. "short") between the presentation of the to-be-executed sequence and the cue to initiate the sequence. We found that the beta ERD was stronger immediately after the cue to move in the contralateral postcentral gyrus and bilateral parietal cortices during the short compared with long planning time condition. During movement execution, the beta ERD was stronger in the premotor cortex and the SMA in the short relative to long condition. Finally, peak latency in the SMA significantly correlated with RT, such that the closer the peak beta ERD was to the cue to move, the quicker the participant responded. The results of this study establish that peri-movement beta ERD activity across the cortical motor circuit is highly sensitive to cue related temporal factors, with a direct link to motor performance. PMID- 26967949 TI - Protein Binding Bends the Gold Nanoparticle Capped DNA Sequence: Toward Novel Energy-Transfer-Based Photoelectrochemical Protein Detection. AB - In this work, we present a novel energy-transfer (ET)-based photoelectrochemical (PEC) probing of DNA-protein interactions, which associates intimately with many important intracellular processes in transcriptional regulatory networks. Specifically, Au nanoparticles (NPs) were confined onto the CdS quantum dots (QDs) functionalized PEC surface by the formation of duplex DNA, the subsequent binding of the TATA binding protein (TBP) and the resulting distortion of the Au NPs capped DNA sequence could adjust the interparticle distance and thereby modulate the PEC performance of CdS QDs through the ET process between the CdS QDs and Au NPs. Using the duplex DNA sequence as a rigid spacer, the relationship between the photocurrent quenching effect and the spacing distance was also studied and some experimental conditions were optimized, on the basis of which a novel ET-based PEC TBP biosensor was realized with high sensitivity and selectivity. PMID- 26967950 TI - Chiral NHC Ligands Bearing a Pyridine Moiety in Copper-Catalyzed 1,2-Addition of Dialkylzinc Reagents to beta-Aryl-alpha,beta-unsaturated N-Tosylaldimines. AB - Asymmetric 1,2-addition of dialkylzinc reagents to alpha,beta-unsaturated N tosylaldimines was catalyzed by copper salt in the presence of chiral imidazolium salts having a pyridine ring, which were derived from amino acid, to afford the corresponding chiral allylic amines with up to 91% ee in reasonably high yields. The chiral N-heterocyclic carbene (NHC) ligand played an important role in controlling chemoselectivity. PMID- 26967948 TI - Simulation Testing for Selection of Critical Care Medicine Trainees. A Pilot Feasibility Study. AB - RATIONALE: Selection of physicians into anesthesiology, intensive care, and emergency medicine training has traditionally relied on evaluation of curriculum vitae, letters of recommendation, and interviews, despite these methods being poor predictors of subsequent workplace performance. OBJECTIVES: In this study, we evaluated the feasibility and face validity of incorporating assessment of nontechnical skills in simulation and personality traits into an existing junior doctor selection framework. METHODS: Candidates short-listed for a critical care residency position were invited to participate in the study. On the interview day, consenting candidates participated in a simulation scenario and debriefing and completed a personality test (16 Personality Factor Questionnaire) and a survey. Timing of participants' progression through the stations and faculty staff numbers were evaluated. Nontechnical skills were evaluated and candidates ranked using the Ottawa Crisis Resource Management Global Rating Scale (Ottawa GRS). Nontechnical skills ranking and traditional selection method ranking were compared using the concordance correlation coefficient. Interrater reliability was assessed using the concordance correlation coefficient. MEASUREMENTS AND MAIN RESULTS: Thirteen of 20 eligible participants consented to study inclusion. All participants completed the necessary stations without significant time delays. Eighteen staff members were required to conduct interviews, simulation, debriefing, and personality testing. Participants rated the simulation station to be acceptable, fair, and relevant and as providing an opportunity to demonstrate abilities. Personality testing was rated less fair, less relevant, and less acceptable, and as giving less opportunity to demonstrate abilities. Participants reported that simulation was equally as stressful as the interview, whereas personality testing was rated less stressful. Assessors rated both personality testing and simulation as acceptable and able to provide additional information about candidates. The Ottawa GRS showed moderate interrater concordance. There was moderate concordance between rankings based on traditional selection methods and Ottawa GRS rankings (rho = 0.52; 95% confidence interval, -0.02 to 0.82; P = 0.06). CONCLUSIONS: A multistation selection process involving interviews, simulation, and personality testing is feasible and has face validity. A potential barrier to adoption is the high number of faculty required to conduct the process. PMID- 26967951 TI - Deformation and rupture of Dunaliella salina at high shear rates without the use of thickeners. AB - BACKGROUND: High-density cultures require operating below the critical threshold of shear stress, in order to avoid reducing the specific growth rate of the cells. When determining this threshold, direct inspection of the cells in flow provides insight into the conditions of shearing. OBJECTIVE: Aim of this study was using a novel rheo-optical setup for the observation of cells in laminar shear flow and the determination of the critical shear stress required to damage them in their natural environment. METHODS: Dunaliella salina cells were sheared and observed in flow for shear stresses of up to 90 Pa, at ambient temperature, without adding thickeners. The critical shear stress was determined by fitting a hydrodynamics-based criterion to the experimental data on the percentage of deformed cells after shearing. RESULTS: Single cells, clusters and strings of cells were visible in shear flow. The strings formed at maximum shear stresses of 10 Pa or higher. Cells lost motility for maximum shear stresses higher than 15 Pa, and more than 80% of the cells were deformed at maximum shear stresses higher than 60 Pa. The estimated critical shear stress was 18 Pa. CONCLUSIONS: Shear stresses higher than 18 Pa should be avoided when cultivating D. salina. PMID- 26967952 TI - Effects of betaine, organic acids and inulin as single feed additives or in combination on bacterial populations in the gastrointestinal tract of weaned pigs. AB - A study was carried out to investigate whether blends of betaine, organic acids and inulin may improve their efficacy to modulate intestinal bacterial populations in weaned pigs compared with the single application of these additives. Moreover, potential postprandial diurnal variations in ileal bacterial numbers were determined in piglets fed the control diet. Twenty-four piglets in two consecutive experiments received a wheat-barley-soybean meal control diet (Con) or the Con diet supplemented with betaine (BET; 0.2%), an organic acid blend (AC; 0.4%) or inulin (IN; 0.2%) as single additives or in combination. Ileal bacterial numbers of total bacteria, lactobacilli, bifidobacteria (p < 0.05) and enterobacteria (p < 0.10) showed a postprandial diurnal variation, thus spot sampling of ileal digesta for the determination of bacterial numbers may not be representative. There were only small effects of BET, AC and IN on ileal and faecal bacterial populations. BET + AC increased total ileal bacterial numbers compared to the Con and AC treatments. BET reduced lactobacilli numbers in faeces, whereas BET + IN increased ileal numbers of bifidobacteria compared to AC and IN. There is evidence that BET, AC, IN and their combinations may affect proliferation of beneficial bacterial populations, although this has to be confirmed in further studies. PMID- 26967953 TI - Development of equations for predicting metabolisable energy concentrations in compound feeds for pigs. AB - In 2006 in Germany new recommendations for the supply of energy and nutrients to pigs were published, including a modification of the energy evaluation on the basis of metabolisable energy for pigs (MES). It was the objective of this meta analysis to calculate equations that can be used for predicting MES in compound feeds for pigs on the basis of their nutrient concentrations. Data from digestibility studies with a total of 290 compound feeds were provided by different research institutions. Feeds for both piglets and growing-finishing pigs were contained in the data set. The MES concentration ranged from 10.4-16.6 MJ/kg DM, with the majority of data ranging between 15 and 16 MJ/kg DM. The data were processed with a cross validation method and a multiple regression approach by using MES as the independent variable. A corrected Akaike-Information Criterion (AIC_ cor) was used for model evaluation. Various models were developed and validated independently. Calculations were made both for piglet and growing finishing pig feeds, separately and together, for all feeds. It was shown that the MES concentration in compound feeds can be predicted with good accuracy if the concentrations of crude protein, crude fat, crude fibre, and starch are known. Prediction equations were presented. The lack of data for highly fibrous feeds as well as the analysis of different fibre fractions was identified as a challenge for further improvement of the prediction equations. PMID- 26967954 TI - Effect of dietary crude protein level on jejunal brush border enzyme activities in weaned pigs. AB - Forty weaned pigs (7.0 +/- 0.5 kg, mean +/- SD) were used to determine the effects of feeding a low crude protein, amino acid-supplemented diet to piglets on the activities of jejunal brush border enzymes. Pigs were randomly allotted to two diets: a 222 g crude protein (HCP) per kg diet, or a 173 g crude protein per kg diet supplemented with amino acids (LCP). Pigs fed the HCP diet had higher small intestine weight compared with those fed the LCP diet on day 7 after weaning. Diet had no effect on the specific activities of jejunal sucrase, lactase, leucine aminopeptidase, aminopeptidase A, aminopeptidase N and dipeptidyl peptidase IV. The activities of sucrase and lactase decreased (p < 0.05) from day 3 after weaning to day 7, but the activities of leucine aminopeptidase and aminopeptidase N increased. The results showed that feeding a low protein diet supplemented with amino acids according to the ideal protein ratio to piglets had no negative effect on the development of jejunal brush border enzymes. PMID- 26967955 TI - Tryptophan metabolism and related B vitamins in the multiparous sow fed ad libitum after farrowing. AB - Although dietary content of tryptophan has been related to variations of feed intake in lactating sows, the mechanisms remain to be elucidated. Twenty multiparous crossbred Landrace * Large White sows were used to assess variations of tryptophan metabolism around farrowing. Sows were fed 3 kg/d of a standard gestation diet from insemination until farrowing. They were then fed ad libitum a standard lactation diet until weaning. Sows were catheterised on day 70 of gestation and blood samples were drawn on day 37 before parturition, daily during the week before and the week after farrowing, and on days 14 and 21 of lactation. Plasma concentrations of amino acids, kynurenine, niacin, haptoglobin, urea, and vitamin B6 concentration in red blood cells were determined. During the week following parturition, plasma tryptophan and niacin decreased while plasma kynurenine increased (p < 0.05). On the 2nd and 3rd weeks of lactation, plasma tryptophan and kynurenine returned to pre-farrowing concentrations, while niacin increased throughout lactation (p < 0.05). Vitamin B6 increased progressively during the week after farrowing (p < 0.05) and remained constant at a high concentration thereafter. The average feed intake of the sow during lactation was positively correlated with the mean concentrations of niacin (r(2) = 0.25; p < 0.001) and kynurenine (r(2) = 0.31; p < 0.001) in plasma and with vitamin B6 in red blood cells (r(2) = 0.68; p < 0.001). This study suggests that tryptophan catabolism presumably through the kynurenine pathway is high during the 1st week after farrowing, and that dietary supply of niacin and vitamin B6 could be transiently suboptimal in early lactation. PMID- 26967957 TI - Accuracy of the use of energy conversion factors for compound fish diets. AB - Conversion factors of 23.6, 39.5 and 17.2 MJ/kg for protein, lipid and carbohydrate contents, respectively, are frequently used in fish studies to calculate the gross energy (GE) content of compound diets. Values predicted according to the above resulted in linear relationships of observed GE values with similar R (2) and mean prediction error (MPE) values when using either nitrogen-free extract (NFE) (R (2) = 0.5713, RMSE = 1.3134, MPE = 0.0741, n = 129, 32 studies) or starch (R (2) = 0.5665, RMSE = 1.6768, MPE = 0.0839, n = 190, 45 studies) as measurements of carbohydrate content. Apparent digestible carbohydrate content (either NFE or starch) was found to be linearly-related (R (2) values of 0.7531 and 0.7460, respectively) to its dietary content in compound fish diets. Predicted apparent digestible protein (ADP), lipid (DL) and carbohydrate contents, together with energy conversion factors, presented R (2) and MPE values of 0.6205 (RMSE = 1.2606) and 0.2051, respectively, between observed and predicted apparent digestible energy (ADE) content with NFE as measurement of carbohydrate content (n = 97, 17 studies, eight fish species). However, with carbohydrates quantified by starch content, an R (2) value of 0.7017 (RMSE = 1.7556) and MPE of 0.1055 were obtained (n = 37, 10 studies, five fish species). PMID- 26967956 TI - Comparison of different methods for determination of the duodenal and ileal flows of endogenous nitrogen and amino acids in growing goats. AB - The objective of the present study was to compare the isotope dilution, the difference and the amino acid profile (AAP) methods for the quantification of duodenal and ileal flows of endogenous nitrogen (N) and amino acids (AA) in growing goats. Nine growing goats were fed the same diet containing maize stover, ground corn and soybean meal. The duodenal flow of endogenous N determined by the isotope dilution method was significantly (p < 0.01) higher than that determined by the difference and AAP methods, while there was no difference between the difference and the AAP methods. The duodenal flows of individual endogenous AA determined by the isotope dilution method exceed those determined by the difference and the AAP method by 10 to 106%. The endogenous flow at the ileum determined by the isotope dilution method was not significantly different to those determined by the water-soluble method, but tended to be lower for N and all amino acids. It is concluded that the difference method and AAP method underestimate the duodenal flow of endogenous N and AA compared to the isotope dilution method. PMID- 26967958 TI - Recognizing postural orthostatic tachycardia syndrome. AB - This article describes the pathophysiology, clinical presentation, differential diagnosis, diagnosis, and management of postural orthostatic tachycardia syndrome (POTS), a potentially debilitating autonomic disorder that can have many causes and presentations. POTS can be mistaken for panic disorder, inappropriate sinus tachycardia, and chronic fatigue syndrome. Clinician suspicion for the syndrome is key to prompt patient diagnosis and treatment. PMID- 26967959 TI - DENTEX: The emergence of dental therapists in the United States. AB - Dental therapists were introduced into Alaska in 2005 to meet the basic oral health needs of Alaska Native communities. Deployed in 54 countries, dental therapists are well distributed throughout their respective societies. In Alaska, they provide effective, quality, and safe care for children in an economical manner and are generally accepted both by the public and by the dental profession. Dental therapists are increasingly employed in other states. Historical parallels exist between the physician assistant movement and dental therapists in the United States. PMID- 26967960 TI - Clinical and histological results in the treatment of atrophic and hypertrophic scars using a combined method of radiofrequency, ultrasound, and transepidermal drug delivery. AB - Scars are problematic for thousands of patients. Scarring is a natural part of the healing process after an injury. However, the appearance of a scar and its treatment depend on multiple factors and on the experience of the therapist and the options available. Despite a plethora of rapidly evolving treatment options and technical advances, the management of atrophic and hypertrophic scars remains difficult. Innovative technologies provide an attractive alternative to conventional methods in the treatment of scars. The purpose of this trial was to determine the clinical and histological results of a method of treatment that combines radiofrequency, ultrasound, and transepidermal drug delivery. This was a prospective study conducted on 14 patients with scars of different sizes, types, and characteristics. All patients underwent six treatment sessions with the Legato device. Atrophic scars were treated with retinoic acid and hypertrophic scars with triamcinolone. Photographs and biopsies were taken before treatment and at 6 months after the last treatment session. The scars improved significantly (P < 0.0001). The mean attenuation in the severity of scars was 67% (range: 50-75%), where 100% indicates complete disappearance of the scar. Clinical and histological images of scar tissue in six patients in whom attenuation in the range of 55-75% was achieved are shown. Biopsies show regenerative changes in the scar tissue, in both the epidermis and dermis. The method makes it possible to treat extensive, heterogeneous scars on different sites with good results that are similar and predictable. PMID- 26967962 TI - Error in Table. PMID- 26967963 TI - MULTIFOCAL CHOROIDITIS IN DISSEMINATED SPOROTRICHOSIS IN PATIENTS WITH HIV/AIDS. AB - PURPOSE: In this article, the authors describe multifocal choroiditis related to disseminated sporotrichosis in patients with HIV/AIDS. METHODS: We conducted a retrospective observational study of three patients infected with HIV who presented with disseminated sporotrichosis characterized by cutaneous lesions, multifocal choroiditis, and other manifestations, including osteomyelitis and involvement of the bone marrow, larynx, pharynx, and nasal and oral mucosa. RESULTS: Five eyes of three patients with HIV/AIDS showed multifocal choroiditis related to disseminated sporotrichosis. The CD4 counts ranged from 25 to 53 mm. All patients were asymptomatic visually. The ocular disease was bilateral in two patients. The lesion size ranged from 1/3 to 2 disc diameters. None of the patients had vitritis. Of the 12 lesions, 9 were localized in the posterior pole (Zone 1) and 3 were localized in the mild periphery (Zone 2). CONCLUSION: Multifocal choroiditis due to disseminated sporotrichosis can occur in profoundly immunosuppressed patients with HIV/AIDS. PMID- 26967964 TI - SUBRETINAL CANNULATION AS A COMPLICATION OF SUTURE TRABECULOTOMY SURGERY IN A PEDIATRIC PATIENT. AB - PURPOSE: To report a case of inadvertent subretinal cannulation of ab externo suture trabeculotomy surgery associated with serous macular detachment. METHODS: Retrospective case report. Ophthalmic examination and portable spectral domain optical coherence tomography (Envisu C2300; Bioptogen, Morrisville, NC) were performed under general anesthesia. RESULTS: A 5-year-old girl with uveitis secondary to oligoarticular juvenile idiopathic arthritis underwent trabeculotomy surgery of the left eye for steroid-induced glaucoma refractory to medical management. The surgery was complicated by inadvertent subretinal cannulation with the prolene suture. Multiple, arcuate, hypopigmented subretinal tracks, originating from the ora serrata, were observed. Spectral domain optical coherence tomography images through the macula revealed subretinal fluid overlying funduscopically visible tracks, defects in photoreceptor outer segments overlying the tracks, and normal choroidal anatomy. The serous macular detachment resolved spontaneously after 4 months and visual acuity returned to baseline 20/25 in the left eye, consistent with reversible localized damage to the outer retina and retinal pigment epithelium. CONCLUSION: We report a case of inadvertent subretinal cannulation during suture trabeculotomy surgery that resulted in serous macular detachment which resolved spontaneously. The inadvertent complication demonstrated a pathway for administration of therapeutics to the subretinal space. PMID- 26967966 TI - SPONTANEOUS CLOSURE OF A LARGE STAGE III MACULAR HOLE AFTER PANRETINAL PHOTOCOAGULATION IN A PATIENT WITH SEVERE PROLIFERATIVE DIABETIC RETINOPATHY. AB - PURPOSE: To report spontaneous closure of a tractional Stage III macular hole (MH) in a patient with proliferative diabetic retinopathy (PDR) after panretinal photocoagulation (PRP). METHODS: Case report of a 43-year-old man with poorly controlled Type I diabetes and bilateral severe proliferative diabetic retinopathy. RESULTS: On presentation, visual acuity was 20/400 and fundus examination was significant for a Stage III tractional MH in the left eye. Vision in the right eye was light perception from neovascular glaucoma. Fluorescein angiography showed extremely severe macular and peripheral ischemia, disk neovascularization, and macular traction from fibroglial tissue. After 5 panretinal photocoagulation sessions over 3 months, the MH spontaneously closed; however, vision remained 20/400. Fluorescein angiography showed regressed disk neovascularization and mild diffuse macular leakage. After a 13-month loss to follow-up, he presented with 20/300 vision, and, despite extensive macular traction from fibroglial tissue, the MH remained closed. Owing to progressive traction from the fibroglial tissue, macular retinal detachment occurred and vision decreased to hand motions. The patient underwent pars plana vitrectomy, scar tissue removal, silicone oil tamponade, and laser. Postoperatively, visual acuity decreased to no light perception because of neovascular glaucoma complications and lack of proper follow-up. CONCLUSION: Spontaneous closure of a Stage III MH may occur in patients with PDR after PRP; however, it may not result in long-term visual improvement. PMID- 26967961 TI - Ratiometric Array of Conjugated Polymers-Fluorescent Protein Provides a Robust Mammalian Cell Sensor. AB - Supramolecular complexes of a family of positively charged conjugated polymers (CPs) and green fluorescent protein (GFP) create a fluorescence resonance energy transfer (FRET)-based ratiometric biosensor array. Selective multivalent interactions of the CPs with mammalian cell surfaces caused differential change in FRET signals, providing a fingerprint signature for each cell type. The resulting fluorescence signatures allowed the identification of 16 different cell types and discrimination between healthy, cancerous, and metastatic cells, with the same genetic background. While the CP-GFP sensor array completely differentiated between the cell types, only partial classification was achieved for the CPs alone, validating the effectiveness of the ratiometric sensor. The utility of the biosensor was further demonstrated in the detection of blinded unknown samples, where 121 of 128 samples were correctly identified. Notably, this selectivity-based sensor stratified diverse cell types in minutes, using only 2000 cells, without requiring specific biomarkers or cell labeling. PMID- 26967965 TI - TUBULOINTERSTITIAL NEPHRITIS AND UVEITIS SYNDROME WITH A PRIMARY PRESENTATION OF ACUTE POSTERIOR MULTIFOCAL PLACOID PIGMENT EPITHELIOPATHY. AB - PURPOSE: To report a case of tubulointerstitial nephritis and uveitis syndrome with a primary presentation of acute posterior multifocal placoid pigment epitheliopathy after use of lamotrigine. METHODS: Retrospective case report with ultra-widefield fundus imaging, optical coherence tomography, and fluorescein angiography. RESULTS: A 19-year-old woman presented with decreased visual acuity and acute renal failure after starting lamotrigine. Her examination demonstrated 1+ anterior chamber cell and numerous white deep retinal plaque-like lesions predominantly in the macula in both eyes. After extensive ophthalmic and systemic evaluation, the patient was diagnosed with tubulointerstitial nephritis and uveitis syndrome with a primary presentation of acute posterior multifocal placoid pigment epitheliopathy. She had excellent visual recovery with topical and systemic steroids. CONCLUSION: Acute posterior multifocal placoid pigment epitheliopathy is a rare but important clinical presentation of tubulointerstitial nephritis and uveitis syndrome. Oral corticosteroid treatment can be considered for tubulointerstitial nephritis but is generally not necessary for acute posterior multifocal placoid pigment epitheliopathy. PMID- 26967967 TI - tRNA-targeting ribonucleases: molecular mechanisms and insights into their physiological roles. AB - Most bacteria produce antibacterial proteins known as bacteriocins, which aid bacterial defence systems to provide a physiological advantage. To date, many kinds of bacteriocins have been characterized. Colicin has long been known as a plasmidborne bacteriocin that kills other Escherichia coli cells lacking the same plasmid. To defeat other cells, colicins exert specific activities such as ion channel, DNase, and RNase activity. Colicin E5 and colicin D impair protein synthesis in sensitive E. coli cells; however, their physiological targets have not long been identified. This review describes our finding that colicins E5 and D are novel RNases targeting specific E. coli tRNAs and elucidates their enzymatic properties based on biochemical analyses and X-ray crystal structures. Moreover, tRNA cleavage mediates bacteriostasis, which depends on trans translation. Based on these results and others, cell growth regulation depending on tRNA cleavage is also discussed. PMID- 26967969 TI - Blebbishield emergency program: an apoptotic route to cellular transformation. PMID- 26967970 TI - Quantitative assessment of the association between XRCC1 Arg399Gln and Arg194Trp polymorphisms and risk of cutaneous melanoma. AB - Accumulating evidence has suggested that the XRCC1 Arg399Gln and Arg194Trp polymorphisms might be related to cutaneous melanoma susceptibility. However, epidemiologic findings have been inconsistent. We have assessed reported studies by meta-analysis to perform a more precise estimation of the association between the XRCC1 two polymorphisms (Arg399Gln, Arg194Trp) and risk of cutaneous melanoma. A total of seven eligible articles were selected for this meta analysis, including 3454 cases and 3811 controls for the XRCC1 Arg399Gln polymorphism and 1256 cases and 1575 controls for the XRCC1 Arg194Trp polymorphism. Overall, no significant associations were found in all genetic models when the studies were pooled into the meta-analysis for the Arg399Gln and Arg194Trp polymorphisms. When stratified by source of control, significant associations were found for the Arg399Gln polymorphism in the population-based subgroup under AA versus GG [odds ratio (OR)=1.43, 95% confidence interval (CI)=1.08-1.88]; the dominant model AA/GA versus GG (OR=1.25, 95% CI=1.04-1.51); and the recessive model AA versus GA/GG (OR=1.31, 95% CI=1.01-1.68). No significant associations were found for the Arg194Trp polymorphism in the subgroup analysis. This meta-analysis suggested that the XRCC1 Arg399Gln polymorphism was a risk factor for cutaneous melanoma in population-based subgroup. PMID- 26967971 TI - Biodegradability and Molecular Composition of Dissolved Organic Nitrogen in Urban Stormwater Runoff and Outflow Water from a Stormwater Retention Pond. AB - Dissolved organic nitrogen (DON) can be a significant part of the reactive N in aquatic ecosystems and can accelerate eutrophication and harmful algal blooms. A bioassay method was coupled with Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) to determine the biodegradability and molecular composition of DON in the urban stormwater runoff and outflow water from an urban stormwater retention pond. The biodegradability of DON increased from 10% in the stormwater runoff to 40% in the pond outflow water and DON was less aromatic and had lower overall molecular weight in the pond outflow water than in the stormwater runoff. More than 1227 N-bearing organic formulas were identified with FT-ICR-MS in the stormwater runoff and pond outflow water, which were only 13% different in runoff and outflow water. These molecular formulas represented a wide range of biomolecules such as lipids, proteins, amino sugars, lignins, and tannins in DON from runoff and pond outflow water. This work implies that the urban infrastructure (i.e., stormwater retention ponds) has the potential to influence biogeochemical processes in downstream water bodies because retention ponds are often a junction between the natural and the built environment. PMID- 26967968 TI - Emerging roles for lipids in non-apoptotic cell death. AB - Non-apoptotic regulated cell death (RCD) is essential to maintain organismal homeostasis and may be aberrantly activated during certain pathological states. Lipids are emerging as key components of several non-apoptotic RCD pathways. For example, a direct interaction between membrane phospholipids and the pore-forming protein mixed lineage kinase domain-like (MLKL) is needed for the execution of necroptosis, while the oxidative destruction of membrane polyunsaturated fatty acids (PUFAs), following the inactivation of glutathione peroxidase 4 (GPX4), is a requisite gateway to ferroptosis. Here, we review the roles of lipids in the initiation and execution of these and other forms of non-apoptotic cell death. We also consider new technologies that are allowing for the roles of lipids and lipid metabolism in RCD to be probed in increasingly sophisticated ways. In certain cases, this new knowledge may enable the development of therapies that target lipids and lipid metabolic processes to enhance or suppress specific non apoptotic RCD pathways. PMID- 26967972 TI - Pitavastatin and carbohydrate metabolism: what is the evidence? AB - Statins are the cornerstone of hypolipidemic treatment but recently have been associated with increased risk of developing diabetes mellitus. However, the risk of incident diabetes is not the same among statins. Pitavastatin lowers low density lipoprotein cholesterol and increases high-density lipoprotein cholesterol but also seems to be neutral in terms of risk of incident diabetes. Clinical and experimental evidence shows that pitavastatin increases adiponectin levels and reduces oxidative stress, effects that seem to be implicated in the beneficial effect of the drug on carbohydrate metabolism variables. Pitavastatin is a useful hypolipidemic drug, which is promising for patients with increased diabetes risk or established diabetes. PMID- 26967973 TI - Myrosin cells are differentiated directly from ground meristem cells and are developmentally independent of the vasculature in Arabidopsis leaves. AB - Myrosin cells accumulate myrosinases in their vacuoles to catalyze the production of toxic compounds when tissues are damaged by herbivores. Myrosin cells are positioned adjacent to the abaxial side of the vasculature but their origin is unclear. To determine whether the myrosin cells are differentiated from vascular precursor cells, we generated a transgenic Arabidopsis line that expressed a myrosin cell reporter together with one of 3 vascular precursor cell reporters. The myrosin-positive cells were discontinuously distributed while the vascular precursor-positive cells were continuously distributed. The fluorescent signals of the myosin and vascular reporters did not overlap. Furthermore, the shape of myrosin-positive cells was different from the shape of vascular precursor positive cells. These results indicate that myosin cells develop independently of the vasculature. PMID- 26967974 TI - Stable and Efficient Genetic Modification of Cells in the Adult Mouse V-SVZ for the Analysis of Neural Stem Cell Autonomous and Non-autonomous Effects. AB - Relatively quiescent somatic stem cells support life-long cell renewal in most adult tissues. Neural stem cells in the adult mammalian brain are restricted to two specific neurogenic niches: the subgranular zone of the dentate gyrus in the hippocampus and the ventricular-subventricular zone (V-SVZ; also called subependymal zone or SEZ) in the walls of the lateral ventricles. The development of in vivo gene transfer strategies for adult stem cell populations (i.e. those of the mammalian brain) resulting in long-term expression of desired transgenes in the stem cells and their derived progeny is a crucial tool in current biomedical and biotechnological research. Here, a direct in vivo method is presented for the stable genetic modification of adult mouse V-SVZ cells that takes advantage of the cell cycle-independent infection by LVs and the highly specialized cytoarchitecture of the V-SVZ niche. Specifically, the current protocol involves the injection of empty LVs (control) or LVs encoding specific transgene expression cassettes into either the V-SVZ itself, for the in vivo targeting of all types of cells in the niche, or into the lateral ventricle lumen, for the targeting of ependymal cells only. Expression cassettes are then integrated into the genome of the transduced cells and fluorescent proteins, also encoded by the LVs, allow the detection of the transduced cells for the analysis of cell autonomous and non-autonomous, niche-dependent effects in the labeled cells and their progeny. PMID- 26967977 TI - Office hysteroscopy: an update. PMID- 26967975 TI - A cationic liposome-DNA complexes adjuvant (JVRS-100) enhances the immunogenicity and cross-protective efficacy of pre-pandemic influenza A (H5N1) vaccine in ferrets. AB - Influenza A (H5N1) viruses continue to pose a public health threat. As inactivated H5N1 vaccines are poorly immunogenic, adjuvants are needed to improve the immunogenicity of H5N1 vaccine in humans. Here, we investigated the immunogenicity and cross-protective efficacy in ferrets of a clade 2.2-derived vaccine with addition of JVRS-100, an adjuvant consisting of cationic liposome DNA complexes (CLDC). After the first vaccination, significantly higher levels of hemagglutination-inhibition (HAI) and neutralizing antibody titers were detected in ferrets immunized with adjuvanted vaccine compared to unadjuvanted vaccine. Following a second dose of adjuvanted vaccine, HAI antibody titers of >= 40 were detected against viruses from multiple H5N1 clades. HAI antibodies against newly isolated H5N2 and H5N8 viruses were also augmented by JVRS-100. Ferrets were challenged with a heterologous H5N1 virus. All ferrets that received two doses of adjuvanted vaccine exhibited mild illness, significantly reduced nasal wash virus titers and protection from lethal challenge. In contrast, ferrets that received unadjuvanted vaccine showed greater weight loss, high viral titers and 3 of 6 animals succumbed to the lethal challenge. Our results indicate that the addition of JVRS-100 to H5N1 vaccine enhanced immunogenicity and cross-protection against lethal H5N1 virus disease in ferrets. JVRS-100 warrants further investigation as a potential adjuvant for influenza vaccines. PMID- 26967976 TI - HIV-1 nucleocapsid protein localizes efficiently to the nucleus and nucleolus. AB - The HIV-1 nucleocapsid (NC) is an essential viral protein containing two highly conserved retroviral-type zinc finger (ZF) motifs, which functions in multiple stages of the HIV-1 life cycle. Although a number of functions for NC either in its mature form or as a domain of Gag have been revealed, little is known about the intracellular localization of NC and, moreover, its role in Gag protein trafficking. Here, we have investigated various forms of HIV-1 NC protein for its cellular localization and found that the NC has a strong nuclear and nucleolar localization activity. The linker region, composed of a stretch of basic amino acids between the two ZF motifs, was necessary and sufficient for the activity. PMID- 26967979 TI - CTNNB1 mutation associated with familial exudative vitreoretinopathy (FEVR) phenotype. PMID- 26967978 TI - Synthesis of Gold Nanoparticle Integrated Photo-responsive Liposomes and Measurement of Their Microbubble Cavitation upon Pulse Laser Excitation. AB - Photo-responsive nanoparticles (NPs) have received considerable attention because of their potential in providing spatial, temporal, and dosage control over the drug release. However, most of the relevant technologies are still in the development process and are unprocurable by clinics. Here, we describe a facile fabrication of these photo-responsive NPs with commercially available gold NPs and thermo-responsive liposomes. Calcein is used as a model drug to evaluate the encapsulation efficiency and the release kinetic profile upon heat/light stimulation. Finally, we show that this photo-triggered release is due to the membrane disruption caused by microbubble cavitation, which can be measured with hydrophone. PMID- 26967981 TI - The Development and Validation of the Rational and Intuitive Decision Styles Scale. AB - Decision styles reflect the typical manner by which individuals make decisions. The purpose of this research was to develop and validate a decision style scale that addresses conceptual and psychometric problems with current measures. The resulting 10-item scale captures a broad range of the rational and intuitive styles construct domain. Results from 5 independent samples provide initial support for the dimensionality and reliability of the new scale, as demonstrated by a clear factor structure and high internal consistency. In addition, our results show evidence of convergent and discriminant validity through expected patterns of correlations across decision-making individual differences and the International Personality Item Pool (IPIP) Big Five traits. Research domains that would benefit from incorporating the concept of decision styles are discussed. PMID- 26967980 TI - Sclerotiamide: The First Non-Peptide-Based Natural Product Activator of Bacterial Caseinolytic Protease P. AB - Caseinolytic protease P (ClpP) maintains essential roles in bacterial homeostasis. As such, both the inhibition and activation of this enzyme result in bactericidal activity, making ClpP a promising target for antibacterial drug development. Herein, we report the results of a fluorescence-based screen of ~450 structurally diverse fungal and bacterial secondary metabolites. Sclerotiamide (1), a paraherquamide-related indolinone, was identified as the first non-peptide based natural product activator of ClpP. Structure-activity relationships arising from the initial screen, preliminary biochemical evaluation of 1, and rationale for the exploitation of this chemotype to develop novel ClpP activators are presented. PMID- 26967982 TI - The relationship between blood pressure dipping status and carotid plaque in senior essential hypertensive individuals of different sexes: a cross-sectional study. AB - OBJECTIVE: To investigate the associations of the blood pressure (BP) dipping status with carotid plaque in senior essential hypertensive patients of different sexes. PARTICIPANTS AND METHODS: A total of 512 patients (275 men and 237 women) with essential hypertension who underwent ambulatory BP monitoring and carotid ultrasound assessment were recruited in our study. Binary logistic regression was used to analyze the associations of multiple risk factors with carotid plaque. RESULTS: Abnormal dipping [odds ratio (OR)=2.138, 95% confidence interval (CI) 1.170-3.908, P<0.05] and circadian decline rate of systolic BP (SBP) (OR=0.925, 95% CI 0.884-0.968, P<0.01) were found to be associated with carotid plaque in men. The level of night-time SBP (OR=1.022, 95% CI 1.003-1.042, P<0.05) and carotid plaque were associated with each other in women. In addition, as for all the patients in our study, abnormal dipping (OR=1.743, 95% CI 1.114-2.725, P<0.05), circadian decline rate of SBP (OR=0.950, 95% CI 0.922-0.980, P<0.01), the level of night-time SBP (OR=1.030, 95% CI 1.014-1.047, P<0.001), and the level of daytime diastolic BP (OR=0.971, 95% CI 0.946-0.998, P<0.05) were associated with carotid plaque, respectively. CONCLUSION: Our results suggested that the abnormal dipping status of BP and circadian decline rate of SBP might serve as independent risk factors for carotid plaque, respectively, in men, as does night-time SBP in women. Therefore, personalized BP management may be necessary for hypertensive patients. PMID- 26967983 TI - Elucidation of Genetic Interactions in the Yeast GATA-Factor Network Using Bayesian Model Selection. AB - Understanding the structure and function of complex gene regulatory networks using classical genetic assays is an error-prone procedure that frequently generates ambiguous outcomes. Even some of the best-characterized gene networks contain interactions whose validity is not conclusively proven. Founded on dynamic experimental data, mechanistic mathematical models are able to offer detailed insights that would otherwise require prohibitively large numbers of genetic experiments. Here we attempt mechanistic modeling of the transcriptional network formed by the four GATA-factor proteins, a well-studied system of central importance for nitrogen-source regulation of transcription in the yeast Saccharomyces cerevisiae. To resolve ambiguities in the network organization, we encoded a set of five interactions hypothesized in the literature into a set of 32 mathematical models, and employed Bayesian model selection to identify the most plausible set of interactions based on dynamic gene expression data. The top ranking model was validated on newly generated GFP reporter dynamic data and was subsequently used to gain a better understanding of how yeast cells organize their transcriptional response to dynamic changes of nitrogen sources. Our work constitutes a necessary and important step towards obtaining a holistic view of the yeast nitrogen regulation mechanisms; on the computational side, it provides a demonstration of how powerful Monte Carlo techniques can be creatively combined and used to address the great challenges of large-scale dynamical system inference. PMID- 26967985 TI - Utility of a custom screw insertion guide and a full-scale, color-coded 3D plaster model for guiding safe surgical exposure and screw insertion during spine revision surgery. AB - Several articles have described the use of screw insertion guides during primary spine surgery; however, the use of such a guide during revision surgeries has not been described. The purpose of this study is to describe the utility of a custom screw insertion (CSI) guide assembled using a novel method and a full-scale, color-coded 3D plaster (FCTP) model for safe and accurate revision surgery. The authors applied the CSI guide and the FCTP model in 3 cases. In the first case, a patient with multiple failed cervical spine surgeries underwent occipitocervicothoracic fusion. After a successful result for this patient, the authors applied the CSI guide in 2 other patients who underwent revision lumbar fusion surgeries to confirm the accuracy and the efficacy of the CSI guides in such cases. The models and guides were fabricated using rapid prototyping technology. The effectiveness of these methods was examined. The FCTP model was designed using CT data. During model assembly, implants inserted during previous surgery were removed virtually, and for the cervical spine, vertebral arteries were colored red for planning. The CSI guide was designed with 5 or 6 arms to fit the bone surface precisely after removing artifacts. Surgery was performed by referring to the FCTP model. Because the actual structure of the bone surface was almost identical to that of the FCTP model, surgical exposure around the complex bone shape proceeded smoothly. The CSI guides were positioned accurately to aid the successful insertion of a pedicle screw into the C-2 vertebra in the case of cervical revision surgery, and 4 pedicle screws for lumbar vertebrae in the 2 other patients. Postoperative CT scans showed that all screw positions closely matched those predicted during the preoperative planning. In conclusion, the FCTP models and the novel CSI guides were effective for safe and accurate revision surgery of the spine. PMID- 26967984 TI - Distributional analysis of semantic interference in picture naming. AB - In picture-word interference experiments, participants name pictures (e.g., of a cat) while trying to ignore distractor words. Mean response time (RT) is typically longer with semantically related distractor words (e.g., dog) than with unrelated words (e.g., shoe), called semantic interference. Previous research has examined the RT distributional characteristics of distractor effects by performing ex-Gaussian analyses, which reveal whether effects are present in the normal part of the distribution (the MU parameter), its long right tail (the tau parameter), or both. One previous study linked the semantic interference effect selectively to the distribution tail. In the present study, we replicated the semantic interference effect in the mean picture naming RTs. Distributional analysis of the RTs and those of a previous study revealed that semantic interference was present in both MU and tau. These results provide evidence that the effect is not selectively linked to the tau parameter, and they warn against any simple one-to-one mapping between semantic interference and distributional parameters. PMID- 26967986 TI - A comparison of commercially available demineralized bone matrices with and without human mesenchymal stem cells in a rodent spinal fusion model. AB - OBJECTIVE The efficacy of some demineralized bone matrix (DBM) substances has been demonstrated in the spinal fusion of rats; however, no previous comparative study has reported the efficacy of DBM with human mesenchymal stem cells (hMSCs). There is an added cost to the products with stem cells, which should be justified by improved osteogenic potential. The purpose of this study is to prospectively compare the fusion rates of 3 different commercially available DBM substances, both with and without hMSCs. METHODS Posterolateral fusion was performed in 32 mature athymic nude rats. Three groups of 8 rats were implanted with 1 of 3 DBMs: Trinity Evolution (DBM with stem cells), Grafton (DBM without stem cells), or DBX (DBM without stem cells). A fourth group with no implanted material was used as a control group. Radiographs were obtained at 2, 4, and 8 weeks. The rats were euthanized at 8 weeks. Overall fusion was determined by manual palpation and micro-CT. RESULTS The fusion rates at 8 weeks on the radiographs for Trinity Evolution, Grafton, and DBX were 8 of 8 rats, 3 of 8 rats, and 5 of 8 rats, respectively. A significant difference was found between Trinity Evolution and Grafton (p = 0.01). The overall fusion rates as determined by micro-CT and manual palpation for Trinity Evolution, Grafton, and DBX were 4 of 8 rats, 3 of 8 rats, and 3 of 8 rats, respectively. The Trinity Evolution substance had the highest overall fusion rate, however no significant difference was found between groups. CONCLUSIONS The efficacies of these DBM substances are demonstrated; however, the advantage of DBM with hMSCs could not be found in terms of posterolateral fusion. When evaluating spinal fusion using DBM substances, CT analysis is necessary in order to not overestimate fusion. PMID- 26967987 TI - Transdiscal mid- and upper thoracic vertebroplasty: first description of 2 exemplary cases. AB - Kyphoplasty and vertebroplasty are established treatment methods to reinforce fractured vertebral bodies. In cases of previous pedicle screw instrumentation, vertebral body cannulation may be challenging. The authors describe, for the first time, an approach through the adjacent inferior vertebra and disc space in the thoracic spine for cement augmentation. A 78-year-old woman underwent posterior fusion with pedicle screws after vertebrectomy and reconstruction with cement and Steinmann pins for a pathological T-7 fracture. Two months later she developed a compression fracture of the vertebral body at the lower part of the construct, and a vertebroplasty was performed. Because a standard transpedicular route was not available, an inferior transdiscal trajectory was used for the cement injection. A 73-year-old man with a history of rheumatoid arthritis underwent cervicothoracic fusion posteriorly for subluxation. He developed pain in the upper thoracic area, and the authors performed a transdiscal vertebroplasty at T-2. The standard transpedicular route was not possible. The vertebral body was satisfactorily filled up with cement. Clinically both patients benefited significantly in terms of back pain and showed an uneventful follow-up of 3 months. Transdiscal vertebroplasty can achieve good results in the mid- and upper thoracic spine when a standard transpedicular trajectory is not possible, and can therefore be a good alternative in select cases. PMID- 26967988 TI - Factors associated with improvement in sagittal spinal alignment after microendoscopic laminotomy in patients with lumbar spinal canal stenosis. AB - OBJECTIVE Little is known about the relationship between sagittal spinal alignment in patients with lumbar spinal canal stenosis (LSS) and objective findings such as spinopelvic parameters, lumbar back muscle degeneration, and clinical data. The purpose of this study was to identify the preoperative clinical and radiological factors that predict improvement in sagittal spinal alignment after decompressive surgery in patients with LSS. METHODS The records of 61 patients with LSS who underwent microendoscopic laminotomy and had pre- and postoperative clinical data collected were retrospectively reviewed. Spinopelvic parameters, including sagittal vertical axis (SVA), lumbar lordosis (LL), sacral slope, pelvic tilt, and pelvic incidence (PI), were evaluated. On T2-weighted MRI, the cross-sectional area and the percentage of fat infiltration of the paravertebral muscles (PVMs) before surgery were calculated. For patients with preoperative SVA > 40 mm (n = 30), the correlation between SVA improvement and preoperative clinical and radiographic parameters was calculated. RESULTS SVA improvement correlated with preoperative LL (r = -0.39) and PI -LL (r = 0.54). Multiple regression analysis showed that preoperative PI -LL (beta = 0.62; p < 0.01) and symptom duration (beta = -0.40; p < 0.05) were independently associated with SVA improvement. The percentage of fat infiltration of the PVM at L4-5 was significantly greater in patients with preoperative SVA >= 40 mm than in those patients with SVA < 40 mm. CONCLUSIONS Preoperative PI -LL and symptom duration were independently associated with SVA improvement in LSS patients with forward bending posture. PVM degeneration at the lower lumbar level was significantly greater among patients with preoperative SVA >= 40 mm than in patients with SVA < 40 mm. PMID- 26967989 TI - Letter to the Editor: Atlantoaxial instability. PMID- 26967990 TI - History of the current understanding and management of tethered spinal cord. AB - An understanding of the underlying pathophysiology of tethered cord syndrome (TCS) and modern management strategies have only developed within the past few decades. Current understanding of this entity first began with the understanding and management of spina bifida; this later led to the gradual recognition of spina bifida occulta and the symptoms associated with tethering of the filum terminale. In the 17th century, Dutch anatomists provided the first descriptions and initiated surgical management efforts for spina bifida. In the 19th century, the term "spina bifida occulta" was coined and various presentations of spinal dysraphism were appreciated. The association of urinary, cutaneous, and skeletal abnormalities with spinal dysraphism was recognized in the 20th century. Early in the 20th century, some physicians began to suspect that traction on the conus medullaris caused myelodysplasia-related symptoms and that prophylactic surgical management could prevent the occurrence of clinical manifestations. It was not, however, until later in the 20th century that the term "tethered spinal cord" and the modern management of TCS were introduced. This gradual advancement in understanding at a time before the development of modern imaging modalities illustrates how, over the centuries, anatomists, pathologists, neurologists, and surgeons used clinical examination, a high level of suspicion, and interest in the subtle and overt clinical appearances of spinal dysraphism and TCS to advance understanding of pathophysiology, clinical appearance, and treatment of this entity. With the availability of modern imaging, spinal dysraphism can now be diagnosed and treated as early as the intrauterine stage. PMID- 26967991 TI - Congenital scoliosis treated with posterior vertebral column resection in patients younger than 18 years: longer than 10-year follow-up. AB - OBJECTIVE There have been no reports on the long-term radiographic outcomes of posterior vertebral column resection (PVCR) in patients with congenital scoliosis. The purpose of this study was to evaluate the surgical outcomes and complications after PVCR and its long-term effects on correcting this deformity in children with congenital scoliosis. METHODS The authors retrospectively analyzed the medical records of 45 patients with congenital scoliosis who were younger than 18 years at the time of surgery and who underwent PVCR and fusion with pedicle screw fixation (PSF). The mean age of the patients at the time of surgery was 11.3 years (range 2.4-18.0 years), and the mean length of follow-up was 12.8 years (range 10.1-18.2 years). RESULTS The mean Cobb angle of the main curve was 46.5 degrees before PVCR, 13.7 degrees immediately after PVCR, and 17.6 degrees at the last follow-up. For the compensatory cranial curve, PVCR corrected the preoperative Cobb angle of 21.2 degrees to 9.1 degrees postoperatively and maintained it at 10.9 degrees at the last follow-up. For the compensatory caudal curve, the preoperative Cobb angle of 23.8 degrees improved to 7.7 degrees postoperatively and was 9.8 degrees at the last follow-up. The authors noted 22 complications, and the overall incidence of complications was 48.9%. CONCLUSIONS Posterior vertebral column resection is an effective procedure for managing congenital scoliosis in patients younger than 18 years. Use of PVCR and fusion with PSF for congenital scoliosis achieved rigid fixation and satisfactory deformity correction that was maintained over the long term. However, the authors note that PVCR is a technically demanding procedure and entails risks for major complications and excessive blood loss. PMID- 26967992 TI - Risk of adjacent-segment disease requiring surgery after short lumbar fusion: results of the French Spine Surgery Society Series. AB - OBJECTIVE Adjacent-segment disease (ASD) is an increasingly problematic complication following lumbar fusion surgery. The purpose of the current study was to determine the risk of ASD requiring surgical treatment after short lumbar or lumbosacral fusion. Primary spinal disease and surgical factors associated with an increased risk of revision were also investigated. METHODS This was a retrospective cohort study using the French Spine Surgery Society clinical data that included 3338 patients, with an average follow-up duration of 7 years (range 4-10 years). Clinical ASD requiring surgery was the principal judgment criterion; the length of follow-up time and initial spinal disease were also recorded. Kaplan-Meier survival analysis was performed. The correlation between primary spinal disease and surgery with an increased risk of revision was investigated. RESULTS During the follow-up period, 186 patients required revision surgery for ASD (5.6%). The predicted risk of ASD requiring revision surgery was 1.7% (95% CI 1.3%-2.2%) at 2 years, 3.8% (95% CI 4.9%-6.7%) at 4 years, 5.7% (95% CI 4.9% 6.7%) at 6 years, and 9% (95% CI 8.7%-10.6%) at 8 years. Initial spinal disease affected the risk of ASD requiring surgery (p = 0.0003). The highest risk was observed for degenerative spondylolisthesis. CONCLUSIONS ASD requiring revision surgery was predicted in 5.6% of patients 7 years after index short lumbar spinal fusion in the French Spine Surgery Society retrospective series. An increased risk of ASD requiring revision surgery associated with initial spinal disease showed the significance of the influence of natural degenerative history on adjacent-segment pathology. PMID- 26967993 TI - Robot Guided 'Pen Skill' Training in Children with Motor Difficulties. AB - Motor deficits are linked to a range of negative physical, social and academic consequences. Haptic robotic interventions, based on the principles of sensorimotor learning, have been shown previously to help children with motor problems learn new movements. We therefore examined whether the training benefits of a robotic system would generalise to a standardised test of 'pen-skills', assessed using objective kinematic measures [via the Clinical Kinematic Assessment Tool, CKAT]. A counterbalanced, cross-over design was used in a group of 51 children (37 male, aged 5-11 years) with manual control difficulties. Improved performance on a novel task using the robotic device could be attributed to the intervention but there was no evidence of generalisation to any of the CKAT tasks. The robotic system appears to have the potential to support motor learning, with the technology affording numerous advantages. However, the training regime may need to target particular manual skills (e.g. letter formation) in order to obtain clinically significant improvements in specific skills such as handwriting. PMID- 26967996 TI - Extracorporeal heart perfusion before heart transplantation: the heart in a box. AB - PURPOSE OF REVIEW: Cold static storage is a time-tested and simple method of preserving hearts retrieved from optimal donors after brain death (DBD). The increasing gap between supply and demand for donor organs together with changing donor and recipient characteristics have led to renewed interest in the use of machine perfusion to increase both the quality and quantity of donor hearts for transplantation. RECENT FINDINGS: Two major approaches to machine perfusion of donor hearts have been investigated - hypothermic (HMP) and normothermic machine perfusion (NMP). Recent preclinical studies with HMP confirm that it provides superior donor heart preservation to cold static storage. HMP systems have been developed for human heart preservation but have yet to be tested clinically. In contrast, NMP has undergone extensive clinical evaluation in human heart transplantation, including optimal and higher risk DBD donors. In addition, NMP has enabled distant procurement and successful transplantation of hearts retrieved from human donation after circulatory death donors. SUMMARY: Initial clinical experience suggests that NMP of donor hearts retrieved from higher risk DBD and donation after circulatory death donors enables well tolerated ex-vivo reanimation, preservation, and assessment of these organs. In particular, this technology allows successful utilization of extended-criteria donor hearts that would otherwise be discarded. PMID- 26967995 TI - Microvascular injury after lung transplantation. AB - PURPOSE OF REVIEW: Airway microvessel injury following transplantation has been implicated in the development of chronic rejection. This review focuses on the most recent developments in the field describing preclinical and clinical findings that further implicate the loss of microvascular integrity as an important pathological event in the evolution of irreversible fibrotic remodeling. RECENT FINDINGS: When lungs are transplanted, the airways appear vulnerable from the perspective of perfusion. Two vascular systems are lost, the bronchial artery and the lymphatic circulations, and the remaining vasculature in the airways expresses donor antigens susceptible to alloimmune-mediated injury via innate and adaptive immune mechanisms. Preclinical studies indicate the importance of hypoxia-inducible factor-1alpha in mediating microvascular repair and that hypoxia-inducible factor-1alpha can be upregulated to bolster endogenous repair. SUMMARY: Airway microvascular injury is a feature of lung transplantation that limits short-term and long-term organ health. Although some problems are attributable to a missing bronchial artery circulation, another significant issue involves alloimmune-mediated injury to transplant airway microvessels. For a variety of reasons, bronchial artery revascularization surgery at the time of transplantation has not been widely adopted, and the current best hope for this era may be new medical approaches that offer protection against immune-mediated vascular injury or that promote microvascular repair. PMID- 26967994 TI - Short Hairpin RNA Silencing of PHD-2 Improves Neovascularization and Functional Outcomes in Diabetic Wounds and Ischemic Limbs. AB - The transcription factor hypoxia-inducible factor 1-alpha (HIF-1alpha) is responsible for the downstream expression of over 60 genes that regulate cell survival and metabolism in hypoxic conditions as well as those that enhance angiogenesis to alleviate hypoxia. However, under normoxic conditions, HIF-1alpha is hydroxylated by prolyl hydroxylase 2, and subsequently degraded, with a biological half-life of less than five minutes. Here we investigated the therapeutic potential of inhibiting HIF-1alpha degradation through short hairpin RNA silencing of PHD-2 in the setting of diabetic wounds and limb ischemia. Treatment of diabetic mouse fibroblasts with shPHD-2 in vitro resulted in decreased levels of PHD-2 transcript demonstrated by qRT-PCR, higher levels of HIF-1alpha as measured by western blot, and higher expression of the downstream angiogenic genes SDF-1 and VEGFalpha, as measured by qRT-PCR. In vivo, shPHD-2 accelerated healing of full thickness excisional wounds in diabetic mice compared to shScr control, (14.33 +/- 0.45 days vs. 19 +/- 0.33 days) and was associated with an increased vascular density. Delivery of shPHD-2 also resulted in improved perfusion of ischemic hind limbs compared to shScr, prevention of distal digit tip necrosis, and increased survival of muscle tissue. Knockdown of PHD-2 through shRNA treatment has the potential to stimulate angiogenesis through overexpression of HIF-1alpha and upregulation of pro-angiogenic genes downstream of HIF-1alpha, and may represent a viable, non-viral approach to gene therapy for ischemia related applications. PMID- 26967997 TI - Humoral responses after lung transplantation. AB - PURPOSE OF REVIEW: In recent years, there has been increasing awareness and appreciation for the role of humoral immune responses in lung allograft rejection. This review summarizes our current understanding of this role and the associated challenges. RECENT FINDINGS: Recent studies have described a syndrome of acute antibody-mediated rejection with a generally poor response to therapy and a high mortality. In addition, there is significant evidence implicating donor-specific human leukocyte antigen antibodies in the development of chronic lung allograft dysfunction. However, the optimal intervention to mitigate the risk of chronic lung allograft dysfunction after donor-specific human leukocyte antigen antibodies development remains unclear. SUMMARY: There is mounting evidence that humoral immune responses play an important role in lung allograft rejection. However, therapeutic implications of this increased awareness have been limited. Indeed, there is insufficient evidence to adequately guide therapy, and the optimal treatment is unknown. PMID- 26967998 TI - Lung xenotransplantation: a review. AB - PURPOSE OF REVIEW: This article reviews recent progress in the field of lung xenotransplantation, including mechanisms of xenograft injury, and the influence of mechanism-directed genetic modifications and other interventions that may soon enable therapeutic use of pig lungs in humans. RECENT FINDINGS: An extensive series of lung xenotransplantation experiments demonstrates that multiple genetic modifications targeting known xenogeneic lung injury mechanisms are associated with incremental improvements in lung survival or function. Addition of human complement (hCD46, hCD55), coagulation (hEPCR, hTBM, hTFPI, hCD39), or anti inflammatory pathway regulatory genes (HO-1, HLA-E), and GalT and Neu5Gc gene knockout has each demonstrated protective effects on lung survival or function. In addition, drug treatments targeting key inflammatory and clotting pathways have been shown to attenuate residual mechanisms of lung injury. Work with other pig organs in primate models show that regimens based on costimulatory pathway blocking antibodies prolong xenograft function for months to years, suggesting that once initial lung inflammation mechanisms are fully controlled, clinically useful application of pig lung xenografts may soon be feasible. SUMMARY: Genetic modification of pigs coupled with drugs targeting complement activation, coagulation, and inflammation have significantly increased duration of pig lung function in ex-vivo human blood perfusion models, and life-supporting lung xenograft survival in vivo. PMID- 26967999 TI - From GenBank to GBIF: Phylogeny-Based Predictive Niche Modeling Tests Accuracy of Taxonomic Identifications in Large Occurrence Data Repositories. AB - Accuracy of taxonomic identifications is crucial to data quality in online repositories of species occurrence data, such as the Global Biodiversity Information Facility (GBIF), which have accumulated several hundred million records over the past 15 years. These data serve as basis for large scale analyses of macroecological and biogeographic patterns and to document environmental changes over time. However, taxonomic identifications are often unreliable, especially for non-vascular plants and fungi including lichens, which may lack critical revisions of voucher specimens. Due to the scale of the problem, restudy of millions of collections is unrealistic and other strategies are needed. Here we propose to use verified, georeferenced occurrence data of a given species to apply predictive niche modeling that can then be used to evaluate unverified occurrences of that species. Selecting the charismatic lichen fungus, Usnea longissima, as a case study, we used georeferenced occurrence records based on sequenced specimens to model its predicted niche. Our results suggest that the target species is largely restricted to a narrow range of boreal and temperate forest in the Northern Hemisphere and that occurrence records in GBIF from tropical regions and the Southern Hemisphere do not represent this taxon, a prediction tested by comparison with taxonomic revisions of Usnea for these regions. As a novel approach, we employed Principal Component Analysis on the environmental grid data used for predictive modeling to visualize potential ecogeographical barriers for the target species; we found that tropical regions conform a strong barrier, explaining why potential niches in the Southern Hemisphere were not colonized by Usnea longissima and instead by morphologically similar species. This approach is an example of how data from two of the most important biodiversity repositories, GenBank and GBIF, can be effectively combined to remotely address the problem of inaccuracy of taxonomic identifications in occurrence data repositories and to provide a filtering mechanism which can considerably reduce the number of voucher specimens that need critical revision, in this case from 4,672 to about 100. PMID- 26968000 TI - How Honey Bee Colonies Survive in the Wild: Testing the Importance of Small Nests and Frequent Swarming. AB - The ectoparasitic mite, Varroa destructor, and the viruses that it transmits, kill the colonies of European honey bees (Apis mellifera) kept by beekeepers unless the bees are treated with miticides. Nevertheless, there exist populations of wild colonies of European honey bees that are persisting without being treated with miticides. We hypothesized that the persistence of these wild colonies is due in part to their habits of nesting in small cavities and swarming frequently. We tested this hypothesis by establishing two groups of colonies living either in small hives (42 L) without swarm-control treatments or in large hives (up to 168 L) with swarm-control treatments. We followed the colonies for two years and compared the two groups with respect to swarming frequency, Varroa infesttion rate, disease incidence, and colony survival. Colonies in small hives swarmed more often, had lower Varroa infestation rates, had less disease, and had higher survival compared to colonies in large hives. These results indicate that the smaller nest cavities and more frequent swarming of wild colonies contribute to their persistence without mite treatments. PMID- 26968001 TI - Sensorless adaptive optics implementation in widefield optical sectioning microscopy inside in vivo Drosophila brain. AB - We present an implementation of a sensorless adaptive optics loop in a widefield fluorescence microscope. This setup is designed to compensate for aberrations induced by the sample on both excitation and emission pathways. It allows fast optical sectioning inside a living Drosophila brain. We present a detailed characterization of the system performances. We prove that the gain brought to optical sectioning by realizing structured illumination microscopy with adaptive optics down to 50 MUm deep inside living Drosophila brain. PMID- 26968003 TI - A Functional Bacterium-to-Plant DNA Transfer Machinery of Rhizobium etli. AB - Different strains and species of the soil phytopathogen Agrobacterium possess the ability to transfer and integrate a segment of DNA (T-DNA) into the genome of their eukaryotic hosts, which is mainly mediated by a set of virulence (vir) genes located on the bacterial Ti-plasmid that also contains the T-DNA. To date, Agrobacterium is considered to be unique in its capacity to mediate genetic transformation of eukaryotes. However, close homologs of the vir genes are encoded by the p42a plasmid of Rhizobium etli; this microorganism is related to Agrobacterium, but known only as a symbiotic bacterium that forms nitrogen-fixing nodules in several species of beans. Here, we show that R. etli can mediate functional DNA transfer and stable genetic transformation of plant cells, when provided with a plasmid containing a T-DNA segment. Thus, R. etli represents another bacterial species, besides Agrobacterium, that encodes a protein machinery for DNA transfer to eukaryotic cells and their subsequent genetic modification. PMID- 26968005 TI - A safety evaluation of ivacaftor for the treatment of cystic fibrosis. AB - INTRODUCTION: Ivacaftor is indicated for treatment of cystic fibrosis (CF) mediated by 10 mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene that causes gating or partial function abnormalities. In placebo-controlled and open-label studies, ivacaftor-treated subjects showed improved pulmonary function, nutrition and quality of life measures. This article reviews ivacaftor safety. AREAS COVERED: Safety findings in ivacaftor clinical trials, and reported subsequently, were accessed by a PubMed search using key words "VX-770" or "ivacaftor". Additional information was accessed via Google Search. Transaminitis was noted in ivacaftor and combination lumacaftor-ivacaftor trials. Ivacaftor was associated with cataracts in juvenile rat pups in pre clinical studies; non-congenital cataracts have been found in children taking ivacaftor. Ivacaftor is a CYP3A substrate; CYP3A inhibitors and inducers should be avoided during its administration. Ivacaftor and its M1 metabolite may inhibit CYP3A and P-gp; therefore, ivacaftor may increase systemic exposure to drugs which are substrates of CYP3A and/or P-gp, increasing the potential for adverse events. EXPERT OPINION: Ivacaftor therapy may be associated with ocular and hepatic side effects; specific recommendations for monitoring are available. Potential drug interactions should be evaluated in patients taking ivacaftor. High clinical efficacy suggests that the risk benefit ratio of ivacaftor favors therapy. PMID- 26968002 TI - Paternal B Vitamin Intake Is a Determinant of Growth, Hepatic Lipid Metabolism and Intestinal Tumor Volume in Female Apc1638N Mouse Offspring. AB - BACKGROUND: The importance of maternal nutrition to offspring health and risk of disease is well established. Emerging evidence suggests paternal diet may affect offspring health as well. OBJECTIVE: In the current study we sought to determine whether modulating pre-conception paternal B vitamin intake alters intestinal tumor formation in offspring. Additionally, we sought to identify potential mechanisms for the observed weight differential among offspring by profiling hepatic gene expression and lipid content. METHODS: Male Apc1638N mice (prone to intestinal tumor formation) were fed diets containing replete (control, CTRL), mildly deficient (DEF), or supplemental (SUPP) quantities of vitamins B2, B6, B12, and folate for 8 weeks before mating with control-fed wild type females. Wild type offspring were euthanized at weaning and hepatic gene expression profiled. Apc1638N offspring were fed a replete diet and euthanized at 28 weeks of age to assess tumor burden. RESULTS: No differences in intestinal tumor incidence or burden were found between male Apc1638N offspring of different paternal diet groups. Although in female Apc1638N offspring there were no differences in tumor incidence or multiplicity, a stepwise increase in tumor volume with increasing paternal B vitamin intake was observed. Interestingly, female offspring of SUPP and DEF fathers had a significantly lower body weight than those of CTRL fed fathers. Moreover, hepatic trigylcerides and cholesterol were elevated 3-fold in adult female offspring of SUPP fathers. Weanling offspring of the same fathers displayed altered expression of several key lipid metabolism genes. Hundreds of differentially methylated regions were identified in the paternal sperm in response to DEF and SUPP diets. Aside from a few genes including Igf2, there was a striking lack of overlap between these genes differentially methylated in sperm and differentially expressed in offspring. CONCLUSIONS: In this animal model, modulation of paternal B vitamin intake prior to mating alters offspring weight gain, lipid metabolism and tumor growth in a sex-specific fashion. These results highlight the need to better define how paternal nutrition affects the health of offspring. PMID- 26968004 TI - Morphine-Induced Preconditioning: Involvement of Protein Kinase A and Mitochondrial Permeability Transition Pore. AB - BACKGROUND: Morphine induces myocardial preconditioning (M-PC) via activation of mitochondrial large conductance Ca2+-sensitive potassium (mKCa) channels. An upstream regulator of mKCa channels is protein kinase A (PKA). Furthermore, mKCa channel activation regulates mitochondrial bioenergetics and thereby prevents opening of the mitochondrial permeability transition pore (mPTP). Here, we investigated in the rat heart in vivo whether 1) M-PC is mediated by activation of PKA, and 2) pharmacological opening of the mPTP abolishes the cardioprotective effect of M-PC and 3) M-PC is critically dependent on STAT3 activation, which is located upstream of mPTP within the signalling pathway. METHODS: Male Wistar rats were randomised to six groups (each n = 6). All animals underwent 25 minutes of regional myocardial ischemia and 120 minutes of reperfusion. Control animals (Con) were not further treated. Morphine preconditioning was initiated by intravenous administration of 0.3 mg/kg morphine (M-PC). The PKA blocker H-89 (10 MUg/kg) was investigated with and without morphine (H-89+M-PC, H-89). We determined the effect of mPTP opening with atractyloside (5 mg/kg) with and without morphine (Atr+M-PC, Atr). Furthermore, the effect of morphine on PKA activity was tested in isolated adult rat cardiomyocytes. In further experiments in isolated hearts we tested the protective properties of morphine in the presence of STAT3 inhibition, and whether pharmacological prevention of the mPTP opening by cyclosporine A (CsA) is cardioprotective in the presence of STAT3 inhibition. RESULTS: Morphine reduced infarct size from 64+/-5% to 39+/-9% (P<0.05 vs. Con). H-89 completely blocked preconditioning by morphine (64+/-9%; P<0.05 vs. M-PC), but H-89 itself had not effect on infarct size (61+/-10%; P>0.05 vs. Con). Also, atractyloside abolished infarct size reduction of morphine completely (65+/-9%; P<0.05 vs. M-PC) but had no influence on infarct size itself (64+/-5%; P>0.05 vs. Con). In isolated hearts STAT3 inhibitor Stattic completely abolished morphine-induced preconditioning. Administration of Stattic and mPTP inhibitor cyclosporine A reduced infarct size to 31+/-6% (Stat+CsA, P<0.05 vs. Con). Cyclosporine A alone reduced infarct size to 26+/-7% (CsA P<0.05 vs. Con). In cardiomyocytes, PKA activity was increased by morphine. CONCLUSION: Our data suggest that morphine-induced cardioprotection is mediated by STAT3-activation and inhibition of mPTP, with STA3 located upstream of mPTP. There is some evidence that protein kinase A is involved within the signalling pathway. PMID- 26968006 TI - Ethical Considerations When Counseling Patients With Thyroid Cancer About Surgery vs Observation. PMID- 26968007 TI - Numeracy moderates the influence of task-irrelevant affect on probability weighting. AB - Statistical numeracy, defined as the ability to understand and process statistical and probability information, plays a significant role in superior decision making. However, recent research has demonstrated that statistical numeracy goes beyond simple comprehension of numbers and mathematical operations. On the contrary to previous studies that were focused on emotions integral to risky prospects, we hypothesized that highly numerate individuals would exhibit more linear probability weighting because they would be less biased by incidental and decision-irrelevant affect. Participants were instructed to make a series of insurance decisions preceded by negative (i.e., fear-inducing) or neutral stimuli. We found that incidental negative affect increased the curvature of the probability weighting function (PWF). Interestingly, this effect was significant only for less numerate individuals, while probability weighting in more numerate people was not altered by decision-irrelevant affect. We propose two candidate mechanisms for the observed effect. PMID- 26968008 TI - Three-Dimensionally Printed Microfluidic Cross-flow System for Ultrafiltration/Nanofiltration Membrane Performance Testing. AB - Minimization and management of membrane fouling is a formidable challenge in diverse industrial processes and other practices that utilize membrane technology. Understanding the fouling process could lead to optimization and higher efficiency of membrane based filtration. Here we show the design and fabrication of an automated three-dimensionally (3-D) printed microfluidic cross flow filtration system that can test up to 4 membranes in parallel. The microfluidic cells were printed using multi-material photopolymer 3-D printing technology, which used a transparent hard polymer for the microfluidic cell body and incorporated a thin rubber-like polymer layer, which prevents leakages during operation. The performance of ultrafiltration (UF), and nanofiltration (NF) membranes were tested and membrane fouling could be observed with a model foulant bovine serum albumin (BSA). Feed solutions containing BSA showed flux decline of the membrane. This protocol may be extended to measure fouling or biofouling with many other organic, inorganic or microbial containing solutions. The microfluidic design is especially advantageous for testing materials that are costly or only available in small quantities, for example polysaccharides, proteins, or lipids due to the small surface area of the membrane being tested. This modular system may also be easily expanded for high throughput testing of membranes. PMID- 26968010 TI - Comparison of Therapeutic Response and Clinical Outcome between HCV Patients with Normal and Abnormal Alanine Transaminase Levels. AB - BACKGROUND AND AIMS: Patients with chronic hepatitic C (HCV) infection and normal serum alanine transaminase (ALT) levels were considered to have mild disease. In Taiwan, these patients were not suggested for interferon (IFN) based therapies. The aim of study is to compare therapeutic outcomes between HCV patients with normal and elevated ALT levels. METHODS: We conducted a retrospective study on 3241 HCV patients treated by IFN based therapies. Patients with normal ALT levels were classified as group A (n = 186) while those with elevated ALT levels were group B (n = 3055). RESULTS: At baseline, incidence of diabetes mellitus, low platelet counts and cirrhosis were significantly higher in group B patients. The sustained virologic response (SVR) rate was comparable between the 2 groups (65.3% vs. 65.3%, P = .993). But significantly higher incidence of HCC development after HCV treatment was observed in group B (7.4% vs. 3.2%, P = .032). No significant differences with respect to the outcome of liver decompensation, spontaneous bacterial peritonitis, and mortality were noted between 2 groups. Multivariate analysis showed younger age, female gender, non HCV genotype 1, lower viral load, higher platelet counts and non-cirrhosis were favorable factors for achieving SVR, rather than ALT levels. Further analysis revealed older age, cirrhosis, lower platelet levels and non- peg-interferon treatment are risk factors of HCC development. CONCLUSIONS: HCV patients with normal ALT levels had similar response to antiviral therapy and low rate of HCC development after therapy. Antiviral therapies begun at early course of HCV infection may be beneficial to prevent disease progression. PMID- 26968012 TI - Serial 1- and 2-Dimensional Cerebral MRI Measurements in Full-Term Infants after Perinatal Asphyxia. AB - OBJECTIVE: Cranial magnetic resonance imaging (MRI) is associated with neurodevelopmental outcome in full-term infants with neonatal encephalopathy (NE) following presumed perinatal asphyxia. The aim of this study is to relate 2 dimensional measurements of the basal ganglia and thalami (BGT) and cerebellum in the first week after birth and after 3 months with neurodevelopmental outcome at 18 months. METHODS: Retrospectively, 29 full-term infants with NE following presumed perinatal asphyxia who had a cranial MRI in the first week after birth were studied serially. One- and 2-dimensional measurements were obtained and related to different patterns of brain injury, and neurodevelopmental outcome at 18 months. A Griffiths developmental quotient <85 or cerebral palsy was considered adverse. RESULTS: On the first MRI, the adverse outcome group showed increased basal ganglia width (42.1 +/- 0.1 vs. 40.3 +/- 0.3 mm, p < 0.001), thalamic width (40.3 +/- 0.1 vs. 39.3 +/- 1.0 mm, p < 0.001), and basal ganglia surface (1,230 +/- 21 vs. 1,199 +/- 36 mm2, p = 0.007) compared to the favorable outcome group. In the BGT lesions group, basal ganglia width and thalamic width were increased compared to the watershed infarction group (42.1 +/- 0.1 vs. 40.9 +/- 0.8 mm, p < 0.001, and 40.3 +/- 0.1 vs. 39.9 +/- 0.5 mm, p = 0.01, respectively). On the second MRI, cerebellar width was larger in the favorable outcome group (p = 0.025). There was a greater increase in dimensions between both MRI time points for basal ganglia width (p = 0.014), basal ganglia surface (p = 0.028) and thalamic width (p = 0.012) in the favorable outcome group. CONCLUSIONS: One- and 2-dimensional measurements for basal ganglia surface, BGT width and cerebellar width are associated with neurodevelopmental outcome at 18 months. PMID- 26968011 TI - Minimum Effective Dose of Cattle and Sheep BSE for Oral Sheep Infection. AB - The minimum dose required to cause infection of Romney and Suffolk sheep of the ARQ/ARQ or ARQ/ARR prion protein gene genotypes following oral inoculation with Romney or Suffolk a sheep Bovine spongiform encephalopathy (BSE)-derived or cattle BSE-derived agent was investigated using doses ranging from 0.0005g to 5g. ARQ/ARQ sheep which were methionine (M) / threonine (T) heterozygous or T/T homozygous at codon 112 of the Prnp gene, dosed ARQ/ARR sheep and undosed controls did not show any evidence of infection. Within groups of susceptible sheep, the minimum effective oral dose of BSE was found to be 0.05g, with higher attack rates following inoculation with the 5g dose. Surprisingly, this study found no effect of dose on survival time suggesting a possible lack of homogeneity within the inoculum. All clinical BSE cases showed PrPd accumulation in brain; however, following cattle BSE inoculation, LRS involvement within Romney recipients was found to be significantly lower than within the Suffolk sheep inoculated group which is in agreement with previous reports. PMID- 26968009 TI - Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene. AB - Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13 * 10(-14) for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32 1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94-1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47-9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions. PMID- 26968013 TI - Determination of GHB levels in breast milk and correlation with blood concentrations. AB - The sodium salt of GHB or sodium oxybate is approved and registered in some countries as a therapeutic substance (Xyrem((r))) for the treatment of narcolepsy associated cataplexy. This study was designed to measure the GHB endogenous levels in blood and breast milk of 20 breastfeeding women. In addition, blood and breast milk samples of a 32-year-old narcoleptic nursing mother, who was on sodium oxybate treatment, were simultaneously collected at 0.5, 1, 3, 4 and 5h following a 4.5g GHB dose and analyzed, in order to establish the safety interval of time to breastfeed. A GC-MS method for the detection and quantification of GHB in blood and breast milk was developed and fully validated. The geometric mean of endogenous GHB levels in blood and breast milk detected at time 0 were 0.57mg/L; 95% Reference Interval (RI): 0.21-1.52mg/L and 0.36mg/L; 95% RI: 0.13-1.03mg/L, respectively. The geometric mean of the concentration of GHB in milk was 37% less (95% RI: from 14 to 53%) compared to that found in the blood. The analysis of blood and breast milk samples collected from the 32 years-old female showed the following results: GHB blood concentration 0.5h after medication intake was 80.10mg/L, reaching the peak 1h after the drug administration (108.34mg/L) and it steadily decreased to reach a level of 1.75mg/L, 5h after the medication intake. The GHB concentration found in breast milk followed the same pattern as for the blood, with the highest concentration being 23.19mg/L, 1h after sodium oxybate administration and the lowest 0.99mg/L, 5h after the medication's intake. The comparison between blood and breast milk GHB levels in the 32-year-old woman, showed significant lower GHB levels in milk at 0.5, 1 and 3h, ranging from 71 to 80% less. It is interesting to note that only at 4 and 5h the difference between blood and breast milk GHB levels fell within the 95% RI (14-53%) of endogenous levels. Taking into consideration the absence of reference values for endogenous GHB in milk, we suggest the following reference interval: 0.13-1.03mg/L. We would recommend, following these preliminary data, that nursing mothers under sodium oxybate treatment should breastfeed at least 5h after the last GHB administration. However, further studies are necessary in order to confirm these findings. PMID- 26968014 TI - Medical therapy of heart failure with reduced ejection fraction: current evidence and new developments. AB - Heart failure with reduced ejection fraction (HFrEF) is a common cardiovascular condition with a significant individual and societal burden. Although it was previously known as a palliative condition, medical drug therapies that were developed in the last four decades significantly reduced morbidity and mortality of the disease. The cornerstone of HFrEF therapy remains the blockade of the renin-angiotensin-aldosterone and the beta-adrenergic systems. This review aims to give an overview and update on established disease-modifying therapies in HFrEF, discuss advances and setbacks in the treatment of selected comorbidities and provide an outlook on upcoming therapies including the new concept of dual angiotensin receptor and neprilysin inhibition. PMID- 26968015 TI - Outcome of chemotherapy in advanced synovial sarcoma patients: Review of 15 clinical trials from the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group; setting a new landmark for studies in this entity. AB - INTRODUCTION: Previous studies in metastatic soft tissue sarcomas (STS) showed that synovial sarcomas tend to have better survival rates and a higher chemosensitivity than other STS subtypes. However, data are derived from relatively small subgroups and statistical significance of these observations is lacking. Larger cohorts are necessary to define and confirm the specific characteristics of this subtype. PATIENTS AND METHODS: Patient data were retrieved from 15 European Organisation for Research and Treatment of Cancer advanced first-line STS trials. Patient characteristics, survival and treatment response of synovial sarcoma patients were compared to other STS patients. Univariable and multivariable analyses were performed to evaluate prognostic factors. RESULTS: In total, 3330 advanced STS patients were retrieved, of whom 313 had a synovial sarcoma. Synovial sarcoma patients were significantly younger (median 40 versus 52 years), more often had extremity primary tumours and had a better performance status (PS 0: 50.2 versus 43.4%) compared to other STS patients. Additionally, synovial sarcoma patients had a significantly better response to chemotherapy (responders: 27.8 versus 18.8%) and better survival rates (progression free survival [PFS]: 6.3 versus 3.7 months; Overall survival [OS]: 15.0 versus 11.7 months). Age, PS, and presence of metastatic disease were defined as prognostic factors for PFS and OS in the univariable analysis. The last two factors were confirmed in the multivariable analysis for OS. DISCUSSION: Advanced synovial sarcomas are a distinct subgroup of STS, with a better response to systemic chemotherapy and longer PFS and OS. These results should be taken into account in the design of future synovial sarcoma specific studies. PMID- 26968016 TI - Sensational biofilms: surface sensing in bacteria. AB - The first step in the development of a bacterial biofilm is contact with the surface on which the microbe will form this community. We review recent progress on 'surface sensing', and engage the question of 'how does a microbe know it is on a surface?' PMID- 26968018 TI - Soil examination for a forensic trace evidence laboratory-Part 3: A proposed protocol for the effective triage and management of soil examinations. AB - In the past, forensic soil examination was a routine aspect of forensic trace evidence examinations. The apparent need for soil examinations then went through a period of decline and with it the capability of many forensic laboratories to carry out soil examinations. In more recent years, interest in soil examinations has been renewed due-at least in part-to soil examinations contributing to some high profile investigations. However, much of this renewed interest has been in organisations with a primary interest in soil and geology rather than forensic science. We argue the need to reinstate soil examinations as a trace evidence sub discipline within forensic science laboratories and present a pathway to support this aim. An examination procedure is proposed that includes: (i) appropriate sample collection and storage by qualified crime scene examiners; (ii) exclusionary soil examinations by trace evidence scientists within a forensic science laboratory; (iii) inclusionary soil examinations by trace evidence scientists within a forensic science laboratory; and (iv) higher-level examination of soils by specialist soil scientists and palynologists. Soil examinations conducted by trace evidence scientists will be facilitated if the examinations are conducted using the instrumentation routinely used by these examiners. Hence, the proposed examination protocol incorporates instrumentation in routine use in a forensic trace evidence laboratory. Finally, we report on an Australian soil scene variability study and a blind trial that demonstrate the utility of the proposed protocol for the effective triage and management of soil samples by forensic laboratories. PMID- 26968017 TI - About 42% of 154 remains from the "Battle of Le Mans", France (1793) belong to women and children: Morphological and genetic evidence. AB - Mass graves were discovered in Le Mans and 154 skeletons were exhumed, representing a remarkable historical series of human remains from western France. We aimed to characterise the age-class and sex of these subjects, and to determine whether their profile fits with that of the Catholic and Royal Army of Vendee, who fought against the Republican Army during the Battle of Le Mans (12th 13th December, 1793). This atypical army was composed of male soldiers, but also of civilian people who followed the troops, including the elderly, children and women. In total 154 skeletons from nine mass graves were exhumed from 2009 to 2010. Two morphological methods were used to determine the sex of the subjects: the Probabilist Sexual Diagnosis (DSP) and Secondary Sexual Diagnosis (DSS) methods. Samples were handled cautiously to avoid any pre-laboratory contamination. Molecular genetic sex-typing using a recently developed assay was used to maximise sex-diagnosis of the ancient DNA samples, and 97 successful profiles including immatures were generated. Using morphological and genetic data combined, we successfully determined the sex of 93% of the subjects; 62% were male and 31% female. About 87% of subjects could be considered adults (>18 years old), 6% adolescents (15-19 years old) and 7% infants (<15 years old). Our results of an unexpected population profile for an armed conflict (42% were women and children), in addition to traumatological and historical elements, tend to confirm that these subjects were involved in the Battle of Le Mans, either actively (Republican Army, the Catholic and Royal Army) or passively (collateral victims from the civilian population of Le Mans). They represent 5-6% of the estimated 2500-3000 victims. PMID- 26968019 TI - An Improved Method for Rapid Intubation of the Trachea in Mice. AB - Despite some anatomical and physiological differences, mouse models continue to be an essential tool for studying human lung disease. Bleomycin toxicity is a commonly used model to study both acute lung injury and fibrosis, and multiple methods have been developed for administering bleomycin (and other toxic agents) into the lungs. However, many of these approaches, such as transtracheal instillation, have inherent drawbacks, including the need for strong anesthetics and survival surgery. This paper reports a quick, reproducible method of intratracheal intubation that involves mild inhaled anesthesia, visualization of the trachea, and the use of a surrogate spirometer to confirm exposure. As a proof of concept, 8-12 week old C57BL/6 mice were administered either 2.0 U/kg of bleomycin or an equivalent volume of PBS, and both damage and fibrotic endpoints were measured post-exposure. This procedure allows researchers to treat a large cohort of mice in a relatively short period with little expense and minimal post procedure care. PMID- 26968020 TI - PET/CT scan revealing active idiopathic inflammatory myopathy with normal serum sarcoplasmic enzymes levels. PMID- 26968021 TI - Role of MiR-126a-3p in Endothelial Injury in Endotoxic Mice. AB - OBJECTIVE: Sepsis poses a serious global health problem with an overall mortality rate of 30%, in which the vascular injury is a major contributor. The study is to determine the expression profile of micro-RNAs in endotoxic vascular walls and their potential roles in sepsis-related vascular injury. DESIGN: Prospective randomized study. SETTING: Laboratory investigation. SUBJECTS: Male C57BL/6 mice, average weight 26.5 +/- 1.8 g. INTERVENTIONS: Endotoxemia was induced in mice via lipopolysaccharide injection (20 mg/kg, intraperitoneal) (Sigma, St. Louis, MO). The control mice were injected with the same amount of saline (500 MUL, intraperitoneal). In a subgroup of mice, a high dose of lipopolysaccharide (30 mg/kg, intraperitoneal) was applied to induce endotoxin-related death. MEASUREMENTS AND MAIN RESULTS: The mi-RNA expression profiles in aortas from lipopolysaccharide-induced endotoxic mice were determined. The result demonstrated that some micro-RNAs were aberrantly expressed in endotoxic mouse arteries. Among them, the endothelial cell-enriched/endothelial cell-specific miR 126a-3p was significantly down-regulated in endotoxic mouse arteries, septic human vessels, as well as vascular endothelial cells isolated from endotoxic mice or treated with lipopolysaccharide. The down-regulation of miR-126a-3p occurred at transcriptional level via the decreased expression of Kruppel-like factor 2, which could be inhibited by Kruppel-like factor 2 over-expression via adenovirus expressing Kruppel-like factor 2. The down-regulation of miR-126a-3p in endothelial cells resulted in the increased apoptosis, and decreased proliferation and migration, which were inhibited by miR-126a-3p mimics. In vivo, over-expression of miR-126a-3p via lentivirus attenuated endotoxemia-induced injuries on endothelial function and vascular permeability. We found that SPRED1 and VCAM-1 were two direct target genes of miR-126a-3p related to miR-126a-3p mediated effects in endotoxemia. Finally, the survival rate of endotoxic mice was significantly increased by the over-expression of miR-126a-3p. CONCLUSIONS: The results suggest that vascular micro-RNAs such as miR-126a-3p may represent novel mechanisms and new therapeutic targets for endotoxemia-induced vascular injury and endotoxic mortality. PMID- 26968022 TI - A One-Nearest-Neighbor Approach to Identify the Original Time of Infection Using Censored Baboon Sepsis Data. AB - OBJECTIVES: Sepsis therapies have proven to be elusive because of the difficulty of translating biologically sound and effective interventions in animal models to humans. A part of this problem originates from the fact that septic patients present at various times after the onset of sepsis, whereas the exact time of infection is controlled in animal models. We sought to determine whether data mining longitudinal physiologic data in a nonhuman primate model of Escherichia coli-induced sepsis could help inform the time of onset of infection. DESIGN: A nearest-neighbor approach was used to back cast the time of onset of infection in animal models of sepsis. Animal data were censored to simulate prospective monitoring at any moment along the septic infection. This was compared against an uncensored database to find the most similar animal in order to estimate the infection onset time. Leave-one-out cross-validation was used for validation. Biomarker selection was performed based on the criteria of estimation accuracy and/or ease of measurement. SETTING: Computational experimental on existing experimental data. SUBJECTS: Retrospective data from 33 septic baboons (Papio ursinus) subjected to Escherichia coli infusion. Validation was performed using 14 pigs that were subjected to surgically induced fecal peritonitis and 22 pigs that were subjected to lipopolysaccharide infusion. MEASUREMENTS AND MAIN RESULTS: Longitudinal physiologic and serum markers, time of death. The presence of uniquely changing biomarkers during septic infection enabled the estimation of infection onset time in the datasets. Various combinations of temporal biomarkers, such as WBC, oxygen content, mean arterial pressure, and heart rate, yielded estimation accuracies of up to 97.8%. The use of temporal vital signs and a single measurement of serum biomarkers yielded highly accurate estimates without the need for invasive measurements. Validation in the pig data revealed similar results despite the heterogeneity of multiple experimental cohorts. This suggests that the method may be effective if sufficiently similar subjects are present in the database. CONCLUSIONS: One nearest-neighbor analysis showed promise in accurately identifying the onset of infection given a database of known infection times and of sufficient breadth. We suggest that this approach is ready for evaluation within the clinical setting using human data. PMID- 26968024 TI - A Binational Multicenter Pilot Feasibility Randomized Controlled Trial of Early Goal-Directed Mobilization in the ICU. AB - OBJECTIVES: To determine if the early goal-directed mobilization intervention could be delivered to patients receiving mechanical ventilation with increased maximal levels of activity compared with standard care. DESIGN: A pilot randomized controlled trial. SETTING: Five ICUs in Australia and New Zealand. PARTICIPANTS: Fifty critically ill adults mechanically ventilated for greater than 24 hours. INTERVENTION: Patients were randomly assigned to either early goal directed mobilization (intervention) or to standard care (control). Early goal directed mobilization comprised functional rehabilitation treatment conducted at the highest level of activity possible for that patient assessed by the ICU mobility scale while receiving mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: The ICU mobility scale, strength, ventilation duration, ICU and hospital length of stay, and total inpatient (acute and rehabilitation) stay as well as 6 month post-ICU discharge health-related quality of life, activities of daily living, and anxiety and depression were recorded. The mean age was 61 years and 60% were men. The highest level of activity (ICU mobility scale) recorded during the ICU stay between the intervention and control groups was mean (95% CI) 7.3 (6.3-8.3) versus 5.9 (4.9-6.9), p = 0.05. The proportion of patients who walked in ICU was almost doubled with early goal-directed mobilization (intervention n = 19 [66%] vs control n = 8 [38%]; p = 0.05). There was no difference in total inpatient stay (d) between the intervention versus control groups (20 [15-35] vs 34 [18-43]; p = 0.37). There were no adverse events. CONCLUSIONS: Key Practice Points: Delivery of early goal-directed mobilization within a randomized controlled trial was feasible, safe and resulted in increased duration and level of active exercises. PMID- 26968023 TI - Longitudinal Changes in ICU Admissions Among Elderly Patients in the United States. AB - OBJECTIVES: Changes in population demographics and comorbid illness prevalence, improvements in medical care, and shifts in care delivery may be driving changes in the composition of patients admitted to the ICU. We sought to describe the changing demographics, diagnoses, and outcomes of patients admitted to critical care units in the U.S. hospitals. DESIGN: Retrospective cohort study. SETTING: U.S. hospitals. PATIENTS: There were 27.8 million elderly (age, > 64 yr) fee-for service Medicare beneficiaries hospitalized with an intensive care or coronary care room and board charge from 1996 to 2010. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We aggregated primary International Classification of Diseases, 9th Revision, Clinical Modification discharge diagnosis codes into diagnoses and disease categories. We examined trends in demographics, primary diagnosis, and outcomes among patients with critical care stays. Between 1996 and 2010, we found significant declines in patients with a primary diagnosis of cardiovascular disease, including coronary artery disease (26.6 to 12.6% of admissions) and congestive heart failure (8.5 to 5.4% of admissions). Patients with infectious diseases increased from 8.8% to 17.2% of admissions, and explicitly labeled sepsis moved from the 11th-ranked diagnosis in 1996 to the top-ranked primary discharge diagnosis in 2010. Crude in-hospital mortality rose (11.3 to 12.0%), whereas discharge destinations among survivors shifted, with an increase in discharges to hospice and postacute care facilities. CONCLUSIONS: Primary diagnoses of patients admitted to critical care units have substantially changed over 15 years. Funding agencies, physician accreditation groups, and quality improvement initiatives should ensure that their efforts account for the shifting epidemiology of critical illness. PMID- 26968025 TI - Autonomic Impairment in Severe Traumatic Brain Injury: A Multimodal Neuromonitoring Study. AB - OBJECTIVES: Autonomic impairment after acute traumatic brain injury has been associated independently with both increased morbidity and mortality. Links between autonomic impairment and increased intracranial pressure or impaired cerebral autoregulation have been described as well. However, relationships between autonomic impairment, intracranial pressure, impaired cerebral autoregulation, and outcome remain poorly explored. Using continuous measurements of heart rate variability and baroreflex sensitivity we aimed to test whether autonomic markers are associated with functional outcome and mortality independently of intracranial variables. Further, we aimed to evaluate the relationships between autonomic functions, intracranial pressure, and cerebral autoregulation. DESIGN: Retrospective analysis of a prospective database. SETTING: Neurocritical care unit in a university hospital. SUBJECTS: Sedated patients with severe traumatic brain injury. MEASUREMENTS AND MAIN RESULTS: Waveforms of intracranial pressure and arterial blood pressure, baseline Glasgow Coma Scale and 6 months Glasgow Outcome Scale were recorded. Baroreflex sensitivity was assessed every 10 seconds using a modified cross-correlational method. Frequency domain analyses of heart rate variability were performed automatically every 10 seconds from a moving 300 seconds of the monitoring time window. Mean values of baroreflex sensitivity, heart rate variability, intracranial pressure, arterial blood pressure, cerebral perfusion pressure, and impaired cerebral autoregulation over the entire monitoring period were calculated for each patient. Two hundred and sixty-two patients with a median age of 36 years entered the analysis. The median admission Glasgow Coma Scale was 6, the median Glasgow Outcome Scale was 3, and the mortality at 6 months was 23%. Baroreflex sensitivity (adjusted odds ratio, 0.9; p = 0.02) and relative power of a high frequency band of heart rate variability (adjusted odds ratio, 1.05; p < 0.001) were individually associated with mortality, independently of age, admission Glasgow Coma Scale, intracranial pressure, pressure reactivity index, or cerebral perfusion pressure. Baroreflex sensitivity showed no correlation with intracranial pressure or cerebral perfusion pressure; the correlation with pressure reactivity index was strong in older patients (age, > 60 yr). The relative power of high frequency correlated significantly with intracranial pressure and cerebral perfusion pressure, but not with pressure reactivity index. The relative power of low frequency correlated significantly with pressure reactivity index. CONCLUSIONS: Autonomic impairment, as measured by heart rate variability and baroreflex sensitivity, is significantly associated with increased mortality after traumatic brain injury. These effects, though partially interlinked, seem to be independent of age, trauma severity, intracranial pressure, or autoregulatory status, and thus represent a discrete phenomenon in the pathophysiology of traumatic brain injury. Continuous measurements of heart rate variability and baroreflex sensitivity in the neuromonitoring setting of severe traumatic brain injury may carry novel pathophysiological and predictive information. PMID- 26968026 TI - Intermittent severe hypoxia induces plasticity within serotonergic and catecholaminergic neurons in the neonatal rat ventrolateral medulla. AB - 5-HT neurons contribute to autoresuscitation and survival during intermittent severe hypoxia (IsH). In adults, catecholaminergic neurons in the ventrolateral medulla (VLM) contribute to the autonomic response to hypoxia. We hypothesized that 1) catecholaminergic neurons in the neonatal VLM are activated following IsH, 2) this activation is compromised following an acute loss of brain stem 5 HT, and 3) IsH induces cellular and/or transcriptomic plasticity within catecholaminergic and serotonergic neurons that are within or project to the VLM, respectively. To test these hypotheses, we treated rat pups with 6 fluorotryptophan, a tryptophan hydroxylase (TPH) inhibitor, and then exposed treated and vehicle controls to IsH or air. Along with immunohistochemistry to detect tyrosine hydroxylase (TH)- or Fos-positive neurons, we used RNA sequencing to resolve the effects of IsH and 5-HT deficiency on the expression of serotonergic and catecholaminergic system genes in the VLM. 5-HT deficiency compromised autoresuscitation and survival. IsH significantly increased the number of identifiable TH-positive VLM neurons, an effect enhanced by 5-HT deficiency (P = 0.003). Contrary to our hypothesis, 5-HT-deficient pups had significantly more Fos-positive neurons following IsH (P = 0.008) and more activated TH-positive neurons following IsH or air (P = 0.04). In both groups the expression of the 5-HT transporter and TPH2 was increased following IsH. In 5-HT deficient pups, the expression of the inhibitory 5-HT1A receptor was decreased following IsH, while the expression of DOPA decarboxylase was increased. These data show that the serotonergic and catecholaminergic systems in the VLM of the neonatal rat are dynamically upregulated by IsH, potentially adapting cardiorespiratory responses to severe hypoxia. PMID- 26968028 TI - Living altitude influences endurance exercise performance change over time at altitude. AB - For sea level based endurance athletes who compete at low and moderate altitudes, adequate time for acclimatization to altitude can mitigate performance declines. We asked whether it is better for the acclimatizing athlete to live at the specific altitude of competition or at a higher altitude, perhaps for an increased rate of physiological adaptation. After 4 wk of supervised sea level training and testing, 48 collegiate distance runners (32 men, 16 women) were randomly assigned to one of four living altitudes (1,780, 2,085, 2,454, or 2,800 m) where they resided for 4 wk. Daily training for all subjects was completed at a common altitude from 1,250 to 3,000 m. Subjects completed 3,000-m performance trials on the track at sea level, 28 and 6 days before departure, and at 1,780 m on days 5, 12, 19, and 26 of the altitude camp. Groups living at 2,454 and 2,800 m had a significantly larger slowing of performance vs. the 1,780-m group on day 5 at altitude. The 1,780-m group showed no significant change in performance across the 26 days at altitude, while the groups living at 2,085, 2,454, and 2,800 m showed improvements in performance from day 5 to day 19 at altitude but no further improvement at day 26 The data suggest that an endurance athlete competing acutely at 1,780 m should live at the altitude of the competition and not higher. Living ~300-1,000 m higher than the competition altitude, acute altitude performance may be significantly worse and may require up to 19 days of acclimatization to minimize performance decrements. PMID- 26968029 TI - The Lasting Influences of Early Food-Related Variety Experience: A Longitudinal Study of Vegetable Acceptance from 5 Months to 6 Years in Two Populations. AB - Children's vegetable consumption falls below current recommendations, highlighting the need to identify strategies that can successfully promote better acceptance of vegetables. Recently, experimental studies have reported promising interventions that increase acceptance of vegetables. The first, offering infants a high variety of vegetables at weaning, increased acceptance of new foods, including vegetables. The second, offering an initially disliked vegetable at 8 subsequent meals markedly increased acceptance for that vegetable. So far, these effects have been shown to persist for at least several weeks. We now present follow-up data at 15 months, 3 and 6 years obtained through questionnaire (15 mo, 3y) and experimental (6y) approaches. At 15 months, participants who had been breast-fed were reported as eating and liking more vegetables than those who had been formula-fed. The initially disliked vegetable that became accepted after repeated exposure was still liked and eaten by 79% of the children. At 3 years, the initially disliked vegetable was still liked and eaten by 73% of the children. At 6 years, observations in an experimental setting showed that children who had been breast-fed and children who had experienced high vegetable variety at the start of weaning ate more of new vegetables and liked them more. They were also more willing to taste vegetables than formula-fed children or the no or low variety groups. The initially disliked vegetable was still liked by 57% of children. This follow-up study suggests that experience with chemosensory variety in the context of breastfeeding or at the onset of complementary feeding can influence chemosensory preferences for vegetables into childhood. PMID- 26968027 TI - Vitamin D3 intake modulates diaphragm but not peripheral muscle force in young mice. AB - Recent data support an important role for vitamin D in respiratory health. We tested the hypothesis that dietary vitamin D3 (VD3) intake modulates diaphragm (DIA) strength. Four-week-old female A/J mice (n = 10/group) were randomized to receive diets containing 100 IU VD3/kg (low), 1,000 IU VD3/kg (reference), or 10,000 IU VD3/kg (pharmacologic). After 6 wk of dietary intervention, plasma 25 hydroxyvitamin D3 (25D3) levels, DIA and extensor digitorum longus (EDL) in vitro contractile properties, and fiber cross-sectional area (CSA) were measured. Myosin heavy chain (MHC) composition and Akt/Foxo3A growth signaling were studied in the DIA and tibialis anterior. Mice fed the low, reference, and pharmacologic diets had average 25D3 levels of 7, 21, and 59 ng/ml, respectively. Maximal DIA force, twitch force, and fiber CSA were reduced 26%, 28%, and 10% (P < 0.01), respectively, in mice receiving the low-VD3 diet compared with the reference and pharmacologic diets. EDL force parameters were unaltered by diet. Effects of VD3 intake on DIA force were not observed in mice that began dietary intervention at 12 wk of age. VD3 intake did not alter the MHC composition of the DIA, indicating that decreases in force and CSA in young mice were not due to a switch in fiber type. Paradoxically, low VD3 intake was associated with activation of anabolic signaling in muscle (hyperphosphorylation of Akt and Foxo3A and decreased expression of autophagy marker LC3). These studies identify a potential role of dietary VD3 in regulating DIA development and insulin sensitivity. PMID- 26968031 TI - Reconstructing the Mexican Tropical Dry Forests via an Autoecological Niche Approach: Reconsidering the Ecosystem Boundaries. AB - We used Ecological Niche Modeling (ENM) of individual species of two taxonomic groups (plants and birds) in order to reconstruct the climatic distribution of Tropical Dry Forests (TDFs) in Mexico and to analyze their boundaries with other terrestrial ecosystems. The reconstruction for TDFs' distribution was analyzed considering the prediction and omission errors based upon the combination of species, obtained from the overlap of individual models (only plants, only birds, and all species combined). Two verifications were used: a primary vegetation map and 100 independent TDFs localities. We performed a Principal Component (PCA) and Discriminant Analysis (DA) to evaluate the variation in the environmental variables and ecological overlap among ecosystems. The modeling strategies showed differences in the ecological patterns and prediction areas, where the "all species combined" model (with a threshold of >=10 species) was the best strategy to use in the TDFs reconstruction. We observed a concordance of 78% with the primary vegetation map and a prediction of 98% of independent locality records. Although PCA and DA tests explained 75.78% and 97.9% of variance observed, respectively, we observed an important overlap among the TDFs with other adjacent ecosystems, confirming the existence of transition zones among them. We successfully modeled the distribution of Mexican TDFs using a number of bioclimatic variables and co-distributed species. This autoecological niche approach suggests the necessity of rethinking the delimitations of ecosystems based on the recognition of transition zones among them in order to understand the real nature of communities and association patterns of species. PMID- 26968030 TI - The Combination of Marketed Antagonists of alpha1b-Adrenergic and 5-HT2A Receptors Inhibits Behavioral Sensitization and Preference to Alcohol in Mice: A Promising Approach for the Treatment of Alcohol Dependence. AB - Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, alpha1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies. We show that the association of ifenprodil (1 mg/kg) and cyproheptadine (1 mg/kg) (alpha1-adrenergic and 5-HT2 receptor antagonists marketed as Vadilex (r) and Periactine (r) in France, respectively) blocks behavioral sensitization to amphetamine in C57Bl6 mice and to alcohol in DBA2 mice. Moreover, this combination of antagonists inhibits alcohol intake in mice habituated to alcohol (10% v/v) and reverses their alcohol preference. Finally, in order to verify that the effect of ifenprodil was not due to its anti-NMDA receptors property, we have shown that a combination of prazosin (0.5 mg/kg, an alpha1b-adrenergic antagonist, Mini-Press (r) in France) and cyproheptadine (1 mg/kg) could also reverse alcohol preference. Altogether these findings strongly suggest that combined prazosin and cyproheptadine could be efficient as a therapy to treat alcoholism in humans. Finally, because alpha1b-adrenergic and 5-HT2A receptors blockade also inhibits behavioral sensitization to psychostimulants, opioids and tobacco, it cannot be excluded that this combination will exhibit some efficacy in the treatment of addiction to other abused drugs. PMID- 26968032 TI - Leading the Game, Losing the Competition: Identifying Leaders and Followers in a Repeated Game. AB - We explore a new method for identifying leaders and followers, LF, in repeated games by analyzing an experimental, repeated (50 rounds) game where Row player shifts the payoff between small and large values-a type of "investor" and Column player determines who gets the payoff-a type of "manager". We found that i) the Investor (Row) most often is a leading player and the manager (Column) a follower. The longer the Investor leads the game, the higher is both player's payoff. Surprisingly however, it is always the Manager that achieves the largest payoff. ii) The game has an efficient cooperative strategy where the players alternate in receiving a high payoff, but the players never identify, or accept, that strategy. iii) Under the assumption that the information used by the players is closely associated with the leader- follower sequence, and that information is available before the player's decisions are made, the players switched LF- strategy primarily as a function of information on the Investor's investment and moves and secondly as a function of the Manager's payoff. PMID- 26968033 TI - Correction: Dimerization-Induced Allosteric Changes of the Oxyanion-Hole Loop Activate the Pseudorabies Virus Assemblin pUL26N, a Herpesvirus Serine Protease. PMID- 26968035 TI - Photochemical control of microphase structure in biocompatible polyester membranes generated by ultraviolet irradiation. AB - The morphologies of PEMA-RB/PHEMA semi-interpenetrating polymeric network (semi IPN) blended membranes prepared via ultraviolet (UV) promoted in situ photopolymerization were investigated using laser scanning confocal fluorescence microscopy (LSCFM). The results show that the semi-IPN morphology generated through UV light irradiation-induced microphase separation is considerably dependent on the relative rates of the photochemical reaction and microphase separation in the reactive precursor mixtures, which are determined by reactive dynamic factors. Changing the dynamic conditions, such as the UV light intensity, content of cross-linker and concentration of HEMA photopolymerization monomer resulted in a corresponding alteration of the morphological structure in the semi IPN membranes. The hierarchical morphology appearing in the PEMA-RB/PHEMA semi IPN should be related to the inhomogeneous photoreaction dynamics of the mixed system. Desired morphologies of the semi-IPN blend membranes can be obtained by controlling the corresponding dynamic conditions of both the photochemical reaction and microphase separation. PMID- 26968034 TI - Ultrasensitive Time-Resolved Fluoroimmunoassay for Saikosaponin a in Chaihu (Bupleuri Radix). AB - The aim of this study is to establish a time-resolved fluoroimmunoassay (TRFIA) system for quantitative analysis of saikosaponin a (SSa) in the crude drug of Chaihu (Bupleuri Radix). A 96-well microplate coated with rabbit anti-mouse IgG was incubated with the methanol extracts of Chaihu samples and a mouse anti-SSa monoclonal antibody, and a Eu3+-labeled SSa-human serum albumin conjugate was used as the tracer. The established competitive TRFIA showed a good fourth order polynomial fitting from 0.01 to 10.0 MUg/mL for standard SSa sample with a detection limit of 0.006 MUg/mL. The intra- and inter-assay coefficients of variation of the assay were 7.3% and 8.9%, respectively, and the average SSa recovery was 119.2%. For samples of Chaihu extract, the results of this assay showed a good correlation with those by enzyme-linked immunosorbent assay established previously. This TRFIA system is ultrasensitive for detecting SSa with a wide detection range and a good stability and represents the first attempt of using TRFIA for quality evaluation of the crude drug of Chaihu. PMID- 26968036 TI - The Effect of Exercise on the Early Stages of Mesenchymal Stromal Cell-Induced Cartilage Repair in a Rat Osteochondral Defect Model. AB - The repair of articular cartilage is challenging owing to the restriction in the ability of articular cartilage to repair itself. Therefore, cell supplementation therapy is possible cartilage repair method. However, few studies have verified the efficacy and safety of cell supplementation therapy. The current study assessed the effect of exercise on early the phase of cartilage repair following cell supplementation utilizing mesenchymal stromal cell (MSC) intra-articular injection. An osteochondral defect was created on the femoral grooves bilaterally of Wistar rats. Mesenchymal stromal cells that were obtained from male Wistar rats were cultured in monolayer. After 4 weeks, MSCs were injected into the right knee joint and the rats were randomized into an exercise or no-exercise intervention group. The femurs were divided as follows: C group (no exercise without MSC injection); E group (exercise without MSC injection); M group (no exercise with MSC injection); and ME group (exercise with MSC injection). At 2, 4, and 8 weeks after the injection, the femurs were sectioned and histologically graded using the Wakitani cartilage repair scoring system. At 2 weeks after the injection, the total histological scores of the M and ME groups improved significantly compared with those of the C group. Four weeks after the injection, the scores of both the M and ME groups improved significantly. Additionally, the scores in the ME group showed a significant improvement compared to those in the M group. The improvement in the scores of the E, M, and ME groups at 8 weeks were not significantly different. The findings indicate that exercise may enhance cartilage repair after an MSC intra-articular injection. This study highlights the importance of exercise following cell transplantation therapy. PMID- 26968037 TI - High-Resolution Mapping of Homologous Recombination Events in rad3 Hyper Recombination Mutants in Yeast. AB - The Saccharomyces cerevisae RAD3 gene is the homolog of human XPD, an essential gene encoding a DNA helicase of the TFIIH complex involved in both nucleotide excision repair (NER) and transcription. Some mutant alleles of RAD3 (rad3-101 and rad3-102) have partial defects in DNA repair and a strong hyper-recombination (hyper-Rec) phenotype. Previous studies showed that the hyper-Rec phenotype associated with rad3-101 and rad3-102 can be explained as a consequence of persistent single-stranded DNA gaps that are converted to recombinogenic double strand breaks (DSBs) by replication. The systems previously used to characterize the hyper-Rec phenotype of rad3 strains do not detect the reciprocal products of mitotic recombination. We have further characterized these events using a system in which the reciprocal products of mitotic recombination are recovered. Both rad3-101 and rad3-102 elevate the frequency of reciprocal crossovers about 100 fold. Mapping of these events shows that three-quarters of these crossovers reflect DSBs formed at the same positions in both sister chromatids (double sister-chromatid breaks, DSCBs). The remainder reflects DSBs formed in single chromatids (single chromatid breaks, SCBs). The ratio of DSCBs to SCBs is similar to that observed for spontaneous recombination events in wild-type cells. We mapped 216 unselected genomic alterations throughout the genome including crossovers, gene conversions, deletions, and duplications. We found a significant association between the location of these recombination events and regions with elevated gamma-H2AX. In addition, there was a hotspot for deletions and duplications at the IMA2 and HXT11 genes near the left end of chromosome XV. A comparison of these data with our previous analysis of spontaneous mitotic recombination events suggests that a sub-set of spontaneous events in wild-type cells may be initiated by incomplete NER reactions, and that DSCBs, which cannot be repaired by sister-chromatid recombination, are a major source of mitotic recombination between homologous chromosomes. PMID- 26968038 TI - Intima-Media Thickness Does Not Differ between Two Common Carotid Artery Segments in Children. AB - Carotid intima-media thickness (cIMT) is a surrogate marker of early atherosclerotic changes in children. cIMT-studies are hard to compare, due to variations in ultrasound protocols, especially regarding the common carotid artery (CCA) segment measured in relation to the bulb. This study's purpose was therefore to compare two distinct CCA segments in children, to see if cIMT values differ substantially according to the site of measurement. cIMT was assessed after power calculation in 30 children (15 girls) aged 8-17, using B-Mode ultrasound (5-13 MHz) at two CCA locations. The first measurement was performed over a distance of 1 cm immediately after the bulb (A), the second 1cm proximal the bulb (B) over the same distance of 1cm length. Means of end-diastolic far wall cIMT were compared between measurement A and B. cIMT in 30 participants was 0.51+/-0.06 mm for measurement A and 0.51+/-0.05 mm for measurement B. Results did not differ significantly (p = .947) over a distance of 2 cm after the bulb. According to our results, studies measuring CCA IMT within the first 2 cm, either close to the bulb or further proximal, can be compared. This will improve interpretation of data and application of reference values. PMID- 26968039 TI - Reproducibility of Heart Rate Variability Indices in Children with Cystic Fibrosis. AB - Fundamental to the potential utilisation of heart rate variability (HRV) indices as a prognostic tool is the reproducibility of these measures. The purpose of the present study was therefore to investigate the reproducibility of 24-hour derived HRV indices in a clinical paediatric population. Eighteen children (10 boys; 12.4 +/- 2.8 years) with mild to moderate Cystic Fibrosis (CF; FVC: 83 +/- 12% predicted; FEV1: 80 +/- 9% predicted) and eighteen age- and sex-matched controls (10 boys; 12.5 +/- 2.7 years) wore a combined ECG and accelerometer for two consecutive days. Standard time and frequency domain indices of HRV were subsequently derived. Reproducibility was assessed by Bland-Altman plots, 95% limits of agreement and intra-class correlation coefficients (ICC). In both groups, there was no systematic difference between days, with the variables demonstrating a symmetrical, homoscedastic distribution around the zero line. The time domain parameters demonstrated a good to excellent reproducibility irrespective of the population considered (ICC: 0.56 to 0.86). In contrast, whilst the frequency domain parameters similarly showed excellent reproducibility in the healthy children (ICC: 0.70 to 0.96), the majority of the frequency domain parameters illustrated a poor to moderate reproducibility in those with CF (ICC: 0.22 to 0.43). The exceptions to this trend were the normalised LF and HF components which were associated with a good to excellent reproducibility. These findings thereby support the utilisation of time and relative frequency domain HRV indices as a prognostic tool in children with CF. Furthermore, the present results highlight the excellent reproducibility of HRV in healthy children, indicating that this may be a useful tool to assess intervention effectiveness in this population. PMID- 26968040 TI - Secretoneurin Serum Levels in Healthy Term Neonates and Neonates with Hypoxic Ischaemic Encephalopathy. AB - BACKGROUND: Hypoxic-ischaemic encephalopathy is a major cause of neurologic impairment and mortality in neonates. Early knowledge of brain injury is important to guide therapeutic decisions and reliably inform the parents. Increased secretoneurin levels have been detected in adult patients suffering from brain injury and it has also been shown to be a promising early serum biomarker of unfavourable neurological outcome. However, no data are available in neonates. OBJECTIVE: The aim of this study was to obtain reference values for secretoneurin in healthy term neonates and then to assess the potential of this neuropeptide as a biomarker in the context of hypoxic-ischaemic encephalopathy in asphyxiated term neonates. METHODS: A total number of 139 term neonates, of which 7 were asphyxiated and 132 were healthy, were prospectively enrolled. Secretoneurin serum concentrations were assessed by radioimmunoassay. RESULTS: In healthy controls, secretoneurin serum concentrations were influenced by the mode of delivery (highest in infants born per vacuum extraction and lowest in infants born per caesarean section) and abnormal cardiotocography. In asphyxiated term neonates, secretoneurin concentrations were higher in umbilical cord blood and significantly lower 48 h after birth in comparison to healthy controls. CONCLUSION: Secretoneurin levels are elevated in cord blood in infants suffering from hypoxic-ischaemic encephalopathy following perinatal asphyxia. The potential of secretoneurin as a marker of neonatal hypoxic-ischaemic brain injury should be further evaluated in larger trials. PMID- 26968041 TI - Identifying candidate genes involved in osteoarthritis through bioinformatics analysis. AB - OBJECTIVES: This study aims to identify candidate genes and critical pathways involved in osteoarthritis (OA). METHODS: Gene expression data of synovial membrane from OA patients and normal controls (NCs) were downloaded from database. Totally, 15 OA and 14 NC chips were available. Differentially expressed genes (DEGs) were identified through limma package (log2 fold change >0.585, false discovery rate (FDR) < 0.05), and protein-protein interaction (PPI) network was constructed using STRING. Moreover, perturbation and pathway enrichment analyses were performed through PerturbationAnalyzer in Cytoscape (iterative criteria <1*e-10) and clusterProfiler package (FDR <0.05), respectively. RESULTS: Totally, 236 up-regulated and 290 down-regulated DEGs were identified. In PPI network, 10 hub genes were found, including VEGFA, IL6, JUN, IL1B, ICAM1, ATF3, IL8, EGR1, CDKN1A, and JUNB. After perturbation analysis, 32 DEGs were passively and significantly changed, like PISD, RARRES3, EIF4G1, and EPHA3. Furthermore, 526 DEGs were enriched in 176 pathways, and pathway cross-talk network was constructed, involving 12 pathways and 66 cross-talks. CONCLUSIONS: Pathways like rheumatoid arthritis, osteoclast differentiation, and cytokine-cytokine receptor interaction might play critical roles in OA, and previously unreported genes VEGFA, JUN, JUNB, PISD, RARRES3, EIF4G1, and EPHA3 might participate in OA, providing novel directions for drug targeting. PMID- 26968042 TI - Patient and Caregiver Priorities for Outcomes in Hemodialysis: An International Nominal Group Technique Study. AB - BACKGROUND: In the context of clinical research, investigators have historically selected the outcomes that they consider to be important, but these are often discordant with patients' priorities. Efforts to define and report patient centered outcomes are gaining momentum, though little work has been done in nephrology. We aimed to identify patient and caregiver priorities for outcomes in hemodialysis. STUDY DESIGN: Nominal group technique. SETTING & PARTICIPANTS: Patients on hemodialysis therapy and their caregivers were purposively sampled from 4 dialysis units in Australia (Sydney and Melbourne) and 7 dialysis units in Canada (Calgary). METHODOLOGY: Identification and ranking of outcomes. ANALYTICAL APPROACH: Mean rank score (of 10) for top 10 outcomes and thematic analysis. RESULTS: 82 participants (58 patients, 24 caregivers) aged 24 to 87 (mean, 58.4) years in 12 nominal groups identified 68 outcomes. The 10 top-ranked outcomes were fatigue/energy (mean rank score, 4.5), survival (defined by patients as resilience and coping; 3.7), ability to travel (3.6), dialysis-free time (3.3), impact on family (3.2), ability to work (2.5), sleep (2.3), anxiety/stress (2.1), decrease in blood pressure (2.0), and lack of appetite/taste (1.9). Mortality ranked only 14th and was not regarded as the complement of survival. Caregivers ranked mortality, anxiety, and depression higher than patients, whereas patients ranked ability to work higher. Four themes underpinned their rankings: living well, ability to control outcomes, tangible and experiential relevance, and severity and intrusiveness. LIMITATIONS: Only English-speaking participants were eligible. CONCLUSIONS: Although trials in hemodialysis have typically focused on outcomes such as death, adverse events, and biological markers, patients tend to prioritize outcomes that are more relevant to their daily living and well-being. Researchers need to consider interventions that are likely to improve these outcomes and measure and report patient-relevant outcomes in trials, and clinicians may become more patient-orientated by using these outcomes in their clinical encounters. PMID- 26968043 TI - The association of congenital tracheobronchial stenosis and cardiovascular anomalies. AB - OBJECTIVES: Congenital tracheobronchial stenosis (CTBS) is a rare disorder characterized by the presence of focal or diffuse complete tracheal or bronchial cartilage rings resulting in a fixed lumen narrowing. The aim of this study was to expose the association of various cardiovascular (CV) anomalies with various types of CTBS. METHODS: A retrospective review of 58 patients who had bronchoscopically proven CTBS between 1997 and 2011 was conducted. Totally, 48 cases who had received echocardiography, computed tomography and other examinations including cardiac catheterization were enrolled. There were 33 boys and 15 girls, and the median age of diagnosis was 4 months (0-44 months). The image findings of associated CV anomalies were reviewed and analyzed, along with the clinical manifestations and patients' outcome. RESULTS: There were 14 generalized hypoplasia (29.2%), 10 funnel type (20.8%), 15 segmental type (31.3%), and 9 isolated bronchial stenosis cases (18.7%). Among 48 cases of CTBS, 32 patients (66.7%) had various CV anomalies including atrial septal defect (n=9), pulmonary artery sling (n=7), ventricular septal defect (n=7), patent ductus arteriosus (n=6), tetralogy of Fallot (n=3), peripheral pulmonary stenosis (n=3), etc. No significant difference existed in the incidence and types of comorbid CV anomalies among 4 types of CTBS, except that funnel type had significantly higher comorbidity of pulmonary artery sling (50%, p<0.01). CONCLUSION: Patients with CTBS had high incidence of various associated CV anomalies. Isolated bronchial stenosis had similar high comorbidity of CV anomalies as did the 3 classical categories of congenital tracheal stenosis. The higher comorbidity of pulmonary artery sling in patients with funnel CTBS might be related to its gradual caudal narrowing of the trachea. PMID- 26968044 TI - Congenital nasal pyriform aperture stenosis: Elaboration of a management algorithm from 25 years of experience. AB - INTRODUCTION: Congenital nasal pyriform aperture stenosis (CNPAS) is a rare disease presenting with neonatal respiratory distress, often associated with other anomalies. MATERIALS AND METHODS: This study reports the clinical and radiological characteristics of the patients managed in The Department of Pediatric Otolaryngology Head and Neck Surgery of La Timone Children's Hospital in Marseille between 1988 and 2014. Pyriform aperture (PA) widths were measured on CT-scans, obtained by using hand calipers at the largest portion of the PA in a plan parallel to the Francfort plan. RESULTS: 10 patients were included. Average PA width was 6.6mm, 5/10 patients presented with single central maxillary median incisor, 6/10 patients had associated abnormalities. 8 patients underwent a surgical intervention and 2 patients were medically managed. All the patients had satisfactory nasal airway permeability on late follow-up. A management algorithm was elaborated. CNPAS should be evoked when breathing difficulties are associated with impossibility of passing fiberscope or nasogastric tube at the nasal inlet. Craniofacial CT-scanning is necessary to make the diagnosis and look for associated abnormalities. Medical treatment associating nasal wash and decongestants should be performed. Surgical intervention is necessary when failure of the medical management. DISCUSSION AND CONCLUSIONS: Our results were close to those found in the literature in terms of clinical characteristics, associated abnormalities and PA width. However, no objective criterion to decide whether a surgical intervention is necessary or not, has been established so far. The algorithm we propose offers guidelines from diagnosis to treatment, but the management should be adapted based on clinical tolerance. PMID- 26968045 TI - DEFB1 polymorphisms and susceptibility to recurrent tonsillitis in Italian children. AB - INTRODUCTION: The tonsils are secondary lymphoid organs fundamental for immune system response against pathogens within the oral cavity. Tonsillitis refers to inflammation of the pharyngeal tonsils that may include the adenoids and the lingual tonsils and that can be acute, recurrent, and chronic. Viral or bacterial infections, as well as immunologic factors are the main trigger to tonsillitis and disease's chronicity: the host immune responses, especially the innate one, could play an important role in susceptibility to the disease. OBJECTIVES: The current study aims at investigating the role of functional polymorphisms in the 5'UTR (c.-52G>A, c.-44G>C and c.-20G>A) of DEFB1 gene, encoding for the antimicrobial peptide human beta-defensin 1, in the predisposition to recurrent tonsillitis in children from North Eastern Italy. RESULTS: No significant correlation was found between DEFB1 allele, genotype and haplotype frequencies and recurrent tonsillitis susceptibility with the exception of an increased risk to disease development in patients carrying DEFB1 rare haplotypes. CONCLUSION: Our results may suggest that DEFB1 polymorphisms alone may not influence pathology susceptibility, however they could possibly concur, together with other factors involved in the genetic control of innate immune system, in the predisposition towards recurrent tonsillitis. PMID- 26968046 TI - Language skills and phonological awareness in children with cochlear implants and normal hearing. AB - OBJECTIVES: Early auditory experience plays a major role in language acquisition. Linguistic and metalinguistic abilities of children aged 5-5.5 years with cochlear implants (CIs) were compared to age-matched children with normal hearing (NH) to investigate the effect of hearing on development of these two skills. METHODS: Eighteen children with NH and 18 children with CIs took part in the study. The Test of Language Development-Primary, third edition, was used to assess language and metalinguistic skills by assessment of phonological awareness (PA). Language skills and PA were then compared between groups. Hierarchical linear regression was conducted to determine whether the language skills explained the unique variance in PA. RESULTS: There were significant differences between children with NH and those with CIs for language skills and PA (p<=0.001). All language skills (semantics, syntax, listening, spoken language, organizing, and speaking) were uniquely predictive of PA outcome in the CI children. Linear combinations of listening and semantics and listening, semantics, and syntax correlated significantly with PA. CONCLUSION: The results show that children with CIs may have trouble with language skills and PA. Listening, semantics, and syntax, among other skills, are significant indicators of the variance in PA for children with CIs. PMID- 26968047 TI - Uncommon situation and presentation of chronic sclerosing sialadenitis. AB - Chronic sclerosing sialadenitis of the parotid gland is a very uncommon chronic inflammatory salivary gland disease. Clinically, it presents as a slow-growing painful. Histologically, it showed a chronic inflammation and fibrosis. This case report highlights the clinical, radiological and histological aspects of this disease. We report unusual case of chronic sclerosing sialadenitis of the parotid in a 12-year-old man. CT detected a mass of tissue density in the right parotid. The evolution was marked by spontaneous fistula allowing a surgical biopsy. The mass regressed after corticosteroids. The follow-up was normal. The location, age and presentation make our case very interesting. PMID- 26968048 TI - Polysomnography results in pediatric patients with mild obstructive sleep apnea: Adenotonsillectomy vs. watchful waiting. AB - OBJECTIVE: There is a lack of consensus and a paucity of data regarding how to best treat pediatric patients with mild obstructive sleep apnea. The objective of our study was to compare outcomes following adenotonsillectomy vs. observation in children with mild obstructive sleep apnea based on polysomnography results. METHODS: A retrospective chart review was performed on children ages 9 months to 9 years with 2 or more polysomnograms completed at a tertiary care academic center. Children diagnosed with mild obstructive sleep apnea (obstructive apnea hypopnea index 1-5) on polysomnography performed from 1999 to 2013 were included. Patients underwent adenotonsillectomy or watchful waiting for obstructive sleep apnea. The primary outcome was the change in apnea-hypopnea index. RESULTS: There were 62 patients who met inclusion criteria for the study; 19 of the 62 patients were obese, while 15 had a craniofacial syndrome or hypotonia. Eighteen patients underwent adenotonsillectomy for mild obstructive sleep apnea while 44 were observed. The mean apnea-hypopnea index of patients after adenotonsillectomy improved from 3.50 (95% Confidence Interval [CI] 2.97-4.03) to 2.69 (95% CI 1.48 3.90), while the mean apnea-hypopnea index of the observation group worsened from 3.09 (95% CI 2.76-3.42) to 5.18 (95% CI 2.46-7.90). Between-group analysis showed significant improvement in the surgery group (p=0.03), with a persistent improvement on multivariate analysis adjusting for baseline apnea-hypopnea index (p=0.05). This difference was seen mostly in non-obese, non-syndromic children (p=0.04). There was no significant difference between groups amongst obese (p=0.25) and syndromic (p=0.36) patients. CONCLUSIONS: Adenotonsillectomy leads to a significant improvement in apnea-hypopnea index on follow-up polysomnography over an observational approach, especially in non-obese, non-syndromic children. A prospective, randomized trial is necessary to help determine appropriate treatment strategies for pediatric mild obstructive sleep apnea. PMID- 26968049 TI - Protective effects of the seaweed phlorotannin polyphenolic compound dieckol on gentamicin-induced damage in auditory hair cells. AB - OBJECTIVES: Drug-induced ototoxicity from compounds such as aminoglycosides and platinum can damage the inner ear resulting in hearing loss, tinnitus or balance problems and may be caused by the formation of reactive oxygen species (ROS). Dieckol is a phlorotannin polyphenolic compound with strong antioxidant effects found in edible brown algae. This study investigated the protective effects of dieckol on drug-induced ototoxicity in cochlear cultures obtained from neonatal mice. METHODS: Cochlear explants were pretreated with dieckol and exposed to gentamicin for 48h. The explants were then fixed and stained with fluorescein isothiocyanate-phalloidin and the intact hair cells counted. The free radical scavenging activity of dieckol was assessed using a 1,1-diphenyl-2-picrylhydrazyl assay. E. coli (Escherichia coli) cultures were used to evaluate the effect of dieckol on the antibiotic activity of gentamicin. RESULTS: Gentamicin treatment resulted in dose-dependent hair cell loss that was partially protected by dieckol. Moreover, at concentrations >67MUM dieckol had significant radical scavenging activity. Dieckol did not compromise the antibiotic effect of gentamicin. CONCLUSIONS: These findings suggest that dieckol can be used as a therapeutic agent that reduces the damage caused by drug-induced ototoxicity. PMID- 26968050 TI - Value of radiofrequency ablation in the management of retropharyngeal lymphatic malformation. AB - Lymphatic malformations are benign malformations frequently occurring in the head and neck. Retropharyngeal location is rare, can be life threating and its management is particularly challenging. Over a three-year period, three patients presented with symptomatic (dyspnea and/or dysphagia) retropharyngeal lymphatic malformation. All were treated using a radiofrequency ablation of lymphatic malformation through a trans-oral approach. No major complications occurred following the surgery. During the follow-up, no recurrence was noted and all patients were asymptomatic. Radiofrequency ablation in the management of retropharyngeal lymphatic malformations is a simple technique with very good results and allows a fast recovery with minimum morbidity and a short hospital stay. PMID- 26968051 TI - Nasal fluid secretory immunoglobulin A levels in children with allergic rhinitis. AB - OBJECTIVES: There is growing knowledge about the immunoregulatory and possibly preventative roles of immunoglobulin A (IgA) in allergic diseases. This study aimed to investigate secretory immunoglobulin A (SIgA) levels in the nasal fluid of children who were either being treated for their allergic rhinitis (AR) with intranasal mometasone furoate or were not receiving treatment. METHODS: The study population contained 55 children with persistent AR. Group I included 27 newly diagnosed AR patients not taking any medication and group II included 28 patients treated with intranasal steroids for at least 6 months. 27 healthy control subjects were also enrolled in the study. Total symptom scores (TSS) were calculated for each patient. Nasal secretions were obtained using a new modified polyurethane sponge absorption method, and samples were analysed by ELISA. RESULTS: The median value for nasal fluid SIgA level in each group was 127.2MUg/ml (interquartile range; 67.3-149.6) in group I, 133.9MUg/ml (102.1 177.8) in group II and 299.8MUg/ml (144.5-414.0) in the control group. Groups I and II both had statistically significant reductions in nasal fluid SIgA levels compared to the control group (p<0.001). However, there was no statistically significant difference between groups I and II (p=0.35). A statistically significant and negative correlation also existed between TSS and nasal fluid SIgA levels in both groups I and II (p=0.006, rho=-0.512 and p=0.01, rho=-0.481, respectively). CONCLUSIONS: SIgA levels in the nasal fluid are significantly reduced in children with AR independent of treatment and are negatively correlated with the TSS. PMID- 26968052 TI - Sleep-disordered breathing in children with Down syndrome: Usefulness of home polysomnography. AB - OBJECTIVE: To investigate the technical feasibility of unattended home polysomnography (HPSG) in children with Down syndrome. METHODS: Data from children with Down syndrome under 10 years of age referred to a diagnostic sleep study was analyzed. A full sleep-lab based polysomnography (PSG) or a HPSG with a portable device was performed. Uninterpretable HPSGs were defined as: recordings with (i) loss of >=2 of the following channels: nasal flow, or thoracoabdominal sensors, or (ii) HPSG with less than 4h of artifact-free recording time or (iii) less than 4h SpO2 (peripheral capillary oxygen saturation) signal. RESULTS: A total of 44 children (68% males) were included in the study, with a mean age of 3.6 (0.1-10) years. PSG was performed in 8 cases and HPSG in 36 cases. Six HPSG recordings were classified as uninterpretable and had to be repeated. Age, gender and BMI were no significant predictors of uninterpretability of the HPSG. Obstructive sleep apnea (OSA) was present in 61% (n=27) of all subjects, and classified as mild, moderate, and severe in 43% (n=19), 11% (n=5), and 7% (n=3) of cases, respectively. Interpretable and technically acceptable HPSGs were obtained in 30 subjects (83%). Age, gender and BMI were no significant predictors for interpretability of the HPSG. DISCUSSION: This study demonstrates that a portable polysomnographic home device may be helpful for diagnosing OSA in children with Down syndrome. Considering the potential consequences of untreated OSA, this screening test may be helpful for early diagnosis of OSA in children with Down syndrome. PMID- 26968053 TI - Evaluation of the effect of intranasal infiltrated botulinum toxin-A on a model of allergic rhinitis in rabbits: An Experimental Study. AB - INTRODUCTION: Allergic Rhinitis (AR) effects 20-40% of the global population and its prevalance increases. Medical treatment and immunotherapy could be used in AR management. But they are not definitive solution. Medical treatment must be used a long time and has side effects. Immunotherapy cannot be applied to every patient and it also takes a long time. The aim of this study is to evaluate symptomatic and histopathological effects of intranasal infiltrated Botulinum Toxin-A (Btx-A) on an animal model of AR. MATERIAL-METHOD: 15 rabbits were divided into 3 groups as control, disease and treatment. AR was formed in disease and treatment groups by intraperitoneal and intranasal ovalbumine. Allergic symptoms were observed and serum IgE levels were estimated to prove forming of AR. Btx-A was infiltrated in inferior turbinates of rabbits in treatment group. Rabbits were sacrified on 32nd day. Paranasal structures were disected and investigated histopathologically. RESULTS: Serous nasal discharge and sneezing were observed after ovalbumine applying in disease and treatment groups. Serum IgE levels on 21st day were higher than 1st day and this difference was significant statistically in disease and treatment groups. Serous discharge and sneezing decreased after Btx-A infiltration in treatment group. In histopathological examination, there were significant difference between disease and treatment group in terms of some histopathological findings. CONCLUSION: Considering the effect of Btx-A on AR in animal, it can be said that Btx-A can decrease symptoms and reorganize histopathological findings of AR. PMID- 26968054 TI - Treatment of severe tracheobronchomalacia: Ten-year experience. AB - INTRODUCTION: Paediatric tracheobronchomalacia is a rare but potentially serious condition. Severe tracheobronchomalacia requires intervention or operation. This is an evaluation of a ten-year experience at an institution. METHODS: In this retrospective study all patients were included that required an intervention for severe tracheobronchomalacia from 2003 to 2012. Symptoms, aetiology, comorbidities, localisation of the malacia, age at diagnosis, therapeutic measures and associated complications were evaluated. RESULTS: Forty-four patients with severe tracheobronchomalacia underwent intervention/operation. The predominant aetiology was vascular compression in 48%. The majority of patients had complex comorbidities, most importantly cardiac pathology in 66%. The median age at diagnosis was 3 months. A total of 17 aortopexies, 21 tracheostomies and 25 stent placements were performed. The mean follow-up was 2.6 years. Severe complications occurred in 12 patients. The most common complications were stent obstruction/fracture and tracheostomy tube obstruction. CONCLUSION: The management of severe tracheobronchomalacia is complex and the population of patients is very heterogeneous. Therefore the treatment has to be adapted for each patient individually. The decision strategies are discussed in this article. The surgical techniques for placement and safe removal of expandable bare metallic stents employed in our institution are presented. A multidisciplinary team of ENT surgeons, Intensivists, Cardiologists and Cardiac surgeons is of great importance. PMID- 26968055 TI - Bedside tests to predict laryngoscopic difficulty in pediatric patients. AB - BACKGROUND AND OBJECTIVES: Pediatric airway management is a priority during anesthesia, critical care and emergency medicine. The purpose of this study is to validate bedside tests that predict airway management difficulty in anesthetized children. METHODS: Children under 12 years of age were recruited in a cross sectional study to assess the value of some anthropometric measures as predictors of laryngoscopic difficulty. The patients were divided into three groups by age. Weight, height, neck circumference, BMI (body mass index), inter incisors distance thyromental distance, sternomental distance, frontal plane to chin distance (FPCD) and the Mallampati index were determined and were correlated with the CML (Cormack & Lehane classification). RESULTS: The incidence of difficult laryngoscopy (CML 3 or 4) was 3.58%. Factors that were significantly associated with laryngoscopic difficulty included short inter incisors distance, high FPCD, thyromental distance, sternomental distance and the Mallampati index. The FPCD/weight index exhibited a higher area under the ROC curve than any other variable considered. CONCLUSIONS: This study confirms that the FPCD and the FPCD/weight ratio are the most consistent predictors of laryngoscopic difficulty in pediatric patients. For patients over 6 months of age, the IID also correlated with laryngoscopic difficulty. For children who were capable of obeying simple orders, the Mallampati test correlated better with laryngoscopic difficulty than did the Mallampati test with phonation. Our results strongly suggest that skilled professionals should perform airway management in children, especially in patients with a high FPCD or a high FPCD/weight ratio. PMID- 26968056 TI - Are the patients with anatomic variation of the sublingual/Wharton's duct system predisposed to ranula formation? AB - OBJECTIVE: To evaluate ranula development according to anatomic variation of the ductal system of sublingual gland (SLG), especially the presence of Bartholin's duct. METHODS: The anatomic variation of SLG duct was prospectively investigated and compared between 55 consecutive patients with ranulas treated by SLG excision (group 1) and another 15 consecutive patients undergoing similar surgeries for other conditions (group 2). The ductal structures of SLGs and submandibular glands (SMG) were also compared between the pediatric patients and adult patients with ranulas. RESULTS: In 32 of 55 patients with ranulas (58.2%) and 1 of 15 patients without ranulas (6.7%), the SLG showed an anatomic variation of the main duct called Bartholin's duct structure (P<0.01). Seventeen of 22 (77.3%) pediatric patients with ranulas had Bartholin's ducts and 15 of 33 (45.5%) adult patients with ranulas had Bartholin's ducts (0.0130 days from symptom onset. RESULTS: Patients were 5-19 years old (mean 13.1+/-5.34) and included 6 boys and 5 girls. All presented with a sudden rotational vertigo, imbalance, and nausea for an average of 10 days without other associated symptoms. Testing included rotary chair (8 of 9 abnormal), caloric (2 of 2 abnormal), video head impulse (5 of 8 abnormal), subjective visual vertical (4 of 8 abnormal), and cervical vestibular evoked myogenic potential (0 of 6 abnormal) tests. All patients with incomplete recovery (n=4; 36%) were >=15 years old at symptom onset. All patients with incomplete recovery that underwent vestibular rehabilitation (n=2) initiated it >=90 days from symptom onset, while 3 out of 4 patients with complete recovery that underwent vestibular rehabilitation initiated it <=14 days from symptom onset. Two patients received oral steroids, neither of whom had incomplete recovery. CONCLUSION: Vestibular neuritis should be considered in pediatric patients with vertigo and may result in longstanding symptoms, particularly in adolescents. The treatment of pediatric vestibular neuritis with rehabilitation and steroids deserves further study. PMID- 26968064 TI - Is there a correlation between nasal septum deviation and maxillary transversal deficiency? A retrospective study on prepubertal subjects. AB - INTRODUCTION: Deviated nasal septum may cause a reduction of the nasal airflow, thus, during the craniofacial development, a reduced nasal airflow could originate a chronic mouth-breathing pattern, related with moderate to severe maxillary constriction. The aim of this retrospective study is to analyze the correlation between maxillary transverse deficiency and nasal septum deviation. METHODS: Frontal cephalograms were performed on 66 posterior-anterior radiographs of subjects (34M, 32F; mean age 9.95+/-2.50 years) with maxillary transverse deficiency and on a control group of 31 posterior-anterior radiographs of subjects (13M, 18F; 9.29+/-2.08 years). Angular parameters of the nasal cavities were recorded and compared between the two groups using a Student's t-test. RESULTS: Generally all the parameters are very similar between the two groups except for the ASY angle that differs for about the 27%; anyway the Student's t test showed no statistically significant differences between the two groups (mostly p>0.20). CONCLUSIONS: This study failed to show an association between transverse maxillary deficiencies and nasal septum deviations. Moreover, no significant differences were found between the mean nasal cavities dimensions in subjects with transverse maxillary deficiency and the control group. PMID- 26968065 TI - Precision-scored parental report questions and HL-scaled tympanometry as informative measures of hearing in otitis media 1: Large-sample evidence on determinants and complementarity to pure-tone audiometry. AB - INTRODUCTION: In otitis media with effusion (OME), hearing loss is a core sign/symptom and basis of concern, with absolute pure-tone threshold sensitivity (in dB HL) by air-conduction providing the default measure of hearing. However several fundamental problems limiting the value of HL measures in otitis media are insufficiently appreciated. To appraise the joint value and implications of multiple hearing measures towards more comprehensive hearing assessment in OM, we examine in two related articles the interrelations and common or diverging determinants of three measures, two of them objective: binaural HL, and ACET (the published quasi-continuous scaling of binaural tympanometry to HL). The third measure is partly subjective: parentally reported hearing difficulties (RHD-4); this is the precision-scored total of the 4 items selected for the OM8-30 general purpose questionnaire for parents in OM. METHODS: The Eurotitis-2 study (Total N=2886) internationally standardises OM8-30 and its OMQ-14 short form. The clinical and parent-response variables acquired cover many issues in diagnosis, symptomatology and impact of OM. Data acquisition was built upon routine clinic practice, enabling us also to document some properties of that practice, such as patterns of missing HL data. To address possible confounding or loss of representativeness from this, we investigated the implications of substituting tympanometry-based ACET for missing HL to give an HL/ACET hybrid. ACET is the mapping of categorical tympanometry to continuous HL. We simulated degrees of artificial missingness of HL up to 35% on the 1430 complete-data cases, using random deletion, with 1000-version bootstrapping. Correlations of this HL/ACET hybrid with pure (100%) HL then documented the degree of correlation retained under dilution of HL by an admixture of ACET; we also documented distribution shapes. For RHD-4, we then probed the determining influences on severity of score as an auditory disability measure, both background ones (from centre, age, sex, socio-economic status, length of history, diagnosis and season) and the two underlying objective hearing measures (HL, ACET). We ran these multiple regressions (GLMs), for representativeness and generality, both on 1430 complete data cases (i.e. all 3 hearing variables present) and also on supplemented samples according to data required only for particular analyses (N increased by +56% to +68%). A further method of sample supplementation (by up to +96%) used the HL/ACET hybrid. RESULTS: Sex made negligible difference in any analysis. The particular collaborating centre, age, season and diagnosis collectively influenced presence/absence of HL data very strongly. (Area under ROC 0.944). Socio-economic status did not influence HL presence; surprisingly, nor did RHD, ACET or length of history, after control for centre, age, diagnosis and season. Of the inter-correlations between hearing measures, only the one between ACET and RHD was influenced (slightly reduced) by the inclusion of cases without HL data. In the simulated substitutions, Pearson correlation of hybrid HL/ACET with true HL remained above 0.90 for substitution by ACET of up to 30% rate of artificially 'missing' HL. Centre differences were adequately summarised by simple absolute additive differences in mean local case severity. In the determinant models for RHD on the 1430 complete-data cases, HL and the set of background determinants collectively explained broadly similar proportions of RHD's variability, totalling 36.8% explained. On the larger maximum case samples, slightly less absolute variability was explicable than on complete-case data, but relative magnitudes of contribution from individual determinants, both background and hearing measures, remained similar. The expected mean differences in RHD between diagnoses (RAOM, OME, and combined) were found, but the patterns of background and objective measure influences determining RHD did not differ significantly between the diagnoses. CONCLUSIONS: (1) In the Eurotitis-2 database, descriptive differences in various background demographic and clinical measures between cases on whom HL data were obtained versus not, were only of material magnitude for length of history and reported hearing difficulties. Such descriptive differences are not necessarily bases of confounding, so using our framework of 6 background adjuster variables, (particular collaborating centre, age, season, diagnosis, socioeconomic status and length of history) we isolated the determinants of HL data presence. The first four listed strongly predicted HL data presence/absence so are sufficient to control analyses well for any bias or confounding by HL data presence. (2) Diagnoses as OME and combined (OME+RAOM) had higher probability of HL data being present relative to RAOM, indicating that HL acquisition is chiefly seen as confirming and quantifying hearing loss in (suspect) OME, not as ruling it out (e.g. in suspected RAOM). Given this, also using RHD and or ACET as pre triage to efficiently target capacity and/or reduce costs and opportunity costs of acquiring HL would be rational, but there was no evidence of such precise use of initial hearing-related information to decide on HL acquisition. (3) The full six background variables explained comparable variance in Reported Hearing Difficulties (RHD) to what was explained by ACET, but not quite as much as by HL. Achieving a high percentage explained (32-37% from good models) required both classes of determinant to be entered as predictors. The pattern of background determining influences for RHD was largely stable, with or without objective measures as additional predictors, and on maximum or complete-data cases. Length of history strongly determines RHD for a given concurrent HL. (4) Accepting ACET as substitute where HL was missing in OM cases gave a sample-size enhancement of 17% in Eurotitis-2, with negligible difference in the pattern of determinants. This hybrid measure can be recommended as reasonable next-best when moderate percentages of HL data are missing. (5) The stable pattern of prediction of RHD suggests that our six background determinants provide a very promising low-cost yet comprehensive framework for determination. It hence offers pluripotent statistical adjustment against confounding, applicable to RAOM, OME and combined diagnoses in any analysis using this database. Claims that it thereby offers a sufficient framework for full European standardisation of all the scores from the OM8-30 questionnaire measures await parallel demonstrations for symptom areas other than RHD. As 25% of the variance in RHD severity can be explained by the six adjusters in our framework, none of the six variables should be omitted from acquisition and analytic use in future OM research. PMID- 26968066 TI - The role of polysomnography in tracheostomy decannulation of the paediatric patient. AB - INTRODUCTION: Tracheostomy decannulation in the paediatric patient is usually considered when there is resolution or significant improvement in the original indication for the tracheostomy. The child's cardiorespiratory function needs to be optimized and assessment of the readiness for decannulation is generally by endoscopic evaluation to confirm airway patency and vocal cord mobility. Functional airway assessment procedures include downsizing the tracheostomy, adding fenestration, speaking valves and capping the tracheostomy tube. Few objective measures have been demonstrated to accurately predict the likelihood of successful decannulation. This study aims to evaluate the usefulness of polysomnography (PSG) with a capped tracheostomy tube, as an adjunct to airway endoscopy and traditional decannulation procedures, to predict decannulation outcome. METHODS: A retrospective review was conducted for patients who underwent "capped" PSG prior to a trial of tracheostomy decannulation at the Sydney Children's Hospitals Network. The charts were reviewed for clinical data and PSG results. RESULTS: 30 children with a total of 40 PSG reports were included in this study. There was a statistically significant difference in mean oxygen saturation, minimum oxygen saturation, total apnoea/hypopnoea index, desaturations >3%, and desaturations >3% index between those that had successful decannulation compared to failed decannulation. The measures with the greatest significance, and therefore, the best predictors of decannulation outcome were total apnoea/hypopnoea index (3.35events/h vs. 18.5events/h, p=0.004) and desaturation events (20.33 events vs. 192 events, p=0.001). CONCLUSIONS: PSG with a capped tracheostomy tube is a useful, objective tool to complement endoscopy and functional airway assessment in the consideration of decannulation in the paediatric population. PMID- 26968068 TI - Adaptation and validation of Common Object Token (COT) test into the Sinhalese language. AB - OBJECTIVES: This manuscript presents a translation and adaptation of the Common Object Token (COT) test, which assesses speech perception, into the Sinhalese language and an attempt to validate it for use on children with normal hearing (NH) and children with a cochlear implant (CI). METHODS: Ninety-five children (70 with NH, 25 with a CI) participated in the study. The COT test was translated, back-translated, and evaluated by a team of experts until the Sinhalese translation was deemed acceptable. Data of Sinhalese children with NH and values of children with a CI were analysed. Internal reliability and consistency of the COT total score were determined. Lastly, a quick version of the COT test was created. RESULTS: The total mean scores and subtest mean scores improved with age for children with NH. For children with a CI, a strong relationship between the COT total score and device experience, i.e. hearing age, was found. A Quick Sinhalese COT test version, suitable for children with a CI, could be created from Subtests 2, 3, and 4. CONCLUSION: The Sinhalese COT test is valid for assessing the age-related development of speech perception and identification skills of children with NH. Results suggest that the COT is valid for use in children with a CI. PMID- 26968067 TI - Long-term functional and behavioral-emotional outcomes in children with early cochlear implants: Parental testimonies. AB - OBJECTIVES: (1) To assess the long-term effects of cochlear implantation (CI) on speech perception and school life, and (2) to evaluate behavioral and emotional development, including social skills, post-implantation. METHODS: We telephoned caregivers and asked them a standardized questionnaire. We used the data to explore the daily lives (including school life) of children who had undergone CI before the age of 4 years and who had used the device for >10 years. We also evaluated behavioral/emotional development. RESULTS: Most children used CI devices for virtually all their waking moments and attended mainstream schools. Moreover, more than 75% of them could comprehend common phrases or conversations without lip-reading and carry out a telephone conversation with a person known to them. The mean T-scores for all scales of behavioral/emotional assessment, including those concerning social skills, were within the normal ranges, although scores on the competence scale were lower than those on other scales. CONCLUSIONS: This long-term study of early-CI children shows that CI improves not only speech perception, but also behavioral/emotional development, including social skills. PMID- 26968069 TI - Chronic suppurative otitis media, middle ear pathology and corresponding hearing loss in a cohort of Greenlandic children. AB - BACKGROUND: Otitis media (OM) has been observed at elevated prevalence rates in Greenlandic children. OM associated hearing loss (HL) may compromise the children's linguistic skills, social development and educational achievements. OBJECTIVES: We investigated the prevalence of chronic suppurative otitis media (CSOM), otitis media with effusion (OME) and tympanic membrane sequelae of OM, and compared the corresponding hearing thresholds. METHODS: In 2010 we examined a cohort of 223 Greenlandic children aged 4-10 years by video otoscopy, tympanometry and tested hearing thresholds for the low-frequencies: 500, 1000 and 2000Hz and the high-frequencies: 4000 and 6000Hz. HL was categorized according to the worst hearing ear and was compared within the groups: CSOM, OME, tympanic membrane sequelae of OM and normal. RESULTS: Of 207 children, 5.8% had CSOM, 13.9% had OME and 55.6% had tympanic membrane sequelae of OM. The median pure tone average in low-frequencies/high-frequencies were: CSOM: 34.2/31.3dB, OME: 23.3/22.5dB, Sequelae of OM: 13.3/15dB and normal ears: 11.7/12.5dB. We found a significant difference (p<0.05) between the four groups. In 56.5% of all children a HL>15dB in any frequency was found, while 6.5% suffered from a bilateral low frequency HL>25dB. CONCLUSION: The severity of OM significantly corresponded to increased HL. The burden of CSOM and HL remains high in young Greenlandic children. Aggressive treatment with antibiotics, improved hearing rehabilitation, sound field amplification in classrooms and otosurgical capacity should be further promoted in Greenland. PMID- 26968070 TI - ACE grading-A proposed endoscopic grading system for adenoids and its clinical correlation. AB - OBJECTIVES: To propose a novel endoscopic adenoid grading system using a rigid nasal endoscope and to study its correlation with the clinical diagnosis. METHODOLOGY: Prerecorded video clips of rigid nasal endoscopy taken during endoscopic adenoidectomy were retrieved. Otolaryngology consultants blinded to the clinical diagnosis of the child were presented these videos and asked to grade the adenoid hypertrophy as per the proposed endoscopic ACE (Airway/Choana/Eustachian tube) grading system. The clinical diagnosis was correlated with the different aspects of the descriptive endoscopic grading system. RESULTS: 152 video clips were presented to the otolaryngology consultants for grading. The average age was 8.6 years (SD-3.48), while the male female ratio was 3:2. The A subcomponent of the ACE grading showed significant correlation with the diagnosis of sleep disordered breathing and chronic adenotonsillitis, C subcomponent with sleep disordered breathing and the E subcomponent with the diagnosis of otitis media. CONCLUSION: The proposed endoscopic grading is easily applicable and at the same time clearly describes the relation of the adenoids to the nasopharynx, choana and Eustachian tube. Different aspects of the grading system correlated differently with the clinical diagnosis emphasizing that a descriptive scoring rather than a comprehensive scoring is a more relevant clinical tool. PMID- 26968071 TI - Auditory training program for Arabic-speaking children with auditory figure ground deficits. AB - OBJECTIVE: Listening to speech in noise makes up a great challenge for school children with auditory processing disorders mainly those with deficit in auditory figure ground (AFG) ability. These children are candidates for auditory training programs targeting AFG such as noise-desensitization programs. This work aimed to develop a new training material in Arabic language targeting this ability. METHODS: A noise-desensitization semi-formal training program was developed and standardized on normal children in a pilot study preceding the main one. Seventeen school children with AFG deficit were submitted to the program for eight weeks then reevaluated. RESULTS: The paired sample t-test revealed significant improvement of all trained children after training period in their psychophysical and electrophysiological results. The electrophysiological threshold of signal to noise ratio decreased from -5.3dB to -11.3dB after training. CONCLUSION: The newly developed training material revealed efficacy in managing children with AFG deficit. The other affected auditory abilities improved also because of the multi-ability tapping character of the program. PMID- 26968072 TI - Embryotoxicity and hair cell toxicity of silver nanoparticles in zebrafish embryos. AB - OBJECTIVES: The purpose of the present study was to evaluate silver nanoparticles (AgNP)-induced embryotoxicity and hair cell toxicity during zebrafish development. METHODS: We exposed zebrafish embryos to various AgNP concentrations (30, 60, 120, and 240nM) and evaluated embryotoxicity at 72h and ototoxicity at 120h. Embryotoxicity parameters including abnormal morphology, mortality, hatching rate, and heart rate were investigated. Hair cells within four neuromasts were evaluated. In the present study, the average number of hair cells of zebrafish exposed to AgNP was compared with that of an unexposed control group. RESULTS: The hatching rate was not significantly different between groups (control: 90%; AgNP 240nM: 89%). The control group showed 2% mortality and 0% teratogenicity, while the AgNP 240nM group showed increased mortality (11%) and teratogenicity (15%) at 72h (n=100). The heart rate of AgNP-exposed embryos tended to be lower than that of the control group (n=38). Furthermore, AgNP induced apoptotic hair cell damage in the neuromasts (control: 50.7+/-7.4 cells; 240nM AgNP: 41.1+/-6.3 cells, n=23). TUNEL positive cell counts increased significantly as AgNP concentration increases (p<0.001, n=20 in each group). CONCLUSIONS: The results of this study indicate that AgNP exposure causes embryotoxicity and hair cell toxicity in zebrafish embryos. PMID- 26968073 TI - Chloral hydrate sedation for auditory brainstem response (ABR) testing in children: Safety and effectiveness. AB - INTRODUCTION: The auditory brainstem response (ABR) test is used to identify hearing loss and measure hearing thresholds of infants and children who cannot be tested using standard behavioral hearing testing methods. In order for the ABR to yield useful data, a child must be asleep throughout the duration of the test. In many centers, this is achieved through the use of a general anesthetic, with its inherent risks and costs. Since 2004, ABRs have been routinely conducted at BC Children's Hospital in an ambulatory care setting under oral chloral hydrate sedation, with monitoring by a specialist nurse. The aim of this retrospective study was to assess the effectiveness and safety of nurse-led sedation with chloral hydrate for ABR testing at our tertiary pediatric center. METHODS: Medical and audiology records were reviewed for children aged 6 months to 17 years who underwent ABR testing from 2004 to 2012. We reviewed the dosage of drug used, condition of the child after chloral hydrate administration, adverse effects, audiological results, patients' vital signs, and the effectiveness of the sedative in keeping the child asleep throughout the duration of the test. Frequency distributions were derived for adverse outcomes. RESULTS: 725 ABR records encompassing 635 children (multiple ABR tests in some children) were reviewed. The average dose of chloral hydrate used was 52mg/kg. The majority of sedated ABR's (80.8%) were completed without any incident. Significant events [apnea and/or bradycardia], minor complications [vomiting, hypoxemia, prolonged sedation, and/or tachypnea] and restlessness were noted in 3.4%, 6.2%, and 5.0% of the cases, respectively. The majority of these issues resolved without medical intervention, such as the need to provide supplementary oxygen. In 95.9% of ABRs, chloral hydrate was successful in sedating the child adequately to answer the audiological question. CONCLUSIONS: This forms the largest study to date on oral sedation for ABR testing. Based on our results, the use of chloral hydrate in the presence of a sedation nurse was a safe and reliable method of performing ABR in infants and children. This may be of significant value to centres worldwide exploring alternatives to general anesthesia for ABR testing. PMID- 26968074 TI - Novel compound heterozygous mutations in MYO7A gene associated with autosomal recessive sensorineural hearing loss in a Chinese family. AB - OBJECTIVES: Mutations in MYO7A gene have been reported to be associated with Usher Syndrome type 1B (USH1B) and nonsyndromic hearing loss (DFNB2, DFNA11). Most mutations in MYO7A gene caused USH1B, whereas only a few reported mutations led to DFNB2 and DFNA11. The current study was designed to investigate the mutations among a Chinese family with autosomal recessive hearing loss. METHODS: In this study, we present the clinical, genetic and molecular characteristics of a Chinese family. Targeted capture of 127 known deafness genes and next generation sequencing were employed to study the genetic causes of two siblings in the Chinese family. Sanger sequencing was employed to examine those variant mutations in the members of this family and other ethnicity-matched controls. RESULTS: We identified the novel compound heterozygous mutant alleles of MYO7A gene: a novel missense mutation c.3671C>A (p.A1224D) and a reported insert mutation c.390_391insC (p.P131PfsX9). Variants were further confirmed by Sanger sequencing. These two compound heterozygous variants were co-segregated with autosomal recessive hearing loss phenotype. The gene mutation analysis and protein sequence alignment further supported that the novel compound heterozygous mutations were pathogenic. CONCLUSION: The novel compound heterozygous mutations (c.3671C>A and c.390_391insC) in MYO7A gene identified in this study were responsible for the autosomal recessive sensorineural hearing loss of this Chinese family. PMID- 26968075 TI - Tracheobronchial stents in mucopolysaccharidosis. AB - INTRODUCTION: The mucopolysaccharidoses are a group of hereditary disorders pathologically characterized by tissue accumulation of glycosaminoglycans due to deficient lysosomal metabolism which often leads to progressive airway stenosis and respiratory insufficiency. Relentless and treatment-refractory narrowing of the lower airways with ensuing severe limitation of quality of life is a challenging problem in mucopolysaccharidoses. CASE REPORTS: We report 2 cases of MPS (Hunter's and Maroteaux-Lamy's syndrome resp.) in whom tracheal stents were placed to relieve severe tracheal obstruction. The first patient could be weaned from mechanical ventilation after stent placement but showed significant long term stent-related morbidity. The second patient suffered a severe procedure related complication due to positioning problems typical for MPS. CONCLUSIONS: Very good short-term success can be achieved with airway stent placement in patients with MPS and severe lower airway stenosis but a high risk of severe complications and important long-term morbidity have to be weighed against potential individual benefit. PMID- 26968076 TI - A multicentre clinical evaluation of paediatric cochlear implant users upgrading to the Nucleus((r)) 6 system. AB - OBJECTIVES: The aim of this study was to investigate whether experienced paediatric cochlear implant users could show benefits to speech perception outcomes from the introduction of noise reduction and automated scene classification technologies as implemented in the Nucleus((r)) 6 sound processor. Previous research with adult cochlear implant users had shown significant improvements in speech intelligibility for listening in noisy conditions and good user acceptance for upgrading to the Nucleus 6 processor. In adults, these improvements for listening in noise were primarily attributed to the use of a range of new input processing technologies including noise reduction, as well as introduction of automatic scene classification technology. METHODS: Experienced paediatric cochlear implant users (n=25) were recruited from four clinics located in three countries. Research participants were evaluated on three occasions, an initial session using their Nucleus 5 sound processor; a second session in which participants used the Nucleus 6 processor programmed with the same technologies as were used in their Nucleus 5 sound processor; and a final session in which participants used the Nucleus 6 processor programmed with the default technologies including automatic scene classification (SCAN) which automatically selects the microphone directionality, noise reduction (SNR-NR), and wind noise reduction (WNR) technologies. Prior to both the second and third evaluations, research participants had approximately two weeks take-home experience with the new system. Speech perception performances on monosyllabic word tests presented in quiet and in noise, and a sentence test presented in noise, were compared across the three processor conditions. Acceptance of the Nucleus 6 default settings was assessed in a final session. RESULTS: No group mean difference in performance was found for monosyllabic words in quiet. A significant improvement in speech perception was found for both monosyllabic words and sentences in noise with the default Nucleus 6 program condition as compared with the Nucleus 5 condition. No acceptance issues were noted for any of the children. CONCLUSIONS: Experienced paediatric cochlear implant users showed a significant improvement in speech perception in listening in noise when upgraded to the Nucleus 6 sound processor primarily due to the introduction of a noise reduction technology, and all children accepted the default program. These findings suggest that school aged children may benefit from upgrading to the Nucleus 6 sound processor using the default program. PMID- 26968077 TI - Serum cytokine biomarkers accurately predict presence of acute otitis media infection and recovery caused by Haemophilus influenzae. AB - OBJECTIVE: We sought to develop an optimal model using a combination of serum biomarker pro-inflammatory and dampening inflammatory cytokine proteins to predict the presence of acute otitis media (AOM) infection and recovery caused by Nontypeable Haemophilus influenzae (NTHi). METHODS: 88 serum samples were studied from 34 children 6-36 months of age at healthy visits, at onset of AOM diagnosed by qualified pediatricians and confirmed by tympanocentesis to be caused by NTHi and follow up 3 weeks to 4 months later. Immunoassays were used to quantitate serum S100A12, IL-10 and sICAM-1 cytokine levels. Middle ear fluids permitted identification of otopathogens. Logistic regression was used to develop a predictive model for infection probability and recovery. RESULTS: A significant association between serum S100A12 and IL-10 cytokine levels as biomarkers of AOM infection was found for NTHi. Almost all NTHi positive AOMs could be predicted by calculations using serum S100A12 and IL-10 levels in a statistical model we derived. Including measurements of sICAM-1 did not improve predictability of NTHi AOM or recovery beyond that achieved using S100A12 and IL-10. The model showed clearly the ability of low biomarker scores to predict cure at follow-up once biomarker lag was correctly modeled. CONCLUSION: We developed a serum molecular biomarker risk score that can predict the presence and recovery from AOM caused by the common respiratory bacteria NTHi that causes the infection in the clinical context of possible AOM. PMID- 26968078 TI - Neurocognitive outcomes after pediatric adenotonsillectomy for obstructive sleep apnea: A systematic review and meta-analysis. AB - OBJECTIVE: To provide an up-to-date systematic review and critical appraisal of prospectively performed studies evaluating neurocognitive function in children treated with adenotonsillectomy. DATA SOURCES: PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library. REVIEW METHODS: Searches were performed from inception through September 2, 2015. RESULTS: Nineteen prospective studies (898 adenotonsillectomy patients) met criteria and reported neurocognitive outcomes. The average age of children was 6.6+/-2.3 years (range 2.5-14 years) and 51.1% were male. Pre- and post-operative data utilizing the Neuropsychological Developmental Assessment score demonstrated an increase from a means+/-standard deviations of 101.5+/-14.7 [95% CI 100.0, 103.0] to 108.8+/-13.4 [95% CI 107.4, 110.2], p-value <0.0001 (375 children, three studies). Pre- and post-operative data utilizing the Stanford-Binet Intelligence Scales (IQ) demonstrated an increase in IQ scores from a means+/-standard deviations of 97.1+/-13.8 [95% CI 91.6, 95.4] to 100.7+/-11.1 [95% CI 100.4, 103.4], p-value <0.0001 (254 children, three studies). The mean pre- and post-adenotonsillectomy apnea-hypopnea index (AHI) decreased from 8.0 to 1.8 (274 children, six studies). CONCLUSIONS: This meta-analysis found an improvement in neurocognitive function and IQ after pediatric adenotonsillectomy, especially in pre-school aged children. However, this must be interpreted with caution as only three studies were performed in pre school aged children. The decreased effectiveness in older children suggests possibly a threshold age when neurocognitive deficits become irreversible. PMID- 26968079 TI - Long-term follow-up of vocal fold movement impairment and feeding after neonatal cardiac surgery. AB - OBJECTIVE: To determine the long-term prognosis of children with vocal fold mobility impairment (VFMI) after cardiac surgery, with respect to time to normal feeding and incidence of admissions for pneumonia and feeding difficulties. METHODS: A retrospective chart review was conducted of all neonates who had otolaryngology exam after cardiac surgery at a tertiary children's hospital from May 2007 to May 2008. Charts were reviewed for demographics, type of cardiac surgery, vocal fold mobility, diet at time of discharge and at last follow-up, time to full oral feeding, and hospital admissions. RESULTS: There were a total of 94 patients included in the study, 17 of whom had VFMI. While significantly more patients with VFMI required modified diet at discharge, 48% compared to 19% of patients with normal vocal fold mobility; there was no statistically significant difference in time to regular diet on long-term follow-up, 0.8 years (VFMI) compared to 0.4 years (normal vocal fold mobility). Of the 25 patients with modified diet or gastrostomy tube at discharge, 52% returned to full feeds within a year. There was no difference in hospitalizations for pneumonia in patients with or without VFMI. However in patients with VFMI, 35% required readmission for feeding difficulty or poor weight gain compared to only 5% in the infants with normal vocal fold mobility. CONCLUSION: After neonatal cardiac surgery, there do not appear to be long-term effects of VFMI with regards to readmission for pneumonia. However, there is an increased risk for hospitalization with respect to feeding difficulties in those neonates with VFMI. The overall prognosis for time to oral feeding is good. PMID- 26968080 TI - Intraoperative hypotension associated with massive deep space neck abscesses in a 9-month old: A case report. AB - The neck is divided into multiple compartments by cervical fasciae. The deep space compartments, which all have a potential for becoming infected, are interconnected, providing a mechanism for the spread of infections. Thus, infections of the deep spaces can lead to devastating consequences, especially when there is extension to the mediastinum. Here we report a case of intraoperative hypotension in a 9-month-old child with extensive bilateral parapharyngeal and retropharyngeal abscesses with mediastinal extension with a focus on when hemodynamic monitoring should be considered. PMID- 26968081 TI - Intraoperative neuroprotective interventions prevent spinal cord ischemia and injury in thoracic endovascular aortic repair. AB - OBJECTIVE: Transient and permanent paraparesis and paraplegia (spinal cord injury [SCI]) are reported in up to 13% of patients undergoing thoracic endovascular aortic repair (TEVAR) for descending thoracic aortic aneurysm, thoracoabdominal aortic aneurysm, and thoracic aortic dissection. We hypothesize that aggressive intraoperative and postoperative neuroprotective interventions prevent or significantly reduce all SCI in TEVAR. METHODS: Using a prospectively maintained, Institutional Review Board-approved database, we retrospectively reviewed all TEVARs performed in a university tertiary referral center from 2005 to 2014 to study the incidence of all transient and permanent lower extremity SCI. Only TEVARs for traumatic aortic tear were excluded. Arch debranching and carotid subclavian bypass were performed before TEVAR in patients with arch involvement. All patients had moderate systemic hypothermia (34 degrees C), mean arterial pressure >=90 mm Hg, and hemoglobin >=10 g/dL. Patients received mannitol (12.5 g), methylprednisolone (30 mg/kg), and naloxone (1 MUg/kg/h). Patients in whom >12 cm of aortic coverage was planned had spinal fluid drained to a pressure of <8 mm Hg intraoperatively and postoperatively until normal leg strength was confirmed. The main outcome measure was transient or permanent SCI. RESULTS: One hundred fifty-five patients had TEVAR between 2005 and 2014. Mean age was 74 years, and 56.1% were male. Descending thoracic aortic aneurysm was present in 91.6%, thoracoabdominal aortic aneurysm in 8.4%, and dissection in 28.8%. Presentation was acute in 42.5%. The procedure included carotid-subclavian bypass in 18.7% of patients. Seventy-two percent of patients had spinal fluid drainage. Mean aortic coverage was 25 cm. Eighty-one percent of patients had >12 cm aortic coverage, and 49% had complete coverage of the thoracic aorta (coverage from subclavian to celiac artery). In-hospital mortality was 1.94%. Stroke occurred in 1.32% of patients. No patient had renal failure. SCI occurred in 0.65% (1 of 154) of patients. CONCLUSIONS: SCI in TEVAR can be significantly reduced by using proactive intraoperative and postoperative neuroprotective interventions that prolong spinal cord ischemic tolerance and increase spinal cord perfusion and oxygen delivery. PMID- 26968082 TI - Evidence for the role of cyclic electron flow in photoprotection for oxygen evolving complex. AB - Cyclic electron flow (CEF) alleviates PSII photo-inhibition under high light by at least two different mechanisms: one is liked to thermal energy dissipation (qE) and the other one is independent of qE. However, the latter mechanism is unclear. Because the photodamage to PSII primarily occurred at the oxygen evolving complex (OEC), and the stability of OEC is dependent on proton gradient across thylakoid membrane (DeltapH), we hypothesize that the CEF-dependent generation of DeltapH can alleviate photodamage to OEC. To test this hypothesis, we determined the effects of antimycin A (AA), methyl viologen (MV), chloramphenicol (CM), nigericin (Nig) on PSII activity and the stability of OEC for leaves of a light-demanding tropical tree species Erythrophleum guineense by the analysis of OKJIP chlorophyll a fluorescence transient. After high light treatment, the stronger decrease in Fv/Fm in the AA-, CM-, MV-, and Nig-treated samples was accompanied with larger photo damage of OEC. The AA-treated samples significantly showed lower CEF activity than the H2O-treated samples. Although the AA-treated leaves significantly showed stronger PSII photo-inhibition and photo-damage of OEC compared to the H2O-treated leaves, the value of non photochemical quenching did not differ between them. Therefore, CEF activity was partly inhibited in the AA-treated samples, and the stronger PSII photo inhibition in the AA-treated leaves was independent of qE. Taking together, we propose a hypothesis that CEF-dependent generation of DeltapH under high light plays an important role in photoprotection for the OEC activity. PMID- 26968083 TI - A possible link between life and death of a xeric tree in desert. AB - Understanding the interactions between drought and tree ontogeny or size remains an essential research priority because size-specific mortality patterns have large impacts on ecosystem structure and function, determine forest carbon storage capacity, and are sensitive to climatic change. Here we investigate a xerophytic tree species (Haloxylon ammodendron (C.A. Mey.)) with which the changes in biomass allocation with tree size may play an important role in size specific mortality patterns. Size-related changes in biomass allocation, root distribution, plant water status, gas exchange, hydraulic architecture and non structural carbohydrate reserves of this xerophytic tree species were investigated to assess their potential role in the observed U-shaped mortality pattern. We found that excessively negative water potentials (<-4.7MPa, beyond the P50leaf of -4.1MPa) during prolonged drought in young trees lead to hydraulic failure; while the imbalance of photoassimilate allocation between leaf and root system in larger trees, accompanied with declining C reserves (<2% dry matter across four tissues), might have led to carbon starvation. The drought-resistance strategy of this species is preferential biomass allocation to the roots to improve water capture. In young trees, the drought-resistance strategy is not well developed, and hydraulic failure appears to be the dominant driver of mortality during drought. With old trees, excess root growth at the expense of leaf area may lead to carbon starvation during prolonged drought. Our results suggest that the drought-resistance strategy of this xeric tree is closely linked to its life and death: well-developed drought-resistance strategy means life, while underdeveloped or overdeveloped drought-resistance strategy means death. PMID- 26968085 TI - Big data, data science, and big contributions. PMID- 26968084 TI - Effect of caspofungin and micafungin in combination with farnesol against Candida parapsilosis biofilms. AB - The in vitro activities of caspofungin and micafungin were determined with and without farnesol against Candida parapsilosis biofilms. Drug interactions were examined using the XTT colorimetric assay-based broth microdilution chequerboard method. Drug-drug interactions were assessed utilising the FICI, Bliss independence models and time-kill experiments. Median sessile MICs of five C. parapsilosis clinical isolates ranged between 32-256 mg/L, 16-512 mg/L and >300 MUM for caspofungin, micafungin and farnesol, respectively. Median MICs for caspofungin and micafungin in combination with farnesol showed 8-64- and 4-64 fold decreases, respectively. Paradoxical growth noticed with both echinocandins was eliminated by farnesol. Based on FICIs for sessile clinical isolates, synergism was observed for caspofungin (range of median FICIs, 0.155-0.5) and micafungin (range of median FICIs, 0.093-0.5). Concordantly, MacSynergy analysis and global fitting of non-linear regression based on a Bliss independence models also showed synergism for caspofungin and micafungin. In line with FICI findings and the Bliss independence model, synergistic interactions were confirmed by time kill experiments. The metabolic activity of fungal cells was significantly inhibited by caspofungin+farnesol at all three tested combinations (4 mg/L+75 MUM, 8 mg/L+75 MUM and 16 mg/L+75 MUM) between 3 and 24 h compared with the control (P<0.05-0.001). Significant inhibition was observed for micafungin+farnesol between 3 and 12h (P<0.001) but not at 24 h. Despite the favourable effect of farnesol in combination with echinocandins, further in vivo studies are needed to confirm its therapeutic advantage in catheter-associated infections caused by C. parapsilosis. PMID- 26968086 TI - Valuing primary care practice. PMID- 26968087 TI - A new method for sudden mechanical perturbation with axial load, to assess postural control in sitting and standing. AB - Sudden application of load along a sagittal or coronal axis has been used to study trunk stiffness, but not axial (vertical) load. This study introduces a new method for sudden-release axial load perturbation. Prima facie validity was supported by comparison with standard mechanical systems. We report the response of the human body to axial perturbation in sitting and standing and within-day repeatability of measures. Load of 20% of body weight was released from light contact onto the shoulders of 22 healthy participants (10 males). Force input was measured via force transducers at shoulders, output via a force plate below the participant, and kinematics via 3-D motion capture. System identification was used to fit data from the time of load release to time of peak load-displacement, fitting with a 2nd-order mass-spring-damper system with a delay term. At peak load-displacement, the mean (SD) effective stiffness measured with this device for participants in sitting was 12.0(3.4)N/mm, and in standing was 13.3(4.2)N/mm. Peak force output exceeded input by 44.8 (10.0)% in sitting and by 30.4(7.9)% in standing. Intra-class correlation coefficients for within-day repeatability of axial stiffness were 0.58 (CI: -0.03 to 0.83) in sitting and 0.82(0.57-0.93) in standing. Despite greater degrees of freedom in standing than sitting, standing involved lesser time, downward displacement, peak output force and was more repeatable in defending upright postural control against the same axial loads. This method provides a foundation for future studies of neuromuscular control with axial perturbation. PMID- 26968088 TI - Outcome of lower trapezius transfer to reconstruct massive irreparable posterior superior rotator cuff tear. AB - BACKGROUND: Management of massive irreparable posterior-superior rotator cuff tear can be very challenging. This study reports the outcome of the lower trapezius transfer to reconstruct massive irreparable posterior-superior rotator cuff tear. METHODS: Included were 33 patients with an average age of 53 years (range, 31-66 years). All patients had symptomatic massive irreparable rotator cuff tear that failed conservative or prior surgical treatment and underwent reconstruction with lower trapezius transfer prolonged by Achilles tendon allograft. The tear was considered irreparable based on the magnetic resonance imaging finding of >=2 full-thickness rotator cuff tears associated with shortening and retraction of the tendon to the level of the glenoid and a high grade of fatty infiltration of the muscles. This was confirmed at the time of the surgery. RESULTS: At an average follow-up of 47 months, 32 patients had significant improvement in pain, subjective shoulder value, and Disabilities of the Arm, Shoulder and Hand score and shoulder range of motion, including flexion, 120 degrees ; abduction, 90 degrees ; and external rotation 50 degrees . One patient, with a body mass index of 36 kg/m(2), required debridement for an infection and then later underwent shoulder fusion. Patients with >60 degrees of preoperative flexion had more significant gains in their range of motion. Shoulder external rotation improved in all patients regardless of the extent of the preoperative loss of motion. CONCLUSIONS: Transfer of the lower trapezius prolonged with Achilles tendon allograft to reconstruct massive irreparable posterior-superior rotator cuff tear may lead to good outcome in most patients, specifically for those who have preoperative flexion of >60 degrees . PMID- 26968090 TI - Short-term outcomes after arthroscopic capsular release for adhesive capsulitis. AB - BACKGROUND: Little is known about the short-term temporal outcomes of an arthroscopic capsular release for adhesive capsulitis (frozen shoulder). Specifically, it is not known how immediate the improvements are and how quickly patients return to normal function after an arthroscopic release. METHODS: The study included 140 shoulders in 133 patients with idiopathic adhesive capsulitis who underwent a complete arthroscopic release of the shoulder capsule, performed by a single surgeon in a day surgery setting. Patient-reported pain and shoulder function were evaluated with the use of Likert scales, and an independent examiner assessed shoulder strength and range of motion preoperatively and at 1 week, 6 weeks, 12 weeks, and 24 weeks postoperatively. RESULTS: Arthroscopic capsular release resulted in immediate improvements in pain, functional outcomes, and range of motion (P < .0001). External rotation increased from 21 degrees +/- 17 degrees (mean +/- standard deviation) to 76 degrees +/- 17 degrees at 1 week. Passive range of shoulder motion improved at 1 week, deteriorated slightly at 6 weeks, and then continued to improve at 12 and 24 weeks. Before surgery, 38% of patients reported that they "always" experienced extreme pain. This proportion reduced to 30% (P < .0001) at 1 week postoperatively and 2% (P < .0001) at 24 weeks postoperatively. There were no complications. CONCLUSIONS: Patients who underwent an arthroscopic capsular release for idiopathic adhesive capsulitis experienced significant reductions in pain, improvements in range of motion, and improvements in overall shoulder function in the first postoperative week. These immediate improvements in pain and function continue to improve at 6, 12, and 24 weeks postoperatively. PMID- 26968089 TI - Arthroplasty for the surgical management of complex proximal humerus fractures in the elderly: a cost-utility analysis. AB - BACKGROUND: Shoulder hemiarthroplasty (HA) has been the standard treatment for complex proximal humerus fractures in the elderly requiring surgery but not amenable to fixation. Reverse total shoulder arthroplasty (RTSA) has also emerged as a costly albeit highly effective alternative. The purpose of this study was to compare the cost-effectiveness of nonoperative fracture care, HA, and RTSA for complex proximal humerus fractures from the perspective of both U.S. payors and hospitals. METHODS: A Markov model was constructed for the treatment alternatives. Costs were expressed in 2013 U.S. dollars and effectiveness in quality-adjusted life-years (QALYs). The principal outcome measure was incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed to evaluate model assumptions. RESULTS: In the base case, from the payor perspective, RTSA was associated with an ICER of $8100/QALY; HA was eliminated from payor analysis as a cost-ineffective strategy. From the hospital perspective, however, HA was not cost-ineffective and the ICER for HA was $36,700/QALY, with RTSA providing incremental effectiveness at $57,400/QALY. RTSA was the optimal strategy in 61% and 54% of payor and hospital probabilistic sensitivity analyses, respectively. The preferred strategy was dependent on associated QALY gains, primary RTSA cost, and failure rates for RTSA. CONCLUSIONS: RTSA can be a cost-effective intervention in the surgical treatment of complex proximal humerus fractures. HA can also be a cost-effective intervention, depending on the cost perspective (cost-ineffective for payor but cost-effective for the hospital). This analysis highlights the opportunities for increased cost-sharing strategies to alleviate the cost burden on hospitals. PMID- 26968092 TI - Exploring the relationship between criminogenic risk assessment and mental health court program completion. AB - The two primary goals of mental health courts are to engage individuals with severe mental illness in the criminal justice system with clinical mental health services and to prevent future involvement with the criminal justice system. An important factor in helping to achieve both goals is to identify participants' level of clinical needs and criminogenic risk/needs. This study seeks to better understand how criminogenic risk affects outcomes in a mental health court. Specifically, we explore if high criminogenic risk is associated with failure to complete mental health court. Our subjects are participants of a municipal mental health court (MHC) who completed the Level of Services Inventory-Revised (LSI-R) upon entry to the program (N=146). We used binary logistic regression to determine the association between termination from the program with the total LSI R. Our findings suggest that, net of prior criminal history, time in the program and clinical services received, high criminogenic risk/need is associated with failure to complete mental health court. In addition to providing clinical services, our findings suggest the need for MHCs to include criminogenic risk assessment to identify criminogenic risk. For participants to succeed in MHCs, both their clinical and criminogenic needs should be addressed. PMID- 26968091 TI - Prevention of postoperative seromas with dead space obliteration: A case-control study. AB - INTRODUCTION: Excision of soft tissue masses in the subcutaneous space is a common surgical procedure. Postoperative seromas may occur and often result in additional visits, procedures, and impaired wound healing. METHODS: A retrospective chart review (2001-2011) identified patients who underwent resection of a soft tissue mass in the subcutaneous tissues. Patients undergoing breast surgery, head and neck surgery, and lymph node dissections were excluded. Patients (n = 100) with seromas were identified. These patients were matched to patients not having postoperative seroma (n = 100). RESULTS: We identified 100 patients with seroma and 100 controls without seroma after soft tissue resection. Patients had no difference in wound characteristics. Patients with a dead space obliterating stitch were less likely to have a postoperative seroma (26% vs 74%, P < 0.001). CONCLUSIONS: Dead space closure was associated with a decreased rate of postoperative seroma in subcutaneous resections. Postoperative seroma was associated with increased cost and provider visits. PMID- 26968093 TI - Acupuncture for substance use disorders: A systematic review and meta-analysis. AB - BACKGROUND: This systematic review aims to estimate the effects of acupuncture for adults with substance use disorders (SUDs). METHODS: We searched 7 electronic databases and bibliographies of previous studies to identify eligible randomized trials. Two independent reviewers screened citations, extracted data, and assessed risks of bias. We performed random effects meta-analyses. We assessed quality of evidence using the GRADE approach. RESULTS: We included 41 studies with 5,227 participants. No significant differences were observed between acupuncture and comparators (passive controls, sham acupuncture, treatment as usual, and active interventions) at post-intervention for relapse (SMD -0.12; 95%CI -0.46 to 0.22; 10 RCTs), frequency of substance use (SMD -0.27; -2.67 to 2.13; 2 RCTs), quantity of substance use (SMD 0.01; -0.40 to 0.43; 3 RCTs), and treatment dropout (OR 0.82; 0.63 to 1.09; 22 RCTs). We identified a significant difference in favor of acupuncture versus comparators for withdrawal/craving at post-intervention (SMD -0.57, -0.93 to -0.20; 20 RCTs), but we identified evidence of publication bias. We also identified a significant difference in favor of acupuncture versus comparators for anxiety at post-intervention (SMD 0.74, -1.15 to -0.33; 6 RCTs). Results for withdrawal/craving and anxiety symptoms were not significant at longer follow-up. Safety data (12 RCTs) suggests little risk of serious adverse events, though participants may experience slight bleeding or pain at needle insertion sites. CONCLUSIONS: Available evidence suggests no consistent differences between acupuncture and comparators for substance use. Results in favor of acupuncture for withdrawal/craving and anxiety symptoms are limited by low quality bodies of evidence. PMID- 26968094 TI - Spatial relationships between alcohol-related road crashes and retail alcohol availability. AB - BACKGROUND: This study examines spatial relationships between alcohol outlet density and the incidence of alcohol-related crashes. The few prior studies conducted in this area used relatively large spatial units; here we use highly resolved units from Melbourne, Australia (Statistical Area level 1 [SA1] units: mean land area=0.5 km(2); SD=2.2 km(2)), in order to assess different micro-scale spatial relationships for on- and off-premise outlets. METHODS: Bayesian conditional autoregressive Poisson models were used to assess cross-sectional relationships of three-year counts of alcohol-related crashes (2010-2012) attended by Ambulance Victoria paramedics to densities of bars, restaurants, and off-premise outlets controlling for other land use, demographic and roadway characteristics. RESULTS: Alcohol-related crashes were not related to bar density within local SA1 units, but were positively related to bar density in adjacent SA1 units. Alcohol-related crashes were negatively related to off-premise outlet density in local SA1 units. CONCLUSIONS: Examined in one metropolitan area using small spatial units, bar density is related to greater crash risk in surrounding areas. Observed negative relationships for off-premise outlets may be because the origins and destinations of alcohol-affected journeys are in distal locations relative to outlets. PMID- 26968095 TI - Determination of Sulfoxaflor in Animal Origin Foods Using Dispersive Solid-Phase Extraction and Multiplug Filtration Cleanup Method Based on Multiwalled Carbon Nanotubes by Ultraperformance Liquid Chromatography/Tandem Mass Spectrometry. AB - In the present study, a rapid analytical method was developed to determine the residue of sulfoxaflor in milk, pork, eggs, porcine liver, porcine kidney, porcine fat, and chicken. The dispersive solid-phase extraction (d-SPE) and multiplug filtration cleanup (m-PFC) based on multiwalled carbon nanotubes (MWCNTs) were compared for sulfoxaflor in the above matrix and then detected by ultraperformance liquid chromatography coupled with tandem mass spectrometry. The analyte was eluted within 5 min using a Waters Acquity UHPLC HSS T3 column under ESI(+) conditions. The limits of detection were 1 MUg kg(-1) for all of the matrices. Good linearities of sulfoxaflor were obtained in the range of 1-100 MUg L(-1), and the correlation coefficients (R(2)) were higher than 0.9988 in all matrices. The average recoveries of the target compound were between 75.5% and 114.9%, and the intraday and interday relative standard deviation values were <14%. Both methods have purification ability. While considering the cost of analysis and the applicability of the method, d-SPE was selected to purify the samples in the present study. The method was successfully used to analyze the residue of sulfoxaflor in foods of animal origin. PMID- 26968096 TI - HDL functionality in reverse cholesterol transport--Challenges in translating data emerging from mouse models to human disease. AB - Whereas LDL-derived cholesterol accumulates in atherosclerotic lesions, HDL particles are thought to facilitate removal of cholesterol from the lesions back to the liver thereby promoting its fecal excretion from the body. Because generation of cholesterol-loaded macrophages is inherent to atherogenesis, studies on the mechanisms stimulating the release of cholesterol from these cells and its ultimate excretion into feces are crucial to learn how to prevent lesion development or even induce lesion regression. Modulation of this key anti atherogenic pathway, known as the macrophage-specific reverse cholesterol transport, has been extensively studied in several mouse models with the ultimate aim of applying the emerging knowledge to humans. The present review provides a detailed comparison and critical analysis of the various steps of reverse cholesterol transport in mouse and man. We attempt to translate this in vivo complex scenario into practical concepts, which could serve as valuable tools when developing novel HDL-targeted therapies. PMID- 26968097 TI - Dietary DHA supplementation causes selective changes in phospholipids from different brain regions in both wild type mice and the Tg2576 mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is of major concern in ageing populations and we have used the Tg2576 mouse model to understand connections between brain lipids and amyloid pathology. Because dietary docosahexaenoic acid (DHA) has been identified as beneficial, we compared mice fed with a DHA-supplemented diet to those on a nutritionally-sufficient diet. Major phospholipids from cortex, hippocampus and cerebellum were separated and analysed. Each phosphoglyceride had a characteristic fatty acid composition which was similar in cortex and hippocampus but different in the cerebellum. The biggest changes on DHA-supplementation were within ethanolamine phospholipids which, together with phosphatidylserine, had the highest proportions of DHA. Reciprocal alterations in DHA and arachidonate were found. The main diet-induced alterations were found in ethanolamine phospholipids, (and included their ether derivatives), as were the changes observed due to genotype. Tg mice appeared more sensitive to diet with generally lower DHA percentages when on the standard diet and higher relative proportions of DHA when the diet was supplemented. All four major phosphoglycerides analysed showed age-dependent decreases in polyunsaturated fatty acid contents. These data provide, for the first time, a detailed evaluation of phospholipids in different brain areas previously shown to be relevant to behaviour in the Tg2576 mouse model for AD. The lipid changes observed with genotype are consistent with the subtle alterations found in AD patients, especially for the ethanolamine phospholipid molecular species. They also emphasise the contrasting changes in fatty acid content induced by DHA supplementation within individual phospholipid classes. PMID- 26968098 TI - Mutations in jasmonoyl-L-isoleucine-12-hydroxylases suppress multiple JA dependent wound responses in Arabidopsis thaliana. AB - Plants rapidly perceive tissue damage, such as that inflicted by insects, and activate several key defense responses. The importance of the fatty acid-derived hormone jasmonates (JA) in dictating these wound responses has been recognized for many years. However, important features pertaining to the regulation of the JA pathway are still not well understood. One key unknown is the inactivation mechanism of the JA pathway and its relationship with plant response to wounding. Arabidopsis cytochrome P450 enzymes in the CYP94 clade metabolize jasmonoyl-L isoleucine (JA-Ile), a major metabolite of JA responsible for many biological effects attributed to the JA signaling pathway; thus, CYP94s are expected to contribute to the attenuation of JA-Ile-dependent wound responses. To directly test this, we created the double and triple knock-out mutants of three CYP94 genes, CYP94B1, CYP94B3, and CYP94C1. The mutations blocked the oxidation steps and caused JA-Ile to accumulate 3-4-fold the WT levels in the wounded leaves. Surprisingly, over accumulation of JA-Ile did not lead to a stronger wound response. On the contrary, the mutants displayed a series of symptoms reminiscent of JA-Ile deficiency, including resistance to wound-induced growth inhibition, decreased anthocyanin and trichomes, and increased susceptibility to insects. The mutants, however, responded normally to exogenous JA treatments, indicating that JA perception or signaling pathways were intact. Untargeted metabolite analyses revealed >40% reduction in wound-inducible metabolites in the mutants. These observations raise questions about the current JA signaling model and point toward a more complex model perhaps involving JA derivatives and/or feedback mechanisms. This article is part of a Special Issue entitled: Plant Lipid Biology edited by Kent D. Chapman and Ivo Feussner. PMID- 26968101 TI - Development and validation of the Korean version of CKD-EPI equation to estimate glomerular filtration rate. AB - BACKGROUND: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was derived mostly from Caucasian, African-American, and Hispanic populations, whereas Asian populations were excluded. The aim of this study was to develop and validate a Korean version of the CKD-EPI equation. METHODS: The study enrolled 960 individuals 18years old and older who underwent chromium-51 ethylenediaminetetraacetic-acid-based glomerular filtration rate (GFR) measurements. They were divided randomly into two groups: a development set (n=768, 80%) and a validation set (n=192, 20%). The Korean CKD-EPI equation was developed using a non-linear mixed-effect model. The performance of the equation was evaluated by calculating the bias (estimated GFR-measured GFR). The +/-10% (P10) and +/-30% (P30) accuracies and root mean square errors (RMSEs) of the original and Korean CKD-EPI equations were compared. RESULTS: The Korean CKD-EPI equation was as follows: male, serum creatinine (Scr) <=80MUmol/L, GFR=141*(Scr/0.9)(-0.642)*(0.993)(Age); male, Scr>80MUmol/L, GFR=141*(Scr/0.9)( 1.128)*(0.993)(Age); female, Scr<=62MUmol/L, GFR=144*(Scr/0.7)( 0.465)*(0.993)(Age); female, Scr>62MUmol/L, GFR=144*(Scr/0.7)( 1.382)*(0.993)(Age). The mean bias (mL/min/1.73m(2)) of the original CKD-EPI equation was -3.0+/-13.5 and that of the Korean CKD-EPI equation -2.3+/-13.3. The P10 and P30 of the original CKD-EPI equation were 33.9% and 82.8%; for the Korean CKD-EPI equation, the corresponding values were 35.4% and 85.9%. The RMSEs of the original and Korean CKD-EPI equations were 13.7 and 13.5, respectively. CONCLUSIONS: The overall analytical performance of the Korean CKD-EPI equation was equivalent to that of the original CKD-EPI equation. The original CKD-EPI equation is therefore also valid for the Korean population. PMID- 26968100 TI - Coenzyme world model of the origin of life. AB - The origin of life means the emergence of heritable and evolvable self reproduction. However the mechanisms of primordial heredity were different from those in contemporary cells. Here I argue that primordial life had no nucleic acids; instead heritable signs were represented by isolated catalytically active self-reproducing molecules, similar to extant coenzymes, which presumably colonized surfaces of oil droplets in water. The model further assumes that coenzyme-like molecules (CLMs) changed surface properties of oil droplets (e.g., by oxidizing terminal carbons), and in this way created and sustained favorable conditions for their own self-reproduction. Such niche-dependent self reproduction is a necessary condition for cooperation between different kinds of CLMs because they have to coexist in the same oil droplets and either succeed or perish together. Additional kinds of hereditary molecules were acquired via coalescence of oil droplets carrying different kinds of CLMs or via modification of already existing CLMs. Eventually, polymerization of CLMs became controlled by other polymers used as templates; and this kind of template-based synthesis eventually resulted in the emergence of RNA-like replicons. Apparently, oil droplets transformed into the outer membrane of cells via engulfing water, stabilization of the surface, and osmoregulation. In result, the metabolism was internalized allowing cells to accumulate free-floating resources (e.g., animoacids, ATP), which was a necessary condition for the development of protein synthesis. Thus, life originated from simple but already functional molecules, and its gradual evolution towards higher complexity was driven by cooperation and natural selection. PMID- 26968099 TI - miRNA regulation of LDL-cholesterol metabolism. AB - In the past decade, microRNAs (miRNAs) have emerged as key regulators of circulating levels of lipoproteins. Specifically, recent work has uncovered the role of miRNAs in controlling the levels of atherogenic low-density lipoprotein LDL (LDL)-cholesterol by post-transcriptionally regulating genes involved in very low-density lipoprotein (VLDL) secretion, cholesterol biosynthesis, and hepatic LDL receptor (LDLR) expression. Interestingly, several of these miRNAs are located in genomic loci associated with abnormal levels of circulating lipids in humans. These findings reinforce the interest of targeting this subset of non coding RNAs as potential therapeutic avenues for regulating plasma cholesterol and triglyceride (TAG) levels. In this review, we will discuss how these new miRNAs represent potential pre-disposition factors for cardiovascular disease (CVD), and putative therapeutic targets in patients with cardiometabolic disorders. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernandez-Hernando and Yajaira Suarez. PMID- 26968102 TI - Multiple approaches to assess fourteen non-invasive serum indexes for the diagnosis of liver fibrosis in chronic hepatitis C patients. AB - BACKGROUND: The aim of this study was to compare fourteen non-invasive indexes/scores: AAR, APRI, Fibroindex, MODEL3, Forns index, FIB4, GUCI, FI, FCI, Pohl score, AP index, CDS, HGM-1 and HGM-2, in order to diagnose the hepatic fibrosis stage in a survey of patients with chronic hepatitis C. METHODS: 84 patients with chronic hepatitis C were studied. Liver fibrosis was staged according to the Scheuer scoring system. The diagnostic accuracy of these indexes/scores was evaluated by AUROC, contingency tables and logistic regression analysis. RESULTS: The best AUROCs (>0.9) to discriminate cirrhosis (F=4), were observed for CDS, FI, AAR, MODEL3, FIB4, HGM-2 and FCI. To discriminate at least advance fibrosis (F>=3), the best AUROCs (>0.89) were for CDS, FI, FIB4, HGM2-2, MODEL3 and FCI. To discriminate at least significant fibrosis (F>=2), the best AUROCs (>0.8) were for FIB4, GUCI, APRI, FI, Forns index, HGM-2 and FCI. Contingency tables and logistic regression analysis supported the results obtained by AUROC. CONCLUSIONS: This study compares the diagnostic performance of fourteen indexes for the diagnosis of liver fibrosis stage in the same group of CHC patients. These results allow the selection of the best indexes for further studies in larger populations, in order to build diagnostic algorithms as an alternative to liver biopsy for fibrosis staging in patients with chronic HCV infection. These algorithms would allow to take therapeutical decisions and the continuous follow-up of hepatic fibrosis in these patients. PMID- 26968103 TI - Genetic polymorphisms in the Wnt/beta-catenin pathway genes as predictors of tumor development and survival in patients with hepatitis B virus-associated hepatocellular carcinoma. AB - OBJECTIVES: Wnt/beta-catenin signaling has a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC). The present study aimed to determine whether genetic variation in the Wnt/beta-catenin signaling pathway is associated with the development and/or progression of HCC and the survival of patients with hepatitis B virus (HBV)-associated HCC. DESIGN AND METHODS: We assessed seven single nucleotide polymorphisms (SNPs) of the AXIN1, AXIN2, CTNNB1, and WNT2 genes in 245 patients with HBV-associated HCC and 483 chronic HBV carriers without HCC. We analyzed the association of each SNP with HCC development or progression and overall survival. RESULTS: The CTNNB1 rs3864004 A allele was associated with a decreased risk of HCC development (P=0.049). Haplotype analysis revealed a significantly higher frequency of CTNNB1 G-A/G-A haplotype at rs3864004 and rs4135385 positions in patients with HCC than in chronic HBV carriers without HCC (P=0.042). The AXIN1 rs1805105 T>C SNP was associated with small tumor size and early tumor stage and the WNT2 rs39315 G allele was associated with advanced tumor stage in HCC. In Kaplan-Meier analysis, carriers of the AXIN1 rs214252 C allele showed longer survival than those with the TT genotype (P=0.020). In multivariate Cox regression analysis, absence of CTNNB1 haplotype A-A at rs3864004 and rs4135385 positions and advanced tumor stage were independent poor predictors of patient survival in patients with HCC. CONCLUSION: These findings suggest that the genetic polymorphisms in CTNNB1 gene might affect tumor development and survival in patients with HBV-associated HCC. PMID- 26968105 TI - A novel FN1 variant associated with familial hematuria: TBMN? AB - OBJECTIVE: Thin basement membrane nephropathy (TBMN), an autosomal dominant inherited condition in general, is characterized clinically by persistent hematuria and pathologically by thinning of glomerular basement membrane. TBMN is occasionally accompanied with proteinuria, hypertension and renal impairment in some cases. The aim of this study is to explore the genetic defect in a Chinese pedigree with familial hematuria. DESIGN AND METHODS: A four-generation Chinese Han pedigree with familial hematuria was recruited. Exome sequencing was conducted in the proband diagnosed as TBMN, followed by verification in the proband and other family members with Sanger sequencing. RESULTS: A novel missense variant, c.4616C>G (p.S1539C), in the fibronectin 1 gene (FN1), was identified, and it co-segregated with the disease condition in the family. It was not observed in 100 normal controls. CONCLUSIONS: A missense variant in the FN1 gene is possibly responsible for familial hematuria or TBMN in this family, which may broaden the phenotype and mutation spectrums of the FN1 gene. A male patient in this family progressed to end-stage renal disease requiring kidney transplantation, supporting that familial hematuria or TBMN may not always be as benign as generally thought. The findings may have new implications for clinical monitoring and genetic counseling of the family, and may also help understand the pathogenesis. PMID- 26968106 TI - Heterophile antibody interference in qualitative urine/serum hCG devices: Case report. AB - OBJECTIVES: This case report investigates the origin of a false positive result on a serum qualitative human chorionic gonadotropin (hCG) device. PATIENT AND METHODS: A 46-year-old woman diagnosed with chronic myeloid leukemia presented with nausea and vomiting. A qualitative serum hCG test was interpreted as positive; however, a quantitative serum hCG test was negative (<5IU/L). To further investigate this discrepancy, the sample was pretreated with heterophilic blocking reagent (HBR). Additionally, the sample was tested on other qualitative hCG devices composed of antibodies from different animal sources. Blocking reagent from an automated quantitative immunoassay was also tested for its ability to inhibit the heterophile antibody interference. RESULTS: The qualitative test result was negative after pretreatment with heterophilic blocking reagent. Other devices composed of antibodies from different animal sources also demonstrated mixed results with the patient's sample. Blocking reagent obtained from the automated quantitative assay inhibited the heterophile antibody interference in the patient's sample. CONCLUSION: This case demonstrates that positive serum point-of-care hCG results should be interpreted with caution and confirmed with a quantitative serum hCG immunoassay when clinical suspicion is raised. PMID- 26968104 TI - Plasma miR-124-3p and miR-16 concentrations as prognostic markers in acute stroke. AB - OBJECTIVES: This study aimed to investigate plasma concentrations of miR-124-3p and miR-16 as prognostic markers in emergency department patients with acute stroke. DESIGN AND METHODS: Plasma concentrations of miR-124-3p and miR-16 of 84 stroke patients (presenting to the emergency department within 24h from onset of symptoms) were determined by RT-qPCR. The primary outcome measure was 3-month mortality and the secondary outcome measure was post-stroke modified Rankin Score (mRS). RESULTS: Twelve patients (14.3%) died within 3months of hospital admission and forty-one (48.8%) patients as achieved a 3-month mRS>2. Median plasma miR-124 3p concentrations were elevated in patients who died compared to patients who survived (p=0.0052), and its levels were found to be higher in patients with a 3 month mRS>2 compared with patients with mRS<=2 (p=0.0312). Higher plasma miR-16 concentrations were observed in patients who survived than in patients who died (p=0.0394), while its concentrations were lower in patients achieving mRS>2 than in patients with mRS<=2 (p=0.0124). For a subgroup of cases presenting to the emergency department within 6h from time of symptom onset (n=36), plasma miR-124 3p concentrations predicted 3-month mortality with an area under the ROC curve of 0.87 (95%CI: 0.72-0.96). CONCLUSIONS: Plasma miR-124-3p and miR-16 are molecular markers which could be useful for the early prediction of mortality and mRS. PMID- 26968107 TI - B-type natriuretic peptide signal peptide (BNPsp) in patients presenting with chest pain. AB - OBJECTIVES: We assessed the ability of B-type natriuretic peptide signal peptide (BNPsp) to assist with the identification of patients with myocardial infarction (MI) and unstable angina pectoris (UAP). DESIGN AND METHODS: We studied 505 patients who presented to hospital within 4h of onset of chest pain suspicious of ACS. Blood samples were drawn at 0, 1, 2 and 24h from presentation and assayed for BNPsp, NT-proBNP, TnI and high sensitivity TnT. The ability of BNPsp and other markers to diagnose acute myocardial infarction (MI) and unstable angina pectoris (UAP) and predict subsequent events within one year was assessed. Statistical analysis was made using ROC AUC in SPSS, v.22. RESULTS: Receiver operator area under the curve (AUC) data for the discrimination of MI was 0.69 for BNPsp and 0.97 for troponin, with BNPsp failing to add to troponin. However, in non-MI patients, BNPsp had discriminative power for UAP (p<0.05), and when combined with presentation values of NT-proBNP, white cell count and potassium into a unique parameter (UARatio), generated an AUC of 0.76 for UAP in patients with normal ECG results (p<0.001). In non-MI patients, the UARatio was significantly predictive of subsequent stroke (AUC=0.70, p<0.05) and heart failure (AUC=0.82, p<0.01) within one year. CONCLUSIONS: In patients with chest pain, BNPsp is predictive of MI but is not a useful adjunct to troponin. However, the ability of BNPsp, in conjunction with NT-proBNP and key analytes, to diagnose UAP and other ischemic syndromes merits further investigation. PMID- 26968108 TI - Serum activin B concentration as predictive biomarker for ectopic pregnancy. AB - We evaluated the diagnostic accuracy of activin B in discriminating tubal ectopic pregnancy (tEP) from intrauterine miscarriages (IUM), and normal viable intrauterine pregnancy (IUP). We included 28 women with tEP, 31 women with IUM, and 29 normal IUP, confirmed both by clinical examination and ultrasonography. Serum activin B concentration was measured at the time of admission using the ELISA kit. The median serum activin B concentration was found to be significantly decreased in both tEP (p=0.004) and IUM (p=0.022) compared to normal IUP. When compared between tEP and IUM, activin B concentrations did not differ significantly. ROC analysis of activin B and free beta-hCG demonstrated AUC of 0.722 and 0.805, respectively to discriminate tEP from viable IUP. The model including both activin B and free beta-hCG improved the discriminating potential with greater AUC (0.824), and specificity (93%) than individual one. To discriminate tEP from IUM, activin B, free beta-hCG and combination of both performed poorly. We conclude that serum activin B concentration is lower in tubal ectopic pregnancy, and can discriminate it from normal pregnancy with moderate accuracy. It also shows improved diagnostic potential along with free beta-hCG, but cannot distinguish tEP from IUM reliably. PMID- 26968109 TI - KIAA0101 mRNA expression in the peripheral blood of hepatocellular carcinoma patients: Association with some clinicopathological features. AB - OBJECTIVES: The development of hepatocellular carcinoma (HCC) is multi-factorial, multi-step and involving many genes. Recent studies have revealed the involvement of KIAA0101 in HCC development and progression. KIAA0101 is involved in the regulation of DNA repair, cell cycle progression, and cell proliferation. This study aims to elucidate the clinicopathological significance of KIAA0101 mRNA expression in the whole blood of HCC patients. DESIGN AND METHODS: This study was conducted on 77 patients with proven HCC who presented to the outpatient clinic at the National Cancer Institute - Cairo University over a period of 8 consecutive months. Thirty patients with cirrhosis and forty apparently healthy volunteers were included as control groups. Detection of KIAA0101 mRNA was done on whole blood collected on EDTA for all patients and control subjects using real time PCR. RESULTS: KIAA0101 mRNA was over-expressed in the HCC group compared to the control groups. Overexpression of KIAA0101 mRNA was significantly associated with distant metastasis, advanced stage, high serum alkaline phosphatase and low serum albumin levels. Both sensitivity and specificity of KIAA0101 mRNA were higher than those of AFP and CEA. CONCLUSION: Being associated with some of the prognostic factors of HCC which reflect tumor progression; as advanced stage, distant metastasis, hypoalbuminemia and elevated serum alkaline phosphatase, together with its relatively high diagnostic performance; KIAA0101 mRNA might be nominated to play a probable role in the diagnosis and prognosis prediction of HCC. Further studies on a wider scale are recommended to confirm these results. PMID- 26968110 TI - Rheumatoid arthritis and antisynthetase syndrome. A three cases report. PMID- 26968111 TI - Trafficking of antigens from gut to sacroiliac joints and spine in reactive arthritis and spondyloarthropathies: Mainly through lymphatics? AB - Bacterial trafficking from gut to mesenteric lymph nodes is physiologic only for a few commensal species, like Alcaligenes which produces antimicrobial-substances inhibiting growth of pathogenic bacteria. In reactive arthritis, some living bacteria transiently manage to travel from gut to joints/enthesis within dendritic cells and/or macrophages. Migration of dead or dormant bacteria outside the gut in spondyloarthropathies, including those associated with Crohn's disease, can occur either through blood or lymphatics. Migration through lymphatics instead of blood depends on the host, but also on the subset of pathogen, as shown for Salmonella. Retrograde trafficking within lymphatics of immune cells infected by dormant or dead bacteria, from mesenteric lymph nodes or thoracic duct to sacroiliac joint and spine, might contribute to axial involvement in some spondyloarthropathies and related disorders, since: 1- large influxes of pathogens can overwhelm lymph nodes, and Yersinia can even replicate within lymph nodes; 2- Whipple cells have been shown to circulate in thoracic duct lymph; 3- expansion of lymphatics is a prominent feature of gastro intestinal inflammation, and obstruction of gut lymphatics a hallmark of Crohn's disease; 4- lymph reflux has been demonstrated in models of mesenteric lymph vessel obstruction; 5- reflux to sacroiliac has been observed in patients with chyluria undergoing lymphography; 6- lymphatics are present in the outer periosteum and paraspinal ligaments surrounding intervertebral discs and connected to thoracic duct. Accordingly, further studies on the trafficking of dendritic cells, macrophages and lymphocytes from gut to joints and spine in animal models of reactive arthritis or spondyloarthropathies should also focus on lymphatic routes. PMID- 26968112 TI - Van Buchem's Disease. PMID- 26968113 TI - Serotonin Is Involved in Autoimmune Arthritis through Th17 Immunity and Bone Resorption. AB - Rheumatoid arthritis is a chronic disease that results in a disabling and painful condition as it progresses to destruction of the articular cartilage and ankylosis of the joints. Although the cause of the disease is still unknown, evidence argues that autoimmunity plays an important part. There are increasing but contradictory views regarding serotonin being associated with activation of immunoinflammatory pathways and the onset of autoimmune reactions. We studied serotonin's involvement during collagen-induced arthritis in wild-type and Tph1( /-) mice, which have markedly reduced peripheral serotonin levels. In wild-type mice, induction of arthritis triggered a robust increase in serotonin content in the paws combined with less inflammation. In Tph1(-/-) mice with arthritis, a marked increase in the clinical and pathologic arthritis scores was noticed. Specifically, in Tph1(-/-) mice with arthritis, a significant increase in osteoclast differentiation and bone resorption was observed with an increase in IL-17 levels in the paws and in Th17 lymphocytes in the draining lymph nodes, whereas T-regulatory cells were dampened. Ex vivo serotonin and agonists of the 5 HT2A and 5-HT2B receptors restored IL-17 secretion from splenocytes and Th17 cell differentiation in Tph1(-/-) mice. These findings indicate that serotonin plays a fundamental role in arthritis through the regulation of the Th17/T-regulatory cell balance and osteoclastogenesis. PMID- 26968115 TI - The influence of potato endophytes on Leptinotarsa decemlineata endosymbionts promotes mortality of the pest. AB - Plants are exposed to pervasive attack by diverse attackers, such as pathogens and pests. But plants have their own endophytic microflora as well as the attacking insects. These microbiomes contact face to face in the nature. It has been found that the endophytic strain Bacillus subtilis 26D increases mortality of Colorado potato beetles, disturbing the development of insect microsymbionts Enterobacter ssp. and Acinetobacter ssp. PMID- 26968116 TI - Editorial Comment. PMID- 26968114 TI - Epigallocatechin-3-Gallate Inhibition of Myeloperoxidase and Its Counter Regulation by Dietary Iron and Lipocalin 2 in Murine Model of Gut Inflammation. AB - Green tea-derived polyphenol (-)-epigallocatechin-3-gallate (EGCG) has been extensively studied for its antioxidant and anti-inflammatory properties in models of inflammatory bowel disease, yet the underlying molecular mechanism is not completely understood. Herein, we demonstrate that EGCG can potently inhibit the proinflammatory enzyme myeloperoxidase in vitro in a dose-dependent manner over a range of physiologic temperatures and pH values. The ability of EGCG to mediate its inhibitory activity is counter-regulated by the presence of iron and lipocalin 2. Spectral analysis indicated that EGCG prevents the peroxidase catalyzed reaction by reverting the reactive peroxidase heme (compound I:oxoiron) back to its native inactive ferric state, possibly via the exchange of electrons. Further, administration of EGCG to dextran sodium sulfate-induced colitic mice significantly reduced the colonic myeloperoxidase activity and alleviated proinflammatory mediators associated with gut inflammation. However, the efficacy of EGCG against gut inflammation is diminished when orally coadministered with iron. These findings indicate that the ability of EGCG to inhibit myeloperoxidase activity is one of the mechanisms by which it exerts mucoprotective effects and that counter-regulatory factors such as dietary iron and luminal lipocalin 2 should be taken into consideration for optimizing clinical management strategies for inflammatory bowel disease with the use of EGCG treatment. PMID- 26968117 TI - The effect of bleaching gel and (940 nm and 980 nm) diode lasers photoactivation on intrapulpal temperature and teeth whitening efficiency. AB - This in vitro study aimed to investigate the whitening efficacy of 940 nm and 980 nm diode laser photoactivation in tooth bleaching by analysing pulp chamber temperature, as well as the change in tooth colour. Root canals of thirty extracted human lower premolars were prepared. Laserwhite* 20 bleaching agent containing 38% of hydrogen peroxide was photoactivated with 7 W output power of 940 nm and 980 nm diode lasers for 120 s. Bleaching gel reduced 27-29% of the temperature from reaching the pulp chamber. For shade assessment, only the groups photoactivated using diode lasers showed statistically significant differences from control group P < 0.001. Within the studied parameters, both 940 nm and 980 nm diode lasers produced a safe pulp temperature increase. Diode laser photoactivation of bleaching gel resulted in more efficient teeth whitening. Photoactivation with 940 nm diode laser yielded the highest change in colour with only minor increase in pulp chamber temperature. PMID- 26968118 TI - Analytical method for 44 pesticide residues in spinach using multi-plug filtration cleanup based on multiwalled carbon nanotubes with liquid chromatography and tandem mass spectrometry detection. AB - Spinach is one of the most commonly planted vegetables worldwide. A high chlorophyll content makes spinach a complicated matrix in pesticide residue analysis. In this study, a rapid clean-up method was developed for the analysis of pesticide multi-residues in spinach followed by liquid chromatography with tandem mass spectrometry. A modified QuEChERS method with multiwalled carbon nanotubes and carbon material was adopted in the multi-Plug Filtration Cleanup procedure. This method was validated for 44 representative pesticides spiked at two concentration levels of 10 and 100 MUg/kg. The pesticides of different physicochemical properties were registered on spinach in China. The recoveries were between 76 and 114% for major pesticides with relative standard deviations of less than 15%, except for quizalofop-P-ethyl, pyrimethanil, and carbendazim. Matrix-matched calibration curves were performed with the coefficients of determination higher than 0.995 for the studied pesticides for concentration levels of 10-500 MUg/kg. The limits of quantitation ranged from 2 to 10 MUg/kg. The developed method was successfully applied to determine pesticide residues in Chinese market spinach samples. PMID- 26968119 TI - Delayed awakening due to stroke. PMID- 26968120 TI - Botulinum toxin in the treatment of orofacial pain. PMID- 26968121 TI - Kinetic studies on degradation of Reactive Red 120 dye in immobilized packed bed reactor by Bacillus cohnii RAPT1. AB - The degradation of Reactive Red 120 using Bacillus cohnii RAPT1 immobilized on polyurethane was studied. Initial experiments indicated that the percentage removal of dye in immobilized batch was significantly higher than batch (without immobilization). The optimum process parameters such as effect of dye concentration, time of immobilization on Poly Urethane Foam, initial inoculum size, pH and temperature for removal of dye were investigated and was found as 200ppm, 36h, 300*10(6) colony forming units/ml, 8.0 and 35 degrees C respectively. Under optimum conditions, 100% removal of dye was obtained within 4h. The kinetics of biodegradation for the batch with free cells and immobilised packed batch was found to be IInd order with kinetic constant and initial rate of reaction as 0.0408, 0.084L/(mgday) and 1632, 3360 (mg/Lday) respectively. PMID- 26968122 TI - Ferritin nanocages: A biological platform for drug delivery, imaging and theranostics in cancer. AB - Nowadays cancer represents a prominent challenge in clinics. Main achievements in cancer management would be the development of highly accurate and specific diagnostic tools for early detection of cancer onset, and the generation of smart drug delivery systems for targeted chemotherapy release in cancer cells. In this context, protein-based nanocages hold a tremendous potential as devices for theranostics purposes. In particular, ferritin has emerged as an excellent and promising protein-based nanocage thanks to its unique architecture, surface properties and high biocompatibility. By exploiting natural recognition of the Transferrin Receptor 1, which is overexpressed on tumor cells, ferritin nanocages may ensure a proper drug delivery and release. Moreover, researchers have applied surface functionalities on ferritin cages for further providing active tumor targeting. Encapsulation strategies of non metal-containing drugs within ferritin cages have been explored and successfully performed with encouraging results. Various preclinical studies have demonstrated that nanoformulation within ferritin nanocages significantly improved targeted therapy and accurate imaging of cancer cells. Aims of this review are to describe structure and functions of ferritin nanocages, and to provide an overview about the nanotechnological approaches implemented for applying them to cancer diagnosis and treatment. PMID- 26968123 TI - Effects of transplanted circulating endothelial progenitor cells and platelet microparticles in atherosclerosis development. AB - BACKGROUND INFORMATION: Atherosclerosis is an inflammatory disease, in which risk factors such as hyperlipidemia and hypertension affect the arterial endothelium, resulting in dysfunction, cell damage or both. The number of circulating endothelial progenitor cells and microparticles provides invaluable outcome prediction for atherosclerosis disease. However, evidence for the therapeutic potential of endothelial progenitor cells and microparticles in atherosclerosis development is limited. Our study was designed to investigate the possible protective role of a cell therapy-based approach, using endothelial progenitor cells and the dual behaviour of circulating platelet microparticles, on atherosclerosis development in hypertensive-hypercholesterolemic hamster model. Consequently, control hamsters received four intravenous inoculations of: (1) 1*10(5) endothelial progenitor cells of healthy origins in one dose per month, during four months of diet-induced atherosclerosis, and after hypertensive hypercholesterolemic diet for further four months; (2) in a second set of experiments, 1*10(5) endothelial progenitor cells of healthy origins or/and 1*10(5) platelet microparticles of atherosclerotic origins were inoculated every other month during hypertensive-hypercholesterolemic diet. RESULTS: Endothelial progenitor cell treatment had the following effects: (1) re-established plasmatic parameters: cholesterol and triglyceride concentrations, blood pressure, heart rate, cytokine and chemokine profiles, platelet microparticle pro-thrombotic activity and endothelial progenitor cell paracrine activity reflected by cytokine/chemokine detection; (2) reduced lipid, macrophage and microparticle accumulation in liver; (3) reduced atherosclerosis development, revealed by decreased lipid, macrophage and microparticle content of arterial wall; (4) induced the recruitment and incorporation of endothelial progenitor cells into liver and arterial wall; (5) improved arterial dysfunction by increasing contraction and relaxation; (6) reduced the protein expression of specific pro inflammatory molecules in liver and arterial wall. Platelet microparticle transplantation aggravated the above-mentioned biomarkers and atherosclerosis process, which were partially reverted with co-inoculation of platelet microparticles and endothelial progenitor cells. CONCLUSIONS: With this study, we demonstrate in a hypertensive-hypercholesterolemic hamster model, that the endothelial progenitor cell-based therapy suppresses the development of atherosclerosis and reduces hepatic lipid and macrophage accumulation with the consequent alleviation of dyslipidaemia and hypertension. SIGNIFICANCE: Our results support the notion that increasing the number of circulating endothelial progenitor cells by different ways could be a promising therapeutic tool for atherosclerosis. PMID- 26968124 TI - Desynchronization of Cartesian k-space sampling and periodic motion for improved retrospectively self-gated 3D lung MRI using quasi-random numbers. AB - PURPOSE: To demonstrate that desynchronization between Cartesian k-space sampling and periodic motion in free-breathing lung MRI improves the robustness and efficiency of retrospective respiratory self-gating. METHODS: Desynchronization was accomplished by reordering the phase (ky ) and partition (kz ) encoding of a three-dimensional FLASH sequence according to two-dimensional, quasi-random (QR) numbers. For retrospective respiratory self-gating, the k-space center signal (DC signal) was acquired separately after each encoded k-space line. QR sampling results in a uniform distribution of k-space lines after gating. Missing lines resulting from the gating process were reconstructed using iterative GRAPPA. Volunteer measurements were performed to compare quasi-random with conventional sampling. Patient measurements were performed to demonstrate the feasibility of QR sampling in a clinical setting. RESULTS: The uniformly sampled k-space after retrospective gating allows for a more stable iterative GRAPPA reconstruction and improved ghost artifact reduction compared with conventional sampling. It is shown that this stability can either be used to reduce the total scan time or to reconstruct artifact-free data sets in different respiratory phases, both resulting in an improved efficiency of retrospective respiratory self-gating. CONCLUSION: QR sampling leads to desynchronization between repeated data acquisition and periodic respiratory motion. This results in an improved motion artifact reduction in shorter scan time. Magn Reson Med 77:787-793, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26968126 TI - Effects of macroporous hydroxyapatite carriers on the growth and function of human hepatoblasts derived from fetal hepatocytes. AB - Improvement of three-dimensional (3D) culture conditions, including substrates for cell growth, is needed for various cell-based applications. In this study, we developed hydroxyapatite (HAp) macroporous carriers having several pore size distributions and tried to obtain the findings about the effective pore sizes for the growth and function of hepatoblasts derived from human fetal hepatocytes. Cellular CYP3A4 activity was significantly enhanced when 20% HAp macroporous carrier was used, reaching 1.49+/-0.28 pmol/10(6) cells/min of benzyloxyresorufin O-dealkylation activity, which is comparable to that of primary human hepatocytes from livers of adult donors. Analysis of the pore size (the radius of curvature) distribution of each HAp carrier using a 3D-electron beam surface roughness analyzer revealed two peaks of pore size distribution at 30-40 MUm and 70-80 MUm, respectively. Thirty-five percent of the pores in the 20% carrier had a size distribution within 50-80 MUm. Especially, pores of 70-80 MUm were more abundant in the 20% HAp carrier than in the 10% and 30% HAp carriers. These results suggested that a HAp carrier with the pore size distribution of 50-80 MUm might be effective for cell growth and function in human hepatoblasts derived from fetal hepatocytes. PMID- 26968125 TI - Optimization of RNA-based c-di-GMP fluorescent sensors through tuning their structural modules. AB - Cyclic diguanylate (c-di-GMP) is a second messenger of bacteria and its detection is an important issue in basic and applied microbiology. As c-di-GMP riboswitch ligand-binding domains (aptamer domains) capture c-di-GMP with high affinity and selectivity, they are promising platforms for the development of RNA-based c-di GMP sensors. We analyzed two previously reported c-di-GMP sensor RNAs derived from the Vc2 riboswitch. We also designed and tested their variants, some of which showed improved properties as RNA-based c-di-GMP sensors. PMID- 26968127 TI - In vitro effects of 1alpha,25(OH)2D3-glycosides from Solbone A (Solanum glaucophyllum leaves extract; Herbonis AG) compared to synthetic 1alpha,25(OH)2D3 on myogenesis. AB - The presence of glycoside derivatives of 1alpha,25(OH)2D3 endows plants to gradual release of the free bioactive form of 1alpha,25(OH)2D3 from its glycoconjugates by endogenous animal tissue glycosidases. This results in increased half-life of the hormone in blood when purified plant fractions are administered for therapeutic purposes. In this work, we evaluated the role 1alpha,25(OH)2D3-glycosides enriched natural product (Solbone A) from Solanum glaucophyllum leaf extract compared with synthetic 1alpha,25(OH)2D3 on myogenic differentiation in C2C12 myoblasts. For these, differentiation markers and myogenic parameters were studied in C2C12 myoblasts. Results showed that Solbone A, likewise the synthetic hormone, increased creatine kinase activity at day 2 after differentiation induction (60%, p<0.05). Solbone A and synthetic 1alpha,25(OH)2D3 increased vitamin D3 receptor protein expression at 10nM (50% and 30%, respectively) and the transcription factor myogenin (80%, p<0.05). However, tropomyosin expression was not affected by both compounds. In addition, myosin heavy chain (MHC) protein expression was increased 30% at day 2 of differentiation. Solbone A or synthetic 1alpha,25(OH)2D3 had no effects on myogenin nor MHC cell localization. Cellular mass increased with myogenesis progression, being Solbone A more effective than synthetic 1alpha,25(OH)2D3. Finally, Solbone A, as well as synthetic 1alpha,25(OH)2D3, augmented the index fusion of cultured muscle fibers. In conclusion, these results demonstrated that Solbone A exhibit at least equal or greater effects on early myoblast differentiation as synthetic hormone, suggesting that plant glycosides could be an effective, accessible and cheaper substitute for synthetic 1alpha,25(OH)2D3 to promote muscle growth. PMID- 26968128 TI - A highly stereoselective synthesis of C-24 and C-25 oxysterols from desmosterol. AB - A new highly stereoselective construction of the side chain of the C-24 and C-25 oxysterols has been achieved by using desmosterol acetate as the starting material and an improved Sharpless catalytic asymmetric dihydroxylation with 100% d.e. (diastereomeric excess) as the key step. The result is much better than the usual asymmetric dihydroxylation procedure. t-Butyl nitrite/2,2,6,6 tetramethylpiperidine N-oxyl radical/FeCl3 catalyst system was developed to activate molecular oxygen for the aerobic oxidation of 24-hydroxycholesterol and the 24-ketocholesterol was obtained in 86.2% yield. The oxidation system has never been reported before. The mechanism for the catalytic aerobic oxidation was also proposed. PMID- 26968129 TI - Design and synthesis of polyhydroxy steroids as selective inhibitors against AKR1B10 and molecular docking. AB - AKR1B10 is a member of the human aldo-keto reductase superfamily which is highly expressed in several types of cancers, and has been regarded as a promising cancer therapeutic target. In this paper, a series of polyhydroxy steroids were designed and synthesized to selectively inhibit AKR1B10 activity. The most selective compound, novel compound 6, has an IC50 of 0.83+/-0.07MUM and a selectivity of more than 120-fold for AKR1B10/AKR1B1. Structure-activity relation analyses indicate that hydroxyl at C-19 can significantly improve the selective inhibition of AKR1B10. The binding mode of AKR1B10 and its inhibitors were studied. PMID- 26968130 TI - Synthesis, NMR and crystal characterization of dimeric terephthalates derived from epimeric 4,5-seco-cholest-3-yn-5-ols. AB - Two dimeric steroidal terephthalates derived from epimeric 4,5-seco-cholest-3-yn 5-ols were prepared starting from cholesterol in a five-step synthetic sequence. X-ray crystallography shows that the obtained compounds display novel supramolecular networks in the solid state in which the facial hydrophobicity of the steroidal skeletons plays an important role. Unambiguous NMR characterization of the obtained dimers is also provided. PMID- 26968131 TI - Histiocytosis with mixed cell populations. AB - Langerhans cell histiocytosis (LCH) and juvenile xanthogranuloma (JXG) are thought to originate from a common stem cell precursor, with divergent differentiation under different microenvironmental conditions. We describe an exceptional case of multiple cutaneous lesions in a 10-year-old boy, in which the coexistence of both LCH and JXG cell populations is found in every single lesion. The presence of Birbeck granules and CD207 (langerin) immunostaining in the LCH component would argue against the diagnosis of indeterminate cell histiocytosis (ICH). This unique case gives additional support to the hypothesis of a potentially common histogenesis for LCH and JXG. PMID- 26968132 TI - Foliar phosphite application has minor phytotoxic impacts across a diverse range of conifers and woody angiosperms. AB - Phytophthora plant pathogens cause tremendous damage in planted and natural systems worldwide. Phosphite is one of the only effective chemicals to control broad-scale Phytophthora disease. Little work has been done on the phytotoxic effects of phosphite application on plant communities especially in combination with plant physiological impacts. Here, we tested the phytotoxic impact of phosphite applied as foliar spray at 0, 12, 24 and 48 kg a.i. ha(-1) . Eighteen month-old saplings of 13 conifer and angiosperm species native to New Zealand, and two exotic coniferous species were treated and the development of necrotic tissue and chlorophyll-a-fluorescence parameters (optimal quantum yield, Fv /Fm ; effective quantum yield of photosystem II, PhiPSII ) were assessed. In addition, stomatal conductance (gs ) was measured on a subset of six species. Significant necrosis assessed by digital image analysis occurred in only three species: in the lauraceous canopy tree Beilschmiedia tawa (8-14%) and the understory shrub Dodonaea viscosa (5-7%) across phosphite concentrations and solely at the highest concentration in the myrtaceous pioneer shrub Leptospermum scoparium (66%). In non-necrotic tissue, Fv /Fm , PhiPSII and gs remained unaffected by the phosphite treatment. Overall, our findings suggest minor phytotoxic effects resulting from foliar phosphite application across diverse taxa and regardless of concentration. This study supports the large-scale use of phosphite as a management tool to control plant diseases caused by Phytophthora pathogens in plantations and natural ecosystems. Long-term studies are required to ascertain potential ecological impacts of repeated phosphite applications. PMID- 26968133 TI - Ethnicity and pre-hospital care for people with suspected cardiac pain: cross sectional study. AB - OBJECTIVES: Few studies have investigated the quality of pre-hospital care by ethnicity. We aimed to investigate ethnic differences in pre-hospital ambulance care of patients with suspected cardiac pain. METHODS: We conducted a cross sectional analysis of retrospective electronic clinical data for patients with suspected cardiac pain over one year (August 2011 to July 2012) extracted from a single regional ambulance service. This included patient demographic data, clinical measurements, drugs administered and outcomes, such as transportation to hospital or referral to primary care. We used multivariate regression to investigate differences in care by ethnicity comparing non-White with White patients. RESULTS: There were 7046 patients with suspected cardiac pain, with 4825 who had ethnicity recorded including 4661 (96.6%) White and 164 (3.4%) non White. After correcting for age, sex, socio-economic status and whether transported to hospital, non-White patients were significantly more likely to have temperature [odds ratio (OR) 2.96, P = 0.007], blood glucose (OR 3.95, P = 0.003), respiratory rate (OR 4.94, P = 0.03) and oxygen saturation (OR 2.43, P = 0.006) recorded. Non-White patients were significantly less likely to be transported to hospital (OR 0.43, P = 0.03). CONCLUSION: There were significant differences in pre-hospital ambulance care for non-White compared with White patients with suspected cardiac pain. These differences could be due to differences in clinical condition or case-mix, language and cultural barriers, limited understanding of appropriate use of health care services, recording bias or true differences in provider management. Further analysis should involve larger and more complete data sets to explore ethnic differences in greater detail. PMID- 26968135 TI - Frequency-dependent alterations in regional homogeneity in major depression. AB - Previous studies using resting-state functional magnetic resonance imaging (fMRI) have found abnormal spontaneous neural activity in patients with major depressive disorder (MDD). Yet, the frequency-dependent neural activity in MDD is largely unknown. Here, we used resting-state fMRI and regional homogeneity (ReHo) methods to investigate spontaneous neural activity in specific frequency bands of 31 MDD patients and 31 age-, gender- and education-matched healthy controls. We examined spontaneous neural activity in three frequency bands: slow-4 (0.027-0.073Hz), slow-5 (0.010-0.027Hz), and the typical band (0.01-0.08Hz). Compared to controls, MDD patients showed increased ReHo in the middle frontal gyrus (MFG) and decreased ReHo in the fusiform and postcentral gyrus at the typical band. Importantly, MDD patients showed increased ReHo in the middle occipital gyrus (MOG) and decreased ReHo in the anterior cingulate cortex (ACC), inferior frontal gyrus (IFG), superior frontal gyrus (SFG) and the bilateral thalamus in the slow 4 band, while they showed increased ReHo in the medial prefrontal cortex (mPFC) in the slow-5 band. Our results suggest that the abnormality of ReHo in MDD is associated with the frequency band and that future studies should take frequency band effect into account when examining spontaneous neural activity. PMID- 26968136 TI - Graphene Porous Foam Loaded with Molybdenum Carbide Nanoparticulate Electrocatalyst for Effective Hydrogen Generation. AB - A facile method is developed for the synthesis of graphene porous foam (Gr PF) loaded with dispersed molybdenum carbide (Mo2 C) nanoparticles; the material exhibits effective catalytic activity in the hydrogen evolution reaction (HER). Mo2 C/Gr PF is synthesized by the carbonization of glucose and the carbothermal reduction of hexaammonium molybdate in a confined space defined by the intervals between sodium chloride nanoparticles. The synthesis in the confined space results in thin Gr PF (~8 nm) loaded with aggregation-free small Mo2 C nanoparticles [(13+/-2) nm]. The overpotential required for a current density of 20 mA cm(-2) in the electrochemical hydrogen generation is as small as 199 mV in acidic solution and 380 mV in basic solution. The performance is superior to that of a Mo2 C/C composite and compares favorably to those reported for Mo2 C nanostructures. The Mo2 C/Gr PF affords stable water electrolysis in both acidic and basic solution and exhibits nearly 100 % faradaic efficiency. The prominent performance, long-term stability, and high faradic efficiency make Mo2 C/Gr PF a promising HER catalyst for practical hydrogen generation from water electrolysis. PMID- 26968134 TI - P66SHC deletion improves fertility and progeric phenotype of late-generation TERC deficient mice but not their short lifespan. AB - Oxidative stress and telomere attrition are considered the driving factors of aging. As oxidative damage to telomeric DNA favors the erosion of chromosome ends and, in turn, telomere shortening increases the sensitivity to pro-oxidants, these two factors may trigger a detrimental vicious cycle. To check whether limiting oxidative stress slows down telomere shortening and related progeria, we have investigated the effect of p66SHC deletion, which has been shown to reduce oxidative stress and mitochondrial apoptosis, on late-generation TERC (telomerase RNA component)-deficient mice having short telomeres and reduced lifespan. Double mutant (TERC(-/-) p66SHC(-/-) ) mice were generated, and their telomere length, fertility, and lifespan investigated in different generations. Results revealed that p66SHC deletion partially rescues sterility and weight loss, as well as organ atrophy, of TERC-deficient mice, but not their short lifespan and telomere erosion. Therefore, our data suggest that p66SHC-mediated oxidative stress and telomere shortening synergize in some tissues (including testes) to accelerate aging; however, early mortality of late-generation mice seems to be independent of any link between p66SHC-mediated oxidative stress and telomere attrition. PMID- 26968137 TI - Are premorbid abnormal personality traits associated with behavioural and psychological symptoms in dementia? AB - OBJECTIVE: The study aims to investigate associations between behavioural and psychological symptoms of dementia (BPSD) and abnormal premorbid personality traits. METHODS: Data were obtained from 217 patients with a diagnosis of probable Alzheimer's disease. Behavioural and psychological symptoms of late onset dementia were assessed with the Neuropsychiatric Inventory. Premorbid personality traits were assessed using the Standardised Assessment of Personality. Abnormal premorbid personality traits were categorised with Diagnostic and Statistical Manual of Mental Disorders fourth edition and International Statistical Classification of Diseases and Related Health Problems 10 diagnostic criteria for personality disorders. RESULTS: Abnormal premorbid personality traits were associated with increased behavioural and psychological symptoms in dementia. Cluster A (solitary/paranoid) premorbid personality traits were associated with anxiety, depression and hallucinations. Cluster C (anxious/dependent) traits were associated with a syndrome of depression. CONCLUSIONS: The presence of Clusters A (solitary/paranoid) and C (anxious/dependent) abnormal premorbid personality traits seems to affect the expression of certain behavioural and psychological symptoms in dementia, depression in particular. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26968138 TI - The impact of psychological distance on integrative internal dialogs. AB - Negotiators more distanced from the negotiated goal more often exhibit integrative behavior, which maximizes both their individual and joint outcomes. Based on the assumption of an analogy between interpersonal negotiations and internal dialogs simulating social relationships, an experiment was carried out. It aimed to verify if psychological distance (proximal vs. distant perspective on the situation enacted in an internal dialog) affects the processes of integration and confrontation and, consequently, increases the frequency of integrative dialogs. Data from 115 participants (56 women) were analyzed. An increase in psychological distance was found to reduce the intensity of the confrontation process and to cause an increase in the number of integrative internal dialogs. PMID- 26968139 TI - Estimation of turbulent kinetic energy using 4D phase-contrast MRI: Effect of scan parameters and target vessel size. AB - Quantifying turbulence velocity fluctuation is important because it indicates the fluid energy dissipation of the blood flow, which is closely related to the pressure drop along the blood vessel. This study aims to evaluate the effects of scan parameters and the target vessel size of 4D phase-contrast (PC)-MRI on quantification of turbulent kinetic energy (TKE). Comprehensive 4D PC-MRI measurements with various velocity-encoding (VENC), echo time (TE), and voxel size values were carried out to estimate TKE distribution in stenotic flow. The total TKE (TKEsum), maximum TKE (TKEmax), and background noise level (TKEnoise) were compared for each scan parameter. The feasibility of TKE estimation in small vessels was also investigated. Results show that the optimum VENC for stenotic flow with a peak velocity of 125cm/s was 70cm/s. Higher VENC values overestimated the TKEsum by up to six-fold due to increased TKEnoise, whereas lower VENC values (30cm/s) underestimated it by 57.1%. TE and voxel size did not significantly influence the TKEsum and TKEnoise, although the TKEmax significantly increased as the voxel size increased. TKE quantification in small-sized vessels (3-5-mm diameter) was feasible unless high-velocity turbulence caused severe phase dispersion in the reference image. PMID- 26968140 TI - A visualization study on two-phase gravity drainage in porous media by using magnetic resonance imaging. AB - Gravity drainage characteristics are important to improve our understanding of gas-liquid or liquid-liquid two-phase flow in porous media. Stable or unstable displacement fronts that controlled by the capillary force, viscous force, gravitational force, etc., are relevant features of immiscible two-phase flow. In this paper, three dimensionless parameters, namely, the gravity number, the capillary number and the Bond number, were used to describe the effect of the above mentioned forces on two-phase drainage features, including the displacement front and final displacing-phase saturation. A series of experiments on the downward displacement of a viscous fluid by a less viscous fluid in a vertical vessel that is filled with quartz beads are performed by using magnetic resonance imaging (MRI). The experimental results indicate that the wetting properties at both high and low capillary numbers exert remarkable control on the fluid displacement. When the contact angle is lower than 90 degrees , i.e., the displaced phase is the wetting phase, the average velocity Vf of the interface of the two phases (displacement front velocity) is observably lower than when the displaced phase is the non-wetting phase (contact angle higher than 90 degrees ). The results show that a fingering phenomenon occurs when the gravity number G is less than the critical gravity number G'=DeltaMU/MUg. Moreover, the higher Bond number results in higher final displacing-phase saturation, whereas the capillary number has an opposite effect. PMID- 26968141 TI - Quantification of breast tumor heterogeneity for ER status, HER2 status, and TN molecular subtype evaluation on DCE-MRI. AB - PURPOSE: Recognizing molecular markers is helpful for guiding treatment plans for breast cancer. This study correlated estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and triple-negative breast cancer (TNBC) statuses to the degree of heterogeneity on breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: A total of 102 biopsy-proven cancers from 102 patients between October 2010 and December 2012 were used in this study, including ER (59 positive, 43 negative), HER2 (47 positive, 55 negative), and TNBC (22 TNBC, 80 non-TNBC). At first, the tumor region was segmented by using a region growing method. Then, the region-based features were extracted by the proposed regionalization method to quantify intra tumoral heterogeneity on breast DCE-MRI. The three-dimensional morphological features (texture features and shape feature) and the pharmacokinetic model were also extracted from the segmented tumor region. After feature extraction, a logistic regression was used to classify ER, HER2, and TNBC statuses respectively. The performances were evaluated by using receiver operating characteristic (ROC) curve analysis. RESULTS: The proposed region-based features achieved the accuracy of 73.53%, 82.35%, and 77.45% for ER, HER2, and TNBC classifications. The corresponding area under the ROC curves (Az) achieves 0.7320, 0.8458, and 0.8328 that were better than those of texture features, shape features, and Tofts pharmacokinetic model. CONCLUSION: The intra-tumoral heterogeneity quantified by the region-based features can be used to reflect the vasculature complexity of different molecular markers and to provide prediction information of cell surface receptors on clinical examination. PMID- 26968142 TI - Accelerated cardiac cine MRI using locally low rank and finite difference constraints. AB - PURPOSE: To evaluate the potential value of combining multiple constraints for highly accelerated cardiac cine MRI. METHODS: A locally low rank (LLR) constraint and a temporal finite difference (FD) constraint were combined to reconstruct cardiac cine data from highly undersampled measurements. Retrospectively undersampled 2D Cartesian reconstructions were quantitatively evaluated against fully-sampled data using normalized root mean square error, structural similarity index (SSIM) and high frequency error norm (HFEN). This method was also applied to 2D golden-angle radial real-time imaging to facilitate single breath-hold whole-heart cine (12 short-axis slices, 9-13s single breath hold). Reconstruction was compared against state-of-the-art constrained reconstruction methods: LLR, FD, and k-t SLR. RESULTS: At 10 to 60 spokes/frame, LLR+FD better preserved fine structures and depicted myocardial motion with reduced spatio-temporal blurring in comparison to existing methods. LLR yielded higher SSIM ranking than FD; FD had higher HFEN ranking than LLR. LLR+FD combined the complimentary advantages of the two, and ranked the highest in all metrics for all retrospective undersampled cases. Single breath-hold multi-slice cardiac cine with prospective undersampling was enabled with in-plane spatio-temporal resolutions of 2*2mm(2) and 40ms. CONCLUSION: Highly accelerated cardiac cine is enabled by the combination of 2D undersampling and the synergistic use of LLR and FD constraints. PMID- 26968143 TI - Compressed sensing for rapid late gadolinium enhanced imaging of the left atrium: A preliminary study. AB - Current late gadolinium enhancement (LGE) imaging of left atrial (LA) scar or fibrosis is relatively slow and requires 5-15min to acquire an undersampled (R=1.7) 3D navigated dataset. The GeneRalized Autocalibrating Partially Parallel Acquisitions (GRAPPA) based parallel imaging method is the current clinical standard for accelerating 3D LGE imaging of the LA and permits an acceleration factor ~R=1.7. Two compressed sensing (CS) methods have been developed to achieve higher acceleration factors: a patch based collaborative filtering technique tested with acceleration factor R~3, and a technique that uses a 3D radial stack of-stars acquisition pattern (R~1.8) with a 3D total variation constraint. The long reconstruction time of these CS methods makes them unwieldy to use, especially the patch based collaborative filtering technique. In addition, the effect of CS techniques on the quantification of percentage of scar/fibrosis is not known. We sought to develop a practical compressed sensing method for imaging the LA at high acceleration factors. In order to develop a clinically viable method with short reconstruction time, a Split Bregman (SB) reconstruction method with 3D total variation (TV) constraints was developed and implemented. The method was tested on 8 atrial fibrillation patients (4 pre-ablation and 4 post ablation datasets). Blur metric, normalized mean squared error and peak signal to noise ratio were used as metrics to analyze the quality of the reconstructed images, Quantification of the extent of LGE was performed on the undersampled images and compared with the fully sampled images. Quantification of scar from post-ablation datasets and quantification of fibrosis from pre-ablation datasets showed that acceleration factors up to R~3.5 gave good 3D LGE images of the LA wall, using a 3D TV constraint and constrained SB methods. This corresponds to reducing the scan time by half, compared to currently used GRAPPA methods. Reconstruction of 3D LGE images using the SB method was over 20 times faster than standard gradient descent methods. PMID- 26968144 TI - Targeted brain activation using an MR-compatible wrist torque measurement device and isometric motor tasks during functional magnetic resonance imaging. AB - Dedicated pairs of isometric wrist flexion tasks, with and without visual feedback of the exerted torque, were designed to target activation of the CBL and BG in healthy subjects during functional magnetic resonance imaging (fMRI). Selective activation of the cerebellum (CBL) and basal ganglia (BG), often implicated in movement disorders such as tremor and dystonia, may help identify pathological changes and expedite diagnosis. A prototyped MR-compatible wrist torque measurement device, free of magnetic and conductive materials, allowed safe execution of tasks during fMRI without causing artifacts. A significant increase of activity in CBL and BG was found in healthy volunteers during a constant torque task with visual feedback compared to a constant torque task without visual feedback. This study shows that specific pairs of motor tasks using MR-compatible equipment at the wrist allow for targeted activation of CBL and BG, paving a new way for research into the pathophysiology of movement disorders. PMID- 26968145 TI - Mapping blood flow directionality in the human brain. AB - Diffusion properties of tissue are often expressed on the basis of directional variance, i.e., diffusion tensor imaging. In comparison, common perfusion weighted imaging such as arterial spin labeling yields perfusion in a scalar quantity. The purpose of this study was to test the feasibility of mapping cerebral blood flow directionality using alternate ascending/descending directional navigation (ALADDIN), a recently-developed arterial spin labeling technique with sensitivity to blood flow directions. ALADDIN was applied along 3 orthogonal directions to assess directional blood flow in a vector form and also along 6 equally-spaced directions to extract blood flow tensor matrix (P) based on a blood flow ellipsoid model. Tensor elements (eigenvalues, eigenvectors, etc) were calculated to investigate characteristics of the blood flow tensor, in comparison with time-of-flight MR angiogram. While the directions of the main eigenvectors were heterogeneous throughout the brain, regional clusters of blood flow directionality were reproducible across subjects. The technique could show heterogeneous blood flow directionality within and around brain tumor, which was different from that of the contralateral normal side. The proposed method is deemed to provide information of blood flow directionality, which has not been demonstrated before. The results warrant further studies to assess changes in the directionality map as a function of scan parameters, to understand the signal sources, to investigate the possibility of mapping local blood perfusion directionality, and to evaluate its usefulness for clinical diagnosis. PMID- 26968147 TI - Transfrontal Transaqueductal, Transtrigonal, and Suboccipital Infratentorial Supracerebellar Endoscopic Fenestration of Posterior Fossa Arachnoid Cysts: Three Surgical Cases. AB - Symptomatic intracranial arachnoid cysts are commonly treated using neuroendoscopy. Cysts located within the posterior fossa may present a greater surgical challenge to the neurosurgeon due to the numerous vital neurovascular structures located within this confined space. Adding neuronavigation during endoscopy helps a neurosurgeon to visualize and utilize both anterior and posterior corridors safely to access and manage these lesions. We present three symptomatic posterior fossa arachnoid cysts that were treated successfully using minimally invasive neuronavigation-guided endoscopic neurosurgery utilizing the anterior transfrontal transaqueductal, anterior transfrontal transtrigonal, and posterior suboccipital infratentorial supracerebellar approaches. PMID- 26968146 TI - Altered intraoperative cerebrovascular reactivity in brain areas of high-grade glioma recurrence. AB - INTRODUCTION: Current MRI sequences are limited in identifying brain areas at risk for high grade glioma recurrence. We employed intraoperative 3-Tesla functional MRI to assess cerebrovascular reactivity (CVR) after high-grade glioma resection and analyzed regional CVR responses in areas of tumor recurrence on clinical follow-up imaging. METHODS: Five subjects with high-grade glioma that underwent an intraoperative Blood Oxygen-Level Dependent (BOLD) MRI CVR examination and had a clinical follow-up of at least 18months were selected from a prospective database. For this study, location of tumor recurrence was spatially matched to the intraoperative imaging to assess CVR response in that particular area. CVR is defined as the percent BOLD signal change during repeated cycles of apnea. RESULTS: Of the 5 subjects (mean age 44, 2 females), 4 were diagnosed with a WHO grade III and 1 subject with a WHO grade IV glioma. Three subjects exhibited a tumor recurrence on clinical follow-up MRI (mean: 15months). BOLD CVR measured in the spatially matched area of tumor recurrence was on average 94% increased (range-32% to 183%) as compared to contralateral hemisphere CVR response, 1.50+/-0.81 versus 1.03+/-0.46 respectively (p=0.31). CONCLUSION: For this first analysis in a small cohort, we found altered intraoperative CVR in brain areas exhibiting high grade glioma recurrence on clinical follow-up imaging. PMID- 26968148 TI - The Relationship between Carotid Stump Pressure and Changes in Motor-Evoked Potentials in Carotid Endarterectomy Patients. AB - Background The threshold of ischemic tolerance has not been completely identified in human clinical studies. Distal carotid artery pressure can be easily measured through the internal shunt tube during carotid endarterectomy (CEA). To confirm the critical threshold of intracranial arterial pressure and its maximum duration, we investigated the distal internal carotid artery (ICA) pressure and motor-evoked potential (MEP) changes during ICA clamping. Material and Methods Between September 2012 and March 2014, 9 patients (10 sides) with carotid stenosis (70-99%) were surgically treated at our hospital. All CEAs were performed under general anesthesia, and we routinely used a carotid shunt with the intraoperative MEP monitors. When the MEP amplitude decreased to < 50% of the control during carotid clamping, the MEP amplitude was defined as significantly reduced. Results The MEP amplitude significantly decreased in 2 of the 10 procedures (20%) during ICA clamping. The mean distal ICA pressure varied widely, ranging from 13 to 48 mm Hg. In seven cases with a mean distal ICA pressure > 20 mm Hg, there were no significant changes in the MEP during ICA clamping. However, there were three cases with a mean distal ICA pressure < 20 mm Hg, and the MEP amplitude significantly decreased in two of those three patients from 4 to 5 minutes after clamping. Conclusions The present study provides considerable information about a higher incidence of MEP amplitude deterioration in CEA patients with a mean distal ICA pressure < 20 mm Hg during ICA clamping. PMID- 26968149 TI - The art of design. PMID- 26968150 TI - Genetic parameters for milk fatty acids, milk yield and quality traits of a Holstein cattle population reared under tropical conditions. AB - Information about genetic parameters is essential for selection decisions and genetic evaluation. These estimates are population specific; however, there are few studies with dairy cattle populations reared under tropical and sub-tropical conditions. Thus, the aim was to obtain estimates of heritability and genetic correlations for milk yield and quality traits using pedigree and genomic information from a Holstein population maintained in a tropical environment. Phenotypic records (n = 36 457) of 4203 cows as well as the genotypes for 57 368 single nucleotide polymorphisms from 755 of these cows were used. Covariance components were estimated using the restricted maximum likelihood method under a mixed animal model, considering a pedigree-based relationship matrix or a combined pedigree-genomic matrix. High heritabilities (around 0.30) were estimated for lactose and protein content in milk whereas moderate values (between 0.19 and 0.26) were obtained for percentages of fat, saturated fatty acids and palmitic acid in milk. Genetic correlations ranging from -0.38 to -0.13 were determined between milk yield and composition traits. The smaller estimates compared to other similar studies can be due to poor environmental conditions, which may reduce genetic variability. These results highlight the importance in using genetic parameters estimated in the population under evaluation for selection decisions. PMID- 26968153 TI - Detection of Echinococcus multilocularis by MC-PCR: evaluation of diagnostic sensitivity and specificity without gold standard. AB - INTRODUCTION: A semi-automated magnetic capture probe-based DNA extraction and real-time PCR method (MC-PCR), allowing for a more efficient large-scale surveillance of Echinococcus multilocularis occurrence, has been developed. The test sensitivity has previously been evaluated using the sedimentation and counting technique (SCT) as a gold standard. However, as the sensitivity of the SCT is not 1, test characteristics of the MC-PCR was also evaluated using latent class analysis, a methodology not requiring a gold standard. MATERIALS AND METHODS: Test results, MC-PCR and SCT, from a previous evaluation of the MC-PCR using 177 foxes shot in the spring (n=108) and autumn 2012 (n=69) in high prevalence areas in Switzerland were used. Latent class analysis was used to estimate the test characteristics of the MC-PCR. Although it is not the primary aim of this study, estimates of the test characteristics of the SCT were also obtained. RESULTS AND DISCUSSION: This study showed that the sensitivity of the MC-PCR was 0.88 [95% posterior credible interval (PCI) 0.80-0.93], which was not significantly different than the SCT, 0.83 (95% PCI 0.76-0.88), which is currently considered as the gold standard. The specificity of both tests was high, 0.98 (95% PCI 0.94-0.99) for the MC-PCR and 0.99 (95% PCI 0.99-1) for the SCT. In a previous study, using fox scats from a low prevalence area, the specificity of the MC-PCR was higher, 0.999% (95% PCI 0.997-1). One reason for the lower estimate of the specificity in this study could be that the MC-PCR detects DNA from infected but non-infectious rodents eaten by foxes. When using MC-PCR in low prevalence areas or areas free from the parasite, a positive result in the MC-PCR should be regarded as a true positive. CONCLUSION: The sensitivity of the MC-PCR (0.88) was comparable to the sensitivity of SCT (0.83). PMID- 26968152 TI - Self-Reported bruxism and associated factors in Israeli adolescents. AB - Little is known about the epidemiological characteristics of sleep and awake bruxism (SB and AB) in adolescents. The aims of the study were: to assess the prevalence rates of self-reported SB and AB in Israeli adolescents; to determine the associations between SB/AB and several demographical, exogenous and psychosocial factors in Israeli adolescents; and to investigate the possible concordance between SB and AB. The study made use of a questionnaire. The study population included 1000 students from different high schools in the centre of Israel. Prevalence of self-reported SB and AB in the Israeli adolescents studied was 9.2% and 19.2%, respectively. No gender difference was found regarding the prevalence of SB and AB. Multiple variable regression analysis revealed that the following predicting variables were related to SB: temporomandibular joint sounds (P = 0.002) and feeling stressed (P = 0.001). The following predicting variables were related to AB: age (P = 0.018), temporomandibular joint sounds (P = 0.002), oro-facial pain (P = 0.006), and feeling stressed (P = 0.002) or sad (P = 0.006). A significant association was found between SB and AB; that is, an individual reporting SB had a higher probability of reporting AB compared with an individual who did not report SB (odds ratio = 5.099). Chewing gum was the most common parafunction reported by adolescents. The results of this study demonstrate that self-reports of AB and SB are common in the Israeli adolescents population studied and are not related to gender. The significant correlation found between SB and AB may be a confounding bias that affects proper diagnosis of bruxism through self-reported questionnaires only. PMID- 26968151 TI - An examination of the language construct in NIMH's research domain criteria: Time for reconceptualization! AB - The National Institute of Mental Health's Research Domain Criteria (RDoC) Initiative "calls for the development of new ways of classifying psychopathology based on dimensions of observable behavior." As a result of this ambitious initiative, language has been identified as an independent construct in the RDoC matrix. In this article, we frame language within an evolutionary and neuropsychological context and discuss some of the limitations to the current measurements of language. Findings from genomics and the neuroimaging of performance during language tasks are discussed in relation to serious mental illness and within the context of caveats regarding measuring language. Indeed, the data collection and analysis methods employed to assay language have been both aided and constrained by the available technologies, methodologies, and conceptual definitions. Consequently, different fields of language research show inconsistent definitions of language that have become increasingly broad over time. Individually, they have also shown significant improvements in conceptual resolution, as well as in experimental and analytic techniques. More recently, language research has embraced collaborations across disciplines, notably neuroscience, cognitive science, and computational linguistics and has ultimately re-defined classical ideas of language. As we move forward, the new models of language with their remarkably multifaceted constructs force a re-examination of the NIMH RDoC conceptualization of language and thus the neuroscience and genetics underlying this concept. (c) 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. PMID- 26968154 TI - Seroepidemiology of toxoplasmosis in rural and urban communities from Los Rios Region, Chile. AB - BACKGROUND: Toxoplasmosis is a prevalent protozoan infection with a complex lifecycle and wide profile of risk factors. The impact of congenital infection is well documented; however, there is increasing evidence of a much broader range of potential health outcomes and the need to improve our understanding of the transmission patterns and infection sources in the overall population. This study examined the epidemiology of toxoplasmosis in distinct community types from a highly endemic area of Chile. METHODS: A cross-sectional serosurvey was carried out in households from urban slums, rural villages, and farms which included collection of blood samples, as well as data on sociodemographic, behavioral, and spatial variables. Blood samples were analyzed for the presence of T. gondii specific IgG antibodies. Avidity index was obtained for IgG-positive samples. Mixed-effects regression modeling was used to identify associations with relevant risk factors. RESULTS: Crude seroprevalence was 55.9% (95% CI: 52.6-59.1%) with no difference by community type. Results are indicative of early exposure to the parasite, including 40% of 13- to 17-year olds who were already seropositive. Sociodemographic factors associated with seropositivity included age, occupations, and income. However, sex modified the effect of occupation as well as of income. Practices associated with increased seropositivity were consumption of sheep and locally produced vegetables as well as cleaning household barns or sheds. Boiling water for household use was a protective factor. Living on a sloped terrain without vegetation was a protective factor, while living in an area with high flow accumulation index was a risk factor. CONCLUSIONS: Seroprevalence of infection was high in both rural and urban slum communities with unique risk factor profiles for each community type. Findings highlight the role of the household and the community environment as influential factors in the epidemiology of the infection. Increasing awareness is needed at the health care and public health levels to establish disease burden and options for suitable control programs. PMID- 26968155 TI - Long-term trends of suicide by choice of method in Norway: a joinpoint regression analysis of data from 1969 to 2012. AB - BACKGROUND: Suicide mortality and the rates by specific methods in a population may change over time in response to concurrent changes in relevant factors in society. This study aimed to identify significant changing points in method specific suicide mortality from 1969 to 2012 in Norway. METHOD: Data on suicide mortality by specific methods and by sex and age were retrieved from the Norwegian Cause-of-Death Register. Long-term trends in age-standardized rates of suicide mortality were analyzed by using joinpoint regression analysis. RESULTS: The most frequently used suicide method in the total population was hanging, followed by poisoning and firearms. Men chose suicide by firearms more often than women, whereas poisoning and drowning were more frequently used by women. The joinpoint analysis revealed that the overall trend of suicide mortality significantly changed twice along the period of 1969 to 2012 for both sexes. The male age-standardized suicide rate increased by 3.1% per year until 1989, and decreased by 1.2% per year between 1994 and 2012. Among females the long-term suicide rate increased by 4.0% per year until 1988, decreased by 5.5% through 1995, and then stabilized. Both sexes experienced an upward trend for suicide by hanging during the 44-year observation period, with a particularly significant increase in 15-24 year old males. The most distinct change among men was seen for firearms after 1988 with a significant decrease through 2012 of around 5% per year. For women, significant reductions since 1985-88 were observed for suicide by drowning and poisoning. CONCLUSIONS: The present study demonstrates different time trends for different suicide methods with significant reductions in suicide by firearms, drowning and poisoning after the peak in the suicide rate in the late 1980s. Suicide by means of hanging continuously increased, but did not fully compensate for the reduced use of other methods. This lends some support for the effectiveness of method-specific suicide preventive measures, such as restrictions to the access to firearms, which had been implemented in Norway during the relevant time period. PMID- 26968156 TI - Lack of efficacy of imiquimod in patients with basal cell carcinoma previously treated with rituximab for B cell lymphoma: two case reports. AB - BACKGROUND: Non-Hodgkin lymphomas are a heterogeneous group, which involve either B or T lymphocytes. The most used treatment is a chemotherapy regimen, which includes cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone combined with rituximab - a monoclonal antibody specific for CD20 - an antigen expressed on B lymphocyte membrane. Nonmelanoma skin cancers are the most common forms in patients who have lymphomas. CASE PRESENTATION: We reported the cases of two Caucasian men affected by non-Hodgkin disease, treated with chemotherapy and rituximab. After treatment, they both presented superficial basal cell carcinoma and we prescribed imiquimod 5 % cream. Unfortunately, the drug was not effective in either patient and the tumors were excised. CONCLUSIONS: We speculated about the effect of rituximab on B lymphocytes, on a particular population of T cells and on antigen-presenting dendritic cells that may have determined a lower expression of some surface antigens involved in antigen presentation. These cells are the specific targets of imiquimod to promote skin cancer cells apoptosis. A lack of action by imiquimod on skin cancer after treatment with rituximab is likely due to its transitory inhibitory effects on lymphocytes and Langherans cells. Further studies could be useful to understand the mechanism behind the lack of response. PMID- 26968158 TI - De novo transcriptome assembly of the grapevine phylloxera allows identification of genes differentially expressed between leaf- and root-feeding forms. AB - BACKGROUND: Grapevine phylloxera, an insect related to true aphids, is a major historic pest of viticulture only controlled through the selection of resistant rootstocks or through quarantine regulations where grapevine is cultivated own rooted. Transcriptomic data could help understand the bases of its original life traits, including a striking case of polyphenism, with forms feeding on roots and forms feeding in leaf-galls. Comparisons with true aphids (for which complete genomes have been sequenced) should also allow to link differences in life-traits of the two groups with changes in gene repertoires or shifts in patterns of expression. RESULTS: We sequenced transcriptomes of the grapevine phylloxera (Illumina technology), choosing three life-stages (adults on roots or on leaf galls, and eggs) to cover a large catalogue of transcripts, and performed a de novo assembly. This resulted in 105,697 contigs, which were annotated: most contigs had a best blastx hit to the pea aphid (phylogenetically closest complete genome), while very few bacterial hits were recorded (except for Probionibacterium acnes). Coding sequences were predicted from this data set (17,372 sequences), revealing an extremely high AT-bias (at the third codon position). Differential expression (DE) analysis among root-feeding and gall feeding showed that i) the root-feeding form displayed a much larger number of differentially expressed transcripts ii) root-feeding biased genes were enriched in some categories, for example cuticular proteins and genes associated with cell cell signaling iii) leaf-galling-biased genes were enriched in genes associated with the nucleus and DNA-replication, suggesting a metabolism more oriented towards fast and active multiplication. We also identified a gene family with a very high expression level (copies totaling nearly 10% of the reads) in the grapevine phylloxera (both in root and leaf galling forms), but usually expressed at very low levels in true aphids (except in sexual oviparous females). These transcripts thus appear to be associated with oviparity. CONCLUSIONS: Our study illustrated major intraspecific changes in transcriptome profiles, related with different life-styles (and the feeding on roots versus in leaf-galls). At a different scale, we could also illustrate one major shift in expression levels associated with changes in life-traits that occurred along evolution and that respectively characterize (strictly oviparous) grapevine phylloxera and (mostly viviparous) true aphids. PMID- 26968159 TI - Symptom severity of patients with advanced cancer in palliative care unit: longitudinal assessments of symptoms improvement. AB - BACKGROUND: This study assessed the symptom severity of patients with advanced cancer in a palliative care unit and explored the factors associated with symptom improvement. METHODS: This study was conducted in a palliative care unit in Taiwan between October 2004 and December 2009. Symptom intensity was measured by the "Symptom Reporting Form", and graded on a scale of 0 to 4 (0 = none, and 4 = extreme). These measures were assessed on the 1(st), 3(rd), 5(th), and 7(th) Day in the palliative care unit. The study data comprised routine clinical records and patients' demographic data. Generalized estimating equation (GEE) was used to assess the symptom improvement, and investigate the factors associated with the symptom reporting form scores. RESULTS: Among the 824 recruited patients with advanced cancer, pain (78.4%), anorexia (64.4%) and constipation (63.5%) were the most common and severe symptom. After controlling for other factors in the multivariate GEE model, the day of palliative care administration was a significant factor associated with all of the scales, except Days 7 on the dyspnoea and oedema scales and Day 5 on the anxiety scale. In addition, patients aged >= 65 years exhibited significantly lower scores on the pain, sleep disturbance, depression, and anxiety scales than did those aged < 65 years. Moreover, female patients exhibited higher scores on the vomiting, anorexia, oedema, depression, and anxiety scales than did male patients. Furthermore, patients with gastrointestinal tract cancer exhibited higher scores on the constipation, vomiting, anorexia, oedema, depression, and anxiety scales and lower scores on the dyspnoea scale than did those with lung cancer. Patients with breast cancer exhibited higher scores on the oedema scale and lower scores on the anxiety scale. Patients with genitourinary cancer exhibited higher scores on the vomiting and oedema scales and lower scores on the dyspnoea scale. Patients with head, neck, and oral cancer exhibited lower scores on the oedema scale alone. CONCLUSION: The symptom severity declined during the first week in the palliative care unit. In addition, differences in sex and primary cancer sites may contribute to varying degrees of symptom improvement. PMID- 26968157 TI - Scoping review of complexity theory in health services research. AB - BACKGROUND: There are calls for better application of theory in health services research. Research exploring knowledge translation and interprofessional collaboration are two examples, and in both areas, complexity theory has been identified as potentially useful. However, how best to conceptualize and operationalize complexity theory in health services research is uncertain. The purpose of this scoping review was to explore how complexity theory has been incorporated in health services research focused on allied health, medicine, and nursing in order to offer guidance for future application. Given the extensiveness of how complexity theory could be conceptualized and ultimately operationalized within health services research, a scoping review of complexity theory in health services research is warranted. METHODS: A scoping review of published research in English was conducted using CINAHL, EMBASE, Medline, Cochrane, and Web of Science databases. We searched terms synonymous with complexity theory. RESULTS: We included 44 studies in this review: 27 were qualitative, 14 were quantitative, and 3 were mixed methods. Case study was the most common method. Long-term care was the most studied setting. The majority of research was exploratory and focused on relationships between health care workers. Authors most commonly used complexity theory as a conceptual framework for their study. Authors described complexity theory in their research in a variety of ways. The most common attributes of complexity theory used in health services research included relationships, self-organization, and diversity. A common theme across descriptions of complexity theory is that authors incorporate aspects of the theory related to how diverse relationships and communication between individuals in a system can influence change. CONCLUSION: Complexity theory is incorporated in many ways across a variety of research designs to explore a multitude of phenomena.. Although complexity theory shows promise in health services research, particularly related to relationships and interactions, conceptual confusion and inconsistent application hinders the operationalization of this potentially important perspective. Generalizability from studies that incorporate complexity theory is, therefore, difficult. Heterogeneous conceptualization and operationalization of complexity theory in health services research suggests there is no universally agreed upon approach of how to use this theory in health services research. Future research should include clear definitions and descriptions of complexity and how it was used in studies. Clear reporting will aid in determining how best to use complexity theory in health services research. PMID- 26968161 TI - What helps or hinders the transformation from a major tertiary center to a major trauma center? Identifying barriers and enablers using the Theoretical Domains Framework. AB - BACKGROUND: Major Trauma Centers (MTCs), as part of a trauma system, improve survival and functional outcomes from injury. Developing such centers from current teaching hospitals is likely to generate diverse beliefs amongst staff. These may act as barriers or enablers. Prior identification of these may make the service development process more efficient. The importance of applying theory to systematically identify barriers and enablers to changing clinical practice in emergency medicine has been emphasized. This study systematically explored theory based barriers and enablers towards implementing the transformation of a tertiary hospital into a MTC. Our goal was to demonstrate the use of a replicable method to identify targets that could be addressed to achieve a successful transformation from an organization evolved to provide a particular type of clinical care into a clinical system with different demands, requirements and expectations. METHODS: The Theoretical Domains Framework (TDF) is a tool designed to elicit and analyze beliefs affecting behavior. Semi-structured interviews based around the TDF were conducted in a major tertiary hospital in Scotland due to become a MTC with a purposive sample of major stakeholders including clinicians and nurses from specialties involved in trauma care, clinical managers and administration. Belief statements were identified through qualitative analysis, and assessed for importance according to prevalence, discordance and evidence base. RESULTS AND DISCUSSION: 1728 utterances were recorded and coded into 91 belief statements. 58 were classified as important barriers/enablers. There were major concerns about resource demands, with optimism conditional on these being met. Distracting priorities abound within the Emergency Department. Better communication is needed. Staff motivation is high and they should be engaged in skills development and developing performance improvement processes. CONCLUSIONS: This study presents a systematic and replicable method of identifying theory-based barriers and enablers towards complex service development. It identifies multiple barriers/enablers that may serve as a basis for developing an implementation intervention to enhance the development of MTCs. This method can be used to address similar challenges in developing specialist centers or implementing clinical practice change in emergency care across both developing and developed countries. PMID- 26968160 TI - Novel spotted fever group rickettsiae in Haemaphysalis qinghaiensis ticks from Gansu, Northwest China. AB - BACKGROUND: Rickettsia spp. are obligate intracellular bacteria and well known as transmitted by arthropods. These pathogens have a broad geographic distribution and a high degree of biological and clinical diversity. This study was conducted to determine the prevalence and molecular characterization of Rickettsia spp. in ticks collected from Gansu, where Borrelia burgdorferi sensu lato and Anaplasma phagocytophilum were previously reported in ticks and ruminants. METHODS: A total of 1,583 questing Haemaphysalis qinghaiensis ticks were collected and tested for the presence of Rickettsia spp. gltA gene by PCR. Samples positive for gltA were examined by specific primers targeted for the ompA gene of SFG rickettsiae. The infections were further validated by sequencing and positive samples were genetically characterized based on the gltA and ompA genes. RESULTS: In total, Rickettsia spp. infection was found in 179 (18.5 %) H. qinghaiensis tick pools by using PCR and primers specific for the gltA gene. Of those, 157 (16.3 %) tick pools were positive for SFG rickettsiae by PCR based on ompA gene. Amplification and molecular analysis of the nucleotide sequences of gltA and ompA genes indicated three potential novel spotted fever group rickettsiae in H. qinghaiensis ticks. These three potential novel spotted fever group rickettsiae were clustered together in a subgroup, which represents a sister taxon to and separates from other known four SFG rickettsiae subgroups. CONCLUSIONS: This study revealed a high infection rate of SFG rickettsiae in H. qinghaiensis ticks in northwest China. Three potential novel spotted fever group rickettsiae classified into a novel SFG rickettsiae subgroup were identified and named "Candidatus Rickettsia gannanii" related strains in recognition of the location where it was first detected. PMID- 26968162 TI - Acute cholangitis in an old patient with Crigler-Najjar syndrome type II - a case report. AB - BACKGROUND: Crigler-Najjar syndrome (CN) is a very rare genetic disorder characterized by an inability to conjugate bilirubin. Contrary to CN type I, patients with CN II exhibit residual capacity to conjugate bilirubin and may present a normal life expectancy. CASE PRESENTATION: We report an unusual late diagnosis of CN type II in an 80-year-old female admitted with severe acute cholangitis. While the patient present typical clinical and radiologic signs of bile duct obstruction and cholangitis, her blood analysis showed severe unconjugated hyperbilirubinemia. Endoscopic retrograde cholangiopancreatography confirmed the diagnosis and allowed therapeutic intervention. The anatomopathologic examination of her gallbladder following cholecystectomy showed signs of chronic cholecystitis. CONCLUSION: The risk of gallstone disease may be increased in patients with CN syndrome. While unusual, we alert to this curious and potential life-threatening presentation. PMID- 26968166 TI - Characteristics and Correlates of Word Use in Physician-Patient Communication. AB - BACKGROUND: Numerous studies have described and evaluated communication in healthcare contexts, but these studies have focused on broad content and complex units of behavior. Growing evidence reveals the predictive power and importance of precise linguistic characteristics of communication. PURPOSE: This study aims to document characteristics, predictors, and correlates of word use within specific linguistic categories by physicians and patients during a healthcare visit. METHODS: Conversations between patients (n = 145) and their physician (n = 6) were audio recorded, transcribed, and analyzed using Linguistic Inquiry Word Count software. Patients also completed questionnaires prior to and immediately following the visit and (for a subset of patients) at a follow-up visit, which assessed patients' demographics, how much they liked the physician, and self reported adherence. Physicians completed a questionnaire following the initial visit that assessed the patient's health status, the physician's optimism regarding the upcoming treatment, and satisfaction with the productivity of the visit. RESULTS: Patients and physicians differed in the extent of their word use in key linguistic categories, while also maintaining significant linguistic synchrony. Demographic characteristics and health status predicted variability in patients' and physicians' word use, and word use predicted key visit outcomes. Most notably, patients liked their physician more when physicians used fewer negative emotion words and were less adherent when physicians used more singular first-person pronouns. CONCLUSIONS: These findings reveal patterns in the way physicians speak to patients who vary in their demographic characteristics and health status and point to potentially fruitful targets for linguistic interventions with both physicians and patients. PMID- 26968164 TI - A de novo CTNNB1 nonsense mutation associated with syndromic atypical hyperekplexia, microcephaly and intellectual disability: a case report. AB - BACKGROUND: In addition to its role in cell adhesion and gene expression in the canonical Wingless/integrated Wnt signaling pathway, beta-catenin also regulates genes that underlie the transmission of nerve impulses. Mutations of CTNNB1 (beta catenin) have recently been described in patients with a wide range of neurodevelopmental disorders (intellectual disability, microcephaly and other syndromic features). We for the first time associate CTNNB1 mutation with hyperekplexia identifying it as an additional candidate for consideration in patients with startle syndrome. CASE PRESENTATION: We describe an 11 year old male Polish patient with a de novo nonsense mutation in CTNNB1 who in addition to the major features of CTNNB1-related syndrome including intellectual disability and microcephaly, exhibited hyperekplexia and apraxia of upward gaze. The patient became symptomatic at the age of 20 months exhibiting delayed speech and psychomotor development. Social and emotional development was normal but mild hyperactivity was noted. Episodic falls when startled by noise or touch were observed from the age of 8.5 years, progressively increasing but never with loss of consciousness. Targeted gene panel next generation sequencing (NGS) and patient-parents trio analysis revealed a heterozygous de novo nonsense mutation in exon 3 of CTNNB1 identifying a novel association of beta-catenin with hyperekplexia. CONCLUSION: We report for the first time a clear association of mutation in CTNNB1 with an atypical syndromic heperekplexia expanding the phenotype of CTNNB1-related syndrome. Consequently CTNNB1 should be added to the growing list of genes to be considered as a cause of startle disease or syndromic hyperekplexia. PMID- 26968165 TI - Vitamin D supplementation in breastfed infants from Montreal, Canada: 25 hydroxyvitamin D and bone health effects from a follow-up study at 3 years of age. AB - Whether infant vitamin D supplementation may have long-term bone benefits is unclear. In this study, breastfed infants who received vitamin dosages greater than 400 IU/day did not have higher bone mineralization at 3 years. This study provides important data to inform pediatric public health recommendations for vitamin D. INTRODUCTION: North American health agencies recommend breastfed infants should be supplemented with 400 IU of vitamin D/day to support bone health. Few studies examined the long-term benefits of early life vitamin D supplementation on bone mineralization. The objective of this study was to determine if a dose-response relationship exists between infant vitamin D supplementation, vitamin D status, and bone outcomes at 3 years of age. METHODS: This was a double-blind randomized trial of 132, 1-month-old healthy, breastfed infants from Montreal, Canada, between 2007 and 2010. In this longitudinal analysis, 87 infants (66 %) returned for follow-up at 3 years of age, between 2010 and 2013. At 1 month of age, participants were randomly assigned to receive oral cholecalciferol (vitamin D3) supplements of 400, 800, 1200, or 1600 IU/day until 12 months of age. Lumbar spine vertebrae 1-4 (LS) bone mineral density (BMD), LS and whole body bone mineral content (BMC), and mineral accretion were measured by dual-energy x-ray absorptiometry at 3 years. RESULTS: At follow-up, the treatment groups were similar in terms of diet, sun exposure, and demographics. There were no significant differences among the groups in LS or whole body BMC, BMD, or accretion. Although, 25(OH)D concentrations were not different among the groups, higher doses (1200 and 1600 IU/day) achieved higher 25(OH)D area under the curve from 1 to 36 months vs. 400 IU/day. CONCLUSIONS: This is the first longitudinal follow-up of an infant vitamin D dose-response study which examines bone mineralization at 3 years of age. Dosages higher than 400 IU/day do not appear to provide additional benefits to the bone at follow-up. Larger studies with more ethnically diverse groups are needed to confirm these results. PMID- 26968167 TI - "There is no free here, you have to pay": actual and perceived costs as barriers to intermittent preventive treatment of malaria in pregnancy in Mali. AB - BACKGROUND: "There is no free here," the words of a Malian husband, illustrate how perceptions of cost can deter uptake of intermittent preventive treatment of malaria in pregnancy (IPTp). The Malian Ministry of Health (MOH) recommends a minimum of three doses of IPTp at monthly intervals. However, despite a national policy that IPTp be provided free of charge, only 35% of pregnant women receive at least one dose and less than 20% receive two or more doses. METHODS: This study explored perceptions and experiences of IPTp cost in Mali and their impact on uptake, using qualitative interviews and focus groups with pregnant women, husbands and mothers-in-law. Study team members also interviewed and observed health workers at four health centres, two in Sikasso Region and two in Koulikoro. RESULTS: Despite national-level policies, actual IPTp costs varied widely at study sites-between facilities, and visits. Pregnant women may pay for IPTp, receive it free, or both at different times. Health centres often charge a lump sum for antenatal care (ANC) visits that includes both free and fee-based drugs and services. This makes it difficult for women and families to distinguish between free services and those requiring payment. As a result, some forego free care that, because it is bundled with other fee-based services and medications, appears not to be free. Varying costs also complicate household budgeting for health care, particularly as women often rely on their husbands for money. Finally, while health facilities operating under the cost-recovery model strive to provide free IPTp, their own financial constraints often make this impossible. CONCLUSIONS: Both actual and perceived costs are currently barriers to IPTp uptake. Given the confusion around cost of services in the two study regions, more detailed national-level studies of both perceived and actual costs could help inform policy and programme decisions promoting IPTp. These studies should evaluate both quantitatively and qualitatively the cost information provided to and understood by pregnant women and their families. Meanwhile, unbundling free and fee-based services, making clear that IPTp is free, and ensuring that it is provided at no cost could help increase uptake. Free community-based distribution might be another route to increased uptake and adherence. PMID- 26968168 TI - Single-pollen genotyping to estimate mode of unreduced pollen formation in Citrus tamurana cv. Nishiuchi Konatsu. AB - KEY MESSAGE: 2n pollen formed by FDR in citrus. The Japanese local citrus cultivar, Nishiuchi Konatsu (Citrus tamurana hort. ex Tanaka; NK hereafter), has the ability to produce unreduced 2n pollen grains, allowing generation of polyploid progenies via sexual polyploidization. In this study, we developed a method of single-pollen genotyping for citrus and applied it to the analysis of transmission of heterozygosity in NK 2n pollen grains. Heterozygosity transmission was expressed as the percentage inheritance of a set of heterozygous alleles from the parent to the 2n gamete. The pathway of 2n pollen development was investigated by applying the observed heterozygosity transmission and genetic distance to two different map functions, for first division restitution (FDR) and second division restitution (SDR). The fit of the values observed for both functions was calculated, while virtually moving the centromere position. We screened for six heterozygous SSR (codominant microsatellite marker loci) in NK, all of which were expected to lie within the same linkage group. Pollen germination prior to DNA extraction was essential for this work, and 6-h incubation proved to be optimal for subsequent PCR amplification. Single-pollen genotyping unreduced NK 2n pollen grains revealed that heterozygosity transmission exceeded 50 % in all six alleles, and fitness tests indicated that the FDR map function better fitted the heterozygosity transmission observed rather than the SDR function. Our data thus strongly indicate that 2n pollen in NK is a result of first division restitution. PMID- 26968170 TI - Severe catheter kinking and entrapment during transbrachial angiography: percutaneous retrieval with a slender approach. AB - A 74-year-old man previously treated with bilateral femoro-popliteal bypass was referred to our hospital for the treatment of a severely tangled 4-Fr diagnostic catheter in the right brachial artery. We inserted a 5-Fr sheath introducer from the proximal right femoral artery and advanced a 5-Fr JR catheter to the right brachial artery. A Sion coronary guidewire was then advanced for the tip of the tangled catheter, and a 4-mm gooseneck snare catheter was inserted through the guidewire. The tip of the catheter was caught and successfully removed after clockwise untwisting. The patient was discharged the next day without any complications. PMID- 26968169 TI - Reduction in incomplete stent apposition area caused by jailed struts after single stenting at left main bifurcation lesions: micro-CT analysis using a three dimensional elastic bifurcated coronary artery model. AB - Stent struts protruding into ostial side branch called "jailed strut" at bifurcation lesions is a likely cause of thrombus formation. We aimed to investigate the influences of multiple kissing balloon inflation (KBI) for stent expansion, and stent platform design, respectively, on the reduction of incomplete stent apposition area (ISA area) caused by jailed struts at a side branch ostium, using a three-dimensional elastic left main (LM) bifurcated coronary artery model. The referenced LM bifurcation angle data of 209 patients were stratified by tertiles focusing on the angle between the LM trunk (LMT) and left anterior descending artery (LAD). A bifurcation model was fabricated with angles of 129 degrees , 122.2 degrees , and 76.4 degrees for LMT-LAD, LMT-left circumflex (LCx), and LAD-LCx, respectively, and with diameters of 5, 3.75, and 3.5 mm for LMT, LAD, and LCx, respectively; these diameters fulfill Murray's law. A 75 % stenosis was included along the LMT. One-time and three-time KBIs were conducted using two-link Nobori and three-link Xience Xpedition (n = 6 each). The ISA area was quantified using micro-CT. Three-time KBI was effective in reducing the ISA area compared with one-time KBI for both the Nobori (p = 0.05) and Xience Xpedition (p = 0.07). The ISA area was smaller in the Nobori than in the Xience Xpedition, both in one-time and three-time KBI (one-time KBI: p = 0.003; three time KBI: p = 0.001). Our findings of this study on reducing the ISA area by focusing on an interventional technique and stent design may help to improve coronary bifurcation intervention for a possibly better long-term clinical outcome. PMID- 26968171 TI - Transradial retrieval of unintentionally extracted stent deployed 8 months prior during percutaneous coronary intervention to the stent-jailed side branch. AB - We experienced a case in which a previously deployed stent was extracted during a percutaneous coronary intervention to the stent-jailed side branch by the transradial approach. The stent was dislodged in the radial artery, was fully expanded, and partially deformed, making it difficult to retrieve via the radial sheath. Using a handmade flared guiding catheter, the expanded deformed stent was successfully retrieved via a 6-Fr radial sheath. PMID- 26968173 TI - Immunohistochemistry on IDH 1/2, ATRX, p53 and Ki-67 substitute molecular genetic testing and predict patient prognosis in grade III adult diffuse gliomas. AB - The molecular subgrouping of diffuse gliomas was recently found to stratify patients into prognostically distinct groups better than histological classification. Among several molecular parameters, the key molecules for the subtype diagnosis of diffuse gliomas are IDH mutation, 1p/19q co-deletion, and ATRX mutation; 1p/19q co-deletion is undetectable by immunohistochemistry, but is mutually exclusive with ATRX and p53 mutation in IDH mutant gliomas. Therefore, we applied ATRX and p53 immunohistochemistry instead of 1p/19q co-deletion analysis. The prognostic value of immunohistochemical diagnosis for Grade III gliomas was subsequently investigated. Then, the same immunohistochmical diagnostic approach was expanded for the evaluation of Grade II and IV diffuse glioma prognosis. The results indicate immunohistochemical analysis including IDH1/2, ATRX, p53, and Ki-67 index is valuable for the classification of diffuse gliomas, which is useful for the evaluation of prognosis, especially Grade III gliomas and lower-grade gliomas (i.e., Grade II and III). PMID- 26968174 TI - Fentanyl Iontophoretic Transdermal System: A Review in Acute Postoperative Pain. AB - Fentanyl iontophoretic transdermal system (ITS) [Ionsys((r))] is indicated for the management of acute postoperative pain in adults requiring opioid analgesia in the hospital setting. This article reviews the clinical use of fentanyl ITS for postoperative pain management, and summarizes the pharmacology of fentanyl and the characteristics of the two-component fentanyl ITS (Ionsys((r))) device. In well-designed, multicentre clinical trials, fentanyl ITS was an effective and generally well tolerated method for managing acute postoperative pain in inpatients who had undergone major abdominal, thoracic or orthopaedic surgery. Overall, fentanyl ITS provided equivalent analgesic efficacy to that with morphine patient-controlled intravenous analgesia (PCIA), but was perceived to be more convenient/easier to use than morphine PCIA by patients, nurses and physical therapists. Patients receiving fentanyl ITS also had a greater ability to mobilize after surgery than patients receiving morphine PCIA. In addition, relative to morphine PCIA, fentanyl ITS offers advantages in terms of the noninvasive administrative route (i.e. transdermal needle-free administration), pre-programmed delivery (no risk of programming errors/incorrect dosing) and improved tolerability with regard to the overall incidence of opioid-related adverse events (ORAEs) and some individual ORAEs. Hence, fentanyl ITS is a useful option for the management of acute postoperative pain in adults requiring opioid analgesia in the hospital setting. PMID- 26968176 TI - A case of brain calcifications in postsurgical hypoparathyroidism. PMID- 26968172 TI - MicroRNA and extracellular vesicles in glioblastoma: small but powerful. AB - To promote the tumor growth, angiogenesis, metabolism, and invasion, glioblastoma (GBM) cells subvert the surrounding microenvironment by influencing the endogenous activity of other brain cells including endothelial cells, macrophages, astrocytes, and microglia. Large number of studies indicates that the intra-cellular communication between the different cell types of the GBM microenvironment occurs through the functional transfer of oncogenic components such as proteins, non-coding RNAs, DNA and lipids via the release and uptake of extracellular vesicles (EVs). Unlike the communication through the secretion of chemokines and cytokines, the transfer and gene silencing activity of microRNAs through EVs is more complex as the biogenesis and proper packaging of microRNAs is crucial for their uptake by recipient cells. Although the specific mechanism of EV-derived microRNA uptake and processing in recipient cells is largely unknown, the screening, identifying and finally targeting of the EV-associated pro-tumorigenic microRNAs are emerging as new therapeutic strategy to combat the GBM. PMID- 26968177 TI - Stimulant medication and postural orthostatic tachycardia syndrome: a tale of two cases. AB - Stimulant medication may mimic the tachycardia of postural orthostatic tachycardia syndrome. Two case histories illustrate how missing the clinical distinction between a primary dysautonomia and a medication effect may have avoidable adverse consequences. PMID- 26968178 TI - Impaired orthostatic blood pressure recovery and cognitive performance at two year follow up in older adults: The Irish Longitudinal Study on Ageing. AB - BACKGROUND: Prospective investigations of the association between impaired orthostatic blood pressure (BP) regulation and cognitive decline in older adults are limited, and findings to-date have been mixed. The aim of this study was to determine whether impaired recovery of orthostatic BP was associated with change in cognitive function over a 2-year period, in a population based sample of community dwelling older adults. METHODS: Data from the first two waves of the Irish Longitudinal Study on Ageing were analysed. Orthostatic BP was measured during a lying to standing orthostatic stress protocol at wave 1 using beat-to beat digital plethysmography, and impaired recovery of BP at 40 s post stand was investigated. Cognitive function was assessed at wave 1 and wave 2 (2 years later) using the Mini-Mental State Exam (MMSE), verbal fluency and word recall tasks. RESULTS: After adjustment for measured, potential confounders, and multiple imputation for missing data, the change in the number of errors between waves on the MMSE was 10 % higher [IRR (95 % CI) = 1.10 (0.96, 1.26)] in those with impaired recovery at 40 s. However, this was not statistically significant (p = 0.17). Impaired BP recovery was not associated with change in performance on any of the other cognitive measures. CONCLUSIONS: There was no clear evidence for an association between impaired recovery of orthostatic BP and change in cognition over a 2-year period in this nationally representative cohort of older adults. Longer follow-up and more detailed cognitive testing would be advantageous to further investigate the relationship between orthostatic BP and cognitive decline. PMID- 26968179 TI - Postoperative pain in patients undergoing a transcutaneous active bone conduction implant (Bonebridge). AB - The objective of the study was to evaluate postoperative pain following a transcutaneous active conductive hearing implant. 27 patients undergoing Bonebridge (BB) bone conduction implantation were evaluated with two pain-related questionnaires. The Headache Impact Test (HIT-6) was used to measure the degree of disability including none or little impact (<=49), mild (50-55), moderate (56 59), and severe (>=60). The Brief Pain Inventory (BPI) was used to assess pain severity score and function interference (0 = no pain to 10 = worst pain); meaningful pain was considered to be >=3. The impact of surgical factors on postoperative pain was analyzed. Postoperative BB pain results were compared with 11 Vibrant SoundbridgeTM (VSB) and 103 cochlear implant (CI) users. The mean pre- and postoperative HIT-6 scores for BB implantation were 42.6 and 41.8, respectively and the mean preoperative BPI pain severity score changed from 0.6 to 0.9 postoperatively, whereas the preoperative interference score changed from 0.1 to 0.3. None of the mean postoperative values revealed significant pain. The retrosigmoid approach, the need for dural or sinus compression, and the use of bone conduction implant lifts had no significant impact on pain scores. The mean postoperative HIT-6 pain scores for patients with BB, VSB, and CI were 41.8, 46.4, and 42.8, respectively, with the differences not being significant. BB implantation causes no significant postoperative pain irrespective of sinus or dura compression. Pain scores were similar to those experienced by patients with other transcutaneous auditory implants such as middle ear or CIs. PMID- 26968181 TI - Organic pollution of the Buyuk Menderes River, Turkey and effects on aquaculture. AB - Water quality was measured at eight stations on the Buyuk Menderes River in Turkey (Adiguzel dam, Yenice regulator, Saraykoy bridge, Feslek regulator, Yenipazar bridge, Aydin bridge, Kocarli bridge, Soke regulator) between 2000 and 2013 in February, April, June, August, October and December. The resulting data were evaluated in terms of biochemical oxygen demand (BOD), chemical oxygen demand (COD), dissolved oxygen (DO), ammoniac-nitrogen (NH3-N), nitrite-nitrogen (NO2-N), nitrate-nitrogen (NO3-N) and orthophosphate (o-PO4) aquaculture. According to the analysis, while river water pollution generally varied during each year, samples from certain measurement points demonstrated high pollution levels throughout the year. In this study, water parameters were classified according to the "Turkish water pollution control regulation." The studied parameters are also compared with TS 266 and WHO guidelines. While levels at Saraykoy station were generally higher than other stations, values at Adiguzel dam were the lowest, giving it the best water quality of the eight stations. The highest values on a yearly basis were obtained in 2007 due to the severe drought in the Menderes basin within which irrigation water levels fell to 4255 m(3)/ha. The BOD, COD levels are the lowest in 2009 and highest in 2007; the DO level is lowest in 2007 and highest in 2009; NH3-N, NO2-N, and NO3-N parameters are the lowest in 2007 and highest in 2009; and the o-PO4 are at the lowest level in 2004 and seen as the highest in 2007. Analysis of the data was performed by SPSS 21 statistics program. One direction ANOVA was applied to the data, which were also subject to Tukey multiple comparison tests. Differences between groups were evaluated at p < 0.05. Box-plot graphs were used to demonstrate the data distribution. In the study, it was analyzed, the effect of fish species and pollution involved in the Buyuk Menderes River so far on fish species. PMID- 26968180 TI - Iterative metal artifact reduction improves dose calculation accuracy : Phantom study with dental implants. AB - PURPOSE: Metallic dental implants cause severe streaking artifacts in computed tomography (CT) data, which affect the accuracy of dose calculations in radiation therapy. The aim of this study was to investigate the benefit of the metal artifact reduction algorithm iterative metal artifact reduction (iMAR) in terms of correct representation of Hounsfield units (HU) and dose calculation accuracy. MATERIALS AND METHODS: Heterogeneous phantoms consisting of different types of tissue equivalent material surrounding metallic dental implants were designed. Artifact-containing CT data of the phantoms were corrected using iMAR. Corrected and uncorrected CT data were compared to synthetic CT data to evaluate accuracy of HU reproduction. Intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans were calculated in Oncentra v4.3 on corrected and uncorrected CT data and compared to GafchromicTM EBT3 films to assess accuracy of dose calculation. RESULTS: The use of iMAR increased the accuracy of HU reproduction. The average deviation of HU decreased from 1006 HU to 408 HU in areas including metal and from 283 HU to 33 HU in tissue areas excluding metal. Dose calculation accuracy could be significantly improved for all phantoms and plans: The mean passing rate for gamma evaluation with 3 % dose tolerance and 3 mm distance to agreement increased from 90.6 % to 96.2 % if artifacts were corrected by iMAR. CONCLUSION: The application of iMAR allows metal artifacts to be removed to a great extent which leads to a significant increase in dose calculation accuracy. PMID- 26968182 TI - Individual exposure of graduate students to PM2.5 and black carbon in Shanghai, China. AB - The personal exposure of 51 graduate students to PM2.5 and BC in Shanghai was evaluated using portable PM2.5 and BC samplers. Global positioning systems and activity diaries were used to evaluate the microenvironments/activities that contributed to the total daily exposure of the participants, as well as to accurately estimate the PM2.5 and BC doses received by each participant. The mean PM2.5 and BC exposure concentrations were 110.0 and 5.3 MUg m(-3), respectively. These exposure levels were considered extremely high and comparable to those measured in a busy urban street canyon for 24 h. High daily inhaled doses in terms of both PM2.5 and BC concentrations were measured, obtaining 1062.2 and 45.9 MUg day(-1), respectively. Indoor activities significantly contributed to the students' daily dose. Eating contributed the least to PM2.5 and BC exposure, whereas outdoor activities contributed the most. PM2.5 dose intensity from indoor eating slightly exceeded BC dose intensity; conversely, transportation showed higher exposure for BC than PM2.5. PMID- 26968184 TI - Solitary immunoglobulin G4-related inflammatory pseudotumor in the abdomen wall. PMID- 26968183 TI - Evidence for a Complex Relationship Among Weight Retention, Cortisol and Breastfeeding in Postpartum Women. AB - Objective To assess the relationship between cortisol slope, a biologic marker of stress, and postpartum weight retention. Methods We included 696 women in a secondary analysis from a multi-site study conducted using principles of community-based participatory research to study multi-level sources of stress on pregnancy outcomes. As a stress marker, we included salivary cortisol slope; the rate of cortisol decline across the day. Pre-pregnancy weight and demographic data were obtained from the medical records. At 6 months postpartum, patients were weighed and returned saliva samples. We built stepwise regression models to assess the effect of demographic variables, cortisol slope and cortisol covariates (wake time, tobacco use and breastfeeding) on postpartum weight retention. Results 45.5 % of participants were African American, 29.2 % White, and 25.3 % Hispanic. Of the Hispanic women 62.5 % were Spanish speaking and 37.5 % were English speaking. In general, participants were young, multiparous, and overweight. Postpartum, almost half (47.6 %) of women studied retained >10 lbs. In multivariable analysis including age, pre-pregnancy BMI and public insurance, cortisol slope was significantly associated with weight retention (beta = -1.90, 95 % CI = 0.22-3.58). However, when the model was adjusted for the cortisol covariates, breastfeeding (beta = -0.63, 95 % CI = -1.01 to -0.24) and public insurance (beta = 0.62, 95 % CI = 0.20-1.04) were the two strongest correlates of weight retention. Conclusions for Practice The association between cortisol slope and postpartum weight retention appears to be influenced breastfeeding status. PMID- 26968185 TI - Expressive aphasia as the manifestation of hyperglycemic crisis in type 2 diabetes. PMID- 26968187 TI - Xanthoma striatum palmare. PMID- 26968186 TI - Occurrence of sarcoidosis after chemotherapy for non-Hodgkin lymphoma. PMID- 26968188 TI - Clinicopathologic significance of tumor microenvironment CD11c, and FOXP3 expression in diffuse large B-cell lymphoma patients receiving rituximab, cyclophosphamide, anthracycline, vincristine, and prednisone (R-CHOP) combination chemotherapy. AB - BACKGROUND/AIMS: CD11c is a dendritic cell marker in humans, which potentially induces a cytotoxic effect on lymphoma cells. Forkhead boxP3 (FOXP3) is a regulator of T lymphocyte in the microenvironment of the lymphoma. The principal objective of this study was to determine whether the tumors' microenvironment expressions of CD11c and FOXP3 are predictive of clinical outcomes in diffuse large B-cell lymphoma (DLBCL) patients receiving treatment with rituximab, cyclophosphamide, anthracycline, vincristine, and prednisone (R-CHOP) combination chemotherapy. METHODS: The study population consisted of 100 patients with DLBCL. The CD11c and FOXP3 expression in primary tumors' microenvironment were evaluated using an immunohistochemistry (IHC). RESULTS: CD11c and FOXP3 expression positivity in microenvironment were 25% and 35%, respectively. Each one counted for 1 point. In CD11c and FOXP3 stain, positive was counted as 0 and negative was 1. The points were separated into low risk (0 to 1) and high risk (2) groups. Only the extranodal DLBCL patient group analysis conveyed significant differences of progression-free survival (p = 0.019) and overall survival (p = 0.039) between the two groups. CONCLUSIONS: We can achieve possible clinical significance of lymphoma tumor microenvironments through CD11c and FOXP3 IHC stains in extranodal DLBCL patients receiving R-CHOP therapy. PMID- 26968189 TI - Intermediate risk of multidrug-resistant organisms in patients who admitted intensive care unit with healthcare-associated pneumonia. AB - BACKGROUND/AIMS: Healthcare-associated pneumonia (HCAP) was proposed asa new pneumonia category in 2005, and treatment recommendations includebroad-spectrum antibiotics directed at multidrug-resistant (MDR) pathogens.However, this concept continues to be controversial, and microbiological data arelacking for HCAP patients in the intensive care unit (ICU). This study was conductedto determine the rate and type of antibiotic-resistant organisms and theclinical outcomes in patients with HCAP in the ICU, compared to patients withcommunity-acquired pneumonia (CAP) or hospital-acquired pneumonia (HAP). METHODS: We conducted a retrospective cohort analysis of patients with pneumonia(n = 195) who admitted to medical ICU in tertiary teaching hospital fromMarch 2011 to February 2013. Clinical characteristics, microbiological distributions,treatment outcomes, and prognosis of HCAP (n = 74) were compared tothose of CAP (n = 75) and HAP (n = 46). RESULTS: MDR pathogens were significantly higher in HCAP patients (39.1%) thanin CAP (13.5%) and lower than in HAP (79.3%, p < 0.001). The initial use of inappropriateantibiotic treatment occurred more frequently in the HCAP (32.6%) andHAP (51.7%) groups than in the CAP group (11.8%, p = 0.006). There were no differencesin clinical outcomes. The significant prognostic factors were pneumoniaseverity and treatment response. CONCLUSIONS: MDR pathogens were isolated in HCAP patients requiring ICU admissionat intermediate rates between those of CAP and HAP. PMID- 26968190 TI - Safety and immunologic benefits of conversion to sirolimus in kidney transplant recipients with long-term exposure to calcineurin inhibitors. AB - BACKGROUND/AIMS: Sirolimus (SRL) is a promising immunosuppressant replacingcalcineurin inhibitors (CNIs). This study was performed to evaluate the safetyand immunologic benefits of conversion to SRL in stable kidney transplant (KT)recipients exposed to CNIs for long periods. METHODS: Fourteen CNI-treated KT recipients with stable renal function for morethan 10 years were included. Either 2 or 3 mg per day of SRL was administeredwhile CNIs were reduced by half starting on day 1, and then stopped 2 weeks afterSRL introduction. The safety of SRL conversion was assessed considering thegraft function, acute rejection, and graft loss. Immunologic alterations were measuredvia serial changes of T cell and B cell subsets after SRL conversion. Adverseeffects of SRL conversion were also evaluated. RESULTS: Conversion to SRL was successful in nine patients (64.2%). Conversionto SRL preserved graft function as compared to the baseline value (p = 0.115). Noacute rejection or allograft loss was observed during the follow-up period. Immunemonitoring of T and B cells revealed a regulatory T cells increase after SRL conversion (p = 0.028). Most adverse events developed within 6 weeks after SRLconversion, and oral mucositis was the main cause of SRL withdrawal. CONCLUSIONS: Conversion to SRL can be safe and has immunologic benefits in KTrecipients with long-term CNI exposure. Close monitoring of mucocutaneous adverseevents is, however, required in the early period after SRL conversion. PMID- 26968191 TI - Relapsing polychondritis presenting with inflammatory pseudotumor. PMID- 26968192 TI - Hyperglycemic hyperosmolar state associated with invasive rhino-orbital aspergillosis in a patient with end-stage renal disease. PMID- 26968194 TI - Perspectives of family members of people with an intellectual disability to a major reconfiguration of living arrangements for people with intellectual disability in Ireland. AB - AIM: To document the views of family members of people with an intellectual disability regarding implementation of a personalized model of social support in Ireland. METHOD: Forty family members participated in six focus groups. Data were thematically analysed. RESULTS: Family members' preference for particular types of living arrangements were highly reflective of their lived experience. Facilitators to community living included timely information on proposed moves, adequate staffing, suitable properties and locations and consideration of the characteristics of individuals who share a property. Barriers included high support needs, advanced age, a fear of relinquishing current supports, a fear of the sustainability of newer models of residential support and concerns about community opposition. CONCLUSION: The family perspective to reform is characterized by fear and suspicion of the motivation behind these reforms, with cost efficiencies being perceived as a main driver. Greater information is required to empower families to make informed decisions. PMID- 26968193 TI - Metronomic chemotherapy with capecitabine for metastatic colorectal cancer in very elderly patients. PMID- 26968195 TI - Long-Term Blockade of Cocaine Self-Administration and Locomotor Activation in Rats by an Adenoviral Vector-Delivered Cocaine Hydrolase. AB - A promising approach in treating cocaine abuse is to metabolize cocaine in the blood using a mutated butyrylcholinesterase (BChE) that functions as a cocaine hydrolase (CocH). In rats, a helper-dependent adenoviral (hdAD) vector-mediated delivery of CocH abolished ongoing cocaine use and cocaine-primed reinstatement of drug-seeking for several months. This enzyme also metabolizes ghrelin, an effect that may be beneficial in maintaining healthy weights. The effect of a single hdAD-CocH vector injection was examined in rats on measures of anxiety, body weight, cocaine self-administration, and cocaine-induced locomotor activity. To examine anxiety, periadolescent rats were tested in an elevated-plus maze. Weight gain was then examined under four rodent diets. Ten months after CocH injection, adult rats were trained to self-administer cocaine intravenously and, subsequently, cocaine-induced locomotion was tested. Viral gene transfer produced sustained plasma levels of CocH for over 13 months of testing. CocH-treated rats did not differ from controls in measures of anxiety, and only showed a transient reduction in weight gain during the first 3 weeks postinjection. However, CocH treated rats were insensitive to cocaine. At 10 months postinjection, none of the CocH-treated rats initiated cocaine self-administration, unlike 90% of the control rats. At 13 months postinjection, CocH-treated rats showed no cocaine induced locomotion, whereas control rats showed a dose-dependent enhancement of locomotion. CocH vector produced a long-term blockade of the rewarding and behavioral effects of cocaine in rats, emphasizing its role as a promising therapeutic intervention in cocaine abuse. PMID- 26968196 TI - Sneddon's syndrome: it is all in the ectoderm. AB - A 51-year-old man gave a 2-year history of worsening mobility, cognitive decline and headaches. He had a history of thromboembolic stroke, recurrent transient ischaemic attacks and a spontaneous intraventricular haemorrhage. On examination, he had livedo reticularis and perniosis and a systolic murmur. Catheter cerebral angiography showed peripheral small-vessel and medium-vessel vasculopathy resulting in pruning of the distal cortical vessels and tortuous irregular distal collaterals. Skin biopsy showed subtle vasculopathy with ectasia of capillaries and postcapillary venules but no frank vasculitis or arterial thrombosis. Repeated serum antiphospholipid antibody titres were negative. The clinical features, skin biopsy and angiogram findings strongly supported a diagnosis of Sneddon's syndrome. Clinicians should consider Sneddon's syndrome in patients with livedo reticularis and stroke. There are treatment dilemmas in this situation when ischaemic and haemorrhagic cerebral events coexist. PMID- 26968198 TI - Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients. PMID- 26968197 TI - Targeting the podocyte cytoskeleton: from pathogenesis to therapy in proteinuric kidney disease. AB - Glomerular injury often incites a progression to chronic kidney disease, which affects millions of patients worldwide. Despite our current understanding of this disease's pathogenesis, there is still a lack of therapy available to curtail its progression. However, exciting new data strongly suggest the podocyte-an actin rich, terminally differentiated epithelial cell that lines the outside of the glomerular filtration barrier-as a therapeutic target. The importance of podocytes in the pathogenesis of human nephrotic syndrome is best characterized by identification of genetic mutations, many of which regulate the actin cytoskeleton. The intricate regulation of the podocyte actin cytoskeleton is fundamental in preserving an intact glomerular filtration barrier, and this knowledge has inspired new research targeting actin-regulating proteins in these cells. This review will shed light on recent findings, which have furthered our understanding of the molecular mechanisms regulating podocyte actin dynamics, as well as discoveries that have therapeutic implications in the treatment of proteinuric kidney disease. PMID- 26968200 TI - Association of objectively measured occupational walking and standing still with low back pain: a cross-sectional study. AB - OBJECTIVES: This cross-sectional study investigated the association of objectively measured walking and standing still time at work with low back pain (LBP) intensity among blue-collar workers. DESIGN: A cross-sectional study. METHODS: 187 workers attached two accelerometers for diurnal standing still and walking measurements, which were categorised using tertiles. Workers' self reported LBP intensity (scale 0-9) was categorised into low (0-5) and high pain (6-9). RESULTS: Of the 187 workers, 17% reported a high level of LBP. Results of the multi-adjusted logistic regression analysis demonstrated a negative association between walking and high LBP intensity (OR 0.24 CL 95% 0.07 to 0.79). The results between standing still and high LBP intensity were mixed and non significant. CONCLUSION: Blue-collar workers who walk more at work tend to have low LBP. These results should be verified using objective measures in a prospective design. Practitioner Summary: Most studies on the association of occupational walking and standing still with LBP have used poor self-reported measures. This study investigated the association of objectively measured time spent walking and standing still at work with LBP among blue-collar workers. A significant negative association between walking and LBP was found. However, because of the cross-sectional design, these results should be further investigated in prospective studies. PMID- 26968199 TI - Most microRNAs in the single-cell alga Chlamydomonas reinhardtii are produced by Dicer-like 3-mediated cleavage of introns and untranslated regions of coding RNAs. AB - We describe here a forward genetic screen to investigate the biogenesis, mode of action, and biological function of miRNA-mediated RNA silencing in the model algal species,Chlamydomonas reinhardtii Among the mutants from this screen, there were three at Dicer-like 3 that failed to produce both miRNAs and siRNAs and others affecting diverse post-biogenesis stages of miRNA-mediated silencing. The DCL3-dependent siRNAs fell into several classes including transposon- and repeat derived siRNAs as in higher plants. The DCL3-dependent miRNAs differ from those of higher plants, however, in that many of them are derived from mRNAs or from the introns of pre-mRNAs. Transcriptome analysis of the wild-type and dcl3 mutant strains revealed a further difference from higher plants in that the sRNAs are rarely negative switches of mRNA accumulation. The few transcripts that were more abundant in dcl3 mutant strains than in wild-type cells were not due to sRNA targeted RNA degradation but to direct DCL3 cleavage of miRNA and siRNA precursor structures embedded in the untranslated (and translated) regions of the mRNAs. Our analysis reveals that the miRNA-mediated RNA silencing in C. reinhardtii differs from that of higher plants and informs about the evolution and function of this pathway in eukaryotes. PMID- 26968201 TI - Nuclear Receptor Corepressor 1 Expression and Output Declines with Prostate Cancer Progression. AB - PURPOSE: Castration therapy in advanced prostate cancer eventually fails and leads to the development of castration-resistant prostate cancer (CRPC), which has no cure. Characteristic features of CRPC can be increased androgen receptor (AR) expression and altered transcriptional output. We investigated the expression of nuclear receptor corepressor 1 (NCOR1) in human prostate and prostate cancer and the role of NCOR1 in response to antiandrogens. EXPERIMENTAL DESIGN: NCOR1 protein levels were compared between matched normal prostate and prostate cancer in 409 patient samples. NCOR1 knockdown was used to investigate its effect on bicalutamide response in androgen-dependent prostate cancer cell lines and transcriptional changes associated with the loss of NCOR1. NCOR1 transcriptional signature was also examined in prostate cancer gene expression datasets. RESULTS: NCOR1 protein was detected in cytoplasm and nuclei of secretory epithelial cells in normal prostate. Both cytoplasmic and nuclear NCOR1 protein levels were lower in prostate cancer than in normal prostate. Prostate cancer metastases show significant decrease in NCOR1 transcriptional output. Inhibition of LNCaP cellular proliferation by bicalutamide requires NCOR1. NCOR1 regulated genes suppress cellular proliferation and mediate bicalutamide resistance. In the mouse, NCOR1 is required for bicalutamide-dependent regulation of a subset of the AR target genes. CONCLUSIONS: In summary, we demonstrated that NCOR1 function declines with prostate cancer progression. Reduction in NCOR1 levels causes bicalutamide resistance in LNCaP cells and compromises response to bicalutamide in mouse prostate in vivo Clin Cancer Res; 22(15); 3937-49. (c)2016 AACR. PMID- 26968203 TI - Hope in the Long Road Toward the Development of a Therapeutic Human Papillomavirus Vaccine. AB - A pool of long synthetic peptides derived from HPV16 proteins induce objective partial or complete histologic regression of lesions in more than 50% of patients with high-grade vulvar (VuVIN3) and vaginal intraepithelial neoplasia (VaIN3). The intensity of T-cell response induced by the vaccine was correlated with clinical response. Clin Cancer Res; 22(10); 2317-9. (c)2016 AACRSee related article by van Poelgeest et al., p. 2342. PMID- 26968202 TI - Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFNalpha Combined with Chemotherapy. AB - PURPOSE: "In situ vaccination" using immunogene therapy has the ability to induce polyclonal antitumor responses directed by the patient's immune system. EXPERIMENTAL DESIGN: Patients with unresectable malignant pleural mesothelioma (MPM) received two intrapleural doses of a replication-defective adenoviral vector containing the human IFNalpha2b gene (Ad.IFN) concomitant with a 14-day course of celecoxib followed by chemotherapy. Primary outcomes were safety, toxicity, and objective response rate; secondary outcomes included progression free and overall survival. Biocorrelates on blood and tumor were measured. RESULTS: Forty subjects were treated: 18 received first-line pemetrexed-based chemotherapy, 22 received second-line chemotherapy with pemetrexed (n = 7) or gemcitabine (n = 15). Treatment was generally well tolerated. The overall response rate was 25%, and the disease control rate was 88%. Median overall survival (MOS) for all patients with epithelial histology was 21 months versus 7 months for patients with nonepithelial histology. MOS in the first-line cohort was 12.5 months, whereas MOS for the second-line cohort was 21.5 months, with 32% of patients alive at 2 years. No biologic parameters were found to correlate with response, including numbers of activated blood T cells or NK cells, regulatory T cells in blood, peak levels of IFNalpha in blood or pleural fluid, induction of antitumor antibodies, nor an immune-gene signature in pretreatment biopsies. CONCLUSIONS: The combination of intrapleural Ad.IFN, celecoxib, and chemotherapy proved safe in patients with MPM. OS rate was significantly higher than historical controls in the second-line group. Results of this study support proceeding with a multicenter randomized clinical trial of chemo-immunogene therapy versus standard chemotherapy alone. Clin Cancer Res; 22(15); 3791-800. (c)2016 AACR. PMID- 26968204 TI - Therapist-supported Internet cognitive behavioural therapy for anxiety disorders in adults. AB - BACKGROUND: Cognitive behavioural therapy (CBT) is an evidence-based treatment for anxiety disorders. Many people have difficulty accessing treatment, due to a variety of obstacles. Researchers have therefore explored the possibility of using the Internet to deliver CBT; it is important to ensure the decision to promote such treatment is grounded in high quality evidence. OBJECTIVES: To assess the effects of therapist-supported Internet CBT (ICBT) on remission of anxiety disorder diagnosis and reduction of anxiety symptoms in adults as compared to waiting list control, unguided CBT, or face-to-face CBT. Effects of treatment on quality of life and patient satisfaction with the intervention were also assessed. SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review Group Specialised Register (CCDANCTR) to 16 March 2015. The CCDANCTR includes relevant randomised controlled trials from MEDLINE, EMBASE, PsycINFO and CENTRAL. We also searched online clinical trial registries and reference lists of included studies. We contacted authors to locate additional trials. SELECTION CRITERIA: Each identified study was independently assessed for inclusion by two authors. To be included, studies had to be randomised controlled trials of therapist-supported ICBT compared to a waiting list, attention, information, or online discussion group; unguided CBT (that is, self-help); or face-to-face CBT. We included studies that treated adults with an anxiety disorder (panic disorder, agoraphobia, social phobia, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, obsessive compulsive disorder, and specific phobia) defined according to the Diagnostic and Statistical Manual of Mental Disorders III, III-R, IV, IV-TR or the International Classification of Disesases 9 or 10. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias of included studies and judged overall study quality. We used data from intention-to-treat analyses wherever possible. We assessed treatment effect for the dichotomous outcome of clinically important improvement in anxiety using a risk ratio (RR) with 95% confidence interval (CI). For disorder-specific and general anxiety symptom measures and quality of life we assessed continuous scores using standardized mean differences (SMD). We examined statistical heterogeneity using the I(2) statistic. MAIN RESULTS: We screened 1736 citations and selected 38 studies (3214 participants) for inclusion. The studies examined social phobia (11 trials), panic disorder with or without agoraphobia (8 trials), generalized anxiety disorder (5 trials), post-traumatic stress disorder (2 trials), obsessive compulsive disorder (2 trials), and specific phobia (2 trials). Eight remaining studies included a range of anxiety disorder diagnoses. Studies were conducted in Sweden (18 trials), Australia (14 trials), Switzerland (3 trials), the Netherlands (2 trials), and the USA (1 trial) and investigated a variety of ICBT protocols. Three primary comparisons were identified, therapist-supported ICBT versus waiting list control, therapist supported versus unguided ICBT, and therapist-supported ICBT versus face-to-face CBT.Low quality evidence from 11 studies (866 participants) contributed to a pooled risk ratio (RR) of 3.75 (95% CI 2.51 to 5.60; I(2) = 50%) for clinically important improvement in anxiety at post-treatment, favouring therapist-supported ICBT over a waiting list, attention, information, or online discussion group only. The SMD for disorder-specific symptoms at post-treatment (28 studies, 2147 participants; SMD -1.06, 95% CI -1.29 to -0.82; I(2) = 83%) and general anxiety symptoms at post-treatment (19 studies, 1496 participants; SMD -0.75, 95% CI 0.98 to -0.52; I(2) = 78%) favoured therapist-supported ICBT; the quality of the evidence for both outcomes was low.One study compared unguided CBT to therapist supported ICBT for clinically important improvement in anxiety at post-treatment, showing no difference in outcome between treatments (54 participants; very low quality evidence). At post-treatment there were no clear differences between unguided CBT and therapist-supported ICBT for disorder-specific anxiety symptoms (5 studies, 312 participants; SMD -0.22, 95% CI -0.56 to 0.13; I(2) = 58%; very low quality evidence) or general anxiety symptoms (2 studies, 138 participants; SMD 0.28, 95% CI -2.21 to 2.78; I(2) = 0%; very low quality evidence).Compared to face-to-face CBT, therapist-supported ICBT showed no significant differences in clinically important improvement in anxiety at post-treatment (4 studies, 365 participants; RR 1.09, 95% CI 0.89 to 1.34; I(2) = 0%; low quality evidence). There were also no clear differences between face-to-face and therapist supported ICBT for disorder-specific anxiety symptoms at post-treatment (7 studies, 450 participants; SMD 0.06, 95% CI -0.25 to 0.37; I(2) = 60%; low quality evidence) or general anxiety symptoms at post-treatment (5 studies, 317 participants; SMD 0.17, 95% CI -0.35 to 0.69; I(2) = 78%; low quality evidence).Overall, risk of bias in included studies was low or unclear for most domains. However, due to the nature of psychosocial intervention trials, blinding of participants and personnel, and outcome assessment tended to have a high risk of bias. Heterogeneity across a number of the meta-analyses was substantial, some was explained by type of anxiety disorder or may be meta-analytic measurement artefact due to combining many assessment measures. Adverse events were rarely reported. AUTHORS' CONCLUSIONS: Therapist-supported ICBT appears to be an efficacious treatment for anxiety in adults. The evidence comparing therapist supported ICBT to waiting list, attention, information, or online discussion group only control was low to moderate quality, the evidence comparing therapist supported ICBT to unguided ICBT was very low quality, and comparisons of therapist-supported ICBT to face-to-face CBT were low quality. Further research is needed to better define and measure any potential harms resulting from treatment. These findings suggest that therapist-supported ICBT is more efficacious than a waiting list, attention, information, or online discussion group only control, and that there may not be a significant difference in outcome between unguided CBT and therapist-supported ICBT; however, this latter finding must be interpreted with caution due to imprecision. The evidence suggests that therapist-supported ICBT may not be significantly different from face-to-face CBT in reducing anxiety. Future research should explore heterogeneity among studies which is reducing the quality of the evidence body, involve equivalence trials comparing ICBT and face-to-face CBT, examine the importance of the role of the therapist in ICBT, and include effectiveness trials of ICBT in real-world settings. A timely update to this review is needed given the fast pace of this area of research. PMID- 26968205 TI - TCR Sequencing Can Identify and Track Glioma-Infiltrating T Cells after DC Vaccination. AB - Although immunotherapeutic strategies are emerging as adjunctive treatments for cancer, sensitive methods of monitoring the immune response after treatment remain to be established. We used a novel next-generation sequencing approach to determine whether quantitative assessments of tumor-infiltrating lymphocyte (TIL) content and the degree of overlap of T-cell receptor (TCR) sequences in brain tumors and peripheral blood were predictors of immune response and overall survival in glioblastoma patients treated with autologous tumor lysate-pulsed dendritic cell immunotherapy. A statistically significant correlation was found between a higher estimated TIL content and increased time to progression and overall survival. In addition, we were able to assess the proportion of shared TCR sequences between tumor and peripheral blood at time points before and after therapy, and found the level of TCR overlap to correlate with survival outcomes. Higher degrees of overlap, or the development of an increased overlap following immunotherapy, was correlated with improved clinical outcome, and may provide insights into the successful, antigen-specific immune response. Cancer Immunol Res; 4(5); 412-8. (c)2016 AACR. PMID- 26968206 TI - Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC. AB - Immune cells that infiltrate a tumor may be a prognostic factor for patients who have had surgically resected hepatocellular carcinoma (HCC). The density of intratumoral total (CD3(+)) and cytotoxic (CD8(+)) T lymphocytes was measured in the tumor interior and in the invasive margin of 65 stage I to IV HCC tissue specimens from a single cohort. Immune cell density in the interior and margin was converted to a binary score (0, low; 1, high), which was correlated with tumor recurrence and relapse-free survival (RFS). In addition, the expression of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) was correlated with the density of CD3(+) and CD8(+) cells and clinical outcome. High densities of both CD3(+) and CD8(+) T cells in both the interior and margin, along with corresponding Immunoscores, were significantly associated with a low rate of recurrence (P = 0.007) and a prolonged RFS (P = 0.002). In multivariate logistic regression models adjusted for vascular invasion and cellular differentiation, both CD3(+) and CD8(+) cell densities predicted recurrence, with odds ratios of 5.8 [95% confidence interval (CI), 1.6-21.8] for CD3(+) and 3.9 (95% CI, 1.1 14.1) for CD8(+) Positive PD-L1 staining was correlated with high CD3 and CD8 density (P = 0.024 and 0.005, respectively) and predicted a lower rate of recurrence (P = 0.034), as well as prolonged RFS (P = 0.029). Immunoscore and PD L1 expression, therefore, are useful prognostic markers in patients with HCC who have undergone primary tumor resection. Cancer Immunol Res; 4(5); 419-30. (c)2016 AACR. PMID- 26968207 TI - General control nonderepressible 2 deletion predisposes to asparaginase associated pancreatitis in mice. AB - Treatment with the antileukemic agent asparaginase can induce acute pancreatitis, but the pathophysiology remains obscure. In the liver of mice, eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2) is essential for mitigating metabolic stress caused by asparaginase. We determined the consequences of asparaginase treatment on the pancreata of wild-type (WT, GCN2-intact) and GCN2-deleted (DeltaGcn2) mice. Mean pancreas weights in DeltaGcn2 mice treated with asparaginase for 8 days were increased (P < 0.05) above all other groups. Histological examination revealed acinar cell swelling and altered staining of zymogen granules in DeltaGcn2, but not WT, mice. Oil Red O staining and measurement of pancreas triglycerides excluded lipid accumulation as a contributor to acini appearance. Instead, transmission electron microscopy revealed dilatation of the endoplasmic reticulum (ER) and accumulation of autophagic vacuoles in the pancreas of DeltaGcn2 mice treated with asparaginase. Consistent with the idea that loss of GCN2 in a pancreas exposed to asparaginase induced ER stress, phosphorylation of protein kinase R-like ER kinase (PERK) and its substrate eIF2 was increased in the pancreas of asparaginase-treated DeltaGcn2 mice. In addition, mRNA expression of PERK target genes, activating transcription factors 4, 3, and 6 (Atf4, Atf3, and Atf6), fibroblast growth factor 21 (Fgf21), heat shock 70-kDa protein 5 (Hspa5), and spliced Xbp1 (sXbp1), as well as pancreas mass, was elevated in the pancreas of asparaginase-treated DeltaGcn2 mice. Furthermore, genetic markers of oxidative stress [sirtuin (Sirt1)], inflammation [tumor necrosis factor-alpha (Tnfalpha)], and pancreatic injury [pancreatitis-associated protein (Pap)] were elevated in asparaginase treated DeltaGcn2, but not WT, mice. These data indicate that loss of GCN2 predisposes the exocrine pancreas to a maladaptive ER stress response and autophagy during asparaginase treatment and represent a genetic basis for development of asparaginase-associated pancreatitis. PMID- 26968208 TI - Postprandial lymphatic pump function after a high-fat meal: a characterization of contractility, flow, and viscosity. AB - Dietary lipids are transported from the intestine through contractile lymphatics. Chronic lipid loads can adversely affect lymphatic function. However, the acute lymphatic pump response in the mesentery to a postprandial lipid meal has gone unexplored. In this study, we used the rat mesenteric collecting vessel as an in vivo model to quantify the effect of lipoproteins on vessel function. Lipid load was continuously monitored by using the intensity of a fluorescent fatty-acid analog, which we infused along with a fat emulsion through a duodenal cannula. The vessel contractility was simultaneously quantified. We demonstrated for the first time that collecting lymphatic vessels respond to an acute lipid load by reducing pump function. High lipid levels decreased contraction frequency and amplitude. We also showed a strong tonic response through a reduction in the end diastolic and systolic diameters. We further characterized the changes in flow rate and viscosity and showed that both increase postprandially. In addition, shear-mediated Ca(2+) signaling in lymphatic endothelial cells differed when cultured with lipoproteins. Together these results show that the in vivo response could be both shear and lipid mediated and provide the first evidence that high postprandial lipid has an immediate negative effect on lymphatic function even in the acute setting. PMID- 26968209 TI - Enhanced ethanol catabolism in orphan nuclear receptor SHP-null mice. AB - Deficiency of the orphan nuclear hormone receptor small heterodimer partner (SHP, NR0B2) protects mice from diet-induced hepatic steatosis, in part, via repression of peroxisome proliferator-activated receptor (PPAR)-gamma2 (Pparg2) gene expression. Alcoholic fatty liver diseases (AFLD) share many common pathophysiological features with non-AFLD. To study the role of SHP and PPARgamma2 in AFLD, we used a strategy of chronic ethanol feeding plus a single binge ethanol feeding to challenge wild-type (WT) and SHP-null (SHP(-/-)) mice with ethanol. The ethanol feeding induced liver fat accumulation and mRNA expression of hepatic Pparg2 in WT mice, which suggests that a high level of PPARgamma2 is a common driving force for fat accumulation induced by ethanol or a high-fat diet. Interestingly, ethanol-fed SHP(-/-) mice displayed hepatic fat accumulation similar to that of ethanol-fed WT mice, even though their Pparg2 expression level remained lower. Mortality of SHP(-/-) mice after ethanol binge feeding was significantly reduced and their acetaldehyde dehydrogenase (Aldh2) mRNA level was higher than that of their WT counterparts. After an intoxicating dose of ethanol, SHP(-/-) mice exhibited faster blood ethanol clearance and earlier wake-up time than WT mice. Higher blood acetate, the end product of ethanol metabolism, and lower acetaldehyde levels were evident in the ethanol challenged SHP(-/-) than WT mice. Ethanol-induced inflammatory responses and lipid peroxidation were also lower in SHP(-/-) mice. The current data show faster ethanol catabolism and extra fat storage through conversion of acetate to acetyl CoA before its release into the circulation in this ethanol-feeding model in SHP( /-) mice. PMID- 26968210 TI - Intestinal inflammation requires FOXO3 and prostaglandin E2-dependent lipogenesis and elevated lipid droplets. AB - Intestinal inflammation has been recently characterized by the dysregulation of lipids as metabolic and energy sources, revealing a novel feature of its pathophysiology. Because intracellular lipids, stored in dynamic lipid droplets (LDs), provide energy for cellular needs, we investigated whether they play a role in intestinal inflammation. In the inflamed intestine of mice, elevated LDs were found in colonic and infiltrating immune cells as shown by staining for the LD coat protein PLIN2 and for lipids with BODIPY. In colonic cells, TNF stimulated LD increases by receptor signaling rely on phosphatidylinositol 3 kinase activation. Downstream, TNF triggered a negative regulatory loop between LDs and the transcription factor FOXO3. This was shown in the colon of Foxo3 deficient mice, where elevation in PLIN2 and lipids were further facilitated by inflammation and were more prominent relative to wild-type, whereas, in colonic cells, inhibition of lipogenesis blocked the TNF-mediated loss of FOXO3. Furthermore, blockade of PGE2 synthesis abrogated TNF-stimulated increases in LDs and FOXO3 inactivation. We found in colonic tissue of Foxo3-deficient mice higher levels of cyclooxygenase-2, a mediator of prostaglandin E2 (PGE2) synthesis, supporting involvement of PGE2 in the LD-FOXO3 regulatory loop. Ultimately, TNF stimulated lipogenesis leading to elevated LDs facilitated NF-kappaB-mediated increases in IL-8 protein, which is associated with the surface of LDs found in the lumina of the endoplasmic reticulum and Golgi apparatus. This novel immunometabolic mechanism of colonic inflammation involving elevated LDs could provide opportunities for new treatment options. PMID- 26968212 TI - Ions and solvation at biointerfaces. PMID- 26968211 TI - Liver-specific loss of Perilipin 2 alleviates diet-induced hepatic steatosis, inflammation, and fibrosis. AB - Hepatic inflammation and fibrosis are key elements in the pathogenesis of nonalcoholic steatohepatitis (NASH), a progressive liver disease initiated by excess hepatic lipid accumulation. Lipid droplet protein Perilipin 2 (Plin2) alleviates dietary-induced hepatic steatosis when globally ablated; however, its role in the progression of NASH remains unknown. To investigate this further, we challenged Plin2 liver-specific knockout mice (designated L-KO) and their respective wild-type (WT) controls with a methionine-choline-deficient (MCD) diet for 15 days to induce a NASH phenotype of increased hepatic triglyceride levels through impaired phosphatidylcholine (PC) synthesis and very-low-density lipoprotein (VLDL) secretion. Results on liver weights, body weights, fat tissue mass, and histology in WT and L-KO mice fed the MCD diet revealed signs of hepatic steatosis, fibrosis, and inflammation; however, these effects were blunted in L-KO mice. In addition, levels of PC and VLDL were unchanged, and hepatic steatosis was reduced in L-KO mice fed the MCD diet, due in part to an increase in remodeling of PE to PC via the enzyme phosphatidylethanolamine N methyltransferase (PEMT). These mice also exhibited decreased hepatic expression of proinflammatory markers cyclooxygenase 2, IL-6, TNF-alpha, IL-1beta, and reduced expression of endoplasmic reticulum (ER) stress proteins C/EBP homologous protein and cleaved caspase-1. Taken together, these results suggest that Plin2 liver-specific ablation alleviates diet-induced hepatic steatosis and inflammation via a PEMT-mediated mechanism that involves compensatory changes in proteins involved in phospholipid remodeling, inflammation, and ER stress that work to alleviate diet-induced NASH. Overall, these findings support a role for Plin2 as a target for NASH therapy. PMID- 26968213 TI - Differential surface activation of the A1 domain of von Willebrand factor. AB - The clotting protein von Willebrand factor (VWF) binds to platelet receptor glycoprotein Ibalpha (GPIbalpha) when VWF is activated by chemicals, high shear stress, or immobilization onto surfaces. Activation of VWF by surface immobilization is an important problem in the failure of cardiovascular implants, but is poorly understood. Here, the authors investigate whether some or all surfaces can activate VWF at least in part by affecting the orientation or conformation of the immobilized GPIbalpha-binding A1 domain of VWF. Platelets binding to A1 adsorbed onto polystyrene surfaces translocated rapidly at moderate and high flow, but detached at low flow, while platelets binding to A1 adsorbed onto glass or tissue-culture treated polystyrene surfaces translocated slowly, and detached only at high flow. Both x-ray photoelectron spectroscopy and conformation independent antibodies reported comparable A1 amounts on all surfaces. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) and near-edge x-ray absorption fine structure spectra suggested differences in orientation on the three surfaces, but none that could explain the biological data. Instead, ToF SIMS data and binding of conformation-dependent antibodies were consistent with the stabilization of an alternative more activated conformation of A1 by tissue culture polystyrene and especially glass. These studies demonstrate that different material surfaces differentially affect the conformation of adsorbed A1 domain and its biological activity. This is important when interpreting or designing in vitro experiments with surface-adsorbed A1 domain, and is also of likely relevance for blood-contacting biomaterials. PMID- 26968215 TI - Trusting systematic reviews and meta-analyses: all that glitters is not gold! PMID- 26968214 TI - Uptake of early infant diagnosis in Thailand's national program for preventing mother-to-child HIV transmission and linkage to care, 2008-2011. AB - INTRODUCTION: Early infant diagnosis (EID) has been a component of Thailand's prevention of mother-to-child HIV transmission (PMTCT) programme since 2007. This study assessed the uptake, EID coverage, proportion of HIV-exposed infants receiving a definitive HIV diagnosis, mother-to-child transmission (MTCT) rates and linkage to HIV care and treatment. METHODS: Infant polymerase chain reaction (PCR) testing data from the National AIDS Program database were analyzed. EID coverage was calculated as the percentage of number of HIV-exposed infants receiving >= 1 HIV PCR test divided by the number of HIV-exposed infants estimated from HIV prevalence and live-birth registry data. Definitive HIV diagnosis was defined as having two concordant PCR results. MTCT rates were calculated based on infants tested with PCR and applied as a best-case scenario, and a sensitivity analysis was used to adjust these rates in average and worst scenarios. We defined linkage to HIV care as infants with at least one PCR positive test who were registered with Thailand's National AIDS Program. Chi squared tests for linear trend were used to analyze changes in programme coverage. RESULTS: For 2008 to 2011, the average EID coverage rate increased from 54 to 76% (p < 0.001), with 65% coverage (13,761/21,099) overall. The number of hospitals submitting EID samples increased from 458 to 645, and the percentage of community hospitals submitting samples increased from 75 to 78% (p = 0.044). A definitive HIV diagnosis was made for 10,854 (79%) infants during this period. The adjusted MTCT rates had significantly decreasing trends in all scenarios. Overall, an estimated 53% (429/804) of HIV-infected infants were identified through the EID programme, and 80% (341/429) of infants testing positive were linked to care. The overall rate of antiretroviral treatment (ART) initiation within one year of age was 37% (157/429), with an increasing trend from 28 to 52% (p < 0.001). CONCLUSIONS: EID coverage increased and MTCT rates decreased during 2008 to 2011; however, about half of HIV-infected infants still did not receive EID. Most HIV-infected infants were linked to care but less than half initiated ART within one year of age. Active follow-up of HIV-exposed infants to increase early detection of HIV infection and early initiation of ART should be more widely implemented. PMID- 26968216 TI - Vancouver data supports a weak association between tendon pathology and serum lipid profiles. PMID- 26968217 TI - Review of the Local Organizing Committee (LOC) medical services during the 12th FINA World Swimming Championships (25 m) in Doha, Qatar. AB - BACKGROUND: One of the primary roles of Federation Internationale de Natation (FINA) is to promote athlete health. The planning and delivery of major international event medical services is carried out in collaboration with the Local Organizing Committee Medical Commission (LOCMC). Aspetar Orthopaedic and Sports Medicine Hospital provided the medical services to the 12th FINA World Swimming Championships (25 m) creating a unique opportunity for collaboration with FINA. AIM: The purpose of this paper is to review the planning and delivery of medical services and athlete health promotion projects during the 12th FINA World Swimming Championships (25 m) to facilitate the planning of future sporting events of this size and scope. METHODS: The 12th FINA World Swimming Championships (25 m) hosted 974 athletes from 166 countries. The LOC medical team recorded all medical encounters-newly incurred (or acute exacerbations of chronic) injuries and illnesses as well as follow-up consultations. RESULTS: More than 90% of teams did not travel with a team physician and relied on the LOCMC for diagnosis and treatment of injuries and illnesses in athletes and accredited team officials. The LOC medical team had a total of 554 medical encounters: 385 therapy, 34 athlete injury, 65 athlete illness and 70 non-athlete encounters. CONCLUSIONS: The LOCMC in collaboration with FINA delivered comprehensive medical services to athletes, officials and spectators attending the 12th FINA World Swimming Championships (25 m). This review paper provides information relevant to the planning and delivery of LOCMC medical services for future international swimming events contributing to the FINA objective of promoting athlete health. PMID- 26968218 TI - Incidence and aetiology of acute injuries during competitive road cycling. AB - INTRODUCTION: Despite the ever-increasing popularity of bicycle racing, the high perceived risk of acute injuries and the recent media attention, studies of acute injuries in road cyclists are rather scarce. The goal of this study is to evaluate the incidence, aetiology and patterns of acute injuries in non professional competitive road cyclists during cycling races in Flanders. MATERIAL AND METHODS: All acute injuries that occurred during competition in Flanders in 2002 and 2012, collected in the injury registry, were analysed. The incidence, injury rate, diagnosis, circumstances and level of performance were evaluated. RESULTS: A total of 777 documented reports of accidents (1230 injuries) were retrieved for the years 2002 and 2012. There was no significant difference between incidence and injury rate between 2002 and 2012. There was a strong significant difference in the incidence between the different levels of performance in both seasons. Severe injuries were seen in 29.5% in 2002 and in 30.1% in 2012. The most common location of a severe injury was the hand. Collision with another rider was the most common cause of injury. CONCLUSIONS: Almost 1 out of 6 non-professional competitive road cyclists had an accident during cycling races in 2002 and 2012 in Flanders and collision with other riders was the most important cause of a crash. The most common lesion was abrasion, but almost one out of three riders had a severe injury. PMID- 26968219 TI - Sharing decision-making between patient and clinician: the next step in evidence based practice for patellofemoral pain? PMID- 26968220 TI - Improving physical performance tests: time to include a psychologist. PMID- 26968222 TI - [Retrobulbar optic neuropathy as presenting sign of recurrence of a large b-cell lymphoma considered to be in complete remission: A case report]. PMID- 26968221 TI - Inhibiting microRNA-449 Attenuates Cisplatin-Induced Injury in NRK-52E Cells Possibly via Regulating the SIRT1/P53/BAX Pathway. AB - BACKGROUND: Acute kidney injury (AKI) is quite common in the patients who frequently use the anticancer drug cisplatin. microRNAs (miRNAs) are powerful tools in modulating the expression of key factors in disease progression, but little is known about roles of miRNAs in AKI. This study explored the expression and function of miR-449 in cisplatin-induced AKI. MATERIAL/METHODS: Rat renal proximal tubular cell line NRK-52E was used for cisplatin treatment and miR-449 sponge transfection. MTT assay and flow cytometry were performed to detect cell viability and apoptosis in different cell groups. Protein expression of sirtuin 1 (SIRT1), acetylated p53, and BCL-associated X protein (BAX) was detected to deduce the possible regulatory mechanism of miR-449. RESULTS: Results showed that cisplatin treatment in NRK-52E cells significantly up-regulated miR-449 levels (P<0.05), inhibited cell viability (P<0.05), accelerated cell apoptosis (P<0.05), and changed SIRT1, acetylated p53, and BAX protein levels (P<0.01). However, inhibiting miR-449 by its sponge transfection in cisplatin-treated cells significantly promoted cell viability (P<0.05), suppressed cell apoptosis (P<0.05), elevated SIRT1 expression (P<0.01), and inhibited acetylated p53 and BAX protein levels (P<0.001). CONCLUSIONS: These results indicate that inhibiting miR-449 allows the attenuation of cisplatin-induced injury in NRK-52E cells, suggesting that miR-449 is a potential target for treating AKI. miR-449 regulates the SIRT1/p53/BAX pathway, which may be its possible mechanism in modulating cell apoptosis of cisplatin-induced AKI. Further verification and a thorough understanding are necessary for targeting miR-449 in AKI treatment. PMID- 26968224 TI - Garlic decreases liver and kidney receptor for advanced glycation end products expression in experimental diabetes. AB - The up-regulation of the receptor for advanced glycation end products (RAGE) has been implicated as a major mediator in the development and progression of diabetic nephropathy and hepatic fibrogenesis. The present study was designed to investigate the potential of garlic (Allium sativum L.) to modulate the level of expression of RAGE in renal and hepatic tissues of diabetic rats. Three groups of rats were studied after 8 weeks following diabetes induction: normal, streptozotocin-induced diabetic (control diabetic), and garlic-treated diabetic rats. A polyclonal antibody of proven specificity to RAGE indicated in immunohistochemical assays that RAGE labeling was significantly increased in renal and hepatic tissues of control diabetic rats compared to the normal group. The increased RAGE labeling involved mesangial cells in glomeruli exhibiting signs of mesangial expansion, mesangial nodule formation and glomerulosclerosis. In the liver, a significant up-regulation of RAGE was observed in hepatocytes and bile ducts and vessels in portal tracts. In 2-dimensional Western blots, RAGE expression in both tissues was dominated by heterogeneous charge variants, represented by 46-50kDa isoforms with more basic pIs compared to their counterparts in normal rats. Compared to control diabetic rats, RAGE labeling in the garlic-treated diabetic group was significantly reduced throughout renal and hepatic regions and was marked by the expression of 43-50kDa acidic charge variants comparable to those observed in normal rats. The capacity of garlic to modulate diabetes-induced up-regulation of selective RAGE polymorphic variants may be implicated in attenuating the detrimental consequences of excessive RAGE signaling manifested by diabetes-associated disorders. PMID- 26968223 TI - [Uveitis associated with spondylitis: It may be tuberculosis!]. PMID- 26968225 TI - Perioperative nutrition in cancer patients. PMID- 26968226 TI - Systematic review of health-related quality of life in patients undergoing pelvic exenteration. AB - BACKGROUND: Pelvic exenteration is a radical operative treatment reserved for the management of a number of advanced primary and recurrent pelvic malignancies, including, rectal, gynaecological and urological. The advances in radiological staging, surgical techniques and greater use of chemotherapeutic agents haves translated clinically into improvements in the overall survival of this cohort of patients, irrespective of underlying disease pathology. Consequently, a greater proportion of the surviving population will present to healthcare professionals with a range of physical and psychological issues, therefore the profiling and understanding of the health-related quality of life (HrQoL) is integral to the long term management of this cohort of patients. The aim of this systematic review is to identify HrQoL themes from the current literature relevant to patients undergoing a pelvic exenteration. METHODS: Literature searches were performed in three databases: MEDLINE (1975-November 2015), EMBASE and CINAHL. Each study was evaluated with regards to its design and statistical methodology. Data quality was reviewed in accordance with the Newcastle-Ottowa score and Critical Appraisal Skills Programme Checklist (CAPS) for quantitative and qualitative data accordingly. A narrative synthesis of all identified HrQoL issues was undertaken using the principles of content analysis. RESULTS: A total of 24 studies were identified; 20 quantitative and 4 qualitative with 976 patients assessed in total. HrQoL was assessed as the main primary endpoint in 15 studies. The majority of studies were retrospective. Baseline data prior to the initiation of treatments were available in 6 studies alone. Nine themes were identified across the literature, which included body image, social impact, sexual function, treatment expectations, symptoms, communication, psychological impact, relationships and work and finance. CONCLUSIONS: Pelvic exenteration has a wide ranging impact on patients HrQoL affecting a range of physical and psychological domains. PMID- 26968227 TI - Radiofrequency ablation and surgical resection of liver metastases from uveal melanoma. AB - BACKGROUND: The resection of liver metastasis from uveal melanoma (LMUM) remains controversial. In this study, we evaluated treatment with radiofrequency ablation (RFA) for liver metastases alone or in combination with surgical liver resection. METHODS: A total of 72 patients with LMUM were evaluated in this study. Of these, 57 patients underwent surgical resection (S) while 15 patients had RFA +/- S. Clinicopathologic factors were evaluated in terms of recurrence and survival using Chi-square and log-rank tests, respectively. RESULTS: We studied 22 metastases treated by RFA. There were no statistically significant differences between the groups in terms of median age of onset, synchronous nature of the metastases, time from primary tumour treatment to liver metastasis, diameter of the largest metastasis, presence of liver miliary disease, and the type of liver resection. There was a statistically lower number of liver metastases and more bilobar metastases in the RFA group than in the S group. The median overall survival after liver surgery was 27 months in group S and 28 months in the RFA group +/- S. The median disease-free survival was 10 months in group S and 7 months in the RFA group +/- S. There were no statistically significant differences in the median overall survival and disease-free survival between groups. CONCLUSIONS: The results of this retrospective analysis show that RFA can be used to treat liver metastases to spare the hepatic parenchyma. RFA +/- liver surgery and liver surgery alone demonstrate similar survival times. PMID- 26968229 TI - Flow modulation comprehensive two-dimensional gas chromatography-mass spectrometry using ~4 mL min(-1) gas flows. AB - The main objective of the herein described research was focused on performing satisfactory flow modulation (FM), in comprehensive two-dimensional gas chromatography-mass spectrometry (GC*GC-MS), using an MS-compatible second dimension gas flow of approx. 4 mL min(-1). The FM model used was based on that initially proposed by Seeley et al. [3]. The use of limited gas flows was enabled through fine tuning of the FM parameters, in particular the duration of the re injection (or flushing) process. Specifically, the application of a long re injection period (i.e., 700 ms) enabled efficient accumulation-loop flushing with gas flows of about 4 mL min(-1). It was possible to apply such extended re injection periods by using different restrictor lengths in the connections linking the modulator to the auxiliary pressure source. FM GC*GC-MS applications were performed on a mixture containing C9-10 alkanes, and on a sample of essential oil. GC*GC-MS sensitivity was compared with that attained by using conventional GC-MS analysis, in essential oil applications. It was observed that signal intensities were, in general, considerably higher in the FM GC*GC-MS experiments. PMID- 26968228 TI - Early results of multicenter phase II trial of perioperative oxaliplatin and capecitabine without radiotherapy for high-risk rectal cancer: CORONA I study. AB - BACKGROUNDS: Perioperative introduction of developed chemotherapy into the treatment strategy for locally advanced rectal cancer (LARC) may be a promising option. However, the most prevalent treatment for high-risk LARC remains preoperative chemoradiotherapy (CRT) in Western countries. PATIENTS AND METHODS: A phase II trial was undertaken to evaluate safety and efficacy of perioperative XELOX without radiotherapy (RT) for patients with high-risk LARC. Patients received 4 cycles of XELOX before and after surgery, respectively. Primary endpoint was disease-free survival. RESULTS: We enrolled 41 patients between June 2012 and April 2014. The completion rate of the preoperative XELOX was 90.3%. Twenty-nine patients (70.7%) could start postoperative XELOX, 15 of these patients (51.7%) completed 4 cycles. Allergic reaction to oxaliplatin was experienced by 5 patients (17.2%) during postoperative XELOX. One patient received additional RT after preoperative XELOX. Consequently, the remaining 40 patients underwent primary resection. Major complications occurred in 6 of 40 patients (15.0%). Pathological complete response (pCR) rate was 12.2%, and good tumor regression was exhibited in 31.7%. N down-staging (cN+ to ypN0) and T down staging were detected in 56.7% and 52.5%, respectively. Clinical T4 tumor was a predictor of poor pathological response (p < 0.001). CONCLUSIONS: We could show the favorable pCR rate after preoperative XELOX alone. However, the T and N down staging rate was likely to be insufficient. When tumor regression is essential for curative resection, the use of preoperative CRT is likely to be recommended. For patients with massive LN metastasis, the additional Bev to NAC might be a promising option. PMID- 26968230 TI - A practical gas chromatography flame ionization detection method for the determination of octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, and dodecamethylcyclohexasiloxane in silicone emulsions. AB - A gas chromatography with flame ionization detection (GC-FID) method for analysis of D4, D5, and D6 cyclic siloxanes in silicone emulsions is described. Sample preparation involves breaking the emulsion with methanol and hexanes, and then analyzing the hexanes phase after derivatization with hexamethyldisilazane (HMDS). Silylation is performed to reduce the potential for formation of cyclic siloxanes during the course of the GC analysis. The accuracy of the method was verified by performing analyses on samples spiked with known levels of D4, D5 and D6 and by comparison to a referee method using atmospheric pressure chemical ionization liquid chromatography with mass spectrometry detection (APCI-LC-MS). Absolute differences of the results obtained between the two techniques were 0.03 weight percent or less, and relative differences were 15% or less. The reproducibility and ruggedness of the method was demonstrated by performing a global round robin test at four different geographic sites on four different types of silicone emulsions. The %RSDs obtained were less than 10% for all analytes and all emulsions examined. PMID- 26968231 TI - Re: Tumour progression or pseudoprogression? A review of posttreatment radiological appearances of glioblastoma. A reply. PMID- 26968232 TI - Fusion of the First Metatarsophalangeal Joint: Precontoured or Straight Plate? AB - Precontoured, low-profile plates with fixed dorsiflexion angles are becoming increasingly popular for first metatarsophalangeal joint fusion. We have concerns that the routine use of a precontoured plate can lead to excessive clinical dorsiflexion. The aim of our study was to investigate the relationship between the first metatarsophalangeal joint dorsiflexion intramedullary angle and the angle formed at the dorsal cortices where the plate is applied. We hypothesized that the dorsal cortical angle was significantly less dorsiflexed than the intramedullary angle. We measured both angles on lateral weightbearing radiographs of 40 consecutive individuals presenting with forefoot symptoms. The results demonstrated that the mean dorsal cortical angle was significantly smaller (mean 0.2 degrees plantarflexion) compared with the intramedullary angle (mean 10.6 degrees dorsiflexion; p < .001). The interobserver and intraobserver reliability of both the intramedullary and the dorsal cortical measurements was very good. In conclusion, the dorsal cortical angle is, on average, 10.8 degrees smaller than the intramedullary angle, with a mean angle of almost 0 degrees . This finding should be considered when selecting plates for first metatarsophalangeal joint fusion. PMID- 26968233 TI - Value of Early Postoperative Computed Tomography Assessment in Ankle Fractures Defining Joint Congruity and Criticizing the Need for Early Revision Surgery. AB - Previous investigators have questioned the reliability of plain radiographs in assessing the accuracy of ankle fracture reduction when these were compared with the computed tomography (CT) evaluation in the preoperative setting, in particular, in fractures with syndesmosis injuries or trimalleolar fragments. The role of CT assessment, however, has not been investigated in the early postoperative setting. In the early postoperative setting, reduction still relies most commonly on fluoroscopy and plain radiographs alone. In the present study, we hypothesized that early postoperative CT assessment of ankle fractures with syndesmosic injuries and posterior malleolar fragments can add valuable information about the joint congruity compared with plain radiographs alone and that this information could affect the decisions regarding the need for early revision surgery. A total of 352 consecutive operated ankle fractures were reviewed. Of these, 68 (19%) underwent early postoperative CT assessment and were studied further to identify the causes that prompted revision surgery. Of the 68 cases, despite acceptable reduction found on the plain radiographs, 20 (29%) underwent early (within 1 week) revision surgery after studying the CT scans, which revealed malreduction of the syndesmosis, malreduction of the posterior lip fragment, and intra-articular fragments. We concluded that in ankle fractures involving disruptions of the syndesmosis or posterior malleolar fragments, early postoperative CT assessment could be justified, because it will reveal malreduction and prompt early revision intervention for a substantial proportion of these patients. PMID- 26968234 TI - The challenge of diagnosing a mixed asthma-COPD phenotype (ACOS) in clinical practice. PMID- 26968237 TI - Long-Term Health-Related Quality of Life in Patients With Rectal Cancer After Preoperative Short-Course and Long-Course (Chemo) Radiotherapy. AB - BACKGROUND: Both preoperative short-course radiotherapy (SC-PRT) and preoperative long-course chemo radiotherapy (CRT) have shown to reduce local recurrence rates after total mesorectal excision (TME), but neither resulted in improved survival. This study compared the long-term health-related quality of life (HRQL) and symptoms between CRT and SC-PRT. METHODS: Patients who were preoperatively treated with a total dose of 50.0 to 50.4 Gy for locally advanced rectal cancers were identified from 2 hospital registries. Starting from 2011, all patients who were disease-free in the study population (n = 105) were sent a HRQL questionnaire composed of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and questions on bowel and urinary function. Patients who underwent SC-PRT in the TME trial were used as a reference group. RESULTS: HRQL results from 85 patients receiving CRT (81.0%), with a median follow-up time of 58 months, were compared with the results of patients who underwent SC-PRT (n = 306). Apart from more nausea and vomiting reported by patients receiving CRT (mean score for CRT 5.9 vs. 1.3 for SC-PRT; P < .01; not clinically relevant) and less satisfaction with urinary function indicated by patients who received CRT (mean score for CRT 71.2 vs. 81.2 for SC-PRT; P < .01), no significant differences were found in HRQL and symptoms between patients who received CRT and SC-PRT. CONCLUSIONS: This analysis of HRQL in patients who received CRT shows no clinically relevant differences in long-term HRQL and symptoms between patients who received CRT and SC-PRT, apart from less satisfaction with urinary function reported by patients who received CRT. These results indicate that both approaches have a comparable impact on long-term HRQL. PMID- 26968239 TI - Non-traumatic L4-L5 spondyloptosis. PMID- 26968235 TI - The role of octamer binding transcription factors in glioblastoma multiforme. AB - A group of transcription factors (TF) that are master developmental regulators of the establishment and maintenance of pluripotency during embryogenesis play additional roles to control tissue homeostasis and regeneration in adults. Among these TFs, members of the octamer-binding transcription factor (OCT) gene family are well documented as major regulators controlling the self-renewal and pluripotency of stem cells isolated from different adult organs including the brain. In the last few years a large number of studies show the aberrant expression and dysfunction of OCT in different types of cancers including glioblastoma multiforme (GBM). GBM is the most common malignant primary brain tumor, and contains a subpopulation of undifferentiated stem cells (GSCs), with self-renewal and tumorigenic potential that contribute to tumor initiation, invasion, recurrence, and therapeutic resistance. In this review, we have summarized the current knowledge about OCT family in GBM and their crucial role in the initiation, maintenance and drug resistance properties of GSCs. This article is part of a Special Issue entitled: The Oct Transcription Factor Family, edited by Dr. Dean Tantin. PMID- 26968238 TI - Extraosseous Ewing sarcoma in the lumbar epidural space: an uncommon malignant tumor mimicking a spinal schwannoma. PMID- 26968236 TI - Impact of Primary Tumor Site on Bevacizumab Efficacy in Metastatic Colorectal Cancer. AB - BACKGROUND: With an ever-increasing focus on personalized medicine, all factors known to affect treatment response need to be considered when defining optimal therapy for individual patients. While the prognostic impact of primary tumor site on colorectal cancer (CRC) outcomes is established, emerging data suggest potential differences in response to biologic therapies. We studied the impact of tumor site on bevacizumab efficacy in patients with metastatic CRC. PATIENTS AND METHODS: We analyzed data of patients in an Australian prospective multicenter metastatic CRC (mCRC) registry who received first-line chemotherapy. Tumor site was defined as right colon, cecum to transverse; left colon, splenic flexure to rectosigmoid; and rectum. Kaplan-Meier and Cox models were used for survival analyses. RESULTS: Of 926 patients, 297 had right colon, 354 left colon, and 275 rectum primary disease. Median age was 68.6, 65.9, and 63.3 years, respectively (P = .001). Right colon disease was significantly associated with intraperitoneal spread (P < .0001), while left colon and rectum disease preferentially metastasized to the liver and lungs, respectively (P < .0001 in both settings). A total of 636 patients (68.7%) received bevacizumab. Progression-free survival was superior for bevacizumab-treated patients in all groups but appeared greatest in right colon disease (hazard ratio, 0.46; 95% confidence interval, 0.36-0.60; P <= .001). Overall survival was longest in patients with disease of the rectum, followed by left colon and right colon (median, 26.2, 23.6, and 18.2 months, respectively; P = .0004). CONCLUSION: Tumor site appears to be prognostic in mCRC, with rectum and right colon disease associated with the best and worst outcomes, respectively. Patients who received bevacizumab in addition to chemotherapy had superior outcomes, with the effect appearing greatest in patients with right colon disease. PMID- 26968240 TI - Barriers That Impede the Provision of Pain Care to Neonates by Nurses in Jordan. AB - OBJECTIVE: To describe perceived barriers to neonatal pain care and suggest strategies to overcome these barriers among NICU nurses in Jordan. DESIGN: Descriptive study. SETTING: Eighteen NICUs in Jordan. PARTICIPANTS: One hundred eighty-four neonatal nurses. METHODS: Nurses completed a questionnaire on perceived barriers to neonatal pain care. Descriptive statistics were used to analyze the data. RESULTS: One of the main issues that hindered the effective practice of neonatal pain care was the underuse of structured pain measurements, especially for painful procedures (72%). Furthermore, participants indicated minimal knowledge about pain medication for neonates (66%) and feared adverse effects (50%). The participants received inadequate training about neonatal pain care during their initial orientation (24%) and while in service (19%). Participants perceived low interprofessional appreciation of any input into pain care decisions (72%). Finally, only 39% of participants supported the involvement of parents in pain care for their neonates, and 82% were against it during painful procedures. CONCLUSION: Efforts to improve neonatal pain care should focus on improving nurses' knowledge about neonatal pain, increasing competencies and involvement in pain management options, and improving channels of professional communication about neonatal pain. PMID- 26968241 TI - Perceived Fertility Control and Pregnancy Outcomes Among Abused Women. AB - OBJECTIVE: To describe the degree of perceived fertility control and associated likelihood of unintended pregnancy and poor pregnancy outcomes among women who report intimate partner violence. DESIGN: Cross-sectional cohort study design. SETTING: Five domestic violence shelters and one district attorney's office in a large urban metropolis in the United States. PARTICIPANTS: A total of 282 women who reported intimate partner violence and reached out for the first time to a shelter or district attorney's office for assistance. METHODS: This 7-year prospective longitudinal study began in 2011. Participants in the overarching study are being interviewed every 4 months. During the 32-month interview period, participants responded to a one-time, investigator-developed, fertility control questionnaire in addition to the ongoing repeated measures. RESULTS: Almost one third (29%) of the participants reported at least one unintended pregnancy attributed to their abusers' refusal to use birth control, and 14.3% of the participants reported at least one unintended pregnancy as a result of their abusers' refusal to allow them to use birth control. Participants were 28 times more likely to have abuse-induced miscarriages if their pregnancies resulted because their abusers did not use birth control (OR = 28.70, p < .05). Finally, participants were 8 times more likely to report premature births if they were abused because of their use of birth control (OR = 8.340, p < .05). CONCLUSION: Women in abusive relationships reported compromised fertility control associated with abuse and increased risk for unintended pregnancy as well as the adverse pregnancy outcomes of premature birth and miscarriage. PMID- 26968242 TI - A Call to Action to Prevent Cardiovascular Disease in Women. PMID- 26968243 TI - A Review of the Literature on Cardiac Symptoms in Older and Younger Women. AB - OBJECTIVE: To describe acute and prodromal cardiac symptoms in older and younger women. DATA SOURCES: PubMed, CINAHL, MEDLINE, and Web of Science databases were searched for articles published between January 2000 and January 2015. STUDY SELECTION: A combination of the MESH terms acute coronary syndrome, myocardial infarction, symptoms, prodromal symptoms, sex, gender, and age was used. The search was limited to studies on humans published in English and original articles related to symptoms of acute coronary syndrome (ACS) in women with symptoms stratified by age or analyses adjusted for age and/or sex. DATA EXTRACTION: A total of 432 articles were identified, and 20 met the inclusion criteria. DATA SYNTHESIS: Key findings for differences in acute ACS symptoms for women based on age included the following: (a) typical chest pain and pain of any kind were less likely in older women (>=65 years); (b) women were more likely to have nonpain symptoms of nausea, dyspnea, and fatigue after adjustment for age; (c) most researchers did not adjust for menopausal status or hormone replacement therapy; and (d) findings were consistent across international cohorts. The most common prodromal symptoms in women after adjustment for age included unusual fatigue, discomfort in arms, sleep disturbance, anxiety, general chest discomfort, discomfort in jaws/teeth, and shortness of breath. Although chest symptoms were reported by some women, they were not reported by most women. CONCLUSION: Women older than 65 years with ACS experienced fewer symptoms, more ambiguous symptoms, less chest pain, and more dyspnea. Women older than 50 years were more likely to report prodromal symptoms that include sleep disturbance. Many symptom differences that were statistically significant by age, such as chest pain and shortness of breath, may not be clinically relevant. PMID- 26968244 TI - Impacts of incorporation of follicle stimulating hormone into an estrous synchronization protocol for timed artificial insemination of crossbred beef cattle. AB - One-hundred-eighty crossbred beef cows and 66 crossbred beef heifers across three locations were stratified by body weight (BW), body condition score (BCS), and age (within location) to evaluate administration of follicle stimulating hormone (FSH) on Day 2 using a modified 7-day CO-Synch plus CIDR((r)) protocol (Day 0=CIDR insertion) with timed-artificial insemination (TAI) at 72 h (cows) or 54 h (heifers) following CIDR removal. Estrous response following CIDR removal was determined using an Estrotect patch and TAI and final pregnancy rates were determined by transrectal ultrasonography 42-45 days following TAI and >= 45 days following removal of clean-up bulls. Estrous response rate, TAI and final pregnancy rates for cows were not affected (P >= 0.65) by treatment. Cows that exhibited estrus had greater (P<0.01) TAI pregnancy rate (66%) than cows not exhibiting estrus (38%). There was an estrous response by postpartum length interaction (P=0.02) where cows exhibiting estrus and >= 55 days postpartum had greater TAI pregnancy rates (75%) compared to cows not exhibiting estrus and < 55 days postpartum (39%) or >= 55 days postpartum (28%). For heifers, timed AI (P=0.46) and final pregnancy rates (P=0.45) were similar across treatments and estrous response had no effect (P=0.30) on TAI pregnancy rates. In conclusion, the addition of FSH to the CO-Synch plus CIDR estrous synchronization protocol did not increase TAI pregnancy rates in beef cows or heifers. However, a positive estrous response to the synchronization protocol was associated with increased TAI pregnancy rates in cows. PMID- 26968245 TI - Change of uterine histroph proteins during follicular and luteal phase in pigs. AB - The aim of this study was to examine protein expression patterns of uterine histroph (UH) during the follicular phase (FP) and luteal phase (LP) in pigs. Forty-nine common proteins were identified from FP and LP samples; five were significantly down-regulated (>1.5-fold), while 15 were significantly up regulated (>1.5-fold) in LPUH compared with FPUH (P<0.05). The 20 differentially expressed proteins are involved in cell proliferation, cell responses, translation, transport, and metabolism and their molecular functions include nucleic acid binding, oxygen activity, enzymatic activity, growth activity, iron binding, and redox binding. Protein expression of vascular endothelial growth factor D (VEGFD), coatomer subunit gamma-2 (G2COP), collagen alpha 4 chain (COL4), cysteine rich protein 2 (CRP2), myoglobin (MYG), and galactoside 3-L fucosyltransferase 4 (FUT4) was analyzed by Western blotting. These proteins were significantly higher in LPUH compared to FPUH (P<0.05). These data expand our understanding of changes in the intrauterine environment during the pre implantation period in pigs. PMID- 26968246 TI - Effect of supplemental trace mineral level and form on peripubertal bulls. AB - Objectives were to determine if supplemental trace mineral levels and/or forms (sulfate and metal amino acid complexes) influence age at puberty, semen quality, endocrine status, and scrotal circumference in peripubertal bulls. Fifty peripubertal bulls were blocked by age and scrotal circumference and assigned to one of five treatments: (1) 1x sulfate form (1S); (2) 1x complexed form (1C); (3) 1S+1C (2SC); (4) 1S + 2 * 1 C (3SCC); and (5) 3 * 1S (3S). Each 1x supplementation level contained 360 mg Zn, 125 mg Cu, 200mg Mn and 12.5mg Co. Liver biopsies were collected on d -21 and 100, and scrotal circumference, semen, and blood samples were collected on d -14, 14, 42, 70, and 98. All bulls were deficient in Cu yet adequate in Zn on d -21. Following 100 d on treatment, liver Zn concentrations decreased (P<0.01) and liver Cu concentrations increased (P<0.01) in bulls regardless of treatment. Day 100 liver Zn concentrations were similar (P=0.50) across treatments, but liver Cu concentrations were greater (P=0.07) in 3SCC and 3S bulls compared to 1C and 1S bulls, whereas 2SC bulls were intermediate. Bulls fed complexed minerals tended to reach puberty after fewer (P=0.11) days on treatment (43.9 +/- 5.7 d) than bulls fed only sulfate minerals (58.5 +/- 6.7 d). Supplementing complexed Cu and Zn to prepubertal bulls may lower the age at puberty, however, no differences (P >= 0.40) in semen characteristics or scrotal measurements (P >= 0.11) were observed. PMID- 26968247 TI - Combined inhibition of the mevalonate pathway with statins and zoledronic acid potentiates their anti-tumor effects in human breast cancer cells. AB - Amino-bisphosphonates are antiresorptive drugs for the treatment of osteolytic bone metastases, which are frequently caused by breast and other solid tumors. Like statins, amino-bisphosphonates inhibit the mevalonate pathway. Direct anti tumor effects of amino-bisphosphonates and statins have been proposed, although high concentrations are required to achieve these effects. Here, we demonstrate that the treatment of different human breast cancer cell lines (MDA-MB-231, MDA Bone, and MDA-Met) by combined inhibition of the mevalonate pathway using statins and zoledronic acid at the same time significantly reduces the concentrations required to achieve a meaningful anti-tumor effect over a single agent approach (50% reduction of cell vitality and 4-fold increase of apoptosis; p < 0.05). The effects were mediated by suppressed protein geranylation that caused an accumulation of GTP-bound RhoA and CDC42. Importantly, the knockdown of both proteins prior to mevalonate pathway inhibition reduced apoptosis by up to 65% (p < 0.01), indicating the accumulation of the GTP-bound GTPases as the mediator of apoptosis. Our results point to effective anti-tumor effects in breast cancer by the combination of statins and zoledronic acid and warrant further validation in preclinical settings. PMID- 26968248 TI - Screening and identification of molecular targets for cancer therapy. AB - In recent decades, targeted therapeutics have significantly improved therapy results in patients with malignant tumors of different origins. However, malignant diseases characterized by aggressiveness and increased capacity for metastatic spread still require basic researchers and clinicians to direct enormous efforts toward the development of novel therapeutic targets. Potential targets should be selected with the clinical endpoint in view; targeted therapeutics can be developed: for use in combination with currently existing therapeutic approaches in order to improve their efficacy; to overcome the treatment resistance of tumor cells and thus protect the patient from recurrence; to repress molecular mechanisms related to immune escape of cancer cells; and to combat the metastatic dissemination of carcinoma cells. Taking into account the specific clinical aim that should be achieved, different strategies and techniques can be proposed to identify the most promising candidate molecules for further development as therapeutic targets. Since cellular membranes contain a large number of druggable molecules, evaluation of the membrane protein profiles of carcinoma cells having different properties can provide a basis for further development of therapeutic targets. This review considers how cellular membranes obtained from different pre-clinical and clinical samples can be used in screening and to identify targets for cancer therapy. PMID- 26968250 TI - Prevailing over T cell exhaustion: New developments in the immunotherapy of pancreatic cancer. AB - Pancreatic cancer is one of the most aggressive malignancies and has been considered poorly immunogenic for decades. However, this characterization might be over-simplistic. A more sophisticated approach is needed in order to develop new treatment strategies. In this review, we will focus on T cell exhaustion as a phenomenon of immune failure that is a useful paradigm to characterize immunosuppressive effects. Cancer creates an environment of constant antigen exposure and inflammation. In this setting, T cells transform into a differentiation state that has been termed T cell exhaustion, which is characterized by upregulation of inhibitory receptors, resulting in loss of effector function. The discovery of receptor-mediated immune checkpoints, which prevent uncontrolled T cell reactions, led to the development of a new class of antibodies termed checkpoint inhibitors. Unprecedented results in patients with metastatic melanoma and lung cancer have renewed interest in the immunotherapy of other solid tumor entities, including pancreatic cancer. Data on the efficacy of checkpoint inhibitors in pancreatic cancer are still sparse and indicate limited efficacy as single agents. Combination of checkpoint inhibitors with other immune activating strategies or cytotoxic drugs might be a way to overcome therapy resistance in the treatment of pancreatic cancer. PMID- 26968249 TI - C/EBPbeta regulates sensitivity to bortezomib in prostate cancer cells by inducing REDD1 and autophagosome-lysosome fusion. AB - The purpose of this study was to ascertain the mechanisms by which advanced prostate cancer cells resist bortezomib therapy. Several independent studies have shown that cells are protected from proteasome inhibition by increased autophagic activity. We investigated whether C/EBPbeta, a transcription factor involved in the control of autophagic gene expression, regulates resistance to proteasome inhibition. In PC3 cells over-expressing C/EBPbeta, turnover of autophagic substrates and expression of core autophagy genes were increased. Conversely, C/EBPbeta knockdown suppressed autophagosome-lysosome fusion. We also found that C/EBPbeta knockdown suppressed REDD1 expression to delay early autophagy, an effect rescued by exogenous REDD1. Cells with suppressed C/EBPbeta levels showed delayed autophagy activation upon bortezomib treatment. Knockdown of C/EBPbeta sensitized PC3 cells to bortezomib, and blockade of autophagy by chloroquine did not further increase cell death in cells expressing shRNA targeting C/EBPbeta. Lastly, we observed a decreased growth of PC3 cells and xenografts with C/EBPbeta knockdown and such xenografts were sensitized to bortezomib treatment. Our results demonstrate that C/EBPbeta is a critical effector of autophagy via regulation of autolysosome formation and promotes resistance to proteasome inhibitor treatment by increasing autophagy. PMID- 26968252 TI - Development of sheep primordial follicles encapsulated in alginate or in ovarian tissue in fresh and vitrified samples. AB - In vitro follicle growth is a promising strategy for female fertility preservation. This study was conducted to compare the development of ovine follicles either isolated or in the context of ovarian cortical pieces after short term (8 days) three-dimensional culture in fresh and vitrified samples. Four different experiments were conducted; I) culture of ovarian cortical pieces encapsulated in 0.5% and 1% alginate and without alginate encapsulation (CP-0.5%, CP-1% and CP, respectively), II) culture of isolated primordial and primary follicles encapsulated in 1% and 2% alginate (IF-1% and IF-2%, respectively), III) culture of fresh and vitrified-warmed cortical pieces (F-CP and Vit-CP, respectively), and IV) culture of fresh and vitrified-warmed encapsulated isolated follicles (F-IF and Vit-IF, respectively). The number of secondary follicles after culture was negatively influenced by encapsulation of ovarian cortical pieces (6.3 +/- 3.3 and 10.6 +/- 0.9 vs 21.5 +/- 2.3 in CP-0.5% and CP 1% vs CP, respectively). The diameter of follicles in IF-2% was higher than IF-1% (54.06 +/- 2 vs 41.9 +/- 1.5) and no significant difference in follicular viability was observed between the two groups. The proportions of different follicular types and their viability after culture in vitrified-warmed cortical pieces were comparable with fresh ones. The viability of vitrified-warmed isolated follicles was lower than fresh counterparts. The growth rate of fresh follicles was higher than vitrified-warmed follicles after culture (47.9 +/- 1 vs 44.6 +/- 1). In conclusion, while encapsulation of ovarian cortical pieces decreased the follicles' development, it could better support the growth of isolated follicles. Moreover, the viability and growth rate of isolated encapsulated follicles was decreased by vitrification. PMID- 26968253 TI - Recent progress on third generation covalent EGFR inhibitors. AB - First generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (gefitinib and erlotinib) demonstrate excellent clinical efficacy for NSCLC patients carrying EGFR oncogenic mutations (L858R, del exon 19 deletions between amino acids 746 and 750). Invariable, drug resistance occurs with around 60% of it driven by the EGFR-T790M gatekeeper mutation. To counter the T790M dependent resistance, third generation covalent EGFR inhibitors have been developed with high potency toward T790M containing mutants and selectivity over WT EGFR. This review provides an overview of the third generation drugs currently in clinical trials and also encompasses novel methodologies developed to discover third generation covalent EGFR drugs. PMID- 26968251 TI - Using a public health station for screening of undiagnosed dysglycemia and hypertension. AB - AIM: Dysglycemia, diabetes and abnormal blood pressure screening can be conducted by trained volunteers and may identify unknown cases. The aim of the study was to examine the feasibility and effectiveness of operating a screening station in pubic setting supervised by diabetes unit. METHODS: A cross-sectional analysis of a program offering free screening services to non-hospitalized subjects. From 1.1.2011 through 31.12.2013 trained volunteers measured height, weight, blood glucose and blood pressure at the main entrance of the hospital. Subjects were asked whether they had diabetes or hypertension. Dysglycemia was defined as blood glucose 141-199mg/dL and probable newly-identified diabetes as >=200mg/dL. RESULTS: 13,112 adults underwent screening. Among the screened individuals (age 55.3+/-14.9 years) 2215 (16.9%) reported diabetes and 3037 (23.2%) hypertension. Among subjects without known hypertension, 9.6% had blood pressure >=140/90. Among the subjects without known diabetes, 5012 (46%) had glucose <=110mg/dL, 2873 (26.4%) >=126mg/dL, 1553 (14.3%) >140mg/dL and 170 (1.6%) >=200mg/dL. Compared to subjects with blood glucose <=140mg/dL, those with dysglycemia or diabetes were older (58.9+/-13.4 vs. 52.7+/-15.2 years, P<0.001), had elevated BMI (27.5+/-4.6kg/m(2) vs. 26.6+/-4.6kg/m(2), P<0.001), higher systolic (137.5+/ 22.2mmHg vs. 132.2+/-21.3mmHg, P<0.001) and diastolic blood pressure (80.3+/ 15.6mmHg vs. 78.6+/-13.7mmHg, P<0.001). Compared to subjects with blood glucose<200mg/dL, those with probable newly-identified diabetes were older (58.6+/-10.9 vs. 53.5+/-15.2, P<0.001), had elevated BMI (28.4+/-4.8kg/m(2) vs. 26.7+/-4.6kg/m(2), P<0.001), higher systolic (139.4+/-24.0mmHg vs. 132.8+/ 21.4mmHg, P<0.001) and diastolic blood pressure (85.4+/-20.7mmHg vs. 78.8+/ 13.9mmHg, P<0.001). CONCLUSIONS: Screening supervised by healthcare center can identify individuals at high-risk for dysglycemia and abnormal blood pressure, who are referred for further diagnosis and treatment and may serve as a complementary step in primary health care setting. PMID- 26968254 TI - Status of underrepresented minority and female faculty at medical schools located within Historically Black Colleges and in Puerto Rico. AB - BACKGROUND AND OBJECTIVES: To assess the impact of medical school location in Historically Black Colleges and Universities (HBCU) and Puerto Rico (PR) on the proportion of underrepresented minorities in medicine (URMM) and women hired in faculty and leadership positions at academic medical institutions. METHOD: AAMC 2013 faculty roster data for allopathic medical schools were used to compare the racial/ethnic and gender composition of faculty and chair positions at medical schools located within HBCU and PR to that of other medical schools in the United States. Data were compared using independent sample t-tests. RESULTS: Women were more highly represented in HBCU faculty (mean HBCU 43.5% vs. non-HBCU 36.5%, p=0.024) and chair (mean HBCU 30.1% vs. non-HBCU 15.6%, p=0.005) positions and in PR chair positions (mean PR 38.23% vs. non-PR 15.38%, p=0.016) compared with other allopathic institutions. HBCU were associated with increased African American representation in faculty (mean HBCU 59.5% vs. non-HBCU 2.6%, p=0.011) and chair (mean HBCU 73.1% vs. non-HBCU 2.2%, p<=0.001) positions. PR designation was associated with increased faculty (mean PR 75.40% vs. non-PR 3.72%, p<=0.001) and chair (mean PR 75.00% vs. non-PR 3.54%, p<=0.001) positions filled by Latinos/Hispanics. CONCLUSIONS: Women and African Americans are better represented in faculty and leadership positions at HBCU, and women and Latino/Hispanics at PR medical schools, than they are at allopathic peer institutions. PMID- 26968255 TI - [A prospective study to compare the efficiency of oocyte vitrification using closed or open devices]. AB - OBJECTIVES: Oocyte vitrification using an open device is thought to be a source of microbiological and chemical contaminations that can be avoided using a closed device. The principal purpose of this study was to compare the two vitrification protocols: closed and open system. The secondary aim was to study the effects of the storage in the vapor phase of nitrogen (VPN) on oocytes vitrified using an open system and to compare it to those of a storage in liquid nitrogen (LN). METHODS: Forty-four patients have been included in our study between November 2014 and May 2015. Two hundred and fourteen oocytes have been vitrified at germinal vesicle (GV), metaphase I (0PB) and metaphase II (1PB) stages. We vitrified 96 oocytes (59 GV/37 0PB) using a closed vitrification device and 118 oocytes (57 GV/31 0PB/30 1PB) using an open device. The vitrified oocytes were then stored either in LN or in VPN. The main outcome measures were the survival rate after warming (SR), meiosis resumption rate (MRR) and maturation rate (MR). RESULTS: The global post-thaw SR was significantly higher for oocytes vitrified using an open system (93.2%) compared to those vitrified using a closed one (64.5%; P<0.001). On the contrary, there was no significant difference in terms of global MRR and MR (82.1% vs. 87.5% and 60.7% vs. 61.2% using closed and open system respectively). The SR, MRR and the MR were not significantly different when vitrified oocytes were stored in VPN or LN (91.6, 83.8, 64.5% vs. 93.9, 89.8, 59.1% respectively). CONCLUSION: Taking into account the limits of our protocol, the open vitrification system remains the more efficient system. The use of sterile liquid nitrogen for oocyte vitrification and the subsequent storage in vapor phase of nitrogen could minimize the hypothetical risks of biological and chemical contaminations. PMID- 26968256 TI - Is the main lacrimal gland indispensable? Contributions of the corneal and conjunctival epithelia. AB - The ocular surface system is responsible for ensuring that the precorneal tear film is sufficient in both quality and quantity to preserve optimal vision. Tear secretion is a complex, multifactorial process, and dysfunction of any component of the ocular surface system can result in tear film instability and hyperosmolarity with resultant dry eye disease. The tear film is primarily composed of lipids, aqueous, and mucins, with aqueous accounting for most of its thickness. The aqueous is produced by the main lacrimal gland, accessory lacrimal glands, and corneal and conjunctival epithelia. Although the main lacrimal gland has long been considered an indispensable source of the aqueous component of tears, there is evidence that adequate tear secretion can exist in the absence of the main lacrimal gland. We review and discuss the basics of tear secretion, the tear secretory capacity of the ocular surface, and emerging treatments for dry eye disease. PMID- 26968257 TI - Influence of Sorafenib and Bevacizumab on pancreatic volume - A monocentric CT based analysis. AB - BACKGROUND/OBJECTIVES: Angiogenesis plays a central role in tumor growth and metastasis and tyrosine kinases are crucial in the modulation of growth factor signaling. Several side effects of tyrosine kinase inhibitors have been reported, including diarrhea due to pancreatic insufficiency. The suspected mechanism is the anti-angiogenetic effect of the inhibited vascular endothelial growth factor (VEGF) causing a disturbance of the microvasculation. The aim of the present study was to determine the volume of the pancreas before and after a therapy both with the multi-tyrosine kinase inhibitor Sorafenib and Bevacizumab, which is a humanized monoclonal immunoglobulin G1 antibody against VEGF. METHODS: Retrospective monocentric study including 42 patients who received either Sorafenib, Bevacizumab combined with Flourouracil and/or Irinotecan, or singly Flourouracil and Irinotecan for different non-pancreatic malignancies. The volume of the pancreas was measured before and after therapy by CT-scan based volumetry. RESULTS: The pancreatic volume was statistically significantly lower after treatment with Sorafenib (75.4 mL vs. 71.0 mL; p = 0.006) or Bevacizumab and Fluorouracil +/- Irinotecan (71.8 mL vs. 62.6 mL; p = 0.020). The pancreatic volume did not change statistically significantly after treatment with Fluorouracil +/- Irinotecan only (51.1 mL vs. 49.9 mL; p = 0.142). CONCLUSIONS: Pancreatic volume decreases statistically significantly under treatment with both the multi-tyrosine kinase inhibitor Sorafenib and the angiogenesis inhibitor Bevacizumab. This volume reduction is most likely due to a reduced microvasculation by inhibition of VEGF. PMID- 26968258 TI - Prevalence of Skin Cancer and Related Skin Tumors in High-Risk Kidney and Liver Transplant Recipients in Queensland, Australia. AB - The increased skin cancer incidence in organ transplant recipients is well-known, but the skin cancer burden at any one time is unknown. Our objective was to estimate the period prevalence of untreated skin malignancy and actinic keratoses in high-risk kidney and liver transplant recipients and to assess associated factors. Organ transplant recipients underwent full skin examinations by dermatologically trained physicians. The proportion of examined organ transplant recipients with histopathologically confirmed skin cancer in the 3-month baseline period was estimated. Prevalence ratios with 95% confidence intervals indicated significant associations. Of 495 high-risk organ transplant recipients (average age = 54 years, time immunosuppressed = 8.9 years), 135 (27%) had basal cell carcinoma, squamous cell carcinoma or Bowen's disease (intraepidermal carcinoma) present and confirmed in the baseline period, with respective prevalence proportions of 10%, 11%, and 18% in kidney transplant recipients and 10%, 9%, and 13% in liver transplant recipients. Over 80% had actinic keratosis present, with approximately 30% having 5 or more actinic keratoses. Organ transplant recipients with the highest skin cancer burden were Australian born, were fair skinned (prevalence ratio = 1.61, 95% confidence interval = [1.07, 2.43]), reported past skin cancer (prevalence ratio =3.39, 95% confidence interval = [1.93, 5.95]), and were receiving the most frequent skin checks (prevalence ratio = 1.76, 95% confidence interval = [1.15, 2.70]). In conclusion, high-risk organ transplant recipients carry a substantial measurable skin cancer burden at any given time and require frequent review through easily accessible, specialized services. PMID- 26968259 TI - Whole Genome Linkage Analysis Followed by Whole Exome Sequencing Identifies Nicastrin (NCSTN) as a Causative Gene in a Multiplex Family with gamma-Secretase Spectrum of Autoinflammatory Skin Phenotypes. PMID- 26968260 TI - Regulation of Melanoma Progression through the TCF4/miR-125b/NEDD9 Cascade. AB - Melanoma progression from a primary lesion to a distant metastasis is a complex process associated with genetic alterations, epigenetic modifications, and phenotypic switches. Elucidation of these phenomena may indicate how to interfere with this fatal disease. The role of microRNAs as key negative regulators of gene expression, controlling all cellular processes including cell migration and invasion, is now being recognized. Here, we used in silico analysis of microRNA expression profiles of primary and metastatic melanomas and functional experiments to show that microRNA-125b (miR-125b) is a determinant candidate of melanoma progression: (i) miR-125b is more strongly expressed in aggressive metastatic than primary melanomas, (ii) there is an inverse correlation between the amount of miR-125b and overall patient survival, (iii) invasion/migration potentials in vitro are inversely correlated with the amount of miR-125b in a series of human melanoma cell lines, and (iv) inhibition of miR-125b reduces migratory and invasive potentials without affecting cell proliferation in vitro. Furthermore, we show that neural precursor cell expressed developmentally down regulated protein 9 (i.e., NEDD9) is a direct target of miR-125b and is involved in modulating melanoma cell migration and invasion. Also, transcription factor 4, associated with epithelial-mesenchymal transition and invasion, induces the transcription of miR-125b-1. In conclusion, the transcription factor 4/miR 125b/NEDD9 cascade promotes melanoma cell migration/invasion. PMID- 26968261 TI - Cartilage Oligomeric Matrix Protein Increases in Photodamaged Skin. AB - Cartilage oligomeric matrix protein (COMP) is a structural component of cartilage. Recent studies have described COMP as a pathogenic factor that promotes collagen deposition in fibrotic skin disorders such as scleroderma and keloid skin. Although collagen, a major dermis component, is thought to decrease in photoaged skin, recent reports have demonstrated the presence of tightly packed collagen fibrils with a structural resemblance to fibrosis in the papillary dermis of photoaged skin. Here we examined how photoaging damage relates to COMP expression and localization in photoaged skin. In situ hybridization revealed an increase in COMP-mRNA-positive cells with the progress of photoaging in preauricular skin (sun-exposed skin). The signal intensity of immunostaining for COMP increased with photoaging in not only the papillary dermis but also the reticular dermis affected by advancing solar elastosis. Immunoelectron microscopy detected the colocalization of COMP with both elastotic materials and collagen fibrils in photoaged skin. Ultraviolet light A irradiation of human dermal fibroblasts induced COMP expression at both the mRNA and protein levels. Ultraviolet light A-induced COMP expression was inhibited by an anti transforming growth factor-beta antibody or SB431542, an activin receptor-like kinase 5 inhibitor. These results suggest that the transforming growth factor beta-mediated upregulation of COMP expression may contribute to the modulation of dermal extracellular matrix in the photoaging process. PMID- 26968262 TI - Pseudouridylation meets next-generation sequencing. AB - The isomerization of uridine to pseudouridine (Psi), known as pseudouridylation, is the most abundant post-transcriptional modification of stable RNAs. Due to technical limitations in pseudouridine detection methods, studies on pseudouridylation have historically focused on ribosomal RNAs, transfer RNAs, and spliceosomal small nuclear RNAs, where Psis play a critical role in RNA biogenesis and function. Recently, however, a series of deep sequencing methods Pseudo-seq, Psi-seq, PSI-seq, and CeU-seq-has been published to map Psi positions across the entire transcriptome with single nucleotide resolution. These data have greatly expanded the catalogue of pseudouridylated transcripts, which include messenger RNAs and noncoding RNAs. Furthermore, these methods have revealed conditionally-dependent sites of pseudouridylation that appear in response to cellular stress, suggesting that pseudouridylation may play a role in dynamically modulating RNA function. Collectively, these methods have opened the door to further study of the biological relevance of naturally occurring Psis. However, an in-depth comparison of these techniques and their results has not yet been undertaken despite all four methods relying on the same basic principle: Psi detection through selective chemical labeling by the carbodiimide known as CMC. In this article, we will outline the currently available high-throughput Psi detection methods and present a comparative analysis of their results. We will then discuss the merits and limitations of these approaches, including those inherent in CMC conjugation, and their potential to further elucidate the function of this ubiquitous and dynamic modification. PMID- 26968263 TI - [Updates on prevention and treatment of melanoma: Pharmacist involvements and challenges]. AB - Melanoma is a skin cancer that represents an actual public health problem. Its incidence is increasing every year. Environmental risk factors have been clearly identified. Early diagnosis of a suspicious skin lesion should be possible by any health professionals because the prognosis is correlated with the evolution of the disease and the presence of metastases. The advent of new therapies in metastatic forms with the development of immunotherapies and kinases inhibitors has significantly changed the management of this disease. New therapies are available in retail pharmacies and involve health professionals out of the hospital. This article is intended for community and hospital pharmacists and summarizes recommendations for primary and secondary prevention. It updates on new targeted therapies. It wants to give advices to the community pharmacists about the effective use of those treatments for melanoma. PMID- 26968264 TI - The redox-active drug metronidazole and thiol-depleting garlic compounds act synergistically in the protist parasite Spironucleus vortens. AB - Spironucleus vortens is a protozoan parasite associated with significant mortalities in the freshwater angelfish, Pterophyllum scalare. Control of this parasite is especially problematic due to restrictions on the use of the drug of choice, metronidazole (MTZ), on fish farms. Use of garlic (Allium sativum) is undergoing a renaissance following experimental validations of its antimicrobial efficiency. Ajoene ((E,Z)-4,5,9-trithiadodeca-1,6,11-triene 9-oxide), is a stable transformation product of allicin, the primary biologically active component of garlic. In the current study, an ajoene oil crude extract had a minimum inhibitory concentration (MIC) of 40MUg/ml against S. vortens. GC-MS and NMR spectroscopy revealed this ajoene extract contained a mixture of the (E) and (Z) ajoene isomers along with diallyl disulphide (DADS) and diallyl trisulphide (DATS). The only component of the ajoene crude oil found to substantially inhibit S. vortens growth by optical density monitoring (Bioscreen C Reader) was (Z) ajoene (MIC 16MUg/ml). Ajoene oil acted in synergy with MTZ in vitro, reducing the individual MIC of this drug (4MUg/ml) by 16-fold, and that of ajoene oil by 200-fold with a fractional inhibitory concentration (FIC) index of 0.263. This synergistic interaction was confirmed in vivo. S. vortens-infected Pterophyllum scalare angelfish dosed orally with 0.5% (v/w) MTZ combined with 0.05% (v/w) ajoene displayed a significant reduction in faecal trophozoite count, whilst those fed on 0.5% MTZ flakes (half the recommended oral dose) alone did not. This study demonstrates for the first time the synergistic interaction between the synthetic drug MTZ and natural ajoene oil both in vitro and in vivo. Future work should evaluate the potential synergy of ajoene and MTZ against MTZ-resistant bacteria and protists. PMID- 26968266 TI - Changes in oral health-related quality of life during implant treatment in partially edentulous patients: A prospective study. AB - PURPOSE: The aim of this prospective study was to evaluate the changes in oral health-related quality of life (OHRQoL) during implant treatment for partially edentulous patients, and to evaluate the influence of the type of partially edentulous arch. METHODS: Twenty patients with a small number of lost teeth (fewer than 4 teeth) who underwent implant treatment were selected. Chronological QOL change during implant treatment was measured. The subjects completed the shortened Japanese version of the Oral Health Impact Profile (OHIP-J14) before the surgery (T0), 1 week after the surgery (T1), 1 week after interim prosthesis placement (T2), and 1 week after definitive prosthesis placement (T3). Complete data of the twenty subjects were analyzed with the Wilcoxon signed-rank test. RESULTS: The total OHIP-J14 score was significantly reduced only at T3 (P<0.05). "Physical pain" and "Physical disability" scores significantly decreased at T3, and "Psychological discomfort" scores also significantly dropped at T2. However, "Functional limitation" scores significantly increased at T1. "Psychological disability", "Social disability", and "Handicap" scores remained the same. On the other hand, in the comparison depending on the type of partially edentulous arch, the total OHIP-J14 score significantly decreased at T3 in the unilateral free-end edentulous space, whereas no significant difference was observed in the bounded edentulous space. CONCLUSION: Although there is a temporary functional limitation after implant placement in overall OHRQoL improvement was observed after the definitive prosthesis placement. Moreover, implant treatment was more effective in the unilateral free-end edentulous space. PMID- 26968265 TI - Alternative splicing and nonsense-mediated mRNA decay enforce neural specific gene expression. AB - Alternative pre-mRNA splicing is a fundamental regulatory process for most mammalian multi-exon genes to increase proteome diversity. Nonsense-mediated mRNA decay (NMD) is a conserved mRNA surveillance mechanism to mitigate deleterious effects caused by gene mutations or transcriptional errors. Coupling alternative splicing and NMD (AS-NMD), in which alternative splicing switches between translational and NMD isoforms, results in fine-tuning overall gene expression to, in turn, expand the functional activities of these two post-transcriptional regulatory processes. AS-NMD is known for maintaining homeostatic expression of many RNA-binding proteins. We further show that AS-NMD is a conserved mechanism among mammals to induce developmental expression of the synaptic scaffold protein PSD-95. Comparing gene sequences between human Psd-95 and its ancestral orthologues indicates that AS-NMD regulation of mammalian Psd-95 is a product of selective pressure and that it enforces neural-specific expression of PSD-95 proteins in mammals. Invertebrate homolog of Psd-95 is not subjected to AS-NMD regulation and its protein product does not exhibit neural-specific expression. Given the prevalence of alternative splicing regulation in the mammalian nervous system, neural-specific expression of many other genes could be controlled by AS NMD in a similar manner. We discuss the implication of these discoveries, as well as the challenges in generalizing the regulation and functional activity of AS NMD. PMID- 26968267 TI - Motherhood; blessing or a curse! A nephrologists' view. PMID- 26968268 TI - Paroxetine: An update of response on intestinal motility. AB - OBJECTIVE: To find out the possible effects of paroxetine on gastrointestinal smooth muscles in vitro as they can cause severe nausea and vomiting at the start of therapy which later settles down. METHODS: Power lab (USA) was used for recording the contractions of ileal smooth muscle of rabbits in response to acetylcholine, serotonin and paroxetine. RESULTS: The percent responses with acetylcholine, serotonin and paroxetine were 100, 158.7 and 6.45 percent respectively indicating that acetylcholine and serotonin causes an increase in contractility of isolated ileal smooth muscle in comparison to paroxetine which has a depressant effect on motility. CONCLUSIONS: Inability of paroxetine to enhance the serotonergic transmission in vitro causes a decrease in its qualitative response. PMID- 26968269 TI - Response to nebulized salbutamol versus combination with ipratropium bromide in children with acute severe asthma. AB - OBJECTIVE: To compare the efficacy of nebulised salbutamol alone and in combination with ipratropium bromide in acute severe asthma in children. METHODS: The randomised controlled trial was conducted at the National Institute of Child Health, Karachi, from October 2012 to March 2013, and comprised patients with acute severe asthma who were randomised into two equal groups. Group A patients received 3 doses of nebulised salbutamol alone (0.03 ml/kg/dose) at 15-minute intervals and Group B received 3 similar doses of salbutamol along with ipratropium (250 ug/dose). Acute severe asthma was categorised as serve exacerbation (clinical score >10) and moderate (5-10 score) based on Bentur Modification. Efficacy was measured after 5minutes of the last dose by change in severity score from severe exacerbation (baseline) to low score. SPSS 10 was used for statistical analysis. RESULTS: There were two groups of 100(50%) patients each. The mean age in Group A was 9.1+/-3 years and 9.3+/-2.8 years in Group B. Male-Female ratio in Group A was 1.5:1 and in Group B it was 1.2:1. In Group B, 93(93%) children showed improvement in clinical score (<10 score) while it was 84(84%) in Group A. There was better response in clinical score in Group A than Group B, but it was not significant (p>0.05). CONCLUSIONS: The combination of nebulised salbutamol along with ipratropium bromide in the treatment of acute asthma exacerbation was not superior to salbutamol alone. PMID- 26968270 TI - Surgical management of inflammatory bowel disease: A low prevalence, developing country perspective. AB - OBJECTIVE: To determine the outcomes of surgical management of inflammatory bowel disease. METHODS: The retrospective case series was conducted at Aga Khan University Hospital, Karachi, and comprised medical record of adult patients operated between January 1986 and December 2010 for inflammatory bowel disease. Outcomes consisted of complications till last follow-up and 30-day mortality (disease or procedure related). Functional status of patients with ileal pouch was determined via telephone. SPSS 16 was used to analyse data. RESULTS: Of the 36 patients whose records were reviewed, 21(58%) were males, and body mass index was less than 23 in 34(91%). A total of 27(75%) patients underwent elective surgery for their condition. Ileal pouch was formed in 9(25%). Overall mortality was 14(38.8%). Overall incidence of complications was 26(72%), with wound infection being the most common early morbidity in 11(30.5%). Late morbidity included pouchitisin 4/9 (44.9%) and strictures 2/36 (5.5%).On telephonic follow up, 6 of the remaining 7patients (85%) with ileal pouch were satisfied with the functional results of the procedure. CONCLUSIONS: The retrospective case series represents results from a developing country with low prevalence of inflammatory bowel disease and hence limited experience. PMID- 26968271 TI - Home-based rehabilitation of severely malnourished children using indigenous high density diet. AB - OBJECTIVE: To evaluate the efficacy, cost-effectiveness and acceptability of a 'high-density diet made from indigenous ingredients. METHODS: The retrospective study was carried out from September 2009 to May 2010 in District Sanghar, Sindh, Pakistan. A field office was established and staff was recruited and trained. A baseline survey was done to screen for malnourished children aged 6-23 months using mid-upper arm circumference, for which a cut-off value of 115mm was adopted. The screened children with a weight-for-height z score <-3 were registered and were supplied the high-density diet and micronutrients. Their mothers were counselled on infant and young child feeding practices. RESULTS: The mean age of 123 children in the study was 15.5+/-8.5 months, and mean weight was 5.91+/-1.18kg. Overall, 85(69%) children attained the target weight in a mean duration of 5.08+/-3.2 months. Besides, 29(23.5%) children were gaining weight, but had not achieved the target by the end of the study. The mean rate of weight gain of children who recovered was 3.30+/-3.59 g/kg/day. No significant adverse effects were noted. There was no documented refusal of the therapeutic supplement. The net cost of rehabilitating a child was $34.31. CONCLUSIONS: The high-density diet was reasonably efficacious in improving the nutritional status of severely malnourished children. PMID- 26968272 TI - Effects of bupivacaine infiltration on postoperative tramadol consumption in elective day care unilateral inguinal hernia repair. AB - OBJECTIVE: To determine the difference in analgesic requirement in terms of mean postoperative narcotic consumption and mean postoperative pain score in patients undergoing unilateral inguinal hernia repair with or without bupivacaine infiltration as day-care patients. METHODS: The randomised controlled trial was conducted at Aga Khan University Hospital, Karachi, from June to December 2011, and comprised patients who were randomly divided into groups A and B. Tramadol 1.5 mgkg-1 was used as intraoperative analgesia. At the time of closure of surgical incision, 20ml of bupivacaine 0.25% plain was infiltrated in the subcutaneous tissue sub-facially and in the deeper layers along the incision line in patients of group A. In group B, which was the control group, the surgical wound was closed without infiltrating bupivacaine. On arrival in post-anaesthesia care unit, the patient's pain scores was assessed using Visual Analogue Scale every 15 minutes for the first hour, every 30 minutes for next one hour, and hourly for the next two hours by a blinded observer. Postoperative narcotic consumption was also noted. RESULTS: There were 80 patients in the study; 40(50%) in each of the two groups. Mean postoperative narcotic consumption and mean pain scores were high in group B in all follow-ups (up to 4 hours) compared to group A patients (p<0.05). CONCLUSIONS: Wound infiltration with 0.25% bupivacaine diminished post-operative pain and decreased narcotic analgesic consumption for the first four hours after unilateral inguinal hernia repair. PMID- 26968273 TI - Ultrasonographic pattern of plasma leak in dengue haemorrhagic fever. AB - OBJECTIVE: To note ultrasonographic findings used for diagnosing plasma leakage in dengue haemorrhagic fever patients. METHODS: The observational retrospective study was conducted at the Holy Family Hospital, Rawalpindi and comprised records of patients with confirmed dengue infection who were screened for dengue haemorrhagic fever according to Dengue Expert Advisory Group criteria from July 1 to December 31, 2013. Each patient underwent ultrasonography for the detection of ascites, gall bladder wall thickness, pleural and/or pericardial effusion along with their quantification and localisation. RESULTS: Of the 240 patients, 166(69.2%) were men. The overall mean age was 28.9+/-12.4 years. Of the total, 215(89.5%) had ultrasonographic abnormalities, suggestive of plasma leakage. Quantification and localisation wise, mild abdominal ascites 68(47.2%), right pleural effusion 82(74.5%) and mild pleural effusion 98(89%) were commonly noted. None had pericardial effusion. CONCLUSIONS: Mild ascites and mild right pleural effusion were the commonest pattern of ultrasonographic leak in dengue haemorrhagic fever patients. PMID- 26968274 TI - Educational status and awareness among tuberculosis patients of Karachi. AB - OBJECTIVE: To investigate and analyse patients' educational status and awareness regarding tuberculosis in the context of demographic distribution. METHODS: The survey-based study was conducted at Tuberculosis Diagnostic Centres in Karachi from March to October 2013. A predesigned questionnaire was used as the data collection tool. It was filled through face-to-face interviews. Data was anylsed using SPSS 20. RESULTS: Of the 1260 respondents, 646(51.2%) were women and 614(48.7%) were men. Women were more affected by extra pulmonary tuberculosis (65%; n=123) compared to men (35%; n=65), while the reverse was the case for pulmonary tuberculosis, with men accounting for 52% (n=557) and women 48% (n=514). Pulmonary tuberculosis was prevalent in all age groups of both genders, but was most notable in the 11-30 years age group. Educational status of tuberculosis patients indicated men as being more educated with 52% (n=91) and 55% (n=258) for above and below secondary school certificate level or education respectively. The level of awareness and pursuance of precautionary measures was higher among literate males (58%; n=108 and 54%; n=347) compared to females at 42% (n=77) and 46% (n=296) respectively. CONCLUSIONS: The findings may prove helpful in convincing the educated tuberculosis patients to reform their lifestyles in order to improve their living environments to prevent the spread of the infectious disease, thereby improving the quality of life in the city. PMID- 26968275 TI - Comparison of tuberculin skin test and quantiferon-TB gold in tube test for diagnosis of latent tuberculosis infection in health care workers: A cross sectional study. AB - OBJECTIVE: To compare the diagnostic efficacy and agreement of the traditional tuberculin skin test with QuantiFERON-Tuberculosis Gold In-Tube test for latent tuberculosis infection in healthcare workers. METHODS: The cross-sectional analytical study was conducted between March 1 and 31, 2008, at a specialist tuberculosis hospital in Istanbul, Turkey, and comprised healthcare workers who had been employed for at least one year at the hospital and volunteered to take part. Tuberculin skin test and QuantiFERON-Tuberculosis Gold In-Tube test were both performed simultaneously and their results were compared Using SPSS 12. RESULTS: Out of 34 subjects, 20(58.8%) had a positive tuberculin skin test, and 7(20.6%) had a positive QuantiFERON-Tuberculosis Gold In-Tube test. The two tests agreed in only 15(44.1%) cases and disagreed in 19(55.9%). In 16(47.1%) subjects, the QuantiFERON-Tuberculosis Gold In-Tube test was negative and tuberculin skin testwas positive, while in 3(8.8%) participants QuantiFERON-Tuberculosis Gold In Tube test was positive and tuberculin skin test was negative. Kappa test revealed discordance between the two tests (k=-0.13; p=0.92). CONCLUSIONS: Latent tuberculosis infection prevalence was higher based on tuberculin skin test than QuantiFERON-Tuberculosis Gold In-Tube test. The results of the two tests were discordant. PMID- 26968276 TI - Intra-articular distal radius fractures: Postoperative roentgenographic and functional outcomes. AB - OBJECTIVE: To assess the outcome of volarlocking compression plate fixation for intra-articular distal radius fractures with respect to function of hand and roentgenographic parameters. METHODS: The retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised patients who underwent locking compression plate fixation for intra-articular distal radius fractures between June 2009 and July 2012. Case notes, radiographic assessment and functional outcomes were noted. Functional outcome was determined with the help of telephone-based quick-dash score questionnaire administered atleast 6 months post-surgery. Radiological assessment of radial inclination, radial height and volar tilt was measured on immediate postoperative radiographs and then again measured at last available follow-up which ranged from 4 to 116 weeks. RESULTS: The mean age of the 43 patients in the study was 47.31+/-14.24 years (range: 20 95 years) at the time of injury. Mean Quick Dash score at 6-month follow-up was 17.2+/-8.8 (range: 4-40). The outcome was very good in 1(2.2%), good in 30(66.7%), satisfactory in 10(22.2%) and poor in 4(8.9%) patients. Mean immediate postoperative radial inclination, volar tilt and radial height were 17.26+/-3.23 degrees , 7.6+/-3.87 degrees and 10.2+/-1.95mm respectively. Corresponding values at the last follow-up were 17+/-3.89 degrees , 7.67+/-4.28 degrees and 9.8+/-1.8mm. CONCLUSIONS: Use of locking compression plate for intra-articular distal radius fracture showed good results comparable with global literature. PMID- 26968277 TI - Anti-inflammatory effects of conjugated linoleic acid on young athletic males. AB - OBJECTIVE: To explore the efficacy of conjugated linoleic acid supplementation on some inflammatory factors in young healthy males during exhaustive exercise. METHODS: The randomised double-blind controlled study was conducted at Ardabil University of Medical Sciences, Iran, from December 2012 to March2013, and comprised healthy male athletes 18-24 years of age. The subjects were randomly distributed into control and intervention groups. About 5.6 g/day conjugated linoleic acid supplement and oral paraffin (placebo) were given to intervention and control groups respectively daily for two weeks. Fasting blood samples were taken at baseline and at the end of the two weeks of intervention. The subjects underwent exhaustive exercise and then fasting blood samples were taken. Serum levels of tumour necrosis factor alpha, interleukin-6, high-sensitivity C reactive protein, matrix metalloproteinases-2 and 9 were measured. RESULTS: There were 23 subjects in the study, with 13(56.5%) in the supplemented group and 10(43.4%) in the control group. Serum levels of matrix metalloproteinases-2 and tumour necrosis factor alpha were significantly decreased in the supplemented group (p<0.05). After exhaustive exercise, serum levels of matrix metalloproteinases-2, high-sensitivity C-reactive protein and tumour necrosis factor alpha significantly decreased in the supplemented group compared to the control group(p<0.05). CONCLUSIONS: Two-week administration of conjugated linoleic acid reduced the inflammatory factors following exhaustive exercise in young healthy males. PMID- 26968278 TI - Comparison of colony formation of human spermatogonial stem cells (SSCs) with and without collagen. AB - OBJECTIVE: To investigate the effects of collagen and growth factors on in vitro proliferation of human spermatogonial stem cells obtained from patients with non obstructive azoospermia. METHODS: The experimental cross-sectional study was conducted from February 2013 to April 2015 after obtaining approval from the ethics committee of Ahvaz Jundishapur University of Medical Sciences, Iran. Testicular sperm extractions of non-obstructive azoospermic patients were obtained from the Clinical Urology and Embryology, In Vitro Fertilization Department of Imam Khomeini Hospital. Spermatogonial stem cells and Sertoli cells, obtained from human testis biopsies by a two-step enzymatic digestion method, were purified using fluorescence- activated cell-sorting and daturastramonium-lectin, and were cultured separately. To investigate a more direct influential factor on colony formation, one control and two experimental groups were formed. Group 1 acted as the control in which spermatogonial stem cells were co-cultured with Sertoli cells alone. In group 2 they were co-cultured with Sertoli cells and growth factors such as leukaemia inhibitory factor, epidermal growth factor and glial cell-derived neurotrophic factor, and in group 3 with Sertoli cells along with growth factors in the presence of collagen-coated dishes. Number and diameter of the colonies were evaluated after 7 weeks. RESULTS: Specimens obtained related to 21 patients. Number and diameter of the colonies in group 3 (18+/-2.6 and 276.6+/-45.5) were significantly more than both groups 1 (3.5+/-1 and D1:81.6+/-12) and group 2(11+/-2.2 and 165.2+/-32.5) (p<0.05 each). Also, the number and diameter of colony in group 2 were significantly better than the control group (p<0.05).Expression profile of the VASA, promyelocytic leukaemia zinc-finger (PLZF), Octamer-binding transcription factor 4 (OCT4) and integrin a6 (INTGa6) were detected in all groups. Based on cytochemical findings, OCT4 was expressed in the colonies of all three groups. CONCLUSIONS: According to positive effects of collagen and growth factors on the colonisation of spermatogonial stem cells, it seems that using the cells may lead to better colonisation of this type of stem cells. PMID- 26968279 TI - Comparison of diagnostic accuracy of touch imprint cytology and frozen section techniques in detecting breast malignancies. AB - OBJECTIVE: To compare the diagnostic accuracy of touch imprint cytology and frozen section in the diagnosis of malignant breast lumps keeping histopathological diagnosis as the gold standard. METHODS: The cross-sectional validation study was conducted at Foundation University Medical College, Islamabad, from February 2011 to February 2012, and comprised patients undergoing mastectomy/lumpectomy. The specimens were collected from the operation theatre of Fauji Foundation Hospital, Rawalpindi. After tissue fixation, three representative sections were processed and the slides were stained with haematoxylin and eosin stain. The person analysing touch imprint cytology slides was blinded to the frozen section and histopathological slide results and vice versa. Data was analysed using SPSS 17. RESULTS: Out of 76 patients with a mean age of 49+/-15.14 years, 61(80%) were diagnosed with malignant breast diseases. The sensitivity, specificity, positive predictive value, negative predictive value and true positives of touch imprint cytology were 96.72%, 100%, 100%, 88.24% and 96.72% respectively. The corresponding values of the frozen section were 100% each. The diagnostic accuracy calculated for touch imprints and frozen section was 97.37% and 100% respectively. CONCLUSIONS: The diagnostic accuracy of frozen section was better than touch imprint cytology in rapid intra-operative diagnosis. However, touch imprints can safely be used as an alternative intra operative procedure to ensure satisfactory results. PMID- 26968280 TI - Islet transplantation restores the damage of glomerulus filtration membrane in a rat model of streptozotocin-induced diabetic nephropathy. AB - OBJECTIVE: To evaluate the effects on filtration membrane of glomerulus after islet transplantation in a rat model of streptozotocin-induced diabetic nephropathy. METHODS: The experimental case-control study was conducted at Wenzhou Medical University, Wenzhou, China from January to May 2015, and comprised male Sprague Dawley rats obtained from the Laboratory Animal Centre of Wenzhou Medical University. The rats were intraperitoneally injected with streptozotocin to induce diabetic nephropathy. Diabetic rats were divided into two groups; the islets group received islets transplantation under the kidney capsule; and the diabetic nephropathy (DN) group consisted of untreated diabetic nephropathy rats. The control group consisted of non-diabetic rats. Islets were surgically transplanted under the kidney capsule. Kidney function and blood glucose were measured and pathological changes in the kidney were observed by electron microscope, while the expressions of Wilms' tumour-1, caspase-3 and transforming growth factor-beta 1 were tested by immunohistochemical method and Western blot analysis. RESULTS: Each of the three groups had 6 rats each with body weights ranging from 180g to 220g. Reduced urinary protein excretion and alleviated damage of podocytes and glomerular basement membrane were seen in the islet-transplanted rats. The alleviation of podocyte damage was related to alteration in the synthesis of caspase-3, transforming growth factor-beta 1, and Wilms' tumour-1 protein in the glomerulus. CONCLUSIONS: Diabetic nephropathy rats after islet transplantation can ameliorate the damage of podocytes and basement membrane by inhibiting the pathway of transforming growth factor-beta 1. PMID- 26968281 TI - Does folinic acid ameliorates retinoic acid induced teratogenicity in chick embryo? AB - OBJECTIVE: To investigate the protective effect of folinic acid on the hatching ability and developmental defects in a retinoic acid-induced teratogenic model of chick embryo. METHODS: The experimental study was conducted at the Department of Anatomy, Regional Centre of the College of Physicians and Surgeons Pakistan, Islamabad, from February 2009 to February 2010. Chicken eggs were divided into two experimental groups and a control group. The first experimental group was injected with retinoic acid to induce a defective model, while the second experimental group was concomitantly injected folinic acid to observe its protective effects on retinoic acid-induced defects in the development and hatching process. Both groups were compared with the age-matched control group. RESULTS: A total of 90 fertilised eggs were divided into three groups. The experimental groups had significantly more delayed and assisted hatchings compared to the control group (p<0.05) but the difference between the experimental groups regarding the mode and day of hatching was insignificant (p>0.05). CONCLUSIONS: Irrespective of the presence of folinic acid, prenatal retinoic acid exposure significantly altered the hatchability characteristics in the experimental groups compared to the control. PMID- 26968282 TI - The role of NT-proBNP and Apelin in the assessment of right ventricular dysfunction in acute pulmonary embolism. AB - OBJECTIVE: To investigate the role of N-terminal pro-brain natriuretic peptide and apelin in the assessment of right ventricular dysfunction in acute pulmonary embolism. METHODS: The prospective case-control study was conducted at Ondokuz Mayis University, Samsun, Turkey, from January 2008 to June 2009, and comprised adult patients with acute pulmonary embolism. A smaller group of healthy adults served as the control. Blood N-terminal pro-brain natriuretic peptide and apelin levels were measured on admission to the Emergency Department. SPSS 15 was used for data analysis. RESULTS: There were 56 cases and 20 controls in the study. Blood N-terminal pro-brain natriuretic peptide levels were higher in cases than the controls (p<0.05). Apelin levels were not different between the groups (p>0.05). Patients with right ventricular dysfunction had significantly higher peptide levels than those without the dysfunction (p<0.05). The cut-off value of peptide for the prediction of right ventricular dysfunction was 1000 pg/ml, with a sensitivity of 92.1% and specificity of 77.8%. CONCLUSIONS: There was no significant change in plasma apelin levels in acute pulmonary embolism. The blood N-terminal pro-brain natriuretic peptide maybe a useful parameter in the assessment of right ventricular dysfunction in acute pulmonary embolism. PMID- 26968283 TI - Preputial bacterial colonisation in uncircumcised male children: Is it related to phimosis? AB - OBJECTIVE: To evaluate the presence of uropathogens in the periurethral skin and the effect of phimosis on bacterial colonisation. METHODS: The observational cohort study was conducted in Samsun Research and Training Hospital, Samsun, Turkey from June to December, 2014, and comprised patients undergoing circumcision. Before circumcision, all children were examined in the operating room and the presence of phimosis was recorded. All patients had circumcision performed by the same surgical team under general anaesthesia. Before the procedure, samples were taken from preputial skin of all patients by swab before cleansing with polyvidone-iodine. The samples were inoculated on 5% sheep blood agar and eosin-methylene blue agar. RESULTS: The median age of the 117 children was 5 years (range: 1-12). Of the total, 19(16.2%) children had complete phimosis, and 72(61.5%) had partial phimosis. In all,91(77.7%) children had phimosis and 26(22.3%) had no phimosis. Of the 91 patients with different degrees of phimosis, 52(57.1%) had clinically significant uropathogenic bacterial colonisation >100,000 colony-forming units per millilitre [cfu/ml]). Of the 26 patients without phimosis, 13(50%) had clinically significant colonisation. Thus, there was no effect of the presence of phimosis on bacteria colonisation (p=0.655). CONCLUSIONS: Important uropathogens colonise the preputium in uncircumcised male children. There was no effect of phimosis on colonisation. PMID- 26968284 TI - Tale of two cities: comparison of educational environment of two colleges (Jeddah and Rabigh) affiliated with one university. AB - OBJECTIVE: To evaluate students' perception about the educational environment at two medical colleges. METHODS: The cross-sectional study was conducted at King Abdulaziz University, Rabigh and Jeddah campuses, in Saudi Arabia, during the first semester of the year 2014 using Dundee Ready Education Environment Measure inventory. Data was collected from undergraduate medical students and analysed using SPSS 16. RESULTS: Of the 279 subjects in the study, 141(50.5%) belonged to the Rabigh campus, and 138(49.5%) to the Jeddah campus. Overall mean Dundee Ready Education Environment Measure inventory score was 124.90+/-20.66. The score for Jeddah was 131.38+/-21.37 and for Rabigh it was 118.56+/-17.85 (p=0.0001). The difference was also statistically significant in all domains of the inventory (p<0.05 each). CONCLUSIONS: Students' perception of their educational environment was positive in both campuses, it was more positive in Jeddah compared to Rabigh. PMID- 26968285 TI - Efficacy of immediate postoperative intramasseteric dexamethasone injection on postoperative swelling after mandibular impacted third molar surgery: A preliminary split-mouth study. AB - OBJECTIVE: To evaluate the efficacy of immediate intramasseteric injection of dexamethasone on postoperative oedema. METHODS: The prospective study was conducted at the Department of Oral and Maxillofacial Surgery, Ankara University, Ankara, Turkey, in July 2012, and comprised patients aged 15-32 years who presented for the removal of bilateral vertical impacted mandibular third molar teeth.The right and left impacted third molars of each patient were randomly allocated into study and control groups. The impacted teeth in the study group were extracted with surgical bone removal, and 2ml of 8mg/2ml dexamethasone was injected into the ipsilateral masseter muscle immediately after suturing.In the control group, dexamethasone was replaced with 2ml of sterile saline solution. Postoperative facial oedema was measured with a tape scale by calculating the distance between several facial landmarks on postoperative day 2. SPSS 15 was used for data analysis. RESULTS: The mean age of 20 patients was 21.35+/-4.18 years, and there were 9(45%) patients between 15-20 years of age, while 11(55%) were 21-32 years. IN terms of gender, 9(45%) patients were male and 11(55%) were female. Postoperative oedema was significantly reduced in the study group compared to the control group (p<0.05). CONCLUSIONS: Immediate intramasseteric injection of dexamethasone was effective in reducing postoperative oedema after mandibular impacted third molar surgery. PMID- 26968286 TI - Is laparoscopic pyeloplasty a comparable option to treat Ureteropelvic junction obstruction (UPJO)? A comparative study. AB - OBJECTIVE: To compare laparoscopic with open pyeloplasty. METHODS: The retrospective study was conducted at Aga Khan University Hospital, Karachi, and comprised records of patients who underwent surgical correction of ureteropelvic junction obstruction between during January 2008 and December 2012. Patients with laparoscopic pyeloplasty were placed in group 1 and those with open pyeloplasty in group 2.The groups were compared for operative time, hospital stay, perioperative complications, blood loss, duration of surgery, outcome and follow up. Data was analysed using SPSS 19. RESULTS: Of the 73 patients, 29(40%) were in group 1, and 44(60%) in group 2. A crossing vessel could be identified in 25(86.2%) in group 1 and in 33(75 %) in group 2. Laparoscopic procedures were associated with a longer mean operating time (p=0.04), median estimated blood loss (p<0.001) and a shorter mean hospital stay (p<0.001). Follow-up mercaptoacetyltriglycinescan was done in 21(74.5%) patients in group 1 and 23(52.2%) in group 2. Only 2(7%) patients in group 1 and 2(4.5%) in group 2 had poor response on mercaptoacetyltriglycine scan. Mean follow-up was 2.71+/-1.2 months. Postoperative complications were 5(13%) in group 1 and 9(20%) in group 2(p=0.141). CONCLUSIONS: Laparoscopic pyeloplasty was associated with shorter hospital stay, less pain and less blood loss. The efficacy in term of success rate and perioperative complications of laparoscopic pyeloplasty was comparable to that of open pyeloplasty. PMID- 26968287 TI - Regression in polio eradication in Pakistan: A national tragedy. AB - Polio is one out of 200 infections results to lasting paralysis, usually in the legs. The year 2014 has been the saddest year for the Pakistan when the World was about to eliminate Polio from all over the World. In year 1994 Pakistan took the initiative to eliminate Polio from the country. The efforts were going well until 2005, when Pakistan was on the wedge to overcome the Disease. The hopes were high that soon Pakistan will become a polio-virus-free country, but the drone strikes in FATA and the rise of different militant groups as a reaction of the drone attacks in FATA made it difficult for the health workers to continue their vaccination campaigns in these areas. However various factors ruined the efforts made to eradicate Polio. In Pakistan, polio is widespread to three sections. These are Karachi, Quetta block (Quetta, Pishin and Killah Abdullah district) and FATA and Peshawar district. Numerous things are accountable for polio flourishing in these regions. These comprise near to the ground socioeconomic rank of the families, not having the knowledge concerning hazard caused by polio and disinformation by limited significant people concerning how polio vaccines fabricate damage. In 2014, only 3 countries in the world remain polio-endemic: Nigeria, Pakistan and Afghanistan. From year 2012-2014 the number of registered Polio cases is on rise contrary to rest of the other two Polio-endemic countries. In spite of the extensive work done by Polio workers the number of Polio cases has broken the 16 year record. The situation is getting worse because it can also be threatening to the rest of the World. PMID- 26968288 TI - Maternal outcome of early intervention in women with prom at term (37 weeks or more). AB - Pre-labour rupture of membranes (PROM) is associated with complications as increase in the rate of induction of labour, foetal distress, foetal and maternal infection, and caesarean section. The objective of this case series was to determine the maternal outcome of early intervention with prostaglandin E2 in women with PROM at term in a Tertiary Care Hospital. The study period was six months from 2nd July 2014 to 1st January 2015. A total of 183 women with spontaneous PROM were selected. Detailed history was taken and clinical examination was performed. Prostaglandins 3mg tablet was kept in the posterior fornix of the vagina, which was repeated 6 hours later. The average age of the patients was 27.68+/-1.19 years. Chorioamniotis was observed in 2.19% (4/183) women and caesarean section in 8.2% (15/183) cases. It was concluded that Vaginal PGE2 tablet was very effective for labour induction in patients with PROM at term. PMID- 26968289 TI - Sepsis management: An evidence-based approach. AB - The Surviving Sepsis Campaign (SSC) guidelines have outlined an early goal directed therapy (EGDT) which demonstrates a standardized approach to ensure prompt and effective management of sepsis. Having said that, there are barriers associated with the application of evidence-based practice, which often lead to an overall poorer adherence to guidelines. Considering the global burden of disease, data from low- to middle-income countries is scarce. Asia is the largest continent but most Asian countries do not have a well-developed healthcare system and compliance rates to resuscitation and management bundles are as low as 7.6% and 3.5%, respectively. Intensive care units are not adequately equipped and financial concerns limit implementation of expensive treatment strategies. Healthcare policy-makers should be notified in order to alleviate financial restrictions and ensure delivery of standard care to septic patients. PMID- 26968291 TI - Adrenal myelolipoma in a young male - a rare case scenerio. AB - Adrenal myelolipomas are rare non functional benign tumours which are incidentally diagnosed in asymptomatic patients. Despite the fact that several theories have been discussed, the origin of myelolipoma remains unclear. Our patient, 19 years old male presented with history of abdominal pain for past 7 years. Computed tomography scan of abdomen with oral and intravenous contrast revealed well defined round heterogenous enhancing mass seen in right supra renal area involving the adrenal gland. Patient underwent surgery by open access through thoracoabdominal approach. Histopathology of resected mass showed myelolipoma along with trilineage haematopoesis with mature adipose tissues. PMID- 26968290 TI - A rare case: Congenital thoracic ectopic kidney with diaphragmatic eventration. AB - Thoracic ectopic kidney is a rare developmental anomaly that is the least frequent one among all forms of ectopic kidneys. The condition is generally asymptomatic. If a kidney image is missing on one side in renalor pelvic region in sonographic examination, the possibility of thoracic ectopic kidney should be taken into consideration. For final diagnosis, chest radiography and thorax computerised tomography should be obtained. We herein report a rare case of intra thoracic kidney accompanied by diaphragm eventration. PMID- 26968292 TI - Reduction of isolated zygomatic arch fractures using dental instrument: Report of 2 cases and review of the literature. AB - To assess the effectiveness of a dental instrument for reduction of isolated zygomatic arch fractures. Two patients were admitted to our clinic representing isolated unilateral zygomatic arch fracture. The common presenting complaints were pain, swelling and difficulty in mouth opening. Fractures were confirmed with plain radiography and computerized tomography. The fractures were reduced with upper buccal sulcus approach by dental instrument. Patients achieved satisfactory maximum mouth opening within 10 days. At follow up after 6 months, there was complete healing without any complication. This procedure is cost effective, time saving, safe and effective to manage isolated zygomatic arch fractures under local anaesthesia with satisfactory outcomes. PMID- 26968293 TI - Haemoglobin sickle D disease: A presentation with ischaemic stroke. AB - Haemoglobin-D, Los Angeles or Haemoglobin D-Punjab is not a rare variant of haemoglobin worldwide especially in Punjab, North western India, and South Asian continent. It can be inherited rarely as homozygous causing no symptoms or heterozygous with Haemoglobin A, commonly not related to clinical symptomatology. However, these variants can co-exist rarely with other haemoglobinopathies such as thalassemia or haemoglobin-S. We describe the case of doubly heterozygous Hb SD Punjab in a 8 year old girl who presented with ischaemic stroke. Before this case, only one case has been reported but it was with reversible hyperbilirubinaemia in Hb-SD from Rawalpindi, Pakistan. This case images the propensity for occurrence of rare phenotype within our population and underlines the importance of genotyping to avoid erroneous management and poor counseling hence preventing life altering complications which our case developed. PMID- 26968294 TI - Severe acute respiratory distress syndrome secondary to Plasmodium vivax malaria. AB - Plasmodium Vivax malaria is generally considered as a benign self-limiting illness and is less often associated with more severe disease and complications. Amongst these, acute respiratory distress syndrome (ARDS) is a particularly rare complication. The few cases reported describe the onset of ARDS after initiation of anti-malarial therapy as a post inflammatory response. Here we report the case of a 45 year old male who was a victim of severe Plasmodium vivax malaria culminating into ARDS, prior to the initiation of anti-malarial therapy. He was treated with invasive ventilation and anti-malarial therapy and made a complete and uneventful recovery. PMID- 26968295 TI - From syncope episode to the diagnosis of ovarian dermoid cyst associated with a cystadenoma. AB - Ovarian teratoma has various presentations. We present a 28-year female diagnosed with a tumour after a fainting episode. Medical history was non-contributory except for mild intermittent pelvic pain. Cardiologic and neurological evaluation found no cause of syncope. Abdominal ultrasound revealed a right ovarian tumour that was laparoscopically removed. The menses continued to be normal. The pathological exam showed an encapsulated tumour of 8 cm with hair and small bone parts (mature teratoma with a cystadenoma). Immunohistochemistry was positive for CK34beta E12 in stratified squamous epithelium of skin glands; positive CK7 in kidney tubular parts; positive actin in smooth muscle. The endocrine profile was normal and the patient remained asymptomatic. The challenging in the pathological report was to differentiate a cystic part of a solid tumour to a teratoma associated cystadenoma. No apparent cause of syncope was found so a possible tumour related local pain and inflammation mechanism might be involved. PMID- 26968296 TI - Endocrine and metabolic effects of Glucagon like peptide 1 receptor agonists (GLP1RA). AB - This brief review describes the potential non-glycaemic effects and benefits of glucagon like peptide 1 receptor agonists (GLP1RA). It lists various indications in which this class of drugs has been used, and explains the rationale behind this use. The potential uses of GLP1RA extend across the entire spectrum of endocrinology and metabolism, from hypothalamic obesity to non-alcoholic steatohepatitis (NASH) to polycystic ovary syndrome (PCOS). The article also discusses and addresses endocrine-related concerns related to the GLP1RAs. PMID- 26968297 TI - A patient centred approach to basal insulin choice for the management of type 2 diabetes mellitus. AB - Basal insulins are first line injectable therapy by all international guidelines. Basal insulins can be used alone, in combination with metformin, dual or triple oral therapy, glucagon-like peptide receptor agonists, or prandial insulin. However, all basal insulins are not similar. This article proposes objective parameters, and suggests a simple checklist, using history, physical examination, and investigations, to help choose the appropriate preparation, viz degludec, detemir, glargine or NPH insulin, for persons requiring basal insulin. PMID- 26968298 TI - Are we prepared for next heat wave? PMID- 26968299 TI - Enteric cyst in the left posterior mediastinum mimicking a hydatid cyst on chest Computed Tomography scan. AB - Mediastinal enteric cysts are a rare occurrence among adults and are usually asymptomatic. In most cases they are an incidental finding in the right hemi mediastinum and are associated with vertebral anomalies. We report the unusual case of a 23 year old male who had a mediastinal mass on chest X-ray as an incidental finding. Chest Computed Tomography (CT) scan revealed no vertebral anomalies and a cystic mass in the left posterior mediastinum with features similar to those of a hydatid cyst.Posterolateral thoracotomy was done and the cyst was excised. Histopathology report revealed it to be an enteric cyst. PMID- 26968300 TI - Nose and Nasal Planum Neoplasia, Reconstruction. AB - Most intranasal lesions are best treated with radiation therapy. Computed tomographic imaging with intravenous contrast is critical for treatment planning. Computed tomographic images of the nose will best assess the integrity of the cribriform plate for central nervous system invasion by a nasal tumor. Because of an owner's emotional response to an altered appearance of their dog's face, discussions need to include the entire family before proceeding with nasal planectomy or radical planectomy. With careful case selection, nasal planectomy and radical planectomy surgeries can be locally curative. PMID- 26968301 TI - [Juvenile idiopathic arthritis: Definition and classification]. AB - Juvenile idiopathic arthritis (JIA) is a group of diseases defined by the presence of arthritis of more than 6 weeks duration in patients aged less than 16 years and with unknown etiology. The international classification based on clinical and biological criteria define each type of JIA: systemic, oligoarticular, polyarticular with and without rheumatoid factor, enthesitis related arthritis, and psoriatic arthritis. However, some discussions persist concerning systemic-onset juvenile idiopathic arthritis, whose clinical symptoms and pathogenic mechanisms are quite similar to those observed in autoinflammatory diseases, arthritis with antinuclear factors (poly- and oligoarticular) that could be considered as a homogenous group, and a family history of psoriasis that frequently led to unclassified arthritis. Better knowledge of the pathogenic mechanisms should improve the initial clinical classification with more homogeneous groups of patients and reduce the number of unclassified cases of arthritis. PMID- 26968302 TI - [Diagnostic criteria for obstructive sleep apnea syndrome]. AB - The prevalence of obstructive sleep apnea syndrome (OSAS) is 1-4 % in school-aged children. Adenotonsillar hypertrophy is the most common etiology of OSAS in children. Other causes are obesity; facial or skeletal malformations; and neuromuscular, respiratory, or metabolic diseases. OSAS has been associated with sleep quality disturbance (frequent arousals) and nocturnal gas exchange abnormalities (hypoxemia and sometimes hypercapnia), which can both result in negative health outcomes. The analysis of clinical symptoms and physical examination cannot always distinguish between children with primary snoring and children with OSAS. However, the association of at least one sign of nocturnal upper airway obstruction with other diurnal or nocturnal symptoms can be sufficient to establish OSAS diagnosis in a child more than 3 years of age with clear enlarged tonsils but who is otherwise healthy. In all other cases, polysomnography (the gold standard for the diagnosis of sleep-disordered breathing) must be performed either to declare the diagnosis when clinical assessment is not conclusive or when risk factors are present, or to follow up children with an associated health condition or initial severe OSAS. The equipment used to record sleep and the interpretation criteria are all pediatric specific. Other methods, such as respiratory polygraphy, are simpler to implement, but further studies are warranted to validate the interpretation criteria of these methods in children. However, in centers with experienced personnel, polygraphy can be used in place of polysomnography. In all cases, the analysis of sleep traces must be manual and performed by personnel under the supervision of medical staff trained to interpret pediatric sleep studies. PMID- 26968303 TI - [Parental separation in infant and childhood clinical practice]. AB - Parental separation is a painful and unmanageable moment of rupture for children regardless of their age. This experience can be traumatic, but it can sometimes be only a transitional stage that the child can surpass by adjusting to this new reality. In recent years, we have increasingly encountered disorders originating in this familial context. A better understanding of this social reality should facilitate the early detection of mental disorders requiring specialized support, which should in turn promote their prevention. This article presents clinical illustrations of children of separated parents and reviews recent data from the international literature. PMID- 26968304 TI - [Early origins of adult disease]. PMID- 26968305 TI - [Isolated unilateral cranial nerve palsy during childhood acute lymphoblastic leukemia treatment: What does it mean?]. PMID- 26968306 TI - [Fever in children returning from travel]. AB - Child travelers are numerous, exposed to the risk of diseases, both infectious and noninfectious, for which practitioners often lack experience. The assessment of febrile returning child travelers is becoming more frequent and challenging. The question of previous travel should be foremost in the checklist of the interview of any febrile child traveler, because this implies a possible tropical disease such as malaria that may be life-threatening. These need to be investigated and treated effectively and rapidly. There are highly contagious infections that could pose public health risks requiring implementation of hygienic and public health measures. A detailed immunization, medical, and travel history for exposure to infectious risks using geographic, seasonal, environmental, sociocultural, and epidemiological data are needed. Along with clinical examination and elementary first-line investigations, the history should guide second-line exams, which will provide the etiology and optimal treatment in approximately 75 % of cases. The majority of children will have a cosmopolitan infection that resolves spontaneously or is simple to treat. Malaria will need urgent and specific treatment. This article describes guidance on first-line evaluation and management of febrile child travelers as recommended in France. PMID- 26968307 TI - [Does consumption of tobacco, alcohol, and cannabis in adolescents and young adults with cancer affect the use of analgesics during hospitalizations?]. AB - INTRODUCTION: The specificities of adolescents and young adults (AYAs) aged 15-25 years with cancer are now well recognized. Dedicated care was initiated in 2012 in France under the leadership of the INCa (National Cancer Institute). Research on supportive care and particularly pain management are still rare. This study aimed to evaluate the consumption of toxic substances (tobacco, cannabis, alcohol) in AYAs with cancer as well as its progression during the month following the diagnosis and to analyze its influence on opioid analgesic prescriptions during treatment. METHODS: This is a prospective study including all new patients aged 15-25 years in two centers between January and June 2013. Data on consumption of psychoactive substances were obtained during an individual interview with a questionnaire. National surveys were used to compare this cohort with the general population. Data on opioid treatments were collected from the computerized prescription software and computerized patient record. RESULTS: Thirty-seven AYAs were eligible and 30 were included; 67% of them were male and the median age was 18.7 years. The questionnaire on tobacco, alcohol, and cannabis consumption at diagnosis was well accepted. Consumption profiles were comparable to the general population. Changes in behavior were observed during the 1st month after diagnosis, with a decrease or cessation of consumption, particularly among young people. This study showed differences in the use and requirements for opioid analgesics during hospitalization according to these consumption data. CONCLUSION: Prevention and support for AYAs who are regular consumers of toxic substances must be organized during initial care in oncology. PMID- 26968308 TI - Surgical Outcome of Pincer Femoroacetabular Impingement With and Without Labral Ossification. AB - PURPOSE: To describe the clinical findings associated with labral ossification (LO), report the outcomes of arthroscopic treatment, and compare this condition to a control group with femoroacetabular impingement (FAI). METHODS: A retrospective review of hip arthroscopy patients from 2004 to 2013 was performed to identify patients with a diagnosis of pincer FAI with LO and at least 2 years of follow-up. Diagnosis was made by plain radiograph, computed tomography, magnetic resonance imaging, or intraoperatively. The LO cohort was compared to a chronologically matched control group of FAI patients with pincer FAI but no LO. Patients were prospectively assessed with modified Harris Hip Score (mHHS) preoperatively and then postoperatively at 3, 12, 24, 60, and 120 months. RESULTS: The LO group included 56 hips in 52 patients whereas the control group included 56 hips in 56 patients. Mean follow-up was 36 months for the LO group and 38 for the control group (P = .28). Patients in the LO group were older than those in the control group, with a mean age of 45 versus 30 years (P < .0001), and had more women: 58% female versus 32% male (P < .0001). The LO group patients were more likely to have pain while sitting (65% v 18%) and restricted activities of daily living (40% v 11%) than the control group (P < .0001), and more likely to have pain during a flexion, abduction, external rotation (FABER) test (67% v 36%) (P = .002). Both groups experienced a similar magnitude of improvement in mHHS, but the LO group had a significantly lower preoperative mHHS (49 v 63, P < .001) and final postoperative mHHS (75 v 87, P < .0001) than the control group. CONCLUSIONS: Patients with LO represent a unique subset of pincer FAI and are more likely to be older, female, and have more severe symptoms. Hip arthroscopy can be used to treat LO with excision of the ossified fragments or rim, with a reasonable expectation of improvement of symptoms. LEVEL OF EVIDENCE: III, retrospective case-control. PMID- 26968309 TI - Anterior Cruciate Ligament Reconstruction Using the Transphyseal Technique in Prepubescent Athletes: Midterm, Prospective Evaluation of Results. AB - PURPOSE: To evaluate the efficacy, results, and complications of transphyseal technique of anterior cruciate ligament (ACL) reconstruction in prepubertal patients and to assess a possible influence of children's growth on the outcome. METHODS: Between 2005 and 2009, 22 (16 boys and 6 girls) prepubescent patients, Tanner stage 1 and 2, underwent ACL reconstruction and the follow-up 6, 12, and 24 months after surgery and after growth plate closure. The average age of the girls was 11.2 years, and of the boys, 12.3 years. The average follow-up period was 77.2 months. Clinical outcome was evaluated by Lysholm, Tegner, and International Knee Documentation Committee (IKDC) objective and subjective knee scores. Standard radiograms were performed for potential axial growing disturbance. RESULTS: The average follow-up period was 77.2 months (range, 54 to 102 months), and IKDC subjective scores changed from 58 (range, 44 to 69) before surgery to 87 (range, 86 to 87; P = .00) at 6 months, 93 (range, 88 to 97; P = .00) at 12 months, and 95 (range, 92 to -98; P = .5) at final examination. Lysholm score increased from 58 (range, 53 to 64) before surgery to 89 (range, 85 to 92; P = .00) at 6 months and 96 (range, 94 to 100; P = .00) at 12 months, 24 months (P = .9), and final examination (P = .8). Before injury, all patients were graded 7 on the Tegner scale. Nineteen athletes reached at least grade 7 and returned to the level of activity a mean of 9 months after the surgery. No patient had deformity or growth disturbances observed clinically. CONCLUSIONS: Arthroscopic-assisted transphyseal ACL reconstruction in prepubescent patient is a promising technique, provided that all technical details are respected. It gives excellent subjective and objective knee scores and provides a very good function of the knee joint in the midterm period with no or only minor effect on the leg length. The rate of growth after surgery did not influence the results. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 26968310 TI - Outerbridge Grade IV Cartilage Lesions in the Hip Identified at Arthroscopy. AB - PURPOSE: To determine factors associated with grade IV cartilage defects in the hip in patients undergoing hip arthroscopy with joint pain. METHODS: Data from consecutive patients who underwent hip arthroscopy performed by a single surgeon over a period of 4 years were included in this study. The study group included 1,097 patients (491 women and 606 men; mean age, 37 years) who underwent hip arthroscopy for pain, had no prior hip surgery, and were aged 18 years or older. Preoperative radiographs, patient demographic characteristics, and operative details were used to identify risk factors for cartilage defects. RESULTS: Grade IV chondral defects were present in 308 of 1,097 hips (28%). Isolated chondral lesions were more frequently observed on the acetabulum (76%) than on the femoral head (24%). Defects of the acetabulum were more commonly anterosuperior (94.7%) and less commonly posterolateral (5.3%). Patients with less than 2 mm of joint space on preoperative radiographs were 8 times more likely to have a grade IV lesion than those with more than 2 mm. Men were more likely than women to have grade IV lesions (35% v 19%, P = .0001); patients with grade IV lesions were older than those without (42 years v 34 years, P = .0001). Hips with grade IV lesions had significantly higher alpha angles than those without (74 degrees v 70 degrees , P = .0001). Patients with grade IV defects reported a longer duration of symptoms than those without (37 months v 27 months, P = .007). Independent risk factors for the presence of grade IV chondral defects were less than 2 mm of joint space, male gender, increasing age, larger alpha angle, and longer duration of symptoms. CONCLUSIONS: Grade IV chondral defects in patients undergoing hip arthroscopy were associated with decreased joint space, increased time from symptom onset to arthroscopy, male gender, and larger alpha angles associated with femoroacetabular impingement. LEVEL OF EVIDENCE: Level IV, prognostic case series. PMID- 26968311 TI - Spectrophotometric analysis of tooth discolouration induced by mineral trioxide aggregate after final irrigation with sodium hypochlorite: An in vitro study. AB - The aim of this study was to evaluate specific chromatic alterations induced by white mineral trioxide aggregate after final irrigation with sodium hypochlorite. Sixty specimens were prepared mechanically and filled with mineral trioxide aggregate after different final irrigation protocols: Group 1 - distilled water, Group 2 - sodium hypochlorite followed by distilled water, Group 3 - sodium hypochlorite, only. Colour changes were recorded with a spectrophotometer at baseline, and then after 1, 2 and 4 months. The Commision Internationale de l'eclairage colour system was used and the total colour changes DeltaE were calculated. In groups where sodium hypochlorite was used, parameter L* decreased significantly after the first month (Group 2 (P < 0.006), Group 3 (P < 0.009)). Group 3 demonstrated greater colour change DeltaE than Group 1, after the first month (P < 0.02). In conclusion, white mineral trioxide aggregate can lead to tooth discolouration by contact with sodium hypochlorite residues in dentinal tubules. PMID- 26968313 TI - Executive functioning - a key construct for understanding developmental psychopathology or a 'catch-all' term in need of some rethinking? AB - For the past few decades, the role of executive functions in developmental psychopathology has been the focus of considerable research and a feature of conceptual models for a range of conditions including, but not limited to, ADHD, autism, schizophrenia, bipolar disorder, learning disorders, and aggression/conduct problems. Consistent with its prominence throughout the field, executive functioning plays a central role in approximately a third of the papers in this issue of JCPP, and notably, with foci largely on different conditions. These papers, all of which make valuable contributions to the field, propose or test the possibility of a causal role for executive functions in the emergence of psychopathology. PMID- 26968312 TI - Non-invasive electromechanical activation imaging as a tool to study left ventricular dyssynchronous patients: Implication for CRT therapy. AB - AIMS: Electromechanical de-coupling is hypothesized to explain non-response of dyssynchrony patient to cardiac resynchronization therapy (CRT). In this pilot study, we investigated regional electromechanical uncoupling in 10 patients referred for CRT using two non-invasive electrical and mechanical imaging techniques (CMR tissue tracking and ECGI). METHODS AND RESULTS: Reconstructed regional electrical and mechanical activation captured delayed LBBB propagation direction from septal to anterior/inferior and finally to lateral walls as well as from LV apical to basal. All 5 responders demonstrated significantly delayed mechanical and electrical activation on the lateral LV wall at baseline compared to the non-responders (P<.05). On follow-up ECGI, baseline electrical activation patterns were preserved in native rhythm and global LV activation time was reduced with biventricular pacing. CONCLUSIONS: The combination of novel imaging techniques of ECGI and CMR tissue tracking can be used to assess spatial concordance of LV electrical and mechanical activation to gain insight into electromechanical coupling. PMID- 26968314 TI - Editorial Perspective: How to optimise frequency band neurofeedback for ADHD. AB - Attention deficit/hyperactivity disorder (ADHD) is one of the most prevalent paediatric neuropsychiatric disorders and is characterised by hyperactivity, inattention and increased impulsivity. Children with ADHD are often also characterised by deficits in a variety of cognitive domains, including problems in working memory, a generally slower and more variable style of information processing and deficits in temporal processing, inhibitory functions and delay processing. Overarching executive functions like information updating, response inhibition and mental set shifting are also impaired in many, but not all, children with ADHD, demonstrating the neuropsychological heterogeneity characterising this disorder. Deficits in executive functions can persist into adulthood and have a substantial negative impact on everyday life. A variety of approaches are commonly considered for the treatment of ADHD (including pharmacological interventions, patient-centred cognitive-behavioural therapy approaches and specific teacher/parent training programmes). More recently, adding to this multimodal treatment approach, neurofeedback has grown in popularity as an intervention option for patients with ADHD. This article considers this intervention approach and the opportunities for optimising treatment for executive control dysfunctions in ADHD using theta/beta neurofeedback. PMID- 26968315 TI - Commentary: Conduct disorder and perceiving harm to others - a reflection on Michalska et al. (2016). AB - The study by Michalska et al. () reported in this issue of JCPP focused on how children with conduct disorder (CD) process harm to other people. Many children with CD lack empathy for their victims and this behavioural profile has encouraged the investigation of potential underpinnings of atypical empathy in this group. Michalska et al. () administered an fMRI task depicting harm to other people to a large sample of children with CD and typically developing peers. The authors found that CD symptom severity and degree of callousness were negatively associated with right posterior insula response to other people experiencing harm. Furthermore, CD and callousness ratings were negatively associated with anterior insula, anterior midcingulate cortex and posterior superior temporal sulcus response to intentional harm. Reactive aggression scores, in contrast, were associated with increased positive insula reactivity when processing harm to others. Finally, the authors reported a sex difference in the engagement of brain areas associated with computations of intentionality when children processed intentional harm. In females (but not males) with CD, higher CD symptomatology was associated with lower activity in pSTS and middle frontal gyrus (MFG). This study is novel in focusing on a preadolescent sample of children and testing for sex differences in the neural underpinnings of conduct disorder (CD) symptomatology. We look forward to further work in this area and are certain that the important study by Michalska et al. () will motivate a host of new investigations that help us uncover the neural underpinnings of CD. PMID- 26968316 TI - Commentary: How can family-based quasi-experimental designs and national registers be used to address confounding in risk factor studies of psychopathology? A reflection on Obel et al. (2016). AB - Standard observational studies have reported a robust correlation between maternal smoking during pregnancy and risk of ADHD in offspring. In the accompanying article, Obel et al. used sibling-comparisons to explore the extent to which unmeasured familial confounding explains this association. This commentary highlights three important implications of the study. At a general level, Obel et al. illustrates how (1) family-based quasi-experimental designs and (2) national registers can be used to address confounding in risk factor studies of psychopathology. At a more specific level, the study suggests that maternal smoking during pregnancy is probably not a causal risk factor for ADHD. PMID- 26968317 TI - HAWAIIAN SKIRT regulates the quiescent center-independent meristem activity in Arabidopsis roots. AB - Root apical meristem (RAM) drives post-embryonic root growth by constantly supplying cells through mitosis. It is composed of stem cells and their derivatives, the transit-amplifying (TA) cells. Stem cell organization and its maintenance in the RAM are well characterized, however, their relationships with TA cells remain unclear. SHORTROOT (SHR) is critical for root development. It patterns cell types and promotes the post-embryonic root growth. Defective root growth in the shr has been ascribed to the lack of quiescent center (QC), which maintains the surrounding stem cells. However, our recent investigation indicated that SHR maintains TA cells independently of QC by modulating PHABULOSA (PHB) through miRNA165/6. PHB controls TA cell activity by modulating cytokinin levels and type B Arabidopsis Response Regulator activity, in a dosage-dependent manner. To further understand TA cell regulation, we conducted a shr suppressor screen. With an extensive mutagenesis screen followed by genome sequencing of a pooled F2 population, we discovered two suppressor alleles with mutations in HAWAIIAN SKIRT (HWS). HWS, encoding an F-box protein with kelch domain, is expressed, partly depending on SHR, in the root cap and in the pericycle of the differentiation zone. Interestingly, root growth in the shr hws was more active than the wild type roots for the first 7 days after germination, without recovering QC. Contrary to shr phb, shr hws did not show a recovery of cytokinin signaling. These indicate that HWS affects QC-independent TA cell activities through a pathway distinctive from PHB. PMID- 26968318 TI - Dual-Pathway sequences for MR thermometry: When and where to use them. AB - PURPOSE: Dual-pathway sequences have been proposed to help improve the temperature-to-noise ratio (TNR) in MR thermometry. The present work establishes how much of an improvement these so-called "PSIF-FISP" sequences may bring in various organs and tissues. METHODS: Simulations and TNR calculations were validated against analytical equations, phantom, abdomen, and brain scans. Relative TNRs for PSIF-FISP, as compared to a dual-FISP reference standard, were calculated for flip angle (FA) = 1 to 85 o and repetition time (TR) = 6 to 60 ms, for gray matter, white matter, cervix, endometrium, myometrium, prostate, kidney medulla and cortex, bone marrow, pancreas, spleen, muscle, and liver tissues. RESULTS: PSIF-FISP was TNR superior in the kidney, pelvis, spleen, or gray matter at most tested TR and FA settings, and benefits increased at shorter TRs. PSIF FISP was TNR superior in other tissues, e.g., liver, muscle, pancreas, for only short TR settings (20 ms or less). The TNR benefits of PSIF-FISP increased slightly with FA, and strongly with decreasing TR. Up to two- to three-fold reductions in TR with 20% TNR gains were achievable. In any given tissue, TNR performance is expected to further improve with heating, due to changes in relaxation rates. CONCLUSION: Dual-pathway PSIF-FISP can improve TNR and acquisition speed over standard gradient-recalled echo sequences, but optimal acquisition parameters are tissue dependent. Magn Reson Med 77:1193-1200, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26968319 TI - Laparoscopic Proximal Gastrectomy with Double-Tract Reconstruction by Intracorporeal Anastomosis with Linear Staplers. PMID- 26968320 TI - A Skin-Sparing Approach to the Treatment of Necrotizing Soft-Tissue Infections: Thinking Reconstruction at Initial Debridement. PMID- 26968322 TI - Should Children with Suspected Nonaccidental Injury Be Admitted to a Surgical Service? AB - BACKGROUND: In many hospitals, children with suspected nonaccidental trauma (sNAT) are admitted to nonsurgical services (NSS). Although the surgical service (SS) initially admitted sNAT patients at our American College of Surgeons (ACS) verified level 1 pediatric trauma center (vPTC), a change in hospital policy allowed admission to NSS. The objective of this study was to determine if the rate of care-related indicators (CRIs) varies by admission to an SS vs an NSS in the sNAT patient population. STUDY DESIGN: We conducted a retrospective review of patients admitted to an ACS vPTC with a final diagnosis of sNAT between January 2009 and December 2013. The primary study outcome was the presence of a CRI. Surgical service and NSS admissions were compared on age, Injury Severity Score, and Abbreviated Injury Scale to account for population differences among admissions by service and type of CRIs, using chi-square or Fisher's exact and Mann-Whitney tests. Rates of CRIs over time were also evaluated. RESULTS: During the study period, 5,340 total patients were admitted-671 (13%) with sNAT. Nonsurgical services admitted 306 patients (46%) of these patients, but 71% (n = 102) of the CRIs occurred in patients admitted to an NSS. The rate of CRIs per 100 patients was 33 for NSS compared with 12 for SS (p < 0.001). The overall rate of CRIs for sNAT increased from 18 to 26 (p = 0.07) per 100 patients after the policy change. CONCLUSIONS: Nonaccidental trauma patients admitted to an NSS were shown to have more CRIs than those admitted to an SS. This study supports an ACS requirement of admission of sNAT to an SS. PMID- 26968321 TI - The Impact of the 2011 Accreditation Council for Graduate Medical Education Duty Hour Reform on Quality and Safety in Trauma Care. AB - BACKGROUND: In 2011, the ACGME limited duty hours for residents. Although studies evaluating the 2011 policy have not shown improvements in general measures of morbidity or mortality, these outcomes might not reflect changes in specialty specific practice patterns and secondary quality measures. STUDY DESIGN: All trauma admissions from July 2009 through June 2013 at an academic Level I trauma center were evaluated for 5 primary outcomes (eg, mortality and length of stay), and 10 secondary quality measures and practice patterns (eg, operating room [OR] visits). All variables were compared before and after the reform (July 1, 2011). Piecewise regression was used to study temporal trends in quality. RESULTS: There were 11,740 admissions studied. The reform was not strongly associated with changes in any primary outcomes except length of stay (7.98 to 7.36 days; p = 0.01). However, many secondary quality metrics changed. The total number of OR and bedside procedures per admission (6.72 to 7.34; p < 0.001) and OR visits per admission (0.76 to 0.91; p < 0.001) were higher in the post-reform group, representing an additional 9,559 procedures and 1,584 OR visits. Use of minor bedside procedures, such as laboratory and imaging studies, increased most significantly. CONCLUSIONS: Although most major outcomes were unaffected, quality of care might have changed after the reform. Indeed, a consistent change in resource use patterns was manifested by substantial post-reform increases in measures such as bedside procedures and OR visits. No secondary quality measures exhibited improvements strongly associated with the reform. Several factors, including attending oversight, might have insulated major outcomes from change. Our findings show that some less-commonly studied quality metrics related to costs of care changed after the 2011 reform at our institution. PMID- 26968323 TI - Breast Cancer Genetics for the Surgeon: An Update on Causes and Testing Options. PMID- 26968324 TI - Integrating Geriatric Consults into Routine Care of Older Trauma Patients: One Year Experience of a Level I Trauma Center. AB - BACKGROUND: Although involvement of geriatricians in the care of older trauma patients is associated with changes in processes of care and improved outcomes, few geriatrician consultations were ordered on our service. STUDY DESIGN: Mandatory geriatric consults were initiated in September 2013 for all trauma patients 70 years and older admitted to our hospital. We prospectively collected data on patients admitted from October 2013 through September 2014 (postintervention) and compared their data with those of patients admitted from June 2011 through June 2012 (preintervention). We collected data on processes of care (DNR and do not intubate status, delirium, and referral for cognitive evaluation) and patient outcomes (mortality, readmission, and length of stay). Descriptive statistics and post-hoc power analyses were performed. RESULTS: There were 215 and 191 patients included in the preintervention and postintervention cohorts, respectively. After the intervention, geriatric consults increased from 3.26% to 100%. Patients with DNR and do not intubate status increased from 10.23% to 38.22% (p < 0.01). Referral for formal cognitive evaluation increased from 2.33% to 14.21% (p < 0.01) and delirium documentation increased from 31.16% to 38.22% (p = 0.14). In-hospital mortality and 30-day mortality in the pre- and postintervention periods were 9.30% vs 5.24% (p = 0.12) and 11.63% vs 6.81% (p = 0.10), respectively. Intensive care unit readmission rate was 8.26% preintervention and 1.96% postintervention (p = 0.06). There were no changes in 30-day hospital readmission and length of stay. Power analyses showed more patients were needed to show statistically significant outcomes. CONCLUSIONS: The initiation of mandatory geriatric consults on our trauma service was associated with improved advance care planning and increased multidisciplinary care. Ensuring involvement of geriatricians can aid in reducing adverse outcomes among geriatric trauma patients. PMID- 26968327 TI - Histopathological clues in the diagnosis of fungal infection by Scedosporium in a case of endophthalmitis starting as conjunctivitis. AB - Cutaneous fungal infections can result in disastrous episodes if improperly diagnosed and treated, especially in immunosuppressed patients. Although dermatopathologists are highly familiar with some filamentous fungi - such as Aspergillus and Zygomycetes - they are not so aware of other less common species. We report a case of ocular infection by Scedosporium apiospermum that started as conjunctivitis and resulted in Phthisis bulbi and subsequent exeresis of the left eye. We describe some of the main morphological features of the fungus as well as the important morphological clues for the differential diagnosis with some similar species, such as Aspergillus, Scopulariopsis, Fusarium, Paecilomyces and Zygomycetes. PMID- 26968326 TI - Detection and Phylogenetic Analysis of Porcine Deltacoronavirus in Korean Swine Farms, 2015. AB - This study applied molecular-based method to investigate the presence of porcine deltacoronavirus (PDCoV) in 59 commercial pig farms in South Korea. The results of RT-PCR screening on a relatively large collection of faeces samples (n = 681) from January 2013 to March 2015 did not reveal the presence of PDCoV until the end of 2014. However, on March 2015, PDCoV-positive samples (SL2, SL5) were detected from SL swine farm in Gyeongbuk province. The phylogenetic trees based on the complete spike- and nucleocapsid protein-coding genes showed that SL2 and SL5 closely related to the US PDCoV strains rather than those in China. Thought Korean strains of PDCoV isolated in 2014 (KNU14.04) and in 2015 (SL2 and SL5) grouped within US PDCoV cluster, the reconstruction of ancestral amino acid changes suggested that they are different. PMID- 26968325 TI - Predictors of Safety and Efficacy of 2-Stage Hepatectomy for Bilateral Colorectal Liver Metastases. AB - BACKGROUND: In patients with bilateral colorectal liver metastases (CLM) not resectable in 1 operation, 2-stage hepatectomy is the standard surgical approach. The objective of this study was to determine factors associated with safety and efficacy of 2-stage hepatectomy. STUDY DESIGN: The study included all 109 patients for whom 2-stage hepatectomy for CLM was planned during 2003 to 2014. The RAS mutation status and other clinicopathologic factors were evaluated for association with major complications and survival using multivariate analysis. RESULTS: Two-stage hepatectomy was completed in 89 of 109 patients (82%). Reasons for dropout after the first stage were disease progression (n = 12), insufficient liver growth (n = 5), and complications after first stage or portal vein embolization (n = 3). More than 6 cycles of preoperative chemotherapy were associated with failure to proceed to the second stage (p = 0.009). Rates of major complications (26% vs 6%; p < 0.001) and 90-day mortality (7% vs 0%; p = 0.006) were higher after the second stage. The cumulative rate of major complications was 15% (n = 29). Factors independently associated with major complications were rectal primary tumor, metachronous CLM, and more than 1 lesion resected at first stage. At median follow-up of 29.5 months, 3-year (68% vs 6%; p < 0.001) and 5-year overall survival rates (49% vs 0%; p < 0.001) were better after 2-stage hepatectomy completion than noncompletion. Factors independently associated with poor overall survival were rectal primary tumor (p = 0.044), more than 5 CLMs (p = 0.043), need for chemotherapy after first stage (p = 0.046), and RAS mutation (p < 0.001). CONCLUSIONS: The RAS mutation independently predicts the oncologic efficacy of 2-stage hepatectomy and may help guide patient selection for this aggressive surgical strategy. PMID- 26968328 TI - Pulmonology Teaching in Medical Schools and the Future of the Specialty. PMID- 26968329 TI - Benefits in tasks related to everyday life competences after a working memory training in older adults. AB - OBJECTIVE: The impact of working memory (WM) training on everyday life functioning has rarely been examined, and it is not clear whether WM training gains are transferred to reasoning abilities. The aim of this study was to assess the efficacy of a verbal WM training in older adults, in terms of specific gains and transfer effects to everyday life and reasoning abilities. METHOD: Thirty-six community dwelling older adults (from 65 to 75 years of age) were randomly assigned to a training or an active control group. The specific gains in a WM task similar to the one trained were assessed. Transfer effects to everyday life and reasoning abilities were also examined using (i) objective performance-based tasks (the Everyday Problem Test and the Timed Instrumental Activities of Daily Living Scale) and (ii) the Cattell test and Raven's Standard Progressive Matrices, respectively. RESULTS: Only the trained group showed specific benefits and transfer effects to one of the everyday abilities measures (the Everyday Problem Test) and in the two reasoning tasks. CONCLUSION: These results suggest that WM training can positively impact cognitive functioning and, more importantly, older adults' abilities in everyday living. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26968330 TI - Distinct metabolic changes between wheat embryo and endosperm during grain development revealed by 2D-DIGE-based integrative proteome analysis. AB - Two Chinese bread wheat cultivars, Jinghua 9 and Zhongmai 175, distinct in grain weight and dough quality, were used to study proteome changes in the embryo and endosperm during grain development using a two-dimensional difference gel electrophoresis (2D-DIGE)-based proteomics approach. In total, 138 and 127 differentially expressed protein (DEP) spots representing 116 and 113 unique DEPs were identified in the embryo and endosperm, respectively. Among them, 54 (31%) DEPs were commonly present in both organs while 62 (35%) and 59 (34%) DEPs occurred only in the embryo and endosperm, respectively. Embryonic DEPs are primarily stress-related proteins and involved in carbohydrate and lipid metabolism, while those from the endosperm are related primarily to carbohydrate metabolism and storage. Principal component analysis (PCA) indicated that the proteome differences in the endosperm caused by different cultivars were greater than those by development stages, while the differences in the embryo showed the opposite pattern. Protein-protein interaction (PPI) analysis revealed a complex network centered primarily on enzymes involved in carbohydrate and protein metabolism. The transcriptional levels of fourteen important DEPs encoding genes showed high similarity between organs and cultivars. In particular, some key DEPs of the endosperm, such as phosphoglucomutase, ADP-glucose pyrophosphorylase (AGPase), and sucrose synthase (SUS), showed significantly upregulated expression, indicating their key roles in starch biosynthesis and grain yield. Moreover, upregulated expression of some storage proteins in the endosperm could improve wheat bread-making quality. PMID- 26968331 TI - Dose site reactions and related findings after vaccine administration in safety studies. AB - Potential new human vaccines undergo toxicology testing to evaluate local reactogenicity and systemic toxicity. A review of 30 recently published and in house repeat dose toxicity studies with a variety of vaccines was performed. Species tested were generally rat or rabbit, usually by intramuscular (although occasionally subcutaneous) injection. Results showed no unexpected findings indicating vaccine toxicity, but classic signs of enhanced acute and/or chronic inflammation at the dose site compared with that seen in injected control animals, often accompanied by changes in draining lymph nodes and the spleen (lymphoid hyperplasia and/or increased weight). Other associated signs of a response to vaccine dosing were altered clinical pathology parameters (commonly raised blood neutrophil count and altered globulin level). No obvious difference in dose site or systemic reaction was seen across vaccine, species or the dose route used. A non-dose recovery period of 2 to 4 weeks was sufficient to show evidence of reversibility of dose site effects. Injection site, lymphoid tissue and clinical pathological changes can be interpreted as related to an expected reaction after vaccine dosing, with generation of an immune response largely as a result of the presence of adjuvant, although direct vaccine antigen involvement was also occasionally demonstrated by the presence of a slightly increased inflammatory response seen over adjuvant treatment only. Overall, the need for toxicity testing of vaccines is in line with current regulatory guideline requirements and has proven to be a valuable part of the safety evaluation process prior to human use. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26968332 TI - Trend of Incidence of Second Primary Malignancies following Breast Cancer in Taiwan: A 12-year Nationwide Cohort Study. PMID- 26968333 TI - Choosing the best image processing method for masticatory performance assessment when using two-coloured specimens. AB - Objective masticatory performance assessment using two-coloured specimens relies on image processing techniques; however, just a few approaches have been tested and no comparative studies are reported. The aim of this study was to present a selection procedure of the optimal image analysis method for masticatory performance assessment with a given two-coloured chewing gum. Dentate participants (n = 250; 25 +/- 6.3 years) chewed red-white chewing gums for 3, 6, 9, 12, 15, 18, 21 and 25 cycles (2000 samples). Digitalised images of retrieved specimens were analysed using 122 image processing methods (IPMs) based on feature extraction algorithms (pixel values and histogram analysis). All IPMs were tested following the criteria of: normality of measurements (Kolmogorov Smirnov), ability to detect differences among mixing states (anova corrected with post hoc Bonferroni) and moderate-to-high correlation with the number of cycles (Spearman's Rho). The optimal IPM was chosen using multiple criteria decision analysis (MCDA). Measurements provided by all IPMs proved to be normally distributed (P < 0.05), 116 proved sensible to mixing states (P < 0.05), and 35 showed moderate-to-high correlation with the number of cycles (|rho| > 0.5; P < 0.05). The variance of the histogram of the Hue showed the highest correlation with the number of cycles (rho = 0.792; P < 0.0001) and the highest MCDA score (optimal). The proposed procedure proved to be reliable and able to select the optimal approach among multiple IPMs. This experiment may be reproduced to identify the optimal approach for each case of locally available test foods. PMID- 26968335 TI - Cryptococcal osteomyelitis: a report of 5 cases and a review of the recent literature. AB - Cryptococcus neoformans is a fungal pathogen associated with advanced HIV disease and other disorders associated with immune dysfunction. The pulmonary and the central nervous system are the most common manifestations of the disease. Localised osteomyelitis as the sole manifestation of extrapulmonary disease is rare. Herein, we present five cases of Cryptococcus osteomyelitis as the only manifestation of extrapulmonary disease. We also identified 84 additional cases of isolated cryptococcal osteomyelitis in the literature. Using these data, we have made some general recommendations regarding an approach to treatment of this uncommon clinical entity. PMID- 26968334 TI - 15q13.3 duplication in two patients with childhood-onset schizophrenia. AB - We report two cases of paternally inherited 15q13.3 duplications in carriers diagnosed with childhood-onset schizophrenia (COS), a rare neurodevelopmental disorder of proposed polygenic origin with onset in children before age 13. This study documents that the 15q13.3 deletion and duplication exhibit pathogenicity for COS, with both copy number variants (CNVs) sharing a disrupted CHRNA7 gene. CHRNA7 encodes the neuronal alpha7 nicotinic acetylcholine receptor (alpha7nAChR) and is a candidate gene that has been suggested as a pathophysiological process mediating adult-onset schizophrenia (AOS) and other neurodevelopmental disorders. These results support the incomplete penetrance and variable expressivity of this CNV and represent the first report of 15q13.3 duplication carriers exhibiting COS. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc. PMID- 26968336 TI - Autophagy as a target for therapeutic uses of multifunctional peptides. AB - The emergence of complex diseases is promoting a change from one-target to multitarget drugs and peptides are ideal molecules to fulfill this polypharmacologic role. Here we review current status in the design of polypharmacological peptides aimed to treat complex diseases, focusing on tuberculosis. In this sense, combining multiple activities in single molecules is a two-sided sword, as both positive and negative side effects might arise. These polypharmacologic compounds may be directed to regulate autophagy, a catabolic process that enables cells to eliminate intracellular microbes (xenophagy), such as Mycobacterium tuberculosis (MBT). Here we review some strategies to control MBT infection and propose that a peptide combining both antimicrobial and pro autophagic activities would have a greater potential to limit MBT infection. This endeavor may complement the knowledge gained in understanding the mechanism of action of antibiotics and may lead to the design of better polypharmacological peptides to treat complex diseases such as tuberculosis. PMID- 26968337 TI - Post-anaesthetic emergence delirium in adults: incidence, predictors and consequences. AB - BACKGROUND: Emergence delirium (ED) after general anaesthesia (GA) is a well known phenomenon, yet the risk factors are still unclear. The aims of this study were to determine the incidence and independent predictors of ED and secondly to determine to which degree ED has any relevant, clinical consequences to medical staff as well as to patients. METHOD: This prospective, observational cohort study assessed adult patients emerging from GA in the operating room, using the Richmond Agitation-Sedation Scale (RASS). Signs of ED, defined as RASS>=1 along with possible clinical consequences were noted. Patients with ED were re evaluated in the post-anaesthesia care unit (PACU) and concomitant patient and anaesthesia related factors were noted. RESULTS: Among the 1970 patients enrolled, 73 (3.7%) showed signs of ED when emerging from anaesthesia. When reassessed in PACU, the number had declined to 25 patients (1.3%). Male sex, endotracheal tube (ETT) and volatile anaesthetics were found to be significantly related to developing ED after anaesthesia. In 20 cases, additional staff had to be called for and in one case, an i.v. access was accidentally removed. Neither patients nor staff were hurt. CONCLUSION: Male sex, volatile anaesthetics and ETT were factors significantly related to ED. Whether gender, choice of respiratory devices and anaesthetics are true predictors or derived factors of surgery procedures, duration of surgery and the patients' physical condition need further investigation. The most notable clinical consequence of ED was the need of additional staff in order to restrain the agitated patient. PMID- 26968339 TI - Understanding the Financial Implications of Immunization Reminder/Recall in a Multipractice Pediatric Group. AB - OBJECTIVE: Immunization reminder/recall is widely recommended as an effective strategy for increasing vaccination rates. We examined the revenue generated from well-child visits scheduled as a result of reminder/recall activities implemented in a multipractice pediatric organization. METHODS: Patients aged 19 to 35 months who were due or overdue for vaccines were identified from participating practices and assigned to either standard or enhanced reminder/recall activities. Participants who received standard reminder/recall were observed for the 6-week study period, and the number of appointments in which vaccines were administered was tracked. Participants who received enhanced reminder/recall were contacted up to 3 times and received a letter followed by up to 2 phone calls. Financial information associated with appointments scheduled during the study period was obtained, and revenue was calculated for each dose of vaccine administered. Reminder/recall costs were calculated and overall revenue generated was calculated. RESULTS: We identified 3916 children who were potentially due or overdue for immunizations. After review and manual uploading of missing historical vaccines, a total of 1892 participants received the reminder/recall initiative; 942 received standard reminder/recall, and 950 received enhanced reminder/recall. One hundred eighty-two (19%) standard and 277 (29%) enhanced reminder/recall participants scheduled an appointment by the end of the study period (P < .001). After subtracting the cost of reminder/recall activities, an additional $20,066 and $20,235 were generated by standard and enhanced reminder/recall, respectively. CONCLUSIONS: We show that conducting reminder/recall is at a minimum financially neutral, and might increase revenue generated by vaccine administration. PMID- 26968338 TI - End-of-life care decisions for haemodialysis patients - 'We only tend to have that discussion with them when they start deteriorating'. AB - BACKGROUND: Haemodialysis patients receive very little involvement in their end of-life care decisions. Issues relating to death and dying are commonly avoided until late in their illness. This study aimed to explore the experiences and perceptions of doctors and nurses in nephrology for involving haemodialysis patients in end-of-life care decisions. METHODS: A semi-structured qualitative interview study with 15 doctors and five nurses and thematic analysis of their accounts was conducted. The setting was a large teaching hospital in Wales, UK. RESULTS: Prognosis is not routinely discussed with patients, in part due to a difficulty in estimation and the belief that patients do not want or need this information. Advance care planning is rarely carried out, and end-of-life care discussions are seldom initiated prior to patient deterioration. There is variability in end-of-life practices amongst nephrologists; some patients are felt to be withdrawn from dialysis too late. Furthermore, the possibility and implications of withdrawal are not commonly discussed with well patients. Critical barriers hindering better end-of-life care involvement for these patients are outlined. CONCLUSIONS: The study provides insights into the complexity of end-of-life conversations and the barriers to achieving better end of-life communication practices. The results identify opportunities for improving the lives and deaths of haemodialysis patients. PMID- 26968340 TI - Trehalose 6,6-Dimycolate from Mycobacterium tuberculosis Induces Hypercoagulation. AB - Tuberculosis (TB) remains a global health concern. Trehalose 6'6-dimycolate (TDM) activates innate inflammation and likely also stimulates chronic inflammation observed during disease progression. Noninfectious models using purified TDM oil/water emulsions elicit pathologic findings observed in patients with TB. We introduce a new TDM model that promotes inflammatory lung pathologic findings and vascular occlusion and hemorrhage. C57BL/6 and BALB/c mice were injected with 10 MUg of i.p. TDM in light mineral oil (TDM-IP). At day 7, another injection of 10 MUg of i.v. TDM in oil/water emulsion was given (TDM-IV). The i.p./i.v. TDM (TDM IVIP) group was compared with mice injected once with i.v. or i.p. TDM. The responses to TDM-IP, TDM-IV, or TDM-IPIV were consistent between mouse strains. Mice that received TDM-IV and TDM-IPIV had inflammatory pathologic findings with increases in inflammatory and T-cell cytokines, and the TDM-IPIV group had further enhancement of IL-10 and granulocyte-macrophage colony-stimulating factor. The TDM-IPIV group had increased CD4(+) T cells in lung tissue, significantly increased coagulation, decreased clot formation time, and increased maximum clot firmness. Masson's trichrome staining revealed increased deposition of collagen in the occluded vasculature. TDM-IPIV promotes a hypercoagulopathy state, independent of inflammation. This new model argues that TDM is sufficient to generate the hypercoagulopathy observed in patients with TB. PMID- 26968341 TI - Cardiac Tropism of Borrelia burgdorferi: An Autopsy Study of Sudden Cardiac Death Associated with Lyme Carditis. AB - Fatal Lyme carditis caused by the spirochete Borrelia burgdorferi rarely is identified. Here, we describe the pathologic, immunohistochemical, and molecular findings of five case patients. These sudden cardiac deaths associated with Lyme carditis occurred from late summer to fall, ages ranged from young adult to late 40s, and four patients were men. Autopsy tissue samples were evaluated by light microscopy, Warthin-Starry stain, immunohistochemistry, and PCR for B. burgdorferi, and immunohistochemistry for complement components C4d and C9, CD3, CD79a, and decorin. Post-mortem blood was tested by serology. Interstitial lymphocytic pancarditis in a relatively characteristic road map distribution was present in all cases. Cardiomyocyte necrosis was minimal, T cells outnumbered B cells, plasma cells were prominent, and mild fibrosis was present. Spirochetes in the cardiac interstitium associated with collagen fibers and co-localized with decorin. Rare spirochetes were seen in the leptomeninges of two cases by immunohistochemistry. Spirochetes were not seen in other organs examined, and joint tissue was not available for evaluation. Although rare, sudden cardiac death caused by Lyme disease might be an under-recognized entity and is characterized by pancarditis and marked tropism of spirochetes for cardiac tissues. PMID- 26968342 TI - An Essential Role for SHARPIN in the Regulation of Caspase 1 Activity in Sepsis. AB - Sepsis is burdened by high mortality due to uncontrolled inflammatory response to pathogens. Increased caspase 1 activation causing maturation of IL1beta/18 remains a therapeutic challenge in sepsis. SHARPIN (shank-associated regulator of G-protein signaling homology domain-interacting protein), a component of the LUBAC (linear ubiquitin chain-assembly complex), regulates inflammation, with unknown effects on caspase 1 activation. Mice lacking Casp1, Casp11, or both in a Sharpin-deficient background were generated, exposed to lipopolysaccharide induced endotoxemia, and injected with caspase 1 inhibitor. We monitored survival, Il1beta/18, and caspase 1/11 levels in plasma and organs and deciphered mechanisms of SHARPIN-dependent caspase 1 inhibition. A correlation between LUBAC and active caspase 1 was found in blood mononuclear cells from septic patients. SHARPIN bound caspase 1 and disrupted p20/p10 dimer formation, the last step of caspase 1 processing, thereby inhibiting enzyme activation and maturation of IL1beta/18 in a LUBAC-independent manner. In septic patients, LUBAC-independent decline in SHARPIN correlated with enhancement of active caspase 1 in circulating mononuclear cells. Septic Sharpin-deficient mice displayed enrichment in mature Il1beta/18 and active caspase 1, and shortened survival. Inhibition of caspase 1 reduced levels of Il1beta/18 and splenic cell death, and prolonged survival in septic Sharpin-deficient mice. Our findings identify SHARPIN as a potent in vivo caspase 1 inhibitor and propose the caspase 1-SHARPIN interaction as a target in sepsis. PMID- 26968343 TI - Glucocorticoid Receptor as a Potential Target to Decrease Aromatase Expression and Inhibit Leydig Tumor Growth. AB - Leydig cell tumors are the most frequent interstitial neoplasms of the testis with increased incidence in recent years. They are hormonally active and are considered one of the steroid-secreting tumors. Although usually benign, the malignant phenotype responds poorly to conventional chemotherapy or radiation, highlighting the need to identify new therapeutic targets for treatment. Here, we identified a novel glucocorticoid-mediated mechanism that controls cell growth in Leydig cell tumors. We found that a synthetic glucocorticoid receptor agonist, dexamethasone, reduces cell proliferation in rat Leydig tumor cells by decreasing the expression and the enzymatic activity of the estrogen-producing enzyme aromatase. This inhibitory effect relies on the ability of activated glucocorticoid receptor to regulate the aromatase gene transcriptional activity through the recruitment of nuclear receptor corepressor protein and silencing mediator of retinoid and thyroid hormone receptors to a newly identified putative glucocorticoid responsive element within the aromatase promoter II. Our in vivo studies reveal a reduction of tumor growth, after dexamethasone treatment, in animal xenografts. Tumors from dexamethasone-treated mice exhibit a decrease in the expression of the proliferation marker Ki-67 and the aromatase enzyme. Our data demonstrate that activated glucocorticoid receptor, decreasing aromatase expression, induces Leydig tumor regression both in vitro and in vivo, suggesting that glucocorticoid receptor might be a potential target for the therapy of Leydig cell tumors. PMID- 26968344 TI - Deficiency of IkappaB Kinase beta in Myeloid Cells Reduces Severity of Experimental Autoimmune Encephalomyelitis. AB - In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), peripherally developed myelin-reactive T lymphocytes stimulate myeloid cells (ie, microglia and infiltrated macrophages) to trigger an inflammatory reaction in the central nervous system, resulting in demyelination and neurodegeneration. IkappaB kinase beta (IKKbeta) is a kinase that modulates transcription of inflammatory genes. To investigate the pathogenic role of IKKbeta in MS, we developed strains in which IKKbeta was conditionally ablated in myeloid cells and established active or passive EAE in these animals. Deficiency of IKKbeta in myeloid cells ameliorated EAE symptoms and suppressed neuroinflammation, as shown by decreased infiltration of T lymphocytes and macrophages and reduced inflammatory gene transcription in the spinal cord at the peak or end stage of EAE. Myeloid deficiency of IKKbeta also reduced the transcription of Rorc or Il17 genes in T lymphocytes isolated from lymph nodes, spleen, and spinal cord of EAE mice. Moreover, cultured splenocytes isolated from myeloid IKKbeta-deficient EAE mice released less IL-17, interferon-gamma, and granulocyte-macrophage colony-stimulating factor after treatment with myelin peptide than splenocytes from IKKbeta wild-type EAE mice. Thus, deficiency of myeloid IKKbeta attenuates the severity of EAE by inhibiting both the neuroinflammatory activity and the activation of encephalitogenic T lymphocytes. These results suggest IKKbeta may be a potential target for MS patients, especially when neuroinflammation is the primary problem. PMID- 26968345 TI - Targeted Recycling of the Lateral Border Recycling Compartment Precedes Adherens Junction Dissociation during Transendothelial Migration. AB - Leukocyte transendothelial migration (TEM) requires two major events: local dissociation of adherens junctions manifested as gaps in vascular endothelial (VE)-cadherin staining at the site of TEM and targeted trafficking of the lateral border recycling compartment (LBRC) to the site of TEM. However, the association between LBRC recycling and VE-cadherin gaps remains unknown. We found that when targeting of the LBRC is selectively inhibited using established methods, such as a function blocking anti-platelet endothelial cell adhesion molecule 1 antibody, depolymerizing microtubules, or microinjection of an antibody that inhibits kinesin, VE-cadherin gaps do not form around the blocked leukocyte. This is the first time that the LBRC has been implicated in this process. We obtained similar results for neutrophils and monocytes and in studies using live cell imaging microscopy conducted under fluid shear conditions. Depolymerizing microtubules did not affect the ability of leukocytes to induce tyrosine phosphorylation of VE cadherin. A VE-cadherin double mutant (Y658F, Y731F) expressed in endothelial cells acted as a dominant negative and inhibited VE-cadherin gap formation and TEM, yet targeting of the LBRC still occurred. These data suggest that targeting of the LBRC to the site of TEM precedes VE-cadherin clearance. Recruitment of the LBRC may play a role in clearing VE-cadherin from the site of TEM. PMID- 26968347 TI - Applicability of the Movement Assessment Battery for Children-Second Edition to Japanese children: A study of the Age Band 2. AB - BACKGROUND: The diagnosis of Developmental Coordination Disorder (DCD) requires a precise assessment of motor skills via a standardized tool such as the Movement Assessment Battery for Children-Second Edition (MABC-2). Although the MABC-2 has been widely used in English-speaking countries, to the best of our knowledge, no studies have examined its applicability to Japanese children. Thus, it has been difficult to diagnose DCD in Japan. AIMS: As a preliminary investigation preceding its formal standardization in Japan, we examined the applicability of the MABC-2. METHODS AND PROCEDURES: Participants comprised 132 typically developing Japanese children who completed a test set of the MABC-2 for Age Band 2. We analyzed both internal consistency and factorial validity for our Japanese sample. We also included a comparison between our sample of Japanese children and the normative sample of the MABC-2, as well as an examination of gender differences. OUTCOMES AND RESULTS: Our results indicated acceptable internal consistency and scale homogeneity. High factorial validity, which has not been examined in other populations, was also confirmed for the test set. Moreover, we found differences in component scores between the Japanese and normative children with respect to Manual Dexterity and Balance. We also found that girls obtained superior Manual Dexterity and Balance scores compared with boys. CONCLUSIONS AND IMPLICATIONS: The present findings represent the first step towards the standardization of the MABC-2 in a Japanese population. PMID- 26968348 TI - Reactive oxygen species mediate insulin signal transduction in mouse hypothalamus. AB - In the hypothalamus, several reports have implied that ROS mediate physiological effects of insulin. In this study, we investigated the mechanisms of insulin induced ROS production and the effect of ROS on insulin signal transduction in mouse hypothalamic organotypic cultures. Insulin increased intracellular ROS, which were suppressed by NADPH oxidase inhibitor. H2O2 increased phospho-insulin receptor beta (p-IRbeta) and phospho-Akt (p-Akt) levels. Insulin-induced increases in p-IRbeta and p-Akt levels were attenuated by ROS scavenger or NADPH oxidase inhibitor. Our data suggest that insulin-induced phosphorylation of IRbeta and Akt is mediated via ROS which are predominantly produced by NADPH oxidase in mouse hypothalamus. PMID- 26968349 TI - Health IT vendors and the academic community: The 2014 ACMI debate. AB - The American College of Medical Informatics (ACMI) periodically hosts a debate at the American Medical Informatics Association (AMIA) fall symposium on a timely topic in biomedical informatics. In 2014 a panel of ACMI fellows debated the following proposition: "The lack of interaction and collaboration between health IT vendors and academic clinical informatics units is stifling innovation and will continue to have a detrimental effect on the evolution of commercial products." Debaters disagreed on the level of interaction and collaboration between the health IT sector and academia and disagreed on whether and by whom innovation was actually taking place. While collaboration between industry and academia was seen as desirable by all of the debaters, there was an acknowledgment that these groups have notably different roles and responsibilities. There was consensus that a path forward should be found, and that AMIA itself has an important role to play in effecting this. PMID- 26968346 TI - The Autophagy-Lysosomal Pathway in Neurodegeneration: A TFEB Perspective. AB - The autophagy-lysosomal pathway (ALP) is involved in the degradation of long lived proteins. Deficits in the ALP result in protein aggregation, the generation of toxic protein species, and accumulation of dysfunctional organelles, which are hallmarks of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and prion disease. Decades of research have therefore focused on enhancing the ALP in neurodegenerative diseases. More recently, transcription factor EB (TFEB), a major regulator of autophagy and lysosomal biogenesis, has emerged as a leading factor in addressing disease pathology. We review the regulation of the ALP and TFEB and their impact on neurodegenerative diseases. We also offer our perspective on the complex role of autophagy and TFEB in disease pathogenesis and its therapeutic implications through the examination of prion disease. PMID- 26968350 TI - The association between tumor-infiltrating lymphocytes (TILs) and metastatic course in neuroendocrine neoplasms. PMID- 26968351 TI - Pandora bullata (Entomophthoromycota: Entomophthorales) affecting calliphorid flies in central Brazil. AB - Fungi are where one finds them, and if one seeks fungal pathogens affecting flies, then a garbage dump may be an ideal place to find both persistent, abundant fly populations and their fungal pathogens. An obvious fungal epizootic affecting the oriental latrine fly, Chrysomya megacephala (Diptera: Calliphoridae), was observed over several days in mid-February 2015 at the local garbage dump adjacent to the city of Cavalcante, northern Goias. This site harbored large populations of both C. megacephala and a Musca sp. (Diptera: Muscidae) but only the population of oriental latrine fly was affected by any fungal pathogen and presented unusually dense populations of fresh cadavers. The fungus was identifiable as Pandora bullata (Entomophthorales: Entomophthoraceae) only after a very small number of characteristically decorated resting spores were found in these flies two months later; this represents the first Brazilian (and South American) record of this species. P. bullata is known previously from a small number of North American, European and Australian collections, all of which have included relatively abundant production of resting spores. We cannot dismiss the possibility that the extremely sparse formation of resting spores at this Brazilian site may be due to abiotic factors such as latitude (13 degrees 46'40.53"S), day length, ambient temperatures, or even the precipitation patterns in this mid-tropical montaine site. Epizootic events affecting calliphorids in Brazil strengthen the interest in entomophthoran pathogens for biological control of flies. PMID- 26968352 TI - A nurse-initiated pain protocol in the ED improves pain treatment in patients with acute musculoskeletal pain. AB - While acute musculoskeletal pain is a frequent complaint, its management is often neglected. An implementation of a nurse-initiated pain protocol based on the algorithm of a Dutch pain management guideline in the emergency department might improve this. A pre-post intervention study was performed as part of the prospective PROTACT follow-up study. During the pre- (15 months, n = 504) and post-period (6 months, n = 156) patients' self-reported pain intensity and pain treatment were registered. Analgesic provision in patients with moderate to severe pain (NRS >=4) improved from 46.8% to 68.0%. Over 10% of the patients refused analgesics, resulting into an actual analgesic administration increase from 36.3% to 46.1%. Median time to analgesic decreased from 10 to 7 min (P < 0.05), whereas time to opioids decreased from 37 to 15 min (P < 0.01). Mean pain relief significantly increased to 1.56 NRS-points, in patients who received analgesic treatment even up to 2.02 points. The protocol appeared to lead to an increase in analgesic administration, shorter time to analgesics and a higher clinically relevant pain relief. Despite improvements, suffering moderate to severe pain at ED discharge was still common. Protocol adherence needs to be studied in order to optimize pain management. PMID- 26968353 TI - Receptor tyrosine phosphatase CLR-1 acts in skin cells to promote sensory dendrite outgrowth. AB - Sensory dendrite morphogenesis is directed by intrinsic and extrinsic factors. The extracellular environment plays instructive roles in patterning dendrite growth and branching. However, the molecular mechanism is not well understood. In Caenorhabditis elegans, the proprioceptive neuron PVD forms highly branched sensory dendrites adjacent to the hypodermis. We report that receptor tyrosine phosphatase CLR-1 functions in the hypodermis to pattern the PVD dendritic branches. Mutations in clr-1 lead to loss of quaternary branches, reduced secondary branches and increased ectopic branches. CLR-1 is necessary for the dendrite extension but not for the initial filopodia formation. Its role is dependent on the intracellular phosphatase domain but not the extracellular adhesion domain, indicating that it functions through dephosphorylating downstream factors but not through direct adhesion with neurons. Genetic analysis reveals that clr-1 also functions in parallel with SAX-7/DMA-1 pathway to control PVD primary dendrite development. We provide evidence of a new environmental factor for PVD dendrite morphogenesis. PMID- 26968355 TI - Association of the Laminin, Alpha 5 (LAMA5) rs4925386 with height and longevity in an elderly population from Southern Italy. AB - Studies in animal models and humans suggest that reduced growth and adult stature are associated with lifespan extension. Moreover, epidemiological studies reported a positive association between adult height and risk of multiple cancers. Yet, it is unclear which factors mediate these relationships. Laminins are major components of the basement membranes and cooperate with growth factors and matrix-dependent receptors in cell proliferation and differentiation. Previously, we reported the association of rs659822-C/T in LAMA5, encoding the laminin-alpha5 chain, with weight and height in a cohort of healthy 64-107 aged Italian individuals. Notably, two independent meta-analyses of genome-wide association studies found the C-allele of LAMA5 rs4925386-C/T correlated with the risk of colorectal cancer. We tested additional SNPs within the LAMA5 gene for association with anthropometric traits and longevity in our cohort of elderly subjects (N=624). Under an additive model, the rs2427283-C allele (P=0.02) and the rs4925386-T allele (P=0.01) were associated with shorter stature. Age stratified analyses showed that the rs4925386-T allele was also positively associated with longevity (P=0.001). The association of LAMA5 rs4925386 alleles with both inter-individual differences in height and in longevity suggests that laminins may be among the factors linking stature and cancer susceptibility. PMID- 26968356 TI - Novel trial designs for high-risk myelodysplastic syndromes. PMID- 26968354 TI - Dancing with the Stars: How Choreographed Bacterial Interactions Dictate Nososymbiocity and Give Rise to Keystone Pathogens, Accessory Pathogens, and Pathobionts. AB - Many diseases that originate on mucosal membranes ensue from the action of polymicrobial communities of indigenous organisms working in concert to disrupt homeostatic mechanisms. Multilevel physical and chemical communication systems among constituent organisms underlie polymicrobial synergy and dictate the community's pathogenic potential or nososymbiocity, that is, disease arising from living together with a susceptible host. Functional specialization of community participants, often originating from metabolic codependence, has given rise to several newly appreciated designations within the commensal-to-pathogen spectrum. Accessory pathogens, while inherently commensal in a particular microenvironment, nonetheless enhance the colonization or metabolic activity of pathogens. Keystone pathogens (bacterial drivers or alpha-bugs) exert their influence at low abundance by modulating both the composition and levels of community participants and by manipulating host responses. Pathobionts (or bacterial passengers) exploit disrupted host homeostasis to flourish and promote inflammatory disease. In this review we discuss how commensal or pathogenic properties of organisms are not intrinsic features, and have to be considered within the context of both the microbial community in which they reside and the host immune status. PMID- 26968357 TI - Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial. AB - BACKGROUND: Hypomethylating drugs are the standard treatment for patients with high-risk myelodysplastic syndromes. Survival is poor after failure of these drugs; there is no approved second-line therapy. We compared the overall survival of patients receiving rigosertib and best supportive care with that of patients receiving best supportive care only in patients with myelodysplastic syndromes with excess blasts after failure of azacitidine or decitabine treatment. METHODS: We did this randomised controlled trial at 74 hospitals and university medical centres in the USA and Europe. We enrolled patients with diagnosis of refractory anaemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukaemia based on local site assessment, and treatment failure with a hypomethylating drug in the past 2 years. Patients were randomly assigned (2:1) to receive rigosertib 1800 mg per 24 h via 72-h continuous intravenous infusion administered every other week or best supportive care with or without low-dose cytarabine. Randomisation was stratified by pretreatment bone marrow blast percentage. Neither patients nor investigators were masked to treatment assignment. The primary outcome was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT01241500. FINDINGS: From Dec 13, 2010, to Aug 15, 2013, we enrolled 299 patients: 199 assigned to rigosertib, 100 assigned to best supportive care. Median follow-up was 19.5 months (IQR 11.9-27.3). As of Feb 1, 2014, median overall survival was 8.2 months (95% CI 6.1-10.1) in the rigosertib group and 5.9 months (4.1-9.3) in the best supportive care group (hazard ratio 0.87, 95% CI 0.67-1.14; p=0.33). The most common grade 3 or higher adverse events were anaemia (34 [18%] of 184 patients in the rigosertib group vs seven [8%] of 91 patients in the best supportive care group), thrombocytopenia (35 [19%] vs six [7%]), neutropenia (31 [17%] vs seven [8%]), febrile neutropenia (22 [12%] vs ten [11%]), and pneumonia (22 [12%] vs ten [11%]). 41 (22%) of 184 patients in the rigosertib group and 30 (33%) of 91 patients in the best supportive care group died due to adverse events and three deaths were attributed to rigosertib treatment. INTERPRETATION: Rigosertib did not significantly improve overall survival compared with best supportive care. A randomised phase 3 trial of rigosertib (NCT 02562443) is underway in specific subgroups of patients deemed to be at high risk, including patients with very high risk per the Revised International Prognostic Scoring System criteria. FUNDING: Onconova Therapeutics, Leukemia & Lymphoma Society. PMID- 26968358 TI - Hypofractionation for prostate cancer: a word of caution. PMID- 26968359 TI - Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non inferiority, phase 3 trial. AB - BACKGROUND: Several studies have reported a low alpha to beta ratio for prostate cancer, suggesting that hypofractionation could enhance the biological tumour dose without increasing genitourinary and gastrointestinal toxicity. We tested this theory in the phase 3 HYPRO trial for patients with intermediate-risk and high-risk prostate cancer. We have previously reported acute incidence of genitourinary and gastrointestinal toxicity; here we report data for late genitourinary and gastrointestinal toxicity. METHODS: In this randomised non inferiority phase 3 trial, done in seven radiotherapy centres in the Netherlands, we enrolled intermediate-risk or high-risk patients aged between 44 and 85 years with histologically confirmed stage T1b-T4 NX-0MX-0 prostate cancer, a prostate specific antigen concentration of 60 ng/mL or lower, and WHO performance status of 0-2. A web-based application was used to randomly assign (1:1) patients to receive either standard fractionation with 39 fractions of 2 Gy in 8 weeks (five fractions per week) or hypofractionation with 19 fractions of 3.4 Gy in 6.5 weeks (three fractions per week). Randomisation was done with the minimisation procedure, stratified by treatment centre and risk group. The primary endpoint was to detect a 10% enhancement in 5-year relapse-free survival with hypofractionation. A key additional endpoint was non-inferiority of hypofractionation in cumulative incidence of grade 2 or worse acute and late genitourinary and gastrointestinal toxicity. We planned to reject inferiority of hypofractionation for late genitourinary toxicity if the estimated hazard ratio (HR) was less than 1.11 and for gastrointestinal toxicity was less than 1.13. We scored toxicity with the Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer (RTOG/EORTC) criteria from both physicians' records (clinical record form) and patients' self-assessment questionnaires. Analyses were done in the intention-to-treat population. Patient recruitment for the HYPRO trial was completed in 2010. The trial was registered with www.controlled-trials.com, number ISRCTN85138529. FINDINGS: Between March 19, 2007, and Dec 3, 2010, 820 patients (410 in both groups) were randomly assigned. Analyses for late toxicity included 387 assessable patients in the standard fractionation group and 395 in the hypofractionation group. The median follow-up was 60 months (IQR 51.2-67.3). The database for all analyses (both groups and both genitourinary and gastrointestinal toxicities) was locked on March 26, 2015. The incidence of grade 2 or worse genitourinary toxicity at 3 years was 39.0% (95% CI 34.2-44.1) in the standard fractionation group and 41.3% (36.6-46.4) in the hypofractionation group. The estimated HR for the cumulative incidence of grade 2 or worse late genitourinary toxicity was 1.16 (90% CI 0.98 1.38), suggesting that non-inferiority could not be shown. The incidence of grade 2 or worse gastrointestinal toxicity at 3 years was 17.7% (14.1-21.9) in standard fractionation and 21.9% (18.1-26.4) hypofractionation. With an estimated HR of 1.19 (90% CI 0.93-1.52) for the cumulative incidence of grade 2 or worse late gastrointestinal toxicity, we could not confirm non-inferiority of hypofractionation for cumulative late gastrointestinal toxicity. Cumulative grade 3 or worse late genitourinary toxicity was significantly higher in the hypofractionation group than in the standard fractionation group (19.0% [95% CI 15.2-23.2] vs 12.9% [9.7-16.7], respectively; p=0.021), but there was no significant difference between cumulative grade 3 or worse late gastrointestinal toxicity (2.6% [95% CI 1.2-4.7]) in the standard fractionation group and 3.3% [1.7-5.6] in the hypofractionation group; p=0.55). INTERPRETATION: Our data could not confirm that hypofractionation was non-inferior for cumulative late genitourinary and gastrointestinal toxicity compared with standard fractionation. Before final conclusions can be made about the utility of hypofractionation, efficacy outcomes need to be reported. FUNDING: The Dutch Cancer Society. PMID- 26968360 TI - Distinct Roles of Mic12 and Mic27 in the Mitochondrial Contact Site and Cristae Organizing System. AB - The mitochondrial inner membrane consists of two morphologically distinct domains, the inner boundary membrane and large invaginations termed cristae. Narrow membrane structures, the crista junctions, link these two domains. Maintenance of this elaborate architecture depends on the evolutionarily conserved mitochondrial contact site and cristae organizing system (MICOS), a multisubunit inner membrane protein complex. MICOS consists of two functional modules, a Mic60-Mic19 subcomplex that forms Mic60-mediated contact sites with the outer mitochondrial membrane and a Mic10-Mic12-Mic26-Mic27 membrane-sculpting subcomplex that contains large Mic10 oligomers. Deletion of MIC10 or MIC60 results in the loss of most crista junctions. Distinct views have been discussed about how the MICOS modules cooperate with each other. We searched for components required for the structural organization of MICOS and identified Mic12 and Mic27 as crucial factors with specific roles in MICOS complex formation. Mic27 promotes the stability of the Mic10 oligomers in the membrane-sculpting subcomplex, whereas Mic12 is required for the coupling of the two MICOS subcomplexes. We conclude that in addition to the MICOS core components Mic10 and Mic60, Mic12 and Mic27 play specific roles in the organization of the MICOS complex. PMID- 26968361 TI - The phenomenological method in qualitative psychology and psychiatry. AB - This article will closely examine the phenomenological method as applied to qualitative inquiry in psychology and psychiatry. In a critical comparison between Amedeo Giorgi's and Larry Davidson's qualitatively methods, conclusions were drawn with regard to how different kinds of qualitative inquiry are possible while remaining faithful to Husserlian philosophical foundations. Utilizing Lester Embree's recent articulation of how Husserl's method of the epoche can be disclosed as specific to a discipline, varieties of these two qualitative methods were seen in their relation to the original scientific aim instigated by the developer. PMID- 26968362 TI - Solution structure of an "open" E. coli Pol III clamp loader sliding clamp complex. AB - Sliding clamps are opened and loaded onto primer template junctions by clamp loaders, and once loaded on DNA, confer processivity to replicative polymerases. Previously determined crystal structures of eukaryotic and T4 clamp loader-clamp complexes have captured the sliding clamps in either closed or only partially open interface conformations. In these solution structure studies, we have captured for the first time the clamp loader-sliding clamp complex from Escherichia coli using size exclusion chromatography coupled to small angle X-ray scattering (SEC-SAXS). The data suggests the sliding clamp is in an open conformation which is wide enough to permit duplex DNA binding. The data also provides information about spatial arrangement of the sliding clamp with respect to the clamp loader subunits and is compared to complex crystal structures determined from other organisms. PMID- 26968363 TI - Structure of gamma-tubulin small complex based on a cryo-EM map, chemical cross links, and a remotely related structure. AB - Modeling protein complex structures based on distantly related homologues can be challenging due to poor sequence and structure conservation. Therefore, utilizing even low-resolution experimental data can significantly increase model precision and accuracy. Here, we present models of the two key functional states of the yeast gamma-tubulin small complex (gammaTuSC): one for the low-activity "open" state and another for the higher-activity "closed" state. Both models were computed based on remotely related template structures and cryo-EM density maps at 6.9A and 8.0A resolution, respectively. For each state, extensive sampling of alignments and conformations was guided by the fit to the corresponding cryo-EM density map. The resulting good-scoring models formed a tightly clustered ensemble of conformations in most regions. We found significant structural differences between the two states, primarily in the gamma-tubulin subunit regions where the microtubule binds. We also report a set of chemical cross-links that were found to be consistent with equilibrium between the open and closed states. The protocols developed here have been incorporated into our open-source Integrative Modeling Platform (IMP) software package (http://integrativemodeling.org), and can therefore be applied to many other systems. PMID- 26968364 TI - Analysis of the interface variability in NMR structure ensembles of protein protein complexes. AB - NMR structures consist in ensembles of conformers, all satisfying the experimental restraints, which exhibit a certain degree of structural variability. We analyzed here the interface in NMR ensembles of protein-protein heterodimeric complexes and found it to span a wide range of different conservations. The different exhibited conservations do not simply correlate with the size of the systems/interfaces, and are most probably the result of an interplay between different factors, including the quality of experimental data and the intrinsic complex flexibility. In any case, this information is not to be missed when NMR structures of protein-protein complexes are analyzed; especially considering that, as we also show here, the first NMR conformer is usually not the one which best reflects the overall interface. To quantify the interface conservation and to analyze it, we used an approach originally conceived for the analysis and ranking of ensembles of docking models, which has now been extended to directly deal with NMR ensembles. We propose this approach, based on the conservation of the inter-residue contacts at the interface, both for the analysis of the interface in whole ensembles of NMR complexes and for the possible selection of a single conformer as the best representative of the overall interface. In order to make the analyses automatic and fast, we made the protocol available as a web tool at: https://www.molnac.unisa.it/BioTools/consrank/consrank-nmr.html. PMID- 26968365 TI - Crystal structures of Apo and GMP bound hypoxanthine-guanine phosphoribosyltransferase from Legionella pneumophila and the implications in gouty arthritis. AB - Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (EC 2.4.2.8) reversibly catalyzes the transfer of the 5-phophoribosyl group from 5-phosphoribosyl-alpha-1 pyrophosphate (PRPP) to hypoxanthine or guanine to form inosine monophosphate (IMP) or guanosine monophosphate (GMP) in the purine salvage pathway. To investigate the catalytic mechanism of this enzyme in the intracellular pathogen Legionella pneumophila, we determined the crystal structures of the L. pneumophila HGPRT (LpHGPRT) both in its apo-form and in complex with GMP. The structures reveal that LpHGPRT comprises a core domain and a hood domain which are packed together to create a cavity for GMP-binding and the enzymatic catalysis. The binding of GMP induces conformational changes of the stable loop II. This new binding site is closely related to the Gout arthritis-linked human HGPRT mutation site (Ser103Arg). Finally, these structures of LpHGPRT provide insights into the catalytic mechanism of HGPRT. PMID- 26968366 TI - Discoveries, metabolic roles and diseases of mitochondrial carriers: A review. AB - Mitochondrial carriers (MCs) are a superfamily of nuclear-encoded proteins that are mostly localized in the inner mitochondrial membrane and transport numerous metabolites, nucleotides, cofactors and inorganic anions. Their unique sequence features, i.e., a tripartite structure, six transmembrane alpha-helices and a three-fold repeated signature motif, allow MCs to be easily recognized. This review describes how the functions of MCs from Saccharomyces cerevisiae, Homo sapiens and Arabidopsis thaliana (listed in the first table) were discovered after the genome sequence of S. cerevisiae was determined in 1996. In the genomic era, more than 50 previously unknown MCs from these organisms have been identified and characterized biochemically using a method consisting of gene expression, purification of the recombinant proteins, their reconstitution into liposomes and transport assays (EPRA). Information derived from studies with intact mitochondria, genetic and metabolic evidence, sequence similarity, phylogenetic analysis and complementation of knockout phenotypes have guided the choice of substrates that were tested in the transport assays. In addition, the diseases associated to defects of human MCs have been briefly reviewed. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou. PMID- 26968368 TI - Embolization of a Large Rapidly Growing Aortic Pseudo-Aneurysm Not Amenable to Open or Endovascular Repair. AB - BACKGROUND: To report the case of a rapidly growing aortic false aneurysm because of Q fever infection that was managed by embolization. CASE REPORT: An 80-year old man was admitted to our unit for an aortic false aneurysm from a chronic Q fever infection. During his stay, the aneurysm showed rapid progression necessitating urgent treatment. The patient was unfit for surgical repair; moreover, the location of the aneurysm at the level of the superior mesenteric artery prohibited the use of an endovascular graft. He was managed by coiling of the aneurysmal cavity with multiple detachable coils after positioning of a bare aortic stent to lock the coils and prevent their migration into the aortic lumen. The false aneurysm was successfully thrombosed with no complications. The patient was then put on doxycycline and hydroxychloroquine to target Coxiella burnetii. CONCLUSIONS: Aortic false aneurysm coiling is feasible in cases where an endograft is not possible or an open repair is contraindicated. The use of a bare metal stent may help as a barrier to prevent the coils from migrating into the aneurysm and thus avoiding embolization into the systemic circulation. PMID- 26968367 TI - Molecular structure and pathophysiological roles of the Mitochondrial Calcium Uniporter. AB - Mitochondrial Ca(2+) uptake regulates a wide array of cell functions, from stimulation of aerobic metabolism and ATP production in physiological settings, to induction of cell death in pathological conditions. The molecular identity of the Mitochondrial Calcium Uniporter (MCU), the highly selective channel responsible for Ca(2+) entry through the IMM, has been described less than five years ago. Since then, research has been conducted to clarify the modulation of its activity, which relies on the dynamic interaction with regulatory proteins, and its contribution to the pathophysiology of organs and tissues. Particular attention has been placed on characterizing the role of MCU in cardiac and skeletal muscles. In this review we summarize the molecular structure and regulation of the MCU complex in addition to its pathophysiological role, with particular attention to striated muscle tissues. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou. PMID- 26968369 TI - Treatment of an Abdominal Aortic Aneurysm Infected by Coxiella Burnetii Using a Cryopreserved Allograft. AB - Q fever is a worldwide zoonosis caused by an intracellular bacillus named Coxiella burnetii (CB) and is a rare cause of vascular infections. We report a case of abdominal aortic aneurysm infected by CB with bilateral paravertebral abscesses and contiguous spondylodiscitis treated by open repair using a cryopreserved allograft and long-term antibiotic therapy by oral doxycycline and oral hydroxychloroquine for a duration of 18 months. Twenty months after the operation, the patient had no infections signs and vascular complication. PMID- 26968370 TI - Effect of Endovascular Interventions on General Surgery Trainee Operative Experience; a Comparison of Case Log Reports. AB - BACKGROUND: Vascular surgery fellowship training has evolved with the widespread adoption of endovascular interventions. The purpose of this study is to examine how general surgery trainee exposure to vascular surgery has changed over time. METHODS: Review of the Accreditation Council for Graduate Medical Education national case log reports for graduating Vascular Surgery Fellows (VF), and general surgery residents (GSR) from 2001 to 2012 was performed. RESULTS: The number of GSR increased from 1021 to 1098, and the number of VF increased from 96 to 121 from 2001 to 2012. The total number of vascular cases done by VF increased by 1161 since 2001 (298-762), whereas the total number of vascular cases done by GSR has decreased by 40% during this time period (186-116). Vascular fellows increase was due primarily to an increase in endovascular experience; a finding not noted in general surgery residents. CONCLUSIONS: Vascular fellow case log changes are due primarily to an increase in endovascular experience that has not been mirrored by general surgery trainees. Open surgery experience has decreased overall for general surgery residents in all major categories, a change not seen in vascular surgery fellows. PMID- 26968371 TI - Hybrid Treatment of Acute Abdominal Aortic Thrombosis Presenting with Paraplegia. AB - Acute thrombotic or embolic occlusion of the abdominal aorta is a rare vascular emergency associated with high morbidity and mortality rates. Classically, the clinical presentation is a severe peripheral ischemia with bilateral leg pain as the predominant feature. Aortic occlusion presenting as an isolated acute onset of paraplegia due to spinal cord ischemia is very rare and requires improved awareness to prevent adverse outcomes associated with delayed diagnosis. We report the case of a 54-year-old man who presented with sudden paraplegia due to the thrombotic occlusion of the infrarenal aorta involving the first segment of the common iliac arteries on both sides; emergent transperitoneal aorto iliac thrombectomy combined with the endovascular iliac kissing-stent technique were performed achieving perioperative complete regression of the symptoms. PMID- 26968372 TI - Modeling the transboundary risk of feed ingredients contaminated with porcine epidemic diarrhea virus. AB - BACKGROUND: This study describes a model developed to evaluate the transboundary risk of PEDV-contaminated swine feed ingredients and the effect of two mitigation strategies during a simulated transport event from China to the US. RESULTS: Ingredients imported to the USA from China, including organic & conventional soybeans and meal, lysine hydrochloride, D-L methionine, tryptophan, Vitamins A, D & E, choline, carriers (rice hulls, corn cobs) and feed grade tetracycline, were inoculated with PEDV. Control ingredients, and treatments (ingredients plus a liquid antimicrobial (SalCURB, Kemin Industries (LA) or a 2% custom medium chain fatty acid blend (MCFA)) were tested. The model ran for 37 days, simulating transport of cargo from Beijing, China to Des Moines, IA, US from December 23, 2012 to January 28, 2013. To mimic conditions on land and sea, historical temperature and percent relative humidity (% RH) data were programmed into an environmental chamber which stored all containers. To evaluate PEDV viability over time, ingredients were organized into 1 of 4 batches of samples, each batch representing a specific segment of transport. Batch 1 (segment 1) simulated transport of contaminated ingredients from manufacturing plants in Beijing (day 1 post-contamination (PC)). Batch 2 (segments 1 and 2) simulated manufacturing and delivery to Shanghai, including time in Anquing terminal awaiting shipment (days 1-8 PC). Batch 3 (segments 1, 2 and 3) represented time in China, the crossing of the Pacific and entry to the US at the San Francisco, CA terminal (day 1-27 PC). Batch 4 (segments 1-4) represented the previous events, including transport to Des Moines, IA (days 1-37 PC). Across control (non-treated) ingredients, viable PEDV was detected in soybean meal (organic and conventional), Vitamin D, lysine hydrochloride and choline chloride. In contrast, viable PEDV was not detected in any samples treated with LA or MCFA. CONCLUSIONS: These results demonstrate the ability of PEDV to survive in a subset of feed ingredients using a model simulating shipment from China to the US. This is proof of concept suggesting that contaminated feed ingredients could serve as transboundary risk factors for PEDV, along with the identification of effective mitigation options. PMID- 26968373 TI - Associations between non-discrimination and training policies and physicians' attitudes and knowledge about sexual and gender minority patients: a comparison of physicians from two hospitals. AB - BACKGROUND: Some physicians lack knowledge and awareness about health issues specific to sexual and gender minority (SGM) individuals. To help improve this, hospitals have implemented policies that mandate non-discrimination and training to promote sexual and gender minority health. There is limited evidence about how such policies relate to physicians' knowledge, attitudes, and gender and sexual minority affirmative practices. METHOD: A random sample of 1000 physicians was recruited from a complete list of physicians affiliated with one of two university Hospitals located in Tennessee and 180 physicians completed the survey concerning attitudes and knowledge about SGM individuals. Physicians were affiliated with either Hospital A that had not implemented policies for non discrimination and training, or Hospital B that did. RESULTS: Physicians held different attitudes about SGM patients than non-patients. Physicians affiliated with Hospital A held more negative attitudes about SGM individuals who were non patients than physicians affiliated with Hospital B. There were no differences between the two hospitals in physicians' attitudes and knowledge about SGM patients. CONCLUSION: Policies that mandate non-discrimination and training as they currently exist may not improve physicians' attitudes and knowledge about SGM individuals. Additional research is needed to understand how these policies and trainings relate to physicians' SGM affirmative practices. PMID- 26968375 TI - Influence of the cause of the revision on the outcome after revision knee arthroplasty with condylar constrained implant. AB - INTRODUCTION: Revision total knee arthroplasty (TKA) is a common procedure with varying results depending on the cause. Our objective was to compare the clinical and radiological outcomes in patients undergoing aseptic revision versus revision due to prosthetic infection. MATERIAL AND METHODS: The study included 41 patients who underwent TKA revision with the same varus-valgus constrained implant. In all cases a clinical evaluation was performed including pain, range of motion (ROM), Knee Society Score (KSS), complications, as well as radiological study. A comparative analysis was performed on the pre- and postoperative results between septic and aseptic groups. The mean follow-up was 6 years. RESULTS: ROM had a mean increase of 17 degrees (p<.01). KSS and functional KSS improved significantly postoperatively. In the radiological study, joint interline and limb alignment were restored in all cases. Radiolucencies were found in 36.5% of cases; however they were unrelated to the appearance of loosening of the implant. There were complications in 29.2% of cases, mostly related to the surgical wound. Mobility, KSS, KSS functional and satisfaction at follow-up were better in the septic group. Implant survival was 95% at follow-up. CONCLUSION: Revision arthroplasty with constrained varus-valgus implant is safe, and has successful mid-term results despite the cause of the replacement procedure. PMID- 26968374 TI - Clinical evaluation of dengue and identification of risk factors for severe disease: protocol for a multicentre study in 8 countries. AB - BACKGROUND: The burden of dengue continues to increase globally, with an estimated 100 million clinically apparent infections occurring each year. Although most dengue infections are asymptomatic, patients can present with a wide spectrum of clinical symptoms ranging from mild febrile illness through to severe manifestations of bleeding, organ impairment, and hypovolaemic shock due to a systemic vascular leak syndrome. Clinical diagnosis of dengue and identification of which patients are likely to develop severe disease remain challenging. This study aims to improve diagnosis and clinical management through approaches designed a) to differentiate between dengue and other common febrile illness within 72 h of fever onset, and b) among patients with dengue to identify markers that are predictive of the likelihood of evolving to a more severe disease course. METHOD/DESIGN: This is a prospective multi-centre observational study aiming to enrol 7-8000 participants aged >= 5 years presenting with a febrile illness consistent with dengue to outpatient health facilities in 8 countries across Asia and Latin America. Patients presenting within 72 h of fever onset who do not exhibit signs of severe disease are eligible for the study. A broad range of clinical and laboratory parameters are assessed daily for up to 6 days during the acute illness, and also at a follow up visit 1 week later. DISCUSSION: Data from this large cohort of patients, enrolled early with undifferentiated fever, will be used to develop a practical diagnostic algorithm and a robust clinical case definition for dengue. Additionally, among patients with confirmed dengue we aim to identify simple clinical and laboratory parameters associated with progression to a more severe disease course. We will also investigate early virological and serological correlates of severe disease, and examine genetic associations in this large heterogeneous cohort. In addition the results will be used to assess the new World Health Organization classification scheme for dengue in practice, and to update the guidelines for "Integrated Management of Childhood Illness" used in dengue-endemic countries. TRIAL REGISTRATION: NCT01550016. Registration Date: March 7, 2012. PMID- 26968376 TI - Occurrence, molecular characterization and predominant genotypes of Enterocytozoon bieneusi in dairy cattle in Henan and Ningxia, China. AB - BACKGROUND: Enterocytozoon bieneusi is the most frequently diagnosed microsporidian species in humans and a wide range of animals. This study was conducted to assess the prevalence and molecular characteristics of E. bieneusi in dairy cattle in Henan Province of central China and the Ningxia Hui Autonomous Region of northwest China. FINDINGS: Of 879 fresh fecal specimens, 24.3 % (214/879) tested positive for E. bieneusi by nested polymerase chain reaction (PCR) based on the internal transcriber spacer (ITS) gene. The highest infection rate, 46.8 % (51/109, P < 0.0001), was observed in a group of dairy cattle with diarrhea, located in Ningxia. The age groups with higher infection rates were pre weaned calves (29.3 %, 127/434, P < 0.0001) and post-weaned calves (23.9 %, 63/264, P = 0.006). Sequencing and phylogenetic analysis revealed 20 E. bieneusi ITS genotypes (15 known and five new), including members of Group 1 and Group 2. Genotypes I and J were detected in 64.5 % (138/214) of the E. bieneusi positive specimens. CONCLUSIONS: Genotypes I and J were the dominant genotypes in dairy cattle in the present study. The detection of zoonotic genotypes of E. bieneusi in dairy farms indicates that cattle may play an important role as a reservoir host for zoonotic infections. PMID- 26968377 TI - Detailed phenotyping identifies genes with pleiotropic effects on body composition. AB - BACKGROUND: Genetic variation in both the composition and distribution of fat and muscle in the body is important to human health as well as the healthiness and value of meat from cattle and sheep. Here we use detailed phenotyping and a multi trait approach to identify genes explaining variation in body composition traits. RESULTS: A multi-trait genome wide association analysis of 56 carcass composition traits measured on 10,613 sheep with imputed and real genotypes on 510,174 SNPs was performed. We clustered 71 significant SNPs into five groups based on their pleiotropic effects across the 56 traits. Among these 71 significant SNPs, one group of 11 SNPs affected the fatty acid profile of the muscle and were close to 8 genes involved in fatty acid or triglyceride synthesis. Another group of 23 SNPs had an effect on mature size, based on their pattern of effects across traits, but the genes near this group of SNPs did not share any obvious function. Many of the likely candidate genes near SNPs with significant pleiotropic effects on the 56 traits are involved in intra-cellular signalling pathways. Among the significant SNPs were some with a convincing candidate gene due to the function of the gene (e.g. glycogen synthase affecting glycogen concentration) or because the same gene was associated with similar traits in other species. CONCLUSIONS: Using a multi-trait analysis increased the power to detect associations between SNP and body composition traits compared with the single trait analyses. Detailed phenotypic information helped to identify a convincing candidate in some cases as did information from other species. PMID- 26968378 TI - Beneficial effects of cocoa, coffee, green tea, and garcinia complex supplement on diet induced obesity in rats. AB - BACKGROUND: Cocoa, coffee, green tea and garcinia contain large amounts of polyphenols. Polyphenols are well-known phytochemicals and found in plants, and have modulated physiological and molecular pathways that are involved in energy metabolism, adiposity, and obesity. METHODS: To evaluate the obesity-lowering effect of a combined extract (comprising cocoa, coffee, green tea and garcinia; CCGG) in high-energy diet (HED)-induced obese rats. Male Sprague Dawley rats (8 weeks old) were randomly divided into four groups (n = 12 per group): normal diet with vehicle treatment (Control), and HED to receive vehicle or CCGG by oral gavage at 129, 258, or 517 mg/kg/day for 4 weeks, designated the HED, 0.5X, 1X and 1X groups, respectively. RESULTS: HED induced macrovesicular fat in the liver and the formation of adipose tissues, and significantly increased the levels of serum free fatty acids (FFA), triacylglycerol (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and LDL-C/HDL-C, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and ketone bodies in serum, and hepatic TG and TC levels, and decreased the levels of high density lipoprotein cholesterol (HDL-C) in serum and lipase activity in fat tissues. Treatment with CCGG could significantly decrease the levels of FFA, TG, TC, LDL C, and LDL-C/HDL-C, AST, ALT, and ketone bodies in serum, and hepatic TG and TC contents, and increase the levels of HDL-C in serum and lipase activity in fat tissues compared to the HED group. Liver histopathology also showed that CCGG could significantly reduce the incidence of liver lesions. CONCLUSION: These results suggested that CCGG stimulated lipid metabolism in HED-induced obese rats, which is attributable to fat mobilization from adipose tissue. PMID- 26968380 TI - Moderate hyperoxic versus near-physiological oxygen targets during and after coronary artery bypass surgery: a randomised controlled trial. AB - BACKGROUND: The safety of perioperative hyperoxia is currently unclear. Previous studies in patients undergoing coronary artery bypass surgery suggest reduced myocardial damage when avoiding extreme perioperative hyperoxia (>400 mmHg). In this study we investigated whether an oxygenation strategy from moderate hyperoxia to a near-physiological oxygen tension reduces myocardial damage and improves haemodynamics, organ dysfunction and oxidative stress. METHODS: This was a single-blind, single-centre, open-label, randomised controlled trial in patients undergoing elective coronary artery bypass surgery. Fifty patients were randomised to a partial pressure of oxygen in arterial blood (PaO2) target of 200 220 mmHg during cardiopulmonary bypass and 130-150 mmHg during intensive care unit (ICU) admission (control group) versus lower targets of 130-150 mmHg during cardiopulmonary bypass and 80-100 mmHg at the ICU (conservative group). Primary outcome was myocardial injury (CK-MB and Troponin-T) at ICU admission and 2, 6 and 12 hours thereafter. RESULTS: Weighted PaO2 during cardiopulmonary bypass was 220 mmHg (interquartile range (IQR) 211-233) vs. 157 (151-162) in the control and conservative group, respectively (P < 0.0001). During ICU admission, weighted PaO2 was 107 mmHg (86-141) vs. 90 (84-98) (P = 0.03), respectively. Area under the curve of CK-MB was median 23.5 MUg/L/h (IQR 18.4-28.1) vs. 21.5 (15.8-26.6) (P = 0.35) and 0.30 MUg/L/h (0.25-0.44) vs. 0.39 (0.24-0.43) (P = 0.81) for Troponin-T. Cardiac index, systemic vascular resistance index, creatinine, lactate and F2-isoprostane levels were not different between groups. CONCLUSIONS: Compared to moderate hyperoxia, a near-physiological oxygen strategy does not reduce myocardial damage in patients undergoing coronary artery bypass surgery. Conservative oxygen administration was not associated with increased lactate levels or hypoxic events. TRIAL REGISTRATION: Netherlands Trial Registry NTR4375, registered on 30 January 2014. PMID- 26968381 TI - Neurodevelopmental outcomes among 2- to 3-year-old children in Bangladesh with elevated blood lead and exposure to arsenic and manganese in drinking water. AB - BACKGROUND: The people of Bangladesh are currently exposed to high concentrations of arsenic and manganese in drinking water, as well as elevated lead in many regions. The objective of this study was to investigate associations between environmental exposure to these contaminants and neurodevelopmental outcomes among Bangladeshi children. METHODS: We evaluated data from 524 children, members of an ongoing prospective birth cohort established to study the effects of prenatal and early childhood arsenic exposure in the Sirajdikhan and Pabna Districts of Bangladesh. Water was collected from the family's primary drinking source during the first trimester of pregnancy and at ages 1, 12 and 20-40 months. At age 20-40 months, blood lead was measured and neurodevelopmental outcomes were assessed using a translated, culturally-adapted version of the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). RESULTS: Median blood lead concentrations were higher in Sirajdikhan than Pabna (7.6 vs. to predict phase function influence on backscattering and reveal ambiguities related to the established phase function parameter gamma. Through the use of high-order similarity relations, we introduce a new parameter that more accurately relates a scattering phase function to its subdiffusive backscattering intensity. Using extensive analytical forward calculations based on solutions to the radiative transfer equation in the spatial domain and spatial frequency domain, we demonstrate the superiority of our empirically derived quantifier sigma over the established parameter gamma. PMID- 26968383 TI - Hypoxic conditioned medium from mesenchymal stem cells promotes lymphangiogenesis by regulation of mitochondrial-related proteins. AB - BACKGROUND: Recently, cell-based therapeutic lymphangiogenesis has emerged and provided hope for lymphatic regeneration. Previous studies have demonstrated that secretomes of mesenchymal stem cells (MSCs) facilitate the regeneration of various damaged tissues. This study was conducted to evaluate the lymphangiogenic potential of hypoxic conditioned media (HCM) from MSCs. METHODS: To investigate the effects of MSC-secreted factors in starved human lymphatic endothelial cells (hLEC), hLECs were treated with endothelial basal medium (EBM)-2 (control), normoxic conditioned media (NCM), or HCM in vitro and in vivo. RESULTS: MSCs expressed lymphangiogenic factors including EGF, FGF2, HGF, IGF-1, and VEGF-A and -C. hLECs were treated with each medium. hLEC proliferation, migration, and tube formation were improved under HCM compared with NCM. Moreover, expression of mitochondrial-related factors, MFN1and 2, were improved in HCM-treated hLECs. Lymphedema mice injected with HCM showed markedly decreased lymphedema via increased lymphatic vessel formation when compared with EBM-2- or NCM-treated mice. CONCLUSIONS: This study suggested that HCM from MSCs contain high levels of secreted lymphangiogenic factors and promote lymphangiogenesis by regulating mitochondrial-related factors. Thus, treatment with HCM may be a therapeutic strategy for lymphedema. PMID- 26968386 TI - Optical coherence tomography use in the diagnosis of enamel defects. AB - Molar incisor hypomineralization (MIH) affects the permanent incisors and molars, whose undermineralized matrix is evidenced by lesions ranging from white to yellow/brown opacities to crumbling enamel lesions incapable of withstanding normal occlusal forces and function. Diagnosing the condition involves clinical and radiographic examination of these teeth, with known limitations in determining the depth extent of the enamel defects in particular. Optical coherence tomography (OCT) is an emerging hard and soft tissue imaging technique, which was investigated as a new potential diagnostic method in dentistry. A comparison between the diagnostic potential of the conventional methods and OCT was conducted. Compared to conventional imaging methods, OCT gave more information on the structure of the enamel defects as well as the depth extent of the defects into the enamel structure. Different types of enamel defects were compared, each type presenting a unique identifiable pattern when imaged using OCT. Additionally, advanced methods of OCT image analysis including backscattered light intensity profile analysis and enface reconstruction were performed. Both methods confirmed the potential of OCT in enamel defects diagnosis. In conclusion, OCT imaging enabled the identification of the type of enamel defect and the determination of the extent of the enamel defects in MIH with the advantage of being a radiation free diagnostic technique. PMID- 26968385 TI - Characterization and standardization of tissue-simulating protoporphyrin IX optical phantoms. AB - Optical devices for measuring protoporphryin IX (PpIX) fluorescence in tissue are routinely validated by measurements in optical phantoms. Yet there exists limited data to form a consensus on the recipe for phantoms that both mimic the optical properties found in tissue and yield a reliable and stable relationship between PpIX concentration and the fluorescence remission intensity. This study characterizes the influence of multiple phantom components on PpIX fluorescence emission intensity, using Intralipid as the scattering source, bovine whole blood as the background absorber, and Tween as a surfactant to prevent PpIX aggregation. Optical measurements showed a linear proportionality (r > 0.99) between fluorescence intensity and PpIX concentration (0.1 to 10 MUg/mL) over a range of Intralipid (1 to 2%) and whole blood (0.5 to 3%) for phantoms containing low surfactant (<= 0.1%), with fluorescence intensities and scattering and absorption properties stable for 5 h after mixing. The role of surfactant in PpIX phantoms was found to be complex, as aggregation was evident in aqueous nonturbid phantoms with no surfactant (0% Tween), and avoided in phantoms containing Intralipid as the scattering source with no additional or low amounts of added surfactant (<= 0.1% Tween). Conversely, phantoms containing higher surfactant content (>0.1% Tween) and whole blood showed interactions that distorted the fluorescence emissions. PMID- 26968387 TI - Intervolume analysis to achieve four-dimensional optical microangiography for observation of dynamic blood flow. AB - We demonstrate in vivo volumetric optical microangiography at ~ 200 volumes/s by the use of 1.6 MHz Fourier domain mode-locking swept source optical coherence tomography and an effective 36 kHz microelectromechanical system (MEMS) scanner. We propose an intervolume analysis strategy to contrast the dynamic blood flow signal from the static tissue background. The proposed system is demonstrated by imaging cerebral blood flow in mice in vivo. For the first time, imaging speed, sensitivity, and temporal resolution become possible for a direct four dimensional observation of microcirculations within live body parts. PMID- 26968388 TI - Teratogenic effect of cisplatin in rats and the protective role of sodium selenate. AB - Eighty pregnant Sprague-Dawley rats were used in this study. They were allotted to four equal groups. The first group served as a control without any treatment while the other groups were given cisplatin, sodium selenate, and cisplatin+sodium selenate, respectively. Cisplatin was injected intraperitoneally in a dose of 5mg/kgb wt. on the 12th day of gestation while sodium selenate was administered orally in a dose of 0.5mg/kgb wt throughout gestation. Animals were sacrificed on the 20th day of gestation for fetal examination. Cisplatin produced significant elevation in the percentages of late resorption sites and dead foetuses compared with the control group. The mean foetal and placental weights were significantly reduced. Dwarf foetuses and subcutaneous (s/c) haemorrhage were also recorded in cisplatin-treated group. Visceral abnormalities were revealed in the form of dilated nares, anophthalmia and/or microphthalmia, dilated brain ventricles, hypertrophy of the heart, hypoplasia of the lung, hepatomegaly and dilated renal pelvis. Skeletal examination showed wide open fontanel, incomplete ossification of parietal and interparietal bones, incomplete ossification of sternum, reduction in the number or even complete absence of phalanges, sacral and/or caudal vertebrae. Histopathological examination of placentas in cisplatin-treated group revealed severe pathological alterations. Administration of sodium selenate significantly alleviated the afore-mentioned adverse effects of cisplatin on the fetuses and their placentas so we conclude that sodium selenate as an antioxidant has an effective protective role in cisplatin teratogenic effects. PMID- 26968389 TI - Retardation of quality changes in camel meat sausages by phenolic compounds and phenolic extracts. AB - Impact of tannic acid (TA), date seed extract (DSE), catechin (CT) and green tea extract (GTE) on lipid oxidation, microbial load and textural properties of camel meat sausages during 12 days of refrigerated storage was investigated. TA and CT showed higher activities in all antioxidative assays compared to DSE and GTE. Lipid oxidation and microbial growth was higher for control sausages when compared to other samples. TA and CT at a level of 200 mg/kg were more effective in retarding lipid oxidation and lowering microbial count (P < 0.05). Sausages treated with TA and DSE were found to have higher hardness, gumminess and chewiness values compared to other treatments (P < 0.05). Addition of different phenolic compounds or extract did not influence the sensory color of sausages. Furthermore, sensory quality was also found to be superior in TA and CT treated sausages. Therefore, pure phenolic compounds (TA and CT) proved to be more effective in retaining microbial and sensorial qualities of camel meat sausages compared to phenolic extracts (GTE and DSE) over 12 days of storage at 4 degrees C. PMID- 26968390 TI - Hospital Readmission of Patients With Congenital Heart Disease in Canada. AB - BACKGROUND: Risk factors for hospital readmission in children or adults with congenital heart disease (CHD) are poorly understood. We assessed readmission rates among patients with CHD stratified by age, sex, and severity of CHD and identified risk factors associated with hospital readmission. METHODS: A retrospective cohort study was conducted among patients with CHD identified from the Discharge Abstract Database of the Canadian Institute for Health Information from fiscal years 2003-2013. Index hospitalizations were identified and patients followed to identify readmissions. Poisson regression was used to analyze readmission rates by age, sex, and severity of CHD. Logistic regression analysis was performed to identify risk factors associated with readmission within 1 month after discharge. RESULTS: There were 67,940 index hospitalizations. The readmission rate per 1000 patients with CHD was 48 within 2 weeks, 83 within 1 month, 163 within 3 months, and 351 within 1 year. Patients aged >= 65 years had the highest readmission rate at 1 month (12.6%) followed by 40- to 64-year old adults (8.5%), and infants (8.3%). Readmission rates were 2.3-4.1 times higher in patients with complex CHD (P < 0.001) and 1.3-1.8 times higher in patients with moderate CHD (P < 0.001) than in simple patients with CHD. Risk factors for readmission were age >= 40 years, age < 1 year, male sex, longer index hospitalization stay, and complex CHD. Increasing Charlson comorbidity score was a risk factor for readmission among adults. CONCLUSIONS: Greater than one third of hospitalized patients with CHD were readmitted within 1 year. Age, sex, and CHD complexity influence readmission risk. Future studies should investigate the reasons for unplanned readmission. PMID- 26968391 TI - From Coronary Care Units to Cardiac Intensive Care Units: Recommendations for Organizational, Staffing, and Educational Transformation. AB - Medical care in Canadian cardiac units has changed considerably over the past 3 decades in response to an increasingly complex and diverse patient population admitted with acute cardiac pathology. To maintain the highest level of care for these patients, there is a pressing need to evolve traditional coronary care units into contemporary cardiac intensive care units. In this article we aim to highlight the current variations in Canadian units, develop approaches to overcome logistical and infrastructural obstacles, and propose staffing and training recommendations that would allow for the establishment of contemporary cardiac intensive care units. PMID- 26968392 TI - Canadian Cardiovascular Society Quality Indicators for Heart Failure. AB - A working group was convened by the Canadian Cardiovascular Society (CCS) in 2010 to identify quality indicators (QIs) for heart failure (HF). Using the CCS "Best Practices for Developing Cardiovascular Quality Indicators" methodology, a total of 49 "long-list" QIs was identified and rated. Subsequent ranking and discussion led to the selection of an initial "short-list" of 6 QIs to evaluate quality care, including daily assessment of blood chemistry indicators, chest radiography, patient education, in-hospital use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, assessment of left ventricular function, and 30-day hospital readmission. The short-list QIs were selected as being important for quality assurance and because the patient information, for the most part, can be captured during the inpatient setting, which would allow these QIs to be adopted more easily. These 6 QIs were subjected to a feasibility test that found that even within the inpatient setting, there is a significant gap between the existing knowledge infrastructure and the necessary information tracking processes to measure QIs. Only 1 QI (30-day hospital readmission) can currently be measured comparatively across Canada, although the other 5 of 6 short-list QIs can be measured using other data collected by jurisdictions. Standardization and enhancements to knowledge infrastructure are essential to provide the comprehensive patient data necessary to evaluate the quality of HF care across Canada. PMID- 26968394 TI - Do TASER Electrical Weapons Actually Electrocute? PMID- 26968393 TI - Vascular Complications of Cancer Chemotherapy. AB - Development of new anticancer drugs has resulted in improved mortality rates and 5-year survival rates in patients with cancer. However, many of the modern chemotherapies are associated with cardiovascular toxicities that increase cardiovascular risk in cancer patients, including hypertension, thrombosis, heart failure, cardiomyopathy, and arrhythmias. These limitations restrict treatment options and might negatively affect the management of cancer. The cardiotoxic effects of older chemotherapeutic drugs such as alkylating agents, antimetabolites, and anticancer antibiotics have been known for a while. The newer agents, such as the antiangiogenic drugs that inhibit vascular endothelial growth factor signalling are also associated with cardiovascular pathology, especially hypertension, thromboembolism, myocardial infarction, and proteinuria. Exact mechanisms by which vascular endothelial growth factor inhibitors cause these complications are unclear but impaired endothelial function, vascular and renal damage, oxidative stress, and thrombosis might be important. With increasing use of modern chemotherapies and prolonged survival of cancer patients, the incidence of cardiovascular disease in this patient population will continue to increase. Accordingly, careful assessment and management of cardiovascular risk factors in cancer patients by oncologists and cardiologists working together is essential for optimal care so that prolonged cancer survival is not at the expense of increased cardiovascular events. PMID- 26968395 TI - Prelinguistic foundations of verb learning: Infants discriminate and categorize dynamic human actions. AB - Action categorization is necessary for human cognition and is foundational to learning verbs, which label categories of actions and events. In two studies using a nonlinguistic preferential looking paradigm, 10- to 12-month-old English learning infants were tested on their ability to discriminate and categorize a dynamic human manner of motion (i.e., way in which a figure moves; e.g., marching). Study 1 results reveal that infants can discriminate a change in path and actor across instances of the same manner of motion. Study 2 results suggest that infants categorize the manner of motion for dynamic human events even under conditions in which other components of the event change, including the actor's path and the actor. Together, these two studies extend prior research on infant action categorization of animated motion events by providing evidence that infants can categorize dynamic human actions, a skill foundational to the learning of motion verbs. PMID- 26968396 TI - Investigating racial disparities in use of NK1 receptor antagonists to prevent chemotherapy-induced nausea and vomiting among women with breast cancer. AB - Chemotherapy-induced nausea and vomiting (CINV) is a major concern for cancer patients and, if uncontrolled, can seriously compromise quality of life (QOL) and other treatment outcomes. Because of the expense of antiemetic medications used to prevent CINV (particularly oral medications filled through Medicare Part D), disparities in their use may exist. We used 2006-2012 SEER-Medicare data to evaluate the use of neurokinin-1 receptor antagonists (NK1s), a potent class of antiemetics, among black and white women initiating highly emetogenic chemotherapy for the treatment of early-stage breast cancer. We used modified Poisson regression to assess the relationship between race and (1) any NK1 use, (2) oral NK1 (aprepitant) use, and (3) intravenous NK1 (fosaprepitant) use. We report adjusted risk ratios (aRR) and 95 % confidence intervals (CI). The study included 1130 women. We observed racial disparities in use of any NK1 (aRR: 0.68, 95 % CI 0.51-0.91) and in use of oral aprepitant specifically (aRR: 0.54, 95 % CI 0.35-0.83). We did not observe disparities in intravenous fosaprepitant use. After controlling for variables related to socioeconomic status, disparities in NK1 and aprepitant use were reduced but not eliminated. We found racial disparities in women's use of oral NK1s for the prevention of CINV. These disparities may be partly explained by racial differences in socioeconomic status, which may translate into differential ability to afford the medication. PMID- 26968397 TI - The clinical value of HER-2 overexpression and PIK3CA mutations in the older breast cancer population: a FOCUS study analysis. AB - Studies to confirm the effect of acknowledged prognostic markers in older breast cancer patients are scarce. The aim of this study was to evaluate the prognostic value of HER-2 overexpression and PIK3CA mutations in older breast cancer patients. Female breast cancer patients aged 65 years or older, diagnosed between 1997 and 2004 in a geographical region in The Netherlands, with an invasive, non metastatic tumour and tumour material available, were included in the study. The primary endpoint was relapse-free period and secondary endpoint was relative survival. Determinants were immunochemical HER-2 scores (0/1+, 2+ or 3+) and PIK3CA as a binary measure. Overall, 1698 patients were included, and 103 had a HER-2 score of 3+. HER-2 overexpression was associated with a higher recurrence risk (5 years recurrence risk 34 % vs. 12 %, adjusted p = 0.005), and a worse relative survival (10 years relative survival 48 % vs. 84 % for HER-2 negative; p = 0.004). PIK3CA mutations had no significant prognostic effect. We showed, in older breast cancer patients, that HER-2 overexpression was significantly associated with a worse outcome, but PIK3CA mutations had no prognostic effect. These results imply that older patients with HER-2 overexpressing breast cancer might benefit from additional targeted anti-HER-2 therapy. PMID- 26968400 TI - AABB Committee Report: reducing transfusion-transmitted cytomegalovirus infections. AB - Transfusion-transmitted cytomegalovirus (TT-CMV) is often asymptomatic, but certain patient populations, such as very low birth weight neonates, fetuses requiring intrauterine transfusion, pregnant women, patients with primary immunodeficiencies, transplant recipients, and patients receiving chemotherapy or transplantation for malignant disease, may be at risk of life-threatening CMV infection. It is unclear whether leukoreduction of cellular blood components is sufficient to reduce TT-CMV or whether CMV serological testing adds additional benefit to leukoreduction. The AABB CMV Prevention Work Group commissioned a systematic review to address these issues and subsequently develop clinical practice guidelines. However, the data were of poor quality, and no studies of significant size have been performed for over a decade. Rather than creating guidelines of questionable utility, the Work Group (with approval of the AABB Board of Directors) voted to prepare this Committee Report. There is wide variation in practices of using leukoreduced components alone or combining CMV serology and leukoreduction to prevent TT-CMV for at-risk patients. Other approaches may also be feasible to prevent TT-CMV, including plasma nucleic acid testing, pathogen inactivation, and patient blood management programs to reduce the frequency of inappropriate transfusions. It is unlikely that future large scale clinical trials will be performed to determine whether leukoreduction, CMV serology, or a combination of both is superior. Consequently, alternative strategies including pragmatic randomized controlled trials, registries, and collaborations for electronic data merging, nontraditional approaches to inform evidence, or development of a systematic approach to inform expert opinion may help to address the issue of CMV-safe blood components. PMID- 26968399 TI - Differential effects of IGF-1 deficiency during the life span on structural and biomechanical properties in the tibia of aged mice. AB - Advanced aging is associated with the loss of structural and biomechanical properties in bones, which increases the risk for bone fracture. Aging is also associated with reductions in circulating levels of the anabolic signaling hormone, insulin-like growth factor (IGF)-1. While the role of IGF-1 in bone development has been well characterized, the impact of the age-related loss of IGF-1 on bone aging remains controversial. Here, we describe the effects of reducing IGF-1 at multiple time points in the mouse life span--early in postnatal development, early adulthood, or late adulthood on tibia bone aging in both male and female igf (f/f) mice. Bone structure was analyzed at 27 months of age using microCT. We find that age-related reductions in cortical bone fraction, cortical thickness, and tissue mineral density were more pronounced when IGF-1 was reduced early in life and not in late adulthood. Three-point bone bending assays revealed that IGF-1 deficiency early in life resulted in reduced maximum force, maximum bending moment, and bone stiffness in aged males and females. The effects of IGF 1 on bone aging are microenvironment specific, as early-life loss of IGF-1 resulted in decreased cortical bone structure and strength along the diaphysis while significantly increasing trabecular bone fraction and trabecular number at the proximal metaphysis. The increases in trabecular bone were limited to males, as early-life loss of IGF-1 did not alter bone fraction or number in females. Together, our data suggest that the age-related loss of IGF-1 influences tibia bone aging in a sex-specific, microenvironment-specific, and time-dependent manner. PMID- 26968398 TI - Developmental signaling pathways regulating mammary stem cells and contributing to the etiology of triple-negative breast cancer. AB - Cancer has been considered as temporal and spatial aberrations of normal development in tissues. Similarities between mammary embryonic development and cell transformation suggest that the underlying processes required for mammary gland development are also those perturbed during various stages of mammary tumorigenesis and breast cancer (BC) development. The master regulators of embryonic development Cripto-1, Notch/CSL, and Wnt/beta-catenin play key roles in modulating mammary gland morphogenesis and cell fate specification in the embryo through fetal mammary stem cells (fMaSC) and in the adult organism particularly within the adult mammary stem cells (aMaSC), which determine mammary progenitor cell lineages that generate the basal/myoepithelial and luminal compartments of the adult mammary gland. Together with recognized transcription factors and embryonic stem cell markers, these embryonic regulatory molecules can be inappropriately augmented during tumorigenesis to support the tumor-initiating cell (TIC)/cancer stem cell (CSC) compartment, and the effects of their deregulation may contribute for the etiology of BC, in particular the most aggressive subtype of BC, triple-negative breast cancer (TNBC). This in depth review will present evidence of the involvement of Cripto-1, Notch/CSL, and Wnt/beta-catenin in the normal mammary gland morphogenesis and tumorigenesis, from fMaSC/aMaSC regulation to TIC generation and maintenance in TNBC. Specific therapies for treating TNBC by targeting these embryonic pathways in TICs will be further discussed, providing new opportunities to destroy not only the bulk tumor, but also TICs that initiate and promote the metastatic spread and recurrence of this aggressive subtype of BC. PMID- 26968401 TI - Dolichol: A Component of the Cellular Antioxidant Machinery. AB - Dolichol, an end product of the mevalonate pathway, has been proposed as a biomarker of aging, but its biological role, not to mention its catabolism, has not been fully understood. UV-B radiation was used to induce oxidative stress in isolated rat hepatocytes by the collagenase method. Effects on dolichol, phospholipid-bound polyunsaturated fatty acids (PL-PUFA) and known lipid soluble antioxidants [coenzyme Q (CoQ) and alpha-tocopherol] were studied. The increase in oxidative stress was detected by a probe sensitive to reactive oxygen species (ROS). Peroxidation of lipids was assessed by measuring the release of thiobarbituric acid reactive substances (TBARS). Dolichol, CoQ, and alpha tocopherol were assessed by high-pressure liquid chromatography (HPLC), PL-PUFA by gas-liquid chromatography (GC). UV-B radiation caused an immediate increase in ROS as well as lipid peroxidation and a simultaneous decrease in the levels of dolichol and lipid soluble antioxidants. Decrease in dolichol paralleled changes in CoQ levels and was smaller to that in alpha-tocopherol. The addition of mevinolin, a competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoAR), magnified the loss of dolichol and was associated with an increase in TBARS production. Changes in PL-PUFA were minor. These findings highlight that oxidative stress has very early and similar effects on dolichol and lipid soluble antioxidants. Lower levels of dolichol are associated with enhanced peroxidation of lipids, which suggest that dolichol may have a protective role in the antioxidant machinery of cell membranes and perhaps be a key to understanding some adverse effects of statin therapy. PMID- 26968403 TI - Causes, consequences, and cures for neuroinflammation mediated via the locus coeruleus: noradrenergic signaling system. AB - Aside from its roles in as a classical neurotransmitter involved in regulation of behavior, noradrenaline (NA) has other functions in the CNS. This includes restricting the development of neuroinflammatory activation, providing neurotrophic support to neurons, and providing neuroprotection against oxidative stress. In recent years, it has become evident that disruption of physiological NA levels or signaling is a contributing factor to a variety of neurological diseases and conditions including Alzheimer's disease (AD) and Multiple Sclerosis. The basis for dysregulation in these diseases is, in many cases, due to damage occurring to noradrenergic neurons present in the locus coeruleus (LC), the major source of NA in the CNS. LC damage is present in AD, multiple sclerosis, and a large number of other diseases and conditions. Studies using animal models have shown that experimentally induced lesion of LC neurons exacerbates neuropathology while treatments to compensate for NA depletion, or to reduce LC neuronal damage, provide benefit. In this review, we will summarize the anti-inflammatory and neuroprotective actions of NA, summarize examples of how LC damage worsens disease, and discuss several approaches taken to treat or prevent reductions in NA levels and LC neuronal damage. Further understanding of these events will be of value for the development of treatments for AD, multiple sclerosis, and other diseases and conditions having a neuroinflammatory component. The classical neurotransmitter noradrenaline (NA) has critical roles in modulating behaviors including those involved in sleep, anxiety, and depression. However, NA can also elicit anti-inflammatory responses in glial cells, can increase neuronal viability by inducing neurotrophic factor expression, and can reduce neuronal damage due to oxidative stress by scavenging free radicals. NA is primarily produced by tyrosine hydroxylase (TH) expressing neurons in the locus coeruleus (LC), a relatively small brainstem nucleus near the IVth ventricle which sends projections throughout the brain and spinal cord. It has been known for close to 50 years that LC neurons are lost during normal aging, and that loss is exacerbated in neurological diseases including Parkinson's disease and Alzheimer's disease. LC neuronal damage and glial activation has now been documented in a variety of other neurological conditions and diseases, however, the causes of LC damage and cell loss remain largely unknown. A number of approaches have been developed to address the loss of NA and increased inflammation associated with LC damage, and several methods are being explored to directly minimize the extent of LC neuronal cell loss or function. In this review, we will summarize some of the consequences of LC loss, consider several factors that likely contribute to that loss, and discuss various ways that have been used to increase NA or to reduce LC damage. This article is part of the 60th Anniversary special issue. PMID- 26968405 TI - Reply: Which is the Best Chemotherapeutic Agent for Transarterial Chemoembolization of Hepatocellular Carcinoma? PMID- 26968402 TI - Sources and Bioactive Properties of Conjugated Dietary Fatty Acids. AB - The group of conjugated fatty acids known as conjugated linoleic acid (CLA) isomers have been extensively studied with regard to their bioactive potential in treating some of the most prominent human health malignancies. However, CLA isomers are not the only group of potentially bioactive conjugated fatty acids currently undergoing study. In this regard, isomers of conjugated alpha-linolenic acid, conjugated nonadecadienoic acid and conjugated eicosapentaenoic acid, to name but a few, have undergone experimental assessment. These studies have indicated many of these conjugated fatty acid isomers commonly possess anti carcinogenic, anti-adipogenic, anti-inflammatory and immune modulating properties, a number of which will be discussed in this review. The mechanisms through which these bioactivities are mediated have not yet been fully elucidated. However, existing evidence indicates that these fatty acids may play a role in modulating the expression of several oncogenes, cell cycle regulators, and genes associated with energy metabolism. Despite such bioactive potential, interest in these conjugated fatty acids has remained low relative to the CLA isomers. This may be partly attributed to the relatively recent emergence of these fatty acids as bioactives, but also due to a lack of awareness regarding sources from which they can be produced. In this review, we will also highlight the common sources of these conjugated fatty acids, including plants, algae, microbes and chemosynthesis. PMID- 26968406 TI - Diagnostic Ability of Percutaneous Needle Biopsy Immediately After Radiofrequency Ablation for Malignant Lung Tumors: An Initial Experience. AB - PURPOSE: To evaluate the safety and diagnostic ability of percutaneous needle biopsy performed immediately after lung radiofrequency ablation (RFA). MATERIALS AND METHODS: From May 2013 to April 2014, percutaneous needle biopsy was performed immediately after RFA for 3 patients (2 men and 1 woman, aged 57-76 years) who had lung tumors measuring 1.3-2.6 cm in diameter. All patients had prior history of malignancy, and all tumors were radiologically diagnosed as malignant. Obtained specimens were pathologically classified using standard hematoxylin and eosin staining. RESULTS: We completed three planned sessions of RFA followed by percutaneous needle biopsy, all of which obtained tumor tissue that could be pathologically diagnosed. Two tumors were metastatic from renal clear cell carcinoma and rectal adenocarcinoma, respectively; one tumor was primary lung adenocarcinoma. There was no death or major complication related to the procedures. Although pneumothorax occurred in two patients, these resolved without the need for aspiration or chest tube placement. Tumor seeding was not observed, but 21 months after the procedure, one case developed local tumor progression that was treated by additional RFA. CONCLUSION: Pathologic diagnosis was possible by needle biopsy immediately after RFA for lung tumors. This technique may reduce the risks and efforts of performing biopsy and RFA on separate occasions. PMID- 26968404 TI - Targeting Retinoid Receptors to Treat Schizophrenia: Rationale and Progress to Date. AB - This review provides the rationale and reports on the progress to date regarding the targeting of retinoid receptors for the treatment of schizophrenia and schizoaffective disorder and the role of retinoic acid in functions of the normal brain, and in psychotic states. After a brief introduction, we describe the normal function of retinoic acid in the brain. We then examine the evidence regarding retinoid dysregulation in schizophrenia. Finally, findings from two add on clinical trials with a retinoid (bexarotene) are discussed. The authors of this review suggest that targeting retinoid receptors may be a novel approach to treat schizophrenia and schizoaffective disorder. Further studies are warranted. PMID- 26968407 TI - Ultrasound findings in critical care patients: the "liver sign" and other abnormal abdominal air patterns. AB - In critical care patients, point of care abdominal ultrasound examination, although it has been practiced for over 30 years, is not as widespread as its cardiac or pulmonary counterparts. We report two cases in which detection of air during abdominal ultrasound allowed the early detection of life-threatening pathologies. In the first case, a patient with severe Clostridium difficile was found to have portal venous gas but its significance was confounded by a recent surgery. Serial ultrasonographic exams triggered a surgical intervention. In the second case, we report what we call the "liver sign" a finding in patients with pneumoperitoneum. These findings, all obtained prior to conventional abdominal imaging, had immediate clinical impact and avoided unnecessary delays and radiation. Detection of abdominal air should be part of the routine-focused ultrasonographic exam and for critically ill patients an algorithm is proposed. PMID- 26968409 TI - Mammals consumed by bonobos (Pan paniscus): new data from the Iyondji forest, Tshuapa, Democratic Republic of the Congo. AB - Findings of regional variations in the behavioral patterns of non-human primates have led to the vigorous study of animal traditions (or culture), which contribute to a biological understanding of diversity in human cultures. Although our knowledge of behavioral variations of the bonobo (Pan paniscus) is limited compared with its sister species, the chimpanzee (P. troglodytes), variations in the prey of this species have been reported across study sites. This study describes evidence of mammals consumed by bonobos in the Iyondji site, which was established in 2010. We found evidence that Iyondji bonobos consumed duikers (Cephalophus dorsalis, C. monticola) and diurnal monkeys (Cercopithecus ascanius), which is notable because only anomalures (Anomalurus spp.) are consumed by bonobos in Wamba, a long-term study site established in 1973, located in an area adjacent to Iyondji. Moreover, bonobos do not transfer between the two populations due to the river between the sites. According to our census of duikers and diurnal monkeys, Iyondji bonobos appeared to encounter diurnal monkeys more frequently than did Wamba bonobos. Although humans have apparently had a more pronounced impact on the habitats in Wamba than on those in Iyondji, it remains unclear how such environmental conditions may have contributed to the differences in the prey consumed by bonobos in different sites. Our findings suggest that additional research at various sites could reveal the nature of the variations in the behavior of bonobos. PMID- 26968408 TI - Social media to supplement point-of-care ultrasound courses: the "sandwich e learning" approach. A randomized trial. AB - BACKGROUND: Point-of-care ultrasound (POC-US) is gaining importance in almost all specialties. E-learning has been used to teach theoretical knowledge and pattern recognition. As social media are universally available, they can be utilized for educational purposes. We wanted to evaluate the utility of the sandwich e learning approach defined as a pre-course e-learning and a post-course learning activity using Facebook after a one-day point-of-care ultrasound (POC-US) course and its effect on the retention of knowledge. METHODS: A total of 62 medial students were recruited for this study and randomly assigned to one of four groups. All groups received an identical hands-on training and performed several tests during the study period. The hands-on training was performed in groups of five students per instructor with the students scanning each other. Group 1 had access to pre-course e-learning, but not to post-course e-learning. Instead of a pre-course e-learning, group 2 listened to presentations at the day of the course (classroom teaching) and had access to the post-course learning activity using Facebook. Group 3 had access to both pre- and post-course e-learning (sandwich e learning) activities, while group 4 listened classroom presentations only (classroom teaching only). Therefore only groups 2 and 3 had access to post course learning via Facebook by joining a secured group. Posts containing ultrasound pictures and videos were published to this group. The students were asked to "like" the posts to monitor attendance. Knowledge retention was assessed 6 weeks after the course. RESULTS: After 6 weeks, group 3 achieved comparable results when compared to group 2 (82.2 % + -8.2 vs. 84.3 + -8.02) (p = 0.3). Students who participated in the post-course activity were more satisfied with the overall course than students without post-course learning (5.5 vs. 5.3 on a range from 1 to 6). CONCLUSIONS: In this study, the sandwich e-learning approach led to equal rates of knowledge retention compared to classroom lectures and post course learning. Students appreciate new media for learning experiences and are more satisfied with their learning activity. The sandwich e-learning can be used to maximize hands-on training during courses. PMID- 26968410 TI - Daily travel distances of zoo-housed chimpanzees and gorillas: implications for welfare assessments and space requirements. AB - The degree to which the relatively smaller area of artificial environments (compared with natural habitats) has measureable effects on the behavior and welfare of captive animals has been debated for many years. While there is little question that these spaces provide far less opportunity for natural ranging behavior and travel, less is known about the degree to which captive animals travel within their environments and what factors influence these travel patterns. We intensively studied the movement of zoo-housed chimpanzees and gorillas using a computer map interface and determined their mean daily travel and found they travelled similar distances each day when restricted to their indoor areas, but when provided additional outdoor space, chimpanzees tended to increase their travel to a greater extent than did gorillas. Both species travelled shorter distances than has been recorded for their wild counterparts, however, when given access to their full indoor-outdoor exhibit; those differences were not as substantive. These findings suggest that while large, complex naturalistic environments might not stimulate comparable species-typical travel patterns in captive apes, larger spaces that include outdoor areas may be better at replicating this behavioral pattern than smaller, indoor areas. PMID- 26968411 TI - Effect of blue light-filtering intraocular lens on color vision in patients with macular diseases after vitrectomy. AB - To evaluate the color vision of patients with macular diseases after implanting a blue light-filtering intraocular lens (IOL) during vitrectomy. Twenty-seven patients had a blue light-filtering IOL implanted during vitrectomy for macular diseases (macular disease group), and 40 patients without macular disease had the same type of IOL implanted (non-macular disease group). The postoperative best corrected visual acuity (BCVA) was >= 16/20 in all patients. The Farnsworth Munsell 100-hue test was used to determine total error scores (TES) and mean error scores under photopic and mesopic conditions in both groups. The TES under mesopic conditions was significantly higher than that under photopic conditions in both groups (P < 0.05). However, the TES in the macular disease group was not significantly different from that of the non-macular disease group under both photopic and mesopic conditions. The mean error scores under photopic conditions for hues 11, 14, 16, 17, 18, and 20 (yellowish-red to yellow) were significantly higher in the macular disease group than in the non-macular disease group. The mean error scores for hues 7 and 85 (red) were significantly higher in the non macular disease group than in the macular disease group. Under mesopic conditions, the mean error scores for hues 30, 60, and 61 were significantly higher in the non-macular disease group than in the macular disease group (P < 0.05). Our results indicate that blue light-filtering IOLs do not alter color discrimination in eyes with macular diseases, and these patients had good postoperative BCVA even under mesopic conditions. PMID- 26968412 TI - Efficacy of dexamethasone intravitreal implant for the treatment of persistent diffuse diabetic macular edema. AB - To investigate the efficiency and safety of a single injection of intravitreal dexamethasone implant in eyes with persistent diffuse diabetic macular edema (DME). In this retrospective study, 25 eyes of 20 patients, who underwent a single injection of intravitreal dexamethasone implant for the treatment of persistent diffuse DME, were reviewed. Main outcome measures included the changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT) from baseline at scheduled visits following injection. The mean BCVA showed improvement from baseline (0.97 +/- 0.26 logMAR) at every visit; the difference was significant at day 7 (0.85 +/- 0.3 logMAR, p = 0.003), month 1 (0.77 +/- 0.32 logMAR, p < 0.001), month 3 (0.77 +/- 0.34 logMAR, p = 0.001), and month 4 (0.85 +/- 0.31 logMAR, p = 0.014). The mean CMT was significantly lower than baseline (616 +/- 132 MUm) at day 1 (518 +/- 144 MUm), day 7 (414 +/- 134 MUm), month 1 (306 +/- 95 MUm), month 3 (339 +/- 88 MUm), month 4 (420 +/- 116 MUm), and month 6 (494 +/- 128 MUm) following the injection (p < 0.001, for all). Thirteen eyes on the 4-month follow-up and ten eyes on the 6-month follow-up experienced recurrence of macular edema requiring retreatment. No serious ocular and systemic adverse events were observed. In patients with persistent DME, switching to intravitreal dexamethasone implant injection provides functional and anatomical improvement, and might be an effective therapeutic option for long-standing diffuse DME. PMID- 26968414 TI - Human vulnerability in medical contexts. PMID- 26968413 TI - Evolutionary history of the mammalian synaptonemal complex. AB - The synaptonemal complex (SC), a key structure of meiosis that assembles during prophase I, has been initially described 60 years ago. Since then, the structure has been described in many sexually reproducing organisms. However, the SC protein components were characterized in only few model organisms. Surprisingly, they lacked an apparent evolutionary relationship despite the conserved structural organization of the SC. For better understanding of this obvious discrepancy, the evolutionary history of the SC and its individual components has been investigated in Metazoa in detail. The results are consistent with the notion of a single origin of the metazoan SC and provide evidence for a dynamic evolutionary history of the SC components. In this mini review, we recapitulate and discuss new insights into metazoan SC evolution. PMID- 26968416 TI - Complications Following Radical Nephroureterectomy. AB - Radical nephroureterectomy (RNU) is the gold standard treatment strategy for bulky, high-grade, or muscle-invasive upper tract urothelial carcinoma (UTUC). Many patients with UTUC who require RNU are elderly, comorbid, and at risk for perioperative complications. Recognition of likelihood and extent of such complications guides preoperative counseling, decision-making process for major surgery, and perioperative care. A critical review of such data is essential, given the inevitable impact of complications on hospital duration, need for readmission, resource utilization, and costs associated with management. PMID- 26968417 TI - Neoadjuvant Treatment of High-Risk, Clinically Localized Prostate Cancer Prior to Radical Prostatectomy. AB - Multimodal strategies combining local and systemic therapy offer the greatest chance of cure for many with men with high-risk prostate cancer who may harbor occult metastatic disease. However, no systemic therapy combined with radical prostatectomy has proven beneficial. This was in part due to a lack of effective systemic agents; however, there have been several advancements in the metastatic and castrate-resistant prostate cancer that might prove beneficial if given earlier in the natural history of the disease. For example, novel hormonal agents have recently been approved for castration-resistant prostate cancer with some early phase II neoadjuvant showing promise. Additionally, combination therapy with docetaxel-based chemohormonal has demonstrated a profound survival benefit in metastatic hormone-naive patients and might have a role in eliminating pre existing ADT-resistant tumor cells in the neoadjuvant setting. The Cancer and Leukemia Group B (CALGB)/Alliance 90203 trial has finished accrual and should answer the question as to whether neoadjuvant docetaxel-based chemohormonal therapy provides an advantage over prostatectomy alone. There are also several promising targeted agents and immunotherapies under investigation in phase I/II trials with the potential to provide benefit in the neoadjuvant setting. PMID- 26968418 TI - Experience with Sequential Intravesical Gemcitabine and Docetaxel as Salvage Therapy for Non-Muscle Invasive Bladder Cancer. AB - Patients with high-grade muscle invasive bladder cancer (NMIBC) receive intravesical therapy with bacillus Calmette-Guerin (BCG) as the well-established standard-of-care. However, even with prompt induction of intravesical therapy, approximately 40 % of patients will recur within 2 years. For patients who fail BCG, options include radical cystectomy, repeat BCG therapy, or alternative intravesical salvage therapy. In this review, we will discuss the most recent published evidence on salvage intravesical therapy with an emphasis on a more in depth report of our therapeutic strategy with sequential gemcitabine and docetaxel intravesical therapy for this treatment-refractory population. In addition, we will provide practical advice on our approach to this challenging patient population including the use of operative staging to aid early identification of treatment failures. PMID- 26968420 TI - Selective Arterial Clamping Versus Hilar Clamping for Minimally Invasive Partial Nephrectomy. AB - Partial nephrectomy has become an accepted treatment of cT1 renal masses as it provides improved long-term renal function compared to radical nephrectomy (Campbell et al. J Urol. 182:1271-9, 2009). Hilar clamping is utilized to help reduce bleeding and improve visibility during tumor resection. However, concern over risk of kidney injury with hilar clamping has led to new techniques to reduce length of warm ischemia time (WIT) during partial nephrectomy. These techniques have progressed over the years starting with early hilar unclamping, controlled hypotension during tumor resection, selective arterial clamping, minimal margin techniques, and off-clamp procedures. Selective arterial clamping has progressed significantly over the years. The main question is what are the exact short- and long-term renal effects from increasing clamp time. Moreover, does it make sense to perform these more time-consuming or more complex procedures if there is no long-term preservation of kidney function? More recent studies have shown no difference in renal function 6 months from surgery when selective arterial clamping or even hilar clamping is employed, although there is short-term improved decline in estimated glomerular filtration rate (eGFR) with selective clamping and off-clamp techniques (Komninos et al. BJU Int. 115:921-8, 2015; Shah et al. 117:293-9, 2015; Kallingal et al. BJU Int. doi: 10.1111/bju.13192, 2015). This paper reviews the progression of total hilar clamping to selective arterial clamping (SAC) and the possible difference its use makes on long-term renal function. SAC may be attempted based on surgeon's decision-making, but may be best used for more complex, larger, more central or hilar tumors and in patients who have renal insufficiency at baseline or a solitary kidney. PMID- 26968419 TI - Minimally Invasive Techniques for the Management of Adult UPJ Obstruction. AB - Ureteropelvic junction obstruction (UPJO) is a common congenital abnormality that often presents in adulthood. Open dismembered pyeloplasty was considered the gold standard for the management of this condition; however, recent advancements in laparoscopic and robotic surgery have dramatically shifted the landscape to more minimally invasive techniques. A literature search of ureteropelvic junction obstruction, pyeloplasty, endopyelotomy, laparoscopic pyeloplasty, robotic pyeloplasty, and microlaparoscopic pyeloplasty was performed. A focus was placed on literature published since 2013. Minimally invasive laparoscopic and robotic techniques have become the gold standard for the management of UPJO. With the rise of robotic pyeloplasty, open repairs are becoming less frequent, while endoscopic treatments have remained stable. Minimally invasive (robotic) techniques have become the gold standard for the management of UPJO. Newer, even less-invasive techniques are also showing promise, but technical challenges still exist. PMID- 26968421 TI - Robotic Primary RPLND for Stage I Testicular Cancer: a Review of Indications and Outcomes. AB - Patients diagnosed with stage I non-seminomatous germ cell tumor (NSGCT) face the task of selecting a management strategy. Whereas these options all offer excellent survival, unfortunately, each has drawbacks. Retroperitoneal lymph node dissection (RPLND) is a major operation with low, but significant risks of bleeding, chylous ascites, and retrograde ejaculation. Platinum-based chemotherapy is associated with a number of long-term side effects, not all of which are quantified, but include secondary malignancy and early cardiovascular disease. While surveillance minimizes the chances of exposure to unnecessary treatment, it is not infrequently salvaged with chemotherapy and requires a compliant patient willing to undergo serial imaging often with ionizing radiation. Although fewer than one-third of patients will relapse without intervention, the current guidelines propose treatment for stage I patients with high-risk features. New developments in minimally invasive techniques may mitigate the harms of RPLND and avoid the side effects of chemotherapy, making it an ideal option for this cohort of patients. Unlike laparoscopic RPLND, which was introduced as a staging procedure and heavily criticized for the advanced skill set required to achieve oncologic equivalence, robotic RPLND may offer the benefits of a minimally invasive technique without a steep learning curve and a true therapeutic operation in experienced hands. PMID- 26968423 TI - Cutaneous metastasis of pleomorphic liposarcoma to the scalp: an elusive diagnosis. AB - Liposarcomas are one of the most common sarcomas arising in the extremities of the elderly. Various subtypes of liposarcomas include well-differentiated liposarcomas, dedifferentiated liposarcomas, myxoid liposarcomas and pleomorphic liposarcomas. Pleomorphic liposarcomas are the rarest subtype and have the highest malignant potential compared with the other subtypes of liposarcomas. Metastases to internal organs are common but cutaneous metastasis is very rare with only few cases in the literature. We present a patient with a known diagnosis of stage IV metastatic liposarcoma who presented to our clinic with a rapidly growing nodule on the scalp. A biopsy showed a high-grade poorly differentiated spindled cell neoplasm sparing the epidermis with scattered lipoblasts. Immunostaining for S100, SOX10, and MNF-116 were negative. To further characterize the neoplasm, immunostaining with MDM-2 was performed and was also found to be negative. The histologic appearance, immunohistochemical staining, and clinical history support a diagnosis of metastatic pleomorphic liposarcoma to the scalp. The diagnosis of pleomorphic liposarcoma is challenging. It is often difficult to differentiate from myxofibrosarcoma or other high-grade pleomorphic sarcomas based on histology alone. However, the presence of bizarre lipoblasts and negative MDM-2 staining can be helpful clues to differentiate this neoplasm from histologic mimics. PMID- 26968422 TI - Flexible proton 3D MR spectroscopic imaging of the prostate with low-power adiabatic pulses for volume selection and spiral readout. AB - PURPOSE: Cartesian k-space sampling in three-dimensional magnetic resonance spectroscopic imaging (MRSI) of the prostate limits the selection of voxel size and acquisition time. Therefore, large prostates are often scanned at reduced spatial resolutions to stay within clinically acceptable measurement times. Here we present a semilocalized adiabatic selective refocusing (sLASER) sequence with gradient-modulated offset-independent adiabatic (GOIA) refocusing pulses and spiral k-space acquisition (GOIA-sLASER-Spiral) for fast prostate MRSI with enhanced resolution and extended matrix sizes. METHODS: MR was performed at 3 tesla with an endorectal receive coil. GOIA-sLASER-Spiral at an echo time (TE) of 90 ms was compared to a point-resolved spectroscopy sequence (PRESS) with weighted, elliptical phase encoding at an TE of 145 ms using simulations and measurements of phantoms and patients (n = 9). RESULTS: GOIA-sLASER-Spiral acquisition allows prostate MR spectra to be obtained in ~5 min with a quality comparable to those acquired with a common Cartesian PRESS protocol in ~9 min, or at an enhanced spatial resolution showing more precise tissue allocation of metabolites. Extended field of views (FOVs) and matrix sizes for large prostates are possible without compromising spatial resolution or measurement time. CONCLUSION: The flexibility of spiral sampling enables prostate MRSI with a wide range of resolutions and FOVs without undesirable increases in acquisition times, as in Cartesian encoding. This approach is suitable for routine clinical exams of prostate metabolites. Magn Reson Med 77:928-935, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26968424 TI - In vitro assessment of 24 CYP2D6 allelic isoforms on the metabolism of methadone. AB - CYP2D6 is an important member of the cytochrome P450 (CYP450) enzyme super family, with at least 100 CYP2D6 alleles being previously identified. Genetic polymorphisms of CYP2D6 significantly influence the efficacy and safety of some drugs, which might cause adverse effects and therapeutic failure. The aim of this study was to clarify the catalytic activities of 24 CYP2D6 alleles on the oxidative in vitro metabolism of methadone. Reactions were incubated with 50-2000 uM methadone for 30 min at 37 degrees C and terminated by cooling to -80 degrees C immediately. Methadone and the major metabolite EDDP were analyzed by an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) system. Compared with wild-type CYP2D6*1, most variants showed significantly altered values in Vmax and intrinsic clearance (Vmax /Km ). Only three variants (CYP2D6*88, *91 and E215K) exhibited markedly increased intrinsic clearance values, and one variant CYP2D6*94 showed no significant difference. On the other hand, the kinetic parameters of two CYP2D6 variants (CYP2D6*92 and *96) could not be determined because they had no detectable enzyme activity, whereas 18 variants exhibited significantly decreased values. To sum up, this study demonstrated that more attention should be paid in clinical administration of methadone to individuals carrying these CYP2D6 alleles. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26968425 TI - Interleukin-27-Producing CD4(+) T Cells Regulate Protective Immunity during Malaria Parasite Infection. AB - Interleukin-27 (IL-27) is a heterodimeric regulatory cytokine of the IL-12 family, which is produced by macrophages, dendritic cells, and B cells upon stimulation through innate immune receptors. Here, we described regulatory CD4(+) T cells that produce IL-27 in response to T cell receptor stimulation during malaria infection, inhibiting IL-2 production and clonal expansion of other T cells in an IL-27-dependent manner. IL-27-producing CD4(+) T cells were Foxp3( )CD11a(+)CD49d(+) malaria antigen-specific CD4(+) T cells and were distinct from interferon-gamma (IFN-gamma) producing Th1 or IL-10 producing Tr1 cells. In mice lacking IL-27 in T cells, IL-2 production was restored and clonal expansion and IFN-gamma production by specific CD4(+) T cells were improved, culminating in reduced parasite burden. This study highlights a unique population of IL-27 producing regulatory CD4(+) T cells and their critical role in the regulation of the protective immune response against malaria parasites. PMID- 26968427 TI - Anuran tadpoles learn to recognize injury cues from members of the same prey guild. AB - Recognition of predation risk from cues released from injured heterospecific could be beneficial when prey belongs to the same prey guild. Here, we performed three experiments. Experiment 1 showed that P. thaul tadpoles reduced their activity levels when exposed to conspecific injury cues, but not when exposed to amphipod injury cues. Experiment 2 tested whether P. thaul tadpoles can learn to recognize predation risk from chemical cues released from injured heterospecifics from the same prey guild (amphipod, Hyalella patagonica). A group of tadpoles were conditioned by exposing them to a specific concentration of amphipod injury cues paired with conspecific injury cues. Two days later, we evaluated changes in the activity of tadpoles when they were exposed to amphipod cues. As a control of learning, we used an unpaired group. Additionally, we used more control groups to fully investigate the learning mechanism. Our results showed that tadpoles can learn to recognize predation risk from injured amphipods and that the mechanism underlying the observed learned response could be associative. Experiment 3 replicated Experiment 2 and also showed that a low concentration of amphipod cues did not sustain that learning. PMID- 26968426 TI - A Regulatory Feedback between Plasmacytoid Dendritic Cells and Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus. AB - Signals controlling the generation of regulatory B (Breg) cells remain ill defined. Here we report an "auto"-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells. In healthy individuals, pDCs drive the differentiation of CD19(+)CD24(hi)CD38(hi) (immature) B cells into IL 10-producing CD24(+)CD38(hi) Breg cells and plasmablasts, via the release of IFN alpha and CD40 engagement. CD24(+)CD38(hi) Breg cells conversely restrained IFN alpha production by pDCs via IL-10 release. In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells. This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-alpha. Defective pDC-mediated expansion of CD24(+)CD38(hi) Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation. Both altered pDC-CD24(+)CD38(hi) Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab. We propose that alteration in pDC-CD24(+)CD38(hi) Breg cell interaction contributes to the pathogenesis of SLE. PMID- 26968429 TI - Comparison of service utilisation and costs of working age adults and older adults receiving treatment for psychosis and severe non-psychotic conditions in England: implications for commissioning. AB - OBJECTIVE: Current plans in the English National Health Service are to replace block contracts for mental health providers with a single tariff for each 'cluster' of conditions. A single tariff will not take into account the potential additional complexity and costs inherent in caring for older people. To examine the basis for a uniform tariff, differences in service utilisation and costs between working age adults and older adults in two populous clusters (non psychotic, psychotic) were investigated across five mental health healthcare providers in and around London. METHODS: Retrospective review of records over 3 months assessing service utilisation and costs using the Client Services Receipt Inventory. RESULTS: Records of 362 patients were reviewed, 179 older adults (90 non-psychotic, 89 psychotic) and 183 adults of working age (83 non-psychotic, 100 psychotic). Older adults in both clusters had more tests, assessments and home visits. Overall costs of care of older adults were significantly higher in the non-psychotic cluster (L5634, vs L4405 psychotic, p = 0.044). CONCLUSIONS: An appropriate age-related tariff is required for each cluster. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26968428 TI - Treatment of endometrioma for improving fertility. AB - Endometrioma is a frequent clinical manifestation of endometriosis. It is controversial how endometriomas may affect women's fertility. This review addresses: the impact of the endometrioma per se and of its surgical treatment on ovarian physiology, on the ovarian reserve, on spontaneous conception and pregnancy outcomes, and on IVF/ICSI outcomes. Based on current evidence, although there are plausible biological detrimental effects on the ovarian cortex surrounding the endometrioma and an impairment of the normal ovarian physiology, the clinical impact of the endometrioma per se is not significantly altered. There is a negligible detrimental effect on ovarian reserve with spontaneous ovulation not being impaired. Conversely, surgical excision of an endometrioma reduces ovarian reserve as measured by AMH levels. Studies investigating the impact of the endometrioma per se and of its surgical treatment in women requiring IVF/ICSI show similar implantation rates, clinical pregnancy rates and live birth rates between women with endometrioma and controls. PMID- 26968430 TI - The clinical experience for treating post-burn depigmentation with tiny epidermal particles graft. AB - The critical problem of post-burn depigmentation is the lacking normal melanocytes. Auto-skin grafting and autologous non-cultured epidermal cell suspension have been used to improve the appearance. However, a large amount of skin graft is required of donor sites in the former method, while the latter method is thought to be complicated and costly. This study is designed to generalise the experience of tiny epidermal particles graft (TEPG) for treating post-burn depigmentation. From 2012 to 2013, 30 consecutive patients with depigmentation caused by burn injuries were divided into I and II group. I group: 15 cases (11 males and 4 females) were treated by the TEPG. II group: 15 patients (10 males and 5 females) were treated by suction blister epidermal skin graft (SBEG). Imagine-Pro Plus software was used to evaluate the size of repigmentation (RP) 12 months post-surgery. SPSS software 13.0 was used to evaluate the data. The optimum rate of RP was defined as more than 75% (RP > 75%) when excellent RP was defined as more than 90% (>90%). All patients were followed up for 12 months. The mean size of RP in two groups demonstrated that there were statistically significant differences in pigmentation between the two groups (P = 0.002), while there was no significant difference in the other factors (gender, site and age). No infection occurred in the recipient site. Pathological result showed that melanocytes existed at the basal layer of resurfacing skin. Optimum RP (RP > 75%) was seen in 12 patients in I group and 9 patients in II group. Excellent RP was achieved in 14 cases in I group and 10 patients in II group. Excellent RP can be obtained by the abovementioned two surgical techniques. In contrast to SBEG, TEPG is less traumatic, and definite effects can be guaranteed. It is a preferred treatment, especially for those patients who suffer from large depigmented lesions. PMID- 26968431 TI - Silver nanoparticles induce pro-inflammatory gene expression and inflammasome activation in human monocytes. AB - A complete cytotoxic profile of exposure to silver (AgNP) nanoparticles investigating their biological effects on the innate immune response of circulating white blood cells is required to form a complete understanding of the risk posed. This was explored by measuring AgNP-stimulated gene expression of the pro-inflammatory cytokines interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) in THP-1 monocytes. A further study, on human monocytes extracted from a cohort of blood samples, was carried out to compare with the AgNP immune response in THP-1 cells along with the detection of pro-IL 1beta which is a key mediator of the inflammasome complex. The aims of the study were to clearly demonstrate that AgNP can significantly up-regulate pro inflammatory cytokine gene expression of IL-1, IL-6 and TNF-alpha in both THP-1 cells and primary blood monocytes thus indicating a rapid response to AgNP in circulation. Furthermore, a role for the inflammasome in AgNP response was indicated by pro-IL-1beta cleavage and release. These results highlight the potential inflammatory effects of AgNP exposure and the responses evoked should be considered with respect to the potential harm that exposure may cause. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26968432 TI - Comparative data on the differentiation and growth of bone ornamentation in gnathostomes (Chordata: Vertebrata). AB - Bone ornamentation, in the form of rounded pits framed by a network of ridges, is a frequent feature among a great diversity of gnathostome taxa. However, the basic osteogenic processes controlling the differentiation and development of these reliefs remain controversial. The present study is a broad comparative survey of this question with the classical methods used in hard tissue histology and paleohistology. Distinct processes, unevenly distributed among taxa, are involved in the creation and growth of pits and ridges. The simplest one is mere differential growth between pit bottom (slow growth) and ridge top (faster growth). The involvement of several complex remodeling processes, with the local succession of resorption and reconstruction cycles, is frequent and occurs in all major gnathostome clades. Some broad, inclusive clades (e.g., Temnospondyli) display consistency in the mechanisms controlling ornamentation, whereas other clades (e.g., Actinopterygii) are characterized by the diversity of the mechanisms involved. If osteogenic mechanisms are taken into account, bone ornamentation should be considered as a character extremely prone to homoplasy. Maximum likelihood (ML) optimizations reveal that the plesiomorphic mechanism creating ornamentation is differential apposition rate over pits (slow growth) and ridges (faster growth). In some taxas e.g., temnospondyls vs lissamphibians or pseudosuchians, bone ornamentation is likely to be a homoplastic feature due to a convergence process driven by similar selective pressures. ML models of character evolution suggest that the presence of resorption in the development of ornamentation may be selectively advantageous, although support for this conclusion is only moderate. PMID- 26968433 TI - Number of four-hour waits almost doubles in a single year. AB - The number of people in England who have spent more than four hours waiting for emergency treatment has almost doubled in the past year, government figures show. PMID- 26968434 TI - Youth project launched to reduce gang-related violence in London. AB - The effect of a youth-violence prevention project involving people who present for emergency care is being analysed by researchers at Kingston University, Surrey. PMID- 26968435 TI - Too many people with minor ailments use emergency departments. AB - Inappropriate use of emergency services is putting a strain on emergency departments (EDs), according to the Belfast Telegraph. PMID- 26968436 TI - An end to violence. AB - While watching the English city riots unfold on television last month, I was struck by the perpetrators' lack of regard for the danger in which they placed innocent people. They clearly thought nothing of attacking emergency service staff trying to respond to the chaos. PMID- 26968438 TI - Properties of nanofiller-loaded poly (methyl methacrylate) bone cement composites for orthopedic applications: a review. AB - There is a large body of literature on new generations of poly (methyl methacrylate) bone cements that address one or more of the material's shortcomings. Among these are cements in which one of the constituents is a nanofiller, such as nano-sized barium sulfate, multiwalled carbon nanotubes, natural nanoclay, mesoporous silica nanoparticles, or oleic acid-capped silver nanoparticles. This article is a review of the literature on the properties of these nanofiller-loaded bone cements (NFLBCs). Some key characteristics of the literature are that (1) in a number of studies, clinically relevant properties were determined, examples being maximum exotherm, setting time, fatigue life, and compressive modulus; (2) in some studies, properties were not determined in accordance with approved bone cement testing specifications, an example being fatigue life; and (3) there are a number of clinically relevant properties that were not determined in any of the studies, examples being fatigue crack propagation rate and dynamic compression creep life. These observations, as well as other considerations, suggest 12 areas for future study, such as determination of dynamic creep compliance (using nanoindentation), determination of compressive fatigue life for cements to be used in vertebral compression fracture augmentation, elucidation of toughening mechanism(s) in each type of NFLBC, and conducting well-designed clinical trials. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1260-1284, 2017. PMID- 26968437 TI - Does ability to walk reflect general functionality in inflammatory neuropathies? AB - The "ability to walk" is considered a benchmark for good clinical recovery and prognosis, particularly in patients with Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However, it has never been determined whether being "able to walk" represents general functionality. The purpose of this study was to examine whether the ability to walk outside independently reflects general functional improvement in patients with GBS, CIDP, and gammopathy-related neuropathy (MGUSP). A total of 137 patients with newly diagnosed (or relapsing) GBS (55), CIDP (59), and MGUSP (23) were serially examined (1-year). Predefined arbitrary cut-offs (so-called patients' Functional-Acceptable-Clinical-Thresholds [FACTs]) were taken at the 50th, 75th, and 90th percentile of the Inflammatory-Rasch-built-Overall Disability-Scale (I-RODS((c)) ). We determined the proportion of patients able to walk outside independently that reached the postulated cut-offs. A mean total of 85%, 39%, and 12% of all patients able to walk reached 50th, 75th, and 90th percentile thresholds, respectively. These findings were not neuropathy type related. Our findings show that assessing only one construct of functionality (e.g., walking ability) does not reflect the full scope of daily/social functional deficits perceived by patients. The ability to walk shows a patient is doing better, but not necessarily doing well. The I-RODS((c)) bypasses these limitations. PMID- 26968439 TI - Letter to the Editor. PMID- 26968440 TI - Response. PMID- 26968441 TI - SCAI position statement concerning coverage policies for percutaneous coronary interventions based on the appropriate use criteria. PMID- 26968442 TI - Preserved vagus nerve stimulator function after radiation therapy. AB - BACKGROUND: Epilepsy and breast cancer are both prevalent conditions. A subset of women with medically refractory epilepsy and vagus nerve stimulators (VNS) may later develop breast cancer and may require adjuvant radiation as part of their treatment regimen. However, to date, little data are available on the effects of radiation on VNS function. CASE PRESENTATION: We present a young woman with tuberous sclerosis, developmental delay, and medically refractory epilepsy who developed left-sided breast cancer. Her epilepsy became controlled with a recent addition of a VNS implanted in her left chest wall. She required adjuvant radiation therapy to her left breast, and this raised the novel question of the safety of radiation on the integrity and functioning of the device, which we explore in this article. CONCLUSION: This case is the first report of a patient with VNS for epilepsy and breast cancer who received radiation therapy proximal to the device. The device continued to function properly despite the exposure. PMID- 26968443 TI - Surface Coordination of Black Phosphorus for Robust Air and Water Stability. AB - A titanium sulfonate ligand is synthesized for surface coordination of black phosphorus (BP). In contrast to serious degradation observed from the bare BP, the BP after surface coordination exhibits excellent stability during dispersion in water and exposure to air for a long period of time, thereby significantly extending the lifetime and spurring broader application of BP. PMID- 26968446 TI - Maximizing the Potential of Social Media and Social Networks in Neurosurgery. PMID- 26968445 TI - Anterior Spinal Reconstruction to the Clivus Using an Expandable Cage After C2 Chordoma Resection Via a Labiomandibular Glossotomy Approach: A Technical Report. AB - INTRODUCTION: En bloc resection of high-cervical chordomas is a technically challenging procedure associated with significant morbidity. Two key components of this procedure include the approach and the method of spinal reconstruction. A limited number of reported cases of en bloc resection of high-cervical chordomas have been reported in the literature. CASE PRESENTATION: We report a novel case using an expandable cage to reconstruct the anterior spinal column above C2 with fixation to the clivus. We also report a novel anterior approach to the high cervical spine via a midline labiomandibular glossotomy. We detail the management of complications related to 2 instances of wound dehiscence and hardware exposure requiring two additional operations. The final surgical procedure involved explantation of the anterior cervical plate and use of a vascularized radial graft to close the posterior pharyngeal defect and protect the hardware. At 26 month follow-up, the patient remained disease free without any neurologic deficit. DISCUSSION: We report the novel use of the midline labiomandibular glossotomy for surgical approach and reconstruction of the anterior column to the clivus with an expandable cage. The unique features of this operative strategy allowed the surgical team to tailor the construct intraoperatively, resulting in solid arthrodesis without significant neurologic sequelae. CONCLUSIONS: Labiomandibular glossotomy for approach to high anterior cervical chordomas followed by craniospinal reconstruction to the clivus with an expandable cage represents a novel technique for managing high cervical chordomas. PMID- 26968444 TI - 1,2-Dichlorobenzene affects the formation of the phosphoenzyme stage during the catalytic cycle of the Ca(2+)-ATPase from sarcoplasmic reticulum. AB - BACKGROUND: 1,2-Dichlorobenzene (1,2-DCB) is a benzene-derived molecule with two Cl atoms that is commonly utilized in the synthesis of pesticides. 1,2-DCB can be absorbed by living creatures and its effects on naturally-occurring enzymatic systems, including the effects on Ca(2+)-ATPases, have been poorly studied. Therefore, we aimed to study the effect of 1,2-DCB on the Ca(2+)-ATPase from sarcoplasmic reticulum (SERCA), a critical regulator of intracellular Ca(2+) concentration. RESULTS: Concentrations of 0.05-0.2 mM of 1,2-DCB were able to stimulate the hydrolytic activity of SERCA in a medium-containing Ca(2+) ionophore. At higher concentrations (0.25-0.75 mM), 1,2-DCB inhibited the ATP hydrolysis to ~80 %. Moreover, ATP hydrolysis and Ca(2+) uptake in a medium supported by K-oxalate showed that starting at 0.05 mM,1,2-DCB was able to uncouple the ratio of hydrolysis/Ca(2+) transported. The effect of this compound on the integrity of the SR membrane loaded with Ca(2+) remained unaffected. Finally, the analysis of phosphorylation of SERCA by [gamma-(32)P]ATP, starting under different conditions at 0 degrees or 25 degrees C showed a reduction in the phosphoenzyme levels by 1,2-DCB, mostly at 0 degrees C. CONCLUSIONS: The temperature-dependent decreased levels of phosphoenzyme by 1,2-DCB could be due to the acceleration of the dephosphorylation mechanism - E2P . Ca2 state to E2 and Pi, which explains the uncoupling of the ATP hydrolysis from the Ca(2+) transport. PMID- 26968447 TI - Feasibility of the Combined Application of Navigated Probabilistic Fiber Tracking and Navigated Ultrasonography in Brain Tumor Surgery. AB - BACKGROUND: Surgical resection of intra-axial tumors is a challenging procedure because of indistinct tumor margins, infiltration, and displacement of white matter tracts surrounding the lesion. Hence, gross total tumor resection without causing new neurologic deficits is demanding, especially in tumor sites adjoining eloquent structures. Feasibility of the combination of navigated probabilistic fiber tracking to identify eloquent fiber pathways and navigated ultrasonography to control brain shift was tested. METHODS: Eleven patients with lesions adjacent to eloquent white matter structures (pyramidal tract, optic radiation and arcuate fascicle) were preoperatively subjected to magnetic resonance imaging including diffusion-weighted imaging on a 3-T magnetic resonance system (Trio [Siemens, Erlangen, Germany]). Probabilistic fiber tracking was performed using the tools of the FMRIB Software Library (FSL). Results of probabilistic fiber tracking and high-resolution anatomic images were integrated into the neuronavigation system Stealth Station (Medtronic, Minneapolis, Minnesota, USA) together with the navigated ultrasonography (SonoNav [Medtronic]). RESULTS: FSL-based probabilistic fiber tracking depicted the pyramidal tract, the optic radiation, and arcuate fascicle anatomically plausibly. Integration of the probabilistic fiber tracking into neuronavigation was technically feasible and allowed visualization of the reconstructed fiber pathways. Navigated ultrasonography controlled brain shift. CONCLUSIONS: Integration of probabilistic fiber tracking and navigated ultrasonography into intraoperative neuronavigation facilitated anatomic orientation during glioma resection. FSL-based probabilistic fiber tracking integrated sophisticated fiber tracking algorithms, including modeling of crossing fibers. Combination with navigated ultrasonography provided a three dimensional estimation of intraoperative brain shift and, therefore, improved the reliability of neuronavigation. PMID- 26968448 TI - Pathology-Based Approach to Seizure Outcome After Surgery for Pharmacoresistant Medial Temporal Lobe Epilepsy. AB - BACKGROUND: Hippocampal sclerosis (HS) is the most common cause of drug-resistant medial temporal lobe epilepsy (MTLE). Structural abnormalities such as HS, granule cell pathology (GCP), and focal cortical dysplasia (FCD) have been classified histopathologically, possibly allowing a more accurate assessment of prognostic seizure and neuropsychologic outcomes. We correlated seizure outcome with comprehensive temporal lobe pathologic findings, identified according to the most recent classification systems of HS, GCP, and FCD. METHODS: All the 83 patients who underwent anterior temporal lobectomy (ATL) for drug-resistant MTLE and with a proven diagnosis of HS between April 2001 and May 2014 were collected. Patients were divided in 2 main groups: 1) isolated HS with/without GCP (HS +/- GCP); and 2) HS associated with FCD with/without GCP (HS+FCD +/- GCP). Patients were followed up at least 1 year, and seizure outcome was reported in accordance with Engel classification. RESULTS: Group I: HS +/- GCP: Statistical analysis confirmed a better outcome in HS + GCP patients than in HS-no GCP (P < 0.05). Moreover, a better outcome for the patients affected by GCP type I was observed (P < 0.05). Group II: HS+FCD +/- GCP: Patients with HS variant type I presented a better seizure outcome than the patients with HS type II (Engel class IA HS type I vs. type II: 69% vs. 40%). CONCLUSIONS: A pathology-based approach to epilepsy surgery might improve the interpretation of the results, could predict which cases will enjoy a better seizure outcome, and could help to the comprehension of the causes of failures. PMID- 26968449 TI - Spontaneous Regression of a Third Ventricle Colloid Cyst. AB - BACKGROUND: Colloid cysts represent 0.5%-1% of intracranial tumors and most commonly occur in the third ventricle near the Monro foramen. Although benign, if the lesion obstructs the foramen abruptly, sudden death may ensue. Evolution of these cysts is poorly understood. Spontaneous regression has been reported in only 2 other cases. Management of such cysts depends on whether the cyst continues to grow, its location, and clinical presentation. Incidental asymptomatic colloid cysts are typically followed with neuroimaging surveillance. CASE DESCRIPTION: We present a case of an incidental third ventricle colloid cyst in a 46-year-old patient who was managed conservatively with neuroimaging surveillance. Thereafter, she started developing some working memory deficits and intermittent headaches, with the cyst volume increasing, leading to the decision to perform a resection. However, the cyst underwent spontaneous regression before the scheduled surgery date, 3 years after initial diagnosis. CONCLUSIONS: This case confirms that some colloid cysts could regress spontaneously. Disappearance of the cyst is not necessarily accompanied by clinical worsening, as was reported by other investigators who noted deteriorating neurologic deficits as a result of worsening hydrocephalus. Assuming the cysts rupture, some patients tolerate the contents of the cyst leaking into the ventricular system, whereas others may mount an inflammatory reaction, causing a disruption in cerebrospinal fluid flow. In addition, it is still unclear what factors increase the likelihood of cysts to suddenly rupture. PMID- 26968450 TI - Redefining the Prevalence of Dural Involvement in Rosai-Dorfman Disease of the Central Nervous System. AB - BACKGROUND: Sinus histiocytosis with massive lymphadenopathy, also known as Rosai Dorfman disease, is a rare condition, classically characterized by painless, massive cervical lymphadenopathy. Histologically, the pathognomonic findings include a dense, mixed inflammatory infiltrate with areas of emperipolesis. Albeit infrequent, when Rosai-Dorfman disease affects the central nervous system, it typically manifests as an isolated dural lesion, often mimicking a meningioma. A purely intraparenchymal manifestation of Rosai-Dorfman disease of the brain and spine with absent dural involvement is exceedingly rare. CASE DESCRIPTION: In this report, we describe a 59-year-old woman who underwent surgical excision of an intraparenchymal cerebellar lesion. Histologic analysis of the resected specimen diagnosed isolated Rosai-Dorfman disease with absent systemic involvement. We also provide an updated review of the literature of nondural based Rosai-Dorfman disease in the central nervous system. CONCLUSIONS: With the recent increase of such reported cases, it becomes imperative that Rosai-Dorfman be considered more than as a dural lesion that may mimic meningioma. Diagnostic and therapeutic challenges surrounding this disease entity are also discussed. PMID- 26968451 TI - Multimorbidity Combinations and Disability in Older Adults. AB - BACKGROUND: Multimorbidity (multiple co-occurring chronic diseases) is associated with greater likelihood of disability and mortality, above and beyond the risk attributable to individual diseases. This study identifies prevalent multimorbidity patterns and evaluates their association with disability among U.S. older adults. METHODS: Prospective cohort study using longitudinal Health and Retirement Study data (2010-2012). We included 8,782 participants aged 65 years and older and used negative binomial models to examine prospective disability, measured by the combined activities of daily living-instrumental activities of daily living index. Multimorbidity was defined as the co-occurring combination of at least two of the following chronic diseases: hypertension, cardiovascular disease, lung disease, diabetes, cancer, arthritis, stroke, cognitive impairment, or high depressive symptoms (CES-D score >= 4). RESULTS: We found 291 unique disease combinations with 1 to 1,167 older adults per disease combination. The three most prevalent combinations were: (a) hypertension and arthritis (n = 1,167); (b) hypertension, arthritis, and cardiovascular disease (n = 510); and (c) hypertension, arthritis, and diabetes (n = 430). Only one of the prevalent combinations included depressive symptoms (in combination with arthritis, hypertension; n = 129). This group showed the highest level of activities of daily living-instrumental activities of daily living disability compared to healthy participants or participants with a single disease (either included in the combination or different from diseases in the combination) even after adjusting for age, gender, education, race/ethnicity, and body mass index. CONCLUSIONS: Clinicians stand to gain from a better understanding of which disease combinations are more and less disabling among older adults. Understanding how multimorbidity combinations relate to functional status is an important step towards reducing disability and sustaining independent living among older adults. PMID- 26968454 TI - The Influence of Acquisition Delay for Calibration-Free Laser-Induced Breakdown Spectroscopy. AB - Time-resolved spectra of neutral and ionized atomic emissions from slag sample are measured by laser-induced breakdown spectroscopy (LIBS). Various factors affecting the calibration-free CF-LIBS method are carefully analyzed, and subsequently these factors are either avoided or corrected. Plasma temperature and electron density are calculated by Saha-Boltzmann plot and Stark broadening of Ca, respectively. At the same time, self-absorption and local thermodynamic equilibrium have been carefully studied. An automatic spectral lines elimination algorithm is applied to calculate plasma temperature and element concentration. The calculated element concentrations show marked changes with acquisition time increasing. Due to the influence of continuous spectrum at early times and self absorption at late times, the large absolute errors sum is obtained in these two periods. The smallest absolute errors sum corresponds to the gate delay time 1.5 MUs < td < 2 MUs for our experimental setup. PMID- 26968452 TI - ASP2408 and ASP2409, novel CTLA4-Ig variants with CD86-selective ligand binding activity and improved immunosuppressive potency, created by directed evolution. AB - The CTLA4-Ig therapeutics abatacept and belatacept inhibit CD28-mediated T cell activation by binding CD80 (B7-1) and CD86 (B7-2) co-stimulatory ligands. Both compounds preferentially bind CD80, yet CD86 has been implicated as the dominant co-stimulatory ligand. Using directed evolution methods, novel CTLA4-Ig variants were created with selective CD86 binding affinity, a property that confers increased immunosuppressive potency and potentially improved efficacy and safety profiles. Relative to abatacept (wild-type CTLA4-Ig), ASP2408 and ASP2409 have 83 fold and 220-fold enhanced binding affinity to CD86 while retaining 1.5-fold and 5.6-fold enhanced binding affinity to CD80, respectively. Improvements in CD86 binding affinity correlates with increased immunosuppressive potencyin vitroandin vivo Our results highlight the power of directed evolution methods to obtain non intuitive protein engineering solutions and represent the first examples of CD86 selective CTLA4-Ig compounds that have entered clinical trials. PMID- 26968455 TI - Effect of Shear Applied During a Pharmaceutical Process on Near Infrared Spectra. AB - This study describes changes observed in the near-infrared (NIR) diffuse reflectance (DR) spectra of pharmaceutical tablets after these tablets were subjected to different levels of strain (exposure to shear) during the mixing process. Powder shearing is important in the mixing of powders that are cohesive. Shear stress is created in a system by moving one surface over another causing displacements in the direction of the moving surface and is part of the mixing dynamics of particulates in many industries including the pharmaceutical industry. In continuous mixing, shear strain is developed within the process when powder particles are in constant movement and can affect the quality attributes of the final product such as dissolution. These changes in the NIR spectra could affect results obtained from NIR calibration models. The aim of the study was to understand changes in the NIR diffuse reflectance spectra that can be associated with different levels of strain developed during blend shearing of laboratory samples. Shear was applied using a Couette cell and tablets were produced using a tablet press emulator. Tablets with different shear levels were measured using NIR spectroscopy in the diffuse reflectance mode. The NIR spectra were baseline corrected to maintain the scattering effect associated with the physical properties of the tablet surface. Principal component analysis was used to establish the principal sources of variation within the samples. The angular dependence of elastic light scattering shows that the shear treatment reduces the size of particles and produces their uniform and highly isotropic distribution. Tablet compaction further reduces the diffuse component of scattering due to realignment of particles. PMID- 26968456 TI - Double Jeopardy: Hearing Loss and Tinnitus Among Noise-Exposed Workers. AB - The purpose of this study was to determine the prevalence and characteristics of tinnitus and assess the relationship between tinnitus and hearing loss among firefighters and operating engineers, who are exposed to noise on-the-job. The study analyzed existing data from two different populations (154 firefighters and 769 operating engineers) who completed a survey and audiometric tests as part of a hearing loss prevention intervention study. Approximately 40% of both groups reported tinnitus; 34% of firefighters and 59% of operating engineers showed hearing loss at noise-sensitive frequencies (4 kHz and 6 kHz). Firefighters with high frequency hearing loss (odds ratio [OR] = 2.31; 95% confidence interval [CI] = [1.05, 5.11]) and those with perceived impaired hearing status (OR = 3.53; 95% CI = [1.27, 9.80]) were significantly more likely to report tinnitus. Similarly, operating engineers who had hearing loss at both low (OR = 2.10; 95% CI = [1.40, 3.15]) and high frequencies (OR = 2.00; 95% CI = [1.37, 2.90]), and perceived impaired hearing status (OR = 2.17; 95% CI = [1.55, 3.05]) were twice as likely to report tinnitus. This study demonstrated that tinnitus is a considerable problem for noise-exposed workers. Workers with hearing loss demonstrated significantly higher rates of tinnitus. Comprehensive workplace hearing conservation programs should include tinnitus management for noise-exposed workers, along with other key elements such as noise control and hearing protection. PMID- 26968457 TI - Mindfulness-Based Approaches for Children and Youth. AB - Mindfulness meditation is a useful adjunct to behavioral and medical interventions to manage a range of symptoms, including psychological and physical responses to stress, anxiety, depression, and disruptive behavior. Mindfulness approaches can be taught to children, adolescents, and their parents to improve self-regulation, particularly in response to stress. Mindfulness may be particularly relevant for youth and families who have an increased risk for exposure to chronic stress and unique stressors associated with medical and/or social-contextual considerations. Moreover, mindfulness parenting techniques can augment traditional behavioral approaches to improve children's behavior through specific parent-child interactions. A growing body of empirical studies and clinical experience suggest that incorporating mindfulness practices will enable clinicians to more effectively treat youth and their families in coping optimally with a range of challenging symptoms. PMID- 26968458 TI - Impact of a pilot team on patients' pain reduction and satisfaction in an emergency department: A before-and-after observational study. AB - BACKGROUND: Pain management and patient satisfaction were targeted in the emergency department of a Paris university hospital. In 1999, 77.0% of patients complained of pain on arrival and more than half of patients did not experience pain relief at discharge. The purpose of the study was to evaluate the outcomes of the implementation of a team piloting pain management on pain reduction and pain care satisfaction. METHOD: Two cross-sectional surveys (04/10/1999 to 19/10/1999 and 03/04/2007 to 18/04/2007) were conducted before and after a team piloting pain management was deployed in the emergency department. Consecutive patients age 18 years and older who visited the department suffering from pain were given structured questionnaires that validated scales scoring pain upon arrival and at discharge. Patients' files were analyzed using structured forms. The parameters associated with pain reduction and patient satisfaction were sought. RESULTS: In 2007, 65.0% of patients had their pain relieved vs. 35.1% in 1999 (P<0.001); 60.2% were satisfied with the pain care received vs. 39.8%. Pain management (e.g. waiting time <= 20 min: 47.6% vs. 20.8%; interventions on pain before the physician's examination: 63.0% vs. 13.8%; and pain reassessment after intervention: 13.8% vs. 4.5%) improved. Both pain reduction and patient satisfaction were significantly associated with intervention before the physician's examination. Pain reduction was independently and positively associated with time of survey, triage level (depending on the severity of their condition), pain intensity on arrival, and negatively associated with discharge without hospitalization. Satisfaction was independently and positively associated with waiting time before examination (0-20 min) and the absence of procedural pain. CONCLUSION: The implementation of a team piloting pain management seemed to have had positive effects on pain management in the emergency department. However, respectively, 56.2% and 39.8% of patients remained without pain relief and dissatisfied with pain management at the end of their visit. PMID- 26968459 TI - Short O-GalNAc glycans: regulation and role in tumor development and clinical perspectives. AB - BACKGROUND: While the underlying causes of cancer are genetic modifications, changes in cellular states mediate cancer development. Tumor cells display markedly changed glycosylation states, of which the O-GalNAc glycans called the Tn and TF antigens are particularly common. How these antigens get over-expressed is not clear. The expression levels of glycosylation enzymes fail to explain it. SCOPE OF REVIEW: We describe the regulation of O-GalNAc glycosylation initiation and extension with emphasis on the initiating enzymes ppGalNAcTs (GALNTs), and introduce the GALA pathway--a change in GALNTs compartmentation within the secretory pathway that regulates Tn levels. We discuss the roles of O-GalNAc glycans and GALNTs in tumorigenic processes and finally consider diagnostic and therapeutic perspectives. MAJOR CONCLUSIONS: Contrary to a common hypothesis, short O-glycans in tumors are not the result of an incomplete glycosylation process but rather reveal the activation of regulatory pathways. Surprisingly, high Tn levels reveal a major shift in the O-glycoproteome rather than a shortening of O-glycans. These changes are driven by membrane trafficking events. GENERAL SIGNIFICANCE: Many attempts to use O-glycans for biomarker, antibody and therapeutic vaccine development have been made, but suffer limitations including poor sensitivity and/or specificity that may in part derive from lack of a mechanistic understanding. Deciphering how short O-GalNAc glycans are regulated would open new perspectives to exploit this biology for therapeutic usage. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc. PMID- 26968460 TI - Zebrafish Tg(hb9:MTS-Kaede): a new in vivo tool for studying the axonal movement of mitochondria. AB - OBJECTIVES: Deregulation of axonal transport in neurons is emerging as the major cause of many neurodegenerative diseases in human, such as Charcot-Marie-Tooth (CMT) neuropathy. However, little is known about how mitochondria move in vivo and whether cell culture systems truly represent what happens in living animals. Here we describe the generation of a new zebrafish transgenic line that specifically allows to study mitochondrial dynamics in motor neurons and its application to analyse mitochondrial movement in zebrafish models expressing CMT2A causing mutations. METHODS: The Tol2 transposon system was used to generate a transgenic zebrafish line expressing the photoconvertible fluorescent protein Kaede in mitochondria of motor neurons. Mitochondrial shape and movement were monitored by time-lapse confocal live imaging and measured by kymograph analysis. The effects of two well-known CMT causing mutations, L76P and R94Q substitutions in MFN2, were then investigated with the same methods. RESULTS: We generated the transgenic zebrafish Tg(hb9:MTS-Kaede) line with genetically labelled mitochondria in motor neurons. Kaede protein was correctly and stably targeted to mitochondrial matrix while retaining its photoconvertibility, thus qualifying this model for in vivo studies. Expression of the L76P and R94Q mutations reduced mitochondrial movement in axons and altered mitochondrial distribution in distinct ways. CONCLUSIONS AND GENERAL SIGNIFICANCE: These findings confirm previously published data obtained in cell cultures and strengthen the hypothesis of different mechanism of action of the two MFN2 mutations. Considering the number of neurodegenerative diseases associated to mitochondrial dynamics, the Tg(hb9:MTS-Kaede) zebrafish line is a promising model to study in vivo alterations of mitochondrial transport underlying human diseases. PMID- 26968461 TI - Glycoblotting method allows for rapid and efficient glycome profiling of human Alzheimer's disease brain, serum and cerebrospinal fluid towards potential biomarker discovery. AB - BACKGROUND: Understanding of the significance of posttranslational glycosylation in Alzheimer's disease (AD) is of growing importance for the investigation of the pathogenesis of AD as well as discovery research of the disease-specific serum biomarkers. METHODS: We designed a standard protocol for the glycoblotting combined with MALDI-TOFMS to perform rapid and quantitative profiling of the glycan parts of glycoproteins (N-glycans) and glycosphingolipids (GSLs) using human AD's post-mortem samples such as brain tissues (dissected cerebral cortices such as frontal, parietal, occipital, and temporal domains), serum and cerebrospinal fluid (CSF). RESULTS: The structural profiles of the major N glycans released from glycoproteins and the total expression levels of the glycans were found to be mostly similar between the brain tissues of the AD patients and those of the normal control group. In contrast, the expression levels of the serum and CSF protein N-glycans such as bisect-type and multiply branched glycoforms were increased significantly in AD patient group. In addition, the levels of some gangliosides such as GM1, GM2 and GM3 appeared to alter in the AD patient brain and serum samples when compared with the normal control groups. CONCLUSION: Alteration of the expression levels of major N- and GSL-glycans in human brain tissues, serum and CSF of AD patients can be monitored quantitatively by means of the glycoblotting-based standard protocols. GENERAL SIGNIFICANCE: The changes in the expression levels of the glycans derived from the human post-mortem samples uncovered by the standardized glycoblotting method provides potential serum biomarkers in central nervous system disorders and can contribute to the insight into the molecular mechanisms in the pathogenesis of neurodegenerative diseases and future drug discovery. Most importantly, the present preliminary trials using human post-mortem samples of AD patients suggest that large-scale serum glycomics cohort by means of various-types of human AD patients as well as the normal control sera can facilitate the discovery research of highly sensitive and reliable serum biomarkers for an early diagnosis of AD. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc. PMID- 26968462 TI - Constitutive hyperactivity of histone deacetylases enhances radioresistance in Lepidopteran Sf9 insect cells. AB - BACKGROUND: Lepidopteran insect cells withstand multifold higher radiation doses and suffer far less DNA damage despite carrying numerous structural/functional homologies with mammalian cells. Since DNA-histone interactions significantly influence radiation-induced DNA damage, we investigated the role of histones in insect cell radioresistance. METHODS: Modified comet assay was used to assess the gamma-radiation-induced DNA damage following serial histone depletion by varied salt concentrations. Acid-Urea-Triton (AUT) gel analysis combined with in silico predictions was used to compare mammalian and insect histones and acetylation status while HDAC activity was assessed/modified for studying the latter's role in radioresistance. Cell death was measured by morphological analysis and flow cytometry. RESULTS: High-salt extraction pattern from Sf9 nuclei suggested stronger DNA-histone affinity as the two core histones H2A/H2B could be extracted at much higher (2M) concentration as compared to 1.2M NaCl in mammalian (AA8) cells. Electrophoretic mobility of unirradiated Sf9 cells remained unaltered at all salt concentrations (0.14M-2M NaCl), and radiation-induced DNA damage increased only by 2M-NaCl pre-treatment. In silico analysis confirmed excellent conservation of Lepidopteran H2A/H2B sequence with human histones including comparable N-terminal lysine residues, yet these had ~60% lower acetylation. Importantly, insect cells showed ~70% higher histone deacetylase activity whose inhibition by Trichostatin-A reversed hypo-acetylation state and caused significant radiosensitization, thereby confirming the protective contribution of reduced acetylation. CONCLUSION: Our study reveals that the hypo-acetylated state of well-conserved core histones, maintained by considerable HDAC activity, contributes significantly in Lepidopteran radioresistance. GENERAL SIGNIFICANCE: This investigation shows constitutively high activity of HDACs as a potential radioprotective mechanism existing in insect cells. PMID- 26968463 TI - Characterization of insulin-degrading enzyme-mediated cleavage of Abeta in distinct aggregation states. AB - To enhance our understanding of the potential therapeutic utility of insulin degrading enzyme (IDE) in Alzheimer's disease (AD), we studied in vitro IDE mediated degradation of different amyloid-beta (Abeta) peptide aggregation states. Our findings show that IDE activity is driven by the dynamic equilibrium between Abeta monomers and higher ordered aggregates. We identify Met(35)-Val(36) as a novel IDE cleavage site in the Abeta sequence and show that Abeta fragments resulting from IDE cleavage form non-toxic amorphous aggregates. These findings need to be taken into account in therapeutic strategies designed to increase Abeta clearance in AD patients by modulating IDE activity. PMID- 26968464 TI - It's All in the Mix: Diagnosis and Management of Food Intolerance. PMID- 26968465 TI - Understanding Breath Tests for Small Intestinal Bacterial Overgrowth. PMID- 26968466 TI - Evidence for Life Before Inflammatory Bowel Disease. PMID- 26968467 TI - Agreement Between Results of Home Sleep Testing for Obstructive Sleep Apnea with and Without a Sleep Specialist. AB - BACKGROUND: Obstructive sleep apnea is a prevalent yet underdiagnosed condition associated with cardiovascular morbidity and mortality. Home sleep testing offers an efficient means for diagnosing obstructive sleep apnea but has been deployed primarily in clinical samples with a high pretest probability. The present study sought to assess whether obstructive sleep apnea can be diagnosed with home sleep testing in a nonreferred sample without involvement of a sleep medicine specialist. METHODS: A study of community-based adults with untreated obstructive sleep apnea was undertaken. Misclassification of disease severity according to home sleep testing with and without involvement of a sleep medicine specialist was assessed, and agreement was characterized using scatter plots, Pearson's correlation coefficient, Bland-Altman analysis, and the kappa statistic. Analyses were also conducted to assess whether any observed differences varied as a function of pretest probability of obstructive sleep apnea or subjective sleepiness. RESULTS: The sample consisted of 191 subjects, with more than half (56.5%) having obstructive sleep apnea. Without involvement of a sleep medicine specialist, obstructive sleep apnea was not identified in only 5.8% of the sample. Analyses comparing the categorical assessment of disease severity with and without a sleep medicine specialist showed that in total, 32 subjects (16.8%) were misclassified. Agreement in the disease severity with and without a sleep medicine specialist was not influenced by the pretest probability or daytime sleep tendency. CONCLUSION: Obstructive sleep apnea can be reliably identified with home sleep testing in a nonreferred sample, irrespective of the pretest probability of the disease. PMID- 26968468 TI - Methylprednisolone-Induced Lymphocytosis in Patients with Immune-Mediated Inflammatory Disorders. AB - BACKGROUND: Transient acute reversible lymphopenia occurring within hours after glucocorticoid administration is a well-known phenomenon. The objective of this study was to establish the impact of chronic methylprednisolone (mPDN) administration on lymphocyte counts in patients with immune-mediated inflammatory disorders. METHODS: The charts of 44 women and 17 men (median age, 59 years) with several immune-mediated inflammatory disorders receiving oral mPDN for at least 4 months were reviewed. Morning lymphocyte counts measured during treatment (LP) were compared with pretreatment values (LA). In addition, the acute effect of mPDN on lymphocyte counts was evaluated in 43 of these patients by quantifying lymphocyte subpopulations before and 8 hours after mPDN administration. Values are expressed as median with 25%-75% interquartile range. RESULTS: The initial daily oral mPDN dose was 28 mg (12-32 mg). An increase in morning lymphocyte counts was detected 13 days (8.5-16 days) after initiation of mPDN treatment (LP: 2130/MUL vs LA: 1650/MUL; P = .0121) and persisted over time. Morning lymphocytosis (LP >=4000/MUL) was observed in 15 patients, including 7 with hyperlymphocytosis (LP >=5000/MUL). The increase in morning lymphocyte counts during treatment was most marked for CD4 T cells. In the subset of patients who agreed to a second blood test after mPDN absorption, a 49% decrease in the lymphocyte count (P <.0001) was transiently observed at the 8-hour time point. CONCLUSIONS: A significant increase of the morning lymphocyte count is frequently observed in patients with immune-mediated inflammatory disorders chronically treated with oral mPDN. Heightened awareness that the timing of blood sampling in corticosteroid-treated patients affects lymphocyte counts, with possible hyperlymphocytosis before absorption, should help avoid unnecessary investigations and worry. PMID- 26968469 TI - A Tool to Assess Risk of De Novo Opioid Abuse or Dependence. AB - BACKGROUND: Determining risk factors for opioid abuse or dependence will help clinicians practice informed prescribing and may help mitigate opioid abuse or dependence. The purpose of this study is to identify variables predicting opioid abuse or dependence. METHODS: A retrospective cohort study using de-identified integrated pharmacy and medical claims was performed between October 2009 and September 2013. Patients with at least 1 opioid prescription claim during the index period (index claim) were identified. We ascertained risk factors using data from 12 months before the index claim (pre-period) and captured abuse or dependency diagnosis using data from 12 months after the index claim (postperiod). We included continuously eligible (pre- and postperiod) commercially insured patients aged 18 years or older. We excluded patients with cancer, residence in a long-term care facility, or a previous diagnosis of opioid abuse or dependence (identified by International Classification of Diseases 9th revision code or buprenorphine/naloxone claim in the pre-period). The outcome was a diagnosis of opioid abuse (International Classification of Diseases 9th revision code 304.0x) or dependence (305.5). RESULTS: The final sample consisted of 694,851 patients. Opioid abuse or dependence was observed in 2067 patients (0.3%). Several factors predicted opioid abuse or dependence: younger age (per decade [older] odds ratio [OR], 0.68); being a chronic opioid user (OR, 4.39); history of mental illness (OR, 3.45); nonopioid substance abuse (OR, 2.82); alcohol abuse (OR, 2.37); high morphine equivalent dose per day user (OR, 1.98); tobacco use (OR, 1.80); obtaining opioids from multiple prescribers (OR, 1.71); residing in the South (OR, 1.65), West (OR, 1.49), or Midwest (OR, 1.24); using multiple pharmacies (OR, 1.59); male gender (OR, 1.43); and increased 30-day adjusted opioid prescriptions (OR, 1.05). CONCLUSIONS: Readily available demographic, clinical, behavioral, pharmacy, and geographic information can be used to predict the likelihood of opioid abuse or dependence. PMID- 26968470 TI - Persistence Pays Off: Adult Langerhans Cell Histiocytosis. PMID- 26968472 TI - Quantification of the External Validity of Randomized Controlled Trials Supporting Clinical Care Guidelines: The Case of Thromboprophylaxis. AB - BACKGROUND: Clinical guidelines are based on the results of several randomized controlled trials. However, due to the stringent exclusion criteria of these trials, their external validity may be low. We aimed to evaluate the external validity of the randomized controlled trials cited in the American College of Chest Physicians guidelines for the use of pharmacological thromboprophylaxis in hospitalized medical patients. METHODS: We conducted a cross-sectional, chart review study of a random sample of patients admitted between July 1, 2013 and June 30, 2014 to the Internal Medicine ward of a large Canadian teaching university hospital. We identified the proportion of our population presenting exclusion criteria used in the randomized controlled trials cited in support of clinical care guidelines on thromboprophylaxis in the medical setting. RESULTS: Nine trials were identified for a total of 28,793 included patients following 23 distinct exclusion criteria. We included 429 patients. Median age was 65 years (interquartile ratio 51-77 years), and 236 (55%) were males. Of those not already anticoagulated at admission (n = 351), between 26% and 67% (weighted average, 51%) of our population presented at least one exclusion criterion, making them ineligible to be enrolled in randomized controlled trials. When restricting our population to patients with an indication for thromboprophylaxis based on a Padua risk score at admission >=4, 21% to 76% (weighted average 55%) were ineligible to be enrolled in individual trials. CONCLUSIONS: Our cross-sectional study illustrates that the external validity of randomized controlled trials cited in the guidelines was low in our population, and lower when applying the risk stratification tool recommended by guidelines. This can bias the clinicians toward treating patients that were not represented in the supporting evidence. PMID- 26968473 TI - Postparacentesis Genital Edema. PMID- 26968471 TI - Restricting Symptoms Before and After Admission to Hospice. AB - BACKGROUND: Prior work has shown that symptoms leading to restrictions in daily activities are common at the end of life. Hospice is a Medicare benefit designed to alleviate distressing symptoms in the last 6 months of life. The effect of hospice on the burden of such symptoms is uncertain. METHODS: From an ongoing cohort study of 754 community-dwelling older persons, aged >=70 years, we evaluated 241 participants who were admitted to hospice from March 1998 to December 2013. A set of 15 physical and psychological symptoms leading to restricted activity (ie, cut down on usual activities or spend at least half the day in bed) were ascertained during monthly telephone interviews in the year before and 3 months after hospice admission. RESULTS: The prevalence and mean number of restricting symptoms increased progressively until about 2 months before hospice admission, before increasing precipitously to a peak around the time of hospice admission. After the start of hospice, both the prevalence and the mean number of restricting symptoms dropped markedly. For several symptoms deemed most amenable to hospice treatment, including depression and anxiety, the prevalence dropped to levels comparable to or lower than those observed 12 months before the start of hospice. The trends observed in symptom prevalence and mean number of symptoms before and after hospice did not differ appreciably according to hospice admission diagnosis or sex. The median duration of hospice (before death) was only 15 days. CONCLUSION: The burden of restricting symptoms increases progressively several months before the start of hospice, peaks around the time of hospice admission, and decreases substantially after the start of hospice. These results, coupled with the short duration of hospice, suggest that earlier referral to hospice may help to alleviate the burden of distressing symptoms at the end of life. PMID- 26968474 TI - Renal embolization. AB - Recent developments in endovascular radiological techniques and devices make embolization as a major therapeutic option in many renal vascular or neoplastic diseases, before surgery. These techniques show a very good efficacy with a low morbidity and a better renal tolerance. Indications of embolization in nephrology are post-biopsy arteriovenous fistulas, renal graft intolerance, functional exclusion and polycystic kidney disease before transplantation. Others are at the interface between nephrology and urology as angiomyolipomas (mostly in tuberous sclerosis context), arterial aneurysms and arteriovenous malformations. PMID- 26968475 TI - [New aspects of HLA compatibility in organ transplantation]. AB - In organ transplantation, HLA compatibility between a donor and a recipient is currently assessed through the comparison of their HLA antigens and the sole count of incompatible HLA antigens. Similarly, antibodies were originally described as antigenic-specific. With solid phase assays detection of anti-HLA antibodies and crystallographic studies, it is now recognized that anti-HLA antibodies are not specific for antigens, but for epitopes, i.e. short polymorphic sequences of amino acids that are more often in positions accessible to allo-antibodies. These epitopes, due to the distribution of HLA molecules polymorphism, may be shared by different HLA antigens. This explains why an immunization towards a given HLA antigen can lead to synthesis of antibodies reactive towards other antigens sharing one or more epitopes. Similarly, structural comparison of the HLA molecules of a recipient and his donor defines the epitope load, i.e. the number of incompatible epitopes. This epitope load is correlated with the risk of developing antibodies specific for the donor after transplantation. New tools, such as the HLAMatchmaker software, allow to determine the epitopic load and to analyze the epitopic specificity of alloantibodies. These tools will possibly lead to rethink the method of graft allocation, or at least to take differently into account HLA compatibility in allocation algorythms. PMID- 26968476 TI - [Fibromuscular dysplasia of renal arteries]. AB - Fibromuscular dysplasia is non-atherosclerotic, non-inflammatory disease of the medium caliber arteries causing segmental stenosis, and sometimes aneurysm and/or dissection. Renal involvement is either asymptomatic or revealed by hypertension, rarely acute complications (renal infarction/hemorrhage). Cross-sectional imaging or angiography differentiates multifocal fibromuscular dysplasia (pearl necklace appearance) and focal fibromuscular dysplasia (tubular stenosis). Several differential diagnoses are to be mentioned. Carotid and vertebral involvement are possible. Smoking cessation must be encouraged. Selected patients benefit from renal revascularization. The best indications are recent or resistant hypertension, and progressive renal atrophy. Angioplasty without stent revascularization is the technique of choice in purely stenotic forms. PMID- 26968477 TI - [Role of cannabinoid receptors in renal diseases]. AB - Chronic kidney disease remains a major challenge for public health systems and corresponds to the replacement of renal functional tissue by extracellular matrix proteins such as collagens and fibronectin. There is no efficient treatment to date for chronic kidney disease except nephroprotective strategies. The cannabinoid system and more specifically the cannabinoid receptors 1 (CB1) and 2 (CB2) may represent a new therapeutic target in chronic kidney disease. Experimental data obtained in models of diabetes and obesity suggested that CB1 blockade and CB2 stimulation may slow the development of diabetic nephropathy. In human kidneys, CB1 expression is increased in various chronic nephropathies and correlates with renal function. Moreover, endogenous CB1 and CB2 ligands are greatly increased during renal fibrogenesis. A microarray analysis performed in an experimental model of renal fibrosis found that the gene encoding for the CB1 receptor was among the most upregulated genes. We also demonstrated that renal fibrogenesis could be reduced by CB1 inhibition and CB2 stimulation in an experimental model through a direct mechanism involving CB1 on myofibroblasts, which are the major effector cells during renal fibrosis. Therefore, CB1 blockers may represent a novel therapeutic target in chronic kidney disease and diabetes. PMID- 26968478 TI - [Treatment of Fabry disease: Successes, failures, and expectations]. AB - Fabry disease, an X-linked lysosomal storage disease, results from alpha galactosidase A deficiency. Two different recombinant enzyme treatments (algalsidase alpha agalsidase beta) have been available since 2001 to treat a disease that affects not only men but also women. Enzyme replacement therapy promotes cell clearance of susbtrate, and improves some clinical parameters (heart, kidney damage, pain, quality of life). However, there is no proven efficacy to date on central nervous system lesions, on cardiac morbidity and mortality, nor on renal damage beyond a certain stage (proteinuria>1g/day and/or estimated glomerular filtration rate<60mL/min/1.73m(2)). In this review, we discuss the potential benefit of an early intervention, the vascular protective measures to be associated with enzyme therapy and their rationale, and some alternative treatments under development, such as chaperones and substrate molecules inhibitors. PMID- 26968479 TI - In vivo microscopy. AB - This article summarizes the past, present, and future promise of multiphoton excitation fluorescence microscopy for intravital kidney imaging. During the past 15years, several high-power visual research approaches have been developed using multiphoton imaging to study the normal functions of the healthy, intact, living kidney, and the various molecular and cellular mechanisms of the development of kidney diseases. In this review, the main focus will be on intravital multiphoton imaging of the glomerulus, the structure and function of the glomerular filtration barrier, especially the podocyte. Examples will be given for the combination of two powerful research tools, in vivo multiphoton imaging and mouse genetics using commercially available whole animal models for the detailed characterization of glomerular cell types, their function and fate, and for the better understanding of the molecular mechanisms of glomerular pathologies. One of the new modalities of multiphoton imaging, serial imaging of the same glomerulus in the same animal over several days will be emphasized for its potential for further advancing the field of nephrology research. PMID- 26968481 TI - Childhood school performance, education and occupational complexity: a life course study of dementia in the Kungsholmen Project. AB - BACKGROUND: Cognitive reserve hypothesis predicts that intellectually demanding activities over the life course protect against dementia. We investigate if childhood school performance remains associated with dementia once education and occupational complexity are taken into account. METHODS: A cohort of 440 individuals aged 75+ from the Kungsholmen Project was followed up for 9 years to detect dementia. To measure early-life contributors to reserve, we used grades at age 9-10 extracted from the school archives. Data on formal education and occupational complexity were collected at baseline and first follow-up. Dementia was ascertained through comprehensive clinical examination. Cox models estimated the relationship between life-course cognitive reserve measures and dementia. RESULTS: Dementia risk was elevated [hazard ratio (HR): 1.54, 95% confidence interval (CI): 1.03 to 2.29] in individuals with low early-life school grades after adjustment for formal educational attainment and occupational complexity. Secondary education was associated with a lower risk of dementia (HR: 0.72, 95% CI: 0.50 to 1.03), although the effects of post-secondary and university degrees were indistinguishable from baseline. Occupational complexity with data and things was not related to dementia. However, an association was found between high occupational complexity with people and dementia, albeit only in women (HR: 0.39, 95% CI: 0.14 to 0.99). The pattern of results remained unchanged after adjustment for genetic susceptibility, comorbidities and depressive symptoms. CONCLUSION: Low early-life school performance is associated with an elevated risk of dementia, independent of subsequent educational and occupational attainment. PMID- 26968482 TI - Comparing online and telephone survey results in the context of a skin cancer prevention campaign evaluation. AB - Background: A large proportion of health promotion campaign evaluation research has historically been conducted via telephone surveys. However, there are concerns about the continued viability of this form of surveying in providing relevant and representative data. Online surveys are an increasingly popular alternative, and as such there is a need to assess the comparability between data collected using the two different methods to determine the implications for longitudinal comparisons. The present study compared these survey modes in the context of health promotion evaluation research. Methods: Data were collected via computer-assisted telephone interviewing and an online panel. In total, 688 and 606 respondents aged between 14 and 45 years completed the online and telephone surveys, respectively. Results: Online respondents demonstrated higher awareness of the advertisement, rated the advertisement as more personally relevant and had better behavioural outcomes compared with the telephone respondents. Conclusion: The results indicate significant differences between the telephone and online surveys on most measures used to assess the effectiveness of a health promotion advertising campaign. Health promotion practitioners could consider the combination of both methods to overcome the deterioration in telephone survey response rates and the likely differences in respondent outcomes. PMID- 26968480 TI - Data Resource Profile: Network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA Network). PMID- 26968483 TI - Syndromic surveillance for influenza in Tianjin, China: 2013-14. AB - Background: Diverse sources of syndromic surveillance including over-the-counter (OTC) drug sales, hospital and school-based influenza-like illness (ILI) and Baidu search queries estimate influenza activity in Tianjin, China. The purpose of this study was to determine which syndromic surveillance systems had the strongest correlation with laboratory-confirmed influenza activity. Methods: Data were obtained from sentinel hospitals and laboratories; sentinel hospitals also reported percentage of ILI. OTC sales and school-based ILI absentee data were provided by public pharmacies and schools. Baidu search queries for influenza surveillance were analyzed. Spearman correlation analysis examined correlations of syndromic systems with laboratory-confirmed data. Results: Syndromic data for hospital ILI%, OTC sales and school-based ILI correlated well with laboratory data (r = 0.732, 0.490 and 0.693, respectively; P < 0.05). Baidu, the predominant Chinese Internet service, searches for 'influenza', 'cough' and 'fever' correlated best with laboratory-confirmed activity; queries for 'fever' were strongest (r = 0.924, P < 0.001). Correlations between school-based ILI and laboratory-confirmed influenza increased from 0.693 to 0.795 after a 1-week lag (P < 0.05). Conclusions: A Baidu query of 'fever' provided the strongest correlation to laboratory surveillance. School-based ILI absence reporting detected influenza virus activity 1 week earlier than laboratory confirmation. Use of diverse syndromic surveillance systems in conjunction with traditional surveillance systems can improve influenza surveillance. PMID- 26968484 TI - In vitro and in vivo study of hydralazine, a potential anti-angiogenic agent. AB - Hydralazine (HYD), an old routine clinical anti-hypertension drug, is rarely used in clinic nowadays. Since the strategy of repositioning old drugs was put forward, HYD has been reported to possess various biological activities, including antitumor efficacy and reducing intra-tumor microvessel. Here, we investigated that whether HYD had the ability of anti-angiogeneis and its underlying mechanism. Cells proliferation, wound-healing, Transwell migration and invasion, tube formation and rat aortic ring assays in vitro and chicken chorioallantoic membrane (CAM) model in vivo were designed to investigated HYD's anti-angiogenic effect. Levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were assessed by enzyme-linked immune sorbent assay (ELISA). Hepatocellular carcinoma (HCC) mice model was used to evaluate HYD's effect on tumor growth and microvessel density. Our results showed that HYD not only inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, wound-healing, Transwell migration and invasion and tube formation, but also suppressed the microvessel outgrowth of rat aortic ring in vitro and the neovascularzation of CAM in vivo. Furthermore, we demonstrated that HYD attenuated tumor angiogenesis and tumor growth. In the co-culture system of Transwell migration, the secretion of VEGF and bFGF was reduced by HYD respectively. In sum, our data indicate that HYD has the pharmacological effect of ant-angiogenesis by interference with VEGF and bFGF signaling pathways in endothelial cells. These findings suggest that HYD might be a promising angiogenesis inhibitor and a potential effective therapeutic agent for cancer therapy. PMID- 26968485 TI - Graft bending angle is correlated with femoral intraosseous graft signal intensity in anterior cruciate ligament reconstruction using the outside-in technique. AB - BACKGROUND: The purposes of this study were as follows: 1) to determine the correlation between the bending angle of the anterior cruciate ligament (ACL) graft at the femoral tunnel and the magnetic resonance imaging (MRI) signal intensity of the ACL graft and 2) to analyze the difference in the MRI signal intensity of the reconstructed ACL graft in different areas of the graft after single-bundle hamstring autograft ACL (SB ACL) reconstruction using an outside-in (OI) technique with bone-sparing retro-reaming. METHODS: Thirty-eight patients who underwent SB ACL reconstruction with the hamstring tendon autograft using the OI technique were enrolled in this study. All patients were assessed using three dimensional computed tomography (CT) to evaluate femoral tunnel factors, including tunnel placement, tunnel length, tunnel diameter, and femoral tunnel bending angle. At a mean of 6.3+/-0.8months after surgery, 3.0-T MRI was used to evaluate the graft signal intensity using signal/noise quotient for high-signal intensity lesions. RESULTS: Among various femoral tunnel factors, only the femoral tunnel bending angle in the coronal plane was significantly (p=0.003) correlated with the signal/noise quotient of the femoral intraosseous graft. The femoral intraosseous graft had significantly (p=0.009) higher signal intensity than the other graft zone. Five cases (13.2%) showed high-signal-intensity zones around the femoral tunnel but not around the tibial tunnel. CONCLUSION: After ACL reconstruction using the OI technique, the graft bending angle was found to be significantly correlated with the femoral intraosseous graft signal intensity, indicating that increased signal intensity by acute graft bending might be related to the maturation of the graft. LEVEL OF EVIDENCE: This was a retrospective comparative study with Level III evidence. PMID- 26968486 TI - Prevalence and risk factors of infections caused by extended-spectrum beta lactamase (ESBL)-producing Enterobacteriaceae. AB - OBJECTIVE: To study the clinical characteristics and associated risk factors of infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. METHODS: A case-control study at a large university hospital in Japan, comparing patients who were infected or colonized with ESBL-producing Enterobacteriaceae (n = 212) and non-ESBL-producing Enterobacteriaceae (n = 2089) in 2010-2013. Data were collected from medical charts, retrospectively. Multivariate logistic regression analysis was used to explore risk factors of ESBL-producing Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis) infection or colonization for each pathogen, respectively. RESULTS: ESBL-producing Enterobacteriaceae [E. coli (n = 113), K. oxytoca (n = 46), K. pneumoniae (n = 41), P. mirabilis (n = 12)] were taken from patients were identified in 1409 outpatient and 892 inpatients. Infection or colonization caused by ESBL-producing Enterobacteriaceae was considered to be hospital-acquired, healthcare-associated and community-acquired in 60.4%, 17.9% and 21.7% patients, respectively. Independent risk factors for ESBL-producing Enterobacteriaceae infection or colonization were male sex, cerebrovascular disease, intubation/tracheostomy, major surgery within 60 days (p < 0.001). Moreover, antimicrobial usage (more than 4 days) during preceding 60 days, especially aminoglycoside, oxazolidinone, tetracycline, fluoroquinolone, trimethoprim/sulfamethoxazole, and second- and fourth-generation cephalosporin were risk factors (p < 0.001). However, acquisition location of infection (hospital-acquired and community-onset) was not a risk factor (p > 0.05). CONCLUSION: The problem of ESBL production is no longer limited to hospital acquired infections. The presence of chronic illness, such as cerebrovascular disease, and recent antimicrobial use were independent risk factors for ESBL producing Enterobacteriaceae infection or colonization. PMID- 26968487 TI - The Role of Pelvic Lymph Node Dissection During Radical Prostatectomy in Patients With Gleason 6 Intermediate-risk Prostate Cancer. AB - OBJECTIVE: To analyze the benefit of pelvic lymph node dissection (PLND) in patients with biopsy Gleason grade <= 6, cT <= 2b, and prostate-specific antigen (PSA) 10-20 ng/mL (main study cohort), as the indication for PLND during radical prostatectomy remains uncertain in patients with nonhigh-risk tumors. MATERIALS AND METHODS: The main study cohort included 1383 patients with low intermediate risk cancer undergoing radical prostatectomy with or without PLND between 1994 and 2013. Positive lymph node (LN) rates were reported and compared to patients with higher (>=20 ng/mL; n = 314) and lower (<10 ng/mL; n = 6861) PSA. Oncological outcome was assessed by Cox regressions in patients with a minimum follow-up of 5years. RESULTS: In the main study cohort (PSA 10-20 ng/mL), PLND was performed in 867 (62.7%) patients with a median number of removed LNs of 11 (interquartile range 16-6). Positive LNs were detected in 3.3% of these patients. Compared to the main study cohort, patients with preoperatively higher PSA >= 20 ng/mL (or lower PSA < 10 ng/ml) underwent PLND in 83.8% (32.7%) of the cases, with 8.0% (1.8%) showing positive LNs. Median follow-up in the main study cohort was 84.5 months. Biochemical recurrence (BCR) occurred in 20.6% of these men. The 5-year and 10-year BCR-free survival rates were 82.2% and 75.6% for those with PLND, and 83.4% and 75.8% for patients without PLND. PLND was not a significant factor influencing BCR-free, metastasis-free, or cancer-specific survival in the main study cohort. CONCLUSION: Positive LNs are rare in patients with Gleason grade <= 6, cT <= 2b, and PSA 10-20 ng/mL. Performing PLND had no statistical influence on oncologic outcome and therefore should be decided upon on an individual basis. PMID- 26968488 TI - Irreversible Renal Function Impairment Due to Silent Ureteral Stones. AB - OBJECTIVE: To evaluate if renal function loss and hydronephrosis due to a silent ureteral stone might be reversed. MATERIALS AND METHODS: We prospectively selected patients with silent ureteral stones between January 2006 and January 2014. A silent case was considered if there were no specific or subjective symptoms related to the ureteral stone. Patient, stone, and kidney characteristics were evaluated preoperatively, 3 and 12 months postoperatively. Renal function was accessed in the same intervals with serum creatinine (SCr), glomerular filtration rate (GFR), and (99m)Tc-dimercaptosuccinic acid. Patients without complete pre- and postoperative evaluation were excluded. Primary end point was midterm progress of global and ipsilateral renal function. Secondary end points included the evaluation of renal and collecting system anatomy from diagnosis to 12 months after treatment. Analysis of variance with repeated measures and marginal homogeneity test were used to evaluate renal function and hydronephrosis progression. RESULTS: Twenty-six patients met our inclusion criteria. Mean preoperative SCr and GFR were 1.24 mg/dL and 72.5 mL/min, respectively. At initial scintigraphy, mean renal function was 33.4%. Laser ureterolithotripsy was performed in 84.6% of cases and all patients were rendered stone free. Two patients (8%) developed ureteral stenosis. There was no difference regarding SCr (P = .89), GFR (P = .48), and renal function at scintigraphy (P = .19) during follow-up. Hydronephrosis significantly improved from preoperatively to 3 months postoperatively (P < .0001), but not from 3 to 12 months (P = .065). CONCLUSION: Patients with silent ureteral stones present with significant impairment of ipsilateral renal function and hydronephrosis at diagnosis. On midterm follow-up evaluation, renal function of the affected unit remains stable whereas hydronephrosis improves after treatment. PMID- 26968490 TI - Renal and Adrenal Minilaparoscopy: A Prospective Multicentric Study. AB - OBJECTIVE: To investigate the role of contemporary minilaparoscopy (ML; 3 mm instruments and laparoscope) and to identify predictive factors for complications in a prospective multicenter series for renal and adrenal surgeries. MATERIALS AND METHODS: From July 2013 to December 2014, 110 patients from 6 laparoscopic Spanish centers were enrolled. A common database was used and data were collected in a prospective manner. Standard approach was defined as 3 to 4 3-mm trocars with a 3-mm laparoscope and 3-mm instruments (Karl Storz, Tuttlingen, Germany). Descriptive variables were analyzed and statistical analysis was performed for predictive factors for complications. RESULTS: Patient mean age was 57.8 +/- 14.6 years, with an average body mass index of 25.3 +/- 3.6 kg/m(2). Median American Society of Anesthesiologists score was II and 32% (n = 35) of the patients had a previous surgery. A total of 59 nephrectomies, 20 partial nephrectomies, 9 nephroureterectomies, 13 pyeloplasties, 3 pyelolithotomies, and 6 adrenalectomies were performed. Overall operative time was 180 +/- 64 minutes. There were 12 clampless partials and 8 with a mean warm ischemia time of 14 +/- 7 min. There were 5% of intraoperative and 8% of postoperative complications (Clavien II-IV). Mean hospital stay was 5 +/- 2.3 days, with optimal pain and cosmetic control. CONCLUSION: To our knowledge, this is one of the largest prospective series of ML for renal and adrenal surgeries. Despite a mean operative time possibly longer than in standard laparoscopy, clinical and safety outcomes are not compromised. Furthermore, ML results in excellent pain control and cosmetic outcomes. PMID- 26968491 TI - The Scientist as Illustrator. AB - Proficiency in art and illustration was once considered an essential skill for biologists, because text alone often could not suffice to describe observations of biological systems. With modern imaging technology, it is no longer necessary to illustrate what we can see by eye. However, in molecular and cellular biology, our understanding of biological processes is dependent on our ability to synthesize diverse data to generate a hypothesis. Creating visual models of these hypotheses is important for generating new ideas and for communicating to our peers and to the public. Here, I discuss the benefits of creating visual models in molecular and cellular biology and consider steps to enable researchers to become more effective visual communicators. PMID- 26968489 TI - Efficacy and Safety of Intraoperative Tranexamic Acid Infusion for Reducing Blood Transfusion During Open Radical Cystectomy. AB - OBJECTIVE: To evaluate the safety and efficacy of intraoperative tranexamic acid (TA), an antifibrinolytic, in reducing perioperative blood transfusion (PBT) for patients undergoing open radical cystectomy (RC) for bladder cancer. MATERIALS AND METHODS: We instituted a change in our institutional clinical practice starting in April 2013, whereby all patients undergoing open RC were administered intraoperative intravenous TA. Patients with a history of venous thromboembolism (VTE) or coronary stent insertion within the year prior to RC did not receive TA. Receipt of a PBT, defined as transfusion of red blood cells during RC or within the postoperative hospitalization, and VTE within 30 days of RC were recorded and compared with a matched cohort of patients treated with RC at our center prior to the initiation of TA utilization. RESULTS: A total of 103 patients received TA during open RC between April 2013 and July 2015. These patients were matched 1:2 to historic controls. We found that TA infusion was associated with a significantly decreased rate of PBT, as 32 of 103 (31.1%) patients treated with TA received a PBT, versus 115 of 200 (57.7%) matched controls (P < .0001). Importantly, TA did not significantly increase the rate of perioperative VTE, as 5 patients (4.9%) who received TA were diagnosed with a VTE within 30 days of RC, compared with 6 (3.0%) of the matched controls (P = .52). CONCLUSION: We noted that the use of intraoperative TA during open RC was associated with a significant reduction in PBT, and did not significantly increase perioperative VTE risk. PMID- 26968492 TI - What Can Vampires Teach Us about Immunology? AB - Speculative fiction examines the leading edge of science and can be used to introduce ideas into the classroom. For example, most students are already familiar with the fictional infectious diseases responsible for vampire and zombie outbreaks. The disease dynamics of these imaginary ailments follow the same rules we see for real diseases and can be used to remind students that they already understand the basic rules of disease ecology and immunology. By engaging writers of this sort of fiction in an effort to solve problems in immunology we may be able to perform a directed evolution experiment where we follow the evolution of plots rather than genetic traits. PMID- 26968493 TI - The dual effect of ephaptic coupling on cardiac conduction with heterogeneous expression of connexin 43. AB - Decreased and heterogeneous expression of connexin 43 (Cx43) are common features in animal heart failure models. Ephpatic coupling, which relies on the presence of junctional cleft space between the ends of adjacent cells, has been suggested to play a more active role in mediating intercellular electrical communication when gap junctions are reduced. To better understand the interplay of Cx43 expression and ephaptic coupling on cardiac conduction during heart failure, we performed numerical simulations on our model when Cx43 expression is reduced and heterogeneous. Under severely reduced Cx43 expression, we identified three new phenomena in the presence of ephaptic coupling: alternating conduction, in which ephaptic and gap junction-mediated mechanisms alternate; instability of planar fronts; and small amplitude action potential (SAP), which has a smaller potential amplitude than the normal action potential. In the presence of heterogeneous Cx43 expression, ephaptic coupling can either prevent or promote conduction block (CB) depending on the Cx43 knockout (Cx43KO) content. When Cx43KO content is relatively high, ephaptic coupling reduces the probabilities of CB. However, ephaptic coupling promotes CB when Cx43KO and wild type cells are mixed in roughly equal proportion, which can be attributed to an increase in current-to load mismatch. PMID- 26968495 TI - Success importance and urge magnitude as determinants of cardiovascular response to a behavioral restraint challenge. AB - Decades of research have investigated a conceptual analysis concerned with determinants and cardiovascular correlates of effort in people confronted with performance challenges, that is, opportunities to alter some course of events by acting. One suggestion is that effort and associated cardiovascular responses should be determined jointly by the difficulty of meeting a challenge and the importance of doing so. The present experiment tested this in a context involving behavioral restraint, that is, effortful resistance against a behavioral impulse or urge. Participants were presented a mildly evocative violent film clip (restraint difficulty low) or a strongly evocative violent film clip (restraint difficulty high) with instructions to refrain from showing any facial response. Success was made more or less important through coordinated manipulations of outcome expectancy, ego-involvement and social evaluation. As expected, SBP responses assessed during the work period were proportional to clip evocativeness - i.e., the difficulty of the restraint challenge - when importance was high, but low regardless of clip evocativeness when importance was low. Findings conceptually replicate previous cardiovascular results and support extension of the guiding analysis to the behavioral restraint realm. PMID- 26968494 TI - Immunity decreases, antioxidant system damages and tight junction changes in the intestine of grass carp (Ctenopharyngodon idella) during folic acid deficiency: Regulation of NF-kappaB, Nrf2 and MLCK mRNA levels. AB - This investigation used the same growth trial as the previous study, which showed that folic acid deficiency retarded growth in young grass carp (the percent weight gain of Groups 1-6 were 102.32 +/- 3.41%, 137.25 +/- 10.48%, 179.78 +/- 3.95%, 164.33 +/- 3.21%, 143.35 +/- 8.12% and 115.28 +/- 2.66%) [1]. In the present study, we investigated the effects of dietary folic acid on the immune response, antioxidant status and tight junctions in the intestine of young grass carp (Ctenopharyngodon idella). A total of 540 young grass carp were fed diets containing graded levels of folic acid at 0.10, 0.47, 1.03, 1.48, 1.88 and 3.12 mg kg(-1) diet for 8 weeks. The results indicated that acid phosphatase and lysozyme activities, and the complement component 3 content in the proximal intestine (PI), mid intestine (MI) and distal intestine (DI) were decreased with folic acid deficiency (0.1 mg kg(-1)) (P < 0.05). Folic acid deficiency (0.1 mg kg(-1)) up-regulated interleukin 1beta, interleukin 8, tumor necrosis factor alpha, nuclear factor kappaB p65 (NF-kappaB p65), IkappaB kinase alpha (IKK alpha), IKK-beta and IKK-gamma gene expression, meanwhile down-regulated interleukin 10, transforming growth factor beta, IkappaB and target of rapamycin gene expression in the PI, MI and DI (P < 0.05). These data suggested that folic acid deficiency decreased fish intestinal innate immune function may be partly contributed to the regulation of NF-kappaB p65 pathway. Moreover, the activities and corresponding gene expression of glutathione content, Cu/Zn superoxide dismutase, catalase, glutathione peroxidase, glutathione s-transferases and glutathione reductase in fish intestine were depressed by deficient folic acid diet (0.1 mg kg(-1)) (P < 0.05). Furthermore, folic acid deficiency (0.1 mg kg( 1)) down-regulated NF-E2-related factor 2 (Nrf2) gene expression, up-regulated Kelch-like-ECH-associated protein 1a (Keap1a) and Keap1b gene expression in fish intestine (P < 0.05). These data indicated that deficient folic acid diet damaged fish intestinal antioxidant capacity partly by regulating Nrf2/Keap1 pathway. Additionally, folic acid deficiency (0.1 mg kg(-1)) down-regulated claudin-b, claudin-c, claudin-3, occludin and zonula occludens 1 gene expression; whereas folic acid deficiency (0.1 mg kg(-1)) up-regulated claudin-12, claudin-15, myosin light chain kinase (MLCK) and p38 mitogen activated protein kinase (p38 MAPK) gene expression in the PI, MI and DI (P < 0.05), suggesting that folic acid deficiency may damage fish intestinal tight junctions associated with the mediation of MLCK and p38 MAPK gene expression. In conclusion, folic acid deficiency (0.1 mg kg(-1)) impaired fish intestinal immunity, antioxidant capacity and tight junctions. PMID- 26968496 TI - The effect of auditory and visual training on the mismatch negativity in schizophrenia. AB - BACKGROUND: The mismatch negativity (MMN) is an electrophysiological index of early auditory attention and has repeatedly been suggested to be associated with cognitive functioning. Despite the frequently reported finding of reduced MMN amplitude in schizophrenia, up to now, studies assessing the impact of perceptual discrimination training aiming to improve MMN measures in schizophrenia patients are scarce. METHOD: In the present study, the effect of auditory training (AUD, n=14) on the MMN was compared to that of visual-spatial training (VIS, n=14) and a treatment-as-usual (TAU, n=14) condition in schizophrenia patients. Training consisted of ten 50-min sessions over two weeks. Assessments took place before and after training and at a two-month follow-up. They comprised clinical measures and MMN recordings to frequency and duration deviant stimuli. RESULTS: There was a significant main effect for type of stimulus deviance with a more negative MMN to frequency than duration deviants. In contrast to our hypotheses, we did not find training specific effects on MMN amplitude or latency. CONCLUSION: The visual, as well as the auditory training program failed to result in treatment related MMN changes in schizophrenia patients when compared to treatment-as-usual as a control condition. In contrast to reports in healthy subjects, the induction of training related MMN changes in schizophrenia patients may constitute a specific challenge and require more extensive training protocols. PMID- 26968497 TI - Exposure to aflatoxin B1 in late gestation alters protein kinase C and apoptotic protein expression in murine placenta. AB - Mycotoxins are chemicals with diverse toxicities that are produced by fungi. Aflatoxin B1 is commonly found in plant food, and is generally regarded as one of the most toxic mycotoxins. In the present study, pregnant ICR mice were given p.o. daily doses of aflatoxin B1 at 0, 0.05, 0.5, 5mg/kg for 4days (from E13.5 to E16.5). Compared to the control group, time of delivery was shortened and low birth weight was induced in mice treated with 0.5 and 5mg aflatoxin B1/kg, respectively. Placental tissue isolated from pregnant mice at E17.5 showed that the mRNA expression of crh was increased in aflatoxin-treated groups. This upregulation might signify premature delivery. Further analysis indicated that Pkc proteins were activated and Bcl-2 was reduced in the placental tissue of the aflatoxin-treated groups. Reduction of the anti-apoptotic proteins, on the other hand, might affect the morphorgenesis and maintenance of the placenta. PMID- 26968498 TI - Comorbidity of personality disorders and attention-deficit hyperactivity disorder in adults. AB - INTRODUCTION: A high comorbidity has been observed among attention-deficit hyperactivity disorder (ADHD) and categorical personality disorders (PD). A study is conducted on the dimensional traits associated with ADHD and PD, in order to determine whether there are any differences. METHODOLOGY: A cross-sectional study was conducted on 78 outpatients attending a Mental Health Clinic in Arganda (Madrid) from January 2013 to June 2015. ADHD diagnosis was evaluated with the CAARS, the CAADID, and the WURS scales, and the PD with the SCID-II-DSM-IV questionnaire. None of the patients were receiving any stimulant or atomoxetine before the study, and all patients signed the informed consent before the study. RESULTS: A high comorbidity was found with all PD clusters, especially with hyperactive and combined type ADHD. Depressive PD was associated with inattentive ADHD. CONCLUSIONS: In spite of using a questionnaire to evaluate PD, some differences can be observed between specific ADHD types and PD. More studies are needed to investigate dimensional personality traits in order to improve the diagnosis and therapeutics goals. PMID- 26968499 TI - Psychometric study of the Required Care Levels for People with Severe Mental Disorder Assessment Scale (ENAR-TMG). AB - INTRODUCTION: People with severe mental disorder have significant difficulties in everyday life that involve the need for continued support. These needs are not easily measurable with the currently available tools. Therefore, a multidimensional scale that assesses the different levels of need for care is proposed, including a study of its psychometric properties. METHOD: One-hundred and thirty-nine patients (58% men) with a severe mental disorder were assessed using the Required Care Levels for People with Severe Mental Disorder Assessment Scale (ENAR-TMG), the Camberwell Assessment of Need scale, and the Health of the Nation Outcome Scales. ENAR-TMG's psychometric features were examined by: a) evaluating 2 sources of validity evidence (evidence based on internal structure and evidence based on relations to other variables), and b) estimating the internal consistency, temporal stability, inter-rater reliability, and sensitivity to change of scores of the ENAR-TMG's subscales. RESULTS: Exploratory factor analyses revealed a one-factor structure for each of the theoretical dimensions of the scale, in which all but one showed a significant and positive correlation with the Camberwell Assessment of Need (range of r: 0.143-0.557) and Health of the Nation Outcome Scales (range of r: 0.241-0.474) scales. ENAR-TMG subscale scores showed acceptable internal consistency (range of ordinal alpha coefficients: 0.682-0.804), excellent test-retest (range of intraclass correlation coefficients: 0.889-0.999) and inter-rater reliabilities (range of intraclass correlation coefficients: 0.926-0.972), and satisfactory sensitivity to treatment-related changes (range of eta2: 0.003-0.103). CONCLUSIONS: The satisfactory psychometric behaviour of the ENAR-TMG makes the scale a promising tool to assess global functioning in people with a severe mental disorder. PMID- 26968500 TI - ASMBS position statement on alcohol use before and after bariatric surgery. PMID- 26968502 TI - Comment on: Rhabdomyolysis after bariatric surgery: a multicenter, prospective study on incidence, risk factors, and therapeutic strategy in a cohort from South Italy. PMID- 26968501 TI - Comparative physiogenomic analyses of weight loss in response to 2 modes of bariatric surgery: demonstration with candidate neuropsychiatric and cardiometabolic genes. AB - BACKGROUND: Surgical weight loss response is variable, with suboptimal outcomes in some patients. We hypothesized that genetic biomarkers may be related to weight change. METHODS: We tested 330 single nucleotide polymorphisms (SNPs) in genes relevant to metabolic regulation in 161 patients whose decrease in body mass index (BMI), 1 year after laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB), was small (lowest quartile response) or large (highest quartile response). LAGB patients whose BMI decreased<=4.7 or>=10.2 units comprised groups I (n = 43) and II (n = 40), respectively. RYGB patients whose BMI decreased<=13.6 or>=19.8 units comprised groups III (n = 39) and IV (n = 39), respectively. Within each surgery, SNPs with large differences in reference allele frequency (z score>2, corresponding to values displaced 2 standard deviations [SD] from the mean for all SNPs) in low versus high quartiles, were identified. We compared reference allele frequencies, within surgical procedure, using the chi(2) test (using Bonferroni correction for multiple testing). RESULTS: The mean percent excess weight losses (+/-SD) corresponding to groups I, II, III, and IV were: 16 (+/-12), 64 (+/-30), 55 (+/ 16), and 75 (+/-17), respectively. SNPs with z score>2 were identified in genes involved in LAGB response, lipid metabolic regulation (APOE, rs439401; APOC4, rs2288911), neural processes (DRD3, rs167771; HTR3 B, rs3758987), and xeno- or endobiotic metabolism (CYP3 A4, rs12333983); and for RYGB response, in lipid transport (SCARB1, rs10846744), folate metabolism (MTHFR, rs2066470), regulation of glycolysis in immune cells (HIF1 A, rs1951795), vitamin K cycling (VKORC1, rs2359612), and xeno- or endobiotic metabolism (CYP3 A4, rs2242480). For LAGB response, APOE SNP frequencies were significantly different. CONCLUSIONS: With further validation, information derived from patient DNA may be useful to predict surgical weight loss outcomes and guide selection of surgical approach. PMID- 26968503 TI - Effectiveness of intragastric balloon for obesity: A systematic review and meta analysis based on randomized control trials. AB - BACKGROUND: Obesity has become a worldwide epidemic, and many methods are currently used to reduce obesity. This systematic review shows the effectiveness of the intragastric balloon (IGB) method compared to the sham/diet (s/d) method. OBJECTIVE: To demonstrate the effectiveness of the IGB method compared to the s/d method. SETTING: Hospital das Clinicas da Universidade de Sao Paulo, Brazil, Public Hospital. METHODS: After searching MEDLINE, Embase, Cochrane, Lilacs, Scopus, and CINAHL, only enrolled randomized control trials comparing IGB/diet with s/d were analyzed. For qualitative analysis, 12 studies were selected, and 9 of these were acceptable for quantitative analysis. RESULTS: The IGB/diet is more effective than s/d when comparing body mass index (BMI) loss with a mean difference of 1.1 kg/m(2) by the Student's t test and 1.41 kg/m(2) by the meta analysis, with significant differences in both. It is also more effective in weight loss (WL), with a mean difference of 2 kg by the Student's t test and 3.55 kg by the meta-analysis. In the qualitative analysis of % excess WL (%EWL), the mean %EWL is 14.0% in favor of the IGB group compared to the s/d group by the Student's t test; however, no significant difference was found between these groups by quantitative analysis. CONCLUSION: Based on randomized control trial data alone, IGB>400 mL is more effective than sham/diet in achieving BMI loss, WL, and %EWL. PMID- 26968505 TI - Hypopharyngeal perforation with mediastinal dissection during orogastric tube placement: a rare complication of bariatric surgery. PMID- 26968506 TI - The association between serum beta-hydroxybutyrate and milk fatty acid profile with special emphasis on conjugated linoleic acid in postpartum Holstein cows. AB - BACKGROUND: Ketogenesis is a secondary metabolic pathway to provide energy to dairy cows during early lactation; however when the production of ketone bodies (acetoacetate, acetone, beta- hydroxybutyrate) is above certain levels a subclinical disorder may appear. The aim of the present study was to investigate the association between serum concentrations of beta- hydroxybutyrate (BHBA) and fatty acid (FA) profile of milk with emphasis in conjugated linoleic acid (CLA) in a population of early lactation Holstein cows. Fifty cows between parity 1 and 5, ranging from 14 to 21 days in milk, were randomly selected from 3 farms of the central area of Chile for determination of serum BHBA concentrations, milk fat content, and milk FA profiles. RESULTS: Cows were divided in low (n = 26) and high (n = 24) BHBA groups considering the median value of the serum concentration of BHBA (0.7 mmol/L) (SEM = 0.094). Mean milk fat % was 3.45% and 3.60% for cows in the low and high BHBA groups, respectively (P = 0.15). Concentrations of several FA were significantly different between both groups. Specifically, mean CLA concentrations were 0.40% (4 +/- 0.03 g/kg) and 0.33% (3.3 +/- 0.03 g/kg) for the low and high BHBA groups, respectively (P = 0.05). CONCLUSIONS: It is concluded that early postpartum cows with serum BHBA > 0.7 mmol/L tended to have higher milk fat % and had significantly lower concentrations of CLA than early postpartum cows with BHBA <= 0.7 mmol/L. PMID- 26968507 TI - A survey of the governance capacity of national public health associations to enhance population health. AB - BACKGROUND: National public health associations (PHAs) are key partners with governments and communities to improve, protect and promote the public's health. Governance and organizational capacity are among the key determinants of a PHA's effectiveness as an advocate for appropriate public health policies and practice. METHODS: During 2014, the World Federation of Public Health Associations (WFPHA) conducted an on-line survey of its 82 PHA members, to identify the state of organizational governance of national public health associations, as well as the factors that influence optimal organizational governance. The survey consisted of 13 questions and focused on the main elements of organizational governance: cultivating accountability; engaging stakeholders; setting shared direction; stewarding resources; and, continuous governance enhancement. Four questions included a qualitative open-ended response for additional comments. The survey data were analyzed using Microsoft Excel. The qualitative data was analyzed using thematic content analysis RESULTS: Responses were received from 62 PHAs, constituting a 75.6 % response rate. The two most important factors that support governance effectiveness were a high degree of integrity and ethical behavior of the PHA's leaders (77 %) and the competence of people serving on the PHA's governing body (76 %). The lack of financial resources was considered as the most important factor that negatively affected organizational governance effectiveness (73 %). The lack of mentoring for future PHA leaders; ineffective or incompetent leadership; lack of understanding about good governance practices; and lack of accurate information for strategic planning were identified as factors influencing PHA governance effectiveness. Critical elements for PHA sustainability included diversity, gender-responsiveness and inclusive governance practices, and strategies to build the future generation of public health leaders. CONCLUSION: National PHA have a responsibility to put into place the practices and infrastructure that enhance organizational governance. This will enhance their ability to be effective advocates for policies and practices that enhance, protect and promote the public's health. The WFPHA has an important role to play in providing the technical assistance and financial resources to assist PHAs in attaining and sustaining a higher level of governance capacity. PMID- 26968509 TI - Thomas James Walker (1835-1916): Surgeon and general practitioner. AB - Thomas James Walker was a surgeon and general practitioner who worked in the city of Peterborough at a time when there were changes and innovations in the practice of medicine. After training in medicine and surgery at Edinburgh University, he qualified in London in 1857. He was a pioneer of laryngoscopy. He played an important role in introducing antiseptic surgery to the Peterborough Infirmary and was instrumental in the development of the operating theatre which opened in 1894. He was a philanthropist and collector of Roman and Saxon artefacts. In 1915, he was recognized as an outstanding member of the Peterborough community when he was offered the Freedom of the City. PMID- 26968508 TI - Differentiation of Mycobacterium tuberculosis complex from non-tubercular mycobacteria by nested multiplex PCR targeting IS6110, MTP40 and 32kD alpha antigen encoding gene fragments. AB - BACKGROUND: Control of the global burden of tuberculosis is obstructed due to lack of simple, rapid and cost effective diagnostic techniques that can be used in resource poor-settings. To facilitate the early diagnosis of TB directly from clinical specimens, we have standardized and validated the use of nested multiplex PCR, targeting gene fragments IS6110, MTP40 and 32kD alpha-antigen encoding genes specific for Mycobacterium tuberculosis complex and non-tubercular mycobacteria (NTM), in comparison to smear microscopy, solid culture and single step multiplex PCR. The results were evaluated in comparison to a composite reference standard (CRS) comprising of microbiological results (smear and culture), clinical, radiological and cytopathological findings, clinical treatment and response to anti-tubercular therapy. METHODS: The nested multiplex PCR (nMPCR) assay was evaluated to test its utility in 600 (535 pulmonary and 65 extra-pulmonary specimens) clinically suspected TB cases. All specimens were processed for smear, culture, single step multiplex PCR and nested multiplex PCR testing. RESULTS: Out of 535 screened pulmonary and 65 extra-pulmonary specimens, 329 (61.5%) and 19 (29.2%) cases were culture positive for M. tuberculosis. Based on CRS, 450 patients had "clinical TB" (definitive-TB, probable-TB and possible TB). Remaining 150 were confirmed "non-TB" cases. For culture, the sensitivity was low, 79.3% for pulmonary and 54.3% for extra-pulmonary cases. The sensitivity and specificity results for nMPCR test were evaluated taken composite reference standard as a gold standard. The sensitivity of the nMPCR assay was 97.1% for pulmonary and 91.4% for extra-pulmonary TB cases with specificity of 100% and 93.3% respectively. CONCLUSION: Nested multiplex PCR using three gene primers is a rapid, reliable and highly sensitive and specific diagnostic technique for the detection and differentiation of M. tuberculosis complex from NTM genome and will be useful in diagnosing paucibacillary samples. Nested multiplex PCR assay was found to be better than single step multiplex PCR for assessing the diagnosis of TB. PMID- 26968510 TI - Agostino Gemelli and the scientific study of courage in the First World War. AB - Agostino Gemelli (1878-1959) is known as the founder of the Catholic University in Italy. Franciscan monk and doctor he had a central role in promoting studies on human behavior, thanks to his solid scientific training as a student of Camillo Golgi at the University of Pavia. His research activities during the years of the First World War involved studying the motivation, courage and psychological adaptation of the soldiers, engaged in trench warfare, laying the foundations of modern studies of behavior and trauma. PMID- 26968511 TI - 'How well, not how much': The life and career of Maksymilian Rutkowski (1867 1947). AB - Maksymilian Rutkowski (1867-1947) was a distinguished graduate of the Jagiellonian University and a pioneer in the early days of surgery in interwar Poland. He was a long-standing leader in both clinical and academic surgery. In addition, he played an important role in the founding of the School for Nurses and Healthcare Workers in Cracow supported by the Rockefeller Foundation. Among his best known surgical techniques, one may list the novel procedure of bladder exstrophy, new techniques of gastroenterostomy and plastic restoration of the oesophagus. Although Rutkowski's reputation as a medical figure is well established within Polish medical history, his achievements are hardly recognized by international scholars. Thus, in the absence of adequate historical information on this eminent surgeon, we have researched the main facts about his life and seminal contribution to Polish and international surgery. PMID- 26968512 TI - Doreen Norton OBE, MSc, SRN, FRCN (1922-2007): Pioneer who revolutionised pressure sore management and geriatric nursing to international acclaim. AB - Doreen Norton was a delightful, widely respected nurse who devoted her life to improving the care of elderly people. She researched the neglected problem of pressure sores, revolutionised their nursing care, and thus achieved international fame. Her Pressure Sore Scale was established as a management tool and is still used today. She was a key member of the design team that produced the 'King's Fund Bed', researched equipment required on geriatric wards, assessed all geriatric long stay units in Scotland and established research as a valuable nursing tool within her profession and health authorities. She lectured extensively and her publications attracted worldwide acclamation. After her retirement, she was subsequently appointed to the world's first Chair of Gerontological Nursing in Cleveland, Ohio. PMID- 26968514 TI - Bilateral sequential peripheral vestibulopathy. PMID- 26968513 TI - Systemic right-to-left shunts, ischemic brain lesions, and persistent migraine activity. AB - OBJECTIVE: To assess whether migraine in the general population is associated with increased risk of systemic right-to-left shunts (RLS) and whether RLS are associated with increased prevalence of brain infarcts and persistent recurrence of migraine attacks at older age. METHODS: Brain MRI and transcranial Doppler with air contrast in 166 unselected migraineurs (mean age +/- SD 56 +/- 7.7 years; 70% women; n = 96 migraine with aura) and 69 controls (mean age +/- SD 55 +/- 7.6 years; 65% women) from the general population. RESULTS: Participants with migraine with aura more frequently had Valsalva-induced RLS (60%), in particular large-sized, compared to controls (42%; odds ratio [OR] 2.1; 95% confidence interval [CI] 1.1-3.9; p = 0.02) and participants with migraine without aura (40%; OR 2.3; 95% CI 1.2-4.3; p = 0.01). They also more frequently had spontaneous RLS (35%) than participants with migraine without aura (17%; OR 2.6; 95% CI 1.3-5.6; p = 0.01) but not compared to controls (26%; OR 1.6; 95% CI 0.8 3.1; p = 0.2). Participants with migraine with aura and spontaneous RLS more frequently had persistent migraine activity (85%) than participants with migraine without spontaneous RLS (63%; OR 3.4; 95% CI 1.2-10.1; p = 0.03). Nine percent of participants with RLS had silent posterior circulation infarcts compared to 3% of participants without RLS (OR 2.8; 95% CI 0.9-9.3; p = 0.08), independent of migraine status. RLS were not associated with white matter lesions. CONCLUSIONS: RLS are more prevalent in migraineurs with aura but do not explain the increased prevalence of silent posterior circulation infarcts or white matter lesions in migraineurs. Spontaneous RLS are associated with persistent migraine. PMID- 26968516 TI - Supernumerary phantom limbs in ICU patients with acute inflammatory demyelinating polyneuropathy. AB - OBJECTIVE: To explore the previously undescribed phenomenon of phantom limb generation in patients with severe acute inflammatory demyelinating polyradiculoneuropathy (AIDP). METHODS: Between April 2011 and January 2014, we encountered 3 patients with AIDP in our intensive care unit who experienced features of self-limited supernumerary phantom limbs (SPLs) during their course. RESULTS: The following case series describes the phenomenon of SPLs in AIDP. CONCLUSIONS: This report aims to raise awareness of the possibility of SPLs in the course of AIDP. The pathophysiology and management strategies for this clinical phenomenon are unknown. PMID- 26968517 TI - Spatio-temporal genetic variation of the biting midge vector species Culicoides imicola (Ceratopogonidae) Kieffer in France. AB - BACKGROUND: Introduction of vector species into new areas represents a main driver for the emergence and worldwide spread of vector-borne diseases. This poses a substantial threat to livestock economies and public health. Culicoides imicola Kieffer, a major vector species of economically important animal viruses, is described with an apparent range expansion in Europe where it has been recorded in south-eastern continental France, its known northern distribution edge. This questioned on further C. imicola population extension and establishment into new territories. Studying the spatio-temporal genetic variation of expanding populations can provide valuable information for the design of reliable models of future spread. METHODS: Entomological surveys and population genetic approaches were used to assess the spatio-temporal population dynamics of C. imicola in France. Entomological surveys (2-3 consecutive years) were used to evaluate population abundances and local spread in continental France (28 sites in the Var department) and in Corsica (4 sites). We also genotyped at nine microsatellite loci insects from 3 locations in the Var department over 3 years (2008, 2010 and 2012) and from 6 locations in Corsica over 4 years (2002, 2008, 2010 and 2012). RESULTS: Entomological surveys confirmed the establishment of C. imicola populations in Var department, but indicated low abundances and no apparent expansion there within the studied period. Higher population abundances were recorded in Corsica. Our genetic data suggested the absence of spatio-temporal genetic changes within each region but a significant increase of the genetic differentiation between Corsican and Var populations through time. The lack of intra-region population structure may result from strong gene flow among populations. We discussed the observed temporal variation between Corsica and Var as being the result of genetic drift following introduction, and/or the genetic characteristics of populations at their range edge. CONCLUSIONS: Our results suggest that local range expansion of C. imicola in continental France may be slowed by the low population abundances and unsuitable climatic and environmental conditions. PMID- 26968519 TI - A mixed methods approach to developing and evaluating oncology trainee education around minimization of adverse events and improved patient quality and safety. AB - BACKGROUND: Adverse events are a significant quality and safety issue in the hospital setting due to their direct impact on patients. Additionally, such events are often handled by junior doctors due to their direct involvement with patients. As such, it is important for health care organizations to prioritize education and training for junior doctors on identifying adverse events and handling them when they occur. The Cancer Cup Challenge is an educational program focuses on quality improvement and adverse event awareness targeting for junior oncology doctors across three international sites. METHODS: A mixed methodology was used to develop and evaluate the program. The Qstream spaced learning platform was used to disseminate information to participants, as it has been demonstrated to impact on both knowledge and behavior. Eight short case based scenarios with expert feedback were developed by a multidisciplinary advisory committee containing representatives from the international sites. At the conclusion of the course impact on participant knowledge was evaluated using analysis of the metrics collected by the Qstream platform. Additionally, an online survey and semi-structured interviews were used to evaluate engagement and perceived value by participants. RESULTS: A total of 35 junior doctors registered to undertake the Qstream program, with 31 (88.57 %) successfully completing it. Analysis of the Qstream metrics revealed 76.57 % of cases were answered correctly on first attempt. The post-program survey received 17 responses, with 76.47 % indicating cases for the course were interesting and 82.35 % feeling cases were relevant. Finally, 14 participants consented to participate in semi-structured interviews about the program, with feedback towards the course being generally very positive. CONCLUSIONS: Our study demonstrates that an online game is well accepted by junior doctors as a method to increase their quality improvement awareness. Developing effective and sustainable training for doctors is important to ensure positive patient outcomes are maintained in the hospital setting. This is particularly important for junior doctors as they are working closely with patients and learning skills and behaviors, which will influence their practice throughout their careers. PMID- 26968518 TI - Genome-wide analysis of MATE transporters and expression patterns of a subgroup of MATE genes in response to aluminum toxicity in soybean. AB - BACKGROUND: Multidrug and toxic compound extrusion (MATE) family is an important group of the multidrug efflux transporters that extrude organic compounds, transporting a broad range of substrates such as organic acids, plant hormones and secondary metabolites. However, genome-wide analysis of MATE family in plant species is limited and no such studies have been reported in soybean. RESULTS: A total of 117 genes encoding MATE transporters were identified from the whole genome sequence of soybean (Glycine max), which were denominated as GmMATE1 - GmMATE117. These 117 GmMATE genes were unevenly localized on soybean chromosomes 1 to 20, with both tandem and segmental duplication events detected, and most genes showed tissue-specific expression patterns. Soybean MATE family could be classified into four subfamilies comprising ten smaller subgroups, with diverse potential functions such as transport and accumulation of flavonoids or alkaloids, extrusion of plant-derived or xenobiotic compounds, regulation of disease resistance, and response to abiotic stresses. Eight soybean MATE transporters clustered together with the previously reported MATE proteins related to aluminum (Al) detoxification and iron translocation were further analyzed. Seven stress-responsive cis-elements such as ABRE, ARE, HSE, LTR, MBS, as well as a cis-element of ART1 (Al resistance transcription factor 1), GGNVS, were identified in the upstream region of these eight GmMATE genes. Differential gene expression analysis of these eight GmMATE genes in response to Al stress helps us identify GmMATE75 as the candidate gene for Al tolerance in soybean, whose relative transcript abundance increased at 6, 12 and 24 h after Al treatment, with more fold changes in Al-tolerant than Al-sensitive cultivar, which is consistent with previously reported Al-tolerance related MATE genes. CONCLUSIONS: A total of 117 MATE transporters were identified in soybean and their potential functions were proposed by phylogenetic analysis with known plant MATE transporters. The cis-elements and expression patterns of eight soybean MATE genes related to Al detoxification/iron translocation were analyzed, and GmMATE75 was identified as a candidate gene for Al tolerance in soybean. This study provides a first insight on soybean MATE family and their potential roles in soybean response to abiotic stresses especially Al toxicity. PMID- 26968520 TI - Collaborative approach to Optimise MEdication use for Older people in Nursing homes (COME-ON): study protocol of a cluster controlled trial. AB - BACKGROUND: Ageing has become a worldwide reality and presents new challenges for the health-care system. Research has shown that potentially inappropriate prescribing, both potentially inappropriate medications and potentially prescribing omissions, is highly prevalent in older people, especially in the nursing home setting. The presence of potentially inappropriate medications/potentially prescribing omissions is associated with adverse drug events, hospitalisations, mortality and health-care costs. The Collaborative approach to Optimise MEdication use for Older people in Nursing homes (COME-ON) study aims to evaluate the effect of a complex, multifaceted intervention, including interdisciplinary case conferences, on the appropriateness of prescribing of medicines for older people in Belgian nursing homes. METHODS/DESIGN: A multicentre cluster-controlled trial is set up in 63 Belgian nursing homes (30 intervention; 33 control). In each of these nursing homes, 35 residents (>=65 years) are selected for participation. The complex, multifaceted intervention comprises (i) health-care professional education and training, (ii) local concertation (discussion on the appropriate use of at least one medication class at the level of the nursing home) and (iii) repeated interdisciplinary case conferences between general practitioner, nurse and pharmacist to perform medication review for each included nursing home resident. The control group works as usual. The study period lasts 15 months. The primary outcome measures relate to the appropriateness of prescribing and are defined as (1) among residents who had at least one potentially inappropriate medication/potentially prescribing omission at baseline, the proportion of them for whom there is a decrease of at least one of these potentially inappropriate medications/potentially prescribing omissions at the end of study, and (2) among all residents, the proportion of them for whom at least one new potentially inappropriate medication/potentially prescribing omission is present at the end of the study, compared to baseline. The secondary outcome measures include individual components of appropriateness of prescribing, medication use, outcomes of the case conferences, clinical outcomes and costs. A process evaluation (focusing on implementation, causal mechanisms and contextual factors) will be conducted alongside the study. DISCUSSION: The COME-ON study will contribute to a growing body of knowledge concerning the effect of complex interventions on the use of medicines in the nursing home setting, and on factors influencing their effect. The results will inform policymakers on strategies to implement in the near future. TRIAL REGISTRATION: Current Controlled Trials ISRCTN66138978. PMID- 26968515 TI - Amyloid negativity in patients with clinically diagnosed Alzheimer disease and MCI. AB - OBJECTIVE: To examine the clinical and biomarker characteristics of patients with amyloid-negative Alzheimer disease (AD) and mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a prospective cohort study. METHODS: We first investigated the reliability of florbetapir- PET in patients with AD and patients with MCI using CSF-Abeta1-42 as a comparison amyloid measurement. We then compared florbetapir- vs florbetapir+ patients with respect to several AD-specific biomarkers, baseline and longitudinal cognitive measurements, and demographic and clinician report data. RESULTS: Florbetapir and CSF-Abeta1-42 +/- status agreed for 98% of ADs (89% of MCIs), indicating that most florbetapir- scans were a reliable representation of amyloid status. Florbetapir- AD (n = 27/177; 15%) and MCI (n = 74/217, 34%) were more likely to be APOE4-negative (MCI 83%, AD 96%) than their florbetapir+ counterparts (MCI 30%, AD 24%). Florbetapir- patients also had less AD-specific hypometabolism, lower CSF p-tau and t-tau, and better longitudinal cognitive performance, and were more likely to be taking medication for depression. In MCI only, florbetapir participants had less hippocampal atrophy and hypometabolism and lower functional activity questionnaire scores compared to florbetapir+ participants. CONCLUSIONS: Overall, image analysis problems do not appear to be a primary explanation of amyloid negativity. Florbetapir- ADNI patients have a variety of clinical and biomarker features that differ from their florbetapir+ counterparts, suggesting that one or more non-AD etiologies (which may include vascular disease and depression) account for their AD-like phenotype. PMID- 26968521 TI - Liver function predicts survival in patients undergoing extracorporeal membrane oxygenation following cardiovascular surgery. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) represents a valuable and rapidly evolving therapeutic option in patients with severe heart or lung failure following cardiovascular surgery. However, despite significant advances in ECMO techniques and management, prognosis remains poor and accurate risk stratification challenging. We therefore evaluated the predictive value of liver function variables on all-cause mortality in patients undergoing venoarterial ECMO support after cardiovascular surgery. METHODS: We included into our single center registry a total of 240 patients undergoing venoarterial ECMO therapy following cardiovascular surgery at a university-affiliated tertiary care center. RESULTS: The median follow-up was 37 months (interquartile range 19-67 months), and a total of 156 patients (65%) died. Alkaline phosphatase and total bilirubin were the strongest predictors for 30-day mortality, with adjusted hazard ratios (HRs) per 1-standard deviation increase of 1.36 (95% confidence interval [CI] 1.10-1.68; P = 0.004) and 1.22 (95% CI 1.07-1.40; P = 0.004), respectively. The observed associations persisted for long-term mortality, with adjusted HRs of 1.27 (95% CI 1.03-1.56; P = 0.023) for alkaline phosphatase and 1.22 (95% CI 1.07 1.39; P = 0.003) for total bilirubin. CONCLUSIONS: The present study demonstrates that elevated values of alkaline phosphatase and total bilirubin are sensitive parameters for predicting the short-term and long-term outcomes of ECMO patients. PMID- 26968523 TI - Functional morphology of gill ventilation of the goosefish, Lophius americanus (Lophiiformes: Lophiidae). AB - The goosefish, Lophius americanus, is a dorso-ventrally compressed marine fish that spends most of its life sitting on the substrate waiting to ambush prey. Species in the genus Lophius have some of the slowest ventilatory cycles recorded in fishes, with a typical cycle lasting more than 90s. They have a large gill chamber, supported by long branchiostegal rays and ending in a siphon-like gill opening positioned underneath and behind the base of the pectoral fin. Our goals were to characterize the kinematics of gill ventilation in L. americanus relative to those of more typical ray-finned fishes, address previous assertions about ventilation in this genus, and describe the anatomy of the gill opening. We found that phase 1 of ventilation (during which both the buccal and gill chamber are expanding) is greatly increased in duration relative to that of typical ray finned fishes (ranging from 62 to 127s), and during this phase, the branchiostegal rays are slowly expanding. This slow expansion is almost visually imperceptible, especially from a dorsal view. Despite this unusually long phase 1, the pattern of skeletal movements follows that of a typical actinopterygian, refuting previous assertions that Lophius does not use its jaws, suspensorium, and operculum during ventilation. When individuals were disturbed from the sediment, they tended to breathe more rapidly by decreasing the duration of phase 1 (to 18-30s). Dissections of the gill opening revealed a previously undocumented dorsal extension of the adductor hyohyoideus muscle, which passes from between the branchiostegal rays, through the ventro-medial wall of the gill opening, and to the dorsal midline of the body. This morphology of the adductor hyohyoideus shares similarities with that of many Tetraodontiformes, and we suggest that it may be a synapomorphy for Lophiiformes+Tetraodontiformes. The specialized anatomy and function of the gill chamber of Lophius represents extreme modifications that provide insight into the potential limits of the actinopterygian gill ventilatory system. PMID- 26968522 TI - Biologic agents in juvenile spondyloarthropathies. AB - The juvenile spondyloarthropathies (JSpA) are a group of related rheumatic diseases characterized by involvement of peripheral large joints, axial joints, and entheses (enthesitis) that begin in the early years of life (prior to 16(th) birthday).The nomenclature and concept of spondyloarthropathies has changed during the last few decades. Although there is not any specific classification of JSpA, diseases under the spondyloarthropathy nomenclature umbrella in the younger patients include: the seronegative enthesitis and arthropathy (SEA) syndrome, juvenile ankylosing spondylitis, reactive arthritis, and inflammatory bowel disease-associated arthritis. Moreover, the ILAR criteria for Juvenile Idiopathic Arthritis includes two categories closely related to spondyloarthritis: Enthesitis-related arthritis and psoriatic arthritis.We review the pathophysiology and the use of biological agents in JSpA. JSpA are idiopathic inflammatory diseases driven by an altered balance in the proinflammatory cytokines. There is ample evidence on the role of tumor necrosis factor (TNF) and interleukin-17 in the physiopathology of these entities. Several non-biologic and biologic agents have been used with conflicting results in the treatment of these complex diseases. The efficacy and safety of anti-TNF agents, such as etanercept, infliximab and adalimumab, have been analysed in controlled and uncontrolled trials, usually showing satisfactory outcomes. Other biologic agents, such as abatacept, tocilizumab and rituximab, have been insufficiently studied and their role in the therapy of SpA is uncertain. Interleukin-17-blocking agents are promising alternatives for the treatment of JSpA patients in the near future. Recommendations for the treatment of patients with JSpA have recently been proposed and are discussed in the present review. PMID- 26968524 TI - Surgical treatment of renal-cell carcinoma in elderly people. AB - OBJECTIVE: To describe the oncological characteristics and evolution of patients 65 years or older who underwent surgery for renal-cell carcinoma (RCC). METHODS: We reviewed our prospectively maintained database of patients with RCC treated surgically. Those >= 65 years old were selected. We analyzed clinical and pathological characteristics as well as oncological and functional outcomes. Overall survival (OS) was estimated with the Kaplan-Meier method. Multivariate Cox-proportional hazards model was used to determine predictors of OS. RESULTS: A total of 156 elderly patients with mean age 72.0+/-5.5 years (range 65-92) and median follow-up of 33 months were included. Surgical approach was open radical nephrectomy in 114 (73.5%), laparoscopic radical nephrectomy in 13 (8.4%), open partial nephrectomy in 23 (14.2%) and laparoscopic partial nephrectomy in 6 (3.9%). Pathological stage was: Stage I, 71 (45.5%); Stage II, 27 (17.3%); Stage III, 48 (30.8%); and Stage IV, 10 (6.4%). Lastly, 51 (32.6%) patients died, 22 (43.1%) from cancer. The 5-year OS according to pathological stage was 77.6%, 71.9%, 45.1% and 11.7% for stage I, II, III and IV, respectively (P<.001). On multivariate analysis, pathological stage independently predicted OS (HR 1.96, 95% CI [1.36-2.84], P=.0003). CONCLUSIONS: The surgical management of RCC appears to be safe in properly selected patients 65 years or older. Pathological stage predicts survival in this population. PMID- 26968526 TI - Urgent surgery after emergency presentation for colorectal cancer has no impact on overall and disease-free survival: a propensity score analysis. AB - BACKGROUND: It remains a matter of debate whether colorectal cancer resection in an emergency setting negatively impacts on survival. Our objective was therefore to assess the impact of urgent versus elective operation on overall and disease free survival in patients undergoing resection for colorectal cancer by using propensity score adjusted analysis. METHODS: In a single-center study patients operated for colorectal cancer between 1989 and 2013 were identified from a prospectively maintained database. Median follow-up was 44 months. Patients with neoadjuvant treatment were excluded. The impact of urgent operation on overall and disease-free survival was assessed using both Cox regression and propensity score analyses. RESULTS: Of 747 patients with colorectal cancer, 84 (11%) had urgent and 663 elective cancer resection. The propensity score revealed strongly biased patient characteristics (0.22 +/- 0.16 vs. 0.10 +/- 0.09; P < 0.001). In unadjusted analysis urgent operation was associated with a 35% increased risk of overall mortality (hazard ratio(HR) of death = 1.35, 95% confidence interval(CI):1.02-1.78, P = 0.045). In risk-adjusted Cox regression analysis urgent operation was not associated with poor overall (HR = 1.08, 95%CI:0.79 1.48; P = 0.629) or disease-free survival (HR = 1.02, 95%CI:0.76-1.38; P = 0.877). Similarly in propensity score analysis urgent operation did not influence overall (HR = 0.98, 95% CI:0.74-1.29), P = 0.872) and disease-free survival (HR = 0.89, 95%CI:0.68 to 1.16, P = 0.387). CONCLUSIONS: This study provides evidence that worse oncologic outcomes after urgent operation for colorectal cancer are caused by clinical circumstances and not due to the urgent operation itself. Urgent operation is not a risk factor for colorectal cancer resection. PMID- 26968525 TI - Can one size fit all? Approach to bacterial vaginosis in sub-Saharan Africa. AB - Bacterial vaginosis (BV) is the most common vaginal disorder affecting women of reproductive age and is associated with increased risk of sexually transmitted infections such as human immunodeficiency syndrome (HIV-1). Sub-Saharan Africa has the highest BV and HIV-1 burden and yet very few studies have focused on understanding the aetiology of BV and its association with HIV in this region. It has been suggested that we need to accurately diagnose and treat BV to lower the risk of HIV infection globally. However, effective diagnosis requires knowledge of what constitutes a "healthy" cervicovaginal microbiome and current studies indicate that Lactobacillus crispatus might not be the only commensal protective against BV: healthy women from different countries and ethnicities harbour alternative commensals. Microbiotas associated with BV have also shown global variation, further complicating effective diagnosis via culture-based assays as some species are difficult to grow. Antibiotics and probiotics have been suggested to be key in controlling BV infection, but the efficacy of this treatment might rely on reconstituting endogenous commensals while targeting a specific species of BV-associated bacteria (BVAB). Alternatively, therapy could inhibit essential BV bacterial growth factors e.g. sialidases or provide anti microbial compounds e.g. lactic acid associated with a healthy cervicovaginal microbiome. But without global investigation into the mechanism of BV pathogenesis and its association with HIV, selection of such compounds could be limited to Caucasian women from certain regions. To confirm this suggestion and guide future therapy we require standardised diagnostic assays and research methodologies. This review will focus on research papers that describe the global variation of BV aetiology and how this influences the identification of determinants of BV pathogenesis and potential probiotic and antimicrobial therapy. PMID- 26968527 TI - Identification of risk factors influencing Clostridium difficile prevalence in middle-size dairy farms. AB - Farm animals have been suggested to play an important role in the epidemiology of Clostridium difficile infection (CDI) in the community. The purpose of this study was to evaluate risk factors associated with C. difficile dissemination in family dairy farms, which are the most common farming model in the European Union. Environmental samples and fecal samples from cows and calves were collected repeatedly over a 1 year period on 20 mid-size family dairy farms. Clostridium difficile was detected in cattle feces on all farms using qPCR. The average prevalence between farms was 10% (0-44.4%) and 35.7% (3.7-66.7%) in cows and calves, respectively. Bacterial culture yielded 103 C. difficile isolates from cattle and 61 from the environment. Most C. difficile isolates were PCR-ribotype 033. A univariate mixed effect model analysis of risk factors associated dietary changes with increasing C. difficile prevalence in cows (P = 0.0004); and dietary changes (P = 0.004), breeding Simmental cattle (P = 0.001), mastitis (P = 0.003) and antibiotic treatment (P = 0.003) in calves. Multivariate analysis of risk factors found that dietary changes in cows (P = 0.0001) and calves (P = 0.002) increase C. difficile prevalence; mastitis was identified as a risk factor in calves (P = 0.001). This study shows that C. difficile is common on dairy farms and that shedding is more influenced by farm management than environmental factors. Based on molecular typing of C. difficile isolates, it could also be concluded that family dairy farms are currently not contributing to increased CDI incidence. PMID- 26968528 TI - Mental health among younger and older caregivers of dementia patients. AB - AIM: Caregiver burden in dementia is an important issue, but few studies have examined the mental health of younger and older family caregivers by comparing them with age- and gender-matched community residents. We aimed to compare the mental health of dementia caregivers with that of community residents and to clarify factors related to mental health problems in younger and older caregivers. METHODS: We studied 104 dementia caregivers; 46 were younger (<65 years) and 58 were older (>=65 years). A total of 104 community residents who were matched for age and gender were selected. We compared depression (Center for Epidemiologic Studies Depression Scale for younger participants; Geriatric Depression Scale for older participants), health-related quality of life (QOL) short-form health survey (SF-8), sleep problems, and suicidal ideation between the caregivers and community residents by age. Behavioural and psychological symptoms of dementia, activities of daily living (ADL), and instrumental ADL were assessed among patients with dementia using the Neuropsychiatric Inventory, Physical Self-Maintenance Scale, and Lawton Instrumental ADL Scale, respectively. RESULTS: According to SF-8 results, both younger and older caregivers had significantly worse mental QOL than community residents (younger caregivers: 46.3 vs community residents: 49.7, P = 0.017; older caregivers: 48.2 vs community residents: 51.1, P = 0.024) but were not more depressive. Sleep problems were significantly more frequent in younger caregivers (39.1%) than in community residents (17.0%) (P = 0.017). Multiple regression analysis revealed that caregivers' deteriorated mental QOL was associated with patients' behavioural and psychological symptoms of dementia in younger caregivers and with dementia patients' instrumental ADL and female gender in older caregivers. CONCLUSIONS: Dementia caregivers had a lower mental QOL than community residents. To maintain caregivers' mental QOL, it is necessary to provide younger caregivers with skills or professional interventions for dealing with behavioural and psychological symptoms of dementia, and older caregivers must be offered adequate care support. PMID- 26968529 TI - Low-Income Children, Adolescents, and Caregivers Facing Respiratory Problems: Support Needs and Preferences. AB - Burdens of poverty are often compounded by respiratory problems. This study aimed to identify the support needs and intervention preferences for low-income families facing this challenge. DESIGN AND METHODS: Interviews were conducted in two Canadian provinces with low-income children/adolescents (n=32) diagnosed with respiratory health problems and their parents or family caregiver (n=37). RESULTS: These vulnerable children and parents described non-supportive interactions with some health service providers and inadequate information. They reported isolation and support deficits, exacerbated by limited resources and health restrictions. Children/adolescents felt isolated and excluded and wanted to connect with peers. Group or dyadic level support, delivered by peers and health professionals, was desired. The importance of logistics to enhance accessibility and appeal of group or dyadic support interventions was clearly identified. CONCLUSIONS: The findings of this study reveal that low-income children and their families encounter challenges to accessing support and to utilizing support resources. PRACTICE IMPLICATIONS: Partnerships with low-income children/adolescents and family caregivers in provision of education and social support can combat isolation and ignorance. Reducing inequities for this high risk population could be achieved by providing support from experienced peers, in combination with health professional guidance, and knowledge about pulmonary health. PMID- 26968530 TI - Bartonella henselae transmission by blood transfusion in mice. AB - BACKGROUND: Bartonella spp. are neglected fastidious Gram-negative bacilli. We isolated Bartonella henselae from 1.2% of 500 studied blood donors and demonstrated that the bacteria remain viable in red blood cell units after 35 days of experimental infection. Now, we aim to evaluate the possibility of B. henselae transmission by blood transfusion in a mouse model. STUDY DESIGN AND METHODS: Eight BALB/c mice were intraperitoneal inoculated with a 30 uL of suspension with 10(4) CFU/mL of B. henselae and a second group of eight mice were inoculated with saline solution and used as control. After 96 hours of inoculation, the animals were euthanized. We collected blood and tissue samples from skin, liver, and spleen. Thirty microliters of blood from four Bartonella inoculated animals were transfused into a new group (n = 4). Another group received blood from the control animals. B. henselae infection was investigated by conventional and nested polymerase chain reaction (PCR). RESULTS: Blood samples from all 24 mice were negative by molecular tests though half of the tissue samples were positive by nested PCR in the intraperitoneal Bartonella investigated animals. Tissues from two of the four mice that received blood transfusions from Bartonella-inoculated animals were also nested PCR positives. CONCLUSIONS: Transmission of B. henselae by transfusion is possible in mice even when donor animals have undetectable bloodstream infection. The impact of human Bartonella sp. transmission through blood transfusion recipients must be evaluated. PMID- 26968532 TI - RNA-sequencing analysis of core binding factor AML identifies recurrent ZBTB7A mutations and defines RUNX1-CBFA2T3 fusion signature. PMID- 26968531 TI - Bioenergetics and redox adaptations of astrocytes to neuronal activity. AB - Neuronal activity is a high-energy demanding process recruiting all neural cells that adapt their metabolism to sustain the energy and redox balance of neurons. During neurotransmission, synaptic cleft glutamate activates its receptors in neurons and in astrocytes, before being taken up by astrocytes through energy costly transporters. In astrocytes, the energy requirement for glutamate influx is likely to be met by glycolysis. To enable this, astrocytes are constitutively glycolytic, robustly expressing 6-phosphofructo-2-kinase/fructose-2,6 bisphosphatase-3 (PFKFB3), an enzyme that is negligibly present in neurons by continuous degradation because of the ubiquitin-proteasome pathway via anaphase promoting complex/cyclosome (APC)-Cdh1. Additional factors contributing to the glycolytic frame of astrocytes may include 5'-AMP-activated protein kinase (AMPK), hypoxia-inducible factor-1 (HIF-1), pyruvate kinase muscle isoform-2 (PKM2), pyruvate dehydrogenase kinase-4 (PDK4), lactate dehydrogenase-B, or monocarboxylate transporter-4 (MCT4). Neurotransmission-associated messengers, such as nitric oxide or ammonium, stimulate lactate release from astrocytes. Astrocyte-derived glycolytic lactate thus sustains the energy needs of neurons, which in contrast to astrocytes mainly rely on oxidative phosphorylation. Neuronal activity unavoidably triggers reactive oxygen species, but the antioxidant defense of neurons is weak; hence, they use glucose for oxidation through the pentose-phosphate pathway to preserve the redox status. Furthermore, neural activity is coupled with erythroid-derived erythroid-derived 2-like 2 (Nrf2) mediated transcriptional activation of antioxidant genes in astrocytes, which boost the de novo glutathione biosynthesis in neighbor neurons. Thus, the bioenergetics and redox programs of astrocytes are adapted to sustain neuronal activity and survival. Developing therapeutic strategies to interfere with these pathways may be useful to combat neurological diseases. Our current knowledge on brain's management of bioenergetics and redox requirements associated with neural activity is herein revisited. The astrocyte-neuronal lactate shuttle (ANLS) explains the energy needs of neurotransmission. Furthermore, neurotransmission unavoidably triggers increased mitochondrial reactive oxygen species in neurons. By coupling glutamatergic activity with transcriptional activation of antioxidant genes, astrocytes provide neurons with neuroprotective glutathione through an astrocyte-neuronal glutathione shuttle (ANGS). This article is part of the 60th Anniversary special issue. PMID- 26968534 TI - Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL. AB - Although agents targeting B-cell receptor signaling have provided practice changing results in relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), they require prolonged administration and provide incomplete responses. Given synergistic preclinical activity with phosphatidylinositol 3 kinase delta and spleen tyrosine kinase inhibition, this phase 2 study evaluated the safety and efficacy of the combination of idelalisib and entospletinib. Eligible patients with relapsed or refractory CLL or NHL underwent intrapatient dose escalation with each agent. With a median treatment exposure of 10 weeks, 60% and 36% of patients with CLL or follicular lymphoma, respectively, achieved objective responses. However, the study was terminated early because of treatment emergent pneumonitis in 18% of patients (severe in 11 of 12 cases). Although most patients recovered with supportive measures and systemic steroids, 2 fatalities occurred and were attributed to treatment-emergent pneumonitis. Increases of interferon-gamma and interleukins 6, 7, and 8 occurred over time in patients who developed pneumonitis. Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/biomarker monitoring. These investigations should also prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01796470. PMID- 26968533 TI - How I treat respiratory viral infections in the setting of intensive chemotherapy or hematopoietic cell transplantation. AB - The widespread use of multiplex molecular diagnostics has led to a significant increase in the detection of respiratory viruses in patients undergoing cytotoxic chemotherapy and hematopoietic cell transplantation (HCT). Respiratory viruses initially infect the upper respiratory tract and then progress to lower respiratory tract disease in a subset of patients. Lower respiratory tract disease can manifest itself as airflow obstruction or viral pneumonia, which can be fatal. Infection in HCT candidates may require delay of transplantation. The risk of progression differs between viruses and immunosuppressive regimens. Risk factors for progression and severity scores have been described, which may allow targeting treatment to high-risk patients. Ribavirin is the only antiviral treatment option for noninfluenza respiratory viruses; however, high-quality data demonstrating its efficacy and relative advantages of the aerosolized versus oral form are lacking. There are significant unmet needs, including data defining the virologic characteristics and clinical significance of human rhinoviruses, human coronaviruses, human metapneumovirus, and human bocavirus, as well as the need for new treatment and preventative options. PMID- 26968535 TI - Development and validation of a rapid, aldehyde dehydrogenase bright-based cord blood potency assay. AB - Banked, unrelated umbilical cord blood provides access to hematopoietic stem cell transplantation for patients lacking matched bone marrow donors, yet 10% to 15% of patients experience graft failure or delayed engraftment. This may be due, at least in part, to inadequate potency of the selected cord blood unit (CBU). CBU potency is typically assessed before cryopreservation, neglecting changes in potency occurring during freezing and thawing. Colony-forming units (CFUs) have been previously shown to predict CBU potency, defined as the ability to engraft in patients by day 42 posttransplant. However, the CFU assay is difficult to standardize and requires 2 weeks to perform. Consequently, we developed a rapid multiparameter flow cytometric CBU potency assay that enumerates cells expressing high levels of the enzyme aldehyde dehydrogenase (ALDH bright [ALDH(br)]), along with viable CD45(+) or CD34(+) cell content. These measurements are made on a segment that was attached to a cryopreserved CBU. We validated the assay with prespecified criteria testing accuracy, specificity, repeatability, intermediate precision, and linearity. We then prospectively examined the correlations among ALDH(br), CD34(+), and CFU content of 3908 segments over a 5-year period. ALDH(br) (r = 0.78; 95% confidence interval [CI], 0.76-0.79), but not CD34(+) (r = 0.25; 95% CI, 0.22-0.28), was strongly correlated with CFU content as well as ALDH(br) content of the CBU. These results suggest that the ALDH(br) segment assay (based on unit characteristics measured before release) is a reliable assessment of potency that allows rapid selection and release of CBUs from the cord blood bank to the transplant center for transplantation. PMID- 26968536 TI - Elevated D-dimer levels in African Americans with sickle cell trait. PMID- 26968537 TI - Epigallocatechin gallate inhibits hepatitis B virus via farnesoid X receptor alpha. AB - Plants possess various natural antiviral properties. Epigallocatechin-3-gallate (EGCG), a major component of green tea, inhibits a variety of viruses. However, the clinical application of EGCG is currently hindered by a scarcity of information on its molecular mechanism of action. In the present study, we examined the anti-HBV (hepatitis B virus) effects of catechins from green tea at the transcriptional and antigen-expression levels, as well as the associated molecular mechanisms, because HBV-associated liver diseases have become a key public health issue due to their serious impact on human physical and mental health. By using fluorescence quenching and affinity binding, we demonstrated that EGCG is an important transcriptional regulator of the HBV genome, which it achieves by interacting with farnesoid X receptor alpha (FXRalpha). Luciferase assay showed that EGCG effectively inhibited the transcription of the HBV promoter dose-dependently when expression plasmids of FXRalpha and retinoid X receptor alpha (RXRalpha) were co-transfected into HEK293 cells. These results indicate that the downregulation of the HBV antigen and the decrease in the transcriptional activation of the HBV EnhII/core promoter by FXRalpha/RXRalpha are mainly due to the interaction between EGCG and FXRalpha. Therefore, EGCG, an antagonist of FXRalpha in liver cells, has the potential to be employed as an effective anti-HBV agent. PMID- 26968539 TI - When is pneumonia not pneumonia: a clinicopathologic study of the utility of lung tissue biopsies in determining the suitability of cadaveric tissue for donation. AB - Healthcare-associated pneumonia (HCAP) represents a major diagnostic challenge because of the relatively low sensitivity and specificity of clinical criteria, radiological findings, and microbiologic culture results. It is often difficult to distinguish between pneumonia, underlying pulmonary disease, or conditions with pulmonary complications; this is compounded by the often-subjective clinical diagnosis of pneumonia. We conducted this study to determine the utility of post mortem lung biopsies for diagnosing pneumonia in tissue donors diagnosed with pneumonia prior to death. Subjects were deceased patients who had been hospitalized at death and diagnosed with pneumonia. Post-mortem lung biopsies were obtained from the anatomic portion of the cadaveric lung corresponding to chest radiograph abnormalities. Specimens were fixed, stained with hematoxylin and eosin, and read by a single board-certified pathologist. Histological criteria for acute pneumonia included intense neutrophilic infiltration, fibrinous exudates, cellular debris, necrosis, or bacteria in the interstitium and intra-alveolar spaces. Of 143 subjects with a diagnosis of pneumonia at time of death, 14 (9.8 %) had histological evidence consistent with acute pneumonia. The most common histological diagnoses were emphysema (53 %), interstitial fibrosis (40 %), chronic atelectasis (36 %), acute and chronic passive congestion consistent with underlying cardiomyopathy (25 %), fibro-bullous disease (12 %), and acute bronchitis (11 %). HCAP represents a major diagnostic challenge because of the relatively low sensitivity and specificity of clinical criteria, radiological findings, and microbiologic testing. We found that attending physician-diagnosed pneumonia did not correlate with post-mortem pathological diagnosis. We conclude that histological examination of cadaveric lung tissue biopsies enables ascertainment or rule out of underlying pneumonia and prevents erroneous donor deferrals. PMID- 26968538 TI - Hypolipidemic and antioxidant activity of the aqueous extract from the uneaten pulp of the fruit from Cordia dichotoma in healthy and hyperlipidemic Wistar albino rats. AB - Hyperlipidemia is a major risk factor for coronary heart disease. Hyperlipidemia increases the incidence of myocardial ischemia and cardiac events. This study evaluated the potential hypolipidemic and antioxidant action of the aqueous extract from the uneaten pulp of the fruit from Cordia dichotoma ("CDNP extract"). In vivo studies were performed for 10 weeks on dietary hyperlipidemic and healthy Wistar albino rat models that received two dose levels of the CDNP extract (0.50 and 1.00 g/kg body weight). Serum lipid profiles were determined for the experimental animals. Dietary hyperlipidemic rats were characterized by an elevated lipid profile compared to the healthy control, i.e., increased levels of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), and triglycerides (TG), although the level of high-density lipoprotein (HDL-C) was reduced. Levels of antioxidant enzymes, i.e., glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST), superoxide dismutase (SOD), and catalase (CAT), were significantly higher in the dietary hyperlipidemic rats than in the normal healthy ones, while the level of malondialdehyde (MDA) was significantly lower. Force-feeding hyperlipidemic Wistar albino rats with the CDNP extract at two doses decreased TC, LDL-C, VLDL-C, and TG to normal levels. The risk ratio, which was as high as 870 % for the hyperlipidemic rats was decreased by the treatment to levels close to that calculated for the healthy control rats. Levels of high-density lipoprotein cholesterol (HDL-C) were very low in the hyperlipidemic Wistar albino rats but increased significantly when CDNP extract was adminstered, attaining similar HDL-C levels to those of healthy control rats. Treatment with the CDNP extract also improved the levels of antioxidant enzymes (GR, GST, GPx, SOD, and CAT) in hyperlipidemic Wistar albino rats. Thus, the CDNP extract improves the lipid metabolism of healthy and hyperlipidemic Wistar albino rats and can be employed in the management of dietary hyperlipidemia. PMID- 26968541 TI - Universal Correction for QT/RR Hysteresis. AB - INTRODUCTION: Clinical pharmacology QT/QTc studies can be smaller if they more efficiently use the data generated. OBJECTIVE: The aim was to use large sets of electrocardiograms (ECGs) deposited at the US Food and Drug Administration to investigate the implications of heart rate measurement on the accuracy of QTc data. METHODS: Using the data of 80 thorough QT studies, we investigated whether placing study subjects in supine positions during short-term time points stabilizes heart rate (part I, based on 73 studies with 747,912 measured ECGs in 6786 healthy subjects) and whether heart rate measurements different from RR intervals captured simultaneously with QT intervals decrease QTc variability (part II, based on seven studies with 897,570 ECG measurements in 751 healthy subjects). RESULTS: In the part I data, when subjects were placed in supine undisturbed positions, heart rate instability (max-min of repeatedly measured heart rates within the same study time point) exceeding 5 beats per minute (bpm) was observed 40 % of the time and exceeded 10 bpm 10 % of the time. In the part II data, even when including QT measurements preceded by variable heart rates, correction of QT durations for RR interval values derived through a simple QT/RR hysteresis model with 95 % adaptation in 120 s led to mean intra-subject standard deviation of QTc (Fridericia formula) of only 7.14 +/- 1.98 and 6.38 +/- 1.50 ms in women and men, respectively. CONCLUSION: The QT/RR hysteresis model with 95 % adaptation in 120 s is universally applicable to healthy subjects, providing small QTc variability. Supine positions do not generally stabilize heart rates in healthy subjects. Universally applicable QT/RR hysteresis correction allows clinical QT/QTc studies to include variable heart rate episodes in the time points. PMID- 26968540 TI - A right thoracotomy approach for mitral and tricuspid valve surgery in patients with previous standard sternotomy: comparison with a re-sternotomy approach. AB - BACKGROUND: To compare the outcomes of mitral and/or tricuspid valve surgery in patients with previous sternotomy between those who underwent a right thoracotomy and those who underwent re-sternotomy. METHODS: Between October 2009 and May 2015, eighteen patients underwent a right thoracotomy (R group) and 28 underwent re-sternotomy (re-S group). The right thoracotomy was prioritized for previous coronary artery bypass grafting. Follow-up was 100 % complete with a mean follow up of 1.9 +/- 1.5 years for the R group and 2.5 +/- 1.4 years for the re-S group (p = 0.2137). RESULTS: Hypothermic ventricular fibrillation was applied in 33.3 % in the R group and in 7.1 % in the re-S group (p = 0.0424). Hospital mortality, the median intensive care unit stay, and the median postoperative hospital stay were 0 % versus 7.1 % (p = 0.5130), 3 days versus 2 days (p = 0.2370), and 28 days versus 29.5 days (p = 0.8043) for the R group versus the re-S group, respectively. Although the rate of major complications was comparable (R group 33.3 % versus re-S group 25.0 %, p = 0.5401), those contents were not equal. Deep sternum infection developed only in the re-S group (3.6 %) and reoperation for bleeding was required only in the R group (11.1 %). No significant difference was observed in the 2-year cardiac-related mortality-free rate (R group 93.3 +/- 6.4 % versus re-S group 90.8 +/- 6.4 %, p = 0.7516). CONCLUSIONS: Given study limitations, the right thoracotomy approach after previous sternotomy provided favorable outcomes as well as re-sternotomy. When selecting a right thoracotomy for re-do mitral and/or tricuspid surgery, the surgical strategy needs to be thoroughly planned. PMID- 26968542 TI - Drug-Induced QT/QTc Interval Shortening: Lessons from Drug-Induced QT/QTc Prolongation. AB - The review discusses safety implications of drugs found to shorten the QT/QTc interval. It uses parallels with drug-induced QT/QTc prolongation. It summarizes the evidence that increases in repolarization heterogeneity are likely more important for arrhythmia induction and maintenance than the absolute changes in the QT/QTc duration. The review further compares the direct evidence of proarrhythmia caused by QT-prolonging and -shortening drugs. At present, there is little proof of QT-shortening drugs causing ventricular fibrillation in more than rare isolated instances. Comparisons of the incidence of the congenital syndromes show that short QT syndrome is much rarer than long QT syndrome, similar to the findings of short QT intervals compared with long QT intervals in the general population. Nevertheless, potential concerns come from experimental drugs developed to increase the current of potassium-rectifying channels. Some of these drugs were found to cause ventricular fibrillation in isolated hearts. Still, population exposure to drug-induced QT shortening is likely substantially lower compared with QT prolongation, especially if considering that most of the processes that decrease the so-called repolarization reserve are associated with QT prolongation. Finally, the review lists reasons why purely theoretical concepts of pharmaceutical risk cannot be used to develop regulatory guidance and concludes that at present, no additional tests and/or general acceptance restrictions are needed for the approval of QT-shortening drugs. PMID- 26968543 TI - Thrombospondin-4 knockout in hypertension protects small-artery endothelial function but induces aortic aneurysms. AB - Thrombospondin-4 (TSP-4) is a multidomain calcium-binding protein that has both intracellular and extracellular functions. As an extracellular matrix protein, it is involved in remodeling processes. Previous work showed that, in the cardiovascular system, TSP-4 expression is induced in the heart in response to experimental pressure overload and infarction injury. Intracellularly, it mediates the endoplasmic reticulum stress response in the heart. In this study, we explored the role of TSP-4 in hypertension. For this purpose, wild-type and TSP-4 knockout (Thbs4(-/-)) mice were treated with angiotensin II (ANG II). Hearts from ANG II-treated Thbs4(-/-) mice showed an exaggerated hypertrophic response. Interestingly, aortas from Thbs4(-/-) mice treated with ANG II showed a high incidence of aneurysms. In resistance arteries, ANG II-treated wild-type mice showed impaired endothelial-dependent relaxation. This was not observed in ANG II-treated Thbs4(-/-) mice or in untreated controls. No differences were found in the passive pressure-diameter curves or stress-strain relationships, although ANG II-treated Thbs4(-/-) mice showed a tendency to be less stiff, associated with thicker diameters of the collagen fibers as revealed by electron microscopy. We conclude that TSP-4 plays a role in hypertension, affecting cardiac hypertrophy, aortic aneurysm formation, as well as endothelial-dependent relaxation in resistance arteries. PMID- 26968544 TI - Dilated cardiomyopathy mutations in delta-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability. AB - Delta-sarcoglycan is a component of the sarcoglycan subcomplex within the dystrophin-glycoprotein complex located at the plasma membrane of muscle cells. While recessive mutations in delta-sarcoglycan cause limb girdle muscular dystrophy 2F, dominant mutations in delta-sarcoglycan have been linked to inherited dilated cardiomyopathy (DCM). The purpose of this study was to investigate functional cellular defects present in adult cardiac myocytes expressing mutant delta-sarcoglycans harboring the dominant inherited DCM mutations R71T or R97Q. This study demonstrates that DCM mutant delta sarcoglycans can be stably expressed in adult rat cardiac myocytes and traffic similarly to wild-type delta-sarcoglycan to the plasma membrane, without perturbing assembly of the dystrophin-glycoprotein complex. However, expression of DCM mutant delta-sarcoglycan in adult rat cardiac myocytes is sufficient to alter cardiac myocyte plasma membrane stability in the presence of mechanical strain. Upon cyclical cell stretching, cardiac myocytes expressing mutant delta sarcoglycan R97Q or R71T have increased cell-impermeant dye uptake and undergo contractures at greater frequencies than myocytes expressing normal delta sarcoglycan. Additionally, the R71T mutation creates an ectopic N-linked glycosylation site that results in aberrant glycosylation of the extracellular domain of delta-sarcoglycan. Therefore, appropriate glycosylation of delta sarcoglycan may also be necessary for proper delta-sarcoglycan function and overall dystrophin-glycoprotein complex function. These studies demonstrate that DCM mutations in delta-sarcoglycan can exert a dominant negative effect on dystrophin-glycoprotein complex function leading to myocardial mechanical instability that may underlie the pathogenesis of delta-sarcoglycan-associated DCM. PMID- 26968545 TI - Magnetic resonance-compatible model of isolated working heart from large animal for multimodal assessment of cardiac function, electrophysiology, and metabolism. AB - To provide a model close to the human heart, and to study intrinsic cardiac function at the same time as electromechanical coupling, we developed a magnetic resonance (MR)-compatible setup of isolated working perfused pig hearts. Hearts from pigs (40 kg, n = 20) and sheep (n = 1) were blood perfused ex vivo in the working mode with and without loaded right ventricle (RV), for 80 min. Cardiac function was assessed by measuring left intraventricular pressure and left ventricular (LV) ejection fraction (LVEF), aortic and mitral valve dynamics, and native T1 mapping with MR imaging (1.5 Tesla). Potential myocardial alterations were assessed at the end of ex vivo perfusion from late-Gadolinium enhancement T1 mapping. The ex vivo cardiac function was stable across the 80 min of perfusion. Aortic flow and LV-dP/dtmin were significantly higher (P < 0.05) in hearts perfused with loaded RV, without differences for heart rate, maximal and minimal LV pressure, LV-dP/dtmax, LVEF, and kinetics of aortic and mitral valves. T1 mapping analysis showed a spatially homogeneous distribution over the LV. Simultaneous recording of hemodynamics, LVEF, and local cardiac electrophysiological signals were then successfully performed at baseline and during electrical pacing protocols without inducing alteration of MR images. Finally, (31)P nuclear MR spectroscopy (9.4 T) was also performed in two pig hearts, showing phosphocreatine-to-ATP ratio in accordance with data previously reported in vivo. We demonstrate the feasibility to perfuse isolated pig hearts in the working mode, inside an MR environment, allowing simultaneous assessment of cardiac structure, mechanics, and electrophysiology, illustrating examples of potential applications. PMID- 26968546 TI - Bilateral common carotid artery stenosis in normotensive rats impairs endothelium dependent dilation of parenchymal arterioles. AB - Chronic cerebral hypoperfusion is a risk factor for cognitive impairment. Reduced blood flow through the common carotid arteries induced by bilateral carotid artery stenosis (BCAS) is a physiologically relevant model of chronic cerebral hypoperfusion. We hypothesized that BCAS in 20-wk-old Wistar-Kyoto (WKY) rats would impair cognitive function and lead to reduced endothelium-dependent dilation and outward remodeling in the parenchymal arterioles (PAs). After 8 wk of BCAS, both short-term memory and spatial discrimination abilities were impaired. In vivo assessment of cerebrovascular reserve capacity showed a severe impairment after BCAS. PA endothelial function and structure were assessed by pressure myography. BCAS impaired endothelial function in PAs, as evidenced by reduced dilation to carbachol. Addition of nitric oxide synthase and cyclooxygenase inhibitors did not change carbachol-mediated dilation in either group. Inhibiting CYP epoxygenase, the enzyme that produces epoxyeicosatrienoic acid (EETs), a key determinant of endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation, abolished dilation in PAs from Sham rats, but had no effect in PAs from BCAS rats. Expression of TRPV4 channels, a target for EETs, was decreased and maximal dilation to a TRPV4 agonist was attenuated after BCAS. Together these data suggest that EET-mediated dilation is impaired in PAs after BCAS. Thus impaired endothelium-dependent dilation in the PAs may be one of the contributing factors to the cognitive impairment observed after BCAS. PMID- 26968547 TI - The influence of acute unloading on left ventricular strain and strain rate by speckle tracking echocardiography in a porcine model. AB - Noninvasive measurements of myocardial strain and strain rate by speckle tracking echocardiography correlate to cardiac contractile state but also to load, which may weaken their value as indices of inotropy. In a porcine model, we investigated the influence of acute dynamic preload reductions on left ventricular strain and strain rate and their relation to the pressure-conductance catheter-derived preload recruitable stroke work (PRSW) and peak positive first derivative of left ventricular pressure (LV-dP/dtmax). Speckle tracking strain and strain rate in the longitudinal, circumferential, and radial directions were measured during acute dynamic reductions of end-diastolic volume during three different myocardial inotropic states. Both strain and strain rate were sensitive to unloading of the left ventricle (P < 0.001), but the load dependency for strain rate was modest compared with strain. Changes in longitudinal and circumferential strain correlated more strongly to changes in end-diastolic volume (r = -0.86 and r = -0.72) than did radial strain (r = 0.35). Longitudinal, circumferential, and radial strain significantly correlated with LV-dP/dtmax (r = -0.53, r = -0.46, and r = 0.86), whereas only radial strain correlated with PRSW (r = 0.55). Strain rate in the longitudinal, circumferential and radial direction significantly correlated with both PRSW (r = -0.64, r = -0.58, and r = 0.74) and LV-dP/dtmax (r = -0.95, r = -0.70, and r = 0.85). In conclusion, the speckle tracking echocardiography-derived strain rate is more robust to dynamic ventricular unloading than strain. Longitudinal and circumferential strain could not predict load-independent contractility. Strain rates, and especially in the radial direction, are good predictors of preload-independent inotropic markers derived from conductance catheter. PMID- 26968548 TI - DNA methylation profiles in preeclampsia and healthy control placentas. AB - Preeclampsia is a hypertensive disorder of pregnancy that affects 3-5% of all pregnancies. There is evidence to suggest that epigenetic mechanisms, such as DNA methylation, play a role in placental development and function. This study compared DNA methylation profiles of placentas from preeclampsia-affected pregnancies with placentas from healthy pregnancies to identify gene-specific changes in DNA methylation that may contribute to the development of preeclampsia. The methylation status of eight placental biopsies taken from preeclampsia-affected and 16 healthy pregnancies was analyzed using the Illumina Infinium Methylation 450 BeadChip array. Bisulfite pyrosequencing was used to confirm regions found to be differentially methylated between preeclampsia and healthy placentas. A total of 303 differentially methylated regions, 214 hypermethylated and 89 hypomethylated, between preeclampsia cases and controls were identified, after adjusting for gestational age (adjusted P < 0.05). Functional annotation found cell adhesion, wingless type MMTV Integration Site family member 2 (Wnt) signaling pathway, and regulation of transcription were significantly enriched in these gene regions. Hypermethylation of WNT2, sperm equatorial segment protein (SPESP1), NADPH oxidase 5 (NOX5), and activated leukocyte cell adhesion molecule (ALCAM) in preeclampsia placentas was confirmed with pyrosequencing. This study found differences in methylation in gene regions involved in cell signaling (WNT2), fertilization and implantation (SPESP1), reactive oxygen species signaling (NOX5), and cell adhesion (ALCAM). These results build on recently published studies that have reported significant differences in DNA methylation in preeclampsia placentas. PMID- 26968549 TI - Identification of a novel putative mitochondrial protein FAM210B associated with erythroid differentiation. AB - The transcription factor GATA-1 plays an essential role in erythroid differentiation. To identify novel GATA-1 target genes, we analyzed a merged ChIP seq and expression profiling dataset. We identified FAM210B as a putative novel GATA-1 target gene. Study results demonstrated that GATA-1 directly regulates FAM210B expression, presumably by binding to an intronic enhancer region. Both human and murine FAM210B are abundantly expressed in the later stages of erythroblast development. Moreover, the deduced amino acid sequence predicted that FAM210B is a membrane protein, and Western blot analysis demonstrated its mitochondrial localization. Loss-of-function analysis in erythroid cells suggested that FAM210B may be involved in erythroid differentiation. The identification and characterization of FAM210B provides new insights in the study of erythropoiesis and hereditary anemias. PMID- 26968550 TI - Expression of activated molecules on CD5(+)B lymphocytes in autoimmune hemolytic anemia. AB - To investigate the expression of activation molecules on CD5(+)B lymphocytes in peripheral blood of autoimmune hemolytic anemia (AIHA)/Evans patients. The expression of CD80, CD86, and CD69 on CD5(+)B lymphocytes was detected using flow cytometry in 30 AIHA/Evans patients, 18 normal controls (NC) and nine chronic lymphocytic leukemia (CLL) patients. CD80 on CD5(+)B lymphocytes in untreated patients was higher than that in remission patients (P < 0.05), NC (P < 0.01) and CLL patients (P < 0.01). CD80 on CD5(+)B lymphocytes was higher than that on CD5( )B lymphocytes in untreated patients (P > 0.05), but lower than those of CD5(-)B lymphocytes in remission patients and NC (P < 0.05). CD86 on CD5(+)B lymphocytes of untreated patients was higher than that of remission patients (P < 0.05), NC (P < 0.01). CD86 on CD5(+)B lymphocytes of CLL was higher than that of NC, remission (P < 0.05), and untreated patients (P > 0.05). CD80 and CD86 on CD5(+)B lymphocytes was negatively correlated with hemoglobin (HB), C3, C4 (P < 0.05) and positively correlated with reticulocyte (Ret) (P < 0.05). CD69 on CD5(+) and CD5( )B lymphocytes of CLL was higher than those of AIHA/Evans patients and NC (P < 0.05). The active molecules on CD5(+)B lymphocytes in peripheral blood of AIHA/Evans patients differ from those on CD5(-) and clonal CD5(+)B lymphocytes. PMID- 26968551 TI - Cyclosporine restores hematopoietic function by compensating for decreased Tregs in patients with pure red cell aplasia and acquired aplastic anemia. AB - Most patients with acquired pure red cell aplasia (PRCA) and some with acquired aplastic anemia (AA) respond well to cyclosporine (CsA), but thereafter often show CsA dependency. The mechanism underlying this dependency remains unknown. We established a reliable method for measuring the regulatory T cell (Treg) count using FoxP3 and Helios expression as markers and determined the balance between Tregs and other helper T cell subsets in 16 PRCA and 29 AA patients. The ratios of interferon-gamma-producing CD4(+) (Th1) T cells to Tregs in untreated patients and CsA-dependent patients were significantly higher (PRCA 5.77 +/- 1.47 and 7.38 +/- 2.58; AA 6.18 +/- 2.35 and 8.94 +/- 4.06) than in healthy volunteers (HVs; 3.33 +/- 0.90) due to the profound decrease in the percentage of Tregs. In contrast, the ratios were comparable to HVs in convalescent CsA-treated AA patients (4.74 +/- 2.10) and AA patients in remission after the cessation of CsA treatment (4.24 +/- 1.67). Low-dose CsA (100 ng/ml) inhibited the proliferation of conventional T cells (Tconv) to a similar degree to the inhibition by Tregs in a co-culture with a 1:1 Treg/Tconv ratio. The data suggest that CsA may reverse the hematopoietic suppression in PRCA and AA patients by compensating for the inadequate immune regulatory function that occurs due to a profound decrease in the Treg count. PMID- 26968552 TI - Non-invasive prenatal diagnosis of beta-thalassemia by detection of the cell-free fetal DNA in maternal circulation: a systematic review and meta-analysis. AB - The discovery of fetal DNA (f-DNA) opens the possibility of early non-invasive procedure for detection of paternally inherited mutation of beta-thalassemia. Since 2002, some studies have examined the sensitivity and specificity of this method for detection of paternally inherited mutation of thalassemia in pregnant women at risk of having affected babies. We conducted a systematic review of published articles that evaluated using this method for early detection of paternally inherited mutation in maternal plasma. A sensitive search of multiple databases was done in which nine studies met our inclusion criteria. The sensitivity and specificity was 99 and 99 %, respectively. The current study found that detection of paternally inherited mutation of thalassemia using analysis of cell-free fetal DNA is highly accurate. This method could replace conventional and invasive methods. PMID- 26968554 TI - Erratum to: Elevated growth differentiation factor 15 expression predicts poor prognosis in epithelial ovarian cancer patients. PMID- 26968553 TI - c-Met and ERbeta expression differences in basal-like and non-basal-like triple negative breast cancer. AB - Basal-like breast cancer (BLBC) and triple-negative breast cancer (TNBC) are two entities of breast cancer that share similar poor prognosis. Even though both cancers have overlaps, there are still some differences between those two types. It has been reported that the c-Met high expression was associated with poor prognosis not only in breast cancer but also in many other cancers. The role of ERbeta in pathogenesis and treatment of breast cancer has remained controversial. In this study, we firstly distinguished basal-like from nonbasal-like cancer patients in TNBC patients using CK5/6 and EGFR as markers and next determined the relationship of basal-like breast cancer with c-Met or ERbeta expression levels and prognosis in TNBC patients. One hundred twenty-seven patients who had been diagnosed with TNBC were enrolled. The clinical and pathological characteristics of the patients were recorded. The expression of EGFR, CK5/6, ERbeta, and c-Met were evaluated with immunohistochemical methods using paraffin blocks. The median age of patients was 50.7 years. CK5/6 immunopositivity was 31.5 % (40/127), and EGFR was 40.2 % (51/127). Of the TNBC cases, 55.1 % (71/127) were positive for either CK5/6 or EGFR and were thus classified as basal-like breast cancer. C-Met (P < 0.001) and ERbeta (P = 0.002) overexpression, small tumor sizes, a ductal subtype, and high-grade tumor were significantly correlated with BLBC. High c-Met expression was detected in 43.3 % patients. Metastatic lymph nodes and tumor size (>5 cm), which were both important prognostic predictors, were significantly associated with recurrence and mortality. BLBC typically demonstrates a unique profile. CK5/6 and EGFR expression combination indicates a higher basal-like phenotype possibility. The expression of c-Met and ERbeta were significantly related to the basal-like phenotype. The classical markers, lymph node metastasis, and tumor size were found to have important prognostic value. However, high c-Met expression and basal-like phenotypes did not show a direct correlation with poor prognosis. PMID- 26968555 TI - Where to Now for One Health and Ecohealth? PMID- 26968556 TI - [Inflammatory Bowel Disease Competence Network]. AB - The Inflammatory Bowel Disease Competence Network is a network of more than 500 physicians and scientists from university clinics, hospitals and gastroenterology practices. The focus extends from the two major forms of inflammatory bowel diseases, Crohn's disease and ulcerative colitis, into other chronic inflammatory conditions affecting the intestine, including coeliac disease and microscopic colitis. The network translates basic science discoveries (in particular in the molecular epidemiology research) into innovative diagnostics and therapy. Through its strong networking structures it supports a continuous process to improve quality and standardisation in patient care that is implemented in close interaction with European networks addressing this disease group.Optimisation of patient care based on scientifically proven evidence is a main focus of the network. Therefore, it supports and coordinates translational research and infrastructure projects that investigate aetiology, improvement of diagnostic methods, and development of new or improved use of established therapies. Members participate in various training projects, thus ensuring the rapid transfer of research results into clinical practice.The competence network cooperates with the main patient organisations to engage patients in all levels of activities. The network and the patient organisations have interest in promoting public awareness about the disease entities, because their importance and burden is underestimated in non-specialised medical fields and among the general public. PMID- 26968557 TI - Optimal experimental design for filter exchange imaging: Apparent exchange rate measurements in the healthy brain and in intracranial tumors. AB - PURPOSE: Filter exchange imaging (FEXI) is sensitive to the rate of diffusional water exchange, which depends, eg, on the cell membrane permeability. The aim was to optimize and analyze the ability of FEXI to infer differences in the apparent exchange rate (AXR) in the brain between two populations. METHODS: A FEXI protocol was optimized for minimal measurement variance in the AXR. The AXR variance was investigated by test-retest acquisitions in six brain regions in 18 healthy volunteers. Preoperative FEXI data and postoperative microphotos were obtained in six meningiomas and five astrocytomas. RESULTS: Protocol optimization reduced the coefficient of variation of AXR by approximately 40%. Test-retest AXR values were heterogeneous across normal brain regions, from 0.3 +/- 0.2 s-1 in the corpus callosum to 1.8 +/- 0.3 s-1 in the frontal white matter. According to analysis of statistical power, in all brain regions except one, group differences of 0.3-0.5 s-1 in the AXR can be inferred using 5 to 10 subjects per group. An AXR difference of this magnitude was observed between meningiomas (0.6 +/- 0.1 s 1 ) and astrocytomas (1.0 +/- 0.3 s-1 ). CONCLUSIONS: With the optimized protocol, FEXI has the ability to infer relevant differences in the AXR between two populations for small group sizes. Magn Reson Med 77:1104-1114, 2017. (c) 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. PMID- 26968559 TI - Cytokeratin 17 is highly sensitive in discriminating cutaneous lymphadenoma (a distinct trichoblastoma variant) from basal cell carcinoma. AB - BACKGROUND: Cutaneous lymphadenoma (CL) is rare neoplasm that clinically and histologically resembles basal cell carcinoma (BCC). CL, composed of dermal basaloid epithelial islands with prominent admixed lymphocytes, characteristically contains cytokeratin 20 (CK20)-positive Merkel cells (MCs). However, CK20 may be of limited use because of low MC density in small samples. CK17 is expressed diffusely throughout BCC. We investigated the discriminatory utility of CK17 and CK20 in CL and BCC. METHODS: A retrospective clinicopathological review of 11 cases of CL and 14 BCC was performed. CK20 positive MCs within basaloid tumor lobules and CK17 immunohistochemical staining and pattern of expression were recorded. RESULTS: Intratumoral CK20-positive MCs were identified in 4/11 CL cases (36.4%) and 0/14 BCC cases (p = 0.012, sensitivity = 0.36). CK17 showed diffuse positive staining in all 14 BCC cases. CK17 showed a distinct patchy and peripheral rim staining in basaloid islands of 10/11 CL cases (p < 0.001, sensitivity = 0.91); one case showed patchy staining throughout tumor lobules. CONCLUSIONS: In cases with a differential diagnosis of CL and BCC, CK20 staining of intratumoral MCs has a high positive predictive value for CL but is of low sensitivity. The pattern of CK17 expression is a highly sensitive marker for distinguishing CL from BCC in small samples. PMID- 26968558 TI - Calcitriol regulates angiotensin-converting enzyme and angiotensin converting enzyme 2 in diabetic kidney disease. AB - To investigate the effects of calcitriol on angiotensin-converting enzyme (ACE) and ACE2 in diabetic nephropathy. Streptozotocin (STZ) induced diabetic rats were treated with calcitriol for 16 weeks. ACE/ACE2 and mitogen activated protein kinase (MAPK) enzymes were measured in the kidneys of diabetic rats and rat renal tubular epithelial cells exposed to high glucose. Calcitriol reduced proteinuria in diabetic rats without affecting calcium-phosphorus metabolism. ACE and ACE2 levels were significantly elevated in diabetic rats compared to those in control rats. The increase in ACE levels was greater than that of ACE2, leading to an elevated ACE/ACE2 ratio. Calcitriol reduced ACE levels and ACE/ACE2 ratio and increased ACE2 levels in diabetic rats. Similarly, high glucose up-regulated ACE expression in NRK-52E cells, which was blocked by the p38 MAPK inhibitor SB203580, but not the extracellular signal-regulated kinase (ERK) inhibitor FR180204 or the c-Jun N-terminal kinase (JNK) inhibitor SP600125. High glucose down-regulated ACE2 expression, which was blocked by FR180204, but not SB203580 or SP600125. Incubation of cells with calcitriol significantly inhibited p38 MAPK and ERK phosphorylation, but not JNK phosphorylation, and effectively attenuated ACE up-regulation and ACE2 down-regulation in high glucose conditions. The renoprotective effects of calcitriol in diabetic nephropathy were related to the regulation of tubular levels of ACE and ACE2, possibly by p38 MAPK or ERK, but not JNK pathways. PMID- 26968560 TI - Cocaine and benzoylecgonine oral fluid on-site screening and confirmation. AB - Accurate on-site devices to screen for drug intake are critical for establishing whether an individual is driving under the influence of drugs (DUID); however, on site oral fluid (OF) cocaine device performance is variable. We evaluated the performance of a newly developed benzoylecgonine (BE) test-strip for the Draeger(r) DrugTest 5000 device (20 ug/L cut-off) with equivalent cross reactivity for cocaine and BE. Ten cocaine users provided OF, collected with the Draeger cassette and Oral-Eze(r) and StatSure Saliva Sampler(TM) devices, up to 69 h following 25 mg intravenous cocaine administration. All screening results were confirmed by a validated two-dimensional-gas chromatography-mass spectrometry (2D-GC-MS) method for cocaine and/or BE. Cocaine test-strip median Tlast for screening only results was 6.5 h, and 6.5 h with Oral-Eze(r) and 4 h for StatSure OF confirmation for cocaine and/or BE at 1, 8, and 10 ug/L; sensitivity, specificity, and efficiency ranged from 85.5 to 100% and 83.3 to 100% for cocaine only confirmation at 8 and 10 ug/L. For the BE test-strip, median Tlast was 12.5 h for screening only and confirmation for cocaine and/or BE at all three cut-offs; sensitivity, specificity, and efficiency ranged from 85.5 to 97.5% and 78.4 to 97.4% with cocaine and/or BE confirmation at 8 and 10 ug/L cut-offs, respectively. The Draeger cocaine test-strip with cocaine only confirmation offers a useful option for monitoring the acute intoxication phase of DUID; additionally the BE test-strip with cocaine and/or BE confirmation increases the length of detection of cocaine intake for workplace drug testing, drug court, parole, pain management, drug treatment programs and both the acute cocaine intoxication and cocaine crash/fatigue phase of DUID. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26968562 TI - Influence of pesticide physicochemical properties on the association between plasma and hair concentration. AB - Although the relationship between chemical intake and resulting concentration in hair remains incompletely elucidated, the transfer from blood to hair bulb living cells is generally considered the main route of incorporation. The present work investigated the correlation between blood and hair concentration of 23 pesticides/metabolites from different chemical classes in rats submitted to chronic controlled exposure. Long-Evans rats were administered pesticides by gavage three times per week over a 90-day period. After hair sample decontamination, pulverization, and extraction, compounds were analyzed by gas chromatography tandem mass spectrometry (GC-MS/MS). Blood was collected at sacrifice, immediately turned into plasma, and analyzed after extraction for the same compounds by GC-MS/MS. The data obtained for all the investigated compounds demonstrated significant association between plasma and hair concentrations (P value of 2.97E-45 and R(Pearson) of 0.875), with the exception of three outliers. For all the target compounds, water solubility, lipophilicity, molecular weight, and charge were therefore investigated in order to understand the role of these parameters in outliers' specific behavior. Although a possible change in the charge through the transfer from blood to hair might be suspected for two outliers, on the whole the physicochemical parameters investigated here did not seem to influence incorporation of chemicals into hair. Our results support that the concentration of chemicals in hair mainly depends on the respective concentration in plasma and suggest that for most compounds, the transfer from blood to hair would not represent a limiting step in the incorporation. PMID- 26968561 TI - Analysis of open and intracorporeal robotic assisted radical cystectomy shows no significant difference in recurrence patterns and oncological outcomes. AB - OBJECTIVES: To report and compare early oncological outcomes and cancer recurrence sites among patients undergoing open radical cystectomy (ORC) and robotic-assisted radical cystectomy with intracorporeal urinary diversion (iRARC). METHODS AND MATERIALS: A total of 184 patients underwent radical cystectomy for bladder cancer. ORC cases (n = 94) were performed between June 2005 and July 2014 while iRARC cases (n = 90) were performed between June 2011 and July 2014. Primary outcome was recurrence free survival (RFS). Secondary outcomes were sites of local and metastatic recurrence, cancer specific survival (CSS) and overall survival (OS). RESULTS: Median follow-up for patients without recurrence was 33.8 months (interquartile range [IQR]: 20.5-45.4) for ORC; and 16.1 months (IQR: 11.2-27.0) for iRARC. No significant difference in age, sex, precystectomy T stage, precystectomy grade, or lymph node yield between ORC and iRARC was observed. The ORC cohort included more patients with>=pT2 (64.8% ORC vs. 38.9% iRARC) but fewer pT0 status (8.5% ORC vs.vs. 22.2% iRARC) due to lower preoperative chemotherapy use (22.3% ORC vs. 34.4% iRARC). Positive surgical margin rate was significantly higher in the ORC cohort (19.3% vs. 8.2%; P = 0.042). Kaplan-Meir analysis showed no significant difference in RFS (69.5% ORC vs. 78.8% iRARC), cancer specific survival (80.9% ORC vs. 84.4% iRARC), or OS (73.5% ORC vs.vs. iRARC 83.8%) at 24 months. Cox regression analysis showed RFS, cancer specific survival and OS were not influenced by cystectomy technique. No significant difference between local and metastatic RFS between ORC and iRARC was observed. CONCLUSION: This study has found no difference in recurrence patterns or oncological outcomes between ORC and iRARC. Recurrent metastatic sites vary, but are not related to surgical technique. PMID- 26968563 TI - LC-quadrupole/Orbitrap high-resolution mass spectrometry enables stable isotope resolved simultaneous quantification and 13C-isotopic labeling of acyl-coenzyme A thioesters. AB - Acyl-coenzyme A (acyl-CoA) thioesters are evolutionarily conserved, compartmentalized, and energetically activated substrates for biochemical reactions. The ubiquitous involvement of acyl-CoA thioesters in metabolism, including the tricarboxylic acid cycle, fatty acid metabolism, amino acid degradation, and cholesterol metabolism highlights the broad applicability of applied measurements of acyl-CoA thioesters. However, quantitation of acyl-CoA levels provides only one dimension of metabolic information and a more complete description of metabolism requires the relative contribution of different precursors to individual substrates and pathways. Using two distinct stable isotope labeling approaches, acyl-CoA thioesters can be labeled with either a fixed [(13)C3(15)N1] label derived from pantothenate into the CoA moiety or via variable [(13)C] labeling into the acyl chain from metabolic precursors. Liquid chromatography-hybrid quadrupole/Orbitrap high-resolution mass spectrometry using parallel reaction monitoring, but not single ion monitoring, allowed the simultaneous quantitation of acyl-CoA thioesters by stable isotope dilution using the [(13)C3(15)N1] label and measurement of the incorporation of labeled carbon atoms derived from [(13)C6]-glucose, [(13)C5(15)N2]-glutamine, and [(13)C3] propionate. As a proof of principle, we applied this method to human B cell lymphoma (WSU-DLCL2) cells in culture to precisely describe the relative pool size and enrichment of isotopic tracers into acetyl-, succinyl-, and propionyl CoA. This method will allow highly precise, multiplexed, and stable isotope resolved determination of metabolism to refine metabolic models, characterize novel metabolism, and test modulators of metabolic pathways involving acyl-CoA thioesters. PMID- 26968565 TI - High precision attachment of silver nanoparticles on AFM tips by dielectrophoresis. AB - AFM tips are modified with silver nanoparticles using an AC electrical field. The used technique works with sub-micron precision and also does not require chemical modification of the tip. Based on the electrical parameters applied in the process, particle density and particle position on the apex of the tip can be adjusted. The feasibility of the method is proven by subsequent tip-enhanced Raman spectroscopy (TERS) measurements using the fabricated tips as a measurement probe. Since this modification process itself does not require any lithographic processing, the technique can be easily adapted to modify AFM tips with a variety of nanostructures with pre-defined properties, while being parallelizable for a potential commercial application. PMID- 26968564 TI - Determination of fatty acid ethyl esters in dried blood spots by LC-MS/MS as markers for ethanol intake: application in a drinking study. AB - The forensic utility of fatty acid ethyl esters (FAEEs) in dried blood spots (DBS) as short-term confirmatory markers for ethanol intake was examined. An LC MS/MS method for the determination of FAEEs in DBS was developed and validated to investigate FAEE formation and elimination in a drinking study, whereby eight subjects ingested 0.66-0.84 g/kg alcohol to reach blood alcohol concentrations (BAC) of 0.8 g/kg. Blood was taken every 1.5-2 h, BAC was determined, and dried blood spots were prepared, with 50 MUL of blood, for the determination of FAEEs. Lower limits of quantitation (LLOQ) were between 15 and 37 ng/mL for the four major FAEEs. Validation data are presented in detail. In the drinking study, ethyl palmitate and ethyl oleate proved to be the two most suitable markers for FAEE determination. Maximum FAEE concentrations were reached in samples taken 2 or 4 h after the start of drinking. The following mean peak concentrations (c(max)) were reached: ethyl myristate 14 +/- 4 ng/mL, ethyl palmitate 144 +/- 35 ng/mL, ethyl oleate 125 +/- 55 ng/mL, ethyl stearate 71 +/- 21 ng/mL, total FAEEs 344 +/- 91 ng/mL. Detectability of FAEEs was found to be on the same time scale as BAC. In liquid blood samples containing ethanol, FAEE concentrations increase post-sampling. This study shows that the use of DBS fixation prevents additional FAEE formation in blood samples containing ethanol. Positive FAEE results obtained by DBS analysis can be used as evidence for the presence of ethanol in the original blood sample. PMID- 26968566 TI - Cyclic volatile methylsiloxanes in human blood as markers for ruptured silicone gel-filled breast implants. AB - The replacement of medical-grade silicone with industrial-grade silicone material in some silicone gel-filled breast implants (SBI) manufactured by Poly Implant Prothese and Rofil Medical Nederland B.V., reported in 2010, which resulted in a higher rupture tendency of these SBI, demonstrates the need for non-invasive, sensitive monitoring and screening methods. Therefore a sensitive method based on large volume injection-gas chromatography coupled to mass spectrometry (LVI GC/MS) was developed to determine octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclo-hexasiloxane (D6) in blood samples from women with intact (n = 13) and ruptured SBI (n = 11). With dichloromethane extraction, sample cooling during preparation, and analysis extraction efficiencies up to 100 % and limits of detection of 0.03-0.05 ng D4 D6/g blood were achieved. Blood samples from women with SBI were investigated. In contrast to women with intact SBI, in blood from women with ruptured SBI higher D4 and D6 concentrations up to 0.57 ng D4/g blood and 0.16 ng D6/g blood were detected. With concentrations above 0.18 D4 ng/blood and 0.10 ng D6/g blood as significant criteria for ruptured SBI, this developed analytical preoperative diagnostic method shows a significant increase of the recognition rate. Finally a higher precision (error rate 17%) than the commonly used clinical diagnostic method, mamma sonography (error rate 46%), was achieved. PMID- 26968568 TI - Determination of thiophenols with a novel fluorescence labelling reagent: analysis of industrial wastewater samples with SPE extraction coupled with HPLC. AB - A simple, sensitive, and selective high-performance liquid chromatography (HPLC) method using 9-(2-iodoethyl)acridone (IEA) as a novel fluorescence derivatizing agent for the simultaneous determination of six thiophenols has been developed. An efficient Pb(2+)-modified OASIS-MCX cartridge was used and could get good recoveries. IEA was successfully used to label thiophenols with high sensitivity and excellent selectivity. The effects of different solvents, pH, and surfactants on fluorescence properties of derivatives were investigated. To obtain the best labeling efficiency, derivatizing parameters including pH value, temperature, and concentration of IEA, as well as types of catalysts were also evaluated in detail. Under the optimal conditions, the separation could be achieved within 12 min with limits of detection (LODs) in the range of 0.6-5.8 MUg L(-1) and relative standard deviations (RSDs) < 3.9%. This is the first time that IEA was applied to the analysis of thiophenols, and the established method has been successfully applied to the trace level detection of thiophenols in industrial wastewater samples. PMID- 26968569 TI - ATR-FT-IR spectral collection of conservation materials in the extended region of 4000-80 cm-1. AB - In this paper, a spectral collection of over 150 ATR-FT-IR spectra of materials related to cultural heritage and conservation science has been presented that have been measured in the extended region of 4000-80 cm(-1) (mid-IR and far-IR region). The applicability of the spectra and, in particular, the extended spectral range, for investigation of art-related materials is demonstrated on a case study. This collection of ATRFT-IR reference spectra is freely available online (http://tera.chem.ut.ee/IR_spectra/) and is meant to be a useful tool for researchers in the field of conservation and materials science. PMID- 26968567 TI - Plasma eicosanoid profiles determined by high-performance liquid chromatography coupled with tandem mass spectrometry in stimulated peripheral blood from healthy individuals and sickle cell anemia patients in treatment. AB - Eicosanoids play an important role in homeostasis and in the pathogenesis of various human diseases. Pharmacological agents such as Ca(2+) ionophores and Ca(2+)-ATPase inhibitors, as well as natural agonists such as formylmethionine leucyl-phenylalanine (fMLP), can stimulate eicosanoid biosynthesis. The aims of this work were to develop a method to determine the eicosanoid profile of human plasma samples after whole blood stimulation and to assess differences between healthy and sick individuals. For this purpose, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was partially validated for the quantification of 22 eicosanoids using human plasma from healthy volunteers. In addition, we optimized a method for the stimulation of eicosanoids in human whole blood. LC-MS/MS analyses were performed by negative electrospray ionization and multiple reaction monitoring. An assumption of linearity resulted in a regression coefficient >=0.98 for all eicosanoids tested. The mean intra-assay and inter assay accuracy and precision values had relative standard deviations and relative errors of <=15%, except for the lower limit of quantification, where these values were <=20%. For whole blood stimulation, four stimuli (fMLP, ionomycin, A23187, and thapsigargin) were tested. Results of the statistical analysis showed that A23187 and thapsigargin were potent stimuli for the production or liberation of eicosanoids. We next compared the eicosanoid profiles of stimulated whole blood samples of healthy volunteers to those of patients with sickle cell anemia (SCA) under treatment with hydroxyurea (HU) or after chronic red blood cell (RBC) transfusion. The results indicate that the method was sufficient to find a difference between lipid mediators released in whole blood of SCA patients and those of healthy subjects, mainly for 5-HETE, 12-HETE, LTB4, LTE4, TXB2, and PGE2. In conclusion, our analytical method can detect significant changes in eicosanoid profiles in stimulated whole blood, which will contribute to establishing the eicosanoid profiles associated with different inflammatory and infectious diseases. PMID- 26968570 TI - Simultaneous identification and quantification of new psychoactive substances in blood by GC-APCI-QTOFMS coupled to nitrogen chemiluminescence detection without authentic reference standards. AB - A novel platform is introduced for simultaneous identification and quantification of new psychoactive substances (NPS) in blood matrix, without the necessity of using authentic reference standards. The instrumentation consisted of gas chromatography (GC) coupled to nitrogen chemiluminescence detection (NCD) and atmospheric pressure chemical ionization quadrupole time-of-flight mass spectrometry (APCI-QTOFMS). In this concept, the GC flow is divided in appropriate proportions between NCD for single-calibrant quantification, utilizing the detector's equimolar response to nitrogen, and QTOFMS for accurate mass-based identification. The principle was proven by analyzing five NPS, bupropion, desoxypipradrol (2-DPMP), mephedrone, methylone, and naphyrone, in sheep blood. The samples were spiked with the analytes post-extraction to avoid recovery considerations at this point. All the NPS studies produced a protonated molecule in APCI resulting in predictable fragmentation with high mass accuracy. The N-equimolarity of quantification by NCD was investigated by using external calibration with the secondary standard caffeine at five concentration levels between 0.17 and 1.7 mg/L in blood matrix as five replicates. The equimolarity was on average 98.7%, and the range of individual equimolarity determinations was 76.7-130.1%. The current analysis platform affords a promising approach to instant simultaneous qualitative and quantitative analysis of drugs in the absence of authentic reference standards, not only in forensic and clinical toxicology but also in other bioanalytical applications. PMID- 26968571 TI - Site-specific quantification of lysine acetylation in the N-terminal tail of histone H4 using a double-labelling, targeted UHPLC MS/MS approach. AB - We developed a targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the site-specific quantification of lysine acetylation in the N terminal region of histone H4 by combining chemical derivatization at the protein and peptide levels with digestion using chymotrypsin and trypsin. Unmodified epsilon-amino groups were first modified with propionic acid anhydride and the derivatized protein digested with trypsin and chymotrypsin. The newly formed peptide N-termini were subjected to a second derivatization step with d6- (heavy) or d0- (light) acetic acid anhydride. Samples were mixed at different ratios and peptides monitored by multiple reaction monitoring (MRM) LC-MS/MS. The method was validated in terms of linearity (R(2) >= 0.94), precision (RSD <= 10%), and accuracy (<=27%) and used to assess the effect of the histone deacetylase (HDAC) inhibitors SAHA and MS-275 in the murine macrophage-like cell line RAW 264.7. SAHA and MS-275 showed site-specific effects on the acetylation levels of K5 and K8 with the K5(Ac)-K8 and K5-K8(Ac) peptides increasing 2.5-fold and 5-fold upon treatment with SAHA and MS-275, respectively. Assessing lysine acetylation in a site-specific manner is important for gaining a better understanding of the effects of HDAC inhibitors and for clarifying disease mechanisms where lysine acetylation plays a role. PMID- 26968572 TI - Will Life Be Worth Living in a World Without Work? Technological Unemployment and the Meaning of Life. AB - Suppose we are about to enter an era of increasing technological unemployment. What implications does this have for society? Two distinct ethical/social issues would seem to arise. The first is one of distributive justice: how will the (presumed) efficiency gains from automated labour be distributed through society? The second is one of personal fulfillment and meaning: if people no longer have to work, what will they do with their lives? In this article, I set aside the first issue and focus on the second. In doing so, I make three arguments. First, I argue that there are good reasons to embrace non-work and that these reasons become more compelling in an era of technological unemployment. Second, I argue that the technological advances that make widespread technological unemployment possible could still threaten or undermine human flourishing and meaning, especially if (as is to be expected) they do not remain confined to the economic sphere. And third, I argue that this threat could be contained if we adopt an integrative approach to our relationship with technology. In advancing these arguments, I draw on three distinct literatures: (1) the literature on technological unemployment and workplace automation; (2) the antiwork critique which I argue gives reasons to embrace technological unemployment; and (3) the philosophical debate about the conditions for meaning in life-which I argue gives reasons for concern. PMID- 26968573 TI - Upland habitat loss as a threat to Pantanal wetlands. PMID- 26968574 TI - Povidone-iodine ointment demonstrates in vitro efficacy against biofilm formation. AB - Anti-infectives used to treat chronic exuding wounds are diluted by wound exudates, absorbed into dressings, metabolised by proteases and destroyed by pH. In order to mimic such effects of exudates, the efficacy of six topical wound agents was assessed undiluted and at 10% concentrations, including povidone iodine ointment and a silver-impregnated wound dressing, to remove biofilms of Pseudomonas aeruginosa, multi-species biofilms of Candida albicans and methicillin-resistant Staphylococcus aureus (MRSA) in vitro in a Centers for Disease Control and Prevention (CDC) reactor. Povidone-iodine was also diluted to 3.3% and 33.3% of the commercial concentrations. Viable microorganisms in each preparation were quantified by colony count. No viable P. aeruginosa biofilm material was recovered after 4 and 24 hours of treatment with povidone-iodine ointment at the 100% and 10% concentrations. No C. albicans/MRSA biofilm material was recovered after 4 and 24 hours of treatment with povidone-iodine ointment at the 100% concentration. In general, following dilution, povidone-iodine ointment appeared to exhibit greater biofilm removal than the other agents tested. Further research involving different microorganisms in vitro and in vivo over a longer period of time will help elucidate the full potential of povidone-iodine ointment and liposomal hydrogel. PMID- 26968575 TI - Predictors of mortality in patients with isolated severe traumatic brain injury. AB - BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Many prognostic models predicting mortality in patients with TBI were developed, which also include patients with mild or moderate TBI and patients who suffered major extracranial injuries. METHODS: From a prospective database, we conducted a retrospective medical chart review covering the period between January 2000 and December 2012 of patients with isolated severe TBI (Abbreviated Injury Score for head, AISH >= 3) without extracranial injuries, who were intubated in the field using the rapid sequence intubation method and were of age 16 or more. Prehospital vital signs, Injury Severity Score (ISS) and laboratory tests were compared in two study groups: survivors (n = 25) and non-survivors (n = 27). Selected variables identified during univariate analysis (p < 0.1) were then subjected to multivariate analysis logistic regression model. RESULTS: Univariate analysis showed that in-hospital mortality was statistically significantly associated with male sex (p = 0.040), ISS (p = 0.005) and mydriasis (p = 0.012). For predicting mortality, area under the curve (AUC) was calculated: for ISS 0.76 (95 % confidence interval, CI; 0.63-0.90; p < 0.001) and for initial Glasgow Coma Scale (GCS) 0.64 (95 % CI, 0.49-0.80, p = 0.079). In the multivariate analysis, ISS (odds ratio, OR; 1.19, 95 % CI, 1.06 1.35; p = 0.004) and mydriasis (OR, 5.73; 95 % CI, 1.06-30.88; p = 0.042) were identified as independent risk factors for in-hospital mortality. The AUC for the regression model was 0.83 (95 % CI, 0.71-0.94; p < 0.001). CONCLUSIONS: In prehospital intubated patients with isolated severe TBI only ISS and mydriasis were found to be independent predictors of in-hospital mortality. PMID- 26968577 TI - Rapid and prodium iodide-compatible optical clearing method for brain tissue based on sugar/sugar-alcohol. AB - The developed optical clearing methods show great potential for imaging of large volume tissues, but these methods present some nonnegligible limitations such as complexity of implementation and long incubation times. In this study, we tried to screen out rapid optical clearing agents by means of molecular dynamical simulation and experimental demonstration. According to the optical clearing potential of sugar and sugar-alcohol,we further evaluated the improvement in the optical clearing efficacy of mouse brain samples, imaging depth, fluorescence preservation, and linear deformation. The results showed that drops of sorbitol, sucrose, and fructose could quickly make the mouse brain sample transparent within 1 to 2 min, and induce about threefold enhancement in imaging depth. The former two could evidently enhance the fluorescence intensity of green fluorescent protein (GFP) and prodium iodide (PI) nuclear dye. Fructose could significantly increase the fluorescence intensity of PI, but slightly decrease the fluorescence intensity of GFP. Even though the three agents caused some shrinkage in samples, the contraction in horizontal and longitudinal directions are almost the same. PMID- 26968576 TI - PlGF knockdown inhibited tumor survival and migration in gastric cancer cell via PI3K/Akt and p38MAPK pathways. AB - The molecular signalling of placental growth factor (PlGF), a member of the vascular endothelial growth factor family, was not uncovered in human adenocarcinoma gastric cell line (AGS). The purpose of this study was to examine the inhibitory effects of PlGF knockdown on cell proliferation, apoptosis and migration through p38 mitogen-activated protein kinase (p38MAPK) and PI3K pathways in human adenocarcinoma gastric cell line (AGS). To study PlGF knockdown effect, AGS cells were treated with 40 pmol of small interfering RNA (siRNA) related to PlGF gene and also a scrambled siRNA as control. Trypan Blue and Anexin V staining of AGS cells treated with PlGF-specific siRNA showed induction of apoptosis. Wound healing assay and zymography indicated that cellular migration and matrix metalloproteinases activities were reduced in response to PlGF knockdown. Phosphorylation of Akt and p38MAPK was reduced in AGS cells treated with PlGF-specific siRNA. PlGF knockdown decreased transcripts of PI3K, Akt, p38MAPK, PCNA, Caspase-3, OCT3/OCT4 and CD44, but elevated p53 and SOX2 transcripts. Our results indicated that PlGF knockdown decreased migration and induced apoptosis through PI3K/Akt1 and p38MAPK signal transduction in AGS cells. PMID- 26968579 TI - Digital service offers rapid transfer of X-rays between hospitals. AB - Nurses and doctors across Wales will soon be able to transfer digital X-rays and scans quickly and easily between hospitals. PMID- 26968578 TI - The comparative gastrointestinal morphology of Jaculus jaculus (Rodentia) and Paraechinus aethiopicus (Erinaceomorpha). AB - Jaculus jaculus (Lesser Egyptian jerboa) and Paraechinus aethiopicus (Desert hedgehog) are small mammals which thrive in desert conditions and are found, among others, in the Arabian Peninsula. Jaculus jaculus is omnivorous while P. aethiopicus is described as being insectivorous. The study aims to describe the gastrointestinal tract (GIT) morphology of these animals which differ in diet and phylogeny. The GITs of J. jaculus (n = 8) and P. aethiopicus (n = 7) were weighed, photographed, and the length, basal surface areas, and luminal surface areas of each of the anatomically distinct gastrointestinal segments were determined. The internal aspects of each area were examined and photographed while representative histological sections of each area were processed to wax and stained using haematoxylin and eosin. Both species had a simple unilocular stomach which was confirmed as wholly glandular on histology sections. Paraechinus aethiopicus had a relatively simple GIT which lacked a caecum. The caecum of J. jaculus was elongated, terminating in a narrow cecal appendix which contained lymphoid tissue on histological examination. The internal aspect of the proximal colon of J. jaculus revealed distinct V-shaped folds. Stomach content analysis of J. jaculus revealed mostly plant and seed material and some insects, whereas P. aethiopicus samples showed plant material in addition to insects, indicating omnivorous feeding tendencies in areas where insects may be scarce. PMID- 26968580 TI - Legislation on tackling abusive behaviour has shown good results. AB - The powers granted to NHS staff to help them deal with antisocial behaviour on hospital premises are proving effective, according to security agency NHS Protect. PMID- 26968581 TI - Staff advised to avoid crowding by boarding patients in corridors. AB - Patients awaiting hospital admission should be moved to trolleys in ward corridors rather than being left in overcrowded emergency departments (EDs), new guidance states. PMID- 26968583 TI - Nurses welcome legal change that frees up prescribing practice. AB - Changes to the law that allow nurses to prescribe controlled drugs in any circumstances should benefit emergency nurses working at scenes of accidents and in out-of-hours care. PMID- 26968582 TI - Trauma network expected to save 600 lives a year. AB - A network of 22 centres specialising in the treatment of patients with major trauma has been formed across England with the aim of saving 600 lives a year. PMID- 26968584 TI - After discharge, men need urgent care more than women. AB - Men are significantly more likely than women to need urgent hospital care, including readmission, within a month of being discharged, according to research. PMID- 26968585 TI - Setting an example. AB - In 1992, when I was a member of the first Emergency Nurse editorial board, I had recently been appointed as a charge nurse. I was probably the most junior nurse on the team and, although my contributions from the clinical shop floor were welcomed, I was keen to learn from the more seasoned board members. PMID- 26968586 TI - PD-1/PD-L1 blockage in cancer treatment-from basic research to clinical application. PMID- 26968587 TI - Anti-PD-L1/PD-1 immune therapies in ovarian cancer: basic mechanism and future clinical application. AB - Tumor immune therapy, especially anti-programmed cell death ligand-1/programmed cell death-1 (PD-L1/PD-1) treatment, is currently the focus of substantial attention. Ovarian cancer is the leading cause of mortality from gynecological malignancies, and novel treatment modalities, including immune therapy, are needed. However, a basic understanding of tumor immunity associated with the PD L1/PD-1 signal has only recently emerged. In this review, we first discuss the importance of local tumor immunity, which affects the clinical outcome of ovarian cancer. We subsequently provide an overview of the basic findings regarding how the PD-L1/PD-1 signal influences local tumor immunity in ovarian cancer. Finally, we discuss what is needed to apply immune therapy in future clinical medicine. PMID- 26968589 TI - Fampridine-PR (prolonged released 4-aminopyridine) is not effective in patients with inflammatory demyelination of the peripheral nervous system. AB - Fampridine-PR is a voltage-gated potassium channel inhibitor potentially improving nerve conduction in demyelinated axons. Based on its established clinical efficacy in patients with demyelination in the central nervous system, we assessed if fampridine-PR is also effective in patients with inflammatory demyelination of the peripheral nerve. In this small open-label study, 10 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) were treated with fampridine-PR 10 mg BID for 28 days and assessed clinically as well as by nerve conduction studies. In this study, Fampridine-PR failed to improve CIDP based on clinical measures and nerve conduction studies. Our findings suggest that Fampridine-PR appears to be ineffective in demyelinating polyneuropathies. These observations may indicate a more complex mode of action beyond improving action potential conduction in demyelinated axons. PMID- 26968588 TI - Mothers' attitudes in Japan regarding cervical cancer screening correlates with intention to recommend cervical cancer screening for daughters. AB - BACKGROUND: Cervical cancer and its precancerous lesions caused by human papilloma virus (HPV) are steadily increasing in women in Japan. In comparison with women in other resource-rich countries, young women in Japan have a dismally low screening rate for cervical cancer. Our preliminary research has shown that 20-year-old women in Japan usually ask their mothers for advice regarding their initial cervical cancer screening. The objective of our current research is to determine the social factors among mothers in Japan that are causing them to give advice to their daughters regarding the HPV vaccine and cervical cancer screening. METHODS: The survey's targets were mothers who had 20-year-old daughters. We recruited respondents from the roster of a commercial internet survey panel. We analyzed for correlations between a mother's knowledge concerning cervical cancer, her recent cancer screening history, and the advice she gave to her daughter regarding cervical cancer screening. RESULTS: We obtained 618 valid answers to the survey. Compared with mothers who did not get screening, mothers who had cervical cancer screening had significantly more knowledge about cervical cancer and its screening (p < 0.05). The daughters of mothers with recent screening had received HPV vaccination more often than those of mothers without recent screening (p = 0.018). Mothers with recent screening histories tended more often to encourage their daughters to have cervical cancer screening (p < 0.05). When mothers were properly educated concerning cervical cancer and its screening, they were significantly more likely than before to recommend that their daughters have it (p < 0.0001). CONCLUSIONS: In young Japanese women, given the important role their mothers have in their lives, it is probable that we could improve their cervical cancer screening rate significantly by giving their mothers better medical information, and a chance to experience cervical cancer screening for themselves. PMID- 26968590 TI - Development and characterization of a xenograft material from New Zealand sourced bovine cancellous bone. AB - A xenograft (bovine hydroxyapatite [BHA]) was developed from New Zealand sourced bovine cancellous bone by a successful defatting and deproteinizing procedure. The BHA was chemically, compositionally and structurally characterized. Fourier transform infrared spectroscopy confirmed the removal of organic matter from the bone matrix and the presence of carbonate ( CO32-), hydroxyl (OH- ), and phosphate ( PO43-) functional groups. X-ray diffraction analysis suggested that the processed bone corresponds characteristically to hydroxyapatite (HA). SEM analysis showed that the BHA has an interconnected porous architecture with a pore diameter ranging from 100 to 700 MUm while uCT analysis calculated the total porosity as 73.46% +/- 1.08. Furthermore, the BHA was stable up to 1000 degrees C and lost only 1.8% of its weight. The Ca/P molar ratio of the BHA was 1.58, which is comparable with commercially available natural HA-Endobon(r) . After 28 days of incubation in simulated body fluid (SBF), the pH value only fluctuated between 7.1 and 7.5 and the BHA scaffold did not degrade significantly by weight indicating the scaffold had excellent chemical and structural stability. In vitro studies showed the BHA was cytocompatible and supported the proliferative growth of Saos-2 osteoblast cells. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1054-1062, 2017. PMID- 26968591 TI - Nanostructured MoS2 Nanorose/Graphene Nanoplatelet Hybrids for Electrocatalysis. AB - Tailoring and enhancing electrocatalytic activity is of the utmost importance from the viewpoints of sustainable energy and sensing. MoS2 and graphene show great promise for the electrocatalysis of many reactions. Given that both graphene and MoS2 are highly anisotropic in nature, with edge planes that are several orders of magnitude more catalytically active than basal planes, a new hybrid material with maximized edge-plane density to provide efficient electron transfer, high catalytic activity, and conductive cores was engineered. The hybrid material consists of radial MoS2 nanosheets with a high density of edge planes and unsaturated active sulfur atoms as well as interspersed with conductive graphene nanoplatelets. This hybrid material exhibits excellent activity for the hydrogen evolution reaction and the detection of DNA nucleobases. Such a nanoengineered, nanostructured hybrid material may play a major role in future electrocatalytic devices. PMID- 26968593 TI - The threat of litigation as a possible barrier to innovation. PMID- 26968592 TI - Effect of Ga3+ and Gd3+ ions substitution on the structural and optical properties of Ce3+ -doped yttrium aluminium garnet phosphor nanopowders. AB - The structural and optical properties of commercially obtained Y3 Al5 O12 :Ce3+ phosphor were investigated by replacing Al3+ with Ga3+ and Y3+ with Gd3+ in the Y3 Al5 O12 :Ce3+ structure to form Y3 (Al,Ga)5 O12 :Ce3+ and (Y,Gd)3 Al5 O12 :Ce3+ . X-Ray diffraction (XRD) results showed slight 2-theta peak shifts to lower angles when Ga3+ was used and to higher angles when Gd3+ was used, with respect to peaks from Y3 Al5 O12 :Ce3+ and JCPDS card no. 73-1370. This could be attributed to induced crystal-field effects due to the different ionic sizes of Ga3+ and Gd3+ compared with Al3+ and Y3+ . The photoluminescence (PL) spectra showed broad excitation from 350 to 550 nm with a maximum at 472 nm, and broad emission bands from 500 to 650 nm, centred at 578 nm for Y3 Al5 O12 :Ce3+ arising from the 5d -> 4f transition of Ce3+ . PL revealed a blue shift for Ga3+ substitution and a red shift for Gd3+ substitution. UV-Vis showed two absorption peaks at 357 and 457 nm for Y3 Al5 O12 :Ce3+ , with peaks shifting to 432 nm for Ga3+ and 460 nm for Gd3+ substitutions. Changes in the trap levels or in the depth and number of traps due to Ce3+ were analysed using thermoluminescence (TL) spectroscopy. This revealed the existence of shallow and deep traps. It was observed that Ga3+ substitution contributes to the shallowest traps at 74 degrees C and fewer deep traps at 163 degrees C, followed by Gd3+ with shallow traps at 87 degrees C and deep traps at 146 degrees C. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26968594 TI - Editor's note. PMID- 26968595 TI - Characterisation and therapeutic manipulation of the gut microbiome in inflammatory bowel disease. AB - Inflammatory bowel diseases are thought to develop as a result of dysregulation of the relationship that exists between the gut microbiota, host genetics and the immune system. The advent of culture-independent techniques has revolutionised the ability to characterise the role of the gut microbiota in health and disease based on the microbiota's genetic make-up. Inflammatory bowel diseases are characterised by dysbiosis which is an imbalance between pro- and anti inflammatory bacteria and a reduction in bacterial diversity. Emerging data suggest that it is not only the presence of the gut microbiota but the functional activity of the microbiota that appears to play an important role in health and disease. Current strategies to manipulate therapeutically the gut microbiota using dietary modification, prebiotics, probiotics, antibiotics and faecal microbiota transplantation aim to restore the balance to a state of normobiosis. However, the ability of such strategies to correct dysbiosis and thereby achieve therapeutic benefit is yet to be fully characterised. PMID- 26968596 TI - Substantial variation in post-engraftment infection prophylaxis and revaccination practice in autologous stem cell transplant patients. AB - There is a paucity of evidence supporting the necessity or duration of Pneumocystis jirovecii and antiviral prophylaxis as well as revaccination following autologous stem cell transplant (ASCT). A survey aimed at evaluating these policies was distributed to 34 ASCT centres across Australasia. The 26 survey respondents demonstrated significant heterogeneity in their infection prophylaxis and revaccination strategy post-transplant despite the availability of consensual guidelines. PMID- 26968597 TI - Safety and efficacy of a novel short occlusive regimen of imiquimod for selected non-melanotic skin lesions in renal transplant patients. AB - Australian patients remain at very high risk of non-melanotic skin cancer after renal transplantation. Surgical excision offers a cure but destroys tissue and may jeopardise function and cosmesis. We report excellent safety and efficacy using topical imiquimod in a novel short intensive regimen in 10 renal transplant patients with superficial basal cell carcinomas, Bowen disease or actinic keratosis. Outcomes compare well to those reported with extended-use imiquimod protocols. PMID- 26968598 TI - Acute adrenal insufficiency: an aide-memoire of the critical importance of its recognition and prevention. AB - Adrenal crisis is a life-threatening emergency that causes significant excess mortality in patients with adrenal insufficiency. Delayed recognition by medical staff of an impending adrenal crisis and failure to give timely hydrocortisone therapy within the emergency department continue to be commonly encountered, even in metropolitan teaching hospitals. Within the authors' institutions, several cases of poorly handled adrenal crises have occurred over the last 2 years. Anecdotal accounts from members of the Addison's support group suggest that these issues are common in Australia. This manuscript is a timely reminder for clinical staff on the critical importance of the recognition, treatment and prevention of adrenal crisis. The manuscript: (i) outlines a case and the clinical outcome of sub-optimally managed adrenal crisis, (ii) summarises the clinical features and acute management of adrenal crisis, (iii) provides recommendations on the prevention of adrenal crisis and (iv) provides guidance on the management of 'sick days' in patients with adrenal insufficiency. PMID- 26968600 TI - Cardiovascular risk reduction in hypertension: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers. Where are we up to? AB - Previously, management of hypertension has concentrated on lowering elevated blood pressure. However, the target has shifted to reducing absolute cardiovascular (CV) risk. It is estimated that two in three Australian adults have three or more CV risk factors at the same time. Moderate reductions in several risk factors can, therefore, be more effective than major reductions in one. When managing hypertension, therapy should be focused on medications with the strongest evidence for CV event reduction, substituting alternatives only when a primary choice is not appropriate. Hypertension management guidelines categorise angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) interchangeably as first-line treatments in uncomplicated hypertension. These medications have different mechanisms of action and quite different evidence bases. They are not interchangeable and their prescription should be based on clinical evidence. Despite this, currently ARB prescriptions are increasing at a higher rate than those for ACEI and other antihypertensive classes. Evidence that ACEI therapy prevents CV events and death, in patients with coronary artery disease or multiple CV risk factors, emerged from the European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA) and Heart Outcomes Prevention Evaluation (HOPE) trials respectively. The consistent benefit has been demonstrated in meta-analyses. The clinical trial data for ARB are less consistent, particularly regarding CV outcomes and mortality benefit. The evidence supports the use of ACEI (Class 1a) compared with ARB despite current prescribing trends. PMID- 26968599 TI - Severe hypocalcaemia and hypophosphataemia following intravenous iron and denosumab: a novel drug interaction. AB - We present the case of a 59-year-old woman with chronic kidney disease who suffered severe hypocalcaemia and hypophosphataemia after receiving denosumab and intravenous iron. This potentially life-threatening adverse drug interaction has never been reported before. We propose a mechanism to explain it with reference to the physiological derangements caused by both agents on calcium and phosphate homeostasis. PMID- 26968601 TI - Screening for coeliac disease in elderly inpatients with minimal trauma fracture is not indicated. PMID- 26968602 TI - Traumatic superior gluteal artery pseudoaneurysm following a bone marrow biopsy. PMID- 26968603 TI - Liquid biopsies: advancing cancer research through drops of blood. PMID- 26968605 TI - Errata. PMID- 26968606 TI - Errata. PMID- 26968604 TI - Conflict of interest: real and perceived--a more mature consideration is needed. PMID- 26968607 TI - Survey on testing for gestational diabetes mellitus in Australia. AB - We surveyed members of National Association of Diabetes Centres (NADC) assessing use of new Australasian Diabetes In Pregnancy Society (ADIPS) and Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) Gestational Diabetes Mellitus (GDM) diagnostic guidelines in Australia. We found piecemeal adoption of recommended changes, with cessation of the 50 g glucose challenge test (GCT) universal, early screening implementation common, but by varied methodologies, and new diagnostic criteria acceptance far from complete with significant workload increases almost universal. PMID- 26968608 TI - Functional Magnetic Stimulation of Inspiratory and Expiratory Muscles in Subjects With Tetraplegia. AB - BACKGROUND: Respiratory complications are major causes of morbidity and mortality in persons with a spinal cord injury, partly because of respiratory muscle paralysis. Earlier investigation has demonstrated that functional magnetic stimulation (FMS) can be used as a noninvasive technology for activating expiratory muscles, thus producing useful expiratory functions (simulated cough) in subjects with spinal cord injury. OBJECTIVE: To evaluate the effectiveness of FMS for conditioning inspiratory and expiratory muscles in persons with tetraplegia. DESIGN: A prospective before and after trial. SETTING: FMS Laboratory, Louis Stokes Cleveland VA Medical Center, Cleveland, OH. PARTICIPANTS: Six persons with tetraplegia. METHOD: Each subject participated in a 6-week FMS protocol for conditioning the inspiratory and expiratory muscles. A magnetic stimulator was used with the center of a magnetic coil placed at the C7 T1 and T9-T10 spinous processes, respectively. Pulmonary function tests were performed before, during, and after the protocol. MAIN OUTCOME MEASUREMENTS: Respiratory variables included maximal inspiratory pressure (MIP), inspiratory reserve volume (IRV), peak inspiratory flow (PIF), maximal expiratory pressure (MEP), expiratory reserve volume (ERV), and peak expiratory flow (PEF). RESULTS: After 6 weeks of conditioning, the main outcome measurements (mean +/- standard error) were as follows: MIP, 89.6 +/- 7.3 cm H2O; IRV, 1.90 +/- 0.34 L; PIF, 302.4 +/- 36.3 L/min; MEP, 67.4 +/- 11.1 cm H2O; ERV, 0.40 +/- 0.06 L; and PEF, 372.4 +/- 31.9 L/min. These values corresponded to 117%, 107%, 136%, 109%, 130%, and 124% of pre-FMS conditioning values, respectively. Significant improvements were observed in MIP (P = .022), PIF (P = .0001), and PEF (P = .0006), respectively. When FMS was discontinued for 4 weeks, these values showed decreases from their values at the end of the conditioning protocol, which suggests that continual FMS may be necessary to maintain improved respiratory functions. CONCLUSION: FMS conditioning of the inspiratory and expiratory muscles improved voluntary inspiratory and expiratory functions. FMS may be a noninvasive technology for respiratory muscle training in persons with tetraplegia. PMID- 26968609 TI - Feasibility of Using Tetrax Biofeedback Video Games for Balance Training in Patients With Chronic Hemiplegic Stroke. AB - BACKGROUND: Decreased weight bearing on the affected lower limb and poor weight shifting are common after a stroke occurs. The Tetrax biofeedback system is a center-of-pressure controlled video game system designed for patients with balance deficits. Although it is a commercial product, information about its clinical use for patients affected by stroke is limited. OBJECTIVE: To investigate the feasibility and potential efficacy of the Tetrax biofeedback system for balance training in patients with chronic stroke. DESIGN: Feasibility study. SETTING: Rehabilitation department of a medical center. PARTICIPANTS: Participants who had sustained a hemiplegic stroke at least 6 months prior to enrollment but were still able to stand independently for more than 5 minutes. METHODS: Participants were randomly assigned to an intervention group (IG) or control group (CG). All participants received conventional rehabilitation training. The IG also received 20 minutes of exposure to Tetrax biofeedback games controlled by change in center of pressure 3 times a week for 6 weeks. MAIN OUTCOME MEASUREMENTS: The primary outcome was feasibility, addressed by adherence, safety, and satisfaction. The secondary outcome was efficacy, which was evaluated by the subtests of physiological profile assessment, posturography, Timed Up and Go, and Forward Reach tests. We used percentage change (post training score - pretraining score/pretraining score) to quantify the intervention effects. Mann-Whitney U tests were used to analyze differences in percentage of change between groups. RESULTS: A total of 14 participants were assigned to the IG, and 13 were assigned to the CG; 12 participants in the IG and 11 in the CG completed the study. In the IG group, those who completed the 6-week intervention attended 89.5% of planned sessions. No major adverse events or falls occurred within the intervention sessions. With use of 5-point Likert scales, participants rated their enjoyment of Tetrax games as 4.33 +/- 0.78, their motivation as 4.17 +/- 1.03, and perceived helpfulness as 4.25 +/- 0.97. The IG demonstrated a significantly greater improvement in reaction time (P = .002), proprioception (P < .001), symmetric weight bearing (P = .027), Timed Up and Go (P < .001), and Forward Reach (P < .001) compared with the CG. CONCLUSIONS: Using Tetrax biofeedback video games for balance training is a feasible adjunctive program that may augment conventional therapy in persons affected by chronic hemiplegic stroke. LEVEL OF EVIDENCE: II. PMID- 26968610 TI - Pelvic Pain Due to Ischial Tuberosity and Acetabular Melorheostosis-Multimodal Image Presentation. PMID- 26968611 TI - Efficacy and Safety of Autologous Blood Products Compared With Corticosteroid Injections in the Treatment of Lateral Epicondylitis: A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: To compare the efficacy and safety of autologous blood products (ABPs) and corticosteroid injections (CSIs) in the treatment of lateral epicondylitis. TYPE OF STUDY: Meta-analysis. LITERATURE SURVEY: We systematically searched EMBASE, PubMed, the Cochrane Library, and Web of Science to identify randomized controlled trials (RCTs) that compared ABPs with CSIs for the treatment of lateral epicondylitis without language and publication date restriction through April 2015. METHODOLOGY: Two investigators independently included and assessed the quality of each eligible study according to the method recommended by the Cochrane Collaboration. Available data about the main outcomes were extracted from each study and heterogeneity was assessed using the Q statistic and the inconsistency index (I(2)). We also evaluated the publication bias and conducted a subgroup analysis. Review Manager 5.2 software was used for data syntheses and analyses, and the standardized mean difference (SMD) or mean difference (MD) was estimated by using random effects models with a 95% confidence interval (CI). To investigate the efficacy among different trial durations, the follow-up times were divided into short periods (2-4 weeks), intermediate periods (6-24 weeks) and long-term periods (>=24 weeks). SYNTHESIS: Ten RCTs (n = 509) were included in this meta-analysis. The pooled analysis showed that CSIs were more effective than ABPs for pain relief in the short term (SMD = 0.88; 95% CI = 0.31-1.46%; P = .003). However, in the intermediate term, ABPs exhibited a better therapeutic effect for pain relief (SMD = -0.38; 95% CI = -0.70 to -0.07%; P = .02), function (SMD = -0.60; 95% CI = -1.13 to -0.08%; P = .03), disabilities of the arm, shoulder, and hand (MD = -11.04; 95% CI = -21.72 to -0.36%; P = .04), and Nirschl stage (MD = -0.81; 95% CI = -1.11 to -0.51%; P < .0001). In the long term, ABPs were superior to CSIs for pain relief (SMD = -0.94; 95% CI = -1.32 to -0.57%; P < .0001) and Nirschl stage (MD = -1.04; 95% CI = -1.66 to -0.42%; P = .001). Moreover, for grip strength recovery, no significant difference was found between the 2 therapies (P > .05). CONCLUSIONS: Limited evidence supports the conclusion that CSIs are superior to ABPs for pain relief in the short term; however, this result was reversed in the intermediate and long term. ABPs seemed to be more effective at restoring function in the intermediate term. Because of the small sample size and the limited number of high-quality RCTs, more high-quality RCTs with large sample sizes are required to validate this result. PMID- 26968613 TI - Haloalkaline Bioconversions for Methane Production from Microalgae Grown on Sunlight. AB - Microalgal biomass can be converted to biofuels to replace nonsustainable fossil fuels, but the widespread use of microalgal biofuels remains hampered by the high energetic and monetary costs related to carbon dioxide supply and downstream processing. Growing microalgae in mixed culture biofilms reduces energy demands for mixing, maintaining axenic conditions, and biomass concentration. Furthermore, maintaining a high pH improves carbon dioxide absorption rates and inorganic carbon solubility, thus overcoming the carbon limitation and increasing the volumetric productivity of the microalgal biomass. Digesting the microalgal biomass anaerobically at high pH results in biogas that is enriched in methane, while the dissolved carbon dioxide is recycled to the phototrophic reactor. All of the required haloalkaline conversions are known in nature. PMID- 26968612 TI - Redefining Signaling Pathways with an Expanding Single-Cell Toolbox. AB - Genetically identical cells respond heterogeneously to uniform environmental stimuli. Consequently, investigating the signaling networks that control these cell responses using 'average' bulk cell measurements can obscure underlying mechanisms and misses information emerging from cell-to-cell variability. Here we review recent technological advances including live-cell fluorescence imaging based approaches and microfluidic devices that enable measurements of signaling networks, dynamics, and responses in single cells. We discuss how these single cell tools have uncovered novel mechanistic insights for canonical signaling pathways that control cell proliferation (ERK), DNA-damage responses (p53), and innate immune and stress responses (NF-kappaB). Future improvements in throughput and multiplexing, analytical pipelines, and in vivo applicability will all significantly expand the biological information gained from single-cell measurements of signaling pathways. PMID- 26968614 TI - GOexpress: an R/Bioconductor package for the identification and visualisation of robust gene ontology signatures through supervised learning of gene expression data. AB - BACKGROUND: Identification of gene expression profiles that differentiate experimental groups is critical for discovery and analysis of key molecular pathways and also for selection of robust diagnostic or prognostic biomarkers. While integration of differential expression statistics has been used to refine gene set enrichment analyses, such approaches are typically limited to single gene lists resulting from simple two-group comparisons or time-series analyses. In contrast, functional class scoring and machine learning approaches provide powerful alternative methods to leverage molecular measurements for pathway analyses, and to compare continuous and multi-level categorical factors. RESULTS: We introduce GOexpress, a software package for scoring and summarising the capacity of gene ontology features to simultaneously classify samples from multiple experimental groups. GOexpress integrates normalised gene expression data (e.g., from microarray and RNA-seq experiments) and phenotypic information of individual samples with gene ontology annotations to derive a ranking of genes and gene ontology terms using a supervised learning approach. The default random forest algorithm allows interactions between all experimental factors, and competitive scoring of expressed genes to evaluate their relative importance in classifying predefined groups of samples. CONCLUSIONS: GOexpress enables rapid identification and visualisation of ontology-related gene panels that robustly classify groups of samples and supports both categorical (e.g., infection status, treatment) and continuous (e.g., time-series, drug concentrations) experimental factors. The use of standard Bioconductor extension packages and publicly available gene ontology annotations facilitates straightforward integration of GOexpress within existing computational biology pipelines. PMID- 26968615 TI - Modeling the spinal pudendo-vesical reflex for bladder control by pudendal afferent stimulation. AB - Electrical stimulation of the pudendal nerve (PN) is a promising approach to restore continence and micturition following bladder dysfunction resulting from neurological disease or injury. Although the pudendo-vesical reflex and its physiological properties are well established, there is limited understanding of the specific neural mechanisms that mediate this reflex. We sought to develop a computational model of the spinal neural network that governs the reflex bladder response to PN stimulation. We implemented and validated a neural network architecture based on previous neuroanatomical and electrophysiological studies. Using synaptically-connected integrate and fire model neurons, we created a network model with realistic spiking behavior. The model produced expected sacral parasympathetic nucleus (SPN) neuron firing rates from prescribed neural inputs and predicted bladder activation and inhibition with different frequencies of pudendal afferent stimulation. In addition, the model matched experimental results from previous studies of temporal patterns of pudendal afferent stimulation and selective pharmacological blockade of inhibitory neurons. The frequency- and pattern-dependent effects of pudendal afferent stimulation were determined by changes in firing rate of spinal interneurons, suggesting that neural network interactions at the lumbosacral level can mediate the bladder response to different frequencies or temporal patterns of pudendal afferent stimulation. Further, the anatomical structure of excitatory and inhibitory interneurons in the network model was necessary and sufficient to reproduce the critical features of the pudendo-vesical reflex, and this model may prove useful to guide development of novel, more effective electrical stimulation techniques for bladder control. PMID- 26968617 TI - The UK National Neonatal Research Database: using neonatal data for research, quality improvement and more. PMID- 26968618 TI - [Comamonas testosteroni appendicitis]. PMID- 26968616 TI - Optimizing operational efficiencies in early phase trials: The Pediatric Trials Network experience. AB - Performing drug trials in pediatrics is challenging. In support of the Best Pharmaceuticals for Children Act, the Eunice Kennedy Shriver National Institute of Child Health and Human Development funded the formation of the Pediatric Trials Network (PTN) in 2010. Since its inception, the PTN has developed strategies to increase both efficiency and safety of pediatric drug trials. Through use of innovative techniques such as sparse and scavenged blood sampling as well as opportunistic study design, participation in trials has grown. The PTN has also strived to improve consistency of adverse event reporting in neonatal drug trials through the development of a standardized adverse event table. We review how the PTN is optimizing operational efficiencies in pediatric drug trials to increase the safety of drugs in children. PMID- 26968620 TI - The early stress responses in fish larvae. AB - During the life cycle of fish the larval stages are the most interesting and variable. Teleost larvae undergo a daily increase in adaptability and many organs differentiate and become active. These processes are concerted and require an early neuro-immune-endocrine integration. In larvae communication among the nervous, endocrine and immune systems utilizes several known signal molecule families which could be different from those of the adult fish. The immune neuroendocrine system was studied in several fish species, among which in particular the sea bass (Dicentrarchus labrax), that is a species of great commercial interest, very important in aquaculture and thus highly studied. Indeed the immune system of this species is the best known among marine teleosts. In this review the data on main signal molecules of stress carried out on larvae of fish are considered and discussed. For sea bass active roles in the early immunological responses of some well-known molecules involved in the stress, such as ACTH, nitric oxide, CRF, HSP-70 and cortisol have been proposed. These molecules and/or their receptors are biologically active mainly in the gut before complete differentiation of gut-associated lymphoid tissue (GALT), probably acting in an autocrine/paracrine way. An intriguing idea emerges from all results of these researches; the molecules involved in stress responses, expressed in the adult cells of the hypothalamic-pituitary axis, during the larval life of fish are present in several other localizations, where they perform probably the same role. It may be hypothesized that the functions performed by hypothalamic pituitary system are particularly important for the survival of the larva and therefore they comprises several other localizations of body. Indeed the larval stages of fish are very crucial phases that include many physiological changes and several possible stress both internal and environmental. PMID- 26968621 TI - [The impact of adverse events on health primary care professionals and institutions]. PMID- 26968619 TI - Necroptosis: an alternative cell death program defending against cancer. AB - One of the hallmarks of cancer is resistance to programmed cell death, which maintains the survival of cells en route to oncogenic transformation and underlies therapeutic resistance. Recent studies demonstrate that programmed cell death is not confined to caspase-dependent apoptosis, but includes necroptosis, a form of necrotic death governed by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL) protein. Necroptosis serves as a critical cell-killing mechanism in response to severe stress and blocked apoptosis, and can be induced by inflammatory cytokines or chemotherapeutic drugs. Genetic or epigenetic alterations of necroptosis regulators such as RIP3 and cylindromatosis (CYLD), are frequently found in human tumors. Unlike apoptosis, necroptosis elicits a more robust immune response that may function as a defensive mechanism by eliminating tumor-causing mutations and viruses. Furthermore, several classes of anticancer agents currently under clinical development, such as SMAC and BH3 mimetics, can promote necroptosis in addition to apoptosis. A more complete understanding of the interplay among necroptosis, apoptosis, and other cell death modalities is critical for developing new therapeutic strategies to enhance killing of tumor cells. PMID- 26968622 TI - Cross-cultural adaptation and validation of the Sinus and Nasal Quality of Life Survey (SN-5) into Brazilian Portuguese. AB - INTRODUCTION: The concept of quality of life is subjective and variable definition, which depends on the individual's perception of their state of health. Quality of life questionnaires are instruments designed to measure quality of life, but most are developed in a language other than Portuguese. Questionnaires can identify the most important symptoms, focus on consultation, and assist in defining the goals of treatment. Some of these have been validated for the Portuguese language, but none in children. OBJECTIVE: To validate the translation with cross-cultural adaptation and validation of the Sinus and Nasal Quality of Life Survey (SN-5) into Portuguese. METHODS: Prospective study of children aged 2-12 years with sinonasal symptoms of over 30 days. The study comprised two stages: (I) translation and cross-cultural adaptation of the SN-5 into Portuguese (SN-5p); and (II) validation of the SN5-p. Statistical analysis was performed to assess internal consistency, test-retest reliability, and sensitivity, as well as construct and discriminant validity and standardization. RESULTS: The SN-5 was translated and adapted into Portuguese (SN-5p) and the author of the original version approved the process. Validation was carried out by administration of the SN-5p to 51 pediatric patients with sinonasal complaints (mean age, 5.8+/-2.5 years; range, 2-12 years). The questionnaire exhibited adequate construct validity (0.62, p<0.01), internal consistency (Cronbach's alpha=0.73), and discriminant validity (p<0.01), as well as good test-retest reproducibility (Goodman-Kruskal gamma=0.957, p<0.001), good correlation with a visual analog scale (r=0.62, p<0.01), and sensitivity to change. CONCLUSION: This study reports the successful translation and cross-cultural adaptation of the SN 5 instrument into Brazilian Portuguese. The translated version exhibited adequate psychometric properties for assessment of disease-specific quality of life in pediatric patients with sinonasal complaints. PMID- 26968624 TI - The exponential effect. PMID- 26968623 TI - Mometasone furoate in the treatment of mild, moderate, or severe persistent allergic rhinitis: a non-inferiority study (PUMA). AB - INTRODUCTION: Allergic rhinitis is considered the most prevalent respiratory disease in Brazil and worldwide, with great impact on quality of life, affecting social life, sleep, and also performance at school and at work. OBJECTIVE: To compare the efficacy and safety of two formulations containing mometasone furoate in the treatment of mild, moderate, or severe persistent allergic rhinitis after four weeks of treatment. METHODS: Phase III, randomized, non-inferiority, national, open study comparing mometasone furoate in two presentations (control drug and investigational drug). The primary endpoint was the percentage of patients with reduction of at least 0.55 in nasal index score (NIS) after four weeks of treatment. Secondary outcomes included total nasal index score score after four and 12 weeks of treatment; individual scores for symptoms of nasal obstruction, rhinorrhea, sneezing, and nasal pruritus; as well as score for pruritus, lacrimation, and ocular redness after four and 12 weeks of treatment. The study was registered at clinicaltrials.gov with the reference number NCT01372865. RESULTS: The efficacy primary analysis demonstrated non-inferiority of the investigational drug in relation to the control drug, since the upper limit of the confidence interval (CI) of 95% for the difference between the success rates after four weeks of treatment (12.6%) was below the non-inferiority margin provided during the determination of the sample size (13.7%). Adverse events were infrequent and with mild intensity in most cases. CONCLUSION: The efficacy and safety of investigational drug in the treatment of persistent allergic rhinitis were similar to the reference product, demonstrating its non inferiority. PMID- 26968625 TI - The optimal gestation for pertussis vaccination during pregnancy: a prospective cohort study. AB - BACKGROUND: There is an increasing incidence of pertussis infection in infants too young to be adequately protected via vaccination. Maternal pertussis vaccination during the third trimester of pregnancy is a new strategy to provide protection to newborn infants. OBJECTIVE: This study sought to determine the optimal gestational window for vaccination in the third trimester. STUDY DESIGN: This prospective study recruited 3 groups of women: an early vaccination group, vaccinated between 28-32 weeks' gestation; a late vaccination group, vaccinated between 33-36 weeks' gestation; and an unvaccinated control group. Maternal venous blood was taken prior to pertussis vaccination. At birth, infant cord blood was collected to determine antibody levels to pertussis toxin (PT), pertactin (PRN), and filamentous hemagglutinin (FHA). RESULTS: In all, 154 women were recruited from April through September 2014. There was no significant difference between maternal PRN and FHA antibody levels among the 3 groups, however, PT was higher in the early compared to late vaccination group (P = .05). Cord blood antibody levels to PT, PRN, and FHA were significantly higher in those born to vaccinated women compared with unvaccinated controls (P < .001, P = .001, and P < .001, respectively). Vaccination between 28-32 weeks' gestation resulted in significantly higher cord blood PT (4.18.0 vs 3.50 IU/mL, P = .009), PRN (5.83 vs 5.31 IU/mL, P = .03), and FHA (5.56 vs 5.03 IU/mL, P = .03) antibody levels than vaccination between 33-36 weeks' gestation. When adjusted for maternal prevaccination antibody levels, PT levels in early vs late vaccination approached significance (P = .06). PRN levels were significantly higher in the early vaccination group (P = .003). There was no significant difference for FHA antibody levels between the 2 groups (P = .16). CONCLUSION: Maternal vaccination during the third trimester is effective in affording higher levels of pertussis antibody protection to the newborn infant. Vaccination early in the third trimester appears more effective than later in pregnancy. PMID- 26968626 TI - Use of the MS2 aptamer and coat protein for RNA localization in yeast: A response to "MS2 coat proteins bound to yeast mRNAs block 5' to 3' degradation and trap mRNA decay products: implications for the localization of mRNAs by MS2-MCP system". AB - The MS2 system has been extensively used to visualize single mRNA molecules in live cells and follow their localization and behavior. In their Letter to the Editor recently published, Garcia and Parker suggest that use of the MS2 system may yield erroneous mRNA localization results due to the accumulation of 3' decay products. Here we cite published works and provide new data which demonstrate that this is not a phenomenon general to endogenously expressed MS2-tagged transcripts, and that some of the results obtained in their study could have arisen from artifacts of gene expression. PMID- 26968629 TI - From Mutational Mechanisms in Single Cells to Mutational Patterns in Cancer Genomes. AB - Analysis of mutations in thousands of cancer genomes has revealed many characteristic patterns of mutagenesis. The search for the molecular mechanisms underlying these mutational patterns has not only generated novel biological insight but also led to the development of new experimental strategies to study cell-to-cell variation and genome evolution. In this essay, we discuss recent progress in the study of mutational mechanisms with a particular emphasis on the analysis of mutagenesis at the single-cell level. PMID- 26968628 TI - Regulation of RORgammat in Inflammatory Lymphoid Cell Differentiation. AB - T-helper 17 (Th17) cells differentiate from naive CD4(+) T cells in response to signals from commensal microbiota and produce cytokines critical for the integrity of mucosal barriers. These cells also disseminate throughout the body, and are key participants in numerous inflammatory processes. A key challenge is to elucidate the mechanisms that govern Th17 cell beneficial versus pathogenic functions, characterized by different cytokine profiles. Mucosal Th17 cells require the nuclear hormone receptor RORgammat for their differentiation in draining lymph nodes. Cytokine expression is enabled in select tissues, to which these cells migrate, by external cues, such as the serum amyloid A proteins produced in response to commensal bacteria by epithelial cells in the small intestine. Additional cell-intrinsic cues contributing to production of Th17 cytokines during both homeostasis and inflammation include the RORgammat associated DEAD-box RNA helicase DDX5 and long noncoding RNA (lncRNA) Rmrp. The helicase activity of DDX5 is required for Rmrp-mediated assembly of the complex and colocalization with RORgammat throughout the genome to regulate key Th17 genes. How these are regulated in diverse microenvironments may provide insights for therapeutic intervention in autoimmune disease. PMID- 26968630 TI - Abdominal Pain in a 17-Year-Old Girl With Pancreatic Insufficient Cystic Fibrosis. PMID- 26968627 TI - Prp8 retinitis pigmentosa mutants cause defects in the transition between the catalytic steps of splicing. AB - Pre-mRNA splicing must occur with high fidelity and efficiency for proper gene expression. The spliceosome uses DExD/H box helicases to promote on-pathway interactions while simultaneously minimizing errors. Prp8 and Snu114, an EF2-like GTPase, regulate the activity of the Brr2 helicase, promoting RNA unwinding by Brr2 at appropriate points in the splicing cycle and repressing it at others. Mutations linked to retinitis pigmentosa (RP), a disease that causes blindness in humans, map to the Brr2 regulatory region of Prp8. Previous in vitro studies of homologous mutations in Saccharomyces cerevisiaes how that Prp8-RP mutants cause defects in spliceosome activation. Here we show that a subset of RP mutations in Prp8 also causes defects in the transition between the first and second catalytic steps of splicing. Though Prp8-RP mutants do not cause defects in splicing fidelity, they result in an overall decrease in splicing efficiency. Furthermore, genetic analyses link Snu114 GTP/GDP occupancy to Prp8-dependent regulation of Brr2. Our results implicate the transition between the first and second catalytic steps as a critical place in the splicing cycle where Prp8-RP mutants influence splicing efficiency. The location of the Prp8-RP mutants, at the "hinge" that links the Prp8 Jab1-MPN regulatory "tail" to the globular portion of the domain, suggests that these Prp8-RP mutants inhibit regulated movement of the Prp8 Jab1/MPN domain into the Brr2 RNA binding channel to transiently inhibit Brr2. Therefore, in Prp8-linked RP, disease likely results not only from defects in spliceosome assembly and activation, but also because of defects in splicing catalysis. PMID- 26968631 TI - Brief Client-Centered Motivational and Behavioral Intervention to Promote HPV Vaccination in a Hard-to-Reach Population: A Pilot Randomized Controlled Trial. AB - Objective To evaluate the impact of a client-centered behavioral intervention (Brief Negotiated Interviewing) on mothers' human papillomavirus (HPV) vaccine knowledge and vaccination initiation for their adolescent daughters. Methods We randomized mothers to intervention (n = 100) and control (n = 100) groups, and followed them over 12 months. Electronic medical records were reviewed to determine vaccination status. The primary outcome was receipt of the first vaccine. The secondary outcome was HPV vaccine knowledge among mothers. Results Brief Negotiated Interviewing intervention mothers demonstrated increased knowledge about HPV (pre/post mean score of 5 to 10 out of a possible 11; P < .001) and significantly higher mean knowledge scores (10 vs 6, P < .001) than control mothers. However, initiation and completion rates of the vaccine were not significantly different between groups. Conclusions Increasing HPV vaccine knowledge did not translate into increased vaccine uptake or completion of vaccination series. Future intervention must explore vaccine reminders to increase HPV vaccination rates. PMID- 26968632 TI - Radiological properties of nanocomposite Fricke gel dosimeters for heavy ion beams. AB - The radiological properties of nanocomposite Fricke gel (NC-FG) dosimeters prepared with different concentrations of nano-clay, perchloric acid and ferrous ions in deaerated conditions were investigated under carbon and argon ion beam irradiation covering a linear-energy-transfer (LET) range of 10 to 3000 eV/nm. We found that NC-FG exhibits radiological properties distinct from those of conventional Fricke gel. The radiation sensitivity of NC-FG is independent of the LET and is nearly constant even at very high LET (3000 eV/nm) values in the Bragg peak region of the argon ion beam. In addition, whereas conventional Fricke gel dosimeters only operate under acidic conditions, NC-FG dosimeters function under both acidic and neutral conditions. The radiation sensitivity decreases with decreasing nano-clay concentration in NC-FG, which indicates that the nano-clay plays a vital role in the radiation-induced oxidation of Fe(2.) PMID- 26968633 TI - Inflammasome-independent NLRP3 is required for epithelial-mesenchymal transition in colon cancer cells. AB - Inflammasome NLRP3 plays a crucial role in the process of colitis and colitis- associated colon cancer. Even though much is known regarding the NLRP3 inflammasome that regulates pro-inflammatory cytokine release in innate immune cells, the role of NLRP3 in non-immune cells is still unclear. In this study, we showed that NLRP3 was highly expressed in mesenchymal-like colon cancer cells (SW620), and was upregulated by tumor necrosis factors-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) respectively, during EMT in colon cancer epithelial cells HCT116 and HT29. Knockdown of NLRP3 retained epithelial spindle-like morphology of HCT116 and HT29 cells and reversed the mesenchymal characteristic of SW620 cells, indicated by the decreased expression of vimentin and MMP9 and increased expression of E-cadherin. In addition, knockdown of NLRP3 in colorectal carcinoma cells displayed diminished cell migration and invasion. Interestingly, during the EMT process induced by TNF-alpha or TGF-beta1, the cleaved caspase-1 and ASC speck were not detected, indicating that NLRP3 functions in an inflammasome-independent way. Further studies demonstrated that NLRP3 protein expression was regulated by NF-kappaB signaling in TNF-alpha or TGF beta1-induced EMT, as verified by the NF-kappaB inhibitor Bay 11-7082. Moreover, NLRP3 knockdown reduced the expression of Snail1, indicating that NLRP3 may promote EMT through regulating Snail1. In summary, our results showed that the NLRP3 expression, not the inflammasome activation, was required for EMT in colorectal cancer cells. PMID- 26968634 TI - Dual effect of LPS on murine myeloid leukemia cells: Pro-proliferation and anti proliferation. AB - Modification of the bone marrow microenvironment is considered as a promising strategy to control leukemic cell proliferation, diseases progression and relapse after treatment. However, due to the diversity and complexity of the cellular and molecular compartments in the leukemic microenvironment, it is extremely difficult to dissect the role of each individual molecule or cell type in vivo. Here we established an in vitro system to dissect the role of lipopolysaccharide (LPS), stromal cells and endothelial cells in the growth of mouse myeloid tumor cells and B-lymphoma cells. We found that either LPS or bone marrow stromal cells as a feeder layer in culture is required for the proliferation of myeloid tumor cells. Surprisingly, the growth of myeloid leukemic cells on stromal cells is strongly inhibited when coupled with LPS in culture. This opposing effect of LPS, a complete switch from pro-proliferation to antitumor growth is due, at least in part, to the rapidly increased production of interleukin 12, Fas ligand and tissue inhibitor of metalloproteinases-2 from stromal cells stimulated by LPS. These results demonstrate that LPS can either facilitate or attenuate tumor cell proliferation, thus changing the disease course of myeloid leukemias through its direct effect or modulation of the tumor microenvironment. PMID- 26968636 TI - Targeting the replisome with transduced monoclonal antibodies triggers lethal DNA replication stress in cancer cells. AB - Although chemical inhibition of the DNA damage response (DDR) in cancer cells triggers cell death, it is not clear if the fork blockade achieved with inhibitors that neutralise proteins of the replisome is sufficient on its own to overcome the DDR. Monoclonal antibodies to PCNA, which block the DNA elongation process in vitro, have been developed. When these antibodies were transduced into cancer cells, they are able to inhibit the incorporation of nucleoside analogues. When co-delivered with anti-PCNA siRNA, the cells were flattened and the size of their nuclei increased by up to 3-fold, prior to cell death. Analysis of these nuclei by super-resolution microscopy revealed the presence of large numbers of phosphorylated histone H2AX foci. A senescence-like phenotype of the transduced cells was also observed upon delivery of the corresponding Fab molecules or following PCNA gene disruption or when the Fab fragment of an antibody that neutralises DNA polymerase alpha was used. Primary melanoma cells and leukaemia cells that are resistant to chemical inhibitors were similarly affected by these antibody treatments. These results demonstrate that transduced antibodies can trigger a lethal DNA replication stress, which kills cancer cells by abolishing the biological activity of several constituents of the replisome. PMID- 26968635 TI - Allopurinol and oxypurinol promote osteoblast differentiation and increase bone formation. AB - Allopurinol and its active metabolite, oxypurinol are widely used in the treatment of gout and hyperuricemia. They inhibit xanthine oxidase (XO) an enzyme in the purine degradation pathway that converts xanthine to uric acid. This investigation examined the effect of allopurinol and oxypurinol on bone formation, cell number and viability, gene expression and enzyme activity in differentiating and mature, bone-forming osteoblasts. Although mRNA expression remained relatively constant, XO activity decreased over time with mature osteoblasts displaying reduced levels of uric acid (20% decrease). Treatment with allopurinol and oxypurinol (0.1-1 uM) reduced XO activity by up to 30%. At these concentrations, allopurinol and oxypurinol increased bone formation by osteoblasts ~4-fold and ~3-fold, respectively. Cell number and viability were unaffected. Both drugs increased tissue non-specific alkaline phosphatase (TNAP) activity up to 65%. Osteocalcin and TNAP mRNA expression was increased, 5-fold and 2-fold, respectively. Expression of NPP1, the enzyme responsible for generating the mineralisation inhibitor, pyrophosphate, was decreased 5-fold. Col1alpha1 mRNA expression and soluble collagen levels were unchanged. Osteoclast formation and resorptive activity were not affected by treatment with allopurinol or oxypurinol. Our data suggest that inhibition of XO activity promotes osteoblast differentiation, leading to increased bone formation in vitro. PMID- 26968637 TI - Diverse effects of G-protein-coupled free fatty acid receptors on the regulation of cellular functions in lung cancer cells. AB - Free fatty acids (FFAs) are dietary nutrients which mediate a variety of biological effects through binding to G-protein-coupled FFA receptors (FFARs). G protein-coupled receptor 120 (GPR120) and GPR40 are identified as FFARs for long- and medium-chain fatty acids. Here we investigated whether GPR120 and GPR40 are involved in the acquisition of malignant properties in lung cancer cells. Three lung cancer RLCNR, LL/2 and A549 cells used in this study expressed GPR120 and GPR40 genes. The cell motile activities of all cells were significantly suppressed by a GPR40 antagonist GW1100. In addition, GPR40 knockdown inhibited the cell motile activity of A549 cells. In gelatin zymography, matrix metalloproteinase-2 (MMP-2) activity in GPR40 knockdown was significantly lower than that in control cells. Next, to evaluate effects of GPR120 and GPR40 on cellular functions induced by anti-cancer drug, the long-term cisplatin (CDDP) treated (A549-CDDP) cells were generated. The expression levels of GPR120 and GPR40 were significantly decreased in A549-CDDP cells. While A549-CDDP cells showed the high cell motile activity, GW1100 suppressed the cell motile activity of A549-CDDP cells. These results demonstrate that GPR120 negatively and GPR40 positively regulate cellular functions during tumor progression in lung cancer cells. PMID- 26968638 TI - Disability Rises Gradually for a Cohort of Older Americans. AB - OBJECTIVES: We study changes in average disability over nearly two decades for a large epidemiological cohort of older Americans. As some people exit by mortality, do average disability levels for the living cohort rise rapidly, rise gradually, stay steady, or decline? METHOD: Data are from the Study of Asset and Health Dynamics Among the Oldest Old (AHEAD) cohort for 1993-2010. Cohort members are aged 70+ in 1993 (mean = 77.5 years), and the survivors are aged 87+ in 2010 (mean = 90.2 years). Personal care disability (activities of daily living), household management disability (instrumental activities of daily living), and physical limitations are studied. We study average disability for the living cohort over time and the disability histories for decedent and survivor groups. RESULTS: Average disability rises gradually over time for the living cohort. Earlier decedent groups have higher average disability than later ones. Near death, disability rises sharply for all decedent groups. Longer surviving groups have less average disability, and slower disability increases, than shorter surviving groups. All results are repeated for younger cohort members (baseline age = 70-79 years), older ones (baseline age = 80+ years), women, and men. DISCUSSION: As a cohort ages, average disability among living members increases gradually, signaling behavioral, psychological, and biological fitness in very old persons. PMID- 26968639 TI - Exportation and Validation of Latent Constructs for Dementia Case Finding in a Mexican American Population-based Cohort. AB - Background: The latent variable "delta" has been validated as a dementia phenotype. delta can be extracted from Spearman's general intelligence factor "g" in any data set that contains measures of cognition and instrumental activities of daily living (IADL). We used delta composites ("d-scores") to estimate the prevalence of dementia in the Hispanic Established Population for Epidemiological Studies in the Elderly (H-EPESE). Method: delta was constructed from Mini-Mental State Examination, a clock-drawing task (CLOX), and IADL. delta's H-EPESE factor weights were validated in the well-characterized Texas Alzheimer's Research and Care Consortium (TARCC). Optimal thresholds for the discrimination between "Alzheimer's disease" (AD) versus normal controls (NCs) were determined by receiver operating characteristic curve. Those thresholds were used to estimate the prevalence of dementia in H-EPESE. Results: Each delta homolog fits its source's data well. d-scores were strongly associated with Clinical Dementia Rating scale Sum of Boxes (r = .74-.85, all p < .001], and accurately distinguished AD cases from NCs, in both Mexican Americans (MAs) and non-Hispanic Whites (NHWs) [c = 0.94-0.96]. The TARCC MA threshold estimated the prevalence of dementia at 21.4% in H-EPESE. The NHW threshold estimated the prevalence of dementia at 21.0%. Conclusions: It is possible to export delta composites from populations to well-characterized cohorts for validation. PMID- 26968640 TI - Decision Support for Joint Replacement: Implications for Decisional Conflict and Willingness to Undergo Surgery. AB - Objectives: The present study investigates age differences in the types of decision support that total joint replacement (TJR) candidates desire and receive when making the decision to pursue surgery. We consider the social structural (relationship to the patient) and experiential factors (network members' experience with TJR) that influence individuals' support preferences and the interactions of these factors with age. We also examine whether a lack of support is linked with increased decisional conflict and reduced willingness to undergo surgery. Method: A telephone survey was conducted with 100 individuals (aged 40+) who were contemplating knee or hip replacement. Results: TJR candidates desired and received decision support from health care providers, family members, and individuals who had previously undergone TJR. They reported higher deficits in informational and emotional support than in instrumental support. Overall, a lack of instrumental support was associated with greater decisional conflict; a lack of instrumental support and a lack of informational support were associated with reduced willingness to undergo TJR. Discussion: Our findings point to the importance of involving both formal and informal network members in TJR discussions, and the need for informational guidance and practical assistance to reduce decisional conflict and uncertainty among individuals considering TJR. PMID- 26968641 TI - Characteristics of 10-year survivors of high-grade serous ovarian carcinoma. AB - OBJECTIVE: High-grade serous carcinoma (HGSC) generally presents at an advanced stage with poor long-term (LT) survival. Here we describe clinical features found in women surviving HGSC for ten or more years. METHODS: A multi-center research consortium was established between five participating academic centers. Patient selection criteria included high-grade serous ovarian, fallopian tube, or peritoneal carcinoma with at least ten years of follow up. Non-serous, borderline tumors and low-grade serous subtypes were excluded. RESULTS: The 203 identified LT ten-year survivors with HGSC were diagnosed at a median age of 57years (range 37-84years). The majority of patients had stage IIIC (72.4%) disease at presentation. Of those who underwent primary cytoreductive surgery, optimal cytoreduction was achieved in 143 (85.6%) patients. After a median follow up of 144months, 88 (46.8%) patients did not develop recurrent disease after initial treatment. Unexpected findings from this survey of LT survivors includes 14% of patients having had suboptimal cytoreduction, 11% of patients having an initial platinum free interval of <12months, and nearly 53% of patients having recurrent disease, yet still surviving more than ten years after diagnosis. CONCLUSIONS: LT survivors of HGSC of the ovary generally have favorable clinical features including optimal surgical cytoreduction and primary platinum sensitive disease. The majority of patients will develop recurrent disease, however many remained disease free for more than 10years. Future work will compare the clinical features of this unusual cohort of LT survivors with the characteristics of HGSC patients having less favorable outcomes. PMID- 26968642 TI - The Role of Xenobiotic-Metabolizing Enzymes in Anthelmintic Deactivation and Resistance in Helminths. AB - Xenobiotic-metabolizing enzymes (XMEs) modulate the biological activity and behavior of many drugs, including anthelmintics. The effects of anthelmintics can often be abolished by XMEs when the drugs are metabolized to an inefficient compound. XMEs therefore play a significant role in anthelmintic efficacy. Moreover, differences in XMEs between helminths are reflected by differences in anthelmintic metabolism between target species. Taking advantage of the newly sequenced genomes of many helminth species, progress in this field has been remarkable. The present review collects up to date information regarding the most important XMEs (phase I and phase II biotransformation enzymes; efflux transporters) in helminths. The participation of these XMEs in anthelmintic metabolism and their possible roles in drug resistance are evaluated. PMID- 26968643 TI - Parasitism as a Driver of Trophic Niche Specialisation. AB - The population trophic niche of free-living species can be subdivided into smaller niches comprising individuals specialising on specific food items. The roles of parasites in creating these specialised subgroups remain unclear. Intrapopulation differences in parasite infections can develop from specialist individuals within populations. Their differences in morphology and habitat can increase their exposure to intermediate hosts via infected prey, altering their parasite fauna. However, we also suggest that parasite infections can drive this niche specialisation. Through mechanisms including parasite manipulation, altered host phenotypes, and/ or parasite-mediated competition, parasites can alter the resource availability of their hosts, altering their trophic niches. Thus, trophic niche specialisations could result from parasitism via varying influences on host traits, raising questions for future research. PMID- 26968644 TI - A Phase II Study of the Efficacy and Safety of the Novel Oral SHIP1 Activator AQX 1125 in Subjects with Moderate to Severe Interstitial Cystitis/Bladder Pain Syndrome. AB - PURPOSE: In this 6-week, randomized, double-blind, placebo controlled, multicenter trial we assessed the effect of the novel SHIP1 (SH2-containing inositol-5'-phosphatase 1) activator AQX-1125 on bladder pain and urinary symptoms in patients with interstitial cystitis/bladder pain syndrome. MATERIALS AND METHODS: Women with interstitial cystitis/bladder pain syndrome and a mean pain score of 5 or greater on an 11-point scale despite treatment were randomized to AQX-1125 or placebo orally once daily for 6 weeks. Average and maximum pain scores (daily) and urinary frequency (before visits) were recorded by e-diary and at clinic visits. The O'Leary-Sant ICSI (Interstitial Cystitis Symptom Index) and ICPI (Interstitial Cystitis Problem Index), BPIC-SS (Bladder Pain Interstitial Cystitis Symptom Score) and SF-12v2(r) questionnaires were administered. Safety was monitored through 6 weeks of treatment and 4 weeks of followup. RESULTS: A total of 37 patients received oral AQX-1125 and 32 received placebo. At 6 weeks average daily pain on an e-diary decreased by 2.4 points for AQX-1125 vs 1.4 for placebo (p = 0.061), while average pain at clinic decreased by 2.6 vs 1.1 (p = 0.008), maximum daily pain on e-diary diary decreased by 2.6 vs 1.4 (p = 0.030) and maximum pain at clinic decreased by 2.8 vs 1.1 (p = 0.028). AQX-1125 reduced ICSI by 3.8 points vs 1.4 for placebo (p = 0.005), ICPI by 3.6 points vs 1.6 (p = 0.014) and BPIC-SS by 8.8 points vs 4.0 (p = 0.011). Urinary frequency decreased on AQX-1125 by 3.6 voids per 24 hours vs 0.8 for placebo (p = 0.040). Adverse event rates were similar for AQX-1125 and placebo (51.4% and 78.1%, respectively). No serious adverse events were reported. CONCLUSIONS: Women with moderate to severe interstitial cystitis/bladder pain syndrome who were treated with the oral SHIP1 activator AQX-1125 reported significantly reduced bladder pain and improved urinary symptoms at 6 weeks. AQX-1125 was well tolerated. AQX 1125 may be a potential new treatment for interstitial cystitis/bladder pain syndrome. It warrants further investigation. PMID- 26968645 TI - Urethral Reconstruction with Rectal Mucosa Graft Onlay: A Novel, Minimally Invasive Technique. AB - PURPOSE: Alternative grafts are needed for patients who are not suitable candidates for oral mucosa graft harvest or who have a paucity of oral mucosa graft available for reconstruction. Circumferential colonic mucosal grafts have demonstrated feasibility for urethral reconstruction, although sigmoid resection has been required for graft retrieval. We report the feasibility and short-term outcomes of urethral reconstruction using a rectal mucosa graft harvested by a novel, minimally invasive, transanal endoscopic microsurgical technique. MATERIALS AND METHODS: We retrospectively reviewed the records of all patients who underwent transanal endoscopic microsurgical rectal mucosa graft harvest and onlay urethroplasty since the technique was first implemented in 2013. Graft failure was defined as inability to pass a 16Fr cystoscope in the grafted urethra. RESULTS: All 4 strictures were bulbopendulous with a median length of 13.5 cm (range 10 to 21). Median followup was 18 months (range 12 to 28). Stricture etiology was lichen sclerosus in 3 patients and failed hypospadias interventions in 1. Three patients had undergone at least 1 prior urethroplasty. In 1 patient stricture recurred in the graft 10 months following reconstruction. There were no colorectal complications. CONCLUSIONS: To our knowledge this is the first study demonstrating urethral reconstruction using a rectal mucosa graft harvested by the transanal endoscopic microsurgical technique. Initial data revealed that this technique is feasible and safe, and minimizes graft harvest morbidity. Transanal endoscopic microsurgical harvest of a rectal mucosa graft may provide an alternative graft material for patients with long segment urethral strictures who are not candidates for oral mucosa graft harvest. Further experience and longer followup are needed to validate these findings. PMID- 26968646 TI - TiO2-NiO p-n nanocomposite with enhanced sonophotocatalytic activity under diffused sunlight. AB - TiO2-NiO composites with p-n junction were developed by assembling p-type NiO on n-type TiO2 using ultrasound assisted wet impregnation method. The sonophotocatalytic efficiencies of pure TiO2 and TiO2-NiO composites were evaluated under diffused sunlight using methyl orange (MO) as a model pollutant. The impregnation of NiO nanoparticles on TiO2 considerably enhanced the optical absorption in visible region (500-800nm) due to the formation of p-n junctions at the interface between TiO2 and NiO. The internal electric field induced by the p n junction led to effective separation of electron-hole pairs and thereby generating a large amount of reactive species for the degradation of MO. The individual effect of ultrasound and diffused sunlight for the degradation of MO was found to be 30% and 6%, respectively. A synergy of 4.8 fold was achieved when ultrasound was combined with photocatalytic degradation process in the presence of diffused sunlight. The sonophotocatalytic activity of TiO2-NiO photocatalysts with different NiO loading was also evaluated and 10wt% NiO loading was found to be optimal. Moreover, 66% of Total Organic Carbon (TOC) removal was achieved with the optimized TiO2-NiO composite in 140min. In addition, the TiO2-NiO composite exhibited an enhanced photocurrent response under visible light illumination. PMID- 26968647 TI - Design and synthesis of small molecule-sulfotyrosine mimetics that inhibit HIV-1 entry. AB - In the absence of a cure or vaccine for HIV/AIDS, small molecule inhibitors remain an attractive choice for antiviral therapeutics. Recent structural and functional studies of the HIV-1 surface envelope glycoprotein gp120 have revealed sites of vulnerability that can be targeted by small molecule and peptide inhibitors, thereby inhibiting HIV-1 infection. Here we describe a series of small molecule entry inhibitors that were designed to mimic the sulfated N terminal peptide of the HIV-1 coreceptor CCR5. From a panel of hydrazonothiazolyl pyrazolinones, we demonstrate that compounds containing naphthyl di- and tri sulfonic acids inhibit HIV-1 infection in single round infectivity assays with the disulfonic acids being the most potent. Molecular docking supports the observed structure activity relationship, and SPR confirmed binding to gp120. In infectivity assays treatment with a representative naphthyl disulfonate and a disulfated CCR5 N-terminus peptide results in competitive inhibition, with combination indices >2. In total this work shows that gp120 and HIV-1 infection can be inhibited by small molecules that mimic the function of, and are competitive with the natural sulfated CCR5 N-terminus. PMID- 26968648 TI - Quinoxalinone (Part II). Discovery of (Z)-3-(2-(pyridin-4-yl)vinyl)quinoxalinone derivates as potent VEGFR-2 kinase inhibitors. AB - Inhibition of VEGFR-2 kinase has been highlighted as one of the well-defined strategies to suppress tumor growth via blockade of angiogenesis. Guided by the principles of bioisosteric replacement and pharmacophoric fragment migration, a series of novel quinoxalinone derivates were designed, synthesized and evaluated for their VEGFR-2 inhibitory potencies. Among them, compounds 7c, 8b, 8c, 8e and 10b displayed antiangiogenic abilities via the in vitro tube formation assay (cellular level) and ex vivo rat aortic ring assay (tissue level) at a low concentration (0.1 MUM). By means of in vivo zebrafish embryo model, two (Z)-3-(2 (pyridin-4-yl)vinyl)quinoxalinone derivates 8c and 8e showed significant antiangiogenesis effects, suggesting they have potentials to be developed into antiangiogenesis agents via further structural optimization. Moreover, these two compounds also demonstrated potent inhibition toward VEGFR-2 and B-raf kinases in a low concentration (1 MUM). A possible interpretation of our evaluation result has been presented by a molecular docking study by docking representative compound 8c with VEGFR-2. PMID- 26968650 TI - Novel squaramides with in vitro liver stage antiplasmodial activity. AB - A structure-activity relationship study was performed with ten 8-aminoquinoline squaramides compounds active against liver stage malaria parasites, using human hepatoma cells (Huh7) infected by Plasmodium berghei parasites. In addition, their blood-schizontocidal activity was assessed against chloroquine-resistant W2 strain Plasmodium falciparum. Compound 3 was 7.3-fold more potent than the positive control primaquine against liver-stage parasites, illustrating the importance of the squarate moiety to activity. PMID- 26968651 TI - Molecular simulation of cyclohexanyl nucleic acid (CNA) duplexes with CNA, DNA and RNA and CNA triloop and tetraloop hairpin structures. AB - As part of a selection strategy for artificial nucleic acids (XNA) (to be considered as potential new information systems in vivo), we have carried out a modelling study on cyclohexanyl nucleic acids (CNA) duplexes and hairpins. CNA may form a duplex as well as hairpin structures, having the carbocyclic nucleosides in the (4)C1 conformation (with equatorial basis). The geometry of ds CNA is close to that of a HNA:RNA duplex. We demonstrated that CNA triphosphates function as a substrate for polymerases. Modelling experiments indicate that the monomers are probably presented to the polymerase in the (1)C4 conformation. PMID- 26968649 TI - Donor substrate promiscuity of bacterial beta1-3-N-acetylglucosaminyltransferases and acceptor substrate flexibility of beta1-4-galactosyltransferases. AB - beta1-3-N-Acetylglucosaminyltransferases (beta3GlcNAcTs) and beta1-4 galactosyltransferases (beta4GalTs) have been broadly used in enzymatic synthesis of N-acetyllactosamine (LacNAc)-containing oligosaccharides and glycoconjugates including poly-LacNAc, and lacto-N-neotetraose (LNnT) found in the milk of human and other mammals. In order to explore oligosaccharides and derivatives that can be synthesized by the combination of beta3GlcNAcTs and beta4GalTs, donor substrate specificity studies of two bacterial beta3GlcNAcTs from Helicobacter pylori (Hpbeta3GlcNAcT) and Neisseria meningitidis (NmLgtA), respectively, using a library of 39 sugar nucleotides were carried out. The two beta3GlcNAcTs have complementary donor substrate promiscuity and 13 different trisaccharides were produced. They were used to investigate the acceptor substrate specificities of three beta4GalTs from Neisseria meningitidis (NmLgtB), Helicobacter pylori (Hpbeta4GalT), and bovine (Bbeta4GalT), respectively. Ten of the 13 trisaccharides were shown to be tolerable acceptors for at least one of these beta4GalTs. The application of NmLgtA in one-pot multienzyme (OPME) synthesis of two trisaccharides including GalNAcbeta1-3Galbeta1-4GlcbetaProN3 and Galbeta1 3Galbeta1-4Glc was demonstrated. The study provides important information for using these glycosyltransferases as powerful catalysts in enzymatic and chemoenzymatic syntheses of oligosaccharides and derivatives which can be useful probes and reagents. PMID- 26968652 TI - C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors. AB - A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3'3'-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC50=16 nM for 9a compared to 10nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI. PMID- 26968653 TI - Safety of indwelling pleural catheter use in patients undergoing chemotherapy: a five-year retrospective evaluation. AB - BACKGROUND: Indwelling pleural catheters (IPC) are increasingly becoming a first line treatment in the management of malignant pleural effusions. Ambulatory management using IPC are increasingly used in this patient group whilst they are receiving concurrent chemotherapy. There are currently no prospective trials examining IPC safety in chemotherapy. This study's objective is to determine if IPC insertion is safe in patients undergoing chemotherapy. METHODS: We conducted a retrospective analysis of all patients who underwent IPC insertion for malignant pleural effusion at our trust from September 2010 to December 2014. Data was collected on IPC insertion and removal, tumour type, systemic chemotherapy, pleural infection and other complications. RESULTS: One hundred four patients were identified, 43 in chemotherapy group and 61 in non chemotherapy group. The incidence of pleural infection in chemotherapy group vs non-chemotherapy group, 4 (9.3%) vs 3 (4.9%) respectively, was not statistically different (Fisher's exact p = 0.311). There was no significant difference in six month infection-free duration from the date of IPC insertion (log rank p = 0.394). Overall six-month mortality in chemotherapy group was significantly lower than in non-chemotherapy group (log rank p = 0.007). CONCLUSIONS: This is the second largest retrospective case-control series that concludes systemic chemotherapy is safe in patients with IPC undergoing chemotherapy. PMID- 26968655 TI - Intrahippocampal infusion of spermidine improves memory persistence: Involvement of protein kinase A. AB - Spermidine (SPD) is an endogenous aliphatic amine that modulates GluN2B containing NMDA receptors and improves memory. Recent evidence suggests that systemic SPD improves the persistence of the long term memory of fear. However, the role of hippocampal polyamines and its binding sites in the persistence of fear memory is to be determined, as well as its putative underlying mechanisms. This study investigated whether the intrahippocampal (i.h.) infusion of spermidine or arcaine, modulators of polyamine binding site at GluN2B-containing NMDA receptors, alters the persistence of the memory of contextual fear conditioning task in rats. We also investigated whether protein synthesis and cAMP dependent protein kinase (PKA) play a role in SPD-induced improvement of the fear memory persistence. While 12h post-training infusion of spermidine facilitated, arcaine and the inhibitor of protein synthesis (anisomycin) impaired the memory of fear assessed 7days after training. The infusion of arcaine, anisomycin or a selective PKA inhibitor (H-89), at doses that have no effect on memory per se, prevented the SPD-induced improvement of memory persistence. H-89 prevented the stimulatory effect of SPD on phospho-PKA/total-PKA ratio. These results suggests that the improvement of fear memory persistence induced by spermidine involves GluN2B-containing NMDA receptors, PKA pathway and protein synthesis in rats. PMID- 26968654 TI - Does tuberculosis threaten our ageing populations? AB - BACKGROUND: The global population is ageing quickly and our understanding of age related changes in the immune system suggest that the elderly will have less immunological protection from active tuberculosis (TB). DISCUSSION: Ongoing global surveillance of TB notifications shows increasing age of patients with active TB. This effect of age is compounded by changes to clinical manifestations of disease, confounding of diagnostic tests and increased rates of adverse reactions to antimicrobial treatment of TB. Future epidemiological surveillance, development of diagnostic tests and trials of treatment shortening should all include a focus on ageing people. More detailed surveillance of TB notifications in elderly people should be undertaken and carefully evaluated. Risk stratification will help target care for those in greatest need, particularly those with comorbidities or on immunosuppressive therapies. Novel diagnostics and treatment regimes should be designed specifically to be used in this cohort. PMID- 26968656 TI - Exercise prevents high-fat diet-induced impairment of flexible memory expression in the water maze and modulates adult hippocampal neurogenesis in mice. AB - Obesity is currently one of the most serious threats to human health in the western civilization. A growing body of evidence suggests that obesity is associated with cognitive dysfunction. Physical exercise not only improves fitness but it has also been shown in human and animal studies to increase hippocampus-dependent learning and memory. High-fat diet (HFD)-induced obesity and physical exercise both modulate adult hippocampal neurogenesis. Adult neurogenesis has been demonstrated to play a role in hippocampus-dependent learning and memory, particularly flexible memory expression. Here, we investigated the effects of twelve weeks of HFD vs. control diet (CD) and voluntary physical activity (wheel running; -R) vs. inactivity (sedentary; -S) on hippocampal neurogenesis and spatial learning and flexible memory function in female C57Bl/6 mice assessed in the Morris water maze. HFD was initiated either in adolescent mice combined with long-term concurrent exercise (preventive approach) or in young adult mice with 14days of subsequent exercise (therapeutic approach). HFD resulted in impaired flexible memory expression only when initiated in adolescent (HFD-S) but not in young adult mice, which was successfully prevented by concurrent exercise (HFD-R). Histological analysis revealed a reduction of immature neurons in the hippocampus of the memory impaired HFD-S mice of the preventive approach. Long-term physical exercise also led to accelerated spatial learning during the acquisition period, which was accompanied by increased numbers of newborn mature neurons (HFD-R and CD-R). Short-term exercise of 14days in the therapeutic group was not effective in improving spatial learning or memory. We show that (1) alterations in learning and flexible memory expression are accompanied by changes in the number of neuronal cells at different maturation stages; (2) these neuronal cells are in turn differently affected by HFD; (3) adolescent mice are specifically susceptible to the negative effects of HFD. Thus, physical exercise, by modulating adult neurogenesis in the hippocampus, might represent a potential preventive approach for treating cognitive impairments associated with adolescent obesity. PMID- 26968658 TI - Axonal activity-dependent myelination in development: Insights for myelin repair. AB - Recent advances in transgenic tools have allowed us to peek into the earliest stages of vertebrate development to study axon-glial communication in the control of peri-natal myelination. The emerging role of neuronal activity in regulating oligodendrocyte progenitor cell behavior during developmental myelination has opened up an exciting possibility-a role for neuronal activity in the early stages of remyelination. Recent work from our laboratory and others has also shown that contrary to previously established dogma in the field, complete remyelination up to pre-demyelination levels can be achieved in mouse models of MS by oligodendrogenic neural precursor cells that derive from the adult subventricular zone. These cells are electrically active and can be depolarized, suggesting that neuronal activity may have a modulatory role in their development and remyelination potential. In this review, we summarize recent advances in our understanding of the development of axon-glia communication and apply those same concepts to remyelination, with an emphasis on the particular roles of different sources of oligodendrocyte progenitor cells. PMID- 26968657 TI - Laboratory investigations into the origin of Mycoplasma synoviae isolated from a lesser flamingo (Phoeniconaias minor). AB - BACKGROUND: The role of wild birds in the transmission and spread of mycoplasmas is not clear. Up to now different Mycoplasma species have been isolated from wild birds many of which are not considered pathogens sensu stricto for domestic flocks. This report describes the first isolation of Mycoplasma synoviae in a captive lesser flamingo (Phoeniconaias minor) held in a zoo in Italy and the laboratory investigations performed to elucidate its origin. Results showed that the strain was similar to the MS-H vaccine strain using the vlhA methods although no vaccination with this product was used in the zoo. CASE PRESENTATION: This paper describes investigations into a case in which 10 of 12 adult lesser flamingos (Phoeniconaias minor) died after having recently been moved from the Netherlands to a new zoo in Northern Italy. While most of the birds appeared to have died from the stress of movement and poor adaptation to their new environment, Mycoplasma synoviae, an important poultry pathogen in the layer and meat industry, was isolated for the first time from the trachea of one animal presenting catarrhal tracheitis and fibrinous airsacculitis. Genetic analysis of the conserved region of the vlhA was not able to differentiate the flamingo strain from the MS-H vaccine strain. However differences in the sequences of the obg gene of the flamingo and vaccine strain were detected. A test for temperature sensitivity (ts) gave a ts (-) phenotype for the flamingo strain, in contrast to the ts (+) status of the MS-H strain. Based on this information and knowing that the flamingos were not vaccinated against M. synoviae, it is highly likely that the flamingo was infected with a genetically similar wild strain by contact with infected birds. CONCLUSIONS: This case provides evidence for the potential role of international trade of ornamental birds as a possible route of introduction of new mycoplasma strains between countries, and moreover highlight that vlhA gene sequencing was not sufficient to discriminate the wild strain isolated from the flamingo from the MS-H vaccine strain. PMID- 26968659 TI - De novo transcriptomic analysis of the female and male adults of the blood fluke Schistosoma turkestanicum. AB - BACKGROUND: Schistosoma turkestanicum is a parasite of considerable veterinary importance as an agent of animal schistosomiasis in many countries, including China. The S. turkestanicum cercariae can also infect humans, causing cercarial dermatitis in many countries and regions of the world. In spite of its significance as a pathogen of animals and humans, there is little transcriptomic and genomic data in the public databases. METHODS: Herein, we performed the transcriptome Illumina RNA sequencing (RNA-seq) of adult males and females of S. turkestanicum and de novo transcriptome assembly. RESULTS: Approximately 81.1 (female) and 80.5 (male) million high-quality clean reads were obtained and then 29,526 (female) and 41,346 (male) unigenes were assembled. A total of 34,624 unigenes were produced from S. turkestanicum females and males, with an average length of 878 nucleotides (nt) and N50 of 1480 nt. Of these unigenes, 25,158 (72.7 %) were annotated by blast searches against the NCBI non-redundant protein database. Among these, 21,995 (63.5 %), 22,189 (64.1 %) and 13,754 (39.7 %) of the unigenes had significant similarity in the NCBI non-redundant protein (NR), non-redundant nucleotide (NT) and Swiss-Prot databases, respectively. In addition, 3150 unigenes were identified to be expressed specifically in females and 1014 unigenes were identified to be expressed specifically in males. Interestingly, several pathways associated with gonadal development and sex maintenance were found, including the Wnt signaling pathway (103; 2 %) and progesterone-mediated oocyte maturation (77; 1.5 %). CONCLUSIONS: The present study characterized and compared the transcriptomes of adult female and male blood fluke, S. turkestanicum. These results will not only serve as valuable resources for future functional genomics studies to understand the molecular aspects of S. turkestanicum, but also will provide essential information for ongoing whole genome sequencing efforts on this pathogenic blood fluke. PMID- 26968661 TI - Identifying Barriers Among Childhood Cancer Survivors Transitioning to Adult Health Care. AB - The aim of this study was to identify and describe barriers of young adult childhood cancer survivors transitioning to adult health care within 5 years of leaving a pediatric oncology practice. Several barriers have been identified in the literature, but other obstacles as to why this vulnerable population may be avoiding health care are unknown. This is a descriptive pilot study of a convenience sample of childhood cancer survivors, currently 20 to 25 years of age, who were diagnosed at less than 21 years of age. The Transition to Adult Care Survey assessing survivor barriers is an online survey consisting of 15 questions, with a drop-down menu for answers and 2 open-ended questions. The survey was accessible by smartphone or computer. Standard descriptive statistics were used to describe variables of interest. Our population consisted of 48 childhood cancer survivors. Their mean age was 23.21 years. Only 74% reported following through with annual preventive screening, and 57% reported that they consider themselves at risk for further medical problems as a result of their cancer treatment. Lack of knowledge of the importance of health screening may be a potential barrier to consistent follow-up care. PMID- 26968662 TI - Risk Factors and Genetics of Atrial Fibrillation. AB - Atrial fibrillation (AF) is by far the most common sustained tachyarrhythmia, affecting 1% to 2% of the general population. AF prevalence and the total annual cost for treatment are alarming, emphasizing the need for an urgent attention to the problem. Thus, having up-to-date information on AF risk factors and appreciating how they promote maintenance of AF maintenance are essential. This article presents a simplified examination of AF risk factors, including emerging genetic risks. PMID- 26968660 TI - ChlamyNET: a Chlamydomonas gene co-expression network reveals global properties of the transcriptome and the early setup of key co-expression patterns in the green lineage. AB - BACKGROUND: Chlamydomonas reinhardtii is the model organism that serves as a reference for studies in algal genomics and physiology. It is of special interest in the study of the evolution of regulatory pathways from algae to higher plants. Additionally, it has recently gained attention as a potential source for bio-fuel and bio-hydrogen production. The genome of Chlamydomonas is available, facilitating the analysis of its transcriptome by RNA-seq data. This has produced a massive amount of data that remains fragmented making necessary the application of integrative approaches based on molecular systems biology. RESULTS: We constructed a gene co-expression network based on RNA-seq data and developed a web-based tool, ChlamyNET, for the exploration of the Chlamydomonas transcriptome. ChlamyNET exhibits a scale-free and small world topology. Applying clustering techniques, we identified nine gene clusters that capture the structure of the transcriptome under the analyzed conditions. One of the most central clusters was shown to be involved in carbon/nitrogen metabolism and signalling, whereas one of the most peripheral clusters was involved in DNA replication and cell cycle regulation. The transcription factors and regulators in the Chlamydomonas genome have been identified in ChlamyNET. The biological processes potentially regulated by them as well as their putative transcription factor binding sites were determined. The putative light regulated transcription factors and regulators in the Chlamydomonas genome were analyzed in order to provide a case study on the use of ChlamyNET. Finally, we used an independent data set to cross-validate the predictive power of ChlamyNET. CONCLUSIONS: The topological properties of ChlamyNET suggest that the Chlamydomonas transcriptome posseses important characteristics related to error tolerance, vulnerability and information propagation. The central part of ChlamyNET constitutes the core of the transcriptome where most authoritative hub genes are located interconnecting key biological processes such as light response with carbon and nitrogen metabolism. Our study reveals that key elements in the regulation of carbon and nitrogen metabolism, light response and cell cycle identified in higher plants were already established in Chlamydomonas. These conserved elements are not only limited to transcription factors, regulators and their targets, but also include the cis-regulatory elements recognized by them. PMID- 26968663 TI - Mechanisms of Atrial Fibrillation: Rotors, Ionic Determinants, and Excitation Frequency. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia; however, therapy is suboptimal. We review recent data on dynamics of wave propagation during AF and its mechanistic link to the substrate. Data show that the dominant frequency (DF) increase during transition to persistent AF may be explained by rotor acceleration. We discuss how translation of experimentally derived understanding of the rotors may find its way into the clinic, focusing on studies analyzing spatial distribution of DF in the atria of patients with paroxysmal versus persistent AF, and how that knowledge might contribute to improve the outcome of AF ablation procedures. PMID- 26968664 TI - Diagnostic Evaluation and Follow-Up of Patients with Atrial Fibrillation. AB - In this article, a review of the diagnostic evaluation and outpatient follow-up of patients with atrial fibrillation is presented. After exploring details of symptoms, past medical history, quality of life, and physical exam findings, diagnostic tools are then discussed. Furthermore, important considerations after the initial diagnosis and treatment of patients with atrial fibrillation are discussed. PMID- 26968665 TI - Rate Versus Rhythm Control for Atrial Fibrillation. AB - Treatment of patients with symptomatic atrial fibrillation (AF) with antiarrhythmic drug therapy in general improves their symptom scores and exercise tolerance; however, large randomized trials have failed to show a mortality benefit with a rhythm-control compared with a rate-control strategy. Catheter ablation in patients who have failed or not tolerated medical therapy has been shown to alleviate symptoms and improve quality of life. However, catheter ablation cannot undo the structural remodeling that contributed to the arrhythmia in the first place. Patients should be alerted to modifiable factors that may decrease the likelihood of unchecked structural remodeling and AF recurrence. PMID- 26968666 TI - Antiarrhythmic Drug Therapy for Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most frequently encountered arrhythmia. Prevalence increases with advancing age and so as its associated comorbidities, like heart failure. Choice of pharmacologic therapy depends on whether the goal of treatment is maintaining sinus rhythm or tolerating AF with adequate control of ventricular rates. Antiarrhythmic therapy and conversion of AF into sinus rhythm comes with the side effect profile, and we should select best antiarrhythmic therapy, individualized to the patient. New antiarrhythmic drugs are being tested in clinical trials. Drugs that target remodeling and inflammation are being tested for their use as prevention of AF or as upstream therapy. PMID- 26968667 TI - Catheter Ablation of Atrial Fibrillation. AB - Strategies and technology related to catheter ablation for atrial fibrillation (AF) continue to advance since its inception nearly 20 years ago. Broader selections of patients are now offered ablation with a similar level of procedural outcome and safety standards. It is hoped that improved understanding of the pathophysiologic processes of the initiation and maintenance of AF will refine target selection during ablation and improve long-term procedural efficacy, particularly in patients with persistent and long-standing persistent AF. PMID- 26968668 TI - Surgery for Atrial Fibrillation. AB - Atrial fibrillation is the most common cardiac arrhythmia, and its treatment options include drug therapy or catheter-based or surgical interventions. The surgical treatment of atrial fibrillation has undergone multiple evolutions over the last several decades. The Cox-Maze procedure went on to become the gold standard for the surgical treatment of atrial fibrillation and is currently in its fourth iteration (Cox-Maze IV). This article reviews the indications and preoperative planning for performing a Cox-Maze IV procedure. This article also reviews the literature describing the surgical results for both approaches including comparisons of the Cox-Maze IV to the previous cut-and-sew method. PMID- 26968669 TI - Atrioventricular Junction Ablation for Atrial Fibrillation. AB - Atrioventricular junction (AVJ) ablation is an effective therapy in patients with symptomatic atrial fibrillation who are intolerant to or unsuccessfully managed with rhythm control or medical rate control strategies. A drawback is that the procedure mandates a pacing system. Overall, the safety and efficacy of AVJ ablation is high with a majority of the patients reporting significant improvement in symptoms and quality-of-life measures. Risk of sudden cardiac death after device implantation is low, especially with an appropriate postprocedure pacing rate. Mortality benefit with AVJ ablation has been shown in patients with heart failure and cardiac resynchronization therapy devices. PMID- 26968670 TI - Antithrombotic and Anticoagulant Therapy for Atrial Fibrillation. AB - As atrial fibrillation (AF) substantially increases the risk of stroke and other thromboembolic events, most AF patients require appropriate antithrombotic prophylaxis. Oral anticoagulation (OAC) with either dose-adjusted vitamin K antagonists (VKAs) (eg, warfarin) or non-VKA oral anticoagulants (eg, dabigatran, apixaban, rivaroxaban) can be used for this purpose unless contraindicated. Therefore, risk assessment of stroke and bleeding is an obligatory part of AF management, and risk has to be weighed individually. Antiplatelet drugs (eg, aspirin and clopidogrel) are inferior to OAC, both alone and in combination, with a comparable risk of bleeding events. PMID- 26968671 TI - Left Atrial Appendage Exclusion for Atrial Fibrillation. AB - Percutaneous left atrial appendage (LAA) closure is being increasingly used as a treatment strategy to prevent stroke in patients with atrial fibrillation (AF) who have contraindications to anticoagulants. Several approaches and devices have been developed in the last few years, each with their own unique set of advantages and disadvantages. In this article, the published studies on surgical and percutaneous approaches to LAA closure are reviewed, focusing on stroke mechanisms in AF, LAA structure and function relevant to stroke prevention, practical differences in procedural approach, and clinical considerations surrounding management. PMID- 26968672 TI - Postoperative Atrial Fibrillation: Incidence, Mechanisms, and Clinical Correlates. AB - Atrial fibrillation is the most commonly encountered arrhythmia after cardiac surgery. Although usually self-limiting, it represents an important predictor of increased patient morbidity, mortality, and health care costs. Numerous studies have attempted to determine the underlying mechanisms of postoperative atrial fibrillation (POAF) with varied success. A multifactorial pathophysiology is hypothesized, with inflammation and postoperative beta-adrenergic activation recognized as important contributing factors. The management of POAF is complicated by a paucity of data relating to the outcomes of different therapeutic interventions in this population. This article reviews the literature on epidemiology, mechanisms, and risk factors of POAF, with a subsequent focus on the therapeutic interventions and guidelines regarding management. PMID- 26968673 TI - Novel Upstream Approaches to Prevent Atrial Fibrillation Perpetuation. AB - The mechanisms underlying atrial fibrillation (AF) in humans are poorly understood. In particular, we simply do not understand how atrial AF becomes persistent or permanent. The objective of this brief review is to address the most important factors involved in the mechanism of AF perpetuation, including structural remodeling in the form of fibrosis and electrical remodeling secondary to ion channel expression changes. In addition, I discuss the possibility that both fibrosis and electrical remodeling might be preventable when intervening pharmacologically early enough before the remodeling process reaches a point of no return. PMID- 26968674 TI - Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study. AB - BACKGROUND: Use of CT for assessment of extracellular volume fraction (ECV) is a new approach toward the evaluation of diffuse and focal myocardial fibrosis. It has recently been demonstrated that a hybrid algorithm of half- and full-scan reconstruction can improve image quality of delayed-phase CT. OBJECTIVE: The purpose of this study was to evaluate reproducibility of CT measurement of ECV of the myocardium using pre-contrast and delayed-phase CT, and to investigate the association between ECV and location, age and gender in subjects without clinical coronary artery disease. METHODS: Thirty-eight subjects (ages 45-78, mean 65 years, 14 females) without coronary artery stenosis, stress perfusion deficits or myocardial delayed enhancement on comprehensive cardiac CT comprise the study population. Delayed-phase CT was reconstructed with the hybrid algorithm. ECV was calculated as a ratio of the change in Hounsfield unit of the myocardium and the left ventricular (LV) blood before and after contrast administration, multiplied by (1-hematocrit). RESULTS: Good inter- and intra-observer agreement was observed in CT measurement of ECV (intraclass correlation coefficient: 0.968 and 0.971, respectively). Mean ECV was 26.1 +/- 2.0% (range 22.6-30.0%), and was positively related to age (r = 0.46, p = 0.003). Mean ECV in males was lower compared with females (25.5 +/- 2.0% vs. 27.1 +/- 1.8%, p = 0.02). There was no statistically significant difference in ECV between anterior, septal, inferior, and lateral segments. CONCLUSIONS: CT measurement of myocardial ECV showed high inter- and intra-observer reproducibility, and age-related increase and gender-related difference of ECV were demonstrated. This might enable additional CT evaluation of diffuse and focal myocardial fibrosis in various pathological conditions as part of a comprehensive cardiac CT examination. PMID- 26968676 TI - Antimicrobial metabolites from marine microorganisms. AB - Marine ecological niches have recently been described as "particularly promising" sources for search of new antimicrobials to combat antibiotic-resistant strains of pathogenic microorganisms. Marine organisms are excellent sources for many industrial products, but they are partly explored. Over 30 000 compounds have been isolated from marine sources. Bacteria, fungi, and cyanobacteria obtained from various marine sources secret several industrially useful bioactive compounds, possessing antibacterial, antifungal, and antimycobacterial activities. Sustainable cultivation methods for promising marine organisms and biotechnological processes for selected compounds can be developed, along with the establishment of biosensors for monitoring the target compounds. The semisynthetic modifications of marine-based bioactive compounds produce their new derivatives, structural analogs and mimetics that could serve as novel lead compounds against resistant pathogens. The present review focuses on promising antimicrobial compounds isolated from marine microbes from 1991-2013. PMID- 26968677 TI - Comparative analysis of chemical constituents, antimicrobial and antioxidant activities of ethylacetate extracts of Polygonum cuspidatum and its endophytic actinomycete, Streptomyces sp. A0916. AB - The present study investigated the chemical composition of ethylacetate extracts from an endophytic actinomycete Streptomyces sp. A0916 and its host Polygonum cuspidatum. A comparative analysis of the antimicrobial and antioxidant properties of the extracts was also conducted. 32 compounds of P. cuspidatum and 23 compounds of Streptomyces sp. A0916 were isolated and identified by GC/MS. Antimicrobial activities of the extracts were evaluated using eight microbial strains (3 Gram-positive bacteria, 3 Gram-negative bacteria, and 2 fungi). The Streptomyces sp. A0916 extracts showed a wide range of antimicrobial activities and presented greater antimicrobial effectiveness than the P. cuspidatum extracts. The minimum inhibitory concentration (MIC) of Streptomyces sp. A0916 extracts against the ampicillin-resistant strain Enterococcus faecium SIIA843 was 32 MUg.mL(-1). Furthermore, the extracts had greater antimicrobial effect against Gram-positive bacteria than Gram-negative bacteria. Finally, the antioxidant activity of the Streptomyces sp. A0916 extracts was equal to that of the P. cuspidatum extracts. In conclusion, our results suggest that the endophytic actinomycetes of the medicinal plants are an important source of bioactive substances. PMID- 26968678 TI - Ge-Gen Decoction attenuates oxytocin-induced uterine contraction and writhing response: potential application in primary dysmenorrhea therapy. AB - The uterine tetanic contraction and uterine artery blood flow reduction are possible reasons for primary dysmenorrhea (PD). In the present study, we aimed to evaluate the uterine relaxant effect and the influence on uterine artery blood velocity of Ge-Gen Decoction (GGD), a well-known Chinese herbal formula. In female ICR mice, uterine contraction was induced by oxytocin exposure following estradiol benzoate pretreatment, and the uterine artery blood velocity was detected by Doppler ultrasound. Histopathological examination of the uterine tissue samples were performed by H&E staining. Ex vivo studies demonstrated that oxytocin, posterior pituitary, or acetylcholine induced contractions in isolated mouse uterus. GGD inhibited both spontaneous and stimulated contractions. In vivo study demonstrated that GGD significantly reduced oxytocin-induced writhing responses with a maximal inhibition of 87%. Further study demonstrated that GGD normalized oxytocin-induced abnormalities of prostaglandins F2 alpha (PGF2alpha) and Ca(2+) in mice. In addition, injection of oxytocin induced a decrease in uterine artery blood flow velocity. Pretreatment with GGD reversed the oxytocin response on blood flow velocity. Histopathological examination showed pretreatment with GGD alleviated inflammation and edema in the uterus when compared with the model group. Both ex vivo and in vivo results indicated that GGD possessed a significant spasmolytic effect on uterine tetanic contraction as well as improvement on uterine artery blood velocity which may involve PGF2alpha and Ca(2+) signaling, suggesting that GGD may have a clinic potential in PD therapy. PMID- 26968675 TI - Bitter melon: a panacea for inflammation and cancer. AB - Nature is a rich source of medicinal plants and their products that are useful for treatment of various diseases and disorders. Momordica charantia, commonly known as bitter melon or bitter gourd, is one of such plants known for its biological activities used in traditional system of medicines. This plant is cultivated in all over the world, including tropical areas of Asia, Amazon, east Africa, and the Caribbean and used as a vegetable as well as folk medicine. All parts of the plant, including the fruit, are commonly consumed and cooked with different vegetables, stir-fried, stuffed or used in small quantities in soups or beans to give a slightly bitter flavor and taste. The plant is reported to possess anti-oxidant, anti-inflammatory, anti-cancer, anti-diabetic, anti bacterial, anti-obesity, and immunomodulatory activities. The plant extract inhibits cancer cell growth by inducing apoptosis, cell cycle arrest, autophagy and inhibiting cancer stem cells. The plant is rich in bioactive chemical constituents like cucurbitane type triterpenoids, triterpene glycosides, phenolic acids, flavonoids, essential oils, saponins, fatty acids, and proteins. Some of the isolated compounds (Kuguacin J, Karaviloside XI, Kuguaglycoside C, Momordicoside Q-U, Charantin, alpha-eleostearic acid) and proteins (alpha Momorcharin, RNase MC2, MAP30) possess potent biological activity. In the present review, we are summarizing the anti-oxidant, anti-inflammatory, and anti-cancer activities of Momordica charantia along with a short account of important chemical constituents, providing a basis for establishing detail biological activities of the plant and developing novel drug molecules based on the active chemical constituents. PMID- 26968680 TI - Chemical profiling of Qixue Shuangbu Tincture by ultra-performance liquid chromatography with electrospray ionization quadrupole-time-of-flight high definition mass spectrometry (UPLC-QTOF/MS). AB - The present study was designed to develop and validate a sensitive and reliable ultra high performance liquid chromatography coupled with quadrupole time-of flight mass spectrometry (UPLC-QTOF/MS) method to separate and identify the chemical constituents of Qixue Shuangbu Tincture (QXSBT), a classic traditional Chinese medicine (TCM) prescription. Under the optimized UPLC and QTOF/MS conditions, 56 components in QXSBT, including chalcones, triterpenoids, protopanaxatriol, flavones and flavanones were identified and tentatively characterized within a running time of 42 min. The components were identified by comparing the retention times, accurate mass, and mass spectrometric fragmentation characteristic ions, and matching empirical molecular formula with that of the published compounds. In conclusion, the established UPLC-QTOF/MS method was reliable for a rapid identification of complicated components in the TCM prescriptions. PMID- 26968679 TI - Comparative analysis of volatile oils in the stems and roots of Ephedra sinica via GC-MS-based plant metabolomics. AB - With a great difference in therapeutic effects of Mahuang (MH, the stems of Ephedra sinica) and Mahuanggen (MHG, the roots of Ephedra sinica), chemical differences between MH and MHG should be investigated. In the present study, gas chromatography-mass spectrometry (GC-MS)-based plant metabolomics was employed to compare volatile oil profiles of MH and MHG. The antioxidant activities of volatile oils from MH and MHG were also compared. 32 differential chemical markers were identified according to the variable importance in the projection (VIP) value of orthogonal partial least squares discriminant analysis (OPLS-DA) and P value of Mann-Whitney test. Among them, chemical markers of tetramethylpyrazine (TMP) and alpha-terpineol were quantified. Their contents were much higher in most MH samples compared with MHG. The antioxidant assay demonstrated that MH had significantly higher free radical-scavenging activity than MHG. Although MH and MHG derived from the same medicinal plant, there was much difference in their volatile oil profiles. MH samples had significantly higher content of two reported pharmacologically important chemical markers of TMP and alpha-terpineol, which may account for their different antioxidant activities. PMID- 26968681 TI - Rapid separation and identification of multiple constituents in Danhong Injection by ultra-high performance liquid chromatography coupled to electrospray ionization quadrupole time-of-flight tandem mass spectrometry. AB - To characterize and identify multiple constituents in Danhong injection (DHI), a fast ultra-high performance liquid chromatography coupled to electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-QTOF/MS) method was established and validated in the present study. A total of 63 compounds, including 33 phenolic acids, 2 C-glycosyl quinochalcones, 6 flavonoid O-glycosides, 4 iridoid glycosides, 6 organic acids, 5 amino acids, and 3 nucleosides, were identified or tentatively characterized. In conclusion, the UHPLC-ESI-QTOF/MS method is useful and efficient for in-depth structural elucidation of chemical compounds in complex matrices of herbal medicines such as DHI. PMID- 26968682 TI - A longitudinal study of psychological stress among undergraduate dental students at the University of Jordan. AB - BACKGROUND: The purpose of this study was to identify whether psychological stress increased as undergraduate dental students progressed through their studies from first to fifth year. Another objective was to determine if the perceived sources of stress have changed along the years. METHODS: To achieve these aims, a cohort of students at the University of Jordan were followed from first to fifth year of dental school. Fifth year students completed both the General Health Questionnaire 'GHQ-12' which was used to assess psychological stress and the Dental Environment Stress questionnaire 'DES' which was used to examine the perceived sources of stress. The same cohort of students had completed similar questionnaires during their first year of study. Chi-square analysis and independent t-test analysis were performed to compare GHQ-12 and DES scores between first and fifth year. RESULTS: Results showed that psychological stress increased from first to fifth year of study. Eighty- nine percent of fifth year students scored over the cut-off point of three in the GHQ-12 compared to 58 % in the first year. The difference between the years was statistically significant at p = 0.05. Mean score for DES also increased between first and fifth year of study and the difference was statistically significant at p = 0.05. CONCLUSIONS: Results of this study demonstrated that stress in dental students at the University of Jordan increased along the years. Fifth year students showed a high level of psychological stress and methods to reduce that stress should be further investigated and utilized. PMID- 26968683 TI - Observations on quality senior health business: success patterns and policy implications. AB - OBJECTIVE: Population ageing is a global issue that affects almost every country. Most ageing researches focused on demand side and studies related to supply side were relatively scarce. This study selected quality enterprises focus on ageing health and analysed their patterns on providing quality services successfully. DESIGN: Our study selected quality senior health enterprises and explored their success patterns through face-to-face semi-structured in-depth interviews with CEO of each enterprise in 2013. SETTING: Thirty-three quality senior health enterprises in Taiwan. PARTICIPANTS: Thirty-three CEO's of enterprises were interviewed individually. INTERVENTION: None. MAIN OUTCOME MEASURES: Core values and vision, historical development, organization structure, services/products provided, delivering channels, customer relationships and further development strategies. RESULTS: Our results indicated success patterns for senior enterprises that there were meeting diversified lifestyles and substitutive needs for the elderly and their caregivers, providing a total solution for actual/virtual integration and flexible one-stop shopping services. We classified these enterprises by used degree of clicks-and-mortar of services and residing situation of the elderly. Industry characteristics and policy implications were summarized. CONCLUSIONS: Our observations will serve as a primary evidenced base for enterprises developing their senior market, and also for opening dialogue between customers and enterprises to facilitate valuable opportunities for co creation between the supply and demand sides. PMID- 26968684 TI - Added value of involving patients in the first step of multidisciplinary guideline development: a qualitative interview study among infertile patients. AB - BACKGROUND: Patient involvement in scoping the guideline is emphasized, but published initiatives actively involving patients are generally limited to the writing and reviewing phase. OBJECTIVE: To assess patients' added value to the scoping phase of a multidisciplinary guideline on infertility. DESIGN: Qualitative interview study. SETTING AND PARTICIPANTS: We conducted interviews among 12 infertile couples and 17 professionals. INTERVENTION: We listed and compared the couples' and professionals' key clinical issues (=care aspects that need improvement) to be addressed in the guideline according to four domains: current guidelines, professionals, patients and organization of care. MAIN OUTCOME MEASURES: Main key clinical issues suggested by more than three quarters of the infertile couples and/or at least two professionals were identified and compared. RESULTS: Overall, we identified 32 key clinical issues among infertile couples and 23 among professionals. Of the defined main key clinical issues, infertile couples mentioned eight issues that were not mentioned by the professionals. These main key clinical issues mainly concerned patient-centred (e.g. poor information provision and poor alignment of care) aspects of care on the professional and organizational domain. Both groups mentioned two main key clinical issues collectively that were interpreted differently: the lack of emotional support and respect for patients' values. CONCLUSIONS: Including patients from the first phase of the guideline development process leads to valuable additional main key clinical issues for the next step of a multidisciplinary guideline development process and broadens the scope of the guideline, particularly regarding patient-centredness and organizational issues from a patients' perspective. PMID- 26968686 TI - Are Irish therapists at heightened risk for low back pain? AB - BACKGROUND: Within the international literature, no studies have been identified that compare prevalence rates of low back pain (LBP) in chartered physiotherapists, physical and athletic therapists and those in the national working population, making it unclear whether such therapists are an occupational group at high risk of developing LBP. AIMS: To establish the prevalence of LBP among therapists (both employed and self-employed) in Ireland, to compare the employment status-, gender- and age-specific LBP prevalence rates between therapists and the national working population and to estimate the adjusted odds of developing LBP among therapists relative to the national working population. METHODS: An analysis of data from the Health In Hand Intensive Tasks and Safety (HITS) study and the third national Survey on Lifestyle, Attitudes and Nutrition (SLAN). The HITS study was a cross-sectional study investigating work-related musculoskeletal disorders in practising therapists. The SLAN 2007 was a face-to face interview study of adults. RESULTS: LBP prevalence in therapists was 49% with no significant difference by employment status. Therapists had a much higher prevalence compared with the national working population across all demographic strata, with therapists nearly five times more likely to suffer from LBP than the national working population after careful adjustment for differences in sociodemographic factors. CONCLUSIONS: Therapists in Ireland are an occupational group at high risk of developing LBP, warranting further research into their physical and psychosocial work-related risk factors. PMID- 26968685 TI - Influence of patient-assessed quality of chronic illness care and patient activation on health-related quality of life. AB - OBJECTIVE: To examine the association of the Patient Assessment of Chronic Illness Care (PACIC) with health-related quality of life (HRQoL) and the modulating effect of patient activation on this association. DESIGN AND PARTICIPANTS: A population-based prospective cohort study of people with Type 2 diabetes in Queensland, Australia, using data from self-report questionnaires, collected annually from 2008 (n = 3761) to 2010 (n = 3040). MAIN OUTCOME MEASURES: Predictors were the 20-item PACIC (dichotomized at the score of 3), and the 13-item Patient Activation Measure (PAM), dichotomized into activation Levels 1 and 2 versus Levels 3 and 4. Analyses were restricted to participants whose PACIC and PAM categories did not change over 2 years of follow-up. Outcome variables were EQ-5D index and EQ VAS dichotomized at the uppermost quartile, and EQ-5D index also dichotomized at the median. STATISTICAL ANALYSES: An inverse probability weighted Poisson regression with a log-link function and a binary response variable for each outcome was used to obtain risk ratios (RRs), and the interaction between PACIC and PAM was statistically modelled, taking into consideration patient characteristics and the respective baseline outcome variable. RESULTS: The positive association between the PACIC and EQ VAS was seen only in participants with low activation (adjusted RR: 3.91; 95% CI: 1.40-10.95; P = 0.009), and not in those with high activation, indicating the non-synergistic interaction effect of the PACIC and PAM. This association was not found with EQ 5D index. CONCLUSIONS: Chronic care received consistently over time can positively affect health status, and benefit patients with low activation. PMID- 26968688 TI - [Family-centered care: A model for approaching dementia care in the community]. AB - Along with ageing population, there has been an increase in the prevalence and incidence of chronic and debilitating conditions, such as dementia which, in turn, has increased the demands for long term care in the community. This is challenging current health care systems that wish to provide an appropriate response whilst intensify its efforts to contain costs. This paper, through a critical reflection, argues for an integrative, positive, and systemic care approach, focused not only on the person with dementia but also on the entire family unit. For this purpose, it approaches the impact that dementia has for the family, and therefore for Primary Health Care professional. In addition care strategies aimed at strengthening the whole family system are suggested. PMID- 26968687 TI - Personalized treatment planning with a model of radiation therapy outcomes for use in multiobjective optimization of IMRT plans for prostate cancer. AB - PURPOSE: To build a new treatment planning approach that extends beyond radiation transport and IMRT optimization by modeling the radiation therapy process and prognostic indicators for more outcome-focused decision making. METHODS: An in house treatment planning system was modified to include multiobjective inverse planning, a probabilistic outcome model, and a multi-attribute decision aid. A genetic algorithm generated a set of plans embodying trade-offs between the separate objectives. An influence diagram network modeled the radiation therapy process of prostate cancer using expert opinion, results of clinical trials, and published research. A Markov model calculated a quality adjusted life expectancy (QALE), which was the endpoint for ranking plans. RESULTS: The Multiobjective Evolutionary Algorithm (MOEA) was designed to produce an approximation of the Pareto Front representing optimal tradeoffs for IMRT plans. Prognostic information from the dosimetrics of the plans, and from patient-specific clinical variables were combined by the influence diagram. QALEs were calculated for each plan for each set of patient characteristics. Sensitivity analyses were conducted to explore changes in outcomes for variations in patient characteristics and dosimetric variables. The model calculated life expectancies that were in agreement with an independent clinical study. CONCLUSIONS: The radiation therapy model proposed has integrated a number of different physical, biological and clinical models into a more comprehensive model. It illustrates a number of the critical aspects of treatment planning that can be improved and represents a more detailed description of the therapy process. A Markov model was implemented to provide a stronger connection between dosimetric variables and clinical outcomes and could provide a practical, quantitative method for making difficult clinical decisions. PMID- 26968689 TI - The association between lactate, mean arterial pressure, central venous oxygen saturation and peripheral temperature and mortality in severe sepsis: a retrospective cohort analysis. AB - BACKGROUND: During resuscitation in severe sepsis and septic shock, several goals are set. However, usually not all goals are equally met. The aim of this study is to determine the relative importance of the different goals, such as mean arterial pressure (MAP), lactate, central venous oxygen saturation (ScvO2) and central to forefoot temperature (delta-T), and how they relate to intensive care unit (ICU) and hospital mortality. METHODS: In a retrospective cohort study in a 20-bed mixed medical and surgical ICU of a teaching hospital we studied consecutive critically ill patients who were admitted for confirmed infection and severe sepsis or septic shock between 2008 and 2014. All validated MAP, lactate levels, ScvO2 and delta-T for the first 24 hours of ICU treatment were extracted from a clinical database. Logistic regression analyses were performed on validated measurements in the first hour after admission and on mean values over 24 hours. Patients were categorized by MAP (24-hour mean below or above 65 mmHg) and lactate (24-hour mean below or above 2 mmol/l) for Cox regression analysis. RESULTS: From 837 patients, 821 were eligible for analysis. All had MAP and lactate measurements. The delta-T was available in 812 (99%) and ScvO2 was available for 193 out of these patients (23.5%). Admission lactate (p < 0.001) and admission MAP (p < 0.001) were independent predictors of ICU and hospital mortality. The 24-hour mean values for lactate, MAP and delta-T were all independent predictors of ICU mortality. Hospital mortality was independently predicted by the 24-hour mean lactate (odds ratio (OR) 1.34, 95% confidence interval (CI) 1.30-1.40, p = 0.001) mean MAP (OR 0.96, 95% CI 0.95-0.97, p = 0.001) and mean delta-T (OR 1.09, 95% CI 1.06-1.12, p = 0.001). Patients with a 24-hour mean lactate below 2 mmol/l and a 24-hour mean MAP above 65 mmHg had the best survival, followed by patients with a low lactate and a low MAP. CONCLUSIONS: Admission MAP and lactate independently predicted ICU and hospital mortality. The 24-hour mean lactate, mean MAP and mean delta-T independently predicted hospital mortality. A Cox regression analysis showed that 24-hour mean lactate above 2 mmol/l is the strongest predictor for ICU mortality. PMID- 26968691 TI - Stimulus-induced pacemaker activity in interstitial cells of Cajal associated with the deep muscular plexus of the small intestine. AB - BACKGROUND: The ICC-DMP have been proposed to generate stimulus-dependent pacemaker activity, rhythmic transient depolarizations, that take part in orchestrating segmentation and clustered propulsive motor patterns in the small intestine. However, little is known about the fundamental properties of ICC-DMP. METHODS: This study was undertaken to increase our understanding of intrinsic properties of the ICC-DMP through calcium imaging and intracellular electrical recordings. KEY RESULTS: Without stimulation, most ICC-DMP were quiescent. In some preparations ICC-DMP generated rhythmic low-frequency calcium oscillations (<10 cpm) with or without high frequency activity superimposed (>35 cpm). Immunohistochemistry proved the existence of NK1R on the ICC-DMP and close contacts between ICC-DMP and substance P-positive nerves. Substance P (25 nM) induced low-frequency calcium oscillations that were synchronized across the ICC DMP network. Substance P also induced low frequency rhythmic transient depolarizations (<10cpm) in circular muscle cells close to the ICC-DMP. An intracellular recording from a positively identified ICC-DMP showed rhythmic transient depolarizations with superimposed high frequency activity. To investigate if quiescent ICC-DMP were chronically inhibited by nitrergic activity, nNOS was inhibited, but without effect. CONCLUSIONS & INFERENCES: Substance P changes non-synchronized high frequency flickering or quiescence in ICC-DMP into strong rhythmic calcium transients that are synchronized within the network; they are associated with rhythmic transient depolarizations within the same frequency range. We hypothesize that Substance P, released from nerves, can evoke rhythmicity in ICC-DMP, thereby providing it with potential pacemaker activity. PMID- 26968692 TI - Agreement Between Proximal Femoral Geometry and Component Design in Total Hip Arthroplasty: Implications for Implant Choice. AB - BACKGROUND: The present study aimed to analyze the agreement between proximal femoral geometry of adult hips and femoral component design in total hip arthroplasty. METHODS: Anatomical femoral offset (FOAnat) and the anatomical neck shaft angle (NSAAnat) of 800 adult hips were measured by computed tomography scans, and anatomical femoral neck height (FHAnat) was calculated. Corresponding best-fit implants of the most common hip system (standard, high offset and varus variant) were identified for each hip. Finally, the precision of the best possible anatomic reconstruction was assessed. RESULTS: The mean FOAnat was 38.0 mm (range: 19.8-57.9 mm, standard deviation [SD]: 6.4 mm), the mean NSAAnat was 130.8 degrees (range: 107.1 degrees -151.9 degrees ; SD: 6.5 degrees ), and the mean FHAnat was 32.6 mm (range: 14.4-52.0 mm; SD: 5.5 mm). In 450 (56.3%) hips, the standard variant was identified to be the best-fit implant, followed by the varus (n = 282, 35.3%) and the high offset (n = 68, 8.5%) variants. The mean minimal distance from the best-fit implant was 4.5 mm (range: 0.1-20.2 mm, SD: 3.4 mm). Excellent agreement (distance: <2 mm) between hip anatomy and best-fit implant was found in 203 (25.4%) hips, combined excellent and acceptable agreement (distance: <6 mm) in 569 (71.1%) hips, whereas 213 (28.9%) hips were graded as poor (distance: >=6 mm). CONCLUSION: The present study revealed a mismatch between proximal femoral anatomy of a relevant proportion of adult hips and implant geometry of the most common femoral component in total hip arthroplasty. PMID- 26968690 TI - Does high level youth sports participation increase the risk of femoroacetabular impingement? A review of the current literature. AB - Sports participation can be an integral part of adolescent development with numerous positive short and long-term effects. Despite these potential benefits very high levels of physical activity, during skeletal maturation, have been proposed as a possible cause of cam-type femoroacetabular impingement (FAI). The influence of physical activity on the developing physis has been previously described both in animal studies and epidemiological studies of adolescent athletes. It is therefore important to determine whether the development of FAI is secondary to excessive physical activity or a combination of a vulnerable physis and a set level of physical activity. A review of the current literature suggests that adolescent males participating in ice-hockey, basketball and soccer, training at least three times a week, are at greater risk than their non athletic counterparts of developing the femoral head-neck deformity associated with femoroacetabular impingement. PMID- 26968693 TI - Feasibility and Safety of 2-Day Discharge After Fast-Track Total Hip Arthroplasty: A Chinese Experience. AB - BACKGROUND: A fast-track program (FT) can shorten hospital stay after total hip arthroplasty. The aim of this prospective randomized study was to investigate the feasibility and safety of 2-day discharge after fast-track total hip arthroplasty in a Chinese population. METHODS: A total of 258 selected patients who underwent unilateral primary total hip arthroplasty were enrolled into the final cohort and were randomized into the FT (n = 126) and standard program group (n = 132). In the FT group, the patients received a multidisciplinary FT, whereas the patients in the standard program group only followed a standard care program. After setting restricted discharge criteria, we undertook follow-up evaluations to investigate the length of hospital stay, clinical performance, 30-day and 90-day complications, and 90-day admissions in both groups. A multivariate regression model was used to assess independent predictors of delayed discharge (>2 days). RESULTS: The mean length of stay was reduced from 5.8 to 2.1 days after implementation of our FT (P < .001). Most patients in the FT group (82.5%) were discharged within 2 days postoperatively. However, the complications and readmissions appeared no difference between the two groups. The multivariate regression analysis identified age (P = .041), operative time (P < .001), intraoperative blood loss (P = .026), and total blood loss (P < .001) as the predictive factors for delayed discharge. CONCLUSION: A 2-day discharge protocol after fast-track total hip arthroplasty can be safe and feasible in selected patients, without increasing the risk of complications and readmissions. Further efforts are needed to shorten operative time and reduce perioperative blood loss and eventually to shorten hospital stay. PMID- 26968695 TI - Utilization of Femoral Nerve Blocks for Total Knee Arthroplasty. AB - BACKGROUND: Little information exists on national trends in the utilization of femoral nerve blocks (FNBs) in total knee arthroplasties (TKAs). We sought to describe the variations in anesthetic practice for FNB using the National Anesthesia Clinical Outcomes Registry. METHODS: We used the National Anesthesia Clinical Outcomes Registry to obtain patient, procedural, and provider information from January 2010 to June 2015. Case characteristics and clinical outcomes were compared using chi-square or t tests. We used logistic regression to identify associations between patient and case characteristics with anesthetic technique. RESULTS: Overall, 219,327 cases met the inclusion criteria, in which 72.7% and 27.3% did not or did receive a FNB, respectively. Patients less than 18 years old and those with higher American Society of Anesthesiologists physical status class (>=III) were less likely to receive a FNB. Surgeries performed after 5:00 PM also were less likely to receive the block. Cases with urban zip code had approximately 20% increased odds of receiving a FNB. General or neuraxial anesthesia types were not associated with utilization of FNB. FNB was associated with decreased percentage of extended recovery room stays and postoperative nausea and/or vomiting. CONCLUSION: There is considerable practice variation in the use of FNB for TKA, which is associated with various factors such as geographic location, time of day, and patient-specific comorbidities. Approximately one fourth of TKA cases include FNB. Overall, our study supports the clinical utility of FNB in TKA. As more data are compiled, it will be important to examine how national trends shift in the future. PMID- 26968694 TI - Severe Hand Osteoarthritis Strongly Correlates With Major Joint Involvement and Surgical Intervention. AB - BACKGROUND: The presence of hand osteoarthritis (OA) increases the risk for developing OA in other major joints. Although genetic predisposition has been implicated in its causation, its exact role has yet to be established. The association of hand OA with symptomatic and asymptomatic major joints has not been previously studied. METHODS: Hundred consecutive patients had a hand photo taken for visual documentation of the hand joints. Radiographs of hand and all major symptomatic joints were analyzed and classified using the Kellgren-Lawrence scale by 2 independent observers including an orthopedic radiologist. RESULTS: Severe hand OA was present in 91% of the patients. Radiographic analysis showed that the hip was involved in 88% of the patients, of whom 85.2% (75) were symptomatic and 14.7% (13) were asymptomatic. Hip arthroplasty was required by 62.5% (55) of symptomatic hip patients. Knee involvement was present in 37% of the patients; all were symptomatic and 81.1% (30) of these required knee arthroplasty. Bilateral surgery was performed in 33% (28) and "2 joint (hip and knee)" surgery was performed in 6% (5). Spine involvement was present in 72% of the patients. There was a significant correlation between hand radiographic findings of OA and hip (r = 0.68; P = .03), knee (r = 0.58; P = .042), and spine (r = .39; P = .05) involvement. CONCLUSION: There was a significant correlation between severe hand OA and hip, knee, and spine involvement. Severity of Hand OA can have a predictive value on multiple joint involvement and risk of surgical intervention. This study emphasizes the need to investigate the genetic predisposition in causation of OA. PMID- 26968696 TI - Parasitic contamination of fresh vegetables sold at central markets in Khartoum state, Sudan. AB - BACKGROUND: Fresh vegetables are considered as vital nutrients of a healthy diet as they supply the body with essential supplements. The consumption of raw vegetables is the main way for transmission of intestinal parasitic organisms. This study was aimed at detecting the parasitic contamination in fresh vegetables sold in two central open-aired markets in Khartoum state, Sudan. METHODS: In this prospective cross-sectional study, a total of 260 fresh vegetable samples and 50 water samples used to sprinkle vegetable(s) were collected from two central open aired markets (namely; Elshaabi and Central markets) during November 2011 to May 2012. The samples were microscopically examined for detection of parasitic life forms using standardized parasitological techniques for protozoans and helminthes worms. RESULTS: Of the 260 fresh vegetable samples, 35 (13.5 %) were microscopically positive for intestinal parasites whereas 7/50 (14 %) of water samples used to sprinkle vegetable(s) were found positives. Remarkably, high level of contamination in fresh vegetable samples was recorded in lettuce (Lactuca sativa) 36.4 % (4/11) while cayenne pepper (Capsicum annuum) and cucumber (Cucumis sativus) were not contaminated. The identified protozoans and helminthes were Entamoeba histolytica/dispar, Entamoeba coli, Giardia lamblia, Ascaris lumbricoides, Strongyloides stercoralis, T. trichiura and hookworms. The most predominant parasite encountered was E. histolytica/dispar (42.9 %) whereas both T. trichiura and A. lumbricoides (2.9 %) were the least detected parasites. None of the fresh vegetables had single parasitic contamination. The highest percentages found in water samples used to sprinkle vegetable(s) was for Strongyloides larvae 60 % (3/5). It is worth-mentioned that the rate of contamination in Elshaabi market was higher compared with Central market. However, there was no significant correlation between the type of vegetables and existence of parasites in both markets and a high significant relationship was observed between the type of parasite and total prevalence in fresh vegetables (p = 0.000). CONCLUSION: The study has identified a moderate rate of fresh vegetables contaminated with protozoan and helminthes. Contaminated fresh vegetables in central markets of Khartoum state may play a significant role in transmission of intestinal parasitic infections to humans, and the water used by greengrocers to sprinkle vegetable(s) can be implicated in vegetable contamination. PMID- 26968697 TI - Hemoglobin assessment: precision and practicability evaluated in the Netherlands the HAPPEN study. AB - BACKGROUND: Most donors do not like the invasive hemoglobin (Hb) measurement in fingerstick capillary samples. Alternative noninvasive devices have recently become available. In this study we assessed the precision and practicability of noninvasive devices and compared them with measurements in capillary and venous samples. STUDY DESIGN AND METHODS: A total of 2589 blood donors were included in the study. Hb levels were measured with the noninvasive devices NBM 200 or Haemospect and compared with values obtained with the invasive devices HemoCue 201 and HemoCue 301 and with venous values. Precision was evaluated in terms of sensitivity and specificity for detection of Hb levels below the cutoff level for donation, taking venous values as "reference values." RESULTS: Hb levels measured with both invasive and noninvasive devices differed significantly from venous measurements. Measurements with invasive devices correlated stronger with venous values and were more precise. Sensitivity ranged from 30.1% (HemoCue 201) to 3.5% (Haemospect) in men and from 36.6% (HemoCue 201) to 10.8% (Haemospect) in women. Specificity ranged from 99.8% (HemoCue 201) to 95.5% (Haemospect) in men and from 98.9% (HemoCue 201) to 94.6% (NBM 200) in women. Most donors preferred the noninvasive measurement. CONCLUSION: Measurements with invasive devices showed stronger correlation and better agreement with venous values than noninvasive devices. Sensitivity was low for all measurement devices, particularly the noninvasive ones. In terms of precision invasive measurement would be preferred for donor screening, although a majority of donors preferred the noninvasive measurement. PMID- 26968698 TI - Normalization of cardiac substrate utilization and left ventricular hypertrophy precede functional recovery in heart failure regression. AB - AIMS: Impaired cardiac substrate metabolism plays an important role in heart failure (HF) pathogenesis. Since many of these metabolic changes occur at the transcriptional level of metabolic enzymes, it is possible that this loss of metabolic flexibility is permanent and thus contributes to worsening cardiac function and/or prevents the full regression of HF upon treatment. However, despite the importance of cardiac energetics in HF, it remains unclear whether these metabolic changes can be normalized. In the current study, we investigated whether a reversal of an elevated aortic afterload in mice with severe HF would result in the recovery of cardiac function, substrate metabolism, and transcriptional reprogramming as well as determined the temporal relationship of these changes. METHODS AND RESULTS: Male C57Bl/6 mice were subjected to either Sham or transverse aortic constriction (TAC) surgery to induce HF. After HF development, mice with severe HF (% ejection fraction < 30) underwent a second surgery to remove the aortic constriction (debanding, DB). Three weeks following DB, there was a near complete recovery of systolic and diastolic function, and gene expression of several markers for hypertrophy/HF were returned to values observed in healthy controls. Interestingly, pressure-overload-induced left ventricular hypertrophy (LVH) and cardiac substrate metabolism were restored at 1 week post-DB, which preceded functional recovery. CONCLUSIONS: The regression of severe HF is associated with early and dramatic improvements in cardiac energy metabolism and LVH normalization that precede restored cardiac function, suggesting that metabolic and structural improvements may be critical determinants for functional recovery. PMID- 26968699 TI - Evaluating a management strategy for malrotation in heterotaxy patients. AB - BACKGROUND: There is disagreement over the management of malrotation in children with heterotaxy and congenital heart disease (CHD). We sought to evaluate the outcomes of management with a Ladd procedure compared to observation in this cohort of patients. METHODS: We performed a retrospective review of CHD children with heterotaxy and malrotation identified on radiographs treated from 8/2002 until 4/2014. Primary outcomes evaluated were readmission for small bowel obstruction (SBO) or volvulus. RESULTS: We identified 88 patients with cardiac heterotaxy and malrotation. Sixty-eight (77%) had a Ladd procedure. Eighteen (26%) of the 68 had abdominal symptoms, but only one had an underlying volvulus without ischemia. Twenty (23%) patients died of cardiopulmonary complications, 8 before and 12 after the Ladd procedure. Sixty-eight patients survived to the review date (median: 5years): 56 in the Ladd cohort and 12 observed. Six of the 56 (11%) surviving Ladd patients were readmitted to hospital with an SBO, and 2 required surgical intervention. None of the 12 surviving nonoperative patients developed a volvulus. CONCLUSION: Eleven percent of patients developed SBO after their Ladd procedure. Conversely, no observed patients developed a volvulus. This suggests that complications from a Ladd procedure occur with higher frequency than complications from observing heterotaxy patients with malrotation. PMID- 26968701 TI - Physical activity in advanced cancer patients: a systematic review protocol. AB - BACKGROUND: Progressive, incurable cancer is associated with increased fatigue, increased muscle weakness, and reduced physical functioning, all of which negatively impact quality of life. Physical activity has demonstrated benefits on cancer-related fatigue and physical functioning in early-stage cancer patients; however, its impact on these outcomes in end-stage cancer has not been established. The aim of this systematic review is to determine the potential benefits, harms, and effects of physical activity interventions on quality of life outcomes in advanced cancer patients. METHODS/DESIGN: A systematic review of peer-reviewed literature on physical activity in advanced cancer patients will be undertaken. Empirical quantitative studies will be considered for inclusion if they present interventional or observational data on physical activity in advanced cancer patients. Searches will be conducted in the following electronic databases: CINAHL; CIRRIE Database of International Rehabilitation Research; Cochrane Database of Systematic Reviews (CDSR); Database of Abstracts of Reviews of Effects (DARE); Cochrane Central Register of Controlled Trials (CENTRAL); EMBASE; MEDLINE; PEDro: the Physiotherapy Evidence Database; PQDT; PsycInfo; PubMed; REHABDATA; Scopus; SPORTDiscus; and Web of Science, to identify relevant studies of interest. Additional strategies to identify relevant studies will include citation searches and evaluation of reference lists of included articles. Titles, abstracts, and keywords of identified studies from the search strategies will be screened for inclusion criteria. Two independent reviewers will conduct quality appraisal using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies (EPHPP) and the Cochrane risk of bias tool. A descriptive summary of included studies will describe the study designs, participant and activity characteristics, and objective and patient-reported outcomes. DISCUSSION: This systematic review will summarize the current evidence base on physical activity interventions in advanced cancer patients. The findings from this systematic review will identify gaps to be explored by future research studies and inform future practice guideline development of physical activity interventions in advanced cancer patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015026281. PMID- 26968700 TI - Bioenergetics and metabolism: a bench to bedside perspective. AB - 'Metabolism' refers to the vast collection of chemical processes that occur within a living organism. Within this broad designation, one can identify metabolism events that relate specifically to energy homeostasis, whether they occur at the subcellular, cellular, organ, or whole organism level. This review operationally refers to this type of metabolism as 'energy metabolism' or 'bioenergetics.' Changes in energy metabolism/bioenergetics have been linked to brain aging and a number of neurodegenerative diseases, and research suggests mitochondria may uniquely contribute to this. Interventions that manipulate energy metabolism/bioenergetic function and mitochondria may have therapeutic potential and efforts intended to accomplish this are playing out at basic, translational, and clinical levels. This review follows evolving views of energy metabolism's role in neurodegenerative diseases but especially Alzheimer's disease, with an emphasis on the bench-to-bedside process whose ultimate goal is to develop therapeutic interventions. It further considers challenges encountered during this process, which include linking basic concepts to a medical question at the initial research stage, adapting conceptual knowledge gained to a disease associated application in the translational stage, extending what has been learned to the clinical arena, and maintaining support for the research at each of these fundamentally linked but functionally distinct stages. A bench-to bedside biomedical research process is discussed that moves through conceptual, basic, translational, and clinical levels. For example, herein a case was made that bioenergetics is a valid Alzheimer's disease therapeutic target. Following this, a fundamental strategy for manipulating bioenergetics was defined, potential implications studied, and the approach extended to the clinical arena. This article is part of the 60th Anniversary special issue. PMID- 26968703 TI - Survival after kidney transplant from non-matching live donor is good. PMID- 26968702 TI - Association between alcohol intake and the risk of pancreatic cancer: a dose response meta-analysis of cohort studies. AB - BACKGROUND: Studies examining the association between alcohol intake and the risk of pancreatic cancer have given inconsistent results. The purpose of this study was to summarize and examine the evidence regarding the association between alcohol intake and pancreatic cancer risk based on results from prospective cohort studies. METHODS: We searched electronic databases consisting of PubMed, Ovid, Embase, and the Cochrane Library identifying studies published up to Aug 2015. Only prospective studies that reported effect estimates with 95% confidence intervals (CIs) for the risk of pancreatic cancer, examining different alcohol intake categories compared with a low alcohol intake category were included. Results of individual studies were pooled using a random-effects model. RESULTS: We included 19 prospective studies (21 cohorts) reporting data from 4,211,129 individuals. Low-to-moderate alcohol intake had little or no effect on the risk of pancreatic cancer. High alcohol intake was associated with an increased risk of pancreatic cancer (risk ratio [RR], 1.15; 95% CI: 1.06-1.25). Pooled analysis also showed that high liquor intake was associated with an increased risk of pancreatic cancer (RR, 1.43; 95% CI: 1.17-1.74). Subgroup analyses suggested that high alcohol intake was associated with an increased risk of pancreatic cancer in North America, when the duration of follow-up was greater than 10 years, in studies scored as high quality, and in studies with adjustments for smoking status, body mass index, diabetes mellitus, and energy intake.. CONCLUSIONS: Low to-moderate alcohol intake was not significantly associated with the risk of pancreatic cancer, whereas high alcohol intake was associated with an increased risk of pancreatic cancer. Furthermore, liquor intake in particular was associated with an increased risk of pancreatic cancer. PMID- 26968705 TI - Economic Evaluation of Childhood Obesity Interventions: Reflections and Suggestions. AB - Rising levels of childhood obesity present a serious global public health problem amounting to 7 % of GDP in developed countries and affecting 14 % of children. As such, many countries are investing increasingly large quantities of resource towards treatment and prevention. Whilst it is important to demonstrate the clinical effectiveness of any intervention, it is equally as important to demonstrate cost effectiveness as policy makers strive to get the best value for money from increasingly limited public resources. Economic evaluation assists with making these investment decisions and whilst it can offer considerable support in many healthcare contexts, applying it to a childhood obesity context is not straightforward. Childhood obesity is a complex disease with interventions being multi-component in nature. Furthermore, the interventions are implemented in a variety of settings such as schools, the community, and the home, and have costs and benefits that fall outside the health sector. This paper provides a reflection from a UK perspective on the application of the conventional approach to economic evaluation to childhood obesity. It offers suggestions for how evaluations should be designed to fit better within this context, and to meet the needs of local decision makers. An excellent example is the need to report costs using a micro-costing format and for benefit measurement to go beyond a health focus. This is critical as the organisation and commissioning of childhood obesity services is done from a Local Authority setting and this presents further challenges for what is the most appropriate economic evaluation approach to use. Given that adult obesity is now of epidemic proportions, the accurate assessment of childhood obesity interventions to support public health decision making is critical. PMID- 26968704 TI - Microtubule-stabilizing properties of the avocado-derived toxins (+)-(R)-persin and (+)-(R)-tetrahydropersin in cancer cells and activity of related synthetic analogs. AB - The avocado toxin (+)-R-persin (persin) is active at low micromolar concentrations against breast cancer cells and synergizes with the estrogen receptor modulator 4-hydroxytamoxifen. Previous studies in the estrogen receptor positive breast cancer cell line MCF-7 indicate that persin acts as a microtubule stabilizing agent. In the present study, we further characterize the properties of persin and several new synthetic analogues in human ovarian cancer cells. Persin and tetrahydropersin cause G2M cell cycle arrest and increase intracellular microtubule polymerization. One analog (4-nitrophenyl) deshydroxypersin prevents cell proliferation and blocks cells in G1 of the cell cycle rather than G2M, suggesting an additional mode of action of these compounds independent of microtubules. Persin can synergize with other microtubule stabilizing agents, and is active against cancer cells that overexpress the P glycoprotein drug efflux pump. Evidence from Flutax-1 competition experiments suggests that while the persin binding site on beta-tubulin overlaps the classical taxoid site where paclitaxel and epothilone bind, persin retains activity in cell lines with single amino acid mutations that affect these other taxoid site ligands. This implies the existence of a unique binding location for persin at the taxoid site. PMID- 26968708 TI - Chimeric antigen receptor-modified T cells for the immunotherapy of patients with EGFR-expressing advanced relapsed/refractory non-small cell lung cancer. AB - The successes achieved by chimeric antigen receptor-modified T (CAR-T) cells in hematological malignancies raised the possibility of their use in non-small lung cancer (NSCLC). In this phase I clinical study (NCT01869166), patients with epidermal growth factor receptor (EGFR)-positive (>50% expression), relapsed/refractory NSCLC received escalating doses of EGFR-targeted CAR-T cell infusions. The EGFR-targeted CAR-T cells were generated from peripheral blood after a 10 to 13-day in vitro expansion. Serum cytokines in peripheral blood and copy numbers of CAR-EGFR transgene in peripheral blood and in tissue biopsy were monitored periodically. Clinical responses were evaluated with RECIST1.1 and immune- related response criteria, and adverse events were graded with CTCAE 4.0. The EGFR-targeted CAR-T cell infusions were well-tolerated without severe toxicity. Of 11 evaluable patients, two patients obtained partial response and five had stable disease for two to eight months. The median dose of transfused CAR(+) T cells was 0.97*10(7) cells kg(-1) (interquartile range (IQR), 0.45 to 1.09*10(7) cells kg(-1)). Pathological eradication of EGFR positive tumor cells after EGFR-targeted CAR-T cell treatment can be observed in tumor biopsies, along with the CAR-EGFR gene detected in tumor-infiltrating T cells in all four biopsied patients. The EGFR-targeted CAR-T cell therapy is safe and feasible for EGFR-positive advanced relapsed/refractory NSCLC. PMID- 26968706 TI - Dual role of ribosome-associated chaperones in prion formation and propagation. AB - Chaperones of the diverse ubiquitous Hsp70 family are involved in the regulation of ordered self-perpetuating protein aggregates (amyloids and prions), implicated in both devastating diseases and protein-based inheritance. Yeast ribosome associated chaperone complex (RAC), composed of the Hsp40 protein Zuo1 and non canonical Hsp70 protein Ssz1, mediates association of the Hsp70 chaperone Ssb with translating ribosomes. Ssb participates in co-translational protein folding, regulation of premature translation termination, and ribosome biogenesis. The loss of Ssb or disruption of RAC results in the increased formation of [PSI +], a prion form of the translation termination factor Sup35 (eRF3). This implicates co translational protein misfolding in de novo prion formation. However, RAC disruption also destabilizes pre-existing [PSI +] prions, as Ssb, released from ribosomes to the cytosol in the absence of RAC, antagonizes the function of the major cytosolic chaperone, Ssa, in prion propagation. The mechanism of the Ssa/Ssb antagonism is currently under investigation and may include a competition for substrates and/or co-chaperones. Notably, yeast cells with wild-type RAC also release Ssb to the cytosol in certain unfavorable growth conditions, and Ssb contributes to increased prion loss in these conditions. This indicates that the circulation of Ssb between the ribosome and cytosol may serve as a physiological regulator of the formation and propagation of self-perpetuating protein aggregates. Indeed, RAC and Ssb modulate toxicity of some aggregating proteins in yeast. Mammalian cells lack the Ssb ortholog but contain a RAC counterpart, apparently recruiting other Hsp70 protein(s). Thus, amyloid modulation by ribosome-associated chaperones could be applicable beyond yeast. PMID- 26968707 TI - Orthocaspase and toxin-antitoxin loci rubbing shoulders in the genome of Microcystis aeruginosa PCC 7806. AB - Programmed cell death in multicellular organisms is a coordinated and precisely regulated process. On the other hand, in bacteria we have little clue about the network of interacting molecules that result in the death of a single cell within a population or the death of almost complete population, such as often observed in cyanobacterial blooms. With the recent discovery that orthocaspase MaOC1 of the cyanobacterium Microcystis aeruginosa is an active proteolytic enzyme, we have gained a possible hint about at least one step in the process, but the picture is far from complete. Interestingly, the genomic context of MaOC1 revealed the presence of multiple copies of genes that belong to toxin-antitoxin modules. It has been speculated that these also play a role in bacterial programmed cell death. The discovery of two components linked to cell death within the same genomic region could open new ways to deciphering the underlying mechanisms of cyanobacterial cell death. PMID- 26968709 TI - Treatment of solid tumors with chimeric antigen receptor-engineered T cells: current status and future prospects. AB - Chimeric antigen receptors (CARs) are artificial recombinant receptors that generally combine the antigen-recognition domain of a monoclonal antibody with T cell activation domains. Recent years have seen great success in clinical trials employing CD19-specific CAR-T cell therapy for B cell leukemia. Nevertheless, solid tumors remain a major challenge for CAR-T cell therapy. This review summarizes the preclinical and clinical studies on the treatment of solid tumors with CAR-T cells. The major hurdles for the success of CAR-T and the novel strategies to address these hurdles have also been described and discussed. PMID- 26968710 TI - Robust diffusion tensor imaging by spatiotemporal encoding: Principles and in vivo demonstrations. AB - PURPOSE: Evaluate the usefulness of single-shot and of interleaved spatiotemporally encoded (SPEN) methods to perform diffusion tensor imaging (DTI) under various preclinical and clinical settings. METHODS: A formalism for analyzing SPEN DTI data is presented, tailored to account for the spatially dependent b-matrix weightings introduced by the sequence's use of swept pulses acting while in the presence of field gradients. Using these b-matrix calculations, SPEN's ability to deliver DTI measurements was tested on phantoms as well as ex vivo and in vivo. In the latter case, DTI involved scans on mice brains and on human lactating breasts. RESULTS: For both ex vivo and in vivo investigations, SPEN data proved less sensitive to distortions arising from Bo field inhomogeneities and from eddy currents, than conventional single-shot alternatives. Further resolution enhancement could be achieved using referenceless methods for interleaved SPEN data acquisitions. CONCLUSION: The robustness of SPEN-based sequences vis-a-vis field instabilities and heterogeneities, enables the implementation of DTI experiments with good sensitivity and resolution even in challenging environments in both preclinical and clinical settings. Magn Reson Med 77:1124-1133, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26968713 TI - Tissue Factor Pathway Inhibitor Gene Polymorphism -33T -> C Predicts Improved Disease-Free Survival in Colorectal Cancer. AB - BACKGROUND: Tissue factor pathway inhibitor (TFPI) is an anticoagulant with antimetastatic properties. The homozygous CC polymorphism of TFPI (-33T -> C) is associated with higher TFPI levels and lower venous thromboembolism risk. This study was the first to evaluate the impact of this polymorphism on disease-free survival (DFS) in cancer patients after curative resection. METHODS: A prospectively maintained tumor bank with clinical data was used to identify patients who underwent curative surgery for colorectal cancer between 1994 and 2006. Germline DNA was extracted from formalin-fixed, paraffin-embedded normal colonic mucosa. Single nucleotide polymorphisms for TFPI (-33T -> C), factor V Leiden (G1691A), and prothrombin (G20210A) were determined by polymerase chain reaction. Survival analysis was described using the Kaplan-Meier method. Multivariable regression analysis was performed using the Cox proportional hazard model. RESULTS: Of the 127 patients identified, the CC genotype was found in 11 %. Venous thromboembolism incidence was 18 % in the TT/TC (wild type/heterozygous) genotypes and 7 % in the CC genotype (p = 0.46). The CC genotype was associated with superior DFS (hazard ratio 0.34, 95 % confidence interval 0.14-0.84; p = 0.02) with 5-year DFS of 63 vs. 24 % for CC vs. TT/TC, respectively. In multivariate analysis, CC polymorphism (hazard ratio 0.28, p = 0.008) was independently associated with improved DFS. The prevalence of factor V Leiden (0.8 %) and prothrombin (1.6 %) polymorphisms was too low to detect interaction with TFPI polymorphism or DFS. CONCLUSIONS: These findings indicate that the inherited anticoagulant homozygous -33T -> C TFPI polymorphism may protect against colon cancer recurrence and suggests a mediating role for the coagulation system in cancer outcomes. PMID- 26968712 TI - Interpreting potential markers of storage and rehearsal: Implications for studies of verbal short-term memory and neuropsychological cases. AB - Neuropsychological studies of verbal short-term memory have often focused on two signature effects - phonological similarity and word length - the absence of which has been taken to indicate problems in phonological storage and rehearsal respectively. In the present study we present a possible alternative reading of such data, namely that the absence of these effects can follow as a consequence of an individual's poor level of recall. Data from a large normative sample of 251 adult participants were re-analyzed under the assumption that the size of phonological similarity and word length effects are proportional to an individual's overall level of recall. For both manipulations, when proportionalized effects were plotted against memory span, the same function fit the data in both auditory and visual presentation conditions. Furthermore, two additional sets of single-case data were broadly comparable to those that would be expected for an individual's level of verbal short-term memory performance albeit with some variation across tasks. These findings indicate that the absolute magnitude of phonological similarity and word length effects depends on overall levels of recall, and that these effects are necessarily eliminated at low levels of verbal short-term memory performance. This has implications for how one interprets any variation in the size of these effects, and raises serious questions about the causal direction of any relationship between impaired verbal short-term memory and the absence of phonological similarity or word length effects. PMID- 26968711 TI - A fresh pair of eyes on prospective memory monitoring. AB - Remembering to complete one's future intentions is termed prospective memory. We employed a new eyetracking paradigm to concretely observe the impact of environmental cues on strategic monitoring within a visual prospective memory task. Participants worked on a continuous living-count task comprising images, while simultaneously being asked to respond to a prospective memory target when it appeared. Importantly, the prospective memory target appeared in a different area of the participant's visual field than did the continuous task, which is consistent with prospective memory in many real-world situations, and further allows for a clear index of strategic monitoring processes. Subtle cues in the form of semantically related images were embedded in the continuous task to prompt monitoring for the prospective memory target. Overt strategic monitoring was operationalized as the number of times participants fixated on the designated target area, and cue-driven monitoring was defined by the number of fixations on the prospective memory target region directly after fixating on a related cue. Overt strategic monitoring for the prospective memory target was directly observed for participants in the prospective memory condition, and cue-driven monitoring was also observed in these participants, since they were more likely to initiate monitoring immediately after fixating on a semantically related cue, relative to an unrelated cue. This psychophysiological approach afforded precise measurement of the strategic monitoring process and revealed how contextual cues in the environment interact with the cognitive mechanisms supporting prospective memory. PMID- 26968714 TI - Incidental finding of cutaneous meningeal heterotopia in aplasia cutis congenita. AB - Aplasia cutis congenita and cutaneous meningeal heterotopia are both rare congenital conditions that most commonly occur on the scalp and may appear clinically and histologically similar. A subtype of aplasia cutis congenita, membranous aplasia cutis congenita, and cutaneous meningeal heterotopia are both proposed to result from neural tube closure errors. However, neither non membranous nor membranous aplasia cutis congenita are known to occur together with cutaneous meningeal heterotopia in the same lesion. We report the incidental finding of cutaneous meningeal heterotopia within a lesion of aplasia cutis congenita. PMID- 26968715 TI - Cross-sectional observation of the relationship of depressive symptoms with lifestyles and parents' status among Japanese junior high school students. AB - OBJECTIVES: Students' depressive symptoms might be related to their own risk factors and to their parents' status. The objective of this cross-sectional study was to examine the relationship of depressive symptoms with lifestyle variables and parents' psychological and socio-demographic status among Japanese junior high school students. METHODS: Of 477 students and their parents, 409 (85.7 %) students and 314 (65.8 %) parents participated in the study. Students answered self-reported questionnaire on depressive symptoms, their heights and weights, subjective stress, body dissatisfaction, lifestyles including sleep duration and extracurricular physical activity in school and other physical activity outside the school, and nutritional intake. Parents responded to questionnaire on depressive symptoms and socio-demographic status. RESULTS: The prevalence of depressive symptoms was 24.9 %. Students with depressive symptoms were more likely to have stress. Students in shorter and longer sleep duration groups were more likely to have depressive symptoms. The students with depressive symptoms had smaller amount of energy intake than did those without depressive symptoms. Multiple logistic regression analysis revealed significant relationships between students' depressive symptoms and some independent variables. Sex, subjective stress, "almost-never"-categorized extracurricular physical activity in school and other physical activity outside the school, and having a parent with depressive symptoms were significantly associated with students' depressive symptoms. CONCLUSION: Reducing mental stress and taking care of lifestyles, especially, "almost-everyday"-categorized extracurricular physical activity in school and other physical activity outside the school, may have benefits for students' mental health, and having a parent with depressive symptoms may be associated with students' depressive symptoms. PMID- 26968716 TI - Predictors of survival for patients with cancer after cryptogenic stroke. AB - Patients with active cancer experience ischemic stroke via cryptogenic mechanisms, with cancer-associated hypercoagulability being considered a major contributor to such strokes. Despite the remarkably shortened survival of these patients, the clinical predictors of survival are poorly understood. We determined the clinical factors including D-dimer levels serving as the predictors of overall survival in these patients. Retrospective study was conducted on cancer patients who visited our hospital for acute ischemic stroke with cryptogenic mechanisms from April 2012 through November 2014. Demographics, clinical characteristics, imaging and laboratory results including coagulation markers were collected, and overall survival was calculated from the patient medical records and a governmental national database. A high D-dimer level was defined as a D-dimer level exceeding the median value from the study population (>5.50 MUg/ml). A total of 93 patients were identified, with a median survival of 62 days (interquartile range 32-223 days). A high D-dimer level (p = 0.004; hazard ratio [HR] 2.01, 95 % confidence interval [CI] 1.26-3.21), systemic metastases (p = 0.02; HR 2.08, 95 % CI 1.11-3.90), and diabetes mellitus (p = 0.03; HR 1.78, 95 % CI 1.03-3.10) were identified as independent predictors of poor overall survival using multivariate Cox proportional hazard analysis. Most of the patients (87 %) were primarily treated with low-molecular-weight heparin (dalteparin, n = 49; enoxaparin, n = 32). The type of low-molecular-weight heparin had no association with survival. A high D-dimer level, systemic metastases, and diabetes are independent predictors of poor survival in cancer patients with cryptogenic stroke. PMID- 26968717 TI - Long-term outcomes of myopic choroidal neovascularisation treated with combined ranibizumab and dexamethasone characterised by multi-modal imaging. AB - AIM: To characterise the long-term outcomes of myopic choroidal neovascularisation (mCNV) treated with combined ranibizumab and dexamethasone, with the use of multi-modal imaging. METHODS: A retrospective study of 20 eyes with mCNV treated with intra-vitreal ranibizumab and dexamethasone on a treat-as needed basis were followed up for a mean period of 47 months (range 19-81 months). RESULTS: The mean age was 55 +/- 16 years, with mean refractive error of -9.0 diopters. Subfoveal mCNV was seen in 11 eyes (52 %) and the others were juxtafoveal. At the final visit, 13 patients (65 %) had improvement, while four patients (20 %) had worsening in vision. The average number of ranibizumab and dexamethasone injections required was 3 +/- 1.7. There was a significant improvement in the mean visual acuity, reduction of the central retinal thickness, and an enlargement of the area of chorioretinal atrophy. The mean rate of increase in chorioretinal atrophy area was 0.05 +/- 0.09 mm2/month. Disruption of the photoreceptor layer, fragmentation of the retinal pigment epithelium, and breaks in the Bruch's membrane with a hyper-reflective lesion causing separation of the outer retinal layers were changes associated with active mCNV seen on optical coherence tomography (OCT). CONCLUSION: Visual outcomes of mCNV treated with ranibizumab and dexamethasone on a treat-as-needed basis have favourable visual acuity outcomes. Using multi-modal imaging to monitor treatment response, chorioretinal atrophy, which may be related to visual function, should be used as an additional outcome measure to study the effect of combination treatment versus monotherapy. PMID- 26968718 TI - Comparison of four surgical techniques for management of pseudophakic and aphakic retinal detachment: a multicenter clinical trial. AB - PURPOSE: To compare the visual and anatomical outcomes of four surgical techniques to manage pseudophakic and aphakic retinal detachment (PARD). METHODS: In a multicenter randomized clinical trial, 211 eyes of 211 patients with PARD and proliferative vitreoretinopathy (PVR) grade B or less were randomly assigned to one of the four treatment groups: (1) scleral buckling (SB), 50 eyes, (2) vitrectomy without band, 51 eyes, (3) vitrectomy with encircling band (EB), 58 eyes, and (4) triamcinolone acetonide (TA) assisted vitrectomy, 52 eyes. Patients were followed for 12 months after the surgery. The best-corrected visual acuity (BCVA) and retinal reattachment rate at each follow-up time point were considered as the primary outcome measures. PVR, macular pucker, and cystoid macular edema were considered as the secondary outcomes. RESULTS: Visual improvement was achieved in all treatment groups relative to the baseline at all time points (all Ps < 0.001). There were no statistically significant differences among the groups with regard to BCVA changes. However, there was a significant difference in the slope of visual improvement curve: the SB group had a more rapid visual improvement compared to the vitrectomy with buckle group at month 12 (P = 0.032). The retinal reattachment rates at month 12 were 75, 64.7, 68.5, and 66.7 % in SB, vitrectomy without buckle, vitrectomy with EB, and TA-assisted vitrectomy groups respectively (P > 0.99). There were no statistically significant differences among the groups in terms of adverse events. CONCLUSIONS: SB, TA-assisted vitrectomy, and vitrectomy with and without buckle had comparable outcomes in the management of PARD. PMID- 26968719 TI - Prevalence of ocular hypertension and glaucoma in patients with chronic ocular graft-versus-host disease. AB - PURPOSE: To evaluate the prevalence of ocular hypertension (OHT) and glaucoma in patients with chronic ocular graft-versus-host disease (GVHD). METHODS: We performed a retrospective chart review of 218 patients diagnosed with chronic ocular GVHD. Ocular hypertension was defined as intraocular pressure (IOP) >= 24 mmHg in either eye without any glaucomatous optic disc changes. Glaucoma suspect was defined as optic disc changes with a cup-to-disc ratio >= 0.7 in either eye or asymmetry of >= 0.3 between the two eyes. Glaucoma was defined by glaucomatous optic disc changes plus glaucomatous visual field defects in two consecutive reliable visual field tests. The number of cases of ocular hypertension, glaucoma, and glaucoma suspects was evaluated. RESULTS: Thirty-three patients (15 %) were diagnosed with OHT, eight patients (3.6 %) with suspicion of glaucoma, and one patient (0.4 %) with glaucoma. OHT occurred within 6 months of developing ocular GVHD in 60 % of the cases and within the first year in 76 %. High IOP normalized in 67 % of patients when the dosage of topical or systemic corticosteroids was lowered, and 27 % of patients required anti-glaucoma therapy. CONCLUSIONS: Ocular hypertension is a common complication in patients with ocular GVHD, with a prevalence of 15 %. The rise in intraocular pressure is often transient and resolves with management of corticosteroids in most cases. However, clinicians should be aware that nearly one-third of the patients with OHT might require anti-glaucoma treatment. The prevalences of glaucoma and suspicion of glaucoma were not higher than in the general population. PMID- 26968720 TI - Factors influencing the pupillary light reflex in healthy individuals. AB - PURPOSE: To determine the ocular anatomical factors influencing the pupillary light reactions to different wavelengths of light, measured with chromatic pupillometry. METHODS: Community-based, cross-sectional study including subjects with normal ocular health (ages 50-79 years). Direct pupillary responses to continuously increasing irradiances (6.8 to 13.8 log photons cm(-2) s(-1)) of red (631 nm) and blue (469 nm) light were measured, using a dedicated infrared pupillometer. All subjects underwent swept source optical coherence tomography (SS-OCT, CASIA SS-1000, Tomey Corporation, Nagoya, Japan) and noncontact partial coherence laser interferometry (Lenstar LS900, Haag-Streit AG, Switzerland). Univariate and multivariable regression analyses were performed to determine the anatomical features influencing pupillographic parameters. RESULTS: Among the 177 included subjects, 167 (94.4 %) were Chinese and 116 (65.5 %) female. The average baseline pupil diameter in darkness (beta = -0.080, p < 0.001) and the amplitude of the relative pupillary constriction (beta = -0.233, p = 0.006) to blue light decreased with age. The amplitude of pupillary constriction was significantly larger in patients with a thinner iris, in response to stimulation with blue (beta = -0.321, p < 0.001) and red light (beta = -0.336, p < 0.001). Other ocular parameters (i.e., lens vault, anterior chamber depth width, iris volume, iris curvature, and lens thickness) were not significantly associated with pupillometric outcomes. CONCLUSIONS: The amplitude of the pupillary light constriction to chromatic photic stimuli is reduced with increasing age and iris thickness in subjects with normal ocular health, a finding which needs to be integrated into future pupillometric studies. PMID- 26968722 TI - Dynamic torsional misalignment of eyes during laser in-situ keratomileusis. AB - PURPOSE: To determine the amount and characteristics of dynamic torsional misalignment of eyes during excimer ablation in laser in-situ keratomileusis (LASIK). METHODS: Retrospective trial for evaluation of dynamic intraoperative torsional misalignment of 179 eyes that underwent LASIK for correction of myopia and/or astigmatism. Patients were treated with the Keracor 217z excimer laser implementing 25 Hz dynamic eye tracker ACE 100 (both Technolas Perfect Vision, Munich, Germany). From dynamic torsional misalignments, temporal power spectra were obtained by Fourier analysis up to a frequency of 12.5 Hz and an amplitude of +/-15 degrees from initial torsional status (limited by the tracking system). The f90, f95, and f99 criteria were defined as the frequency below which 90 %, 95 %, and 99 % of misalignments occur. A Wilcoxon rank sum test was performed to detect differences of f90, f95, and f99 in groups' gender, age, and eye (if both eyes underwent surgery at same day). Multiple regression analysis (MRA) was performed to evaluate possible preoperative predictors of f90, f95, and f99. RESULTS: Fourier analysis showed a dominance of high-frequency, low-power dynamic torsional misalignment. Mean f95 threshold of rotational movements was 4.89+/ 2.12 Hz (median 4.54, ranging from 0.44 to 9.23 Hz). Wilcoxon rank sum test showed no differences in f90, f95, and f99 between groups' gender, age, and eye. MRA revealed age, gender, and optical zone as preoperative predictors on intraoperative f90, f95, and f99. CONCLUSIONS: Dynamic intraoperative torsional misalignments of eyes undergoing LASIK are dominated by low-frequency (slow), high-power (large) movements, with 95 % being slower than 4.89Hz regarding the spectrum analyzed (0-12.5Hz, +/-15 degrees ). Movements can be predicted preoperatively by eye treated, patients' gender, and age in pre-LASIK diagnostics. PMID- 26968723 TI - Your Best Life: Tolstoy's Three Questions for Life. PMID- 26968721 TI - Intraocular cytokines imbalance in congenital cataract and its impact on posterior capsule opacification. AB - BACKGROUND: Congenital cataract is of particular interest because of the variability of etiologies and the inflammatory reaction that are often observed. The aim of the study was to describe intraocular levels of various inflammation related cytokines of patients with congenital cataract and to study their correlations with clinical determinants. METHODS: We followed a cohort of 18 patients (18 eyes) with congenital cataract from a University hospital and measured levels of various inflammation-related cytokines in the aqueous humor of patients with congenital cataract, and compared these levels to those observed in a control group (patients with senile cataract) using multiplex immunoassay. Correlation analysis was used to study the possible correlation between intraocular levels of cytokines and clinical determinants. RESULTS: Compared with the control group, the group with congenital cataract showed clear and significantly elevated concentrations of inflammatory markers (IL-1beta, IL-15, IFN-gamma, IL-12, IL-6, IL-5, IL-9, MIP-1alpha, MCP-1 and IP-10). Postoperative intraocular inflammation and opacification of the posterior capsule seemed to be correlated with preoperative IL-1beta, TNF-alpha and IL-6 levels. CONCLUSIONS: An inflammatory condition may occur in eyes with congenital cataract. The cytokine profiles are really different than those observed in senile cataract. Moreover, cytokines levels may be of interest to predict posterior capsule opacification and to complete the etiological workup. PMID- 26968724 TI - CORR Insights((r)): Does Teriparatide Improve Femoral Neck Fracture Healing: Results From A Randomized Placebo-controlled Trial. PMID- 26968725 TI - Editor's Spotlight/Take 5: Universal Health Insurance Coverage in Massachusetts Did Not Change the Trajectory of Arthroplasty Use or Costs. PMID- 26968726 TI - Fouling control in a lab-scale MBR system: Comparison of several commercially applied coagulants. AB - The Membrane bioreactors (MBRs) integrate the biological degradation of pollutants with membrane filtration-separation during wastewater treatment. Membrane fouling, which is considered as the main process drawback, stems from the interaction between the membrane material and the (organic or inorganic) foulants, leading to membrane's efficiency deterioration. It is widely recognized that the mixed liquor colloidal and Soluble Microbial Products (SMP) are in principal responsible for this undesirable situation. As a result, the appropriate pretreatment of wastewater feed is often considered as necessary procedure and the coagulation/flocculation (C/F) process is regarded as a relevant viable option for wastewater treatment by MBRs in order to improve the effective removal of suspended solids (SS), of colloidal particles, of natural organic matter (NOM), as well as of other soluble materials. The objective of this study is the application of coagulation/flocculation for fouling control of MBR systems by using several commercially available chemical coagulant/flocculant agents. For this purpose, an appropriate lab-scale continuous-flow, fully automatic MBR system has been assembled and various (inorganic) coagulants (i.e. FeCl3?6H2O, Fe2(SO4)3.5H2O, FeClSO4, PFS0.3, PAC A9-M, PAC-A16, Al2(SO4)3.18H2O, FO4350SSH, NaAlO2) have been examined. Filterability tests and SMP concentration measurements were also conducted in order to investigate the reversible, as well as the irreversible fouling, respectively. Based upon the obtained results and after selecting the most efficient coagulants (FeCl3.6H2O, Fe2(SO4)3.5H2O, FeClSO4, PAC-A9, PAC-A16), an attempt was subsequently performed to correlate the major fouling indices (i.e. TMP, TTF, SMP concentration) in order to improve the overall process operability by this fouling control method. PMID- 26968727 TI - Early administration of nifedipine protects against angiotensin II-induced cardiomyocyte hypertrophy through regulating CaMKII-SERCA2a pathway and apoptosis in rat cardiomyocytes. AB - The calcium channel blocker (CCB), nifedipine, is a more effective treatment for early- than late-stage cardiac hypertrophy. We investigated the effects of early- and late-stage nifedipine administration on calcium homeostasis, CaMKII (Ca(2+) /calmodulin-dependent protein kinase II) activity and apoptosis of cardiomyocytes under hypertrophic stimulation with angiotensin II (AngII). Primary rat cardiomyocytes were divided into five treatment groups: AK, AngII plus the CaMKII inhibitor, KN-93; AN-1 (early-stage), AngII plus nifedipine * 48 h; AN-2 (late stage), AngII * 48 h, then AngII plus nifedipine * 48 h; C, untreated; and A, AngII * 48 h. The t1/2beta [time required for intracellular Ca(2+) concentration ([Ca(2+) ]i) to decline to one half of the peak value] decreased; however, CaMKII and SERCA2a (sarcoplasmic reticulum Ca(2+) -ATPase 2a) activities increased in the AN-1 group compared with the AK group. In the AN-2 group compared with the AN 1 group, CaMKII activity, t1/2alpha [time required for [Ca(2+) ]i to increase from the bottom to one half of peak value], t1/2beta, and apoptosis increased. These results indicate that the timing of CCB administration affects the calcium concentration and apoptosis of hypertrophic cardiomyocytes through the CaMKII SERCA2a signalling pathway, thereby influencing the drug's protective activity against cardiomyocyte hypertrophy. PMID- 26968728 TI - Identification of three cannabimimetic indazole and pyrazole derivatives, APINACA 2H-indazole analogue, AMPPPCA, and 5F-AMPPPCA. AB - This paper reports analytical properties of three cannabimimetic indazole and pyrazole derivatives seized from a clandestine laboratory. These three new synthetic cannabinoids include N-(1-adamantyl)-2-pentyl-2H-indazole-3-carboxamide (APINACA 2H-indazole analogue, 1), N-(1-adamantyl)-4-methyl-1-pentyl-5-phenyl-1H pyrazole-3-carboxamide (AMPPPCA, 2), and N-(1-adamantyl)-1-(5-fluoropentyl)-4 methyl-5-phenyl-1H-pyrazole-3-carboxamide (5F-AMPPPCA, 3). These compounds were identified by liquid chromatography-quadrupole time-of-flight-mass spectrometry (LC-QTOF-MS), gas chromatography-time-of-flight-mass spectrometry (GC-TOF-MS), and nuclear magnetic resonance (NMR) spectroscopy. No analytical properties and pharmacological activities about compounds 1-3 have appeared until now, making this the first report on these compounds. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26968729 TI - Subacute sclerosing panencephalitis presenting as acute cerebellar ataxia and brain stem hyperintensities. AB - BACKGROUND: Subacute sclerosing panencephalitis is a devastating neurodegenerative disease with a characteristic clinical course. Atypical presentations may be seen in 10% of the cases. AIMS: To describe the atypical clinical and radiological features of SSPE in a child form endemic country. METHODS: A 5-year-old boy presented with acute-onset cerebellar ataxia without associated encephalopathy, focal motor deficits, seizures or cognitive decline. He had varicella-like illness with vesicular, itchy truncal rash erupting one month prior to the onset of these symptoms. He underwent detailed neurological assessment, relevant laboratory and radiological investigations. RESULTS: Neuroimaging revealed peculiar brain stem lesions involving the pons and cerebellum suggestive of demyelination. With a presumptive diagnosis of clinically isolated syndrome of demyelination, he was administered pulse methylprednisolone (30 mg/kg/day for 5 days). Four weeks later he developed myoclonic jerks. Electroencephalogram showed characteristic periodic complexes time-locked with myoclonus. CSF and serum anti-measles antibody titres were elevated (1:625). CONCLUSION: Our report highlights that subacute sclerosing panencephalitis can present atypically as isolated acute cerebellar ataxia and peculiar involvement of longitudinal and sparing of transverse pontine fibres. The predominant brainstem abnormalities in the clinical setting may mimick acute demyelinating syndrome. Hence, it is important to recognize these features of subacute sclerosing panencephalitis in children, especially in the endemic countries. PMID- 26968730 TI - What should be the antibiotic prescription protocol for burn patients admitted in the department of burns, plastic and reconstructive surgery. AB - This is a prospective study with the aim to determine specific patterns of burn wound bacterial colonisation and antimicrobial resistance profiles. There is a high incidence of infections and septicaemia in post-burn patients, which, in turn, are associated with high morbidity and mortality, a fact that compelled us to undertake this study. The study was conducted over a period 11 months, from 1 August 2014 to 30 June 2015, in 50 burn patients admitted in our burn unit. Wound cultures were taken after 72 hours of admission from all the patients, and then, empirical systemic antibiotics were administered. For wound cultures; 1 cubic cm tissue was taken and placed in aerobic and anaerobic culture vials and transported to the microbiology lab under all aseptic precautions as soon as possible. At the time of fever any time after 72 hours of admission, 16 ml of blood was drawn under all aseptic precautions. Both aerobic and anaerobic blood culture vials were filled with 8 ml of blood each and transported to the microbiology lab. The results of culture and sensitivity reports of 50 patients were recorded. The data obtained was analysed using appropriate statistical analytical tests. The most common organism responsible for bacteraemia is Pseudomonas (43%). Most of the strains of organisms isolated were resistant to commonly used antibiotics in the hospital; Pseudomonas was found 100% resistant to a combination of ampicillin + sulbactum, ceftriaxone and was most often sensitive to imipenem, amikacin and vancomycin. Methicillin-resistant Staphylococcus aureus (MRSA) was also found resistant to commonly used antibiotics like ceftriaxone, ampicillin + sulbactum and ceftazidime + calvulanic acid. Linzolid and vancomycin were effective in 83% and 100% cases, respectively. We conclude that similar institution-specific studies should be conducted, and such studies will be helpful in providing useful guidelines for choosing effective empirical therapy that will have a great impact on the prevention of infection and its complications in burn patients because of bacteraemia. PMID- 26968731 TI - Evaluation of long-term side effects after shock-wave lithotripsy for renal calculi using a third generation electromagnetic lithotripter. AB - To assess the incidence of long-term side effects after shock-wave lithotripsy treatment performed with an electromagnetic Dornier Lithotripter S device. A specific follow-up was undertaken on a cohort of 100 selected patients that underwent SWL for a single renal stone in our center from 2002 to 2004. Previous and current data were compared using the Student t test. Factors associated with the incidence of hypertension and diabetes mellitus were determined. Ten years after treatment, mean serum creatinine level and glomerular filtration rate remained similar to previous values (serum creatinine level: 0.96 +/- 0.22 vs. 0.92 +/- 0.19 mg/dL; glomerular filtration rate: 92.8 +/- 17.8 vs. 88.1 +/- 21.7 mL/min). There were marked increases in blood cholesterol, blood pressure, and blood glucose levels, while smoking decreased. Age, glomerular filtration rate, body mass index, blood glucose and blood pressure at the time of treatment were significantly associated with the presence of hypertension and diabetes mellitus at follow-up; blood cholesterol was associated with diabetes mellitus development. After 10 years, overall renal function appeared to have been unaffected by shock-wave lithotripsy treatment. The increased rate of hypertension and diabetes mellitus were consistent with the incidence in the global population. This is the first report on the long-term safety of a third generation electromagnetic lithotripter, and indicates that there are no long term sequelae. PMID- 26968733 TI - Corneal Biomechanical Response Following Collagen Cross-Linking With Rose Bengal Green Light and Riboflavin-UVA. AB - PURPOSE: To compare the biomechanical corneal response of two different corneal cross-linking (CXL) treatments, rose bengal-green light (RGX) and riboflavin-UVA (UVX), using noninvasive imaging. METHODS: A total of 12 enucleated rabbit eyes were treated with RGX and 12 with UVX. Corneal dynamic deformation to an air puff was measured by high speed Scheimpflug imaging (Corvis ST) before and after treatment. The spatial and temporal deformation profiles were evaluated at constant intraocular pressure of 15 mm Hg, and several deformation parameters were estimated. The deformation profiles were modeled numerically using finite element analysis, and the hyperelastic corneal material parameters were obtained by inverse modeling technique. RESULTS: The corneal deformation amplitude decreased significantly after both CXL methods. The material parameters obtained from inverse modeling were consistent with corneal stiffening after both RGX and UVX. Within the treated corneal volume, we found that the elasticity decreased by a factor of 11 after RGX and by a factor of 6.25 after UVX. CONCLUSIONS: The deformation of UVX-treated corneas was smaller than the RGX-treated corneas. However, the reconstructed corneal mechanical parameters reveal that RGX produced in fact larger stiffening of the treated region (100-MUm depth) than UVX (137-MUm depth). Rose bengal-green light stiffens the cornea effectively, with shorter treatment times and shallower treated areas. Dynamic air puff deformation imaging coupled with mechanical simulations is a useful tool to characterize corneal biomechanical properties, assess different treatments, and possibly help optimize the treatment protocols. PMID- 26968734 TI - A New Alternative to Riboflavin/Ultraviolet-A: Collagen Cross-Linking With Rose Bengal/Green Light. PMID- 26968732 TI - A Homozygous RAB3GAP1:c.743delC Mutation in Rottweilers with Neuronal Vacuolation and Spinocerebellar Degeneration. AB - BACKGROUND: A variety of presumed hereditary, neurologic diseases have been reported in young Rottweilers. Overlapping ages of onset and clinical signs have made antemortem diagnosis difficult. One of these diseases, neuronal vacuolation and spinocerebellar degeneration (NVSD) shares clinical and histological features with polyneuropathy with ocular abnormalities and neuronal vacuolation (POANV), a recently described hereditary disease in Black Russian Terriers (BRTs). Dogs with POANV harbor mutations in RAB3GAP1 which codes for a protein involved in membrane trafficking. HYPOTHESIS: Rottweilers with NVSD will be homozygous for the RAB3GAP1:c.743delC allele associated with POANV in BRTs. ANIMALS: Eight Rottweilers with NVSD confirmed at necropsy, 128 Rottweilers without early onset neurologic signs, and 468 randomly selected dogs from 169 other breeds. METHODS: Retrospective case-control study. Dogs were genotyped for the RAB3GAP1:c.743delC allele with an allelic discrimination assay. RESULTS: All 8 NVSD-affected dogs were homozygous for the RAB3GAP1:c.743delC allele while the 128 NVSD-free Rottweilers were either homozygous for the reference allele (n = 105) or heterozygous (n = 23) and the 468 genotyped dogs from other breeds were all homozygous for the reference allele. CONCLUSIONS AND CLINICAL IMPORTANCE: The RAB3GAP1:c.743delC mutation is associated with a similar phenotype in Rottweilers and BRTs. Identification of the mutation permits a DNA test that can aid in the diagnosis of NVSD and identify carriers of the trait so that breeders can avoid producing affected dogs. Disruption of membrane trafficking could explain the neuronal vacuolation seen in NVSD and other spongiform encephalopathies. PMID- 26968735 TI - Nonsyndromic Retinal Dystrophy due to Bi-Allelic Mutations in the Ciliary Transport Gene IFT140. AB - PURPOSE: Mutations in the ciliary transporter gene IFT140, usually associated with a severe syndromic ciliopathy, may also cause isolated retinal dystrophy. A series of patients with nonsyndromic retinitis pigmentosa (RP) due to IFT140 was investigated in this study. METHODS: Five probands and available affected family members underwent detailed phenotyping including retinal imaging and electrophysiology. Whole exome sequencing was performed on two probands, a targeted sequencing panel of 176 retinal genes on a further two, and whole genome sequencing on the fifth. Missense mutations of IFT140 were further investigated in vitro using transient plasmid transfection of hTERT-RPE1 cells. RESULTS: Eight affected patients from five families had preserved visual acuity until at least the second decade; all had normal development without skeletal manifestations or renal failure at age 13 to 67 years (mean, 42 years; median, 44.5 years). Bi allelic mutations in IFT140 were identified in all families including two novel mutations: c.2815T > C (p.Ser939Pro) and c.1422_23insAA (p.Arg475Asnfs*14). Expression studies demonstrated a significantly reduced number of cells showing localization of mutant IFT140 with the basal body for two nonsyndromic mutations and two syndromic mutations compared with the wild type and a polymorphism. CONCLUSIONS: This study highlights the phenotype of nonsyndromic RP due to mutations in IFT140 with milder retinal dystrophy than that associated with the syndromic disease. PMID- 26968736 TI - Heterochromatic Flicker Photometry for Objective Lens Density Quantification. AB - PURPOSE: Although several methods have been proposed to evaluate lens transmittance, to date there is no consensual in vivo approach in clinical practice. The aim of this study was to compare ocular lens density and transmittance measurements obtained by an improved psychophysical scotopic heterochromatic flicker photometry (sHFP) technique to the results obtained by three other measures: a psychophysical threshold technique, a Scheimpflug imaging technique, and a clinical assessment using a validated subjective scale. METHODS: Forty-three subjects (18 young, 9 middle aged, and 16 older) were included in the study. Individual lens densities were measured and transmittance curves were derived from sHFP indexes. Ocular lens densities were compared across methods by using linear regression analysis. RESULTS: The four approaches showed a quadratic increase in lens opacification with age. The sHFP technique revealed that transmittance decreased with age over the entire visual spectrum. This decrease was particularly pronounced between young and older participants in the short (53.03% decrease in the 400-500 nm range) wavelength regions of the light spectrum. Lens density derived from sHFP highly correlated with the values obtained with the other approaches. Compared to other objective measures, sHFP also showed the lowest variability and the best fit with a quadratic trend (r2 = 0.71) of lens density increase as a function of age. CONCLUSIONS: The sHFP technique offers a practical, reliable, and accurate method to measure lens density in vivo and predict lens transmittance over the visible spectrum. An accurate quantification of lens transmittance should be obtained in clinical practice, but also in research in visual and nonvisual photoreception. PMID- 26968738 TI - Diagnostic Efficacy of Normalization of Corneal Deformation Variables by the Intraocular Pressure in Glaucomatous Eyes. AB - PURPOSE: To analyze the diagnostic efficacy of normalization of corneal deformation variables by the IOP in healthy, primary-angle closure (PACG), and primary open angle glaucoma (POAG) patients. METHODS: Fifty-nine healthy, 83 POAG, and 57 PACG eyes, matched for age and pachymetry, were included in a prospective, observational, cross-sectional study. Goldmann applanation tonometry (GAT-IOP), Corvis-ST IOP, IOPg (Goldmann correlated), and IOPcc (cornea compensated) from the ocular response analyzer were acquired. Corneal hysteresis (CH) and corneal resistance factor (CRF) from the ORA, and deformation amplitude (DA) from Corvis-ST were analyzed. Further, ratios of CH, CRF, and DA to IOP were assessed among the groups and defined as new variables (e.g., ratio [CH, IOPcc] was the ratio of CH to IOPcc). RESULTS: Goldmann applanation tonometry-IOP, IOPcc, and IOPg of PACG and POAG eyes were significantly higher than normal (P < 0.05). Corvis-ST IOP of healthy eyes was similar to POAG (P > 0.05) but lower than PACG (P = 0.02). Corneal hysteresis and CRF of PACG and POAG were significantly lower than normal (P < 0.0001). The ratio (CH, IOPcc), ratio (CRF, IOPcc), and ratio (DA, IOPcc) of healthy eyes were significantly higher than those of PACG and POAG eyes (P < 0.0001). The sensitivity and specificity of ratio (CRF, IOPcc) and ratio (DA, IOPcc) was significantly better than CRF and DA alone in PACG eyes (P < 0.001). However in POAG, only the sensitivity and specificity of ratio (DA, IOPcc) was significantly better than DA alone (P < 0.001). CONCLUSIONS: Presence of glaucoma may be indicated better by ratio variables than by CH, CRF, or DA alone. PMID- 26968737 TI - AP-2beta Is a Downstream Effector of PITX2 Required to Specify Endothelium and Establish Angiogenic Privilege During Corneal Development. AB - PURPOSE: The homeodomain transcription factor, PITX2, is at the apex of a genetic pathway required for corneal development, but the critical effector genes regulated by the PITX2 remain unknown. The purpose of this study was to discover and validate PITX2-dependent mechanisms required for specifying cell lineages and establishing angiogenic privilege within the developing cornea. METHODS: Microarrays were used to compare gene expression in corneas isolated from temporal Pitx2 knockout embryos and control littermates. Quantitative RT-PCR and immunohistochemistry was used to further validate Tfap2b expression differences in Pitx2 knockout versus control corneas. In situ hybridization and protein immunohistochemistry were used to assay eyes of a Tfap2b allelic series of embryos to identify differentiated cellular lineages in the cornea, blood vessel endothelium, or lymphatic vessel endothelium. RESULTS: We show that PITX2 is required for the expression of Tfap2b, encoding the AP-2beta transcription factor, in the neural crest during corneal development. Markers of differentiated corneal epithelium and stroma are expressed in the absence of AP-2beta. In contrast, markers of differentiated corneal endothelium are not expressed in the absence of AP-2beta. Endomucin+ blood vessels are present throughout the developing corneal stroma in the absence of AP-2beta, whereas LYVE1+ lymphatic vessels are not found. CONCLUSIONS: The AP-2beta transcription factor is an important effector of PITX2 function during corneal development, required for differentiation of corneal endothelium and establishment of angiogenic privilege. Unlike PITX2, AP-2beta is not required for the early expression of available lineage specific markers for the corneal epithelium and stroma during embryogenesis, nor establishment of lymphangiogenic privilege. Therefore, additional PITX2-dependent factors likely regulate these latter processes during embryonic development. These results extend our understanding of the genetic mechanisms regulating cornea development. PMID- 26968740 TI - Revisiting Ciliary Muscle Tendons and Their Connections With the Trabecular Meshwork by Two Photon Excitation Microscopic Imaging. AB - PURPOSE: To elucidate the anatomy of the trabecular meshwork (TM) and its connection to ciliary muscle (CM) tendons with two photon excitation microscopic (TPEM) imaging. METHODS: The human aqueous outflow pathway was imaged in an unfixed and nonembeded state by using an inverted TPEM. Laser (Ti:Sapphire) was tuned at 850 nm for emission. Backscatter signals of second harmonic generation (SHG) and autofluorescence (AF) were collected through 425/30-nm and 525/45 emission filters, respectively. Multiple, consecutive, and overlapping image stacks (z-stacks) were acquired to generate three-dimensional data sets. RESULTS: Collagen and elastin structures of the TM were successfully visualized with TPEM. The TM and CM tendons were found to contain both collagen and elastin fibers. What appears to be juxtacanalicular tissue (JCT) was identified by its honeycomb like appearance in AF images. Tracing CM tendons from their origins and to their insertions revealed that elastin fibers of CM tendons were connected to the elastin network within the trabecular lamellae. The CM tendons converged or diverged along their course, forming intricate networks with the TM. The CM tendon fiber density varied depending on its location within the aqueous outflow pathway with tendons near the JCT found to be the most dense, and in a fine-tooth comb arrangement. CONCLUSIONS: By using TPEM imaging, new details of the human aqueous outflow pathway were elucidated. This high-resolution imaging technique revealed the intricate interconnections between the TM and CM tendons. PMID- 26968739 TI - Influence of Target Parameters on Fixation Stability in Normal and Strabismic Monkeys. AB - PURPOSE: The purpose of this study was to assess the effect of fixation target parameters on fixation instability in strabismic monkeys. METHODS: One normal and three exotropic monkeys were presented with four differently shaped fixation targets, with three diameters, during monocular or binocular viewing. Fixation targets were white on a black background or vice versa. Binocular eye movements were recorded using the magnetic search coil technique and fixation stability quantified by calculating the bivariate contour ellipse area (BCEA). RESULTS: Fixation instability was greater in all the strabismic monkeys compared with the normal monkey. During monocular viewing, strabismic monkeys showed significantly greater instability in the covered eye compared to the fixating eye. Multifactorial ANOVA suggested statistically significant target parameter influences, although effect sizes were small. Thus, a disk-shaped target resulted in greater instability than other target shapes in the viewing eyes of the normal monkey and two of three strabismic monkeys. A similar target-shape effect was also observed in the covered eye. Least instability was elicited with a 0.5 degrees target in the normal monkey and a 1.0 degrees target in the strabismic monkeys, both in the viewing and the covered eye. Target/background polarity effects were idiosyncratic. In strabismic monkeys, stability of the fixating eye during binocular viewing was not different from the stability of the same eye during monocular viewing. CONCLUSIONS: Abnormal drifts and nystagmus contribute to increased fixation instability in strabismic monkeys. Target parameters (shape and size) that influence fixation stability in a normal animal also affected fixation stability in our sample of strabismic monkeys. PMID- 26968741 TI - Changes in Extraocular Muscle Volume During Ocular Duction. AB - PURPOSE: It has been tacitly assumed that overall extraocular muscle (EOM) volume is conserved during contraction and relaxation, yet this assumption has been untested up to now. We used high-resolution magnetic resonance imaging (MRI) to determine if total EOM volume changes during relaxation and contraction. METHODS: Surface coil MRI in quasi-coronal planes was obtained in target-controlled, maximal secondary gaze positions in 30 orbits of 15 normal subjects at 312-MUm resolution. Ductions were quantified by changes in globe-optic nerve positions. Cross-sections of EOM were manually outlined in contiguous image planes so that volumes could be calculated by multiplying summed cross sections by the 2-mm slice thickness. Three-dimensional reconstruction allowed measurement of the lengths of terminal, unresolvable EOM segments, providing estimates of terminal EOM volumes to be summed with measured midorbital volumes to obtain total EOM volumes. RESULTS: Duction range averaged 44.3 +/- 4.8 degrees from relaxation to contraction. There was a significant increase in total volume in each rectus EOM from relaxation to contraction: superior rectus (SR) 92 +/- 36 mm3 (+18%, P < 10 11); inferior rectus (IR) 51 +/- 18 mm3 (+9%, P < 10-11); medial rectus (MR) 78 +/- 36 mm3 (+11%, P < 10-5); and lateral rectus (LR) 47 +/- 45 mm3 (+7%, P = 0.005). Because volume changes for SR and MR exceed IR and LR, total rectus EOM volume increases in supraduction 41 +/- 42 mm3 (+3.7%) and adduction 32 +/- 63 mm3 (+2.3%). CONCLUSIONS: Total EOM volume is not conserved but instead increases with contraction and decreased with relaxation. Contractile volume increases may be secondary to increased actin-myosin lattice spacing, so that density decreases. This effect is opposite that of possible hemodynamic changes. PMID- 26968742 TI - Characterization of the reproductive mode and life cycle of the whitish truffle T. borchii. AB - Truffles are the fruiting structures of ascomycetes in the genus Tuber. Because of their economic importance, truffles have been cultivated for many years using artificially inoculated host plants. Nevertheless, the life cycle and reproductive mode of Tuber spp. are still poorly understood. In filamentous ascomycetes, sexual reproduction is genetically controlled by the mating-type (MAT) locus. Among Tuber spp., the MAT locus has been recently characterized in the black truffles Tuber melanosporum and Tuber indicum. Here, by using sequence information derived from these species and from a Tuber borchii expressed sequence tag (EST) showing similarity to the mat1 gene of Alternaria brassicicola, we embarked on a chromosome-walking procedure to sequence the complete MAT region of T. borchii. This fungus produces highly commercialized whitish truffles and represents a model species for addressing basic questions concerning the life cycle of Tuber spp. We show that T. borchii is heterothallic, as its MAT locus is organized into two idiomorphs, each harbored by different mycelial strains. The alignment of the MAT locus from black truffles and T. borchii reveals that extensive sequence rearrangements and inversions occurred between these species. Moreover, by coupling mating-type analyses to karyological observation, we show that mycelia isolated from ascocarps and mycorrhizae are formed by homokaryotic hyphae. PMID- 26968743 TI - Revisiting phylogenetic diversity and cryptic species of Cenococcum geophilum sensu lato. AB - The fungus Cenococcum geophilum Fr. (Dothideomycetes, Ascomycota) is one of the most common ectomycorrhizal fungi in boreal to temperate regions. A series of molecular studies has demonstrated that C. geophilum is monophyletic but a heterogeneous species or a species complex. Here, we revisit the phylogenetic diversity of C. geophilum sensu lato from a regional to intercontinental scale by using new data from Florida (USA) along with existing data in GenBank from Japan, Europe, and North America. The combination of internal transcribed spacer (ITS) ribosomal DNA and the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene resolved six well-supported lineages (87-100 % bootstrap values) that are closely related to each other and a seventh lineage that is phylogenetically distinct. A multi-locus analysis (small subunit (SSU), large subunit (LSU), translational elongation factor (TEF), and the largest and second-largest subunits of RNA polymerase II (RPB1 and RPB2)) revealed that the divergent lineage is the sister group to all other known Cenococcum isolates. Isolates of the divergent lineage grow fast on nutrient media and do not form ectomycorrhizas on seedlings of several pine and oak species. Our results indicate that C. geophilum sensu lato includes more phylogenetically distinct cryptic species than have previously been reported. Furthermore, the divergent lineage appears to be a non-mycorrhizal sister group. We discuss the phylogenetic diversity of C. geophilum sensu lato and argue in favor of species recognition based on phylogenetic and ecological information in addition to morphological characteristics. A new genus and species (Pseudocenococcum floridanum gen. et sp. nov.) is proposed to accommodate a divergent and putatively non-mycorrhizal lineage. PMID- 26968745 TI - Reproductive system of females of the Magdalena river endemic stingray Potamotrygon magdalenae: Anatomical and functional aspects. AB - We studied anatomical and functional aspects of the reproductive system of females of the Magdalena river stingray Potamotrygon magdalenae using microscopic and macroscopic analysis of each organ. Although the reproductive tract was fully functional on both side, the left organs possibly have a greater contribution to reproductive success, because left ovary and uterus were more developed and had higher number of oocytes and embryos, respectively, than the right ones. This species has histotrophic viviparity given by the presence of uterine trophonemata and by glandular character in pregnant and postpartum females. We suggest that the epigonal organ is involved in the degradation of components of atretic follicles and the embryos begin to develop surrounded by a gelatinous tertiary envelope produced by the oviducal gland. This latter organ is composed by three zones in mature females, club, papillary, and baffle zone, as described for other elasmobranchs. From the anatomical observations, a maturity scale comprising six sexual maturity stages (Immature I, Immature II, early mature, pregnant, post partum, and regenerating) was established for female P. magdalenae, and it can be useful as basis for reproductive studies of other potamotrygonid species. Finally, we propose a continuous reproductive cycle for P. magdalenae. PMID- 26968744 TI - Arbutoid mycorrhizas of the genus Cortinarius from Costa Rica. AB - Arbutoid mycorrhizas of Comarostaphylis arbutoides (Arbutoidea, Ericaceae) from neotropical montane forests are rarely described. To date, only mycorrhizal associations with the fungal species Leccinum monticola, Leotia lubrica and Sebacina sp. are known from literature. The genus Cortinarius is one of the most species-rich ectomycorrhizal taxa with over 2000 assumed species. In this study, two sites in the Cordillera de Talamanca of Costa Rica were sampled, where Com. arbutoides is endemic and grows together with Quercus costaricensis. Using a combined method of rDNA sequence analysis and morphotyping, 33 sampled mycorrhizal systems of Cortinarius were assigned to the subgenera Dermocybe, Phlegmacium and Telamonia. Specific plant primers were used to identify the host plant. Here, we present the phylogenetic data of all found Cortinarii and describe four of the arbutoid mycorrhizal systems morphologically and anatomically. PMID- 26968746 TI - Assessment scales for the diagnosis of polyneuropathy. AB - Epidemiological studies that investigate the occurrence and determinants of chronic length-dependent polyneuropathy are scarce. Population-based studies on polyneuropathy require a valid and reliable screening protocol with both good sensitivity and specificity. Several questionnaires and scoring scales have been developed for the detection of polyneuropathy, grading the severity of the disease, or evaluating the clinical course during follow-up. This review summarizes the aims and content of existing diagnostic polyneuropathy screening tools in order to help future studies decide which scale to use for screening in specific situations. We searched the PubMed database and identified 27 scales, 13 are based on symptoms alone, 8 on neurological signs alone, and 6 on a combination of symptoms and signs. Scales that combine questions concerning symptoms and a neurological examination with a focus on sensory alterations seem to have the best discriminatory power. However, all scoring scales were developed for and investigated in prespecified patient populations. Therefore, the generalizability of specific findings to the general population may be limited. We also discuss other limitations of existing scales. Future studies are required to determine which clinimetrically well-developed scales are preferred for use in population-based studies. PMID- 26968747 TI - Toward a skin-material interface with vacuum-integrated capped macroporous scaffolds. AB - Avulsion, epidermal marsupialization, and infection cause failure at the skin material interface. A robust interface would permit implantable robotics, prosthetics, and other medical devices; reconstruction of surgical defects, and long-term access to blood vessels and body cavities. Torus-shaped cap-scaffold structures were designed to work in conjunction with negative pressure to address the three causes of failure. Six wounds were made on the backs of each of four 3 month old pigs. Four unmodified (no caps) scaffolds were implanted along with 20 cap-scaffolds. Collagen type 4 was attached to 21 implants. Negative pressure then was applied. Structures were explanted and assessed histologically at day 7 and day 28. At day 28, there was close tissue apposition to scaffolds, without detectable reactions from defensive or interfering cells. Three cap-scaffolds explanted at day 28 showed likely attachment of epidermis to the cap or cap scaffold junction, without deeper marsupialization. The combination of toric shaped cap-scaffolds with negative pressure appears to be an intrinsically biocompatible system, enabling a robust skin-material interface. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1307-1318, 2017. PMID- 26968749 TI - Transition-metal-catalyzed Chelation-assisted C-H Functionalization of Aromatic Substrates. AB - In the past decade, transition-metal-catalyzed C-H activations have been very popular in the research field of organometallic chemistry, and have been considered as efficient and convenient strategies to afford complex natural products, functional advanced materials, fluorescent compounds, and pharmaceutical compounds. In this account, we begin with a brief introduction to the development of transition-metal-catalyzed C-H activation, especially the development of transition-metal-catalyzed chelation-assisted C-H activation. Then, a more detailed discussion is directed towards our recent studies on the transition-metal-catalyzed chelation-assisted oxidative C-H/C-H functionalization of aromatic substrates bearing directing functional groups. PMID- 26968748 TI - Asymmetric Palladium-Catalyzed Alkene Carboamination Reactions for the Synthesis of Cyclic Sulfamides. AB - The synthesis of cyclic sulfamides by enantioselective Pd-catalyzed alkene carboamination reactions between N-allylsulfamides and aryl or alkenyl bromides is described. High levels of asymmetric induction (up to 95:5 e.r.) are achieved using a catalyst composed of [Pd2 (dba)3 ] and (S)-Siphos-PE. Deuterium-labelling studies indicate the reactions proceed through syn-aminopalladation of the alkene and suggest that the control of syn- versus anti-aminopalladation pathways is important for asymmetric induction. PMID- 26968750 TI - A randomised crossover trial of minimising medical terminology in secondary care correspondence in patients with chronic health conditions: impact on understanding and patient reported outcomes. AB - BACKGROUND: There is little existing research on the role that secondary care letters have in ensuring patient understanding of chronic health conditions. AIM: To determine whether minimising the use of medical terminology in medical correspondence improved patient understanding and anxiety/depression scores. METHODS: A single-centre, non-blinded, randomised crossover design assessed health literacy, EQ-5D scores and the impact of the 'translated' letter on the doctor's professionalism, the patient's relationship with their general practitioner (GP) and their perceived impact on chronic disease management. Patients were crossed over between their 'translated' and original letter. RESULTS: Sixty patients were recruited. Use of a 'translated' letter reduced mean terms not understood from 7.78 to 1.76 (t(58) = 4.706, P < 0.001). Most patients (78.0%) preferred the 'translated' letter, with 69.5% patients perceiving an enhancement in their doctor's professionalism (z = 2.864, P = 0.004), 69.0% reporting a positive influence on relationship with their GP (z = 2.943, P = 0.003) and 79.7% reporting an increase in perceived ability to manage their chronic health condition with the 'translated' letter (z = 4.601, P < 0.001). There was no effect on EQ-5D depression/anxiety scores. CONCLUSION: Minimising the use of medical terminology in medical correspondence significantly improved patient understanding and perception of their ability to manage their chronic health condition. Although there was no impact on EQ-5D depression/anxiety scores, overwhelming patient preference for the 'translated' letter indicates a need for minimisation of medical terminology in medical correspondence for patients with chronic health conditions. PMID- 26968751 TI - The role of visual and spatial working memory in forming mental models derived from survey and route descriptions. AB - This study examines the involvement of spatial and visual working memory (WM) in the construction of flexible spatial models derived from survey and route descriptions. Sixty young adults listened to environment descriptions, 30 from a survey perspective and the other 30 from a route perspective, while they performed spatial (spatial tapping [ST]) and visual (dynamic visual noise [DVN]) secondary tasks - believed to overload the spatial and visual working memory (WM) components, respectively - or no secondary task (control, C). Their mental representations of the environment were tested by free recall and a verification test with both route and survey statements. Results showed that, for both recall tasks, accuracy was worse in the ST than in the C or DVN conditions. In the verification test, the effect of both ST and DVN was a decreasing accuracy for sentences testing spatial relations from the opposite perspective to the one learnt than if the perspective was the same; only ST had a stronger interference effect than the C condition for sentences from the opposite perspective from the one learnt. Overall, these findings indicate that both visual and spatial WM, and especially the latter, are involved in the construction of perspective-flexible spatial models. PMID- 26968753 TI - EuroSurg-1 study: an opportunity to encourage student-driven surgical research in Italy. PMID- 26968752 TI - Epidemiology of fractures in the United Kingdom 1988-2012: Variation with age, sex, geography, ethnicity and socioeconomic status. AB - Rates of fracture worldwide are changing. Using the Clinical Practice Research Datalink (CPRD), age, and gender, geographical, ethnic and socioeconomic trends in fracture rates across the United Kingdom were studied over a 24-year period 1988-2012. Previously observed patterns in fracture incidence by age and fracture site were evident. New data on the influence of geographic location, ethnic group and socioeconomic status were obtained. INTRODUCTION: With secular changes in age and sex-specific fracture incidence observed in many populations, and global shifts towards an elderly demography, it is vital for health care planners to have an accurate understanding of fracture incidence nationally. We aimed to present up to date fracture incidence data in the UK, stratified by age, sex, geographic location, ethnicity and socioeconomic status. METHODS: The Clinical Practice Research Datalink (CPRD) contains anonymised electronic health records for approximately 6.9% of the UK population. Information comes from General Practitioners, and covers 11.3 million people from 674 practices across the UK, demonstrated to be representative of the national population. The study population consisted of all permanently registered individuals aged >=18years. Validated data on fracture incidence were obtained from their medical records, as was information on socioeconomic deprivation, ethnicity and geographic location. Age- and sex-specific fracture incidence rates were calculated. RESULTS: Fracture incidence rates by age and sex were comparable to those documented in previous studies and demonstrated a bimodal distribution. Substantial geographic heterogeneity in age- and sex adjusted fracture incidence was observed, with rates in Scotland almost 50% greater than those in London and South East England. Lowest rates of fracture were observed in black individuals of both sexes; rates of fragility fracture in white women were 4.7 times greater than in black women. Strong associations between deprivation and fracture risk were observed in hip fracture in men, with a relative risk of 1.3 (95% CI 1.21-1.41) in Index of Multiple Deprivation category 5 (representing the most deprived) compared to category 1. CONCLUSIONS: This study presents robust estimates of fracture incidence across the UK, which will aid decisions regarding allocation of healthcare provision to populations of greatest need. It will also assist the implementation and design of strategies to reduce fracture incidence and its personal and financial impact on individuals and health services. PMID- 26968754 TI - Individual tumor volume responses to short-course oxaliplatin-containing induction chemotherapy in locally advanced rectal cancer - Targeting the tumor for radiation sensitivity? AB - BACKGROUND: Neoadjuvant treatment of locally advanced rectal cancer (LARC) involves chemoradiotherapy (CRT), which may cause significant toxicity, and the potential role and sequential placement of neoadjuvant chemotherapy (NACT) relative to CRT is under debate. PATIENTS AND METHODS: In a non-randomized study of 72 LARC patients, short-course oxaliplatin-containing NACT was administered prior to CRT. Tumor volumes were calculated from magnetic resonance images before and after NACT, and four weeks after CRT, and associations between tumor volume responses and outcome were analyzed. Additionally, the impact of oxaliplatin exposure on radiosensitivity was examined in colorectal carcinoma cell lines. RESULTS: All tumors except one responded to NACT, with better responses in T3 than T4 cases, and 69/72 patients obtained additional tumor volume reduction after subsequent CRT. However, no associations were found between tumor volume reduction and long-term outcome. Of note, oxaliplatin-resistant cells were significantly more radiosensitive than the oxaliplatin-sensitive counterparts. CONCLUSIONS: Oxaliplatin-containing NACT led to substantial tumor volume reduction with particularly good responses in T3 cases. NACT did not impede subsequent CRT response, and experimental results rather suggested enhanced radiosensitivity in oxaliplatin-exposed cells, encouraging studies to explore the administration of NACT prior to CRT. Data are still lacking to support omitting radiation in LARC management. PMID- 26968755 TI - Incidence of Interstitial Pregnancy After In Vitro Fertilization/Embryo Transfer and the Outcome of a Consecutive Series of 38 Cases Managed by Laparoscopic Cornuostomy or Cornual Repair. AB - STUDY OBJECTIVE: To determine the incidence of interstitial pregnancy after in vitro fertilization/embryo transfer (ET) treatment and report on our experience of laparoscopic cornuostomy or cornual repair for interstitial pregnancy. DESIGN: Single-center, retrospective review (Canadian Task Force classification II-3). SETTING: University hospital. PATIENTS: Thirty-eight women diagnosed with interstitial pregnancy, which developed after 10,143 ET cycles, managed in our center between April 2011 and April 2014. INTERVENTIONS: All 38 cases of interstitial pregnancy were managed by laparoscopic cornuostomy or cornual repair. No patient was converted to laparotomy. MEASUREMENTS AND MAIN RESULTS: Of 43 cases of interstitial pregnancy, 38 were managed in our department. The overall incidence of interstitial pregnancy was .4% per ET cycle (43/10 143), or .8% per pregnancy (43/5297), but comprising 35.5% of all ectopic pregnancy cases. The risk factors for interstitial pregnancy included tubal infertility, cleavage ET, and frozen ET. Twenty-seven subjects (71.1%) had undergone bilateral salpingectomy. Among the 38 cases, 27 were intact, with no persistent ectopic pregnancy after surgery, but there were 3 cases (28.3%) of persistent pregnancy in the 11 ruptured cases. Among the 38 subjects, 15 conceived again with 14 live births and 1 ongoing pregnancy, without uterine rupture. CONCLUSION: Laparoscopic cornuostomy or cornual repair appears to be an effective treatment in intact cases, although it sometimes needs to be combined with methotrexate therapy in ruptured cases complicated by persistent disease. PMID- 26968756 TI - Illumina error profiles: resolving fine-scale variation in metagenomic sequencing data. AB - BACKGROUND: Illumina's sequencing platforms are currently the most utilised sequencing systems worldwide. The technology has rapidly evolved over recent years and provides high throughput at low costs with increasing read-lengths and true paired-end reads. However, data from any sequencing technology contains noise and our understanding of the peculiarities and sequencing errors encountered in Illumina data has lagged behind this rapid development. RESULTS: We conducted a systematic investigation of errors and biases in Illumina data based on the largest collection of in vitro metagenomic data sets to date. We evaluated the Genome Analyzer II, HiSeq and MiSeq and tested state-of-the-art low input library preparation methods. Analysing in vitro metagenomic sequencing data allowed us to determine biases directly associated with the actual sequencing process. The position- and nucleotide-specific analysis revealed a substantial bias related to motifs (3mers preceding errors) ending in "GG". On average the top three motifs were linked to 16 % of all substitution errors. Furthermore, a preferential incorporation of ddGTPs was recorded. We hypothesise that all of these biases are related to the engineered polymerase and ddNTPs which are intrinsic to any sequencing-by-synthesis method. We show that quality-score-based error removal strategies can on average remove 69 % of the substitution errors - however, the motif-bias remains. CONCLUSION: Single-nucleotide polymorphism changes in bacterial genomes can cause significant changes in phenotype, including antibiotic resistance and virulence, detecting them within metagenomes is therefore vital. Current error removal techniques are not designed to target the peculiarities encountered in Illumina sequencing data and other sequencing-by synthesis methods, causing biases to persist and potentially affect any conclusions drawn from the data. In order to develop effective diagnostic and therapeutic approaches we need to be able to identify systematic sequencing errors and distinguish these errors from true genetic variation. PMID- 26968757 TI - A preliminary study for novel use of two Mg alloys (WE43 and Mg3Gd). AB - In this study, two types of magnesium alloys (WE43 and Mg3Gd) were compared with Heal-All membrane (a biodegradable membrane used in guided bone regeneration) in vitro to determine whether the alloys could be used as biodegradable membranes. Degradation behavior was assessed using immersion testing with simulated body fluid (SBF). Microstructural characteristics before and after immersion were evaluated through scanning electron microscopy, and degradation products were analyzed with energy dispersive spectrometry (EDS). To evaluate the biocompatibility of the three types of materials, we performed cytotoxicity, adhesion, and mineralization tests using human osteoblast-like MG63 cells. Immersion testing results showed no significant difference in degradation rate between WE43 and Mg3Gd alloys. However, both Mg alloys corroded faster than the Heal-All membrane, with pitting corrosion as the main corrosion mode for the alloys. Degradation products mainly included P- and Ca-containing apatites on the surface of WE43 and Mg3Gd, whereas these apatites were rarely detected on the surface of the Heal-All membrane. All three type of materials exhibited good biocompatibility. In the mineralization experiment, the alkaline phosphatase (ALP) activity of 10 % Mg3Gd extract was significantly higher than the extracts of the two other materials and the negative control. This study highlighted the potential of these Mg-REE alloys for uses in bone regeneration and further studies and refinements are obviously required. PMID- 26968758 TI - Simvastatin-doped pre-mixed calcium phosphate cement inhibits osteoclast differentiation and resorption. AB - Simvastatin, a cholesterol lowering drug, has been shown to have positive effects on fracture healing and bone regeneration based on its dual effect; bone anabolic and anti-resorptive. In this study the focus has been on the anti-resorptive effect of the drug and its impact on the degradation of acidic calcium phosphate cement. The drug was added to the pre-mixed acidic cement in three different doses (0.1, 0.25 and 0.5 mg/g cement) and the release was measured. Furthermore the effect of the loaded cements on osteoclast differentiation and resorption was evaluated by TRAP activity, number of multinucleated cells, gene expression and calcium ion concentration in vitro using murine bone marrow macrophages. The simvastatin did not affect the cell proliferation while it clearly inhibited osteoclastic differentiation at all three doses as shown by TRAP staining, TRAP activity and gene expression. Consistent with these results, simvastatin also impaired resorption of cements by osteoclasts as indicated by reduced calcium ion concentrations. In conclusion, our findings suggest that simvastatin-doped pre mixed acidic calcium phosphate cement inhibits the osteoclastic mediated resorption of the cement thus slowing down the degradation rate. In addition with simvastatin's bone anabolic effect it makes the cement-drug combination a promising bone graft material, especially useful for sites with compromised bone formation. PMID- 26968760 TI - Natural product derived immune-regulatory agents. AB - We can now declare that the clinical goal of immune intervention as a therapeutic strategy for neoplastic, infectious, autoimmune and inflammatory diseases, has been achieved and in many instances obtained regulatory approval. Although, interest in and optimism for this approach has fluctuated, in the last 20years, immunotherapy has progressed from trials with crude microbial mixtures and extracts to the sophisticated use of pure cultured bacterial, synthetized active moieties identified from crude extracts, analogues therefrom and agonists and antagonists identified during screening resulting in reproducible pharmacologically active compounds with multiple mechanisms of action. Our current understanding of the mechanism of action for immunoregulatory agents contributes to the future discovery of improved strategies to use these and future immunotherapies. In this review we have identified and discussed, those drugs that have been approved and or are in clinical development as immunoregulatory agents, emphasizing those derived from or associated with natural product. PMID- 26968759 TI - 1,4-Butanediol diglycidyl ether-cross-linked hyaluronan inhibits fibrosis in rat primary tenocytes by down-regulating autophagy modulation. AB - Epidural fibrosis, an inevitable part of the postoperative healing process, is one of the important causes of failed back surgery syndrome after spinal surgery. The aim of this study was to examine the inhibitory effect of a novel material 1,4-butanediol diglycidyl ether-cross-linked hyaluronan (cHA) on fibrosis in primary tenocytes. cHA inhibited migration, cell proliferation, and suppressed the expression of fibronectin, but not transforming growth factor-beta, in primary tenocytes. cHA significantly increased matrix metalloproteinase-3 but decreased collagen-1 and microtubule-associated protein light chain 3-II expression in a dose-dependent manner compared with control groups. We therefore concluded that suppressing autophagy activity may be involved in the anti fibrotic effect of cHA in primary tenocytes. Further, cHA may have the potential for preventing epidural fibrosis and subsequent failed back syndrome in patients with laminectomy in the future. PMID- 26968762 TI - Mean platelet volume is decreased in adults with active lupus disease. AB - BACKGROUND: Only a few biomarkers are available for assessing disease activity in systemic lupus erythematosus (SLE). Mean platelet volume (MPV) has been recently studied as an inflammatory biomarker. It is currently unclear whether MPV may also play a role as a biomarker of disease activity in adult patients with SLE. OBJECTIVE: We investigated the association between MPV and disease activity in adult patients with SLE. METHODS: In this retrospective study, we compared two groups of adult patients divided according to disease activity (36 per group). Subjects were age- and gender-matched. RESULTS: MPV was significantly decreased with respect to those of inactive patients (7.16+/-1.39 vs. 8.16+/-1.50, p=0.005). At a cutoff level of 8.32 fL, MPV has a sensitivity of 86% and a specificity of 41% for the detection of disease activity. A modest positive correlation was found between MPV and albumin (r=0.407, p=0.001), which in turn is inversely associated with disease activity. CONCLUSIONS: In summary, MPV is decreased in adult patients with active lupus disease, and positively correlated with albumin, another biomarker of disease activity. Prospective studies are needed to evaluate the prognostic value of this biomarker. PMID- 26968761 TI - Optimal timing of surgery for active infective endocarditis with cerebral complications: a Japanese multicentre study. AB - OBJECTIVES: The aim of this study was to investigate the effect of the timing of valve surgery on the clinical outcomes of patients with active infective endocarditis (IE) accompanied by cerebral complications. METHODS: We retrospectively analysed a cohort of 568 patients, comprising 118 with non haemorrhagic cerebral infarction (CI), 54 with intracranial haemorrhage (ICH) and 396 without cerebral events (C; control), who underwent surgery for left-sided active IE in 15 Japanese institutes from 2000 to 2011. The mean age was 58.4 +/- 16.9 years in the CI group; 54.5 +/- 17.4 years in the ICH group and 56.9 +/- 16.0 years in the C group. Clinical outcomes were analysed according to the timing of surgery after the diagnosis of CI or ICH was made. RESULTS: In the CI group, there were 9 (7.6%) hospital deaths, 13 (11%) new cerebral events and 1 (0.8%) redo valve surgery. In the ICH group, there were 3 (5.6%) hospital deaths, 8 (14.8%) new cerebral events and 2 (3.7%) redo valve surgeries. In the C group, there were 36 (9.1%) hospital deaths, 23 (5.8%) new cerebral events and 9 (2.3%) redo valve surgeries. Risk factors for hospital death were prosthetic valve endocarditis (P = 0.045), high C-reactive protein (CRP; P < 0.001) and the elderly (P < 0.001) in the CI group. Delayed surgery (2 weeks after CI) seemed result in a higher incidence of hospital death in the CI group. Patients who had surgery between 15 and 28 days or after 29 days from the onset of CI had higher incidences of hospital death [odds ratio 5.90 (P = 0.107) and 4.92 (P = 0.137), respectively] compared with those who had surgery within 7 days. In the ICH group, risk factors for hospital death were high CRP (P = 0.002) and elderly (P < 0.001). Contrary to CI patients, patients who had surgery between 8 and 21 days or after 22 days after the onset of ICH had lower incidences of hospital death [odds ratio 0.79 (P = 0.843) and 0.12 (P = 0.200), respectively] compared with those who had surgery within 7 days. CONCLUSIONS: Although statistically insignificant, early surgery in active IE patients with CI is safe, but very early surgery (within 7 days) should be avoided in patients with ICH. PMID- 26968764 TI - Differences in the central-nervous processing of olfactory stimuli according to their hedonic and arousal characteristics. AB - Given the strong relationship between human olfaction and emotion, it is not surprising that numerous studies have investigated human response to hedonic and arousing qualities of odors. However, neuropsychological research addressed rather the pleasant-unpleasant, and not the arousing-calming dimension of emotional states generated by odorants. The purpose of the presented fMRI study was to evaluate the differences in cerebral processing of olfactory stimuli, focusing on both of these dimensions of emotional experiences, i.e., pleasantness and arousal. We investigated the patterns of activation generated by odors differing in hedonic tone and generated arousal while controlling the stimuli intensity. This design allowed for a new insight to the emotional odor processing with imaging techniques. The pleasantness was related to activation in the cingulate gyrus, the insula, the hippocampal area, the amygdala, and the superior temporal gyrus, whereas arousal affected activation in the thalamic relay. The present study showed also that the emotional states generated by arousing qualities of odorants are an important determinant of magnitude of cerebral activation. PMID- 26968763 TI - Ablation of fast-spiking interneurons in the dorsal striatum, recapitulating abnormalities seen post-mortem in Tourette syndrome, produces anxiety and elevated grooming. AB - Tic disorders, including Tourette syndrome (TS), are thought to involve pathology of cortico-basal ganglia loops, but their pathology is not well understood. Post mortem studies have shown a reduced number of several populations of striatal interneurons, including the parvalbumin-expressing fast-spiking interneurons (FSIs), in individuals with severe, refractory TS. We tested the causal role of this interneuronal deficit by recapitulating it in an otherwise normal adult mouse using a combination transgenic-viral cell ablation approach. FSIs were reduced bilaterally by ~40%, paralleling the deficit found post-mortem. This did not produce spontaneous stereotypies or tic-like movements, but there was increased stereotypic grooming after acute stress in two validated paradigms. Stereotypy after amphetamine, in contrast, was not elevated. FSI ablation also led to increased anxiety-like behavior in the elevated plus maze, but not to alterations in motor learning on the rotorod or to alterations in prepulse inhibition, a measure of sensorimotor gating. These findings indicate that a striatal FSI deficit can produce stress-triggered repetitive movements and anxiety. These repetitive movements may recapitulate aspects of the pathophysiology of tic disorders. PMID- 26968765 TI - Hippocampal neuronal subtypes develop abnormal dendritic arbors in the presence of Fragile X astrocytes. AB - Astrocytes are now recognized as key players in the neurobiology of neurodevelopmental disorders such as Fragile X syndrome. However, the nature of Fragile X astrocyte-mediated control of dendrite development in subtypes of hippocampal neurons is not yet known. We used a co-culture procedure in which wildtype primary hippocampal neurons were cultured with astrocytes from either a wildtype or Fragile X mouse, for either 7, 14 or 21 days. The neurons were processed for immunocytochemistry with the dendritic marker MAP2, classified by morphological criteria into one of five neuronal subtypes, and subjected to Sholl analyses. Both linear and semi-log methods of Sholl analyses were applied to the neurons in order to provide an in depth analysis of the dendritic arborizations. We found that Fragile X astrocytes affect the development of dendritic arborization of all subtypes of wildtype hippocampal neurons. Furthermore, we show that hippocampal neurons with spiny stellate neuron morphology exhibit the most pervasive developmental delays, with significant dendritic arbor alterations persisting at 21 days in culture. The results further dictate the critical role astrocytes play in governing neuronal morphology including altered dendrite development in Fragile X. PMID- 26968766 TI - Striatal mRNA expression patterns underlying peak dose L-DOPA-induced dyskinesia in the 6-OHDA hemiparkinsonian rat. AB - L-DOPA is the primary pharmacological treatment for relief of the motor symptoms of Parkinson's disease (PD). With prolonged treatment (?5 years) the majority of patients will develop abnormal involuntary movements as a result of L-DOPA treatment, known as L-DOPA-induced dyskinesia. Understanding the underlying mechanisms of dyskinesia is a crucial step toward developing treatments for this debilitating side effect. We used the 6-hydroxydopamine (6-OHDA) rat model of PD treated with a three-week dosing regimen of L-DOPA plus the dopa decarboxylase inhibitor benserazide (4 mg/kg and 7.5 mg/kgs.c., respectively) to induce dyskinesia in 50% of individuals. We then used RNA-seq to investigate the differences in mRNA expression in the striatum of dyskinetic animals, non dyskinetic animals, and untreated parkinsonian controls at the peak of dyskinesia expression, 60 min after L-DOPA administration. Overall, 255 genes were differentially expressed; with significant differences in mRNA expression observed between all three groups. In dyskinetic animals 129 genes were more highly expressed and 14 less highly expressed when compared with non-dyskinetic and untreated parkinsonian controls. In L-DOPA treated animals 42 genes were more highly expressed and 95 less highly expressed when compared with untreated parkinsonian controls. Gene set cluster analysis revealed an increase in expression of genes associated with the cytoskeleton and phosphoproteins in dyskinetic animals compared with non-dyskinetic animals, which is consistent with recent studies documenting an increase in synapses in dyskinetic animals. These genes may be potential targets for drugs to ameliorate L-DOPA-induced dyskinesia or as an adjunct treatment to prevent their occurrence. PMID- 26968767 TI - Reduced mucociliary clearance in old mice is associated with a decrease in Muc5b mucin. AB - Respiratory infections are a major cause of morbidity and mortality in the elderly. Previous reports have suggested that mucociliary clearance (MCC) is impaired in older individuals, but the cause is unclear. To unravel the mechanisms responsible for the age-associated decline in MCC, we investigated the MCC system in young (3 mo) and old (2 yr) C57BL/6 mice. We found that old mice had significantly reduced MCC function in both the upper and lower airways compared with young mice. Measurement of bioelectric properties of isolated tracheal and bronchial tissue revealed a significant decrease in Cl(-) secretion, suggesting that the older mice may have a reduced ability to maintain a sufficiently hydrated airway surface for efficient MCC. Ciliary beat frequency was also observed to be reduced in the older animals; however, this reduction was small relative to the reduction in MCC. Interestingly, the level of the major secreted mucin, Muc5b, was found to be reduced in both bronchioalveolar lavage and isolated tracheal tissue. Our previous studies of Muc5b(-/-) mice have demonstrated that Muc5b is essential for normal MCC in the mouse. Furthermore, examination of Muc5b(+/-) and wild-type animals revealed that heterozygous animals, which secrete ~50% of the wild-type level of Muc5b, also demonstrate a markedly reduced level of MCC, confirming the importance of Muc5b levels to MCC. These results demonstrate that aged mice exhibit a decrease in MCC and suggest that a reduced level of secretion of both Cl(-) and Muc5b may be responsible. PMID- 26968769 TI - Calcium-dependent phospholipase A2 modulates infection-induced diaphragm dysfunction. AB - Calpain activation contributes to the development of infection-induced diaphragm weakness, but the mechanisms by which infections activate calpain are poorly understood. We postulated that skeletal muscle calcium-dependent phospholipase A2 (cPLA2) is activated by cytokines and has downstream effects that induce calpain activation and muscle weakness. We determined whether cPLA2 activation mediates cytokine-induced calpain activation in isolated skeletal muscle (C2C12) cells and infection-induced diaphragm weakness in mice. C2C12 cells were treated with the following: 1) vehicle; 2) cytomix (TNF-alpha 20 ng/ml, IL-1beta 50 U/ml, IFN gamma 100 U/ml, LPS 10 MUg/ml); 3) cytomix + AACOCF3, a cPLA2 inhibitor (10 MUM); or 4) AACOCF3 alone. At 24 h, we assessed cell cPLA2 activity, mitochondrial superoxide generation, calpain activity, and calpastatin activity. We also determined if SS31 (10 MUg/ml), a mitochondrial superoxide scavenger, reduced cytomix-mediated calpain activation. Finally, we determined if CDIBA (10 MUM), a cPLA2 inhibitor, reduced diaphragm dysfunction due to cecal ligation puncture in mice. Cytomix increased C2C12 cell cPLA2 activity (P < 0.001) and superoxide generation; AACOCF3 and SS31 blocked increases in superoxide generation (P < 0.001). Cytomix also activated calpain (P < 0.001) and inactivated calpastatin (P < 0.01); both AACOCF3 and SS31 prevented these changes. Cecal ligation puncture reduced diaphragm force in mice, and CDIBA prevented this reduction (P < 0.001). cPLA2 modulates cytokine-induced calpain activation in cells and infection induced diaphragm weakness in animals. We speculate that therapies that inhibit cPLA2 may prevent diaphragm weakness in infected, critically ill patients. PMID- 26968768 TI - Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension. AB - An increase in cytosolic free Ca(2+) concentration ([Ca(2+)]cyt) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and a critical stimulation for PASMC proliferation and migration. Previously, we demonstrated that expression and function of calcium sensing receptors (CaSR) in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH) and animals with experimental pulmonary hypertension (PH) were greater than in PASMC from normal subjects and control animals. However, the mechanisms by which CaSR triggers Ca(2+) influx in PASMC and the implication of CaSR in the development of PH remain elusive. Here, we report that CaSR functionally interacts with TRPC6 to regulate [Ca(2+)]cyt in PASMC. Downregulation of CaSR or TRPC6 with siRNA inhibited Ca(2+)-induced [Ca(2+)]cyt increase in IPAH-PASMC (in which CaSR is upregulated), whereas overexpression of CaSR or TRPC6 enhanced Ca(2+)-induced [Ca(2+)]cyt increase in normal PASMC (in which CaSR expression level is low). The upregulated CaSR in IPAH-PASMC was also associated with enhanced Akt phosphorylation, whereas blockade of CaSR in IPAH PASMC attenuated cell proliferation. In in vivo experiments, deletion of the CaSR gene in mice (casr(-/-)) significantly inhibited the development and progression of experimental PH and markedly attenuated acute hypoxia-induced pulmonary vasoconstriction. These data indicate that functional interaction of upregulated CaSR and upregulated TRPC6 in PASMC from IPAH patients and animals with experimental PH may play an important role in the development and progression of sustained pulmonary vasoconstriction and pulmonary vascular remodeling. Blockade or downregulation of CaSR and/or TRPC6 with siRNA or miRNA may be a novel therapeutic strategy to develop new drugs for patients with pulmonary arterial hypertension. PMID- 26968773 TI - Transfer RNA: From pioneering crystallographic studies to contemporary tRNA biology. AB - Transfer RNAs (tRNAs) play a key role in protein synthesis as adaptor molecules between messenger RNA and protein sequences on the ribosome. Their discovery in the early sixties provoked a worldwide infatuation with the study of their architecture and their function in the decoding of genetic information. tRNAs are also emblematic molecules in crystallography: the determination of the first tRNA crystal structures represented a milestone in structural biology and tRNAs were for a long period the sole source of information on RNA folding, architecture, and post-transcriptional modifications. Crystallographic data on tRNAs in complex with aminoacyl-tRNA synthetases (aaRSs) also provided the first insight into protein:RNA interactions. Beyond the translation process and the history of structural investigations on tRNA, this review also illustrates the renewal of tRNA biology with the discovery of a growing number of tRNA partners in the cell, the involvement of tRNAs in a variety of regulatory and metabolic pathways, and emerging applications in biotechnology and synthetic biology. PMID- 26968770 TI - Combination therapy with cystic fibrosis transmembrane conductance regulator modulators augment the airway functional microanatomy. AB - Recently approved therapies that modulate CFTR function have shown significant clinical benefit, but recent investigations regarding their molecular mechanism when used in combination have not been consistent with clinical results. We employed micro-optical coherence tomography as a novel means to assess the mechanism of action of CFTR modulators, focusing on the effects on mucociliary clearance. Primary human airway monolayers from patients with a G551D mutation responded to ivacaftor treatment with increased ion transport, airway surface liquid depth, ciliary beat frequency, and mucociliary transport rate, in addition to decreased effective viscosity of the mucus layer, a unique mechanism established by our findings. These endpoints are consistent with the benefit observed in G551D patients treated with ivacaftor, and identify a novel mechanism involving mucus viscosity. In monolayers derived from F508del patients, the situation is more complicated, compounded by disparate effects on CFTR expression and function. However, by combining ion transport measurements with functional imaging, we establish a crucial link between in vitro data and clinical benefit, a finding not explained by ion transport studies alone. We establish that F508del cells exhibit increased mucociliary transport and decreased mucus effective viscosity, but only when ivacaftor is added to the regimen. We further show that improvement in the functional microanatomy in vitro corresponds with lung function benefit observed in the clinical trials, whereas ion transport in vitro corresponds to changes in sweat chloride. Functional imaging reveals insights into clinical efficacy and CFTR biology that significantly impact our understanding of novel therapies. PMID- 26968771 TI - A three-dimensional human model of the fibroblast activation that accompanies bronchopulmonary dysplasia identifies Notch-mediated pathophysiology. AB - Bronchopulmonary dysplasia (BPD) is a leading complication of premature birth and occurs primarily in infants delivered during the saccular stage of lung development. Histopathology shows decreased alveolarization and a pattern of fibroblast proliferation and differentiation to the myofibroblast phenotype. Little is known about the molecular pathways and cellular mechanisms that define BPD pathophysiology and progression. We have developed a novel three-dimensional human model of the fibroblast activation associated with BPD, and using this model we have identified the Notch pathway as a key driver of fibroblast activation and proliferation in response to changes in oxygen. Fetal lung fibroblasts were cultured on sodium alginate beads to generate lung organoids. After exposure to alternating hypoxia and hyperoxia, the organoids developed a phenotypic response characterized by increased alpha-smooth muscle actin (alpha SMA) expression and other genes known to be upregulated in BPD and also demonstrated increased expression of downstream effectors of the Notch pathway. Inhibition of Notch with a gamma-secretase inhibitor prevented the development of the pattern of cellular proliferation and alpha-SMA expression in our model. Analysis of human autopsy tissue from the lungs of infants who expired with BPD demonstrated evidence of Notch activation within fibrotic areas of the alveolar septae, suggesting that Notch may be a key driver of BPD pathophysiology. PMID- 26968774 TI - Metabolic syndrome and its association with obesity and lifestyle factors in Sudanese population. AB - Although modern life style factors affecting health is a crucial problem globally, little information about metabolic syndrome (MetS) is available for the Sudanese population. With this consideration the study was planned to assess the prevalence of MetS among young people of Sudan and their association with obesity and lifestyle factors. Serum lipid profile, blood glucose and clinically established parameters for obesity were assessed in 179 young adult male and 201 females at National Ribat University, Sudan. Relevant statistical test were applied using SPSS software. Based on anthropometric measurements, 137 students were obese. Amongst the 243 non-obese students 5 were under weight, 135 normal weight and 103 were over weight. In the study population, 317 students were normal (83.4%) and 63 students had MetS (16.6%) as defined by ATP III definition of MetS classification. MetS was found only in obese individuals (45.98%) and no case was detected in underweight, normal and overweight individual. The mean of cholesterol level in subjects with MetS was 159 as compared to those without it (149.93). Life style modification as healthy diet, regular exercise and preventive strategies may help reduce MetS, thus improving general health conditions in young individuals of Sudan. PMID- 26968775 TI - Trypanosoma evansi contains two auxiliary enzymes of glycolytic metabolism: Phosphoenolpyruvate carboxykinase and pyruvate phosphate dikinase. AB - Trypanosoma evansi is a monomorphic protist that can infect horses and other animal species of economic importance for man. Like the bloodstream form of the closely related species Trypanosoma brucei, T. evansi depends exclusively on glycolysis for its free-energy generation. In T. evansi as in other kinetoplastid organisms, the enzymes of the major part of the glycolytic pathway are present within organelles called glycosomes, which are authentic but specialized peroxisomes. Since T. evansi does not undergo stage-dependent differentiations, it occurs only as bloodstream forms, it has been assumed that the metabolic pattern of this parasite is identical to that of the bloodstream form of T. brucei. However, we report here the presence of two additional enzymes, phosphoenolpyruvate carboxykinase and PPi-dependent pyruvate phosphate dikinase in T. evansi glycosomes. Their colocalization with glycolytic enzymes within the glycosomes of this parasite has not been reported before. Both enzymes can make use of PEP for contributing to the production of ATP within the organelles. The activity of these enzymes in T. evansi glycosomes drastically changes the model assumed for the oxidation of glucose by this parasite. PMID- 26968772 TI - (-)-Epicatechin improves insulin sensitivity in high fat diet-fed mice. AB - Obesity constitutes a major public health concern, being frequently associated with type 2 diabetes (T2D). Evidence from studies in humans and experimental animals suggest that consumption of the flavan-3-ol (-)-epicatechin (EC) and of EC-rich foods may improve insulin sensitivity. To further understand the potential benefits of dietary EC consumption on insulin resistance, this study investigated the capacity of EC supplementation to prevent high fat diet (HFD) induced insulin resistance in mice. To assess the underlying mechanisms, the effects of HFD and EC consumption on the activation of the insulin cascade and of its negative modulators were evaluated. HFD consumption for 15 w caused obesity and insulin resistance in C57BL/6J mice as evidenced by high fasted and fed plasma glucose and insulin levels, and impaired ITT and GTT tests. This was associated with alterations in the activation of components of the insulin triggered signaling cascade (insulin receptor, IRS1, ERK1/2, Akt) in adipose and liver tissues. EC supplementation prevented/ameliorated all these parameters. EC acted improving insulin sensitivity in the HFD-fed mice in part through a downregulation of the inhibitory molecules JNK, IKK, PKC and protein tyrosine phosphatase 1B (PTP1B). Thus, the above results suggest that consumption of EC rich foods could constitute a dietary strategy to mitigate obesity-associated insulin resistance. PMID- 26968776 TI - Real-time PCR for Leishmania species identification: Evaluation and comparison with classical techniques. AB - BACKGROUND: Cutaneous leishmaniasis (CL) is a parasitic disease caused by various Leishmania species. Several studies have shown that real time quantitative PCR (qPCR) can be used for Leishmania spp. identification by analyzing the melting temperature (Tm). Thus, the aim of this study was to evaluate the viability of qPCR for differentiating eight closely related Leishmania species that cause the same clinical form of the disease and to compare the results with classical techniques. METHODS: qPCR assays for standardizing the Tm using reference strains were performed. After the CL diagnosis on blood samples of domestic animals, positive samples were analyzed by their Tm and qPCR products were purified and sequenced. Ten human samples previously characterized by Multilocus Enzyme Electrophoresis (MLEE) were also analyzed by Tm. A Restriction Fragment Length Polymorphism (RFLP) assay, a reference test, was also standardized, by using the reference strains. RESULTS: Through standardization of Tm for Leishmania spp., two Tm ranges were created for analysis: 1 (Tm = 78-79.99 degrees C) included Leishmania (V.) braziliensis, Leishmania (V.) panamensis, Leishmania (V.) lainsoni, Leishmania (V.) guyanensis and Leishmania (V.) shawi; and 2 (Tm = 80 82.2 degrees C) included Leishmania (V.) naiffi, Leishmania (L.) amazonensis and Leishmania (L.) mexicana. A total of 223 positive blood samples were analyzed, with 58 included in range 1 and 165 in range 2. L. (V.) braziliensis, L. (V.) panamensis and L. (V.) guyanensis were identified by sequencing, while L. (V.) braziliensis, L. (L.) mexicana and L. (V.) panamensis were identified by RFLP analysis. Ten human samples previously characterized by Multilocus Enzyme Electrophoresis (MLEE) were also analyzed by qPCR Tm analysis; five were classified in range 1 and five in range 2. A concordance of 80% was calculated between qPCR and the gold-standard (MLEE) with no significant difference between the methods (p = 0.6499); a similar result was observed for sequencing and qPCR (p = 0.2566). In contrast, a highly significant difference was observed for qPCR and RFLP (p < 0.001). CONCLUSIONS: In this study, we demonstrated the potential use of qPCR as a tool for Leishmania species identification using two Tm ranges. PMID- 26968777 TI - Toxoplasma gondii isolates from chickens in an area with human toxoplasmic retinochoroiditis. AB - The aim of this study was to detect, isolate and genetically characterize Toxoplasma gondii from tissues obtained from free range chickens which were breed in farms from patients with toxoplasmic retinochoroiditis in Misiones, Argentina. Thirty three samples of head (refrigerated = 18 and frozen = 15) from free range chickens were processed. Refrigerated (n = 18) chicken central nervous systems (CNS) were bioassay in mice. DNA was obtained from all samples (n = 33) and PCR was performed using TOX5-TOX8 T. gondii specific primers. Positive PCR samples were characterized by nested-PCR and restriction fragment length polymorphism using the markers SAG2, BTUB, GRA6, SAG3, PK1, L358, C22-8, C29-2 and Apico. T. gondii DNA was amplified in 30.3% (10/33) of CNS samples. Isolates were obtained in 27.7% (5/18) of inoculated CNS samples (TgCk11-9Arg, TgCk13-5Arg, TgCk14-5Arg, TgCk14-6Arg and TgCk14-7Arg). Seven samples showed a restriction pattern to all markers and were identified as atypical with several alleles type III. Genotyping of T. gondii from samples of patients with retinochoroiditis in the same area could improve the understanding of the epidemiology of toxoplasmosis in the region. PMID- 26968779 TI - Devil in disguise: Does drinking lead to a disability pension? AB - OBJECTIVES: To examine whether alcohol consumption in adulthood is related to the incidence of receiving a disability pension later in life. METHODS: Twin data for Finnish men and women born before 1958 were matched to register-based individual information on disability pensions. Twin differences were used to eliminate both shared environmental and genetic factors. The quantity of alcohol consumption was measured as the weekly average consumption using self-reported data from three surveys (1975, 1981 and 1990). The disability pension data were evaluated from 1990-2004. RESULTS: The models that account for shared environmental and genetic factors reveal that heavy drinkers are significantly more likely to receive a disability pension than moderate drinkers or constant abstainers. Heavy drinking that leads to passing out is also positively related to receiving a disability pension. The results were robust to the use of potential confounders that twins do not share, such as education years, the number of chronic diseases, physical activity at work and leisure, and stressful life events. CONCLUSION: Drinking profiles in early adulthood are an important predictor of receiving a disability pension later in life. PMID- 26968778 TI - Pyschosocial factors associated with children's cycling for transport: A cross sectional moderation study. AB - Promoting children's cycling for transport is a useful strategy to increase their physical activity levels. No studies have examined to which extent children's psychosocial characteristics play a role in their transportation cycling. Furthermore, insights into the association between children's independent mobility (IM) and transportation cycling is lacking in Europe. This study examined (1) the association of children's psychosocial characteristics with transportation cycling and its moderating effect of child's gender, parents' educational attainment and IM, and (2) the association between children's IM and transportation cycling. Children (n=1232, aged 10-12yrs) completed an online questionnaire at school assessing their psychosocial characteristics related with transportation cycling. Parents reported child's usual transportation cycling and the distance their child is allowed to cycle unsupervised (IM). Hurdle models were used to estimate associations between independent variables and odds of being a cyclist and with minutes of transportation cycling among those cycling. Data were collected during November-December 2014 across Flanders, Belgium. Children's perceived parental modeling, parental norm, peers' co-participation, self-efficacy and IM were positively related to the odds of being a cyclist, perceived benefits were negatively associated. Parental modeling, siblings' modeling, self-efficacy and parental norm were more strongly related to the odds of being a cyclist among children with a low IM. Friends' modeling was significantly related with odds of being a cyclist among boys. IM and parental norm (only among boys) were positively related to the time spent cycling. Targeting children, their friends and parents seems therefore most appropriate when aiming to increase children's transportation cycling. PMID- 26968780 TI - A scoping study to explore the application and impact of grading practice in pre registration midwifery programmes across the United Kingdom. AB - Grading of practice is a mandatory element of programmes leading to registration as a midwife in the United Kingdom, required by the Nursing and Midwifery Council. This validates the importance of practice by placing it on an equal level with academic work, contributing to degree classification. This paper discusses a scoping project undertaken by the Lead Midwives for Education group across the 55 Higher Education Institutions in the United Kingdom which deliver pre-registration midwifery programmes. A questionnaire was circulated and practice tools shared, enabling exploration of the application of the standards and collation of the views of the Lead Midwives. Timing and individuals involved in practice assessment varied as did the components and the credit weighting applied to practice modules. Sign-off mentor confidence in awarding a range of grades had increased over time, and mentors seemed positive about the value given to practice and their role as professional gatekeepers. Grading was generally felt to be more robust and meaningful than pass/refer. It also appeared that practice grading may contribute to an enhanced student academic profile. A set of guiding principles is being developed with the purpose of enhancing consistency of the application of the professional standards across the United Kingdom. PMID- 26968781 TI - MicroRNA-30c promotes natural killer cell cytotoxicity via up-regulating the expression level of NKG2D. AB - AIMS: Natural killer (NK) cells play critical roles in antitumor immunity. Our previous study showed that over-expression of miR-30c-1* enhanced NKL cell cytotoxicity through up-regulation of tumor necrosis factor-alpha via directly targeting transcription factor homeobox containing 1. MiR-30c, the complimentary microRNA of miR-30c-1*, has been found to exert regulatory effect on T cell function. However, the effect of miR-30c on NK cells is unknown. Therefore, this study aimed to investigate whether miR-30c could play a role to enhance NK cell activation and cytotoxicity. MAIN METHODS: Chemosynthesis exogenous miR-30c mimics and miR-30c inhibitor were transfected into NKL cells and isolated human peripheral blood NK cells, respectively. The expression levels of NK group 2, member D (NKG2D), CD107a and FasL on cell surface and cytotoxic ability of miRNAs transfected NKL cells against SMMC-7721 cells were evaluated. KEY FINDINGS: MiR 30c could increase the expression of NKG2D and CD107a on NKL cells, and enhance cytotoxic ability of NKL cells to kill SMMC-7721 cells. Moreover, miR-30c could up-regulate the expression of FasL on both NKL cells and human peripheral blood NK cells. However, the peripheral blood NK cells from only four in ten healthy donors appeared high expression levels of NKG2D and CD107a after miR-30c transfection. SIGNIFICANCE: MiR-30c could promote the cytotoxicity of NKL cells in vitro by up-regulating the expression levels of NKG2D, CD107a and FasL. However, the effect of miR-30c on ex vivo NK cells from different human individuals is diverse, indicating that miR-30c may play complicate and fine adjustment in immune system. PMID- 26968782 TI - dl-3-n-butylphthalide suppresses PDGF-BB-stimulated vascular smooth muscle cells proliferation via induction of autophagy. AB - AIMS: Vascular smooth muscle cells (VSMCs) played an important role in vascular remodeling. dl-3-n-butylphthalide (NBP) was extracted as a pure component from seeds of Apium graveolens Linn (Chinese celery) for protecting neurons activity, but the role of NBP on VSMCs was not clearly clarified. MAIN METHODS: Cell proliferation was measured by MTS and flow cytometry. Western blot analysis and transmission electron microscopy were performed to analyze the relative protein expression and autophagosome. Moreover, the autophagic inhibitor and beta-catenin inhibitor were used to evaluate the effects of NBP on autophagy and the function of beta-catenin on cell proliferation respectively. KEY FINDINGS: NBP significantly suppressed platelet derived growth factor-BB (PDGF-BB)-stimulated VSMC proliferation, and the inhibitory effects of NBP on proliferation were caused by inducing autophagy. In addition, the inhibitory effects of NBP on proliferation were associated with the beta-catenin signaling pathway. Moreover, beta-catenin overexpression reversed the induction effect of NBP on autophagy and the beta-catenin inhibitor JW74 enhanced these effects. SIGNIFICANCE: Our findings demonstrated that NBP protected VSMC from PDGF-BB-stimulated proliferation by inducing autophagy through suppression of the beta-catenin signaling pathway, confirming the induction of autophagy might be a therapeutic strategy for use in the proliferative cardiovascular diseases. PMID- 26968783 TI - Noradrenaline microinjected into the dorsal periaqueductal gray matter causes anxiolytic-like effects in rats tested in the elevated T-maze. AB - AIMS: The dorsal periaqueductal gray matter (dPAG) is involved in the integration of behavioral and cardiovascular responses caused by fear and anxiety situations. Some studies suggest an involvement of noradrenergic neurotransmission in the dPAG in anxiety modulation, however, there is no evidence about its role in panic attacks. The goal of this work was to study the effect of NA microinjection in dPAG in rats submitted to the elevated T-maze (ETM). MATERIALS AND METHODS: Male Wistar had a cannula implanted in the PAG where it was injected NA in the doses of 1, 3, 15, 45nmol/50nl or artificial cerebrospinal fluid previous the ETM test. KEY FINDINGS: NA intra-dPAG decreased inhibitory avoidance behavior in the ETM without changing escape, indicating only an anxiolytic-like effect. Furthermore, the microinjection of NA did not change the general exploratory activity of the animals submitted to the open field test, suggesting that the anxiolytic-like effect is not due to an increase in exploratory activity. SIGNIFICANCE: The results indicate an involvement of noradrenergic neurotransmission in the dPAG in defensive reactions associated with generalized anxiety, but not as main mechanisms for the panic, in rats submitted to the elevated T-maze providing support for other research aimed at improving the treatment of generalized anxiety. PMID- 26968784 TI - Finite element analysis of the lumbar destabilization following pedicle subtraction osteotomy. AB - This study aims to analyze the destabilization produced following a pedicle subtraction osteotomy (PSO), with a calibrated numerical model. A 30 degrees resection was created on L3 and L4. Range of Motion (ROM) and the force acting on the vertebral body were calculated. Osteotomies consistently increased the ROMs. In the intact model, 87% of the compressive load was acting on the vertebral bodies whereas in the destabilized models all the load was on the fractured surface. Osteotomies at both levels induced a marked instability but the PSO at L4 seemed to have a greater influence on the ROM. Despite the significant deformity corrections which could be achieved with PSO, this technique needs further analyses. PMID- 26968785 TI - Does Gene Tree Discordance Explain the Mismatch between Macroevolutionary Models and Empirical Patterns of Tree Shape and Branching Times? AB - Classic null models for speciation and extinction give rise to phylogenies that differ in distribution from empirical phylogenies. In particular, empirical phylogenies are less balanced and have branching times closer to the root compared to phylogenies predicted by common null models. This difference might be due to null models of the speciation and extinction process being too simplistic, or due to the empirical datasets not being representative of random phylogenies. A third possibility arises because phylogenetic reconstruction methods often infer gene trees rather than species trees, producing an incongruity between models that predict species tree patterns and empirical analyses that consider gene trees. We investigate the extent to which the difference between gene trees and species trees under a combined birth-death and multispecies coalescent model can explain the difference in empirical trees and birth-death species trees. We simulate gene trees embedded in simulated species trees and investigate their difference with respect to tree balance and branching times. We observe that the gene trees are less balanced and typically have branching times closer to the root than the species trees. Empirical trees from TreeBase are also less balanced than our simulated species trees, and model gene trees can explain an imbalance increase of up to 8% compared to species trees. However, we see a much larger imbalance increase in empirical trees, about 100%, meaning that additional features must also be causing imbalance in empirical trees. This simulation study highlights the necessity of revisiting the assumptions made in phylogenetic analyses, as these assumptions, such as equating the gene tree with the species tree, might lead to a biased conclusion. PMID- 26968786 TI - Epidemiological typing of Neisseria gonorrhoeae and detection of markers associated with antimicrobial resistance directly from urine samples using next generation sequencing. AB - OBJECTIVES: To investigate the potential for next generation sequencing (NGS) to be used directly on clinical specimens that have tested positive for Neisseria gonorrhoeae by nucleic acid amplification testing (NAAT), to generate information on epidemiological genotyping and antimicrobial resistance (AMR) markers. METHODS: DNA was extracted from 13 N. gonorrhoeae NAAT-positive urine specimens, enriched for microbial DNA and sequenced using the Ion Torrent PGM workflow. Sequences that aligned to the human genome were filtered out and the remaining sequences were de novo assembled. The resulting contigs were searched for regions of interest using Ridom SeqSphere. MLST and NG-MAST alleles were assigned according to the schemes at PubMLST.org and NG-MAST.net, respectively. RESULTS: In total, 11 of the 13 samples tested generated a sufficient number of N. gonorrhoeae sequence reads to provide full coverage of the genome at a depth of 6 130*. Complete MLST and NG-MAST sequence types could be generated for each of these samples. The presence of 10 different AMR markers was investigated, and both previously reported and novel mutations were identified in genes associated with reduced susceptibility to several antimicrobials. CONCLUSIONS: We found that sequencing the entire genome of N. gonorrhoeae directly from clinical samples is possible using NGS, and that multiple levels of N. gonorrhoeae typing information can be generated. As NAAT only testing becomes more common, this method could be used to detect both known and novel mutations associated with AMR and to generate genotyping information, supporting AMR and epidemiological surveillance in the absence of culturing. PMID- 26968787 TI - New and emerging technologies for the diagnosis and monitoring of chronic obstructive pulmonary disease: A horizon scanning review. AB - There is a need for straightforward, novel diagnostic and monitoring technologies to enable the early diagnosis of COPD and its differentiation from other respiratory diseases, to establish the cause of acute exacerbations and to monitor disease progression. We sought to establish whether technologies already in development could potentially address these needs. A systematic horizon scanning review was undertaken to identify technologies in development from a wide range of commercial and non-commercial sources. Technologies were restricted to those likely to be available within 18 months, and then evaluated for degree of innovation, potential for impact, acceptability to users and likelihood of adoption by clinicians and patients with COPD. Eighty technologies were identified, of which 25 were considered particularly promising. Biomarker tests, particularly those using sputum or saliva samples and/or available at the point of care, were positively evaluated, with many offering novel approaches to early diagnosis and to determining the cause for acute exacerbations. Several wrist worn devices and smartphone-based spirometers offering the facility for self monitoring and early detection of exacerbations were also considered promising. The most promising identified technologies have the potential to improve COPD care and patient outcomes. Further research and evaluation activities should be focused on these technologies. PMID- 26968788 TI - An unusual presentation of recurring metastatic melanoma. AB - A 53-year-old non-distressed Caucasian female complains of dyspnea and palpitations for 5 days. Past medical history includes Stage IV melanoma with adequate resection 23 years prior. The patient suddenly became increasingly tachycardic in mild respiratory distress while maintaining hemodynamic stability. TTE depicted 10.5 * 7.5 * 9.5 cm(3) mass within her left ventricle and a large volume of pericardial effusion, which progressed to cardiac tamponade. Pericardial window was performed. Metastatic involvement should be ruled out for all symptomatic patients with a history of melanoma. PMID- 26968789 TI - Survival after Hematopoietic Stem Cell Transplant in Patients with Dyskeratosis Congenita: Systematic Review of the Literature. AB - Dyskeratosis congenita (DC) is a multisystem disorder, with a disruption in telomere biology leading to very short telomeres underpinning its pathophysiology. Bone marrow failure is a key feature in DC and is the leading cause of mortality. Hematopoietic stem cell transplantation (HSCT) is the only curative option for bone marrow failure in DC; however, small case reports and series have suggested a poor outcome after HSCT. We undertook a systematic review of all reported patients with DC who underwent HSCT to better characterize outcome and to identify factors associated with improved survival. The outcome of 109 patients found in the literature was poor, with 5- and 10-year survival estimates of only 57% and 23%, respectively. Patients transplanted after 2000 had improved early survival, with 5-year survival estimates of 70%; however, longer term survival was similar (28%). Pulmonary disease, infection, and graft failure were the leading causes of death. Prognosis after development of pulmonary disease post-HSCT was poor, with only 4 of 15 patients surviving at last follow up. Multivariate analysis identified age >20 years at HSCT, HSCT before 2000, and alternate donor source to be poor prognostic markers. Reduced-intensity conditioning was not significantly found to be associated with improved survival. This review shows the poor outcome after HSCT in patients with DC and highlights the need for future collaborative clinical trials and extended follow-up of this rare patient population to define whether changes in therapy will lead to improved survival. PMID- 26968790 TI - Association of Cumulative Steroid Dose with Risk of Infection after Treatment for Severe Acute Graft-versus-Host Disease. AB - This study aimed to characterize the incidence and risk factors of invasive fungal disease, cytomegalovirus infection, other viral diseases, and gram negative rod infection after glucocorticoid treatment for severe acute graft versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation and to elucidate the associations of cumulative steroid dose with the risks of individual infections. The study cohort included 91 consecutive patients who developed maximum grades III and IV acute GVHD at our center. The mean cumulative prednisolone-equivalent dose was 41 mg/kg during the first 4 weeks. The cumulative incidence rates of fungal disease, cytomegalovirus disease, other viral diseases, and gram-negative rod infection at 6 months after glucocorticoid treatment were remarkably high, at 14%, 21%, 28%, and 20%, respectively. GVHD within 26 days after transplantation and low lymphocyte count at GVHD treatment were associated with increased risks of several infections. Cumulative prednisolone-equivalent steroid doses >= 55 mg/kg during the first 4 weeks were associated with an increased risk of fungal disease (hazard ratio, 3.65; P = .03) and cumulative doses >= 23 mg/kg were associated with an increased risk of non cytomegalovirus viral diseases (hazard ratio, 4.14; P = .02). Strategies to reduce the risk of infectious complications are needed, particularly for patients who have risk factors and those who receive high cumulative steroid doses. PMID- 26968792 TI - Safety, Pharmacokinetics, and Efficacy of Palifermin in Children and Adolescents with Acute Leukemias Undergoing Myeloablative Therapy and Allogeneic Hematopoietic Stem Cell Transplantation: A Pediatric Blood and Marrow Transplant Consortium Trial. AB - Currently, effective pharmacologic treatment to reduce severe oral mucositis (OM) resulting from high-dose myeloablative cytotoxic therapy in the pediatric population is not available. Palifermin has been proven to decrease the incidence and duration of severe OM in adults with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT). In the pediatric population, however, data on palifermin treatment are limited. A phase I dose-escalation study of palifermin in pediatric patients with acute leukemias undergoing myeloablative HSCT with total body irradiation, etoposide, and cyclophosphamide was performed to determine a safe and tolerable dose and to characterize the pharmacokinetic (PK) profile and efficacy of palifermin. Twenty-seven patients in 3 age groups (1 to 2, 3 to 11, and 12 to 16 years) and 3 dose levels (40, 60, and 80 MUg/kg/day) were studied. There were no deaths, dose-limiting toxicities, or treatment-related serious adverse events. Long-term safety outcomes did not differ from what would be expected in this population. PK data showed no differences between the 3 age groups. Exposure did not increase with increase in dose. The maximum severity of OM (WHO grade 4) occurred in 6 patients (22%), none of whom was in the 80-MUg/kg/day dosing group. This study showed that all doses were well tolerated and a good safety profile in all 3 pediatric age groups was seen. PMID- 26968791 TI - Clinical and Genetic Determinants of Cardiomyopathy Risk among Hematopoietic Cell Transplantation Survivors. AB - Cardiomyopathy has been recognized as a complication after hematopoietic cell transplantation (HCT). Using a nested case-cohort design, we examined the relationships between demographic, therapeutic, and selected cardiovascular disease risk factors among >=1-year HCT survivors who developed cardiomyopathy before (n = 43) or after (n = 89) 1 year from HCT as compared to a randomly selected subcohort of survivors without cardiomyopathy (n = 444). Genomic data were available for 79 cases and 267 noncases. Clinical and genetic covariates were examined for association with the risk of early or late cardiomyopathy. Clinical risk factors associated with both early- and late-onset cardiomyopathy included anthracycline exposure >=250 mg/m(2) and pre-existing hypertension. Among late-onset cardiomyopathy cases, the development of diabetes and ischemic heart disease further increased risk. We replicated several previously reported genetic associations among early-onset cardiomyopathy cases, including rs1786814 in CELF4, rs2232228 in HAS3, and rs17863783 in UGT1A6. None of these markers were associated with risk of late-onset cardiomyopathy. A combination of demographic, treatment, and clinical covariates predicted early-onset cardiomyopathy with reasonable accuracy (area under the curve [AUC], .76; 95% confidence interval [CI], .68 to .83), but prediction of late cardiomyopathy was poor (AUC, .59; 95% CI .53 to .67). The addition of genetic polymorphisms with marginal associations (odds ratios >=1.3) did not enhance prediction for either early- or late-onset cardiomyopathy. Conventional cardiovascular risk factors influence the risk of both early- and late-onset cardiomyopathy in HCT survivors. Although certain genetic markers may influence the risk of early-onset disease, further work is required to validate previously reported findings and to determine how genetic information should be incorporated into clinically useful risk prediction models. PMID- 26968793 TI - Redox proteomic profiling of neuroketal-adducted proteins in human brain: Regional vulnerability at middle age increases in the elderly. AB - Protein lipoxidation was assessed in the parietal cortex (PC), frontal cortex (FC), and cingulate gyrus (CG) in middle-aged and old-aged individuals with no clinical manifestations of cognitive impairment, in order to increase understanding of regional brain vulnerability to oxidative damage during aging. Twenty-five lipoxidized proteins were identified in all the three regions although with regional specificities, by using redox proteomics to detect target proteins of neuroketals (NKT) adduction. The number of cases with NKT-adducted proteins was higher in old-aged individuals but most oxidized proteins were already present in middle-aged individuals. Differences in vulnerability to oxidation were dependent on the sub-cellular localization, secondary structure, and external exposition of certain amino acids. Lipoxidized proteins included those involved in energy metabolism, cytoskeleton, proteostasis, neurotransmission and O2/CO2, and heme metabolism. Total NKT and soluble oligomer levels were estimated employing slot-blot, and these were compared between age groups. Oligomers increased with age in PC and FC; NKT significantly increased with age in FC, whereas total NKT and oligomer levels were not modified in CG, thus highlighting differences in brain regional vulnerability with age. Oligomers significantly correlated with NKT levels in the three cortical regions, suggesting that protein NKT adduction parallels soluble oligomer formation. PMID- 26968794 TI - Glucagon-like peptide-1 improves beta-cell antioxidant capacity via extracellular regulated kinases pathway and Nrf2 translocation. AB - Oxidative stress plays an important role in the development of beta-cell dysfunction and insulin resistance, two major pathophysiological abnormalities of type 2 diabetes. Expression levels of antioxidant enzymes in beta cells are very low, rendering them more susceptible to damage caused by reactive oxygen species (ROS). Although the antioxidant effects of glucagon-like peptide-1 (GLP-1) and its analogs have been previously reported, the exact mechanisms involved are still unclear. In this study, we demonstrated that GLP-1 was able to effectively inhibit oxidative stress and cell death of INS-1E beta cells induced by the pro oxidant tert-butyl hydroperoxide (tert-BOOH). Incubation with GLP-1 enhanced cellular levels of glutathione and the activity of its related enzymes, glutathione-peroxidase (GPx) and -reductase (GR) in beta cells. However, inhibition of ERK, but not of the PI3K/AKT pathway abolished, at least in part, the antioxidant effect of GLP-1. Moreover, ERK activation seems to be protein kinase A (PKA)-dependent because inhibition of PKA with H-89 was sufficient to block the GLP-1-derived protective effect on beta cells. GLP-1 likewise increased the synthesis of GR and favored the translocation of the nuclear transcription factor erythroid 2p45-related factor (Nrf2), a transcription factor implicated in the expression of several antioxidant/detoxificant enzymes. Glucose-stimulated insulin secretion was also preserved in beta-cells challenged with tert-BOOH but pre-treated with GLP-1, probably through the down-regulation of the mitochondrial uncoupling-protein2 (UCP2). Thus, our results provide additional mechanisms of action of GLP-1 to prevent oxidative damage in beta cells through the modulation of signaling pathways involved in antioxidant enzyme regulation. PMID- 26968795 TI - Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial cell dysfunction. AB - The use of HIV protease inhibitors (PIs) has extended the duration and quality of life for HIV-positive individuals. However there is increasing concern that this antiviral therapy may promote premature cardiovascular disease by impairing endothelial cell (EC) function. In the present study, we investigated the effect of HIV PIs on EC function and determined if the enzyme heme oxygenase (HO-1) influences the biological action of these drugs. We found that three distinct PIs, including ritonavir, atazanavir, and lopinavir, stimulated the expression of HO-1 protein and mRNA. The induction of HO-1 was associated with an increase in NF-E2-related factor-2 (Nrf2) activity and reactive oxygen species (ROS). PIs also stimulated HO-1 promoter activity and this was prevented by mutating the antioxidant responsive element or by overexpressing dominant-negative Nrf2. In addition, the PI-mediated induction of HO-1 was abolished by N-acetyl-l-cysteine and rotenone. Furthermore, PIs blocked EC proliferation and migration and stimulated the expression of intercellular adhesion molecule-1 and the adhesion of monocytes on ECs. Inhibition of HO-1 activity or expression potentiated the anti-proliferative and inflammatory actions of PIs which was reversed by bilirubin but not carbon monoxide. Alternatively, adenovirus-mediated overexpression of HO-1 attenuated the growth-inhibitory and inflammatory effect of PIs. In contrast, blocking HO-1 activity failed to modify the anti-migratory effect of the PIs. Thus, induction of HO-1 via the ROS-Nrf2 pathway in human ECs counteracts the anti-proliferative and inflammatory actions of PIs by generating bilirubin. Therapeutic approaches targeting HO-1 may provide a novel approach in preventing EC dysfunction and vascular disease in HIV-infected patients undergoing antiretroviral therapy. PMID- 26968797 TI - Characterisation of a household norovirus outbreak occurred in Valencia (Spain). AB - BACKGROUND: Human noroviruses (NoVs) are the main cause of non-bacterial gastroenteritis worldwide. Several studies have linked human susceptibility to NoVs with the expression of histo-blood group antigens (HBGAs). In January 2012, a NoV gastroenteritis outbreak affected a household in Valencia, Spain, and the personal susceptibility to NoV was investigated. METHODS: To reach this aim 8 members of the affected household were recruited for this study and their secretor status, ABO and Lewis antigens were determined. NoV-specific saliva IgA and serum IgG antibody titers were analyzed. Their capacity to block viral binding to saliva receptors was analyzed, using virus-like particles (VLPs) of the NoV GII.4 genotype, 2006b variant, and saliva from a secretor O blood type donor. RESULTS: The most relevant finding was that an asymptomatic non-secretor individual shed NoVs in his stools. Interestingly, anti-NoV IgA antibody titers in saliva from secretor and non-secretor individuals showed no differences. On the contrary, high titers of NoV-specific IgG antibody were found in both convalescent sera and in sera collected 1 year post-infection, but only from secretor individuals. NoV GII.4-2006b VLP binding to receptors present in the saliva was efficiently blocked only by sera from secretor positive individuals. CONCLUSIONS: Despite the small number of individuals involved in this outbreak, this study reinforces the idea that susceptibility to human NoV is both dependent on the HBGA profile of the individuals as well as on the viral genotype and variant. We also show that the immunity to NoV lasts for at least 1 year after infection, demonstrating that symptomatic infections strongly stimulate immune responses. PMID- 26968798 TI - Challenges in horizontal model integration. AB - BACKGROUND: Systems Biology has motivated dynamic models of important intracellular processes at the pathway level, for example, in signal transduction and cell cycle control. To answer important biomedical questions, however, one has to go beyond the study of isolated pathways towards the joint study of interacting signaling pathways or the joint study of signal transduction and cell cycle control. Thereby the reuse of established models is preferable, as it will generally reduce the modeling effort and increase the acceptance of the combined model in the field. RESULTS: Obtaining a combined model can be challenging, especially if the submodels are large and/or come from different working groups (as is generally the case, when models stored in established repositories are used). To support this task, we describe a semi-automatic workflow based on established software tools. In particular, two frequent challenges are described: identification of the overlap and subsequent (re)parameterization of the integrated model. CONCLUSIONS: The reparameterization step is crucial, if the goal is to obtain a model that can reproduce the data explained by the individual models. For demonstration purposes we apply our workflow to integrate two signaling pathways (EGF and NGF) from the BioModels Database. PMID- 26968796 TI - Shoulder proprioception - lessons we learned from idiopathic frozen shoulder. AB - BACKGROUND: Of all the most frequent soft tissue disorders of the shoulder, idiopathic frozen shoulder (IFS) offers the greatest potential for studying proprioception. Studies concerning the presence of proprioception dysfunctions have failed to determine the potential for spontaneous healing of passive shoulder stabilizers (anterior and posterior capsule, middle and inferior gleno humeral ligaments), its relationship with passive (PJPS) and active (AJPS) shoulder proprioception for internal and external rotation (IR, ER), as well as the isokinetic muscle performance of the internal and external rotators. This study investigates these dependencies in the case of arthroscopic release of IFS. METHODS: The study group comprised 23 patients (average aged 54.2) who underwent arthroscopic release due to IFS and 20 healthy volunteers. The average follow-up time was 29.2 months. The Biodex system was used for proprioception measurement in a modified neutral arm position and isokinetic evaluation. The results were analysed using the T-test, Wilcoxon and interclass correlation coefficient. P values lower than 0.05 were considered significant. RESULTS: Statistically significant differences were found between involved (I) and uninvolved (U) shoulders only in the cases of PJPS and AJPS, peak torque, time to peak torque and acceleration time for ER (p < 0.05). No statistically significant difference was noted between PJPS IR and PJPS ER or between AJPS IR and AJPS ER (p > 0.05) for the U shoulders. CONCLUSIONS: The anatomical structure of anterior (capsule, middle and anterior band of inferior gleno-humeral ligament) and posterior (capsule and posterior band of inferior gleno-humeral ligament) passive shoulder restraints has no impact on the difference in PJPS values between ER and IR in a modified neutral shoulder position. The potential for spontaneous healing of the anterior and posterior passive shoulder restraints influences PJPS recovery after arthroscopic release of IFS. ER peak torque deficits negatively affect AJPS values. PJPS and AJPS of ER and IR can be measured with a high level of reproducibility using an isokinetic dynamometer with the arm in a modified neutral shoulder position. Differences greater than 15 % for PJPS and >24 % for AJPS for ER and IR can be helpful for future studies as baseline data for identification of particular passive and active shoulder stabilizers at risk. PMID- 26968799 TI - Hyaluronic acid-coated liposomes for targeted delivery of paclitaxel, in-vitro characterization and in-vivo evaluation. AB - Breast cancer is the leading cause of cancer death in women. Chemotherapy is regarded as the most essential strategy in inhibiting the proliferation of tumor cells. Paclitaxel is a widely used taxane; however, the side effects of available Cremophor-based formulations and also the limitations of passive targeting uncovered an essential need to develop tumor-specific targeted nanocarriers. A hyaluronic acid targeted liposomal formulation of paclitaxel was prepared in which, hyaluronic acid was electrostatistically attracted to the surface of liposomes. Liposomes, had a particle size of 106.4+/-3.2nm, a weakly negative zeta potential of -9.7+/-0.8mV and an acceptable encapsulation efficiency of 92.1+/-1.7%. The release profile of liposomes in buffer showed that 95% of PTX was released during 40h. Confocal laser scanning microscopy and flow cytometry analysis showed the greater cellular internalization of coumarin-loaded liposomes compared to free coumarin. MTT assay on 4T1 and T47D cells demonstrated the stronger cytotoxic activity of liposomes in comparison to free paclitaxel. Cell cycle analysis showed that cells were mainly blocked at G2/M phases after 48h treatment with liposomes. In vivo real time imaging on 4T1 tumor-bearing mice revealed that the liposomal formulation mainly accumulated in the tumor area. Liposomes also had better antitumor efficacy against Cremophor-based formulation. In conclusion, hyaluronic acid targeted paclitaxel liposome can serve as a promising targeted formulation of paclitaxel for future cancer chemotherapy. PMID- 26968801 TI - Regarding "Significantly Decreased Recurrence Rates in Keratocystic Odontogenic Tumor With Simple Enucleation and Curettage Using Carnoy's Versus Modified Carnoy's Solution". PMID- 26968803 TI - Re: "Significantly Decreased Recurrence Rates in Keratocystic Odontogenic Tumor With Simple Enucleation and Curettage Using Carnoy's Versus Modified Carnoy's Solution". PMID- 26968802 TI - Anesthesia Complications of Diazepam Use for Adolescents Receiving Extraction of Third Molars. AB - PURPOSE: To evaluate the safety of midazolam and diazepam for adolescents during third molar extraction and whether any differences in perioperative complications exist when using the 2 benzodiazepines alone or in combination. MATERIALS AND METHODS: A prospective study was performed in adolescents (<21 yr old) who underwent at least 1 third molar extraction by an oral and maxillofacial surgeon in the ambulatory setting from January 2001 through December 2010 using the Oral and Maxillofacial Surgery Outcomes System. The primary predictor variable was type of benzodiazepine used, divided into the total number of patients who received diazepam with or without midazolam. The outcome of interest was adverse complications resulting from anesthesia. Multivariable logistic regression was applied to measure the association between benzodiazepine type and adverse complications. RESULTS: Patients in the diazepam group (n = 4,213) and in the combination group (n = 426) had a complication rate of 1.4%, whereas those in the midazolam group (n = 13,451) had a complication rate of 1.0% (P = .027). Multiple logistic regression analysis showed a 50% increased odds of adverse complications in patients receiving diazepam (adjusted odds ratio = 1.50; 95% confidence interval, 1.05 to 2.16; P = .027). CONCLUSIONS: Adolescent patients who received intravenous diazepam during third molar procedures had an increased odds of anesthesia-related complications compared with those given midazolam. PMID- 26968800 TI - The interleukin-20 receptor axis in early rheumatoid arthritis: novel links between disease-associated autoantibodies and radiographic progression. AB - BACKGROUND: Rheumatoid arthritis (RA) is often characterized by the presence of rheumatoid factor, anti-citrullinated protein antibodies, and bone erosions. Current therapies can compromise immunity, leading to risk of infection. The interleukin-20 receptor (IL-20R) axis comprising IL-19, IL-20, and IL-24 and their shared receptors activates tissue homeostasis processes but not the immune system. Consequently, modulation of the IL-20R axis may not lead to immunosuppression, making it an interesting drug target. We evaluated the role of the IL-20R axis in RA and associations between plasma cytokine levels and clinical disease. METHODS: Plasma IL-19, IL-20, and IL-24 levels were measured in early RA patients during a treat-to-target strategy by enzyme-linked immunosorbent assays. The IL-20R1 and IL-22R1 levels in paired peripheral blood mononuclear cells and synovial fluid mononuclear cells from a different cohort of RA patients were evaluated by flow cytometry and confocal microscopy. Monocytes/macrophages were stimulated with heat-aggregated human immunoglobulin immune complexes and immune complexes containing citrullinated fibrinogen, and osteoclasts were incubated with IL-19, IL-20, and IL-24. RESULTS: The plasma concentrations of IL-20 and IL-24 (but not IL-19) were increased in early RA patients compared with healthy controls (both P < 0.002) and decreased after 6 months of treatment (both P < 0.0001). The expression of IL-22R1 (but not IL 20R1) was increased on monocytes from RA synovial fluid compared with monocytes from both RA and healthy control peripheral blood. The plasma concentrations of IL-20 and IL-24 were increased in rheumatoid factor and anti-citrullinated protein antibody positive compared with negative early RA patients (all P < 0.0001). Immune complexes stimulated the production of the IL-20R cytokines by monocytes/macrophages. Increased baseline plasma concentrations of IL-20 and IL 24 were associated with Sharp-van der Heijde score progression after 24 months (Spearman's rho = 0.19 and 0.26, both P < 0.05) in the early RA patients. The IL 22R1 was expressed by osteoclast precursors and in multinucleated osteoclasts. IL 20 and IL-24 increased the secretion of monocyte chemoattractant protein 1 by these cells. CONCLUSIONS: This study suggests that IL-20 and IL-24 link RA associated autoantibodies with radiographic progression via the IL-22R1. Modulation of this axis holds promise as feasible anti-erosive treatment modalities in seropositive RA. PMID- 26968804 TI - In Reply. PMID- 26968805 TI - Programming Deep Brain Stimulation for Tremor and Dystonia: The Toronto Western Hospital Algorithms. AB - BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for essential tremor (ET) and dystonia. After surgery, a number of extensive programming sessions are performed, mainly relying on neurologist's personal experience as no programming guidelines have been provided so far, with the exception of recommendations provided by groups of experts. Finally, fewer information is available for the management of DBS in ET and dystonia compared with Parkinson's disease. OBJECTIVE/HYPOTHESIS: Our aim is to review the literature on initial and follow-up DBS programming procedures for ET and dystonia and integrate the results with our current practice at Toronto Western Hospital (TWH) to develop standardized DBS programming protocols. METHODS: We conducted a literature search of PubMed from inception to July 2014 with the keywords "balance", "bradykinesia", "deep brain stimulation", "dysarthria", "dystonia", "gait disturbances", "initial programming", "loss of benefit", "micrographia", "speech", "speech difficulties" and "tremor". Seventy-six papers were considered for this review. RESULTS: Based on the literature review and our experience at TWH, we refined three algorithms for management of ET, including: (1) initial programming, (2) management of balance and speech issues and (3) loss of stimulation benefit. We also depicted algorithms for the management of dystonia, including: (1) initial programming and (2) management of stimulation-induced hypokinesia (shuffling gait, micrographia and speech impairment). CONCLUSIONS: We propose five algorithms tailored to an individualized approach to managing ET and dystonia patients with DBS. We encourage the application of these algorithms to supplement current standards of care in established as well as new DBS centers to test the clinical usefulness of these algorithms in supplementing the current standards of care. PMID- 26968806 TI - Programming Deep Brain Stimulation for Parkinson's Disease: The Toronto Western Hospital Algorithms. AB - BACKGROUND: Deep brain stimulation (DBS) is an established and effective treatment for Parkinson's disease (PD). After surgery, a number of extensive programming sessions are performed to define the most optimal stimulation parameters. Programming sessions mainly rely only on neurologist's experience. As a result, patients often undergo inconsistent and inefficient stimulation changes, as well as unnecessary visits. OBJECTIVE/HYPOTHESIS: We reviewed the literature on initial and follow-up DBS programming procedures and integrated our current practice at Toronto Western Hospital (TWH) to develop standardized DBS programming protocols. We propose four algorithms including the initial programming and specific algorithms tailored to symptoms experienced by patients following DBS: speech disturbances, stimulation-induced dyskinesia and gait impairment. METHODS: We conducted a literature search of PubMed from inception to July 2014 with the keywords "deep brain stimulation", "festination", "freezing", "initial programming", "Parkinson's disease", "postural instability", "speech disturbances", and "stimulation induced dyskinesia". Seventy papers were considered for this review. RESULTS: Based on the literature review and our experience at TWH, we refined four algorithms for: (1) the initial programming stage, and management of symptoms following DBS, particularly addressing (2) speech disturbances, (3) stimulation-induced dyskinesia, and (4) gait impairment. CONCLUSIONS: We propose four algorithms tailored to an individualized approach to managing symptoms associated with DBS and disease progression in patients with PD. We encourage established as well as new DBS centers to test the clinical usefulness of these algorithms in supplementing the current standards of care. PMID- 26968807 TI - Reduced Affective Biasing of Instrumental Action With tDCS Over the Prefrontal Cortex. AB - BACKGROUND: Instrumental action is well known to be vulnerable to affective value. Excessive transfer of affective value to instrumental action is thought to contribute to psychiatric disorders. The brain region most commonly implicated in overriding such affective biasing of instrumental action is the prefrontal cortex. OBJECTIVE: The aim of the present study was to reduce affective biasing of instrumental action using transcranial direct current stimulation (tDCS) in young healthy human volunteers. METHODS: In a double-blind, randomized between group design, 120 participants received anodal, cathodal and sham tDCS while at the same time (online) performing a task that assessed affective biasing of instrumental action. We placed tDCS electrodes over the anterior part of the prefrontal cortex based on evidence from brain stimulation work demonstrating the role of this brain region in controlling affective biasing of instrumental action. RESULTS: We showed that prefrontal tDCS reduced affective biasing of instrumental action. Specifically, prefrontal tDCS reduced the degree to which aversive (versus appetitive) cues potentiated instrumental avoidance and suppressed instrumental approach. Contrary to our hypothesis, this effect was seen for cathodal tDCS rather than anodal tDCS. CONCLUSION: The results demonstrate the potential utility of prefrontal tDCS as a tool for reducing affective biasing of instrumental behavior, thus opening avenues for interventional research on psychiatric disorders that implicate excessive transfer of affective value. PMID- 26968809 TI - A Randomized Trial of the Effects of Schema-Based Instruction on Proportional Problem-Solving for Students With Mathematics Problem-Solving Difficulties. AB - This article reports results from a study investigating the efficacy of a proportional problem-solving intervention, schema-based instruction (SBI), in seventh grade. Participants included 806 students with mathematical difficulties in problem solving (MD-PS) from an initial pool of 1,999 seventh grade students in a larger study. Teachers and their students in the larger study were randomly assigned to an SBI or control condition and teachers in both conditions then provided instruction on the topics of ratio, proportion, and percent. We found that students with MD-PS in SBI classrooms scored on average higher than their counterparts in control classrooms on a posttest and delayed posttest administered 9 weeks later. Given students' difficulties with proportional problem-solving and the consequences of these difficulties, an important contribution of this research is the finding that when provided with appropriate instruction, students with MD-PS are capable of enhanced proportional problem solving performance. PMID- 26968808 TI - Long genes and genes with multiple splice variants are enriched in pathways linked to cancer and other multigenic diseases. AB - BACKGROUND: The role of random mutations and genetic errors in defining the etiology of cancer and other multigenic diseases has recently received much attention. With the view that complex genes should be particularly vulnerable to such events, here we explore the link between the simple properties of the human genes, such as transcript length, number of splice variants, exon/intron composition, and their involvement in the pathways linked to cancer and other multigenic diseases. RESULTS: We reveal a substantial enrichment of cancer pathways with long genes and genes that have multiple splice variants. Although the latter two factors are interdependent, we show that the overall gene length and splicing complexity increase in cancer pathways in a partially decoupled manner. Our systematic survey for the pathways enriched with top lengthy genes and with genes that have multiple splice variants reveal, along with cancer pathways, the pathways involved in various neuronal processes, cardiomyopathies and type II diabetes. We outline a correlation between the gene length and the number of somatic mutations. CONCLUSIONS: Our work is a step forward in the assessment of the role of simple gene characteristics in cancer and a wider range of multigenic diseases. We demonstrate a significant accumulation of long genes and genes with multiple splice variants in pathways of multigenic diseases that have already been associated with de novo mutations. Unlike the cancer pathways, we note that the pathways of neuronal processes, cardiomyopathies and type II diabetes contain genes long enough for topoisomerase-dependent gene expression to also be a potential contributing factor in the emergence of pathologies, should topoisomerases become impaired. PMID- 26968810 TI - MicroRNA-543 suppresses colorectal cancer growth and metastasis by targeting KRAS, MTA1 and HMGA2. AB - miR-543 has been implicated as having a critical role in the development of breast cancer, endometrial cancer and hepatocellular carcinoma. However, the exact clinical significance and biological functions of miR-543 in colorectal cancer (CRC) remain unclear. Here, we found that miR-543 expression significantly downregulated in tumors from patients with CRC, APCMin mice and a mouse model of colitis-associated colon cancer. miR-543 level was inversely correlated with the metastatic status of patients with CRC and the metastatic potential of CRC cell lines. Moreover, ectopic expression of miR-543 inhibited the proliferation and metastasis of CRC cells in vitro and in vivo by targeting KRAS, MTA1 and HMGA2. Conversely, miR-543 knockdown promoted the proliferation, migration and invasion of CRC cells in vitro and augmented tumor growth and metastasis in vivo. Furthermore, we found that miR-543 expression was negatively correlated with the levels of KRAS, MTA1 and HMGA2 in clinical samples. Collectively, these data show that miR-543 inhibits the proliferation and metastasis of CRC cells by targeting KRAS, MTA1 and HMGA2. Our study highlights a pivotal role for miR-543 as a suppressor in the regulation of CRC growth and metastasis and suggests that miR 543 may serve as a novel diagnostic and prognostic biomarker for CRC metastasis. PMID- 26968811 TI - Increased amyloid beta-peptide uptake in skeletal muscle is induced by hyposialylation and may account for apoptosis in GNE myopathy. AB - GNE myopathy is an autosomal recessive muscular disorder of young adults characterized by progressive skeletal muscle weakness and wasting. It is caused by a mutation in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, which encodes a key enzyme in sialic acid biosynthesis. The mutated hypofunctional GNE is associated with intracellular accumulation of amyloid beta-peptide (Abeta) in patient muscles through as yet unknown mechanisms. We found here for the first time that an experimental reduction in sialic acid favors Abeta1-42 endocytosis in C2C12 myotubes, which is dependent on clathrin and heparan sulfate proteoglycan. Accordingly, Abeta1-42 internalization in myoblasts from a GNE myopathy patient was enhanced. Next, we investigated signal changes triggered by Abeta1-42 that may underlie toxicity. We observed that p-Akt levels are reduced in step with an increase in apoptotic markers in GNE myopathy myoblasts compared to control myoblasts. The same results were experimentally obtained when Abeta1-42 was overexpressed in myotubes. Hence, we propose a novel disease mechanism whereby hyposialylation favors Abeta1-42 internalization and the subsequent apoptosis in myotubes and in skeletal muscle from GNE myopathy patients. PMID- 26968812 TI - Is internal target volume accurate for dose evaluation in lung cancer stereotactic body radiotherapy? AB - PURPOSE: 4DCT delineated internal target volume (ITV) was applied to determine the tumor motion and used as planning target in treatment planning in lung cancer stereotactic body radiotherapy (SBRT). This work is to study the accuracy of using ITV to predict the real target dose in lung cancer SBRT. MATERIALS AND METHODS: Both for phantom and patient cases, the ITV and gross tumor volumes (GTVs) were contoured on the maximum intensity projection (MIP) CT and ten CT phases, respectively. A SBRT plan was designed using ITV as the planning target on average projection (AVG) CT. This plan was copied to each CT phase and the dose distribution was recalculated. The GTV_4D dose was acquired through accumulating the GTV doses over all ten phases and regarded as the real target dose. To analyze the ITV dose error, the ITV dose was compared to the real target dose by endpoints of D99, D95, D1 (doses received by the 99%, 95% and 1% of the target volume), and dose coverage endpoint of V100(relative volume receiving at least the prescription dose). RESULTS: The phantom study shows that the ITV underestimates the real target dose by 9.47%~19.8% in D99, 4.43%~15.99% in D95, and underestimates the dose coverage by 5% in V100. The patient cases show that the ITV underestimates the real target dose and dose coverage by 3.8%~10.7% in D99, 4.7%~7.2% in D95, and 3.96%~6.59% in V100 in motion target cases. CONCLUSIONS: Cautions should be taken that ITV is not accurate enough to predict the real target dose in lung cancer SBRT with large tumor motions. Restricting the target motion or reducing the target dose heterogeneity could reduce the ITV dose underestimation effect in lung SBRT. PMID- 26968813 TI - In vitro and in vivo effects of a recombinant anti-PSMA immunotoxin in combination with docetaxel against prostate cancer. AB - Docetaxel (DOC) is used for the first-line treatment of castration resistant prostate cancer (CPRC). However, the therapeutic effects are limited, only about one half of patients respond to the therapy and severe side effects possibly lead to discontinuation of treatment. Therefore, actual research is focused on the development of new DOC-based combination treatments. In this study we investigated the antitumor effects of a recombinant immunotoxin targeting the prostate specific membrane antigen (PSMA) in combination with DOC in vitro and in vivo. The immunotoxin consists of an anti-PSMA single chain antibody fragment (scFv) as binding and a truncated form of Pseudomonas aeruginosa Exotoxin A (PE40) as toxin domain. The immunotoxin induced apoptosis and specifically reduced the viability of androgen-dependent LNCaP and androgen-independent C4-2 prostate cancer cells. A synergistic cytotoxic activity was observed in combination with DOC with IC50 values in the low picomolar or even femtomolar range. Moreover, combination treatment resulted in an enhanced antitumor activity in a C4-2 SCID mouse xenograft model. This highlights the immunotoxin as a promising therapeutic agent for a future DOC-based combination therapy of CPRC. PMID- 26968814 TI - Determination of somatic oncogenic mutations linked to target-based therapies using MassARRAY technology. AB - Somatic mutation analysis represents a useful tool in selecting personalized therapy. The aim of our study was to determine the presence of common genetic events affecting actionable oncogenes using a MassARRAY technology in patients with advanced solid tumors who were potential candidates for target-based therapies. The analysis of 238 mutations across 19 oncogenes was performed in 197 formalin-fixed paraffin-embedded samples of different tumors using the OncoCarta Panel v1.0 (Sequenom Hamburg, Germany). Of the 197 specimens, 97 (49.2%) presented at least one mutation. Forty-nine different oncogenic mutations in 16 genes were detected. Mutations in KRAS and PIK3CA were detected in 40/97 (41.2%) and 30/97 (30.9%) patients respectively. Thirty-one patients (32.0%) had mutations in two genes, 20 of them (64.5%) initially diagnosed with colorectal cancer. The co-occurrence of mutation involved mainly KRAS, PIK3CA, KIT and RET. Mutation profiles were validated using a customized panel and the Junior Next Generation Sequencing technology (GS-Junior 454, Roche). Twenty-eight patients participated in early clinical trials or received specific treatments according to the molecular characterization (28.0%). MassARRAY technology is a rapid and effective method for identifying key cancer-driving mutations across a large number of samples, which allows for a more appropriate selection for personalized therapies. PMID- 26968817 TI - l-Lysine supplementation does not affect the bioavailability of copper or iron in rats. AB - l-lysine (Lys) is an essential amino acid that is added to foods and dietary supplements. Lys may interact with mineral nutrients and affect their metabolism. This study examined the effect of dietary Lys supplementation on the bioavailability of copper (Cu) and iron (Fe). Weanling male Sprague-Dawley rats were fed one of five diets (20% casein) for 4 weeks containing normal Cu and Fe (control) or low Cu or Fe without (LCu, LFe) or with (LCu+Lys, LFe+Lys) addition of 1.5% Lys. Final body weights, body weight gains and food consumption of the rats did not differ (P>=0.05) among diet groups. Rats fed the low Cu or Fe diets showed changes in nutritional biomarkers compared to control rats, demonstrating reduced Cu and Fe status, respectively. Hematological parameters, serum ceruloplasmin activity and Cu and Fe concentrations in serum, liver, kidney and intestinal mucosa were unaffected (P>=0.05) by Lys supplementation. These results indicate that in the context of an adequate protein diet, Lys supplementation at a relatively high level does not affect Cu or Fe bioavailability in rats. PMID- 26968815 TI - Heparanase 2 expression inversely correlates with bladder carcinoma grade and stage. AB - While the pro-tumorigenic function of heparanase is well taken, the role of its close homolog, heparanase 2 (Hpa2) in cancer is by far less investigated. Utilizing immunohistochemical analysis we found that Hpa2 is expressed by normal bladder transitional epithelium and its levels are decreased substantially in bladder cancer. Notably, tumors that retain high levels of Hpa2 were diagnosed as low grade (p=0.001) and low stage (p=0.002), suggesting that Hpa2 is required to preserve cell differentiation and halt cell motility. Indeed, migration of 5637 bladder carcinoma cells was attenuated significantly by exogenous addition of purified Hpa2, and over expression of Hpa2 in 5637 cells resulted in smaller tumors that were diagnosed as low grade. We also noted that tumors produced by Hpa2 over expressing cells are abundantly decorated with stromal cells and collagen deposition evident by Masson's/Trichrome staining, correlating with a marked increase in lysyl oxidase (LOX) staining. The association between Hpa2 and LOX was further confirmed clinically, because of the 16 cases that exhibited strong staining of Hpa2, 14 (87.5%) were also stained strongly for LOX (p=0.05). Collectively, our results suggest that Hpa2 functions as a tumor suppressor in bladder cancer, maintaining cellular differentiation and decreasing cell motility in a manner that appears to be independent of regulating heparanase activity. PMID- 26968816 TI - Perceptions of preparedness for the first medical clerkship: a systematic review and synthesis. AB - BACKGROUND: The transition from university-based to clerkship-based education can be challenging. Medical schools have introduced strategies to ease the transition, but there has been no systematic review synthesizing the evidence on the perceptions of preparedness of medical students for their first clerkship to support these interventions. This study therefore aimed to (1) identify and synthesize the published evidence on medical students' perceptions of preparedness for their first clerkship, and (2) identify factors that may impact on preparedness for clerkship, to better inform interventions aimed at easing this transition. METHODS: Electronic databases (Medline, Journals@Ovid, CINAHL, ERIC, Web of Science, Embase) were searched without restriction and secondary searching of reference lists of included studies was also conducted. Included studies used quantitative or qualitative methodologies, involved medical students and addressed student/supervisor perceptions of preparedness for first clerkship. The first clerkship was defined as the first truly immersive educational experience during which the majority of learning was vocational and self directed, as per the MeSH term 'clinical clerkship' and associated definition. Using an inductive thematic synthesis approach, 2 researchers independently extracted data, coded text (from results and discussion sections), and identified themes related to preparedness. Any disagreements were resolved by discussion and findings were then narratively synthesized. RESULTS: The initial search identified 1214 papers. After removing duplicates and assessing abstracts and full articles against the inclusion criteria, 8 articles were included in the review. In general, the body of evidence was of sound methodological quality. Ten themes relating to perceptions of preparedness of medical students for their first clerkship were identified; competence, disconnection, links to the future, uncertainty, part of the team, time/workload, adjustment, curriculum, prior life experiences and learning. CONCLUSIONS: Eight of the ten themes related to perceptions of preparedness are potentially amenable to curricula strategies to improve the transition experience. The evidence supports clinical skills refreshers, clarification of roles and expectations, demystification of healthcare hierarchy and assessment processes and student-student handovers. Evidence also supports preclinical educational strategies such as enhancing content contextualization, further opportunities for the application of knowledge and skills, and constructive alignment of assessment tasks and pedagogical aims. PMID- 26968819 TI - Spontaneous recanalisation of a chronic internal carotid artery occlusion. PMID- 26968820 TI - Cognitive profile of a child with SOS1 mutation in Noonan syndrome. PMID- 26968818 TI - Mutational spectrum of Duchenne muscular dystrophy in Spain: Study of 284 cases. AB - INTRODUCTION: Duchenne muscular dystrophy (DMD) is a severe X-linked recessive neuromuscular disease that affects one in 3500 live-born males. The total absence of dystrophin observed in DMD patients is generally caused by mutations that disrupt the reading frame of the DMD gene, and about 80% of cases harbour deletions or duplications of one or more exons. METHODS: We reviewed 284 cases of males with a genetic diagnosis of DMD between 2007 and 2014. These patients were selected from 8 Spanish reference hospitals representing most areas of Spain. Multiplex PCR, MLPA, and sequencing were performed to identify mutations. RESULTS: Most of these DMD patients present large deletions (46.1%) or large duplications (19.7%) in the dystrophin gene. The remaining 34.2% correspond to point mutations, and half of these correspond to nonsense mutations. In this study we identified 23 new mutations in DMD: 7 large deletions and 16 point mutations. CONCLUSIONS: The algorithm for genetic diagnosis applied by the participating centres is the most appropriate for genotyping patients with DMD. The genetic specificity of different therapies currently being developed emphasises the importance of identifying the mutation appearing in each patient; 38.7% of the cases in this series are eligible to participate in current clinical trials. PMID- 26968822 TI - Extrapyramidal syndrome with generalized chorea as an atypical presentation of progressive multifocal leukoencephalopathy. PMID- 26968823 TI - Hospital stroke registers: Similarities and differences. PMID- 26968821 TI - Microsurgical treatment of trigeminal neuralgia in patients older than 70 years: An efficacy and safety study. AB - INTRODUCTION: The increasing incidence of trigeminal neuralgia (TN) with age together with population ageing call for reexamination of surgical treatment options for refractory TN in elderly patients. METHODS: Retrospective review of a consecutive series of patients older than 70 who underwent microvascular decompression (MVD) for refractory TN between 1997 and 2015. Outcomes based on the Barrow Neurological Institute pain intensity score (BNI score) and surgical complications were compared to those of patients younger than 70 undergoing MVD in the same period. RESULTS: Forty patients older than 70 (mean = 74.8 years) underwent interventions. At a mean follow-up time of 34 months, 73% of the patients presented complete absence of pain without medication (BNI I) and 85% had good pain control with or without medication (BNI I-III). A comparison of these patients with the 85 patients younger than 70 treated surgically during the same period did not find a significant association between age and achievement of pain control (BNI I-II). However, there was a significant association between age older than 70 and complete pain relief (BNI I; P=.03). The mean hospital stay in patients over 70 was also significantly longer (P=.04), although the postsurgical complication rate was similar to that in younger patients. CONCLUSIONS: Elderly patients with refractory TN may benefit from treatment with MVD and the probability of success and surgical risk are comparable to those in younger patients. PMID- 26968824 TI - Parkinsonism hyperpyrexia syndrome. PMID- 26968825 TI - Decreased spasticity in primary lateral sclerosis after botulinum toxin injection: A case report. PMID- 26968826 TI - Auditory hallucinations in cognitive neurology. AB - INTRODUCTION: Different types and localisations of neurological lesions can produce tinnitus and verbal or musical hallucinations (VMH). METHOD: These symptoms were screened for in 1,000 outpatients at a cognitive neurology clinic, and epidemiological and neuroimaging data were recorded. RESULTS: Tinnitus was present in 6.9% of the total and VMH in 0.9%. The paracusia group was predominantly female but the difference was not statistically significant. Patients with tinnitus were younger and those with VMH were older than the rest of the sample (mean ages). Hearing loss was more prevalent in the paracusia group (difference was significant in VMH subgroup). There were no intergroup differences in the prevalence of psychotic and obsessive-compulsive disorders, or of leukoaraiosis. Treatment with acetylsalicylic acid was more frequent in the VMH group, whereas other non-opioid analgesics and benzodiazepines were more commonly prescribed to patients with tinnitus. The suspected cause of VMH was dementia with Lewy bodies (n=2, one with vascular disease), Alzheimer disease (n=2, one with vascular disease), isolated cerebrovascular disease (n=3), traumatic brain injury (n=1), and surgical brainstem lesion (n=1). All VMH cases displayed an underlying factor that might prompt this symptom, eg, hearing loss (n=6), a predisposing drug (n=9), and polypharmacy (n=9). CONCLUSIONS: Treatment with benzodiazepines and non-opioid analgesics was more frequent in the tinnitus group, whereas the VMH group showed a higher prevalence of hearing loss and treatment with acetylsalicylic acid. The causes of VMH were dementia with Lewy bodies, Alzheimer disease, and focal lesions in the mesencephalon, pons, left temporal lobe, or left claustrum. PMID- 26968828 TI - Synchronized functional anal sphincter assessment: maximizing the potential of anal vector manometry and 3-D anal endosonography. AB - BACKGROUND: Understanding the association between structure and function is vital before considering surgery involving anal sphincter division. By correlating three-dimensional anal endosonography (AES) and three-dimensional anal canal vector volume manometry (VVM), this study details a method to produce measurements of both sphincter length and pressure leading to identification of the functionally important areas of the anal canal. The aim of this study was to provide combined detailed information on anal canal anatomy and physiology. METHODS: Twelve males and 12 nulliparous females with no bowel symptoms underwent VVM (using a water-perfused, eight-channel radially arranged catheter) and AES. KEY RESULTS: The synchronization of AES and VVM identified that the majority of rest and squeeze anal pressure is present in the portion of the anal canal covered by both anal sphincters. Nearly, 20% of overall resting anal pressure is produced distal to the caudal termination of the internal anal sphincter. Puborectalis accounts for a significantly greater percentage volume of pressure in females both at rest and when squeezing, though the total volume of pressure is not significantly greater. CONCLUSIONS AND INFERENCES: The majority of resting and squeezing pressure and the least asymmetry, in both sexes, is in the portion of the anal canal covered by external anal sphincter. In females, the external anal sphincter is shorter and a proportionately longer puborectalis accounts for a greater percentage of pressure. Sphincter targeted fistula surgery in females must be performed with special caution. A protective role for puborectalis following obstetric anal sphincter injury is suggested. PMID- 26968827 TI - Short-course PET based simultaneous integrated boost for locally advanced cervical cancer. AB - BACKGROUND: Patients with large, locally advanced cervical cancers (LACC) are challenging to treat. The purpose of this work is to use 18F-FDG PET as planning basis for a short-course simultaneous integrated boost (SIB) in external beam radiotherapy of LACC in order to increase tumour shrinkage and likelihood of local control. METHODS: Ten previously treated patients with LACC were included, all with pre-treatment FDG PET/CT images available. The FDG avid tumour volume, MTV50, was dose escalated in silico by intensity modulated radiotherapy from the standard 1.8 Gy to 2.8 Gy per fraction for the 10 first fractions; a short-course SIB. For the 18 remaining external fractions, standard pelvic treatment followed to total PTV and MTV50 doses of 50.4 Gy and 60.4 Gy, respectively. Photon and proton treatment were considered using volumetric modulated arc treatment (VMAT) and intensity-modulated proton therapy (IMPT), respectively. All treatment plans were generated using the Eclipse Treatment Planning System (TPS). The impact of tumour shrinkage on doses to organs at risk (OARs) was simulated in the TPS for the SIB plans. RESULTS: Dose escalation could be implemented using both VMAT and IMPT, with a D98 >= 95 % for MTV50 being achieved in all cases. The sum of the 10 fraction short-course SIB and subsequent 18 standard fractions was compared to the standard non-SIB approach by dose volume histogram (DVH) analysis. Only marginal increase of dose to OARs was found for both modalities and a small further increase estimated from tumour shrinkage. Most DVH parameters showed a mean difference below 2 %. IMPT had, compared to VMAT, reduced OAR doses in the low to intermediate dose range, but showed no additional advantage in dose escalation. CONCLUSIONS: Planning of dose escalation based on a FDG avid boost volume was here demonstrated feasible. The concept may allow time for enhanced tumour shrinkage before brachytherapy. Thus, this strategy may prove clinically valuable, in particular for patients with large tumours. PMID- 26968829 TI - New Insights Into the Treatment of Glanzmann Thrombasthenia. AB - Glanzmann thrombasthenia (GT) is a rare inherited autosomal recessive bleeding disorder of platelet function caused by a quantitative or qualitative defect of platelet membrane glycoprotein IIb/IIIa (integrin alphaIIbbeta3), a fibrinogen receptor required for platelet aggregation. Bleeds in GT are variable and may be severe and unpredictable. Bleeding not responsive to local and adjunctive measures, as well as surgical procedures, is treated with platelets, recombinant activated factor VII (rFVIIa), or antifibrinolytics, alone or in combination. Although platelets are the standard treatment for GT, their use is associated with the risk of blood-borne infection transmission and may also cause the development of platelet antibodies (to human leukocyte antigens and/or alphaIIbbeta3), potentially resulting in platelet refractoriness. Currently, where rFVIIa is approved for use in GT, this is mostly for patients with platelet antibodies and/or a history of platelet refractoriness. However, data from the prospective Glanzmann's Thrombasthenia Registry (829 bleeds and 206 procedures in 218 GT patients) show that rFVIIa was frequently used in nonsurgical and surgical bleeds, with high efficacy rates, irrespective of platelet antibodies/refractoriness status. The mechanisms underpinning rFVIIa effectiveness in GT have been studied. At therapeutic concentrations, rFVIIa binds to activated platelets and directly activates FX to FXa, resulting in a burst of thrombin generation. Thrombin converts fibrinogen to fibrin and also enhances GT platelet adhesion and aggregation mediated by the newly converted (polymeric) fibrin, leading to primary hemostasis at the wound site. In addition, thrombin improves the final clot structure and activates thrombin-activatable fibrinolysis inhibitor to decrease clot lysis. PMID- 26968830 TI - Sequence analysis of two variable cytomegalovirus genes for distinction between transfusion- and breast milk-transmitted infections in a very-low-birthweight infant. AB - BACKGROUND: Cytomegalovirus (CMV) infections in very-low-birthweight infants can lead to serious clinical consequences. When CMV-related symptoms occur after transfusion, CMV transmission is often attributed to the transfusion products rather than to breast milk. However, it is sometimes difficult to distinguish between transfusion-transmitted and breast milk-transmitted CMV infections. PATIENT AND METHODS: A patient was born at 27 gestational weeks with a weight of 689 g. He was transfused with leukoreduced red blood cells (LR-RBCs), which were later found to be CMV seropositive and CMV DNA positive. He was also fed with CMV DNA-positive breast milk. Thereafter, he developed CMV disease with thrombocytopenia and jaundice. To determine the route of transmission, we analyzed the sequences of two variable CMV genes, UL139 and UL146, by direct sequence analysis. We also performed deep sequence analysis to determine whether there were polyclonal CMV strains in the LR-RBCs transfused. RESULTS: CMV DNA sequence-matching rates for the LR-RBCs and the patient's blood were 64.6% for the UL139 gene and 68.6% for the UL146 gene. In contrast, the sequences of these genes in the patient's blood were 100% matched with those in the breast milk. Furthermore, by deep sequence analysis, the CMV strain found in the patient's blood was not detected in the LR-RBCs transfused. CONCLUSION: The results indicate that the pathogenic CMV strain was transmitted through breast milk, which is consistent with the claims that transfusion-transmitted CMV infection due to leukoreduced blood products is uncommon. PMID- 26968832 TI - Footloose: Spinal Myoclonus after Myelomeningocele Repair. PMID- 26968831 TI - Selective isolation and characterization of primary cells from normal breast and tumors reveal plasticity of adipose derived stem cells. AB - BACKGROUND: There is a need to establish more cell lines from breast tumors in contrast to immortalized cell lines from metastatic effusions in order to represent the primary tumor and not principally metastatic biology of breast cancer. This investigation describes the simultaneous isolation, characterization, growth and function of primary mammary epithelial cells (MEC), mesenchymal cells (MES) and adipose derived stem cells (ADSC) from four normal breasts, one inflammatory and one triple-negative ductal breast tumors. METHODS: A total of 17 cell lines were established and gene expression was analyzed for MEC and MES (n = 42) and ADSC (n = 48) and MUC1, pan-KRT, CD90 and GATA-3 by immunofluorescence. DNA fingerprinting to track cell line identity was performed between original primary tissues and isolates. Functional studies included ADSC differentiation, tumor MES and MEC invasion co-cultured with ADSC-conditioned media (CM) and MES adhesion and growth on 3D-printed scaffolds. RESULTS: Comparative analysis showed higher gene expression of EPCAM, CD49f, CDH1 and KRTs for normal MEC lines; MES lines e.g. Vimentin, CD10, ACTA2 and MMP9; and ADSC lines e.g. CD105, CD90, CDH2 and CDH11. Compared to the mean of all four normal breast cell lines, both breast tumor cell lines demonstrated significantly lower ADSC marker gene expression, but higher expression of mesenchymal and invasion gene markers like SNAI1 and MMP2. When compared with four normal ADSC differentiated lineages, both tumor ADSC showed impaired osteogenic and chondrogenic but enhanced adipogenic differentiation and endothelial-like structures, possibly due to high PDGFRB and CD34. Addressing a functional role for overproduction of adipocytes, we initiated 3D-invasion studies including different cell types from the same patient. CM from ADSC differentiating into adipocytes induced tumor MEC 3D-invasion via EMT and amoeboid phenotypes. Normal MES breast cells adhered and proliferated on 3D-printed scaffolds containing 20 fibers, but not on 2.5D-printed scaffolds with single fiber layers, important for tissue engineering. CONCLUSION: Expression analyses confirmed successful simultaneous cell isolations of three different phenotypes from normal and tumor primary breast tissues. Our cell culture studies support that breast-tumor environment differentially regulates tumor ADSC plasticity as well as cell invasion and demonstrates applications for regenerative medicine. PMID- 26968833 TI - Multimodal Outcome at 7 Years of Age after Neonatal Arterial Ischemic Stroke. AB - OBJECTIVES: To evaluate the epileptic, academic, and developmental status at age 7 years in a large population of term-born children who sustained neonatal arterial ischemic stroke (NAIS), and to assess the co-occurrence of these outcomes. STUDY DESIGN: A cohort study including 100 term newborns with NAIS was designed. Two infants died during the neonatal period, 13 families were lost to follow-up, and 5 families declined to participate in this evaluation. Thus, 80 families completed the 7-year clinical assessment. Epileptic status, schooling, motor abilities, global intellectual functioning, spoken language, and parental opinions were recorded. Principal component analysis was applied. RESULTS: Rates of impaired language, cerebral palsy, low academic skills, active epilepsy, and global intellectual deficiency were 49%, 32%, 28%, 11%, and 8%, respectively. All were highly correlated. Eventually, 59% of children were affected by at least 1 of the aforementioned conditions. In 30% of cases, the viewpoints of health practitioners and parents did not match. CONCLUSION: The prevalence of severe disabilities at 7 years after NAIS is low, but most children exhibit some impairment in developmental profile. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02511249), Programme Hospitalier de Recherche Clinique Regional (0308052), Programme Hospitalier de Recherche Clinique Interregional (1008026), and EudraCT (2010-A00329-30). PMID- 26968834 TI - Risk and Protective Factors for Late Talking: An Epidemiologic Investigation. AB - OBJECTIVE: To identify risk and protective factors for late talking in toddlers between 24 and 30 months of age in a large community-based cohort. STUDY DESIGN: A prospective, longitudinal pregnancy cohort of 1023 mother-infant pairs in metropolitan Calgary, Canada, were followed across 5 time points: before 25 weeks gestation, between 34-36 weeks gestation, and at 4, 12, and 24 months postpartum. Toddlers who scored <=10th percentile on The MacArthur-Bates Communicative Development Inventories: Words and Sentences between 24 and 30 months of age were identified as late talkers. Thirty-four candidate characteristics theoretically and/or empirically linked to language development and/or language impairment were collected using survey methodology. RESULTS: The prevalence of late talking was 12.6%. Risk factors for late talking in the multivariable model included: male sex (P = .017) and a family history of late talking and/or diagnosed speech or language delay (P = .002). Toddlers were significantly less likely to be late talkers if they engaged in informal play opportunities (P = .013), were read to or shown picture books daily (P < .001), or cared for primarily in child care centers (P = .001). CONCLUSIONS: Both biological and environmental factors were associated with the development of late talking. Biological factors placed toddlers at risk for late talking, and facets of the environment played a protective role. Enveloping infants and toddlers in language-rich milieus that promote opportunities for playing, reading, and sharing books daily may decrease risk for delayed early vocabulary. PMID- 26968835 TI - The next step in translational research: lessons learned from the first preclinical randomized controlled trial. AB - For years, low reproducibility of preclinical trials and poor translation of promising preclinical therapies to the clinic have posed major challenges to translational research in most biomedical fields. To overcome the limitations that stand between experimental and clinical research, international consortia have attempted to establish standardized guidelines for study design and for reporting the resulting data. In addition, multicenter preclinical randomized controlled trials (pRCTs) have been proposed as a suitable tool for 'bridging the gap' between experimental research and clinical trials. We recently reported the design and results of the first such pRCT in which we confirmed the feasibility of using a coordinated approach with standardized protocols in collaboration with independent multinational research centers. However, despite its successes, this first pRCT also had several difficulties, particularly with respect to following the protocols established in the study design and analyzing the data. Here, we review our experiences performing the study, and we analyze and discuss the lessons learned from performing the first pRCT. Moreover, we provide suggestions regarding how obstacles can be overcome to improve the performance and outcome of future pRCT studies. Translational research is hampered by low reproducibility of preclinical studies and countless failed clinical trials. International consortia have proposed preclinical multicenter trials as an intermediate step to overcome this 'translational roadblock'. We have recently performed the first such preclinical randomized controlled trial (pRCT) by adopting key elements of clinical study design to preclinical research. In this review, we discuss the lessons learned from this trial and provide suggestions how to optimize future pRCTs. This article is part of the 60th Anniversary special issue. PMID- 26968837 TI - SNPs in FNDC5 (irisin) are associated with obesity and modulation of glucose and lipid metabolism in Saudi subjects. AB - BACKGROUND: Irisin is a recently identified myokine that plays an important role in preventing obesity and insulin resistance. We investigated whether the common FNDC5 (irisin precursor) gene variants influence susceptibility to obesity and type 2 diabetes (T2D) and verified the impact of FNDC5 gene variants on serum irisin levels, glucose and lipid metabolism in a Saudi population. METHODS: Genomic DNA from 814 (394 T2DM and 414 controls) subjects were genotyped for the five common SNPs (rs3480A/G, rs1746661G/T, rs1298190A/G, rs726344A/G and rs1570569G/T) of the FNDC5 gene using the TaqMan genotyping assay. Biochemical parameters and hematic concentrations of irisin and insulin as well as anthropometric indices were collected. RESULTS: Serum irisin levels were higher in T2DM patients compared to controls (p < 0.0001). Analyses of FNDC5 SNPs showed that: 1) The rs3480 GG associates with decreased risk of obesity (p = 0.005; odds ratio: 0.48) and lower body mass index (BMI) values (p = 0.03). In addition, GGAAG was identified as the protective haplotype against risk of obesity (p = 0.001; odds ratio: 0.23). 2) The rs1746661 G allele associates with higher triglyceride (TG) levels (p = 0.019). 3) The rs157069 TT genotype associates with higher fasting insulin (p = 0.029) and HOMA-IR (p = 0.002) as well as with lower circulating irisin levels (p = 0.016). CONCLUSIONS: SNPs in FNDC5 gene correlates with obesity and glucose-lipid metabolism possibly because they modulate the serum levels of irisin. PMID- 26968838 TI - Restart the heart. AB - Early bystander cardiopulmonary resuscitation and rapid defibrillation are the most important factors for favourable outcomes after out of hospital cardiac arrest (OHCA)-as the new American Heart Association/European Resuscitation Council (AHA/ERC) guidelines emphasise. The patient in our case was a healthy young man who had a witnessed cardiac arrest due to a chest collision with the goalkeeper during a football match. Basic life support was immediately provided by his teammates until an automated external defibrillator was brought to the scene. Blunt cardiac injury (BCI) may result in injured myocardium or arrhythmias. Ventricular fibrillation due to BCI in absence of structural cardiac disease is one of the main causes of OHCA in young healthy athletes with high mortality rates. We demonstrate important aspects of the recently released guidelines on cardiac arrest and the chain of survival by the leading societies. PMID- 26968836 TI - Treatment with TO901317, a synthetic liver X receptor agonist, reduces brain damage and attenuates neuroinflammation in experimental intracerebral hemorrhage. AB - BACKGROUND: Intracerebral hemorrhage (ICH) induces a series of inflammatory processes that contribute to neuronal damage and neurological deterioration. Liver X receptors (LXRs) are nuclear receptors that negatively regulate transcriptional processes involved in inflammatory responses, but their role in the pathology following ICH remains unclear. The present study investigated the neuroprotective effects and anti-inflammatory actions of TO901317, a synthetic LXR agonist, in a model of collagenase-induced ICH and in microglial cultures. METHODS: Mice subjected to collagenase-induced ICH injury were injected with either TO901317 (30 mg/kg) or vehicle 10 min after ICH and subsequently daily for 2 days. Behavioral studies, histology analysis, and assessments of hematoma volumes, brain water content, and blood-brain barrier (BBB) permeability were performed. The protein expression of LXR-alpha, LXR-beta, ATP binding cassette transporter-1 (ABCA-1), and inflammatory molecules was analyzed. The anti inflammatory mechanism of TO901317 was investigated in cultured microglia that were stimulated with either lipopolysaccharide (LPS) or thrombin. RESULTS: ICH induced an increase in LXR-alpha protein levels in the hemorrhagic hemisphere at 6 h whereas LXR-beta expression remained unaffected. Both LXR-alpha and LXR-beta were expressed in neurons and microglia in the peri-ICH region and but rarely in astrocytes. TO901317 significantly attenuated functional deficits and brain damage up to 28 days post-ICH. TO901317 also reduced neuronal death, BBB disruption, and brain edema at day 4 post-ICH. These changes were associated with marked reductions in microglial activation, neutrophil infiltration, and expression levels of inflammatory mediators at 4 and 7 days. However, TO901317 had no effect on matrix metalloproteinase-9 activity. In BV2 microglial cultures, TO901317 attenuated LPS- and thrombin-stimulated nitric oxide production and reduced LPS-induced p38, JNK, MAPK, and nuclear factor-kappa B (NF-kappaB) signaling. Moreover, delaying administration of TO901317 to 3 h post-ICH reduced brain tissue damage and neuronal death. CONCLUSIONS: Our results suggest that enhancing LXR activation may provide a potential therapy for ICH by modulating the cytotoxic functions of microglia. PMID- 26968840 TI - The design of empirical studies: towards a unified view. AB - A broad review is given of the general principles underlying study design with emphasis on applications in medical and epidemiological contexts. The main theme of the paper is that, while the distinction between interventionist studies, that is experiments, and purely observational ones is important, there are many common threads. A wide range of specific applications are used in outline to illustrate the discussion. PMID- 26968839 TI - An update on the clinical diagnostic value of beta-hCG and alphaFP for intracranial germ cell tumors. AB - BACKGROUND: Pathological examination combined with tumor markers has become a standard for the diagnosis of intracranial germ cell tumors (ICGCTs), but the current concept of 'secreting germ cell tumors' and three empirically highly specific diagnostic criteria (beta-hCG >= 50 IU/L or alphaFP >= 10 ng/mL; beta hCG >= 100 IU/L or alphaFP >= 50 ng/mL; beta-hCG > 50 IU/L or alphaFP > 25 ng/mL) are not based upon pathology examination or CSF cytology. Further investigation is needed to re-evaluate their value. METHODS: A multidisciplinary diagnostic team was created. Valid beta-hCG/alphaFP data were collected from cases of ICGCTs confirmed by pathology and CSF cytology (n = 58) between 1991 and 2012, and from suspected ICGCTs cases (n = 17) between 2011 and 2012 as controls [Langerhans cell histiocytosis (LCH), n = 12; and other intracranial tumor (ICT), n = 5]. The cut-off points for beta-hCG and alphaFP were calculated using receiver operating characteristic (ROC) curves. RESULTS: This study clarifies the relative rationality of one criteria (beta-hCG > 50 IU/L and alphaFP > 25 ng/mL); confirms new beta-hCG diagnostic cut-off points: CSF beta-hCG >= 8.2 IU/L and serum beta hCG >= 2.5 IU/L (sensitivity of 47 and 34%, respectively, specificity of 100%, both; P < 0.05); and empirically adjusts the criteria for alphaFP to >= 3.8 ng/mL in CSF and to >= 25 ng/mL in serum. The total diagnostic sensitivity for ICGCTs finally increased from 34.6 to 65.4% (P < 0.05, diagnostic value of CSF beta-hCG exceeds 90%). Subtype diagnosis improved with alphaFP in 16.7% of non geminomatous germ cell tumor cases. CONCLUSION: New evidence-based criteria of beta-hCG and alphaFP can help improving early and formal diagnosis of ICGCTs, and is of great clinical significance. PMID- 26968842 TI - Teenage pregnancy rate falls to record low. PMID- 26968841 TI - Physical activity and risk of Amyotrophic Lateral Sclerosis in a prospective cohort study. AB - Previous case-control studies have suggested a possible increased risk of Amyotrophic Lateral Sclerosis (ALS) with physical activity (PA), but this association has never been studied in prospective cohort studies. We therefore assessed the association between PA and risk of death from ALS in the European Prospective Investigation into Cancer and Nutrition. A total of 472,100 individuals were included in the analysis, yielding 219 ALS deaths. At recruitment, information on PA was collected thorough standardised questionnaires. Total PA was expressed by the Cambridge Physical Activity Index (CPAI) and analysed in relation to ALS mortality, using Cox hazard models. Interactions with age, sex, and anthropometric measures were assessed. Total PA was weakly inversely associated with ALS mortality with a borderline statistically significant trend across categories (p = 0.042), with those physically active being 33% less likely to die from ALS compared to those inactive: HR = 0.67 (95% CI 0.42-1.06). Anthropometric measures, sex, and age did not modify the association with CPAI. The present study shows a slightly decreased-not increased like in case-control studies-risk of dying from ALS in those with high levels of total PA at enrolment. This association does not appear confounded by age, gender, anthropometry, smoking, and education. Ours was the first prospective cohort study on ALS and physical activity. PMID- 26968843 TI - Mutational status of synchronous and metachronous tumor samples in patients with metastatic non-small-cell lung cancer. AB - BACKGROUNDS: Despite reported discordance between the mutational status of primary lung cancers and their metastases, metastatic sites are rarely biopsied and targeted therapy is guided by genetic biomarkers detected in the primary tumor. This situation is mostly explained by the apparent stability of EGFR activating mutations. Given the dramatic increase in the range of candidate drugs and high rates of drug resistance, rebiopsy or liquid biopsy may become widespread. The purpose of this study was to test genetic biomarkers used in clinical practice (EGFR, ALK) and candidate biomarkers identified by the French National Cancer Institute (KRAS, BRAF, PIK3CA, HER2) in patients with metastatic non-small-cell lung cancer for whom two tumor samples were available. METHODS: A retrospective study identified 88 tumor samples collected synchronously or metachronously, from the same or two different sites, in 44 patients. Mutation analysis used SNaPshot (EGFR, KRAS, BRAF missense mutations), pyrosequencing (EGFR and PIK3CA missense mutations), sizing assays (EGFR and HER2 indels) and IHC and/or FISH (ALK rearrangements). RESULTS: About half the patients (52%) harbored at least one mutation. Five patients had an activating mutation of EGFR in both the primary tumor and the metastasis. The T790M resistance mutation was detected in metastases in 3 patients with acquired resistance to EGFR tyrosine kinase inhibitors. FISH showed discordance in ALK status between a small biopsy sample and the surgical specimen. KRAS mutations were observed in 36% of samples, six patients (14%) having discordant genotypes; all discordances concerned sampling from different sites. Two patients (5%) showed PI3KCA mutations. One metastasis harbored both PI3KCA and KRAS mutations, while the synchronously sampled primary tumor was mutation free. No mutations were detected in BRAF and HER2. CONCLUSIONS: This study highlighted noteworthy intra-individual discordance in KRAS mutational status, whereas EGFR status was stable. Intratumoral heterogeneity for ALK rearrangement suggests a limitation of single-biopsy analysis for therapeutic strategy with crizotinib. PMID- 26968844 TI - Assessment of clinical efficacy and safety in a randomized double-blind study of etanercept and sulfasalazine in patients with ankylosing spondylitis from Eastern/Central Europe, Latin America, and Asia. AB - Despite the demonstrated efficacy of etanercept for the treatment of ankylosing spondylitis (AS), sulfasalazine is often prescribed, especially in countries with limited access to biologic agents. The objective of this subset analysis of the ASCEND trial was to compare the efficacy of etanercept and sulfasalazine in treating patients with AS from Asia, Eastern/Central Europe, and Latin America. A total of 287 patients, 190 receiving etanercept 50 mg once weekly and 97 receiving sulfasalazine 3 g daily, from eight countries were included in this subset analysis. Differences in disease activity and patient-reported outcomes assessing health-related quality-of-life (HRQoL) parameters in response to treatment were analyzed using the Cochran-Mantel-Haenszel test for categorical efficacy endpoints and analysis of covariance model for continuous variables. At week 16, a significantly greater proportion of patients receiving etanercept achieved ASAS20 (79.0 %) compared with patients receiving sulfasalazine (61.9 %; p = 0.002). At week 16, treatment with etanercept also resulted in significantly better responses than sulfasalazine for ASAS40 (64.7 vs. 35.1 %; p < 0.001), ASAS5/6 (48.1 vs. 26.3 %; p < 0.001), proportion of patients achieving 50 % response in Bath AS Disease Activity Index (65.8 vs. 42.3 %; p < 0.001), partial remission (35.3 vs. 17.5 %; p = 0.002), and all HRQoL parameters. Both treatments were well tolerated. Etanercept was significantly more effective than sulfasalazine in the treatment of patients with AS from Asia, Central/Eastern Europe, and Latin America. PMID- 26968845 TI - Diagnostic value of progranulin in patients with lupus nephritis and its correlation with disease activity. AB - The aim of this study was to explore whether progranulin (PGRN) can be a useful marker not only for accurate diagnosis of patients with active lupus nephritis (LN), but also for prediction of the disease activity in this population. A total of 154 LN patients were enrolled in this study, 76 of which were diagnosed as having active LN and 78 as having stable LN. Additionally, 71 age-matched non-LN patients were enrolled as controls. The serum and urine PGRN levels of each study population were measured using the enzyme-linked immunosorbent assay method. The diagnostic performance of both indicators and their correlation with the disease activity of LN were systematically investigated using receiver operating characteristic (ROC) analysis and correlation analysis. The active LN population had significantly higher serum and urine PGRN levels than the other two populations. ROC analysis further demonstrated that these two indicators, particularly in combination, appear to have a strong performance in discriminating active LN patients from the rest of the LN population. In the active LN population, serum and urine PGRN levels were not only significantly correlated with SLEDAI score, rSLEDAI score, and activity index, but also had a considerable association with several key markers reflecting the disease activity of LN, including serum levels of complement component 3 and ds-DNA. Nevertheless, neither of the two indicators were correlated with the pathological classification of LN, chronicity index, serum creatinine level, and 24-h urine protein levels. Our findings demonstrate that PGRN may have great potential as a diagnostic factor for active LN and as a predictor for its disease activity. PMID- 26968846 TI - Efficient parallel reconstruction for high resolution multishot spiral diffusion data with low rank constraint. AB - PURPOSE: To propose a novel reconstruction method using parallel imaging with low rank constraint to accelerate high resolution multishot spiral diffusion imaging. THEORY AND METHODS: The undersampled high resolution diffusion data were reconstructed based on a low rank (LR) constraint using similarities between the data of different interleaves from a multishot spiral acquisition. The self navigated phase compensation using the low resolution phase data in the center of k-space was applied to correct shot-to-shot phase variations induced by motion artifacts. The low rank reconstruction was combined with sensitivity encoding (SENSE) for further acceleration. The efficiency of the proposed joint reconstruction framework, dubbed LR-SENSE, was evaluated through error quantifications and compared with l1 regularized compressed sensing method and conventional iterative SENSE method using the same datasets. RESULTS: It was shown that with a same acceleration factor, the proposed LR-SENSE method had the smallest normalized sum-of-squares errors among all the compared methods in all diffusion weighted images and DTI-derived index maps, when evaluated with different acceleration factors (R = 2, 3, 4) and for all the acquired diffusion directions. CONCLUSION: Robust high resolution diffusion weighted image can be efficiently reconstructed from highly undersampled multishot spiral data with the proposed LR-SENSE method. Magn Reson Med 77:1359-1366, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26968848 TI - The 22nd Scientific Conference of the Society on Neuroimmune Pharmacology. PMID- 26968847 TI - The self-reported use of immunostains and cytogenetic testing in the diagnosis of melanoma by practicing U.S. pathologists of 10 selected states. AB - BACKGROUNDS: The diagnosis of melanoma can be challenging, especially in lesions for which the histopathologic criteria bridge two or more taxonomic categories. Newer genomic analytical methods of fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) have been introduced as ancillary techniques to differentiate benign and malignant melanocytic proliferations. METHODS: We evaluated how pathologists perceive and are incorporating these new cytogenetic testing technologies into their practices. We conducted a study of 207 U.S. pathologists who interpret melanocytic lesions in clinical practice in 10 SEER states. Pathologists were surveyed regarding perceptions and utilization of FISH and/or CGH in their clinical practices. RESULTS: Results showed that 38% of pathologists use FISH and/or CGH in interpreting melanocytic lesions. Pathologists reporting FISH and/or CGH use were significantly younger (p < 0.05), were fellowship trained or board certified in dermatopathology (p < 0.001) and were affiliated with an academic institute (p < 0.001). Pathologists reporting that their colleagues consider them an expert in the assessment of melanocytic lesions were more likely to employ FISH and/or CGH in their practices than non experts. CONCLUSIONS: Early users of cytogenetic testing technologies in cutaneous pathology are more likely to be younger, affiliated with an academic institution and fellowship trained or board certified in dermatopathology. PMID- 26968851 TI - "Chronic Pain and the Brain" Impairment: Introducing a Translational Neuroscience Based Metric. PMID- 26968849 TI - Chemokine CCL2 enhances NMDA receptor-mediated excitatory postsynaptic current in rat hippocampal slices-a potential mechanism for HIV-1-associated neuropathy? AB - Human immunodeficiency virus type 1 (HIV-1)-infected mononuclear phagocytes (brain macrophages and microglial cells) release proinflammatory cytokines and chemokines. Elevated levels of chemokine CC motif ligand 2 (CCL2, known previously as monocyte chemoattractant protein-1) have been detected in serum and cerebrospinal fluid (CSF) of HIV-1-infected individuals and the raised CCL2 in the CSF correlates with HIV-1-associated neurocognitive disorders. To understand how elevated CCL2 induces HIV-1-associated neuropathy, we studied effects of CCL2 on excitatory postsynaptic current (EPSCs) in the CA1 region of rat hippocampal brain slices using whole-cell patch recording techniques. The AMPA receptor (AMPAR)-mediated EPSC (EPSCAMPAR) and N-Methyl-D-aspartate (NMDA) receptor (NMDAR)-mediated EPSCs (EPSCNMDAR) were isolated pharmacologically. Bath application of CCL2 produced a significant enhancement of the amplitudes of EPSCs, EPSCAMPAR and EPSCNMDAR. Further studies revealed that CCL2 potentiated NMDAR subtype NR2A-mediated EPSC (EPSCNR2AR) and NR2B-mediated EPSC (EPSCNR2BR). To determine the site of action, we recorded spontaneous mini EPSCs (mEPSC) before and during bath application of CCL2. Our results showed that CCL2 decreased inter event interval (IEI) and increased the frequency of mEPSCs without change on the amplitude, suggesting a presynaptic site of CCL2 action. CCL2 was also found to injure primary rat hippocampal neuronal cultures and neuronal dendrites in the CA1 region of hippocampal slices. The CCL2-associated neuronal and dendritic injuries were blocked by a specific NMDAR antagonist or by a CCR2 receptor antagonist, indicating that CCL2-associated neural injury was mediated via NMDARs and/or CCR2 receptors. Taken together, these results suggest a potential role CCL2 may play in HIV-1-associated neuropathology. PMID- 26968852 TI - The Particular Role of Ultrasound in the Diagnosis of Painful Ankle in an Athetoid Patient. PMID- 26968853 TI - A simple introduction to Markov Chain Monte-Carlo sampling. AB - Markov Chain Monte-Carlo (MCMC) is an increasingly popular method for obtaining information about distributions, especially for estimating posterior distributions in Bayesian inference. This article provides a very basic introduction to MCMC sampling. It describes what MCMC is, and what it can be used for, with simple illustrative examples. Highlighted are some of the benefits and limitations of MCMC sampling, as well as different approaches to circumventing the limitations most likely to trouble cognitive scientists. PMID- 26968850 TI - Mindfulness Meditation and Cognitive Behavioral Therapy Intervention Reduces Pain Severity and Sensitivity in Opioid-Treated Chronic Low Back Pain: Pilot Findings from a Randomized Controlled Trial. AB - OBJECTIVE: To assess benefits of mindfulness meditation and cognitive behavioral therapy (CBT)-based intervention for opioid-treated chronic low back pain (CLBP). DESIGN: 26-week parallel-arm pilot randomized controlled trial (Intervention and Usual Care versus Usual Care alone). SETTING: Outpatient. SUBJECTS: Adults with CLBP, prescribed >=30 mg/day of morphine-equivalent dose (MED) for at least 3 months. METHODS: The intervention comprised eight weekly group sessions (meditation and CLBP-specific CBT components) and 30 minutes/day, 6 days/week of at-home practice. Outcome measures were collected at baseline, 8, and 26 weeks: primary-pain severity (Brief Pain Inventory) and function/disability (Oswestry Disability Index); secondary-pain acceptance, opioid dose, pain sensitivity to thermal stimuli, and serum pain-sensitive biomarkers (Interferon-gamma; Tumor Necrosis Factor-alpha; Interleukins 1beta and 6; C-reactive Protein). RESULTS: Thirty-five (21 experimental, 14 control) participants were enrolled and completed the study. They were 51.8 +/- 9.7 years old, 80% female, with severe CLBP-related disability (66.7 +/- 11.4), moderate pain severity (5.8 +/- 1.4), and taking 148.3 +/- 129.2 mg/day of MED. Results of the intention-to-treat analysis showed that, compared with controls, the meditation-CBT group reduced pain severity ratings during the study (P = 0.045), with between-group difference in score change reaching 1 point at 26 weeks (95% Confidence Interval: 0.2,1.9; Cohen's d = 0.86), and decreased pain sensitivity to thermal stimuli (P < 0.05), without adverse events. Exploratory analyses suggested a relationship between the extent of meditation practice and the magnitude of intervention benefits. CONCLUSIONS: Meditation-CBT intervention reduced pain severity and sensitivity to experimental thermal pain stimuli in patients with opioid-treated CLBP. PMID- 26968854 TI - Is cognitive control automatic? New insights from transcranial magnetic stimulation. AB - Cognitive control has been classically considered as a flexible process engaged to pursue intentional behaviors, as distinct from automatic processes, which are unintentional, inflexible, and triggered by unconscious mechanisms. Our study challenged this view, showing that such a distinction may not be so clear-cut. We analyzed motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation to investigate the neurocognitive mechanisms occurring in a conflict task during trials that either required or did not require a response. We observed a Simon effect on MEPs and sequential modulations of such effects on both kinds of trials. Sequential modulations are usually explained as resulting from the engagement of intentional control mechanisms. Our findings rule against this idea, suggesting that these effects are the result of a mechanism that detects and resolves conflict even when there is no intention to select any response. Accordingly, cognitive control also seems to operate without intention, acting in an automatic fashion. PMID- 26968855 TI - A Computational Framework for Personalized Blood Flow Analysis in the Human Left Atrium. AB - Atrial fibrillation (AF), the most common human arrhythmia, is a marker of an increased risk of embolic stroke. However, recent studies suggest that AF may not be mechanistically responsible for the stroke events. An alternative explanation for the mechanism of intracardiac thrombosis and stroke in patients with AF is structural remodeling of the left atrium (LA). Nevertheless, a mechanistic link between LA structural remodeling and intracardiac thrombosis is unclear, because there is no clinically feasible methodology to evaluate the complex relationship between these two phenomena in individual patients. Computational fluid dynamics (CFD) is a powerful tool that could potentially link LA structural remodeling and intracardiac thrombosis in individual patients by evaluating the patient-specific LA blood flow characteristics. However, the lack of knowledge of the material and mechanical properties of the heart wall in specific patients makes it challenging to solve the complexity of fluid-structure interaction. In this study, our aim was to develop a clinically feasible methodology to perform personalized blood flow analysis within the heart. We propose an alternative computational approach to perform personalized blood flow analysis by providing the three-dimensional LA endocardial surface motion estimated from patient-specific cardiac CT images. In two patients (case 1 and 2), a four-dimensional displacement vector field was estimated using nonrigid registration. The LA blood outflow across the mitral valve (MV) was calculated from the LV volume, and the flow field within the LA was derived from the incompressible Navier-Stokes equation. The CFD results successfully captured characteristic features of LA blood flow observed clinically by transesophageal echocardiogram. The LA global flow characteristics and vortex structures also agreed well with previous reports. The time course of LAA emptying was similar in both cases, despite the substantial difference in the LA structure and function. We conclude that our CT-based, personalized LA blood flow analysis is a clinically feasible methodology that can be used to improve our understanding of the mechanism of intracardiac thrombosis and stroke in individual patients with LA structural remodeling. PMID- 26968856 TI - Diving accidents: a cohort study from the Netherlands. AB - BACKGROUND: Diving is, besides professional reasons, an increasingly popular leisure activity. Whilst statistically compared to other sports safe, diving accidents can result in serious complications. In order to treat this specific patient category adequately, early diagnosis is important. In this study, we explore various medical aspects of diving accidents. By sharing our experiences, we intend to create awareness and enhance urgent medical care for this specific category of patients. METHODS: We conducted a retrospective cohort study using anonymized patient records from the emergency department (ED) of the Admiraal De Ruyter Hospital (ADRZ) and affiliated Medical Centre Hyperbaric Oxygen Therapy (MCHZ1) both in Goes, Netherlands. We evaluated all patients that presented to our ED as a diving accident from 1 November 2011 to 30 August 2015. RESULTS: In the selected period, 43 patients presented to our ED with complaints after diving; 84 % were male and 49 % older than 40 years, and they came by ambulance or referred by a general practitioner or other medical centres in the area; 70 % presented the same date as their dive, 21 % 1 to 3 days and 9 % later than 3 days after having dived. Pain was the most frequently reported symptom (44 %), followed by constitutional symptoms (42 %). Numbness or paraesthesia was reported in 33 %. Respiratory symptoms, dizziness, a change in mental status (e.g. apathy, confused or restlessness) and problems with coordination were present in 10-21 % of the cases. Symptoms that were apparent in less than 10 % of the cases were cutis marmorata, visual or auditory complaints, muscle weakness, cardiovascular symptoms or a malfunction of the anal sphincter or urinary bladder. Most of our patients exhibited more than one symptom; 70 % of all patients received hyperbaric oxygen recompression therapy. CONCLUSIONS: The limited number of patients presenting with complaints after a diving incident, the difficulty of recognition and the (potential) huge impact if not recognized and treated adequately make us believe that every diving accident should be discussed with a centre of expertise. PMID- 26968857 TI - [Catheter-based mitral valve repair by MitraClip implantation : Development, studies, and use in clinical practice]. AB - The percutaneous edge-to-edge mitral valve repair with MitraClip(r) is evolving as a potential alternative to conventional surgery in high-risk patients with significant mitral regurgitation (MR). The randomized controlled EVEREST II-trial which compared percutaneous repair versus surgery in operable patients with symptomatic severe MR demonstrated superior safety of MitraClip(r) implantation but better MR reduction after surgery at 12 months. However, large registries on MitraClip(r) therapy showed that real-world MitraClip(r) patients differ significantly from the EVEREST II-cohort: they are older, in more advanced stages of heart failure, present predominantly with secondary MR, and exhibit a higher burden of comorbidities. For these patients, registry data confirm a low incidence of peri-interventional complications and a significant improvement of heart failure symptoms and quality of life measures after MitraClip(r) implantation. The ongoing RESHAPE trial with randomization of MitraClip(r) implantation against optimal medical therapy investigates a possible survival benefit after MitraClip(r) in patients with secondary MR. PMID- 26968858 TI - Investigating posttraumatic stress disorder as a psychological maintaining factor of eating disorders. PMID- 26968859 TI - Research program for a search of the origin of Darwinian evolution : Research program for a vesicle-based model of the origin of Darwinian evolution on prebiotic early Earth. AB - The search for origin of 'life' is made even more complicated by differing definitions of the subject matter, although a general consensus is that an appropriate definition should center on Darwinian evolution (Cleland and Chyba 2002). Within a physical approach which has been defined as a level-4 evolution (Tessera and Hoelzer 2013), one mechanism could be described showing that only three conditions are required to allow natural selection to apply to populations of different system lineages. This approach leads to a vesicle- based model with the necessary properties. Of course such a model has to be tested. Thus, after a brief presentation of the model an experimental program is proposed that implements the different steps able to show whether this new direction of the research in the field is valid and workable. PMID- 26968860 TI - Evaluation of brain tissue responses because of the underwash overpressure of helmet and faceshield under blast loading. AB - Head protective tools such as helmets and faceshields can induce a localized high pressure region on the skull because of the underwash of the blast waves. Whether this underwash overpressure can affect the brain tissue response is still unknown. Accordingly, a computational approach was taken to confirm the incidence of underwash with regards to blast direction, as well as examine the influence of this effect on the mechanical responses of the brain. The variation of intracranial pressure (ICP) as one of the major injury predictors, as well as the maximum shear stress were mainly addressed in this study. Using a nonlinear finite element (FE) approach, generation and interaction of blast waves with the unprotected, helmeted, and fully protected (helmet and faceshield protected) FE head models were modeled using a multi-material arbitrary Lagrangian-Eulerian (ALE) method and a fluid-structure interaction (FSI) coupling algorithm. The underwash incidence overpressure was found to greatly change with the blast direction. Moreover, while underwash induced ICP (U-ICP) did not exceed the peak ICP of the unprotected head, it was comparable and even more than the peak ICP imposed on the protected heads by the primary shockwaves (Coup-ICP). It was concluded that while both helmet and faceshield protected the head against blast waves, the underwash overpressure affected the brain tissue response and altered the dynamic load experienced by the brain as it led to increased ICP levels at the countercoup site, imparted elevated skull flexure, and induced high negative pressure regions. Copyright (c) 2016 John Wiley & Sons, Ltd. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26968861 TI - [Accuracy and reliability between glucose meters: A study under normal clinical practice conditions]. AB - INTRODUCTION: The glucose meters usually show a high accuracy, and in clinical practice, capillary and plasma glucose (PG) are used interchangeably. However, many variables can affect the validity of these devices. The aim of this study was to determine the accuracy and reliability of 3 glucose meters that are currently used in a primary care centre. MATERIAL AND METHODS: A sample of venous blood and a drop of capillary blood were obtained from 59 participants. The drop was analysed in 3 glucose meters: 2 FreeStyle(r) Optium (OP1 and OP2), and one Accu-Chek(r) Aviva. The PG acted as the reference value, and the haematocrit and plasma levels of urea, bilirubin, uric acid and triglycerides were also analysed. We used the Passing-Bablok regression for accuracy and the intraclass correlation coefficient and the Bland-Altman method for reliability. The current American Diabetes Association standard of a total error of+/-5% was applied. RESULTS: Differences in mean+/-standard deviation (mg/dL) and the systematic error were 5.8+/-7 and 5.8% (OP1); 6.2+/-8 and 5.9% (OP2); 8.3+/-8 and 6.3% (Accu-Chek(r)). The OP1/OP2 pair showed the highest level of reliability, with an intraclass correlation coefficient=0.97, bias=-0.4mg/dL, and a width of the 95% limits of agreement of 28.6mg/dL. The highest levels of accuracy and reliability were observed in high glucose ranges (PG>=126mg/dL). CONCLUSIONS: Despite their clinically acceptable mean difference compared to the PG, the 3 glucose meters did not fulfill the current American Diabetes Association standard. The regular performance of quality control tests of these devices is recommended. PMID- 26968862 TI - [A randomized trial of intensive versus standard blood pressure control]. PMID- 26968864 TI - Reduction of paediatric inguinal hernias. PMID- 26968863 TI - Indocyanine green fluorescence angiography for intraoperative assessment of gastrointestinal anastomotic perfusion: a systematic review of clinical trials. AB - PURPOSE: Anastomotic leakage following gastrointestinal surgery remains a frequent and serious complication associated with a high morbidity and mortality. Indocyanine green fluorescence angiography (ICG-FA) is a newly developed technique to measure perfusion intraoperatively. The aim of this paper was to systematically review the literature concerning ICG-FA to assess perfusion during the construction of a primary gastrointestinal anastomosis in order to predict anastomotic leakage. METHODS: The following four databases PubMed, Scopus, Embase, and Cochrane were independently searched by two authors. Studies were included in the review if they assessed anastomotic perfusion intraoperatively with ICG-FA in order to predict anastomotic leakage in humans. RESULTS: Of 790 screened papers 14 studies were included in this review. Ten studies (n = 916) involved patients with colorectal anastomoses and four studies (n = 214) patients with esophageal anastomoses. All the included studies were cohort studies. Intraoperative ICG-FA assessment of colorectal anastomoses was associated with a reduced risk of anastomotic leakage (n = 23/693; 3.3 % (95 % CI 1.97-4.63 %) compared with no ICG-FA assessment (n = 19/223; 8.5 %; 95 % CI 4.8-12.2 %). The anastomotic leakage rate in patients with esophageal anastomoses and intraoperative ICG-FA assessment was 14 % (n = 30/214). None of the studies involving esophageal anastomoses had a control group without ICG-FA assessment. CONCLUSION: No randomized controlled trials have been published. ICG-FA seems like a promising method to assess perfusion at the site intended for anastomosis. However, we do not have the sufficient evidence to determine that the method can reduce the leak rate. PMID- 26968865 TI - Comparison of Serum Spec fPL(TM) and 1,2-o-Dilauryl-Rac-Glycero-3-Glutaric Acid (6'-Methylresorufin) Ester Assay in 60 Cats Using Standardized Assessment of Pancreatic Histology. AB - BACKGROUND: Feline pancreas-specific lipase (Spec fPL) is considered a useful test for the antemortem diagnosis of pancreatitis in cats. A recent study found good agreement between the results of the Spec fPL and catalytic 1,2-o-dilauryl rac-glycero-3-glutaric acid-(6'-methylresorufin) ester (DGGR) lipase assay. Prospective studies evaluating their sensitivity and specificity are lacking. OBJECTIVES: To compare the results of the Spec fPL and the DGGR assays with a standardized histologic assessment of the pancreas. ANIMALS: Sixty client-owned cats presented for necropsy. METHODS: PROSPECTIVE STUDY: Spec fPL concentrations and serum DGGR lipase activity were measured from the same blood sample. The pancreas was removed within 3 hours after euthanasia; serial transverse sections were made every 0.5 cm throughout the entire pancreas and reviewed using a histologic grading scheme. Sensitivity and specificity for the Spec fPL and DGGR assay results were determined. RESULTS: The sensitivity and specificity for the Spec fPL assay (cutoff value >=5.4 MUg/L) was 42.1 [95% confidence interval (95% CI), 29.4-55.9%] and 100% (95% CI, 31.0-100.0%). The sensitivity and specificity for the DGGR assay (cutoff value >26 U/L) was 36.8 (95% CI, 24.7-50.7%) and 100% (95% CI, 31.0-100.0%). When lymphocytic inflammation up to 10% of a section was considered normal, the sensitivity and specificity for Spec fPL assay (cutoff value >=5.4 MUg/L) was 61.1 (95% CI, 36.1-81.7%) and 69.0% (95% CI, 52.8-81.9%) and the sensitivity and specificity for the DGGR assay (cutoff value >26 U/L) was 66.7 (95% CI, 41.2-85.6%) and 78.6% (95% CI, 62.8-89.2%). CONCLUSIONS AND CLINICAL IMPORTANCE: Both lipase assays performed similarly well, but their agreement with histologic pancreatic inflammation was limited. PMID- 26968866 TI - Testing models of peripheral encoding using metamerism in an oddity paradigm. AB - Most of the visual field is peripheral, and the periphery encodes visual input with less fidelity compared to the fovea. What information is encoded, and what is lost in the visual periphery? A systematic way to answer this question is to determine how sensitive the visual system is to different kinds of lossy image changes compared to the unmodified natural scene. If modified images are indiscriminable from the original scene, then the information discarded by the modification is not important for perception under the experimental conditions used. We measured the detectability of modifications of natural image structure using a temporal three-alternative oddity task, in which observers compared modified images to original natural scenes. We consider two lossy image transformations, Gaussian blur and Portilla and Simoncelli texture synthesis. Although our paradigm demonstrates metamerism (physically different images that appear the same) under some conditions, in general we find that humans can be capable of impressive sensitivity to deviations from natural appearance. The representations we examine here do not preserve all the information necessary to match the appearance of natural scenes in the periphery. PMID- 26968867 TI - To reuse or not to reuse - that is the question. AB - Aims and intended learning outcomes The aim of this article is to develop or update nurses' knowledge of the legal, professional and ethical issues relating to the reuse of products that are designed and designated for single use. Nurses are becoming increasingly responsible for risk management and an awareness of the implications for nursing practice of reusing single use products is paramount. The potential benefits and disadvantages of reuse are discussed to help nurses make informed, objective decisions that focus on ensuring that practice is safe, as well as cost effective. After reading this article you should be able to: ? Explain what is meant by reuse and how it relates to nursing practice. ? Suggest examples from nursing practice of potentially hazardous reuse. ? Discuss the potential benefits and disadvantages of reuse. ? Outline the legal, professional and ethical considerations relating to reuse. ? Critically examine your own practice and identify potential risks relating to reuse. PMID- 26968868 TI - Synthesis of isotopically labeled daclatasvir for use in human clinical studies. AB - Daclatasvir is a novel hepatitis C virus NS5A inhibitor developed by Bristol Myers Squibb and marketed as Daklinza(r). The need to support the development of daclatasvir required the synthesis of carbon-14 labeled material for use in human absorption, distribution, metabolism, and excretion studies. A total of 7.53 mCi of [(14) C]-daclatasvir was synthesized in eight steps from commercially available [(14) C]-copper cyanide. The radiochemical purity was 99.6%, and specific activity was 3.86 MUCi/mg. To support a human absolute bioavailability study, 5.56 g of [(13) C2 , (15) N4 ]-daclatasvir was synthesized in four steps. PMID- 26968869 TI - Two Distinct Stimulus Frequencies Delivered Simultaneously at Low Intensity Generate Robust Locomotor Patterns. AB - OBJECTIVES: Explore the primary characteristics of afferent noisy stimuli, which optimally activate locomotor patterns at low intensity. MATERIALS AND METHODS: Intracellular and extracellular electrophysiological traces were derived from single motoneurons and from ventral roots, respectively. From these recordings, we obtained noisy stimulating protocols, delivered to a dorsal root (DR) of an isolated neonatal rat spinal cord, while recording fictive locomotion (FL) from ventral roots. RESULTS: We decreased complexity of efficient noisy stimulating protocols down to single cell spikes. Then, we identified four main components within the power spectrum of these signals and used them to construct a basic multifrequency protocol of rectangular impulses, able to induce FL. Further disassembling generated the minimum stimulation paradigm that activated FL, which consisted of a pair of 35 and 172 Hz frequency pulse trains, strongly effective at low intensity when delivered either jointly to one lumbosacral DR or as single simultaneous trains to two distinct DRs. This simplified pulse schedule always activated a locomotor rhythm, even when delivered for a very short time (500 ms). One prerequisite for the two-frequency protocol to activate FL at low intensity when applied to sacrocaudal afferents was the ability to induce ascending volleys of greater amplitude. CONCLUSION: Multifrequency protocols can support future studies in defining the most effective characteristics for electrical stimulation to reactivate stepping following motor injury. PMID- 26968870 TI - Ethics and social acceptability of a proposed clinical trial using maternal gene therapy to treat severe early-onset fetal growth restriction. AB - OBJECTIVE: To evaluate the ethical and social acceptability of a proposed clinical trial using maternal uterine artery vascular endothelial growth factor (VEGF) gene therapy to treat severe early-onset fetal growth restriction (FGR) in pregnant women. METHODS: We conducted a literature review on the ethics and legality of experimental treatments in pregnant women, in particular advanced therapeutics. Issues that were identified from the literature helped develop interview guides for semistructured, qualitative interviews, carried out in four European countries, with 34 key stakeholders (disability groups, professional bodies and patient support groups) and 24 women/couples who had experienced a pregnancy affected by severe early-onset FGR. RESULTS: The literature review identified two main questions: 'is it ethical to give a pregnant woman a potentially risky treatment from which she does not benefit directly?' and 'is it ethical to treat a condition of the unborn child, who may then be born with a serious disability when, without treatment, they would have died?'. The review concluded that there were no ethical or legal objections to the intervention, or to a trial of this intervention. Overall, respondents viewed the proposed trial in positive terms. Women were generally interested in participating in clinical trials that conferred a potential benefit to their unborn child. The risk of disability of the premature child was a concern, but not considered a major stumbling block for maternal VEGF gene therapy. CONCLUSIONS: This study did not identify any fundamental or insurmountable objections to a trial of maternal gene therapy for severe early-onset FGR. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26968872 TI - A case of a large splenic epithelial cyst. PMID- 26968871 TI - Production of CCL20 from lung cancer cells induces the cell migration and proliferation through PI3K pathway. AB - Tumour inflammatory microenvironment is considered to play a role in the sensitivity of tumour cells to therapies and prognosis of patients with lung cancer. The expression of CCL20, one of the critical chemoattractants responsible for inflammation cells recruitment, has been shown overexpressed in variety of tumours. This study aimed at investigating potential mechanisms of CCL20 function and production in human non-small cell lung cancer (NSCLC). Expression of CCL20 gene and protein in lung tissues of patients with NSCLC and NSCLC cells (A549) were determined. The interleukin (IL)-1beta-induced signal pathways in A549 and the effect of CCL20-induced A549 cell migration and proliferation were determined using migration assays and cell-alive monitoring system. Mechanisms of signal pathways involved in the migration of CCL20 were also studied. We initially found that NSCLC tumour tissues markedly overexpressed CCL20 in comparison with normal lung samples. In addition, IL-1beta could directly promote CCL20 production in lung cancer cells, which was inhibited by extracellular signal-regulated kinase (ERK)1/2 inhibitor, p38 mitogen-activated protein kinase (p38 MARP) inhibitor or PI3K inhibitors. CCL20 promoted lung cancer cells migration and proliferation in an autocrine manner via activation of ERK1/2-MAPK and PI3K pathways. Our data indicated that IL-1beta could stimulate CCL20 production from lung cancer cells through the activation of MAPKs and PI3K signal pathways, and the auto-secretion of CCL20 could promote lung cancer cell migration and proliferation through the activation of ERK and PI3K signal pathways. Our results may provide a novel evidence that CCL20 could be a new therapeutic target for lung cancer. PMID- 26968874 TI - Experimental validation of a patient-specific model of orthotic action in adolescent idiopathic scoliosis. AB - PURPOSE: Personalized modeling of brace action has potential in improving brace efficacy in adolescent idiopathic scoliosis (AIS). Model validation and simulation uncertainty are rarely addressed, limiting the clinical implementation of personalized models. We hypothesized that a thorough validation of a personalized finite element model (FEM) of brace action would highlight potential means of improving the model. METHODS: Forty-two AIS patients were included retrospectively and prospectively. Personalized FEMs of pelvis, spine and ribcage were built from stereoradiographies. Brace action was simulated through soft cylindrical pads acting on the ribcage and through displacements applied to key vertebrae. Simulation root mean squared errors (RMSEs) were calculated by comparison with the actual brace action (quantified through clinical indices, vertebral positions and orientations) observed in in-brace stereoradiographies. RESULTS: Simulation RMSEs of Cobb angle and vertebral apical axial rotation was lower than measurement uncertainty in 79 % of the patients. Pooling all patients and clinical indices, 87 % of the indices had lower RMSEs than the measurement uncertainty. CONCLUSIONS: In-depth analysis suggests that personalization of spinal functional units mechanical properties could improve the simulation's accuracy, but the model gave good results, thus justifying further research on its clinical application. PMID- 26968873 TI - The role of preoperative vascular embolization in surgery for metastatic spinal tumours. AB - PURPOSE: To determine the effect of preoperative embolization on intraoperative blood loss in surgery for metastatic spinal tumours stratified by tumour type, type of surgical approach and extent of surgery. METHODS: We retrospectively analysed 218 patients undergoing open surgery for metastatic spine tumours in our institution between 2005 and 2014. The cohort was divided to those who underwent preoperative embolization and those who did not. The patients were further stratified into different subgroups by tumour types, types of surgical procedure, levels of instrumentation and levels of decompression. Estimated blood loss, duration of surgery and length of hospital stay were compared between embolized and non-embolized cases in each subgroup. The impact of embolization extent, the time gap between embolization and index surgery on blood loss were also studied. RESULTS: Preoperative embolization was performed in 45 out of 218 patients. Non embolized cases had insignificantly lesser blood loss and shorter duration of surgery compared to embolized cases in all subgroups. Embolization, however, conferred reduction in length of hospital stay in some of the subgroups, yet the differences were not significant. The patients who achieved total embolization bled less than those who achieved subtotal or partial embolization. The effectiveness of the embolization procedure in reducing intraoperative blood loss was found to be profound when the gap between embolization and surgery was within 24 h. CONCLUSIONS: Our study demonstrated that success of embolization in reducing blood loss depends on the extent of embolization and time interval between embolization and index surgery. PMID- 26968875 TI - Adjacent segment degeneration after lumbar spinal fusion compared with motion preservation procedures: a meta-analysis. AB - PURPOSE: This meta-analysis aimed to evaluate the efficacy of motion-preservation procedures to prevent the adjacent segment degeneration (ASDeg) or adjacent segment disease (ASDis) compared with fusion in lumbar spine. METHODS: PubMed, Embase and the Cochrane Library were comprehensively searched and a meta-analysis was performed of all randomized controlled trials and well designed prospective or retrospective comparative cohort studies assessing the lumbar fusion and motion-preservation procedures. We compared the ASDeg and ASDis rate, reoperation rate, operation time, blood loss, length of hospital stay, visual analogue scale (VAS) and oswestry disability index (ODI) improvement of the two procedures. RESULTS: A total of 15 studies consisting of 1474 patients were included in this study. The meta-analysis indicated that the prevalence of ASDeg, ASDis and reoperation rate on the adjacent level were lower in motion-preservation procedures group than in the fusion group (P = 0.001; P = 0.0004; P < 0.0001). Moreover, shorter length of hospital stay was found in motion-preservation procedures group (P < 0.0001). No difference was found in terms of operation time (P = 0.57), blood loss (P = 0.27), VAS (P = 0.76) and ODI improvement (P = 0.71) between the two groups. CONCLUSIONS: The present evidences indicated that the motion-preservation procedures had an advantage on reducing the prevalence of ASDeg, ASDis and the reoperation rate due to the adjacent segment degeneration compared with the lumbar fusion. And the clinical outcomes of the two procedures are similar. PMID- 26968876 TI - Comparison of a zero-profile anchored spacer (ROI-C) and the polyetheretherketone (PEEK) cages with an anterior plate in anterior cervical discectomy and fusion for multilevel cervical spondylotic myelopathy. AB - PURPOSE: We aimed to analyze the clinical and radiographic efficacy of a new zero profile anchored spacer called the ROI-C in anterior discectomy and fusion (ACDF) for multilevel cervical spondylotic myelopathy (MCSM). METHOD: We retrospectively reviewed the clinical, radiological outcomes and complications of multilevel ACDF with the ROI-C or with the polyetheretherketone (PEEK) cages with an anterior plate. From April 2011 to April 2014, 60 patients with MCSM were operated on using ACDF, with the ROI-C in 28 patients and PEEK cages with an anterior plate in 32 patients. The operative time, intraoperative blood loss, and clinical and radiological results were compared between the ROI-C group and the cage-plate group. RESULTS: The mean follow-up time was 23.8 +/- 6.6 months, ranging from 12 to 36 months. At the first month and the last follow-up, the neck disability index (NDI) scores were decreased, and the Japanese Orthopedic Association (JOA) scores were significantly increased, compared with the presurgical measurements in both groups. There were no significant differences in NDI scores or JOA scores between the two groups (P > 0.05), but there were significant differences in the operation time, blood loss and the presence of dysphagia (P < 0.05). In addition, the cervical Cobb angle and disk height showed significant corrections, compared to those measured before the operation. There was no adjacent disc degeneration observed in the ROI-C group, and one patient with skip levels showed disc degeneration of the normal level between the skip levels in the cage-plate group. The degeneration rate of the cage-plate group was 3.1 %. CONCLUSIONS: The primary clinical and radiographic efficacies of both ROI-C and cages with plates in ACDF for MCSM were satisfactory; both approaches could improve and maintain cervical lordosis and disk height. However, the ROI-C was associated with a simpler operation, a shorter operation time, less blood loss, and a lower risk of postoperative dysphagia compared to the PEEK cage with an anterior plate. PMID- 26968877 TI - The prevalence of neuromuscular disease in the paediatric population in Yorkshire, UK; variation by ethnicity and deprivation status. AB - AIM: Previous studies suggest a higher prevalence of neurological disease within certain ethnic communities, but have not specifically considered neuromuscular diseases (NMDs). The aim of this study was to calculate the prevalence and relationship of NMDs to ethnicity and deprivation status. METHOD: We undertook a retrospective case-note review of those younger than 16 years with a confirmed diagnosis of NMD in a single centre in Yorkshire in 2010. RESULTS: Two-hundred and sixty-one cases were included. The population (0-16y) in Yorkshire was 707 961. The overall prevalence was 36.9 per 100 000 (95% confidence interval [CI] 34.6-39.1). Dystrophin-related muscle disease was the most common condition, with a prevalence of 16.9 per 100 000 males (95% CI 14.7-19.1). There was a significant difference between ethnic groups, with a total NMD prevalence of 91.2 per 100 000 (95% CI 81.6-100.7) in the South Asian ethnic group compared with 28.7 per 100 000 (95% CI 26.4-30.9) in the White group. Prevalence of non dystrophin-related NMDs was four times higher in South Asian than in White children. There was a linear relation between increased prevalence and increased deprivation. INTERPRETATION: This study confirms higher levels of NMD, particularly recessively inherited NMDs within the South Asian population, as well as a link with higher deprivation. This has implications for service provision and resource allocation. PMID- 26968878 TI - Synthesis and Applications of pi-Extended Naphthalene Diimides. AB - Naphthalene diimides have received much attention due to their high electron affinities, high electron mobility, and good thermal and oxidative stability, therefore making them promising candidates for a variety of organic electronic applications. However, pi-extended naphthalene diimides with lower HOMO-LUMO gaps and higher stability have only been developed recently because of the synthetic difficulties. This account describes recent developments in the structures, synthesis, properties, and applications of pi-extended naphthalene diimides, including pure-carbon and heterocyclic acene diimides, from our research group. PMID- 26968881 TI - Metronidazole in conjunction with penicillin neither prevents recurrence nor enhances recovery from peritonsillar abscess when compared with penicillin alone: a prospective, double-blind, randomized, placebo-controlled trial. AB - OBJECTIVES: The objectives of this study were to evaluate the efficacy of metronidazole in conjunction with penicillin in preventing the recurrence of peritonsillar abscess (PTA) and to learn whether metronidazole enhances the recovery from PTA when compared with penicillin alone. METHODS: In this prospective, double-blind, randomized, placebo-controlled trial, 200 adult outpatients with PTA at our ear, nose and throat emergency department received either penicillin (1 000 000IU) * 3 and metronidazole (400 mg) * 3 for 10 and 7 days orally (combination group, N = 100) or penicillin and placebo (penicillin group, N = 100) after incision and drainage of the PTA. Afterwards they received a symptom questionnaire via e-mail daily for 2 weeks, then weekly for 6 weeks. The primary outcome was efficacy of metronidazole in conjunction with penicillin in preventing PTA recurrence in 56 days; the secondary outcome was ability of metronidazole plus penicillin to enhance recovery from PTA in 28 days. All healthcare contacts were registered during follow-up. Registered on www.clinicaltrials.gov with the identifier NCT01255670. RESULTS: Of the 200 patients, 20 returned to hospital with recurrent symptoms, 10 in each group (P = 1.00). In the combination group, the mean (SD) duration of throat-related symptoms was 5.6 (5.0) days and in the penicillin group it was 5.3 (2.7) days, values for fever were 1.5 (0.9) and 1.6 (1.0) days, respectively, and those for poor overall physical condition were 4.0 (3.9) and 4.5 (4.9) days; there were no significant differences between groups. The adverse effects nausea and diarrhoea lasted longer in the combination group (P = 0.01). CONCLUSIONS: For healthy adult PTA patients treated with incision and drainage, metronidazole neither prevents recurrence nor enhances recovery when combined with penicillin compared with penicillin alone, but instead leads to increased adverse effects. PMID- 26968879 TI - Web-Based Interventions Targeting Cardiovascular Risk Factors in Middle-Aged and Older People: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Web-based interventions can improve single cardiovascular risk factors in adult populations. In view of global aging and the associated increasing burden of cardiovascular disease, older people form an important target population as well. OBJECTIVE: In this systematic review and meta analysis, we evaluated whether Web-based interventions for cardiovascular risk factor management reduce the risk of cardiovascular disease in older people. METHODS: Embase, Medline, Cochrane and CINAHL were systematically searched from January 1995 to November 2014. Search terms included cardiovascular risk factors and diseases (specified), Web-based interventions (and synonyms) and randomized controlled trial. Two authors independently performed study selection, data extraction and risk of bias assessment. In a meta-analysis, outcomes regarding treatment effects on cardiovascular risk factors (blood pressure, glycated hemoglobin A1c (HbA1C), low-density lipoprotein (LDL) cholesterol, smoking status, weight and physical inactivity) and incident cardiovascular disease were pooled with random effects models. RESULTS: A total of 57 studies (N=19,862) fulfilled eligibility criteria and 47 studies contributed to the meta-analysis. A significant reduction in systolic blood pressure (mean difference -2.66 mmHg, 95% CI -3.81 to -1.52), diastolic blood pressure (mean difference -1.26 mmHg, 95% CI 1.92 to -0.60), HbA1c level (mean difference -0.13%, 95% CI -0.22 to -0.05), LDL cholesterol level (mean difference -2.18 mg/dL, 95% CI -3.96 to -0.41), weight (mean difference -1.34 kg, 95% CI -1.91 to -0.77), and an increase of physical activity (standardized mean difference 0.25, 95% CI 0.10-0.39) in the Web-based intervention group was found. The observed effects were more pronounced in studies with short (<12 months) follow-up and studies that combined the Internet application with human support (blended care). No difference in incident cardiovascular disease was found between groups (6 studies). CONCLUSIONS: Web based interventions have the potential to improve the cardiovascular risk profile of older people, but the effects are modest and decline with time. Currently, there is insufficient evidence for an effect on incident cardiovascular disease. A focus on long-term effects, clinical endpoints, and strategies to increase sustainability of treatment effects is recommended for future studies. PMID- 26968880 TI - Trough concentration of voriconazole and its relationship with efficacy and safety: a systematic review and meta-analysis. AB - OBJECTIVES: The optimum trough concentration of voriconazole for clinical response and safety is controversial. The objective of this review was to determine the optimum trough concentration of voriconazole and evaluate its relationship with efficacy and safety. METHODS: MEDLINE, EMBASE, ClinicalTrials.gov, the Cochrane Library and three Chinese literature databases were searched. Observational studies that compared clinical outcomes below and above the trough concentration cut-off value were included. We set the trough concentration cut-off value for efficacy as 0.5, 1.0, 1.5, 2.0 and 3.0 mg/L and for safety as 3.0, 4.0, 5.0, 5.5 and 6.0 mg/L. The efficacy outcomes were invasive fungal infection-related mortality, all-cause mortality, rate of successful treatment and rate of prophylaxis failure. The safety outcomes included incidents of hepatotoxicity, neurotoxicity and visual disorders. RESULTS: A total of 21 studies involving 1158 patients were included. Compared with voriconazole trough concentrations of >0.5 mg/L, levels of <0.5 mg/L significantly decreased the rate of treatment success (risk ratio = 0.46, 95% CI 0.29-0.74). The incidence of hepatotoxicity was significantly increased with trough concentrations >3.0, >4.0, >5.5 and >6.0 mg/L. The incidence of neurotoxicity was significantly increased with trough concentrations >4.0 and >5.5 mg/L. CONCLUSIONS: A voriconazole level of 0.5 mg/L should be considered the lower threshold associated with efficacy. A trough concentration >3.0 mg/L is associated with increased hepatotoxicity, particularly for the Asian population, and >4.0 mg/L is associated with increased neurotoxicity. PMID- 26968882 TI - Prospective evaluation of the OXA-48 K-SeT assay, an immunochromatographic test for the rapid detection of OXA-48-type carbapenemases. AB - OBJECTIVES: There is an urgent need for accurate and fast diagnostic tests to identify MDR bacteria. Here, we evaluated an immunochromatographic assay (the OXA 48 K-SeT assay) to detect OXA-48-like carbapenemase-producing Enterobacteriaceae from culture colonies. METHODS: One hundred and sixty-one collection isolates with characterized beta-lactamase content and 185 non-duplicate consecutive clinical isolates referred to the Associated French National Reference Center between 15 February and 15 March 2015 were used to evaluate the OXA-48 K-SeT assay. Among these 346 isolates, 100 were OXA-48-like carbapenemase producers, 3 were OXA-48-like producers lacking carbapenemase activity and 243 were ESBL, AmpC, oxacillinase and/or non-OXA-48 carbapenemase producers. RESULTS: All 100 OXA-48-like carbapenemase producers were correctly detected by the OXA-48 K-SeT assay, including OXA-48 (n = 73), OXA-181 (n = 18), OXA-162 (n = 1), OXA-204 (n = 4), OXA-232 (n = 2) and OXA-244 (n = 2) variants. The three OXA-48 variants lacking carbapenemase activity, OXA-163 (n = 2) and OXA-405 (n = 1), were not detected. All non-OXA-48 producers gave a negative result with the OXA-48 K-SeT assay. No cross-reaction was evidenced with the carbapenemases (VIM, IMP, NDM and KPC), ESBLs (TEM, SHV and CTX-M), AmpCs (CMY-2, DHA-2 and ACC-1) and oxacillinases (OXA-1, -2, -9 and -10). Overall, the sensitivity and specificity of the assay were 100% for OXA-48-like carbapenemase detection. CONCLUSIONS: The OXA-48 K-SeT assay was efficient, rapid and easy to implement in the routine workflow of a clinical microbiology laboratory for the confirmation of OXA-48 like carbapenemase-producing Enterobacteriaceae. It could complete the existing panel of tests available for the confirmation of OXA-48-like carbapenemases, especially in countries with high OXA-48 prevalence. PMID- 26968884 TI - Whole-genome typing and characterization of blaVIM19-harbouring ST383 Klebsiella pneumoniae by PFGE, whole-genome mapping and WGS. AB - OBJECTIVES: We utilized whole-genome mapping (WGM) and WGS to characterize 12 clinical carbapenem-resistant Klebsiella pneumoniae strains (TGH1-TGH12). METHODS: All strains were screened for carbapenemase genes by PCR, and typed by MLST, PFGE (XbaI) and WGM (AflII) (OpGen, USA). WGS (Illumina) was performed on TGH8 and TGH10. Reads were de novo assembled and annotated [SPAdes, Rapid Annotation Subsystem Technology (RAST)]. Contigs were aligned directly, and after in silico AflII restriction, with corresponding WGMs (MapSolver, OpGen; BioNumerics, Applied Maths). RESULTS: All 12 strains were ST383. Of the 12 strains, 11 were carbapenem resistant, 7 harboured blaKPC-2 and 11 harboured blaVIM-19. Varying the parameters for assigning WGM clusters showed that these were comparable to STs and to the eight PFGE types or subtypes (difference of three or more bands). A 95% similarity coefficient assigned all 12 WGMs to a single cluster, whereas a 99% similarity coefficient (or >=10 unmatched-fragment difference) assigned the 12 WGMs to eight (sub)clusters. Based on a difference of three or more bands between PFGE profiles, the Simpson's diversity indices (SDIs) of WGM (0.94, Jackknife pseudo-values CI: 0.883-0.996) and PFGE (0.93, Jackknife pseudo-values CI: 0.828-1.000) were similar (P = 0.649). However, the discriminatory power of WGM was significantly higher (SDI: 0.94, Jackknife pseudo values CI: 0.883-0.996) than that of PFGE profiles typed on a difference of seven or more bands (SDI: 0.53, Jackknife pseudo-values CI: 0.212-0.849) (P = 0.007). CONCLUSIONS: This study demonstrates the application of WGM to understanding the epidemiology of hospital-associated K. pneumoniae. Utilizing a combination of WGM and WGS, we also present here the first longitudinal genomic characterization of the highly dynamic carbapenem-resistant ST383 K. pneumoniae clone that is rapidly gaining importance in Europe. PMID- 26968883 TI - Emergence of a small colony variant of vancomycin-intermediate Staphylococcus aureus in a patient with septic arthritis during long-term treatment with daptomycin. AB - OBJECTIVES: Small colony variants (SCVs) of Staphylococcus aureus are associated with persistent and drug-resistant infections. We demonstrated for the first time the emergence of SCVs in a patient with vancomycin-intermediate S. aureus (VISA) infection during long-term treatment with daptomycin. METHODS: A 73-year-old man with septic arthritis was infected with VISA. The patient was treated with daptomycin; however, the patient remained infected with VISA, with continuous isolation of VISA from his blood during long-term treatment. Five VISA isolates were characterized by: PFGE; genotyping including staphylococcal cassette chromosome mec (SCCmec), spa and MLST; antimicrobial susceptibility testing; and scanning and transmission electron microscopy. WGS and fatty acid analysis were also performed. RESULTS: The five VISA isolates were from a single clone of ST239/spa3(t037) and, of these, the first three were SCCmecIII positive and daptomycin susceptible, whereas the last two were SCCmecIII negative and daptomycin resistant and exhibited the characteristics of SCVs. The first and last isolates showed 13 remarkable genetic differences in SCCmec and the mprF, cls2, clpX and fabF genes. Of these, mutation of fabF (encoding the fatty acid synthase) seemed to be partially responsible for the slow growth and ultrastructural features, including an abnormal intercellular substance, and for the daptomycin resistance of SCVs. CONCLUSIONS: For the first time, we identified SCVs of VISA in a patient with septic arthritis during long-term treatment with daptomycin. Daptomycin-resistant SCVs of VISA were evolved in a stepwise manner and the mutation of fabF is likely responsible for the physical and ultrastructural characteristics and daptomycin resistance. PMID- 26968885 TI - Exhaled Breath Analysis for Monitoring Response to Treatment in Advanced Lung Cancer. AB - INTRODUCTION: The Response Evaluation Criteria in Solid Tumors (RECIST) serve as the accepted standard to monitor treatment efficacy in lung cancer. However, the time intervals between consecutive computerized tomography scans might be too long to allow early identification of treatment failure. This study examines the use of breath sampling to monitor responses to anticancer treatments in patients with advanced lung cancer. METHODS: A total of 143 breath samples were collected from 39 patients with advanced lung cancer. The exhaled breath signature, determined by gas chromatography/mass spectrometry and a nanomaterial-based array of sensors, was correlated with the response to therapy assessed by RECIST: complete response, partial response, stable disease, or progressive disease. RESULTS: Gas chromatography/mass spectrometry analysis identified three volatile organic compounds as significantly indicating disease control (PR/stable disease), with one of them also significantly discriminating PR/stable disease from progressive disease. The nanoarray had the ability to monitor changes in tumor response across therapy, also indicating any lack of further response to therapy. When one-sensor analysis was used, 59% of the follow-up samples were identified correctly. There was 85% success in monitoring disease control (stable disease/partial response). CONCLUSION: Breath analysis, using mainly the nanoarray, may serve as a surrogate marker for the response to systemic therapy in lung cancer. As a monitoring tool, it can provide the oncologist with a quick bedside method of identifying a lack of response to an anticancer treatment. This may allow quicker recognition than does the current RECIST analysis. Early recognition of treatment failure could improve patient care. PMID- 26968887 TI - Bioaccumulation and analytics of pharmaceutical residues in the environment: A review. AB - The presence of pharmaceutical residues in various environmental compartments is an issue of increasing concern. The widespread occurrence of these compounds in water and soil samples has been demonstrated in a number of analytical studies. However, the data about their concentrations in biota samples is scarce. Moreover, the trophic transfer of pharmaceuticals remains largely unexplored, despite increasing evidence of the potential bioaccumulation of those compounds. Therefore, the main aim of this review is to present an overview of the current state of data about the bioaccumulation and analytical methodologies used for the determination of pharmaceutical residues in biota samples. This work focuses on the most commonly found pharmaceuticals in the environment: antibiotics, analgesic and anti-inflammatory drugs, steroid hormones, antihypertensives and antidepressants. We do hope that the collected data will allow a better understanding of pharmaceutical pollution and the exposure of non-target organisms. However, although impressive progress has undoubtedly been made, in order to fully understand the behavior of these chemicals in the environment, there are still numerous gaps to be filled in our overall knowledge in this field. PMID- 26968888 TI - Quantitative structure-retention relationship of selected imidazoline derivatives on alpha1-acid glycoprotein column. AB - The retention behaviour of 22 selected imidazoline drugs and derivatives was investigated on alpha1-acid glycoprotein (AGP) column using Sorensen phosphate buffer (pH 7.0) and 2-propanol as organic modifier. Quantitative Structure Retention Relationships (QSRR) models were built using extrapolated logkw values as well as isocratic retention factors (logk5, logk8, logk10, logk12, logk15 obtained for 5%, 8%, 10%, 12%, and 15%, of 2-propanol in mobile phase, respectively) as dependant variables and calculated physicochemical parameters as independant variables. The established QSRR models were built by stepwise multiple linear regression (MLR) and partial least squares regression (PLS). The performance of the stepwise and PLS models was tested by cross-validation and the external test set prediction. The validated QSRR models were compared and the optimal PLS-QSRR model for logkw and each isocratic retention factors (PLS QSRR(logk5), PLS-QSRR(logk8), PLS-QSRR(logk10), MLR-QSRR(logk12), MLR QSRR(logk15)) were selected. The QSRR results were further confirmed by Linear Solvation Energy Relationships (LSER). LSER analysis indicated on hydrogen bond basicity, McGowan volume and excess molar refraction as the most significant parameters for all AGP chromatographic retention factors and logkw values of 22 selected imidazoline drugs and derivatives. PMID- 26968886 TI - Rare renal ciliopathies in non-consanguineous families that were identified by targeted resequencing. AB - BACKGROUND: Nephronophthisis-related ciliopathies (NPHP-RC) are a frequent cause of renal failure for children and adolescents. Although diagnosing these diseases clinically is difficult, a comprehensive genetic screening approach of targeted resequencing can uncover the genetic background in this complicated family of diseases. METHODS: We studied three Japanese female patients with renal insufficiency from non-consanguineous parents. A renal biopsy for clinical reasons was not performed. Therefore, we did not know the diagnosis of these patients from a clinical aspect. We performed comprehensive genetic analysis using the TruSight One Sequencing Panel next generation sequencing technique. RESULTS: We identified three different rare NPHP-RC variants in the following genes: SDCCAG8, MKKS, and WDR35. Patient 1 with SDCCAG8 homozygous deletions showed no ciliopathy-specific extrarenal manifestations, such as retinitis pigmentosa or polydactyly prior to genetic analysis. Patient 2 with a MKKS splice site homozygous mutation and a subsequent 39-amino acid deletion in the substrate binding apical domain, had clinical symptoms of Bardet-Biedl syndrome. She and her deceased elder brother had severe renal insufficiency soon after birth. Patient 3 with a compound heterozygous WDR35 mutation had ocular coloboma and intellectual disability. CONCLUSIONS: Our results suggest that a comprehensive genetic screening system using target resequencing is useful and non-invasive for the diagnosis of patients with an unknown cause of pediatric end-stage renal disease. PMID- 26968890 TI - Study of pathway cross-talk interactions with NF-kappaB leading to its activation via ubiquitination or phosphorylation: A brief review. AB - NFkappaB has been known to be a necessary transcription factor for the functioning of nearly all cells in a living organism. For its proper functioning, it talks to several other molecular cofactors and interacts with their functionalities resulting in a convoluted cross talking mesh of signalling networks. To completely understand the working of nuclear factor-kappa B protein, one needs to understand the interactions that occur during its lifecycle, with cofactors from various biological processes. This study attempts to elaborate and bridge the gaps on the cross-talk interactions that NFkB is a part of, during its activation pathway. For this Cytoscape and its various plugins (Cytocopter, Allegro, AgilentLitSearch and Styles) are employed. Other related pathways were also collated and analysed for cross-talk between NfkappaB and interacting molecules. NFkappaB was found to mainly interact with E3 ubiquitin ligase, NIK, RIP, TCR, IRAK-1, TLR, TRAF-6, NLR and IL-1, details of which are discussed as a part of this study. PMID- 26968889 TI - Identification of NUCKS1 as a putative oncogene and immunodiagnostic marker of hepatocellular carcinoma. AB - Although the molecular mechanisms underpinning hepatocellular carcinoma (HCC) are unknown, gene copy number and associated mRNA expression changes are frequently reported. Comparative genomic hybridization arrays spotted with 4041 bacterial artificial chromosome clones were used to assess copy number changes in 45 HCC tissues. Seventy more HCC tissues were used to validate candidate genes by using western blots and immunohistochemistry. A total of 259 clones were associated with copy number changes that significantly differed between normal liver and HCC samples. The chromosomal region 1q32.1 containing the nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) gene was associated with tumor vascular invasion. Western blot analysis demonstrated that NUCKS1 was up regulated in 37 of 70 (52.8%) HCC tissues compared with adjacent non-tumor tissues, and over-expressed in a vast majority of HCCs (44/52, 84.6%) as determined by immunohistochemical staining. Furthermore, immunostaining of both NUCKS1 and glypican-3 improved the diagnostic prediction of HCC. Knock-down of NUCKS1 by siRNA implied the decrease in cell viability of the Hep3B cell line and reduced tumor formation in a xenograft mouse model. NUCKS1 was identified as a potential oncogene at chromosomal 1q32.1 in patients with HCC, and it might be a valuable immunodiagnostic marker for HCC. PMID- 26968891 TI - Comprehensive selection of reference genes for expression studies in meniscus injury using quantitative real-time PCR. AB - The meniscus plays critical roles in the knee function. Meniscal tears can lead to knee osteoarthritis. Gene expression analysis may be a useful tool for understanding meniscus tears, and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) has become an effective method for such studies. However, this technique requires the use of suitable reference genes for data normalization. We evaluated the suitability of six reference genes (18S, ACTB, B2M, GAPDH, HPRT1 and TBP) using meniscus samples of (1) 19 patients with isolated meniscal tears, (2) 20 patients with meniscal tears and combined anterior cruciate ligament injury (ACL), and (3) 11 controls without meniscal tears. The stability of the candidate reference genes was determined using the NormFinder, geNorm, BestKeeper DataAssist and RefFinder software packages and comparative DeltaCt method. Overall, HPRT1 was the best single reference gene. However, GenEx software demonstrated that two or more reference genes should be used for gene expression normalization, which was confirmed when we evaluated TGFbetaR1 expression using several reference gene combinations. HPRT1+TBP was the most frequently identified pair from the analysis of samples of (1) meniscal tear samples of patients with a concomitant ACL tears, (2) all meniscal tears, and (3) all samples. HPRT1+GAPDH was the most frequently identified pair from the analysis of samples of isolated meniscal tear samples and controls. In the analysis involving only controls, GAPDH+18S was the most frequently identified pair. In the analysis of only isolated meniscal tear samples and in the analysis of meniscal tear samples of patients with concomitant ACL tears and controls, both HPRT1+TBP and HPRT1+GAPDH were identified as suitable pairs. If the gene expression study aims to compare non-injured meniscus, isolated meniscal tears and meniscal tears of patients with ACL tears as three independent groups, the trio of HPRT1+TBP+GAPDH is the most suitable combination of reference genes. PMID- 26968892 TI - Genetic variability in E6, E7, and L1 genes of human papillomavirus genotype 52 from Southwest China. AB - Human papillomavirus (HPV) is the major causative agent of cervical cancer, which accounts for the second highest cancer burden in women worldwide. HPV-52, the prevalent subtype in Asia, especially in southwest China, was analyzed in this study. To analyze polymorphisms, intratypic variants, and genetic variability in the E6-E7 (n=26) and L1 (n=53) genes of HPV-52, these genes were sequenced and the sequences were submitted to GenBank. Phylogenetic trees were constructed using the neighbor-joining and Kimura 2-parameters methods, followed by analysis of the diversity of secondary structure. Finally, we estimated the selection pressures acting on the E6-E7 and L1 genes. Fifty-one novel variants of HPV-52 L1, and two novel variants of HPV-52 E6-E7 were identified in this study. Thirty single nucleotide changes were observed in HPV-52 E6-E7 sequences with 19/30 non synonymous mutations and 11/30 synonymous mutations (five in the alpha helix and five in the beta sheet). Fifty-five single nucleotide changes were observed in HPV-52 L1 sequences with 17/55 non-synonymous mutations (seven in the alpha helix and fourteen in the beta sheet) and 38/55 synonymous mutations. Selective pressure analysis predicted that most of these mutations reflect positive selection. Identifying new variants in HPV-52 may inform the rational design of new vaccines specifically for women in southwest China. Knowledge of genetic variation in HPV may be useful as an epidemiologic correlate of cervical cancer risk, or may even provide critical information for developing diagnostic probes. PMID- 26968893 TI - From the desktop to the grid: scalable bioinformatics via workflow conversion. AB - BACKGROUND: Reproducibility is one of the tenets of the scientific method. Scientific experiments often comprise complex data flows, selection of adequate parameters, and analysis and visualization of intermediate and end results. Breaking down the complexity of such experiments into the joint collaboration of small, repeatable, well defined tasks, each with well defined inputs, parameters, and outputs, offers the immediate benefit of identifying bottlenecks, pinpoint sections which could benefit from parallelization, among others. Workflows rest upon the notion of splitting complex work into the joint effort of several manageable tasks. There are several engines that give users the ability to design and execute workflows. Each engine was created to address certain problems of a specific community, therefore each one has its advantages and shortcomings. Furthermore, not all features of all workflow engines are royalty-free -an aspect that could potentially drive away members of the scientific community. RESULTS: We have developed a set of tools that enables the scientific community to benefit from workflow interoperability. We developed a platform-free structured representation of parameters, inputs, outputs of command-line tools in so-called Common Tool Descriptor documents. We have also overcome the shortcomings and combined the features of two royalty-free workflow engines with a substantial user community: the Konstanz Information Miner, an engine which we see as a formidable workflow editor, and the Grid and User Support Environment, a web based framework able to interact with several high-performance computing resources. We have thus created a free and highly accessible way to design workflows on a desktop computer and execute them on high-performance computing resources. CONCLUSIONS: Our work will not only reduce time spent on designing scientific workflows, but also make executing workflows on remote high performance computing resources more accessible to technically inexperienced users. We strongly believe that our efforts not only decrease the turnaround time to obtain scientific results but also have a positive impact on reproducibility, thus elevating the quality of obtained scientific results. PMID- 26968894 TI - Insights into furanose solution conformations: beyond the two-state model. AB - A two-state model is commonly used for interpreting ring conformations of furanoses based on NMR scalar (3) J-coupling constants, with the ring populating relatively narrow distributions in the North and the South of the pseudorotation itinerary. The validity of this simple approach has been questioned, and is examined here in detail employing molecular dynamics (MD) simulations with a new GLYCAM force field parameter set for furanoses. Theoretical (3) J-coupling constants derived from unrestrained MD simulations with the new furanose-specific parameters agreed with the experimental coupling constants to within 1 Hz on average. The results confirm that a two state model is a reasonable description for the ring conformation in the majority of methyl furanosides. However, in the case of methyl alpha-D-arabinofuranoside the ring populates a continuum of states from North to South via the eastern side of the pseudorotational itinerary. Two key properties are responsible for these differences. Firstly, East and West regions in beta- and alpha-anomers, respectively, are destabilized by the absence of the anomeric effect. And, secondly, East or West conformations can be further destabilized by repulsive interactions among vicinal hydroxyl groups and ring oxygen atoms when the vicinal hydroxyl groups are in syn-configurations (such as in ribose and lyxose) more so than when in anti (arabinose, xylose). PMID- 26968896 TI - On the structural possibility of pore-forming mitochondrial FoF1 ATP synthase. AB - The mitochondrial permeability transition is an inner mitochondrial membrane event involving the opening of the permeability transition pore concomitant with a sudden efflux of matrix solutes and breakdown of membrane potential. The mitochondrial F(o)F(1) ATP synthase has been proposed as the molecular identity of the permeability transition pore. The likeliness of potential pore-forming sites in the mitochondrial F(o)F(1) ATP synthase is discussed and a new model, the death finger model, is described. In this model, movement of a p-side density that connects the lipid-plug of the c-ring with the distal membrane bending Fo domain allows reversible opening of the c-ring and structural cross-talk with OSCP and the catalytic (alphabeta)(3) hexamer. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. PMID- 26968895 TI - Resveratrol inhibits lipogenesis of 3T3-L1 and SGBS cells by inhibition of insulin signaling and mitochondrial mass increase. AB - Resveratrol is attracting much interest because of its potential to decrease body weight and increase life span, influencing liver and muscle function by increasing mitochondrial mass and energy expenditure. Even though resveratrol was already shown to reduce the adipose tissue mass in animal models, its effects on mitochondrial mass and network structure in adipocytes have not yet been studied. For this purpose, we investigated the effect of resveratrol on mitochondrial mass increase and remodeling during adipogenic differentiation of two in vitro models of adipocyte biology, the murine 3T3-L1 cell line and the human SGBS cell strain. We confirm that resveratrol inhibits lipogenesis in differentiating adipocytes, both mouse and human. We further show that this is linked to inhibition of the normally observed mitochondrial mass increase and mitochondrial remodeling. At the molecular level, the anti-lipogenic effect of resveratrol seems to be mediated by a blunted expression increase and an inhibition of acetyl-CoA carboxylase (ACC). This is one of the consequences of an inhibited insulin induced signaling via Akt, and maintained signaling via AMP-activated protein kinase. The anti-lipogenic effect of resveratrol is further modulated by expression levels of mitochondrial ATAD3, consistent with the emerging role of this protein as an important regulator of mitochondrial biogenesis and lipogenesis. Our data suggest that resveratrol acts on differentiating preadipocytes by inhibiting insulin signaling, mitochondrial biogenesis, and lipogenesis, and that resveratrol-induced reduction of mitochondrial biogenesis and lipid storage contribute to adipose tissue weight loss in animals and humans. PMID- 26968898 TI - Cooperative action of bioactive components in milk fat with PPARs may explain its anti-diabetogenic properties. AB - Type 2 diabetes and its comorbidity insulin resistance is a major public health problem in developed countries and those with the disorder have up to a fourfold increased risk of cardiovascular disease relative to those without the disease. The cardiovascular complications are believed to be due largely to multiple mechanisms relating to hyperglycemia that defines the disease. Overweight and obesity are the predominant risk factors and lifestyle changes aimed at reducing weight and increasing physical activity are the basis for prevention and treatment of type 2 diabetes. The role of diet in type 2 diabetes has been investigated widely, but the results have been inconclusive. Recently two large meta-analyses of prospective cohort studies found that dairy product consumption was inversely associated with the risk of type 2 diabetes. Numerous observational studies including large prospective studies found that a high intake of dairy fat or markers of dairy fat were inversely associated with the risk of type 2 diabetes. These observations suggest that dairy fat could contain components with anti-diabetogenic properties. Candidates for the antidiabetic affect are rumenic and vaccenic acids, phytanic and pristanic acids vitamin A and beta-carotene and butyric acid. The role of these compounds in glucose homeostasis and energy balance is discussed. A common feature is that all are agonists for one or more of the three PPAR isoforms that are expressed in metabolically active tissue, such as the liver, skeletal muscle and adipose tissue where they play a critical role in regulating energy balance and the metabolism of fatty acids and glucose, the main energy sources. Because PPARs have a larger ligand binding pocket than other nuclear receptors they can be activated by a wide range of agonists. Whereas individual components may not be present in sufficient concentration to produce a physiological effect such an effect may be obtained by several components acting in concert, and forms the basis of the hypothesis. PPAR agonists such as anthocyanidins and resveratrol present in nondairy items may also contribute to outcome. In addition, PPAR-alpha, -beta and -gamma are abundant in brown adipose tissue where agonists and cold exposure induce uncoupling protein-1 expression in the mitochondria where it acts to generate heat at the expense of storing energy. Animal studies demonstrated that most milk fat bioactive compounds induced uncoupling protein-1 expression in brown adipose tissue, which was associated with suppression of diet-induced obesity and improvement in insulin sensitivity. PMID- 26968899 TI - Insulin resistance is a two-sided mechanism acting under opposite catabolic and anabolic conditions. AB - The survival of multi-cellular organisms depends on the organism ability to maintain glucose homeostasis for time of low/high nutrient availability or high energy needs, and the ability to fight infections or stress. These effects are realized through the insulin controlled transport of blood glucose into the insulin-responsive cells such as muscle, fat and liver cells. Reduction in the ability of these cells to take glucose from the blood in response to normal circulating levels of insulin is known as insulin resistance (IR). Chronic IR is a key pathological feature of obesity, type 2 diabetes, sepsis and cancer cachexia, however temporal IR are widely met in fasting/ hibernation, pregnancy, anti-bacterial immunity, exercise and stress. Paradoxically, a certain part of the IR-cases is associated with catabolic metabolism, whereas the other is related to anabolic pathways. How can this paradoxical IR-response be explained? What is the metabolic basis of this IR variability and its physiological and pathological impacts? An answer to these questions might be achieved through the hypothesis in which IR is considered as a two-sided mechanism acting under opposite metabolic conditions (catabolism and anabolism) but with the common aim to sustain glucose homeostasis in a wide metabolic range. To test this hypothesis, I examined the main metabolic distinctions between the varied IR cases and their dependence on the blood glucose concentration, level of the IR threshold, and catabolic/anabolic activation. On the basis of the established interrelations, a simple model of IR-distribution has been developed. The model revealed the "U-type distribution" form with separation into two main IR-groups, each determined in the catabolic or anabolic conditions with one exception - type 2 diabetes and its paradoxical catabolic activation in anabolic conditions. The dual opposing (or complementary) role for the IR opens a new possibility for better understanding the cause and consequences of transition from adaptive IR responses to its pathological forms. PMID- 26968897 TI - New genes and pathomechanisms in mitochondrial disorders unraveled by NGS technologies. AB - Next Generation Sequencing (NGS) technologies are revolutionizing the diagnostic screening for rare disease entities, including primary mitochondrial disorders, particularly those caused by nuclear gene defects. NGS approaches are able to identify the causative gene defects in small families and even single individuals, unsuitable for investigation by traditional linkage analysis. These technologies are contributing to fill the gap between mitochondrial disease cases defined on the basis of clinical, neuroimaging and biochemical readouts, which still outnumber by approximately 50% the cases for which a molecular-genetic diagnosis is attained. We have been using a combined, two-step strategy, based on targeted genes panel as a first NGS screening, followed by whole exome sequencing (WES) in still unsolved cases, to analyze a large cohort of subjects, that failed to show mutations in mtDNA and in ad hoc sets of specific nuclear genes, sequenced by the Sanger's method. Not only this approach has allowed us to reach molecular diagnosis in a significant fraction (20%) of these difficult cases, but it has also revealed unexpected and conceptually new findings. These include the possibility of marked variable penetrance of recessive mutations, the identification of large-scale DNA rearrangements, which explain spuriously heterozygous cases, and the association of mutations in known genes with unusual, previously unreported clinical phenotypes. Importantly, WES on selected cases has unraveled the presence of pathogenic mutations in genes encoding non mitochondrial proteins (e.g. the transcription factor E4F1), an observation that further expands the intricate genetics of mitochondrial disease and suggests a new area of investigation in mitochondrial medicine. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. PMID- 26968900 TI - Diagnosis of cancer multidrug resistance by bacterium-mediated imaging. AB - Multidrug resistance (MDR) is a phenomenon expressed by many tumors affecting the chemotherapy efficacy, treatment decision, and the disease prognosis. Considering its great implication, non-invasive approaches are needed to identify this phenomenon in early stages of the disease. This article discusses the potential of the emerging non-invasive bacterium-mediated imaging of cancer in diagnosis of MDR. This potential is derived from the effect of cancer MDR on the pharmacokinetics of certain antibiotics, which are substrates of the MDR proteins. Since MDR proteins actively pump their substrates outside the resistant cancer cells, the elimination of the employed reporter bacteria, proliferating within MDR cancer cells, would require a larger dose of these antibiotics compared to those inside non-MDR cancer cells. These bacteria bear reporter genes that produce specific signals such as bioluminescent, fluorescent, magnetic, or radioactive signals that can be detected by non-invasive imaging modalities. Therefore, the presence, degree, and mechanism of MDR can be estimated by comparing the concentration of the employed antibiotic, required to cease these signals (reflecting the elimination of the bacteria), to a pre-determined reference. The real time imaging of MDR cancer and the early diagnosis of MDR, offered by this approach, would provide a better tool for preclinical studies of MDR, and allow a prompt choice of the most appropriate therapy. PMID- 26968901 TI - Well begun is half done: Rubella virus perturbs autophagy signaling, thereby facilitating the construction of viral replication compartments. AB - The rubella virus is the causative agent of postnatal German measles and the congenital rubella syndrome. The majority of the rubella virus replication complexes originate from the endomembrane system. The rubella virus perturbs the signaling pathways regulating the formation of autophagic membranes in the infected cells, including the Ras/Raf/MEK/ERK and PI3K/Akt pathways. It is widely accepted that these pathways inhibit autophagy. In contrast, the class III PI3K enzymes are essential for autophagy initiation. By manipulating the Ras/Raf/MEK/ERK, class I PI3K/Akt and class III PI3K axes of signal transduction, the rubella virus may differentially regulate the autophagic cascade, with consequent stimulation of the initiation and strong suppression of the later phases. Dysregulation of autophagy by this virus can have a significant impact on the construction of replication compartments by regulating membrane trafficking. We hypothesize that the rubella virus perturbs the autophagic process in order to prevent the degradation of the virus progeny, and to ensure its replication by hijacking omegasomes for the construction of the replication complexes. The virus is therefore able to utilize an antiviral mechanism to its own advantage. Therapeutic modalities targeting the autophagic process may help to ameliorate the serious consequences of the congenital rubella syndrome. PMID- 26968902 TI - Is postoperative encephalopathy with choreoathetosis an acquired form of neuroacanthocytosis? AB - Postoperative encephalopathy with choreoathetosis ("postpump chorea") is a rare complication of open-heart surgery and, in particular, the employment of a cardiopulmonary bypass pump. It almost exclusively occurs in young children. While risk factors and the underlying histopathology have been identified, the pathogenesis of postpump chorea, crucially, remains largely unknown. Transient cerebral hypoperfusion associated with cardiopulmonary bypass is considered a likely candidate mechanism, but the evidence is insufficient and inconclusive. It is hypothesized in this article, that postpump chorea may be caused by mechanical trauma to red blood cells and resulting acanthocytosis. These dysfunctional erythrocytes could then lead to damage to the globus pallidus and disease development akin to that presumed in neuroacanthocytosis. In patients with neuroacanthocytosis an association between acanthocytosis and basal ganglia pathology has been suggested. To test the mechanism hypothesized here, the effects of cardiopulmonary bypass on erythrocyte morphology and function could be systematically tested in children undergoing cardiac surgery. Ideally, the extent of erythrocyte damage could be correlated with the risk of developing postpump chorea. Finally, if the proposed hypothesis is supported by empirical findings, efforts to reduce blood cell damage during extracorporeal circulation in children might prevent this devastating complication. PMID- 26968903 TI - Fibroblasts induced epithelial to mesenchymal transition of tumor cells and their extra circulation traveling behavior. AB - It is believed that tumor cells can detach from primary tumor site and disseminate in the circulation and tissues. These disseminated tumor cells can reside in the tissues for a long period that do not form the tumor mass, however, the potential of metastasis still remains. It is pivotal to tumor diagnosis and therapy to explore how these tumor cells behave after departing from the primary site. Once detached from the maternal site, the tumor cells firstly enter into the circulation and then into the tissues surrounded by the stromal cells, which may influence the tumor behaviors. In our previous study, we found that the normal fibroblasts were capable of inducting the epithelial into mesenchymal cells of the gastric tumor cells by the down regulation of the E-cadherin. The transformed gastric cancer cells exhibited impaired tumor colonization but increased metastasis, providing the preliminary cues for the fact that the transformed tumor cells exist in not only the circulation, but the tissue as well. Emerging studies have been focused on the biological behaviors of tumor cells in the circulation, while it is still not clear about of those cells out of circulation, especially in the early stage of cancer. In this article, we propose a hypothesis of the "traveling tumor cells" to include these tumor cells in the tissues based on our previous findings, which describe the tumor cells that migrate through the tissue with no evidence of tumor metastasis. Furthermore, we discuss the generation and underlying mechanisms of the "traveling tumor cells", which we believe that they would be of great value to refresh our understanding of tumor metastasis. PMID- 26968904 TI - Alzheimer's disease via enhanced calcium signaling caused by the decrease of endoplasmic reticulum-mitochondrial distance. AB - It has long been recognized that Ca(2+) dysregulation is relevant to the initiation of Alzheimer's disease (AD), and most recent works have suggested that increased cross-talk between endoplasmic reticulum (ER) and mitochondria plays an important role in the pathogenesis of the disease. However, the detailed mechanism involved has not been fully elucidated. Owing to its importance in the regulation of Ca(2+) signaling, ER-mitochondrial distance in the neurons is tightly controlled in the physiological conditions. When the distance is decreased, Ca(2+) overload occurs both in the cytosol and mitochondria. The cytosolic Ca(2+) overload can (1) hyperactivate Ca(2+)-dependent enzymes, which in turn regulate activities of pro-apoptotic BCL-2 family proteins, causing mitochondrial outer membrane permeabilization and thereby resulting in the release of cytochrome c to activate caspase-3; (2) indirectly activate caspase-3 through the activation of caspase-12; and (3) promote the production and aggregation of beta-amyloid. The three pathways eventually trigger neuronal apoptotic cell death. The mitochondrial Ca(2+) overload can lead to increased generation of reactive oxygen species, inducing the opening of the mitochondrial permeability transition pore and ultimately causing neuronal apoptotic and necrotic cell death. The resultant death of neurons which are responsible for memory and cognition would contribute to the pathogenesis of AD. Therefore, we propose that the reduction in the distance between ER and mitochondria may be implicated in AD pathology by enhanced Ca(2+) signaling, which provides a more complete picture of the Ca(2+) hypothesis of AD. PMID- 26968905 TI - Dehydroascorbic acid for the treatment of acute ischemic stroke. AB - In animal models of acute ischemic stroke, intravenous dehydroascorbic acid (DHAA), unlike ascorbic acid (AA), readily enters brain and is converted in both normal and ischemic brain into protective ascorbic acid. When given parenterally DHAA minimizes infarct volume and facilitates functional recovery. I hypothesize the same effect will occur in humans with acute ischemic stroke. Efficacy in reducing infarct volume is demonstrable in mice and rats even when DHAA is infused three hours after the experimental infarct. Moreover, there is fivefold mechanistic rational for DHA beside excellent pharmacokinetics and rapid penetration of brain and conversion to protective AA: (1) in ischemic brain, there is a precipitous decline in AA which can be reversed by intravenous DHAA; (2) after reduction of DHAA to AA in both normal and ischemic brain, AA can reduce oxidized vitamin E and glutathione, other protectors of brain against damaging reactive oxygen species which build up in ischemic brain; (3) AA itself can protect brain against damaging reactive oxygen species; (4) AA is an essential cofactor for several enzymes in brain including ten-eleven translocase 2 which upregulates production of protective molecules like brain-derived neurotrophic factor; and (5) DHAA after conversion to AA prevents both lipid oxidation and presumably oxidation of other labile substances (e.g., dopamine) in ischemic brain. In terms of safety, based on all available animal information, DHAA is safe in the proposed dosing regimen. For human clinical trials, the methodology for conducting the proposed animal safety, clinical pharmacology and phase II efficacy studies is straightforward. Finally, if DHAA preserved brain substance and function in humans, it could be employed in pre-hospital stroke patients. PMID- 26968906 TI - Therapeutic iron restriction in sepsis. AB - Sepsis represents the systemic immune response to an infection. Mortality of sepsis slightly decreased over the past years, but due to the growing incidence, the absolute number of deaths still increases and belongs to the three most frequent causes of death worldwide. To date, there is no specific treatment for sepsis available yet. Iron is essential to both human beings and microbes and of great significance in many physiological and biochemical processes. Since iron is involved in the bacterial proliferation and immune dysregulation, we hypothesize that restricting host iron levels by application of iron chelators attenuates bacterial growth and improves the detrimental dysregulation of the systemic immune response in sepsis. PMID- 26968907 TI - Is violence in part a lithium deficiency state? AB - Violence, particularly firearm violence, leading to suicide and homicide is a significant problem worldwide. A majority of suicidal and homicidal violence involves males; homicidal violence is prevalent among young men and suicide is the leading cause of violence worldwide. Lithium, in pharmacological doses, has been used successfully for decades in treating bipolar disorders, and has been shown to decrease violent crime in this situation. Interestingly, lithium, in trace amounts, as occurs in some drinking water, has been inversely related to aggression, and suicidal and homicidal violence. Lithium is naturally found in vegetables, grains and drinking water, and dietary intake varies from nearly zero to 3mg daily. Elemental lithium, in trace doses, has been shown to improve mood in weeks. Moreover, lithium, in trace amounts, has no toxicity. In order to ensure adequate dietary intakes of elemental lithium daily for the purpose of decreasing aggression and violence, we propose considering the fortification of cereal grain products with lithium and also the addition of lithium to vitamin preparations for adults. Importantly, randomized trials in various populations are needed to test this hypothesis. PMID- 26968909 TI - Subsistence-patterns, gender roles, effective temperature, and the evolutionary timing of a post reproductive life span. AB - Evolutionary anthropologists explain menopause and the start of a post reproductive lifespan (PRLS), as beneficiary for older women who can now help contribute to their children/grandchildren's wellbeing. This paper presents a new model with the aim to elucidate when, where, and for whom, such benefits may have arisen. In foraging societies, women contribute nutrients to their social groups/family units to a greater degree as overall effective temperatures (ETs) rise. Where the ET is favorable for women's contributions (ETs between 15 and 20), selection does lengthen the PRLS of women because women contribute sufficiently to enhance their own inclusive fitness. Paleo-environment records suggest that the climate necessary to encourage an increase PRLS occurred shortly after the younger dryad in emerging subtropical settings. Subsistence patterns and gender roles may have played a role in the evolution of PRLS in human females. PMID- 26968908 TI - Autonomic denervation: A new aetiological framework for clinical obstetrics and gynaecology. AB - The hypothesis is that many clinical conditions in obstetrics and gynaecology result from the diverse and varying consequences of injuries to pelvic autonomic nerves. These injuries result from difficult first labours, persistent physical efforts during defaecation, and, medical and surgical techniques for evacuation of the uterus. The neuro-immunohistochemical "signatures" of these injuries are variations of the Dixon-Robertson-Brosens (DRB) lesion in preeclampsia, where there is hyperplasia of the tunica intima and media of arterioles with narrowing of the lumen of the vessel. In stage IV, nulliparous "endometriosis" (and other gynaecological conditions) there are circumferential layers of abnormal nerves around a narrowed arteriole, whereas in early-onset preeclampsia (and other obstetric conditions) there are similar histological findings in uterine arterioles but there is no sign of injured nerves. During pregnancy there is elongation of blood vessels but no elongation of injured nerves leading to relative denervation of the myometrium. These lesions are detectable in most of the "great" obstetric syndromes, and, across the spectrum of gynaecological syndromes. They provide a coherent explanation of the natural history and clinical presentations of many of these syndromes. Clinical features vary with the site, nature and extent of the injury; a minor injury may enable pregnancy though it is complicated by late-onset pre-eclampsia whereas a more extensive injury may prevent pregnancy and present with chronic pelvic pain with, or without, endometriosis. PMID- 26968910 TI - Salt and miscarriage: Is there a link? AB - Salt is a major mineral element that plays fundamental roles in health and disease. Excessive salt intake is a major cause of hypertension, cardiovascular disease and stroke. Miscarriage and preeclampsia are the most common pregnancy complications with multiple etiological factors, including inflammatory and autoimmune conditions. More recently, different studies indicated that excessive salt intake is involved in the development of inflammatory processes through induction of T helper-17 pathway and their inflammatory cytokines. On the other hand, several studies indicated the pivotal role of inflammation in the etiology of miscarriage, preeclampsia and adverse pregnancy outcome. Here, it is hypothesized that excessive salt intake around the time of conception or during pregnancy can trigger inflammatory processes, which consequently associated with increased risk of miscarriage, preeclampsia or adverse pregnancy outcome. Thus, this hypothesis suggests that low salt intake around the time of conception or during pregnancy can decrease the risk of miscarriage or adverse pregnancy outcome. This hypothesis also offers new insights about the role of salt in the etiology of miscarriage and preeclampsia. PMID- 26968911 TI - A hybrid fever therapy for increased tumor selectivity. AB - Lipopolysaccharide (LPS), mediator of the Coley and Shwartzman fever therapies, is a potent endotoxin capable of inducing sepsis at moderate intravenous doses, which currently limits its experimental and clinical use. By exploiting elevated G-CSF concentrations and neutrophil numbers within tumors, it may be possible to selectively trigger a sepsis-like syndrome in malignant tissues using only moderate hyperthermia and low-dose LPS, leaving normal organs unaffected. Analogous to the organ failure that can result from severe sepsis, repeated application of the proposed procedure could lead to tumor necrosis and regression. Biomarkers including heat shock proteins and circulating endothelial cells, and intravital microscopy of intravascular NETs, microthrombi, and bleeding in tumors can be used to test predicted consequences of this therapy. The two components of this hybrid approach, hyperthermia and acute but mild endotoxemia, could provide a tumor-specific therapeutic modality with relatively mild side effects, and therefore permit repeated application over an extended treatment period. PMID- 26968912 TI - Melanoma can control development of metastasis--Fact or myth? AB - The malignant melanoma spreading process cannot explain occurrence of metastases several years following local surgical therapy of primary malignancy. But, this complex process of delayed metastases is still challenging and not completely understood. We hypotheses that melanoma metastases occur early in disease, probably at the same time with the occurrence of the primary melanoma. We suggest that dissemination of metastatic "seed cells" occur at an early stage of the disease together with the development of primary melanoma and cannot be detected by standard diagnostic methods. These cells are masked between healthy cells and have the potential to proceed in true metastasis following the activation triggered by signal from primary tumor or other source. Other possibility includes the existence of two different genes, one responsible for development of primary melanoma, and the other with a roll in development of metastases. We believe that future investigation should be directed toward better understanding of mechanisms involved in metastases development keeping in mind that melanoma behavior is irrational and defies logical thinking. PMID- 26968913 TI - Wernicke's encephalopathy in crack-cocaine addiction. AB - HYPOTHESIS: Crack-cocaine addiction is associated with a variety of conditions that increase risk of thiamine deficiency and Wernicke's encephalopathy. EVIDENCE: We report a case of Wernicke's encephalopathy in a crack-cocaine addict who did not habitually consume alcohol. We list some conditions associated with crack-cocaine addiction that may contribute to thiamine deficiency. IMPLICATIONS: Clinicians should bear in mind that crack-cocaine addiction may be associated with Wernicke's encephalopathy, mainly due to malnutrition. We suggest that routine Wernicke's encephalopathy prophylaxis with parenteral thiamine be provided to patients with chronic crack-cocaine addiction, as is already established practice in chronic alcoholics, so as to prevent cognitive damage in this population. PMID- 26968914 TI - Autologous tumor immunizing devascularization in cancer therapy. AB - Tumor vaccination depending on specific antigens, autologous tumor vaccination involving wide range of antigens, immunomodulating cytokines and bacterial agents have been studied extensively with the purpose of stimulating the antitumor immune response. Unfortunately these therapies showed disappointing results mainly due to undesirable mechanisms tending to dampen the antitumor immune response. We will discuss a novel approach of autologous tumor immunization using a surgical technique: autologous tumor immunizing devascularization (ATID). This approach involves complete surgical devascularization of a tumor which is then left isolated in situ in the body. The stressing pathophysiological condition of the completely isolated tumor provokes a generalized immune response which, as shown from clinical cases, leads to the elimination of the devascularized tumor and distant metastases without causing sepsis. Until now no clinical study was properly executed. The possible significance of this method which resides in its curative potential has thus escaped attention in the field of cancer therapy. This article will hypothesize optimal physiological criteria and necessary clinical conditions for ATID to be performed effectively. The main criteria are (1) complete isolation of the tumor from the vascular system, (2) sufficient devascularized tumor load to trigger a sustained generalized immune response to cancer antigens until elimination of all cancer loci, (3) tumor cell killing rate corresponding to the elicited immune response is higher than the tumor cell growth rate, and (4) patients with an uncompromised immune system. Future studies have to be performed under the indicated conditions in order to confirm the efficacy and safety of ATID as a novel approach in the treatment of cancer. PMID- 26968915 TI - Promising link between selenium and peroxisome proliferator activated receptor gamma in the treatment protocols of obesity as well as depression. AB - Considerable interest has been given to the significance of peroxisome proliferator activated receptors (PPARs) in macronutrient metabolism, however, there is not sufficient data concerning the interactions between PPARs and micronutrients. Investigations performed on PPARgamma and one of the essential micronutrients selenium (Se) have shown that both parameters may lead to alterations in obesity-related or mood disorders. Therefore, it is plausible to consider PPARgamma and Se together as a powerful combination during the treatment of two associated diseases; obesity and depression. PPARgamma has been shown to be involved in the antidepressant-like activity. It is also an important parameter to be considered in obesity as the master regulator of adipogenesis. The mechanism of action of PPARgamma is initiated by ligand binding which induces a conformational change in the receptor. Se is capable of alleviating inflammatory signaling pathways. Obesity is associated with chronic low-grade inflammation. Depression is also defined as an inflammatory disorder. Inflammatory mediators such as tumor necrosis factor-alpha (TNFalpha) participate in the progression of depression. They are also obesity-associated parameters. Due to TNFalpha induced depressive-like behaviors and the positive association between this proinflammatory cytokine and obesity, TNFalpha-activated signaling pathways and those inhibiting them have recently gained importance as potential targets and therapeutic tools, respectively. More studies are necessary to develop compounds with therapeutic nature against depressive disorders and obesity. PPARgamma is an important signaling pathway that occurs at the crossroads of depression and obesity. Se, aside from its anti-inflammatory, anticarcinogenic and antioxidative nature, affects also the way of PPARgamma action. Se supplementation or fortification as well as the development of the partial agonists of PPARgamma in which lipophilic Se compounds are used as ligand followed by experimental trials and human studies using the newly developed compounds will be promising approaches for future hope during the treatment of these diseases. PMID- 26968916 TI - Altered isotope charge distribution of acetylcholine neurotransmitter and Myasthenia Gravis. AB - Acetylcholine (ACh) is a central neurotransmitter that is used for signal transmission among neurons. For signal transmission in neurons, a neurotransmitter must bind to its receptor in order to produce an action potential. It is known that in Myasthenia Gravis (MG) cases, autoantibodies could block this binding. In the future, the treatment of MG could be achieved via modulation of molecular interaction between ACh and acetylcholine receptor (AChR). This study suggests that if an atom on a ligand (i.e. a neurotransmitter) is replaced with its isotope, it may cause charge redistribution such as that the binding between ligand and its receptor may be improved. Hence suggesting that with replacement of atoms with their isotopes in any biologically important ligand could alter its affinity towards its corresponding receptor, which would have a wide array of applications in medicine. PMID- 26968917 TI - A new concentric double prosthesis for sutureless, magnetic-assisted aortic arch inclusion. AB - Acute dissection of the ascending aorta is a life-threatening condition in which the aortic wall develops one or more tears of the intima associated with intramural rupture of the media layer with subsequent formation of a two lumina vessel. The remaining outer layer is just the adventitia, with high risk of complete rupture. Vital organs may be under-perfused. Mortality rate in this acute event is about 50% if an emergent surgical procedure is not performed as soon as possible to replace the tract affected by the primary rupture. Nevertheless, the emergent surgical procedure is affected by high risk of mortality or severe neurologic sequelae, due to the need for deep hypothermia and cardiocirculatory arrest and different methods of cerebral protection. If the patient survives the acute event, a frequent outcome is the establishment of a chronic aortic dissection in the remaining aorta and late chronic dissecting aneurysm, usually starting from the surgical suture itself. Traumatism of surgical stitches and of direct blood flow pressure on weak aortic wall can be important contributing factors of the chronic disease. In conclusions, the majority of these patients undergoes a high risk operation without a complete solution of the disease. We hypothesize that excluding the aortic layers from the blood direct flow and using an anastomotic technique which does not include surgical stitches could help to significantly reduce the recurrence of aortic dissection after the acute event and shorten hypothermic arrest duration. We devised a double tubular prosthesis consisting of two concentric artificial tubes between which the aortic wall is confined and excluded from direct blood flow. We also devised a magnetic assisted sutureless anastomotic technique that seals the aortic tissue between the two prostheses and avoids the perforation of the fragile aortic wall with surgical stitches. We are presenting here this new prototype and draw a few different models. Both acute and chronic diseases of the aorta could benefit from the proposed technique, although acute dissection is the ideal scenario for its use. PMID- 26968918 TI - Re: DPP-4 inhibition improves a sexual condition? PMID- 26968920 TI - Understanding a role of folliculotropic viral infections in the pathogenesis of psoriasis. PMID- 26968919 TI - Salivary proteomics: A new adjuvant approach to the early diagnosis of familial juvenile systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic multisystemic disease characterized by autoimmune inflammatory disturbance. Pleomorphic manifestations are present and a potentially progressive and debilitating course can be detected. SLE rarely manifests before age 5, and its onset peaks is around puberty. Although clinical manifestations, immunological alterations and treatment do not differ between juvenile and adult SLE, children tend to present with a more aggressive disease course than adults. Hence, autoimmune rheumatic diseases are the most common cause of morbidity and mortality in pediatric populations. Blood serum analysis plays an especially important role in the detection and monitoring of autoantibodies in SLE. However, since blood sampling is an uncomfortable procedure, especially in children, novel less invasive techniques and approaches are of utmost importance to evaluate pediatric subjects. In this regard, saliva samples have several advantages, such as: easy access, fast collection, painless and riskless procedure. Saliva has antimicrobial, immunomodulatory and anti-inflammatory properties, as well as several other relevant features. The whole saliva is a complex mixture of major and minor salivary gland secretion, gingival crevicular fluid, transudates plasma protein, keratinocyte products and oral microbiota. This biological fluid reflects the physiological state of the body, including the emotional condition, and endocrine, nutritional and metabolic changes. Therefore, salivary proteomics is becoming increasingly used for the early diagnosis of several diseases such as breast cancer, oral cancer, Sjogren's syndrome, diffuse systemic sclerosis, rheumatoid arthritis, among others. Considering the detection of some potential markers related to SLE in serum and urine, this study aims to conduct an initial evaluation of the possible presence of such biomarkers in saliva. Furthermore, it is expected to track down new salivary proteins that could be correlated with the disease. As such, it is important to evaluate whether the analysis of the salivary proteome of children whose mothers have SLE may help identify biomarkers for the early detection and monitoring of the condition. PMID- 26968921 TI - Carry-over fluency induced by extreme prolongations: A new behavioral paradigm. AB - Extreme prolongations, which can be generated via extreme delayed auditory feedback (DAF) (e.g., 250-500 ms) or mediated cognitively with timing applications (e.g., analog stopwatch) at 2 s per syllable, have long been behavioral techniques used to inhibit stuttering. Some therapies have used this rate solely to establish initial fluency, while others use extremely slowed speech to establish fluency and add other strategic techniques such as easy onsets and diaphragmatic breathing. Extreme prolongations generate effective, efficient, and immediate forward flowing fluent speech, removing the signature behaviors of discrete stuttering (i.e., syllable repetitions and audible and inaudible postural fixations). Prolonged use of extreme prolongations establishes carry-over fluency, which is spontaneous, effortless speech absent of most, if not all, overt and covert manifestations of stuttering. The creation of this immediate fluency and the immense potential of extreme prolongations to generate long periods of carry-over fluency have been overlooked by researchers and clinicians alike. Clinicians depart from these longer prolongation durations as they attempt to achieve the same fluent results at a near normal rate of speech. Clinicians assume they are re-teaching fluency and slow rates will give rise to more normal rates with less control, but without carry-over fluency, controls and cognitive mediation are always needed for the inherently unstable speech systems of persons who stutter to experience fluent speech. The assumption being that the speech system is untenable without some level of cognitive and motoric monitoring that is always necessary. The goal is omnipresent "near normal rate sounding fluency" with continuous mediation via cognitive and motoric processes. This pursuit of "normal sounding fluency" continues despite ever-present relapse. Relapse has become so common that acceptance of stuttering is the new therapy modality because relapse has come to be understood as somewhat inevitable. Researchers and clinicians fail to recognize that immediate amelioration of stuttering and its attendant carry-over fluency are signs of a different pathway to fluency. In this path, clinicians focus on extreme prolongations and the extent of their carry-over. While fluency is automatically generated under these extreme prolongations, the realization is that communication at this rate in routine speaking tasks is not feasible. The perceived solution is a systematic reduction in the duration of these prolongations, which attempts to approximate "normal speech." Typically, the reintroduction of speech at a normalized rate precipitates a laborious style that is undesirable to the person who stutters (PWS) and is discontinued, once departed from the comforts of the clinical setting. The inevitable typically occurs; the well-intentioned therapist instructs the PWS to focus on the techniques while speaking at a rate that is nearest normal speech, but the overlooked extreme prolongations are unlikely to ever be revisited. The foundation of this hypothesis is that the departure from fluency generators (e.g. extreme prolongations) is the cause of regression to the stuttering set point. In turn, we postulate that the continued use of extreme prolongations, as a solitary practice method, will establish and nurture different neural pathways that will create a modality of fluent speech, able to be experienced without cognitive or motoric mediation. This would therefore result in fewer occurrences of stuttering due to a phenomenon called carry-over fluency. Thus, we hypothesize that the use of extreme prolongations fosters neural pathways for fluent speech, which will result in carry-over fluency that does not require mediation by the speaker. PMID- 26968922 TI - Accounting for disagreements on average cone loss rates in retinitis pigmentosa with a new kinetic model: Its relevance for clinical trials. AB - Since 1985, at least nine studies of the average rate of cone loss in retinitis pigmentosa (RP) populations have yielded conflicting average rate constant values (-k), differing by 90-160%. This is surprising, since, except for the first two investigations, the Harvard or Johns Hopkins' protocols used in these studies were identical with respect to: use of the same exponential decline model, calculation of average -k from individual patient k values, monitoring patients over similarly large time frames, and excluding data exhibiting floor and ceiling effects. A detailed analysis of Harvard's and Hopkins' protocols and data revealed two subtle differences: (i) Hopkins' use of half-life t0.5 (or t(1/e)) for expressing patient cone-loss rates rather than k as used by Harvard; (ii) Harvard obtaining substantially more +k from improving fields due to dormant-cone recovery effects and "small -k" values than Hopkins' ("small -k" is defined as less than -0.040 year(-1)), e.g., 16% +k, 31% small -k, vs. Hopkins' 3% and 6% respectively. Since t0.5=0.693/k, it follows that when k=0, or is very small, t0.5 (or t(1/e)) is respectively infinity or a very large number. This unfortunate mathematical property (which also prevents t0.5 (t(1/e)) histogram construction corresponding to -k to +k) caused Hopkins' to delete all "small -k" and all +k due to "strong leverage". Naturally this contributed to Hopkins' larger average -k. Difference (ii) led us to re-evaluate the Harvard/Hopkins' exponential unchanging -k model. In its place we propose a model of increasing biochemical stresses from dying rods on cones during RP progression: increasing oxidative stresses and trophic factor deficiencies (e.g., RdCVF), and RPE malfunction. Our kinetic analysis showed rod loss to follow exponential kinetics with unchanging -k due to constant genetic stresses, thereby providing a theoretical basis for Clarke et al.'s empirical observation of such kinetics with eleven animal models of RP. In contrast to this, we show that cone loss occurs in patients with increasing -k values during RP progression. And as the Hopkins' protocol selects more advanced RP cases than Harvard's to assure avoidance of ceiling effects (Harvard does this by kinetic monitoring), we show increasing -k kinetics to be the reason Harvard obtains more +k and small -k values. Thus the combined effects of (i) and (ii) produce Harvard's smaller average -k value. The relevance of the increasing biochemical stress model for optimizing clinical trials is discussed. PMID- 26968923 TI - Preparation and characterization of aminoethyl hydroxypropyl methyl cellulose modified with nisin. AB - Nisin grafted aminoethyl hydroxypropyl methyl cellulose (AEHPMC) was prepared by an enzyme-catalyzed reaction in the presence of microbial transglutaminase (MTGase). AEHPMC was synthesized with 2-chloroethylamine hydrochloride (CEH) which was as an intermediate reactant. The parameters, which influenced the NH2% and the degree of substitution (DS), including reaction time, reaction temperature and the mass ratio of the reactants were investigated. Antioxidant activities of AEHPMC-nisin were evaluated by the scavenging activity of hydroxyl and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical. With the DS and concentration increasing of AEHPMC-nisin, the radical scavenging activity increased. The Methylthiazol tetrazolium (MTT) assay indicated that AEHPMC-nisin had low toxicity to L929 cells. Therefore, the derivative of HPMC may show a promising potential application in biomedical, food and pharmaceutical fields. PMID- 26968924 TI - Different effects of lipoteichoic acid from C. butyricum and S. aureus on inflammatory responses of HT-29 cells. AB - Lipoteichoic acid (LTA) is an important cell wall component of Gram-positive bacteria and represents one of the most critical microbe-associated molecular pattern (MAMP) molecules. In this study, we isolated and purified LTA from Clostridium butyricum (bLTA) and compared its effects on the inflammatory responses of HT-29 cells with those of LTA from Staphylococcus aureus (aLTA). We also compared the effects of bLTA and aLTA on cell growth, proliferation, and apoptosis. The results showed that the length and saturation degree of the acyl chains in the two LTA molecules were obviously different. aLTA stimulated the phosphorylation of p65 and activated the NF-kappaB signaling pathway, inducing the expression and secretion of cytokines. Moreover, aLTA also inhibited the growth and proliferation of HT-29 cells and induced cell apoptosis. However, bLTA had no significant effects on the NF-kappaB signaling pathway in HT-29 cells and did not stimulate cellular inflammatory responses or induce apoptosis. These differences in activity may result from the different lengths and saturation degrees of the acyl fatty acid chains of the two LTA molecules. These differences may also account for the distinct effects elicited by probiotic bacteria and pathogenic bacteria on host cells. PMID- 26968925 TI - Synthesis and characterization of hydrolysed starch-g-poly(methacrylic acid) composite. AB - A novel method for the synthesis of starch-g-poly(methacrylic acid) composite was adopted by graft polymerization of hydrolysed starch (HS) and methacrylic acid (MAA) in aqueous medium using an efficient sodium perborate (SPB)-thiourea (TU) redox initiation system. The parameters influencing the redox system efficiency and thence the polymerization method were considered. These parameters comprehended the concentrations of MAA, SPB, TU and SPB/TU molar ratio as well as the polymerization temperature. The polymerization reaction was scrutinized through calculation of the MAA total conversion percent (TC%). The resultant poly(MAA-HS) composite was assessed by evaluating the polymer criteria (the graft yield, GY%; the grafting efficiency, GE%; the homopolymer, HP%; and the total conversion). The comportment of the apparent viscosity of the cooked poly(MAA) starch composite paste, obtained under diverse polymerization conditions, was examined. Tentative mechanisms, which depict all occasions that happen amid the entire course of the polymerization reaction, have been proffered. PMID- 26968926 TI - Shape and size engineered cellulosic nanomaterials as broad spectrum anti microbial compounds. AB - Oxidized celluloses have been used for decades as antimicrobial wound gauzes and surgical cotton. We now report the successful synthesis of a next generation narrow size range (25-35nm) spherical shaped nanoparticles of 2,3,6 tricarboxycellulose based on cellulose I structural features, for applications as new antimicrobial materials. This study adds to our previous study of 6 carboxycellulose. A wide range of bacteria such as Escherichia coli, Staphloccocus aureus, Bacillus subtilis and Mycobacterium tuberculosis (non pathogenic as well as pathogenic strains) were affected by these polymers in in vitro studies. Activity against Mycobacteria were noted at high concentrations (MIC99 values 250-1000MUg/ml, as compared to anti-TB drug Isoniazid 0.3MUg/ml). However, the broad spectrum activity of oxidized celluloses and their nanoparticles against a wide range of bacteria, including Mycobacteria, show that these materials are promising new biocompatible and biodegradable drug delivery vehicles wherein they can play the dual role of being a drug encapsulant as well as a broad spectrum anti-microbial and anti-TB drug. PMID- 26968927 TI - Transmyometrial versus very difficult transcervical embryo transfer: efficacy and safety. AB - A difficult and traumatic embryo transfer can negatively impact on embryo implantation. This study retrospectively compared the outcomes of "very difficult transcervical embryo transfer" (vdTCET) versus transmyometrial embryo transfer (TMET) in a single centre over 10 years, reporting on 128 patients with vdTCET and 46 patients with TMET. The definition of vdTCET was a procedure rated by an experienced practitioner (with more than 100 transfers per year for >2 years) as very difficult and required two or more of the following: use of tenaculum, change of embryo transfer catheter and use of a stylet, reloading of the embryos or cancelling the procedure and freezing the embryo to transfer after cervical dilatation. The clinical pregnancy rates for TMET and vdTCET were 32.6% and 25%, respectively and the live birth rates were 26.1% and 16.4%, respectively. There was only one case of minor bleeding in the TMET group (2.2%). This study showed that TMET is a good alternative option in cases of vdTCET where it is impossible to achieve transcervical embryo transfer and may benefit cases with repeated failed cycles after vdTCET. Its superiority over vdTCET however could not be demonstrated. PMID- 26968928 TI - Assisted reproductive outcomes in women with different polycystic ovary syndrome phenotypes: the predictive value of anti-Mullerian hormone. AB - This cross-sectional study aimed to evaluate IVF/intracytoplasmic sperm injection (ICSI) outcomes in different polycystic ovary syndrome (PCOS) phenotypes (A, B, C and D) compared with a control group and the predictive values of serum anti Mullerian hormone (AMH) in PCOS phenotypes for main outcomes. This study evaluated 386 PCOS women and 350 patients with male factor infertility. Women with phenotypes A and C had significantly higher concentrations of AMH than those with phenotype B (P < 0.001). Clinical pregnancy rate (CPR) in the phenotype D group (53.3%) was higher than other groups (32.5%, 26.4% and 36.8%, respectively, in phenotypes A, B and C), but not to a significant level. Multivariable regression analysis, after adjusting for women's age and body mass index, revealed that PCOS phenotypes A and B were associated with a decreased CPR compared with the control group (odds ratio [OR]: 0.46, confidence interval [CI]: 0.26-0.8, P = 0.007 and OR: 0.34, CI: 0.18-0.62, P = 0.001, respectively). It seems a combination of hyperandrogenism and chronic anovulation is associated with a negative impact on the CPR in these patients. These results demonstrated that AMH concentration is related to PCO morphology but not predictive for CPR and live birth rate. PMID- 26968929 TI - Inverse problem studies of biochemical systems with structure identification of S systems by embedding training functions in a genetic algorithm. AB - An efficient inverse problem approach for parameter estimation, state and structure identification from dynamic data by embedding training functions in a genetic algorithm methodology (ETFGA) is proposed for nonlinear dynamical biosystems using S-system canonical models. Use of multiple shooting and decomposition approach as training functions has been shown for handling of noisy datasets and computational efficiency in studying the inverse problem. The advantages of the methodology are brought out systematically by studying it for three biochemical model systems of interest. By studying a small-scale gene regulatory system described by a S-system model, the first example demonstrates the use of ETFGA for the multifold aims of the inverse problem. The estimation of a large number of parameters with simultaneous state and network identification is shown by training a generalized S-system canonical model with noisy datasets. The results of this study bring out the superior performance of ETFGA on comparison with other metaheuristic approaches. The second example studies the regulation of cAMP oscillations in Dictyostelium cells now assuming limited availability of noisy data. Here, flexibility of the approach to incorporate partial system information in the identification process is shown and its effect on accuracy and predictive ability of the estimated model are studied. The third example studies the phenomenological toy model of the regulation of circadian oscillations in Drosophila that follows rate laws different from S-system power law. For the limited noisy data, using a priori information about properties of the system, we could estimate an alternate S-system model that showed robust oscillatory behavior with predictive abilities. PMID- 26968930 TI - Formulating spread of species with habitat dependent growth and dispersal in heterogeneous landscapes. AB - Habitat heterogeneity can have profound effects on the spreading dynamics of invasive species. Using integro-difference equations, we investigate the spreading dynamics in a one-dimensional heterogeneous landscape comprising alternating favourable and unfavourable habitat patches or randomly generated habitat patches with given spatial autocorrelation. We assume that population growth and dispersal (including emigration probability and dispersal distance) are dependent on habitat quality. We derived an approximation of the rate of spread in such heterogeneous landscapes, suggesting the sensitivity of spread to the periodic length of the alternating favourable and unfavourable patches, as well as their spatial autocorrelation. A dispersal-limited population tends to spread faster in landscapes with shorter periodic length. The spreading dynamics in a heterogeneous landscape was found to be not only dependent on the availability of favourable habitats, but also the dispersal strategy. Estimates of time lag before detection and the condition for boom-and-bust spreading dynamics were explained. Furthermore, rates of spread in heterogeneous landscapes and corresponding homogeneous landscapes were compared, using weighted sums of vital rates. PMID- 26968931 TI - Disease dynamics of honeybees with Varroa destructor as parasite and virus vector. AB - The worldwide decline in honeybee colonies during the past 50 years has often been linked to the spread of the parasitic mite Varroa destructor and its interaction with certain honeybee viruses carried by Varroa mites. In this paper, we propose a honeybee-mite-virus model that incorporates (1) parasitic interactions between honeybees and the Varroa mites; (2) five virus transmission terms between honeybees and mites at different stages of Varroa mites: from honeybees to honeybees, from adult honeybees to the phoretic mites, from brood to the reproductive mites, from the reproductive mites to brood, and from adult honeybees to the phoretic mites; and (3) Allee effects in the honeybee population generated by its internal organization such as division of labor. We provide completed local and global analysis for the full system and its subsystems. Our analytical and numerical results allow us have a better understanding of the synergistic effects of parasitism and virus infections on honeybee population dynamics and its persistence. Interesting findings from our work include: (a) due to Allee effects experienced by the honeybee population, initial conditions are essential for the survival of the colony. (b) Low adult honeybees to brood ratios have destabilizing effects on the system which generate fluctuating dynamics that lead to a catastrophic event where both honeybees and mites suddenly become extinct. This catastrophic event could be potentially linked to Colony Collapse Disorder (CCD) of honeybee colonies. (c) Virus infections may have stabilizing effects on the system, and parasitic mites could make disease more persistent. Our model illustrates how the synergy between the parasitic mites and virus infections consequently generates rich dynamics including multiple attractors where all species can coexist or go extinct depending on initial conditions. Our findings may provide important insights on honeybee viruses and parasites and how to best control them. PMID- 26968932 TI - A Cellular Potts Model of single cell migration in presence of durotaxis. AB - Cell migration is a fundamental biological phenomenon during which cells sense their surroundings and respond to different types of signals. In presence of durotaxis, cells preferentially crawl from soft to stiff substrates by reorganizing their cytoskeleton from an isotropic to an anisotropic distribution of actin filaments. In the present paper, we propose a Cellular Potts Model to simulate single cell migration over flat substrates with variable stiffness. We have tested five configurations: (i) a substrate including a soft and a stiff region, (ii) a soft substrate including two parallel stiff stripes, (iii) a substrate made of successive stripes with increasing stiffness to create a gradient and (iv) a stiff substrate with four embedded soft squares. For each simulation, we have evaluated the morphology of the cell, the distance covered, the spreading area and the migration speed. We have then compared the numerical results to specific experimental observations showing a consistent agreement. PMID- 26968933 TI - Crescentic flap for the reconstruction of the nose after skin cancer resection. AB - PURPOSE: Non-melanoma skin cancers are the most frequent skin tumours; in 25.5% of cases, they are reported to affect the nasal area. For an excellent surgical outcome, first of all the radical excision of the lesion is important, with appropriate margins of healthy skin in order to avoid recurrences. Moreover is important to achieve a good aesthetical result, avoiding distortion of the aesthetic units and preserving their functions. MATERIAL AND METHODS: We have applied the modified crescentic flap, described by Smadja in 2007, to 24 nasal skin defects left by oncologic surgery. It consists of the crescent-shaped resection of Burow's triangle all around the alar groove that allows the advancement of the flap to the tip of the nose, hiding the scar in the alar groove. RESULTS: The outcome and the long-term follow-up were completely satisfactory both for patients and for surgeons. CONCLUSION: For skin defects localized in the midline or paramedian line of the dorsum of the nose, the crescentic flap seems to be a good solution to obtain the better aesthetic result with respect to both anatomy and function of the nasal area, sparing the patient a second intervention or an overly invasive procedure. PMID- 26968935 TI - Weighted cumulative exposure models helped identify an association between early knee-pain consultations and future knee OA diagnosis. AB - OBJECTIVE: To establish the association between prior knee-pain consultations and early diagnosis of knee osteoarthritis (OA) by weighted cumulative exposure (WCE) models. STUDY DESIGN AND SETTING: Data were from an electronic health care record (EHR) database (Consultations in Primary Care Archive). WCE functions for modeling the cumulative effect of time-varying knee-pain consultations weighted by recency were derived as a predictive tool in a population-based case-control sample and validated in a prospective cohort sample. Two WCE functions ([i] weighting of the importance of past consultations determined a priori; [ii] flexible spline-based estimation) were comprehensively compared with two simpler models ([iii] time since most recent consultation; total number of past consultations) on model goodness of fit, discrimination, and calibration both in derivation and validation phases. RESULTS: People with the most recent and most frequent knee-pain consultations were more likely to have high WCE scores that were associated with increased risk of knee OA diagnosis both in derivation and validation phases. Better model goodness of fit, discrimination, and calibration were observed for flexible spline-based WCE models. CONCLUSION: WCE functions can be used to model prediagnostic symptoms within routine EHR data and provide novel low-cost predictive tools contributing to early diagnosis. PMID- 26968936 TI - Selection bias was reduced by recontacting nonparticipants. AB - OBJECTIVE: One of the main goals of health examination surveys is to provide unbiased estimates of health indicators at the population level. We demonstrate how multiple imputation methods may help to reduce the selection bias if partial data on some nonparticipants are collected. STUDY DESIGN AND SETTING: In the FINRISK 2007 study, a population-based health study conducted in Finland, a random sample of 10,000 men and women aged 25-74 years were invited to participate. The study included a questionnaire data collection and a health examination. A total of 6,255 individuals participated in the study. Out of 3,745 nonparticipants, 473 returned a simplified questionnaire after a recontact. Both the participants and the nonparticipants were followed up for death and hospitalizations. The follow-up data allowed to check the assumptions on the missing data mechanism, and tailored multiple imputation methods were used to handle the missing data. RESULTS: Nonparticipation is a strong predictor for mortality in the five-year follow-up. However, the recontact response does not predict mortality or morbidity among the nonparticipants when adjusted for age and sex. The result suggests that the recontact respondents can be used as proxy for all nonparticipants. A comparison of raw estimates and estimates adjusted for selection bias reveals clear differences in the estimated population prevalences of smoking and heavy alcohol usage. CONCLUSION: All efforts to collect data on nonparticipants are likely to be useful even if the response rate for the recontact remains low. Statistical analysis of the recontact respondents provides an indication of the extent of the selection bias, even in studies where follow up data are not available to check the assumptions. PMID- 26968934 TI - Development, function and fate of fetal Leydig cells. AB - During fetal testis development, fetal Leydig cells (FLCs) are found to be originated from multiple progenitor cells. FLC specification and function are under tight regulation of specific genes and signaling proteins. Furthermore, Sertoli cells play a crucial role to regulate FLC differentiation during fetal testis development. FLC progenitor- and FLC-produced biomolecules are also involved in the differentiation and activity of rodent FLCs. The main function of FLCs is to produce androgens to masculinize XY embryos. However, FLCs are capable of producing androstenedione but not testosterone due to the lack of 17beta-HSD (17beta-hydroxysteroid dehydrogenase), but fetal Sertoli cells express 17beta-HSD which thus transforms androstenedione to testosterone in the fetal testis. On the other hand, FLCs produce activin A to regulate Sertoli cell proliferation, and Sertoli cells in turn modulate testis cord expansion. It is now generally accepted that adult Leydig cells (ALCs) gradually replace FLCs during postnatal development to produce testosterone to support spermatogenesis as FLCs undergo degeneration in neonatal and pre-pubertal testes. However, based on studies using genetic tracing mouse models, FLCs are found to persist in adult testes, making up ~20% of total Leydig cells. In this review, we evaluate the latest findings regarding the development, function and fate of FLCs during fetal and adult testis development. PMID- 26968937 TI - A 40-Year History of End-of-Life Offerings in US Medical Schools: 1975-2015. AB - The purpose of this longitudinal study of US medical schools over a 40-year period was to ascertain their offerings on end-of-life (EOL) issues. At 5-year intervals, beginning in 1975, US medical schools were surveyed via a questionnaire to determine their EOL offerings. Data were reported with frequency distributions. The Institute of Medicine has encouraged more emphasis on EOL issues over the past 2 decades. Findings revealed that undergraduate medical students in the United States are now exposed to death and dying, palliative care, and geriatric medicine. The inclusion of EOL topics has definitely expanded over the 40-year period as findings reveal that US undergraduate medical students are currently exposed in over 90% of programs to death and dying, palliative care, and geriatric medicine, with the emphasis on these topics varying with the medical programs. Such inclusion should produce future favorable outcomes for undergraduate medical students, patients, and their families. PMID- 26968938 TI - Efficient quantitative assessment of facial paralysis using iris segmentation and active contour-based key points detection with hybrid classifier. AB - BACKGROUND: Facial palsy or paralysis (FP) is a symptom that loses voluntary muscles movement in one side of the human face, which could be very devastating in the part of the patients. Traditional methods are solely dependent to clinician's judgment and therefore time consuming and subjective in nature. Hence, a quantitative assessment system becomes apparently invaluable for physicians to begin the rehabilitation process; and to produce a reliable and robust method is challenging and still underway. METHODS: We introduce a novel approach for a quantitative assessment of facial paralysis that tackles classification problem for FP type and degree of severity. Specifically, a novel method of quantitative assessment is presented: an algorithm that extracts the human iris and detects facial landmarks; and a hybrid approach combining the rule based and machine learning algorithm to analyze and prognosticate facial paralysis using the captured images. A method combining the optimized Daugman's algorithm and Localized Active Contour (LAC) model is proposed to efficiently extract the iris and facial landmark or key points. To improve the performance of LAC, appropriate parameters of initial evolving curve for facial features' segmentation are automatically selected. The symmetry score is measured by the ratio between features extracted from the two sides of the face. Hybrid classifiers (i.e. rule-based with regularized logistic regression) were employed for discriminating healthy and unhealthy subjects, FP type classification, and for facial paralysis grading based on House-Brackmann (H-B) scale. RESULTS: Quantitative analysis was performed to evaluate the performance of the proposed approach. Experiments show that the proposed method demonstrates its efficiency. CONCLUSIONS: Facial movement feature extraction on facial images based on iris segmentation and LAC-based key point detection along with a hybrid classifier provides a more efficient way of addressing classification problem on facial palsy type and degree of severity. Combining iris segmentation and key point based method has several merits that are essential for our real application. Aside from the facial key points, iris segmentation provides significant contribution as it describes the changes of the iris exposure while performing some facial expressions. It reveals the significant difference between the healthy side and the severe palsy side when raising eyebrows with both eyes directed upward, and can model the typical changes in the iris region. PMID- 26968939 TI - Use of an embedded, micro-randomised trial to investigate non-compliance in telehealth interventions. AB - BACKGROUND/AIMS: Many types of telehealth interventions rely on activity from the patient in order to have a beneficial effect on their outcome. Remote monitoring systems require the patient to record regular measurements at home, for example, blood pressure, so clinicians can see whether the patient's health changes over time and intervene if necessary. A big problem in this type of intervention is non-compliance. Most telehealth trials report compliance rates, but they rarely compare compliance among various options of telehealth delivery, of which there may be many. Optimising telehealth delivery is vital for improving compliance and, therefore, clinical outcomes. We propose a trial design which investigates ways of improving compliance. For efficiency, this trial is embedded in a larger trial for evaluating clinical effectiveness. It employs a technique called micro randomisation, where individual patients are randomised multiple times throughout the study. The aims of this article are (1) to verify whether the presence of an embedded secondary trial still allows valid analysis of the primary research and (2) to demonstrate the usefulness of the micro-randomisation technique for comparing compliance interventions. METHODS: Simulation studies were used to simulate a large number of clinical trials, in which no embedded trial was used, a micro-randomised embedded trial was used, and a factorial embedded trial was used. Each simulation recorded the operating characteristics of the primary and secondary trials. RESULTS: We show that the type I error rate of the primary analysis was not affected by the presence of an embedded secondary trial. Furthermore, we show that micro-randomisation is superior to a factorial design as it reduces the variation caused by within-patient correlation. It therefore requires smaller sample sizes - our simulations showed a requirement of 128 patients for a micro-randomised trial versus 760 patients for a factorial design, in the presence of within-patient correlation. CONCLUSION: We believe that an embedded, micro-randomised trial is a feasible technique that can potentially be highly useful in telehealth trials. PMID- 26968940 TI - The bicipital groove as a landmark for reconstruction of complex proximal humeral fractures with hybrid double plate osteosynthesis. AB - BACKGROUND: Complex proximal humerus fractures with metaphyseal comminution remain challenging regarding reduction and stability. In most fracture patterns the hard bone of the bicipital groove remains intact. In this case series, we describe a novel technique of hybrid double plate osteosynthesis of complex proximal humerus fractures with metaphyseal comminution. METHODS: In randomly chosen shoulder specimens and synthetic bones, pilot studies for evaluation of the feasibility of the technique were performed. Between 4/2010 and 1/2012 10 patients underwent hybrid double plate osteosynthesis. Seven patients (4 male, 3 female, mean age was 50 years (range 27-73)) were available for retrospective analysis. Based on plain radiographs (anterior-posterior and axial view), the fractures were classified according to the Orthopaedic Trauma Association classification (OTA) and by descriptive means (head-split variant (HS), diaphyseal extension or comminution (DE)). RESULTS: Follow-up radiographs demonstrated complete fracture healing in six patients and one incomplete avascular necrosis. None of the patients sustained loss of reduction. Three patients where reoperated. The medium, not adapted, Constant score was 80 Points (58-94). Patients subjective satisfaction was graded mean 3 (range: 0-6) in the visual analog scoring system (VAS). CONCLUSION: The technique of hybrid double plate osteosynthesis using the bicipital groove as anatomic landmark may re establish shoulder function after complex proximal humerus fractures in two dimensions. Firstly the anatomy is restored due to a proper reduction based on intraoperative landmarks. Secondly additional support by the second plate may provide a higher stability in complex fractures with metaphyseal comminution. PMID- 26968941 TI - Multi-objective optimization framework to obtain model-based guidelines for tuning biological synthetic devices: an adaptive network case. AB - BACKGROUND: Model based design plays a fundamental role in synthetic biology. Exploiting modularity, i.e. using biological parts and interconnecting them to build new and more complex biological circuits is one of the key issues. In this context, mathematical models have been used to generate predictions of the behavior of the designed device. Designers not only want the ability to predict the circuit behavior once all its components have been determined, but also to help on the design and selection of its biological parts, i.e. to provide guidelines for the experimental implementation. This is tantamount to obtaining proper values of the model parameters, for the circuit behavior results from the interplay between model structure and parameters tuning. However, determining crisp values for parameters of the involved parts is not a realistic approach. Uncertainty is ubiquitous to biology, and the characterization of biological parts is not exempt from it. Moreover, the desired dynamical behavior for the designed circuit usually results from a trade-off among several goals to be optimized. RESULTS: We propose the use of a multi-objective optimization tuning framework to get a model-based set of guidelines for the selection of the kinetic parameters required to build a biological device with desired behavior. The design criteria are encoded in the formulation of the objectives and optimization problem itself. As a result, on the one hand the designer obtains qualitative regions/intervals of values of the circuit parameters giving rise to the predefined circuit behavior; on the other hand, he obtains useful information for its guidance in the implementation process. These parameters are chosen so that they can effectively be tuned at the wet-lab, i.e. they are effective biological tuning knobs. To show the proposed approach, the methodology is applied to the design of a well known biological circuit: a genetic incoherent feed-forward circuit showing adaptive behavior. CONCLUSION: The proposed multi-objective optimization design framework is able to provide effective guidelines to tune biological parameters so as to achieve a desired circuit behavior. Moreover, it is easy to analyze the impact of the context on the synthetic device to be designed. That is, one can analyze how the presence of a downstream load influences the performance of the designed circuit, and take it into account. PMID- 26968942 TI - The Natural History of Human Polyomaviruses and Herpesviruses in Early Life--The Rhea Birth Cohort in Greece. AB - Sparse data exist on the patterns and determinants of acquisition of polyomaviruses and herpesviruses in childhood. We measured immunoglobulin G seroreactivity against 10 polyomaviruses (BKPyV, JCPyV, KIPyV, WUPyV, MCPyV, HPyV6, HPyV7, TSPyV, HPyV9, HPyV10) and 5 herpesviruses (Epstein Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus types 1 and 2, human herpesvirus 8) using multiplex serology on blood samples collected at birth (cord blood, n = 626) and at follow-up at 3 years (n = 81) and 4 years (n = 690) of age among the Rhea birth cohort recruited in Greece from pregnant women in 2007-2008. We used Poisson regression with robust variance to identify determinants of seropositivity at age 4. Seroprevalence of polyomaviruses ranged from 38.5% to 99.8% in cord blood and from 20.9% to 82.3% at age 4. Seroprevalence of EBV, CMV, herpes simplex virus types 1 and 2, and human herpesvirus 8 was 99.4%, 74.9%, 26.2%, 8.0%, and 1.6% in cord blood and 52.5%, 25.8%, 3.6%, 1.4%, and 0% at age 4, respectively. Determinants of seropositivity at age 4 were cord seropositivity (JCPyV, HPyV7, HPyV10, CMV), vaginal delivery (HPyV10), breastfeeding (CMV), younger age at day-care entry (BKPyV, KIPyV, WUPyV, TSPyV, HPyV10, HPyV9, EBV, CMV), and swimming pool attendance (BKPyV, KIPyV, WUPyV, HPyV10). Television viewing, parental stress, and hygiene practices were inversely associated with the seroprevalence of polyomaviruses and herpesviruses. PMID- 26968943 TI - Straight Metalworking Fluids and All-Cause and Cardiovascular Mortality Analyzed by Using G-Estimation of an Accelerated Failure Time Model With Quantitative Exposure: Methods and Interpretations. AB - Straight metalworking fluids have been linked to cardiovascular mortality in analyses using binary exposure metrics, accounting for healthy worker survivor bias by using g-estimation of accelerated failure time models. A cohort of 38,666 Michigan autoworkers was followed (1941-1994) for mortality from all causes and ischemic heart disease. The structural model chosen here, using continuous exposure, assumes that increasing exposure from 0 to 1 mg/m(3) in any single year would decrease survival time by a fixed amount. Under that assumption, banning the fluids would have saved an estimated total of 8,468 (slope-based 95% confidence interval: 2,262, 28,563) person-years of life in this cohort. On average, 3.04 (slope-based 95% confidence interval: 0.02, 25.98) years of life could have been saved for each exposed worker who died from ischemic heart disease. Estimates were sensitive to both model specification for predicting exposure (multinomial or logistic regression) and characterization of exposure as binary or continuous in the structural model. Our results provide evidence supporting the hypothesis of a detrimental relationship between straight metalworking fluids and mortality, particularly from ischemic heart disease, as well as an instructive example of the challenges in obtaining and interpreting results from accelerated failure time models using a continuous exposure in the presence of competing risks. PMID- 26968944 TI - Severe Human Parechovirus Infections in Infants and the Role of Older Siblings. AB - Human parechovirus (HPeV) is a cause of severe morbidity among infants and young children. To evaluate the associations between early environmental risk factors and HPeV infections, we carried out a nationwide cohort study linking registry data on birth and sibship characteristics with a laboratory surveillance database, covering all HPeV infections detected in Denmark during 2009-2012 among children <5 years of age. Incidence rate ratios were calculated in log-linear Poisson regression analyses. Overall, 133 HPeV infections, 85 caused by human parechovirus type 3 (HPeV-3) and 48 by human parechovirus other than type 3 (non HPeV-3), were detected among 132 children. Neither birth weight, mode of delivery, Apgar score, nor gestational age was associated with the risk of HPeV infections. Compared with firstborn children, secondborn children were at a 9 fold increased risk (incidence rate ratio = 8.68, 95% confidence interval: 3.85, 19.53) of contracting HPeV-3 infections, but at no increased risk of contracting non-HPeV-3 infections. However, the shorter the age gap to the nearest older sibling, the higher the risk of HPeV-3 as well as non-HPeV-3 infections, although the trend was strongest for HPeV-3 infections. Our study is the first to suggest that having a slightly older sibling increases the risk for severe neonatal HPeV infections. This new knowledge might lead to new preventive measures. PMID- 26968947 TI - Extra-tympanic electrocochleography in a normal population. A descriptive study. AB - INTRODUCTION AND OBJECTIVES: Extra-tympanic electrocochleography is an electrophysiological register obtained after stimulating the cochlea with an audible stimulus. This stimulus is applied using an earphone over the external auditory canal, while the electrical activity is registered by surface electrodes. There are few studies that analyse normal electrocochleography in our environment. Thus, the main objective of our study was to regularize the values obtained with electrocochleography in ears without any otoneurological diseases. We explain in detail the process of obtaining the register. METHODS: Sixty healthy ears were studied by extratympanic electrocochleography. Statistical results were analysed. While 30 ears were studied with a stimulus at 90dB, another 30 ears were studied with a stimulus at 80dB. RESULTS: Summating potential and action potential latencies and amplitudes were measured. Summating potential/action potential ratios were calculated. Wave I and wave II latencies were also determined. These results were analysed in function of stimulus intensity, patient gender, patient age group and ear side studied. CONCLUSIONS: This study collected extra-tympanic electrocochleography data in a normal population and the results were in the range of other international studies obtained in other countries. These data can be used as a reference to evaluate illnesses that affect cochlear structure or functions. PMID- 26968945 TI - Dexamethasone attenuates echinococcosis-induced allergic reactions via regulatory T cells in mice. AB - BACKGROUND: Cystic echinococcosis (CE), caused by infection with Echinococcus granulosus larvae, is a potentially life-threatening disease in humans. Anaphylactic shock caused by CE is very dangerous, and is highly prevalent during surgery. Dexamethasone (DEX) is used clinically before operations to prevent allergic reactions; Regulatory T cells (Treg cells) are believed to be associated with negative immune response, which play an important role in alleviating allergic reactions. However, the association of Treg cells with DEX remains unknown. METHODS: In this study, C57BL/6 mice were divided into uninfected group, untreated group and DEX group which were inoculated with protoscoleces from E. granulosus and sensitized using a cyst fluid suspension to induce anaphylactic shock. In addition, the mice in DEX group were treated with 10 mg/kg DEX by intraperitoneal injection 30 min before being sensitized. RESULTS: It was found that 93.75 % of all sensitized mice experienced allergic symptoms. The levels of IgE, IgE/IgG, and IgE/IgG1 were significantly higher in both untreated group and DEX group. The proportion of CD4 + CD25 + FOXP3 + Treg cells relative to CD4+ Treg cells, and the levels of interleukin-10 (IL-10) and tumor growth factor-beta (TGF-beta1) were significantly higher in DEX group. The level of IL-13 was significantly higher in the sensitized mice than in the other groups. These cells may play a key role in alleviating the immune response in CE-induced anaphylactic shock. CONCLUSIONS: The protective effect of DEX may be due to Treg cell upregulating IL-10 and TGF-beta1 levels, and inhibiting helper T cell 2 cytokines. PMID- 26968946 TI - HLA-G and classical HLA class I expression in primary colorectal cancer and associated liver metastases. AB - De novo expression of HLA-G has been demonstrated in colorectal cancer. HLA-G, amongst others, inhibits natural killer cell function, contributing to host immune defense evasion. Another mechanism to escape anti-tumor immunity is loss of HLA class I. Therefore, we determined HLA-G and HLA class I expression on primary colorectal tumors and associated liver metastases, in order to get insight in the metastasizing process regarding escaping anti-tumor immunity. HLA G expression was evaluated using three mAbs; 4H84, MEM-G/1 and MEM-G/2. In total 81 colorectal cancer patients were evaluated. Formalin-fixed paraffin-embedded tissue sections of primary tumors and associated liver metastases, were immunohistochemically stained. A concordance between expression or loss/downregulation in the primary tumor and associated liver metastasis regarding HLA class I expression was observed in 80% of the cases. In contrast with the hypothesis of escaping NK cell-killing, we demonstrated for each HLA-G detecting mAbs used in this study, that the majority of the primary tumors that positively stained for HLA-G did not express HLA-G in the associated liver metastasis. Furthermore, we revealed the existence of non-specific binding and in addition we found that the different epitopes of HLA-G detected by 4H84, MEM-G/1 and MEM-G/2 mAbs were expressed differentially in colorectal tumor tissues. PMID- 26968948 TI - Outbreak definition by change point analysis: a tool for public health decision? AB - BACKGROUND: Most studies of epidemic detection focus on their start and rarely on the whole signal or the end of the epidemic. In some cases, it may be necessary to retrospectively identify outbreak signals from surveillance data. Our study aims at evaluating the ability of change point analysis (CPA) methods to locate the whole disease outbreak signal. We will compare our approach with the results coming from experts' signal inspections, considered as the gold standard method. METHODS: We simulated 840 time series, each of which includes an epidemic-free baseline (7 options) and a type of epidemic (4 options). We tested the ability of 4 CPA methods (Max-likelihood, Kruskall-Wallis, Kernel, Bayesian) methods and expert inspection to identify the simulated outbreaks. We evaluated the performances using metrics including delay, accuracy, bias, sensitivity, specificity and Bayesian probability of correct classification (PCC). RESULTS: A minimum of 15 h was required for experts for analyzing the 840 curves and a maximum of 25 min for a CPA algorithm. The Kernel algorithm was the most effective overall in terms of accuracy, bias and global decision (PCC = 0.904), compared to PCC of 0.848 for human expert review. CONCLUSIONS: For the aim of retrospectively identifying the start and end of a disease outbreak, in the absence of human resources available to do this work, we recommend using the Kernel change point model. And in case of experts' availability, we also suggest to supplement the Human expertise with a CPA, especially when the signal noise difference is below 0. PMID- 26968949 TI - miR-101 targeting ZFX suppresses tumor proliferation and metastasis by regulating the MAPK/Erk and Smad pathways in gallbladder carcinoma. AB - Gallbladder cancer (GBC), the most common malignancy of the bile duct, is highly aggressive and has an extremely poor prognosis, which is a result of early metastasis. As it is regulated being at multiple levels, the metastatic cascade in GBC is complex. Recent evidence suggests that microRNAs (miRNAs) are involved in cancer metastasis and are promising therapeutic targets. In this study, miR 101 was significantly downregulated in tumor tissues, particularly in metastatic tissues. In GBC patients, low miR-101 expression was correlated with tumor size, tumor invasion, lymph node metastasis, TNM stage, and poor survival. Moreover, miR-101 was an independent prognostic marker for GBC. Additionally, miR-101 inhibited GBC cell proliferation, migration, invasion, and TGF-beta-induced epithelial-mesenchymal transition (EMT) in vitro and in vivo. Mechanistically, the gene encoding the zinc finger protein X-linked (ZFX) was identified as a direct target of miR-101. More importantly, miR-101 significantly reduced activation of the MAPK/Erk and Smad signaling pathways, resulting in inhibition of TGF-beta-mediated induction of EMT. Altogether, our findings demonstrate a novel mechanism by which miR-101 attenuates the EMT and metastasis in GBC cells and suggest that miR-101 can serve as a potential biomarker and therapeutic target for GBC management. PMID- 26968950 TI - Noninvasive bioluminescence imaging of the dynamics of sanguinarine induced apoptosis via activation of reactive oxygen species. AB - Most chemotherapeutic drugs exert their anti-tumor effects primarily by triggering a final pathway leading to apoptosis. Noninvasive imaging of apoptotic events in preclinical models would greatly facilitate the development of apoptosis-inducing compounds and evaluation of their therapeutic efficacy. Here we employed a cyclic firefly luciferase (cFluc) reporter to screen potential pro apoptotic compounds from a number of natural agents. We demonstrated that sanguinarine (SANG) could induce apoptosis in a dose- and time-dependent manner in UM-SCC-22B head and neck cancer cells. Moreover, SANG-induced apoptosis was associated with the generation of reactive oxygen species (ROS) and activation of c-Jun-N-terminal kinase (JNK) and nuclear factor-kappaB (NF-kappaB) signal pathways. After intravenous administration with SANG in 22B-cFluc xenograft models, a dramatic increase of luminescence signal can be detected as early as 48 h post-treatment, as revealed by longitudinal bioluminescence imaging in vivo. Remarkable apoptotic cells reflected from ex vivo TUNEL staining confirmed the imaging results. Importantly, SANG treatment caused distinct tumor growth retardation in mice compared with the vehicle-treated group. Taken together, our results showed that SANG is a candidate anti-tumor drug and noninvasive imaging of apoptosis using cFluc reporter could provide a valuable tool for drug development and therapeutic efficacy evaluation. PMID- 26968951 TI - Serum Helicobacter pylori FliD antibody and the risk of gastric cancer. AB - FliD and CagA are important virulence factors of H. pylori. We aimed to evaluate the screening values of FliD and CagA for gastric cancer (GC). Serum samples were obtained from 232 cases and 266 controls in a case-control study. Unconditional multivariate logistic regression with odds ratios (ORs) and 95% confidence intervals (CIs) was used to analyze the relationships between FliD, CagA and GC. The sensitivities, specificities and receiver operating characteristic (ROC) curves were calculated. Finally, the combined screening values of FliD, FlaA, NapA and CagA were assessed based on discriminant analysis. In all subjects, the associations of FliD and CagA with GC were evident with ORs (95% CIs) of 7.6 (4.7 12.3) and 2.5 (1.6-3.8), respectively (*p<0.001). The areas under ROC curves (AUCs) for FliD and CagA were 0.800 and 0.653, respectively. The AUC for the combination of FliD, FlaA and NapA was 0.915, which represented an increase of 0.115 over that of FliD alone (*p<0.001). These findings indicate that the FliD antibody is associated with GC and could exhibit high validity as a biomarker in screening for GC patients. The combination of FliD, FlaA and NapA improved the screening validity. PMID- 26968952 TI - In vitro and in vivo anti-tumor activity of CoQ0 against melanoma cells: inhibition of metastasis and induction of cell-cycle arrest and apoptosis through modulation of Wnt/beta-catenin signaling pathways. AB - Coenzyme Q0 (CoQ0, 2,3-dimethoxy-5-methyl-1,4-benzoquinone), a novel quinone derivative, has been shown to modulate cellular redox balance. However, effect of this compound on melanoma remains unclear. This study examined the in vitro or in vivo anti-tumor, apoptosis, and anti-metastasis activities of CoQ0 (0-20 MUM) through inhibition of Wnt/beta-catenin signaling pathway. CoQ0 exhibits a significant cytotoxic effect on melanoma cell lines (B16F10, B16F1, and A2058), while causing little toxicity toward normal (HaCaT) cells. The suppression of beta-catenin was seen with CoQ0 administration accompanied by a decrease in the expression of Wnt/beta-catenin transcriptional target c-myc, cyclin D1, and survivin through GSK3beta-independent pathway. We found that CoQ0 treatment caused G1 cell-cycle arrest by reducing the levels of cyclin E and CDK4. Furthermore, CoQ0 treatment induced apoptosis through caspase-9/-3 activation, PARP degradation, Bcl-2/Bax dysregulation, and p53 expression. Notably, non- or sub-cytotoxic concentrations of CoQ0 markedly inhibited migration and invasion, accompanied by the down-regulation of MMP-2 and -9, and up-regulation of TIMP-1 and -2 expressions in highly metastatic B16F10 cells. Furthermore, the in vivo study results revealed that CoQ0 treatment inhibited the tumor growth in B16F10 xenografted nude mice. Histological analysis and western blotting confirmed that CoQ0 significantly decreased the xenografted tumor progression as demonstrated by induction of apoptosis, suppression of beta-catenin, and inhibition of cell cycle , apoptotic-, and metastatic-regulatory proteins. The data suggest that CoQ0 unveils a novel mechanism by down-regulating Wnt/beta-catenin pathways and could be used as a potential lead compound for melanoma chemotherapy. PMID- 26968953 TI - Short- and long-term outcomes in onco-hematological patients admitted to the intensive care unit with classic factors of poor prognosis. AB - Although the overall mortality of patients admitted to intensive care units (ICU) with hematological malignancy has decreased over the years, some groups of patients still have low survival rates. We performed a monocentric retrospective study including all patients with hematological malignancy in a ten-year period, to identify factors related to the outcome for the whole cohort and for patients with allogeneic hematopoietic stem cell transplantation (HSCT), neutropenia, or those requiring invasive mechanical ventilation (IMV). A total of 418 patients with acute leukemia (n=239; 57%), myeloma (n=69; 17%), and lymphoma (n=53; 13%) were studied. Day-28 and 1-year mortality were 49% and 72%, respectively. The type of disease was not associated with outcome. The disease status was independentlty associated with 1-year mortality only. Independent predictors of day-28 mortality were IMV, renal replacement therapy (RRT), and performance status. For allogeneic HSCT recipients (n=116), neutropenic patients (n=124) and patients requiring IMV (n=196), day-28 and 1-year mortality were 52%, 54%, 74% and 81%, 78%, 87%, respectively. Multivariate analysis showed that IMV and RRT for allogeneic HSCT recipients, performance status and IMV for neutropenic patients, and RRT for patients requiring IMV were independently associated with short-term mortality (p<0.05).These results suggest that IMV is the strongest predictor of mortality in hematological patients admitted to ICUs, whereas allogeneic HSCT and neutropenia do not worsen their short-term outcome. PMID- 26968954 TI - ChIP-on-chip analysis of thyroid hormone-regulated genes and their physiological significance. AB - Triiodothyronine (T3) and its receptor (TR) modulate several physiological processes, including cell development, proliferation, differentiation and metabolism. The regulatory mechanism of T3/TR involves binding to the thyroid hormone response element (TRE) within the target gene promoter. However, the number of target genes directly regulated by TRalpha1 and the specific pathways of TR-regulated target genes remain largely unknown. Here, we expressed TRalpha1 in a HepG2 cell line and used chromatin immunoprecipitation coupled with microarray to determine the genes that are directly regulated by TRalpha1 and also involved in cell metabolism and proliferation. Our analysis identified E74 like factor 2 (ELF2), a transcription factor associated with tumor growth, as a direct target downregulated by T3/TR. Overexpression of ELF2 enhanced tumor cell proliferation, and conversely, its knockdown suppressed tumor growth. Additionally, ELF2 restored the proliferative ability of hepatoma cells inhibited by T3/TR. Our findings collectively support a potential role of T3/TR in tumor growth inhibition through regulation of ELF2. PMID- 26968955 TI - Distribution of prostate nodes: a PET/CT-derived anatomic atlas of prostate cancer patients before and after surgical treatment. AB - BACKGROUND: In order to define adequate radiation portals in nodal positive prostate cancer a detailed knowledge of the anatomic lymph-node distribution is mandatory. We therefore systematically analyzed the localization of Choline PET/CT positive lymph nodes and compared it to the RTOG recommendation of pelvic CTV, as well as to previous work, the SPECT sentinel lymph node atlas. METHODS: Thirty-two patients being mostly high risk patients with a PSA of 12.5 ng/ml (median) received PET/CT before any treatment. Eighty-seven patients received PET/CT for staging due to biochemical failure with a median PSA of 3.12 ng/ml. Each single PET-positive lymph node was manually contoured in a "virtual" patient dataset to achieve a 3-D visualization, resulting in an atlas of the cumulative PET positive lymph node distribution. Further the PET-positive lymph node location in each patient was assessed with regard to the existence of a potential geographic miss (i.e. PET-positive lymph nodes that would not have been treated adequately by the RTOG consensus on CTV definition of pelvic lymph nodes). RESULTS: Seventy-eight and 209 PET positive lymph nodes were detected in patients with no prior treatment and in postoperative patients, respectively. The most common sites of PET positive lymph nodes in patients with no prior treatment were external iliac (32.1 %), followed by common iliac (23.1 %) and para-aortic (19.2 %). In postoperative patients the most common sites of PET positive lymph nodes were common iliac (24.9 %), followed by external iliac (23.0 %) and para-aortic (20.1 %). In patients with no prior treatment there were 34 (43.6 %) and in postoperative patients there were 77 (36.8 %) of all detected lymph nodes that would not have been treated adequately using the RTOG CTV. We compared the distribution of lymph nodes gained by Choline PET/CT to the preexisting SPECT sentinel lymph node atlas and saw an overall good congruence. CONCLUSIONS: Choline PET/CT and SPECT sentinel lymph node atlas are comparable to each other. More than one-third of the PET positive lymph nodes in patients with no prior treatment and in postoperative patients would not have been treated adequately using the RTOG CTV. To reduce geographical miss, image based definition of an individual target volume is necessary. PMID- 26968956 TI - Clinical characteristics and genetic subtypes of Fanconi anemia in Saudi patients. AB - We reviewed our institutional experience from 2011 to 2015 on new cases of Fanconi anemia (FA). Ten unrelated cases were diagnosed during this period. Four patients with severe aplastic anemia (SAA) had c.2392C > T (p.Arg798*) BRIP1/FANCJ mutation. Another child with SAA had novel c.1475T > C (p.Leu492Pro) FANCC mutation. One individual with SAA and acute myeloid leukemia had c.637_643del (p.Tyr213Lysfs*6) FANCG mutation. Three patients presented with early onset of cancer, two had BRCA2 mutation c.7007G > A (p.Arg2336His) and one had a novel c.3425del (p.Leu1142Tyrfs*21) PALB2 mutation. Another infant with c.3425del PALB2 mutation had clonal aberration with partial trisomy of the long arm of chromosome 17. Mutations in FA downstream pathway genes are more frequent in our series than expected. Our preliminary observation will be confirmed in a large multi-institutional study. PMID- 26968958 TI - The Natural History of Food Allergy. AB - On a population level, it is well recognized that some IgE-mediated childhood food allergies, such as milk and egg allergies, are more likely to resolve than others, such as peanut and tree nuts allergies. Unfortunately, some studies suggest that resolution rates may have slowed compared with impressions from past decades. The clinician can apply the knowledge of the epidemiology of these allergies to describe likely patient outcomes, and direct management in a general manner. However, the ability to evaluate and predict the natural course of specific food allergies for individual patients is essential to inform personalized patient care. Data are accumulating to assist in identifying whether a child's allergy has likely resolved, informing the timing of oral food challenges or subsequent testing. Exciting recent studies are increasingly identifying early prognostic markers as well. Emerging food allergy therapies carry risks and costs. Identifying which egg-allergic patient has likely persistent allergy, and which patient with peanut allergy may experience natural resolution, is becoming an important goal to identify the best candidates for these therapies. Although more work needs to be done to identify reliable predictive markers and validate them, there is already much known about the natural course of food allergies that can be applied by the clinician to improve patient care. PMID- 26968957 TI - Community and District Empowerment for Scale-up (CODES): a complex district-level management intervention to improve child survival in Uganda: study protocol for a randomized controlled trial. AB - BACKGROUND: Innovative and sustainable strategies to strengthen districts and other sub-national health systems and management are urgently required to reduce child mortality. Although highly effective evidence-based and affordable child survival interventions are well-known, at the district level, lack of data, motivation, analytic and planning capacity often impedes prioritization and management weaknesses impede implementation. The Community and District Empowerment for Scale-up (CODES) project is a complex management intervention designed to test whether districts when empowered with data and management tools can prioritize and implement evidence-based child survival interventions equitably. METHODS: The CODES strategy combines management, diagnostic, and evaluation tools to identify and analyze the causes of bottlenecks to implementation, build capacity of district management teams to implement context specific solutions, and to foster community monitoring and social accountability to increase demand for services. CODES combines UNICEF tools designed to systematize priority setting, allocation of resources and problem solving with Community dialogues based on Citizen Report Cards and U-Reports used to engage and empower communities in monitoring health service provision and to demand for quality services. Implementation and all data collection will be by the districts teams or local Community-based Organizations who will be supported by two local implementing partners. The study will be evaluated as a cluster randomized trial with eight intervention and eight comparison districts over a period of 3 years. Evaluation will focus on differences in uptake of child survival interventions and will follow an intention-to-treat analysis. We will also document and analyze experiences in implementation including changes in management practices. DISCUSSION: By increasing the District Health Management Teams' capacity to prioritize and implement context-specific solutions, and empowering communities to become active partners in service delivery, coverage of child survival interventions will increase. Lessons learned on strengthening district-level managerial capacities and mechanisms for community monitoring may have implications, not only in Uganda but also in other similar settings, especially with regard to accelerating effective coverage of key child survival interventions using locally available resources. TRIAL REGISTRATION NUMBER: ISRCTN15705788 , Date of registration; 24 July 2015. PMID- 26968959 TI - Clinical Management of Psychosocial Concerns Related to Food Allergy. AB - Current estimates indicate that 4% to 8% of children in the United States are diagnosed with food allergy, and more than 40% of US children with food allergy experience severe allergic reactions. Families trying to avoid foods that may trigger an allergic reaction and ensure adequate treatment of allergic reactions that do occur face numerous challenges. The rise in the number of children diagnosed with food allergies underscores the importance of food allergy-related interventions to address elevated psychosocial concerns, such as parenting stress, anxiety, and worries about bullying. This review provides an overview of common psychosocial concerns among children with food allergy and their families across the developmental spectrum, and offers guidance to medical providers regarding the identification and treatment of food allergy-related psychosocial challenges. PMID- 26968961 TI - Elimination Diets in Eczema--A Cautionary Tale. PMID- 26968960 TI - The Complexities of Early Peanut Introduction for the Practicing Allergist. AB - Recommendations for the timing of introducing major food allergens, such as peanut, into the diet of at-risk infants have undergone major changes in the past decade. The most substantial modification has been a shift toward advice that delaying beyond 4 to 6 months does not prevent and might actually increase the risk of food allergy. The Learning Early About Peanut (LEAP) study published last year provided strong evidence that early peanut introduction with regular ingestion has a potentially dramatic benefit. Although there is little current doubt of the effectiveness of early peanut introduction, many unanswered questions remain. Previous guidelines defined infants at risk as those with a first-degree relative with allergic disease, whereas the LEAP study defined high risk as severe eczema or egg allergy. The LEAP study chose to screen infants but did not have a comparison group randomized without screening. In the following case-based discussion, we explore the complexities of LEAP implementation for the practicing allergist. These include nonuniformity in the literature for defining at-risk infants, difficulties in assessing eczema severity objectively, variable adherence to current guidelines, proposed peanut screening methods contrasting with existing food allergy guidelines to not routinely screen before ingestion, unclear interpretation of positive test results if screened, risks of screening extending to foods not studied in the LEAP study, and uncertainties about the optimal dose and duration of peanut once introduced. PMID- 26968962 TI - A Tale of 2 Tails: The Interpretation of Changes in Allergen-Specific IgE Following Incidental Allergen Exposure. PMID- 26968963 TI - Monitoring Allergic Patients on Omalizumab with Free and Total Serum IgE Measurements. PMID- 26968964 TI - Eosinophilic Gastrointestinal Diseases. PMID- 26968965 TI - Reply. PMID- 26968966 TI - Inhaled Corticosteroids for Asthma Therapy in Young Children: Does Aerosol Particle Size Matter? PMID- 26968968 TI - Imatinib mesylate for unmutated hypereosinophilic syndromes: Does it work? PMID- 26968969 TI - The pulmonary endothelium in acute respiratory distress syndrome: insights and therapeutic opportunities. AB - The pulmonary endothelium is a dynamic, metabolically active layer of squamous endothelial cells ideally placed to mediate key processes involved in lung homoeostasis. Many of these are disrupted in acute respiratory distress syndrome (ARDS), a syndrome with appreciable mortality and no effective pharmacotherapy. In this review, we consider the role of the pulmonary endothelium as a key modulator and orchestrator of ARDS, highlighting advances in our understanding of endothelial pathobiology and their implications for the development of endothelial-targeted therapeutics including cell-based therapies. We also discuss mechanisms to facilitate the translation of preclinical data into effective therapies including the application of biomarkers to phenotype patients with ARDS with a predominance of endothelial injury and emerging biotechnologies that could enhance delivery, discovery and testing of lung endothelial-specific therapeutics. PMID- 26968971 TI - Reduced physical activity in lymphangioleiomyomatosis compared with COPD and healthy controls: disease-specific impact and clinical correlates. AB - RATIONALE: Sporadic lymphangioleiomyomatosis (LAM) is an orphan lung disease for which daily physical activity has not been studied so far and it is unclear whether a disease-specific impact beyond airflow limitation exists. Clinical correlates indicating reduced physical activity in addition to established parameters like airflow limitation and hypoxaemia are largely undetermined. METHOD: We measured physical activity (steps per day, SPD; physical activity level, PAL; minutes of moderate activity, MMA) in 34 women with LAM, 32 FEV1 matched female patients with COPD and 15 age-matched healthy women for 1 week using an accelerometer. In addition, we assessed lung function measurements, questionnaires for generic and respiratory health status (12-Item Short Form Survey, SF-12; St. George's Respiratory Questionnaire, SGRQ), dyspnoea (modified Medical Research Council dyspnoea scale, mMRC) and fatigue (Multidimensional Fatigue Inventory, MFI-20). RESULTS: Patients with LAM (mean age 52.7 years, mean FEV1 62.7% predicted) showed reduced SPD, PAL and MMA (p<0.01) compared with healthy controls and reduced MMA (p=0.032) compared with female patients with COPD (mean age 65.2 years, mean FEV1 62.6% predicted). In multivariate regression analyses, adjusting for FEV1 and long-term oxygen therapy, either generic health status (SF-12 physical health) or fatigue (MFI-20) were the strongest independent predictors for SPD in patients with LAM (p=0.006 and p=0.004, respectively). CONCLUSIONS: Physical activity in daily life is substatially reduced in LAM, when compared with healthy controls and COPD - indicating a disease specific impact. The regular assessment of fatigue and generic health status may improve disease management in LAM by taking daily physical activity of patients with LAM more adequately into account. PMID- 26968970 TI - Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis. AB - BACKGROUND: The assessment of treatment response in idiopathic pulmonary fibrosis (IPF) is complicated by the variable clinical course. We examined the variability in the rate of disease progression and evaluated the effect of continued treatment with pirfenidone in patients who experienced meaningful progression during treatment. METHODS: The source population included patients enrolled in the ASCEND and CAPACITY trials (N=1247). Pearson's correlation coefficients were used to characterise the relationship between changes in FVC during consecutive 6 month intervals in the placebo population. Outcomes following a >=10% decline in FVC were evaluated by comparing the proportion of patients in the pirfenidone and placebo groups who experienced a >=10% decline in FVC or death during the subsequent 6 months. RESULTS: A weak negative correlation was observed between FVC changes during consecutive intervals in the placebo population (coefficient, 0.146, p<0.001), indicating substantial variability. Thirty-four (5.5%) and 68 (10.9%) patients in the pirfenidone and placebo groups, respectively, experienced a >=10% decline in FVC by month 6. During the subsequent 6 months, fewer patients in the pirfenidone group compared with placebo experienced a >=10% decline in FVC or death (5.9% vs 27.9%; relative difference, 78.9%). There was one (2.9%) death in the pirfenidone group and 14 (20.6%) deaths in the placebo group (relative difference, 85.7%). CONCLUSIONS: Longitudinal FVC data from patients with IPF showed substantial intrasubject variability, underscoring the inability to reliably assess therapeutic response using serial FVC trends. In patients who progressed during treatment, continued treatment with pirfenidone resulted in a lower risk of subsequent FVC decline or death. TRIAL REGISTRATION NUMBERS: NCT01366209, NCT00287729, NCT00287716. PMID- 26968967 TI - Fish consumption in mid-childhood and its relationship to neuropsychological outcomes measured in 7-9 year old children using a NUTRIMENTHE neuropsychological battery. AB - BACKGROUND: Long-chain polyunsaturated fatty acids (LCPUFA), particularly n-3 LCPUFA, play a central role in neuronal growth and the development of the human brain. Fish is the main dietary source of n-3 LCPUFA. To assess the relation between fish consumption, estimated dietary n-3 LCPUFA intake and cognition and behaviour in childhood in a multi-centre European sample. METHODS: Children from 2 European studies, CHOP and NUHEAL, were assessed at 8 and 7.5 years of age, respectively. Different outcomes of neuropsychological development (assessed with the standardized NUTRIMENTHE Neuropsychological Battery (NNB) consisting of 15 subtests) were related with outcomes from a food-frequency questionnaire (FFQ) focussing on the consumption of fish. RESULTS: A total of 584 children completed the FFQ and the neuropsychological tests. We found no associations with calculated DHA or EPA intakes for any of the neuropsychological domains. Children who consumed 2 fish meals per week including one of fatty fish, showed no substantive differences in the cognitive domains from the children who did not. However negative associations with fatty fish consumption were found for social problems (p = 0.019), attention problems (p = 0.012), rule-breaking problems (p = 0.019) and aggressive behaviour problems (p = 0.032). No association was observed with internalizing problems. Higher levels of externalizing problems (p = 0.018) and total problems (p = 0.018) were associated with eating less fatty fish. CONCLUSIONS: Children who consumed 2 fish meals per week including one of fatty fish were less likely to show emotional and behavioural problems than those who did not. PMID- 26968972 TI - Breaking the link between provocation and aggression: The role of mitigating information. AB - In two experimental studies, we examine the extent to which strong or weak mitigating information after a provocation alters aggressive responding. In Study 1, we randomly assigned 215 (108 female) college-aged participants to a strong or weak provocation by having a research assistant talk to the participant about failing a task in a harsh or confused tone. This was followed by a second research assistant giving a strong or weak excuse to the participant regarding the first research assistant's behavior. Then, aggressive behavior was assessed using a researcher rating task. In Study 2, 63 (25 female) college-aged participants interacted with a confederate on the CRT. All participants were strongly provoked by receiving strong noise blasts. After five CRT trials, the confederate delivered weak or strong mitigating information to the participant regarding the noises blasts. The results indicated that: (i) strong provocations are more likely to increase aggression than weak provocations; (ii) strong mitigating information is more likely to decrease aggression than weak mitigating information; and (iii) the varying strength of mitigating information is important in situations involving weak, but not strong provocations: strong mitigating information is more likely than weak mitigating information reduce aggression when provocation is strong, but not when provocation is weak. We discuss the importance of mitigating information in decreasing aggressive behavior and the conditions in which mitigating information is especially likely to be effective. Aggr. Behav. 42:555-562, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26968973 TI - Assessment of enlarged perivascular spaces and their relation to target organ damage and mild cognitive impairment in patients with hypertension. AB - BACKGROUND AND PURPOSE: Enlarged perivascular spaces (EPVS) have been recently considered a feature of cerebral small vessel disease. They have been related to aging, hypertension and dementia but their relationship with hypertension related variables (i.e. target organ damage, treatment compliance) and mild cognitive impairment (MCI) is not fully elucidated. Our aims were to investigate the relation between basal ganglia (BG) and centrum semiovale (CSO) EPVS with vascular risk factors, hypertension related variables and MCI. METHODS: In all, 733 hypertensive individuals free of stroke and dementia from the Investigating Silent Strokes in Hypertensives, a magnetic resonance imaging Study (ISSYS) underwent brain magnetic resonance imaging and cognitive testing to diagnose MCI or normal cognitive aging. RESULTS: The numbers of participants presenting high grade (>10) EPVS at the BG and CSO were 23.3% and 40.0%, respectively. After controlling for vascular risk factors, high grade BG EPVS were associated with age (odds ratio 1.68; 95% confidence interval 1.37, 2.06), poor antihypertensive compliance (1.49; 1.03, 2.14) and the presence of microalbuminuria (1.95; 1.16, 3.28), whereas in the CSO only age (1.38; 1.18, 1.63) and male sex were associated with EPVS (1.73; 1. 24, 2.42). MCI was diagnosed in 9.3% of the participants and it was predicted by EPVS in the BG (1.87; 1.03, 3.39) but not in the CSO. This last association was greatly attenuated after correction for lacunes and white matter hyperintensities. CONCLUSIONS: Basal ganglia EPVS are associated with the presence of microalbuminuria and poor adherence to antihypertensive drugs. The BG EPVS relation with MCI is not independent of the presence of other cerebral small vessel disease markers. PMID- 26968974 TI - Effects of Polyoxyethylene Alkyl Ethers on the Intestinal Transport and Absorption of Rhodamine 123: A P-glycoprotein Substrate by In Vitro and In Vivo Studies. AB - We examined the effects of polyoxyethylene alkyl ethers (Brijs) on the intestinal transport and absorption of rhodamine 123, a P-glycoprotein (P-gp) substrate, by in vitro and in vivo studies. Brijs increased the absorptive transport of rhodamine 123 and decreased its secretory transport in the in vitro diffusion chamber method. However, Brijs did not change the transport of 5(6) carboxyfluorescein, a non-P-gp substrate, indicating that the effect of Brijs on the transport of drugs was P-gp substrate-specific. The effects of Brijs on rhodamine 123 transport across Caco-2 cell monolayers were also examined. Secretory transport of rhodamine 123 was enhanced and its absorptive transport was significantly reduced in the presence of Brijs. Furthermore, in the in vivo studies, Brijs also enhanced the intestinal absorption of rhodamine 123 in rats. The intestinal membrane damage produced by Brijs was also evaluated by measuring the activity of lactate dehydrogenase and the release of protein. We found almost no intestinal damage in the presence of various Brijs. These findings suggest that Brijs might inhibit the function of intestinal P-gp, thereby increasing the intestinal transport and absorption of P-gp substrates without serious intestinal membrane damage. PMID- 26968976 TI - Predictors of Triptan Response in Pediatric Migraine. AB - BACKGROUND: Migraine is common in children and adolescents and can be disabling. Being able to predict which patients will respond to triptans based on their clinical phenotype would be helpful. Adult data suggest cranial autonomic symptoms and aura predict triptan response. This study examined clinical predictors of triptan response in pediatric migraineurs. METHODS: This chart review study included all patients less than 18 years old with migraine who were seen at the University of California, San Francisco Headache Center in 2014. Univariate chi(2) analyses were performed, followed by multivariate logistic regression modeling. RESULTS: Of 127 pediatric migraineurs, 70 (55%) had chronic migraine and 24 (19%) had aura. The majority (55%) had at least one cranial autonomic symptom. Of 65 with triptan outcome data, 47 (73%) benefitted from a triptan. In univariate analyses, triptan benefit was seen in 65% with chronic migraine versus 88% with episodic migraine (P = 0.048), 67% with aura versus 74% without (P = 0.66), and 70% with cranial autonomic symptom versus 74% without (P = 0.76). In a multivariate logistic regression model, chronic migraine, aura, and cranial autonomic symptom were not statistically significant predictors of triptan benefit: chronic migraine: 0.25 (0.06-1.04); aura: 0.65 (0.09-4.45); cranial autonomic symptom: 0.75 (0.22-2.52). CONCLUSIONS: In univariate analysis, individuals with chronic migraine were less likely to benefit from triptans. In contrast to what has been documented in adults, cranial autonomic symptoms and aura did not predict triptan response, although our small sample size limited the study's power. Larger pediatric studies are needed, and future pediatric triptan trials should provide response rates stratified by clinical variables such as aura. PMID- 26968975 TI - Systemic pro-inflammatory response facilitates the development of cerebral edema during short hypoxia. AB - BACKGROUND: High-altitude cerebral edema (HACE) is the severe type of acute mountain sickness (AMS) and life threatening. A subclinical inflammation has been speculated, but the exact mechanisms underlying the HACE are not fully understood. METHODS: Human volunteers ascended to high altitude (3860 m, 2 days), and rats were exposed to hypoxia in a hypobaric chamber (5000 m, 2 days). Human acute mountain sickness was evaluated by the Lake Louise Score (LLS), and plasma corticotrophin-releasing hormone (CRH) and cytokines TNF-alpha, IL-1beta, and IL 6 were measured in rats and humans. Subsequently, rats were pre-treated with lipopolysaccharide (LPS, intraperitoneal (ip) 4 mg/kg, 11 h) to induce inflammation prior to 1 h hypoxia (7000 m elevation). TNF-alpha, IL-1beta, IL-6, nitric oxide (NO), CRH, and aquaporin-4 (AQP4) and their gene expression, Evans blue, Na(+)-K(+)-ATPase activity, p65 translocation, and cell swelling were measured in brain by ELISA, Western blotting, Q-PCR, RT-PCR, immunohistochemistry, and transmission electron micrography. MAPKs, NF-kappaB pathway, and water permeability of primary astrocytes were demonstrated. All measurements were performed with or without LPS challenge. The release of NO, TNF alpha, and IL-6 in cultured primary microglia by CRH stimulation with or without PDTC (NF-kappaB inhibitor) or CP154,526 (CRHR1 antagonist) were measured. RESULTS: Hypobaric hypoxia enhanced plasma TNF-alpha, IL-1beta, and IL-6 and CRH levels in human and rats, which positively correlated with AMS. A single LPS injection (ip, 4 mg/kg, 12 h) into rats increased TNF-alpha and IL-1beta levels in the serum and cortex, and AQP4 and AQP4 mRNA expression in cortex and astrocytes, and astrocyte water permeability but did not cause brain edema. However, LPS treatment 11 h prior to 1 h hypoxia (elevation, 7000 m) challenge caused cerebral edema, which was associated with activation of NF-kappaB and MAPKs, hypoxia-reduced Na(+)-K(+)-ATPase activity and blood-brain barrier (BBB) disruption. Both LPS and CRH stimulated TNF-alpha, IL-6, and NO release in cultured rat microglia via NF-kappaB and cAMP/PKA. CONCLUSIONS: Preexisting systemic inflammation plus a short severe hypoxia elicits cerebral edema through upregulated AQP4 and water permeability by TLR4 and CRH/CRHR1 signaling. This study revealed that both infection and hypoxia can cause inflammatory response in the brain. Systemic inflammation can facilitate onset of hypoxic cerebral edema through interaction of astrocyte and microglia by activation of TLR4 and CRH/CRHR1 signaling. Anti-inflammatory agents and CRHR1 antagonist may be useful for prevention and treatment of AMS and HACE. PMID- 26968977 TI - Eligibility for PCSK9 treatment in 734 Hypercholesterolemic patients referred to a regional cholesterol treatment center with LDL cholesterol >= 70 mg/dl despite maximal tolerated cholesterol lowering therapy. AB - BACKGROUND: LDL cholesterol (LDLC) lowering has been revolutionized by PCSK9 inhibitors, Alirocumab (Praluent) and Evolocumab (Repatha), approved as adjuncts to maximally tolerated cholesterol lowering therapy in heterozygous (HeFH) or homozygous (HoFH) familial hypercholesterolemia, and/or clinical atherosclerotic cardiovascular disease (CVD) where LDLC lowering is insufficient. METHODS: We applied FDA and insurance eligibility criteria for PCSK9 inhibitor use in 734 hypercholesterolemic patients serially referred over 3 years who then received >= 2 months maximally tolerated LDLC lowering therapy with follow up LDLC >= 70 mg/dl, and in 50 patients approved by insurance for PCSK9 inhibitors. We documented the percentage of patients with HeFH and/or CVD who met FDA and insurance criteria for PCSK9 inhibitor therapy using LDLC goal-based guidelines. RESULTS: Of 734 patients with LDLC >= 70 mg/dl after >= 2 months maximally tolerated LDLC lowering therapy, 220 (30%) had HeFH and/or CVD with LDLC > 100 mg/dl, meeting FDA-insurance criteria for PCSK9 inhibitor therapy. Another 66 (9%) patients were statin intolerant, without HeFH or CVD. Of the 50 patients whose PCSK9 inhibitor therapy was approved for insurance coverage, 45 (90%) had LDLC > 100 mg/dl after >= 2 months on maximally tolerated LDLC lowering therapy. Seventeen of these 50 patients (34%) had HeFH without CVD (LDLC on treatment 180 +/- 50 mg/dl), 15 (30%) had CVD without HeFH (LDLC on treatment 124 +/- 26 mg/dl), 14 (28%) had both HeFH and CVD (LDLC on treatment 190 +/- 53 mg/dl), and 4 (8%) had neither HeFH nor CVD (LCLC 142 +/- 11 mg/dl). CONCLUSION: Of 734 patients referred for LDLC reduction, with LDLC >= 70 mg/dl after >= 2 months on maximally tolerated therapy, 220 (30%) had HeFH and/or CVD with LDLC > 100 mg/dl, meeting FDA-insurance criteria for PCSK9 inhibitor therapy as an adjunct to diet maximally tolerated cholesterol lowering therapy in HeFH or CVD. If 30% of patients with high LDLC and HeFH-CVD are eligible for PCSK9 inhibitors, then specialty pharmaceutical pricing models (~$14,300/year) will collide with tens of millions of HeFH-CVD patients. We speculate that if there was a 50 % reduction in CVD, then there would be savings of $245 billion, in the middle of the range of estimated PCSK9 inhibitor costs of $185-342 billion. Whether the health care savings arising from the anticipated reduction of CVD events by PCSK9 inhibitors justify their extraordinary costs in broad population use remains to be determined. PMID- 26968978 TI - Exogenous hydrogen sulphide ameliorates diabetic cardiomyopathy in rats by reversing disordered calcium-handling system in sarcoplasmic reticulum. AB - OBJECTIVES: Hydrogen sulphide (H2 S) has been found to be involved in cardiovascular diseases, but the exact mechanism has not been clarified. The purpose of this study was to investigate whether sodium hydrogen sulphide (NaHS), the donor of H2 S, can improve diabetic cardiomyopathy by reversing disordered calcium-handling system in sarcoplasmic reticulum (SR). METHODS: Sprague Dawley rats were injected with streptozotocin (STZ, 60 mg/kg, i.p.) to build diabetic model. Treatment groups included: aminoguanidine group (AG, 100 mg/kg, p.o.) and NaHS group (5 mg/kg per day, s.c.). KEY FINDINGS: Cardiac dysfunction and myocardial hypertrophy were found in diabetic model (DM) group, along with increased ROS levels and upregulated mRNA and protein expressions of NADPH p22(phox) , endothelin A receptor (ETA ) and protein kinase Cepsilon (PKCepsilon). Expressions of calcium-handling proteins in SR including FK506 binding proteins (FKBP12.6), sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) and calsequestrin 2 (CASQ2) were downregulated in DM group, accompanied by elevated concentration of diastolic free calcium in high glucose-incubated cardiomyocytes, indicating of calcium leak. After treated by NaHS, these abnormalities were attenuated significantly. CONCLUSIONS: Exogenous H2 S played a protective role in diabetic cardiomyopathy by inhibiting abnormal calcium-handling system in SR and ET-NADPH oxidase-PKCepsilon pathway. PMID- 26968979 TI - Fatal chilli bite. AB - A healthy 2-year-old girl bit a green chilli accidentally following which she had many bouts of vomiting. She became unconscious and was immediately admitted to hospital. In spite of all medical intervention, she died after one day. The autopsy confirmed that the death was caused by respiratory failure due to acute respiratory distress syndrome following aspiration of gastric contents into tracheobronchial tree. Aspiration of gastric contents resulting in acute respiratory distress syndrome and death is not uncommon; however, death following the accidental bite of a chilli is rarely reported in medical-legal literature. PMID- 26968980 TI - Ligature mark on the face - forensic implications. AB - In deaths due to hanging and strangulation, the position, course and direction of the ligature mark, the kind of knot used and injuries to the neck structures help in deducing the cause and manner of death. Two cases of suicidal hanging are reported where the unusual positioning of ligature and presence of the ligature mark on the face raise doubts concerning the circumstances of death. The presence of a ligature mark on the face is an unusual and rarely reported phenomenon that can have serious medico-legal implications. PMID- 26968982 TI - DNA binding to SMC ATPases-trapped for release. AB - The SMC/Rad50/RecN proteins are universal DNA-associated ABC-type ATPases with crucial functions in genome maintenance. New insights into Rad50-DNA complex structure and cohesin regulation inspire a speculative look at the entire superfamily. Identification of a continuous DNA binding site across the Rad50 dimer interface (Liu et al, 2016; Seifert et al, 2016) suggests a similar site in cohesin. The localization of this site hints a DNA-activated mechanism for cohesin removal from chromosomes. PMID- 26968981 TI - Schizophrenia and reelin: a model based on prenatal stress to study epigenetics, brain development and behavior. AB - Schizophrenia is a severe psychiatric disorder that results in a significant disability for the patient. The disorder is characterized by impairment of the adaptive orchestration of actions, a cognitive function that is mainly dependent on the prefrontal cortex. This behavioral deficit, together with cellular and neurophysiological alterations in the prefrontal cortex, as well as reduced density of GABAergic cells and aberrant oscillatory activity, all indicate structural and functional deficits of the prefrontal cortex in schizophrenia. Among the several risk factors for the development of schizophrenia, stress during the prenatal period has been identified as crucial. Thus, it is proposed that prenatal stress induces neurodevelopmental alterations in the prefrontal cortex that are expressed as cognitive impairment observed in schizophrenia. However, the precise mechanisms that link prenatal stress with the impairment of prefrontal cortex function is largely unknown. Reelin is an extracellular matrix protein involved in the development of cortical neural connectivity at embryonic stages, and in synaptic plasticity at postnatal stages. Interestingly, down regulation of reelin expression has been associated with epigenetic changes in the reelin gene of the prefrontal cortex of schizophrenic patients. We recently showed that, similar to schizophrenic patients, prenatal stress induces down expression of reelin associated with the methylation of its promoter in the rodent prefrontal cortex. These alterations were paralleled with altered prefrontal cortex functional connectivity and impairment in prefrontal cortex dependent behavioral tasks. Therefore, considering molecular, cellular, physiological and behavioral evidence, we propose a unifying framework that links prenatal stress and prefrontal malfunction through epigenetic alterations of the reelin gene. PMID- 26968984 TI - When Myc's asleep, embryonic stem cells are dormant. PMID- 26968983 TI - Tyrosination of alpha-tubulin controls the initiation of processive dynein dynactin motility. AB - Post-translational modifications (PTMs) of alpha/beta-tubulin are believed to regulate interactions with microtubule-binding proteins. A well-characterized PTM involves in the removal and re-ligation of the C-terminal tyrosine on alpha tubulin, but the purpose of this tyrosination-detyrosination cycle remains elusive. Here, we examined the processive motility of mammalian dynein complexed with dynactin and BicD2 (DDB) on tyrosinated versus detyrosinated microtubules. Motility was decreased ~fourfold on detyrosinated microtubules, constituting the largest effect of a tubulin PTM on motor function observed to date. This preference is mediated by dynactin's microtubule-binding p150 subunit rather than dynein itself. Interestingly, on a bipartite microtubule consisting of tyrosinated and detyrosinated segments, DDB molecules that initiated movement on tyrosinated tubulin continued moving into the segment composed of detyrosinated tubulin. This result indicates that the alpha-tubulin tyrosine facilitates initial motor-tubulin encounters, but is not needed for subsequent motility. Our results reveal a strong effect of the C-terminal alpha-tubulin tyrosine on dynein dynactin motility and suggest that the tubulin tyrosination cycle could modulate the initiation of dynein-driven motility in cells. PMID- 26968985 TI - ER strikes again: Proteostasis Dysfunction In ALS. PMID- 26968987 TI - Cutaneous metastasis of breast adenoid cystic carcinoma to the scalp. AB - Adenoid cystic carcinoma (ACC) is a tumor that can be of primary cutaneous origin or secondary to metastatic disease, most commonly salivary origin. Aside from primary cutaneous and salivary types, ACC of the breast is a rare, more indolent variant. Cutaneous metastases secondary to breast ACC is exceedingly uncommon and not previously reported to our knowledge. We present the case of a 67-year-old woman who developed cutaneous metastasis from primary breast ACC. PMID- 26968986 TI - Distinct modes of recruitment of the CCR4-NOT complex by Drosophila and vertebrate Nanos. AB - Nanos proteins repress the expression of target mRNAs by recruiting effector complexes through non-conserved N-terminal regions. In vertebrates, Nanos proteins interact with the NOT1 subunit of the CCR4-NOT effector complex through a NOT1 interacting motif (NIM), which is absent in Nanos orthologs from several invertebrate species. Therefore, it has remained unclear whether the Nanos repressive mechanism is conserved and whether it also involves direct interactions with the CCR4-NOT deadenylase complex in invertebrates. Here, we identify an effector domain (NED) that is necessary for the Drosophila melanogaster (Dm) Nanos to repress mRNA targets. The NED recruits the CCR4-NOT complex through multiple and redundant binding sites, including a central region that interacts with the NOT module, which comprises the C-terminal domains of NOT1-3. The crystal structure of the NED central region bound to the NOT module reveals an unanticipated bipartite binding interface that contacts NOT1 and NOT3 and is distinct from the NIM of vertebrate Nanos. Thus, despite the absence of sequence conservation, the N-terminal regions of Nanos proteins recruit CCR4-NOT to assemble analogous repressive complexes. PMID- 26968988 TI - The roles of HOXB7 in promoting migration, invasion, and anti-apoptosis in gastric cancer. AB - BACKGROUND AND AIM: The aim of this study was to compare HOXB7 expression level between gastric cancer and non-cancerous gastric tissues. Additionally, the functional effects of HOXB7, including its pro-migration or invasion and anti apoptosis roles, were evaluated in gastric cancer cells. METHODS: Both gene and protein expression levels of HOXB7 were examined in gastric cancer cell lines, and HOXB7 expression was compared between primary or metastatic gastric cancer tissues and chronic gastritis or intestinal metaplasia tissues. Functional studies included a wound healing assay, a Matrigel invasion assay, and an Annexin V assay were performed, and Akt/PTEN activity was measured by western blotting. RESULTS: Both gene and protein expression levels of HOXB7 could be clearly detected in various gastric cancer cell lines except MKN-28 cell. HOXB7 expression was significantly higher in primary or metastatic gastric cancer tissues than in chronic gastritis or intestinal metaplasia tissues. HOXB7 knockdown led to inhibition of cell invasion and migration, had an apoptotic effect, downregulated phosphor-Akt, and upregulated PTEN in AGS and SNU-638 cells. Reinforced expression of HOXB7 caused the opposite effects in MKN-28 and MKN-45 cells. CONCLUSION: Our study suggests that HOXB7 has an oncogenic role in gastric cancer, which might be related to the modulation of Akt/PTEN activity to induce cell migration/invasion and anti-apoptotic effects. PMID- 26968989 TI - The moral concerns of biobank donors: the effect of non-welfare interests on willingness to donate. AB - Donors to biobanks are typically asked to give blanket consent, allowing their donation to be used in any research authorized by the biobank. This type of consent ignores the evidence that some donors have moral, religious, or cultural concerns about the future uses of their donations - concerns we call "non-welfare interests". The nature of non-welfare interests and their effect on willingness to donate to a biobank is not well understood.In order to better undersand the influence of non-welfare interests, we surveyed a national sample of the US population (in June 2014) using a probability-based internet panel. Logistic regression models assessed the demographic and attitudinal characteristics associated with participants' willingness to give consent for unspecified future uses of their donation when presented with 7 research scenarios that raised possible non-welfare interest concerns. Most people had non-welfare interests that significantly affect their willingness to donate to a biobank using blanket consent. Some non-welfare interests are associated with subgroups but others are not. A positive attitude toward biomedical research in general was associated with increased willingness to donate, while concerns about privacy and being African American were associated with decreased willingness.Non-welfare interests matter and can diminish willingness to donate to a biobank. Our data suggest that trust in research promotes willingness to donate. Ignoring non-welfare interests could erode this trust. Donors' non-welfare interests could be accommodated through greater transparency and easier access to information about the uses of donations. PMID- 26968991 TI - Propaganda or the cost of innovation? Challenging the high price of new drugs. PMID- 26968990 TI - A genetic variant of the NTCP gene is associated with HBV infection status in a Chinese population. AB - BACKGROUND: To investigate whether genetic variants of the HBV receptor gene NTCP are associated with HBV infection in the Han Chinese population. METHODS: We sequenced the entire 23 kb NTCP gene from 111 HBeAg-positive HBsAg carriers (PSE group), 110 HBeAg-negative HBsAg carriers (PS group), and 110 control subjects. Then, we performed association analyses of suggestively significant SNPs with HBV infection in 1075 controls, 1936 PSs and 639 PSEs. RESULTS: In total, 109 rare variants (74 novel) and 38 single nucleotide polymorphisms (SNPs, one novel) were screened. Of the seven non-synonymous rare variants, six were singletons and one was a double hit. All three damaging rare singletons presented exclusively in the PSE group. Of the five SNPs validated in all 3650 subjects, the T allele of rs4646287 was significantly decreased (p = 0.002) in the PS group (10.1%) and PSE group (8.1%) compared to the controls (10.9%) and was decreased to 7.4% in the PSE hepatocellular carcinoma (HCC) subgroup. Additionally, rs4646287-T was associated with a 0.68-fold (95% CI = 0.51-0.89, p = 0.006) decreased risk of PSE compared with the controls. The NTCP mRNA level was lower in HCC tissues in "CT + TT" carriers than in "CC" carriers. CONCLUSIONS: We found a genetic variant (rs4646287) located in intron 1 of NTCP that may be associated with increased risk of HBV infection in Han Chinese. PMID- 26968992 TI - Impact of left ventricular systolic dysfunction on the outcomes of percutaneous edge-to-edge mitral valve repair using MitraClip. AB - Left ventricular systolic dysfunction (LVD) is associated with poor outcomes after mitral regurgitation (MR) surgery. MitraClip (MC) is a novel treatment option for MR patients with a high surgical risk. However, outcomes of LVD patients underwent MC remain unclear. In total of 194 patients after MC implantation, 75 patients (39 %) had severe LVD (LV ejection fraction <=30 %). Patients with severe LVD were primarily male and also younger. Logistic euroSCOREs were comparable between the two groups. Functional MR was more common in patients with severe LVD, while New York Heart Association (NYHA) class was similar between the two groups. N-terminal pro-B-type natriuretic peptide (NT proBNP) was significantly higher in patients with LVD. In addition to similar improvements in MR severity, NYHA class, and NT-proBNP levels, the survival rates were not different between patients with and without severe LVD. Among patients with severe LVD, the long-term survival rates were significantly lower in patients aged >=75 years, those with NT-proBNP >5000 pg/mL, and those with atrial fibrillation (AF). In conclusion, severe LVD was not associated with the mortality after MC implantation. MC might be feasible and effective even in the patients with severe MR and low LVEF. However, we need to carefully observe severe LVD patients who are elderly, have a high NT-proBNP level, and have AF, as these might be considered high-risk subjects. PMID- 26968996 TI - Degradation of thiamethoxam by the synergetic effect between anodic oxidation and Fenton reactions. AB - In this work, a comparative study using anodic oxidation, Fenton and electro Fenton treatments was performed in order to determine the synergic effect for the removal of thiamethoxan. The results determined that electro-Fenton process showed high efficiency in comparison with Fenton or anodic oxidation. After that, this hybrid process was optimized and the influence of iron catalyst concentration and applied current intensity on the degradation and mineralization were evaluated. Degradation profiles were monitored by high performance liquid chromatography (HPLC) being satisfactorily described by pseudo-first order kinetic model. At the optimal experimental conditions (300mA and 0.2mM Fe(+2)), the complete degradation of thiamethoxam was achieved after 10min. On the other hand, mineralization of thiamethoxam was monitored by total organic carbon (TOC) decay reaching more than 92% of TOC removal after 8h. Furthermore, a plausible mineralization pathway for the thiamethoxam degradation was proposed based on the identification of by-products such as aromatic intermediates, carboxylic acids and inorganic ions released throughout electro-Fenton process. PMID- 26968993 TI - Insight into specific pro-arrhythmic triggers in Brugada and early repolarization syndromes: results of long-term follow-up. AB - The pro-arrhythmic triggers in Brugada and early repolarization syndromes (BrS, ERS) have not been analyzed systematically except for case reports. We clinically investigated the circumstances which precede/predispose to arrhythmic events in these syndromes during long-term follow-up. A detailed history from the patients/witnesses was taken to investigate the antecedent events in the last few hours that preceded syncope/ventricular fibrillation (VF); medical records, ECG and blood test from the emergency room (ER) were reviewed. 19 patients that fulfilled the investigation criteria were followed up for 71 +/- 49 months (34 190 months). Prior to the event (syncope/VF), the patients were partaking different activities in the following decreasing order; drinking alcoholic beverage, having meal, and getting up from sleep, exercise. 3 patients reported mental/physical stress prior to the event and 2 patients developed VF several days after starting oral steroid for treatment of bronchial asthma. In the ER, elevated J-wave amplitude (0.27 +/- 0.15 mV) was found with 58 % of the patients having hypokalemia. After electrolyte correction and cessation of steroids, the following day plasma K+ (4.2 +/- 0.3 mEq/L, P < 0.001) was significantly increased and J-wave amplitude (0.13 +/- 0.1 mV, P < 0.001) was remarkably reduced. Three patients were kept on oral spironolactone/potassium supplements. During follow-up for 71 +/- 49 (34-190) months, among 4 patients with VF recurrence, one patient developed VF after taking oral steroid. In ERS and BrS, hypokalemia and corticosteroid therapy add substantial pro-arrhythmic effects, but potentially treatable. Stopping steroid therapy and avoiding hypokalemia had excellent long-term outcome. PMID- 26968994 TI - Moderate vasomotor response to acetylcholine provocation test as an indicator of long-term prognosis. AB - The acetylcholine (ACh) provocation test (ACh-test) is used for the diagnosis of vasospastic angina (VSA). However, subjects often show a moderate spasm (MS) response for which diagnosis of VSA is not definitive, and the clinical significance of this response is unknown. We assessed moderate coronary vasomotor response to the ACh test as an indicator of long-term prognosis. A total of 298 consecutive patients who underwent the ACh test for suspected VSA were retrospectively investigated. Coronary spasm severity after intracoronary administration of isosorbide dinitrate was evaluated by measuring epicardial coronary artery diameter reduction after ACh injection. Patients were divided into three groups according to the diameter reduction during the ACh test: severe spasm (SS) showing >=75 % diameter reduction, MS showing >=50 % diameter reduction, and others (N). In Kaplan-Meier analysis, the major adverse cardiac event (MACE) rates with a median follow-up of 4.6 years were significantly worse in SS (11.1 %) and MS (8.5 %) than N (1.9 %), (SS vs N; P = 0.009, MS vs N; P = 0.029). Significant difference in MACE rates was not observed between SS and MS (P = 0.534). Cox regression analysis revealed that MS remained an independent predictor of MACE after adjustment for other confounders (HR: 7.18, 95 % CI 1.42 36.4, P = 0.017). Patients with MS by ACh test had a cardiac event rate comparable with that of patients with SS and significantly worse than that of patients with normal vasomotor responses. PMID- 26968997 TI - Preparation of IrO2-Ta2O5|Ti electrodes by immersion, painting and electrophoretic deposition for the electrochemical removal of hydrocarbons from water. AB - After intense years of great development, the electrochemical technologies have become very suitable alternatives in niche markets like industrial wastewater reclamation and soil remediation. A key role to achieve a high efficiency in such treatments is played by the characteristics of the coating of the electrodes employed. This paper compares three techniques, namely immersion, painting and electrophoresis, for the preparation of IrO2-Ta2O5|Ti, so-called dimensionally stable anodes (DSA((r))). The quality of the coatings has been investigated by means of surface and electrochemical analysis. Their ability to generate hydroxyl radicals and degrade aqueous solutions of hydrocarbons like phenanthrene, naphthalene and fluoranthene has been thoroughly assessed. Among the synthesis techniques, electrophoretic deposition yielded the best results, with DSA((r)) electrodes exhibiting a homogeneous surface coverage that led to a good distribution of active sites, thus producing hydroxyl radicals that were able to accelerate the degradation of hydrocarbons. PMID- 26968995 TI - Rapid atrial pacing induces myocardial fibrosis by down-regulating Smad7 via microRNA-21 in rabbit. AB - Tachycardia-induced atrial fibrosis is a hallmark of the structural remodeling of atrial fibrillation (AF). The mechanisms underlying tachycardia-induced atrial fibrosis remain unclear. In our previous study, we found that Smad7 downregulation promoted the development of atrial fibrosis in AF. Fibroblasts are enriched in microRNA-21 (miR-21), which contributes to the development of fibrosis and heart failure in the cardiovascular system. Our study was designed to test the hypothesis that miR-21 reinforces the TGF-beta1/Smad signaling pathway in AF-induced atrial fibrosis by down-regulating Smad7. Rapid atrial pacing (RAP, 1000 ppm) was applied to the left atrium of the rabbit heart to induce atrial fibrillation and fibrosis. qRT-PCR and northern blot analysis revealed that RAP caused a marked increase in the expression of miR-21. Transfection with a miR-21 inhibitor significantly increased the expression of Smad7, while the expression of collagen I/III significantly decreased. These changes were implicated in the AF-induced release of miR-21 and down-regulation of Smad7. Adult rat cardiac fibroblasts treated with TGF-beta1 showed increased miR-21 expression and decreased Smad7 expression. Pretreatment with a TGF-beta1 inhibitor reduced the TGF-beta1-induced up-regulation of miR-21. Pretreatment with pre-miR-21 and a miR-21 inhibitor significantly decreased and increased Smad7 expression, respectively. This result was negatively correlated with the expression of collagen I/III in fibroblasts. Moreover, the results of a luciferase activity assay suggest that Smad7 is a validated miR-21 target in CFs. Our results provide compelling evidence that the miR-21 specific degradation of Smad7 may decrease the inhibitory feedback regulation of TGF-beta1/Smad signaling and serves as a new insight of the mechanism of atrial fibrosis in atrial fibrillation. PMID- 26968998 TI - Impairment due to eating disorder pathology: Identifying the cut-off score on the Clinical Impairment Assessment in a clinical and community sample. AB - OBJECTIVE: The Clinical Impairment Assessment (CIA) is a self-report measure of impairment secondary to eating disorder (ED) features. The purpose of this study was to identify the global CIA cut-off score that maximized sensitivity and specificity to discriminate impairment due to eating disorder pathology in a community versus clinical ED sample using receiver operating characteristic (ROC) analyses. METHOD: Participants were 1,468 female community participants and 552 eating disorder patients. RESULTS: Mean global CIA scores were 5.17 (SD 7.61) and 32.50 (SD 10.20). The ROC analysis demonstrated excellent accuracy of the global CIA score (AUC = 0.97; 95% CI: 0.96-0.98). A cut-off score of 16.0 yielded a sensitivity of 0.91 (95% CI: 0.88-0.93) and a specificity of 0.91 (95% CI: 0.89 0.93). DISCUSSION: This study is the first to replicate findings from the original development study of the CIA and lends support to initial recommendations. Data provide strong evidence of the discriminant validity of the CIA and suggest the utility of assessing eating-disorder related impairment for classification purposes. (c) 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:635-638). PMID- 26968999 TI - The imaging features of protruding esophageal lesions. AB - Except for squamous cell carcinoma and adenocarcinoma, lesions that protrude into the esophagus are rare, and include benign and malignant tumors. The imaging findings of these lesions on esophagography, computed tomography (CT), and magnetic resonance imaging (MRI) are often non-specific. However, some of them reveal characteristic imaging findings. In addition, esophagography, CT, and MRI are useful to evaluate location, extent, invasion, vascularity, lymphadenopathy, and metastasis. Knowledge of the imaging features of protruding esophageal lesions helps to narrow the differential diagnosis. We describe the main features of esophageal protruding lesions. PMID- 26969000 TI - HLA-B*40:326, a novel variant of HLA-B*40, discovered in a Taiwanese blood donor. AB - One nucleotide substitution at residue 476 of HLA-B*40:01:01 results in a new allele, HLA-B*40:326. PMID- 26969001 TI - Reasons People Give for Using (or Not Using) Condoms. AB - Study participants (N = 348) were asked about 46 reasons that have been suggested for why people use or do not use condoms. Participants were asked which of these reasons motivated them when they were deciding whether to use condoms in 503 sexual relationships. Participants were classified into one of three roles based on their HIV status and the status of each sexual partner: HIV+ people with HIV- partners; HIV- people with HIV+ partners; and HIV- people with HIV- partners. Motivations were looked at in the context of each of these roles. Of the 46 reasons, only 15 were selected by at least 1/3 of the participants, and only seven were selected by at least half. Frequently reported reasons primarily concern protecting self and partner from STDs including HIV. Less frequently reported reasons involved social norms, effects of condoms on sex, and concern for the relationship. These findings have implications for clinical interventions. PMID- 26969002 TI - A new method to quantify tau pathologies with (11)C-PBB3 PET using reference tissue voxels extracted from brain cortical gray matter. AB - BACKGROUND: Quantitative in vivo imaging of tau pathologies potentially improves diagnostic accuracy of neurodegenerative tauopathies and would facilitate evaluation of disease-modifying drugs targeting tau lesions in these diseases. Tau pathology can be quantified by reference tissue models without arterial blood sampling when reference tissue devoid of target binding sites is available. The cerebellar cortex has been used as a reference region in analyses of tau positron emission tomography (PET) data in Alzheimer's disease (AD). However, in a significant subset of tauopathies such as progressive supranuclear palsy and corticobasal degeneration, tau accumulation may occur in diverse brain regions including the cerebellar cortex. This hampers selection of a distinctive reference region lacking binding sites for a tau PET ligand. The purpose of this study was to develop a new method to quantify specific binding of a PET radioligand, (11)C-PBB3, to tau deposits using reference voxels extracted from cortical gray matter, which have a low likelihood of containing tau accumulations. METHODS: We reanalyzed (11)C-PBB3 PET data of seven mild AD patients (ADs) and seven elderly healthy control subjects (HCs) acquired in a previous study. As a standard method, parametric images of binding potential ([Formula: see text]) were initially generated using reference tissue manually defined on the cerebellar cortex. We then constructed a frequency histogram of [Formula: see text] values in these parametric images and selected cortical gray matter voxels contained in a certain range of the histogram with a low likelihood of having (11)C-PBB3 binding sites. Finally, these reference voxels were used for generating new [Formula: see text] parametric images. RESULTS: Reference tissue voxels defined by the histogram analysis spread throughout the cortical gray matter of AD and HC brains. The [Formula: see text] values determined by our new method correlated very well with those estimated by the standard method (r (2) = 0.94), although the binding estimates by the current method were slightly higher by ~0.14 than those by the standard method. CONCLUSIONS: We developed and validated a new method enabling quantification of tau lesions that can accumulate in the cerebellum and other extensive brain areas. This method may be applicable to all tauopathy subtypes and various tau PET ligands besides (11)C-PBB3. TRIAL REGISTRATION: The number is UMIN000009052. PMID- 26969004 TI - The nature of the redshift and directly observed quasar statistics. AB - The nature of the cosmic redshift is one of the most fundamental questions in modern science. Hubble's discovery of the apparent Expansion of the Universe is derived from observations on a small number of galaxies at very low redshifts. Today, quasar redshifts have a range more than 1000 times greater than those in Hubble's sample, and represent more than 100 times as many objects. A recent comprehensive compilation of published measurements provides the basis for a study indicating that quasar observations are not in good agreement with the original predictions of the Expanding Universe theory, but are well fit by the predictions of an alternative theory having fewer adjustable parameters. PMID- 26969003 TI - miR2118-triggered phased siRNAs are differentially expressed during the panicle development of wild and domesticated African rice species. AB - BACKGROUND: Rice exhibits a wide range of panicle structures. To explain these variations, much emphasis has been placed on changes in transcriptional regulation, but no large-scale study has yet reported on changes in small RNA regulation in the various rice species. To evaluate this aspect, we performed deep sequencing and expression profiling of small RNAs from two closely related species with contrasting panicle development: the cultivated African rice Oryza glaberrima and its wild relative Oryza barthii. RESULTS: Our RNA-seq analysis revealed a dramatic difference between the two species in the 21 nucleotide small RNA population, corresponding mainly to miR2118-triggered phased siRNAs. A detailed expression profiling during the panicle development of O. glaberrima and O. barthii using qRT-PCRs and in situ hybridization, confirmed a delayed expression of the phased siRNAs as well as their lncRNA precursors and regulators (miR2118 and MEL1 gene) in O. glaberrima compared to O. barthii. We provide evidence that the 21-nt phasiRNA pathway in rice is associated with male gametogenesis but is initiated in spikelet meristems. CONCLUSION: Differential expression of the miR2118-triggered 21-nt phasiRNA pathway between the two African rice species reflects differential rates of determinate fate acquisition of panicle meristems between the two species. PMID- 26969005 TI - [Not Available]. AB - The long storage time of charged particles in a well-controlled environment by ion traps provides ideal conditions for precision spectroscopy. After an introduction to the properties of traps we present examples in mass spectroscopy, and measurements of microwave and optical transition frequencies. The application to novel frequency standards will be discussed and we sketch briefly some fundamental aspects of light-atom interactions. PMID- 26969006 TI - A chemical structure for humic substances. PMID- 26969007 TI - De novo biosynthesis of Delta(3)-Isoxazolin-5-one and 3-Nitropropanoic acid derivatives inChrysomela tremulae. PMID- 26969009 TI - Chemical defence and genetic bariation : Interpopulational Study ofOreina gloriosa (Coleoptera: Chrysomelidae). PMID- 26969008 TI - 5,11-Dimethylheptadecane and 2,5-Dimethyl-heptadecane: Sex pheromone components of the geometrid moth,Lambdina fiscellaria fiscellaiia. PMID- 26969010 TI - Response to humidity change of deutocerebral interneurons of the honeybee,Apis mellifera L. PMID- 26969011 TI - Functioning of normal and ectopic electroreceptors. PMID- 26969012 TI - How do bees shiver? PMID- 26969013 TI - Spontaneous speciation through an overwintering change in a sawfly. PMID- 26969014 TI - Retardation of homing pigeons' ephemerides? PMID- 26969015 TI - [Not Available]. PMID- 26969017 TI - Effects of 0.5% Timolol Maleate Ophthalmic Solution on Heart Rate and Selected Echocardiographic Indices in Apparently Healthy Cats. AB - BACKGROUND: Echocardiographic assessment of diastolic function is challenging in cats, partially because of transmitral flow pattern fusion associated with high heart rates. With heart rate (HR) reduction, transmitral flow waveforms separate, allowing identification of diastolic dysfunction. Timolol, an ophthalmic, nonselective beta-blocker used in glaucoma is safe and transiently decreases HR in clinical trials. HYPOTHESIS: Administration of timolol ophthalmic solution decreases HR and facilitates echocardiographic assessment of diastolic function in cats without inducing clinically relevant adverse effects. ANIMALS: Twenty five apparently healthy cats. METHODS: Electrocardiograms and echocardiograms including transmitral flow patterns were evaluated before and 20 minutes after ocular administration of 1 drop of timolol 0.5% solution. Twenty cats underwent treatment with timolol, and 5 different cats served as untreated controls to evaluate the effects of acclimation to the hospital environment on HR. RESULTS: Acclimation to the hospital had no effect on HR in control cats. After timolol administration, a significant median HR reduction of 25 bpm was observed (P < .0001). Timolol had no effect on E/A ratio in cats without E/A fusion (7/20, P = .44). Of the 13 cats with E and A waves that were fused before timolol application, separation of these waves was identified in 8 cats (62%) after timolol treatment. No bradyarrhythmias were noted after timolol administration, but 2 cats had first-degree atrioventricular block. Timolol resulted in resolution of dynamic outflow tract obstruction in 6 of 6 cats. CONCLUSIONS AND CLINICAL IMPORTANCE: Ocular administration of timolol safely decreases HR in cats and could facilitate assessment of diastolic function. PMID- 26969018 TI - The Role of Lexical Frequency in the Acceptability of Syntactic Variants: Evidence From that-Clauses in Polish. AB - A number of studies report that frequency is a poor predictor of acceptability, in particular at the lower end of the frequency spectrum. Because acceptability judgments provide a substantial part of the empirical foundation of dominant linguistic traditions, understanding how acceptability relates to frequency, one of the most robust predictors of human performance, is crucial. The relation between low frequency and acceptability is investigated using corpus- and behavioral data on the distribution of infinitival and finite that-complements in Polish. Polish verbs exhibit substantial subordination variation and for the majority of verbs taking an infinitival complement, the that-complement occurs with low frequency (<0.66 ipm). These low-frequency that-clauses, in turn, exhibit large differences in how acceptable they are to native speakers. It is argued that acceptability judgments are based on configurations of internally structured exemplars, the acceptability of which cannot reliably be assessed until sufficient evidence about the core component has accumulated. PMID- 26969016 TI - The proteome and phosphoproteome of maize pollen uncovers fertility candidate proteins. AB - Maize is unique since it is both monoecious and diclinous (separate male and female flowers on the same plant). We investigated the proteome and phosphoproteome of maize pollen containing modified proteins and here we provide a comprehensive pollen proteome and phosphoproteome which contain 100,990 peptides from 6750 proteins and 5292 phosphorylated sites corresponding to 2257 maize phosphoproteins, respectively. Interestingly, among the total 27 overrepresented phosphosite motifs we identified here, 11 were novel motifs, which suggested different modification mechanisms in plants compared to those of animals. Enrichment analysis of pollen phosphoproteins showed that pathways including DNA synthesis/chromatin structure, regulation of RNA transcription, protein modification, cell organization, signal transduction, cell cycle, vesicle transport, transport of ions and metabolisms, which were involved in pollen development, the following germination and pollen tube growth, were regulated by phosphorylation. In this study, we also found 430 kinases and 105 phosphatases in the maize pollen phosphoproteome, among which calcium dependent protein kinases (CDPKs), leucine rich repeat kinase, SNF1 related protein kinases and MAPK family proteins were heavily enriched and further analyzed. From our research, we also uncovered hundreds of male sterility-associated proteins and phosphoproteins that might influence maize productivity and serve as targets for hybrid maize seed production. At last, a putative complex signaling pathway involving CDPKs, MAPKs, ubiquitin ligases and multiple fertility proteins was constructed. Overall, our data provides new insight for further investigation of protein phosphorylation status in mature maize pollen and construction of maize male sterile mutants in the future. PMID- 26969019 TI - Granular swollen epithelial cells in the kidney allograft: A clinicopathological study with special emphasis on possible marker for kidney allograft aging. AB - AIM: To elucidate the clinicopathological significance of granular swollen epithelial cells (GSECs), which provides histological evidence in the diagnosis of mitochondrial nephropathy, but incidentally observed in renal allografts, we evaluated GSECs as a surrogate histological marker for kidney allograft aging, as previously reported for p16, p21, and beta-galactosidase. METHODS: We retrospectively reviewed 426 kidney allograft biopsy specimens diagnosed at our university from January 2009 to April 2015. The prevalence and density of GSECs were compared with an age-matched control group of 508 native kidney biopsies. GSECs were defined as swollen (>2 times larger than normal renal tubular cells) epithelial cells best observed using Masson trichrome staining. Morphometric analyses were performed using digital microscopy software. RESULTS: The prevalence of GSECs was 7.7% in allograft kidneys and 8.1% in native kidneys. GSECs in kidney allografts were predominantly detected in medullary renal tubules, but not in the Bowman's capsular epithelium or podocytes. GSECs were observed in the following cases; no remarkable changes, n = 11; interstitial fibrosis and tubular atrophy, n = 7; chronic calcineurin inhibitor toxicity, n = 5; antibody-mediated rejection, n = 3; T cell-mediated rejection grade IA, n = 1; and others, n = 6. Compared with control specimens, medullary density of GSECs in kidney allografts was significantly increased. The prevalence of GSECs slightly increased with post-transplant duration; however, this trend was not statistically significant. CONCLUSIONS: The present study does not provide pathological significance of GSEC in kidney allografts in terms of allograft aging, and warrant the further research with molecular approach. PMID- 26969020 TI - Chemotherapeutic outcomes for metastatic colorectal cancer in elderly patients aged >=75 years: A single-institutional retrospective analysis. PMID- 26969023 TI - Modelling the vasculature of the stem of Cyperus involucratus Rottb.: evidence for three patterns of vascular bundles. AB - MAIN CONCLUSION: Three independent patterns of vein formation in Cyperus involucratus Rottb. were identified based on rare spontaneous interruptions of scape vein development. A number of developmental anomalies of vascular bundles in Cyperus involucratus Rottb. were identified and they include "turnabout", "absent", "twins", "doublet", amphivasal and various stages of "arrested". These were used to develop a computer program to explain the three vasculature patterns of the scape of (a) ordered deployment of vascular bundles, (b) arrangement of tissues within vascular bundles and (c) orientation of vascular bundles with respect to stem edge. The computer model is a cell-by-cell determination of cell types and facet states. PMID- 26969021 TI - Membrane proteins involved in transport, vesicle traffic and Ca(2+) signaling increase in beetroots grown in saline soils. AB - MAIN CONCLUSION: By separating plasma membrane proteins according to their hydropathy from beetroots grown in saline soils, several proteins probably involved in salt tolerance were identified by mass spectrometry. Beetroots, as a salt-tolerant crop, have developed mechanisms to cope with stresses associated with saline soils. To observe which plasma membrane (PM) proteins were more abundant in beet roots grown in saline soils, beet root plants were irrigated with water or 0.2 M NaCl. PM-enriched membrane preparations were obtained from these plants, and their proteins were separated according to their hydropathy by serial phase partitioning with Triton X-114. Some proteins whose abundance increased visibly in membranes from salt-grown beetroots were identified by mass spectrometry. Among them, there was a V-type H(+)-ATPase (probably from contaminating vacuolar membranes), which increased with salt at all stages of beetroots' development. Proteins involved in solute transport (an H(+) transporting PPase and annexins), vesicle traffic (clathrin and synaptotagmins), signal perception and transduction (protein kinases and phospholipases, mostly involved in calcium signaling) and metabolism, appeared to increase in salt-grown beetroot PM-enriched membranes. These results suggest that PM and vacuolar proteins involved in transport, metabolism and signal transduction increase in beet roots adapted to saline soils. In addition, these results show that serial phase partitioning with Triton X-114 is a useful method to separate membrane proteins for their identification by mass spectrometry. PMID- 26969024 TI - MicroRNA-30a promotes extracellular matrix degradation in articular cartilage via downregulation of Sox9. AB - OBJECTIVES: Sox9 has recently been reported to be a key mediator during cartilage degradation in osteoarthritis (OA). Our aim was to clarify the role of microRNA 30a (miR-30a) and its target gene Sox9 in regulation of extracellular matrix (ECM) degradation in OA. MATERIALS AND METHODS: Expression of miR-30a in cartilage tissues and in primary chondrocytes from healthy and OA donors, was determined by real-time PCR, and levels of Sox9 mRNA and protein were analyzed by real-time PCR and western blotting, respectively. Subsequently, the target of miR 30a was predicted by bioinformatics and confirmed using a luciferase assay. Expression of ECM-related genes was determined by tissue-specific staining, immunofluorescence, real-time PCR, and western blotting. The role of miR-30a in OA was examined in vivo using a collagenase-induced OA rat model. RESULTS: miR 30a was significantly upregulated and Sox9 was downregulated in primary chondrocytes from cartilage taken from OA donors compared to healthy controls. We showed that miR-30a specifically bound to the 3' UTR of Sox9, and overexpression of miR-30a downregulated expression levels of Sox9, proteoglycan aggrecan, and Col II compared to those induced by small interfering RNA transfection to knockdown Sox9. miR-30a inhibition reversed the effects of ECM degradation in vitro and in vivo. CONCLUSIONS: miR-30a acts as a virulence MRA in OA, promoting ECM degradation by targeting Sox9 and by modulating activity of its downstream effectors Col II and proteoglycan aggrecan. PMID- 26969022 TI - Towards development of new ornamental plants: status and progress in wide hybridization. AB - MAIN CONCLUSION: The present review provides insights into the key findings of the hybridization process, crucial factors affecting the adaptation of new technologies within wide hybridization of ornamental plants and presents perspectives of further development of this strategy. Wide hybridization is one of the oldest breeding techniques that contributed enormously to the development of modern plant cultivars. Within ornamental breeding, it represents the main source of genetic variation. During the long history of wide hybridization, a number of methods were implemented allowing the evolution from a conventional breeding tool into a modern methodology. Nowadays, the research on model plants and crop species increases our understanding of reproductive isolation among distant species and partly explains the background of the traditional approaches previously used for overcoming hybridization barriers. Characterization of parental plants and hybrids is performed using molecular and cytological techniques that strongly facilitate breeding processes. Molecular markers and sequencing technologies are used for the assessment of genetic relationships among plants, as the genetic distance is typically depicted as one of the most important factors influencing cross-compatibility in hybridization processes. Furthermore, molecular marker systems are frequently applied for verification of hybrid state of the progeny. The flow cytometry and genomic in situ hybridization are used in the assessment of hybridization partners and characterization of hybrid progeny in relation to genome stabilization as well as genome recombination and introgression. In the future, new research and technologies are likely to provide more detailed information about genes and pathways responsible for interspecific reproductive isolation. Ultimately, this knowledge will enable development of strategies for obtaining compatible lines for hybrid production. Recent development in sequencing technologies and availability of sequence data will also facilitate creation of new molecular markers that will advance marker assisted selection in hybridization process. PMID- 26969026 TI - Characterisation of the clinical and activated T cell response to repeat delayed type hypersensitivity skin challenges in human subjects, with KLH and PPD, as a potential model to test T cell-targeted therapies. AB - OBJECTIVE: To characterise the delayed-type hypersensitivity (DTH) skin reaction to repeated challenges of keyhole limpet hemocyanin (KLH) and tuberculin purified protein derivative (PPD) in healthy volunteers, as a potential model to test T cell-targeted investigational agents. SUBJECTS, TREATMENT AND METHODS: Forty-nine subjects received either KLH, PPD, or PBS repeat skin challenges, and clinical assessments including induration, erythema and Laser Doppler Imaging. Skin biopsies or suction blisters were taken after challenge to investigate the cellular infiltrate of the challenge site, the T cell activation status, as determined by LAG-3 expression, and, specifically for the blister, the concentrations of inflammatory cytokines. Point estimates, estimates of variation and corresponding 95% confidence intervals were constructed for each type of challenge and timepoint. RESULTS: The DTH response could be measured at 48 and 120 h post-KLH and PPD challenge with induration, erythema and Laser Doppler Imaging, with 48 h post-challenge demonstrating the peak of the response. PPD was well tolerated in subjects after multiple challenges, however, a significant number of KLH-treated subjects demonstrated an injection site reaction 6-7 days following the SC injection. PPD demonstrated a boost effect on the second challenge as measured by increased induration, where as this was not noted consistently for KLH. Compared to unchallenged and PBS control-injected skin, increased T cell numbers were detected in the challenge site by both the skin suction blister and biopsy technique, at either time point following KLH or PPD challenge. Use of the T cell activation marker LAG-3 demonstrated the activated phenotype of these cells. In skin blisters, higher numbers of LAG-3+ T cells were detected at 48 h post-challenge, whereas in the biopsies, similar numbers of LAG 3+ cells were observed at both 48 and 120 h. Analysis of blister T cell subpopulations revealed some differences in phenotypes between the time points and between the CD4 and CD8 T cells. Blister cytokine analysis revealed a pro inflammatory dominated signature in PPD-challenged skin. CONCLUSIONS: In summary, our data support the use of a repeat KLH and PPD DTH challenge in clinical trials and that the clinical measures of induration and to a lesser extent erythema are appropriate to monitor the clinical DTH response. Both the blister and biopsy can be utilised to assess and quantify activated T cells and at the dose used, PPD was better tolerated than KLH and hence may be optimal for future studies. PMID- 26969028 TI - Divided by more than a common language. PMID- 26969027 TI - Knockdown of cullin 4A inhibits growth and increases chemosensitivity in lung cancer cells. AB - Cullin 4A (Cul4A) has been observed to be overexpressed in various cancers. In this study, the role of Cul4A in the growth and chemosensitivity in lung cancer cells were studied. We showed that Cul4A is overexpressed in lung cancer cells and tissues. Knockdown of the Cul4A expression by shRNA in lung cancer cells resulted in decreased cellular proliferation and growth in lung cancer cells. Increased sensitivity to gemcitabine, a chemotherapy drug, was also noted in those Cul4A knockdown lung cancer cells. Moreover, increased expression of p21, transforming growth factor (TGF)-beta inducible early gene-1 (TIEG1) and TGF beta induced (TGFBI) was observed in lung cancer cells after Cul4A knockdown, which may be partially related to increased chemosensitivity to gemcitabine. G0/G1 cell cycle arrest was also noted after Cul4A knockdown. Notably, decreased tumour growth and increased chemosensitivity to gemcitabine were also noted after Cul4A knockdown in lung cancer xenograft nude mice models. In summary, our study showed that targeting Cul4A with RNAi or other techniques may provide a possible insight to the development of lung cancer therapy in the future. PMID- 26969025 TI - Critical Link Between Epigenetics and Transcription Factors in the Induction of Autoimmunity: a Comprehensive Review. AB - Autoimmune diseases occur when the immune system loses tolerance to self antigens, inducing inflammation and tissue damage. The pathogenesis of autoimmune diseases has not been elucidated. A growing mountain of evidence suggests the involvement of genetic and epigenetic factors in the development of these disorders. Genetic mapping has identified several candidate variants in autoimmune conditions. However, autoimmune diseases cannot be explained by genetic susceptibility alone. The fact that there is only 20 % of concordance for systemic lupus erythematosus (SLE) in homozygotic twins is an indication that epigenetics and environment may also play significant roles. Epigenetics refer to inheritable and potentially reversible changes in DNA and chromatin that regulate gene expression without altering the DNA sequence. The primary mechanisms of epigenetic regulation include DNA methylation, histone modification, and non coding RNA-mediated regulation. The regulation on gene expression by epigenetics is similar to that by transcription factors (TFs), and the normal execution of biological event is controlled by a combination of epigenetic modifications and TFs. These two mechanisms share similar regulatory logistics and cooperate in part by influencing activity of the binding sites of target genes. In addition, the promoters of TFs have been found themselves to be modified by epigenetic regulators and TFs can also induce epigenetic changes. There is a two-way street in which interplay between epigenetic regulation and TFs plays a role in the pathogenesis of SLE, rheumatoid arthritis, type 1 diabetes, systemic sclerosis, and multiple sclerosis. Understanding of pathogenesis of these autoimmune diseases will help define potential targets for therapeutic strategies. PMID- 26969029 TI - Be better with public health campaigns (and taxpayers' money). PMID- 26969030 TI - To PSA or not to PSA? Still a question for men with a family history of prostate cancer. PMID- 26969031 TI - Some like it safe. PMID- 26969032 TI - New possibilities for urinary molecular diagnostics. PMID- 26969033 TI - Urethral atrophy is fiction! Time to focus on the capsule? PMID- 26969034 TI - Corrigendum. PMID- 26969035 TI - Corrigendum. PMID- 26969036 TI - Event-related potential study of intentional and incidental retrieval of item and source memory during early childhood. AB - The event related potential (ERP) technique is a useful methodology for studying neural changes underlying memory development during childhood. However, systematic comparisons of differences in memory tasks and retrieval demands are lacking. To address this gap, the present study explored the effects of memory task (i.e., item versus source) and retrieval paradigm (i.e., intentional versus incidental) on 4- to 5-year-old children's memory performance and associated electrophysiological responses. Children were familiarized with items in a play like setting and then asked to retrieve item or source memory details while their brain activity was recorded (intentional retrieval) or while they passively viewed images of the items with no explicit task (incidental retrieval). Memory assessments for the incidental groups followed ERP recording. Analyses of the ERP data suggested that the brain's response during intentional retrieval of source information differed from the other three conditions. These results are discussed within a two-component framework of memory development (e.g., Shing et al., 2010), and implications for future methodological decisions are presented. (c) 2016 Wiley Periodicals, Inc. Dev Psychobiol 58: 556-567, 2016. PMID- 26969037 TI - Pilot-scale cultivation of wall-deficient transgenic Chlamydomonas reinhardtii strains expressing recombinant proteins in the chloroplast. AB - Microalgae have emerged as potentially powerful platforms for the production of recombinant proteins and high-value products. Chlamydomonas reinhardtii is a potentially important host species due to the range of genetic tools that have been developed for this unicellular green alga. Transformation of the chloroplast genome offers important advantages over nuclear transformation, and a wide range of recombinant proteins have now been expressed in the chloroplasts of C. reinhardtii strains. This is often done in cell wall-deficient mutants that are easier to transform. However, only a single study has reported growth data for C. reinhardtii grown at pilot scale, and the growth of cell wall-deficient strains has not been reported at all. Here, we report the first pilot-scale growth study for transgenic, cell wall-deficient C. reinhardtii strains. Strains expressing a cytochrome P450 (CYP79A1) or bifunctional diterpene synthase (cis-abienol synthase, TPS4) were grown for 7 days under mixotrophic conditions in a Tris acetate-phosphate medium. The strains reached dry cell weights of 0.3 g/L within 3-4 days with stable expression levels of the recombinant proteins during the whole upscaling process. The strains proved to be generally robust, despite the cell wall-deficient phenotype, but grew poorly under phototrophic conditions. The data indicate that cell wall-deficient strains may be highly amenable for transformation and suitable for commercial-scale operations under mixotrophic growth regimes. PMID- 26969038 TI - NAD(+)-specific glutamate dehydrogenase (EC.1.4.1.2) in Streptomyces coelicolor; in vivo characterization and the implication for nutrient-dependent secondary metabolism. AB - While glutamate and glutamate-rich compounds are widely used for culturing Streptomyces sp., little is known regarding glutamate catabolism at molecular level. Noting the presence of two distinct putative glutamate dehydrogenases (GDH), we constructed knockout mutants of each gene with Streptomyces coelicolor M145 and examined the functionality related to antibiotic production. Out of the two, the sco2999 knockout (DeltagdhB, NAD(+)-specific) showed outstanding effects; it decreased the growth sevenfold but initiated the undecylprodigiosin (RED) production in complex Difco nutrient media which otherwise does not support the production from M145. With glucose supplementation, the growth difference by DeltagdhB disappeared but we could obtain significantly increased actinorhodin (ACT) and RED biosynthesis with the mutant by limiting the glucose content (0.5~1.0 %, w/v). Complementing the gene to the knockout mutant inhibited the production, confirming its gene specificity. Along with the extended impacts on overall nitrogen metabolism based on the intracellular metabolite analysis and enzyme assays, GdhB and glutamate utilization were shown to interfere with N acetylglucosamine metabolism and the activity of its associated global transcriptional regulator (DasR). Taken together, GdhB-subjected to the nutritional context-dependent regulation-is proposed as a key member of central nitrogen metabolism to control the secondary metabolism initiation in exploiting the organic nitrogen sources. PMID- 26969039 TI - Display of fungal hydrophobin on the Pichia pastoris cell surface and its influence on Candida antarctica lipase B. AB - To modify the Pichia pastoris cell surface, two classes of hydrophobins, SC3 from Schizophyllum commune and HFBI from Trichoderma reesei, were separately displayed on the cell wall. There was an observable increase in the hydrophobicity of recombinant strains. Candida antarctica lipase B (CALB) was then co-displayed on the modified cells, generating strains GS115/SC3-61/CALB-51 and GS115/HFBI 61/CALB-51. Interestingly, the hydrolytic and synthetic activities of strain GS115/HFBI-61/CALB-51 increased by 37 and 109 %, respectively, but decreased by 26 and 43 %, respectively, in strain GS115/SC3-61/CALB-51 compared with the hydrophobin-minus recombinant strain GS115/CALB-GCW51. The amount of glycerol by product from the transesterification reaction adsorbed on the cell surface was significantly decreased following hydrophobin modification, removing the glycerol barrier and allowing substrates to access the active sites of lipases. Electron micrographs indicated that the cell wall structures of both recombinant strains appeared altered, including changes to the inner glucan layer and outer mannan layer. These results suggest that the display of hydrophobins can change the surface structure and hydrophobic properties of P. pastoris and affect the catalytic activities of CALB displayed on the surface of P. pastoris cells. PMID- 26969040 TI - Application of locked nucleic acid-based probes in fluorescence in situ hybridization. AB - Fluorescence in situ hybridization (FISH) employing nucleic acid mimics as probes is becoming an emerging molecular tool in the microbiology area for the detection and visualization of microorganisms. However, the impact that locked nucleic acid (LNA) and 2'-O-methyl (2'-OMe) RNA modifications have on the probe that is targeting microorganisms is unknown. In this study, the melting and hybridization efficiency properties of 18 different probes in regards to their use in FISH for the detection of the 16S rRNA of Helicobacter pylori were compared. For the same sequence and target, probe length and the type of nucleic acid mimics used as mixmers in LNA-based probes strongly influence the efficiency of detection. LNA probes with 10 to 15 mers showed the highest efficiency. Additionally, the combination of 2'-OMe RNA with LNA allowed an increase on the fluorescence intensities of the probes. Overall, these results have significant implications for the design and applications of LNA probes for the detection of microorganisms. PMID- 26969041 TI - Regulative roles of glutathione reductase and four glutaredoxins in glutathione redox, antioxidant activity, and iron homeostasis of Beauveria bassiana. AB - Multiple glutaredoxins (Grx) and glutathione reductase (Glr) are vital for the thiol-disulfide redox system in budding yeast but generally unexplored in filamentous fungi. Here we characterized the Beauveria bassiana redox system comprising dithiol Grx1, monothiol Grx2-4, Grx-like Grx5, and Glr orthologue. Each grx or glr deletion was compensated by increased transcripts of some other grx genes in normal cultures. Particularly, grx3 compensated the absence of grx1, grx2, grx5, or glr under oxidative stress while its absence was compensated only by undeletable grx4 under normal conditions but by most of other undeleted grx and glr genes in response to menadione. Consequently, the redox state was disturbed in Deltaglr more than in Deltagrx3 but not in Deltagrx1/2/5. Superoxide dismutases were more active in normal Deltagrx1-3 cultures but less in Deltagrx5 or Deltaglr response to menadione. Total catalase activity increased differentially in all the mutant cultures stressed with or without H2O2 while total peroxidase activity decreased more in the normal or H2O2-stressed culture of Deltaglr than of Deltagrx3. Among the mutants, Deltagrx3 showed slightly increased sensitivity to menadione or H2O2; Deltaglr exhibited greater sensitivity to thiol-oxidizing diamide than thiol-reducing 1-chloro-2,4 dinitrobenzene as well as increased sensitivity to the two oxidants. Intriguingly, all the mutants grew slower in a Fe(3+)-inclusive medium perhaps due to elevated transcripts of two Fe(3+) transporter genes. More or fewer phenotypes linked with biocontrol potential were altered in four deletion mutants excluding Deltagrx5. All the changes were restored by targeted gene complementation. Overall, Grx3 played more critical role than other Grx homologues in the Glr-dependent redox system of the fungal entomopathogen. PMID- 26969042 TI - Synthesis of Organofluoro Compounds Using Methyl Perfluoroalk-2-ynoates as Building Blocks. AB - This review provides an overview of several synthetic applications of methyl perfluoroalk-2-ynoates, leading to convenient preparation of many perfluoroalkylated compounds. The use of these important substrates in the synthesis of various five-, six-, and seven-membered heterocycles, cyclopentadienes, and biphenyls is described, alongside a discussion of the mechanistic aspects of these reactions. PMID- 26969043 TI - Acceptability of Mental Health Apps for Aboriginal and Torres Strait Islander Australians: A Qualitative Study. AB - BACKGROUND: Aboriginal and Torres Strait Islander Australians experience high rates of mental illness and psychological distress compared to their non Indigenous counterparts. E-mental health tools offer an opportunity for accessible, effective, and acceptable treatment. The AIMhi Stay Strong app and the ibobbly suicide prevention app are treatment tools designed to combat the disproportionately high levels of mental illness and stress experienced within the Aboriginal and Torres Strait Islander community. OBJECTIVE: This study aimed to explore Aboriginal and Torres Strait Islander community members' experiences of using two culturally responsive e-mental health apps and identify factors that influence the acceptability of these approaches. METHODS: Using qualitative methods aligned with a phenomenological approach, we explored the acceptability of two culturally responsive e-mental health apps through a series of three 3 hour focus groups with nine Aboriginal and Torres Strait Islander community members. Thematic analysis was conducted and coresearcher and member checking were used to verify findings. RESULTS: Findings suggest strong support for the concept of e-mental health apps and optimism for their potential. Factors that influenced acceptability related to three key themes: personal factors (eg, motivation, severity and awareness of illness, technological competence, and literacy and language differences), environmental factors (eg, community awareness, stigma, and availability of support), and app characteristics (eg, ease of use, content, graphics, access, and security and information sharing). Specific adaptations, such as local production, culturally relevant content and graphics, a purposeful journey, clear navigation, meaningful language, options to assist people with language differences, offline use, and password protection may aid uptake. CONCLUSIONS: When designed to meet the needs of Aboriginal and Torres Strait Islander Australians, e-mental health tools add an important element to public health approaches for improving the well-being of Aboriginal and Torres Strait Islander people. PMID- 26969044 TI - Benefits and risks associated with consumption of Great Lakes fish containing omega-3 fatty acids and polychlorinated biphenyls (PCBs). PMID- 26969045 TI - Distribution and contamination of metals and biogenic elements in sediments from Zhifu Bay of the Yellow Sea, China. AB - Metals and biogenic elements were analyzed from surface sediments of sixteen stations and a 32cm core collected from Zhifu Bay in July 2009. High concentrations of biogenic silica (BSi) reflected the high diatom productivity in the Bay. Meanwhile, total organic carbon (TOC) in Zhifu Bay was mainly from terrestrial sources. All metals were lower than the marine sediment quality guidelines. Based on the vertical profiles of biogenic elements, there was a clear increase of TOC, total nitrogen (TN), and total phosphate (TP) between 1985 and 2000. TN concentrations decreased after the start of the operation of the sewage treatment plant in 1998; however TOC and BSi remained at high levels. Metal concentrations showed a general increase from the bottom to the top of the core. Most anthropogenic metals reached a maximum during 1996 and 2000, and decreased after the startup of the sewage plant; however, they have increased again recently. The results from correlation analysis and principal component analysis show that industrial pollution is the main source of Cd, Cr, Cu, Ni, Pb and Zn contamination in Zhifu Bay, and Yantai Port and ship transportation also contribute a lot to Cd, Cu, Hg, and Pb pollution. PMID- 26969046 TI - Enhancement of Fenton oxidation for removing organic matter from hypersaline solution by accelerating ferric system with hydroxylamine hydrochloride and benzoquinone. AB - Fenton oxidation is generally inhibited in the presence of a high concentration of chloride ions. This study investigated the feasibility of using benzoquinone (BQ) and hydroxylamine hydrochloride (HA) as Fenton enhancers for the removal of glycerin from saline water under ambient temperature by accelerating the ferric system. It was found that organics removal was not obviously affected by chloride ions of low concentration (less than 0.1mol/L), while the mineralization rate was strongly inhibited in the presence of a large amount of chloride ions. In addition, ferric hydrolysis-precipitation was significantly alleviated in the presence of HA and BQ, and HA was more effective in reducing ferric ions into ferrous ions than HA, while the H2O2 decomposition rate was higher in the BQ Fenton system. Electron spin resonance analysis revealed that OH production was reduced in high salinity conditions, while it was enhanced after the addition of HA and BQ (especially HA). This study provided a possible solution to control and alleviate the inhibitory effect of chloride ions on the Fenton process for organics removal. PMID- 26969047 TI - The relationship between the black carbon and bisphenol A in sea and river sediments (Southern Baltic). AB - This study was derived from field investigations to assess bisphenol A (BPA) concentrations in the sea and river sediments of the Gulf of Gdansk. Black carbon (BC) and total organic carbon (TOC) were identified as influencing factors on the accumulation. As a result of the transportation of BC with organic matter via rivers into the Gulf of Gdansk, the highest mean concentrations (11.26ngBPA/(gdryweight (dw))), were determined in the sediments of river estuaries. Sediments in coastal stations were characterized by the lowest mean concentrations (5.73ngBPA/(gdw)). TOC content below 0.1% determined the sorption of BPA on BC particles in sediments, and statistically significant correlation between the concentration of BPA and the BC/TOC ratio was found in these cases. In addition, dependency between the concentration of BPA and the content of BC was discovered in sediments where the BC/TOC ratio was >0.33. PMID- 26969048 TI - Ammonium sulfide-assisted hydrothermal activation of palygorskite for enhanced adsorption of methyl violet. AB - Herein, palygorskite (PAL) was activated via a simple hydrothermal process in the presence of ammonium sulfide, and the effects of activation on the microstructure, physico-chemical feature and adsorption behaviors of PAL were intensively investigated. The hydrothermal process evidently improved the dispersion of PAL crystal bundles, increased surface negative charges and built more active -Si-O(-) groups served as the new "adsorption sites". The adsorption property of the activated PAL for Methyl Violet (MV) was systematically investigated by optimizing the adsorption variables, including pH, ionic strength, contact time and initial MV concentration. The activated PAL exhibited a superior adsorption capability to the raw PAL for the removal of MV (from 156.05 to 218.11mg/g). The kinetics for MV adsorption followed pseudo second order kinetic models, while the isotherm and thermodynamics results showed that the adsorption pattern well followed the Langmuir model. The structure analysis of PAL before and after adsorption demonstrated that electrostatic interaction and chemical association of -X-O(-) are the prominent driving forces for the adsorption process. PMID- 26969049 TI - Development of natural treatment system consisting of black soil and Kentucky bluegrass for the post-treatment of anaerobically digested strong wastewater. AB - To develop a sound post-treatment process for anaerobically-digested strong wastewater, a novel natural treatment system comprising two units is put forward. The first unit, a trickling filter, provides for further reduction of biochemical oxygen demand and adjustable nitrification. The subsequent soil-plant unit aims at removing and recovering the nutrients nitrogen (N), phosphorus (P) and potassium (K). As a lab-scale feasibility study, a soil column test was conducted, in which black soil and valuable Kentucky bluegrass were integrated to treat artificial nutrient-enriched wastewater. After a long-term operation, the nitrification function was well established in the top layers, despite the need for an improved denitrification process prior to discharge. P and K were retained by the soil through distinct mechanisms. Since they either partially or totally remained in plant-available forms in the soil, indirect nutrient reuse could be achieved. As for Kentucky bluegrass, it displayed better growth status when receiving wastewater, with direct recovery of 8%, 6% and 14% of input N, P and K, respectively. Furthermore, the indispensable role of Kentucky bluegrass for better treatment performance was proved, as it enhanced the cell-specific nitrification potential of the soil nitrifying microorganisms inhabiting the rhizosphere. After further upgrade, the proposed system is expected to become a new solution for strong wastewater pollution. PMID- 26969050 TI - Numerical evaluation of the effectiveness of NO2 and N2O5 generation during the NO ozonation process. AB - Wet scrubbing combined with ozone oxidation has become a promising technology for simultaneous removal of SO2 and NOx in exhaust gas. In this paper, a new 20 species, 76-step detailed kinetic mechanism was proposed between O3 and NOx. The concentration of N2O5 was measured using an in-situ IR spectrometer. The numerical evaluation results kept good pace with both the public experiment results and our experiment results. Key reaction parameters for the generation of NO2 and N2O5 during the NO ozonation process were investigated by a numerical simulation method. The effect of temperature on producing NO2 was found to be negligible. To produce NO2, the optimal residence time was 1.25sec and the molar ratio of O3/NO about 1. For the generation of N2O5, the residence time should be about 8sec while the temperature of the exhaust gas should be strictly controlled and the molar ratio of O3/NO about 1.75. This study provided detailed investigations on the reaction parameters of ozonation of NOx by a numerical simulation method, and the results obtained should be helpful for the design and optimization of ozone oxidation combined with the wet flue gas desulfurization methods (WFGD) method for the removal of NOx. PMID- 26969051 TI - Application of high silica zeolite ZSM-5 in a hybrid treatment process based on sequential adsorption and ozonation for VOCs elimination. AB - In this study, a hydrophobic synthetic zeolite, namely ZSM-5 is chosen as an adsorbent/catalyst for toluene removal. Experimental results showed that toluene adsorption onto ZSM-5 was favourable, following a Langmuir adsorption isotherm model. ZSM-5 zeolite was regenerated using gaseous ozone at low temperature. Adsorbed toluene was oxidised, releasing mainly CO2 and H2O. Traces of oxidation by-products such as acetic acid and acetaldehyde were formed and remained adsorbed after the oxidativate regeneration with ozone. After four successive cycles of adsorption/ozonation, the adsorption efficiency was not affected (92% 99%). These results showed that volatile organic compound (VOC) removal by adsorption onto ZSM-5 zeolite followed by ozone regeneration could be used as a promising hybrid process for the control of VOC emissions in terms of efficiency. PMID- 26969052 TI - A case study of development and application of a streamlined control and response modeling system for PM2.5 attainment assessment in China. AB - This article describes the development and application of a streamlined air control and response modeling system with a novel response surface modeling linear coupled fitting method and a new module to provide streamlined model data for PM2.5 attainment assessment in China. This method is capable of significantly reducing the dimensions required to establish a response surface model, as well as capturing more realistic response of PM2.5 to emission changes with a limited number of model simulations. The newly developed module establishes a data link between the system and the Software for Model Attainment Test-Community Edition (SMAT-CE), and has the ability to rapidly provide model responses to emission control scenarios for SMAT-CE using a simple interface. The performance of this streamlined system is demonstrated through a case study of the Yangtze River Delta (YRD) in China. Our results show that this system is capable of reproducing the Community Multi-Scale Air Quality (CMAQ) model simulation results with maximum mean normalized error<3.5%. It is also demonstrated that primary emissions make a major contribution to ambient levels of PM2.5 in January and August (e.g., more than 50% contributed by primary emissions in Shanghai), and Shanghai needs to have regional emission control both locally and in its neighboring provinces to meet China's annual PM2.5 National Ambient Air Quality Standard. The streamlined system provides a real-time control/response assessment to identify the contributions of major emission sources to ambient PM2.5 (and potentially O3 as well) and streamline air quality data for SMAT-CE to perform attainment assessments. PMID- 26969053 TI - Fungal diversity in major oil-shale mines in China. AB - As an insufficiently utilized energy resource, oil shale is conducive to the formation of characteristic microbial communities due to its special geological origins. However, little is known about fungal diversity in oil shale. Polymerase chain reaction cloning was used to construct the fungal ribosomal deoxyribonucleic acid internal transcribed spacer (rDNA ITS) clone libraries of Huadian Mine in Jilin Province, Maoming Mine in Guangdong Province, and Fushun Mine in Liaoning Province. Pure culture and molecular identification were applied for the isolation of cultivable fungi in fresh oil shale of each mine. Results of clone libraries indicated that each mine had over 50% Ascomycota (58.4%-98.9%) and 1.1%-13.5% unidentified fungi. Fushun Mine and Huadian Mine had 5.9% and 28.1% Basidiomycota, respectively. Huadian Mine showed the highest fungal diversity, followed by Fushun Mine and Maoming Mine. Jaccard indexes showed that the similarities between any two of three fungal communities at the genus level were very low, indicating that fungi in each mine developed independently during the long geological adaptation and formed a community composition fitting the environment. In the fresh oil-shale samples of the three mines, cultivable fungal phyla were consistent with the results of clone libraries. Fifteen genera and several unidentified fungi were identified as Ascomycota and Basidiomycota using pure culture. Penicillium was the only genus found in all three mines. These findings contributed to gaining a clear understanding of current fungal resources in major oil-shale mines in China and provided useful information for relevant studies on isolation of indigenous fungi carrying functional genes from oil shale. PMID- 26969054 TI - Comparison of using polyurethane foam passive samplers and tree bark samples from Western China to determine atmospheric organochlorine pesticide. AB - Polyurethane foam (PUF) passive samplers were deployed and tree bark samples were collected at 15 sites across western China in 2013, and the organochlorine pesticide (OCP) concentrations in the samples were determined. Dichlorodiphenyltrichloroethane and its degradation products (collectively called DDTs), hexachlorocyclohexanes (HCHs), and hexachlorobenzene (HCB) were the dominant OCPs in the PUF samples and tree bark samples. The mean DDTs, HCHs and HCB concentrations were 33, 22 and 18ng/sample in the PUF samples, and 428, 74, and 43ng/(g lipid weight (lw)) in the tree bark, respectively. The OCP concentrations in the air, calculated using PUF-air and tree-bark-air partitioning models, were of the same order of magnitude. Both sample types showed that relatively fresh inputs of DDT and HCHs to the environment have occurred in western China. Meanwhile, PUF passive samplers were compared with the use of tree bark samples as passive samplers. The OCP compositions in the PUF and tree bark samples were different. Only the relatively stable OCPs (such as HCB, beta-HCH and p,p'-dichlorodiphenyldichloro-ethylene (DDE)) were consistent in the PUF and tree bark samples. PMID- 26969055 TI - CO2 sequestration utilizing basic-oxygen furnace slag: Controlling factors, reaction mechanisms and V-Cr concerns. AB - Basic-oxygen furnace slag (BOF-slag) contains >35% CaO, a potential component for CO2 sequestration. In this study, slag-water-CO2 reaction experiments were conducted with the longest reaction duration extending to 96hr under high CO2 pressures of 100-300kg/cm(2) to optimize BOF-slag carbonation conditions, to address carbonation mechanisms, and to evaluate the extents of V and Cr release from slag carbonation. The slag carbonation degree generally reached the maximum values after 24hr slag-water-CO2 reaction and was controlled by slag particle size and reaction temperature. The maximum carbonation degree of 71% was produced from the experiment using fine slag of <=0.5mm under 100 degrees C and a CO2 pressure of 250kg/cm(2) with a water/slag ratio of 5. Vanadium release from the slag to water was significantly enhanced (generally >2 orders) by slag carbonation. In contrast, slag carbonation did not promote chromium release until the reaction duration exceeded 24hr. However, the water chromium content was generally at least an order lower than the vanadium concentration, which decreased when the reaction duration exceeded 24hr. Therefore, long reaction durations of 48-96hr are proposed to reduce environmental impacts while keeping high carbonation degrees. Mineral textures and water compositions indicated that Mg-wustite, in addition to CaO-containing minerals, can also be carbonated. Consequently, the conventional expression that only considered carbonation of the CaO-containing minerals undervalued the CO2 sequestration capability of the BOF slag by ~20%. Therefore, the BOF-slag is a better CO2 storage medium than that previously recognized. PMID- 26969056 TI - Antimicrobial activity of silver loaded MnO2 nanomaterials with different crystal phases against Escherichia coli. AB - Silver-loaded MnO2 nanomaterials (Ag/MnO2), including Ag/alpha-MnO2, Ag/beta MnO2, Ag/gamma-MnO2 and Ag/delta-MnO2 nanorods, were prepared with hydrothermal and impregnation methods. The bactericidal activities of four types of Ag/MnO2 nanomaterials against Escherichia coli were investigated and an inactivation mechanism involving Ag(+) and reactive oxygen species (ROS) was also proposed. The bactericidal activities of Ag/MnO2 depended on the MnO2 crystal phase. Among these nanomaterials, Ag/beta-MnO2 showed the highest bactericidal activity. There was a 6-log decrease in E. coli survival number after treatment with Ag/beta-MnO2 for 120min. The results of 5,5-dimethyl-1-pyrroline-N-oxide spin-trapping measurements by electron spin resonance indicate OH and O2? formation with addition of Ag/beta-MnO2, Ag/gamma-MnO2 or Ag/delta-MnO2. The strongest peak of OH appeared for Ag/beta-MnO2, while no OH or O2? signal was found over Ag/alpha MnO2. Through analysis of electron spin resonance (ESR) and Ag(+) elution results, it could be deduced that the toxicity of Ag(+) eluted from Ag/MnO2 nanomaterials and ROS played the main roles during the bactericidal process. Silver showed the highest dispersion on the surface of beta-MnO2, which promoted ROS formation and the increase of bactericidal activity. Experimental results also indicated that Ag/MnO2 induced the production of intracellular ROS and disruption of the cell wall and cell membrane. PMID- 26969057 TI - Biodegradation of pendimethalin by Bacillus subtilis Y3. AB - A bacterium strain Y3, capable of efficiently degrading pendimethalin, was isolated from activated sludge and identified as Bacillus subtilis according to its phenotypic features and 16S rRNA phylogenetic analysis. This strain could grow on pendimethalin as a sole carbon source and degrade 99.5% of 100mg/L pendimethalin within 2.5days in batch liquid culture, demonstrating a greater efficiency than any other reported strains. Three metabolic products, 6 aminopendimethalin, 5-amino-2-methyl-3-nitroso-4-(pentan-3-ylamino) benzoic acid, and 8-amino-2-ethyl-5-(hydroxymethyl)-1,2-dihydroquinoxaline-6-carboxylic acid, were identified by HPLC-MS/MS, and a new microbial degradation pathway was proposed. A nitroreductase catalyzing nitroreduction of pendimethalin to 6 aminopendimethalin was detected in the cell lysate of strain Y3. The cofactor was nicotinamide adenine dinucleotide phosphate (NADPH) or more preferably nicotinamide adenine dinucleotide (NADH). The optimal temperature and pH for the nitroreductase were 30 degrees C and 7.5, respectively. Hg(2+), Ni(2+), Pb(2+), Co(2+), Mn(2+) Cu(2+), Ag(+), and EDTA severely inhibited the nitroreductase activity, whereas Fe(2+), Mg(2+), and Ca(2+) enhanced it. This study provides an efficient pendimethalin-degrading microorganism and broadens the knowledge of the microbial degradation pathway of pendimethalin. PMID- 26969058 TI - Seasonal comparison of moss bag technique against vertical snow samples for monitoring atmospheric pollution. AB - This is the first study seasonally applying Sphagnum papillosum moss bags and vertical snow samples for monitoring atmospheric pollution. Moss bags, exposed in January, were collected together with snow samples by early March 2012 near the Harjavalta Industrial Park in southwest Finland. Magnetic, chemical, scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX), K-means clustering, and Tomlinson pollution load index (PLI) data showed parallel spatial trends of pollution dispersal for both materials. Results strengthen previous findings that concentrate and slag handling activities were important (dust) emission sources while the impact from Cu-Ni smelter's pipe remained secondary at closer distances. Statistically significant correlations existed between the variables of snow and moss bags. As a summary, both methods work well for sampling and are efficient pollutant accumulators. Moss bags can be used also in winter conditions and they provide more homogeneous and better controlled sampling method than snow samples. PMID- 26969059 TI - In vitro evaluation of inorganic and methyl mercury mediated cytotoxic effect on neural cells derived from different animal species. AB - To extend the current understanding of the mercury-mediated cytotoxic effect, five neural cell lines established from different animal species were comparatively analyzed using three different endpoint bioassays: thiazolyl blue tetrazolium bromide, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay (MTT), neutral red uptake assay (NRU), and Coomassie blue assay (CB). Following a 24-hr exposure to selected concentrations of mercury chloride (HgCl2) and methylmercury (II) chloride (MeHgCl), the cytotoxic effect on test cells was characterized by comparing their 50% inhibition concentration (IC50) values. Experimental results indicated that both these forms of mercury were toxic to all the neural cells, but at very different degrees. The IC50 values of MeHgCl among these cell lines ranged from 1.15+/-0.22 to 10.31+/-0.70MUmol/L while the IC50 values for HgCl2 were much higher, ranging from 6.44+/-0.36 to 160.97+/-19.63MUmol/L, indicating the more toxic nature of MeHgCl. The IC50 ratio between HgCl2 and MeHgCl ranged from 1.75 to 96.0, which confirms that organic mercury is much more toxic to these neural cells than inorganic mercury. Among these cell lines, HGST-BR and TriG44 derived from marine sea turtles showed a significantly high tolerance to HgCl2 as compared to the three mammalian neural cells. Among these neural cells, SK-N-SH represented the most sensitive cells to both chemical forms of mercury. PMID- 26969060 TI - UV light tolerance and reactivation potential of tetracycline-resistant bacteria from secondary effluents of a wastewater treatment plant. AB - Tetracycline-resistant bacteria (TRB) are of concern as emerging microbial contaminants in reclaimed water. To understand the effects of UV disinfection on TRB, both inactivation and reactivation profiles of TRB, as well as 16 tetracycline-resistant isolates from secondary effluent, were characterized in this study. The inactivation ratio of TRB was significantly lower (3.0-log) than that of heterotrophic bacteria (>4.0-log) in the secondary effluent. Additionally, the proportion of TRB significantly increased from 1.65% to 15.51% under 20mJ/cm(2) ultraviolet (UV) exposure. The inactivation rates of tetracycline-resistant isolates ranged from 0.57/s to 1.04/s, of which tetracycline-resistant Enterobacter-1 was the most tolerant to UV light. The reactivation of TRB, tetracycline-resistant isolated strains, as well as heterotrophic bacteria commonly occurred in the secondary effluent even after 20mJ/cm(2) UV exposure. The colony forming ability of TRB and heterotrophic bacteria reached 3.2-log and 3.0-log under 20mJ/cm(2) UV exposure after 22hr incubation. The final inactivation ratio of tetracycline-resistant Enterobacter-1 was 1.18-log under 20mJ/cm(2) UV exposure after 22hr incubation, which is similar to those of TRB (1.18-log) and heterotrophic bacteria (1.19-log). The increased proportion of TRB and the reactivation of tetracycline-resistant enterobacteria in reclaimed water could induce a microbial health risk during wastewater reuse. PMID- 26969061 TI - Estimating the combined toxicity of flufenacet and imazaquin to sorghum with pore water herbicide concentration. AB - Combined toxicity of herbicides to non-target crops is usually resulted from their successive application. The present study was conducted to assess the combined toxicity of flufenacet (FLU) and imazaquin (IMA) to sorghum with their concentration in soil pore water. The concentrations that inhibited growth by 50% (IC50) of FLU and IMA individually and their combination estimated from the herbicide concentrations in soil pore water notably differed from those based on the amended concentrations, due to the decline in bioavailability resulting from adsorption of the herbicides onto soil. According to the amended concentrations, the combined effect of FLU and IMA in soil on sorghum growth was identified as additive action. Based on the concentration in soil pore water, however, it was determined to be antagonism, which was identical to that observed in a test using culture solution. The results revealed that pore water herbicide concentration might be an effective tool to assess the combined toxicity of herbicides in soil to rotational crops. PMID- 26969062 TI - Bioaccumulation characterization of uranium by a novel Streptomyces sporoverrucosus dwc-3. AB - The biosorption mechanisms of uranium on an aerobic bacterial strain Streptomyces sporoverrucosus dwc-3, isolated from a potential disposal site for (ultra-)low uraniferous radioactive waste in Southwest China, were evaluated by using transmission electron microscopy (TEM), energy dispersive X-ray (EDX) analysis, Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), proton induced X-ray emission (PIXE) and enhanced proton backscattering spectrometry (EPBS). Approximately 60% of total uranium at an initial concentration of 10mg/L uranium nitrate solution could be absorbed on 100mg S. sporoverrucosus dwc-3 with an adsorption capacity of more than 3.0mg/g (wet weight) after 12hr at room temperature at pH3.0. The dynamic biosorption process of S. sporoverrucosus dwc-3 for uranyl ions was well described by a pseudo second order model. S. sporoverrucosus dwc-3 could accumulate uranium on cell walls and within the cell, as revealed by SEM and TEM analysis as well as EDX spectra. XPS and FT-IR analysis further suggested that the absorbed uranium was bound to amino, phosphate and carboxyl groups of the cells. Additionally, PIXE and EPBS results confirmed that ion exchange also contributed to the adsorption process of uranium. PMID- 26969063 TI - Synchrotron micro-scale measurement of metal distributions in Phragmites australis and Typha latifolia root tissue from an urban brownfield site. AB - Liberty State Park in New Jersey, USA, is a "brownfield" site containing various levels of contaminants. To investigate metal uptake and distributions in plants on the brownfield site, Phragmites australis and Typha latifolia were collected in Liberty State Park during the growing season (May-September) in 2011 at two sites with the high and low metal loads, respectively. The objective of this study was to understand the metal (Fe, Mn, Cu, Pb and Zn) concentration and spatial distributions in P. australis and T. latifolia root systems with micro meter scale resolution using synchrotron X-ray microfluorescence (MUXRF) and synchrotron X-ray computed microtomography (MUCMT) techniques. The root structure measurement by synchrotron MUCMT showed that high X-ray attenuation substance appeared in the epidermis. Synchrotron MUXRF measurement showed that metal concentrations and distributions in the root cross-section between epidermis and vascular tissue were statistically different. Significant correlations were found between metals (Cu, Mn, Pb and Zn) and Fe in the epidermis, implying that metals were scavenged by Fe oxides. The results from this study suggest that the expression of metal transport and accumulation within the root systems may be element specific. The information derived from this study can improve our current knowledge of the wetland plant ecological function in brownfield remediation. PMID- 26969064 TI - Comparison of surface water chemistry and weathering effects of two lake basins in the Changtang Nature Reserve, China. AB - The geochemistry of natural waters in the Changtang Nature Reserve, northern Tibet, can help us understand the geology of catchments, and provide additional insight in surface processes that influence water chemistry such as rock weathering on the Qinghai-Tibet Plateau. However, severe natural conditions are responsible for a lack of scientific data for this area. This study represents the first investigation of the chemical composition of surface waters and weathering effects in two lake basins in the reserve (Lake Dogaicoring Qiangco and Lake Longwei Co). The results indicate that total dissolved solids (TDS) in the two lakes are significantly higher than in other gauged lakes on the Qinghai Tibet Plateau, reaching 20-40g/L, and that TDS of the tectonic lake (Lake Dogaicoring Qiangco) is significantly higher than that of the barrier lake (Lake Longwei Co). Na(+) and Cl(-) are the dominant ions in the lake waters as well as in the glacier-fed lake inflows, with chemical compositions mainly affected by halite weathering. In contrast, ion contents of inflowing rivers fed by nearby runoff are lower and concentrations of dominant ions are not significant. Evaporite, silicate, and carbonate weathering has relatively equal effects on these rivers. Due to their limited scope, small streams near the lakes are less affected by carbonate than by silicate weathering. PMID- 26969065 TI - Microcystin-degrading bacteria affect mcyD expression and microcystin synthesis in Microcystis spp. AB - Cyanobacterial blooms occur increasingly often and cause ecological, economic and human health problems worldwide. Microcystins (MCs) are the dominant toxins produced by cyanobacteria and are implicated in epidemic disease and environmental problems. Extensive research has been reported on the various regulating factors, e.g., light, temperature, nutrients such as nitrogen and phosphorus, pH, iron, xenobiotics, and predators, that influence microcystin (MC) synthesis, but little is known about the effects of cyanobacteria-associated bacteria on MC synthesis. A considerable number of studies have focused on interactions between Microcystis species and their associated bacteria. In this study, we evaluated the effects of MC-degrading bacteria (MCDB) on MC synthesis gene mcyD expression and MC synthesis in axenic strain PCC7806, non-axenic strain FACHB905, and colony strain FACHB1325 of Microcystis by quantitative real-time polymerase chain reaction (RT-PCR) assay and enzyme-linked immunosorbent assay (ELISA). We demonstrate for the first time that MCDB can induce and up-regulate the MC production and transcriptional response of the mcyD gene of toxic Microcystis. On day 4 of the culturing experiment, the intracellular MC concentration and transcriptional response of mcyD of FACHB1325 were up-regulated 1.9 and 5.3-fold over that of the control, and for FACHB905 were up-regulated 1.8 and 4.2-fold over that of the control, respectively. On day 10, the transcriptional response of mcyD was up-regulated 21.3-fold in PCC7806. These results indicate that there are interactions between toxic Microcystis and MCDB, and MCDB may play a role in regulating mcyD expression in toxic Microcystis. PMID- 26969066 TI - Removal of heavy metals and arsenic from a co-contaminated soil by sieving combined with washing process. AB - Batch experiments were conducted with a heavy metals and arsenic co-contaminated soil from an abandoned mine to evaluate the feasibility of a remediation technology that combines sieving with soil washing. Leaching of the arsenic and heavy metals from the different particle size fractions was found to decrease in the order: <0.1, 2-0.1, and >2mm. With increased contact time, the concentration of heavy metals in the leachate was significantly decreased for small particles, probably because of adsorption by the clay soil component. For the different particle sizes, the removal efficiencies for Pb and Cd were 75%-87%, and 61%-77% for Zn and Cu, although the extent of removal was decreased for As and Cr at <45%. The highest efficiency by washing for Pb, Cd, Zn, and As was from the soil particles >2mm, although good metal removal efficiencies were also achieved in the small particle size fractions. Through SEM-EDS observations and correlation analysis, the leaching regularity of the heavy metals and arsenic was found to be closely related to Fe, Mn, and Ca contents of the soil fractions. The remediation of heavy metal-contaminated soil by sieving combined with soil washing was proven to be efficient, and practical remediation parameters were also recommended. PMID- 26969067 TI - Dispersive liquid-liquid microextraction of silver nanoparticles in water using ionic liquid 1-octyl-3-methylimidazolium hexafluorophosphate. AB - Using the ionic liquid (IL) 1-octyl-3-methylimidazolium hexafluorophosphate as the extractant and methanol as the dispersion solvent, a dispersive liquid-liquid microextraction method was developed to extract silver nanoparticles (AgNPs) from environmental water samples. Parameters that influenced the extraction efficiency such as IL concentration, pH and extraction time were optimized. Under the optimized conditions, the highest extraction efficiency for AgNPs was above 90% with an enrichment factor of >90. The extracted AgNPs in the IL phase were identified by transmission electron microscopy and ultraviolet-visible spectroscopy, and quantified by inductively coupled plasma mass spectrometry after microwave digestion, with a detection limit of 0.01MUg/L. The spiked recovery of AgNPs was 84.4% with a relative standard deviation (RSD) of 3.8% (n=6) at a spiked level of 5MUg/L, and 89.7% with a RSD of 2.2% (n=6) at a spiked level of 300MUg/L, respectively. Commonly existed environmental ions had a very limited influence on the extraction efficiency. The developed method was successfully applied to the analysis of AgNPs in river water, lake water, and the influent and effluent of a wastewater treatment plant, with recoveries in the range of 71.0%-90.9% at spiking levels of 0.11-4.7MUg/L. PMID- 26969069 TI - Removal of C.I. Reactive Red 2 by low pressure UV/chlorine advanced oxidation. AB - Azo dyes are commonly found as pollutants in wastewater from the textile industry, and can cause environmental problems because of their color and toxicity. The removal of a typical azo dye named C.I. Reactive Red 2 (RR2) during low pressure ultraviolet (UV)/chlorine oxidation was investigated in this study. UV irradiation at 254nm and addition of free chlorine provided much higher removal rates of RR2 and color than UV irradiation or chlorination alone. Increasing the free chlorine dose enhanced the removal efficiency of RR2 and color by UV/chlorine oxidation. Experiments performed with nitrobenzene (NB) or benzoic acid (BA) as scavengers showed that radicals (especially OH) formed during UV/chlorine oxidation are important in the RR2 removal. Addition of HCO3( ) and Cl(-) to the RR2 solution did not inhibit the removal of RR2 during UV/chlorine oxidation. PMID- 26969068 TI - Carbonyl compounds in dining areas, kitchens and exhaust streams in restaurants with varying cooking methods in Kaohsiung, Taiwan. AB - Eighteen carbonyl species in C1-C10 were measured in the dining areas, kitchens and exhaust streams of six different restaurant types in Kaohsiung, southern Taiwan. Measured results in the dining areas show that Japanese barbecue (45.06ppb) had the highest total carbonyl concentrations (sum of 18 compounds), followed by Chinese hotpot (38.21ppb), Chinese stir-frying (8.99ppb), Western fast-food (8.22ppb), Chinese-Western mixed style (7.38ppb), and Chinese buffet (3.08ppb), due to their different arrangements for dining and cooking spaces and different cooking methods. On average, low carbon-containing species (C1-C4), e.g., formaldehyde, acetaldehyde, acetone and butyraldehyde were dominant and contributed 55.01%-94.52% of total carbonyls in the dining areas of all restaurants. Meanwhile, Chinese-Western mixed restaurants (45.48ppb) had high total carbonyl concentrations in kitchens mainly because of its small kitchen and poor ventilation. However, high carbon-containing species (C5-C10) such as hexaldehyde, heptaldehyde and nonanaldehyde (16.62%-77.00% of total carbonyls) contributed comparatively with low carbon-containing compounds (23.01%-83.39% of total carbonyls) in kitchens. Furthermore, Chinese stir-frying (132.10ppb), Japanese barbecue (125.62ppb), Western fast-food (122.67ppb), and Chinese buffet (119.96ppb) were the four restaurant types with the highest total carbonyl concentrations in exhaust streams, indicating that stir-frying and grilling are inclined to produce polluted gases. Health risk assessments indicate that Chinese hotpot and Japanese barbecue exceeded the limits of cancer risk (10(-6)) and hazard index (=1), mainly due to high concentrations of formaldehyde. The other four restaurants were below both limits. PMID- 26969070 TI - Insights into properties of activated carbons prepared from different raw precursors by pyrophosphoric acid activation. AB - Low-cost activated carbons (ACs) were prepared from four kinds of solid wastes: petroleum coke, Enteromorpha prolifera, lignin from papermaking black liquid and hair, by pyrophosphoric acid (H4P2O7) activation. Thermo-gravimetric analysis of the pyrolysis of H4P2O7-precursor mixtures implied that H4P2O7 had different influences on the pyrolysis behavior of the four raw materials. N2 adsorption/desorption isotherms, scanning electron microscopy, Fourier transform infrared spectroscopy and adsorption capacities for dyes were used to characterize the prepared activated carbons. AC derived from E. prolifera exhibited the highest surface area (1094m(2)/g) and maximum monolayer adsorption capacity for malachite green (1250mg/g). Kinetic studies showed that the experimental data were in agreement with the pseudo-second-order model. The adsorption isotherms were well described by the Langmuir isotherm model, indicating the adsorption of dye onto the ACs proceeded by monolayers. PMID- 26969071 TI - Optimizing the crystallinity and acidity of H-SAPO-34 by fluoride for synthesizing Cu/SAPO-34 NH3-SCR catalyst. AB - A series of H-SAPO-34 zeolites were synthesized by a hydrothermal method in fluoride media. The as-synthesized H-SAPO-34 zeolites were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), N2 physisorption, temperature-programmed desorption of NH3 (NH3-TPD) and nuclear magnetic resonance (NMR) measurements. The results showed that a certain concentration of F(-) anions promoted the nucleation and crystallization of H-SAPO-34. The H-SAPO-34 synthesized in the fluoride media showed high crystallinity, uniform particle size distribution, large specific surface area and pore volume, and enhanced acidity. Therefore, Cu/SAPO-34 based on the fluoride-assisted zeolite showed a broadened temperature window for the selective catalytic reduction of NO by NH3 (NH3-SCR) reaction due to the enhanced acidity of the zeolite and the improved dispersion of copper species. PMID- 26969072 TI - Lambda-cyhalothrin disrupts the up-regulation effect of 17beta-estradiol on post synaptic density 95 protein expression via estrogen receptor alpha-dependent Akt pathway. AB - Lambda-cyhalothrin (LCT), one of the type II pyrethroids, has been widely used throughout the world. The estrogenic effect of LCT to increase cell proliferation has been well established. However, whether the estrogenic effect of LCT will influence neurodevelopment has not been investigated. In addition, 17beta Estradiol (E2) plays a crucial role in neurodevelopment and induces an increase in synaptic proteins. The post-synaptic density 95 (PSD95) protein, which is involved in the development of the structure and function of new spines and localized with estrogen receptor alpha (ERalpha) at the post-synaptic density (PSD), was detected in our study by using hippocampal neuron cell line HT22. We found that LCT up-regulated PSD95 and ERalpha expression, estrogen receptor (ER) antagonist ICI182,780 and phosphatidylinositol-4; 5-bisphosphate 3-kinase (PI3K) inhibitor LY294,002 blocked this effect. In addition, LCT disrupted the promotion effect of E2 on PSD95. To investigate whether the observed changes are caused by ERalpha-dependent signaling activation, we next detected the effects of LCT on the ERalpha-mediated PI3K-Protein kinase B (PKB/Akt)-eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) pathway. There existed an activation of Akt and the downstream factor 4E-BP1 after LCT treatment. In addition, LCT could disrupt the activation effect of E2 on the Akt pathway. However, no changes in cAMP response element-binding protein (CREB) activation and PSD95 messenger ribonucleic acid (mRNA) were observed. Our findings demonstrated that LCT could increase the PSD95 protein level via the ERalpha-dependent Akt pathway, and LCT might disrupt the up-regulation effect of E2 on PSD95 protein expression via this signaling pathway. PMID- 26969073 TI - Historical records of polycyclic aromatic hydrocarbon deposition in a shallow eutrophic lake: Impacts of sources and sedimentological conditions. AB - Sediment core samples collected from Lake Chaohu were analyzed for 15 priority polycyclic aromatic hydrocarbons (PAHs) to assess the spatial and temporal distributions of the PAHs during lacustrine sedimentary processes and regional economic development. Assessing the PAH sedimentary records over an approximately 100-year time span, we identified two stages in the PAH inputs and sources (before the 1970s and after the 1970s) in the eastern lake region near a village, whereas three stages (before the 1950s, 1950s-1990s and after the 1990s) were identified in the western lake region near urban and industrial areas. Rapid increases in the PAH depositional fluxes occurred during the second stage due to increased human activities in the Lake Chaohu basin. The composition and isomeric ratios of the PAHs revealed that pyrolysis is the main source of PAHs in this lake. Strong positive relationships between PAH concentration and the total organic carbon concentration, sediment grain size (<4MUm), as well as the local population and Gross Domestic Product indicated that the sedimentary conditions impact the depositional characteristics of the PAHs; simultaneously, socioeconomic activities, such as energy consumption and the levels of urban industrialization and civilization, affect both the composition and abundance of the PAHs. PMID- 26969075 TI - Younger age predicts greater effectiveness of spinal cord stimulation for chronic pain. AB - BACKGROUND: Spinal cord stimulation (SCS) is an accepted surgical treatment for neuropathic pain in failed back syndrome or complex regional pain syndrome. However, even in the best selected surgical cases the predictors of adequate pain control are not well defined. The aim of this study was to identify predictors of outcome in patients who underwent SCS in our center. METHODS: We performed a retrospective analysis of our neurosurgical database for patients who underwent SCS over the last 8 years in an attempt to identify factors predictive of outcome. RESULTS: Forty-one patients underwent implantation of epidural electrodes, 34 patients had a successful stimulation trial and received permanent devices. Nine patients experienced a late failure at a median time of 7.8 months (range, 4.5-19 months) after implantation. Age was significantly associated with outcome. Younger patients had a significantly lower rate of treatment failure, and none of the patients above 65 years had a successful long-term outcome. CONCLUSIONS: Our results suggest that younger age is associated with greater long term effectiveness of spinal cord stimulation and therefore age may influence the success of SCS therapy with older patients having a greater tendency to failure. Earlier intervention may be beneficial in these chronic pain patients. PMID- 26969074 TI - Polychlorinated biphenyls and omega-3 fatty acid exposure from fish consumption, and thyroid cancer among New York anglers. AB - Fish from the Great Lakes contain polychlorinated biphenyls (PCBs) which have been shown to disrupt endocrine function and mimic thyroid hormones, but they also contain beneficial omega-3 fatty acids that may offer protection against endocrine cancers. The purpose of this study was to examine the effects of Lake Ontario fish consumption and the estimated consumption of PCBs and omega-3 fatty acids on the risk of thyroid cancer in a group of sport fishermen. Anglers from the New York State Angler Cohort Study were followed for cancer incidence from 1991-2008. Twenty-seven cases of incident thyroid cancer and 108 controls were included in the analyses. Total estimated fish consumption, estimated omega-3 fatty acid consumption, and estimated PCB consumption from Lake Ontario fish were examined for an association with the incidence of thyroid cancer, while matching on sex, and controlling for age and smoking status. Results from logistic regression indicate no significant associations between fish consumption, short term estimated omega-3 fatty acids, or estimated PCB consumption from Great Lakes fish and the development of thyroid cancer, but it was suggested that long-term omega-3 fatty acid from Great Lakes fish may be protective of the development of thyroid cancer. In conclusion, fish consumption, with the possible concomitant PCBs, from the Great Lakes does not appear to increase the risk of thyroid cancer in New York anglers. Further research is needed in order to separate the individual health effects of PCBs from omega-3 fatty acids contained within the fish. PMID- 26969078 TI - The pivotal role of a pre-admission electrocardiogram for the diagnosis of Takotsubo syndrome in the ED. PMID- 26969076 TI - Expression of forkhead box transcription factor genes Foxp1 and Foxp2 during jaw development. AB - Development of the face is regulated by a large number of genes that are expressed in temporally and spatially specific patterns. While significant progress has been made on characterizing the genes that operate in the oral region of the face, those regulating development of the aboral (lateral) region remain largely unknown. Recently, we discovered that transcription factors LIM homeobox (LHX) 6 and LHX8, which are key regulators of oral development, repressed the expression of the genes encoding forkhead box transcription factors, Foxp1 and Foxp2, in the oral region. To gain insights into the potential role of the Foxp genes in region-specific development of the face, we examined their expression patterns in the first pharyngeal arch (primordium for the jaw) of mouse embryos at a high spatial and temporal resolution. Foxp1 and Foxp2 were preferentially expressed in the aboral and posterior parts of the first pharyngeal arch, including the developing temporomandibular joint. Through double immunofluorescence and double fluorescent RNA in situ hybridization, we found that Foxp1 was expressed in the progenitor cells for the muscle, bone, and connective tissue. Foxp2 was expressed in subsets of bone and connective tissue progenitors but not in the myoblasts. Neither gene was expressed in the dental mesenchyme nor in the oral half of the palatal shelf undergoing extensive growth and morphogenesis. Together, we demonstrated for the first time that Foxp1 and Foxp2 are expressed during craniofacial development. Our data suggest that the Foxp genes may regulate development of the aboral and posterior regions of the jaw. PMID- 26969077 TI - Adrenocortical carcinoma: Retrospective analysis of the last 22 years. AB - BACKGROUND: Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. The clinical experience acquired, even from a small number of cases, has improved understanding of this condition. The purpose of this study is to characterize patients with ACC followed up at a Portuguese reference center over the past 22 years. METHODS: Retrospective analysis of clinical records of patients with histopathological diagnosis of ACC followed up from 1992 to 2014. RESULTS: The study sample consisted of 22 patients, 20 of them female. Eleven patients were in stage II, four in stage III, and five in stage IV; 13 patients had functioning lesions. Adrenalectomy was performed in 20 patients, with complete tumor resection in 90% of the cases. During follow-up, eight patients experienced recurrence of local disease, and 12 distant metastases. Fourteen patients received mitotane, 35.7% (n=5) as adjuvant therapy and 64.3% (n=9) after recurrence; therapeutic plasma mitotane levels were achieved in 70% of patients. Stage III patients who received adjuvant therapy had longer survival time (13.5 vs. 2.5 months). Two patients were given chemotherapy associated to mitotane. Median survival was 11 months (0-257 months); it was slightly longer in younger patients or patients with non-functioning tumors. Six patients are still alive, four of them with no evidence of disease. CONCLUSION: Despite the overall poor prognosis, some patients with ACC may have a long survival time. Although complete tumor removal remains the only potentially curative treatment, diagnosis at a younger age, presence of non-functioning tumors, and mitotane treatment also seemed to be associated to longer survival in our patients. PMID- 26969079 TI - Seventy-two-hour antibiotic retrieval from the ED: a randomized controlled trial of discharge instructional modality. AB - BACKGROUND: Limited health literacy is a risk factor for poor outcomes in numerous health care settings. Little is known about the impact of instructional modality and health literacy on adherence to emergency department (ED) discharge instructions. PURPOSE: To examine the impact of instructional modality on 72-hour antibiotic retrieval among ED patients prescribed outpatient antibiotics for infections. METHODS: English-speaking ED patients diagnosed as having acute infections and prescribed outpatient antibiotics were randomized to standard discharge instructions, standard instructions plus text-messaged instructions, or standard instructions plus voicemailed instructions targeting ED prescriptions. Health literacy was determined by validated instrument. Seventy-two-hour antibiotic retrieval, 30-day report of prescription completion, and discharge instructional modality preference were assessed. RESULTS: Nearly one-quarter of the 2521 participants demonstrated low health literacy. Low health literacy predicted decreased 72-hour antibiotic retrieval (chi(2) = 9.56, P=.008). No significant association with antibiotic retrieval was noted across the 3 treatment groups (chi(2) = 5.112, P=.078). However, patients randomized to the text message group retrieved antibiotic prescriptions within 72 hours more frequently than did those randomized to the voicemail treatment group (chi(2) = 4.345, P=.037), and patients with low health literacy randomized to voicemailed instructions retrieved their antibiotic prescriptions less frequently than did those randomized to standard of care instructions (chi(2) = 5.526, P=.019). Reported instructional modality preferences were inconsistent with the primary findings of the study. CONCLUSIONS: Discharge instructional modality impacts antibiotic retrieval in patients with low health literacy. Preference for discharge instructional modality varies by degree of health literacy, but does not predict which modality will optimize 72-hour antibiotic retrieval. PMID- 26969080 TI - Magnetic solid lipid nanoparticles in hyperthermia against colon cancer. AB - A reproducible double emulsion/solvent evaporation procedure is developed to formulate magnetic solid lipid nanoparticles (average size~180 nm) made of iron oxide cores embedded within a glyceryl trimyristate solid matrix. The physicochemical characterization of the nanocomposites ascertained the efficacy of the preparation conditions in their production, i.e. surface properties (electrokinetic and thermodynamic data) were almost indistinguishable from those of the solid lipid nanomatrix, while electron microscopy characterizations and X ray diffraction patterns confirmed the satisfactory coverage of the magnetite nuclei. Hemocompatibility of the particles was established in vitro. Hysteresis cycle determinations defined the appropriate magnetic responsiveness of the nanocomposites, and their heating characteristics were investigated in a high frequency alternating gradient of magnetic field: a constant maximum temperature of 46 degrees C was obtained within 40 min. Finally, in vitro tests performed on human HT29 colon adenocarcinoma cells demonstrated a promising decrease in cell viability after treatment with the nanocomposites and exposure to that alternating electromagnetic field. To the best of our knowledge, this is the first time that such type of nanoformulation with very promising hyperthermia characteristics has been developed for therapeutic aims. PMID- 26969081 TI - Expanding transplant options to patients over 50 years. Improved outcome after reduced intensity conditioning mismatched-unrelated donor transplantation for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the EBMT. AB - The outcome of patients undergoing HLA-matched unrelated donor allogeneic hematopoietic cell transplantation following reduced-intensity conditioning or myeloablative regimens is reported to be equivalent; however, it is not known if the intensity of the conditioning impacts outcomes after mismatched unrelated donor transplantation for acute myeloid leukemia. Eight hundred and eighty three patients receiving reduced-intensity conditioning were compared with 1041 myeloablative conditioning regimen recipients in the setting of mismatched unrelated donor transplantation. The donor graft was HLA-matched at 9/10 in 872 (83.8%) and at 8/10 in 169 (16.2%) myeloablative conditioning recipients, while in the reduced-intensity conditioning cohort, 754 (85.4%) and 129 (14.6%) were matched at 9/10 and 8/10 loci, respectively. Myeloablative conditioning regimen recipients were younger, 70% being <50 years of age compared to only 30% in the reduced-intensity conditioning group (P=0.0001). Significantly, more patients had secondary acute myeloid leukemia (P=0.04) and Karnofsky Performance Status score <90% (P=0.02) in the reduced-intensity conditioning group. Patients <50 and >=50 years were analyzed separately. On multivariate analysis and after adjusting for differences between the two groups, reduced-intensity conditioning in patients age >=50 years was associated with higher overall survival (HR 0.78; P=0.01), leukemia-free survival (HR 0.82; P=0.05), and decreased non-relapse mortality (HR 0.73; P=0.03). Relapse incidence (HR 0.91; P=0.51) and chronic graft-versus-host disease (HR 1.31; P=0.11) were, however, not significantly different. In patients <50 years old, there were no statistically significant differences in overall survival, leukemia-free survival, relapse incidence, non-relapse mortality, and chronic graft-versus-host-disease between the groups. Our study shows no significant outcome differences in patients younger than 50 years receiving reduced-intensity vs myeloablative conditioning regimens after mismatched unrelated donor transplantation. Furthermore, the data support the superiority of reduced-intensity conditioning regimens in older adults receiving transplants from mismatched unrelated donors. PMID- 26969083 TI - Bio-engineered and native red blood cells from cord blood exhibit the same metabolomic profile. PMID- 26969082 TI - Late thyroid complications in survivors of childhood acute leukemia. An L.E.A. study. AB - Thyroid complications are known side effects of irradiation. However, the risk of such complications in childhood acute leukemia survivors who received either central nervous system irradiation or hematopoietic stem cell transplantation is less described. We prospectively evaluated the incidence and risk factors for thyroid dysfunction and tumors in survivors of childhood acute myeloid or lymphoid leukemia. A total of 588 patients were evaluated for thyroid function, and 502 individuals were assessed for thyroid tumors (median follow-up duration: 12.6 and 12.5 years, respectively). The cumulative incidence of hypothyroidism was 17.3% (95% CI: 14.1-21.1) and 24.6% (95% CI: 20.4-29.6) at 10 and 20 years from leukemia diagnosis, respectively. Patients who received total body irradiation (with or without prior central nervous system irradiation) were at higher risk of hypothyroidism (adjusted HR: 2.87; P=0.04 and 2.79, P=0.01, respectively) as compared with transplanted patients who never received any irradiation. Patients transplanted without total body irradiation who received central nervous system irradiation were also at higher risk (adjusted HR: 3.39; P=0.02). Patients irradiated or transplanted at older than 10 years of age had a lower risk (adjusted HR: 0.61; P=0.02). Thyroid malignancy was found in 26 patients (5.2%). Among them, two patients had never received any type of irradiation: alkylating agents could also promote thyroid cancer. The cumulative incidence of thyroid malignancy was 9.6% (95% CI: 6.0-15.0) at 20 years. Women were at higher risk than men (adjusted HR: 4.74; P=0.002). In conclusion, thyroid complications are frequent among patients who undergo transplantation after total body irradiation and those who received prior central nervous system irradiation. Close monitoring is thus warranted for these patients. Clinicaltrials.gov identifier: NCT 01756599. PMID- 26969084 TI - LIN28B is over-expressed in specific subtypes of pediatric leukemia and regulates lncRNA H19. PMID- 26969085 TI - Efficient CRISPR-Cas9 mediated gene disruption in primary erythroid progenitor cells. PMID- 26969086 TI - A distinct plasmablast and naive B-cell phenotype in primary immune thrombocytopenia. AB - Primary immune thrombocytopenia is an autoimmune disorder in which platelet destruction is a consequence of both B- and T-cell dysregulation. Flow cytometry was used to further characterize the B- and T-cell compartments in a cross sectional cohort of 26 immune thrombocytopenia patients including antiplatelet antibody positive (n=14) and negative (n=12) patients exposed to a range of therapies, and a cohort of matched healthy volunteers. Markers for B-cell activating factor and its receptors, relevant B-cell activation markers (CD95 and CD21) and markers for CD4(+) T-cell subsets, including circulating T-follicular helper-like cells, were included. Our results indicate that an expanded population of CD95(+) naive B cells correlated with disease activity in immune thrombocytopenia patients regardless of treatment status. A population of CD21 naive B cells was specifically expanded in autoantibody-positive immune thrombocytopenia patients. Furthermore, the B-cell maturation antigen, a receptor for B-cell activating factor, was consistently and strongly up-regulated on plasmablasts from immune thrombocytopenia patients. These observations have parallels in other autoantibody-mediated diseases and suggest that loss of peripheral tolerance in naive B cells may be an important component of immune thrombocytopenia pathogenesis. Moreover, the B-cell maturation antigen represents a potential target for plasma cell directed therapies in immune thrombocytopenia. PMID- 26969087 TI - Computational studies of plasma lipoprotein lipids. AB - Plasma lipoproteins are macromolecular assemblies of proteins and lipids found in the blood. The lipid components of lipoproteins are amphipathic lipids such as phospholipids (PLs), and unesterified cholesterols (UCs) and hydrophobic lipids such as cholesteryl esters (CEs) and triglycerides (TGs). Since lipoproteins are soft matter supramolecular assemblies easily deformable by thermal fluctuations and they also exist in varying densities and protein/lipid components, a detailed understanding of their structure/function is experimentally difficult. Molecular dynamics (MD) simulation has emerged as a particularly promising way to explore the structure and dynamics of lipoproteins. The purpose of this review is to survey the current status of computational studies of the lipid components of the lipoproteins. Computational studies aim to explore three levels of complexity for the 3-dimensional structural dynamics of lipoproteins at various metabolic stages: (i) lipoprotein particles consist of protein with minimal lipid; (ii) lipoprotein particles consist of PL-rich discoidal bilayer-like lipid particles; (iii) mature circulating lipoprotein particles consist of CE-rich or TG-rich spheroidal lipid-droplet-like particles. Due to energy barriers involved in conversion between these species, other biomolecules also participate in lipoprotein biological assembly. For example: (i) lipid-poor apolipoprotein A-I (apoA-I) interacts with ATP-binding cassette transporter A1 (ABCA1) to produce nascent discoidal high density lipoprotein (dHDL) particles; (ii) lecithin cholesterol acyltransferase (LCAT) mediates the conversion of UC to CE in dHDL, driving spheroidal HDL (sHDL) formation; (iii) transfer proteins, cholesterol ester transfer protein (CETP) and phospholipid transfer protein (PLTP), transfer both CE and TG and PL, respectively, between lipoprotein particles. Computational studies have the potential to explore different lipoprotein particles at each metabolic stage in atomistic detail. This review discusses the current status of computational methods including all-atom MD (AAMD), coarse-grain MD (CGMD), and MD-simulated annealing (MDSA) and their applications in lipoprotein structural dynamics and biological assemblies. Results from MD simulations are discussed and compared across studies in order to identify key findings, controversies, issues and future directions. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Rog. PMID- 26969088 TI - Membrane bending by protein crowding is affected by protein lateral confinement. AB - Crowding of asymmetrically-distributed membrane proteins has been recently recognized as an important factor in remodeling of biological membranes, for example during transport vesicle formation. In this paper, we theoretically analyze the effect of protein crowding on membrane bending and examine its dependence on protein size, shape, transmembrane asymmetry and lateral confinement. We consider three scenarios of protein lateral organization, which are highly relevant for cellular membranes in general: freely diffusing membrane proteins without lateral confinement, the presence of a diffusion barrier and interactions with a vesicular coat. We show that protein crowding affects vesicle formation even if the proteins are distributed symmetrically across the membrane and that this effect depends significantly on lateral confinement. The largest crowding effect is predicted for the proteins that are confined to the forming vesicle by a diffusion barrier. We calculate the bending properties of a crowded membrane and find that its spontaneous curvature depends primarily on the degree of transmembrane asymmetry, and its effective bending modulus on the type of lateral confinement. Using the example of COPII vesicle formation from the endoplasmic reticulum, we analyze the energetic cost of vesicle formation. The results provide a novel insight into the effects of lateral and transmembrane organization of membrane proteins, and can guide data interpretation and future experimental approaches. PMID- 26969089 TI - Gut bacteria dysbiosis and necrotising enterocolitis in very low birthweight infants: a prospective case-control study. AB - BACKGROUND: Gut bacteria might predispose to or protect from necrotising enterocolitis, a severe illness linked to prematurity. In this observational prospective study we aimed to assess whether one or more bacterial taxa in the gut differ between infants who subsequently develop necrotising enterocolitis (cases) and those who do not (controls). METHODS: We enrolled very low birthweight (1500 g and lower) infants in the primary cohort (St Louis Children's Hospital) between July 7, 2009, and Sept 16, 2013, and in the secondary cohorts (Kosair Children's Hospital and Children's Hospital at Oklahoma University) between Sept 12, 2011 and May 25, 2013. We prospectively collected and then froze stool samples for all infants. Cases were defined as infants whose clinical courses were consistent with necrotising enterocolitis and whose radiographs fulfilled criteria for Bell's stage 2 or 3 necrotising enterocolitis. Control infants (one to four per case; not fixed ratios) with similar gestational ages, birthweight, and birth dates were selected from the population after cases were identified. Using primers specific for bacterial 16S rRNA genes, we amplified and then pyrosequenced faecal DNA from stool samples. With use of Dirichlet multinomial analysis and mixed models to account for repeated measures, we identified host factors, including development of necrotising enterocolitis, associated with gut bacterial populations. FINDINGS: We studied 2492 stool samples from 122 infants in the primary cohort, of whom 28 developed necrotising enterocolitis; 94 infants were used as controls. The microbial community structure in case stools differed significantly from those in control stools. These differences emerged only after the first month of age. In mixed models, the time-by-necrotising-enterocolitis interaction was positively associated with Gammaproteobacteria (p=0.0010) and negatively associated with strictly anaerobic bacteria, especially Negativicutes (p=0.0019). We studied 1094 stool samples from 44 infants in the secondary cohorts. 18 infants developed necrotising enterocolitis (cases) and 26 were controls. After combining data from all cohorts (166 infants, 3586 stools, 46 cases of necrotising enterocolitis), there were increased proportions of Gammaproteobacteria (p=0.0011) and lower proportions of both Negativicutes (p=0.0013) and the combined Clostridia-Negativicutes class (p=0.0051) in infants who went on to develop necrotising enterocolitis compared with controls. These associations were strongest in both the primary cohort and the overall cohort for infants born at less than 27 weeks' gestation. INTERPRETATION: A relative abundance of Gammaproteobacteria (ie, Gram-negative facultative bacilli) and relative paucity of strict anaerobic bacteria (especially Negativicutes) precede necrotising enterocolitis in very low birthweight infants. These data offer candidate targets for interventions to prevent necrotising enterocolitis, at least among infants born at less than 27 weeks' gestation. FUNDING: National Institutes of Health (NIH), Foundation for the NIH, the Children's Discovery Institute. PMID- 26969091 TI - Adjuvant therapy for renal-cell carcinoma: settled for now. PMID- 26969092 TI - Gut microbiome and necrotising enterocolitis: time for intervention? PMID- 26969093 TI - Is waiting bad for subjective health? AB - The present study examined the possibility that waiting is bad for one's subjective health. Specifically, we examined longitudinal trends in the self reported health, self-reported sleep disruption, distress, and emotion regulation strategies of law school graduates waiting for their bar exam results. Multilevel analyses suggest that waiting was particularly detrimental to participants' self reported health and sleep disruption at the beginning and end of the waiting period. Moreover, distress and most emotion regulation efforts were associated with poorer subjective health on average, and personal increases in distress and emotion regulation were largely associated with personal increases in poor self reported health and sleep disruption. Our results suggest that waiting periods can take a toll on subjective health and that individual and temporal variations in distress and emotion regulation efforts are associated with these health trajectories. PMID- 26969094 TI - Blood pressure outcomes of medication adherence interventions: systematic review and meta-analysis. AB - This systematic review applied meta-analytic procedures to integrate primary research that examined blood pressure outcomes of medication adherence interventions. Random-effects model analysis calculated standardized mean difference effect sizes. Exploratory dichotomous and continuous moderator analyses using meta-analytic analogues of ANOVA and regression were performed. Codable data were extracted from 156 reports with 60,876 participants. The overall weighted mean difference systolic effect size was 0.235 across 161 treatment versus control comparisons. The diastolic effect size was 0.189 from 181 comparisons. Effect sizes were significantly heterogeneous. Common risks of bias included lack of allocation concealment, unmasked data collectors, and absent intention-to-treat analyses. Exploratory moderator analyses suggested that habit-based interventions may be most effective. The largest effect sizes were for interventions delivered by pharmacists. The modest magnitude effect sizes suggest future research should explore novel higher dose interventions that might address multiple levels of influence on adherence behavior. PMID- 26969095 TI - RNA-seq reveals a diminished acclimation response to the combined effects of ocean acidification and elevated seawater temperature in Pagothenia borchgrevinki. AB - PURPOSE: The IPCC has reasserted the strong influence of anthropogenic CO2 contributions on global climate change and highlighted the polar-regions as highly vulnerable. With these predictions the cold adapted fauna endemic to the Southern Ocean, which is dominated by fishes of the sub-order Notothenioidei, will face considerable challenges in the near future. Recent physiological studies have demonstrated that the synergistic stressors of elevated temperature and ocean acidification have a considerable, although variable, impact on notothenioid fishes. The present study explored the transcriptomic response of Pagothenia borchgrevinki to increased temperatures and pCO2 after 7, 28 and 56days of acclimation. We compared this response to short term studies assessing heat stress alone and foretell the potential impacts of these stressors on P. borchgrevinki's ability to survive a changing Southern Ocean. RESULTS: P. borchgrevinki did demonstrate a coordinated stress response to the dual-stressor condition, and even indicated that some level of inducible heat shock response may be conserved in this notothenioid species. However, the stress response of P. borchgrevinki was considerably less robust than that observed previously in the closely related notothenioid, Trematomus bernacchii, and varied considerably when compared across different acclimation time-points. Furthermore, the molecular response of these fish under multiple stressors displayed distinct differences compared to their response to short term heat stress alone. CONCLUSIONS: When exposed to increased sea surface temperatures, combined with ocean acidification, P. borchgrevinki demonstrated a coordinated stress response that has already peaked by 7days of acclimation and quickly diminished over time. However, this response is less dramatic than other closely related notothenioids under identical conditions, supporting previous research suggesting that this notothenioid species is less sensitive to environmental variation. PMID- 26969096 TI - Fistula formation after EUS-guided hepaticogastrostomy. PMID- 26969090 TI - Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. AB - BACKGROUND: Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. METHODS: In this double-blind, placebo controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. FINDINGS: Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5.8 years (IQR 1.6-8.2) for sunitinib (hazard ratio [HR] 1.02, 97.5% CI 0.85-1.23, p=0.8038), 6.1 years (IQR 1.7-not estimable [NE]) for sorafenib (HR 0.97, 97.5% CI 0.80-1.17, p=0.7184), and 6.6 years (IQR 1.5-NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue 110 [18%] patients on sunitinib [corrected]. There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity. INTERPRETATION: Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis. FUNDING: US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer. PMID- 26969097 TI - Retrieval and reuse of a dislodged lumen-apposing metal stent during endoscopic necrosectomy for pancreatic necrosis. PMID- 26969098 TI - Endoscopic necrosectomy of an infected lymph node. PMID- 26969099 TI - Cryotherapy for refractory malignant rectal bleeding: a novel solution. PMID- 26969100 TI - Temperament and arousal systems: A new synthesis of differential psychology and functional neurochemistry. AB - This paper critically reviews the unidimensional construct of General Arousal as utilised by models of temperament in differential psychology for example, to underlie 'Extraversion'. Evidence suggests that specialization within monoamine neurotransmitter systems contrasts with the attribution of a "general arousal" of the Ascending Reticular Activating System. Experimental findings show specialized roles of noradrenaline, dopamine, and serotonin systems in hypothetically mediating three complementary forms of arousal that are similar to three functional blocks described in classical models of behaviour within kinesiology, clinical neuropsychology, psychophysiology and temperament research. In spite of functional diversity of monoamine receptors, we suggest that their functionality can be classified using three universal aspects of actions related to expansion, to selection-integration and to maintenance of chosen behavioural alternatives. Monoamine systems also differentially regulate analytic vs. routine aspects of activities at cortical and striatal neural levels. A convergence between main temperament models in terms of traits related to described functional aspects of behavioural arousal also supports the idea of differentiation between these aspects analysed here in a functional perspective. PMID- 26969101 TI - Diabetes and Alzheimer's disease crosstalk. AB - Despite intensive research efforts over the past few decades, the mechanisms underlying the etiology of sporadic Alzheimer's disease (AD) remain unknown. This fact is of major concern because the number of patients affected by this medical condition is increasing exponentially and the existing treatments are only palliative in nature and offer no disease modifying affects. Interestingly, recent epidemiological studies indicate that diabetes significantly increases the risk of developing AD, suggesting that diabetes may play a causative role in the development of AD pathogenesis. Therefore, elucidating the molecular interactions between diabetes and AD is of critical significance because it might offer a novel approach to identifying mechanisms that may modulate the onset and progression of sporadic AD cases. This review highlights the involvement of several novels pathological molecular mechanisms induced by diabetes that increase AD pathogenesis. Furthermore, we discuss novel findings in animal model and clinical studies involving the use of anti-diabetic compounds as promising therapeutics for AD. PMID- 26969102 TI - Molecular genetic analysis of the Jk(a-b-) phenotype in Chinese: A novel silent recessive JK allele. AB - The Jk(a-b-) phenotype, referred to as Jknull, is rare in most populations. This blood type is characterized by the absence of Kidd glycoprotein on the surface of red blood cells (RBCs) and moderately reduced ability to concentrate urine. The molecular basis for Jknull phenotype includes splice-site mutations, missense mutations, and a partial gene deletion in the JK(SLC14A1) gene that encodes the human urea transporter protein. In this study, we have analyzed 10 Chinese Jknull samples to determine their molecular bases. In addition to the well known Polynesian Jknull allele, three Jknull alleles were detected including one novel Jknull allele: JKA (130A, 220G). PMID- 26969103 TI - Treatment of acute graft versus host disease with mesancyhmal stem cells: Questions and answers. PMID- 26969104 TI - Dynamic nailfold videocapillaroscopy may be used for early detection of microvascular dysfunction in obesity. AB - OBJECTIVES: It has been hypothesized that obesity is the primary cause of microvascular dysfunction (MD), which could be a pathway to increase blood pressure and decrease insulin sensitivity. Due to the high prevalence of this metabolic disorder in the world today, the aim of this study was to investigate which is the most appropriate videocapillaroscopic method, between nailfold and dorsal finger, to assess microvascular function in obese patients since both techniques are non-invasive and could be used for early detection as well as for follow-up. METHODS: Eighteen lean [27.8+/-6.2years, body mass index (BMI) 21.8+/ 1.8kg/m(2)] and nineteen obese (30.8+/-4.6years; BMI 32.3+/-1.5kg/m(2)) women participated in the study. Dynamic nailfold videocapillaroscopy assessed morphological (capillary diameters) and functional [functional capillary density (FCD); red blood cell velocity (RBCV) at baseline and peak and time (TRBCVmax) taken to reach it during the post-occlusive reactive hyperemia (PORH) response, after 1-min ischemia] parameters; while dorsal finger videocapillaroscopy assessed FCD at rest and capillary recruitment during PORH and post-venous occlusion. RESULTS: RBCV (0.32+/-0.01 vs. 0.30+/-0.01mm/s; p<0.0001) and RBCVmax (0.32+/-0.01 vs. 0.30+/-0.015mm/s; p=0.0020) were significantly higher in control subjects compared to the obese group. Moreover, TRBCVmax was prolonged in the obese group compared to control one (3.5+/-1.4 vs. 5.5+/-1.3s; p=0.0001). Multiple regression analysis showed that these variables were influenced by some others, especially those related to adiposity and metabolic disease. On the other hand, dorsal finger videocapillaroscopy did not show any significant differences between groups. CONCLUSION: Our results strongly suggest that microvascular dysfunction consequent to obesity could be better detected by dynamic nailfold videocapillaroscopy than by dorsal finger videocapillaroscopy. PMID- 26969106 TI - Recovery of cell-free layer and wall shear stress profile symmetry downstream of an arteriolar bifurcation. AB - Unequal RBC partitioning at arteriolar bifurcations contributes to dissimilar flow developments between daughter vessels in a bifurcation. Due to the importance of the cell-free layer (CFL) and the wall shear stress (WSS) to physiological processes such as vasoregulation and gas diffusion, we investigated the effects of a bifurcation disturbance on the development of the CFL width and WSS in bifurcation daughter branches. The analysis was performed on a two dimensional (2-D) computational model of a transverse arteriole at three different flow rates corresponding to parent branch (PB) pseudoshear rates of 60, 170 and 470s(-1), while maintaining a 2-D hematocrit of about 55% in the PB. Flow symmetry was defined using the statistical similarity of the CFL and WSS distributions between the two walls of the vessel branch. In terms of the flow symmetry recovery, higher flow rates caused larger reductions in the flow symmetry indices in the MB and subsequently required longer vessel lengths for complete recovery. Lower tube hematocrits in the SB led to complete symmetry recovery for all flow rates despite the higher initial asymmetry in the SB than in the MB. Arteriolar bifurcations produce unavoidable local CFL asymmetry and the persistence of the asymmetry downstream may increase effective blood viscosity which is especially significant at higher physiological flow rates. PMID- 26969105 TI - Vasopressin V1A receptors mediate the stabilization of intestinal mucosal oxygenation during hypercapnia in septic rats. AB - BACKGROUND: Microvascular oxygen saturation (MUHBO2) plays an essential role in the development and outcome of sepsis. Hypercapnia (HC) improves the microvascular oxygenation of the mucosa in both healthy and septic animals. Vasopressin V1A receptor blockade prevents this positive effect under otherwise physiological conditions. The aim of this study was to investigate the effects and mechanisms of the vasopressin system during hypercapnia under septic conditions. METHODS: 80 rats were randomized into 8 groups (N=10). Colon ascendens stent peritonitis (CASP) or sham surgery was performed on 40 animals each to establish a moderate polymicrobial sepsis or sham control, respectively. 24h after sepsis induction the animals were subjected to 120min of volume controlled and pressure-limited ventilation with either normocapnic (pCO2 35 45mmHg) or moderate hypercapnic (pCO2 of 65-75mmHg) ventilation targets. Animals received either vasopressin V1A receptor blockade (SR 49059, 1mgkg(-1) i.v.) or vehicle solution (dimethyl sulfoxide, 1%). Blood pressure, heart rate, pO2 and pCO2 were measured and microcirculatory oxygenation (MUHBO2) and microcirculatory flow (MUflow) were recorded using tissue reflectance spectrophotometry. Oxygen supply (MUDO2) and consumption (MUVO2) were calculated from intermittent blood gas analysis. RESULTS: In septic animals, MUHBO2 declined during normocapnia ( 11+/-10.3) but remained unchanged during hypercapnia. MUHBO2 declined with vasopressin V1A receptor blockade both during normocapnia (-7.4+/-10.6) and hypercapnia (-9.2+/-9.8). Microcirculatory oxygen consumption was significantly reduced by hypercapnia in septic animals (-2.4.10(5) [AU]+/-2.4.10(5) [AU]). In sham animals, MUHBO2 and MUVO2 did not change. CONCLUSION: Vasopressin V1A receptors mediate the beneficial effects of hypercapnia on microcirculatory oxygenation during sepsis. The effects of vasopressin on MUHBO2 might be related to decreased oxygen consumption during hypercapnia. PMID- 26969108 TI - Two novel soluble trehalase genes cloned from Harmonia axyridis and regulation of the enzyme in a rapid changing temperature. AB - In previous studies, we have cloned two soluble trehalase genes (HaTreh1-1 and HaTreh1-2) from the harlequin ladybird Harmonia axyridis. Here, we obtained the other two novel genes (HaTreh1-3 and HaTreh1-4) by transcriptome sequencing and rapid amplification of cDNA ends. Generally, anabolism enhancement and catabolism inhibition together contribute to accumulation of trehalose, and trehalase is the key enzyme to start the catabolism of trehalose. To characterize the metabolism of trehalose in H. axyridis and how these trehalase genes are regulated under cold stress conditions, a comparison of trehalose content and trehalase levels in two different rapidly changing temperature environments was carried out to explore the regulation of these genes. We found that an accumulation of trehalose could be observed at 5 degrees C, 0 degrees C and -5 degrees C and trehalase was suppressed in these temperature points during a gradually cooling environment. Then, in a gradually warming environment, trehalose levels increased slightly from -5 degrees C to 15 degrees C and then decreased at 25 degrees C; however, no significant negative association was observed between trehalase and trehalose. Additionally, we found that glycogen could be converted into trehalose to help the individual resist the low temperature. Analysis of the expression of soluble trehalase showed that HaTreh1-1, HaTreh1-2, HaTreh1-3 and HaTreh1-4 were involved in trehalose metabolism; but the gene HaTreh1-4 plays the most important role in the cooling process, and HaTreh1-2 and HaTreh1-4 play the most important role in the warming process. Finally, we found that 5 degrees C might be a temperature signal for H. axyridis; prior to this temperature, individuals must make enough physical preparations to resist cold stress during the winter. PMID- 26969107 TI - Correlation between PD-L1 expression and outcome of NSCLC patients treated with anti-PD-1/PD-L1 agents: A meta-analysis. AB - BACKGROUND: A meta analysis of the correlation between PD-L1 levels and outcomes of PD-1/PD-L1 inhibitors in advanced non small cell lung cancer (NSCLC) has been performed. METHODS: Eligible studies included those evaluating PD-1/PD-L1 inhibitors in advanced NSCLC and correlating the outcomes to PD-L1 levels. RESULTS: The search strategy yielded 250 potentially relevant citations from searched databases. After preclusion of ineligible studies, 12 studies were included. Comparing PD-1/PD-L1 inhibitors to docetaxel in second line treatment, the pooled hazard ratio (HR) for progression free survival (PFS) and overall survival (OS) was 0.75 (95% CI 0.62-0.90; p=0.002) and 0.61 (95% CI 0.50-75; p=0.00001) respectively; while the pooled odds ratio (OR) for objective response rate (ORR) was 1.98 (95% CI 1.28-3.07; p=0.002) in the PD-L1>1% population. Moreover, for PD-L1>1% patients versus PD-L1<1% patients treated with PD-1/PD-L1 targeted agents, the OR of ORR was 2.18 (95% CI 1.45-3.29; p=0.0002); while for PD-L1>5% patients versus PD-L1<5% patients, it was 2.66 (95% CI 1.74-4.07; p<0.00001); and for PD-L1>10% versus PD-L1<10% patients, it was 3.38 (95% CI 2.23 5.13; p<0.00001); and for PD-L1>50% versus PD-L1<50% patients, it was 3.99 (95% CI 2.81-5.66; p<0.00001). CONCLUSIONS: The current analysis of data indicates that the benefit from PD-1 inhibitors versus docetaxel in second line treatment of NSCLC is limited to the PD-L1>1% subpopulation. Moreover, a possible dose effect relationship between the intensity of PD-L1 staining and the potential benefit from PD-1/PD-L1 targeted agents does exist with higher intensity associated with higher ORR. PMID- 26969109 TI - Identification and expression characterization of three Wnt signaling genes in pearl oyster (Pinctada fucata). AB - The Wnt signaling pathway plays an important role in animal development and in the biomineralization process. At present, although the biomineralization mechanism in pearl oyster (Pinctada fucata) has been extensively studied, there is little research on the Wnt signaling pathway in pearl oyster. To understand the potential role of the Wnt signaling pathway in pearl oyster, we cloned and sequenced three genes from the Wnt signaling pathway in pearl oyster that encode the following proteins: beta-catenin, Dishevelled (Dvl) and T-cell factor (TCF). Genomic structure analysis revealed that Pf-beta-catenin genomic DNA contained 15 exons, Pf-Dvl genomic DNA contained 16 exons, and Pf-TCF genomic DNA contained 7 exons. Their deduced amino acid sequences all showed the highest identity with homologs in Crassostrea gigas. Yeast two-hybrid analysis verified that Pf-beta catenin interacted with Pf-TCF. These three genes were ubiquitously expressed in seven pearl oyster tissues analyzed with the highest expression in the gill and a certain amount of expression in the mantle, a tissue related to shell formation. After shell notching, the dynamic changes in expression of these three genes showed that they reached a maximum at 4days, indicating their response to shell regeneration. All three genes were constitutively expressed during five developmental stages of the pearl oyster, with high levels at the early embryonic development stage. Taken together, these results suggested that Pf-beta-catenin, Pf-Dvl and Pf-TCF might participate in shell formation and early embryonic and larval development in the pearl oyster. PMID- 26969110 TI - Bioavailability enhancement of atovaquone using hot melt extrusion technology. AB - Emerging parasite resistance and poor oral bioavailability of anti-malarials are the two cardinal issues which hinder the clinical success of malaria chemotherapy. Atovaquone-Proguanil is a WHO approved fixed dose combination used to tackle the problem of emerging resistance. However, Atovaquone is a highly lipophilic drug having poor aqueous solubility (less than 0.2 MUg/ml) thus reducing its oral bioavailability. The aim of the present investigation was to explore hot melt extrusion (HME) as a solvent-free technique to enhance solubility and oral bioavailability of Atovaquone and to develop an oral dosage form for Atovaquone-Proguanil combination. Solid dispersion of Atovaquone was successfully developed using HME. The solid dispersion was characterized for DSC, FTIR, XRD, SEM, and flow properties. It was filled in size 2 hard gelatin capsules. The formulation showed better release as compared to Malarone(r) tablets, and 3.2-fold and 4.6-fold higher bioavailability as compared to Malarone(r) tablets and Atovaquone respectively. The enhanced bioavailability also resulted in 100% anti-malarial activity in murine infection model at 1/8(th) therapeutic dose. Thus the developed methodology shows promising potential to solve the problems associated with Atovaquone therapy, namely its high cost and poor oral bioavailability, resulting in increased therapeutic efficacy of Atovaquone. PMID- 26969111 TI - PINK1 and FLNA mutations association: A role for atypical parkinsonism? PMID- 26969112 TI - Cognitive tasks and cerebral blood flow through anterior cerebral arteries: a study via functional transcranial Doppler ultrasound recordings. AB - BACKGROUND: Functional transcanial Doppler ultrasound (fTCD) is a convenient approach to examine cerebral blood flow velocity (CBFV) in major cerebral arteries. METHODS: In this study, the anterior cerebral artery (ACA) was insonated on both sides, that is, right ACA (R-ACA) and left ACA (L-ACA). The envelope signals (the maximum velocity) and the raw signals were analyzed during cognitive processes, i.e. word-generation tasks, geometric tasks and resting state periods separating each task. Data which were collected from 20 healthy participants were used to investigate the changes and the hemispheric functioning while performing cognitive tasks. Signal characteristics were analyzed in time domain, frequency domain and time-frequency domain. RESULTS: Significant results have been obtained through the use of both classic/modern methods (i.e. envelope/raw, time and frequency/information-theoretic and time-frequency domains). The frequency features extracted from the raw signals highlighted sex effects on cerebral blood flow which revealed distinct brain response during each process and during resting periods. In the time-frequency analysis, the distribution of wavelet energies on the envelope signals moved around the low frequencies during mental processes and did not experience any lateralization during cognitive tasks. CONCLUSIONS: Even if no lateralization effects were noticed during resting-state, verbal and geometric tasks, understanding CBFV in ACA during cognitive tasks could complement information extracted from cerebral blood flow in middle cerebral arteries during similar cognitive tasks (i.e. sex effects). PMID- 26969113 TI - Emerging aspects of nanotoxicology in health and disease: From agriculture and food sector to cancer therapeutics. AB - Nanotechnology is an evolving scientific field that has allowed the manufacturing of materials with novel physicochemical and biological properties, offering a wide spectrum of potential applications. Properties of nanoparticles that contribute to their usefulness include their markedly increased surface area in relation to mass, surface reactivity and insolubility, ability to agglomerate or change size in different media and enhanced endurance over conventional-scale substance. Here, we review nanoparticle classification and their emerging applications in several fields; from active food packaging to drug delivery and cancer research. Nanotechnology has exciting therapeutic applications, including novel drug delivery for the treatment of cancer. Additionally, we discuss that exposure to nanostructures incorporated to polymer composites, may result in potential human health risks. Therefore, the knowledge of processes, including absorption, distribution, metabolism and excretion, as well as careful toxicological assessment is critical in order to determine the effects of nanomaterials in humans and other biological systems. Expanding the knowledge of nanoparticle toxicity will facilitate designing of safer nanocomposites and their application in a beneficial manner. PMID- 26969114 TI - Scalpels Versus Balloons in Failing Hearts: Case Closed? PMID- 26969115 TI - Development of phytase-expressing chlamydomonas reinhardtii for monogastric animal nutrition. AB - BACKGROUND: In plant-derived animal feedstuffs, nearly 80 % of the total phosphorus content is stored as phytate. However, phytate is poorly digested by monogastric animals such as poultry, swine and fish, as they lack the hydrolytic enzyme phytase; hence it is regarded as a nutritionally inactive compound from a phosphate bioavailability point of view. In addition, it also chelates important dietary minerals and essential amino acids. Therefore, dietary supplementation with bioavailable phosphate and exogenous phytases are required to achieve optimal animal growth. In order to simplify the obtaining and application processes, we developed a phytase expressing cell-wall deficient Chlamydomonas reinhardtii strain. RESULTS: In this work, we developed a transgenic microalgae expressing a fungal phytase to be used as a food supplement for monogastric animals. A codon optimized Aspergillus niger PhyA E228K phytase (mE228K) with improved performance at pH 3.5 was transformed into the plastid genome of Chlamydomonas reinhardtii in order to achieve optimal expression. We engineered a plastid-specific construction harboring the mE228K gene, which allowed us to obtain high expression level lines with measurable in vitro phytase activity. Both wild-type and cell-wall deficient strains were selected, as the latter is a suitable model for animal digestion. The enzymatic activity of the mE228K expressing lines were approximately 5 phytase units per gram of dry biomass at pH 3.5 and 37 degrees C, similar to physiological conditions and economically competitive for use in commercial activities. CONCLUSIONS: A reference basis for the future biotechnological application of microalgae is provided in this work. A cell-wall deficient transgenic microalgae with phytase activity at gastrointestinal pH and temperature and suitable for pellet formation was developed. Moreover, the associated microalgae biomass costs of this strain would be between US$5 and US$60 per ton of feedstuff, similar to the US$2 per ton of feedstuffs of commercially available phytases. Our data provide evidence of phytate-hydrolyzing microalgae biomass for use as a food additive without the need for protein purification. PMID- 26969116 TI - Atraumatic splenic rupture: an atypical presentation in a previously healthy patient. AB - Atraumatic splenic rupture represents a life-threatening abdominal event that requires immediate diagnosis and prompt surgical treatment to ensure the survival of the patient. Atraumatic rupture is relatively uncommon and can occur either in pathological spleens or, more rarely, in normal ones. It has a high morbidity, frequently with few and non specific signs suggesting its presence, can be associated to other pathologies incidentally discovered by imaging. We present a case, successfully treated, of a 51-year-old man, previously healthy, that referred to our hospital for arterial hypertension and abdominal pain; the patient, for an idiopathic splenic rupture with haemoperitoneum, underwent an open splenectomy whose histology examination showed a normal spleen. KEY WORDS: Atraumatic splenic rupture, Normal spleen, Spontaneos haemoperitoneum - Full text is available at: www.annaliitalianidichirurgia.it. PMID- 26969118 TI - Added value of MRI for the prenatal diagnosis of isolated orofacial clefts and comparison with ultrasound. AB - OBJECTIVES: To evaluate the added value of fetal magnetic resonance imaging (MRI) in diagnosing and assessing isolated orofacial clefts and compare MRI with second line diagnostic ultrasound. MATERIALS AND METHODS: In a two-year prospective bicenter study, fetuses with isolated orofacial clefts were reassessed using second-line diagnostic ultrasound and MRI. The results of second line ultrasound and those MRI were compared to each other. The gestational age at the time of ultrasound and MRI, and the final diagnosis for each of the imaging modalities were recorded. Finally, the results of second line ultrasound and those of MRI were compared to the results of neonatal clinical examination after delivery that served as standard of reference. RESULTS: Twenty-two women were included after informed consent was obtained. On average, diagnostic ultrasound was performed at 25.5weeks of gestation (range: 24-34weeks) and MRI at 29.5weeks of gestation (range: 27-34weeks). The results of ultrasound and those of MRI findings were strictly consistent in 20 women (20/22; 91%) but differed in 2 women (2/22; 9%). For all fetuses, the final radiological diagnosis was confirmed by clinical examination after delivery. CONCLUSION: If ultrasound examination proves technically challenging, fetal MRI can be used to obtain the same diagnostic information in 91% of cases and can help surgeons and interdisciplinary teams provide appropriate antenatal counseling. PMID- 26969119 TI - Tetralogy of Fallot: Preoperative assessment with MR and CT imaging. AB - Tetralogy of Fallot has a broad anatomical spectrum. In mild forms of the condition the obstruction is only located in the right ventricular infundibulum, whereas in severe forms the pulmonary valve is atretic, the pulmonary arteries are absent and the lung is supplied by aorto-pulmonary collateral arteries. Surgical management differs from conventional surgery in the former situation, whereas in the latter it is complex and requires reconstruction of the pulmonary arteries (unifocalization) carried out in more than one stage and with a high morbidity rate. The key factors to establish before corrective surgery are the levels and degree of obstruction of the right ventricular outflow tract, the development of the pulmonary arteries and the presence of collateral arteries. The main role of magnetic resonance imaging along with that of computed tomography angiography are discussed and illustrated. PMID- 26969117 TI - Systems biology of the structural proteome. AB - BACKGROUND: The success of genome-scale models (GEMs) can be attributed to the high-quality, bottom-up reconstructions of metabolic, protein synthesis, and transcriptional regulatory networks on an organism-specific basis. Such reconstructions are biochemically, genetically, and genomically structured knowledge bases that can be converted into a mathematical format to enable a myriad of computational biological studies. In recent years, genome-scale reconstructions have been extended to include protein structural information, which has opened up new vistas in systems biology research and empowered applications in structural systems biology and systems pharmacology. RESULTS: Here, we present the generation, application, and dissemination of genome-scale models with protein structures (GEM-PRO) for Escherichia coli and Thermotoga maritima. We show the utility of integrating molecular scale analyses with systems biology approaches by discussing several comparative analyses on the temperature dependence of growth, the distribution of protein fold families, substrate specificity, and characteristic features of whole cell proteomes. Finally, to aid in the grand challenge of big data to knowledge, we provide several explicit tutorials of how protein-related information can be linked to genome-scale models in a public GitHub repository ( https://github.com/SBRG/GEMPro/tree/master/GEMPro_recon/). CONCLUSIONS: Translating genome-scale, protein-related information to structured data in the format of a GEM provides a direct mapping of gene to gene-product to protein structure to biochemical reaction to network states to phenotypic function. Integration of molecular-level details of individual proteins, such as their physical, chemical, and structural properties, further expands the description of biochemical network-level properties, and can ultimately influence how to model and predict whole cell phenotypes as well as perform comparative systems biology approaches to study differences between organisms. GEM-PRO offers insight into the physical embodiment of an organism's genotype, and its use in this comparative framework enables exploration of adaptive strategies for these organisms, opening the door to many new lines of research. With these provided tools, tutorials, and background, the reader will be in a position to run GEM-PRO for their own purposes. PMID- 26969120 TI - Cardiac CT or MRI in pediatric practice: Which one to choose? AB - The different factors involved in the choice of the best cardiovascular imaging examination for pediatric patients are justification, radiation protection, sedation, resolutions (spatial and contrast), morphology or function, intervention and contrast enhancement. Computed tomography is preferable for all coronary artery conditions, any arterial or venous abnormalities in newborns and infants and in the preoperative assessment for tetralogy of Fallot. Magnetic resonance imaging is used for any tumoral or functional assessment, cardiomyopathy or arrhythmia or if the child's participation and/or size of the structures being examined allows using this technique. PMID- 26969121 TI - A phase II study of capecitabine and oxaliplatin combination chemotherapy in patients with inoperable adenocarcinoma of the gall bladder or biliary tract. AB - BACKGROUND: Advanced biliary tract carcinomas are associated with a poor prognosis, and palliative chemotherapy has only modest benefit. This multi-centre phase II study was conducted to determine the efficacy of capecitabine in combination with oxaliplatin in patients with inoperable gall bladder or biliary tract cancer. METHODS: This was a Phase II, non-randomised, two-stage Simon design, multi-centre study. Ethics approval was sought and obtained by the North West MREC, and then locally by the West Glasgow Hospitals Research Ethics Committee. Eligible patients with inoperable locally advanced or metastatic adenocarcinoma of the gall bladder or biliary tract and with adequate performance status, haematologic, renal, and hepatic function were treated with capecitabine (1000 mg/m(2) po, twice daily, days 1-14) and oxaliplatin (130 mg/m(2) i.v., day 1) every 3 weeks for up to six cycles. The primary objective of the study was to determine the objective tumour response rates (complete and partial). The secondary objectives included assessment of toxicity, progression-free survival, and overall survival. RESULTS: Forty-three patients were recruited between July 2003 and December 2005. The regimen was well tolerated with no grade 3/4 neutropenia or thrombocytopenia. Grade 3/4 sensory neuropathy was observed in six patients. Two-thirds of patients received their chemotherapy without any dose delays. Overall response rate was 23.8% (95% CI 12.05-39.5%). Stable disease was observed in a further 13 patients (31%) and progressive disease observed in 12 (28.6%) of patients. The median progression-free survival was 4.6 months (95% CI 2.8-6.4 months; Fig. 1) and the median overall survival 7.9 months (95% CI 5.3 10.4 months; Fig. 2). Fig. 1 Progression-free survival Fig. 2 Overall survival CONCLUSION: Capecitabine combined with oxaliplatin has a lower disease control and shorter overall survival than the combination of cisplatin with gemcitabine which has subsequently become the standard of care in this disease. However, capecitabine in combination with oxaliplatin does have modest activity in this disease, and can be considered as an alternative treatment option for patients in whom cisplatin and/or gemcitabine are contra-indicated. PMID- 26969123 TI - Return to Play After Periacetabular Osteotomy for Treatment of Acetabular Dysplasia in Adolescent and Young Adult Athletes. AB - BACKGROUND: The Bernese periacetabular osteotomy (PAO) is an effective surgical treatment option for symptomatic acetabular dysplasia. Little evidence exists regarding the results of PAO and rates of return to play (RTP) in an athletic population. HYPOTHESIS: The majority of athletes will demonstrate improvements in functional outcome measures, such as the modified Harris Hip Score and Hip Disability and Osteoarthritis Outcome Score, and will be able to return to sports after PAO. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A comprehensive surgical hip database at an academic referral center was used to identify a subpopulation of athletes on whom PAO was performed. Data analyzed included preceding surgeries, reoperations, and RTP timing and features. Standard pre- and postoperative radiologic parameters and validated functional outcome measures were assessed, and a regression model assessed risk factors for prolonged time to RTP. RESULTS: Of 245 PAOs performed over the 5-year study period, 46 were performed in 41 patients who met inclusion criteria for being an athlete (mean age, 26.2 years; range, 13-41 years; 36 females; 19% of all PAOs), representing a variety of sports. Prior surgery had been performed on 9 hips (20%). Only 1 post-PAO procedure (2%), excision of heterotopic ossification, was performed during the study period. At final follow-up (median, 3.1 years; range, 1.2-4.4 years), significant mean improvements were observed in modified Harris Hip Score (from 71 to 90; P < .001) and Hip Disability and Osteoarthritis Outcome Score (from 64 to 89; P < .001). The University of California-Los Angeles Activity Scale scores were maintained at a high level (range, 8.0-8.2; P = .28). RTP was reported in 80% of patients (37 of 46) at a median of 9 months postoperatively, with increased postoperative pain as the only independent predictor of longer time to RTP. Of these 37 athletes, 27 (73%) returned to the same level, although this was significantly less common (P = .06) in competitive athletes (11 of 19; 58%) than in recreational athletes (16 of 18; 89%). Among those who did return at the same level, 23 of 27 (85%) were able to maintain this level over time, but this was not significantly different between competitive (8 of 11; 73%) and recreational (15 of 16; 94%) athletes (P = .27). CONCLUSION: Most athletic patients undergoing PAO are female patients and show postoperative improvements in function and return to athletic play. However, although there was no decline in overall activity level at a mean of 3 years, self-assessed athletic performance was attained and maintained in approximately one-half of the study population. PMID- 26969122 TI - Relation between tetR and tetA expression in tetracycline resistant Escherichia coli. AB - BACKGROUND: Tetracyclines are among the most used antibiotics in livestock worldwide. Resistance is widely disseminated in Escherichia coli, where it is generally mediated by tetracycline efflux pumps, such as TetA. Expression of tetracycline efflux pumps is tightly controlled by the repressor TetR, which has been shown to be tetracycline-responsive at sub-MIC tetracycline concentrations. The objective of this study was to investigate the effects of increasing tetracycline concentrations on the growth of TetA-producing E. coli, and to determine how expression of tetA and tetR related to each other in different growth phases in the presence of tetracycline. RESULTS: A tetracycline resistant E. coli strain containing tetA and tetR on the chromosome was constructed and cultured in the presence of increasing concentrations of tetracycline. Expression of tetR and tetA was measured at four time points in different growth phases by quantitative real-time PCR. The TetA-producing E. coli exhibited prolonged lag phase with increasing concentrations of tetracycline, while expression of tetA and tetR increased and decreased, respectively, with increasing tetracycline concentration. The levels of tetA and tetR mRNA varied depending on growth phase, resulting in a gradual decrease of the tetA/tetR ratio from approximately 4 in the lag phase to approximately 2 in the stationary phase. CONCLUSION: This study shows that the expression of tetR and tetA is tetracycline concentration- and growth phase-dependent, contributing to improved understanding of the relationships between E. coli growth, tetracycline exposure and expression of tetracycline resistance. PMID- 26969125 TI - Adolescent inhalant use prevention, assessment, and treatment: A literature synthesis. AB - Inhalant use refers to the use of substances such as gases, glues, and aerosols in order to achieve intoxication, while inhalant use disorder (IUD) encompasses both DSM-IV-TR criteria for inhalant abuse and dependence. Inhalant use among adolescents is an international public health concern considering the severe medical and cognitive consequences and biopsychosocial correlates. In this paper, we summarize the current state of the literature on inhalant use among adolescents focusing on social context, prevention, assessment, and treatment strategies. Psychoeducation, skills training, and environmental supply reduction are helpful strategies for preventing adolescent inhalant use, while parent and adolescent self-report as well as physician report of medical signs and symptoms can aid in assessment and diagnosis. Although research has only begun to explore the treatment of inhalant use, preliminary findings suggest that a multimodal approach involving individual counselling (i.e., CBT brief intervention), family therapy, and activity and engagement programs is the first-line treatment, with residential treatment programs indicated for more severe presentations. The limited nature of treatments developed specifically for inhalant use combined with high prevalence rates and potential for significant impairment within the adolescent population indicate the need for further research. Research should focus on understanding the social context of use, establishing the efficacy of current adolescent substance use treatments adapted for inhalant use, and exploring long-term outcomes. PMID- 26969124 TI - Utility of linking primary care electronic medical records with Canadian census data to study the determinants of chronic disease: an example based on socioeconomic status and obesity. AB - BACKGROUND: Electronic medical records (EMRs) used in primary care contain a breadth of data that can be used in public health research. Patient data from EMRs could be linked with other data sources, such as a postal code linkage with Census data, to obtain additional information on environmental determinants of health. While promising, successful linkages between primary care EMRs with geographic measures is limited due to ethics review board concerns. This study tested the feasibility of extracting full postal code from primary care EMRs and linking this with area-level measures of the environment to demonstrate how such a linkage could be used to examine the determinants of disease. The association between obesity and area-level deprivation was used as an example to illustrate inequalities of obesity in adults. METHODS: The analysis included EMRs of 7153 patients aged 20 years and older who visited a single, primary care site in 2011. Extracted patient information included demographics (date of birth, sex, postal code) and weight status (height, weight). Information extraction and management procedures were designed to mitigate the risk of individual re-identification when extracting full postal code from source EMRs. Based on patients' postal codes, area-based deprivation indexes were created using the smallest area unit used in Canadian censuses. Descriptive statistics and socioeconomic disparity summary measures of linked census and adult patients were calculated. RESULTS: The data extraction of full postal code met technological requirements for rendering health information extracted from local EMRs into anonymized data. The prevalence of obesity was 31.6 %. There was variation of obesity between deprivation quintiles; adults in the most deprived areas were 35 % more likely to be obese compared with adults in the least deprived areas (Chi-Square = 20.24(1), p < 0.0001). Maps depicting spatial representation of regional deprivation and obesity were created to highlight high risk areas. CONCLUSIONS: An area based socio-economic measure was linked with EMR-derived objective measures of height and weight to show a positive association between area-level deprivation and obesity. The linked dataset demonstrates a promising model for assessing health disparities and ecological factors associated with the development of chronic diseases with far reaching implications for informing public health and primary health care interventions and services. PMID- 26969126 TI - Anti-platelet therapy in small animal medicine. AB - Thromboembolism is a significant complication in many commonly encountered diseases, and can be a devastating sequel to otherwise treatable conditions. Platelets play an essential role in the hemostatic process and, consequently, are associated with thrombus formation. Platelets adhere to denuded vascular subendothelium, recruit additional platelets and cells, aggregate, and provide the catalytic surface for thrombin production and fibrin formation. Therapy to prevent unwanted thrombus formation and thromboembolic crises is essential in the management of hypercoagulable patients. Unfortunately, many of the medications used in veterinary medicine that inhibit or modulate coagulation factors, such as the heparins, are cost prohibitive, only effective when administered by injection or require frequent drug monitoring, and are therefore poor choices for long term at home therapy. While the role of the platelet in pathologic thrombus formation is not fully understood, veterinarians often resort to anti-platelet therapy in the management of patients at risk for thromboembolic complications, because many anti-platelet medications are inexpensive, require minimal drug monitoring, and can be given orally. The aim of this review is to discuss the anti-platelet therapies that are currently being used or being considered for use to inhibit platelet function and reduce thromboembolic complications in hypercoagulable dogs and cats. PMID- 26969127 TI - Is deltoid muscle biopsy useful in isolated camptocormia? A prospective study. AB - BACKGROUND AND PURPOSE: Camptocormia is a marked anterior curvature of the thoracolumbar spine that may be caused by parkinsonism, amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG) and muscle disease. The interest of a systematic muscle biopsy has not been evaluated until now. In our study, the aim was to prospectively evaluate the proportion of patients with isolated camptocormia without ALS, MG and parkinsonism who have an underlying myopathy. METHODS: Twenty consecutive patients (75% female, mean age 70 years) with isolated camptocormia were enrolled in a single centre in this 5-year prospective study. ALS, MG and parkinsonism had been excluded in all cases. A left deltoid muscle biopsy was performed in all patients and processed with standard techniques for histology and immunohistochemistry. Additional biochemical and genetic studies were performed when pathological analysis was consistent with myopathy. RESULTS: A myopathy was identified in seven patients (35%). Three patients presented with mitochondrial myopathy, including two patients harbouring a heterozygous POLG gene pathogenic variant and one patient with a heterozygous RRM2B gene pathogenic variant. Two patients presented with an inflammatory myopathy, including one with anti-PM/Scl antibodies. One patient presented with facioscapulohumeral muscular dystrophy and one patient with an MYH7 gene-related myofibrillar myopathy. No obvious myopathy was found in the 13 remaining cases. DISCUSSION: In this prospective study, an underlying myopathy was found in 35% of patients with isolated camptocormia. These results suggest that a muscle biopsy should be systematically performed in patients with isolated camptocormia when ALS, MG and parkinsonism have been excluded. PMID- 26969128 TI - The efficacy of a new translational treatment for persecutory delusions: study protocol for a randomised controlled trial (The Feeling Safe Study). AB - BACKGROUND: Persecutory delusions (strong unfounded fears that others intend harm to the person) occur in more than 70 % of the patients diagnosed with schizophrenia. This major psychotic experience is a key clinical target, for which substantial improvement in treatment is needed. Our aim is to use advances in theoretical understanding to develop a much more efficacious treatment that leads to recovery in at least 50 % of people with persistent persecutory delusions. Our cognitive conceptualisation is that persecutory delusions are threat beliefs, developed in the context of genetic and environmental risk, maintained by a number of psychological processes including excessive worry, low self-confidence, intolerance of anxious affect and other internal anomalous experiences, reasoning biases, and safety-seeking strategies. The clinical implication is that safety has to be relearned, by entering the feared situations after reduction of the influence of the maintenance factors. We have been individually evaluating modules targeting causal factors. These will now be tested together as a full treatment, called The Feeling Safe Programme. The treatment is modular, personalised, and includes patient preference. We will test whether the new treatment leads to greater recovery in persistent persecutory delusions, psychological well-being, and activity levels compared to befriending (that is, controlling for therapist attention). METHODS/DESIGN: The Feeling Safe Study is a parallel group randomised controlled trial for 150 patients who have persecutory delusions despite previous treatment in mental health services. Patients will be randomised (1:1 ratio) to The Feeling Safe Programme or befriending (both provided in 20 sessions over 6 months). Standard care will continue as usual. Online randomisation will use a permuted blocks algorithm, with randomly varying block size, stratified by therapist. Assessments, by a rater blind to allocation, will be conducted at 0, 6 (post treatment), and 12 months. The primary outcome is the level of delusional conviction at 6 months. Secondary outcomes include levels of psychological well-being, suicidal ideation, and activity. All main analyses will be intention-to-treat. The trial is funded by the NHS National Institute for Health Research. DISCUSSION: The Feeling Safe study will provide a Phase II evaluation of a new targeted translational psychological treatment for persecutory delusions. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18705064 (registered 11 November 2015). PMID- 26969130 TI - When in doubt ... ask the patient: Patient-reported measures and prognosis in esophageal cancer. PMID- 26969131 TI - A model of early transient pressure overload simulating repair of aortic coarctation in childhood. PMID- 26969129 TI - Enlarged dendritic spines and pronounced neophobia in mice lacking the PSD protein RICH2. AB - BACKGROUND: The majority of neurons within the central nervous system receive their excitatory inputs via small, actin-rich protrusions called dendritic spines. Spines can undergo rapid morphological alterations according to synaptic activity. This mechanism is implicated in learning and memory formation as it is ultimately altering the number and distribution of receptors and proteins at the post-synaptic membrane, thereby regulating synaptic input. The Rho-family GTPases play an important role in regulating this spine plasticity by the interaction with cytoskeletal components and several signaling pathways within the spine compartment. Rho-GAP interacting CIP4 homologue2/RICH2 is a Rho-GAP protein regulating small GTPases and was identified as an interaction partner of the scaffolding protein SHANK3 at post-synaptic densities. RESULTS: Here, we characterize the loss of RICH2 in a novel mouse model. Our results show that RICH2 KO animals display a selective and highly significant fear of novel objects and increased stereotypic behavior as well as impairment of motor learning. We found an increase in multiple spine synapses in the hippocampus and cerebellum along with alterations in receptor composition and actin polymerization. Furthermore, we observed that the loss of RICH2 leads to a disinhibition of synaptic RAC1 in vivo. CONCLUSIONS: The results are in line with the reported role of RAC1 activity being essential for activity-dependent spine enlargement. Since SHANK3 mutations are known to be causative for neuropsychiatric diseases of the Autism Spectrum (ASD), a disintegrated SHANK3/RICH2 complex at synaptic sites might at least in part be responsible for abnormal spine formation and plasticity in ASDs. PMID- 26969132 TI - Thymectomy using the subxiphoid approach. PMID- 26969133 TI - Does size matter? PMID- 26969134 TI - One-stop hybrid coronary revascularization versus off-pump coronary artery bypass in patients with diabetes mellitus. AB - OBJECTIVES: To compare in-hospital and midterm outcomes after one-stop hybrid coronary revascularization (HCR) and off-pump coronary artery bypass (OPCAB) in patients with diabetes mellitus (DM). METHODS: The series included 120 patients with DM who underwent one-stop HCR at Fuwai Hospital between June 2007 and September 2014. These patients were 1:2 matched with 240 patients who underwent OPCAB using propensity score matching. The primary endpoint was a major adverse cardiac or cerebrovascular event (MACCE) over midterm follow-up, and secondary endpoints were in-hospital outcomes. Accounting for matched-pairs design, the survival analysis was evaluated with a marginal Cox model, and the continuous and dichotomous variables of in-hospital outcomes were compared with the Wilcoxon signed-rank test and a logistic regression model using generalized estimating equations, respectively. RESULTS: Compared with OPCAB, one-stop HCR was associated with less chest tube drainage (median, 748 mL [interquartile range (IQR), 540-1080 mL] vs 990 mL [IQR, 730-1250 mL]; P < .001), a lower packed red blood cell transfusion rate (18.3% vs 29.6%; P = .032), shorter mechanical ventilation time (median, 13.7 hours [IQR, 10.3-16.9 hours] vs 16.8 hours [IQR, 13.0-19.6 hours]; P < .001), and shorter stay in intensive care unit (median 21.7 hours [IQR, 19.0-44.3 hours] vs 46.7 hours [IQR, 24.3-72.7 hours]; P < .001). Over 30 months of follow-up, one-stop HCR and OPCAB had a similar rate of MACCE (7.4% vs 8.0% at 3 years; hazard ratio, 0.807; 95% confidence limit, 0.352-1.849; P = .612), but one-stop HCR had a lower stroke rate (0% vs 3.6% at 3 years; P = .046). CONCLUSIONS: For selected patients with DM, one-stop HCR provided safe and reproducible revascularization, with less perioperative invasiveness and similar and favorable midterm outcomes compared with OPCAB. PMID- 26969135 TI - Air embolism during air flight in a passenger with bronchogenic cyst. PMID- 26969136 TI - Ventricular ectopic burden in comatose survivors of out-of-hospital cardiac arrest treated with targeted temperature management at 33 degrees C and 36 degrees C. AB - PURPOSE: Life threatening arrhythmias are increasingly frequent with lower body temperature. While targeted temperature management (TTM) with mild hypothermia following out-of-hospital cardiac arrest (OHCA) is generally considered safe and has been suggested as a potential antiarrhythmic add-on therapy, it is unknown whether the level of TTM affects the burden of ventricular ectopic activity. We sought to assess the ventricular ectopic burden between patients treated with TTM at 33 degrees C or 36 degrees C for 24h. METHODS: Continuous 12-lead digital Holter electrocardiograms performed during the intervention were analyzed blinded to treatment allocation in 115 comatose OHCA-survivors from a single center of the TTM-trial. The main study showed no difference with regards to mortality. RESULTS: Fifty-eight patients were randomized to 33 degrees C and 57 to 36 degrees C. Cardiac arrest characteristics were similar between the groups. The number of isolated ventricular ectopic beats (VEB) per hour was similar at the beginning of the maintenance phase of TTM and decreased over time in both groups (both ptime<0.001). The reduction in VEB per hour was significantly affected by target temperature (pinteraction<0.0001), with fewer VEB in the 36 degrees C group. The total number of isolated, couplets and number of runs of VEB per hour showed similar results, with less ventricular ectopic activity in the 36 degrees C-group (pinteraction<0.0001). Increasing numbers of pre-hospital defibrillations (log2) were associated with a 46% increase in ventricular ectopic activity (p<0.01), adjusted for potential confounders. CONCLUSIONS: Ventricular ectopic activity was reduced in comatose OHCA-survivors treated with TTM at 36 degrees C compared to 33 degrees C. Higher numbers of pre-hospital defibrillations were associated with higher incidence of ventricular ectopic activity. PMID- 26969137 TI - Quantification of Right Ventricular Volume and Function Using Single-Beat Three Dimensional Echocardiography: A Validation Study with Cardiac Magnetic Resonance. AB - BACKGROUND: Because of the unique geometry of the right ventricle, assessment of right ventricular (RV) volume and function is clinically challenging. The aim of this study was to investigate the feasibility of single-beat three-dimensional echocardiography (sb3DE) for RV volume and functional assessment in patients with dilated right ventricles. METHODS: Fifty-two patients with severe tricuspid regurgitation or atrial septal defects were enrolled. Fifty patients underwent sb3DE and cardiac magnetic resonance (CMR) within 24 hours under a euvolemic state, and the results of sb3DE were compared with those of CMR, the reference method. Fifteen normal subjects were also recruited for a broader validation of sb3DE. RESULTS: Of the 67 individuals, data from 59 study participants (44 patients and 15 normal subjects) with adequate image quality were analyzed (mean age, 46.9 +/- 19.3 years; 58% women). The correlation was excellent between sb3DE and CMR for measuring RV volumes and RV ejection fraction (RVEF) (r = 0.96, r = 0.93, and r = 0.93 [P < .001 for all] for RV end-diastolic volume, RV end systolic volume, and RVEF, respectively). Bland-Altman analysis revealed that RV volumes, but not RVEF, tended to be slightly underestimated by sb3DE (-5.8 +/- 9.6%, -3.8 +/- 14.1%, and -1.2 +/- 9.4% for RV end-diastolic volume, RV end systolic volume, and RVEF, respectively). Intra- and interobserver variability was acceptable for all indices (4.9% and 6.1% for RV end-diastolic volume, 4.2% and 7.9% for RV end-systolic volume, and 5.7% and 2.8% for RVEF, respectively). Among patients with RV dilation, the difference in RVEF between sb3DE and CMR was more pronounced in patients with atrial fibrillation than those in sinus rhythm ( 5.9% vs 0.9%, P = .041). CONCLUSIONS: In patients with dilated right ventricles and in normal subjects, assessment of RV volume and systolic function by sb3DE is feasible in terms of accuracy and reproducibility. RV analysis using sb3DE can be performed in patients with atrial fibrillation, with the possibility of RVEF underestimation. PMID- 26969138 TI - Prediction of Outcomes in Patients with Chronic Ischemic Cardiomyopathy by Layer Specific Strain Echocardiography: A Proof of Concept. AB - BACKGROUND: Cardiac magnetic resonance imaging (CMR) has been established as a powerful tool for predicting mortality. However, its application is limited by availability and various contraindications. The aim of this study was to evaluate the predictive value of layer-specific myocardial deformation analysis as assessed by strain echocardiography for cardiac events in patients with chronic ischemic left ventricular dysfunction in comparison with CMR. METHODS: Three hundred ninety patients (mean age, 63 +/- 4 years; 69% men; mean left ventricular ejection fraction [LVEF], 41 +/- 7%) with chronic ischemic cardiomyopathy were prospectively enrolled and underwent strain echocardiography and CMR within 3 +/- 1 days. LVEF, wall motion score index, and circumferential strain (CS), longitudinal strain, and radial strain for total wall thickness and for three myocardial layers (endocardial, midmyocardial, and epicardial) were determined by echocardiography. The extent of total myocardial scar (TMS) was determined by CMR. Follow-up was obtained for a mean of 4.9 +/- 2.2 years. Cardiac events were defined as readmission for worsening of heart failure, ventricular arrhythmias, or death of any cause. The incremental value of LVEF, strain parameters, and TMS to relevant clinical variables was determined in nested Cox models. RESULTS: There were 133 cardiac events (34%). Baseline clinical data associated with outcomes were age (hazard ratio [HR], 1.27; P = .04), diabetes mellitus (HR, 1.52; P = .001), and renal insufficiency (HR, 1.77; P = .001) by multivariate analysis. The addition of LVEF, global and endocardial strain parameters, and TMS increased the predictive power, but endocardial CS (HR, 1.52; P < .01) caused the greatest increment in model power (chi(2) = 39.2, P < .001). Endocardial CS < 20% was found to be the optimal predictor of prognosis. CONCLUSIONS: Endocardial CS is a powerful predictor of cardiac events and appears to be a better parameter than LVEF, TMS by CMR, and other strain variables by echocardiography. PMID- 26969139 TI - Fact or Artifact in Two-Dimensional Echocardiography: Avoiding Misdiagnosis and Missed Diagnosis. AB - Two-dimensional transthoracic echocardiography is the most widely used noninvasive imaging modality for the evaluation and diagnosis of cardiac pathology. However, because of the physical properties of ultrasound waves and specifics in ultrasound image reconstruction, cardiologists are often confronted with ultrasound image artifacts. It is particularly important to recognize such artifacts in order to avoid misdiagnosis of conditions ranging from aortic dissection to thrombosis and endocarditis. This overview article summarizes the most common image artifacts encountered in routine clinical practice, along with explanations of their physical mechanisms and guidance in avoiding their misinterpretation. PMID- 26969140 TI - Tannic acid activates the Kv7.4 and Kv7.3/7.5 K(+) channels expressed in HEK293 cells and reduces tension in the rat mesenteric arteries. AB - OBJECTIVES: This study investigated the effect of tannic acid (TA), a plant derived hydrolyzable polyphenol, on Kv7.4 and Kv7.5 K(+) channels and rat mesenteric artery. METHODS: Whole-cell patch clamp experiments were used to record the Kv7.4 and Kv7.3/7.5 K(+) currents expressed in HEK293 cells; and the tension changes of mesenteric arteries isolated from rats were recorded using small vessel myography apparatus. KEY FINDINGS: Tannic acid increases the Kv7.4 and Kv7.3/7.5 K(+) currents in a concentration-dependent manner (median effective concentration (EC50 ) = 27.3 +/- 3.6 MUm and EC50 = 23.1 +/- 3.9 MUm, respectively). In addition, 30 MUm TA shifts the G-V curve of Kv7.4 and Kv7.3/7.5 K(+) currents to the left by 14.18 and 25.24 mV, respectively, and prolongs the deactivation time constants by 184.44 and 154.77 ms, respectively. Moreover, TA relaxes the vascular tension of rat mesenteric arteries in a concentration dependent manner (half inhibitory concentration (IC50 ) = 148.7 +/- 13.4 MUm). CONCLUSION: These results confirms the vasodilatory effects of TA on rat mesenteric artery and the activating effects on the Kv7.4 and Kv7.3/7.5 K(+) channels, which may be a mechanism to explain the vasodilatory effect and this mechanism can be used in the research of antihypertension. PMID- 26969141 TI - Psychological Reactions Associated With Continuous Glucose Monitoring in Youth. AB - Glucose monitoring is prerequisite to all other diabetes self-care behaviors and helps patients to reduce their risk for diabetes-related complications due to elevated glycemia. Because of the amount of information available and the ability to deliver glucose results in real-time, continuous glucose monitoring (CGM) has the ability to improve on self-monitoring blood glucose. However, epidemiologic data demonstrate slow uptake of CGM by patients, especially among youth. Several new diabetes therapies rely on CGM for feedback on patients' glucose levels to optimize treatment (eg, the low-glucose suspend insulin pump) and there are new technologies currently in development that will also need this information to work (eg, the artificial pancreas). To help patients to realize the potential benefits of these new treatments, it is essential to explore patients' psychological and behavioral reactions to CGM and then target device enhancements and/or the development of behavioral therapies to minimize negative reactions and to improve patients' CGM adoption rates. Limited research is available examining the psychological and behavioral reactions of CGM use in youth exclusively, but there are more studies examining these reactions in mixed samples of youth, parents, and adults. The purpose of this review is to summarize the available literature examining psychological and behavioral reactions to CGM use in young people with diabetes and to highlight how the results of past and future studies can inform device updates and/or behavioral intervention development to minimize barriers. PMID- 26969142 TI - Is Psychological Stress a Factor for Incorporation Into Future Closed-Loop Systems? AB - BACKGROUND: The relationship between daily psychological stress and BG fluctuations in type 1 diabetes (T1DM) is unclear. More research is needed to determine if stress-related BG changes should be considered in glucose control algorithms. This study in the usual free-living environment examined relationships among routine daily stressors and BG profile measures generated from CGM readings. METHODS: A total of 33 participants with T1DM on insulin pumps wore a CGM device for 1 week and recorded daily ratings of psychological stress, carbohydrates, and insulin boluses. RESULTS: Within-subjects ANCOVAs found a significant relationship between daily stress and indices of BG variability/instability (r = .172 to .185, P = .011 to .018, r(2) = 2.97% to 3.43%), increased % time in hypoglycemia (r = .153, P = .036, r(2) = 2.33%) and decreased carbohydrate consumption (r = -.157, P = .031, r(2) = 2.47%). Models accounted for more variance for individuals reporting the highest daily stress. There was no relationship between stress and mean daily glucose or low/high glucose risk indices. CONCLUSIONS: These preliminary findings suggest that naturally occurring daily stressors can be associated with increased glucose instability and hypoglycemia, as well as decreased food consumption. In addition, findings support the hypothesis that some individuals are more metabolically reactive to stress. More rigorous studies using CGM technology are needed to understand whether the impact of daily stress on BG is clinically meaningful and if it is a behavioral factor that should be considered in glucose control systems for some individuals. PMID- 26969143 TI - Understanding the challenges of addressing intimate partner violence in the Dominican Republic. PMID- 26969144 TI - Efficacy of early induced medical abortion with mifepristone when beginning progestin-only contraception on the same day. AB - OBJECTIVES: To investigate whether starting progestin-only contraception immediately after mifepristone reduced the efficacy of early medical abortion with a mifepristone-misoprostol regimen. METHODS: A review of patient records from October 1, 2012 to March 31, 2013 from four Marie Stopes Mexico clinics in Mexico City was conducted. Patients were eligible for inclusion if they had undergone a medical abortion with mifepristone-misoprostol at no later than 63days of pregnancy, had a recorded outcome, and had either started progestin only contraception immediately after mifepristone administration or had not started contraception. The primary outcome-successful induced abortion-was defined as the complete evacuation of uterine contents without the need for further intervention. A secondary outcome was the number of induced abortions completed without the need for manual vacuum aspiration. RESULTS: Records from 2204 patients were included; 448 (20.3%) patients had started progestin-only contraception, and 1756 (79.7%) had not. Patients not taking progestin-only contraception were significantly more likely to be primigravidas and nulliparous. Medical abortion success did not vary between the two groups; 1890 (85.8%) were successful and 2085 (94.6%) were completed without the need for manual vacuum aspiration. Different methods of progestin-only contraception did not affect medical abortion outcomes. CONCLUSION: Beginning progestin-only contraception immediately following mifepristone for early medical abortion was not associated with reduced medical abortion effectiveness. PMID- 26969145 TI - Ambulance referral for emergency obstetric care in remote settings. AB - OBJECTIVE: To evaluate the functionality of an ambulance service dedicated to emergency obstetric care (EmOC) that referred pregnant women to health centers for delivery assistance or to a hospital for the management of obstetric complications. METHODS: A retrospective study investigated an ambulance referral system for EmOC in a rural area of Ethiopia between July 1 and December 31, 2013. The service was available 24h a day and was free of charge. Women requesting referral were transported to nearby health centers. Assistance was provided locally for uncomplicated deliveries. Women with obstetric complications were referred from health centers to a hospital. RESULTS: A total of 528 ambulance referrals were recorded. The majority of patients (314 [59.5%]) were transported from villages to health centers. The remaining individuals were brought to a hospital, having been referred from health centers (179 [33.9%]) or were referred directly from villages owing to hospital proximity (35 [6.6%]). Of the 179 patients referred to the hospital from health centers, 84 (46.9%) were diagnosed with major direct obstetric complications. No maternal deaths were recorded among patients using the ambulance service. The cost of the ambulance service was US$ 18.47 per referred patient. CONCLUSIONS: An ambulance service dedicated to EmOC that interconnected health centers and a hospital facilitated referrals and better utilized local resources. PMID- 26969147 TI - Ultrasonography estimates of fetal growth in fetuses affected by trisomy 21. AB - OBJECTIVE: To construct growth curves specific for fetuses with trisomy 21 (T21) and to compare them with the reference-based standard. METHODS: A retrospective cohort study was conducted of ultrasonography examinations from women with singleton pregnancies with a confirmed diagnosis of T21 who sought care at an academic tertiary-care center in the USA between January 1, 2003, and December 31, 2013. Growth curves were constructed using linear regression and compared with the Hadlock standard. RESULTS: The study included 425 ultrasonography examinations from 235 women. The head circumference and femur length were smaller than the reference standards at all gestational ages (head circumference: P=0.017; femur length: P<0.001). The abdominal circumference was larger than the reference standard from 29weeks onward (P<0.001). The biparietal diameter was smaller in the second trimester and in the late third trimester (P<0.001). The overall estimated fetal weight was not different from the reference standard. CONCLUSION: The T21-specific growth curves indicate anthropometric differences between T21 fetuses and the general population. Once validated, such individual growth curves could allow for more accurate prenatal assessment and management of fetuses affected by T21. PMID- 26969146 TI - Advanced breast cancer following alternative medicine. PMID- 26969148 TI - Population-based evaluation of the effectiveness of two regimens for emergency contraception. AB - OBJECTIVE: To estimate and compare the effectiveness of the levonorgestrel and Yuzpe regimens for hormonal emergency contraception in routine clinical practice. METHODS: A retrospective population-based study included women who accessed emergency contraceptives for immediate use prescribed by community pharmacists in British Columbia, Canada, between December 2000 and December 2002. Linked administrative healthcare data were used to discern the timings of menses, unprotected intercourse, and any pregnancy-related health services. A panel of experts evaluated the compatibility of observed pregnancies with the timing of events. The two regimens were compared with statistical adjustments for potential confounding. RESULTS: Among 7493 women in the cohort, 4470 (59.7%) received levonorgestrel and 3023 (40.3%) the Yuzpe regimen. There were 99 (2.2%) compatible pregnancies in the levonorgestrel group and 94 (3.1%) in the Yuzpe group (P=0.017). The estimated odds ratio for levonorgestrel compared with the Yuzpe regimen after adjusting for potential confounders was 0.64 (95% confidence interval 0.47-0.87). Against an expected pregnancy rate of approximately 5%, the relative and absolute risk reductions were 56.0% and 2.8%, respectively, for levonorgestrel and 36.7% and 1.8% for the Yuzpe regimen. CONCLUSION: The levonorgestrel regimen is more effective than the Yuzpe regimen in routine use. The data suggest that both regimens are less effective than has been observed in randomized trials. PMID- 26969151 TI - Radiological-pathological correlation study of hepatocellular carcinoma undergoing local chemoradiotherapy and surgery. AB - BACKGROUND AND AIMS: Optimal response criteria and assessment timing were investigated through radiologic-pathologic correlation in hepatocellular carcinoma (HCC) treated with localized chemoradiotherapy (CRT). METHODS: We reviewed 19 consecutive HCC patients who underwent surgical resection after radiotherapy and concurrent hepatic arterial infusion chemotherapy. Patients who received transarterial chemoembolization before RT or surgery were excluded from evaluation. Tumor diameters and total and enhancing tumor volumes were measured from CT images obtained 1, 3, 6, and 9 months after CRT. Percent changes calculated using size (RECIST and WHO) and enhancement criteria (mRECIST and EASL) were correlated with percent changes in total and enhancing tumor volumes, and with percent viable tumor in surgical specimens. RESULTS: Median time between CRT and resection was 4.1 months (range, 1.5-15.4 months). CR and PR rates were 0 and 68% by RECIST, 0 and 63% by WHO, 53% and 37% by mRECIST, and 53% and 42% by EASL. Pathologic CR (pCR) rate was 52.6%. Radiologic criteria showed strong correlation with tumor volumes at 1 and 3 months after CRT; at 6 months, however, size and enhancement criteria showed strong correlation only with total and enhancing tumor volumes, respectively. Enhancement criteria were better predictors of pathologic response at all times including preoperative evaluation (RECIST: R(2) = 0.303, P = 0.015 and WHO: R(2) = 0.366, P = 0.006 vs. mRECIST: R(2) = 0.760, P < 0.0001 and EASL: R(2) = 0.768, P < 0.0001). Time interval >6 months before resection showed significant correlation with pCR (P = 0.013). CONCLUSIONS: We recommend using enhancement criteria in assessing tumor viability, especially if the tumor was to be resected <6 months after CRT. PMID- 26969149 TI - Reflectance confocal microscopy features of mycosis fungoides and Sezary syndrome: correlation with histopathologic and T-cell receptor rearrangement studies. AB - BACKGROUND: Mycosis fungoides/Sezary syndrome (MF/SS) often requires multiple skin biopsies for definitive diagnosis. In vivo reflectance confocal microscopy (RCM) visualizes high-resolution cellular detail of the skin. The objective of this study is to evaluate the morphologic features of MF/SS using RCM and to correlate RCM features with histopathology and T-cell receptor (TCR) gene rearrangement studies. METHODS: A cohort of patients with active/recurrent or suspicious MF/SS disease was prospectively recruited for RCM imaging and histopathologic/RCM images were evaluated. Statistical analyses were performed to identify unique RCM features and to correlate RCM features with histopathologic findings and TCR rearrangement studies. RESULTS: Eighty-three lesions were evaluated. Correlation between RCM and histopathology was moderate for all relatable features (kappa = 0.41, p<0.001), almost perfect for intraepidermal atypical lymphocytes [prevalence and bias-adjusted kappa (PABAK) = 0.90], and fair for Pautrier collections (kappa = 0.32, p = 0.03). Lesions with Pautrier collections identified by RCM were significantly more likely to show TCR clonality (p = 0.04) and diagnostic features of MF/SS on histopathology (p = 0.03). CONCLUSIONS: Our study captures morphologic RCM criteria for a variety of skin lesions. Pautrier collections visualized by RCM are associated with improved histopathologic diagnosis and detection of TCR gene clonality. Although further studies are needed to validate the diagnostic implications of RCM for MF/SS, our study highlights the potential utility of RCM. PMID- 26969150 TI - TLR8 regulation of LILRA3 in monocytes is abrogated in human immunodeficiency virus infection and correlates to CD4 counts and virus loads. AB - BACKGROUND: LILRA3 is an immunostimulatory molecule which can conditionally induce the proliferation of cytotoxic cells. LILRA3 has a deletion genotype which is associated with multiple immune disorders. In this study, we wanted to analyze the regulation of LILRA3 and its significance in the context of HIV infection. RESULTS: We analyzed a panel of TLR agonists and found that ssRNA40, a TLR8 agonist, is a potent inducer of LILRA3 in healthy individuals. However, this regulation is much diminished in HIV. Comparison of TLR8 to TLR4 induction of LILRA3 indicated that LPS induces less LILRA3 than ssRNA40 among healthy controls, but not HIV patients. Levels of LILRA3 induction correlated to virus load and CD4 counts in untreated patients. Recombinant LILRA3 can induce a host of proinflammatory genes which include IL-6 and IL-1alpha, as well as alter the expression of MHC and costimulatory molecules in monocytes and B-cells. CONCLUSION: Our experiments point towards a beneficial role for LILRA3 in virus infections, especially in ssRNA viruses, like HIV, that engage TLR8. However, the potentially beneficial role of LILRA3 is abrogated during a HIV infection. We believe that more work has to be done to study the role of LILRA3 in infectious diseases and that there is a potential for exploring the use of LILRA3 in the treatment of virus infections. PMID- 26969152 TI - Noninvasive targeting delivery and in vivo magnetic resonance tracking method for live apoptotic cells in cerebral ischemia with functional Fe2O3 magnetic nanoparticles. AB - BACKGROUND: Apoptotic neuronal death is known as programmed cell death. Inhibition of this progression might contribute to a new treatment strategy. However, methods for in vivo detection of live apoptotic cells are in need to be developed and established. CONTEXT AND PURPOSE: The purpose of this study is to develop a new method for in vivo brain imaging for live apoptotic lesions using magnetic resonance imaging (MRI). We focused on the specific accumulation of our recently developed functional magnetic nanoparticles (FMNPs) into apoptotic cells using a rat cerebral ischemia model. Sulphorhodamine B, fluorescent dye was linked to valylalanylaspartic acid fluoromethyl ketone as a pan-caspase inhibitor to form SR-FLIVO. SR-FLIVO was bound with FMNPs to develop SR-FLIVO-FMNP probe. Ischemic rat brains were scanned by 7T MRI before and after intravenous injection of SR-FLIVO-FMNP and the distribution was evaluated by subtraction images of T2* colored mapping. SR-FLIVO, intracellular FMNPs, and T2* reduction area were histologically analyzed. The distribution of SR-FLIVO-FMNP was evaluated by subtracting the T2* signal images and was significantly correlated with the histological findings by TUNEL staining. RESULTS: Our experimental results revealed several findings where our newly developed probe SR-FLIVO-FMNP was intravenously administered into ischemic rats and FLIVO expression was tracked and found in apoptotic cells in rat brains after cerebral ischemia. A remarkable T2* reduction within the ischemic lesion was recorded using MRI based SR-FLIVO FMNP probe as a contrasting agent due to the specific probe accumulation in apoptotic cells whereas, no observation of T2* reduction within the non-ischemic lesion due to no probe accumulation in non-apoptotic cells. Histological analysis based on the correlation between FLIVO and TUNEL staining showed that almost all FLIVO-positive cells were positive for TUNEL staining. These findings suggest the possibility for establishment of in vivo targeting delivery methods to live apoptotic cells based on conjugation of magnetic and fluorescent dual functional probes. CONCLUSION: A newly developed probe SR-FLIVO-FMNP might be considered as a useful probe for in vivo apoptotic detection, and FMNPs might be a strong platform for noninvasive imaging and targeting delivery. PMID- 26969153 TI - Shenhua Tablet inhibits mesangial cell proliferation in rats with chronic anti Thy-1 nephritis. AB - BACKGROUND: In China, mesangial proliferative glomerulonephritis (MsPGN) is one of the most common kidney diseases. In this study, we treated a rat model of chronic anti-Thy-1 MsPGN with Shenhua Tablet and evaluated whether the tablet was able to protect the kidney function. Thirty-six Wistar rats were randomly divided into six groups: (1) Sham surgery (Sham); (2) anti-Thy-1 nephritis model (Thy-1); (3) anti-Thy-1 nephritis model + irbesartan-treated (Irb); (4) anti-Thy-1 nephritis model + low-dose of Shenhua Tablet (SHL); (5) anti-Thy-1 nephritis model + medium-dose of Shenhua Tablet (SHM); (6) anti-Thy-1 nephritis model + high-dose of Shenhua Tablet (SHH). RESULTS: Thirteen weeks after drug treatment, urinary proteins were quantified and renal pathological changes were thoroughly examined at the time point of 24 h. Meanwhile, the expression levels of p-Erk1/2, cyclin D1 and p21 at the renal cortex were also tested. The levels of urinary proteins and total cholesterol in the blood were significantly reduced in rats treated with any drug tested in this study. The level of triglyceride was significantly reduced in all three Shenhua Tablet-treated groups. Renal pathomorphological scores were significantly improved in groups of Irb, SHM and SHH. Mesangial cell proliferation was significantly inhibited in any drug-treated group. p-Erk1/2 and cyclin D1 were downregulated whereas p21 was upregulated in the renal cortex. CONCLUSIONS: Our study indicated that Shenhua Tablet is able to inhibit the abnormal proliferation of mesangial cells and to prevent kidney damage, which is likely associated with downregulation of p-Erk1/2 and reduced activity of its downstream target-cyclin D1. PMID- 26969154 TI - Valorization of a treated soil via amendments: fractionation and oral bioaccessibility of Cu, Ni, Pb, and Zn. AB - The present study aims to transform a treated soil (TS) into a more desirable resource by modifying physico-chemical properties via amendments while reducing toxic metals' mobility and oral bioaccessibility. A hydrocarbon-contaminated soil submitted to treatment (TS) but still containing elevated concentrations of Cu, Ni, Pb, and Zn has been amended with compost, sand, and Al2(SO4)3 to render it usable for horticulture. Characterization and sequential extraction were performed for TS and four amended mixtures (AM1-4). P and K availability and metal bioaccessibility were investigated in TS and AM2. Amendment improved soil properties for all mixtures and yielded a usable product (AM2 20 % TS, 49 % compost, 30 % sand, 1 % Al2(SO4)3) satisfying regulatory requirements except for Pb content. In particular, AM2 had improved organic matter (OM) and cation exchange capacity (CEC), highly increased P and K availability, and reduced total metal concentrations. Furthermore, amendment decreased metal mobile fraction likely to be plant-available (in mg kg(-1), assumed as soluble/exchangeable + carbonates fractions). For AM2, estimated Pb bioavailability decreased from 1.50 * 10(3) mg kg(-1) (TS) to 238 mg kg(-1) (52.4 % (TS) to 34.2 %). Bioaccessible concentrations of Cu, Ni, and Zn (mg kg(-1)) were lower in AM2 than in TS, but there was no significant decrease for Pb. The results suggest that amendment improved soil by modifying its chemistry, resulting in lower metal mobile fraction (in %, for Cu and Zn) and bioaccessibility (in %, for Cu only). Amending soils having residual metal contamination can be an efficient valorization method, indicating potential for reducing treatment cost and environmental burden by rendering disposal/additional treatment unnecessary. Further studies including plant bioavailability are recommended to confirm results. PMID- 26969156 TI - Variation of phytoplankton assemblages of Kongsfjorden in early autumn 2012: a microscopic and pigment ratio-based assessment. AB - Phytoplankton species distribution and composition were determined by using microscopy and pigment ratios in the Kongsfjorden during early autumn 2012. Variation in sea surface temperature (SST) was minimal and matched well with satellite-derived SST. Nutrients were generally limited. Surface phytoplankton abundance ranged from 0.21 * 10(3) to 10.28 * 10(3) cells L(-1). Phytoplankton abundance decreased with depth and did not show any significant correlation with chlorophyll a (chl a). Column-integrated phytoplankton cell counts (PCC) ranged from 94.3 * 10(6) cells m(-2) (Kf4) to 13.7 * 10(6) cells m(-2) (Kf5), while chl a was lowest at inner part of the fjord (6.3 mg m(-2)) and highest towards the mouth (24.83 mg m(-2)). Biomass from prymnesiophytes and raphidophytes dominated at surface and 10 m, respectively. The contribution of Bacillariophyceae to biomass was low. Generally, heterotrophic dinoflagellates were great in abundance (12.82 %) and ubiquitous in nature and were major contributors to biomass. Various chl pigments (chl b, chl c, phaeopigments (phaeo)) were measured to obtain pigment/chl a ratios to ascertain phytoplankton composition. Phaeo were observed only in inner fjord. Chl b:a ratios and microscopic observations indicated dominance of Chlorophyceae at greater depths than surface. Furthermore, microscopic observations confirmed dominance of chl c containing algae throughout the fjord. The study indicates that pigment ratios can be used as a tool for preliminary identification of major phytoplankton groups. However, under the presence of a large number of heterotrophic dinoflagellates such as Gymnodinium sp. and Gyrodinium sp., pigment signatures need to be supplemented by microscopic observations. PMID- 26969155 TI - Preparation of functionalized graphene oxide and its application as a nanoadsorbent for Hg(2+) removal from aqueous solution. AB - A poly(allyl acetoacetate)-grafted graphene oxide (GO-GAA) was successfully synthesized using Hummer's method by divinyl sulfone modification and allyl acetoacetate polymerizaton. This novel functionalized graphene oxide was characterized thoroughly by FTIR, XRD, FE-SEM, TEM, and TG-DT analyses. GO-GAA was then employed as an adsorbent for Hg(2+) removal from aqueous solutions. It exhibited higher adsorption capacity with regard to the pristine graphene oxide because of its effective functionalities, especially the dicarbonyl groups which are significant chelating agents. The effects of pH, temperature, and contact time on Hg(2+) adsorption were also investigated. The optimum Hg(2+) adsorption was obtained at pH 4 and T = 20-30 degrees C. The adsorption isotherm and kinetics were found to follow the Langmuir and pseudo-second-order models, respectively, with a correlation coefficient of 0.99 for both. The calculated maximum adsorption capacity of the adsorbent was 282.7 mg Hg(2+) per unit mass of GO-GAA, which is much more than 56 mg/g of that obtained for GO. The results showed that adsorption reaches up to 95 % of its maximum in less than 2 min. The synthesized GO-GAA as a novel and efficient adsorbent has been regenerated by HNO3 and reused. It retained its performance for Hg(2+) removal for several times and a less than 5 % decrease in removal efficiency was observed after four cycles of adsorption-desorption. PMID- 26969157 TI - Soil loss estimation and prioritization of sub-watersheds of Kali River basin, Karnataka, India, using RUSLE and GIS. AB - Most of the mountainous regions in tropical humid climatic zone experience severe soil loss due to natural factors. In the absence of measured data, modeling techniques play a crucial role for quantitative estimation of soil loss in such regions. The objective of this research work is to estimate soil loss and prioritize the sub-watersheds of Kali River basin using Revised Universal Soil Loss Equation (RUSLE) model. Various thematic layers of RUSLE factors such as rainfall erosivity (R), soil erodibility (K), topographic factor (LS), crop management factor (C), and support practice factor (P) have been prepared by using multiple spatial and non-spatial data sets. These layers are integrated in geographic information system (GIS) environment and estimated the soil loss. The results show that ~42 % of the study area falls under low erosion risk and only 6.97 % area suffer from very high erosion risk. Based on the rate of soil loss, 165 sub-watersheds have been prioritized into four categories-very high, high, moderate, and low erosion risk. Anthropogenic activities such as deforestation, construction of dams, and rapid urbanization are the main reasons for high rate of soil loss in the study area. The soil erosion rate and prioritization maps help in implementation of a proper watershed management plan for the river basin. PMID- 26969158 TI - Play interventions to reduce anxiety and negative emotions in hospitalized children. AB - BACKGROUND: Hospitalization is a stressful and threatening experience, which can be emotionally devastating to children. Hospital play interventions have been widely used to prepare children for invasive medical procedures and hospitalization. Nevertheless, there is an imperative need for rigorous empirical scrutiny of the effectiveness of hospital play interventions, in particular, using play activities to ease the psychological burden of hospitalized children. This study tested the effectiveness of play interventions to reduce anxiety and negative emotions in hospitalized children. METHODS: A non-equivalent control group pre-test and post-test, between subjects design was conducted in the two largest acute-care public hospitals in Hong Kong. A total of 304 Chinese children (ages 3-12) admitted for treatments in these two hospitals were invited to participate in the study. Of the 304 paediatric patients, 154 received hospital play interventions and 150 received usual care. RESULTS: Children who received the hospital play interventions exhibited fewer negative emotions and experienced lower levels of anxiety than those children who received usual care. CONCLUSION: This study addressed a gap in the literature by providing empirical evidence to support the effectiveness of play interventions in reducing anxiety and negative emotions in hospitalized children. Findings from this study emphasize the significance of incorporating hospital play interventions to provide holistic and quality care to ease the psychological burden of hospitalized children. TRIAL REGISTRATION: ClinicalTrials.gov NCT02665403 . Registered 22 January 2016. PMID- 26969159 TI - Factors that Influence Autism Knowledge in Hispanic Cultures: a Pilot Study. AB - Although the diagnosis of autism spectrum disorder (ASD) is rising, Hispanic children are diagnosed at a disproportionately lower rate compared to other ethnic and racial groups. Lack of ASD knowledge in the Hispanic community may contribute to this disparity. The study objective was to determine whether sociocultural and environmental factors linked to ASD diagnostic disparities were related to Hispanic parents' ASD knowledge. A 60-item survey assessing demographic information, acculturation, religiosity, social support, and ASD knowledge was administered to 64 Hispanic patients (84 % female; 76 % uninsured; 82 % Catholic) visiting a southwest clinic. Socioeconomic status (SES), social support, language of questionnaire, spiritual attribution of child diagnosis, and religious importance predicted ASD knowledge, accounting for 43 % of variance. Results contribute to understanding how sociocultural and environmental factors influence ASD knowledge within at-risk Hispanic individuals, which can be used to improve information dissemination and ultimately reduce disparity in ASD services. PMID- 26969160 TI - Persistent Disparities in Hispanics with Cervical Cancer in a Major City. AB - OBJECTIVES: Despite an overall improvement in cervical cancer screening, incidence, and mortality rates for minorities in the USA, regional differences in screening and stage at presentation have been observed. This study evaluated cervical cancer disparities in a predominately Hispanic population treated in a major treatment center in San Antonio, Texas. METHODS AND MATERIALS: Data on 446 patients with cervical cancer treated between 2000 and 2011 at the Cancer Therapy and Research Center in San Antonio, Texas, were reviewed. Sufficient information was obtained on 319 patients and was compared with the Surveillance, Epidemiology, and End Results (SEER) data. RESULTS: Of 319 patients treated for cervical cancer between 2000 and 2011, 209 were Hispanics and 110 were Whites (82), Blacks (20), Asians (7), and others (1). The median and mean ages at diagnosis were 47 and 49, respectively. Only 36 % were known to have screening Pap tests prior to diagnosis, of which only 24 had yearly Pap tests. Forty-two patients (20 %) of those with no known screening Pap tests presented with stage IV disease at diagnosis (vs. 3 % of those with known Pap tests). Among the Hispanics, 68 % presented with regional disease (vs. 37 % SEER) and 46 % were stage III or higher disease, with stage IIIB accounting for 30 % of total. Although the overall age-adjusted death rates were higher in Hispanics due to a higher percentage of more advanced disease, survival rates appear similar, stage for stage, to the SEER data. CONCLUSION: Even in a major city, Hispanics often present with more advanced cervical cancer than the general population. In order to minimize the cervical cancer disparities, efforts and strategies are needed to study the cultural and locale effects and to implement preventive measures and adaptive health education. PMID- 26969161 TI - Inhibition of PRL-2.CNNM3 Protein Complex Formation Decreases Breast Cancer Proliferation and Tumor Growth. AB - The oncogenic phosphatase of regenerating liver 2 (PRL-2) has been shown to regulate intracellular magnesium levels by forming a complex through an extended amino acid loop present in the Bateman module of the CNNM3 magnesium transporter. Here we identified highly conserved residues located on this amino acid loop critical for the binding with PRL-2. A single point mutation (D426A) of one of those critical amino acids was found to completely disrupt PRL-2.human Cyclin M 3 (CNNM3) complex formation. Whole-cell voltage clamping revealed that expression of CNNM3 influenced the surface current, whereas overexpression of the binding mutant had no effect, indicating that the binding of PRL-2 to CNNM3 is important for the activity of the complex. Interestingly, overexpression of the CNNM3 D426A binding mutant in cancer cells decreased their ability to proliferate under magnesium-deprived situations and under anchorage-independent growth conditions, demonstrating a PRL-2.CNNM3 complex-dependent oncogenic advantage in a more stringent environment. We further confirmed the importance of this complex in vivo using an orthotopic xenograft breast cancer model. Finally, because molecular modeling showed that the Asp-426 side chain in CNNM3 buries into the catalytic cavity of PRL-2, we showed that a PRL inhibitor could abrogate complex formation, resulting in a decrease in proliferation of human breast cancer cells. In summary, we provide evidence that this fundamental regulatory aspect of PRL-2 in cancer cells could potentially lead to broadly applicable and innovative therapeutic avenues. PMID- 26969162 TI - Rab13 Traffics on Vesicles Independent of Prenylation. AB - Rab GTPases are critical regulators of membrane trafficking. The canonical view is that Rabs are soluble in their inactive GDP-bound form, and only upon activation and conversion to their GTP-bound state are they anchored to membranes through membrane insertion of a C-terminal prenyl group. Here we demonstrate that C-terminal prenylation is not required for Rab13 to associate with and traffic on vesicles. Instead, inactive Rab13 appears to associate with vesicles via protein protein interactions. Only following activation does Rab13 associate with the plasma membrane, presumably with insertion of the C-terminal prenyl group into the membrane. PMID- 26969163 TI - The N-terminal Part of Arabidopsis thaliana Starch Synthase 4 Determines the Localization and Activity of the Enzyme. AB - Starch synthase 4 (SS4) plays a specific role in starch synthesis because it controls the number of starch granules synthesized in the chloroplast and is involved in the initiation of the starch granule. We showed previously that SS4 interacts with fibrillins 1 and is associated with plastoglobules, suborganelle compartments physically attached to the thylakoid membrane in chloroplasts. Both SS4 localization and its interaction with fibrillins 1 were mediated by the N terminal part of SS4. Here we show that the coiled-coil region within the N terminal portion of SS4 is involved in both processes. Elimination of this region prevents SS4 from binding to fibrillins 1 and alters SS4 localization in the chloroplast. We also show that SS4 forms dimers, which depends on a region located between the coiled-coil region and the glycosyltransferase domain of SS4. This region is highly conserved between all SS4 enzymes sequenced to date. We show that the dimerization seems to be necessary for the activity of the enzyme. Both dimerization and the functionality of the coiled-coil region are conserved among SS4 proteins from phylogenetically distant species, such as Arabidopsis and Brachypodium This finding suggests that the mechanism of action of SS4 is conserved among different plant species. PMID- 26969164 TI - GUN4-Protoporphyrin IX Is a Singlet Oxygen Generator with Consequences for Plastid Retrograde Signaling. AB - The genomes uncoupled 4 (GUN4) protein is a nuclear-encoded, chloroplast localized, porphyrin-binding protein implicated in retrograde signaling between the chloroplast and nucleus, although its exact role in this process is still unclear. Functionally, it enhances Mg-chelatase activity in the chlorophyll biosynthesis pathway. Because GUN4 is present only in organisms that carry out oxygenic photosynthesis and because it binds protoporphyrin IX (PPIX) and Mg PPIX, it has been suggested that it prevents production of light- and PPIX- or Mg PPIX-dependent reactive oxygen species. A chld-1/GUN4 mutant with elevated PPIX has a light-dependent up-regulation of GUN4, implicating this protein in light dependent sensing of PPIX, with the suggestion that GUN4 reduces PPIX-generated singlet oxygen, O2(a(1)Deltag), and subsequent oxidative damage (Brzezowski, P., Schlicke, H., Richter, A., Dent, R. M., Niyogi, K. K., and Grimm, B. (2014) Plant J. 79, 285-298). In direct contrast, our results show that purified GUN4 and oxidatively damaged ChlH increase the rate of PPIX-generated singlet oxygen production in the light, by a factor of 5 and 10, respectively, when compared with PPIX alone. Additionally, the functional GUN4-PPIX-ChlH complex and ChlH PPIX complexes generate O2(a(1)Deltag) at a reduced rate when compared with GUN4 PPIX. As O2(a(1)Deltag) is a potential plastid-to-nucleus signal, possibly through second messengers, light-dependent O2(a(1)Deltag) generation by GUN4-PPIX is proposed to be part of a signal transduction pathway from the chloroplast to the nucleus. GUN4 thus senses the availability and flux of PPIX through the chlorophyll biosynthetic pathway and also modulates Mg-chelatase activity. The light-dependent O2(a(1)Deltag) generation from GUN4-PPIX is thus proposed as the first step in retrograde signaling from the chloroplast to the nucleus. PMID- 26969165 TI - Regulation of CNGA1 Channel Gating by Interactions with the Membrane. AB - Cyclic nucleotide-gated (CNG) channels are expressed in rod photoreceptors and open in response to direct binding of cyclic nucleotides. We have previously shown that potentiation of CNGA1 channels by transition metals requires a histidine in the A' helix following the S6 transmembrane segment. Here, we used transition metal ion FRET and patch clamp fluorometry with a fluorescent, noncanonical amino acid (3-(6-acetylnaphthalen-2-ylamino)-2-aminopropanoic acid (Anap)) to show that the potentiating transition metal Co(2+) binds in or near the A' helix. Adding high-affinity metal-binding sites to the membrane (stearoyl nitrilotriacetic acid (C18-NTA)) increased potentiation for low Co(2+) concentrations, indicating that the membrane can coordinate metal ions with the A' helix. These results suggest that restraining the A' helix to the plasma membrane potentiates CNGA1 channel opening. Similar interactions between the A' helix and the plasma membrane may underlie regulation of structurally related hyperpolarization-activated cyclic nucleotide-gated (HCN) and voltage-gated potassium subfamily H (KCNH) channels by plasma membrane components. PMID- 26969167 TI - Giant Malignant Insulinoma. AB - The role of debulking resections in giant malignant insulinoma is still controversial. Here, we report the case of a 49-year-old patient woman with a giant malignant symptomatic insulinoma, who underwent debulking surgery, realizing a total pancreatectomy, splenectomy, partial gastrectomy and cholecystectomy. PMID- 26969166 TI - Peroxisome Proliferator-activated Receptor-gamma Coactivator 1-alpha (PGC1alpha) Protects against Experimental Murine Colitis. AB - Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1alpha) is the primary regulator of mitochondrial biogenesis and was recently found to be highly expressed within the intestinal epithelium. PGC1alpha is decreased in the intestinal epithelium of patients with inflammatory bowel disease, but its role in pathogenesis is uncertain. We now hypothesize that PGC1alpha protects against the development of colitis and helps to maintain the integrity of the intestinal barrier. We selectively deleted PGC1alpha from the intestinal epithelium of mice by breeding a PGC1alpha(loxP/loxP) mouse with a villin-cre mouse. Their progeny (PGC1alpha(DeltaIEC) mice) were subjected to 2% dextran sodium sulfate (DSS) colitis for 7 days. The SIRT1 agonist SRT1720 was used to enhance PGC1alpha activation in wild-type mice during DSS exposure. Mice lacking PGC1alpha within the intestinal epithelium were more susceptible to DSS colitis than their wild type littermates. Pharmacologic activation of PGC1alpha successfully ameliorated disease and restored mitochondrial integrity. These findings suggest that a depletion of PGC1alpha in the intestinal epithelium contributes to inflammatory changes through a failure of mitochondrial structure and function as well as a breakdown of the intestinal barrier, which leads to increased bacterial translocation. PGC1alpha induction helps to maintain mitochondrial integrity, enhance intestinal barrier function, and decrease inflammation. PMID- 26969169 TI - Top 10 (+1) tips to get started with in situ simulation in emergency and critical care departments. AB - Simulation is increasingly valued as a teaching and learning tool in emergency medicine. Bringing simulation into the workplace to train in situ offers a unique and effective training opportunity for the emergency department (ED) multiprofessional workforce. Integrating simulation in a busy department is difficult but can be done. In this article, we outline 10 tips to help make it happen. PMID- 26969168 TI - Neuromuscular electrical stimulation acutely mobilizes endothelial progenitor cells in critically ill patients with sepsis. AB - BACKGROUND: Endothelial progenitor cells (EPCs) have been suggested to constitute a restoration index of the disturbed endothelium in ICU patients. Neuromuscular electric stimulation (NMES) is increasingly employed in ICU to prevent comorbidities such as ICU-acquired weakness, which is related to endothelial dysfunction. The role of NMES to mobilize EPCs has not been investigated yet. The purpose of this study was to explore the NMES-induced effects on mobilization of EPCs in septic ICU patients. METHODS: Thirty-two septic mechanically ventilated patients (mean +/- SD, age 58 +/- 14 years) were randomized to one of the two 30 min NMES protocols of different characteristics: a high-frequency (75 Hz, 6 s on 21 s off) or a medium-frequency (45 Hz, 5 s on-12 s off) protocol both applied at maximally tolerated intensity. Blood was sampled before and immediately after the NMES sessions. Different EPCs subpopulations were quantified by cytometry markers CD34(+)/CD133(+)/CD45(-), CD34(+)/CD133(+)/CD45(-)/VEGFR2 (+) and CD34(+)/CD45( )/VEGFR2 (+). RESULTS: Overall, CD34(+)/CD133(+)/CD45(-) EPCs increased from 13.5 +/- 10.2 to 20.8 +/- 16.9 and CD34(+)/CD133(+)/CD45(-)/VEGFR2 (+) EPCs from 3.8 +/- 5.2 to 6.4 +/- 8.5 cells/10(6) enucleated cells (mean +/- SD, p < 0.05). CD34(+)/CD45(-)/VEGFR2 (+) EPCs also increased from 16.5 +/- 14.5 to 23.8 +/- 19.2 cells/10(6) enucleated cells (mean +/- SD, p < 0.05). EPCs mobilization was not affected by NMES protocol and sepsis severity (p > 0.05), while it was related to corticosteroids administration (p < 0.05). CONCLUSIONS: NMES acutely mobilized endothelial progenitor cells, measures of the endothelial restoration potential, in septic ICU patients. PMID- 26969170 TI - Never, always and maybe. Addressing attitudes of patients towards emergency medicine research. PMID- 26969171 TI - Developing antitobacco mass media campaign messages in a low-resource setting: experience from the Kingdom of Tonga. AB - Tobacco use has become the leading cause of preventable death in Tonga, a small island nation in the South Pacific. One pragmatic and economical strategy to address this worrying trend is to adapt effective antitobacco mass media materials developed in high-income countries for local audiences. Using Tonga as an example, this paper shares the practical steps involved in adapting antitobacco campaign materials for local audiences with minimal resources, a limited budget and without the need for an external production team. The Tongan experience underscores the importance of an adaptation process that draws from evidence-based best-practice models and engages local and regional stakeholders to ensure that campaign materials are tailored to the local context and are embedded within a mix of antitobacco strategies. PMID- 26969172 TI - Tobacco outlet density and converted versus native non-daily cigarette use in a national US sample. AB - OBJECTIVE: Investigate whether non-daily smokers' (NDS) cigarette price and purchase preferences, recent cessation attempts, and current intentions to quit are associated with the density of the retail cigarette product landscape surrounding their residential address. PARTICIPANTS: Cross-sectional assessment of N=904 converted NDS (CNDS). who previously smoked every day, and N=297 native NDS (NNDS) who only smoked non-daily, drawn from a national panel. OUTCOME MEASURES: Kernel density estimation was used to generate a nationwide probability surface of tobacco outlets linked to participants' residential ZIP code. Hierarchically nested log-linear models were compared to evaluate associations between outlet density, non-daily use patterns, price sensitivity and quit intentions. RESULTS: Overall, NDS in ZIP codes with greater outlet density were less likely than NDS in ZIP codes with lower outlet density to hold 6-month quit intentions when they also reported that price affected use patterns (G2=66.1, p<0.001) and purchase locations (G2=85.2, p<0.001). CNDS were more likely than NNDS to reside in ZIP codes with higher outlet density (G2=322.0, p<0.001). Compared with CNDS in ZIP codes with lower outlet density, CNDS in high-density ZIP codes were more likely to report that price influenced the amount they smoke (G2=43.9, p<0.001), and were more likely to look for better prices (G2=59.3, p<0.001). NDS residing in high-density ZIP codes were not more likely to report that price affected their cigarette brand choice compared with those in ZIP codes with lower density. CONCLUSIONS: This paper provides initial evidence that the point-of-sale cigarette environment may be differentially associated with the maintenance of CNDS versus NNDS patterns. Future research should investigate how tobacco control efforts can be optimised to both promote cessation and curb the rising tide of non-daily smoking in the USA. PMID- 26969173 TI - Adaptation and Fidelity: a Recipe Analogy for Achieving Both in Population Scale Implementation. AB - Balancing adherence to fidelity of evidence-based programs and adaptation to local context is one of the key debates in the adoption and implementation of effective programs. Concern about maintaining fidelity to achieve outcomes can result in replication of research-based models that can be a poor fit with the real world. Equally, unplanned adaptation can result in program drift away from the core elements needed to achieve outcomes. To support implementation of the Maternal Early Childhood Sustained Home-visiting (MECSH) program in multiple sites in three countries, an analogy was developed to identify how both fidelity and adaptation can be managed and successfully achieved. This article presents the Commonsense Cookery Book Basic Plain Cake with Variations recipe analogy to articulate the dual requirements of both fidelity and adaptation to achieve quality implementation of the MECSH program. Components classified by the analogy include identification of core ingredients, methods, and equipment that contribute to fundamental outcomes and fidelity to the evidence-based program, and a planned, collaborative approach to identification of needed variations to suit locally sourced capacity, needs, and tastes. Quality is achieved by identifying and measuring the core ingredients and the variations. Sourcing local ingredients and honoring of context support sustainability of quality practice. Using this analogy has assisted adopters of the MECSH program to understand that effective implementation requires uncompromised commitment to expectations of fidelity to the core components and methods; planned, proactive adaptation; systematic monitoring of both core program and agreed variations; and local ownership and sustainability. PMID- 26969176 TI - Fetal segmental spinal dysgenesis and unusual segmental agenesis of the anterior spinal artery. AB - Segmental spinal dysgenesis (SSD) is a rare congenital spinal abnormality characterized by segmental dysgenesis or agenesis of the thoracolumbar or lumbar spine, congenital kyphosis, and abnormal configuration of the underlying spinal cord. A unique feature of SSD is that the vertebrae are present above and below the defect, and there is often a lower cord segment in the caudal spinal canal. We report a fetal MRI case of SSD with postmortem and neuropathological correlations. Our report confirms already published findings including the presence of a neurenteric cyst but is the first to document anterior spinal artery segmental agenesis in SSD. PMID- 26969174 TI - Urodynamic outcomes of detethering in children: experience with 46 pediatric patients. AB - AIM: Tethered cord syndrome (TCS) manifests with neurological and urological complaints. Surgical detethering is the main treatment for TCS. Children with urological symptoms are required objective pre- and postoperative evaluations in order to predict urological outcome. The aims of this study are to investigate the effects of detethering procedure on the urodynamic tests and to determine the relationship between the changes of urodynamic tests and the patients' age and gender. MATERIAL AND METHODS: The data of urodynamic tests in 46 pediatric patients, who underwent surgery for TCS, were retrospectively evaluated. Bladder capacity, post-voiding residual urine volume, maximum intravesical pressure, and bladder compliance of each patient were measured in preoperative period and at the third month after surgery. These parameters were statistically compared, and the correlations of these parameters with age, gender, and etiology of the TCS were also investigated. RESULTS: Bladder capacity and post-voiding residual urine volume were decreased and maximum intravesical pressure and bladder compliance were increased after surgery for TCS. The decrease in bladder capacity was significant in patients older than 10 years (p < 0.05). The increase in maximum intravesical pressure was also positively correlated with age (p < 0.05). But the increase in bladder compliance was negatively correlated with age (p < 0.05). CONCLUSION: Bladder capacity, post-voiding residual urine volume, and bladder compliance are mainly affected by surgery in patients with TCS. From the urological viewpoint, children older than 10 years are most likely to benefit from surgery for TCS. PMID- 26969177 TI - A Stress Management Program for Higher Risk Medical Students: Preliminary Findings. AB - Approximately 10 % of first year medical students have clinically relevant anxiety or depression which may affect academic success and quality of life. This study tested the effects of a stress management intervention on indicators of anxiety, depression and self-efficacy in self-selected first year medical students. Forty two medical students volunteered to participate and provided informed consent. An eight session intervention was offered and focused on building relaxation skills, adaptive coping, and basic nutrition. Anxiety, depression, and self-efficacy were assessed pre and post intervention. This group of students had significantly higher baseline values of depression and anxiety but lower self-efficacy compared to a previous study of medical students at the same institution (p < 0.03). After the intervention, statistically significant improvements were observed in anxiety (p < 0.05), and self-efficacy (p < 0.05), but not in depression. The entering levels of anxiety and depression in this group suggested that these students were at risk for later clinical syndromes. Intervention directed to decreasing the effects of stress was associated with improvement in indicators of distress and may modify the longer term risk. PMID- 26969175 TI - Ectopic recurrence of pediatric craniopharyngiomas after gross total resection: a report of two cases and a review of the literature. AB - INTRODUCTION: Ectopic recurrent craniopharyngioma is rare. We reported two pediatric cases and reviewed the related literature. METHOD: We retrospectively studied 177 craniopharyngioma cases treated by the senior author (Yuan X) between years 2003 and 2013. Two ectopic recurrent craniopharyngiomas were identified. One was discovered under the right frontal lobe and the other was found in the fourth ventricle. Both patients underwent a second radical resection without complications. Then we conducted an extensive review of peer-reviewed, English language literatures in the US National Library of Medicine, focusing on the treatment modalities, recurrent sites, and clinical outcomes. RESULTS: Sixty ectopic recurrent tumors have been reported so far (including this study). Thirty three tumors were located in the previous surgical corridors and 27 were disseminated along the cerebrospinal fluid pathway. All recurrent tumors were surgically removed. The gross total resection (GTR) rates were 87 and 63 %, respectively. CONCLUSION: The natural course of recurrent ectopic craniopharyngiomas is progressive. GTR is the treatment of choice. Regular follow ups are strongly recommended to detect any further recurrence. PMID- 26969178 TI - Description of new types of sphaeractinomyxon actinospores (Myxozoa: Myxosporea) from marine tubificid oligochaetes, with a discussion on the validity of the tetraspora and the endocapsa as actinospore collective group names. AB - Ten new types of sphaeractinomyxon actinospores are morphologically and molecularly described from the coelomic cavity of two marine oligochaete hosts, Limnodriloides agnes (Hrabe, 1967) and Tubificoides pseudogaster (Dahl, 1960), from Aveiro estuary, Portugal. The smallest sphaeractinomyxon type measured 17 MUm (length) * 19 MUm (width) * 19 MUm (apical diameter), whereas the largest type measured 61 MUm * 76 MUm * 80 MUm. While considering the 10 types of sphaeractinomyxon, it was found that the number of spores developing inside pansporocysts varied between 1, 2, 4, and 8. The total prevalence of infection was of 19 % for the two host species, with a maximum recorded for spring and summer (25-26 %). While considering each type of sphaeractinomyxon individually, it was found that the prevalence values ranged between 0.3 and 1.7 %. All described sphaeractinomyxons were most similar to Myxobolus species. The validity of the tetraspora and endocapsa collective group names is discussed. PMID- 26969180 TI - US drug costs are rising faster than overall health spending, officials report. PMID- 26969179 TI - Can community-based integrated vector control hasten the process of LF elimination? AB - Community-based integrated vector control (IVC) using polystyrene beads (EPS) and pyrethroid impregnated curtains (PIC) as an adjunct to mass drug administration (MDA) was implemented for lymphatic filariasis elimination, in the filaria endemic villages of Tirukoilur, south India. In all the villages, MDA was carried out by the state health machinery, as part of the national filariasis elimination programme. Thirty-six difficult-to-control villages were grouped as, viz, MDA alone, MDA + EPS and MDA + EPS + PIC arms. Implementation and monitoring of IVC was carried out by the community. After 3 years of IVC, higher reductions in filariometric indices were observed in both the community and vector population. Decline in antigenaemia prevalence was higher in MDA + IVC as compared to MDA alone arm. Vector density dropped significantly (P < 0.05) in both the IVC arms, and nil transmission was observed during post-IVC period. Almost 53.8 and 75.8 % of the cesspits in MDA + EPS and MDA + EPS + PIC arms were closed by the householders, due to the enhanced awareness on vector breeding. The paper presents the key elements of IVC implementation through social mobilization in a LF prevalent area. Thus, community-based IVC strategy can hasten LF elimination, as it reduced the transmission and filariometric indices significantly. Indices were maintained at low level with nil transmission, by the community through IVC tools. PMID- 26969181 TI - Changes in Binding of [(123)I]CLINDE, a High-Affinity Translocator Protein 18 kDa (TSPO) Selective Radioligand in a Rat Model of Traumatic Brain Injury. AB - After traumatic brain injury (TBI), secondary injuries develop, including neuroinflammatory processes that contribute to long-lasting impairments. These secondary injuries represent potential targets for treatment and diagnostics. The translocator protein 18 kDa (TSPO) is expressed in activated microglia cells and upregulated in response to brain injury and therefore a potential biomarker of the neuroinflammatory processes. Second-generation radioligands of TSPO, such as [(123)I]CLINDE, have a higher signal-to-noise ratio as the prototype ligand PK11195. [(123)I]CLINDE has been employed in human studies using single-photon emission computed tomography to image the neuroinflammatory response after stroke. In this study, we used the same tracer in a rat model of TBI to determine changes in TSPO expression. Adult Sprague-Dawley rats were subjected to moderate controlled cortical impact injury and sacrificed at 6, 24, 72 h and 28 days post surgery. TSPO expression was assessed in brain sections employing [(123)I]CLINDE in vitro autoradiography. From 24 h to 28 days post surgery, injured animals exhibited a marked and time-dependent increase in [(123)I]CLINDE binding in the ipsilateral motor, somatosensory and parietal cortex, as well as in the hippocampus and thalamus. Interestingly, binding was also significantly elevated in the contralateral M1 motor cortex following TBI. Craniotomy without TBI caused a less marked increase in [(123)I]CLINDE binding, restricted to the ipsilateral hemisphere. Radioligand binding was consistent with an increase in TSPO mRNA expression and CD11b immunoreactivity at the contusion site. This study demonstrates the applicability of [(123)I]CLINDE for detailed regional and quantitative assessment of glial activity in experimental models of TBI. PMID- 26969182 TI - [Pancreatitis: An update]. AB - BACKGROUND: Acute and chronic pancreatitis are becoming increasingly more severe diseases in the western world with far-reaching consequences for the individual patient as well as the socioeconomic situation. This article gives an overview of the contribution of radiological imaging to the diagnostics and therapy of both forms of the disease. RESULTS: Acute pancreatitis can be subdivided into severe (20%) and mild manifestations. The diagnostics should be performed with computed tomography (CT) or magnetic resonance imaging (MRI) for assessing necrosis or potential infections only in severe forms of pancreatitis. In chronic pancreatitis transabdominal ultrasound should initially be adequate for assessment of the pancreas. For the differential diagnosis between pancreatic carcinoma and chronic pancreatitis, MRI with magnetic resonance cholangiopancreatography (MRCP) followed by an endoscopic ultrasound-guided fine needle aspiration is the method of choice. CONCLUSION: For the primary diagnosis for acute and chronic pancreatitis ultrasound examination is the modality of first choice followed by radiological CT and MRI with MRCP examinations. PMID- 26969183 TI - Genetic Targeting in Cerebellar Purkinje Cells: an Update. AB - Since the last review paper published in Cerebellum in 2002 [1], there has been a substantial increase in the number of experiments utilizing transgenic manipulations in murine cerebellar Purkinje cells. Most of these approaches were made possible with the use of the Cre/loxP methodology and pcp2/L7 based Cre recombinase expressing transgenic mouse strains. This review aims to summarize all studies which used Purkinje cell specific transgenesis since the first use of mouse strain with Purkinje cell specific Cre expression in 2002. PMID- 26969184 TI - Impaired Tilt Suppression of Post-Rotatory Nystagmus and Cross-Coupled Head Shaking Nystagmus in Cerebellar Lesions: Image Mapping Study. AB - We sought to determine the cerebellar structures responsible for tilt suppression of post-rotatory nystagmus. We investigated ocular motor findings and MRI lesions in 73 patients with isolated cerebellar lesions who underwent recording of the vestibulo-ocular reflex (VOR) using rotatory chair tests. Tilt suppression of post-rotatory nystagmus was diminished in 27 patients (27/73, 37.0 %). The gains of the VOR and the TCs of per- and post-rotatory nystagmus did not differ between the patients with diminished and with normal tilt suppression. The patients with impaired tilt suppression showed perverted ("cross-coupled") head-shaking nystagmus (pHSN) and central positional nystagmus (CPN) more frequently than those with normal responses. Tilt suppression was impaired in five (71.4 %) of the seven patients with isolated nodulus and uvular infarction. Probabilistic lesion-mapping analysis showed that the nodulus and uvula are responsible for tilt suppression. Impaired tilt suppression may be ascribed to disruption of cerebellar contribution to the vestibular velocity-storage mechanism, which integrates information from the semicircular canals and otolith organs to help derive the brain's estimate of the head orientation relative to the pull of gravity. PMID- 26969185 TI - Field testing primary stabbing headache criteria according to the 3rd beta edition of International Classification of Headache Disorders: a clinic-based study. AB - BACKGROUND: The diagnostic criteria for primary stabbing headache (PSH) in the 3rd beta edition of International Classification of Headache Disorders (ICDH-3 beta) were recently revised. In the ICDH-3 beta, PSH is defined as short-lasting head pain spontaneous occurring as a single stab or series of stabs without autonomic symptoms and involving all head areas (i.e., not limited to the ophthalmic branch region of the trigeminal nerve). The aim of this study was to investigate the validity of the ICHD-3 beta criteria for PSH in a clinic-based setting. METHODS: We prospectively collected data from patients with complaint of headache with stabbing pain without apparent cause at an initial visit to a secondary-care hospital from March 2009 to March 2014. Patients were followed up for 2 weeks to assess changes in clinical characteristics and secondary causes of pain. RESULTS: Data from 280 patients with headache with stabbing pain without apparent cause were collected, and 245 patients were followed up for 2 weeks. Secondary causes for stabbing headache were observed in 9 patients (herpes zoster in 7 patients and Bell's palsy in 2 patients) after 2 weeks. The remaining 236 patients fulfilled the diagnostic criteria for PSH according to ICHD-3 beta. Only 22 patients met the diagnostic criteria for PSH according to ICHD-2. CONCLUSIONS: All patients with headache with stabbing pain without cranial autonomic symptoms fulfilled the diagnostic criteria for PSH according to ICHD-3 beta at the initial visit. Secondary causes for headache with stabbing pain were revealed in a small proportion (3.7 %) of patients after 2 weeks of follow-up. PMID- 26969186 TI - Erratum to: Right fronto-insular white matter tracts link cognitive reserve and pain in migraine patients. PMID- 26969187 TI - Chronic cluster headache and the pituitary gland. AB - BACKGROUND: Cluster headache is classified as a primary headache by definition not caused by an underlying pathology. However, symptomatic cases of otherwise typical cluster headache have been reported. CASE PRESENTATION: A 47-year-old male suffered from primary chronic cluster headache (CCH, ICHD-3 beta criteria fulfilled) since the age of 35 years. A magnetic resonance imaging (MRI) study of the brain in 2006 came back normal. He tried several prophylactic treatments but was never longer than 1 month without attacks. He was under chronic treatment with verapamil with only a limited effect on the attack frequency. Subcutaneous sumatriptan 6 mg injections were very effective in aborting attacks. By February 2014 the patient developed a continuous interictal pain ipsilateral to the right sided cluster headache attacks. An indomethacin test (up to 225 mg/day orally) was negative. Because of the change in headache pattern we performed a new brain MRI, which showed a cystic structure in the pituitary gland. The differential diagnosis was between a Rathke cleft cyst and a cystic adenoma. Pituitary function tests showed an elevated serum prolactin level. A dopamine agonist (cabergoline) was started and the headache subsided completely. Potential pathophysiological mechanisms of pituitary tumor-associated headache are discussed. CONCLUSION: Neuroimaging should be considered in all patients with CCH, especially those with an atypical presentation or evolution. Response to acute treatment does not exclude a secondary form of cluster headache. There may be shared pathophysiological mechanisms of primary and secondary cluster headache. PMID- 26969188 TI - Structured education can improve primary-care management of headache: the first empirical evidence, from a controlled interventional study. AB - BACKGROUND: Headache disorders are under-recognized and under-diagnosed. A principal factor in their suboptimal management is lack of headache-related training among health-care providers, especially in primary care. In Estonia, general practitioners (GPs) refer many headache patients to neurological specialist services, mostly unnecessarily. GPs request "diagnostic" investigations, which are usually unhelpful and therefore wasteful. GP-made headache diagnoses are often arcane and non-specific, and treatments based on these are inappropriate. The aim of this study was to develop, implement and test an educational model intended to improve headache-related primary health care in Estonia. METHODS: This was a controlled study consisting of baseline observation, intervention and follow-up observation using the same measures of effect. It involved six GPs in Polva and the surrounding region in Southern Estonia, together with their future patients presenting consecutively with headache as their main complaint, all with their consent. The primary outcome measure was referral rate (RR) to neurological specialist services. Secondary measures included number of GP-requested investigations, GP-made headache diagnoses and how these conformed to standard terminology (ICD-10), and GP-recommended or initiated treatments. RESULTS: RR at baseline (n = 490) was 39.5 %, falling to 34.7 % in the post-intervention group (n = 295) (overall reduction 4.8 %; p = 0.21). In the large subgroup of patients (88 %) for whom GPs made clearly headache-related ICD-10 diagnoses, RR fell by one fifth (from 40 to 32 %; p = 0.08), but the only diagnosis-related RR that showed a statistically significant reduction was (pericranial) myalgia (19 to 3 %; p = 0.03). There was a significant increase towards use of more specific diagnoses. Use of investigations in diagnosing headache reduced from 26 to 4 % (p < 0.0001). Initiation of treatment by GPs increased from 58 to 81 % (p < 0.0001). CONCLUSIONS: These were modest changes in GPs' entrenched behaviour. Nevertheless they were empirical evidence that GPs' practice in the field of headache could be improved by structured education. Furthermore, the changes were likely to be cost saving. To our knowledge this study is the first to produce such evidence. PMID- 26969189 TI - The importance of loss of control while eating in adolescents with purging disorder. AB - OBJECTIVE: Although many individuals with purging disorder (PD) report loss of control (LOC) eating, it is unclear whether they differ from those who do not, or from other eating disorders involving purging and/or LOC. METHOD: We compared PD with LOC (PD-LOC), PD without LOC (PD-noLOC), bulimia nervosa (BN), and anorexia nervosa-binge/purge subtype (AN-B/P) on measures of eating-related and general psychopathology in treatment-seeking adolescents. RESULTS: PD-LOC comprised ~30% of PD diagnoses. PD-LOC and PD-noLOC did not differ from one another, or from BN and AN-B/P, on most measures of psychopathology, with some exceptions. PD-noLOC was similar to AN-B/P (p = 0.99) and significantly different from BN on eating concerns (p < 0.001), while PD-LOC was similar to BN, AN-B/P, and PD-noLOC on this measure (ps >= 0.06). PD-LOC reported higher self-esteem than BN, AN-B/P, and PD-noLOC (ps < 0.001). DISCUSSION: PD was largely similar to other eating disorders characterized by purging, regardless of whether LOC eating was present. (c) 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:801-804). PMID- 26969190 TI - Sensing of redox status by TRP channels. AB - Cellular redox status is maintained by the balance between series of antioxidant systems and production of reactive oxygen/nitrogenous species. Cells utilize this redox balance to mediate diverse physiological functions. Transient receptor potential (TRP) channels are non-selective cation channels that act as biosensors for environmental and noxious stimuli, such as capsaicin and allicin, as well as changes in temperature and conditions inside the cell. TRP channels also have an emerging role as essential players in detecting cellular redox status to regulate cellular signals mediating physiological phenomena. Reactive species activate TRP channels either directly through oxidative amino acid modifications or indirectly through second messengers. For instance, TRPA1, TRPV1 and TRPC5 channels are directly activated by oxidizing agents through cysteine modification; whereas, TRPM2 channel is indirectly activated by production of ADP-ribose. One intriguing property of several TRP channels is susceptibility to both oxidizing and reducing stimuli, suggesting TRP channels could potentially act as a bidirectional sensor for detecting deviations in redox status. In this review, we discuss the unique chemical physiologies of redox sensitive TRP channels and their physiological significance in Ca(2+) signaling. PMID- 26969191 TI - Male infertility in mice lacking the store-operated Ca(2+) channel Orai1. AB - Store-operated calcium entry (SOCE) is an important Ca(2+) influx pathway in somatic cells. In addition to maintaining endoplasmic reticulum (ER) Ca(2+) stores, Ca(2+) entry through store-operated channels regulates essential signaling pathways in numerous cell types. Patients with mutations in the store operated channel subunit ORAI1 exhibit defects in store-operated Ca(2+) influx, along with severe immunodeficiency, congenital myopathy and ectodermal dysplasia. However, little is known about the functional role of ORAI1 in germ cells and reproductive function in mice, or in men, since men with loss-of-function or null mutations in ORAI1 rarely survive to reproductive age. In this study, we investigated the role of ORAI1 in male reproductive function. We reveal that Orai1(-/-) male mice are sterile and have severe defects in spermatogenesis, with prominent deficiencies in mid- to late-stage elongating spermatid development. These studies establish an essential in vivo role for store-operated ORAI1 channels in male reproductive function and identify these channels as potential non-steroidal regulators of male fertility. PMID- 26969192 TI - HIF-1alpha-mediated upregulation of SERCA2b: The endogenous mechanism for alleviating the ischemia-induced intracellular Ca(2+) store dysfunction in CA1 and CA3 hippocampal neurons. AB - Pyramidal neurons of the hippocampus possess differential susceptibility to the ischemia-induced damage with the highest vulnerability of CA1 and the lower sensitivity of CA3 neurons. This damage is triggered by Ca(2+)-dependent excitotoxicity and can result in a delayed cell death that might be potentially suspended through activation of endogenous neuroprotection with the hypoxia inducible transcription factors (HIF). However, the molecular mechanisms of this neuroprotection remain poorly understood. Here we show that prolonged (30min) oxygen and glucose deprivation (OGD) in situ impairs intracellular Ca(2+) regulation in CA1 rather than in CA3 neurons with the differently altered expression of genes coding Ca(2+)-ATPases: the mRNA level of plasmalemmal Ca(2+) ATPases (PMCA1 and PMCA2 subtypes) was downregulated in CA1 neurons, whereas the mRNA level of the endoplasmic reticulum Ca(2+)-ATPases (SERCA2b subtype) was increased in CA3 neurons at 4h of re-oxygenation after prolonged OGD. These demonstrate distinct susceptibility of CA1 and CA3 neurons to the ischemic impairments in intracellular Ca(2+) regulation and Ca(2+)-ATPase expression. Stabilization of HIF-1alpha by inhibiting HIF-1alpha hydroxylation prevented the ischemic decrease in both PMCA1 and PMCA2 mRNAs in CA1 neurons, upregulated the SERCA2b mRNA level and eliminated the OGD-induced Ca(2+) store dysfunction in these neurons. Cumulatively, these findings reveal the previously unknown HIF 1alpha-driven upregulation of Ca(2+)-ATPases as a mechanism opposing the ischemic impairments in intracellular Ca(2+) regulation in hippocampal neurons. The ability of HIF-1alpha to modulate expression of genes coding Ca(2+)-ATPases suggests SERCA2b as a novel target for HIF-1 and may provide potential implications for HIF-1alpha-stabilizing strategy in activating endogenous neuroprotection. PMID- 26969193 TI - Healing at implants installed concurrently to maxillary sinus floor elevation with Bio-Oss(r) or autologous bone grafts. A histo-morphometric study in rabbits. AB - OBJECTIVE: To compare the healing at elevated sinus floors augmented either with deproteinized bovine bone mineral (DBBM) or autologous bone grafts and followed by immediate implant installation. MATERIAL AND METHODS: Twelve albino New Zealand rabbits were used. Incisions were performed along the midline of the nasal dorsum. The nasal bone was exposed. A circular bony widow with a diameter of 3 mm was prepared bilaterally, and the sinus mucosa was detached. Autologous bone (AB) grafts were collected from the tibia. Similar amounts of AB or DBBM granules were placed below the sinus mucosa. An implant with a moderately rough surface was installed into the elevated sinus bilaterally. The animals were sacrificed after 7 (n = 6) or 40 days (n = 6). RESULTS: The dimensions of the elevated sinus space at the DBBM sites were maintained, while at the AB sites, a loss of 2/3 was observed between 7 and 40 days of healing. The implants showed similar degrees of osseointegration after 7 (7.1 +/- 1.7%; 9.9 +/- 4.5%) and 40 days (37.8 +/- 15%; 36.0 +/- 11.4%) at the DBBM and AB sites, respectively. Similar amounts of newly formed mineralized bone were found in the elevated space after 7 days at the DBBM (7.8 +/- 6.6%) and AB (7.2 +/- 6.0%) sites while, after 40 days, a higher percentage of bone was found at AB (56.7 +/- 8.8%) compared to DBBM (40.3 +/- 7.5%) sites. CONCLUSIONS: Both Bio-Oss(r) granules and autologous bone grafts contributed to the healing at implants installed immediately in elevated sinus sites in rabbits. Bio-Oss(r) maintained the dimensions, while autologous bone sites lost 2/3 of the volume between the two periods of observation. PMID- 26969194 TI - Cerebral aneurysm debuting as rupture during diagnostic CT angiography: An unexpected worst-case scenario. AB - Previously-asymptomatic intracranial aneurysm rupture during cerebral angiography is an extremely rare phenomenon. There is a small risk of rupture of these aneurysms during digital subtraction angiography (DSA), but no case of spontaneous rupture during computed tomographic angiography (CTA) has been reported. A concise case of a 40-year-old woman referred for workup of an asymptomatic intracranial aneurysm who experienced acute rupture at the time of identification of a second aneurysm is described. This case highlights the potential for rupture at the time of scan acquisition and the importance of maintaining a high level of suspicion in the setting of neurological deterioration, as well as the potential need by all medical imaging professionals to identify an emergency and activate an urgent response. PMID- 26969195 TI - The role of 4D CT angiography for preoperative screening in patients with intracranial tumors. AB - INTRODUCTION: Four-dimensional computed tomography angiography (4D CTA) is now becoming an often used diagnostic imaging modality for the assessment of patients with intracranial tumors. The purpose of this study was to demonstrate the utility of 4D CTA for preoperative screening in patients with intracranial tumors as well as to examine the correlation between perfusion data and grading of gliomas. METHODS: We performed preoperative screening using 320-row detector CT scanner in 186 patients with intracranial tumors, and 115 patients were finally included in the study. Time-resolved subtracted maximum intensity projection images and volume-rendered images were reconstructed to evaluate vascular structures, tumor staining and incidental lesions. We also evaluated the perfusion functional map for gliomas to find correlations between their vascularity and tumor grading. RESULTS: We evaluated gliomas in 70 patients, meningiomas in 29, and other tumors in 16. Patients with gliomas of a pathologically higher grade showed high cerebral blood volume (p < 0.05). Tumor staining was observed on MIP images for 12 meningiomas, 4 gliomas, and 3 other tumors. Fifty patients showed a mass effect on vascular structures, seven had cerebral venous sinus obstruction, and two had aneurysms. No iatrogenic accidents with the CT procedure were reported. CONCLUSIONS: The 4D CTA technique is effective and safe for depicting vascular structures such as arteries, veins, tumor-related vessels, and direct and indirect anatomical complications such as vascular obstruction or vascular compression. This information is useful for preoperative screening. Although 4D CTA also provides perfusion data correlating with the tumor vascularity and grading of gliomas, its clinical value remains limited. PMID- 26969196 TI - Subarachnoid and intracerebral hemorrhage from intracranial hemangiopericytoma: An uncommon cause of intracranial hemorrhage. AB - BACKGROUND: Hemorrhage from an intracranial tumor is well known but uncommon. In cases of subarachnoid hemorrhage, aneurysm rupture is a main cause. CASE DESCRIPTION: A 64-year-old woman presented with sudden-onset motor aphasia. Computed tomography revealed subarachnoid hemorrhage, and intracerebral hemorrhage in the left temporal lobe. From the findings of pre-enhancement computed tomography, hemorrhage from a left middle cerebral artery aneurysm was initially suspected. Further radiological examinations demonstrated an enhanced mass with dural attachment in the left temporal region, but no vascular abnormality. Emergency craniotomy was performed, and the tumor and intracerebral hematoma were removed. The hemorrhage from fragile tumor vessels may destroy the tumor tissue and spread into the temporal lobe and subarachnoid space. Pathological examination of the tumor yielded findings consistent with hemangiopericytoma. Post-operatively, the patient was treated to prevent vasospasm. CONCLUSION: Although an intracranial tumor including hemangiopericytoma uncommonly causes subarachnoid hemorrhage, it should be taken into consideration as a source of intracranial hemorrhage. PMID- 26969197 TI - Melanotic schwannoma of the L5 root. AB - Melanotic neoplasm of the central nervous system is rare and the majority of them are metastatic. Melanotic schwannoma (MS) is an unusual variant of nerve sheath neoplasm accounting for less than 1% of primary nerve sheath tumors. A case involving a 36-year-old man with MS at the L5 root is presented. Surgery, differential diagnosis, radiology, histology, and treatment of this rare entity are discussed. PMID- 26969198 TI - An economic analysis of immediate delivery and expectant monitoring in women with hypertensive disorders of pregnancy, between 34 and 37 weeks of gestation (HYPITAT-II). AB - OBJECTIVE: To assess the economic consequences of immediate delivery compared with expectant monitoring in women with preterm non-severe hypertensive disorders of pregnancy. DESIGN: A cost-effectiveness analysis alongside a randomised controlled trial (HYPITAT-II). SETTING: Obstetric departments of seven academic hospitals and 44 non-academic hospitals in the Netherlands. POPULATION: Women diagnosed with non-severe hypertensive disorders of pregnancy between 340/7 and 370/7 weeks of gestation, randomly allocated to either immediate delivery or expectant monitoring. METHODS: A trial-based cost-effectiveness analysis was performed from a healthcare perspective until final maternal and neonatal discharge. MAIN OUTCOME MEASURES: Health outcomes were expressed as the prevalence of respiratory distress syndrome, defined as the need for supplemental oxygen for >24 hours combined with radiographic findings typical for respiratory distress syndrome. Costs were estimated from a healthcare perspective until maternal and neonatal discharge. RESULTS: The average costs of immediate delivery (n = 352) were ?10 245 versus ?9563 for expectant monitoring (n = 351), with an average difference of ?682 (95% confidence interval, 95% CI -?618 to ?2126). This 7% difference predominantly originated from the neonatal admissions, which were ?5672 in the immediate delivery arm and ?3929 in the expectant monitoring arm. CONCLUSION: In women with mild hypertensive disorders between 340/7 and 370/7 weeks of gestation, immediate delivery is more costly than expectant monitoring as a result of differences in neonatal admissions. These findings support expectant monitoring, as the clinical outcomes of the trial demonstrated that expectant monitoring reduced respiratory distress syndrome for a slightly increased risk of maternal complications. TWEETABLE ABSTRACT: Expectant management in preterm hypertensive disorders is less costly compared with immediate delivery. PMID- 26969199 TI - Social Media for e-Government in the Public Health Sector: Protocol for a Systematic Review. AB - BACKGROUND: Public sector organizations worldwide are engaging with social media as part of a growing e-government agenda. These include government departments of health, public health agencies, and state-funded health care and research organizations. Although examples of social media in health have been described in the literature, little is known about their overall scope or how they are achieving the objectives of e-government. A systematic literature review is underway to capture and synthesize existing evidence on the adoption, use, and impacts of social media in the public health sector. A series of parallel scoping exercises has taken place to examine (1) relevant existing systematic reviews, to assess their focus, breadth, and fit with our review topic, (2) existing concepts related to e-government, public health, and the public health sector, to assess how semantic complexity might influence the review process, and (3) the results of pilot searches, to examine the fit of social media within the e-government and health literatures. The methods and observations of the scoping exercises are reported in this protocol, alongside the methods and interim results for the systematic review itself. OBJECTIVE: The systematic review has three main objectives: To capture the corpus of published studies on the uses of social media by public health organizations; to classify the objectives for which social media have been deployed in these contexts and the methods used; and to analyze and synthesize evidence of the uptake, use, and impacts of social media on various outcomes. METHODS: A set of scoping exercises were undertaken, to inform the search strategy and analytic framework. Searches have been carried out in MEDLINE, the Cochrane Library, Web of Science, and the Scopus international electronic databases, and appropriate gray literature sources. Articles published between January 1, 2004, and July 12, 2015, were included. There was no restriction by language. One reviewer (AT) has independently screened citations generated by the search terms and is extracting data from the selected articles. A second author (CP) is cross-checking the outputs to ensure the fit of selected articles with the inclusion criteria and appropriate data extraction. A PRISMA flow diagram will be created, to track the study selection process and ensure transparency and replicability of the review. RESULTS: Scoping work revealed that the literature on social media for e-government in the public health sector is complicated by heterogeneous terminologies and concepts, although studies at the intersection of these three topics exist. Not all types of e-government are evident in the health care literature. Interim results suggest that most relevant articles focus on usage alone. CONCLUSIONS: Public health organizations may be taking it for granted that social media deliver benefits, rather than attempting to evaluate their adoption or impacts. Published taxonomies of e-government hold promise for organizing and interpreting the review results. The systematic review is underway and completion is expected in the beginning of 2016. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews: CRD42015024731; http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015024731 (Archived by WebCite at http://www.webcitation.org/6dV1Cin91). PMID- 26969203 TI - The Paddington rail disaster On Tuesday, October 5, 1999, two passenger trains collided near Ladbroke Grove Station. Kathy Horsfall and Aidan Slowie relate how their hospital responded to a major incident. AB - On Tuesday, October 5, 1999, two passenger trains collided near Ladbroke Grove Station. Kathy Horsfall and Aidan Slowie relate how their hospital responded to a major incident. PMID- 26969202 TI - Conflicting HLA assignment by three different typing methods due to the apparent loss of heterozygosity in the MHC region. AB - Loss of heterozygosity (LOH) has been reported to cause false human leukocyte antigen (HLA) homozygous typing results in pre-transplant patients suffering from haematological malignancies, who in fact are HLA heterozygous. This poses a challenge for histocompatibility testing, as a stem cell graft from a genuinely HLA homozygous donor to a mistyped patient may lead to acute life-threatening graft-vs-host disease. LOH in the HLA region on chromosome 6 is known to be quite common in solid tumours, helping malignant cells to escape T-cell surveillance, but the incidence in haematological malignancies is less well known and the estimates vary. Here we report LOH in the HLA region of five patients with haematological malignancy. We found considerable differences in sensitivity between the three different HLA typing methods used in our laboratory: SSP was clearly the most sensitive method for detecting the lost haplotype, followed by rSSO, while SBT was the least sensitive technique. A subsequent, retrospective genotyping of 65 HLA homozygous haematological patients by SSP method showed no mistyped LOH cases in our laboratory in the past 10 years. The frequency of HLA homozygosity was found to be similar between haematological patients and control groups. It is important for an HLA laboratory to be aware of the differences in various HLA typing techniques' sensitivity for detecting an under-represented haplotype between HLA typing techniques when genotyping patients with haematological diseases. It is advisable for HLA laboratories to have at least two different methods with different sensitivities in their repertoire to be able to retype samples when a false homozygous result is suspected. PMID- 26969204 TI - Emergency contraception. AB - Emergency contraception is often misunderstood by the general public and nurses alike. This article outlines information about methods of post-coital contraception that all nurses need to provide appropriate health advice to women in any nursing setting. This article first appeared in Nursing Standard. 14, 7, 38-43. Readers who successfully completed a written 'practice profile assessment' on that occasion may not do so again. PMID- 26969200 TI - Plantar talar head contusions and osteochondral fractures: associated findings on ankle MRI and proposed mechanism of injury. AB - OBJECTIVE: To evaluate the significance of plantar talar head injury (PTHI) in predicting osseous and soft tissue injuries on ankle MRI. MATERIALS AND METHODS: The IRB approved this HIPAA-compliant retrospective study. The study group consisted of 41 ankle MRIs with PTHI that occurred at our institution over a 5 1/2 year period. Eighty MRIs with bone injuries in other locations matched for age, time interval since injury, and gender formed a control group. Injuries to the following structures were recorded: medial malleolus, lateral malleolus/distal fibula, posterior malleolus, talus, calcaneus, navicular, cuboid, lateral, medial and syndesmotic ligaments, spring ligament complex, and extensor digitorum brevis (EDB) muscle. Twenty separate logistic regressions determined which injuries PTHI predicted, using the Holm procedure to control for family-wise alpha at 0.05. RESULTS: PTHI strongly predicted the occurrence of injuries involving the anterior process of the calcaneus [24 % of cases, odds ratio (OR) 12.66], plantar components of the spring ligament (27 %, OR 9.43), calcaneal origin of the EDB and attachment of the dorsolateral calcaneocuboid ligament (22 %, OR 7.22), cuboid (51 %, OR 6.58), EDB (27 %, OR 5.49), anteromedial talus (66 %, OR 4.78), and posteromedial talus (49 %, OR 4.48). PTHI strongly predicted lack of occurrence of syndesmotic ligament injury (OR 19.6). The PTHI group had a high incidence of lateral ligamentous injury (78 %), but not significantly different from the control group (53 %). CONCLUSIONS: PTHI is strongly associated with injury involving the transverse tarsal joint complex. We hypothesize it results from talo-cuboid and/or talo-calcaneal impaction from a supination injury of the foot and ankle. PMID- 26969205 TI - Is determination of the hip rotation center during computer-assisted surgery influenced by the pinless femoral sensor attachment method? An in vitro preliminary study comparing osseous pin fixation. AB - INTRODUCTION: Computer-assisted surgery improves the positioning of hip prostheses but requires use of transosseous pins requiring a complementary approach exposing the patient to rare but at times serious complications. The use of sensor arrays attached to the skin could advantageously replace pins provided that comparable results are obtained, but their validity has not yet been assessed. We conducted a prospective in vitro study to: measure the possible error of a cutaneous versus transosseous fixation to determine the hip rotation center (HRC) position and determine the inter- and intraobserver reproducibility of the cutaneous versus the transosseous fixation. HYPOTHESIS: Use of cutaneous sensor arrays while recording the HRC is sufficiently reliable for its calculation algorithm to provide measurement accuracy within 5mm. MATERIALS AND METHODS: A rigid array attached with either a silicone strap or an adhesive were compared to a transosseous array. Four series of 96 HRC measurements were collected by four operators on two cadavers, half with an array attached with a strap and half with an adhesive. The results were compared to those obtained by a sensor attached with transosseous pins. RESULTS: On condition that the hip-knee is mobilized in extension, a sensor array attached with an adhesive gives results with comparable accuracy (standard deviation [SD]: 2.89mm [1.9-4.8]) to the results obtained with a transosseous fixation (SD: 1.2mm [0.9-1.6]), with no significant inter- or intraobserver variation (0.971, P=0.006; disease-free survival 66% if N<3 vs 47% if N3, P=0.046). CONCLUSION: The association of induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil and concomitant chemoradiotherapy shows satisfying results with an acceptable toxicity. The terms of the chemopotentiation and its superiority to a single concomitant chemoradiotherapy treatment still remain to be clarified. PMID- 26969245 TI - [Combined radiation therapy and androgen deprivation in the management of prostate cancer: Where do we stand?]. AB - Radiotherapy and androgen deprivation therapy play a major role in the management of prostate cancer. Indeed, radiotherapy and hormone therapy are combined in a neoadjuvant and concomitant setting for intermediate risk cancers but also in an adjuvant setting in high risk or locally advanced prostate cancer. The benefice of this association was suggested by preclinical studies and demonstrated later by several randomized trials. However, as these trials were conducted before the era of dose escalation the role of androgen deprivation therapy in this case is less clear. Moreover, as hormonal therapy can lead to a significant morbidity and a decrement in quality of life its indications must be carefully weighed especially in case of intermediate risk cancer witch represent a heterogeneous group with distinct prognostic subgroups. PMID- 26969246 TI - [Oral cavity cancers among young people: Clinical results and prognostic analysis]. AB - PURPOSE: Squamous cell carcinomas of the oral cavity occurring in young people represent a specific entity. Its management and prognosis are controversial. We performed a retrospective chart review of all patients aged less than 40 years old and treated at Gustave-Roussy Cancer Centre for a squamous cell carcinomas of the oral cavity between 1999 and 2011. METHODS: Patients and tumour characteristics, type of treatment and follow-up data were collected. Survival data were analysed according to the methods of Kaplan-Meier and both univariate and multivariate analyses were performed to look for prognostic factors regarding overall survival and progression-free survival. RESULTS: Sixty-three patients were identified. Median follow-up was 64 months. Most of the tumours were initially located in the mobile tongue (n=54, 85.7%). Overall 17 patients had died, including 15 from the treated cancer. Overall and progression-free survival rates at 5 years were respectively 79.6% and 68.6%. The corresponding 5 years local, regional and metastatic relapse free survival rates were 80%, 91% and 89% respectively. In the multivariate analysis only the absence of initial surgery (hazard ratio [HR]: 13.5 [2.0; 90.5]; P=0.007) was prognostic for overall survival, while alcohol abuse (HR: 0.37 [0.15; 0.9]; P=0.03) and the absence of surgery (HR: 13.6 [2.5; 74.2]; P=0.002) were associated with a decreased progression-free survival. A younger age (less than 30 year old) was not associated with the risk of recurrence or death. CONCLUSION: Survival rates and tumour control probabilities are relatively high among young patients suffering from squamous cell carcinomas of the oral cavity treated at a tertiary centre. The early identification of patients at risk of relapse is currently difficult. The balance between recurrence and treatment toxicity warrants further studies, both on the clinical level and for the development of prognostic biomarkers. PMID- 26969247 TI - [Bacterial etiology of acute otitis media in Spain in the post-pneumococcal conjugate vaccine era]. AB - INTRODUCTION: Acute otitis media (AOM) is common in children aged <3 years. A pneumococcal conjugate vaccine (PCV) (PCV7; Prevenar, Pfizer/Wyeth, USA) has been available in Spain since 2001, which has a coverage rate of 50-60% in children aged <5 years. MATERIALS AND METHODS: Children aged >=3 to 36 months with AOM confirmed by an ear-nose-throat specialist were enrolled at seven centers in Spain (February 2009-May 2012) (GSK study identifier: 111425). Middle-ear-fluid samples were collected by tympanocentesis or spontaneous otorrhea and cultured for bacterial identification. Culture-negative samples were further analyzed using polymerase chain reaction (PCR). RESULTS: Of 125 confirmed AOM episodes in 124 children, 117 were analyzed (median age: 17 months (range: 3-35); eight AOM episodes were excluded from analyses. Overall, 69% (81/117) episodes were combined culture- and PCR-positive for >=1 bacterial pathogen; 44% (52/117) and 39% (46/117) were positive for Haemophilus influenzae (Hi) and Streptococcus pneumoniae (Spn), respectively. 77 of 117 episodes were cultured for >=1 bacteria, of which 63 were culture-positive; most commonly Spn (24/77; 31%) and Hi (32/77; 42%). PCR on culture-negative episodes identified 48% Hi- and 55% Spn positive episodes. The most common Spn serotype was 19F (4/24; 17%) followed by 19A (3/24; 13%); all Hi-positive episodes were non-typeable (NTHi). 81/117 AOM episodes (69%) occurred in children who had received >=1 pneumococcal vaccine dose. CONCLUSIONS: NTHi and Spn were the main etiological agents for AOM in Spain. Impact of pneumococcal vaccination on AOM requires further evaluation in Spain, after higher vaccination coverage rate is reached. PMID- 26969248 TI - [Food allergies in paediatrics: Current concepts]. AB - The concept of allergic reaction currently includes all those where an immunological reaction depends on a reaction mediated by IgE, as well as those that involve other immune mechanisms, such as T-cell regulators. There are many different clinical situations, like the classic immediate reactions (IgE mediated) such as urticaria, angioedema, immediate vomiting, abdominal pain, both upper respiratory (aphonia or rhinitis) and lower (wheezing or dyspnoea) symptom, and cardiovascular symptoms. The reactions that involve more than one organ, such as anaphylaxis, which could be an anaphylactic shock if there is cardiovascular involvement. The clinical signs and symptoms produced by non-IgE mediated reactions are usually more insidious in how they start, such as vomiting hours after the ingestion of food in enterocolitis, diarrhoea after days or weeks from starting food, dermatitis sometime after starting food. In these cases it is more difficult to associate these clinical symptoms directly with food. In this article, we attempt to clarify some concepts such as sensitisation/allergy, allergen/allergenic source, or the relationship of different clinical situations with food allergy, in order to help the paediatrician on the one hand, to prescribe strict diets in case of a suspicion based on the cause/effect relationship with the food, and on the other hand not to introduce unnecessary diets that very often have to last an excessively long time, and could lead to nutritional deficiencies in the children. PMID- 26969249 TI - Enhanced salinomycin production by adjusting the supply of polyketide extender units in Streptomyces albus. AB - The anticoccidial salinomycin is a polyketide produced by Streptomyces albus and requires malonyl-CoAs, methylmalonyl-CoAs, and ethylmalonyl-CoAs for the backbone assembly. Genome sequencing of S. albus DSM 41398 revealed a high percentage of genes involved in lipid metabolism, supporting the high salinomycin yield in oil rich media. Seven PKS/PKS-NRPS gene clusters in the genome were found to be actively transcribed and had been individually deleted, which resulted in significantly improved salinomycin production. However, a combined deletion of PKS-NRPS-2 and PKS-6 showed no further improvement. Whereas the concentrations of malonyl-CoA and methylmalonyl-CoA were increased, the concentration of ethylmalonyl-CoA remained low in the mutants. An endogenous crotonyl-CoA reductase gene (ccr) was overexpressed in the DeltaPKS-NRPS-2/DeltaPKS-6 mutant, resulting in improved production. Combination of cluster deletions and over expression of ccr gene led to an overall titer improvement of salinomycin from 0.60 to 6.60g/L. This engineering strategy can be implemented for various natural polyketides production. PMID- 26969250 TI - Engineering cofactor and transport mechanisms in Saccharomyces cerevisiae for enhanced acetyl-CoA and polyketide biosynthesis. AB - Synthesis of polyketides at high titer and yield is important for producing pharmaceuticals and biorenewable chemical precursors. In this work, we engineered cofactor and transport pathways in Saccharomyces cerevisiae to increase acetyl CoA, an important polyketide building block. The highly regulated yeast pyruvate dehydrogenase bypass pathway was supplemented by overexpressing a modified Escherichia coli pyruvate dehydrogenase complex (PDHm) that accepts NADP(+) for acetyl-CoA production. After 24h of cultivation, a 3.7-fold increase in NADPH/NADP(+) ratio was observed relative to the base strain, and a 2.2-fold increase relative to introduction of the native E. coli PDH. Both E. coli pathways increased acetyl-CoA levels approximately 2-fold relative to the yeast base strain. Combining PDHm with a ZWF1 deletion to block the major yeast NADPH biosynthesis pathway resulted in a 12-fold NADPH boost and a 2.2-fold increase in acetyl-CoA. At 48h, only this coupled approach showed increased acetyl-CoA levels, 3.0-fold higher than that of the base strain. The impact on polyketide synthesis was evaluated in a S. cerevisiae strain expressing the Gerbera hybrida 2-pyrone synthase (2-PS) for the production of the polyketide triacetic acid lactone (TAL). Titers of TAL relative to the base strain improved only 30% with the native E. coli PDH, but 3.0-fold with PDHm and 4.4-fold with PDHm in the Deltazwf1 strain. Carbon was further routed toward TAL production by reducing mitochondrial transport of pyruvate and acetyl-CoA; deletions in genes POR2, MPC2, PDA1, or YAT2 each increased titer 2-3-fold over the base strain (up to 0.8g/L), and in combination to 1.4g/L. Combining the two approaches (NADPH generating acetyl-CoA pathway plus reduced metabolite flux into the mitochondria) resulted in a final TAL titer of 1.6g/L, a 6.4-fold increase over the non engineered yeast strain, and 35% of theoretical yield (0.16g/g glucose), the highest reported to date. These biological driving forces present new avenues for improving high-yield production of acetyl-CoA derived compounds. PMID- 26969251 TI - Efficient production of the Nylon 12 monomer omega-aminododecanoic acid methyl ester from renewable dodecanoic acid methyl ester with engineered Escherichia coli. AB - The expansion of microbial substrate and product scopes will be an important brick promoting future bioeconomy. In this study, an orthogonal pathway running in parallel to native metabolism and converting renewable dodecanoic acid methyl ester (DAME) via terminal alcohol and aldehyde to 12-aminododecanoic acid methyl ester (ADAME), a building block for the high-performance polymer Nylon 12, was engineered in Escherichia coli and optimized regarding substrate uptake, substrate requirements, host strain choice, flux, and product yield. Efficient DAME uptake was achieved by means of the hydrophobic outer membrane porin AlkL increasing maximum oxygenation and transamination activities 8.3 and 7.6-fold, respectively. An optimized coupling to the pyruvate node via a heterologous alanine dehydrogenase enabled efficient intracellular L-alanine supply, a prerequisite for self-sufficient whole-cell transaminase catalysis. Finally, the introduction of a respiratory chain-linked alcohol dehydrogenase enabled an increase in pathway flux, the minimization of undesired overoxidation to the respective carboxylic acid, and thus the efficient formation of ADAME as main product. The completely synthetic orthogonal pathway presented in this study sets the stage for Nylon 12 production from renewables. Its effective operation achieved via fine tuning the connectivity to native cell functionalities emphasizes the potential of this concept to expand microbial substrate and product scopes. PMID- 26969253 TI - Pathway construction and metabolic engineering for fermentative production of ectoine in Escherichia coli. AB - Ectoine is a protective agent and stabilizer whose synthesis pathway exclusively exists in select moderate halophiles. A novel established process called "bacterial milking" efficiently synthesized ectoine in moderate halophiles, however, this method places high demands on equipment and is cost prohibitive. In this study, we constructed an ectoine producing strain by introducing the ectoine synthesis pathway into Escherichia coli and improved its production capacity. Firstly, the ectABC gene cluster from Halomonas elongata was introduced into E. coli W3110 and the resultant strain synthesized 4.9g/L ectoine without high osmolarity. Subsequently, thrA encoding the bifunctional aspartokinase/homoserine dehydrogenase was deleted to weaken the competitive l-threonine branch, resulting in an increase of ectoine titer by 109%. Furthermore, a feedback resistant lysC from Corynebacterium glutamicum encoding the aspartate kinase was introduced to complement the enzymatic activity deficiency caused by thrA deletion and a 9% increase of ectoine titer was obtained. Finally, the promoter of ppc that encodes phosphoenolpyruvate carboxylase was replaced by a trc promoter, and iclR, a glyoxylate shunt transcriptional repressor gene, was deleted. The oxaloacetate pool, was thus reinforced and ectoine titer increased by 21%. The final engineered strain ECT05 (pTrcECT, pSTVLysC-CG) produced 25.1g/L ectoine by fed batch fermentation in low salt concentration with glucose as a carbon source. The specific ectoine production and productivity was 0.8g/g DCW and 0.84gL(-)(1)h( )(1) respectively. The overall ectoine yield was 0.11g/g of glucose. PMID- 26969252 TI - Employing bacterial microcompartment technology to engineer a shell-free enzyme aggregate for enhanced 1,2-propanediol production in Escherichia coli. AB - Bacterial microcompartments (BMCs) enhance the breakdown of metabolites such as 1,2-propanediol (1,2-PD) to propionic acid. The encapsulation of proteins within the BMC is mediated by the presence of targeting sequences. In an attempt to redesign the Pdu BMC into a 1,2-PD synthesising factory using glycerol as the starting material we added N-terminal targeting peptides to glycerol dehydrogenase, dihydroxyacetone kinase, methylglyoxal synthase and 1,2 propanediol oxidoreductase to allow their inclusion into an empty BMC. 1,2-PD producing strains containing the fused enzymes exhibit a 245% increase in product formation in comparison to un-tagged enzymes, irrespective of the presence of BMCs. Tagging of enzymes with targeting peptides results in the formation of dense protein aggregates within the cell that are shown by immuno-labelling to contain the vast majority of tagged proteins. It can therefore be concluded that these protein inclusions are metabolically active and facilitate the significant increase in product formation. PMID- 26969254 TI - Combining metabolic engineering and biocompatible chemistry for high-yield production of homo-diacetyl and homo-(S,S)-2,3-butanediol. AB - Biocompatible chemistry is gaining increasing attention because of its potential within biotechnology for expanding the repertoire of biological transformations carried out by enzymes. Here we demonstrate how biocompatible chemistry can be used for synthesizing valuable compounds as well as for linking metabolic pathways to achieve redox balance and rescued growth. By comprehensive rerouting of metabolism, activation of respiration, and finally metal ion catalysis, we successfully managed to convert the homolactic bacterium Lactococcus lactis into a homo-diacetyl producer with high titer (95mM or 8.2g/L) and high yield (87% of the theoretical maximum). Subsequently, the pathway was extended to (S,S)-2,3 butanediol (S-BDO) through efficiently linking two metabolic pathways via chemical catalysis. This resulted in efficient homo-S-BDO production with a titer of 74mM (6.7g/L) S-BDO and a yield of 82%. The diacetyl and S-BDO production rates and yields obtained are the highest ever reported, demonstrating the promising combination of metabolic engineering and biocompatible chemistry as well as the great potential of L. lactis as a new production platform. PMID- 26969255 TI - Chemical tags for site-specific fluorescent labeling of biomolecules. AB - This review focuses on the various approaches to covalently attach a chromophore to a biomolecule of interest in site-specific manner. Novel methods like inverse electron-demand Diels-Alder reaction, Pictet-Spengler ligation and enzyme tags like SNAP and Halo-tags are critically discussed and compared to established techniques like copper-free click reaction and native chemical ligation. Selected examples in which the tags have been exploited for in vitro or in vivo imaging are reviewed and evaluated. PMID- 26969256 TI - Homocysteinemia control by cysteine in cerebral vascular patients after methionine loading test: evidences in physiological and pathological conditions in cerebro-vascular and multiple sclerosis patients. AB - The toxicity risk of hyperhomocysteinemia is prevented through thiol drug administration which reduces plasma total homocysteine (tHcy) concentrations by activating thiol exchange reactions. Assuming that cysteine (Cys) is a homocysteinemia regulator, the hypothesis was verified in healthy and pathological individuals after the methionine loading test (MLT). The plasma variations of redox species of Cys, Hcy, cysteinylglycine, glutathione and albumin (reduced, HS-ALB, and at mixed disulfide, XSS-ALB) were compared in patients with cerebral small vessels disease (CSVD) (n = 11), multiple sclerosis (MS) (n = 12) and healthy controls (n = 11) at 2-4-6 h after MLT. In MLT-treated subjects, the activation of thiol exchange reactions provoked significant changes over time in redox species concentrations of Cys, Hcy, and albumin. Significant differences between controls and pathological groups were also observed. In non methionine-treated subjects, total Cys concentrations, tHcy and thiol-protein mixed disulfides (CSS-ALB, HSS-ALB) of CSVD patients were higher than controls. After MLT, all groups displayed significant cystine (CSSC) increases and CSS-ALB decreases, that in pathological groups were significantly higher than controls. These data would confirm the Cys regulatory role on the homocysteinemia; they also explain that the Cys-Hcy mixed disulfide excretion is an important point of hyperhomocysteinemia control. Moreover, in all groups after MLT, significant increases in albumin concentrations, named total albumin (tALB) and measured as sum of HS-ALB (spectrophometric), and XSS-ALB (assayed at HPLC) were observed. tALB increases, more pronounced in healthy than in the pathological subjects, could indicate alterations of albumin equilibria between plasma and other extracellular spaces, whose toxicological consequences deserve further studies. PMID- 26969257 TI - Isavuconazole: an azole active against mucormycosis. PMID- 26969259 TI - Impulse noise injury prediction based on the cochlear energy. AB - The current impulse noise criteria for the protection against impulse noise injury do not incorporate an objective measure of hearing protection. A new biomechanically-based model has been developed based on improvement of the Auditory Hazard Assessment Algorithm for the Human (AHAAH) using the integrated cochlear energy (ICE) as the damage risk correlate (DRC). The model parameters have been corrected using the latest literature data. The anomalous dose-response inversion behavior of the AHAAH model was eliminated. The modeling results show that the annular ligament (AL) parameters are the dominant cause of the non monotonic dose-response behavior of AHAAH. Based on parametric optimization analysis, a 40% reduction of the AL compliance from the AHAAH default value removed the dose-response inversion problem, and this value was found to be within the physiological range when compared with experimental data. The transfer functions from the new model are in good agreement with those of the human ear. A dose-response curve based on ICE was developed using the human walk-up temporary threshold shift (TTS) data. Furthermore, the ICE values calculated for the German rifle noise tests show excellent comparison with the injury outcomes, hence providing a significant independent validation of the improved model. The ICE was found to be the best DRC to both large weapons and small arms noise injury data, covering both protected and unprotected exposures, respectively. The new AHAAH model with ICE as the dose metric is adequate for use as a medical standard against impulse noise injury. PMID- 26969258 TI - Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case control analysis. AB - BACKGROUND: Mucormycosis is an uncommon invasive fungal disease with high mortality and few treatment options. Isavuconazole is a triazole active in vitro and in animal models against moulds of the order Mucorales. We assessed the efficacy and safety of isavuconazole for treatment of mucormycosis and compared its efficacy with amphotericin B in a matched case-control analysis. METHODS: In a single-arm open-label trial (VITAL study), adult patients (>=18 years) with invasive fungal disease caused by rare fungi, including mucormycosis, were recruited from 34 centres worldwide. Patients were given isavuconazole 200 mg (as its intravenous or oral water-soluble prodrug, isavuconazonium sulfate) three times daily for six doses, followed by 200 mg/day until invasive fungal disease resolution, failure, or for 180 days or more. The primary endpoint was independent data review committee-determined overall response-ie, complete or partial response (treatment success) or stable or progressive disease (treatment failure)-according to prespecified criteria. Mucormycosis cases treated with isavuconazole as primary treatment were matched with controls from the FungiScope Registry, recruited from 17 centres worldwide, who received primary amphotericin B-based treatment, and were analysed for day-42 all-cause mortality. VITAL is registered with ClinicalTrials.gov, number NCT00634049. FungiScope is registered with ClinicalTrials.gov, number NCT01731353. FINDINGS: Within the VITAL study, from April 22, 2008, to June 21, 2013, 37 patients with mucormycosis received isavuconazole for a median of 84 days (IQR 19-179, range 2-882). By day 42, four patients (11%) had a partial response, 16 (43%) had stable invasive fungal disease, one (3%) had invasive fungal disease progression, three (8%) had missing assessments, and 13 (35%) had died. 35 patients (95%) had adverse events (28 [76%] serious). Day-42 crude all-cause mortality in seven (33%) of 21 primary treatment isavuconazole cases was similar to 13 (39%) of 33 amphotericin B treated matched controls (weighted all-cause mortality: 33% vs 41%; p=0.595). INTERPRETATION: Isavuconazole showed activity against mucormycosis with efficacy similar to amphotericin B. Isavuconazole can be used for treatment of mucormycosis and is well tolerated. FUNDING: Astellas Pharma Global Development, Basilea Pharmaceutica International. PMID- 26969260 TI - Disrupted functional brain connectome in unilateral sudden sensorineural hearing loss. AB - Sudden sensorineural hearing loss (SSNHL) is generally defined as sensorineural hearing loss of 30 dB or greater over at least three contiguous audiometric frequencies and within a three-day period. This hearing loss is usually unilateral and can be associated with tinnitus and vertigo. The pathogenesis of unilateral sudden sensorineural hearing loss is still unknown, and the alterations in the functional connectivity are suspected to involve one possible pathogenesis. Despite scarce findings with respect to alterations in brain functional networks in unilateral sudden sensorineural hearing loss, the alterations of the whole brain functional connectome and whether these alterations were already in existence in the acute period remains unknown. The aim of this study was to investigate the alterations of brain functional connectome in two large samples of unilateral sudden sensorineural hearing loss patients and to investigate the correlation between unilateral sudden sensorineural hearing loss characteristics and changes in the functional network properties. Pure tone audiometry was performed to assess hearing ability. Abnormal changes in the peripheral auditory system were examined using conventional magnetic resonance imaging. The graph theoretical network analysis method was used to detect brain connectome alterations in unilateral sudden sensorineural hearing loss. Compared with the control groups, both groups of unilateral SSNHL patients exhibited a significantly increased clustering coefficient, global efficiency, and local efficiency but a significantly decreased characteristic path length. In addition, the primary increased nodal strength (e.g., nodal betweenness, hubs) was observed in several regions primarily, including the limbic and paralimbic systems, and in the auditory network brain areas. These findings suggest that the alteration of network organization already exists in unilateral sudden sensorineural hearing loss patients within the acute period and that the functional connectome of unilateral SSNHL patients is characterized by a shift toward small-worldization. Additionally, we hope that these findings will help to elucidate unilateral SSNHL through a new research perspective and provide insight for the potential pathophysiology of unilateral SSNHL. PMID- 26969261 TI - Evaluating and optimizing oral formulations of live bacterial vaccines using a gastro-small intestine model. AB - Gastrointestinal (GI) models that mimic physiological conditions in vitro are important tools for developing and optimizing biopharmaceutical formulations. Oral administration of live attenuated bacterial vaccines (LBV) can safely and effectively promote mucosal immunity but new formulations are required that provide controlled release of optimal numbers of viable bacterial cells, which must survive gastrointestinal transit overcoming various antimicrobial barriers. Here, we use a gastro-small intestine gut model of human GI conditions to study the survival and release kinetics of two oral LBV formulations: the licensed typhoid fever vaccine Vivotif comprising enteric coated capsules; and an experimental formulation of the model vaccine Salmonella Typhimurium SL3261 dried directly onto cast enteric polymer films and laminated to form a polymer film laminate (PFL). Neither formulation released significant numbers of viable cells when tested in the complete gastro-small intestine model. The poor performance in delivering viable cells could be attributed to a combination of acid and bile toxicity plus incomplete release of cells for Vivotif capsules, and to bile toxicity alone for PFL. To achieve effective protection from intestinal bile in addition to effective acid resistance, bile adsorbent resins were incorporated into the PFL to produce a new formulation, termed BR-PFL. Efficient and complete release of 4.4*10(7) live cells per dose was achieved from BR-PFL at distal intestinal pH, with release kinetics controlled by the composition of the enteric polymer film, and no loss in viability observed in any stage of the GI model. Use of this in vitro GI model thereby allowed rational design of an oral LBV formulation to maximize viable cell release. PMID- 26969262 TI - Hydrogel-forming microneedle arrays: Potential for use in minimally-invasive lithium monitoring. AB - We describe, for the first time, hydrogel-forming microneedle (s) (MN) arrays for minimally-invasive extraction and quantification of lithium in vitro and in vivo. MN arrays, prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co maleic anhydride) and crosslinked by poly(ethyleneglycol), imbibed interstitial fluid (ISF) upon skin insertion. Such MN were always removed intact. In vitro, mean detected lithium concentrations showed no significant difference following 30min MN application to excised neonatal porcine skin for lithium citrate concentrations of 0.9 and 2mmol/l. However, after 1h application, the mean lithium concentrations extracted were significantly different, being appropriately concentration-dependent. In vivo, rats were orally dosed with lithium citrate equivalent to 15mg/kg and 30mg/kg lithium carbonate, respectively. MN arrays were applied 1h after dosing and removed 1h later. The two groups, having received different doses, showed no significant difference between lithium concentrations in serum or MN. However, the higher dosed rats demonstrated a lithium concentration extracted from MN arrays equivalent to a mean increase of 22.5% compared to rats which received the lower dose. Hydrogel forming MN clearly have potential as a minimally-invasive tool for lithium monitoring in outpatient settings. We will now focus on correlation between serum and MN lithium concentrations. PMID- 26969263 TI - A heuristic model to quantify the impact of excess cyclodextrin on oral drug absorption from aqueous solution. AB - The intestinal drug solubilising capacity (Dtot(SC)) of a drug formulated as an aqueous cyclodextrin solution is a recently proposed quantity to predict the cyclodextrin concentration needed to fully solubilise the drug in the intestinal lumen. According to this concept, the cyclodextrin concentration in the drug product must be higher than the amount needed to solubilise the compound, due to the displacement of the drug from the cyclodextrin cavity by bile salts in the intestinal lumen. On the other hand, dosing cyclodextrin at >Dtot(SC) is expected to result in decreased free intestinal drug concentrations and thus potentially a lower fraction absorbed. In this study, data from three previous in vivo studies in rats with fixed concentrations of three compounds (danazol, cinnarizine and benzo[A]pyrene) and various cyclodextrin concentrations >Dtot(SC) were analysed. The model was developed for danazol and applied to the two other compounds. Absorption, as quantified from the area under the plasma concentration-time profile, was predicted by the model to decrease at elevated concentrations of co administered cyclodextrin in accordance with the in vivo data. In addition, at high cyclodextrin concentrations a delay in Tmax and a decrease in Cmax were predicted, again in accordance with the experimental observations. These observations were rationalised in terms of the free intestinal drug concentration by a chemical equilibrium model for Dtot(SC). This model depends on the quantity termed the dimensionless dose concentration, Dtot(*)=Do/Pn, given as the fraction of the permeation number (Pn) and dose number (Do). The model provides the formulation scientist with a critical quality attribute for assessing the implication of having excess cyclodextrin in an oral solution. PMID- 26969264 TI - An investigation of how fungal infection influences drug penetration through onychomycosis patient's nail plates. AB - The treatment of onychomycosis remains problematic even though there are several potent antifungal agents available for patient use. The aim of this investigation was to understand whether the structural modifications that arise when a patient's nail become infected plates influences the permeation of drugs into the nail following topical application. It was hoped that through improving understanding of the nail barrier in the diseased state, the development of more effective topical treatments for onychomycosis could be facilitated. The permeation of three compounds with differing hydrophobicities, caffeine, terbinafine and amorolfine (clogD at pH 7.4 of -0.55, 3.72 and 4.49 respectively), was assessed across both healthy and onychomycosis infected, full thickness, human nail plate sections. Transonychial water loss (TOWL) measurements performed on the healthy and diseased nails supported previous observations that the nail behaves like a porous barrier given the lack of correlation between TOWL values with the thicker, diseased nails. The flux of the more hydrophilic caffeine was twofold greater across diseased in comparison with the healthy nails, whilst the hydrophobic molecules terbinafine and amorolfine showed no statistically significant change in their nail penetration rates. Caffeine flux across the nail was found to correlate with the TOWL measurements, though no correlation existed for the more hydrophobic drugs. These data supported the notion that the nail pores, opened up by the infection, facilitated the passage of hydrophilic molecules, whilst the keratin binding of hydrophobic molecules meant that their transport through the nail plate was unchanged. Therefore, in order to exploit the structural changes induced by nail fungal infection it would be beneficial to develop a small molecular weight, hydrophilic antifungal agent, which exhibits low levels of keratin binding. PMID- 26969265 TI - Examinations of maternal uniparental disomy and epimutations for chromosomes 6, 14, 16 and 20 in Silver-Russell syndrome-like phenotypes. AB - BACKGROUND: Silver-Russell syndrome (SRS) is a growth retardation disorder with a very broad molecular and clinical spectrum. Whereas the association of SRS with imprinting disturbances of chromosomes 11p15.5 and 7 is generally accepted, there are controversial discussions on the involvement of other molecular changes. The recent reports on the occurrence of maternal uniparental disomies of chromosomes 6, 16 and 20 (upd(6, 16, 20)mat), as well as 14q32 imprint alterations in patients with SRS phenotypes raise the question on the involvement of these mutations in the etiology of SRS. METHODS: A cohort of 54 growth retarded patients with SRS features was screened for aberrant methylation patterns of chromsomes 6, 14, 16 and 20. RESULTS: One carrier of a 14q32 epimutation was identified whereas epimutations and maternal UPD for chromosomes 6, 16 and 20 were excluded. CONCLUSIONS: Our data and those from the literature confirm that 14q32 disturbances significantly contribute to the mutation spectrum in this cohort. Furthermore, maternal uniparental disomy of chromosomes 6, 16 and 20 can be observed, but are rare. In case they occur they can be regarded as causative for clinical features. PMID- 26969267 TI - Are Antibiotics Useful for Chronic Rhinosinusitis? PMID- 26969266 TI - Evolutionary genetics of maternal effects. AB - Maternal genetic effects (MGEs), where genes expressed by mothers affect the phenotype of their offspring, are important sources of phenotypic diversity in a myriad of organisms. We use a single-locus model to examine how MGEs contribute patterns of heritable and nonheritable variation and influence evolutionary dynamics in randomly mating and inbreeding populations. We elucidate the influence of MGEs by examining the offspring genotype-phenotype relationship, which determines how MGEs affect evolutionary dynamics in response to selection on offspring phenotypes. This approach reveals important results that are not apparent from classic quantitative genetic treatments of MGEs. We show that additive and dominance MGEs make different contributions to evolutionary dynamics and patterns of variation, which are differentially affected by inbreeding. Dominance MGEs make the offspring genotype-phenotype relationship frequency dependent, resulting in the appearance of negative frequency-dependent selection, while additive MGEs contribute a component of parent-of-origin dependent variation. Inbreeding amplifies the contribution of MGEs to the additive genetic variance and, therefore enhances their evolutionary response. Considering evolutionary dynamics of allele frequency change on an adaptive landscape, we show that this landscape differs from the mean fitness surface, and therefore, under some condition, fitness peaks can exist but not be "available" to the evolving population. PMID- 26969268 TI - Psychometric Field Study of Hereditary Angioedema Quality of Life Questionnaire for Adults: HAE-QoL. AB - BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) may affect health-related quality of life (HRQoL). A specific HRQoL questionnaire for adult patients with C1-INH-HAE, the HAE-QoL, has recently been developed in Spain. OBJECTIVE: The objective of this study was to perform a cross-cultural validation and psychometric study of the HAE-QoL in an international setting. METHODS: Cross-cultural adaptation of the Spanish HAE-QoL draft version and an international rating phase with experts were performed. The resultant version of the HAE-QoL, a clinical questionnaire, and Short Form 36-item Health Survey Version 2.0 (SF-36v2) were pilot tested internationally. Item reduction was based on both descriptive and exploratory factor analysis. Psychometric properties were assessed. RESULTS: Cross-cultural adaptation of the HAE-QoL was performed in 18 countries. The draft version of the HAE-QoL was pilot tested in 332 patients, and accurate data were obtained from 290 patients from 11 countries. The reduction process resulted in a new version with 25 items and 7 dimensions (treatment difficulties, physical functioning and health, disease-related stigma, emotional role and social functioning, concern about offspring, perceived control over illness, and mental health). Strong psychometric properties were observed (Cronbach's alpha 0.92; test-retest reliability 0.87). Convergent validity showed mild to moderate correlations with SF-36v2 physical and mental component summaries (0.45 and 0.64, respectively) and with SF-36v2 dimensions (P < .004). HAE-QoL scores discriminated significantly among severity groups (median: asymptomatic 133.5 vs severe 84.0; P < .001); between patients with and without long-term prophylaxis (median: 101 vs 90; P = .001); and between patients with and without psychiatric and/or psychological care (median: 74 vs 103; P <= .001). CONCLUSIONS: The HAE-QoL, currently available in 18 languages, showed good reliability and validity evidence. PMID- 26969269 TI - Revisiting Desensitization and Allergen Immunotherapy Concepts for the International Classification of Diseases (ICD)-11. AB - Allergy and hypersensitivity intervention management procedures, such as desensitization and/or tolerance induction and immunotherapy, have not been pondered up to now in the content of International Classification of Diseases (ICD) context because the focus has been on prioritizing the condition implementations. Tremendous efforts have been devoted to implementing allergic and hypersensitivity conditions in the forthcoming ICD-11. However, we consider that it is crucial now to have nomenclature and classification universally accepted for these procedures to be able to provide scientifically consistent proposals into the new ICD-11 platform for the best practice parameters of our specialty. With the aim of promoting a harmonized comprehension and aligning it with the ICD-11 revision, we have reviewed the definitions and concepts currently used for desensitization and/or tolerance induction and immunotherapy. We strongly believe that this review is a key instrument to support the allergy specialty identity into the ICD-11 framework and serves as a platform to perform positive quality improvement in clinical practice. PMID- 26969270 TI - Awareness of nonalcoholic steatohepatitis and associated practice patterns of primary care physicians and specialists. AB - BACKGROUND: The hepatic manifestation of metabolic syndrome is nonalcoholic fatty liver disease. Patients with nonalcoholic steatohepatitis, the progressive form of nonalcoholic fatty liver disease, have increased risk of fibrosis, cirrhosis and end-stage liver disease. Estimates of prevalence in the United States range from 20-30% for nonalcoholic fatty liver disease and 2-5% for nonalcoholic steatohepatitis; however, physician awareness of these diseases is limited. The purpose of this study was to determine the current level of physician awareness and practices in the diagnosis and management of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis within the United States. METHODS: Physicians were asked to participate in an online, 35-question survey about their awareness of various liver conditions and current practices. RESULTS: Of the 302 responding physicians, 152 were primary care physicians, and 150 were specialists (comprised of gastroenterologists and hepatologists). More specialists than primary care physicians reported that they were aware of the differences between nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (p < 0.001) and that they routinely screened for nonalcoholic fatty liver disease (p < 0.001) and nonalcoholic steatohepatitis (p < 0.001). Almost half of the responding primary care physicians reported being unfamiliar with the nonalcoholic fatty liver disease and nonalcoholic steatohepatitis differences even though they were aware of both, yet 58% of those primary care physicians were treating patients with nonalcoholic fatty liver disease and/or nonalcoholic steatohepatitis. In addition, those primary care physicians who reported being unfamiliar with nonalcoholic steatohepatitis were treating an average of 3.7 patients and reported being as likely as familiar primary care physicians to treat new patients with nonalcoholic steatohepatitis. More than half of the specialists used noninvasive diagnostic test to confirm nonalcoholic steatohepatitis, and 10% of the specialists reported treating patients with drugs not recommended by the current guidelines. CONCLUSIONS: Despite reporting they were not familiar with nonalcoholic steatohepatitis, primary care physicians reported they would likely continue to diagnose and manage patients with nonalcoholic steatohepatitis; therefore, more physician education on the recent practice guideline for nonalcoholic fatty liver disease and nonalcoholic steatohepatitis is needed. PMID- 26969271 TI - Effect of Sibling Birth on BMI Trajectory in the First 6 Years of Life. AB - BACKGROUND AND OBJECTIVE: This study examined the longitudinal association between birth of a sibling and changes in body mass index z-score (BMIz) trajectory during the first 6 years of life. METHODS: Children (n = 697) were recruited across 10 sites in the United States at the time of birth. Sibship composition was assessed every 3 months. Anthropometry was completed when the child was age 15 months, 24 months, 36 months, 54 months, and in first grade. Children were classified based on the timing of their sibling's birth. A piecewise quadratic regression model adjusted for potential confounders examined the association of the birth of a sibling with subsequent BMIz trajectory. RESULTS: Children whose sibling was born when they were 24 to 36 months or 36 to 54 months old, compared with children who did not experience the birth of a sibling by first grade, had a lower subsequent BMIz trajectory and a significantly lower BMIz at first grade (0.27 vs 0.51, P value = 0.04 and 0.26 vs 0.51, P value = 0.03, respectively). Children who did not experience the birth of a sibling by the time they were in first grade had 2.94 greater odds of obesity (P value = 0.046) at first grade compared with children who experienced the birth of a sibling when they were between 36 to 54 months old. CONCLUSIONS: A birth of a sibling when the child is 24 to 54 months old is associated with a healthier BMIz trajectory. Identifying the underlying mechanism of association can help inform intervention programs. PMID- 26969273 TI - Antimicrobial Resistance and Urinary Tract Infection Recurrence. AB - BACKGROUND: The Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial found that recurrent urinary tract infections (rUTI) with resistant organisms were more common in the trimethoprim-sulfamethoxazole prophylaxis (TSP) arm. We describe factors associated with trimethoprim-sulfamethoxazole (TMP-SMX) resistance of rUTIs in RIVUR. METHODS: Children aged 2 to 71 months with first or second UTI (index UTI) and grade I to IV vesicoureteral reflux (VUR) were randomized to TSP or placebo and followed for 2 years. Factors associated with TMP-SMX-resistant rUTI were evaluated. RESULTS: Among 571 included children, 48% were <12 months old, 43% had grade II VUR, and 38% had grade III VUR. Recurrent UTI occurred in 34 of 278 children receiving TSP versus 67 of 293 children receiving placebo. Among those with rUTI, 76% (26/34) of subjects receiving TSP had TMP-SMX-resistant organisms versus 28% (19/67) of subjects receiving placebo (P < .001). The proportion of TMP-SMX-resistant rUTI decreased over time: in the TSP arm, 96% were resistant during the initial 6 months versus 38% resistant during the final 6 months; corresponding proportions for the placebo arm were 32% and 11%. Among children receiving TSP, 7 (13%) of 55 with TMP-SMX-resistant index UTI had rUTI, whereas 27 (12%) of 223 with TMP-SMX-susceptible index UTI had rUTI (adjusted hazard ratio 1.38, 95% confidence interval 0.54-3.56). Corresponding proportions in placebo arm were 17 (26%) of 65 and 50 (22%) of 228 (adjusted hazard ratio 1.33, 95% confidence interval 0.74-2.38). CONCLUSIONS: Although TMP SMX resistance is more common among children treated with TSP versus placebo, resistance decreased over time. Among children treated with TSP, there was no significant difference in UTI recurrence between those with TMP-SMX-resistant index UTI versus TMP-SMX-susceptible UTI. PMID- 26969274 TI - MAPK13 is preferentially expressed in gynecological cancer stem cells and has a role in the tumor-initiation. AB - Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as small subpopulation of cancer cells that are endowed with higher tumor-initiating ability. CSCs/CICs are resistant to standard cancer therapies including chemotherapy and radiotherapy, and they are thus thought to be responsible for cancer recurrence and metastasis. Therefore, elucidation of molecular mechanisms of CSCs/CICs is essential to cure cancer. In this study, we analyzed the gene expression profiles of gynecological CSCs/CICs isolated as aldehyde dehydrogenase high (ALDH(high)) cells, and found that MAPK13, PTTG1IP, CAPN1 and UBQLN2 were preferentially expressed in CSCs/CICs. MAPK13 is expressed in uterine, ovary, stomach, colon, liver and kidney cancer tissues at higher levels compared with adjacent normal tissues. MAPK13 gene knockdown using siRNA reduced the ALDH(high) population and abrogated the tumor-initiating ability. These results indicate that MAPK13 is expressed in gynecological CSCs/CICs and has roles in the maintenance of CSCs/CICs and tumor-initiating ability, and MAPK13 might be a novel molecular target for treatment-resistant CSCs/CICs. PMID- 26969272 TI - Leukocyte Telomere Length in Newborns: Implications for the Role of Telomeres in Human Disease. AB - BACKGROUND AND OBJECTIVE: In adults, leukocyte telomere length (LTL) is variable, familial, and longer in women and in offspring conceived by older fathers. Although short LTL is associated with atherosclerotic cardiovascular disease, long LTL is associated with major cancers. The prevailing notion is that LTL is a "telomeric clock," whose movement (expressed in LTL attrition) reflects the pace of aging. Accordingly, individuals with short LTL are considered to be biologically older than their peers. Recent studies suggest that LTL is largely determined before adulthood. We examined whether factors that largely characterize LTL in adults also influence LTL in newborns. METHODS: LTL was measured in blood samples from 490 newborns and their parents. RESULTS: LTL (mean +/- SD) was longer (9.50 +/- 0.70 kb) in newborns than in their mothers (7.92 +/- 0.67 kb) and fathers (7.70 +/- 0.71 kb) (both P < .0001); there was no difference in the variance of LTL among the 3 groups. Newborn LTL correlated more strongly with age-adjusted LTL in mothers (r = 0.47; P < .01) than in fathers (r = 0.36; P < .01) (P for interaction = .02). Newborn LTL was longer by 0.144 kb in girls than in boys (P = .02), and LTL was longer by 0.175 kb in mothers than in fathers (P < .0001). For each 1-year increase in father's age, newborn LTL increased by 0.016 kb (95% confidence interval: 0.04 to 0.28) (P = .0086). CONCLUSIONS: The large LTL variation across newborns challenges the telomeric clock model. Having inherently short or long LTL may be largely determined at birth, anteceding by decades disease manifestation in adults. PMID- 26969275 TI - Hippocampal Src kinase is required for novelty-induced enhancement of contextual fear extinction. AB - Exposure to a novel environment enhances the extinction of contextual fear through the "tagging-and-capture" process. However, the underlying molecular mechanisms of novelty-induced enhancement of fear extinction are still unclear. NMDA receptor activity was recently revealed to be required for the enhancement of fear extinction caused by exposure to novelty. Src family kinases (SFKs) act as a molecular hub for regulation of NMDA receptors. We hypothesized that SFKs might be involved in novelty-induced enhancement of fear extinction. We found that the enhancement of fear extinction induced by novelty exposure is accompanied by Src kinase phosphorylation and activation in a restricted time window. Furthermore, intrahippocampal infusion of SFKs inhibitor PP2 inhibits Src kinase phosphorylation and activation, attenuates the activation of NR2B containing NMDA receptors, and thereby reverses the enhancement of fear extinction induced by novelty exposure. These results suggested that Src kinase may serve as a behavioral tag in the procedural enhancement of fear extinction by novelty exposure. PMID- 26969276 TI - Inhibition of deubiquitinating activity of USP14 decreases tyrosine hydroxylase phosphorylated at Ser19 in PC12D cells. AB - Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis, and its stability is a fundamental factor to maintain the level of the catecholamines in cells. However, the intracellular stability determined by the degradation pathway remains unknown. In this study, we investigated the mechanism by which phosphorylation of TH affected the proteasome pathway. The inhibition of proteasomes by MG-132 increased the percentage of TH molecules phosphorylated at their Ser19, Ser31 and/or Ser40 among the total TH proteins to about 70% in PC12D cells over a 24-hr period; although the percentage of phosphorylated TH molecules was about 20% under basal conditions. Moreover, the inhibition of proteasomes by epoxomicin with high specificity increased primarily the quantity of TH molecules phosphorylated at their Ser19. The phosphorylation of Ser19 potentiated Ser40 phosphorylation in cells by a process known as hierarchical phosphorylation. Therefore, the proteasome inhibition might result in an increase in the levels of all 3 phosphorylated TH forms, thus complicating interpretation of data. Conversely, activation of proteasome degradation by IU-1, which is an inhibitor for the deubiquitinating activity of USP14, decreased only the quantity of TH molecules phosphorylated at their Ser19, although it did not decrease that of TH phosphorylated at its Ser31 and Ser40 or that of TH molecules. These results suggest that the phosphorylation of Ser19 in the N terminal portion of TH is critical as a trigger for the degradation of this enzyme by the ubiquitin-proteasome pathway. PMID- 26969277 TI - A Woman With a Purpuric Rash and Weakness. PMID- 26969278 TI - Recognizing Cyanosis. PMID- 26969279 TI - Wilkie's syndrome An uncommon cause of small bowel obstruction in a young patient. AB - Superior mesenteric artery (SMA) syndrome, also named as Wilkie's syndrome, is a rare, potentially life-threatening gastro- vascular disorder and an uncommon cause of proximal bowel obstruction characterized by a compression of the third and final portion of the duodenum by the abdominal aorta and the overlying superior mesenteric artery. There isn't a consensus regarding to the optimal treatment of this condition. We describe a case of Wilkie's syndrome in a young female with characteristic symptoms of upper intestinal obstruction, whose diagnosis was delayed for 2 years. KEY WORDS: Superior mesenteric artery, Upper intestinal occlusion, Young female. PMID- 26969280 TI - Decreasing translation error rate in Escherichia coli increases protein function. AB - BACKGROUND: Over-expressed native or recombinant proteins are commonly used for industrial and pharmaceutical purposes, as well as for research. Proteins of interest need to be purified in sufficient quantity, quality and specific activity to justify their commercial price and eventual medical use. Proteome quality was previously positively correlated with ribosomal fidelity, but not on a single protein level. Here, we show that decreasing translational error rate increases the activity of single proteins. In order to decrease the amount of enzyme needed for catalysis, we propose an expression system bearing rpsL141 mutation, which confers high ribosomal fidelity. Using alpha-glucosidase (exo alpha-1,4-glucosidase) and beta-glucanase (beta-D-glucanase) as examples, we show that proteins purified from Escherichia coli bearing rpsL141 mutation have superior activity compared to those purified from wild type E. coli, as well as some commercially available industrial enzymes. RESULTS: Our results indicate that both alpha-glucosidase and beta-glucanase isolated from E. coli bearing rpsL141 mutation have increased activity compared to those isolated from wild type E. coli. Alpha-glucosidase from rpsL141 background has a higher activity than the purchased enzymes, while beta-glucanase from the same background has a higher activity compared to the beta-glucanase purchased from Sigma, but not compared to the one purchased from Megazyme. CONCLUSION: Reduction of the error rate in protein biosynthesis via ribosomal rpsL141 mutation results in superior functionality of single proteins. We conclude that this is a viable system for expressing proteins with higher activity and that it can be easily scaled up and combined with other expression systems to meet the industrial needs. PMID- 26969281 TI - Lipoprotein binding to anionic biopolyelectrolytes and the effect of glucose on nanoplaque formation in arteriosclerosis and Alzheimer's disease. AB - Arteriosclerosis with its clinical sequelae (cardiac infarction, stroke, peripheral arterial occlusive disease) and vascular/Alzheimer dementia not only result in far more than half of all deaths but also represent dramatic economic problems. The reason is, among others, that diabetes mellitus is an independent risk factor for both disorders, and the number of diabetics strongly increases worldwide. More than one-half of infants in the first 6months of life have already small collections of macrophages and macrophages filled with lipid droplets in susceptible segments of the coronary arteries. On the other hand, the authors of the Bogalusa Heart Study found a strong increase in the prevalence of obesity in childhood that is paralleled by an increase in blood pressure, blood lipid concentration, and type 2 diabetes mellitus. Thus, there is a clear linkage between arteriosclerosis/Alzheimer's disease on the one hand and diabetes mellitus on the other hand. Furthermore, it has been demonstrated that distinct apoE isoforms on the blood lipids further both arteriosclerotic and Alzheimer nanoplaque formation and therefore impair flow-mediated vascular reactivity as well. Nanoplaque build-up seems to be the starting point for arteriosclerosis and Alzheimer's disease in their later full clinical manifestation. In earlier work, we could portray the anionic biopolyelectrolytes syndecan/perlecan as blood flow sensors and lipoprotein receptors in cell membrane and vascular matrix. We described extensively molecular composition, conformation, form and function of the macromolecule heparan sulfate proteoglycan (HS-PG). In two supplementary experimental settings (ellipsometry, myography), we utilized isolated HS-PG for in vitro nanoplaque investigations and isolated human coronary artery segments for in vivo tension measurements. With the ellipsometry-based approach, we were successful in establishing a direct connection on a molecular level between diabetes mellitus on the one side and arteriosclerosis/Alzheimer's disease on the other side. Application of glucose at a concentration representative for diabetics and leading to glycation of proteins and lipids, entailed a significant increase in arteriosclerotic and Alzheimer nanoplaque formation. IDLapoE4/E4 was by far superior to IDLapoE3/E3 in plaque build-up, both in diabetic and non diabetic patients. Recording vascular tension of flow-dependent reactivity in blood substitute solution and under application of different IDLapoE isoforms showed an impaired vasorelaxation for pooled IDL and IDLapoE4/E4, thus confirming the ellipsometric investigations. Incubation in IDLapoE0/E0 (apoE "knockout man"), however, resulted in a massive flow-mediated contraction, also complemented by strongly aggregated nanoplaques. In contrast, HDL was shown to present a powerful protection against nanoplaque formation on principle, both in the in vitro model and the in vivo scenario on the endothelial cell membrane. The competitive interplay with LDL is highlighted through the flow experiment, where flow-mediated, HDL-induced vasodilatation remains untouched by additional incubation with LDL. This is due to the four times higher affinity for the proteoglycan receptor of HDL as compared to LDL. Taken together, the studies demonstrate that while simplistic, the ellipsometry approach and the endothelial mimicking proteoglycan-modified surfaces provide information on the initial steps of lipoprotein-related plaque formation, which correlates with findings on endothelial cells and blood vessels, and afford insight into the role of lipoprotein deposition and exchange phenomena at the onset of these pathophysiologies. PMID- 26969282 TI - Surfactant adsorption to soil components and soils. AB - Soils are complex and widely varying mixtures of organic matter and inorganic materials; adsorption of surfactants to soils is therefore related to the soil composition. We first discuss the properties of surfactants, including the critical micelle concentration (CMC) and surfactant adsorption on water/air interfaces, the latter gives an impression of surfactant adsorption to a hydrophobic surface and illustrates the importance of the CMC for the adsorption process. Then attention is paid to the most important types of soil particles: humic and fulvic acids, silica, metal oxides and layered aluminosilicates. Information is provided on their structure, surface properties and primary (proton) charge characteristics, which are all important for surfactant binding. Subsequently, the adsorption of different types of surfactants on these individual soil components is discussed in detail, based on mainly experimental results and considering the specific (chemical) and electrostatic interactions, with hydrophobic attraction as an important component of the specific interactions. Adsorption models that can describe the features semi quantitatively are briefly discussed. In the last part of the paper some trends of surfactant adsorption on soils are briefly discussed together with some complications that may occur and finally the consequences of surfactant adsorption for soil colloidal stability and permeability are considered. When we seek to understand the fate of surfactants in soil and aqueous environments, the hydrophobicity and charge density of the soil or soil particles, must be considered together with the structure, hydrophobicity and charge of the surfactants, because these factors affect the adsorption. The pH and ionic strength are important parameters with respect to the charge density of the particles. As surfactant adsorption influences soil structure and permeability, insight in surfactant adsorption to soil particles is useful for good soil management. PMID- 26969284 TI - Quantification of chemical contaminants in the paper and board fractions of municipal solid waste. AB - Chemicals are used in materials as additives in order to improve the performance of the material or the production process itself. The presence of these chemicals in recyclable waste materials may potentially affect the recyclability of the materials. The addition of chemicals may vary depending on the production technology or the potential end-use of the material. Paper has been previously shown to potentially contain a large variety of chemicals. Quantitative data on the presence of chemicals in paper are necessary for appropriate waste paper management, including the recycling and re-processing of paper. However, a lack of quantitative data on the presence of chemicals in paper is evident in the literature. The aim of the present work is to quantify the presence of selected chemicals in waste paper derived from households. Samples of paper and board were collected from Danish households, including both residual and source-segregated materials, which were disposed of (e.g., through incineration) and recycled, respectively. The concentration of selected chemicals was quantified for all of the samples. The quantified chemicals included mineral oil hydrocarbons, phthalates, phenols, polychlorinated biphenyls, and selected toxic metals (Cd, Co, Cr, Cu, Ni, and Pb). The results suggest large variations in the concentration of chemicals depending on the waste paper fraction analysed. Research on the fate of chemicals in waste recycling and potential problem mitigation measures should be focused on in further studies. PMID- 26969286 TI - A system dynamics-based environmental performance simulation of construction waste reduction management in China. AB - A huge amount of construction waste has been generated from increasingly higher number of construction activities than in the past, which has significant negative impacts on the environment if they are not properly managed. Therefore, effective construction waste management is of primary importance for future sustainable development. Based on the theory of planned behaviors, this paper develops a system dynamic model of construction waste reduction management at the construction phase to simulate the environmental benefits of construction waste reduction management. The application of the proposed model is shown using a case study in Shenzhen, China. Vensim is applied to simulate and analyze the model. The simulation results indicate that source reduction is an effective waste reduction measure which can reduce 27.05% of the total waste generation. Sorting behaviors are a premise for improving the construction waste recycling and reuse rates which account for 15.49% of the total waste generated. The environmental benefits of source reduction outweigh those of sorting behaviors. Therefore, to achieve better environmental performance of the construction waste reduction management, attention should be paid to source reduction such as low waste technologies and on-site management performance. In the meantime, sorting behaviors encouragement such as improving stakeholders' waste awareness, refining regulations, strengthening government supervision and controlling illegal dumping should be emphasized. PMID- 26969285 TI - The challenges of municipal solid waste management systems provided by public private partnerships in mature tourist destinations: The case of Mallorca. AB - This article analyzes the influence of tourism on the municipal solid waste management (MSWM) system taking as reference the case study of Mallorca, an internationally renowned destination. The characteristics of tourism such as seasonality and land scarcity, set interesting challenges to public-private partnerships related to MSWM system. The analysis of Mallorca's experience shows that land endowment strongly influences the choice of treatment technologies in tourism destinations. Furthermore, tourism seasonality significantly affects management costs which should be considered on PPP contracts. Finally, the tariff system in this kind of environmental PPPs in tourist destinations still need to improve to promote waste minimization and recycling. PMID- 26969283 TI - Plasmodium falciparum parasitaemia and clinical malaria among school children living in a high transmission setting in western Kenya. AB - BACKGROUND: Malaria among school children is increasingly receiving attention, yet the burden of malaria in this age group is poorly defined. This study presents data on malaria morbidity among school children in Bungoma county, western Kenya. METHOD: This study investigated the burden and risk factors of Plasmodium falciparum infection, clinical malaria, and anaemia among 2346 school children aged 5-15 years, who were enrolled in an individually randomized trial evaluating the effect of anthelmintic treatment on the risks of malaria. At baseline, children were assessed for anaemia and nutritional status and information on household characteristics was collected. Children were followed-up for 13 months to assess the incidence of clinical malaria by active detection, and P. falciparum infection and density evaluated using repeated cross-sectional surveys over 15 months. RESULTS: On average prevalence of P. falciparum infection was 42% and ranged between 32 and 48% during the five cross-sectional surveys. Plasmodium falciparum prevalence was significantly higher among boys than girls. The overall incidence of clinical malaria was 0.26 episodes per person year (95% confidence interval, 0.24-0.29) and was significantly higher among girls (0.23 versus 0.31, episodes per person years). Both infection prevalence and clinical disease varied by season. In multivariable analysis, P. falciparum infection was associated with being male, lower socioeconomic status and stunting. The risk of clinical malaria was associated with being female. CONCLUSION: These findings show that the burden of P. falciparum parasitaemia, clinical malaria and anaemia among school children is not insignificant, and suggest that malaria control programmes should be expanded to include this age group. PMID- 26969288 TI - A study on synthesis of energy fuel from waste plastic and assessment of its potential as an alternative fuel for diesel engines. AB - The demand for plastic is ever increasing and has produced a huge amount of plastic waste. The management and disposal of plastic waste have become a major concern, especially in developing cities. The idea of waste to energy recovery is one of the promising techniques used for managing the waste plastic. This paper assesses the potential of using Waste Plastic Oil (WPO), synthesized using pyrolysis of waste plastic, as an alternative for diesel fuel. In this research work, the performance and emission characteristics of a single cylinder diesel engine fuelled with WPO and its blends with diesel are studied. In addition to neat plastic oil, three blends (PO25, PO50 and PO75) were prepared on a volumetric basis and the engine was able to run on neat plastic oil. Brake thermal efficiency of blends was lower compared to diesel, but PO25 showed similar performance to that of diesel. The emissions were reduced considerably while using blends when compared to neat plastic oil. The smoke and NOX were reduced by 22% and 17.8% respectively for PO25 than that of plastic oil. PMID- 26969287 TI - Investigation on an innovative technology for wet separation of plastic wastes. AB - This paper presents an original device for the separation of plastic polymers from mixtures. Due to the combination of a characteristic flow pattern developing within the apparatus and density, shape and size differences among two or more polymers, this device allows their separation into two products, one collected within the instrument and the other one expelled through its outlet ducts. Experimental tests have been conducted to investigate the effectiveness of the apparatus, using two geometric arrangements, nine hydraulic configurations and three selections of polymers at three stages of a material life cycle. Tests with samples composed of a single typology of polymer have been used to understand the interaction between the particles and the carrying fluid within the apparatus in different hydraulic configurations and geometric arrangements. Multi-material tests are essential to simulate the real conditions in an industrial recycling plant. The separation results have been evaluated in terms of grade and recovery of a useful material. Under the proper hydraulic configurations, the experimentation showed that it is possible to produce an almost pure concentrate of Polyethylene Terephthalate (PET) from a mixture of 85% PET and 15% Polycarbonate (PC) (concentrate grade and recovery equal to 99.5% and 95.1%) and a mixture of 85% PET and 15% Polyvinyl Chloride (PVC) (concentrate grade and recovery equal to 97.9% and 100.0%). It is further demonstrated that almost pure concentrates of PVC and PC can be produced from a mixture of 85% PVC and 15% PC (PVC grade and recovery equal to 99.9% and 99.7%) and a mixture of 85% PC and 15% PVC (PC grade and recovery equal to 99.0% and 99.5%). PMID- 26969289 TI - Copper leaching from electronic waste for the improvement of gold recycling. AB - Gold recovery from electronic waste material with high copper content was investigated at ambient conditions. A chemical preliminary treatment was found necessary to remove the large quantities of copper before the precious metal can be extracted. For this purpose inorganic acids (HCl, HNO3 and H2SO4) and two organic substances EDTA and citrate, were tested. The effect of auxiliary oxidants such as air, ozone and peroxide hydroxide was studied. In pretreatments with peroxide and HCl or citrate, copper extractions greater than 90% were achieved. In the second leaching stage for gold recovery, the solid residue of the copper extraction was contacted with thiourea solutions, resulting in greater than 90% gold removal after only one hour of reaction. PMID- 26969291 TI - Re: Atrophy of the anterior digastric muscle: response to a prospective clinical study. PMID- 26969292 TI - Blood lead concentrations as a result of retained lead pellets in the craniomaxillofacial region in Benin City, Nigeria. AB - Patients who survive gunshot wounds often retain pellets in their bodies, which cause delayed morbidity from lead poisoning, and even death. Our aim was to find out whether there is a high concentration of lead in the blood of patients who have asymptomatic retention of lead pellets in the craniomaxillofacial region. We prospectively studied 28 patients who were admitted to our hospital with gunshot injuries to the region, and 28 control subjects. Each was originally recruited three days after injury. The control subjects were chosen from people who lived in the same household or worked in the same place as the patients. Any previous exposure to lead was excluded. Blood samples were collected three days and three months after injury and analysed for the presence of lead by atomic absorption spectrophotometry. The mean (SD) age for both patients and control subjects was 33 (12) years. The mean (SD) and range of concentrations of lead in patients three days after injury was 0.11 (0.07), range 0.01-0.32MUmol/L, while those of the control subjects were 0.03 (0.02) and 0-0.06, respectively. Three months after injury, the mean (SD) and range of concentrations of the patients were 0.30 (0.11) and 0.12-0.59MUmol/L, while those of the control subjects were 0-1.25 and 0.12 (0.006) MUmol/L, respectively (p= 0.000). The study showed a higher mean blood lead concentration in patients with gunshot injuries than in control subjects, but lower than the threshold values published by the Centers for Disease Control/Occupational Health and Safety Administration in the United States. PMID- 26969293 TI - The role of primary care providers in patient activation and engagement in self management: a cross-sectional analysis. AB - BACKGROUND: The increasing burden of chronic illness highlights the importance of self-care and shifts from hierarchical and patriarchal models to partnerships. Primary care providers (PCPs) play an important role in supporting patients in self-management, enabling activation and supporting chronic care. We explored the extent to which PCPs' beliefs about the importance of the patients' role relate to the frequency in which they report engaging in collaborative and partnership building behaviors with patients. METHODS: PCPs' beliefs were measured using the Clinician Support for Patient Activation Measure (CS-PAM). We also assessed whether PCPs' CS-PAM scores were positively associated with changes in their patients' Patient Activation Measure (PAM) scores. Participants included 181 PCPs from a single accountable care organization in Minnesota who completed an online survey. We conducted bivariate analyses and multivariate regression models to examine relationships between CS-PAM and PCP self-management support behaviors and changes in level of patient activation. RESULTS: PCPs with high CS-PAM scores were much more likely to engage in supportive self-management and patient behavior change approaches, such as involving the patient in agenda-setting, problem-solving, and collaboratively setting behavioral goals, than were PCPs with low CS-PAM scores. More positive PCPs' belief in the patients' role in self management was positively correlated with improvements in their patients' level of patient activation. CONCLUSIONS: More positive PCP beliefs about the patients' role in self-management was strongly related to PCP behaviors geared towards increasing patient activation. PMID- 26969295 TI - Response to Kottek and Kilpatrick, 'Estimating Occupational Exposure to Asbestos in Australia'. PMID- 26969296 TI - Behavioral flexibility predicts increased ability to resist excessive methamphetamine self-administration. AB - Drug addiction is often associated with cognitive deficits and behavioral inflexibility that may contribute to the development and maintenance of addictive behaviors by reducing addicts' ability to control their behavior toward the drug. In this study, we investigated the relationships between pre-drug levels of behavioral flexibility and the risk to develop uncontrolled methamphetamine (METH) self-administration. First, we measured individual performance in an inter dimensional set-shifting procedure in which animals have to switch between an external visual rule and an internal side rule in order to obtain food pellets. Then we allowed rats to self-administer METH for twenty long 14-hour sessions, and we investigated the relationships between behavioral flexibility and measures of control over drug intake. Rats rapidly acquired to self-administer high levels of METH which resulted in moderate weight loss. After several sessions of self administration, whereas some rats progressively increased their METH intake, other rats showed very long voluntary pauses between drug injections and showed no escalation in METH self-administration. Interestingly, we found that behavioral flexibility is correlated with METH self-administration and that more flexible rats take less METH and do not escalate drug taking. These results suggest that traits of behavioral flexibility may protect against the development of excessive and dysregulated drug taking. Conversely, the inability to adapt behavioral responses as a function of the environmental contingencies may contribute to the risks to develop addiction to METH. PMID- 26969294 TI - High genetic diversity of Staphylococcus aureus strains colonising the nasopharynx of Gambian villagers before widespread use of pneumococcal conjugate vaccines. AB - BACKGROUND: With the global efforts of reducing pneumococcal disease through widespread introduction of pneumococcal vaccines, concerns have emerged on the potential increase of morbidity and mortality from S. aureus disease. Little is known however, of the carriage rates of S. aureus or of its' relationship with carriage of S. pneumoniae in rural Africa, and West Africa in particular where very high rates of carriage of S. pneumoniae have been reported. This study aims to evaluate the prevalence, antibiotic susceptibility patterns and genotypes of S. aureus isolated from the nasopharynx of healthy individuals in rural Gambia before the introduction of routine use of pneumococcal conjugate vaccines in the country. RESULTS: Overall prevalence of S. aureus nasopharyngeal carriage was 25.2%. All S. aureus isolates tested were susceptible to methicillin. Resistant was observed for sulphamethoxazole-trimethoprim (15%) and tetracycline (34.3%). We found 59 different sequence types (ST), 35 of which were novel. The most prevalent sequence types were ST 15 (28%) and ST 5 (4%). Eighty two percent (494/600) of study individuals were S. pneumoniae carriers with S. pneumoniae carriage rates decreasing with increasing age groups. S. aureus carriage among pneumococcal carriers was slightly lower than among non-pneumococcal carriers (24.3 versus 29.3%; p = 0.324). There were no associations of carriage between these two bacteria across the 4 age groups. However, analysis of pooled data children < 2 years and children 2 to < 5 years of age showed a statistically significant inverse association (24.1 and 50.0% for S. aureus carriage among S. pneumoniae carriers and non-carriers respectively; p = 0.015). CONCLUSIONS: We report that nasopharyngeal carriage of S. aureus in rural Gambia is high in all age groups, with approximately 1 out of 4 individuals being carriers in the pre pneumococcal vaccination era. There are indications that nasopharyngeal carriage of S.aureus could be inversely related to carriage of S. pneumoniae amongst younger children in The Gambian and that S. aureus clones in The Gambia show significant genetic diversity suggesting worldwide dissemination. Findings from this study provide a useful background for impact studies evaluating the introduction of pneumococcal vaccines or other interventions targeting the control of S. aureus infections and disease. PMID- 26969297 TI - The reference phantoms: voxel vs polygon. AB - The International Commission on Radiological Protection (ICRP) reference male and female adult phantoms, described in Publication 110, are voxel phantoms based on whole-body computed tomography scans of a male and a female patient, respectively. The voxel in-plane resolution and the slice thickness, of the order of a few millimetres, are insufficient for proper segmentation of smaller tissues such as the lens of the eye, the skin, and the walls of some organs. The calculated doses for these tissues therefore present some limitations, particularly for weakly penetrating radiation. Similarly, the Publication 110 phantoms cannot represent 8-40-um-thick target regions in respiratory or alimentary tract organs. Separate stylised models have been used to represent these tissues for calculation of the ICRP reference dose coefficients (DCs). ICRP Committee 2 recently initiated a research project, the ultimate goal of which is to convert the Publication 110 phantoms to a high-quality polygon-mesh (PM) format, including all source and target regions, even those of the 8-40-um-thick alimentary and respiratory tract organs. It is expected that the converted phantoms would lead to the same or very similar DCs as the Publication 110 reference phantoms for penetrating radiation and, at the same time, provide more accurate DCs for weakly penetrating radiation and small tissues. Additionally, the reference phantoms in the PM format would be easily deformable and, as such, could serve as a starting point to create phantoms of various postures for use, for example, in accidental dose calculations. This paper will discuss the current progress of the phantom conversion project and its significance for ICRP DC calculations. PMID- 26969298 TI - Measures for environmental conservation in enclosed coastal seas. AB - With putting a focus on the balance among the nutrient salts such as nitrogen and phosphorus, the Ministry of the Environment (MOE) developed the Action Plan for Healthy Material Circulation in Ocean (just called the Healthy Plan). The plan aims to facilitate the healthy and smooth circulation of the nutrients with an integrated management over land and sea as a package in respective sea areas. The Healthy Plan is now in a pilot phase and is to be implemented for some selected model regions. Meanwhile, devastating tsunamis caused by the Great East Japan Earthquake on March 11th, 2011 severely damaged the natural environments in the affected regions. In the affected bays, seaweed beds and spawning grounds disappeared in a blink. MOE has launched on the recovery activities of Zostera (eelgrass) beds, using the concepts and the methods used in the "Sato-umi Creation" activity which is a purposeful environmental recovery project. PMID- 26969299 TI - Cognitive remediation versus active computer control in bipolar disorder with psychosis: study protocol for a randomized controlled trial. AB - BACKGROUND: Cognitive dysfunction is a major feature of bipolar disorder with psychosis and is strongly associated with functional outcomes. Computer-based cognitive remediation has shown promise in improving cognition in patients with schizophrenia. However, despite similar neurocognitive deficits between patients with schizophrenia and bipolar disorder, few studies have extended neuroscience based cognitive remediation programs to this population. METHODS/DESIGN: The Treatment to Enhance Cognition in Bipolar Disorder study is an investigator initiated, parallel group, randomized, blinded clinical trial of an Internet based cognitive remediation protocol for patients with bipolar disorder I with psychosis (n = 100). We also describe the development of our dose-matched active control paradigm. Both conditions involve 70 sessions of computer-based activities over 24 weeks. The control intervention was developed to mirror the treatment condition in dose and format but without the neuroplasticity-based task design and structure. All participants undergo neuropsychological and clinical assessment at baseline, after approximately 25 hours of study activities, post treatment, and after 6 months of no study contact to assess durability. Neuroimaging at baseline and post treatment are offered in an "opt-in" format. The primary outcomes are scores on the MATRICS battery; secondary and exploratory outcomes include measures of clinical symptoms, community functioning, and neuroimaging changes. Associations between change in cognitive measures and change in community functioning will be assessed. Baseline predictors of treatment response will be examined. DISCUSSION: The present study is the first we are aware of to implement an Internet-based cognitive remediation program in patients with bipolar disorder with psychosis and to develop a comparable web based control paradigm. The mixed online and study-site format allows accessible treatment while providing weekly staff contact and bridging. Based on user provided feedback, participant blinding is feasible. TRIAL REGISTRATION: ClinicalTrials.gov NCT01470781 ; 11 July 2011. PMID- 26969300 TI - Inhibition of SOX2 induces cell apoptosis and G1/S arrest in Ewing's sarcoma through the PI3K/Akt pathway. AB - BACKGROUND: Ewing's sarcoma is an aggressive bone and soft tissue tumor with a high incidence in children and adolescents. Due to its high malignancy and poor prognosis, identification of novel biomarkers for intervention therapies is necessary to improve outcome. The EWS/FLI1 fusion gene is a characteristic of Ewing's sarcoma in most cases. Sex determining region Y-box 2 (SOX2) is a primary target of EWS/FLI1. It has been identified as an oncogene and linked to apoptotic resistance in several types of cancer. However, its role and regulatory mechanisms in Ewing's sarcoma are largely unknown. METHODS: We systematically investigated the role of SOX2 in Ewing's sarcoma cell lines, human tissue samples and xenograft models. The expression of SOX2 was detected in Ewing's sarcoma samples by WB and IHC. siRNAs were used to knockdown EWS/FLI1 and SOX2 in A673 and RD-ES cell lines with the efficiencies tested by qRT-PCR and WB. The effect of SOX2 on cell cycle and apoptosis was determined by Flow cytometric and TUNEL assays. Akt overexpression was performed with plasmid. The protein expression of the corresponding factors was examined by WB analysis. Inhibition of SOX2 in vivo was performed by siRNA against SOX2 in xenograft models, and the protein expression of the regulators testified in vitro was examined in xenograft tumors by IHC and WB. RESULTS: The results confirmed that SOX2 was highly expressed in Ewing's sarcoma and was the target of EWS/FLI1. SOX2 advanced Ewing's sarcoma cell survival and proliferation by regulating p21, p27 and cyclin-E to facilitate G1/S phase transition and mediating caspase-3, PARP via both extrinsic (Fas and caspase-8) and intrinsic (caspase-9, Bad, Bcl-2 and XIAP) apoptotic pathways to restrain cell apoptosis. Additionally, SOX2 regulated the cell-cycle progression and apoptosis via activation of the PI3K/Akt signaling pathway. The mechanisms were proved both in vitro and in vivo. CONCLUSIONS: The results demonstrate that SOX2 played a central role in promoting Ewing's sarcoma cell proliferation in vitro and in vivo with the underlying mechanisms expounded. These findings suggest that SOX2 may serve as a potential biomarker for targeted intervention in Ewing's sarcoma. PMID- 26969301 TI - Association of serum electrolytes and smoking with salivary gland stone formation. AB - To further define potential factors that may contribute to stone formation in salivary glands (sialolithiasis), a retrospective chart review was performed of patients diagnosed with sialolithiasis between March 1, 1998 and February 29, 2012. Information on salivary gland stone number, location and size, medical history, medications, and serum electrolyte levels were collected. Associations between electrolyte levels and stone characteristics (such as stone number and size) were examined. Fifty-nine patients were identified; their median age was 58 years (range 25-89 years) and most were male (95%). Salivary stones were most commonly located in the submandibular glands (83%). Thirty-five patients (59%) had a smoking history, with 16 (27%) reported as current smokers. There was a significant association between current smoker status and stone size (mean largest stone size 12.4+/-8.8mm vs. 7.5+/-4.8mm in current smokers vs. non smokers; P=0.03). Serum sodium levels (r=0.32, P=0.014) and serum potassium levels (r=0.31, P=0.017) showed significant positive correlations with stone size. While the aetiology of sialolithiasis remains unclear, smoking (which can contribute to reduced saliva flow) and higher serum sodium levels (which can reflect volume depletion) are associated with larger salivary stones. PMID- 26969304 TI - Optical models of the human eye. AB - Optical models of the human eye have been used in visual science for purposes such as providing a framework for explaining optical phenomena in vision, for predicting how refraction and aberrations are affected by change in ocular biometry and as computational tools for exploring the limitations imposed on vision by the optical system of the eye. We address the issue of what is understood by optical model eyes, discussing the 'encyclopaedia' and 'toy train' approaches to modelling. An extensive list of purposes of models is provided. We discuss many of the theoretical types of optical models (also schematic eyes) of varying anatomical accuracy, including single, three and four refracting surface variants. We cover the models with lens structure in the form of nested shells and gradient index. Many optical eye models give accurate predictions only for small angles and small fields of view. If aberrations and image quality are important to consider, such 'paraxial' model eyes must be replaced by 'finite model' eyes incorporating features such as aspheric surfaces, tilts and decentrations, wavelength-dependent media and curved retinas. Many optical model eyes are population averages and must become adaptable to account for age, gender, ethnicity, refractive error and accommodation. They can also be customised for the individual when extensive ocular biometry and optical performance data are available. We consider which optical model should be used for a particular purpose, adhering to the principle that the best model is the simplest fit for the task. We provide a glimpse into the future of optical models of the human eye. This review is interwoven with historical developments, highlighting the important people who have contributed so richly to our understanding of visual optics. PMID- 26969303 TI - Incidence of atypical nevi in Olmsted County: an epidemiological study. AB - BACKGROUND: The association of atypical nevi with melanoma and other forms of skin cancer has not been clearly defined. METHODS: We studied 631 patients with first lifetime diagnosis of mild, moderate or severely atypical nevus from 2000 through 2005, identified through a population-based approach. RESULTS: Age at first diagnosis differed significantly between men and women (p<.001). Incidence rates peaked in the second through fourth decades in women and in the third, sixth and seventh decades in men. From 2000 through 2005, the overall age- and sex-adjusted incidence rate of all degrees of atypical nevi was 76.0 per 100,000 person-years. There were no statistically significant associations identified between the degree of atypia and the future development of basal cell carcinoma, squamous cell carcinoma or MM (p = 0.51, p = 0.28 and p = 0.19, respectively). CONCLUSION: There is no association between atypical nevi and the subsequent development of non-melanoma skin cancer and MM. Incidence rates of atypical nevi are higher among younger women and older men. The association between degree of atypia and malignant melanoma warrants further study. PMID- 26969305 TI - Abortion experiences among Zanzibari women: a chain-referral sampling study. AB - BACKGROUND: In Zanzibar, a semi-autonomous region of Tanzania, induced abortion is illegal but common, and fewer than 12% of married reproductive-aged women use modern contraception. As part of a multi-method study about contraception and consequences of unwanted pregnancies, the objective of this study was to understand the experiences of Zanzibari women who terminated pregnancies. METHODS: The cross-sectional study was set in Zanzibar, Tanzania. Participants were a community-based sample of women who had terminated pregnancies. We carried out semi-structured interviews with 45 women recruited via chain-referral sampling. We report the characteristics of women who have had abortions, the reasons they had abortions, and the methods used to terminate their pregnancies. RESULTS: Women in Zanzibar terminate pregnancies that are unwanted for a range of reasons, at various points in their reproductive lives, and using multiple methods. While clinical methods were most effective, nearly half of our participants successfully terminated a pregnancy using non-clinical methods and very few had complications requiring post abortion care (PAC). CONCLUSIONS: Even in settings where abortion is illegal, some women experience illegal abortions without adverse health consequences, what we might call 'safer' unsafe abortions; these kinds of abortion experiences can be missed in studies about abortion conducted among women seeking PAC in hospitals. PMID- 26969302 TI - Presynaptic BK channels control transmitter release: physiological relevance and potential therapeutic implications. AB - BK channels are large conductance potassium channels characterized by four pore forming alpha subunits, often co-assembled with auxiliary beta and gamma subunits to regulate Ca(2+) sensitivity, voltage dependence and gating properties. Abundantly expressed in the CNS, they have the peculiar characteristic of being activated by both voltage and intracellular calcium rise. The increase in intracellular calcium via voltage-dependent calcium channels (Cav ) during spiking triggers conformational changes and BK channel opening. This narrows the action potential and induces a fast after-hyperpolarization that shuts calcium channels. The tight coupling between BK and Cav channels at presynaptic active zones makes them particularly suitable for regulating calcium entry and neurotransmitter release. While in most synapses, BK channels exert a negative control on transmitter release under basal conditions, in others they do so only under pathological conditions, serving as an emergency brake to protect against hyperactivity. In particular cases, by interacting with other channels (i.e. limiting the activation of the delayed rectifier and the inactivation of Na(+) channels), BK channels induce spike shortening, increase in firing rate and transmitter release. Changes in transmitter release following BK channel dysfunction have been implicated in several neurological disorders including epilepsy, schizophrenia, fragile X syndrome, mental retardation and autism. In particular, two mutations, one in the alpha and one in the beta3 subunit, resulting in a gain of function have been associated with epilepsy. Hence, these discoveries have allowed identification of BK channels as new drug targets for therapeutic intervention. PMID- 26969306 TI - Health-related quality of life and its association with medication adherence in active pulmonary tuberculosis- a systematic review of global literature with focus on South Africa. AB - INTRODUCTION: Tuberculosis (TB) is a leading cause of morbidity and mortality in South Africa. Clinical parameters are important objective outcomes in TB; however they often are not directly correlated with subjective well-being of the patient, but can be assessed using patient-reported outcome (PRO) measures. Health-related quality of life (HRQOL) is a specific PRO generally multi-dimensional in nature and includes physical, mental and social health domains. The inclusion of HRQOL PROs in trials and clinical practice can provide additional information beyondclinical and microbiological parameters. Furthermore, HRQOL may be associated with medication adherence. This review focuses on patient-reported HRQOL and its association with medication adherence in TB patients in South Africa. METHODS: A comprehensive search strategy was developed focusing on the impact of TB on patient-reported HRQOL,the existence of a conceptual framework of TB-specific HRQOL, determinants of medication adherence and the association of HRQOL with medication adherence. Data were extracted from all identified articles and additionaldata extraction was performed by two independent reviewers with special focus on longitudinal studies in order to understand changes of HRQOL and adherence over time. Research gaps were identified with regard to patient reported HRQOL and medication adherence. RESULTS: A total of 66 articles met the eligibility criteria. Ten HRQOL studies and one adherence study used a longitudinal design, none of these in South Africa. A variety of different generic and disease-specific HRQOL measures were identified in the articles. In South Africa four HRQOL and five adherence studies (non-longitudinal) were published. Similar factors (socio-demographic, socio-economic, disease-related, therapy-related and psycho-social aspects) affect HRQOL and adherence. Although standard TB treatment improved all health domains, psychological well-being and social functioning remained impaired in microbiologically cured patients after treatment. CONCLUSION: While evidence of TB impact on HRQOL and medication adherence and their association exists, it is verylimited for the South African situation. No valid and reliable TB-specific HRQOL measures were identified in this systematicreview. An assessment of HRQOL in TB patients in South Africa is required as this may assist with improving current disease management programmes, medication adherence and national treatment guidelines. PMID- 26969307 TI - Antitumor and anti-angiogenic potentials of isolated crude saponins and various fractions of Rumex hastatus D. Don. AB - BACKGROUND: Cancer, being the foremost challenge of the modern era and the focus of world-class investigators, gargantuan research is in progress worldwide to explore novel therapeutic for its management. The exploitation of natural sources has been proven to be an excellent approach to treat or minify the excessive angiogenesis and proliferation of cells. Similarly, based the ethnomedicinal uses and literature survey, the current study is designed to explore the anti-tumor and anti-angiogenic potentials of Rumex hastatus. Anti-tumor and anti-angiogenic activities were carried out using potato-disc model and chorioallantoic membrane (CAM) assay respectively. Moreover, R. hastatus was also assessed for antibacterial activity against Agrobacterium tumefaciens (tumor causing bacterial strain). The positive controls used in anti-tumor, anti-angiogenic and antibacterial activities were vincristine sulphate, dexamethasone and cefotaxime respectively. RESULTS: The crude saponins (Rh.Sp), methanolic extract (Rh.Cr) and other solvent extracts like n-hexane (Rh.Hex), chloroform (Rh.Chf), ethylacetate (Rh.EtAc) and aqueous fraction (Rh.Aq) exhibited notable anti-tumor and anti angiogenic activities. In potato tumor assay, the chloroform and saponin fractions were observed to be the most effective showing 86.7 and 93.3 % tumor inhibition at 1000 ug/ml with IC50 values 31.6 and 18.1 ug/ml respectively. Similarly, these two samples i.e., chloroform and saponins also excelled among the entire test samples in anti-angiogenic evaluation exhibiting 81.6 % (IC50 = 17.9 ug/ml) and 78.9 % (IC50 = 64.9 ug/ml) at 1000 ug/ml respectively. In contrast, the antibacterial investigations revealed a negligible potential against A. tumefaciens. CONCLUSION: Based on our results we can claim that R. hastatus possesses both anti-tumor and anti-angiogenic potentials. In all of the solvent fractions, Rh.Chf and Rh.Sp were most effective against tumor and angiogenesis while having negligible activity against A. tumefaciens. It can be concluded that Rh.Chf and Rh.Sp might be potential targets in the isolation of natural product having anti-neoplastic action. PMID- 26969308 TI - Patient and genetic counselor perceptions of in-person versus telephone genetic counseling for hereditary breast/ovarian cancer. AB - Telephone genetic counseling (TC) for high-risk women interested in BRCA1/2 testing has been shown to yield positive outcomes comparable to usual care (UC; in-person) genetic counseling. However, little is known about how genetic counselors perceive the delivery of these alternate forms of genetic counseling. As part of a randomized trial of TC versus UC, genetic counselors completed a 5 item genetic counselor process questionnaire (GCQ) assessing key elements of pre test sessions (information delivery, emotional support, addressing questions and concerns, tailoring of session, and facilitation of decision-making) with the 479 female participants (TC, N = 236; UC, N = 243). The GCQ scores did not differ for TC vs. UC sessions (t (477) = 0.11, p = 0.910). However, multivariate analysis showed that participant race/ethnicity significantly predicted genetic counselor perceptions (beta = 0.172, p < 0.001) in that the GCQ scores were lower for minorities in TC and UC. Exploratory analyses suggested that GCQ scores may be associated with patient preference for UC versus TC (t (79) = 2.21, p = 0.030). Additionally, we found that genetic counselor ratings of session effectiveness were generally concordant with patient perceptions of the session. These data indicate that genetic counselors perceive that key components of TC can be delivered as effectively as UC, and that these elements may contribute to specific aspects of patient satisfaction. However, undefined process differences may be present which account for lower counselor perceptions about the effectiveness of their sessions with minority women (i.e., those other than non Hispanic Whites). We discuss other potential clinical and research implications of our findings. PMID- 26969309 TI - Genetic counseling and cascade genetic testing in Lynch syndrome. AB - Lynch syndrome is the most common cause of inherited colorectal and endometrial cancers. Individuals with Lynch syndrome have a 10-80 % lifetime risk for colorectal cancer and a 15-60 % lifetime risk for endometrial cancer. Both cancers are preventable through chemoprevention, intensive cancer surveillance, and risk-reducing surgery options. Efforts to identify as many individuals with Lynch syndrome as possible will prevent cancers and save lives. This includes the traditional cancer genetic counseling model whereby individuals with and without cancer are evaluated for a possible Lynch syndrome diagnosis based on their personal and family history of colon polyps and cancers. It also includes universal tumor screening for Lynch syndrome whereby all individuals with colorectal or endometrial cancer are screened for tumor features of Lynch syndrome at the time of diagnosis. Those with tumors suspicious for Lynch syndrome are referred for cancer genetic counseling regardless of their family history of cancer. This two approaches must be maximized to attain high patient reach. Finally, and perhaps most importantly, cascade testing among the at-risk relatives of those diagnosed with Lynch syndrome is critically important to maximize the diagnosis of individuals with Lynch syndrome. In fact, the cost effectiveness of universal tumor screening for Lynch syndrome relies entirely on counseling and testing as many at-risk individuals as possible since young unaffected individuals stand to benefit the most from an early diagnosis of Lynch syndrome. This approach must be optimized to achieve high family reach. It will take a concerted effort from patients, clinicians and public health officials to improve current approaches to the diagnosis of Lynch syndrome and the prevention and treatment of Lynch syndrome-associated cancer but these lessons can be applied to other conditions as the ultimate example of personalized medicine. PMID- 26969310 TI - Developmental brain trajectories in children with ADHD and controls: a longitudinal neuroimaging study. AB - BACKGROUND: The symptom profile and neuropsychological functioning of individuals with Attention Deficit/Hyperactivity Disorder (ADHD), change as they enter adolescence. It is unclear whether variation in brain structure and function parallels these changes, and also whether deviations from typical brain development trajectories are associated with differential outcomes. This paper describes the Neuroimaging of the Children's Attention Project (NICAP), a comprehensive longitudinal multimodal neuroimaging study. Primary aims are to determine how brain structure and function change with age in ADHD, and whether different trajectories of brain development are associated with variations in outcomes including diagnostic persistence, and academic, cognitive, social and mental health outcomes. METHODS/DESIGN: NICAP is a multimodal neuroimaging study in a community-based cohort of children with and without ADHD. Approximately 100 children with ADHD and 100 typically developing controls will be scanned at a mean age of 10 years (range; 9-11years) and will be re-scanned at two 18-month intervals (ages 11.5 and 13 years respectively). Assessments include a structured diagnostic interview, parent and teacher questionnaires, direct child cognitive/executive functioning assessment and magnetic resonance imaging (MRI). MRI acquisition techniques, collected at a single site, have been selected to provide optimized information concerning structural and functional brain development. DISCUSSION: This study will allow us to address the primary aims by describing the neurobiological development of ADHD and elucidating brain features associated with differential clinical/behavioral outcomes. NICAP data will also be explored to assess the impact of sex, ADHD presentation, ADHD severity, comorbidities and medication use on brain development trajectories. Establishing which brain regions are associated with differential clinical outcomes, may allow us to improve predictions about the course of ADHD. PMID- 26969311 TI - "Deterioration to Door Time": An Exploratory Analysis of Delays in Escalation of Care for Hospitalized Patients. AB - BACKGROUND: Timely escalation of care for patients experiencing clinical deterioration in the inpatient setting is challenging. Deterioration on a general floor has been associated with an increased risk of death, and the early period of deterioration may represent a time during which admission to the intensive care unit (ICU) improves survival. Previous studies examining the association between delay from onset of clinical deterioration to ICU transfer and mortality are few in number and were conducted more than 10 years ago. OBJECTIVE: We aimed to evaluate the impact of delays in the escalation of care among clinically deteriorating patients in the current era of inpatient medicine. DESIGN AND PARTICIPANTS: This was a retrospective cohort study that analyzed data from 793 patients transferred from non-intensive care unit (ICU) inpatient floors to the medical intensive care unit (MICU), from 2011 to 2013 at an urban, tertiary, academic medical center. MAIN MEASURES: "Deterioration to door time (DTDT)" was defined as the time between onset of clinical deterioration (as evidenced by the presence of one or more vital sign indicators including respiratory rate, systolic blood pressure, and heart rate) and arrival in the MICU. KEY RESULTS: In our sample, 64.6 % had delays in care escalation, defined as greater than 4 h based on previous studies. Mortality was significantly increased beginning at a DTDT of 12.1 h after adjusting for age, gender, and severity of illness. CONCLUSIONS: Delays in the escalation of care for clinically deteriorating hospitalized patients remain frequent in the current era of inpatient medicine, and are associated with increased in-hospital mortality. Development of performance measures for the care of clinically deteriorating inpatients remains essential, and timeliness of care escalation deserves further consideration. PMID- 26969312 TI - Trends in Costs of Depression in Adults with Diabetes in the United States: Medical Expenditure Panel Survey, 2004-2011. AB - OBJECTIVE: To investigate differences in healthcare cost trends over 8 years in adults with diabetes and one of four categories of comorbid depression: no depression, unrecognized depression, asymptomatic depression, or symptomatic depression. RESEARCH DESIGN AND METHODS: Data from the 2004-2011 Medical Expenditure Panel Survey (MEPS) was used to create nationally representative estimates. The dependent variable was total healthcare expenditures for the calendar year, including office-based, hospital outpatient, emergency room, inpatient hospital, prescription, dental, and home health care expenditures. The 2004-2011 direct medical costs were adjusted to a common 2014 dollar value. The primary independent variable was four mutually exclusive depression categories created from ICD-9-CM codes and the PHQ-2 depression screening tool. Healthcare expenditures were estimated using a two-part model and were adjusted for age, sex, race, marital status, education, health insurance, metropolitan statistical area status, region, income level, and comorbidities. RESULTS: Based on a national sample of adults with diabetes (unweighted sample of 15,548, weighted sample of 17,465,579), 10.2 % had unrecognized depression, 13.6 % had asymptomatic depression, and 8.9 % had symptomatic depression. In the pooled sample, after adjusting for covariates, the incremental cost of unrecognized depression was $2872 (95 % CI 1660-4084), asymptomatic depression increased by $3347 (95 % CI 2568-4386), and symptomatic depression increased by $5170 (CI 95 % 3610-6731) compared to patients with no depression. CONCLUSIONS: Adjusted analyses showed that expenditures were $2000-3000 higher for unrecognized and asymptomatic depression than no depression, and $5000 higher for symptomatic depression. Higher medical expenditures persisted over time, with only symptomatic depression showing a sustained decrease over time. PMID- 26969313 TI - Total Synthesis of Dimeric HPI Alkaloids. AB - In this paper, we report a full account of the synthesis of dimeric hexahydropyrroloindole alkaloids and its analogues. The key feature of our new strategy is the novel catalytic copper (10 %) mediated intramolecular arylations of o-haloanilides followed by intermolecular oxidative dimerization of the resulting oxindoles in one pot. This sequential reaction leads to the key intermediates for the synthesis of (+)-chimonanthine, (+)-folicanthine, (-) calycanthine and (-)-ditryptophenaline. In the presence of catalytic amount of cuprous iodide (10 %), an intramolecular arylation of o-haloanilides followed by an intermolecular oxidative dimerization of the resulting oxindoles leads to a common intermediate for the synthesis of (+)-chimonanthine, (+)-folicanthine and (-)-calycanthine. Based on this cascade sequence, we also developed a flexible strategy towards the asymmetric syntheses of dimeric HPI alkaloids (-) ditryptophenaline and its analogues. PMID- 26969314 TI - Improved milk production performance of smallholder farms in West Java (Indonesia). AB - In Indonesia, because of the rapidly growing demand for dairy products, the development of milk production in rural communities can play a strong role in reducing poverty. However, the development of smallholder dairy production requires adequate support from the government, development organizations, and private firms. To assess the needs and situations of poor dairy farmers, we conducted a study in Ciater sub-district in West Java Province to compare the current situation with the situation that prevailed 4 years ago, i.e., before the implementation of a dairy development project. Data were collected from 61 farms in June 2014. The average number of cows on the farms surveyed was three to four, and each relied on cultivating an average of 0.4 ha of forage. Results showed that thanks to the project activities, milk productivity per cow and net income from milk production increased by 25% between 2010 and 2014. These results underline the importance of providing training and technical support for the development of the livelihoods of dairy smallholders. PMID- 26969315 TI - Fixed-time induction of ovulation in camels superovulated by different eCG modalities during the transition period in Egypt : Superovulation in camels during the transition period. AB - The current investigation aimed to establish a fixed-time induction of ovulation/ insemination protocol in camels superovulated by different equine chorionic gonadotropin (eCG) regimens during the transition period in Egypt (mid-October to mid-November). Seventeen pluriparous camels, Camelus dromedarius, were used. All females retained controlled intra-vaginal drug releasers (CIDRs) for 13 consecutive days, and at CIDR withdrawal, the camels were randomly divided into three groups. The control group (n = 5) received 1 ml saline intra-muscularly (i.m.), whereas remaining camels were superovulated by 2500 IU eCG either in a single shot (SS, n = 6) or in serial decreasing doses over 3 days (DD, n = 6). Ovarian dynamics were monitored by transrectal ultrasonography at 2-day intervals, and ovulation was induced by 5000 IU hCG i.m. The changes in reproductive hormones throughout the period of the study were determined. The results showed that mean values of total no. of follicles and size of dominant follicles remained low (P < 0.05) in all groups until day of CIDR removal. Thereafter, total follicle no. increased (P < 0.05) in both superovulated groups compared to the control, where the dominant follicles attained the highest (P < 0.05) diameter 12 days after the eCG treatment. Double-ovulation rate was higher (P < 0.05) in SS (50%) and DD (66.6%) groups compared to that of control (0.0%). However, 33.3% of the SS group developed large anovulatory follicles (o > 25 mm), which did not respond to induction to ovulation. These results elucidate that eCG administration in serial decreasing doses generates a reliable superovulatory response in camels, and ovulation can be blindly induced 12 days after the gonadotropin treatment. This fixed-time hormonal protocol represents a sufficient alternative to conventional day-to-day ultrasonography and would have profound implication for enhanced fertility in dromedary camels by facilitating infield application of embryo transfer technique. PMID- 26969316 TI - Net requirements of calcium, phosphorus, magnesium, and sulphur for growth of non descript breed hair lambs of different sex classes in the Brazilian semiarid conditions. AB - The aim of this study was to determine the net requirements of calcium (Ca), phosphorus (P), magnesium (Mg), and sulphur (S) for weight gain of non-descript breed hair lambs (NDBL) of different sex classes reared under Brazilian semiarid conditions. Sixty NDBL (20 intact males, 20 castrated males, and 20 females), with an average initial body weight of 18.1 +/- 0.4 kg and average age of 5 months were used. The macromineral requirements were determined by the differences in body composition through comparative slaughter direct method. The animals were confined for 58 days, and the average fasting body weight (FBW) and average daily gain (ADG) of lambs fed ad libitum were 29.2 +/- 0.6 and 0.19 +/- 0.01 kg, respectively. The net requirements of macrominerals for gain of NDBL did not differ between sex classes (P > 0.05), and ranged from 1.83 to 1.46 g/day of Ca, 1.21 to 1.01 g/day of P, 37 to 30 mg/day of Mg, and 0.31 to 0.28 g/day of S, for lambs with an ADG of 0.200 kg and 15 or 30 kg of FBW, respectively (P < 0.05). The N to S net ratio reduced and increased, respectively, as the body weight and ADG increase. The net requirements of Ca, P, Mg, and S for gain of NDBL slaughtered young and at the same age did not differ between sex classes and decreased as the body weight increased. The net requirements for gain of Ca and P were similar to those recommended by NRC (2007). PMID- 26969317 TI - Presentation and management of pulmonary sequestration with total visceral inflow and outflow. AB - Two of the most common types of congenital thoracic malformations are congenital pulmonary airway malformations (CPAMs) and bronchopulmonary sequestrations (BPS). Here we present the first known case of a hybrid lesion, with coexisting features of an extralobar sequestration (ELS) and CPAM type 2, with arterial inflow from the celiac trunk and venous outflow to the portal vein. The clinical presentation, investigative imaging and timing of surgery are discussed. PMID- 26969318 TI - Use of an Ecological Model to Study Sexual Satisfaction in a Heterosexual Spanish Sample. AB - Sexual satisfaction is a key factor in sexual health and has been associated with quality of life. However, few studies have focused on the factors related to sexual satisfaction in the population in Spain. The main goal of this research was to analyze the predictive capacity of an ecological model for the study of sexual satisfaction in a Spanish sample of 723 men and 851 women, with mean age equal to 36.28 (SD = 12.59) and who were in a heterosexual relationship. We analyzed, using structural equation modeling, the degree to which sexual satisfaction was related to different variables. These variables were the following: personal variables (depression and sexual attitudes); interpersonal variables (relationship satisfaction, sexual function, and sexual assertiveness); social variables (social support, parenthood, and annual income); and cultural variables (political ideology, religion, and religious practice). In men, sexual satisfaction was directly predicted by relationship satisfaction and sexual function. Furthermore, political ideology, religious practice, social support, annual income, initiation sexual assertiveness, and sexual attitudes were indirectly associated with sexual satisfaction. In women, sexual satisfaction was directly predicted by relationship satisfaction, sexual function, sexual assertiveness, and sexual attitudes. In addition, political ideology, religious practice, and social support were indirectly associated with sexual satisfaction. Implications for research and therapy are also discussed. PMID- 26969320 TI - Sexual Arousal and Sexual Activity Frequency: Implications for Understanding Hypersexuality. PMID- 26969319 TI - Geosocial Networking App Use Among Men Who Have Sex With Men in Serious Romantic Relationships. AB - Geosocial networking (GSN) mobile phone applications ("apps") are used frequently among men who have sex with men (MSM) to socialize and meet sexual partners. Though GSN apps are used by some MSM in partnered relationships, little is known about how the use of GSN apps among MSM in serious romantic relationships can influence couples' sexual and relationship health. MSM in serious relationships (N = 323; M age = 40 years) were recruited through a popular GSN app for MSM. Participants completed open-ended items regarding the costs and benefits of app use to their relationships, discussions of app use with their partners, and preferences for relationship education related to app use. Reported benefits of app use included improving sex and communication with one's primary partner and fulfilling unmet sexual needs. Although approximately half had not discussed app use with their partners, citing app use as a "non-issue," many cited various drawbacks to app use, including jealousy and being a distraction from the relationship. Few described sexual health concerns as a drawback to meeting partners through apps. Regarding relationship education preferences, most wanted help with general communication skills and how to express one's sexual needs to a partner. Although GSN app use can enhance relationships and sex among partnered MSM, unclear communication about app use may contribute to negative relationship outcomes and could prevent partners from having sexual needs met. Relationship and sexual health education programs for male couples should consider addressing social media and technology use in their curricula. PMID- 26969321 TI - On the Relationship Between Domain-Specific Creative Achievement and Sexual Orientation in Swedish Twins. AB - Despite the commonly held belief that homosexual males and females are more creative compared to heterosexuals, empirical studies on homosexuality and its relationship to creativity have been sparse, often with questionable methodology and very small sample sizes, reporting mixed findings. No study till date has explored the associations described above in a large population-based and genetically informative sample. Here, we examined such potential associations between sexual orientation and creative achievement in several different domains (music, writing, dance, visual arts, science, invention, and theater) using a large cohort of 4494 Swedish twins (of which 7.5 % were not exclusively heterosexual). Data were analyzed for the sexes separately as well as pooled. Results showed significant associations between sexual orientation and two of the creative domains-theater and writing-with non-heterosexuals being more creative in these domains. In all other domains, no significant differences were found between the non-heterosexual and heterosexual groups. Findings from co-twin control analyses suggested that the significant associations may not be causal in nature (i.e., homosexual orientation leads to higher creativity) but due to shared liability. However, we lacked power to differentiate between shared genetic and shared environmental influences. Results and potential implications are discussed critically. PMID- 26969323 TI - A New Surface Plasmon Resonance Assay for In Vitro Screening of Mannose-Binding Lectin Inhibitors. AB - Mannose-binding lectin (MBL) is a circulating protein that acts as a soluble pattern recognition molecule of the innate immunity. It binds to carbohydrate patterns on the surface of pathogens or of altered self-cells, with activation of the lectin pathway of the complement system. Recent evidence indicates that MBL contributes to the pathophysiology of ischemia-reperfusion injury and other conditions. Thus, MBL inhibitors offer promising therapeutic strategies, since they prevent the interaction of MBL with its target sugar arrays. We developed and characterized a novel assay based on surface plasmon resonance for in vitro screening of these compounds, which may be useful before the more expensive and time-consuming in vivo studies. The assay measures the inhibitor's ability to interfere with the binding of murine MBL-A or MBL-C, or of human recombinant MBL, to mannose residues immobilized on the sensor chip surface. We have applied the assay to measure the IC50 of synthetic glycodendrimers, two of them with neuroprotective properties in animal models of MBL-mediated injuries. PMID- 26969322 TI - Integration of Affinity Selection-Mass Spectrometry and Functional Cell-Based Assays to Rapidly Triage Druggable Target Space within the NF-kappaB Pathway. AB - The primary objective of early drug discovery is to associate druggable target space with a desired phenotype. The inability to efficiently associate these often leads to failure early in the drug discovery process. In this proof-of concept study, the most tractable starting points for drug discovery within the NF-kappaB pathway model system were identified by integrating affinity selection mass spectrometry (AS-MS) with functional cellular assays. The AS-MS platform Automated Ligand Identification System (ALIS) was used to rapidly screen 15 NF kappaB proteins in parallel against large-compound libraries. ALIS identified 382 target-selective compounds binding to 14 of the 15 proteins. Without any chemical optimization, 22 of the 382 target-selective compounds exhibited a cellular phenotype consistent with the respective target associated in ALIS. Further studies on structurally related compounds distinguished two chemical series that exhibited a preliminary structure-activity relationship and confirmed target driven cellular activity to NF-kappaB1/p105 and TRAF5, respectively. These two series represent new drug discovery opportunities for chemical optimization. The results described herein demonstrate the power of combining ALIS with cell functional assays in a high-throughput, target-based approach to determine the most tractable drug discovery opportunities within a pathway. PMID- 26969324 TI - [Epidemiology of caprine and ovine brucellosis in Formosa province, Argentina]. AB - An epidemiological study of brucellosis was carried out in 516 goats and mixed flocks (goat/sheep) from the three agro-ecological regions of Formosa province, Argentina. Serum samples from a total of 25401 goats and 2453 sheeps were analyzed using buffered plate agglutination test (BPAT) and complement fixation test (CFT). Bacteriological and PCR analyses on milk samples from goats in three flocks with a history of brucellosis and recent abortions were also performed. Brucellosis was detected in four of the nine departments of the province with an overall prevalence of 2% and an intra-flock prevalence ranging between 1% and 40%. The proportion of infected flocks was 3.6%, 12% and 36% for the eastern, central and western regions, respectively. Brucella melitensis bv. 1 was isolated efrom goats for the first time in the province. The expected fragments of 827bp from the omp2ab gene (Brucella spp.) and 731bp from the insert IS711 (B. melitensis) were amplified by PCR. Detection of antibodies by BPAT and FCT in sheep cohabiting with goats suggests that infections could have been caused by B. melitensis, posing an additional risk to public health. Control and eradication programs for brucellosis should consider mixed flocks as a single epidemiological unit. The results indicate that brucellosis by B. melitensis bv1 is highly endemic in the central and western regions of Formosa province. PMID- 26969325 TI - No correlation between NF1 mutation position and risk of optic pathway glioma in 77 unrelated NF1 patients. AB - Neurofibromatosis type 1 (NF1) is a common monogenic disorder whereby affected individuals are predisposed to developing CNS tumors, including optic pathway gliomas (OPGs, occurring in ~15 to 20 % of cases). So far, no definite genotype phenotype correlation determining NF1 patients at risk for tumor formation has been described, although enrichment for mutations in the 5' region of the NF1 gene in OPG patients has been suggested. We used whole exome sequencing, targeted sequencing, and copy number analysis to screen 77 unrelated NF1 patients with (n = 41) or without (n = 36; age >=10 years) optic pathway glioma for germline NF1 alterations. We identified germline NF1 mutations in 69 of 77 patients (90 %), but no genotype-phenotype correlation was observed. Our data using a larger patient cohort did not confirm the previously reported clustering of mutations in the 5' region of the NF1 gene in patients with OPG. Thus, NF1 mutation location should not currently be used as a clinical criterion to assess the risk of developing OPGs. PMID- 26969326 TI - Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. AB - Hearing loss is the most common sensory deficit in humans, affecting 1 in 500 newborns. Due to its genetic heterogeneity, comprehensive diagnostic testing has not previously been completed in a large multiethnic cohort. To determine the aggregate contribution inheritance makes to non-syndromic hearing loss, we performed comprehensive clinical genetic testing with targeted genomic enrichment and massively parallel sequencing on 1119 sequentially accrued patients. No patient was excluded based on phenotype, inheritance or previous testing. Testing resulted in identification of the underlying genetic cause for hearing loss in 440 patients (39%). Pathogenic variants were found in 49 genes and included missense variants (49%), large copy number changes (18%), small insertions and deletions (18%), nonsense variants (8%), splice-site alterations (6%), and promoter variants (<1%). The diagnostic rate varied considerably based on phenotype and was highest for patients with a positive family history of hearing loss or when the loss was congenital and symmetric. The spectrum of implicated genes showed wide ethnic variability. These findings support the more efficient utilization of medical resources through the development of evidence-based algorithms for the diagnosis of hearing loss. PMID- 26969327 TI - MYBPH acts as modifier of cardiac hypertrophy in hypertrophic cardiomyopathy (HCM) patients. AB - Left ventricular hypertrophy is a risk factor for cardiovascular morbidity and mortality. Hypertrophic cardiomyopathy (HCM) is considered a model disease to study causal molecular factors underlying isolated cardiac hypertrophy. However, HCM manifests with various clinical symptoms, even in families bearing the same genetic defects, suggesting that additional factors contribute to hypertrophy. The gene encoding the cardiac myosin binding protein C (cMYBPC) is one of the most frequently implicated genes in HCM. Recently another myosin binding protein, myosin binding protein H (MYBPH) was shown to function in concert with cMYBPC in regulating cardiomyocyte contraction. Given the similarity in sequence, structure and the critical role MYBPH plays in sarcomere contraction, we proposed that MYBPH may be involved in HCM pathogenesis. Family-based genetic association analysis was employed to investigate the contribution of MYBPH in modifying hypertrophy. Seven single nucleotide polymorphisms and haplotypes in MYBPH were investigated for hypertrophy modifying effects in 388 individuals (27 families), in which three unique South African HCM-causing founder mutations (p.R403W and pA797T in beta-myosin heavy chain gene (MYH7) and p.R92W in the cardiac troponin T gene (TNNT2)) segregate. We observed a significant association between rs2250509 and hypertrophy traits in the p.A797T MYH7 mutation group. Additionally, haplotype GGTACTT significantly affected hypertrophy within the same mutation group. MYBPH was for the first time assessed as a candidate hypertrophy modifying gene. We identified a novel association between MYBPH and hypertrophy traits in HCM patients carrying the p.A797T MYH7 mutation, suggesting that variation in MYBPH can modulate the severity of hypertrophy in HCM. PMID- 26969329 TI - Poor leadership is blamed for failure to reshape Scotland's health service. PMID- 26969330 TI - [Decision aids for patients are widely accepted by German urologists : A survey among members of the German Society of Urology (DGU) and the Federation of German Urologists (BDU)]. AB - BACKGROUND: Treatment decision making remains a complex task for localized prostate cancer. Decision aids for patients can support the medical consultation. However, it is not known if German urologists accept decision aids for patients. Comparative data exist from a current survey among american urologists and radio oncologists. MATERIALS AND METHODS: From October through November 2014 we conducted an online survey consisting of 11 multiple-choice questions and an optional free text commentary among the members of DGU and BDU. All data was processed anonymously. We received 464 complete responses for a 6.6 % return rate. For group comparison we applied the Chi2-test. RESULTS: Respondents' median age was 50 (range 26-87) years and 15 % were female. 7 % were residents, 31 % employed at a clinic, and 57 % in private practice. Due to the low response rate of younger colleagues the results were not representative for the basic population. Regardless of age (p = 0.2) and professional environment (p = 1) shared decision making was preferred by 89 %. When counseling their patients with localized prostate cancer 20 % relied exclusively on conversation. To support their conversation 63 % used print media, 49 % decision aids, 33 % contact offers to support groups, 24 % Internet resources and 13 % video material. From using decision aids 86 % expected positive effects for patients and 78 % for physicians (p = 0.017). 15 % expected a change of the treatment decision. 77 % would motivate their patients to use a decision aid. CONCLUSIONS: In comparison to the opinion of american urologists and radio oncologists the acceptance of decision aids for patients among German urologists is significantly higher. PMID- 26969331 TI - Molecular Docking and Molecular Dynamics Simulation Studies to Predict Flavonoid Binding on the Surface of DENV2 E Protein. AB - Dengue infections are currently estimated to be 390 million cases annually. Yet, there is no vaccine or specific therapy available. Envelope glycoprotein E (E protein) of DENV mediates viral attachment and entry into the host cells. Several flavonoids have been shown to inhibit HIV-1 and hepatitis C virus entry during the virus-host membrane fusion. In this work, molecular docking method was employed to predict the binding of nine flavonoids (baicalin, baicalein, EGCG, fisetin, glabranine, hyperoside, ladanein, quercetin and flavone) to the soluble ectodomain of DENV type 2 (DENV2) E protein. Interestingly, eight flavonoids were found to dock into the same binding pocket located between the domain I and domain II of different subunits of E protein. Consistent docking results were observed not only for the E protein structures of the DENV2-Thai and DENV2 Malaysia (a homology model) but also for the E protein structures of tick-borne encephalitis virus and Japanese encephalitis virus. In addition, molecular dynamics simulations were performed to further evaluate the interaction profile of the docked E protein-flavonoid complexes. Ile4, Gly5, Asp98, Gly100 and Val151 residues of the DENV2-My E protein that aligned to the same residues in the DENV2 Thai E protein form consistent hydrogen bond interactions with baicalein, quercetin and EGCG during the simulations. This study demonstrates flavonoids potentially form interactions with the E protein of DENV2. PMID- 26969333 TI - Erratum. PMID- 26969332 TI - Treatment cost and life expectancy of diffuse large B-cell lymphoma (DLBCL): a discrete event simulation model on a UK population-based observational cohort. AB - BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the commonest non-Hodgkin lymphoma. Previous studies examining the cost of treating DLBCL have generally focused on a specific first-line therapy alone; meaning that their findings can neither be extrapolated to the general patient population nor to other points along the treatment pathway. Based on empirical data from a representative population-based patient cohort, the objective of this study was to develop a simulation model that could predict costs and life expectancy of treating DLBCL. METHODS: All patients newly diagnosed with DLBCL in the UK's population-based Haematological Malignancy Research Network ( www.hmrn.org ) in 2007 were followed until 2013 (n = 271). Mapped treatment pathways, alongside cost information derived from the National Tariff 2013/14, were incorporated into a patient-level simulation model in order to reflect the heterogeneities of patient characteristics and treatment options. The NHS and social services perspective was adopted, and all outcomes were discounted at 3.5 % per annum. RESULTS: Overall, the expected total medical costs were L22,122 for those treated with curative intent, and L2930 for those managed palliatively. For curative chemotherapy, the predicted medical costs were L14,966, L23,449 and L7376 for first-, second- and third-line treatments, respectively. The estimated annual cost for treating DLBCL across the UK was around L88-92 million. CONCLUSIONS: This is the first cost modelling study using empirical data to provide 'real world' evidence throughout the DLBCL treatment pathway. Future application of the model could include evaluation of new technologies/treatments to support healthcare decision makers, especially in the era of personalised medicine. PMID- 26969334 TI - Pharmacokinetics, Efficacy, and Safety of Nonacog Alfa in Previously Treated Patients with Moderately Severe to Severe Hemophilia B. AB - PURPOSE: Nonacog alfa, a recombinant factor IX (FIX) product, is used for FIX replacement in the treatment and prevention of bleeding events in patients with hemophilia B. This study aimed to provide supplemental pharmacokinetic (PK), efficacy, and safety data for nonacog alfa when administered as part of usual hemophilia care, including on-demand treatment, routine prophylaxis, and surgical prophylaxis. METHODS: Men with previously treated severe or moderately severe hemophilia B (FIX activity <=2%) were enrolled in this prospective, open-label, nonrandomized, multicenter study. An initial 72-hour PK assessment was performed wherein patients received a single dose of nonacog alfa (75 IU/kg) as an infusion over 10 minutes. A final 72-hour PK assessment was performed at the patient's last visit, after a minimum washout period of 4 days. Correlations between Cmax after the first dose and body weight and body mass index (BMI) were assessed post hoc using Spearman test after evaluating normality. FINDINGS: In total, 23 patients (age, 12-59 years; weight, 44-173 kg; and BMI, 16.3-45.1) with previous exposure to FIX products (median, 460 days; range, 150-2400 days) were enrolled; 21 were evaluable for efficacy. The median number of exposure days per efficacy evaluable patient in this study was 48 (range, 31-103). The FIX activity profiles showed multiphasic disposition characteristics, with initial mean (SD) PK profiles as follows: Cmax, 61.4 (12.5) IU/dL; AUCinfinity, 1055 (227) IU.h/dL; t1/2, 23.7 (5.6) hours; and recovery, 0.818 (0.167) IU/dL. Mean plasma FIX activity versus time profiles were essentially identical upon initial exposure and after repeated use (n = 17), and bioequivalence was confirmed. No apparent relationship was observed between Cmax and either body weight (P > 0.1732) or BMI (P > 0.1235). IMPLICATIONS: The FIX activity profile after administration of nonacog alfa is predictable and is not altered after repeated exposure during usual hemophilia care. PK parameters are consistent with nonacog alfa use for FIX replacement in on-demand treatment, routine prophylaxis, and surgical prophylaxis in patients with hemophilia B. PMID- 26969335 TI - A Trait-Based Approach to Advance Coral Reef Science. AB - Coral reefs are biologically diverse and ecologically complex ecosystems constructed by stony corals. Despite decades of research, basic coral population biology and community ecology questions remain. Quantifying trait variation among species can help resolve these questions, but progress has been hampered by a paucity of trait data for the many, often rare, species and by a reliance on nonquantitative approaches. Therefore, we propose filling data gaps by prioritizing traits that are easy to measure, estimating key traits for species with missing data, and identifying 'supertraits' that capture a large amount of variation for a range of biological and ecological processes. Such an approach can accelerate our understanding of coral ecology and our ability to protect critically threatened global ecosystems. PMID- 26969336 TI - Gestational hypertension and donor eggs: elusive yet dangerous. PMID- 26969337 TI - Transgenic mouse lines help decipher the roles of EGFR ligands in the skin. PMID- 26969328 TI - Microtubule plus-end tracking proteins in neuronal development. AB - Regulation of the microtubule cytoskeleton is of pivotal importance for neuronal development and function. One such regulatory mechanism centers on microtubule plus-end tracking proteins (+TIPs): structurally and functionally diverse regulatory factors, which can form complex macromolecular assemblies at the growing microtubule plus-ends. +TIPs modulate important properties of microtubules including their dynamics and their ability to control cell polarity, membrane transport and signaling. Several neurodevelopmental and neurodegenerative diseases are associated with mutations in +TIPs or with misregulation of these proteins. In this review, we focus on the role and regulation of +TIPs in neuronal development and associated disorders. PMID- 26969340 TI - Inclusion of Ethnic Minorities in Telehealth Trials for Type 2 Diabetes: Protocol for a Systematic Review Examining Prevalence and Language Issues. AB - BACKGROUND: Type 2 diabetes is common, on the rise, and disproportionately affects ethnic minority groups. Telehealth interventions may mitigate diabetes related complications, but might under-recruit or even exclude ethnic minorities, in part because of English language requirements. The under-representation of minority patients in trials could threaten the generalizability of the findings, whereby the patients who might stand to benefit most from such interventions are not being included in their evaluation. OBJECTIVE: The aims of this systematic review are twofold: (1) to assess the reporting and prevalence of ethnic minorities in published telehealth trials for type 2 diabetes, including identifying trial features associated with successful patient recruitment; and (2) to determine the proportion of such trials that report English language proficiency as an inclusion/exclusion criterion, including how and why they do so. METHODS: Randomized controlled trials (RCTs) of adults with type 2 diabetes in Western, English-speaking countries that included telehealth interventions targeting diabetes as a primary condition, and those that did not specifically recruit minority groups will be included. Search strategies were devised for indexed and keyword terms capturing type 2 diabetes, telehealth/health technology, and RCTs in English language publications from 2000 to July 2015 in MEDLINE, PsycINFO, EMBASE, CINAHL, and CENTRAL. Reference lists of included studies will also be searched. Two reviewers will independently screen abstracts and full-text articles against inclusion criteria, mediated by a third reviewer if consensus cannot be reached. Data extracted from included studies will be checked by a second reviewer and will be summarized using narrative synthesis. RESULTS: This research is in progress, with findings expected by Spring 2016. CONCLUSIONS: This review will address research reporting and recruitment practices of ethnic minorities in telehealth RCTs for type 2 diabetes. Prevalence estimates will elucidate generalizability of existing research, with implications for researchers, health professionals, and policy makers. Identifying trial or intervention features that appear to facilitate ethnic minority recruitment, as well as language barriers that impede it might suggest ways to improve recruitment in future trials. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews: CRD42015024899; http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015024899 (Archived by WebCite at http://www.webcitation.org/6fUMqbJ0f). PMID- 26969341 TI - Three-year trend survey of psychological distress, post-traumatic stress, and problem drinking among residents in the evacuation zone after the Fukushima Daiichi Nuclear Power Plant accident [The Fukushima Health Management Survey]. AB - AIM: Prolonged periods of instability in terms of living environment can lead to a serious increase in mental health issues among disaster-affected individuals. The aim of this study was to assess long-term trends in mental health among adult residents in a nuclear-disaster-affected area. METHODS: Mail-based, self administered questionnaire surveys were conducted three times (T1-T3), targeting all residents registered with the municipalities in the evacuation zone in Fukushima prefecture at the time of the disaster. Age-adjusted prevalences of the following were analyzed by sex: risk of psychological distress by the Kessler 6 item Scale, post-traumatic stress by the Post-traumatic Stress Disorder Checklist, and problem drinking by CAGE. RESULTS: The numbers of respondents and response rates were: 73 568, 40.7% (T1); 55 076, 29.9% (T2); and 46 386, 25.0% (T3). Compared with normal Japanese levels in non-disaster settings (4.7%), the prevalence of general psychological distress by Kessler 6-item Scale >= 13 was still high 3 years after the event in both men (11.4%) and women (15.8%). Although the age-adjusted prevalence of psychological distress and post-traumatic stress (Post-traumatic Stress Disorder Checklist >= 44) had decreased over time (from 19.0% [T1] to 17.8% [T3] for men, and from 25.3% [T1] to 23.3% [T3] for women), the age-adjusted prevalence of problem drinking (CAGE >= 2) remained steady in both men (20.7% [T2] and 20.4% [T3]; P = 0.18) and women (10.5% [T2] and 10.5% [T3]; P = 0.91). CONCLUSION: Our results suggest that long-term interventions focused on post-traumatic stress as well as other mental health problems are strongly needed for disaster-affected individuals. PMID- 26969342 TI - Identification of a novel HLA-DRB1*14 allele, HLA-DRB1*14:150, in a Chinese individual. AB - HLA-DRB1*14:150 shows one nucleotide difference when compared with DRB1*14:54:01 at codon 49 (A > P). PMID- 26969343 TI - Muscle strengthening for hemiparesis after stroke: A meta-analysis. AB - INTRODUCTION: Muscle weakness is a common consequence of stroke and can result in a decrease in physical activity. Changes in gait performance can be observed, especially a reduction in gait speed, and increased gait asymmetry, and energy cost is also reported. OBJECTIVE: The aim was to determine whether strengthening of the lower limbs can improve strength, balance and walking abilities in patients with chronic stroke. METHOD: Five databases (Pubmed, Cinhal, Cochrane, Web of Science, Embase) were searched to identify eligible studies. Randomized controlled trials were included and the risk of bias was evaluated for each study. Pooled standardized mean differences were calculated using a random effects model. The PRISMA statement was followed to increase clarity of reporting. RESULTS: Ten studies, including 355 patients, reporting on the subject of progressive resistance training, specific task training, functional electrical stimulation and aerobic cycling at high-intensity were analysed. These interventions showed a statistically significant effect on strength and the Timed Up-and-Go test, and a non-significant effect on walking and the Berg Balance Scale. CONCLUSION: Progressive resistance training seemed to be the most effective treatment to improve strength. When it is appropriately targeted, it significantly improves strength. PMID- 26969345 TI - The Blood-Brain Barrier: Regulatory Roles in Wakefulness and Sleep. AB - Sleep and its disorders are known to affect the functions of essential organs and systems in the body. However, very little is known about how the blood-brain barrier (BBB) is regulated. A few years ago, we launched a project to determine the impact of sleep fragmentation and chronic sleep restriction on BBB functions, including permeability to fluorescent tracers, tight junction protein expression and distribution, glucose and other solute transporter activities, and mediation of cellular mechanisms. Recent publications and relevant literature allow us to summarize here the sleep-BBB interactions in five sections: (1) the structural basis enabling the BBB to serve as a huge regulatory interface; (2) BBB transport and permeation of substances participating in sleep-wake regulation; (3) the circadian rhythm of BBB function; (4) the effect of experimental sleep disruption maneuvers on BBB activities, including regional heterogeneity, possible threshold effect, and reversibility; and (5) implications of sleep disruption-induced BBB dysfunction in neurodegeneration and CNS autoimmune diseases. After reading the review, the general audience should be convinced that the BBB is an important mediating interface for sleep-wake regulation and a crucial relay station of mind body crosstalk. The pharmaceutical industry should take into consideration that sleep disruption alters the pharmacokinetics of BBB permeation and CNS drug delivery, being attentive to the chrono timing and activation of co-transporters in subjects with sleep disorders. PMID- 26969344 TI - Long sleep duration and afternoon napping are associated with higher risk of incident diabetes in middle-aged and older Chinese: the Dongfeng-Tongji cohort study. AB - BACKGROUND: In this study, we investigated the independent and combined effects of sleep duration and afternoon napping on the risk of incident diabetes among a cohort of middle-aged and older Chinese adults. METHODS: Information of sleep and napping was obtained by questionnaires during face-to-face interviews. We categorized sleep duration into <7 h, 7~<8 h (reference), 8~<9 h, 9~<10 h, and >= 10 h. Afternoon napping was divided into no napping (0 min) (reference), 1-30 min, 31-60 min, 61-90 min, and > 90 min. Cox proportional hazard regression models were used. RESULTS: Compared with referential sleeping group, subjects sleeping >=10 h had a 42% higher risk of developing diabetes. The HR was 1.28 for napping > 90 min when compared with no napping. These associations were more pronounced in individuals without hypertension. Combined effects of long sleep duration and afternoon napping were further identified. Individuals with both sleep duration >= 10 h and napping > 60 min had a 72% higher risk of incident diabetes than those with sleeping 7~<8 h and napping 0 min (all above p < 0.05). CONCLUSIONS: Both long sleep duration and afternoon napping were independently and jointly associated with higher risk of incident diabetes. Key messages Sleep duration was associated with diabetes, but whether it is a real cause of incident diabetes especially in Chinese still remains to be elucidated. The association of afternoon napping and diabetes was not consistent and definite, we clarified this association in a large prospective study. Long sleep duration and afternoon napping were independently and jointly associated with higher risk of incident diabetes. PMID- 26969346 TI - Uphill and Downhill in a Flat World: The Conceptual Topography of the Yupno House. AB - Speakers of many languages around the world rely on body-based contrasts (e.g., left/right) for spatial communication and cognition. Speakers of Yupno, a language of Papua New Guinea's mountainous interior, rely instead on an environment-based uphill/downhill contrast. Body-based contrasts are as easy to use indoors as outdoors, but environment-based contrasts may not be. Do Yupno speakers still use uphill/downhill contrasts indoors and, if so, how? We report three studies on spatial communication within the Yupno house. Even in this flat world, uphill/downhill contrasts are pervasive. However, the terms are not used according to the slopes beyond the house's walls, as reported in other groups. Instead, the house is treated as a microworld, with a "conceptual topography" that is strikingly reminiscent of the physical topography of the Yupno valley. The phenomenon illustrates some of the distinctive properties of environment based reference systems, as well as the universal power and plasticity of spatial contrasts. PMID- 26969347 TI - (18)F-FDG PET/MRI evaluation of retroperitoneal fibrosis: a simultaneous multiparametric approach for diagnosing active disease. AB - PURPOSE: The aim of this study was to evaluate integrated (18)F-FDG PET/MRI as a one-stop diagnostic procedure in the assessment of (active) idiopathic retroperitoneal fibrosis (RPF) METHODS: A total of 22 examinations comprising a PET/CT scan followed by a PET/MRI scan in 17 patients (13 men, 4 women, age 58 +/ 11 years) with histopathologically confirmed RPF at diagnosis or during follow up under steroid therapy were analysed in correlation with laboratory inflammation markers (ESR, CRP). The patient cohort was subdivided into two groups: 6 examinations in untreated and 16 in treated patients. Tissue formations in typically periaortic localization suggestive of RPF were visually and quantitatively evaluated. The PET analysis included the assessment of SUVmax and a qualitative score for FDG uptake in RPF tissue in relation to the uptake in the liver. MRI analysis included evaluation of the T2-weighted image signal intensity, contrast enhancement and diffusion restriction (ADC values). Mean values were compared using the Mann-Whitney U test. ADC, SUVmax and ESR values were correlated using Pearson's correlation. RESULTS: MRI analysis revealed restricted diffusion in 100 % and 56 %, hyperintense T2 signal in 100 % and 31 %, and contrast enhancement in the periaortic tissue formation suggestive of RPF in 100 % and 62.5 % in the untreated and treated patients, respectively. In the qualitative and quantitative PET analysis, statistically significant differences were found for mean FDG uptake scores (2.5 +/- 0.8 in untreated patients and 1.1 +/- 0.9 in treated patients) and mean SUVmax (7.8 +/- 3.5 and 4.1 +/- 2.2, respectively). A strong correlation was found between the ADC values and SUVmax (Pearson r -0.65, P = 0.0019), and between ESR and CRP values and SUVmax (both r = 0.45, P = 0.061). CONCLUSION: Integrated (18)F-FDG PET/MRI shows high diagnostic potential as a one-stop diagnostic procedure for the assessment of (active) RPF providing multiparametric supportive information. PMID- 26969349 TI - Synthetic Reactions Using Low-valent Titanium Reagents Derived from Ti(OR)4 or CpTiX3 (X = O-i-Pr or Cl) in the Presence of Me3SiCl and Mg. AB - In the presence of Me3SiCl, Ti(OR)4 or CpTiX3 (X = O-i-Pr or Cl) is reduced by Mg powder in THF to gradually generate a specific low-valent titanium (LVT) species that mediates several synthetic reactions. The LVT-catalyzed C-O bond-cleaving reactions of allyl and propargyl ethers and esters generate parent alcohols and carboxylic acids, respectively. O-allyl and propargyl carbamates are also readily deprotected by the LVT to afford parent amines. In addition, the respective reductive N-S or O-S bond cleavage of sulfonamides or sulfonyl esters mediated by the LVT was developed as a novel facile deprotection method. The reagent catalyzes intra- and intermolecular alkyne or alkyne/nitrile cycloaddition to produce substituted benzenes and pyridines, while epoxides and oxetanes are reduced to alcohols via an LVT-mediated homolytic ring opening. The McMurry coupling of aryl aldehydes and ketones proceeds with the LVT under homogeneous and mild reaction conditions and is effective for the polymerization of aromatic dialdehydes, generating conjugated polymers. Finally, imino-pinacol coupling of imines is mediated by the LVT to provide 1,2-diamines. PMID- 26969348 TI - Uncontrolled risk factors and worsening perfusion pattern on SPECT myocardial perfusion imaging in medically treated patients with stable chronic ischaemic heart disease. AB - PURPOSE: Few data exist on the correlation between the effectiveness of risk factor control and the evolution of myocardial perfusion over time in patients with stable ischaemic heart disease. The aim of the study was to evaluate the changes in stress-rest myocardial perfusion in medically treated patients with stable chronic ischaemic heart disease and the relationship with risk factor control. METHODS: The study cohort included 174 consecutive patients (age 60 +/- 9 years, 68 % men) undergoing stress-rest myocardial perfusion imaging (MPI) (study 1), who also underwent repeat evaluation (study 2) and who were clinically stable on medical therapy. Summed stress, rest and difference scores were calculated. According to the evolution of perfusion pattern from study 1 to study 2, patients were classified as improved, stable or worsened. RESULTS: Study 2 was performed on average 2.7 years after study 1. Of the 174 patients, 47 (26.9 %), 53 (30.8 %) and 74 (42.5 %) were classified as stable, improved and worsened, respectively. A significant trend was observed between the number of risk factors at the time of study 1 and worsening of myocardial perfusion (24 % of patients with zero or one risk factor showed worsening, 31 % with two, and 59 % with three or more; p = 0.03). Moreover, patients with worsened perfusion had a higher number of poorly controlled risk factors. CONCLUSION: Despite medical therapy and clinical stability, myocardial perfusion worsened in 42.5 % of patients. The risk profile was reclassified in half of the patients. Worsening occurred more frequently in patients with three or more risk factors at the time of study 1 and in those with poorly controlled risk factors at the time of study 2; in this subset of patients, even if clinically stable, reassessment after 2 years could be considered. PMID- 26969351 TI - Preparation of a graphene oxide/silica composite modified with nitro-substituted tris(indolyl)methane as a solid-phase extraction sorbent for the extraction of organic acids. AB - This paper describes the use of graphene oxide/silica modified with nitro substituted tris(indolyl)methane as a solid-phase extraction sorbent for the determination of organic acids. The resultant graphene oxide/silica modified with nitro-substituted tris(indolyl)methane was characterized by FTIR spectroscopy and adsorption experiments. Solid-phase extraction parameters such as sorbent type, sample solution pH, sample loading rate, eluent salt concentration, eluent methanol concentration, elution rate, sample loading, and elution volume were optimized. The method showed good precision, accuracy, sensitivity, and linear response for organic acids analysis over a concentration range of 1-100 MUg/L for benzoic acid, p-methoxybenzoic acid, and salicylic acid and 5-100 MUg/L for the remaining organic acids (cinnamic acid, p-chlorobenzoic acid, and p-bromobenzoic acid) with coefficients of determination (r(2) ) of higher than 0.9957. Limits of detection from 0.50 to 1.0 MUg/L for six organic acids were achieved. The developed method was successfully applied to determine organic acids in real samples. PMID- 26969350 TI - Reduced expression of granule proteins during extended survival of eosinophils in splenocyte culture with GM-CSF. AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multifaceted hematopoietic cytokine and the culture of mouse bone marrow with GM-CSF produces a variety of myeloid cells including granulocytes, macrophages, and dendritic cells. In the present study, we cultured mouse splenocytes with GM-CSF and examined the changes in hematopoietic cell populations over a week. Most of the splenic hematopoietic cells disappeared significantly from culture within 6days with or without the presence of GM-CSF. Among the splenic granulocyte populations, only eosinophils fully survived throughout the culture with GM-CSF for more than a week. During 10days of culture with GM-CSF, splenic eosinophils maintained their morphology as well as most of their surface molecules at high levels, including CCR3 and Siglec F. Meanwhile, the expression of mRNAs encoding major basic protein-1 (MBP-1) and eosinophil peroxidase (EPO), two major eosinophil-derived granule proteins, was diminished significantly from the cultured eosinophils. EPO assays also revealed that eosinophils in culture for more than 5days retained 30% or less EPO activity compared to those in uncultured splenocytes. In contrast, culture of splenocytes with GM-CSF did not change the capacity of eosinophils to migrate in response to eotaxin-1. Our results indicate that mouse splenic eosinophils are effectively cultured for lengthy periods while their expression of eosinophil-derived granule proteins is specifically suppressed. The relevance of these findings to eosinophilic inflammatory response is discussed. PMID- 26969352 TI - Psychosis secondary to tuberculosis meningitis. AB - We report a case of a 19-year-old immunocompetent Malay woman who presented with a worsening psychotic disorder of 1-year duration. She initially presented with social isolation with subsequent mutism and stupor. Physical examination revealed a stuporous, emaciated, dehydrated woman with Glasgow Coma Scale of 11/15 (E4V2M5). She had a blank stare, mutism and akinesia. Motor examination revealed upper motor neuron findings. Neck stiffness was present, however, Kernig's and Brudzinski's signs were negative. There were no other findings on other systems. Brain imaging and EEG were normal. Cerebrospinal fluid investigations revealed positive cerebrospinal fluid Mycobacterium tuberculosis PCR (MTB PCR). The patient was treated with empirical antituberculosis drugs and steroids. On follow up visit 1 month later, her psychotic symptoms had fully resolved. She was able to ambulate and care for herself; she was unable to recall the symptoms she had experienced before and during admission. PMID- 26969353 TI - Anterior humeral circumflex artery avulsion with brachial plexus injury following an isolated traumatic anterior shoulder dislocation. AB - A 70-year-old man presented to accident and emergency with an isolated anteriorly dislocated shoulder, in the absence of a concomitant fracture. There was no neurovascular deficit at presentation, and the shoulder was reduced under sedation, using the Kocher's technique. Following this, the patient developed signs of hypovolaemic shock. Clinical examination revealed an expanding fullness in the deltopectoral area, with compromise of the limb neurovascular status. CT imaging confirmed an expanding haematoma from the axillary vessels, restricting left lung expansion. Once resuscitated, the patient was transferred to theatre for exploration of the bleeding vessels. Intraoperative findings included an avulsed anterior circumflex humeral artery that was subsequently ligated. Postoperatively, the patient developed axillary, radial, median and ulnar nerve neuropraxia, which improved clinically prior to discharge. The patient was ultimately discharged home after a lengthy inpatient stay. PMID- 26969354 TI - Case of tracheal cartilage necrosis as a complication of chemoradiotherapy for oesophageal cancer. PMID- 26969355 TI - Intrauterine lower extremity gangrene in a newborn with Tetralogy of Fallot. PMID- 26969356 TI - Eight-year-old boy presenting with abdominal distention after blunt trauma in Liberia. PMID- 26969357 TI - Congenital methemoglobinaemia due to Hb F-M-Fort Ripley in a preterm newborn. AB - Methemoglobinaemia is a rare cause of cyanosis in newborns. Congenital methemoglobinaemias due to M haemoglobin or deficiency of cytochrome b5 reductase are even rarer. We present a case of congenital methemoglobinaemia presenting at birth in a preterm infant. A baby boy born at 29 weeks and 3 days of gestation had persistent central cyanosis immediately after delivery, not attributable to a respiratory or cardiac pathology. Laboratory methemoglobin levels were not diagnostic. Cytochrome b5 reductase levels were normal and a newborn screen was unable to pick up any abnormal variants of fetal haemoglobin. Genetic testing showed a gamma globin gene mutation resulting in the M haemoglobin, called Hb F-M Fort Ripley. The baby had no apparent cyanosis at a corrected gestational age of 42 weeks. Although rare, congenital methaemoglobin aemia should be considered in the differential in a preterm with central cyanosis and investigated with genetic testing for gamma globin chain mutations if other laboratory tests are non conclusive. PMID- 26969359 TI - Exertional heat stroke and acute liver failure: a late dysfunction. AB - Heat stroke (HS) is defined as a severe elevation of core body temperature along with central nervous system dysfunction. Exertional heat stroke (EHS) with acute liver failure (ALF) is a rare condition. The authors report the case of a 25-year old man with a history of cognitive enhancers' intake who developed hyperthermia and neurological impairment while running an outdoor marathon. The patient was cooled and returned to normal body temperature after 6 h. He subsequently developed ALF and was transferred to the intensive care unit. Over-the-counter drug intake may have been related to heat intolerance and contributed to the event. The patient was successfully treated with conservative measures. In the presence of EHS, it is crucial to act promptly with aggressive total body cooling, in order to prevent progression of the clinical syndrome. Liver function must also be monitored, since it can be a late organ dysfunction. PMID- 26969358 TI - Arterioureteral fistula: an unusual clinical case. AB - Arterioureteral fistulas (AUFs) are abnormal communications between a major artery and the mid to distal ureter. It is a rare but potentially life threatening condition that is seldom recognised. We present a case of a 66-year old man who was admitted to the surgical ward owing to infection of an aortic bifemoral bypass graft. During admission, the patient developed persistent haematuria with considerable loss of haemoglobin. He was submitted to urgent surgical exploration of the graft. An ascending pyelography performed at the beginning of the surgery clearly shows a communication between the left ureter and the vascular graft. Open surgical exploration was undertaken, the fistulised section of the ureter resected and an end-to-end ureteroplasty was performed. The vascular graft was removed and the patient later submitted to left supracondylar amputation. Urinary drainage remained intact. PMID- 26969360 TI - Rare case of radiation-induced trigeminal schwannoma occurring in a long-term glioblastoma multiforme survivor. AB - Glioblastoma multiforme (GBM) is a high-grade primary brain tumour with a notably poor prognosis. Research demonstrates a median survival of just over 1 year following aggressive treatment. Long-term survival is notably rare. Cranial radiotherapy and postexcisional prophylactic treatment is associated with the development of second, histologically distinct tumours in rare cases. Radiation induced intracranial schwannomas are uncommon, with only a small number of cranial nerve schwannoma cases reported in recent decades. To our knowledge, this is the first reported case of a radiation-induced benign trigeminal schwannoma occurring following long-term survival from glioblastoma. Here we present (1) a rare case of 14-year survival following treatment of a right parietal glioblastoma and the development of a radiation-induced benign trigeminal schwannoma in a 35-year-old man, and (2) a review of radiation-induced schwannoma cases reported in the existing literature. PMID- 26969361 TI - Cardiac tamponade, an unusual complication of acute pancreatitis. AB - A 41-year-old Hispanic man was admitted to our hospital with the diagnosis of acute pancreatitis due to hypertriglyceridemia. During his stay, he developed sudden haemodynamic instability and clinical presentation suggestive of cardiac tamponade. A transthoracic echocardiogram confirmed the diagnosis. Echocardiography-guided pericardiocentesis was performed with immediate haemodynamic improvement. The patient's condition underwent favourable evolution. The pancreatitis was resolved and a control transthoracic echocardiography was performed showing no pericardial effusion. The pathophysiology of this rare entity is unknown. Early diagnosis and treatment are crucial. Although pericardiocentesis is the treatment of choice, there have been a few reports of medical treatment with encouraging results. Although the association of acute pancreatitis and tamponade are anecdotal in literature, medics should be aware of this association in order to perform prompt diagnosis. PMID- 26969363 TI - Clivus erosions following Gradenigo's syndrome-mastoiditis causing VI nerve palsy. PMID- 26969362 TI - Minimally invasive esophagectomy in a patient with end-stage renal disease. AB - Renal failure has been identified as a major predictor of surgical complications and esophagectomy carries high morbidity for patients. We discuss the preoperative and postoperative considerations for performing a minimally invasive Ivor-Lewis esophagectomy for a benign long-segment stricture in a patient with end-stage renal failure. PMID- 26969364 TI - Laryngeal schwannoma as an acute airway presentation. AB - A schwannoma is a neurogenic tumour arising from nerve sheaths. Between 25% and 45% of schwannomas occur in the head and neck region. Schwannomas of the larynx are extremely rare. They usually occur in women during the fourth and fifth decades of life. We present a case of a laryngeal schwannoma in a 76-year-old patient with acute stridor, hoarseness and dysphagia. Laryngeal conservation surgery was performed without the need for a tracheostomy. One year later, the patient remains symptom-free with no evidence of recurrence. Clinical presentation, diagnosis and management are discussed and the literature is reviewed. PMID- 26969365 TI - Bilateral renal angiomyolipoma presenting as tuberous sclerosis syndrome. PMID- 26969366 TI - Primary neuroendocrine tumour of the right ventricle presenting with heart failure and cyanosis. AB - A 68-year-old woman presented to the emergency department owing to exertional dyspnoea and bilateral leg oedema for 3 weeks. Her vital signs included the following: heart rate of 95 bpm, respiratory rate of 24 breaths/min, oxygen saturation of 73% on room air and a blood pressure of 184/108 mm Hg. Physical examination revealed tachypnoea with clear lungs to auscultation, elevated jugular veins, cyanosis and bilateral pitting oedema. A chest X-ray demonstrated cardiomegaly without obvious pulmonary oedema. A CT of the chest was negative for pulmonary embolus; however, the scan did reveal a large right ventricular (RV) mass. An echocardiogram with bubble study confirmed a patent foramen ovale with significant right-to-left shunting and a large RV mass that significantly obstructed the pulmonary outflow tract. A cardiac biopsy revealed a low-grade neuroendocrine tumour. The patient underwent successful debridement and adjuvant chemotherapy. She improved greatly and was asymptomatic at a 9-month follow-up visit. PMID- 26969367 TI - Blinding, brunescent traumatic cataract: overcoming barriers to care for a refugee from Myanmar. PMID- 26969368 TI - Carbamazepine induced Stevens-Johnson syndrome. PMID- 26969369 TI - In Vitro L6 Irritation Assay Predicts Clinical Injection Site Reactions for Small Molecules. AB - Injection site reactions (ISRs) are commonly encountered in the development of parenteral drugs, and severe ISRs can lead to preclinical and clinical dose limiting toxicities. Tools to assess the risk of clinical ISRs during drug development are not well established. We developed an in vitro ISR screen using L6 rat myotubes to assess compounds for irritation risk. Reference compounds that were either known to induce ISRs or were non-irritating in the clinical setting were used to validate this method. We evaluated three compounds, two with known clinical ISRs (mitoxantrone and doxorubicin) and one without clinical ISR (metoprolol), using a preclinical in vivo rat model and the L6 in vitro model at clinically relevant concentrations, and showed that the L6 assay is a better prognostic indicator for clinical ISR risk. We then utilized this assay during early preclinical development to guide optimization of structure activity relationship (SAR), selection of dose concentrations for pre-clinical in vivo experiments, and prioritization of alternative formulations to minimize ISR risk. Our studies indicate that the L6 assay is a better measure of clinical ISR risk than current in vivo preclinical models, and that it can help guide not only compound selection, but also selection of dose concentration and formulation. PMID- 26969370 TI - Using ToxCast to Explore Chemical Activities and Hazard Traits: A Case Study With Ortho-Phthalates. AB - US EPA's Toxicity Forecaster (ToxCastTM) is a tool with potential use in evaluating safer consumer products, conducting chemical alternatives analyses, prioritizing chemicals for exposure monitoring, and ultimately performing screening-level risk assessments. As a case study exploring a potential use of ToxCast, we evaluated ToxCast results for ortho-phthalates focused on the well established toxicological endpoints of some members of this class. We compared molecular perturbations measured in ToxCast assays with the known apical toxicity endpoints of o-phthalates reported in the open literature to broadly reflect on the predictive capability of the high-throughput screening (HTS) assays. We grouped the ToxCast assays into defined sets to examine o-phthalate activity and potency. This study revealed several links between key molecular events assayed in vitro and chemical-specific hazard traits. In general, parent o-phthalates are more active than their monoester metabolites. The medium-chain length o-phthalate group is also more active than other o-phthalate groups, as supported by Toxicological Priority Index ranking and statistical methods. Some HTS assay results correlated with in vivo findings, but others did not. For example, there was a notable lack of assay activity to explain the known male reproductive toxicity of these compounds. Ultimately, HTS data resources such as ToxCast may inform us of sensitive upstream toxicity endpoints and may assist in the rapid identification of environmental chemical hazards for screening and prioritization. However, this case study shows that the absence of positive results in ToxCast in vitro assays cannot be interpreted as absence of related in vivo toxicity, and limited biological coverage by the assays remains a concern. PMID- 26969371 TI - Proposed Mode of Action for Acrolein Respiratory Toxicity Associated with Inhaled Tobacco Smoke. AB - This article presents a mode of action (MOA) analysis that identifies key mechanisms in the respiratory toxicity of inhaled acrolein and proposes key acrolein-related toxic events resulting from the inhalation of tobacco smoke. Smoking causes chronic obstructive pulmonary disorder (COPD) and acrolein has been previously linked to the majority of smoking-induced noncancer respiratory toxicity. In contrast to previous MOA analyses for acrolein, this MOA focuses on the toxicity of acrolein in the lower respiratory system, reflecting the exposure that smokers experience upon tobacco smoke inhalation. The key mechanisms of acrolein toxicity identified in this proposed MOA include (1) acrolein chemical reactivity with proteins and other macromolecules of cells lining the respiratory tract, (2) cellular oxidative stress, including compromise of the important anti oxidant glutathione, (3) chronic inflammation, (4) necrotic cell death leading to a feedback loop where necrosis-induced inflammation leads to more necrosis and oxidative damage and vice versa, (5) tissue remodeling and destruction, and (6) loss of lung elasticity and enlarged lung airspaces. From these mechanisms, the proposed MOA analysis identifies the key cellular processes in acrolein respiratory toxicity that consistently occur with the development of COPD: inflammation and necrosis in the middle and lower regions of the respiratory tract. Moreover, the acrolein exposures that occur as a result of smoking are well above exposures that induce both inflammation and necrosis in laboratory animals, highlighting the importance of the role of acrolein in smoking-related respiratory disease. PMID- 26969373 TI - Changes in cerebral oxygen saturation during transcatheter aortic valve replacement. AB - Cerebral oxygen saturation (rSO2) is a non-invasive monitor used to monitor cerebral oxygen balance and perfusion. Decreases in rSO2 >20 % from baseline have been associated with cerebral ischemia and increased perioperative morbidity. During transcatheter aortic valve replacement (TAVR), hemodynamic manipulation with ventricular pacing up to 180 beats per minute is necessary for valve deployment. The magnitude and duration of rSO2 change during this manipulation is unclear. In this small case series, changes in rSO2 in patients undergoing TAVR are investigated. Ten ASA IV patients undergoing TAVR with general anesthesia at a university hospital were prospectively observed. Cerebral oximetry values were analyzed at four points: pre-procedure (baseline), after tracheal intubation, during valve deployment, and at procedure end. Baseline rSO2 values were 54.5 +/- 6.9 %. After induction of general anesthesia, rSO2 increased to a mean of 66.0 +/ 6.7 %. During valve deployment, the mean rSO2 decreased <20 % below baseline to 48.5 +/- 13.4 %. In two patients, rSO2 decreased >20 % of baseline. Cerebral oxygenation returned to post-induction values in all patients 13 +/- 10 min after valve deployment. At procedure end, the mean rSO2 was 67.6 +/- 8.1 %. As expected, rapid ventricular pacing resulting in the desired decrease in cardiac output during valve deployment was associated with a significant decrease in rSO2 compared to post-induction values. However, despite increased post-induction values in all patients, whether related to increased inspired oxygen fraction or reduced cerebral oxygen consumption under anesthesia, two patients experienced a significant decrease in rSO2 compared to baseline. Recovery to baseline was not immediate, and took up to 20 min in three patients. Furthermore, baseline rSO2 in this population was at the lower limit of the published normal range. Significant cerebral desaturation during valve deployment may potentially be limited by maximizing rSO2 after anesthetic induction. Future studies should attempt to correlate recovery in rSO2 with recovery of hemodynamics and cardiac function, provide detailed neurological assessments pre and post procedure, determine the most effective method of maximizing rSO2 prior to hemodynamic manipulation, and provide the most rapid method of recovery of rSO2 following valve deployment. PMID- 26969375 TI - From intention to perception: The case of anosognosia for hemiplegia. AB - Brain-damaged patients with anosognosia for hemiplegia deny their motor deficit and believe they can still move the paralyzed limb. Previous studies suggest that anosognosia can arise from intact motor intentionality and planning for the plegic hand. However, few studies focused on the relationship between this spared intentionality and perception. To further investigate this topic, we used an apparent motion paradigm, where a stimulus generated an ambiguous motion and participants were simply asked to judge its direction (right or left). We confirmed that, when healthy participants are asked to press a key either with their right or left hand, triggering the apparent motion, they show a perceptual bias toward the direction of the moving hand. Both bimanual and unimanual modalities (i.e. key pressing with-both-hands or with-one-hand, respectively) of the same apparent motion paradigm were administered to two groups of healthy participants. Interestingly, only in the bimanual modality, participants showed a significant perceptual bias. Hemiplegic patients with and without anosognosia, were requested to perform the bimanual task. Patients without anosognosia, fully aware of their left motor deficit, only programed right hand movements, behaving similarly to healthy controls performing the unimanual task. On the contrary, in patients with anosognosia, an effective motor intentionality for the left (plegic) hand influenced visual perception, giving rise to similar perceptual bias as that found in healthy controls actually performing bimanual movements. These findings suggest that having a specific motor representation can lead to different outcomes in the perception of the outside world. PMID- 26969376 TI - Editorial: Family Research and the Practice of Family Therapy. PMID- 26969372 TI - Integrating RNA-seq and ChIP-seq data to characterize long non-coding RNAs in Drosophila melanogaster. AB - BACKGROUND: Recent advances in sequencing technology have opened a new era in RNA studies. Novel types of RNAs such as long non-coding RNAs (lncRNAs) have been discovered by transcriptomic sequencing and some lncRNAs have been found to play essential roles in biological processes. However, only limited information is available for lncRNAs in Drosophila melanogaster, an important model organism. Therefore, the characterization of lncRNAs and identification of new lncRNAs in D. melanogaster is an important area of research. Moreover, there is an increasing interest in the use of ChIP-seq data (H3K4me3, H3K36me3 and Pol II) to detect signatures of active transcription for reported lncRNAs. RESULTS: We have developed a computational approach to identify new lncRNAs from two tissue specific RNA-seq datasets using the poly(A)-enriched and the ribo-zero method, respectively. In our results, we identified 462 novel lncRNA transcripts, which we combined with 4137 previously published lncRNA transcripts into a curated dataset. We then utilized 61 RNA-seq and 32 ChIP-seq datasets to improve the annotation of the curated lncRNAs with regards to transcriptional direction, exon regions, classification, expression in the brain, possession of a poly(A) tail, and presence of conventional chromatin signatures. Furthermore, we used 30 time course RNA-seq datasets and 32 ChIP-seq datasets to investigate whether the lncRNAs reported by RNA-seq have active transcription signatures. The results showed that more than half of the reported lncRNAs did not have chromatin signatures related to active transcription. To clarify this issue, we conducted RT-qPCR experiments and found that ~95.24% of the selected lncRNAs were truly transcribed, regardless of whether they were associated with active chromatin signatures or not. CONCLUSIONS: In this study, we discovered a large number of novel lncRNAs, which suggests that many remain to be identified in D. melanogaster. For the lncRNAs that are known, we improved their characterization by integrating a large number of sequencing datasets (93 sets in total) from multiple sources (lncRNAs, RNA-seq and ChIP-seq). The RT-qPCR experiments demonstrated that RNA-seq is a reliable platform to discover lncRNAs. This set of curated lncRNAs with improved annotations can serve as an important resource for investigating the function of lncRNAs in D. melanogaster. PMID- 26969374 TI - Avoidant coping and self-efficacy mediate relationships between perceived social constraints and symptoms among long-term breast cancer survivors. AB - OBJECTIVE: Many breast cancer survivors feel constrained in discussing their cancer experience with others. Limited evidence suggests that social constraints (e.g., avoidance and criticism) from loved ones may negatively impact breast cancer survivors' global health, but research has yet to examine relationships between social constraints and common physical symptoms. Informed by social cognitive processing theory, this study examined whether perceived social constraints from partners and healthcare providers (HCPs) were associated with fatigue, sleep disturbance, and attentional functioning among long-term breast cancer survivors (N = 1052). In addition, avoidant coping and self-efficacy for symptom management were examined as potential mediators of these relationships. METHODS: Long-term breast cancer survivors (mean years since diagnosis = 6) completed questionnaires assessing social constraints from partners and HCPs, avoidant coping, self-efficacy for symptom management, and symptoms (i.e., fatigue, sleep disturbance, and attentional functioning). Structural equation modeling was used to evaluate the hypothesized relationships among variables in two models: one focused on social constraints from partners and one focused on social constraints from HCPs. RESULTS: Both models demonstrated good fit. Consistent with theory and prior research, greater social constraints from both partners and HCPs were associated with greater symptom burden (i.e., greater fatigue and sleep disturbance, poorer attentional functioning). In addition, all relationships were mediated by avoidant coping and self-efficacy for symptom management. CONCLUSIONS: Findings are consistent with social cognitive processing theory and suggest that symptom management interventions may be enhanced by addressing the impact of social constraints from survivors' partners and HCPs on their coping and self-efficacy. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969377 TI - Resveratrol improves the anticancer effects of doxorubicin in vitro and in vivo models: A mechanistic insight. AB - BACKGROUND: Resveratrol (RSVL), a well known dietary compound and in combination with doxorubicin (DOX) has gained a global importance for cancer prevention. However, mechanism of action by this combination is not well understood till date. HYPOTHESIS: The synergistic combination of RSVL and DOX might be more effective in anti-cancer activity by modulating the diverse cancer signaling pathways as compared to their alone treatments. METHODS: The cytotoxicity of alone and combination doses of RSVL and DOX were analyzed by colorimetric MTT(3 (4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) cell proliferation assay. The migration and colony forming abilities were evaluated by wound healing and clonogenic assays. Apoptosis was detected by Annexin V/PI and DAPI stainings. The cell cycle and intracellular reactive oxygen species (ROS) generation were measured by flow cytometry. The differential expression of genes and proteins were measured by qRT-PCR and western blotting analyses. Finally, in-vivo studies were performed in Ehrlich ascitic carcinoma (EAC) mouse model. RESULTS: The synergistic combination of DOX (IC20) and RSVL (IC30) was selected based on the combination index values in MCF-7 and MDA-MB-231 cell lines. This combination showed potent growth inhibition with ~2.5 fold of dose advantage and also significantly decreased the wound healing and clonogenic potential of breast cancer cells. The combination treatment was also found to inhibit the inflammatory response (NF-kB, COX-2), autophagic flux (LC3, Beclin-1), redox regulation (Nrf2) and induces apoptosis (BAX: BCL-2 ratio and Caspase-9) in breast cancer cells. Further, combined dosages of DOX (5 mg/kg b.wt) and RSVL (10 mg/kg b.wt) inhibited tumor volume with increased life span (139%, p value<0.05) in Ehrlich ascitic carcinoma (EAC) cells bearing mice. CONCLUSION: In brief, our results suggested that resveratrol chemosensitizes doxorubicin in combination, through inhibiting breast cancer cells proliferation and invasion, and inducing apoptosis via suppression of chronic inflammation and autophagy. PMID- 26969378 TI - Diosgenin induces ROS-dependent autophagy and cytotoxicity via mTOR signaling pathway in chronic myeloid leukemia cells. AB - BACKGROUND: Diosgenin, a steroidal saponin isolated from legumes and yams, has been confirmed to possess potent anticancer effect on multifarious tumors including chronic myeloid leukemia (CML). PURPOSE: We aimed to further determine the anti-cancer activity of diosgenin and its mechanisms in CML cells. METHODS: The cell vitality was detected by MTT assay. Autophagic flux and reactive oxygen species (ROS) production were analyzed by laser scanning confocal microscope. Apoptosis was observed by flow cytometry. All proteins expression was examined by western blotting. RESULTS: Autophagy induction was demonstrated by examination of autophagic flux including autophagosomes accumulation, autophagosome-lysosome fusion and degradation of autophagosomes. Moreover, blocking autophagy with inhibitor chloroquine (CQ) and 3-methyladenine (3-MA), enhanced diosgenin-induced apoptosis, indicating the protective effect of autophagy in diosgenin-treated CML cells. Further study suggested that diosgenin-induced autophagy and cytotoxicity were accompanied by reactive oxygen species (ROS) generation and mammalian target of rapamycin (mTOR) signaling pathway inhibition. N-acetyl-L-cysteine (NAC) administration, a scavenger agent of ROS, could down-regulate diosgenin-induced autophagy via reversion of mTOR pathway inhibition. CONCLUSION: These results indicate that diosgenin obviously generates ROS and this oxidative pressure not only produces cytotoxic effect on CML cells but also induces autophagy. What's more, autophagy functions as a cytoprotective mechanism to overcome cytotoxicity of diosgenin in tumor cells and inhibition of autophagy can enhance the anti-CML activity of diosgenin. PMID- 26969379 TI - Comparative cytotoxicity of chelidonine and homochelidonine, the dimethoxy analogues isolated from Chelidonium majus L. (Papaveraceae), against human leukemic and lung carcinoma cells. AB - BACKGROUND: The search for new anticancer compounds is a crucial element of natural products research. PURPOSE: In this study the effects of naturally occurring homochelidonine in comparison to chelidonine on cell cycle progression and cell death in leukemic T-cells with different p53 status are described. METHODS: The mechanism of cytotoxic, antiproliferative, apoptosis-inducing effects and the effect on expressions of cell cycle regulatory proteins was investigated using XTT assay, Trypan blue exclusion assay, flow cytometry, Western blot analysis, xCELLigence, epi-fluorescence and 3D super resolution microscopy. A549 cells were used for xCELLigence, clonogenic assay and for monitoring microtubule stability. RESULTS: We found that homochelidonine and chelidonine displayed significant cytotoxicity in examined blood cancer cells with the exception of HEL 92.1.7 and U-937 exposed to homochelidonine. Unexpectedly, homochelidonine and chelidonine-induced cytotoxicity was more pronounced in Jurkat cells contrary to MOLT-4 cells. Homochelidonine showed an antiproliferative effect on A549 cells but it was less effective compared to chelidonine. Biphasic dose-depended G1 and G2/M cell cycle arrest along with the population of sub-G1 was found after treatment with homochelidonine in MOLT-4 cells. In variance thereto, an increase in G2/M cells was detected after treatment with homochelidonine in Jurkat cells. Treatment with chelidonine induced cell cycle arrest in the G2/M cell cycle in both MOLT-4 and Jurkat cells. MOLT-4 and Jurkat cells treated with homochelidonine and chelidonine showed features of apoptosis such as phosphatidylserine exposure, a loss of mitochondrial membrane potential and an increase in the caspases -3/7, -8 and -9. Western blots indicate that homochelidonine and chelidonine exposure activates Chk1 and Chk2. Studies conducted with fluorescence microscopy demonstrated that chelidonine and homochelidonine inhibit tubulin polymerization in A549 cells. CONCLUSION: Collectively, the data indicate that chelidonine and homochelidonine are potent inducers of cell death in cancer cell lines, highlighting their potential relevance in leukemic cells. PMID- 26969380 TI - Sinapine reverses multi-drug resistance in MCF-7/dox cancer cells by downregulating FGFR4/FRS2alpha-ERK1/2 pathway-mediated NF-kappaB activation. AB - BACKGROUND: Sinapine, an alkaloid derived from seeds of the cruciferous species, shows favorable biological properties, such as antioxidant and radio-protective activities. The inhibitory effect of sinapine on acquired chemoresistance in tumor cells and the underlying molecular mechanisms remain unknown. AIM: We examined the effect of sinapine on reversal of chemoresistance in Michigan Cancer Foundation 7 (MCF-7)/dox breast cancer cells. RESULTS: Combination treatment with sinapine and doxorubicin synergistically increased the cytotoxicity of doxorubicin in MCF-7/dox cells, as shown using a cell apoptosis assay. An accumulation assay demonstrated that sinapine increased the intracellular concentration of doxorubicin in a dose-dependent manner. Immunoblotting and real time polymerase chain reaction (RT-PCR) analysis showed that sinapine downregulated multi-drug resistance 1 (MDR1) expression. A significant correlation was observed between the expression of MDR1, phospho-factor receptor substrate (FRS), phospho-extracellular signal regulated kinase (ERK)1/2, and nuclear factor kappa B (NF-kappaB). Chromatin immunoprecipitation (ChIP) assay indicated that sinapine inhibited binding of the transcription factor NF-kappaB to the MDR1 promoter. CONCLUSIONS: Our findings indicated that sinapine played an important role in the downregulation of MDR1 expression through suppression of fibroblast growth factor receptor (FGFR)4/FRS2alpha-ERK1/2 mediated NF-kappaB activation in MCF-7/dox cancer cells. PMID- 26969381 TI - Potent effects of dioscin against gastric cancer in vitro and in vivo. AB - BACKGROUND: We previously reported the effect of dioscin on human gastric carcinoma SGC-7901 cells, but its effects on other gastric cancers are still unknown. PURPOSE: The present paper aimed to demonstrate the activity of dioscin against human gastric carcinoma MGC-803 and MKN-45. STUDY DESIGN: In our study, MGC-803 and MKN-45 cells were used to examine the effects of dioscin on human gastric carcinoma in vitro. The effects of dioscin against human gastric carcinoma in vivo were accomplished by the xenografts of MGC-803 cells in BALB/c nude mice. METHODS: AO/EB and DAPI staining, TEM, single cell gel electrophoresis and flow cytometry assays were used in cell experiments. Then, an iTRAQ-based proteomics approach, DNA and siRNA transfection experiments were carried out for mechanism investigation. RESULTS: In MGC-803 cells, dioscin caused DNA damage and mitochondrial change, induced ROS generation, Ca(2+) release and cell apoptosis, and blocked cell cycle at S phase. In vivo results showed that dioscin significantly suppressed the tumor growth of MGC-803 cell xenografts in nude mice. In addition, dioscin markedly inhibited cell migration, caused Cytochrome c release and adjusted mitochondrial signal pathway. Then, an iTRAQ-based proteomics approach was carried out and 121 differentially expressed proteins were found, in which five biomarkers associated with cell cycle, apoptosis and migration were evaluated. Dioscin significantly up-regulated the levels of GALR-2 and RBM-3, and down-regulated CAP-1, Tribbles-2 and CliC-3. Furthermore, overexpressed DNA transfection of CAP-1 enhanced cell migration and invasion, which was decreased by dioscin. SiRNA to Tribbles-2 affected the protein levels of Bcl-2, Bax and MAPKs, suggesting that dioscin decreased Tribbles-2 level leading to cell apoptosis. CONCLUSION: Our works confirmed the activity of dioscin against gastric cancer. In addition, this work also provided that dioscin is a new potent candidate for treating gastric cancer in the future. PMID- 26969382 TI - Anti-angiogenic activity and mechanism of kaurane diterpenoids from Wedelia chinensis. AB - BACKGROUND: Wedelia chinensis is a traditional medicinal herb used in Asia and it has been reported to possess various bioactivities including anti-inflammatory and anticancer effects. However, its anti-angiogenic activity has never been reported. PURPOSE: To determine the most potent anti-angiogenic component in W. chinensis and its molecular mechanism of action. STUDY DESIGN: Initially, the active fraction of the plant was studied. Then, we determined the active components of the fraction and explored the mechanism of the most active compound. METHODS: The ethanol extract of W. chinensis and its four fractions with different polarities were evaluated for their anti-angiogenic activity in the Zebrafish model using quantitative endogenous alkaline phosphatase (EAP) assay. The molecular mechanism of the most active compound from the active fraction was studied using the real-time polymerase chain reaction (PCR) assay on Zebrafish embryos. The inhibitory effect of the most active compound on the proliferation, invasion and tube formation steps of angiogenesis was evaluated using the vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cells (HUVECs) model, and the influences of the active compound on tyrosine phosphorylation of VEGF receptor (VEGFR-2) and its downstream signal pathway were evaluated by western blotting assay. Moreover, its anti-angiogenic effect was further evaluated by the VEGF-induced sprouts formation on aortic ring assay and the VEGF-induced vessel formation of mice on matrigel plug assay, respectively. RESULTS: Petroleum ether (PE) fraction of the plant displayed potent anti-angiogenic activity. Twelve kaurane diterpenoids (1-12) isolated from this fraction showed quite different effects. Compounds 9-12 could dose dependently inhibit vessel formation in the Zebrafish embryos while the others showed little inhibitory effect. Among the active diterpenoids, compound 10, 3alpha-cinnamoyloxy-9beta-hydroxy-ent-kaura-16-en-19-oic acid (CHKA), possessed the strongest effect, and it affected multiple molecular targets related to angiogenesis including VEGF and angiopoietin in Zerbrafish. Moreover, CHKA significantly inhibited a series of VEGF-induced angiogenesis processes including proliferation, invasion, and tube formation of endothelial cells. Besides, it directly inhibited VEGFR-2 tyrosine kinase activity and its downstream signaling pathways in HUVECs. CHKA also obviously inhibited sprouts formation of aortic ring, and block vessel formation in mice. CONCLUSION: Our findings demonstrate that kaurane diterpenoids is one of anti-angiogenic components in W. chinensis, and CHKA may become a promising candidate for the development of anti-angiogenic agent. PMID- 26969383 TI - Evaluating ancient Egyptian prescriptions today: Anti-inflammatory activity of Ziziphus spina-christi. AB - BACKGROUND: Ziziphus spina-christi (L.) Desf. (Christ's Thorn Jujube) is a wild tree today found in Jordan, Israel, Egypt, and some parts of Africa, which was already in use as a medicinal plant in Ancient Egypt. In ancient Egyptian prescriptions, it was used in remedies against swellings, pain, and heat, and thus should have anti-inflammatory effects. Nowadays, Z. spina-christi, is used in Egypt (by Bedouins, and Nubians), the Arabian Peninsula, Jordan, Iraq, and Morocco against a wide range of illnesses, most of them associated with inflammation. Pharmacological research undertaken to date suggests that it possesses anti-inflammatory, hypoglycemic, hypotensive and anti-microbial effects. The transcription factor NF-kappaB (nuclear factor kappa-light-chain enhancer of activated B cells) is critical in inflammation, proliferation and involved in various types of cancer. Identification of new anti-inflammatory compounds might be an effective strategy to target inflammatory disorders and cancer. Therefore, extracts from Z. spina-christi are investigated in terms of their anti-inflammatory effects. Our intention is to evaluate the effects of Z. spina-christi described in ancient Egyptian papyri, and to show whether the effects can be proven with modern pharmacological methods. Furthermore, we determine the active ingredients in crude extracts for their inhibitory activity toward NF-kappaB pathway. MATERIALS AND METHODS: To determine the active ingredients of Z. spina-christi, we fractionated the extracts for bioassays and identified the active compounds. Epigallocatechin, gallocatechin, spinosin, 6''' feruloylspinosin and 6''' sinapoylspinosin and crude extracts of seed, leaf, root or stem were analyzed for their effect on NF-kappaB DNA binding by electromobility shift assay (EMSA) and nuclear translocation of NF-kappaB-p65 by Western blot analysis. The binding mode of the compounds to NF-kappaB pathway proteins was compared with the known inhibitor, MG-132, by in silico molecular docking calculations. Log10IC50 values of gallocatechin and epigallocatechin as two main compounds of the plant were correlated to the microarray-based mRNA expression of 79 inflammation-related genes in cell lines of the National Cancer Institute (NCI, USA) as determined. The expression of 17 genes significantly correlated to the log10IC50 values for gallocatechin or epigallocatechin. RESULTS: Nuclear p65 protein level decreased upon treatment with each extract and compound. Root and seed extracts inhibited NF-kappaB-DNA binding as shown by EMSA. The compounds showed comparable binding energies and similar docking poses as MG-132 on the target proteins. CONCLUSION: Z. spina-christi might possess anti inflammatory activity as assumed by ancient Egyptian prescriptions. Five compounds contributed to this bioactivity, i.e. epigallocatechin, gallocatechin, spinosin, 6''' feruloylspinosin and 6''' sinapoylspinosin as shown in vitro and in silico. PMID- 26969384 TI - A Myrtus communis extract enriched in myrtucummulones and ursolic acid reduces resistance of Propionibacterium acnes biofilms to antibiotics used in acne vulgaris. AB - BACKGROUND: Recent works present evidence of Propionibacterium acnes growing as a biofilm in cutaneous follicles. This formation of clusters is now considered as an explanation for the in vivo resistance of P. acnes to the main antimicrobials prescribed in acne vulgaris. PURPOSE: Our objective was to explore this hypothesis and propose a new therapeutic approach focusing on anti-biofilm activity of Myrtacine((r)) New Generation (Mediterranean Myrtle extract-Botanical Expertise P. Fabre) alone or combined with antibiotics. METHODS/RESULTS: Using in vitro models able to promote the growth of adhered bacteria, the loss of sensitivity of P. acnes biofilms (48 h) towards erythromycin and clindamycin was checked considering either sensitive or resistant strains. In the same time, the activity of Myrtacine((r)) New Generation against biofilm formation and mature biofilm (48 h) was evaluated. Using a dynamic model of biofilm formation, we noted an inhibition of biofilm formation (addition of Myrtacine((r)) New Generation at T 0) and a significant effect on mature biofilm (48 h) for 5 min of contact. This effect was also checked using the static model of biofilm formation for Myrtacine((r)) New Generation concentrations ranging from 0.03% to 0.0001%. A significant, dose-dependent anti-biofilm effect was observed and notable even at a concentration lower than the active concentration on planktonic cells, i.e. 0.001%. Finally, the interest of the combination of Myrtacine((r)) New Generation with antibiotics was explored. An enhanced efficacy was noted when erythromycin (1000 mg/l) or clindamycin (500 mg/l) was added to 0.001% Myrtacine((r)), leading to significant differences in comparison to each compound used alone. CONCLUSION: The efficiency of Myrtacine((r)) New Generation on P. acnes biofilm alone or combined with antibiotics was demonstrated and can lead to consider it as a potent adjunctive product efficient during the antibiotic course for acne vulgaris treatment. PMID- 26969386 TI - Methyl syringate, a TRPA1 agonist represses hypoxia-induced cyclooxygenase-2 in lung cancer cells. AB - BACKGROUND: We have previously found that methyl syringate is a specific and selective agonist of the human transient receptor potential channel ankyrin 1 (TRPA1) and suppresses food intake and gastric emptying in imprinting control region mice. Because TRPA1 has been implicated in inflammatory responses, and inflammation and tumorigenesis are stimulated by the cyclooxygenase-2 (COX 2)/prostaglandin E2 pathway in hypoxic cancer cells. PURPOSE: This study examined the effects of methyl syringate on hypoxia-induced COX-2 in human distal lung epithelial A549 cells. STUDY DESIGN: The effect of the methyl syringate on suppression of hypoxia-induced COX-2 in A549 cells were determined by Western blot and/or quantitative real-time polymerase chain reaction. The anti-invasive effect of methyl syringate was evaluated on A549 cells using matrigel invasion assay. RESULTS: Methyl syringate suppressed hypoxia-induced COX-2 protein and mRNA expression and promoter activity and reduced hypoxia-induced cell migration and invasion and secretion of vascular endothelial growth factor. These effects were antagonized by a TRPA1 antagonist, implying their mediation by the TRPA1 pathway. CONCLUSION: Together, these results indicate that methyl syringate inhibits the hypoxic induction of COX-2 expression and cell invasion through TRPA1 activation. These findings suggest that methyl syringate could be effective to suppress hypoxia-induced inflammation and indicate an additional functional effect of methyl syringate. PMID- 26969385 TI - beta-carotene reverses multidrug resistant cancer cells by selectively modulating human P-glycoprotein function. AB - BACKGROUND: The issue of multidrug resistance (MDR) cancer is one of the major barriers to successful chemotherapy treatment. The ATP-binding cassette (ABC) efflux transporters play an important role in the chemotherapeutic failure. Several generations of ABC efflux transporter inhibitors have been developed, however, none of them could provide better clinical outcome due to systemic toxicities and significant drug-drug interactions. Therefore, the present study focused on identifying the effect of the natural carotenoid on ABC transporters and may provide a safer choice to defeat MDR cancer. PURPOSE: The aim of the present study was to evaluate the inhibitory potency of beta-carotene on the ABC efflux transporters, as well as the reversal effect of beta-carotene toward MDR cancers. The underlying molecular mechanisms and inhibitory kinetics of beta carotene on the major ABC efflux transporter, P-glycoprotein, were further investigated. METHODS: The human P-gp (ABCB1/Flp-In(TM)-293), MRP1 (ABCC1/Flp In(TM)-293) and BCRP (ABCG2/Flp-In(TM)-293) stable expression cells were established by using the Flp-In(TM) system. The cytotoxicity of beta-carotene was evaluated by MTT assay in the established cell lines, sensitive cancer cell lines (HeLaS3 and NCI-H460) and resistant cancer cell lines (KB-vin and NCI-H460/MX20). Surface protein detection assay and eFluxx-ID Green Dye assay were applied for confirmation of surface expression and function of the transporters. The transporter inhibition potency of beta-carotene was evaluated by calcein-AM uptake assay and mitoxantrone accumulation assay. Further interaction kinetics between beta-carotene and P-gp were analyzed by rhodamine123 and doxorubicin efflux assay. The influence of beta-carotene on ATPase activity was evaluated by Pgp-Glo(TM) Assay System. RESULTS: Among the tested ABC efflux transporters, beta carotene significantly inhibited human P-gp efflux function without altering ABCB1 mRNA expression. Furthermore, beta-carotene stimulated both P-gp basal ATPase activity and the verapamil-stimulated P-gp ATPase activity. In addition, beta-carotene exerted partially inhibitory effect on BCRP efflux function. The combination of beta-carotene and chemotherapeutic agents significantly potentiated their cytotoxicity in both cell stably expressed human P-gp (ABCB1/Flp-In(TM)-293) and MDR cancer cells (KB-vin and NCI-H460/MX20). CONCLUSION: The present study indicated that beta-carotene may be considered as a chemo-sensitizer and regarded as an adjuvant therapy in MDR cancer treatment. PMID- 26969387 TI - A new cell line for high throughput HIV-specific antibody-dependent cellular cytotoxicity (ADCC) and cell-to-cell virus transmission studies. AB - Several lines of evidence indicate that antibody-dependent cellular cytotoxicity (Wren et al., 2013) is important in the pathogenesis of HIV-1 infection. Namely, ADCC is induced during natural HIV-1 infection or in HIV-1 vaccine studies, the latter demonstrated by the RV144 vaccine trial. To expedite the assessment of ADCC in studies of HIV, we have developed a high throughput assay. We have optimized the rapid fluorometric antibody-mediated cytotoxicity assay (RFADCC) by transfecting the EGFP-CEM-NKr cell line to constitutively express SNAP-tagged CCR5. This cell line can then serve as a source of HIV-specific targets when coated with monomeric gp120, spinoculated with inactivated intact virions, infected by cell-free viral diffusion or infected by cell-to-cell transmission of virus. The optimized strategy has two significant advantages over the original RFADCC method: First, the preparation of detectable target cells is less labor intensive and faster as it does not rely on multiple staining and washing steps for target cells. Second, because the target cell markers GFP and SNAP are constitutively expressed, the assay provides highly reproducible data. These strengths make the optimized RFADCC assay suitable not only for studies of HIV-1 specific cytotoxicity but also for studies of cell-cell transmission of virus. In conclusion, this assay provides a new generation T cell line that can expedite large clinical studies as well as research studies in humans or non-human primates. PMID- 26969389 TI - Do anti-smooth muscle antibodies predict development of autoimmune hepatitis in patients with normal liver function? - A retrospective cohort review. AB - BACKGROUND: The presence of anti-smooth muscle autoantibody (SMA) in Autoimmune Hepatitis (AIH) is well established. However, there are no data demonstrating the clinical significance in patients with normal liver function and few showing positive predictive value for AIH when alanine aminotransferase (ALT) is raised. METHODS: We retrospectively established outcomes in a cohort of 251 consecutive patients with positive tubular or glomerular SMA. Patient records were checked for 12years after the positive SMA result to identify development of AIH. RESULTS: Of 202 patients with SMA and ALT <55IU/L, one (0.5%) had a subsequent diagnosis of AIH and this patient probably had abnormal ALT at the time of SMA detection. 22% of 45 patients with raised ALT (>55IU/L) and 23% of 43 patients with persistently raised ALT (>3months duration), had a diagnosis of AIH on follow up. Of 10 patients with AIH, 80% were diagnosed within three months of the positive SMA. CONCLUSIONS: Progression to AIH in patients with normal liver function and positive SMA-T/G is rare but patients with positive SMA and raised ALT (>55IU/L) should be referred to secondary care for investigation. Positive predictive value of SMA with raised ALT for AIH was 22%. PMID- 26969390 TI - [A strange facial mutilation]. PMID- 26969391 TI - Aluminum, the genetic apparatus of the human CNS and Alzheimer's disease (AD). AB - The genomes of eukaryotes orchestrate their expression to ensure an effective, homeostatic and functional gene signaling program, and this includes fundamentally altered patterns of transcription during aging, development, differentiation and disease. These actions constitute an extremely complex and intricate process as genetic operations such as transcription involve the very rapid translocation and polymerization of ribonucleotides using RNA polymerases, accessory transcription protein complexes and other interrelated chromatin proteins and genetic factors. As both free ribonucleotides and polymerized single stranded RNA chains, ribonucleotides are highly charged with phosphate, and this genetic system is extremely vulnerable to disruption by a large number of electrostatic forces, and primarily by cationic metals such as aluminum. Aluminum has been shown by independent researchers to be particularly genotoxic to the genetic apparatus, and it has become reasonably clear that aluminum disturbs genetic signaling programs in the CNS that bear a surprising resemblance to those observed in Alzheimer's disease (AD) brain. This paper will focus on a discussion of two molecular-genetic aspects of aluminum genotoxicity: (1) the observation that micro-RNA (miRNA)-mediated global gene expression patterns in aluminum treated transgenic animal models of AD (Tg-AD) strongly resemble those found in AD; and (2) the concept of "human biochemical individuality" and the hypothesis that individuals with certain gene expression patterns may be especially sensitive and perhaps predisposed to aluminum genotoxicity. PMID- 26969392 TI - Bone resorptive activity of human peripheral blood mononuclear cells after fusion with polyethylene glycol. AB - The bone remodeling process occurs through bone formation by osteoblasts and bone resorption by osteoclasts, a process involving the contribution of endocrine and nervous systems. The mechanisms associated to differentiation and proliferation of osteoclasts and osteoblasts are considered a potential therapeutic target for treating some erosive bone diseases. The aim of the present study is to explore the feasibility of generating active osteoclast-like cells from peripheral blood mononuclear cells (PBMCs) following polyethylene glycol (PEG)-induced fusion. PEG fused PBMCs showed TRAP+-multinucleated cells and bone resorption activity, and were also positive for osteoclast markers such as carbonic anhydrase II, calcitonin receptor, vacuolar ATPase, and cathepsin K, when examined by reverse transcription-polymerase chain reaction, immunochemistry and Western blotting. TRAP expression and bone resorptive activity were higher in whole PEG-fused PBMCs than in separated T lymphocytes, B lymphocytes or monocytes. Both TRAP expression and bone resorptive activity were also higher in osteogenesis imperfecta patients compared to PEG-fused PBMCs from healthy individuals. PEG-induced fusion was more efficient in inducing TRAP and bone resorptive activities than macrophage colony stimulating factor or dexamethasone treatment. Bone resorptive activity of PEG fused PMBCs was inhibited by bisphosphonates. Evidence is provided that the use of PEG-based cell fusion is a straightforward and amenable method for studying human osteoclast differentiation and testing new therapeutic strategies. PMID- 26969393 TI - Predicting bone mineral acquisition during puberty: data from a 3-year follow-up study in Hamamatsu, Japan. AB - Although most adult bone mass is acquired before adolescence, only a few studies have assessed bone turnover markers in children. Thus, the utility of bone markers to evaluate and predict bone mineral accrual in children is unclear. The present study assessed the association between serum bone markers at 11 years of age and subsequent changes in bone gain. Information on bone minerals and bone markers at baseline and at the 3-year follow-up were obtained from 121 children who registered as fifth-grade students in 2010, in Hamamatsu, Japan. Whole-body bone mineral content (WBBMC) and whole-body bone mineral density (WBBMD) were measured using dual-energy X-ray absorptiometry. Boys showed significant (P < 0.05) positive relationships between intact osteocalcin at baseline and WBBMC at follow-up (beta = 0.24), between tartrate-resistant acid phosphatase isoenzyme 5b (TRAP5b) and WBBMC (beta = 0.34), and between TRAP5b and WBBMD (beta = 0.34), after adjusting for potential confounding factors. In girls, adjusted means of 3 year gain in both WBBMC and WBBMD significantly increased from the lowest to highest quartiles of type 1 collagen cross-linked C-terminal telopeptide. In boys, adjusted means of 3-year gain in both WBBMC and WBBMD significantly increased from the lowest to highest quartiles of TRAP5b. Children with a high concentration of bone turnover markers tended to exhibit substantial accrual of bone minerals. These results suggest that serum levels of circulating biomarkers at age 11 predict subsequent bone mineral accrual. PMID- 26969394 TI - The current progress in understanding the molecular functions and mechanisms of visfatin in osteoarthritis. AB - Osteoarthritis, (OA), also known as degenerative arthritis or degenerative joint disease, is the most common form of arthritis, affecting millions of people worldwide. It is a group of mechanical abnormalities involving degradation of the joints and occurs when the protective cartilage (articular cartilage) on the ends of bones such as the knees, hips and fingers abrades over time. It mainly affects the whole joint structure, including the articular cartilage, subchondral bone and synovial tissue. Extensive work has been done in the past decades to investigate the cellular mechanism of this disease. However, to date, it is still poorly understood, and there is no effective treatment. Recently, both in vitro and in vivo studies have confirmed adipokines play critical roles during OA development. Among these, leptin and adiponectin have been well investigated, whereas the effect of the novel adipokine, visfatin, on OA still needs to be revealed. Therefore, in this short review, we will focus on visfatin and summarize the current progress in the research on its role in OA development. PMID- 26969395 TI - Cost-effectiveness of dual-energy X-ray absorptiometry plus antiresorptive treatment in Australian women with breast cancer who receive aromatase inhibitors. AB - Postmenopausal women with breast cancer on aromatase inhibitor (AI) treatment are at increased risk of bone mineral density loss, which may lead to minimal trauma fractures. We examined the cost-effectiveness of dual energy X-ray absorptiometry (DXA) with antiresorptive (AR) therapy compared with fracture risk assessment, lifestyle advice, and vitamin supplementation. We used a hypothetical Markov cohort model of lifetime duration for 60-year-old women with early stage breast cancer receiving AIs. The data to inform the model came from medical literature, epidemiological reports, and costing data sets. Two eligibility scenarios for AR therapy were considered: (A) osteoporosis and (B) osteopenia or osteoporosis. The main outcomes were incremental cost per quality-adjusted life years gained and cumulative fractures per 1000 women, calculated relative to the comparator. Key aspects of the model were explored in sensitivity analyses. Due to relatively low effectiveness gains, the outcomes were primarily driven by the costs. The incremental cost per quality-adjusted life year gained was A$47,556 and A$253,000 for scenarios A and B, respectively. The numbers of fractures avoided were 56 and 77 per 1000 women, respectively. The results were most sensitive to the initial probability of osteoporosis, baseline risk of fracture, and cohort starting age. Compared with risk assessment and lifestyle advice only, a DXA scan followed by an AR treatment is potentially cost-effective for women aged 60 and over undergoing AI therapy for early breast cancer. However, the number of fractures averted through this intervention is small. PMID- 26969396 TI - Variability in Rheumatology day care hospitals in Spain: VALORA study. AB - OBJECTIVE: To describe the variability of the day care hospital units (DCHUs) of Rheumatology in Spain, in terms of structural resources and operating processes. MATERIAL AND METHODS: Multicenter descriptive study with data from a self completed questionnaire of DCHUs self-assessment based on DCHUs quality standards of the Spanish Society of Rheumatology. Structural resources and operating processes were analyzed and stratified by hospital complexity (regional, general, major and complex). Variability was determined using the coefficient of variation (CV) of the variable with clinical relevance that presented statistically significant differences when was compared by centers. RESULTS: A total of 89 hospitals (16 autonomous regions and Melilla) were included in the analysis. 11.2% of hospitals are regional, 22,5% general, 27%, major and 39,3% complex. A total of 92% of DCHUs were polyvalent. The number of treatments applied, the coordination between DCHUs and hospital pharmacy and the post graduate training process were the variables that showed statistically significant differences depending on the complexity of hospital. The highest rate of rheumatologic treatments was found in complex hospitals (2.97 per 1,000 population), and the lowest in general hospitals (2.01 per 1,000 population). The CV was 0.88 in major hospitals; 0.86 in regional; 0.76 in general, and 0.72 in the complex. CONCLUSIONS: there was variability in the number of treatments delivered in DCHUs, being greater in major hospitals and then in regional centers. Nonetheless, the variability in terms of structure and function does not seem due to differences in center complexity. PMID- 26969398 TI - Regulation of vitamin D receptor expression by retinoic acid receptor alpha in acute myeloid leukemia cells. AB - Acute myeloid leukemia (AML) is the predominant acute leukemia among adults, characterized by an accumulation of malignant immature myeloid precursors. A very promising way to treat AML is differentiation therapy using either all-trans retinoic acid (ATRA) or 1,25-dihydroxyvitamin D3 (1,25D), or the use of both these differentiation-inducing agents. However, the effect of combination treatment varies in different AML cell lines, and this is due to ATRA either down or up-regulating transcription of vitamin D receptor (VDR) in the cells examined. The mechanism of transcriptional regulation of VDR in response to ATRA has not been fully elucidated. Here, we show that the retinoic acid receptor alpha (RARalpha) is responsible for regulating VDR transcription in AML cells. We have shown that a VDR transcriptional variant, originating in exon 1a, is regulated by RARalpha agonists in AML cells. Moreover, in cells with a high basal level of RARalpha protein, the VDR gene is transcriptionally repressed as long as RARalpha agonist is absent. In these cells down-regulation of the level of RARalpha leads to increased expression of VDR. We consider that our findings provide a mechanistic background to explain the different outcomes from treating AML cell lines with a combination of ATRA and 1,25D. PMID- 26969399 TI - Uterine fibroid: from pathogenesis to clinical management. PMID- 26969397 TI - Age, APOE and sex: Triad of risk of Alzheimer's disease. AB - Age, apolipoprotein E epsilon4 (APOE) and chromosomal sex are well-established risk factors for late-onset Alzheimer's disease (LOAD; AD). Over 60% of persons with AD harbor at least one APOE-epsilon4 allele. The sex-based prevalence of AD is well documented with over 60% of persons with AD being female. Evidence indicates that the APOE-epsilon4 risk for AD is greater in women than men, which is particularly evident in heterozygous women carrying one APOE-epsilon4 allele. Paradoxically, men homozygous for APOE-epsilon4 are reported to be at greater risk for mild cognitive impairment and AD. Herein, we discuss the complex interplay between the three greatest risk factors for Alzheimer's disease, age, APOE-epsilon4 genotype and chromosomal sex. We propose that the convergence of these three risk factors, and specifically the bioenergetic aging perimenopause to menopause transition unique to the female, creates a risk profile for AD unique to the female. Further, we discuss the specific risk of the APOE-epsilon4 positive male which appears to emerge early in the aging process. Evidence for impact of the triad of AD risk factors is most evident in the temporal trajectory of AD progression and burden of pathology in relation to APOE genotype, age and sex. Collectively, the data indicate complex interactions between age, APOE genotype and gender that belies a one size fits all approach and argues for a precision medicine approach that integrates across the three main risk factors for Alzheimer's disease. PMID- 26969400 TI - Varicella zoster virus related deaths and hospitalizations before the introduction of universal vaccination with the tetraviral vaccine. AB - OBJECTIVE: To characterize varicella zoster virus-related deaths and hospitalizations in Brazil before universal vaccination with the tetravalent (measles, mumps, rubella, and varicella) vaccine, attempting to collect baseline data on varicella morbidity and mortality in order to evaluate the impact of the varicella vaccination program. METHODS: Varicella-associated mortality data were evaluated between 1996 and 2011 and varicella zoster virus-associated hospitalizations between 1998 and 2013. Data were gathered from the Informatics Department of the Unified Health System, considering the International Classification of Diseases, 10th Revision, code B01. All age groups were assessed. Varicella-specific mortality rates were calculated and seasonality of varicella-zoster virus-associated hospitalizations was described. RESULTS: There were 2334 varicella deaths between 1996 and 2011, 19.3% in infants aged less than 1 year and 36% in children from 1 to 4 years. In infants under 1 year, varicella mortality rates reached 3.2/100,000/year. In children aged 1-4 years, varicella mortality rates reach 1.64/100,000/year. Average annual mortality rates for varicella in Brazil are 0.88/100,000 in infants under 1 year and 0.40/100,000 in children aged 1-4 years. The total number of hospitalizations associated with varicella zoster virus was 62,246 from 2008 to 2013. Varicella-associated hospitalizations have a seasonal distribution in children, peaking in November. In the elderly, monthly averages of herpes zoster-associated hospitalizations present no significant seasonal variation. CONCLUSIONS: Varicella is associated, in the pre-vaccine period, to significant morbidity and mortality in Brazil. The universal vaccination program is expected to decrease the disease burden from varicella. PMID- 26969401 TI - Reply: Vertical segmental tetrapolar bioimpedance for excess body fat assessment in adolescents. PMID- 26969402 TI - Ethnobotanical study on the medicinal plants in the Mainarde Mountains (central southern Apennine, Italy). AB - ETHNOPHARMACOLOGICAL RELEVANCE: New documentation of the uses of plants in the popular medicine of the Mainarde Mountain, a protected area of the central southern Apennine characterised by a high floristic richness, is here reported. MATERIALS AND METHODS: Field data were collected through semi-structured and open interviews with native People between 2011 and 2014. The plants were identified and vouchers specimens were scanned to create a Virtual Herbarium. The Ethnobotanicity Index (EI), the Relative Importance Index (RI) and the Fidelity Level Index (FL) were calculated. The plant uses surveyed in the study area were compared with those described in medical and ethnobotanical literature. RESULTS: Seventy-one interviews were conducted, the age range of the informants was between 21 and 98 years. The inventory included 106 taxa belonging to 45 families; among these, 87 were wild species and 20 were cultivated species. The uses recorded were 429, among these, 69.1% of the uses concerned internal applications to treat digestive system disorders, infections and respiratory system disorders mainly, while 31.9% concerned external applications, especially to treat skin/subcutaneous cellular tissue disorders and injuries. In particular, 17 new uses and 16 unusual and rarely mentioned plants are documented. CONCLUSION: The data collected support evidence on traditional uses for plant in the Apennine. Findings from medical flora and from new or rare medical uses reinforce the usefulness of such research efforts. PMID- 26969404 TI - Decreased risk of stroke in patients receiving traditional Chinese medicine for vertigo: A population-based cohort study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Patients with vertigo are reported to exhibit a higher risk of subsequent stroke. However, it remains unclear if Traditional Chinese Medicine (TCM), the most common form of complementary and alternative medicine, can help lower the risk of stroke for these patients. So the aim of the study was to investigate the effects of TCM on stroke risk among patients with vertigo. MATERIALS AND METHODS: This longitudinal cohort study used the Taiwanese National Health Insurance Research Database to identify 112,458 newly diagnosed vertigo patients aged >=20 years who received treatment between 1998 and 2007. Among these patients, 53,203 (47.31%) received TCM after vertigo onset (TCM users), and the remaining 59,201 patients were designated as a control group (non TCM users). All enrollees received follow-up until the end of 2012 to measure stroke incidence. Cox proportional hazards regression was used to compute the hazard ratio (HR) of stroke in recipients of TCM services. RESULTS: During 15 year follow-up, 5532 TCM users and 12,295 non-TCM users developed stroke, representing an incidence rate of 13.10% and 25.71% per 1000 person-years. TCM users had a significantly reduced risk of stroke compared to non-TCM users (adjusted HR=0.64; 95% confidence interval CI=0.59-0.74). The predominant effect was observed for those receiving TCM for more than 180 days (adjusted HR=0.52; 95% CI=0.49-0.56). Commonly used TCM formulae, including Ban-Xia-Bai-Zhu-Tian-Ma Tang, Ling-Gui-Zhu-Gan-Tang, Bai Zhi (Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., root), Ge Gen (Pueraria lobata (Willd.) Ohwi, root) and Hai Piao Xiao (Endoconcha Sepiae, Cuttlefish Bone) were significantly associated with lower risk of stroke. CONCLUSIONS: Results of this population-based study support the effects of TCM on reducing stroke risk, and may provide a reference for stroke prevention strategies. The study results may also help to integrate TCM into clinical intervention programs that provide a favorable prognosis for vertigo patients. PMID- 26969403 TI - Effects of the roots of Liriope Platyphylla Wang Et tang on gastrointestinal motility function. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Liriope platyphylla Wang et Tang continues to be used in Korea as a traditional medicine for the treatment of gastrointestinal (GI) disorders related to constipation and abnormal GI motility. AIM OF THE STUDY: Because GI disorders, especially GI motility dysfunctions, are major lifelong problems, the authors investigated the effects of a water extract of the roots of L. platyphylla Wang et Tang (LPE) on the pacemaker potentials (PPTs) of interstitial cells of Cajal (ICCs) and on GI motility in male ICR mice. MATERIALS AND METHODS: Enzymatic digestions were used to dissociate ICCs from small intestines, and the whole-cell patch-clamp configuration was used to record PPTs generated by cultured ICCs in vitro. In vivo effects of LPE on GI motility were investigated by measuring intestinal transit rates (ITRs) of Evans blue in normal mice and in acetic acid (AA) and streptozotocin (STZ)-induced diabetic mouse models of GI motility dysfunction. RESULTS: LPE dose-dependently depolarized PPTs in ICCs. Pretreatment with methoctramine (a muscarinic M2 receptor antagonist) did not block LPE-induced PPT depolarization. However, pretreatment with 4-DAMP (a muscarinic M3 receptor antagonist) blocked LPE-induced PPT depolarization. In addition, treatment with LY294002 (a phosphoinositide 3-kinase (PI3K) inhibitor) also blocked LPE-induced PPT depolarization. Intracellular GDPbetaS inhibited LPE induced PPT depolarization, and LPE-induced PPT depolarization was found to occur in a phospholipase C (PLC)- and a protein kinase C (PKC)-dependent manner. Pretreatment with Ca(2+)free solution or thapsigargin (a Ca(2+)-ATPase inhibitor in endoplasmic reticulum) abolished PPTs, and under these conditions, LPE did not depolarize ICC PPTs. In normal mice, ITRs were significantly and dose-dependently increased by LPE (0.01-1g/kg administered intragastrically (i.g.)). In addition, LPE (i.g.) significantly recovered GI motility dysfunctions in both animal models. CONCLUSION: LPE dose-dependently depolarizes ICC PPTs through M3 receptors via external and internal Ca(2+)regulation and via G protein-, PI3K-, PLC- and PKC- dependent pathways in vitro. Also, in vivo, LPE increased ITRs in treatment naive mice and our two mouse models of GI dysfunction. Therefore, this study shows that LPE offers a basis for the development of a prokinetic agent that prevents or alleviates GI motility dysfunctions. PMID- 26969405 TI - Antimicrobial and antioxidant activity and chemical characterisation of Erythrina stricta Roxb. (Fabaceae). AB - ETHNOPHARMACOLOGICAL RELEVANCE: The bark of Erythrina stricta Roxb. (Fabaceae) has been used in Indian indigenous systems as a remedy for rheumatism, stomach ache, asthma, dysentery, contact dermatitis, eczema and skin infections. However, there have been limited phytochemical or biological studies on the bark of E. stricta and there are no studies that align with its traditional medicinal uses. AIM OF THE STUDY: The aim of this study was to assess the antimicrobial and antioxidant activity of the stem bark of E. stricta to support its topical use in the treatment of contact dermatitis, eczema and skin infections and to isolate and identify any bioactive compounds. MATERIALS AND METHODS: MTT microdilution and disc diffusion assays were used to determine the antimicrobial activities of n-hexane, dichloromethane, ethyl acetate, methanol and water extracts of the bark of E. stricta. Column and preparative thin layer chromatography were used for the purification of the dichloromethane extract. The structures of the compounds isolated were elucidated by extensive 1D and 2D NMR spectroscopic techniques and comparison with published data. The antioxidant activities of the extracts were determined by DPPH free radical scavenging and FRAP assays and the antioxidant activity of the pure compounds by dot-blot and DPPH staining methods. RESULTS: The dichloromethane, ethyl acetate, and n-hexane extracts showed the most significant activity with MIC values of 7.8ug/mL, 125ug/mL, and 125ug/mL against a sensitive strain of Staphylococcus aureus. The dichloromethane and ethyl acetate extracts also showed significant activity against Candida albicans with MIC values of 125ug/mL and 1mg/mL respectively. GC-MS analysis of the n-hexane extract showed the presence of the antibacterial and antifungal compounds beta caryophyllene, caryophyllene oxide, alpha-selinene, beta-selinene, selin-11-en-4 alpha-ol, alpha-copaene and delta-cadenine. Phytochemical studies of the dichloromethane extract led to the isolation of the novel compound erynone (1), together with six known compounds; wighteone (2), alpinum isoflavone (3), luteone (4), obovatin (5), erythrinassinate B (6) and isovanillin (7). Luteone (4) exhibited the most significant antibacterial activity with minimum inhibitory quantity (MIQ) values of 1.88ug, 1.88ug and 3.75ug, respectively, against sensitive (MSSA) and resistant strains (MRSA and MDRSA) of S. aureus using a TLC bioautography assay. Erynone (1) exhibited the greatest DPPH free radical scavenging activity. CONCLUSIONS: Seven compounds, including a new chromanone, were isolated from the antimicrobial dichloromethane extract of the stem bark of E. stricta. Six of the seven compounds showed antibacterial and/or antioxidant activities. These findings provide support for the customary (traditional and contemporary) use of E. stricta bark for the treatment of skin and wound infections. PMID- 26969406 TI - Taking forward the World TB Day 2016 theme 'Unite to End Tuberculosis' for the WHO Africa Region. AB - Tuberculosis (TB) remains a global emergency, with an estimated 9.6 million new TB cases worldwide reported in 2014. Twenty-eight percent of these cases were in the World Health Organization (WHO) Africa Region, where the annual case detection rate was 281 per 100000 population-more than double the global average of 133 per 100000. Of the 9.6 million people who developed TB, an estimated 1.2 million (12%) were HIV-positive, and the Africa Region accounted for 74% of these cases. Three million people with TB remain undiagnosed and untreated. Globally, an estimated 480000 had multidrug-resistant TB (MDR-TB). Whilst of the African countries, only South Africa has reported a high prevalence of MDR-TB, it is likely that all of Sub-Saharan Africa has an unreported high load of drug resistant TB. Tragically, in 2014, only 48% of individuals diagnosed with MDR-TB had successful treatment and an estimated 190000 people died of MDR-TB. Of the global TB funding gap of US$ 0.8 billion, the largest funding gap was in the Africa Region, amounting to US$ 0.4 billion in 2015. The MDR-TB pandemic in particular now threatens to devastate entire regions and may fundamentally alter the life-expectancy and demographic profile of many countries in Sub-Saharan Africa. The theme designated for this year's World TB Day, March 24, 2016, is 'Unite to End TB'. From the Africa Region, there is an urgent need to seriously address the political, economic, and social factors that influence host Mycobacterium tuberculosis interactions and result in disease. Recent political and funder initiatives that provide renewed hope for the alleviation of Africa's TB and TB/HIV problems are discussed. PMID- 26969409 TI - Autophagy for the quality control of adult hippocampal neural stem cells. AB - Autophagy plays an important role in neurodegeneration, as well as in normal brain development and function. Recent studies have also implicated autophagy in the regulation of stemness and neurogenesis in neural stem cells (NSCs). However, little is known regarding the roles of autophagy in NSC biology. It has been shown that in addition to cytoprotective roles of autophagy, pro-death autophagy, or 'autophagic cell death (ACD),' regulates the quantity of adult NSCs. A tight regulation of survival and death of NSCs residing in the neurogenic niches through programmed cell death (PCD) is critical for maintenance of adult neurogenesis. ACD plays a primary role in the death of adult hippocampal neural stem (HCN) cells following insulin withdrawal. Despite the normal apoptotic capability of HCN cells, they are committed to death by autophagy following insulin withdrawal, suggesting the existence of a unique regulatory program that controls the mode of cell death. We propose that dual roles of autophagy for maintenance of NSC pluripotency, as well as for elimination of defective NSCs, may serve as a combined NSC quality control mechanism. This article is part of a Special Issue entitled SI:Autophagy. PMID- 26969407 TI - Polymorphisms at the F12 and KLKB1 loci have significant trait association with activation of the renin-angiotensin system. AB - BACKGROUND: Plasma coagulation Factor XIIa (Hageman factor; encoded by F12) and kallikrein (KAL or Fletcher factor; encoded by KLKB1) are proteases of the kallikerin-kinin system involved in converting the inactive circulating prorenin to renin. Renin is a key enzyme in the formation of angiotensin II, which regulates blood pressure, fluid and electrolyte balance and is a biomarker for cardiovascular, metabolic and renal function. The renin-angiotensin system is implicated in extinction learning in posttraumatic stress disorder. METHODS & RESULTS: Active plasma renin was measured from two independent cohorts- civilian twins and siblings, as well as U.S. Marines, for a total of 1,180 subjects. Genotyping these subjects revealed that the carriers of the minor alleles at the two loci- F12 and KLKB1 had a significant association with reduced levels of active plasma renin. Meta-analyses confirmed the association across cohorts. In vitro studies verified digestion of human recombinant pro-renin by kallikrein (KAL) to generate active renin. Subsequently, the active renin was able to digest the synthetic substrate angiotensinogen to angiotensin-I. Examination of mouse juxtaglomerular cell line and mouse kidney sections showed co-localization of KAL with renin. Expression of either REN or KLKB1 was regulated in cell line and rodent models of hypertension in response to oxidative stress, interleukin or arterial blood pressure changes. CONCLUSIONS: The functional variants of KLKB1 (rs3733402) and F12 (rs1801020) disrupted the cascade of enzymatic events, resulting in diminished formation of active renin. Using genetic, cellular and molecular approaches we found that conversion of zymogen prorenin to renin was influenced by these polymorphisms. The study suggests that the variant version of protease factor XIIa due to the amino acid substitution had reduced ability to activate prekallikrein to KAL. As a result KAL has reduced efficacy in converting prorenin to renin and this step of the pathway leading to activation of renin affords a potential therapeutic target. PMID- 26969410 TI - Maturation of nitrogenase cofactor-the role of a class E radical SAM methyltransferase NifB. AB - Nitrogenase catalyzes the important reactions of N2-reduction, CO-reduction and CO2-reduction at its active cofactor site. Designated the M-cluster, this complex metallocofactor is assembled through the generation of a characteristic 8Fe-core before the insertion of Mo and homocitrate that completes the stoichiometry of the M-cluster. NifB catalyzes the crucial step of radical SAM-dependent carbide insertion that occurs concomitant with the insertion a '9th' sulfur and the rearrangement/coupling of two 4Fe-clusters into a complete 8Fe-core of the M cluster. Further categorization of a family of NifB proteins as a new class of radical SAM methyltransferases suggests a general function of these proteins in complex metallocofactor assembly and provides a new platform for unveiling unprecedented chemical reactions catalyzed by biological systems. PMID- 26969408 TI - Locus coeruleus: From global projection system to adaptive regulation of behavior. AB - The brainstem nucleus locus coeruleus (LC) is a major source of norepinephrine (NE) projections throughout the CNS. This important property was masked in very early studies by the inability to visualize endogenous monoamines. The development of monoamine histofluorescence methods by Swedish scientists led to a plethora of studies, including a paper published in Brain Research by Loizou in 1969. That paper was highly cited (making it a focal point for the 50th anniversary issue of this journal), and helped to spark a large and continuing set of investigations to further refine our understating of the LC-NE system and its contribution to brain function and behavior. This paper very briefly reviews the ensuing advances in anatomical, physiological and behavioral aspects of the LC-NE system. Although its projections are ubiquitously present throughout the CNS, recent studies find surprising specificity within the organizational and operational domains of LC neurons. These and other findings lead us to expect that future work will unmask additional features of the LC-NE system and its roles in normative and pathological brain and behavioral processes. This article is part of a Special Issue entitled SI:50th Anniversary Issue. PMID- 26969411 TI - HiView: an integrative genome browser to leverage Hi-C results for the interpretation of GWAS variants. AB - BACKGROUND: Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with complex traits and diseases. However, most of them are located in the non-protein coding regions, and therefore it is challenging to hypothesize the functions of these non-coding GWAS variants. Recent large efforts such as the ENCODE and Roadmap Epigenomics projects have predicted a large number of regulatory elements. However, the target genes of these regulatory elements remain largely unknown. Chromatin conformation capture based technologies such as Hi-C can directly measure the chromatin interactions and have generated an increasingly comprehensive catalog of the interactome between the distal regulatory elements and their potential target genes. Leveraging such information revealed by Hi-C holds the promise of elucidating the functions of genetic variants in human diseases. RESULTS: In this work, we present HiView, the first integrative genome browser to leverage Hi-C results for the interpretation of GWAS variants. HiView is able to display Hi-C data and statistical evidence for chromatin interactions in genomic regions surrounding any given GWAS variant, enabling straightforward visualization and interpretation. CONCLUSIONS: We believe that as the first GWAS variants-centered Hi-C genome browser, HiView is a useful tool guiding post-GWAS functional genomics studies. HiView is freely accessible at: http://www.unc.edu/~yunmli/HiView . PMID- 26969412 TI - Predictors of physicians' satisfaction with their management of uncertainty during a decision-making encounter with a simulated advanced stage cancer patient. AB - OBJECTIVES: To optimize their training, predictors of physicians' satisfaction with their management of uncertainty should be examined. This study investigated these predictors by using a simulated advanced stage cancer patient. METHODS: Physicians (n=85) rated their satisfaction with their management of uncertainty (Visual Analog Scale-100mm) after a decision-making encounter. Communication predictors were examined with the: Observing Patient Involvement scale (OPTION), Multidimensional analysis of Patient Outcome Predictions (MD.POP) and Communication Content Analysis Software (LaComm). Psychological predictors were assessed with the: Intolerance of Uncertainty Inventory (IUI), Physicians' Reactions to Uncertainty scale (PRU), Decisional Conflict Scale (DCS), and Jefferson Scale of Physician Empathy (JSPE). RESULTS: Physicians' satisfaction (mean=67mm; standard deviation=17mm) was not predicted by their communication, but by their anxiety due to uncertainty (PRU) (beta=-.42; p=<.001) and their perceived empathy (JSPE) (beta=.26; p=.009). These variables accounted for 25% of variance in physicians' satisfaction. CONCLUSIONS: Physicians' satisfaction with their management of uncertainty was not affected by their communication performance, but by their psychological characteristics. PRACTICE IMPLICATIONS: Training programs should increase physicians' awareness regarding the communication performance required in decision-making encounters under conditions of uncertainty. PMID- 26969413 TI - Astrocytes as new targets to improve cognitive functions. AB - Astrocytes are now viewed as key elements of brain wiring as well as neuronal communication. Indeed, they not only bridge the gap between metabolic supplies by blood vessels and neurons, but also allow fine control of neurotransmission by providing appropriate signaling molecules and insulation through a tight enwrapping of synapses. Recognition that astroglia is essential to neuronal communication is nevertheless fairly recent and the large body of evidence dissecting such role has focused on the synaptic level by identifying neuro- and gliotransmitters uptaken and released at synaptic or extrasynaptic sites. Yet, more integrated research deciphering the impact of astroglial functions on neuronal network activity have led to the reasonable assumption that the role of astrocytes in supervising synaptic activity translates in influencing neuronal processing and cognitive functions. Several investigations using recent genetic tools now support this notion by showing that inactivating or boosting astroglial function directly affects cognitive abilities. Accordingly, brain diseases resulting in impaired cognitive functions have seen their physiopathological mechanisms revisited in light of this primary protagonist of brain processing. We here provide a review of the current knowledge on the role of astrocytes in cognition and in several brain diseases including neurodegenerative disorders, psychiatric illnesses, as well as other conditions such as epilepsy. Potential astroglial therapeutic targets are also discussed. PMID- 26969415 TI - CORRECTION. PMID- 26969416 TI - A VOYAGER Meta-Analysis of the Impact of Statin Therapy on Low-Density Lipoprotein Cholesterol and Triglyceride Levels in Patients With Hypertriglyceridemia. AB - Elevated triglyceride (TG) levels are associated with increased cardiovascular disease risk. In patients with mild-to-moderate hypertriglyceridemia, defined by the European Atherosclerosis Society Consensus Panel as a TG level of 177 to 885 mg/dl (2.0 to 10.0 mmol/L), low-density lipoprotein cholesterol (LDL-C) reduction remains the primary treatment goal. Using data from the indiVidual patient meta analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin and simvastatin (VOYAGER) meta-analysis, we analyzed LDL-C and TG reductions in patients with baseline TG >=177 mg/dl (>=2.0 mmol/L). Least squares mean percentage change from baseline in LDL-C and TG was compared using 15,800 patient exposures to rosuvastatin 5 to 40 mg, atorvastatin 10 to 80 mg, and simvastatin 10 to 80 mg in patients with baseline TG >=177 mg/dl (>=2.0 mmol/L). Comparisons were made using mixed-effects models with data only from studies directly comparing treatments by randomized design. Mean LDL-C reductions ranged from -26.9% to -55.5%. Rosuvastatin 10 to 40 mg resulted in significantly greater LDL-C reductions than equal or double doses of atorvastatin and simvastatin (p <0.05). Mean TG reductions ranged from -15.1% to -31.3%. Rosuvastatin 10 mg resulted in significantly greater TG reductions than atorvastatin 10 mg (p <0.05). Rosuvastatin 20 and 40 mg resulted in TG reductions similar to those with equal doses of atorvastatin. Rosuvastatin 10 to 40 mg resulted in significantly greater TG reductions than equal or double doses of simvastatin (p <0.05). In conclusion, in patients with hypertriglyceridemia, LDL-C reduction was substantial and dependent on the choice and dose of statin. TG reduction was numerically less than for LDL-C, and additional TG-lowering therapy may be considered to further reduce residual cardiovascular risk. PMID- 26969417 TI - Single-Dose Interaction Study of the Arginine Vasopressin Type 1B Receptor Antagonist ABT-436 and Alcohol in Moderate Alcohol Drinkers. AB - BACKGROUND: ABT-436, a potent and selective arginine vasopressin (AVP) type 1B receptor (V1B ) antagonist, has previously demonstrated basal hypothalamic pituitary-adrenal (HPA) axis attenuation in man. A V1B antagonist is hypothesized as an alcohol-dependent treatment based on the role of the V1B receptor in stress regulation and the finding that stress is a trigger for relapse in alcoholics. A V1B antagonist has shown favorable effects in rat models of alcohol dependence. A single-dose clinical study was conducted to assess the potential for pharmacokinetic or pharmacodynamic interaction between ABT-436 and alcohol. METHODS: Twenty moderate alcohol drinkers each received the 4 possible combinations of a single 1,000 mg ABT-436 dose (or matching placebo) and a single 0.5 g/kg alcohol dose (or placebo for alcohol) in a double-blind, randomized, 4 period crossover study. Plasma ABT-436 and blood alcohol levels were measured to assess pharmacokinetic interactions. A computerized cognitive test battery (CDR System), Bond-Lader Visual Analog Scales scales, and a postural stability test were used to measure the effects of alcohol and the potential interaction with ABT-436. The pharmacologic effect of ABT-436 was assessed by measuring serum cortisol. RESULTS: Neither ABT-436 nor alcohol affected the blood levels of the other. Alcohol reduced performance on 2 of 5 CDR System composite variables (power of attention, p = 0.002; quality of secondary episodic memory, p < 0.001), and decreased postural stability (p = 0.043). ABT-436 did not exacerbate those deleterious effects. ABT-436 reduced serum cortisol (p < 0.001), and alcohol did not significantly diminish this expected effect on the HPA axis. CONCLUSIONS: No pharmacokinetic or pharmacodynamic interaction between ABT-436 and alcohol was observed. PMID- 26969418 TI - Aberrant interhemispheric functional and structural connectivity in heroin dependent individuals. AB - Models of heroin addiction emphasize the role of disrupted frontostriatal circuitry supporting cognitive control processes. However, heroin addiction related alterations in functional and structural interactions among brain regions, especially between the cerebral hemispheres, are rarely examined directly. Resting-state functional magnetic resonance imaging (fMRI) approaches, which reveal patterns of coherent spontaneous fluctuations in the fMRI signal, offer a means to quantify directly functional interactions between the hemispheres. The corpus callosum (CC), which connects homologous regions of the cortex, is the major conduit for information transfer between the cerebral hemispheres and represents a structural connectivity index between hemispheres. We compared interhemispheric voxel-mirrored homotopic connectivity (VMHC) and CC volume between 45 heroin dependent-individuals (HDIs) and 35 non-addict individuals. We observed significant reduction of VMHC in a number of regions, particularly the striatum/limbic system regions, and significant decrease in splenium and genu sub-regions of CC in HDI. Importantly, within HDI, VMHC in the dorsal lateral prefrontal cortex (DLPFC) correlated with genu CC volume, VMHC in the putamen, VMHC in the DLPFC and genu CC volume and splenium CC volume were negatively correlated with heroin duration and impulsivity traits. Further analyses demonstrated that impairment of VMHC of bilateral DLPFC partially mediated the association between genu CC volumes decreased and increased impulsivity in HDI. Our results reveal a substantial impairment of interhemispheric coordination in the HDI. Further, interhemispheric connectivity correlated with the duration of heroin abuse and higher impulsivity behavior in HDI. Our findings provide insight into a heroin addicts' related pathophysiology and reinforce an integrative view of the interhemispheric cerebral functional and structural organization. PMID- 26969419 TI - RCTs are here to stay. PMID- 26969420 TI - Reply to Dr H. Madsen's Letter. PMID- 26969422 TI - Effects of fixed orthodontic treatment using conventional (two-piece) versus metal injection moulding brackets on hair nickel and chromium levels: a double blind randomized clinical trial. AB - INTRODUCTION: Although nickel and chromium are known as allergen and cytotoxic orthodontic metals, very few and controversial studies have assessed the effect of orthodontic treatment on their systemic levels especially those reflected by their best biomarker of exposure, hair. Additionally, metal injection moulding (MIM) brackets are not studied, and there is no study on systemic ion changes following their usage. METHODS: In this double-blind randomized clinical trial, scalp hair samples of 24 female and 22 male fixed orthodontic patients [as two groups of conventional (two-piece) versus MIM brackets, n = 23*2] were collected before treatment and 6 months later. Randomization was carried out using a computer-generated random number table. The patients, laboratory expert, and author responsible for analyses were blinded of the bracket allocations. Hair nickel and chromium levels were measured using atomic absorption spectrophotometry. The effects of treatment, bracket types, gender, and age on hair ions were analysed statistically (alpha = 0.05, beta <= 0.02). RESULTS: In both groups combined (n = 46), nickel increased from 0.1600+/-0.0890 ug/g dry hair mass (pre-treatment) to 0.3199+/-0.1706 (6th month). Chromium increased from 0.1657+/-0.0884 to 0.3066+/-0.1362 ug/g. Both of these increases were significant (paired t-test, P = 0.0000). Bracket types, age, and gender had no significant influence on ion levels (P > 0.05). ANCOVA indicated different patterns of chromium increases in different genders (P = 0.033) and ages (P = 0.056). LIMITATIONS: Sample size determination should have accounted for the grouping as well. CONCLUSION: Hair nickel and chromium levels might increase about 185-200% after 6 months. They might not be affected by bracket types. Gender and age might not influence the baseline or 6th-month levels of both metals. Gender might however interact with orthodontic treatment, only in the case of chromium. REGISTRATION: The research is registered offline (thesis) and online (IR.AJUMS.REC.1394.516). PROTOCOL: The protocol was pre-determined before any experiments begin. FUNDING: The study was self-funded by the authors. PMID- 26969421 TI - A comparative assessment of enamel mineral content and Streptococcus mutans population between conventional composites and composites containing nano amorphous calcium phosphate in fixed orthodontic patients: a split-mouth randomized clinical trial. AB - OBJECTIVES: The aim of this 'split-mouth design' trial was to evaluate the effect of the nano amorphous calcium phosphate (NACP) containing composite on enamel mineral contents and streptococcus mutans population in fixed orthodontic patients. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: Randomized, prospective, single-center controlled trial. Twenty-four patients between the ages of 13-18 years participated in this study. The control and test sides were randomly selected by a coin toss (1:1 ratio). On the control side orthodontic brackets were bonded on the buccal surfaces of upper premolars and laterals using an orthodontic composite (Transbond XT), and on the study side NACP-containing composite was used. Outcome measures were the mineral content around the brackets and S.mutans count. The later were calculated in the plaque around the brackets by real-time PCR at 3 months, and 6 months after the initiation of treatment. All stages of the study were blind using coding system. Paired t-test and repeated measurements were used for data analysis. RESULTS: In the third and sixth month, the bacterial population was significantly lower in the study side than the control side (P = 0.01 and 0.000).The mineral content of the study side was significantly higher than the controls, 6 months after brocket bonding (P = 0.004). There were no significant differences between the premolars and lateral teeth for all measurements. LIMITATIONS: This research was performed in a single center by one experienced clinician. CONCLUSION: NACP-containing composites have the potential to inhibit mineral content loss and S.mutans colonization around orthodontic brackets during fixed orthodontic treatments. TRIAL REGISTRATION: This trial was not registered. PROTOCOL: The protocol was not published before trial commencement. PMID- 26969423 TI - A survey of general dentists regarding orthodontic retention procedures. AB - AIM: To explore 1. how Swiss general dentists deal with complications associated with fixed orthodontic retainers, 2. collaboration between general dentists and orthodontists with regards to the organization and responsibility for long-term follow-up of orthodontic retainers, and 3. the need for standardized clinical guidelines regarding orthodontic retention. METHODS: A structured questionnaire was sent to 201 randomly selected dentists. They were asked about their experience with retainers, opinions regarding the advantages and disadvantages of different types of retainers, responsibility for patients wearing bonded retention and the communication between orthodontists and general dentists. Statistical analysis was carried out using SPSS software. RESULTS: The response rate was 61 per cent. About 55 per cent of the respondents had had experience with bonding fixed retainers and even more were familiar with their follow-up and repair. In case of complications, dentists usually contacted orthodontists according to the following rule: the more severe the complication, the more intense the communication. Most dentists hesitated to remove retainers when requested to do so by the patient and attempted to convince them to continue wearing them. Retainers bonded to all six anterior teeth were considered more efficient than those bonded to canines only; however, possible side effects (e.g. unwanted changes of the torque) were not well known. 66.4 per cent respondents were willing to take responsibility for patients in retention as early as 6 months after retainer placement. 93.2 per cent respondents would welcome the establishment of standardized guidelines. CONCLUSIONS: Swiss general dentists have good knowledge of orthodontic retention and follow-up procedures. Nevertheless, introduction of clinical guidelines including information on the possible side-effects of bonded retention is justified. PMID- 26969414 TI - Epigenetics: A primer for clinicians. AB - With recent advances in cellular biology, we now appreciate that modifications to DNA and histones can have a profound impact on transcription and function, even in the absence of changes to DNA sequence. These modifications, now commonly referred to as "epigenetic" alterations, have changed how we understand cell behavior, reprogramming and differentiation and have provided significant insight into the mechanisms underlying carcinogenesis. Epigenetic alterations, to this point, are largely identified by changes in DNA methylation and hydroxymethylation as well as methylation, acetylation, and phosphorylation of histone tails. These modifications enable significant flexibility in gene expression, rather than just turning genes "ON" or "OFF." Herein we describe the epigenetic landscape in the regulation of gene expression with a particular focus on interrogating DNA methylation in myeloid malignancy. PMID- 26969424 TI - [CEA and early detection of relapse in breast cancer subtypes: Comparison with CA 15-3]. AB - This retrospective study evaluates the interest of CEA measurement for early detection of breast cancer recurrences. Among 804 patients with invasive breast cancer, we selected 97 patients without recurrence (WR) for 5 years or more, 32 with a local recurrence (LR) and 131 with at least one distant metastasis (DM). Elevated CEA and CA 15-3 levels (>3.1 MUg/L and >26 kU/L respectively) were found in 6 % and 22 % of patients with RL respectively and in 49 % and 69 % of patients with DM. Both CEA and CA 15-3 retained a significant value in predicting DM by univariate and multivariate analysis. Higher sensitivity of CEA and CA 15-3 were found in tumors with positive hormonal receptor status. CEA and CA 15-3 levels at DM were raised respectively in 23 and 65 % of the triple negative group, 58 and 75 % of the luminal, 56 and 78 % of the luminal-HER2 and 50 and 30 % of HER2 enriched group (P=0.0094 and 0.0252 respectively). The combination of CEA and CA 15-3 increased CA 15-3 sensitivity in especially luminal and HER2-enriched groups. In conclusion, elevated CA 15-3 and CEA levels at initial diagnosis of recurrence were found to be associated with hormonal receptor status and breast cancer subtypes. The combination of CEA and CA 15-3 appeared useful especially luminal and HER2-enriched groups. PMID- 26969425 TI - [Tyrosine kinase inhibitors and pregnancy: A risk to the fetus?]. AB - The association of cancer and pregnancy is increasingly frequent. This is related, partially, to the increasingly belated age of pregnancy. The management of cancer in pregnancy is a complicated issue. The use of tyrosine kinase inhibitors (TKIs) during pregnancy remains rare and only few data are available concerning their transplacental passage. The aim of this work is to review the data described in the literature, in order to highlight the risks incurred by the fetus, associated with these TKIs' treatment. Up to 189 pregnancies of women treated with TKIs during part or throughout their pregnancy have been described. Clinical data are reassuring and would be in favor of taking the treatment in terms of the balance maternal profit versus fetal risk. These data must, nevertheless, be interpreted with caution. PMID- 26969426 TI - [Fitness and quality of life in kidney transplant recipients: case-control study]. AB - BACKGROUND AND OBJECTIVES: We analyzed the levels of fitness, muscle structure and quality of life of adults after kidney transplant and healthy adults. PATIENTS AND METHODS: A total of 16 kidney transplant patients and 21 healthy controls performed several fitness test, isokinetic evaluation of knee flexion and extension and ultrasonography muscle thickness assessment. They also completed the quality of life questionnaire SF-36. RESULTS: Physical fitness, muscle structure and quality of life of the kidney transplant recipients were significantly poorer than the controls. The transplant patients performed less well in the "get up and go" and "sit to stand" test (p<.001) as well as in assessments of muscle structure, strength and power. The patients had a poorer score in their quality of life assessments, differing from the controls in domains of physical function, physical role, general health and social function (p<.001). DISCUSSION: Fitness, strength and muscle mass are diminished in kidney transplant patients, resulting in a poorer quality of life which might entail an increased risk to their health. PMID- 26969427 TI - [Brain damage after general anesthesia]. AB - BACKGROUND AND OBJECTIVE: S100B protein is a serum marker of cerebral damage. The objective was to evaluate the brain damage caused by general anaesthesia, by determining the concentration of serum S100B protein before and after of general anaesthesia. PATIENTS AND METHOD: Patients with chronic adenotonsillar hypertrophy and indications for tonsillectomy were included. A venous blood sample was taken from the patients before general anaesthesia (basal sample). The patients were anaesthetised using the following intravenous anaesthetic drugs: midazolam, fentanyl and propofol; and inhaled sevoflurane. A second venous blood sample (postoperative sample) was taken from patients after the surgery, in the operating room. The concentration of serum S100B protein was determined in the basal sample (S100Bb) and postoperative sample (S100Bp) by immunoassay electro chemiluminescence in MODULAR E-170 (Roche Diagnostics). RESULTS: Seventy-six patients were included, 46 males and 30 females, aged between 3 to 14 (median 5 years). In all the patients, serum S100B protein levels increased after general anaesthesia. The values of S100Bp (median 164.0 ng/L) were significantly higher than the values of S100Bb (median 94.5 ng/L). The median of the difference between S100Bp and S100Bb was 58.0 ng/L. There were statistically significant differences between S100Bb and S100Bp using the Wilcoxon test (P<.0001). CONCLUSIONS: The concentration of serum S100B protein increased significantly after general anaesthesia. This indicates that general anaesthesia may cause brain damage. PMID- 26969429 TI - Achieving behaviour change for detection of Lynch syndrome using the Theoretical Domains Framework Implementation (TDFI) approach: a study protocol. AB - BACKGROUND: Lynch syndrome is an inherited disorder associated with a range of cancers, and found in 2-5 % of colorectal cancers. Lynch syndrome is diagnosed through a combination of significant family and clinical history and pathology. The definitive diagnostic germline test requires formal patient consent after genetic counselling. If diagnosed early, carriers of Lynch syndrome can undergo increased surveillance for cancers, which in turn can prevent late stage cancers, optimise treatment and decrease mortality for themselves and their relatives. However, over the past decade, international studies have reported that only a small proportion of individuals with suspected Lynch syndrome were referred for genetic consultation and possible genetic testing. The aim of this project is to use behaviour change theory and implementation science approaches to increase the number and speed of healthcare professional referrals of colorectal cancer patients with a high-likelihood risk of Lynch syndrome to appropriate genetic counselling services. METHODS: The six-step Theoretical Domains Framework Implementation (TDFI) approach will be used at two large, metropolitan hospitals treating colorectal cancer patients. Steps are: 1) form local multidisciplinary teams to map current referral processes; 2) identify target behaviours that may lead to increased referrals using discussion supported by a retrospective audit; 3) identify barriers to those behaviours using the validated Influences on Patient Safety Behaviours Questionnaire and TDFI guided focus groups; 4) co design interventions to address barriers using focus groups; 5) co-implement interventions; and 6) evaluate intervention impact. Chi square analysis will be used to test the difference in the proportion of high-likelihood risk Lynch syndrome patients being referred for genetic testing before and after intervention implementation. A paired t-test will be used to assess the mean time from the pathology test results to referral for high-likelihood Lynch syndrome patients pre-post intervention. Run charts will be used to continuously monitor change in referrals over time, based on scheduled monthly audits. DISCUSSION: This project is based on a tested and refined implementation strategy (TDFI approach). Enhancing the process of identifying and referring people at high likelihood risk of Lynch syndrome for genetic counselling will improve outcomes for patients and their relatives, and potentially save public money. PMID- 26969428 TI - Purification and genetic characterization of gassericin E, a novel co-culture inducible bacteriocin from Lactobacillus gasseri EV1461 isolated from the vagina of a healthy woman. AB - BACKGROUND: Lactobacillus gasseri is one of the dominant Lactobacillus species in the vaginal ecosystem. Some strains of this species have a high potential for being used as probiotics in order to maintain vaginal homeostasis, since they may confer colonization resistance against pathogens in the vagina by direct inhibition through production of antimicrobial compounds, as bacteriocins. In this work we have studied bacteriocin production of gassericin E (GasE), a novel bacteriocin produced by L. gasseri EV1461, a strain isolated from the vagina of a healthy woman, and whose production was shown to be promoted by the presence of certain specific bacteria in co-culture. Biochemical and genetic characterization of this novel bacteriocin are addressed. RESULTS: We found that the inhibitory spectrum of L. gasseri EV1461 was broad, being directed to species both related and non-related to the producing strain. Interestingly, L. gasseri EV1461 inhibited the grown of pathogens usually associated with bacterial vaginosis (BV). The antimicrobial activity was due to the production of a novel bacteriocin, gassericin E (GasE). Production of this bacteriocin in broth medium only was achieved at high cell densities. At low cell densities, bacteriocin production ceased and only was restored after the addition of a supernatant from a previous bacteriocin-producing EV1461 culture (autoinduction), or through co cultivation with several other Gram-positive strains (inducing bacteria). DNA sequence of the GasE locus revealed the presence of two putative operons which could be involved in biosynthesis and immunity of this bacteriocin (gaeAXI), and in regulation, transport and processing (gaePKRTC). The gaePKR encodes a putative three-component regulatory system, involving an autoinducer peptide (GaeP), a histidine protein kinase (GaeK) and a response regulator (GaeR), while the gaeTC encodes for an ABC transporter (GaeT) and their accessory protein (GaeC), involved in transport and processing of the bacteriocin. The gaeAXI, encodes for the bacteriocin gassericin E (GasE), a putative peptide bacteriocin (GaeX), and their immunity protein (GaeI). CONCLUSIONS: The origin of the strain (vagina of healthy woman) and its ability to produce bacteriocins with inhibitory activity against vaginal pathogens may be an advantage for using L. gasseri EV1461 as a probiotic strain to fight and/or prevent bacterial infections as bacterial vaginosis (BV), since it could be better adapted to live and compete into the vaginal environment. PMID- 26969430 TI - Frequent blood feeding enables insecticide-treated nets to reduce transmission by mosquitoes that bite predominately outdoors. AB - BACKGROUND: The effectiveness of vector control on malaria transmission by long lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) depends on the vectors entering houses to blood feed and rest when people are inside houses. In the Solomon Islands, significant reductions in malaria have been achieved in the past 20 years with insecticide-treated bed nets, IRS, improved diagnosis and treatment with artemisinin combination therapies; despite the preference of the primary vector, Anopheles farauti, to feed outdoors and early in the evening and thereby avoid potential exposure to insecticides. Rational development of tools to complement LLINs and IRS by attacking vectors outdoor requires detailed knowledge of the biology and behaviours of the target species. METHODS: Malaria transmission in Central Province, Solomon Islands was estimated by measuring the components comprising the entomological inoculation rate (EIR) as well as the vectorial capacity of An. farauti. In addition, the daily and seasonal biting behaviour of An. farauti, was examined and the duration of the feeding cycle was estimated with a mark-release-recapture experiment. RESULTS: Anopheles farauti was highly exophagic with 72% captured by human landing catches (HLC) outside of houses. Three-quarters (76%) of blood feeding on humans was estimated to occur before 21.00 h. When the hourly location of humans was considered, the proportion of exposure to mosquito bites on humans occurring indoors (pii) was only 0.130 +/ 0.129. Peak densities of host seeking An. farauti occurred between October and January. The annual EIR was estimated to be 2.5 for 2012 and 33.2 for 2013. The length of the feeding cycle was 2.1 days. CONCLUSIONS: The short duration of the feeding cycle by this species offers an explanation for the substantial control of malaria that has been achieved in the Solomon Islands by LLINs and IRS. Anopheles farauti is primarily exophagic and early biting, with 13% of mosquitoes entering houses to feed late at night during each feeding cycle. The two-day feeding cycle of An. farauti requires females to take 5-6 blood meals before the extrinsic incubation period (EIP) is completed; and this could translate into substantial population-level mortality by LLINs or IRS before females would be infectious to humans with Plasmodium falciparum and Plasmodium vivax. Although An. farauti is primarily exophagic, the indoor vector control tools recommended by the World Health Organization (LLINs and IRS) can still provide an important level of control. Nonetheless, elimination will likely require vector control tools that target other bionomic vulnerabilities to suppress transmission outdoors and that complement the control provided by LLINs and IRS. PMID- 26969431 TI - No difference in the competitive ability of introduced and native Trifolium provenances when grown with soil biota from their introduced and native ranges. AB - The evolution of increased competitive ability (EICA) hypothesis could explain why some introduced plant species perform better outside their native ranges. The EICA hypothesis proposes that introduced plants escape specialist pathogens or herbivores leading to selection for resources to be reallocated away from defence and towards greater competitive ability. We tested the hypothesis that escape from soil-borne enemies has led to increased competitive ability in three non agriculturalTrifolium(Fabaceae) species native to Europe that were introduced to New Zealand in the 19th century.Trifoliumperformance is intimately tied to rhizosphere biota. Thus, we grew plants from one introduced (New Zealand) and two native (Spain and the UK) provenances for each of three species in pots inoculated with soil microbiota collected from the rhizosphere beneath conspecifics in the introduced and native ranges. Plants were grown singly and in competition with conspecifics from a different provenance in order to compare competitive ability in the presence of different microbial communities. In contrast to the predictions of the EICA hypothesis, we found no difference in the competitive ability of introduced and native provenances when grown with soil microbiota from either the native or introduced range. Although plants from introduced provenances of two species grew more slowly than native provenances in native-range soils, as predicted by the EICA hypothesis, plants from the introduced provenance were no less competitive than native conspecifics. Overall, the growth rate of plants grown singly was a poor predictor of their competitive ability, highlighting the importance of directly quantifying plant performance in competitive scenarios, rather than relying on surrogate measures such as growth rate. PMID- 26969432 TI - Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd proteins which influence the long-term positioning and dendritic maturation of cerebral cortical neurons. AB - BACKGROUND: The development of neural circuits within the embryonic cerebral cortex relies on the timely production of neurons, their positioning within the embryonic cerebral cortex as well as their terminal differentiation and dendritic spine connectivity. The RhoA GTPases Rnd2 and Rnd3 are important for neurogenesis and cell migration within the embryonic cortex (Nat Commun 4:1635, 2013), and we recently identified the BTB/POZ domain-containing Adaptor for Cul3-mediated RhoA Degradation family member Bacurd2 (also known as Tnfaip1) as an interacting partner to Rnd2 for the migration of embryonic mouse cortical neurons (Neural Dev 10:9, 2015). FINDINGS: We have extended this work and report that Bacurd1/Kctd13 and Bacurd2/Tnfaip1 are interacting partners to Rnd2 and Rnd3 in vitro. Given that these genes are expressed during cortical development, we performed a series of in utero electroporation studies in mice and found that disruptions to Bacurd1/Kctd13 or Bacurd2/Tnfaip1 expression impair the long-term positioning of E14.5-born cortical neurons within the postnatal (P17) mouse cerebral cortex. We also find that forced expression of Bacurd1/Kctd13 and Bacurd2/Tnfaip1 alters the branching and dendritic spine properties of layer II/III projection neurons. CONCLUSIONS: We identify Bacurd1/Kctd13 and Bacurd2/Tnfaip1 as interacting partners to Rnd proteins which influence the development of cortical neurons. Their neurodevelopmental functions are likely to be relevant to human brain development and disease. PMID- 26969433 TI - Molecular characterization, fitness and mycotoxin production of Fusarium graminearum laboratory strains resistant to benzimidazoles. AB - Six benzimidazole (BMZ)-resistant Fusarium graminearum strains were obtained after UV mutagenesis and selection on carbendazim (MBC)-amended medium. In vitro bioassays resulted in the identification of two resistant phenotypes that were highly HR (Rf: 40-170, based on EC50) and moderately MR (Rf: 10-20) resistant to carbendazim. Cross resistance studies with other fungicides showed that all mutant strains tested were also resistant to other BMZs, such as benomyl and thiabendazole, but retained their parental sensitivity to fungicides belonging to other chemical groups. A point mutation at codon 6 (His6Asn) was found in the beta2-tubulin gene of MR isolates while another mutation at codon 200 (Phe200Tyr) was present in one MR and one HR isolates. Interestingly, low temperatures suppressed MBC-resistance in all isolates bearing the H6N mutation. The three dimensional homology model of the wild-type and mutants of beta-tubulins were constructed, and the possible carbendazim binding site was analyzed. Studies on fitness parameters showed that the mutation(s) for resistance to BMZs did not affect the mycelial growth rate whereas adverse effects were found in sporulation and conidial germination in most of the resistant mutants. Pathogenicity tests on corn cobs revealed that mutants were less or equally aggressive to the wild-type strain but expressed their BMZ-resistance after inoculation on maize cobs treated with MBC. Analysis of mycotoxin production by high performance liquid chromatography revealed that only two HR strains produced zearalenone (ZEA) at concentrations similar to that of the wild-type strain, while no ZEA levels were detected in the rest of the mutants. PMID- 26969434 TI - Target-site basis for resistance to imazethapyr in redroot amaranth (Amaranthus retroflexus L.). AB - Experiments were conducted to confirm imazethapyr resistance in redroot amaranth (Amaranthus retroflexus L.) and study the target-site based mechanism for the resistance. Whole-plant response experiments revealed that the resistant (R) population exhibited 19.16 fold resistance to imazethapyr compared with the susceptible (S) population. In vitro ALS activity assay demonstrated that the imazethapyr I50 value of the R population was 21.33 times greater than that of the S population. However, qRT-PCR analysis revealed that there is no difference in ALS gene expression between the R and S populations. Sequence analysis revealed an Asp-376-Glu substitution in ALS in the R population. In order to verify that the imazethapyr resistance was conferred by Asp-376-Glu mutation, the ALS-R and ALS-S genes were fused to the CaMV 35S promoter and introduced into Arabidopsis respectively. The expression of ALS-R in transgenic Arabidopsis plants exhibited 13.79 fold resistance to imazethapyr compared to ALS-S transgenic Arabidopsis. PMID- 26969435 TI - Effects of fungicides on the yeast-like symbiotes and their host, Nilaparvata lugens Stal (Hemiptera: Delphacidae). AB - Yeast-like symbiotes (YLS) are endosymbionts that are closely related to the growth, development and reproduction of their host, the brown planthopper (BPH), Nilaparvata lugens Stal (Hemiptera: Delphacidae). In order to understand the relationship between the population of YLS in BPH cells and the survival rate of BPH, eight different fungicides were applied to rice plants infested by BPH, and the number of YLS and mortality of BPH were determined. Three of the fungicides, 27% toyocamycin & tetramycin P & tetrin B & tetramycin A, 0.01% trichodermin, and 75% trifloxystrobin & tebuconazole WG, were found to significantly reduce the number of YLS in BPH, subsequently causing a high mortality of BPH. The three fungicides were each mixed with a commonly used insecticide-imidacloprid, and the fungicide/insecticide mixtures could cause a marked reduction in YLS number in BPH, resulting in a significantly higher mortality of BPH than did the imidacloprid alone. The mixture of 27% toyocamycin & tetramycin P & tetrin B & tetramycin A with imidacloprid showed the best inhibitory effect on BPH population. Our study demonstrated a high dependence of the BPH survival rate on the number of YLS harbored in BPH fat-body cells. It implies that using specific fungicides as an additive to imidacloprid for controlling BPH could be a novel way to enhance the efficacy of insecticide, minimizing the use of imidacloprid in paddy fields. PMID- 26969436 TI - Survival, growth, detoxifying and antioxidative responses of earthworms (Eisenia fetida) exposed to soils with industrial DDT contamination. AB - The survival, growth, activity of the biotransformation system phase II enzyme glutathione-S-transferase (GST) and the oxidative defense enzyme catalase (CAT) of earthworms exposed to the contaminated soils from a former DDT plant and reference soils were investigated, and compared with the corresponding indicators in simulated soil-earthworm system, unpolluted natural soils with spiked-in DDT series, to identify the toxic effects of DDT on earthworms and their cellular defense system in complex soil system. The results indicated that DDT level in the contaminated soils was significantly higher than that in the reference soils with similar level of other pollutants and soil characters. The mortality, growth inhibition rates, GST and CST activities of earthworms exposed to the contaminated soils were significantly higher than that in reference soils. The contribution of historical DDT in contaminated soils to earthworms was confirmed by the DDT spiked tests. DDT spiked in soils at rates of higher than 200 mg.kg( 1) was significantly toxic to both the survival and the growth of earthworms. DDT significantly stimulated GST and CAT activity in earthworms after 14 days. The CAT and GST activities were also stimulated by DDT exposure at rates of 100 mg.kg(-1) after chronic exposure (42 days). The results provide implications for validating the extrapolation from laboratory simulated soils criteria to contaminated soils and for making site risk assessments. PMID- 26969437 TI - Effects of juvenile hormone (JH) analog insecticides on larval development and JH esterase activity in two spodopterans. AB - Juvenile hormone analog (JHA) insecticides are biological and structural mimics of JH, a key insect developmental hormone. Toxic and anti-developmental effects of the JHA insecticides methoprene, fenoxycarb, and pyriproxyfen were investigated on the larval and pupal stages of Spodoptera littoralis and Spodoptera frugiperda. Bioassays showed that fenoxycarb has the highest toxicity and fastest speed of kill in 2nd instar S. littoralis. All three JHAs affected the development of 6th instar (i.e., final instar) and pupal S. frugiperda. JH esterase (JHE) is a critical enzyme that helps to regulate JH levels during insect development. JHE activity in the last instar S. littoralis and S. frugiperda was 11 and 23 nmol min(-1) ml(-1) hemolymph, respectively. Methoprene and pyriproxyfen showed poor inhibition of JHE activity from these insects, whereas fenoxycarb showed stronger inhibition. The inhibitory activity of fenoxycarb, however, was more than 1000-fold lower than that of OTFP, a highly potent inhibitor of JHEs. Surprisingly, topical application of methoprene, fenoxycarb or pyriproxyfen on 6th instars of S. littoralis and S. frugiperda prevented the dramatic reduction in JHE activity that was found in control insects. Our findings suggest that JHAs may function as JH agonists that play a disruptive role or a hormonal replacement role in S. littoralis and S. frugiperda. PMID- 26969438 TI - Staurosporine shows insecticidal activity against Mythimna separata Walker (Lepidoptera: Noctuidae) potentially via induction of apoptosis. AB - Staurosporine (STS), a wide-spectrum kinase inhibitor, is widely used in studies of apoptosis in mammalian cells. However, its physiological and mechanistic effects have never been clearly defined in insect cells, and other applications of STS have rarely been reported. The present study reveals the insecticidal activity of STS on larvae of Mythimna separata Walker, and the apoptotic mechanism induced by STS on lepidopteran Sf9 cell lines. We demonstrate that the viability of Sf9 cells is inhibited by STS in a time- and concentration-dependent manner. Intracellular biochemical assays show that STS-induced apoptosis of Sf9 cells coincides with a decrease in the mitochondrial membrane potential, the release of cytochrome c into the cytosol, a significant increase of the Bax/Bcl-2 ratio, and a marked activation of caspase-9 and caspase-3. These results indicate that a mitochondrial-dependent intrinsic pathway contributes to STS induced caspase-3 activation and apoptosis in Sf9 cells which is homologous to the mechanisms in mammalian cells. This study contributes to our understanding of the mechanism of insect cell apoptosis and suggests a possible new application of STS as a potential insecticide against Lepidopteran insect pests in agriculture. PMID- 26969439 TI - Evaluating the combined effects of pretilachlor and UV-B on two Azolla species. AB - The present study assessed the comparative responses of two agronomic species of Azolla (A.microphylla and A. pinnata) exposed to man-made and natural stressors by evaluating biomass accumulation, pigments (chlorophyll a and b and carotenoid contents), photosynthetic activity and nitrogen metabolism. The study was carried out in field where two species of Azolla were cultured and treated with various concentrations (5, 10 and 20 MUg ml(-1)) of herbicide; pretilachlor [2-chloro-2,6 diethyl-N-(2-propoxyethyl) acetanilide] and enhanced levels (UV-B1: ambient +2.2 kJ m(-2) day(-1) and UV-B2: ambient +4.4 kJ m(-2) day(-1)) of UV-B, alone as well as in combination. Biomass accumulation, photosynthetic pigments; chlorophyll a, b and carotenoids, photosynthetic oxygen yield and photosynthetic electron transport activities i.e. photosystem II (PS II) and photosystem I (PS I) in both the species declined with the increasing doses of pretilachlor and UV-B radiation, which further declined when applied in combination. The lower doses (5 and 10 MUg ml(-1)) of pretilachlor and UV-B (UV-B1 and UV-B2) alone, damaged mainly the oxidation side of PS II, whereas higher dose (20 MUg ml(-1)) of pretilachlor alone and in combination with UV-B1 and UV-B2 caused damage to PS II reaction centre and beyond this towards the reduction side. A significant enhancement in respiration was also noticed in fronds of both the Azolla species following pretilachlor and UV-B treatment, hence indicating strong damaging effect. The nitrate assimilating enzymes - nitrate reductase and nitrite reductase and ammonium assimilating enzymes - glutamine synthetase and glutamate synthase were also severely affected when treated either with pretilachlor and/or UV-B while glutamate dehydrogenase exhibited a stimulatory response. The study suggests that both the species of Azolla showed considerable damage under pretilachlor and UV-B treatments alone, however, in combination the effect was more intense. Further, in comparison to A. pinnata, A. microphylla exhibited greater resistance against tested doses of both the stresses, either alone or in combination. PMID- 26969440 TI - Reduction of chlorpyrifos-induced toxicity in human lymphocytes by selected phosphodiesterase inhibitors. AB - One of the most famous and commonly used compounds from organophosphate (OP) family is chlorpyrifos (CP) which is widespreadly used as a powerful insecticide. Previous studies have shown that OPs induce oxidative stress, inflammation and apoptosis by generating the free radicals. The protective effects of three members of phosphodiesterase inhibitor (PDEI) family, including rolipram (RLP), milrinon (MLR) and pentoxifylline (PTX) were evaluated in the human lymphocytes against CP's toxicity. In this case, the level of oxidative stress biomarkers, the viability of the cells and the rate of apoptosis by flow cytometry were investigated. The results of this study revealed that CP makes a significant increase in the level of inflammatory and oxidative stress markers such as meyloperoxidase (MPO), lipid peroxidation (LPO), total thiol molecules (TTM) and total antioxidant potential (TAP), and also makes an enhancement in the rate of apoptosis process. On the other hand, PDEIs and specifically the combination of them restored the negative effects of CP and significantly prevented the apoptosis and oxidative stress imbalance. It is concluded that these PDEIs have positive effects in attenuation, recovery, and protection of CP-induced toxicity in the human lymphocytes. PMID- 26969442 TI - Prochloraz and coumaphos induce different gene expression patterns in three developmental stages of the Carniolan honey bee (Apis mellifera carnica Pollmann). AB - The Carniolan honey bee, Apis mellifera carnica, is a Slovenian autochthonous subspecies of honey bee. In recent years, the country has recorded an annual loss of bee colonies through mortality of up to 35%. One possible reason for such high mortality could be the exposure of honey bees to xenobiotic residues that have been found in honey bee and beehive products. Acaricides are applied by beekeepers to control varroosis, while the most abundant common agricultural chemicals found in honey bee and beehive products are fungicides, which may enter the system when applied to nearby flowering crops and fruit plants. Acaricides and fungicides are not intrinsically highly toxic to bees but their action in combination might lead to higher honey bee sensitivity or mortality. In the present study we investigated the molecular immune response of honey bee workers at different developmental stages (prepupa, white-eyed pupa, adult) exposed to the acaricide coumaphos and the fungicide prochloraz individually and in combination. Expression of 17 immune-related genes was examined by quantitative RT-PCR. In treated prepupae downregulation of most immune-related genes was observed in all treatments, while in adults upregulation of most of the genes was recorded. Our study shows for the first time that negative impacts of prochloraz and a combination of coumaphos and prochloraz differ among the different developmental stages of honey bees. The main effect of the xenobiotic combination was found to be upregulation of the antimicrobial peptide genes abaecin and defensin-1 in adult honey bees. Changes in immune-related gene expression could result in depressed immunity of honey bees and their increased susceptibility to various pathogens. PMID- 26969441 TI - The in vitro effect of cypermethrin on quality and oxidative stress indices of rainbow trout Oncorhynchus mykiss spermatozoa. AB - There is limited information on the scientific literature about the effect of in vitro exposure of fish sperm to pesticides. In vitro effect of cypermethrin on sperm quality and oxidative stress has not yet been fully investigated. Therefore, the effects of cypermethrin, a type II pyrethroid insecticide, on quality and oxidative stress of spermatozoa were examined in vitro. To explore the potential in vitro toxicity of cypermethrin, fish spermatozoa were incubated with different concentrations of cypermethrin (1.025, 2.05 and 4.1 MUg/l) for 2 h. The motility rate and duration of sperm were determined after exposure to cypermethrin. Reduced glutathione (GSH), glutathione peroxidase (GSH-Px), catalase (CAT) and malondialdehyde (MDA) in spermatozoa were analyzed for determination of oxidant and antioxidant balance. Our results indicated that spermatozoa motility and duration significantly decreased with exposure to cypermethrin. Additionally, activity of GSH-Px (P<0.05) and MDA and GSH levels increased in a concentration-dependent manner while CAT activity decreased (P<0.05). Consequently, the oxidant and antioxidant status and sperm quality were affected by quantitative changes and different concentrations of cypermethrin. PMID- 26969443 TI - Silencing of ACO decreases reproduction and energy metabolism in triazophos treated female brown plant hoppers, Nilaparvata lugens Stal (Hemiptera: Delphacidae). AB - The brown plant hopper (BPH), Nilaparvata lugens Stal (Hemiptera: Delphacidae), is a major pest affecting rice in Asia, and outbreaks of this pest are closely linked to pesticide-induced stimulation of reproduction. Therefore, the BPH is a classic example of a resurgent pest. However, the effects of different genes on the regulation of pesticide-induced reproductive stimulation in the BPH are unclear. In this study, the regulatory effects of acyl-coenzyme A oxidase (ACO) on the reproduction and biochemistry of the BPH were investigated with gene silencing. The number of eggs laid per female by triazophos (TZP)+dsACO BPH females was significantly lower than those of TZP-treated (without ACO silencing) or TZP+GFP females (negative control), with the number of eggs decreasing by 30.8% (from 529.5 to 366.3) and 32.0% (from 540.5 to 366.3), respectively. The preoviposition period, oviposition period, and longevity of the TZP-treated females were also influenced by dsACO treatment. Additionally, the amounts of crude fat, protein, and some fatty acids (oleic acid, palmitic acid, linoleic acid, stearic acid, and myristoleic acid) in TZP+dsACO females were significantly lower than in TZP-treated females. Thus, ACO is one of the key genes regulating the TZP-induced stimulation of reproduction in BPH females. PMID- 26969444 TI - A urinary metabonomics analysis of long-term effect of acetochlor exposure on rats by ultra-performance liquid chromatography/mass spectrometry. AB - The study was to assess the long-term toxic effects of acetochlor on rats. Two different doses (42.96 and 107.4 mg/kg body weight/day) of acetochlor were administered to Wistar rats through their food for over 24 weeks. Rat urine samples were collected at two time-points for the measurements of the metabonomics profiles with ultra-performance liquid chromatography-mass spectrometry (UPLC-MSMS). The results of clinical chemistry and histopathology suggested that long-term use of acetochlor in rats caused liver and kidney damage, and dysfunction of antioxidant system. The urinary metabonomics analysis indicated that the high and low-dose exposure of acetochlor could cause alterations of these metabonomics in urine in the rat. Significant changes of the levels of hippuric acid (0.403-fold decrease), citric acid (0.430-fold decrease), pantothenic acid (0.486-fold decrease), uracil (0.419-fold decrease), beta Alanine (0.325-fold decrease), nonanedioic acid (0.445-fold decrease), L-tyrosine (0.410-fold decrease), D-glucuronic acid (8.389-fold increase) and 2-ethyl-6 methyl-N-methyl-2-chloro-acetanilide in urine were observed. In addition, it may interfere with the fatty acid synthesis, the pyrimidine degradation and pantothenate biosynthesis. The level of 2-ethyl-6-methyl-N-methyl-2-chloro acetanilide is detected in all treated groups which is not found in the control groups, indicating which can be used as an early, sensitive marker of acetochlor exposure in rat. This study illustrates the important utility of metabonomics approaches to understand the toxicity of long-term exposure of acetochlor. PMID- 26969446 TI - Diabetic eye care: need and opportunity for systematic change to improve access. PMID- 26969447 TI - Obstructive sleep apnoea: patients' experiences of oral appliance treatment. AB - Over the past few decades, there has been a pronounced increase in the number of patients being treated by general dental practitioners for obstructive sleep apnoea (OSA). The purpose of this study was to survey the care and patient experiences and the self-reported effectiveness of OSA treatment with an oral appliance (OA) incorporating mandibular advancement. The design was a retrospective, cross-sectional study, with follow-up between 6 months to 1 year after commencement of treatment. A survey form was posted to 1150 subjects, identified in the regional register over a 1-year period as having been treated with an OA for OSA. The questionnaire comprised 70 questions and assertions in various domains, such as general health/lifestyle, changes in symptoms/quality of life and sleep-related experiences, daytime sleepiness, changes in life situation, evaluation of treatment and the value of treatment. The overall response rate was 64% (n = 738). Treatment with OA gave relief of symptoms in 83% of the respondents. Quality of life, somatic and cognitive symptoms improved significantly in patients who used the appliance frequently (P < 0.001). Daytime sleepiness decreased significantly (P < 0.001). Treatment satisfaction and willingness to recommend the similar treatment to a friend were high (>85%). OA treatment of OSA by general dental practitioners is a safe procedure. Most of the survey respondents experienced relief of symptoms. Those who used their appliance frequently reported improvement in quality of life, somatic and cognitive symptoms. Excessive daytime sleepiness was reduced in the majority of the patients under treatment. PMID- 26969445 TI - The effect of FSH and activin A on Akt and MAPK1/3 phosphorylation in cultured bovine ovarian cortical strips. AB - BACKGROUND: rhFSH and rhActA have been used in mammalian ovarian follicle culture systems for activation of follicular growth in vitro and suggested to be responsible for primordial follicle survival through MAPK and Akt pathways. The aim of our study was to determine the effects of rhFSH and rhActA on Akt, pAkt, MAPK1/3 and pMAPK1/3 protein levels in bovine ovarian cortical strips cultured in vitro. METHODS: Ovarian cortical strips from heifers were cultured in the presence of rhFSH (50 ng/mL), rhActA (100 ng/mL) or combination of these factors for 6 days. The strips were embedded in paraffin for histological observations and homogenized for western blot to determine Akt, pAkt, MAPK1/3 and pMAPK1/3 protein levels after the culture. Determination of primordial, primary and secondary follicle proportions at the end of culture as well as comparison of healthy follicle for each developmental stage after the culture was performed to quantify follicle survival and activation. RESULTS: pAkt protein levels were significantly lower in rhFSH + rhActA group among the other groups, whereas pMAPK1/3 levels were not significantly changed. Follicular activation and survival was measured to be significantly lower in rhFSH + rhActA group. Percentage of healthy primordial follicles was higher in control group whereas healthy secondary follicle proportion was higher in both rhActA and rhFSH groups. rhActA alone had a better impact on follicular activation, since the percentage of the secondary follicles was significantly higher than other treatment groups. CONCLUSIONS: The use of rhActA and rhFSH alone or in the combined form results in differential levels of Akt and MAPK proteins. Both rhActA and rhFSH alone has a remarkable contribution in survival and activation of the follicles in accordance with higher levels of these proteins. Thus, the manipulation of Akt and MAPK pathways with appropriate activators might contribute to proper activation and development of ovarian follicles in vitro. PMID- 26969448 TI - Traditional birth attendants (TBAs) as potential agents in promoting male involvement in maternity preparedness: insights from a rural community in Uganda. AB - BACKGROUND: Since the 1994 International Conference on Population and Development, male involvement in reproductive health issues has been advocated as a means to improve maternal and child health outcomes, but to date, health providers have failed to achieve successful male involvement in pregnancy care especially in rural and remote areas where majority of the underserved populations live. In an effort to enhance community participation in maternity care, TBAs were trained and equipped to ensure better care and quick referral. In 1997, after the advent of the World Health Organization's Safe Motherhood initiative, the enthusiasm turned away from traditional birth attendants (TBAs). However, in many developing countries, and especially in rural areas, TBAs continue to play a significant role. This study explored the interaction between men and TBAs in shaping maternal healthcare in a rural Ugandan context. METHODS: This study employed ethnographic methods including participant observation, which took place in the process of everyday life activities of the respondents within the community; 12 focus group discussions, and 12 in-depth interviews with community members and key informants. Participants in this study were purposively selected to include TBAs, men, opinion leaders like village chairmen, and other key informants who had knowledge about the configuration of maternity services in the community. Data analysis was done inductively through an iterative process in which transcribed data was read to identify themes and codes were assigned to those themes. RESULTS: Contrary to the thinking that TBA services are utilized by women only, we found that men actively seek the services of TBAs and utilize them for their wives' healthcare within the community. TBAs in turn sensitize men using both cultural and biomedical health knowledge, and become allies with women in influencing men to provide resources needed for maternity care. CONCLUSION: In this study area, men trust and have confidence in TBAs; closer collaboration with TBAs may provide a suitable platform through which communities can be sensitized and men actively brought on board in promoting maternal health services for women in rural communities. PMID- 26969449 TI - Intervals between response choices on a single-item measure of quality of life. AB - BACKGROUND: A single overall rating of quality of life (QoL) is a sensitive method that is often used in population surveys. However, the exact meaning of response choices is unclear. In particular, uneven spacing may affect the way QoL ratings should be analyzed and interpreted. This study aimed to determine the intervals between response choices to a single-item QoL assessment. METHODS: A secondary analysis was conducted on data from the Lc65+ cohort study and two additional, population-based, stratified random samples of older people (N = 5,300). Overall QoL was rated as excellent, very good, good, fair or poor. A QoL score (range 0-100) was derived from participants' answers to a 28-item QoL assessment tool. A transformed QoL score ranging from 1 (poor) to 5 (excellent) was calculated. The same procedure was repeated to compute seven domain-specific QoL subscores (Feeling of safety; Health and mobility; Autonomy; Close entourage; Material resources; Esteem and recognition; Social and cultural life). RESULTS: Mean (95 % confidence intervals) QoL scores were 96.23 (95.81-96.65) for excellent, 93.09 (92.74-93.45) for very good, 81.45 (80.63-82.27) for good, 65.44 (62.67-68.20) for fair and 54.52 (45.31-63.73) for poor overall QoL, corresponding to transformed QoL scores of respectively 5.00, 4.70, 3.58, 2.05, and 1.00. Ordinality of the categories excellent to poor was preserved in all seven QoL subscores. CONCLUSIONS: The excellent-to-poor rating scale provides an ordinal measure of overall QoL. The intervals between response choices are unequal, but an interval scale can be obtained after adequate recoding of excellent, very good, good, fair and poor. PMID- 26969450 TI - Therapeutic intervention for internalized stigma of severe mental illness: A systematic review and meta-analysis. AB - OBJECTIVE: Internalized stigma can lead to pervasive negative effects among people with severe mental illness (SMI). Although prevalence of internalized stigma is high, there is a dearth of interventions and meanwhile a lack of evidence as to their effectiveness. This study aims at unraveling the existence of different therapeutic interventions and the effectiveness internalized stigma reduction in people with SMI via a systematic review and meta-analysis. METHODS: Five electronic databases were searched. Studies were included if they (1) involved community or hospital based interventions on internalized stigma, (2) included participants who were given a diagnosis of SMI>50%, and (3) were empirical and quantitative in nature. RESULTS: Fourteen articles were selected for extensive review and five for meta-analysis. Nine studies showed significant decrease in internalized stigma and two showed sustainable effects. Meta-analysis showed that there was a small to moderate significant effect in therapeutic interventions (SMD=-0.43; p=0.003). Among the intervention elements, four studies suggested a favorable effect of psychoeducation. Meta-analysis showed that there was small to moderate significant effect (SMD=-0.40; p=0.001). CONCLUSION: Most internalized stigma reduction programs appear to be effective. This systematic review cannot make any recommendation on which intervention is more effective although psychoeducation seems most promising. More Randomized Controlled Trials (RCT) on particular intervention components using standard outcome measures are recommended in future studies. PMID- 26969451 TI - Risk of psychosis and internal migration: Results from the Bologna First Episode Psychosis study. AB - BACKGROUND: Incidence of psychotic disorders is higher in many migrant groups; however little is known about internal migrants (IM). This study aims to describe the IR in natives (NA), IM and external migrants (EM). METHOD: All patients aged 18-64years, with First Episode Psychosis (FEP), who made contact with the Bologna West psychiatric services, between 2002 and 2010, were included. RESULTS: 187 cases were included. Age and sex adjusted IR of psychosis per 100,000per year were: 12.6 for NA, 25.3 for IM and 21.4 for EM. The IRR was 1.93 (1.19-3.13, P=0.007) for IM and 1.79 (1.06-3.02, P=0.03) for EM compared to NA. CONCLUSION: Rates of psychosis were significantly elevated in IM as well as in EM. This result adds evidence as to the role of migration itself (versus ethnicity) on the risk of psychosis. PMID- 26969453 TI - Long-term Voice Outcomes of Early Thyroplasty for Unilateral Vocal Fold Paralysis Following Aortic Arch Surgery. AB - OBJECTIVE: To describe this institution's experience with and the long-term outcomes of early type 1 thyroplasty for unilateral vocal fold paralysis (UVFP) following surgery on the aortic arch. STUDY DESIGN: Retrospective chart review with telephone questionnaire. SETTING: Academic tertiary care center. SUBJECTS AND METHODS: Three hundred forty-eight patients with UVFP following surgery on the aortic arch since 1999 were identified; 40 were available for follow-up. The number of revision procedures following initial thyroplasty was ascertained, and the Voice Handicap Index (VHI) was administered by telephone. The hypothesis that early thyroplasty produced voice outcomes and revision rates comparable to injection laryngoplasty was established prior to the initiation of data collection. RESULTS: Six out of the 40 patients (15%) required revision thyroplasty following their initial procedure. Mean VHI of all patients was 36.0 (SD, 27.2). Mean VHI was significantly different in the 18 to 39 age group (13.1) when compared to the 40 to 59 (51.8) and 60+ (37.7) age groups (P = .013). Mean follow-up since initial thyroplasty was 46.5 months (SD, 42.2). CONCLUSIONS: In the setting of aortic arch surgery with injury to the recurrent laryngeal nerve, early thyroplasty produces voice outcomes comparable to those achieved in the literature with repeated injection and delayed thyroplasty and can be considered in select populations. PMID- 26969454 TI - Compound Motor Action Potential Quantifies Recurrent Laryngeal Nerve Innervation in a Canine Model. AB - OBJECTIVE: The compound motor action potential (CMAP) is the summated action potential from multiple muscle fibers activated by a single nerve impulse. The utility of laryngeal muscle CMAP for quantifying innervation following recurrent laryngeal nerve (RLN) injury was investigated. METHOD: In a series of 21 canine hemi-laryngeal preparations, RLNs were exposed and a stimulating electrode placed. Maximum CMAP amplitudes and area under the curve from the thyroarytenoid (TA) muscles were obtained at baseline and at 6 months following injury to the RLN. Injury mechanisms included crush, stretch, cautery, and complete transection with microsuture repair. RESULTS: Prior to injury, baseline CMAP amplitudes and area under the curve were 15.81 mV and 15.49mVms, respectively. Six months following injury, CMAP amplitude and area under curve were 105.1% and 102.1% of baseline for stretch, 98.7% and 112.7% for crush, 93.3% and 114.3% for cautery. The CMAP amplitude and area under the curve in the transection/repair group had a 54.3% and 69.4% recovery, respectively, which were significantly different than baseline (P < .01, P < .05). These values were correlated with vocal fold motion. CONCLUSION: The CMAP is a measure of vocal fold innervation. The technique could be further developed for clinical and experimental applications. PMID- 26969455 TI - Sir William Wilde: an enlightened editor. AB - This paper examines Sir William Wilde's peculiar genius as editor, his contribution to the Irish Journal of Medical Science in ensuring its endurance and making it a treasure-house of the history of medicine in Ireland. PMID- 26969452 TI - Framing the grid: effect of boundaries on grid cells and navigation. AB - Cells in the mammalian hippocampal formation subserve neuronal representations of environmental location and support navigation in familiar environments. Grid cells constitute one of the main cell types in the hippocampal formation and are widely believed to represent a universal metric of space independent of external stimuli. Recent evidence showing that grid symmetry is distorted in non symmetrical environments suggests that a re-examination of this hypothesis is warranted. In this review we will discuss behavioural and physiological evidence for how environmental shape and in particular enclosure boundaries influence grid cell firing properties. We propose that grid cells encode the geometric layout of enclosures. PMID- 26969456 TI - Screening for asymptomatic urogenital Chlamydia trachomatis infection at a large Dublin maternity hospital: results of a pilot study. AB - BACKGROUND: There are currently no Irish guidelines on screening for Chlamydia trachomatis infection in pregnancy. Prevalence rates in the antenatal population are not known which has prevented the development of screening recommendations for this group. AIMS: The objective of this study was to determine the prevalence of asymptomatic urogenital C. trachomatis infection in young women attending for care at a large maternity hospital. METHODS: All patients aged 25 years and under attending the Hospital between December 2011 and December 2013 were offered screening for urogenital C. trachomatis infection. Nucleic acid amplification testing of the C. trachomatis cryptic plasmid was performed on either endocervical swabs or first void urine samples. RESULTS: There were 2687 women tested for C. trachomatis infection, 83.4 % (2241/2687) through the antenatal clinics, 7.1 % (193/2687) through the gynaecology clinic, and 9.4 % (253/2687) through the emergency department. The rate of a positive test result was 5.6 % (151/2687) overall. The rates in women ages 16-18, 19-21 and 22-25 years were 9.1 % (31/340), 6.5 % (50/774) and 4.4 % (69/1561), respectively. A positive test result was more likely in those who were unemployed (p = 0.04), those who were Irish (p = 0.03) and those who were unmarried (p < 0.01). There were no cases of neonatal C. trachomatis infection in babies born to mothers who were screened in early pregnancy. CONCLUSIONS: The prevalence rate of detected C. trachomatis infection was 5.6 % in the study population. Screening of antenatal patients may have a role in preventing vertical transmission of infection to the neonate. PMID- 26969457 TI - William Wilde: Historian. AB - This essay attempts to assess William Wilde as a social historian. It examines some of his contributions to the discipline of history and looks particularly at 'The food of the Irish', which was published in the Dublin University Magazine in February 1854. PMID- 26969459 TI - Concomitant cervical fractures without neurological symptoms: a case report. AB - BACKGROUND: Non-contiguous spinal fractures are rare and most frequently occur in a fall from a height, or high energy trauma such as a road traffic accident (Reid, J Trauma 27:980-986, 1987). Cervical spine fractures tend to occur at two levels, one-third of injuries occur at the level of C2, and one-half of injuries occur at the level of C6 or at C7 (Wittenberg, Spine 27:254-257, 2002). The most devastating and fatal cervical spine injuries occur in upper cervical levels, either at craniocervical junction C1 or C2. CASE REPORT: The case we present is of a young man involved in a road traffic accident in Ireland who had a concomitant non-displaced C2 vertebral body fracture and a C6-C7 fracture dislocation. The patient had no neurological symptoms. CONCLUSION: Following concurrent ACDF at C6/7 and peg screw fixation of C2 through the same incision the patient made a full recovery. PMID- 26969458 TI - Use of a web-based dietary assessment tool in early pregnancy. AB - BACKGROUND: Maternal diet is critical to fetal development and lifelong health outcomes. In this context, dietary quality indices in pregnancy should be explicitly underpinned by data correlating food intake patterns with nutrient intakes known to be important for gestation. AIMS: Our aim was to assess the correlation between dietary quality scores derived from a novel online dietary assessment tool (DAT) and nutrient intake data derived from the previously validated Willett Food Frequency Questionnaire (WFFQ). METHODS: 524 women completed the validated semi-quantitive WFFQ and online DAT questionnaire in their first trimester. Spearman correlation and Kruskal-Wallis tests were used to test associations between energy-adjusted and energy-unadjusted nutrient intakes derived from the WFFQ, and diet and nutrition scores obtained from the DAT. RESULTS: Positive correlations were observed between respondents' diet and nutrition scores derived from the online DAT, and their folate, vitamin B12, iron, calcium, zinc and iodine intakes/MJ of energy consumed derived from the WFFQ (all P < 0.001). Negative correlations were observed between participants' diet and nutrition scores and their total energy intake (P = 0.02), and their percentage energy from fat, saturated fat, and non-milk extrinsic sugars (NMES) (all P <= 0.001). Median dietary fibre, beta carotene, folate, vitamin C and vitamin D intakes derived from the WFFQ, generally increased across quartiles of diet and nutrition score (all P < 0.001). CONCLUSIONS: Scores generated by this web-based DAT correlate with important nutrient intakes in pregnancy, supporting its use in estimating overall dietary quality among obstetric populations. PMID- 26969460 TI - Quantification of sialic acids in red meat by UPLC-FLD using indoxylsialosides as internal standards. AB - Herein we describe a UPLC-FLD-based method for the quantification of the sialic acid content of red meat, using a synthetic neuraminic acid derivative as an internal standard. X-Gal-alpha-2,6-N-propionylneuraminic acid was synthesized via a chemoenzymatic pathway and its hydrolytic stability was characterized. Known quantities of this compound were incubated with samples of red meat under sialic acid-releasing conditions. The released sialic acids were derivatized, analyzed by UPLC-FLD, and the Neu5Ac/Neu5Gc content of the meat sample was determined by comparison with the internal standard. A number of red meats were analyzed by this method with the following results (Neu5Ac MUg/g tissue, Neu5Gc MUg/g tissue +/- s.d.): pork (68 +/- 3, 15.2 +/- 0.7), beef (69 +/- 8, 36 +/- 5), lamb (46 +/- 2, 33 +/- 1), rabbit (59 +/- 2, 0.4 +/- 0.4), and hare (50 +/- 4, 1 +/- 1). We envisage that this methodology will find application in investigating the health effects of dietary Neu5Gc. Graphical abstract ?. PMID- 26969461 TI - A possible connection between tumor necrosis factor alpha and adropin levels in polycystic ovary syndrome. AB - CONTEXT: Adropin is a peptide hormone implicated in the regulation of insulin sensitivity and energy homeostasis. Polycystic ovary syndrome (PCOS) is a metabolic and reproductive disease associated with insulin resistance. It has been demonstrated that various inflammatory markers increased in PCOS including TNF-alpha. TNF-alpha regulates the secretion of certain peptides which play a crucial role in glucose and lipid homeostasis. There is also some evidence of a link between TNF-alpha and adropin. OBJECTIVE: To ascertain whether there is an association between circulating adropin levels and TNF-alpha in PCOS. PATIENTS AND DESIGN: 152 women with PCOS and 152 age- and body mass index-matched controls without PCOS were recruited for this cross-sectional study. MAIN OUTCOME MEASURES: Adropin and TNF-alpha levels were measured using ELISA. RESULTS: Adropin levels were lower in the PCOS group compared with the control group (7.43 +/- 0.79 vs. 9.42 +/- 0.76 ng/ml, P < 0.001), whereas TNF-alpha levels were higher (49.93 +/- 3.39 vs. 35.83 +/- 2.47 pg/ml, P < 0.001). A strongly negative correlation was found between circulating adropin levels and TNF-alpha levels in women with PCOS (r = -0.407, P < 0.001). Binary logistic regression analysis revealed that decreased adropin levels were significantly associated with high odds of having PCOS, although, after adjustment for TNF-alpha, this link vanished. Additionally, multiple linear regression analysis showed that HOMA-IR and TFN-alpha independently predicted adropin levels. CONCLUSIONS: Serum adropin levels are significantly decreased in PCOS and are inversely associated with TNF alpha. Further dissection of the nature of this association can open new therapeutic options for metabolic diseases. PMID- 26969463 TI - Actual sexual risk and perceived risk of HIV acquisition among HIV-negative men who have sex with men in Toronto, Canada. AB - BACKGROUND: Theory suggests that perceived human immunodeficiency virus (HIV) risk and actual HIV risk behaviour are cyclical whereby engaging in high risk behaviour can increase perceived risk, which initiates precautionary behaviour that reduces actual risk, and with time reduces perceived risk. While current perceived risk may impact future actual risk, it is less clear how previous actual risk shapes current perceived risk. If individuals do not base their current perceived risk on past behaviour, they lose the protective effect of perceived risk motivating precautionary behaviour. Our goal was to determine the impact of actual risk on perceived risk. METHODS: Sexually active men who have sex with men (MSM) were recruited at the Maple Leaf Medical Clinic in downtown Toronto from September 2010 to June 2012. Participants completed a socio behavioural questionnaire using an Audio Computer Assisted Self-Interview (ACASI). Actual HIV risk (primary predictor) was constructed by applying principal component analysis (PCA) to eight sexual risk survey questions and comprised three components which reflected sex with casual partners, sex with HIV positive regular partners and sex with HIV unknown status regular partners. Perceived HIV risk (outcome) was measured by asking participants what the chances were that they would ever get HIV. Multivariable logistic regression was used to measure the association between actual and perceived HIV risk. RESULTS: One hundred and fifty HIV-negative MSM were recruited (median age 44.5 years [IQR 37 50 years]). Twenty percent of MSM perceived their HIV risk to be high. The odds of having a high perceived risk was significantly higher in those with high actual HIV risk indicated by low condom use with an HIV-positive regular partner compared to those with low actual HIV risk indicated by high condom use with an HIV-positive regular partner (Odds Ratio (OR) 18.33, 95% confidence interval (CI) 1.65-203.45). Older age was associated with lower perceived risk but only age 40 49 compared to less than 30 was statistically significant (OR 0.12, 95% CI 0.016 0.86). The odds of having high perceived risk was significantly associated with men who used poppers in the previous 6 months compared to those who did not use poppers (OR 5.64, 95% CI 1.20-26.48). CONCLUSIONS: Perceived HIV risk increased significantly as condom use with an HIV-positive regular partner decreased. However, perceived HIV risk was not associated with condom use with casual partners or HIV unknown status regular partners, even though these behaviours could be considered risky. The relationship between perceived and actual risk in HIV studies is complex and has implications on how health care workers address the issue of risky sexual behaviour and perceived risk. PMID- 26969464 TI - Clinical tests and magnetic resonance imaging have limited diagnostic value for triangular fibrocartilaginous complex lesions. AB - INTRODUCTION: The diagnostic value of clinical tests and magnetic resonance (MR) imaging for the investigation of triangular fibrocartilaginous complex (TFCC) lesions is not clear due to a lack of clinical data. MATERIALS AND METHODS: We retrospectively analyzed 908 patients who underwent clinical tests and arthroscopy for suspected TFCC lesions at our institution. Further, MR imaging findings concerning the TFCC were gathered. We correlated clinical tests and MR imaging findings with those obtained during arthroscopy, and we calculated sensitivity, specificity, as well as positive and negative predictive values. RESULTS: In the whole cohort, the positive predictive values of all clinical tests were low, ranging from 0.53 to 0.55. The ulna grinding test had the highest sensitivity, but lowest specificity. Sensitivity and specificity of the ulnar fovea sign and magnetic resonance imaging were similar, ranging from 0.73 to 0.76, and from 0.41 to 0.44, respectively. To some degree, the diagnostic value seemed to depend on the Palmer class of TFCC lesion. CONCLUSIONS: According to this study, clinical tests and MR imaging findings are of very limited diagnostic value for the diagnosis of TFCC lesions. PMID- 26969465 TI - The role of vulnerability factors in individuals with an at-risk mental state of psychosis. AB - BACKGROUND: Several indicators of heightened vulnerability to psychosis and relevant stressors have been identified. However, it has rarely been studied prospectively to what extent these vulnerability factors are in fact more frequently present in individuals with an at-risk mental state for psychosis. Moreover, it remains unknown whether any of these contribute to the prediction of psychosis onset in at-risk mental state individuals. METHODS: There were 28 healthy controls, 86 first-episode psychosis patients and 127 at-risk mental state individuals recruited within the Basel "Fruherkennung von Psychosen" project. Relative frequencies of selected vulnerability factors for psychosis were compared between healthy controls, psychosis patients, those at-risk mental state individuals with subsequent psychosis onset (n = 31) and those without subsequent psychosis onset (n = 55). Survival analyses were applied to determine associations between time to transition to psychosis and vulnerability factors in all 127 at-risk mental state individuals. RESULTS: The vulnerability factors/indicators such as "difficulties during school education or vocational training", "difficulties during employment", "being single", "difficulties with intimate relationships" and "being burdened with specific stressful situations" were more commonly found in the at-risk mental state and first-episode psychosis group than in healthy controls. CONCLUSIONS: At-risk mental state and first episode psychosis individuals more frequently present with vulnerability factors. Individual vulnerability factors appear, however, not to be predictive for an onset of psychosis. PMID- 26969467 TI - Erratum to: Predicting technique and patient survival over 12 months in peritoneal dialysis: the role of anxiety and depression. PMID- 26969466 TI - Hsp70 suppresses apoptosis of BRL cells by regulating the expression of Bcl-2, cytochrome C, and caspase 8/3. AB - During cold stress, liver cells undergo apoptotic injury as a result of oxidative stress. Heat shock 70 kDa protein (Hsp70) is a protein involved in modulating a variety of physiological processes, including stress responses, proliferation, and apoptosis. In addition, Hsp70 regulates apoptotic signaling pathways in different manners, promoting or suppressing apoptosis. In this study, we investigated the effects of Hsp70 overexpression on hydrogen peroxide (H2O2) induced apoptosis of Buffalo rat liver (BRL) cells and the underlying mechanisms of these effects. Our results show that in comparison with the control group, Hsp70 overexpression displayed increased protein levels of Bcl-2, and decreased cytochrome c (Cyt c), cleaved caspase 3, and cleaved caspase 8, but no apparent differences were found in levels of Bax. Furthermore, Hsp70 overexpression significantly suppresses the amount of apoptotic cells. Such findings indicate that overexpression of Hsp70 inhibits H2O2-mediated activation of caspase 8 and caspase 3, upregulates the expression of Bcl-2 which is a known anti-apoptotic protein, and decreases the release of Cyt c from the mitochondria into the cytoplasm, collectively decreasing cell apoptosis. PMID- 26969462 TI - Italian association of clinical endocrinologists (AME) position statement: drug therapy of osteoporosis. AB - Treatment of osteoporosis is aimed to prevent fragility fractures and to stabilize or increase bone mineral density. Several drugs with different efficacy and safety profiles are available. The long-term therapeutic strategy should be planned, and the initial treatment should be selected according to the individual site-specific fracture risk and the need to give the maximal protection when the fracture risk is highest (i.e. in the late life). The present consensus focused on the strategies for the treatment of postmenopausal osteoporosis taking into consideration all the drugs available for this purpose. A short revision of the literature about treatment of secondary osteoporosis due both to androgen deprivation therapy for prostate cancer and to aromatase inhibitors for breast cancer was also performed. Also premenopausal females and males with osteoporosis are frequently seen in endocrine settings. Finally particular attention was paid to the tailoring of treatment as well as to its duration. PMID- 26969468 TI - Direct brain infusion can be enhanced with focused ultrasound and microbubbles. AB - The delivery of most therapeutic agents is rendered ineffective for the treatment of brain diseases due to the presence of the blood-brain barrier (BBB). The goal of this study was to investigate the effect of pre-infusion focused ultrasound (FUS) and microbubbles on the distribution of direct brain infusion in vivo. A single-element FUS transducer was used in all sonications, which were carried out immediately prior to direct infusion procedures. Mice received direct infusion of either Gadolinium-labeled albumin (Gd-albumin, 74 kDa) or adeno-associated virus (AAV, ~4 MDa). The volumes of Gd-albumin at 30 min were deemed comparable ( P = 0.334) between the direct infusion (DI)-only group and the FUS + DI group. At 120 min, the FUS + DI group showed significantly higher contrast-enhanced volume (9.76 +/- 0.74 mm3) than the DI-only group (7.14 +/- 0.34 mm3). For mice infused with AAV, the total volume of transduction was estimated as GFP-positive regions and FUS + DI group demonstrated significantly higher ( P = 0.017) transduction efficiency in vivo. In conclusion, enhanced bio-distribution of directly infused agents was observed when the targeted region was pre-conditioned with FUS and microbubbles. Focused ultrasound has the potential, as an adjuvant technique, to significantly enhance direct brain infusion and achieve the desired therapeutic outcomes. PMID- 26969469 TI - Expression Profile and Tissue-Specific Distribution of the Receptor-Interacting Protein 3 in BALB/c Mice. AB - RIP3, a member of receptor-interacting protein family, is serine/threonine kinase that contributes to necrosis and promotes systematic inflammation. However, detailed information of the expression pattern and tissue distribution in BALB/c mice, a commonly used laboratory animal model, is still unavailable. Here, we provided the basic data of expression profile and histologic distribution of RIP3 in tissues of BALB/c mice. Rip3 mRNA expression levels and tissue distribution were detected by real-time quantitative PCR and immunohistochemical detection, respectively. Rip3 mRNA expression showed the highest level in the spleen and duodenum, while with the lowest level in brain. Immunohistochemical detection revealed this protein located in different type cells in different tissues. What's more, the obvious positive staining in nuclear was detected in liver cells and neurons in cerebral cortex of the brain, while cells in other organs, including heart, spleen, lung, kidney, stomach, duodenum and trachea, showed strong positive mainly in cytoplasm. The results will help us to further understand the site-specific functions of RIP3 in necrosis and inflammatory responses. PMID- 26969470 TI - Inter-annual and inter-individual variations in survival exhibit strong seasonality in a hibernating rodent. AB - Most research on the demography of wild animal populations has focused on characterizing the variation in the mortality of organisms as a function of intrinsic and environmental characteristics. However, such variation in mortality is difficult to relate to functional life history components (e.g. reproduction, dispersal, hibernation) due to the difficulty in monitoring biological processes at a sufficiently fine timescale. In this study, we used a 10-year individual based data set with an infra-annual timescale to investigate both intra- and inter-annual survival patterns according to intrinsic and environmental covariates in an introduced population of a small hibernating rodent, the Siberian chipmunk. We compared three distinct periods related to particular life history events: spring reproduction, summer reproduction and hibernation. Our results revealed strong interactions between intrinsic and temporal effects. First, survival of male chipmunks strongly decreases during the reproduction periods, while survival is high and equal between sexes during hibernation. Second, the season of birth affects the survival of juveniles during their first hibernation, which does not have long-lasting consequences at the adult stage. Third, at an inter-annual scale, we found that high food resource availability before hibernation and low chipmunk densities specifically favour subsequent winter survival. Overall, our results confirm that the well-known patterns of yearly and inter-individual variation of mortality observed in animals are themselves strongly variable within a given year, suggesting that they are associated with various functional components of the animals' life history. PMID- 26969472 TI - Opioids: an unexplored option for treatment of dyspnea in IPF. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common among the idiopathic interstitial pneumonias and has the worst prognosis, with a median survival of 3-5 years. The most common symptom in IPF is dyspnea, impacting on the patient's quality of life and life expectancy. Morphine in the treatment of dyspnea has been investigated but with conflicting results. This review aims to clarify the role of opioids in the treatment of dyspnea in patients with IPF. METHODS: A literature search was performed using the MeSH and PubMed databases. As only very few studies included patients with IPF, studies conducted primarily with patients with chronic obstructive pulmonary disease were also included. In total, 14 articles were found. RESULTS: Seven studies reported use of systemic morphine and seven studies of inhaled morphine. Five of the seven studies investigating systemic administration detected an improvement in either dyspnea or exercise capacity, whereas no beneficial effect on dyspnea was detected in any study using inhaled morphine. No severe adverse effects such as respiratory depression were reported in any study, although constipation was reported as a notable adverse effect. CONCLUSIONS: Results were inconsistent, but in some studies systemic morphine administration showed a significant improvement in the dyspnea score on a visual analog scale without observation of severe side effects. Nebulized morphine had no effect on dyspnea. PMID- 26969474 TI - Absent Ring Finger Flexor Digitorum Profundus Presenting as a Jersey Finger. AB - We report the case of a patient who presented with an apparent acute avulsion of the ring finger flexor digitorum profundus (FDP), or jersey finger. At surgery, the FDP to the ring finger was found to be absent; also absent were the lumbrical to the ring finger and the A5 pulley. Absence of the FDP was confirmed with postoperative imaging. Although absent profundus tendons have been previously reported, none have involved the FDP to the ring finger. However, various reports have described abnormal connections between the ring and little finger flexor tendons. PMID- 26969473 TI - Different rate-limiting activities of intracellular pH regulators for HCO3- secretion stimulated by forskolin and carbachol in rat parotid intralobular ducts. AB - Intracellular pH (pHi) regulation fundamentally participates in maintaining HCO3- release from HCO3--secreting epithelia. We used parotid intralobular ducts loaded with BCECF to investigate the contributions of a carbonic anhydrase (CA), anion channels and a Na+-H+ exchanger (NHE) to pHi regulation for HCO3- secretion by cAMP and Ca2+ signals. Resting pHi was dispersed between 7.4 and 7.9. Forskolin consistently decreased pHi showing the dominance of pHi-lowering activities, but carbachol gathered pHi around 7.6. CA inhibition suppressed the forskolin-induced decrease in pHi, while it allowed carbachol to consistently increase pHi by revealing that carbachol prominently activated NHE via Ca2+-calmodulin. Under NHE inhibition, forskolin and carbachol induced the remarkable decreases in pHi, which were slowed predominantly by CA inhibition and by CA or anion channel inhibition, respectively. Our results suggest that forskolin and carbachol primarily activate the pHi-lowering CA and pHi-raising NHE, respectively, to regulate pHi for HCO3- secretion. PMID- 26969475 TI - Editorial. PMID- 26969471 TI - Liquid Biopsy and its Potential for Management of Hepatocellular Carcinoma. AB - PURPOSE: We summarized the recent findings of liquid biopsy in cancer field and discussed its potential utility in hepatocellular carcinoma. METHODS: Literature published in MEDLINE, EMBASE, and Science Direct electronic databases was searched and reviewed. RESULTS: Liquid biopsy specially referred to the detection of nucleic acids (circulating cell-free DNA, cfDNA) and circulating tumor cells (CTCs) in the blood of cancer patients. Compared to conventional single-site sampling or biopsy method, liquid biopsy had the advantages such as non invasiveness, dynamic monitoring, and the most important of all, overcoming the limit of spatial and temporal heterogeneity. The genomic information of cancer could be profiled by genotyping cfDNA/CTC and subsequently applied to make molecular classification, targeted therapy guidance, and unveil drug resistance mechanisms. The serial sampling feature of liquid biopsy made it possible to monitor treatment response in a real-time manner and predict tumor metastasis/recurrence in advance. CONCLUSIONS: Liquid biopsy is a non-invasive, dynamic, and informative sampling method with important clinical translational significance in cancer research and practice. Much work needs to be done before it is used in the management of HCC. PMID- 26969476 TI - [Teledermatology: The French model?]. PMID- 26969478 TI - [Atypical scleromyxedema with a granulomatous histological pattern and delayed sclerosis]. AB - BACKGROUND: Papular mucinosis is characterised by primary mucin deposition in the dermis. The classification distinguishes between the localised form and the systemic form, which alone can result in complications, but this classification occasionally proves to be inadequate. Herein we report the progression of papular mucinosis, initially atypical due to the absence of cutaneous sclerosis and of misleading granulomatous histological features, which subsequently developed into characteristic scleromyxedema. PATIENTS AND METHODS: A 55-year-old male developed a rash comprising countless acral papules. Several biopsies were necessary before a diagnosis of papular mucinosis was made, due to the initial granulomatous appearance at histology. Tests showed monoclonal immunoglobulin of indeterminate significance, but, due to the absence of cutaneous sclerosis, we were able to conclude on typical localised papular mucinosis. Two years later, extensive sclerotic induration of the skin appeared and the diagnosis was modified to one of scleromyxedema. Treatment with intravenous immunoglobulins was given and proved efficacious, but relapse occurred on discontinuation of the therapy. DISCUSSION: Papular mucinosis is a rare disease of unknown physiopathology. The disease classification distinguishes between the localised and systemic forms, but it occasionally proves to be inadequate. Our case suggests a continuum between the localised and systemic forms of the disease. Further, the initial biopsies of acral papules in our patient had a misleading granulomatous appearance, as has been reported numerous times for the systemic forms. This granulomatous histological variant thus appears to constitute a diagnostic criterion for scleromyxedema. PMID- 26969477 TI - [Severe crusted scabies: A "historic" case involving the death of a 52-year-old patient]. AB - BACKGROUND: Crusted scabies, also known as Norwegian scabies, is a rare and extremely debilitating form of Sarcoptes scabiei var. hominis infestation that generally occurs in immunosuppressed patients. Herein, we report a "historic" and fatal case. PATIENTS AND METHODS: A 52-year-old woman was admitted to the emergency department presenting crusted dermatitis together with extreme deterioration of her general condition. Her general practitioner had initiated dermo-corticosteroid therapy for suspected atopic dermatitis two months earlier, and she had been confined to bed for the previous 10 days. Her son presented pruritus that became worse at night. On examination the patient was moaning, dehydrated and confused and her entire skin was hyperkeratotic, with very thick, yellowish, cracked crusts covering 40 % of her body. Tests indicated severe water and electrolytic disorders as well as Staphylococcus aureus bacteremia. A tape test established the diagnosis of crusted scabies. The severity was grade III on the Davis clinical grading scale. The patient showed signs of multi-organ failure and was transferred to intensive care, but she died during the night. DISCUSSION: This case is remarkable for its historic severity. In France, scabies infestation is a re-emerging disease and has been a public health priority since 2012. The rare hyperkeratotic form is not fully understood and frequently diagnosed late, in some cases with a fatal outcome. PMID- 26969479 TI - [Impact of sex and age on the clinical and epidemiological aspects of childhood psoriasis: Data from a French cross-sectional multicentre study]. AB - BACKGROUND: The prevalence of childhood psoriasis is estimated at between 0.4% and 0.7%. Clinical aspects of the diseases depend on age. The aim of this study was to investigate the clinical aspects of psoriasis according to age and sex. PATIENTS AND METHODS: A cross-sectional, multicentre study of children with psoriasis was performed by investigators belonging to the Research Group of the French Society of Paediatric Dermatology. The study was conducted from April 2012 to March 2013. Inclusion criteria were age less than 18 years and clinical diagnosis of psoriasis. The children were classified into 3 groups by age: infants: <2 years; children: >=2 years and <13 years; adolescents>=13 years. The information collected included demographic data, clinical, epidemiological, and therapeutic aspects of the psoriasis, as well as analysis of comorbidities. RESULTS: Three hundred and thirteen children were included: 27 (8.6%) infants, 207 (66.1%) children, and 79 (25.2%) adolescents. Plaque psoriasis was the most frequent clinical type of psoriasis seen in children and adolescents (>41%), but it accounted for only 25.9% of psoriasis of infants (P<0.0001). Napkin psoriasis (37.0%) and inverse psoriasis (22.2%) were the most common forms of psoriasis seen in infants and were described significantly more frequently in this group than in the two other groups (P<0.003). Nail involvement was more common in adolescents (37.2%, P=0.03) and children (32.9%) than in infants (14.8%) and affected boys more than girls (43.6% vs 22.0%, P<0.0001). Girls presented scalp psoriasis more frequently (17.7% vs 8.7%, P=0.02). Local vitamin-D treatment and systemic therapies were used more frequently in children and adolescents than in infants. There was no significant difference for treatment use, including for acitretin, according to gender. DISCUSSION: Plaque psoriasis was the most common clinical type of psoriasis in children but affected less than 50% of the children. Age had a significant impact on extra-cutaneous skin disorders and on treatment used, while sex had little incidence. The frequency of comorbidities was not affected by age. CONCLUSION: Childhood psoriasis thus presents specific characteristics dependent on the age of the child. The results of studies exclusively dealing with adults cannot be extrapolated to children. PMID- 26969480 TI - Metabolic comorbidities and hypertension in psoriasis patients in France. Comparisons with French national databases. AB - INTRODUCTION: Several studies have shown a high prevalence of cardiovascular and metabolic comorbidities in psoriasis. Our study aimed to evaluate the association of psoriasis with key comorbidities such as smoking, obesity, hypertension, dyslipidaemia and diabetes comparatively with French national data. MATERIAL AND METHODS: This multicentre noninterventional observational study of adults with psoriasis was conducted in 29 dermatology centres in France. A total of 2210 patients were included. The prevalence of comorbidities in psoriatic patients was compared to data from the French national databanks "ObEpi 2012" (obesity, hypertension, dyslipidaemia and diabetes) and "Barometre Sante 2010" (smoking). RESULTS: We reported a higher prevalence of all metabolic comorbidities and high blood pressure in psoriatic patients. Smoking: 32.5% were active smokers; the age of onset and the prevalence of familial psoriasis were significantly lower in the smoking group but the severity of psoriasis was significantly higher. The frequency of smoking was higher than in the general population, particularly among young female patients. Obesity: 24% of patients with psoriasis were obese. Multivariate analysis showed obesity to be significantly associated with other comorbidities, severity of psoriasis and psoriatic arthritis. The incidence of obesity was higher than in general population, occurring chiefly in subjects aged over 45 years. HYPERTENSION: 26% of patients with psoriasis had hypertension. The age of onset of psoriasis and the prevalence of psoriatic arthritis were significantly higher in the hypertension group, although there was less familial psoriasis. The incidence of hypertension was higher than in general population. Dyslipidaemia: 27.5% of patients with psoriasis had dyslipidaemia. The age of onset in the dyslipidaemia group was higher although there was less familial psoriasis. The incidence of dyslipidaemia was higher than in general population. Diabetes: 11.0% of patients with psoriasis had diabetes. The age of onset of psoriasis was significantly higher in the diabetes group although there was less familial psoriasis. The incidence of diabetes was higher than in general population particularly after the age of 35 years. CONCLUSION: These results confirmed that psoriasis is associated with significant metabolic comorbidities and hypertension compared to the general population in France, with certain epidemiological differences for each. PMID- 26969481 TI - New endoscopic classification of the cardiac orifice in esophageal achalasia: Champagne glass sign. AB - BACKGROUND AND AIM: Endoscopy, barium esophagram and manometry are used in the diagnosis of achalasia. In the case of early achalasia, characteristic endoscopic findings are difficult to recognize. As a result, the diagnosis of achalasia is often made several years after symptom onset. Therefore, we examined the endoscopic findings of the cardiac orifice in achalasia and propose a new classification. METHODS: A total of 400 patients with spastic esophageal motility disorders who underwent peroral endoscopic myotomy (POEM) at our hospital between March 2014 and August 2015 were screened for this study. Champagne glass sign (CG) was defined as when the distal end of the lower esophageal sphincter relaxation failure (LESRF) was proximal to the squamocolumnar junction (SCJ) and the SCJ was dilated in the retroflex view. Specifically, CG-1 was defined as a distance from the SCJ to the lower end of LESRF of <1 cm, and CG-2 was defined as a distance >=1 cm. RESULTS: CG-0 was seen in 73 patients (28.0%), whereas the CG sign was seen in 186 patients (71.3%), of whom 170 (65.1%) were CG-1 and 16 (6.1%) were CG-2. CONCLUSIONS: The CG sign is often observed in esophageal achalasia patients. CG-0 (equal to Maki-tsuki) was observed in 28.0% of achalasia patients only. Its absence with dilated SCJ cannot be used to rule out achalasia. Barium esophagram and manometry should be done if esophageal achalasia is strongly suspected. PMID- 26969482 TI - Risk factors and newborn outcomes associated with maternal deaths in the UK from 2009 to 2013: a national case-control study. AB - OBJECTIVES: To identify the risk factors for and adverse newborn outcomes associated with maternal deaths from direct and indirect causes in the UK. DESIGN: Unmatched case-control analysis. SETTING: All hospitals caring for pregnant women in the UK. POPULATION: Comprised 383 women who died (cases) from direct or indirect causes from 2009 to 2013 (Confidential Enquiry into Maternal Deaths in the UK) and 1516 women who did not have any life-threatening complications during pregnancy and childbirth (controls) obtained from UK Obstetric Surveillance System (UKOSS). METHODS: Multivariable regression analyses were undertaken to examine potential risk factors, their incremental effects, and adverse newborn outcomes associated with maternal deaths. OUTCOMES: Odds ratios associated for risk factors for maternal death and newborn outcomes (stillbirth, admission to neonatal intensive care unit [NICU], early neonatal death) and incremental risk. RESULTS: Seven factors, of 13 examined, were independently associated with increased odds of maternal death: pre-existing medical comorbidities (adjusted odds ratio [aOR] 8.65; 95% CI 6.29-11.90), anaemia during pregnancy (aOR 3.58; 95% CI 1.14-11.21), previous pregnancy problems (aOR 1.85; 95% CI 1.33-2.57), inadequate use of antenatal care (aOR 46.85; 95% CI 19.61 111.94), substance misuse (aOR 12.21; 95% CI 2.33-63.98), unemployment (aOR 1.81; 95% CI 1.08-3.04) and maternal age (aOR 1.06; 95% CI 1.04-1.09). There was a four fold increase in the odds of death per unit increase in the number of risk factors. Odds of stillbirth, admission to NICU and early neonatal death were higher among women who died. CONCLUSION: This study reiterates the need for optimal care for women with medical comorbidities and older age, and the importance of adequate antenatal care. It demonstrates the existence of socio economic inequalities in maternal death in the UK. TWEETABLE ABSTRACT: Medical comorbidities and socio-economic inequalities are important risk factors for maternal death in the UK. PMID- 26969483 TI - Use of the frozen section 'jelly-roll' technique to aid in the diagnosis of bullous congenital ichthyosiform erythroderma (epidermolytic hyperkeratosis). AB - Frozen section is a valuable tool that is often underutilized in the setting of in-patient dermatology. Traditionally, frozen section has been used in dermatology to diagnose toxic epidermal necrolysis, with some additional utility in staphylococcal scalded skin syndrome in the new born period. We report a newborn female with ruptured bullae on the face, chest, back and extremities with a clinical differential diagnosis that included staphylococcal scalded skin, bullous congenital ichthyosiform erythroderma/epidermolytic hyperkeratosis and epidermolysis bullosa. A thin detached skin sample ('jelly-roll') taken from a ruptured bulla on the abdomen was prepared for frozen section analysis. Characteristic findings of epidermolytic hyperkeratosis were seen which included hyperkeratosis with granular layer degeneration, vacuolization and eosinophilic globules. The 'jelly-roll' technique can be used for quick diagnosis with minimal trauma to the patient. Epidermolytic hyperkeratosis was subsequently confirmed by a biopsy fixed in formalin and by genetic testing. A novel missense mutation in KRT1 (I479N) was identified. Herein, we discuss the use of the frozen section 'jelly roll' technique for rapid diagnosis in a case of bullous congenital ichthyosis erythroderma/epidermolytic hyperkeratosis. PMID- 26969484 TI - The purinergic receptor P2X7 role in control of Dengue virus-2 infection and cytokine/chemokine production in infected human monocytes. AB - Purinergic signaling has a crucial role in intracellular pathogen elimination. The P2X7 purinergic receptor (P2X7R), once activated by ATP, leads to pro inflammatory responses including reactive oxygen species production. ATP can be released by injured cells, as endogenous danger signals. Dengue fever may evolve to a severe disease, leading to hypovolemic shock and coagulation dysfunctions as a result of a cytokine storm. Our aim was to evaluate the role of P2X7R activation during Dengue virus (DENV) infection. Extracellular ATP inhibited viral load in pretreated monocytes, as measured by NS1 secretion and by decrease in DENV(+) P2X7(+) cell frequencies, suggesting that P2X7R is involved in the antiviral response. Nitric oxide (NO) has anti-DENV properties and is decreased after DENV infection. NO production after ATP stimulation is abrogated by KN62 treatment, a specific P2X7R inhibitor, indicating that P2X7R likely is acting in the virus containment process. Additionally, TNF, CXCL8, CCL2 and CXCL10 factors that are associated with dengue severity were modulated by the P2X7R activation. We conclude that P2X7R is directly involved in the modulation of the antiviral and inflammatory process that occurs during DENV infection in vitro, and may have an important role in patient recovery in a first moment. PMID- 26969485 TI - Eosinophilic airway inflammation is common in subacute cough following acute upper respiratory tract infection. AB - BACKGROUND AND OBJECTIVE: Patients presenting with refractory postinfectious cough may respond to glucocorticosteroids but it is unclear whether airway eosinophilic inflammation exists in those patients. We aimed to determine the airway inflammation and causes of subacute cough following acute upper respiratory tract infection (AURTI). METHODS: One hundred and sixteen patients with persistent cough lasting 3-8 weeks after upper respiratory tract infection were evaluated with differential cell count in induced sputum, spirometry and methacholine bronchial challenge testing. RESULTS: In patients with subacute cough, sputum eosinophilia (median 8.5%,3.0-73.0%) was identified in 35 (33.6%) patients, 22 (18.5%) without bronchial hyperresponsiveness (BHR) were diagnosed as non-asthmatic eosinophilic bronchitis (NAEB), 13 (14.3%) of whom with BHR were diagnosed as cough variant asthma (CVA). Cough in patients with sputum eosinophilia improved after treatment with corticosteroids. Compared with postinfectious cough (PIC) and NAEB, CVA had significantly higher median eosinophil count in induced sputum (0.5% vs 7.5% vs 20.0%, P < 0.01). MMEF in CVA was significantly lower than PIC and NAEB (P < 0.05). The common causes of subacute cough following acute upper respiratory tract infection (AURTI) were PIC (37.8%), NAEB (18.5%), CVA (14.3%) and upper airway cough syndrome (UACS) (10.1%). Atopic cough (AC) (5.2%) and gastroesophageal reflux-related cough (GERC) (3.4%) were less common in subacute cough following AURTI, while 9 (7.8%) patients had unexplained cough. CONCLUSION: Subacute cough following AURTI can be attributed to different entities, eosinophilic airway inflammation is common. Induced sputum should be considered when evaluating patients with subacute cough following acute upper respiratory tract infection. PMID- 26969486 TI - The role of leptin in diabetes: metabolic effects. AB - While it is well established that the adiposity hormone leptin plays a key role in the regulation of energy homeostasis, growing evidence suggests that leptin is also critical for glycaemic control. In this review we examine the role of the brain in the glucose-lowering actions of leptin and the potential mediators responsible for driving hyperglycaemia in states of uncontrolled insulin deficient diabetes (uDM). These considerations highlight the possibility of targeting leptin-sensitive pathways as a therapeutic option for the treatment of diabetes. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Christoffer Clemmensen and colleagues, DOI: 10.1007/s00125-016-3906-7 , and by Gerald Shulman and colleagues, DOI: 10.1007/s00125-016-3909-4 ) and an overview by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016-3894-7 ). PMID- 26969488 TI - Identification of a novel allele, HLA-A*24:02:50, by sequence-based typing. AB - HLA-A*24:02:50 has one synonymous nucleotide change from HLA-A*24:02:01:01 at nucleotide 429 (codon 119 aspartic acid). PMID- 26969487 TI - Elevated circulating stearic acid leads to a major lipotoxic effect on mouse pancreatic beta cells in hyperlipidaemia via a miR-34a-5p-mediated PERK/p53 dependent pathway. AB - AIMS/HYPOTHESIS: Serum stearic acid (C18:0) is elevated in individuals with hyperlipidaemia and type 2 diabetes. However, the lipotoxicity induced by increased stearic acid in beta cells has not been well described. This study aimed to examine the adverse effects of stearic acid on beta cells and the potential mechanisms through which these are mediated. METHODS: Three groups of C57BL/6 mice were fed a normal diet or a high-stearic-acid/high-palmitic-acid diet for 24 weeks, respectively. The microRNA (miR) profiles of islets were determined by microarray screening. Islet injury was detected with co-staining using the TUNEL assay and insulin labelling. A lentiviral vector expressing anti miRNA-34a-5p oligonucleotide (AMO-34a-5p) was injected into mice via an intraductal pancreatic route. RESULTS: In both mouse islets and cultured rat insulinoma INS-1 cells, stearic acid exhibited a stronger lipotoxic role than other fatty acids, owing to repression of B cell CLL/lymphoma 2 (BCL-2) and BCL-2 like 2 (BCL-W) by stearic acid stimulation of miR-34a-5p. The stearic-acid induced lipotoxicity and reduction in insulin secretion were alleviated by AMO 34a-5p. Further investigations in INS-1 cells revealed that p53 was involved in stearic-acid-induced elevation of miR-34a-5p, owing in part to activation of protein kinase-like endoplasmic reticulum kinase (PERK). Conversely, silencing PERK alleviated stearic-acid-induced p53, miR-34a-5p and lipotoxicity. CONCLUSIONS/INTERPRETATION: These findings provide new insight for understanding the molecular mechanisms underlying not only the deleterious impact of stearic acid-induced lipotoxicity but also apoptosis in beta cells and progression to type 2 diabetes. PMID- 26969489 TI - Molecular detection of Theileria, Babesia, and Hepatozoon spp. in ixodid ticks from Palestine. AB - Ixodid ticks transmit various infectious agents that cause disease in humans and livestock worldwide. A cross-sectional survey on the presence of protozoan pathogens in ticks was carried out to assess the impact of tick-borne protozoa on domestic animals in Palestine. Ticks were collected from herds with sheep, goats and dogs in different geographic districts and their species were determined using morphological keys. The presence of piroplasms and Hepatozoon spp. was determined by PCR amplification of a 460-540bp fragment of the 18S rRNA gene followed by RFLP or DNA sequencing. A PCR-RFLP method based on the 18S rRNA was used in order to detect and to identify Hepatozoon, Babesia and Theileria spp. A total of 516 ticks were collected from animals in six Palestinian localities. Five tick species were found: Rhipicephalus sanguineus sensu lato, Rhipicephalus turanicus, Rhipicephalus bursa, Haemaphysalis parva and Haemaphysalis adleri. PCR based analyses of the ticks revealed Theileria ovis (5.4%), Hepatozoon canis (4.3%), Babesia ovis (0.6%), and Babesia vogeli (0.4%). Theileria ovis was significantly associated with ticks from sheep and with R. turanicus ticks (p<0.01). H. canis was detected only in R. sanguineus s.l. and was significantly associated with ticks from dogs (p<0.01). To our knowledge, this is the first report describing the presence of these pathogens in ticks collected from Palestine. Communicating these findings with health and veterinary professionals will increase their awareness, and contribute to improved diagnosis and treatment of tick-borne diseases. PMID- 26969491 TI - Pension funds: tobacco investment up in smoke. PMID- 26969490 TI - Development of a serodiagnostic multi-species ELISA against tick-borne encephalitis virus using subviral particles. AB - Tick-borne encephalitis virus (TBEV) is a zoonotic agent causing severe encephalitis in humans. A wide range of animal species could be infected with TBEV in endemic areas. A serological survey of wild animals is effective in identifying TBEV-endemic areas. Safe, simple, and reliable TBEV serodiagnostic tools are needed to test animals. In this study, ELISA was developed to detect anti-TBEV specific antibodies in multi-species of animals, using recombinant subviral particles (SPs) with an affinity tag and protein A/G. A Strep-tag was fused at the N terminus of the E protein of the plasmid coding TBEV prME. The E proteins with Strep-tag were secreted as SPs, of which Strep-tag was exposed on the surface. The tagged E proteins were associated with prM. The SPs with Strep tag were applied as the antigen of ELISA, and TBEV-specific antibodies were detected by the protein A/G. Compared to neutralization test results, the ELISA showed 96.8% sensitivity and 97.7% specificity in rodents and 95.1% sensitivity and 96.0% specificity in humans, without cross-reactivity with antibodies to Japanese encephalitis virus. These results indicate that our ELISA would be useful to detect TBE-specific antibodies in a wide range of animal species. PMID- 26969492 TI - Heartbeat: Inflammatory biomarkers in atrial fibrillation. PMID- 26969494 TI - CT urography in evaluation of urothelial tumors of the kidney. PMID- 26969493 TI - Administration of bone marrow stromal cells in sepsis attenuates sepsis-related coagulopathy. AB - INTRODUCTION: Coagulopathy plays an important role in sepsis. The aim of this study was to determine whether bone marrow stromal cell (BMSC) administration could attenuate coagulopathy in sepsis. MATERIALS AND METHODS: In vitro: endothelial cells were cultured with/without BMSCs for 6 h following LPS stimulation and were collected for thrombomodulin (TM) and endothelial protein C receptor (EPCR) measurements. In vivo: Thirty-six mice were randomized into sham, sepsis, and sepsis + BMSC groups (n = 12 each group). Sepsis was induced through cecal ligation and puncture (CLP). BMSC infusion was started at 6 h after CLP. Lung tissues and plasma samples were collected at 24 h after CLP for enzyme linked immunosorbent assay (ELISA), quantitative real-time RT-PCR, western blot, and immunohistochemistry analysis. RESULTS: In vitro: BMSCs attenuated the decrease in TM and EPCR mRNA and protein expression levels in LPS-stimulated endothelial cells. In vivo: BMSC treatment decreased lung injury and mesenteric perfusion impairment, and ameliorated coagulopathy, as suggested by the reduction in elevated TF, vWF, and TAT circulation levels. BMSC infusion decreased TF mRNA transcription and protein expression levels in lung tissues, and increased TM and EPCR mRNA transcription and expression levels. DISCUSSION: BMSC administration attenuated coagulopathy, and decreased lung injury and mesenteric perfusion impairment in sepsis. Key messages BMSCs increased the expression of TM and EPCR from endothelium cells exposed to LPS in vitro. BMSC treatment attenuated lung injury and coagulopathy in the mice cecal ligation and puncture (CLP) model. BMSC administration-attenuated coagulopathy is related to the reduced expression of TF and increased expression of TM and EPCR. PMID- 26969495 TI - Role of contrast-enhanced ultrasound (CEUS) in evaluation of thermal ablation zone. AB - PURPOSE: Thermal ablation has emerged as a mainstay therapy for primary and metastatic liver malignancy. Percutaneous thermal ablation is usually performed under CT and/or ultrasound guidance. CT guidance frequently utilizes iodinated contrast for tumor targeting, with additional radiation and contrast required at the end of the procedure to ensure satisfactory ablation margins. Contrast enhanced ultrasound (CEUS) is an imaging technique utilizing microbubble contrast agents to demonstrate blood flow and tissue perfusion. In this study, we performed a retrospective review to assess the utility of CEUS in the immediate post ablation detection of residual tumor. METHODS: Sixty-four ablations were retrospectively reviewed. 6/64 ablations (9.4%) had residual tumor on the first follow-up imaging after thermal ablation. There were two groups of patients. Group 1 underwent standard protocol thermal ablation with CT and/or ultrasound guidance. Group 2 not only had thermal ablation with a protocol identical to group 1, but also had CEUS assessment at the conclusion of the procedure to ensure satisfactory ablation zone. RESULTS: The residual tumor rate in group 1 was 16.7% and the residual tumor rate in group 2 was 0%. The difference between the groups was statistically significant with a p value of 0.023. The results suggest that using CEUS assessment immediately after the ablation procedure reduces the rate of residual tumor after thermal ablation. CONCLUSION: CEUS evaluation at the end of an ablation procedure is a powerful technique providing critical information to the treating interventional radiologist, without additional nephrotoxic contrast or ionizing radiation. PMID- 26969496 TI - Increase in post-therapy tumor calcification on CT scan is not an indicator of response to therapy in low-grade serous ovarian cancer. AB - PURPOSE: The aim of the study was to determine if increasing post-therapy calcification in peritoneal metastases in recurrent low-grade serous ovarian carcinomas indicated response to therapy. MATERIALS AND METHODS: Retrospective analysis of patients with histologically confirmed, recurrent low-grade serous ovarian carcinoma who received treatment at our institution between 2000 and 2014 was performed. Only patients who had calcified tumor implants and showed either interval increase or decrease in tumor calcification following therapy were included in the study. Pre- and post-therapy CT scans of these patients were reviewed by 2 radiologists independently. Changes in the tumor calcification status and tumor deposits size were correlated with serum CA-125 levels. Fisher's exact test was used to assess the association between peritoneal deposit and calcification status with serum CA-125 status. RESULTS: 35 Patients were included in the study. Based on serial serum CA 125 levels, 22 patients (63%) had progressive disease, 12 (34%) had partial response and 1 (3%) had stable disease. Using RECIST 1.1, 16 had progressive disease, 3 had partial response and 16 had stable disease. In the patients with progressive disease, post-therapy tumor calcification increased in 77% and decreased in 23%. Fischer's exact test showed that serum CA 125 change was significantly associated with change in size of peritoneal deposits and calcification change. CONCLUSIONS: This preliminary study shows that post-therapy increase in peritoneal implant calcification in low-grade serous ovarian carcinomas is not an indicator of response to therapy. PMID- 26969497 TI - The Convergence of a Virus, Mosquitoes, and Human Travel in Globalizing the Zika Epidemic. AB - The Zika virus was first identified in 1947 in the Zika Forest of Uganda. It was discovered in a rhesus monkey that had been placed in a cage on a sentinel platform in the forest by the Virus Research Institute. When this writer visited the institute and the Zika Forest in 1961, work was underway to identify mosquito species at various levels of the tree canopy. This was done through the placement of traps at various levels of a 120-foot-high steel tower which this writer climbed. At that time, researchers isolated 12 strains of Zika virus from traps on the tower. Over the next six decades, the virus spread slowly to other parts of Africa, and eventually appeared in Southeast Asia, transmitted by Aedes aegypti and other Aedes mosquito species. By 1981, only 14 cases of illness had been reported as due to the Zika virus. Since most infections with this virus are either mild or asymptomatic, its true geographic spread was not fully appreciated. The current globalization of the Zika epidemic began on the Pacific island of Yap in the Federated States of Polynesia in 2007. This was the first known presence of the Zika virus outside of Africa and Southeast Asia. It was estimated that 73 % of the island's population had been infected. In 2013, the virus spread to French Polynesia where an estimated 28,000 cases occurred in a population of 270,000. During that year and afterwards, microcephaly and other congenital abnormalities were observed in the infants of women who were pregnant when they contracted the virus. It is currently not known if cases of microcephaly have resulted from infection of pregnant women or from infection plus some other co-factor. The epidemic rapidly spread to the Cook Islands and Easter Island. In 2015, Zika virus infection was diagnosed in Brazil where it was associated with microcephaly in the infants of some women who were pregnant when they contracted the disease. Cases of the Guillain-Barre syndrome were also found to be associated with Zika virus infection. How the disease entered Brazil is a matter of conjecture. However, the strain responsible for the epidemic in Brazil and elsewhere in South and Central America is phylogenetically identical to that which caused the epidemic in French Polynesia. The wide distribution of Aedes aegypti, a principal vector of the virus, and other Aedes species has greatly facilitated the spread of the disease. Aedes aegypti is an invasive species of mosquito in the Western Hemisphere that has adapted well to densely-populated urban environments. In addition, male-to-female human sexual transmission has increasingly been demonstrated in the US and elsewhere. In February 2016, the World Health Organization (WHO) declared the current Zika outbreak a Public Health Emergency of international concern. On the recommendation of its Emergency Committee on Zika Virus and Observed Increase in Neurological Disorders and Neonatal Malformations, WHO issued a group of recommendations to contain the epidemic. The globalization of the Zika virus was made possible by the widespread presence in various parts of the world of Aedes vectors and increased human travel that facilitated geographic spread. This globalization of Zika follows upon that of West Nile, Ebola, Dengue, and Chikungunya. Its ultimate spread is difficult to predict, but will hopefully be restricted through vigorous preventive measures. PMID- 26969501 TI - Transition Metal-Catalyzed Carbonylative C-H Bond Functionalization of Arenes and C(sp(3))-H Bond of Alkanes. AB - In this article, we present the progress made in the area of carbonylative C-H functionalization, with special emphasis on arenes and alkanes. The importance of directing group assistance and C-H functionalization using CO surrogates is also included. The budding development in the area of transition metal-catalyzed C(sp(3))-H activation makes us feel it necessary to file a summary on the past, as well as current, contributions and a prospective outlook on the transition metal-catalyzed carbonylative transformation of C-H bonds, which is the focus of this review. PMID- 26969500 TI - The effect of different collagen modifications for titanium and titanium nitrite surfaces on functions of gingival fibroblasts. AB - OBJECTIVES: Targeted modifications of the bulk implant surfaces using bioactive agents provide a promising tool for improvement of the long-term bony and soft tissue integration of dental implants. In this study, we assessed the cellular responses of primary human gingival fibroblasts (HGF) to different surface modifications of titanium (Ti) and titanium nitride (TiN) alloys with type I collagen or cyclic-RGDfK-peptide in order to define a modification improving long term implants in dental medicine. MATERIALS AND METHODS: Employing Ti and TiN implants, we compared the performance of simple dip coating and anodic immobilization of type I collagen that provided collagen layers of two different thicknesses. HGF were seeded on the different coated implants, and adhesion, proliferation, and gene expression were analyzed. RESULTS: Although there were no strong differences in initial cell adhesion between the groups at 2 and 4 hours, we found that all surface modifications induced higher proliferation rates as compared to the unmodified controls. Consistently, gene expression levels of cell adhesion markers (focal adhesion kinase (FAK), integrin beta1, and vinculin), cell differentiation markers (FGFR1, TGFb-R1), extracellular protein markers (type I collagen, vimentin), and cytoskeletal protein marker aktinin-1 were consistently higher in all surface modification groups at two different time points of investigation as compared to the unmodified controls. CONCLUSION: Our results indicate that simple dip coating of Ti and TiN with collagen is sufficient to induce in vitro cellular responses that are comparable to those of more reliable coating methods like anodic adsorption, chemical cross-linking, or RGD coating. TiN alloys do not possess any positive or adverse effects on HGF. CLINICAL RELEVANCE: Our results demonstrate a simple, yet effective, method for collagen coating on titanium implants to improve the long term integration and stability of dental implants. PMID- 26969498 TI - Photoreceptor proliferation and dysregulation of cell cycle genes in early onset inherited retinal degenerations. AB - BACKGROUND: Mitotic terminally differentiated photoreceptors (PRs) are observed in early retinal degeneration (erd), an inherited canine retinal disease driven by mutations in the NDR kinase STK38L (NDR2). RESULTS: We demonstrate that a similar proliferative response, but of lower magnitude, occurs in two other early onset disease models, X-linked progressive retinal atrophy 2 (xlpra2) and rod cone dysplasia 1 (rcd1). Proliferating cells are rod PRs, and not microglia or Muller cells. Expression of the cell cycle related genes RB1 and E2F1 as well as CDK2,4,6 was up-regulated, but changes were mutation-specific. Changes in cyclin expression differed across all genes, diseases and time points analyzed, although CCNA1 and CCNE1 expression increased with age in the three models suggesting that there is a dysregulation of cell cycle gene expression in all three diseases. Unique to erd, however, are mutation-specific changes in the expression of NDR kinases and Hippo signaling members with increased expression of MOB1 and LATS1 in the newly generated hybrid rod/S-cones. CONCLUSIONS: Our data raise the intriguing possibility that terminally differentiated normal PRs are kept from dividing by NDR2-MOB1 interaction. Furthermore, they provide the framework for the selection of candidate genes for further investigation as potential targets of therapy. PMID- 26969499 TI - Influence of proximal box elevation on bond strength of composite inlays. AB - OBJECTIVES: The objective of the present study was to evaluate the influence of proximal box elevation on microtensile bond strength (mTBS) of composite inlays to the proximal box floor, using either a total-etch or a self-adhesive resin cement. MATERIALS AND METHODS: Twenty-five human molars were selected, and a class II OM (inlay) cavity preparation was performed in each tooth. Cavities were randomly assigned into four experimental groups, according to the location of the proximal cervical margin (located 1 mm below cementoenamel junction (CEJ), or with proximal box elevation with composite resin) and the resin cement used for luting (a total-etch resin cement RelyX ARC or a self-adhesive resin cement G Cem). After 1-week water storage, samples were subjected to mTBS test. Results were analyzed by Kruskal-Wallis and Mann-Whitney U tests (p < 0.05). RESULTS: Kruskal-Wallis revealed statistically significant differences among experimental groups (p = 0.007). Both resin cements showed similar bond strength values when cervical margin was located below CEJ. The proximal box elevation improved the bond strength of composite inlays for both resin cements. However, only for G-Cem was this improvement statistically significant. CONCLUSIONS: The proximal box elevation improved the bond strength attained by G-Cem resin cement. For RelyX ARC, the position of the cervical margin did not affect composite inlays bond strength. CLINICAL RELEVANCE: Proximal box elevation does not decline bond strength of composite inlays to the proximal floor when a total-etch or a self adhesive resin cement is used. PMID- 26969502 TI - Corrigendum: Swanson MA, Coughlin CR Jr, Scharer GH, et al: Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia. Ann Neurol 2015;78:606-618. PMID- 26969503 TI - The p.Phe174Ser mutation is associated with mild forms of Smith Lemli Opitz Syndrome. AB - BACKGROUND: Smith Lemli Opitz syndrome (SLOS; OMIM #270400) is an autosomal recessive metabolic disorder caused by mutations in the DHCR7 gene. SLOS is characterized by a plethora of abnormalities involving mainly the brain and the genitalia but also the cardiac, skeletal and gastroenteric system, typical dysmorphic facial features, and variable degrees of developmental delay and intellectual disability (ID). SLOS has a broad phenotypic spectrum, ranging from multiple congenital malformation syndrome, to mild developmental delay and minor malformations. A large number of mutations have been described in the DHCR7 gene, with few common mutations accounting for the majority of mutated alleles found in patients and a large number of very rare or even private variants. Due to the wide variety of clinical presentations, diagnosis can be difficult, especially in the milder forms of the disorder. Furthermore, establishing a molecular diagnosis can be complicated by finding variants of unknown clinical significance in such cases. CASE PRESENTATION: We report a case of SLOS at the mild end of the clinical spectrum, presenting with bilateral pelvis ectasia, mild dysmorphic features and mild intellectual disability. The case is compound heterozygous for a known pathogenic mutation (c.724C > T, p.Arg242Cys) and a mutation that has only been reported once in a Portuguese patient (c.521 T > C, p.Phe174Ser) whose pathogenicity has not been yet assessed. We compared the two patients carrying the p.Phe174Ser variant and concluded that this variant is associated with mild forms of SLOS. CONCLUSION: We report a patient with a mild case of SLOS, highlighting the importance of recognizing subtle anomalies of the genitourinary system, associated with mild dysmorphic features and mild intellectual disability in establishing the diagnosis of mild forms of SLOS. With this report, we confirm the pathogenicity of the p.Phe174Ser variant and we also provide evidence of its association with mild forms of SLOS. This finding further facilitates the establishment of a genotype-phenotype correlation for SLOS. This helps in counselling for this disorder and in predicting therapeutic responses. PMID- 26969504 TI - Validated multi-drug determination using liquid chromatography with tandem mass spectrometry for the evaluation of a commercial drug disposal product. AB - Currently, there are limited effective means of drug disposal for consumers, and this creates a gateway to illicit use and environmental contamination. Here, we evaluated the efficacy of a new drug disposal product, composed from a slurry of activated carbon, which claims to sequester up to 100% of a drug's active ingredient when the loading capacity is not exceeded, making it safe to dispose in landfill. High-performance liquid chromatography with tandem mass spectrometry was applied to quantify as many as 24 drugs (opiates, barbiturates, statins, amphetamine, and benzodiazepine drugs) in the residual solvent solution from the product. Calibration curves were established in the concentration ranges of 0.25 7.0 MUg/mL and showed good linearity. The limits of detection varied from 0.001 to 0.02 MUg/mL, depending on the drug. Accuracy ranged from 80 to 111% for quality control samples, with a few minor exceptions. Precision overall varied between 0.2 to 12.7%. In sample bottles tested, where active ingredient of the loaded drug was below the maximum sorption capacity stated on the label, 98 to >99.9% of the active ingredient was sequestered. Percent active ingredient adsorbed was slightly lower in bottles loaded in excess of label specifications. PMID- 26969506 TI - Erratum to: Structuprint: a scalable and extensible tool for two-dimensional representation of protein surfaces. PMID- 26969505 TI - Lessons learned from respondent-driven sampling recruitment in Nairobi: experiences from the field. AB - BACKGROUND: Respondent-driven sampling (RDS) is used in a variety of settings to study hard-to-reach populations at risk for HIV and sexually transmitted infections. However, practices leading to successful recruitment among diverse populations in low-resource settings are seldom reported. We implemented the first, integrated, bio-behavioural surveillance survey among men who have sex with men, female sex workers and people who injected drugs in Nairobi, Kenya. METHODS: The survey period was June 2010 to March 2011, with a target sample size of 600 participants per key populations. Formative research was initially conducted to assess feasibility of the survey. Weekly monitoring reports of respondent characteristics and recruitment chain graphs from NetDraw illustrated patterns and helped to fill recruitment gaps. RESULTS: RDS worked well with men who have sex with men and female sex workers with recruitment initiating at a desirable pace that was maintained throughout the survey. Networks of people who injected drugs were well-integrated, but recruitment was slower than the men who have sex with men and female sex workers surveys. CONCLUSION: By closely monitoring RDS implementation and conducting formative research, RDS studies can effectively develop and adapt strategies to improve recruitment and improve adherence to the underlying RDS theory and assumptions. PMID- 26969507 TI - Confidence intervals construction for difference of two means with incomplete correlated data. AB - BACKGROUND: Incomplete data often arise in various clinical trials such as crossover trials, equivalence trials, and pre and post-test comparative studies. Various methods have been developed to construct confidence interval (CI) of risk difference or risk ratio for incomplete paired binary data. But, there is little works done on incomplete continuous correlated data. To this end, this manuscript aims to develop several approaches to construct CI of the difference of two means for incomplete continuous correlated data. METHODS: Large sample method, hybrid method, simple Bootstrap-resampling method based on the maximum likelihood estimates (B 1) and Ekbohm's unbiased estimator (B 2), and percentile Bootstrap resampling method based on the maximum likelihood estimates (B 3) and Ekbohm's unbiased estimator (B 4) are presented to construct CI of the difference of two means for incomplete continuous correlated data. Simulation studies are conducted to evaluate the performance of the proposed CIs in terms of empirical coverage probability, expected interval width, and mesial and distal non-coverage probabilities. RESULTS: Empirical results show that the Bootstrap-resampling based CIs B 1, B 2, B 4 behave satisfactorily for small to moderate sample sizes in the sense that their coverage probabilities could be well controlled around the pre-specified nominal confidence level and the ratio of their mesial non coverage probabilities to the non-coverage probabilities could be well controlled in the interval [0.4, 0.6]. CONCLUSIONS: If one would like a CI with the shortest interval width, the Bootstrap-resampling-based CIs B 1 is the optimal choice. PMID- 26969508 TI - Psychological distress in informal caregivers of patients with dementia in primary care: course and determinants. AB - BACKGROUND: The course of psychological distress in informal caregivers of patients with dementia has been investigated in longitudinal studies with conflicting outcomes. OBJECTIVES: We investigated the course and determinants of psychological distress in informal caregivers of patients with dementia in primary care. METHODS: In this prospective observational cohort study, data were collected at baseline, after 9 and 18 months. We assessed cognition and neuropsychiatric symptoms (NPS) of the patient (Mini-Mental State Examination and Neuropsychiatric Inventory) and psychological distress (Sense of Competence Questionnaire, Center for Epidemiological Studies Depression scale and General Health Questionnaire 12-tem version) of the informal caregivers. Determinants for the course of psychological distress were caregivers' age, gender and relationship with the patient, patients' cognition and NPS, participation in a care program and admission to long-term care facilities (LTCF). With linear mixed models, the course over time for psychological distress and its determinants were explored. RESULTS: We included 117 informal caregivers, of whom 23.1% had a high risk for depression and 41.0% were identified to be likely to have mental problems at baseline. We found a stable pattern of psychological distress over time. Higher frequency of NPS, informal caregivers' age between 50 and 70 years and being female or spouse were associated with higher psychological distress. For patients who were admitted to a LTCF during the study psychological distress of the informal caregivers improved. CONCLUSIONS: GPs should focus on NPS in patients with dementia and on caregivers' psychological distress and be aware of their risk for depression and mental problems, specifically to those who are spouse, female or between 50 and 70 years of age. PMID- 26969510 TI - A method to preserve low parasitaemia Plasmodium-infected avian blood for host and vector infectivity assays. AB - BACKGROUND: Avian malaria vector competence studies are needed to understand more succinctly complex avian parasite-vector-relations. The lack of vector competence trials may be attributed to the difficulty of obtaining gametocytes for the majority of Plasmodium species and lineages. To conduct avian malaria infectivity assays for those Plasmodium spp. and lineages that are refractory to in vitro cultivation, it is necessary to obtain and preserve for short periods sufficient viable merozoites to infect naive donor birds to be used as gametocyte donors to infect mosquitoes. Currently, there is only one described method for long-term storage of Plasmodium spp.-infected wild avian blood and it is reliable at a parasitaemia of at least 1%. However, most naturally infected wild-caught birds have a parasitaemia of much less that 1%. To address this problem, a method for short-term storage of infected wild avian blood with low parasitaemia (even <= 0.0005%) has been explored and validated. METHODS: To obtain viable infective merozoites, blood was collected from wild birds using a syringe containing the anticoagulant and the red blood cell preservative citrate phosphate dextrose adenine solution (CPDA). Each blood sample was stored at 4 degrees C for up to 48 h providing sufficient time to determine the species and parasitaemia of Plasmodium spp. in the blood by morphological examination before injecting into donor canaries. Plasmodium spp.--infected blood was inoculated intravenously into canaries and once infection was established, Culex stigmatosoma, Cx. pipiens and Cx. quinquefasciatus mosquitoes were then allowed to feed on the infected canaries to validate the efficacy of this method for mosquito vector competence assays. RESULTS: Storage of Plasmodium spp.--infected donor blood at 4 degrees C yielded viable parasites for 48 h. All five experimentally-infected canaries developed clinical signs and were infectious. Pathologic examination of three canaries that later died revealed splenic lesions typical of avian malaria infection. Mosquito infectivity assays demonstrated that Cx. stigmatosoma and Cx. pipiens were competent vectors for Plasmodium cathemerium. CONCLUSIONS: A simple method of collecting and preserving avian whole blood with malaria parasites of low parasitaemia (<= 0.0005%) was developed that remained viable for further experimental bird and mosquito infectivity assays. This method allows researchers interested in conducting infectivity assays on target Plasmodium spp. to collect these parasites directly from nature with minimal impact on wild birds. PMID- 26969509 TI - Assessing cancer patients' quality of life and supportive care needs: Translation revalidation of the CARES in Flemish and exhaustive evaluation of concurrent validity. AB - BACKGROUND: The prevalence of cancer increases every year, leading to a growing population of patients and survivors in need for care. To achieve good quality care, a patient-centered approach is essential. Correct and timely detection of needs throughout the different stages of the care trajectory is crucial and can be supported by the use of screening and assessment in a stepped-care approach. The Cancer Rehabilitation Evaluation System (CARES) is a valuable and comprehensive quality of life and needs assessment instrument. For use in Flemish research and clinical practice, the CARES tool was translated for the Dutch speaking part of Belgium (Flanders) from its original English format. This protocol paper describes the translation and revalidation of this Flemish CARES version. METHODS: After forward-backward translation of the CARES into Flemish we aim to recruit 150 adult cancer patients with a primary cancer diagnosis (stage I, II or III) for validation. In this study with a combination of qualitative and a quantitative approach, qualitative data will be collected through focus groups and supplemented by two phases of quantitative data collection: i) an initial patient survey containing questions on socio-demographic and medical data, the CARES and seven concurrent instruments; and ii) a second survey administered after 1 week containing the CARES and supplementary questions to explore their impressions on the content and the feasibility of the CARES. DISCUSSION: With this extensive data collection process, psychometric validity of the Flemish CARES can be tested thoroughly using classical test theory. Internal consistency of summary scales, test-retest reliability, content validity, construct validity, concurrent validity and feasibility of the instrument will be examined. If the Flemish CARES version is found reliable, valid and feasible, it will be used in future research and clinical practice. Comprehensive assessment with the CARES in a stepped-care approach can facilitate timely identification of cancer patients' psychosocial concerns and care needs so it can contribute to efficient provision of patient-centered quality care. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02282696 (July 16, 2014). PMID- 26969512 TI - Barriers in the implementation of the Resuscitation Guidelines: European survey of defibrillation techniques. AB - BACKGROUND: The European Resuscitation Council (ERC) Guidelines recommend providing chest compressions during defibrillator charging and using adhesive pads for defibrillation to increase the effectiveness of resuscitation. However, the most common defibrillation technique in each European country is unknown, as are the potential barriers in implementation of the guidelines. The aim of this study was to assess the techniques of defibrillation procedures performed by professional European healthcare providers and to estimate how frequently adhesive pads are used. METHODS: We sent an online questionnaire to the ERC National Representatives that contained 12 questions regarding the techniques of defibrillation and monitoring heart rhythm during cardiac arrest. We also evaluated the frequency and indications of manual paddles use. RESULTS: We collected questionnaires from 27 out of 33 invited ERC member countries. The response rate was 82%. Seventeen (17/27; 63%) declared the use of adhesive pads. The leading cause for not using adhesive pads was economic reason (9/17; 53%). Some respondents declared resistance to using adhesive pads by healthcare providers or tradition connected with manual paddles use. We found three leading techniques of defibrillation with manual paddles: Charging paddles keeping them on the defibrillator during chest compressions being delivered (9/21; 43%), Charging paddles keeping them on the patient chest during chest compressions being delivered (6/21; 29 %), Charging paddles on the patient chest without chest compressions (5/21; 24%). Respondents from 11 countries declared the use of gel or electrode pastes during defibrillation with manual paddles. DISCUSSION: This study collected preliminary data showing how defibrillation is performed in Europe. It revealed the recommeded techniques underuse and identyfied barriers in the Resuscitation Guidelines implementation. The survey should be open to a wider group of respondents. in each country in future. CONCLUSIONS: There are limitations and barriers in the implementation of the defibrillation technique guidelines. There are still countries where the use of adhesive pads is low due to economic and traditional reasons. There is a need for further efforts focused on guidelines implementation. PMID- 26969511 TI - Study of Leishmania pathogenesis in mice: experimental considerations. AB - Although leishmaniases are endemic in 98 countries, they are still considered neglected tropical diseases. Leishmaniases are characterized by the emergence of new virulent and asymptomatic strains of Leishmania spp. and, as a consequence, by a very diverse clinical spectrum. To fight more efficiently these parasites, the mechanisms of host defense and of parasite virulence need to be thoroughly investigated. To this aim, animal models are widely used. However, the results obtained with these models are influenced by several experimental parameters, such as the mouse genetic background, parasite genotype, inoculation route/infection site, parasite dose and phlebotome saliva. In this review, we propose an update on their influence in the two main clinical forms of the disease: cutaneous and visceral leishmaniases. PMID- 26969513 TI - Item response theory analysis of Centers for Disease Control and Prevention Health-Related Quality of Life (CDC HRQOL) items in adults with arthritis. AB - BACKGROUND: Examine the feasibility of performing an item response theory (IRT) analysis on two of the Centers for Disease Control and Prevention health-related quality of life (CDC HRQOL) modules - the 4-item Healthy Days Core Module (HDCM) and the 5-item Healthy days Symptoms Module (HDSM). Previous principal components analyses confirm that the two scales both assess a mix of mental (CDC-MH) and physical health (CDC-PH). The purpose is to conduct item response theory (IRT) analysis on the CDC-MH and CDC-PH scales separately. METHODS: 2182 patients with self-reported or physician-diagnosed arthritis completed a cross-sectional survey including HDCM and HDSM items. Besides global health, the other 8 items ask the number of days that some statement was true; we chose to recode the data into 8 categories based on observed clustering. The IRT assumptions were assessed using confirmatory factor analysis and the data could be modeled using an unidimensional IRT model. The graded response model was used for IRT analyses and CDC-MH and CDC-PH scales were analyzed separately in flexMIRT. RESULTS: The IRT parameter estimates for the five-item CDC-PH all appeared reasonable. The three item CDC-MH did not have reasonable parameter estimates. CONCLUSIONS: The CDC-PH scale is amenable to IRT analysis but the existing The CDC-MH scale is not. We suggest either using the 4-item Healthy Days Core Module (HDCM) and the 5-item Healthy days Symptoms Module (HDSM) as they currently stand or the CDC-PH scale alone if the primary goal is to measure physical health related HRQOL. PMID- 26969514 TI - Delivering triple prevention: a health system responsibility. PMID- 26969516 TI - Non-insulin drugs to treat hyperglycaemia in type 1 diabetes mellitus. AB - Insulin treatment of individuals with type 1 diabetes has shortcomings and many patients do not achieve glycaemic and metabolic targets. Consequently, the focus is on novel non-insulin therapeutic approaches that reduce hyperglycaemia and improve metabolic variables without increasing the risk of hypoglycaemia or other adverse events. Several therapies given in conjunction with insulin have been investigated in clinical trials, including pramlintide, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sodium-glucose co transporter inhibitors, metformin, sulfonylureas, and thiazolidinediones. These drugs have pleiotropic effects on glucose metabolism and different actions complementary to those of insulin-this Review reports the effects of these drugs on glycaemic control, glucose variability, hypoglycaemia, insulin requirements, and bodyweight. Existing studies are of short duration with few participants; evidence for the efficacy of concomitant treatments is scarce and largely clinically insignificant. A subgroup of patients with type 1 diabetes for whom non-insulin antidiabetic drugs could significantly benefit glycaemic control cannot yet be defined, but we suggest that obese patients prone to hypoglycaemia and patients with residual beta-cell function are populations of interest for future trials. PMID- 26969518 TI - Measures of sleep and cardiac functioning during sleep using a multi-sensory commercially-available wristband in adolescents. AB - To validate measures of sleep and heart rate (HR) during sleep generated by a commercially-available activity tracker against those derived from polysomnography (PSG) in healthy adolescents. Sleep data were concurrently recorded using FitbitChargeHRTM and PSG, including electrocardiography (ECG), during an overnight laboratory sleep recording in 32 healthy adolescents (15 females; age, mean+/-SD: 17.3+/-2.5years). Sleep and HR measures were compared between FitbitChargeHRTM and PSG using paired t-tests and Bland-Altman plots. Epoch-by-epoch analysis showed that FitbitChargeHRTM had high overall accuracy (91%), high sensitivity (97%) in detecting sleep, and poor specificity (42%) in detecting wake on a min-to-min basis. On average, FitbitChargeHRTM significantly but negligibly overestimated total sleep time by 8min and sleep efficiency by 1.8%, and underestimated wake after sleep onset by 5.6min (p<0.05). Within FitbitChargeHRTM epochs of sleep, the average HR was 59.3+/-7.5bpm, which was significantly but negligibly lower than that calculated from ECG (60.2+/-7.6bpm, p<0.001), with no change in mean discrepancies throughout the night. FitbitChargeHRTM showed good agreement with PSG and ECG in measuring sleep and HR during sleep, supporting its use in assessing sleep and cardiac function in healthy adolescents. Further validation is needed to assess its reliability over prolonged periods of time in ecological settings and in clinical populations. PMID- 26969519 TI - Analysis of cardiorespiratory phase coupling and cardiovascular autonomic responses during food ingestion. AB - The present study analyzed whether the phase coherency (lambda) of respiratory sinus arrhythmia (RSA) is altered by food ingestion in healthy young subjects. After 5min of resting control, 13 healthy volunteers were asked to eat a solid meal with access to water at their own pace, followed by 5min of the postprandial state. The R-R interval (RRI), beat-to-beat blood pressure (BP), and respiratory activity were recorded using electrocardiography, a Finapres device, and inductance plethysmography, respectively. The stroke volume was calculated by the pulse-contour method from continuous BP measurement, and the cardiac output (CO) was obtained by multiplying the stroke volume by the heart rate. From the oscillatory signals of RSA and respiration, lambda was computed; additionally, frequency domain indexes of the heart rate variability (HRV) were calculated using a short-time Fourier transform. A steady-state 3-min resting period (R), food ingestion period (FOOD), and the first 2-min and the last 3-min of the post prandial period were analyzed separately. We also compared the responses to gum chewing (GUM) and water intake (WATER) using the same protocol on separate days. A shortening of RRI and increases in BP and CO were observed in FOOD compared to R, suggesting a shift of sympathovagal balance toward sympathetic activation. Similar responses but smaller magnitudes were observed in the GUM condition, whereas only transient shortening of RRI was observed in the WATER condition. The HRV indexes did not show any significant changes in response to GUM and WATER but sympathovagal balance was shifted in favor of sympathetic dominance in FOOD. lambda decreased during all of the conditions. There was a significant negative correlation between lambda and the indirect measure of sympathovagal balance. These results suggest that ingestion of food induces enhanced cardiac sympathetic activity and that a phase coherence of RSA could provide a sensitive measure for evaluating the cardiac autonomic profile. PMID- 26969520 TI - Protective effect of allyl methyl disulfide on acetaminophen-induced hepatotoxicity in mice. AB - Multiple sulfur compounds of garlic have shown versatile medicinal activities in the prevention and treatment of various diseases. Allyl methyl disulfide (AMDS) was identified as one of the bioactive components in fresh garlic paste in our previous study. The purpose of this study was to investigate the hepatoprotective effect of AMDS against acetaminophen (APAP)-induced acute liver damage in mice. Results reveal that AMDS significantly alleviates APAP-induced elevation of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels in mice. Furthermore, AMDS significantly (p < 0.05) reduced the maleic dialdehyde (MDA) level in liver tissues and restored the activities of antioxidant enzymes SOD, GSH-PX and GSH towards normal levels. IL-6 and TNF-alpha (TNF-alpha) levels in the serum and liver were clearly increased by acetaminophen-damage (p < 0.05) and AMDS intake significantly suppressed acetaminophen-induced increase of the two cytokines (p < 0.05). The immunohistochemical and pathological analyses showed that AMDS could ameliorate the liver injury through the strong attenuation of the CD45 expression and HNE formation. All the results indicate that AMDS had the ability to protect hepatocytes from APAP-induced liver damage. PMID- 26969517 TI - Pericytes: A newly recognized player in wound healing. AB - Pericytes have generally been considered in the context of stabilizing vessels, ensuring the blood barriers, and regulating the flow through capillaries. However, new reports suggest that pericytes may function at critical times to either drive healing with minimal scarring or, perversely, contribute to fibrosis and ongoing scar formation. Beneficially, pericytes probably drive much of the vascular involution that occurs during the transition from the regenerative to the resolution phases of healing. Pathologically, pericytes can assume a fibrotic phenotype and promote scarring. This perspective will discuss pericyte involvement in wound repair and the relationship pericytes form with the parenchymal cells of the skin. We will further evaluate the role pericytes may have in disease progression in relation to chronic wounds and fibrosis. PMID- 26969521 TI - Murine breast carcinoma 4T1 cells are more sensitive to atranorin than normal epithelial NMuMG cells in vitro: Anticancer and hepatoprotective effects of atranorin in vivo. AB - The aim of this study was to evaluate the anticancer effect of atranorin (ATR) on murine 4T1 breast carcinoma cells and compare its sensitivity with normal mammary epithelial NMuMG cells in vitro. Anti-tumor and hepatoprotective activity of ATR therapy was examined on mouse model of 4T1-induced cancer disease. ATR significantly reduced clonogenic ability of carcinoma 4T1 cells at the concentration of 75 MUM, but clonogenicity of normal NMuMG cells was not affected by any of ATR concentrations tested. Moreover, flow cytometric and BrdU incorporation analysis did not confirm the inhibited entry into S-phase of the cell cyle after ATR incubation, and on the contrary, it induced apoptosis associated with the activation of caspase-3 and PARP cleavage in 4T1 cells. Although ATR did not cause any significant changes in Bcl-xL protein expression in NMuMG cells, an apparent depletion of Bcl-xL protein in 4T1 cells after 48 h ATR therapy was confirmed. Based on this result as well as the result of the total cell number decline, we can conclude that 4T1 cells are more sensitive to ATR therapy than NMuMG cells. ATR administration resulted in significantly longer survival time of BALB/c mice inoculated with 4T1 cells, what was associated with reduced tumor size and the higher numbers of apoptotic 4T1 cells. No differences were recorded in the number of BrdU-positive tumor cells between ATR-treated group and controls. Results indicate that ATR has rather proapoptotic than antiproliferative effect on 4T1 cells in vitro and in vivo and normal NMuMG cells are less sensitive to ATR. Furthermore, our studies revealed protective effect of ATR against oxidative stress in the livers of the tumor-bearing mice. PMID- 26969522 TI - Development of an in-process UV-crosslinked, electrospun PCL/aPLA-co-TMC composite polymer for tubular tissue engineering applications. AB - Cardiovascular diseases remain the largest cause of death worldwide, and half of these deaths are the result of failure of the vascular system. Tissue engineering promises to provide new, and potentially more effective therapeutic strategies to replace damaged or degenerated vessels with functional vessels. However, these engineered vessels have substantial performance criteria, including vessel-like tubular shape, structure and mechanical property slate. Further, whether implanted without or with prior in vitro culture, such tubular scaffolds must provide a suitable environment for cell adhesion and growth and be of sufficient porosity to permit cell colonization. This study investigates the fabrication of slowly degradable, composite tubular polymer scaffolds made from polycaprolactone (PCL) and acrylated l-lactide-co-trimethylene carbonate (aPLA-co-TMC). The addition of acrylate groups permits the 'in-process' formation of crosslinks between aPLA-co-TMC chains during electrospinning of the composite system, exemplifying a novel process to produce multicomponent, elastomeric electrospun polymer scaffolds. Although PCL and aPLA-co-TMC were miscible in a co-solvent, a criteria for electrospinning, due to thermodynamic incompatibility of the two polymers as melts, solvent evaporation during electrospinning drove phase separation of these two systems, producing 'core-shell' fibres, with the core being composed of PCL, and the shell of crosslinked elastomeric aPLA-co-TMC. The resulting elastic fibrous scaffolds displayed burst pressures and suture retention strengths comparable with human arteries. Cytocompatibility testing with human mesenchymal stem cells confirmed adhesion to, and proliferation on the three-dimensional fibrous network, as well as alignment with highly-organized fibres. This new processing methodology and resulting mechanically-robust composite scaffolds hold significant promise for tubular tissue engineering applications. STATEMENT OF SIGNIFICANCE: Autologous small diameter blood vessel grafts are unsuitable solutions for vessel repair. Engineered solutions such as tubular biomaterial scaffolds however have substantial performance criteria to meet, including vessel-like tubular shape, structure and mechanical property slate. We detail herein an innovative methodology to co-electrospin and 'in process' crosslink composite mixtures of Poly(caprolactone) and a newly synthesised acrylated-Poly(lactide-co-trimethylene-carbonate) to create elastomeric, core-shell nanofibrous porous scaffolds in a one-step process. This novel composite system can be used to make aligned scaffolds that encourage stem cell adhesion, growth and morphological control, and produce robust tubular scaffolds of tunable internal diameter and wall thickness that possess mechanical properties approaching those of native vessels, ideal for future applications in the field of vessel tissue engineering. PMID- 26969523 TI - Influencing chondrogenic differentiation of human mesenchymal stromal cells in scaffolds displaying a structural gradient in pore size. AB - Articular cartilage lesions have a limited ability to heal by themselves. Yet, golden standard treatments for cartilage repair such as drilling, microfracture and mosaicplasty provide further damage and an unstable solution that degenerates into fibrocartilage in time. Articular cartilage presents a number of gradients in cell number and size along with structural gradients in extra cellular matrix (ECM) composition. Therefore, creating scaffolds that display a structural gradient can be an appealing strategy for cartilage tissue regeneration treatments. In the present study, a scaffold with an in-built discrete gradient in pore size was produced by additive manufacturing. Human mesenchymal stromal cells (hMSCs) were seeded within the gradient scaffolds and their proliferation, differentiation and ECM deposition was evaluated with respect to 2 non-gradient scaffolds. Glycosaminoglycan (GAG) deposition was significantly higher in gradient scaffolds and non-gradient scaffolds with the smallest pore size compared to non-gradient scaffolds with the largest pore size. A gradual increase of chondrogenic markers was observed within the gradient structures with decreasing pore size, which was also accompanied by an increasingly compact ECM formation. Therefore, scaffolds displaying a structural gradient in pore size seem to be a promising strategy to aid in the process of hMSC chondrogenic differentiation and could be considered for improved cartilage tissue regeneration applications. STATEMENT OF SIGNIFICANCE: We present the development of a novel hierarchical scaffold obtained by additive manufacturing. Structural hierarchy is obtained by changing pore size within the pore network characterizing the fabricated scaffolds and proves to be a functional element in the scaffold to influence adult stem cell differentiation in the chondrogenic lineage. Specifically, in regions of the scaffolds presenting smaller pores an increasing differentiation of stem cells toward the chondrogenic differentiation is displayed. Taking inspiration from the zonal organization of articular cartilage tissue, pore size gradients could, therefore, be considered as a new and important element in designing 3D scaffolds for regenerative medicine applications, in particular for all those tissues where gradient physical properties are present. PMID- 26969524 TI - Investigation of ethanol infiltration into demineralized dentin collagen fibrils using molecular dynamics simulations. AB - The purpose of this study is to investigate the interaction of neat ethanol with bound and non-bound water in completely demineralized dentin that is fully hydrated, using molecular dynamics (MD) simulation method. The key to creating ideal resin-dentin bonds is the removal of residual free water layers and its replacement by ethanol solvent in which resin monomers are soluble, using the ethanol wet-bonding technique. The test null hypotheses were that ethanol cannot remove any collagen-bound water, and that ethanol cannot infiltrate into the spacing between collagen triple helix due to narrow interlayer spacing. Collagen fibrillar structures of overlap and gap regions were constructed by aligning the collagen triple helix of infinite length in hexagonal packing. Three layers of the water molecules were specified as the layers of 0.15-0.22nm, 0.22-0.43nm and 0.43-0.63nm from collagen atoms by investigating the water distribution surrounding collagen molecules. Our simulation results show that ethanol molecules infiltrated into the intermolecular spacing in the gap region, which increased due to the lateral shrinkage of the collagen structures in contact with ethanol solution, while there was no ethanol infiltration observed in the overlap region. Infiltrated ethanol molecules in the gap region removed residual water molecules via modifying mostly the third water layer (50% decrease), which would be considered as a loosely-bound water layer. The first and second hydration layers, which would be considered as tightly bound water layers, were not removed by the ethanol molecules, thus maintaining the helical structures of the collagen molecules. PMID- 26969525 TI - Significantly reduced adsorption and activation of blood components in a membrane oxygenator system coated with crosslinkable zwitterionic copolymer. AB - A crosslinkable zwitterionic copolymer PMBT was coated onto the surfaces of polypropylene hollow fiber membrane (PP-HFM) oxygenator and its connecting tubes. The PMBT copolymer coating on the oxygenator circuit formed a cell outer membrane mimetic surface with excellent stability. The hemocompatibility of the PMBT copolymer coated PP-HFM oxygenator circuit was evaluated by animal extracorporeal circulation. The concentrations of clotting components fibrinogen and platelet in the blood were almost unchanged during the circulation through the PMBT copolymer coated oxygenator circuits. By contrast, the concentrations of fibrinogen and platelet were significantly reduced to 52% and 56% respectively in the uncoated oxygenator group due to adsorption and thrombogenesis of the blood during 2h circulation. Moreover, concentration of activation marker beta-thromboglobulin for platelet in the blood was remarkably lower in the PMBT group than the uncoated control group (p<0.01). All the results strongly supported that the hemocompatibility of the PP-HFM oxygenator circuit could be improved significantly by coating a stable and densely assembled zwitterionic polymer film. This simple, stable and highly effective cell membrane mimetic coating strategy may be applicable in developing advanced oxygenator systems and other artificial organs. STATEMENT OF SIGNIFICANCE: Although a number of studies have reported the fabrication of zwitterionic phosphorylcholine coated oxygenators to resist the adsorption and activation of blood components and eliminate heparin induced thrombocytopenia, none of them have fabricated stable and densely assembled film, especially with crosslinkable amphiphilic random copolymer described in our manuscript. The novel features of our work include. PMID- 26969527 TI - Longitudinal determinants of client treatment satisfaction in an intensive first episode psychosis treatment programme. AB - AIM: Previous evidence demonstrates that higher treatment satisfaction is strongly associated with improved clinical outcomes and functioning. The aim of the current study is to explore potential associations between clinical and demographic attributes, as well as changes in role, social and cognitive functioning occurring over the course of treatment, on self-reported treatment satisfaction within the context of an intensive first-episode psychosis intervention programme. METHODS: Forty-four young adults attending a first episode psychosis treatment programme completed a battery of clinical and neuropsychological measures at intake to the programme and again after 6 months of treatment. A modified version of the Client Satisfaction Questionnaire was administered at 6 months. Baseline, 6-month and change scores across the clinical and demographic measures were examined relative to the satisfaction questionnaire to evaluate determinants of treatment satisfaction. RESULTS: Better premorbid adjustment during childhood and early adolescence was associated with higher treatment satisfaction, as did positive changes in clients' cognitive performance and their use of humour as a coping strategy. Clients' use of emotional support as a coping strategy at 6 months was also positively associated with treatment satisfaction. Although clients' social and role functioning improved significantly during the 6-month treatment window, changes in functional outcomes were not significantly associated with treatment satisfaction. CONCLUSIONS: The current study highlights the role of premorbid adjustment and changes in coping and neurocognition as factors influencing treatment satisfaction. Future research designs might be able to more specifically ascertain causal relationships between patient characteristics, treatment components, client satisfaction and clinical effects. PMID- 26969526 TI - Quantitative evaluation for spasticity of calf muscle after botulinum toxin injection in patients with cerebral palsy: a pilot study. AB - BACKGROUND: Cerebral palsy (CP) is the most common pediatric disease to cause motor disability. Two common symptoms in CP are spasticity and contracture. If this occurred in the ankle plantar flexors of children with CP, it will impair their gait and active daily living profoundly. Most children with CP receive botulinum toxin type A (BoNT-A) injection to reduce muscle tone, but a knowledge gap exists in the understanding of changes of neural and non-neural components of spasticity after injection. The purpose of this study was to determine if our device for quantitative modified Tardieu approach (QMTA) is a valid method to assess spasticity of calf muscles after botulinum toxin injection. METHODS: In this study, we intended to develop a device for quantitative measurement of spasticity in calf muscles based on the modified Tardieu scale (MTS) and techniques of biomedical engineering. Our QMTA measures the angular displacement and resistance of stretched joint with a device that is light, portable and can be operated similar to conventional approaches for MTS. The static (R2), dynamic (R1) and R2-R1 angles derived from the reactive signals collected by the miniature sensors are used to represent the non-neural and neural components of stretched spastic muscles. Four children with CP were recruited to assess the change in spasticity in their gastrocnemius muscles before and 4 weeks after BoNT A injection. RESULTS: A simulated ankle model validated the performance of our device in measuring joint displacement and estimating the angle of catch. Data from our participants with CP showed that R2 and R2-R1 improved significantly after BoNT-A administration. It indicates both neural and non-neural components of the spastic gastrocnemius muscles improved at four weeks after BoNT-A injection in children with CP. CONCLUSION: Our device for QMTA can objectively measure the changes in spasticity of the gastrocnemius muscle in children with cerebral palsy after BoNT-A injection. PMID- 26969528 TI - Effects of neuromuscular electrical stimulation combined with effortful swallowing on post-stroke oropharyngeal dysphagia: a randomised controlled trial. AB - Neuromuscular electrical stimulation (NMES) has been used as a therapeutic intervention for dysphagia. However, the therapeutic effects of NMES lack supporting evidence. In recent years, NMES combined with traditional swallowing therapy has been used to improve functional recovery in patients with post-stroke dysphagia. This study aimed to investigate the effects of effortful swallowing combined with neuromuscular electrical stimulation on hyoid bone movement and swallowing function in stroke patients. Fifty stroke patients with mild dysphagia who were able to swallow against the resistance applied by using NMES and cooperate actively in training were included. This study was designed as a 6-week single-blind, randomised, controlled study. In the experimental group, two pairs of electrodes were placed horizontally in the infrahyoid region to depress the hyoid bone. The NMES intensity was increased gradually until the participants felt a grabbing sensation in their neck and performed an effortful swallow during the stimulation. In the placebo group, the same procedure was followed except for the intensity, which was increased gradually until the participants felt an electrical sensation. All participants underwent this intervention for 30 min per session, 5 sessions per week, for 6 weeks. Videofluoroscopic swallowing studies (VFSS) were carried out before and after the intervention and kinematics of the hyoid bone and swallowing function were analysed based on the VFSS. The experimental group revealed a significant increase in anterior and superior hyoid bone movement and the pharyngeal phase of the swallowing function. This intervention can be used as a novel remedial approach in dysphagic stroke patients. PMID- 26969529 TI - Effectiveness of hydrogen peroxide and electron-beam irradiation treatment for removal and inactivation of viruses in equine-derived xenografts. AB - Bone grafting is a common procedure for bone reconstruction in dentistry, orthopedics, and neurosurgery. A wide range of grafts are currently used, and xenografts are regarded as an interesting alternative to autogenous bone because all mammals share the same bone mineral component composition and morphology. Antigens must be eliminated from bone grafts derived from animal tissues in order to make them biocompatible. Moreover, the processing method must also safely inactivate and/or remove viruses or other potential infectious agents. This study assessed the efficacy of two steps applied in manufacturing some equine-derived xenografts: hydrogen-peroxide and e-beam sterilization treatments for inactivation and removal of viruses in equine bone granules (cortical and cancellous) and collagen and pericardium membranes. Viruses belonging to three different human viral species (Herpes simplex virus type 1, Coxsackievirus B1, and Influenzavirus type A H1N1) were selected and used to spike semi-processed biomaterials. For each viral species, the tissue culture infective dose (TCID50) on cell lines and the number of genome copies through qPCR were assessed. Both treatments were found to be effective at virus inactivation. Considering the model viruses studied, the application of hydrogen peroxide and e-beam irradiation could also be considered effective for processing bone tissue of human origin. PMID- 26969531 TI - A novel multi-modal platform to image molecular and elemental alterations in ischemic stroke. AB - Stroke is a major global health problem, with the prevalence and economic burden predicted to increase due to aging populations in western society. Following stroke, numerous biochemical alterations occur and damage can spread to nearby tissue. This zone of "at risk" tissue is termed the peri-infarct zone (PIZ). As the PIZ contains tissue not initially damaged by the stroke, it is considered by many as salvageable tissue. For this reason, much research effort has been undertaken to improve the identification of the PIZ and to elucidate the biochemical mechanisms that drive tissue damage in the PIZ in the hope of identify new therapeutic targets. Despite this effort, few therapies have evolved, attributed in part, to an incomplete understanding of the biochemical mechanisms driving tissue damage in the PIZ. Magnetic resonance imaging (MRI) has long been the gold standard to study alterations in gross brain structure, and is frequently used to study the PIZ following stroke. Unfortunately, MRI does not have sufficient spatial resolution to study individual cells within the brain, and reveals little information on the biochemical mechanisms driving tissue damage. MRI results may be complemented with histology or immuno-histochemistry to provide information at the cellular or sub-cellular level, but are limited to studying biochemical markers that can be successfully "tagged" with a stain or antigen. However, many important biochemical markers cannot be studied with traditional MRI or histology/histochemical methods. Therefore, we have developed and applied a multi-modal imaging platform to reveal elemental and molecular alterations that could not previously be imaged by other traditional methods. Our imaging platform incorporates a suite of spectroscopic imaging techniques; Fourier transform infrared imaging, Raman spectroscopic imaging, Coherent anti stoke Raman spectroscopic imaging and X-ray fluorescence imaging. This approach does not preclude the use of traditional imaging techniques, and rather it should be use to complement traditional methods such as MRI or histology and immunohistochemistry, to gain a greater insight into disease mechanisms. We demonstrate the potential of this approach by characterizing biochemical alterations within the PIZ 24h after the induction of photothrombotic stroke in mice. Substantial molecular and elemental alterations were identified in the PIZ 24h after stroke that are consistent with tissue swelling and edema, but not oxidative stress. This reveals important mechanistic information, that could not previously be obtained, which should be considered in future studies aimed at developing therapeutic intervention from this model. PMID- 26969530 TI - Anti-NMDA receptor autoantibodies and associated neurobehavioral pathology in mice are dependent on age of first exposure to Toxoplasma gondii. AB - BACKGROUND: Toxoplasma gondii is a pathogen implicated in psychiatric disorders. As elevated antibodies to T. gondii are also present in non-symptomatic individuals, we hypothesized that the age during first exposure to the pathogen may affect symptom manifestation. We tested this hypothesis by evaluating neurobehavioral abnormalities and the immune response in mice following adolescent or adult T. gondii infection. METHODS: Mice were infected with T. gondii at postnatal day 33 (adolescent/juvenile) or 61 (adult). At 8weeks post infection (wpi), pre-pulse inhibition of the acoustic startle (PPI) in mice administered MK-801 (0.1 and 0.3mg/kg) and amphetamine (5 and 10mg/kg) was assessed. Peripheral (anti-T. gondii, C1q-associated IgG and anti-GLUN2 antibodies) and central (C1q and Iba1) markers of the immune response were also evaluated. In addition, regional brain expression of N-methyl-d-aspartate receptor (NMDAR) subunits (GLUN1 and GLUN2A), glutamatergic (vGLUT1, PSD95) and GABAergic (GAD67) markers, and monoamines (DA, NE, 5-HT) and their metabolites were measured. RESULTS: Juvenile and adult infected mice exhibited opposite effects of MK-801 on PPI, with decreased PPI in juveniles and increased PPI in adults. There was a significantly greater elevation of GLUN2 autoantibodies in juvenile-compared to adult-infected mice. In addition, age-dependent differences were found in regional expression of NMDAR subunits and markers of glutamatergic, GABAergic, and monoaminergic systems. Activated microglia and C1q elevations were found in both juvenile- and adult-T. gondii infected mice. CONCLUSIONS: Our study demonstrates that the age at first exposure to T. gondii is an important factor in shaping distinct behavioral and neurobiological abnormalities. Elevation in GLUN2 autoantibodies or complement protein C1q may be a potential underlying mechanism. A better understanding of these age-related differences may lead to more efficient treatments of behavioral disorders associated with T. gondii infection. PMID- 26969533 TI - Recognizing the Spectrum of Cognitive Impairment to Advance Drug Discovery. PMID- 26969532 TI - Nuclear translocation of histone deacetylase 4 induces neuronal death in stroke. AB - Mounting evidence suggests that epigenetic modifications play critical roles in the survival/death of stressed neurons. Chief among these modifications is the deacetylation of histones within the chromatin by histone deacetylases (HDACs). HDAC4 is highly expressed in neurons and is usually trapped in cytosol. However, tightly regulated signal-dependent shuttling of this molecule between cytosol and nucleus occurs. Here, we studied the intracellular trafficking of HDAC4 and regulatory mechanisms during stroke. HDAC4 translocated from the cytosol into the nucleus of neurons in response to stroke induced by middle cerebral artery occlusion (MCAO) in mice. Similar translocation was seen after oxygen-glucose deprivation (OGD) in cultured mouse neurons. Expression of nuclear-restricted HDAC4 increased neuronal death after OGD and worsened infarcts and functional deficits in mice following MCAO; however, expression of cytosolic-restricted HDAC4 did not affect outcome after ischemia. In contrast, HDAC4 knockdown with siRNA improved neuronal survival after OGD. Furthermore, expression of nuclear restricted HDAC4 reduced the acetylation of histones 3 and 4 as well as the levels of pro-survival downstream molecules after OGD. Finally, genetic deletion of calcium/calmodulin-dependent protein kinase IV (CaMKIV) increased the nuclear accumulation of HDAC4 in MCAO model, while overexpression of CaMKIV reduced the levels of nuclear HDAC4 following OGD. When HDAC4 was inhibited, the neuroprotection provided by CaMKIV overexpression was absent during OGD. Our data demonstrate a detrimental role of the nuclear accumulation of HDAC4 following stroke and identify CaMKIV as a key regulator of neuronal intracellular HDAC4 trafficking during stroke. PMID- 26969536 TI - Letter to the Editor on the Maastricht Sarcopenia Study. PMID- 26969535 TI - Lack of Energy and Negative Health-Related Outcomes in Nursing Home Residents: Results From the INCUR Study. AB - OBJECTIVE: "Lack of energy" or anergia is a common complaint associated with adverse outcomes in older people. There is a lack of knowledge on this symptom in the nursing home (NH) setting. The aim of this study was to investigate whether lack of energy was associated with hospitalization and mortality in NH residents. DESIGN: Longitudinal observational cohort study. SETTING AND PARTICIPANTS: A total of 575 NH residents (72% women) in 13 French NHs from the Incidence of pNeumonia and related ConseqUences in nursing home Residents (INCUR) study cohort. MEASUREMENTS: Lack of energy was measured at the baseline visit as part of the 10-item Geriatric Depression Scale. Unadjusted and adjusted Cox proportional hazard regression models were performed to test the association of lack of energy with hospitalization events and mortality over 12 months of follow up. RESULTS: The mean age of the study sample was 86.3 (SD = 7.5) years. At the baseline, 250 (43.5%) residents complained about lack of energy. Overall, 192 (33.4%) individuals experienced at least 1 hospitalization event and 98 (17.0%) died during the 12-month follow-up. Lack of energy was significantly associated with a higher risk of hospitalization (HR 1.35; 95% CI 1.02-1.80; P = .03), even after adjustment for potential confounders (HR 1.41; 95% CI 1.04-1.91; P = .02). No statistically significant association was found between lack of energy and 12 month mortality. CONCLUSION: Lack of energy is a predictor of hospitalization in older people living in NHs. It may be considered a relevant clinical feature for identifying individuals at risk of adverse health outcomes, thus potentially serving as a screening tool for subsequently conducting a comprehensive geriatric assessment in this highly vulnerable and complex population. PMID- 26969534 TI - Nursing Home Provider Perceptions of Telemedicine for Reducing Potentially Avoidable Hospitalizations. AB - OBJECTIVE: Potentially avoidable hospitalizations (PAHs) of nursing home (NH) residents are common, costly, and can have significant economic consequences. Telemedicine has been shown to reduce emergency department and hospitalization of NH residents, yet adoption has been limited and little is known about provider's perceptions and desired functionality for a telemedicine program. The goal of this study was to survey a nationally representative sample of NH physicians and advanced practice providers to quantify provider perceptions and desired functionality of telemedicine in NHs to reduce PAHs. DESIGN/SETTING/PARTICIPANTS/MEASUREMENT: We surveyed physicians and advanced practice providers who attended the 2015 AMDA-The Society for Post-Acute and Long Term Care Medicine Annual Conference about their perceptions of telemedicine and desired attributes of a telemedicine program for managing acute changes of condition associated with PAHs. RESULTS: We received surveys from 435 of the 947 conference attendees for a 45.9% response rate. Providers indicated strong agreement with the potential for telemedicine to improve timeliness of care and fill existing service gaps, while disagreeing most with the ideas that telemedicine would reduce care effectiveness and jeopardize resident privacy. Responses indicated clear preferences for the technical requirements of such a program, such as high-quality audio and video and inclusion of an electronic stethoscope, but with varying opinions about who should be performing the consults. CONCLUSION: Among NH providers, there is a high degree of confidence in the potential for a telemedicine solution to PAHs in NHs, as well as concrete views about features of such a solution. Such consensus could be used to drive an approach to telemedicine for PAHs in NHs that retains the theoretical strengths of telemedicine and reflects the needs of facilities, providers, and patients. Further research is needed to objectively study the impact of successful telemedicine implementations on patient, provider, and economic outcomes. PMID- 26969538 TI - Sources, chemistry, impacts and regulations of complex air pollution: Preface. PMID- 26969537 TI - Retinoblastoma: An update. AB - Retinoblastoma is the most common ocular malignancy in children, and is initiated by mutation of the RB1 gene. The tumor may be unilateral or bilateral and can be inherited. Overall survival, eye salvage, and preservation of vision are largely dependent on the stage of disease at presentation. Despite a recently enhanced understanding of the etiology of retinoblastoma, the mortality associated with it remains high worldwide. This may relate to a continuing lack of awareness of the lesion by laypersons, and unavailability of modern treatment facilities. Adverse outcomes are also caused by the occurrence of secondary malignancies after treatment of retinoblastoma in childhood. Early diagnosis, multidisciplinary treatment, and genetic counseling are all priorities in the management of this tumor. PMID- 26969539 TI - Kinetic and products study of the gas-phase reaction of Lewisite with ozone under atmospheric conditions. AB - The rate constant for the gas-phase reaction of O3 and Lewisite was studied in air using the smog chamber technique. The experiments were carried out under pseudo-first-order reaction conditions with [O3]?[Lewisite]. The observed rate constant of O3 with Lewisite was (7.83 +/- 0.38) * 10(-19)cm(3)/(molecule.sec) at 298 +/- 2K. Lewisite was discussed in terms of reactivity with O3 and its relationship with the ionization potential. Our results show that the rate constant for the gas-phase reaction of O3 with Lewisite is in line with the trend of the rate constants of O3 with haloalkenes. PMID- 26969540 TI - Changes in visibility with PM2.5 composition and relative humidity at a background site in the Pearl River Delta region. AB - In fall-winter, 2007-2013, visibility and light scattering coefficients (bsp) were measured along with PM2.5 mass concentrations and chemical compositions at a background site in the Pearl River Delta (PRD) region. The daily average visibility increased significantly (p<0.01) at a rate of 1.1 km/year, yet its median stabilized at ~13 km. No haze days occurred when the 24-hr mean PM2.5 mass concentration was below 75 MUg/m(3). By multiple linear regression on the chemical budget of particle scattering coefficient (bsp), we obtained site specific mass scattering efficiency (MSE) values of 6.5 +/- 0.2, 2.6 +/- 0.3, 2.4 +/- 0.7 and 7.3 +/- 1.2m(2)/g, respectively, for organic matter (OM), ammonium sulfate (AS), ammonium nitrate (AN) and sea salt (SS). The reconstructed light extinction coefficient (bext) based on the Interagency Monitoring of Protected Visual Environments (IMPROVE) algorithm with our site-specific MSE revealed that OM, AS, AN, SS and light-absorbing carbon (LAC) on average contributed 45.9% +/- 1.6%, 25.6% +/- 1.2%, 12.0% +/- 0.7%, 11.2% +/- 0.9% and 5.4% +/- 0.3% to light extinction, respectively. Averaged bext displayed a significant reduction rate of 14.1/Mm.year (p<0.05); this rate would be 82% higher if it were not counteracted by increasing relative humidity (RH) and hygroscopic growth factor (f(RH)) at rates of 2.5% and 0.16/year(-1) (p<0.01), respectively, during the fall-winter, 2007-2013. This growth of RH and f(RH) partly offsets the positive effects of lowered AS in improving visibility, and aggravated the negative effects of increasing AN to impair visibility. PMID- 26969541 TI - Impact of dicyandiamide on emissions of nitrous oxide, nitric oxide and ammonia from agricultural field in the North China Plain. AB - Nitrous oxide (N2O), nitric oxide (NO) and ammonia (NH3) emissions from an agricultural field in the North China Plain were compared for three treatments during a whole maize growing period from 26 June to 11 October, 2012. Compared with the control treatment (without fertilization, designated as CK), remarkable pulse emissions of N2O, NO and NH3 were observed from the normal fertilization treatment (designated as NP) just after fertilization, whereas only N2O and NH3 pulse emissions were evident from the nitrification inhibitor treatment (designated as ND). The reduction proportions of N2O and NO emissions from the ND treatment compared to those from the NP treatment during the whole maize growing period were 31% and 100%, respectively. A measurable increase of NH3 emission from the ND treatment was found with a cumulative NH3 emission of 3.8 +/- 1.2 kg N/ha, which was 1.4 times greater than that from the NP treatment (2.7 +/- 0.7 kg N/ha). PMID- 26969542 TI - Characteristics of particulate-bound polycyclic aromatic hydrocarbons emitted from industrial grade biomass boilers. AB - Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic or mutagenic and are important toxic pollutants in the flue gas of boilers. Two industrial grade biomass boilers were selected to investigate the characteristics of particulate bound PAHs: one biomass boiler retro-fitted from an oil boiler (BB1) and one specially designed (BB2) biomass boiler. One coal-fired boiler was also selected for comparison. By using a dilution tunnel system, particulate samples from boilers were collected and 10 PAH species were analyzed by gas chromatography mass spectrometry (GC-MS). The total emission factors (EFs) of PAHs ranged from 0.0064 to 0.0380 mg/kg, with an average of 0.0225 mg/kg, for the biomass boiler emission samples. The total PAH EFs for the tested coal-fired boiler were 1.8 times lower than the average value of the biomass boilers. The PAH diagnostic ratios for wood pellets and straw pellets were similar. The ratio of indeno(1,2,3 cd)pyrene/[indeno(1,2,3-cd)pyrene+benzo(g,h,i)perylene] for the two biomass boilers was lower than those of the reference data for other burning devices, which can probably be used as an indicator to distinguish the emission of biomass boilers from that of industrial coal-fired boilers and residential stoves. The toxic potential of the emission from wood pellet burning was higher than that from straw pellet burning, however both of them were much lower than residential stove exhausts. PMID- 26969543 TI - An intensive study on aerosol optical properties and affecting factors in Nanjing, China. AB - The optical properties of aerosol as well as their impacting factors were investigated at a suburb site in Nanjing during autumn from 14 to 28 November 2012. More severe pollution was found together with lower visibility. The average scattering and absorption coefficients (Bsca and Babs) were 375.7 +/- 209.5 and 41.6 +/- 18.7 Mm(-1), respectively. Higher Angstrom absorption and scattering exponents were attributed to the presence of more aged aerosol with smaller particles. Relative humidity (RH) was a key factor affecting aerosol extinction. High RH resulted in the impairment of visibility, with hygroscopic growth being independent of the dry extinction coefficient. The hygroscopic growth factor was 1.8 +/- 1.2 with RH from 19% to 85%. Light absorption was enhanced by organic carbon (OC), elemental carbon (EC) and EC coatings, with contributions of 26%, 44% and 75% (532 nm), respectively. The Bsca and Babs increased with increasing N100 (number concentration of PM2.5 with diameter above 100 nm), PM1 surface concentration and PM2.5 mass concentration with good correlation. PMID- 26969544 TI - Heterogeneous uptake of gaseous hydrogen peroxide on mineral dust. AB - The heterogeneous uptake processes of hydrogen peroxide on Arizona test dust and two types of authentic Chinese mineral dusts, i.e., Inner Mongolia desert dust and Xinjiang calciferous dust, were investigated using a Knudsen cell reactor coupled with a quadrupole mass spectrometer. The uptake coefficients were measured as a function of the initial concentration of H2O2 from 2.6 * 10(11) to 1.2 * 10(12)molecules/cm(3), and the temperature dependence of the uptake coefficients was investigated over a range from 253 to 313K. The concentration of H2O2 showed little effect on the uptake coefficients of these heterogeneous processes. As a function of temperature, the initial uptake coefficients decrease with increasing temperature, whereas the steady state uptake coefficients of Arizona test dust and Inner Mongolia desert dust increase with increasing temperature. Implications for the understanding of the uptake processes onto mineral dust samples were also discussed. PMID- 26969545 TI - Infrared spectroscopic probing of dimethylamine clusters in an Ar matrix. AB - Amines have many atmospheric sources and their clusters play an important role in aerosol nucleation processes. Clusters of a typical amine, dimethylamine (DMA), of different sizes were measured with matrix isolation IR (infrared) and NIR (near infrared) spectroscopy. The NIR vibrations are more separated and therefore it is easier to distinguish different sizes of clusters in this region. The DMA clusters, up to DMA tetramer, have been optimized using density functional methods, and the geometries, binding energies and thermodynamic properties of DMA clusters were obtained. The computed frequencies and intensities of NH-stretching vibrations in the DMA clusters were used to interpret the experimental spectra. We have identified the fundamental transitions of the bonded NH-stretching vibration and the first overtone transitions of the bonded and free NH-stretching vibration in the DMA clusters. Based on the changes in vibrational intensities during the annealing processes, the growth of clusters was clearly observed. The results of annealing processes indicate that DMA molecules tend to form larger clusters with lower energies under matrix temperatures, which is also supported by the calculated reaction energies of cluster formation. PMID- 26969546 TI - A quantum cascade laser infrared spectrometer for CO2 stable isotope analysis: Field implementation at a hydrocarbon contaminated site under bio-remediation. AB - Real-time methods to monitor stable isotope ratios of CO2 are needed to identify biogeochemical origins of CO2 emissions from the soil-air interface. An isotope ratio infra-red spectrometer (IRIS) has been developed to measure CO2 mixing ratio with delta(13)C isotopic signature, in addition to mixing ratios of other greenhouse gases (CH4, N2O). The original aspects of the instrument as well as its precision and accuracy for the determination of the isotopic signature delta(13)C of CO2 are discussed. A first application to biodegradation of hydrocarbons is presented, tested on a hydrocarbon contaminated site under aerobic bio-treatment. CO2 flux measurements using closed chamber method is combined with the determination of the isotopic signature delta(13)C of the CO2 emission to propose a non-intrusive method to monitor in situ biodegradation of hydrocarbons. In the contaminated area, high CO2 emissions have been measured with an isotopic signature delta(13)C suggesting that CO2 comes from petroleum hydrocarbon biodegradation. This first field implementation shows that rapid and accurate measurement of isotopic signature of CO2 emissions is particularly useful in assessing the contribution of contaminant degradation to the measured CO2 efflux and is promising as a monitoring tool for aerobic bio-treatment. PMID- 26969548 TI - Seasonal, diurnal and nocturnal variations of carbonyl compounds in the semi urban environment of Orleans, France. AB - Atmospheric carbonyls were measured at a semi-urban site in Orleans, France, from October 2010 to July 2011. Formaldehyde, acetaldehyde and acetone were found to be the most abundant carbonyls, with average concentrations of 3.1, 1.0, 2.0 ppb, respectively in summer, 2.3, 0.7, 2.2 ppb, respectively in autumn, 2.2, 1.0, 2.1 ppb, respectively in spring, and 1.5, 0.7, 1.1 ppb, respectively in winter. Photo oxidation of volatile organic compounds (VOCs) was found to make a remarkable contribution to atmospheric carbonyls in the semi-urban site based on the distinct seasonal and diurnal variations of the carbonyls, as well as the significantly positive correlations between the carbonyls and ozone. The significantly negative correlations between NOx and O3 as well as the carbonyls and the positive correlations between wind speed and O3 as well as the carbonyls implied that the carbonyls and O3 at the semi-urban site were probably formed during air mass transport from neighboring cities. PMID- 26969547 TI - Chemical composition and source apportionment of PM10 and PM2.5 in different functional areas of Lanzhou, China. AB - To elucidate the air pollution characteristics of northern China, airborne PM10 (atmospheric dynamic equivalent diameter <= 10 MUm) and PM2.5 (atmospheric dynamic equivalent diameter <= 2.5 MUm) were sampled in three different functional areas (Yuzhong County, Xigu District and Chengguan District) of Lanzhou, and their chemical composition (elements, ions, carbonaceous species) was analyzed. The results demonstrated that the highest seasonal mean concentrations of PM10 (369.48 MUg/m(3)) and PM2.5 (295.42 MUg/m(3)) were detected in Xigu District in the winter, the lowest concentration of PM2.5 (53.15 MUg/m(3)) was observed in Yuzhong District in the fall and PM10 (89.60 MUg/m(3)) in Xigu District in the fall. The overall average OC/EC (organic carbon/elemental carbon) value was close to the representative OC/EC ratio for coal consumption, implying that the pollution of Lanzhou could be attributed to the burning of coal. The content of SNA (the sum of sulfate, nitrate, ammonium, SNA) in PM2.5 in Yuzhong County was generally lower than that at other sites in all seasons. The content of SNA in PM2.5 and PM10 in Yuzhong County was generally lower than that at other sites in all seasons (0.24-0.38), indicating that the conversion ratios from precursors to secondary aerosols in the low concentration area was slower than in the area with high and intense pollutants. Six primary particulate matter sources were chosen based on positive matrix factorization (PMF) analysis, and emissions from dust, secondary aerosols, and coal burning were identified to be the primary sources responsible for the particle pollution in Lanzhou. PMID- 26969549 TI - Organic aerosol molecular composition and gas-particle partitioning coefficients at a Mediterranean site (Corsica). AB - Molecular speciation of atmospheric organic matter was investigated during a short summer field campaign performed in a citrus fruit field in northern Corsica (June 2011). Aimed at assessing the performance on the field of newly developed analytical protocols, this work focuses on the molecular composition of both gas and particulate phases and provides an insight into partitioning behavior of the semi-volatile oxygenated fraction. Limonene ozonolysis tracers were specifically searched for, according to gas chromatography-mass spectrometry (GC-MS) data previously recorded for smog chamber experiments. A screening of other oxygenated species present in the field atmosphere was also performed. About sixty polar molecules were positively or tentatively identified in gas and/or particle phases. These molecules comprise a wide range of branched and linear, mono and di carbonyls (C3-C7), mono and di-carboxylic acids (C3-C18), and compounds bearing up to three functionalities. Among these compounds, some can be specifically attributed to limonene oxidation and others can be related to alpha- or beta pinene oxidation. This provides an original snapshot of the organic matter composition at a Mediterranean site in summer. Furthermore, for compounds identified and quantified in both gaseous and particulate phases, an experimental gas/particle partitioning coefficient was determined. Several volatile products, which are not expected in the particulate phase assuming thermodynamic equilibrium, were nonetheless present in significant concentrations. Hypotheses are proposed to explain these observations, such as the possible aerosol viscosity that could hinder the theoretical equilibrium to be rapidly reached. PMID- 26969550 TI - NitroMAC: An instrument for the measurement of HONO and intercomparison with a long-path absorption photometer. AB - NitroMAC (French acronym for continuous atmospheric measurements of nitrogenous compounds) is an instrument which has been developed for the semi-continuous measurement of atmospheric nitrous acid (HONO). This instrument relies on wet chemical sampling and detection using high performance liquid chromatography (HPLC)-visible absorption at 540 nm. Sampling proceeds by dissolution of gaseous HONO in a phosphate buffer solution followed by derivatization with sulfanilamide/N-(1-naphthyl)-ethylenediamine. The performance of this instrument was found to be as follows: a detection limit of around 3 ppt with measurement uncertainty of 10% over an analysis time of 10 min. Intercomparison was made between the instrument and a long-path absorption photometer (LOPAP) during two experiments in different environments. First, air was sampled in a smog chamber with concentrations up to 18 ppb of nitrous acid. NitroMAC and LOPAP measurements showed very good agreement. Then, in a second experiment, ambient air with HONO concentrations below 250 ppt was sampled. While NitroMAC showed its capability of measuring HONO in moderate and highly polluted environments, the intercomparison results in ambient air highlighted that corrections must be made for minor interferences when low concentrations are measured. PMID- 26969551 TI - PM2.5 source apportionment in a French urban coastal site under steelworks emission influences using constrained non-negative matrix factorization receptor model. AB - The constrained weighted-non-negative matrix factorization (CW-NMF) hybrid receptor model was applied to study the influence of steelmaking activities on PM2.5 (particulate matter with equivalent aerodynamic diameter less than 2.5 MUm) composition in Dunkerque, Northern France. Semi-diurnal PM2.5 samples were collected using a high volume sampler in winter 2010 and spring 2011 and were analyzed for trace metals, water-soluble ions, and total carbon using inductively coupled plasma--atomic emission spectrometry (ICP-AES), ICP--mass spectrometry (ICP-MS), ionic chromatography and micro elemental carbon analyzer. The elemental composition shows that NO3(-), SO4(2-), NH4(+) and total carbon are the main PM2.5 constituents. Trace metals data were interpreted using concentration roses and both influences of integrated steelworks and electric steel plant were evidenced. The distinction between the two sources is made possible by the use Zn/Fe and Zn/Mn diagnostic ratios. Moreover Rb/Cr, Pb/Cr and Cu/Cd combination ratio are proposed to distinguish the ISW-sintering stack from the ISW-fugitive emissions. The a priori knowledge on the influencing source was introduced in the CW-NMF to guide the calculation. Eleven source profiles with various contributions were identified: 8 are characteristics of coastal urban background site profiles and 3 are related to the steelmaking activities. Between them, secondary nitrates, secondary sulfates and combustion profiles give the highest contributions and account for 93% of the PM2.5 concentration. The steelwork facilities contribute in about 2% of the total PM2.5 concentration and appear to be the main source of Cr, Cu, Fe, Mn, Zn. PMID- 26969552 TI - Analysis of the origin of peak aerosol optical depth in springtime over the Gulf of Tonkin. AB - By aggregating MODIS (moderate-resolution imaging spectroradiometer) AOD (aerosol optical depth) and OMI (ozone monitoring instrument) UVAI (ultra violet aerosol index) datasets over 2010-2014, it was found that peak aerosol loading in seasonal variation occurred annually in spring over the Gulf of Tonkin (17-23 degrees N, 105-110 degrees E). The vertical structure of the aerosol extinction coefficient retrieved from the spaceborne lidar CALIOP (cloud-aerosol lidar with orthogonal polarization) showed that the springtime peak AOD could be attributed to an abrupt increase in aerosol loading between altitudes of 2 and 5 km. In contrast, aerosol loading in the low atmosphere (below 1 km) was only half of that in winter. Wind fields in the low and high atmosphere exhibited opposite transportation patterns in spring over the Gulf of Tonkin, implying different sources for each level. By comparing the emission inventory of anthropogenic sources with biomass burning, and analyzing the seasonal variation of the vertical structure of aerosols over the Northern Indo-China Peninsula (NIC), it was concluded that biomass burning emissions contributed to high aerosol loading in spring. The relatively high topography and the high surface temperature in spring made planetary boundary layer height greater than 3 km over NIC. In addition, small-scale cumulus convection frequently occurred, facilitating pollutant rising to over 3 km, which was a height favoring long-range transport. Thus, pollutants emitted from biomass burning over NIC in spring were raised to the high atmosphere, then experienced long-range transport, leading to the increase in aerosol loading at high altitudes over the Gulf of Tonkin during spring. PMID- 26969553 TI - Process analysis of characteristics of the boundary layer during a heavy haze pollution episode in an inland megacity, China. AB - Ground observation data from 8 meteorological stations in Xi'an, air mass concentration data from 13 environmental quality monitoring sites in Xi'an, as well as radiosonde observation and wind profile radar data, were used in this study. Thereby, the process, causes and boundary layer meteorological characteristics of a heavy haze episode occurring from 16 to 25 December 2013 in Xi'an were analyzed. Principal component analysis showed that this haze pollution was mainly caused by the high-intensity emission and formation of gaseous pollutants (NO2, CO and SO2) and atmospheric particles (PM2.5 (fine particles) and PM10 (respirable suspended particle). The second cause was the relative humidity and continuous low temperature. The third cause was the allocation of the surface pressure field. The presence of a near-surface temperature inversion at the boundary layer formed favorable stratification conditions for the formation and maintenance of heavy haze pollution. The persistent thick haze layer weakened the solar radiation. Meanwhile, a warming effect in the urban canopy layer and in the transition zone from the urban friction sublayer to the urban canopy was indicated. All these conditions facilitated the maintenance and reinforcement of temperature inversion. The stable atmospheric stratification finally acted on the wind field in the boundary layer, and further weakened the exchange capacity of vertical turbulence. The superposition of a wind field with the horizontal gentle wind induced the typical air stagnation and finally caused the deterioration of air quality during this haze event. PMID- 26969554 TI - Characteristics of atmospheric single particles during haze periods in a typical urban area of Beijing: A case study in October, 2014. AB - To investigate the composition and possible sources of particles, especially during heavy haze pollution, a single particle aerosol mass spectrometer (SPAMS) was deployed to measure the changes of single particle species and sizes during October of 2014, in Beijing. A total of 2,871,431 particles with both positive and negative spectra were collected and characterized in combination with the adaptive resonance theory neural network algorithm (ART-2a). Eight types of particles were classified: dust particles (dust, 8.1%), elemental carbon (EC, 29.0%), organic carbon (OC, 18.0%), EC and OC combined particles (ECOC, 9.5%), Na K containing particles (NaK, 7.9%), K-containing particles (K, 21.8%), organic nitrogen and potassium containing particles (KCN, 2.3%), and metal-containing particles (metal, 3.6%). Three haze pollution events (P1, P2, P3) and one clean period (clean) were analyzed, based on the mass and number concentration of PM2.5 and the back trajectory results from the hybrid single particle Lagrangian integrated trajectory model (Hysplit-4 model). Results showed that EC, OC and K were the major components of single particles during the three haze pollution periods, which showed clearly increased ratios compared with those in the clean period. Results from the mixing state of secondary species of different types of particles showed that sulfate and nitrate were more readily mixed with carbon containing particles during haze pollution episodes than in clean periods. PMID- 26969555 TI - Gravimetric analysis for PM2.5 mass concentration based on year-round monitoring at an urban site in Beijing. AB - Daily PM2.5 (particulate matter with an aerodynamic diameter of below 2.5 MUm) mass concentrations were measured by gravimetric analysis in Chinese Research Academy of Environmental Sciences (CRAES), in the northern part of the Beijing urban area, from December 2013 to April 2015. Two pairs of Teflon (T1/T2) and Quartz (Q1/Q2) samples were obtained, for a total number of 1352 valid filters. Results showed elevated pollution in Beijing, with an annual mean PM2.5 mass concentration of 102 MUg/m(3). According to the calculated PM2.5 mass concentration, 50% of our sampling days were acceptable (PM2.5<75 MUg/m(3)), 30% had slight/medium pollution (75-150 MUg/m(3)), and 7% had severe pollution (> 250 MUg/m(3)). Sampling interruption occurred frequently for the Teflon filter group (75%) in severe pollution periods, resulting in important data being missing. Further analysis showed that high PM2.5 combined with high relative humidity (RH) gave rise to the interruptions. The seasonal variation of PM2.5 was presented, with higher monthly average mass concentrations in winter (peak value in February, 422 MUg/m(3)), and lower in summer (7 MUg/m(3) in June). From May to August, the typical summer period, least severe pollution events were observed, with high precipitation levels accelerating the process of wet deposition to remove PM2.5. The case of February presented the most serious pollution, with monthly averaged PM2.5 of 181 MUg/m(3) and 32% of days with severe pollution. The abundance of PM2.5 in winter could be related to increased coal consumption for heating needs. PMID- 26969557 TI - Important considerations in chest wall reconstruction. AB - Chest wall reconstruction represents one of the most challenging tasks in plastic surgery. Over the past several decades, a more profound understanding of surgical anatomy and physiology along with tremendous advances in surgical technique have resulted in substantial improvements in postoperative outcomes. Conceptually, the reconstructive goals include dead space obliteration, restoration of skeletal stability with protection of intrathoracic structures, and stable soft tissue coverage. Ideally, these goals are achieved with minimal aesthetic deformity. J. Surg. Oncol. 2016;113:913-922. (c) 2016 Wiley Periodicals, Inc. PMID- 26969556 TI - Size and elemental composition of dry-deposited particles during a severe dust storm at a coastal site of Eastern China. AB - Dry-deposited particles were collected during the passage of an extremely strong dust storm in March, 2010 at a coastal site in Qingdao (36.15 degrees N, 120.49 degrees E), a city located in Eastern China. The size, morphology, and elemental composition of the particles were quantified with a scanning electron microscope equipped with an energy dispersive X-ray instrument (SEM-EDX). The particles appeared in various shapes, and their size mainly varied from 0.4 to 10 MUm, with the mean diameters of 0.5, 1.5, and 1.0 MUm before, during, and after the dust storm, respectively. The critical size of the mineral particles settling on the surface in the current case was about 0.3-0.4 MUm before the dust storm and about 0.5-0.7 MUm during the dust storm. Particles that appeared in high concentration but were smaller than the critical size deposited onto the surface at a small number flux. The elements Al, Si and Mg were frequently detected in all samples, indicating the dominance of mineral particles. The frequency of Al in particles collected before the dust storm was significantly lower than for those collected during and after the dust storm. The frequencies of Cl and Fe did not show obvious changes, while those of S, K and Ca decreased after the dust arrival. These results indicate that the dust particles deposited onto the surface were less influenced by anthropogenic pollutants in terms of particle number. PMID- 26969559 TI - Challenges to clinical pharmacy practice in Nigerian hospitals: a qualitative exploration of stakeholders' views. AB - RATIONALE, AIMS AND OBJECTIVES: In Nigeria, a shift from the traditional pharmacists' role of dispensing and compounding of medications began in the 1980s with the introduction of drug information services and unit dose-dispensing systems in some hospitals. More than three decades after this, clinical pharmacy practice is still underdeveloped. This study was conducted to explore stakeholders' views on the barriers to the development of clinical pharmacy practice in Nigerian hospitals. METHODS: Qualitative, semi-structured interviews were conducted with 44 purposefully sampled Nigerian stakeholders including pharmacists, pharmacy technicians, doctors, policymakers and patient group representatives. Transcribed interviews were entered into the QSR (Burlington, MA, USA) NVivo 10 software and analysed thematically. RESULTS: Three major themes emerged from the study: pharmacists' professional identity, the structure of pharmacy practice and external barriers. The results revealed an ongoing struggle by Nigerian hospital pharmacists to establish their clinical identities as many non-pharmacy stakeholders viewed pharmacists' roles to be mainly supply based. Barriers to the development of clinical pharmacy practice identified included pharmacists' lack of confidence, shortage of pharmacy staff, underutilisation of pharmacy technicians, lack of specialisation and clinical career structure, medical dominance and opposition and lack of policies that support clinical pharmacy practice. CONCLUSION: Several years after its introduction, clinical pharmacy practice is yet to be fully developed in Nigerian hospitals. The barriers identified in this study need to be addressed in order for clinical pharmacy practice to flourish. PMID- 26969558 TI - Neighborhood Context and Binge Drinking by Race and Ethnicity in New York City. AB - BACKGROUND: Neighborhood context is associated with binge drinking and has significant health, societal, and economic costs. Both binge drinking and neighborhood context vary by race and ethnicity. We examined the relations between neighborhood characteristics--neighborhood norms that are accepting of drunkenness, collective efficacy, and physical disorder--and binge drinking, with a focus on examining race and ethnic-specific relationships. METHODS: Respondent data were collected through 2005 random digit-dial-telephone survey for a representative sample of New York City residents; neighborhood data were based on the 2005 New York City Housing and Vacancy Survey. Participants were 1,415 past year drinkers; Whites (n = 877), Blacks (n = 292), and Hispanics (n = 246). Generalized estimating equations were used to estimate population average models. RESULTS: For the overall sample, neighborhood norms that were more accepting of drunkenness were associated with greater binge drinking (odds ratio [OR] = 1.22; 95% confidence interval [CI] = 1.09, 1.37); collective efficacy and physical disorder were not significant. However, when examining this by race/ethnicity, greater collective efficacy (OR = 0.75; 95% CI = 0.62, 0.91) and greater physical disorder (OR = 0.76; 95% CI = 0.62, 0.93) were associated with less binge drinking for Whites only. Neighborhood norms that were more accepting of drunkenness were associated with binge drinking among Whites (OR = 1.20; 95% CI = 1.05, 1.38) and, while not significant (perhaps due to power), the associations were similar for Hispanics (OR = 1.18; 95% CI = 0.83, 1.68) and slightly lower for Blacks (OR = 1.11; 95% CI = 0.67, 1.84). CONCLUSIONS: Overall, results suggest that neighborhood characteristics and binge drinking are shaped, in part, by factors that vary across race/ethnicity. Thus, disaggregating data by race/ethnicity is important in understanding binge drinking behaviors. PMID- 26969560 TI - A novel approach to the measurement of surfactant parameters in arthropod digestive juices. AB - In arthropods, the determination of two important parameters of digestive juices, i.e. the total surfactant concentration and the critical micelle concentration (CMC), is challenging due to small sample volumes and low surfactant concentrations. In this work, we report a successful implementation of potentiometric titrations using the surfactant ion-selective electrode (SISE) and the pyrene fluorescence method (PFM) for the determination of the total surfactant concentration and CMC in the digestive juice of terrestrial isopod crustaceans Porcellio scaber. Pooled digestive juice extracts of four (SISE) or two (PFM) animals were used per measurement run. In both cases, digestive juice extracts in 100 MUL of deionized water were sufficient for one measurement run. The total surfactant concentration of P. scaber digestive juice was determined to be 9.2 +/- 3.5mM and the CMC was approximately 90 MUM. Our work presents an important improvement towards easy CMC determination in small volume samples in comparison with the commonly used stalagmometric technique, where much larger sample volumes are usually needed. To date, the total surfactant concentration was not measured in the digestive juices of arthropods other than Homarus vulgaris, Astacus leptodactylus and Cancer pagurus, for which complex separation and analytical techniques were required. Our results obtained by SISE and PFM therefore present the first successful quantification of surfactants and their CMC in small volumes of arthropod digestive juice without prior separation or purification techniques. PMID- 26969561 TI - Is hypertension a risk factor of hemifacial spasm? AB - OBJECTIVES: The published data on the relation between arterial hypertension (AH) and hemifacial spasm (HFS) are controversial. The aim of the study was to determine the prevalence of AH in HFS patients and the relation of AH and compression of the brainstem at the region of vasomotor center. MATERIALS AND METHODS: The study included 60 of primary HFS patients and 60 healthy controls matched by age. AH was defined according to WHO criteria. The vessel compression of the brainstem was measure on MRI scans in selected region of vasomotor center located in the ventro-lateral medulla (VLM), between the pontomedullary junction, retro-olivary sulcus and the root entry zone (REZ) of the IX and X nerves. Modeling and compression severity of the VLM was graded in the 0-3 scale. RESULTS: The prevalence of AH in HFS patients did not differ significantly from the control group (61.6% vs 45.0%, p=ns). VML compression by vessel was frequently found in HFS patients with AH than without AH (97.2% vs 60.9%, chi(2)=11.0, p=0.0009). A similar relation was also found in the control group. The higher rate of VML vascular compression was related to the presence of AH in both, HFS patients and control group. CONCLUSION: The prevalence of AH in HFS patients does not differ from controls. The VLM compression in HFS patients and controls is related to AH diagnosis. The association between AH and VLM compression is stronger in patients with higher degree of VLM compression. PMID- 26969562 TI - Epidermoid cysts of the cerebellopontine angle: Clinical features and treatment outcomes. AB - OBJECTIVE: To report clinical characteristics, treatment outcomes and risk of recurrence in patients with surgically treated cerebellopontine angle epidermoids. METHODS: In 1994-2013, we operated 17 patients, including 7 with tumor limited to the cerebellopontine angle, 7 with cerebellopontine angle tumor penetrating supratentorially, and 3 with cerebellopontine angle tumor extending along skull base to contralateral cerebellopontine angle. All patients were followed-up for the mean duration of 126 months. RESULTS: On admission cranial nerve symptoms predominated. Total tumor removal was achieved in 5 patients, and incomplete removal (with small tumor remnants left on vessels, nerves, or brainstem) in 12 patients. Postoperatively, preoperative deficits worsened in 2 and new postoperative deficits occurred in 10 patients. The extent of tumor expansion had no effect on postoperative morbidity and risk of recurrence. During long-term follow-up, improvement or resolution of preoperative deficits was seen in 11 of 17 patients, and new postoperative deficits in 8 of 10 patients. Symptomatic recurrences after an average of more than 9 years were noted in 5 patients, 3 of whom were reoperated. Recurrences occurred in some younger patients and always in area of primary tumor. No effect of extent of tumor removal on risk of recurrence was found. CONCLUSIONS: The extent of tumor removal had no effect on the risk of recurrence, and thus it may be acceptable to leave tumor capsule fragments adhering closely to nerves, vessels, or brainstem. During long-term follow-up, resolution or improvement of present preoperatively and new postoperative neurological deficits may be expected in most patients. PMID- 26969563 TI - Surgery for sporadic vestibular schwannoma. Part I: General outcome and risk of tumor recurrence. AB - BACKGROUND: Vestibular schwannomas are slow growing, benign tumors. There are three possible management options: surgery, radiation treatment or active surveillance. The aim of this study was to assess the general outcome and risk of tumor recurrence. MATERIALS AND METHODS: The study included 220 consecutive patients (134 women, 86 men; the age ranged from 18 to 74) operated with the retrosigmoid transmeatal approach. The largest extrameatal diameter of the tumor ranged from 8 to 72mm (mean 30mm). According to the Samii grading scale, the tumors were classified as follows: T2-12 (6%), T3-51 (23%) and T4-157 (71%). Gross total resection was performed in 217 patients and neartotal in 3. RESULTS: Two hundred and eighteen (99.1%) patients were discharged home in a satisfactory neurological condition (GR or MD in GOS). One (0.5%) patient died due to brainstem infarction. One (0.5%) patient had unchanged severe cerebellar syndrome in comparison to the preoperative period (SD in GOS). In long-term follow-up, one patient went blind within a few months after surgery. Including the results of further neurosurgical procedures for CSF leak, shunt implantation, tumor regrowth and facial nerve reanimation, 98.6% of the patients were fully independent but with different neurological deficits. Tumor recurrence was observed in 5 (2.3%) patients during the follow-up period (mean term: 6.4 years). The average time to recurrence diagnosis was 8.8 years. All those patients were operated on again without any adjuvant therapy and there was no further re-growth at mean follow-up of 5.2 years. CONCLUSIONS: Complete removal of VS is usually curative and poses very low risks of severe disability (if audio-facial sequels are not included), mortality and long-term recurrence. For recurrent tumors, carefully tailored revision surgery without irradiation offers a high efficacy with low risk of complications. PMID- 26969564 TI - Surgery for sporadic vestibular schwannoma. Part II. Complications (not related to facial and auditory nerves). AB - INTRODUCTION: The aim of this study was to analyze the frequency and consequences of postoperative complications (PC) after surgery for sporadic vestibular schwannoma and to find factors that increase the risk of PC occurrence. MATERIALS AND METHODS: The study included 220 consecutive patients (134 women, 86 men; age ranged from 18 to 74) operated on with the retrosigmoid (217) or translabyrinthine (3) approach. Complicated postoperative period was defined as an occurrence of at least one of: cerebrospinal fluid (CSF) leakage, hematoma in the tumor bed, intracerebellar hematoma, cerebellar swelling, brainstem stroke, hydrocephalus (HCP), healing problems, meningitis and cranial nerves (excluding VII-VIII) palsies or cerebellar symptoms. Correlation studies and multivariate regression analysis were performed. RESULTS: PC occurred in 55 patients (25%). PC included lower cranial nerve (LCN) palsy (8.2%), cerebellar symptoms (7.3%), CSF leakage (5.9%), HCP (5%), CNVI palsy (3.1%), meningitis (1.8%), cerebellar swelling (1.4%), CNV dysfunction (0.9%), intracerebellar hematoma (0.5%) and lethal brainstem stroke (0.5%). In long term follow-up, LCN deficit was present in 2 patients (0.9%), cerebellar syndrome in 4(1.8%) and facial hypoesthesia in 2(0.9%). One patient (0.5%) developed bilateral blindness, secondary to preoperative optic nerve atrophy. As a result of PC, 10 patients (4.5%) required 11 additional surgical procedures. In statistical analysis, PC were independently related to preoperative cerebellar syndrome (p=0.002) and tumor size (>30 mm vs.<30 mm, p<0.05). The risk of PC diminished significantly with the increased number of performed procedures from 40% at the beginning to 16.4% in the last 55 cases. CONCLUSIONS: Tumor size, cerebellar syndrome at presentation and experience of the team were the three most important risk factors for PC occurrence. Permanent deficit secondary to PC remained in only 4% of the patients. PMID- 26969565 TI - Executive functioning pattern as a prognostic indicator for shunt implantation surgery in patients with normal pressure hydrocephalus - A preliminary report. AB - The problem of executive functions in patients with normal pressure hydrocephalus (NPH) was investigated in the study. Executive function parameters were assumed to be among factors that may differentiate the clinical pattern in NPH. Two major indicators of executive functioning, i.e. flexibility and productivity of thinking, were assessed in neuropsychological examination using the Trail Making Test (TMT), Verbal Fluency Test (COWAT), and the Wisconsin Card Sorting Test (WCST). Participants in the study were 18 patients with NPH divided using a set of diagnostic criteria into two subgroups: with idiopathic active hydrocephalus (ACT) or with arrested hydrocephalus (ARR). Executive functioning patterns were found to differentiate between the two NPH subgroups. Namely, patients diagnosed with active hydrocephalus (who qualify for shunt implantation surgery) tended to present lower levels of verbal fluency in all semantic categories, which suggests a decreased productivity of thinking. Besides, ACT patients' performance on the WCST was significantly inferior on two measures: (1) they committed more non perseverative errors (which indicates their chaotic way of working on the test and the occurrence of random responses) and (2) displayed lower ability of "learning to learn" (which suggests their impaired flexibility of thinking). These aspects of executive function, with productivity and flexibility of thinking first and foremost, seem promising as additional prognostic indicators to consider in patient selection for shunt implantation. PMID- 26969566 TI - Treatment of lumbar disc herniation with radiculopathy. Clinical practice guidelines endorsed by The Polish Society of Spinal Surgery. AB - INTRODUCTION: Herniated lumbar disc (HLD) is arguably the most common spinal disorder requiring surgical intervention. Although the term is fairly straightforward, the exact pathology and thus the clinical picture and natural history may vary. Therefore, it is immensely difficult to formulate universal guidelines for surgical treatment. AIM: The aim of this paper is to organize the terminology and clear the inconsistencies in phraseology, review treatment options and gather available published evidence to address the clinical questions to create a set of clinical guidelines in relevant to the topic. METHODS AND RESULTS: Twelve queries, addressing optimal surgical treatment of the HLD have been formulated. The results, based on the literature review are described in the present work. The final product of the analysis was a set of guidelines for the surgical treatment of symptomatic HLD. Categorized into four tiers based on the level of evidence (I-III and X), they have been designed to assist in the selection of optimal, effective treatment leading to the successful outcome. CONCLUSIONS: The evidence based medicine (EBM) is becoming ever more popular among spinal surgeons. Unfortunately this is not always feasible. Lack of uniform guidelines and numerous conflicts of interest introduce flaws in the decision making process. The key role of experts and professional societies is to provide high value recommendation based on the most current literature. Present work contains a set of guidelines for the surgical treatment of HLD officially endorsed by the Polish Spine Surgery Society. PMID- 26969567 TI - Treatment of degenerative cervical spondylosis with radiculopathy. Clinical practice guidelines endorsed by The Polish Society of Spinal Surgery. AB - INTRODUCTION: Degenerative cervical spondylosis (DCS) with radiculopathy is the most common indication for cervical spine surgery despite favorable natural history. Advances in spinal surgery in conjunction with difficulties in measuring the outcomes caused the paucity of uniform guidelines for the surgical management of DCS. AIMS: The aim of this paper is to develop guidelines for surgical treatment of DCS. For this purpose the available up-to-date literature relevant on the topic was critically reviewed. METHODS AND RESULTS: Six questions regarding most important clinical questions encountered in the daily practice were formulated. They were answered based upon the systematic literature review, thus creating a set of guidelines. The guidelines were categorized into four tiers based on the level of evidence (I-III and X). They were designed to assist in the selection of optimal and effective treatment leading to the most successful outcome. CONCLUSIONS: The evidence based medicine (EBM) is increasingly popular among spinal surgeons. It allows making unbiased, optimal clinical decisions, eliminating the detrimental effect of numerous conflicts of interest. The key role of opinion leaders as well as professional societies is to provide guidelines for practice based on available clinical evidence. The present work contains a set of guidelines for surgical treatment of DCS officially endorsed by the Polish Spine Surgery Society. PMID- 26969568 TI - Deep brain stimulation for intractable tardive dystonia: Literature overview. AB - BACKGROUND: Tardive dystonia (TD) represents a side effect of prolonged intake of dopamine receptor blocking compounds. TD can be a disabling movement disorder persisting despite available medical treatment. Deep brain stimulation (DBS) has been reported successful in this condition although the number of treated patients with TD is still limited to small clinical studies or case reports. The aim of this study was to present the systematical overview of the existing literature regarding DBS for intractable TD. METHODS AND RESULTS: A literature search was carried out in PudMed. Clinical case series or case reports describing the patients with TD after DBS treatment were included in the present overview. Literature search revealed 19 articles reporting 59 individuals operated for TD. GPi was the target in 55 patients, while subthalamic nucleus (STN) was the target in the remaining 4. In most studies the motor part of Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) was improved by more than 80% when compared to preoperative BFMDRS scores. CONCLUSIONS: The performed literature analysis indicates that bilateral GPi DBS is an effective treatment for disabling TD. The response of TD to bilateral GPi DBS may be very rapid and occurs within days/weeks after the procedure. The efficacy of bilateral GPi DBS in TD patients is comparable to results achieved in patients with primary generalized dystonia. PMID- 26969569 TI - What you cannot get from routine MRI of MS patient and why - The growing need for atrophy assessment and seeing beyond the plaque. AB - Multiple sclerosis is a disease that still has not been fully understood and calls for better diagnostic procedures for the improvement of everyday patient care and drug development. Routine magnetic resonance examinations reveal demyelinating focal lesions, but they do not correlate sufficiently with the patients' disability and cognitive impairment. For more than 100 years it has been known that demyelination affects not only white but also grey matter of the brain. Recent research has confirmed the serious consequences of grey matter pathology. Over the last several years, atrophy of the brain and especially of its grey matter has become a most promising marker of the patients' clinical status. The paper discusses the concept and importance of atrophy assessment in relation to the standard magnetic resonance results. PMID- 26969570 TI - Spinal tuberculosis with severe neurological symptoms as a complication of intravesical BCG therapy for carcinoma of the bladder. AB - INTRODUCTION: Non-invasive bladder cancer is effectively treated with intravesical BCG therapy. The administration of the BCG vaccine is to destroy the neoplastic lesion or prevent further recurrences. The activity of the vaccine involves boosting the immune system through the stimulation of the inflammation in the bladder. Adverse reactions after this immunotherapy are rare. The aim of the study was to present complications in the form of spinal tuberculosis and serious neurological symptoms that occurred during intravesical BCG immunotherapy for carcinoma of the bladder. The manuscript also describes a method for neurosurgical spinal cord decompression of the thoracic spine. MATERIAL AND METHODS: In the first patient, aged 66, after intravesical BCG therapy for bladder carcinoma, back pain and spastic paralysis of the lower limbs were observed. The MRI and CT revealed destruction of the intervertebral disc and vertebral endplates Th11-Th12. Mycobacterium tuberculosis complex bacilli were cultured from the material obtained by puncture aspiration. In the second patient, aged 35 years, during intravesical BCG immunotherapy for carcinoma of the bladder, girdle thoracic spine pain was observed. The MRI and CT of the spine showed visible lesions characteristic of tuberculosis. Immobilization in a plaster corset and implementation of antituberculous treatment resulted in quick relief of the pain and healing of the tuberculosis focus in the spine. CONCLUSION: The cases described in the work are the first documented reports in the Polish literature of spinal tuberculosis which occurred as a complication of intravesical administration of bacilli Calmette-Guerin. The diagnosis was based on the finding of BCG vaccine bacillus with molecular methods or PCR. Full antimycobacterial treatment was implemented. PMID- 26969571 TI - Subarachnoid hemorrhage occurring after bee sting. PMID- 26969572 TI - On antithrombotic mechanisms of statins: Are they relevant in intracerebral or subarachnoid bleedings? PMID- 26969573 TI - Teacher candidates' mastery of phoneme-grapheme correspondence: massed versus distributed practice in teacher education. AB - Matching phonemes (speech sounds) to graphemes (letters and letter combinations) is an important aspect of decoding (translating print to speech) and encoding (translating speech to print). Yet, many teacher candidates do not receive explicit training in phoneme-grapheme correspondence. Difficulty with accurate phoneme production and/or lack of understanding of sound-symbol correspondence can make it challenging for teachers to (a) identify student errors on common assessments and (b) serve as a model for students when teaching beginning reading or providing remedial reading instruction. For students with dyslexia, lack of teacher proficiency in this area is particularly problematic. This study examined differences between two learning conditions (massed and distributed practice) on teacher candidates' development of phoneme-grapheme correspondence knowledge and skills. An experimental, pretest-posttest-delayed test design was employed with teacher candidates (n = 52) to compare a massed practice condition (one, 60-min session) to a distributed practice condition (four, 15-min sessions distributed over 4 weeks) for learning phonemes associated with letters and letter combinations. Participants in the distributed practice condition significantly outperformed participants in the massed practice condition on their ability to correctly produce phonemes associated with different letters and letter combinations. Implications for teacher preparation are discussed. PMID- 26969574 TI - Risk of recurrence of idiopathic calcium kidney stones: analysis of data from the literature. AB - BACKGROUND: Nephrolithiasis is a frequent condition. While it is generally accepted that such condition carries a risk of recurrence over time, the exact risk and its predictors have been rarely quantitated. We aimed to estimate recurrence of kidney stones, overall and in specific subgroups, from randomized controlled trials (RCTs) of calcium stone formers. METHODS: Systematic review of RCTs of adult patients with idiopathic calcium kidney stones. Recurrence rates analyzed in subgroups based on type of intervention and other characteristics, using Poisson regression models. RESULTS: The analysis included 21 RCTs with 2168 participants over a median follow-up of 3.2 years (range 0.5-9.7). The median recurrence of kidney stones was 15 per 100 person-years (range 0-110). Recurrence was higher in those with two or more previous stone episodes compared to those with a single episode at enrolment (16 vs. 6 per 100 person-years, p < 0.001) and in those untreated or treated with dietary changes compared to those treated with drugs (26 vs. 23 vs. 9 per 100 person-years, p < 0.001). The effect of drugs on recurrence seemed to be beneficial only among those with two or more previous stone episodes. CONCLUSIONS: The overall recurrence rate of stones depends on factors such as previous stone history and type of treatment. Dietary approaches seem to be more effective among single stone formers, whereas drugs seem to be more effective among recurrent stone formers. PMID- 26969575 TI - "I am Your Mother and Your Father!" In Vitro Derived Gametes and the Ethics of Solo Reproduction. AB - In this paper, we will discuss the prospect of human reproduction achieved with gametes originating from only one person. According to statements by a minority of scientists working on the generation of gametes in vitro, it may become possible to create eggs from men's non-reproductive cells and sperm from women's. This would enable, at least in principle, the creation of an embryo from cells obtained from only one individual: 'solo reproduction'. We will consider what might motivate people to reproduce in this way, and the implications that solo reproduction might have for ethics and policy. We suggest that such an innovation is unlikely to revolutionise reproduction and parenting. Indeed, in some respects it is less revolutionary than in vitro fertilisation as a whole. Furthermore, we show that solo reproduction with in vitro created gametes is not necessarily any more ethically problematic than gamete donation-and probably less so. Where appropriate, we draw parallels with the debate surrounding reproductive cloning. We note that solo reproduction may serve to perpetuate reductive geneticised accounts of reproduction, and that this may indeed be ethically questionable. However, in this it is not unique among other technologies of assisted reproduction, many of which focus on genetic transmission. It is for this reason that a ban on solo reproduction might be inconsistent with continuing to permit other kinds of reproduction that also bear the potential to strengthen attachment to a geneticised account of reproduction. Our claim is that there are at least as good reasons to pursue research towards enabling solo reproduction, and eventually to introduce solo reproduction as an option for fertility treatment, as there are to do so for other infertility related purposes. PMID- 26969576 TI - Locoregional cancer therapy using polymer-based drug depots. AB - Locoregional delivery of anticancer drugs is an attractive approach to minimize adverse effects associated with intravenous chemotherapy. Polymer-based drug depots injected or implanted intratumorally or adjacent to the tumor can provide long-term local drug exposure. This review highlights studies in which drug eluting depots have been applied locally in the treatment of cancer. In many cases such drug depots are used for prevention of tumor recurrence after surgery to eradicate remaining tumor cells. Clinical success has been reported for the treatment of brain cancer and liver cancer, and preclinical studies showed proof of-concept for inhaled drug depots in lung cancer and intraperitoneally injected depots for the treatment of abdominal cancer. PMID- 26969577 TI - Carotid atherosclerosis progression and cerebrovascular events in patients with diabetes. AB - AIM: Carotid atherosclerosis progression is associated with a higher risk of cerebrovascular events but there is no specific data for diabetes. We assessed in a cohort of patients with diabetes the rate of atherosclerosis progression by Doppler ultrasonography and the association with cerebrovascular events. METHODS: We analyzed a retrospective cohort of 342 patients with a mean duration of diabetes of 13.6 +/- 10.6 years. The mean delay between the first and last Doppler ultrasonography was 6.4 +/- 4.6 years, with a mean of 3.4 examinations per person. Cerebrovascular events were noted. RESULTS: A progression of carotid atherosclerosis was observed in 20.1% of cases. No factor was significantly associated with progression. A prophylactic carotid endarterectomy was performed on 6 of the 27 patients with a stenosis >=50%. A cerebrovascular event occurred in 1.2% of patients; none of them had carotid atherosclerosis progression. CONCLUSIONS: Carotid atherosclerosis progression in patients with diabetes is frequent but surgical treatment and cerebrovascular events are low. The benefit of a systematic follow-up of carotid atherosclerosis seems limited. PMID- 26969579 TI - Enzymes in therapy of biofilm-related oral diseases. AB - Biofilm-related infections of the oral cavity, including dental caries and periodontitis, represent the most prevalent health problems. For years, the treatment thereof was largely based on antibacterial chemical agents. Recently, however, there has been growing interest in the application of more preventive and minimally invasive biotechnological methods. This review focuses on the potential applications of enzymes in the treatment and prevention of oral diseases. Dental plaque is a microbial community that develops on the tooth surface, embedded in a matrix of extracellular polymeric substances of bacterial and host origin. Both cariogenic microorganisms and the key components of oral biofilm matrix may be the targets of the enzymes. Oxidative salivary enzymes inhibit or limit the growth of oral pathogens, thereby supporting the natural host defense system; polysaccharide hydrolases (mutanases and dextranases) degrade important carbohydrate components of the biofilm matrix, whereas proteases disrupt bacterial adhesion to oral surfaces or affect cell-cell interactions. The efficiency of the enzymes in in vitro and in vivo studies, advantages and limitations, as well as future perspectives for improving the enzymatic strategy are discussed. PMID- 26969578 TI - Understanding Racial and Ethnic Disparities in Postsurgical Complications Occurring in U.S. Hospitals. AB - OBJECTIVE: To examine the role of patient, hospital, and community characteristics on racial and ethnic disparities in in-hospital postsurgical complications. DATA SOURCES: Healthcare Cost and Utilization Project, 2011 State Inpatient Databases; American Hospital Association Annual Survey of Hospitals; Area Health Resources Files; Centers for Medicare & Medicaid Services Hospital Compare database. METHODS: Nonlinear hierarchical modeling was conducted to examine the odds of patients experiencing any in-hospital postsurgical complication, as defined by Agency for Healthcare Research and Quality Patient Safety Indicators. PRINCIPAL FINDINGS: A total of 5,474,067 inpatient surgical discharges were assessed using multivariable logistic regression. Clinical risk, payer coverage, and community-level characteristics (especially income) completely attenuated the effect of race on the odds of postsurgical complications. Patients without private insurance were 30 to 50 percent more likely to have a complication; patients from low-income communities were nearly 12 percent more likely to experience a complication. Private, not-for-profit hospitals in small metropolitan or micropolitan areas and higher nurse-to-patient ratios led to fewer postsurgical complications. CONCLUSIONS: Race does not appear to be an important determinant of in-hospital postsurgical complications, but insurance and community characteristics have an effect. A population-based approach that includes improving the socioeconomic context may help reduce disparities in these outcomes. PMID- 26969580 TI - Interleukin-33: increasing role in dermatological conditions. AB - Interleukin-33 is a novel and an unconventional member of IL-1 family. It is an inflammation-induced factor with dual function exercising its role as an intracellular regulator of gene expression, as well as, an extracellular alarm mediator. It is a ligand for ST2, a heterodimeric membrane-bound receptor of the orphan IL-1 family receptor. Interleukin-33/ST2 signaling has been studied in a wide range of inflammatory skin conditions for its crucial role in immune responses and tissue homeostasis. In this review, we report the current knowledge regarding the complex biology of interleukin-33 and its function in the skin and in clinical settings. PMID- 26969581 TI - Attention training to pleasant stimuli in anxiety. AB - Attentional bias for threatening stimuli in anxiety is a common finding in the literature. The present study addressed whether attention training toward pleasant stimuli can reduce anxiety symptoms and induce a processing bias in favor of pleasant information in nonpatients who were selected to score similarly to individuals with generalized anxiety or panic disorder on a measure of worry or physiological arousal, respectively. Participants were randomly assigned to attention training to pleasant (ATP) stimuli or to a placebo control (PC) condition. All participants completed baseline and post-test dot-probe measures of attentional bias while event-related brain potentials were recorded. As expected, worry symptoms decreased in the ATP and not PC condition. ATP was also associated with early evidence (P100 amplitude) of greater attentional prioritization of probes replacing neutral stimuli within threat-neutral word pairs from pre-to-post intervention and later RT evidence of facilitated processing of probes replacing pleasant stimuli within pleasant-threat word pairs at post compared to PC. PC was associated with later evidence (P300 latency) of less efficient evaluation of probes following pleasant stimuli within pleasant threat word pairs from pre-to-post and later RT evidence of facilitated processing of probes following threat stimuli within pleasant-threat word pairs at post compared to ATP. Results highlight early and later mechanisms of attention processing changes and underscore the potential of pleasant stimuli in optimizing attention-training interventions for anxiety. PMID- 26969582 TI - Topical Retinoids: Therapeutic Mechanisms in the Treatment of Photodamaged Skin. AB - Retinoids are a group of substances comprising vitamin A and its natural and synthetic derivatives. Retinoids were first used in dermatology in 1943 by Straumfjord for acne vulgaris. Since that time, retinoids have been utilized in the management and treatment of various skin conditions, including photoaging. Photodamage of the skin occurs as a consequence of cumulative exposure to solar ultraviolet radiation (UVR) and is characterized by deep wrinkles, easy bruising, inelasticity, mottled pigmentation, roughness, and telangiectasias. The mechanism of UVR-induced photodamage is multifactorial. Retinoids have demonstrated efficacy in the treatment of photoaged skin. Indeed, understanding the pathophysiology of photoaging and the molecular mechanism of retinoids can not only provide insight into the effects retinoids can exert in treating photoaging but also provide the rationale for their use in the treatment of other dermatologic diseases. PMID- 26969583 TI - Screening for autism. PMID- 26969584 TI - Night-to-night variation of pulse oximetry in children with sleep-disordered breathing. AB - BACKGROUND: Sleep-disordered breathing is a common and serious feature of many paediatric conditions and is particularly a problem in children with Down syndrome. Overnight pulse oximetry is recommended as an initial screening test, but it is unclear how overnight oximetry results should be interpreted and how many nights should be recorded. METHODS: This retrospective observational study evaluated night-to-night variation using statistical measures of repeatability for 214 children referred to a paediatric respiratory clinic, who required overnight oximetry measurements. This included 30 children with Down syndrome. We measured length of adequate trace, basal SpO2, number of desaturations (>4% SpO2 drop for >10 s) per hour ('adjusted index') and time with SpO2<90%. We classified oximetry traces into normal or abnormal based on physiology. RESULTS: 132 out of 214 (62%) children had three technically adequate nights' oximetry, including 13 out of 30 (43%) children with Down syndrome. Intraclass correlation coefficient for adjusted index was 0.54 (95% CI 0.20 to 0.81) among children with Down syndrome and 0.88 (95% CI 0.84 to 0.91) for children with other diagnoses. Negative predictor value of a negative first night predicting two subsequent negative nights was 0.2 in children with Down syndrome and 0.55 in children with other diagnoses. CONCLUSIONS: There is substantial night-to-night variation in overnight oximetry readings among children in all clinical groups undergoing overnight oximetry. This is a more pronounced problem in children with Down syndrome. Increasing the number of attempted nights' recording from one to three provides useful additional clinical information. PMID- 26969585 TI - Development and evaluation of the efficacy of a web-based 'social norms' intervention for the prevention and reduction of substance use in a cluster controlled trial conducted at eight German universities. AB - BACKGROUND: Previous research suggests that perceptions of peer substance use are associated with personal use. Specifically, overestimating use in the peer group is predictive of higher rates of personal substance use. 'Social norms' interventions are based on the premise that changing these misperceived social norms regarding substance use by providing feedback on actual norms is associated with a reduction in personal substance use. Studies conducted in the U.S.A. suggest that 'social norms'-feedback is an effective strategy for reducing substance use among university students. It is unknown whether the effects of a 'social norms'-feedback on substance use can be replicated in a sample of German university students. The objective of this article is to describe the study design and aims of the 'INternet-based Social norms-Intervention for the prevention of substance use among Students' (INSIST)-study, a cluster-controlled trial examining the effects of a web-based 'social norms'- intervention in students enrolled at four intervention universities with those enrolled at four delayed intervention control universities. The INSIST-study is funded by the German Federal Ministry of Health. METHODS/DESIGN: Eight universities in four regions in Germany will take part in the study, four serving as intervention and four as delayed intervention control universities (randomly selected within a geographic region). Six hundred students will be recruited at each university and will be asked to complete a web-based survey assessing personal and perceived substance use/attitudes towards substance use at baseline. These data will be used to develop the web-based 'social norms'-feedback tailored to gender and university. Three months after the baseline survey, students at intervention universities will receive the intervention. Two months after the launch of the intervention, students of all eight universities will be asked to complete the follow-up questionnaires to assess changes in perceptions of/attitudes toward peer substance use and rates of personal substance use. DISCUSSION: This study is the first German cluster-controlled trial investigating the influence of a web based 'social norms'-intervention on perceptions of/attitudes towards substance use and substance use behavior in a large university student sample. This study will provide new information on the efficacy of this intervention strategy in the German university context. TRIAL REGISTRATION: DRKS00007635 at the 'German Clinical Trials Register' (17.12.2014). PMID- 26969586 TI - A safety assessment of Coriolus versicolor biomass as a food supplement. AB - BACKGROUND: Coriolus versicolor (CV) is a common mushroom with antitumor, anti inflammatory, antioxidant, antiviral, antibacterial, and immunomodulatory properties. The existence of these properties has been extensively proven mainly using CV extract; research on the biomass form is scarce. OBJECTIVE: The aim of this study was to investigate the safety of the CV biomass form, as it is commonly used as a food supplement. DESIGN: CV biomass powder was dissolved in distilled water and administered daily (2.5, 5.0, and 7.5 g/kg live weight) in single doses by gavage to both female and male Charles River albino rats. RESULTS: No adverse or lethal effects were observed as a consequence of the daily administration of CV biomass. In addition, compared with the control group, no abnormal findings were observed at necropsy and histopathological examination. CONCLUSIONS: A safe profile of CV biomass for human consumption can be inferred from the absence of any remarkable adverse effects in rats. PMID- 26969587 TI - Identification of key research needs for topical therapy treatment of psoriasis - a consensus paper by the International Psoriasis Council. AB - In this age of expanding choices of therapy for psoriasis, topical therapies still play an important part in the management of patients. There are many knowledge gaps in topical therapy for psoriasis with regard to efficacy and safety as well as various combinations including topical therapy with phototherapy or with systemic agents. Councillors of the International Psoriasis Council comprised a topical therapy working group to describe these gaps in order to help direct future research endeavours. Herein, we present the results of this analysis, discuss topical agents in clinical development and the attributes of the ideal topical treatment for psoriasis. PMID- 26969588 TI - Role of extracellular cysteine residues in the adenosine A2A receptor. AB - The G protein-coupled A2A adenosine receptor represents an important drug target. Crystal structures and modeling studies indicated that three disulfide bonds are formed between ECL1 and ECL2 (I, Cys71(2.69)-Cys159(45.43); II, Cys74(3.22) Cys146(45.30), and III, Cys77(3.25)-Cys166(45.50)). However, the A2BAR subtype appears to require only disulfide bond III for proper function. In this study, each of the three disulfide bonds in the A2AAR was disrupted by mutation of one of the cysteine residues to serine. The mutant receptors were stably expressed in Chinese hamster ovary cells and analyzed in cyclic adenosine monophosphate (cAMP) accumulation and radioligand binding studies using structurally diverse agonists: adenosine, NECA, CGS21680, and PSB-15826. Results were rationalized by molecular modeling. The observed effects were dependent on the investigated agonist. Loss of disulfide bond I led to a widening of the orthosteric binding pocket resulting in a strong reduction in the potency of adenosine, but not of NECA or 2 substituted nucleosides. Disruption of disulfide bond II led to a significant reduction in the agonists' efficacy indicating its importance for receptor activation. Disulfide bond III disruption reduced potency and affinity of the small adenosine agonists and NECA, but not of the larger 2-substituted agonists. While all the three disulfide bonds were essential for high potency or efficacy of adenosine, structural modification of the nucleoside could rescue affinity or efficacy at the mutant receptors. At present, it cannot be excluded that formation of the extracellular disulfide bonds in the A2AAR is dynamic. This might add another level of G protein-coupled receptor (GPCR) modulation, in particular for the cysteine-rich A2A and A2BARs. PMID- 26969589 TI - Optimization of aeration for biodiesel production by Scenedesmus obliquus grown in municipal wastewater. AB - Despite the significant breakthroughs in research on microalgae as a feedstock for biodiesel, its production cost is still much higher than that of fossil diesel. One possible solution to overcome this problem is to optimize algal growth and lipid production in wastewater. The present study examines the optimization of pretreatment of municipal wastewater and aeration conditions in order to enhance the lipid productivity of Scenedesmus obliquus. Results showed that no significant differences were recorded in lipid productivity of S. obliquus grown in primary settled or sterilized municipal wastewater; however, ultrasound pretreatment of wastewater significantly decreased the lipid production. Whereas, aeration rates of 0.2 vvm significantly increased lipid content by 51 %, with respect to the non-aerated culture, which resulted in maximum lipid productivity (32.5 mg L(-1) day(-1)). Furthermore, aeration enrichment by 2 % CO2 resulted in increase of lipid productivity by 46 % over the CO2 non-enriched aerated culture. Fatty acid profile showed that optimized aeration significantly enhanced monounsaturated fatty acid production, composed mainly of C18:1, by 1.8 times over the non-aerated S. obliquus culture with insignificant changes in polyunsaturated fatty acid proportion; suggesting better biodiesel characteristics for the optimized culture. PMID- 26969592 TI - Influence of Silica Nanoparticles on Antioxidant Potential of Bacillus subtilis IMV B-7023. AB - It was found that if introduced into a nutrient medium of 0.05-1 g/L nano-SiO2, the oxidant activity (OA) of the culture medium (CM) of bacilli increased by 43.2 60.1 % and the antioxidant activity (AA) decreased by 4.5-11.8 %. SiO2 nanoparticles had different effects on antiradical activity (ARA) of the CM of Bacillus subtilis IMV B-7023. In particular, nano-SiO2 had no significant effect on the ability of the CM of bacilli to inactivate the 2.2-diphenyl-1 picrylhydrazyl (DPPH.) free radical. However, for the content of the nanomaterial of 0.01-1 g/L decreased hydroxyl radical scavenging in the CM of B. subtilis IMV B-7023 on 7.2-17.6 % compared with a control. Low doses of silica nanoparticles stimulated the reducing power of the CM of bacteria and then highly suppressed it. PMID- 26969591 TI - CdSe/ZnS Quantum Dot-Labeled Lateral Flow Strips for Rapid and Quantitative Detection of Gastric Cancer Carbohydrate Antigen 72-4. AB - Carbohydrate antigen 72-4 (CA72-4) is an important biomarker associated closely with diagnosis and prognosis of early gastric cancer. How to realize quick, sensitive, specific, and quantitative detection of CA72-4 in clinical specimens has become a great requirement. Herein, we reported a CdSe/ZnS quantum dot labeled lateral flow test strip combined with a charge-coupled device (CCD)-based reader was developed for rapid, sensitive, and quantitative detection of CA72-4. Two mouse monoclonal antibodies (mAbs) against CA72-4 were employed. One of them was coated as a test line, while another mAb was labeled with quantum dots and coated onto conjugate pad. The goat anti-mouse IgG was immobilized as a control line. After sample was added, a sandwich structure was formed with CA72-4 and these two mAbs. The fluorescent signal from quantum dots (QD)-labeled mAb in sandwich structure was related to the amount of detected CA72-4. A CCD-based reader was used to realize quantitative detection of CA72-4. Results showed that developed QD-labeled lateral flow strips to detect CA72-4 biomarker with the sensitivity of 2 IU/mL and 10 min detection time. One hundred sera samples from clinical patients with gastric cancer and healthy people were used to confirm specificity of this strip method; results showed that established strip method own 100 % reproducibility and 100 % specificity compared with Roche electrochemiluminescence assay results. In conclusion, CdSe/ZnS quantum dot labeled lateral flow strips for detection of CA72-4 could realize rapid, sensitive, and specific detection of clinical samples and could own great potential in clinical translation in near future. PMID- 26969593 TI - Synthesis, Characterization, and Photocatalytic Properties of Sulfur- and Carbon Codoped TiO2 Nanoparticles. AB - One-step TiO2 nanoparticle synthesis based on the interaction between thiourea and metatitanic acid is applied for sulfur and carbon anatase codoping. The synthesis of the doped TiO2 has been monitored by means of differential thermal analysis and thermogravimetric analysis (DTA-TG), which allows determining the optimal thermal conditions for the process. Electron microscopy showed micrometer sized (5-15 MUm) randomly distributed crystal aggregates, consisting of many 15 40-nm TiO2 nanoparticles. The obtained phase composition and chemical states of the doping elements are analyzed by means of X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), infrared (IR) and Raman spectroscopies, and electron paramagnetic resonance (EPR). XRD displays in both samples (doped and pristine) the existence of only one crystalline phase-the tetragonal modification of TiO2-anatase. Further data assessment by means of Rietveld refinement allowed detection of a slight c lattice parameter and volume increase related to incorporation of the doping elements. XPS demonstrated the presence of carbon and sulfur as doping elements in the material. It was confirmed that carbon is in elemental form and also present in oxygen-containing compounds, which are adsorbed on the particle surface. The binding energy for sulfur electron core shell corresponds to the established data for sulfate compounds, where sulfur is in 6+ oxidation state. The synthesized S- and C-codoped TiO2 showed excellent photocatalytic performance during the degradation of organic dyes (rhodamine B, methylene blue), gas-phase oxidation of ethanol under visible light, and photocatalytic hydrogen generation from ethanol under ultraviolet light. PMID- 26969594 TI - Synthesis, Characterization, and Microwave Absorption Properties of Reduced Graphene Oxide/Strontium Ferrite/Polyaniline Nanocomposites. AB - Strontium ferrite nanoparticles were prepared by a coprecipitation method, and reduced graphene oxide/strontium ferrite/polyaniline (R-GO/SF/PANI) ternary nanocomposites were prepared by in situ polymerization method. The morphology, structure, and magnetic properties of the ternary nanocomposites were investigated by X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), TEM, Raman, and VSM. The microwave-absorbing properties of the composites were measured by a vector network analyzer. The XRD patterns show the single phase of strontium hexaferrite without other intermediate phases. TEM photographs reveal that strontium ferrite nanoparticles are uniformly dispersed on the surfaces of R-GO sheets. The R-GO/SF/PANI nanocomposite exhibited the best absorption property with the optimum matching thickness of 1.5 mm in the frequency of 2-18 GHz. The value of the maximum RL was -45.00 dB at 16.08 GHz with the 5.48-GHz bandwidth. The excellent absorption properties of R-GO/SF/PANI nanocomposites indicated their great potential as microwave-absorbing materials. PMID- 26969590 TI - The Metabolism, Analysis, and Targeting of Steroid Hormones in Breast and Prostate Cancer. AB - Breast and prostate cancers are malignancies in which steroid hormones drive cellular proliferation. Over the past century, this understanding has led to successful treatment strategies aimed to inhibit hormone-mediated tumor growth. Nonetheless, disease relapse and progression still pose significant clinical problems, with recurrent and metastatic tumors often exhibiting resistance to current drug therapies. The central role of androgens and estrogens in prostate and breast cancer etiology explains not only why endocrine therapies are often initially successful but also why many tumors ultimately become resistant. It is hypothesized that reducing the concentration of active hormones in the systemic circulation may be insufficient to block cancer progression, as this action selects for tumor cells that can generate active steroids from circulating precursors. This review aims to highlight the currently known differences of steroid biosynthesis in normal physiology versus hormone-dependent cancers, modern approaches to the assessment and targeting of these pathways, and priorities for future research. PMID- 26969595 TI - Versatile, Reusable, and Inexpensive Ultrasound Phantom Procedural Trainers. AB - We have constructed simple and inexpensive models for ultrasound-guided procedural training using synthetic ballistic gelatin. These models are durable, leak resistant, and able to be shaped to fit a variety of simulation scenarios to teach procedures. They provide realistic tactile and sonographic training for our learners in a safe, idealized setting. PMID- 26969597 TI - Predictors of Malignancy in Hyperechoic Breast Lesions. AB - OBJECTIVES: Hyperechogenicity has been strongly associated with benign breast lesions. Although it is correct in most cases, hyperechogenicity must not always be considered synonymous with benignancy, as hyperechoic breast cancers do occur. The purpose of this study was to review clinical and imaging characteristics of hyperechoic breast lesions, looking for features associated with malignancy. METHODS: Institutional Review Board approval was granted for this research. A total of 19,417 sonographic examinations were performed between January 2009 and June 2013. Among these, hyperechoic lesions with histologic diagnoses, stability on long-term followup, or characteristic imaging appearances were included in the study. The patients' clinical charts, mammograms, and sonograms were reviewed. The clinical and imaging features were recorded, and the data was analyzed by the chi(2) test, Fisher exact test, and independent-samples t test, looking for statistically significant predictors of malignancy. RESULTS: Among the 19,417 scans, 42 patients (0.2%) with 44 hyperechoic lesions were identified. Twenty-six lesions fulfilling the inclusion criteria were included in the study: 5 malignancies (3 invasive ductal carcinomas, 1 invasive lobular carcinoma, and 1 invasive mucinous cancer) and 21 benign lesions. An irregular shape, a nonparallel orientation, and noncircumscribed margins were significantly associated with the risk of malignancy (P = .002, .02, and .01, respectively). CONCLUSIONS: A hyperechoic breast lesion must not always be assumed to be benign. Instead, a full sonographic assessment according to the American College of Radiology Breast Imaging Reporting and Data System descriptors is needed for correct characterization and avoidance of misdiagnosis. PMID- 26969596 TI - Quantitative Evaluation for Differentiating Malignant and Benign Thyroid Nodules Using Histogram Analysis of Grayscale Sonograms. AB - OBJECTIVES: To evaluate the diagnostic value of histogram analysis using grayscale sonograms for differentiation of malignant and benign thyroid nodules. METHODS: From July 2013 through October 2013, 579 nodules in 563 patients who had undergone ultrasound-guided fine-needle aspiration were included. For the grayscale histogram analysis, pixel echogenicity values in regions of interest were measured as 0 to 255 (0, black; 255, white) with in-house software. Five parameters (mean, skewness, kurtosis, standard deviation, and entropy) were obtained for each thyroid nodule. With principal component analysis, an index was derived. Diagnostic performance rates for the 5 histogram parameters and the principal component analysis index were calculated. RESULTS: A total of 563 patients were included in the study (mean age +/- SD, 50.3 +/- 12.3 years;range, 15-79 years). Of the 579 nodules, 431 were benign, and 148 were malignant. Among the 5 parameters and the principal component analysis index, the standard deviation (75.546 +/- 14.153 versus 62.761 +/- 16.01; P < .001), kurtosis (3.898 +/- 2.652 versus 6.251 +/- 9.102; P < .001), entropy (0.16 +/- 0.135 versus 0.239 +/- 0.185; P < .001), and principal component analysis index (-0.386+/-0.774 versus 0.134 +/- 0.889; P < .001) were significantly different between the malignant and benign nodules. With the calculated cutoff values, the areas under the curve were 0.681 (95% confidence interval, 0.643-0.721) for standard deviation, 0.661 (0.620-0.703) for principal component analysis index, 0.651 (0.607-0.691) for kurtosis, 0.638 (0.596-0.681) for entropy, and 0.606 (0.563 0.647) for skewness. The subjective analysis of grayscale sonograms by radiologists alone showed an area under the curve of 0.861 (0.833-0.888). CONCLUSIONS: Grayscale histogram analysis was feasible for differentiating malignant and benign thyroid nodules but did not show better diagnostic performance than subjective analysis performed by radiologists. Further technical advances will be needed to objectify interpretations of thyroid grayscale sonograms. PMID- 26969598 TI - Color Doppler Sonographic and Cadaveric Study of the Arterial Vascularity of the Lateral Upper Arm Flap. AB - OBJECTIVES: To determine the importance of adequate preoperative assessment with color Doppler sonography to assist in the successful transfer of lateral upper arm flaps by studying the lateral upper arm flap with color Doppler sonography and analyzing the anatomic features of the radial collateral artery. METHODS: A clinical case-control study was performed. The radial collateral artery was studied with color Doppler sonography in 15 healthy volunteers. The origins, courses, variations, and locations of the perforators of the radial collateral artery were recorded. The results and data from the color Doppler sonographic investigation were compared with an anatomic study that was performed on 22 adult cadaveric upper limb specimens. RESULTS: The volunteer group (14 of 15 volunteers) and the cadaveric group (19 of 22 upper arm specimens) clearly showed that the branch pattern of the arterial supply was as follows: brachial artery -> deep brachial artery -> radial collateral artery -> posterior radial collateral artery -> myocutaneous perforator. Variations in the origin of the radial collateral artery were identified in 1 volunteer bilaterally and in 3 upper arm specimens. The diameters of the artery and vein measured at the distal insertion of the deltoid and the origin of the deep brachial artery were not significantly different between the volunteer and cadaver groups (P > .05). Due to the difference in measuring methods, the length of the vascular pedicles was significantly different between the groups (P < .05). CONCLUSIONS: Color Doppler sonography can facilitate the preoperative assessment of the origin, course, variations, and locations of the radial collateral artery and therefore may increase the success rate of lateral upper arm flap transfer. PMID- 26969599 TI - Fetal Cardiac Screening: What Are We (and Our Guidelines) Doing Wrong? PMID- 26969600 TI - A IHE-Like Approach Method for Quantitative Analysis of PACS Usage. AB - Today, many hospitals have a running enterprise picture archiving and communication system (PACS) and their administrators should have the tools to measure the system activity and, in particular, how much it is used. The information would be valuable for decision-makers to address asset management and the development of policies for its correct utilization and eventually start training initiatives to get the best in resource utilization and operators' satisfaction. On the economic side, a quantitative method to measure the usage of the workstations would be desirable to better redistribute existing resources and plan the purchase of new ones. The paper exploits in an unconventional way the potential of the IHE Audit Trail and Node Authentication (ATNA) profile: it uses the data generated in order to safeguard the security of patient data and to retrieve information about the workload of each PACS workstation. The method uses the traces recorded, according to the profile, for each access to image data and to calculate how much each station is used. The results, constituted by measures of the frequency of PACS station usage suitably classified and presented according to a convenient format for decision-makers, are encouraging. In the time of the spending review, the careful management of available resources is the top priority for a healthcare organization. Thanks to our work, a common medium such as the ATNA profile appears a very useful resource for purposes other than those for which it was born. This avoids additional investments in management tools and allows optimization of resources at no cost. PMID- 26969602 TI - RETRACTED ARTICLE: MiR-124 Functions as a Tumor Suppressor via Targeting hCLOCK1 in Glioblastoma. PMID- 26969603 TI - Investigating the role of aspirin resistance in obstetrics may optimise prevention of pre-eclampsia. PMID- 26969601 TI - A Point Mutation in SCN1A 5' Genomic Region Decreases the Promoter Activity and Is Associated with Mild Epilepsy and Seizure Aggravation Induced by Antiepileptic Drug. AB - The SCN1A gene with 1274 point mutations in the coding regions or genomic rearrangements is the most clinically relevant epilepsy gene. Recent studies have demonstrated that variations in the noncoding regions are potentially associated with epilepsies, but no distinct mutation has been reported. We sequenced the 5' upstream region of SCN1A in 166 patients with epilepsy and febrile seizures who were negative for point mutations in the coding regions or genomic rearrangements. A heterozygous mutation h1u-1962 T > G was identified in a patient with partial epilepsy and febrile seizures, which was aggravated by oxcarbazepine. This mutation was transmitted from the patient's asymptomatic mother and not found in the 110 normal controls. h1u-1962 T > G was located upstream the most frequently used noncoding exon and within the promoter sequences. Further experiments showed that this mutation decreased the promoter activity by 42.1 % compared with that of the paired haplotype (P < 0.001). In contrast to the null expression that results in haploinsufficiency and severe phenotype, this mutation caused relatively less impairment, explaining the mild epilepsy with incomplete penetrance. The antiepileptic drug-induced seizure aggravation in this patient suggests clinical attention for mutations or variations in noncoding regions that may affect SCN1A expression. PMID- 26969604 TI - Resazurin-based 96-well plate microdilution method for the determination of minimum inhibitory concentration of biosurfactants. AB - OBJECTIVES: To develop and validate a microdilution method for measuring the minimum inhibitory concentration (MIC) of biosurfactants. RESULTS: A standardized microdilution method including resazurin dye has been developed for measuring the MIC of biosurfactants and its validity was established through the replication of tetracycline and gentamicin MIC determination with standard bacterial strains. CONCLUSION: This new method allows the generation of accurate MIC measurements, whilst overcoming critical issues related to colour and solubility which may interfere with growth measurements for many types of biosurfactant extracts. PMID- 26969605 TI - Cutaneous presentation of disseminated histoplasmosis as a solitary peri-anal ulcer. Case report and discussion. AB - Disseminated histoplasmosis has a diverse and non-specific range of clinical signs and symptoms. In a significant minority of patients, cutaneous lesions are apparent at the time of initial presentation, affording an opportunity to establish the diagnosis from a skin biopsy. The most frequently reported clinical scenario in immunocompromised patients with cutaneous involvement is that of multiple papulo-nodular lesions on the face, trunk or extremities. The following report features an immunocompetent patient who presented with a solitary ulcerated plaque on the buttocks close to the anal verge. This case presentation underscores the broad spectrum of clinical presentations as well as the potential for diagnostic confusion with protozoa such as Leishmania or Trypanosoma species during histopathologic examination if special stains for fungal organisms are not performed. PMID- 26969606 TI - Bleeding Risk Profile in Patients With Symptomatic Peripheral Artery Disease. AB - PURPOSE: To assess the bleeding risk profile using the HAS-BLED score in patients with symptomatic peripheral artery disease (PAD). METHODS: A post hoc analysis was performed using data from a series of 115 consecutive patients (mean age 72.4+/-11.4 years; 68 men) with symptomatic PAD undergoing endovascular revascularization. The endpoint of the study was to assess bleeding risk using the 9-point HAS-BLED score, which was previously validated in cohorts of patients with and without atrial fibrillation. For the purpose of this study, the low (0 1), intermediate (2), and high-risk (>=3) scores were stratified as low/intermediate risk (HAS-BLED <3) vs high risk (HAS-BLED >=3). RESULTS: The mean HAS-BLED score was 2.76+/-1.16; 64 (56%) patients had a HAS-BLED score >=3.0. Patients with PAD Rutherford category 5/6 ischemia had an even higher mean HAS-BLED score (3.20+/-1.12). Logistic regression analysis revealed aortoiliac or femoropopliteal segment involvement, chronic kidney disease, as well as Rutherford category 5/6, to be independent risk factors associated with a HAS BLED score >=3. CONCLUSION: Patients with PAD, especially those presenting with Rutherford category 5/6 ischemic symptoms, have high HAS-BLED scores, suggesting increased risk for major bleeding. Prospective clinical validation of the HAS BLED score in patients with PAD may help with the risk-benefit assessment when prescribing antithrombotic therapy. PMID- 26969608 TI - Detection of HLA-DRB1*04:207, a novel HLA-DRB1*04 variant, in a Taiwanese hematopoietic stem cell donor. AB - Recombination may result in the formation of HLA-DRB1*04:207. PMID- 26969607 TI - Increased oxidative stress in patients with severe disability: Association with nutrition. AB - BACKGROUND: Previous studies have described a role of oxidative stress in the pathogenesis of various pediatric disorders, but investigation into oxidative stress status in patients with severe disability remains limited. The aim of the present study was therefore to clarify the oxidative stress status in patients with severe disability, focusing specifically on intake of three major nutrients and micronutrients with antioxidant activities. METHODS: Thirty-one patients with severe disability (mean age, 14.1 +/- 7.8 years) were enrolled. Three in vivo biomarkers, plasma biological antioxidant potential (BAP), plasma reactive oxygen metabolite-derived compounds (d-ROM), and urinary 8-hydroxydeoxyguanosine (8 OHdG), were determined for evaluating oxidative status. The dietary intake of three major nutrients and various micronutrients was estimated from dietary records over a 3 day period. RESULTS: In patients with severe disability, BAP was significantly lower and d-ROM and 8-OHdG significantly higher than in historical controls. Among these markers, a significant positive correlation was found in BAP versus d-ROM and d-ROM versus 8-OHdG. On multiple regression analysis, a significant inverse association between 8-OHdG and carotenoid intake was seen. CONCLUSION: The oxidative/antioxidative balance shifts towards oxidative status dominance in patients with severe disability. More research is needed on nutritional intake of antioxidative nutrients to determine whether they can be used to reduce oxidative stress. PMID- 26969609 TI - Use of cadA-Specific Primers and DNA Probes as Tools to Select Cadmium Biosorbents with Potential in Remediation Strategies. AB - Biosorption, using cadmium-resistant bacterial isolates, is often regarded as a relatively inexpensive and efficient way of cleaning up wastes, sediments, or soils polluted with cadmium. Therefore, many efforts have been devoted to the isolation of cadmium-resistant isolates for the efficient management of cadmium remediation processes. However, isolation, identification and in situ screening of efficient cadmium-resistant isolates are primary challenges. To overcome these challanges, in this study, cadA, cadmium resistance coding gene, specific primers and DNA probes were used to identify and screen cadmium-resistant bacteria in the cadmium-polluted river waters through polymerase chain reaction (PCR) and fluorescein in situ hybridization (FISH). PCR amplification of the cadA amplicon coupled with 16S rRNA sequencing revealed various gram-positive and -negative bacterial isolates harboring cadA. Accordingly, a cadA-mediated DNA probe was prepared and used for in situ screening of cadmium-resistant isolates from water samples collected from cadmium-polluted river waters. The FISH analyses of cadA probe showed highly specific and efficient hybridization with cadA harboring isolates. The use of primers and DNA probes specific for cadA gene seems to be very helpful tools for the selection and screening of cadmium biosorbents with potential to be used in the remediation of cadmium-polluted sites. PMID- 26969610 TI - Molecular mechanisms of membrane interaction at implantation. AB - Successful pregnancy is dependent upon the implantation of a competent embryo into a receptive endometrium. Despite major advancement in our understanding of reproductive medicine over the last few decades, implantation failure still occurs in both normal pregnancies and those created artificially by assisted reproductive technology (ART). Consequently, there is significant interest in elucidating the etiology of implantation failure. The complex multistep process of implantation begins when the developing embryo first makes contact with the plasma membrane of epithelial cells within the uterine environment. However, although this biological interaction marks the beginning of a fundamental developmental process, our knowledge of the intricate physiological and molecular processes involved remains sparse. In this synopsis, we aim to provide an overview of our current understanding of the morphological changes which occur to the plasma membrane of the uterine endothelium, and the molecular mechanisms that control communication between the early embryo and the endometrium during implantation. A multitude of molecular factors have been implicated in this complex process, including endometrial integrins, extracellular matrix molecules, adhesion molecules, growth factors, and ion channels. We also explore the development of in vitro models for embryo implantation to help researchers investigate mechanisms which may underlie implantation failure. Understanding the precise molecular pathways associated with implantation failure could help us to generate new prognostic/diagnostic biomarkers, and may identify novel therapeutic targets. PMID- 26969611 TI - Real-time free-breathing cardiac imaging with self-calibrated through-time radial GRAPPA. AB - PURPOSE: Real-time free-breathing cardiac imaging with highly undersampled radial trajectories has previously been successfully demonstrated using calibrated radial generalized autocalibrating partially parallel acquisition (rGRAPPA). A self-calibrated approach for rGRAPPA is proposed that removes the need for the calibration prescan. METHODS: To investigate the effect of various parameters on image quality, a comprehensive imaging study on one normal swine was performed. Root mean squared errors (RMSEs) were computed with respect to gold standard acquisitions, and several acquisition/reconstruction strategies were compared. Additionally, the method was tested on 13 human subjects, and RMSEs relative to standard through-time radial GRAPPA were computed. RESULTS: Real-time images with high spatiotemporal resolution were obtained. Image quality was comparable to calibrated through-time rGRAPPA with endocardial and epicardial borders clearly delineated. In the swine, the average RMSE between self-calibrated and gold standard calibrated images was 5.18 +/- 0.84%. In normal human subjects, the average RMSE between self-calibrated and calibrated through-time rGRAPPA was 3.79 +/- 0.64%. For lower accelerations rates (R = 6-8) image quality was similar to comparable calibrated scans though RMSE increased for higher degrees of undersampling (R = 12-16). CONCLUSION: Highly accelerated real-time imaging with undersampled radial trajectories without additional calibration data is feasible. Image quality was acceptable for real-time cardiac MRI applications demanding high speed. Magn Reson Med 77:250-264, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26969613 TI - Natural killer cells, ageing and cancer. AB - Natural killer (NK) cells are key components of innate immunity and substantially contribute to anti-tumor immune responses. The role of NK cells in immune surveillance is linked to many aspects of NK cell biology, but the age of the animal being studied or the human under treatment is rarely taken into account. The solicited reviews constituting a collection of papers presented here as a "Symposium-in-Writing" on the topic of NK cells, ageing and cancer were inspired by the increasing knowledge of NK cell biology and genetics, and emerging data on their impact in the clinic (disease associations and therapies), together with the realization that older individuals also differ from younger ones regarding innate as well as adaptive immunity. PMID- 26969612 TI - The tumor antigen N-glycolyl-GM3 is a human CD1d ligand capable of mediating B cell and natural killer T cell interaction. AB - The expression of N-glycolyl-monosialodihexosyl-ganglioside (NGcGM3) in humans is restricted to cancer cells; therefore, it is a tumor antigen. There are measurable quantities of circulating anti-NGcGM3 antibodies (aNGcGM3 Abs) in human serum. Interestingly, some people have circulating Ag-specific immunoglobulins G (IgGs) that are capable of complement mediated cytotoxicity against NGcGM3 positive cells, which is relevant for tumor surveillance. In light of the chemical nature of Ag, we postulated it as a candidate ligand for CD1d. Furthermore, we hypothesize that the immune mechanism involved in the generation of these Abs entails cross talk between B lymphocytes (Bc) and invariant natural killer T cells (iNKT). Combining cellular techniques, such as flow cytometry and biochemical assays, we demonstrated that CD1d binds to NGcGM3 and that human Bc present NGcGM3 in a CD1d context according to two alternative strategies. We also showed that paraformaldehyde treatment of cells expressing CD1d affects the presentation. Finally, by co-culturing primary human Bc with iNKT and measuring Ki-67 expression, we detected a reproducible increment in the proliferation of the iNKT population when Ag was on the medium. Our findings identify a novel, endogenous, human CD1d ligand, which is sufficiently competent to stimulate iNKT. We postulate that CD1d-restricted Bc presentation of NGcGM3 drives effective iNKT activation, an immunological mechanism that has not been previously described for humans, which may contribute to understanding aNGcGM3 occurrence. PMID- 26969614 TI - Dietary Profiles of First-Generation South Asian Indian Adolescents in the United States. AB - This study aimed to describe the dietary profile and health characteristics of first-generation South Asian Indian (SAI) adolescents in the United States because SAIs have a high prevalence of cardiovascular disease and diabetes, and dietary risk factors for those diseases begin in youth. A descriptive cross sectional design was used to examine age, gender, usual dietary intake, body composition, blood pressure, blood glucose, and length of residency among 56 first-generation, urban SAI adolescents. Intake of saturated fat exceeded recommendations for all participants, and potassium, magnesium, calcium, vitamin D, and fiber intakes were insufficient in nearly all. Sodium intake exceeded recommendations for most males. Cholesterol intake and sweets consumption was lower among those who lived in the U.S. longer. There were no associations of dietary patterns with health characteristics. Dietary patterns that may increase future disease risk included high saturated fats and low potassium, magnesium, calcium, vitamin D, and fiber. PMID- 26969615 TI - Modeling the Influence of Early Skin-to-Skin Contact on Exclusive Breastfeeding in a Sample of Hispanic Immigrant Women. AB - Using data from a longitudinal study of breastfeeding in Hispanics, this study evaluated the influence of early skin-to-skin contact (SSC) on initiation and sustained exclusive breastfeeding (EBF) at 1 month postpartum. Two-thirds of the women in the sample participated in early SSC. At discharge, over half of the women were EBF; this proportion decreased to one-third at 1 month postpartum. Controlling for demographic and clinical variables in the model, participation in early SSC was associated with a greater than sevenfold increase in the odds of EBF at discharge (p = .005) but was not predictive of EBF at 1 month post discharge (p = .7). Younger maternal age and increased prenatal infant feeding intention were associated with an increased likelihood of EBF across both timepoints. Promoting early SSC may help with initiation of EBF, while further breastfeeding support may be needed to maintain EBF following discharge for this vulnerable population. PMID- 26969616 TI - Total monitoring of the constituents of Danshen tablet using micellar electrokinetic chromatography fingerprinting for antioxidant activity profiling. AB - A micellar electrokinetic chromatography fingerprint coupled with quantification was developed for assessing the quality consistency of Danshen tablets, a traditional Chinese medicine, with pharmacological activities of activating blood to remove blood stasis and regulating the flow of vital energy to alleviate pain. Square optimization method was proposed to select the suitable background electrolyte. Subsequently, the index of chromatographic fingerprints F was simultaneously employed as an objective function to evaluate capillary electrophoresis conditions. After that, the method was proved to meet the fingerprint analysis criteria by evaluating stability, linearity, limit of detection, limit of quantification, precision, accuracy, and repeatability. Moreover, systematic quantified fingerprint method was used to evaluate chromatographic fingerprints of 30 batches of samples in terms of both quality and quantitation. The result indicated that the chemical compositions of samples were basically similar while their contents showed marked variation. In addition, the fingerprint-efficacy relationship was established using partial least squares model, which can serve as anti-oxidant activity evaluation of Danshen tablets as well as a reference for the selection of active constituents. The proposed method can be applied for the holistic quality control of Danshen tablets. PMID- 26969618 TI - Psychological treatments for depression in pre-adolescent children (12 years and younger): systematic review and meta-analysis of randomised controlled trials. AB - The objective of this study was to evaluate the efficacy of psychological treatments for depression in pre-adolescent children, a disorder affecting 1-2 % of children in this age range. A systematic review of studies of psychological interventions to treat depressive disorder in pre-adolescent children (aged up to 12-years-old) was carried out. The primary outcome was level of depressive symptoms. Studies were found using Medline, PsycINFO, EMBASE and Web of Knowledge databases and selected on several criteria. Only randomised controlled trials were included. Where individual studies covered a broader age range (usually including adolescents up to age 18 years), authors of those studies were contacted and requested to provide individual patient level data for those aged 12 years and younger. 2822 abstracts were reviewed, and from these 124 full text articles were reviewed, yielding 7 studies for which we were able to access appropriate data for this review. 5 of these studies evaluated cognitive behaviour therapy (CBT). Combined results from these studies suggest that there is a lack of evidence that CBT is better than no treatment [standard mean difference -0.342 (95 % confidence interval -0.961, 0.278)], although the number of participants included in the trials was relatively small. The evidence for efficacy of family therapy and psychodynamic therapy is even more limited. The very limited number of participants in randomised controlled trials means that there is inconclusive evidence for the psychological treatment of depression in children aged 12 years and below. Given the prevalence and significant impact of this disorder, there is an urgent need to establish the effectiveness or otherwise of psychological intervention. PMID- 26969617 TI - Parent-of-origin effects on genome-wide DNA methylation in the Cape honey bee (Apis mellifera capensis) may be confounded by allele-specific methylation. AB - BACKGROUND: Intersexual genomic conflict sometimes leads to unequal expression of paternal and maternal alleles in offspring, resulting in parent-of-origin effects. In honey bees reciprocal crosses can show strong parent-of-origin effects, supporting theoretical predictions that genomic imprinting occurs in this species. Mechanisms behind imprinting in honey bees are unclear but differential DNA methylation in eggs and sperm suggests that DNA methylation could be involved. Nonetheless, because DNA methylation is multifunctional, it is difficult to separate imprinting from other roles of methylation. Here we use a novel approach to investigate parent-of-origin DNA methylation in honey bees. In the subspecies Apis mellifera capensis, reproduction of females occurs either sexually by fertilization of eggs with sperm, or via thelytokous parthenogenesis, producing female embryos derived from two maternal genomes. RESULTS: We compared genome-wide methylation patterns of sexually-produced, diploid embryos laid by a queen, with parthenogenetically-produced diploid embryos laid by her daughters. Thelytokous embryos inheriting two maternal genomes had fewer hypermethylated genes compared to fertilized embryos, supporting the prediction that fertilized embryos have increased methylation due to inheritance of a paternal genome. However, bisulfite PCR and sequencing of a differentially methylated gene, Stan (GB18207) showed strong allele-specific methylation that was maintained in both fertilized and thelytokous embryos. For this gene, methylation was associated with haplotype, not parent of origin. CONCLUSIONS: The results of our study are consistent with predictions from the kin theory of genomic imprinting. However, our demonstration of allele-specific methylation based on sequence shows that genome-wide differential methylation studies can potentially confound imprinting and allele-specific methylation. It further suggests that methylation patterns are heritable or that specific sequence motifs are targets for methylation in some genes. PMID- 26969619 TI - "I have to live like I'm old." Young adults' perspectives on managing hypertension: a multi-center qualitative study. AB - BACKGROUND: In the U.S., young adults (18-39 year-olds) have the lowest hypertension control rates among hypertensive adults. Understanding young adults' unique perceptions about hypertension and perceived barriers to hypertension control is critical to develop effective interventions for this population. This multi-center study explored young adults': 1) emotions and reactions after a hypertension diagnosis, 2) attitudes about managing hypertension (lifestyle changes, follow-up visits, antihypertensive medication use), 3) opinions about their healthcare system's hypertension education materials, and 4) opinions about using social media to manage hypertension. METHODS: Young adults (18-39 year olds) with a diagnosis of hypertension and regular primary care access were recruited by the Wisconsin Research and Education Network (WREN). Two focus groups (one per age range: 18-29 years, 30-39 years) were conducted in three Midwestern Family Medicine Clinics (academic, rural, and urban). Conventional content analysis was performed. RESULTS: Thirty-eight young adults (mean: 26.7 [9.6] years old, 34% male, 45% Black, 42% with >=1 year of college) identified barriers to managing hypertension. Emergent themes overlapped across age groups and geographic regions. Most respondents were surprised and angry about a hypertension diagnosis; they expected to develop hypertension, but at a much older age. A hypertension diagnosis negatively altered their "young" self identity; suggested behavior changes and antihypertensive medications made them feel "older" than their peers. Young adults missed blood pressure follow-up visits due to co-payments, transportation barriers, and longer than desired wait times for brief visits. Contrary to our hypothesis, most young adults disliked social media or text messaging to support self-management; they were most concerned that their peers would see the hypertension communication. Current hypertension education materials were described as not addressing young adults' health questions and are often discarded before leaving the clinic. CONCLUSIONS: Targeting interventions to young adults' unique needs is necessary to improve hypertension control and cardiovascular preventive healthcare delivery. PMID- 26969621 TI - Intracerebroventricular administration of chondroitinase ABC reduces acute edema after traumatic brain injury in mice. AB - BACKGROUND: Brain edema is a significant challenge facing clinicians managing severe traumatic brain injury (TBI) in the acute period. If edema reaches a critical point, it leads to runaway intracranial hypertension that, in turn, leads to severe morbidity or death if left untreated. Clinical data on the efficacy of standard interventions is mixed. The goal of this study was to validate a novel therapeutic strategy for reducing post-traumatic brain edema in a mouse model. Prior in vitro work reported that the brain swells due to coupled electrostatic and osmotic forces generated by large, negatively charged, immobile molecules in the matrix that comprises brain tissue. Chondroitinase ABC (ChABC) digests chondroitin sulfate proteoglycan, a molecule that contributes to this negative charge. Therefore, we administered ChABC by intracerebroventricular (ICV) injection after controlled cortical impact TBI in the mouse and measured associated changes in edema. RESULTS: Almost half of the edema induced by injury was eliminated by ChABC treatment. CONCLUSIONS: ICV administration of ChABC may be a novel and effective method of treating post-traumatic brain edema in the acute period. PMID- 26969620 TI - Pretreatment oral hygiene habits and survival of head and neck squamous cell carcinoma (HNSCC) patients. AB - BACKGROUND: The survival time of patients with head and neck squamous cell carcinoma (HNSCC) is related to health behavior, such as tobacco smoking and alcohol consumption. Poor oral health (OH), dental care (DC) and the frequent use of mouthwash have been shown to represent independent risk factors for head and neck cancerogenesis, but their impact on the survival of HNSCC patients has not been systematically investigated. METHODS: Two hundred seventy-six incident HNSCC cases recruited for the ARCAGE study were followed through a period of 6-10 years. Interview-based information on wearing of dentures, gum bleeding, teeth brushing, use of floss and dentist visits were grouped into weighted composite scores, i.e. oral health (OH) and dental care (DH). Use of mouthwash was assessed as frequency per day. Also obtained were other types of health behavior, such as smoking, alcohol drinking and diet, appreciated as both confounding and study variables. Endpoints were progression-free survival, overall survival and tumor specific survival. Prognostic values were estimated using Kaplan-Meier analysis and Cox proportional hazards regression models. RESULTS: A good dental care score, summarizing annual dental visits, daily teeth cleaning and use of floss was associated with longer overall survival time (p = .001). The results of the Cox regression models similarly suggested a higher risk of tumor progression and shortened overall survival in patients with poor dental care, but the results lost their statistical significance after other types of health behavior had been controlled for. Frequent use of mouthwash (>= 2 times/day) significantly increased the risk of tumor-specific death (HR = 2.26; CI = 1.19-4.32). Alcohol consumption and tobacco smoking were dose-dependently associated with tumor progression and shorter overall survival. CONCLUSION: Frequent mouthwash use of >= 2 times/day seems to elevate the risk of tumor-specific death in HNSCC patients. Good dental care scores are associated with longer overall survival. PMID- 26969622 TI - Patient information and emotional needs across the hip osteoarthritis continuum: a qualitative study. AB - BACKGROUND: Osteoarthritis (OA) is the most common form of arthritis worldwide, affecting a growing number of people in the ageing populations. Currently, it affects about 50 % of all people over 65 years of age. There are no disease modifying treatments for OA; hence preference-sensitive treatment options include symptom reduction, self-management and surgical joint replacement for suitable individuals. People have both ethical and legal rights to be informed about treatment choices and to actively participate in decision-making. Individuals have different needs; they differ in their ability to understand and make use of the provided information and to sustain behaviour change-dependent treatments over time. METHODS: As a part of a larger research project that aims to develop and test a web-based support tool for patients with hip OA, this paper is a qualitative in-depth study to investigate patients' need for information and their personal emotional needs. We invited 13 patients to participate in individual interviews, which were audiotaped. The audio-tapes were transcribed verbatim and analysed using an inductive thematic analysis approach. RESULTS: The thematic analysis revealed a pattern of patients' information and emotional needs, captured in several key questions relevant to the different stages of the disease experience. Based on these results and research literature, we developed a model illustrating the patients' disease experience and treatment continuum. Six phases with accompanying key questions were identified, displaying how patients information and emotional needs arise and change in line with the progression of the disease experience, the clinical encounters and the decision making process. We also identified and included in the model an alternative route that bypasses the surgical treatment option. CONCLUSION: Patients with hip OA are in great need of information both at the time of diagnosis and further throughout the disease development and care continuum. Lack of information may result in unnecessary and dysfunctional misconceptions, underuse of potentially helpful treatment options and uninformed decisions. Patients need continuous support from health professionals and their families in order to find and consider effective treatment strategies. PMID- 26969623 TI - Genetic diversity of Plasmodium falciparum isolates from concurrent malaria and arbovirus co-infections in Kedougou, southeastern Senegal. AB - BACKGROUND: Concurrent malaria and arbovirus infections are common and represent an important public health concern in regions where both diseases are endemic. The present study investigates the genetic diversity and complexity of Plasmodium falciparum infection in concurrent malaria-arbovirus infections in Kedougou region, southeastern Senegal. METHODS: Parasite DNA was extracted from 60 to 27 sera samples collected from P. falciparum isolates of malaria and concurrent malaria-arbovirus infected patients, respectively, and followed by PCR-genotyping targeting the msp-1 (block2) and msp-2 (block3) allelic families. RESULTS: The mean number of genotype per allelic family was comparable between the two groups. K1 was the predominant msp-1 allelic type both in malaria (94.91%) and arbovirus malaria (92.59%) groups, whereas IC/3D7 was the most prevalent msp-2 allelic type in malaria (94.91%) and arbovirus-malaria (96.29%) groups. Frequencies of msp-1 and msp-2 allelic types were statistically comparable between the two groups (Fisher exact test, P > 0.05) and were not associated with age. FC27 was strikingly the least prevalent in both groups and was absent in children under 5 years of age. The proportions of P. falciparum isolates from malaria-infected patients carrying the three msp-1 allelic types (67.44%) or the two msp-2 allelic types (76.47%) were significantly higher than those from arbovirus-malaria co infected patients (Exact binomial test, P < 0.05). The multiplicities of infection (MOI) were low and comparable for msp-1 (1.19 vs 1.22) and msp-2 (1.11 vs 1.10), respectively between malaria and arbovirus-malaria groups. CONCLUSION: The study showed no difference in the genetic diversity between P. falciparum isolates from malaria and concurrent malaria-arbovirus infected patients in Kedougou. The MOI was low despite intense malaria transmission in Kedougou. The overall results suggest a limited or no influence of arbovirus infections on P. falciparum diversity and complexity of malaria infection. PMID- 26969624 TI - Genetic diversity and population genetics of the warble flies Hypoderma bovis and H. sinense in Qinghai Province, China. AB - BACKGROUND: Hypoderma bovis and H. sinense (Diptera: Oestridae) mainly parasitise cattle and yaks. The two parasites are pathogenic and cause economic losses that result from reduced amounts of livestock products, including milk, meat, and skin. Genetic diversity and population genetic structure of H. bovis and H. sinense have not been evaluated, but could be used to inform appropriate strategies to control these parasites. METHODS: We cloned and sequenced part of the mitochondrial cytochrome c oxidase subunit I (COI) gene from 60 H. bovis isolates and 52 H. sinense isolates from five locations in Qinghai Province, China, to identify polymorphisms, and infer their phylogenetic relationships, historical population expansions, and divergence time. RESULTS: We identified 17 COI haplotypes from the H. bovis samples, and 23 COI haplotypes from the H. sinense samples. The haplotype and nucleotide diversities were 0.738 and 0.00202 for H. bovis, and 0.867 and 0.00300 for H. sinense, respectively, which indicates rich genetic diversity in H. bovis and H. sinense populations. Bayesian phylogenetic analysis revealed that the two species are monophyletic, and geographical structuring of haplotypes was significantly different in H. sinense (P < 0.05), but not H. bovis. Neutrality tests and mismatch distribution statistical analysis revealed that populations of the two species have undergone demographic expansions. The divergence three Hypoderma spp. (H. bovis, H. lineatum, and H. sinense) was estimated to have occurred approximately 4.5 million years ago (Mya), which indicates that the rapid uplift of the Qinghai Tibetan Plateau during the late Miocene-Pliocene was associated with divergence of Hypoderma species. CONCLUSIONS: Results of the present study revealed that both H. bovis and H. sinense displayed high genetic diversity and widespread population genetic differentiation within and among populations; these data, along with the molecular phylogeny, demographic history, and divergence time estimation, provide new insight into evolutionary history of these species. These findings will help elucidate speciation in Hypoderma and provide theoretical basis for epidemiological surveillance and control of these species on the Qinghai-Tibetan Plateau. PMID- 26969625 TI - Prognostic value of microRNA-21 in pancreatic ductal adenocarcinoma: a meta analysis. AB - BACKGROUND: Recently, microRNA-21 (miR-21) has been reported to be associated with prognosis of pancreatic ductal adenocarcinoma (PDAC). The present studies aimed to evaluate the prognostic value of miR-21 for PDAC with meta-analysis. METHODS: A systematic search in the PubMed and other databases was conducted to identify eligible studies. The pooled hazard ratios (HRs) with 95% confidence interval (CI) were calculated. The meta-analysis was conducted using the STATA 12.0 software. RESULTS: A total of 12 articles (13 studies) which included 963 cases were selected for the meta-analysis. Elevated miR-21 expression was significantly predictive of poor overall survival (HR = 2.05, 95% CI 1.71-2.46, P < 0.001). In the subgroup analyses, similar results were observed in Asian (HR = 2.09, 95% CI 1.62-2.71, P < 0.001) and Caucasian (HR = 2.36, 95% CI 1.53-3.65, P < 0.001); in tissue sample (HR = 2.14, 95% CI 1.73-2.65, P < 0.001) and serum sample (HR = 1.84, 95% CI 1.30-2.60, P = 0.001); with quantitative real-time polymerase chain reaction assay method (HR = 2.31, 95% CI 1.86-2.86, P < 0.001); and in patients receiving adjuvant chemotherapy (HR = 2.37, 95% CI 1.88-3.00, P < 0.001). The association between miR-21 expression level and lymph node metastasis was statistically significant (OR = 1.45, 95% CI 1.02-2.06, P = 0.038). However, no significant relationship between miR-21 expression level and sex or vascular invasion or neural infiltration was observed (P > 0.05). CONCLUSIONS: Our meta analysis indicated that elevated miR-21 expression level can predict poor prognosis in patients with PDAC. PMID- 26969626 TI - Language Evolution: Constraints and Opportunities From Modern Genetics. AB - Our understanding of language, its origins and subsequent evolution (including language change), is shaped not only by data and theories from the language sciences, but also fundamentally by the biological sciences. Recent developments in genetics and evolutionary theory offer both very strong constraints on what scenarios of language evolution are possible and probable, but also offer exciting opportunities for understanding otherwise puzzling phenomena. Due to the intrinsic breathtaking rate of advancement in these fields, and the complexity, subtlety, and sometimes apparent non-intuitiveness of the phenomena discovered, some of these recent developments have either being completely missed by language scientists or misperceived and misrepresented. In this short paper, we offer an update on some of these findings and theoretical developments through a selection of illustrative examples and discussions that cast new light on current debates in the language sciences. The main message of our paper is that life is much more complex and nuanced than anybody could have predicted even a few decades ago, and that we need to be flexible in our theorizing instead of embracing a priori dogmas and trying to patch paradigms that are no longer satisfactory. PMID- 26969627 TI - Fibrinogen levels in trauma patients during the first seven days after fibrinogen concentrate therapy: a retrospective study. AB - BACKGROUND: Fibrinogen concentrate (FC) is increasingly used as first line therapy in bleeding trauma patients. It remains unproven whether FC application increases post-traumatic plasma fibrinogen concentration (FIB) in injured patients, possibly constituting a prothrombotic risk. Thus, we investigated the evolution of FIB following trauma in patients with or without FC therapy. METHODS: At the AUVA Trauma Centre, Salzburg, we performed a retrospective study of patients admitted to the emergency room and whose FIB levels were documented thereafter up to day 7 post-trauma. Patients were categorized into those with (treatment group) or without (control group) FC therapy during the first 24 h after hospital admission. A subgroup analysis was carried out to investigate the influence of the amount of FC given. RESULTS: The study enrolled 435 patients: treatment group, n = 242 (56 %); control group, n = 193 (44%), with median Injury Severity Score of 34 vs. 22 (P < 0.001) and massive transfusion rate of 18.4% vs. 0.2% (P < 0.001). In the treatment group (median FC dose 6 g), FIB was lower on admission and up to day 2 compared with the control group. In patients receiving high (>=10 g) doses of FC, FIB was lower up to day 5 as compared to controls. At other timepoints, FIB did not differ significantly between the groups. In the treatment vs. the control group, other coagulation parameters such as prothrombin time index and platelet count were consistently lower, while activated partial thromboplastin time was consistently prolonged at most timepoints. Inflammatory parameters such as C-reactive protein, interleukin-6 and procalcitonin were generally lower in controls. DISCUSSION: The rise of FIB levels from day 2 onwards in our study can be attributed to an upregulated fibrinogen synthesis in the liver, occurring in both study groups as part of the acute phase response after tissue injury. CONCLUSIONS: The treatment of severe trauma patients with FC during bleeding management in the first 24 h after hospital admission does not lead to higher FIB levels post-trauma beyond that occurring naturally due to the acute phase response. PMID- 26969629 TI - Sex and Genotype Differences in Odor Detection in the 3*Tg-AD and 5XFAD Mouse Models of Alzheimer's Disease at 6 Months of Age. AB - Deficits in odor identification and detection are early symptoms of Alzheimer's disease (AD). Two transgenic mouse models of AD, the 5XFAD and the 3*Tg-AD mice and their wildtype controls, were assessed for olfactory detection with decreasing concentrations of ethyl acetate in a go no-go operant olfactometer task at 6 months of age. For both the 5XFAD and their B6SJLF1 wildtype littermates, females made fewer errors in detecting the ethyl acetate than males on all but the lowest odor concentrations. Female 5XFAD mice performed slightly better than their female wildtype littermates on the higher odor concentrations, though not at the lowest concentration. The 3*Tg-AD females showed decreased olfactory detection compared with their wildtype B6129S1 controls, whereas there was no difference in the males. Therefore, although the 5XFAD mice showed no olfactory detection deficits, female 3*Tg-AD mice had impaired olfactory detection at low odor concentrations but males did not. This difference in odor detection should be considered in studies of olfactory learning and memory, as differences in performance may be due to sensory rather than cognitive factors, though detection seems unimpaired at high odor concentrations. PMID- 26969628 TI - A systematic review of the characteristics and validity of monitoring technologies to assess Parkinson's disease. AB - BACKGROUND: There is growing interest in having objective assessment of health related outcomes using technology-based devices that provide unbiased measurements which can be used in clinical practice and scientific research. Many studies have investigated the clinical manifestations of Parkinson's disease using such devices. However, clinimetric properties and clinical validation vary among the different devices. METHODS: Given such heterogeneity, we sought to perform a systematic review in order to (i) list, (ii) compare and (iii) classify technological-based devices used to measure motor function in individuals with Parkinson's disease into three groups, namely wearable, non-wearable and hybrid devices. A systematic literature search of the PubMed database resulted in the inclusion of 168 studies. These studies were grouped based on the type of device used. For each device we reviewed availability, use, reliability, validity, and sensitivity to change. The devices were then classified as (i) 'recommended', (ii) 'suggested' or (iii) 'listed' based on the following criteria: (1) used in the assessment of Parkinson's disease (yes/no), (2) used in published studies by people other than the developers (yes/no), and (3) successful clinimetric testing (yes/no). RESULTS: Seventy-three devices were identified, 22 were wearable, 38 were non-wearable, and 13 were hybrid devices. In accordance with our classification method, 9 devices were 'recommended', 34 devices were 'suggested', and 30 devices were classified as 'listed'. Within the wearable devices group, the Mobility Lab sensors from Ambulatory Parkinson's Disease Monitoring (APDM), Physilog(r), StepWatch 3, TriTrac RT3 Triaxial accelerometer, McRoberts DynaPort, and Axivity (AX3) were classified as 'recommended'. Within the non-wearable devices group, the Nintendo Wii Balance Board and GAITRite(r) gait analysis system were classified as 'recommended'. Within the hybrid devices group only the Kinesia(r) system was classified as 'recommended'. PMID- 26969630 TI - Olfactory Responses of Southern House Mosquito, Culex quinquefasciatus, to Human Odorants. AB - Mosquito control is essential to protect humans from mosquito-borne diseases. The host recognition between mosquitoes and humans is achieved by the mosquito olfactory system. Antennal sensilla, which house olfactory receptor neurons, are responsible for detecting chemical cues from hosts. To deepen our understanding of the mechanisms involved in the host seeking behavior of mosquitoes, we conducted an electrophysiological study to investigate the response profile of each type of antennal sensilla to human odorants using single sensillum recording. In this study, more than 100 human odorants have been applied as stimuli to 5 morphological types of sensilla, long sharp trichoid (LST), short sharp trichoid (SST), short blunt trichoid I (SBTI), short blunt trichoid II (SBTII), and grooved peg (GP). Different types of sensilla present distinctive response profiles to the human odorants tested. In particular, SST, SBTI, and SBTII sensilla responded to more than 1 category of human odorants, while GP and LST were narrowly tuned to amines and methyl nonanoate, respectively. The dose dependent patterns and odorant-specific/chemical structure-specific temporal dynamics of SBTI and SBTII antennal sensilla to human odorants had been further detected. Taken together, our study provides the new information on the olfactory physiology of Culex quinquefasciatus (Diptera: Culicidae) to human odorants, leading to a better understanding of mosquito-host recognition and being important for future development of new reagents in the mosquito control. PMID- 26969632 TI - The promise of electronic health records in economic analyses: a peek inside the black box. PMID- 26969631 TI - Effects of a transitional palliative care model on patients with end-stage heart failure: a randomised controlled trial. AB - OBJECTIVE: To examine the effects of home-based transitional palliative care for patients with end-stage heart failure (ESHF) after hospital discharge. METHODS: This was a randomised controlled trial conducted in three hospitals in Hong Kong. The recruited subjects were patients with ESHF who had been discharged home from hospitals and referred for palliative service, and who met the specified inclusion criteria. The interventions consisted of weekly home visits/telephone calls in the first 4 weeks then monthly follow-up, provided by a nurse case manager supported by a multidisciplinary team. The primary outcome measures were any readmission and count of readmissions within 4 and 12 weeks after index discharge, compared using chi(2) tests and Poisson regression, respectively. Secondarily, change in symptoms over time between control and intervention groups were evaluated using generalised estimating equation analyses of data collected using the Edmonton Symptom Assessment Scale (ESAS). RESULTS: The intervention group (n=43) had a significantly lower readmission rate than the control group (n=41) at 12 weeks (intervention 33.6% vs control 61.0% chi(2)=6.8, p=0.009). The mean number (SE) of readmissions for the intervention and control groups was, respectively, 0.42 (0.10) and 1.10 (0.16) and the difference was significant (p=0.001). The relative risk (CI) for 12-week readmissions for the intervention group was 0.55 (0.35 to 0.88). There was no significant difference in readmissions between groups at 4 weeks. However, when compared with the control group, the intervention group experienced significantly higher clinical improvement in depression (45.9% vs 16.1%, p<0.05), dyspnoea (62.2% vs 29.0%, p<0.05) and total ESAS score (73.0% vs 41.4%, p<0.05) at 4 weeks. There were significant differences between groups in changes over time in quality of life (QOL) measured by McGill QOL (p<0.05) and chronic HF (p<0.01) questionnaires. CONCLUSIONS: This study provides evidence of the effectiveness of a postdischarge transitional care palliative programme in reducing readmissions and improving symptom control among patients with ESHF. TRIAL REGISTRATION NUMBER: HKCTR-1562; Results. PMID- 26969633 TI - Significance of apical cavity obliteration in apical hypertrophic cardiomyopathy. AB - OBJECTIVE: Apical hypertrophic cardiomyopathy (HCM) is characterised by apical systolic obliteration and is associated with atrial fibrillation (AF), stroke, heart failure (HF), and mortality. We investigated whether apical obliteration of the left ventricular (LV) cavity could have an unfavourable impact on the clinical course of apical HCM. METHODS: 188 patients with apical HCM (114 males, median age 67 years) were identified retrospectively from January 2008 to December 2010. The rate of apical obliteration was defined as the net obliteration to end-diastolic apical cap thickness, and the ratio of obliteration to cavity was defined as the end-systolic obliteration to cavity height. Events were defined as a composite of new onset of AF, stroke, HF, and cardiovascular (CV) death. RESULTS: There were 43 clinical events (19 AFs, 11 HFs, 9 strokes, and 4 deaths) during a follow-up of median 4.4 years. The events patients were older, had larger left atrial volume index (LAVI), lower late diastolic mitral annular tissue Doppler velocity (a'), and higher LV end-diastolic pressure (E/e'). They had greater apical thickness and obliteration, smaller systolic cavity height, higher rate of obliteration, and higher ratio of obliteration to cavity; events were significantly higher (54%) in the upper tertiles of the ratio of obliteration to cavity. Age, E/e', a', LAVI, apical thickness, rate of obliteration, and ratio of obliteration to cavity were associated with events. On multivariable analysis, the ratio of obliteration to cavity remained a significant predictor. CONCLUSIONS: The ratio of obliteration to cavity could provide useful information to predict the occurrence of adverse events in apical HCM. PMID- 26969634 TI - The Association Between Built Environment Attributes and Physical Activity in East Asian Adolescents: A Systematic Review. AB - Asian adolescents living in Australia and England were found to be less active than their Western peers. We aimed to systematically examine evidence of the associations between attributes of the built environment and physical activity in adolescents dwelling in East Asian countries. A total of 10 electronic databases for relevant observational studies without time limit were searched. Five studies met the eligibility criteria, which involved a total of 43 817 schoolchildren aged 11 to 17 years. The majority of the built environment attributes measured was significantly associated with reported physical activity. Difficult access to public facilities was associated with physical inactivity. Inconsistent finding of the association between residential density and physical activity was found. Further studies comparing participants from different Asian countries using a longitudinal design with an appropriate period of follow-up and both objective and reported measures of built environment attributes and physical activity are needed. PMID- 26969635 TI - Gender Issues and Public Health. PMID- 26969636 TI - Estimating Suicide Rates in Developing Nations: A Low-Cost Newspaper Capture Recapture Approach in Cambodia. AB - This study tested a low-cost method for estimating suicide rates in developing nations that lack adequate statistics. Data comprised reported suicides from Cambodia's 2 largest newspapers. Capture-recapture modeling estimated a suicide rate of 3.8/100 000 (95% CI = 2.5-6.7) for 2012. That compares to World Health Organization estimates of 1.3 to 9.4/100 000 and a Cambodian government estimate of 3.5/100 000. Suicide rates of males were twice that of females, and rates of those <40 years were twice that of those >=40 years. Capture-recapture modeling with newspaper reports proved a reasonable method for estimating suicide rates for countries with inadequate official data. These methods are low-cost and can be applied to regions with at least 2 newspapers with overlapping reports. Means to further improve this approach are discussed. These methods are applicable to both recent and historical data, which can benefit epidemiological work, and may also be applicable to homicides and other statistics. PMID- 26969637 TI - The Effects of Social Reforms on Mental Disability in China: Population-Based Study. AB - Few studies have explored how mental disabilities have changed with the waves of Chinese social reforms that occurred between 1912 and 2006. The present study evaluated population-based data from the Second China National Sample Survey on Disability to investigate these trends and their effects on mental disabilities. The Cox proportional hazards model was used to estimate the association between social reforms and mental disabilities. The confounding variables considered were as follows: survey age, gender, residence in 2006, ethnicity, and living arrangements in 2006. The highest risks of mental disabilities were observed in subjects born during the Mao Zedong era. Subjects who experienced social turbulence during their early development may have increased risks of mental disabilities in adulthood. The results and discussion herein contribute to our understanding of mental disabilities in China within the context of changing political, socioeconomic, and health system conditions and a developing mental health system. PMID- 26969638 TI - "Back to Basics" Approach for Improving Maternal Health Care Services Utilization in Lao PDR. AB - Earlier studies claim inadequate knowledge and understanding of maternal health care service among women and families account for low demand and utilization of these services. This study explores maternal service utilization in Lao PDR by interviewing women, families, health service providers, and community members in Xiengkhuang province. In general, women's attitude and acceptance of maternal health care were positive, with many expressing appreciation and need for maternal health services. Nevertheless, utilization of maternal health services remained poor largely due to dissatisfaction with services: inaccessibility, irregular services, fund shortage, poor facilities, and problems dealing with male health service providers. It appears that utilization of maternal health care services in Lao PDR is as much a health system concern as it is a user preference issue. This article advocates a "back to basics" approach for reviewing maternal health care infrastructure systems in developing countries to improve community health services and utilization. PMID- 26969639 TI - Wave Upon Wave: Fiji's Experiments in Decentralizing Its Health Care System. AB - Decentralization in the health sector has been widely implemented since the 1970s as a reform mechanism with mixed results. This study describes Fiji's 2 attempts at decentralizing its health sector and examines the implications they have had for the functions of planning, financing, and delivery of health services. The first wave attempted a major restructure by devolving Fiji's health system. Political instability, along with a lack of acceptance, stalled its implementation resulting in a delegated system. While the functions of planning and financing remained centralized, the function of delivery was delegated to geographic regions. The second wave was a more focused effort that targeted the deconcentration of outpatient services in one division. This attempt also decentralized the delivery function while keeping the other 2 functions centralized. Fiji's incremental approach to decentralization could provide lessons for Asia-Pacific countries that have had failed attempts in large scale decentralization efforts. PMID- 26969640 TI - Quantification of perflutren microsphere contrast destruction during transit through an ex vivo extracorporeal membrane oxygenation circuit. AB - BACKGROUND: Echocardiography is a key investigation in the management of patients on extracorporeal membrane oxygenation (ECMO). However, echocardiographic images are often non-diagnostic in this patient population. Contrast-enhanced echocardiography may overcome many of these limitations but contrast microspheres are hydrodynamically labile structures prone to destruction from shear forces and turbulent flow, which may exist within an ECMO circuit. This study sought to evaluate microsphere destruction (utilising signal intensity as a marker of contrast concentration) during transit through an ECMO circuit. METHODS: Activated Definity(r) contrast was diluted to 50 ml with normal saline and infused into a crystalloid primed ex vivo ECMO with a Quadrox oxygenator at 150 ml/h. Imaging was performed on pre- and post-pump head/oxygenator sections of the circuit using a Philips iE33 scanner and S5-1 transducer. Five-millimetre regions of interest were placed in the centre of the ultrasound field. Average signal intensity (decibels) was calculated at speeds of 1000, 2000, 3000 and 4000 rpm and then repeated with an infusion rate of 300 ml/h. The oxygenator was then spliced out of the circuit and the measures repeated. RESULTS: There was a significant reduction in contrast concentration during passage through the ECMO circuit at all speeds (with higher pump head speeds resulting in greater microsphere destruction). In a circuit with an oxygenator, relative decrease in signal intensity was 21.4 versus 5.2 % without an oxygenator. There was significant destruction of contrast microspheres during passage through the ECMO circuit at all pump head speeds. An oxygenator contributed to microsphere destruction at a significantly greater level than the pump head alone. There was no significant difference in mean signal intensity reduction in the circuit between an infusion of 150 or 300 ml/h (3.5 +/- 3.2 versus 3.6 +/- 2.5 dB, respectively, p = 0.79). CONCLUSIONS: Flow of contrast through an ECMO circuit results in significant destruction of microspheres. Circuits with an oxygenator result in significantly greater levels of contrast destruction than by the pump head alone. Clinicians should be cognisant of the relationship between ECMO circuit configurations, pump head speed and contrast destruction when performing a contrast-enhanced echocardiogram in patients supported with ECMO. PMID- 26969641 TI - The effects of shifting tasks from pharmacy to non-pharmacy personnel for providing antiretroviral therapy to people living with HIV: a systematic review protocol. AB - INTRODUCTION: Shifting selected antiretroviral therapy (ART) tasks from specialised healthcare workers to those with shorter or less formal training has been implemented in resource-limited settings to alleviate critical shortages of human resources for health. However, the specifics of shifting ART dispensing from pharmacy to non-pharmacy personnel have not been addressed in a systematic review, although this can potentially increase access to ART. We will assess the effects of shifting dispensing and distribution of ART and adherence assessment from pharmacy to non-pharmacy personnel in low and middle-income countries. METHODS AND ANALYSIS: We will search PubMed, CENTRAL, EMBASE, WHO Global Health Library and relevant grey literature for eligible controlled trials. Two authors will screen the search output, select eligible studies, assess risk of bias and extract data from included studies, resolving discrepancies by discussion and consensus. We will perform meta-analysis using both fixed and random effects models, investigate clinical and statistical heterogeneity, and assess our confidence in the overall evidence using standard Cochrane methods, including GRADE. ETHICS AND DISSEMINATION: Only secondary data will be included in this review and ethics approval is not required. We will disseminate the review findings in various scientific fora, including peer-reviewed journals. The findings may help to inform policy makers in defining the scope of work of healthcare workers, and global recommendations for shifting the dispensing and distribution of ART from pharmacy to non-pharmacy personnel. TRIAL REGISTRATION NUMBER: CRD42015017034. PMID- 26969642 TI - Role of students' context in predicting academic performance at a medical school: a retrospective cohort study. AB - OBJECTIVES: This study examines associations between medical students' background characteristics (postcode-based measures of disadvantage, high school attended, sociodemographic characteristics), and academic achievement at a Russell Group University. DESIGN: Retrospective cohort analysis. SETTING: Applicants accepted at the University of Liverpool medical school between 2004 and 2006, finalising their studies between 2010 and 2011. PARTICIPANTS: 571 students (with an English home postcode) registered on the full-time Medicine and Surgery programme, who successfully completed their medical degree. MAIN OUTCOME MEASURES: Final average at year 4 of the medical programme (represented as a percentage). RESULTS: Entry grades were positively associated with final attainment (p<0.001). Students from high-performing schools entered university with higher qualifications than students from low-performing schools (p<0.001), though these differences did not persist at university. Comprehensive school students entered university with higher grades than independent school students (p<0.01), and attained higher averages at university, though differences were not significant after controlling for multiple effects. Associations between school type and achievement differed between sexes. Females attained higher averages than males at university. Significant academic differences were observed between ethnic groups at entry level and university. Neither of the postcode-based measures of disadvantage predicted significant differences in attainment at school or university. CONCLUSIONS: The findings of this study suggest that educational attainment at school is a good, albeit imperfect, predictor of academic attainment at medical school. Most attainment differences observed between students either decreased or disappeared during university. Unlike previous studies, independent school students did not enter university with the highest grades, but achieved the lowest attainment at university. Such variations depict how patterns may differ between subjects and higher-education institutions. Findings advocate for further evidence to help guide the implementation of changes in admissions processes and widen participation at medical schools fairly. PMID- 26969646 TI - Is it too early for a major change? A critical objection to the freeze all policy. PMID- 26969644 TI - Associations of cigarette smoking, betel quid chewing and alcohol consumption with high-sensitivity C-reactive protein in early radiographic knee osteoarthritis: a cross-sectional study. AB - OBJECTIVES: High-sensitivity C-reactive protein (hsCRP) is possibly related to osteoarthritis (OA) progression and a variety of OA-related symptoms. This study aimed to examine associations between cigarette smoking, betel quid chewing and alcohol consumption and hsCRP in early radiographic knee OA. DESIGN: Cross sectional health examination survey. SETTING: This primary study was conducted in a health examination centre in China. PARTICIPANTS: 936 (656 men and 280 women) patients with early radiographic knee OA were included in this cross-sectional study. PRIMARY AND SECONDARY OUTCOME MEASURES: Smoking status was classified into four levels based on daily smoking habit: 0/day, 1-10/day, 11-20/day and >20/day. Betel quid chewing and alcohol consumption status was divided into 'Yes' or 'No'. Early radiographic knee OA was defined as Kellgren Lawrence (K-L) grade 1 or 2 in at least one leg, and elevated hsCRP was assessed as >= 3.0 mg/L. RESULTS: After adjustment for a number of potential confounding factors, a significant positive association between cigarette smoking and hsCRP was observed in the multivariable model. The multivariable-adjusted ORs (95% CI) of elevated hsCRP (>= 3.0 mg/L) in the second (1-10/day, n=133), third (11-20/day, n=59) and highest (>20/day, n=104) cigarette smoking categories were 1.54 (95% CI 0.91 to 2.61), 1.27 (95% CI 0.57 to 2.79) and 2.09 (95% CI 1.20 to 3.64), respectively, compared with the non smoker category (n=640). In addition, there was a positive dose-response relationship between cigarette smoking and elevated hsCRP (p for trend=0.01). No significant associations between betel quid chewing and alcohol consumption and hsCRP were observed in the multivariable model. CONCLUSIONS: This study indicated that cigarette smoking was positively associated with serum hsCRP level in patients with early radiographic knee OA. However, in view of the nature of cross sectional designs, the results need to be confirmed by further prospective studies. PMID- 26969645 TI - Is the peripapillary retinal perfusion related to myopia in healthy eyes? A prospective comparative study. AB - OBJECTIVES: The aim of this study was to evaluate the peripapillary and parafoveal perfusion of young, healthy myopic subjects with spectral domain optical coherence tomography (OCT) angiography. DESIGN: A prospective comparative study was conducted from December 2014 to January 2015. SETTING: Participants recruited from a population-based study performed by the Eye, Ear, Nose and Throat Hospital of Fudan University in Shanghai. PARTICIPANTS: A total of 78 Chinese normal subjects (78 eyes) with different refraction were included. Myopia was divided into 4 groups on the basis of the refractive status: 20 eyes with emmetropia (mean spherical equivalent (MSE) 0.50D to -0.50D), 20 eyes with mild myopia (MSE -0.75D to -2.75D), 20 eyes with moderate myopia (MSE -3.00D to 5.75D), and 18 eyes with high myopia (MSE<=-6.00D). MAIN OUTCOME MEASURES: Peripapillary and parafoveal retinal and choroidal perfusion parameters and their relationships with axial length (AL) and retinal nerve fibre layer (RNFL) thickness were analysed. RESULTS: Significant differences were found for the retinal flow index and vessel density in the peripapillary area among the 4 groups, but not in the parafoveal area. The high myopia group had the lowest peripapillary retinal flow index and vessel density. In addition, there was a negative correlation (beta=-0.002, p=0.047) between the AL and peripapillary retinal flow index and a positive correlation between RNFL thickness and the peripapillary retinal perfusion parameters (flow index: beta=0.001, p=0.006; vessel density: beta=0.350, p=0.002) even after adjustment for other variables. CONCLUSIONS: Highly myopic eyes have a decreased peripapillary retinal perfusion compared with emmetropic eyes. Such vascular features might increase the susceptibility to vascular-related eye diseases. PMID- 26969647 TI - Correlation of fetal scalp blood sampling pH with neonatal outcome umbilical artery pH value. AB - PURPOSE: Fetal scalp blood sampling is considered as a complimentary tool in addition to cardiotocography to assess fetal well-being. This blood sampling is important as the obstetrician has to judge and make decisions regarding the further management of the delivery based on this pH result. The aim of this study was to analyze the correlation between fetal scalp blood pH and the umbilical artery pH after birth. Furthermore, it was investigated whether tocolysis, a performed episiotomy or cord encirclement have an influence on the umbilical artery pH. METHODS: This retrospective study over a period of 11 years included all singleton pregnancies without fetal anomalies, which were monitored by fetal scalp blood sampling during labor. RESULTS: 844 out of 1502 deliveries were included for analysis. The analysis demonstrates a good correlation between fetal scalp pH value and outcome pH value. Subgroup analysis with fetal scalp blood pH <7.20 showed a difference in 40 of 82 cases, with an outcome pH value >=7.20, but this difference was statistically insignificant. Neither did tocolysis, episiotomy or the presence of cord encirclement show an overall effect, nor did they have an impact on the subgroup. CONCLUSION: Obstetricians must consider that the values of fetal scalp blood are not always reliable and can be false. However, on the basis of CTG and fetal scalp blood pH, decisions are made regarding delivery interventions. Therefore, we would encourage the consideration of taking two samples routinely at every attempt of fetal blood sampling. PMID- 26969648 TI - Pregnancy outcomes of blastocysts cultured overnight after thawing. AB - PURPOSE: To compare embryo quality and outcomes of blastocysts thawed and transferred the same day with those thawed and cultured overnight before transfer. METHODS: In this retrospective study, patients with infertility who underwent thawed embryo transfer (TET) the same day as thawing (0TET group) and those that received TET after embryos were thawed and cultured overnight before transfer (1TET group) were enrolled. Univariable and multivariable logistic regression were performed to detect the factors associated with the clinical pregnancy rate (CPR), implantation rate, miscarriage rate, and multiple pregnancy rate. RESULTS: A total of 489 patients (489 cycles) were included with 234 in the 0TET group and 255 in the 1TET group. There were no significant differences between the two groups with respect to age, body mass index (BMI), basal FSH and estradiol (E2) level, and causes of infertility (all, p > 0.05). There were no significant differences in the CPR, implantation rate, miscarriage rate, or multiple pregnancy rate between the two groups (all, p > 0.05), and this finding was irrespective of the endometrial preparation method. CONCLUSIONS: Pregnancy outcomes are the same for blastocysts thawed and cultured overnight 1 day before transfer and those thawed and transferred on the same day. PMID- 26969649 TI - Bakri balloon vs. B-Lynch suture as hemostatic procedures for atonic bleeding: clarification and concerns. PMID- 26969650 TI - Robotic assisted vs laparoscopic and/or open myomectomy: systematic review and meta-analysis of the clinical evidence. AB - INTRODUCTION: Uterine myomas are relative frequent in premenopausal women. The development of advanced minimally invasive surgical techniques proposed robotic assisted myomectomy as an equally safe and effective treatment option. METHODS: PubMed, Scopus and Cochrane databases were systematically searched and 15 studies met the inclusion criteria for our meta-analysis. RESULTS: Eight studies compared robotic technique to laparoscopic, while nine studies to open/abdominal technique. In total, 2,027 patients were included. In studies referring to the comparison between the robotic myomectomy and the open one, the robotic technique showed a significant inferiority in operative time [84.85 min per operation (95 % confidence intervals (CI) 60.41-109.29)], but superiority in estimated blood loss [92.78 ml/operation (95 % CI 47.26-138.29)], the need for transfusion [981 patients; odd ratio (OR) 0.20; 95 % CI 0.09-0.43], total complications (1101 patients; OR 0.31; 95 % CI 0.11-0.87) and in the length of hospital stay [1.84 days/patient (95 % CI 1.40-2.29)] over the open myomectomy. CONCLUSION: Regarding the comparison between robotic assisted and laparoscopic technique, no significant difference was found between the two in comparison groups. Minimally invasive techniques have the advantage of less blood loss, less need for blood transfusion and less hospital stay. Additionally, long-term outcomes still need to be clarified including pain control, fertility and pregnancy rates postoperatively, as well as possible recurrence rates. PMID- 26969651 TI - Gender-based workplace assessment in gynecology and obstetrics in Germany: results from the iCEPT Study. AB - PURPOSE: In the field of gynecology and obstetrics, studies exploring the workplace situation are important. We conducted this study with the overall aim to assess the subjective perception of working conditions of OB/GYNs in German hospitals. Since gender ratios are changing among German physicians in general and among OB/GYNs in particular, a special focus was put on gender-based differences. METHODS: This study uses data from the iCEPT Study (n = 7090). From this database, data from physicians working in the field of gynecology and obstetrics (n = 381) were analyzed. The iCEPT questionnaire was based upon established questionnaires. RESULTS: 92.1 % (95 % CI 89.2-95.3) of respondents stated to be often under time pressure and 89.8 % (95 % CI 87.6-93.3) stated frequent disturbances during work time. Women felt significantly more often under time pressure than men (OR = 2.73; 95 % CI 1.25-5.92; p = 0.009). Moreover, only about every third respondent stated to be in control of his or her work. Feedback about their work was received by 27.6 % (95 % CI 23.4-32.1) of respondents. However, male physicians got significantly more often feedback with an odds ratio of OR = 2.03 (95 % CI 1.21-3.41; p = 0.007). In regard to job satisfaction, about one in two (55.1 %; 95 % CI 50.4-60.2) stated to be satisfied with his or her job. However, men seemed more often satisfied than women with an OR = 1.98 (95 % CI 1.18-3.32; p = 0.009). No significant gender difference was seen in the analysis of the social climate and the social support. CONCLUSIONS: It is important to be aware of the documented gender differences regarding perception of working conditions. In order to sustain the gender diversity in the specialty of OB/GYNs these differences should be resolved. Special attention should be drawn to the improvement of job demands and control of employees. PMID- 26969652 TI - Development and validation of an objective structured assessment of technical skill tool for the practice of breech presentation delivery. AB - OBJECTIVE: To develop and test the validity of an Objective Structured Assessment of Technical Skills (OSATS) tool for breech presentation delivery. MATERIALS AND METHODS: Monocentric prospective study conducted in the Department of Gynecology, Obstetrics, Fetal Medicine and Reproductive Medicine at the University Hospital of Nice. The study consisted of two parts, the development of the OSATS scoring system and its objective validation. Several experts in obstetrics from university hospital centers and private French hospitals were invited to participate in the development phase of the scoring system. For the validation phase, we formed a group of 20 novices and a group of 20 experts, who had to perform a breech presentation delivery on a simulator, according to a standardized scenario. Each participant was filmed and two experts would then evaluate their performance by viewing anonymized videos and using the OSATS score. RESULTS: The scores obtained by the expert group were significantly higher than those of the novice group, with a total score of 21.73/25 versus 6.95/25 (p < 0.0001), a task-specific score of 87.2/110 versus 44.3/110 (p < 0.0001) and an overall score of 108.93/135 versus 51.25/135 (p < 0.0001), respectively. CONCLUSION: The OSATS score developed in this study for breech presentation delivery is a reliable model to assess the competence level in procedural skills using a simulator. PMID- 26969643 TI - Measurement of Exercise Tolerance before Surgery (METS) study: a protocol for an international multicentre prospective cohort study of cardiopulmonary exercise testing prior to major non-cardiac surgery. AB - INTRODUCTION: Preoperative functional capacity is considered an important risk factor for cardiovascular and other complications of major non-cardiac surgery. Nonetheless, the usual approach for estimating preoperative functional capacity, namely doctors' subjective assessment, may not accurately predict postoperative morbidity or mortality. 3 possible alternatives are cardiopulmonary exercise testing; the Duke Activity Status Index, a standardised questionnaire for estimating functional capacity; and the serum concentration of N-terminal pro-B type natriuretic peptide (NT pro-BNP), a biomarker for heart failure and cardiac ischaemia. METHODS AND ANALYSIS: The Measurement of Exercise Tolerance before Surgery (METS) Study is a multicentre prospective cohort study of patients undergoing major elective non-cardiac surgery at 25 participating study sites in Australia, Canada, New Zealand and the UK. We aim to recruit 1723 participants. Prior to surgery, participants undergo symptom-limited cardiopulmonary exercise testing on a cycle ergometer, complete the Duke Activity Status Index questionnaire, undergo blood sampling to measure serum NT pro-BNP concentration and have their functional capacity subjectively assessed by their responsible doctors. Participants are followed for 1 year after surgery to assess vital status, postoperative complications and general health utilities. The primary outcome is all-cause death or non-fatal myocardial infarction within 30 days after surgery, and the secondary outcome is all-cause death within 1 year after surgery. Both receiver-operating-characteristic curve methods and risk reclassification table methods will be used to compare the prognostic accuracy of preoperative subjective assessment, peak oxygen consumption during cardiopulmonary exercise testing, Duke Activity Status Index scores and serum NT pro-BNP concentration. ETHICS AND DISSEMINATION: The METS Study has received research ethics board approval at all sites. Participant recruitment began in March 2013, and 1-year follow-up is expected to finish in 2016. Publication of the results of the METS Study is anticipated to occur in 2017. PMID- 26969653 TI - Cost Implications for Subsequent Perinatal Outcomes After IVF Stratified by Number of Embryos Transferred: A Five Year Analysis of Vermont Data. AB - BACKGROUND: In states in the USA without in vitro fertilzation coverage (IVF) insurance coverage, more embryos are transferred per cycle leading to higher risks of multi-fetal pregnancies and adverse pregnancy outcomes. OBJECTIVE: To determine frequency and cost of selected adverse perinatal complications based on number of embryos transferred during IVF, and calculate incremental cost per IVF live birth. METHODS: Medical records of patients who conceived with IVF (n = 116) and delivered at >20 weeks gestational age between 2007 and 2011 were evaluated. Gestational age at delivery, low birth weight (LBW) term births, and delivery mode were tabulated. Healthcare costs per cohort, extrapolated costs assuming 100 patients per cohort, and incremental costs per infant delivered were calculated. RESULTS: The highest prematurity and cesarean section rates were recorded after double embryo transfers (DET), while the lowest rates were found in single embryo transfers (SET). Premature singleton deliveries increased directly with number of transferred embryos [6.3 % (SET), 9.1 % (DET) and 10.0 % for >=3 embryos transferred]. This trend was also noted for rate of cesarean delivery [26.7 % (SET), 36.6 % (DET), and 47.1 % for >=3 embryos transferred]. The proportion of LBW infants among deliveries after DET and for >=3 embryos transferred was 3.9 and 9.1 %, respectively. Extrapolated costs per cohort were US$718,616, US$1,713,470 and US$1,227,396 for SET, DET, and >=3 embryos transferred, respectively. CONCLUSION: Attempting to improve IVF pregnancy rates by permitting multiple embryo transfers results in sharply increased rates of multiple gestation and preterm delivery. This practice yields a greater frequency of adverse perinatal outcomes and substantially increased healthcare spending. Better efforts to encourage SET are necessary to normalize healthcare expenditures considering the frequency of very high cost sequela associated with IVF where multiple embryo transfers occur. PMID- 26969654 TI - First nationwide web-based surveillance system for influenza-like illness in pregnant women: participation and representativeness of the French G-GrippeNet cohort. AB - BACKGROUND: Pregnancy is a risk factor for severe influenza resulting in increased risks of hospitalisation and death in mothers and their new-borns. Our objective was to assess the representativeness and participation of French women to a new web-based collaborative tool for data collection and monitoring of Influenza Like Illness (ILI) during pregnancy. METHODS: During the 2014/2015 influenza season, pregnant women living in metropolitan France were enrolled through a web platform ( https://www.grippenet.fr/). Then throughout the season, participants were asked to report, on a weekly basis, if they had experienced symptoms of ILI. Representativeness was assessed by comparing the characteristics of participants to those of the French National Perinatal Survey. For each participant, the participation rate was the number of weekly questionnaires completed, divided by the length of follow-up (in weeks). Predictors of active participation (participation rate >15%) were assessed by multivariate logistic regression. RESULTS: A total of 153 women were enrolled. Participants were older (mean age 34 years vs. 29 years) and more highly educated (high school level 89% versus 52%) than the general population of pregnant women in France, but the sample did not differ on pregnancy-related characteristics (parity, history of hospitalisation during a previous pregnancy). The median rate of participation was high (78%, interquartile range: 34-96). Higher educational level and participation to a previous GrippeNet.fr season were associated with active participation. CONCLUSION: Despite small sample size and lack of representativeness, the retention rate was high, suggesting that pregnant women are prone to adhere to a longitudinal follow-up of their health status via the Internet. PMID- 26969656 TI - Identification of metabolic pathways using pathfinding approaches: a systematic review. AB - Metabolic pathways have become increasingly available for various microorganisms. Such pathways have spurred the development of a wide array of computational tools, in particular, mathematical pathfinding approaches. This article can facilitate the understanding of computational analysis of metabolic pathways in genomics. Moreover, stoichiometric and pathfinding approaches in metabolic pathway analysis are discussed. Three major types of studies are elaborated: stoichiometric identification models, pathway-based graph analysis and pathfinding approaches in cellular metabolism. Furthermore, evaluation of the outcomes of the pathways with mathematical benchmarking metrics is provided. This review would lead to better comprehension of metabolism behaviors in living cells, in terms of computed pathfinding approaches. PMID- 26969657 TI - REM-related sleep-disordered breathing is associated with depressive symptoms in men but not in women. AB - PURPOSE: The purposes of the present study are to determine the prevalence and demographic features of rapid eye movement (REM)-related sleep-disordered breathing (SDB) in Korean adults with newly diagnosed obstructive sleep apnea (OSA) and determine if REM-related SDB is associated with depressive symptoms and health-related quality of life (HRQoL) in OSA patients. METHODS: In this cross sectional study, we evaluated 1281 OSA adults who were consecutively recruited. REM-related SDB was defined as an overall apnea-hypopnea index (AHI) >=5, an AHINREM <15, and AHIREM to AHINREM ratio of >2. The Epworth Sleepiness Scale (ESS), Beck Depression Inventory (BDI), and Medical Outcomes Study Short-Form Health survey (SF-36) were used to evaluate all patients. Multiple regression analyses were performed to determine the associations between REM-related SDB and clinical outcomes. RESULTS: The prevalence of REM-related SDB was 18 % in this study. REM-related SDB was more commonly observed in patients with mild or moderate OSA (p < 0.001) and women (p < 0.001). The linear regression analysis showed that the presence of REM-related SDB was significantly associated with higher BDI scores, but only in men. AHIREM was positively associated with the BDI scores, but only in men with REM-related SDB. There were no differences in ESS and SF-36 scores between patients with and without REM-related SDB. CONCLUSIONS: Patients with REM-related SDB account for 18 % of Korean OSA adults. REM-related SDB was associated with depressive symptoms, but only in men. AHIREM is positively related to the degree of depressive symptoms in men with REM-related SDB. PMID- 26969658 TI - Comparison of American Academy of Sleep Medicine (AASM) versus Center for Medicare and Medicaid Services (CMS) polysomnography (PSG) scoring rules on AHI and eligibility for continuous positive airway pressure (CPAP) treatment. AB - BACKGROUND: Obstructive sleep apnea (OSA) is an important clinical condition. Eligibility for treatment usually depends on disease severity, measured as the apnea-hypopnea index (AHI), equal to the sum of apneas plus hypopneas per hour of sleep. There is divergence on scoring rules for hypopneas between the recommendations of the American Academy of Sleep Medicine (AASM) and the Center for Medicare Services (CMS), the latter being more restrictive. Thus, patients could be eligible for treatment under AASM rules, but not under CMS rules. METHODS: Sleep laboratory records of 112 consecutive patients were reviewed (85 < 65, 27 >= 65 years old). AHI was calculated both by AASM and by CMS criteria. Information on demographics, and important comorbidities, was also reviewed. RESULTS: AHI was lower in younger patients using CMS criteria. However, differences in AHI using the two sets of criteria were not significantly different in the older patients. Incorporating all criteria for eligibility (severity, presence of certain comorbid conditions) for treatment, we found that fewer younger patients would be eligible using CMS criteria, but among the older patients, eligibility for treatment was the same whether AASM or CMS criteria were used. CONCLUSIONS: Use of CMS criteria for scoring hypopneas results in lower estimates of OSA severity, with fewer younger patients eligible for treatment. However, among Medicare age patients, the rate of treatment eligibility was the same whether AASM or CMS scoring rules were used. PMID- 26969659 TI - Glove port, how do we do it? A low-cost alternative to the single-port approach. AB - BACKGROUND: The need for cosmetic results in our society and the necessity of an early recovery have promoted the development of minimally invasive techniques, including single-port approach. Some studies have tried to demonstrate the advantages of this access compared with conventional laparoscopic approach. This type of approach requires a high-cost multi-port device, so that some surgeons have tried to create a low-cost homemade device. MATERIALS AND METHODS: With this video we intend to show how to build a glove port, a low-cost alternative for the approach by a single port. CONCLUSIONS: A glove port is a cost effective approach that could be use instead of multi-port device. PMID- 26969660 TI - Prospective, randomized and controlled trial on magnesium sulfate administration during laparoscopic gastrectomy: effects on surgical space conditions and recovery profiles. AB - BACKGROUND: The degree of neuromuscular blockade is one of the important factors that determine the condition of surgical space during laparoscopic surgery. Magnesium sulfate potentiates the actions of neuromuscular blocking agent, and we hypothesized that intraoperative magnesium sulfate infusion may improve surgical space condition during laparoscopic surgery. METHODS: Eighty-four patients undergoing elective laparoscopic gastrectomy were randomized to receive isotonic saline (group C) or magnesium sulfate (group M, loading dose with 50 mg/kg over 10 min and then 15 mg/kg/h by continuous infusion) to maintain the moderate neuromuscular blockade using rocuronium. Two experienced surgeons scored the quality of surgical space condition using a 5-point surgical rating scale (SRS). The secondary outcomes included recovery profiles, postoperative pain and adverse events. RESULTS: The SRS in group M was higher than that of group C. The proportion of patients with a SRS of 5 (optimal) was 2.7 % in the group C and 40.5 % in the group M (P < 0.0001) although a lower amount of rocuronium was required in group M than group C [24.2 (6.5) mg/h for group M vs. 27.5 (6) mg/h for group C; P = 0.017]. Pain after operation site was less severe in group M than in group C at postoperative 24 h (P = 0.009). Recovery profiles and adverse events were similar between the two groups. CONCLUSION: Intraoperative administration of magnesium sulfate improved the quality of surgical space conditions and decreased neuromuscular blocking agent requirement and postoperative pain in patients undergoing laparoscopic gastrectomy. PMID- 26969661 TI - EUS-guided choledochoduodenostomy for malignant distal biliary obstruction using a lumen-apposing fully covered metal stent after failed ERCP. AB - BACKGROUND: A novel lumen-apposing, self-expanding metal stent to perform EUS guided drainage procedures has been recently developed. The aim of this study was to analyze the safety, technical and clinical effectiveness of this device for EUS-guided choledochoduodenostomy (EUS-CD) with palliative intent. METHODS: Retrospective analysis of all consecutive patients with unresectable malignant distal bile duct obstruction who, between March 2012 and September 2014, underwent EUS-CD using the study devices (AXIOSTM and Hot AXIOSTM, Xlumena Inc., Mountain View, CA, USA) after unsuccessful ERCP in seven European centers was carried out. RESULTS: Fifty-seven patients (M/F 31/26; median age 73) underwent EUS-CD using the AXIOSTM stent or the Hot AXIOSTM delivery system. ERCP failure was due to duodenal obstruction in 41 patients (71.9 %) and to inability to cannulate the papilla in the remaining 16 patients (28.1 %). The procedure was technically successful in 56/57 patients (98.2 %), with a mean procedural time of 22.4 min (range 11-65). Clinical success was achieved in 54 of these 56 patients (96.4 %; 94.7 % of the entire cohort). Overall major procedural complication rate was 7 % (two duodenal perforations, one bleeding and one transient cholangitis). During follow-up, 5 out of 54 (9.3 %) patients with clinica success required re intervention for stent migration in one case and a sump syndrome with transient increase in serum bilirubin concentrations with sludge in the distal duct reservoir in the remaining four patients. CONCLUSIONS: Our study shows that EUS CD using the AXIOSTM and the Hot AXIOSTM devices is a safe procedure, with high technical and clinical success rates. PMID- 26969662 TI - Outcomes of bariatric surgery in the young: a single-institution experience caring for patients under 21 years old. AB - BACKGROUND: Medical weight loss options are rarely successful long term in young patients. Bariatric surgery has been shown to be safe and effective in this population. METHODS: Patients <=21 years old who had bariatric surgery at our institution between January 2009 and December 2013 were evaluated to determine the safety and efficacy of bariatric surgery in this population. The primary end point was excess weight loss (EWL). Secondary end points included surgical morbidity, improvement in obesity-related metabolic parameters, and subjective obesity-related symptoms at 1 year. RESULTS: Fifty-four patients were identified who had a laparoscopic Roux-en-Y gastric bypass (LGBP) or laparoscopic sleeve gastrectomy (LSG). Fourteen patients were male (25.9 %), and 40 patients were female (74.1 %). Thirty-seven patients (68.5 %) underwent LGBP, and 17 patients (31.5 %) underwent LSG. Median follow-up was 13.3 months. The baseline BMI was 51.7 kg/m2 for the LGBP group and 51.0 kg/m2 for the LSG group. EWL was 35.2, 47.6, 62.4, 58.1, and 61.8 % for the LGBP group; 29.7, 44.7, 57.4, 60.3, and 59.0 % for the LSG group at 3, 6, 12, 24, and 36 months, respectively. Our complications included 1 anastomotic bleed, 1 postoperative stricture, and 1 patient who developed vitamin deficiency that manifested as a peripheral neuropathy in the LGBP group. LGBP was more successful than LSG in improving lipid panel parameters and HbA1c at 1 year, and it also seemed to offer better subjective improvement in obesity-related symptoms. CONCLUSIONS: LGBP and LSG seem to confer comparable weight loss benefit in patients <=21 years old with acceptable surgical morbidity. PMID- 26969663 TI - Congenital anomaly rectified at birth: one-stage single-incision laparoscopic assisted anorectoplasty for newborns with anorectal malformations and recto urethral fistula. AB - OBJECTIVE: Currently, staged procedures involving stoma formation and closure are the widely accepted treatment for newborns suffering from anorectal malformations (ARM) with recto-urethral fistula. This study aims to evaluate the safety and efficacy of one-stage single-incision laparoscopic-assisted anorectoplasty (SILAARP) as an alternative to the conventional approach. METHODS: Newborns with ARMs and recto-urethral fistula who underwent one-stage SILAARP between June 2013 and December 2014 were reviewed. The procedure involved decompression of the meconium via a small temporary incision of the proximal sigmoid colon followed by a laparoscopic-assisted pull-through. RESULTS: Sixteen ARM newborns [recto prostatic fistula (6), recto-bulbar fistula (10)] successfully underwent a one stage SILAARP. The mean age of the neonates at operation was 42.1 h. The average operative time was 2.4 h. The actual pull-through took 1.7 h, which did not differ significantly from 1.9 h in the pull-through procedure of our three-stage SILAARP control group. The median follow-up period was 16 months (8-26 months). No complications were encountered. Postoperative pelvic magnetic resonance imaging verified the centrally placed rectum within the muscle complex. Most patients started having bowel movements on postoperative day 1. Two constipated patients periodically required an enema for 1-3 months. CONCLUSIONS: One-stage SILAARP is safe and effective. It provides complete rectification of ARM with recto-urethral fistula immediately after birth with good cosmesis. PMID- 26969664 TI - Off-site training of laparoscopic skills, a scoping review using a thematic analysis. AB - BACKGROUND: The focus of research in simulation-based laparoscopic training has changed from examining whether simulation training works to examining how best to implement it. In laparoscopic skills training, portable and affordable box trainers allow for off-site training. Training outside simulation centers and hospitals can increase access to training, but also poses new challenges to implementation. This review aims to guide implementation of off-site training of laparoscopic skills by critically reviewing the existing literature. METHODS: An iterative systematic search was carried out in MEDLINE, EMBASE, ERIC, Scopus, and PsychINFO, following a scoping review methodology. The included literature was analyzed iteratively using a thematic analysis approach. The study was reported in accordance with the STructured apprOach to the Reporting In healthcare education of Evidence Synthesis statement. RESULTS: From the search, 22 records were identified and included for analysis. A thematic analysis revealed the themes: access to training, protected training time, distribution of training, goal setting and testing, task design, and unsupervised training. The identified themes were based on learning theories including proficiency-based learning, deliberate practice, and self-regulated learning. CONCLUSIONS: Methods of instructional design vary widely in off-site training of laparoscopic skills. Implementation can be facilitated by organizing courses and training curricula following sound education theories such as proficiency-based learning and deliberate practice. Directed self-regulated learning has the potential to improve off-site laparoscopic skills training; however, further studies are needed to demonstrate the effect of this type of instructional design. PMID- 26969665 TI - Long-term quality of life and functionality after ventral hernia mesh repair. AB - BACKGROUND: The absence of recurrence and pain are important for good quality of life (QoL) after ventral hernia mesh repair. We wanted to study long-term outcome after laparoscopic (LVHR) and open ventral hernia mesh repair (OVHR) using validated scales to measure QoL and functional outcome. METHODS: We conducted a single-center follow-up study of 194 consecutive patients after LVHR and OVHR between March 2000 and June 2010. Of these, 27 patients (13.9 %) died and 14 (7.2 %) failed to attend their follow-up appointment. Of 153 (78.9 %) patients who attended, 81 (52.9 %) patients had LVHR and 72 (47.1 %) patients had OVHR, including 11 conversions (surgery group). One hundred and twelve patients with non-recurrent ventral hernia were also enrolled consecutively as controls (non surgery group). Quality of life was measured by the SF-36 short form questionnaire and functional outcome by the Activities Assessment Scale (AAS) with the revised Life Orientation Test to measure the influence of dispositional optimism on pain and functionality. Assessment of pain was done using a 100-mm visual analogue scale ruler anchored by word descriptors. RESULTS: Median time from hernia mesh repair to follow-up was 48 and 52 months after LVHR and OVHR, respectively. There were no long-term differences between LVHR and OVHR measured by SF-36 and AAS. Physical dimensions in SF-36: physical function, restrictions in physical function and bodily pain, were significantly better in the surgery group compared to the non-surgery group, but only for incisional hernia. Recurrence was associated with a significant reduction in QoL in all dimensions of SF-36 in both hernia repair cohorts. Chronic pain and impairment were closely related. Optimistic patients had less impairment than pessimistic patients. CONCLUSION: LVHR and OVHR reduce chronic pain and physical impairment and improve long-term QoL. Hernia recurrence and persistent pain reduce the beneficial effect of hernia surgery. Dispositional optimism can modulate QoL reporting and improve functionality. PMID- 26969666 TI - Outcomes associated with preoperative weight loss after laparoscopic Roux-en-Y gastric bypass. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is an effective treatment for achieving and maintaining weight loss and for improving obesity related comorbidities. As part of the approval process for bariatric surgery, many insurance companies require patients to have documented recent participation in a supervised weight loss program. The goal of this study was to evaluate the relationship of preoperative weight changes with outcomes following LRYGB. METHODS: A retrospective review was conducted of adult patients undergoing LRYGB between 2008 and 2012 at a single institution. Patients were stratified into quartiles based on % excess weight gain (0-4.99 % and >=5 % EWG) and % excess weight loss (0-4.99 % and >=5 % EWL). Generalized linear models were used to examine differences in postoperative weight outcomes at 6, 12, and 24 months. Covariates included in the final adjusted models were determined using backwards stepwise selection. RESULTS: Of the 300 patients included in the study, there were no significant demographic differences among the quartiles. However, there was an increased time to operation for patients who gained or lost >=5 % excess body weight (p < 0.001). Although there was no statistical significance in postoperative complications, there was a higher rate of complications in patients with >=5 % EWG compared to those with >=5 % EWL (12.5 vs. 4.8 %, respectively; p = 0.29). Unadjusted and adjusted generalized linear models showed no statistically significant association between preoperative % excess weight change and weight loss outcomes at 24 months. CONCLUSION: Patients with the greatest % preoperative excess weight change had the longest intervals from initial visit to operation. No significant differences were seen in perioperative and postoperative outcomes. This study suggests preoperative weight loss requirements may delay the time to operation without improving postoperative outcomes or weight loss. PMID- 26969668 TI - Decision-tree analysis of clinical data to aid diagnostic reasoning for equine laminitis: a cross-sectional study. AB - The objective of this cross-sectional study was to compare the prevalence of selected clinical signs in laminitis cases and non-laminitic but lame controls to evaluate their capability to discriminate laminitis from other causes of lameness. Participating veterinary practitioners completed a checklist of laminitis-associated clinical signs identified by literature review. Cases were defined as horses/ponies with veterinary-diagnosed, clinically apparent laminitis; controls were horses/ponies with any lameness other than laminitis. Associations were tested by logistic regression with adjusted odds ratios (ORs) and 95% confidence intervals, with veterinary practice as an a priori fixed effect. Multivariable analysis using graphical classification tree-based statistical models linked laminitis prevalence with specific combinations of clinical signs. Data were collected for 588 cases and 201 controls. Five clinical signs had a difference in prevalence of greater than +50 per cent: 'reluctance to walk' (OR 4.4), 'short, stilted gait at walk' (OR 9.4), 'difficulty turning' (OR 16.9), 'shifting weight' (OR 17.7) and 'increased digital pulse' (OR 13.2) (all P<0.001). 'Bilateral forelimb lameness' was the best discriminator; 92 per cent of animals with this clinical sign had laminitis (OR 40.5, P<0.001). If, in addition, horses/ponies had an 'increased digital pulse', 99 per cent were identified as laminitis. 'Presence of a flat/convex sole' also significantly enhanced clinical diagnosis discrimination (OR 15.5, P<0.001). This is the first epidemiological laminitis study to use decision-tree analysis, providing the first evidence base for evaluating clinical signs to differentially diagnose laminitis from other causes of lameness. Improved evaluation of the clinical signs displayed by laminitic animals examined by first-opinion practitioners will lead to equine welfare improvements. PMID- 26969669 TI - Effects of Dopamine and Serotonin Systems on Modulating Neural Oscillations in Hippocampus-Prefrontal Cortex Pathway in Rats. AB - Theta and gamma oscillations are believed to play an important role in cognition and memory, and their phase coupling facilitates the information transmission in hippocampal-cortex network. In a rat model of chronic stress, the phase coupling of both theta and gamma oscillations between ventral hippocampal CA1 (vCA1) and medial prefrontal cortex (mPFC) was found to be disrupted, which was associated with the impaired synaptic plasticity in the pathway. However, little was known about the mechanisms underlying the process. In order to address this issue, both dopamine and serotonin as monoaminergic neurotransmitters were involved in this study, since they were crucial factors in pathological basis of depressive disorder. Local field potentials (LFPs) were recorded simultaneously at both vCA1 and mPFC regions under anesthesia, before and after the injection of dopamine D1 receptor antagonist and 5-HT1A receptor agonist, respectively. The results showed that the blockage of D1 receptor could lead to depression-like decrement on theta phase coupling. In addition, the activation of 5-HT1A receptor enhanced vCA1-mPFC coupling on gamma oscillations, and attenuated CA1 theta-fast gamma cross frequency coupling. These data suggest that the theta phase coupling between vCA1 and mPFC may be modulated by dopamine system that is an underlying mechanism of the cognitive dysfunction in depression. Besides, the serotonergic system is probably involved in the regulation of gamma oscillations coupling in vCA1-mPFC network. PMID- 26969667 TI - Comprehensive profiling of EBV gene expression in nasopharyngeal carcinoma through paired-end transcriptome sequencing. AB - The latent expression pattern of Epstein-Barr Virus (EBV) genes in nasopharyngeal carcinoma (NPC) has been extensively investigated, and the expression of several lytic genes in NPC has been reported. However, comprehensive information through EBV transcriptome analysis in NPC is limited. We performed paired-end RNA-seq to systematically and comprehensively characterize the expression of EBV genes in NPC tissue and C666-1 NPC cell line, which consistently carries EBV. In addition to the transcripts restricted to type II latency infection, the type III latency EBNA3s genes and a substantial number of lytic genes, such as BZLF1, BRLF1, and BMRF1, were detected through RNA-seq and were further verified in C666-1 cells and NPC tissue through realtime PCR.We also performed clustering analysis to classify NPC patient groups in terms of EBV gene expression, which presented two subtypes of NPC samples. Results revealed interesting patterns of EBV gene expression in NPC patients. This clustering was correlated with many signaling pathways, such as those related to heterotrimeric G-protein signaling, inflammation mediated by chemokine and cytokine signaling, ribosomes, protein metabolism, influenza infection, and ECM-receptor interaction. Our combined findings suggested that the expression of EBV genes in NPC is restricted not only to type II latency genes but also to type III latency and lytic genes. This study provided further insights into the potential role of EBV in the development of NPC. PMID- 26969670 TI - ARDS in the brain-injured patient: what's different? PMID- 26969672 TI - What's new about circulating biomarkers in pediatric acute lung disease. PMID- 26969671 TI - Use of high-flow nasal cannula oxygenation in ICU adults: a narrative review. AB - Oxygen therapy can be delivered using low-flow, intermediate-flow (air entrainment mask), or high-flow devices. Low/intermediate-flow oxygen devices have several drawbacks that cause critically ill patients discomfort and translate into suboptimal clinical results. These include limitation of the FiO2 (due to the high inspiratory flow often observed in patients with respiratory failure), and insufficient humidification and warming of the inspired gas. High flow nasal cannula oxygenation (HFNCO) delivers oxygen flow rates of up to 60 L/min and over the last decade its effect on clinical outcomes has widely been evaluated, such as in the improvement of respiratory distress, the need for intubation, and mortality. Mechanisms of action of HFNCO are complex and not limited to the increased oxygen flow rate. The main aim of this review is to guide clinicians towards evidence-based clinical practice guidelines. It summarizes current knowledge about HFNCO use in ICU patients and the potential areas of uncertainties. For instance, it has been recently suggested that HFNCO could improve the outcome of patients with hypoxemic acute respiratory failure. In other settings, research is ongoing and additional evidence is needed. For instance, if intubation is required, studies suggest that HFNCO may help to improve preoxygenation and can be used after extubation. Likewise, HFNCO might be used in obese patients, or to prevent respiratory deterioration in hypoxemic patients requiring bronchoscopy, or for the delivery of aerosol therapy. However, areas for which conclusive data exist are limited and interventions using standardized HFNCO protocols, comparators, and relevant clinical outcomes are warranted. PMID- 26969674 TI - Sequential tests for non-proportional hazards data. AB - In clinical trials survival endpoints are usually compared using the log-rank test. Sequential methods for the log-rank test and the Cox proportional hazards model are largely reported in the statistical literature. When the proportional hazards assumption is violated the hazard ratio is ill-defined and the power of the log-rank test depends on the distribution of the censoring times. The average hazard ratio was proposed as an alternative effect measure, which has a meaningful interpretation in the case of non-proportional hazards, and is equal to the hazard ratio, if the hazards are indeed proportional. In the present work we prove that the average hazard ratio based sequential test statistics are asymptotically multivariate normal with the independent increments property. This allows for the calculation of group-sequential boundaries using standard methods and existing software. The finite sample characteristics of the new method are examined in a simulation study in a proportional and a non-proportional hazards setting. PMID- 26969673 TI - Usefulness of Preoperative Plasma Fibrinogen Versus Other Prognostic Markers for Predicting Gastric Cancer Recurrence. AB - BACKGROUND: Hypercoagulation is associated with tumor progression and metastasis in various types of malignancy. We compared the prognostic value of preoperative plasma fibrinogen level with those of other prognostic markers in patients with gastric cancer and assessed whether fibrinogen level was an independent prognostic indicator. METHODS: We collected preoperative data from 609 consecutive patients with gastric cancer who underwent curative gastrectomy. A receiver operating curve (ROC) was used to compare the sensitivity and specificity of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19 9), C-reactive protein (CRP), platelet count, platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and fibrinogen level in predicting recurrence. Recurrence-free survival (RFS) and overall survival (OS) were compared between the normal and high fibrinogen groups. RESULTS: In the ROC analysis, the area under the curve (AUC) was 0.534 for CEA, 0.552 for CA19-9, 0.587 for CRP, 0.565 for platelet count, 0.567 for PLR, 0.522 for NLR, and 0.692 for fibrinogen. Plasma fibrinogen level increased with tumor stage. The high fibrinogen (>=350 mg/dl) group had significantly worse RFS (p < 0.001) and OS (p < 0.001) than the normal fibrinogen (<350 mg/dl) group. Cox multivariate analysis of RFS revealed that fibrinogen level was an independent prognostic factor (p < 0.001) in addition to sex, pT stage, and pN stage. CONCLUSIONS: Preoperative plasma fibrinogen level had the highest predictive value for recurrence among seven known prognostic markers. Since fibrinogen level is an independent factor for RFS, it would be useful for predicting prognosis after gastric cancer surgery. PMID- 26969675 TI - Reconstruction of gene regulatory modules from RNA silencing of IFN-alpha modulators: experimental set-up and inference method. AB - BACKGROUND: Inference of gene regulation from expression data may help to unravel regulatory mechanisms involved in complex diseases or in the action of specific drugs. A challenging task for many researchers working in the field of systems biology is to build up an experiment with a limited budget and produce a dataset suitable to reconstruct putative regulatory modules worth of biological validation. RESULTS: Here, we focus on small-scale gene expression screens and we introduce a novel experimental set-up and a customized method of analysis to make inference on regulatory modules starting from genetic perturbation data, e.g. knockdown and overexpression data. To illustrate the utility of our strategy, it was applied to produce and analyze a dataset of quantitative real-time RT-PCR data, in which interferon-alpha (IFN-alpha) transcriptional response in endothelial cells is investigated by RNA silencing of two candidate IFN-alpha modulators, STAT1 and IFIH1. A putative regulatory module was reconstructed by our method, revealing an intriguing feed-forward loop, in which STAT1 regulates IFIH1 and they both negatively regulate IFNAR1. STAT1 regulation on IFNAR1 was object of experimental validation at the protein level. CONCLUSIONS: Detailed description of the experimental set-up and of the analysis procedure is reported, with the intent to be of inspiration for other scientists who want to realize similar experiments to reconstruct gene regulatory modules starting from perturbations of possible regulators. Application of our approach to the study of IFN-alpha transcriptional response modulators in endothelial cells has led to many interesting novel findings and new biological hypotheses worth of validation. PMID- 26969676 TI - N-H bond cleavage of ammonia on graphene-like B36 borophene: DFT studies. AB - Ammonia N-H bond cleavage at metal-free substrates has attracted great attention because of its industrial importance. Here, we investigate the dissociative adsorption of ammonia onto the surface of a B36 borophene sheet by means of density functional theory calculations. We show that the N-H bond may be broken at the edges of B36 even at room temperature, regarding the small energy barrier of 14.1-19.3 kcal mol(-1) at different levels of theory, and more negative Gibbs free energy change. Unlike basis set size, the kind of exchange correlation functional significantly affects the electronic properties of the studied systems. Also, by increasing the percentage of Hartree Fock (HF) exchange of density functionals, the activation and adsorption energies are lowered. A linear relationship between the highest occupied molecular orbital or lowest unoccupied molecular orbital of B36 borophene and the %HF exchange of functionals is predicted. Our work reveals that pure whole boron nanosheets may be promising metal-free materials in N-H bond cleavage, which would raise the potential application of these sheets. PMID- 26969677 TI - Modeling of babesipain-1 and identification of natural and synthetic leads for bovine babesiosis drug development. AB - Babesiosis is a tick-borne, zoonotic disease caused by species of the intraerythrocytic protozoan Babesia. It is distributed all around the world and affects various domestic and wild animals, mainly cattle. Recently, the cysteine protease enzyme, babesipain-1 from Babesia bigemina has been identified as a potential target for designing new anti-babesiosis drugs. In the present study, a three-dimensional structural model of babesipain-1 was developed. An active site with three pockets (S1, S2, and S3), which is congruent with its homolog, falcipain-3, was also identified. Moreover, the conservation of active site residues was consistent with the cysteine protease family. In order to identify potential inhibitors, a virtual screening workflow was employed with a chemical library containing natural and synthetic compounds. Potential inhibitors interacting with all the three subsites were identified. Further, molecular dynamic simulations were carried out to assess the interactions and stability of the inhibitors. The informatics approach, and the findings presented in this study will assist researchers in further development of potential anti-babesiosis molecules. PMID- 26969678 TI - PDP-CON: prediction of domain/linker residues in protein sequences using a consensus approach. AB - The prediction of domain/linker residues in protein sequences is a crucial task in the functional classification of proteins, homology-based protein structure prediction, and high-throughput structural genomics. In this work, a novel consensus-based machine-learning technique was applied for residue-level prediction of the domain/linker annotations in protein sequences using ordered/disordered regions along protein chains and a set of physicochemical properties. Six different classifiers-decision tree, Gaussian naive Bayes, linear discriminant analysis, support vector machine, random forest, and multilayer perceptron-were exhaustively explored for the residue-level prediction of domain/linker regions. The protein sequences from the curated CATH database were used for training and cross-validation experiments. Test results obtained by applying the developed PDP-CON tool to the mutually exclusive, independent proteins of the CASP-8, CASP-9, and CASP-10 databases are reported. An n-star quality consensus approach was used to combine the results yielded by different classifiers. The average PDP-CON accuracy and F-measure values for the CASP targets were found to be 0.86 and 0.91, respectively. The dataset, source code, and all supplementary materials for this work are available at https://cmaterju.org/cmaterbioinfo/ for noncommercial use. PMID- 26969679 TI - The impact of position and number of methoxy group(s) to tune the nonlinear optical properties of chalcone derivatives: a dual substitution strategy. AB - Using the state-of-art computational techniques, we limelight a structure property relationship for the position and number of methoxy group(s) to tune the optical and nonlinear optical (NLO) properties (first hyperpolarizability) of chalcone derivatives. Based on our previously synthesized chalcones [system 1 ((E)-1-(2,5-dimethylthiophen-3-yl)-3-(2-methoxyphenyl)prop-2-en-1-one and system 4 (E)-1-(2,5-dimethylthiophen-3-yl)-3-(2,4,5-trimethoxyphenyl)prop-2-en-1-one)], we systematically design several novel derivatives with tuned optical and NLO properties. For instance, the rotation of methoxy group substitutions at three different possible ortho, meta, and para positions on phenyl ring show significant changes in NLO properties of these chalcones derivatives. The system 3 has shown beta tot amplitude of 1776 a.u. with terminal 4-methoxyphenyl group (para-methoxy substitution), which is ~2.2 and 2.4 times larger than that of ortho- and meta-methoxyphenyl systems 1 and 2, respectively. Additionally, systems 3a and 4a, which are cyano derivatives of the systems 3 and 4 show significantly large beta tot amplitudes of 3280 and 4388 a.u., respectively, which are about 3 and 4 times larger than that of para-nitro aniline (PNA) molecule (a typical donor-acceptor molecule) at the same LC-wPBE/6-311G** level of theory. The origin of larger beta tot amplitudes has been traced in lower transition energies and higher oscillator strengths for crucial transitions of designed derives. Thus, our investigation reveals that the chalcones derivatives with para-methoxyphenyl groups possess reasonably large amplitudes of their first hyperpolarizability and good optical transparency (3.0-4.7 eV), which can make them attractive candidates for nonlinear optical applications. PMID- 26969680 TI - Free energy calculation provides insight into the action mechanism of selective PARP-1 inhibitor. AB - Selective poly (ADP-ribose) polymerase (PARP)-1 inhibitor represents promising therapy against cancers with a good balance between efficacy and safety. Owing to the conserved structure between PARP-1 and PARP-2, most of the clinical and experimental drugs show equivalent inhibition against both targets. Most recently, it's disclosed a highly selective PARP-1 inhibitor (NMS-P118) with promising pharmacokinetic properties. Herein, we combined molecular simulation with free energy calculation to gain insights into the selective mechanism of NMS P118. Our results suggest the reduction of binding affinity for PARP-2 is attributed to the unfavorable conformational change of protein, which is accompanied by a significant energy penalty. Alanine-scanning mutagenesis study further reveals the important role for a tyrosine residue of donor loop (Tyr889(PARP-1) and Tyr455(PARP-2)) in contributing to the ligand selectivity. Retrospective structural analysis indicates the ligand-induced movement of Tyr455(PARP-2) disrupts the intra-molecule hydrogen bonding network, which partially accounts for the "high-energy" protein conformation in the presence of NMS-P118. Interestingly, such effect isn't observed in other non-selective PARP inhibitors including BMN673 and A861695, which validates the computational prediction. Our work provides energetic insight into the subtle variations in the crystal structures and could facilitate rational design of new selective PARP inhibitor. PMID- 26969681 TI - Dimension reduction techniques for the integrative analysis of multi-omics data. AB - State-of-the-art next-generation sequencing, transcriptomics, proteomics and other high-throughput 'omics' technologies enable the efficient generation of large experimental data sets. These data may yield unprecedented knowledge about molecular pathways in cells and their role in disease. Dimension reduction approaches have been widely used in exploratory analysis of single omics data sets. This review will focus on dimension reduction approaches for simultaneous exploratory analyses of multiple data sets. These methods extract the linear relationships that best explain the correlated structure across data sets, the variability both within and between variables (or observations) and may highlight data issues such as batch effects or outliers. We explore dimension reduction techniques as one of the emerging approaches for data integration, and how these can be applied to increase our understanding of biological systems in normal physiological function and disease. PMID- 26969683 TI - Simultaneous Quantification of 13 Compounds in Guanxin Shutong Capsule by HPLC Method. AB - Guanxin Shutong (GXST) capsule, which is frequently used in clinical therapy, has a certain and positive therapeutic effect against coronary heart disease. However, the existing quality standard of GXST capsule is inadequate to control the quality of GXST capsule. In this paper, a new high-performance liquid chromatographic (HPLC) method for simultaneous determination of 13 compounds (gallic acid, danshensu, protocatechuic acid, procatechuic aldehyde, ellagic acid, rosmarinic acid, salvianolic acid A and salvianolic acid B, eugenol, dihydrotanshinone I, cryptotanshinone, tanshinone I and tanshinone IIA) in GXST capsule was developed and validated. The analytes were successfully separated and quantified with an Agilent TC-C18 column (250 * 4.6 mm, 5 um) by gradient elution using 0.05% phosphoric acid and acetonitrile as mobile phase. The flow rate was 1 mL/min and the detection wavelength was set at 280 nm. All the compounds showed good linearity (r > 0.9991) in a relatively wide concentration range. The intra and the inter-day variability were in the range of 0.85-2.68 and 1.47-2.86%, respectively. The recoveries of the selected compounds were in the range of 95.24 104.75%. This method was successfully applied to quantify the 13 components in GXST capsule and was conducive to controlling the quality of GXST capsule. PMID- 26969682 TI - Simultaneous Determination and Pharmacokinetic Study of Protocatechuic Aldehyde and Its Major Active Metabolite Protocatechuic Acid in Rat Plasma by Liquid Chromatography-Tandem Mass Spectrometry. AB - A very simple and selective high-performance liquid chromatography electrospray ionization tandem mass spectrometry (LC-MS-MS) method was developed for simultaneous determination and pharmacokinetic study of protocatechuic aldehyde (PAL) and its active metabolite protocatechuic acid (PCA). The method involves a simple liquid-liquid extraction with ethyl acetate. The separation was performed on a Hypersil GOLD C18 column (2.1 * 150 mm, 3.0 um; particle, Thermo, USA) with isocratic elution using a mobile phase consisted of methanol and water (containing 0.1% formic acid) at a flow rate of 0.2 mL/min. The detection of target compounds was done by using low-energy collision dissociation tandem mass spectrometry (CID-MS-MS) using the selective reaction monitoring scan mode. The method was linear for all analytes over the investigated range for all correlation coefficients greater than 0.9950. The lower limits of quantification were 2.0 ng/mL for PAL and PCA. The intra- and interday precisions (relative standard deviation, RSD %) were <6.84 and 5.54%, and the accuracy (relative error, RE %) was between -2.85 and 0.74% (n = 6). The developed method was applied to study the pharmacokinetics of PAL and its major active metabolite PCA in rat plasma after oral and intravenous administration of PAL. PMID- 26969684 TI - Is Huntington's disease a tauopathy? AB - Tauopathies are a subclass of neurodegenerative diseases typified by the deposition of abnormal microtubule-associated tau protein within the cerebral tissue. Alzheimer's disease, progressive supranuclear palsy, chronic traumatic encephalopathy and some fronto-temporal dementias are examples of the extended family of tauopathies. In the last decades, intermittent reports of cerebral tau pathology in individuals afflicted with Huntington's disease-an autosomal dominant neurodegenerative disorder that manifests by severe motor, cognitive and psychiatric problems in adulthood-have also begun to surface. These observations remained anecdotal until recently when a series of publications brought forward compelling evidence that this monogenic disorder may, too, be a tauopathy. Collectively, these studies reported that: (i) patients with Huntington's disease present aggregated tau inclusions within various structures of the brain; (ii) tau haplotype influences the cognitive function of Huntington's disease patients; and (iii) that the genetic product of the disease, the mutant huntingtin protein, could alter tau splicing, phosphorylation, oligomerization and subcellular localization. Here, we review the past and current evidence in favour of the postulate that Huntington's disease is a new member of the family of tauopathies. PMID- 26969686 TI - Increased expression of alphav integrin as a regulator of fibrosis in Dupuytren's nodules. AB - : Although Dupuytren's contracture is characterized by increased transforming growth factor-beta1 (TGF-beta1) and fibrosis in the palmar fascia, the relationship between TGF-beta1 and integrins, which are considered to be related to fibrosis, remains unclear. We investigated the involvement of TGF-beta1 and integrins in the pathological palmar fascia of Dupuytren's contracture. Seven patients underwent partial fasciectomy for treatment of this disease. The nodule and cord were isolated from the fascial tissues of the patients. Control fasciae were obtained from seven patients with carpal tunnel syndrome. Immunohistochemical analysis was performed to detect the fibrosis marker alpha smooth muscle actin and integrins in the fascial tissues. The expression of TGF beta1 and integrins was assessed by real-time polymerase chain reaction. The results suggest that nodules may be areas involved in activation of fibrosis in the fascia, associated with increased expression of TGF-beta1 and alphav integrin. Thus, alphav integrin may contribute to fibrosis in Dupuytren's contracture by activating TGF-beta1. LEVEL OF EVIDENCE: IV. PMID- 26969687 TI - Cross-Cultural Validation of the Modified Practice Attitudes Scale: Initial Factor Analysis and a New Factor Model. AB - OBJECTIVE: The objective of this study was to create the Korean version of the Modified Practice Attitudes Scale (K-MPAS) to measure clinicians' attitudes toward evidence-based treatments (EBTs) in the Korean mental health system. METHOD: Using 189 U.S. therapists and 283 members from the Korean mental health system, we examined the reliability and validity of the MPAS scores. We also conducted the first exploratory and confirmatory factor analysis on the MPAS and compared EBT attitudes across U.S. and Korean therapists. RESULTS: Results revealed that the inclusion of both "reversed-worded" and "non-reversed-worded" items introduced significant method effects that compromised the integrity of the one-factor MPAS model. Problems with the one-factor structure were resolved by eliminating the "non-reversed-worded" items. Reliability and validity were adequate among both Korean and U.S. therapists. Korean therapists also reported significantly more negative attitudes toward EBTs on the MPAS than U.S. therapists. CONCLUSIONS: The K-MPAS is the first questionnaire designed to measure Korean service providers' attitudes toward EBTs to help advance the dissemination of EBTs in Korea. The current study also demonstrated the negative impacts that can be introduced by incorporating oppositely worded items into a scale, particularly with respect to factor structure and detecting significant group differences. PMID- 26969685 TI - Glial and axonal changes in systemic lupus erythematosus measured with diffusion of intracellular metabolites. AB - Systemic lupus erythematosus is an inflammatory autoimmune disease with multi organ involvement. Central nervous system involvement in systemic lupus erythematosus is common and results in several neurological and psychiatric symptoms that are poorly linked to standard magnetic resonance imaging outcome. Magnetic resonance imaging methods sensitive to tissue microstructural changes, such as diffusion tensor imaging and magnetization transfer imaging, show some correlation with neuropsychiatric systemic lupus erythematosus (NPSLE) symptoms. Histological examination of NPSLE brains reveals presence of cerebral oedema, loss of neurons and myelinated axons, microglial proliferation and reactive astrocytosis, microinfacrts and diffuse ischaemic changes, all of which can affect both diffusion tensor imaging and magnetization transfer imaging in a non specific manner. Here we investigated the underlying cell-type specific microstructural alterations in the brain of patients with systemic lupus erythematosus with and without a history of central nervous system involvement. We did so combining diffusion tensor imaging with diffusion-weighted magnetic resonance spectroscopy, a powerful tool capable of characterizing cell-specific cytomorphological changes based on diffusion of intracellular metabolites. We used a 7 T magnetic resonance imaging scanner to acquire T1-weighted images, diffusion tensor imaging datasets, and single volume diffusion-weighted magnetic resonance spectroscopy data from the anterior body of the corpus callosum of 13 patients with systemic lupus erythematosus with past NPSLE, 16 patients with systemic lupus erythematosus without past NPSLE, and 19 healthy control subjects. Group comparisons were made between patients with systemic lupus erythematosus with/without past NPSLE and healthy controls on diffusion tensor imaging metrics and on diffusion coefficients of three brain metabolites: the exclusively neuronal/axonal N-acetylaspartate, and the predominantly glial creatine + phosphocreatine and choline compounds. In patients with systemic lupus erythematosus with past NPSLE, significantly higher diffusion tensor imaging mean and radial diffusivities were accompanied by a significantly higher intracellular diffusion of total creatine (0.202 +/- 0.032 MUm(2)/ms, P = 0.018) and total choline (0.142 +/- 0.031 MUm(2)/ms, P = 0.044) compared to healthy controls (0.171 +/- 0.024 MUm(2)/ms, 0.124 +/- 0.018 MUm(2)/ms, respectively). Total N acetylaspartate, total creatine and total choline diffusion values from all patients with systemic lupus erythematosus correlated positively with systemic lupus erythematosus disease activity index score (P = 0.033, P = 0.040, P = 0.008, respectively). Our results indicate that intracellular alterations, and in particular changes in glia, as evidenced by increase in the average diffusivities of total choline and total creatine, correlate with systemic lupus erythematosus activity. The higher diffusivity of total creatine and total choline in patients with NPSLE, as well as the positive correlation of these diffusivities with the systemic lupus erythematosus disease activity index are in line with cytomorphological changes in reactive glia, suggesting that the diffusivities of choline compounds and of total creatine are potentially unique markers for glial reactivity in response to inflammation. PMID- 26969688 TI - Evaluating the Construct Validity of the Levenson Self-Report Psychopathy Scale in China. AB - The Levenson Self-Report Psychopathy (LSRP) scale is an efficient measure of psychopathy with promising psychometric properties. However, the cross-cultural utility of the LSRP has not been well documented, and no study has explored measurement invariance of the LSRP across East Asian and North American samples. We translated the LSRP into Chinese (Study 1) and investigated the validity and reliability of the Chinese LSRP using a sample of 226 university students in China (Study 2). Confirmatory factor analyses supported Brinkley, Diamond, Magaletta, and Heigel's (2008) three-factor model (Egocentricity, Callousness, and Antisocial). Evidence for configural and partial metric (but not scalar) invariance of the factor structure was observed when comparing Chinese and U.S. university samples. However, response thresholds were significantly different between the two samples. The Chinese LSRP scores also demonstrated encouraging convergent and discriminate validity in terms of their associations with external criteria. We discuss the implications for cross-cultural assessment of psychopathy. PMID- 26969689 TI - Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy. AB - "Liquid biopsy" focusing on the analysis of circulating tumor cells (CTC) and circulating cell-free tumor DNA (ctDNA) in the blood of patients with cancer has received enormous attention because of its obvious clinical implications for personalized medicine. Analyses of CTCs and ctDNA have paved new diagnostic avenues and are, to date, the cornerstones of liquid biopsy diagnostics. The present review focuses on key areas of clinical applications of CTCs and ctDNA, including detection of cancer, prediction of prognosis in patients with curable disease, monitoring systemic therapies, and stratification of patients based on the detection of therapeutic targets or resistance mechanisms. SIGNIFICANCE: The application of CTCs and ctDNA for the early detection of cancer is of high public interest, but it faces serious challenges regarding specificity and sensitivity of the current assays. Prediction of prognosis in patients with curable disease can already be achieved in several tumor entities, particularly in breast cancer. Monitoring the success or failure of systemic therapies (i.e., chemotherapy, hormonal therapy, or other targeted therapies) by sequential measurements of CTCs or ctDNA is also feasible. Interventional studies on treatment stratification based on the analysis of CTCs and ctDNA are needed to implement liquid biopsy into personalized medicine. Cancer Discov; 6(5); 479-91. (c)2016 AACR. PMID- 26969690 TI - Mid-Treatment Reduction in Trauma-Related Guilt Predicts PTSD and Functioning Following Cognitive Trauma Therapy for Survivors of Intimate Partner Violence. AB - Intimate partner violence (IPV) results in severe and chronic posttraumatic psychological symptoms, maladaptive trauma-related guilt (TRG) and functional impairment for many women. Cognitive Trauma Therapy (CTT) was developed to specifically address empirically identified contributors of distress and functioning difficulties specific to IPV and has been found to be efficacious in treating posttraumatic stress disorder (PTSD) and reducing TRG. The primary aim of this study was to investigate to what extent reductions in TRG contribute to improvements in PTSD and functioning, given evidence of the important role that TRG plays in posttraumatic distress in IPV survivors and the emphasis placed on TRG in CTT. Twenty women with IPV-related chronic and functionally impairing posttraumatic distress were recruited from the community and completed CTT as part of a larger neurobiological study of PTSD. Women experienced statistically and clinically significant improvements in functioning as well as expected reductions in PTSD and TRG with large effect sizes at post-treatment, and improvements were maintained at 3-month follow-up, with no participant meeting full PTSD criteria. Pre- to mid-treatment reductions in TRG predicted post treatment PTSD and functioning outcomes. These findings support the efficacy of CTT and provide preliminary evidence for the importance of addressing TRG. Dismantling research is indicated to identify the active ingredient(s) of this multi-module treatment. PMID- 26969691 TI - Refined Analysis of Brain Energy Metabolism Using In Vivo Dynamic Enrichment of 13C Multiplets. AB - Carbon-13 nuclear magnetic resonance spectroscopy in combination with the infusion of (13)C-labeled precursors is a unique approach to study in vivo brain energy metabolism. Incorporating the maximum information available from in vivo localized (13)C spectra is of importance to get broader knowledge on cerebral metabolic pathways. Metabolic rates can be quantitatively determined from the rate of (13)C incorporation into amino acid neurotransmitters such as glutamate and glutamine using suitable mathematical models. The time course of multiplets arising from (13)C-(13)C coupling between adjacent carbon atoms was expected to provide additional information for metabolic modeling leading to potential improvements in the estimation of metabolic parameters.The aim of the present study was to extend two-compartment neuronal/glial modeling to include dynamics of (13)C isotopomers available from fine structure multiplets in (13)C spectra of glutamate and glutamine measured in vivo in rats brain at 14.1 T, termed bonded cumomer approach. Incorporating the labeling time courses of (13)C multiplets of glutamate and glutamine resulted in elevated precision of the estimated fluxes in rat brain as well as reduced correlations between them. PMID- 26969692 TI - Isolation of Endohyphal Bacteria from Foliar Ascomycota and In Vitro Establishment of Their Symbiotic Associations. AB - Endohyphal bacteria (EHB) can influence fungal phenotypes and shape the outcomes of plant-fungal interactions. Previous work has suggested that EHB form facultative associations with many foliar fungi in the Ascomycota. These bacteria can be isolated in culture, and fungi can be cured of EHB using antibiotics. Here, we present methods for successfully introducing EHB into axenic mycelia of strains representing two classes of Ascomycota. We first establish in vitro conditions favoring reintroduction of two strains of EHB (Luteibacter sp.) into axenic cultures of their original fungal hosts, focusing on fungi isolated from healthy plant tissue as endophytes: Microdiplodia sp. (Dothideomycetes) and Pestalotiopsis sp. (Sordariomycetes). We then demonstrate that these EHB can be introduced into a novel fungal host under the same conditions, successfully transferring EHB between fungi representing different classes. Finally, we manipulate conditions to optimize reintroduction in a focal EHB-fungal association. We show that EHB infections were initiated and maintained more often under low-nutrient culture conditions and when EHB and fungal hyphae were washed with MgCl2 prior to reassociation. Our study provides new methods for experimental assessment of the effects of EHB on fungal phenotypes and shows how the identity of the fungal host and growth conditions can define the establishment of these widespread and important symbioses. PMID- 26969693 TI - Comparative Single-Cell Genomics of Chloroflexi from the Okinawa Trough Deep Subsurface Biosphere. AB - Chloroflexi small-subunit (SSU) rRNA gene sequences are frequently recovered from subseafloor environments, but the metabolic potential of the phylum is poorly understood. The phylum Chloroflexi is represented by isolates with diverse metabolic strategies, including anoxic phototrophy, fermentation, and reductive dehalogenation; therefore, function cannot be attributed to these organisms based solely on phylogeny. Single-cell genomics can provide metabolic insights into uncultured organisms, like the deep-subsurface Chloroflexi Nine SSU rRNA gene sequences were identified from single-cell sorts of whole-round core material collected from the Okinawa Trough at Iheya North hydrothermal field as part of Integrated Ocean Drilling Program (IODP) expedition 331 (Deep Hot Biosphere). Previous studies of subsurface Chloroflexi single amplified genomes (SAGs) suggested heterotrophic or lithotrophic metabolisms and provided no evidence for growth by reductive dehalogenation. Our nine Chloroflexi SAGs (seven of which are from the order Anaerolineales) indicate that, in addition to genes for the Wood Ljungdahl pathway, exogenous carbon sources can be actively transported into cells. At least one subunit for pyruvate ferredoxin oxidoreductase was found in four of the Chloroflexi SAGs. This protein can provide a link between the Wood Ljungdahl pathway and other carbon anabolic pathways. Finally, one of the seven Anaerolineales SAGs contains a distinct reductive dehalogenase homologous (rdhA) gene. IMPORTANCE: Through the use of single amplified genomes (SAGs), we have extended the metabolic potential of an understudied group of subsurface microbes, the Chloroflexi These microbes are frequently detected in the subsurface biosphere, though their metabolic capabilities have remained elusive. In contrast to previously examined Chloroflexi SAGs, our genomes (several are from the order Anaerolineales) were recovered from a hydrothermally driven system and therefore provide a unique window into the metabolic potential of this type of habitat. In addition, a reductive dehalogenase gene (rdhA) has been directly linked to marine subsurface Chloroflexi, suggesting that reductive dehalogenation is not limited to the class Dehalococcoidia This discovery expands the nutrient-cycling and metabolic potential present within the deep subsurface and provides functional gene information relating to this enigmatic group. PMID- 26969694 TI - Detection and Diversity of Fungal Nitric Oxide Reductase Genes (p450nor) in Agricultural Soils. AB - Members of the Fungi convert nitrate (NO3 (-)) and nitrite (NO2 (-)) to gaseous nitrous oxide (N2O) (denitrification), but the fungal contributions to N loss from soil remain uncertain. Cultivation-based methodologies that include antibiotics to selectively assess fungal activities have limitations, and complementary molecular approaches to assign denitrification potential to fungi are desirable. Microcosms established with soils from two representative U.S. Midwest agricultural regions produced N2O from added NO3 (-) or NO2 (-) in the presence of antibiotics to inhibit bacteria. Cultivation efforts yielded 214 fungal isolates belonging to at least 15 distinct morphological groups, 151 of which produced N2O from NO2 (-) Novel PCR primers targeting the p450nor gene, which encodes the nitric oxide (NO) reductase responsible for N2O production in fungi, yielded 26 novel p450nor amplicons from DNA of 37 isolates and 23 amplicons from environmental DNA obtained from two agricultural soils. The sequences shared 54 to 98% amino acid identity with reference P450nor sequences within the phylum Ascomycota and expand the known fungal P450nor sequence diversity. p450nor was detected in all fungal isolates that produced N2O from NO2 (-), whereas nirK (encoding the NO-forming NO2 (-) reductase) was amplified in only 13 to 74% of the N2O-forming isolates using two separate nirK primer sets. Collectively, our findings demonstrate the value of p450nor-targeted PCR to complement existing approaches to assess the fungal contributions to denitrification and N2O formation. IMPORTANCE: A comprehensive understanding of the microbiota controlling soil N loss and greenhouse gas (N2O) emissions is crucial for sustainable agricultural practices and addressing climate change concerns. We report the design and application of a novel PCR primer set targeting fungal p450nor, a biomarker for fungal N2O production, and demonstrate the utility of the new approach to assess fungal denitrification potential in fungal isolates and agricultural soils. These new PCR primers may find application in a variety of biomes to assess the fungal contributions to N loss and N2O emissions. PMID- 26969695 TI - Complementation of Arginine Auxotrophy for Genetic Transformation of Coxiella burnetii by Use of a Defined Axenic Medium. AB - Host cell-free (axenic) culture of Coxiella burnetii in acidified citrate cysteine medium-2 (ACCM-2) has provided important opportunities for investigating the biology of this naturally obligate intracellular pathogen and enabled the development of tools for genetic manipulation. However, ACCM-2 has complex nutrient sources that preclude a detailed study of nutritional factors required for C. burnetii growth. Metabolic reconstruction of C. burnetii predicts that the bacterium cannot synthesize all amino acids and therefore must sequester some from the host. To examine C. burnetii amino acid auxotrophies, we developed a nutritionally defined medium with known amino acid concentrations, termed ACCM-D. Compared to ACCM-2, ACCM-D supported longer logarithmic growth, a more gradual transition to stationary phase, and approximately 5- to 10-fold greater overall replication. Small-cell-variant morphological forms generated in ACCM-D also showed increased viability relative to that generated in ACCM-2. Lack of growth in amino acid-deficient formulations of ACCM-D revealed C. burnetii auxotrophy for 11 amino acids, including arginine. Heterologous expression of Legionella pneumophila argGH in C. burnetii permitted growth in ACCM-D missing arginine and supplemented with citrulline, thereby providing a nonantibiotic means of selection of C. burnetii genetic transformants. Consistent with bioinformatic predictions, the elimination of glucose did not impair C. burnetii replication. Together, these results highlight the advantages of a nutritionally defined medium in investigations of C. burnetii metabolism and the development of genetic tools. IMPORTANCE: Host cell-free growth and genetic manipulation of Coxiella burnetii have revolutionized research of this intracellular bacterial pathogen. Nonetheless, undefined components of growth medium have made studies of C. burnetii physiology difficult and have precluded the development of selectable markers for genetic transformation based on nutritional deficiencies. Here, we describe a medium, containing only amino acids as the sole source of carbon and energy, which supports robust growth and improved viability of C. burnetii Growth studies confirmed that C. burnetii cannot replicate in medium lacking arginine. However, genetic transformation of the bacterium with constructs containing the last two genes in the L. pneumophila arginine biosynthesis pathway (argGH) allowed growth on defined medium missing arginine but supplemented with the arginine precursor citrulline. Our results advance the field by facilitating studies of C. burnetii metabolism and allowing non-antibiotic-based selection of C. burnetii genetic transformants, an important achievement considering that selectable makers based on antibiotic resistance are limited. PMID- 26969696 TI - Control of Legionella Contamination and Risk of Corrosion in Hospital Water Networks following Various Disinfection Procedures. AB - Physical and chemical disinfection methods have been proposed with the aim of controlling Legionella water contamination. To date, the most effective procedures for reducing bacterial contamination have not yet been defined. The aim of this study was to assess the long-term effectiveness of various disinfection procedures in order to reduce both culturable and nonculturable (NC) legionellae in different hospital water networks treated with heat, chlorine dioxide, monochloramine, and hydrogen peroxide. The temperature levels and biocide concentrations that proved to give reliable results were analyzed. In order to study the possible effects on the water pipes, we verified the extent of corrosion on experimental coupons after applying each method for 6 months. The percentage of positive points was at its lowest after treatment with monochloramine, followed by chlorine dioxide, hydrogen peroxide, and hyperthermia. Different selections of Legionella spp. were observed, as networks treated with chlorine-based disinfectants were contaminated mainly by Legionella pneumophila serogroup 1, hyperthermia was associated with serogroups 2 to 14, and hydrogen peroxide treatment was associated mainly with non-pneumophila species. NC cells were detected only in heat-treated waters, and also when the temperature was approximately 60 degrees C. The corrosion rates of the coupons were within a satisfactory limit for water networks, but the morphologies differed. We confirm here that chemical disinfection controls Legionella colonization more effectively than hyperthermia does. Monochloramine was the most effective treatment, while hydrogen peroxide may be a promising alternative to chlorine-based disinfectants due to its ability to select for other, less virulent or nonpathogenic species. PMID- 26969697 TI - Development of a Real-Time PCR for a Sensitive One-Step Coprodiagnosis Allowing both the Identification of Carnivore Feces and the Detection of Toxocara spp. and Echinococcus multilocularis. AB - Studying the environmental occurrence of parasites of concern for humans and animals based on coprosamples is an expanding field of work in epidemiology and the ecology of health. Detecting and quantifying Toxocara spp. and Echinococcus multilocularis, two predominant zoonotic helminths circulating in European carnivores, in feces may help to better target measures for prevention. A rapid, sensitive, and one-step quantitative PCR (qPCR) allowing detection of E. multilocularis and Toxocara spp. was developed in the present study, combined with a host fecal test based on the identification of three carnivores (red fox, dog, and cat) involved in the life cycles of these parasites. A total of 68 coprosamples were collected from identified specimens from Vulpes vulpes, Canis lupus familiaris, Canis lupus, Felis silvestris catus, Meles meles, Martes foina, and Martes martes With DNA coprosamples, real-time PCR was performed in duplex with a qPCR inhibitor control specifically designed for this study. All the coprosample host identifications were confirmed by qPCR combined with sequencing, and parasites were detected and confirmed (E. multilocularis in red foxes and Toxocara cati in cats; 16% of samples presented inhibition). By combining parasite detection and quantification, the host fecal test, and a new qPCR inhibitor control, we created a technique with a high sensitivity that may considerably improve environmental studies of pathogens. PMID- 26969698 TI - Cellar-Associated Saccharomyces cerevisiae Population Structure Revealed High Level Diversity and Perennial Persistence at Sauternes Wine Estates. AB - Three wine estates (designated A, B, and C) were sampled in Sauternes, a typical appellation of the Bordeaux wine area producing sweet white wine. From those wine estates, 551 yeast strains were collected between 2012 and 2014, added to 102 older strains from 1992 to 2011 from wine estate C. All the strains were analyzed through 15 microsatellite markers, resulting in 503 unique Saccharomyces cerevisiae genotypes, revealing high genetic diversity and a low presence of commercial yeast starters. Population analysis performed using Fst genetic distance or ancestry profiles revealed that the two closest wine estates, B and C, which have juxtaposed vineyard plots and common seasonal staff, share more related isolates with each other than with wine estate A, indicating exchange between estates. The characterization of isolates collected 23 years ago at wine estate C in relation to recent isolates obtained at wine estate B revealed the long-term persistence of isolates. Last, during the 2014 harvest period, a temporal succession of ancestral subpopulations related to the different batches associated with the selective picking of noble rotted grapes was highlighted. IMPORTANCE: High genetic diversity of S. cerevisiae isolates from spontaneous fermentation on wine estates in the Sauternes appellation of Bordeaux was revealed. Only 7% of all Sauternes strains were considered genetically related to specific commercial strains. The long-term persistence (over 20 years) of S. cerevisiae profiles on a given wine estate is highlighted. PMID- 26969699 TI - Recognition of Histo-Blood Group Antigen-Like Carbohydrates in Lettuce by Human GII.4 Norovirus. AB - Human norovirus (HuNoV) genogroup II genotype 4 (GII.4) strains account for about 80% of the gastroenteritis outbreaks in the United States. Contaminated food is a major transmission vehicle for this virus. In humans, pigs, and oysters, histo blood group antigens (HBGAs) act as attachment factors for HuNoVs. In lettuce, although the virus-like particles (VLPs) of a GII.4 HuNoV were found to bind to cell wall carbohydrates, the exact binding site has not been investigated. Here, we show the presence of HBGA-like carbohydrates in the cell wall of lettuce. The digestion of lettuce leaves with cell wall-degrading enzymes exposed more binding sites and significantly increased the level of binding of GII.4 HuNoV VLPs. Competition assays showed that both the HBGA monoclonal antibody, recognizing the H type, and plant lectins, recognizing alpha-l-fucose in the H type, effectively inhibited VLP binding to lettuce tissues. Lettuce cell wall components were isolated and their NoV VLP binding characteristics were tested by enzyme-linked immunosorbent assays. The binding was inhibited by pretreatment of the lettuce cell wall materials with alpha-1,2-fucosidase. Collectively, our results indicate that H-type HBGA-like carbohydrates exist in lettuce tissues and that GII.4 HuNoV VLPs can bind the exposed fucose moiety, possibly in the hemicellulose component of the cell wall. IMPORTANCE: Salad crops and fruits are increasingly recognized as vehicles for human norovirus (HuNoV) transmission. A recent study showed that HuNoVs specifically bind to the carbohydrates of the lettuce cell wall. Histo blood group antigens (HBGAs) are carbohydrates and are known as the attachment factors for HuNoV infection in humans. In this study, we show the presence of HBGA-like carbohydrates in lettuce, to which HuNoVs specifically bind. These results suggest that specifically bound HuNoVs cannot be removed by simple washing, which may allow viral transmission to consumers. Our findings provide new information needed for developing potential inhibitors to block binding and prevent contamination. PMID- 26969700 TI - Transcriptional Profile during Deoxycholate-Induced Sporulation in a Clostridium perfringens Isolate Causing Foodborne Illness. AB - Clostridium perfringens type A is a common source of foodborne illness (FBI) in humans. Vegetative cells sporulate in the small intestinal tract and produce the major pathogenic factor C. perfringens enterotoxin. Although sporulation plays a critical role in the pathogenesis of FBI, the mechanisms inducing sporulation remain unclear. Bile salts were shown previously to induce sporulation, and we confirmed deoxycholate (DCA)-induced sporulation in C. perfringens strain NCTC8239 cocultured with human intestinal epithelial Caco-2 cells. In the present study, we performed transcriptome analyses of strain NCTC8239 in order to elucidate the mechanism underlying DCA-induced sporulation. Of the 2,761 genes analyzed, 333 were up- or downregulated during DCA-induced sporulation and included genes for cell division, nutrient metabolism, signal transduction, and defense mechanisms. In contrast, the virulence-associated transcriptional regulators (the VirR/VirS system, the agr system, codY, and abrB) were not activated by DCA. DCA markedly increased the expression of signaling molecules controlled by Spo0A, the master regulator of the sporulation process, whereas the expression of spo0A itself was not altered in the presence or absence of DCA. The phosphorylation of Spo0A was enhanced in the presence of DCA. Collectively, these results demonstrated that DCA induced sporulation, at least partially, by facilitating the phosphorylation of Spo0A and activating Spo0A-regulated genes in strain NCTC8239 while altering the expression of various genes. IMPORTANCE: Disease caused by Clostridium perfringens type A consistently ranks among the most common bacterial foodborne illnesses in humans in developed countries. The sporulation of C. perfringens in the small intestinal tract is a key event for its pathogenesis, but the factors and underlying mechanisms by which C. perfringens sporulates in vivo currently remain unclear. Bile salts, major components of bile, which is secreted from the liver for the emulsification of lipids, were shown to induce sporulation. However, the mechanisms underlying bile salt-induced sporulation have not yet been clarified. In the present study, we demonstrate that deoxycholate (one of the bile salts) induces sporulation by facilitating the phosphorylation of Spo0A and activating Spo0A-regulated genes using a transcriptome analysis. Thus, this study enhances our understanding of the mechanisms underlying sporulation, particularly that of bile salt-induced sporulation, in C. perfringens. PMID- 26969702 TI - Biological Low-pH Mn(II) Oxidation in a Manganese Deposit Influenced by Metal Rich Groundwater. AB - The mechanisms, key organisms, and geochemical significance of biological low-pH Mn(II) oxidation are largely unexplored. Here, we investigated the structure of indigenous Mn(II)-oxidizing microbial communities in a secondary subsurface Mn oxide deposit influenced by acidic (pH 4.8) metal-rich groundwater in a former uranium mining area. Microbial diversity was highest in the Mn deposit compared to the adjacent soil layers and included the majority of known Mn(II)-oxidizing bacteria (MOB) and two genera of known Mn(II)-oxidizing fungi (MOF). Electron X ray microanalysis showed that romanechite [(Ba,H2O)2(Mn(4+),Mn(3+))5O10] was conspicuously enriched in the deposit. Canonical correspondence analysis revealed that certain fungal, bacterial, and archaeal groups were firmly associated with the autochthonous Mn oxides. Eight MOB within the Proteobacteria, Actinobacteria, and Bacteroidetes and one MOF strain belonging to Ascomycota were isolated at pH 5.5 or 7.2 from the acidic Mn deposit. Soil-groundwater microcosms demonstrated 2.5-fold-faster Mn(II) depletion in the Mn deposit than adjacent soil layers. No depletion was observed in the abiotic controls, suggesting that biological contribution is the main driver for Mn(II) oxidation at low pH. The composition and species specificity of the native low-pH Mn(II) oxidizers were highly adapted to in situ conditions, and these organisms may play a central role in the fundamental biogeochemical processes (e.g., metal natural attenuation) occurring in the acidic, oligotrophic, and metalliferous subsoil ecosystems. IMPORTANCE: This study provides multiple lines of evidence to show that microbes are the main drivers of Mn(II) oxidation even at acidic pH, offering new insights into Mn biogeochemical cycling. A distinct, highly adapted microbial community inhabits acidic, oligotrophic Mn deposits and mediates biological Mn oxidation. These data highlight the importance of biological processes for Mn biogeochemical cycling and show the potential for new bioremediation strategies aimed at enhancing biological Mn oxidation in low-pH environments for contaminant mitigation. PMID- 26969701 TI - Biofilms on Hospital Shower Hoses: Characterization and Implications for Nosocomial Infections. AB - Although the source of drinking water (DW) used in hospitals is commonly disinfected, biofilms forming on water pipelines are a refuge for bacteria, including possible pathogens that survive different disinfection strategies. These biofilm communities are only beginning to be explored by culture independent techniques that circumvent the limitations of conventional monitoring efforts. Hence, theories regarding the frequency of opportunistic pathogens in DW biofilms and how biofilm members withstand high doses of disinfectants and/or chlorine residuals in the water supply remain speculative. The aim of this study was to characterize the composition of microbial communities growing on five hospital shower hoses using both 16S rRNA gene sequencing of bacterial isolates and whole-genome shotgun metagenome sequencing. The resulting data revealed a Mycobacterium-like population, closely related to Mycobacterium rhodesiae and Mycobacterium tusciae, to be the predominant taxon in all five samples, and its nearly complete draft genome sequence was recovered. In contrast, the fraction recovered by culture was mostly affiliated with Proteobacteria, including members of the genera Sphingomonas, Blastomonas, and Porphyrobacter.The biofilm community harbored genes related to disinfectant tolerance (2.34% of the total annotated proteins) and a lower abundance of virulence determinants related to colonization and evasion of the host immune system. Additionally, genes potentially conferring resistance to beta-lactam, aminoglycoside, amphenicol, and quinolone antibiotics were detected. Collectively, our results underscore the need to understand the microbiome of DW biofilms using metagenomic approaches. This information might lead to more robust management practices that minimize the risks associated with exposure to opportunistic pathogens in hospitals. PMID- 26969703 TI - Nanomechanical Characterization of Bacillus anthracis Spores by Atomic Force Microscopy. AB - The study of structures and properties of bacterial spores is important to understanding spore formation and biological responses to environmental stresses. While significant progress has been made over the years in elucidating the multilayer architecture of spores, the mechanical properties of the spore interior are not known. Here, we present a thermal atomic force microscopy (AFM) study of the nanomechanical properties of internal structures of Bacillus anthracis spores. We developed a nanosurgical sectioning method in which a stiff diamond AFM tip was used to cut an individual spore, exposing its internal structure, and a soft AFM tip was used to image and characterize the spore interior on the nanometer scale. We observed that the elastic modulus and adhesion force, including their thermal responses at elevated temperatures, varied significantly in different regions of the spore section. Our AFM images indicated that the peptidoglycan (PG) cortex of Bacillus anthracis spores consisted of rod-like nanometer-sized structures that are oriented in the direction perpendicular to the spore surface. Our findings may shed light on the spore architecture and properties. IMPORTANCE: A nanosurgical AFM method was developed that can be used to probe the structure and properties of the spore interior. The previously unknown ultrastructure of the PG cortex of Bacillus anthracis spores was observed to consist of nanometer-sized rod-like structures that are oriented in the direction perpendicular to the spore surface. The variations in the nanomechanical properties of the spore section were largely correlated with its chemical composition. Different components of the spore materials showed different thermal responses at elevated temperatures. PMID- 26969705 TI - Application of a Euryarchaeota-Specific Helicase from Thermococcus kodakarensis for Noise Reduction in PCR. AB - DNA/RNA helicases, which are enzymes for eliminating hydrogen bonds between bases of DNA/DNA, DNA/RNA, and RNA/RNA using the energy of ATP hydrolysis, contribute to various biological activities. In the present study, the Euryarchaeota specific helicase EshA (TK0566) from the hyperthermophilic archaeon Thermococcus kodakarensis (Tk-EshA) was obtained as a recombinant form, and its enzymatic properties were examined. Tk-EshA exhibited maximal ATPase activity in the presence of RNA at 80 degrees C. Unwinding activity was evaluated with various double-stranded DNAs (forked, 5' overhung, 3' overhung, and blunt end) at 50 degrees C. Tk-EshA unwound forked and 3' overhung DNAs. These activities were expected to unwind the structured template and to peel off misannealed primers when Tk-EshA was added to a PCR mixture. To examine the effect of Tk-EshA on PCR, various target DNAs were selected, and DNA synthesis was investigated. When 16S rRNA genes were used as a template, several misamplified products (noise DNAs) were detected in the absence of Tk-EshA. In contrast, noise DNAs were eliminated in the presence of Tk-EshA. Noise reduction by Tk-EshA was also confirmed when Taq DNA polymerase (a family A DNA polymerase, PolI type) and KOD DNA polymerase (a family B DNA polymerase, alpha type) were used for PCR. Misamplified bands were also eliminated during toxA gene amplification from Pseudomonas aeruginosa DNA, which possesses a high GC content (69%). Tk-EshA addition was more effective than increasing the annealing temperature to reduce misamplified DNAs during toxA amplification. Tk-EshA is a useful tool to reduce noise DNAs for accurate PCR. IMPORTANCE: PCR is a technique that is useful for genetic diagnosis, genetic engineering, and detection of pathogenic microorganisms. However, troubles with nonspecific DNA amplification often occur from primer misannealing. In order to achieve a specific DNA amplification by eliminating noise DNAs derived from primer misannealing, a thermostable Euryarchaeota-specific helicase (Tk-EshA) was included in the PCR mixture. The addition of Tk-EshA has reduced noise DNAs in PCR. PMID- 26969704 TI - Isolation and Complete Genome Sequence of Algibacter alginolytica sp. nov., a Novel Seaweed-Degrading Bacteroidetes Bacterium with Diverse Putative Polysaccharide Utilization Loci. AB - The members of the phylum Bacteroidetes are recognized as some of the most important specialists for the degradation of polysaccharides. However, in contrast to research on Bacteroidetes in the human gut, research on polysaccharide degradation by marine Bacteroidetes is still rare. The genus Algibacter belongs to the Flavobacteriaceae family of the Bacteroidetes, and most species in this genus are isolated from or near the habitat of algae, indicating a preference for the complex polysaccharides of algae. In this work, a novel brown-seaweed-degrading strain designated HZ22 was isolated from the surface of a brown seaweed (Laminaria japonica). On the basis of its physiological, chemotaxonomic, and genotypic characteristics, it is proposed that strain HZ22 represents a novel species in the genus Algibacter with the proposed name Algibacter alginolytica sp. nov. The genome of strain HZ22, the type strain of this species, harbors 3,371 coding sequences (CDSs) and 255 carbohydrate-active enzymes (CAZymes), including 104 glycoside hydrolases (GHs) and 18 polysaccharide lyases (PLs); this appears to be the highest proportion of CAZymes (~7.5%) among the reported strains in the class Flavobacteria Seventeen polysaccharide utilization loci (PUL) are predicted to be specific for marine polysaccharides, especially algal polysaccharides from red, green, and brown seaweeds. In particular, PUL N is predicted to be specific for alginate. Taking these findings together with the results of assays of crude alginate lyases, we prove that strain HZ22(T) can completely degrade alginate. This work reveals that strain HZ22(T) has good potential for the degradation of algal polysaccharides and that the structure and related mechanism of PUL in strain HZ22(T) are worth further research. PMID- 26969706 TI - The apt/6-Methylpurine Counterselection System and Its Applications in Genetic Studies of the Hyperthermophilic Archaeon Sulfolobus islandicus. AB - Sulfolobus islandicus serves as a model for studying archaeal biology as well as linking novel biology to evolutionary ecology using functional population genomics. In the present study, we developed a new counterselectable genetic marker in S. islandicus to expand the genetic toolbox for this species. We show that resistance to the purine analog 6-methylpurine (6-MP) in S. islandicus M.16.4 is due to the inactivation of a putative adenine phosphoribosyltransferase encoded by M164_0158 (apt). The application of the apt gene as a novel counterselectable marker was first illustrated by constructing an unmarked alpha amylase deletion mutant. Furthermore, the 6-MP counterselection feature was employed in a forward (loss-of-function) mutation assay to reveal the profile of spontaneous mutations in S. islandicus M.16.4 at the apt locus. Moreover, the general conservation of apt genes in the crenarchaea suggests that the same strategy can be broadly applied to other crenarchaeal model organisms. These results demonstrate that the apt locus represents a new tool for genetic manipulation and sequence analysis of the hyperthermophilic crenarchaeon S. islandicus IMPORTANCE: Currently, the pyrEF/5-fluoroorotic acid (5-FOA) counterselection system remains the sole counterselection marker in crenarchaeal genetics. Since most Sulfolobus mutants constructed by the research community were derived from genetic hosts lacking the pyrEF genes, the pyrEF/5-FOA system is no longer available for use in forward mutation assays. Demonstration of the apt/6-MP counterselection system for the Sulfolobus model renders it possible to again study the mutation profiles in mutants that have already been constructed by the use of strains with a pyrEF-deficient background. Furthermore, additional counterselectable markers will allow us to conduct more sophisticated genetic studies, i.e., investigate mechanisms of chromosomal DNA transfer and quantify recombination frequencies among S. islandicus strains. PMID- 26969707 TI - Kinetics of Inactivation of Bacillus subtilis subsp. niger Spores and Staphylococcus albus on Paper by Chlorine Dioxide Gas in an Enclosed Space. AB - Bacillus subtilis subsp. niger spore and Staphylococcus albus are typical biological indicators for the inactivation of airborne pathogens. The present study characterized and compared the behaviors of B. subtilis subsp. niger spores and S. albus in regard to inactivation by chlorine dioxide (ClO2) gas under different gas concentrations and relative humidity (RH) conditions. The inactivation kinetics under different ClO2 gas concentrations (1 to 5 mg/liter) were determined by first-order and Weibull models. A new model (the Weibull-H model) was established to reveal the inactivation tendency and kinetics for ClO2 gas under different RH conditions (30 to 90%). The results showed that both the gas concentration and RH were significantly (P < 0.05) and positively correlated with the inactivation of the two chosen indicators. There was a rapid improvement in the inactivation efficiency under high RH (>70%). Compared with the first order model, the Weibull and Weibull-H models demonstrated a better fit for the experimental data, indicating nonlinear inactivation behaviors of the vegetative bacteria and spores following exposure to ClO2 gas. The times to achieve a six log reduction of B. subtilis subsp. niger spore and S. albus were calculated based on the established models. Clarifying the kinetics of inactivation of B. subtilis subsp. niger spores and S. albus by ClO2 gas will allow the development of ClO2 gas treatments that provide an effective disinfection method. IMPORTANCE: Chlorine dioxide (ClO2) gas is a novel and effective fumigation agent with strong oxidization ability and a broad biocidal spectrum. The antimicrobial efficacy of ClO2 gas has been evaluated in many previous studies. However, there are presently no published models that can be used to describe the kinetics of inactivation of airborne pathogens by ClO2 gas under different gas concentrations and RH conditions. The first-order and Weibull (Weibull-H) models established in this study can characterize and compare the behaviors of Bacillus subtilis subsp. niger spores and Staphylococcus albus in regard to inactivation by ClO2 gas, determine the kinetics of inactivation of two chosen strains under different conditions of gas concentration and RH, and provide the calculated time to achieve a six-log reduction. These results will be useful to determine effective conditions for ClO2 gas to inactivate airborne pathogens in contaminated air and other environments and thus prevent outbreaks of airborne illness. PMID- 26969708 TI - Soybean Ferritin Expression in Saccharomyces cerevisiae Modulates Iron Accumulation and Resistance to Elevated Iron Concentrations. AB - Fungi, including the yeast Saccharomyces cerevisiae, lack ferritin and use vacuoles as iron storage organelles. This work explored how plant ferritin expression influenced baker's yeast iron metabolism. Soybean seed ferritin H1 (SFerH1) and SFerH2 genes were cloned and expressed in yeast cells. Both soybean ferritins assembled as multimeric complexes, which bound yeast intracellular iron in vivo and, consequently, induced the activation of the genes expressed during iron scarcity. Soybean ferritin protected yeast cells that lacked the Ccc1 vacuolar iron detoxification transporter from toxic iron levels by reducing cellular oxidation, thus allowing growth at high iron concentrations. Interestingly, when simultaneously expressed in ccc1Delta cells, SFerH1 and SFerH2 assembled as heteropolymers, which further increased iron resistance and reduced the oxidative stress produced by excess iron compared to ferritin homopolymer complexes. Finally, soybean ferritin expression led to increased iron accumulation in both wild-type and ccc1Delta yeast cells at certain environmental iron concentrations. IMPORTANCE: Iron deficiency is a worldwide nutritional disorder to which women and children are especially vulnerable. A common strategy to combat iron deficiency consists of dietary supplementation with inorganic iron salts, whose bioavailability is very low. Iron-enriched yeasts and cereals are alternative strategies to diminish iron deficiency. Animals and plants possess large ferritin complexes that accumulate, detoxify, or buffer excess cellular iron. However, the yeast Saccharomyces cerevisiae lacks ferritin and uses vacuoles as iron storage organelles. Here, we explored how soybean ferritin expression influenced yeast iron metabolism, confirming that yeasts that express soybean seed ferritin could be explored as a novel strategy to increase dietary iron absorption. PMID- 26969710 TI - Enlargement of the superior rectus and superior oblique muscles causes intorsion in Graves' eye disease. AB - PURPOSE: To review the prevalence of preoperative and postoperative intorsion in patients with strabismus and Graves' eye disease (GED), and to correlate the intorsion with coexisting superior rectus (SR) and superior oblique (SO) muscle enlargement as a possible mechanism causing intorsion in these patients. METHODS: Charts of consecutive patients with GED who underwent strabismus surgery between 1 January 2010 and 1 April 2013 were retrospectively reviewed. Of these, patients with orbital CT or MRI scan were identified for further analysis. Clinical characteristics documented included age, gender, horizontal and vertical deviation, subjective torsional deviation, specific extraocular muscles (EOMs) operated upon, EOM enlargement on CT/MRI scans and width and thickness of SO, SR group and inferior rectus (IR). RESULTS: Charts of 45 patients (14 males and 31 females) were reviewed. Mean age was 56.8+/-12.5 years. Of these, seven (15.6%) patients demonstrated intorsion, and 38 (84.4%) patients demonstrated extorsion preoperatively. But after strabismus surgery, 15 (39.5%) of the 38 patients with preoperative extorsion demonstrated postoperative intorsion and 23 (60.5%) patients continued to show postoperative extorsion. On analysis of CT/MRI scans in these patients, only an increase in the thickness of SR group and the thickness/width of SO muscle were significantly associated with preoperative and postoperative intorsion; while age, gender, preoperative horizontal or vertical deviation and IR recession were unrelated to preoperative or postoperative intorsion. Postoperative intorsion was also associated with smaller degrees of preoperative extorsion (<3.5 degrees ). CONCLUSIONS: Preoperative SR and/or SO muscle enlargement appear to be a primary contributing factor relating to preoperative and postoperative intorsion in patients with GED-associated strabismus. Patients with only small amounts of preoperative extorsion (<3.5 degrees ) in the presence of tight IRs should be carefully evaluated for possible SR and/or SO involvement by CT or MRI scan to predict those at risk for and plan for prevention/treatment of postoperative intorsion. PMID- 26969709 TI - Overproduction of Magnetosomes by Genomic Amplification of Biosynthesis-Related Gene Clusters in a Magnetotactic Bacterium. AB - Magnetotactic bacteria biosynthesize specific organelles, the magnetosomes, which are membrane-enclosed crystals of a magnetic iron mineral that are aligned in a linear chain. The number and size of magnetosome particles have to be critically controlled to build a sensor sufficiently strong to ensure the efficient alignment of cells within Earth's weak magnetic field while at the same time minimizing the metabolic costs imposed by excessive magnetosome biosynthesis. Apart from their biological function, bacterial magnetosomes have gained considerable interest since they provide a highly useful model for prokaryotic organelle formation and represent biogenic magnetic nanoparticles with exceptional properties. However, potential applications have been hampered by the difficult cultivation of these fastidious bacteria and their poor yields of magnetosomes. In this study, we found that the size and number of magnetosomes within the cell are controlled by many different Mam and Mms proteins. We present a strategy for the overexpression of magnetosome biosynthesis genes in the alphaproteobacterium Magnetospirillum gryphiswaldense by chromosomal multiplication of individual and multiple magnetosome gene clusters via transposition. While stepwise amplification of the mms6 operon resulted in the formation of increasingly larger crystals (increase of ~35%), the duplication of all major magnetosome operons (mamGFDC, mamAB, mms6, and mamXY, comprising 29 genes in total) yielded an overproducing strain in which magnetosome numbers were 2.2-fold increased. We demonstrate that the tuned expression of the mam and mms clusters provides a powerful strategy for the control of magnetosome size and number, thereby setting the stage for high-yield production of tailored magnetic nanoparticles by synthetic biology approaches. IMPORTANCE: Before our study, it had remained unknown how the upper sizes and numbers of magnetosomes are genetically regulated, and overproduction of magnetosome biosynthesis had not been achieved, owing to the difficulties of large-scale genome engineering in the recalcitrant magnetotactic bacteria. In this study, we established and systematically explored a strategy for the overexpression of magnetosome biosynthesis genes by genomic amplification of single and multiple magnetosome gene clusters via sequential chromosomal insertion by transposition. Our findings also indicate that the expression levels of magnetosome proteins together limit the upper size and number of magnetosomes within the cell. We demonstrate that tuned overexpression of magnetosome gene clusters provides a powerful strategy for the precise control of magnetosome size and number. PMID- 26969711 TI - Five years of treatment for retinopathy of prematurity in Sweden: results from SWEDROP, a national quality register. AB - BACKGROUND/AIMS: Retinopathy of prematurity (ROP) is a sight-threatening disease, requiring efficient screening and treatment. The present study aims to describe various aspects on treatment for ROP in Sweden. METHODS: Data on treatment for ROP in infants born in 2008-2012 were extracted from Swedish national register for retinopathy of prematurity, a web-based national register. RESULTS: During 2008-2012, 3488 infants with a gestational age (GA) at birth of <31 weeks had been screened for ROP in Sweden. Altogether, 30.3% (1057/3488) of the infants developed ROP and 5.2% (181/3488) were treated. Type 1 ROP was found in at least one eye in 83.2% (149/179) of the treated infants. One third of the eyes (32.2% right, 29.9% left eyes) were treated more than once. Laser was the only treatment in 90% of the eyes. Mean number of laser spots at first laser session was 1177 and 1386 in right and left eyes, respectively. Number of laser spots correlated negatively with GA at birth (p=0.01). There was no change in frequency of treatment or number of laser spots during the 5-year period. Anti-vascular endothelial growth factor injections were performed in 28 eyes, encircling band was used in five eyes and vitrectomies were performed in seven eyes. Twenty-six retinal surgeons performed 9.4 (range 1-37) treatment sessions in the 181 infants. CONCLUSIONS: The present study reveals similar incidences of ROP and frequencies of treatment during the 5-year study period. Many surgeons were involved in treatment of a rather limited number of infants. The results call for national discussions on organisation of ROP treatment. PMID- 26969712 TI - Glaucoma laser and surgical procedure rates in Australia. AB - AIM: To determine trends in the number of glaucoma laser and surgical procedures performed in Australia between 1994 and 2014. METHODS: Medicare claims were analysed to determine the number of glaucoma-related procedures reimbursed in Australia between 1994 and 2014. Glaucoma procedures were identified by Medicare Benefits Schedule item number and analysed by age range, gender, state, month and year. RESULTS: Laser trabeculoplasty rates declined 60% between 1994 and 2003 before increasing a dramatic 353% between 2003 and 2014. Laser iridotomies increased 281% over the study period while cyclodestructive procedures increased 207%. The number of primary filtering operations for glaucoma fell 68% from a peak in 1996 to a low in 2006 and then remained stable. However, the number of filtering operations in eyes where a previous filtering operation had been performed increased 27%. There was a marked increase in glaucoma drainage device insertion, increasing 234% over the study period. CONCLUSIONS: There has been a substantial increase in laser trabeculoplasty procedures in Australia, following a decline between 1994 and 2003. Primary filtering operations for glaucoma have declined in number while glaucoma drainage devices are playing an increasingly prominent role in the surgical management of glaucoma. PMID- 26969714 TI - Climate stories: Why do climate scientists and sceptical voices participate in the climate debate? AB - Public perceptions of the climate debate predominantly frame the key actors as climate scientists versus sceptical voices; however, it is unclear why climate scientists and sceptical voices choose to participate in this antagonistic and polarised public battle. A narrative interview approach is used to better understand the underlying rationales behind 22 climate scientists' and sceptical voices' engagement in the climate debate, potential commonalities, as well as each actor's ability to be critically self-reflexive. Several overlapping rationales are identified including a sense of duty to publicly engage, agreement that complete certainty about the complex assemblage of climate change is unattainable and that political factors are central to the climate debate. We argue that a focus on potential overlaps in perceptions and rationales as well as the ability to be critically self-reflexive may encourage constructive discussion among actors previously engaged in purposefully antagonistic exchange on climate change. PMID- 26969713 TI - FLNC myofibrillar myopathy results from impaired autophagy and protein insufficiency. AB - Myofibrillar myopathy is a progressive muscle disease characterized by the disintegration of muscle fibers and formation of protein aggregates. Causative mutations have been identified in nine genes encoding Z-disk proteins, including the actin binding protein filamin C (FLNC). To investigate the mechanism of disease in FLNCW2710X myopathy we overexpressed fluorescently tagged FLNC or FLNCW2710X in zebrafish. Expression of FLNCW2710X causes formation of protein aggregates but surprisingly, our studies reveal that the mutant protein localizes correctly to the Z-disk and is capable of rescuing the fiber disintegration phenotype that results from FLNC knockdown. This demonstrates that the functions necessary for muscle integrity are not impaired, and suggests that it is the formation of protein aggregates and subsequent sequestration of FLNC away from the Z-disk that results in myofibrillar disintegration. Similar to those found in patients, the aggregates in FLNCW2710X expressing fish contain the co-chaperone BAG3. FLNC is a target of the BAG3-mediated chaperone assisted selective autophagy (CASA) pathway and therefore we investigated its role, and the role of autophagy in general, in clearing protein aggregates. We reveal that despite BAG3 recruitment to the aggregates they are not degraded via CASA. Additionally, recruitment of BAG3 is sufficient to block alternative autophagy pathways which would otherwise clear the aggregates. This blockage can be relieved by reducing BAG3 levels or by stimulating autophagy. This study therefore identifies both BAG3 reduction and autophagy promotion as potential therapies for FLNCW2710X myofibrillar myopathy, and identifies protein insufficiency due to sequestration, compounded by impaired autophagy, as the cause. PMID- 26969717 TI - The Daring John Cooper Forster (1823-1886): The First Case of "Esophagus Blockage Gastrostomy" With Ligatures in England. PMID- 26969716 TI - Quantitative Proteomics Reveals beta2 Integrin-mediated Cytoskeletal Rearrangement in Vascular Endothelial Growth Factor (VEGF)-induced Retinal Vascular Hyperpermeability. AB - Retinal vascular hyperpermeability causes macular edema, leading to visual deterioration in retinal diseases such as diabetic retinopathy and retinal vascular occlusion. Dysregulation of junction integrity between endothelial cells by vascular endothelial growth factor (VEGF) was shown to cause retinal vascular hyperpermeability. Accordingly, anti-VEGF agents have been used to treat retinal vascular hyperpermeability. However, they can confer potential toxicity through their deleterious effects on maintenance and survival of neuronal and endothelial cells in the retina. Thus, it is important to identify novel therapeutic targets for retinal vascular hyperpermeability other than VEGF. Here, we prepared murine retinas showing VEGF-induced vascular leakage from superficial retinal vascular plexus and prevention of VEGF-induced leakage by anti-VEGF antibody treatment. We then performed comprehensive proteome profiling of these samples and identified retinal proteins for which abundances were differentially expressed by VEGF, but such alterations were inhibited by anti-VEGF antibody. Functional enrichment and network analyses of these proteins revealed the beta2 integrin pathway, which can prevent dysregulation of junction integrity between endothelial cells through cytoskeletal rearrangement, as a potential therapeutic target for retinal vascular hyperpermeability. Finally, we experimentally demonstrated that inhibition of the beta2 integrin pathway salvaged VEGF-induced retinal vascular hyperpermeability, supporting its validity as an alternative therapeutic target to anti-VEGF agents. PMID- 26969718 TI - A Novel Ultrasound-Based Registration for Image-Guided Laparoscopic Liver Ablation. AB - Background Patient-to-image registration is a core process of image-guided surgery (IGS) systems. We present a novel registration approach for application in laparoscopic liver surgery, which reconstructs in real time an intraoperative volume of the underlying intrahepatic vessels through an ultrasound (US) sweep process. Methods An existing IGS system for an open liver procedure was adapted, with suitable instrument tracking for laparoscopic equipment. Registration accuracy was evaluated on a realistic phantom by computing the target registration error (TRE) for 5 intrahepatic tumors. The registration work flow was evaluated by computing the time required for performing the registration. Additionally, a scheme for intraoperative accuracy assessment by visual overlay of the US image with preoperative image data was evaluated. Results The proposed registration method achieved an average TRE of 7.2 mm in the left lobe and 9.7 mm in the right lobe. The average time required for performing the registration was 12 minutes. A positive correlation was found between the intraoperative accuracy assessment and the obtained TREs. Conclusions The registration accuracy of the proposed method is adequate for laparoscopic intrahepatic tumor targeting. The presented approach is feasible and fast and may, therefore, not be disruptive to the current surgical work flow. PMID- 26969719 TI - Aretaeus of Cappadocia (Circa First Century bc or Fourth Century ad), Operating Hepatic Abscesses in Ancient Greece: A Reintroduction. PMID- 26969720 TI - Critical Roles of Vacuolar Invertase in Floral Organ Development and Male and Female Fertilities Are Revealed through Characterization of GhVIN1-RNAi Cotton Plants. AB - Seed number and quality are key traits determining plant fitness and crop yield and rely on combined competence in male and female fertilities. Sucrose metabolism is central to reproductive success. It remains elusive, though, how individual sucrose metabolic enzymes may regulate the complex reproductive processes. Here, by silencing vacuolar invertase (VIN) genes in cotton (Gossypium hirsutum) reproductive organs, we revealed diverse roles that VIN plays in multiple reproductive processes. A set of phenotypic and genetic studies showed significant reductions of viable seeds in GhVIN1-RNAi plants, attributed to pollination failure and impaired male and female fertilities. The former was largely owing to the spatial mismatch between style and stamen and delayed pollen release from the anthers, whereas male defects came from poor pollen viability. The transgenic stamen exhibited altered expression of the genes responsible for starch metabolism and auxin and jasmonic acid signaling. Further analyses identified the reduction of GhVIN expression in the seed coat as the major cause for the reduced female fertility, which appeared to disrupt the expression of some key genes involved in trehalose and auxin metabolism and signaling, leading to programmed cell death or growth repression in the filial tissues. Together, the data provide an unprecedented example of how VIN is required to synchronize style and stamen development and the formation of male and female fertilities for seed development in a crop species, cotton. PMID- 26969721 TI - TOPOISOMERASE1alpha Acts through Two Distinct Mechanisms to Regulate Stele and Columella Stem Cell Maintenance. AB - TOPOISOMERASE1 (TOP1), which releases DNA torsional stress generated during replication through its DNA relaxation activity, plays vital roles in animal and plant development. In Arabidopsis (Arabidopsis thaliana), TOP1 is encoded by two paralogous genes (TOP1alpha and TOP1beta), of which TOP1alpha displays specific developmental functions that are critical for the maintenance of shoot and floral stem cells. Here, we show that maintenance of two different populations of root stem cells is also dependent on TOP1alpha-specific developmental functions, which are exerted through two distinct novel mechanisms. In the proximal root meristem, the DNA relaxation activity of TOP1alpha is critical to ensure genome integrity and survival of stele stem cells (SSCs). Loss of TOP1alpha function triggers DNA double-strand breaks in S-phase SSCs and results in their death, which can be partially reversed by the replenishment of SSCs mediated by ETHYLENE RESPONSE FACTOR115 In the quiescent center and root cap meristem, TOP1alpha is epistatic to RETINOBLASTOMA-RELATED (RBR) in the maintenance of undifferentiated state and the number of columella stem cells (CSCs). Loss of TOP1alpha function in either wild-type or RBR RNAi plants leads to differentiation of CSCs, whereas overexpression of TOP1alpha mimics and further enhances the effect of RBR reduction that increases the number of CSCs Taken together, these findings provide important mechanistic insights into understanding stem cell maintenance in plants. PMID- 26969723 TI - Navigating moral distress using the moral distress map. AB - The plethora of literature on moral distress has substantiated and refined the concept, provided data about clinicians' (especially nurses') experiences, and offered advice for coping. Fewer scholars have explored what makes moral distress moral If we acknowledge that patient care can be distressing in the best of ethical circumstances, then differentiating distress and moral distress may refine the array of actions that are likely to ameliorate it. This article builds upon scholarship exploring the normative and conceptual dimensions of moral distress and introduces a new tool to map moral distress from emotional source to corrective actions. The Moral Distress Map has proven useful in clinical teaching and ethics-related debriefings. PMID- 26969724 TI - Daniel Halliday, 'The Ethics of a Smoking License'. PMID- 26969722 TI - Anisotropic Cell Expansion Is Affected through the Bidirectional Mobility of Cellulose Synthase Complexes and Phosphorylation at Two Critical Residues on CESA3. AB - Here we report that phosphorylation status of S211 and T212 of the CESA3 component of Arabidopsis (Arabidopsis thaliana) cellulose synthase impacts the regulation of anisotropic cell expansion as well as cellulose synthesis and deposition and microtubule-dependent bidirectional mobility of CESA complexes. Mutation of S211 to Ala caused a significant decrease in the length of etiolated hypocotyls and primary roots, while root hairs were not significantly affected. By contrast, the S211E mutation stunted the growth of root hairs, but primary roots were not significantly affected. Similarly, T212E caused a decrease in the length of root hairs but not root length. However, T212E stunted the growth of etiolated hypocotyls. Live-cell imaging of fluorescently labeled CESA showed that the rate of movement of CESA particles was directionally asymmetric in etiolated hypocotyls of S211A and T212E mutants, while similar bidirectional velocities were observed with the wild-type control and S211E and T212A mutant lines. Analysis of cell wall composition and the innermost layer of cell wall suggests a role for phosphorylation of CESA3 S211 and T212 in cellulose aggregation into fibrillar bundles. These results suggest that microtubule-guided bidirectional mobility of CESA complexes is fine-tuned by phosphorylation of CESA3 S211 and T212, which may, in turn, modulate cellulose synthesis and organization, resulting in or contributing to the observed defects of anisotropic cell expansion. PMID- 26969725 TI - Sp5 and Sp8 recruit beta-catenin and Tcf1-Lef1 to select enhancers to activate Wnt target gene transcription. AB - The ancient, highly conserved, Wnt signaling pathway regulates cell fate in all metazoans. We have previously shown that combined null mutations of the specificity protein (Sp) 1/Klf-like zinc-finger transcription factors Sp5 and Sp8 (i.e., Sp5/8) result in an embryonic phenotype identical to that observed when core components of the Wnt/beta-catenin pathway are mutated; however, their role in Wnt signal transduction is unknown. Here, we show in mouse embryos and differentiating embryonic stem cells that Sp5/8 are gene-specific transcriptional coactivators in the Wnt/beta-catenin pathway. Sp5/8 bind directly to GC boxes in Wnt target gene enhancers and to adjacent, or distally positioned, chromatin bound T-cell factor (Tcf) 1/lymphoid enhancer factor (Lef) 1 to facilitate recruitment of beta-catenin to target gene enhancers. Because Sp5 is itself directly activated by Wnt signals, we propose that Sp5 is a Wnt/beta-catenin pathway-specific transcript on factor that functions in a feed-forward loop to robustly activate select Wnt target genes. PMID- 26969726 TI - Hierarchy and extremes in selections from pools of randomized proteins. AB - Variation and selection are the core principles of Darwinian evolution, but quantitatively relating the diversity of a population to its capacity to respond to selection is challenging. Here, we examine this problem at a molecular level in the context of populations of partially randomized proteins selected for binding to well-defined targets. We built several minimal protein libraries, screened them in vitro by phage display, and analyzed their response to selection by high-throughput sequencing. A statistical analysis of the results reveals two main findings. First, libraries with the same sequence diversity but built around different "frameworks" typically have vastly different responses; second, the distribution of responses of the best binders in a library follows a simple scaling law. We show how an elementary probabilistic model based on extreme value theory rationalizes the latter finding. Our results have implications for designing synthetic protein libraries, estimating the density of functional biomolecules in sequence space, characterizing diversity in natural populations, and experimentally investigating evolvability (i.e., the potential for future evolution). PMID- 26969727 TI - Kinesin-12 motors cooperate to suppress microtubule catastrophes and drive the formation of parallel microtubule bundles. AB - Human Kinesin-12 (hKif15) plays a crucial role in assembly and maintenance of the mitotic spindle. These functions of hKif15 are partially redundant with Kinesin-5 (Eg5), which can cross-link and drive the extensile sliding of antiparallel microtubules. Although both motors are known to be tetramers, the functional properties of hKif15 are less well understood. Here we reveal how single or multiple Kif15 motors can cross-link, transport, and focus the plus-ends of intersecting microtubules. During transport, Kif15 motors step simultaneously along both microtubules with relative microtubule transport driven by a velocity differential between motor domain pairs. Remarkably, this differential is affected by the underlying intersection geometry: the differential is low on parallel and extreme on antiparallel microtubules where one motor domain pair becomes immobile. As a result, when intersecting microtubules are antiparallel, canonical transport of one microtubule along the other is allowed because one motor is firmly attached to one microtubule while it is stepping on the other. When intersecting microtubules are parallel, however, Kif15 motors can drive (biased) parallel sliding because the motor simultaneously steps on both microtubules that it cross-links. These microtubule rearrangements will focus microtubule plus-ends and finally lead to the formation of parallel bundles. At the same time, Kif15 motors cooperate to suppress catastrophe events at polymerizing microtubule plus-ends, raising the possibility that Kif15 motors may synchronize the dynamics of bundles that they have assembled. Thus, Kif15 is adapted to operate on parallel microtubule substrates, a property that clearly distinguishes it from the other tetrameric spindle motor, Eg5. PMID- 26969728 TI - Programmed chloroplast destruction during leaf senescence involves 13 lipoxygenase (13-LOX). AB - Leaf senescence is the terminal stage in the development of perennial plants. Massive physiological changes occur that lead to the shut down of photosynthesis and a cessation of growth. Leaf senescence involves the selective destruction of the chloroplast as the site of photosynthesis. Here, we show that 13-lipoxygenase (13-LOX) accomplishes a key role in the destruction of chloroplasts in senescing plants and propose a critical role of its NH2-terminal chloroplast transit peptide. The 13-LOX enzyme identified here accumulated in the plastid envelope and catalyzed the dioxygenation of unsaturated membrane fatty acids, leading to a selective destruction of the chloroplast and the release of stromal constituents. Because 13-LOX pathway products comprise compounds involved in insect deterrence and pathogen defense (volatile aldehydes and oxylipins), a mechanism of unmolested nitrogen and carbon relocation is suggested that occurs from leaves to seeds and roots during fall. PMID- 26969730 TI - Left ventricular assist device: a bridge to transplant or destination therapy? AB - Heart failure is a major problem worldwide; it is the leading cause of hospitalisation and is posing a huge financial burden. Advances in healthcare have contributed to increased life expectancy, with a resultant increase in the number of patients with chronic heart failure. For many patients who are still severely symptomatic despite optimal medical therapy and cardiac resynchronisation therapy, cardiac transplantation would be the preferred treatment option. However, hopes are cut short with a limited donor pool of hearts for the increasing number of patients requiring cardiac transplantation. One uprising method to fill this treatment void for patients with advanced end stage heart failure (ESHF) is the Left Ventricular Assist Device (LVAD). Although traditionally used as a bridge to transplantation, owing to limitation of suitable donors, evidence suggests increasing potential for the use of LVAD as destination therapy (DT), that is, lifelong permanent support. Exploration of DT is a promising avenue to many patients suffering with ESHF who may never be fortunate enough to receive a heart transplant, but not without reservations of its efficacy, safety, effects on quality-adjusted life years and cost effectiveness, especially in comparison to heart transplantation. PMID- 26969729 TI - Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility. AB - The signaling events that drive familial breast cancer (FBC) risk remain poorly understood. While the majority of genomic studies have focused on genetic risk variants, known risk variants account for at most 30% of FBC cases. Considering that multiple genes may influence FBC risk, we hypothesized that a pathway-based strategy examining different data types from multiple tissues could elucidate the biological basis for FBC. In this study, we performed integrated analyses of gene expression and exome-sequencing data from peripheral blood mononuclear cells and showed that cell adhesion pathways are significantly and consistently dysregulated in women who develop FBC. The dysregulation of cell adhesion pathways in high-risk women was also identified by pathway-based profiling applied to normal breast tissue data from two independent cohorts. The results of our genomic analyses were validated in normal primary mammary epithelial cells from high-risk and control women, using cell-based functional assays, drug response assays, fluorescence microscopy, and Western blotting assays. Both genomic and cell-based experiments indicate that cell-cell and cell-extracellular matrix adhesion processes seem to be disrupted in non-malignant cells of women at high risk for FBC and suggest a potential role for these processes in FBC development. PMID- 26969732 TI - Substrate requirements for let-7 function in the developing zebrafish embryo. PMID- 26969731 TI - Structural characterization of the virulence factor Sda1 nuclease from Streptococcus pyogenes. AB - Infection by Group A Streptococcus pyogenes (GAS) is a leading cause of severe invasive disease in humans, including streptococcal toxic shock syndrome and necrotizing fasciitis. GAS infections lead to nearly 163,000 annual deaths worldwide. Hypervirulent strains of S. pyogenes have evolved a plethora of virulence factors that aid in disease-by promoting bacterial adhesion to host cells, subsequent invasion of deeper tissues and blocking the immune system's attempts to eradicate the infection. Expression and secretion of the extracellular nuclease Sda1 is advantageous for promoting bacterial dissemination throughout the host organism, and evasion of the host's innate immune response. Here we present two crystal structures of Sda1, as well as biochemical studies to address key structural features and surface residues involved in DNA binding and catalysis. In the active site, Asn211 is observed to directly chelate a hydrated divalent metal ion and Arg124, on the putative substrate binding loop, likely stabilizes the transition state during phosphodiester bond cleavage. These structures provide a foundation for rational drug design of small molecule inhibitors to be used in prevention of invasive streptococcal disease. PMID- 26969733 TI - Opportunities in the design and application of RNA for gene expression control. AB - The past decade of synthetic biology research has witnessed numerous advances in the development of tools and frameworks for the design and characterization of biological systems. Researchers have focused on the use of RNA for gene expression control due to its versatility in sensing molecular ligands and the relative ease by which RNA can be modeled and designed compared to proteins. We review the recent progress in the field with respect to RNA-based genetic devices that are controlled through small molecule and protein interactions. We discuss new approaches for generating and characterizing these devices and their underlying components. We also highlight immediate challenges, future directions and recent applications of synthetic RNA devices in engineered biological systems. PMID- 26969734 TI - Selection of DNA nanoparticles with preferential binding to aggregated protein target. AB - High affinity and specificity are considered essential for affinity reagents and molecularly-targeted therapeutics, such as monoclonal antibodies. However, life's own molecular and cellular machinery consists of lower affinity, highly multivalent interactions that are metastable, but easily reversible or displaceable. With this inspiration, we have developed a DNA-based reagent platform that uses massive avidity to achieve stable, but reversible specific recognition of polyvalent targets. We have previously selected these DNA reagents, termed DeNAno, against various cells and now we demonstrate that DeNAno specific for protein targets can also be selected. DeNAno were selected against streptavidin-, rituximab- and bevacizumab-coated beads. Binding was stable for weeks and unaffected by the presence of soluble target proteins, yet readily competed by natural or synthetic ligands of the target proteins. Thus DeNAno particles are a novel biomolecular recognition agent whose orthogonal use of avidity over affinity results in uniquely stable yet reversible binding interactions. PMID- 26969735 TI - Repurposing the CRISPR-Cas9 system for targeted DNA methylation. AB - Epigenetic studies relied so far on correlations between epigenetic marks and gene expression pattern. Technologies developed for epigenome editing now enable direct study of functional relevance of precise epigenetic modifications and gene regulation. The reversible nature of epigenetic modifications, including DNA methylation, has been already exploited in cancer therapy for remodeling the aberrant epigenetic landscape. However, this was achieved non-selectively using epigenetic inhibitors. Epigenetic editing at specific loci represents a novel approach that might selectively and heritably alter gene expression. Here, we developed a CRISPR-Cas9-based tool for specific DNA methylation consisting of deactivated Cas9 (dCas9) nuclease and catalytic domain of the DNA methyltransferase DNMT3A targeted by co-expression of a guide RNA to any 20 bp DNA sequence followed by the NGG trinucleotide. We demonstrated targeted CpG methylation in a ~35 bp wide region by the fusion protein. We also showed that multiple guide RNAs could target the dCas9-DNMT3A construct to multiple adjacent sites, which enabled methylation of a larger part of the promoter. DNA methylation activity was specific for the targeted region and heritable across mitotic divisions. Finally, we demonstrated that directed DNA methylation of a wider promoter region of the target loci IL6ST and BACH2 decreased their expression. PMID- 26969737 TI - Cell cycle-dependent changes in localization and phosphorylation of the plasma membrane Kv2.1 K+ channel impact endoplasmic reticulum membrane contact sites in COS-1 cells. PMID- 26969736 TI - Noncanonical registers and base pairs in human 5' splice-site selection. AB - Accurate recognition of splice sites is essential for pre-messenger RNA splicing. Mammalian 5' splice sites are mainly recognized by canonical base-pairing to the 5' end of U1 small nuclear RNA, yet we described multiple noncanonical base pairing registers by shifting base-pair positions or allowing one-nucleotide bulges. By systematic mutational and suppressor U1 analyses, we prove three registers involving asymmetric loops and show that two-nucleotide bulges but not longer can form in this context. Importantly, we established that a noncanonical uridine-pseudouridine interaction in the 5' splice site/U1 helix contributes to the recognition of certain 5' splice sites. Thermal melting experiments support the formation of noncanonical registers and uridine-pseudouridine interactions. Overall, we experimentally validated or discarded the majority of predicted noncanonical registers, to derive a list of 5' splice sites using such alternative mechanisms that is much different from the original. This study allows not only the mechanistic understanding of the recognition of a wide diversity of mammalian 5' splice sites, but also the future development of better splice-site scoring methods that reliably predict the effects of disease-causing mutations at these sequences. PMID- 26969738 TI - Longevity and admission to nursing home according to age after isolated coronary artery bypass surgery: a nationwide cohort study. AB - OBJECTIVES: Data on nursing home admission in patient's >=80 years after isolated coronary artery bypass grafting (CABG) are scarce. The purpose of this study was to evaluate longevity and subsequent admission to a nursing home stratified by age in a nationwide CABG cohort. METHODS: All patients who underwent isolated CABG from 1996 to 2012 in Denmark were identified through nationwide registers. The cumulative incidence of admission to a nursing home after CABG was estimated. A Cox regression model was constructed to identify predictors for living in a nursing home 1 year after CABG. Kaplan-Meier estimates were used for survival analysis. Subanalysis on home care usage was performed in the period 2008-2012. RESULTS: A total of 38 487 patients were included. The median age was 65.4 +/- 9.5 years (1455 > 80 years) and 80% were males. The 30-day mortality rate was 2.8%, increasing with age (1.2% in patients <60 years and 7.8% in patients >=80 years). The mortality rate at 1 year was 2.2% among patients aged <60 and 14.1% among patients >=80 years. At the 1-year follow-up, 4.2% of patients <60 years, 7.9% of patients 60-70 years, 14.4% of patients 70-74 years, 18.5% of patients 75 79 years and 29.1% of patients >=80 years had received home care. The proportion of patients admitted to a nursing home at 1, 5 and 10 years after CABG was 0.1, 0.4 and 1.0% (<60 years), and 1.4, 7.5 and 16.8% (>=80 years), respectively. Main predictors for living in a nursing home 1 year postoperatively were: age >=80 years [hazard ratio (HR) 17.8, 95% confidence interval (CI) 7.4-42.8], female sex (HR 1.7, 95% CI 1.1-2.6), previous heart failure (HR 1.6, 95% CI 1.0-2.4), previous myocardial infarction (HR 2.0, 95% CI 1.3-3.2) and previous stroke (HR 3.3, 95% CI 2.1-4.9). Neither urgent nor emergency surgeries were significant predictors for living in a nursing home 1 year postoperatively. CONCLUSIONS: The majority of all patients selected for CABG surgery in Denmark between 1996-2012, including the elderly, were able to live independently at home without the need of home care for many years after CABG. The risk of nursing home admission was small and dependent on the patient's age, sex and preoperative comorbidities. PMID- 26969739 TI - Tissue-engineered artificial oesophagus patch using three-dimensionally printed polycaprolactone with mesenchymal stem cells: a preliminary report. AB - OBJECTIVES: There has been a recent focus on 3D printing with regard to tissue engineering. We evaluated the efficacy of a 3D-printed (3DP) scaffold coated with mesenchymal stem cells (MSCs) seeded in fibrin for the repair of partial oesophageal defects. METHODS: MSCs from rabbit bone marrow were cultured, and a 3DP polycaprolactone (PCL) scaffold was coated with the MSCs seeded in fibrin. The fibrin/MSC-coated 3DP PCL scaffold was implanted on a 5 * 10 mm artificial oesophageal defect in three rabbits (3DP/MSC group) and 3DP PCL-only scaffolds were implanted in three rabbits (3DP-only group). Three weeks post-procedure, the implanted sites were evaluated radiologically and histologically. RESULTS: None of the rabbits showed any infection, stenosis or granulation on computed tomography. In the 3DP/MSC group, the replaced scaffolds were completely covered with regenerating mucosal epithelium and smooth muscle cells as determined by haematoxylin and eosin and Desmin staining. However, mucosal epithelium and smooth muscle cell regeneration was not evident in the 3DP-only group. CONCLUSIONS: Use of the 3DP scaffold coated with MSCs seeded in fibrin resulted in successful restoration of the shape and histology of the cervical oesophagus without any graft rejection; thus, this is a promising material for use as an artificial oesophagus. PMID- 26969742 TI - Protein phosphorylation in chloroplasts - a survey of phosphorylation targets. AB - The development of new software tools, improved mass spectrometry equipment, a suite of optimized scan types, and better-quality phosphopeptide affinity capture have paved the way for an explosion of mass spectrometry data on phosphopeptides. Because phosphoproteomics achieves good sensitivity, most studies use complete cell extracts for phosphopeptide enrichment and identification without prior enrichment of proteins or subcellular compartments. As a consequence, the phosphoproteome of cell organelles often comes as a by-product from large-scale studies and is commonly assembled from these in meta-analyses. This review aims at providing some guidance on the limitations of meta-analyses that combine data from analyses with different scopes, reports on the current status of knowledge on chloroplast phosphorylation targets, provides initial insights into phosphorylation site conservation in different plant species, and highlights emerging information on the integration of gene expression with metabolism and photosynthesis by means of protein phosphorylation. PMID- 26969741 TI - Can cyanobacteria serve as a model of plant photorespiration? - a comparative meta-analysis of metabolite profiles. AB - Photorespiration is a process that is crucial for the survival of oxygenic phototrophs in environments that favour the oxygenation reaction of Rubisco. While photorespiration is conserved among cyanobacteria, algae, and embryophytes, it evolved to different levels of complexity in these phyla. The highest complexity is found in embryophytes, where the pathway involves four cellular compartments and respective transport processes. The complexity of photorespiration in embryophytes raises the question whether a simpler system, such as cyanobacteria, may serve as a model to facilitate our understanding of the common key aspects of photorespiration. In this study, we conducted a meta analysis of publicly available metabolite profiles from the embryophyte Arabidopsis thaliana and the cyanobacterium Synechocystis sp. PCC 6803 grown under conditions that either activate or suppress photorespiration. The comparative meta-analysis evaluated the similarity of metabolite profiles, the variability of metabolite pools, and the patterns of metabolite ratios. Our results show that the metabolic signature of photorespiration is in part conserved between the compared model organisms under conditions that favour the oxygenation reaction. Therefore, our findings support the claim that cyanobacteria can serve as prokaryotic models of photorespiration in embryophytes. PMID- 26969740 TI - The expression of arginase-1, keratin (K) 8 and K18 in combined hepatocellular cholangiocarcinoma, subtypes with stem-cell features, intermediate-cell type. AB - AIMS: The WHO classification describes that combined hepatocellular cholangiocarcinoma, subtypes with stem-cell features, intermediate-cell subtype (CHC-INT) is composed of tumour cells with features intermediate between hepatocytes and cholangiocytes. However, we previously reported that CHC-INT showed a high positive rate of biliary markers, but the expression of hepatocyte paraffin (HepPar)-1 was low. In this study, we examined the expression of other hepatocyte markers, such as arginase-1 (Arg-1), keratin (K) 8 and K18 in CHC-INT in order to examine the utility of pathological diagnosis in CHC-INT. METHODS: We performed immunohistochemistry (IHC) of Arg-1, K8 and K18 using 32 previously diagnosed as CHC-INT. Immunoreactivity was evaluated with grading from 0 to 4 according to the distribution area of positive cells. The obtained findings of Arg-1, K8 and K18 were compared with those of K7, K19 and HepPar-1. RESULTS: Out of the 32 cases, 22 (68.8%) cases were positive for Arg-1. Twenty-five (78.1%) were positive for K8. The IHC scores of Arg-1 and K8 were significantly higher than those of HepPar-1, but significantly lower than those of K7 and K19. The K18 expression was widely observed in all cases (100%). The IHC score of Arg-1 and K8 in CHC-INT was intermediate between hepatocellular carcinoma and cholangiocarcinoma. CONCLUSIONS: Arg-1 and K8 were good markers to identify intermediate cells between hepatocytes and cholangiocytes. These can be useful markers for pathological diagnosis of CHC-INT, which usually has wide histological diversities, in combination with other hepatocytic and/or cholangiocytic markers. PMID- 26969743 TI - Overexpression of the rice AKT1 potassium channel affects potassium nutrition and rice drought tolerance. AB - Potassium (K(+)) is the most important cationic nutrient for all living organisms and has roles in most aspects of plant physiology. To assess the impact of one of the main K(+) uptake components, the K(+) inward rectifying channel AKT1, we characterized both loss of function and overexpression of OsAKT1 in rice. In many conditions, AKT1 expression correlated with K(+) uptake and tissue K(+) levels. No salinity-related growth phenotype was observed for either loss or gain of function mutants. However, a correlation between AKT1 expression and root Na(+) when the external Na/K ratio was high suggests that there may be a role for AKT1 in Na(+) uptake in such conditions. In contrast to findings with Arabidopsis thaliana, we did not detect any change in growth of AKT1 loss of function mutants in the presence of NH4 (+) Nevertheless, NH4 (+)-dependent inhibition was detected during K(+) uptake assays in loss of function and wild type plants, depending on pre-growth conditions. The most prominent result of OsAKT1 overexpression was a reduction in sensitivity to osmotic/drought stress in transgenic plants: the data suggest that AKT1 overexpression improved rice osmotic and drought stress tolerance by increasing tissue levels of K(+), especially in the root. PMID- 26969744 TI - Temperature response of bundle-sheath conductance in maize leaves. AB - A small bundle-sheath conductance (g bs) is essential for the C4 CO2 concentrating mechanism to suppress photorespiration effectively. To predict the productivity of C4 crops accurately under global warming, it is necessary to examine whether and how g bs responds to temperature. We investigated the temperature response of g bs in maize by fitting a C4 photosynthesis model to combined gas exchange and chlorophyll fluorescence measurements of irradiance and CO2 response curves at 21% and 2% O2 within the range of 13.5-39 degrees C. The analysis was based on reported kinetic constants of C4 Rubisco and phosphoenolpyruvate carboxylase and temperature responses of C3 mesophyll conductance (g m). The estimates of g bs varied greatly with leaf temperature. The temperature response of g bs was well described by the peaked Arrhenius equation, with the optimum temperature being ~34 degrees C. The assumed temperature responses of g m had only a slight impact on the temperature response of g bs In contrast, using extreme values of some enzyme kinetic constants changed the shape of the response, from the peaked optimum response to the non peaked Arrhenius pattern. Further studies are needed to confirm such an Arrhenius response pattern from independent measurement techniques and to assess whether it is common across C4 species. PMID- 26969745 TI - The regulatory interplay between photorespiration and photosynthesis. AB - The Calvin-Benson cycle and the photorespiratory pathway form the photosynthetic photorespiratory supercycle that is responsible for nearly all biological CO2 fixation on Earth. In essence, supplementation with the photorespiratory pathway is necessary because the CO2-fixing enzyme of the Calvin-Benson cycle, ribulose 1,5-bisphosphate carboxylase (Rubisco), catalyses several side reactions including the oxygenation of ribulose 1,5-bisphosphate, which produces the noxious metabolite phosphoglycolate. The photorespiratory pathway recycles the phosphoglycolate to 3-phosphoglycerate and in this way allows the Calvin-Benson cycle to operate in the presence of molecular oxygen generated by oxygenic photosynthesis. While the carbon flow through the individual and combined subprocesses is well known, information on their regulatory interaction is very limited. Regulatory feedback from the photorespiratory pathway to the Calvin Benson cycle can be presumed from numerous inhibitor experiments and was demonstrated in recent studies with transgenic plants. This complexity illustrates that we are not yet ready to rationally engineer photosynthesis by altering photorespiration since despite massive understanding of the core photorespiratory pathway our understanding of its interaction with other pathways and processes remains fragmentary. PMID- 26969747 TI - PHOTO QUIZ. A 19-Year-Old Woman With Fever, Cough, and a Rash. PMID- 26969749 TI - Bone mineral density and biochemical markers of bone metabolism in predialysis patients with chronic kidney disease. AB - The aim of the study was to evaluate the usefulness of serum bone turnover markers (BTM) and bone mineral density (BMD) determined by dual-energy X-ray absorptiometry (DEXA) in predialysis patients with chronic kidney disease (CKD). We enrolled 83 patients with CKD, 41 (49.4%) males, 42 (50.6%) females, with mean estimated glomerular filtration rate (eGFR) 23.90 +/- 12 (range = 6.0-56.0). BMD of the lumbar spine (LS) (anteroposterior, L2 through L4), femoral neck (FN) and femoral trochanter (FT) were measured by DEXA. Biochemical BTM, including calcium (Ca), phosphorus (P), intact parathyroid hormone (PTH), serum specific alkaline phosphatase (serum AP), bone-specific AP (BSAP), plasma bicarbonate and 25 hydroxy-vitamin D (25hD) were used for the prediction of BMD loss. T score results of LS and FN were worse than FT. BMD levels were lower in females than in males (all p < 0.05). According to different BMD T score levels, patients with age >= 65 years and patients in menopause were significantly more osteopenic (p = 0.026) and there was no relation between different BMD T scores and presence of diabetes (p = 0.654). A positive correlation was identified between the BMD of FN T-Z scores (r = 0.270, p = 0.029, r = 0.306, p = 0.012), FT T-Z scores (r = 0.220, p = 0.076, r:0.250, p = 0.043) and serum HCO3, while the correlation with serum alkaline phosphatase (AP) and BSAP was considered to be negative. No statistically significant association was found between BMD of all the measured skeletal sites and eGFR. Loss of BMD was identified mostly in females over >= 65 years of age and after menopause. Higher serum levels of BSAP and AP can be determined in the advanced stages of renal failure and they reflect fracture risk of the femur, but not spine. Measurements of BMD by DEXA are useful to demonstrate bone loss, but not technical enough to distinguish the quantity of bone loss between different stages of CKD. PMID- 26969746 TI - Transfer of the cytochrome P450-dependent dhurrin pathway from Sorghum bicolor into Nicotiana tabacum chloroplasts for light-driven synthesis. AB - Plant chloroplasts are light-driven cell factories that have great potential to act as a chassis for metabolic engineering applications. Using plant chloroplasts, we demonstrate how photosynthetic reducing power can drive a metabolic pathway to synthesise a bio-active natural product. For this purpose, we stably engineered the dhurrin pathway from Sorghum bicolor into the chloroplasts of Nicotiana tabacum (tobacco). Dhurrin is a cyanogenic glucoside and its synthesis from the amino acid tyrosine is catalysed by two membrane-bound cytochrome P450 enzymes (CYP79A1 and CYP71E1) and a soluble glucosyltransferase (UGT85B1), and is dependent on electron transfer from a P450 oxidoreductase. The entire pathway was introduced into the chloroplast by integrating CYP79A1, CYP71E1, and UGT85B1 into a neutral site of the N. tabacum chloroplast genome. The two P450s and the UGT85B1 were functional when expressed in the chloroplasts and converted endogenous tyrosine into dhurrin using electrons derived directly from the photosynthetic electron transport chain, without the need for the presence of an NADPH-dependent P450 oxidoreductase. The dhurrin produced in the engineered plants amounted to 0.1-0.2% of leaf dry weight compared to 6% in sorghum. The results obtained pave the way for plant P450s involved in the synthesis of economically important compounds to be engineered into the thylakoid membrane of chloroplasts, and demonstrate that their full catalytic cycle can be driven directly by photosynthesis-derived electrons. PMID- 26969750 TI - Adipose tissue hypoxia and insulin resistance. AB - Despite the well-established association of obesity with insulin resistance and inflammation, the underlying mechanisms and sequence of events leading to inflammation and insulin resistance remain unknown. Adipose tissue hypoxia has been proposed as one of the possible key events during the process of fat expansion that leads to adipose tissue dysfunction. The focus of this paper is reviewing the evidence on adipose tissue hypoxia in obesity and its relation to insulin resistance. PMID- 26969751 TI - International Genome-Wide Association Study Consortium Identifies Novel Loci Associated With Blood Pressure in Children and Adolescents. AB - BACKGROUND: Our aim was to identify genetic variants associated with blood pressure (BP) in childhood and adolescence. METHODS AND RESULTS: Genome-wide association study data from participating European ancestry cohorts of the Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium was meta-analyzed across 3 epochs; prepuberty (4-7 years), puberty (8-12 years), and postpuberty (13-20 years). Two novel loci were identified as having genome-wide associations with systolic BP across specific age epochs: rs1563894 (ITGA11, located in active H3K27Ac mark and transcription factor chromatin immunoprecipitation and 5'-C phosphate-G-3' methylation site) during prepuberty (P=2.86*10(-8)) and rs872256 during puberty (P=8.67*10(-9)). Several single-nucleotide polymorphism clusters were also associated with childhood BP at P<5*10(-3). Using a P value threshold of <5*10(-3), we found some overlap in variants across the different age epochs within our study and between several single-nucleotide polymorphisms in any of the 3 epochs and adult BP-related single-nucleotide polymorphisms. CONCLUSIONS: Our results suggest that genetic determinants of BP act from childhood, develop over the lifecourse, and show some evidence of age-specific effects. PMID- 26969752 TI - Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome Associated Calmodulin Missense Variant, E141G. AB - BACKGROUND: Calmodulin (CaM) is encoded by 3 genes, CALM1, CALM2, and CALM3, all of which harbor pathogenic variants linked to long QT syndrome (LQTS) with early and severe expressivity. These LQTS-causative variants reduce CaM affinity to Ca(2+) and alter the properties of the cardiac L-type calcium channel (CaV1.2). CaM also modulates NaV1.5 and the ryanodine receptor, RyR2. All these interactions may play a role in disease pathogenesis. Here, we determine the spectrum and prevalence of pathogenic CaM variants in a cohort of genetically elusive LQTS, and functionally characterize the novel variants. METHODS AND RESULTS: Thirty-eight genetically elusive LQTS cases underwent whole-exome sequencing to identify CaM variants. Nonsynonymous CaM variants were over represented significantly in this heretofore LQTS cohort (13.2%) compared with exome aggregation consortium (0.04%; P<0.0001). When the clinical sequelae of these 5 CaM-positive cases were compared with the 33 CaM-negative cases, CaM positive cases had a more severe phenotype with an average age of onset of 10 months, an average corrected QT interval of 676 ms, and a high prevalence of cardiac arrest. Functional characterization of 1 novel variant, E141G-CaM, revealed an 11-fold reduction in Ca(2+)-binding affinity and a functionally dominant loss of inactivation in CaV1.2, mild accentuation in NaV1.5 late current, but no effect on intracellular RyR2-mediated calcium release. CONCLUSIONS: Overall, 13% of our genetically elusive LQTS cohort harbored nonsynonymous variants in CaM. Genetic testing of CALM1-3 should be pursued for individuals with LQTS, especially those with early childhood cardiac arrest, extreme QT prolongation, and a negative family history. PMID- 26969753 TI - Combinatorial Synthetic Peptide Vaccine Strategy Protects against Hypervirulent CovR/S Mutant Streptococci. AB - Cluster of virulence responder/sensor (CovR/S) mutant group A streptococci (GAS) are serious human pathogens of multiple M protein strains that upregulate expression of virulence factors, including the IL-8 proteaseStreptococcus pyogenescell envelope proteinase (SpyCEP), thus blunting neutrophil-mediated killing and enabling ingress of bacteria from a superficial wound to deep tissue. We previously showed that a combination vaccine incorporating J8-DT (conserved peptide vaccine from the M protein) and a recombinant SpyCEP fragment protects against CovR/S mutants. To enhance the vaccine's safety profile, we identified a minimal epitope (S2) that was the target for anti-SpyCEP Abs that could protect IL-8 from SpyCEP-mediated proteolysis. Abs from healthy humans and from mice experimentally infected with GAS also recognized S2, albeit at low titers. Native SpyCEP may be poorly immunogenic (cryptic or subdominant), and it would be to the organism's advantage if the host did not induce a strong Ab response against it. However, S2 conjugated to diphtheria toxoid is highly immunogenic and induces Abs that recognize and neutralize SpyCEP. Hence, we describe a two-component peptide vaccine that induces Abs (anti-S2) that protect IL-8 from proteolysis and other Abs (anti-J8) that cause strain-independent killing in the presence of neutrophils. We show that either component alone is ineffectual in preventing skin infection and bacteremia due to CovR/S mutants but that the combination induces complete protection. This protection correlated with a significant influx of neutrophils to the infection site. The data strongly suggest that the lack of natural immunity to hypervirulent GAS strains in humans could be rectified by this combination vaccine. PMID- 26969754 TI - Propranolol Attenuates Surgical Stress-Induced Elevation of the Regulatory T Cell Response in Patients Undergoing Radical Mastectomy. AB - Surgical stress and inflammatory response induce the release of catecholamines and PGs, which may be key factors in facilitating cancer recurrence through immunosuppression. Animal studies have suggested the efficacy of perioperative blockades of catecholamines and PGs in reducing immunosuppression. In this study, to our knowledge, we present the first report of the effects of perioperative propranolol and/or parecoxib on peripheral regulatory T cells (Tregs) in breast cancer patients. Patients were randomly assigned to control, propranolol, parecoxib, and propranolol plus parecoxib groups. We demonstrated that levels of circulating epinephrine, norepinephrine, and PGE2increased in response to surgery. Meanwhile, peripheral FOXP3 mRNA level and Treg frequencies were elevated on postoperative day 7. Propranolol administration, rather than parecoxib, attenuated such elevation of Tregs, indicating the critical roles for catecholamines in surgery-induced promotion of Tregs. Besides, propranolol plus parecoxib treatment demonstrated no additive or synergistic effects. Furthermore, a study of Treg activity on CD4(+)T cell responses to specific tumor Ags was performed in the control and propranolol groups. Propranolol abrogated the increased Treg activity and accompanying suppression of CD4(+)T cell responses after surgery. Finally, we conducted ex vivo experiments on the effects of varying concentrations of epinephrine and/or propranolol on Treg proliferation over PBMCs from breast cancer patients, to provide further direct evidence strengthening our clinical observations. Epinephrine markedly promoted Treg proliferation, whereas propranolol prevented such enhancement effect. In conclusion, our study highlights beneficial roles for propranolol in inhibiting Treg responses in vivo and in vitro, and demonstrates that propranolol could alleviate surgical stress-induced elevation of Tregs in breast cancer patients. PMID- 26969756 TI - Resolvin D1 Polarizes Primary Human Macrophages toward a Proresolution Phenotype through GPR32. AB - Resolvin D1 (RvD1) was shown to be a potent anti-inflammatory and proresolution lipid mediator in several animal models of inflammation, but its mechanism of action in humans is not clear. We show that the RvD1 receptor GPR32 is present on resting, proinflammatory M(LPS) and alternatively activated primary human M(IL-4) macrophages, whereas TGF-beta and IL-6 reduce its membrane expression. Accordingly, stimulation of resting primary human macrophages with 10 nM RvD1 for 48 h maximally reduced the secretion of the proinflammatory cytokines IL-1beta and IL-8; abolished chemotaxis to several chemoattractants like chemerin, fMLF, and MCP-1; and doubled the phagocytic activity of these macrophages toward microbial particles. In contrast, these functional changes were not accompanied by surface expression of markers specific for alternatively activated M(IL-4) macrophages. Similar proresolution effects of RvD1 were observed when proinflammatory M(LPS) macrophages were treated with RvD1. In addition, we show that these RvD1-mediated effects are GPR32 dependent because reduction of GPR32 expression by small interfering RNA, TGF-beta, and IL-6 treatment ablated these proresolution effects in primary human macrophages. Taken together, our results indicate that in humans RvD1 triggers GPR32 to polarize and repolarize macrophages toward a proresolution phenotype, supporting the role of this mediator in the resolution of inflammation in humans. PMID- 26969755 TI - Bacterial DNA Protects Monocytic Cells against HIV-Vpr-Induced Mitochondrial Membrane Depolarization. AB - Monocytes and macrophages are important HIV reservoirs, as they exhibit marked resistance to apoptosis upon infection. However, the mechanism underlying resistance to apoptosis in these cells is poorly understood. Using HIV-viral protein R-52-96 aa peptide (Vpr), we show that primary monocytes and THP-1 cells treated with Vpr are highly susceptible to mitochondrial depolarization, but develop resistance following stimulation with bacterial DNA or CpG oligodeoxynucleotide. We have shown that Vpr-induced mitochondrial depolarization is mediated by TNFR-associated factor-1 (TRAF-1) and TRAF-2 degradation and subsequent activation of caspase-8, Bid, and Bax. To provide the mechanism governing such resistance to mitochondrial depolarization, our results show that prior stimulation with CpG oligodeoxynucleotide or Escherichia coli DNA prevented: 1) TRAF-1/2 downregulation; 2) activation of caspase-8, Bid, and Bax; and 3) subsequent mitochondrial depolarization and release of apoptosis-inducing factor and cytochrome c Furthermore, this protection was mediated by upregulation of antiapoptotic protein (c-IAP-2) through calmodulin-dependent kinase-II activation. Thus, c-IAP-2 may prevent Vpr-mediated mitochondrial depolarization through stabilizing TRAF-1/2 expression and sequential inhibition of caspase-8, Bid, and Bax. PMID- 26969757 TI - Drug-Eluting Stents in the Superficial Femoral Artery: The Long and Winding Road. PMID- 26969759 TI - Changes in Arterial Access Site and Association With Mortality in the United Kingdom: Observations From a National Percutaneous Coronary Intervention Database. AB - BACKGROUND: The transradial access (TRA) site has become the default access site for percutaneous coronary intervention in the United Kingdom, with randomized trials and national registry data showing reductions in mortality associated with TRA use. This study evaluates regional changes in access site practice in England and Wales over time, examines whether changes in access site practice have been uniform nationally and across different patient subgroups, and provides national estimates for the potential number of lives saved or lost associated with regional differences in access site practice. METHODS AND RESULTS: Using the British Cardiovascular Intervention Society database, we investigated outcomes for growth of TRA in different regions in England and Wales in 448 853 patients who underwent percutaneous coronary intervention from 2005 to 2012. Multiple logistic regression was used to quantify the effect of TRA on 30-day mortality and quantify lives saved and lost by differences in TRA adoption. TRA use increased from 14.0% to 58.6% in 417 038 PCI patients with large variations in different parts of the country. TRA was independently associated with a decreased risk of 30-day mortality (odds ratio=0.70; 95% confidence interval=0.66-0.74), with significant but small differences observed across different regions. The number of estimated lives saved was 450 (95% confidence interval=275-650), and we estimate that an additional 264 (95% confidence interval=153-399) lives would have been saved if TRA adoption were uniform nationally. CONCLUSIONS: TRA has become the dominant percutaneous coronary intervention approach in the United Kingdom, with a wide variation in different parts of the country. Changes in practice have contributed to mortality reductions, and inequalities have resulted in missed opportunities for further improvements. PMID- 26969758 TI - Durable Clinical Effectiveness With Paclitaxel-Eluting Stents in the Femoropopliteal Artery: 5-Year Results of the Zilver PTX Randomized Trial. AB - BACKGROUND: This randomized controlled trial evaluated clinical durability of Zilver PTX, a paclitaxel-coated drug-eluting stent (DES), for femoropopliteal artery lesions. Outcomes compare primary DES versus percutaneous transluminal angioplasty (PTA), overall DES (primary and provisional) versus standard care (PTA and provisional Zilver bare metal stent [BMS]), and provisional DES versus provisional BMS. METHODS AND RESULTS: Patients with symptomatic femoropopliteal artery disease were randomly assigned to DES (n=236) or PTA (n=238). Approximately 91% had claudication; 9% had critical limb ischemia. Patients experiencing acute PTA failure underwent secondary randomization to provisional BMS (n=59) or DES (n=61). The 1-year primary end points of event-free survival and patency showed superiority of primary DES in comparison with PTA; these results were sustained through 5 years. Clinical benefit (freedom from persistent or worsening symptoms of ischemia; 79.8% versus 59.3%, P<0.01), patency (66.4% versus 43.4%, P<0.01), and freedom from reintervention (target lesion revascularization, 83.1% versus 67.6%, P<0.01) for the overall DES group were superior to standard care in nonrandomized comparisons. Similarly, clinical benefit (81.8% versus 63.8%, P=0.02), patency (72.4% versus 53.0%, P=0.03), and freedom from target lesion revascularization (84.9% versus 71.6%, P=0.06) with provisional DES were improved over provisional BMS. These results represent >40% relative risk reduction for restenosis and target lesion revascularization through 5 years for the overall DES in comparison with standard care and for provisional DES in comparison with provisional BMS. CONCLUSIONS: The 5-year results from this large study provide long-term information previously unavailable regarding endovascular treatment of femoropopliteal artery disease. The Zilver PTX DES provided sustained safety and clinical durability in comparison with standard endovascular treatments. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00120406. PMID- 26969760 TI - Nonlinear Mathematics of Death and Vascular Access. PMID- 26969761 TI - Use of Oral Anticoagulants for Stroke Prevention in Patients With Atrial Fibrillation Who Have a History of Intracranial Hemorrhage. AB - BACKGROUND: The risk of further intracranial hemorrhage (ICH) and the benefit of stroke risk reduction with the use of oral anticoagulants for patients who have atrial fibrillation with a history of ICH remain unclear. We aimed to investigate the risks and benefits in patients who have atrial fibrillation with a previous ICH treated with warfarin or antiplatelet drugs in comparison with no antithrombotic therapies. METHODS AND RESULTS: This study used the National Health Insurance Research Database in Taiwan. Among 307 640 patients who have atrial fibrillation with a CHA2DS2-VASc score ?2, 12 917 patients with a history of ICH were identified and were assigned to 1 of 3 groups, that is, no treatment, antiplatelet therapy, and warfarin. Among patients with previous ICH, the rate of ICH and ischemic stroke in untreated patients was 4.2 and 5.8 per 100 person years, respectively. The annual ICH and ischemic stroke rates in warfarin users were 5.9% and 3.4%, respectively. Among users of antiplatelet agents, the rates were 5.3% per year and 5.2% per year, respectively. The number needed to treat for preventing 1 ischemic stroke was lower than the number needed to harm for producing 1 ICH with warfarin use for patients with a CHA2DS2-VASc score ?6 (37 versus 56). The number needed to treat was higher than the number needed to harm for patients with a CHA2DS2-VASc score <6 (63 versus 53). CONCLUSIONS: Warfarin use may be beneficial for patients who have atrial fibrillation with a previous ICH having a CHA2DS2-VASc score ?6. Whether the use of non-vitamin K antagonist oral anticoagulants could lower the threshold for treatment deserves further study. PMID- 26969762 TI - Correlation between subjective and objective assessment of magnetic resonance (MR) images. AB - Medical Image Quality Assessment (IQA) plays an important role in assisting and evaluating the development of any new hardware, imaging sequences, pre-processing or post-processing algorithms. We have performed a quantitative analysis of the correlation between subjective and objective Full Reference - IQA (FR-IQA) on Magnetic Resonance (MR) images of the human brain, spine, knee and abdomen. We have created a MR image database that consists of 25 original reference images and 750 distorted images. The reference images were distorted with six types of distortions: Rician Noise, Gaussian White Noise, Gaussian Blur, DCT compression, JPEG compression and JPEG2000 compression, at various levels of distortion. Twenty eight subjects were chosen to evaluate the images resulting in a total of 21,700 human evaluations. The raw scores were then converted to Difference Mean Opinion Score (DMOS). Thirteen objective FR-IQA metrics were used to determine the validity of the subjective DMOS. The results indicate a high correlation between the subjective and objective assessment of the MR images. The Noise Quality Measurement (NQM) has the highest correlation with DMOS, where the mean Pearson Linear Correlation Coefficient (PLCC) and Spearman Rank Order Correlation Coefficient (SROCC) are 0.936 and 0.938 respectively. The Universal Quality Index (UQI) has the lowest correlation with DMOS, where the mean PLCC and SROCC are 0.807 and 0.815 respectively. Student's T-test was used to find the difference in performance of FR-IQA across different types of distortion. The superior IQAs tested statistically are UQI for Rician noise images, Visual Information Fidelity (VIF) for Gaussian blur images, NQM for both DCT and JPEG compressed images, Peak Signal-to-Noise Ratio (PSNR) for JPEG2000 compressed images. PMID- 26969763 TI - Protection of donor lung inflation in the setting of cold ischemia against ischemia-reperfusion injury with carbon monoxide, hydrogen, or both in rats. AB - AIMS: Lung ischemia-reperfusion injury (IRI) may be attenuated through carbon monoxide (CO)'s anti-inflammatory effect or hydrogen (H2)'s anti-oxidant effect. In this study, the effects of lung inflation with CO, H2, or both during the cold ischemia phase on graft function were observed. MATERIALS AND METHODS: Rat donor lungs, inflated with 40% oxygen (control group), 500ppm CO (CO group), 3% H2 (H2 group) or 500ppm CO+3% H2 (COH group), were kept at 4 degrees C for 180min. After transplantation, the recipients' artery blood gas and pressure-volume (P-V) curves were analyzed. The inflammatory response, oxidative stress and apoptosis in the recipients were assessed at 180min after reperfusion. KEY FINDINGS: Oxygenation in the CO and H2 groups were improved compared with the control group. The CO and H2 groups also exhibited significantly improved P-V curves, reduced lung injury, and decreased inflammatory response, malonaldehyde content, and cell apoptosis in the grafts. Furthermore, the COH group experienced enhanced improvements in oxygenation, P-V curves, inflammatory response, lipid peroxidation, and graft apoptosis compared to the CO and H2 groups. SIGNIFICANCE: Lung inflation with CO or H2 protected against IRI via anti-inflammatory, anti oxidant and anti-apoptotic mechanisms in a model of lung transplantation in rats, which was enhanced by combined treatment with CO and H2. PMID- 26969764 TI - Miltirone induced mitochondrial dysfunction and ROS-dependent apoptosis in colon cancer cells. AB - AIMS: To study the characteristics of miltirone-induced anti-colon cancer effects. MATERIALS AND METHODS: Cell viability was detected using MTT assay. LDH (lactate dehydrogenase) leakage was detected using CytoTox96(r) non-radioactive cytotoxicity kit. Apoptosis was detected by FCM (flow cytometry). Caspase activation was determined by chemiluminescence or western blotting. AIF (apoptosis-inducing factor) expression in the cell fraction was determined by western blotting. ROS (reactive oxygen species), MMP (mitochondrial membrane potential) and mitochondrial mass were determined by confocal microscope. Intracellular calcium was detected by both FCM and confocal microscope. To determine the roles of ROS and Ca(2+) in the pro-apoptotic activity of miltirone, colon cancer cells were pretreated with kinds of antioxidants, dicoumarol, calpeptin or BAPTA-AM in some cases. KEY FINDINGS: Miltirone exhibited potent cytotoxicity on colon cancer cells with a better selectivity than that of dihydrotanshinone. The pro-apoptotic activity of miltirone was p53- and ROS dependent. In detail, miltirone induced direct mitochondrial damage, including significant decrease of mitochondrial ROS, MMP, mass and increase of intracellular ROS and Ca(2+). NQO1 (quinone oxidoreductase1) was supposed to be a defender for the cytotoxicity induced by miltirone in colon cancer cells. Furthermore, miltirone induced time- and concentration-dependent translocation of AIF and activation of caspases. SIGNIFICANCE: In this study, ROS- and p53 dependent apoptosis induced by miltirone on colon cancer cells was firstly revealed. Strong positive feedback between mitochondrial dysfunction and accumulation of intracellular Ca(2+) was suggested to be the characteristic of the anti-colon cancer activity of miltirone. PMID- 26969765 TI - Protective role of cannabinoid CB1 receptors and vascular effects of chronic administration of FAAH inhibitor URB597 in DOCA-salt hypertensive rats. AB - AIMS: This study examined whether the fall in blood pressure (BP) induced by the chronic inhibition of fatty acid amide hydrolase (FAAH) by URB597 in deoxycorticosterone acetate (DOCA-salt) hypertensive rats correlates with endocannabinoid-mediated vascular changes. MAIN METHODS: Functional studies were performed in isolated endothelium-intact aortas and small mesenteric arteries (sMAs) using organ bath technique and wire myography, respectively. KEY FINDINGS: In the DOCA-salt rats, methanandamide-stimulated relaxation was enhanced in sMAs or diminished in aortas. Its vasorelaxant effect in sMAs was sensitive to the antagonist of the Transient Receptor Potential Vanilloid type 1 (TRPV1), capsazepine, in normo- and hypertensive animals and to the antagonist of the cannabinoid CB1 receptors, AM6545, only in DOCA-salt rats. Cannabinoid CB1 receptors were up-regulated merely in DOCA-salt sMAs. URB597 decreased elevated BP in DOCA-salt rats, medial hypertrophy in DOCA-salt aortas. In sMAs it reduced FAAH expression and restored the augmented phenylephrine-induced contraction in the DOCA-salt rats to the level obtained in normotensive controls. In normotensive rats it diminished endothelium-dependent relaxation and increased phenylephrine-induced contraction. SIGNIFICANCE: The study showed the protective role of cannabinoid CB1 receptors in DOCA-salt sMAs. Reduction in BP after chronic administration of the FAAH inhibitor URB597 in DOCA-salt hypertensive rats only partially correlates with structural and functional changes in conductance and resistance vessels, respectively. Caution should be taken in studying cannabinoids and FAAH inhibitors as potential therapeutics, because of their vessel- and model-specific activities, and side effects connected with off target response and activation of alternative pathways of anandamide metabolism. PMID- 26969766 TI - Acute and chronic glue sniffing effects and consequences of withdrawal on aggressive behavior. AB - Drug abuse act on brain mechanisms that cause a high-risk individual to engage in aggressive and violent behavior. While a drug-violence relationship exists, the nature of this relationship is often complex, with intoxication, neurotoxic, and withdrawal effects often being confused and/or confounded. Glue sniffing is often a springboard to the abuse of more addictive drugs. Despite its high prevalence and serious consequences, we know relatively little about the aggressive behavioral effects of volatile inhalants abuse, especially glue. The aim of the present study was to investigate the link between the duration of glue exposure, a common substance abuse problem in Morocco, and the level of aggressive behavior during withdrawal. For this we used the isolation-induced aggression model "residents" in three groups of mice. The first group served as control resident animals (n=10, without exposure); the second group as experimental resident mice (n=10) tested before and after acute (first day) and chronic exposure to the glue, and at 1 and 2weeks of withdrawal; and the third group of 10 intruder animals. The results showed that the number of attacks decreased (halved) and the latency of the first attack increased (doubled) following acute glue sniffing. However, the effects of chronic exposure and of 1week of withdrawal led to an increase in the intensity of agonistic encounters. After 2weeks of withdrawal, the intensity of aggressive behavior decreased again. These results indicated that chronic glue exposure and the first week of withdrawal are associated with increased aggression in mice. PMID- 26969767 TI - Genotyping of Toxoplasma gondii: DNA extraction from formalin-fixed paraffin embedded autopsy tissues from AIDS patients who died by severe disseminated toxoplasmosis. AB - This study investigated the genetic features of Toxoplasma gondii isolated directly in autopsies of HIV-infected patients who died with severe disseminated toxoplasmosis. This retrospective analysis was conducted in a cohort of 15 HIV infected patients with clinical and laboratory data. They had previous cerebral toxoplasmosis at least 6 months before the disseminated toxoplasmosis episode. The hypothesis was that they were infected with highly virulent parasites due to the condition in which they died. T. gondii genotyping was done directly in DNA extracted from 30 autopsy brain and lung samples (2 per patient) and mutilocus PCR-RFLP genotyping was done using 12 molecular markers. The 30 clinical samples were genotyped successfully in 8 or more loci and six suggestive genotypes were identified. One of them was Toxo DB #11, previously identified in different domestic animals and virulent in experimental animals. The other five suggestive genotypes identified in 14 patients were not described. TgHuDis1 was the most frequent and was determined in 8 patients. TgHuDis3 and TgHuDis5 were identified in two patients each. TgHuDis2 and TgHuDis4 have been identified in one patient each. These suggestive genotypes could be considered as virulent, since they caused severe tissue damage and had similar characteristics as Toxo # DB 11. PMID- 26969768 TI - Determination of an unrelated donor pool size for human leukocyte antigen-matched platelets in Brazil. AB - BACKGROUND: Successful transfusion of platelet refractory patients is a challenge. Many potential donors are needed to sustain human leukocyte antigen matched-platelet transfusion programs because of the different types of antigens and the constant needs of these patients. For a highly mixed population such as the Brazilian population, the pool size required to provide adequate platelet support is unknown. METHODS: A mathematical model was created to estimate the appropriate size of an unrelated donor pool to provide human leukocyte antigen compatible platelet support for a Brazilian population. A group of 154 hematologic human leukocyte antigen-typed patients was used as the potential patient population and a database of 65,500 human leukocyte antigen-typed bone marrow registered donors was used as the donor population. Platelet compatibility was based on the grading system of Duquesnoy. RESULTS: Using the mathematical model, a pool containing 31,940, 1710 and 321 donors would be necessary to match more than 80% of the patients with at least five completely compatible (no cross reactive group), partial compatible (one cross-reactive group) or less compatible (two cross-reactive group) donors, respectively. CONCLUSION: The phenotypic diversity of the Brazilian population has probably made it more difficulty to find completely compatible donors. However, this heterogeneity seems to have facilitated finding donors when cross-reactive groups are accepted as proposed by the grading system of Duquesnoy. The results of this study may help to establish unrelated human leukocyte antigen-compatible platelet transfusions, a procedure not routinely performed in most Brazilian transfusion services. PMID- 26969770 TI - Erythropoietin reduces storage lesions and decreases apoptosis indices in blood bank red blood cells. AB - BACKGROUND: Recent evidence shows a selective destruction of the youngest circulating red blood cells (neocytolysis) trigged by a drop in erythropoietin levels. OBJECTIVE: The aim of this study was to evaluate the effect of recombinant human erythropoietin beta on the red blood cell storage lesion and apoptosis indices under blood bank conditions. METHODS: Each one of ten red blood cell units preserved in additive solution 5 was divided in two volumes of 100mL and assigned to one of two groups: erythropoietin (addition of 665IU of recombinant human erythropoietin) and control (isotonic buffer solution was added). The pharmacokinetic parameters of erythropoietin were estimated and the following parameters were measured weekly, for six weeks: Immunoreactive erythropoietin, hemolysis, percentage of non-discocytes, adenosine triphosphate, glucose, lactate, lactate dehydrogenase, and annexin-V/esterase activity. The t test or Wilcoxon's test was used for statistical analysis with significance being set for a p-value <0.05. RESULTS: Erythropoietin, when added to red blood cell units, has a half-life >6 weeks under blood bank conditions, with persistent supernatant concentrations of erythropoietin during the entire storage period. Adenosine triphosphate was higher in the Erythropoietin Group in Week 6 (4.19+/ 0.05MUmol/L vs. 3.53+/-0.02MUmol/L; p-value=0.009). The number of viable cells in the Erythropoietin Group was higher than in the Control Group (77%+/-3.8% vs. 71%+/-2.3%; p-value <0.05), while the number of apoptotic cells was lower (9.4%+/ 0.3% vs. 22%+/-0.8%; p-value <0.05). CONCLUSIONS: Under standard blood bank conditions, an important proportion of red blood cells satisfy the criteria of apoptosis. Recombinant human erythropoietin beta seems to improve storage lesion parameters and mitigate apoptosis. PMID- 26969769 TI - Nutritional assessment as predictor of complications after hematopoietic stem cell transplantation. AB - INTRODUCTION: Nutritional support is pivotal in patients submitted to hematopoietic stem cell transplantation. Nutritional status has been associated with time of engraftment and infection rates. In order to evaluate the association between nutritional parameters and clinical outcomes after transplantation a cohort of transplant patients was retrospectively evaluated. METHODS: All 50 patients transplanted between 2011 and 2014 were included. The nutritional status before transplantation, ten days after transplantation and before discharge was assessed including anthropometry, body mass index, albumin, prealbumin and total urinary nitrogen. RESULTS: The median follow-up time was 41 months and the median age of patients was 41 years. Thirty-two underwent allogeneic and 18 autologous transplants. Diagnoses included acute leukemias (n=27), lymphoma (n=7), multiple myeloma (n=13), and aplastic anemia (n=3). Thirty-seven patients developed mucositis (three Grade 1, 15 Grade 2, 18 Grade 3 and one Grade 4), and twenty-two allogeneic, and five autologous transplant patients required total parenteral nutrition. Albumin and total urinary nitrogen were associated with length of hospital stay and platelet and neutrophil engraftment. None of the nutritional parameters evaluated were associated with overall survival. Non-relapse mortality was 14% and overall survival was 79% at 41 months of follow-up. CONCLUSIONS: After hematopoietic stem cell transplantation, high catabolism was associated with longer length of hospital stay, the need of total parenteral nutrition and platelet and neutrophil engraftment times. Nutritional parameters were not associated with overall survival. PMID- 26969771 TI - Relationship between pulmonary and cardiac abnormalities in sickle cell disease: implications for the management of patients. AB - OBJECTIVE: To evaluate the association between clinical, pulmonary, and cardiovascular findings in patients with sickle cell disease and, secondarily, to compare these findings between sickle cell anemia patients and those with other sickle cell diseases. METHODS: Fifty-nine adults were included in this cross sectional study; 47 had sickle cell anemia, and 12 had other sickle cell diseases. All patients underwent pulmonary function tests, chest computed tomography, and echocardiography. RESULTS: Abnormalities on computed tomography, echocardiography, and pulmonary function tests were observed in 93.5%, 75.0%; and 70.2% of patients, respectively. A higher frequency of restrictive abnormalities was observed in patients with a history of acute chest syndrome (85% vs. 21.6%; p value<0.0001) and among patients with increased left ventricle size (48.2% vs. 22.2%; p-value=0.036), and a higher frequency of reduced respiratory muscle strength was observed in patients with a ground-glass pattern (33.3% vs. 4.3%; p value=0.016). Moreover, a higher frequency of mosaic attenuation was observed in patients with elevated tricuspid regurgitation velocity (61.1% vs. 24%; p value=0.014). Compared to patients with other sickle cell diseases, sickle cell anemia patients had suffered increased frequencies of acute pain episodes, and acute chest syndrome, and exhibited mosaic attenuation on computed tomography, and abnormalities on echocardiography. CONCLUSION: A significant interrelation between abnormalities of the pulmonary and cardiovascular systems was observed in sickle cell disease patients. Furthermore, the severity of the cardiopulmonary parameters among patients with sickle cell anemia was greater than that of patients with other sickle cell diseases. PMID- 26969772 TI - Hematopoietic progenitor cell mobilization for autologous transplantation - a literature review. AB - The use of high-dose chemotherapy with autologous support of hematopoietic progenitor cells is an effective strategy to treat various hematologic neoplasms, such as non-Hodgkin lymphomas and multiple myeloma. Mobilized peripheral blood progenitor cells are the main source of support for autologous transplants, and collection of an adequate number of hematopoietic progenitor cells is a critical step in the autologous transplant procedure. Traditional strategies, based on the use of growth factors with or without chemotherapy, have limitations even when remobilizations are performed. Granulocyte colony-stimulating factor is the most widely used agent for progenitor cell mobilization. The association of plerixafor, a C-X-C Chemokine receptor type 4 (CXCR4) inhibitor, to granulocyte colony stimulating factor generates rapid mobilization of hematopoietic progenitor cells. A literature review was performed of randomized studies comparing different mobilization schemes in the treatment of multiple myeloma and lymphomas to analyze their limitations and effectiveness in hematopoietic progenitor cell mobilization for autologous transplant. This analysis showed that the addition of plerixafor to granulocyte colony stimulating factor is well tolerated and results in a greater proportion of patients with non-Hodgkin lymphomas or multiple myeloma reaching optimal CD34(+) cell collections with a smaller number of apheresis compared the use of granulocyte colony stimulating factor alone. PMID- 26969775 TI - Hemolytic vascular inflammation: an update. PMID- 26969773 TI - Serum free light chain assays not total light chain assays are the standard of care to assess Monoclonal Gammopathies. AB - The diagnosis of Multiple Myeloma is a challenge to the physician due to the non specific symptoms (anemia, bone pain and recurrent infections) that are commonplace in the elderly population. However, early diagnosis is associated with less severe disease, including fewer patients presenting with acute renal injury, pathological fractures and severe anemia. Since 2006, the serum free light chain test Freelite((r)) has been included alongside standard laboratory tests (serum and urine protein electrophoresis, and serum and urine immunofixation) as an aid in the identification of monoclonal proteins, which are a cornerstone for the diagnosis of Multiple Myeloma. The serum free light chain assay recognizes the light chain component of the immunoglobulin in its free form with high sensitivity. Other assays that measure light chains in the free and intact immunoglobulin forms are sensitive, but unfortunately, due to the nomenclature used, these assays (total light chains) are sometimes used in place of the free light chain assay. This paper reviews the available literature comparing the two assays and tries to clarify hypothetical limitations of the total assay to detect Multiple Myeloma. Furthermore, we elaborate on our study comparing the two assays used in 11 Light Chain Multiple Myeloma patients at presentation and 103 patients taken through the course of their disease. The aim of this article is to provide a clear discrimination between the two assays and to provide information to physicians and laboratory technicians so that they can utilize the International Myeloma Working Group guidelines. PMID- 26969774 TI - Modern techniques of magnetic resonance in the evaluation of primary central nervous system lymphoma: contributions to the diagnosis and differential diagnosis. AB - In addition to findings from conventional magnetic resonance imaging, modern magnetic resonance imaging techniques have provided important information about tumor metabolism, in vivo metabolite formation, water molecule diffusion, microvascular density, and blood-brain barrier permeability, all of which have improved the in vivo diagnostic accuracy of this method in the evaluation of primary central nervous system lymphoma. These nonconventional magnetic resonance techniques are useful in the clinical practice because they enhance conventional magnetic resonance imaging by reinforcing the possibility of a diagnosis and by allowing the early detection of disease recurrence. This report is a review of the most relevant contributions of nonconventional magnetic resonance techniques to the imaging diagnosis of primary central nervous system lymphoma, the differential diagnosis of this disease, and the prognosis of patients. This paper aims to describe a wide range of presentations of primary central nervous system lymphoma, their appearance in imaging, and the differential diagnoses of this disease. PMID- 26969777 TI - Hematological manifestations of human T lymphotropic virus type 1 infection: a possible association with autoimmune myelofibrosis. PMID- 26969776 TI - Guidelines on the treatment of acute myeloid leukemia: Associacao Brasileira de Hematologia, Hemoterapia e Terapia Celular: Project guidelines: Associacao Medica Brasileira - 2015. PMID- 26969778 TI - RHD*weak D type 38: a family study. PMID- 26969780 TI - Systemic fungal infection by Histoplasma capsulatum: intracellular fungus in peripheral leukocytes. PMID- 26969781 TI - What is the adequate mononuclear cell content for selecting umbilical cord blood units for cryopreservation? PMID- 26969779 TI - A difficult case of angioimmunoblastic T-cell lymphoma to diagnose. PMID- 26969782 TI - Zika virus and its implication in transfusion safety. PMID- 26969783 TI - Cardiac sympathetic denervation for intractable ventricular arrhythmias in Chagas disease. AB - BACKGROUND: Autonomic modulation is a valuable therapeutic option for the management of ventricular arrhythmias. Bilateral cardiac sympathetic denervation (BCSD) has shown promising results in the acute, intermediate, and long-term management of polymorphic and monomorphic ventricular tachycardia (VT) in patients with structural heart disease. Cardiomyopathy (CM) due to Chagas disease (CD), and associated VT, is thought to be in part due to autonomic neuronal destruction and dysfunction. OBJECTIVE: The purpose of this study was to assess whether BCSD is a safe and effective treatment modality in patients with CD and VT storm or refractory VT. METHODS: A retrospective analysis of data from patients with chagasic CM who underwent BCSD between 2009 and 2015 at 2 international centers was performed. RESULTS: Of 75 patients who underwent BCSD for VT storm or refractory VT in the setting of CM, 7 (9.3%) patients had CD as the etiology of CM. All patients had monomorphic VT. Median follow-up was 7 months (range 1-46 months). All patients either underwent previous unsuccessful catheter ablation or were not candidates for ablation. The median number of implantable cardioverter-defibrillator (ICD) shocks 1 month before BCSD was 4 (range 2-30) and decreased to 0 (range 0-2) during available follow-up after BCSD. When antitachycardia pacing therapies were included in the analysis, the median number of ICD therapies (shocks + antitachycardia pacing) still decreased to 1 (range 0-3). CONCLUSION: In patients with chagasic CM presenting with refractory monomorphic VT, early evidence suggests that BCSD reduces appropriate ICD therapy and may represent a valuable treatment option. PMID- 26969784 TI - The role of the C-terminal region on the oligomeric state and enzymatic activity of Trypanosoma cruzi hypoxanthine phosphoribosyl transferase. AB - Hypoxanthine phosphoribosyl transferase from Trypanosoma cruzi (TcHPRT) is a critical enzyme for the survival of the parasite. This work demonstrates that the full-length form in solution adopts a stable and enzymatically active tetrameric form, exhibiting large inter-subunit surfaces. Although this protein irreversibly aggregates during unfolding, oligomerization is reversible and can be modulated by low concentrations of urea. When the C-terminal region, which is predicted as a disordered stretch, is excised by proteolysis, TcHPRT adopts a dimeric state, suggesting that the C-terminal region acts as a main guide for the quaternary arrangement. These results are in agreement with X-ray crystallographic data presented in this work. On the other hand, the C-terminal region exhibits a modulatory role on the enzyme, as attested by the enhanced activity observed for the dimeric form. Bisphosphonates act as substrate-mimetics, uncovering long range communications among the active sites. All in all, this work contributes to establish new ways applicable to the design of novel inhibitors that could eventually result in new drugs against parasitic diseases. PMID- 26969785 TI - Dual mechanism of action of the atypical tetracycline chelocardin. AB - Classical tetracyclines targeting the protein biosynthesis machinery are commonly applied in human and veterinary medicine. The development and spread of resistance seriously compromise the successful treatment of bacterial infections. The atypical tetracycline chelocardin holds promise as it retains activity against tetracycline-resistant strains. It has been suggested that chelocardin targets the bacterial membrane, thus differing in mode of action from that of classical tetracyclines. We investigated the mechanism of action of chelocardin using global proteome analysis. The proteome profiles after sublethal chelocardin stress were compared to a reference compendium containing antibiotic response profiles of Bacillus subtilis. This approach revealed a concentration-dependent dual mechanism of action. At low concentrations, like classical tetracyclines, chelocardin induces the proteomic signature for peptidyl transferase inhibition demonstrating that protein biosynthesis inhibition is the dominant physiological challenge. At higher concentrations B. subtilis mainly responds to membrane stress indicating that at clinically relevant concentrations the membrane is the main antibiotic target of chelocardin. Studying the effects on the membrane in more detail, we found that chelocardin causes membrane depolarization but does not lead to formation of large pores. We conclude that at growth inhibiting doses chelocardin not only targets protein biosynthesis but also corrupts the integrity of the bacterial membrane. This dual mechanism of action might prove beneficial in slowing the development of new resistance mechanisms against this atypical tetracycline. PMID- 26969786 TI - The importance of the benzoic acid carboxylate moiety for substrate recognition by CYP199A4 from Rhodopseudomonas palustris HaA2. AB - BACKGROUND: The cytochrome P450 enzyme CYP199A4 can efficiently demethylate 4 methoxybenzoic acid. The substrate is positioned in the enzyme active site with the methoxy group ideally positioned for demethylation. This occurs through interactions of hydrophobic benzene ring with aromatic phenylalanine residues and the charged carboxylate group with polar and basic amino acids. METHODS: In vitro substrate binding and kinetic turnover assays coupled with HPLC and GC-MS analysis and whole-cell oxidation turnovers. RESULTS: Modification of the carboxylate group to an amide or aldehyde resulted in substrate binding, as judged by the almost total shift of the spin state to the high-spin form, but binding was three orders of magnitude weaker. Changing the carboxylate to phenol alcohol, ketone, ester and nitro groups and boronic, sulfinic and sulfonic acids resulted in a dramatic reduction in the binding affinity. Even phenylacetic acids were mediocre substrates for CYP199A4, despite maintaining a carboxylate group. The weaker binding of all of these substrates results in lower levels of turnover activity and product formation compared to 4-methoxybenzoic acid. CONCLUSION: Substrate binding to CYP199A4 is tightly regulated by interactions between the 4 methoxybenzoic acid and the amino acids in the active site. The benzoic acid carboxylate moiety is critical for optimal substrate binding and turnover activity with CYP199A4. GENERAL SIGNIFICANCE: An understanding of how the CYP199A4 enzyme has evolved to be highly selective for para-substituted benzoic acids. This provides valuable insight into how other, as yet structurally uncharacterised, monooxygenase enzymes may bind benzoic acid substrates. PMID- 26969787 TI - Diterpenoids from the branch and leaf of Abies fargesii. AB - Five new abietane diterpenoids, named abifadines A-E (1-5), and nine known ones (6-14), together with two known podocarpenes (15 and 16), were isolated from the branch and leaf of Abies fargesii. Their structures including the relative configurations were established on the basis of extensive spectroscopic analyses. The absolute configuration of 1 was determined through single-crystal X-ray diffraction analysis with Cu Kalpha irradiation. All the isolates were evaluated for their in vitro cytotoxicities. Only compounds 5 and 12 exhibited weak anti proliferative effects against three cancer cell lines (B16, MCF7, and HepG2) with IC50 values range from 14.8 to 42.8 MUM. The antimicrobial activities against Staphylococcus aureus, Escherichia coli and Monilia albicans of all compounds were also tested, but none of them showed significant activities. PMID- 26969790 TI - Design, synthesis, and characterization of new cyclic d,l-alpha-alternate amino acid peptides by capillary electrophoresis coupled to electrospray ionization mass spectrometry. AB - The self-assembly of peptide nanotubes (PNTs) depends on the structure and chemistry of cyclic peptide (CP) monomers, having an impact on their properties, making the choice of their monomers and their characterization a great challenge. We synthesized for the first time a new set of eight original CP sequences of 8, 10, and 12 d,l-alpha-alternate amino acids with a controlled internal diameter from 7 to 13 A. They present various properties (e.g., diameter, global surface charge, hydrophobicity) that can open the way to new applications. Their structure and purity were determined thanks to a capillary electrophoresis coupled to electrospray ionization mass spectrometry (CE-ESI-MS) methodology developed for the first time for this purpose. The CPs were successfully separated in a basic hydro-organic background electrolyte (BGE, pH 8.0, H2O/EtOH 50:50, v/v) and analyzed in MS positive mode. The effect of CP structure on electrophoretic mobility was studied, and the mass spectra were deeply analyzed. This methodology allowed verifying their purity and the absence of linear peptide precursors as well as their stability when stored over several months. Therefore, we have developed a new CE-ESI-MS methodology for the structure and purity control of interesting potential precursors for PNTs that could be employed as nanoplatforms in diagnostics or as pseudo sieving tools for separative purposes. PMID- 26969788 TI - New cycloartane saponin and monoterpenoid glucoindole alkaloids from Mussaenda luteola. AB - A new cycloartane-type saponin with unusual hydroxylation at C-17 and a unique side chain, 9 (R), 19, 22 (S), 24 (R) bicyclolanost-3beta, 12alpha, 16beta, 17alpha tetrol-25-one 3-O-beta-d-glucopyranosyl-(1->2)-beta-d-glucopyranoside (1) and two new monoterpenoid glucoindole alkaloids, 10-methoxy pumiloside (2) and the previously chemically synthesized, 10-methoxy strictosidine (3) along with other five known compounds, 7alpha-morroniside (4), 7-epi-loganin (5), (7beta)-7 O-methylmorroniside (6), 5(S)-5-carboxystrictisidine (7) and apigenin-7-O neohesperidoside (8) were isolated from the aerial parts of Mussaenda luteola (Rubiaceae). The structural elucidation of the isolates was accomplished by extensive (1D and 2D NMR) spectroscopic data analysis and HR-ESI-MS. Compounds 4 8 were reported for the first time from the genus Mussaenda. Interestingly, this is the first report for the occurrence of the monoterpenoid glucoindole-type alkaloids in the genus which might be useful for the chemotaxonomic evaluation of the genus Mussaenda. All isolates were evaluated for their antiprotozoal activities. Compound 7 showed good antitrypanosomal activity with IC50 and IC90 values of 13.7 and 16.6 MUM compared to IC50 and IC90 values of 13.06 and 28.99 MUM for the positive control DFMO, difluoromethylornithine. PMID- 26969789 TI - Comparison of RNA isolation and associated methods for extracellular RNA detection by high-throughput quantitative polymerase chain reaction. AB - MicroRNAs (miRNAs) are small noncoding RNA molecules that function in RNA silencing and posttranscriptional regulation of gene expression. miRNAs in biofluids are being used for clinical diagnosis as well as disease prediction. Efficient and reproducible isolation methods are crucial for extracellular RNA detection. To determine the best methodologies for miRNA detection from plasma, the performance of four RNA extraction kits, including an in-house kit, were determined with miScript miRNA assay technology; all were measured using a high throughput quantitative polymerase chain reaction (qPCR) platform (BioMark System) with 90 human miRNA assays. In addition, the performances of complementary DNA (cDNA) and preamplification kits for TaqMan miRNA assays and miScript miRNA assays were compared using the same 90 miRNAs on the BioMark System. There were significant quantification cycle (Cq) value differences for the detection of miRNA targets between isolation kits. cDNA, preamplification, and qPCR performances were also varied. In summary, this study demonstrates differences among RNA isolation methods as measured by reverse transcription (RT) qPCR. Importantly, differences were also noted in cDNA and preamplification performance using TaqMan and miScript. The in-house kit performed better than the other three kits. These findings demonstrate significant variability between isolation and detection methods for low-abundant miRNA detection from biofluids. PMID- 26969791 TI - NADPH oxidase activation is required for pentylenetetrazole kindling-induced hippocampal autophagy. AB - Growing evidence indicates that alterations in autophagy are present in a variety of neurological disorders, ranging from neurodegenerative diseases to acute neurological insults. Only recently has the role of autophagy in epilepsy started to be recognized. In this study, we used pentylenetetrazole (PTZ) kindling, which provides a model of chronic epilepsy, to investigate the involvement of autophagy in the hippocampus and the possible mechanisms involved. Our western blot results showed that autophagy-related proteins were significantly increased after the mice were fully kindled. In addition, immunofluorescence studies revealed a significant increase in the punctate accumulation of LC3 in the hippocampal CA1 region of fully PTZ-kindled mice. Consistent with the upregulation of ATG proteins and punctate accumulation of LC3 in the hippocampal CA1 region, autophagosomal vacuole formation was observed by an ultrastructural analysis, verifying the presence of a hippocampal autophagic response in PTZ-kindled mice. Increased oxidative stress has been postulated to play an important role in the pathogenesis of a number of neurological diseases, including epilepsy. In this study, we demonstrate that PTZ kindling induced reactive oxygen species (ROS) production and lipid peroxidation, which were accompanied by mitochondrial ultrastructural damage due to the activation of NADPH oxidase. Pharmacological inhibition of NADPH oxidase by apocynin significantly suppressed the oxidative stress and ameliorated the hippocampal autophagy in PTZ-kindled mice. Interestingly, pharmacological induction of autophagy suppressed PTZ-kindling progress and reduced PTZ-kindling-induced oxidative stress while inhibition of autophagy accelerated PTZ kindling progress and increased PTZ-kindling-induced oxidative stress. These results suggest that the oxidative stress induced by NADPH oxidase activation may play a pivotal role in PTZ-kindling process as well as in PTZ kindling-induced hippocampal CA1 autophagy. PMID- 26969792 TI - Fibrin self-assembly is adapted to oxidation. AB - Fibrinogen is extremely susceptible to attack by reactive oxygen species (ROS). Having been suffered an oxidative modification, the fibrinogen molecules, now with altered spatial structure and function of fibrin network, affect hemostasis differently. However, the potential effects of the oxidative stress on the early stages of the fibrin self-assembly process remain unexplored. To clarify the damaging influence of ROS on the knob 'A': hole 'a' and the D:D interactions, the both are operating on the early stages of the fibrin polymerization, we have used a novel approach based on exploration of FXIIIa-mediated self-assembly of the cross-linked fibrin oligomers dissolved in the moderately concentrated urea solutions. The oligomers were composed of monomeric desA fibrin molecules created by cleaving the fibrinopeptides A off the fibrinogen molecules with a thrombin like enzyme, reptilase. According to the UV-absorbance and fluorescence measurements data, the employed low ozone/fibrinogen ratios have induced only a slight fibrinogen oxidative modification that was accompanied by modest chemical transformations of the aromatic amino acid residues of the protein. Else, a slight consumption of the accessible tyrosine residues has been observed due to intermolecular dityrosine cross-links formation. The set of experimental data gathered with the aid of electrophoresis, elastic light scattering and analytical centrifugation has clearly witnessed that the oxidation can serve as an effective promoter for the observed enhanced self-assembly of the covalently cross-linked oligomers. At urea concentration of 1.20M, the pristine and oxidized fibrin oligomers were found to comprise a heterogeneous set of the double-stranded protofibrils that are cross-linked only by gamma-gamma dimers and the fibers consisting on average of four strands that are additionally linked by alpha polymers. The amounts of the oxidized protofibrils and the fibers accumulated in the system were higher than those of the non-oxidized counterparts. Moreover, the gamma and alpha polypeptide chains of the oxidized molecules were more readily crosslinked by the FXIIIa. Upon increasing the urea solution concentration to 4.20M, the cross-linked double-stranded desA fibrin protofibrils have dissociated into the single-stranded fibrin oligomers, whereas the fibers dissociated into both the double-stranded desA fibrin oligomers, the structural integrity of the latter being maintained by means of the intermolecular alpha polymers, and the single-stranded fibrin oligomers cross-linked only by gamma-gamma dimers. The data we have obtained in this study indicate that the FXIIIa-mediated process of assembling the cross-linked protofibrils and the fibers constructed from the oxidized monomeric fibrin molecules was facilitated due to the strengthening of D:D interactions. The findings infer that the enhanced longitudinal D:D interactions become more essential in the assembly of soluble protofibrils when the interactions knobs 'A': holes 'a' are injured by oxidation. The new experimental findings presented here could be of help for elucidating the essential adaptive molecular mechanisms capable of mitigating the detrimental action of ROS in the oxidatively damaged fibrin self-assemblage processes. PMID- 26969794 TI - Transient Loss of Ventricular Pacing Capture Caused by Vagal Induced Ventricular Refractoriness: A Novel Mechanism for Pacemaker Failure in Vasovagal Syncope. PMID- 26969793 TI - Berberine ameliorates chronic relapsing dextran sulfate sodium-induced colitis in C57BL/6 mice by suppressing Th17 responses. AB - Ulcerative colitis (UC) is an increasingly common condition particularly in developed countries. The lack of satisfactory treatment has fueled the search for alternative therapeutic strategies. In recent studies, berberine, a plant alkaloid with a long history of medicinal use in Chinese medicine, has shown beneficial effects against animal models of acute UC. However, UC usually presents as a chronic condition with frequent relapse in patients. How berberine will act on chronic UC remains unclear. In the present study, we adopted dextran sulfate sodium (DSS)-induced chronic relapsing colitis model to assess the ameliorating activity of berberine. Colitis was induced by two cycles of 2.0% DSS for five days followed by 14days of drinking water plus a third cycle consisting of DSS only for five days. The colitis mice were orally administered 20mg/kg berberine from day 13 onward for 30days and monitored daily. The body weight, stool consistency, and stool bleeding were recorded for determination of the disease activity index (DAI). At the end of treatment, animals were sacrificed and samples were collected and subjected to histological, RT-qPCR, Western blot, and LC-MS analyses. Lymphocytes were isolated from spleens and mesenteric lymph nodes (MLN) and cultured for flow cytometry analysis of IL-17 secretion from CD4(+) cells and the Th17 cell differentiation. Results showed that berberine significantly ameliorated the DAI, colon shortening, colon tissue injury, and reduction of colonic expression of tight junction (TJ) protein ZO-1 and occludin of colitis mice. Notably, berberine treatment pronouncedly reduced DSS upregulated Th17-related cytokine (IL-17 and ROR-gammat) mRNAs in the colon. Furthermore, the mRNA expression of IL-6 and IL-23, and the phosphorylation of STAT3 in colon tissues from DSS-treated mice were pronouncedly inhibited by berberine. Moreover, the up-regulation of IL-17 secretion from CD4(+) cells of spleens and MLNs caused by DSS were significantly reversed by berberine treatment. Furthermore, Th17 cell differentiation from naive CD4(+) cells isolated from above DSS colitis mice were suppressed by berberine in a concentration-dependent manner. In summary, we demonstrated for the first time that berberine reduced the severity of chronic relapsing DSS-induced colitis by suppressing Th17 responses. The demonstration of activity in this mouse model supports the possibility of clinical efficacy of berberine in treating chronic UC. PMID- 26969796 TI - Metalloproteinase production from macrophages - a perfect storm leading to atherosclerotic plaque rupture and myocardial infarction. AB - What is the topic of this review? The review discusses how in atherosclerotic plaques, a combination of inflammatory mediators together with loss of anti inflammatory factors is most likely to be responsible for the excess of MMP over TIMP expression that causes plaque rupture and myocardial infarction. What advances does it highlight? Regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs) is divergent between human and mouse macrophages. There is prostaglandin E2 -dependent and -independent regulation. Inflammatory cytokines act through distinct (albeit overlapping) signalling pathways to elicit different patterns of MMP and TIMP expression. Transcriptional and epigenetic regulation occurs. Matrix metalloproteinases (MMPs) produced from macrophages contribute to plaque rupture, atherothrombosis and myocardial infarction. New treatments could emerge from defining the mediators and underlying mechanisms. In human monocytes, prostaglandin E2 (PGE2 ) stimulates MMP production, and inflammatory mediators such as tumour necrosis factor alpha, interleukin-1 and Toll-like receptor ligands can act either through or independently of PGE2 . Differentiation of human monocytes to non-foamy macrophages increases constitutive expression of MMP-7, -8, -9, -14 and -19 and tissue inhibitor of MMP (TIMP)-1 to -3 through unknown, PGE2 -independent mechanisms. Human macrophages express more MMP-1, -7 and -9 and TIMP-3 and less MMP-12 and -13 than mouse macrophages. Inflammatory mediators working through activator protein-1 and nuclear factor-kappaB transcription factor pathways upregulate MMP-1, -3, -10, -12 and -14 in human macrophages (MMP-9, -12 and -13 in mice), and studies with plaque tissue sections and isolated foam cells confirm this conclusion in vivo. Classical activation with granulocyte-macrophage colony stimulating factor upregulates MMP-12, whereas interferon-gamma upregulates MMP 12, -14 and -25 and downregulates TIMP-3 in human but not mouse macrophages. Alternative activation with interleukin-4 markedly stimulates the expression of only MMP-12 in humans and MMP-19 in mice. The anti-inflammatory cytokines interleukin-10 and transforming growth factor-beta decrease production of several MMPs. Epigenetic upregulation of MMP-14 during foam cell formation or by granulocyte-macrophage colony-stimulating factor occurs by decreasing miRNA-24. A 'perfect storm' caused by a combination of these mechanisms is most likely to promote MMP-mediated macrophage invasion, tissue destruction and atherosclerotic plaque rupture. PMID- 26969798 TI - Use of high sensitivity cardiac troponin assays as an adjunct to cardiac stress testing. PMID- 26969797 TI - Percentage of colorectal cancer diagnosed in adults aged younger than 50 years. PMID- 26969799 TI - Atypical profiles and modulations of heme-enzymes catalyzed outcomes by low amounts of diverse additives suggest diffusible radicals' obligatory involvement in such redox reactions. AB - BACKGROUND: Peroxidations mediated by heme-enzymes have been traditionally studied under a single-site (heme distal pocket), non-sequential (ping-pong), two substrates binding scheme of Michaelis-Menten paradigm. We had reported unusual modulations of peroxidase and P450 reaction outcomes and explained it invoking diffusible reactive species [Manoj, 2006; Manoj et al., 2010; Andrew et al., 2011, Parashar et al., 2014 & Venkatachalam et al., 2016]. METHODS: A systematic investigation of specific product formation rates was undertaken to probe the hypothesis that involvement of diffusible reactive species could explain undefined substrate specificities and maverick modulations (sponsored by additives) of heme-enzymes. RESULTS: When the rate of specific product formation was studied as a function of reactants' concentration or environmental conditions, we noted marked deviations from normal profiles. We report that heme enzyme mediated peroxidations of various substrates are inhibited (or activated) by sub-equivalent concentrations of diverse redox-active additives and this is owing to multiple redox equilibriums in the milieu. At low enzyme and peroxide concentrations, the enzyme is seen to recycle via a one-electron (oxidase) cycle, which does not require the substrate to access the heme centre. Schemes are provided that explain the complex mechanistic cycle, kinetics & stoichiometry. CONCLUSION: It is not obligatory for an inhibitor or substrate to interact with the heme centre for influencing overall catalysis. Roles of diffusible reactive species explain catalytic outcomes at low enzyme and reactant concentrations. SIGNIFICANCE: The current work highlights the scope/importance of redox enzyme reactions that could occur "out of the active site" in biological or in situ systems. PMID- 26969795 TI - The birth of new neurons in the maternal brain: Hormonal regulation and functional implications. AB - The maternal brain is remarkably plastic and exhibits multifaceted neural modifications. Neurogenesis has emerged as one of the mechanisms by which the maternal brain exhibits plasticity. This review highlights what is currently known about peripartum-associated changes in adult neurogenesis and the underlying hormonal mechanisms. We also consider the functional consequences of neurogenesis in the peripartum brain and extent to which this process may play a role in maternal care, cognitive function and postpartum mood. Finally, while most work investigating the effects of parenting on adult neurogenesis has focused on mothers, a few studies have examined fathers and these results are also discussed. PMID- 26969800 TI - Molecular pathogenesis of human amyloidosis: Lessons from beta2 -microglobulin related amyloidosis. AB - Amyloidosis refers to a group of diseases with amyloid fibrils deposited in various organs and is classified into more than 30 diseases in humans based on the kind of amyloid protein. In order to elucidate the molecular pathogenesis of human amyloidosis, we studied the molecular mechanism of amyloid fibril formation in vitro. We first developed a novel fluorometric method to determine amyloid fibrils in vitro based on the unique characteristics of thioflavin T. We next proposed a nucleation-dependent polymerization model to explain the general mechanism of amyloid fibril formation in vitro. Based on this model, we characterized the biological molecular interactions that promote or inhibit amyloid fibril formation in vitro and developed models of pathological molecular environment for inducing human beta2-microglobulin-related amyloidosis in long term hemodialysis patients. We also proposed a novel and attractive cytotoxic mechanism of beta2-microglobulin amyloid fibrils, that is, the disruption of endosomal/lysosomal membranes by endocytosed amyloid fibrils. These findings may be useful to elucidate the molecular pathogenesis of other kinds of human amyloidosis. PMID- 26969801 TI - Evaluation of a fibrate, specific stimulant of PPARalpha, as a therapeutic alternative to the treatment of clinical ovine pregnancy toxaemia. AB - Ovine pregnancy toxaemia is a metabolic disorder affecting sheep in their last 6 weeks of pregnancy as a result of their inability to maintain adequate energy homoeostasis. Different alternative treatments are available with variable results. The aim of this research was to evaluate a peroxisome proliferator activated receptor alpha (PPARalpha) stimulant as an alternative to treat clinical pregnancy toxaemia. Thirty-three adult sheep, with known gestation date and carrying a single foetus, were fasted from day 130 of gestation until animals showed clinical disease. From that moment onwards, sheep were treated during 6 days with three different therapeutic alternatives: 10 mg/kg of 2-methyl-2 phenoxy-propionic acid; 10 mg/kg of 2-methyl-2-phenoxy-propionic acid + 100 mL of propylene glycol oral; or 100 mL of propylene glycol oral. Glycaemia and serum beta-hydroxybutyrate (BHOB) were determined daily. Liver biopsies were taken at day 130 of gestation, at the beginning and end of treatments and at 5 days postpartum, evaluating the extent and degree of the steatosis lesion. Even though in sheep treated with 2-methyl-2-phenoxy-propionic acid, serum concentrations of glucose and BHOB recovered more slowly, we conclude that 2-methyl-2-phenoxy propionic acid alone or combined with propylene glycol can be used as an alternative to effectively treat fatty liver, and therefore pregnancy toxaemia. PMID- 26969802 TI - Comparative multidimensional assessment of laryngeal function and quality of life after radiotherapy and laser surgery for early glottic cancer. AB - BACKGROUND: This study was designed to comparatively assess laryngeal function and quality of life (QOL) of patients after laser surgery (LS) or radiotherapy (RT) for early glottic cancer. METHODS: Sixty-four patients with T1 glottic cancer treated with RT or type II cordectomy underwent both subjective and objective vocal assessments. The LS group was divided into the following: (1) vaporization with defocused mode (laser surgery [LS]-Vap); and (2) excision with focused mode using lower power (LS-Ex). RESULTS: Auditory-perceptual evaluation and videostroboscopic images in the LS-Ex group worsened shortly after treatment and time-dependent recovery was quicker than in the LS-Vap group. The LS-Ex group showed equivalent posttherapeutic vocal function with the RT group by acoustics, aerodynamics, and self-assessment questionnaire analysis, whereas the LS-Vap group showed statistically significant worse function. CONCLUSION: The multidimensional assessment showed that early glottic cancer could be successfully treated by either RT or LS-Ex with equivalent posttherapeutic laryngeal function and QOL. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 1085 1090, 2016. PMID- 26969803 TI - Simulation study of electric-guided delivery of 0.4um monodisperse and polydisperse aerosols to the ostiomeatal complex. AB - Despite the high prevalence of rhinosinusitis, current inhalation therapy shows limited efficacy due to extremely low drug delivery efficiency to the paranasal sinuses. Novel intranasal delivery systems are needed to enhance targeted delivery to the sinus with therapeutic dosages. An optimization framework for intranasal drug delivery was developed to target polydisperse charged aerosols to the ostiomeatal complex (OMC) with electric guidance. The delivery efficiency of a group of charged aerosols recently reported in the literature was numerically assessed and optimized in an anatomically accurate nose-sinus model. Key design variables included particle charge number, particle size and distribution, electrode strength, and inhalation velocity. Both monodisperse and polydisperse aerosol profiles were considered. Results showed that the OMC delivery efficiency was highly sensitive to the applied electric field and electrostatic charges carried by the particles. Through the synthesis of electric-guidance and point drug release, focused deposition with significantly enhanced dosage in the OMC can be achieved. For 0.4 um charged aerosols, an OMC delivery efficiency of 51.6% was predicted for monodisperse aerosols and 34.4% for polydisperse aerosols. This difference suggested that the aerosol profile exerted a notable effect on intranasal deliveries. Sensitivity analysis indicated that the OMC deposition fraction was highly sensitive to the charge and size of particles and was less sensitive to the inhalation velocity considered in this study. Experimental studies are needed to validate the numerically optimized designs. Further studies are warranted to investigate the targeted OMC delivery with both electric and acoustics controls, the latter of which has the potential to further deliver the drug particles into the sinus cavity. PMID- 26969804 TI - Some of the most interesting things we know, and don't know, about the biochemistry and physiology of elasmobranch fishes (sharks, skates and rays). AB - The urea-retaining strategy of elasmobranchs has shaped their biochemistry and physiology; from their metabolic organization to the structure of their membranes. It has also affected their capacity to live in freshwater. Although much new information has been uncovered in the past 30years, many unanswered questions remain. These include: a) why was urea selected as the major organic osmolyte, b) why is glutamine used as a nitrogen donor, c) why was plasma albumin lost in marine elasmobranchs, d) what membranes are involved in urea retention in the gills, e) how do urea and trimethylamine N-oxide (TMAO) affect membranes, and f) why retain urea in freshwater. Hypotheses are presented for future investigations but some questions may require a time machine to answer. PMID- 26969806 TI - Molecular characterization of antibiotic resistance in Escherichia coli strains from a dairy cattle farm and its surroundings. AB - BACKGROUND: This study describes the phenotypic and genotypic characteristics of 78 genetically different Escherichia coli recovered from air and exudate samples of a dairy cattle farm and its surroundings in Spain, in order to gain insight into the flow of antimicrobial resistance through the environment and food supply. RESULTS: Antimicrobial resistance was detected in 21.8% of the 78 E. coli isolates analyzed (resistance for at least one of the 14 agents tested). The highest resistance rates were recorded for ampicillin, nalidixic acid, trimethoprim/sulfamethoxazole and tetracycline. The resistance genes detected were as follows (antibiotic (number of resistant strains), gene (number of strains)): ampicillin (9), blaTEM-1 (6); tetracycline (15), tet(A) (7), tet(B) (4), tet(A) + tet(B) (1); chloramphenicol (5), cmlA (2), floR (2); trimethoprim/sulfamethoxazole (10), sul2 (4), sul1 (3), sul3 (2), sul1 + sul2 (1); gentamicin-tobramycin (1), ant(2") (1). About 14% of strains showed a multidrug-resistant phenotype and, of them, seven strains carried class 1 integrons containing predominantly the dfrA1-aadA1 array. One multidrug-resistant strain was found in both inside and outside air, suggesting that the airborne spread of multidrug-resistant bacteria from the animal housing facilities to the surroundings is feasible. CONCLUSIONS: This study gives a genetic background of the antimicrobial resistance problem in a dairy cattle farm and shows that air can act as a source for dissemination of antimicrobial-resistant bacteria. (c) 2016 Society of Chemical Industry. PMID- 26969805 TI - Effect of anthocyanidins on myogenic differentiation in induced and non-induced primary myoblasts from rainbow trout (Oncorhynchus mykiss). AB - A study was conducted to test whether an anthocyanidin mixture (peonidin, cyanidin and pelargonidin chloride) modulates myogenesis in both induced and non induced myogenic cells from juvenile rainbow trout (Oncorhynchus mykiss). We evaluated three different anthocyanidin concentrations (1*, 2.5* and 10*) at two sampling times (24 and 36h). To test for treatment effects, we analyzed the expression of myoD and pax7 as well as two target genes of the Notch signaling pathway, hey2 and her6. In induced myogenic cells, the lowest and middle anthocyanidin doses caused significantly greater expression of myoD after 24h of treatment compared to control. A significantly higher expression of pax7 in cells exposed to either anthocyanidin treatment during 36h compared was observed. Similarly, the pax7/myoD ratio was significantly lower in cells exposed to the lowest anthocyanidin doses during 24h compared to control. No significant effect of anthocyanidin treatments on the expression of hey2 and her6 at either sampling point was detected. In non-induced cells, we observed no effect of anthocyanidins on myoD expression and significant down-regulation on pax7 expression in cells exposed to either anthocyanidin mixture concentrations after 24 and 36h of treatment compared to control. Further, the pax7/myoD ratio was significantly lower in cells exposed to either anthocyanidin doses at both sampling time. In non-induced cells, the highest anthocyanidin dose provoked significantly greater expression of hey2 after 24h of treatment compared to control. We detected no such effect in non-induced cells exposed to the lowest and middle anthocyanidin doses during 24h of treatment. The expression of her6 was unaffected by anthocyanidin treatments at either sampling time or doses compared to control. Collectively, these findings provide evidence that anthocyanidins modulate specific components of the myogenic programming in fish, thereby potentially affecting somatic growth in fish fed plant-derived extracts rich in this type of polyphenols. Moreover, in early differentiating myogenic cells, the anthocyanidin effect on myogenic programming appears to differ based upon the exposure time and the differentiation stage of the myogenic cells by boosting myogenic differentiation signaling after 24h treatment while pausing differentiation, potentially favoring cell survival after 36h treatment. Further research to determine whether plant-derived secondary metabolites including alkaloids, terpenoids, tannins, saponins, glycosides, flavonoids, phenolics, steroids and essential oils can modulate myogenic programming in myogenic cells isolated from finfish species is warranted. PMID- 26969807 TI - Number of positive nodes is superior to the lymph node ratio and American Joint Committee on Cancer N staging for the prognosis of surgically treated head and neck squamous cell carcinomas. AB - BACKGROUND: Recent changes in head and neck cancer epidemiology have created a need for improved lymph node prognostics. This article compares the prognostic value of the number of positive nodes (pN) with the value of the lymph node ratio (LNR) and American Joint Committee on Cancer (AJCC) N staging in surgical patients. METHODS: The Surveillance, Epidemiology, and End Results database was used to identify cases of head and neck squamous cell carcinomas from 2004 to 2012. The sample was grouped by the AJCC N stage, LNR, and pN and was analyzed with Kaplan-Meier and multivariate Cox proportional hazards models. The sample was also analyzed by the site of the primary tumor. RESULTS: This study identified 12,437 patients. Kaplan-Meier survival curves showed superior prognostic ability for LNR and pN staging in comparison with AJCC staging. Patients with a pN value > 5 had the worst overall survival (5-year survival rate, 16%). Patients with oropharyngeal tumors had better outcomes for all groupings, and a pN value > 5 for oropharyngeal cancers was associated with decreased survival. Multivariate regressions demonstrated larger hazard ratios (HRs) and a lower Akaike information criterion for the pN model versus the AJCC stage and LNR models. The HRs were 1.78 (95% confidence interval, 1.62-1.95) for a pN value of 1, 2.53 (95% confidence interval, 2.32-2.75) for a pN value of 2 to 5, and 4.64 (95% confidence interval, 4.18-5.14) for a pN value > 5. CONCLUSIONS: The pN models demonstrated superior prognostic value in comparison with the LNR and AJCC N staging. Future modifications of the nodal staging system should be based on the pN with a separate system for oropharyngeal cancers. Future trials should consider examining adjuvant treatment escalation in patients with >5 lymph nodes. Cancer 2016;122:1388-1397. (c) 2016 American Cancer Society. PMID- 26969808 TI - Air pollution exposure, cause-specific deaths and hospitalizations in a highly polluted Italian region. AB - BACKGROUND: The Lombardy region in northern Italy ranks among the most air polluted areas of Europe. Previous studies showed air pollution short-term effects on all-cause mortality. We examine here the effects of particulate matter with aerodynamic diameter <=10um (PM10) and nitrogen dioxide (NO2) exposure on deaths and hospitalizations from specific causes, including cardiac, cerebrovascular and respiratory diseases. METHODS: We considered air pollution, mortality and hospitalization data for a non-opportunistic sample of 18 highly polluted and most densely populated areas of the region in the years 2003-2006. We obtained area-specific effect estimates for PM10 and NO2 from a Poisson regression model on the daily number of total deaths or cause-specific hospitalizations and then combined them in a Bayesian random-effects meta analysis. For cause-specific mortality, we applied a case-crossover analysis. Age and season-specific analyses were also performed. Effect estimates were expressed as percent variation in mortality or hospitalizations associated with a 10ug/m(3) increase in PM10 or NO2 concentration. RESULTS: Natural mortality was positively associated with both pollutants (0.30%, 90% Credibility Interval [CrI]: -0.31; 0.78 for PM10; 0.70%, 90%CrI: 0.10; 1.27 for NO2). Cardiovascular deaths showed a higher percent variation in association with NO2 (1.12%, 90% Confidence Interval [CI]: 0.14; 2.11), while the percent variation for respiratory mortality was highest in association with PM10 (1.64%, 90%CI: 0.35; 2.93). The effect of both pollutants was more evident in the summer season. Air pollution was also associated to hospitalizations, the highest variations being 0.77% (90%CrI: 0.22; 1.43) for PM10 and respiratory diseases, and 1.70% (90%CrI: 0.39; 2.84) for NO2 and cerebrovascular diseases. The effect of PM10 on respiratory hospital admissions appeared to increase with age. For both pollutants, effects on cerebrovascular hospitalizations were more evident in subjects aged less than 75 years. CONCLUSIONS: Our study provided a sound characterization of air pollution exposure and its potential effects on human health in the most polluted, and also most populated and productive, Italian region, further documenting the need for effective public health policies. PMID- 26969809 TI - Characterization of fungi isolated from the equipment used in the International Space Station or Space Shuttle. AB - As a part of a series of studies regarding the microbial biota in manned space environments, fungi were isolated from six pieces of equipment recovered from the Japanese Experimental Module "KIBO" of the International Space Station and from a space shuttle. Thirty-seven strains of fungi were isolated, identified and investigated with regard to morphological phenotypes and antifungal susceptibilities. The variety of fungi isolated in this study was similar to that of several previous reports. The dominant species belonged to the genera Penicillium, Aspergillus and Cladosporium, which are potential causative agents of allergy and opportunistic infections. The morphological phenotypes and antifungal susceptibilities of the strains isolated from space environments were not significantly different from those of reference strains on Earth. PMID- 26969810 TI - Risk-taking propensity and sensitivity to punishment in adolescents with attention deficit and hyperactivity disorder symptoms and/or reading disability. AB - Many studies reported that adolescents with ADHD/RD more frequently engage in risk-taking behaviors. Very few have examined their risk taking patterns and the impact of their comorbidity. The present study compared the risk-taking propensity, sensitivity to punishment and delinquency outcome in Chinese adolescents with ADHD symptoms (AS) and/or RD using a simulated risk task, the Balloon Analogous Risk Task (BART). Adolescents with AS (n=37), RD (n=35), AS+RD (n=35), and control (n=36) were recruited from local secondary schools. Results showed that adolescents with ADHD, despite their great risk-taking propensity, were sensitive to immediate punishment whereas adolescents with RD were found to display normal risk-taking propensity, yet showed a tendency of being less sensitive to punishment. The comorbidity ADHD+RD group had the highest delinquency score, and exhibited greatest risk taking and least sensitivity to punishment, which provided further support that comorbid condition might have stronger impact on risk taking or even delinquency than the pure groups. The present findings provides a useful picture of the risk taking pattern associated with different groups, allowing for effective matching for future prevention and intervention program. PMID- 26969811 TI - Survival outcomes with concurrent chemoradiation for elderly patients with locally advanced head and neck cancer according to the National Cancer Data Base. AB - BACKGROUND: The overall survival (OS) benefit of concurrent chemoradiotherapy (CRT) for head and neck squamous cell carcinoma patients older than 70 years is debated. This study examines the outcomes of elderly patients receiving CRT versus radiotherapy (RT) alone. METHODS: The National Cancer Data Base was queried for patients older than 70 years with nonmetastatic oropharyngeal, laryngeal, or hypopharyngeal cancer (T3-4 or N(+)). CRT was defined as chemotherapy started within 14 days of the initiation of RT. Univariate analysis, multivariate analysis (MVA), propensity score matching (PSM), and recursive partitioning analysis (RPA) were performed. RESULTS: The study included 4042 patients: 2538 (63%) received CRT. The median follow-up was 19 months. The unadjusted median OS was longer with the addition of CRT (P < .001). OS was superior with CRT in the MVA (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.58-0.68; P < .001) and PSM analyses (HR, 0.73; 95% CI, 0.66-0.80; P < .001) in comparison with RT alone. According to RPA, CRT was associated with longer OS for patients 81 years or younger with low comorbidity scores and either T1-2/N2-3 disease or T3-4/N0-3 disease. The survival benefit with CRT disappeared for 2 subgroups in the 71- to 81-year age range: those with T1-2, N1, and Charlson-Deyo 0-1 (CD0-1) disease and those with T3-4, N1+, and CD1+ disease. Patients who were older than 81 years did not have increased survival with CRT. The receipt of CRT was associated with a longer duration of RT (odds ratio, 1.74; 95% CI, 1.50-2.01; P < .001). CONCLUSIONS: Patients older than 70 years should not be denied concurrent chemotherapy solely on the basis of age; additional factors, including the performance status and the tumor stage, should be taken into account. Cancer 2016;122:1533-43. (c) 2016 American Cancer Society. PMID- 26969812 TI - Relationship between weight change and glycaemic control in patients with type 2 diabetes receiving once-weekly dulaglutide treatment. AB - AIM: To assess the relationship between weight change and glycated haemoglobin (HbA1c) change in dulaglutide-treated patients by analysing data from six head-to head phase III AWARD clinical trials. METHODS: At 26 weeks, the relationship between weight and HbA1c was analysed in each trial rather than by pooling data because of differences in design and background therapy. The effect of baseline characteristics was also evaluated with regard to weight and HbA1c response. RESULTS: Across the studies, 87-97% and 83-95% of patients treated with dulaglutide 1.5 and 0.75 mg, respectively, had reductions in HbA1c levels, while 57-88% and 43-84% of patients treated with dulaglutide 1.5 and 0.75 mg, respectively, experienced weight loss. The majority (55-83%) of patients receiving dulaglutide 1.5 mg experienced weight loss and HbA1c reductions, while 41-79% of patients in the dulaglutide 0.75 mg arm lost weight and had reductions in HbA1c level. A weak and inconsistent correlation was observed between the changes in weight and HbA1c (range from -0.223 to 0.267) in patients treated with dulaglutide. The baseline characteristics of gender, age, duration of diabetes, HbA1c, body weight and BMI were not related to different combinations of weight and HbA1c responses. CONCLUSIONS: Dulaglutide is an effective treatment option across the type 2 diabetes treatment spectrum. Dulaglutide showed dose-dependent effects on both weight loss and HbA1c reduction. These effects had a weak correlation and appeared to be independent. PMID- 26969813 TI - Case of paraneoplastic pemphigus with immunoglobulin (Ig)G and IgA antibodies to various antigens. AB - A 63-year-old Japanese man with non-Hodgkin B-cell lymphoma presented with erythematous skin lesions on his entire body, with oral, ocular and anal mucosal lesions. The patient was diagnosed with paraneoplastic pemphigus. Immunofluorescence showed both immunoglobulin (Ig)G and IgA antibodies to keratinocyte cell surfaces. Various immunoblot and enzyme-linked immunosorbent assays showed both IgG and IgA antibodies to various autoantigens, including desmogleins, desmocollins, envoplakin, periplakin and bullous pemphigoid antigens. This was a unique case with a very rare autoantibody profile in paraneoplastic pemphigus. PMID- 26969814 TI - Screening CEST contrast agents using ultrafast CEST imaging. AB - A chemical exchange saturation transfer (CEST) experiment can be performed in an ultrafast fashion if a gradient field is applied simultaneously with the saturation pulse. This approach has been demonstrated for studying dia- and para magnetic CEST agents, hyperpolarized Xe gas and in vivo spectroscopy. In this study we present a simple method for the simultaneous screening of multiple samples. Furthermore, by interleaving a number of saturation and readout periods within the TR, a series of images with different saturation times can be acquired, allowing for the quantification of exchange rates using the variable saturation time (QUEST) approach in a much accelerated fashion, thus enabling high throughput screening of CEST contrast agents. PMID- 26969815 TI - Exposure-response estimate for lung cancer and asbestosis in a predominantly chrysotile-exposed Chinese factory cohort. AB - BACKGROUND: Cumulative fiber exposures, predominantly chrysotile, were estimated in a Chinese asbestos worker cohort and exposure-response relationships with lung cancer mortality and cumulative incidence of asbestosis were determined. METHODS: Individual time-dependent cumulative exposures were estimated for 577 asbestos workers, followed prospectively for 37 years. Occupational history and smoking data were obtained from company records and personal interviews; vital status and causes of death were ascertained from death registries and hospital records. Hazard ratios were generated for disease outcomes, with adjustments for smoking and age. RESULTS: Median cumulative fiber exposure for the cohort was 132.6 fiber years/ml (IQR 89.3-548.4). Exposure-response relationships were demonstrated for both disease outcomes, with nearly sixfold and threefold increased risks seen at the highest exposure level for lung cancer deaths and asbestosis, respectively. CONCLUSION: Evidence using quantitative exposure estimates was provided for increased risks of lung cancer mortality and development of asbestosis in a predominantly chrysotile-exposed cohort. PMID- 26969816 TI - Resolution of Rac-Bambuterol via Diastereoisomeric Salt Formation with o Chloromandelic Acid and Differences in the Enantiomers' Pharmacodynamical Effects in Guinea Pigs and Beagles. AB - In this study an enantioseparation method for rac-bambuterol (5-(2-(tert butylamino)-1-hydroxyethyl)-1,3-phenylene bis(dimethylcarbamate)) via diastereoisomeric salt formation with o-chloromandelic acid was developed. The enantiomeric excess (ee) values and chemical purities of the desired products were confirmed by high-performance liquid chromatography (HPLC) using chiral stationary phase and reverse-phase HPLC analyses, respectively. The ee values and the chemical purities both exceeded 99%. Animal experiments showed that (R) bambuterol was a potent inhibitor for histamine-induced asthma reactions. (S) bambuterol was ineffective in relaxing the airways. Both enantiomers increased heart rates in beagles. Therefore, replacing rac-bambuterol with (R)-bambuterol could be beneficial for asthma patients. PMID- 26969817 TI - Liver biopsy for diagnosis of presumed benign hepatocellular lesions lacking magnetic resonance imaging diagnostic features of focal nodular hyperplasia. AB - BACKGROUND & AIMS: The contribution of liver biopsy for the diagnosis of presumed benign hepatocellular lesions lacking the diagnostic features of focal nodular hyperplasia (FNH) on magnetic resonance imaging (MRI) is unknown. We evaluated liver biopsy and MRI performances in this setting. METHODS: Magnetic resonance imaging and slides of liver biopsies performed for a presumed benign hepatocellular lesion (2006-2013) without the typical features of FNH on MRI were blindly reviewed (n = 45). Eighteen lesions were surgically removed and also analyzed. The final diagnosis was the diagnosis established after surgery or on the biopsy in the absence of surgery. RESULTS: The final diagnosis was FNH (n = 19), hepatocellular adenoma (HCA, n = 15), hepatocellular carcinoma (n = 3) and indefinite (n = 4). Four lesions corresponded to non hepatocellular lesions. FNH, HNF1A mutated and inflammatory HCA were diagnosed accurately on the biopsy in 95%, 67% and 100% of the cases respectively. Diagnostic performance of liver biopsy for HNF1A mutated HCA was lower because of the lack of non-tumoral tissue. Diagnosis based on morphological analysis was certain and correct in 27 cases. Immunostaining allowed a definite diagnosis in 12 additionnal cases. Radiological diagnosis was in agreement with the histological diagnosis in 75.6% of the cases, with a very high sensitivity (97%) and specificity (100%) for the diagnosis of HNF1A mutated HCA. CONCLUSIONS: Liver biopsy has a good diagnostic performance particularly for FNH and inflammatory HCA, and sampling of non-lesional tissue is highly recommended. A biopsy does not seem necessary if H-HCA is diagnosed on MRI. PMID- 26969819 TI - 'Depression is not an illness. It's up to you to make yourself happy': Perceptions of Chinese health professionals and community workers about older Chinese immigrants' experiences of depression and anxiety. AB - AIM: The aim of this study was to improve our understanding of depression and anxiety among older immigrant Chinese Australians. METHODS: The study was based on the National Ageing Research Institute's Cultural Exchange Model, an iterative process of exchange between researchers and stakeholders. The project involved a range of components including consultations with health professionals and community workers about perceptions of depression and anxiety within the Chinese community. This paper reports on these consultation findings. RESULTS: Thematic analysis generated five main categories to explain participants' perceptions of depression and anxiety within the Chinese community. Themes included: lack of knowledge; personal weakness rather than illness; stigma; somatisation; and experience of migration in later life. Responses to questions about education and information dissemination were collated separately and reported. CONCLUSION: Views of depression and anxiety among older Chinese people suggest that educating the community may be an important way to improve mental health literacy and help seeking behaviour. PMID- 26969818 TI - Estimating the Risks and Benefits of Implantable Cardioverter Defibrillator Generator Replacement: A Systematic Review. AB - BACKGROUND: Every 4-7 years an implantable cardioverter defibrillator (ICD) pulse generator must be replaced surgically. This procedure is not without risk. In some cases, the risk versus benefit ratio may be against replacement. We aimed to synthesize the evidence on risks, benefits, and costs related to ICD replacement. METHODS: A systematic review was conducted using electronic databases from 2000 onward. Literature screening, quality appraisal, and data extraction were independently conducted by two reviewers. Outcomes included major and minor complications, ICD therapies, and costs, which were synthesized descriptively. RESULTS: Of 1,483 citations, 17 nonrandomized studies met criteria. Median rate of major complications was 4.05% (range 0.55-7.37%) and minor complications was 3.50% (range 0.36-7.37%). Without non-ICD control groups, the true risk reduction provided by the ICD following replacement is unknown. Following ICD replacement, annualized rate of appropriate ICD therapy was 10.52% (range 2.42-75.00%). Of these, patients without therapies during their first generator life and those no longer meeting ICD criteria received appropriate therapies at nontrivial rates. CONCLUSION: Rates of complications associated with ICD replacement are substantial. No study had nonreplacement groups, hence the true risk reduction provided by the ICD following replacement is unknown. Our analysis did not identify a subgroup at low risk of therapies following replacement. Shared discussions should occur with patients about the evidence, healthcare goals, risk tolerances, and feelings about life and death trade-offs to enable high-quality decisions about ICD replacement. PMID- 26969820 TI - Epigenetic and lncRNA regulation of cardiac pathophysiology. AB - Our developmental studies provide an insight into the pathogenesis of heart failure in adults. These studies reveal a mechanistic link between fetal cardiomyocytes and pathologically stressed adult cardiomyocytes at the level of chromatin regulation. In embryos, chromatin-regulating factors within the cardiomyocytes respond to developmental signals to program cardiac gene expression to promote cell proliferation and inhibit premature cell differentiation. In the neonatal period, the activity of these developmental chromatin regulators is quickly turned off in cardiomyocytes, coinciding with the cessation of cell proliferation and advance in cell differentiation toward adult maturity. When the mature hearts are pathologically stressed, those chromatin regulators essential for cardiomyocyte development in embryos are reactivated, triggering gene reprogramming to a fetal-like state and pathological cardiac hypertrophy. Furthermore, in the study of chromatin regulation and cardiac gene expression, we identified a long noncoding RNA that interacts with chromatin remodeling factor to regulate the cardiac response to environmental changes. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. PMID- 26969821 TI - Adenosine and Preexcitation Variants: Reappraisal of Electrocardiographic Changes. AB - Intravenous adenosine is a short-acting blocker of the atrioventricular node that has been used to unmask subtle or latent preexcitation, and also to enable catheter ablation in selected patients with absent or intermittent preexcitation. Depending on the accessory pathway characteristics, intravenous adenosine may produce specific electrocardiographic changes highly suggestive of the preexcitation variant. Herein, we view different ECG responses to this pharmacological test in various preexcitation patterns that were confirmed by electrophysiological studies. Careful analysis of electrocardiographic changes during adenosine test, with emphasis on P-delta interval, preexcitation degree, and atrioventricular block, can be helpful to diagnose the preexcitation variant/pattern. PMID- 26969822 TI - Training bottlenose dolphins to overcome avoidance of environmental enrichment objects in order to stimulate play activities. AB - Enrichment programs may contribute to the quality of life and stress reduction in bottlenose dolphins (Tursiops truncatus) kept in zoos and aquaria. The results of these programs are generally positive in terms of welfare, but the magnitude of their effects may vary greatly between individuals of the same species, especially when the enrichment plans are based on the introduction of manipulative objects. Some animals will interact spontaneously with novel objects, even without food rewards and in the absence of the trainers, while others show no interest or even aversion toward the objects. To determine if formal training can improve these conditions, we measured the effects of an operant conditioning program in the manipulation of objects by dolphins that initially avoided them. This program took place between April and October 2013 at Zoomarine Portugal. Subjects were two female and two male bottlenose dolphins (adults with ages from 17 to 35 years) that after a preliminary analysis showed avoidance or low interest in the manipulation of various toys. The level of interaction with introduced enrichment objects was observed before and after formal training to explore the toys (sixteen 20-min observation sessions per animal "before" and "after training"). In all subjects, an index of interest in object manipulation, in the absence of trainers, increased significantly after the application of the training techniques. The results show that an initial reinforcement program focused on the manipulation of toys may overcome resistance, improving the effects of environmental enrichment plans, and it is a potentially useful strategy to increase the welfare of some captive animals. Zoo Biol. 35:210-215, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26969823 TI - Identification and characterization of an atypical 2-cys peroxiredoxin from the silkworm, Bombyx mori. AB - Peroxiredoxins (Prxs) play an important role in the protection of insects against the toxicity of reactive oxygen species. Here, we identified and characterized a novel, atypical 2-cysteine (Cys) peroxiredoxin (BmPrx3) from an expressed sequence tag database in a lepidopteran insect, Bombyx mori. The BmPrx3 cDNA contained an open reading frame of 684 bp that encodes a 228-amino-acid protein with a calculated molecular mass of 25 kDa. Sequence comparison revealed that BmPrx3 belongs to the atypical 2-Cys Prxs. Quantitative real-time PCR revealed that BmPrx3 can be detected in all tissues and developmental stages. Recombinant BmPrx3 purified from Escherichia coli exhibited antioxidant activity that removed hydrogen peroxide and protected DNA from oxidative damage. Disc diffusion and viability assays revealed that recombinant BmPrx3 increased bacterial survival under H2 O2 -mediated oxidative stress. In addition, quantitative real-time PCR analysis indicated that BmPrx3 transcription levels were significantly increased in response to various oxidative stresses. Furthermore, BmPrx3 transcription levels in the midgut were regulated by bacterial infection. Taken together, these results suggest that BmPrx3 acts as an antioxidant enzyme to protect the silkworm from various oxidative stresses. PMID- 26969824 TI - Erratum. PMID- 26969825 TI - Pemphigus vulgaris-associated interstitial lung disease. AB - Autoimmune bullous diseases (AIBDs)-associated interstitial lung disease (ILD) is extremely rare. Pemphigus vulgaris (PV) is an intraepidermal autoimmune blistering disease caused by circulating autoantibodies against desmoglein. To date, PV-associated ILD has rarely been reported in English literature. We report a rare association of PV and ILD. A 53-year-old Chinese female with PV for 8 months developed ILD after a relapse of PV for 2 months due to discontinuation of oral prednisone by herself. She was successfully treated by systemic methylprednisolone. Taken previously reported bullous pemphigoid-associated ILD and linear IgA/IgG bullous dermatosis-associated ILD together, in general, AIBDs associated ILD occurs when AIBDs relapse or are not controlled, responds well to systemic corticosteroids, and has a relatively better prognosis when compared with rheumatoid arthritis- or dermatomyositis-associated ILD. PMID- 26969827 TI - Cardiac Vein Accessibility According to Heart Diseases and Sex: Implications for Cardiac Resynchronization Therapy. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) is an important therapy in patients with heart failure (HF) and dyssynchrony. We performed the present study to elucidate clinical factors associated with cardiac vein accessibility. METHODS: In 255 consecutive patients (age, 48.7 +/- 19.4 years; male, 126), cardiac venography was performed during CRT implantation or an electrophysiological study. We measured the diameters and the proximal branching angles of the lateral cardiac and posterior ventricular veins. Easy accessibility of the cardiac vein was defined as a lumen diameter >=1.6 mm with an angle of >=90 degrees . We compared baseline characteristics between patients with and without easily accessible cardiac veins. We compared cardiac vein accessibility between patients with and without HF, including ischemic and nonischemic HF, and between males and females. RESULTS: In 189 (74.1%) patients, the cardiac veins were easily accessible. The cardiac veins were more easily accessible in patients with HF (n = 75) compared with patients without HF (n = 180; 89.3% and 67.8%, respectively; P < 0.001). The cardiac veins were more easily accessible in patients with nonischemic HF (n = 56) compared with patients with ischemic HF (n = 19; 96.4% and 68.4%, respectively; P = 0.003). The cardiac veins were more easily accessible in females compared with males (79.8% and 68.3%, respectively; P = 0.035). CONCLUSIONS: Accessing the cardiac veins for CRT implantation was difficult in ~10% of patients with HF. Cardiac vein accessibility was high in patients with nonischemic HF and in females. PMID- 26969826 TI - Substitution of general practitioners by nurse practitioners in out-of-hours primary care: a quasi-experimental study. AB - AIM: To provide insight into the impact of substituting general practitioners with nurse practitioners in out-of-hours services on: (1) the number of patients; and (2) general practitioners' caseload (patient characteristics, urgency levels, types of complaints). BACKGROUND: General practitioners' workload during out-of hours care is high, and the number of hours they work out-of-hours has increased, which raises concerns about maintaining quality of care. One response to these challenges is shifting care to nurse practitioners. DESIGN: Quasi-experimental study comparing differences between and within out-of-hours teams: experimental, one nurse practitioner and four general practitioners; control, five general practitioners. METHODS: Data of 12,092 patients from one general practitioners cooperative were extracted from medical records between April 2011 and July 2012. RESULTS: The number of patients was similar in the two study arms. In the experimental arm, the nurse practitioner saw on average 16.3% of the patients and each general practitioner on average 20.9% of the patients. General practitioners treated more older patients; higher urgency levels; and digestive, cardiovascular and neurological complaints. Nurse practitioners treated more patients with skin and respiratory complaints. Substitution did not lead to a meaningful increase of general practitioners' caseload. CONCLUSION: The results show that nurse practitioners can make a valuable contribution to patient care during out-of hours. The patients managed and care provided by them is roughly the same as general practitioners. In areas with a shortage of general practitioners, administrators could consider employing nurses who are competent to independently treat patients with a broad range of complaints to offer timely care to patients with acute problems. PMID- 26969829 TI - Role of 5-HT1A receptor in insular cortex mediating stress - induced visceral sensory dysfunction. AB - BACKGROUND: 5-HT1A receptors (HTR1As) in the insular cortex are thought to be related with the generation of stress-induced functional gastrointestinal disorders (FGIDs), but its mechanism is not clear. Visceral hypersensitivity is one important pathophysiological mechanism of FGIDs. This study aimed to explore the role of HTR1As in mediating stress-induced visceral hypersensitivity and its mechanism in the insular cortex. METHODS: Visceral hypersensitivity rat model was established by water avoidance stress (WAS) and the visceral sensitivity was measured by electromyogram. The activities of HTR1As were regulated by microinjecting the HTR1A agonist and antagonist into the insular cortex. The expression levels of 5-HT, HTR1A, N-methyl-d-aspartic acid receptor subtype 2B (NR2B) and c-fos were observed by RT-PCR, Western Blot and immunohistochemical staining. KEY RESULTS: In WAS rats, the expression levels of 5-HT and HTR1As in the insular cortex were significantly lower (p < 0.05) than that in sham WAS and normal rats, but the levels of c-fos and NR2B were significantly higher (p < 0.05). After microinjecting HTR1As agonist into the insular cortex of WAS rats, the visceral sensitivity and the expression levels of NR2B and c-fos in insular cortex significantly decreased (p < 0.05). CONCLUSIONS & INFERENCES: The HTR1As NR2B signal pathway of insular cortex plays an important role in regulating stress-induced visceral hypersensitivity. PMID- 26969830 TI - Non-medical needs of older patients in the emergency department. AB - AIM: To determine the non-medical needs of older patients in the emergency department (ED). METHODS: We undertook a cross-sectional survey of three age groups (50-64, 65-79, 80+ years) using a self-administered questionnaire with five response options (strongly agree-strongly disagree) for 31 items. RESULTS: There were 548 patients enrolled. Significantly fewer older patients knew how to call for assistance (P < 0.01), knew how the ED works (P < 0.01), felt frightened by their illness (P < 0.01) or felt that the ED lights were too bright (P < 0.03). A substantial proportion of all patients did not agree that their illness and/or treatment had been well explained. CONCLUSION: Older patients appear resilient but need to be told to call for assistance when needed, to know how to call for this assistance and how the ED works. Clear information regarding their illness and treatment should be provided, particularly to younger patients who may be anxious. PMID- 26969828 TI - Down-regulation of TRPS1 stimulates epithelial-mesenchymal transition and metastasis through repression of FOXA1. AB - The tricho-rhino-phalangeal syndrome 1 gene (TRPS1), which was initially found to be associated with tricho-rhino-phalangeal syndrome, is critical for the development and differentiation of bone, hair follicles and kidney. However, its role in cancer progression is largely unknown. In this study, we demonstrated that down-regulation of TRPS1 correlated with distant metastasis, tumour recurrence and poor survival rate in cancer patients. TRPS1 was frequently down regulated in high-metastatic cancer cell lines from the breast, colon and nasopharynx. Silencing of TRPS1 stimulated epithelial-mesenchymal transition (EMT), migration and invasion in vitro and metastasis in vivo, while TRPS1 over expression exhibited the opposite effects. Using quantitative proteomics, FOXA1, a negative regulator of epithelial-mesenchymal transition (EMT), was shown to be down-regulated by TRPS1 knockdown. Ectopic expression of FOXA1 blocked the enhancement of EMT, migration and invasion induced by TRPS1 silencing. Mechanistically, TRPS1, acting as a transcription activator, directly induced FOXA1 transcription by binding to the FOXA1 promoter. We further showed that down regulation of TRPS1 was induced by miR-373 binding to the 3' UTR of TRPS1. Over expression of TRPS1, but not TRPS1 3' UTR, blocked the enhancement of migration and invasion induced by miR-373. Taken together, we consider that down-regulation of TRPS1 by miR-373, acting as a transcriptional activator, promotes EMT and metastasis by repressing FOXA1 transcription, expanding upon its previously reported role as a transcription repressor. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 26969831 TI - Photosensitizer-Free Visible-Light-Mediated Gold-Catalyzed 1,2 Difunctionalization of Alkynes. AB - Under visible-light irradiation, the gold-catalyzed intermolecular difunctionalization of alkynes with aryl diazonium salts in methanol affords a variety of alpha-aryl ketones in moderate to good yields. In contrast to previous reports on gold-catalyzed reactions that involve redox cycles, no external oxidants or photosensitizers are required. The reaction proceeds smoothly under mild reaction conditions and shows broad functional-group tolerance. Further applications of this method demonstrate the general applicability of the arylation of a vinyl gold intermediate instead of the commonly used protodemetalation step. This step provides facile access to functionalized products in one-pot processes. With a P,N-bidentate ligand, a stable aryl gold(III) species was obtained, which constitutes the first direct experimental evidence for the commonly postulated direct oxidative addition of an aryl diazonium salt to a pyridine phosphine gold(I) complex. PMID- 26969832 TI - Broadband Black-Phosphorus Photodetectors with High Responsivity. AB - An array of black-phosphorus photodetectors with channel lengths down to 100 nm is fabricated, and temperature-dependent photodetection measurements from 300 K down to 20 K are carried out. The devices show high photoresponse in a broadband spectral range with a record-high photoresponsivity of 4.3 * 10(6) A W(-1) at 300 K for the 100 nm device. PMID- 26969833 TI - Myotonic dystrophy type 1 presenting with asymmetric winged scapulae. PMID- 26969834 TI - Demodex mites in acne rosacea: reflectance confocal microscopic study. AB - BACKGROUND/OBJECTIVES: Demodex mite density is emphasised in the aetiopathogenesis of acne rosacea. Reflectance confocal microscopy (RCM) has been shown to be a good method for determining demodex mite density. The objective was to determine demodex mite density using RCM in acne rosacea patients and compare them with controls. METHODS: In all, 30 papulopustular rosacea (PPR) and 30 erythematotelangiectatic rosacea (ETR) totally 60 acne rosacea patients and 40 controls, were enrolled in the study. The right cheek was selected for imaging and RCM was used for scanning. Ten images of 1000 * 1000 MUm (total 10 mm2 ) area were scanned from adjacent areas. The numbers of follicles, infested follicles and mites were counted. The mean numbers of mites per follicle and infested follicles were calculated and compared in the patients and control groups. RESULTS: The mean number of mites was 44.30 +/- 23.22 in PPR, 14.57 +/- 15.86 in ETR and 3.55 +/- 6.48 in the control group (P < 0.001). The mean number of mites per follicle was 1.77 +/- 0.90 in PPR, 0.57 +/- 0.63 in ETR and 0.13 +/- 0.23 in the control group (P < 0.001). The cut-off for the mean number of mites for determining mite infestation was 0.17 and above. CONCLUSIONS: Demodex mite density was markedly increased in both ETR and PPR patients. It is believed that the presence of demodex mites plays an important role in rosacea aetiopathogenesis. Demodex mite treatment may reduce the severity of the disease and slow its progressive nature. PMID- 26969835 TI - Sexual selection on skeletal shape in Carnivora. AB - Lifetime reproductive success of males is often dependent upon the ability to physically compete for mates. However, species variation in social structure leads to differences in the relative importance of intraspecific aggression. Here, we present a large comparative dataset on sexual dimorphism in skeletal shape in Carnivora to test the hypotheses that carnivorans exhibit sexual dimorphism in skeletal anatomy that is reflective of greater specialization for physical aggression in males relative to females and that this dimorphism is associated with the intensity of sexual selection. We tested these hypotheses using a set of functional indices predicted to improve aggressive performance. Our results indicate that skeletal shape dimorphism is widespread within our sample. Functional traits thought to enhance aggressive performance are more pronounced in males. Phylogenetic model selection suggests that the evolution of this dimorphism is driven by sexual selection, with the best-fitting model indicating greater dimorphism in polygynous versus nonpolygynous species. Skeletal shape dimorphism is correlated with body size dimorphism, a common indicator of the intensity of male-male competition, but not with mean body size. These results represent the first evidence of sexual dimorphism in the primary locomotor system of a large sample of mammals. PMID- 26969836 TI - Stimulation of the nitrate-nitrite-NO-metabolism by repeated lettuce juice consumption decreases gingival inflammation in periodontal recall patients: a randomized, double-blinded, placebo-controlled clinical trial. AB - AIM: This prospective, parallel group, two-armed, double-blind, placebo controlled randomized trial evaluated the impact of dietary nitrate consumption on gingival inflammation in periodontal recall patients. MATERIAL AND METHODS: Forty-four (23 test/21 placebo) periodontal recall patients with chronic gingivitis were enrolled. At baseline, gingival index (GI), plaque control record (PCR) and salivary nitrate level (SNL) were recorded, followed by sub- and supragingival debridement. Subsequently, participants were randomly provided with 100 ml bottles of a lettuce juice beverage to be consumed 3* daily over 14 days, containing either a standardized amount of nitrate resulting in an intake of approximately 200 mg nitrate per day (test) or being devoid of nitrate (placebo). RESULTS: At baseline, mean GI, PCR and SNL did not differ significantly between the groups. At day 14, mean GI of the test group was significantly reduced compared to baseline and significantly lower (p = 0.002) than in the placebo group (GI 0.3 versus 0.5). Also, mean SNL in the test group was significantly higher than in the placebo group (54.0 MUg/ml versus 27.8 MUg/ml; p < 0.035). Mean PCR did not change significantly in both groups. CONCLUSIONS: Dietary nitrate consumption may be a useful adjunct in the control of chronic gingivitis. PMID- 26969837 TI - Behavioral variant of frontotemporal dementia: Fundamental clinical issues associated with prediction of pathological bases. AB - Behavioral variant of frontotemporal dementia (bvFTD) is a clinical syndrome characterized mainly by behavioral symptoms due to frontal dysfunction. Major neurodegenerative bases of bvFTD include Pick's disease, frontotemporal lobar degeneration with trans-activation response DNA protein 43-positive inclusions, corticobasal degeneration, and progressive supranuclear palsy. Early disinhibition characterized by socially inappropriate behaviors, loss of manners, and impulsive, rash and careless actions is the most important clinical feature of bvFTD. On the other hand, it was reported that clinical presentations of some Alzheimer's disease cases and patients with psychiatric disorders (e.g., addictive disorders, gambling disorder and kleptomania) often resemble that of bvFTD. Although clinical differentiation of 'true' bvFTD cases with frontotemporal lobar degeneration (FTLD) pathology from mimicking cases without it is not always easy, evaluation of the following features, which were noted in autopsy-confirmed FTLD cases and/or clinical bvFTD cases with circumscribed lobar atrophy, may often provide clues for the diagnosis. (i) The initial symptoms frequently develop at 65 years or younger, and (ii) 'socially inappropriate behaviors' can be frequently interpreted as contextually inappropriate behaviors prompted by environmental visual and auditory stimuli. Taking a detailed history usually reveals various kinds of such behaviors in various situations in everyday life rather than the repetition of a single kind of behavior (e.g., repeated shoplifting). (iii) A correlation between the distribution of cerebral atrophy and neurological and behavioral symptoms is usually observed, and the proportion of FTLD cases with right side-predominant cerebral atrophy may be higher in a psychiatric setting than a neurological setting. Finally, (iv) whether the previous course and the combination of symptoms observed at the first medical visit can be explained by major evolution patterns of clinical syndromes in pathologically confirmed FTLD cases should be considered. These views may provide clues to differentiate FTLD from Alzheimer's disease and to predict a subsequent clinical course and therapeutic interventions needed in the future. PMID- 26969838 TI - Shotgun proteomic analysis of soybean embryonic axes during germination under salt stress. AB - Seed imbibition and radicle emergence are generally less affected by salinity in soybean than in other crop plants. In order to unveil the mechanisms underlying this remarkable salt tolerance of soybean at seed germination, a comparative label-free shotgun proteomic analysis of embryonic axes exposed to salinity during germination sensu stricto (GSS) was conducted. The results revealed that the application of 100 and 200 mmol/L NaCl stress was accompanied by significant changes (>2-fold, P<0.05) of 97 and 75 proteins, respectively. Most of these salt responsive proteins (70%) were classified into three major functional categories: disease/defense response, protein destination and storage and primary metabolism. The involvement of these proteins in salt tolerance of soybean was discussed, and some of them were suggested to be potential salt-tolerant proteins. Furthermore, our results suggest that the cross-protection against aldehydes, oxidative as well as osmotic stress, is the major adaptive response to salinity in soybean. PMID- 26969840 TI - Risk of relapse of endometrial hyperplasia is high and long-term treatment and follow up are recommended. PMID- 26969839 TI - Zonal variation in primary cilia elongation correlates with localized biomechanical degradation in stress deprived tendon. AB - Tenocytes express primary cilia, which elongate when tendon is maintained in the absence of biomechanical load. Previous work indicates differences in the morphology and metabolism of the tenocytes in the tendon fascicular matrix (FM) and the inter-fascicular matrix (IFM). This study tests the hypothesis that primary cilia in these two regions respond differently to stress deprivation and that this is associated with differences in the biomechanical degradation of the extracellular matrix. Rat tail tendon fascicles were examined over a 7-day period of either stress deprivation or static load. Seven days of stress deprivation induced cilia elongation in both regions. However, elongation was greater in the IFM compared to the FM. Stress deprivation also induced a loss of biomechanical integrity, primarily in the IFM. Static loading reduced both the biomechanical degradation and cilia elongation. The different responses to stress deprivation in the two tendon regions are likely to be important for the aetiology of tendinopathy. Furthermore, these data suggest that primary cilia elongate in response to biomechanical degradation rather than simply the removal of load. This response to degradation is likely to have important consequences for cilia signalling in tendon and as well as in other connective tissues. (c) 2016 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 34:2146-2153, 2016. PMID- 26969841 TI - Systematic procedure for the classification of proven and potential teratogens for use in research. AB - BACKGROUND: Although there is strong evidence that some medications are teratogenic, the current lists of teratogens to be used in research are outdated. The objective of this study was to develop an updatable and systematic procedure to the classification of medications proven and potentially teratogenic in the first trimester of pregnancy, for use in research. METHODS: We developed a two step procedure for teratogen classification. Step 1 includes classifying the medications from Drugs in Pregnancy and Lactation: a Reference Guide to Fetal and Neonatal Risk (9th ed.) into two provisional lists: (1) teratogenic medications, and (2) potentially teratogenic medications. We also searched other references to add other medications. In Step 2, the Teratology Information System (TERIS) database was searched, and the medication was classified as teratogenic or potentially teratogenic according to a newly developed scheme. Expert consensus was used if a medication was not recorded in TERIS. RESULTS: A total of 114 medications were identified in Drugs in Pregnancy and Lactation: a Reference Guide to Fetal and Neonatal Risk, with 57 medications in each provisional list. Seventy-eight medications were identified in other sources. A total of 135 medications were included in Step 2; the TERIS scheme classified 23 medications, and 112 medications required expert opinion. The two experts agreed on 78.6% of the medications (kappa = 0.63). We identified 91 teratogenic and 81 potentially teratogenic medications. CONCLUSION: Using reliable references, we established a systematic procedure to the classification of medications with evidence of or potential teratogenic risk. These exhaustive lists will be useful in teratology research and related fields. PMID- 26969843 TI - Drone based measurement system for radiofrequency exposure assessment. AB - For the first time, a method to assess radiofrequency (RF) electromagnetic field (EMF) exposure of the general public in real environments with a true free-space antenna system is presented. Using lightweight electronics and multiple antennas placed on a drone, it is possible to perform exposure measurements. This technique will enable researchers to measure three-dimensional RF-EMF exposure patterns accurately in the future and at locations currently difficult to access. A measurement procedure and appropriate measurement settings have been developed. As an application, outdoor measurements are performed as a function of height up to 60 m for Global System for Mobile Communications (GSM) 900 MHz base station exposure. Bioelectromagnetics. 37:195-199, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26969842 TI - RASA1 somatic mutation and variable expressivity in capillary malformation/arteriovenous malformation (CM/AVM) syndrome. AB - Germline mutations in RASA1 are associated with capillary malformation arteriovenous malformation (CM-AVM) syndrome. CM-AVM syndrome is characterized by multi-focal capillary malformations and arteriovenous malformations. Lymphatic anomalies have been proposed as part of the phenotype. Intrafamilial variability has been reported, suggesting modifiers and somatic events. The objective of the study was to identify somatic RASA1 "second hits" from vascular malformations associated with CM-AVM syndrome, and describe phenotypic variability. Participants were examined and phenotyped. Genomic DNA was extracted from peripheral blood on all participants. Whole-exome sequencing was performed on the proband. Using Sanger sequencing, RASA1 exon 8 was PCR-amplified to track the c.1248T>G, p.Tyr416X germline variant through the family. A skin biopsy of a capillary malformation from the proband's mother was also obtained, and next generation sequencing was performed on DNA from the affected tissue. A familial germline heterozygous novel pathogenic RASA1 variant, c.1248T>G (p.Tyr416X), was identified in the proband and her mother. The proband had capillary malformations, chylothorax, lymphedema, and overgrowth, while her affected mother had only isolated capillary malformations. Sequence analysis of DNA extracted from a skin biopsy of a capillary malformation of the affected mother showed a second RASA1 somatic mutation (c.2245C>T, p.Arg749X). These results and the extreme variable expressivity support the hypothesis that somatic "second hits" are required for the development of vascular anomalies associated with CM-AVM syndrome. In addition, the phenotypes of the affected individuals further clarify that lymphatic manifestations are also part of the phenotypic spectrum of RASA1 related disorders. (c) 2016 Wiley Periodicals, Inc. PMID- 26969844 TI - Synthesis of Amaryllidaceae Constituents and Unnatural Derivatives. AB - This update covers the syntheses of Amaryllidaceae alkaloids since the publication of the last major review in 2008. A short summary of past syntheses and their step count is provided for the major constituents; pancratistatin, 7 deoxypancratistatin, narciclasine, lycoricidine, lycorine, and for other natural constituents, as well as for unnatural derivatives. Discussion of biological activities is provided for unnatural derivatives. Future prospects and further developments in this area are covered at the end of the review. The literature is covered to the end of August 2015. PMID- 26969845 TI - Removal of foreign bodies in children's airways using flexible bronchoscopic CO2 cryotherapy. AB - BACKGROUND: The present retrospective study investigated the safety and efficacy of removing foreign bodies from children's airways using flexible bronchoscopic CO2 cryotherapy instead of traditional foreign body aspiration. METHODS: Between October 2012 and June 2014 in the Shanghai Children's Medical Center, we performed flexible bronchoscopic CO2 cryotherapy to remove foreign bodies from the airways of 12 children who ranged in age from 10 to 40 months and analyzed outcomes and complications. RESULTS: Using cryotherapy, we successfully and without complications removed the foreign bodies in eight of 12 children. In two cases, the foreign bodies were removed successfully, but cryotherapy partially damaged the airway mucosa, which caused partial airway obstruction because of the newly developed granulation tissue. We incompletely removed the foreign body in one case and failed to remove the foreign body in another case. No serious adverse reactions or complications were observed after the treatments. CONCLUSION: Removal of foreign bodies from children's airways using flexible bronchoscopic CO2 cryotherapy may be a safe, easy, and effective method. Pediatr Pulmonol. 2016; 51:943-949. (c) 2016 Wiley Periodicals, Inc. PMID- 26969847 TI - What Proportion of Incident Radiographic Vertebral Fractures in Older Men Is Clinically Diagnosed and Vice Versa: A Prospective Study. AB - To determine the proportion of incident radiographic vertebral fractures (vfx) also diagnosed as incident clinical vfx in older men and vice-versa, we used data from 4398 community-dwelling men age >=65 years enrolled in the Osteoporotic Fractures in Men (MrOS) study. Incident radiographic vfx were identified by comparing baseline and follow-up lateral thoracic and lumbar spine study films (average 4.6 years between films) using a semiquantitative (SQ) method and defined as a change in SQ reading of >=1 at a given vertebral level from baseline to follow-up study radiograph. Participants were contacted triannually to ascertain incident clinical vfx; community spinal imaging studies were obtained and clinical vfx were confirmed when the study radiologist determined that the community imaging study showed a new deformity of higher grade than was present in the same vertebra on the baseline study radiograph. A total of 237 incident radiographic vfx were identified in 197 men, whereas 31 men experienced 37 confirmed incident clinical vfx. Of incident radiographic vfx, 13.5% were also clinically diagnosed as incident fractures, with clinical diagnoses made for 16.3% of the radiographic vfx with SQ grade change >=2. Of incident clinical vfx, 86.5% were identified as incident radiographic vfx, most of them with SQ grade change >=2. In summary, less than 15% of incident radiographic vfx were also clinically diagnosed, whereas the majority of incident clinical vfx were identified as severe radiographic vfx. These results in men supplement those previously published for women and suggest a complex relationship between clinical and radiographic vfx in older adults. Published 2016.(?) American Society for Bone and Mineral Research. PMID- 26969848 TI - Treatment of in vitro enterohemorrhagic Escherichia coli infection using phage and probiotics. AB - AIMS: To assay the combination of phage and probiotics against EHEC in vitro on infected Hep-2 cells. METHODS AND RESULTS: Phage and probiotics treatments on EHEC O157:H7-infected Hep-2 cells were assayed individually or combined. The effect of freeze-drying on phage and probiotic antimicrobial activity was also studied. While treatment with phage alone increased cell detachment caused by EHEC infection, the treatments with MM alone or in combination with phage proved to effectively diminish cell damage caused by EHEC infection. Combined treatment showed a decrease in apoptotic cell count of 57.3% and a reduction in EHEC adhesion to cell monolayer of 1.2 log CFU. The simultaneous use of phage and probiotics showed no antagonistic effect, and freeze-drying did not affect their antipathogenic activity. CONCLUSIONS: The combination of phage and probiotics has great potential for reducing the number of pathogens adhered to epithelial cells during EHEC O157:H7 infection and attenuating the cytotoxic effect derived from it. Further in vivo assays are needed for assessing the actual effectiveness of the treatment. SIGNIFICANCE AND IMPACT OF THE STUDY: This study presents a freeze dried formulation of phage and probiotics capable of controlling EHEC infections and reducing epithelial cell damage in vitro. PMID- 26969849 TI - Feral Swine Leptospira Seroprevalence Survey in Hawaii, USA, 2007-2009. AB - Leptospirosis is considered the most widespread of zoonotic diseases. It was a notifiable disease in the United States until 1995 and was reinstated to the list of nationally notifiable diseases in 2014. During the time of national surveillance, Hawaii consistently led the nation in reported annual incidence rates. Leptospirosis has remained a reportable disease in Hawaii. Significant changes have been documented since the early 1970s in the predominant serogroup infecting humans in Hawaii: infections due to Icterohaemorrhagiae have declined while infections due to Australis have increased. A recent study from Hawaii demonstrated that Australis was an uncommon infecting serogroup for small mammal hosts. Swine have not been previously studied in Hawaii but are well-recognized maintenance hosts for leptospires belonging to the Australis serogroup. This study was undertaken to assess the prevalence of Leptospira antibody in feral swine in Hawaii. From January 2007 through December 2009, blood samples were collected opportunistically from feral swine. Using the microscopic agglutination test, we found antibody titres >=1 : 100 to leptospires in 272 (33.8%) of 804 feral swine. The most frequently reacting serovars to the swine sera were Icterohaemorrhagiae (Icterohaemorrhagiae serogroup) (41.5%) and Bratislava (Australis serogroup) (33.8%). The high seroprevalence and presumptively infecting serovars suggest a link between swine and human infection. PMID- 26969846 TI - Molecular genetics of childhood, adolescent and young adult non-Hodgkin lymphoma. AB - Molecular genetic abnormalities are ubiquitous in non-Hodgkin lymphoma (NHL), but genetic changes are not yet used to define specific lymphoma subtypes. Certain recurrent molecular genetic abnormalities in NHL underlie molecular pathogenesis and/or are associated with prognosis or represent potential therapeutic targets. Most molecular genetic studies of B- and T-NHL have been performed on adult patient samples, and the relevance of many of these findings for childhood, adolescent and young adult NHL remains to be demonstrated. In this review, we focus on NHL subtypes that are most common in young patients and emphasize features actually studied in younger NHL patients. This approach highlights what is known about NHL genetics in young patients but also points to gaps that remain, which will require cooperative efforts to collect and share biological specimens for genomic and genetic analyses in order to help predict outcomes and guide therapy in the future. PMID- 26969850 TI - Tracking changes in chromosomal arrangements and their genetic content during adaptation. AB - There is considerable evidence for an adaptive role of inversions, but how their genetic content evolves and affects the subsequent evolution of chromosomal polymorphism remains controversial. Here, we track how life-history traits, chromosomal arrangements and 22 microsatellites, within and outside inversions, change in three replicated populations of Drosophila subobscura for 30 generations of laboratory evolution since founding from the wild. The dynamics of fitness-related traits indicated adaptation to the new environment concomitant with directional evolution of chromosomal polymorphism. Evidence of selective changes in frequency of inversions was obtained for seven of 23 chromosomal arrangements, corroborating a role for inversions in adaptation. The evolution of linkage disequilibrium between some microsatellites and chromosomes suggested that adaptive changes in arrangements involved changes in their genetic content. Several microsatellite alleles increased in frequency more than expected by drift in targeted inversions in all replicate populations. In particular, there were signs of selection in the O3+4 arrangement favouring a combination of alleles in two loci linked to the inversion and changing along with it, although the lack of linkage disequilibrium between these loci precludes epistatic selection. Seven other alleles increased in frequency within inversions more than expected by drift, but were not in linkage disequilibrium with them. Possibly these alleles were hitchhiking along with alleles under selection that were not specific to those inversions. Overall, the selection detected on the genetic content of inversions, despite limited coverage of the genome, suggests that genetic changes within inversions play an important role in adaptation. PMID- 26969852 TI - Quiet diffusion-weighted head scanning: Initial clinical evaluation in ischemic stroke patients at 1.5T. AB - PURPOSE: To compare the quality and diagnostic value of routine single-shot, echo planar imaging, diffusion-weighted imaging (ss-EPI-DWI) to those of quiet readout segmented EPI-DWI (q-DWI) in magnetic resonance imaging (MRI) of acute stroke. MATERIALS AND METHODS: Twenty-six patients with acute stroke underwent a 1.5T MRI including diffusion-weighted ss-EPI and q-DWI. The two sequences were protocolled to have identical spatial resolution and spatial coverage. q-DWI was tested with (regular q-DWI) and without (fast q-DWI) averaging in 13 patients each. The acoustic noise generated by each sequence was measured. Quantitative and qualitative assessments regarding signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), lesion conspicuity, level of artifacts, overall image quality as well as diagnostic content were performed. RESULTS: SNR and CNR values of the q DWI scans were considerably higher than those of ss-EPI DWI (P <= 0.0078). No statistical difference was found for lesion conspicuity (P >= 0.125). Statistical differences were found for level of artifacts (P >= 0.0078) and overall image quality (P >= 0.002). Both were evaluated better in the ss-EPI DWI than in the regular and fast q-DWI. Apart from one fast q-DWI patient, radiologists voted the images to have the same diagnostic content, with upper 90% confidence limits of 0.238 for regular q-DWI and 0.429 for fast q-DWI. CONCLUSION: If the acoustic burden is critical to the patient, q-DWI is an equivalent quiet alternative to ss EPI DWI for use in stroke patients. J. Magn. Reson. Imaging 2016;44:1238-1243. PMID- 26969853 TI - The design of a history of pharmacy course in the bachelor of pharmacy curriculum in the UAE experience. PMID- 26969851 TI - Simplifying a wing: diversity and functional consequences of digital joint reduction in bat wings. AB - Bat wings, like other mammalian forelimbs, contain many joints within the digits. These joints collectively affect dynamic three-dimensional (3D) wing shape, thereby affecting the amount of aerodynamic force a wing can generate. Bats are a speciose group, and show substantial variation in the number of wing joints. Additionally, some bat species have joints with extensor but no flexor muscles. While several studies have examined the diversity in number of joints and presence of muscles, musculoskeletal variation in the digits has not been interpreted in phylogenetic, functional or ecological contexts. To provide this context, the number of joints and the presence/absence of muscles are quantified for 44 bat species, and are mapped phylogenetically. It is shown that, relative to the ancestral state, joints and muscles were lost multiple times from different digits and in many lineages. It is also shown that joints lacking flexors undergo cyclical flexion and extension, in a manner similar to that observed in joints with both flexors and extensors. Comparison of species with contrasting feeding ecologies demonstrates that species that feed primarily on non-mobile food (e.g. fruit) have fewer fully active joints than species that catch mobile prey (e.g. insects). It is hypothesized that there is a functional trade-off between energetic savings and maneuverability. Having fewer joints and muscles reduces the mass of the wing, thereby reducing the energetic requirements of flapping flight, and having more joints increases the assortment of possible 3D wing shapes, thereby enhancing the range and fine control of aerodynamic force production and thus maneuverability. PMID- 26969854 TI - Diarylheptanoids Rich Fraction of Alnus nepalensis Attenuates Malaria Pathogenesis: In-vitro and In-vivo Study. AB - Diarylheptanoids from Alnus nepalensis leaves have been reported for promising activity against filariasis, a mosquito-borne disease, and this has prompted us to investigate its anti-malarial and safety profile using in-vitro and in-vivo bioassays. A. nepalensis leaf extracts were tested in-vitro against chloroquine sensitive Plasmodium falciparum NF54 by measuring the parasite specific lactate dehydrogenase activity. Among all, the chloroform extract (ANC) has shown promising anti-plasmodial activity (IC50 8.06 +/- 0.26 ug/mL). HPLC analysis of ANC showed the presence of diarylheptanoids. Efficacy and safety of ANC were further validated in in-vivo system using Plasmodium berghei-induced malaria model and acute oral toxicity in mice. Malaria was induced by intra-peritoneal injection of P. berghei infected red blood cells to the female Balb/c mice. ANC was administered orally at doses of 100 and 300 mg/kg/day following Peter's 4 day suppression test. Oral administration of ANC showed significant reduction of parasitaemia and increase in mean survival time. It also attributed to inhibition of the parasite induced pro-inflammatory cytokines as well as afford to significant increase in the blood glucose and haemoglobin level when compared with vehicle-treated infected mice. In-vivo safety evaluation study revealed that ANC is non-toxic at higher concentration. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969856 TI - Counting the cost of dementia-related hospital admissions: A regional investigation. AB - AIM: At a time of increasing dementia prevalence, this research explores the cost of treatment and length of stay associated with the syndrome in a large regional hospital. METHODS: Database analysis of 4332 recorded admissions to a large regional Australian hospital among adults aged 55 years and older during winter 2013 and 2014. RESULTS: Costs of hospital treatment and length of stay for people with a diagnosis of dementia who presented to a regional hospital were significantly greater than people with no diagnosis over two years. Costs were unrelated to age or likelihood of death in hospital. Prevalence of dementia admissions was low, but treated conditions indicate that the syndrome may be an underlying, and potentially unrecognised, factor in many admissions. CONCLUSION: Dementia imposes a large cost and resource burden on a regional hospital. Improved identification of the syndrome on admission and implementation of best evidence management of dementia in regional hospitals may improve care efficiency. PMID- 26969857 TI - On the Emergence of Syntactic Structures: Quantifying and Modeling Duality of Patterning. AB - The complex organization of syntax in hierarchical structures is one of the core design features of human language. Duality of patterning refers, for instance, to the organization of the meaningful elements in a language at two distinct levels: a combinatorial level, where meaningless forms are combined into meaningful forms; and a compositional level, where meaningful forms are composed into larger lexical units. The question remains wide open regarding how such structures could have emerged. The aim of this paper is to address these two aspects in a self consistent way. First, we introduce suitable measures to quantify the level of combinatoriality and compositionality in a language, and we present a framework to estimate these observables in human natural languages. Second, we show that a recently introduced multi-agent modeling scheme, namely the Blending Game, provides a mathematical framework to address the problem of how a population of individuals can bootstrap combinatoriality and compositionality. Theoretical predictions based on this model turn out to be in good agreement with empirical data. It is remarkable that the two sides of duality of patterning emerge simultaneously as a consequence of a pure cultural dynamics in a simulated environment that contains meaningful relations, provided a simple constraint on message transmission fidelity is also considered. PMID- 26969855 TI - Longitudinal study of maternal body mass index, gestational weight gain, and offspring asthma. AB - BACKGROUND: Sparse data are available on the relationship between prenatal exposures and asthma during later childhood. In a longitudinal study of adolescents and their mothers, we examined the association of (i) maternal prepregnancy body mass index (BMI) and (ii) gestational weight gain (GWG), with incidence of allergic and nonallergic asthma in offspring. METHODS: Analyses were conducted using data from 12 963 children aged 9-14 years at enrolment in the Growing Up Today Study, and their mothers, who are participants in the Nurses' Health Study II. Physician-diagnosed asthma and allergies were assessed by questionnaires sent regularly to participants and their mothers. Logistic regression was used to evaluate associations of maternal BMI and GWG with offspring asthma, overall and by subtype. RESULTS: Physician-diagnosed asthma during childhood or adolescence was reported by 2694 children (21%). Maternal prepregnancy overweight (OR: 1.19, 95% CI: 1.03-1.38) and obesity (1.34, 1.08 1.68) were associated with offspring asthma. In asthma subtype analyses, the association was seen only for asthma onset before age 12 years. Moreover, the association of maternal obesity with nonallergic asthma was observed in boys (2.39, 1.40-4.09) and not in girls (0.96, 0.50-1.85; Pinteraction = 0.03); the opposite pattern was suggested for allergic asthma. With regard to GWG, an association was suggested between gains of <15 lb and higher risk of offspring asthma (1.28, 0.98-1.66), without clear allergy- or sex-related patterns. CONCLUSION: The relation of several prenatal factors to risk of childhood asthma supports the early origins hypothesis for asthma. The observed allergy- and sex specific patterns suggest multiple etiologic pathways. PMID- 26969858 TI - PALM-COEIN Nomenclature for Abnormal Uterine Bleeding. AB - Approximately 30% of women will experience abnormal uterine bleeding (AUB) during their life time. Previous terms defining AUB have been confusing and imprecisely applied. As a consequence, both clinical management and research on this common problem have been negatively impacted. In 2011, the International Federation of Gynecology and Obstetrics (FIGO) Menstrual Disorders Group (FMDG) published PALM COEIN, a new classification system for abnormal bleeding in the reproductive years. Terms such as menorrhagia, menometrorrhagia, metrorrhagia, dysfunctional uterine bleeding, polymenorrhea, oligomenorrhea, and uterine hemorrhage are no longer recommended. The PALM-COEIN system was developed to standardize nomenclature to describe the etiology and severity of AUB. A brief description of the PALM-COEIN nomenclature is presented as well as treatment options for each etiology. Clinicians will frequently encounter women with AUB and should report findings utilizing the PALM-COEIN system. PMID- 26969859 TI - Assessing Risk in Graphically Presented Financial Series. AB - It has been argued that traders use their natural sensitivity to the fractal properties of price graphs to assess risk and that they are better able to do this when given price change as well as price level information. This approach implies that risk assessments should be higher when the Hurst exponents are lower, that this relationship should be stronger in the presence of price change information and that risk assessment should depend more strongly on the Hurst exponent than on the standard deviation of the series. Participants in Experiment 1 decided which of two assets was riskier by inspecting graphs of their price series. Graphs with lower Hurst exponents were selected only by those who were less emotionally stable and hence more sensitive to risk. However, when both price series and price change series were presented, the assets with lower Hurst exponents were selected by all participants. In a second experiment, participants were given both price level and price change series for a number of assets and rated the risk of trading in each one. Ratings depended more strongly on Hurst exponents than on other measures of volatility. They also depended on indicators of potential loss. Human risk assessment deviates from the way that risk is measured in modern finance theory: it requires integration of information relevant to both uncertainty and loss aversion, thereby imposing high attentional demands on traders. These demands may impair risk assessment but they can be eased by adding displays of price change information. PMID- 26969860 TI - Ultralight Interconnected Metal Oxide Nanotube Networks. AB - Record-breaking ultralow density aluminum oxide structures are prepared using a novel templating technique. The alumina structures are unique in that they are comprised by highly aligned and interconnected nanotubes yielding anisotropic behavior. Large-scale network structures with complex form-factors can easily be made using this technique. The application of the low density networks as humidity sensing materials as well as thermal insulation is demonstrated. PMID- 26969861 TI - Corrigendum. PMID- 26969862 TI - Binary sensitivity of theta activity for gain and loss when monitoring parametric prediction errors. AB - Several theories have been proposed to account for the medial frontal activity that is elicited during the evaluation of outcomes. Respectively, these theories claim that the medial frontal response reflects (i) the absolute deviation between the value of an outcome and its expected value (i.e. an absolute prediction error); (ii) the deviation between actual and expected outcomes, with a specific sensitivity to outcomes that are worse than expected (i.e. a negative prediction error); (iii) a binary evaluation in terms of good and bad outcomes. In the current electroencephalography study, participants were presented with cues that induced specific predictions for the values of trial outcomes (a gain or loss of points). The actual outcomes occasionally deviated from the predicted values, producing prediction errors with parametrically varying size. Analysis of the medial frontal theta activity in response to the outcomes demonstrated a specific sensitivity to the occurrence of a loss of points when a gain had been predicted. However, the absolute deviation with respect to the predicted value did not modulate the theta response. This finding is consistent with the idea that outcome monitoring activity measured over medial frontal cortex is sensitive to the binary distinction between good and bad outcomes. PMID- 26969863 TI - Neural correlates of individual differences in anxiety sensitivity: an fMRI study using semantic priming. AB - Individuals with high anxiety sensitivity (AS) have an increased risk of developing anxiety disorders and are more biased in how they process fear-related stimuli. This study investigates the neural correlates of fear-related words and word associations in high- and low-AS individuals. We used a semantic priming paradigm during functional magnetic resonance imaging in which three types of target words (fear symptoms, e.g. 'dizziness'; neutral, e.g. 'drink'; and pseudowords, e.g. 'salkom') were preceded by two types of prime words (fear triggers, e.g. 'elevator'; and neutral, e.g. 'bottle'). Subjects with high AS rated fear-symptom words (vs neutral words) as more unpleasant than low-AS individuals; they also related these words more strongly to fear-triggers and showed prolonged reaction times. During the processing of fear-symptom words, greater activation in the left anterior insula was observed in high-AS subjects than in low-AS subjects. Lower activation in the left inferior frontal gyrus, angular gyrus, fusiform gyrus and bilateral amygdalae was found in high-AS subjects when fear-symptom words were preceded by fear-trigger words. The findings suggest that cognitive biases and the anterior insula play a crucial role in high-AS individuals. Furthermore, semantic processes may contribute to high AS and the risk of developing anxiety disorders. PMID- 26969866 TI - Shared neural basis of social and non-social reward deficits in chronic cocaine users. AB - Changed reward functions have been proposed as a core feature of stimulant addiction, typically observed as reduced neural responses to non-drug-related rewards. However, it was unclear yet how specific this deficit is for different types of non-drug rewards arising from social and non-social reinforcements. We used functional neuroimaging in cocaine users to investigate explicit social reward as modeled by agreement of music preferences with music experts. In addition, we investigated non-social reward as modeled by winning desired music pieces. The study included 17 chronic cocaine users and 17 matched stimulant naive healthy controls. Cocaine users, compared with controls, showed blunted neural responses to both social and non-social reward. Activation differences were located in the ventromedial prefrontal cortex overlapping for both reward types and, thus, suggesting a non-specific deficit in the processing of non-drug rewards. Interestingly, in the posterior lateral orbitofrontal cortex, social reward responses of cocaine users decreased with the degree to which they were influenced by social feedback from the experts, a response pattern that was opposite to that observed in healthy controls. The present results suggest that cocaine users likely suffer from a generalized impairment in value representation as well as from an aberrant processing of social feedback. PMID- 26969865 TI - Theory of mind for processing unexpected events across contexts. AB - Theory of mind, or mental state reasoning, may be particularly useful for making sense of unexpected events. Here, we investigated unexpected behavior across both social and non-social contexts in order to characterize the precise role of theory of mind in processing unexpected events. We used functional magnetic resonance imaging to examine how people respond to unexpected outcomes when initial expectations were based on (i) an object's prior behavior, (ii) an agent's prior behavior and (iii) an agent's mental states. Consistent with prior work, brain regions for theory of mind were preferentially recruited when people first formed expectations about social agents vs non-social objects. Critically, unexpected vs expected outcomes elicited greater activity in dorsomedial prefrontal cortex, which also discriminated in its spatial pattern of activity between unexpected and expected outcomes for social events. In contrast, social vs non-social events elicited greater activity in precuneus across both expected and unexpected outcomes. Finally, given prior information about an agent's behavior, unexpected vs expected outcomes elicited an especially robust response in right temporoparietal junction, and the magnitude of this difference across participants correlated negatively with autistic-like traits. Together, these findings illuminate the distinct contributions of brain regions for theory of mind for processing unexpected events across contexts. PMID- 26969867 TI - Realistic aortic phantom to study hemodynamics using MRI and cardiac catheterization in normal and aortic coarctation conditions. AB - PURPOSE: To design and characterize a magnetic resonance imaging (MRI)-compatible aortic phantom simulating normal and aortic coarctation (AoCo) conditions and to compare its hemodynamics with healthy volunteers and AoCo patients. MATERIALS AND METHODS: The phantom is composed of an MRI-compatible pump, control unit, aortic model, compliance chamber, nonreturn, and shutoff valves. The phantom without and with AoCo (13, 11, and 9 mm) was studied using 2D and 3D phase-contrast data and with a catheterization unit to measure pressures. The phantom data were compared with the mean values of 10 healthy volunteers and two AoCo patients. RESULTS: Hemodynamic parameters in the normal phantom and healthy volunteers were: heart rate: 68/61 bpm, cardiac output: 3.5/4.5 L/min, peak flow and peak velocity (Vpeak) in the ascending aorta (AAo): 270/357 mL/s (significantly, P < 0.05) and 97/107 cm/s (not significantly, P = 0.16), and pressure in the AAo of the normal phantom of 131/58 mmHg. Hemodynamic parameters in the 13, 11, and 9 mm coarctation phantoms and Patients 1 and 2 were: heart rate: 75/75/75/97/78 bpm, cardiac output: 3.3/3.0/2.9/4.0/5.8 L/min, peak flow in the AAo: 245/265/215/244/376 mL/s, Vpeak in the AAo: 96/95/81/196/187 cm/s, Vpeak after the AoCo: 123/187/282/247/165 cm/s, pressure in the AAo: 124/56, 127/51, 133/50, 120/51 and 87/39 mmHg, and a trans-coarctation systolic pressure gradient: 7, 10, 30, 20, and 11 mmHg. CONCLUSION: We propose and characterize a normal and an AoCo phantom, whose hemodynamics, including velocity, flow, and pressure data are within the range of healthy volunteers and patients with AoCo. J. Magn. Reson. Imaging 2016;44:683-697. PMID- 26969864 TI - Opposing effects of negative emotion on amygdalar and hippocampal memory for items and associations. AB - Although negative emotion can strengthen memory of an event it can also result in memory disturbances, as in post-traumatic stress disorder (PTSD). We examined the effects of negative item content on amygdalar and hippocampal function in memory for the items themselves and for the associations between them. During fMRI, we examined encoding and retrieval of paired associates made up of all four combinations of neutral and negative images. At test, participants were cued with an image and, if recognised, had to retrieve the associated (target) image. The presence of negative images increased item memory but reduced associative memory. At encoding, subsequent item recognition correlated with amygdala activity, while subsequent associative memory correlated with hippocampal activity. Hippocampal activity was reduced by the presence of negative images, during encoding and correct associative retrieval. In contrast, amygdala activity increased for correctly retrieved negative images, even when cued by a neutral image. Our findings support a dual representation account, whereby negative emotion up regulates the amygdala to strengthen item memory but down-regulates the hippocampus to weaken associative representations. These results have implications for the development and treatment of clinical disorders in which diminished associations between emotional stimuli and their context contribute to negative symptoms, as in PTSD. PMID- 26969868 TI - Transfusion in children: epidemiology and 10-year survival of transfusion recipients. AB - OBJECTIVE: To describe the epidemiology of blood transfusion in children: including the incidence of transfusion, the diagnoses leading to transfusion, donor exposure (DE) and post-transfusion survival. STUDY DESIGN AND METHODS: The Epidemiology and Survival of Transfusion Recipients (EASTR) Study was a multi centre epidemiological study with prospective survival monitoring. Cross sectional sampling of adult and paediatric transfusion recipients in 29 hospitals was used to select three separate cohorts of red cell (RBC), platelet (PLT) and fresh frozen plasma (FFP) recipients between October 2001 and September 2002. This paper presents the analysis of results for children <16 years. RESULTS: Children <16 years comprised 449 (5%) of the RBC, 362 (9%) of the FFP and 452 (13%) of the PLT recipients. In children 54% of RBC, 63% FFP and 45% PLT recipients were under 1 year of age and 57% RBC, 60% FFP and 52% PLT were male. Median (IQR) DEduring the study year was 3(2-8); 5(2-13) and 11(6-21) in the RBC, FFP and PLT cohorts, respectively. A total of 20% of RBC, 31% of FFP and 54% of PLT recipients had been exposed to >10 donors. Perinatal conditions were the commonest indication for transfusion in the RBC (36%) and FFP (44%) cohorts and comprised 31% of the PLT cohort. Medical conditions (48%), predominantly malignancy (33%), were the most frequent indication in the PLT cohort. The 10 year (95% CI) survival rates were 81% (77-85%), 72% (67-76%) and 71% (66-75%)for RBC, FFP and PLT cohorts, respectively. CONCLUSIONS: Around half of paediatric transfusion recipients are under 1 year of age. Exposure to components from multiple donors is common. At least 70% of paediatric recipients are long survivors and are at risk for late complications of transfusion. PMID- 26969869 TI - Salvage transoral laser microsurgery for recurrent glottic carcinoma after primary laser-assisted treatment: Analysis of prognostic factors. AB - BACKGROUND: Treatment for local glottic cancer recurrences after primary transoral laser microsurgery (TLM) has not been standardized. METHODS: In 33 consecutive cases of salvage TLM after laser surgery for early glottic carcinoma failed, we retrospectively considered the potential clinicopathological prognostic factors in univariate statistical setting. RESULTS: Patient age <65 years and pathological involvement of the deep margins were associated with a higher second recurrence rate and shorter disease-free survival. CONCLUSION: The age of the patient and the pathological status of surgical margins after salvage TLM could be useful for planning a closer endoscopic/radiological follow-up in selected patients at high risk of recurrence. Other appropriately designed studies are needed to see if an open surgical approach should be considered for younger patients (<65 years old) with recurrent glottic carcinoma after primary TLM. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 1043-1049, 2016. PMID- 26969871 TI - Two fluoroquinolones and their combinations with hyaluronan: comparison of effects on canine chondrocyte culture. AB - Fluoroquinolones (FQs) are frequently used for septic arthritis. Increased antibacterial activity has been associated with mammalian cell cytotoxicity that may increase the risk of developing osteoarthritis. This study compared the direct effects of two different FQs, enrofloxacin (Enro) and marbofloxacin (Mar), on normal primary canine chondrocytes and inflammatory-stimulated chondrocytes, in addition to their administration in combination with hyaluronan (HA). Cell viability, cell apoptosis, s-GAG production, and expression patterns of inflammatory, extracellular matrix (ECM) component and protease genes were measured. Enro co-culturing with HA could modify s-GAG synthesis compared with the negative control group. Co-treatment with both FQs and HA significantly decreased cell viability and induced more total apoptotic cell death compared with the negative control and pre-IL-1beta-stimulated group. Enro regulated IL 1beta-stimulated cells to overexpress IL-1beta, TNF, and MMP3, whereas Mar induced upregulation of PTGS2 and NFKB1 and enhanced the expression of ECM component genes HAS1, COL2A1, and ACAN as well as TIMP1 and MMP9. Simultaneous use of HA with Enro can effectively reduce the expression of IL-1beta, TNF, and MMP3 in pre-IL-1beta-stimulated chondrocytes. These results suggest the beneficial effects of HA in reducing the adverse effects of Enro treatment at the transcriptional level. PMID- 26969870 TI - Idiopathic histaminergic angioedema without wheals: a case series of 31 patients. AB - Idiopathic histaminergic acquired angioedema (IH-AAE) is a common cause of recurrent angioedema without wheals. It is a mast cell-mediated disease thought to belong to the same clinical entity as chronic urticaria (CU). The objective of this study was to describe the clinical and epidemiological characteristics of IH AAE patients. From 2014 to 2015, 534 patients were seen at our national reference centre for angioedema and/or urticaria. Among them, we identified 31 patients with idiopathic histaminergic acquired angioedema without wheals (IH-AAE). Thirty one patients (15 men and 16 women) with a mean age of 50 years met the criteria for IH-AAE. The average delay in diagnosis was 6.3 years. A history of allergy was found in 12 patients (38.7%), nine suffering from allergic rhinitis. The mean duration of attacks was 28.1 h. The AE attack was located in the upper respiratory tract in 54.8% of cases (17 patients). A lingual location was found in 29% of patients. Men were more likely than women to have an upper airway involvement. No intubations or admissions to intensive care units were reported. The dosage of anti-histamines to control the symptoms was onefold the recommended dose in 51.6% of patients (16 patients), twofold in 32% (10 patients) and three fourfold in 16.1% (five patients). IH-AAE is characterized by an important delay in diagnosis, a frequent involvement of the upper airway and a benign course during attacks. As in CU, a trial of up to fourfold dose of H1-anti-histamines may be necessary to control symptoms. PMID- 26969872 TI - Mother's smoking and complex lung function of offspring in middle age: A cohort study from childhood. AB - BACKGROUND AND OBJECTIVE: Existing evidence that supports maternal smoking to be a potential risk factor for chronic obstructive pulmonary disease (COPD) for adult offspring has barely been mentioned in major guideline documents, suggesting a need for more robust and consistent data. We aimed to examine whether such early life exposure can predispose to COPD in middle age, possibly through its interaction with personal smoking. METHODS: The fifth-decade follow up of the Tasmanian Longitudinal Health Study cohort, which was first studied in 1968 (n = 8583), included a 2004 postal survey (n = 5729 responses) and subsequent laboratory attendance (n = 1389) for comprehensive lung function testing between 2006 and 2008. Multivariable linear and logistic regression models included sampling weights. RESULTS: Post-bronchodilator airflow obstruction (less than fifth percentile) was detected for 9.3% (n = 123) of middle-aged offspring. Its association with heavy maternal smoking (>20 cigarettes/day) during childhood was 2.7-fold higher than for those without exposure (95% confidence interval [1.3, 5.7] P = 0.009). Maternal smoking per se approximately doubled the adverse effect of personal smoking on gas transfer factor (z-score -0.46 [-0.6 to -0.3] vs -0.25 [-0.4 to -0.1], P[interaction] = 0.048) and was paradoxically associated with reduced residual volumes for non smokers. CONCLUSIONS: Heavy maternal smoking during childhood appears to predispose to spirometrically defined COPD. The interplay between maternal and personal smoking on gas transfer factor suggests that early life exposure increases an individual's susceptibility to adult smoking exposure. These findings provide further evidence to suggest that maternal smoking might be a risk factor for COPD and reinforce the public health message advocating smoking abstinence. PMID- 26969874 TI - Counties eliminating racial disparities in colorectal cancer mortality. AB - BACKGROUND: Although colorectal cancer (CRC) mortality rates are declining, racial-ethnic disparities in CRC mortality nationally are widening. Herein, the authors attempted to identify county-level variations in this pattern, and to characterize counties with improving disparity trends. METHODS: The authors examined 20-year trends in US county-level black-white disparities in CRC age adjusted mortality rates during the study period between 1989 and 2010. Using a mixed linear model, counties were grouped into mutually exclusive patterns of black-white racial disparity trends in age-adjusted CRC mortality across 20 three year rolling average data points. County-level characteristics from census data and from the Area Health Resources File were normalized and entered into a principal component analysis. Multinomial logistic regression models were used to test the relation between these factors (clusters of related contextual variables) and the disparity trend pattern group for each county. RESULTS: Counties were grouped into 4 disparity trend pattern groups: 1) persistent disparity (parallel black and white trend lines); 2) diverging (widening disparity); 3) sustained equality; and 4) converging (moving from disparate outcomes toward equality). The initial principal component analysis clustered the 82 independent variables into a smaller number of components, 6 of which explained 47% of the county-level variation in disparity trend patterns. CONCLUSIONS: County-level variation in social determinants, health care workforce, and health systems all were found to contribute to variations in cancer mortality disparity trend patterns from 1990 through 2010. Counties sustaining equality over time or moving from disparities to equality in cancer mortality suggest that disparities are not inevitable, and provide hope that more communities can achieve optimal and equitable cancer outcomes for all. Cancer 2016;122:1735-48. (c) 2016 American Cancer Society. PMID- 26969873 TI - Airway Hyperresponsiveness in Asthma Model Occurs Independently of Secretion of beta1 Integrins in Airway Wall and Focal Adhesions Proteins Down Regulation. AB - The extracellular domains of some membrane proteins can be shed from the cell. A similar phenomenon occurs with beta1 integrins (alpha1beta1 and alpha2beta1) in guinea pig. The putative role of beta1 integrin subunit alterations due to shedding in airway smooth muscle (ASM) in an allergic asthma model was evaluated. Guinea pigs were sensitized and challenged with antigen. Antigenic challenges induced bronchoobstruction and hyperresponsiveness at the third antigenic challenge. Immunohistochemistry and immunoelectronmicroscopy studies showed that the cytosolic and extracellular domains of the beta1 integrin subunit shared the same distribution in airway structures in both groups. Various polypeptides with similar molecular weights were detected with both the cytosolic and extracellular beta1 integrin subunit antibodies in isolated airway myocytes and the connective tissue that surrounds the ASM bundle. Flow cytometry and Western blot studies showed that the expression of cytosolic and extracellular beta1 integrin subunit domains in ASM was similar between groups. An increment of ITGB1 mRNA in ASM was observed in the asthma model group. RACE-PCR of ITGB1 in ASM did not show splicing variants. The expression levels of integrin-linked kinase (ILK) and paxillin diminished in the asthma model, but not talin. The levels of phosphorylation of myosin phosphatase target subunit 1 (MYPT1) at Thr(696) increased in asthma model. Our work suggests that beta1 integrin is secreted in guinea pig airway wall. This secretion is not altered in asthma model; nevertheless, beta1 integrin cytodomain assembly proteins in focal cell adhesions in which ILK and paxillin are involved are altered in asthma model. J. Cell. Biochem. 117: 2385-2396, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26969875 TI - Rheological properties and bread quality of frozen yeast-dough with added wheat fiber. AB - BACKGROUND: The rheological characteristics of frozen dough are of great importance in bread-making quality. The effect of addition of commercial wheat aleurone and bran on rheological properties and final bread quality of frozen dough was studied. Wheat aleurone (A) and bran (B) containing 240 g kg-1 and 200 g kg-1 arabinoxylan (AX), respectively, were incorporated into refined wheat flour at 150 g kg-1 substitution level (composite A and B, respectively). Dough samples of composite A and B in addition to two reference dough samples, refined flour (ref A) and whole wheat flour (ref B) were stored at -18 degrees C for 9 weeks. RESULT: Frozen stored composite dough samples contained higher amounts of bound water, less freezable water and exhibited fewer modifications in gluten network during frozen storage based on data from differential scanning calorimetry and nuclear magnetic resonance spectroscopy. Bread made from composite frozen dough had higher loaf volume compared to ref A or ref B throughout the storage period. CONCLUSION: The incorporation of wheat fiber into refined wheat flour produced dough with minimum alterations in its rheological properties during 9 weeks of frozen storage compared to refined and 100% wheat flour dough samples. (c) 2016 Society of Chemical Industry. PMID- 26969876 TI - Prognostic effects of TERT promoter mutations are enhanced by coexistence with BRAF or RAS mutations and strengthen the risk prediction by the ATA or TNM staging system in differentiated thyroid cancer patients. AB - BACKGROUND: Recent reports suggest that mutations in the promoter of the gene encoding telomerase reverse transcriptase (TERT) affect thyroid cancer outcomes. METHODS: In all, 551 patients with differentiated thyroid cancer (DTC) enrolled in this study. The median follow-up duration was 4.8 years (interquartile range, 3.4-10.6 years). RESULTS: TERT promoter mutations were detected in 25 DTCs (4.5%): 2.8% in neither BRAF-mutated nor RAS-mutated tumors, 4.8% in BRAF-mutated tumors, and 11.3% in RAS-mutated tumors. Moreover, they were frequently observed in American Thyroid Association (ATA) high-risk and TNM stage III/IV groups (9.1% and 12.9%, respectively). The coexistence of BRAF or RAS with TERT promoter mutations increased aggressive clinicopathologic features, recurrence (hazard ratio [HR] for BRAF, 4.64; 95% confidence interval [CI], 1.42-15.18; HR for RAS, 5.36; 95% CI, 1.20-24.02), and mortality (HR for BRAF, 15.13; 95% CI, 1.55 148.23; HR for RAS, 14.75; 95% CI, 1.30-167.00), even after adjustments for the age at diagnosis and sex, although the significance was lost after additional adjustments for pathologic characteristics. Furthermore, TERT promoter mutations significantly increased the risk of both recurrence and mortality in the ATA high risk (HR for recurrence, 5.79; 95% CI, 2.07-16.18; HR for mortality, 16.16; 95% CI, 2.10-124.15) and TNM stage III/IV groups (HR for recurrence, 3.60; 95% CI, 1.19-10.85; HR for mortality, 9.06; 95% CI, 2.09-39.26). CONCLUSIONS: The coexistence of BRAF or RAS mutations enhanced the prognostic effects of TERT promoter mutations. Furthermore, TERT promoter mutations strengthened the predictions of mortality and recurrence by the ATA and TNM staging systems, particularly for high-risk patients with DTC. Cancer 2016;122:1370-1379. (c) 2016 American Cancer Society. PMID- 26969877 TI - Occupational fatalities among young workers in the United States: 2001-2012. AB - BACKGROUND: While adolescent workers in the United States (US) are protected by child labor laws, they continue to suffer fatal occupational injuries. This study was designed to provide a comprehensive profile of occupational fatalities among this sub-population of US workers. METHODS: Using Census of Fatal Occupational Injuries data between 2001 and 2012, we calculated descriptive statistics and rates to examine the magnitude and nature of fatalities among workers under age 18. RESULTS: During the study period, there were 406 fatalities among young workers which translated into 24,790 years of potential life lost; 12,241 of which were in agriculture alone. Rates declined since 2001 yet Hispanics, foreign born workers, males, and those working in agriculture continued to suffer a disproportionate fatality burden. CONCLUSIONS: Efforts to reduce young worker fatalities should focus on male Hispanics, particularly those who are foreign born, as well as agricultural workers as these groups have the greatest fatality risks. Am. J. Ind. Med. 59:445-452, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26969878 TI - Hypoglycemia associated with refeeding syndrome in a cat. AB - OBJECTIVE: To describe the clinical presentation and biochemical abnormalities occurring during the successful treatment of refeeding syndrome in a cat. CASE SUMMARY: A 2-year-old neutered male domestic shorthair cat presented after having been missing for 12 weeks. The cat had clinical signs of severe starvation. Common complications developed during refeeding (eg, hypophosphatemia, hypokalemia, and hemolytic anemia). The cat also developed hypoglycemia, a complication common in people but not previously reported in a cat. Hypoglycemia and electrolyte deficiencies were managed with intravenous supplementation. The cat was successfully treated and was discharged alive 7 days after presentation. NEW OR UNIQUE INFORMATION PROVIDED: Hypoglycemia has not been reported previously as a complication of refeeding in a cat. Frequent monitoring of electrolyte, mineral, and blood glucose concentrations is essential to successful management of refeeding syndrome. The ideal refeeding strategy is unknown at this time. Evidence suggests that a diet low in carbohydrate decreases the likelihood of metabolic derangements commonly associated with refeeding. PMID- 26969879 TI - Intractable leg ulcers in Blau syndrome. PMID- 26969880 TI - Perineal stapled prolapse resection for full-thickness external rectal prolapse: a multicentre prospective study. AB - AIM: Many different surgical techniques have been reported for the surgical treatment of full-thickness external rectal prolapse. Perianal stapled prolapse resection (PSP) is a relatively newly reported technique for full thickness external rectal prolapse. The aim of this prospective multicentre study was to evaluate the results of this procedure. METHOD: Consecutive patients who underwent a PSP resection for full-thickness external rectal prolapse at five centres were recruited to the study. Median operating time, hospital stay, complications, recurrence and functional results according to the Wexner Incontinence Scale and obstructive defaecation syndrome score were recorded. RESULTS: There were 27 patients treated by PSP. The median Wexner incontinence score improved from 10 presurgery to 5 after surgery (P < 0.001); the median obstructed defaecation syndrome score improved from 12 presurgery to 5 (range 4 10) after surgery (P < 0.001). A laparoscopically assisted procedure was performed in three patients (11.1%). The median number of cartridges used was six (range four to nine). The median operating time was 48 min. Early complications occurred in six patients (22.2%) and late complications in two (7.4%). The median length of hospital stay was 5 days. The recurrence rate at a median follow-up of 30.3 months was 14.8%. CONCLUSION: PSP appears to be an easy, fast and safe procedure. Early functional results are good. The recurrence rate compares favourably with other perineal procedures like the Delorme or the Altemeier operations. Long-term functional results need to be investigated further. PMID- 26969881 TI - Factors affecting optimal nutrition and hydration for people living in specialised dementia care units: A qualitative study of staff caregivers' perceptions. AB - AIM: To explore the perceptions of staff caregivers regarding factors affecting optimal nutrition and hydration for individuals living in Specialised Dementia Care Units in New Zealand. METHODS: Qualitative descriptive study using a semi structured interview approach with 11 staff caregivers at two Specialised Dementia Care Units. Data were analysed using a general inductive approach. RESULTS: Two main themes were identified. The first theme 'It's about the individual' encompassed individual factors such as appetite, food appeal, and cognitive and functional abilities. The second theme 'It's about the environment' encompassed factors relating to the dining environment, the social aspects to dining and the provision of support with mealtime activities. CONCLUSIONS: Factors affecting nutrition and hydration in people living with dementia are complex and inter-related. Organisations providing specialised dementia care, their staff and foodservice providers should focus on both the individual and environment to ensure optimal nutrition and hydration for the people in their care. PMID- 26969882 TI - Aldo-keto reductase 1B10 protects human colon cells from DNA damage induced by electrophilic carbonyl compounds. AB - Electrophilic carbonyl compounds are highly cytotoxic and genotoxic. Aldo-keto reductase 1B10 (AKR1B10) is an enzyme catalyzing reduction of carbonyl compounds to less toxic alcoholic forms. This study presents novel evidence that AKR1B10 protects colon cells from DNA damage induced by electrophilic carbonyl compounds. AKR1B10 is specifically expressed in epithelial cells of the human colon, but this study found that AKR1B10 expression was lost or markedly diminished in colorectal cancer, precancerous tissues, and a notable portion of normal adjacent tissues (NAT). SiRNA-mediated silencing of AKR1B10 in colon cancer cells HCT-8 enhanced cytotoxicity of acrolein and HNE, whereas ectopic expression of AKR1B10 in colon cancer cells RKO prevented the host cells against carbonyl cytotoxicity. Furthermore, siRNA-mediated AKR1B10 silencing led to DNA breaks and activation of gamma-H2AX protein, a marker of DNA double strand breaks, particularly in the exposure of HNE (10 MUM). In the AKR1B10 silenced HCT-8 cells, hypoxanthine guanine phosphoribosyl transferase (HPRT) mutant frequency increased by 26.8 times at basal level and by 33.5 times in the presence of 10 MUM HNE when compared to vector control cells. In these cells, the cyclic acrolein deoxyguanosine adducts levels were increased by over 10 times. These findings were confirmed by pharmacological inhibition of AKR1B10 activity by Epalrestat. Taken together, these data suggest that AKR1B10 is a critical protein that protects host cells from DNA damage induced by electrophilic carbonyl compounds. AKR1B10 deficiency in the colon may be an important pathogenic factor in disease progression and carcinogenesis. (c) 2016 Wiley Periodicals, Inc. PMID- 26969883 TI - Necrotizing myopathy: An uncommon initial manifestation of human immunodeficiency virus. PMID- 26969884 TI - Lessons learned about the dissemination of motivational interviewing. PMID- 26969885 TI - Conditional Release Placements of Insanity Acquittees in Oregon: 2012-2014. AB - Between January 1, 2012 and December 31, 2014, there was a large population (N = 200) of insanity acquittees placed on conditional release (CR) in the state of Oregon. This article looks at the demographic and system characteristics of this large group of individuals. The authors then focus on the initial housing placement and what happens to individuals after their release in relation to their housing placement. In Oregon, insanity acquittees are either conditionally released directly by the court or placed in the hospital prior to potential CR by a supervising board. In general, once CR occurs, individuals tend to stay in their initial placement without moving to less structured levels of care, raising concerns about transinstitutionalization. This is especially true for individuals released to the most structured living arrangement (secure residential treatment facility). Those individuals who are conditionally released to less structured settings have a higher rate of revocation back to the hospital. Those individuals who do move to less structured levels of care usually have longer hospital stays and start off in more structured levels of care to start their CR. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969886 TI - Ingenol mebutate gel for the treatment of Bowen's disease: a case report of three patients. AB - We report three Bowen's disease (BD) cases treated with ingenol mebutate (IM), a novel topical chemotherapeutic agent approved for the treatment of actinic keratosis (AK) that is available in two doses: 0.015% and 0.05%. Three women diagnosed with BD exhibited a positive response after 2 or 3 day period of IM treatment, depending on lesion location. In the three cases, clinical resolution was observed 4 or 9 weeks posttreatment, and was confirmed with histopathology. Local skin reactions were common the first week after treatment but they resolved spontaneously. In our opinion these cases, along with another case reported in Germany, support the concept of commencing of clinical trials using IM on patients with BD. PMID- 26969888 TI - Plant biotic Interactions. PMID- 26969887 TI - Effectiveness and safety of silodosin in the treatment of lower urinary tract symptoms in patients with benign prostatic hyperplasia: A European phase IV clinical study (SiRE study). AB - OBJECTIVES: To assess the benefit-risk balance of silodosin in a real-life setting of benign prostatic hyperplasia patients with lower urinary tract symptoms. METHODS: A phase IV trial including men aged >=60 years with a clinical diagnosis of benign prostatic hyperplasia with an International Prostate Symptom Score >=12 was carried out. Patients received silodosin 8 mg for 24 weeks. The primary end-point was a decrease >=25% in the total International Prostate Symptom Score. Secondary end-points were: changes in total, storage and voiding, and quality of life International Prostate Symptom Scores; changes in the International Continence Society-male questionnaire; changes in the frequency/volume chart; and satisfaction according to the Patient Perception of Study Medication questionnaire. Treatment-emergent adverse events were recorded. RESULTS: Overall, 1036 patients were enrolled. Of these, 766 patients (77.1%) had a decrease >=25% in the total International Prostate Symptom Score. The mean total International Prostate Symptom Score, and storage and voiding symptoms subscores decreased from 18.9, 8.1 and 10.8 to 10.6, 4.9 and 5.7. Nocturia decreased from 85.7% to 52.4%. The mean International Prostate Symptom Score quality of life score decreased from 4.0 to 2.2. Half of the patients reported an improvement in the frequency and bothersomeness of the most frequent symptoms reported at baseline (all P < 0.001). A reduction in the number of voids was documented by the frequency/volume chart data. The most common treatment-emergent adverse event was ejaculation failure (185 patients; 17.9%), which led to study discontinuation in 2.4% of patients. Overall, 74.2% of patients were satisfied with the medication. CONCLUSIONS: Silodosin improved lower urinary tract symptoms in three out of four patients, including diurnal voiding and storage symptoms, nocturia, and quality of life. This treatment showed a favorable safety profile in this setting. PMID- 26969889 TI - How often and when Fisher syndrome is overlapped by Guillain-Barre syndrome or Bickerstaff brainstem encephalitis? AB - BACKGROUND AND PURPOSE: Fisher syndrome (FS) may overlap with Guillain-Barre syndrome (GBS), in particular the pharyngeal-cervical-brachial variant form (PCB GBS), or Bickerstaff brainstem encephalitis (BBE). Our aim was to elucidate the frequency of this overlap and the patterns of clinical progression in patients with FS. METHODS: Sixty consecutive patients with FS were studied. FS/PCB-GBS was diagnosed when the patients developed pharyngeal, cervical and/or brachial weakness. Patients with flaccid tetraparesis were diagnosed as having FS/conventional GBS. FS/BBE was defined as the development of consciousness disturbances. RESULTS: All 60 patients initially developed the FS clinical triad alone (pure FS). Of these, 30 (50%) patients had pure FS throughout their course, whereas the remaining 50% of patients showed an overlap: PCB-GBS in 14 (23%) patients, conventional GBS in nine (15%) patients and BBE in seven (12%) patients. The median (range) durations from FS onset to progression to FS/PCB GBS, FS/GBS or FS/BBE were 5 (1-7), 3 (1-4) and 3 (1-5) days, respectively. Patients with overlap syndromes more frequently received immune-modulating treatment, and the outcomes were generally favourable. The frequencies of positivity for anti-GQ1b, GT1a, GD1a, GD1b, GalNAc-GD1a and GM1 antibodies were not significantly different amongst the four groups. CONCLUSIONS: Of the patients with pure FS, 50% later developed an overlap with PCB-GBS, conventional GBS or BBE. The overlap occurred within 7 days of FS onset; thus, physicians should pay attention to the possible development of this overlap during the first week after FS onset. PMID- 26969890 TI - Introducing the Hospitalist Morale Index: A new tool that may be relevant for improving provider retention. AB - OBJECTIVE: To develop a valid instrument to assess morale and explore the relationship between morale and intent to leave employment due to unhappiness. PATIENTS AND METHODS: An expert panel identified 46 drivers of hospitalist morale. In May 2009, responders of our single-site pilot survey rated each driver in terms of current contentment and importance to their morale. With exploratory factor analysis, a 28-item/7-factor instrument emerged. In May 2011, the refined scale was distributed to 108 hospitalists from 2 academic and 3 community hospitals. Confirmatory factor analysis (CFA) was used for internal validation and refinement of the Hospitalist Morale Index. Importance ratings and contentment assessments were used to generate item scores, which were then combined to generate factor scores and personal morale scores. Results were used to validate the instrument and evaluate the relationship between hospitalist morale and intent to leave due to unhappiness. RESULTS: The 2011 response rate was 86%. The final CFA resulted in a 5-factor and 5-stand-alone-item model. Personal morale scores were normally distributed (mean = 2.79, standard deviation = 0.58). For every categorical increase on a global question that assessed overall morale, personal morale scores rose 0.23 points (P < 0.001). Each 1-point increase in personal morale score was associated with an 85% decrease (odds ratio: 0.15, 95% confidence interval: 0.05-0.41, P < 0.001) in the odds of intending to leave because of unhappiness. CONCLUSION: The Hospitalist Morale Index is a validated instrument that evaluates hospitalist morale across multiple dimensions of morale. The Hospitalist Morale Index may help program leaders monitor morale and develop customized and effective retention strategies. Journal of Hospital Medicine 2016;11:425-431. (c) 2016 Society of Hospital Medicine. PMID- 26969891 TI - Visible-Light-Induced Photoredox Catalysis of Dye-Sensitized Titanium Dioxide: Selective Aerobic Oxidation of Organic Sulfides. AB - TiO2 photoredox catalysis has recently attracted much interest for use in performing challenging organic transformations under mild reaction conditions. However, the reaction scheme is hampered by the fact that TiO2 can only be excited by UV light of wavelengths lambda shorter than 385 nm. One promising strategy to overcome this issue is to anchor an organic, preferably metal-free dye onto the surface of TiO2. Importantly, we observed that the introduction of a catalytic amount of the redox mediator TEMPO [(2,2,6,6-tetramethylpiperidin-1 yl)oxyl] ensured the stability of the anchored dye, alizarin red S, thereby resulting in the selective oxidation of organic sulfides with O2. This result affirms the essential role of the redox mediator in enabling the organic transformations by visible-light photoredox catalysis. PMID- 26969894 TI - Catheter Ablation of Ventricular Tachycardia in the Presence of an Old Endocavitary Thrombus Guided by Intracardiac Echocardiography. AB - BACKGROUND: Catheter ablation of ventricular tachycardia (VT) in patients with structural heart disease (SHD) is effective in prevention of arrhythmia recurrences. However, endocardial ablation may be challenging in the presence of organized left ventricular (LV) endocavitary thrombus. Our goal was to analyze the results of VT ablation in patients with identified old thrombus. METHODS AND RESULTS: We reviewed clinical and procedural data of 344 consecutive patients who underwent VT ablation for SHD. Old endocavitary thrombus was identified in four patients by preprocedural transthoracic echocardiography (TTE) and in four more patients by intracardiac echocardiography (ICE). All together, the case series of eight patients with detectable thrombus is reported. All patients (one woman, age: 67 +/- 7 years) had postinfarction aneurysm (20 +/- 8 years after the index myocardial infarction) and the thrombus was well organized without mobile structures. Arrhythmogenic substrate could not be obviously targeted beneath the base of thrombus; however, catheter ablation was successfully performed in the close vicinity. A total of 2.4 +/- 1.2 procedures were necessary to abolish VT recurrences. Epicardial ablation was performed in three of eight (38%) patients as a second elective procedure. No procedural or periprocedural complications were observed. During the follow-up of 14 +/- 15 months, two patients (25%) had sporadic VT recurrences. CONCLUSIONS: ICE seems to be more sensitive for the detection of LV thrombi compared to TTE and is helpful in real-time navigation of mapping/ablation catheter. Besides potential thromboembolic risk, large thrombus may prevent accessibility to the "critical" portion of arrhythmia circuit and epicardial ablation is required in selected cases. PMID- 26969893 TI - Overexpression of MYB drives proliferation of CYLD-defective cylindroma cells. AB - Cutaneous cylindroma is an adnexal tumour with apocrine differentiation. A predisposition to multiple cylindromas is seen in patients with Brooke-Spiegler syndrome, who carry germline mutations in the tumour suppressor gene CYLD. Previous studies of inherited cylindromas have highlighted the frequent presence of bi-allelic truncating CYLD mutations as a recurrent driver mutation. We have previously shown that sporadic cylindromas express either MYB-NFIB fusion transcripts or show evidence of MYB activation in the absence of such fusions. Here, we investigated inherited cylindromas from several families with germline CYLD mutations for the presence of MYB activation. Strikingly, none of the inherited CYLD-defective (n = 23) tumours expressed MYB-NFIB fusion transcripts. However, MYB expression was increased in the majority of tumours (69%) and global gene expression analysis revealed that well-established MYB target genes were up regulated in CYLD-defective tumours. Moreover, knock-down of MYB expression caused a significant reduction in cylindroma cell proliferation, suggesting that MYB is also a key player and oncogenic driver in inherited cylindromas. Taken together, our findings suggest molecular heterogeneity in the pathogenesis of sporadic and inherited cutaneous cylindromas, with convergence on MYB activation. (c) 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 26969892 TI - Deregulated methionine adenosyltransferase alpha1, c-Myc, and Maf proteins together promote cholangiocarcinoma growth in mice and humans(?). AB - c-Myc induction drives cholestatic liver injury and cholangiocarcinoma (CCA) in mice, and induction of Maf proteins (MafG and c-Maf) contributes to cholestatic liver injury, whereas S-adenosylmethionine (SAMe) administration is protective. Here, we determined whether there is interplay between c-Myc, Maf proteins, and methionine adenosyltransferase alpha1 (MATalpha1), which is responsible for SAMe biosynthesis in the liver. We used bile duct ligation (BDL) and lithocholic acid (LCA) treatment in mice as chronic cholestasis models, a murine CCA model, human CCA cell lines KMCH and Huh-28, human liver cancer HepG2, and human CCA specimens to study gene and protein expression, protein-protein interactions, molecular mechanisms, and functional outcomes. We found that c-Myc, MATalpha1 (encoded by MAT1A), MafG, and c-Maf interact with one another directly. MAT1A expression fell in hepatocytes and bile duct epithelial cells during chronic cholestasis and in murine and human CCA. The opposite occurred with c-Myc, MafG, and c-Maf expression. MATalpha1 interacts mainly with Mnt in normal liver, but this switches to c-Maf, MafG, and c-Myc in cholestatic livers and CCA. Promoter regions of these genes have E-boxes that are bound by MATalpha1 and Mnt in normal liver and benign bile duct epithelial cells that switched to c-Myc, c-Maf, and MafG in cholestasis and CCA cells. E-box positively regulates c-Myc, MafG, and c Maf, but it negatively regulates MAT1A. MATalpha1 represses, whereas c-Myc, MafG, and c-Maf enhance, E-box-driven promoter activity. Knocking down MAT1A or overexpressing MafG or c-Maf enhanced CCA growth and invasion in vivo. CONCLUSION: There is a novel interplay between MATalpha1, c-Myc, and Maf proteins, and their deregulation during chronic cholestasis may facilitate CCA oncogenesis. (Hepatology 2016;64:439-455). PMID- 26969896 TI - Advances in understanding the pathogenesis of congenital erythropoietic porphyria. AB - Congenital erythropoietic porphyria (CEP) is a rare genetic disease resulting from the remarkable deficient activity of uroporphyrinogen III synthase, the fourth enzyme of the haem biosynthetic pathway. This enzyme defect results in overproduction of the non-physiological and pathogenic porphyrin isomers, uroporphyrin I and coproporphyrin I. The predominant clinical characteristics of CEP include bullous cutaneous photosensitivity to visible light from early infancy, progressive photomutilation and chronic haemolytic anaemia. The severity of clinical manifestations is markedly heterogeneous among patients; and interdependence between disease severity and porphyrin amount in the tissues has been pointed out. A more pronounced endogenous production of porphyrins concomitant to activation of ALAS2, the first and rate-limiting of the haem synthesis enzymes in erythroid cells, has also been reported. CEP is inherited as autosomal recessive or X-linked trait due to mutations in UROS or GATA1 genes; however an involvement of other causative or modifier genes cannot be ruled out. PMID- 26969895 TI - A metastable structure for the compact 30-nm chromatin fibre. AB - The structure of compact 30-nm chromatin fibres is still debated. We present here a novel unified model that reconciles all experimental observations into a single framework. We propose that compact fibres are formed by the interdigitation of the two nucleosome stacks in a 2-start crossed-linker structure to form a single stack. This process requires that the dyad orientation of successive nucleosomes relative to the helical axis alternates. The model predicts that, as observed experimentally, the fibre-packing density should increase in a stepwise manner with increasing linker length. This model structure can also incorporate linker DNA of varying lengths. PMID- 26969898 TI - Diastereodivergent Reverse Prenylation of Indole and Tryptophan Derivatives: Total Synthesis of Amauromine, Novoamauromine, and epi-Amauromine. AB - A regio- and stereoselective reverse prenylation of indole and tryptophan derivatives is presented. All four possible stereoisomers are accessible through this iridium-catalyzed reaction. The stereoselectivity is controlled by a chiral phosphoramidite ligand in combination with an achiral borane additive and can be switched by changing the nature of the borane. One enantiomer of the ligand is thus sufficient to prepare all possible isomers. The synthetic potential of this method was demonstrated by a short total synthesis of amauromine and its two natural diastereomers. PMID- 26969897 TI - Compound heterozygosity of a paternal submicroscopic deletion and a maternal missense mutation in POR gene: Antley-bixler syndrome phenotype in three sibling fetuses. AB - BACKGROUND: Antley-Bixler syndrome (ABS) is an exceptionally rare craniosynostosis syndrome that can be accompanied by disordered steroidogenesis, and is mainly caused by mutations in the POR gene, inherited in an autosomal recessive manner. Here we report the prenatal and postmortem findings of three sibling fetuses with ABS as a result of compound heterozygosity of a paternal submicroscopic deletion and a maternal missense mutation in the POR gene. METHODS: Prenatal ultrasound and postmortem examination were performed in three sibling fetuses with termination of pregnancy at 22, 23, and 17 weeks of gestation, respectively. Molecular analysis of fetus 2 and 3 included (a) bidirectional sequencing of exon 8 of the POR gene after amplification of the specific locus by polymerase chain reaction, to detect single nucleotide variants (SNVs) and (b) high resolution comparative genomic hybridization (CGH) positive single nucleotide polymorphism array CGH (aCGH) analysis to detect copy number variants (CNVs), copy neutral areas of loss of heterozygosity and uniparental disomy. RESULTS: The diagnosis of ABS was suggested by the postmortem examination findings. The combination of the POR gene molecular analysis and aCGH revealed a compound heterozygous genotype of a maternal SNV (p.A287P) and a paternal CNV (NC_000007.13:g.(?_75608488)_(75615534_?)del). CONCLUSION: To the best of our knowledge, these sibling fetuses add to the few reported cases of ABS, caused by a combination of a SNV and a CNV in the POR gene. The detailed description of the pathologic and radiographic findings of second trimester fetuses affected with ABS adds novel knowledge concerning the early ABS phenotype, in lack of previous relevant reports. Birth Defects Research (Part A) 106:536-541, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26969899 TI - Histological assessment of hard and soft tissues surrounding a novel ceramic implant: a pilot study in the minipig. AB - OBJECTIVE: The aim of this study was to investigate clinical and soft/hard tissues histomorphological outcomes of a ceramic implant comparatively to a titanium implant in a minipig model. MATERIAL AND METHODS: Eighteen soft tissue level implants (9 Ceramic with ZLA((r)) surface as test, and 9 titanium SLActive((r)) as control, Institut Straumann, Basel, Switzerland) were randomly placed into the mandible of 6 minipigs (n = 6). Two months later, animals were sacrificed and block biopsies were obtained to assess histomorphological outcomes. Unadjusted paired comparisons, of both groups were performed using the Wilcoxon signed rank test. The Dunnett-Hsu test was used to adjust for multiple comparisons. RESULTS: All implants showed excellent integration into bone and soft tissue. The fBIC (distance implant shoulder to most coronal implant contact) and BIC% (percentage bone-to-implant contact) were for both groups; test: 3.95 mm and 85.4%; control 3.97 mm and 84.3% respectively. No difference in peri-implant mucosa height was found, however, the sulcular epithelium was significantly shorter for the ZrO2 (mean: 0.76, 95%CI: 0.46-1.06) than for the Ti (mean: 1.40, 95%CI: 1.10-1.70) (p = 0.0090). CONCLUSIONS: Within the limits of this pilot study, no difference was found between the ceramic implant with ZLA((r)) surface and a titanium implant in terms of bone tissue integration. Furthermore, the epithelial attachment favoured this ceramic implant over titanium. PMID- 26969900 TI - Serum translationally controlled tumor protein is involved in rat liver regeneration after hepatectomy. AB - AIM: The translationally controlled tumor protein (TCTP) has been reported to promote progression of many physiological processes. However, whether TCTP is involved in liver regeneration has been rarely studied. This study aimed to investigate the potential role of serum TCTP in liver regeneration after two thirds partial hepatectomy. METHODS: The synthesis rate and accumulated expression of TCTP was assessed by phosphor imaging and Western blot analysis, respectively. The mRNA expression of tctp was analyzed by quantitative real-time PCR. The effect of serum TCTP on hepatocyte proliferation was investigated by bromodeoxyuridine incorporation, liver/body weight ratio, albumin concentration, and histological examination of liver following treatment of rat with anti-TCTP antibody or prokaryotic TCTP protein before hepatectomy. The MTT assay was used to examine effect of TCTP on hepatocyte proliferation in vitro. RESULTS: The results showed that the expression of intracellular and serum TCTP protein was significantly increased in rats after two-thirds partial hepatectomy. In vivo bromodeoxyuridine labeling assay suggested that treatment with anti-TCTP antibody before hepatectomy significantly decreased hepatocyte proliferation and liver/body weight ratio. The prokaryotic TCTP had a potential promoting effect on hepatocyte proliferation both in vivo and in vitro, although prokaryotic TCTP given to rats prior to hepatectomy did not increase the proliferation ratio or liver/body weight ratio. Furthermore, anti-TCTP antibody pretreatment decreased the expression of cyclin E, cdk2, and interleukin-6 in rat liver. CONCLUSION: These findings suggest serum TCTP is involved in rat liver regeneration through promoting hepatocyte proliferation. PMID- 26969901 TI - Comparisons of ultrasound-estimated intramuscular fat with fitness and health indicators. AB - INTRODUCTION: We examined ultrasound-estimated intramuscular fat of 4 muscles: rectus femoris (RF), biceps femoris (BF), tibialis anterior (TA), and medial gastrocnemius (MG), and compared the results with other health measures. METHODS: Forty-two participants were tested. Muscle echo intensity was quantified into percent intramuscular fat using previously published equations. RESULTS: Strong correlations were found in percent intramuscular fat in the 4 muscles (r >= 0.8). Weak to moderate correlations were found between intramuscular fat and body mass index (r >= 0.2), waist/hip ratio (r >= 0.2), muscle thickness (r = -0.5 in RF, r = -0.4 in TA, r = -0.7 in MG), and muscle strength (leg extension: r = 0.4; leg flexion: r = -0.5). A relationship between intramuscular fat in RF and MG and physical activity was also observed (P < 0.05). CONCLUSION: Ultrasound-estimated intramuscular fat was associated with other health measures and may provide physiological insight into the health consequences of obesity. Muscle Nerve 54: 743-749, 2016. PMID- 26969902 TI - Impact of the U.S. Food and Drug Administration's Safety-Related Announcements on the Use of Bisphosphonates After Hip Fracture. AB - The U.S. Food and Drug Administration (FDA) issued several announcements related to potential risk of bisphosphonates including osteonecrosis of the jaw (2005), atrial fibrillation (2007), and atypical femur fracture (2010). We aimed to evaluate the impact of three FDA drug safety announcements on the use of bisphosphonates in patients with hip fracture using claims data from a U.S. commercial health plan (2004-2013). We calculated the proportion of patients in each quarter who received a bisphosphonate or other osteoporosis medication in the 6 months following hospitalization for hip fracture. Segmented logistic regression models examined the time trends. Among 22,598 patients with hip fracture, use of bisphosphonate decreased from 15% in 2004 to 3% in the last quarter of 2013. Prior to the 2007 announcement, there was a 4% increase in the odds of bisphosphonate use every quarter (OR 1.04; 95% CI, 1.02 to 1.07). After the 2007 announcement, there was a 4% decrease in the odds of bisphosphonate use (OR 0.96; 95% CI, 0.93 to 0.99) every quarter. The announcement in 2007 was associated with a significant decline in the rate of change of bisphosphonate uses over time (p < 0.001), but no impact on other osteoporosis medication use (p = 0.2). After the 2010 announcement, the odds of bisphosphonate use continued to decrease by 4% (OR 0.96; 95% CI, 0.94 to 0.98) each quarter and the odds of other osteoporosis medication use remained stable over time (OR 0.99; 95% CI, 0.96 to 1.02). The FDA safety announcement related to atrial fibrillation in 2007 was significantly associated with a decrease in bisphosphonate use among patients with hip fracture. (c) 2016 American Society for Bone and Mineral Research. PMID- 26969904 TI - Mouthparts in Leptotrombidium larvae (Acariformes: Trombiculidae). AB - Mouthparts of Leptotrombidium larvae (Acariformes: Trombiculidae), potential vectors of tsutsugamushi disease agents, were studied in detail using light microscopy, scanning electron microscopy, and transmission electron microscopy. The mouthparts incorporated within the pseudotagma gnathosoma are composed of the infracapitulum ventrally and the chelicerae dorsally. The ventral wall of the infracapitulum is formed by a wide mentum posteriorly and a narrowed malapophysis anteriorly. The malapophysis firmly envelops the distal cheliceral portions by its lateral walls. The lateral lips of the malapophysis are flexible structures hiding the cheliceral blades in inactive condition and turning back forming a type of temporary sucker closely applied to the host skin during feeding. The roof of the infracapitulum is formed by a weakly sclerotized labrum anteriorly and a cervix with the capitular apodemes extending posteriorly. The labral muscles are lacking. The capitular apodemes serve as origin for pharyngeal dilators running to the dorsal wall of the pharynx fused with the bottom of the infracapitulum. The basal cheliceral segments are separated from each other besides the very posterior portions where they are movably joined by the inner walls. The sigmoid pieces serve for insertion of the cheliceral elevators originating at the posterior portions of the basal segments. The movable digits reveal the solid basal sclerite and the cheliceral blade curved upward with a tricuspid cap on its tip. Dendrites of nerve cells run along the digits to their tips. The ganglia are placed within the basal segments just behind the movable digits. The chelicerae also reveal well developed flexible fixed digits overhanging the basal portions of the blades. The gnathosoma possesses several sets of extrinsic muscles originating at the scutum and at the soft cuticle behind it. Laterally, the gnathosoma bears five-segmented palps with a trifurcate palpal claw. PMID- 26969903 TI - Time to bring fetal growth assessment into the 21st century. PMID- 26969905 TI - Public Health Nurses in Israel: A Case Study on a Quality Improvement Project of Nurse's Work Life. AB - Public health nurses (PHNs) working in Well Baby Clinic in Israel's Haifa district were voicing great distress to inspectors-the impossibility of meeting their workload, feeling overwhelmed, poor physical, and technological conditions. They were feeling tired and frustrated and burn-out was rising. The district's nursing management took the decision, together with Tel Aviv University's nursing research unit, to conduct a quality improvement project based on issues that arose from meetings with focus groups on the nurses' difficulties. This paper is a case study of a quality improvement project targeting nurses daily working life. One of its chief contributions is as a study of meeting PHNs' frustration by integrating focus groups and round-table brainstorming (involving nurses, clinic managers and nursing inspectors) in order to identify targets for practical intervention. This strategy has been very successful. It has provided the district's nursing management a battery of forcefully argued and realistically grounded proposals for making the work of Well Baby clinics more relevant to their communities and giving nurses (a) the conditions to meet their assignments and (b) greater professional self-respect. PMID- 26969906 TI - Strength and stress: Positive and negative impacts on caregivers for older adults in Thailand. AB - AIM: To understand the experiences of caregivers with older people living in Thailand, particularly as related to quality of life and stress management. METHOD: In-depth interviews with 17 family caregivers were conducted and then data were thematically analysed. RESULTS: Carers experience not only negative impacts but also positive impacts from caregiving. Negative impacts include emotional stress, financial struggles and worry due to lack of knowledge. Positive impacts include affection from care recipients, good relationships with caregivers before needing care themselves and encouragement from the wider community. Opportunities to show gratitude, build karma (from good deeds) and ideas shaped largely by Buddhist teachings result in positive experiences. Negotiating between the extremes of bliss and suffering and understanding suffering as a part of life may help carers manage their stress. CONCLUSIONS: Temples and centres for older people could be engaged to develop caregiving programs. PMID- 26969907 TI - Disturbed sleep in individuals with idiopathic environmental intolerance attributed to electromagnetic fields (IEI-EMF): Melatonin assessment as a biological marker. AB - Individuals who suffer from idiopathic environmental intolerance attributed to electromagnetic fields (IEI-EMF) complain of a variety of adverse health effects. Troubled sleep remains a recurrent and common symptom in IEI-EMF individuals. Melatonin, a circadian hormone, plays a major role in the sleep process. In this study, we compared levels of melatonin between a sensitive group (IEI-EMF, n = 30) and a non-sensitive control group (non IEI-EMF, n = 25) without exposure to electromagnetic sources. Three questionnaires were used to evaluate the subjective quality and sleep quantity: the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index and the Spiegel Sleep Inventory. Melatonin was quantified in saliva and its major metabolite 6-sulfatoxymelatonin (aMT6s) in urine. Melatonin levels were compared by a two-way analysis of variance at various times between the control and IEI-EMF group. Despite significantly different sleep scores between the two groups, with a lower score in the IEI-EMF group (P < 0.001), no statistical difference was found between the two groups for saliva melatonin (P > 0.05) and urine aMT6s (P > 0.05). Bioelectromagnetics. 37:175-182, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26969908 TI - Clinical utility of serum ferritin thresholds for guiding iron chelation therapy when magnetic resonance imaging is unavailable in patients with non-transfusion dependent thalassaemias - response to Ang et al. PMID- 26969909 TI - Comment on "Chemical and Toxicological Investigations of a Previously Unknown Poisonous European Mushroom Tricholoma terreum". AB - Recent findings casting doubts over the edibility of the European mushroom Tricholoma terreum are questioned on the basis of mycological and mycotoxicological considerations. Accordingly, T. terreum should remain listed among edible mushroom species. PMID- 26969910 TI - The role of ORMDL proteins, guardians of cellular sphingolipids, in asthma. AB - A family of widely expressed ORM-like (ORMDL) proteins has been recently linked to asthma in genomewide association studies in humans and extensively explored in in vivo studies in mice. ORMDL proteins are key regulators of serine palmitoyltransferase, an enzyme catalyzing the initial step of sphingolipid biosynthesis. Sphingolipids play prominent roles in cell signaling and response to stress, and they affect the mechanistic properties of cellular membranes. Deregulation of sphingolipid biosynthesis and their recycling has been proven to support and even cause several diseases including allergy, inflammation, and asthma. ORMDL3, the most extensively studied member of the ORMDL family, has been shown to be important for endoplasmic reticulum homeostasis by regulating the unfolded protein response and calcium response. In immune cells, ORMDL3 is involved in migration and in the production of proinflammatory cytokines. Furthermore, changes in the expression level of ORMDL3 are important in allergen induced asthma pathologies. This review focuses on functional aspects of the ORMDL family proteins, which may serve as new therapeutic targets for the treatment of asthma and some other life-threatening diseases. PMID- 26969911 TI - Is the hook of muroid rodent's sperm related to sperm train formation? AB - Competition between spermatozoa of rival males to gain fertilizations has led to a wide array of modifications in sperm structure and function. Sperm cells of most muroid rodents have hook-shaped extensions in the apical-ventral tip of the head, but the function of this structure is largely unknown. These 'hooks' may facilitate aggregation of spermatozoa in so-called 'trains', as an adaptation to sperm competition, because sperm in trains may swim faster than free-swimming cells. However, there is controversy regarding the role of the hook in train formation, and in relation to whether it is selected by sperm competition. We examined spermatozoa from muroid rodents with varying levels of sperm competition to assess whether (i) sperm aggregates are common in these taxa, (ii) presence of a hook relates to the formation of sperm aggregations, and (iii) formation of sperm aggregations is explained by sperm competition. Our analyses in 25 muroid species revealed that > 92% of spermatozoa swim individually in all species, with the exception of the wood mouse, Apodemus sylvaticus, which has ~50% spermatozoa swimming freely. Species with hooked spermatozoa had higher sperm competition levels and longer sperm than species whose sperm lack a hook. Neither the presence of hook nor sperm competition levels were related to the percentage of sperm in aggregations. Thus, (i) sperm aggregates in muroid rodents are an exceptional trait found only in a few species, (ii) evolution of the sperm hook is associated to sperm competition levels, but (iii) the hook is unlikely to be related to the formation of sperm aggregates. The evolutionary significance of the sperm head hook thus remains elusive, and future studies should examine potential roles of this pervasive structure in sperm's hydrodynamic efficiency and sperm-female tract interactions. PMID- 26969912 TI - Flow Synthesis of Silver Nanowires for Semitransparent Solar Cell Electrodes: A Life Cycle Perspective. AB - Silver nanowires (AgNWs) were prepared on a 5 g scale using either the well-known batch synthesis following the polyol method or a new flow synthesis method. The AgNWs were employed as semitransparent electrode materials in organic photovoltaics and compared to traditional printed silver electrodes based on micron sized silver flakes using life cycle analysis and environmental impact analysis methods. The life cycle analysis of AgNWs confirms that they provide an avenue to low-impact semitransparent electrodes. We find that the benefit of AgNWs in terms of embodied energy is less pronounced than generally assumed but that the toxicological and environmental benefits are significant. PMID- 26969913 TI - Association of BNP, NTproBNP, and early postnatal pulmonary hypertension in very preterm infants. AB - OBJECTIVE: B-type natriuretic peptide (BNP) has been shown to correlate with pulmonary hypertension (PH) in term neonates with persistent pulmonary hypertension of the newborn or congenital diaphragmatic hernia, and in very preterm infants with bronchopulmonary dysplasia. This study investigated the potential association of BNP and N-terminal-pro-BNP (NTproBNP) and PH within the first 72 hr of life in very preterm infants. METHODS: Preterm infants <32 weeks gestational age who received an echocardiogram within the first 72 hr of life were eligible. BNP and NTproBNP were sampled at the time of the echocardiogram. Right ventricular systolic pressure (RVSP) was calculated as a surrogate marker of PH. Simple and multiple linear regression analysis was performed to examine associations and potential confounding factors. RESULTS: Sixty-one infants were included with a median (IQR) birth weight of 983 g (826-1,167) and a median (IQR) gestational age of 27(2) weeks (26(2) -28(6) ). There was no difference between BNP or NTproBNP levels for infants with or without measurable RVSP. There was no significant correlation of BNP and RVSP in multiple linear regression analysis (regression coefficient -0.0035 (95%CI: -0.020 to 0.013), P = 0.67). Also, NTproBNP and RVSP were not significantly correlated in multiple linear regression analysis (regression coefficient 0.0071 (95%CI: -0.019 to 0.033), P = 0.58). CONCLUSION: B-type natriuretic peptides did not correlate with RVSP in the early postnatal period of very preterm infants. Pediatr Pulmonol. 2016;51:820-824. (c) 2016 Wiley Periodicals, Inc. PMID- 26969914 TI - Bending of Responsive Hydrogel Sheets Guided by Field-Assembled Microparticle Endoskeleton Structures. AB - Hydrogel composites that respond to stimuli can form the basis of new classes of biomimetic actuators and soft robotic components. Common latex microspheres can be assembled and patterned by AC electric fields within a soft thermoresponsive hydrogel. The field-oriented particle chains act as endoskeletal structures, which guide the macroscopic bending pattern of the actuators. PMID- 26969915 TI - Costs of Health Damage from Atmospheric Emissions of Toxic Metals: Part 1-Methods and Results. AB - Significant quantities of toxic metals are emitted to the air by the incineration of waste, as well as by the combustion of coal and oil. To optimize the regulations for their emissions one needs to know the cost of their damage. That requires an impact pathway analysis, with realistic dispersion models, exposure response functions, and monetary values. In this article we explain the method and assumptions and present results for arsenic, cadmium, mercury, and lead, the most important toxic metals in terms of damage cost. We also estimate their contribution to the damage cost of waste incineration and electric power from coal for typical situations in Europe. The damage costs of As, Cd, and Pb are much higher than previous estimates because of a large number of new epidemiological studies, implying more and more serious health effects than what had been known before. New cost-benefit studies for the abatement of toxic metal emissions are advisable. The discussion of the epidemiological studies and the derivation of exposure-response functions are presented in two companion articles, one for As and Cd, the other for Hg and Pb. PMID- 26969916 TI - Role of spermatogonial stem cells extract in transdifferentiation of 5-Aza-2' deoxycytidine-treated bone marrow mesenchymal stem cells into germ-like cells. AB - As one of the induced pluripotent stem cells (iPSCs) methods, spermatogonial stem cells (SSCS ) extract is considered as new approach in stem cell therapy of infertility. 5-aza-2'-deoxycytidine (5-aza-dC) inhibits methyltransferase enzyme, and induces gene reprogramming; herein, the effects of SSCS extract incubation in 5-aza-dC-treated bone marrow mesenchymal stem cells (BMMSCs) has been surveyed. BMMSCs were isolated from femurs of three to four weeks old male NMRI mice, and the cells at passage three were treated with 2 uM 5-aza-dC for 72 hours. SSCs were isolated, cultured, and harvested at passage three to collect SSCS extract; BMMSCs were then incubated with SSCS extract in the three time periods: 72 hours, one week and two weeks. There were five groups: control, sham, extract, 5-aza-dC and extract-5-aza-dC. After one week of incubation, flow cytometry and real-time polymerase chain reaction (PCR) exhibited high levels of expression for beta1- and alpha6-integrins and promyelocytic leukaemia zinc finger (PLZF) in extract and extract-5-aza-dC groups (P < 0.05 vs. control and 5-aza-dC), and cells in these two groups had two forms of morphology, round and fusiform, similar to germ like cells. 5-aza-dC had no significant effects during the three time periods of evaluation. These data disclose the effectiveness of SSCs extract incubation in transdifferentiation of BMMSCs into germ-like cells; this strategy could introduce a new approach for treatment of male infertility in clinic. PMID- 26969917 TI - Variety, sex and ontogenetic differences in the pelvic limb muscle architectural properties of leghorn chickens (Gallus gallus domesticus) and their links with locomotor performance. AB - Leghorn (layer) chickens (Gallus gallus domesticus) differ in locomotor morphology and performance due to artificial selection for standard (large) and bantam (small) varieties, sexual dimorphisms and ontogenetic stage. Here, the hind limb skeletal muscle architectural properties of mature and juvenile standard breeds and mature bantams are compared and linked to measures of locomotor performance. Mature males possessed greater relative muscle physiological cross-sectional areas (PCSAs) than their conspecific females, indicative of greater force-generating capacity, and in line with their greater maximum sustainable speeds compared with females. Furthermore, some of the relative fascicle lengths of the pennate muscles were greater in mature males than in mature females, which may permit greater muscle contractibility. Immature standard leghorns, however, did not share the same dimorphisms as their mature forms. The differences in architectural properties between immature and mature standard males indicate that with the onset of male sexual maturity, concomitant with increasing muscle mass in males, the relative fascicle lengths of pennate muscles and the relative PCSAs of the parallel-fibred muscles also increase. The age-related differences in standard breed male muscle architecture are linked to the presence and absence of sex differences in maximum aerobic speeds. Males of bantam and standard varieties shared similar muscle proportions (% body mass), but exhibited intrinsic muscle differences with a tendency for greater force generating capabilities in bantams and greater contractile capabilities in standards. The metabolic costs associated with the longer fascicle lengths, together with more crouched limbs in standard than in bantam males may explain the lack of allometry in the minimum metabolic cost of transport between these birds of different size. PMID- 26969918 TI - Reply. PMID- 26969919 TI - How Evolution May Work Through Curiosity-Driven Developmental Process. AB - Infants' own activities create and actively select their learning experiences. Here we review recent models of embodied information seeking and curiosity-driven learning and show that these mechanisms have deep implications for development and evolution. We discuss how these mechanisms yield self-organized epigenesis with emergent ordered behavioral and cognitive developmental stages. We describe a robotic experiment that explored the hypothesis that progress in learning, in and for itself, generates intrinsic rewards: The robot learners probabilistically selected experiences according to their potential for reducing uncertainty. In these experiments, curiosity-driven learning led the robot learner to successively discover object affordances and vocal interaction with its peers. We explain how a learning curriculum adapted to the current constraints of the learning system automatically formed, constraining learning and shaping the developmental trajectory. The observed trajectories in the robot experiment share many properties with those in infant development, including a mixture of regularities and diversities in the developmental patterns. Finally, we argue that such emergent developmental structures can guide and constrain evolution, in particular with regard to the origins of language. PMID- 26969920 TI - Product ion isotopologue pattern: A tool to improve the reliability of elemental composition elucidations of unknown compounds in complex matrices. AB - RATIONALE: Elucidation of the elemental compositions of unknown compounds (e.g., in metabolomics) generally relies on the availability of accurate masses and isotopic ratios. This study focuses on the information provided by the abundance ratio within a product ion pair (monoisotopic versus the first isotopic peak) when isolating and fragmenting the first isotopic ion (first isotopic mass spectrum) of the precursor. METHODS: This process relies on the capability of the quadrupole within the Q Orbitrap instrument to isolate a very narrow mass window. Selecting only the first isotopic peak (first isotopic mass spectrum) leads to the observation of a unique product ion pair. The lighter ion within such an isotopologue pair is monoisotopic, while the heavier ion contains a single carbon isotope. The observed abundance ratio is governed by the percentage of carbon atoms lost during the fragmentation and can be described by a hypergeometric distribution. RESULTS: The observed carbon isotopologue abundance ratio (product ion isotopologue pattern) gives reliable information regarding the percentage of carbon atoms lost in the fragmentation process. It therefore facilitates the elucidation of the involved precursor and product ions. Unlike conventional isotopic abundances, the product ion isotopologue pattern is hardly affected by isobaric interferences. Furthermore, the appearance of these pairs greatly aids in cleaning up a 'matrix-contaminated' product ion spectrum. CONCLUSIONS: The product ion isotopologue pattern is a valuable tool for structural elucidation. It increases confidence in results and permits structural elucidations for heavier ions. This tool is also very useful in elucidating the elemental composition of product ions. Such information is highly valued in the field of multi-residue analysis, where the accurate mass of product ions is required for the confirmation process. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969921 TI - Single analyzer precursor scans using an ion trap. AB - RATIONALE: Precursor ion and neutral loss scans are general survey methods of tandem mass spectrometry (MS/MS) used for detecting structurally related compounds. Until now they have been performed in multiple analyzer instruments, e.g. triple quadrupoles and hybrid MS/MS instruments. Implementation of precursor ion scans in single mass analyzers would be advantageous in reducing instrument complexity. METHODS: Adoption of secular frequency scanning as a method of mass selective excitation is shown to enable precursor scans in a single ion trap in a miniature mass spectrometer. A small supplementary alternating current (ac) signal is swept in frequency so as to cause mass-selective excitation of trapped ions. Simultaneously, a higher fixed amplitude ac signal is applied at the fixed secular frequency of a product ion, ejecting the mass-selected product ion and providing temporal data corresponding to a precursor ion spectrum. RESULTS: Precursor scanning in a single ion trap is demonstrated using a mixture of three illicit drugs: cocaine, 3,4-methylenedioxyamphetamine (MDA), and 3,4 methylenedioxymethamphetamine (MDMA). Acquisition of the spectra as a function of the frequency of the product ejection waveform demonstrates that the signals acquired represent precursor ion scans. CONCLUSIONS: Secular frequency scanning is a nonconventional method of mass scanning that in combination with product ion ejection enables precursor scans in single ion traps. This phenomenon is demonstrated here for a miniature linear ion trap, but the concepts described also apply to quadrupole mass filters. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969922 TI - Structural characterization of product ions of regulated veterinary drugs by electrospray ionization and quadrupole time-of-flight mass spectrometry. Part 3: Anthelmintics and thyreostats. AB - RATIONALE: Previously, we have reported a liquid chromatography/tandem mass spectrometry method for the identification and quantification of regulated veterinary drugs in food animals. The method uses three selected transition ions per analyte but structural characterization is also needed. This work is a continuation of two previous publications in which we propose structures of the selected transition ions of 130 veterinary drugs altogether. METHODS: In this work, 24 additional veterinary drugs were analyzed by infusion into a high resolution quadrupole time-of-flight (QTOF) mass spectrometer using electrospray ionization (ESI) in positive or negative mode. The TOF analyzer was calibrated to achieve low error mass accuracy in the MS and MS/MS modes. Also, the MS(2) and MS(3) spectra were obtained by using a Q-Trap mass spectrometer to further determine the possible pathways of ion formation. RESULTS: The low error mass spectrometry analysis allowed the elucidation of the ion formulae of selected transition ions for qualitative identification. The rational interpretation of data including a review of the published literature led to the proposed structures of the MS/MS product ions of 24 compounds covering two classes of regulated veterinary drugs (anthelmintics and thyreostats). In addition, the use of MS(2) and MS(3) experiments led to the establishment of fragmentation patterns. CONCLUSIONS: The identification and quantification of veterinary drug residues is helpful information for regulatory monitoring programs in defense of regulatory enforcement actions. Published in 2016. This article is a U.S. Government work and is in the public domain in the USA. PMID- 26969923 TI - Analysis of small molecule antibody-drug conjugate catabolites in rat liver and tumor tissue by liquid extraction surface analysis micro-capillary liquid chromatography/tandem mass spectrometry. AB - RATIONALE: Antibody-drug conjugates (ADCs) are some of the most promising antibody-related therapeutics. The fate of the cytotoxic moiety of ADCs in vivo after proteolytic degradation of the antibody needs to be well understood in order to mitigate toxicity risks and design proper first in patient studies. METHODS: The feasibility of liquid extraction surface analysis micro-capillary liquid chromatography/tandem mass spectrometry (LESA-MULC/MS/MS) was tested for direct surface sampling of two possible ADC catabolites composed of synthetically modified maytansinoid (DM1) and 4-[N-maleimidomethyl]cyclohexane-1-carbonyl (MCC) from rat liver and tumor tissue. Moreover, the iMatrixSpray was incorporated to prepare calibration standards (Cs) and quality control (QC) samples by spraying analyte solution at different concentrations directly on blank tissue. RESULTS: Lys-MCC-DM1 sprayed on blank liver tissue was homogeneously distributed (12.3% variability). The assay was selective (inference <=20%) and linear from 50.0 to 1000 ng/mL without any carry-over. Inter-run accuracy and precision were <=2.3% and <=25.9% meeting acceptance. Lys-MCC-DM1 was the only catabolite detected in liver and tumor tissue and was most likely responsible for the total radioactivity signal in liver tissue 72 h post-dose measured by quantitative whole body autoradiography (QWBA). CONCLUSIONS: Both analytical assays (LESA MULC/MS/MS and QWBA) are complementary to each other and provide useful quantitative and qualitative information in spatial tissue distribution of ADCs and their related catabolites. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969924 TI - Investigation of the selective androgen receptor modulators S1, S4 and S22 and their metabolites in equine plasma using high-resolution mass spectrometry. AB - RATIONALE: Selective androgen receptor modulators (SARMs) are prohibited in sports due to their performance enhancing ability. It is important to investigate the metabolism to determine appropriate targets for doping control. This is the first study where the equine metabolites of SARMs S1, S4 (Andarine) and S22 (Ostarine) have been studied in plasma. METHODS: Each SARM was administered to three horses as an intravenous bolus dose and plasma samples were collected. The samples were pretreated with protein precipitation using cold acetonitrile before separation by liquid chromatography. The mass spectrometric analysis was performed using negative electrospray, quadrupole time-of-flight mass spectrometry operated in MS(E) mode and triple-quadrupole mass spectrometry operated in selected reaction monitoring mode. For the quantification of SARM S1, a deuterated analogue was used as internal standard. RESULTS: The numbers of observed metabolites were eight, nine and four for the SARMs S1, S4 and S22, respectively. The major metabolite was formed by the same metabolic reactions for all three SARMs, namely amide hydrolysis, hydroxylation and sulfonation. The values of the determined maximum plasma concentrations were in the range of 97 170 ng/mL for SARM S1, 95-115 ng/mL for SARM S4 and 92-147 ng/mL for SARM S22 and the compounds could be detected for 96 h, 12 h and 18 h, respectively. CONCLUSIONS: The maximum plasma concentration of SARMs S1, S4 and S22 was measured in the first sample (5 min) after administration and they were eliminated fast from plasma. The proposed targets to be used in equine doping control are the parent compounds for all three SARMs, but with the metabolite yielding the highest response as a complementary target. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969925 TI - Measurement of compound-specific carbon isotope ratios (delta(13) C values) via direct injection of whole crude oil samples. AB - RATIONALE: Stable isotope analysis is a powerful tool in understanding the generation, history and correlation of hydrocarbons. Compound-specific delta(13) C measurements of oils allow detailed comparison of individual compound groupings; however, most studies of these sample materials separate and isolate individual fractions based on the chemistries of particular compound groups, potentially losing considerable valuable isotopic data. Even if all fractions are analyzed, this represents a large increase in the data-processing burden, effectively multiplying data evaluation time and effort by the number of fractions produced. Gas chromatography/isotope ratio mass spectrometry (GC/IRMS) of untreated, whole crude oils allows the immediate collection of a larger suite of valuable isotopic data for these studies. METHODS: Untreated ('neat', undiluted), whole crude oils were directly injected and measured on a GC/IRMS system, using split (40:1) injections and a 50 m HP-PONA column. The GC method, 97 min in duration, was designed to maximize baseline separation of target analyte peaks, while an additional oxygen flow was admitted into the combustion reactor to maximize the lifetime of the combustion chemicals. RESULTS: The method and setup utilized allow the measurement of a much greater range of the n-alkanes (n-C4 to n-C25+ ) than traditional methods, while also retaining important cycloalkane, aromatic and isoprenoid peaks within the same analysis. Carbon isotope (delta(13) C) evaluation of these additional compound classes reveals trends in maturity and origins which are not identifiable when exclusively assessing the traditional n-alkane package (>n-C12 ). CONCLUSIONS: The described setup and method open up new possibilities for assessing the origins and histories of crude oil samples. The data generated for the whole oil n-alkanes by this method is equivalent to that reported for isolated n-alkane studies, while also providing valuable additional data on many other important compounds. The end result of this method is a more complete assessment of the carbon isotopic composition of crude oils. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969926 TI - Development of a surrogate matrix for cerebral spinal fluid for liquid chromatography/mass spectrometry based analytical methods. AB - RATIONALE: In recent years, several liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods have been reported for the quantitative determination of drugs and metabolites in cerebral spinal fluid (CSF). Artificial CSF (aCSF) is often used as a surrogate for preparing calibration curves and quality control samples in these methods. However, aCSF does not accurately represent the composition of real CSF because it is missing all of the proteins and lipids, which may alter the electrospray ionization (ESI) response when performing LC/MS/MS analyses. In the current study we compared the mass spectral response of several compounds with a range of physiochemical properties in aCSF (essentially a mixture of salts and buffers), diluted plasma (ranging from 1:5 to 1:200) and real CSF to find the best surrogate for CSF in LC/MS/MS methods. METHODS: A number of analytes from polar to non-polar, high protein binding to low protein binding, employing different sample preparation methods, were prepared in diluted plasma, actual CSF or aCSF and tested using LC/MS/MS. The analytes included cotinine and its metabolites, quetiapine, norquetiapine, chlorpromazine, efavirenz and lamivudine. The similarity of MS responses from these compounds in aCSF and diluted plasma to CSF was assessed by comparing the slopes of the calibration curves generated from using linear regression modeling. RESULTS: For all compounds, the lowest percent difference in response ratio (0 to 17%) was observed from 1:200 diluted plasma. Our results indicated that, irrespective of the inherent physiochemical properties of the analytes or the method of sample preparation, 1:200 diluted plasma performed as the best surrogate for CSF in LC/MS/MS methods. CONCLUSIONS: The percent difference in response ratio has been established to demonstrate how different compounds behave between CSF, aCSF and dilute plasma. Although among the compounds tested some of them showed a very similar MS response in actual and aCSF, there were analytes that demonstrated significant differences in ESI-MS signal when sprayed from these two matrices. However, even in such cases, 1:200 diluted plasma generated results with no significant difference from CSF. Therefore, we recommend that in order to develop robust and dependable bioanalytical LC/MS methods from CSF samples, it is more appropriate to prepare calibration curves and quality control samples in diluted plasma instead of aCSF. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969928 TI - Measuring (210) Pb by accelerator mass spectrometry: a study of isobaric interferences of (204,205,208) Pb and (210) Pb. AB - RATIONALE: The measurement of (210) Pb provides an assessment of the risk an individual faces of developing lung cancer as a result of their exposure to radon and radon decay products. Existing radiometric techniques are not sensitive enough to detect (210) Pb in many exposures. This report describes the further development of a method of measuring (210) Pb using Accelerator Mass Spectrometry (AMS). METHODS: (204,205,208,) (210) Pb measurements were performed by AMS. Samples were prepared from stock solutions of (204) Pb, (205) Pb, (208) Pb and (210) Pb and measured by making PbF3 (-) ions at the IsoTrace AMS facility using a SIMS-type Cs(+) sputter source. Potential interferences in Pb(3) (+) isotope measurement and the overall efficiency of Pb beam production were determined experimentally. RESULTS: (204) Pb and (205) Pb suffer from molecular and atomic isobaric interferences that cannot be removed without sacrificing the efficiency of (210) Pb measurements whereas (208) Pb suffers from no interferences. The abundance sensitivity of (210) Pb/(208) Pb was 1.3 * 10(-12) . Keeping the (210) Pb/(208) Pb spike below this level resulted in a detection limit of 4.4 mBq of (210) Pb using the IsoTrace AMS facility. CONCLUSIONS: This study identified key interferences in the measurement of PbF3 (-) -> Pb(3) (+) ions and demonstrated a new AMS method to measure (210) Pb. This new AMS technique is about five times more sensitive than gamma and beta spectroscopy measurements of (210) Pb and the measurement time is much shorter. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969927 TI - A new organic reference material, l-glutamic acid, USGS41a, for delta(13) C and delta(15) N measurements - a replacement for USGS41. AB - RATIONALE: The widely used l-glutamic acid isotopic reference material USGS41, enriched in both (13) C and (15) N, is nearly exhausted. A new material, USGS41a, has been prepared as a replacement for USGS41. METHODS: USGS41a was prepared by dissolving analytical grade l-glutamic acid enriched in (13) C and (15) N together with l-glutamic acid of normal isotopic composition. The delta(13) C and delta(15) N values of USGS41a were directly or indirectly normalized with the international reference materials NBS 19 calcium carbonate (delta(13) CVPDB = +1.95 mUr, where milliurey = 0.001 = 1 0/00), LSVEC lithium carbonate (delta(13) CVPDB = -46.6 mUr), and IAEA-N-1 ammonium sulfate (delta(15) NAir = +0.43 mUr) and USGS32 potassium nitrate (delta(15) N = +180 mUr exactly) by on-line combustion, continuous-flow isotope-ratio mass spectrometry, and off-line dual inlet isotope-ratio mass spectrometry. RESULTS: USGS41a is isotopically homogeneous; the reproducibility of delta(13) C and delta(15) N is better than 0.07 mUr and 0.09 mUr, respectively, in 200-MUg amounts. It has a delta(13) C value of +36.55 mUr relative to VPDB and a delta(15) N value of +47.55 mUr relative to N2 in air. USGS41 was found to be hydroscopic, probably due to the presence of pyroglutamic acid. Experimental results indicate that the chemical purity of USGS41a is substantially better than that of USGS41. CONCLUSIONS: The new isotopic reference material USGS41a can be used with USGS40 (having a delta(13) CVPDB value of -26.39 mUr and a delta(15) NAir value of -4.52 mUr) for (i) analyzing local laboratory isotopic reference materials, and (ii) quantifying drift with time, mass-dependent isotopic fractionation, and isotope-ratio-scale contraction for isotopic analysis of biological and organic materials. Published in 2016. This article is a U.S. Government work and is in the public domain in the USA. PMID- 26969929 TI - Applicability of gas chromatography/quadrupole-Orbitrap mass spectrometry in support of pharmaceutical research and development. AB - RATIONALE: Gas chromatography/mass spectrometry (GC/MS) is a fundamental tool used to identify impurities throughout the active pharmaceutical ingredients development process. The coupling of Orbitrap mass spectrometry with GC marks an exciting advance in capability for GC/MS, offering a significant step change in resolving power, mass accuracy, sensitivity and linear range. METHODS: A range of pharmaceutically relevant samples representing typical starting materials has been investigated with particular reference to impurity identification. The mass accuracy in Electron Ionisation (EI) and Chemical Ionisation (CI) was investigated for impurity identification. The linearity and mass accuracy over a wide dynamic range were evaluated. The number of scans obtained across chromatographic peaks was assessed at various resolution settings from 15,000 to 120,000 (full width at half maximum (FWHM) at m/z 200). RESULTS: All the accurate mass measurements for impurities were within <1 ppm of the theoretical m/z value. The scan speed at the highest resolution produced 11 scans across the peak, and the mass accuracy for all scans was consistently <1 ppm - sufficient for impurity investigations and quantitative analysis. Linearity was demonstrated for N,N,N' trimethylethylenediamine over a concentration range of 0.0001 to 0.1250 MUg/mL (w/v) with a correlation coefficient R(2) = 0.9996 and mass accuracy across all concentrations at <1.1 ppm. CONCLUSIONS: GC/Orbitrap MS has been evaluated for both qualitative and quantitative analysis of typical pharmaceutical precursors and impurities. Accurate mass measurement across a wide dynamic range, linearity and the ability to identify impurities in EI and CI illustrate that this instrument is a powerful tool of great benefit to pharmaceutical analysis. PMID- 26969930 TI - Is lipid correction necessary in the stable isotope analysis of fish tissues? AB - RATIONALE: Stable isotope analysis (SIA) is a powerful tool for examining diet and food-web dynamics. SIA assumes "you are what you eat" relative to carbon (C) and nitrogen (N). However, fractionation of carbon during lipid synthesis violates this assumption; high-lipid tissues do not reflect delta(13) C values of diet and therefore have the potential to skew mixing model results and diet interpretations, making corrections necessary. METHODS: Brook Trout (Salvelinus fontinalis) white muscle and liver samples from several fish species representing the temperate North American cold- and warm-water fish community were corrected for lipids via chemical lipid extraction and mathematical lipid normalization. To assess the accuracy of model-predicted lipid-free delta(13) C values calculated from four normalization models, we compared model-predicted values with those measured after lipid extraction. RESULTS: We found that chemical lipid extraction is unnecessary for Brook Trout white muscle tissue with low initial lipid content. However, in tissues with C:N ratios greater than 3.5, lipid extraction increased delta(13) C values in fish liver by more than 1.0 0/00, indicating that liver lipid content is sufficient to bias delta(13) C values. We also found that lipids were accurately accounted for with mathematical normalization and recommend that tissues with C:N ratios greater than 3.5 be corrected mathematically. CONCLUSIONS: Our findings indicate that mathematical normalization is sufficient to account for bias in delta(13) C values associated with lipid content in fish tissues when C:N ratios are above 3.5. C:N ratios below 3.5 indicate that tissues have insufficient levels of lipid to bias the delta(13) C values. Generally, these findings support the use of more timely and cost-effective processing and analysis methods in future aquatic food-web studies utilizing SIA. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969931 TI - Flame-induced atmospheric pressure chemical ionization mass spectrometry. AB - RATIONALE: Charged species such as formylium (CHO(+) ), hydronium (H3 O(+) ), and water clusters [H3 O(+) (H2 O)n ] are commonly found in flames. These highly reactive species can react with analytes via ion-molecule reactions (IMRs) to form analyte ions. A new mass spectrometric technique, named flame-induced atmospheric pressure chemical ionization mass spectrometry (FAPCI-MS), was developed to characterize organic compounds via these mechanisms. METHODS: A commercial corona-discharge atmospheric pressure chemical ionization (APCI) source was modified by replacing the corona needle with a flame to make a FAPCI source. Liquid samples were vaporized in a heated tube and delivered to the IMRs region by nitrogen to react with the charged species generated by a flame. Analytes on surfaces were directly desorbed and ionized by a flame using the technique called desorption-FAPCI-MS (DFAPCI-MS). RESULTS: Intact molecular ions of various chemical and biological compounds were successfully characterized by FAPCI-MS. The FAPCI mass spectra are nearly identical to those obtained by traditional APCI-MS. The limit of detection (LOD) of reserpine by FAPCI-MS was 50 MUg L(-1) with a linear calibration curve (R(2) = 0.9947) from 100 MUg L(-1) to 10 mg L(-1) . The LOD for ketamine by DFAPCI-MS was estimated to be less than 0.1 ng. CONCLUSIONS: In FAPCI, analytes are not incinerated but vaporized and introduced into the ion source to react with the reactive charged species generated by a flame. The features of the FAPCI source include: configuration is very simple, operation is easy, high voltage or inert gas is unnecessary, and the source is maintenance free. Various combustible gases, solvents and solids are useful flame fuels for FAPCI. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969932 TI - Improved analysis of micro- and nanomole-scale sulfur multi-isotope compositions by gas source isotope ratio mass spectrometry. AB - RATIONALE: Multiple sulfur isotope compositions are usually measured on relatively large samples (in the range of micromoles); however, sometimes only small amounts are available and thus it is necessary to analyze small (sub micromole) samples. We report an improved method to measure multiple sulfur isotope compositions: delta(33) S, delta(34) S and delta(36) S values on the SF6 molecule (m/z 127, 128, 129, 131) for quantities down to 0.1 micromole, and delta(33) S and delta(34) S values for quantities down to 20 nanomoles. METHODS: Multiple sulfur isotope analyses including fluorination and purification of two international Ag2 S standards, IAEA-S1 and IAEA-S3, were carried out at various low concentrations on a dual-inlet isotope ratio mass spectrometer using a microvolume and modified resistor capacities. RESULTS: The analyses yielded a narrow range of delta(34) S values vs CDT (the international standard), with an overall standard deviation of +/-0.2 0/00, which was within the range of certified values. This demonstrates the feasibility of determining both Delta(33) S and Delta(36) S values on the sub-micromole scale, and Delta(33) S values on the nanomole scale with similar accuracy to conventional dual-inlet analyses. CONCLUSIONS: The analysis of the three S-isotope ratios on the SF6 molecule using the so-called conventional fluorination method and dual-inlet ion ratio mass spectrometry is reliable for sample sizes down to ~20 nanomoles. Despite being close to the theoretical limits for maintaining the viscous flow regime of gas in the capillary, errors were not limited by counting statistics, but probably relate to sample gas purification. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969933 TI - Rapid identification of seized controlled substances and related compounds by tandem mass spectrometry without chromatography. AB - RATIONALE: This study demonstrates the capability of using tandem mass spectrometry (MS/MS) for the identification of substances of abuse and related compounds without the need for chromatography. The elimination of chromatography is not only cost-effective because of reduced sample work-up and consumables, but also reduces the environmental impact of solvents. METHODS: Two chromatography free techniques were used to screen for a large suite of compounds using a rapid, inexpensive technique: a thermal desorber coupled to a tandem mass spectrometer operated in selected reaction monitoring (SRM) mode. First, questioned materials in solution were introduced via an autosampler; and secondly, the materials were introduced directly by means of disposable toothpicks. The results were compared with those obtained by gas chromatography/mass spectrometry (GC/MS). RESULTS: MS/MS was shown to be capable of the identification of the same drugs within the samples as the conventional method of GC/MS, but with better sensitivity and shorter analysis times. Presented herein is an automated screening method based on an algorithm containing more than 60 precursor ion/product ion 'transitions' (i.e. 30+ compounds simultaneously; two precursor/product ion transitions per analyte), requiring less than 2 min for identification using an autosampler or instantaneously by means of manual sample introduction. Therefore, by eliminating chromatography, a higher laboratory throughput is achievable with simplified sample preparation. CONCLUSIONS: An inexpensive, rapid and reliable method was successfully developed for the identification of controlled substances within unknown matrices using MS/MS without any chromatographic separation. This technique could be further validated with reference to an increasing database of MS/MS spectra to help to identify an expanding suite of compounds. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969934 TI - Tandem mass spectrometric analysis of S- and N-linked glutathione conjugates of pulegone and menthofuran and identification of P450 enzymes mediating their formation. AB - RATIONALE: Menthofuran is a hepatotoxin and a major metabolite of pulegone, a monoterpene found in the essential oils of many mint species. It is bioactivated by cytochrome P450 (CYP) enzymes to reactive metabolites, which may further react with glutathione to form S-linked and N-linked conjugates. The tandem mass spectrometric (MS/MS) fragmentation pathways of rarely observed N-linked conjugates, and the differences to fragmentation of S-linked conjugates, have not been reported in the literature previously, although this information is essential to enable comprehensive MS/MS-based screening methods covering the both types of conjugates. METHODS: (R)-(+)-Pulegone, (S)-(-)-pulegone, and menthofuran were incubated with a human liver S9 fraction with glutathione (GSH) as the trapping agent. Conjugates were searched with ultra-performance liquid chromatography (UPLC)/orbitrap MS and their MS/MS spectra were measured both in the negative and positive ionization polarities. Menthofuran was also incubated with recombinant human CYP enzymes and GSH to elucidate the CYPs responsible for the formation of the reactive metabolites. RESULTS: Four GSH conjugates of menthofuran were detected and identified as S- and N-linked conjugates based on MS/MS spectra. N-linked conjugates lacked the characteristic fragments of S linked conjugates and commonly produced fragments that retained parts of glutamic acid. CYP1A2, 2B6 and 3A4 were observed to produce more GSH conjugates than other CYP isoforms. CONLUSIONS: Furans can form reactive aldehydes that react in Schiff base fashion with the free glutamyl-amine of GSH to form N-linked conjugates that have distinct MS/MS spectra from S-linked adducts. This should be taken into account when setting up LC/MS/MS-based detection of glutathione conjugates to screen for reactive metabolites, at least for compounds with a furan moiety. Neutral loss scanning of 178.0412 Da and 290.0573 Da in the positive ionization mode, or neutral loss scanning of 256.0695 Da and 290.0573 Da and precursor ion scanning of m/z 143.0462 in the negative ionization mode, is recommended. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969935 TI - Quantitative metrics for assessment of chemical image quality and spatial resolution. AB - RATIONALE: Currently objective/quantitative descriptions of the quality and spatial resolution of mass spectrometry derived chemical images are not standardized. Development of these standardized metrics is required to objectively describe the chemical imaging capabilities of existing and/or new mass spectrometry imaging technologies. Such metrics would allow unbiased judgment of intra-laboratory advancement and/or inter-laboratory comparison for these technologies if used together with standardized surfaces. METHODS: Two image metrics, viz., "chemical image contrast" (ChemIC) based on signal-to-noise related statistical measures on chemical image pixels and "corrected resolving power factor" (cRPF) constructed from statistical analysis of mass-to-charge chronograms across features of interest in an image, were developed. These metrics, quantifying chemical image quality and spatial resolution, respectively, were used to evaluate chemical images of a model photoresist patterned surface collected using a laser ablation/liquid vortex capture mass spectrometry imaging system under different instrument operational parameters. RESULTS: The calculated ChemIC and cRPF metrics determined in an unbiased fashion the relative ranking of chemical image quality obtained with the laser ablation/liquid vortex capture mass spectrometry imaging system. These rankings were used to show that both chemical image contrast and spatial resolution deteriorated with increasing surface scan speed, increased lane spacing and decreasing size of surface features. CONCLUSIONS: ChemIC and cRPF, respectively, were developed and successfully applied for the objective description of chemical image quality and spatial resolution of chemical images collected from model surfaces using a laser ablation/liquid vortex capture mass spectrometry imaging system. Published in 2016. This article is a U.S. Government work and is in the public domain in the USA. PMID- 26969936 TI - Mechanistic investigation of charge-remote and charge-driven fragmentation processes in 2,5-diphenyl-3,4-ethylenedioxythiophene diamidines. AB - RATIONALE: Diphenylfuran diamidines represent an important class of DNA minor groove binders of high therapeutic interest as antitumor and antibacterial agents. This study aimed to investigate fragmentation patterns in mass spectra of four diamidine derivatives with significant antitumor activity, in order to gain more insight into the structures and stability of their putative biological metabolites. METHODS: Compounds were investigated by electrospray ionization tandem mass spectrometry (ESI-MS/MS) using low-energy collision-induced dissociation (CID). Density functional theory calculations were performed to confirm the main fragmentation paths. RESULTS: The most abundant ion present in mass spectra is the doubly protonated molecule, whereas singly protonated molecules are present to a lesser extent. In the simplest compound, 2,5-bis(4 amidinophenyl)-3,4-ethylenedioxythiophene, the main fragmentation path was loss of ammonia, followed by loss of HCN where possible. The fragmentation of the N alkyl derivatives (N-isopropyl-, N-isobutyl-, N-cyclopentyl-) includes competition between loss of alkene and the corresponding amine, followed by loss of another alkene and formation of fragment ions present in the pathway of the parent compound. CONCLUSIONS: The primary sites of fragmentations of investigated compounds are amidine groups, while breaking the core 3,4-ethylenedioxythiophene ring system does not take place. Fragmentation of the singly protonated molecule [M + H](+) occurs primarily on the charged side of the molecule, but a charge remote process is energetically viable. The fragmentation mechanism of the alkyl derivatives revealed that singly and doubly protonated molecules cleave to the singly and doubly protonated molecules of the parent compound. Once formed, they are gradually transformed into nitrile. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969938 TI - Characterization of aromatic organosulfur model compounds relevant to fossil fuels by using atmospheric pressure chemical ionization with CS2 and high resolution tandem mass spectrometry. AB - RATIONALE: The chemistry of desulfurization involved in processing crude oil is greatly dependent on the forms of sulfur in the oil. Sulfur exists in different chemical bonding environments in fossil fuels, including those in thiophenes and benzothiophenes, thiols, sulfides, and disulfides. In this study, the fragmentation behavior of the molecular ions of 17 aromatic organosulfur compounds with various functionalities was systematically investigated by using high-resolution tandem mass spectrometry. METHODS: Multiple-stage tandem mass spectrometric experiments were carried out using a linear quadrupole ion trap (LQIT) equipped with an atmospheric pressure chemical ionization (APCI) source. (+)APCI/CS2 was used to generate stable dominant molecular ions for all the compounds studied except for three sulfides that also showed abundant fragment ions. The LQIT coupled with an orbitrap mass spectrometer was used for elemental composition analysis, which facilitated the identification of the neutral molecules lost during fragmentation. RESULTS: The characteristic fragment ions generated in MS(2) and MS(3) experiments provide clues for the chemical bonding environment of sulfur atoms in the examined compounds. Upon collision-induced dissociation (CID), the molecular ions can lose the sulfur atom in a variety of ways, including as S (32 Da), HS(*) (33 Da), H2 S (34 Da), CS (44 Da), (*) CHS (45 Da) and CH2 S (46 Da). These neutral fragments are not only indicative of the presence of sulfur, but also of the type of sulfur present in the compound. Generally, losses of HS(*) and H2 S were found to be associated with compounds containing saturated sulfur functionalities, while losses of S, CS and (*) CHS were more common for heteroaromatic sulfur compounds. CONCLUSIONS: High resolution tandem mass spectrometry with APCI/CS2 ionization is a viable approach to determining the types of organosulfur compounds. It can potentially be applied to analysis of complex mixtures, which is beneficial to improving the desulfurization process of fossil fuels. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969937 TI - A novel high-temperature combustion interface for compound-specific stable isotope analysis of carbon and nitrogen via high-performance liquid chromatography/isotope ratio mass spectrometry. AB - RATIONALE: In aqueous samples compound-specific stable isotope analysis (CSIA) plays an important role. No direct method (without sample preparation) for stable nitrogen isotope analysis (delta(15) N SIA) of non-volatile compounds is known yet. The development of a novel HPLC/IRMS interface based on high-temperature combustion (HTC) for both delta(13) C and delta(15) N CSIA and its proof of principle are described in this study. METHODS: To hyphenate high-performance liquid chromatography (HPLC) with isotope ratio mass spectrometry (IRMS) a modified high-temperature combustion total organic carbon analyzer (HTC TOC) was used. A system to handle a continuously large amount of water (three-step drying system), favorable carrier and reaction gas mix and flow, an efficient high temperature-based oxidation and subsequent reduction system and a collimated beam transfer system were the main requirements to achieve the necessary performance. RESULTS: The proof of principle with caffeine solutions of the system succeeded. In this initial testing, both delta(13) C and delta(15) N values of tested compounds were determined with precision and trueness of <=0.5 0/00. Further tests resulted in lower working limit values of 3.5 MUgC for delta(13) C SIA and 20 MUgN for delta(15) N SIA, considering an accuracy of +/-0.5 0/00 as acceptable. CONCLUSIONS: The development of a novel HPLC/IRMS interface resulted in the first system reported to be suitable for both delta(13) C and delta(15) N direct CSIA of non-volatile compounds. This highly efficient system will probably open up new possibilities in SIA-based research fields. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969939 TI - Quantification of ecosystem C dynamics in a long-term FACE study on permanent grassland. AB - RATIONALE: Because of the wide-ranging appearance and high soil organic carbon (C) content of grasslands, their ecosystems play an important role in the global C cycle. Thus, even small changes in input or output rates lead to significant changes in the soil C content, thereby affecting atmospheric [CO2 ]. Our aim was to examine if a higher C supply provided under elevated CO2 will increase the soil C pool. Special attention was given to respirational processes, where CO2 emission rates and its sources (plant vs. soil) were considered. METHODS: The Giessen-FACE experiment started in 1998 with a moderate CO2 enrichment of +20% and +30% above ambient on an extensively managed grassland. The experiment consists of three control plots where no CO2 is applied, three plots where [CO2 ] is enriched by +20% and one plot receiving [CO2 ] +30%. To exclude initial CO2 step increase effects, a detailed examination of respirational processes over 30 months was carried out after 6 years of CO2 enrichment starting in June 2004. At that time, the delta(13) C signature of the enrichment-CO2 was switched from -25 0/00 to -48 0/00 without a concomitant change in CO2 concentration. RESULTS: After 9 years, the fraction of new C under [CO2 ] +20% was 37 +/- 5.4% in the top 7.5 cm but this decreased with depth. No CO2 effect on soil carbon content was detected. Between June 2004 and December 2006, elevated [CO2 ] +20% increased the ecosystem respiration by 13%. The contribution of root respiration to soil respiration was 37 +/- 13% (5 cm) and 43 +/- 14% (10 cm) for [CO2 ] +20% and 35 +/- 13% and 40 +/- 13% for [CO2 ] +30%, respectively. CONCLUSIONS: Our findings of an increased C turnover without a net soil C sequestration suggest that the sink strength of grassland ecosystems might decrease in the future, because the additional C may quickly be released as CO2 to the atmosphere. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969940 TI - MALDI SpiralTOF high-resolution mass spectrometry and Kendrick mass defect analysis applied to the characterization of poly(ethylene-co-vinyl acetate) copolymers. AB - RATIONALE: Poly(ethylene-co-vinyl acetate) copolymers - usually referred to as EVA - are first class industrial polymers used for applications ranging from padding to photovoltaics as encapsulant for the silicon solar cells. Various techniques have been used for their characterization but the analysis of intact EVA chains using mass spectrometry (MS) has not been reported so far. METHODS: Three copolymers containing 18, 25 and 40 wt% vinyl acetate (VA) have been characterized using an off-line coupling of size-exclusion chromatography (SEC) and matrix-assisted laser desorption/ionization (MALDI) spiral-time-of-flight (TOF) high-resolution mass spectrometry (HRMS). The representativeness of those results for the entire samples has been checked using (13) C NMR spectroscopy. Lastly, Kendrick mass defect analysis has been proposed as an alternative and user-friendly data treatment method. RESULTS: The shortest chains isolated by SEC fractionation and mass-analyzed by HRMS have been thoroughly described in terms of end-groups (found to be hydrogens) and co-monomeric composition. The VA content was successfully derived from the peak assignments in MS spectra for the EVA 40 wt% and 25 wt% while it tended to be overestimated for the latest EVA 18 wt% (increasing poly(ethylene) character). Similar results have been found using a faster data treatment method relying on the Kendrick mass defect analysis of the MS data. CONCLUSIONS: EVA low molecular weight intact oligomers have been extensively characterized by MS for the first time and the structural features confidently extended to the full sample according to NMR data. The Kendrick mass analysis finally constituted an efficient method for a fast evaluation of their VA content with no need for manual assignment. (c) 2016 The Authors. Rapid Communications in Mass Spectrometry Published by John Wiley & Sons Ltd. PMID- 26969941 TI - Nickel in equine sports drug testing - pilot study results on urinary nickel concentrations. AB - RATIONALE: The issue of illicit performance enhancement spans human and animal sport in presumably equal measure, with prohibited substances and methods of doping conveying both ways. Due to the proven capability of unbound ionic cobalt (Co(2) (+) ) to stimulate erythropoiesis in humans, both human and equine anti doping regulations have listed cobalt as a banned substance, and in particular in horse drug testing, thresholds for cobalt concentrations applying to plasma and urine have been suggested or established. Recent reports about the finding of substantial amounts of undeclared nickel in arguably licit performance- and recovery-supporting products raised the question whether the ionic species of this transition metal (Ni(2) (+) ), which exhibits similar prolyl hydroxylase inhibiting properties to Co(2) (+) , has been considered as a substitute for cobalt in doping regimens. METHODS: Therefore, a pilot study with 200 routine post-competition doping control horse urine samples collected from animals participating in equestrian, gallop, and trotting in Europe was conducted to provide a first dataset on equine urinary Ni(2) (+) concentrations. All specimens were analyzed by conventional inductively coupled plasma mass spectrometry (ICP MS) to yield quantitative data for soluble nickel. RESULTS: Concentrations ranging from below the assay's limit of quantification (LOQ, 0.5 ng/mL) up to 33.4 ng/mL with a mean value (+/- standard deviation) of 6.1 (+/-5.1) ng/mL were determined for the total nickel content. CONCLUSIONS: In horses, nickel is considered a micronutrient and feed supplements containing nickel are available; hence, follow-up studies are deemed warranted to consolidate potential future threshold levels concerning urine and blood nickel concentrations in horses using larger sets of samples for both matrices and to provide in-depth insights by conducting elimination studies with soluble Ni(2) (+) -salt species. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969942 TI - Identification of a neutral loss from precursor ions with nearly Gaussian-shaped isotopic patterns via inverted isotopic patterns of product ions. AB - RATIONALE: Direct atomic composition determination of ions with very broad Gaussian-shaped isotopic patterns is challenging because no monoisotopic peak is available for high accurate mass determination and no characteristic shapes in isotopic patterns are visible. METHODS: Isolation and fragmentation of the ions corresponding to one peak (one nominal mass) in the center of the broad Gaussian shaped isotopic pattern lead to a mass spectrum with the product ion signal showing the inverted full isotopic profile of the neutral fragment. RESULTS: We have introduced a convenient method for the fast and straightforward identification of a neutral loss for molecular ions with broad isotopic patterns. The theoretical considerations underlying this method are explained and its practical limitations are considered. The benefits of this method are exemplified by guiding a reader through the analysis of a complex mixture of bridged carborate clusters, compounds with very broad isotopic patterns. CONCLUSIONS: The presented method can be efficiently used for the determination of atomic compositions of compounds with broad isotopic patterns by their fragmentation using mass spectrometry. This method should significantly facilitate the mass spectrometric analysis of compounds containing several atoms with broad isotopic distributions, such as Ge, Sn, Mo, Ru and Hg, and, thus, can considerably broaden the use of mass spectrometry as an analytical method in inorganic and organometallic chemistry. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969943 TI - Identification of hydroxy- and keto-dicarboxylic acids in remote marine aerosols using gas chromatography/quadruple and time-of-flight mass spectrometry. AB - RATIONALE: The identification of hydroxy- and keto-dicarboxylic acids (diacids) in remote marine aerosol samples is important for a better understanding of the composition of organic particulate matter, as this chemical composition is essential for predicting the effects on climate, air quality, and human health. Molecular characterization of these compounds provides insights into sources and formation pathways of organic aerosols. METHODS: The method of chemical derivatization followed by gas chromatography-flame ionization detection (GC FID), gas chromatography/quadruple mass spectrometry (GC/QMS) and gas chromatography/time-of-flight mass spectrometry (GC/TOFMS) was used to identify hydroxy- and keto-diacids in remote marine aerosols. Atmospheric samples were collected at Chichijima Island in the western North Pacific and the diacids and related compounds were extracted with organic-free ultrapure water. A two-step derivatization technique was employed, using 14% BF3 /n-butanol for the butylation of carboxyl groups and acidic ketones followed by N,O bis(trimethylsilyl)trifluoroacetamide (BSTFA) for the trimethylsilylation of hydroxyl groups. RESULTS: Several new peaks were detected in the gas chromatogram after trimethylsilylation of the dibutyl ester fraction. Based on mass spectral interpretation with authentic standards, we successfully identified and quantified a homologous series of hydroxydiacids, including tartaric and oxaloacetic acids. In addition, transformation of oxaloacetic acid into its enol form was elucidated. CONCLUSIONS: Utilizing GC-FID, GC/QMS and GC/TOFMS, hydroxy- and keto-diacids were identified in the remote marine aerosols. A complete structural characterization was achieved with extensive mass spectral analysis. Molecular distributions of hydroxydiacids generally showed the predominance of malic acid followed by tartronic acid. We consider that these hydroxydiacids are important intermediates in the atmospheric oxidation of organic aerosols to result in smaller diacids. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969944 TI - Identification of metabolites of the novel anti-tumor drug candidate MDH-7 in rat urine by liquid chromatography coupled with triple quadrupole linear ion trap mass spectrometry. AB - RATIONALE: Our previous preliminary pharmacokinetic study demonstrated that the novel double pyrimidine tricyclic nucleoside MDH-7 in rats had a very short half life (<30 min) after oral administration. As a result, the in vivo metabolic profile of MDH-7 should be investigated during early stages of drug development to better select drug candidates. METHODS: In this study, a rapid method was developed to identify the metabolites of MDH-7 in rat urine by means of ultra performance liquid chromatography (UPLC) coupled with electrospray ionization mass spectrometry (ESI-MS) using a triple quadrupole linear ion trap instrument. MDH-7 and its metabolites were detected and characterized by the combined use of the multiple reaction monitoring-information-dependent acquisition-enhanced product ion (MRM-IDA-EPI) mode and the precursor scan information-dependent acquisition-enhanced product ion (PREC-IDA-EPI) mode. RESULTS: Ten novel metabolites of MDH-7 were identified and characterized in rat urine by LC/ESI-MS and collision-induced dissociation tandem mass spectrometry (CID-MS/MS) analyses. M1 was identified as 5-fluoro-N(4) -[(pentyloxy)carbonyl]cytosine; M2 and M3 were formed by hydroxylation products of M1. Metabolites M4-M10 were formed by a series of degradation reactions such as: deacetylation, hydroxylation, loss of the defluorocytosine base, oxidative-deamination, loss of the defluorouracil base, N-dealkylation and amide hydrolysis. CONCLUSIONS: Based on the profiles of the metabolites, possible metabolic pathways of MDH-7 in rats were proposed for the first time. This study provides new and available information on the metabolism of MDH-7 which is very useful to further understand its in vivo metabolic fate. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26969945 TI - Mid-term results of total knee replacement with single-radius versus multi-radius posterior-stabilized implants. AB - OBJECTIVE: Single-radius femoral total knee endoprosthesis designs were introduced with the promise of better clinical and functional results by means of superior biomechanical characteristics. The aim of this study was to compare the mid-term clinical, functional, radiologic, and survivorship outcomes of 2 types of posterior-stabilized knee replacement systems: the single-radius Scorpio(r) (Stryker(r), Mahwah, NJ, USA) and the multi-radius NexGen(r) (Zimmer(r), Warsaw, IN, USA). METHODS: This retrospective observational study included 139 patients (164 knees) that underwent total knee replacement (TKR) between October 2004 and December 2010: 94 knees (75 patients) with Scorpio(r) and 70 knees (64 patients) with NexGen(r). The 2 patient groups were similar in terms of age, gender ratio, diagnosis, disease stage, and knee joint alignment. Mean follow-up times were 35 (range: 12-112) months and 32 (range: 13-75) months, respectively. Evaluation was based on the Knee Society scores (KSS) and the Knee Society Total Knee Arthroplasty Roentgenographic Evaluation and Scoring System, with survival data compiled using Kaplan-Meier survival analysis. RESULTS: Clinical and functional improvements were recorded in all cases, with no statistically significant differences between the 2 patient groups. Survivorship was 95.8% (95% confidence interval [CI]: 91.8-99.8%) for the multi-radius implant at 60 months and 92.7% (95% CI: 87.7-97.7%) for the single-radius implant at 84 months, with no significant difference (p=0.31). CONCLUSION: This study demonstrates that both single-radius and multi-radius posterior-stabilized knee endoprostheses can significantly reduce pain and improve knee joint function in patients if used with a proper technique, with the additional benefit of good mid-term survivorship. PMID- 26969946 TI - Fixation of extra-articular distal humeral fractures with a lateral approach and a locked plate: an alternative method. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy of lateral approach and anterolateral anatomical locked plate fixation on clinical and radiological healing of extra-articular distal humeral fractures. METHODS: Twenty three (17 male, 6 female) consecutive patients who underwent surgical management for closed extra-articular comminuted distal humeral fractures between 2006 and 2013 were included in this study. Anterolateral fixation with an anatomical locked plate using a lateral approach was preferred. Mean age was 34 years (range: 17-56 years). AO Foundation/American Orthopaedic Trauma Association (AO/OTA) classification was used; all patients had AO/OTA 12-B1.3 type fractures. Inclusion criteria were patients with polytrauma, late-onset radial nerve injury, and unsatisfactory closed reduction. Patients were followed up at postoperative weeks 6, 12, and 24, and in 3-month intervals thereafter. Mean follow-up period was 16 months (range: 14-18 months). Functional results were evaluated using the Disabilities of the Arm, Shoulder and Hand (DASH) score, visual analog scale (VAS) score, and Mayo elbow performance score. RESULTS: Mean flexion was 135 degrees (range: 128-140 degrees ) at 24 weeks postoperatively; there was no loss of pronation and supination of the forearm. All fractures healed uneventfully in an average of 19.3 weeks (range: 16-24 weeks). Mean Mayo elbow performance score and DASH score at 24 weeks improved from 66.6 (range: 50-85) to 100 and from 53.6 (range: 25.75-80.75) to 12.7 (range: 5-26.5), respectively. VAS score at 24 weeks improved from 4 (range: 3-5) to 0.5 (range: 0-1). Postoperative radial nerve paralysis and infection were not observed. CONCLUSION: We recommend anterolateral anatomical locked plate fixation using a lateral approach as an alternative method in the management of distal humeral extra-articular fractures. This enables rigid fixation of the distal fragment without interfering and impinging on the olecranon fossa, allows early active range of elbow motion, and avoids iatrogenic triceps muscle injury and radial nerve exposure, which prevents surgical radial nerve injury. PMID- 26969947 TI - Treatment of infected nonunion of the juxta-articular region of the distal tibia. AB - OBJECTIVE: The purpose of this study was to summarize our clinical results with distraction osteogenesis for the treatment of infected tibial nonunion around the ankle joint. METHODS: Between 1994 and 2009, 13 patients with a mean age of 50 years (range: 27-79 years) underwent tibial reconstruction for the treatment of infected nonunion of the distal tibia, with a mean bone loss of 4.8 cm (range: 1 7 cm). Lengthening over an intramedullary nail as a second procedure was used in 2 patients, bifocal compression and distraction technique in 5 cases, compression with Ilizarov external fixator in 5 cases, and Taylor Spatial Frame (TSF, Smith Nephew, Memphis, TN, USA) in 1 case. At final follow-up, functional and radiographic results were evaluated according to Paley's bone and functional healing criteria. RESULTS: Mean duration of follow-up was 36 months. Mean external fixation time was 198 days, and mean external fixation index was 29 days/cm. According to Paley's bone healing criteria, there were 10 excellent, 2 good, and 1 poor result(s); additionally, according to Paley's functional healing criteria, there were 5 excellent, 6 good, and 2 fair results. There were 11 problems, 5 obstacles, and 1 sequel according to Paley's classification of complications. There was 1 persisting nonunion, which underwent revision with a retrograde intramedullary nail. CONCLUSION: External fixator and/or combined treatment are effective and reliable methods to treat infected nonunion of the distal tibia. Every patient should be evaluated according to their infection level and bony defects for reconstruction. PMID- 26969949 TI - An emerging etiological factor for hand injuries in the pediatric population: public exercise equipment. AB - OBJECTIVE: The purpose of this study was to describe the role of public exercise equipment in pediatric hand traumas as a preventable etiological factor. METHODS: Pediatric patients with hand injuries referred from the emergency department were evaluated retrospectively. Age and gender of the patients, timing, etiology, mechanism of hand trauma, localization of the injury, diagnoses of the patients, and hospitalization rates were reviewed. RESULTS: Amongst the 310 pediatric patients evaluated, 31 patients (10%) experienced injury related to public exercise equipment. Within this group of patients, most were between 5 to 9 years of age, and all injuries were blunt and crush type. Lacerations and fractures were the main diagnoses. Complex injuries that required inpatient care were reported in 19.3% of the patients. CONCLUSION: Public exercise equipment-related injuries are increasingly prevalent in pediatric hand traumas. Preventive actions such as shielding the moving parts should be taken to reduce these rates. PMID- 26969948 TI - A new complication in volar locking plating of the distal radius: longitudinal fractures of the near cortex. AB - OBJECTIVE: The purpose of this study was to document a new complication in volar locking plating of the distal radius. METHODS: Between January 2007 and January 2014, 223 patients were identified from the department's surgical database with retrospective chart and radiographic review. Sixty-eight patients were over 60 years of age. All fractures were operated with Acu-Loc(r) (Acumed, Hillsboro, OR, USA) wrist volar locking plating systems. Longitudinal fracture lines (LFL) beneath volar plate-extending proximal shafts were documented. Correlations between age groups and LFLs were investigated. Radiographs with LFLs were assessed at final follow-up for the following parameters: volar tilt, radial inclination and radial length. RESULTS: Twenty-eight of 68 patients over age of 60 years had LFLs. Correlation was significant for age groups (p<0.05). The effect of these fracture lines on radiographic parameters was not significant (p>0.05). CONCLUSION: Surgeons should be aware of the complications that may occur with volar locking plates. Understanding of potential complications and their results are important. As a result of aging, thinning, and weakening, the near cortex may become more brittle. When the plate is reduced on the bone with a nonlocking screw, the conical head of diaphyseal locking screws can extend over plate thickness and penetrate the near cortex, acting as a screwing wedge. Additional divergent configuration may promote this effect and crack the cortex. PMID- 26969950 TI - Prognostic factors in sensory recovery after digital nerve repair. AB - OBJECTIVE: The prognostic factors that affect sensory nerve recovery after digital nerve repair are variable because of nonhomogeneous data, subjective tests, and different assessment/scoring methods. The aim of this study was to evaluate the success of sensory nerve recovery after digital nerve repair and to investigate the prognostic factors in sensorial healing. METHODS: Ninety-six digital nerve repairs of 63 patients were retrospectively evaluated. All nerves were repaired with end-to-end neurorraphy. The static two-point discrimination (s2PD) and Semmes Weinstein monofilament (SWM) tests were performed to evaluate sensory recovery. The association between prognostic factors such as gender, age, involved digit, time from injury to repair, length of follow-up, smoking, concomitant injuries, type of injury, and sensory recovery results were assessed. RESULTS: The s2PD test demonstrated excellent results in 26 nerves (27%), good results in 61 nerves (64%), and poor results in 9 nerves (9%). The results of the SWM test according to Imai classification showed that 31 nerves (32%) were normal, light touch was diminished in 38 nerves (40%), protective sensation was diminished in 17 nerves (18%), loss of protective sensation occurred in 5 nerves (5%), and 5 nerves (5%) were anesthetic. There was a negative relationship between age, smoking, concomitant injuries, and sensory recovery. CONCLUSION: Our results demonstrate that concomitant tendon, bone and vascular injuries, older age, and smoking were associated with worse sensory nerve recovery results. However, all digital nerve injuries should be repaired, regardless of these prognostic factors. PMID- 26969951 TI - Practice of tourniquet use in Turkey: a pilot study. AB - OBJECTIVE: The aim of the present pilot study was to evaluate patterns in the current practice of tourniquet use in Turkey. The results of this study can provide detailed information regarding tourniquet use and evaluate the need for guidelines on tourniquet use in Turkey. METHODS: The questionnaire was sent to orthopedic residents and surgeons by either giving printed questionnaires directly or by establishing preliminary communication with surgeons and then sending questionnaires by e-mail. Participating staff consisted of 3 groups: Group 1: orthopedic surgeons; Group 2: orthopedic residents; and Group 3: orthopedic academic staff. Statistical differences in tourniquet use were analyzed among the groups. RESULTS: Use of mechanical tourniquet was significantly higher in Group 1. Plain cuffs were used in orthopedic surgical practice more frequently. Assistant and orthopedic theatre personnel were commonly reported by participants as the tourniquet applicant. Periodic educational practice was not routine. The number of reported complications was higher in Group 3. Cuff padding was generally routine practice. Scientifically valid options at lowest inflation pressure were not observed among the results at the expected rates. CONCLUSION: The results of this pilot study indicate that there is wide variation in some aspects of tourniquet practice in Turkey. The differences are not acceptable because of the potential for significant complications with some practices. There is a need to provide and ensure adequate education to provide the best patient care. Furthermore, protocols should be developed for acceptable standards of tourniquet use. PMID- 26969952 TI - Clinical utilization of arterial occlusion pressure estimation method in lower limb surgery: effectiveness of tourniquet pressures. AB - OBJECTIVE: The effectiveness of the arterial occlusion pressure (AOP) estimation method to set tourniquet inflation pressures was assessed in patients undergoing lower limb surgery. METHODS: One hundred ninety-eight operations were performed in 224 lower extremities of 193 patients. Tourniquet inflation pressures were set using the AOP estimation formula and adding 20 mmHg of safety margin to AOP value. Primary outcome measures were the amount of tourniquet pressure and its effectiveness. The quality of the surgical field and complications were assessed by the surgical team in a blinded fashion. Secondary measures included the time required to set the tourniquet pressure and complications. RESULTS: The initial and maximal tourniquet pressures used were 168.4+/-14.5 and 173.3+/-15.6 mmHg, respectively. The performance of the tourniquets was assessed as "excellent" and "good" in all stages of the procedure in 97.76% of cases. The time required to measure AOP and set the tourniquet cuff pressure was 19.0+/-2.6 sec. No complications occurred during or after surgery until discharge. CONCLUSION: Clinical utilization of the AOP estimation formula is a practical and effective way of setting tourniquet pressures for lower limb surgery. Its usage allows achievement of a bloodless field with inflation pressures lower than those previously recommended in the literature for lower limb tourniquets. PMID- 26969953 TI - Reconstruction of advanced periacetabular metastatic lesions with modified Harrington procedure. AB - OBJECTIVE: The purpose of this study was to assess the outcomes of patients who had been treated by a modified Harrington procedure for advanced periacetabular metastases. METHODS: Between 2006 and 2013, 16 patients with a mean age of 57 years (range: 28-73 years) were treated using a modified Harrington technique. Extensive (class II/III) periacetabular defects were due to metastatic carcinoma or multiple myeloma. Surgical procedure included total hip replacement and acetabular reconstruction using threaded pins, cemented acetabular reinforcement ring, and/or polyethylene cup. RESULTS: All patients improved in regard to pain and walking ability. Mean preoperative and postoperative Musculoskeletal Tumour Society (MSTS) functional scores were 52.8% (range: 33.3-73.3%) and 72% (range: 56.6-90%), respectively (p<0.05). There were 5 (31%) early or late complications requiring additional surgery. Implant survival was 75% and 37.5% at 12 and 18 months, respectively. Mean survival of the patients was 21 months (range: <1-6 years). Six remained alive, with a mean survival of 27 months (range: 18 months to 5 years). CONCLUSION: This modified Harrington procedure can be used for reconstruction of advanced periacetabular metastatic lesions. PMID- 26969954 TI - Effects of anti-osteoporosis treatment in the elderly with anterior cervical discectomy and fusion. AB - OBJECTIVE: The aim of this study was to evaluate the effect of anti-osteoporosis treatment on radiological and functional results following anterior cervical discectomy and fusion (ACDF). METHODS: Medical records of 59 patients (Mean age 68.1 years, 36 males and 23 females) who had ACDF surgery between January 2010 and December 2013 were retrospectively reviewed. Antiosteoporotic treatment group consisted of 31 patients and non-antiosteoporotic treatment group consisted of 28 patients. The height of intervertebral space (HIS), cervical alignment (CA), segmental angle (SA), and Visual Analogue Scale (VAS) were compared between the groups, preoperatively, postoperatively, and at final follow-up. RESULTS: There were significant differences at final follow-up between the 2 groups in SA (p=0.03), HIS (p=0.03), and VAS (p=0.03) for upper limb pain, in favor of antiosteoporotic treatment. CONCLUSION: Anti-osteoporotic treatment appear to improve the radiological and functional results following following anterior cervical discectomy and fusion. PMID- 26969955 TI - The effect of platelet-rich plasma on arthroscopic double-row rotator cuff repair: a clinical study with 12-month follow-up. AB - OBJECTIVE: The aim of the study was to assess the effect of platelet-rich plasma on arthroscopic double-row rotator cuff repair. METHODS: The study included 60 patients with arthroscopic rotator cuff repair. Thirthy patients (mean age: 57.2+/-7.4; 16 males and 14 females) underwent arthroscopic double-row repair alone (Group 1), another 30 (mean age: 56.9+/-6.0; 15 males and 15 females) had an injection of platelet-rich plasma (PRP) (Group 2). The groups were compared with DASH as a primary outcome score and Constant-Murley score, visual analog scale, measurement of active forward flexion, and external and internal rotation as secondary outcome measures. Magnetic resonance imaging was used to assess the integrity of the repair at 12 months postoperatively. RESULTS: Primary and secondary outcome measures statistically improved in both groups postoperatively (p<0.05). Overall mean primary and secondary postoperative outcome measures were not significantly different between the 2 groups. A retear was seen in 9 subjects (30%) in Group 1 and 4 subjects (14%) in Group 2 (p<0.05). CONCLUSION: The local injection of PRP into a primary arthroscopic double-row cuff repair resulted in lower recurrence rates than repairs without the novel biological augmentation material. PMID- 26969956 TI - Oxford Knee Score: cross-cultural adaptation and validation of the Turkish version in patients with osteoarthritis of the knee. AB - OBJECTIVE: The Oxford Knee Score (OKS) is a valid, short, self-administered, and site- specific outcome measure specifically developed for patients with knee arthroplasty. This study aimed to cross-culturally adapt and validate the OKS to be used in Turkish-speaking patients with osteoarthritis of the knee. METHODS: The OKS was translated and culturally adapted according to the guidelines in the literature. Ninety-one patients (mean age: 55.89+/-7.85 years) with knee osteoarthritis participated in the study. Patients completed the Turkish version of the Oxford Knee Score (OKS-TR), Short-Form 36 Health Survey (SF-36), and Western Ontario and McMaster Universities Index (WOMAC) questionnaires. Internal consistency was tested using Cronbach's alpha coefficient. Patients completed the OKS-TR questionnaire twice in 7 days to determine the reproducibility. Correlation between the total results of both tests was determined by Spearman's correlation coefficient and intraclass correlation coefficients (ICC). Validity was assessed by calculating Spearman's correlation coefficient between the OKS, WOMAC, and SF-36 scores. Floor and ceiling effects were analyzed. RESULTS: Internal consistency was high (Cronbach's alpha: 0.90). The reproducibility tested by 2 different methods showed no significant difference (p>0.05). The construct validity analyses showed a significant correlation between the OKS and the other scores (p<0.05). There was no floor or ceiling effect in total OKS score. CONCLUSION: The OKS-TR is a reliable and valid measure for the self assessment of pain and function in Turkish-speaking patients with osteoarthritis of the knee. PMID- 26969957 TI - Validity and reliability of the Turkish version of the Manchester-Oxford Foot Questionnaire for hallux valgus deformity evaluation. AB - OBJECTIVE: The aim of this study was to evaluate the reliability and validity of the Turkish version of the Manchester-Oxford Foot Questionnaire (MOXFQ) in patients affected by hallux valgus in order to assess the accuracy of this cross cultural adaption. METHODS: Thirty female volunteers aged between 18 and 55 years were included in the study. Subjects with hallux valgus were asked to complete the MOXFQ and the Short-Form 36 Health Survey (SF-36). After receiving permission from the author, the MOXFQ was translated into Turkish twice and then back translated to English, after which its compatibility was evaluated. The Turkish version of the MOXFO was applied twice, 1-3 days apart, to the study subjects. Internal consistency and test-retest reliability were assessed using Cronbach's alpha and intraclass correlation coefficient (ICC), respectively. Construct validity was assessed with the use of Spearman's rank correlation coefficient, using a priori hypothesized correlations with SF-36 domains. RESULTS: Subjects achieved similar scores at the first and second administration of the questionnaire (<0.001). The internal consistency reliability was acceptable for all MOXFQ domains (pain, walking/standing, social interaction), with Cronbach's alpha coefficients ranging from 0.775 to 0.779. The assessment of test-retest reliability revealed satisfactory values, with ICCs ranging from 0.91 to 0.96. Construct validity was supported by the presence of all the hypothesized correlations, with SF-36 within its physical parameters. CONCLUSION: The Turkish version of the MOXFQ is a valid and reliable tool for evaluating foot pain and functional status in patients affected by hallux valgus. PMID- 26969958 TI - Three-dimensionally-navigated cross-cannulated screw fixation for traumatic pubic symphysis diastasis: an anatomical study. AB - OBJECTIVE: The aim of this study was to design and optimize the secure corridor of cross-cannulated screw implantation in pubic symphysis through Orbic 3D (Siemens Medical Solutions, Erlangen, Germany) computerized navigation and to provide an anatomic basis through the study of regional anatomy. METHODS: Fifteen embalmed adult cadavers (8 males, 7 females) were used in this study. All pelvic specimens were placed in the supine position on a radiolucent carbon fiber table. The ideal angle of screw placement, appropriate screw diameter, and perfect attachment point were determined by the computerized navigation system. According to the above data, cross-cannulated screws 6.5 mm in diameter were implanted by the guide pins. Based on detailed local dissection, the entry-exit points of double screws were exposed in the pelvis. The distances were measured between the entry-exit points and the major structures. Radiographs and computed tomography (CT) scans of the pelvis were performed to reassess the position of screws. RESULTS: The trajectory of the first screw originated from the trailing edge of the pubic tubercula to the anterior-lower corner of the contralateral pubic tubercula. The second screw was directed from the base of the pubic tubercula to the junctional zone between the pubic tubercula and inferior ramus of the pubis of the opposite side of the body. Both screws maintained a safe distance from the surrounding major structures. All screw corridors were found intact without any damage under X-ray and CT images. CONCLUSION: The Orbic 3D computer navigation system is a reliable and new method of achieving a secure corridor for screw implantation in the pubic symphysis. PMID- 26969959 TI - Anatomic compatibility of femoral intramedullary implants: a cadaveric study. AB - OBJECTIVE: The purpose of this study was to describe the morphology of the proximal and diaphysis of femur, distribution of neck version, neck-shaft angles, and radius of anterior curvature in a Turkish population to compare with that of femoral intramedullary implants. METHODS: Using 84 cadaveric femora, three dimensional (3D) modeling was performed with a light scanner, data were transferred to Solidworks 2013 software (Solidworks, Waltham, MA, USA) to determine the variability in the femoral length (FL), neck version, neck-shaft angle (NSA), and anterior bow. Three independent observers' measurements were tested with a reliability analysis and then evaluated using Cronbach's alpha value, after which they were compared with the neck-shaft angles, and the radii of curvature (RAC) of intramedullary femoral nails, as stated on the official manufacturer websites. RESULTS: Mean FL, femoral neck anteversion (FNA), and NSA had ranges of 346.1-454.1 mm, -11.3-40.4 degrees , and 105.9-149.0 degrees , respectively, and RAC was between 1.0 and 1.2 m. The correlation coefficient and 95% confidence intervals (CI) were 0.89 (CI 0.849-0.928), 0.86 (CI 0.799-0.904), and 0.85 (95% CI 0.785-0.898) for FL, FNA, and NSA, respectively. FNA was <10 degrees in 32 femora (37.6%) and >14 degrees 38 (44.7%). NSA was between 130 degrees and 135 degrees in 40 femora (47.1%), and RAC ranged from 0.5 to 1.5 m in 76 femora (91.6%), <1 m in 38 (45.8%), and >1.5 m in 7 (8.4%). CONCLUSION: FNA and NSA show a wide distribution, mostly out of the range of intramedullary implants. There is a need for implants that are compatible with a range of NSAs and versions, so that they are suitable for use with a variety of morphologies. PMID- 26969960 TI - Role of anti-adhesive barriers following rotator cuff repair surgery: an experimental study. AB - OBJECTIVE: This experimental study investigates the effectiveness of expanded polytetrafluoroethylene (Dualmesh(r), Gore Medical, Flagstaff, AZ, USA), sodium hyaluronate-carboxymethyl cellulose (Seprafilm(r), Genzyme, Cambridge, MA, USA), and polysiloxane (silicone) as anti-adhesive barriers for inhibition of fibrosis in the subacromial area following rotator cuff repair. METHODS: Rabbit rotator cuff tenotomy and repair was conducted on 24 rabbits in 4 groups: control (Group A), Dualmesh(r) (Group B), Seprafilm(r) (Group C), and silicone (Group D). Anti adhesive barrier materials were sutured over the repaired rotator cuff. Macroscopic and histological evaluations were made at the end of the sixth postoperative week. RESULTS: Macroscopic evaluation revealed that minimal adhesion occurred in the control and silicone groups, while the Seprafilm(r) and Dualmesh(r) groups showed evidence of fibrosis. Microscopic evaluation revealed diffuse fibrosis and collagen accumulation in the Dualmesh(r) and Seprafilm(r) groups, whereas minimal collagen deposition and inflammatory cell reaction was found among the silicone and control groups. Significant differences were found between the silicone and Dualmesh(r) (p=0.001) and silicone and Seprafilm(r) groups (p=0.002), as well as between the control and Dualmesh(r) (p=0.002) and control and Seprafilm(r) groups (p=0.002). CONCLUSION: Expanded polytetrafluoroethylene (ePTFE/Dualmesh(r)) and sodium hyaluronate carboxymethyl cellulose (SH-CMC/Seprafilm(r)) did not prevent or attenuate postoperative subacromial fibrosis following cuff tear repair. Nor did silicone prevent or attenuate fibrosis. More detailed research is needed for development of an effective anti-adhesive barrier for use after rotator cuff tear surgery. PMID- 26969961 TI - Effect of bleeding on nerve regeneration and epineural scar formation in rat sciatic nerves: an experimental study. AB - OBJECTIVE: Epineural scar formation is one of the most significant negative factors affecting surgical repair after peripheral nerve injury. The scar tissue mechanically hinders axonal regeneration and causes adhesions between nerves and surrounding tissues. A hemostatic agent Ankaferd Blood Stopper (ABS; Immun Gida Ilac Kozmetik San. ve Tic. Ltd. Sti., Istanbul, Turkey) has not been previously used. Decreasing the postoperative bleeding and adhesions between nerve and surrounding tissues will prevent the formation of scar tissue, as well as corresponding compressive neuropathy and/or deceleration of axonal regeneration. The purpose of this experimental study was to investigate the effects of bleeding on nerve healing and scar tissue after repair of peripheral nerve injuries. METHODS: The right sciatic nerve of 30 Sprague-Dawley male rats (weighing 260-330 g) was cut 1.5 cm proximal to the trifurcation and repaired primarily with 8/0 sutures using epineural technique. The rats were then divided into 3 groups. Saline was applied in Group 1 (n=10), ABS in Group 2 (n=10), and heparin in Group 3 (n=10) for 5 minutes to the repair site and surrounding tissues. In each group, electrophysiological measurements were performed with electromyography (EMG) at postoperative week 12. Magnetic resonance diffusion tensor imaging was used at week 12. Macroscopical and histopathological evaluations were conducted after sacrificing the rats at week 24 with total excision of the repaired sciatic nerves and surrounding tissues. RESULTS: The ABS and saline groups showed better healing than the heparin group. The ABS and saline groups were better in the histopathologic evaluations, but there was no statistically significant difference between the 2 groups. CONCLUSION: Statistically significant differences were not found between the 3 groups. Significant results may be obtained with larger studies. PMID- 26969962 TI - Glomus tumor located in deltoid muscle. AB - Glomus tumors are benign soft tissue neoplasms arising from the glomus body, which are primarily found under the nail bed of the fingers. They are rarely located in other parts of the body. Only 8 cases of glomus tumors around the shoulder have been published in the literature. The purpose of this study was to present a glomus tumor located in the deltoid muscle in a 68-year-old male patient that was surgically treated by marginal excision. The patient remained asymptomatic, and no recurrence was detected at 2-year follow up. PMID- 26969963 TI - Migration of a toothpick along the flexor tendon sheath in a lower extremity. AB - The most common foreign bodies seen in the foot are sewing needles, toothpicks, glass, and materials such as sand or silica. Foreign bodies in the foot are usually embedded, and surgical exploration and removal is usually necessary. Penetrating foreign bodies in the foot-particularly of organic origin, like wood can cause cellulitis, osteomyelitis, abscess formation, and pseudotumor formation. Identification of foreign bodies in the foot can be challenging because they are often not radiopaque. However, foreign bodies in the foot do not migrate, in contrast to upper extremities, where foreign bodies are known to migrate. We report a case of a toothpick penetrating a child's foot and moving proximally along the tendon sheath. PMID- 26969964 TI - A novel biological reconstruction of tibial bone defects arising after resection of tumors. AB - The purpose of this paper is to describe a biologic reconstruction strategy for defects after resection of malignant tibia tumors. Limb-sparing surgery was used for 4 patients with malignant tibia tumors. All patients were male, with an average age of 39.5 years (range: 34-46 years). Mean length of the resected tibia segment was 135 mm (range: 120-150 mm). The defects were primarily reconstructed with bone cement and locked plate until completion of the medical treatment of the tumor. The bone transport was made through locked plate, and the docking site was grafted at the final stage. Mean follow-up period was 49.75 months (range: 71 22 months). Mean distraction index was 1148 mm/days (range: 1130-1175 mm/days), and mean external fixation time was 167 days (range: 152-187 days). According to Paley, functional results were excellent in 2 cases and good in the other 2 cases. Radiological results were excellent in all cases. Two major and 2 minor complications were observed. In this method, stable internal fixation and active usage of extremities are provided until biological reconstruction, and possible wound problems can be completely eliminated during the duration of medical treatment of the tumor. PMID- 26969965 TI - In vivo detection of hyperacute neuronal compaction and recovery by MRI following electric trauma in rats. AB - PURPOSE: To verify the following phenomenon in vivo using quantitative magnetic resonance imaging (MRI). Neuronal compression may occur following brain injuries in the cortex and hippocampus. As well being characterized by previous histological studies in rats, the majority of these neurons undergo hyperacute recovery rather than apoptotic death. MATERIALS AND METHODS: Twenty male Wistar rats were assigned into injured or sham-injured groups (n = 10). The injured group underwent an electric trauma model to provoke compacted neuron formation. A T1 map was acquired prior to the injury and 10 T1 maps were acquired consecutively over a period of 2.5 hours after the injury, using a 3.0T scanner. Voxelwise statistical analyses were performed between timepoints. To enable comparison with the histological appearance of the compacted neurons, silver staining was performed on a sham-injured rat and five injured rats, 10, 40, 90, 150, and 300 minutes after the injury. RESULTS: A significant (corrected P < 0.05) increase in average T1 from the preinjury (895.24 msec) to the first postinjury timepoint (T1 = 951.37 msec) was followed by a significant (corrected P < 0.05) decrease (return) up to the last postinjury timepoint (T1 = 913.16 msec) in the voxels of the cortex and hippocampus. No significant (corrected P < 0.05) change in T1 was found in the sham-injured group. CONCLUSION: The spatial and temporal linkages between the MRI T1 changes and the histological findings suggest that neuronal compaction and recovery is associated with T1 alterations. MRI therefore offers the possibility of in vivo investigations of neuronal compaction and recovery. J. MAGN. RESON. IMAGING 2016;44:814-822. PMID- 26969966 TI - ISUOG Interim Guidance on ultrasound for Zika virus infection in pregnancy: information for healthcare professionals. PMID- 26969968 TI - Serum activin-A as a predictive and prognostic marker in critically ill patients with sepsis. AB - BACKGROUND AND OBJECTIVE: There are limited data regarding serum activin-A as a biomarker for sepsis. We examined whether serum activin-A concentration could predict sepsis severity and prognosis in the management of critically ill patients with sepsis. METHODS: The subjects were adult patients suspected of having sepsis and admitted to intensive care unit (ICU) from January 2013 to March 2014. Serum activin-A concentration was measured in blood sampled within 48 h after ICU admission. The primary and secondary outcomes were the diagnostic value of serum activin-A concentration as a biomarker of sepsis and the prognostic value for predicting the clinical outcomes of sepsis, respectively. RESULTS: One hundred and thirty patients who had clinically suspected sepsis were included. Most (66.2%) were male; their median age was 65 years, and their Acute Physiology and Chronic Health Evaluation II score was 22.3. Serum activin-A concentration tended to increase with sepsis severity and differed significantly between those with non-sepsis and severe sepsis and between those with severe sepsis and septic shock. The risks of sepsis, severe sepsis and septic shock were significantly higher in patients with a serum activin-A concentration of 251, 319 and 432 pg/mL or greater, respectively. Serum activin-A concentration was significantly associated with the Acute Physiology and Chronic Health Evaluation II score, Sequential Organ Failure Assessment score, Charlson comorbidity index and ICU mortality. CONCLUSION: Serum activin-A was a predictor of sepsis severity and a prognostic marker in critically ill patients with sepsis. Serum activin-A concentration in the early phase of sepsis was associated with prognostic indexes on ICU admission and with ICU mortality. PMID- 26969967 TI - 17beta-Oestradiol enhances the expansion and activation of myeloid-derived suppressor cells via signal transducer and activator of transcription (STAT)-3 signalling in human pregnancy. AB - During a successful pregnancy, the maternal immune system plays a critical role in maintaining immunotolerance towards semi-allogeneic fetal antigens. Recent studies have indicated that myeloid-derived suppressor cells (MDSCs) are active players in establishing fetal-maternal tolerance; however, the underlying mechanism remains poorly understood. In this study, we observed a significant expansion of monocytic MDSCs (M-MDSCs) in the peripheral blood of pregnant women, which suppressed T cell responses in a reactive oxygen species-dependent manner and required cell-cell contact. The number of M-MDSCs correlated positively with serum oestrogen and progesterone levels. Administration of 17beta-oestradiol, but not progesterone, enhanced both the expansion and suppressive activity of M-MDSCs through signal transducer and activator of transcription (STAT)-3. Pretreatment with STAT-3 inhibitor JSI-124 almost completely abrogated the effects of 17beta oestradiol on MDSCs. Collectively, these results demonstrate that 17beta oestradiol-induced STAT-3 signalling plays an important role in both the expansion and activation of MDSCs during human pregnancy, which may benefit the development of novel therapeutic strategies for prevention of immune-related miscarriage. PMID- 26969970 TI - Sea Urchin Morphogenesis. AB - In the sea urchin morphogenesis follows extensive molecular specification. The specification controls the many morphogenetic events and these, in turn, precede patterning steps that establish the larval body plan. To understand how the embryo is built it was necessary to understand those series of molecular steps. Here an example of the historical sequence of those discoveries is presented as it unfolded over the last 50 years, the years during which major progress in understanding development of many animals and plants was documented by CTDB. In sea urchin development a rich series of experimental studies first established many of the phenomenological components of skeletal morphogenesis and patterning without knowledge of the molecular components. The many discoveries of transcription factors, signals, and structural proteins that contribute to the shape of the endoskeleton of the sea urchin larva then followed as molecular tools became available. A number of transcription factors and signals were discovered that were necessary for specification, morphogenesis, and patterning. Perturbation of the transcription factors and signals provided the means for assembling models of the gene regulatory networks used for specification and controlled the subsequent morphogenetic events. The earlier experimental information informed perturbation experiments that asked how patterning worked. As a consequence it was learned that ectoderm provides a series of patterning signals to the skeletogenic cells and as a consequence the skeletogenic cells secrete a highly patterned skeleton based on their ability to genotypically decode the localized reception of several signals. We still do not understand the complexity of the signals received by the skeletogenic cells, nor do we understand in detail how the genotypic information shapes the secreted skeletal biomineral, but the current knowledge at least outlines the sequence of events and provides a useful template for future discoveries. PMID- 26969969 TI - Epigenetic Regulation by ATP-Dependent Chromatin-Remodeling Enzymes: SNF-ing Out Crosstalk. AB - Cells utilize precise mechanisms to access genomic DNA with spatiotemporal accuracy. ATP-dependent chromatin-remodeling enzymes (also known simply as "remodelers") comprise a specialized class of enzymes that is intimately involved in genomic organization and accessibility. Remodelers selectively position nucleosomes to either alleviate chromatin compaction or achieve genomic condensation locally, based on a multitude of cellular signals. By dictating nucleosome position, remodelers control local euchromatic and heterochromatic states. These activities govern the accessibility of regulatory regions like promoters and enhancers to transcription factors, RNA polymerases, and coactivators or -repressors. As studies unravel the complexities of epigenetic topography, evidence points to a chromatin-based interactome where regulators interact competitively, cooperatively, and/or codependently through physical and functional means. These types of interactions, or crosstalk, between remodelers raise important questions for tissue development. Here, we briefly review the evidence for remodeler interactions and argue for additional studies examining crosstalk. PMID- 26969972 TI - Applied Developmental Biology: Making Human Pancreatic Beta Cells for Diabetics. AB - Understanding the genes and signaling pathways that determine the differentiation and fate of a cell is a central goal of developmental biology. Using that information to gain mastery over the fates of cells presents new approaches to cell transplantation and drug discovery for human diseases including diabetes. PMID- 26969971 TI - Development of the Mammalian Kidney. AB - The basic unit of kidney function is the nephron. In the mouse, around 14,000 nephrons form in a 10-day period extending into early neonatal life, while the human fetus forms the adult complement of nephrons in a 32-week period completed prior to birth. This review discusses our current understanding of mammalian nephrogenesis: the contributing cell types and the regulatory processes at play. A conceptual developmental framework has emerged for the mouse kidney. This framework is now guiding studies of human kidney development enabled in part by in vitro systems of pluripotent stem cell-seeded nephrogenesis. A near future goal will be to translate our developmental knowledge-base to the productive engineering of new kidney structures for regenerative medicine. PMID- 26969974 TI - When Family History Matters: The Importance of Lineage Analyses and Fate Maps for Explaining Animal Development. AB - Initial interest in understanding how the fertilized egg becomes a multicellular animal suggested two possible answers: either the embryo came from preformed components or it arose through epigenetic processes. Extensive research during the past few decades has identified aspects of development that depend on preformed elements, such as cytoplasmic components and a cell's lineage; it also has identified aspects that depend on epigenetic processes, such as cell interactions and morphogen gradients. These advances have depended on understanding embryonic cell lineage and cell fate. This essay explains how lineage analysis and fate mapping have contributed to our current understanding of embryonic development. PMID- 26969973 TI - The Dishevelled Protein Family: Still Rather a Mystery After Over 20 Years of Molecular Studies. AB - Dishevelled (Dsh) is a key component of Wnt-signaling pathways and possibly also has other functional requirements. Dsh appears to be a key factor to interpret Wnt signals coming via the Wnt-receptor family, the Frizzled proteins, from the plasma membrane and route them into the correct intracellular pathways. However, how Dsh is regulated to relay signal flow to specific and distinct cellular responses upon interaction with the same Wnt-receptor family remains very poorly understood. PMID- 26969976 TI - The Developmental Genetics of Vertebrate Color Pattern Formation: Lessons from Zebrafish. AB - Color patterns are prominent features of many animals; they are highly variable and evolve rapidly leading to large diversities even within a single genus. As targets for natural as well as sexual selection, they are of high evolutionary significance. The zebrafish (Danio rerio) has become an important model organism for developmental biology and biomedical research in general, and it is the model organism to study color pattern formation in vertebrates. The fish display a conspicuous pattern of alternating blue and golden stripes on the body and on the anal and tail fins. This pattern is produced by three different types of pigment cells (chromatophores) arranged in precise layers in the hypodermis of the fish. In this essay, we will summarize the recent advances in understanding the developmental and genetic basis for stripe formation in the zebrafish. We will describe the cellular events leading to the formation of stripes during metamorphosis based on long-term lineage imaging. Mutant analysis has revealed that a number of signaling pathways are involved in the establishment and maintenance of the individual pigment cells. However, the striped pattern itself is generated by self-organizing mechanisms requiring interactions between all three pigment cell types. The involvement of integral membrane proteins, including connexins and potassium channels, suggests that direct physical contacts between chromatophores are involved, and that the directed transport of small molecules or bioelectrical coupling is important for these interactions. This mode of patterning by transmitting spatial information between adjacent tissues within three superimposed cell layers is unprecedented in other developmental systems. We propose that variations in the patterns among Danio species are caused by allelic differences in the genes responsible for these interactions. PMID- 26969977 TI - Defining "Development". AB - Is it possible, and in the first place is it even desirable, to define what "development" means and to determine the scope of the field called "developmental biology"? Though these questions appeared crucial for the founders of "developmental biology" in the 1950s, there seems to be no consensus today about the need to address them. Here, in a combined biological, philosophical, and historical approach, we ask whether it is possible and useful to define biological development, and, if such a definition is indeed possible and useful, which definition(s) can be considered as the most satisfactory. PMID- 26969978 TI - Concepts of Cell Lineage in Mammalian Embryos. AB - Cell lineage is the framework for understanding cellular diversity, stability of differentiation, and its relationship to pluripotency. The special condition of in utero development in mammals has presented challenges to developmental biologists in tracing cell lineages but modern imaging and cell marking techniques have allowed the gradual elucidation of lineage relationships. Early experimental embryology approaches had limited resolution and relied of suboptimal cell markers and considerable disturbance to the embryos. Transgenic technology introduced genetic markers, particularly fluorescent proteins that, combined with sophisticated imaging modalities, greatly increase resolution and allow clonal analysis within lineages. The concept of cell lineage has also undergone evolution as it became possible to trace the lineage of cells based not only on their physical location or attributes but also on their gene expression pattern, thus opening up mechanistic lines of investigation into the determinants of cell lineage. PMID- 26969975 TI - Frizzled Receptors in Development and Disease. AB - Frizzled proteins are the principal receptors for the Wnt family of ligands. They mediate canonical Wnt signaling together with Lrp5 and Lrp6 coreceptors. In conjunction with Celsr, Vangl, and a small number of additional membrane and membrane-associated proteins, they also play a central role in tissue polarity/planar cell polarity (PCP) signaling. Targeted mutations in 9 of the 10 mammalian Frizzled genes have revealed their roles in an extraordinarily diverse set of developmental and homeostatic processes, including morphogenetic movements responsible for palate, ventricular septum, ocular furrow, and neural tube closure; survival of thalamic neurons; bone formation; central nervous system (CNS) angiogenesis and blood-brain barrier formation and maintenance; and a wide variety of processes that orient subcellular, cellular, and multicellular structures relative to the body axes. The last group likely reflects the mammalian equivalent of tissue polarity/PCP signaling, as defined in Drosophila, and it includes CNS axon guidance, hair follicle and tongue papilla orientation, and inner ear sensory hair bundle orientation. Frizzled receptors are ubiquitous among multicellular animals and, with other signaling molecules, they very likely evolved to permit the development of the complex tissue architectures that provide multicellular animals with their enormous selective advantage. PMID- 26969980 TI - Toward a Systems Understanding of Signaling Pathway Function. AB - A small number of developmental signaling pathways are used repeatedly throughout development in many different contexts. How these pathways interact with each other and the specific cell context to generate a wide range of appropriate responses remains an important question. The application of genomic and proteomic approaches and imaging at high spatiotemporal resolution are providing answers to this question and revealing new levels of complexity. Here, we discuss pathways as complex networks and examples of how signaling outcomes can be influenced by the temporal nature of the signal, its spatial regulation, and the cell context. PMID- 26969979 TI - Small Peptides as Newcomers in the Control of Drosophila Development. AB - Throughout the last century, studies using the fruit fly have contributed to the discovery of many key genetic elements that control animal development. Recent work has shed light on an unexpectedly large number of RNAs that lack the classical hallmarks of protein-coding genes and are thus referred to as noncoding RNAs. However, there is mounting evidence that both mRNA and noncoding RNAs often contain small open reading frames (sORFs/smORFs), which can be translated into peptides. While genome-wide profiling supports a pervasive translation of these noncanonical sORF/smORF/SEP peptides, their functions remain poorly understood. Here, we review recent data obtained in Drosophila demonstrating the overlooked role of smORF peptides in the control of development and adult life. Focusing on a few smORF peptides whose functions have been elucidated recently, we discuss the importance of these newly identified regulatory molecules and how they act to regulate the building and function of the whole organism. PMID- 26969981 TI - Implications of Developmental Gene Regulatory Networks Inside and Outside Developmental Biology. AB - The insight that the genomic control of developmental process is encoded in the form of gene regulatory networks has profound impacts on many areas of modern bioscience. Most importantly, it affects developmental biology itself, as it means that a causal understanding of development requires knowledge of the architecture of regulatory network interactions. Furthermore, it follows that functional changes in developmental gene regulatory networks have to be considered as a primary mechanism for evolutionary process. We here discuss some of the recent advances in gene regulatory network biology and how they have affected our current understanding of development, evolution, and regulatory genomics. PMID- 26969982 TI - Evo-Devo: Discovery of Diverse Mechanisms Regulating Development. AB - Evo-devo is a relatively new field focusing on how mechanisms controlling development have changed during evolution. To date, studies of highly conserved members of an animal genetic toolkit have predominated in this field. These toolkit genes were originally identified in a small number of model organisms that do not represent the extant diversity of metazoans. We describe how this research paradigm came to be and what we have learned from it, and then argue that studies of other types of animals and of lineage-specific genes, in both model and nonmodel systems, are needed to expand our understanding of development and evolution. PMID- 26969983 TI - Making the Mouse Blastocyst: Past, Present, and Future. AB - The study of the preimplantation mouse embryo has progressed over the past 50 years from descriptive biology through experimental embryology to molecular biology and genetics. Along the way, the molecular pathways that lead to the establishment of the three cell lineages of the blastocyst have become more clearly understood but the fundamental questions of lineage commitment remain the same as those laid out in early studies. With new tools of genome manipulation, in vivo imaging and single-cell analysis, the mouse blastocyst is an excellent model system to understand how organized cell fate decisions are made in a self organizing developmental context. PMID- 26969984 TI - Two Decades of Ascidian Developmental Biology: A Personal Research Story. AB - Ascidians are the closest relatives of vertebrates. Their utility in experimental embryology has been well recognized because of their simple mode of embryogenesis to form tadpole larvae with a basal chordate body plan. Approximately two decades of research, including decoding of the Ciona genome, have promoted ascidians as one of the best systems for exploring genome-wide mechanisms of developmental transcriptional control and chordate evolution. PMID- 26969985 TI - Lineage Segregation in the Totipotent Embryo. AB - After a spermatozoon enters an oocyte, maternal factors accumulated in the oocyte reprogram the genomes of the terminally differentiated oocyte and spermatozoon epigenetically and turn the zygote into a totipotent cell, with the capacity to differentiate into all types of somatic cells in a highly organized manner and generate the entire organism, a feature referred to as totipotency. Differentiation of the first lineage begins after three cleavages, when the early embryo compacts and becomes polarized, followed by segregation of the first lineages--the inner cell mass (ICM) and the trophectoderm (TE). To date, a full understanding of the molecular mechanisms that underlie the establishment of totipotency and the ICM/TE lineage segregation remains unclear. In this review, we discuss recent findings in the mechanism of transcriptional regulation networks and signaling pathways in the first lineage separation in the totipotent mouse embryo. PMID- 26969986 TI - The Complexities and Unexpected Insights of Developmental Genetic Analysis. AB - The study of development involves many important techniques. Here I am trying to reflect on the strength of genetic analysis and its ability to uncover unexpected relationships and regulatory inputs from seemingly unrelated pathways. PMID- 26969987 TI - Homeodomains, Hedgehogs, and Happiness. AB - Developmental biologists have had a spectacular quarter century of discoveries, building on many decades of work earlier, discovering molecular, cellular, and genetic mechanisms that underlie the magical process by which an egg becomes a plant or animal. Among the discoveries were homeodomains, DNA-binding domains that allow transcription factors to recognize their target genes, and the Hedgehog signaling pathway, which is used in many organs and tissues for communication among cells. The experience of unveiling the mechanisms and molecules connected to both of these findings has been remarkable, joyful, difficult, and a time of great teamwork and collaboration within and between laboratory groups. More than ever it is possible to discern the evolutionary processes, and their mechanisms, that led to the diversity of life on earth. A huge amount of work remains to be done to obtain a broad understanding of what happened and how development works. PMID- 26969988 TI - Turning One Cell Type into Another. AB - The nature of cells in early embryos may be respecified simply by exposure to inducing factors. In later stage embryos, determined cell populations do not respond to inducing factors but may be respecified by other stimuli, especially the introduction of specific transcription factors. Fully differentiated cell types are hard to respecify by any method, but some degree of success can be achieved using selected combinations of transcription factors, and this may have clinical significance in the future. PMID- 26969989 TI - Mechanotransduction During Vertebrate Neurulation. AB - Vertebrate neural tube formation is a complex morphogenetic process, which involves hundreds of genes dynamically coordinating various behaviors in different cell populations of neural tissue. The challenge remains to determine the relative contributions of physical forces and biochemical signaling events to neural tube closure and accompanying cell fate specification. Planar cell polarity (PCP) molecules are prime candidate factors for the production of actomyosin-dependent mechanical signals necessary for morphogenesis. Conversely, physical forces may contribute to the polarized distribution of PCP proteins. Understanding mechanosensory and mechanotransducing properties of diverse molecules should help define the direction and amplitude of physical stresses that are critical for neurulation. PMID- 26969990 TI - Preformation Versus Epigenesis in Early Mammalian Development. AB - Whether or not early mammalian development results from preformation or epigenesis remains an unresolved issue. Evidence for or against either is weak, inconclusive, and often misinterpreted. Yet, one can parsimoniously conceptualize formation of the mouse blastocyst as a series of random, stochastic events stemming from initial and sequential small asymmetries in egg, zygote, and cleavage stages. Differential compartmentalized gene expression does not lead but follows the morphogenesis and cell fate allocation in the mammalian blastocyst. PMID- 26969991 TI - A Thousand and One Receptor Tyrosine Kinases: Wherein the Specificity? AB - Over 20 years ago, a series of seminal studies in PC12 neurons provided a framework for how receptor tyrosine kinases generate many different outcomes despite activating a set of shared intracellular pathways. In this essay, we revisit the question of receptor tyrosine kinase specificity. We first examine the relationship between receptor phosphorylation and intracellular pathway activation. We then consider the mechanisms through which signaling dynamics encode distinct cellular outcomes and finally discuss how two different receptors drive divergent transcriptional responses within the same developmental context. Establishing the key parameters that dictate the response to growth factor stimulation is critical for determining how receptor tyrosine kinases orchestrate development, an essential prerequisite for understanding the pathological consequences when such signaling processes go awry. PMID- 26969992 TI - The Carnegie Department of Embryology at 100: Looking Forward. AB - Biological research has a realistic chance within the next 50 years of discovering the basic mechanisms by which metazoan genomes encode the complex morphological structures and capabilities that characterize life as we know it. However, achieving those goals is now threatened by researchers who advocate an end to basic research on nonmammalian organisms. For the sake of society, medicine, and the science of biology, the focus of biomedical research should place more emphasis on basic studies guided by the underlying evolutionary commonality of all major animals, as manifested in their genes, pathways, cells, and organs. PMID- 26969993 TI - Organ Function as a Modulator of Organ Formation: Lessons from Zebrafish. AB - Organogenesis requires an intricate balance between cell differentiation and tissue growth to generate a complex and fully functional organ. However, organogenesis is not solely driven by genetic inputs, as the development of several organ systems requires their own functionality. This theme is particularly evident in the developing heart as progression of cardiac development is accompanied by increased and altered hemodynamic forces. In the absence or disruption of these forces, heart development is abnormal, suggesting that the heart must sense these changes and respond appropriately. Here, we discuss concepts of how embryonic heart function contributes to heart development using lessons learned mostly from studies in zebrafish. PMID- 26969994 TI - Organizers in Development. AB - An "organizer" is formally defined as a region, or group of cells in an embryo that can both induce (change the fate) and pattern (generate an organized set of structures) adjacent embryonic cells. To date, about four such regions have been demonstrated: the primary or Spemann organizer (Hensen's node in amniotes), the notochord, the zone of polarizing activity of the limb bud, and the mid-hindbrain boundary. Here we review the evidence for these and compare them with a few other regions which have been proposed to represent other organizers and we speculate on why so few such regions have been discovered. PMID- 26969995 TI - The Soft Touch: Low-Affinity Transcription Factor Binding Sites in Development and Evolution. AB - Transcription factor proteins regulate gene expression by binding to specific DNA regions. Most studies of transcription factor binding sites have focused on the highest affinity sites for each factor. There is abundant evidence, however, that binding sites with a range of affinities, including very low affinities, are critical to gene regulation. Here, we present the theoretical and experimental evidence for the importance of low-affinity sites in gene regulation and development. We also discuss the implications of the widespread use of low affinity sites in eukaryotic genomes for robustness, precision, specificity, and evolution of gene regulation. PMID- 26969996 TI - Developmental Competence for Primordial Germ Cell Fate. AB - During mammalian embryonic development, the trophectoderm and primitive endoderm give rise to extraembryonic tissues, while the epiblast differentiates into all somatic lineages and the germline. Remarkably, only a few classes of signaling pathways induce the differentiation of these progenitor cells into diverse lineages. Accordingly, the functional outcome of a particular signal depends on the developmental competence of the target cells. Thus, developmental competence can be defined as the ability of a cell to integrate intrinsic and extrinsic cues to execute a specific developmental program toward a specific cell fate. Downstream of signaling, there is the combinatorial activity of transcription factors and their cofactors, which is modulated by the chromatin state of the target cells. Here, we discuss the concept of developmental competence, and the factors that regulate this state with reference to the specification of mammalian primordial germ cells. PMID- 26969997 TI - Formation of the Embryonic Head in the Mouse: Attributes of a Gene Regulatory Network. AB - The embryonic head is the first major body part to be constructed during embryogenesis. The allocation and the assembly of the progenitor tissues, which start at gastrulation, are accompanied by the spatiotemporal activity of transcription factors and signaling pathways that drives lineage specification, germ layer formation, and cell/tissue movement. The morphogenesis, regionalization, and patterning of the brain and craniofacial structures rely on the function of LIM-domain, homeodomain, and basic helix-loop-helix transcription factors. These factors constitute the central nodes of a gene regulatory network (GRN) which encompasses and intersects with signaling pathways involved with head formation. It is predicted that the functional output of this "head GRN" impacts on cellular function and cell-cell interactions that are essential for lineage differentiation and tissue modeling, which are key processes underpinning the formation of the head. PMID- 26969998 TI - Developmental Biology: We Are All Walking Mutants. AB - What is Developmental Biology? Developmental Biology is a discipline that evolved from the collective fields of embryology, morphology, and anatomy, which firmly established that structure underpins function. In its simplest terms, Developmental Biology has come to describe how a single cell becomes a completely formed organism. However, this definition of Developmental Biology is too narrow. Developmental Biology describes the properties of individual cells; their organization into tissues, organs, and organisms; their homeostasis, regeneration, aging, and ultimately death. Developmental Biology provides a context for cellular reprogramming, stem cell biology, regeneration, tissue engineering, evolutionary development and ecology, and involves the reiterated use of the same cellular mechanisms and signaling pathways throughout the lifespan of an organism. Using neural crest cells as an example, this review explores the contribution of Developmental Biology to our understanding of development, evolution, and disease. PMID- 26969999 TI - A Bespoke Coat for Eggs: Getting Ready for Fertilization. AB - All eggs have an extracellular coat (EC) that plays unique roles during reproduction and development. ECs are designed to protect eggs and support their growth, regulate fertilization of eggs, and protect early embryos. ECs of mammalian and nonmammalian eggs consist of only a few proteins that are closely related to one another. All these proteins possess regulatory elements and a structural domain responsible for processing and assembly of the proteins into ECs. They also possess regions responsible for their functional roles during and after fertilization. Our essay addresses these and other aspects of EC biology. PMID- 26970001 TI - Positional Information and Cell Fate Determination in the Early Drosophila Embryo. AB - During early development in Drosophila, the spatial information of maternal gradients is translated into discrete transcriptional states determining cell fate. Information transfer depends on reproducibility of the gradients themselves, as well as the ability of cells to accurately measure and utilize morphogen concentrations in biologically meaning ways. In the following essay, these issues are discussed in context of the Bicoid gradient. PMID- 26970000 TI - Germ Line Mechanics--And Unfinished Business. AB - Primordial germ cells are usually made early in the development of an organism. These are the mother of all stem cells that are necessary for propagation of the species, yet use highly diverse mechanisms between organisms. How they are specified, and when and where they form, are central to developmental biology. Using diverse organisms to study this development is illuminating for understanding the mechanics these cells use in this essential function and for identifying the breadth of evolutionary changes that have occurred between species. This essay emphasizes how echinoderms may contribute to the patchwork quilt of our understanding of germ line formation during embryogenesis. PMID- 26970002 TI - Segment Identity and Cell Segregation in the Vertebrate Hindbrain. AB - The subdivision of tissues into sharply demarcated regions with distinct and homogenous identity is an essential aspect of embryonic development. Along the anteroposterior axis of the vertebrate nervous system, this involves signaling which induces spatially restricted expression of transcription factors that specify regional identity. The spatial expression of such transcription factors is initially imprecise, with overlapping expression of genes that specify distinct identities, and a ragged border at the interface of adjacent regions. This pattern becomes sharpened by establishment of mutually exclusive expression of transcription factors, and by cell segregation that underlies formation of a straight border. In this review, we discuss studies of the vertebrate hindbrain which have revealed how discrete regional identity is established, the roles of Eph-ephrin signaling in cell segregation and border sharpening, and how cell identity and cell segregation are coupled. PMID- 26970003 TI - Positional Information and Pattern Formation. AB - The concept of positional information proposes that cells acquire positional values as in a coordinate system, which they interpret by developing in particular ways to give rise to spatial patterns. Some of the best evidence for positional information comes from regeneration experiments, and the patterning of the leg and antenna in Drosophila, and the vertebrate limb. Central problems are how positional information is set up, how it is recorded, and then how it is interpreted by the cells. A number of models have been proposed for the setting up of positional gradients, and most are based on diffusion of a morphogen and its interactions with extracellular molecules; however, diffusion may not be reliable mechanism. There are also mechanisms based on timing. There is no good evidence for the quantitative aspects of any of the proposed gradients and details how they are set up. The way in which a signaling gradient regulates differential gene expression in a concentration-dependent manner also raises several technical and quite difficult issues. A key feature of positional information being the basis for pattern formation is that there is no prepattern in the embryo. PMID- 26970004 TI - The Birth of Animal Development: Multicellularity and the Germline. AB - The evolution of multicellular animals has been attributed to many kinds of selective advantage; here I suggest that the evolution of somatic cells to feed and protect the germline was central to the appearance of animals. This would have been driven by selection for extreme anisogamy--the evolution of sperm and egg. Evidence is adduced from the germline stem cells of simple animals (defining germline as any cell that normally produces the next generation via the sexual process) and from the control circuitry ubiquitous in animal germlines. With the soma and its elaboration came animal development, as we understand it. PMID- 26970005 TI - Pli Selon Pli: Mechanochemical Feedback and the Morphogenetic Role of Contractility at Cadherin Cell-Cell Junctions. AB - Cellular contractility, driven by actomyosin networks coupled to cadherin cell cell adhesion junctions, is a major determinant of cellular rearrangement during morphogenesis. It now emerges that contractility arises as the emergent property of a mechanochemical feedback system that encompasses the signals that regulate contractility and the elements of the actomyosin network itself. PMID- 26970006 TI - From Endoderm to Liver Bud: Paradigms of Cell Type Specification and Tissue Morphogenesis. AB - The early specification, rapid growth and morphogenesis, and conserved functions of the embryonic liver across diverse model organisms have made the system an experimentally facile paradigm for understanding basic regulatory mechanisms that govern cell differentiation and organogenesis. This essay highlights concepts that have emerged from studies of the discrete steps of foregut endoderm development into the liver bud, as well as from modeling the steps via embryonic stem cell differentiation. Such concepts include understanding the chromatin basis for the competence of progenitor cells to develop into specific lineages; the importance of combinatorial signaling from different sources to induce cell fates; the impact of inductive signaling on preexisting chromatin states; the ability of separately specified domains of cells to merge into a common tissue; and the marked cell biological dynamics, including interactions with the developing vasculature, which establish the initial morphogenesis and patterning of a tissue. The principles gleaned from these studies, focusing on the 2 days it takes for the endoderm to develop into a liver bud, should be instructive for many other organogenic systems and for manipulating tissues in regenerative contexts for biomedical purposes. PMID- 26970007 TI - The Acquisition of Cell Fate in Mouse Development: How Do Cells First Become Heterogeneous? AB - Specification of cell fate in the early mouse embryo involves the generation of heterogeneities between cells in polarity, position, gene expression, and protein activity. Identifying when and how these differences first become established represents an important challenge for understanding the roles of stochastic and cell history-dependent mechanisms in mammalian development. PMID- 26970008 TI - Preface. PMID- 26970009 TI - FGF-2 deficiency causes dysregulation of Arhgef6 and downstream targets in the cerebral cortex accompanied by altered neurite outgrowth and dendritic spine morphology. AB - Fibroblast growth factor 2 (FGF-2) is an abundant growth factor in the brain and exerts multiple functions on neural cells ranging from cell division, cell fate determination to differentiation. However, many details of the molecular mechanisms underlying the diverse functions of FGF-2 are poorly understood. In a comparative microarray analysis of motor sensory cortex (MSC) tissue of adult knockout (FGF-2(-/-)) and control (FGF-2(+/+)) mice, we found a substantial number of regulated genes, which are implicated in cytoskeletal machinery dynamics. Specifically, we found a prominent downregulation of Arhgef6. Arhgef6 mRNA was significantly reduced in the FGF-2(-/-) cortex, and Arhgef6 protein virtually absent, while RhoA protein levels were massively increased and Cdc42 protein levels were reduced. Since Arhgef6 is localized to dendritic spines, we next analyzed dendritic spines of adult FGF2(-/-) and control mouse cortices. Spine densities were significantly increased, whereas mean length of spines on dendrites of layer V of MSC neurons in adult FGF-2(-/-) mice was significantly decreased as compared to respective controls. Furthermore, neurite length in dissociated cortical cultures from E18 FGF-2(-/-) mice was significantly reduced at DIV7 as compared to wildtype neurons. Despite the fact that altered neuronal morphology and alterations in dendritic spines were observed, FGF-2(-/-) mice behave relatively unsuspicious in several behavioral tasks. However, FGF-2(-/-) mice exhibited decreased thermal pain sensitivity in the hotplate-test. PMID- 26970011 TI - Impact of EUS-FNA for preoperative para-aortic lymph node staging in patients with pancreatobiliary cancer. AB - BACKGROUND AND AIMS: In patients with pancreatobiliary cancer, para-aortic lymph node (PALN) metastasis is considered to be the involvement beyond the regional lymph nodes, namely, distant metastasis. Effective methods for preoperative PALN staging, however, are not established. This study aimed to compare the diagnostic capability for PALN metastasis between EUS-FNA and (18)F-fluorodeoxyglucose positron emission tomography with CT (PET/CT). METHODS: We performed a prospective, nonrandomized, single-center trial. Between December 2010 and March 2014, 208 patients with pancreatobiliary cancer without apparent distant metastasis except for PALNs were assessed for study eligibility before surgery. Among them, 52 consecutive patients with PALN enlargement were enrolled in the study. (18)F-Fluorodeoxyglucose PET/CT and EUS-FNA were performed sequentially as a single combined procedure to evaluate PALN metastases. The primary outcome was to compare the diagnostic capability of EUS-FNA and PET/CT for PALN metastasis. RESULTS: Of 71 enlarged PALNs in the 52 patients, 30 (42.3%) were finally diagnosed as metastases in 21 patients (40.4%). Of the 21 patients with PALN metastases, preoperative EUS-FNA or PET/CT made a correct diagnosis in 20 (95.2%) or 12 (57.1%), respectively. EUS-FNA had higher sensitivity and specificity for the diagnosis of PALN metastasis (sensitivity, 96.7% [29/30]; 95% confidence interval, 82.2%-99.9%; specificity, 100% [39/39]; 95% confidence interval, 91.0% 100%) than PET/CT. CONCLUSIONS: EUS-FNA is superior to PET/CT for preoperative PALN staging in patients with pancreatobiliary cancer. Because of the clinical benefit of EUS-FNA to reduce unnecessary surgery, it should be part of the standard preoperative examination for patients with pancreatobiliary cancer. (UMIN clinical trials registry number: 000006408.). PMID- 26970013 TI - Salient body image concerns of patients with cancer undergoing head and neck reconstruction. AB - BACKGROUND: Patients with cancer undergoing head and neck reconstruction can experience significant distress from alterations in appearance and bodily functioning. We sought to delineate salient dimensions of body image concerns in this patient population preparing for reconstructive surgery. METHODS: Participants completed self-report questionnaires evaluating numerous aspects of body image. We used Bayesian factor analysis modeling methods to identify latent factors emerging from the data. RESULTS: We identified 2 latent factors: appearance distress and functional difficulties. The highest level of preoperative body image concerns were related to distress about appearance changes and its perceived social consequences. Appearance distress items displayed greater variability compared with functional difficulties. CONCLUSION: Appearance and functional changes to body image are important areas of concern for patients with head and neck cancer as they prepare for reconstructive surgery. Knowledge regarding specific body image issues can be used to guide psychosocial assessments and intervention to enhance patient care. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 1035-1042, 2016. PMID- 26970012 TI - Evaluation of the short- and long-term effectiveness and safety of fully covered self-expandable metal stents for drainage of pancreatic fluid collections: results of a Spanish nationwide registry. AB - BACKGROUND AND AIMS: Initial reports suggest that fully covered self-expandable metal stents (FCSEMSs) may be better suited for drainage of dense pancreatic fluid collections (PFCs), such as walled-off pancreatic necrosis. The primary aim was to analyze the effectiveness and safety of FCSEMSs for drainage of different types of PFCs in a large cohort. The secondary aim was to investigate which type of FCSEMS is superior. METHODS: This was a retrospective, noncomparative review of a nationwide database involving all hospitals in Spain performing EUS-guided PFC drainage. From April 2008 to August 2013, all patients undergoing PFC drainage with an FCSEMS were included in a database. The main outcome measurements were technical success, short-term (2 weeks) and long-term (6 months) effectiveness, adverse events, and need for surgery. RESULTS: The study included 211 patients (pseudocyst/walled-off pancreatic necrosis, 53%/47%). The FCSEMSs used were straight biliary (66%) or lumen-apposing (34%). Technical success was achieved in 97% of patients (95% confidence interval [CI], 93%-99%). Short-term- and long-term clinical success was obtained in 94% (95% CI, 89%-97%) and 85% (95% CI, 79%-89%) of patients, respectively. Adverse events occurred in 21% of patients (95% CI, 16%-27%): infection (11%), bleeding (7%), and stent migration and/or perforation (3%). By multivariate analysis, patient age (>58 years) and previous failed drainage were the most important factors associated with negative outcome. CONCLUSIONS: An FCSEMS is effective and safe for PFC drainage. Older patients with a history of unsuccessful drainage are more likely to fail EUS-guided drainage. The type of FCSEMS does not seem to influence patient outcome. PMID- 26970010 TI - Intra-axonal protein synthesis in development and beyond. AB - Proteins can be locally produced in the periphery of a cell, allowing a rapid and spatially precise response to the changes in its environment. This process is especially relevant in highly polarized and morphologically complex cells such as neurons. The study of local translation in axons has evolved from being primarily focused on developing axons, to the notion that also mature axons can produce proteins. Axonal translation has been implied in several physiological and pathological conditions, and in all cases it shares common molecular actors and pathways as well as regulatory mechanisms. Here, we review the main findings in these fields, and attempt to highlight shared principles. PMID- 26970015 TI - Kynurenine pathway metabolites and enzymes involved in redox reactions. AB - Oxido-reduction reactions are a fundamental part of the life due to support many vital biological processes as cellular respiration and glucose oxidation. In the redox reactions, one substance transfers one or more electrons to another substance. An important electron carrier is the coenzyme NAD+, which is involved in many metabolic pathways. De novo biosynthesis of NAD+ is through the kynurenine pathway, the major route of tryptophan catabolism, which is sensitive to redox environment and produces metabolites with redox capacity, able to alter biological functions that are controlled by redox-responsive signaling pathways. Kynurenine pathway metabolites have been implicated in the physiology process and in the physiopathology of many diseases; processes that also share others factors as dysregulation of calcium homeostasis, mitochondrial dysfunction, oxidative stress, inflammation and cell death, which impact the redox environment. This review examines in detail the available evidence in which kynurenine pathway metabolites participate in redox reactions and their effect on cellular redox homeostasis, since the knowledge of the main factors and mechanisms that lead to cell death in many neurodegenative disorders and other pathologies, such as mitochondrial dysfunction, oxidative stress and kynurenines imbalance, will allow to develop therapies using them as targets. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'. PMID- 26970014 TI - Treatment with an activator of hypoxia-inducible factor 1, DMOG provides neuroprotection after traumatic brain injury. AB - Traumatic brain injury (TBI) is one of the major cause of morbidity and mortality and it affects more than 1.7 million people in the USA. A couple of regenerative pathways including activation of hypoxia-inducible transcription factor 1 alpha (HIF-1alpha) are initiated to reduce cellular damage following TBI; however endogenous activation of these pathways is not enough to provide neuroprotection after TBI. Thus we aimed to see whether sustained activation of HIF-1alpha can provide neuroprotection and neurorepair following TBI. We found that chronic treatment with dimethyloxaloylglycine (DMOG) markedly increases the expression level of HIF-1alpha and mRNA levels of its downstream proteins such as Vascular endothelial growth factor (VEGF), Phosphoinositide-dependent kinase-1 and 4 (PDK1, PDK4) and Erythropoietin (EPO). Treatment of DMOG activates a major cell survival protein kinase Akt and reduces both cell death and lesion volume following TBI. Moreover, administration of DMOG augments cluster of differentiation 31 (CD31) staining in pericontusional cortex after TBI, which suggests that DMOG stimulates angiogenesis after TBI. Treatment with DMOG also improves both memory and motor functions after TBI. Taken together our results suggest that sustained activation of HIF-1alpha provides significant neuroprotection following TBI. PMID- 26970018 TI - SGIP1 alters internalization and modulates signaling of activated cannabinoid receptor 1 in a biased manner. AB - Many diseases of the nervous system are accompanied by alterations in synaptic functions. Synaptic plasticity mediated by the endogenous cannabinoid system involves the activation of the cannabinoid receptor 1 (CB1R). The principles of CB1R signaling must be understood in detail for its therapeutic exploration. We detected the Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 (SGIP1) as a novel CB1R partner. SGIP1 is functionally linked to clathrin-mediated endocytosis and its overexpression in animals leads to an energy regulation imbalance resulting in obesity. We report that SGIP1 prevents the endocytosis of activated CB1R and that it alters signaling via the CB1R in a biased manner. CB1R mediated G-protein activation is selectively influenced by SGIP1, beta-arrestin associated signaling is changed profoundly, most likely as a consequence of the prevention of the receptor's internalization elicited by SGIP1. PMID- 26970017 TI - Pharmacological characterization of EN-9, a novel chimeric peptide of endomorphin 2 and neuropeptide FF that produces potent antinociceptive activity and limited tolerance. AB - Mounting evidences indicate the functional interactions between neuropeptide FF (NPFF) and opioids, including the endogenous opioids. In the present work, EN-9, a chimeric peptide containing the functional domains of the endogenous opioid endomorphin-2 (EM-2) and NPFF, was synthesized and pharmacologically characterized. In vitro cAMP assay demonstrated that EN-9 was a multifunctional agonist of kappa-opioid, NPFF1 and NPFF2 receptors. In the mouse tail-flick test, intracerebroventricularly (i.c.v.) administration of EN-9 produced significant antinociception with an ED50 value of 13.44 nmol, which lasted longer than that of EM-2. In addition, EN-9 induced potent antinociception after both intravenous (i.v.) and subcutaneous (s.c.) injection. Furthermore, the experiments using the antagonists of opioid and NPFF receptors indicated that the central antinociception of EN-9 was mainly mediated by kappa-opioid receptor, independently on NPFF receptors. Notably, the central antinociception of EN-9 was not reduced over a period of 6 days repeated i.c.v. injection. Repeated i.c.v. administration of EN-9 with the NPFF1 and NPFF2 receptors antagonist RF9 resulted in a progressive loss of analgesic potency, consistent with the development of tolerance. Moreover, central administration of EN-9 induced the place conditioning aversion only at a high dose of 60 nmol, but not at low doses. At supraspinal level, only high dose of EN-9 (60 nmol, i.c.v.) inhibited gastrointestinal transit via NPFF receptors. Similarly, systemic administration of EN-9 also inhibited gastrointestinal transit at high doses (10 and 30 mg/kg, i.v.). Taken together, the multifunctional agonist of kappa-opioid and NPFF receptors EN-9 produced a potent, non-tolerance forming antinociception with limited side effects. PMID- 26970016 TI - The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: Possible relevance for treatment-resistant depression. AB - Major depression is a highly complex disabling psychiatric disorder affecting millions of people worldwide. Despite the availability of several classes of antidepressants, a substantial percentage of patients are unresponsive to these medications. A better understanding of the neurobiology of depression and the mechanisms underlying antidepressant response is thus critically needed. We previously reported that mice lacking CREB-regulated transcription coactivator 1 (CRTC1) exhibit a depressive-like phenotype and a blunted antidepressant response to the selective serotonin reuptake inhibitor fluoxetine. In this study, we similarly show that Crtc1(-/-) mice are resistant to the antidepressant effect of chronic desipramine in a behavioral despair paradigm. Supporting the blunted response to this tricyclic antidepressant, we found that desipramine does not significantly increase the expression of Bdnf and Nr4a1-3 in the hippocampus and prefrontal cortex of Crtc1(-/-) mice. Epigenetic regulation of neuroplasticity gene expression has been associated with depression and antidepressant response, and histone deacetylase (HDAC) inhibitors have been shown to have antidepressant like properties. Here, we show that unlike conventional antidepressants, chronic systemic administration of the HDAC inhibitor SAHA partially rescues the depressive-like behavior of Crtc1(-/-) mice. This behavioral effect is accompanied by an increased expression of Bdnf, but not Nr4a1-3, in the prefrontal cortex of these mice, suggesting that this epigenetic intervention restores the expression of a subset of genes by acting downstream of CRTC1. These findings suggest that CRTC1 alterations may be associated with treatment resistant depression, and support the interesting possibility that targeting HDACs may be a useful therapeutic strategy in antidepressant development. PMID- 26970019 TI - Interplay between ABA and GA Modulates the Timing of Asymmetric Cell Divisions in the Arabidopsis Root Ground Tissue. AB - In multicellular organisms, controlling the timing and extent of asymmetric cell divisions (ACDs) is crucial for correct patterning. During post-embryonic root development in Arabidopsis thaliana, ground tissue (GT) maturation involves an additional ACD of the endodermis, which generates two different tissues: the endodermis (inner) and the middle cortex (outer). It has been reported that the abscisic acid (ABA) and gibberellin (GA) pathways are involved in middle cortex (MC) formation. However, the molecular mechanisms underlying the interaction between ABA and GA during GT maturation remain largely unknown. Through transcriptome analyses, we identified a previously uncharacterized C2H2-type zinc finger gene, whose expression is regulated by GA and ABA, thus named GAZ (GA- AND ABA-RESPONSIVE ZINC FINGER). Seedlings ectopically overexpressing GAZ (GAZ-OX) were sensitive to ABA and GA during MC formation, whereas GAZ-SRDX and RNAi seedlings displayed opposite phenotypes. In addition, our results indicated that GAZ was involved in the transcriptional regulation of ABA and GA homeostasis. In agreement with previous studies that ABA and GA coordinate to control the timing of MC formation, we also confirmed the unique interplay between ABA and GA and identified factors and regulatory networks bridging the two hormone pathways during GT maturation of the Arabidopsis root. PMID- 26970020 TI - Trends and patterns of antidepressant use in children and adolescents from five western countries, 2005-2012. AB - Following the FDA black box warning in 2004, substantial reductions in antidepressant (ATD) use were observed within 2 years in children and adolescents in several countries. However, whether these reductions were sustained is not known. The objective of this study was to assess more recent trends in ATD use in youth (0-19 years) for the calendar years 2005/6-2012 using data extracted from regional or national databases of Denmark, Germany, the Netherlands, the United Kingdom (UK), and the United States (US). In a repeated cross-sectional design, the annual prevalence of ATD use was calculated and stratified by age, sex, and according to subclass and specific drug. Across the years, the prevalence of ATD use increased from 1.3% to 1.6% in the US data (+26.1%); 0.7% to 1.1% in the UK data (+54.4%); 0.6% to 1.0% in Denmark data (+60.5%); 0.5% to 0.6% in the Netherlands data (+17.6%); and 0.3% to 0.5% in Germany data (+49.2%). The relative growth was greatest for 15-19 year olds in Denmark, Germany and UK cohorts, and for 10-14 year olds in Netherlands and US cohorts. While SSRIs were the most commonly used ATDs, particularly in Denmark (81.8% of all ATDs), Germany and the UK still displayed notable proportions of tricyclic antidepressant use (23.0% and 19.5%, respectively). Despite the sudden decline in ATD use in the wake of government warnings, this trend did not persist, and by contrast, in recent years, ATD use in children and adolescents has increased substantially in youth cohorts from five Western countries. PMID- 26970021 TI - Glycosidases Interact Selectively With Mannose-6-Phosphate Receptors of Bull Spermatozoa. AB - Glycosidases may play a role in sperm maturation during epididymal transit. In this work, we describe the interaction of these enzymes with bull spermatozoa. We found that beta-galactosidase associated to spermatozoa can be released under low ionic strength conditions, whereas the interaction of N-acetyl-beta-D glucosaminidase and beta-glucuronidase with spermatozoa appeared to be stronger. On the other hand, alpha-mannosidase and alpha-fucosidase cannot be removed from the gametes. In addition, part of N-acetyl-beta-D-glucosaminidase, beta galactosidase, and beta-glucuronidase can also be released by mannose-6 phosphate. Taking into account these data, we explored the presence of cation independent- and cation-dependent-mannose-6-phosphate receptors in the spermatozoa and found that cation-independent mannose-6-phosphate receptor is highly expressed in bull spermatozoa and cation-dependent-mannose-6-phosphate receptor is expressed at a lesser extent. In addition, by immunofluorescence, we observed that cation-independent-mannose-6-phosphate receptor is mostly located at the acrosomal zone, whereas cation-dependent-mannose-6-phosphate receptor presents a different distribution pattern on spermatozoa during the epididymal transit. N-acetyl-beta-D-glucosaminidase and beta-glucuronidase isolated from epididymal fluid interacted mostly with cation-independent-mannose-6-phosphate receptor, while beta-galactosidase was recognized by both receptors. We concluded that glycosidases might play different roles in bull spermatozoa and that mannos 6-phosphate receptors may act as recruiters of some enzymes. J. Cell. Biochem. 117: 2464-2472, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26970022 TI - National trends and determinants of proton therapy use for prostate cancer: A National Cancer Data Base study. AB - BACKGROUND: In the current study, the authors sought to both characterize the national trends in proton therapy use for prostate cancer and determine the factors associated with receipt of this limited resource, using what to the best of their knowledge is the largest nationwide cancer registry. METHODS: The National Cancer Data Base was used to identify 187,730 patients diagnosed with nonmetastatic prostate cancer from 2004 through 2012 who received external beam radiotherapy as their initial form of definitive therapy. Multivariable logistic regression analysis adjusted for sociodemographic and clinical factors was used to identify independent determinants of proton therapy use. RESULTS: The rate of proton therapy use increased significantly from 2.3% in 2004 to 5.2% in 2011 and 4.8% in 2012 (P value for trend <.0001). Proton therapy for prostate cancer was much more likely to be delivered at an academic compared with nonacademic center and to patients who were white, younger, healthier, from metropolitan areas, from zip codes with higher median household incomes, and who did not have an advanced stage of or high-grade disease (all P<.0001). Compared with white patients, those who were black and Hispanic were found to be significantly less likely to receive proton therapy even after robust multivariable adjustments (adjusted odds ratio, 0.20 [95% confidence interval, 0.18-0.22; P<.0001] and adjusted odds ratio, 0.57 [95% confidence interval, 0.48-0.66; P<.0001], respectively). CONCLUSIONS: The use of proton therapy to treat patients with prostate cancer more than doubled from 2004 to 2012, with striking racial disparities in its use noted despite robust multivariable adjustments. Long-term follow-up is needed to determine whether the increased use of proton therapy for prostate cancer is justified, and ongoing efforts should be made to ensure equal access to resource-limited oncologic therapies. Cancer 2016;122:1505-12. (c) 2016 American Cancer Society. PMID- 26970023 TI - Unified principle of reinforcement in a neural-network model: Reply to N. T. Calvin and J. J. McDowell. AB - An article published in Behavioural Processes (Calvin and McDowell, 2015) contemplated that the approach to neural networks developed by the present authors cannot simulate certain behavioral findings, notably the Kamin blocking effect and successive conditioning. Here we demonstrate that these concerns are unwarranted as an overall characterization of the approach. In addition, several other more general issues identified in the target article are addressed as well. These include the determination of network architectures, the assignment-of credit problem, the potential for catastrophic interference, and the falsifiability of the model. PMID- 26970024 TI - Cellular and molecular mechanistic insight into the DNA-damaging potential of few layer graphene in human primary endothelial cells. AB - Despite graphene being proposed for a multitude of biomedical applications, there is a dearth in the fundamental cellular and molecular level understanding of how few-layer graphene (FLG) interacts with human primary cells. Herein, using human primary umbilical vein endothelial cells as model of vascular transport, we investigated the basic mechanism underlying the biological behavior of graphene. Mechanistic toxicity studies using a battery of cell based assays revealed an organized oxidative stress paradigm involving cytosolic reactive oxygen stress, mitochondrial superoxide generation, lipid peroxidation, glutathione oxidation, mitochondrial membrane depolarization, enhanced calcium efflux, all leading to cell death by apoptosis/necrosis. We further investigated the effect of graphene interactions using cDNA microarray analysis and identified potential adverse effects by down regulating key genes involved in DNA damage response and repair mechanisms. Single cell gel electrophoresis assay/Comet assay confirmed the DNA damaging potential of graphene towards human primary cells. PMID- 26970025 TI - Antibacterial effects of electrospun chitosan/poly(ethylene oxide) nanofibrous membranes loaded with chlorhexidine and silver. AB - To prevent percutaneous device associated infections (PDAIs), we prepared electrospun chitosan/poly(ethylene oxide) (PEO) nanofibrous membrane containing silver nanoparticles as an implantable delivery vehicle for the dual release of chlorhexidine and silver ions. We observed that the silver nanoparticles were distributed homogeneously throughout the fibers, and a fast release of chlorhexidine in 2days and a sustained release of silver ions for up to 28days. The antibacterial efficacy of the membranes against Staphylococcus aureus showed that the membranes exhibited an obvious inhibition zone upon loading with either chlorhexidine (20MUg or more per membrane) or AgNO3 (1 and 5wt% to polymer). Furthermore, long-term antibacterial effect up to 4days was verified using membranes containing 5wt% AgNO3. The results suggest that the membranes have strong potential to act as an active antibacterial dressing for local delivery of antibacterial agents to prevent PDAIs. PMID- 26970026 TI - Potential application of silver nanoparticles to control the infectivity of Rift Valley fever virus in vitro and in vivo. AB - In this work we have tested the potential antiviral activity of silver nanoparticles formulated as ArgovitTM against Rift Valley fever virus (RVFV). The antiviral activity of Argovit was tested on Vero cell cultures and in type-I interferon receptor deficient mice (IFNAR (-/-) mice) by two different approaches: (i) different dilutions of Argovit were added to previously infected cells or administrated to animals infected with a lethal dose of virus; (ii) virus was pre-incubated with different dilutions of Argovit before inoculation in mice or cells. Though the ability of silver nanoparticles to control an ongoing RVFV infection in the conditions tested was limited, the incubation of virus with Argovit before the infection led to a reduction of the infectivity titers both in vitro and in vivo. These results reveal the potential application of silver nanoparticles to control the infectivity of RVFV, which is an important zoonotic pathogen. PMID- 26970027 TI - In vitro and in vivo evaluation of functionalized chitosan-Pluronic micelles loaded with myricetin on glioblastoma cancer. AB - This study aimed to develop a novel polymeric carrier based on chitosan functionalized Pluronic P123/F68 micelles loaded with myricetin (MYR) to improve the therapeutic index of chemotherapy for glioblastoma cancer. Following characterization and assessment of the cellular uptake and antitumor effects of MYR-loaded micelles (MYR-MCs) in vitro, the acute toxicity, blood-brain barrier (BBB) translocation, brain uptake and biodistribution in vivo were assessed. The results demonstrated that MYR-MCs exhibited improved cellular uptake and antitumor activity compared to free MYR in vitro, with a significantly enhanced anticancer effect in vivo following efficient transport across the BBB. However, MYR-MCs did not affect the brain endothelial, barrier function, the liver, heart or kidneys. Furthermore, MYR-MCs altered the expression of apoptotic proteins, such as Bcl-2, BAD and BAX, in mice. In conclusion, MYR-MCs may be considered an effective and promising drug delivery system for glioblastoma treatment. PMID- 26970028 TI - Intracellular trafficking and exocytosis of a multi-component siRNA nanocomplex. AB - Despite the importance of siRNA delivery systems, understanding of their intracellular fate remains elusive. We recently developed a multi-component siRNA nanocomplex to deliver siRNA to hepatic stellate cells (HSCs). The objective of this study is to study post-internalization trafficking of this siRNA nanocomplex and its multiple components like siRNA, protamine, and streptavidin, in HSCs. After internalization, the nanocomplex entrapped in early endosomes undergoes three possible routes including endosomal escape, exocytosis, and entrapment in lysosomes. Significant amount of siRNA dissociates from the nanocomplex to exert silencing activity. After escaping from endosomes, protamine dissociates from the nanocomplex and stays inside the cytoplasm. Golgi complex plays an important role in exocytosis of the nanocomplex. We also demonstrate that exocytosis is one of the major reasons accounting for the transient silencing activity of nonviral siRNA delivery. Incorporation of exocytosis inhibitors in nonviral siRNA delivery systems may extend the silencing activity of siRNA. PMID- 26970029 TI - The antimicrobial activity of ZnO nanoparticles against Vibrio cholerae: Variation in response depends on biotype. AB - The potency of zinc oxide nanoparticles (NPs), with a core size of ~7-10nm, to inhibit cholera disease was investigated by demonstrating the effect on two biotypes (classical and El Tor) of O1 serogroup of Vibrio cholerae-El Tor was more susceptible both in planktonic and in biofilm forms. Interaction with ZnO NP results in deformed cellular architecture. Increased fluidity and depolarization of membrane, and protein leakage further confirmed the damages inflicted on Vibrio by NP. NP was shown to produce reactive oxygen species (ROS) and induce DNA damage. These results suggest that the antibacterial mechanism of ZnO action is most likely due to generation of ROS and disruption of bacterial membrane. The antimicrobial efficacy of NP has been validated in animal model. The synergistic action of NP and antibiotic suggests an alternative for the treatment of cholera. PMID- 26970030 TI - Quantitative pupillometry and transcranial Doppler measurements in patients treated with hypothermia after cardiac arrest. AB - BACKGROUND: Predicting outcome after cardiac arrest (CA) is particularly difficult when therapeutic hypothermia (TH) is used. We investigated the performance of quantitative pupillometry and transcranial Doppler (TCD) in this context. METHODS: This prospective observational study included 82 post-CA patients. Quantitative assessment of pupillary light reflex (PLR) and TCD measurements of the two middle cerebral arteries were performed at admission (day 1) and after 24h (day 2) during TH (33-35 degrees C) and sedation. Neurological outcome was assessed at 3 months using cerebral performance category (CPC) scores; patients were classified as having good (CPC 1-2) or poor (CPC 3-5) outcome. Prognostic performance was analyzed using area under the receiver operating characteristic curve (AUC-ROC). RESULTS: Patients with good outcome (n=27) had higher PLR amplitude than patients with poor outcome (n=55) both at day 1, 13% (10-18) (median, 25th-75th percentile) vs. 8% (2-11) (P<0.001), and at day 2, 17% (13-20) vs. 8% (5-13) (P<0.001), respectively. The AUC-ROC curves at days 1 and 2 were 0.76 (95% confidence interval [CI] 0.65-0.86) and 0.82 (95% CI 0.73-0.92), respectively. The best cut-off values of PLR amplitude to predict a 3 month poor outcome were <9% and <11%, respectively. A PLR amplitude of <7% at day 2 predicted a 3-month poor outcome with a specificity of 100% (95% CI 86-100) and a sensitivity of 42% (95% CI 28-58). No differences in TCD measurements were found between the two patient groups. CONCLUSION: PLR measurements might be informative in the prediction of outcome of post-CA patients even under sedation and hypothermia. PMID- 26970031 TI - Associations between gender and cardiac arrest outcomes in Pan-Asian out-of hospital cardiac arrest patients. AB - BACKGROUND: The incidence of out-of-hospital cardiac arrest (OHCA) in women is thought to be lower than that of men, with better outcomes in some Western studies. OBJECTIVES: This study aimed to investigate the effect of gender on OHCA outcomes in the Pan-Asian population. METHODOLOGY: This was a retrospective, secondary analysis of the Pan Asian Resuscitation Outcomes Study (PAROS) data between 2009 and 2012. We included OHCA cases which were presumed cardiac etiology, aged 18 years and above and resuscitation attempted by emergency medical services (EMS) systems. We used multi-level mixed-effects logistic regression models to account for the clustering effect of individuals within the country. Primary outcome was survival to hospital discharge. RESULTS: We included a total of 40,159 OHCA cases, 40% of which were women. We found that women were more likely to be older and have an initial non-shockable arrest rhythm; they were more likely to receive bystander cardio-pulmonary resuscitation (CPR). The univariate analysis showed that women were significantly less likely to have return of spontaneous circulation (ROSC) at scene or in the emergency department (ED), and had lower rates of survival-to-admission and discharge, and poorer overall and cerebral performance outcomes. There was however, no significant gender difference on outcomes after adjustment of other confounders. Women in the reproductive age group (age 18-44 years) were significantly more likely to have ROSC at scene or in the ED, higher rates of survival-to-admission and discharge, and have better overall and cerebral performance outcomes after adjustment for differences in baseline and pre-hospital factors. Menopausal women (age 55 years and above) were less likely to survive to admission after adjusting for other pre hospital characteristics but not after age adjustment. CONCLUSION: Differences in survival outcomes between reproductive and menopausal women highlight a need for further investigations into the plausible social, pathologic or hormonal basis. PMID- 26970032 TI - Chromate removal by surface-modified nanoscale zero-valent iron: Effect of different surface coatings and water chemistry. AB - This study investigated the correlation between the colloidal stability and reactivity of surface-modified nano zero-valent iron (SM-nZVI) as affected by the surface coating (i.e., polyacrylic acid [PAA] and starch) under various geochemical conditions. Generally, the colloidal stability of nZVI was enhanced with increasing loading of surface coating, while there is an optimum loading for the most efficient Cr(VI) removal by SM-nZVI. At lower loadings than the optimum loading, the surface coating could enhance the particle stabilization, facilitating the Cr(VI) reduction by providing more available surface sites. However, the over-loaded surface coating on the surface of nZVI particles decreased the Cr(VI) reduction due to the occupation of the reactive sites and the inhibition of the mass transfer of Cr(VI) ions from water to the particle surface by providing the electrostatic or steric repulsion. The effects of Ca(2+) ions or humic acid (HA) on the colloidal stability and reactivity of PAA-modified nZVI (P-nZVI) and starch-modified nZVI (S-nZVI) were examined. Differing stability behavior and reactivity were observed for different SM-nZVI. It was found that the presence of Ca(2+) or HA altered surface chemistry of SM-nZVI, the particle-particle interaction and the particle-contaminant interaction, and hence influencing the stability behavior and reactivity of the particles. PMID- 26970033 TI - Diffusiophoresis of a charged toroidal polyelectrolyte. AB - Considering recent application of concentration driven motion of charged nanoparticles in sensing technology, we model the diffusiophoresis of an isolated toroidal polyelectrolyte (PE) for the first time. Choosing an aqueous KCl solution for illustration, its behavior under various conditions is simulated by varying the double layer thickness, the size of toroid, and its softness and fixed charge density. We show that the behavior of the present PE can be different both quantitatively and qualitatively from that of the corresponding spherical PE. This arises from the competition of the hydrodynamic force and the electric force acting on a PE. The geometry and the nature of a PE can also influence appreciably its behavior, yielding complicated and interesting results. PMID- 26970034 TI - Elucidation of the binding sites of two novel Ru(II) complexes on bovine serum albumin. AB - Hyphenated mass spectrometry (MS) techniques have attained an important position in analysis of covalent and non-covalent interactions of metal complexes with peptides and proteins. The aim of the present study was to qualitatively and quantitatively determine ruthenium binding sites on a protein using tandem mass spectrometry and allied techniques, i.e. liquid chromatography (LC) and inductively coupled plasma optical emission spectrometry (ICP-OES). For that purpose, two newly synthesized Ru(II) complexes of a meridional geometry, namely mer-[Ru(4' Cl-tpy)(en)Cl](+) (1) and mer-[Ru(4' Cl-tpy)(dach)Cl](+) (2) (where 4' Cl-tpy=4'-chloro-2,2':6',2"-terpyridine, en=1,2-diaminoethane and dach=1,2 diaminocyclohexane), and bovine serum albumin were used. The binding of the complexes to the protein was investigated by means of size exclusion- and reversed phase-LC, ICP OES, matrix-assisted laser desorption ionization MS and MS/MS. Ruthenated peptide sequence and a binding target amino acid were revealed through accurate elucidation of MS/MS spectra. The results obtained in this study suggest a high binding capacity of the protein towards both complexes, with up to 5.77+/-0.14 and 6.95+/-0.43mol of 1 and 2 bound per mol of protein, respectively. The proposed binding mechanism for the selected complexes includes the release of Cl ligand, its replacement with water molecule and further coordination to electron donor histidine residue. PMID- 26970035 TI - Sleep Telemedicine: An Emerging Field's Latest Frontier. AB - There is a widening gap between sleep provider access and patient demand for it. An American Academy of Sleep Medicine position paper recently recognized sleep telemedicine as one tool to narrow that divide. We define the term sleep telemedicine as the use of sleep-related medical information exchanged from one site to another via electronic communications to improve a patient's health. Applicable data transfer methods include telephone, video, smartphone applications, and the Internet. Their usefulness for the treatment of insomnia and sleep-disordered breathing is highlighted. Sleep telemedicine programs range in complexity from telephone-based patient feedback systems to comprehensive treatment pathways incorporating real-time video, telephone, and the Internet. While large, randomized trials are lacking, smaller studies comparing telemedicine with in-person care suggest noninferiority in terms of patient satisfaction, adherence to treatment, and symptomatic improvement. Sleep telemedicine is feasible from a technological and quality-driven perspective, but cost uncertainties, complex reimbursement structures, and variable licensing rules remain significant challenges to its feasibility on a larger scale. As legislative reform pends, larger randomized trials are needed to elucidate impact on patient outcomes, cost, and health-care system accessibility. PMID- 26970036 TI - Socioeconomic differences in overweight and weight-related behaviors across adolescence and young adulthood: 10-year longitudinal findings from Project EAT. AB - Reducing socioeconomic disparities in weight-related health is a public health priority. The purpose of this paper was to examine 10-year longitudinal patterns in overweight and weight-related behaviors from adolescence to young adulthood as a function of family-level socioeconomic status (SES) and educational attainment. Project EAT (Eating and Activity in Teens and Young Adults) followed a diverse sample of 2287 adolescents from 1999 to 2009. Mixed-effects regression tested longitudinal trends in overweight, fast food, breakfast skipping, physical inactivity, and screen use by family-level SES. The influence of subsequent educational attainment in young adulthood was examined. Results revealed that the prevalence of overweight increased significantly from adolescence to young adulthood with the greatest change seen in those from low SES (mean change=30.7%, 95% CI=25.6%-35.9%) as compared to high SES families (mean change=21.7%, 95% CI=18.2%-25.1%). Behavioral changes from adolescence to young adulthood also differed by SES background; the prevalence of frequent fast food intake (>=3times/week) increased most dramatically in those from low SES (mean change=6%, 95% CI=0.5%-11%) as compared to high SES families (mean change=-1.2%, 95% CI=-5.2%-2.9%). Overall trends suggest that a higher educational attainment mitigates the negative impacts of a low SES background. These findings suggest that continued effort is needed to ensure that public health strategies addressing obesity and related behaviors reach adolescents and young adults from low SES backgrounds and do not contribute to widening socioeconomic gaps in weight-related health. PMID- 26970037 TI - Cigarette package inserts can promote efficacy beliefs and sustained smoking cessation attempts: A longitudinal assessment of an innovative policy in Canada. AB - BACKGROUND: In June 2012, Canada implemented new pictorial warnings on cigarette packages, along with package inserts with messages to promote response efficacy (i.e., perceived quitting benefits) and self-efficacy (i.e., confidence to quit). This study assessed smokers' attention toward warnings and inserts and its relationship with efficacy beliefs, risk perceptions and cessation at follow-up. METHODS: Data were analyzed in 2015 from a prospective online consumer panel of adult Canadian smokers surveyed every four months between September 2012 and September 2014. Generalized Estimating Equation models were estimated to assess associations between reading inserts, reading warnings and efficacy beliefs (self efficacy, response efficacy), risk perceptions, quit attempts of any length, and sustained quit attempts (i.e., 30days or more) at follow-up. Models adjusted for socio-demographics, smoking-related variables, and time-in-sample effects. RESULTS: Over the study period, reading warnings significantly decreased (p<0.0001) while reading inserts increased (p=0.004). More frequent reading of warnings was associated independently with stronger response efficacy (Boften/very often vs never=0.28, 95% CI: 0.11-0.46) and risk perceptions at follow-up (Boften/very often vs never=0.31, 95% CI: 0.06-0.56). More frequent reading of inserts was associated independently with stronger self-efficacy to quit at follow-up (Btwice or more vs none=0.30, 95% CI: 0.14-0.47), quit attempts (ORtwice or more vs none=1.68, 95% CI: 1.28-2.19), and sustained quit attempts (ORtwice or more vs none=1.48, 95% CI: 1.01-2.17). CONCLUSIONS: More frequent reading of inserts was associated with self-efficacy to quit, quit attempts, and sustained quitting at follow-up, suggesting that inserts complement pictorial HWLs. PMID- 26970038 TI - Perceptions of opportunities for physical activity in 28 European countries. AB - INTRODUCTION: This study examined the relationship between perceptions of opportunities for physical activity in the local area and physical activity levels in European adults. METHODS: Data for 20,673 adults aged 18-64 were taken from the representative Eurobarometer survey (wave 80.2, 2013) of 28 European Union (EU) countries. Achieving recommended levels of physical activity and Metabolic Equivalent of Task-minutes (MET-mins) per week was constructed from self-reports of frequency and duration of walking, moderate and vigorous physical activity. Relationships between these outcomes and perceptions of opportunities for physical activity in the local area were assessed using logistic and linear regressions as appropriate; trends in these perceptions were measured between 2002 and 2013. RESULTS: Respondents stating that their local area offers opportunities for physical activity were more likely to meet recommended levels of physical activity (Adjusted Odds Ratio [AOR]=1.56). Across all EU countries the percentage of people reporting that their local area offers these opportunities increased slightly between 2005 (71.4%) and 2013 (79.3%, p<0.001). Reporting that the local area offers opportunities for physical activity was associated with more moderate (17min/week) and vigorous (15min/week) physical activity and with 23 more minutes of walking per week. CONCLUSION: Perceptions of opportunities for physical activity in the local area were associated with increased levels of all types of physical activity. Despite small improvements in perceptions of opportunities in the local area over the past decade, a variety of further interventions will be required to reduce the disease burden resulting from low physical activity levels. PMID- 26970040 TI - Structure-function studies of the magnetite-biomineralizing magnetosome associated protein MamC. AB - Magnetotactic bacteria are Gram-negative bacteria that navigate along geomagnetic fields using the magnetosome, an organelle that consists of a membrane-enveloped magnetic nanoparticle. Magnetite formation and its properties are controlled by a specific set of proteins. MamC is a small magnetosome-membrane protein that is known to be active in iron biomineralization but its mechanism has yet to be clarified. Here, we studied the relationship between the MamC magnetite interaction loop (MIL) structure and its magnetite interaction using an inert biomineralization protein-MamC chimera. Our determined structure shows an alpha helical fold for MamC-MIL with highly charged surfaces. Additionally, the MamC MIL induces the formation of larger magnetite crystals compared to protein-free and inert biomineralization protein control experiments. We suggest that the connection between the MamC-MIL structure and the protein's charged surfaces is crucial for magnetite binding and thus for the size control of the magnetite nanoparticles. PMID- 26970041 TI - Stereoselective analysis of novel chiral fungicide pyrisoxazole in cucumber, tomato and soil under different application methods with supercritical fluid chromatography/tandem mass spectrometry. AB - Various new chiral pesticides have been registered and used in crop yields. However, few studies have focused on the environmental behavior of such new registered chiral compounds on the stereoisomer level. In this study, an effective and sensitive chiral analytical method was first developed to detect pyrisoxazole stereoisomers and then further applied to investigate the stereoselective dissipation in vegetables and soil using supercritical fluid chromatography/tandem triple quadrupole mass spectrometry. Optimal separation condition was achieved with IA column using CO2/MeOH (75:25) as mobile phase at 2.0 mL/min in 5 min, 35 degrees C and 2400 psi. The average recoveries in all of the matrices at four spiking levels ranged from 84.0% to 105.6%. Significant stereoselective dissipation was observed in cucumber and tomato under both application modes. (-) Pyrisoxazole A and (-) pyrisoxazole B were preferentially degraded in cucumber under foliar spraying mode. In contrast, (+) pyrisoxazole A and (-) pyrisoxazole B were preferentially degraded in cucumber under soil irrigation mode. (-) Pyrisoxazole A and (-) pyrisoxazole B were degraded faster than their antipodes in tomato under both application modes. However, no significant stereoselectivity was observed in soil. The results of this study could help facilitate more accurate risk assessments of pyrisoxazole. PMID- 26970042 TI - Effect of oxalic acid treatment on sediment arsenic concentrations and lability under reducing conditions. AB - Oxalic acid enhances arsenic (As) mobilization by dissolving As host minerals and competing for sorption sites. Oxalic acid amendments thus could potentially improve the efficiency of widely used pump-and-treat (P&T) remediation. This study investigates the effectiveness of oxalic acid on As mobilization from contaminated sediments with different As input sources and redox conditions, and examines whether residual sediment As after oxalic acid treatment can still be reductively mobilized. Batch extraction, column, and microcosm experiments were performed in the laboratory using sediments from the Dover Municipal Landfill and the Vineland Chemical Company Superfund sites. Oxalic acid mobilized As from both Dover and Vineland sediments, although the efficiency rates were different. The residual As in both Dover and Vineland sediments after oxalic acid treatment was less vulnerable to microbial reduction than before the treatment. Oxalic acid could thus improve the efficiency of P&T. X-ray absorption spectroscopy analysis indicated that the Vineland sediment samples still contained reactive Fe(III) minerals after oxalic acid treatment, and thus released more As into solution under reducing conditions than the treated Dover samples. Therefore, the efficacy of enhanced P&T must consider sediment Fe mineralogy when evaluating its overall potential for remediating groundwater As. PMID- 26970043 TI - Cadmium (II) removal mechanisms in microbial electrolysis cells. AB - Cadmium is a toxic heavy metal, causing serious environmental and human health problems. Conventional methods for removing cadmium from wastewater are expensive and inefficient for low concentrations. Microbial electrolysis cells (MECs) can simultaneously treat wastewater, produce hydrogen gas, and remove heavy metals with low energy requirements. Lab-scale MECs were operated to remove cadmium under various electric conditions: applied voltages of 0.4, 0.6, 0.8, and 1.0 V; and a fixed cathode potential of -1.0 V vs. Ag/AgCl. Regardless of the electric condition, rapid removal of cadmium was demonstrated (50-67% in 24 h); however, cadmium concentration in solution increased after the electric current dropped with depleted organic substrate under applied voltage conditions. For the fixed cathode potential, the electric current was maintained even after substrate depletion and thus cadmium concentration did not increase. These results can be explained by three different removal mechanisms: cathodic reduction; Cd(OH)2 precipitation; and CdCO3 precipitation. When the current decreased with depleted substrates, local pH at the cathode was no longer high due to slowed hydrogen evolution reaction (2H(+)+2e(-)->H2); thus, the precipitated Cd(OH)2 and CdCO3 started dissolving. To prevent their dissolution, sufficient organic substrates should be provided when MECs are used for cadmium removal. PMID- 26970039 TI - Validity of PROMIS physical function measured in diverse clinical samples. AB - OBJECTIVES: To evaluate the validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function measures using longitudinal data collected in six chronic health conditions. STUDY DESIGN AND SETTING: Individuals with rheumatoid arthritis (RA), major depressive disorder (MDD), back pain, chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), and cancer completed the PROMIS Physical Function computerized adaptive test or fixed length short form at baseline and at the end of clinically relevant follow-up intervals. Anchor items were also administered to assess change in physical function and general health. Linear mixed-effects models and standardized response means were estimated at baseline and follow-up. RESULTS: A total of 1,415 individuals participated (COPD n = 121; CHF n = 57; back pain n = 218; MDD n = 196; RA n = 521; cancer n = 302). The PROMIS Physical Function scores improved significantly for treatment of CHF and back pain patients but not for patients with MDD or COPD. Most of the patient subsamples that reported improvement or worsening on the anchors showed a corresponding positive or negative change in PROMIS Physical Function. CONCLUSION: This study provides evidence that the PROMIS Physical Function measures are sensitive to change in intervention studies where physical function is expected to change and able to distinguish among different clinical samples. The results inform the estimation of meaningful change, enabling comparative effectiveness research. PMID- 26970044 TI - Low temperature H2S removal with 3-D structural mesoporous molecular sieves supported ZnO from gas stream. AB - A series of 3-dimensional (3-D) structural mesoporous silica materials, SBA-16, MCM-48 and KIT-6, was synthesized and supported with different ZnO loadings (10, 20, 30, and 40 wt%) by the incipient wetness method to evaluate the performances on H2S removal at room temperature. These materials were characterized by N2 adsorption, XRD, and TEM to investigate their textural properties. All the ZnO loaded adsorbents exhibited the H2S removal capacity of bellow 0.1 ppmv. With the best ZnO loading percentage of 30 wt% on MCM-48 and KIT-6, 20 wt% on SBA-16 according to the results of breakthrough test, further increasing ZnO loading caused the decrease of the adsorption capacity due to the agglomeration of ZnO. Besides, the H2S adsorption capacities of the supports materials varied in the order of KIT-6>MCM-48>SBA-16, which was influenced primarily by their pore volume and pore size. With the largest pores in these 3-D arrangement materials, KIT-6 showed the best performance of supported material for ZnO, due to its retained superior physical properties as well as large pore diameter to allow faster gas solid interaction and huge pore volume to disperse ZnO on the surface of it. PMID- 26970045 TI - Oral administration of SR-110, a peroxynitrite decomposing catalyst, enhances glucose homeostasis, insulin signaling, and islet architecture in B6D2F1 mice fed a high fat diet. AB - Peroxynitrite has been implicated in type 2 diabetes and diabetic complications. As a follow-up study to our previous work on SR-135 (Arch Biochem Biophys 577 578: 49-59, 2015), we provide evidence that this series of compounds are effective when administered orally, and their mechanisms of actions extend to the peripheral tissues. A more soluble analogue of SR-135, SR-110 (from a new class of Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes) was orally administered for 2 weeks to B6D2F1 mice fed a high fat-diet (HFD). Mice fed a HFD for 4 months gained significantly higher body weights compared to lean diet-fed mice (52 +/- 1.5 g vs 34 +/- 1.3 g). SR-110 (10 mg/kg daily) treatment significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control or vehicle (peanut butter) group. SR-110 treatment enhanced insulin signaling in the peripheral organs, liver, heart, and skeletal muscle, and reduced lipid accumulation in the liver. Furthermore, SR-110 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration. These results suggest that a peroxynitrite decomposing catalyst is effective in improving glucose homeostasis and restoring islet morphology and beta-cell insulin content under nutrient overload. PMID- 26970046 TI - Prospective study of pathogens in asymptomatic travellers and those with diarrhoea: aetiological agents revisited. AB - Travellers' diarrhoea (TD) remains the most frequent health problem encountered by visitors to the (sub)tropics. Traditional stool culture identifies the pathogen in only 15% of cases. Exploiting PCR-based methods, we investigated TD pathogens with a focus on asymptomatic travellers and severity of symptoms. Pre- and post-travel stools of 382 travellers with no history of antibiotic use during travel were analysed with a multiplex quantitative PCR for Salmonella, Yersinia, Campylobacter, Shigella, Vibrio cholerae and five diarrhoeagenic Escherichia coli: enteroaggregative (EAEC), enteropathogenic (EPEC), enterotoxigenic (ETEC), enterohaemorrhagic (EHEC) and enteroinvasive (EIEC). The participants were categorized by presence/absence of TD during travel and on return, and by severity of symptoms. A pathogen was indentified in 61% of the asymptomatic travellers, 83% of those with resolved TD, and 83% of those with ongoing TD; 25%, 43% and 53% had multiple pathogens, respectively. EPEC, EAEC, ETEC and Campylobacter associated especially with ongoing TD symptoms. EAEC and EPEC proved more common than ETEC. To conclude, modern methodology challenges our perception of stool pathogens: all pathogens were common both in asymptomatic and symptomatic travellers. TD has a multibacterial nature, but diarrhoeal symptoms mostly associate with EAEC, EPEC, ETEC and Campylobacter. PMID- 26970047 TI - Is initial serum (1,3)-beta-d-glucan truly associated with mortality in patients with candidaemia? Authors' response. PMID- 26970048 TI - Three-year retrospective analysis of the incidence of Toxoplasma gondii infection in pregnant women living in the Greater Romagna Area (northeastern Italy). AB - The aim of this study was to assess the incidence of Toxoplasma gondii infection in a population of pregnant women living in the Romagna area of the Emilia Romagna region. From 1 January 2012 to 31 December 2014, 36 876 pregnant women were tested to evaluate the IgG- and IgM-specific anti-T. gondii response. The average incidence was 0.192%, underlining the need for an appropriate and active screening for toxoplasmosis during pregnancy. PMID- 26970049 TI - Functional and Photochemical Characterization of a Light-Driven Proton Pump from the Gammaproteobacterium Pantoea vagans. AB - Photoactive retinal proteins are widely distributed throughout the domains of the microbial world (i.e., bacteria, archaea, and eukarya). Here we describe three retinal proteins belonging to a phylogenetic clade with a unique DTG motif. Light induced decrease in the environmental pH and its inhibition by carbonyl cyanide m chlorophenylhydrazone revealed that these retinal proteins function as light driven outward electrogenic proton pumps. We further characterized one of these proteins, Pantoea vagans rhodopsin (PvR), spectroscopically. Visible spectroscopy and high-performance liquid chromatography revealed that PvR has an absorption maximum at 538 nm with the retinal chromophore predominantly in the all-trans form (>90%) under both dark and light conditions. We estimated the pKa values of the protonated Schiff base of the retinal chromophore and its counterion as approximately 13.5 and 2.1, respectively, by using pH titration experiments, and the photochemical reaction cycle of PvR was measured by time-resolved flash photolysis in the millisecond timeframe. We observed a blue-shifted and a red shifted intermediate, which we assigned as M-like and O-like intermediates, respectively. Decay of the M-like intermediate was highly sensitive to environmental pH, suggesting that proton uptake is coupled to decay of the M-like intermediate. From these results, we propose a putative model for the photoreaction of PvR. PMID- 26970050 TI - Increase in primary surgical treatment of T1 and T2 oropharyngeal squamous cell carcinoma and rates of adverse pathologic features: National Cancer Data Base. AB - BACKGROUND: There has been increasing interest in the primary surgical treatment of patients with early T classification (T1-T2) oropharyngeal squamous cell carcinoma (OPSCC), with the stated goal of de-escalating or avoiding adjuvant treatment. Herein, the authors sought to determine the degree to which this interest has translated into changes in practice patterns, and the rates of adverse postoperative pathologic features. METHODS: Patients with T1 to T2 OPSCC in the National Cancer Data Base who were treated from 2004 through 2013 were categorized as receiving primary surgical or primary radiation-based treatment. Trends in treatment selection and factors related to the selection of primary surgery were examined. The rates of adverse pathologic features including positive surgical margins, extracapsular spread (ECS), and advanced T and N classifications after surgery were analyzed. RESULTS: Of 8768 patients with T1 to T2 OPSCC, 68% underwent primary surgical treatment, increasing from 56% in 2004 to 82% in 2013 (P<.0001). The highest versus lowest volume hospitals treated 78% versus 59% of patients with primary surgery (odds ratio, 2.23; 95% confidence interval, 1.55-3.22 [P<.0001]). Higher lymph node classification was found to be predictive of lower rates of primary surgery, but the majority of patients with clinical N2/N3 disease underwent primary surgery. Among patients treated with surgery, positive surgical margins were present in 24% and ECS in 25% of patients. The rate of positive surgical margins decreased over time (P<.0001) and was observed less often at high-volume centers (P<.0001). Among candidates for single-modality therapy (those with clinical T1-T2/N0-N1 disease), 33% had positive surgical margins and/or ECS and 47% had at least 1 adverse feature (T3 T4 disease, N2-N3 disease, positive surgical margins, and/or ECS). CONCLUSIONS: Primary surgical treatment among patients with early T classification OPSCC has become more widespread. Cancer 2016;122:1523-32. (c) 2016 American Cancer Society. PMID- 26970052 TI - Engineering of Corynebacterium glutamicum to utilize methyl acetate, a potential feedstock derived by carbonylation of methanol with CO. AB - The possibilities to utilize one-carbon substrates (C1) like CO, methane and methanol have been explored as a cheap alternative feedstock in the biotechnology. For the first time, methyl acetate (MeOAc), which can be formed from carbonylation of methanol with CO, was demonstrated to be an alternative carbon source for the cell growth of Corynebacterium glutamicum as a model microbial cell factory. To do so, a carboxyl esterase activity was necessary to hydrolyze MeOAc to methanol and acetate. Although the wild-type has an unknown esterase activity to MeOAc, the activity was not high enough to grow from 270mM MeOAc as sole carbon source, reaching OD600 of 5.28+/-0.2 in 32h. Based on the literatures studied for the esterase, we chose three esterases (MekB of Pseudomonas veronii MEK700, AcmB of Gordonia sp. Strain TY-5, and Est of Pyrobaculum calidifontis VA1) and cloned into the wild-type. As a result, the recombinant C. glutamicum expressing the highly active MekB esterase (28.6+/ 0.77U/mg protein) showed complete degradation of MeOAc and utilization of acetate, resulting in OD600 of 16.5+/-0.02at 24h. In addition, the recombinant strain exhibited the rapid degradation of MeOAc to methanol and acetate in 2h under anaerobic condition. Therefore, MeOAc can be used as another C1-derived carbon source in the biotechnology. PMID- 26970051 TI - Employer reasons for failing to report eligible workers' compensation claims in the BLS survey of occupational injuries and illnesses. AB - BACKGROUND: Little research has been done to identify reasons employers fail to report some injuries and illnesses in the Bureau of Labor Statistics Survey of Occupational Injuries and Illnesses (SOII). METHODS: We interviewed the 2012 Washington SOII respondents from establishments that had failed to report one or more eligible workers' compensation claims in the SOII about their reasons for not reporting specific claims. Qualitative content analysis methods were used to identify themes and patterns in the responses. RESULTS: Non-compliance with OSHA recordkeeping or SOII reporting instructions and data entry errors led to unreported claims. Some employers refused to include claims because they did not consider the injury to be work-related, despite workers' compensation eligibility. Participant responses brought the SOII eligibility of some claims into question. CONCLUSION: Systematic and non-systematic errors lead to SOII underreporting. Insufficient recordkeeping systems and limited knowledge of reporting requirements are barriers to accurate workplace injury records. PMID- 26970053 TI - Complete genome sequence of Pseudoalteromonas rubra SCSIO 6842, harboring a putative conjugative plasmid pMBL6842. AB - Pseudoalteromonas is a genus of Gram-negative and is ubiquitously distributed in the ocean. Many Pseudoalteromonas species are capable of producing pigments, which can serve as an alternative source to replace synthetic pigments used in the food industry. Prodigiosins belong to a family of secondary metabolite characterized by a common pyrrolyl pyrromethane skeleton, and have been successfully applied to yogurt, milk and carbonated drinks as substitutes for synthetic additives. The strain Pseudoalteromonas rubra SCSIO 6842 can produce cycloprodigiosin and harbors a conjugative plasmid. Here we report the complete genome of P. rubra SCSIO 6842 for a better understanding of the molecular basis of cycloprodigiosin production and regulation. PMID- 26970054 TI - Genome-scale reconstruction of the Streptococcus pyogenes M49 metabolic network reveals growth requirements and indicates potential drug targets. AB - Genome-scale metabolic models comprise stoichiometric relations between metabolites, as well as associations between genes and metabolic reactions and facilitate the analysis of metabolism. We computationally reconstructed the metabolic network of the lactic acid bacterium Streptococcus pyogenes M49. Initially, we based the reconstruction on genome annotations and already existing and curated metabolic networks of Bacillus subtilis, Escherichia coli, Lactobacillus plantarum and Lactococcus lactis. This initial draft was manually curated with the final reconstruction accounting for 480 genes associated with 576 reactions and 558 metabolites. In order to constrain the model further, we performed growth experiments of wild type and arcA deletion strains of S. pyogenes M49 in a chemically defined medium and calculated nutrient uptake and production fluxes. We additionally performed amino acid auxotrophy experiments to test the consistency of the model. The established genome-scale model can be used to understand the growth requirements of the human pathogen S. pyogenes and define optimal and suboptimal conditions, but also to describe differences and similarities between S. pyogenes and related lactic acid bacteria such as L. lactis in order to find strategies to reduce the growth of the pathogen and propose drug targets. PMID- 26970055 TI - Evaluation of a virtual pet visit system with live video streaming of patient images over the Internet in a companion animal intensive care unit in the Netherlands. AB - OBJECTIVE: To evaluate the impact of a virtual pet visit system ("TelePet" System, TPS) on owners and staff of a companion animal ICU. DESIGN: Longitudinal interventional study (2010-2013). SETTING: Companion animal ICU at a university veterinary medical teaching hospital. STUDY POPULATIONS: Pet owners, ICU technicians. INTERVENTIONS: The introduction of the TPS, with live video streaming of patient images over the Internet, in a companion animal ICU. MEASUREMENTS AND MAIN RESULTS: Pet owners experienced TPS as a valuable extra service. Most TPS users (72.4%) experienced less anxiety and felt less need (40.4% of TPS users) to visit their hospitalized pet in person. Most users (83.5%) shared TPS access with their family. The introduction of the TPS did not improve overall owner satisfaction, except for the score on "quality of medical treatment." Seven of 26 indicators of owner satisfaction were awarded higher scores by TPS users than by TPS nonusers in the survey after the introduction of the system. However, the lack of randomization of owners might have influenced findings. The enthusiasm of the ICU technicians for the system was tempered by the negative feedback from a small number of owners. Nevertheless they recognized the value of the system for owners. The system was user friendly and ICU staff and TPS users experienced few technical problems. CONCLUSIONS: As veterinary healthcare is moving toward a more client-centered approach, a virtual pet visit system, such as TPS, is a relatively simple application that may improve the well being of most owners during the hospitalization of their pet. PMID- 26970056 TI - Thyroid endocrine disruption of azocyclotin to Xenopus laevis during metamorphosis. AB - Organotin compounds are ubiquitous contaminants that are frequently detected in the environment and in biota, which raises concern about their risk to wildlife and human health. In the present study, Nieuwkoop & Faber stage 51 Xenopus laevis tadpoles were exposed to different concentrations of azocyclotin (0, 0.02, 0.1 and 0.5MUg/L) for 21 days, during which time the tadpoles underwent morphological development. Exposure to azocyclotin caused an inhibitory effect on the pre metamorphic development of X. laevis (e.g., a shortened hind limb length). Azocyclotin induced an alteration of the triiodothyronine (T3) content, which indicated thyroid endocrine disruption. Real-time PCR was performed to examine the expression levels of the genes involved in the thyroid hormone (TH) signaling pathway. Significant down-regulation of the type 2 deiodinase gene was observed, which may be partially responsible for the decreased T3 concentrations. Furthermore, the expression of T3 responsive genes, including thyroid hormone receptor, basic transcription element binding protein, 2tromelysins-3 and matrix metalloproteinase 2, were down-regulated in tadpoles, suggesting that azocyclotin induced a decrease in the T3 contents and, in turn, affected the mRNA expression of downstream genes involved in multiple physiological responses. Chemical analysis showed that azocyclotin could accumulate in X. laevis after 21 days of exposure. In conclusion, the results of the present study showed that azocyclotin could alter the mRNA expression of genes involved in TH signaling as well as the thyroid hormone concentrations in X. laevis tadpoles, leading to endocrine disruption of thyroid system, and that azocyclotin had obvious inhibitory effects on X. laevis metamorphosis. PMID- 26970057 TI - Influence of MRP1 G1666A and GSTP1 Ile105Val genetic variants on the urinary and blood arsenic levels of Turkish smelter workers. AB - To understand the cellular mechanisms responsible for arsenic metabolism and transport pathways plays a fundamental role in order to prevent the arsenic induced toxicity. The effect of MRP1 G1666A and GSTP1 Ile105Val polymorphisms on blood and urinary arsenic levels were determined in 95 Turkish smelter workers. Blood and urinary arsenic concentrations were measured by GF-AAS with Zeeman correction and gene polymorphisms were investigated by PCR-RFLP method. The mean blood and urinary arsenic levels were 21.60+/-12.28MUg/L and 5.58+/-4.37MUg/L, respectively. A significant association between MRP1 1666A allele and urinary arsenic levels was found (p=0.001). GSTP1 Ile105Val polymorphism was detected not to be associated with either blood or urinary arsenic levels (p=0.384, p=0.440, respectively). Significant association was also detected between MRP1A( )/GSTP1Val(-) genotypes and urinary arsenic levels (p=0.001). This study suggested that MRP1 G1666A alone and, also, combined with GSTP1 Ile105Val were associated with inter-individual variations in urinary arsenic levels, but not with blood arsenic levels. PMID- 26970058 TI - Levels of dialkylphosphate metabolites in urine among general U.S. population. AB - Data from National Health and Nutrition Examination Survey for years 2003-2008 were used to study the factors that affect urinary levels of dialkylphosphate (DAP) metabolites in urine. Separate regression models were fitted for children aged 6-11 years, adolescents aged 12-19 years, and adults aged >=20 years. Specifically, DAP metabolites that were analyzed were: dimethylphosphate (DMP), diethylphosphate (DEP), dimethylthiophosphate (DMTP), and diethylthiophosphate (DETP). Males had statistically significantly lower adjusted levels than females for DMP for adolescents, for DEP for adults, for DMTP for both adolescents and adults, and for DETP for both children and adults. Nonsmokers had statistically significantly higher adjusted levels than smokers for DMTP for adolescents and for DMP and DMTP for adults. Exposure to second hand smoke at home was associated with relatively higher levels of DMP among children (p=0.01) but the reverse was found to be true for DMTP (p<0.01) among adolescents as well as adults (p=0.02). Children had higher levels of DMTP than both adolescents and adults (p<0.01) and higher levels of DETP than adolescents (p=0.02). Age was found to be negatively associated with the levels of DMTP (p=0.01) among children and positively associated (p<0.01) with the levels of all four metabolites among adults. PMID- 26970059 TI - Depletion of mitochondrial enzyme system in liver, lung, brain, stomach and kidney induced by benzo(a)pyrene. AB - Mitochondrial dysfunction has recently received considerable attention as it plays an important role in adult human pathology caused by various drugs, endogenous agents and environmental agents. Benzo(a)pyrene (BaP), is a ubiquitous environmental contaminant mainly derived from anthropogenic activity during incomplete combustion of organic materials from various sources. The present study aimed to evaluate the effects of benzo(a)pyrene (BaP) on mitochondrial enzymes in the multiple organs including liver, lung, brain, stomach and kidney. ICR mice were exposed to different doses of BaP (2.5, 5 and 10mg/kg body weight) through oral gavage and intraperitoneal injection treatment for 13 weeks consecutively. The induced mitochondrial damage in the examined organs was assayed in terms of significant increase in lipid peroxidation (LPO) and prominent decrease in antioxidant enzymes. Non enzymatic antioxidants and Krebs cycle's enzymes were also significantly decreased in mitochondria. Additionally, BaP induced the body growth retardation and decrease in relative liver weight, increase in relative lung, stomach, kidney and brain weights, and this was further certified through histopathological lesions. Liver and lungs were more prominently damaged by BaP. The mitochondrial depletion increased in BaP dose dependent manner. PMID- 26970061 TI - Does percutaneous tibial nerve stimulation improve global pelvic function in women with faecal incontinence? AB - AIM: Percutaneous tibial nerve stimulation (PTNS) is a minimally invasive treatment for faecal incontinence. Many patients with faecal incontinence have coexisting pelvic floor disorders such as urinary incontinence and vaginal symptoms. We utilized a pelvic floor assessment tool to analyse any effect of PTNS on global pelvic floor function. METHODS: Patients with faecal incontinence attending our institution who had failed to respond sufficiently to biofeedback were offered a course of PTNS. Patients underwent pre- and post-stimulation assessment with a validated electronic Personal Assessment Questionnaire - Pelvic Floor (ePAQ-PF) for pelvic floor disorders. Scores were compared to assess the effect of treatment on global pelvic floor function. RESULTS: During the study period pre- and post-stimulation ePAQ-PF data were available for 60 patients (55% of all patients starting PTNS). In this cohort there was a significant improvement in bowel continence, bowel related quality of life, irritable bowel syndrome and bowel evacuation with a large effect size for continence and bowel related quality of life. There was also a significant improvement in non-bowel related symptoms, including urinary pain and stress incontinence, urinary related quality of life and bowel related sexual function. Sixty-five per cent of those who answered the question reported improvement in global health after stimulation. CONCLUSION: For patients presenting with faecal incontinence, PTNS appears to have a positive effect on bowel related function in approximately two thirds of patients. However, for treatment responders, improvement appears to relate mainly to improvement in bowel related function rather than a global pelvic floor effect. PMID- 26970060 TI - Ulcerations on abdominal wound scar associated with aflibercept therapy. PMID- 26970062 TI - Prevalence of the geriatric syndromes and frailty in older men living in the community: The Concord Health and Ageing in Men Project. AB - AIM: To describe the age at which the geriatric syndromes and frailty become common in community-dwelling men. METHODS: The Concord Health and Ageing in Men Project involves a population-based sample of 1705 community-dwelling men aged 70 and over from a defined geographic region in Sydney. Data were obtained by physical performance tests, clinical examinations, and questionnaire to determine the prevalence of the following conditions by five-year age group. RESULTS: Poor mobility, recurrent falls, urinary incontinence, dementia and frailty phenotype were all uncommon (less than 10%) in men in their 70s, but the prevalence of each of these conditions exceeded 10% in men aged 85-89. The prevalence of Frailty Index-defined frailty, multimorbidity, polypharmacy and instrumental activities of daily living dependence was constantly high in all age groups. CONCLUSIONS: The different health-care needs of the 'old old' aged 85 years and older should be accounted for in health service planning. PMID- 26970063 TI - Pre-contamination of new gypsum wallboard with potentially harmful fungal species. AB - Gypsum wallboard is a popular building material, but is also very frequently overgrown by Stachybotrys chartarum after severe and/or undetected water damage. The purpose of this study was to determine whether Stachybotrys and other fungi frequently isolated from wet gypsum wallboard are already present in the panels directly from the factory. Surface-disinfected gypsum disks were wetted with sterile water, sealed, and incubated for 70 days. The results showed that Neosartorya hiratsukae (= Aspergillus hiratsukae) was the most dominant fungus on the gypsum wallboard followed by Chaetomium globosum and Stachybotrys chartarum. Our results suggest that these three fungal species are already embedded in the materials, presumably in the paper/carton layer surrounding the gypsum core, before the panels reach the retailers/building site. PMID- 26970066 TI - Mn2FeWO6: A New Ni3TeO6 -Type Polar and Magnetic Oxide. PMID- 26970071 TI - The role of religion in alcohol consumption and demand reduction in Muslim majority countries (MMC). PMID- 26970072 TI - Neuropathy in the spontaneously hypertensive rat: An electrophysiological and histological study. AB - INTRODUCTION: Hypertension is identified as a risk factor for development of polyneuropathy. In this study we examined nerve conduction and morphological alteration of peripheral nerves in spontaneously hypertensive rats (SHR). METHODS: Motor nerve conduction velocity (MNCV) in the sciatic-tibial nerve and sensory nerve conduction velocity (SNCV) in the sural nerve were measured. Pathological investigations included spinal cord, dorsal root ganglion, and hindlimb nerves in SHR and Wistar-Kyoto rats (WKY) aged 4-64 weeks. RESULTS: Blood pressure was significantly higher in SHR than WKY animals at 4 weeks and elevated further with aging. MNCV and SNCV were significantly slower in SHR compared with WKY after age 24 weeks. Prominent morphological changes in SHR nerves included axonal atrophy and myelin splitting. SHR also had endoneurial microangiopathy with reduplication of basement membrane. CONCLUSIONS: SHR showed slowed nerve conduction velocity and pathological abnormalities of hindlimb nerves. Sustained severe hypertension may cause axonal atrophy and endoneurial microangiopathy. Muscle Nerve 54: 756-762, 2016. PMID- 26970073 TI - Genome-wide identification and characterization of odorant-binding protein (OBP) genes in the malaria vector Anopheles sinensis (Diptera: Culicidae). AB - Anopheles sinensis is a major malaria vector. Insect odorant-binding proteins (OBPs) may function in the reception of odorants in the olfactory system. The classification and characterization of the An. sinensis OBP genes have not been systematically studied. In this study, 64 putative OBP genes were identified at the whole-genome level of An. sinensis based on the comparison between OBP conserved motifs, PBP_GOBP, and phylogenetic analysis with An. gambiae OBPs. The characterization of An. sinensis OBPs, including the motif's conservation, gene structure, genomic organization and classification, were investigated. A new gene, AsOBP73, belonging to the Plus-C subfamily, was identified with the support of transcript and conservative motifs. These An. sinensis OBP genes were classified into three subfamilies with 37, 15 and 12 genes in the subfamily Classic, Atypical and Plus-C, respectively. The genomic organization of An. sinensis OBPs suggests a clustered distribution across nine different scaffolds. Eight genes (OBP23-28, OBP63-64) might originate from a single gene through a series of historic duplication events at least before divergence of Anopheles, Culex and Aedes. The microsynteny analyses indicate a very high synteny between An. sinensis and An. gambiae OBPs. OBP70 and OBP71 earlier classified under Plus C in An. gambiae are recognized as belonging to the group Obp59a of the Classic subfamily, and OBP69 earlier classified under Plus-C has been moved to the Atypical subfamily in this study. The study established a basic information frame for further study of the OBP genes in insects as well as in An. sinensis. PMID- 26970075 TI - Predictors of patient satisfaction with inpatient hospital pain management across the United States: A national study. AB - Satisfactory pain management of hospitalized patients remains a national unmet need for the United States. Although prior research indicates that inpatient pain management may be improving nationally, not all populations of patients rate pain management as equally satisfactory. County-level predictors, such as demographics and population density, and hospital-level predictors (eg, hospital-bed number), are understudied determinants of pain management patient satisfaction. We created a multivariate regression model of pain management patient satisfaction scores as indicated by Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey results based on county and hospital level predictors. Number of hospital beds (beta = -0.16), percent foreign-born (beta = -0.16), and population density (beta = -0.08) most strongly predicted unfavorable ratings, whereas African American (beta = 0.23), white (beta= 0.23), and younger population (beta = 0.08) most strongly predicted favorable ratings. Greater attention should be placed on pain management in larger hospitals that serve foreign-born patients in population-dense areas. Journal of Hospital Medicine 2016;11:498-501. (c) 2016 Society of Hospital Medicine. PMID- 26970076 TI - Pomegranate-Inspired Design of Highly Active and Durable Bifunctional Electrocatalysts for Rechargeable Metal-Air Batteries. AB - Rational design of highly active and durable electrocatalysts for oxygen reactions is critical for rechargeable metal-air batteries. Herein, we report the design and development of composite electrocatalysts based on transition metal oxide nanocrystals embedded in a nitrogen-doped, partially graphitized carbon framework. Benefiting from the unique pomegranate-like architecture, the composite catalysts possess abundant active sites, strong synergetic coupling, enhanced electron transfer, and high efficiencies in the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). The Co3O4-based composite electrocatalyst exhibited a high half-wave potential of 0.842 V for ORR, and a low overpotential of only 450 mV at the current density of 10 mA cm(-2) for OER. A single-cell zinc-air battery was also fabricated with superior durability, holding great promise in the practical implementation of rechargeable metal-air batteries. PMID- 26970074 TI - Evidence for climate-driven synchrony of marine and terrestrial ecosystems in northwest Australia. AB - The effects of climate change are difficult to predict for many marine species because little is known of their response to climate variations in the past. However, long-term chronologies of growth, a variable that integrates multiple physical and biological factors, are now available for several marine taxa. These allow us to search for climate-driven synchrony in growth across multiple taxa and ecosystems, identifying the key processes driving biological responses at very large spatial scales. We hypothesized that in northwest (NW) Australia, a region that is predicted to be strongly influenced by climate change, the El Nino Southern Oscillation (ENSO) phenomenon would be an important factor influencing the growth patterns of organisms in both marine and terrestrial environments. To test this idea, we analyzed existing growth chronologies of the marine fish Lutjanus argentimaculatus, the coral Porites spp. and the tree Callitris columellaris and developed a new chronology for another marine fish, Lethrinus nebulosus. Principal components analysis and linear model selection showed evidence of ENSO-driven synchrony in growth among all four taxa at interannual time scales, the first such result for the Southern Hemisphere. Rainfall, sea surface temperatures, and sea surface salinities, which are linked to the ENSO system, influenced the annual growth of fishes, trees, and corals. All four taxa had negative relationships with the Nino-4 index (a measure of ENSO status), with positive growth patterns occurring during strong La Nina years. This finding implies that future changes in the strength and frequency of ENSO events are likely to have major consequences for both marine and terrestrial taxa. Strong similarities in the growth patterns of fish and trees offer the possibility of using tree-ring chronologies, which span longer time periods than those of fish, to aid understanding of both historical and future responses of fish populations to climate variation. PMID- 26970077 TI - Mixed vitiligo of Blaschko lines: a newly discovered presentation of vitiligo responsive to combination treatment. AB - Vitiligo, depigmenting disorder of the skin and mucous membranes, affects up to 1% of the population worldwide. It is classified into four major types: segmental, non-segmental, mixed, and unclassified type. Non-segmental vitiligo refers to non-dermatomal distribution of lesions, while dermatomal distribution of lesions is present in patients with segmental vitiligo. Segmental vitiligo can also follow Blaschko lines - pathways of epidermal cell migration and proliferation during the development of the fetus. Here, we present patient with segmental and non-segmental vitiligo following Blaschko lines with excellent therapeutic response to combined therapy. Prior to our report, a case of segmental and non-segmental vitiligo followed by Blaschko lines was never described, therefore we suggest the term "mixed vitiligo of Blaschko lines" to describe this entity. This is also a rare case in which 90% repigmentation was achieved in patient with segmental and nonsegmental vitiligo following Blaschko lines in only 2 months of combined therapy. PMID- 26970078 TI - Contribution of micro-motion to backside wear in a fixed bearing total knee arthroplasty. AB - This study seeks to identify important factors related to backside wear of tibial inserts in vivo and determine an appropriate wear model for backside wear. An IRB approved database was queried for tibial inserts of a single design from one manufacturer that exhibited evidence of rotatory motion on the backside of the polyethylene. These devices were measured for volumetric wear using a previously established protocol. Features including the change in locking lip width and measurement of micro-motion marks were used to describe the motion pattern. Volumetric wear and implant characteristics were compared using linear regressions by modeling wear theories suggested by Archard and Wang to determine the most appropriate model for backside wear. The Wang model showed that duration, adjusted sliding distance, and cross-shear index accounted for approximately 58% of the volumetric wear variation while adjusted sliding distance and duration in vivo accounted for approximately 35% of the volumetric wear variation in the Archard model. Patient weight (p = 0.750), patient BMI (p = 0.680), and backside area (p = 0.784) of the tibial insert were all found to be non-significant in the Wang model. Similarly, patient weight (p = 0.233), patient BMI (p = 0.162), and backside area (p = 0.796) were found to be non-significant in the Archard model. Multidirectional micro-motion appears to contribute significantly to the wear of these components, supporting the Wang theory of cross-shear for polyethylene wear. Cross-shear of polymers on an unpolished titanium tray can lead to an increase in wear debris in the body. Care should be taken when designing locking mechanisms and tray designs. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1933-1940, 2016. PMID- 26970079 TI - Hedgehog regulates yes-associated protein 1 in regenerating mouse liver. AB - Adult liver regeneration requires induction and suppression of proliferative activity in multiple types of liver cells. The mechanisms that orchestrate the global changes in gene expression that are required for proliferative activity to change within individual liver cells, and that coordinate proliferative activity among different types of liver cells, are not well understood. Morphogenic signaling pathways that are active during fetal development, including Hedgehog and Hippo/Yes-associated protein 1 (Yap1), regulate liver regeneration in adulthood. Cirrhosis and liver cancer result when these pathways become dysregulated, but relatively little is known about the mechanisms that coordinate and control morphogenic signaling during effective liver regeneration. We evaluated the hypothesis that the Hedgehog pathway controls Yap1 activation during liver regeneration by studying intact mice and cultured liver cells. In cultured hepatic stellate cells (HSCs), disrupting Hedgehog signaling blocked activation of Yap1, and knocking down Yap1 inhibited induction of both Yap1- and Hedgehog-regulated genes that enable HSC to become myofibroblasts (MFs). In mice, disrupting Hedgehog signaling in MFs inhibited liver regeneration after partial hepactectomy (PH). Reduced proliferative activity in the liver epithelial compartment resulted from loss of stroma-derived paracrine signals that activate Yap1 and the Hedgehog pathway in hepatocytes. This prevented hepatocytes from up regulating Yap1- and Hedgehog-regulated transcription factors that normally promote their proliferation. CONCLUSIONS: Morphogenic signaling in HSCs is necessary to reprogram hepatocytes to regenerate the liver epithelial compartment post-PH. This discovery identifies novel molecules that might be targeted to correct defective repair during cirrhosis and liver cancer. (Hepatology 2016;64:232-244). PMID- 26970082 TI - Temperature homeostasis in mice lacking the p43 mitochondrial T3 receptor. AB - Thyroid hormones and Thra gene play a key role in energy expenditure regulation, temperature homeostasis, and mitochondrial function. To decipher the function of the mitochondrial TRalpha receptor in these phenomena, we used mice lacking specifically the p43 mitochondrial T3 receptor. We found that these animals were hypermetabolic, hyperphagic, and displayed a down setting of the core body temperature. However, p43-/- animals do not present cold intolerance or defect of facultative thermogenesis. In addition, the mitochondrial function of BAT is slightly affected in the absence of p43. Our study, therefore, suggests a complementarity of action between the mitochondrial receptor and other proteins encoded by the Thra gene in the control of basal metabolism, facultative thermogenesis, and determination of the set point of temperature regulation. PMID- 26970081 TI - Cardiovascular Implantable Electronic Device Infections due to Propionibacterium Species. AB - INTRODUCTION: Propionibacterium species are part of the normal skin flora and often considered contaminants when identified in cultures. However, they can cause life-threatening infections, including prosthetic cardiovascular device infections. Clinical presentation and management of cardiovascular implantable electronic device (CIED) infection due to Propionibacterium species has not been well described. METHODS: Retrospective review of all cases of CIED infection due to Propionibacterium species admitted to Mayo Clinic between January 1, 1990 and December 31, 2014. Patient charts were reviewed for clinical, microbiological, and imaging data. Descriptive analysis was performed. RESULTS: We identified 14 patients with CIED infection due to Propionibacterium species, accounting for 2.3% of all CIED infections. Patients were predominantly male (n = 12, 86%). The median age at admission was 58.5 years (range 22-83). Twelve patients had implantable cardioverter defibrillators (ICDs) and two had permanent pacemaker systems. Twelve patients had generator pocket infection (86%). Two patients met clinical criteria for CIED-related infective endocarditis. Median time between last device manipulation and infection was 9 months (range 1-98). All patients were treated with complete device removal and antibiotic therapy. Six-month follow-up data were available for 10 patients (71%), with no relapses documented. CONCLUSION: CIED infections due to Propionibacterium species accounted for 2.3% of all device infections over a 25-year period. The most common infectious syndrome was generator pocket infection with delayed onset. There was an unanticipated predominance of ICDs in this cohort. Cure was achieved in all cases with complete device removal and antibiotic therapy. PMID- 26970083 TI - A high rate of telomeric sister chromatid exchange occurs in chronic lymphocytic leukaemia B-cells. AB - Cancer cells protect their telomere ends from erosion through reactivation of telomerase or by using the Alternative Lengthening of Telomere (ALT) mechanism that depends on homologous recombination. Chronic lymphocytic leukaemia (CLL) B cells are characterized by almost no telomerase activity, shelterin deregulation and telomere fusions. To characterize telomeric maintenance mechanisms in B-CLL patients, we measured their telomere length, telomerase expression and the main hallmarks of the ALT activity i.e. C-circle concentration, an extra-chromosomal telomere repeat (ECTR), and the level of telomeric sister chromatid exchange (T SCE) rate. Patients showed relative homogenous telomere length although almost no TERT transcript and nearly no C-circle were evidenced. Nevertheless, compared with normal B cells, B-CLL cells showed an increase in T-SCE rate that was correlated with a strong down-regulation of the topoisomerase III alpha (TOP3A) expression, involved in the dissolution of Holliday Junctions (HJ), together with an increased expression of SLX1A, SLX4, MUS81 and GEN1, involved in the resolution of HJ. Altogether, our results suggest that the telomere maintenance mechanism of B-CLL cells do not preferentially use telomerase or ALT. Rather, the rupture of the dissolvasome/resolvasome balance may increase telomere shuffling that could homogenize telomere length, slowing telomere erosion in this disease. PMID- 26970080 TI - Does modulation of the endocannabinoid system have potential therapeutic utility in cerebellar ataxia? AB - Cerebellar ataxias represent a spectrum of disorders which are, however, linked by common symptoms of motor incoordination and typically associated with deficiency in Purkinje cell firing activity and, often, degeneration. Cerebellar ataxias currently lack a curative agent. The endocannabinoid (eCB) system includes eCB compounds and their associated metabolic enzymes, together with cannabinoid receptors, predominantly the cannabinoid CB1 receptor (CB1 R) in the cerebellum; activation of this system in the cerebellar cortex is associated with deficits in motor coordination characteristic of ataxia, effects which can be prevented by CB1 R antagonists. Of further interest are various findings that CB1 R deficits may also induce a progressive ataxic phenotype. Together these studies suggest that motor coordination is reliant on maintaining the correct balance in eCB system signalling. Recent work also demonstrates deficient cannabinoid signalling in the mouse 'ducky(2J) ' model of ataxia. In light of these points, the potential mechanisms whereby cannabinoids may modulate the eCB system to ameliorate dysfunction associated with cerebellar ataxias are considered. PMID- 26970084 TI - In Situ Observation of Thiol Michael Addition to a Reversible Covalent Drug in a Crystalline Sponge. AB - A reversible Michael addition reaction between thiol nucleophiles and cyanoenones has been previously postulated to be the mechanism-of-action of a new family of reversible covalent drugs. However, the hypothetical Michael adducts in this mechanism have only been detected by spectroscopic methods in solution. Herein, the crystallographic observation of reversible Michael addition with a potent cyanoenone drug candidate by means of the crystalline-sponge method is reported. After inclusion of the cyanoenone substrate, the sponge crystal was treated with a thiol solution. Subsequent crystallographic analysis confirmed the single crystal-to-single-crystal transformation of the substrate into the impermanent Michael adduct. PMID- 26970085 TI - Mechanism of pancreatic and liver malformations in human fetuses with short-rib polydactyly syndrome. AB - BACKGROUND: The short-rib polydactyly (SRP) syndromes are rare skeletal dysplasias caused by abnormalities in primary cilia, sometimes associated with visceral malformations. METHODS: The pathogenesis of ductal plate malformation (DPM) varies in different syndromes and has not been investigated in SRP. We have studied liver development in five SRP fetuses and pancreatic development in one SRP fetus, with genetically confirmed mutations in cilia related genes, with and without DPMs, using the immunoperoxidase technique, and compared these to other syndromes with DPM. RESULTS: Acetylated tubulin expression was abnormal in DPM in SRP, Meckel syndrome, and autosomal recessive polycystic kidney disease (ARPKD), confirming ciliary anomalies. SDF-1 was abnormally expressed in SRP and two of three cases of autosomal dominant polycystic kidney disease (ADPKD) but not ARPKD or Meckel. Increased density of quiescent hepatic stellate cells was seen in SRP, Meckel, one of three cases of ARPKD, and two of three cases of ADPKD with aberrant hepatocyte expression of keratin 19 in SRP and ADPKD. Immunophenotypic abnormalities were present even in fetal liver without fully developed DPMs. The SRP case with DPM and pancreatic malformations showed abnormalities in the pancreatic head (influenced by mesenchyme from the septum transversum, similar to liver) but not pancreatic body (influenced by mesenchyme adjacent to the notochord). CONCLUSION: In SRP, there are differentiation defects of hepatocytes, cholangiocytes, and liver mesenchyme and, in rare cases, pancreatic mesenchymal anomalies. The morphological changes were subtle in early gestation but immunophenotypic abnormalities were present. Mesenchymal-epithelial interactions may contribute to the malformations. Birth Defects Research (Part A) 106:549-562, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26970086 TI - Effect of obesity on periodontal attachment loss progression: a 5-year population based prospective study. AB - AIM: The aim of this study was to assess the effect of overweight and obesity on periodontal attachment loss (PAL) progression in an urban population from south Brazil. METHODS: In 2001, a population-based oral health survey entitled "Epidemiology of periodontal diseases: the Porto Alegre Study" was conducted by drawing a probabilistic sample of 1586 individuals. After 5 years, 755 (participation rate: 47.6%) individuals were re-examined. For this analysis, self reported diabetics, underweight individuals, and individuals with <6 teeth were excluded. Poisson regressions were used to calculate relative risks (RR) and 95% confidence intervals (CI) adjusted for sex, age, skin colour, education, socio economic status, smoking and dental care. RESULTS: Five hundred and eighty-two individuals (333 males/249 females, 36.02 +/- 14.97 years) were included. Overall, obese individuals had significantly higher risk of experiencing PAL progression than individuals with normal weight after adjusting for important co factors (RR = 1.36, 95% CI = 1.04-1.78). In a stratified analysis, no statistically significant associations were observed between PAL progression and obesity for males (RR = 1.13, 95% CI = 0.75-1.69), whereas obese females were at statistically significant higher risk than normal weight females (RR = 1.64, 95% CI = 1.11-2.43). CONCLUSION: Obesity appears to be a risk factor for PAL progression for females but not males in this developing country population. PMID- 26970087 TI - Development of algorithms based on serum markers and transient elastography for detecting significant fibrosis and cirrhosis in chronic hepatitis B patients: Significant reduction in liver biopsy. AB - AIM: To develop algorithms for detecting significant fibrosis and cirrhosis in chronic hepatitis B (CHB) patients with the aim of reducing unwarranted liver biopsy. METHODS: For 307 CHB patients, the aspartate aminotransferase-to-platelet ratio index (APRI), the fibrosis index based on four factors (FIB-4), and the result of transient elastography with FibroScan (FS) were obtained when a liver biopsy was carried out. All patients were classified based on APRI or FIB-4 score and further assessed by FS results. Patients who remained unclassified after two steps of evaluation were considered to need liver biopsy. RESULTS: Algorithm implementation found that APRI + FS significantly lowered the requirement for liver biopsy for the detection of significant fibrosis compared to either individual APRI or FS screening (65.1% vs 75.9% or 78.5%, P = 0.003 or <0.001, respectively). The combination of FIB-4 + FS significantly reduced the need for liver biopsy compared to single FIB-4 or FS (58.3% vs 67.4% or 78.5%, P = 0.019 or <0.001, respectively). The FIB-4 + FS algorithm also reduced the need for liver biopsy for detection of significant fibrosis in patients >=50 years old compared to APRI + FS (22.6% vs 56.5%, P < 0.001), with a relatively lower accuracy (83.9% vs 98.4%, P = 0.004). Only 3.6% or 1.3% of patients needed liver biopsy for diagnosis of cirrhosis after screening with APRI + FS or FIB-4 + FS, respectively. CONCLUSION: The APRI + FS and FIB-4 + FS algorithms could significantly reduce the need for liver biopsy with high accuracy, sensitivity, and positive predictive value for diagnosis of significant fibrosis and cirrhosis in CHB patients. PMID- 26970089 TI - Effects of age and insulin-like growth factor-1 on rat neurotrophin receptor expression after nerve injury. AB - INTRODUCTION: Neurotrophin receptors, such as p75(NTR) , direct neuronal response to injury. Insulin-like growth factor-1 receptor (IGF-1R) mediates the increase in p75(NTR) during aging. The aim of this study was to examine the effect of aging and insulin-like growth factor-1 (IGF-1) treatment on recovery after peripheral nerve injury. METHODS: Young and aged rats underwent tibial nerve transection with either local saline or IGF-1 treatment. Neurotrophin receptor mRNA and protein expression were quantified. RESULTS: Aged rats expressed elevated baseline IGF-1R (34% higher, P = 0.01) and p75(NTR) (68% higher, P < 0.01) compared with young rats. Post-injury, aged animals expressed significantly higher p75(NTR) levels (68.5% above baseline at 4 weeks). IGF-1 treatment suppressed p75(NTR) gene expression at 4 weeks (17.2% above baseline, P = 0.002) post-injury. CONCLUSIONS: Local IGF-1 treatment reverses age-related declines in recovery after peripheral nerve injuries by suppressing p75(NTR) upregulation and pro-apoptotic complexes. IGF-1 may be considered a viable adjuvant therapy to current treatment modalities. Muscle Nerve 54: 769-775, 2016. PMID- 26970088 TI - Rare EN1 Variants and Pediatric Bone Mass. AB - A recent whole-genome sequencing study in search of variation associated with adult areal bone mineral density (aBMD) identified rare variants near EN1, with markedly large effect sizes, and a common variant near SOX6. To understand the developmental effects of these loci, we sought to determine if they were associated with pediatric dual-energy X-ray absorptiometry-derived aBMD and bone mineral content (BMC) and if the associations were modified by sex. Our sample comprised 733 females and 685 males of European ancestry enrolled in the longitudinal Bone Mineral Density in Childhood Study (up to 7 annual study visits). Sex- and age-specific Z-scores, adjusted for height, were calculated for the total hip, femoral neck, spine, and distal radius. Total body less head (TBLH) BMC Z-scores were also calculated. The previously reported single nucleotide polymorphisms (SNPs) near EN1 and SOX6 were derived from our imputed data set. Linear mixed-effects models were used to test associations between each SNP and bone Z-scores, plus interactions with sex were explored. The rare T allele of lead EN1 SNP rs11692564 was associated with higher aBMD Z-score for total hip (beta = 0.62, p = 9.0 * 10(-4) ) and femoral neck (beta = 0.53, p = 0.010). In sex-stratified analyses, this variant was associated with higher bone Z-scores in females only, with the associations being strongest for total hip (sex interaction p = 1.9 * 10(-4) ; beta females = 0.86, p = 6.6 * 10(-6) ) and femoral neck (sex interaction p = 0.016; beta females = 0.73, p = 0.001). The common G allele of SOX6 SNP rs11024028 was associated with higher aBMD Z-score for total hip (beta = 0.12, p = 0.009), femoral neck (beta = 0.13, p = 0.003), and TBLH-BMC (beta = 0.09, p = 0.007); furthermore, this association strengthened in males in the sex-stratified analyses. Our findings reveal that rare genetic variation near EN1 and common variation near SOX6 operates in childhood and has implications for the lifelong risk of osteoporosis and fracture. The sex differences observed need to be independently replicated. (c) 2016 American Society for Bone and Mineral Research. PMID- 26970091 TI - Physical Activity, Exercise Motivations, Depression, and Nonsuicidal Self-Injury in Youth. AB - This study explored the relationship between physical activity, depression, and nonsuicidal self-injury (NSSI) in 167 high school and undergraduate students (mean age = 17.37, range 14-25). Results indicated that NSSI frequency had a significant negative relationship with physical activity, and physical activity moderated the relationship between depressive symptoms and self-harm. Specifically, high levels of depressive symptoms and low levels of physical activity had the greatest frequency of NSSI. Lastly, appearance-based exercise motivations were significantly related to increased frequencies of NSSI. Overall, physical activity may possess a protective nature against NSSI, especially in individuals with depressive symptoms. PMID- 26970090 TI - Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. AB - We tested the hypothesis that supplementation of nicotinamide mononucleotide (NMN), a key NAD(+) intermediate, increases arterial SIRT1 activity and reverses age-associated arterial dysfunction and oxidative stress. Old control mice (OC) had impaired carotid artery endothelium-dependent dilation (EDD) (60 +/- 5% vs. 84 +/- 2%), a measure of endothelial function, and nitric oxide (NO)-mediated EDD (37 +/- 4% vs. 66 +/- 6%), compared with young mice (YC). This age-associated impairment in EDD was restored in OC by the superoxide (O2-) scavenger TEMPOL (82 +/- 7%). OC also had increased aortic pulse wave velocity (aPWV, 464 +/- 31 cm s( 1) vs. 337 +/- 3 cm s(-1) ) and elastic modulus (EM, 6407 +/- 876 kPa vs. 3119 +/ 471 kPa), measures of large elastic artery stiffness, compared with YC. OC had greater aortic O2- production (2.0 +/- 0.1 vs. 1.0 +/- 0.1 AU), nitrotyrosine abundance (a marker of oxidative stress), and collagen-I, and reduced elastin and vascular SIRT1 activity, measured by the acetylation status of the p65 subunit of NFkappaB, compared with YC. Supplementation with NMN in old mice restored EDD (86 +/- 2%) and NO-mediated EDD (61 +/- 5%), reduced aPWV (359 +/- 14 cm s(-1) ) and EM (3694 +/- 315 kPa), normalized O2- production (0.9 +/- 0.1 AU), decreased nitrotyrosine, reversed collagen-I, increased elastin, and restored vascular SIRT1 activity. Acute NMN incubation in isolated aortas increased NAD(+) threefold and manganese superoxide dismutase (MnSOD) by 50%. NMN supplementation may represent a novel therapy to restore SIRT1 activity and reverse age-related arterial dysfunction by decreasing oxidative stress. PMID- 26970092 TI - Better way to measure ageing in East Asia that takes life expectancy into account. AB - AIM: The aim of the study was to improve the measurement of ageing taking into account characteristics of populations and in particular changes in life expectancy. METHOD: Using projected life tables, we calculated prospective old age dependency ratios (POADRs) to 2060, placing the boundary to old age at a moving point with a fixed remaining life expectancy (RLE) for all countries of East Asia. RESULTS: POADRs grow less rapidly than old age dependency ratios (OADRs). For example, in the Republic of Korea, the OADR is forecast to increase from around 0.1 in 1980 to around 0.8 in 2060, while the POADR is forecast to increase from around 0.1 to 0.4 over the same period. CONCLUSION: Policy makers may wish to take into account the fact that the increases in measures of ageing will be slower when those measures are adjusted for changes in life expectancy. PMID- 26970093 TI - Estimating absolute-phase maps using ESPIRiT and virtual conjugate coils. AB - PURPOSE: To develop an ESPIRiT-based method to estimate coil sensitivities with image phase as a building block for efficient and robust image reconstruction with phase constraints. THEORY AND METHODS: ESPIRiT is a new framework for calibration of the coil sensitivities and reconstruction in parallel magnetic resonance imaging. Applying ESPIRiT to a combined set of physical and virtual conjugate coils (VCC-ESPIRiT) implicitly exploits conjugate symmetry in k-space similar to VCC-GRAPPA. Based on this method, a new post-processing step is proposed for the explicit computation of coil sensitivities that include the absolute phase of the image. The accuracy of the computed maps is directly validated using a test based on projection onto fully sampled coil images and also indirectly in phase-constrained parallel-imaging reconstructions. RESULTS: The proposed method can estimate accurate sensitivities which include low resolution image phase. In case of high-frequency phase variations VCC-ESPIRiT yields an additional set of maps that indicates the existence of a high-frequency phase component. Taking this additional set of maps into account can improve the robustness of phase-constrained parallel imaging. CONCLUSION: The extended VCC ESPIRiT is a useful tool for phase-constrained imaging. Magn Reson Med 77:1201 1207, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26970095 TI - Rhodium-Catalyzed Synthesis of Chiral Spiro-9-silabifluorenes by Dehydrogenative Silylation: Mechanistic Insights into the Construction of Tetraorganosilicon Stereocenters. AB - Mechanistic insight into the construction of quaternary silicon chiral centers by rhodium-catalyzed synthesis of spiro-9-silabifluorenes through dehydrogenative silylation is reported. The C2 -symmetric bisphosphine ligand, BINAP, was effective in controlling enantioselectivity, and axially chiral spiro-9 silabifluorenes were obtained in excellent yields with high enantiomeric excess. Monitoring of the reaction revealed the presence of a monohydrosilane intermediate as a mixture of two constitutional isomers. The reaction proceeded through two consecutive dehydrogenative silylations, and the absolute configuration was determined in the first silylative cyclization. Competitive reactions with electron-rich and electron-deficient dihydrosilanes indicated that the rate of silylative cyclization increased with decreasing electron density on the silicon atom of the starting dihydrosilane. Further investigation disclosed a rare interconversion between the two constitutional isomers of the monohydrosilane intermediate with retention of the absolute configuration. PMID- 26970094 TI - Neuropathy target esterase in mouse whole blood as a biomarker of exposure to neuropathic organophosphorus compounds. AB - The adult hen is the standard animal model for testing organophosphorus (OP) compounds for organophosphorus compound-induced delayed neurotoxicity (OPIDN). Recently, we developed a mouse model for biochemical assessment of the neuropathic potential of OP compounds based on brain neuropathy target esterase (NTE) and acetylcholinesterase (AChE) inhibition. We carried out the present work to further develop the mouse model by testing the hypothesis that whole blood NTE inhibition could be used as a biochemical marker for exposure to neuropathic OP compounds. Because brain NTE and AChE inhibition are biomarkers of OPIDN and acute cholinergic toxicity, respectively, we compared NTE and AChE 20-min IC50 values as well as ED50 values 1 h after single intraperitoneal (i.p.) injections of increasing doses of two neuropathic OP compounds that differed in acute toxicity potency. We found good agreement between the brain and blood for in vitro sensitivity of each enzyme as well for the ratios IC50 (AChE)/IC50 (NTE). Both OP compounds inhibited AChE and NTE in the mouse brain and blood dose dependently, and brain and blood inhibitions in vivo were well correlated for each enzyme. For both OP compounds, the ratio ED50 (AChE)/ED50 (NTE) in blood corresponded to that in the brain despite the somewhat higher sensitivity of blood enzymes. Thus, our results indicate that mouse blood NTE could serve as a biomarker of exposure to neuropathic OP compounds. Moreover, the data suggest that relative inhibition of blood NTE and AChE provide a way to assess the likelihood that OP compound exposure in a susceptible species would produce cholinergic and/or delayed neuropathic effects. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26970096 TI - von Willebrand disease type1/type 2N compound heterozygotes: diagnostic and management challenges. PMID- 26970097 TI - T follicular helper (Tfh ) cells in normal immune responses and in allergic disorders. AB - Follicular helper T cells (Tfh ) are located within germinal centers of lymph nodes. Cognate interaction between Tfh , B cells, and IL-21 drives B cells to proliferate and differentiate into plasma cells thereby leading to antibody production. Tfh cells and IL-21 are involved in infectious and autoimmune diseases, immunodeficiencies, vaccination, and cancer. Human peripheral blood CXCR5(+) CD4(+) T cells comprise different subsets of Tfh -like cells. Despite the importance of the IgE response in the pathogenesis of allergic disorders, little is known about the role of follicular and blood Tfh cells and IL-21 in human and experimental allergic disease. Here, we review recent advances regarding the phenotypic and functional characteristics of both follicular and blood Tfh cells and of the IL-21/IL-21R system in the context of allergic disorders. PMID- 26970098 TI - Carbon Nanofiber/3D Nanoporous Silicon Hybrids as High Capacity Lithium Storage Materials. AB - Carbon nanofiber (CNF)/3D nanoporous (3DNP) Si hybrid materials were prepared by chemical etching of melt-spun Si/Al-Cu-Fe alloy nanocomposites, followed by carbonization using a pitch. CNFs were successfully grown on the surface of 3DNP Si particles using residual Fe impurities after acidic etching, which acted as a catalyst for the growth of CNFs. The resulting CNF/3DNP Si hybrid materials showed an enhanced cycle performance up to 100 cycles compared to that of the pristine Si/Al-Cu-Fe alloy nanocomposite as well as that of bare 3DNP Si particles. These results indicate that CNFs and the carbon coating layer have a beneficial effect on the capacity retention characteristics of 3DNP Si particles by providing continuous electron-conduction pathways in the electrode during cycling. The approach presented here provides another way to improve the electrochemical performances of porous Si-based high capacity anode materials for lithium-ion batteries. PMID- 26970101 TI - Automated assessment of intranasal trigeminal function. AB - BACKGROUND: The intranasal trigeminal system is a key player in the perception of intranasal airflow. Why it has not been studied very well may be due to the lack of techniques that allow for fast, reliable and inexpensive routine investigation of the system. The basis of the current study is the notion that--within limits- the intranasal trigeminal system detects the overall mass of a stimulus and not just its concentration. Thus, changing the duration of the stimulus at a given concentration has a similar effect as changing its concentration. METHODOLOGY: Ninety-nine normosmic subjects participated [48 women and 51 men; mean (range) age = 45 years (20-88 years)]. In addition, 50 patients with olfactory loss were investigated once (28 women, 22 men; mean age 58 years, SD = 14 years; age range 24-88 years; causes of olfactory loss: viral infections n = 22, head trauma n = 8, chronic sinunasal disease n = 3, idiopathic n = 17). CO2-stimuli with various durations (multiples of 50 ms) were presented through a standard bilateral nasal cannula at an interval of 10 s; stimulus duration was increased by 50 ms from one stimulus presentation to the next, until the subject pushed a button indicating a painful sensation. This was the basis for automated assessment of CO2-pain responsiveness. RESULTS: This current study had four main findings: (1) Using the new, automated device CO2 pain responsiveness can be measured reliably, (2) CO2 pain responsiveness correlates with olfactory function, (3) as with olfaction, women are more sensitive to CO2 , and CO2-pain responsiveness also correlates with aging, (4) CO2-pain responsiveness is lower in patients with olfactory loss compared to normosmic, healthy controls, even when controlling for age. CONCLUSION: We have demonstrated that the current approach is a reliable and valid measure of intranasal trigeminal function. PMID- 26970100 TI - The Role of Insight in Moderating the Association Between Depressive Symptoms in People With Schizophrenia and Stigma Among Their Nearest Relatives: A Pilot Study. AB - BACKGROUND: There is evidence of a positive association between insight and depression among patients with schizophrenia. Self-stigma was shown to play a mediating role in this association. We attempted to broaden this concept by investigating insight as a potential moderator of the association between depressive symptoms amongst people with schizophrenia and stigmatizing views towards people with mental disorders in their close social environment. METHOD: In the initial sample of 120 pairs, data were gathered from 96 patients with a diagnosis of "paranoid schizophrenia" and 96 of their nearest relatives (80% response rate). In this cross-sectional study data were collected by clinical interview using the following questionnaires: "The Scale to Assess Unawareness of Mental Disorder," "Calgary Depression Scale for Schizophrenia," and "Brief Psychiatric Rating Scale." The stigmatizing views of patients' nearest relatives towards people with mental disorders were assessed with the "Mental Health in Public Conscience" scale. RESULTS: Among patients with schizophrenia depressive symptom severity was positively associated with the intensity of nearest relatives' stigmatizing beliefs ("Nonbiological vision of mental illness," tau = 0.24; P < .001). The association was moderated by the level of patients' awareness of presence of mental disorder while controlling for age, sex, duration of illness and psychopathological symptoms. CONCLUSIONS: The results support the hypothesis that the positive association between patients' depression and their nearest relatives' stigmatizing views is moderated by patients' insight. Directions for further research and practical implications are discussed. PMID- 26970102 TI - Negative relationships between population density and metabolic rates are not general. AB - Population density has recently been suggested to be an important factor influencing metabolic rates and to represent an important 'third axis' explaining variation beyond that explained by body mass and temperature. In situations where population density influences food consumption, the immediate effect on metabolism acting through specific dynamic action (SDA), and downregulation due to fasting over longer periods, is well understood. However, according to a recent review, previous studies suggest a more general effect of population density per se, even in the absence of such effects. It has been hypothesized that this results from animals performing anticipatory responses (i.e. reduced activity) to expected declines in food availability. Here, we test the generality of this finding by measuring density effects on metabolic rates in 10 clones from two different species of the zooplankton Daphnia (Daphnia pulex Leydig and D. magna Straus). Using fluorescence-based respirometry, we obtain high-precision measures of metabolism. We also identify additional studies on this topic that were not included in the previous review, compare the results and evaluate the potential for measurement bias in all previous studies. We demonstrate significant variation in mass-specific metabolism among clones within both species. However, we find no evidence for a negative relationship between population density and mass-specific metabolism. The previously reported pattern also disappeared when we extended the set of studies analysed. We discuss potential reasons for the discrepancy among studies, including two main sources of potential bias (microbial respiration and declining oxygen consumption due to reduced oxygen availability). Only one of the previous studies gives sufficient information to conclude the absence of such biases, and consistent with our results, no effect of density on metabolism was found. We conclude that population density per se does not have a general effect on mass-specific metabolic rate. PMID- 26970099 TI - The molecular complexity of fertilization: Introducing the concept of a fertilization synapse. AB - The details of sperm-egg interactions remain a relative mystery despite many decades of research. As new molecular complexities are being discovered, we need to revise the framework in which we think about fertilization. As such, we propose that fertilization involves the formation of a synapse between the sperm and egg. A cellular synapse is a structure that mediates cell adhesion, signaling, and secretion through specialized zones of interaction and polarity. In this review, we draw parallels between the immune synapse and fertilization, and argue that we should consider sperm-egg recognition, binding, and fusion in the context of a "fertilization synapse." Mol. Reprod. Dev. 83: 376-386, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26970103 TI - Oximetric angiosome imaging in diabetic feet. AB - PURPOSE: To develop a noncontrast oximetric angiosome imaging approach to assess skeletal muscle oxygenation in diabetic feet. MATERIALS AND METHODS: In four healthy and five subjects with diabetes, the feasibility of foot oximetry was examined using a 3T clinical magnetic resonance imaging (MRI) scanner. The subjects' feet were scanned at rest and during a toe-flexion isometric exercise. The oxygen extraction fraction of skeletal muscle was measured using a susceptibility-based MRI method. Our newly developed MR foot oximetric angiosome model was compared with the traditional angiosome model in the assessment of the distribution of oxygen extraction fraction. RESULTS: Using the traditional angiosome during the toe-flexion exercise, the oxygen extraction fraction in the medial foot of healthy subjects increased (4.9 +/- 3%) and decreased (-2.7 +/- 4.4%) in subjects with diabetes (difference = 7.6%; 95% confidence interval = 13.7 +/- 1.4; P = 0.02). Using the oximetric angiosome, the percent difference in the areas of oxygen extraction fraction within the 0.7-1.0 range (expected oxygen extraction fraction during exercise) between rest and exercise was higher in healthy subjects (8 +/- 4%) than in subjects with diabetes (4 +/- 4%; P = 0.02). CONCLUSION: This study demonstrates the feasibility of measuring skeletal muscle oxygen extraction fraction in the foot muscle during a toe-flexion isometric exercise. Instead of assessing oxygen extraction fraction in a foot muscle region linked to a supplying artery (traditional angiosome), the foot oximetric angiosome model assesses oxygen extraction fraction by its different levels in all foot muscle regions and thus may be more appropriate for assessing local ischemia in ulcerated diabetic feet. J. Magn. Reson. Imaging 2016. J. MAGN. RESON. IMAGING 2016;44:940-946. PMID- 26970104 TI - Ontogeny constrains phenology: opportunities for activity and reproduction interact to dictate potential phenologies in a changing climate. AB - As global warming has lengthened the active seasons of many species, we need a framework for predicting how advances in phenology shape the life history and the resulting fitness of organisms. Using an individual-based model, we show how warming differently affects annual cycles of development, growth, reproduction and activity in a group of North American lizards. Populations in cold regions can grow and reproduce more when warming lengthens their active season. However, future warming of currently warm regions advances the reproductive season but reduces the survival of embryos and juveniles. Hence, stressful temperatures during summer can offset predicted gains from extended growth seasons and select for lizards that reproduce after the warm summer months. Understanding these cascading effects of climate change may be crucial to predict shifts in the life history and demography of species. PMID- 26970106 TI - Steatosis after liver transplantation: Is it really benign? PMID- 26970105 TI - Whirling agitated single drop microextraction technique for the simultaneous analysis of Paraquat and Maneb in tissue samples of treated mice. AB - A new microextraction technique, whirling agitated single drop microextraction, has been proposed for the simultaneous analysis of Paraquat and Maneb in tissue samples before liquid chromatography with tandem mass spectrometry. This technique is based on the idea that the escalatory motion of the sample solution along with the extraction solvent increases the movement of molecules into the extraction solvent. In this technique, a simple handheld rotator was utilized to rapidly agitate the biphasic extraction system for the instantaneous extraction of targeted analytes. After extraction, the extracted phase was directly solidified by cooling in crushed ice and easily collected using a micro-spatula. The method showed good performance by achieving sensitive detection limits at 4.81 ng g(-1) (Paraquat) and 9.12 ng g(-1) (Maneb). Mean recoveries and enrichment factors were obtained >91.21% and up to 114 that ensured the preconcentration capacity of the method. The method precision was verified by evaluating intraday variation (n = 10) <=4.57 (Paraquat) and <=4.68 (Maneb) in terms of percent relative standard deviation. Additionally, method efficacy was assured by obtaining very little matrix interferences (<=3.11%). Moreover, the method suitability was also checked with its application on tissue samples of intraperitoneally treated mice with Paraquat and Maneb. PMID- 26970107 TI - Empirical extensions of the lasso penalty to reduce the false discovery rate in high-dimensional Cox regression models. AB - Correct selection of prognostic biomarkers among multiple candidates is becoming increasingly challenging as the dimensionality of biological data becomes higher. Therefore, minimizing the false discovery rate (FDR) is of primary importance, while a low false negative rate (FNR) is a complementary measure. The lasso is a popular selection method in Cox regression, but its results depend heavily on the penalty parameter lambda. Usually, lambda is chosen using maximum cross-validated log-likelihood (max-cvl). However, this method has often a very high FDR. We review methods for a more conservative choice of lambda. We propose an empirical extension of the cvl by adding a penalization term, which trades off between the goodness-of-fit and the parsimony of the model, leading to the selection of fewer biomarkers and, as we show, to the reduction of the FDR without large increase in FNR. We conducted a simulation study considering null and moderately sparse alternative scenarios and compared our approach with the standard lasso and 10 other competitors: Akaike information criterion (AIC), corrected AIC, Bayesian information criterion (BIC), extended BIC, Hannan and Quinn information criterion (HQIC), risk information criterion (RIC), one-standard-error rule, adaptive lasso, stability selection, and percentile lasso. Our extension achieved the best compromise across all the scenarios between a reduction of the FDR and a limited raise of the FNR, followed by the AIC, the RIC, and the adaptive lasso, which performed well in some settings. We illustrate the methods using gene expression data of 523 breast cancer patients. In conclusion, we propose to apply our extension to the lasso whenever a stringent FDR with a limited FNR is targeted. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26970109 TI - Study on clear stereo image pair acquisition method for small objects with big vertical size in SLM vision system. AB - Microscopic vision system with stereo light microscope (SLM) has been applied to surface profile measurement. If the vertical size of a small object exceeds the range of depth, its images will contain clear and fuzzy image regions. Hence, in order to obtain clear stereo images, we propose a microscopic sequence image fusion method which is suitable for SLM vision system. First, a solution to capture and align image sequence is designed, which outputs an aligning stereo images. Second, we decompose stereo image sequence by wavelet analysis theory, and obtain a series of high and low frequency coefficients with different resolutions. Then fused stereo images are output based on the high and low frequency coefficient fusion rules proposed in this article. The results show that Deltaw1 (Deltaw2 ) and DeltaZ of stereo images in a sequence have linear relationship. Hence, a procedure for image alignment is necessary before image fusion. In contrast with other image fusion methods, our method can output clear fused stereo images with better performance, which is suitable for SLM vision system, and very helpful for avoiding image fuzzy caused by big vertical size of small objects. PMID- 26970111 TI - Effects of a Mindfulness Intervention on Sports-Anxiety, Pessimism, and Flow in Competitive Cyclists. AB - BACKGROUND: This study investigated whether mindfulness training increases athletes' mindfulness and flow experience and decreases sport-specific anxiety and sport-specific pessimism. METHODS: Cyclists were assigned to an eight-week mindfulness intervention, which incorporated a mindful spin-bike training component, or a wait-list control condition. Participants completed baseline and post-test measures of mindfulness, flow, sport-anxiety, and sport-related pessimistic attributions. RESULTS: Analyses of covariance showed significant positive effects on mindfulness, flow, and pessimism for the 27 cyclists in the mindfulness intervention condition compared with the 20 cyclists in the control condition. Changes in mindfulness experienced by the intervention participants were positively associated with changes in flow. CONCLUSIONS: Results suggest that mindfulness-based interventions tailored to specific athletic pursuits can be effective in facilitating flow experiences. PMID- 26970108 TI - Therapy with proton-pump inhibitors for gastroesophageal reflux disease does not reduce the risk for severe exacerbations in COPD. AB - BACKGROUND AND OBJECTIVE: Gastroesophageal reflux disease (GERD) symptoms are associated with a higher risk of chronic obstructive pulmonary disease (COPD) exacerbation. We hypothesize that treatment with proton pump inhibitors reduces the risk of exacerbation in patients with stable COPD. METHODS: A total of 638 patients with stable COPD for >=6 weeks, >=10 pack-years of smoking and Global Initiative for Chronic Obstructive Lung Disease II-IV seeking care in tertiary hospitals in eight European countries in the Predicting Outcome using Systemic Markers in Severe Exacerbations-COPD cohort was prospectively evaluated by us. Comorbidities including associated medical treatment were assessed at baseline, at exacerbation and at biannual visits. Median observation time was 24 months. The primary study outcomes were exacerbation and/or death. RESULTS: A total of 85 (13.3%) of COPD patients were on anti-GERD therapy. These patients had higher annual and higher severe exacerbation rates (P = 0.009 and P = 0.002), decreased quality of life (SF-36: activity score P = 0.004, St. George's Respiratory Questionnaire: physical functioning P = 0.013 and social functioning P = 0.007), higher body mass airflow obstruction, dyspnea and exercise capacity index (P = 0.033) and Modified Medical Research Council scores (P = 0.002), shorter 6-min walking distance (P = 0.0004) and a higher adjusted Charlson score (P < 0.0001). Anti-GERD therapy was associated with a shorter time to severe exacerbation (HR 2.05 95% CI 1.37-3.08). Using three multivariable Cox-regression models, this association was independent of the following: (i) adjusted Charlson score and FEV1% predicted (HR 1.91 95% CI 1.26-2.90); (ii) adjusted Charlson score, body mass, airflow obstruction, dyspnea and exercise capacity index and Modified Medical Research Council (HR 1.62 95% CI 1.04-2.54); and (iii) adjusted Charlson score, FEV1% predicted and nine classes of medication for comorbidities (HR 1.63 95% CI 1.04-2.53). CONCLUSION: These findings suggest that patients with stable COPD receiving acid-suppressive therapy with proton pump inhibitors remain at high risk of frequent and severe exacerbations. PMID- 26970112 TI - Oops I Did it Again: Examining Self-Licensing Effects in a Subsequent Self Regulation Dilemma. AB - BACKGROUND: Previous studies have mainly examined the immediate effects of self licensing on self-regulation failure. The present vignette studies examined what happens when a second self-regulation dilemma is encountered. METHODS: In Studies 1 (N = 52) and 2 (N = 166), participants read a vignette in which the protagonist chooses to buy a treat while being on a diet, which was preceded by a license (License condition) or not (Control condition). The self-reported likelihood of indulging again when a second dilemma was presented in the same situation served as the dependent variable. Study 2 included measures of self-regulatory ability (motivation and self-efficacy) and also presented the dilemma in a new situation. RESULTS: Study 1 showed that participants were more likely to indulge again after an initial indulgent choice with a license. This was replicated in Study 2, which also showed that self-licensing had no effect on goal re-engagement in a new situation. A marginally significant positive effect of self-licensing was found for self-efficacy. CONCLUSIONS: The results obtained suggest that self-licensing negatively affects goal re-engagement in the same situation, but not in a new situation. Whether self-licensing maintains or increases feelings of self efficacy needs to be validated in future studies. PMID- 26970110 TI - Specific mosaic KRAS mutations affecting codon 146 cause oculoectodermal syndrome and encephalocraniocutaneous lipomatosis. AB - Oculoectodermal syndrome (OES) and encephalocraniocutaneous lipomatosis (ECCL) are rare disorders that share many common features, such as epibulbar dermoids, aplasia cutis congenita, pigmentary changes following Blaschko lines, bony tumor like lesions, and others. About 20 cases with OES and more than 50 patients with ECCL have been reported. Both diseases were proposed to represent mosaic disorders, but only very recently whole-genome sequencing has led to the identification of somatic KRAS mutations, p.Leu19Phe and p.Gly13Asp, in affected tissue from two individuals with OES. Here we report the results of molecular genetic studies in three patients with OES and one with ECCL. In all four cases, Sanger sequencing of the KRAS gene in DNA from lesional tissue detected mutations affecting codon 146 (p.Ala146Val, p.Ala146Thr) at variable levels of mosaicism. Our findings thus corroborate the evidence of OES being a mosaic RASopathy and confirm the common etiology of OES and ECCL. KRAS codon 146 mutations, as well as the previously reported OES-associated alterations, are known oncogenic KRAS mutations with distinct functional consequences. Considering the phenotype and genotype spectrum of mosaic RASopathies, these findings suggest that the wide phenotypic variability does not only depend on the tissue distribution but also on the specific genotype. PMID- 26970113 TI - Predicting Physical Activity-Related Outcomes in Overweight and Obese Adults: A Health Action Process Approach. AB - BACKGROUND: We tested the adequacy of a model based on the Health Action Process Approach (HAPA) in predicting changes in psychological, body composition, and cardiovascular risk outcomes with respect to physical activity participation in overweight and obese adults. METHODS: Measures of HAPA constructs (action and maintenance self-efficacy, outcome expectancies, action planning, risk perceptions, intentions, behaviour), psychological outcomes (quality of life, depression, anxiety, stress symptoms), body composition variables (body weight, body fat mass), cardiovascular risk measures (total cholesterol, low density lipoprotein), and self-reported physical activity behaviour were administered to participants (N = 74) at baseline, and 6 and 12 weeks later. RESULTS: Data were analysed using variance-based structural equation modelling with residualised change scores for HAPA variables. The model revealed effects of action self efficacy and outcome expectancies on physical activity intentions, action self efficacy on maintenance self-efficacy, and maintenance self-efficacy and intentions on action planning. Intention predicted psychological and body composition outcomes indirectly through physical activity behaviour. Action planning was a direct predictor of psychological, cardiovascular, and body composition outcomes. CONCLUSIONS: Data supported HAPA hypotheses in relation to intentions and behaviour, but not the role of action planning as a mediator of the intention-behaviour relationship. Action planning predicted outcomes independent of intentions and behaviour. PMID- 26970114 TI - Prospective first-trimester screening for trisomies by cell-free DNA testing of maternal blood in twin pregnancy. AB - OBJECTIVES: First, to examine in twin pregnancies the performance of first trimester screening for fetal trisomies 21, 18 and 13 by cell-free (cf) DNA testing of maternal blood and, second, to compare twin and singleton pregnancies regarding the distribution of fetal fraction of cfDNA and rate of failure to obtain a result. METHODS: This was a prospective study in 438 twin and 10 698 singleton pregnancies undergoing screening for fetal trisomies by cfDNA testing at 10 + 0 to 13 + 6 weeks' gestation. Chromosome-selective sequencing of cfDNA was used and, in twin pregnancies, an algorithm was applied that relies on the lower fetal fraction contributed by the two fetuses. Multivariate regression analysis was used to determine significant predictors of fetal fraction and a failed result. RESULTS: In twin pregnancies, the median fetal fraction was lower (8.0% (interquartile range (IQR), 6.0-10.4%) vs 11.0% (IQR, 8.3-14.4%); P < 0.0001) and failure rate after first sampling was higher (9.4% vs 2.9%; P < 0.0001) compared to in singletons. Multivariate logistic regression analysis demonstrated that the risk of test failure increased with increasing maternal age and body mass index and decreased with fetal crown-rump length. The risk was increased in women of South Asian racial origin and in pregnancies conceived by in-vitro fertilization (IVF). The main contributor to the higher rate of failure in twins was conception by IVF which was observed in 9.5% of singletons and 56.2% of twins. In the 417 twin pregnancies with a cfDNA result after first or second sampling, the detection rate was 100% (8/8) for trisomy 21 and 60% (3/5) for trisomies 18 or 13, at a false-positive rate (FPR) of 0.25% (1/404). In the 10 530 singleton pregnancies with a cfDNA result after first or second sampling, the detection rate was 98.7% (156/158) for trisomy 21 and 80.3% (49/61) for trisomies 18 or 13, at a FPR of 0.22% (23/10 311). CONCLUSIONS: In twin pregnancies undergoing first-trimester screening for trisomies by cfDNA testing, the fetal fraction is lower and failure rate higher compared to in singletons. The number of trisomic twin pregnancies examined was too small for an accurate assessment of performance of screening, but it may be similar to that in singleton pregnancies. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26970116 TI - Moving a pioneer journal into the future. PMID- 26970115 TI - The transcription factor VpCRZ1 is required for fruiting body formation and pathogenicity in Valsa pyri. AB - Valsa pyri is a fatal pathogenic fungus that causes pear and apple canker disease. To date, its cellular development and pathogenicity have been poorly understood. In this study, a V. pyri Ca(2+)/calcineurin-dependent transcription factor CRZ1 (VpCRZ1) is identified and functionally characterized. The ?VpCRZ1 mutant exhibits impaired pathogenicity and is no longer able to form fruiting body. Interestingly, this mutant also exhibits enhanced pigment deposition and increased resistance to cell wall perturbing agents including SDS, Congo red and calcofluor white (CFW). The expression levels of Congo red resistance genes (VpRCR1 and VpRCR2) and chitin synthetase genes (VpCHS2 and VpCHS6) are upregulated in the ?VpCRZ1 mutant compared to the wild type. Furthermore, We show that a VpCRZ1: eGFP fusion protein localizes to the nucleus in a Ca(2+)-dependent manner similar to its homologs in other fungi, and that the VpFKS1, VpPMC1, VpPMC2, VpPMR1, and VpPMA1 genes are regulated by VpCRZ1 in response to Ca(2+) levels. Together, these results suggest that VpCRZ1 is a Ca(2+)-dependent transcription factor and required for regulating mycelial morphology, fruiting body formation, and virulence of this important pear and apple pathogen. PMID- 26970117 TI - Looking to the future in an unprecedented time for cancer drug development. AB - Basic research in cancer biology, genetics and immunology has resulted in improved insights into mechanisms that drive tumor initiation and growth. This improved biologic understanding of the diseases we treat has led to unprecedented therapeutic breakthroughs across multiple tumor types. In this article, we discuss opportunities and challenges in contemporary cancer drug development, highlighting efficacy endpoints, clinical trial design and the thoughtful inclusion of the patient perspective. As the field re-examines old practices and explores new opportunities, we must continue to efficiently utilize the human and scientific resources at our disposal to foster the development and delivery of safe and effective therapies to cancer patients. PMID- 26970118 TI - A call to oncologists to right the wrongs of the Affordable Care Act. PMID- 26970119 TI - Precision oncology: a strategy we were not ready to deploy. PMID- 26970120 TI - The Bayesian basket design for genomic variant-driven phase II trials. AB - Basket clinical trials are a new category of early clinical trials in which a treatment is evaluated in a population of patients with tumors of various histologic types and primary sites selected for containing specific genomic abnormalities. The objective of such studies is generally to discover histologic types in which the treatment is active. Basket trials are early discovery trials whose results should be confirmed in expanded histology specific cohorts. In this report, we develop a design for planning, monitoring, and analyzing basket trials. A website for using the new design is available at https://brbnci.shinyapps.io/BasketTrials/ and the software is available at GitHub in the "Basket Trials" repository of account brbnci. PMID- 26970121 TI - Introduction: Cancer chemoprevention and its context. PMID- 26970123 TI - The promise of omics-based approaches to cancer prevention. AB - Cancer is a complex category of diseases caused in large part by genetic or genomic, transcriptomic, and epigenetic or epigenomic alterations in affected cells and the surrounding microenvironment. Carcinogenesis reflects the clonal expansion of cells that progressively acquire these genetic and epigenetic alterations-changes that, in turn, lead to modifications at the RNA level. Gradually advancing technology and most recently, the advent of next-generation sequencing (NGS), combined with bioinformatics analytic tools, have revolutionized our ability to interrogate cancer cells. The ultimate goal is to apply these high-throughput technologies to the various aspects of clinical cancer care: cancer-risk assessment, diagnosis, as well as target identification for treatment and prevention. In this article, we emphasize how the knowledge gained through large-scale omics-oriented approaches, with a focus on variations at the level of nucleic acids, can inform the field of chemoprevention. PMID- 26970126 TI - Mechanisms of esophageal adenocarcinoma formation and approaches to chemopreventive intervention. AB - The incidence of esophageal adenocarcinoma (EAC), a debilitating and highly lethal malignancy, has risen dramatically over the past 40 years in the United States and other Western countries. To reverse this trend, EAC prevention and early detection efforts by clinicians, academic researchers and endoscope manufacturers have targeted Barrett's esophagus (BE), the widely accepted EAC precursor lesion. Data from surgical, endoscopic and pre-clinical investigations strongly support the malignant potential of BE. For patients with BE, the risk of developing EAC has been estimated at 11- to 125-fold greater than that of the individual at average risk. Nevertheless, screening for BE in symptomatic patients (ie, with symptoms of reflux) and surveillance in patients diagnosed with BE have not had a substantial impact on the incidence, morbidity or mortality of EAC; the overwhelming majority of EAC patients are diagnosed without a pre-operative diagnosis of BE. This article will discuss the current state of the science of esophageal adenocarcinoma prevention, including ideas about carcinogenesis and its underlying genomic and molecular level mechanisms, and suggest strategies for a systems approach to targeted preventive management. PMID- 26970125 TI - Mechanisms of nonsteroidal anti-inflammatory drugs in cancer prevention. AB - Various clinical and epidemiologic studies show that nonsteroidal anti inflammatory drugs (NSAIDs), including aspirin and cyclooxygenase inhibitors (COXIBs) help prevent cancer. Since eicosanoid metabolism is the main inhibitory targets of these drugs the resulting molecular and biological impact is generally accepted. As our knowledge base and technology progress we are learning that additional targets may be involved. This review attempts to summarize these new developments in the field. PMID- 26970122 TI - The hallmarks of premalignant conditions: a molecular basis for cancer prevention. AB - The hallmarks of premalignant lesions were first described in the 1970s, a time when relatively little was known about the molecular underpinnings of cancer. Yet it was clear there must be opportunities to intervene early in carcinogenesis. A vast array of molecular information has since been uncovered, with much of this stemming from studies of existing cancer or cancer models. Here, examples of how an understanding of cancer biology has informed cancer prevention studies are highlighted and emerging areas that may have implications for the field of cancer prevention research are described. A note of caution accompanies these examples, in that while there are similarities, there are also fundamental differences between the biology of premalignant lesions or premalignant conditions and invasive cancer. These differences must be kept in mind, and indeed leveraged, when exploring potential cancer prevention measures. PMID- 26970124 TI - Retinoids and rexinoids in cancer prevention: from laboratory to clinic. AB - Early in the age of modern medicine the consequences of vitamin A deficiency drew attention to the fundamental link between retinoid-dependent homeostatic regulation and malignant hyperproliferative diseases. The term "retinoid" includes a handful of endogenous and a large group of synthetic derivatives of vitamin A. These multifunctional lipid-soluble compounds directly regulate target genes of specific biological functions and critical signaling pathways to orchestrate complex functions from vision to development, metabolism, and inflammation. Many of the retinoid activities on the cellular level have been well characterized and translated to the regulation of processes like differentiation and cell death, which play critical roles in the outcome of malignant transformation of tissues. In fact, retinoid-based differentiation therapy of acute promyelocytic leukemia was one of the first successful examples of molecularly targeted treatment strategies. The selectivity, high receptor binding affinity and the ability of retinoids to directly modulate gene expression programs present a distinct pharmacological opportunity for cancer treatment and prevention. However, to fully exploit their potential, the adverse effects of retinoids must be averted. In this review we provide an overview of the biology of retinoid (activated by nuclear retinoic acid receptors [RARs]) and rexinoid (engaged by nuclear retinoid X receptors [RXRs]) action concluded from a long line of preclinical studies, in relation to normal and transformed states of cells. We will also discuss the past and current uses of retinoids in the treatment of malignancies, the potential of rexinoids in the cancer prevention setting, both as single agents and in combinations. PMID- 26970129 TI - Novel routes for administering chemoprevention: local transdermal therapy to the breasts. AB - Breast cancer prevention with pharmacologic agents requires that the breast be exposed to an effective drug; systemic exposure is unnecessary, and its harms lead many eligible women to decline preventive therapy. Local transdermal therapy (LTT) to the breast involves the application of active drugs to the breast skin, resulting in high concentrations in the breast but low systemic exposure. It is non-invasive, self-delivered, and not dependent on hepatic metabolism. Existing data on LTT include investigations demonstrating relief of mastalgia with topical 4-hydroxytamoxifen (4-OHT, an active tamoxifen metabolite). Two presurgical window trials in women with invasive breast cancer, and ductal carcinoma in situ (DCIS) demonstrate that LTT decreases proliferation of invasive and non-invasive cancer cells to a similar degree as oral tamoxifen, with low systemic levels, and no effect on coagulation proteins. These data are promising regarding the use of LTT for the primary prevention of breast cancer, and for therapy of DCIS, since systemic exposure is not required for either of these purposes. They also suggest that an LTT approach could be developed for any small, lipophilic molecule with good dermal permeation, thus greatly expanding the menu of drugs that could be tested for breast cancer prevention. PMID- 26970130 TI - Alternate dosing schedules for cancer chemopreventive agents. AB - Pharmacologic interventions for cancer risk reduction involve the chronic administration of synthetic or natural agents to reduce or delay the occurrence of malignancy. Despite the strong evidence for a favorable risk-benefit ratio for a number of agents in several common malignancies such as breast and prostate cancer, the public's attitude toward cancer chemoprevention remains ambivalent, with the issue of toxicity associated with drugs being perceived as the main barrier to widespread use of preventive therapy by high-risk subjects. Among the strategies to overcome such obstacles to preventive therapies, two novel and potentially safer modes of administering agents are discussed in this paper. The first strategy is to lower the dose of drugs that are in common use in the adjuvant setting based on the notion that prevention of cancer cells from developing should require a lower dose than eradicating established tumor cells. A second approach is to adopt an intermittent administration similar to what is used in the chemotherapy setting in an attempt to minimize risks while retaining benefits. This article provides a detailed discussion of the principles and future development of these two approaches in the direction of a precision preventive medicine. PMID- 26970128 TI - The microbiome and its potential as a cancer preventive intervention. AB - It is becoming increasingly clear that microbiota inhabiting our bodies influence cancer predisposition and etiology. In addition to pathogens with oncogenic properties, commensal and symbiotic microbiota have tumor-suppressive properties. Diet and other environmental factors can modulate the abundance of certain members of microbial communities within the gastrointestinal tract and at other anatomical sites. Furthermore, some dietary factors are metabolized by commensal/symbiotic gut microbiota into bioactive food components believed to prevent cancer. For example, dietary fiber undergoes bacterial fermentation in the colon to yield butyrate, which is a short-chain fatty acid and histone deacetylase (HDAC) inhibitor that suppresses the viability and growth of colorectal cancer cell lines. A recent study using gnotobiotic mouse models demonstrates that fiber can protect against colorectal tumorigenesis in a microbiota- and butyrate-dependent manner that involves the Warburg effect. This and other examples suggest that some of the inter-individual variation observed in epidemiology and intervention studies that have investigated associations between diet and cancer risk might be explained by differences in microbiota among the participants. Data from basic research studies also support the idea that probiotics and prebiotics could be plausible chemoprevention strategies that may be utilized to a greater extent in the future. PMID- 26970127 TI - Microbiome and potential targets for chemoprevention of esophageal adenocarcinoma. AB - Esophageal cancer is one of the deadliest cancers, with a dismal prognosis. It is increasingly recognized that esophageal cancer is a heterogeneous disease. It can be subdivided into two distinct groups: squamous cell carcinoma and adenocarcinoma, based on histological appearance. In the Western world, the incidence of squamous cell carcinoma was considerably higher than esophageal adenocarcinoma (EA) until the 1990s when, due to a dramatic increase, the incidence of EA surpassed that of squamous cell carcinoma. EA typically follows a well-established stepwise evolution from chronic inflammation due to reflux esophagitis (RE) that progresses to metaplasia (Barrett's esophagus [BE]) to dysplasia, which often culminates in EA. The pathophysiology of EA is complex and involves diverse factors, including gastroesophageal reflux, gastric acid secretion, dysfunction of the antireflux barrier, gastric emptying disturbances, and abnormalities in esophageal defense mechanisms. The current understanding of the etiology of EA is mainly derived from epidemiological studies of risk factors such as cigarette smoking, obesity, gastroesophageal reflux disorders (GERD), and low fruit and vegetable consumption. Numerous studies have been done, but the factors that drive the dynamic increase in the incidence of EA remain elusive. The advent of widespread antibiotic use occurred in the 1950s, preceding the surge of EA. Based on this temporal sequence, it has been hypothesized that antibiotics alter the microbiome to which the esophagus is exposed in patients who have GERD and that chronic exposure to this abnormal microbiome (ie, changes in species diversity or abundance) accounts for the increase in EA. If changes in the proposed factors alter the stepwise progression (RE-BE-dysplasia-EA), they may represent potential targets for chemoprevention. New discoveries will help improve our understanding of the biology and pathogenesis of these cancers, and aid in finding novel therapeutic targets. PMID- 26970131 TI - Repurposing old drugs to chemoprevention: the case of metformin. AB - Multiple epidemiologic studies have documented an association between the anti diabetic agent metformin and reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models or more recent epidemiological studies. The purpose of this paper is to examine metformin's chemopreventive potential by reviewing relevant mechanisms of action, preclinical evidence of efficacy, updated epidemiologic evidence after correction for potential biases and confounders, and recently completed and ongoing clinical trials. Although repurposing drugs with well described mechanisms of action and safety profiles is an appealing strategy for cancer prevention, there is no substitute for well executed late phase clinical trials to define efficacy and populations that are most likely to benefit from an intervention. PMID- 26970132 TI - Hereditary cancer syndromes as model systems for chemopreventive agent development. AB - Research in chemoprevention has undergone a shift in emphasis for pragmatic reasons from large, phase III randomized studies to earlier phase studies focused on safety, mechanisms, and utilization of surrogate endpoints such as biomarkers instead of cancer incidence. This transition permits trials to be conducted in smaller populations and at substantially reduced costs while still yielding valuable information. This article will summarize some of the current chemoprevention challenges and the justification for the use of animal models to facilitate identification and testing of chemopreventive agents as illustrated though four inherited cancer syndromes. Preclinical models of inherited cancer syndromes serve as prototypical systems in which chemopreventive agents can be developed for ultimate application to both the sporadic and inherited cancer settings. PMID- 26970133 TI - Frugal chemoprevention: targeting Nrf2 with foods rich in sulforaphane. AB - With the properties of efficacy, safety, tolerability, practicability and low cost, foods containing bioactive phytochemicals are gaining significant attention as elements of chemoprevention strategies against cancer. Sulforaphane [1 isothiocyanato-4-(methylsulfinyl)butane], a naturally occurring isothiocyanate produced by cruciferous vegetables such as broccoli, is found to be a highly promising chemoprevention agent against not only a variety of cancers such as breast, prostate, colon, skin, lung, stomach or bladder, but also cardiovascular disease, neurodegenerative diseases, and diabetes. For reasons of experimental exigency, preclinical studies have focused principally on sulforaphane itself, while clinical studies have relied on broccoli sprout preparations rich in either sulforaphane or its biogenic precursor, glucoraphanin. Substantive subsequent evaluation of sulforaphane pharmacokinetics and pharmacodynamics has been undertaken using either pure compound or food matrices. Sulforaphane affects multiple targets in cells. One key molecular mechanism of action for sulforaphane entails activation of the Nrf2-Keap1 signaling pathway although other actions contribute to the broad spectrum of efficacy in different animal models. This review summarizes the current status of pre-clinical chemoprevention studies with sulforaphane and highlights the progress and challenges for the application of foods rich in sulforaphane and/or glucoraphanin in the arena of clinical chemoprevention. PMID- 26970135 TI - Immunologic approaches to cancer prevention-current status, challenges, and future perspectives. AB - The potential of the immune system to recognize and reject tumors has been investigated for more than a century. However, only recently impressive breakthroughs in cancer immunotherapy have been seen with the use of checkpoint inhibitors. The experience with various immune-based strategies in the treatment of late cancer highlighted the importance of negative impact advanced disease has on immunity. Consequently, use of immune modulation for cancer prevention rather than therapy has gained considerable attention, with many promising results seen already in preclinical and early clinical studies. Although not without challenges, these results provide much excitement and optimism that successful cancer immunoprevention could be within our reach. In this review we will discuss the current state of predominantly primary and secondary cancer immunoprevention, relevant research, potential barriers, and future directions. PMID- 26970134 TI - Targeting obesity-related adipose tissue dysfunction to prevent cancer development and progression. AB - The incidence of obesity, a leading modifiable risk factor for common solid tumors, is increasing. Effective interventions are needed to minimize the public health implications of obesity. Although the mechanisms linking increased adiposity to malignancy are incompletely understood, growing evidence points to complex interactions among multiple systemic and tissue-specific pathways including inflamed white adipose tissue. The metabolic and inflammatory consequences of white adipose tissue dysfunction collectively provide a plausible explanation for the link between overweight/obesity and carcinogenesis. Gaining a better understanding of these underlying molecular pathways and developing risk assessment tools that identify at-risk populations will be critical in implementing effective and novel cancer prevention and management strategies. PMID- 26970139 TI - Tracheal exposure: Anticipatory management of the difficult airway. AB - BACKGROUND: When a patient cannot be intubated or ventilated, cricothyrotomy is indicated. Risks associated with emergent cricothyrotomy are significant, and this procedure typically requires revision. Additional options for establishing an emergent airway are limited. Thus, elective tracheotomy to ensure a safe airway after procedures involving the upper aerodigestive tract is common. Although safe and effective overall, this procedure is not without additional risks, added resources, complex cares, and extended hospitalizations. METHODS: We present a case in which exposure of the anterior trachea was performed without tracheotomy in a patient with a high-risk airway undergoing an open partial laryngectomy. RESULTS: The patient did not develop respiratory distress postoperatively and was able to avoid a tracheostomy and its associated cares. CONCLUSION: Pretracheotomy with tracheal exposure simplifies emergent surgical access to the airway. We believe tracheal exposure in the appropriately selected patient is a safe and cost-effective alternative to elective tracheotomy. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: E2446-E2448, 2016. PMID- 26970137 TI - The National Cancer Institute's PREVENT Cancer Preclinical Drug Development Program: overview, current projects, animal models, agent development strategies, and molecular targets. AB - The PREVENT Cancer Preclinical Drug Development Program (PREVENT) is a National Cancer Institute, Division of Cancer Prevention (NCI, DCP)-supported program whose primary goal is to bring new cancer preventive interventions (small molecules and vaccines) and biomarkers through preclinical development towards clinical trials by creating partnerships between the public sector (eg, academia, industry) and DCP. PREVENT has a formalized structure for moving interventions forward in the prevention pipeline using a stage-gate process with go/no go decision points along the critical path for development. This review describes the structure of the program, its focus areas, and provides examples of projects currently in the pipeline. PMID- 26970138 TI - Comparative phenotypical analysis of B cells in fresh and cryopreserved mononuclear cells from blood and tissue of rhesus macaques. AB - Cryopreservation of peripheral blood mononuclear cells (PBMCs) is common for large clinical trials for which phenotypical characterization of lymphocytes is retrospectively performed in specialized core laboratories. It is therefore essential to assess the comparability between fresh and frozen samples. No side by-side comparison of B and plasma cells of rhesus macaques (RM), which serve as useful models for several human diseases has been conducted until now. Hence, we performed an extensive comparative analysis between fresh and thawed mononuclear cells (MNCs) from blood and various tissues of healthy RM to analyze for the possible effects of cryopreservation on phenotype and functionality. Our data demonstrate that -80 degrees C cryopreservation induces profound changes compared to fresh ex vivo-derived material. Percentages of B cells were stable in PBMCs, but were increased in all organs analyzed. The expression of CD27, a marker for differentiation between naive and memory B cells, was massively reduced in PBMCs and MNC from organs with the most severe changes observed in cells from bone marrow (BM). Additionally, similar low percentages of CD27(+) memory B cells were detected in PBMCs and BM samples stored in liquid nitrogen. Therefore, cryopreservation is not suitable for the phenotypical and functional characterization of B cells. Further optimization of cryoconservation protocols monitoring the surface expression of CD27, which was identified as a marker for the quality of cryopreserved material of RM, will be essential. PMID- 26970140 TI - Is that me in the mirror? Depersonalisation modulates tactile mirroring mechanisms. AB - Our sense of self is thought to develop through sensory-motor contingencies provided, not only by observing one's own body, but also by mirroring interactions with others. This suggests that there is a strong link between mirroring mechanisms and the bodily self. The present study tested whether this link is expressed at early, implicit stages of the mirroring process or at later, more cognitive stages. We also provide, to the best of our knowledge, the first demonstration of how inter-individual differences in our sense of bodily self may affect mirroring mechanisms. We used somatosensory event-related potentials (SEPs) to investigate the temporal dynamics of mirroring highly self-related information (viewed touch on one's own face) compared to other-related information (viewed touch on a stranger's face), in individuals with low and high levels of depersonalisation, a mental condition characterised by feeling detached or estranged from one's self and body. For the low-depersonalisation group, mirroring for self-related events (P45) preceded mirroring for other-related events (N80). At later stages (P200), mirroring was stronger for other-related than self-related events. This shows that early, implicit and later, more cognitive processes play different relative roles in mirroring self- and other related bodily events. Critically, mirroring differed in the high depersonalisation group, specifically for self-related events. An absence of early, implicit mirroring for self-related events over P45 suggests that the associated processes may be the neural correlates of the disembodiment experienced in depersonalisation. A lack of differential mirroring for self- and other-related events over P200 may reflect compensatory mechanisms that redress deficiencies in mirroring at earlier stages, which may break down to give rise to symptoms of depersonalisation. Alternatively, or in addition, they may represent an attenuation of processes related to self-other distinction. Our study thus shows that mirroring, especially for events on one's own face, can be strongly affected by how connected the observer feels to their own bodily self. PMID- 26970141 TI - Visual attention in posterior stroke and relations to alexia. AB - Impaired visual attention is common following strokes in the territory of the middle cerebral artery, particularly in the right hemisphere, while attentional effects of more posterior lesions are less clear. Commonly, such deficits are investigated in relation to specific syndromes like visual agnosia or pure alexia. The aim of this study was to characterize visual processing speed and apprehension span following posterior cerebral artery (PCA) stroke. In addition, the relationship between these attentional parameters and single word reading is investigated, as previous studies have suggested that reduced visual speed and span may explain pure alexia. Eight patients with unilateral PCA strokes (four left hemisphere, four right hemisphere) were selected on the basis of lesion location, rather than the presence of any visual symptoms. Visual attention was characterized by a whole report paradigm allowing for hemifield-specific measurements of processing speed and apprehension span. All patients showed reductions in visual span contralateral to the lesion site, and four patients showed bilateral reductions in visual span despite unilateral lesions (2L; 2R). Six patients showed selective deficits in visual span, though processing speed was unaffected in the same field (ipsi- or contralesionally). Only patients with right hemifield reductions in visual span were impaired in reading, and this could follow either right or left lateralized stroke and was irrespective of visual field impairments. In conclusion, visual span may be affected bilaterally by unilateral PCA-lesions. Reductions in visual span may also be confined to one hemifield, and may be affected in spite of preserved visual processing speed. Furthermore, reduced span in the right visual field seems to be related to reading impairment in this group, regardless of lesion lateralization. PMID- 26970136 TI - Cancer prevention in HIV-infected populations. AB - People living with human immunodeficiency virus (HIV) are living longer since the advent of effective combined antiretroviral therapy (cART). While cART substantially decreases the risk of developing some cancers, HIV-infected individuals remain at high risk for Kaposi sarcoma, lymphoma, and several solid tumors. Currently HIV-infected patients represent an aging group, and malignancies have become a leading cause of morbidity and mortality. Tailored cancer-prevention strategies are needed for this population. In this review we describe the etiologic agents and pathogenesis of common malignancies in the setting of HIV, as well as current evidence for cancer prevention strategies and screening programs. PMID- 26970143 TI - Patterns of alpha asymmetry in those with elevated worry, trait anxiety, and obsessive-compulsive symptoms: A test of the worry and avoidance models of alpha asymmetry. AB - Some authors have argued that worry cues lateralization of frontal brain activity leftward, whereas other varieties of avoidance motivation cue lateralization of frontal brain activity rightward. By comparison, more right-than-left parietal activity correlates with anxious arousal. The purpose of the present report was to test two models of brain lateralization and anxiety: one model that proposed that worry correlates with more left-frontal activity and another model that proposed that avoidance motivation (including worry) correlates with more right frontal activity. Undergraduate students were selected for worry, obsessive compulsive symptoms, and trait anxiety using self-report questionnaires. A subset of participants also met DSM-IV criteria for Generalized Anxiety Disorder (GAD) or Obsessive-Compulsive Disorder (OCD). Alpha asymmetry and also a global-power adjusted metric of alpha power were calculated from each participant's resting state EEG. It was expected that participants with elevated worry and participants meeting criteria for GAD would show more left-than-right frontal activity. In contrast, participants with elevated trait anxiety, obsessive-compulsive symptoms, and those with an OCD diagnosis were expected to exhibit more right than-left frontal activity. Participants with elevated worry, participants with a GAD diagnosis, and participants with elevated obsessive-compulsive symptoms, had more left frontal activity than low symptom individuals. Those with high scores on trait anxiety, but low worry, had greater right frontal and parietal activity compared to controls. The present results suggest that brain lateralization is not solely related to avoidance motivation, and suggest that facets of anxiety may cut across dimensions not well-represented by DSM-based categories. PMID- 26970142 TI - Electrical stimulation of the dorsolateral prefrontal cortex improves memory monitoring. AB - The ability to accurately monitor one's own memory is an important feature of normal memory function. Converging evidence from neuroimaging and lesion studies have implicated the dorsolateral prefrontal cortex (DLPFC) in memory monitoring. Here we used high definition transcranial direct stimulation (HD-tDCS), a non invasive form of brain stimulation, to test whether the DLPFC has a causal role in memory monitoring, and the nature of that role. We used a metamemory monitoring task, in which participants first attempted to recall the answer to a general knowledge question, then gave a feeling-of-knowing (FOK) judgment, followed by a forced choice recognition task. When participants received DLPFC stimulation, their feeling-of-knowing judgments were better predictors of memory performance, i.e., they had better memory monitoring accuracy, compared to stimulation of a control site, the anterior temporal lobe (ATL). Effects of DLPFC stimulation were specific to monitoring accuracy, as there was no significant increase in memory performance, and if anything, there was poorer memory performance with DLPFC stimulation. Thus we have demonstrated a causal role for the DLPFC in memory monitoring, and showed that electrically stimulating the left DLPFC led people to more accurately monitor and judge their own memory. PMID- 26970144 TI - Factors Determining Outcome After Trigeminal Nerve Surgery for Neuropathic Pain. AB - PURPOSE: Most patients who seek relief from trigeminal neuropathic pain by trigeminal microneurosurgery techniques do not show permanent pain relief after surgery. However, a small number of patients have permanent relief after surgery. The objective of this study was to determine factors that might be associated with the resolution, decrease, or recurrence of neuropathic pain after trigeminal nerve surgery in those patients who present with neuropathic pain before surgery. PATIENTS AND METHODS: An ambispective study design was used to assess patients who underwent trigeminal nerve repair of the inferior alveolar and lingual nerve who had documented neuropathic pain before surgery from 2006 through 2014. The primary endpoint was the difference in pain intensity at 3, 6, and 12 months after surgery compared with presurgical intensity levels. Explanatory variables, including age at surgery, gender, site of nerve injury, etiology of nerve injury, classification of nerve injury, duration from injury to repair, health comorbidities, and type of repair performed, were evaluated as potential factors in the outcomes. Wilcoxon signed rank analysis was used to compare demographic and injury characteristics of patients who had pain relief, partial pain relief, and no pain relief after surgery. Two-way analysis of variance and logistic regression analysis were used to evaluate the association between neuropathic pain and the explanatory variables. RESULTS: Twenty-eight patients met the inclusion criteria. Three cohorts of patients were identified and analyzed. The no-recurrence cohort included 7 patients who had neuropathic pain before surgery that was resolved with surgery. The complete-recurrence (CR) cohort included 10 patients who had neuropathic pain before surgery and complete recurrence of pain intensity after surgery. The incomplete-recurrence (ICR) cohort included 11 patients who had neuropathic pain before surgery and partial recurrence of pain intensity after surgery. There was no statistical difference in preoperative pain intensity levels among the 3 cohorts (P = .16), but there were statistical differences at 3 months (P = .007), 6 months (P < .0001), and 12 months (P < .0001). There were no statistical differences between the CR and ICR cohorts at 3 months (P = .502), 6 months (P = .1), and 12 months (P = .2). There was no effect by age, gender, injury type, Sunderland classification, injury etiology, duration from injury to repair, health comorbidity, or repair type on the outcome. CONCLUSIONS: The recurrence of neuropathic pain after trigeminal nerve repair for neuropathic pain is likely multifactorial and might not depend on factors that normally affect sensory recovery in patients who have no neuropathic pain (ie, age, duration of injury, type of injury, or repair type) and undergo trigeminal nerve surgery. These differences indicate that the understanding of trigeminal neuropathic pain is incomplete. Predictive outcomes of treatment will probably improve when the etiology is better defined to allow target- and site-specific treatment. In the meantime, trigeminal nerve surgery is a treatment option that offers a chance of decreasing or resolving pain intensity. PMID- 26970145 TI - Spontaneous Regeneration of the Mandible: An Institutional Audit of Regenerated Bone and Osteocompetent Periosteum. AB - PURPOSE: Childhood mandibular lesions are frequently benign; this allows for a conservative surgical approach to their management. Two of the most common approaches for reconstruction of acquired mandibular defects in adolescents are vascularized and nonvascularized osseous flaps or grafts. A third, less commonly used treatment option often used in developing parts of the world that some Western centers are considering as part of their treatment algorithm is spontaneous bone regeneration. This study reports on the authors' experiences with spontaneous bone formation of the resected young mandible. It also attempts to quantify any relation between spontaneous bone regeneration and an aging osteocompetent periosteum. PATIENTS AND METHODS: This was a retrospective study based on consecutive data collated from records of the oral and maxillofacial surgery departments from 2 tertiary institutions. Eligible patients were no older than 18 years and had benign mandibular neoplasms. The surgical procedure was mandibulectomy with subperiosteal dissection and intermaxillary fixation. Regenerated bone evaluation was by clinical examination and periodic panoramic radiographs. RESULTS: Sixteen consecutive cases with mandibular lesions were seen at the 2 institutions, 8 of which met the inclusion criteria. The average age was 10.75 years. The predominant pathology was unicystic ameloblastoma. All cases exhibited spontaneous bone regeneration, with 2 cases exhibiting "incomplete" bone regeneration. CONCLUSION: Immediate reconstruction can be delayed to allow for spontaneous bone regeneration of defects in young patients. In the absence of regeneration, secondary reconstruction can be considered. Although the literature reports more young patients with bone regeneration than adults, increasing age during childhood and adolescence might not necessarily indicate a decrease in periosteal bone-regenerating potential. PMID- 26970146 TI - Costs for TB and MDR-TB: time to convene a WHO Emergency Committee on TB? PMID- 26970147 TI - TB-related mortality: a re-emerging problem in high-income countries? PMID- 26970148 TI - Integrated clinical management tools for respiratory diseases: lessons from PAL in sub-Saharan Africa. PMID- 26970149 TI - Re-inventing adherence: toward a patient-centered model of care for drug resistant tuberculosis and HIV. AB - BACKGROUND: Despite renewed focus on molecular tuberculosis (TB) diagnostics and new antimycobacterial agents, treatment outcomes for patients co-infected with drug-resistant TB and human immunodeficiency virus (HIV) remain dismal, in part due to lack of focus on medication adherence as part of a patient-centered continuum of care. OBJECTIVE: To review current barriers to drug-resistant TB-HIV treatment and propose an alternative model to conventional approaches to treatment support. DISCUSSION: Current national TB control programs rely heavily on directly observed therapy (DOT) as the centerpiece of treatment delivery and adherence support. Medication adherence and care for drug-resistant TB-HIV could be improved by fully implementing team-based patient-centered care, empowering patients through counseling and support, maintaining a rights-based approach while acknowledging the responsibility of health care systems in providing comprehensive care, and prioritizing critical research gaps. CONCLUSION: It is time to re-invent our understanding of adherence in drug-resistant TB and HIV by focusing attention on the complex clinical, behavioral, social, and structural needs of affected patients and communities. PMID- 26970150 TI - Characteristics and costs of multidrug-resistant tuberculosis in-patient care in the United States, 2005-2007. AB - OBJECTIVE: A population-based study of 135 multidrug-resistant tuberculosis (MDR TB) patients reported to the Centers for Disease Control and Prevention (CDC) during 2005-2007 found 73% were hospitalized. We analyzed factors associated with hospitalization. METHODS: We assessed statistically significant multivariable associations with US in-patient TB diagnosis, frequency of hospitalization, length of hospital stay, and in-patient direct costs to the health care system. RESULTS: Of 98 hospitalized patients, 83 (85%) were foreign-born. Blacks, diabetics, or smokers were more likely, and patients with disseminated disease less likely, to receive their TB diagnosis while hospitalized. Patients aged ?65 years, those with the acquired immune-deficiency syndrome (AIDS), or with private insurance, were hospitalized more frequently. Excluding deaths, length of stay was greater for patients aged ?65 years, those with extensively drug-resistant TB (XDR-TB), those residing in Texas, those with AIDS, those who were unemployed, or those who had TB resistant to all first-line medications vs. others. Average hospitalization cost per XDR-TB patient (US$285 000) was 3.5 times that per MDR TB patient (US$81 000), in 2010 dollars. Hospitalization episode costs for MDR-TB rank third highest and those for XDR-TB highest among the principal diagnoses. CONCLUSIONS: Hospitalization was common and remains a critical care component for patients who were older, had comorbidities, or required complex management due to XDR-TB. MDR-TB in-patient costs are among the highest for any disease. PMID- 26970151 TI - Discordance between patient and clinician reports of adverse reactions to MDR-TB treatment. AB - SETTING: An urban out-patient clinic in Durban, South Africa, providing community based treatment for drug-resistant tuberculosis (TB). OBJECTIVE: To describe concordance between patient report and clinician documentation of adverse drug reactions (ADRs) to treatment for multidrug-resistant TB (MDR-TB). DESIGN: ADRs were documented by interview using an 18-item symptom checklist and medical record data abstraction during a cross-sectional parent study with 121 MDR-TB patients, 75% of whom were co-infected with the human immunodeficiency virus. Concordance was analyzed using Cohen's kappa statistic, Gwet's agreement coefficient (AC) 1, and McNemar's test. RESULTS: ADRs were reported much more frequently in patient interviews (MU = 8.6) than in medical records (MU = 1.4). Insomnia was most common (67% vs. 2%), followed by peripheral neuropathy (65% vs. 18%), and confusion (61 vs. 4%). kappa scores were very low, with the highest degree of concordance found in hearing loss (kappa = 0.23), which was the only ADR not found to be significantly different between the two data sources (P = 0.34). CONCLUSIONS: Our study showed a lack of concordance between patient report and clinician documentation of ADRs. These findings indicate the need for improved documentation of ADRs to better reflect patients' experiences during MDR TB treatment. These data have important implications for country-level pharmacovigilance programs that rely on clinician documentation of ADRs for MDR TB policy formation. PMID- 26970152 TI - Use of Xpert((r)) MTB/RIF assay in the first national anti-tuberculosis drug resistance survey in Pakistan. AB - SETTING: The first national anti-tuberculosis drug resistance survey in Pakistan, a high tuberculosis (TB) and low human immunodeficiency virus (HIV) burden country. OBJECTIVE: To determine the proportion of patients with multidrug resistant TB (MDR-TB) and to compare the performance of Xpert((r)) MTB/RIF with conventional phenotypic drug susceptibility testing (DST). METHODS: Sputum samples were collected from 1972 consecutively enrolled pulmonary TB patients from 40 clusters. Phenotypic DST was performed in parallel with Xpert. RESULTS: The proportion of MDR-TB patients was 3.7% (95%CI 2.5-5.0) among new and 18.1% (95%CI 13.0-23.4) among previously treated cases. A valid rifampicin (RMP) testing result was available from substantially more cases with Xpert (n = 1809) than with phenotypic DST (n = 1592). Among strains with discordant results, rpoB sequencing revealed only one false-resistant result (new TB case) with Xpert and 7.7% (8/104) of RMP-resistant cases missed with Xpert against 3.8% (4/14) by phenotypic DST. This difference was not significant. CONCLUSIONS: This survey provides the first representative data for Pakistan on its MDR-TB burden. The Xpert assay had nearly 100% specificity, even in a low MDR-TB prevalence setting. The use of this assay greatly simplifies survey logistics, making it a feasible option for survey implementation, especially in resource-constrained settings. PMID- 26970153 TI - Modified cytospin slide microscopy method for rapid diagnosis of smear-negative pulmonary tuberculosis. AB - OBJECTIVE: To evaluate a modified method of the Ziehl-Neelsen stain and determine whether it improves the detection rate of acid-fast bacilli (AFB) in bronchoalveolar lavage fluid (BALF) specimens. DESIGN: Bronchoscopy of patients with suspected smear-negative pulmonary tuberculosis (PTB) patients was conducted to collect BALF to assess the efficacy and accuracy of the modified method for PTB diagnosis. RESULTS: A total of 106 BALF specimens was collected from 74 PTB patients on the basis of BALF samples that were culture-positive for Mycobacterium tuberculosis. When analysed by patient, the sensitivity and specificity of our modified method were respectively 87.8% and 99.6%, while the positive predictive (PPV) and negative predictive values (NPV) were respectively 98.5% and 96.8%. Conversely, the sensitivity of direct smears and concentrated smears was respectively 16.2% and 37.8%, with 100% specificity. On analysing 106 samples, the culture positivity rate of the direct smear and the concentrated smear methods was respectively 76.4%, 13.2% and 34%, while it was 91.5% for the modified method. CONCLUSION: The sensitivity of our modified method was significantly higher than that of direct or concentrated smears. Overall, the modified method improved the detection rate of AFB in BALF specimens, and provided an efficient and accurate diagnosis of PTB in patients with suspected smear-negative PTB. PMID- 26970154 TI - Rapid colorimetric pyrazinamide susceptibility testing of Mycobacterium tuberculosis. AB - SETTING: Colorimetric methods for detecting drug resistance in Mycobacterium tuberculosis are very attractive, as they are cheap, easy to use and require no costly apparatus. Although the current colorimetric methods have been used for other drugs, such as rifampicin and isoniazid, few of the colorimetric methods have been reported to have been used in performing drug susceptibility testing (DST) against pyrazinamide (PZA). OBJECTIVE: To develop a rapid and reliable colorimetric method for PZA DST using a monotetrazolium redox dye, 5-cyano-2,3 ditolyl tetrazolium chloride (CTC), as indicator of viability. DESIGN: A total of 50 clinical isolates and three standard strains were tested using this colorimetric method and the BACTECTM MGITTM 960 system. RESULTS: Initial test results showed that the PZA DST results were available in 4-6 days; the overall sensitivity and specificity of the CTC colorimetric method were respectively 97.1% and 81.3% in comparison with the MGIT 960 results. CONCLUSION: These results suggest that the CTC colorimetric method is most rapid among the current PZA DST methods based on culture, and could be used for determining susceptibility to PZA of M. tuberculosis isolates. PMID- 26970155 TI - Evaluation of the direct nitrate reductase assay for rapid detection of extensively drug-resistant tuberculosis. AB - SETTING: Jiangxi, China. OBJECTIVE: To evaluate the performance of the direct nitrate reductase assay (D-NRA) for rapid, low-cost detection of multidrug resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) in high burden, resource-limited settings. METHODS: A total of 225 smear-positive sputum samples were collected from consecutive drug-resistant TB subjects. Samples were processed at the Province TB Reference Laboratory and tested for susceptibility to rifampicin (RMP), isoniazid (INH), ofloxacin (OFX), kanamycin (KM) and capreomycin (CPM) by D-NRA, using the indirect Lowenstein-Jensen proportion method (LJ-PM) as reference. RESULTS: Of the 225 smear-positive sputum samples, 214 isolates were identified as Mycobacterium tuberculosis and analysed for further comparison. The sensitivity of the D-NRA in the detection of resistance to RMP, INH, OFX, KM and CPM was respectively 95.1% (97/102), 93.1% (135/145), 97.4% (76/78), 88.9% (40/45) and 90.6% (29/32); specificity was respectively 100% (112/112), 97.1% (67/69), 100% (136/136), 98.8% (167/169) and 96.7% (176/182). The median time to culture positivity was significantly shorter for NRA than for the indirect LJ-PM (14 days vs. 70 days, P < 0.001). CONCLUSION: D-NRA showed high sensitivity and specificity in the rapid diagnosis of MDR- and XDR-TB in a high-burden, resource-limited setting. PMID- 26970156 TI - Treating children for drug-resistant tuberculosis in Tajikistan with Group 5 medications. AB - BACKGROUND: Management of extensively drug-resistant tuberculosis (XDR-TB) and pre-XDR-TB is challenging, as effective drugs are lacking. Group 5 anti tuberculosis drugs have an unclear role in the treatment of drug-resistant TB, and in children the efficacy, safety and effects of long-term use are not well described. We present clinical outcomes and adverse effects of a cohort of children with XDR-TB or pre-XDR-TB treated with Group 5 drugs in Tajikistan. METHODS: We conducted a retrospective analysis of eight children treated with one or more of the Group 5 drugs available under the Tajikistan National TB Programme linezolid, amoxicillin-clavulanate, clofazimine and clarithromycin-given in combination with first- and second-line drugs. Time to sputum culture conversion, clinical outcomes and adverse effects were evaluated. RESULTS: Two children were cured, one completed treatment, four achieved favourable interim outcomes and one died. Adverse effects attributable to linezolid that required drug cessation occurred in one child; adverse effects of the other Group 5 drugs were insignificant or absent, requiring no regimen changes. CONCLUSION: Group 5 drugs can contribute to effective regimens in children with XDR and pre-XDR-TB. With proper monitoring and aggressive management of adverse effects, their safety profile might be acceptable, even in long-term use. PMID- 26970157 TI - Non-completion of latent tuberculous infection treatment among children in Rio de Janeiro State, Brazil. AB - BACKGROUND: Children with latent tuberculous infection (LTBI) are particularly vulnerable to progression to active tuberculosis (TB), and are thus a priority target for isoniazid preventive therapy (IPT). However, adherence to IPT is poor. We hypothesised that children from poorer families, with reduced access to health care and lack of understanding about the disease are more likely to default from IPT. METHODS: A questionnaire was administered to close child contacts or their parents at the time of prescribing IPT in three cities in Rio de Janeiro State. The children were followed prospectively. Treatment adherence was defined as taking 80% of prescribed doses. RESULTS: Among 1078 children screened for LTBI, 97 (8.9%) did not return for tuberculin skin test (TST) reading; 332 (30.8%) were TST-positive; 115/332 (34.6%) were prescribed IPT, 6 of whom did not initiate treatment and 11 did not adhere during the first 2 months; 25 additional children did not complete IPT. Overall non-completion was four times more frequent among those with lower income. Health care access and knowledge did not improve treatment completion. CONCLUSIONS: Substantial losses to follow-up occurred before IPT prescription; this should be further investigated. Among the children who started isoniazid, low income, but not difficult access or poor knowledge, increased the risk of treatment non-completion. PMID- 26970158 TI - Using the TBAg/PHA ratio in the T-SPOT((r)).TB assay to distinguish TB disease from LTBI in an endemic area. AB - SETTING: An important limitation of the T-SPOT((r)).TB assay is its inability to distinguish active tuberculosis (TB) from latent tuberculous infection (LTBI). OBJECTIVE: We proposed a new calculation method for the T-SPOT assay and assessed its effect on distinguishing active TB from LTBI. DESIGN: A total of 162 active TB patients and 97 LTBI individuals were diagnosed according to conventional tests and the T-SPOT assay. RESULTS: The results of early secreted antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) in T-SPOT cannot be recommended for distinguishing TB from LTBI. The number of phytohaemagglutinin (PHA) spot-forming cells (sfc) in the T-SPOT assay was reduced in active TB patients. The ESAT-6/PHA or CFP-10/PHA ratios in active TB patients were significantly higher than in individuals with LTBI. Using 0.295 as the threshold ratio of Mycobacterium tuberculosis-specific antigen (TBAg) sfc to PHA sfc (TBAg/PHA ratio, the larger of ESAT-6/PHA and CFP-10/PHA), the sensitivity and specificity were 82.1% and 90.7% in distinguishing active TB from LTBI. The TBAg/PHA ratio might also be used to monitor the effect of anti-tuberculosis treatment. CONCLUSIONS: Calculating the TBAg/PHA ratio might have the potential to diagnose active TB and distinguish TB disease from LTBI. PMID- 26970159 TI - Diagnostic accuracy of interferon-gamma release assays for tuberculous meningitis: a meta-analysis. AB - OBJECTIVE: To evaluate the diagnostic accuracy of interferon-gamma release assays (IGRAs) for diagnosing tuberculous meningitis (TBM). DESIGN: The EMBASE and PubMed databases were systematically searched to identify studies published by 2 May 2015 investigating the diagnostic accuracy of IGRA for TBM. The quality of the included studies was assessed using the revised Quality Assessment for Studies of Diagnostic Accuracy (QUADAS-2) method. The overall diagnostic accuracies of an IGRA for cerebrospinal fluid (CSF) or blood were pooled using a bivariate model. RESULTS: Eight studies using blood IGRA and 6 studies using CSF IGRA were included. The overall sensitivities for blood and CSF IGRA were respectively 0.78 and 0.77, and the specificities were 0.61 and 0.88. The areas under the summary receiver operating characteristic curves were respectively 0.76 and 0.83 for blood and CSF IGRA. The major design weaknesses of the studies included were patient selection bias and exclusion of uninterpretable results. CONCLUSION: The diagnostic accuracy of blood and CSF IGRA in case of TBM is moderate. PMID- 26970160 TI - Safety and efficacy of tuberculin skin testing with microneedle MicronJet600TM in healthy adults. AB - SETTING: Intradermal injection using a syringe and needle is generally accepted as the most accurate method for the tuberculin skin test (TST). However, the Mantoux technique using a conventional needle is often difficult to perform reliably, affecting testing results and safety. OBJECTIVE: We evaluated the efficacy and safety of a novel intradermal injection device, the MicronJet600(TM) microneedle, compared with conventional injection in terms of skin reactivity to the TST. DESIGN: A prospective, open-label clinical study was conducted. The TST was administered by both methods in the same subject. For pain assessment, participants filled in a visual analogue scale (VAS) after each TST. Any side effects due to TST or injections were observed. RESULTS: TST reaction rates (cut off ?5 mm) from microneedles and needles were respectively 44.0% and 47.2%, with no significant difference between the two. Furthermore, agreement of positivity between the two methods was excellent with both 5 mm and 10 mm cut-off values. However, the level of pain experienced when microneedles were used for TST was significantly lower than with conventional needles. No adverse effects were attributed to the MicronJet device. CONCLUSION: The novel microneedle device used for TST in this study was effective, safe and less painful in healthy adult volunteers. PMID- 26970161 TI - Clinical and molecular epidemiological features of tuberculosis after the 2011 Japan earthquake and tsunami. AB - OBJECTIVE: To investigate clinical characteristics and prognosis in tuberculosis (TB) patients and the transmission dynamics of TB after the 2011 Japan earthquake and tsunami. METHOD: This was a retrospective observational cohort study. Data were analyzed among 93 pulmonary TB patients (tsunami-affected areas 25, non tsunami areas 68) hospitalized during March 2011-March 2012 with 1-year follow-up since treatment commencement. Variable number of tandem repeats (VNTR) typing was conducted for 38 TB strains (tsunami-affected areas 21, non-tsunami areas 17). RESULTS: Patients from tsunami-affected areas were significantly more likely to be refugees (OR 12.8, 95%CI 2.45-67.20), receive oxygenation (OR 5.0, 95%CI 1.68 14.85), and have a unique VNTR (OR 4.6, 95%CI 1.14-18.41). Patients who died within 1 year were significantly more likely to be older (OR 9.8, 95%CI 1.85 180.26), partially dependent or dependent (OR 11.9, 95%CI 4.28-37.62), and to require oxygenation (OR 4.3, 95%CI 1.47-12.89), and had lower serum albumin levels (OR 11.1, 95%CI 2.97-72.32). CONCLUSION: Risk factors for prognosis of TB after the earthquake were associated with advanced age, low serum albumin level, functional status at admission, and oxygen requirement. The VNTR results suggest that most of the cases with pulmonary TB experienced reactivation of latent tuberculous infection, likely due to the impact of the earthquake and tsunami. PMID- 26970162 TI - Mortality among tuberculosis cases in Victoria, 2002-2013: case fatality and factors associated with death. AB - SETTING: The state of Victoria, Australia, is an industrialised setting with low tuberculosis (TB) incidence, universal health care and high levels of migration. OBJECTIVE: To assess case fatality rates (CFRs) and factors associated with death in a cohort of TB cases notified between 2002 and 2013. DESIGN: Retrospective cohort study. Cases who died untreated or during treatment were reviewed to determine whether TB was a primary cause of, contributed to or was unrelated to death. Descriptive and multivariate analyses were used to compare demographic, clinical and pathological characteristics. RESULTS: Of 3956 cases, 198 (5.0%) died of any cause. TB was the primary cause of death in 99 cases (50.3%) and contributed to death in a further 34 cases, giving a TB-related CFR of 3.4%. In multivariate analysis, TB-related mortality reduced over time, and was positively associated with male sex, older age, history of substance use and disseminated or meningeal TB. Factors associated with survival included having a history of past travel to or residence in a high TB risk country, lymph node TB or extra pulmonary TB manifestations, excluding meningeal, genitourinary, pleural and lymphnode TB. CONCLUSIONS: TB CFRs in this setting are among the lowest reported globally. TB mortality steadily decreased from 2002 to 2013. PMID- 26970163 TI - Mortality and predictors in pulmonary tuberculosis with respiratory failure requiring mechanical ventilation. AB - OBJECTIVE: To analyse the predictors and mortality rate among patients receiving mechanical ventilation (MV) for respiratory failure due to pulmonary tuberculosis (TB). DESIGN: We retrospectively compared patients who required MV for TB with patients who required MV for community-acquired pneumonia (CAP). RESULTS: In hospital mortality was significantly different between the two groups: 95.1% in TB vs. 62.7% in CAP (P < 0.001 using the chi(2) test). TB patients had a higher 30-day mortality (P = 0.040 using log-rank test), although the median sequential organ failure assessment (SOFA) (7.0 vs. 6.0, P = 0.842) and mean Acute Physiology and Chronic Health Evaluation (APACHE) II scores (20.0 +/- 6.7 vs. 21.2 +/- 6.7, P = 0.379) for TB and CAP patients were not different. TB patients were more likely to have increased lung lesion intrusions (OR 1.307, 95%CI 1.042 1.641, P = 0.021), and reduced albumin (OR 0.073, 95%CI 0.016-0.335, P = 0.001), C-reactive protein (OR 0.324, 95%CI 0.146-0.716, P = 0.005) and CURB-65 score (confusion, uraemia, respiratory rate, blood pressure and age ?65 years) (OR 0.916, 95%CI 0.844-0.995, P = 0.037). CONCLUSIONS: TB patients showed identical SOFA and APACHE II scores, but higher mortality than CAP patients. The higher mortality was not related to severity, but suggested an association with the extent of destructive lung lesions. PMID- 26970165 TI - Treatment as diagnosis and diagnosis as treatment: empirical management of presumptive tuberculosis in India. AB - BACKGROUND: Mismanagement of TB is a concern in the Indian private sector, and empirical management might be a key contributor. OBJECTIVE: To understand factors associated with empirical diagnosis and treatment of presumed TB in India's private sector and examine their effects on TB care. DESIGN: In this ethnographic study, 110 private practitioners of varying qualification who interacted with TB patients (90 in Mumbai and 20 in Patna) were interviewed, and a subset was observed while providing clinical care. Interviews and observations were analysed for indicators of empirical diagnosis and treatment. RESULTS: All non-specialist practitioners began antibiotic treatment, especially quinolones, for persistent cough before prescribing a test. Several factors contribute to empirical management. These include a common practice use of medications as diagnostic tools, a desire to provide rapid symptom relief to patients, a desire to manage illness costs effectively, uncertainty about the presentation of TB, the effects of broad spectrum antibiotics on TB symptomology, and uncertainty about the accuracy of available TB tests. CONCLUSION: Empiricism in general and in TB care is widespread in the urban private sector in India. Ethnography might offer useful insights for addressing this in public-private mix models. PMID- 26970164 TI - Tuberculosis and immigration in an area of southwest Madrid. AB - OBJECTIVE: To describe differences between Spanish and immigrant tuberculosis (TB) cases. DESIGN: Retrospective descriptive study of Spanish and immigrant TB patients diagnosed in a Madrid hospital from 2004 to 2013. RESULTS: A total of 322 patients were analysed, 183 Spanish-born and 139 immigrants (sub-Saharan Africa 32.4%, Morocco 28.8%, Latin America 20.1% and Eastern Europe 17.3%). Immigrants were younger and had a higher rate of human immunodeficiency virus (HIV) infection (P < 0.05). Spanish TB patients were often smokers and immunosuppressed (not HIV) (P < 0.001). No differences in symptoms and site of disease were detected. A higher proportion with isoniazid (INH) resistance was observed among immigrants (14.6% vs. 3.8%, P < 0.05), regardless of country of origin. Being an immigrant was an independent risk factor for INH resistance (OR 4.8, 95%CI 1.3-17.9). CONCLUSION: There is currently no consensus on whether or not it would be appropriate to treat Spanish and immigrant patients with different regimens. Being an immigrant is a clear risk factor for INH resistance. According to our results, it is necessary to evaluate the impact of changing treatment protocols in Madrid, Spain. It is also important to introduce specific strategies for the management of TB among immigrants. PMID- 26970166 TI - How do patients access the private sector in Chennai, India? An evaluation of delays in tuberculosis diagnosis. AB - SETTING: The diagnosis and treatment of tuberculosis (TB) in India are characterized by heavy private-sector involvement. Delays in treatment remain poorly characterized among patients seeking care in the Indian private sector. OBJECTIVE: To assess delays in TB diagnosis and treatment initiation among patients diagnosed in the private sector, and pathways to care in an urban setting. DESIGN: Cross-sectional survey of 289 consecutive patients diagnosed with TB in the private sector and referred for anti-tuberculosis treatment through a public-private mix program in Chennai from January 2014 to February 2015. RESULTS: Among 212 patients with pulmonary TB, 90% first contacted a formal private provider, and 78% were diagnosed by the first or second provider seen after a median of three visits per provider. Median total delay was 51 days (mean 68). Consulting an informal (rather than formally trained) provider first was associated with significant increases in total delay (absolute increase 22.8 days, 95%CI 6.2-39.5) and in the risk of prolonged delay >90 days (aRR 2.4, 95%CI 1.3-4.4). CONCLUSION: Even among patients seeking care in the formal (vs. informal) private sector in Chennai, diagnostic delays are substantial. Novel strategies are required to engage private providers, who often serve as the first point of contact. PMID- 26970167 TI - The 'Practical Approach to Lung Health' in sub-Saharan Africa: a systematic review. AB - SETTING: There is a high burden of respiratory disease in sub-Saharan Africa. To address this problem, the World Health Organization launched the 'Practical approach to Lung Health' (PAL), i.e., locally applicable integrated syndromic algorithms, to improve primary care management of these diseases. OBJECTIVE: To examine the evidence for the impact of PAL on the diagnosis and management of tuberculosis (TB) and other common respiratory problems in sub-Saharan Africa. DESIGN: A systematic review of MEDLINE (1998-2015), EMBASE (1998-2015) and CINAHL (1998-2015) was conducted to find trials evaluating PAL implementation in sub Saharan Africa. RESULTS: Five studies were found, evaluating three PAL variations: PAL in South Africa (PALSA), PALSA with integrated human immunodeficiency virus treatment (PALSA PLUS) and PAL in Malawi using lay health workers (PALM/LHW). PALSA increased TB diagnosis (OR 1.72, 95%CI 1.04-2.85), as did PALSA PLUS (OR 1.25, 95%CI 1.01-1.55). Cure or completion rates in retreatment cases in PALSA and PALSA PLUS were significantly improved (OR 1.78, 95%CI 1.13-2.76). PALM/LHW, which examined TB treatment success, found no significant improvement (P = 0.578). CONCLUSION: The limited research performed shows that PAL can be effective in TB diagnosis and partial treatment success; however, more evidence is needed to assess its effects on other respiratory diseases, especially in wider sub-Saharan Africa. PMID- 26970168 TI - Lung cancer awareness and anticipated delay before seeking medical help in the middle-belt population of Nigeria. AB - SETTING: Ilorin metropolis in the middle-belt region of Nigeria. OBJECTIVES: To determine the awareness about warning signs and risk factors for lung cancer and the anticipated delay before seeking medical care in the middle-belt population of Nigeria. DESIGN: This was a cross-sectional study performed among 1125 adults. Lung cancer awareness measure (Lung CAM) was administered face to face by trained interviewers. RESULTS: The respondents' Lung CAM score was low for warning signs and risk factors for lung cancer. Apart from tobacco smoking (69.9%) and air pollution (56.4%), other risk factors were poorly recognised by respondents. Higher education and income and having a relative or friends who had previously had lung cancer were significantly associated with awareness about warning signs and risk factors. The majority (66.8%) would seek help before 2 weeks if they noticed a warning sign. Anticipated delay was associated with non-recognition of any warning sign (OR 3.09, 95%CI 2.26-4.22), lower education (OR 1.90, 95%CI 1.40 2.57), lower income (OR 1.86, 95%CI 1.26-2.75) and males (OR 1.50, 95%CI 1.15 1.97). CONCLUSION: The awareness of lung cancer warning signs and risk factors are not satisfactory in Nigeria. There is a need to increase awareness about the condition to prevent delays in seeking medical help. PMID- 26970170 TI - In reply. PMID- 26970169 TI - Read the new microscopy handbook: even the Ziehl-Neelsen technique has changed. PMID- 26970171 TI - Down-regulation of EZH2 expression in myelodysplastic syndromes. AB - EZH2 genetic mutations are common in myelodysplastic syndrome (MDS), which implies that this gene has a pathophysiological role in the disease. To further characterize molecular alterations of EZH2, and their potential prognostic impact in MDS, we assessed EZH2 RNA expression in primary bone marrow CD34+ cells from 78 patients. We found that 47% of patients have reduced EZH2 expression compared to normal controls. Further analyses revealed that EZH2 is significantly underexpressed in patients bearing chromosome 7 or 7q deletions (7-alt) when compared to controls, diploid patients, and patients with other cytogenetic alterations (p<0.05). In survival analysis, we found a non-significant trend toward overall survival (OS) being better among patients with EZH2 underexpression (median OS 55 vs. 36 months; p=0.71). Importantly, this trend became significant when the analysis was restricted to the subset of cases without alterations in chromosome 7 (62 vs. 36 months; p=0.033). Furthermore, our previous work has identified a spectrum of innate immune genes in MDS CD34+ cells that are deregulated via abnormal promoter histone methylation. Because EZH2 is a key regulator of histone methylation, we assessed the relationship between deregulation of these genes and EZH2 underexpression. We observed that the mRNA levels of 11 immune genes were higher in the EZH2 underexpression group and that immune gene expression was significantly higher in patients with concomitant EZH2 underexpression and KDM6B (also known as JMJD3, an H3K27 demethylase) overexpression. Taken together, these data indicate that EZH2 underexpression may have unique impact on the molecular pathogenesis and prognosis in MDS and be an important marker for patients without chromosome 7 alteration. PMID- 26970172 TI - SF3B1-mutated myelodysplastic syndrome with ring sideroblasts harbors more severe iron overload and corresponding over-erythropoiesis. AB - OBJECTIVE: To clarify the possible biological differences and implication of the SF3B1 gene for patients with MDS-RS (myelodysplastic syndromes with ring sideroblasts). METHODS: Sanger sequencing was performed on mutation hotspots of the SF3B1 gene in MDS-RS patients. The differences between the SF3B1 mutated and wild-type subsets, including the ultrastructure of erythroid precursors, iron profile parameters, erythropoiesis-related measurements, as well as clinical features, were analyzed. RESULTS: SF3B1 mutations were detected in 33 out of fifty-two MDS-RS patients (63%). The vast majority of patients with mutations (94%) were categorized in the lower risk group according to the IPSS (International Prognostic Scoring System), in contrast to only fifty-eight percent of the wild-type cases. In addition to the notably higher percentages of erythroblasts and ring sideroblasts in patients with mutations, abundant electron dense granules in the mitochondria of the erythroid precursors were clearly observed. Moreover, patients with mutations presented both improper iron uptake and distribution (lower serum hepcidin-25 concentration, P=0.028) and enhanced erythropoietic activity (higher soluble transferrin receptor level, P=0.132; higher growth differentiation factor 15 concentration, P<0.001). Finally, MDS-RS patients carrying SF3B1 mutations had a better overall survival (median 38 vs. 18 months, P=0.001) compared to those without mutations. By multivariable analysis, the prognostic significance of the SF3B1 mutation was primarily accounted for by IPSS risk categorization. CONCLUSION: MDS-RS patients carrying SF3B1 mutations harbored a more severe iron overload and corresponding over-erythropoiesis. The better overall survival of SF3B1-mutated MDS-RS patients may be mainly due to the clustering of patients with lower risk disease in this group. PMID- 26970173 TI - Expression of Antioxidant Molecules and Heat Shock Protein 27 in Thyroid Tumors. AB - Oxidative stress-induced DNA damage is a known causing factor for many types of tumors, but information on the role of oxidants and antioxidants in thyroid tumors is limited. The aim of this study was to determine antioxidant levels in thyroid tumors. In this study, tumor and its matched non-tumor thyroid tissue samples were obtained from 53 patients with thyroid tumors. The levels of manganese superoxide dismutase (MnSOD), thioredoxin reductase 2 (TXNRD2), glutathione (GSH), glutathione peroxidase (Gpx), catalase (CAT), and 27 kd heat shock protein (hsp27) were determined in both thyroid tissue samples and cultured thyroid cells by immunohistochemical staining and western blot. Hydrogen peroxide (H2 O2 ) was used to generate oxidant stress in the cell culture experiments. We found that the levels of MnSOD, TXNRD2, GSH, Gpx, and Hsp27 were increased in both malignant and benign tumors, while the level of CAT was decreased. To verify the results of the tissue study, we treated cultured thyroid cells with H2 O2 and found the same pattern of antioxidant changes. Hsp27 was also increased after H2 O2 treatment. The expression of hsp27 was upregulated by 8.24-, 6.96-, and 3.09 fold in thyroid cancer, follicular adenoma, multinodular goiter, respectively. Collectively, our study demonstrated that the levels of hsp27 together with MnSOD, TXNRD2, GSH, and Gpx were significantly upregulated by H2 O2 in thyroid tumors. The increase of these antioxidants is observed in both malignant and benign tumors, particularly in the former. The upregulation of antioxidants is likely a protective mechanism of tumor cells to maintain their survival and growth. J. Cell. Biochem. 117: 2473-2481, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26970174 TI - The clinical outcome of pazopanib treatment in Japanese patients with relapsed soft tissue sarcoma: A Japanese Musculoskeletal Oncology Group (JMOG) study. AB - BACKGROUND: Because the efficacy and safety of pazopanib in Japanese patients with soft tissue sarcoma (STS) had not been evaluated previously in a large-scale cohort, the authors investigated the efficacy and safety of pazopanib in 156 Japanese patients with relapsed STS. This was a retrospective study based on the collection of real-life, postmarketing surveillance data. METHODS: Patients received pazopanib with the objective of treating local recurrence (n = 20), metastasis (n = 104), and both (n = 32). The patient median age was 53.8 years. The primary objective of this study was to clarify the efficacy of pazopanib for patients with STS. RESULTS: The median treatment duration was 28.7 weeks, and the average dose intensity of pazopanib was 609 mg. Adverse events occurred in 127 patients (81.4%). In addition to the main common toxicities, such as hypertension and liver disorder, pneumothorax (n = 11) and thrombocytopenia (n = 16) also were observed. The median progression-free survival for all patients was 15.4 weeks. The median progression-free survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 18.6 weeks, 16.4 weeks, 15.3 weeks, and 8 weeks, respectively. The median survival for all patients was 11.2 months. The median survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 20.1 months, 10.6 months, 9.5 months, and 7.3 months, respectively. CONCLUSIONS: There were apparent differences in the efficacy of pazopanib treatment among histologic types of STS. Pazopanib treatment is a new treatment option; however, adverse events like pneumothorax and thrombocytopenia, which did not occur frequently in the PALETTE study (pazopanib for metastatic soft-tissue sarcoma), should be taken into consideration. Cancer 2016;122:1408-16. (c) 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. PMID- 26970175 TI - Analysis of ANKKI (rs1800497) and DRD2 (rs1079597, rs1800498) variants in five ethnic groups from Punjab, North-West India. AB - Dopamine D2 receptor (DRD2) is one of the essential neurotransmitters in the brain studied extensively in the field of psychiatric disorders, alcoholic behaviors and Pharmacology. It is also a promising gene for studying the evolutionary and genetic variation among populations. The present study was an attempt to understand the extent of genetic variation among five different ethnic groups (Bania, Brahmin, Jat Sikh, Khatri and Scheduled caste) of Punjab (North West India). A total of 1012 individuals belonging to the above mentioned groups were analyzed for three TaqI Polymorphic loci of DRD2 and ankyrin repeat and kinase domain containing 1 (ANKKI) using the allele frequencies and haplotype frequency distribution pattern. All the three loci were found to be polymorphic among the studied populations. The average heterozygosity for all loci in these ethnic groups was fairly substantial ranging from 0.3936 to 0.4986. The genetic differentiation among the population was observed to be in order of 0.0053.Among of the eight studied haplotypes, only six were shared by all the ethnic groups. TaqID and TaqIB loci were reported to be in significantly higher linkage disequilibrium (LD) in Scheduled Caste only, whereas TaqIA and TaqID showed modest LD in Brahmin, Jat Sikh and Khatri. Multidimensional scaling analysis revealed that the studied ethnic groups formed a close cluster, suggesting similar genetic structure of these populations which are in close proximity with other Indo European speaking North Indian and western Indian population groups. Overall this study highlights the genomic uniformity among the ethnic groups of Punjab (North-West India) owing to their common ancestral history and geographical closeness. PMID- 26970177 TI - Comparison of the risk prediction systems POSSUM and P-POSSUM with the Surgical Risk Scale: A prospective cohort study of 721 patients. AB - INTRODUCTION: The outcomes of surgery are subject to variability and difficult to be accurately predicted. Different score systems have been developed to estimating the risk of undergoing a surgical procedure. The aim of this study was to assess the predictive ability of POSSUM and P-POSSUM scoring systems, compared to the Surgical Risk Scale (SRS), in Spanish patients undergoing general surgery. PATIENTS AND METHODS: In this prospective observational study, 721 consecutive patients needing a surgical procedure were included. Observed morbidity and mortality after surgery were compared to the expected ones obtained by applying POSSUM, P-POSSUM and SRS. RESULTS: Mean age was 59.2 years (standard deviation (SD): 17.4 years), 43.5% were women. 616 (85.5%) patients underwent elective general surgery and 105 (14.5%) emergency surgery. The 30-day morbidity was 15.4%. The reintervention rate was 2.1% and mortality was 2.1%. The discrimination ability was excellent in predicting mortality. The Area Under the Curve (AUC) values were: POSSUM: AUC = 0.97, C.I.95%: 0.948-0.992, p < 0.0001; P POSSUM: AUC = 0.966, C.I.95%: 0.941-0.991, p < 0.0001; SRS: AUC = 0.91, C.I.95%:0.853-0.967, p < 0.0001. POSSUM was also discriminative in the prediction of morbidity (AUC = 0.772, C.I.95%: 0.719-0.826, p < 0.0001). POSSUM predicted morbidity and mortality were higher than the observed ones (p = 0.01 and p = 0.04). Predicted and observed mortality were very similar for P-POSSUM (p = 0.93) and SRS (p = 0.37). CONCLUSIONS: Expected morbidity and mortality determined by POSSUM score showed values significantly above the observed ones. P-POSSUM and SRS systems were effective in predicting mortality. The SRS application is simple and may contribute to appropriate medical decision making. PMID- 26970178 TI - Physico-chemical properties of corn starch modified with cyclodextrin glycosyltransferase. AB - Cyclodextrin glycosyltransferase (CGTase) has been used to produce cyclodextrins (CDs) from starches, but their ability to modify starches has been barely explored. The effect of CGTase on corn starch at sub-gelatinization temperature (50 degrees C) and at different pH conditions, pH 4.0 and pH 6.0, was evaluated. Biochemical features, thermal and structural analysis, oligosaccharides and CDs content were studied. Microscopic analysis of the granules confirmed the enzymatic modification of the starches obtaining structures with irregular surface and small pinholes. The extent of the starch modification was largely dependent on the pHs, being higher at pH 6.0. This was also confirmed by the low viscosity of the resulting pastes during a heating and cooling cycle. Thermal parameters were not affected due to enzymatic treatment. Modified starches were less susceptible to undergo alpha-amylase hydrolysis. CDs released were higher for samples treated at pH 4.0. Therefore, CGTase modification of corn starches at sub-gelatinization temperature offers an attractive alternative for obtaining porous starches with different properties depending on the pH conditions. PMID- 26970176 TI - Calponin isoforms CNN1, CNN2 and CNN3: Regulators for actin cytoskeleton functions in smooth muscle and non-muscle cells. AB - Calponin is an actin filament-associated regulatory protein expressed in smooth muscle and many types of non-muscle cells. Three homologous genes, CNN1, CNN2 and CNN3, encoding calponin isoforms 1, 2, and 3, respectively, are present in vertebrate species. All three calponin isoforms are actin-binding proteins with functions in inhibiting actin-activated myosin ATPase and stabilizing the actin cytoskeleton, while each isoform executes different physiological roles based on their cell type-specific expressions. Calponin 1 is specifically expressed in smooth muscle cells and plays a role in fine-tuning smooth muscle contractility. Calponin 2 is expressed in both smooth muscle and non-muscle cells and regulates multiple actin cytoskeleton-based functions. Calponin 3 participates in actin cytoskeleton-based activities in embryonic development and myogenesis. Phosphorylation has been extensively studied for the regulation of calponin functions. Cytoskeleton tension regulates the transcription of CNN2 gene and the degradation of calponin 2 protein. This review summarizes our knowledge learned from studies over the past three decades, focusing on the evolutionary lineage of calponin isoform genes, their tissue- and cell type-specific expressions, structure-function relationships, and mechanoregulation. PMID- 26970179 TI - Cdx-2 polymorphism in Vitamin D Receptor gene was associated with serum 25 hydroxyvitamin D levels, bone mineral density and fracture in middle-aged and elderly Chinese women. AB - The aim of the current study was to examine the relationship between Cdx-2 polymorphism in the promoter region of the VDR gene and serum 25-hydroxyvitamin D (25(OH)D) levels, bone mineral density (BMD) and fracture in Chinese population. This was a cross-sectional study, which included 738 individuals (428 women and 310 men) aged 45 years or older. In women, the association of Cdx-2 polymorphism with serum 25(OH)D levels was significant adjusting for age, BMI, estimated glomerular filtration rate, menopausal status and season of blood collection (P = 0.002). Cdx-2 polymorphism was associated with lumbar spine BMD adjusted for age, BMI, menopausal status and serum 25(OH)D in women (P = 0.005). But it was not associated with femoral neck BMD or total hip BMD in women. In women, Cdx-2 polymorphism was also associated with fracture adjusted for age, BMI, menopausal status, serum 25(OH)D and total hip BMD (P = 0.03). Carriers of AA and AG genotypes was associated with a higher odds of fracture compared with the carriers of GG genotype (OR = 2.14, 95% CI 1.04-4.42 and OR = 1.90, 95% CI 1.03 3.51). In men, Cdx-2 polymorphism was not associated with serum 25(OH)D levels, BMD or fracture. Our results indicate that the association of Cdx-2 polymorphism in the VDR gene with serum 25(OH)D levels, BMD and fracture may have sex differences. Cdx-2 polymorphism in the VDR gene may affect the serum 25(OH)D concentrations and the risk of osteoporosis and fracture in middle-aged and elderly Chinese women. PMID- 26970180 TI - KCNQ1 gene variants in the risk for type 2 diabetes and impaired renal function in the Spanish Renastur cohort. AB - Several common KCNQ1 gene polymorphisms have been associated with the risk of type 2 diabetes (T2DM) and diabetic nephropathy. This effect is explained by the role of the kcnq1 protein as a potassium channel that in the pancreatic beta cells drives an electrical signal that facilitates glucose-stimulated insulin secretion. The KCNQ1 gene is also expressed in the kidney, and could thus be implicated in the risk of developing impaired renal function. To test this hypothesis, we genotyped six common KCNQ1 gene variants (three single nucleotide polymorphisms, rs2237892, rs2237895, and rs231362, and three intronic indels) in 681 healthy elderly individuals (>65 years old) from the Spanish Renastur cohort. None of the six variants was associated with T2DM (180 diabetics vs. 581 non diabetics). The intron 12 insertion allele was associated with a reduced estimated glomerular filtration rate (eGFR<60, n = 90 vs. eGFR>=60, n = 591; II vs ID + DD genotypes, p = 0.031, OR = 2.06, 95%CI = 1.12-4.14). We also performed a next generation sequencing search of variants in the coding regions of the KCNQ1 gene in 100 individuals with the extreme eGFR values. We found two rare amino acid changes (p.K393N and p.P408A) and the 393 Asn variant was found only among diabetics (n = 4; p = 0.05). The two rare alleles were present in the two eGFR groups. Our results suggest that a common KCNQ1 intron 12 indel polymorphism is a risk factor for impaired renal function independent of T2DM. If this association is confirmed by others, further research to determine the mechanism that drives this association would be warranted. PMID- 26970182 TI - Role of the dysfunctional ryanodine receptor - Na(+)-Ca(2+)exchanger axis in progression of cardiovascular diseases: What we can learn from pharmacological studies? AB - Abnormal Ca(2+)homeostasis is often associated with chronic cardiovascular diseases, such as hypertension, heart failure or cardiac arrhythmias, and typically contributes to the basic ethiology of the disease. Pharmacological targeting of cardiac Ca(2+)handling has great therapeutic potential offering invaluable options for the prevention, slowing down the progression or suppression of the harmful outcomes like life threatening cardiac arrhythmias. In this review we outline the existing knowledge on the involvement of malfunction of the ryanodine receptor and the Na(+)-Ca(2+)exchanger in disturbances of Ca(2+)homeostasis and discuss important proof of concept pharmacological studies targeting these mechanisms in context of hypertension, heart failure, atrial fibrillation and ventricular arrhythmias. We emphasize the promising results of preclinical studies underpinning the potential benefits of the therapeutic strategies based on ryanodine receptor or Na(+)-Ca(2+)exchanger inhibition. PMID- 26970183 TI - Topical skin treatment with Fab fragments of an allergen-specific IgG1 monoclonal antibody suppresses allergen-induced atopic dermatitis-like skin lesions in mice. AB - Fab fragments (Fabs), which lack effector functions due to the absence of the Fc portion, maintain the ability to bind to specific allergens. In the present study, we examined whether Fabs of an allergen-specific IgG1 monoclonal antibody (mAb) were able to regulate allergen-induced atopic dermatitis-like skin lesions in mice. BALB/c mice passively sensitized with ovalbumin (OVA)-specific IgE mAb were repeatedly challenged with OVA applied to the skin after sodium dodecyl sulfate treatment. Fabs prepared by the digestion of anti-OVA IgG1 mAb (O1-10) with papain were applied to the skin 30min before the OVA challenges followed by measurement of clinical symptoms including erythema/hemorrhage, edema, scarring/dryness, and excoriation/erosion of the skin. Treatment with O1-10 Fabs, but not intact O1-10, showed inhibition of clinical symptoms (P<0.01) induced by the repeated OVA challenges in the sensitized mice; O1-10 Fabs suppressed histological changes such as epidermal hyperplasia (P<0.01) and the accumulation of mast cells (P<0.01) and neutrophils (P<0.01). Furthermore, treatment with O1 10 Fabs inhibited the increase in levels of IL-13 (P<0.01) and IL-17A production (P<0.05) in the lymph nodes of the sensitized mice. Additionally, the increased level of OVA in serum following the repeated OVA challenges in the sensitized mice was reduced by the treatment (P<0.05). These results suggest that topical application of pathogenic allergen-specific IgG1 mAb Fabs to the skin of mice is effective in suppressing allergen-induced atopic dermatitis-like skin lesions, suggesting that allergen-specific mAb Fabs could be used as a tool to regulate allergen-induced atopic dermatitis. PMID- 26970181 TI - A randomized phase II dose-response exercise trial among colon cancer survivors: Purpose, study design, methods, and recruitment results. AB - BACKGROUND: Observational studies indicate that higher volumes of physical activity are associated with improved disease outcomes among colon cancer survivors. The aim of this report is to describe the purpose, study design, methods, and recruitment results of the courage trial, a National Cancer Institute (NCI) sponsored, phase II, randomized, dose-response exercise trial among colon cancer survivors. METHODS/RESULTS: The primary objective of the courage trial is to quantify the feasibility, safety, and physiologic effects of low-dose (150 min.week(-1)) and high-dose (300 min.week(-1)) moderate-intensity aerobic exercise compared to usual-care control group over six months. The exercise groups are provided with in-home treadmills and heart rate monitors. Between January and July 2015, 1433 letters were mailed using a population-based state cancer registry; 126 colon cancer survivors inquired about participation, and 39 were randomized onto the study protocol. Age was associated with inquiry about study participation (P<0.001) and randomization onto the study protocol (P<0.001). No other demographic, clinical, or geographic characteristics were associated with study inquiry or randomization. The final trial participant was randomized in August 2015. Six month endpoint data collection was completed in February 2016. DISCUSSION: The recruitment of colon cancer survivors into an exercise trial is feasible. The findings from this trial will inform key design aspects for future phase 2 and phase 3 randomized controlled trials to examine the efficacy of exercise to improve clinical outcomes among colon cancer survivors. PMID- 26970184 TI - Antihyperglycemic and antidiabetic effects of Ethyl (S)-2-(1-cyclohexylsulfamide carbamoyloxy) propanoate in streptozotocin-induced diabetic Wistar rats. AB - In this study, we examined the antihyperglycemic and antidiabetic effects of a novel synthesized molecule, the Ethyl (S)-2-(1-cyclohexylsulfamide carbamoyloxy) propanoate (ESP1b), in streptozotocin (STZ)-induced diabetic Wistar rats. Experimental diabetes mellitus was produced by a single intraperitoneal injection of STZ (55mg/kg b.w.). Seven day post-injection, animals have received ESP1b orally at the doses of 5, 10 and 20mg/kg b.w. daily for 28 days. This resulted in a clear decline, in a dose dependent manner, of blood glucose levels during the oral glucose tolerance test (OGTT) and the four weeks of treatment period. ESP1b at 20mg/kg b.w. has alleviated body weight loss, improved plasma insulin concentration and at the same time markedly decreased the values of glycosylated hemoglobin, lipoproteins and atherogenic ratios. Additionally, ESP1b notably restored renal as well as hepatic functions tests. Histopathological examinations of pancreatic tissue also confirmed the previous biochemical findings. Considering the obtained results, it may be concluded that ESP1b possess a potent antihyperglycemic activity in STZ-diabetic rats possibly related to an insulin secretagogue effect, which may be responsible for the moderate decrease in blood glucose concentration observed in normal rats administrated with this tested compound. PMID- 26970185 TI - Therapeutic effects of antigen affinity-purified polyclonal anti-receptor of advanced glycation end-product (RAGE) antibodies on cholestasis-induced liver injury in rats. AB - Cholestasis leads to acute hepatic injury, fibrosis/cirrhosis, inflammation, and duct proliferation. We investigated whether blocking receptor of advanced glycation end-products (RAGE) with polyclonal anti-RAGE antibodies (anti-RAGE) could regulate acute liver injury and fibrosis in a rat bile duct ligation (BDL) model. Male Wister rats received 0.5mg/kg rabbit anti-RAGE or an equal amount of rabbit IgG by subcutaneous injection twice a week after BDL. Samples of liver tissue and peripheral blood were collected at 14 days after BDL. Serum biochemistry and histology were used to analyze the degree of liver injury. Quantitative real-time PCR (qPCR) and immunohistochemical staining were used to further analyze liver injury. Anti-RAGE improved the gross appearance of the liver and the rat survival rate. Liver tissue histology and relevant serum biochemistry indicated that anti-RAGE attenuated liver necrosis, inflammation, liver fibrosis, and duct proliferation in the BDL model. qPCR and western blotting showed significant reductions in interleukin-1beta expression levels in the liver by treatment with anti-RAGE. Anti-RAGE also significantly reduced the mRNA levels of alpha1(1) collagen (Col1alpha1) and cholesterol 7alpha hydroxylase, and the ratio of tissue inhibitor of matrix metalloproteinase-1 to matrix metalloproteinases (MMPs) in the liver. In addition, anti-RAGE regulated the transcriptional level of Col1alpha1 and MMP-9 in transforming growth factor beta-induced activated LX-2 cells in vitro. Anti-RAGE was found to inhibit hepatic stellate cell proliferation in vivo and in vitro. Therefore, anti-RAGE can protect the liver from injury induced by BDL in rats. PMID- 26970187 TI - Neural activity during sentence processing as reflected in theta, alpha, beta, and gamma oscillations. AB - We used magnetoencephalography (MEG) to explore the spatiotemporal dynamics of neural oscillations associated with sentence processing in 102 participants. We quantified changes in oscillatory power as the sentence unfolded, and in response to individual words in the sentence. For words early in a sentence compared to those late in the same sentence, we observed differences in left temporal and frontal areas, and bilateral frontal and right parietal regions for the theta, alpha, and beta frequency bands. The neural response to words in a sentence differed from the response to words in scrambled sentences in left-lateralized theta, alpha, beta, and gamma. The theta band effects suggest that a sentential context facilitates lexical retrieval, and that this facilitation is stronger for words late in the sentence. Effects in the alpha and beta bands may reflect the unification of semantic and syntactic information, and are suggestive of easier unification late in a sentence. The gamma oscillations are indicative of predicting the upcoming word during sentence processing. In conclusion, changes in oscillatory neuronal activity capture aspects of sentence processing. Our results support earlier claims that language (sentence) processing recruits areas distributed across both hemispheres, and extends beyond the classical language regions. PMID- 26970188 TI - Flood Catastrophe Model for Designing Optimal Flood Insurance Program: Estimating Location-Specific Premiums in the Netherlands. AB - As flood risks grow worldwide, a well-designed insurance program engaging various stakeholders becomes a vital instrument in flood risk management. The main challenge concerns the applicability of standard approaches for calculating insurance premiums of rare catastrophic losses. This article focuses on the design of a flood-loss-sharing program involving private insurance based on location-specific exposures. The analysis is guided by a developed integrated catastrophe risk management (ICRM) model consisting of a GIS-based flood model and a stochastic optimization procedure with respect to location-specific risk exposures. To achieve the stability and robustness of the program towards floods with various recurrences, the ICRM uses stochastic optimization procedure, which relies on quantile-related risk functions of a systemic insolvency involving overpayments and underpayments of the stakeholders. Two alternative ways of calculating insurance premiums are compared: the robust derived with the ICRM and the traditional average annual loss approach. The applicability of the proposed model is illustrated in a case study of a Rotterdam area outside the main flood protection system in the Netherlands. Our numerical experiments demonstrate essential advantages of the robust premiums, namely, that they: (1) guarantee the program's solvency under all relevant flood scenarios rather than one average event; (2) establish a tradeoff between the security of the program and the welfare of locations; and (3) decrease the need for other risk transfer and risk reduction measures. PMID- 26970189 TI - Probing the Translation Dynamics of Ribosomes Using Zero-Mode Waveguides. AB - In order to coordinate the complex biochemical and structural feat of converting triple-nucleotide codons into their corresponding amino acids, the ribosome must physically manipulate numerous macromolecules including the mRNA, tRNAs, and numerous translation factors. The ribosome choreographs binding, dissociation, physical movements, and structural rearrangements so that they synergistically harness the energy from biochemical processes, including numerous GTP hydrolysis steps and peptide bond formation. Due to the dynamic and complex nature of translation, the large cast of ligands involved, and the large number of possible configurations, tracking the global time evolution or dynamics of the ribosome complex in translation has proven to be challenging for bulk methods. Conventional single-molecule fluorescence experiments on the other hand require low concentrations of fluorescent ligands to reduce background noise. The significantly reduced bimolecular association rates under those conditions limit the number of steps that can be observed within the time window available to a fluorophore. The advent of zero-mode waveguide (ZMW) technology has allowed the study of translation at near-physiological concentrations of labeled ligands, moving single-molecule fluorescence microscopy beyond focused model systems into studying the global dynamics of translation in realistic setups. This chapter reviews the recent works using the ZMW technology to dissect the mechanism of translation initiation and elongation in prokaryotes, including complex processes such as translational stalling and frameshifting. Given the success of the technology, similarly complex biological processes could be studied in near physiological conditions with the controllability of conventional in vitro experiments. PMID- 26970190 TI - -1 Programmed Ribosomal Frameshifting as a Force-Dependent Process. AB - -1 Programmed ribosomal frameshifting is a translational recoding event in which ribosomes slip backward along messenger RNA presumably due to increased tension disrupting the codon-anticodon interaction at the ribosome's coding site. Single molecule physical methods and recent experiments characterizing the physical properties of mRNA's slippery sequence as well as the mechanical stability of downstream mRNA structure motifs that give rise to frameshifting are discussed. Progress in technology, experimental assays, and data analysis methods hold promise for accurate physical modeling and quantitative understanding of -1 programmed ribosomal frameshifting. PMID- 26970186 TI - Common pathways regulate Type III TGFbeta receptor-dependent cell invasion in epicardial and endocardial cells. AB - Epithelial-Mesenchymal Transformation (EMT) and the subsequent invasion of epicardial and endocardial cells during cardiac development is critical to the development of the coronary vessels and heart valves. The transformed cells give rise to cardiac fibroblasts and vascular smooth muscle cells or valvular interstitial cells, respectively. The Type III Transforming Growth Factor beta (TGFbetaR3) receptor regulates EMT and cell invasion in both cell types, but the signaling mechanisms downstream of TGFbetaR3 are not well understood. Here we use epicardial and endocardial cells in in vitro cell invasion assays to identify common mechanisms downstream of TGFbetaR3 that regulate cell invasion. Inhibition of NF-kappaB activity blocked cell invasion in epicardial and endocardial cells. NF-kappaB signaling was found to be dysregulated in Tgfbr3(-/-) epicardial cells which also show impaired cell invasion in response to ligand. TGFbetaR3-dependent cell invasion is also dependent upon Activin Receptor-Like Kinase (ALK) 2, ALK3, and ALK5 activity. A TGFbetaR3 mutant that contains a threonine to alanine substitution at residue 841 (TGFbetaR3-T841A) induces ligand-independent cell invasion in both epicardial and endocardial cells in vitro. These findings reveal a role for NF-kappaB signaling in the regulation of epicardial and endocardial cell invasion and identify a mutation in TGFbetaR3 which stimulates ligand independent signaling. PMID- 26970192 TI - Photocontrolled Intracellular RNA Delivery Using Nanoparticles or Carrier Photosensitizer Conjugates. AB - Small interfering RNA (siRNA) and short hairpin RNA (shRNA) may potentially treat a wide variety of diseases through RNA interference-mediated silencing of specific genes. MicroRNAs (miRNAs) are endogenous regulatory RNA molecules that also modulate gene expression, and thus potential therapeutic approaches using miRNAs have attracted attention. For clinical application of these small RNAs, efficient and safe RNA delivery to target tissues and cells is necessary. Current challenges to RNA delivery are the penetration of negatively charged RNAs through the cell membrane and specific delivery of RNA into target cells. Photocontrolled intracellular RNA delivery is a promising strategy with high target specificity. This strategy includes photodependent endosomal escape of RNA or photodependent release of RNAs from carrier particles. In this chapter, photocontrolled intracellular RNA delivery methods employing gold or silver nanoparticles, upconversion nanoparticles, proteins, or polymers are discussed. PMID- 26970191 TI - Studies of RNA Sequence and Structure Using Nanopores. AB - Nanopores are powerful single-molecule sensors with nanometer scale dimensions suitable for detection, quantification, and characterization of nucleic acids and proteins. Beyond sequencing applications, both biological and solid-state nanopores hold great promise as tools for studying the biophysical properties of RNA. In this review, we highlight selected landmark nanopore studies with regards to RNA sequencing, microRNA detection, RNA/ligand interactions, and RNA structural/conformational analysis. PMID- 26970193 TI - RNA Study Using DNA Nanotechnology. AB - Transcription is one of the fundamental steps of gene expression, where RNA polymerases (RNAPs) bind to their template genes and make RNAs. In addition to RNAP and the template gene, many molecules such as transcription factors are involved. The interaction and the effect of these factors depend on the geometry. Molecular layout of these factors, RNAP and gene is thus important. DNA nanotechnology is a promising technology that allows controlling of the molecular layout in the range of nanometer to micrometer scale with nanometer resolution; thus, it is expected to expand the RNA study beyond the current limit. PMID- 26970194 TI - RNA and RNP as Building Blocks for Nanotechnology and Synthetic Biology. AB - Recent technologies that aimed to elucidate cellular function have revealed essential roles for RNA molecules in living systems. Our knowledge concerning functional and structural information of naturally occurring RNA and RNA-protein (RNP) complexes is increasing rapidly. RNA and RNP interaction motifs are structural units that function as building blocks to constitute variety of complex structures. RNA-central synthetic biology and nanotechnology are constructive approaches that employ the accumulated information and build synthetic RNA (RNP)-based circuits and nanostructures. Here, we describe how to design and construct synthetic RNA (RNP)-based devices and structures at the nanometer-scale for biological and future therapeutic applications. RNA/RNP nanostructures can also be utilized as the molecular scaffold to control the localization or interactions of target molecule(s). Moreover, RNA motifs recognized by RNA-binding proteins can be applied to make protein-responsive translational "switches" that can turn gene expression "on" or "off" depending on the intracellular environment. This "synthetic RNA and RNP world" will expand tools for nanotechnology and synthetic biology. In addition, these reconstructive approaches would lead to a greater understanding of building principle in naturally occurring RNA/RNP molecules and systems. PMID- 26970195 TI - Preface. PMID- 26970196 TI - Patient-reported outcomes and quality of life assessment: New targets for new targeted therapy? PMID- 26970197 TI - Aspirin and loxoprofen relieve refractory pruritus in patients with prurigo nodularis. PMID- 26970199 TI - Transboundary transport of anthropogenic sulfur in PM2.5 at a coastal site in the Sea of Japan as studied by sulfur isotopic ratio measurement. AB - Sulfur isotopic ratios (delta(34)S) in size separated aerosol particles (PM2.5 and coarse particles) were measured at Niigata-Maki facing the Sea of Japan. Non sea salt delta(34)S (delta(34)Snss) in PM2.5 showed seasonal variations with relatively high values in winter (1.0-3.90/00 in spring, 2.8-4.50/00 in summer, 1.3-4.50/00 in autumn, 3.7-5.70/00 in winter). Taking into consideration air mass transport routes, delta(34)Snss in the air masses which originated in the Asian continent and were transported over the Sea of Japan to the monitoring sites were higher than those values for air masses which were transported over the Japanese islands after leaving the Asian continent for each season. Considering that the delta(34)Snss in sulfuric acid derived from domestic emissions in Japan are lower than those of delta(34)Snss in coal, the lower delta(34)Snss for the air mass transported over the Japanese islands suggest that sulfuric acid in PM2.5 modified the delta(34)Snss due to aerosol mixing with sulfuric acid in Japan. Material balance calculations suggested that the relative contribution of transboundary transport in winter was also higher than for other seasons (40-75% in spring, 51-63% in summer, 45-73% in autumn, and 53-81% in winter). In particular, the contribution to the air masses which were transported directly from the Asian continent was relatively large (75% in spring, 59% in autumn, 78% in winter) in comparison with that for the air masses which were transported over Japan. PMID- 26970198 TI - Combined impacts of precipitation and temperature on diffuse phosphorus pollution loading and critical source area identification in a freeze-thaw area. AB - The loss of diffuse phosphorus (P) presented different characteristics in the freeze-thaw area due to the combined impacts of precipitation and temperature, which caused spatiotemporal variations of the critical source area of diffuse P (CSAP). The temperature and precipitation classification (TPC) method was proposed to identify the spatiotemporal characteristics of the CSAP in the cold area, and each year was divided into a freeze-thaw season and a growing season according to the average monthly temperature. The Soil and Water Assessment Tool (SWAT) provided the spatiotemporal patterns of the diffuse P loads. The years were also reclassified into dry, normal and wet years according to the annual precipitation levels. The CSAP with the 1st cumulative load level shared 9.68% of the same area between the two seasons, which had dry land as the dominant land use with direct P fertilization. The spatial distributions of the potential areas and the CSAP with the 2nd cumulative load level were more sensitive to the variation in temperature, which had 30.8%-46.1% of unvaried area between seasons. The cumulative load level analysis indicated that 14 subbasins in the freeze-thaw season and 7 subbasins in the growing season, which covered 61.2% and 48.6% of the total basin area, respectively, changed with the traditional CSAP identification among dry, normal and wet years. The fluctuation level analysis was carried out to compare the distributional difference of the CSAP and the potential areas between the TPC method and the traditional method, which highlighted the advantages of the TPC method. The results would be useful in identifying the distribution of the CSAP in cold areas, which improved the efficiency of diffuse pollution control. PMID- 26970200 TI - Valence state alternation of copper species doped in HY zeolite as revealed by paramagnetic relaxation enhancement NMR spectroscopy. AB - Paramagnetic relaxation enhancement (PRE) solid-state NMR (ssNMR) was used to monitor the valence state alternation of copper species doped in HY zeolite during catalytic reaction processes. The combination of PRE ssNMR and in-situ NMR spectroscopy facilitates the detection of copper species as well as the monitoring of evolution from reactants, intermediates to products in heterogeneously catalyzed processes, which is of great importance for elucidating the detailed catalytic reaction mechanism. PMID- 26970201 TI - Early postnatal testosterone predicts sex-related differences in early expressive vocabulary. AB - During the first few years of life, girls typically have a larger expressive vocabulary than boys. This sex difference is important since a small vocabulary may predict subsequent language difficulties, which are more prevalent in boys than girls. The masculinizing effects of early androgen exposure on neurobehavioral development are well-documented in nonhuman mammals. The present study conducted the first test of whether early postnatal testosterone concentrations influence sex differences in expressive vocabulary in toddlers. It was found that testosterone measured in saliva samples collected at 1-3 months of age, i.e., during the period called mini-puberty, negatively predicted parent report expressive vocabulary size at 18-30 months of age in boys and in girls. Testosterone concentrations during mini-puberty also accounted for additional variance in expressive vocabulary after other predictors such as sex, child's age at vocabulary assessment, and paternal education, were taken into account. Furthermore, testosterone concentrations during mini-puberty mediated the sex difference in expressive vocabulary. These results suggest that testosterone during the early postnatal period contributes to early language development and neurobehavioral sexual differentiation in humans. PMID- 26970202 TI - Assessment of energy density usage during 180W lithium triborate laser photoselective vaporization of the prostate for benign prostatic hyperplasia. Is there an optimum amount of kilo-Joules per gram of prostate? AB - OBJECTIVES: To assess the effect of energy density (kJ/mL) applied on adenoma during photoselective vaporization of the prostate (PVP) treatment for benign prostate hyperplasia (BPH) on functional outcomes, prostate-specific antigen (PSA) reduction and complications. PATIENTS AND METHODS: After exclusions, a total of 440 patients who underwent GreenLight (tm) laser XPS-180W lithium triborate PVP for the treatment of BPH were retrospectively reviewed. Data were collected from seven different international centres (Canada, USA, UK and France). Patients were stratified into four energy density groups (kJ/mL) according to intra-operative energy delivered and prostate volume as determined by preoperative transrectal ultrasonography (TRUS): group 1: <3 kJ/mL; group 2: 3 5 kJ/mL; group 3: 5-7 kJ/mL; and group 4: >=7 kJ/mL. Energy density groups were chosen arbitrarily. PSA reduction and functional outcomes (International Prostate Symptom Score, quality of life, post-void residual urine volume, maximum urinary flow rate) were compared at 6, 12 and 24 months. Peri-operative complications and retreatment rates were also compared among the groups. RESULTS: The PSA reduction rates at 24 months after the procedure were 51, 61, 79 and 83% for the energy density groups <3, 3-5, 5-7 and >=7 kJ/mL, respectively (P <= 0.01). This held true after accounting for baseline confounders. Energy density was not associated with higher complication rates, including haematuria, stricture formation, incontinence, refractory urinary retention, urinary tract infection and conversion to transurethral resection of the prostate. Functional outcomes at 2 years of follow-up were equivalent among the groups (P > 0.05 for all) and similar retreatment rates were observed (P = 0.36). CONCLUSION: Higher energy usage per cc of prostate was associated with a more significant reduction in PSA level (>50%) at 6, 12 and 24 months, suggesting increased vaporization of adenoma tissue; however, this did not translate into differences in functional outcomes at 2-year follow-up. PMID- 26970203 TI - Roles of transcription factors and epigenetic modifications in differentiation and maintenance of regulatory T cells. AB - Regulatory T (Treg) cells are an essential cell subset for the maintenance of immune homeostasis. Treg cells are characterized by a distinct pattern of gene expression, including the upregulation of immune-suppressive genes and the silencing of inflammatory genes. The molecular mechanisms involved in the development and maintenance of Tregs have been extensively investigated. We have identified essential transcription factors NR4a and Smad2/3 in the development of thymic Tregs and induced Tregs, respectively. This article reviews the roles of transcription factors in the differentiation, maintenance, and function of Treg cells. PMID- 26970205 TI - Doxorubicin/gold-loaded core/shell nanoparticles for combination therapy to treat cancer through the enhanced tumor targeting. AB - A combination therapy consisting of radiotherapy and chemotherapy is performed using the core/shell nanoparticles (NPs) containing gold NPs and doxorubicin (DOX). Gold NPs in the core/shell NPs were utilized as a radiosensitizer. To examine the morphology and size distribution of the core/shell NPs, transmittance electron microscopy and dynamic light scattering were used. The in vitro release behavior, cellular uptake and toxicity were also observed to verify the functionality of the core/shell NPs as a nanocarrier. To demonstrate the advantage of the core/shell NPs over traditional gold NPs reported in the combination therapy, we evaluated the accumulation behavior of the core/shell NPs at the tumor site using the biodistribution. Antitumor efficacy was observed with and without radiation to evaluate the role of gold NPs as a radiosensitizer. PMID- 26970204 TI - Immunogenic properties of trivalent recombinant protein composed of B-subunits of LT, STX-2, and CT toxins. AB - Infectious diarrhoea remains an emerging problem in the world health program. Among diarrheagenic agents, Vibrio cholerae and enterotoxigenic and enterohemorrhagic Escherichia coli are critical enteropathogens. AB5 toxin produced by these bacteria, heat-labile enterotoxin (LT), cholera enterotoxin (CT), and shiga-like cytotoxin (STX) can target the immune system and are subunit vaccine candidates. A chemically-synthesized chimeric construct composed of the binding subunits of these toxins (LTB, STXB, and CTXB) was developed based on bioinformatics studies. The whole chimeric protein (rLSC) and each of the segments (rLTB, rSTXB, and rCTXB) were expressed in a prokaryotic expression system (E. coli), purified, and analysed for their immunogenic properties. The results indicate that these recombinant proteins were effectively able to present appropriate epitopes to an animal model of the immune system which could result in and increase IgG in serum and immune responses that protect against the binding activity of these toxins. The immunological assays revealed that the sera of immunized mice prevented toxins from binding to their specific receptors and neutralized their toxic effects. The proposed construct should be considered as a potent immunogen to prevent toxicity and diarrhoea. PMID- 26970206 TI - Bone regeneration in critical-sized bone defect enhanced by introducing osteoinductivity to biphasic calcium phosphate granules. AB - OBJECTIVES: Biphasic calcium phosphate (BCP) is frequently used as bone substitute and often needs to be combined with autologous bone to gain an osteoinductive property for guided bone regeneration in implant dentistry. Given the limitations of using autologous bone, bone morphogenetic protein-2 (BMP2) coprecipitated, layer-by-layer assembled biomimetic calcium phosphate particles (BMP2-cop.BioCaP) have been developed as a potential osteoinducer. In this study, we hypothesized that BMP2-cop.BioCaP could introduce osteoinductivity to BCP and so could function as effectively as autologous bone for the repair of a critical sized bone defect. MATERIALS AND METHODS: We prepared BMP2-cop.BioCaP and monitored the loading and release kinetics of BMP2 from it in vitro. Seven groups (n = 6 animals/group) were established: (i) Empty defect; (ii) BCP; (iii) BCP mixed with biomimetic calcium phosphate particles (BioCaP); (iv) BCP mixed with BMP2-cop.BioCaP; (v) BioCaP; (vi) BMP2-cop.BioCaP; (vii) BCP mixed with autologous bone. They were implanted into 8-mm-diameter rat cranial critical sized bone defects for an in vivo evaluation. Autologous bone served as a positive control. The osteoinductive efficacy and degradability of materials were evaluated using micro-CT, histology and histomorphometry. RESULTS: The combined application of BCP and BMP2-cop.BioCaP resulted in significantly more new bone formation than BCP alone. The osteoinductive efficacy of BMP2-cop.BioCaP was comparable to the golden standard use of autologous bone. Compared with BCP alone, significantly more BCP degradation was found when mixed with BMP2 cop.BioCaP. CONCLUSION: The combination of BCP and BMP2-cop.BioCaP showed a promising potential for guided bone regeneration clinically in the future. PMID- 26970207 TI - Ultrarobust Thin-Film Devices from Self-Assembled Metal-Terpyridine Oligomers. AB - Ultrathin molecular layers of Fe(II) -terpyridine oligomers allow the fabrication of large-area crossbar junctions by conventional electrode vapor deposition. The junctions are electrically stable for over 2.5 years and operate over a wide range of temperatures (150-360 K) and voltages (+/-3 V) due to the high cohesive energy and packing density of the oligomer layer. Electrical measurements reveal ideal Richardson-Shottky emission in surprising agreement with electrochemical, optical, and photoemission data. PMID- 26970208 TI - Cardiorespiratory interactions: Noncontact assessment using laser Doppler vibrometry. AB - The application of a noncontact physiological recording technique, based on the method of laser Doppler vibrometry (LDV), is described. The effectiveness of the LDV method as a physiological recording modality lies in the ability to detect very small movements of the skin, associated with internal mechanophysiological activities. The method is validated for a range of cardiovascular variables, extracted from the contour of the carotid pulse waveform as a function of phase of the respiration cycle. Data were obtained from 32 young healthy participants, while resting and breathing spontaneously. Individual beats were assigned to four segments, corresponding with inspiration and expiration peaks and transitional periods. Measures relating to cardiac and vascular dynamics are shown to agree with the pattern of effects seen in the substantial body of literature based on human and animal experiments, and with selected signals recorded simultaneously with conventional sensors. These effects include changes in heart rate, systolic time intervals, and stroke volume. There was also some evidence for vascular adjustments over the respiration cycle. The effectiveness of custom algorithmic approaches for extracting the key signal features was confirmed. The advantages of the LDV method are discussed in terms of the metrological properties and utility in psychophysiological research. Although used here within a suite of conventional sensors and electrodes, the LDV method can be used on a stand-alone, noncontact basis, with no requirement for skin preparation, and can be used in harsh environments including the MR scanner. PMID- 26970210 TI - From NGS assembly challenges to instability of fungal mitochondrial genomes: A case study in genome complexity. AB - The presence of repetitive or non-unique DNA persisting over sizable regions of a eukaryotic genome can hinder the genome's successful de novo assembly from short reads: ambiguities in assigning genome locations to the non-unique subsequences can result in premature termination of contigs and thus overfragmented assemblies. Fungal mitochondrial (mtDNA) genomes are compact (typically less than 100 kb), yet often contain short non-unique sequences that can be shown to impede their successful de novo assembly in silico. Such repeats can also confuse processes in the cell in vivo. A well-studied example is ectopic (out-of register, illegitimate) recombination associated with repeat pairs, which can lead to deletion of functionally important genes that are located between the repeats. Repeats that remain conserved over micro- or macroevolutionary timescales despite such risks may indicate functionally or structurally (e.g., for replication) important regions. This principle could form the basis of a mining strategy for accelerating discovery of function in genome sequences. We present here our screening of a sample of 11 fully sequenced fungal mitochondrial genomes by observing where exact k-mer repeats occurred several times; initial analyses motivated us to focus on 17-mers occurring more than three times. Based on the diverse repeats we observe, we propose that such screening may serve as an efficient expedient for gaining a rapid but representative first insight into the repeat landscapes of sparsely characterized mitochondrial chromosomes. Our matching of the flagged repeats to previously reported regions of interest supports the idea that systems of persisting, non-trivial repeats in genomes can often highlight features meriting further attention. PMID- 26970209 TI - Potentially inappropriate medications (PIMs) in older hospital in-patients: Prevalence, contribution to hospital admission and documentation of rationale for continuation. AB - AIM: To establish prevalence, sequelae and documentation of potentially inappropriate medication (PIM) use in older hospital in-patients. METHODS: Notes of all patients >=65 years old, admitted to our tertiary teaching hospital (January 2013), were retrospectively reviewed, and the Screening Tool of Older Persons' potentially inappropriate Prescriptions applied. RESULTS: Amongst 534 patients, 54.8% (284) were on >=1 PIM at admission, 26.8% on multiple; 60.8% were discharged on a PIM. Six percent of all admissions were potentially attributable to a PIM; falls associated with risk therapies were commonest (23/30), and often (65.2%) associated with serious injury. Pre-specified subgroup analysis (n = 100) identified 101 PIMs-at-discharge amongst 47 patients. In 82.2%, a clinical rationale for continued prescription was documented, with this communicated to the GP by letter in 71.1%. CONCLUSION: PIMs were common, and contributed to admission and injury. Hospitalisation provides an opportunity for medication rationalisation, and documentation of rationale for any PIM use. PMID- 26970211 TI - Two highly similar LAEDDTNAQKT and LTDKIGTEI epitopes in G glycoprotein may be useful for effective epitope based vaccine design against pathogenic Henipavirus. AB - Nipah virus and Hendra virus, two members of the genus Henipavirus, are newly emerging zoonotic pathogens which cause acute respiratory illness and severe encephalitis in human. Lack of the effective antiviral therapy endorses the urgency for the development of vaccine against these deadly viruses. In this study, we employed various computational approaches to identify epitopes which has the potential for vaccine development. By analyzing the immune parameters of the conserved sequences of G glycoprotein using various databases and bioinformatics tools, we identified two potential epitopes which may be used as peptide vaccines. Using different B cell epitope prediction servers, four highly similar B cell epitopes were identified. Immunoinformatics analyses revealed that LAEDDTNAQKT is a highly flexible and accessible B-cell epitope to antibody. Highly similar putative CTL epitopes were analyzed for their binding with the HLA C 12*03 molecule. Docking simulation assay revealed that LTDKIGTEI has significantly lower binding energy, which bolstered its potential as epitope based vaccine design. Finally, cytotoxicity analysis has also justified their potential as promising epitope-based vaccine candidate. In sum, our computational analysis indicates that either LAEDDTNAQKT or LTDKIGTEI epitope holds a promise for the development of universal vaccine against all kinds of pathogenic Henipavirus. Further in vivo and in vitro studies are necessary to validate the obtained findings. PMID- 26970212 TI - Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential. AB - The Karyopherin superfamily is a major class of soluble transport receptors consisting of both import and export proteins. The trafficking of proteins involved in transcription, cell signalling and cell cycle regulation among other functions across the nuclear membrane is essential for normal cellular functioning. However, in cancer cells, the altered expression or localization of nuclear transporters as well as the disruption of endogenous nuclear transport inhibitors are some ways in which the Karyopherin proteins are dysregulated. The value of nuclear transporters in the diagnosis, prognosis and treatment of cancer is currently being elucidated with recent studies highlighting their potential as biomarkers and therapeutic targets. PMID- 26970213 TI - Physiology of intracellular potassium channels: A unifying role as mediators of counterion fluxes? AB - Plasma membrane potassium channels importantly contribute to maintain ion homeostasis across the cell membrane. The view is emerging that also those residing in intracellular membranes play pivotal roles for the coordination of correct cell function. In this review we critically discuss our current understanding of the nature and physiological tasks of potassium channels in organelle membranes in both animal and plant cells, with a special emphasis on their function in the regulation of photosynthesis and mitochondrial respiration. In addition, the emerging role of potassium channels in the nuclear membranes in regulating transcription will be discussed. The possible functions of endoplasmic reticulum-, lysosome- and plant vacuolar membrane-located channels are also referred to. Altogether, experimental evidence obtained with distinct channels in different membrane systems points to a possible unifying function of most intracellular potassium channels in counterbalancing the movement of other ions including protons and calcium and modulating membrane potential, thereby fine tuning crucial cellular processes. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-7, 2016', edited by Prof. Paolo Bernardi. PMID- 26970214 TI - Coenzyme Q biosynthesis and its role in the respiratory chain structure. AB - Coenzyme Q (CoQ) is a unique electron carrier in the mitochondrial respiratory chain, which is synthesized on-site by a nuclear encoded multiprotein complex. CoQ receives electrons from different redox pathways, mainly NADH and FADH2 from tricarboxylic acid pathway, dihydroorotate dehydrogenase, electron transfer flavoprotein dehydrogenase and glycerol-3-phosphate dehydrogenase that support key aspects of the metabolism. Here we explore some lines of evidence supporting the idea of the interaction of CoQ with the respiratory chain complexes, contributing to their superassembly, including respirasome, and its role in reactive oxygen species production in the mitochondrial inner membrane. We also review the current knowledge about the involvement of mitochondrial genome defects and electron transfer flavoprotein dehydrogenase mutations in the induction of secondary CoQ deficiency. This mechanism would imply specific interactions coupling CoQ itself or the CoQ-biosynthetic apparatus with the respiratory chain components. These interactions would regulate mitochondrial CoQ steady-state levels and function. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. PMID- 26970215 TI - Which cost of alcohol? What should we compare it against? AB - This paper explores and develops issues raised by recent debates about the cost of alcohol to England and Wales. It advances two arguments. First, that the commonly used estimates for alcohol harm in England and Wales are outdated, not fully reliable and in need of revisiting. These estimates rely on data that are between 4 and 12 years out of date and sensitive to questionable assumptions and methodological judgements. Secondly, it argues that policymakers, academics and non-governmental organizations should be more careful in their use of these numbers. In particular, it is imperative that the numbers quoted fit the argument advanced. To help guide such appropriate usage, the different types of cost of alcohol are surveyed, alongside some thoughts on the questions they help us to answer and what they imply for policy. For example, comprehensive estimates of the total social cost of alcohol provide an indication of the scale of the problem, but have limited policy relevance. External cost estimates represent a 'lowest common denominator' approach acceptable to most, but require additional assumptions to guide action. Narrower perspectives, such as fiscal, economic or health costs, may be relevant in specific contexts. However, optimal policy should take a holistic view of all the relevant costs and benefits. Similarly, focusing solely on tangible costs may be less controversial, but will result in an under-estimate of the relevant costs of alcohol. PMID- 26970216 TI - Zinc finger protein rotund deficiency affects development of the thoracic leg in Bombyx mori. AB - The insect limb develops from the imaginal disc or larval leg during metamorphosis. The molecular mechanisms involved in the development from the larval to the adult leg are poorly understood. Herein, we cloned the full length of a zinc finger gene rotund from Bombyx mori (Bmrn), which contained a 1419 bp open reading frame, and encoded a 473 amino acid protein. Reverse transcription polymerase chain reaction and Western blot analyses demonstrated that Bmrn was expressed at higher levels in the epidermis than in other tissues tested, and it showed a very high expression level during metamorphosis. Knock-down of Bmrn produced defects in the tarsus and pretarsus, including the fusion and reduction of tarsomeres, and the developmental arrest of pretarsus. Our data showed that Bmrn is involved in the formation of the tarsus and pretarsus, whereas its homologous gene in Drosophila has been shown to affect three tarsal segments (t2 t4), suggesting that the remodeling of the leg has involved changes in the patterning of gene regulation during evolution. PMID- 26970217 TI - Pilot study aiming to support sleep quality and duration during hospitalizations. AB - BACKGROUND: Sleep is a vital part to healing and recovery, hence poor sleep during hospitalizations is highly undesirable. Few studies have assessed interventions to optimize sleep among hospitalized patients. OBJECTIVE: To assess the effect of sleep-promoting interventions on sleep quality and duration among hospitalized patients. DESIGN: Quasi-experimental prospective study. SETTING: Academic medical center. PARTICIPANTS: Adult patients on the general medicine ward. INTERVENTION: Nurse-delivered sleep-promoting interventions augmented by sleep hygiene education and environmental control to minimize sleep disruption. MEASUREMENTS: Objective and subjective measurement of sleep parameters using validated sleep questionnaires, daily sleep diary, and actigraphy monitor. RESULTS: Of the 112 patients studied, the mean age was 58 years, 55% were female, the mean body mass index was 32, and 43% were in the intervention group. Linear mixed models tested mean differences in 7 sleep measures and group differences in slopes representing nightly changes in sleep outcomes over the course of hospitalization between intervention and control groups. Only total sleep time, computed from sleep diaries, demonstrated significant overall mean difference of 49.6 minutes (standard error [SE] = 21.1, P < 0.05). However, significant differences in average slopes of subjective ratings of sleep quality (0.46, SE = 0.18, P < 0.05), refreshing sleep (0.54, SE = 0.19, P < 0.05), and sleep interruptions (-1.6, SE = 0.6, P < 0.05) indicated improvements during hospitalization within intervention patients compared to controls. CONCLUSION: This study demonstrated that there is an opportunity to identify patients not sleeping well in the hospital. Sleep-promoting initiatives, both at the unit level as well as individualized offerings, may improve sleep during hospitalizations, particularly over the course of the hospitalization. Journal of Hospital Medicine 2016;11:467-472. (c) 2016 Society of Hospital Medicine. PMID- 26970218 TI - Manifestation of tranexamic acid toxicity in chronic kidney disease and kidney transplant patients: A report of four cases and review of literature. AB - AIM: Tranexamic acid (TXA) is a synthetic anti-fibrinolytic agent commonly used for the prevention and treatment of bleeding disorders. The aim of this study is to describe the clinical manifestation of TXA toxicity in chronic kidney disease (CKD) patients. METHODS: From 2005 to 2014, we encountered four CKD patients who experienced severe complications related to TXA. Clinical manifestations and outcome of these patients were recorded. We then performed a qualitative literature review of published cases of TXA toxicity in CKD patients in the PubMed database from 1 January 1972 to 31 December 2015. RESULTS: In our centre, two peritoneal dialysis (PD) patients developed neurotoxicity after intravenous TXA use for surgical bleeding and one PD patient developed neurotoxicity after oral TXA use for post-polypectomy colonic bleeding. One kidney transplant recipient developed acute obstructive uropathy due to retention of blood clot at the pelvi-ureteric junction of graft kidney after taking oral TXA for menorrhagia. Dosage of TXA was not adjusted according to renal function in all cases. All of them recovered without permanent disability after TXA was stopped. From our literature search, we identified two cases of neurotoxicity (one PD, one stage 4 CKD patient), one case of retinal toxicity in a haemolysis (HD) patient, one case of ligneous conjunctivitis in a CKD patient, and one case of toxic epidermal necrolysis in a CKD patient. CONCLUSION: Neurotoxicity is a very common clinical manifestation of TXA toxicity in CKD patients. Thrombotic complication is rare. Dosage adjustment of TXA is essential in CKD patients. PMID- 26970219 TI - Motor unit number index in the nasalis muscle in healthy subjects and patients with amyotrophic lateral sclerosis. AB - INTRODUCTION: Motor unit number index (MUNIX) is a quick and feasible electrophysiological technique that estimates the number of motor neurons in limb muscles in healthy and amyotrophic lateral sclerosis (ALS) subjects. In this study we explored the feasibility, reliability, and differences of MUNIX in nasalis muscles in healthy subjects and ALS patients. METHODS: MUNIX of the nasalis muscle of 50 healthy and 20 ALS subjects with bulbar involvement was compared. Functional impairment was evaluated by the ALS Functional Rating Scale Revised and its bulbar subscore. RESULTS: MUNIX was well tolerated and quickly performed. Bulbar ALS patients showed non-significant lower nasalis MUNIX values and a lower functional bulbar subscore. Intra- and interrater reliability showed high intraclass correlation coefficients (ICCs) in healthy subjects (0.87) and ALS patients (0.92). CONCLUSION: MUNIX of the nasalis muscle is a reproducible method, but it showed no significant difference between healthy and bulbar ALS subjects and seems not to be a useful marker of disease progression in ALS. Muscle Nerve 54: 733-737, 2016. PMID- 26970221 TI - Glutarimidedioxime: A Complexing and Reducing Reagent for Plutonium Recovery from Spent Nuclear Fuel Reprocessing. AB - Efficient separation processes for recovering uranium and plutonium from spent nuclear fuel are essential to the development of advanced nuclear fuel cycles. The performance characteristics of a new salt-free complexing and reducing reagent, glutarimidedioxime (H2A), are reported for recovering plutonium in a PUREX process. With a phase ratio of organic to aqueous of up to 10:1, plutonium can be effectively stripped from 30% tributyl phosphate (TBP) in kerosene into 1 M HNO3 with H2A. The complexation-reduction mechanism is illustrated with the combination of UV/Vis absorption spectra and the crystal structure of a Pu(IV) complex with the reagent. The fast stripping rate and the high efficiency for stripping Pu(IV), through the complexation-reduction mechanism, is suitable for use in centrifugal contactors with very short contact/resident times, thereby offering significant advantages over conventional processes. PMID- 26970220 TI - CD14 is associated with biliary stricture formation. AB - The pathogenesis of intrahepatic biliary stricture formation in patients with primary sclerosing cholangitis (PSC) or after liver transplantation (LTx) remains elusive. CD14 receptor signaling is a key mediator of the innate immune system; its common genetic variant is associated with alcoholic liver disease. PSC and LTx cohort patients and primary biliary cirrhosis (PBC) control patients were genotyped for the CD14 -260C>T (rs2569190) polymorphism, and genotypes were correlated with long-term clinical outcome. Biliary tissue, bile, and whole blood of PSC patients and healthy controls were screened for markers of the innate immune system and bacterial infection. In 121 PSC patients, the CD14 -260C>T genotype was associated with development of dominant bile duct strictures (P = 0.02). In 365 LTx patients, TT carriers (4.1%) were protected against the formation of nonanastomotic biliary strictures versus CC/CT patients (12.6%; P = 0.01). Chemokine ligand 8 (P = 0.04) and chemokine receptor 6 (P = 0.004) were up regulated in biliary tissue of PSC patients with the TT versus the CC/CT genotype. Lipopolysaccharide whole-blood stimulation resulted in a significant change in interleukin (IL)-8 (P = 0.05) and IL-12p40 levels (P = 0.04) in healthy control subjects carrying the TT genotype. TT PSC patients were protected against Gram-negative bacterial biliary infection (TT: 0% vs. CC/CT: 22.5%; P = 0.02). Serum-soluble CD14 levels correlated with the CD14 -260C>T genotype (P = 0.02), representing an independent risk indicator of survival in PSC patients (hazard ratio, 0.40; 95% confidence interval, 0.19-0.86; P =0.01). CONCLUSIONS: The function of the innate immune response by CD14 is crucial during biliary infection and stricture formation. The benefits of CD14 signaling modification should be addressed in future studies. (Hepatology 2016;64:843-852). PMID- 26970223 TI - ECG Challenge: Single or Double Tachycardia? PMID- 26970224 TI - Barriers to and facilitators of diabetes self-management with elderly Korean American immigrants. AB - AIM: The aim of this study was to explore barriers to and facilitators of diabetes self-management among first-generation Korean-American elderly immigrants with type 2 diabetes in the United States Midwest. BACKGROUND: The number of Korean-American elderly immigrants with type 2 diabetes in the United States is expected to increase because they are at risk of adopting a Western lifestyle. METHODS: Three focus groups (N = 18) and five individual interviews were conducted with Korean-American elderly immigrants with type 2 diabetes. Demographic characteristics and diabetes-related medical history information were obtained with a questionnaire. All data were digitally recorded, transcribed verbatim and translated from Korean into English. Transcripts were analysed using standard content-based analysis. RESULTS: Five perceived barriers were identified: the high cost of type 2 diabetes care, language issues, loss of self control, memory loss and limited access to healthcare resources. Three perceived facilitators were time, seeking information, and family and peer supports. LIMITATIONS: The convenience samples and small sample size may limit the study. CONCLUSIONS: The barriers to and facilitators of diabetes self-management identified in this study can be used in the development of more age- and culturally sensitive diabetes interventions and resources. IMPLICATION FOR NURSING AND HEALTH POLICY: Nurses and healthcare providers can use this study's findings to develop patient-centred, age-appropriate and culturally appropriate diabetes interventions. There are urgent needs to train bilingual healthcare providers and staff and to provide translation services for Korean-American elderly immigrants. Finally, communities and social supports within public health policy are urgently needed for this ethnic minority group. PMID- 26970225 TI - Human parvovirus B19-induced transient red cell aplasia in a patient with vitamin B12 deficiency. PMID- 26970222 TI - Programming of maternal and offspring disease: impact of growth restriction, fetal sex and transmission across generations. AB - Babies born small are at an increased risk of developing myriad adult diseases. While growth restriction increases disease risk in all individuals, often a second hit is required to unmask 'programmed' impairments in physiology. Programmed disease outcomes are demonstrated more commonly in male offspring compared with females, with these sex-specific outcomes partly attributed to different placenta-regulated growth strategies of the male and female fetus. Pregnancy is known to be a major risk factor for unmasking a number of conditions and can be considered a 'second hit' for women who were born small. As such, female offspring often develop impairments of physiology for the first time during pregnancy that present as pregnancy complications. Numerous maternal stressors can further increase the risk of developing a maternal complication during pregnancy. Importantly, these maternal complications can have long-term consequences for both the mother after pregnancy and the developing fetus. Conditions such as preeclampsia, gestational diabetes and hypertension as well as thyroid, liver and kidney diseases are all conditions that can complicate pregnancy and have long-term consequences for maternal and offspring health. Babies born to mothers who develop these conditions are often at a greater risk of developing disease in adulthood. This has implications as a mechanism for transmission of disease across generations. In this review, we discuss the evidence surrounding long-term intergenerational implications of being born small and/or experiencing stress during pregnancy on programming outcomes. PMID- 26970226 TI - The efficacy of botulinum toxin type A in the treatment of Hailey-Hailey disease. PMID- 26970228 TI - Identifying Reactive Sites and Transport Limitations of Oxygen Reactions in Aprotic Lithium-O2 Batteries at the Stage of Sudden Death. AB - Discharging of the aprotic Li-O2 battery relies on the O2 reduction reaction (ORR) forming solid Li2 O2 in the positive electrode, which is often characterized by a sharp voltage drop (that is, sudden death) at the end of discharge, delivering a capacity far below its theoretical promise. Toward unlocking the energy capabilities of Li-O2 batteries, it is crucial to have a fundamental understanding of the origin of sudden death in terms of reactive sites and transport limitations. Herein, a mechanistic study is presented on a model system of Au|Li2 O2 |Li(+) electrolyte, in which the Au electrode was passivated with a thin Li2 O2 film by discharging to the state of sudden death. Direct conductivity measurement of the Li2 O2 film and in situ spectroscopic study of ORR using (18) O2 for passivation and (16) O2 for further discharging provide compelling evidence that ORR (and O2 evolution reaction as well) occurs at the buried interface of Au|Li2 O2 and is limited by electron instead of Li(+) and O2 transport. PMID- 26970229 TI - Educating Family Caregivers for Older Adults About Delirium: A Systematic Review. AB - BACKGROUND: Delirium in older adults is considered a medical emergency; it contributes to a cascade of functional decline and to increased mortality. Early recognition of delirium symptoms is critical to prevent these negative consequences. Family caregivers who are educated about delirium could partner with nurses and other healthcare professionals in early recognition of delirium symptoms. Before implementing such partnership models, it is important to examine the effectiveness of educating family caregivers about delirium. AIMS: To examine whether providing education on delirium to family caregivers improved their knowledge, emotional state, or response in reducing the incidence of delirium in older adults. METHODS: For this systematic review, we conducted literature searches in CINAHL, Cochrane Library, Medline, PsycINFO, Web of Science, Social Sciences in ProQuest, Dissertations and Theses, and the Virginia Henderson Global Nursing eRepository for studies published in the English language between January 2000 and June 2015. Criteria for inclusion were: (a) primary focus on educating family caregivers for older adults about delirium; (b) use of experimental, quasi experimental, or comparative design; (c) measured family caregiver outcomes of delirium knowledge, emotional state, or response in reducing delirium incidence in older adults; and (d) published in the English language. Articles were appraised using Melnyk's rapid critical appraisal guides. RESULTS: Seven studies met the review criteria. Four studies found that family caregivers' delirium knowledge increased; two noted that delirium incidence in older adults declined; and one study reported less distress following receipt of education. LINKING EVIDENCE TO ACTION: Providing family caregivers with information about delirium can be beneficial for both family caregivers and older adults. However, rigorous evaluation of education programs for family caregivers about delirium is needed. PMID- 26970227 TI - Effect of simvastatin on rat supraspinatus tendon mechanical and histological properties in a diet-induced hypercholesterolemia model. AB - Hypercholesterolemia is a common condition and is a risk factor for tendon rupture, specifically in the supraspinatus tendon. In the clinic, statins are commonly prescribed to lower cholesterol, but little information is available examining the effect of statin treatment on the musculoskeletal system. Therefore, the objective of this study was to determine the biomechanical and histological effects of statin treatment in a diet-induced hypercholesterolemia model. We hypothesized that hypercholesterolemic rats treated with statins would have improved tendon biomechanical and histological properties compared to hypercholesterolemic rats not receiving daily statin treatment. Thirty adult male Sprague-Dawley rats ate either high-cholesterol (HC) diet (n = 20) or normal chow (CTL, n = 10). After 6 months, a subset of HC rats began daily oral simvastatin dosing (HC+S) at 20 mg/kg. All rats were sacrificed after a total of 9 months (3 months of statin treatment) and evaluated for histology and mechanics. For mechanics, at the insertion region, HC+S group had increased tendon cross sectional area decreased and modulus. No differences were noted in mechanical properties at the midsubstance. For histology, no differences were noted in the insertion region. In the midsubstance region, HC+S group had more spindle shaped cells. Our results suggest that 3 months of simvastatin treatment in a diet induced hypercholesterolemia rat model alters some tendon mechanical and histological properties, although a strong conclusion in support of improved parameters cannot be drawn. Therefore, we conclude that simvastatin treatment does not negatively affect tendon properties. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2009-2015, 2016. PMID- 26970230 TI - Clinical efficacy of probiotics as an adjunctive therapy to non-surgical periodontal treatment of chronic periodontitis: a systematic review and meta analysis. AB - FOCUSED QUESTION: What is the clinical influence of probiotics as an adjunctive therapy of scaling and root planing (SRP) when compared with SRP alone or in combination with placebo in the treatment of chronic periodontitis (CP). METHODS: Electronic databases were searched up to July 2015. Randomized controlled trials (RCTs) comparing SRP + probiotic versusSRP were included. PPD reduction and CAL gain were selected as primary outcome variables. RESULTS: Independent screening resulted in four eligible publications for the systematic review and three were included in the meta-analysis. Meta-analysis showed a statistically significant CAL gain (-0.42 mm, p = 0.002) and bleeding on probing (BOP) reduction (-14.66, p = 0.003) for SRP + probiotic treatment versusSRP at short-term. Only a tendency (p = 0.06) has been observed in terms of overall PPD reduction, whereas results were significant when stratified for moderate (-0.18, p = 0.001) and deep pockets (-0.67, p < 0.001). CONCLUSION: Within the limitations of this study, the findings of this meta-analysis seem to support the adjunctive use of L. reuteri to SRP in CP treatment at short-term, especially in deep pockets. Heterogeneity and limited available data may reduce the impact of these conclusions. Future long-term RCTs evaluating the clinical efficacy of adjunctive probiotics to SRP are needed. PMID- 26970231 TI - Report of the 19th follow-up survey of primary liver cancer in Japan. AB - The 19th Nationwide Follow-up Survey of Primary Liver Cancer in Japan comprised 20 850 primary liver cancer patients newly registered at 482 medical institutions over a period of 2 years (from 1 January 2006 to 31 December 2007). Of these, 94.7% had hepatocellular carcinoma (HCC) and 4.4% had intrahepatic cholangiocarcinoma (ICC). In addition, follow-up data were obtained regarding 34 752 patients who were registered in the previous survey. Epidemiological and clinicopathological factors, diagnosis, and treatment were examined in newly registered patients. Compared with the 18th follow-up survey, the present follow up survey suggested an increase in the number of elderly and female patients, a reduction in the number of hepatitis B surface antigen- and anti-hepatitis C virus antibody-positive patients, and a reduction in tumor size at the time of clinical diagnosis. In terms of local ablation therapy, the number of patients receiving radiofrequency ablation therapy increased. The cumulative survival rates for newly registered patients between 1996 and 2007 were calculated for each histological type (HCC, ICC, and combined HCC and ICC) and stratified according to background factors and treatments. The cumulative survival rates of newly registered patients between 1978 and 2007 were calculated after dividing individuals into groups according to registration date (1978-1987, 1988-1997, and 1998-2007). The data obtained from this follow-up survey will contribute to the medical management of primary liver cancer and facilitate future research. PMID- 26970232 TI - Tension-referenced measures of gastrocnemius slack length and stiffness in Parkinson's disease. AB - BACKGROUND: It is not known how passive muscle length and stiffness contribute to rigidity in Parkinson's disease. The objective of this study was to compare passive gastrocnemius muscle-tendon slack length and stiffness at known tension in Parkinson's disease subjects with ankle rigidity and in able-bodied people. METHODS: Passive ankle torque-angle curves were obtained from 15 Parkinson's disease subjects with rigidity and 15 control subjects. Torque-angle data were used to derive passive gastrocnemius length-tension data and calculate slack length and stiffness of the gastrocnemius muscle. Between-group comparisons were made with linear models. RESULTS: Gastrocnemius muscle-tendon slack lengths (adjusted between-group difference, 0.01 m; 95% CI, -0.02 to 0.04 m; P = 0.37) and stiffness (adjusted between-group difference, 15.7 m-1 ; 95% CI, -8.5 to 39.9 m-1 ; P = 0.19) were not significantly different between groups. CONCLUSIONS: Parkinson's disease subjects with ankle rigidity did not have significantly shorter or stiffer gastrocnemius muscles compared with control subjects. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 26970233 TI - One-step preparation and application of mussel-inspired poly(norepinephrine) coated polydimethylsiloxane microchip for separation of chiral compounds. AB - In this paper, using the self-polymerization of norepinephrine (NE) and its favorable film-forming property, a simple and green preparation approach was developed to modify a PDMS channel for enantioseparation of chiral compounds. After the PDMS microchip was filled with NE solution, poly(norepinephrine) (PNE) film was gradually formed and deposited on the inner wall of microchannel as permanent coating via the oxidation of NE by the oxygen dissolved in the solution. Due to possessing plentiful catechol and amine functional groups, the PNE-coated PDMS microchip exhibited much better wettability, more stable and suppressed EOF, and less nonspecific adsorption. The water contact angle and EOF of PNE-coated PDMS substrate were measured to be 13 degrees and 1.68 * 10(-4) cm(2) V(-1) s(-1) , compared to those of 108 degrees and 2.24 * 10(-4) cm(2) V( 1) s(-1) from the untreated one, respectively. Different kinds of chiral compounds, such as amino acid enantiomer, drug enantiomer, and peptide enantiomer were efficiently separated utilizing a separation length of 37 mm coupled with in column amperometric detection on the PNE-coated PDMS microchips. This facile mussel-inspired PNE-based microchip system exhibited strong recognition ability, high-performance, admirable reproducibility, and stability, which may have potential use in the complex biological analysis. PMID- 26970235 TI - Multimodal study of default-mode network integrity in disorders of consciousness. AB - OBJECTIVE: Understanding residual brain function in disorders of consciousness poses extraordinary challenges, and imaging examinations are needed to complement clinical assessment. The default-mode network (DMN) is known to be dysfunctional, although correlation with level of consciousness remains controversial. We investigated DMN activity with resting-state functional magnetic resonance imaging (rs-fMRI), alongside its structural and metabolic integrity, aiming to elucidate the corresponding associations with clinical assessment. METHODS: We enrolled 119 consecutive patients: 72 in a vegetative state/unresponsive wakefulness state (VS/UWS), 36 in a minimally conscious state (MCS), and 11 with severe disability. All underwent structural MRI and rs-fMRI, and a subset also underwent 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). Data were analyzed with manual and automatic approaches, in relation to diagnosis and clinical score. RESULTS: Excluding the quartile with largest head movement, DMN activity was decreased in VS/UWS compared to MCS, and correlated with clinical score. Independent-component and seed-based analyses provided similar results, although the latter and their combination were most informative. Structural MRI and FDG-PET were less sensitive to head movement and had better diagnostic accuracy than rs-fMRI only when all cases were included. rs-fMRI indicated relatively preserved DMN activity in a small subset of VS/UWS patients, 2 of whom evolved to MCS. The integrity of the left hemisphere appears to be predictive of a better clinical status. INTERPRETATION: rs-fMRI of the DMN is sensitive to clinical severity. The effect is consistent across data analysis approaches, but heavily dependent on head movement. rs-fMRI could be informative in detecting residual DMN activity for those patients who remain relatively still during scanning and whose diagnosis is uncertain. Ann Neurol 2016;79:841-853. PMID- 26970236 TI - Nurturing spiritual well-being among older people in Australia: Drawing on Indigenous and non-Indigenous way of knowing. AB - AIM: The meaning of spiritual well-being as a health dimension is often contested and neglected in policy and practice. This paper explores spiritual well-being from both an Indigenous and a non-Indigenous perspective. METHOD: We drew on Indigenous and non-Indigenous methodologies to explore the existing knowledge around spiritual well-being and its relationship with health. RESULTS: The Indigenous perspective proposed that spiritual well-being is founded in The Dreaming, informs everyday relationships and can impact on health. The non Indigenous perspective suggested that spiritual well-being is shaped by culture and religion, is of increased importance as one ages, and can improve coping and resilience stressors. CONCLUSIONS: Situating these perspectives side by side allows us to learn from both, and understand the importance of spirituality in people's lives. Further research is required to better address the spiritual well being/health connection in policy and practice. PMID- 26970237 TI - Jacobian weighted temporal total variation for motion compensated compressed sensing reconstruction of dynamic MRI. AB - PURPOSE: To eliminate the need of spatial intraframe regularization in a recently reported dynamic MRI compressed-sensing-based reconstruction method with motion compensation and to increase its performance. THEORY AND METHODS: We propose a new regularization metric based on the introduction of a spatial weighting measure given by the Jacobian of the estimated deformations. It shows convenient discretization properties and, as a byproduct, it also provides a theoretical support to a result reported by others based on an intuitive design. The method has been applied to the reconstruction of both short and long axis views of the heart of four healthy volunteers. Quantitative image quality metrics as well as straightforward visual assessment are reported. RESULTS: Short and long axis reconstructions of cardiac cine MRI sequences have shown superior results than previously reported methods both in terms of quantitative metrics and of visual assessment. Fine details are better preserved due to the lack of additional intraframe regularization, with no significant image artifacts even for an acceleration factor of 12. CONCLUSIONS: The proposed Jacobian Weighted temporal Total Variation results in better reconstructions of highly undersampled cardiac cine MRI than previously proposed methods and sets a theoretical ground for forward and backward predictors used elsewhere. Magn Reson Med 77:1208-1215, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26970234 TI - Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic. AB - In the coming decades, a massive shift in the aging segment of the population will have major social and economic consequences around the world. One way to offset this increase is to expedite the development of geroprotectors, substances that slow aging, repair age-associated damage and extend healthy lifespan, or healthspan. While over 200 geroprotectors are now reported in model organisms and some are in human use for specific disease indications, the path toward determining whether they affect aging in humans remains obscure. Translation to the clinic is hampered by multiple issues including absence of a common set of criteria to define, select, and classify these substances, given the complexity of the aging process and their enormous diversity in mechanism of action. Translational research efforts would benefit from the formation of a scientific consensus on the following: the definition of 'geroprotector', the selection criteria for geroprotectors, a comprehensive classification system, and an analytical model. Here, we review current approaches to selection and put forth our own suggested selection criteria. Standardizing selection of geroprotectors will streamline discovery and analysis of new candidates, saving time and cost involved in translation to clinic. PMID- 26970238 TI - Cellular and molecular mechanisms involved in placental separation in the bovine: A review. AB - Retention of fetal membranes (RFM), where the fetal placenta is not expelled within 8-12 hr after calving, lowers bovine productivity and fertility, resulting in significant economic loss to the dairy industry. Several risk factors that predispose an individual to RFM are known, but a unifying pathogenesis remains elusive due to its multifactorial etiology. Fetal membrane separation and expulsion after parturition involves structural and immunological changes of the bovine placentome that are governed predominantly by steroid hormones and the prostaglandin milieu of late pregnancy and parturition. Maturation of the placentome, a gradual and concerted event of late gestation, is likely initiated by the up-regulation of fetal major histocompatibility complex class I in the interplacentomal region-which increases the apoptosis of binucleate and other trophoblastic cells, the degradation of collagen in the extracellular matrix by matrix metalloproteinases, and an influx of phagocytic leukocytes. Shear force further distorts the crypt architecture of the mature placentomes when they are forced against the fetus during the second stage of labor. Cotyledon dehiscence from the caruncular crypts is completed following fetal expulsion as a result of acute shrinkage of the cotelydonary villi as well as reduced perfusion to the caruncle; the secundinae is expelled by uterine contractions. A better understanding of placentomal maturation, intra-partum, and immediate postpartum changes of the placentome should help develop strategies for the treatment and prevention of RFM. The present review proposes a model of placentome maturation and separation of fetal membranes in the dairy cow. PMID- 26970239 TI - One-Pot Fabrication of Hierarchical Nanosheet-Based TiO2 -Carbon Hollow Microspheres for Anode Materials of High-Rate Lithium-Ion Batteries. AB - Hierarchical and hollow nanostructures have recently attracted considerable attention because of their fantastic architectures and tunable property for facile lithium ion insertion and good cycling stability. In this study, a one-pot and unusual carving protocol is demonstrated for engineering hollow structures with a porous shell. Hierarchical TiO2 hollow spheres with nanosheet-assembled shells (TiO2 NHS) were synthesized by the sequestration between the titanium source and 2,2'-bipyridine-5,5'-dicarboxylic acid, and kinetically controlled etching in trifluoroacetic acid medium. In addition, annealing such porous nanostructures presents the advantage of imparting carbon-doped functional performance to its counterpart under different atmospheres. Such highly porous structures endow very large specifics surface area of 404 m(2) g(-1) and 336 m(2) g(-1) for the as-prepared and calcination under nitrogen gas. C/TiO2 NHS has high capacity of 204 mA h g(-1) at 1 C and a reversible capacity of 105 mA h g(-1) at a high rate of 20 C, and exhibits good cycling stability and superior rate capability as an anode material for lithium-ion batteries. PMID- 26970240 TI - Nucleus accumbens core and shell are differentially involved in general and outcome-specific forms of Pavlovian-instrumental transfer with alcohol and sucrose rewards. AB - Alcohol-associated stimuli contribute to relapse risk. Therefore, understanding the behavioural and neural mechanisms underlying the ability of such stimuli to promote alcohol-seeking is important for developing effective treatments for alcohol-use disorders. The Pavlovian-instrumental transfer (PIT) paradigm can be used to study the influence of Pavlovian cues on independently-trained instrumental responses earning reward. The effects can be either general, increasing the vigour of reward-related behaviours, or specific to responses that earn a common outcome. These different forms of PIT are mediated by distinct neural circuits involving the nucleus accumbens (NAC) core and shell, respectively. Here we examined the effects of pharmacological inactivation of either the NAC core or shell on PIT generated by alcohol-predictive and sucrose predictive stimuli in rats. We found that presentations of a stimulus predicting sucrose enhanced responding for sucrose but not alcohol, suggesting an outcome specific effect. In contrast, presentations of an alcohol-predictive stimulus enhanced responding for both alcohol and sucrose, suggesting a generally arousing effect. Inactivation of the NAC core reduced PIT and, in particular, the effect of the alcohol stimulus. Inactivation of the NAC shell reduced the specificity of the stimulus effects but left the ability of the stimuli to non-specifically invigorate responding intact, consistent with a role in mediating the specificity of PIT. Together, these results suggest that the NAC core plays a particularly important role in mediating the influence of alcohol-predictive cues on reward seeking behaviours. PMID- 26970241 TI - Loss of genetic diversity in farmed populations of Colossoma macropomum estimated by microsatellites. AB - The genetic variability of four Colossoma macropomum broodstocks, three from fish farms in different regions and one from the natural environment in Brazil, was analyzed using microsatellite markers. The wild progeny (n = 30) were caught in the Solimoes-Amazonas River, at the varzea lakes; this location is used to mature the fish from larvae to juveniles. The three fish farms were selected according to the age of their lineages and broodstock availability: DNOCS (n = 21) is located in the Ceara State, representing the oldest lineage of cultivated tambaqui in Brazil; Balbina (n = 30) is located in the Amazonas State, representing the youngest stocks of tambaqui farmed in Brazil (approximately 15 years); and UFRPE (n = 30) is located in the Pernambuco State and is considered to be a mixed stock formed from the DNOCS and Balbina lineages. The analysis of 13 microsatellite loci indicated the occurrence of a variability reduction in the farmed populations; the UFRPE stock was the population with the highest diversity level. Low values of molecular coancestry were found in these populations. Additionally, significant differences in the RST values among the populations were detected, as was the occurrence of genetic structure. The genetic loss found in these populations may have been influenced by the founder effect. Because no breeding programs were during the entire production period and no pedigree records were kept for these broodstocks, we suggest that a wild population might be used as an important genetic resource to increase the genetic diversity of renewal stock lineages. PMID- 26970242 TI - A new eosinophilic esophagitis (EoE)-like disease without tissue eosinophilia found in EoE families. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is a rapidly emerging, chronic inflammatory, genetically impacted disease of the esophagus, defined clinically by symptoms of esophageal dysfunction and, pathologically, by an eosinophil predominant tissue infiltration. However, in four EoE families, we have identified patients presenting with EoE-typical and corticosteroid-responsive symptoms, but without tissue eosinophilia. The aim of this study was to clinically and immunologically characterize these patients with EoE-like disease. METHODS: Five patients suffering from an EoE-like disease were evaluated with endoscopic, histologic, functional, and quantitative immunohistological examinations, and mRNA expression determination. RESULTS: The frequency of first generation offspring of patients affected by EoE or EoE-like disease was 40%. Immunofluorescence analysis confirmed an almost complete absence of eosinophils in the esophageal tissues of patients with EoE-like disease, but revealed a considerable T-cell infiltration, comparable to EoE. In contrast to EoE, eotaxin 3 mRNA and protein were markedly reduced in EoE-like disease (P < 0.05). The mRNA expression levels of three selected EoE genes (eotaxin-3, MUC4, and CDH26) allowed to discriminate between EoE-like disease, EoE, and normal epithelium. CONCLUSIONS: Patients suffering from 'EoE without eosinophilia' do not fulfill formally the diagnostic criteria for EoE. However, their clinical manifestation, immunohistology, and gene expression pattern, plus the fact that they bequeath EoE to their offspring, suggest a uniform underlying pathogenesis. Conventional EoE, with its prominent eosinophilia, therefore appears to be only one phenotype of a broader 'inflammatory dysphagia syndrome' spectrum. In this light, the role of the eosinophils, the definition of EoE, and its diagnostic criteria must likely be reconsidered. PMID- 26970244 TI - Time consumed by microscopic and nonmicroscopic tasks in image-assisted gynecologic screening: Implications for workload assessment. AB - BACKGROUND: Gynecologic screening cytology is a complex task that includes microscopic activities and nonmicroscopic activities. The authors sought to determine the amount and percentage of time that cytotechnologists spend on those activities using the ThinPrep imaging system. METHODS: In arm 1, a total of 550 consecutive unselected slides were reviewed by 11 cytotechnologists, and the time used for individual subtasks of the screening process was recorded. In arm 2, a total of 20 unselected slides were each screened by 10 different cytotechnologists (200 slides in total) and total screening times and full manual review (FMR) times were recorded. RESULTS: In arm 1, cases with and without FMR required an average of 5.6 minutes and 3.0 minutes, respectively, to screen. Overall, review of fields of view (FOVs) took 95 seconds. FMR took an average of 2.6 minutes. The average screening times for FOV-only cases was significantly longer than the US Food and Drug Administration/Centers for Medicare and Medicaid Services (FDA/CMS) workload limit of 2.4 minutes (P = .005). However, in arm 2, the time needed to screen a case increased by an average of 1 minute compared with arm 1, including 1.1 minute for FOV-only cases and >2 minutes for FMR plus FOV cases. Approximately 100% of cases screened as FOV only exceeded the FDA/CMS workload limit of 2.4 minutes. CONCLUSIONS: The FDA/CMS workload limits for FOV only cases appears to significantly underestimate the time needed to screen those cases, but seems to be appropriate for the majority of FMR plus FOV cases. Approximately 60% and 30% of the time designated to screening slides was spent on nonmicroscopic activities for FOV-only cases and FMR cases, respectively. Cancer Cytopathol 2016;124:501-7. (c) 2016 American Cancer Society. PMID- 26970245 TI - Intravenous (IV) bortezomib infusion after non-response to subcutaneous bortezomib administration can induce transitory responses in multiple myeloma patients: are some patients more sensitive to IV bortezomib? PMID- 26970243 TI - Embolization of portosystemic shunts for treatment of medically refractory hepatic encephalopathy. AB - Treatment options for refractory hepatic encephalopathy (HE) are limited. Patients who fail medical management may harbor large portosystemic shunts (PSSs) which are possible therapeutic targets. This study aims to describe patient selection, effectiveness, and safety of percutaneous PSS embolization in those with medically refractory HE. A retrospective evaluation of consecutive adult patients with medically refractory HE referred for PSS embolization at a tertiary center was performed (2003-2015). Patient data collected included the type of HE, medications, Model for End-Stage Liver Disease (MELD) score, shunt type, embolization approach, and materials used. Outcomes of interest were immediate (7 days), intermediate (1-4 months), and longer-term (6-12 months) effectiveness and periprocedural safety. Effectiveness was determined based on changes in hospitalization frequency, HE medications, and symptoms. Twenty-five patients with large PSS were evaluated for shunt embolization. Five were excluded due to high MELD scores (n = 1), comorbid conditions (n = 1), or technical considerations (n = 3). Of 20 patients who underwent embolization, 13 had persistent and 7 had recurrent HE; 100% (20/20) achieved immediate improvement. Durable benefit was achieved in 100% (18/18) and 92% (11/12) at 1-4 and 6-12 months, respectively. The majority (67%; 8/12) were free from HE-related hospitalizations over 1 year; 10% developed procedural complications, and all resolved. Six developed new or worsening ascites. In conclusion, PSS embolization is a safe and effective treatment strategy that should be considered for select patients with medically refractory HE. Liver Transplantation 22 723-731 2016 AASLD. PMID- 26970246 TI - The population ecology of male gametophytes: the link between pollination and seed production. AB - The fate of male gametophytes after pollen reaches stigmas links pollination to ovule fertilisation, governing subsequent siring success and seed production. Although male gametophyte performance primarily involves cellular processes, an ecological analogy may expose insights into the nature and implications of male gametophyte success. We elaborate this analogy theoretically and present empirical examples that illustrate associated insights. Specifically, we consider pollen loads on stigmas as localised populations subject to density-independent mortality and density-dependent processes as they traverse complex stylar environments. Different combinations of the timing of pollen-tube access to limiting stylar resources (simultaneous or sequential), the tube distribution among resources (repulsed or random) and the timing of density-independent mortality relative to competition (before or after) create signature relations of mean pollen-tube success and its variation among pistils to pollen receipt. Using novel nonlinear regression analyses (two-moment regression), we illustrate contrasting relations for two species, demonstrating that variety in these relations is a feature of reproductive diversity among angiosperms, rather than merely a theoretical curiosity. Thus, the details of male gametophyte ecology should shape sporophyte reproductive success and hence the dynamics and structure of angiosperm populations. PMID- 26970247 TI - Role of corticosteroids in Functional Endoscopic Sinus Surgery--a systematic review and meta-analysis. AB - BACKGROUND: The aim of our study is to systematically review the existing evidence on the role of corticosteroids in patients undergoing functional endoscopic sinus surgery (FESS). METHODOLOGY: Systematic search of MEDLINE (1950- 2014), EMBASE (1980-2014), metaRegister, Cochrane Library and ISI conference proceedings was carried out. RESULTS: Eighteen randomised controlled trials with 1309 patients were included. Use of local and/or systemic corticosteroids with FESS was reported in four categories; operative, anaesthesia related, post operative outcomes and risk of recurrence. Meta-analysis for operative outcomes demonstrated that, mean operative time (MD -10.70 minutes; 95% CI -15.86, -5.55; P <0.0001) and mean estimated blood loss (MD -28.32 mls; 95% CI -40.93, -15.72; P <0.0001) was significantly lower; and surgical field quality (MD -0.81; 95% CI 1.32, -0.30; P = 0.002) was significantly better in corticosteroid group. Meta analysis showed that post-operative endoscopic scores (SMD -0.39; 95% CI -0.60, 0.17; P = 0.0004) were significantly better in corticosteroid group compared to no corticosteroid group. There was no increase in risk of sinusitis (RR 0.64; 95% CI 0.32, 1.30; P = 0.22) between use of corticosteroids and no corticosteroids; There was no significant difference in recurrence risk of chronic rhinosinusitis (CRS) in mixed population studies (RR 0.77; 95% CI 0.35, 1.70; P = 0.52) between the two groups but analysis of studies reporting on chronic rhinosinusitis with nasal polyps (CRSwNP) (RR 0.64;95% CI 0.45,0.91;P=0.01) showed significant difference in favour of the corticosteroid group. CONCLUSION: Pre-operative use of local and/or systemic corticosteroids in FESS, results in significantly reduced blood loss, shorter operative time and improved surgical field quality. Studies are limited on the intra-operative use of corticosteroids to reduce postoperative pain. Postoperative corticosteroids improve postoperative endoscopic scores in CRS and recurrence rates in cases of CRSwNP. PMID- 26970248 TI - MR spectroscopy for in vivo assessment of the oncometabolite 2-hydroxyglutarate and its effects on cellular metabolism in human brain gliomas at 9.4T. AB - PURPOSE: To examine in vivo metabolic alterations in the isocitrate dehydrogenase (IDH) mutated gliomas using magnetic resonance spectroscopy (MRS) at magnetic field 9.4T. MATERIALS AND METHODS: Spectra were acquired with a 9.4T whole-body scanner with the use of a custom-built head coil (16 channel transmit and 31 channel receive). A modified stimulated echo acquisition mode (STEAM) sequence was used for localization. Eighteen patients with brain tumors of probable glial origin participated in this study. The study was performed in accordance with the guidelines of the local Ethics Committee. RESULTS: The increased spectral resolution allowed us to directly address metabolic alterations caused by the specific pathophysiology of IDH mutations including the presence of the oncometabolite 2-hydroxglutarate (2HG) and a significant decrease of the pooled glutamate and glutamine (20%, P = 0.024), which probably reflects an attempt to replenish alpha-ketoglutarate lost by conversion to 2HG. We also observed significantly reduced glutathione (GSH) levels (39%, P = 0.019), which could be similarly caused by depletion of dihydronicotinamide-adenine dinucleotide phosphate (NADPH) during this conversion in IDH mutant gliomas. CONCLUSION: We demonstrate that MRS at 9.4T provides a noninvasive measure of 2HG in vivo, which may be used for therapy planning and prognostication, and may provide insights into related pathophysiologic metabolic alterations associated with IDH mutations. J. MAGN. RESON. IMAGING 2016;44:823-833. PMID- 26970249 TI - Limitations of empirical calibration of p-values using observational data. AB - Controversy over non-reproducible published research reporting a statistically significant result has produced substantial discussion in the literature. p-value calibration is a recently proposed procedure for adjusting p-values to account for both random and systematic errors that address one aspect of this problem. The method's validity rests on the key assumption that bias in an effect estimate is drawn from a normal distribution whose mean and variance can be correctly estimated. We investigated the method's control of type I and type II error rates using simulated and real-world data. Under mild violations of underlying assumptions, control of the type I error rate can be conservative, while under more extreme departures, it can be anti-conservative. The extent to which the assumption is violated in real-world data analyses is unknown. Barriers to testing the plausibility of the assumption using historical data are discussed. Our studies of the type II error rate using simulated and real-world electronic health care data demonstrated that calibrating p-values can substantially increase the type II error rate. The use of calibrated p-values may reduce the number of false-positive results, but there will be a commensurate drop in the ability to detect a true safety or efficacy signal. While p-value calibration can sometimes offer advantages in controlling the type I error rate, its adoption for routine use in studies of real-world health care datasets is premature. Separate characterizations of random and systematic errors provide a richer context for evaluating uncertainty surrounding effect estimates. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26970250 TI - Post-ovulatory aging of mouse oocytes in vivo and in vitro: Effects of caffeine on exocytosis and translocation of cortical granules. AB - The developmental potential of post-ovulatory oocytes decreases with aging in vivo and in vitro. In this study, we aimed to investigate the effects of a potent antioxidant caffeine on cortical granules (CGs) distribution in mouse oocytes aging in vivo and in vitro. We found that in vivo administration of 150 mg/kg caffeine caused ovulation of some morphologically abnormal oocytes showing premature exocytosis or congregation of CGs, but significantly decreased abnormal distribution of CGs in oocytes aging for 6 h, 12 h and 18 h in vivo compared to those without caffeine treatment. Unexpectedly, supplementation of oocyte culture medium with 10 mmol/L caffeine accelerated CGs release of oocytes and the normal CG distribution rate dramatically decreased from 6 h in oocytes aging in vitro. It appeared that oocytes showed a high degree of abnormal CG distribution by aging for 18 h, and caffeine might delay oocyte CG exocytosis in vivo, but accelerates CG exocytosis in vitro. Our findings may have implications for improving assisted reproduction technologies. PMID- 26970251 TI - Effective extraction and simultaneous determination of Sudan dyes from tomato sauce and chili-containing foods using magnetite/reduced graphene oxide nanoparticles coupled with high-performance liquid chromatography. AB - A simple, effective, and robust magnetic solid-phase extraction method was developed using magnetite/reduced graphene oxide nanoparticles as the adsorbent for the simultaneous determination of Sudan dyes (I, II, III, and IV) in foodstuffs. The magnetite/reduced graphene oxide nanoparticles were characterized by X-ray diffraction, scanning electron microscopy, and vibrating sample magnetometry. The extraction parameters including extraction time, elution solution, and elution time and volume were investigated in detail. Such magnetite/reduced graphene oxide nanoparticles based magnetic solid-phase extraction in combination with high-performance liquid chromatography and variable wavelength detection gave the detection limits of 3-6 MUg/kg for Sudan I IV in chili sauce, tomato sauce, chili powder, and chili flake samples. The recoveries were 79.6-108% at three spiked levels with the intra- and inter-day relative standard deviations of 1.2-8.6 and 4.5-9.6%, respectively. The feasibility was further performed by a comparison with commercial alumina-N. This method is suitable for the routine analysis of Sudan dyes due to its sensitivity, simplicity, and low cost. PMID- 26970252 TI - L-Leucine as an excipient against moisture on in vitro aerosolization performances of highly hygroscopic spray-dried powders. AB - L-Leucine (LL) has been widely used to enhance the dispersion performance of powders for inhalation. LL can also protect powders against moisture, but this effect is much less studied. The aim of this study was to investigate whether LL could prevent moisture-induced deterioration in in vitro aerosolization performances of highly hygroscopic spray-dried powders. Disodium cromoglycate (DSCG) was chosen as a model drug and different amounts of LL (2-40% w/w) were added to the formulation, with the aim to explore the relationship between powder dispersion, moisture protection and physicochemical properties of the powders. The powder formulations were prepared by spray drying of aqueous solutions containing known concentrations of DSCG and LL. The particle sizes were measured by laser diffraction. The physicochemical properties of fine particles were characterized by X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic vapor sorption (DVS). The surface morphology and chemistry of fine particles were analyzed by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and time-of-flight secondary ion mass spectrometry (ToF-SIMS). In vitro aerosolization performances were evaluated by a next generation impactor (NGI) after the powders were stored at 60% or 75% relative humidity (RH), and 25 degrees C for 24h. Spray-dried (SD) DSCG powders were amorphous and absorbed 30 45% (w/w) water at 70-80% RH, resulting in deterioration in the aerosolization performance of the powders. LL did not decrease the water uptake of DSCG powders, but it could significantly reduce the effect of moisture on aerosolization performances. This is due to enrichment of crystalline LL on the surface of the composite particles. The effect was directly related to the percentage of LL coverage on the surface of particles. Formulations having 61-73% (molar percent) of LL on the particle surface (which correspond to 10-20% (w/w) of LL in the bulk powders) could minimize moisture-induced deterioration in the aerosol performance. In conclusion, particle surface coverage of LL can offer short-term protection against moisture on dispersion of hygroscopic powders. PMID- 26970253 TI - Defining post-sternotomy mediastinitis for clinical evidence-based studies. AB - BACKGROUND: Considerable advances have already been made in the treatment of deep thoracic wound infections following a median sternotomy for cardiac surgery. Further improvement in diagnosis, treatment, and outcome will require a targeted approach by multidisciplinary teams. Clear communication and synergy between the various clinical and supportive disciplines would assist in removing the last barriers to standardized evidence-based studies and the development of improved evidence-based guidelines. METHODS: An extensive literature search without language restrictions was carried out on PubMed (Medline), EMBASE, and Web of Science, covering the period 1988 to week 16, 2014, and a manual search of the reference lists was performed regarding all possible definitions and classifications of post-sternotomy mediastinitis. Two hundred and eighteen papers describing post-sternotomy infections in a multitude of terms were identified, and the strengths and weaknesses of the most popular definitions and terms relating specifically to post-sternotomy infections were examined. RESULTS: This study revealed that clinicians use a multitude of terms to describe post sternotomy infections without defining the condition under treatment. Occasionally, older epidemiological (surveillance) definitions were used. It also shows that supportive disciplines have their own definitions, or interpretations of existing definitions, to describe these infections. CONCLUSION: The outcome of this study is that clinicians have adopted no single definition, which is essential for further improvement for evidence-based studies. We suggest that it is possible to adopt a single term for thoracic infection after a sternotomy (and only sternotomy), and propose a clinical definition for this purpose. PMID- 26970255 TI - Cortical chemoarchitecture shapes macroscale effective functional connectivity patterns in macaque cerebral cortex. AB - The mammalian cortex is a complex system of-at the microscale level interconnected neurons and-at the macroscale level-interconnected areas, forming the infrastructure for local and global neural processing and information integration. While the effects of regional chemoarchitecture on local cortical activity are well known, the effect of local neurotransmitter receptor organization on the emergence of large scale region-to-region functional interactions remains poorly understood. Here, we examined reports of effective functional connectivity-as measured by the action of strychnine administration acting on the chemical balance of cortical areas-in relation to underlying regional variation in microscale neurotransmitter receptor density levels in the macaque cortex. Linking cortical variation in microscale receptor density levels to collated information on macroscale functional connectivity of the macaque cortex, we show macroscale patterns of effective corticocortical functional interactions-and in particular, the strength of connectivity of efferent macroscale pathways-to be related to the ratio of excitatory and inhibitory neurotransmitter receptor densities of cortical areas. Our findings provide evidence for the microscale chemoarchitecture of cortical areas to have a direct stimulating influence on the emergence of macroscale functional connectivity patterns in the mammalian brain. Hum Brain Mapp 37:1856-1865, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26970254 TI - Expanding the genotypic spectrum of Perrault syndrome. AB - Perrault syndrome is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) in both sexes and primary ovarian insufficiency in 46, XX karyotype females. Biallelic variants in five genes are reported to be causative: HSD17B4, HARS2, LARS2, CLPP and C10orf2. Here we present eight families affected by Perrault syndrome. In five families we identified novel or previously reported variants in HSD17B4, LARS2, CLPP and C10orf2. The proband from each family was whole exome sequenced and variants confirmed by Sanger sequencing. A female was compound heterozygous for a known, p.(Gly16Ser) and novel, p.(Val82Phe) variant in D-bifunctional protein (HSD17B4). A family was homozygous for mitochondrial leucyl aminocyl tRNA synthetase (mtLeuRS) (LARS2) p.(Thr522Asn), previously associated with Perrault syndrome. A further family was compound heterozygous for mtLeuRS, p.(Thr522Asn) and a novel variant, p.(Met117Ile). Affected individuals with LARS2 variants had low frequency SNHL, a feature previously described in Perrault syndrome. A female with significant neurological disability was compound heterozygous for p.(Arg323Gln) and p.(Asn399Ser) variants in Twinkle (C10orf2). A male was homozygous for a novel variant in CLPP, p.(Cys144Arg). In three families there were no putative pathogenic variants in these genes confirming additional disease-causing genes remain unidentified. We have expanded the spectrum of disease-causing variants associated with Perrault syndrome. PMID- 26970256 TI - Apigenin Reduces Survival of Choriocarcinoma Cells by Inducing Apoptosis via the PI3K/AKT and ERK1/2 MAPK Pathways. AB - Apigenin is a flavonoid found in parsley, onions, oranges, tea, chamomile, wheat, and sprouts. It has a variety of biological properties including anti-oxidant, anti-mutagenic, anti-carcinogenic, anti-inflammatory, anti-proliferative, and anti-spasmodic effects. Based on epidemiological and case-control studies, apigenin is regarded as a novel chemotherapeutic agent against various cancer types. However, little is known about the effects of apigenin on choriocarcinoma cells. Therefore, we investigated the anti-cancer effects of apigenin on choriocarcinoma cells (JAR and JEG3) in the present study. Apigenin reduced viability and migratory properties, increased apoptosis, and suppressed mitochondrial membrane potential in both the JAR and JEG3 cells. In addition, apigenin predominantly decreased phosphorylation of AKT, P70RSK, and S6 whereas the phosphorylation of ERK1/2 and P90RSK was increased by apigenin treatment of JAR and JEG3 cells in a dose-dependent manner. Moreover, treatment of JAR and JEG3 cells with both apigenin and pharmacological inhibitors of PI3K/AKT (LY294002) and ERK1/2 (U0126) revealed synergistic anti-proliferative effects. Collectively, these results indicated that the apigenin is an invaluable chemopreventive agent that inhibits progression and metastasis of choriocarcinoma cells through regulation of PI3K/AKT and ERK1/2 MAPK signal transduction mechanism. J. Cell. Physiol. 231: 2690-2699, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26970257 TI - Subtle Structural Differences Trigger Inhibitory Activity of Propafenone Analogues at the Two Polyspecific ABC Transporters: P-Glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). AB - The transmembrane ABC transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are widely recognized for their role in cancer multidrug resistance and absorption and distribution of compounds. Furthermore, they are linked to drug-drug interactions and toxicity. Nevertheless, due to their polyspecificity, a molecular understanding of the ligand-transporter interaction, which allows designing of both selective and dual inhibitors, is still in its infancy. This study comprises a combined approach of synthesis, in silico prediction, and in vitro testing to identify molecular features triggering transporter selectivity. Synthesis and testing of a series of 15 propafenone analogues with varied rigidity and basicity of substituents provide first trends for selective and dual inhibitors. Results indicate that both the flexibility of the substituent at the nitrogen atom, as well as the basicity of the nitrogen atom, trigger transporter selectivity. Furthermore, inhibitory activity of compounds at P-gp seems to be much more influenced by logP than those at BCRP. Exploiting these differences further should thus allow designing specific inhibitors for these two polyspecific ABC-transporters. PMID- 26970258 TI - Systematic review and meta-analysis of persistent left superior vena cava on prenatal ultrasound: associated anomalies, diagnostic accuracy and postnatal outcome. AB - OBJECTIVES: To quantify the prevalence of chromosomal anomalies in fetuses with persistent left superior vena cava (PLSVC), assess the strength of the association between PLSVC and coarctation of the aorta and ascertain the diagnostic accuracy of antenatal ultrasound in correctly identifying isolated cases of PLSVC. METHODS: MEDLINE, EMBASE, CINHAL and the Cochrane databases were searched from the year 2000 onwards using combinations of keywords 'left superior vena cava' and 'outcome'. Two authors reviewed all abstracts independently. Quality assessment of the included studies was performed using the Newcastle Ottawa Scale for cohort studies. The rates of the following outcomes were analyzed: chromosomal abnormalities; associated intracardiac anomalies (ICAs) and extracardiac anomalies (ECAs) diagnosed prenatally; additional ICAs and ECAs detected only at postnatal imaging or clinical evaluation but missed at prenatal imaging; and association of PLSVC and coarctation of the aorta. Meta-analyses of proportions were used to combine data. RESULTS: In total, 2708 articles were identified and 13 (n = 501) were included in the systematic review. Associated ICAs and ECAs were detected at the prenatal ultrasound examination or at a follow up assessment in 60.7% (95% CI, 44.2-75.9%) and 37.8% (95% CI, 31.0-44.8%) of cases, respectively. Chromosomal anomalies occurred in 12.5% (95% CI, 9.0-16.4%) of cases in the overall population of fetuses with PLSVC and in 7.0% (95% CI, 2.7 13.0%) of isolated cases. Additional ICAs and ECAs were detected only after birth and missed at ultrasound in 2.4% (95% CI, 0.5-5.8%) and 6.7% (95% CI, 2.2-13.2%) of cases, respectively. Coarctation of the aorta was associated with isolated PLSVC in 21.3% (95% CI, 13.6-30.3%) of cases. CONCLUSIONS: PLSVC is commonly associated with ICAs, ECAs and chromosomal anomalies. Fetuses with isolated PLSVC should be followed up throughout pregnancy in order to rule out coarctation of the aorta. As most of the data in this review were derived from high-risk pregnancies, the rate of associated abnormalities is likely to be higher than that in the general population of fetuses with PLSVC, for which more data are needed. Revision sistematica y metaanalisis de la persistencia de la vena cava superior izquierda en la ecografia prenatal: anomalias asociadas, precision del diagnostico y resultado postnatal RESUMEN OBJETIVOS: Cuantificar la prevalencia de anomalias cromosomicas en fetos con vena cava superior izquierda persistente (VCSIP), evaluar la solidez de la asociacion entre la VCSIP y la coartacion aortica, y determinar la precision del diagnostico de la ecografia prenatal como metodo para identificar correctamente casos aislados de VCSIP. METODOS: Se busco en las bases de datos de MEDLINE, EMBASE, CINHAL y Cochrane articulos publicados desde el ano 2000 en adelante, usando combinaciones de las palabras clave "vena cava superior izquierda" y "resultado". Dos de los autores revisaron de forma independiente todos los resumenes encontrados. La evaluacion de calidad de los estudios incluidos se realizo mediante la escala Newcastle-Ottawa para estudios de cohortes. Se analizaron las tasas de los siguientes resultados: anomalias cromosomicas; anomalias intracardiacas (AIC) y anomalias extracardiacas (AEC) asociadas diagnosticadas prenatalmente; AIC y AEC adicionales detectadas solo en ecografias postnatales o mediante evaluacion clinica, pero no observadas en ecografias prenatales; y la asociacion entre la VCSIP y la coartacion aortica. Se utilizo un meta-analisis de proporciones para combinar los datos. RESULTADOS: En total, se identificaron 2708 articulos y se incluyeron 13 (n = 501) en la revision sistematica. En la ecografia prenatal o en una revision de seguimiento se detectaron AIC y AEC asociadas en el 60,7% (IC 95%, 44,2-75,9%) y el 37,8% (IC 95%, 31,0-44,8%) de los casos, respectivamente. Se produjeron anomalias cromosomicas en el 12,5% (IC 95%, 9,0-16,4%) de los casos en la poblacion general de fetos con VCSIP y en el 7,0% (IC 95%, 2,7-13,0%) de casos aislados. Las AIC y AEC adicionales solo se detectaron despues del nacimiento y en el 6,7% (IC 95%, 2,2-13,2%) de los casos, respectivamente. La coartacion aortica se encontro asociada con la VCSIP aislada en un 21,3% (IC 95%, 13,6-30,3%) de los casos. CONCLUSIONES: La VCSIP esta comunmente asociada a AIC, AEC y anomalias cromosomicas. Los fetos con VCSIP aislada deben ser objeto de seguimiento durante todo el embarazo, con el fin de descartar la coartacion aortica. Como la mayoria de los datos de esta revision proceden de embarazos de alto riesgo, es probable que la tasa de anomalias asociadas sea mas alta que la de la poblacion general de fetos con VCSIP, por lo que se necesitan mas datos. PMID- 26970259 TI - LINE-1 gene hypomethylation and p16 gene hypermethylation in HepG2 cells induced by low-dose and long-term triclosan exposure: The role of hydroxyl group. AB - Triclosan (TCS), a frequently used antimicrobial agent in pharmaceuticals and personal care products, exerts liver tumor promoter activities in mice. Previous work showed high-dose TCS (1.25-10MUM) induced global DNA hypomethylation in HepG2 cells. However, whether or how tumor suppressor gene methylation changed in HepG2 cells after low-dose and long-term TCS exposure is still unknown. We investigate here the effects and mechanisms of DNA methylation of global DNA(GDM), repetitive genes, and liver tumor suppressor gene (p16) after exposing HepG2 cells to low-dose TCS (0.625-5nM)for two weeks using HPLC-MS/MS, Methylight, Q-MSP, Pyrosequencing, and Massarray methods. We found that low-dose TCS exposure decreased repetitive elements LINE-1 methylation levels, but not global DNA methylation, through down-regulating DNMT1 (DNA methyltransferase 1) and MeCP2 (methylated DNA binding domain) expression, and up-regulating 8-hydroxy 2-deoxyguanosine (8-OHdG) levels. Interestingly, low-dose TCS elevated p16 gene methylation and inhibited p16 expression, which were not observed in high-dose (10MUM) group. Meanwhile, methyl-triclosan could not induce these two types of DNA methylation changes, suggesting the involvement of hydroxyl in TCS-mediated DNA methylation changes. Collectively, our results suggested low concentrations of TCS adversely affected HepG2 cells through DNA methylation dysregulation, and hydroxyl group in TCS played an important role in the effects. This study provided a better understanding on hepatotoxicity of TCS at environmentally relevant concentrations through epigenetic pathway. PMID- 26970260 TI - Hygienic food to reduce pathogen risk to bumblebees. AB - Bumblebees are ecologically and economically important pollinators, and the value of bumblebees for crop pollination has led to the commercial production and exportation/importation of colonies on a global scale. Commercially produced bumblebee colonies can carry with them infectious parasites, which can both reduce the health of the colonies and spillover to wild bees, with potentially serious consequences. The presence of parasites in commercially produced bumblebee colonies is in part because colonies are reared on pollen collected from honey bees, which often contains a diversity of microbial parasites. In response to this threat, part of the industry has started to irradiate pollen used for bumblebee rearing. However, to date there is limited data published on the efficacy of this treatment. Here we examine the effect of gamma irradiation and an experimental ozone treatment on the presence and viability of parasites in honey bee pollen. While untreated pollen contained numerous viable parasites, we find that gamma irradiation reduced the viability of parasites in pollen, but did not eliminate parasites entirely. Ozone treatment appeared to be less effective than gamma irradiation, while an artificial pollen substitute was, as expected, entirely free of parasites. The results suggest that the irradiation of pollen before using it to rear bumblebee colonies is a sensible method which will help reduce the incidence of parasite infections in commercially produced bumblebee colonies, but that further optimisation, or the use of a nutritionally equivalent artificial pollen substitute, may be needed to fully eliminate this route of disease entry into factories. PMID- 26970261 TI - Distribution of the myrmecoparasitic fungus Rickia wasmannii (Ascomycota: Laboulbeniales) across colonies, individuals, and body parts of Myrmica scabrinodis. AB - The ant species Myrmica scabrinodis plays a markedly important ecological role through much of the humid grasslands of Eurasia. It hosts a species-rich community of pathogens and parasites, including Rickia wasmannii, an enigmatic member of entomoparasitic laboulbenialean fungi. This study provides a descriptive ecology of R. wasmannii by characterizing its prevalence and distribution across several hierarchical levels: colonies, individuals, and anatomic body parts. Infections were restricted to a single ant species, M. scabrinodis, and infected colonies occurred predominantly in wet habitats. Infections tended to be highly prevalent within infected colonies, often reaching 100% sample prevalence among workers. Individual infections exhibited an aggregated distribution typical to host-parasite systems. Workers from the aboveground part of nests (presumably older ones acting as foragers) were more infected than those from the belowground part. Fungal thalli could be found all over the body of the hosts, the head and the abdomen being the most infected parts of the body. The fungi's distribution among host body parts statistically differed between low versus high-intensity infections: the initial dominance of the head decreased with advancing infection. These findings may provide baseline data for future comparative or monitoring studies. PMID- 26970262 TI - Transoral laser microsurgery as primary treatment for selected T3 glottic and supraglottic cancers. AB - BACKGROUND: T3 laryngeal cancer encompasses heterogeneous lesions whose treatment is still debated. The purpose of this study was to evaluate transoral laser microsurgery (TLM) in management of selected T3 glottic and supraglottic cancers. METHODS: Fifty-six patients with selected T3 glottic and supraglottic squamous cell carcinomas (SCCs) treated by TLM +/- selective neck dissection +/- adjuvant therapy were evaluated in terms of overall survival (OS), disease-free survival (DFS), and organ preservation rates. RESULTS: For the entire cohort, 5-year OS and DFS were 63.3% and 72.4%, whereas they were 65.2% and 72.9% for glottic and 59.3% and 76.3% for supraglottic SCC, respectively. No patient required permanent tracheostomy and 1 patient was gastrostomy tube-dependent at last follow-up. CONCLUSION: TLM +/- selective neck dissection +/- adjuvant (chemo)radiotherapy for selected T3 glottic and supraglottic SCC represents an effective alternative treatment to open partial laryngectomies and nonsurgical organ preservation protocols, particularly in elderly and frail patients. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 1107-1112, 2016. PMID- 26970264 TI - Toward a simple risk assessment screening tool for HCV infection in Egypt. AB - Asymptomatic patients with HCV infection identified through screening program could benefit not only from treatment but also from other interventions such as counseling to maintain health and avoid risk behaviors. This might prevent the spread of infection and result in significant public health benefits. However, mass screening would quickly deplete resources. This work aims to develop a brief HCV risk assessment questionnaire that inquires initially about a wide range of risk factors found to be potentially associated with HCV infection in order to identify the few most significant questions that could be quickly used to facilitate cost-effective HCV case-finding in the general population in Egypt. An exhaustive literature search was done to include all reported HCV risk factors that were pooled in a 65 item questionnaire. After an initial pilot study, a case control study was performed that included 1,024 cases and 1,046 controls. In a multivariable model, a list of independent risk factors were found to be significant predictors for being HCV seropositive among two age strata (<45 and >45 years) for each gender. A simplified model that assigned values of the odds ratio as a weight for each factor present predicted HCV infection with high diagnostic accuracy. Attaining the defined cut-off value of the total risk score enhances the effectiveness of screening. HCV risk factors in the Egyptian population vary by age and gender. An accurate prediction screening tool can be used to identify those at high risk who may benefit most from HCV serologic testing. These results are to be further validated in a large scale cross sectional study to assess the wider use of this tool. J. Med. Virol. 88:1767 1775, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26970263 TI - Anti-tubercular therapy for intraocular tuberculosis: A systematic review and meta-analysis. AB - Intraocular tuberculosis remains a diagnostic and management conundrum for both ophthalmologists and pulmonologists. We analyze the efficacy and safety of anti tubercular therapy (ATT) in patients with intraocular tuberculosis and factors associated with favorable outcome. Twenty-eight studies are included in this review, with a total of 1,917 patients. Nonrecurrence of inflammation was observed in pooled estimate of 84% of ATT-treated patients (95% CI 79-89). There was minimal difference in the outcome between patients treated with ATT alone (85% successful outcome; 95% CI 25-100) and those with concomitant systemic corticosteroid (82%; 95% CI 73-90). The use of ATT may be of benefit to patients with suspected intraocular tuberculosis; however, this conclusion is limited by the lack of control group analysis and standardized recruitment and treatment protocols. We propose further prospective studies to better establish the efficacy of ATT and ascertain the factors associated with favorable treatment outcomes. PMID- 26970265 TI - Prevalence of ADHD symptoms across clinical stages of major depressive disorder. AB - BACKGROUND: Depression and ADHD often co-occur in clinical samples. Depression severity may be linked to ADHD symptomatology. We therefore assessed ADHD symptoms across clinical stages of major depressive disorder (MDD). METHODS: We used 4-year follow-up data of the Netherlands Study of Depression and Anxiety (September 2008 until April 2011), including healthy controls, groups with remitted and current MDD (N=2053; age range 21-69 years; 66.8% females). Probable ADHD was defined as having current ADHD symptoms on the Conners Adult ADHD Rating Scale and a positive score on childhood or early-adolescent ADHD indicators. We examined ADHD symptom rates across (i) those with and without lifetime MDD, (ii) clinical characteristics of MDD including severity, course and outcomes, (iii) clinical stages of MDD. RESULTS: (i) The prevalence of ADHD symptoms was 0.4% in healthy controls, 5.7% in remitted MDD and 22.1% in current MDD (OR=4.5; 95% CI 3.1-6.5). (ii) ADHD symptom rates and odds were significantly increased among those with more severe depression (29.4%; OR=6.8; 95% CI 2.9-16.1), chronic depression (21.8%; OR=3.8; 95% CI 2.5-5.7), earlier age of onset of depressive symptoms (9.9%; OR=1.5; 95% CI 1.0-2.3), and comorbid anxiety disorders (29.0%; OR=3.4; 95% CI 2.0-5.7). (iii) ADHD symptom rates increased across clinical stages of MDD, up to 22.5% in chronic MDD. LIMITATIONS: We used self-reports on ADHD symptoms. Also, clinical staging models have not yet been validated for mental disorders. CONCLUSIONS: ADHD symptoms are very common among MDD patients, especially among those in recurrent and chronic stages of MDD. Considering ADHD may be an important step forward in improving the treatment of depression. PMID- 26970266 TI - Long-term safety and efficacy of armodafinil in bipolar depression: A 6-month open-label extension study. AB - BACKGROUND: Safe/well-tolerated treatments for bipolar I depression remain limited. We assessed safety/tolerability of adjunctive open-label armodafinil, a wakefulness-promoting agent evaluated in 3 acute, controlled efficacy studies with variable efficacy results. METHODS: Completers of three 8-week, double blind, placebo-controlled adjunctive armodafinil studies (150-200 mg/day added to ongoing stable maintenance doses of 1 or 2 protocol-defined mood stabilizers) in bipolar I depression could enter this 6-month, open-label extension study. Objectives included evaluation of safety/tolerability (primary) and efficacy (secondary). RESULTS: 867 patients enrolled; 863 received >=1 dose of armodafinil and 506 (58%) completed the 6-month study. Headache, insomnia, and anxiety were the most common adverse events (AEs) reported, whereas akathisia, nausea, sedation/somnolence, and weight increase were uncommon. Mean measures assessing emergence of mania, anxiety, insomnia, or suicidality showed no worsening. Discontinuations due to AEs occurred in 57 (7%) patients. Serious AEs occurred in 27 (3%) patients and were considered treatment-related in 8 (1%) patients. Depressive symptoms improved over the 6 months, as did patient functioning. LIMITATIONS: Lack of placebo control. CONCLUSIONS: Adjunctive armodafinil was generally safe and well tolerated over 6 months of open-label treatment at 150 200 mg/day when taken with protocol-defined mood stabilizers for bipolar I depression. This 6-month open-label study suggested that armodafinil augmentation of bipolar maintenance therapies may have a favorable risk profile and may improve depressive symptoms in some patients with bipolar I depression. PMID- 26970267 TI - Nature and determinants of suicidal ideation among U.S. veterans: Results from the national health and resilience in veterans study. AB - BACKGROUND: Suicidal thoughts and behaviors among U.S. military veterans are a major public health concern. To date, however, scarce data are available regarding the nature and correlates of suicidal ideation (SI) among U.S. veterans. This study evaluated the prevalence and correlates of suicidal ideation in a contemporary, nationally representative, 2-year prospective cohort study. METHOD: Data were analysed from a total of 2157 U.S. veterans who participated in the National Health and Resilience Veterans Study (NHRVS; Wave 1 conducted in 2011; Wave 2 in 2013). Veterans completed measures assessing SI, sociodemographic characteristics, and potential risk and protective correlates. RESULTS: The majority of veterans (86.3%) denied SI at either time point, 5.0% had SI onset (no SI at Wave 1, SI at Wave 2), 4.9% chronic SI (SI at Waves 1 and 2), and 3.8% had remitted SI (SI at Wave 1, no SI Wave 2). Greater Wave 1 psychiatric distress was associated with increased likelihood of chronic SI (relative risk ratio [RRR]=3.72), remitted SI (RRR=3.38), SI onset (RRR=1.48); greater Wave 1 physical health difficulties were additionally associated with chronic SI (RRR=1.64) and SI onset (RRR=1.47); and Wave 1 substance abuse history was associated with chronic SI (RRR 1.57). Greater protective psychosocial characteristics (e.g., resilience, gratitude) at Wave 1 were negatively related to SI onset (RRR=0.57); and greater social connectedness at Wave 1, specifically perceived social support and secure attachment style, was negatively associated with SI onset (RRR=0.75) and remitted SI (RRR=0.44), respectively. LIMITATIONS: Suicidal ideation was assessed using a past two-week timeframe, and the limited duration of follow-up precludes conclusions regarding more dynamic changes in SI over time. CONCLUSIONS: These results indicate that a significant minority (13.7%) of U.S. veterans has chronic, onset, or remitted SI. Prevention and treatment efforts designed to mitigate psychiatric and physical health difficulties, and bolster social connectedness and protective psychosocial characteristics may help mitigate risk for SI. PMID- 26970268 TI - Gray matter brain volumes in childhood-maltreated patients with bipolar disorder type I: A voxel-based morphometric study. AB - BACKGROUND: Childhood maltreatment (CM) may be related to clinical expression and outcome of bipolar disorder (BD). Several neuroimaging studies have detected brain morphological changes in specific neural networks of adults who suffered maltreatment in their childhood. We investigated alterations in gray matter volume (GMV) to determine a possible neuroanatomical basis of vulnerability in patients with CM having type I BD (BD-I). METHODS: We assessed 39 euthymic DSM-IV BD-I patients with (n=20) and without (n=19) a history of CM and 20 healthy controls without maltreatment as defined by the Childhood Trauma Questionnaire (CTQ). Voxel-based morphometry (VBM) was used to compare GMV differences between patients and controls and perform linear correlations in overall BD group between GMV and CTQ scores. RESULTS: BD-I patients had significant negative correlations between CTQ total score and GMV in the right dorsolateral prefrontal cortex (PFC) and the right thalamus; between physical abuse and GMV in the right dorsolateral PFC; between physical neglect and GMV in the thalamus bilaterally; and between emotional neglect and GMV in the right thalamus. LIMITATIONS: Pharmacological treatment could have altered GMV findings. Results emerged only when using SVC approach. CTQ, a retrospective self-report, has the risk of potential recall bias. The cross-sectional design limits longitudinal and neurodevelopmental inferences. CONCLUSIONS: The severity of self-reported CM in BD-I patients is associated with morphological changes in GMV of specific neural networks relevant to responses to stress and to modulate emotional behavior. PMID- 26970270 TI - Pazopanib for patients with advanced soft tissue sarcomas in a real-life setting. PMID- 26970269 TI - Mechanisms underlying the enhancement of toxicity caused by the coincubation of zinc oxide and copper nanoparticles in a fish hepatoma cell line. AB - Ecosystems are exposed to a wide variety of individual substances, including at the nano-scale; and the potential adverse effects of their interactions are an increasing concern. The purpose of the present study was to determine whether zinc oxide nanoparticles (ZnONPs) at a no-observed-effect concentration modulate the cytotoxicity of copper nanoparticles (CuNPs) in the fish hepatoma cell line PLHC-1 after 48 h of exposure and the contribution of the released ions to these effects. Cells were exposed to 50-nm CuNPs (0.39-25.0 ug/mL), alone or in combination with ZnONPs (25 nm or 100 nm), at 6.25 ug/mL. Cells were exposed to suspensions of NPs or to their supernatants, as well as to their combinations. The effects on cell viability were assessed through cytotoxicity assays. Changes in cell morphology and metal internalization were also evaluated. The cytotoxicity exerted by CuNPs was enhanced in the presence of nontoxic concentrations of ZnONPs. On the contrary, Zn ions protected the cell line from the CuNP toxicity, this effect being related to an increase in the intracellular levels of Zn. This increase of metal was not observed in cells exposed to both ZnONPs and CuNPs, even when they were visualized inside the cell. The results indicated that the internalization of ZnONPs, but not the Zn ions, was responsible for the enhanced toxicity of the CuNPs. Environ Toxicol Chem 2016;35:2562-2570. (c) 2016 SETAC. PMID- 26970271 TI - Dual mechanisms of action of the RNA-binding protein human antigen R explains its regulatory effect on melanoma cell migration. AB - Overexpression of wingless-type MMTV integration site family 5A (WNT5A) plays a significant role in melanoma cancer progression; however, the mechanism(s) involved remains unknown. In breast cancer, the human antigen R (HuR) has been implicated in the regulation of WNT5A expression. Here, we demonstrate that endogenous expression of WNT5A correlates with levels of active HuR in HTB63 and WM852 melanoma cells and that HuR binds to WNT5A messenger RNA in both cell lines. Although the HuR inhibitor MS-444 significantly impaired migration in both melanoma cell lines, it reduced WNT5A expression only in HTB63 cells, as did small interfering RNA knockdown of HuR. Consistent with this finding, MS-444 induced inhibition of HTB63 cell migration was restored by the addition of recombinant WNT5A, whereas MS-444-induced inhibition of WM852 cell migration was restored by the addition of recombinant matrix metalloproteinase-9, another HuR regulated protein. Clearly, HuR positively regulates melanoma cell migration via at least 2 distinct mechanisms making HuR an attractive therapeutic target for halting melanoma dissemination. PMID- 26970272 TI - Function of isoprenoid quinones and chromanols during oxidative stress in plants. AB - Isoprenoid quinones and chromanols in plants fulfill both signaling and antioxidant functions under oxidative stress. The redox state of the plastoquinol pool (PQ-pool), which is modulated by interaction with reactive oxygen species (ROS) during oxidative stress, has a major regulatory function in both short- and long-term acclimatory responses. By contrast, the scavenging of ROS by prenyllipids affects signaling pathways where ROS play a role as signaling molecules. As the primary antioxidants, isoprenoid quinones and chromanols are synthesized under high-light stress in response to any increased production of ROS. During photo-oxidative stress, these prenyllipids are continuously synthesized and oxidized to other compounds. In turn, their oxidation products (hydroxy-plastochromanol, plastoquinol-C, plastoquinone-B) can still have an antioxidant function. The oxidation products of isoprenoid quinones and chromanols formed specifically in the face of singlet oxygen, can be indicators of singlet oxygen stress. PMID- 26970273 TI - Sphingosine 1-phosphate and sphingosine kinases in health and disease: Recent advances. AB - Sphingosine kinases (isoforms SK1 and SK2) catalyse the formation of a bioactive lipid, sphingosine 1-phosphate (S1P). S1P is a well-established ligand of a family of five S1P-specific G protein coupled receptors but also has intracellular signalling roles. There is substantial evidence to support a role for sphingosine kinases and S1P in health and disease. This review summarises recent advances in the area in relation to receptor-mediated signalling by S1P and novel intracellular targets of this lipid. New evidence for a role of each sphingosine kinase isoform in cancer, the cardiovascular system, central nervous system, inflammation and diabetes is discussed. There is continued research to develop isoform selective SK inhibitors, summarised here. Analysis of the crystal structure of SK1 with the SK1-selective inhibitor, PF-543, is used to identify residues that could be exploited to improve selectivity in SK inhibitor development for future therapeutic application. PMID- 26970274 TI - Prolactin inhibits a major tumor-suppressive function of wild type BRCA1. AB - Even though mutations in the tumor suppressor, BRCA1, markedly increase the risk of breast and ovarian cancer, most breast and ovarian cancers express wild type BRCA1. An important question is therefore how the tumor-suppressive function of normal BRCA1 is overcome during development of most cancers. Because prolactin promotes these and other cancers, we investigated the hypothesis that prolactin interferes with the ability of BRCA1 to inhibit the cell cycle. Examining six different cancer cell lines with wild type BRCA1, and making use of both prolactin and the growth-inhibiting selective prolactin receptor modulator, S179D PRL, we demonstrate that prolactin activation of Stat5 results in the formation of a complex between phospho-Stat5 and BRCA1. Formation of this complex does not interfere with nuclear translocation or binding of BRCA1 to the p21 promoter, but does interfere with the ability of BRCA1 to transactivate the p21 promoter. Overexpression of a dominant-negative Stat5 in prolactin-stimulated cells resulted in increased p21 expression. We conclude that prolactin inhibits a major tumor-suppressive function of BRCA1 by interfering with BRCA1's upregulation of expression of the cell cycle inhibitor, p21. PMID- 26970276 TI - Borderline resectable pancreatic cancer. AB - Surgery followed by adjuvant chemotherapy remains the only treatment option for pancreatic ductal adenocarcinoma (PDAC) with the chance of long-term survival. If a radical tumor resection is possible, 5-year survival rates of 20-25% can be achieved. Pancreatic surgery has significantly changed during the past years and resection approaches have been extended beyond standard procedures, including vascular and multivisceral resections. Consequently, borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC), which has recently been defined by the International Study Group for Pancreatic Surgery (ISGPS), has become a controversial issue with regard to its management in terms of upfront resection vs. neoadjuvant treatment and sequential resection. Preoperative diagnostic accuracy to define resectability of PDAC is a keypoint in this context as well as the surgical and interdisciplinary expertise to perform advanced pancreatic surgery and manage complications. The present mini-review summarizes the current state of definition, management and outcome of BR-PDAC. Furthermore, the topic of ongoing and future studies on neoadjuvant treatment which is closely related to borderline resectability in PDAC is discussed. PMID- 26970275 TI - The impact of bone morphogenetic protein 4 (BMP4) on breast cancer metastasis in a mouse xenograft model. AB - Bone morphogenetic protein 4 (BMP4) is a key regulator of cell proliferation and differentiation. In breast cancer cells, BMP4 has been shown to reduce proliferation in vitro and interestingly, in some cases, also to induce migration and invasion. Here we investigated whether BMP4 influences breast cancer metastasis formation by using a xenograft mouse model. MDA-MB-231 breast cancer cells were injected intracardially into mice and metastasis formation was monitored using bioluminescence imaging. Mice treated with BMP4 developed metastases slightly earlier as compared to control animals but the overall number of metastases was similar in both groups (13 in the BMP4 group vs. 12 in controls). In BMP4-treated mice, bone metastases were more common (10 vs. 7) but adrenal gland metastases were less frequent (1 vs. 5) than in controls. Immunostaining revealed no differences in signaling activation, proliferation rate, blood vessel formation, EMT markers or the number of cancer-associated fibroblasts between the treatment groups. In conclusion, BMP4 caused a trend towards accelerated metastasis formation, especially in bone. More work is needed to uncover the long-term effects of BMP4 and the clinical relevance of these findings. PMID- 26970277 TI - Multiple splicing pathways of group II trans-splicing introns in wheat mitochondria. AB - Trans-splicing of discontinuous introns in plant mitochondria requires the assembly of independently-transcribed precursor RNAs into splicing-competent structures, and they are expected to be excised as Y-branched molecules ("broken lariats") because these introns belong to the group II ribozyme family. We now demonstrate that this is just one of several trans-splicing pathways for wheat mitochondrial nad1 intron 4 and nad5 intron 2; they also use a hydrolytic pathway and the liberated 5'-half-intron linear molecules are unexpectedly abundant in the RNA population. We also observe a third productive splicing pathway for nad5 intron 2 that yields full-length excised introns in which the termini are joined in vivo and possess non-encoded nucleotides. In the case of trans-splicing nad1 intron 1, which has a weakly-structured and poorly-conserved core sequence, excision appears to be solely through a hydrolytic pathway. When wheat embryos are germinated in the cold rather than at room temperature, an increased complexity in trans-splicing products is seen for nad1 intron 4, suggesting that there can be environmental effects on the RNA folding of bipartite introns. Our observations provide insights into intron evolution and the complexity of RNA processing events in plant mitochondria. PMID- 26970278 TI - Cholecalciterol cholesterol emulsion ameliorates experimental colitis via down regulating the pyroptosis signaling pathway. AB - The therapeutic effect of 1,25(OH)2 vitamin D3 and its analog (paricalcitol) on experimental colitis in animals has been heavily demonstrated. However, the response to Cholecalciterol Cholesterol Emulsion (CCE), a precursor of 1,25(OH)2 vitamin D3, has not yet been reported. Whether pyroptosis is involved in colitic deterioration also remains unclear. Therefore, we adopted molecular biology and histology approaches to examine mechanisms by which CCE was able to regulate experimental colitis in the animal model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). Our data revealed that mice displayed a remarkable reduction in colonic histological scores, colonic inflammation and colonic histological damage. In addition, there was an overall improvement in general status (change in body weight, food and water intake, mental status, activity) and a 30% increase in survival rate due to the downregulation of pyroptosis following treatment with CCE. In conclusion, our data have provided evidence that CCE can attenuate the damage of experimental colitis by suppressing pyroptosis signaling. PMID- 26970279 TI - Protocadherin 10 inhibits cell proliferation and induces apoptosis via regulation of DEP domain containing 1 in endometrial endometrioid carcinoma. AB - Endometrial cancer is the most common gynecologic malignancy and about 80% of these cancers are endometrial endometrioid carcinoma (EEC). Previously, we have demonstrated that protocadherin 10 (PCDH10) is a tumor suppressor gene in EEC, and in this study we further explored the molecular mechanisms of PCDH10 in EEC. We first detect the PCDH10 expression in EEC tissues and then investigate the mechanism in two EEC cell lines. The mRNA and protein expression levels were measured by quantitative real time PCR (qRT-PCR) and western blot, respectively; Cell growth was determined by MTS, CCK-8 and colony formation assays; Cell cycle was determined by flow cytometry, and cell apoptosis was examined by flow cytometry and TUNEL assay. The downstream mediator of PCHD10 was confirmed by Topflash luciferase reporter assay. QRT-PCR and western blot results showed that PCDH10 was down-regulated in EEC clinical tissues. Restoration of PCDH10 suppressed cell growth and induced apoptosis in EEC cells. Dishevelled, EGL-10 and Pleckstrin domain containing 1 (DEPDC1) was a potential downstream mediator of PCDH10 as revealed by RNA-sequencing, and mechanistic studies suggested that DEPDC1 is a downstream mediator and promotes cell growth and induces apoptosis in EEC cells. Western blot further showed that PCDH10 restoration activate apoptotic signaling pathway via caspase signaling in both EEC cell lines and EEC clinical tissues. Collectively, our results suggest that PCDH10-DEPDC1-caspase signaling may be a novel regulatory axis in EEC development and it will be of great interest to explore the clinical significance of PCDH10 and DEPDC1 in the future. PMID- 26970280 TI - Subgroup differences in 'brain-type' transferrin and alpha-synuclein in Parkinson's disease and multiple system atrophy. AB - Two transferrin (Tf) glycan-isoforms were previously found in cerebrospinal fluid (CSF); one appears to be derived from serum (Tf-2) and the other from choroid plexus, a CSF-producing tissue (Tf-1). To analyse metabolic differences associated with the two isoforms, their ratio (Tf-2/Tf-1) was defined as the Tf index. Here we report that Tf indices of patients with tauopathies including Alzheimer's disease (2.29 + 0.64) were similar to those of neurological controls (2.07 + 0.87) (P = 0.147). In contrast, Tf indices with Parkinson's disease (PD, 3.38 +/- 1.87) and multiple system atrophy (MSA, 3.15 +/- 1.72) were higher than those of the controls (2.07 +/- 0.87), the P-values being < 0.001 and 0.024, respectively. Tf indices of PD and MSA did not appear to be normally distributed. Indeed, detrended normal Quantile-Quantile plot analysis revealed the presence of an independent subgroup showing higher Tf indices in PD and MSA. The subgroup of PD showed higher levels of CSF alpha-synuclein (38.3 +/- 17.8 ng/ml) than the rest (25.3 +/- 11.3 ng/ml, P = 0.012). These results suggest that PD (and MSA) includes two subgroups, which show different metabolism of CSF transferrin and alpha-synuclein. PMID- 26970281 TI - The diet-microbiota-metabolite axis regulates the host physiology. AB - The intestinal microbiota has been implicated in a wide range of diseases, including inflammatory bowel disease, obesity and cancer. Food ingredients are considered a major determinant of gut microbial composition, as exemplified by high-fat diet-induced dysbiosis that can affect host physiology. Accumulating studies show that microbial metabolites are key regulators of the intestinal epithelial barrier and gut immunity. In particular, short-chain fatty acids produced by bacterial fermentation of indigestible polysaccharides have profound impacts on host physiology beyond the gut. In this review, we describe the influences of the diet-microbiota-metabolite axis on host physiology, and especially on the immune and metabolic systems. PMID- 26970282 TI - Global kinetic analysis of seeded BSA aggregation. AB - Accelerated aggregation studies were conducted around the melting temperature (Tm) to elucidate the kinetics of seeded BSA aggregation. Aggregation was tracked by SEC-HPLC and intrinsic fluorescence spectroscopy. Time evolution of monomer, dimer and soluble aggregate concentrations were globally analysed to reliably deduce mechanistic details pertinent to the process. Results showed that BSA aggregated irreversibly through both sequential monomer addition and aggregate aggregate interactions. Sequential monomer addition proceeded only via non-native monomers, starting to occur only by 1-2 degrees C below the Tm. Aggregate aggregate interactions were the dominant mechanism below the Tm due to an initial presence of small aggregates that acted as seeds. Aggregate-aggregate interactions were significant also above the Tm, particularly at later stages of aggregation when sequential monomer addition seemed to cease, leading in some cases to insoluble aggregate formation. The adherence (or non-thereof) of the mechanisms to Arrhenius kinetics were discussed alongside possible implications of seeding for biopharmaceutical shelf-life and spectroscopic data interpretation, the latter of which was found to often be overlooked in BSA aggregation studies. PMID- 26970283 TI - Development of a nanosuspension for iv administration: From miniscale screening to a freeze dried formulation. AB - The aim was to develop a nanosuspension of the poorly soluble BI XX. The nanosuspension is intended for intravenous (iv) administration in preclinical studies and should not cause any unwanted side effects. Thus, only stabilizers that are accepted for iv application should be used and isotonicity, euhydria and the absence of living microorganisms were targeted. Suspensions were prepared in a ball-mill (mixing mill MM 400 from Retsch). There were various vials used as containers; HPLC-vials were used for the small scale screening of stabilizers and injection vials for preparation of larger quantities of the nanosuspensions. Particle size distribution was analyzed by laser diffraction measurement (Mastersizer 2000). Lyophilization was used for processing of the suspensions (Christ freeze dryer). Stable nanosuspensions (d90 remained <1MUm up to 7days) were prepared with several FDA-accepted stabilizers. Freeze drying was evaluated for one formulation containing 2% of the API, 0.5% of arginine and 4% of mannitol. The particle size distribution before freeze drying and after re dispersion was comparable. After milling for 2h, no living microorganisms were detected in the nanosuspension. Various FDA accepted excipients were identified which resulted in stable nanosuspensions of BI XX. The most stable formulation was successfully freeze dried. It was proven that milling in the ball-mill decreases the presence of living microorganisms. PMID- 26970284 TI - Gender Roles and the Expression of Driving Anger Among Ukrainian Drivers. AB - The current study investigated the validity of the revised (25-item) version of the driving anger expression inventory (DAX) on a novel sample of 385 drivers from Ukraine. The roles of sex and gender in relation to self-reported aggressive tendencies were also examined. Confirmatory factor analysis supported the four factor structure of the DAX (adaptive/constructive expression; use of the vehicle to express anger; verbal aggressive expression; and personal physical aggressive expression), and the three aggressive factors were found to have positive relationships with trait anger and driving anger, while adaptive/constructive expression was negatively related to trait and driving anger. Drivers who reported recent near-misses or loss of concentration scored higher on verbal aggressive expression. Those who had recently received a traffic ticket also reported higher levels of all three types of aggressive anger expression. Further, the presence of feminine traits, but not sex, predicted more adaptive/constructive behaviors and lower scores for verbal aggressive expression, personal physical aggressive expression, and total aggressive expression. However, masculine traits did not predict any of these factors. This research concludes that the revised DAX is a valid tool to measure the expression of driving anger and that the endorsement of feminine traits is related to less aggressive expression of driving anger. PMID- 26970286 TI - Sensitization of TRPV1 by protein kinase C in rats with mono-iodoacetate-induced joint pain. AB - OBJECTIVE: To assess the functional changes of Transient receptor potential vanilloid 1 (TRPV1) receptor and to clarify its mechanism in a rat mono iodoacetate (MIA)-induced joint pain model (MIA rats), which has joint degeneration with cartilage loss similar to osteoarthritis. METHODS: Sensitization of TRPV1 in MIA rats was assessed by transient spontaneous pain behavior induced by capsaicin injection in knee joints and electrophysiological changes of dorsal root ganglion (DRG) neurons innervating knee joints in response to capsaicin. Mechanisms of TRPV1 sensitization were analyzed by a newly developed sandwich enzyme-linked immunosorbent assay that detects phosphorylated TRPV1, followed by functional and expression analyses of protein kinase C (PKC) in vivo and in vitro, which involves TRPV1 phosphorylation. RESULTS: Pain-related behavior induced by intra-articular injection of capsaicin was significantly increased in MIA rats compared with sham rats. In addition, capsaicin sensitivity, evaluated by capsaicin-induced inward currents, was significantly increased in DRG neurons of MIA rats. Protein levels of TRPV1 remained unchanged, but phosphorylated TRPV1 at Ser800 increased in DRG neurons of MIA rats. Phosphorylated-PKCE (p-PKCE) increased and co-localized with TRPV1 in DRG neurons of MIA rats. Capsaicin-induced pain-related behavior in MIA rats was inhibited by intra-articular pretreatment of the PKC inhibitor bisindolylmaleimide I. In addition, intra-articular injection of the PKC activator phorbol 12-myristate 13 acetate increased capsaicin-induced pain-related behavior in normal rats. CONCLUSION: TRPV1 was sensitized at the knee joint and at DRG neurons of MIA rats through PKC activation. Thus, TRPV1 sensitization might be involved in chronic pain caused by osteoarthritis. PMID- 26970285 TI - Longitudinal analysis of cartilage T2 relaxation times and joint degeneration in African American and Caucasian American women over an observation period of 6 years - data from the Osteoarthritis Initiative. AB - OBJECTIVES: To investigate the change in cartilage T2 values and structural degeneration in knee joints over 72 months in women of African American (AA) vs Caucasian American (CA) ethnicity. METHODS: Knee 3T magnetic resonance imaging (MRIs) from baseline, 24, 48 and 72 months visits of 100 AA and 100 CA women from the Osteoarthritis Initiative (OAI) were assessed for cartilage T2 values and whole-organ magnetic resonance imaging (WORMS) score. Subjects were pair-matched by age, body mass index (BMI), Kellgren-Lawrence (KL) score, clinical site and subcohort within the OAI. We compared the rate of change in whole knee cartilage T2 values and WORMS cartilage, bone marrow edema pattern (BMEP) and meniscus scores between the two ethnic groups using mixed random effects models. RESULTS: At 24 and 48 months 60 subjects and at 72 months 45 subjects per group were available for analysis resulting in 38 complete pairs with data of all time points. Compared to CA, cartilage T2 values in AA increased at a significantly faster rate at baseline (AA: 0.45 ms/y, CA: 0.35 ms/y, P = 0.029) and averaged over 6 years (AA: 0.36 ms/y, CA: 0.27 ms/y, P = 0.039) with changes in both groups reaching a plateau by 48 months. Cartilage, meniscus and BMEP scores tended to increase in both groups during follow up, but rates of change did not differ by ethnicity. CONCLUSION: Cartilage T2 values increased faster over 72 months in AA than CA, however changes in WORMS cartilage, meniscus and BMEP scores did not differ. T2 values may be able to distinguish ethnicity-related differences of cartilage degeneration at an early stage before differences in structural joint degeneration appear. PMID- 26970287 TI - Higher Blood Pressure Partially Links Greater Adiposity to Reduced Brain White Matter Integrity. AB - BACKGROUND: Adiposity and elevated blood pressure (BP) are associated with brain structure abnormalities, but whether these effects are independent is unknown. We tested whether associations between adiposity and white matter integrity were explained by elevated BP. METHODS: A sample of 209 middle-aged adults underwent diffusion tensor imaging to quantify indirect metrics of white matter structural integrity. These included putative markers of global white matter integrity (fractional anisotropy (FA)), axonal integrity (axial diffusivity), and myelin integrity (radial diffusivity). Participants were either normotensive or prehypertensive. RESULTS: After adjusting for age and sex, regression analyses showed that waist circumference was associated with FA (beta = -0.15, P < 0.05) and axial diffusivity (beta = -0.24, P < 0.001), and mean arterial pressure (MAP) was associated with FA (beta = -0.21, P < 0.05). Direct and indirect effect analyses showed that waist circumference was indirectly associated with whole brain FA through MAP (beta = -0.06), and directly related to whole brain axial diffusivity, independent of MAP (beta = -0.24). Examination of specific white matter tracts yielded similar results; waist circumference was indirectly related to FA through MAP and radial diffusivity, and directly related to axial diffusivity, independent of MAP. Supplemental analyses using body mass index, systolic BP, and diastolic BP also yielded similar results. CONCLUSION: These findings suggest at least 2 mechanisms explain the adiposity and white matter association: one pathway through elevated BP impacting global white matter integrity and reducing integrity of the myelin sheath, and at least one other adiposity-specific pathway decreasing axonal integrity. PMID- 26970289 TI - Sonographic features of steatocystoma simplex on the abdomen. PMID- 26970288 TI - Disease-related costs of care and survival among Medicare-enrolled patients with myelodysplastic syndromes. AB - BACKGROUND: Although newer treatments for myelodysplastic syndromes (MDS), particularly hypomethylating agents (HMAs), are expensive, it is unclear whether MDS-related costs of care are associated with overall survival. This study evaluated the relation between MDS-related costs and survival among Medicare beneficiaries with MDS. METHODS: Eligible patients were identified from the Surveillance, Epidemiology, and End Results-Medicare database with codes for MDS from International Classification of Diseases for Oncology, 3rd edition. The patients were diagnosed between January 1, 2005 and December 31, 2011, were 66 years old or older, and were followed through death or the end of study (December 31, 2012). Medicare payments were used to estimate costs. Cumulative costs in a propensity score-matched group of cancer-free Medicare beneficiaries were subtracted from costs in the MDS cohort in each registry to estimate MDS-related costs. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived from multivariate Cox proportional hazards models adjusted for patient and disease characteristics. RESULTS: There were 8580 eligible patients, and 1,267 (14.7%) received HMAs. The overall 2-year survival rate was 48.7%, and the 2-year registry-specific MDS-related cost per patient ranged from $40,793 to $78,156 across 16 registries. The 2-year MDS-related cost was not associated with survival in the overall study population (first tertile, reference; second tertile, HR, 0.96; 95% CI, 0.89-1.04; P = .29; third tertile, HR, 0.98; 95% CI, 0.91-1.06; P = .64) or in subgroups of patients who did or did not receive HMAs. CONCLUSIONS: Medicare expenditures for elderly patients with MDS varied across registries but were not associated with survival. A lack of an association between costs and outcomes warrants additional research because it may help to identify potential areas for cost-saving interventions without compromising patient outcomes. Cancer 2016;122:1598-607. (c) 2016 American Cancer Society. PMID- 26970290 TI - Functional or constructive attitudes: Which type drives consumers' evaluation of meat products? AB - Consumer attitudes towards meat can be divided up into two types: Functional attitudes which are stable and exist over long periods of time, and constructive attitudes which are ephemeral and usually constructed at the point of sale. This research investigated the temporal and situational stability of meat consumers' attitudes by using the same established functional, multidimensional attitude instrument to generate attitude profiles for the four meat types: chicken/beef/lamb/poultry both as an abstracted construct and as a cue on a range of meat and meat-based products. The results showed that strong attitude profile was generated by the meat types as abstracted constructs, but that this profile broke down completely when the food products carrying the same meat types were evaluated. This result indicates that consumer attitudes may not be temporally or situationally stable, which in turn suggests that consumers' evaluation and choice of meat products may be driven to a greater or lesser extent by constructive rather than functional attitudes. PMID- 26970291 TI - Characterization of the fatty acid composition of lamb commercially available in northern Spain: Emphasis on the trans-18:1 and CLA content and profile. AB - A survey of commercially available lamb meat was performed in northern Spain in order to evaluate their fatty acid (FA) composition with emphasis on trans fatty acid (TFA) and conjugated linoleic acid (CLA) isomers. Samples were collected in spring (n=24) and winter (n=24) of 2013, and were obtained in about equal numbers from grocery stores and butcher-shops. Subcutaneous fat, known to be a sensitive indicator of TFA content in ruminants, was analyzed by GC-FID. In general, very few differences were observed between collection periods and type of stores because of the high variability within the groups that was believed to be associated with differences in genetics and feeding strategies. However, the 10t/11t ratio of all samples showed two clearly identifiable groups irrespective of the source: 1) when 10t/11t was >1, 10t-shifted samples; 2) when 10t/11t was <=1, non-shifted samples where 11t-18:1 was the predominant isomer. These two groups were clearly identified and associated with distinct FAs using principal component analysis. PMID- 26970292 TI - The evolution of fishes and corals on reefs: form, function and interdependence. AB - Coral reefs are renowned for their spectacular biodiversity and the close links between fishes and corals. Despite extensive fossil records and common biogeographic histories, the evolution of these two key groups has rarely been considered together. We therefore examine recent advances in molecular phylogenetics and palaeoecology, and place the evolution of fishes and corals in a functional context. In critically reviewing the available fossil and phylogenetic evidence, we reveal a marked congruence in the evolution of the two groups. Despite one group consisting of swimming vertebrates and the other colonial symbiotic invertebrates, fishes and corals have remarkably similar evolutionary histories. In the Paleocene and Eocene [66-34 million years ago (Ma)] most modern fish and coral families were present, and both were represented by a wide range of functional morphotypes. However, there is little evidence of diversification at this time. By contrast, in the Oligocene and Miocene (34-5.3 Ma), both groups exhibited rapid lineage diversification. There is also evidence of increasing reef area, occupation of new habitats, increasing coral cover, and potentially, increasing fish abundance. Functionally, the Oligocene-Miocene is marked by the appearance of new fish and coral taxa associated with high-turnover fast-growth ecosystems and the colonization of reef flats. It is in this period that the functional characteristics of modern coral reefs were established. Most species, however, only arose in the last 5.3 million years (Myr; Plio Pleistocene), with the average age of fish species being 5.3 Myr, and corals just 1.9 Myr. While these species are genetically distinct, phenotypic differences are often limited to variation in colour or minor morphological features. This suggests that the rapid increase in biodiversity during the last 5.3 Myr was not matched by changes in ecosystem function. For reef fishes, colour appears to be central to recent diversification. However, the presence of pigment patterns in the Eocene suggests that colour may not have driven recent diversification. Furthermore, the lack of functional changes in fishes or corals over the last 5 Myr raises questions over the role and importance of biodiversity in shaping the future of coral reefs. PMID- 26970293 TI - Consumers' responses to front-of-pack labels that vary by interpretive content. AB - Previous research has shown that front-of-pack labels (FoPLs) can assist people to make healthier food choices if they are easy to understand and people are motivated to use them. There is some evidence that FoPLs providing an assessment of a food's health value (evaluative FoPLs) are easier to use than those providing only numerical information on nutrients (reductive FoPLs). Recently, a new evaluative FoPL (the Health Star Rating (HSR)) has been introduced to Australia and New Zealand. The HSR features a summary indicator, differentiating it from many other FoPLs being used around the world. The aim of this study was to understand how consumers of all ages use and make sense of reductive FoPLs and evaluative FoPLs including evaluative FoPLs with and without summary indicators. Ten focus groups were conducted in Perth, Western Australia with adults (n = 50) and children aged 10-17 years (n = 35) to explore reactions to one reductive FoPL (the Daily Intake Guide), an existing evaluative FoPL (multiple traffic lights), and a new evaluative FoPL (the HSR). Participants preferred the evaluative FoPLs over the reductive FoPL, with the strongest preference being for the FoPL with the summary indicator (HSR). Discussions revealed the cognitive strategies used when interpreting each FoPL (e.g., using cut offs, heuristics, and the process of elimination), which differed according to FoPL format. Most participants reported being motivated to use the evaluative FoPLs (particularly the HSR) to make choices about foods consumed as part of regular daily meals, but not for discretionary foods consumed as snacks or deserts. The findings provide further evidence of the potential utility of evaluative FoPLs in supporting healthy food choices and can assist policy makers in selecting between alternative FoPL formats. PMID- 26970294 TI - Food-related behavior and intake of adult main meal preparers of 9-10 year-old children participating in iCook 4-H: A five-state childhood obesity prevention pilot study. AB - It is important to understand adult outcomes in childhood obesity prevention programs as parents and caregivers have a significant influence on the eating and physical activity habits of youth. Grounded in the social cognitive theory, the iCook 4-H study was centered on a dyad model (9-10 year-olds and their primary meal preparers) to teach healthy cooking skills, shopping and meal habits, and being active as a family. The program took place in five states and dyads (n = 54) were recruited through flyers, e-mails, and in-person contact. The focus of this article is to provide findings from adult program participants. Demographics and self-reported food intake, procurement, preparation and safety practices, feeding relationships, mealtime routines, and height and weight were collected through surveys at baseline and program completion, which spanned 3 months. Descriptive statistics including two-related samples tests and paired samples t tests were used to assess pre- and post-program survey data responses at p < 0.05 significance level. Most had a bachelor's degree (31%) or some college (29%), about half were white, 66% were married, about 30% of households participated in assistance programs, and 82% were female. At program conclusion, participants significantly improved meal planning, prioritizing healthy meal choices, shopping with a grocery list, and reading Nutrition Facts Labels. There were also significant, positive differences noted in cooking skill confidence (p = 0.015), desire to cook more meals at home, and fewer fast food meals. Adult-youth feeding interactions also significantly improved. There were also significant increases in fruit juice (100%), vegetable soup, and whole grain consumption. Based on results, adults reported improvements in meal planning, cooking, and purchasing skills that were taught in classes. PMID- 26970295 TI - First report of Trypanosoma vegrandis in koalas (Phascolarctos cinereus). AB - The present study describes the first report of Trypanosoma vegrandis in koalas using morphology and sequence analysis of the 18S rRNA gene. The prevalence of T. vegrandis in koalas was 13.6% (6/44). It is likely that the small size of T. vegrandis (<10MUm in length), coupled with the difficulties in amplifying DNA of this parasite in mixed infections using trypanosome generic primers, are the reason why this organism has not been identified in koalas until now. This study highlights the importance of further research comprising a larger sample size to determine the prevalence of T. vegrandis in koalas as well as its potential impacts upon this marsupial species' health. PMID- 26970296 TI - Comparison of patient-centered outcomes after routine implant placement, teeth extraction, and periodontal surgical procedures. AB - OBJECTIVES: To compare patient-centered outcome assessments (POAs) over a 2-week period after five categories of dento-alveolar surgical procedures. METHODS: A total of 339 patients in need of dento-alveolar surgical procedures such as simple tooth extraction (SE), transalveolar extraction (TE), straightforward implant placement (I), implant placement with guided bone regeneration (IGBR), and periodontal surgery (P) in Hong Kong (51.3%) and Nanjing dental clinic were consecutively recruited (2013-2015). POAs in terms of bleeding, swelling, pain, and bruising were obtained using 10 cm visual analog scale (VAS) on each day of the first week and the 14th day postsurgery. Clinical examinations were recorded on the 7th day postoperation. RESULTS: For the first 3 days of healing, area under-the-curve (AUC) analyses showed that transalveolar extraction (TE) resulted in significantly higher overall bleeding and pain (AUC: Bleeding Mean = 5.6, Pain Mean = 7.5). However, implant placement with GBR (IGBR) resulted in significant higher level of swelling (AUC: Mean = 9.1) and bruising (Mean = 4.2) for the same period with also the highest use of painkillers. Healing outcomes of straightforward implant placement (I) were comparable to that of a simple extraction (SE). Two-week overall experience showed the symptoms quickly subsided for all groups. Prevalence for complications 1 week postoperatively was IGBR (20%), P (15.6%), I (12.7%), SE (4.8%), TE (1.5%), respectively. CONCLUSIONS: The highest extent of swelling and bruising was observed in patients who got implant placement with GBR (IGBR), while healing events of straightforward implants were similar to these of simple extraction. The VAS scores for all POAs parameters were generally low and decreased to nearly zero over the study period following all five surgical procedures. Low prevalence of postsurgical complications was reported. PMID- 26970297 TI - Pulsed Lasers Employing Solution-Processed Plasmonic Cu3- x P Colloidal Nanocrystals. AB - A new approach to synthesize self-doped colloidal Cu3-x P NCs with controlled size and localized surface plasmon resonance absorption is reported. These Cu3-x P NCs show ultrafast exciton dynamics and huge optical nonlinearities due to plasmonic resonances, which afford the first demonstration of plasmonic Cu3-x P NCs as simple, effective, and solution-processed nonlinear absorbers for high energy Q-switched fiber laser. PMID- 26970298 TI - Diversity Conceptual Model for aged care: Person-centred and difference-oriented and connective with a focus on benefit, disadvantage and equity. AB - AIM: This project aimed to develop a Diversity Conceptual Model to support the aged care sector to identify diversity characteristics and associated benefits and disadvantages in order to consider greater equity in policy and practice. METHODS: A multi-method approach was used to develop the Diversity Conceptual Model using a literature review, organisation-wide consultation using a questionnaire, focus groups and interviews with key stakeholders. RESULTS: A Diversity Conceptual Model was developed as a visual 'tool', made up of numerous components, with a focus on diversity characteristics that may be creating benefits and disadvantages for a consumer to participate in their health care. Continuous quality improvements and equity are presented as essential overarching components of the Model. CONCLUSION: The Diversity Conceptual Model has many potential applications for aged care. The author proposes that its wider adoption would increase confidence, skills and knowledge, enabling the aged care sector to influence greater equity in policy and care practice. PMID- 26970299 TI - Does cyclic stress and accelerated ageing influence the wear behavior of highly crosslinked polyethylene? AB - First-generation (irradiated and remelted or annealed) and second-generation (irradiated and vitamin E blended or doped) highly crosslinked polyethylenes were introduced in the last decade to solve the problems of wear and osteolysis. In this study, the influence of the Vitamin-E addition on crosslinked polyethylene (XLPE_VE) was evaluated by comparing the in vitro wear behavior of crosslinked polyethylene (XLPE) versus Vitamin-E blended polyethylene XLPE and conventional ultra-high molecular weight polyethylene (STD_PE) acetabular cups, after accelerated ageing according to ASTM F2003-02 (70.0+/-0.1 degrees C, pure oxygen at 5bar for 14 days). The test was performed using a hip joint simulator run for two millions cycles, under bovine calf serum as lubricant. Mass loss was found to decrease along the series XLPE_VE>STD_PE>XLPE, although no statistically significant differences were found between the mass losses of the three sets of cups. Micro-Raman spectroscopy was used to investigate at a molecular level the morphology changes induced by wear. The spectroscopic analyses showed that the accelerated ageing determined different wear mechanisms and molecular rearrangements during testing with regards to the changes in both the chain orientation and the distribution of the all-trans sequences within the orthorhombic, amorphous and third phases. The results of the present study showed that the addition of vitamin E was not effective to improve the gravimetric wear of PE after accelerated ageing. However, from a molecular point of view, the XLPE_VE acetabular cups tested after accelerated ageing appeared definitely less damaged than the STD_PE ones and comparable to XLPE samples. PMID- 26970300 TI - Renal Fibromuscular Dysplasia: A Not So Common Entity of Secondary Hypertension. AB - Fibromuscular dysplasia is a rare noninflammatory vascular disease characterized by nonatheroslerotic stenosis predominantly seen in young women, whereas the majority of cases involve the renal arteries causing secondary hypertension. Most noninvasive screening tests are not quite sensitive or reproducible to rule out renal artery stenosis, but renal angiography usually confirms the diagnosis. Percutaneous renal artery angioplasty is the treatment of choice; however, it may not result in normalization of blood pressure if diagnosis is delayed. Continued follow-up is necessary since stenosis reoccurs. PMID- 26970301 TI - Pterosin B has multiple targets in gluconeogenic programs, including coenzyme Q in RORalpha-SRC2 signaling. AB - Hepatic gluconeogenic programs are regulated by a variety of signaling cascades. Glucagon-cAMP signaling is the main initiator of the gluconeogenic programs, including glucose-6-phosphatase catalytic subunit (G6pc) gene expression. Pterosin B, an ingredient in Pteridium aquilinum, inhibits salt-inducible kinase 3 signaling that represses cAMP-response element-binding protein regulated transcription coactivator 2, an inducer of gluconeogenic programs. As the results, pterosin B promotes G6pc expression even in the absence of cAMP. In this work, however, we noticed that once cAMP signaling was initiated, pterosin B became a strong repressor of G6pc expression. The search for associated transcription factors for pterosin B actions revealed that retinoic acid receptor related orphan receptor alpha-steroid receptor coactivator 2 (RORalpha-SRC2) complex on the G6pc promoter was the target. Meanwhile, pterosin B impaired the oxidation-reduction cycle of coenzyme Q in mitochondrial oxidative phosphorylation (OXPHOS); and antimycin A, an inhibitor of coenzyme Q: cytochrome c-oxidoreductase (termed mitochondrial complex III), also mimicked pterosin B actions on RORalpha-SRC2 signaling. Although other respiratory toxins (rotenone and oligomycin) also suppressed G6pc expression accompanied by lowered ATP levels following the activation of AMP-activated kinase, minimal or no effect of these other toxins on RORalpha-SRC2 activity was observed. These results suggested that individual components in OXPHOS differentially linked to different transcriptional machineries for hepatic gluconeogenic programs, and the RORalpha SRC2 complex acted as a sensor for oxidation-reduction cycle of coenzyme Q and regulated G6Pc expression. This was a site disrupted by pterosin B in gluconeogenic programs. PMID- 26970302 TI - MicroRNA-198 inhibited tumorous behaviors of human osteosarcoma through directly targeting ROCK1. AB - Osteosarcoma is an aggressive primary sarcoma of bone and occurs mainly in adolescents and young adults. The prognosis of OS remains poor, and most of them will die due to local relapse or metastases. The discovery of microRNAs provides a new possibility for the early diagnosis and treatment of OS. Thus, the aim of this study was to explore the expression and functions of microRNA-198 (miR-198) in osteosarcoma. The expression levels of miR-198 were determined by qRT-PCR in osteosarcoma tissues and cell lines. Cell proliferation assays, migration and invasion assays were adopted to investigate the effects of miR-198 on tumorous behaviors of osteosarcoma cells. The results showed that miR-198 expression levels were lower in osteosarcoma tissues and cell lines. In addition, low miR 198 expression levels were correlated with TNM stage and distant metastasis. After miR-198 mimics transfection, cell proliferation, migration and invasion were significantly suppressed in the osteosarcoma cells. Furthermore, ROCK1 was identified as a novel direct target of miR-198 in osteosarcoma. These findings suggested that miR-198 may act not only as a novel prognostic marker, but also as a potential target for molecular therapy of osteosarcoma. PMID- 26970303 TI - Phyhd1, an XPhyH-like homologue, is induced in mouse T cells upon T cell stimulation. AB - We previously identified XPhyH-like as a gene whose expression is enhanced in Xenopus blood cells during the refractory period, in which Xenopus tadpoles transiently lose their tail regenerative ability. Although we hypothesized that some autoreactive immune cells attack tail blastemal cells during the refractory period and XPhyH-like expressing immune cells were involved in the process, the nature of cells expressing XPhyH-like remain unknown, partly due to the lack of leukocyte markers available in Xenopus. In the present study, we used mice to analyze the expression pattern of XPhyH-like homologues. When we used quantitative reverse transcription-polymerase chain reaction (RT--PCR) to analyze the expression of mouse Phyhd1, an XPhyH-like orthologue, and Phyh, a Phyhd1 paralogue, both Phyhd1 and Phyh showed similar tissue-specific expression patterns. The expression pattern in leukocytes, however, differed between Phyhd1 and Phyh; Phyhd1 was considerably expressed in T cells and B cells. Moreover, the expression of Phyhd1 in T cells was up-regulated for approximately 3- to 7-times by T cell stimulation 3-4 days after the stimulation, unlike Phyh. Our findings suggest that Phyhd1 and Phyh have distinct roles in mouse leukocytes and Phyhd1 is related to T cell differentiation and/or function of effector T cells. PMID- 26970304 TI - Calycosin ameliorates diabetes-induced cognitive impairments in rats by reducing oxidative stress via the PI3K/Akt/GSK-3beta signaling pathway. AB - Diabetic encephalopathy is one of the most prevalent chronic complications of diabetes mellitus (DM), but there is currently no effective method of prevention nor proven therapeutic regimen for it. In this study, we investigated the effects of calycosin on cognitive behavior and the potential mechanism involved in streptozocin-induced diabetic rats. The effects of diabetes and calycosin treatment on spatial learning and memory were evaluated using the Morris Water Maze, passive avoidance and motor coordination tests. Histological analysis of the hippocampus cornu ammonis 1 (CA1) region was conducted in rats. The decreased expression of the synapsin (SYN) and postsynatptic density protein (PSD-95), as well as brain-derived neurotrophic factor (BDNF) in diabetic rats was measured by quantitative real-time PCR and western blot. Treatment with calycosin promoted a reduction in the expression of SYN, PSD-95 and BDNF. In addition, diabetic rats showed increased MDA levels, and decreased SOD levels and GSH-Px activities in the hippocampus, as well as increased AChE activity in the cerebral cortex; these changes were reversed by calycosin supplementation. Thus, the impairment of learning and memory in STZ-induced diabetic rats was alleviated by calycosin, and that the degree of alleviation was associated with oxidative stress. We also found that calycosin treatment significantly stimulated Akt phosphorylation and decreased GSK-3beta and tau phosphorylation, and that these changes could be restored by the PI3K/Akt inhibitor LY294002. In conclusion, calycosin had a beneficial effect on the amelioration, prevention and treatment of diabetes associated cognitive deficits, through its involvement in oxidative stress, synaptic function and the PI3K/Akt/GSK-3beta pathway. PMID- 26970305 TI - Demethyleneberberine attenuates non-alcoholic fatty liver disease with activation of AMPK and inhibition of oxidative stress. AB - Non-alcoholic fatty liver disease (NAFLD) has reached an epidemic level globally, which is recognized to form non-alcoholic steatohepatitis (NASH) by the "two-hit" model, including oxidative stress and inflammation. AMP-activated protein kinase (AMPK) has long been regarded as a key regulator of energy metabolism, which is recognized as a critical target for NAFLD treatment. Here we introduce a natural product, demethyleneberberine (DMB), which potentially ameliorated NAFLD by activating AMPK pathways. Our study showed that the intraperitoneal injection of DMB (20 or 40 mg/kg body weight) decreased hepatic lipid accumulation in methionine and choline deficient (MCD) high-fat diet feeding mice and db/db mice. The further investigation demonstrated that DMB activated AMPK by increasing its phosphorylation in vitro and in vivo. Accompanied with AMPK activation, the expression of lipogenic genes were significantly reduced while genes responsible for the fatty acid beta-oxidation were restored in DMB-treated NAFLD mice. In addition, the remarkable oxidative damage and inflammation induced by NAFLD were both attenuated by DMB treatment, which is reflected by decreased lipid oxidative product, malonaldehyde (MDA) and inflammatory factors, tumor necrosis factor alpha (TNFalpha) and interleukin 1beta (IL-1beta). Based on all above, DMB could serve as a novel AMPK activator for treating NAFLD and preventing the pathologic progression from NAFLD to NASH by inhibiting the oxidative stress and inflammation. PMID- 26970306 TI - Klotho inhibits angiotensin II-induced cardiomyocyte hypertrophy through suppression of the AT1R/beta catenin pathway. AB - Myocardial hypertrophy is an independent risk factor for cardiac morbidity and mortality. The antiaging protein klotho reportedly possesses a protective role in cardiac diseases. However, the precise mechanisms underlying the cardioprotective effects of klotho remain unknown. This study was aimed to determine the effects of klotho on angiotensin II (Ang II)-induced hypertrophy in neonatal rat cardiomyocytes and the possible mechanism of actions. We found that klotho significantly inhibited Ang II-induced hypertrophic growth of neonatal cardiomyocytes, as evidenced by decreased [(3)H]-Leucine incorporation, cardiomyocyte surface area and beta-myosin heavy chain (beta-MHC) mRNA expression. Meanwhile, klotho inhibited Ang II-stimulated activation of the Wnt/beta-catenin pathway in cardiomyocytes, as evidenced by decreased protein expression of active beta-catenin, downregulated protein and mRNA expression of the beta-catenin target genes c-myc and cyclin D1, and increased beta-catenin phosphorylation. Inhibition of the Wnt/beta-catenin pathway by the specific inhibitor XAV939 markedly attenuated Ang II-induced cardiomyocyte hypertrophy. The further study revealed that klotho treatment significantly downregulated protein expression of Ang II receptor type I (AT1R) but not type II (AT2R). The AT1R antagonist losartan inhibited Ang II-stimulated activation of the Wnt/beta catenin pathway and cardiomyocyte hypertrophy. Our findings suggest that klotho inhibits Ang II-induced cardiomyocyte hypertrophy through suppression of the AT1R/beta-catenin signaling pathway, which may provide new insights into the mechanism underlying the protective effects of klotho in heart diseases, and raise the possibility that klotho may act as an endogenous antihypertrophic factor by inhibiting the Ang II signaling pathway. PMID- 26970307 TI - Pre-clinical assessment of A-674563 as an anti-melanoma agent. AB - The present study aims to investigate the anti-melanoma activity by an Akt1 specific inhibitor A-674563. We showed that A-674563 was anti-proliferative and cytotoxic when added to human melanoma cells (A375, WM-115 and SK-Mel-2 lines). A 674563 induced caspase-dependent apoptotic death of human melanoma cells, and its cytotoxicity was inhibited with pre-treatment of caspase inhibitors. Further, A 674563 treatment blocked Akt and its downstream S6 Kinase 1 (S6K1) activation in A375 melanoma cells. Significantly, restoring Akt-S6K1 activation via introduction of constitutively-active Akt1 (ca-Akt1) only partially attenuated A 674563's cytotoxicity against A375 cells. Further, A-674563 induced pro-apoptotic ceramide production in A375 cells. Significantly, sphingosine-1-phosphate (S1P) inhibited A-674563-induced ceramide production and subsequent A375 cell apoptosis. On the other hand, co-treatment with the glucosylceramide synthase (GCS) inhibitor PDMP or the cell permeable short-chain ceramide (C6) potentiated A-674563's cytotoxicity against A375 cells. In vivo, A-674563 oral gavage inhibited A375 xenograft growth in severe combined immunodeficiency (scid) mice. Akt inactivation, caspase-3 activation and ceramide production were also observed in A-674563-treated A375 xenografts. Together, these results suggest that A 674563 exerts potent anti-melanoma activity, involving Akt-dependent and Akt independent mechanisms. PMID- 26970309 TI - The origins of stem cells as tools for regenerative medicine. PMID- 26970308 TI - The oxindole Syk inhibitor OXSI-2 blocks nigericin-induced inflammasome signaling and pyroptosis independent of potassium efflux. AB - The inflammasome is a caspase-1-activating complex that is implicated in a growing number of acute and chronic pathologies. Interest has increased in identifying small molecular inhibitors of inflammasome signaling because of its role in clinically relevant diseases. It was recently reported that the protein tyrosine kinase, Syk, regulates pathogen-induced inflammasome signaling by phosphorylating a molecular switch on the adapter protein ASC. However, several aspects of the role of Syk in inflammasome signaling and the effects of its inhibition remain unclear. The aim of the present study is to explore in detail the effects of the oxindole Syk inhibitor OXSI-2 on various aspects of nigericin induced inflammasome signaling. Our results indicate that OXSI-2 inhibits inflammasome assembly, caspase-1 activation, IL-1beta processing and release, mitochondrial ROS generation, and pyroptotic cell death. Using a novel live cell potassium sensor we show that Syk inhibition with OXSI-2 has no effect on potassium efflux kinetics and that blockade of potassium efflux with extracellular potassium alters Syk phosphorylation. The effects of OXSI-2 identified in this study provide context for the role of Syk in inflammasome signaling and demonstrate its importance in oxidative signaling upstream of inflammasome activation and downstream of ion flux. PMID- 26970310 TI - Metastasis-associated protein 1 (MTA1) signaling in rheumatoid synovium: Regulation of inflammatory response and cytokine-mediated production of prostaglandin E2 (PGE2). AB - Abnormal perpetual inflammatory response and sequential cytokine-induced prostaglandin E2 (PGE2) play important roles in the pathogenesis of rheumatoid arthritis (RA). The underlying regulatory mechanism, however, remain largely unknown. Here, we discovered that expression level of Metastasis associated protein 1 (MTA1), an important chromatin modifier that plays a critical role in transcriptional regulation by modifying DNA accessibility for cofactors, was upregulated in human rheumatoid synovial tissues. Furthermore, a knockdown of MTA1 by siRNA in the human fibroblast-like synovial cell line MH7A was found to impair the 4-hydroxynonenal (4-HNE)-induced transcriptional expression levels of certain proinflammatory cytokines including IL-1beta, TNF-alpha and IL-6. Moreover, endogenous MTA1 was required for the cytokines-induced PGE2 synthesis by rheumatoid synoviocytes. Collectively, the coordinated existence of MTA1 inside distinct cascade loops points to its indispensable role in the modulation of the integrated cytokine network along the pathogenesis of RA. Further exploration of the functional details of this master transcriptional regulator should be an attractive strategy to identify novel therapeutic target for RA and warrants execution. PMID- 26970311 TI - The impact of volunteering on the volunteer: findings from a peer support programme for family carers of people with dementia. AB - With an ageing population, there are increasing numbers of experienced family carers (FCs) who could provide peer support to newer carers in a similar care situation. The aims of this paper are to: (i) use a cross-sectional study design to compare characteristics of volunteers and recipients of a peer support programme for FCs of people with dementia, in terms of demographic background, social networks and psychological well-being; and (ii) use a longitudinal study design to explore the overall impact of the programme on the volunteers in terms of psychological well-being. Data were collected from programmes run in Norfolk, Northamptonshire, Berkshire and four London boroughs between October 2009 and March 2013. The volunteer role entailed empathic listening and encouragement over a 10-month period. Both carer support volunteers (N = 87) and recipient FCs (N = 109) provided baseline demographic information. Data on social networks, personal growth, self-efficacy, service use and well-being (SF-12; EuroQol Visual Analogue Scale; Hospital Anxiety and Depression Scale; Control, Autonomy, Self Realisation, Pleasure-19) were collected prior to the start of the intervention (N = 43) and at either 3- to 5 month or 10 month follow-up (N = 21). Volunteers were more likely than recipients of support to be female and to have cared for a parent/grandparent rather than spouse. Volunteers were also more psychologically well than support recipients in terms of personal growth, depression and perceived well-being. The longitudinal analysis identified small but significant declines in personal growth and autonomy and a positive correlation between the volunteers' duration of involvement and perceived well-being. These findings suggest that carers who volunteer for emotional support roles are resilient and are at little psychological risk from volunteering. PMID- 26970312 TI - Validation of the delirium observation screening scale in a hospitalized older population. AB - Delirium is challenging to diagnose in older populations. It is often reversible, and when detected, treatment can improve patient outcomes. Delirium detection currently relies on trained staff to conduct neurocognitive interviews. The Delirium Observation Screening Scale (DOS) is a screen designed to allow faster, easier identification of delirium. In this validation study, conducted at an academic tertiary care center, we attempted to determine the accuracy of the DOS as a delirium screening tool in hospitalized patients over 64 years old. We compared DOS results to a validated delirium diagnostic tool, the Delirium Rating Scale-Revised-98. We also assess the user-friendliness of the DOS by nurses via electronic survey. In 101 assessments of 54 patients, the DOS had sensitivity of 90% and specificity of 91% for delirium. The DOS is an accurate and easy way to screen for delirium in older inpatients. Journal of Hospital Medicine 2016;11:494 497. (c) 2016 Society of Hospital Medicine. PMID- 26970315 TI - Heavy menstrual bleeding on Rivaroxaban - Comparison with Apixaban. PMID- 26970313 TI - Interstitial fibrosis is the critical determinant of impaired renal function in transplant glomerulopathy. AB - AIM: Transplant glomerulopathy (TG) is a feature of chronic antibody-mediated injury in the glomerular capillaries in renal transplant recipients. TG is generally associated with proteinuria; however, renal function at the diagnosis of TG varies. This study aimed to determine which morphological abnormalities are associated with renal function and proteinuria at the diagnosis of TG. METHODS: A total of 871 renal transplantations were performed at Tokyo Women's Medical University between 2005 and 2013. TG was diagnosed in 127 biopsies from 58 (6.7%) recipients. Renal function was evaluated by the estimated glomerular filtration rate (eGFR). Proteinuria was assessed by a dipstick test: positive for +1 and over. RESULTS: At diagnosis, of 127 biopsies, 72, 37, and 18 had mild, moderate, and severe TG (Banff cg). The severity of TG was not associated with decreased eGFR at the time of biopsy (cg1: 36.1 +/- 14.8, cg2-3: 38.8 +/- 14.5 mL/min per 1.73 m(2) , P = 0.25), whereas the severity of interstitial fibrosis (IF) (Banff ci) was significantly associated with decreased eGFR (ci0-1: 42.75 +/- 13.32, ci2 3: 27.69 +/- 11.94 mL/min per 1.73 m(2) , P < 0.0001). The multivariate analysis revealed that IF was the only independent risk factors for decreased eGFR (OR = 4.38, P = 0.0006). Meanwhile, TG was identified as the only independent risk factor for the incidence of proteinuria (OR = 2.67, P = 0.014). CONCLUSION: Interstitial fibrosis was a critical determinant of impaired renal function at the diagnosis of TG. The severity of TG was significantly associated with proteinuria, but did not contribute to renal dysfunction. PMID- 26970314 TI - Effect of finger motion on transverse median nerve movement in the carpal tunnel. AB - INTRODUCTION: We used ultrasonography (US) to investigate the effects of finger motion on movement of the median nerve in patients with carpal tunnel syndrome (CTS) and the correlation between these US parameters and CTS severity. METHODS: Ultrasonographic measures were performed in 23 control wrists and 22 CTS wrists in women. During first through third finger flexion and grip motion, median nerve movements were obtained using US and a tracing program. RESULTS: Nerve movements during third finger flexion in the dorsopalmar axis and grip motion in both axes, and during second finger flexion in the radioulnar axis, differed significantly between the control and CTS groups. US parameters correlated negatively with cross-sectional area. CONCLUSIONS: This study shows that transverse median nerve movements decreased during grip using US and correlated negatively with CTS severity. Muscle Nerve, 2016 Muscle Nerve 54: -, 2016 Muscle Nerve 54: 738-742, 2016. PMID- 26970316 TI - Measurement of wounds - the simplest diagnostic? PMID- 26970318 TI - Characterisation of clinical Staphylococcus aureus isolates harbouring mecA or Panton-Valentine leukocidin genes from four tertiary care hospitals in Indonesia. AB - OBJECTIVES: To determine the prevalence, antimicrobial susceptibility profiles and clonal distribution of either methicillin-resistant Staphylococcus aureus (MRSA) or Panton-Valentine leukocidin (PVL)-positive S. aureus obtained from clinical cultures in Indonesian hospitals. METHODS: S. aureus isolates from clinical cultures of patients in four tertiary care hospitals in Denpasar, Malang, Padang and Semarang were included. We assessed the antimicrobial susceptibility profiles using the Vitek2((r)) system, determined the presence of the mecA gene and genes encoding PVL using PCR and analysed the clonal relatedness with Raman spectroscopy. SCCmec typing was performed for all MRSA isolates. Multilocus sequence typing (MLST) was performed for a subset of isolates. RESULTS: In total, 259 S. aureus strains were collected. Of these, 17/259 (6.6%) and 48/259 (18.5%) were MRSA and PVL-positive methicillin susceptible S. aureus (MSSA), respectively. The prevalence of MRSA and PVL positive MSSA ranged between 2.5-8.9% and 9.5-29.1%, respectively and depended on geographic origin. PVL-positive MRSA were not detected. Raman spectroscopy of the strains revealed multiple Raman types with two predominant clusters. We also showed possible transmission of a ST239-MRSA-SCCmec type III strain and a ST121 PVL-positive MSSA in one of the hospitals. CONCLUSIONS: We showed that MRSA and PVL-positive MSSA are of clinical importance in Indonesian hospitals. A national surveillance system should be set-up to further monitor this. To reduce the prevalence of MRSA in Indonesian hospitals, a bundle of intervention measures is highly recommended. PMID- 26970320 TI - Baseline HCV-RNA levels in genotype 1 chronic hepatitis C patients: The role of different cut-off points. PMID- 26970319 TI - A cross-sectional view of the current state of treatment of youth with type 2 diabetes in the USA: enrollment data from the Pediatric Diabetes Consortium Type 2 Diabetes Registry. AB - OBJECTIVE: To describe the clinical characteristics, treatment approaches, clinical outcomes, and co-morbidities of youth with type 2 diabetes (T2D) enrolled in the Pediatric Diabetes Consortium (PDC) T2D Registry. METHODS: PDC enrolled 598 youth <21 yr of age with T2D from February 2012 to July 2015 at eight centers. Data were collected from medical records and interviews with participants and/or parents and included glycated hemoglobin (HbA1c), diabetes treatments, prevalence of diabetes comorbidities (hypertension (HTN), dyslipidemia (DL), microalbuminuria (MA), and nonalcoholic fatty liver disease (NAFLD). RESULTS: Insulin use was observed in 45% of those with T2D duration <1 yr, 44% for 1-<2 yr, 55% for 2-3 yr and 60% for >=4 yr. Median HbA1c was 6.7% (50 mmol/mol), 8.5% (69 mmol/mol), 9.6% (81 mmol/mol), and 9.7% (82 mmol/mol) in those with disease duration <1, 1-<2, 2-3 and >=4 yr, respectively. Only 33 and 11% of those with HTN and DL respectively, were being treated. MA and NAFLD were observed in 5-6% of the participants. Prevalence of HTN was associated with higher BMI (p < 0.001), DL with higher HbA1c (p < 0.001), and MA with longer diabetes duration (p = 0.001). CONCLUSIONS: Frequency of insulin therapy in youth with T2D was associated with increased disease duration and those with longer duration rarely achieve target HbA1c level. This highlights the aggressive course of T2D in youth and adolescents. Additionally, co-morbidities are not being adequately treated. Follow up data from the PDC will provide additional important information about the natural history of T2D and patterns of gaps in treatment. PMID- 26970321 TI - One- or Two-Electron Transfer? The Ambiguous Nature of the Discharge Products in Sodium-Oxygen Batteries. AB - Rechargeable lithium-oxygen and sodium-oxygen cells have been considered as challenging concepts for next-generation batteries, both scientifically and technologically. Whereas in the case of non-aqueous Li/O2 batteries, the occurring cell reaction has been unequivocally determined (Li2O2 formation), the situation is much less clear in the case of non-aqueous Na/O2 cells. Two discharge products, with almost equal free enthalpies of formation but different numbers of transferred electrons and completely different kinetics, appear to compete, namely NaO2 and Na2O2. Cells forming either the superoxide or the peroxide have been reported, but it is unclear how the cell reaction can be influenced for selective one- or two-electron transfer to occur. In this Minireview, we summarize available data, discuss important control parameters, and offer perspectives for further research. Water and proton sources appear to play major roles. PMID- 26970322 TI - Autonomic Ablation and Neuromodulation: Novel Concepts in Search of Novel Technology. PMID- 26970323 TI - The effect of supplementation with three commercial inactive dry yeasts on the colour, phenolic compounds, polysaccharides and astringency of a model wine solution and red wine. AB - BACKGROUND: Nowadays supplementing red wines with commercial inactive dry yeasts is a widespread practice in winemaking because it leads to better balanced wines through increased mouthfeel and smooth astringency. The aim of this article is to study, in a red wine and in a model wine solution, how supplementation with three commercial inactive dry yeasts affects chemical composition and astringency. This will give us a better understanding of the action mechanism involved. RESULTS: The results suggest that this action mechanism is related to two different phenomena. The first is that inactive yeasts release polysaccharides and oligosaccharides which can increase mouthfeel and inhibit interactions between salivary protein and tannins. The second is that they have a direct effect on the precipitation or absorption of proanthocyanidins, especially the larger polymers, which have been described as the most astringent. CONCLUSION: It can be concluded that supplementation with inactive yeasts is indeed a useful tool for smoothing the astringency of red wines. (c) 2016 Society of Chemical Industry. PMID- 26970324 TI - High strains near femoral insertion site of the superficial medial collateral ligament of the Knee can explain the clinical failure pattern. AB - The three dimensional (3D) deformation of the superficial medial collateral ligament (sMCL) of the knee might play an important role in the understanding of the biomechanics of sMCL lesions. Therefore, the strain and deformation pattern of the sMCL during the range of motion were recorded in five cadaveric knees with digital image correlation. During knee flexion, the sMCL was found to deform in the three planes. In the sagittal plane, a rotation of the proximal part of the sMCL relative to the distal part occurred with the center of this rotation being the proximal tibial insertion site of the sMCL. This deformation generated high strains near the femoral insertion site of the sMCL. These strains were significantly higher than in the other parts and were maximal at 90 degrees with on average +3.7% of strain and can explain why most lesions in clinical practice are seen in this proximal region. The deformation also has important implications for sMCL reconstruction techniques. Only a perfect anatomic restoration of the insertion sites of the sMCL on both the proximal and distal tibial insertion sites will be able to reproduce the isometry of the sMCL and thus provide the adequate stability throughout the range of motion. The fact that knee motion between 15 degrees and 90 degrees caused minimal strain in the sMCL might suggest that early passive range of motion in physical therapy postoperatively should have little risk of stretching a graft out in the case of an anatomical reconstruction. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2016-2024, 2016. PMID- 26970325 TI - Asymmetric Enzymatic Synthesis of Allylic Amines: A Sigmatropic Rearrangement Strategy. AB - Sigmatropic rearrangements, while rare in biology, offer opportunities for the efficient and selective synthesis of complex chemical motifs. A "P411" serine ligated variant of cytochrome P450(BM3) has been engineered to initiate a sulfimidation/[2,3]-sigmatropic rearrangement sequence in whole E. coli cells, a non-natural function for any enzyme, providing access to enantioenriched, protected allylic amines. Five mutations in the enzyme substantially enhance its activity toward this new function, demonstrating the evolvability of the catalyst toward challenging nitrene transfer reactions. The evolved catalyst additionally performs the highly enantioselective imidation of non-allylic sulfides. PMID- 26970326 TI - Extending the Spectrum of Radiological Findings in Patients With Severe Osteopetrosis and Different Genetic Backgrounds. AB - PURPOSE: To evaluate radiological findings in a cohort of 22 patients with infantile malignant osteopetrosis in order to establish the correlation between radiological findings and different genetic backgrounds. MATERIALS AND METHODS: Clinical files, genetic analysis results, and radiological examinations of children treated for osteopetrosis with bone marrow transplantation in a referral center in the last 5 years were retrospectively evaluated. The study received institutional review board (IRB) approval. RESULTS: Twenty-two patients were included in the study: 18 males, four females, ages 1 month-9 years 10 months, and the median age was 11 months (mean 23 months). There were 12 patients with different mutations in the TCIRG1 gene, five with mutations in the SNX10 gene, four children harbored RANK mutations, and one patient had a CLCN7 mutation. We noted more severe radiological findings in patients with TCIRG1 and RANK mutations, including fractures, osteopetrorickets, hydrocephalus, and hepatomegaly. Varus deformity of the femoral neck was seen exclusively in patients with a TCIRG1 mutation. CONCLUSIONS: The variable genetic spectrum of osteopetrosis is associated with a variable radiological presentation. These correlations may be helpful for priorities in genetic analysis. PMID- 26970327 TI - CC chemokine receptor 5 Delta32 polymorphism: association analysis and allele distribution among cutaneous leishmaniasis patients from Pakistan. AB - BACKGROUND: Human immunodeficiency virus (HIV)/leishmaniasis coinfection is a matter of deep concern worldwide. CC chemokine receptor 5 (CCR5) functions as a co-receptor for HIV entry into host immune cells with an elevated expression observed during leishmaniasis, promoting parasite persistence. A 32 bp deletion (Delta32) in the CCR5 gene provides protection against HIV infection and increased resistance to Leishmania infection. METHODS: In this study, CCR5 Delta32 distribution within Pakistani population with cutaneous leishmaniasis was investigated to evaluate genetic susceptibility to HIV infection. CCR5-Delta32 polymorphism was analyzed in 276 leishmaniasis patients and 119 uninfected healthy controls. Genotypic and allelic frequencies were evaluated and tested for Hardy-Weinberg equilibrium (HWE). RESULTS: The overall Delta32 allele frequency was 6.58% of the population (n = 395). There was a significant difference (p < 0.05) in the geographical distribution of Delta32 allele which was higher in the northern region of the country when compared with the south. Five individuals were identified to be homozygous for the Delta32 allele which has not been reported before from Pakistan. However, no significant association was observed between CCR5-Delta32 and cutaneous leishmaniasis. CONCLUSION: The higher frequency of CCR5 wild-type allele among leishmaniasis patients may suggest an increased risk of HIV infection and also support its facilitative role in Leishmania infection. PMID- 26970328 TI - Midwives in India: a delayed cord clamping intervention using simulation. AB - BACKGROUND: Iron deficiency is a prevalent health problem in India affecting women and newborns. Delayed umbilical cord clamping at birth is a safe and effective means for increasing serum iron levels in newborns up to 6 months of age. AIM: The study aim was to increase the utilization of delayed cord clamping in a group of midwives working in Hyderabad, India. METHODS: A single group pre- and post-test design was used to evaluate knowledge, beliefs and practice before and after a delayed cord clamping intervention including follow-up at 10 months after the original intervention. The intervention included lectures and simulation. RESULTS: Results show significant increases in knowledge and positive beliefs about the practice of delayed cord clamping. Simulation was effective for eliciting important feedback related to learning. LIMITATIONS: Results represent a small group of midwives working with a non-profit foundation in Southern India. Language discordancy and cultural norms in this group of midwives may have influenced results. CONCLUSIONS: Knowledge, beliefs and practice related to delayed cord clamping were all significantly improved after the intervention. The Knowledge to Action framework using simulation is an effective cross-cultural method for implementing education about evidence-based practice. Midwives are invested in learning practices that promote public health. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Changing institutional policy may have limitations without first considering normative practice. Using simulation combined with institutional health policy appears to result in significant uptake of practice change. Qualitative studies exploring the interconnections between cultural norms and decision making may be informative about promoting practice change particularly in this setting. Upscaling midwifery has been recommended to improve maternal and child health in India. PMID- 26970329 TI - Measurement of transepidermal water loss in localized scleroderma. AB - Localized scleroderma (LS) is a disease characterized by fibrotic changes in the dermis. Connective tissue growth factor and transforming growth factor beta2 are the main mediators of fibrogenesis; this, along with excessive connective tissue production, affects epidermal keratinocytes, and thereby contributes to the changed quality of skin barrier. The objective of this article was to study the objective measurement of the skin barrier quality in LS with transepidermal water loss (TEWL) meter. The measurements of TEWL were performed on LS plaques in all three stages of various body locations. Control measurements were made on the contralateral side of healthy skin. The difference between TEWL in LS area and the contralateral side of the healthy skin was evaluated. A higher average TEWL 7.86 g/m(2) /h (SD 5.29) was observed on LS plaques compared with the control measurements on healthy skin 6.39 g/m(2) /h (SD 2.77). TEWL average values decreased from the inflammatory stage, through the sclerotic and to the atrophic stage. The mean difference 1.301 g/m(2) /h (SD 5.16) was found between TEWL on LS plaques and on the contralateral healthy skin in 82 measurements, i.e., a higher TEWL was observed in LS. The difference was statistically significant with p = 0.0250. Although fibrogenesis in scleroderma is localized in dermis, the skin barrier changes can be detected. PMID- 26970330 TI - Interferon-beta may ameliorate synucleinopathy. PMID- 26970331 TI - Exploring the glycosaminoglycan-protein interaction network by glycan-mediated pull-down proteomics. AB - Glycosaminoglycans (GAGs) are linear, highly sulfated polysaccharides expressed by almost all animal cells. They occur as soluble molecules, or form proteoglycans by being O-linked to different core proteins on the cell surface and in the extracellular matrix. Due to their ability to interact with diverse proteins and to modulate their biologic functions, GAGs are main drivers of mammalian biology. However, to the present day, the human GAG binding proteome has only been insufficiently explored. The aim of this study was therefore to investigate the human GAG binding proteome of different sources by using the major GAG classes as ligands, and to explore the GAG-binding selectivity of the human plasma proteome. For this purpose, proteins were pulled down from immobilized low molecular weight heparin, heparan sulfate, and dermatan sulfate under different conditions and were identified by nano-LC/MS2. Four hundred and fifty eight human GAG binding proteins have been identified, whereas plasma proteins showed clear differences in their GAG-binding specificity/selectivity and affinity. We were able to differentiate between proteins that bound to all three glycan ligands and proteins that showed selective binding to one or two glycan ligands. Moreover, step-gradient salt elution revealed different binding affinities toward different GAG ligands. On top of proteins with well-known GAG binding properties we have identified formerly unknown GAG binders. Functional annotation of the identified GAG-binding proteins showed clusters of proteins that are involved in a variety of biological processes. The method described here is well suited for identifying GAG-binding proteins and for comparing human subproteomes with respect to binding to different GAG classes. PMID- 26970332 TI - Acute and delayed response to resistance exercise leading or not leading to muscle failure. AB - This study compared the time course of recovery following two resistance exercise protocols differing in the number of repetitions per set with regard to the maximum possible (to failure) number. Ten men performed three sets of 6 versus 12 repetitions with their 70% 1RM (3 * 6 [12] versus 3 * 12 [12]) in the bench press (BP) and squat (SQ) exercises. Mechanical [CMJ height, velocity against the 1 m s 1 load (V1 -load)], biochemical [testosterone, cortisol, growth hormone, prolactin, insulin-like growth factor-1, creatine kinase (CK)] and heart rate variability (HRV) and complexity (HRC) were assessed pre-, postexercise (Post) and at 6, 24 and 48 h-Post. Compared with 3 * 6 [12], the 3 * 12 [12] protocol resulted in significantly: higher repetition velocity loss within each set (BP: 65% versus 26%; SQ: 44% versus 20%); reduced V1 -load until 24 h-Post (BP) and 6 h-Post (SQ); decreased CMJ height up to 48 h-Post; greater increases in cortisol (Post), prolactin (Post, 48 h-Post) and CK (48 h-Post); and reductions in HRV and HRC at Post. This study shows that the mechanical, neuroendocrine and autonomic cardiovascular response is markedly different when manipulating the number of repetitions per set. Halving the number of repetitions in relation to the maximum number that can be completed serves to minimize fatigue and speed up recovery following resistance training. PMID- 26970333 TI - Biochemical effects of the flavanol-rich lychee fruit extract on the melanin biosynthesis and reactive oxygen species. AB - An ingredient of fruit polyphenol, resveratrol, is known to have an inhibitory effect on melanogenesis. In order to examine the functional differences between resveratrol and other fruit polyphenols, we compared biochemical effects of a resveratrol-free polyphenol, flavanol-rich lychee fruit extract (FRLFE), with other phenolic compounds including resveratrol. FRLFE as well as hydroquinone and resveratrol suppressed growth of B16F1 melanoma cells more significantly than rhododendrol or arbutin. Resveratrol suppressed mushroom tyrosinase at the lowest concentration (23.0 MUmol/L) among the compounds tested. FRLFE and hydroquinone suppressed tyrosinase at almost the same concentration (half maximal inhibitory concentration [IC50 ], 83.5 and 94.6 MUmol/L, respectively), which was higher than rhododendrol, ascorbic acid and arbutin (IC50 , 245, 345 and 421 MUmol/L, respectively). Western blot analysis revealed that although resveratrol decreased expressions of tyrosinase and tyrosinase-related protein 1, FRLFE did not affect their expressions. Both FRLFE and resveratrol suppressed antimycin A-mediated reactive oxygen species (ROS) production in melanocytic cells. Resveratrol mediated ROS suppression was inhibited by nicotinamide, a SIRT1 inhibitor. However, FRLFE-mediated suppression was not affected by nicotinamide. Moreover, FRLFE directly decreased superoxide in vitro, as detected by superoxide dismutase like scavenging activity assay. These results suggest that FRLFE can protect melanocytes from cytotoxicity caused by an excess amount of melanin and ROS in a different manner from resveratrol. PMID- 26970334 TI - Aged care managers' perceptions of staff preparedness for caring for older survivors of genocide and mass trauma in Australia: How prepared are aged care workers? AB - OBJECTIVE: To investigate aged care managers' perceptions of staff preparedness for working with older people who experienced genocide or mass trauma earlier in their lives (referred to in this paper as 'older survivors'). METHODS: A survey of 60 aged care service managers was conducted (50% response rate). Trauma knowledge and skills scales with Cronbach's alpha scores of 0.74 and 0.90 respectively, were used. Scores across groups were compared using Student's t tests. RESULTS: Three-quarters of the respondents reported that their agency had provided aged care services for older survivors. The majority of these managers perceived their staff to be moderately informed about trauma-related issues and half rated staff trauma-related skills positively. These ratings were positively associated with trauma-related staff training, service type and service location. CONCLUSION: Results suggest that, overall, managers perceive a need to improve aged care staff's preparedness for providing care for older survivors. PMID- 26970335 TI - High levels of omega-3 fatty acids in milk from omega-3 fatty acid-supplemented mothers are related to less immunoglobulin E-associated disease in infancy. AB - AIM: We previously reported a protective effect of maternal omega-3 fatty acid supplements on the development of immunoglobulin E (IgE)-associated disease in infancy. This study assessed omega-3 long-chain polyunsaturated fatty acids (LCPUFA) in maternal milk in relation to omega-3 LCPUFA supplementation and the development of allergic disease in their infants. METHODS: This study randomised 95 pregnant women at risk of having an allergic infant, to daily supplements of 2.6 g omega-3 LCPUFA or a placebo of 2.7 g soya bean oil from gestational week 25 until 3 months of lactation. Breast milk samples were collected as colostrum, at one and 3 months. Milk fatty acids were related to allergic outcome in the infants at 24 months. RESULTS: Omega-3 milk fatty acids were higher in women who received omega-3 supplements than the placebo group (p < 0.01). Higher proportions of milk eicosapentaenoic acid and docosahexaenoic acid and a lower arachidonic/eicosapentaenoic acid ratio were associated with an absence of IgE associated disease in the infants. None of the children developed IgE-associated atopic eczema above a level of 0.83 mol% eicosapentaenoic acid in colostrum. [Correction added on 7 July 2016, after online publication: In the preceding sentence, the correct word should be "above" instead of "below" and this has been amended in this current version.] CONCLUSION: High omega-3 LCPUFA milk levels in mothers who received omega-3 LCPUFA supplements were related to fewer allergies in their children. PMID- 26970337 TI - Formation and High Reactivity of the anti-Dioxo Form of High-Spin MU Oxodioxodiiron(IV) as the Active Species That Cleaves Strong C-H Bonds. AB - Recently, it was shown that MU-oxo-MU-peroxodiiron(III) is converted to high-spin MU-oxodioxodiiron(IV) through O-O bond scission. Herein, the formation and high reactivity of the anti-dioxo form of high-spin MU-oxodioxodiiron(IV) as the active oxidant are demonstrated on the basis of resonance Raman and electronic absorption spectral changes, detailed kinetic studies, DFT calculations, activation parameters, kinetic isotope effects (KIE), and catalytic oxidation of alkanes. Decay of MU-oxodioxodiiron(IV) was greatly accelerated on addition of substrate. The reactivity order of substrates is toluene=2 years, and 57 either had no follow-up or were followed for <2 years. For statistical purposes, FNA diagnoses of suspicious and malignant were considered positive, and benign lesions were considered negative. The accuracy was 99%, and the sensitivity and specificity were 94% and 100%, respectively. The risk of malignancy, not including papillary microcarcinoma, was 2% for benign aspirates, 21% for AUS, 57% for FN, and 100% for suspicious or malignant aspirates. CONCLUSIONS: This analysis demonstrates that FNA is a sensitive and highly specific modality for evaluating thyroid nodules in pediatric patients. Each diagnostic category can facilitate communication and guide appropriate management. Cancer Cytopathol 2016;124:467-71. (c) 2016 American Cancer Society. PMID- 26970344 TI - Isolation and characterization of Dehalobacter sp. strain UNSWDHB capable of chloroform and chlorinated ethane respiration. AB - Dehalobacter sp. strain UNSWDHB can dechlorinate up to 4 mM trichloromethane at a rate of 0.1 mM per day to dichloromethane and 1,1,2-trichloroethane (1 mM, 0.1 mM per day) with the unprecedented product profile of 1,2-dichloroethane and vinyl chloride. 1,1,1-trichloroethane and 1,1-dichloroethane were slowly utilized by strain UNSWDHB and were not completely removed, with minimum threshold concentrations of 0.12 mM and 0.07 mM respectively under growth conditions. Enzyme kinetic experiments confirmed strong substrate affinity for trichloromethane and 1,1,2-trichloroethane (Km = 30 and 62 uM respectively) and poor substrate affinity for 1,1,1-trichloroethane and 1,1-dichloroethane (Km = 238 and 837 uM respectively). Comparison of enzyme kinetic and growth data with other trichloromethane respiring organisms (Dehalobacter sp. strain CF and Desulfitobacterium sp. strain PR) suggests an adaptation of strain UNSWDHB to trichloromethane. The trichloromethane RDase (TmrA) expressed by strain UNSWDHB was identified by BN-PAGE and functionally characterized. Amino acid comparison of homologous RDases from all three organisms revealed only six significant amino acid substitutions/deletions, which are likely to be crucial for substrate specificity. Furthermore, strain UNSWDHB was shown to grow without exogenous supply of cobalamin confirming genomic-based predictions of a fully functional cobalamin synthetic pathway. PMID- 26970345 TI - Sinus surgery: optimal surgery, optimal outcome? PMID- 26970343 TI - Bevacizumab combined with docetaxel, oxaliplatin, and capecitabine, followed by maintenance with capecitabine and bevacizumab, as first-line treatment of patients with advanced HER2-negative gastric cancer: A multicenter phase 2 study. AB - BACKGROUND: The current study was a multicenter, single-arm, phase 2 study performed to investigate the feasibility and efficacy of bevacizumab combined with docetaxel, oxaliplatin, and capecitabine (B-DOC) in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, previously untreated, gastric or gastroesophageal adenocarcinoma. METHODS: Tumor HER2 status was determined centrally. Patients received 6 cycles of bevacizumab at a dose of 7.5 mg/kg, docetaxel at a dose of 50 mg/m(2) , and oxaliplatin at a dose of 100 mg/m(2) (all on day 1) combined with capecitabine at a dose of 850 mg/m(2) twice daily (days 1-14) every 3 weeks followed by maintenance with capecitabine and bevacizumab in patients with disease control. The primary objective was to demonstrate a progression-free survival (PFS) of >6.5 months, according to the 95% confidence interval (95% CI). Secondary endpoints included safety, objective response rate, overall survival (OS), analyses of circulating tumor cells (CTCs), and pharmacogenetic analyses. RESULTS: Sixty eligible patients were enrolled. The median PFS was 8.3 months (95% CI, 7.2-10.9 months). The objective response rate was 70% (95% CI, 55%-83%) and the disease control rate was 96% (95% CI, 85%-99%). The median OS was 12.0 months (95% CI, 10.2-16.1 months). According to CTC-AE v4.0, the most common treatment-related grade >=3 adverse events were neutropenia (20%), leukocytopenia (18%), diarrhea (15%), and nausea/vomiting (15%). The presence of CTCs at baseline was strongly predictive of PFS (hazard ratio [HR], 3.8; P =.007) and OS (HR, 3.4; P =.014). The methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype was strongly associated with PFS (HR, 4.7 for TT vs CC or CT; P =.0007) and OS (HR, 5.9; P =.0001). CONCLUSIONS: The B-DOC regimen plus maintenance was feasible and active. CTCs were found to be prognostic in patients treated with B-DOC. Docetaxel-based triplet chemotherapy as a backbone for targeted therapies is feasible and deserves further study. Cancer 2016;122:1434 1443. (c) 2016 American Cancer Society. PMID- 26970347 TI - High-performance liquid chromatography with diode array detection method for the simultaneous determination of seven selected phosphodiesterase-5 inhibitors and serotonin reuptake inhibitors used as male sexual enhancers. AB - This work presents a simple, sensitive and generic high-performance liquid chromatography with diode array detection method for the simultaneous determination of seven drugs prescribed for the treatment of erectile dysfunction and premature ejaculation. Investigated drugs include the phosphodiesterase-5 inhibitors: sildenafil, tadalafil, and vardenafil, in addition to the selective serotonin reuptake inhibitors: dapoxetine, duloxetine, fluoxetine, and paroxetine. The drugs were separated using a Waters C8 column (4.6 * 250 mm, 5 MUm) with the mobile phase consisting of phosphate buffer pH 3, acetonitrile and methanol in the ratio 60:33:7. The flow rate was 1.2 mL/min, and quantification was based on measuring peak areas at 225 nm. Peaks were perfectly resolved with retention times 3.3, 3.9, 6.4, 7.5, 9.5, 10.7, and 13.4 min for vardenafil, sildenafil, paroxetine, duloxetine, dapoxetine, fluoxetine, and tadalafil, respectively. The developed method was validated with respect to system suitability, linearity, ranges, accuracy, precision, robustness, and limits of detection and quantification. The proposed method showed good linearity in the ranges 5-500, 2-200, 2-200, 3-300, 1.5-150, 2-200, and 2-200 MUg/mL for sildenafil, tadalafil, vardenafil, dapoxetine, duloxetine fluoxetine, and paroxetine, respectively. The limits of detection were 0.18-0.38 MUg/mL for the analyzed compounds. The applicability of the proposed method to real life situations was assessed through the analysis of commercial tablets, and satisfactory results were obtained. PMID- 26970346 TI - Anticipation of thermal pain in diverticular disease. AB - BACKGROUND: The relative importance of peripheral nerve injury or central pain processing in painful diverticular disease (DD) is unclear. Functional magnetic resonance imaging (fMRI) has demonstrated that dysfunctional central pain processing predominates in irritable bowel syndrome (IBS). This study aims to identify anticipatory changes in symptomatic DD (SDD) compared to asymptomatic DD (ADD) and IBS patients. METHODS: Gastrointestinal symptoms and somatization were evaluated via the Patient Health Question-12 Somatic Symptom and the SDD group divided into low (<=6 [LSDD]) and high (>=7 [HSDD]) somatization. Cued painful cutaneous thermal stimuli were delivered to the left hand and foot during fMRI. Fixed effect group analysis of the 'cued' anticipatory phase was performed. KEY RESULTS: Within the right posterior insula, greater deactivation was found in the ADD compared to other groups. In emotion processing centers, anterior and middle insula, greater activation was identified in all patient compared to the ADD group, and in LSDD compared to IBS and HSDD groups. In comparison, amygdala deactivation was greater in ADD than the IBS and HSDD groups, and in LSDD vs HSDD groups. Descending nociceptive control centers, such as the superior medial frontal and orbitofrontal cortex, also showed greater deactivation in the ADD and LSDD compared to the HSDD and IBS groups. CONCLUSIONS & INFERENCES: The HSDD group have altered anticipatory responses to thermal pain, similar to IBS group. The LSDD are similar to ADD group. This suggests underlying differences in pain pathophysiology, and the need for individualized treatment strategies to target the cause of their chronic pain. PMID- 26970348 TI - Utility of noncontrast-enhanced time-resolved four-dimensional MR angiography with a vessel-selective technique for intracranial arteriovenous malformations. AB - PURPOSE: To evaluate the utility of a vessel-selective four-dimensional (4D) magnetic resonance angiography (MRA) technique for the evaluation of intracranial arteriovenous malformations (AVMs). MATERIALS AND METHODS: Twelve AVM patients were evaluated retrospectively. Time-of-flight (TOF) MRA, nonvessel-selective 4D MRA (NS-4D-MRA), and vessel-selective 4D-MRA (VS-4D-MRA) were performed using a 3T MR unit in all patients, and used to identify feeding arteries and draining veins and measure nidus size. The diagnostic accuracy of the three techniques was compared using digital subtraction angiography (DSA). If a multifeeder was observed, the percentage of blood flow of each feeding artery to the entire nidus was evaluated and compared to the DSA findings using the "error value," defined as the degree of overestimation of the blood flow. All imaging findings were assessed by two neuroradiologists. RESULTS: In both raters, the detectability of feeding arteries by VS-4D-MRA (12 and 11 patients) was significantly higher than those of TOF-MRA (7 and 6 patients) and NS-4D-MRA (8 and 7 patients) (P < 0.016). The detectability of drainer veins by TOF-MRA (10 and 10 patients) was significantly higher than that of VS-4D-MRA (7 and 6 patients). In the percentage of the blood flow of each feed artery to the entire nidus, the DSA findings (error value; 27.1 +/- 5.7) indicated overestimations of the blood flow compared to the VS-4D-MRA (error value; 7.1 +/- 3.9) (P < 0.001). CONCLUSION: VS-4D-MRA was shown to be a useful technique for the evaluation of intracranial AVMs, especially for detecting feed arteries and estimating details of the nidus structure. J. MAGN. RESON. IMAGING 2016;44:834-845. PMID- 26970340 TI - Paving the way of systems biology and precision medicine in allergic diseases: the MeDALL success story: Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015. AB - MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda. PMID- 26970350 TI - Use of Social Desirability Scales in Clinical Psychology: A Systematic Review. AB - OBJECTIVE: There is still an open debate about the utility of social desirability indicators. This report systematically reviewed the use of social desirability scales in studies addressing social desirability in clinical psychology. METHOD: A systematic review (January 2010-March 2015) was conducted, including 35 studies meeting the inclusion criteria of being published in peer-reviewed journals and describing quantitative findings about an association of social desirability with clinical psychology variables using a cross-sectional or longitudinal design. RESULTS: Social desirability was associated with self-reports of various clinical psychological dimensions. Most of the included studies treated social desirability as a 1-dimensional variable and only 10 of 35 disentangled the impression management and self-deception components. Although theoretical literature does not consider social desirability a mere response bias, only 4 of the reviewed articles controlled for the possible suppressor effect of personality variables on social desirability, while the majority focused upon the stylistic (response bias) rather than the substantive (personality) nature of this construct. CONCLUSION: The present review highlighted some limitations in the use of social desirability scales in recent clinical psychology research and tried to offer a few suggestions for handling this issue. PMID- 26970349 TI - Cardiomyocytes display low mitochondrial priming and are highly resistant toward cytotoxic T-cell killing. AB - Following heart transplantation, alloimmune responses can cause graft rejection by damaging donor vascular and parenchymal cells. However, it remains unclear whether cardiomyocytes are also directly killed by immune cells. Here, we used two-photon microscopy to investigate how graft-specific effector CD8(+) T cells interact with cardiomyocytes in a mouse heart transplantation model. Surprisingly, we observed that CD8(+) T cells are completely impaired in killing cardiomyocytes. Even after virus-mediated preactivation, antigen-specific CD8(+) T cells largely fail to lyse these cells although both cell types engage in dynamic interactions. Furthermore, we established a two-photon microscopy-based assay using intact myocardium to determine the susceptibility of cardiomyocytes to undergo apoptosis. This feature, also known as mitochondrial priming reveals an unexpected weak predisposition of cardiomyocytes to undergo apoptosis in situ. These observations together with the early exhaustion phenotype of graft infiltrating specific T cells provide an explanation why cardiomyocytes are largely protected from direct CD8(+) T-cell-mediated killing. PMID- 26970351 TI - Differential involvement of brainstem noradrenergic and midbrain dopaminergic nuclei in cognitive control. AB - Several lines of evidence suggest that the lateral prefrontal cortex (PFC), the dorsal anterior cingulate cortex (dACC), the parietal cortex, and the thalamus are central cortical nodes in a network underlying cognitive control. However, the role of catecholamine producing midbrain and brainstem structures has rarely been addressed by functional magnetic resonance imaging (fMRI). We hypothesized differential activation patterns in the ventral tegmental area (VTA)/substantia nigra (SN) and locus coeruleus (LC) with respect to the degree of cognitive control during a Stroop task in healthy subjects. Forty-five healthy subjects were investigated by the manual version of the Stroop task in an event-related fMRI design. We observed significant BOLD activation of both the SN/VTA and LC during the Stroop interference condition (incongruent vs. congruent condition). LC, but not SN/VTA activation significantly correlated with the Stroop interference. Interestingly, a significant linear decrease in BOLD activation during the incongruent condition during the experiment was mainly observed in the fronto-cingulo-striatal network, but not in SN/VTA and LC. Using psychophysiological (PPI) analyses, a significant functional connectivity during cognitive control was observed between SN/VTA and the nigrostriatal/mesolimbic dopaminergic system. For the LC, distinct functional connectivity pattern was observed mainly to the dorsolateral and ventrolateral PFC. Both regions revealed significant functional connectivity to the dACC, parietal and occipital regions. Thus, we demonstrate for the first time that functional activation patterns in the SN/VTA and the LC are modulated by different demands of cognitive control. In addition, these nuclei exhibit distinguishable functional connectivity patterns to cortical brain networks. Hum Brain Mapp 37:2305-2318, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26970352 TI - Recent Development of Benzimidazole-Containing Antibacterial Agents. AB - Clinically significant antibiotic resistance is one of the greatest challenges of the twenty-first century. However, new antibacterial agents are currently being developed at a much slower pace than our growing need for such drugs. Given their diverse biological activities and clinical applications, many bioactive heterocyclic compounds containing a benzimidazole nucleus have been the focus of interest for many researchers. The benzimidazole nucleus is a structural isostere of naturally occurring nucleotides. This advantage allows benzimidazoles to readily interact with the various biopolymers found in living systems. In view of this situation, much attention has been given to the exploration of benzimidazole based antibacterial agents, leading to the discovery of many new chemical entities with intriguing profiles. In this minireview we summarize novel benzimidazole derivatives active against various bacterial strains. In particular, we outline the relationship between the structures of variously modified benzimidazoles and their antibacterial activity. PMID- 26970353 TI - Cardiac output assessment in pregnancy: comparison of two automated monitors with echocardiography. AB - OBJECTIVE: To compare non-invasive hemodynamic measurements obtained in pregnant and postpartum women using two automated cardiac output monitors against those obtained by two-dimensional (2D) transthoracic echocardiography (TTE). METHODS: This was a cross-comparison study into which we recruited 114 healthy women, either with normal singleton pregnancy (across all three trimesters) or within 72 hours following delivery. Cardiac output estimations were obtained non-invasively using two different monitors, Ultrasound Cardiac Output Monitor (USCOM(r), which uses continuous-wave Doppler analysis of transaortic blood flow) and Non-Invasive Cardiac Output Monitor (NICOM(r), which uses thoracic bioreactance), and 2D-TTE. The performance of each monitor was assessed relative to that of TTE by calculating bias, precision, 95% limits of agreement and mean percentage difference (MPD). Intraobserver repeatability was assessed for both monitors and interobserver reproducibility was assessed for USCOM, NICOM being operator independent. RESULTS: Following exclusions due to poor-quality results of a monitor or TTE, or for medical reasons, our analysis included 98 women (29 in the first trimester, 25 in the second and 21 in the third, and 23 postpartum). For cardiac output estimation, when compared with TTE, USCOM had a bias ranging from 0.4 to 0.9 L/min. The MPD of USCOM was 29% in the third-trimester cohort. NICOM had a bias ranging from -1.0 to 0.6 L/min, with a MPD of 32% in the third trimester group. There was limited agreement between the cardiac output monitors and TTE in the first and second trimesters, with a MPD of 38% for USCOM in both first and second trimesters, and 71% and 61% for NICOM in first and second trimesters, respectively. For cardiac output estimation using USCOM, we found excellent intraobserver repeatability (intraclass correlation coefficient (ICC), 0.97; 95% CI, 0.95-0.98) and interobserver reproducibility (ICC, 0.90; 95% CI, 0.81-0.94), and the repeatability for NICOM was comparable (ICC, 0.95; 95% CI, 0.93-0.97). CONCLUSIONS: We found good agreement of both USCOM and NICOM when compared with 2D-TTE, specifically in the third trimester of pregnancy. Both devices had good intraobserver repeatability and either had good interobserver reproducibility or were operator-independent. Future studies should take into account the significant differences in the precise maternal hemodynamic values obtained by these devices, and consider developing device-specific reference ranges in pregnancy and the postpartum period. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26970354 TI - Associations of low grade inflammation and endothelial dysfunction with depression - The Maastricht Study. AB - BACKGROUND: The pathogenesis of depression may involve low-grade inflammation and endothelial dysfunction. We aimed to evaluate the independent associations of inflammation and endothelial dysfunction with depressive symptoms and depressive disorder, and the role of lifestyle factors in this association. METHODS: In The Maastricht Study, a population-based cohort study (n=852, 55% men, m=59.8+/ 8.5years), depressive symptoms were assessed with the Patient Health Questionnaire-9 and (major and minor) depressive disorder with the Mini International Neuropsychiatric Interview. Plasma biomarkers of inflammation (hsCRP, SAA, sICAM-1, IL-6, IL-8, TNF-alpha) and endothelial dysfunction (sVCAM 1, sICAM-1, sE-selectin, vWF) were measured with sandwich immunoassays and combined into two standardized sum scores. RESULTS: Biomarkers of inflammation (hsCRP, TNF-alpha, SAA, sICAM-1) and endothelial dysfunction (sICAM-1, sE Selectin) were univariately associated with depressive symptoms and depressive disorder. The sum scores of inflammation and endothelial dysfunction were associated with depressive disorder after adjustment for age, sex, type 2 diabetes, kidney function and prior cardiovascular disease (OR 1.54, p=0.001 and 1.40, p=0.006). Both sum scores remained significantly associated with depressive disorder after additional adjustment for lifestyle factors smoking, alcohol consumption and body mass index. The sum score of inflammation was also independently associated with depressive symptoms, while the sum score of endothelial dysfunction was not. CONCLUSIONS: Inflammation and endothelial dysfunction are both associated with depressive disorder, independent of lifestyle factors. Our results might suggest that inflammation and endothelial dysfunction are involved in depression. PMID- 26970356 TI - Cell Cycle Phase-Specific Drug Resistance as an Escape Mechanism of Melanoma Cells. AB - The tumor microenvironment is characterized by cancer cell subpopulations with heterogeneous cell cycle profiles. For example, hypoxic tumor zones contain clusters of cancer cells that arrest in G1 phase. It is conceivable that neoplastic cells exhibit differential drug sensitivity based on their residence in specific cell cycle phases. In this study, we used two-dimensional and organotypic melanoma culture models in combination with fluorescent cell cycle indicators to investigate the effects of cell cycle phases on clinically used drugs. We demonstrate that G1-arrested melanoma cells, irrespective of the underlying cause mediating G1 arrest, are resistant to apoptosis induced by the proteasome inhibitor bortezomib or the alkylating agent temozolomide. In contrast, G1-arrested cells were more sensitive to mitogen-activated protein kinase pathway inhibitor-induced cell death. Of clinical relevance, pretreatment of melanoma cells with a mitogen-activated protein kinase pathway inhibitor, which induced G1 arrest, resulted in resistance to temozolomide or bortezomib. On the other hand, pretreatment with temozolomide, which induced G2 arrest, did not result in resistance to mitogen-activated protein kinase pathway inhibitors. In summary, we established a model to study the effects of the cell cycle on drug sensitivity. Cell cycle phase-specific drug resistance is an escape mechanism of melanoma cells that has implications on the choice and timing of drug combination therapies. PMID- 26970360 TI - Linear Ablation Following Pulmonary Vein Isolation in Patients with Atrial Fibrillation: A Meta-Analysis. AB - Previous studies have given conflicting data regarding the long-term adjunctive efficacy of linear lesions (LLs) on top of pulmonary vein isolation (PVI) as an ablation strategy in patients with atrial fibrillation (AF). The aim of this meta analysis was to provide a detailed analysis of the available randomized controlled trials (RCTs) regarding the efficacy of LL following PVI in AF patients. Current databases were searched until October 2015. The primary outcome end point of the meta-analysis was recurrence of any symptomatic or documented episode of AF or atrial tachycardia after a single ablation procedure with or without the use of antiarrhythmic drugs. Ten RCTs with a total of 1,446 patients were included in the meta-analysis. The pooled analysis of five trials concerning persistent AF (PeAF) patients (400 in PVI plus LL group and 182 in PVI alone group) suggested that the addition of LL following PVI does not lead to a significant reduction in recurrent atrial tachyarrhythmias compared with PVI alone (relative ratio [RR] = 0.73, 95% confidence interval [CI]: 0.44-1.21, P = 0.22). Similarly, there was no incremental benefit of additional LL in long-term outcomes in paroxysmal AF (PAF) patients (RR = 0.85, 95% CI: 0.68-1.05, P = 0.13). Pooling the results of all eligible trials suggested that PVI plus LL compared with PVI alone significantly increased radiofrequency time (P = 0.0002), fluoroscopy time (P < 0.00001), and procedure time (P < 0.0001). This meta analysis suggests that LL following PVI does not provide additional benefit to sinus rhythm maintenance in patients with PeAF and PAF. PMID- 26970355 TI - Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia. AB - Mechanosensory fibers are enveloped by myelin, a unique multilamellar membrane permitting saltatory neuronal conduction. Damage to myelin is thought to contribute to severe pain evoked by innocuous tactile stimulation (i.e., mechanical allodynia). Our earlier (Liu et al., 2012) and present data demonstrate that a single injection of a myelin basic protein-derived peptide (MBP84-104) into an intact sciatic nerve produces a robust and long-lasting (>30days) mechanical allodynia in female rats. The MBP84-104 peptide represents the immunodominant epitope and requires T cells to maintain allodynia. Surprisingly, only systemic gabapentin (a ligand of voltage-gated calcium channel alpha2delta1), but not ketorolac (COX inhibitor), lidocaine (sodium channel blocker) or MK801 (NMDA antagonist) reverse allodynia induced by the intrasciatic MBP84-104. The genome-wide transcriptional profiling of the sciatic nerve followed by the bioinformatics analyses of the expression changes identified interleukin (IL)-6 as the major cytokine induced by MBP84-104 in both the control and athymic T cell-deficient nude rats. The intrasciatic MBP84-104 injection resulted in both unilateral allodynia and unilateral IL-6 increase the segmental spinal cord (neurons and astrocytes). An intrathecal delivery of a function blocking IL-6 antibody reduced the allodynia in part by the transcriptional effects in large-diameter primary afferents in DRG. Our data suggest that MBP regulates IL-6 expression in the nervous system and that the spinal IL-6 activity mediates nociceptive processing stimulated by the MBP epitopes released after damage or disease of the somatosensory nervous system. PMID- 26970361 TI - Marijuana and Madness: Associations Between Cannabinoids and Psychosis. PMID- 26970359 TI - 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol}, 1 a novel resveratrol analog, differentially regulates estrogen receptors alpha and beta in breast cancer cells. AB - Breast cancer is a public health concern worldwide. Prolonged exposure to estrogens has been implicated in the development of breast neoplasms. Epidemiologic and experimental evidence suggest a chemopreventive role of phytoestrogens in breast cancers. Resveratrol, a naturally occurring phytoestrogen, has been shown to have potent anti-cancer properties. However, poor efficacy and bioavailability have prevented the use of resveratrol in clinics. In order to address these problems, we have synthesized a combinatorial library of azaresveratrol analogs and tested them for their ability to inhibit the proliferation of breast cancer cells. We have recently shown that 4-(E)-{(p tolylimino)-methylbenzene-1,2-diol} (TIMBD), has better anti-cancer properties than resveratrol and any other resveratrol analog we have synthesized so far. The objective of this study was to investigate the regulation of estrogen receptors (ERs) alpha and beta by TIMBD in breast cancer cell lines. We demonstrate that TIMBD significantly induces the mRNA and protein expression levels of ERbeta and inhibits that of ERalpha. TIMBD inhibits mRNA and protein expression levels of oncogene c-Myc, and cell cycle protein cyclin D1, which are important regulators of cellular proliferation. TIMBD significantly induces protein expression levels of tumor suppressor genes p53 and p21 in MCF-7 cells. TIMBD inhibits c-Myc in an ERbeta-dependent fashion in MCF-10A and ERbeta1-transfected MDA-MB-231 cells, suggesting regulation of ERs as an important upstream mechanism of this analog. ERbeta plays a partial role in inhibition of proliferation by TIMBD while ERalpha overexpression does not significantly affect TIMBD's inhibition. PMID- 26970362 TI - Cannabis and Psychosis: What Degree of Proof Do We Require? PMID- 26970364 TI - Synthetic Cannabinoids-Further Evidence Supporting the Relationship Between Cannabinoids and Psychosis. AB - Consumption of synthetic mind-altering compounds, also known as "new psychoactive substances," is increasing globally at an alarming rate. Synthetic cannabinoids (SCs) are among the most commonly used new psychoactive substances. They are usually purchased as marijuana-like drugs, marketed as herbal blends and perceived as risk-free by inexperienced users. Yet, contrary to Delta(9) tetrahydrocannabinol, SCs may lead to severe health consequences, including anxiety, tachycardia, hallucinations, violent behavior, and psychosis. This review focuses on the latest (2010-2015) evidence of psychotic symptoms induced by ingestion of products containing SCs. Reports suggesting that SCs may either exacerbate previously stable psychotic symptoms (in vulnerable individuals) or trigger new-onset psychosis (in individuals with no previous history of psychosis) are reviewed. Pharmacology and toxicology of these compounds are discussed, with particular reference to their psychoactive effects. PMID- 26970365 TI - Chemical avoidance responses of fishes. AB - The hydrosphere is a repository for all of our waste and mistakes, be they sewage, garbage, process-affected waters, runoff, and gases. For fish living in environments receiving undesirable inputs, moving away seems an obvious way to avoid harm. While this should occur, there are numerous examples where it will not. The inability to avoid harmful environments may lead to sensory impairments that in turn limit the ability to avoid other dangers or locate benefits. For avoidance to occur, the danger must first be perceived, which may not happen if the fish is 'blinded' in some capacity. Second, the danger must be recognized for what it is, which may also not happen if the fish is cognitively confused or impaired. Third, it is possible that the fish may not be able to leave the area, or worse, learns to prefer a toxic environment. Concerning generating regulations around avoidance, there are two possibilities: that an avoidance threshold be used to set guidelines for effluent release with the intention of driving fishes away; the second is to set a contaminant concentration that would not affect the avoidance or attraction responses to other cues. With the complexities of the modern world in which we release diverse pollutants, from light to municipal effluents full of 1000s of chemicals, to the diversity present in ecosystems, it is impossible to have avoidance data on every stimulus-species combination. Nevertheless, we may be able to use existing avoidance response data to predict the likelihood of avoidance of untested stimuli. Where we cannot, this review includes a framework that can be used to direct new research. This review is intended to collate existing avoidance response data, provide a framework for making decisions in the absence of data, and suggest studies that would facilitate the prediction of risk to fish health in environments receiving intentional and unintentional human-based chemical inputs. PMID- 26970363 TI - Human Laboratory Studies on Cannabinoids and Psychosis. AB - Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blind, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists, including phytocannabinoids and synthetic cannabinoids, produce a wide range of positive, negative, and cognitive symptoms and psychophysiologic deficits in healthy human subjects that resemble the phenomenology of schizophrenia. These effects are time locked to drug administration, are dose related, and are transient and rarely necessitate intervention. The magnitude of effects is similar to the effects of ketamine but qualitatively distinct from other psychotomimetic drugs, including ketamine, amphetamine, and salvinorin A. Cannabinoid agonists have also been shown to transiently exacerbate symptoms in individuals with schizophrenia in laboratory studies. Patients with schizophrenia are more vulnerable than healthy control subjects to the acute behavioral and cognitive effects of cannabinoid agonists and experience transient exacerbation of symptoms despite treatment with antipsychotic medications. Furthermore, laboratory studies have failed to demonstrate any "beneficial" effects of cannabinoid agonists in individuals with schizophrenia-challenging the cannabis self-medication hypothesis. Emerging evidence suggests that polymorphisms of several genes related to dopamine metabolism (e.g., COMT, DAT1, and AKT1) may moderate the effects of cannabinoid agonists in laboratory studies. Cannabinoid agonists induce dopamine release, although the magnitude of release does not appear to be commensurate to the magnitude and spectrum of their acute psychotomimetic effects. Interactions between the endocannabinoid, gamma-aminobutyric acid, and glutamate systems and their individual and interactive effects on neural oscillations provide a plausible mechanism underlying the psychotomimetic effects of cannabinoids. PMID- 26970367 TI - Physiological and cellular responses of oysters (Crassostrea hongkongensis) in a multimetal-contaminated estuary. AB - The Pearl River estuary, southern China, suffers from multiple sources of metal contamination as a result of the rapid industrial development in the region; but the biological impacts of contamination remain unknown. In the present study, a euryhaline oyster, Crassostrea hongkongensis, was collected from different sites of the Pearl River estuary; and various physiological (heart rate, alkaline phosphatase as homeostatic regulation, and glycogen as energy reserve) and cytological (lysosomal membrane stability) biomarkers were quantified to assess this species as a potential bioindicator of metal pollution in contaminated areas. Large variations of metal accumulation levels in the oysters were documented, especially for copper (Cu), zinc (Zn), cadmium (Cd), chromium, and nickel (Ni). Among these metals, the authors demonstrated significant correlations between the digestive gland metal accumulation of Cu, Zn, and Ni and the cellular homeostasis (alkaline phosphatase) and glycogen reserves. Heart rate was positively correlated with Cd but negatively correlated with Cu and Zn concentrations in the gills. Lysosomal membrane stability was significantly inhibited at the most contaminated sites but had no relationship with the accumulated metal concentrations. These measurements indicate that multimetal contamination in the Pearl River estuary impacts the physiological and cytological performance of oysters. Environ Toxicol Chem 2016;35:2577-2586. (c) 2016 SETAC. PMID- 26970366 TI - Personalized symptom goals and response in patients with advanced cancer. AB - BACKGROUND: Improving symptoms is a major goal of cancer medicine; however, symptom response is often based on group differences and not individualized. In the current study, the authors examined the personalized symptom goal (PSG) for 10 common symptoms in patients with advanced cancer, and identified the factors associated with PSG response. METHODS: In this prospective, longitudinal, multicenter study, patients from 5 tertiary care hospitals rated the intensity of 10 symptoms using a numeric rating scale of 0 to 10 at the time of their first clinic visit and then at a second visit 14 to 34 days later. The PSG was determined for each symptom by asking patients: "At what level would you feel comfortable with this symptom?" using the same scale of 0 to 10 for symptom intensity. PSG response was defined as symptom intensity at the time of the second visit that was less than or equal to the PSG. RESULTS: Among 728 patients, the median PSG was 1 for nausea; 2 for depression, anxiety, drowsiness, well being, dyspnea, and sleep; and 3 for pain, fatigue, and appetite. A greater percentage of patients achieved a PSG response at their second visit compared with their first visit (P<.05 except for drowsiness). Symptom response was associated with lower baseline symptom intensity based on PSG criterion but higher baseline symptom intensity based on the traditional minimal clinically important difference definition (P<.001 for all symptoms). In multivariable analysis, higher PSG and nationality were associated with greater PSG response. CONCLUSIONS: The PSG was <=3 for a majority of patients. PSG response allows clinicians to tailor treatment goals while adjusting for individual differences in scale interpretation and factors associated with symptom response. Cancer 2016;122:1774-81. (c) 2016 American Cancer Society. PMID- 26970368 TI - Acceptability of oral solid medicines in older adults with and without dysphagia: A nested pilot validation questionnaire based observational study. AB - Older patients (aged 65years and over) are the major consumers of medicines and many barriers affect their ability in taking medicines orally, especially swallowing difficulties. Moreover, the characteristics of differing medicine formulations might have an impact on their acceptability in older patients. The aims of this study were to validate a Medicines Acceptability Questionnaire (MAQ) and to assess acceptability of oral solid medicines in older ambulatory patients with and without dysphagia. One hundred and fifty six older patients attending community pharmacies were recruited and attended face to face interviews. Two questionnaires were administered during the interviews, the validated Sydney Swallow Questionnaire (SSQ) assessing oral and pharyngeal swallowing function and the newly developed MAQ evaluating patient acceptability of oral solid medicines. Seventeen (11%) participants displayed symptoms compatible with swallowing difficulties identified by the SSQ. Participants with swallowing difficulties were considered themselves more likely to have problems in swallowing tablets and capsules of large sizes (11mm and 13mm tablets and size #00 capsules) compared to participants without dysphagia. Dispersible/effervescent tablets and orally disintegrating tablets were considered to be the most acceptable in this cohort, followed by mini-tablets. Chewable tablets and granules were the least favoured. Consistently higher acceptability scores were seen in the dysphagic population than in the non-dysphagic population for all of the dosage forms that were easier to swallow than tablets and capsules. The development of these formulations will assist in medication taking in older patients with dysphagia and potentially their adherence to drug treatments. PMID- 26970369 TI - How Often Are Parents Counseled About Family Planning During Pediatric Visits? Results of a Nationally Representative Sample. AB - OBJECTIVE: Maternal family planning plays an important role in child, maternal, and family health; children's health care providers are in a unique position to counsel adult caregivers regarding contraception and appropriate birth spacing. We sought to determine the prevalence of caregiver family planning counseling by children's health care providers during preventive care visits for infants and young children. METHODS: Data from the National Ambulatory Medical Care Survey from 2009 to 2012 as well as National Hospital Ambulatory Medical Care Survey from 2009 to 2011 were analyzed to determine the weighted frequency of family planning/contraception counseling provided during preventive, primary care visits for children younger than the age of 2 years. RESULTS: Family planning/contraception counseling or education was documented in only 16 of 4261 preventive care visits in primary care settings for children younger than the age of 2 years, corresponding to 0.30% (95% confidence interval, -0.08% to 0.68%) of visits nationally. Similar frequencies were calculated for preventive visits with children younger than 1 year and with infants younger than 60 days of age. CONCLUSIONS: Despite Bright Futures' recommendations for children's health care providers to address caregiver family planning during well infant visits, documented counseling is rare. The results indicate that there are missed opportunities to promote family health in the pediatric setting. PMID- 26970370 TI - Modulation of Decidual Macrophage Polarization by Macrophage Colony-Stimulating Factor Derived from First-Trimester Decidual Cells: Implication in Preeclampsia. AB - During human pregnancy, immune tolerance of the fetal semiallograft occurs in the presence of abundant maternal leukocytes. At the implantation site, macrophages comprise approximately 20% of the leukocyte population and act as primary mediators of tissue remodeling. Decidual macrophages display a balance between anti-inflammatory and proinflammatory phenotypes. However, a shift to an M1 subtype is reported in preeclampsia. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) are major differentiating factors that mediate M1 and M2 polarization, respectively. Previously, we observed the following: i) the preeclamptic decidua contains an excess of both macrophages and GM-CSF, ii) the preeclampsia-associated proinflammatory cytokines, IL-1beta and tumor necrosis factor-alpha, markedly enhance GM-CSF and M-CSF expression in cultured leukocyte-free first-trimester decidual cells (FTDCs), iii) FTDC-secreted GM-CSF polarizes macrophages toward an M1 subtype. The microenvironment is a key determinant of macrophage phenotype. Thus, we examined proinflammatory stimulation of FTDC-secreted M-CSF and its role in macrophage development. Immunofluorescence staining demonstrated elevated M CSF-positive decidual cell numbers in preeclamptic decidua. In FTDCs, IL-1beta and tumor necrosis factor-alpha signal through the NF-kappaB pathway to induce M CSF production, which does the following: i) enhances differentiation of and elevates CD163 expression in macrophages, ii) increases macrophage phagocytic capacity, and iii) inhibits signal-regulatory protein alpha expression by macrophages. These findings suggest that FTDC-secreted M-CSF modulates the decidual immune balance by inducing M2 macrophage polarization and phagocytic capacity in response to proinflammatory stimuli. PMID- 26970371 TI - A web-based survey of horse owners' perceptions and network analysis of horse movements relating to African horse sickness distribution in Namibia and South Africa. AB - Africa horse sickness (AHS) is the most lethal infectious non-contagious horse disease and has accordingly been declared notifiable by the World Organisation for Animal Health. AHS is endemic to sub-Saharan Africa and causes considerable losses to the equestrian industry. The effect of diseases in livestock on socio economic factors is well researched, but the effect of anthropogenic factors on the distribution of a disease is poorly understood. The purpose of the study was to assess Namibian and South African horse owners' perceptions and the effect of horse movement on AHS distribution. A cross-sectional study was conducted to collect information from horse owners in Namibia and South Africa. To that end 'Fluid survey' was used for survey development. The survey was launched on Facebook and the link shared to horse related focus groups in Namibia and South Africa. A total of 508 responses were collected during the survey period. Of the 417 completed questionnaires received, 22% were from Namibia and 78% from South Africa. The participants comprised of 71% social and 29% professional riders. The most popular precautionary measures used, in addition to vaccination, were chemical repellents (64%) and stabling of horses during dusk and dawn (59%). A network analysis was performed in Gephi 0.8.2.B to illustrate the movement of horses between countries and districts/provinces. Network analysis results indicate that areas with the highest movement of horses corresponded to the areas with a high occurrence of AHS. Although 93% of the participants were aware that AHS is a notifiable and controlled disease, the process and efficiency of reporting is mostly unknown. With this snapshot of horse owners' perceptions and the effect of horse movement on the distribution of AHS, it is clear that a more holistic approach is needed. To that end, all environmental and social factors must be taken into account in effective management strategies. PMID- 26970372 TI - Fasciola gigantica enolase is a major component of worm tegumental fraction protective against sheep fasciolosis. AB - Infection of cattle and sheep with the parasite Fasciola gigantica is a cause of important economic losses throughout Asia and Africa. Many of the available anthelmintics have undesirable side effects, and the parasite may acquire drug resistance as a result of mass and repeated treatments of livestock. Accordingly, the need for developing a vaccine is evident. Triton-soluble surface membrane and tegumental proteins (TSMTP) of 60, 32, and 28 kDa previously shown to elicit protective immunity in mice against challenge F. gigantica infection were found to be strongly immunogenic in sheep eliciting vigorous specific antibody responses to a titer>1:16,000 as assessed by enzyme-linked immunosorbent assay. Furthermore, the 60 kDa fraction induced production of antibodies able to bind to the surface membrane of newly excysted juvenile flukes and mediate their attrition in antibody-dependent complement- and cell-mediated cytotoxicity assays, and significant (P<0.05) 40% protection of sheep against F. gigantica challenge infection. Amino acid micro sequencing of the 60 kDa-derived tryptic peptides revealed the fraction predominantly consists of F. gigantica enolase. The cDNA nucleotide and translated amino acid sequences of F. gigantica enolase showed homology of 92% and 95%, respectively to Fasciola hepatica enolase, suggesting that a fasciolosis vaccine might be effective against both tropical and temperate liver flukes. PMID- 26970373 TI - Spatial association between malaria vector species richness and malaria in Colombia. AB - Malaria transmission in Colombia is highly variable in space and time. Using a species distribution model, we mapped potential distribution of five vector species including Anopheles albimanus, Anopheles calderoni, Anopheles darlingi, Anopheles neivai, and Anopheles nuneztovari in five Departments of Colombia where malaria transmission remains problematic. We overlaid the range maps of the five species to reveal areas of sympatry and related per-pixel species richness to mean annual parasite index (API) for 2011-2014 mapped by municipality (n = 287). The relationship between mean number of vector species per municipality and API was evaluated using a Poisson regression, which revealed a highly significant relationship between species richness and API (p = 0 for Wald Chi-Square statistic). The results suggest that areas of relatively high transmission in Colombia typically contain higher number of vector species than areas with unstable transmission and that future elimination strategies should account for vector species richness. PMID- 26970374 TI - Periodic acid-Schiff granules in the brain of aged mice: From amyloid aggregates to degenerative structures containing neo-epitopes. AB - Brain ageing in mice leads to the progressive appearance and expansion of degenerative granular structures frequently referred as "PAS granules" because of their positive staining with periodic acid-Schiff (PAS). PAS granules are present mainly in the hippocampus, although they have also been described in other brain areas such as piriform and entorhinal cortices, and have been observed in other mammals than mice, like rats and monkeys. PAS granules have been identified as a wide range of brain deposits related to numerous neurodegenerative diseases, such as amyloid deposits, neurofibrillary tangles, Lafora bodies, corpora amylacea and polyglucosan bodies, and these identifications have generated controversy and particular theories about them. We have recently reported the presence of a neo epitope in mice hippocampal PAS granules and the existence of natural IgM auto antibodies directed against the neo-epitope in the plasma of the animals. The significance of the neo-epitope and the autoantibodies is discussed in this review. Moreover, we observed that the IgM anti-neo-epitope is frequently present as a contaminant in numerous commercial antibodies and is responsible of a considerable amount of false positive immunostainings, which may produce misinterpretations in the identification of the granules. Now that this point has been clarified, this article reviews and reconsiders the nature and physiopathological significance of these degenerative granules. Moreover, we suggest that neo-epitopes may turn into a useful brain-ageing biomarker and that autoimmunity could become a new focus in the study of age-related degenerative processes. PMID- 26970375 TI - Immunodetection of the "brown" spider (Loxosceles intermedia) dermonecrotoxin with an scFv-alkaline phosphatase fusion protein. AB - Bites by spiders from Loxosceles genus often lead to a wide variance in envenomation profile of patients and diagnosis is difficult due to the number of diseases that mimic loxoscelism. In such a context, it is of interest to consider the design of standardized recombinant colorimetric antibodies for diagnosis and specific detection of individual circulating toxins in biological fluids of envenomed patients. We have previously prepared a monoclonal murine IgG (LiMab7) that reacts with Loxosceles intermedia venom components of 32-35kDa and neutralizes the dermonecrotic activity of the venom. Here, we re-engineered LiMab7 into a colorimetric bifunctional protein consisting in the corresponding single-chain antibody fragment (scFv) fused to alkaline phosphatase (AP) of Escherichia coli. The immune tracer was tested in two different types of immunoassays and it proved to be efficient in both. Thus, this recombinant fusion protein (scFv-LiMab7/AP) can be used for rapid and specific immunotitration of L. intermedia venom with a linear range of 39-20000ng/mL and a detection limit of 39ng/mL without any cross-reaction. PMID- 26970376 TI - Identification of neutrophil surface marker changes in health and inflammation using high-throughput screening flow cytometry. AB - Neutrophils are the most abundant white blood cell and are an essential component of the innate immune system. A complete cataloguing of cell surface markers has not been undertaken for neutrophils isolated from circulation as well as healthy and inflamed tissues. To identify cell-surface markers specific to human neutrophils, we used high-throughput flow cytometry to screen neutrophil populations isolated from blood and oral rinses from healthy and chronic periodontitis patients against a panel of 374 known cluster of differentiation (CD) antibodies. This screen identified CD11b, CD16, and CD66b as markers that are consistently expressed on neutrophils independent of the cell location, level of activation and disease state. Cell sorting against CD11b, CD16 and CD66b allowed for the enrichment of mature neutrophils, yielding neutrophil populations with up to 99% purity. These findings suggest an ideal surface marker set for isolating mature neutrophils from humans. The screen also demonstrated that tissue neutrophils from chronically inflamed tissue display a unique surface marker set compared to tissue neutrophils present in healthy, non-inflamed tissues. PMID- 26970377 TI - Antimanic-like effects of (R)-(-)-carvone and (S)-(+)-carvone in mice. AB - Carvone is a monoterpene that is present in spearmint (Mentha spicata) and caraway (Carum carvi) essential oils and has been shown to have anticonvulsant effects, likely through the blockade of voltage-gated sodium channels, and anxiolytic-like effects. Considering that some anticonvulsants that blocked voltage-gated sodium channels (e.g., sodium valproate and carbamazepine) exert clinical antimanic effects, the aim of the present study was to evaluate (R)-(-) carvone and (S)-(+)-carvone in animal models of mania (i.e., hyperlocomotion induced by methylphenidate and sleep deprivation). Mice that were treated with methylphenidate (5mg/kg) or sleep-deprived for 24h using a multiple-platform protocol exhibited an increase in locomotor activity in an automated activity box. This effect was blocked by pretreatment with acute (R)-(-)-carvone (50 100mg/kg), (S)-(+)-carvone (50-100mg/kg), and lithium (100mg/kg, positive control). These doses did not alter spontaneous locomotor activity in the methylphenidate-induced experiments while (S)-(+)-carvone decreased spontaneous locomotor activity in sleep deprivation experiment, indicating a sedative effect. Chronic 21-day treatment with (R)-(-)-carvone (100mg/kg), (S)-(+)-carvone (100mg/kg), and lithium also prevented methylphenidate-induced hyperactivity. The present results suggest that carvone may have an antimanic-like effect. PMID- 26970378 TI - An Adaptive Simulation Framework for the Exploration of Extreme and Unexpected Events in Dynamic Engineered Systems. AB - The end states reached by an engineered system during an accident scenario depend not only on the sequences of the events composing the scenario, but also on their timing and magnitudes. Including these additional features within an overarching framework can render the analysis infeasible in practical cases, due to the high dimension of the system state-space and the computational effort correspondingly needed to explore the possible system evolutions in search of the interesting (and very rare) ones of failure. To tackle this hurdle, in this article we introduce a framework for efficiently probing the space of event sequences of a dynamic system by means of a guided Monte Carlo simulation. Such framework is semi-automatic and allows embedding the analyst's prior knowledge about the system and his/her objectives of analysis. Specifically, the framework allows adaptively and intelligently allocating the simulation efforts preferably on those sequences leading to outcomes of interest for the objectives of the analysis, e.g., typically those that are more safety-critical (and/or rare). The emerging diversification in the filling of the state-space by the preference guided exploration allows also the retrieval of critical system features, which can be useful to analysts and designers for taking appropriate means of prevention and mitigation of dangerous and/or unexpected consequences. A dynamic system for gas transmission is considered as a case study to demonstrate the application of the method. PMID- 26970379 TI - Wilms Tumor 1 Expression and Pre-emptive Immunotherapy in Patients with Acute Myeloid Leukemia Undergoing an Allogeneic Hemopoietic Stem Cell Transplantation. AB - Minimal residual disease (MRD) was monitored by Wilms tumor 1 (WT1) expression in 207 patients with acute myeloid leukemia (AML) after an allogeneic hemopoietic stem cell transplantation (HSCT) as a trigger to initiate pre-emptive immunotherapy (IT) with cyclosporin discontinuation and/or donor lymphocyte infusion. The trigger for IT was WT1 >= 180 copies/10(4) Abelson cells in marrow cells in the first group of 122 patients (WT1-180) and >= 100 copies in a subsequent group of 85 patients (WT1-100). Forty patients received IT. The cumulative incidence (CI) of relapse was 76% in WT1-180 (n = 17) versus 29% in WT1-100 patients (n = 23) receiving IT (P = .006); the leukemia-free survival from MRD positivity was 23% versus 74%, respectively (P = .003). We then looked at the entire AML patient population (n = 207). WT1-180 and WT1-100 patients were comparable for disease phase and age. The overall 4-year CI of transplantation related mortality was 13% in both groups; the CI of leukemia relapse was 38% in the WT1-180 and 28% in the WT1-100 patients (P = .05) and leukemia-free survival was 56% versus 48%, respectively (P = .07). In conclusion, we suggests that WT1 based pre-emptive immunotherapy is feasible in patients with undergoing an allogeneic HSCT. The protective effect on relapse is greater when IT is triggered at lower levels of WT1. PMID- 26970380 TI - Outcome after Transplantation According to Reduced-Intensity Conditioning Regimen in Patients Undergoing Transplantation for Myelofibrosis. AB - Allogeneic hematopoietic stem cell transplantation remains the sole curative option for myelofibrosis. Many transplantation recipients receive a reduced intensity conditioning (RIC) regimen owing to age or comorbidities; however, there is little published evidence to guide the choice of RIC regimen. In this study, we compared outcomes in patients who received 1 of 2 frequently used RIC regimens for patients with myelofibrosis: fludarabine-busulfan (FB) and fludarabine-melphalan (FM). A total of 160 patients underwent a RIC allograft procedure (FB group, n = 105; FM group, n = 55). We have developed a complex statistical model involving weighting and adjustment to permit comparison between these 2 groups. After weighting, the incidence of acute graft-versus-host disease (GVHD) was 62% in the FM group and 31% in the FB group (P = .001), and the corresponding incidence of chronic GVHD was 49% and 53%, respectively. The 7-year progression-free survival was were 52% in the FM group versus 33% in the FB group, and the 7-year overall survival rate 52% in the FM group versus 59% in the FB group. Nonrelapse mortality (NRM) was 43% in the FM group and 31% in the FB group. Multivariable analyses revealed no significant differences in PFS between the 2 groups; however, the relapse rate was significantly lower in the FM group (hazard ratio, 9.21; P = .008), whereas a trend toward reduced NRM was seen in the FB group (hazard ratio, 0.51; P = .068). In conclusion, both regimens appear to be efficient in mediating disease control and can be used to successfully condition patients with myelofibrosis. The FM regimen appears to induce more NRM than the FB regimen, but with augmented control of disease, leading to comparable overall survival rates for both regimens. PMID- 26970381 TI - Graft-versus-Host Disease Prophylaxis in Unrelated Peripheral Blood Stem Cell Transplantation with Post-Transplantation Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil. AB - Clinical efficacy of post-transplantation cyclophosphamide (PTCy) as graft-versus host disease (GVHD) prophylaxis has been demonstrated in haploidentical and HLA matched bone marrow but not in unrelated peripheral blood stem cell (PBSC) transplantations. Also, no direct comparisons have been published with current standard of care, combination of antithymocyte globulin (ATG), calcineurin inhibitors, and either methotrexate or mycophenolate mofetil (MMF). Eighty-six adult patients (median age 34 years; range, 18 to 59) with acute myeloblastic and lymphoblastic leukemia underwent unrelated PBSC transplantation with PTCy, tacrolimus, and MMF as GVHD prophylaxis in the single-center trial (clinicaltrial.govNCT02294552). The control group comprised 125 consecutive historical control patients who received ATG, tacrolimus, and methotrexate or MMF. Cumulative incidences of grades II to IV acute (19% versus 45%, P = .0003), grades III to IV acute (4% versus 27%, P < .0001), and chronic GVHD (16% versus 65%, P < .0001) were significantly lower in the PTCy compared with the ATG group. PTCy-based prophylaxis was associated with reduced incidence of nonrelapse mortality (16% versus 36%, P = .005; HR, .55; 95% CI, .34 to .89) and improved overall survival (69% versus 40%, P = .0007; HR, .43; 95% CI, .26 to .70), event free survival (65% versus 38%, P = .0006; HR, .49; 95% CI, .31 to .78), and GVHD relapse-free survival (52% versus 12%, P < .0001). PTCy-based prophylaxis also had a better safety profile compared with ATG with reduced incidence of veno occlusive disease, cytomegalovirus reactivation, invasive mycosis, and reduced severity of mucositis. In this study we demonstrated that PTCy in combination with tacrolimus and MMF is a safe and effective GVHD prophylaxis for unrelated PBSC transplantation. Although there are several limitations of the historical control approach, this study suggests the superiority of a PTCy-based approach over an ATG-based prophylaxis. PMID- 26970382 TI - Early Detection is Key: Is Handheld Spirometry the Answer? PMID- 26970383 TI - Steroids Versus Steroids Plus Additional Agent in Frontline Treatment of Acute Graft-versus-Host Disease: A Systematic Review and Meta-Analysis of Randomized Trials. AB - Despite extensive research in the last few decades, progress in treatment of acute graft-versus-host disease (aGVHD), a common complication of allogeneic hematopoietic cell transplantation (HCT), has been limited and steroids continue to be the standard frontline treatment. Randomized clinical trials (RCTs) have failed to find a beneficial effect of escalating immunosuppression using additional agents. Considering the small number of RCTs, limited sample sizes, and frequent early termination because of anticipated futility, we conducted a systematic review and an aggregate data meta-analysis to explore whether a true efficacy signal has been missed because of the limitations of individual RCTs. Seven reports met our inclusion criteria. The control arm in all studies was 2 mg/kg/day prednisone (or equivalent). The additional agent(s) used in the experimental arm(s) were higher-dose steroids, antithymocyte globulin, infliximab, anti-interleukin-2 receptor antibody (daclizumab and BT563), CD5 specific immunotoxin, and mycophenolate mofetil. Random effects meta-analysis revealed no efficacy signal in pooled response rates at various times points. Overall survival at 100 days was significantly worse in the experimental arm (relative risk [RR], .83; 95% confidence interval [CI], .74 to .94; P = .004, data from 3 studies) and showed a similar trend (albeit not statistically significantly) at 1 year as well (RR, .86; 95% CI, .68 to 1.09; P = .21, data from 5 studies). In conclusion, these results argue against the value of augmented generic immunosuppression beyond steroids for frontline treatment of aGVHD and emphasize the importance of developing alternative strategies. Novel forms of immunomodulation and targeted therapies against non-immune-related pathways may enhance the efficacy of steroids in this setting, and early predictive and prognostic biomarkers can help identify the subgroup of patients who would likely need treatments other than (or in addition to) generic immunosuppression. PMID- 26970384 TI - MAVIN: An Open-Source Tool for Interactive Analysis and Visualization of EMG Data. PMID- 26970385 TI - Patient preferences regarding incidental genomic findings discovered during tumor profiling. AB - BACKGROUND: During the process of tumor profiling, there is the potential to detect germline variants. To the authors' knowledge, there currently is no accepted standard of care for how to deal with these incidental findings. The goal of the current study was to assess disclosure preferences among patients with cancer regarding incidental genomic variants that may be discovered during tumor profiling. METHODS: A 45-item questionnaire was administered to 413 patients in ambulatory oncology clinics. The survey captured demographic and disease variables and personal and family history, and presented case scenarios for different types of incidental germline variants that could theoretically be detected during genomic analysis of a patient's tumor. RESULTS: The possibility of discovering non-cancer-related, germline variants did not deter patients from tumor profiling: 77% wanted to be informed concerning variants that could increase their risk of a serious but preventable illness, 56% wanted to know about variants that cause a serious but unpreventable illness, and 49% wanted to know about variants of uncertain significance. The majority of patients (75%) indicated they would share hereditary information regarding predisposition to preventable diseases with family and 62% would share information concerning unpreventable diseases. The most frequent concerns about incidental findings were ability to obtain health (48%) or life (41%) insurance. Only 21% of patients were concerned about privacy of information. CONCLUSIONS: Patients with cancer appear to prefer to receive information regarding incidental germline variants, but there is substantial variability with regard to what information patients wish to learn. The authors recommend that personal preferences for the disclosure of different types of incidental findings be clarified before a tumor profiling test is ordered. Cancer 2016;122:1588-97. (c) 2016 American Cancer Society. PMID- 26970386 TI - Localized heat urticaria: Positive reaction of preheated autologous serum skin test. PMID- 26970387 TI - Prophylactic Antibiotics for Severe Burns: Are They Safe? PMID- 26970388 TI - Cell cycle control of DNA joint molecule resolution. AB - The establishment of stable interactions between chromosomes underpins vital cellular processes such as recombinational DNA repair and bipolar chromosome segregation. On the other hand, timely disengagement of persistent connections is necessary to assure efficient partitioning of the replicated genome prior to cell division. Whereas great progress has been made in defining how cohesin-mediated chromosomal interactions are disengaged as cells prepare to undergo chromosome segregation, little is known about the metabolism of DNA joint molecules (JMs), generated during the repair of chromosomal lesions. Recent work on Mus81 and Yen1/GEN1, two conserved structure-selective endonucleases, revealed unforeseen links between JM-processing and cell cycle progression. Cell cycle kinases and phosphatases control Mus81 and Yen1/GEN1 to restrain deleterious JM-processing during S-phase, while safeguarding chromosome segregation during mitosis. PMID- 26970391 TI - Realist evaluation caricatured: a reply to Porter. PMID- 26970389 TI - Changes and their possible causes in delta13C of dark-respired CO2 and its putative bulk and soluble sources during maize ontogeny. AB - The issues of whether, where, and to what extent carbon isotopic fractionations occur during respiration affect interpretations of plant functions that are important to many disciplines across the natural sciences. Studies of carbon isotopic fractionation during dark respiration in C3 plants have repeatedly shown respired CO2 to be (13)C enriched relative to its bulk leaf sources and (13)C depleted relative to its bulk root sources. Furthermore, two studies showed respired CO2 to become progressively (13)C enriched during leaf ontogeny and (13)C depleted during root ontogeny in C3 legumes. As such data on C4 plants are scarce and contradictory, we investigated apparent respiratory fractionations of carbon and their possible causes in different organs of maize plants during early ontogeny. As in the C3 plants, leaf-respired CO2 was (13)C enriched whereas root respired CO2 was (13)C depleted relative to their putative sources. In contrast to the findings for C3 plants, however, not only root- but also leaf-respired CO2 became more (13)C depleted during ontogeny. Leaf-respired CO2 was highly (13)C enriched just after light-dark transition but the enrichment rapidly decreased over time in darkness. We conclude that (i) although carbon isotopic fractionations in C4 maize and leguminous C3 crop roots are similar, increasing phosphoenolpyruvate-carboxylase activity during maize ontogeny could have produced the contrast between the progressive (13)C depletion of maize leaf respired CO2 and (13)C enrichment of C3 leaf-respired CO2 over time, and (ii) in both maize and C3 leaves, highly (13)C enriched leaf-respired CO2 at light-to dark transition and its rapid decrease during darkness, together with the observed decrease in leaf malate content, may be the result of a transient effect of light-enhanced dark respiration. PMID- 26970390 TI - Integrating Radiology and Anatomy Teaching in Medical Education in the UK--The Evidence, Current Trends, and Future Scope. AB - This review article presents the current evidence of the importance of integrating radiology and anatomy in medical education in the UK, a recommendation by a number of key anatomy, education, and radiology organizations. Current evidence highlights that on average only 5% of total teaching time in medical education is dedicated to radiology. Often, radiology teaching does not adequately fulfill students' learning needs and potentially leaves them underprepared for medical practice. Benefits of integrating radiology and anatomy include improved clinical application of anatomy, an increase in student's interest in anatomy, and ultimately improved radiological interpretation. Various modalities exist for the integration of radiology and anatomy, facilitated by the vast portability of radiological images. It appears that combining radiological resources with traditional anatomy teaching methodology in a blended approach is most beneficial. PMID- 26970392 TI - Maternal high-fat diet leads to persistent synaptic instability in mouse offspring via oxidative stress during lactation. AB - Maternal obesity has negative effects on the neurodevelopment of the offspring. Pups from high-fat diet (HFD)-fed mice exhibit peroxidized lipid accumulations in the brain and behavioral impairments. However, the synaptic basis of maternal HFD induced brain dysfunction in offspring remains unclear. In the present study, we focused on the dynamics and morphology of postsynaptic dendritic spines and filopodia in the offspring of HFD-fed mouse dams, using in vivo two-photon imaging, chosen because of the involvement of peripheral organs and non-neuronal cells in the abnormal metabolic state. We observed instability of dendritic spines and filopodia in the cerebral cortex of offspring from HFD-fed dams. Interestingly, the synaptic instability persisted into adulthood with a lower spine density even when the offspring were fed with a normal diet after weaning. HFD-fed offspring from HFD-fed dams showed a severe disruption of dendritic spines. Synaptic instability and loss of spines were caused even by HFD exposure exclusively during lactation. The treatment of ascorbic acid, an antioxidant, during lactation ameliorated the synaptic impairments. These results suggest that maternal obesity leads to persistent synaptic impairments in the offspring, which may be associated with behavioral deficits in adulthood, and that these synaptic deficits may be due to oxidative stress from peroxidized lipid accumulations during the lactation period. PMID- 26970393 TI - Hydroxytyrosol induces phase II detoxifying enzyme expression and effectively protects dopaminergic cells against dopamine- and 6-hydroxydopamine induced cytotoxicity. AB - Parkinson's disease (PD) is the second most common late-age onset neurodegenerative disease. Except for the symptomatic alleviating treatment, no disease modifying therapy is currently available. In this study, we investigated the potential neuroprotective role of hydroxytyrosol (HT), a major phenolic compound present in olive oil, against dopaminergic cell death. We found that HT effectively protected dopaminergic SH-SY5Y cells against dopamine (DA) and 6 hydroxydopamine (6-OHDA) induced cell death, but had no apparent effect on 1 methyl-4-phenylpyridinium (MPP(+))-induced cytotoxicity. Furthermore, we have shown that HT efficiently induced the expression of phase II detoxifying enzymes, including NAD(P)H quinone oxidoreductase 1 (NQO1). Using an NQO1 inhibitor, we revealed that increased NQO1 expression contributed to the protective effect of HT against dopaminergic cell death. Together, our findings suggest that HT has a protective effect against DA- and 6-OHDA-induced dopaminergic cell death, supporting the beneficial effect of olive oil in preventing DA-metabolism related dopaminergic neuron dysfunction. PMID- 26970394 TI - Multiple faces of protein interacting with C kinase 1 (PICK1): Structure, function, and diseases. AB - Protein interacting with C-kinase 1 (PICK1) has received considerable attention because it is the only protein that contains both PSD-95/DlgA/ZO-1 (PDZ) domain and Bin-Amphiphysin-Rvs (BAR) domain. Through PDZ and BAR domains, PICK1 binds to a large number of membrane proteins and lipid molecules, and is thereby of multiple functions. PICK1 is widely expressed in various tissues, particularly abundant in the brain and testis. In the central nervous system (CNS), PICK1 interacts with numerous neurotransmitters receptors, transporters, ion channels, and enzymes, and controls their trafficking. The best characterized function of PICK1 is that it regulates trafficking of alpha-amino-3-hydroxy-5-methylisoxazole 4-propionic acid receptor (AMPAR) subunit GluA2 during long-term depression and long-term potentiation. Recent evidence shows that PICK1 participates in various diseases including neurobiological disorders, such as chronic pain, epilepsy, oxidative stress, stroke, Parkinson's disease, amyotrophic lateral sclerosis, schizophrenia, and non-neurological disorders, such as globozoospermia, breast cancer, and heart failure. In this review, we will summarize recent advances focusing on the structure and regulation of PICK1 and its functions in protein trafficking, neurological and non-neurological diseases. PMID- 26970395 TI - Demethylation regulation of BDNF gene expression in dorsal root ganglion neurons is implicated in opioid-induced pain hypersensitivity in rats. AB - Repeated administration of morphine may result in opioid-induced hypersensitivity (OIH), which involves altered expression of numerous genes, including brain derived neurotrophic factor (BDNF) in dorsal root ganglion (DRG) neurons. Yet, it remains unclear how BDNF expression is increased in DRG neurons after repeated morphine treatment. DNA methylation is an important mechanism of epigenetic control of gene expression. In the current study, we hypothesized that the demethylation regulation of certain BDNF gene promoters in DRG neurons may contribute to the development of OIH. Real-time RT-PCR was used to assess changes in the mRNA transcription levels of major BDNF exons including exon I, II, IV, VI, as well as total BDNF mRNA in DRGs from rats after repeated morphine administration. The levels of exon IV and total BDNF mRNA were significantly upregulated by repeated morphine administration, as compared to that in saline control group. Further, ELISA array and immunocytochemistry study revealed a robust upregulation of BDNF protein expression in DRG neurons after repeated morphine exposure. Correspondingly, the methylation levels of BDNF exon IV promoter showed a significant downregulation by morphine treatment. Importantly, intrathecal administration of a BDNF antibody, but not control IgG, significantly inhibited mechanical hypersensitivity that developed in rats after repeated morphine treatment. Conversely, intrathecal administration of an inhibitor of DNA methylation, 5-aza-2'-deoxycytidine (5-aza-dC) markedly upregulated the BDNF protein expression in DRG neurons and enhanced the mechanical allodynia after repeated morphine exposure. Together, our findings suggest that demethylation regulation of BDNF gene promoter may be implicated in the development of OIH through epigenetic control of BDNF expression in DRG neurons. PMID- 26970396 TI - Crimean-Congo haemorrhagic fever in travellers: A systematic review. AB - BACKGROUND: The recent Ebola epidemic has increased public awareness of the risk of travel associated viral haemorrhagic fever (VHF). International preparedness to manage imported cases Ebola virus infection was inadequate, highlighted by cases of nosocomial transmission. Crimean-Congo haemorrhagic fever (CCHF) is a re emerging tick-borne VHF centred in the Eurasian region, affecting a large geographical area and with human-to-human transmission reported, especially in the healthcare setting. OBJECTIVES: To systematically review the characteristics of travel associated Crimean-Congo haemorrhagic fever. METHODS: A systematic review of travel-associated cases of CCHF was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol. PubMed, SCOPUS, Science Citation Index (SCI) and ProMED databases were searched for reports published between January 1960 and January 2016. Three independent reviewers selected and reviewed studies and extracted data. RESULTS: 21 cases of travel associated CCHF were identified, of which 12 died (3 outcome unknown) and 4 secondary (nosocomial) infections were reported. Risk occupations or activities for CCHF infection were reported in 8/12 cases when data were available. Travel from Asia to Asia occurred in 9 cases, Africa to Africa occurred in 5 cases, Africa to Europe in 3 cases, Asia to Europe in 2 cases and Europe to Europe in 2 cases. CONCLUSION: CCHF related to travel is rare, is generally associated with at risk activities/occupation and is frequently fatal. Key to early diagnosis and prevention of nosocomial transmission is an understanding of CCHF risk factors and the geographical distribution of CCHF. International travel to CCHF endemic areas is increasing and clinicians and laboratory personnel managing returning travellers should maintain a high index of suspicion. PMID- 26970397 TI - Meningococcal vaccination for international travellers from Greece visiting developing countries. AB - BACKGROUND: Meningococcal meningitis is a serious disease. Travel-associated infection for the general traveller is low; however regular epidemics in indigenous population, particularly in sub-Saharan Africa are responsible for significant morbidity and mortality. Our aim was to assess meningococcal vaccination for international travellers from Greece. METHODS: A prospective questionnaire-based study was conducted during 2009-2013. RESULTS: A total of 5283 travellers were studied (median age: 39.2 years); Meningococcal tetravalent vaccine (A,C,W135,Y) was delivered to 1150 (21.8%) of them. Of those who travelled to the Middle East and sub-Saharan Africa, 73.1% and 21.2% received meningococcal vaccine, respectively. Of those travellers who travelled to sub Saharan Africa from November to June and from July to October, 22.1% and 20.6% were vaccinated with meningococcal vaccine, respectively. Of all travellers who travelled for <1 month and >=1 month, 23.3%, and 20.5%, were vaccinated, respectively. Meningococcal vaccine was administered to 95.3% of pilgrims, 17.4% of those visiting friends and relatives (VFRs), 16.7% of those who travelled for recreation, and 13.8% of those who travelled for work. Of travellers who stayed in urban, in rural, and in urban and rural areas, 32%, 11.6% and 12.7% were vaccinated, respectively. Meningococcal vaccine was delivered to 29.2%, 21.1%, 19.4% and 5.1% of those who stayed in hotels, at local people's home, in camps, and on ships, respectively. The association of meningococcal vaccine administration with the destination, duration and purpose of travel, area of stay and type of accommodation was statistically significant. CONCLUSION: There is a need to improve meningococcal vaccine recommendations for travellers from Greece, particularly for high risk populations, such as VFRs, business travellers and those visiting sub-Saharan Africa especially during the dry season. PMID- 26970399 TI - Unprecedented Perovskite Oxyfluoride Membranes with High-Efficiency Oxygen Ion Transport Paths for Low-Temperature Oxygen Permeation. AB - Unprecedented perovskite oxyfluoride membranes, a new generation of mixed ionic electronic conducting (MIEC) membranes, feature extraordinary performance for low temperature oxygen permeation, which transcend the performance of state-of-the art MIEC membranes and fulfil commercial requirements. These results provide important progress for MIEC membranes and will potentially open the door to exploring high-performance MIEC compounds. PMID- 26970398 TI - Ciliochoroidal ganglioneuroma in neurofibromatosis type 1: Report of a case and review of the literature. AB - Orbitofacial neurofibromatosis (OFNF) is considered a variant of neurofibromatosis type 1 (NF1). OFNF most often affects the eye, orbit and one side of the face. It is characterized by the development of relatively aggressive and disfiguring lesions, including plexiform and diffuse neurofibromas. Ciliochoroidal ganglioneuromas have not been previously reported in patients with this syndrome. We report the case of a 50-year-old man with OFNF, ciliochoroidal ganglioneuroma and a large ipsilateral frontoethmoidal encephalocele. PMID- 26970401 TI - Telephone-Administered Interpersonal Psychotherapy by Nurse-Midwives for Postpartum Depression. AB - INTRODUCTION: Postpartum depression (PPD) affects 7% to 13% of childbearing women. Access to care may be limited by maternal time constraints and fears of being judged, labeled as mentally ill, and having their infants taken away. The study's objective was to test the feasibility, effectiveness, and acceptability of certified nurse-midwife telephone-administered interpersonal psychotherapy (CNM-IPT) as a treatment for PPD. METHODS: A prospective cohort study was conducted from 2010 to 2014. A sample of women meeting Diagnostic and Statistical Manual of Mental Disorders, Version 4, Text Revision (DSM-IV-TR) criteria for depression was recruited from 8 obstetric practices employing CNMs in the United States. Forty-one women in the treatment group received up to eight 50-minute CNM IPT sessions, and 20 in the control group were referred to mental health professionals. The main outcome measure was the Hamilton Rating Scale for Depression. Secondary outcomes included maternal and marital functioning, mother infant bonding, social support, and client satisfaction. RESULTS: The Hamilton Rating Scale for Depression at 8 and 12 weeks was significantly lower among women in the treatment group compared to the control group (Week 8, P = .047; Week 12, P = .029). Client satisfaction was high in both groups. While only 5 out of 8 CNM IPT counselors continued the intervention until the study's conclusion, CNM-IPT counselor protocol adherence was high. DISCUSSION: CNM-IPT is effective and acceptable as a method of reducing the severity of PPD symptoms. Careful assessment of CNM availability is critical to intervention feasibility. Future research is needed to evaluate translation of this intervention into practice. PMID- 26970400 TI - Are older people prescribed antidepressants on the basis of fewer symptoms of depression, and for longer periods of time? A survey of 1825 New Zealanders. AB - AIM: To determine whether older people are prescribed antidepressants at lower levels of depression and with fewer symptoms, and whether they are more likely to engage in chronic usage than younger adults. METHODS: An online survey about experiences with, and opinions about, depression and antidepressants was completed by 1825 New Zealand adults who had been prescribed antidepressants in the preceding five years. RESULTS: Participants over 55 were prescribed antidepressants with significantly fewer symptoms and were significantly less likely to meet DSM criteria for depression. They were also significantly more likely to have used the drugs for three years and still be using them. CONCLUSION: Prescribing physicians and their older patients might benefit from discussing the pros and cons of antidepressants (including the additional risk factors with this age group) and the alternatives. If prescription does occur, careful monitoring to avoid unnecessary, potentially damaging, long-term use is recommended. PMID- 26970403 TI - How can web-based training facilitate a more carer friendly practice in community based health and social care services in Norway? Staff experiences and implementation challenges. AB - It is a central feature of current Norwegian health and social care policy to see informal carers as active partners. However, research has revealed that carers often experience a lack of recognition by professionals. In 2010, the Norwegian Directorate of Health initiated a web-based competence-building programme (CBP) for health and social care practitioners aimed at facilitating collaboration with carers. The programme comprised case presentations, e-lectures, exercises and topics for discussion, and was introduced in 2012. It was flexible and free of charge. This article is based on a study (2012-2013) that followed the piloting of this CBP in four settings. The study aimed to explore factors that influenced the implementation of the programme and whether or not using it affected health and social care practitioners' attitudes and perceived capacity for collaboration with carers. The study employed a mixed-methods design. A questionnaire was distributed to all staff before and 5 months after the CBP was introduced, followed by focus group interviews with a sample of staff members and individual interviews with the leadership in the involved settings and those who introduced the programme. The quantitative data were analysed using descriptive statistics, which subsequently formed the basis for the focus group interviews. The qualitative data were analysed by means of content analysis. The programme's introduction was similar across all research settings. Nevertheless, whether or not it was adopted depended to a large extent on leadership commitment and engagement. In settings where the programme's use was monitored, supported by management and formed part of on-the-job training, there seemed to be a positive impact on staff attitudes concerning collaboration with carers. Participant staff reported that their awareness of, motivation for and confidence in collaboration with carers were all strengthened. In contrast, the programme was of minimal benefit in settings with low leadership engagement. PMID- 26970402 TI - Selective suppression of the human aryl hydrocarbon receptor function can be mediated through binding interference at the C-terminal half of the receptor. AB - The human aryl hydrocarbon receptor is a cytosolic signaling molecule which affects immune response and aberrant cell growth. Canonical signaling of the receptor requires the recruitment of coactivators to the promoter region to remodel local chromatin structure. We predicted that interference of this recruitment would block the aryl hydrocarbon receptor function. To prove that, we employed phage display to identify nine peptides of twelve-amino-acid in length which target the C-terminal half of the human aryl hydrocarbon receptor, including the region where coactivators bind. Eight 12mer peptides, in the form of GFP fusion, suppressed the ligand-dependent transcription of six AHR target genes (cyp1a1, cyp1a2, cyp1b1, ugt1a1, nqo1, and ahrr) in different patterns in Hep3B cells, whereas the AHR antagonist CH-223191 suppressed all these target genes similarly. Three of the 12mer peptides (namely 11-3, 1-7, and 7-3) suppressed the 3MC-induced, CYP1A1-dependent EROD activity and the ROS production caused by benzo[a]pyrene. These 12mer peptides suppressed the AHR function synergistically with CH-223191. In conclusion, we provide evidence that targeting the C-terminal half of the human aryl hydrocarbon receptor is a viable, new approach to selectively block the receptor function. PMID- 26970404 TI - Pharmacokinetic and Pharmacodynamic Modeling Analysis of Intravenous Esomeprazole in Healthy Volunteers. AB - Esomeprazole is one of the most commonly used drugs to treat gastroesophageal reflux disease and peptic ulcers, but the quantitative relationships among the pharmacokinetics (PK), pharmacodynamics (PD), and pharmacogenomics (PG) of the drug are not fully understood in special patient populations. A clinical PK/PD/PG study of intravenous (IV) esomeprazole in 5 dosing regimens was conducted in 20 healthy Chinese volunteers, who were categorized into Helicobacter pylori (HP) negative and HP-positive subgroups. Plasma esomeprazole concentration and intragastric H(+) concentration were monitored for 24 hours postdosing. Population PK (PopPK) models were tested based on elimination characteristics and other data. For a single-dose IV esomeprazole regimen, a 2-compartment model with nonlinear elimination characteristics fitted the PK data well. The elimination of esomeprazole was found to be significantly linked to CYP2C19 genotype by 11% to 29%. A mechanism-based PD model was first tested to mimic the irreversible inhibition of H(+) /K(+) -ATPase by esomeprazole using a cell-killing mechanism and models of gastric H(+) secretion that included the effects of an asymmetric circadian rhythm and food effects. Results from this PD model showed that the turnover rate of H(+) /K(+) -ATPase was significantly different between HP negative and HP-positive subgroups. In conclusion, the PopPK model quantitatively identified the effects of the CYP2C19 genotype on esomeprazole elimination in healthy subjects for the first time. In addition, the effects of HP status on drug effect, H(+) /K(+) -ATPase turnover, and circadian rhythm amplitude were preliminarily explored using a mechanism-based PD model. PMID- 26970405 TI - Advances in Chemistry and Bioactivity of the Genus Chisocheton Blume. AB - Chisocheton is one of the genera of the family Meliaceae and consists of ca. 53 species; the distribution of most of those are confined to the Indo-Malay region. Species of broader geographic distribution have undergone extensive phytochemical investigations. Previous phytochemical investigations of this genus resulted in the isolation of mainly limonoids, apotirucallane, tirucallane, and dammarane triterpenes. Reported bioactivities of the isolated compounds include cytotoxic, anti-inflammatory, antifungal, antimalarial, antimycobacterial, antifeedant, and lipid droplet inhibitory activities. Aside from chemistry and biological activities, this review also deals briefly with botany, distribution, and uses of various species of this genus. PMID- 26970406 TI - Successful treatment with foscarnet for ganciclovir-resistant cytomegalovirus infection in a kidney transplant recipient: A case report. AB - Cytomegalovirus (CMV) infection is the most common infectious complication following solid organ transplantation. Ganciclovir (GCV)-resistant CMV infection may be fatal, and is difficult to treat while avoiding allograft rejection. A 31 year-old woman received a second ABO-incompatible kidney transplant, from her father. Induction therapy consisted of basiliximab and rituximab followed by maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and methylprednisolone. Her CMV serostatus was D(+) /R(-) at second transplant and she received prophylactic low-dose valganciclovir (VGCV). BK polyoma virus nephropathy (BKVN) developed 7 months after transplant concurrent with CMV hepatitis and retinitis. VGCV was increased to a therapeutic dose combined with reduced immunosuppression with minimal methylprednisolone (2 mg/day) and everolimus (0.5 mg/day). However, pp65 antigenaemia continued to increase for 6 weeks. Her CMV was defined as ganciclovir (GCV)-resistant. Foscarnet was therefore administered and her CMV disease resolved within 2 weeks. Kidney allograft dysfunction developed 9 months after transplant, and graft biopsy showed tubulointerstitial injury with crystal deposition suggesting foscarnet nephrotoxicity, with no findings of BKVN or rejection. Kidney function recovered after cessation of foscarnet and the patient had good graft function 18 months after transplant. This case demonstrates the successful use of foscarnet to treat GCV-resistant CMV infection after ABO-incompatible kidney transplant complicated with BKVN, without acute allograft rejection. This case further highlights the need to establish appropriate management for CMV D(+) /R(-) patients to avoid the acquisition of GCV-resistant gene mutations. PMID- 26970407 TI - Perceived efficacy of salbutamol by persons with spinal muscular atrophy: A mixed methods study. AB - INTRODUCTION: The aim of this study was to assess the perceived effect of salbutamol in adult patients with spinal muscular atrophy and to evaluate the usefulness of the World Health Organization Disability Assessment Schedule II (WHODAS II) and Fatigue Severity Scale (FSS) for its measurement. METHODS: A longitudinal mixed methods study was performed. Ten patients were interviewed and completed WHODAS II and FSS questionnaires to assess disability and fatigue at 2 time-points. Inductive thematic analysis was used for qualitative data. The non parametric Wilcoxon test was performed for quantitative analysis. RESULTS: All participants reported an improvement in their condition after salbutamol consumption. WHODAS II and FSS reliably captured changes in patients' disability and fatigue. CONCLUSIONS: The mixed methods design allowed us to identify the functional domains in which participants experienced effects of salbutamol. Patients were satisfied with the treatment as shown by decreased fatigue, improved functioning, and infrequent side effects. Muscle Nerve, 2016 Muscle Nerve 54: 843-849, 2016. PMID- 26970409 TI - Response to Khan MK. PMID- 26970408 TI - Impact of HIV infection on the haemostatic response during sepsis and malaria. AB - Patients positive for the human immunodeficiency virus (HIV) are more susceptible to sepsis and malaria, two conditions known to activate the coagulation system. As chronic HIV infection also influences haemostatic mechanisms, we determined the influence of HIV co-infection on coagulation, anticoagulation and the endothelium during sepsis or malaria. We performed a prospective observational study in 325 subjects with or without HIV infection (103 with sepsis, 127 with malaria and 95 asymptomatic controls) in an HIV endemic area in Central Africa. We measured plasma biomarkers indicative of activation of distinct haemostatic mechanisms. Sepsis and malaria had similar effects with elevated markers of coagulation, reduced anticoagulation markers and activation of endothelium. In particular, asymptomatic HIV infection reduced the plasma levels of the anticoagulant co-factor free protein S, and increased activation of the vascular endothelium, which were not normalized by combination antiretroviral therapy. HIV co-infection during sepsis and malaria caused more profound changes in free protein S and von Willebrand factor in sepsis and malaria, and ADAMTS13 in sepsis, while not influencing sepsis- or malaria-induced coagulation activation. These results show for the first time that HIV infection augments selective haemostatic changes during sepsis and malaria, which may contribute to the enhanced morbidity of these conditions in HIV patients. PMID- 26970410 TI - An Exploration of Costs of Community-Based Specialist Health Service Provision for the Management of Aggressive Behaviour in Adults with Intellectual Disabilities. AB - BACKGROUND: In the UK, people with intellectual disabilities who exhibit aggressive behaviour often receive community-based specialist health services from a community learning disability team (CLDT). Our aim was to estimate costs associated with this provision and to identify predictors of higher costs. METHOD: Costs were estimated for 60 adults with intellectual disabilities and aggressive behaviour who attended specialist psychiatric outpatient clinics in the West Midlands region of the UK, including contact time with members of the CLDT and use of psychotropic medication over a 12-month period. RESULTS: Mean total cost of 12-month service provision was L418 (95% confidence interval [CI] L299-557). Mean total cost of 12-month psychotropic medication was L369 (95% CI L256-492). Amongst individual members of the CLDT, mean costs were highest for psychiatrists (L181) and relatively lower for community nurses (L70) and clinical psychologists (L30), and lowest for physiotherapists (L13). Male sex, presence of expressive verbal communication and presence of epilepsy were independently associated with 12-month medication and service use costs, accounting for 23% of the variance in cost. CONCLUSIONS: It seems that in terms of costs, there is an overreliance on medication and psychiatrists and a relatively lesser reliance on other CLDT members such as community nurses and clinical psychologists for the management of aggressive behaviour in adults with intellectual disabilities within community settings. Health commissioners may wish to explore this relative cost discrepancy further and try to redress the balance where appropriate. PMID- 26970411 TI - Articular cartilage calcification of the humeral head is highly prevalent and associated with osteoarthritis in the general population. AB - Articular cartilage calcification is considered a pathological albeit incompletely understood process which is known to be associated with osteoarthritis of the knee and hip. The goal of this study was to determine the prevalence of articular cartilage calcification of the shoulder as a non-weight bearing joint and to analyze the interrelationship of calcification with age and histological severity of shoulder osteoarthritis in the general population. In a cross-sectional study of 180 humeral heads from 90 donors (n = 49 male, n = 41 female; mean age 62.7 years [20-93]), cartilage calcification of the humeral head was quantified by digital contact radiography (DCR). Histological OA grade (OARSI) was determined and structural equation modeling (SEM) was used to analyze the interrelationship of cartilage calcification, OARSI and age. The prevalence of articular cartilage calcification was 98.9% (95%CI: [93.96%, 99.97%]) and was independent of gender (p = 0.55). Cartilage calcification of one shoulder correlated significantly with that of the contralateral side (r = 0.61, 95%CI: [0.46, 0.73], p < 0.001). SEM demonstrated significant associations between histological OA grade and cartilage calcification (r = 0.55, p = 0.039), between histological OA grade and age (beta = 0.59, p < 0.001) but not between age and cartilage calcification (beta = 0.24, p = 0.116). In conclusion, the prevalence of shoulder cartilage calcification in the general population is higher than anticipated. The high prevalence, its concomitant bilateral manifestation and the association between the amount of cartilage calcification and OA severity, but not age, suggest that cartilage calcification is a systemically driven process with early onset in life and may be a causative factor in the pathogenesis of OA. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1984-1990, 2016. PMID- 26970412 TI - Controllable Encapsulation of "Clean" Metal Clusters within MOFs through Kinetic Modulation: Towards Advanced Heterogeneous Nanocatalysts. AB - Surfactant-free tiny Pt clusters were successfully encapsulated within MOFs with controllable size and spatial distribution by a novel kinetically modulated one step strategy. Our synthesis relies on the rational manipulation of the reduction rate of Pt ions and/or the growth rate of MOFs by using H2 as assistant reducing agent and/or acetic acid as MOF-formation modulator. The as-prepared Pt@MOF core shell composites exhibited exceedingly high activity and excellent selectivity in the oxidation of alcohols as a result of the ultrafine "clean" Pt clusters, as well as interesting molecular-sieving effects derived from the outer platinum free MOF shell. PMID- 26970414 TI - A Narrow QRS Tachycardia-What Is the Diagnosis? PMID- 26970416 TI - Preparation and structural characterization of corn starch-aroma compound inclusion complexes. AB - BACKGROUND: Six corn starch inclusion complexes were synthesized using small nonpolar or weak polar aroma compounds (heptanolide, carvone and menthone) and small polar aroma compounds (linalool, heptanol and menthol). The objectives of this study were to (a) investigate the ability of corn starch to form inclusion complexes with these aroma compounds and (b) characterize the structure of the corn starch inclusion complexes. RESULTS: The resulting inclusion ratios were 75.6, 36.9, 43.8, 91.9, 67.2 and 54.7% for heptanolide, carvone, menthone, linalool, heptanol and menthol respectively. The inclusion complexes had laminated structures with a certain amount of holes or blocky constructions. Compared with gelatinized corn starch, the transition temperatures, peak temperatures and enthalpies of the inclusion complexes were significantly different. The major peak of C?O at 1771 cm-1 and significant peak shifts revealed the formation of inclusion complexes. X-ray diffractometry (XRD) analyses revealed that the crystallinity of corn starch-polar aroma compound inclusion complexes increased. Based on cross-polarization magic angle spinning 13 C nuclear magnetic resonance (CP-MAS 13 C NMR) results, novel peaks and chemical shifts were attributed to the presence of small aroma compounds, thereby confirming the formation of corn starch inclusion complexes. CONCLUSION: Small nonpolar and polar aroma compounds can be complexed to corn starch. (c) 2016 Society of Chemical Industry. PMID- 26970415 TI - Development and Validation of a Disease-Specific Questionnaire to Assess Patient Reported Symptoms in Polycystic Liver Disease. AB - Treatment of polycystic liver disease (PLD) focuses on symptom improvement. Generic questionnaires lack sensitivity to capture PLD-related symptoms, a prerequisite to determine effectiveness of therapy. We developed and validated a disease-specific questionnaire that assesses symptoms in PLD (PLD-Q). We identified 16 PLD-related symptoms (total score 0-100 points) by literature review and interviews with patients and clinicians. The developed PLD-Q was validated in Dutch (n = 200) and United States (US; n = 203) PLD patients. We assessed the correlation of PLD-Q total score with European Organization for Research and Treatment of Cancer (EORTC) symptom scale, global health visual analogue scale (VAS) of EQ-5D, and liver volume. To test discriminative validity, we compared PLD-Q total scores of patients with different PLD severity stages (Gigot classification) and PLD-Q total scores of PLD patients with general controls and polycystic kidney disease patients without PLD. Reproducibility was tested by comparing original test scores with 2-week retest scores. In total, 167 Dutch and 124 US patients returned the questionnaire. Correlation between PLD-Q total score and EORTC symptom scale (The Netherlands [NL], r = 0.788; US, r = 0.811) and global health VAS (NL, r = -0.517; US, r = -0.593) was good. There was no correlation of PLD-Q total score with liver volume (NL, r = 0.138; P = 0.236; US, r = 0.254; P = 0.052). Gigot type III individuals scored numerically higher than type II patients (NL, 46 vs. 40; P = 0.089; US, 48 vs. 36; P = 0.055). PLD patients scored higher on the PLD-Q total score than general controls (NL, 42 vs. 17; US, 40 vs. 13 points) and polycystic kidney disease patients without PLD (22 points). Reproducibility of PLD-Q was excellent (NL, r = 0.94; US, 0.96). CONCLUSION: PLD-Q is a valid, reproducible, and sensitive disease-specific questionnaire that can be used to assess PLD-related symptoms in clinical care and future research. (Hepatology 2016;64:151-160). PMID- 26970417 TI - Phospholamban p.Arg14del cardiomyopathy is characterized by phospholamban aggregates, aggresomes, and autophagic degradation. AB - AIMS: The non-desmosomal phospholamban PLN p.Arg14del mutation was identified in patients diagnosed with dilated cardiomyopathy (DCM) and/or arrhythmogenic cardiomyopathy (ACM). We aimed to investigate whether this mutation leads to aggregation, aggresome formation and autophagy of mutant PLN protein. METHODS AND RESULTS: We studied 20 complete heart specimens of PLN p.Arg14del mutation carriers [mean age 48 +/- 15 years; 55% males], either from autopsies or from explants. Gross and microscopic examination showed biventricular cardiomyopathy with histopathological features of both ACM and DCM, i.e. a combination of fibrofatty replacement and interstitial fibrosis. Immunohistochemistry for PLN showed large perinuclear PLN protein aggregates in cardiomyocytes in both ventricles in all examined hearts. The median numbers of PLN-containing aggregates were 12 per 5 mm(2) range 3-48 mm2 in right ventricular myocardium and 13 per 5 mm(2) (range 5-89 mm(2) ) in left ventricular myocardium. Double immunohistochemical staining showed colocalization of autophagy markers p62 (sequestosome-1) and microtubule-associated protein light chain 3 with PLN in all aggregates, suggestive of degradation by selective autophagy. On electron microscopy, the ultrastructural appearance of these PLN-containing aggregates was typical of aggresomes; they were not surrounded by a membrane, and were located adjacent to the microtubular organizing centre. PLN-containing aggregates were not found in 10 PLN-negative cases of idiopathic and genetic DCM or in seven cases of desmosomal ACM. CONCLUSIONS: PLN p.Arg14del cardiomyopathy is a biventricular cardiomyopathy characterized by large perinuclear PLN protein aggregates with a typical ultrastructural appearance of aggresomes. PLN detected by immunohistochemistry appears to be a sensitive and specific marker for this disease. PMID- 26970418 TI - Why attend a memory clinic? What do patients and their families want and/or expect? AB - OBJECTIVE: To explore which symptoms led people to seek a memory clinic assessment and what they wanted and expected from that assessment. Did the patient and family want and/or expect diagnostic disclosure and, if so, why? METHODS: Patients scheduled for memory clinic appoint-ments received two questionnaires by post prior to clinic attendance - one for the patient, one for the next-of- kin - regarding symptomatology, wants, expectations and rationale. RESULTS: Ninety-two per cent of patients (n = 47) and 88% (n = 43) of next-of-kin wanted the patient to be informed of the diagnosis; 84% (n = 43) of patients and 86% (n = 42) of next-of-kin expected the patient to be informed. Rationales for diagnostic disclosure were categorised under themes of planning, treatment, information, coping strategies and rights. CONCLUSIONS: Patients and families want diagnostic disclosure in order to plan, receive treatment, receive help and learn strategies to cope. This knowledge is seen as the patient's right. PMID- 26970419 TI - Repeated Blood Cultures in Pediatric Febrile Neutropenia: Would Following the Guidelines Alter the Outcome? AB - BACKGROUND: The Infectious Diseases Society of America (IDSA) guidelines recommend collecting blood cultures for the first 3 days of febrile neutropenia (FN) in the clinically stable oncology patient with persistent fevers. Nonetheless, many physicians send daily blood cultures beyond 3 days, and the impact of that practice is uncertain. PROCEDURE: We reviewed pediatric FN episodes from July 2009 to May 2014 at University of Chicago Comer Children's Hospital. For each positive culture, we determined if it was a pathogen or a contaminant. We reviewed episode and patient demographics to identify risk factors for subsequent positive blood cultures in the setting of an initially negative culture. RESULTS: We identified 381 episodes of FN in 162 patients. Of those, 87 had a positive blood culture on day 1 (21.0% incidence of bacteremia). Of 294 episodes with a negative blood culture on day 1, six (2.04%, 95% confidence interval [CI] 0.42-3.67) had a positive culture after day 3. Of those, three were pathogens (1.02%, 95%CI -0.14 to 2.18), and only one was found in a hemodynamically stable patient (0.34%, 95%CI -0.33 to 1.01) with new mucositis. In the other two patients, Escherichia coli was isolated from blood cultures after day 10 in the setting of significant hemodynamic changes. Risk factor analysis performed in stable patients yielded nonsignificant results. CONCLUSIONS: Of 294 FN episodes with an initial negative blood culture, only one episode of bacteremia occurred without hemodynamic changes past day 3, supporting the IDSA guidelines to discontinue blood cultures in stable FN patients after day 3. PMID- 26970420 TI - Enhancing the provision of health and social care in Europe through eHealth. AB - AIM: To report on the outcomes of the European project ENS4Care, which delivered evidence-based guidelines enabling implementation of eHealth services in nursing and social care. BACKGROUND: Within a policy context of efficiency, safety and quality in health care, this project brought together a diverse group of stakeholders from academia, industry, patient and professional organizations to lead the development of five eHealth guidelines in the areas of prevention, clinical practice, integrated care, advanced roles and nurse ePrescribing. SOURCES OF EVIDENCE: Data were collected through a cross-sectional, online, questionnaire survey of health professionals from 21 countries. Quantitative data were analysed using descriptive and summary statistics, while comments to open questions underwent a process of content analysis. DISCUSSION: Representing an evidence-based consensus statement, the five guidelines outline key steps and considerations for the deployment of eHealth services at different levels of enablement. Through analysis of the data, and sharing of best practices, common deployment processes and implementation lessons were identified. CONCLUSION: Findings reveal the richness, diversity and potential that eHealth holds for enabling the delivery of safer, more efficient and patient-centred health care. Nurses and social care workers as the main proprietors of such practices hold the key to a healthier future for citizens across Europe. IMPLICATIONS FOR NURSING AND HEALTH POLICY: The preparation, agreement and dissemination of the ENS4Care guidelines will enable European Union leaders to diagnose the organizational changes needed and prescribe the development of new skills and roles in the workforce to meet the challenge of eHealth. Nurses and social care workers, with the right knowledge and skills will add considerable value and form an important link between technological innovation, health promotion and disease prevention. PMID- 26970421 TI - Hot topic: PNKP mutations cause ataxia with oculomotor apraxia type 4. PMID- 26970422 TI - Primary cutaneous anaplastic large-cell lymphoma: a case report. AB - Primary cutaneous anaplastic large-cell lymphoma (PCALCL) is a part of the spectrum of CD30+ lymphoproliferative cutaneous processes. The characteristics include single or multifocal nodules that ulcerate as skin lesion, slow disease progression, autoregressive, and recurrent in few years. The present study report the case of a 16-year-old boy presenting PCALCL with single nodules, ulcer, keloid, and scab in his right-side face. He showed a good response to the treatment with systemic chemotherapy and dermatoplasty, and regained confidence after the appearance of recovery. There is no relapse of the primary lesion and organs involved till now. The chemotherapy combining with surgical excision and dermatoplasty is a good method for PCALCL, per the lesion biopsy and positron emission tomography-computed tomography before and after treatment. PMID- 26970423 TI - Rapid amplification of the RM-Yplex assay. AB - A multiplex PCR assay consisting of 13 Rapidly Mutating Y STR loci called RM Yplex was previously developed. Platinum(r) Taq DNA polymerase was used to amplify the 13 Y STR loci in a single reaction at an amplification time of approximately 2.5 h. In order to shorten the process with reliable results, two DNA polymerases were tested with the multiplex. Phusion(r) Flash High Fidelity, TAKARA Z-taqTM , and Platinum(r) Taq DNA polymerases were investigated for conducting RM-Yplex assay at various PCR cycling conditions. Rapid, robust, and efficient amplification of all the markers within the multiplex were achieved. The amplification time was reduced from 2.5 h to less than 28 min with Phusion(r) Flash High Fidelity DNA polymerase using Veriti(r) PCR thermal cycler. PMID- 26970424 TI - Comparison of amplitude-mode ultrasound versus air displacement plethysmography for assessing body composition changes following participation in a structured weight-loss programme in women. AB - The purpose of this study was to compare body composition changes as measured by A-mode ultrasound (US) versus a criterion densitometry-based measure, air displacement plethysmography (ADP), over a 4-week weight-loss protocol in healthy, non-obese young women. Twenty healthy, young female volunteers were provided with customized dietary plans for the length of the study intended to facilitate a 500 calorie-a-day deficit. Subjects also performed 3 h a week of supervised aerobic exercise. Per cent fat mass and lean body mass were obtained via ADP and US both pre- and postintervention. Pretesting, post-testing and delta data for %fat resulted in no significant differences in mean values along with a slope of the regression line no different than one and a y-intercept no different than zero (P<0.05). Similar to %fat values, pretesting, post-testing and delta data for fat-free mass resulted in no significant differences in mean values along with a slope of the regression line no different than one and a y-intercept no different than zero (P<0.05) with the exception of the delta for slope (0.39, P = 0.04). The current findings indicate that US can provide a similar degree of accuracy for tracking group-based fat loss in women compared to ADP. Given the low-cost relative to DXA and ADP, researchers and practitioners therefore can consider US as a viable option for monitoring group-based changes in body fat over time. PMID- 26970425 TI - Clinicopathological study of crateriform verruca: Crateriform epithelial lesions histopathologically distinct from keratoacanthoma. AB - Keratoacanthoma (KA) is a distinct clinicopathological entity, but it is often confused with other crateriform tumors. This study re-examined the clinicopathological features of 380 crateriform epithelial tumors with a central keratin plug. Seventy-six tumors (20%) had histopathological features that differed from solitary KA and were more verruca-like, and we designated these lesions as crateriform verruca (CFV). We performed clinicopathological re examination of these neoplasms with a crateriform architecture and epithelial lip like structures similar to KA, which also displayed histopathological features reminiscent of verruca vulgaris, such as finger-like exophytic projections with hyperkeratosis and acanthosis, focal hypergranulosis and arborization. Clinical data on CFV were also summarized. The main histopathological differences from KA were that CFV showed proliferation of keratinocytes with a similar size and regular arrangement, and the base of CFV was well demarcated without endophytic growth. Interestingly, some CFV were partly composed of epithelial cells with large pink cytoplasm in the upper malpighian layer between papillomatous projections. Furthermore, areas of trichilemmal-like keratinization without formation of the granular layer were seen in some lesions. These types of CFV were hardly distinguishable from KA, unless it is recognized that CFV may contain trichilemmal keratinization-like areas accompanied by large epithelial cells with eosinophilic cytoplasm. We have proposed the term CFV for these verrucous neoplasms to differentiate them from KA. PMID- 26970426 TI - Comparison of the psychometric properties of four dementia knowledge measures: Which test should be used with dementia care staff? AB - OBJECTIVE: To compare the psychometric properties of four measures of dementia institutional knowledge. METHODS: Fifty-eight dementia care staff completed the Dementia Knowledge Assessment Tool Version Two (DKAT2), Alzheimer's Disease Knowledge Test (ADKT), Alzheimer's Disease Knowledge Scale (ADKS) and Dementia Knowledge Twenty (DK-20). The convergent validity and reliability of each measure were examined. RESULTS: The level of dementia knowledge in this sample was similar to that reported in comparable surveys. The ADKT, DKAT-2 and DK-20 had marginal to acceptable internal consistency (alpha >= 0.67), and the ADKT, DK-20 and ADKS were positively correlated with each other (r's = 0.45-0.60), demonstrating convergent validity. The DKAT2 had lower intercorrelations with the other measures (r's = 0.32-0.45). The ADKS had poor internal consistency (alpha = 0.29). CONCLUSION: As the first head-to-head comparison of these tests in a single sample, this study should assist clinicians and researchers to select a dementia knowledge test. PMID- 26970428 TI - Electrophilic Activation of alpha,beta-Unsaturated Amides: Catalytic Asymmetric Vinylogous Conjugate Addition of Unsaturated gamma-Butyrolactones. AB - Although catalytic asymmetric conjugate addition reactions have remarkably advanced over the last two decades, the application of less electrophilic alpha,beta-unsaturated carboxylic acid derivatives in this useful reaction manifold remains challenging. Herein, we report that alpha,beta-unsaturated 7 azaindoline amides act as reactive electrophiles to participate in catalytic diastereo- and enantioselective vinylogous conjugate addition of gamma butyrolactones in the presence of a cooperative catalyst comprising of a soft Lewis acid and a Bronsted base. Reactions mostly reached completion with as little as 1 mol % of catalyst loading to give the desired conjugate adducts in a highly stereoselective manner. PMID- 26970427 TI - The severity of acute bronchiolitis in infants was associated with quality of life nine months later. AB - AIM: Acute bronchiolitis in infancy increases the risk of later asthma and reduced health-related quality of life (QoL). We aimed to see whether the severity of acute bronchiolitis in the first year of life was associated with QoL nine months later. METHODS: The parents of 209 of 404 of children hospitalised for acute bronchiolitis in eight paediatric departments in south-east Norway at a mean four months of age (range 0-12 months) completed the Infant/Toddler Quality of Life Questionnaire sent by mail nine months after the acute illness. Disease severity was measured by length of stay and the need for supportive treatment. Interactions with gender, inclusion age, prematurity, maternal ethnicity and maternal education were examined. RESULTS: Reduced QoL in four domains was associated with increased length of stay and need for ventilatory support. Physical abilities and general health were associated with both severity markers, whereas bodily pain and discomfort and change in health were associated with length of stay. Ventilatory support was more negatively associated with QoL than atopic eczema and also associated with reduced parental emotions and parental time. CONCLUSION: The severity of acute bronchiolitis in infants was associated with reduced QoL nine months later. PMID- 26970429 TI - Paper or Plastic? Exploring the Effects of Natural Enrichment on Behavioural and Neuroendocrine Responses in Long-Evans Rats. AB - Enriched environments are beneficial to neurobiological development; specifically, rodents exposed to complex, rather than standard laboratory, environments exhibit evidence of neuroplasticity and enhanced cognitive performance. In the present study, the nature of elements placed in the complex environment was investigated. Accordingly, rats (n = 8 per group) were housed either in a natural environment characterised by stimuli such as dirt and rocks, an artificial environment characterised by plastic toys and synthetic nesting materials, a natural/artificial environment characterised by a combination of artificial and natural stimuli or a laboratory standard environment characterised by no enrichment stimuli. Following exposure to emotional and cognitive behavioural tasks, including a cricket hunting task, a novel object preference task and a forced swim task, brains were processed for glial fibrillary acidic protein (GFAP)-, neuronal nuclei (NeuN)- and brain-derived neurotrophic factor (BDNF) immunoreactivity. Baseline and stress foecal samples were collected to assess corticosterone (CORT) and dehydroepiandrosterone (DHEA). Natural environment animals exhibited shorter diving latencies and increased diving frequencies in the second forced swimming task, along with higher DHEA/CORT ratios, and higher GFAP immunoreactivity in the hippocampus. The type of environmental enrichment did not influence levels of BDNF immunoreactivity in the CA1, CA3 and dentate gyrus of the hippocampus; however, natural environment animals exhibited higher levels of NeuN immunoreactivity in the retrosplenial cortex, an area involved in spatial memory and other cognitive functions. These results suggest that, in addition to enhancing behavioural and endocrinological variables associated with resilience, exposure to natural stimuli might alter plasticity in brain areas associated with cortical processing and learning. PMID- 26970430 TI - Expression of key glycosphingolipid biosynthesis-globo series pathway genes in Escherichia coli F18-resistant and Escherichia coli F18-sensitive piglets. AB - A pioneering study showed that the glycosphingolipid biosynthesis-globo series pathway genes (FUT1, FUT2, ST3GAL1, HEXA, HEXB, B3GALNT1 and NAGA) may play an important regulatory role in resistance to Escherichia coli F18 in piglets. Therefore, we analysed differential gene expression in 11 tissues of two populations of piglets sensitive and resistant respectively to E. coli F18 and the correlation of differential gene expression in duodenal and jejunal tissues. We found that the mRNA expression of the seven genes was relatively high in spleen, liver, lung, kidney, stomach and intestinal tract; the levels in thymus and lymph nodes were lower, with the lowest levels in heart and muscle. FUT2 gene expression in the duodenum and jejunum of the resistant population was significantly lower than that in the sensitive group (P < 0.01). ST3GAL1 gene expression was also significantly lower in the duodenum of the resistant population than in the sensitive group (P < 0.05). No significant differences were observed among the remaining genes. The expression level of FUT1 was extremely significantly positively correlated with FUT2 and B3GALNT1 expression (P < 0.01) and also had a significant positive correlation with NAGA expression (P < 0.05). The expression level of FUT2 had extremely significant positive correlations with FUT1, ST3GAL1 and B3GALNT1 (P < 0.01). These results suggest that FUT2 plays an important role in E. coli F18 resistance in piglets. FUT1, ST3GAL1, B3GALNT1 and NAGA may also participate in the mechanism of resistance to E. coli F18. PMID- 26970431 TI - Drug allergies documented in electronic health records of a large healthcare system. AB - BACKGROUND: The prevalence of drug allergies documented in electronic health records (EHRs) of large patient populations is understudied. OBJECTIVE: We aimed to describe the prevalence of common drug allergies and patient characteristics documented in EHRs of a large healthcare network over the last two decades. METHODS: Drug allergy data were obtained from EHRs of patients who visited two large tertiary care hospitals in Boston from 1990 to 2013. The prevalence of each drug and drug class was calculated and compared by sex and race/ethnicity. The number of allergies per patient was calculated and the frequency of patients having 1, 2, 3..., or 10+ drug allergies was reported. We also conducted a trend analysis by comparing the proportion of each allergy to the total number of drug allergies over time. RESULTS: Among 1 766 328 patients, 35.5% of patients had at least one reported drug allergy with an average of 1.95 drug allergies per patient. The most commonly reported drug allergies in this population were to penicillins (12.8%), sulfonamide antibiotics (7.4%), opiates (6.8%), and nonsteroidal anti-inflammatory drugs (NSAIDs) (3.5%). The relative proportion of allergies to angiotensin-converting enzyme (ACE) inhibitors and HMG CoA reductase inhibitors (statins) have more than doubled since early 2000s. Drug allergies were most prevalent among females and white patients except for NSAIDs, ACE inhibitors, and thiazide diuretics, which were more prevalent in black patients. CONCLUSION: Females and white patients may be more likely to experience a reaction from common medications. An increase in reported allergies to ACE inhibitors and statins is noteworthy. PMID- 26970432 TI - A win ratio approach to comparing continuous non-normal outcomes in clinical trials. AB - Clinical trials are often designed to compare continuous non-normal outcomes. The conventional statistical method for such a comparison is a non-parametric Mann Whitney test, which provides a P-value for testing the hypothesis that the distributions of both treatment groups are identical, but does not provide a simple and straightforward estimate of treatment effect. For that, Hodges and Lehmann proposed estimating the shift parameter between two populations and its confidence interval (CI). However, such a shift parameter does not have a straightforward interpretation, and its CI contains zero in some cases when Mann Whitney test produces a significant result. To overcome the aforementioned problems, we introduce the use of the win ratio for analysing such data. Patients in the new and control treatment are formed into all possible pairs. For each pair, the new treatment patient is labelled a 'winner' or a 'loser' if it is known who had the more favourable outcome. The win ratio is the total number of winners divided by the total numbers of losers. A 95% CI for the win ratio can be obtained using the bootstrap method. Statistical properties of the win ratio statistic are investigated using two real trial data sets and six simulation studies. Results show that the win ratio method has about the same power as the Mann-Whitney method. We recommend the use of the win ratio method for estimating the treatment effect (and CI) and the Mann-Whitney method for calculating the P value for comparing continuous non-Normal outcomes when the amount of tied pairs is small. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26970433 TI - Aging and autism spectrum disorder: Evidence from the broad autism phenotype. AB - This study investigated for the first time the broad autism phenotype (BAP) in the context of older adulthood and its associations with real-world executive function, social support, and both depression and anxiety symptomatology. Based on self-ratings of autistic traits, 66 older adults (60+ years old, range = 61 88) were split into BAP (n = 20) and control (n = 46) groups. Individuals in the BAP group, even after controlling for age, education level, sex, and health problems, exhibited more real-world executive function problems in multiple domains, reported lower levels of social support, and self-rated increased depression and anxiety symptomatology compared to the control group. Regression analysis revealed that level of social support was the strongest predictor of BAP traits across both groups, although real-world executive function problems and depression symptomatology were also significant predictors. Moreover, when predicting anxiety and depression symptomatology, BAP traits were the strongest predictors above and beyond the effects of demographic factors, real-world executive function problems, and social support levels. These findings suggest that the BAP in older adulthood imparts additional risks to areas of functioning that are known to be crucial to aging-related outcomes in the context of typical development. These results might in turn inform aging in autism spectrum disorder, which has been largely unexplored to date. Autism Res 2016, 9: 1294 1303. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26970435 TI - Mining metagenomic whole genome sequences revealed subdominant but constant Lactobacillus population in the human gut microbiota. AB - The genus Lactobacillus includes over 215 species that colonize plants, foods, sewage, and the gastrointestinal tract (GIT) of humans and animals. In the GIT, Lactobacillus population can be made by true inhabitants or by bacteria occasionally ingested with fermented or spoiled foods, or with probiotics. This study longitudinally surveyed Lactobacillus species and strains in the feces of a healthy subject through whole genome sequencing (WGS) data-mining, in order to identify members of the permanent or transient populations. In three time-points (0, 670 and 700 d), 58 different species were identified, 16 of them being retrieved for the first time in human feces. L. rhamnosus, L. ruminis, L. delbrueckii, L. plantarum, L. casei, and L. acidophilus were the most represented, with estimated amounts ranging between 6 and 8 Log (cells g-1 ), while the other were detected at 4 or 5 Log (cells g-1 ). 86 Lactobacillus strains belonging to 52 species were identified. 43 seemingly occupied the GIT as true residents, since were detected in a time span of almost 2 years in all the three samples or in 2 samples separated by 670 or 700 d. As a whole, a stable community of lactobacilli was disclosed, with wide and understudied biodiversity. This article is protected by copyright. All rights reserved. PMID- 26970436 TI - Circulating makorin ring-finger protein-3 (MKRN3) levels in healthy men and in men with hypogonadotropic hypogonadism. PMID- 26970434 TI - Web-based collaborative care intervention to manage cancer-related symptoms in the palliative care setting. AB - BACKGROUND: The aim of this study was to examine the efficacy of a collaborative care intervention in reducing depression, pain, and fatigue and improve quality of life. METHODS: A total of 261 patients with advanced cancer and 179 family caregivers were randomized to a web-based collaborative care intervention or enhanced usual care. The intervention included the following: 1) a web site with written and audiovisual self-management strategies, a bulletin board, and other resources; 2) visits with a care coordinator during a physician's appointment every 2 months; and 3) telephone follow-up every 2 weeks. Primary patient outcomes included measures of depression, pain, fatigue, and health-related quality of life. Secondary outcomes included Interleukin (IL)-1alpha, IL-1beta, IL-6, and IL-8 levels, Natural Killer (NK) cell numbers, and caregiver stress and depression. RESULTS: At the baseline, 51% of the patients reported 1 or more symptoms in the clinical range. For patients who presented with clinical levels of symptoms and were randomized to the intervention, reductions in depression (Cohen's d = 0.71), pain (Cohen's d = 0.62), and fatigue (Cohen's d = 0.26) and improvements in quality of life (Cohen's d = 0.99) were observed when compared to those in the enhanced usual car arm at 6 months. Reductions in IL-6 (phi = 0.18), IL-1beta (phi = 0.35), IL-1alpha (phi = 0.19), and IL-8 (phi = 0.15) and increases in NK cell numbers (phi = 0.23) were observed in comparison with enhanced usual care arm at 6 months. Reductions in caregiver stress (Cohen's d = 0.75) and depression (Cohen's d = 0.37) were observed at 6 months for caregivers whose loved ones were randomized to the intervention arm. CONCLUSIONS: The integration of screening and symptom management into cancer care is recommended. PMID- 26970437 TI - Potential association of VAMP5 polymorphisms with total colonic aganglionosis in Hirschsprung disease. AB - BACKGROUND: Hirschsprung disease (HSCR) is a congenital bowel disease caused by the absence of nerve cells in portions of the intestine. Our recent genome-wide association study has identified a variant (rs1254900) of vesicle-associated membrane protein 5 (VAMP5) as a potential risk locus for total colonic aganglionosis (TCA) in HSCR. In addition, VAMP5 is a member of the VAMP/synaptobrevin protein complex, which participates in nerve signal transduction by regulating the vesicular fusion of the neurotransmitter in synaptic transmission. METHODS: A total of 11 single nucleotide polymorphisms (SNPs), including those in the functionally important coding region, were selected on the basis of linkage disequilibrium and genotyped in 187 HSCR patients and 283 unaffected controls by using a TaqMan assay. Logistic analysis was conducted to investigate the possible association between VAMP5 SNPs and the risk of HSCR. KEY RESULTS: Genetic variants of VAMP5 showed increased association signals in the TCA subgroup of HSCR patients (minimum p = 9.69 * 10(-5) , OR = 3.93 at rs10206961) compared to other subgroups, even after Bonferroni correction (pcorr = 0.002). In haplotype analysis, three haplotypes (BL1_ht1, BL2_ht1, and BL2_ht2) were associated with the risk of TCA (minimum pcorr = 0.005). In additional combined analysis after imputation based on our previous GWAS, five SNPs still retained significant associations with the TCA subtype (minimum pcorr = 0.006 at rs10206961). CONCLUSIONS & INFERENCES: Considering that differential genetic effects on the development of the enteric nervous system, our results suggest that VAMP5 may be associated with the TCA of HSCR. However, further replications and functional evaluations are required. PMID- 26970438 TI - Protein biomarkers on tissue as imaged via MALDI mass spectrometry: A systematic approach to study the limits of detection. AB - MALDI mass spectrometry imaging (MSI) is emerging as a tool for protein and peptide imaging across tissue sections. Despite extensive study, there does not yet exist a baseline study evaluating the potential capabilities for this technique to detect diverse proteins in tissue sections. In this study, we developed a systematic approach for characterizing MALDI-MSI workflows in terms of limits of detection, coefficients of variation, spatial resolution, and the identification of endogenous tissue proteins. Our goal was to quantify these figures of merit for a number of different proteins and peptides, in order to gain more insight in the feasibility of protein biomarker discovery efforts using this technique. Control proteins and peptides were deposited in serial dilutions on thinly sectioned mouse xenograft tissue. Using our experimental setup, coefficients of variation were <30% on tissue sections and spatial resolution was 200 MUm (or greater). Limits of detection for proteins and peptides on tissue were in the micromolar to millimolar range. Protein identification was only possible for proteins present in high abundance in the tissue. These results provide a baseline for the application of MALDI-MSI towards the discovery of new candidate biomarkers and a new benchmarking strategy that can be used for comparing diverse MALDI-MSI workflows. PMID- 26970439 TI - Contribution of each masticatory muscle to the bite force determined by MRI using a novel metal-free bite force gauge and an index of total muscle activity. AB - PURPOSE: To develop a metal-free bite force gauge that can monitor the bite force in a strong magnetic field and to analyze the correlations between bite-force and total T2 shift of the mastication muscles. MATERIALS AND METHODS: The gauge used a micro-pressure sensor made of optical fiber. Ten subjects performed a 60-s isometric bite task at 40% of maximum clenching in various occlusal support conditions (intact dentition, right molar loss, or left molar loss). Spin-echo images were taken with a 1.5 Tesla scanner before and immediately after the task to correlate the bite force with the mean voxel count, mean shift in transverse relaxation time (DeltaT2), and total T2 shift of each masticatory muscle. RESULTS: Measurements of total T2 shift identified significant correlations between the bite force and activities of the superficial layer of the bilateral masseter muscle, regardless of the occlusion condition (intact dentition: left, P = 0.007 and right, P < 0.001; right molar loss: left, P = 0.02 and right, P = 0.021; and left molar loss: left, P = 0.022 and right, P = 0.049). In contrast, significant correlations were not detected between the bite force and mean DeltaT2 (intact dentition: left, P = 0.102 and right, P = 0.053; right molar loss: left, P = 0.393 and right, P = 0.868; and left molar loss: left, P = 0.531 and right, P = 0.92). CONCLUSION: Measurement of total T2 shift using a metal free bite force gauge is a more sensitive index of individual muscle activity than mean DeltaT2 during a bite task. J. MAGN. RESON. IMAGING 2016;44:804-813. PMID- 26970440 TI - Innate immune memory: Implications for host responses to damage-associated molecular patterns. AB - Cells of the innate immune system build immunological memory via epigenetic reprogramming after stimulations with microbial ligands. This functional readjustment allows for enhanced nonspecific inflammatory responses upon secondary challenges, a process termed "trained immunity." The epigenomic blueprint of trained monocytes has been recently reported, which revealed several important immunologic and metabolic mechanisms that underlie these changes. Interestingly, similar long-term reprogramming of cytokine production has also been described to be induced by endogenous damage-associated molecular patterns (DAMPs). Here, we present an overview of the novel data showing that endogenous alarm signals associated with tissue damage and sterile inflammation can induce trained immunity through epigenetic regulation of transcriptional programs. We describe new and old evidence of persistent effects of DAMPs in driving inflammation and enforce the concept that the influence of tissue-derived signals is critical in adjusting the magnitude and type of immune response built by the host. The better characterization of trained immunity for the persistence of inflammation induced by DAMPs would provide new possibilities for intervention in aging and autoinflammatory disorders. PMID- 26970441 TI - Neural correlates of context-dependent feature conjunction learning in visual search tasks. AB - Many perceptual learning experiments show that repeated exposure to a basic visual feature such as a specific orientation or spatial frequency can modify perception of that feature, and that those perceptual changes are associated with changes in neural tuning early in visual processing. Such perceptual learning effects thus exert a bottom-up influence on subsequent stimulus processing, independent of task-demands or endogenous influences (e.g., volitional attention). However, it is unclear whether such bottom-up changes in perception can occur as more complex stimuli such as conjunctions of visual features are learned. It is not known whether changes in the efficiency with which people learn to process feature conjunctions in a task (e.g., visual search) reflect true bottom-up perceptual learning versus top-down, task-related learning (e.g., learning better control of endogenous attention). Here we show that feature conjunction learning in visual search leads to bottom-up changes in stimulus processing. First, using fMRI, we demonstrate that conjunction learning in visual search has a distinct neural signature: an increase in target-evoked activity relative to distractor-evoked activity (i.e., a relative increase in target salience). Second, we demonstrate that after learning, this neural signature is still evident even when participants passively view learned stimuli while performing an unrelated, attention-demanding task. This suggests that conjunction learning results in altered bottom-up perceptual processing of the learned conjunction stimuli (i.e., a perceptual change independent of the task). We further show that the acquired change in target-evoked activity is contextually dependent on the presence of distractors, suggesting that search array Gestalts are learned. Hum Brain Mapp 37:2319-2330, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26970442 TI - Quantitative Analysis of Major Phytochemicals in Orthodox tea (Camellia sinensis), Oxidized under Compressed Air Environment. AB - This study describes major changes in phytochemical composition of orthodox tea (Camellia sinensis var. Assamica) oxidized under compressed air (CA). The experiments for oxidation were conducted under air pressure (101, 202, and 303 kPa) for 150 min. Relative change in the concentrations of caffeine, catechins, theaflavins (TF), and thearubigins (TR) were analyzed. Effect of CA pressure was found to be nonsignificant in regulating caffeine concentration during oxidation. But degradation in different catechins as well as formation of different TF was significantly affected by CA pressure. At high CA pressure, TF showed highest peak value. TR was found to have slower rate of formation during initial phase of oxidation than TF. Even though the rate of TR formation was significantly influenced by CA, a portion of catechins remained unoxidized at end of oxidation. Except caffeine, the percent change in rate of formation or degradation were more prominent at 202 kPa. PMID- 26970443 TI - Ring Expansion via Cleavage of Benzylic C-C Bonds Enabling Direct Synthesis of Medium Ring-Fused Benzocarbocycles. AB - A fluoride-anion-induced, regioselective ring expansion of benzocyclic ketones and alpha-aryl cycloketones has been developed via insertion of arynes into unactivated benzylic C-C bonds. This reaction provides a straightforward, transition-metal-free avenue to prepare medium ring-fused benzocarbocycles by creating "noble" seven-, eight-, and nine-membered rings. Applications of this method in the creation of medium-sized exocyclic and inner benzocyclic olefins, nine-membered lactones, and lactams are described. PMID- 26970445 TI - Preoperative and Postoperative Evaluation of New Double Mesh Carotid Stents with Contrast-Enhanced Ultrasound and Diffusion-Weighted Imaging. AB - In this case series, we selected 4 patients with asymptomatic severe carotid stenosis due to unstable plaques, which were identified with contrast-enhanced ultrasound. These patients underwent carotid stenting with a new generation double mesh stent. Diffusion-weighted magnetic resonance imaging (DW-MRI) was executed before and after the procedure to detect early cerebral microembolizations. No early neurological complications occurred nor cerebral microembolizations were detected at DW-MRI. New double mesh carotid stents appear to be a safe option also in asymptomatic patients with unstable plaques at high risk for surgery. PMID- 26970446 TI - Predicting catastrophic shifts. AB - Catastrophic shifts are known to pose a serious threat to ecology, and a reliable set of early warning indicators is desperately needed. However, the tools suggested so far have two problems. First, they cannot discriminate between a smooth transition and an imminent irreversible shift. Second, they aimed at predicting the tipping point where a state loses its stability, but in noisy spatial system the actual transition occurs when an alternative state invades. Here we suggest a cluster tracking technique that solves both problems, distinguishing between smooth and catastrophic transitions and to identify an imminent shift in both cases. Our method may allow for the prediction, and thus hopefully the prevention of such transitions, avoiding their destructive outcomes. PMID- 26970444 TI - Toward understanding family-related characteristics of young adults with sickle cell disease or sickle-cell trait in the USA. AB - AIMS AND OBJECTIVES: To describe the family-related characteristics of young adults with sickle-cell disease or sickle-cell trait prior to taking part in a randomised controlled trial on sickle-cell reproductive health education. BACKGROUND: There is a critical need for educational programmes that target the reproductive needs of young adults with sickle-cell disease or trait. However, little is known about the family-related characteristics (i.e., demographic attributes and reproductive health behaviours) in which these young adults live. DESIGN: A descriptive cross-sectional analysis. METHOD: At study enrolment, 234 young adults (mean age = 25.9 years, 65% female) completed the SCKnowIQ questionnaire. Descriptive statistics depict the demographic attributes and reproductive health behaviours of young adults with sickle-cell disease (n = 138) or trait (n = 96). For group comparisons, independent t tests or Fisher's tests were used, as appropriate. RESULTS: Young adults with sickle-cell trait had significantly higher education, income and health insurance than those with sickle-cell disease. Both groups believed that sickle-cell disease was a severe condition. A majority of young adults with sickle-cell disease (65%) had no children compared to 42% of those with sickle-cell trait. Most young adults (85% sickle-cell disease, 82% sickle-cell trait) were not planning a pregnancy in the next six months, and many used condoms, withdrawal or oral contraceptives. CONCLUSIONS: Socioeconomic disparities exist between young adults with sickle cell disease and sickle-cell trait. Future research that advances education about how and when to communicate appropriate genetic risk information to partners and children especially for young adults with sickle-cell trait would be beneficial. RELEVANCE TO CLINICAL PRACTICE: Awareness of the similarities and differences in the family-related characteristics among young adults with sickle-cell disease or trait can allow for more tailored reproductive education. PMID- 26970447 TI - Recurrent Supraventricular Tachycardia: A Missed Diagnosis. PMID- 26970448 TI - Delayed-onset Ureteral Obstruction and Calcification Masquerading as Renal Colic Following Deflux Injection. AB - Vesicoureteral reflux is a common disorder in children, and its management has changed entirely as a result of widespread use of endoscopy procedures to inject filler materials. Complications with this type of treatment, particularly ureteral obstruction, are rare. Very few patients with delayed obstruction have been reported in the literature. We here present the case of an 8-year-old girl who exhibited symptoms of febrile renal colic and renal distension more than 5 years after undergoing endoscopic treatment. This is the first reported case of atypical late presentation combining pyelonephritis with ureteral obstruction and calcification. PMID- 26970449 TI - The Urinary Microbiome Differs Significantly Between Patients With Chronic Prostatitis/Chronic Pelvic Pain Syndrome and Controls as Well as Between Patients With Different Clinical Phenotypes. AB - OBJECTIVE: To study the urinary microbiome of patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) compared with controls. METHODS: We identified 25 patients with CP/CPPS and 25 men who were either asymptomatic or only had urinary symptoms. Midstream urine was collected. Symptom severity was measured with the National Institutes of Health Chronic Prostatitis Symptom Index and clinical phenotype with UPOINT. Total DNA was extracted from the urine pellet and bacterial-specific 16Sr-DNA-capture identified by MiSeq sequencing. Taxonomic and functional bioinformatic analyses used principal coordinate analysis (PCoA)/MacQIIME, LEfSe, and PiCRUSt algorithms. RESULTS: Patients and controls were similar ages (52.3 vs 57.0 years, P = .27). For patients, median duration was 48 months, mean Chronic Prostatitis Symptom Index was 26.0, and mean UPOINT domains was 3.6. Weighted 3D UniFrac PCoA revealed tighter clustering of controls distinct from the wider clustering of cases (P = .001; alpha-diversity P = .005). Seventeen clades were overrepresented in patients, for example, Clostridia, and 5 were underrepresented, eg, Bacilli, resulting in predicted perturbations in functional pathways. PiCRUSt inferred differentially regulated pathways between cases and controls that may be of relevance including sporulation, chemotaxis, and pyruvate metabolism. PCoA derived microbiomic differences were noted for neurologic/systemic domains (P = .06), whereas LEfSe identified differences associated with each of the 6 clinical features. CONCLUSION: Urinary microbiomes from patients with CP/CPPS have significantly higher alpha(phylogenetic) diversity which cluster differently from controls, and higher counts of Clostridia compared with controls, resulting in predicted perturbations of functional pathways which could suggest metabolite specific targeted treatment. Several measures of severity and clinical phenotype have significant microbiome differences. PMID- 26970450 TI - Outcomes of Pyeloplasty in Very Poorly Functioning Kidneys: Examining the Myths. AB - OBJECTIVE: To assess the perioperative complications and functional midterm outcomes after pyeloplasty for poorly functioning kidneys due to ureteropelvic junction obstruction. PATIENTS AND METHODS: We retrospectively analyzed patients who underwent pyeloplasty for primary ureteropelvic junction obstruction in very poorly functioning kidneys in terms of split renal function of <=20% or estimated glomerular filteration rate of <=20 mL/minute. Perioperative complications and postoperative outcomes in terms of symptomatic improvement and functional stabilization or recovery were assessed. RESULTS: A total of 32 patients with estimated glomerular filteration rate <=20 mL/minute or split function <=20% underwent pyeloplasty since January 2010. All patients were followed for a mean period of 26.8 months and none required reintervention for obstructive drainage, deteriorating function, or intractable pain. One patient had persistent pain requiring analgesics and overall success rate (defined as nonobstructive pattern, no deterioration in split function, and no persistent symptoms) was 93.7%. Thirteen patients (40.6%) showed significant improvement in renal function (>5% over preoperative), and in all except 1 (3.1%) case there was no further deterioration of function. CONCLUSION: Pyeloplasty provides high rates of morphological and functional success even in very poorly functioning renal units. There is a possibility of functional recovery in one-third of patients, and in most of the rest, there is no further deterioration. PMID- 26970451 TI - Radical Nephroureterectomy Without Patient or Port Repositioning Using the Da Vinci Xi Robotic System: Initial Experience. AB - OBJECTIVE: To report our initial experience on robot-assisted radical nephroureterectomy, using the da Vinci Xi robotic system without patient or port repositioning. MATERIALS AND METHODS: The patients were in a modified flank position. A Bugbee electrode was used to cauterize and mark the ureteral orifice, aiding in the final robotic excision of the distal ureter. For the first step of the procedure, the second robotic arm holds the scope, the fourth robotic arm holds Port #1 (monopolar curved scissors), the first robotic arm holds Port #2 (Fenestrated bipolar forceps), and the third robotic arm holds Port #4 (Prograsp forceps). After completion of nephrectomy, all robotic arms were released and reconfigured. In the new setting, the third robotic arm and second robotic arm were switched between the camera port and the fourth port. The first port remained working with the monopolar curved scissors whereas Prograsp forceps was moved to the second port and fenestrated bipolar forceps was moved to the third port. RESULTS: Two patients underwent 2 successful radical nephroureterectomies with the above-mentioned technique. The console time for the first patient was 150 minutes whereas the estimated blood loss was 200 mL. The console time and blood loss for the second patient were 140 minutes and 300 mL, respectively. The hospitalization time and catheter removal time were 3 days for both patients and no complications were observed. CONCLUSION: The use of the da Vinci Xi robotic system enabled us to perform both nephrectomy and distal ureterectomy and/or bladder cuff excision without any repositioning of the patient or trocars. PMID- 26970452 TI - An Atypical Presentation of a Typical Arrhythmia. PMID- 26970453 TI - Editorial Comment. PMID- 26970454 TI - Reply by Authors. PMID- 26970456 TI - Health Effects of Unemployment in Denmark, Norway and Sweden 2007-2010: Differing Economic Conditions, Differing Results? AB - This article investigates short-term health effects of unemployment for individuals in Denmark, Norway, and Sweden during an economic downturn (2007 2010) that hit the Scandinavian countries with diverging strength. The longitudinal part of the European Union Statistics on Income and Living Conditions (EU-SILC) data material is analyzed, and results from generalized least squares estimation indicate that Denmark is the only Scandinavian country in which health status deteriorated among the unemployed. The individual-level (and calendar year) fixed-effect results confirm the negative relationship between unemployment and health status in Denmark. This result is robust across different subsamples, model specifications, and changes in both the dependent and independent variable. Health status deteriorated especially among women and people in prime working age (30-59 years). There is, however, only scant evidence of short-term health effects among the recently unemployed in Norway and Sweden. The empirical findings are discussed in light of: (1) the adequacy of the unemployment insurance system, (2) the likelihood of re-employment for the displaced worker, and (3) selection patterns into and out of employment in the years preceding and during the economic downturn. PMID- 26970455 TI - A "Before and After" in the Use of Emergency Services in Spain? The Impact of the Economic Crisis. AB - The objective of this study was to analyse whether variables associated with emergency services (ES) use in Spain have changed in the period 2006-2011 using a comparative analysis of the 2006 and 2011 Spanish National Health Surveys. The measure of association was the prevalence ratio with its 95% confidence interval, obtained by Poisson regression with robust variance. We studied interactions between the explanatory variables for ES use and year and subsequently performed a stratified analysis by year. ES use declined by 2.1% in 2011. Most emergency care (approximately 60% in both surveys) was provided in public hospitals. Between 2006 and 2011, ES use increased by 9% in women (p for interaction = 0.008) [ref. men], 3% in persons with poor mental health (p for interaction = 0.072) [ref. good mental health], and 8% in individuals with limitations on activities of daily living (p for interaction = 0.006) [ref. no limitations]. The change in the effect of the variables sex, mental health, and limitations on activities of daily living on use of ES (2006 and 2011) is not explained by either demographic characteristics or individual socioeconomic indicators. These results could be associated with macroeconomic and structural changes occurring during the period 2006-2011. PMID- 26970457 TI - Tuberculosis control in India: Journey so far and ahead.... PMID- 26970458 TI - WHO's End TB Strategy: From stopping to ending the global TB epidemic. AB - The 67th World Health Assembly of 2014 adopted the "End TB Strategy" with a vision of making the world free of tuberculosis (TB) and with the goal of ending the global TB epidemic by the year 2035. World Health Organization's "End TB Strategy" captures this holistic response in its four principles and three pillars. The three high-level indicators of the "End TB Strategy" - reductions in TB deaths, reductions in the TB incidence rate and the percentage of TB patients and their households experiencing catastrophic costs - are relevant to all countries. PMID- 26970460 TI - Multidrug-resistant TB among previously treated TB cases: A retrospective study in Nagpur, India. AB - BACKGROUND: Multidrug-resistant TB (MDR-TB) is a major public health concern and threat for tuberculosis control efforts worldwide. Globally, 3.6% of new TB cases and 20.2% of previously treated cases, are estimated to have MDR-TB. The prevalence of MDR-TB in India has been estimated to be 1-3% in new TB cases and around 12-14% in previously treated TB cases. There is limited information of the trends of MDRTB among various types of previously treated cases, i.e. relapse, treatment after failure, treatment after default and other cases. This study was conducted to know the trends of MDR-TB among various types of previously treated cases treated as per Revised National TB Control Program (RNTCP) guidelines. METHODS: This was a retrospective record review of MDRTB cases diagnosed during 2007-2011 who were previously treated for anti-TB treatment under RNTCP. RESULTS: A total of 249 retreatment tuberculosis patients diagnosed as having MDRTB were included. Majority 84 (34%) of cases were from 25 to 34 years age group, which is productive age group. Among the MDRTB cases, 177 (71%) were male and 72 (29%) were female. The proportion of MDR-TB among different subcategories of retreatment TB cases were relapse 117 (47%), treatment failure 96 (39%), treatment after default 22 (9%) and others 14 (6%). CONCLUSION: Study findings highlight high proportion of MDRTB among the relapse and treatment failure cases. Further research is needed to understand high occurrence rates of MDRTB among relapse and failure cases treated under RNTCP and need for early detection of MDR TB among these high-risk groups. PMID- 26970459 TI - Standards for TB care in India: A tool for universal access to TB care. AB - In 2014, Government of India in collaboration with World Health Organization Country Office for India released the policy document on Standards for tuberculosis (TB) care in India after in-depth deliberation with national and international experts. The standards for TB care represent what is expected for quality TB care from the Indian healthcare system including both public and private systems. The details of each standard have been compiled in this review article. It is envisioned that the standards detailed in the manuscript are adapted by all TB care providers across the country. PMID- 26970462 TI - Evaluation of use of line probe assay on smear-positive direct specimen from extra-pulmonary tuberculosis site. AB - BACKGROUND: Line probe assay (LPA) is used for first-line drug susceptibility testing (DST) of smear-positive pulmonary tuberculosis (TB) patients. For extra pulmonary (EP) and smear-negative TB patients, the samples are inoculated in culture and isolates of Mycobacterium tuberculosis (MTB) are tested on LPA. This results in considerable delay and loses the benefit of rapid diagnostics. In the present study, smear-positive EP specimens were tested directly on LPA and their results were compared with LPA conducted on culture isolates of same specimens. METHOD: All EP specimens received from different parts of Gujarat State in 2014 were subjected to ZN smear microscopy and inoculated on liquid culture. Smear positive samples were directly tested with LPA. Simultaneously, culture isolates of MTB were also subjected to LPA. Results of LPA conducted on both direct specimen and culture isolates were compared. RESULT: Of 391 extra-pulmonary specimens, 177 were smear positive and tested directly on LPA. Simultaneously, 88 were culture positive and their isolates were tested on LPA. With LPA on direct specimen, 127 (32%) had valid results with median time to diagnose rifampicin resistance of 5 days (IQR 2-7). In comparison, 88 (23%) specimens had valid results with culture isolates tested on LPA and with longer turnaround time (18 40 days). Among 51 samples, with valid LPA results both on direct samples and isolates, 50 (98%) had concordance for drug resistance pattern. CONCLUSION: There is advantage in testing extra-pulmonary smear-positive samples directly on LPA and the results would also be available rapidly. PMID- 26970463 TI - Emerging applications: Screening OSA by Modified Pictorial Epworth Sleepiness Scale in Indian subjects. AB - BACKGROUND: The Epworth Sleepiness Scale (ESS) is a widely used scoring to measure excessive daytime sleepiness. This scale was designed to be self completed by the subjects, but unfortunately in a developing country with low literacy this had affected its outcome interpretation. The Traditional ESS has been translated into a Modified Pictorial version for easy comprehension by the patients. METHOD: Subjects were evaluated for their competence to self-complete the ESS (Conventional and Pictorial) in Sleep Clinic at Respiratory Department of Santosh Medical College and Hospital, Ghaziabad. Modified Pictorial representations were designed along with 5 newer questions incorporated as sub questions in 8 original domains prepared and labelled as Pictorial Scale. The Traditional (ESS) and Pictorial (Modified) representations were compared for agreement by receiver operating curve and the area under curve. RESULTS: It was found that time taken to complete the Traditional ESS was significantly higher in comparison to Modified Pictorial Epworth Sleepiness Scale with reduced errors (Pictorial ESS 4.67min than Traditional ESS 14.43min). CONCLUSIONS: Modified pictures scale showed statistically significant improvements over ESS and hence can be used as an alternative for subjects with low literacy level. PMID- 26970461 TI - Airborne infection control in India: Baseline assessment of health facilities. AB - BACKGROUND: Tuberculosis transmission in health care settings represents a major public health problem. In 2010, national airborne infection control (AIC) guidelines were adopted in India. These guidelines included specific policies for TB prevention and control in health care settings. However, the feasibility and effectiveness of these guidelines have not been assessed in routine practice. This study aimed to conduct baseline assessments of AIC policies and practices within a convenience sample of 35 health care settings across 3 states in India and to assess the level of implementation at each facility after one year. METHOD: A multi-agency, multidisciplinary panel of experts performed site visits using a standardized risk assessment tool to document current practices and review resource capacity. At the conclusion of each assessment, facility-specific recommendations were provided to improve AIC performance to align with national guidelines. RESULT: Upon initial assessment, AIC systems were found to be poorly developed and implemented. Administrative controls were not commonly practiced and many departments needed renovation to achieve minimum environmental standards. One year after the baseline assessments, there were substantial improvements in both policy and practice. CONCLUSION: A package of capacity building and systems development that followed national guidelines substantially improved implementation of AIC policies and practice. PMID- 26970464 TI - Does effect of BCG vaccine decrease with time since vaccination and increase tuberculin skin test reaction? AB - The protective efficacy of BCG was studied for over 15 years, from 1968, in South India. A secondary analysis of data was performed to investigate the relationship between Bacille Calmette-Guerin (BCG) and tuberculosis (TB) disease and between BCG and positive tuberculin skin test for different time periods among children aged less than 10 years. A randomized controlled trial was conducted, where 281,161 persons were allocated to receive BCG 0.1mg, BCG 0.01mg or placebo. Tuberculin skin test was performed at baseline and at 4 years after BCG vaccination. Surveys were conducted every 2.5 years to detect all new cases of culture-positive/smear-positive TB occurring in the community over a 15-year period. Relative risk (RR) was obtained from the ratio of incidence among the vaccinated and the placebo groups. Among those children vaccinated with 0.1mg of BCG, the RR for TB was 0.56 (95% CI: 0.32-0.87, P=0.01) at 12.5 years but increased to 0.73 later. Similar pattern was seen with 0.01mg. The increase in the number of skin test positives with 0.1mg of BCG was 57.8%, 49.4% and 34% for cut-off points at >=10mm, >=12mm and >=15mm, respectively. The study suggests that the effect of BCG may decrease since vaccination and the tuberculin positive was higher at post-vaccination test period due to BCG. PMID- 26970465 TI - Social inclusion: An effort to end loss-to-treatment follow-up in tuberculosis. AB - SITUATION ANALYSIS: Pathanamthitta district is implementing Revised National Tuberculosis Control Program as a pilot district since 1993. The district programme was reporting approximately 5% of their diagnosed smear positive patients as never put on treatment (Initial lost to follow up - ILFU) and 5% of the new smear positive [NSP] Pulmonary TB patients as lost to follow up [LFU] during treatment. Attempts based on reengineering of DOTS were not largely successful in bringing down these proportions. INTERVENTION: A treatment support group [TSG] is a non-statutory body of socially responsible citizens and volunteers to provide social support to each needy TB patient safeguarding his dignity and confidentiality by ensuring access to information, free and quality services and social welfare programs, empowering the patient for making decision to complete treatment successfully. It is a complete fulfilment of social inclusion standards enumerated by Standards for TB Care in India. Pathanamthitta district started implementing this strategy since 2013. OUTCOMES: After intervention, proportion of LFU among NSPTB cases dropped markedly and no LFU were reported among the latest treatment cohorts. Proportion of ILFU keeps similar trend and none were reported among the latest diagnostic cohorts. LESSONS: Social support for TB care is feasible under routine program conditions. Addition of standards for social inclusion in STCI is meaningful. Its meaning is translated well by a society empowered with literacy and political sense. PMID- 26970466 TI - Public-private mix for TB care in India: Concept, evolution, progress. AB - To achieve "Universal access to TB care and treatment for all", Revised National Tuberculosis Control Programme (RNTCP) has taken steps to reach the unreached by synergizing the efforts of all partners and stakeholders. RNTCP is engaging with private sector partners in major cities of India with primary focus on notification through innovative partnership mechanisms. The manuscript details the concept behind the public-private mix for TB Care in RNTCP, its evolution and progress over the decades in India. PMID- 26970468 TI - Reply to percentage of colorectal cancer diagnoses in adults aged younger than 50 years. PMID- 26970467 TI - Transitioning to daily treatment for drug-sensitive TB in India. AB - World Health Organization in its treatment guideline for tuberculosis 2010 recommended daily dosing as the preferred regimen in treatment of drug-sensitive TB patients. The Revised National Tuberculosis Control Program took a decision to implement daily regimen in five states of India in 2015. This article describes the policy-making chronology, evidences used, stakeholders involved, and process of decision making. PMID- 26970470 TI - Finding the correct role for heart transplant in the treatment of hypoplastic left heart syndrome. PMID- 26970469 TI - The 2015 International Society for Heart and Lung Transplantation Guidelines for the management of fungal infections in mechanical circulatory support and cardiothoracic organ transplant recipients: Executive summary. PMID- 26970472 TI - Sex-related differences in age-associated downregulation of human ventricular myocardial beta1-adrenergic receptors. AB - BACKGROUND: With increasing age, human ventricular myocardium exhibits selective downregulation of beta1-adrenergic receptors (beta1-ARs). We tested the hypothesis that sex differences exist in age-related changes in beta1-ARs. METHODS: Left (LV) and right (RV) ventricular tissue was obtained from 61 unplaceable potential organ donor hearts ages 1 to 71 years with no known cardiac history and from LVs removed from 56 transplant recipients with idiopathic dilated cardiomyopathy. beta1-AR and beta2-AR densities, the frequency of beta1 AR389 gene variants, and beta-AR function were determined. RESULTS: Sex had a marked effect on the age-related decrease in beta1-ARs. Female LVs had more pronounced downregulation (by 42% [p < 0.001] vs 22% [p = 0.21] in 31 male LVs) comparing the youngest (average age, 15.3 +/- 5.5 years) to the oldest (average age, 50.8 +/- 9.1 years) sub-groups. On regression analyses, female LVs exhibited a closer relationship between beta1-AR density and age (r = -0.78, p <0.001 vs r = -0.46, p = 0.009 in males), with a second-degree polynomial yielding the best fit. There was no statistically significant relationship of beta1-ARs to age in female or male idiopathic dilated cardiomyopathy LVs. CONCLUSIONS: Sex affects age-related beta-AR downregulation in normal human ventricles, with females exhibiting more profound decreases with increasing age. The curvilinear relationship between age and receptor density that plateaus around age 40 in women suggests an effect of sex hormones on beta1-AR expression in the human heart. PMID- 26970473 TI - Abdominal wall perforation caused by left ventricular assist device driveline insertion: Potential lethal complication. PMID- 26970471 TI - ISHLT pathology antibody mediated rejection score correlates with increased risk of cardiovascular mortality: A retrospective validation analysis. AB - BACKGROUND: Antibody-mediated rejection (AMR) in cardiac transplant recipients is a serious form of rejection with adverse patient outcomes. The International Society of Heart and Lung Transplantation (ISHLT) has published a consensus schema for the pathologic diagnosis of various grades of antibody-mediated rejection (pathology antibody-mediated rejection [pAMR]). We sought to determine whether the ISHLT pAMR grading schema correlates with patient outcomes. METHODS: Using our database, which contains a semi-quantitative scoring of all pathologic descriptors of pAMR, we retrospectively used these descriptors to convert the previous AMR categories to the current ISHLT pAMR categories. Cox proportional hazard models were fit with cardiovascular (CV) death or retransplant as the outcome. The pAMR value was included as a categorical variable, and cellular rejection (CR) values were included in a separate model. RESULTS: There were 13,812 biopsies from 1,014 patients analyzed. The pAMR grades of pAMR1h, pAMR1i, and pAMR2 conferred comparable increased risk for CV mortality. Significantly increased risk of CV mortality was conferred by biopsies graded as severe AMR (pAMR3). CONCLUSIONS: The new ISHLT pAMR grading schema identifies patients at increased risk of CV mortality, consistent with risks published from several programs before 2011. The current schema is validated by this analysis in a large biopsy database. Because pAMR1h, pAMR1i, and pAMR2 have similar CV risks associated with them, the threshold for a positive diagnosis of pAMR should be re evaluated in future iterations of the ISHLT schema. PMID- 26970475 TI - Effects of pulsatile electrical stimulation of the round window on central hyperactivity after cochlear trauma in guinea pig. AB - Partial hearing loss induced by acoustic trauma has been shown in animal models to result in an increased spontaneous firing rate in central auditory structures. This so-called hyperactivity has been suggested to be involved in the generation of tinnitus, a phantom auditory sensation. Although there is no universal cure for tinnitus, electrical stimulation of the cochlea, as achieved by a cochlear implant, can result in significant reduction of the tinnitus percept. However, the mechanism by which this tinnitus suppression occurs is as yet unknown and furthermore cochlear implantation may not be an optimal treatment option for tinnitus sufferers who are not profoundly deaf. A better understanding of the mechanism of tinnitus suppression by electrical stimulation of the cochlea, may lead to the development of more specialised devices for those for whom a cochlear implant is not appropriate. This study aimed to investigate the effects of electrical stimulation in the form of brief biphasic shocks delivered to the round window of the cochlea on the spontaneous firing rates of hyperactive inferior colliculus neurons following acoustic trauma in guinea pigs. Effects during the stimulation itself included both inhibition and excitation but spontaneous firing was suppressed for up to hundreds of ms after the cessation of the shock train in all sampled hyperactive neurons. Pharmacological block of olivocochlear efferent action on outer hair cells did not eliminate the prolonged suppression observed in inferior colliculus neurons, and it is therefore likely that activation of the afferent pathways is responsible for the central effects observed. PMID- 26970474 TI - Effects of high intensity noise on the vestibular system in rats. AB - Some individuals with noise-induced hearing loss (NIHL) also report balance problems. These accompanying vestibular complaints are not well understood. The present study used a rat model to examine the effects of noise exposure on the vestibular system. Rats were exposed to continuous broadband white noise (0-24 kHz) at an intensity of 116 dB sound pressure level (SPL) via insert ear phones in one ear for three hours under isoflurane anesthesia. Seven days after the exposure, a significant increase in ABR threshold (43.3 +/- 1.9 dB) was observed in the noise-exposed ears, indicating hearing loss. Effects of noise exposure on vestibular function were assessed by three approaches. First, fluorescein conjugated phalloidin staining was used to assess vestibular stereocilia following noise exposure. This analysis revealed substantial sensory stereocilia bundle loss in the saccular and utricular maculae as well as in the anterior and horizontal semicircular canal cristae, but not in the posterior semicircular canal cristae. Second, single unit recording of vestibular afferent activity was performed under pentobarbital anesthesia. A total of 548 afferents were recorded from 10 noise-treated rats and 12 control rats. Noise exposure produced a moderate reduction in baseline firing rates of regular otolith afferents and anterior semicircular canal afferents. Also a moderate change was noted in the gain and phase of the horizontal and anterior semicircular canal afferent's response to sinusoidal head rotation (1 and 2 Hz, 45 degrees /s peak velocity). Third, noise exposure did not result in significant changes in gain or phase of the horizontal rotational and translational vestibulo-ocular reflex (VOR). These results suggest that noise exposure not only causes hearing loss, but also causes substantial damage in the peripheral vestibular system in the absence of immediate clinically measurable vestibular signs. These peripheral deficits, however, may lead to vestibular disorders over time. PMID- 26970476 TI - The hemic response of white-spotted bamboo sharks (Chiloscyllium plagiosum) with inflammatory disease. AB - As elasmobranch medicine becomes more commonplace, there continues to be confusion with techniques and evaluation of the shark hemogram and it remains unknown if they are able to mount an inflammatory hemic response. The aims of this study were to compare two total white blood cell (WBC) count techniques, establish a reference interval for captive white-spotted bamboo sharks (Chiloscyllium plagiosum), and determine if elasmobranchs are capable of mounting an inflammatory hemic response. Correlation statistics were performed on hematologic results for healthy female bamboo sharks to assess the use of Natt Herrick's and phloxine methods. Total WBC counts and differentials were obtained from males with severe traumatic clasper wounds and compared to the healthy females. We elected clasper amputation as the preferred treatment intervention and post-operative hematology was performed one month later. There was poor correlation of leukocyte counts between the two WBC count methods. Hematologic values were established for the females and males pre- and post-operatively. Males with wounds had a marked leukocytosis and heterophilia. Post-operative blood work showed a resolution of total WBC count and a trend toward resolution of the heterophilia. This study provides hematologic values for white-spotted bamboo sharks and confirms that the Natt-Herrick's method is preferred for lymphocytic species. Hematologic differences present in males with clasper wounds suggests that elasmobranchs do mount an inflammatory hemic response. Treatment via clasper amputation proved to be a safe and efficient means for clinical treatment that led to a trend toward resolution of the inflammatory leukogram. Zoo Biol. 35:251-259, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26970477 TI - Microsurgical Management of Craniopharyngiomas via a Unilateral Subfrontal Approach: A Retrospective Study of 177 Continuous Cases. AB - OBJECTIVE: To evaluate the outcomes of 177 cases of craniopharyngioma (CP) treated via a unilateral subfrontal approach. METHODS: A total of 177 continuous microscopic surgeries were performed by the senior author (Y.X.). The tumors were divided into 6 groups using the diaphragm sellae and the third ventricle floor as the anatomic references. The preoperative, postoperative, and long-term follow-up data were analyzed to evaluate the extent of tumor resection, recurrence, and functional status. RESULTS: The subfrontal-basal approach was used in 169 (91.4%) cases. Total resection was achieved in 167 (94.4%) cases. A total of 158 patients were followed from 6 to 130 months. There were 3 perioperative and 23 delayed deaths. Twenty-two patients had tumor recurrence (12.7%). The progression-free survival was 80% at 5 years and 72% at 10 years. The overall survival was 84.0% at 2.5 years and 83.2% at 10 years. There was a significant increase of pituitary dysfunction after total resection. Neurologic function was stable in most patients. Rate of hypothalamic dysfunction and mortality were higher in patients with intraventricular CPs. Of the surviving patients, 91.8% were living independently with acceptable morbidities at the end of the study. CONCLUSIONS: Most CPs extend along the intrasellar-suprasellar-third ventricle axis. A subfrontal-basal approach is a simple, safe, and effective approach to resecting CPs extending along the vertical axis. A translamina terminalis approach is an ideal corridor to resect intraventricular CP. The benefit of radical resection remains controversial, especially for CPs involving the infundibulotuberal region. PMID- 26970478 TI - Soft Membrane Sheath for Endoscopic Surgery of Intracerebral Hematomas. AB - BACKGROUND: Although the functional efficacy of surgical evacuation of an intracerebral hematoma (ICH) remains controversial, it has a valuable role for managing ICHs. Endoscopic surgery is increasingly used to evacuate ICHs; however, the narrow rigid sheath may be limiting. We report the usefulness of a soft plastic membrane sheath for endoscopic evacuation of ICHs. METHODS: The 20 * 100 mm flat membrane sheath was made of polyester film. Before introducing the sheath into the ICH cavity under navigation, one side was tucked into the opposite side to make a narrow four-layered tube. After inserting it in the brain, the tucked in leaf was pulled out, and the slit-like tube was ready to remove the hematoma. A rigid endoscope and various instruments were introduced into the sheath. Large ICHs in the putamen and thalamus were evacuated under endoscopic visualization using the same microsurgical instruments. RESULTS: This technique was applied to 41 patients. Nearly complete evacuation of all hematomas was achieved. No surgical complication or rebleeding occurred. The new membrane sheath allowed more room for accommodating and handling the instruments, including bipolar forceps. CONCLUSIONS: This flat membrane sheath is disposable and easy to prepare, which could overcome the limitation of the instruments to allow for efficient evacuation of an ICH using the same microsurgical techniques. PMID- 26970479 TI - Mythology and Neurosurgery. AB - Myths are the keystone of mythology. They are interpretations of events that have been told as stories and legends for thousands of years, inherited from generation to generation, and have reached the present day. Although most myths are considered figments of the imagination or fictitious legends, all of them contain references to facts from the time they occurred. Mythology, which is a collection of figments of imagination concerning nature and human beings, is a product of human effort to perceive, explain, and interpret the universe and the world, much like science. The interaction between mythology and science dates back to the early days of civilization. Mythology, a reflection of human creativity, is extensively used in modern science, particularly in a terminological context. This article aims to reveal the texture of mythology in neurosurgery, by analyzing the birth of medicine in mythology; heroes such as Apollo and Asklepios, the gods of healing and medicine, as well as Hygieia, the goddess of health and hygiene; and mythological terms and phrases such as Achilles tendon, atlas vertebra, gigantism, priapism syndrome, hippocampus, lethargy, syrinx, and arachnoid. Through the use of symbols, mythology has attempted to explain several subjects, such as human nature, disease, birth, and death. In this respect, mythology and medicine dance arm in arm, and this dance has been going on for centuries. As a result, mythology has manifested itself in many fields within medicine, either anatomically or by giving names to various diseases. PMID- 26970480 TI - Normal Pressure Hydrocephalus and Parkinsonism: Preliminary Data on Neurosurgical and Neurological Treatment. AB - OBJECTIVE: Idiopathic normal pressure hydrocephalus (iNPH) may present, besides the classic triad of symptoms, with extrapyramidal parkinsonianlike movement disorders. We present a randomized prospective study comparing adjustable ventriculoperitoneal (VP) shunt insertion plus dopamine oral therapy (group A) versus VP shunt alone (group B) in patients affected by iNPH associated with parkinsonism. METHODS: A detailed screening process included neurologic, neurosurgical, and neuropsychological evaluations, followed by a cerebrospinal fluid tap test and resistance outflow measurement. Outcome was evaluated through the Japanese NPH Grading Scale-Revised (JNPHGSR) and the motor (third) section of the Unified Parkinson's Disease Rating Scale, Motor Section (UPDRS-m). Friedman analysis of variance with a Wilcoxon post hoc test was used to evaluate the difference in JNPHGSR and UPDRS-m scores between pretreatment and follow-up (12 months) in the 2 groups, and a Kruskal-Wallis statistic and post hoc Mann-Whitney test were used to compare the change in JNPHGSR and UPDRS-m scores between the 2 groups. RESULTS: Thirty-two of 54 (59%) patients (mean age, 73.2 years) screened in 36 months met the inclusion criteria, but only 30 were enrolled (2 refused surgery) (15 in each group). Preoperative (123)I-ioflupane-cerebral single-photon emission computed tomography (DaTSCAN) revealed striatal dopaminergic deficit in 14/30 patients (46.5%). At the final 12 months follow-up, both groups improved JNPHGSR and UPRDS-m scores. The UPDRS-m score improvement was significant in both groups, but greater in group A (P = 0.003); JNPHGSR score improvement was similar in the 2 groups. CONCLUSIONS: iNPH associated with parkinsonism may be a frequent finding. In these cases, patients may benefit from VP shunt plus dopamine oral therapy. PMID- 26970481 TI - Acute Renal Failure in Aneurysmal Subarachnoid Hemorrhage: Nationwide Analysis of Hospitalizations in the United States. AB - OBJECTIVE: Medical complications in the setting of aneurysmal subarachnoid hemorrhage (aSAH) are common and associated with poor prognosis. We analyzed the incidence, risk factors, and short-term outcomes associated with acute renal failure (ARF) in aSAH. METHODS: We queried discharge records from all patients admitted to U.S. hospitals between 2002 and 2011 to identify primary diagnoses of aSAH and secondary diagnoses of ARF. The effect of demographics, hospital characteristics, and pre-existing comorbidity on ARF occurrence and the impact of ARF occurrence on length of stay (LOS), in-hospital costs, moderate to severe disability, and in-hospital mortality were explored in both bivariate and multivariable analyses. RESULTS: The incidence of ARF in patients hospitalized for aSAH (N = 260,885) was 4.0% and increased from 2.1% in 2002 to 5.7% in 2011 (P < 0.0001). The strongest predictors of ARF in multivariable analysis were fluid and electrolyte disorder (odds ratio [OR], 3.24; 95% confidence interval [CI], 3.07-3.42), coagulopathy (OR, 2.43; 95% CI, 2.25-2.63), HIV (OR, 2.42; 95% CI, 1.79-3.27), and diabetes (OR, 2.37; 95% CI, 2.08-2.69). ARF onset in aSAH increased the mean length of stay by 7.2 days and mean total costs by $28,813 (all P < 0.0001). After adjusting for confounding factors, patients with ARF had increased likelihood of moderate to severe disability (OR, 2.03; 95% CI, 1.89 2.19) and in-hospital death (OR, 2.14; 95% CI, 2.03-2.26). CONCLUSION: The burden of ARF in hospitalized patients with aSAH has increased in the past decade and is detrimental to patient outcomes and healthcare costs. The identification of patient-centered risk factors may allow for close surveillance of high-risk patients. PMID- 26970482 TI - Usefulness of Suction Decompression Method Combined with Extradural Temporopolar Approach During Clipping of Complicated Internal Carotid Artery Aneurysm. AB - BACKGROUND: Surgical clipping of complicated internal carotid artery (ICA) aneurysms can be very difficult because strong adhesion may hinder dissection of the perforators and surrounding anatomical structures from the aneurysm dome. We describe our experience in the clipping of these aneurysms using retrograde suction decompression (RSD) combined with extradural temporopolar approach (ETA) and discuss its advantages and pitfalls. MATERIALS AND METHODS: This retrospective study included 30 consecutive patients with complicated ICA aneurysms treated by direct clipping with RSD assistance between March 2004 and March 2015. RESULTS: The aneurysms were located on the paraclinoid ICA in 20 cases, the posterior communicating artery bifurcation in 8, ICA bifurcation in 1, and the anterior wall of the ICA in 1. No patient suffered any complication related to the puncture of the common carotid artery. Surgical outcome was good recovery in 20 patients, moderate disability in 4, severe disability in 4, and vegetative state in 1. One patient died of re-rupture of the aneurysm caused by incomplete dome clipping. Two patients suffered cerebral infarction, caused by anterior choroidal artery infarction in 1 patient. CONCLUSIONS: Retrograde suction decompression combined with ETA is a useful technique for clipping of complicated ICA aneurysms. PMID- 26970483 TI - Atomic features of an autoantigen in heparin-induced thrombocytopenia (HIT). AB - Autoantigen development is poorly understood at the atomic level. Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by antibodies to an antigen composed of platelet factor 4 (PF4) and heparin or cellular glycosaminoglycans (GAGs). In solution, PF4 exists as an equilibrium among monomers, dimers and tetramers. Structural studies of these interacting components helped delineate a multi-step process involved in the pathogenesis of HIT. First, heparin binds to the 'closed' end of the PF4 tetramer and stabilizes its conformation; exposing the 'open' end. Second, PF4 arrays along heparin/GAG chains, which approximate tetramers, form large antigenic complexes that enhance antibody avidity. Third, pathogenic HIT antibodies bind to the 'open' end of stabilized PF4 tetramers to form an IgG/PF4/heparin ternary immune complex and also to propagate the formation of 'ultralarge immune complexes' (ULCs) that contain multiple IgG antibodies. Fourth, ULCs signal through FcgammaRIIA receptors, activating platelets and monocytes directly and generating thrombin, which transactivates hematopoietic and endothelial cells. A non-pathogenic anti PF4 antibody prevents tetramer formation, binding of pathogenic antibody, platelet activation and thrombosis, providing a new approach to manage HIT. An improved understanding of the pathogenesis of HIT may lead to novel diagnostics and therapeutics for this autoimmune disease. PMID- 26970484 TI - "Kill" the messenger: Targeting of cell-derived microparticles in lupus nephritis. AB - Immune complex (IC) deposition in the glomerular basement membrane (GBM) is a key early pathogenic event in lupus nephritis (LN). The clarification of the mechanisms behind IC deposition will enable targeted therapy in the future. Circulating cell-derived microparticles (MPs) have been proposed as major sources of extracellular autoantigens and ICs and triggers of autoimmunity in LN. The overabundance of galectin-3-binding protein (G3BP) along with immunoglobulins and a few other proteins specifically distinguish circulating MPs in patients with systemic lupus erythematosus (SLE), and this is most pronounced in patients with active LN. G3BP co-localizes with deposited ICs in renal biopsies from LN patients supporting a significant presence of MPs in the IC deposits. G3BP binds strongly to glomerular basement membrane proteins and integrins. Accordingly, MP surface proteins, especially G3BP, may be essential for the deposition of ICs in kidneys and thus for the ensuing formation of MP-derived electron dense structures in the GBM, and immune activation in LN. This review focuses on the notion of targeting surface molecules on MPs as an entirely novel treatment strategy in LN. By targeting MPs, a double hit may be achieved by attenuating both the autoantigenic fueling of immune complexes and the triggering of the adaptive immune system. Thereby, early pathogenic events may be blocked in contrast to current treatment strategies that primarily target and modulate later events in the cellular and humoral immune response. PMID- 26970485 TI - Incidence of thyroid disorders in mixed cryoglobulinemia: Results from a longitudinal follow-up. AB - No study has evaluated the incidence of new cases of thyroid autoimmunity (AT) and dysfunction (TD) in hepatitis C-associated mixed cryoglobulinemia (MC) patients. We aimed to evaluate the incidence of new cases of AT and TD in a wide group of MC patients vs. age- and gender-matched controls from the same geographic area. After exclusion of MC patients with TD at the initial evaluation, the appearance of new cases of TD was evaluated in 112 MC patients and 112 matched controls, with similar iodine intake (median follow-up 67months in MC vs. 78 in controls). A high incidence (P<0.05) of new cases of hypothyroidism, TD, anti-thyroperoxidase antibody (AbTPO) positivity, appearance of a hypoechoic thyroid pattern, and thyroid autoimmunity in MC patients vs. controls was shown. A logistic regression analysis showed that in MC, the appearance of hypothyroidism was related to female gender, a borderline high initial thyroid-stimulating hormone (TSH), AbTPO positivity, a hypoechoic, and small thyroid. In conclusion, we show a high incidence of new cases of AT and TD in MC patients. MC patients at high risk (female gender, a borderline high initial TSH, AbTPO positivity, a hypoechoic, and small thyroid) should have periodically thyroid function follow-up. PMID- 26970486 TI - Evaluation of automated multi-parametric indirect immunofluorescence assays to detect anti-neutrophil cytoplasmic antibodies (ANCA) in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). AB - OBJECTIVES: The aim of this multicenter EUVAS study was to evaluate the diagnostic performance of multi-parametric indirect immunofluorescence (IIF) assays to detect anti-neutrophil cytoplasmic antibodies (ANCA) in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). PATIENTS AND METHODS: The study included 912 samples from diseased controls and 249 diagnostic samples from GPA (n=183) and MPA (n=66) patients. The performance of two automated multi parametric assays [Aklides (Medipan/Generic Assays) and EuroPattern (Euroimmun)] combining IIF on cellular and purified antigen substrates was compared with two manual IIF analyses and with commercially available ELISAs for MPO- and PR3-ANCA (Euroimmun). RESULTS: The area under the curve (AUC) of the receiver operating characteristics (ROC) curve to discriminate AAV from controls was 0.925, 0.848, 0.855 and 0.904 for, respectively, the two manual analyses, Aklides and EuroPattern, and 0.959, 0.921 and 0.886 for, respectively, antigen-specific ELISA, antigen-coated beads, and microdot, respectively. Variation in pattern assignment between IIF methods was observed. CONCLUSION: The performance of IIF depends on the substrate used and the definition of IIF patterns. The performance of automated IIF is improved by multi-parameter testing (combined IIF and antigen specific testing). Given the variability between IIF methods, the diagnostic importance of this technique is questioned. PMID- 26970487 TI - Primary Sjogren's syndrome: Clinical phenotypes, outcome and the development of biomarkers. AB - Primary Sjogren's syndrome (pSS) is a complex autoimmune disease with distinct clinical phenotypes and variable outcomes. The systemic form of the disease is characterized by immune complex mediated manifestations and is complicated by lymphoma as a result of a polyclonal B cell hyperactivity that is evolving into B cell malignancy. In the past decades, well-established clinical and serological markers have been described in the literature to identify high-risk patients and to predict lymphoma development. However, specific biologic treatments have proven ineffective to control the disease. Significant research effort has been made to reveal the major underlying biological events in this subgroup and identify biomarkers for early diagnosis, prognosis and response to treatment. In this review, we summarize the current data for the proposed histological, molecular and genetic biomarkers. PMID- 26970488 TI - Are there dangers in biologic dose reduction strategies? AB - Biologic dose reduction strategies, for patients with inflammatory rheumatic diseases, have been assessed in multiple studies to assess outcomes compared to ongoing maintenance dosing. Whilst cessation in established disease usually leads to disease flare, dose tapering approaches for those achieving low disease activity often appear to be successful in the short term. However, tapering can be associated with a higher risk of losing disease control and rates of recapture of disease control using the original biologic dose vary between studies. Over relatively short periods of follow-up, a number of studies have shown no statistical difference in radiographic progression in patients tapering or discontinuing biologics. However, a Cochrane review found that radiographic and functional outcomes may be worse after TNF inhibitor discontinuation, and over long-term disease follow-up flares have been associated with radiographic progression and worse patient reported outcomes. To date, no studies of biological therapy dose reduction have specifically investigated the risk of increased immunogenicity or the effects on cardiovascular risk and other co morbidities, although these remain important potential risks. In addition, whether there are greater dangers in certain dose reduction approaches such as a reduction in dose at the same frequency or a spacing of doses is not established. PMID- 26970489 TI - Therapeutic strategies targeting B-cells in multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) that traditionally has been considered to be mediated primarily by T-cells. Increasing evidence, however, suggests the fundamental role of B-cells in the pathogenesis of the disease. Recent strategies targeting B-cells in MS have demonstrated impressive and sometimes surprising results: B-cell depletion by monoclonal antibodies targeting the B-cell surface antigen CD20 (e.g. rituximab, ocrelizumab, ofatumumab) was shown to exert profound anti-inflammatory effect in MS with favorable risk-benefit ratio, with ocrelizumab demonstrating efficacy in both relapsing-remitting (RR) and primary progressive (PP) MS in phase III clinical trials. Depletion of CD52 expressing T- and B-cells and monocytes by alemtuzumab resulted in impressive and durable suppression of disease activity in RRMS patients. On the other hand, strategies targeting B-cell cytokines such as atacicept resulted in increased disease activity. As our understanding of the biology of B-cells in MS is increasing, new compounds that target B-cells continue to be developed which promise to further expand the armamentarium of MS therapies and allow for more individualized therapy for patients with this complex disease. PMID- 26970490 TI - Pathogenesis of ANCA-associated vasculitis: An update. AB - Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes a group of rare diseases characterized by necrotizing inflammation of small blood vessels and the presence of ANCA. Although these autoantibodies were initially used to classify pauci-immune vasculitis, increasing clinical and experimental evidence now supports their pathogenic role, mainly through ANCA induced activation of primed neutrophils and monocytes leading to destructive vascular necrosis. The mechanisms of ANCA generation remain however unclear. Neutrophils play a central role in the pathophysiological process of AAV since they are both effector cells responsible for endothelial damage and targets of autoimmunity. Another role of neutrophils is due to their ability to generate neutrophil extracellular traps, which support the presentation of ANCA autoantigens, could break immune tolerance and induce autoantibody generation. Alternatively, the ANCA autoimmune response is facilitated by insufficient T-cell and B-cell regulation, and the role of complement alternative pathway has recently been emphasized. This review summarizes the main pathogenesis concepts of AAV as well as the putative mechanisms for the origin of ANCA autoimmune response. PMID- 26970491 TI - Autoantibodies in inflammatory arthritis. AB - Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease characterized by extensive synovitis resulting in erosions of articular cartilage and marginal bone with joint destruction. The lack of immunological tolerance in RA represents the first step toward the development of autoimmunity. Susceptible individuals, under the influence of environmental factors, such as tobacco smoke, and silica exposure, develop autoimmune phenomena that result in the presence of autoantibodies. HLA and non-HLA haplotypes play a major role in determining the development of specific autoantibodies differentiating anti-citrullinated antibodies (ACPA)-positive and negative RA patients. Rheumatoid factor (RF) and ACPA are the serological markers for RA, and during the preclinical immunological phase, autoantibody titers increase with a progressive spread of ACPA antigens repertoire. The presence of ACPA represents an independent risk factor for developing RA in patients with undifferentiated arthritis or arthralgia. Moreover, anti-CarP antibodies have been identified in patients with RA as well as in individuals before the onset of clinical symptoms of RA. Several autoantibodies mainly targeting post-translational modified proteins have been investigated as possible biomarkers to improve the early diagnosis, prognosis and response to therapy in RA patients. Psoriatic arthritis (PsA) is distinguished from RA by infrequent positivity for RF and ACPA, together with other distinctive clinical features. Actually, specific autoantibodies have not been described. Recently, anti-CarP antibodies have been reported in sera from PsA patients with active disease. Further investigations on autoantibodies showing high specificity and sensibility as well as relevant correlation with disease severity, progression, and response to therapy are awaited in inflammatory arthritides. PMID- 26970492 TI - The key culprit in the pathogenesis of systemic lupus erythematosus: Aberrant DNA methylation. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple organ involvement. It is characterized by abundant autoantibodies that form immune complex with autoantigens and deposit in organs and cause tissue damage by inducing inflammation. The pathogenesis of SLE has been intensively studied but remains unclear. B and T lymphocyte abnormalities, dysregulation of apoptosis, defects in the clearance of apoptotic materials, and various genetic and epigenetic factors are believed to contribute to the initiation and development of SLE. The up-to-date research findings point to the relationship between abnormal DNA methylation and SLE, which has attracted considerable interest worldwide. Besides the global hypomethylation on lupus T and B cells, the gene specific and site-specific methylation has been identified and documented to be responsible for SLE. The purpose of this review was to present and summarize the association between aberrant DNA methylation of immune cells and SLE, the possible mechanisms of immune dysfunction caused by DNA methylation, and to better understand the roles of aberrant DNA methylation in the initiation and development of SLE and to provide an insight into the related diagnosis biomarkers and therapeutic options in SLE. PMID- 26970493 TI - Vascular hypothesis revisited: Role of stimulating antibodies against angiotensin and endothelin receptors in the pathogenesis of systemic sclerosis. AB - Systemic sclerosis (SSc) is a connective tissue disorder of unknown etiology characterized by the presence of multiple autoantibodies, including those against angiotensin and endothelin receptors. Patients with SSc can develop heterogeneous clinical manifestations including microvascular damage, the dysregulation of innate and adaptive immunity, and generalized fibrosis of multiple organs. Autoantibodies against angiotensin II type I receptor (AT1R) and endothelin-1 type A receptor (ETAR) play important roles in the pathogenesis of SSc. These autoantibodies regulate physiological processes ranging from production of collagen by skin fibroblasts to angiogenesis modulation. Understanding the mechanisms behind autoantibodies against AT1R and ETAR could provide insight to future novel therapies for SSc patients. In this review, we focus on elucidating the immunopathological mechanisms triggered by anti-AT1R and anti-ETAR autoantibodies to summarize current knowledge about vascular abnormalities resulting in progressive damage of organs seen in patients with SSc. PMID- 26970494 TI - Validation of a second-generation multivariate index assay for malignancy risk of adnexal masses. AB - BACKGROUND: Women with adnexal mass suspected of ovarian malignancy are likely to benefit from consultation with a gynecologic oncologist, but imaging and biomarker tools to ensure this referral show low sensitivity and may miss cancer at critical stages. OBJECTIVE: The multivariate index assay (MIA) was designed to improve the detection of ovarian cancer among women undergoing surgery for a pelvic mass. To improve the prediction of benign masses, we undertook the redesign and validation of a second-generation MIA (MIA2G). STUDY DESIGN: MIA2G was developed using banked serum samples from a previously published prospective, multisite registry of patients who underwent surgery to remove an adnexal mass. Clinical validity was then established using banked serum samples from the OVA500 trial, a second prospective cohort of adnexal surgery patients. Based on the final pathology results of the OVA500 trial, this intended-use population for MIA2G testing was high risk, with an observed cancer prevalence of 18.7% (92/493). Coded samples were assayed for MIA2G biomarkers by an external clinical laboratory. Then MIA2G results were calculated and submitted to a clinical statistics contract organization for decoding and comparison to MIA results for each subject. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated, among other measures, and stratified by menopausal status, stage, and histologic subtype. RESULTS: Three MIA markers (cancer antigen 125, transferrin, and apolipoprotein A-1) and 2 new biomarkers (follicle-stimulating hormone and human epididymis protein 4) were included in MIA2G. A single cut-off separated high and low risk of malignancy regardless of patient menopausal status, eliminating potential for confusion or error. MIA2G specificity (69%, 277/401 [n/N]; 95% confidence interval [CI], 64.4 73.4%) and PPV (40%, 84/208; 95% CI, 33.9-47.2%) were significantly improved over MIA (specificity, 54%, 215/401; 95% CI, 48.7-58.4%, and PPV, 31%, 85/271; 95% CI, 26.1-37.1%, respectively) in this cohort. Sensitivity and NPV were not significantly different between the 2 tests. When combined with physician assessment, MIA2G correctly identified 75% of the malignancies missed by physician assessment alone. CONCLUSION: MIA2G specificity and PPV were significantly improved compared with MIA, while sensitivity and NPV were unchanged. The second-generation test significantly improved the predicted efficiency of triage vs MIA without sacrificing high sensitivity and NPV, which are essential for effectiveness. PMID- 26970495 TI - Global "omics" evaluation of human placental responses to preeclamptic conditions. AB - BACKGROUND: Preeclampsia (PE) is a leading cause of maternal death. Its cause is still debated but there is general agreement that the placenta plays a central role. Perhaps the most commonly proposed contributors to PE include placental hypoxia, oxidative stress, and increased proinflammatory cytokines. How the placenta responds to these abnormalities has been considered but not as part of a comprehensive analysis of low-molecular-weight biomolecules and their responses to these accepted PE conditions. OBJECTIVE: Using a peptidomic approach, we sought to identify a set of molecules exhibiting differential expression in consequence of provocative agents/chemical mediators of PE applied to healthy human placental tissue. STUDY DESIGN: Known PE conditions were imposed on normal placental tissue from 13 uncomplicated pregnancies and changes in the low molecular-weight peptidome were evaluated. A t test was used to identify potential markers for each imposed stress. These markers were then submitted to a least absolute shrinkage and selection operator multinomial logistic regression model to identify signatures specific to each stressor. Estimates of model performance on external data were obtained through internal validation. RESULTS: A total of 146 markers were increased/decreased as a consequence of exposure to proposed mediators of PE. Of these 75 changed with hypoxia; 23 with hypoxia reoxygenation/oxidative stress and 48 from exposure to tumor necrosis factor alpha. These markers were chemically characterized using tandem mass spectrometry. Identification rates were: hypoxia, 34%; hypoxia-reoxygenation, 60%; and tumor necrosis factor-alpha, 50%. Least absolute shrinkage and selection operator modeling specified 16 markers that effectively distinguished all groups, ie, the 3 abnormal conditions and control. Bootstrap estimates of misclassification rates, multiclass area under the curve, and Brier score were 0.108, 0.944, and 0.160, respectively. CONCLUSION: Using this approach we found previously unknown molecular changes in response to individual PE conditions that allowed development biomolecular signatures for exposure to each accepted pathogenic condition. PMID- 26970496 TI - 3-(imidazo[1,2-a:5,4-b']dipyridin-2-yl)aniline inhibits pestivirus replication by targeting a hot spot drug binding pocket in the RNA-dependent RNA polymerase. AB - The compound 3-(imidazo[1,2-a:5,4-b']dipyridin-2-yl)aniline (CF02334) was identified as a selective inhibitor of the cytopathic effect (CPE) caused by bovine viral diarrhea virus (BVDV) in a virus-cell-based assay. The EC50-values for inhibition of CPE, viral RNA synthesis and the production of infectious virus progeny were 13.0 +/- 0.6 MUM, 2.6 +/- 0.9 MUM and 17.8 +/- 0.6 MUM, respectively. CF02334 was found to be inactive in the hepatitis C subgenomic replicon system. CF02334-resistant BVDV was obtained and was found to carry the N264D mutation in the viral RNA-dependent RNA polymerase (RdRp). Molecular modeling revealed that N264D is located in a small cavity near the fingertip domain of the pestivirus polymerase. CF02334-resistant BVDV was proven to be cross-resistant to BPIP, AG110 and LZ37, inhibitors that have previously been described to target the same region of the BVDV RdRp. CF02334 did not inhibit the in vitro activity of recombinant BVDV RdRp, but did inhibit the activity of BVDV replication complexes. Taken together, these observations indicate that CF02334 likely interacts with the fingertip of the pestivirus RdRp at the same position as BPIP, AG110 and LZ37, which marks this region of the viral polymerase as a "hot spot" for inhibition of pestivirus replication. PMID- 26970497 TI - Brief light exposure at night disrupts the circadian rhythms in eye growth and choroidal thickness in chicks. AB - Changes in ocular growth that lead to myopia or hyperopia are associated with alterations in the circadian rhythms in eye growth, choroidal thickness and intraocular pressure in animal models of emmetropization. Recent studies have shown that light at night has deleterious effects on human health, acting via "circadian disruptions" of various diurnal rhythms, including changes in phase or amplitude. The purpose of this study was to determine the effects of brief, 2-h episodes of light in the middle of the night on the rhythms in axial length and choroidal thickness, and whether these alter eye growth and refractive error in the chick model of myopia. Starting at 2 weeks of age, birds received 2 h of light between 12:00 am and 2:00 am for 7 days (n = 12; total hours of light: 14 h). Age-matched controls had a continuous dark night (n = 14; 14L/10D). Ocular dimensions were measured using high-frequency A-scan ultrasonography on the first day of the experiment, and again on day 7, at 6-h intervals, starting at noon (12 pm, 6 pm, 12 am, 6 am, 12 pm). Measurements during the night were done under a photographic safe-light. These data were used to determine rhythm parameters of phase and amplitude. 2 groups of birds, both experimental (light at night) and control, were measured with ultrasound at various intervals over the course of 4 weeks to determine growth rates. Refractive errors were measured in 6 experimental and 6 control birds at the end of 2 weeks. Eyes of birds in a normal L/D cycle showed sinusoidal 24-h period diurnal rhythms in axial length and choroid thickness. Light in the middle of the night caused changes in both the rhythms in axial length and choroidal thickness, such that neither could be fit to a sine function having a period of 24 h. Light caused an acute, transient stimulation in ocular growth rate in the subsequent 6-h period (12 am-6 am), that may be responsible for the increased growth rate seen 4 weeks later, and the more myopic refractive error. It also abolished the increase in choroidal thickness that normally occurs between 6 pm and 12 am. We conclude that light at night alters the rhythms in axial length and choroidal thickness in an animal model of eye growth, and that these circadian disruptions might lead to the development of ametropias. These results have implications for the use of light during the night in children. PMID- 26970499 TI - Expression and identification of 10 sarcomeric MyHC isoforms in human skeletal muscles of different embryological origin. Diversity and similarity in mammalian species. AB - In the mammalian genome, among myosin heavy chain (MyHC) isoforms a family can be identified as sarcomeric based on their molecular structure which allows thick filament formation. In this study we aimed to assess the expression of the 10 sarcomeric isoforms in human skeletal muscles, adopting this species as a reference for comparison with all other mammalian species. To this aim, we set up the condition for quantitative Real Time PCR assay to detect and quantify MyHC mRNA expression in a wide variety of human muscles from somitic, presomitic and preotic origin. Specific patterns of expression of the following genes MYH1, MYH2, MYH3, MYH4, MYH6, MYH7, MYH8, MYH13, MYH14/7b and MYH15 were demonstrated in various muscle samples. On the same muscle samples which were analysed for mRNA expression, the corresponding MyHC proteins were studied with SDS PAGE and Western blot. The mRNA-protein comparison allowed the identification of 10 distinct proteins based on the electrophoretic migration rate. Three groups were formed based on the migration rate: fast migrating comprising beta/slow/1, alpha cardiac and fast 2B, slow migrating comprising fast 2X, fast 2A and two developmental isoforms (NEO and EMB), intermediate migrating comprising EO MyHC, slow B (product of MYH15), slow tonic (product of MYH14/7b). Of special interest was the demonstration of a protein band corresponding to 2B-MyHC in laryngeal muscles and the finding that all 10 isoforms are expressed in extraocular muscles. These latter muscles are the unique localization for extraocular, slow B (product of MYH15) and slow tonic (product of MYH14/7b). PMID- 26970500 TI - Neurotrophin-4 in the brain of adult Nothobranchius furzeri. AB - Neurotrophin-4 (NT-4) is a member of the well-known family of neurotrophins that regulate the development of neuronal networks by participating in neuronal survival and differentiation, the growth of neuronal processes, synaptic development and plasticity, as well as myelination. NT-4 interacts with two distinct receptors: TrkB, high affinity receptor and p75 low-affinity neurotrophin receptor (p75(NTR)). In the present survey, we identified the gene encoding NT-4 in the teleost Nothobranchius furzeri, a model species for aging research. The identified gene shows a similarity of about 72% with medaka, the closest related species. The neuroanatomical localization of NT-4 mRNA is obtained by using an LNA probe. NT-4 mRNA expression is observed in neurons and glial cells of the forebrain and hindbrain, with very low signal found in the midbrain. This survey confirms that NT-4 is expressed in the brain of N. furzeri during adulthood, suggesting that it could also be implicated in the maintenance and regulation of neuronal functions. PMID- 26970498 TI - Intrahippocampal administration of a domain antibody that binds aggregated amyloid-beta reverses cognitive deficits produced by diet-induced obesity. AB - BACKGROUND: The prevalence of high fat diets (HFD), diet-induced obesity (DIO) and Type 2 diabetes continues to increase, associated with cognitive impairment in both humans and rodent models. Mechanisms transducing these impairments remain largely unknown: one possibility is that a common mechanism may be involved in the cognitive impairment seen in obese and/or diabetic states and in dementia, specifically Alzheimer's disease (AD). DIO is well established as a risk factor for development of AD. Oligomeric amyloid-beta (Abeta) is neurotoxic, and we showed that intrahippocampal oligomeric Abeta produces cognitive and metabolic dysfunction similar to that seen in DIO or diabetes. Moreover, animal models of DIO show elevated brain Abeta, a hallmark of AD, suggesting that this may be one source of cognitive impairment in both conditions. METHODS: Intrahippocampal administration of a novel anti-Abeta domain antibody for aggregated Abeta, or a control domain antibody, to control or HFD-induced DIO rats. Spatial learning measured in a conditioned contextual fear (CCF) task after domain antibody treatment; postmortem, hippocampal NMDAR and AMPAR were measured. RESULTS: DIO caused impairment in CCF, and this impairment was eliminated by intrahippocampal administration of the active domain antibody. Measurement of hippocampal proteins suggests that DIO causes dysregulation of hippocampal AMPA receptors, which is also reversed by acute domain antibody administration. CONCLUSIONS: Our findings support the concept that oligomeric Abeta within the hippocampus of DIO animals may not only be a risk factor for development of AD but may also cause cognitive impairment before the development of dementia. GENERAL SIGNIFICANCE AND INTEREST: Our work integrates the engineering of domain antibodies with conformational- and sequence-specificity for oligomeric amyloid beta with a clinically relevant model of diet-induced obesity in order to demonstrate not only the pervasive effects of obesity on several aspects of brain biochemistry and behavior, but also the bioengineering of a successful treatment against the long-term detrimental effects of a pre-diabetic state on the brain. We show for the first time that cognitive impairment linked to obesity and/or insulin resistance may be due to early accumulation of oligomeric beta-amyloid in the brain, and hence may represent a pre-Alzheimer's state. PMID- 26970501 TI - Augmentation of the hard palate thin masticatory mucosa in the potential connective tissue donor sites using two collagen materials-Clinical and histological comparison. AB - BACKGROUND: Due to the similarity of keratinized gingival and palatal mucosa the latter can pose as a potential donor site for gingival recession coverage. However, its availability is restricted and a thin transplant bears the risk of being rejected. The aim of the present study was to compare the clinical and histological results of thin palatal mucosa augmentation, using lyophilized Biokol(r) xenogenous collagen sponge and a suspension of xenogenous Gel 0(r) pure collagen with non-augmented tissue from the same patients. MATERIALS AND METHODS: Ten patients simultaneously underwent bilateral augmentation procedures using Biokol(r) and Gel 0(r) collagen material. The donor sites were augmented 8 weeks prior to the harvesting of the connective tissue graft (CTG) for the gingival recession coverage procedures. Prior to the implantation of the collagen material and during the course of harvesting the augmented CTG, tissue specimens were taken for histological examination. Prior to the commencement of the study and after it, the parameters of palatal gingival thickness at 4mm (PGT1), and at 8mm apical to the gingival margin (PGT2) around the teeth neighboring the operating fields were determined. RESULTS: In both groups the palatal mucosa had thickened significantly in both measuring sites. An intergroup comparison revealed greater thickening of the masticatory mucosa in the Biokol(r) group at both measuring points. The histological image of the grafts, obtained from sites augmented using both test methods, revealed a typical pattern of mature fibrous connective tissue. No epithelial cells were found. CONCLUSION: Augmentation of thin masticatory mucosa using Biokol(r) or Gel 0(r) collagen materials resulted in a significant thickening of the mucosa, which could be demonstrated to be greater in the first group. PMID- 26970502 TI - The Anatomical Institute at the University of Greifswald during National Socialism: The procurement of bodies and their use for anatomical purposes. AB - This is the first comprehensive account of body procurement at the Anatomical Institute at Greifswald University during National Socialism (NS). As in all other German anatomical departments, the bodies received during this period included increasing numbers of victims of the NS regime. Prior to 1939, 90% of all bodies came from hospitals, state nursing homes and mental institutions (Heil und Pflegeanstalten), but dropped to less than 30% after 1941. While the total catchment area for body procurement decreased, the number of suppliers increased and included prisons, POW camps, Gestapo offices and military jurisdiction authorities. Among the 432 documented bodies delivered to the institute, 132 came from state nursing homes and mental institutions, mainly from Ueckermunde. These were bodies of persons, who probably were victims of "euthanasia" crimes. The Anatomical Institute also procured 46 bodies of forced laborers, of whom at least twelve had been executed. Other groups of victims included 21 bodies of executed Wehrmacht soldiers and 16 Russian prisoners of war from the camp Stalag II C in Greifswald, who had died of starvation and exhaustion. From 1941 onwards, the number of bodies delivered from prisons and penitentiaries greatly increased. In total, 60 bodies of prisoners, mainly from the penitentiary in Gollnow, were delivered to the Anatomical Institute. Greifswald Anatomical Institute was not just a passive recipient of bodies from all of these sources, but the anatomists actively lobbied with the authorities for an increased body supply for teaching and research purposes. PMID- 26970503 TI - Effect of CArbocisteine in Prevention of exaceRbation of chronic obstructive pulmonary disease (CAPRI study): An observational study. AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a chronic and progressive lung disease characterized by irreversible airflow obstruction, airway inflammation, oxidative stress and, often, mucus hypersecretion. The aim of this study is to determine if carbocisteine, a mucolytic and antioxidant agent, administered daily for 12 months, can reduce exacerbation frequency in COPD patients. METHODS: This observational study was conducted in Naples (population approximately 1000,000), Italy. It included 85 out-patients (mean age of 67.8 +/- 8.6 years) followed by Clinic of Respiratory Diseases of the University Federico II. Every patient underwent spirometry demonstrating airflow obstruction not fully reversible according to ERS/ATS criteria for COPD diagnosis (Tiffenau index less than 70% after administration of salbutamol, a beta2 agonist drug). Patients enrolled had diagnosed COPD since 2 years and suffered at least one exacerbation in the previous year. None of the patients had been treated with carbocisteine or other mucolytic agent for a longer period of time than 7 days and no more than 4 times in the previous year to the enrollment. All of them assumed daily 2.7 g of carbocisteine lysine salt for a year in addition to their basic therapy. RESULTS: The comparison of exacerbation frequency between the previous year (T0) and the end of study treatment (T12), documents a statistically significant reduction of exacerbations(number of exacerbations at T0: 2 [1,3] vs number of exacerbations at T12: 1 [1,2]; p < 0.001).Quality of life was also reported and showed a statistically significant improvement at the end of the study (p < 0.001).We did not find correlation between reducing exacerbation frequency and exposure to cigarette smoking, passive smoking exposure in childhood, the use of inhaled steroids, the level of education of our patients and the GOLD stadium. INTERPRETATION: Daily administration of a mucolytic drug such as carbocisteine for prolonged periods in addition to the bronchodilator therapy can be considered a good strategy for reducing exacerbation frequency in COPD. PMID- 26970504 TI - Pathfinders in oncology from ancient times to the end of the Middle Ages. AB - This commentary highlights the onset and progression of the diagnosis and treatment of cancer from ancient times to the 15th century. During the preparation of this synoptic review of the lives and contributions to oncology of 7 ancient physicians, it became clear that despite separation by centuries, ethnicity, and religion, they had many things in common. For example, with the exception of Chauliac, all were born into wealthy families, had an excellent education in the liberal arts and sciences, and were mentored by outstanding teachers. After they became physicians, they traveled extensively, were polyglots, were sponsored by influential individuals, had inquisitive minds, searched for the true nature of diseases, and were proud to share the results of their observations with others. Except for Galen, all of them were kind and well mannered individuals. They cared with sincere dedication for the poor and those who had untreatable disease, including cancer. Although their understanding of cancer was limited, they were deeply concerned about the neglect and hopelessness of cancer patients. They were aware of their shortcomings in offering effective treatment beyond the surgical excision of early cancers. For advanced cancers, they had nothing to give beyond palliative care with herbals and minerals. All physicians who care for cancer patients owe these pioneer physicians, whatever their shortcomings, an inexpressible debt for their attempts to cure cancer. Cancer 2016;122:1638-46. (c) 2016 American Cancer Society. PMID- 26970505 TI - Quantitative Risk Analysis on the Transport of Dangerous Goods Through a Bi Directional Road Tunnel. AB - A quantitative risk analysis (QRA) regarding dangerous goods vehicles (DGVs) running through road tunnels was set up. Peak hourly traffic volumes (VHP), percentage of heavy goods vehicles (HGVs), and failure of the emergency ventilation system were investigated in order to assess their impact on the risk level. The risk associated with an alternative route running completely in the open air and passing through a highly populated urban area was also evaluated. The results in terms of social risk, as F/N curves, show an increased risk level with an increase the VHP, the percentage of HGVs, and a failure of the emergency ventilation system. The risk curves of the tunnel investigated were found to lie both above and below those of the alternative route running in the open air depending on the type of dangerous goods transported. In particular, risk was found to be greater in the tunnel for two fire scenarios (no explosion). In contrast, the risk level for the exposed population was found to be greater for the alternative route in three possible accident scenarios associated with explosions and toxic releases. Therefore, one should be wary before stating that for the transport of dangerous products an itinerary running completely in the open air might be used if the latter passes through a populated area. The QRA may help decisionmakers both to implement additional safety measures and to understand whether to allow, forbid, or limit circulation of DGVs. PMID- 26970507 TI - [Commitment of The Bulletin du Cancer and the College national des enseignants en cancerologie (CNEC) to publish quality papers from residents' thesis]. PMID- 26970506 TI - [On wales and men...]. PMID- 26970509 TI - A novel capsular tension ring as local sustained-release carrier for preventing posterior capsule opacification. AB - One of the most important and challenging goals in pharmaceutical prevention for posterior capsule opacification is to preserve an effective drug concentration in capsular bag for a long period without affecting the patients' vision. Here, a novel kind of composite, which was prepared by 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA) via a two-step process, was applied for capsular tension ring (CTR) as an implant that could deliver docetaxel (DTX) over a long period of time. The drug release rate of the composite could be controlled by the ethyleneglycol dimethacrylate (EGDMA) content and the ratio of HEMA/MMA as well as the structure of porous PMMA framework. The CTR could continuously release DTX for up to 6 weeks in vitro and maintain DTX in effective concentration in the aqueous humor after 42 days. Docetaxel-load capsular tension ring (DTX-CTR) presented strong inhibition on the lens epithelial cells in-vivo without obvious damage to normal tissues. These results indicate that the drug sustained-release CTR can provide a promising application in posterior capsule opacification prevention. PMID- 26970508 TI - Phylogenetics of family Enterobacteriaceae and proposal to reclassify Escherichia hermannii and Salmonella subterranea as Atlantibacter hermannii and Atlantibacter subterranea gen. nov., comb. nov. AB - Multilocus sequence analysis based on hypervariable housekeeping proteins was utilized to differentiate closely related species in the family Enterobacteriaceae. Of 150 housekeeping proteins, the top 10 hypervariable proteins were selected and concatenated to obtain distance data. Distances between concatenated proteins within the family were 0.9-41.2%, whereas the 16S rRNA and atpD-gyrB-infB-rpoB concatenated sequence (4MLSA) distances were 0.8 6.0% and 0.9-22.1%, respectively. These data indicate that phylogenetic analysis by concatenation of hypervariable proteins is a powerful tool for discriminating species in the family Enterobacteriaceae. To confirm the discriminatory power of the 10 chosen concatenated hypervariable proteins (C10HKP), phylogenetic trees based on C10HKP, 4MLSA, and the 16S rRNA gene were constructed. Comparison of average bootstrap values among C10HKP, 4MLSA and 16S rRNA genes indicated that the C10HKP tree was the most reliable. Location via the C10HKP tree was consistent with existing assignments for almost all species in the family Enterobacteriaceae. However, the C10HKP tree suggested that several species (including Enterobacter massiliensis, Escherichia vulneris, Escherichia hermannii, and Salmonella subterranea) should be reassigned to different clusters than those defined in previous analyses. Furthermore, E. hermannii and S. subterranea appeared to fall onto a branch independent from those occupied by the other Enterobacteriaceae. Therefore, we propose Atlantibacter gen. nov., such that E. hermannii and S. subterranea would be transferred to genus Atlantibacter as Atlantibacter hermannii, comb. nov. and Atlantibacter subterranea. comb. nov., respectively. PMID- 26970510 TI - Improvement of islet engrafts by enhanced angiogenesis and microparticle-mediated oxygenation. AB - A major hindrance in islet transplantation as a feasible therapeutic approach for patients with type 1 diabetes is the insufficient oxygenation of the grafts, which results in cell death in portions of the implant. Here we address this limitation through the application of oxygen-generating microparticles (MP) and a fibrin-conjugated heparin/VEGF collagen scaffold to support cell survival by using a beta cell line and pancreatic rat islets. MP are composed of a polyvinylpyrrolidone/hydrogen peroxide (PVP/H2O2) core and poly(D,L-lactide-co glycolide) (PLGA) shell, along with immobilized catalase on the shell. The presence of MP is sufficient to reduce hypoxia-induced cell dysfunction and death for both cell types, resulting in localization of hypoxia-inducible factor (HIF 1alpha) into the cytoplasm and enhanced metabolic function. After co transplantation of MP and a reduced islet mass (250 islet equivalents) within an angiogenic scaffold in the omental pouch of streptozotocin-induced diabetic nude mice, we have observed significantly promoted graft function as evidenced by improved blood glucose levels, body weight, glucose tolerance, serum C-peptide, and graft revascularization. These results suggest that the developed platform has great potential to enhance the efficacy for implants in cases where the cell dosage is critical for efficacy, such as islet transplantation and ischemic tissues. PMID- 26970511 TI - Bioprocessing of bio-based chemicals produced from lignocellulosic feedstocks. AB - The feedstocks used for the production of bio-based chemicals have recently expanded from edible sugars to inedible and more recalcitrant forms of lignocellulosic biomass. To produce bio-based chemicals from renewable polysaccharides, several bioprocessing approaches have been developed and include separate hydrolysis and fermentation (SHF), simultaneous saccharification and fermentation (SSF), and consolidated bioprocessing (CBP). In the last decade, SHF, SSF, and CBP have been used to generate macromolecules and aliphatic and aromatic compounds that are capable of serving as sustainable, drop-in substitutes for petroleum-based chemicals. The present review focuses on recent progress in the bioprocessing of microbially produced chemicals from renewable feedstocks, including starch and lignocellulosic biomass. In particular, the technological feasibility of bio-based chemical production is discussed in terms of the feedstocks and different bioprocessing approaches, including the consolidation of enzyme production, enzymatic hydrolysis of biomass, and fermentation. PMID- 26970513 TI - Association of CD30 transcripts with Th1 responses and proinflammatory cytokines in patients with end-stage renal disease. AB - High serum sCD30 levels are associated with inflammatory disorders and poor outcome in renal transplantation. The contribution to these phenomena of transcripts and proteins related to CD30-activation and -cleavage is unknown. We assessed in peripheral blood of end-stage renal disease patients (ESRDP) transcripts of CD30-activation proteins CD30 and CD30L, CD30-cleavage proteins ADAM10 and ADAM17, and Th1- and Th2-type immunity-related factors t-bet and GATA3. Additionally, we evaluated the same transcripts and release of sCD30 and 32 cytokines after allogeneic and polyclonal T-cell activation. In peripheral blood, ESRDP showed increased levels of t-bet and GATA3 transcripts compared to healthy controls (HC) (both P<0.01) whereas levels of CD30, CD30L, ADAM10 and ADAM17 transcripts were similar. Polyclonal and allogeneic stimulation induced higher levels of CD30 transcripts in ESRDP than in HC (both P<0.001). Principal component analysis (PCA) in allogeneic cultures of ESRDP identified two correlation clusters, one consisting of sCD30, the Th-1 cytokine IFN-gamma, MIP 1alpha, RANTES, sIL-2Ralpha, MIP-1beta, TNF-beta, MDC, GM-CSF and IL-5, and another one consisting of CD30 and t-bet transcripts, IL-13 and proinflammatory proteins IP-10, IL-8, IL-1Ralpha and MCP-1. Reflecting an activated immune state, ESRDP exhibited after allostimulation upregulation of CD30 transcripts in T cells, which was associated with Th1 and proinflammatory responses. PMID- 26970514 TI - Frequent globular neuronal cytoplasmic inclusions in the medial temporal region as a possible characteristic feature in multiple system atrophy with dementia. AB - Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease, which is characterized clinically by parkinsonism, cerebellar ataxia and/or autonomic dysfunction, and pathologically by alpha-synuclein-related multisystem neurodegeneration, so-called alpha-synucleinopathy, which particularly involves the striatonigral and olivopontocerebellar systems, with glial cytoplasmic inclusions and neuronal cytoplasmic/nuclear inclusions (NCIs/NNIs). In the recent consensus criteria for the diagnosis of MSA, dementia is described as one of the features not supporting a diagnosis of MSA. However, MSA with dementia has been reported, although the location of the lesion responsible for the dementia remains unclear. In the present study, we aimed to investigate where this lesion may be found, by analyzing 12 autopsy-proven MSA cases, with a particular focus on the medial temporal region. Three of 12 cases with MSA had dementia (MSA-D). Compared with MSA cases without dementia, MSA-D cases had frequent globular NCIs (G-NCIs) in the medial temporal region, especially in their subiculum. In addition, MSA-D cases could be divided into two types; MSA-D with distinct fronto temporal lobar degeneration (FTLD type) and without distinct fronto-temporal lobar degeneration (non-FTLD type). There was no association between dementia and Alzheimer pathologies, such as neurofibrillary tangles and senile plaques. We suggest that frequent G-NCIs in the medial temporal region, and particularly the subiculum, is one of the important pathological findings of MSA-D, even when a case with MSA-D reveals no significant cerebral atrophy. PMID- 26970515 TI - Community care for Indigenous older people: An update. AB - In this brief paper, we outline some important messages in the literature pertaining to community care for Indigenous older people. Such literature has been scarce until relatively recently. These key messages are particularly important as aged care sector reforms are implemented. We highlight significant research findings concerning health, care preferences and service delivery challenges for the provision of community care for this population group. To be successful, a service needs to be relevant, and to be relevant, services need to take a community development approach in their development and ongoing management. PMID- 26970512 TI - Ectopic expression of a cytochrome P450 monooxygenase gene PtCYP714A3 from Populus trichocarpa reduces shoot growth and improves tolerance to salt stress in transgenic rice. AB - In Arabidopsis thaliana and Oryza sativa, the cytochrome P450 (CYP) 714 protein family represents a unique group of CYP monooxygenase, which functions as a shoot specific regulator in plant development through gibberellin deactivation. Here, we report the functional characterizations of PtCYP714A3, an OsCYP714D1/Eui homologue from Populus trichocarpa. PtCYP714A3 was ubiquitously expressed with the highest transcript level in cambium-phloem tissues, and was greatly induced by salt and osmotic stress in poplar. Subcellular localization analyses indicated that PtCYP714A3-YFP fusion protein was targeted to endoplasmic reticulum (ER). Expression of PtCYP714A3 in the rice eui mutant could rescue its excessive-shoot growth phenotype. Ectopic expression of PtCYP714A3 in rice led to semi-dwarfed phenotype with promoted tillering and reduced seed size. Transgenic lines which showed significant expression of PtCYP714A3 also accumulated lower GA level than did the wild-type (WT) plants. The expression of some GA biosynthesis genes was significantly suppressed in these transgenic plants. Furthermore, transgenic rice plants exhibited enhanced tolerance to salt and maintained more Na(+) in both shoot and root tissues under salinity stress. All these results not only suggest a crucial role of PtCYP714A3 in shoot responses to salt toxicity in rice, but also provide a molecular basis for genetic engineering of salt-tolerant crops. PMID- 26970516 TI - Spatial Heterogeneity of Cortical Excitability in Migraine Revealed by Multifrequency Neuromagnetic Signals. AB - To investigate the spatial heterogeneity of cortical excitability in adolescents with migraine, magnetoencephalography (MEG) recordings at a sampling rate of 6,000 Hz were obtained from 35 adolescents with an acute migraine and 35 age- and sex-matched healthy control participants during an auditory-motor task. Neuromagnetic activation from low- to high-frequency ranges (5-1,000 Hz) was measured at sensor and source levels. The heterogeneity of cortical excitability was quantified within each functional modality (auditory vs motor) and hemispherical lateralization. MEG data showed that high-frequency, not low frequency neuromagnetic signals, showed heterogeneous cortical activation in migraine subjects compared with control participants (P < .001). The alteration of the heterogeneity of cortical excitability in migraine subjects was independent of age and sex. The degree of the neuromagnetic heterogeneity of cortical activation was significantly correlated with headache frequency (r = .71, P < .005). The alteration of cortical excitability in migraine subjects was spatially heterogeneous and frequency dependent, which previously has not been reported. The finding may be critical for developing spatially targeted therapeutic strategies for normalizing cortical excitability with the purpose of reducing headache attacks. PERSPECTIVE: This article presents a new approach to quantitatively measure the spatial heterogeneity of cortical excitability in adolescents with migraine using MEG signals in a frequency range of 5 to 1,000 Hz. The characteristics of the location and degree of cortical excitability may be critical for spatially targeted treatment for migraine. PMID- 26970517 TI - Aspiration Abortion With Immediate Intrauterine Device Insertion: Comparing Outcomes of Advanced Practice Clinicians and Physicians. AB - INTRODUCTION: Immediate postabortion intrauterine device (IUD) insertion is a safe, effective strategy to prevent subsequent unplanned pregnancy. Oregon is one of 5 US states where advanced practice clinicians perform aspiration abortions. This study compares outcomes of first-trimester aspiration abortion with immediate IUD insertion between advanced practice clinicians and physicians. METHODS: We conducted a historical cohort study of first-trimester aspiration abortions with immediate IUD insertion performed at our center from 2009 to 2011. We extracted demographic and clinical data from patient charts. Immediate complications including excessive blood loss, perforation, and reaspirations were recorded at the time of procedure. We used descriptive statistics and multivariable logistic regression to test for differences in outcomes by clinician type. RESULTS: Data were available on 669 of the 1134 combined procedures. Advanced practice clinicians performed 224 of these. There were no significant differences in immediate outcomes. The only immediate complications were reaspirations; 1.8% (4/224) in the advanced practice clinician group, and 2.0% (9/445) in the physician group (P = .83). DISCUSSION: We found no differences in outcomes between provider type for immediate IUD insertion after first-trimester aspiration abortion. This study helps reinforce that advanced practice clinicians can provide immediate postaspiration abortion IUD insertions with similar outcomes to those of physicians. Many countries do not allow advanced practice clinicians to perform this service, but a change in policy could help address family planning provider shortages. PMID- 26970518 TI - Cancer Cell Membrane-Coated Upconversion Nanoprobes for Highly Specific Tumor Imaging. AB - Cancer cell membrane-coated upconversion nanoprobes (CC-UCNPs) with immune escape and homologous targeting capabilities are used for highly specific tumor imaging. The combination of UCNPs with biomimetic cancer cell membranes embodies a novel materials design strategy and presents a compelling class of advanced materials. PMID- 26970519 TI - Pharmacology-based toxicity assessment: towards quantitative risk prediction in humans. AB - Despite ongoing efforts to better understand the mechanisms underlying safety and toxicity, ~30% of the attrition in drug discovery and development is still due to safety concerns. Changes in current practice regarding the assessment of safety and toxicity are required to reduce late stage attrition and enable effective development of novel medicines. This review focuses on the implications of empirical evidence generation for the evaluation of safety and toxicity during drug development. A shift in paradigm is needed to (i) ensure that pharmacological concepts are incorporated into the evaluation of safety and toxicity; (ii) facilitate the integration of historical evidence and thereby the translation of findings across species as well as between in vitro and in vivo experiments and (iii) promote the use of experimental protocols tailored to address specific safety and toxicity questions. Based on historical examples, we highlight the challenges for the early characterisation of the safety profile of a new molecule and discuss how model-based methodologies can be applied for the design and analysis of experimental protocols. Issues relative to the scientific rationale are categorised and presented as a hierarchical tree describing the decision-making process. Focus is given to four different areas, namely, optimisation, translation, analytical construct and decision criteria. From a methodological perspective, the relevance of quantitative methods for estimation and extrapolation of risk from toxicology and safety pharmacology experimental protocols, such as points of departure and potency, is discussed in light of advancements in population and Bayesian modelling techniques (e.g. non-linear mixed effects modelling). Their use in the evaluation of pharmacokinetics (PK) and pharmacokinetic-pharmacodynamic relationships (PKPD) has enabled great insight into the dose rationale for medicines in humans, both in terms of efficacy and adverse events. Comparable benefits can be anticipated for the assessment of safety and toxicity profile of novel molecules. PMID- 26970520 TI - Brain metabolism as a modulator of autophagy in neurodegeneration. AB - Emerging evidence that autophagy serves as a sweeper for toxic materials in the brain gives us new insight into the pathophysiology of neurodegenerative diseases. Autophagy is important for maintaining cellular homeostasis associated with metabolism. Some neurodegenerative diseases such as Alzheimer's and Parkinson's diseases are accompanied by altered metabolism and autophagy in the brain. In this review, we discuss how hormones and nutrients regulate autophagy in the brain and affect neurodegeneration. This article is part of a Special Issue entitled SI:Autophagy. PMID- 26970521 TI - Severe hypertriglyceridemia does not protect from ischemic brain injury in gene modified hypertriglyceridemic mice. AB - Hypertriglyceridemia (HTG) is a weak risk factor in primary ischemic stroke prevention. However, clinical studies have found a counterintuitive association between a good prognosis after ischemic stroke and HTG. This "HTG paradox" requires confirmation and further explanation. The aim of this study was to experimentally assess this paradox relationship using the gene-modified mice model of extreme HTG. We first used the human Apolipoprotein CIII transgenic (Tg ApoCIII) mice and non-transgenic (Non-Tg) littermates to examine the effect of HTG on stroke. To our surprise, infarct size, neurological deficits, brain edema, BBB permeability, neuron density and lipid peroxidation were the same in Tg ApoCIII mice and Non-Tg mice after temporary middle cerebral artery occlusion (tMCAO). In the late phase (21 days after surgery), no differences were found in brain atrophy, neurological dysfunctions, weight and mortality between the two groups. To confirm the results in Tg-ApoCIII mice, Glycosylphosphatidylinositol anchored high-density lipoprotein-binding protein 1(GPIHBP1) knockout mice, another severe HTG mouse model, were used and yielded similar results. Our study demonstrates for the first time that extreme HTG does not affect ischemic brain injuries in the tMCAO mouse model, indicating that the association between HTG and good outcomes after ischemic stroke probably represents residual unmeasured confounding. Further clinical and prospective population-based studies are needed to explore variables that contribute to the paradox. PMID- 26970522 TI - Sexual selection and assortative mating: an experimental test. AB - Mate choice and mate competition can both influence the evolution of sexual isolation between populations. Assortative mating may arise if traits and preferences diverge in step, and, alternatively, mate competition may counteract mating preferences and decrease assortative mating. Here, we examine potential assortative mating between populations of Drosophila pseudoobscura that have experimentally evolved under either increased ('polyandry') or decreased ('monogamy') sexual selection intensity for 100 generations. These populations have evolved differences in numerous traits, including a male signal and female preference traits. We use a two males: one female design, allowing both mate choice and competition to influence mating outcomes, to test for assortative mating between our populations. Mating latency shows subtle effects of male and female interactions, with females from the monogamous populations appearing reluctant to mate with males from the polyandrous populations. However, males from the polyandrous populations have a significantly higher probability of mating regardless of the female's population. Our results suggest that if populations differ in the intensity of sexual selection, effects on mate competition may overcome mate choice. PMID- 26970524 TI - Childhood Misfortune, Personality, and Heart Attack: Does Personality Mediate Risk of Myocardial Infarction? AB - Objective: Previous research has revealed a link between childhood experiences and adult health, but the mechanisms underlying this relationship are less clear. To elucidate this relationship, we investigated the pathway from childhood misfortune to nonfatal myocardial infarction (MI) via individual differences in personality. Method: Longitudinal data were drawn from the National Survey of Midlife Development in the United States, which sampled 3,032 men and women aged 25-74 years at baseline. Big 5 personality traits and multiple measures of childhood misfortune were used to assess whether personality mediated the effect of childhood misfortune on MI risk. Results: A series of proportional hazards models revealed that neuroticism mediated the effect of additive childhood misfortune on adult MI risk. Discussion: Childhood misfortune may be formative in the development of personality, which, subsequently, can be consequential to health. These findings highlight the salient roles of early-life experiences and personality to shape health and aging. PMID- 26970523 TI - Oral Health-A Neglected Aspect of Subjective Well-Being in Later Life. AB - Objectives: This study examined whether oral health is a neglected aspect of subjective well-being (SWB) among older adults. The key research question was whether deterioration in oral health among dentate older adults living in England was associated with decreases in SWB, using measures of eudemonic, evaluative, and affective dimensions of well-being. Methods: This secondary analysis used data from the third (2006-2007) and fifth (2010-2011) waves of respondents aged 50 and older from the English Longitudinal Study of Ageing (ELSA). We fitted multivariable regression models to examine the effects of changes in oral impacts on daily life and edentulism (complete tooth loss) on SWB (quality of life, life satisfaction, and depressive symptomatology). Results: A worsening in both oral health measures was associated with an increase in depressive symptoms even after adjusting for time-varying confounders including declining health, activities of daily living, and reduced social support. Becoming edentate was also associated with decreases in quality of life and life satisfaction. Discussion: A deterioration in oral health and oral health-related quality of life increases the risk of depressive symptoms among older adults and highlights the importance of oral health as a determinant of subjective well-being in later life. PMID- 26970525 TI - rAAV-mediated combined gene transfer and overexpression of TGF-beta and SOX9 remodels human osteoarthritic articular cartilage. AB - Direct administration of therapeutic candidate gene sequences using the safe and effective recombinant adeno-associated virus (rAAV) vectors is a promising strategy to stimulate the biologic activities of articular chondrocytes as an adapted tool to treat human osteoarthritic (OA) cartilage. In the present study, we developed a combined gene transfer approach based on the co-delivery of the pleiotropic transformation growth factor beta (TGF-beta) with the specific transcription factor SOX9 via rAAV to human normal and OA chondrocytes in vitro and cartilage explants in situ in light of the mitogenic and pro-anabolic properties of these factors. Effective, durable co-overexpression of TGF-beta and SOX9 significantly enhanced the levels of cell proliferation both in human normal and OA chondrocytes and cartilage explants over an extended period of time (21 days), while stimulating the biosynthesis of key matrix components (proteoglycans, type-II collagen) compared with control conditions (reporter lacZ gene transfer, absence of vector treatment). Of further note, expression of hypertrophic type-X collagen significantly decreased following co-treatment by the candidate vectors. The present findings show the value of combining the transfer and expression of potent candidate factors in human OA cartilage as a means to re-establish essential features of normal cartilage and counteract the pathological shift of homeostasis. These observations support the concept of developing dual therapeutic rAAV gene transfer strategies as future, adapted tools for the direct treatment of human OA. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2181-2190, 2016. PMID- 26970530 TI - Porcine circovirus type 2 protective epitope densely carried by chimeric papaya ringspot virus-like particles expressed in Escherichia coli as a cost-effective vaccine manufacture alternative. AB - Porcine circovirus type 2 (PCV2) still represents a major problem to the swine industry worldwide, causing high mortality rates in infected animals. Virus-like particles (VLPs) have gained attention for vaccine development, serving both as scaffolds for epitope expression and immune response enhancers. The commercial subunit vaccines against PCV2 consist of VLPs formed by the self-assembly of PCV2 capsid protein (CP) expressed in the baculovirus vector system. In this work, a PCV2 protective epitope was inserted into three different regions of papaya ringspot virus (PRSV) CP, namely, the N- and C-termini and a predicted antigenic region located near the N-terminus. Wild-type and chimeric CPs were modeled in silico, expressed in Escherichia coli, purified, and visualized by transmission electron microscopy. This is the first report that shows the formation of chimeric VLPs using PRSV as epitope-presentation scaffold. Moreover, it was found that PCV2 epitope localization strongly influences VLP length. Also, the estimated yields of the chimeric VLPs at a small-scale level ranged between 65 and 80 mg/L of culture medium. Finally, the three chimeric VLPs induced high levels of immunoglobulin G against the PCV2 epitope in immunized BALB/c mice, suggesting that these chimeric VLPs can be used for swine immunoprophylaxis against PCV2. PMID- 26970526 TI - Extended-Release Once-Daily Formulation of Tofacitinib: Evaluation of Pharmacokinetics Compared With Immediate-Release Tofacitinib and Impact of Food. AB - Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. An extended-release (XR) formulation has been designed to provide a once-daily (QD) dosing option to patients to achieve comparable pharmacokinetic (PK) parameters to the twice-daily immediate-release (IR) formulation. We conducted 2 randomized, open-label, phase 1 studies in healthy volunteers. Study A characterized single-dose and steady-state PK of tofacitinib XR 11 mg QD and intended to demonstrate equivalence of exposure under single-dose and steady state conditions to tofacitinib IR 5 mg twice daily. Study B assessed the effect of a high-fat meal on the bioavailability of tofacitinib from the XR formulation. Safety and tolerability were monitored in both studies. In study A (N = 24), the XR and IR formulations achieved time to maximum plasma concentration at 4 hours and 0.5 hours postdose, respectively; terminal half-life was 5.9 hours and 3.2 hours, respectively. Area under plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax ) after single- and multiple-dose administration were equivalent between the XR and IR formulations. In study B (N = 24), no difference in AUC was observed for fed vs fasted conditions. Cmax increased by 27% under the fed state. On repeat administration, negligible accumulation (<20%) of systemic exposures was observed for both formulations. Steady state was achieved within 48 hours of dosing with the XR formulation. Tofacitinib administration as an XR or IR formulation was generally well tolerated in these studies. PMID- 26970531 TI - Screening of the anthocyanin profile and in vitro pancreatic lipase inhibition by anthocyanin-containing extracts of fruits, vegetables, legumes and cereals. AB - BACKGROUND: The phytotherapic treatment of overweight and/or moderate obesity is growing widely, thus there is a great interest towards the phenolic compounds of fruits and vegetables which may inhibit pancreatic lipase enzyme. In this study, we report the chemical composition and in vitro pancreatic lipase inhibitory activity of 13 freeze-dried anthocyanin-containing extracts of different Mediterranean plants: fruits (blood orange, pomegranate, blackberry, mulberry and sumac), citrus by-products (blood orange peel), citrus vegetative tissues (young lemon shoots); vegetables (red cabbage and violet cauliflower), legume seeds (black bean), cereals (black rice), and cereal processing by-products (black rice hull). Total phenols and anthocyanins were determined. Individual anthocyanins were identified by UHPLC-PDA-ESI/MSn . RESULTS: Results revealed a wide variation in the distribution of anthocyanin compounds. Blood orange and pomegranate juice extracts had the highest total anthocyanin content and exhibited the strongest inhibition of pancreatic lipase in vitro. CONCLUSION: Inhibitory activity was positively correlated with anthocyanin content. In appropriate formulations, anthocyanin-containing extracts could find a use as anti-obesity agents. (c) 2016 Society of Chemical Industry. PMID- 26970532 TI - Combined Left Atrial Appendage Closure and Pacemaker Implant through a Single Right Femoral Vein Access. AB - Left atrial appendage (LAA) closure is indicated in patients with atrial fibrillation (AF) and high bleeding as well as thromboembolic risks. A subgroup of these patients may also present an indication for a single-chamber permanent pacemaker due to symptomatic low-rate AF or when "ablate and pace" strategy is indicated for rate control. A miniaturized wireless transcatheter pacing system (TPS) is now available as a single-chamber permanent pacemaker. This case presents how combined LAA closure and permanent pacemaker implant, by means of TPS, is feasible through a single femoral venous access. PMID- 26970535 TI - Repeated ischaemic preconditioning: a novel therapeutic intervention and potential underlying mechanisms. AB - What is the topic of this review? This review discusses the effects of repeated exposure of tissue to ischaemic preconditioning on cardiovascular function, the attendant adaptations and their potential clinical relevance. What advances does it highlight? We discuss the effects of episodic exposure to ischaemic preconditioning to prevent and/or attenuate ischaemic injury and summarize evidence pertaining to improvements in cardiovascular function and structure. Discussion is provided regarding the potential mechanisms that contribute to both local and systemic adaptation. Findings suggest that clinical benefits result from both the prevention of ischaemic events and the attenuation of their consequences. Ischaemic preconditioning (IPC) refers to the phenomenon whereby short periods of cyclical tissue ischaemia confer subsequent protection against ischaemia-induced injury. As a consequence, IPC can ameliorate the myocardial damage following infarction and can reduce infarct size. The ability of IPC to confer remote protection makes IPC a potentially feasible cardioprotective strategy. In this review, we discuss the concept that repeated exposure of tissue to IPC may increase the 'dose' of protection and subsequently lead to enhanced protection against ischaemia-induced myocardial injury. This may be relevant for clinical populations, who demonstrate attenuated efficacy of IPC to prevent or attenuate ischaemic injury (and therefore myocardial infarct size). Furthermore, episodic IPC facilitates repeated exposure to local (e.g. shear stress) and systemic stimuli (e.g. hormones, cytokines, blood-borne substances), which may induce improvement in vascular function and health. Such adaptation may contribute to prevention of cardio- and cerebrovascular events. The clinical benefits of repeated IPC may, therefore, result from both the prevention of ischaemic events and the attenuation of their consequences. We provide an overview of the literature pertaining to the impact of repeated IPC on cardiovascular function, related to both local and remote adaptation, as well as potential clinical implications. PMID- 26970533 TI - Rituximab extended schedule or retreatment trial for low tumour burden non follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. AB - The rituximab extended schedule or retreatment trial (RESORT; E4402) was a phase 3 randomized prospective trial comparing maintenance rituximab (MR) versus a retreatment (RR) dosing strategy in asymptomatic, low tumour burden indolent lymphoma. A planned exploratory sub-study compared the two strategies for small lymphocytic (SLL) and marginal zone lymphomas (MZL). Patients responding to rituximab weekly * 4 were randomized to MR (single dose rituximab every 3 months until treatment failure) or RR (rituximab weekly * 4) at the time of each progression until treatment failure. The primary endpoint was time to treatment failure (TTTF). Patients with SLL (n = 57), MZL (n = 71) and unclassifiable small B-cell lymphoma (n = 3) received induction rituximab. The overall response rate (ORR) was 40% [95% confidence interval (CI) 31-49%; SLL ORR 22.8%; MZL ORR 52.1%]; all 52 responders were randomized. At a median of 4.3 years from randomization, treatment failure occurred in 18/23 RR and 15/29 MR. The median TTTF was 1.4 years for RR and 4.8 years for MR (P = 0.012); median time to first cytotoxic therapy was 6.3 years for RR and not reached for MR (P = 0.0002). Survival did not differ (P = 0.72). In low tumour burden SLL and MZL patients responding to rituximab induction, MR significantly improved TTTF as compared with RR. PMID- 26970536 TI - Delta-MELD and survival after liver transplantation: the slope matters. PMID- 26970534 TI - Enhanced Fibril Fragmentation of N-Terminally Truncated and Pyroglutamyl-Modified Abeta Peptides. AB - N-terminal truncation and pyroglutamyl (pE) formation are naturally occurring chemical modifications of the Abeta peptide in Alzheimer's disease. We show herein that these two modifications significantly reduce the fibril length and the transition midpoint of thermal unfolding of the fibrils, but they do not substantially perturb the fibrillary peptide conformation. This observation implies that the N terminus of the unmodified peptide protects Abeta fibrils against mechanical stress and fragmentation and explains the high propensity of pE-modified peptides to form small and particularly toxic aggregates. PMID- 26970537 TI - A Diagnostic Dilemma: Similarity of Neuroradiological Findings in Central Nervous System Hemophagocytic Lymphohistiocytosis and Aspergillosis. AB - Central nervous system (CNS) involvement in the context of hemophagocytic lymphohistiocytosis (HLH) is not uncommon. Given the immunosuppressive nature of HLH therapy, infectious complications are also seen. We describe a 9-year-old male who developed acute neurological decline secondary to aspergillosis while undergoing HLH therapy. The significant overlap observed in CNS neuroimaging of HLH and aspergillosis and the subtleties that may help differentiate the two are discussed. The importance of obtaining tissue for definitive diagnosis is underscored. PMID- 26970538 TI - Defining appropriateness criteria for endoscopic sinus surgery during management of uncomplicated adult chronic rhinosinusitis: a RAND/UCLA appropriateness study. AB - BACKGROUND: Appropriate indications for endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS) are currently poorly defined. The lack of clear surgical indications for ESS likely contributes to the large geographic variation in surgical rates and contributes to reduced quality of care. The objective of this study was to define appropriateness criteria for ESS during management of adult patients with uncomplicated CRS. METHODS: The RAND/UCLA appropriateness methodology was performed. An international, multidisciplinary panel of 10 experts in CRS was formed and completed 2 rounds of a modified Delphi ranking process along with a face-to-face meeting. RESULTS: A total of 624 clinical scenarios were ranked, 312 scenarios each for CRS with and CRS without nasal polyps. For adult patients with uncomplicated CRS with nasal polyps, ESS can be appropriately offered when the CT Lund-Mackay score is >= 1 and there has been a minimum trial of a topical intranasal corticosteroid plus a short-course of systemic corticosteroid with a post-treatment total SNOT-22 score >= 20. For adult patients with uncomplicated CRS without nasal polyps, ESS can be appropriately offered when the CT Lund-Mackay score is >= 1 and there has been a minimum trial of a topical intranasal corticosteroid plus either a short-course of a broad spectrum/culture-directed systemic antibiotic or the use of a prolonged course of systemic low-dose anti-inflammatory antibiotic with a post treatment total SNOT-22 score >= 20. CONCLUSION: This study has developed and reported of list of appropriateness criteria to offer ESS as a treatment "option" during management of uncomplicated adult CRS. The extent or technique of ESS was not addressed in this study and will depend on surgeon and patient factors. Furthermore, these criteria are the minimal threshold to make ESS a treatment "option" and do not imply that all patients meeting these criteria require surgery. The decision to perform ESS should be made after an informed patient makes a preference-sensitive decision to proceed with surgery. Applying these appropriateness criteria for ESS may optimize patient selection, reduce the incidence of unwarranted surgery, and assist clinicians in providing high quality, patient-centered care to patients with CRS. PMID- 26970539 TI - Metal-Organic Framework (MOF) Compounds: Photocatalysts for Redox Reactions and Solar Fuel Production. AB - Metal-organic frameworks (MOFs) are crystalline porous materials formed from bi- or multipodal organic linkers and transition-metal nodes. Some MOFs have high structural stability, combined with large flexibility in design and post synthetic modification. MOFs can be photoresponsive through light absorption by the organic linker or the metal oxide nodes. Photoexcitation of the light absorbing units in MOFs often generates a ligand-to-metal charge-separation state that can result in photocatalytic activity. In this Review we discuss the advantages and uniqueness that MOFs offer in photocatalysis. We present the best practices to determine photocatalytic activity in MOFs and for the deposition of co-catalysts. In particular we give examples showing the photocatalytic activity of MOFs in H2 evolution, CO2 reduction, photooxygenation, and photoreduction. PMID- 26970540 TI - Long-term recovery of muscle strength after denervation in the fibular division of the sciatic nerve. AB - INTRODUCTION: The probability and degree of muscle recovery after lesions of long peripheral nerves have not been assessed quantitatively. METHODS: Twelve adults with closed injuries of the fibular division of the sciatic nerve with complete denervation of associated muscles were followed-up for 2-10 years. The onset of reinnervation was detected electromyographically. Calf circumference and maximum voluntary isometric contraction (MVIC) of foot dorsiflexion were measured on both sides during 2-4 visits. RESULTS: Reinnervation occurred in 11 patients after an average of 13 months. MVIC on the affected side was 2%-27% of that on the unaffected side (average 11%) and remained stable for the following 2-3 years. Correlations and mixed-model regressions confirmed that the degree of recovery was negatively associated with duration of denervation. CONCLUSIONS: Reinnervation occurs in about 90% of patients within about 1 year. About 10% of baseline dorsiflexion strength is permanently recovered, which is functionally relevant. Muscle Nerve, 2016 Muscle Nerve 54: -, 2016 Muscle Nerve 54: 702-708, 2016. PMID- 26970541 TI - Two cases of kidney transplantation-associated thrombotic microangiopathy successfully treated with eculizumab. AB - Transplantation-associated thrombotic microangiopathy (TA-TMA) is relatively rare and requires immediate intervention to avoid irreversible organ damage or death; however, consensus regarding the treatment approach is lacking. Atypical haemolytic uraemic syndrome (aHUS) is a rare disease caused by dysregulation of the alternative complement pathway resulting in TMA. aHUS is histologically similar to TA-TMA; approximately 60% of TA-TMA patients have complement dysregulation. Eculizumab, a humanized anti-C5 monoclonal antibody, inhibits terminal membrane-attack complex formation and TMA progression. Eculizumab has been successfully used to treat aHUS post-transplant. We present two cases of kidney TA-TMA due to unknown causes, suspected antibody-mediated rejection, or calcineurin inhibitor (CNI)-related toxicity that developed on day 1 or 2 post kidney transplantation. Low platelet count and haemoglobin level with red cell fragments were detected. Despite steroid pulse, plasma exchange (PE), and intravenous immunoglobulin therapy, TA-TMA did not improve; therefore, eculizumab was administered despite no genetic testing. Laboratory data, including renal function, improved immediately. TA-TMA treatment primarily involves PE initiation or CNI discontinuation; eculizumab can be used to safely treat TA-TMA and then be ceased in the short term. Therefore, eculizumab administration might be beneficial for kidney TA-TMA as early as the diagnosis of refractory to PE. PMID- 26970542 TI - How do pregnant women justify smoking? A qualitative study with implications for nurses' and midwives' anti-tobacco interventions. AB - AIM: To research the subjective lay justifications expressed by smoking pregnant women to explain why they use cigarettes during pregnancy and to determine a typology for these justifications. BACKGROUND: Smoking pregnant mothers' awareness of the detrimental effects of smoking on foetal health frequently is a source of stress and cognitive dissonance (stemming from the contrast between viewing themselves as responsible mothers and smokers). One possible way to reduce these unpleasant feelings is acceptance or creation of beliefs allowing them to explain rationally why they continue this behaviour during pregnancy. DESIGN: Qualitative design. METHODS: Thematic analysis of the content of posts from the three largest Polish parenting on-line forums written between the time they were founded and 12 November 2012. The data were collected between September - October 2012. During the analysis of the selected 73 posts, each of which included subjective explanations of smoking during pregnancy, 151 fragments, each containing one lay justification, were identified and analysed. FINDINGS: Thirty five subthemes of lay justifications assigned to two main themes were developed. The first main theme includes convictions that undermine the need to break the nicotine addiction and the positive aspects resulting from quitting. The second main theme comprises beliefs that question the possibility to abstain from smoking and exaggerate the barriers in the process of quitting. CONCLUSIONS: The creation of a typology of lay justifications might help nurses and midwives perform more effective anti-tobacco interventions geared specifically towards the thought patterns typical of pregnant women. PMID- 26970543 TI - Hired crop worker injuries on farms in the United States: A comparison of two survey periods from the National Agricultural Workers Survey. AB - BACKGROUND: Hired crop workers in the United States are at high risk of occupational injury. Targeted surveillance is important for effective occupational safety efforts. METHODS: The National Agricultural Workers Survey was utilized to collect injury data during the years 1999, 2002-2004 (period I) and 2008-2010 (period II). RESULTS: The overall injury rate declined between the two periods from 4.3 to 2.9/100 per full-time week-based equivalents (FTEWB ). Injury rates remained high during both periods for those with greater than 20 years farm experience (3.6 and 3.8/100 FTEWB ) and pesticide handling work (4.9 and 5.0/100 FTEWB ). Overexertion, contact with objects and equipment, and falls from height were common during both periods. Older workers comprised a greater proportion of injury cases in period II. CONCLUSION: Overexertion that leads to sprains/strains, dangerous ladder use, and pesticide use should be targeted as important risk exposures on the farm. PMID- 26970544 TI - Characterization of equine cytochrome P450: role of CYP3A in the metabolism of diazepam. AB - Research on drug metabolism and pharmacokinetics in large animal species including the horse is scarce because of the challenges in conducting in vivo studies. The metabolic reactions catalyzed by cytochrome P450s (CYPs) are central to drug pharmacokinetics. This study elucidated the characteristics of equine CYPs using diazepam (DZP) as a model compound as this drug is widely used as an anesthetic and sedative in horses, and is principally metabolized by CYPs. Diazepam metabolic activities were measured in vitro using horse and rat liver microsomes to clarify the species differences in enzyme kinetic parameters of each metabolite (temazepam [TMZ], nordiazepam [NDZ], p-hydroxydiazepam [p-OH DZP], and oxazepam [OXZ]). In both species microsomes, TMZ was the major metabolite, but the formation rate of p-OH-DZP was significantly less in the horse. Inhibition assays with a CYP-specific inhibitors and antibody suggested that CYP3A was the main enzyme responsible for DZP metabolism in horse. Four recombinant equine CYP3A isoforms expressed in Cos-7 cells showed that CYP3A96, CYP3A94, and CYP3A89 were important for TMZ formation, whereas CYP3A97 exhibited more limited activity. Phylogenetic analysis suggested diversification of CYP3As in each mammalian order. Further study is needed to elucidate functional characteristics of each equine CYP3A isoform for effective use of diazepam in horses. PMID- 26970545 TI - Biodegradation of phthalate esters by newly isolated Rhizobium sp. LMB-1 and its biochemical pathway of di-n-butyl phthalate. AB - AIMS: To isolate a novel strain that could degrade many kinds PAEs efficiently and investigate the DBP-degrading pathway in this strain. METHODS AND RESULTS: Based on its 16S rRNA gene sequence, the strain was identified as Rhizobium sp. This strain, named LMB-1, can also utilize phthalates, such as DEHP, DMP, DBP and DEP. During the degradation of DBP, six possible metabolites, diethyl phthalate, mono-ethyl phthalate, di-methyl phthalate, mono-methyl phthalate, phthalic acid and tartaric acid, were identified by gas chromatography-mass spectrometry (GC MS) analysis, and the degradation pathway of DBP was also identified in this study. CONCLUSIONS: In summary, strain LMB-1, identified as Rhizobium sp., was found to be capable of efficiently degrading PAEs, and it was determined that the strain degraded DMP completely within 45 h. DEP, DMP, MEP, MMP, PA and tartaric acid were detected during the course of DBP degradation by LMB-1. We propose that this strain could completely degrade DBP or other PAEs. Our results offer a novel and potential candidate, Rhizobium sp. LMB-1, for use in the bioremediation of cultivated soil contaminated by PAEs. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report concerning the complete degradation of phthalate esters by Rhizobium sp. PMID- 26970547 TI - Flutamide-induced photoleukomelanoderma. PMID- 26970546 TI - Maternal residential exposure to agricultural pesticides and birth defects in a 2003 to 2005 North Carolina birth cohort. AB - BACKGROUND: Birth defects are responsible for a large proportion of disability and infant mortality. Exposure to a variety of pesticides have been linked to increased risk of birth defects. METHODS: We conducted a case-control study to estimate the associations between a residence-based metric of agricultural pesticide exposure and birth defects. We linked singleton live birth records for 2003 to 2005 from the North Carolina (NC) State Center for Health Statistics to data from the NC Birth Defects Monitoring Program. Included women had residence at delivery inside NC and infants with gestational ages from 20 to 44 weeks (n = 304,906). Pesticide exposure was assigned using a previously constructed metric, estimating total chemical exposure (pounds of active ingredient) based on crops within 500 meters of maternal residence, specific dates of pregnancy, and chemical application dates based on the planting/harvesting dates of each crop. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals for four categories of exposure (<10(th) , 10-50(th) , 50-90(th) , and >90(th) percentiles) compared with unexposed. Models were adjusted for maternal race, age at delivery, education, marital status, and smoking status. RESULTS: We observed elevated ORs for congenital heart defects and certain structural defects affecting the gastrointestinal, genitourinary and musculoskeletal systems (e.g., OR [95% confidence interval] [highest exposure vs. unexposed] for tracheal esophageal fistula/esophageal atresia = 1.98 [0.69, 5.66], and OR for atrial septal defects: 1.70 [1.34, 2.14]). CONCLUSION: Our results provide some evidence of associations between residential exposure to agricultural pesticides and several birth defects phenotypes. Birth Defects Research (Part A) 106:240-249, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26970548 TI - Understanding baby boomer workers' well-being in Australia. AB - AIMS: The baby boomer generation poses challenges to understand how to enhance both the well-being and the continuing workforce participation of older workers. We sought to explore the role of social relations both at work and in other domains of life, in relation to the health and well-being of the baby boomer workforce in Australia. METHODS: Employed participants (n = 743) born 1946-1965 inclusive provided information about their work environment, financial security and loneliness. Regressions were used to explore the relationships of those variables to well-being (work-life interference, absenteeism, job satisfaction, life satisfaction, health and psychological distress). RESULTS: Social environment indicators especially supervisor support and worker loneliness reliably increased the variance explained by demographics and work demands and control, in well-being outcomes. CONCLUSION: To maintain the well-being and workforce participation of baby boomer generation workers, employers need to attend to creating worker-friendly environments. PMID- 26970549 TI - Making themselves at home: Support needs of older Germans in Australia. AB - AIM: This paper explores the experiences of older German Australians, with a focus on their support needs and preferences in later life. METHODS: Data were collected through qualitative semi-structured interviews. Data analysis incorporated a systematic concept matrix approach to content analysis. RESULTS: The findings of the study indicate that older German Australians have adapted well to the Australian way of life. Their high English language proficiency allowed them to source services without the barrier of language often reported in studies of older migrants. They did not show high interest in ethno-specific services. CONCLUSION: Few studies have been conducted on older German Australians, and none focuses specifically on their experience of ageing in Australia. This study contributes to the body of knowledge on older migrants and, specifically, on those for whom language is not necessarily a major obstacle to obtaining aged care information or services. PMID- 26970550 TI - The refugee crisis in Europe: will it increase disparity in women's health? PMID- 26970551 TI - Inter-hospital variations in labor induction and outcomes for nullipara: an Australian population-based linkage study. AB - INTRODUCTION: This study aimed to describe variation in inter-hospital induction of labor (IOL) rates, determine whether variation is explained by individual and hospital factors and examine birth outcomes. MATERIAL AND METHODS: Nullipara at term with a singleton cephalic birth were identified using linked hospital discharge and birth data for 66 hospitals in New South Wales, Australia, 2010 2011. Random effects multilevel logistic regression models were fitted for early term, full term, and late term births, adjusting for individual and hospital factors. Hospital intrapartum cesarean rates, and severe maternal and neonatal morbidity outcomes were determined according to hospital IOL rate. RESULTS: Of 69 549 nullipara, 24 673 (35%) had an IOL. For early term births, adjusted hospital IOL (aIOL) rates varied (3.3-13.9%), with 11 of 66 (17%) hospitals having aIOL rates significantly different from the average aIOL rate. For births at full term, the hospital aIOL rates varied (10.6-32.6%), with 29 hospitals (44%) having aIOL rates significantly different from the average aIOL rate. For late term births, the hospital aIOL rates varied (45.1-67.5%), with 11 hospitals (17%) having aIOL rates significantly different from the overall average aIOL rate for women with late term births. There was generally no relationship between higher or lower hospital IOL rates and intrapartum cesarean section rates, or maternal or neonatal adverse outcomes. CONCLUSIONS: Inter-hospital IOL rates for nullipara with a singleton cephalic term birth had high unexplained variation, with no clear association with intrapartum cesarean section rates, or maternal or neonatal adverse outcomes. PMID- 26970552 TI - Obstetrical outcome in women with urinary tract infections in childhood. AB - INTRODUCTION: Urinary tract infections (UTI) during childhood can result in permanent renal damage, with possible implications for future pregnancies. The aim of this prospective study was to investigate pregnancy outcomes in women followed after their first UTI in childhood. MATERIAL AND METHODS: A cohort of 72 parous women was followed from their first UTI in childhood up to a median age of 41 years. Clinical data were obtained from antenatal and hospital records. Renal damage was evaluated by a (99m) Tc-dimercaptosuccinic acid scan. Pregnancy blood pressure (BP), complications and UTIs were compared between women with and without renal damage. RESULTS: All women completed the investigations, 48 with and 24 without renal damage. No woman, irrespective of presence or absence of renal damage, was diagnosed with hypertension before the first pregnancy. Pregnancy-related hypertension was diagnosed in 10 of 151 pregnancies, all in women with renal damage. Preeclampsia occurred in four women. Women with renal damage had significantly higher systolic BP measured at the last antenatal visit of their first pregnancy, compared with women without renal damage (p = 0.005). During subsequent pregnancies both systolic and diastolic BP were significantly higher in women with than without renal damage (p = 0.02 and p = 0.03, respectively). CONCLUSION: In this population-based follow-up study we found a large proportion of women with renal damage after UTI in childhood. Women with renal damage had significantly higher BP during pregnancy compared with women without renal damage. Pregnancy-related hypertension was recorded only in women with renal damage. However, pregnancy complications, including preeclampsia, were few. PMID- 26970553 TI - Site-Selective Acylations with Tailor-Made Catalysts. AB - The acylation of alcohols catalyzed by N,N-dimethylamino pyridine (DMAP) is, despite its widespread use, sometimes confronted with substrate-specific problems: For example, target compounds with multiple hydroxy groups may show insufficient selectivity for one hydroxyl, and the resulting product mixtures are hardly separable. Here we describe a concept that aims at tailor-made catalysts for the site-specific acylation. To this end, we introduce a catalyst library where each entry is constructed by connecting a variable and readily tuned peptide scaffold with a catalytically active unit based on DMAP. For selected examples, we demonstrate how library screening leads to the identification of optimized catalysts, and the substrates of interest can be converted with a markedly enhanced site-selectivity compared with only DMAP. Furthermore, substrate-optimized catalysts of this type can be used to selectively convert "their" substrate in the presence of structurally similar compounds, an important requisite for reactions with mixtures of substances. PMID- 26970554 TI - Laryngeal examination in thyroid and parathyroid surgery: An American Head and Neck Society consensus statement: AHNS Consensus Statement. AB - This American Head and Neck Society (AHNS) consensus statement discusses the techniques of laryngeal examination for patients undergoing thyroidectomy and parathyroidectomy. It is intended to help guide all clinicians who diagnose or manage adult patients with thyroid disease for whom surgery is indicated, contemplated, or has been performed. This consensus statement concludes that flexible transnasal laryngoscopy is the optimal laryngeal examination technique, with other techniques including laryngeal ultrasound and stroboscopy being useful in selected scenarios. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: 811-819, 2016. PMID- 26970555 TI - Vitamin D supplementation for childhood atopic dermatitis. PMID- 26970557 TI - Prevalence of a positive TORCH and parvovirus B19 screening in pregnancies complicated by polyhydramnios. AB - OBJECTIVE: The aim of this study was to evaluate the rate of women with polyhydramnios who eventually screened positive to infectious disease by serum screening testing for TORCH and parvovirus B19. METHODS: This is a retrospective observational study on singleton pregnancies with a diagnosis of polyhydramnios and who had serum screening for TORCH and parvovirus B19. Patients were followed with serial ultrasounds between 2006 and 2013. Maternal characteristics, medical and obstetric history were reviewed. Ultrasound parameters, including amniotic fluid index and fetal anomalies, and the results of serologic tests were reviewed. RESULTS: Two hundred ninety patients met the inclusion criteria. Of these, 56 (19%) presented one of the following pathological conditions associated with polyhydramnios: diabetes (13% of total cases), obstructive gastrointestinal lesions (5%), Rhesus isoimmunization (0.3%), chromosomal abnormalities or genetic syndromes (1%). Among the remaining 234 patients, only three had a positive test result for infectious disease (1%, 95% Confidence Interval (CI) 0-4%): two women were positive for parvovirus B19 and one for toxoplasmosis infection. In none of them the fetus was affected, as confirmed by serum testing after birth and by 3 years follow-up. CONCLUSIONS: Infectious disease screening does not seem beneficial in pregnancies with isolated polyhydramnios. PMID- 26970556 TI - Diffusible iodine-based contrast-enhanced computed tomography (diceCT): an emerging tool for rapid, high-resolution, 3-D imaging of metazoan soft tissues. AB - Morphologists have historically had to rely on destructive procedures to visualize the three-dimensional (3-D) anatomy of animals. More recently, however, non-destructive techniques have come to the forefront. These include X-ray computed tomography (CT), which has been used most commonly to examine the mineralized, hard-tissue anatomy of living and fossil metazoans. One relatively new and potentially transformative aspect of current CT-based research is the use of chemical agents to render visible, and differentiate between, soft-tissue structures in X-ray images. Specifically, iodine has emerged as one of the most widely used of these contrast agents among animal morphologists due to its ease of handling, cost effectiveness, and differential affinities for major types of soft tissues. The rapid adoption of iodine-based contrast agents has resulted in a proliferation of distinct specimen preparations and scanning parameter choices, as well as an increasing variety of imaging hardware and software preferences. Here we provide a critical review of the recent contributions to iodine-based, contrast-enhanced CT research to enable researchers just beginning to employ contrast enhancement to make sense of this complex new landscape of methodologies. We provide a detailed summary of recent case studies, assess factors that govern success at each step of the specimen storage, preparation, and imaging processes, and make recommendations for standardizing both techniques and reporting practices. Finally, we discuss potential cutting-edge applications of diffusible iodine-based contrast-enhanced computed tomography (diceCT) and the issues that must still be overcome to facilitate the broader adoption of diceCT going forward. PMID- 26970558 TI - Mechanistic study of the anti-cancer effect of Gynostemma pentaphyllum saponins in the Apc(Min/+) mouse model. AB - Gynostemma pentaphyllum saponins (GpS) have been shown to have anti-cancer activity. However, the underlying mechanisms remain unclear. In this study, we used the Apc(Min) (/+) colorectal cancer (CRC) mouse model to investigate the anti-cancer effect of GpS and we demonstrated that GpS treatment could significantly reduce the number and size of intestinal polyps in Apc(Min) (/+) mice. In order to identify the potential targets and mechanisms involved, a comparative proteomics analysis was performed and 40 differentially expressed proteins after GpS treatment were identified. Bioinformatics analyses suggested a majority of these proteins were involved in processes related to cellular redox homeostasis, and predicted Raf-1 as a potential target of GpS. The upregulation of two proteins known to be involved in redox homeostasis, peroxiredoxin-1 (Prdx1) and peroxiredoxin-2 (Prdx2), and the downregulation of Raf-1 were validated using Western blot analysis. After further investigation of the associated signaling networks, we postulated that the anti-cancer effect of GpS was mediated through the upregulation of Prdx1 and Prdx2, suppression of Ras, RAF/MEK/ERK/STAT, PI3K/AKT/mTOR signaling and modulation of JNK/p38 MAPK signaling. We also examined the potential combinatorial effect of GpS with the chemotherapeutic 5-fluorouracil (5-FU) and found that GpS could enhance the anti cancer efficacy of 5-FU, further suppressing the number of polyps in Apc(Min/+) mice. Our findings highlight the potential of GpS as an anti-cancer agent, the potential mechanisms of its anti-cancer activities, and its effect as an adjuvant of 5-FU in the chemotherapy of CRC. PMID- 26970561 TI - The accuracy of delivery of target pressures using self-inflating bag manometers in a benchtop study. AB - AIM: We tested whether operators using manometers attached to self-inflating bags could accurately deliver set targeted peak inspiratory pressures (PIPs) compared to the Neopuff(TM) T-piece resuscitator (TPR). METHODS: Participants provided positive pressure ventilation to a leak-free neonatal test lung at a rate of 60 inflations/min and a flow of 8 L/min. Participants used three manometers attached to self-inflating bags and a Neopuff(TM) TPR to target PIPs of 20, 30 and 40 cmH2 O on each device. Mean PIPs delivered with each manometer were compared to the 'gold standard' Neopuff(TM) TPR. RESULTS: In total, 13 991 inflations delivered by 20 participants were analysed. At all target PIPs, the mean PIP delivered using the Mercury Medical manometer attached to a Laerdal self-inflating bag was significantly higher by 5 cmH2 O (p < 0.01) than the Neopuff(TM) TPR. The PIP delivered using both the Ambu(TM) and Parker Healthcare manometers attached to their respective devices was similar to that delivered by the Neopuff(TM) TPR at all targeted PIPs. CONCLUSION: Accurately targeted PIPs can be achieved when a manometer specifically designed for use on a self-inflating bag is used during manual ventilation. This may be useful in settings where access to a Neopuff(TM) TPR or a gas flow source is limited. PMID- 26970560 TI - A post-GWAS confirming the SCD gene associated with milk medium- and long-chain unsaturated fatty acids in Chinese Holstein population. AB - The stearoyl-CoA desaturase (delta-9-desaturase) gene encodes a key enzyme in the cellular biosynthesis of monounsaturated fatty acids. In our initial genome-wide association study (GWAS) of Chinese Holstein cows, 19 SNPs fell in a 1.8-Mb region (20.3-22.1 Mb) on chromosome 26 underlying the SCD gene and were highly significantly associated with C14:1 or C14 index. The aims of this study were to verify whether the SCD gene has significant genetic effects on milk fatty acid composition in dairy cattle. By resequencing the entire coding region of the bovine SCD gene, a total of six variations were identified, including three coding variations (g.10153G>A, g.10213T>C and g.10329C>T) and three intronic variations (g.6926A>G, g.8646G>A and g.16158G>C). The SNP in exon 3, g.10329C>T, was predicted to result in an amino acid replacement from alanine (GCG) to valine (GTG) in the SCD protein. An association study for 16 milk fatty acids using 346 Chinese Holstein cows with accurate phenotypes and genotypes was performed using the mixed animal model with the proc mixed procedure in sas 9.2. All six detected SNPs were revealed to be associated with six medium- and long-chain unsaturated fatty acids (P = 0.0457 to P < 0.0001), specifically for C14:1 and C14 index (P = 0.0005 to P < 0.0001). Subsequently, strong linkage disequilibrium (D' = 0.88 1.00) was observed among all six SNPs in SCD and the five SNPs (rs41623887, rs109923480, rs42090224, rs42092174 and rs42091426) within the 1.8-Mb region identified in our previous GWAS, indicating that the significant association of the SCD gene with milk fatty acid content traits reduced the observed significant 1.8-Mb chromosome region in GWAS. Haplotype-based analysis revealed significant associations of the haplotypes encompassing the six SCD SNPs and one SNP (rs109923480) in a GWAS with C14:1, C14 index, C16:1 and C16 index (P = 0.0011 to P < 0.0001). In summary, our findings provide replicate evidence for our previous GWAS and demonstrate that variants in the SCD gene are significantly associated with milk fatty acid composition in dairy cattle, which provides clear evidence for an increased understanding of milk fatty acid synthesis and enhances opportunities to improve milk-fat composition in dairy cattle. PMID- 26970559 TI - Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study. AB - BACKGROUND: The determinants of outcomes for adult survivors of pediatric low grade glioma (PLGG) are largely unknown. METHODS: This study collected population based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n = 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database. RESULTS: At a median follow up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% +/- 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P < .001) and a thalamic location (P < .001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P = .001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = .013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0; 95% CI, 1.3-7.0; P = .012) and tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P < .001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes. CONCLUSIONS: The course of PLGG is associated with excellent long-term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients. PMID- 26970562 TI - Incidence of Atrial Fibrillation following Alcohol Septal Ablation for Hypertrophic Cardiomyopathy. AB - BACKGROUND: Patients with hypertrophic cardiomyopathy (HCM) are at a fourfold to sixfold higher risk of developing atrial fibrillation (AF) compared to the general population, though incidence rates among patients undergoing alcohol septal ablation (ASA) are not well characterized. The purpose of this study was to evaluate atrial fibrillation incidence following ASA. METHODS: We studied 132 consecutive HCM patients without comorbid AF that underwent 154 ASA procedures. The incidence of AF in follow-up was assessed through chart abstraction including electrocardiography. Survival free of AF was estimated using Kaplan-Meier methodology. RESULTS: Over a mean follow-up of 3.6 +/- 2.7 years (maximum 11.3 years), 10 (7.6%) patients developed new-onset AF. Of those who developed AF, both resting and provoked left ventricular outflow tract (LVOT) gradients had improved significantly (difference -79.78 mm Hg, P <= 0.005). Severity of mitral regurgitation improved in 7 (70%) patients. Survival free of AF was estimated to be 99.1%, 93.7%, and 91.7% at 1, 3, and 5 years. CONCLUSIONS: Despite relieving LVOT obstruction and improving mitral regurgitation severity via ASA, new-onset AF remained a common complication of hypertrophic cardiomyopathy. PMID- 26970563 TI - Identification of potential breast cancer markers in nipple discharge by protein profile analysis using two-dimensional nano-liquid chromatography/nanoelectrospray ionization-mass spectrometry. AB - PURPOSE: This research aimed to establish a diagnostic technique for breast cancer using nipple discharge (ND), with the objective of preventive diagnosis. ND has been proposed as a source of secreted proteomes that reflect early pathological changes in the ductal-lobular epithelial microenvironment, and could thus provide breast-specific cancer biomarkers that could be accessed noninvasively as a new clinical diagnostic technique. EXPERIMENTAL DESIGN: Minute amounts of ND from patients with and without breast cancer (n = 19 and 12, respectively) were collected at the hospital and kept frozen until just before use. They were analyzed using high-pH RP peptide fractionations/low-pH RP 2D nano LC/ESI-MS/MS. Biomarker candidates were also investigated using Western blot analysis and sandwich ELISA on ND and/or sera. RESULTS: We found distinct tendencies in protein expression and three candidate breast cancer biomarkers (carbonic anhydrase 2, catalase, and peroxiredoxin-2) whose levels differed significantly between ND specimens from patients with and without breast cancer. CONCLUSIONS AND CLINICAL RELEVANCE: These tendencies in protein expression and markers provide new ways to identify breast cancer patients. Therefore, RP/RP 2D LC/MS/MS analyses of ND and the above three markers are supported as a new breast cancer diagnostic technique. PMID- 26970564 TI - Sodium and water intake are not affected by GABAC receptor activation in the lateral parabrachial nucleus of sodium-depleted rats. AB - The activation of GABAergic receptors, GABAA and GABAB, in the lateral parabrachial nucleus (LPBN) increases water and sodium intake in satiated and fluid-depleted rats. The present study investigated the presence of the GABAC receptor in the LPBN, its involvement in water and sodium intake, and its effects on cardiovascular parameters during the acute fluid depletion induced by furosemide combined with captopril (Furo/Cap). One group of male Wistar rats (290 300g) with bilateral stainless steel LPBN cannulas was used to test the effects of a GABAC receptor agonist and antagonist on the fluid intake and cardiovascular parameters. We investigated the effects of bilateral LPBN injections of trans-4 aminocrotonic acid (TACA) on the intake of water and 0.3M NaCl induced by acute fluid depletion (subcutaneous injection of Furo/Cap). c-Fos expression increased (P<0.05), suggesting LPBN neuronal activation. The injection of different doses of TACA (0.5, 2.0 and 160 nmol) in the LPBN did not change the sodium or water intake in Furo/Cap-treated rats (P>0.05). Treatment with the GABAC receptor antagonist (Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid sulfate (ZAPA, 10nmol) or with ZAPA (10nmol) plus TACA (160nmol) did not change the sodium or water intake compared with that for vehicle (saline) (P>0.05). Bilateral injections of the GABAC agonist in the LPBN of Furo/Cap-treated rats did not affect the mean arterial pressure (MAP) or heart rate (HR). The GABAC receptor expression in the LPBN was confirmed by the presence of a 50kDa band. Although LPBN neurons might express GABAC receptors, their activation produced no change in water and sodium intake or in the cardiovascular parameters in the acute fluid depletion rats. Therefore, the GABAC receptors in the LPBN might not interfere with fluid and blood pressure regulation. PMID- 26970565 TI - Centroid precision and orientation precision of planar localization microscopy. AB - The concept of localization precision, which is essential to localization microscopy, is formally extended from optical point sources to microscopic rigid bodies. Measurement functions are presented to calculate the planar pose and motion of microscopic rigid bodies from localization microscopy data. Physical lower bounds on the associated uncertainties - termed centroid precision and orientation precision - are derived analytically in terms of the characteristics of the optical measurement system and validated numerically by Monte Carlo simulations. The practical utility of these expressions is demonstrated experimentally by an analysis of the motion of a microelectromechanical goniometer indicated by a sparse constellation of fluorescent nanoparticles. Centroid precision and orientation precision, as developed here, are useful concepts due to the generality of the expressions and the widespread interest in localization microscopy for super-resolution imaging and particle tracking. PMID- 26970566 TI - The Presence of Vascular Mimicry Predicts High Risk of Clear Cell Renal Cell Carcinoma after Radical Nephrectomy. AB - PURPOSE: Vascular mimicry is a type of tumor cell plasticity. The aim of this study was to determine the prognostic value of vascular mimicry in patients with clear cell renal cell carcinoma. MATERIALS AND METHODS: We performed a retrospective cohort study in 387 patients with clear cell renal cell carcinoma who underwent radical nephrectomy at Zhongshan Hospital, Fudan University between 2008 and 2009. Pathological features, baseline patient characteristics and followup data were recorded. Vascular mimicry in clear cell renal cell carcinoma tissue was identified by CD31-periodic acid-Schiff double staining. Univariate and multivariate Cox regression models were used to analyze the impact of prognostic factors on recurrence-free survival. The concordance index and the Akaike information criterion were used to assess the predictive accuracy and sufficiency of different models. RESULTS: Positive vascular mimicry staining occurred in 25 of 387 clear cell renal cell carcinoma cases (6.5%) and it was associated with an increased risk of recurrence (log-rank p <0.001). Incorporating vascular mimicry into pT stage, Fuhrman grade and Leibovich score helped refine individual risk stratification. Moreover, vascular mimicry was identified as an independent prognostic factor (p = 0.001). It was entered into a nomogram together with pT stage, Fuhrman grade, tumor size and necrosis. In the primary cohort the Harrell concordance index for the established nomogram to predict recurrence-free survival was slightly higher than that of the Leibovich model (0.850 vs. 0.823), which failed to reach statistical significance (p = 0.158). CONCLUSIONS: Vascular mimicry could be a potential prognosticator for recurrence-free survival in patients with clear cell renal cell carcinoma after radical nephrectomy. Further external validation and functional analysis should be pursued to assess its potential prognostic and therapeutic values for clear cell renal cell carcinoma. PMID- 26970567 TI - Prognostic impact of clinical tumor size on overall survival for subclassifying stages I and II vaginal cancer: A SEER analysis. AB - PURPOSE: This study accessed the Surveillance, Epidemiology and End Results (SEER) database to determine if tumor size is an independent predictor of overall survival (OS) for patients with stages I and II vaginal cancer (VC). MATERIALS AND METHODS: We identified in the SEER database, patients with available tumor size having stage I or II squamous cell histology from January 2004 through December 2012 with minimum follow-up of six months. Univariate analyses (UA) and multivariable analyses (MVA) evaluated the effect of several prognostic factors, including tumor size, regarding OS. RESULTS: 529 SEER patients were found with recorded tumor sizes, of which 293 (55.4%) were stage I and 236 (44.6%) stage II. UA found the following significant prognostic factors of worse OS: tumor size >2cm (HR=1.80, p=0.02) and older age at diagnosis (p<0.001) in stage I; and tumor size >2cm (HR=2.13, p=0.04) and older age at diagnosis (p<0.001) in stage II. Estimates of 5-year OS in patients with tumor size <=2cm vs. >2cm were 79.2% vs. 66.1% in stage I (p=0.0187) and 80.9% vs. 51.2% in stage II (p=0.0369). MVA confirmed about double risk of death for patients with tumor size >2cm (HRs: 1.88 in stage I and 2.06 in stage II). CONCLUSIONS: Tumor size seems to predict OS outcome in patients with stages I/II VC. Further confirmatory investigations are recommended to firmly establish its incorporation into currently accepted staging criteria for these patients. PMID- 26970568 TI - "Doctor, can I drive?": The need for a rational approach to return to driving after musculoskeletal injury. PMID- 26970569 TI - Danhong injection attenuates isoproterenol-induced cardiac hypertrophy by regulating p38 and NF-kappab pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Danhong injection (DHI), derived from Rhizoma Salviae Miltiorrhizae (Salvia miltiorrhiza Bge., Labiatae, Danshen in Chinese) and Flos Carthami (Carthamus tinctorius L., Compositae, Salvia militiorrhiza Bunge), is an extensively-used Chinese material standardized clinical product for treatment of cardiovascular diseases. AIM OF THE STUDY: Cardiac hypertrophy (CH) is an adaptive response of cardiomyocytes. Long-lasting cardiac hypertrophy results in the loss of compensation by cardiomyocytes which could ultimately develop into heart failure. In the present study, we aimed to investigate the effect and exact mechanisms of DHI on isoproterenol (ISO)-induced CH. MATERIALS AND METHODS: H9c2 cells and male Wistar rats were stimulated by ISO in the present study to establish CH models in vitro and in vivo. CCk-8 assay, Western blot, real time-polymerase chain reaction (RT-PCR), electrophoretic mobility shift assay (EMSA) and Echocardiography were used in the present study. RESULTS: DHI significantly attenuated ISO-induced CH of H9c2 cells (p<0.01). DHI decreased ISO-induced atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) elevation both at the mRNA and protein levels (p<0.05 and p<0.01, respectively). Western blot showed that DHI down-regulated the phosphorylation of p38. Furthermore, we found that DHI inhibited the nuclear translocation and activation of NF-kappab. Echocardiography from ISO-induced CH rats showed that DHI significantly decreased left ventricle (LV) mass, the thickness of the LV end systolic posterior wall (LVPWs), and the LV end-diastolic posterior wall (LVPWd) elevated by ISO (p<0.01 and p<0.05, respectively). CONCLUSION: These data demonstrate that DHI might exert anti-cardiac hypertrophic effects by regulating p38 and NF-kappab pathway. PMID- 26970570 TI - Chrysoeriol and other polyphenols from Tecoma stans with lipase inhibitory activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tecoma stans is traditionally used by several ethnical groups in Mexico and Central America to treat diabetes. This species is mentioned in the majority of the ethnopharmacological studies compiled in Mexico focused in medicinal plants used as anti-diabetic treatment. AIM OF THE STUDY: Recently, this plant was found to display a high level of pancreatic lipase inhibitory activity, in addition to the several action mechanisms already described. Here we show the phytochemical and in vitro pharmacological characterization of some of the compounds responsible for the antilipase activity. MATERIALS AND METHODS: Starting with a hydroalcoholic extract, fractions were obtained by liquid-liquid separation and successive processes of column chromatography purifications. Lipase inhibitory activity was measured employing a spectrophotometric analysis. For structural elucidation (1)H and (13)C NMR experiments were used. HPLC was used to quantify and confirm the identity of the bioactive compounds. RESULTS: Bio-guided chemical purification of the hydroalcoholic extract produced an organic fraction (ethyl acetate, TsEA), flavone fractions (TsC1F13), (TsC1F15), (TsC1F16) and isolated compounds (chrysoeriol, apigenin, luteolin, and verbascoside) with the capability to inhibit the activity of pancreatic lipase. The most active fraction (TsC2F6B) was constituted by a mixture of Chrysoeriol (5,7-dihydroxy-2-[4-hydroxy-3 methoxyphenyl]chromen-4-one, 96% ) and Apigenin (4%). This flavone mixture displayed a percentage of inhibition of 85% when it was eavaluated at 0.25mg/mL. Luteolin and chrysoeriol produced a noncompetitive and mixed inhibition with values of IC50=63 and 158uM respectively. The content of chrysoeriol was also quantified in the hydroalcoholic extract (TsHAE) and organic fraction (TsEA) as 1% and 7% respectively. All of this confirms that high proportion of both flavones produce an increase of the biological activity due to they show the highest inhibition of lipase enzyme in a concentration dependant way. CONCLUSIONS: These results evidence that the medicinal use of T. stans could be in part because of its lipase inhibitory activity allowing to adapt the administration of this plant before meals. Also this data could help to develop a novel phytopharmaceutical drug (standardized in luteolin, chrysoeriol, and apigenin) auxiliary for the Type 2 Diabetes mellitus. PMID- 26970571 TI - Changes in breathing pattern upon 100% oxygen in children at early school age. AB - Nitrogen multiple-breath washout (N2MBW) is an increasingly used tidal breathing test in young children to assess ventilation inhomogeneity. However, the test requires 100% oxygen to perform. We aimed to examine the potential influence of pure oxygen on breathing pattern in school-aged children. We performed tidal breathing measurements under room air followed by N2MBW in 16 former preterm children and 24 healthy controls. We compared tidal volume (VT), coefficient of variation of VT (CVVT), respiratory rate (RR), and minute ventilation (VE) between tidal breathing and N2MBW, and between the start and end of tidal breathing. Mean (range) age was 6.8 (5.9, 9.0) years. VT, RR and VE showed no significant change upon oxygen-exposure, while CVVT significantly decreased by 5% (95% CI: 1.2, 9.0; p=0.012). However CVVT was also the only parameter which significantly decreased during tidal breathing. Overall, pure oxygen has no systematic effect on breathing pattern in young school-aged children. N2MBW can reliably be used as tracer gas in this age group. PMID- 26970572 TI - Risk of graft-versus-host disease with rituximab-containing conditioning regimens in allogeneic hematopoietic stem cell transplant. AB - Graft-versus-host disease represents a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant patients. There is growing evidence that B lymphocytes may play a role in the pathogenesis of acute graft-versus-host disease. The purpose of this retrospective cohort study was to evaluate the efficacy of rituximab-containing conditioning regimens in decreasing graft-versus host disease in allogeneic hematopoietic stem cell transplant patients who received standardized tacrolimus-based graft-versus-host disease prophylaxis regimens. Patients were divided into two cohorts, based on the presence (RTX, n = 54) or absence (No-RTX, n = 105) of rituximab in the conditioning regimen and were matched 1:2 for major graft-versus-host disease risk factors. The incidence of grade II-IV acute graft-versus-host disease was not different between the two groups (37% vs. 26%, p = 0.147). When restricting the analysis to recipients of peripheral blood hematopoietic stem cell transplants, the RTX group had a higher incidence of grade II-IV acute graft-versus-host disease, relapse, or death prior to day 100 (55% vs. 36%, p = 0.037). The median time to the onset of acute graft versus-host disease was no different between the RTX and No-RTX groups (67 vs. 74 days, respectively, p = 0.141). Inhibition of antigen presentation by B cells with rituximab-based conditioning regimens does not appear to reduce the incidence of acute graft-versus-host disease in allogeneic hematopoietic stem cell transplant recipients. PMID- 26970573 TI - Ibrutinib-associated tumor lysis syndrome in a patient with mantle cell lymphoma: A case report. AB - Mantle cell lymphoma accounts for 5-7% of all non-Hodgkin's lymphomas. Under the current WHO classification, it is categorized as an indolent B cell lymphoma, but has an aggressive clinical course. New insights into leukemogenic molecular pathways of mantle cell lymphoma have uncovered unique therapeutic targets. Ibrutinib, a Bruton's tyrosine kinase inhibitor, is the newest drug in the arsenal that has shown promising efficacy in relapsed mantle cell lymphoma. Long term studies have shown that grade 3 or 4 adverse events are infrequent. Asymptomatic lymphocytosis is frequently seen with ibrutinib use in mantle cell lymphoma; however, tumor lysis syndrome is an extremely rare complication. To date, only two patients with ibrutinib-associated tumor lysis syndrome in mantle cell lymphoma have been described in a long-term follow-up study. Both patients met laboratory criteria for tumor lysis syndrome, however, but did not develop clinical tumor lysis syndrome. We, here describe a patient with relapsed mantle cell lymphoma who developed clinical tumor lysis syndrome with ibrutinib monotherapy. PMID- 26970574 TI - Swept-Source Optical Coherence Tomography Correlations Between Retina and Choroid Before and After Vitrectomy for Epiretinal Membranes. AB - PURPOSE: To describe retinal and choroidal morphology before and after surgery for epiretinal membranes (ERM) in swept-source OCT (SS-OCT). Additionally, to evaluate factors responsible for visibility of the suprachoroidal layer (SCL) and suprachoroidal space (SCS). DESIGN: Prospective consecutive case series. METHODS: Twenty-nine eyes of 29 patients with symptomatic, idiopathic ERM were included. Pars plana vitrectomy with ERM removal and ILM peeling was performed. We examined patients with SS-OCT twice preoperatively (9-12 months and 1 week before surgery), then postoperatively at 1 week and 6 and 12 months. RESULTS: Twelve months after surgery visual acuity improved to 20/50 (0.48 logMAR), statistically significantly higher as compared to 1 week preoperatively (P < .001). Preoperative loss of visual acuity was commonly associated with progression of deformation of the plexiform layers, as central retinal thickness (CRT) did not decrease in this period, nor did photoreceptor defects increase. Choroidal thickness decreased 6 months after surgery (P = .02) and remained stable until 12 months postoperatively (P = .2). The outer choroidoscleral boundary was irregular in 16 eyes preoperatively but only in 4 eyes 12 months post surgery. SCS and SCL were visible in 15 eyes. CONCLUSION: During the natural course of idiopathic ERM, deformation of the outer plexiform layer progresses and is associated with decreased visual acuity. Eyes with an initially irregular outer choroidoscleral boundary (CSB) recover visual acuity faster after vitrectomy with ILM peeling for ERM. Three factors are independently associated with the visibility of the SCS: disarrangement of plexiform layers, CRT, and multiple adhesion points between retina and ERM. PMID- 26970575 TI - The atypical antipsychotic blonanserin reverses (+)-PD-128907- and ketamine induced deficit in executive function in common marmosets. AB - Antagonism of the dopamine D3 receptor is considered a promising strategy for the treatment of cognitive impairment associated with schizophrenia. We have previously reported that the atypical antipsychotic blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptor antagonist, highly occupies dopamine D3 receptors at its antipsychotic dose range in rats. In the present study, we evaluated the effects of blonanserin on executive function in common marmosets using the object retrieval with detour (ORD) task. The dopamine D3 receptor-preferring agonist (+) PD-128907 at 1mg/kg decreased success rate in the difficult trial, but not in the easy trial. Since the difference between the two trials is only cognitive demand, our findings indicate that excess activation of dopamine D3 receptors impairs executive function in common marmosets. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by (+)-PD-128907 in the difficult trial. This finding indicates that blonanserin has beneficial effect on executive function deficit induced by activation of the dopamine D3 receptor in common marmosets. Next, and based on the glutamatergic hypothesis of schizophrenia, the common marmosets were treated with the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine. Ketamine at sub-anesthetic doses decreased success rate in the difficult trial, but not in the easy trial. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by ketamine in the difficult trial. The findings of this study suggest that blonanserin might have beneficial effect on executive dysfunction in patients with schizophrenia. PMID- 26970576 TI - The nuclear receptor Tlx regulates motor, cognitive and anxiety-related behaviours during adolescence and adulthood. AB - The nuclear receptor Tlx is a key regulator of embryonic and adult hippocampal neurogenesis and has been genetically linked to bipolar disorder. Mice lacking Tlx (Nr2e1(-/-)) display deficits in adult hippocampal neurogenesis and behavioural abnormalities. However, whether Tlx regulates behaviour during adolescence or in a sex-dependent manner remains unexplored. Therefore, we investigated the role of Tlx in a series of behavioural tasks in adolescent male and female mice with a spontaneous deletion of Tlx (Nr2e1(-/-) mice). Testing commenced at adolescence (postnatal day 28) and continued until adulthood (postnatal day 67). Adolescent male and female Nr2e1(-/-) mice were hyperactive in an open field, an effect that persisted in adulthood. Male but not female Nr2e1(-/-) mice exhibited reduced thigmotaxis during adolescence and adulthood. Impairments in rotarod motor performance developed in male and female Nr2e1(-/-) mice at the onset of adulthood. Spontaneous alternation in the Y-maze, a hippocampus-dependent task, was impaired in adolescent but not adult male and female Nr2e1(-/-) mice. Contextual fear conditioning was impaired in adolescent male Nr2e1(-/-) mice only, but both male and female adolescent Nr2e1(-/-) mice showed impaired cued fear conditioning, a hippocampal-amygdala dependent cognitive process. These deficits persisted into adulthood in males but not females. In conclusion, deletion of Tlx impairs motor, cognitive and anxiety related behaviours during adolescence and adulthood in male and female mice with most effects occurring during adolescence rather than adulthood, independent of housing conditions. This suggests that Tlx has functions beyond regulation of adult hippocampal neurogenesis, and may be an important target in understanding neurobiological disorders. PMID- 26970577 TI - Dizocilpine (MK-801) impairs learning in the active place avoidance task but has no effect on the performance during task/context alternation. AB - The prevention of engram interference, pattern separation, flexibility, cognitive coordination and spatial navigation are usually studied separately at the behavioral level. Impairment in executive functions is often observed in patients suffering from schizophrenia. We have designed a protocol for assessing these functions all together as behavioral separation. This protocol is based on alternated or sequential training in two tasks testing different hippocampal functions (the Morris water maze and active place avoidance), and alternated or sequential training in two similar environments of the active place avoidance task. In Experiment 1, we tested, in adult rats, whether the performance in two different spatial tasks was affected by their order in sequential learning, or by their day-to-day alternation. In Experiment 2, rats learned to solve the active place avoidance task in two environments either alternately or sequentially. We found that rats are able to acquire both tasks and to discriminate both similar contexts without obvious problems regardless of the order or the alternation. We used two groups of rats, controls and a rat model of psychosis induced by a subchronic intraperitoneal application of 0.08mg/kg of dizocilpine (MK-801), a non-competitive antagonist of NMDA receptors. Dizocilpine had no selective effect on parallel/sequential learning of tasks/contexts. However, it caused hyperlocomotion and a significant deficit in learning in the active place avoidance task regardless of the task alternation. Cognitive coordination tested by this task is probably more sensitive to dizocilpine than spatial orientation because no hyperactivity or learning impairment was observed in the Morris water maze. PMID- 26970578 TI - Short-term exposure to a diet high in fat and sugar, or liquid sugar, selectively impairs hippocampal-dependent memory, with differential impacts on inflammation. AB - Chronic high-energy diets are known to induce obesity and impair memory; these changes have been associated with inflammation in brain areas crucial for memory. In this study, we investigated whether inflammation could also be related to diet induced memory deficits, prior to obesity. We exposed rats to chow, chow supplemented with a 10% sucrose solution (Sugar) or a diet high in fat and sugar (Caf+Sugar) and assessed hippocampal-dependent and perirhinal-dependent memory at 1 week. Both high-energy diet groups displayed similar, selective hippocampal dependent memory deficits despite the Caf+Sugar rats consuming 4-5 times more energy, and weighing significantly more than the other groups. Extreme weight gain and excessive energy intake are therefore not necessary for deficits in memory. Weight gain across the diet period however, was correlated with the memory deficits, even in the Chow rats. The Sugar rats had elevated expression of a number of inflammatory genes in the hippocampus and WAT compared to Chow and Caf+Sugar rats but not in the perirhinal cortex or hypothalamus. Blood glucose concentrations were also elevated in the Sugar rats, and were correlated with the hippocampal inflammatory markers. Together, these results indicate that liquid sugar can rapidly elevate markers of central and peripheral inflammation, in association with hyperglycemia, and this may be related to the memory deficits in the Sugar rats. PMID- 26970579 TI - Neurosteroid allopregnanolone attenuates cognitive dysfunctions in 6-OHDA-induced rat model of Parkinson's disease. AB - Cognitive deficits have an extensive influence on the quality of life of the Parkinson's disease (PD) patients. Previous studies have shown that lack of steroid hormones have an important role in the development of PD. Therefore, in this study the effects of neurosteroid allopregnanolone (Allo) on the PD-induced cognitive disorders were assessed. To simulate PD, 6-hydroxydopamine (6-OHDA) was injected into the rat's substantia nigra. Allo (5 and 20mg/kg, orally) were administered on the day after the 6-OHDA injection and continued during the entire treatment period (two months). Cognitive behaviors were assessed by Moris water maze (MWM), novel object recognition (NOR) and object location tasks. The data indicated that Allo significantly improved the 6-OHDA-induced cognitive impairment which revealed by the reduction of time spent to find out platform (escape latency) and the increase of retention time in MWM test and also with increase in the exploration index in NOR and object location tasks. Present study strongly supports the pro-cognitive property of allopregnanolone in PD. PMID- 26970580 TI - Estimating the critical thermal maximum (CTmax) of bed bugs, Cimex lectularius: Comparing thermolimit respirometry with traditional visual methods. AB - Evaluating the critical thermal maximum (CTmax) in insects has provided a number of challenges. Visual observations of endpoints (onset of spasms, loss of righting response, etc.) can be difficult to measure consistently, especially with smaller insects. To resolve this problem, Lighton and Turner (2004) developed a new technique: thermolimit respirometry (TLR). TLR combines real time measurements of both metabolism (V.CO2) and activity to provide two independent, objective measures of CTmax. However, several questions still remain regarding the precision of TLR and how accurate it is in relation to traditional methods. Therefore, we evaluated CTmax of bed bugs using both traditional (visual) methods and TLR at three important metabolic periods following feeding (1d, 9d, and 21d). Both methods provided similar estimates of CTmax, although traditional methods produced consistently lower values (0.7-1 degrees C lower than TLR). Despite similar levels of precision, TLR provided a more complete profile of thermal tolerance, describing changes in metabolism and activity leading up to the CTmax, not available through traditional methods. In addition, feeding status had a significant effect on bed bug CTmax, with bed bugs starved 9d (45.19[+/-0.20] degrees C) having the greatest thermal tolerance, followed by bed bugs starved 1d (44.64[+/-0.28] degrees C), and finally bed bugs starved 21d (44.12[+/-0.28] degrees C). Accuracy of traditional visual methods in relation to TLR is highly dependent on the selected endpoint; however, when performed correctly, both methods provide precise, accurate, and reliable estimations of CTmax. PMID- 26970581 TI - Assessing the reproducibility of fractional rates of protein synthesis in muscle tissue measured using the flooding dose technique. AB - The flooding dose technique of Garlick et al. (1980) has become the main method for measuring tissue and whole-animal rates of protein synthesis in ectotherms. However, single tissue samples are used to determine rates of protein synthesis and no studies have examined the pattern of flooding in large tissues such as the white muscle in fishes, which can comprise up to 55% of the wet body mass of a fish and which is poorly perfused. The present study has examined, for the first time, the patterns of flooding and measured rates of protein synthesis in five different regions of the white muscle in the Arctic charr Salvelinus alpinus ranging in size from 25g to 1.6kg following a flooding dose injection of L-[(3)H] phenylalanine. The results indicate that the degree of flooding (i.e. free pool specific radioactivity relative to that of the injection solution) and elevation in free phenylalanine concentrations can vary between regions but the calculated fractional rates of protein synthesis were similar in four of the five regions studied. The variability in rates of protein synthesis increased with body size with greater variability observed between regions for fish >1kg in body mass. For consistency between studies, it is recommended that samples are taken from the epaxial muscle in the region below the dorsal fin when measuring fractional rates of white muscle synthesis in fishes. PMID- 26970582 TI - Dopamine inhibits somatolactin gene expression in tilapia pituitary cells through the dopamine D2 receptors. AB - Dopamine (DA) is an important neurotransmitter in the central nervous system of vertebrates and possesses key hypophysiotropic functions. Early studies have shown that DA has a potent inhibitory effect on somatolactin (SL) release in fish. However, the mechanisms responsible for DA inhibition of SL gene expression are largely unknown. To this end, tilapia DA type-1 (D1) and type-2 (D2) receptor transcripts were examined in the neurointermediate lobe (NIL) of the tilapia pituitary by real-time PCR. In tilapia, DA not only was effective in inhibiting SL mRNA levels in vivo and in vitro, but also could abolish pituitary adenylate cyclase-activating polypeptide (PACAP)- and salmon gonadotropin-releasing hormone (sGnRH)-stimulated SL gene expression at the pituitary level. In parallel studies, the specific D2 receptor agonists quinpirole and bromocriptine could mimic the DA-inhibited SL gene expression. Furthermore, the D2 receptor antagonists domperidone and (-)-sulpiride could abolish the SL response to DA or the D2 agonist quinpirole, whereas D1 receptor antagonists SCH23390 and SKF83566 were not effective in this respect. In primary cultures of tilapia NIL cells, D2 agonist quinpirole-inhibited cAMP production could be blocked by co-treatment with the D2 antagonist domperidone and the ability of forskolin to increase cAMP production was also inhibited by quinpirole. Using a pharmacological approach, the AC/cAMP pathway was shown to be involved in quinpirole-inhibited SL mRNA expression. These results provide evidence that DA can directly inhibit SL gene expression at the tilapia pituitary level via D2 receptor through the AC/cAMP dependent mechanism. PMID- 26970583 TI - Melatonin not only restores but also prevents the inhibition of the intestinal Ca(2+) absorption caused by glutathione depleting drugs. AB - We have previously demonstrated that melatonin (MEL) blocks the inhibition of the intestinal Ca(2+) absorption caused by menadione (MEN). The purpose of this study were to determine whether MEL not only restores but also prevents the intestinal Ca(2+) absorption inhibited either by MEN or BSO, two drugs that deplete glutathione (GSH) in different ways, and to analyze the mechanisms by which MEN and MEL alter the movement of Ca(2+) across the duodenum. To know this, chicks were divided into four groups: 1) controls, 2) MEN treated, 3) MEL treated, and 4) treated sequentially with MEN and MEL or with MEN and MEL at the same time. In a set of experiments, chicks treated with BSO or sequentially with BSO and MEL or with BSO and MEL at the same time were used. MEL not only restored but also prevented the inhibition of the chick intestinal Ca(2+) absorption produced by either MEN or BSO. MEN altered the protein expression of molecules involved in the transcellular as well as in the paracellular pathway of the intestinal Ca(2+) absorption. MEL restored partially both pathways through normalization of the O2( ) levels. The nitrergic system was not altered by any treatment. In conclusion, MEL prevents or restores the inhibition of the intestinal Ca(2+) absorption caused by different GSH depleting drugs. It might become one drug for the treatment of intestinal Ca(2+) absorption under oxidant conditions having the advantage of low or null side effects. PMID- 26970584 TI - Drebrin A regulates hippocampal LTP and hippocampus-dependent fear learning in adult mice. AB - Structural plasticity of dendritic spines, which underlies higher brain functions including learning and memory, is dynamically regulated by the actin cytoskeleton and its associated proteins. Drebrin A is an F-actin-binding protein preferentially expressed in the brain and localized in the dendritic spines of mature neurons. Isoform conversion from drebrin E to drebrin A and accumulation of the latter in dendritic spines occurs during synapse maturation. We have previously demonstrated that drebrin A plays a pivotal role in spine morphogenesis and plasticity. However, it is unclear whether drebrin A plays a specific role in processes required for structural plasticity, and whether drebrin E can substitute in this role. To answer these questions, we analyzed mutant mice (named DAKO mice), in which isoform conversion from drebrin E to drebrin A is disrupted. In DAKO mouse brain, drebrin E continues to be expressed throughout life instead of drebrin A. Electrophysiological studies using hippocampal slices revealed that long-term potentiation of CA1 synapses was impaired in adult DAKO mice, but not in adolescents. In parallel with this age dependent impairment, DAKO mice exhibited impaired hippocampus-dependent fear learning in an age-dependent manner; the impairment was evident in adult mice, but not in adolescents. In addition, histological investigation revealed that the spine length of the apical dendrite of CA1 pyramidal cells was significantly longer in adult DAKO mice than in wild-type mice. Our data indicate that the roles of drebrin E and drebrin A in brain function are different from each other, that the isoform conversion of drebrin is critical, and that drebrin A is indispensable for normal synaptic plasticity and hippocampus-dependent fear memory in the adult brain. PMID- 26970585 TI - Technical Validation of a Next-Generation Sequencing Assay for Detecting Actionable Mutations in Patients with Gastrointestinal Cancer. AB - Targeted next-generation sequencing is becoming increasingly common as a clinical diagnostic and prognostic test for patient- and tumor-specific genetic profiles as well as to optimally select targeted therapies. Here, we describe a custom developed, next-generation sequencing test for detecting single-nucleotide variants (SNVs) and short insertions and deletions (indels) in 93 genes related to gastrointestinal cancer from routine formalin-fixed, paraffin-embedded clinical specimens. We implemented a validation strategy, based on the College of American Pathologists requirements, using reference DNA mixtures from cell lines with known genetic variants, which model a broad range of allele frequencies. Test sensitivity achieved >99% for both SNVs and indels, with allele frequencies >10%, with high specificity (97.4% for SNVs and 93.6% for indels). We further confirmed test accuracies using primary formalin-fixed, paraffin-embedded colorectal cancer specimens characterized by alternative and conventional clinical diagnostic technologies. Robust performance was observed on the formalin fixed, paraffin-embedded specimens: sensitivity was 97.2% and specificity was 99.2%. We also observed high intrarun and inter-run reproducibility, as well as a low cross-contamination rate. Overall assessment using cell line samples and formalin-fixed, paraffin-embedded samples showed that our custom next-generation sequencing assay has consistent detection sensitivity down to 10% variant frequency. PMID- 26970586 TI - Large-scale reconstitution of a retina-to-brain pathway in adult rats using gene therapy and bridging grafts: An anatomical and behavioral analysis. AB - Peripheral nerve (PN) grafts can be used to bridge tissue defects in the CNS. Using a PN-to-optic nerve (ON) graft model, we combined gene therapy with pharmacotherapy to promote the long-distance regeneration of injured adult retinal ganglion cells (RGCs). Autologous sciatic nerve was sutured onto the transected ON and the distal end immediately inserted into contralateral superior colliculus (SC). Control rats received intraocular injections of saline or adeno associated virus (AAV) encoding GFP. In experimental groups, three bi-cistronic AAV vectors encoding ciliary neurotrophic factor (CNTF) were injected into different regions of the grafted eye. Each vector encoded a different fluorescent reporter to assess retinotopic order in the regenerate projection. To encourage sprouting/synaptogenesis, after 6 weeks some AAV-CNTF injected rats received an intravitreal injection of recombinant brain-derived neurotrophic factor (rBDNF) or AAV-BDNF. Four months after surgery, cholera toxin B was used to visualize regenerate RGC axons. RGC viability and axonal regrowth into SC were significantly greater in AAV-CNTF groups. In some cases, near the insertion site, regenerate axonal density resembled retinal terminal densities seen in normal SC. Complex arbors were seen in superficial but not deep SC layers and many terminals were immunopositive for presynaptic proteins vGlut2 and SV2. There was improvement in visual function via the grafted eye with significantly greater pupillary constriction in both AAV-CNTF+BDNF groups. In both control and AAV CNTF+rBDNF groups the extent of light avoidance correlated with the maximal distance of axonal penetration into superficial SC. Despite the robust regrowth of RGC axons back into the SC, axons originating from different parts of the retina were intermixed at the PN graft/host SC interface, indicating that there remained a lack of order in this extensive regenerate projection. PMID- 26970588 TI - Prediction of winter vitamin D status and requirements in the UK population based on 25(OH) vitamin D half-life and dietary intake data. AB - On a population basis, there is a gradual decline in vitamin D status (plasma 25(OH)D) throughout winter. We developed a mathematical model to predict the population winter plasma 25(OH)D concentration longitudinally, using age-specific values for 25(OH)D expenditure (25(OH)D3t1/2), cross-sectional plasma 25(OH)D concentration and vitamin D intake (VDI) data from older (70+ years; n=492) and younger adults (18-69 years; n=448) participating in the UK National Diet and Nutrition Survey. From this model, the population VDI required to maintain the mean plasma 25(OH)D at a set concentration can be derived. As expected, both predicted and measured population 25(OH)D (mean (95%CI)) progressively declined from September to March (from 51 (40-61) to 38 (36-41)nmol/L (predicted) vs 38 (27-48)nmol/L (measured) in older people and from 59 (54-65) to 34 (31-37)nmol/L (predicted) vs 37 (31-44)nmol/L (measured) in younger people). The predicted and measured mean values closely matched. The predicted VDIs required to maintain mean winter plasma 25(OH)D at 50nmol/L at the population level were 10 (0-20) to 11 (9-14) and 11 (6-16) to 13(11-16)MUg/d for older and younger adults, respectively dependent on the month. In conclusion, a prediction model accounting for 25(OH)D3t1/2, VDI and scaling factor for the 25(OH)D response to VDI, closely predicts measured population winter values. Refinements of this model may include specific scaling factors accounting for the 25(OH)D response at different VDIs and as influenced by body composition and specific values for 25(OH)D3 t1/2 dependent on host factors such as kidney function. This model may help to reduce the need for longitudinal measurements. PMID- 26970587 TI - Hydroxylation of 20-hydroxyvitamin D3 by human CYP3A4. AB - 20S-Hydroxyvitamin D3 [20(OH)D3] is the biologically active major product of the action of CYP11A1 on vitamin D3 and is present in human plasma. 20(OH)D3 displays similar therapeutic properties to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], but without causing hypercalcaemia and therefore has potential for development as a therapeutic drug. CYP24A1, the kidney mitochondrial P450 involved in inactivation of 1,25(OH)2D3, can hydroxylate 20(OH)D3 at C24 and C25, with the products displaying more potent inhibition of melanoma cell proliferation than 20(OH)D3. CYP3A4 is the major drug-metabolising P450 in liver endoplasmic reticulum and can metabolise other active forms of vitamin D, so we examined its ability to metabolise 20(OH)D3. We found that CYP3A4 metabolises 20(OH)D3 to three major products, 20,24R-dihydroxyvitamin D3 [20,24R(OH)2D3], 20,24S-dihydroxyvitamin D3 [20,24S(OH)2D3] and 20,25-dihydroxyvitamin D3 [20,25(OH)2D3]. 20,24R(OH)2D3 and 20,24S(OH)2D3, but not 20,25(OH)2D3, were further metabolised to trihydroxyvitamin D3 products by CYP3A4 but with low catalytic efficiency. The same three primary products, 20,24R(OH)2D3, 20,24S(OH)2D3 and 20,25(OH)2D3, were observed for the metabolism of 20(OH)D3 by human liver microsomes, in which CYP3A4 is a major CYP isoform present. Addition of CYP3A family-specific inhibitors, troleandomycin and azamulin, almost completely inhibited production of 20,24R(OH)2D3, 20,24S(OH)2D3 and 20,25(OH)2D3 by human liver microsomes, further supporting that CYP3A4 plays the major role in 20(OH)D3 metabolism by microsomes. Since both 20,24R(OH)2D3 and 20,25(OH)2D3 have previously been shown to display enhanced biological activity in inhibiting melanoma cell proliferation, our results show that CYP3A4 further activates, rather than inactivates, 20(OH)D3. PMID- 26970589 TI - Maternal dietary exposure to dioxins and polychlorinated biphenyls (PCBs) is associated with language delay in 3year old Norwegian children. AB - BACKGROUND: Prenatal exposure to dioxins and PCBs is potentially harmful to the developing fetus and may increase the risk of delayed or impaired neurodevelopment. Several studies have reported negative associations between prenatal exposure to these compounds and aspects of cognition related to language in early childhood. OBJECTIVES: The aim was to examine the association between maternal low level dietary exposure to dioxins and PCB during pregnancy and language development in 3year old children in a large group of mother-child pairs participating in the Norwegian Mother and Child Cohort Study (MoBa). METHODS: This study includes 44,092 children of women who were recruited to the Norwegian Mother and Child Cohort Study (MoBa) during the years 2002-2009. Maternal dietary exposure to dioxins and PCBs was estimated based on a validated food frequency questionnaire (FFQ) answered mid-pregnancy and a database of dioxin and PCB concentrations in Norwegian foods. Exposure to dioxins and dioxin-like PCBs (dl compounds) was expressed in total toxic equivalents (TEQ), and PCB-153 was used as marker for non-dioxin-like PCBs (ndlPCBs). Children's language skills at age 3 were assessed by parental report including a Dale and Bishop grammar rating and questions about communication skills from the Ages and Stages Questionnaire (ASQ). Logistic regression models adjusted for confounders were used to examine the association between maternal dietary exposure to dl-compounds or PCB-153 and language development in children. RESULTS: The maternal dietary exposure to dl compounds and PCB-153 was generally low, and 98% of women had intakes of dl compounds <=14pg TEQ/kg bw/week, which is the tolerable weekly intake set by EU's Scientific Committee for Food (SCF). High maternal exposure (>14pg TEQ/kg bw/week of dl-compounds (median 2.6pg/kg bw/day, range 2-16) or >97.5-percentile intake of PCB-153 (median 11ng/kg bw/day, range 5-28) was associated with higher odds of incomplete grammar (in boys and girls, adjusted ORs 1.1 to 1.3) and severe language delay in girls, adjusted ORs 2.8 [95% CI 1.1, 7.1] for PCB-153 and 2.9 [95% CI 1.4, 5.9] for dl-compounds. Furthermore, high exposure to dl-compounds was associated with moderate language delay 1.4 [95% CI 1.0, 2.0] and lower communication score (ASQ), adjusted OR 1.4 [95% CI 1.1, 1.9] in girls. CONCLUSIONS: The main findings of this study were: 1) Girls born to mothers who exceeded the tolerable weekly intake for dl-compounds or had a PCB-153 intake above the 97.5 percentile in early pregnancy may have increased risk of language delay at age 3years. 2) Negative associations with maternal exposure to dl compounds or PCB-153 were observed for both boys and girls having incomplete grammar, which is a subtle reduction in language skills. This interesting finding should not be considered as deviant at this age. PMID- 26970590 TI - Gene-gene and gene-environment interactions on risk of male infertility: Focus on the metabolites. AB - Infertility affects about 17% couples, and males contribute to half of the cases. Compared with independent effects of genetic and environmental factors, interactions between them help in the understanding of the susceptibility to male infertility. Thus, we genotyped 25 polymorphisms, measured 16 urinary chemical concentrations and explored interactions between gene-gene and gene-environment in 1039 Han Chinese using metabolomic analysis. We first observed that GSTT1 might interact with GSTM1 (Pinter=6.33*10(-8)). Furthermore, an interaction between GSTM1 and 4-n-octylphenol (4-n-OP) was identified (Pinter=7.00*10(-3)), as well as a 2-order interaction among GSTT1, GSTM1 and 4-n-OP (Pinter=0.04). Subjects with GSTT1-present and GSTM1-null genotypes were susceptible to male infertility when exposed to 4-n-OP (OR=14.05, 95% CI=4.78-60.20, P=2.34*10(-5)). Most metabolites identified were involved in the tricarboxylic acid cycle. In conclusion, it is a novel study of the interaction on male infertility from the aspect of metabolomics. PMID- 26970592 TI - Online tracking and retargeting with applications to optical biopsy in gastrointestinal endoscopic examinations. AB - With recent advances in biophotonics, techniques such as narrow band imaging, confocal laser endomicroscopy, fluorescence spectroscopy, and optical coherence tomography, can be combined with normal white-light endoscopes to provide in vivo microscopic tissue characterisation, potentially avoiding the need for offline histological analysis. Despite the advantages of these techniques to provide online optical biopsy in situ, it is challenging for gastroenterologists to retarget the optical biopsy sites during endoscopic examinations. This is because optical biopsy does not leave any mark on the tissue. Furthermore, typical endoscopic cameras only have a limited field-of-view and the biopsy sites often enter or exit the camera view as the endoscope moves. In this paper, a framework for online tracking and retargeting is proposed based on the concept of tracking by-detection. An online detection cascade is proposed where a random binary descriptor using Haar-like features is included as a random forest classifier. For robust retargeting, we have also proposed a RANSAC-based location verification component that incorporates shape context. The proposed detection cascade can be readily integrated with other temporal trackers. Detailed performance evaluation on in vivo gastrointestinal video sequences demonstrates the performance advantage of the proposed method over the current state-of-the art. PMID- 26970591 TI - China's soil and groundwater management challenges: Lessons from the UK's experience and opportunities for China. AB - There are a number of specific opportunities for UK and China to work together on contaminated land management issues as China lacks comprehensive and systematic planning for sustainable risk based land management, encompassing both contaminated soil and groundwater and recycling and reuse of soil. It also lacks comprehensive risk assessment systems, structures to support risk management decision making, processes for verification of remediation outcome, systems for record keeping and preservation and integration of contamination issues into land use planning, along with procedures for ensuring effective health and safety considerations during remediation projects, and effective evaluation of costs versus benefits and overall sustainability. A consequence of the absence of these overarching frameworks has been that remediation takes place on an ad hoc basis. At a specific site management level, China lacks capabilities in site investigation and consequent risk assessment systems, in particular related to conceptual modelling and risk evaluation. There is also a lack of shared experience of practical deployment of remediation technologies in China, analogous to the situation before the establishment of the independent, non profit organisation CL:AIRE (Contaminated Land: Applications In Real Environments) in 1999 in the UK. Many local technology developments are at lab scale or pilot-scale stage without being widely put into use. Therefore, a shared endeavour is needed to promote the development of technically and scientifically sound land management as well as soil and human health protection to improve the sustainability of the rapid urbanisation in China. PMID- 26970593 TI - Semi-quantitative prediction of a multiple API solid dosage form with a combination of vibrational spectroscopy methods. AB - Quality control (QC) in the pharmaceutical industry is a key activity in ensuring medicines have the required quality, safety and efficacy for their intended use. QC departments at pharmaceutical companies are responsible for all release testing of final products but also all incoming raw materials. Near-infrared spectroscopy (NIRS) and Raman spectroscopy are important techniques for fast and accurate identification and qualification of pharmaceutical samples. Tablets containing two different active pharmaceutical ingredients (API) [bisoprolol, hydrochlorothiazide] in different commercially available dosages were analysed using Raman- and NIR Spectroscopy. The goal was to define multivariate models based on each vibrational spectroscopy to discriminate between different dosages (identity) and predict their dosage (semi-quantitative). Furthermore the combination of spectroscopic techniques was investigated. Therefore, two different multiblock techniques based on PLS have been applied: multiblock PLS (MB-PLS) and sequential-orthogonalised PLS (SO-PLS). NIRS showed better results compared to Raman spectroscopy for both identification and quantitation. The multiblock techniques investigated showed that each spectroscopy contains information not present or captured with the other spectroscopic technique, thus demonstrating that there is a potential benefit in their combined use for both identification and quantitation purposes. PMID- 26970594 TI - Antioxidant capacity and phenolic compounds of Lonicerae macranthoides by HPLC DAD-QTOF-MS/MS. AB - Lonicerae macranthoides with strong antioxidant activity is commonly used in traditional Chinese medicine and folk tea/beverage. However, detailed information about its antioxidant activity and bioactive compounds is limited. Then at first, we comparatively evaluated total phenolic content (TPC), total flavonoid content (TFC) and antioxidant activities of water extract, petroleum ether, ethyl acetate and n-butanol fractions of L. macranthoides. Ethyl acetate fraction exhibited the highest level of TPC (207.38 mg GAE/g DW), TFC (53.06 mg RE/g DW) and the best DPPH scavenge activity and reducing power. n-Butanol fraction showed the best ABTS(+) and O2(-) scavenging activities. Interestingly, water extract, ethyl acetate and n-butanol fractions showed stronger antioxidant activities than positive control, butylated hydroxytoluene (BHT). After that, thirty-one antioxidant phenolic compounds, including twenty-two phenolic acids and nine flavonoids, were screened by DPPH-HPLC experiment and then identified using HPLC DAD-QTOF-MS/MS. It is noted that twenty-one compounds (1, 3-4, 6-17, 19, 23, 26, 28-29, and 31), as far as was known, were discovered from L. macranthoide for the first time, and eleven of them (3-4, 10-17, and 23) were reported in Lonicera species for the first time. Results indicated that L. macranthoides could serve as promising source of rich antioxidants in foods, beverages and medicines for health promotion. PMID- 26970595 TI - Method optimization and validation for the determination of eight sulfonamides in chicken muscle and eggs by modified QuEChERS and liquid chromatography with fluorescence detection. AB - A simple, effective and reliable method for the determination of eight sulfonamide antibiotics (sulfadiazine, sulfapiridine, sulfamerazine, sulfamethazine, sulfachloropiridazine, sulfamethoxazole, sulfadoxine, sulfadimethoxin) in chicken muscle and eggs by liquid chromatography and fluorescence detection has been developed and validated. Sulfonamides do not present native fluorescence, however their direct determination was achieved by on-line post-column photochemical derivatization by UV irradiation. Sample treatment was based on QuEChERS with several modifications depending on the matrix. Egg extracts were cleaned-up using PSA for the dispersive solid phase extraction step. On the other hand, a new clean-up sorbent, SupelTM QuE Z-Sep(+), has been successfully applied in chicken muscle extract and has proved to be effective for interference removal from this matrix. Under optimum conditions, recoveries from 65.9 to 88.1%, relative standard deviations lower than 10% (except for sulfachloropiridazine), and limits of quantification (LOQs) from 14 to 85 MUg kg(-1) were achieved. Thus, the method complies with current European requirements. PMID- 26970597 TI - Development of an inhalation unit risk factor for cadmium. AB - An inhalation unit risk factor (URF) was developed for cadmium. The URF is based on excess lung cancer mortality in a key epidemiological study of cadmium smelter workers (Park et al., 2012). The Park et al. (2012) study is an update of the Thun et al. (1985) cohort that was previously used to derive a URF in USEPA (1985). Park et al. re-analyzed the cadmium smelter worker population (near Denver, CO) using more detailed work history information, a revised cadmium exposure matrix, a detailed retrospective exposure assessment for arsenic (potential confounder), and updated mortality data (through 2002). Grouped observed and expected number of lung cancer mortalities along with cumulative cadmium exposures were used in the current study to obtain the maximum likelihood estimate and asymptotic variance of the slope (beta) for the linear multiplicative relative risk model using Poisson regression modeling. Life-table analyses were used to derive the final URF for cadmium of 4.9E-04 per MUg Cd/m(3). The corresponding lifetime air concentration at the 1 in 100,000 no significant excess risk level is 0.020 MUg Cd/m(3), which can be used to protect the general public in Texas against the potential carcinogenic effects from chronic exposure to cadmium and cadmium compounds. PMID- 26970596 TI - HPLC method development, validation, and impurity characterization of a potent antitumor indenoisoquinoline, LMP776 (NSC 725776). AB - An HPLC method for the assay of a DNA topoisomerase inhibitor, LMP776 (NSC 725776), has been developed and validated. The stress testing of LMP776 was carried out in accordance with International Conference on Harmonization (ICH) guidelines Q1A (R2) under acidic, alkaline, oxidative, thermolytic, and photolytic conditions. The separation of LMP776 from its impurities and degradation products was achieved within 40 min on a Supelco Discovery HS F5 column (150 mm * 4.6 mm i.d., 5 MUm) with a gradient mobile phase comprising 38 80% acetonitrile in water, with 0.1% trifluoroacetic acid in both phases. LC/MS was used to obtain mass data for characterization of impurities and degradation products. One major impurity was isolated through chloroform extraction and identified by NMR. The proposed HPLC assay method was validated for specificity, linearity (concentration range 0.25-0.75 mg/mL, r = 0.9999), accuracy (recovery 98.6-100.4%), precision (RSD <= 1.4%), and sensitivity (LOD 0.13 MUg/mL). The validated method was used in the stability study of the LMP776 drug substance in conformance with the ICH Q1A (R2) guideline. PMID- 26970598 TI - Low-intensity signal in T2-weighted MRI images around syringomyelia in a patient with severe scoliosis associated with Chiari malformation type I. PMID- 26970599 TI - Intradural cavernous lymphangioma of the thoracic spine: case report, technical considerations, and review of the literature. AB - BACKGROUND CONTEXT: Cavernous lymphangioma is a rare slow-growing tumor that can cause neurologic compromise when it involves the central nervous system. Involvement of the spinal column is rare but may involve the osseous structures or the epidural space of the spinal column. PURPOSE: We report the first case of an intradural, extramedullary cavernous lymphangioma involving the thoracic spinal cord. METHODS: An 83-year-old woman presented with progressive gait ataxia, bilateral lower extremity weakness, and a band-like sensation in the middle and lower thoracic dermatomes. Magnetic resonance imaging of the thoracic spinal cord revealed hyperintensity on T2 and enhancement of an intradural cystic mass along the dorsal aspect of the T5-T8 levels with significant compression of the spinal cord. RESULTS: Complete surgical resection was difficult owing to the adherence of the tumor to the pial surface and microvasculature of the thoracic spinal cord. Recurrence of the mass was ultimately treated with cystic fluid diversion into the peritoneum. At her follow-up visit after 28 months, the patient was able to ambulate with minimal assistance. A comparative literature review is presented. There are no reports of intradural thoracic spinal cord involvement in the literature. CONCLUSIONS: Intradural cavernous lymphangioma of the spine poses a unique surgical challenge for complete resection. Cystic fluid diversion appears to be a viable treatment option with lasting benefit if complete resection is not achieved. PMID- 26970600 TI - Paraspinal muscle, facet joint, and disc problems: risk factors for adjacent segment degeneration after lumbar fusion. AB - BACKGROUND CONTEXT: Adjacent segment degeneration (ASD) is one of the major complications after lumbar fusion. Several studies have evaluated the risk factors of ASD. Although the paraspinal muscles play an important role in spine stability, no study has assessed the relationship between paraspinal muscle atrophy and the incidence of ASD after lumbar fusion. PURPOSE: In the present study, we aimed to verify the known risk factors of ASD, such as body mass index (BMI), preoperative adjacent facet joint degeneration, and disc degeneration, and to assess the relationship between paraspinal muscle atrophy and ASD. STUDY DESIGN: This is a retrospective 1:1 pair analysis matched by age, sex, fusion level, and follow-up period. PATIENT SAMPLE: To calculate the appropriate sample size for the study, we performed a pre-study analysis of the paraspinal muscle cross-sectional area (CSA), and estimated that at least 35 cases would be needed for each group. Among the 510 patients who underwent posterior lumbar fusion for degenerative lumbar disease between January 2009 and October 2009, a total of 50 patients with ASD after surgery were selected. Another group of 50 matched patients with degenerative lumbar disease without ASD after spinal fusion were selected as the control group. Each patient in the ASD group was matched with a control patient according to age, sex, fusion level, and follow-up period. OUTCOME MEASURES: Radiographic measurements and demographic data were reviewed. METHODS: The risk factors considered were higher BMI, preoperative adjacent segment disc and facet degeneration, and preoperative paraspinal muscle atrophy and fatty degeneration. The radiographic data were compared between the ASD and control groups to determine the predictive factors of ASD after posterior lumbar fusion by using logistic regression analysis. The study was not externally funded. The authors have no conflict of interest to declare. RESULTS: Multivariate logistic regression analysis indicated that higher BMI (odds ratio [OR]: 1.353, p=.008), preoperative facet degeneration on computed tomography examination (OR: 3.075, p=.011), disc degeneration on magnetic resonance imaging (MRI) (OR: 2.783, p=.003), fatty degeneration (OR: 1.080, p=.044), and a smaller relative CSA of the paraspinal muscle preoperatively (OR: 0.083, p=.003) were significant factors for predicting the development of ASD. CONCLUSIONS: The occurrence of radiological ASD is most likely multifactorial, and is associated with a higher BMI, preexisting facet and disc degeneration on preoperative examination, and a smaller preoperative relative CSA of the paraspinal muscle on MRI. PMID- 26970601 TI - Primary scattered multifocal melanocytomas in spinal canal mimicking neurofibromatosis. AB - BACKGROUND CONTEXT: Meningeal melanocytoma is an extremely rare pigmented tumor derived from leptomeningeal melanocytes. By and large, it is considered to be a well-differentiated and slow-growing benign lesion. Generally, meningeal melanocytomas are solitary lesions, and the occurrence of the primary multifocal form in the central nervous system is exceedingly rare; it has been previously reported in only six cases. PURPOSE: The present report illustrates a 41-year-old woman with primary multifocal meningeal melanocytoma in the spinal canal. Contrary to earlier reports, the tumors presented with a scattered appearance mimicking neurofibromatosis. STUDY DESIGN: This study is a case report and review of literature. METHODS: On admission, the cerebral magnetic resonance images of the patient were normal, whereas the spinal magnetic resonance images showed scattered multifocal nodules mimicking neurofibromatosis. Surgical resection of the responsible lesions was scheduled. In addition to this case presentation, relevant previous reports were reviewed, and the challenging diagnosis, management, and prognosis of meningeal melanocytoma are discussed. RESULTS: Gross total resection of the two largest lesions was achieved, and histopathological examinations confirmed the diagnosis. Despite the benign histopathological findings, the patient had an aggressive clinical course. On follow-up at 18 months after surgery, she succumbed to the disease. CONCLUSION: Clinicians should be alert to a potential aggressive clinical course of meningeal melanocytoma, despite its benign histopathological nature. Of particular note is multifocality and diffuse leptomeningeal hyperpigmentation, which may suggest a poor prognosis. A combined treatment including surgical resection and adjuvant radiotherapy should be considered, and long-term close follow-up is necessary. PMID- 26970602 TI - Successful nonsurgical treatment for highly unstable fracture subluxation of the spine secondary to myeloma. AB - BACKGROUND CONTEXT: In multiple myeloma, patients may develop rapidly progressive, lytic, spinal lesions. These may result in spinal instability, but instrumented stabilization may fail because of poor bone quality. In addition, patients are immunocompromised and are therefore at increased risk of deep infection. PURPOSE: The aim was to describe a patient presenting with an unstable fracture subluxation of the thoracic spine secondary to myeloma, successfully treated with non-surgical management. STUDY DESIGN/SETTING: This is a case report of a patient seen in a specialist spinal myeloma service. METHODS: A 74-year-old Caucasian woman presented with destructive myelomatous lesions of T9 and T10. Greater than 50% of the T9 vertebral body was involved, and there was subluxation and translation of T9 on T10 (Spinal Instability Neoplastic Score of 14). There was a single episode of transient paresthesia of both lower limbs. The patient was in considerable pain, requiring large quantities of opioid analgesia. She was treated non-surgically in a thoracolumbar sacral orthosis for a period of 3 months (strict bed rest for the first 3 weeks). RESULTS: A computed tomography scan at 3 months demonstrated bony fusion and the brace was removed. The patient returned to her normal activities 5 months posttreatment. Her pain and patient reported outcome scores were significantly improved. CONCLUSIONS: We present a successful non-surgical management of an unstable myelomatous vertebral fracture without neurologic deficit. However, surgical stabilization remains the treatment of choice in unstable vertebral fractures and spinal surgical opinion should be sought in all cases. PMID- 26970603 TI - Toxicity analysis of various Pluronic F-68-coated carbon nanotubes on mesenchymal stem cells. AB - Carbon nanotubes (CNTs) have poor colloid stability in biological media and exert cytotoxic effects on mesenchymal stem cells (MSCs). Modification with polymeric surfactant is a widely used strategy to enhance water dispersibility of CNTs. This study investigated the toxic effects of various Pluronic F-68 (PF68)-coated multi-walled CNTs (MWCNTs) on rat bone marrow-derived MSCs.PF68-coated MWCNTs showed favorable biocompatibility to MSCs that the cell viability, apoptosis, and reactive oxygen species (ROS) were not altered after 24 h of co-incubation. Nevertheless, significant apoptosis induction and massive ROS release were found following extended exposure (48 and 72 h), and the toxic impact was dependent on the initial surface properties of the encapsulated MWCNTs. All the types of PF68 coated MWCNTs did not affect the cell-surface markers and in vivo biodistribution of MSCs. Our results suggest that proper polymer coating can reduce the acute toxicity of MWCNTs to MSCs but without altering their biological fate. PMID- 26970604 TI - Evaluation of protective effects of costunolide and dehydrocostuslactone on ethanol-induced gastric ulcer in mice based on multi-pathway regulation. AB - The aim of the present study was to evaluate the anti-ulcerogenic activity of costunolide (Co) and dehydrocostuslactone (De) on ethanol-induced gastric ulcer in mice and to elucidate the potential mechanisms of the action involved. Mice were pretreated orally with Co (5 or 20 mg/kg), De (5 or 20 mg/kg) and omeprazole (OME, 20 mg/kg) for 7 consecutive days, followed by ulcer induction using absolute ethanol (0.2 mL/20 g body weight). Treatment with Co had a remarkable gastroprotection compared to the ethanol-ulcerated mice that significantly reduced the ulcerative lesion index (ULI) and histopathological damage. Daily intragastric administration of Co exerted a powerful anti-inflammatory activity as evidenced by the suppression of nuclear factor (NF)-kappaB, tumor necrosis factor (TNF)-alpha, nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, as well as increased interleukin (IL)-10. Also, pretreatment with Co effectively inhibited ethanol-induced malondialdehyde (MDA) overproduction, increased the depleted superoxide dismutase (SOD) and promoted gastric mucosa epithelial cell proliferation by up-regulating proliferating cell nuclear antigen (PCNA) expression. Similarly, De had a protective effect on ethanol-induced ulcer, which was dependent on the inhibition of inflammatory cytokines and MDA generation, but independent of IL-10, SOD and PCNA improvement. Conclusively, the results have clearly demonstrated the anti-ulcerogenic potential of Co and De on ethanol-induced gastric ulcer; nevertheless, the gastroprotective activity of Co was superior to De due to more multi-pathway regulation than De. These findings suggested that Co or De could be a new useful natural gastroprotective tool against gastric ulcer, which provided a scientific basis for the gastroprotection of sesquiterpene lactones. PMID- 26970605 TI - Infants' representations of same and different in match- and non-match-to-sample. AB - Three experiments investigated the representations that underlie 14-month-old infants' and adults' success at match-to-sample (MTS) and non-match-to-sample (NMTS) tasks. In Experiment 1, 14-month-old infants were able to learn rules based on abstract representations of sameness and/or difference. When presented with one of eighteen sample stimuli (A) and a choice between a stimulus that was the same as the sample (A) and a different stimulus (B), infants learned to choose A in MTS and B in NMTS. In Experiments 2 and 3, we began to explore the nature of the representations at play in these paradigms. Experiment 2 confirmed that abstract representations were at play, as infants generalized the MTS and NMTS rules to stimuli unseen during familiarization. Experiment 2 also showed that infants tested in MTS learned to seek the stimulus that was the same as the sample, whereas infants tested in NMTS did not learn to seek the different stimulus, but instead learned to avoid the stimulus that was the same as the sample. Infants appeared to only use an abstract representation of the relation same in these experiments. Experiment 3 showed that adult participants, despite knowing the words "same" and "different", also relied on representations of sameness in both MTS and NMTS in a paradigm modeled on that of Experiment 2. We conclude with a discussion of how young infants may possibly represent the abstract relation same. PMID- 26970606 TI - Comparison of the Rowe-Kahn Model of Successful Aging With Self-rated Health and Life Satisfaction: The West of Scotland Twenty-07 Prospective Cohort Study. AB - PURPOSE OF THE STUDY: With increasing longevity in industrialized populations, there is growing interest in what defines "successful aging" (SA). Various SA measures have been proposed but no consensus has been reached and many have been criticized for not representing the views and priorities of older people. We consider whether the Rowe-Kahn SA model captures older individual's perceptions of their own health and aging. METHODS: Using two cohorts of 886 and 483 men and women from the West of Scotland Twenty-07 Study, aged around 57 and 76, respectively, we explored associations between Rowe-Kahn SA dimensions (absence of disease/disability; good physical/cognitive functioning; good interpersonal/productive social engagement) and four aspects of self-rated health and satisfaction (current general health; health for age; satisfaction with health; satisfaction with life). RESULTS: Respondents' self-rated health and satisfaction was generally good but few had all six Rowe-Kahn dimensions positive, the conventional definition of SA. All individual positive SA dimensions were associated with better self-rated health and satisfaction. This was consistent across age, gender, manual/nonmanual occupations, and personality. The prevalence of good self-rated health and satisfaction increased with increasing numbers of positive SA dimensions. IMPLICATIONS: The Rowe-Kahn model provides a functional definition of SA. Future work on ageing should include all Rowe-Kahn dimensions and consider SA as a continuum. PMID- 26970608 TI - Medical undergraduates' contributions to publication output of world's top universities in 2013. AB - BACKGROUND: Medical undergraduates' (UGs) involvement in research activities is thought to be mutually beneficial to students, their mentors and the scholarly productivity of their universities. However, most evidence in favor of such assumption relies on subjective measures such as the self-reported gains in skills or knowledge rather than robust objective estimates for assessing impact. AIM: We aimed to objectively track and describe publications with UG co-authors their proportion to the total publication output of world's top universities, their characteristics and their potential impact on biomedical literature. METHODS: We contacted the corresponding authors of the 2013's Medline-indexed publications affiliated to world's top 10 universities to investigate if any of their co-authors was an UG. Articles with UG co-authors were further assessed to determine, along with other variables: the type of study design, field of the article, publishing journal and its impact factor (IF), and number of received citations. RESULTS: Out of 25 152 publications, 2537 articles (10.1%) contained at least one UG co-author who was the first author in 635 papers (25%). Articles with UG co-authors were published in 1114 journals with a median IF of 3.661. Most UGs' co-authored publications (82.7%, n = 2098) were cited at least once within 1 year, for a median of three citations per article. CONCLUSION: UGs contributed to one in every 10 publications affiliated to top universities. Their papers were published in journals with good IFs and received a fair number of citations, which would reflect the relatively good quality and impact of these articles. PMID- 26970607 TI - Sex-, stress-, and sympathetic post-ganglionic-dependent changes in identity and proportions of immune cells in the dura. AB - Aim of investigation Due to compelling evidence in support of links between sex, stress, sympathetic post-ganglionic innervation, dural immune cells, and migraine, our aim was to characterize the impacts of these factors on the type and proportion of immune cells in the dura. Methods Dural immune cells were obtained from naive or stressed adult male and female Sprague Dawley rats for flow cytometry. Rats with surgical denervation of sympathetic post-ganglionic neurons of the dura were also studied. Results Immune cells comprise ~17% of all cells in the dura. These included: macrophages/granulocytes ("Macs"; 63.2% of immune cells), dendritic cells (0.88%), T-cells (4.51%), natural killer T-cells (0.51%), natural killer cells (3.08%), and B-cells (20.0%). There were significantly more Macs and fewer B- and natural killer T-cells in the dura of females compared with males. Macs and dendritic cells were significantly increased by stress in males, but not females. In contrast, T-cells were significantly increased in females with a 24-hour delay following stress. Lastly, Macs, dendritic cells, and T-cells were significantly higher in sympathectomized naive males, but not females. Conclusions It may not only be possible, but necessary to use different strategies for the most effective treatment of migraine in men and women. PMID- 26970609 TI - Changes in bioactive compounds and oxidative enzymes of fresh-cut pomegranate arils during storage as affected by deficit irrigation and postharvest vapor heat treatments. AB - The effect of postharvest vapor heat treatments at 95C (4, 7, and 10 s) regarding a conventional sanitizing treatment with 100 mg NaClO l-1 on enzyme activities (phenylalanine ammonia lyase, polyphenol oxidase, and peroxidase), phenolic content, and total antioxidant capacity of fresh-cut pomegranates arils throughout 18 days at 5C was studied. Furthermore, the effect of two sustained deficit irrigation (SDI) strategies, compared to a standardly irrigated control (CTRL), was also studied on such quality parameters throughout storage. Arils from CTRL-irrigated fruit registered phenylalanine ammonia lyase, peroxidase, and polyphenol oxidase initial activities of 60.6, 382, and 14.4 U g-1 fw, respectively. Arils from sustained deficit irrigation fruit registered 46-58% lower phenylalanine ammonia lyase values while polyphenol oxidase and peroxidase activities did not register great variants (<9%) among both sustained deficit irrigation treatments. Postharvest vapor heat treatments enhanced phenylalanine ammonia lyase activity in those samples from sustained deficit irrigation fruit although no great peroxidase and polyphenol oxidase (<2-5%) increases were observed. Arils from SDI1 fruit registered higher phenolic content than those values reported for CTRL samples. However, phenolic compounds decreased during storage, in a greater extent for sustained deficit irrigation samples, although 7 s arils achieved better phenolic compounds retention in sustained deficit irrigation samples. Vapor heat treatments reduced up to twofold the total antioxidant capacity losses observed in samples sanitized by conventional NaOCl treatment during shelf life. Conclusively, postharvest vapor heat treatment for 7 and 10 s used to extend the shelf life of pomegranate arils up to 18 days at 5C reduced the losses of health-promoting compounds during storage compared to conventional NaOCl sanitizing treatment. PMID- 26970610 TI - Seeing is Believing, or How GFP Changed My Approach to Science. AB - The field of "Developmental Biology" has dramatically changed over the past three decades. While genetic analysis had been center stage in the 1980s and continues to be a corner stone for investigations, the introduction of green fluorescent protein (GFP) in the 1990s has allowed us to look into living, developing embryos, and see how cells form tissues and how organ morphogenesis proceeds in real time. The introduction of protein binders into developmental studies some years ago has raised the precision yet another step, since it will allow the manipulation and study of how proteins function in real time. This chapter is a personal account on how GFP has, and how protein binders may, change the design of studies in the field of developmental biology. PMID- 26970611 TI - The Notch-Mediated Proliferation Circuitry. AB - The essential and highly conserved Notch signaling pathway controls a wide range of cell fate decisions during development, including cellular proliferation. Notch mediates both pro- and anti-proliferative effects in development, stem cells, and cancer depending on cellular context. Furthermore, it can induce proliferation in both cell-autonomous and non-cell-autonomous manners. Interacting genes and crosstalking signaling pathways play essential roles in regulating the proliferative response to Notch signals. A large number of genes that participate in the Notch network to influence proliferation have been identified, including several that activate the JNK signaling pathway, which interacts with Notch to induce both hyperplastic and invasive cellular behaviors. It is clear that dissecting the genetic circuitry surrounding Notch is essential to understanding the proliferative response to Notch in both development and cancer. PMID- 26970612 TI - Defining the Path from Stem Cells to Differentiated Tissue. AB - The molecular events that control the progression from stem cells to differentiated tissue are largely unknown. The root of Arabidopsis is an excellent model to study this process, as cells at every stage of development are present at all times. A network that involves the mobile transcription factor, SHORT-ROOT, controls the asymmetric division of the stem cell that gives rise to endodermis and cortex. After initially interacting with another transcription factor, SCARECROW (SCR), together they activate a D-type cyclin, which specifically regulates this asymmetric cell division. Another direct target of SCR is a MYB transcription factor that regulates formation of the Casparian strip, the signature differentiated feature of the endodermis. Thus, the outline of a regulatory network from stem cell to differentiated tissue has been traced, with much remaining to be filled in. PMID- 26970613 TI - Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair. AB - Myelin is essential for rapid and accurate conduction of electrical impulses by axons in the central and peripheral nervous system (PNS). Myelin is formed in the early postnatal period, and developmental myelination in the PNS depends on axonal signals provided by Nrg1/ErbB receptors. In addition, Nrg1 is required for effective nerve repair and remyelination in adulthood. We discuss here similarities and differences in Nrg1/ErbB functions in developmental myelination and remyelination after nerve injury. PMID- 26970614 TI - Oocyte Meiotic Spindle Assembly and Function. AB - Gametogenesis in animal oocytes reduces the diploid genome content of germline precursors to a haploid state in gametes by discarding 3/4 of the duplicated chromosomes through a sequence of two meiotic cell divisions called meiosis I and II. The assembly of the microtubule-based spindle structure that mediates this reduction in genome content remains poorly understood compared to our knowledge of mitotic spindle assembly and function. In this review, we consider the diversity of oocyte meiotic spindle assembly and structure across animal phylogeny, review recent advances in our understanding of how animal oocytes assemble spindles in the absence of the centriole-based microtubule-organizing centers that dominate mitotic spindle assembly, and discuss different models for how chromosomes are captured and moved to achieve chromosome segregation during oocyte meiotic cell division. PMID- 26970615 TI - Self-Organization of Spatial Patterning in Human Embryonic Stem Cells. AB - The developing embryo is a remarkable example of self-organization, where functional units are created in a complex spatiotemporal choreography. Recently, human embryonic stem cells (ESCs) have been used to recapitulate in vitro the self-organization programs that are executed in the embryo in vivo. This represents an unique opportunity to address self-organization in humans that is otherwise not addressable with current technologies. In this chapter, we review the recent literature on self-organization of human ESCs, with a particular focus on two examples: formation of embryonic germ layers and neural rosettes. Intriguingly, both activation and elimination of TGFbeta signaling can initiate self-organization, albeit with different molecular underpinnings. We discuss the mechanisms underlying the formation of these structures in vitro and explore future challenges in the field. PMID- 26970616 TI - The Neural Crest Migrating into the Twenty-First Century. AB - From the initial discovery of the neural crest over 150 years ago to the seminal studies of Le Douarin and colleagues in the latter part of the twentieth century, understanding of the neural crest has moved from the descriptive to the experimental. Now, in the twenty-first century, neural crest research has migrated into the genomic age. Here, we reflect upon the major advances in neural crest biology and the open questions that will continue to make research on this incredible vertebrate cell type an important subject in developmental biology for the century to come. PMID- 26970618 TI - Cycling in the Cell Fate Landscape. AB - The causal relationship between the cell cycle and cell fate has recently been reconsidered in several developmental systems, now including sex determination. Direct links between cell cycle machinery and developmental factors demonstrate how modulating the cell cycle can have a profound influence on cellular decisions, through phenomena largely divided into phase-specific interactions seen as "priming" and "competence," or global changes in transcription or histone modifications during transitions. This integration challenges the common view of cell fate landscapes. PMID- 26970617 TI - Tissue Differentiation: A Personal Account of Research on Myogenesis and Cardiogenesis. AB - In this essay I trace my own research experience as a developmental biologist, from the study of cell differentiation in vitro to tissue formation and regeneration in vivo. Beginning with a thesis on histone modifications, I went on to study gene regulation during myogenesis, first in muscle cells in culture and then in the mouse embryo. Later, we also worked on muscle regeneration in the adult. Our work on striated muscle genes also led us into the field of cardiogenesis and characterization of cardiac progenitor cells that form the heart. Comments on the state of the art--changing concepts and the technological advances that underlie scientific progress--accompany this account, with concluding remarks about future directions. PMID- 26970619 TI - Securing Neuronal Cell Fate in C. elegans. AB - Transcription factors control neuronal differentiation by acting as "terminal selectors" that determine the specific cell fates of different types of neurons. The specification of cell fate, however, requires high fidelity, which relies on stable and robust expression of the terminal selectors. Our recent studies in C. elegans suggest that a second set of transcription factors function as reinforcing or protecting factors to stabilize the expression and activity of terminal selectors. Some serve as "guarantors" to ensure the activation and continuous expression of the selectors by reducing stochastic fluctuations in gene expression; others safeguard the protein function of selectors by repressing inhibitors that would block their activity. These transcription factors, unlike the terminal selectors, do not induce specification but secure neuronal cell fate and provide reliability in differentiation. PMID- 26970620 TI - Cancer in Drosophila: Imaginal Discs as a Model for Epithelial Tumor Formation. AB - Cancer genomics has greatly increased our understanding of the complexity of the genetic and epigenetic changes found in human tumors. Understanding the functional relationships among these elements calls for the use of flexible genetic models. We discuss the use of Drosophila models to study cooperation among genetic factors that contribute to disease progression. PMID- 26970622 TI - The Chordin Morphogenetic Pathway. AB - The ancestral Chordin/bone morphogenetic protein (BMP) signaling pathway that establishes dorsal-ventral (D-V) patterning in animal development is one of the best understood morphogenetic gradients, and is established by multiple proteins that interact with each other in the extracellular space-including several BMPs, Chordin, Tolloid, Ont-1, Crossveinless-2, and Sizzled. The D-V gradient is adjusted redundantly by regulating the synthesis of its components, by direct protein-protein interactions between morphogens, and by long-range diffusion. The entire embryo participates in maintaining the D-V BMP gradient, so that for each action in the dorsal side there is a reaction in the ventral side. A gradient of Chordin is formed in the extracellular matrix that separates ectoderm from endomesoderm, called Brachet's cleft in Xenopus. The Chordin/BMP pathway is self organizing and able to scale pattern in the dorsal half of bisected embryos or in Spemann dorsal lip transplantation experiments. PMID- 26970621 TI - Genome Duplication: The Heartbeat of Developing Organisms. AB - The mechanism that duplicates the nuclear genome during the trillions of cell divisions required to develop from zygote to adult is the same throughout the eukarya, but the mechanisms that determine where, when and how much nuclear genome duplication occur regulate development and differ among the eukarya. They allow organisms to change the rate of cell proliferation during development, to activate zygotic gene expression independently of DNA replication, and to restrict nuclear DNA replication to once per cell division. They allow specialized cells to exit their mitotic cell cycle and differentiate into polyploid cells, and in some cases, to amplify the number of copies of specific genes. It is genome duplication that drives evolution, by virtue of the errors that inevitably occur when the same process is repeated trillions of times. It is, unfortunately, the same errors that produce age-related genetic disorders such as cancer. PMID- 26970624 TI - Zygotic Genome Activators, Developmental Timing, and Pluripotency. AB - The transcription factors Pou5f1, Sox2, and Nanog are central regulators of pluripotency in mammalian ES and iPS cells. In vertebrate embryos, Pou5f1/3, SoxB1, and Nanog control zygotic genome activation and participate in lineage decisions. We review the current knowledge of the roles of these genes in developing vertebrate embryos from fish to mammals and suggest a model for pluripotency gene regulatory network functions in early development. PMID- 26970625 TI - Topological Domains, Metagenes, and the Emergence of Pleiotropic Regulations at Hox Loci. AB - Hox gene clusters of jaw vertebrates display a tight genomic organization, which has no equivalent in any other bilateria genomes sequenced thus far. It was previously argued that such a topological consolidation toward a condensed, metagenic structure was due to the accumulation of long-range regulations flanking Hox loci, a phenomenon made possible by the successive genome duplications that occurred at the root of the vertebrate lineage, similar to gene neofunctionalization but applied to a coordinated multigenic system. Here, we propose that the emergence of such large vertebrate regulatory landscapes containing a range of global enhancers was greatly facilitated by the presence of topologically associating domains (TADs). These chromatin domains, mostly constitutive, may have been used as genomic niches where novel regulations could evolve due to both the preexistence of a structural backbone poised to integrate novel regulatory inputs, and a highly adaptive transcriptional readout. We propose a scenario for the coevolution of such TADs and the emergence of pleiotropy at ancestral vertebrate Hox loci. PMID- 26970623 TI - From the Eye to the Brain: Development of the Drosophila Visual System. AB - How stem cells produce the huge diversity of neurons that form the visual system, and how these cells are assembled in neural circuits are a critical question in developmental neurobiology. Investigations in Drosophila have led to the discovery of several basic principles of neural patterning. In this chapter, we provide an overview of the field by describing the development of the Drosophila visual system, from the embryo to the adult and from the gross anatomy to the cellular level. We then explore the general molecular mechanisms identified that might apply to other neural structures in flies or in vertebrates. Finally, we discuss the major challenges that remain to be addressed in the field. PMID- 26970627 TI - Dedifferentiation, Redifferentiation, and Transdifferentiation of Striated Muscles During Regeneration and Development. AB - In some rare and striking cases, striated muscle fibers of the skeleton or body wall, which consist of terminally differentiated syncytia with complex ultrastructures, were found to be capable of dedifferentiating and fragmenting into mononucleate cells. Examples of such events will be discussed in which the dedifferentiated cells reenter the cell cycle, proliferate, and rebuilt damaged muscle fibers during limb regeneration or transdifferentiate to generate new types of muscles during normal development. PMID- 26970626 TI - Connectomics, the Final Frontier. AB - How the synaptic connections in the nervous system are genetically encoded and formed during development remains an unsolved problem. The known connectivity of the nervous system of the nematode C. elegans provides an opportunity to search for the genes involved. The circuits for male mating behavior form a complex neural network that would seem to require a large family of molecular cell labels for pre- and postsynaptic cell recognition. It is suggested that a combinatorial code of neural cell adhesion proteins specifying the network of connections may be discovered by comparing the expression patterns of candidate genes with the pattern of connections. PMID- 26970629 TI - Differentiation in Stem Cell Lineages and in Life: Explorations in the Male Germ Line Stem Cell Lineage. AB - I have been privileged to work on cellular differentiation during a great surge of discovery that has revealed the molecular mechanisms and genetic regulatory circuitry that control embryonic development and adult tissue maintenance and repair. Studying the regulation of proliferation and differentiation in the male germ line stem cell lineage has allowed us investigate how the developmental program imposes layers of additional controls on fundamental cellular processes like cell cycle progression and gene expression to give rise to the huge variety of specialized cell types in our bodies. We are beginning to understand how local signals from somatic support cells specify self-renewal versus differentiation in the stem cell niche at the apical tip of the testis. We are discovering the molecular events that block cell proliferation and initiate terminal differentiation at the switch from mitosis to meiosis-a signature event of the germ cell program. Our work is beginning to reveal how the developmental program that sets up the dramatic new cell type-specific transcription program that prepares germ cells for meiotic division and spermatid differentiation is turned on when cells become spermatocytes. I have had the privilege of working with incredible students, postdocs, and colleagues who have discovered, brainstormed, challenged, and refined our science and our ideas of how developmental pathways and cellular mechanisms work together to drive differentiation. PMID- 26970630 TI - How Somatic Adult Tissues Develop Organizer Activity. AB - The growth and patterning of anatomical structures from specific cellular fields in developing organisms relies on organizing centers that instruct surrounding cells to modify their behavior, namely migration, proliferation, and differentiation. We discuss here how organizers can form in adult organisms, a process of utmost interest for regenerative medicine. Animals like Hydra and planarians, which maintain their shape and fitness thanks to a highly dynamic homeostasis, offer a useful paradigm to study adult organizers in steady-state conditions. Beside the homeostatic context, these model systems also offer the possibility to study how organizers form de novo from somatic adult tissues. Both extracellular matrix remodeling and caspase activation play a key role in this transition, acting as promoters of organizer formation in the vicinity of the wound. Their respective roles and the crosstalk between them just start to be deciphered. PMID- 26970628 TI - Epithelial Skin Biology: Three Decades of Developmental Biology, a Hundred Questions Answered and a Thousand New Ones to Address. AB - The mammalian skin epidermis and its hair and sweat gland appendages provide a protective barrier that retains essential body fluids, guards against invasion by harmful microbes, and regulates body temperature through the ability to sweat. At the interface between the external environment and the body, skin is constantly subjected to physical trauma and must also be primed to repair wounds in response to injury. In adults, the skin maintains epidermal homeostasis, hair regeneration, and wound repair through the use of its stem cells. This essay focuses on when stem cells become established during skin development and where these cells reside in adult epithelial tissues of the skin. I explore how skin stem cells maintain tissue homeostasis and repair wounds and how they regulate the delicate balance between proliferation and differentiation. Finally, I tackle the relation between skin cancer and mutations that perturb the regulation of stem cells. PMID- 26970631 TI - Developmental Plasticity and Developmental Symbiosis: The Return of Eco-Devo. AB - Ecological developmental biology is the study of the interactions between developing organisms and their environments. Organisms have evolved to use the environment as a source of important cues that can alter the trajectory of their development. First, developmental plasticity enables the genome to generate a repertoire of possible phenotypes, and environmental cues are often used to select the phenotype that appears most adaptive at that time. This facilitates evolutionary strategies such as phenotypic accommodation, genetic assimilation, and niche construction. Second, developmental symbiosis, wherein the developing animal utilizes cues from other organisms for normal cell differentiation and morphogenesis, has been found to be ubiquitous. The coevolution of symbiotic microbes and animal cells has often led to the dependency of an animal's development on particular microbial signals, making these cues essential and expected components of normal development. PMID- 26970632 TI - Twenty Years in Maine: Integrating Insights from Developmental Biology into Translational Medicine in a Small State. AB - In this chapter, I give my personal reflections on more than 30 years of studying developmental biology in the mouse model, spending 20 of those years doing research in Maine, a small rural state. I also give my thoughts on my recent experience transitioning to a large medical center in Maine, and the issues involved with integrating insights from developmental biology and regenerative medicine into the fabric of translational and clinical patient care in such an environment. PMID- 26970633 TI - Cell Fate Determination by Transcription Factors. AB - Transcription factors fulfill a key role in the formation and maintenance of different cell-types during development. It is known that transcription factors largely dissociate from chromosomes during mitosis. We found, previously, that mitosis is also a time when somatic nuclei can be far more easily reprogrammed after nuclear transfer than the nuclei of interphase cells. We refer to this as a mitotic advantage. Here, the rate of exchange of a transcription factor on its designated DNA-binding site is discussed. It is proposed that the Xenopus oocyte could serve as an experimental system in which the duration of binding site occupancy could be usefully analyzed. In particular, the Xenopus oocyte has several characteristics which make it possible to determine accurately the concentration and duration of transcription factor binding. It is proposed that the concentration and time are the key variables which govern the action of transcription factors when they activate genes needed for cell lineage determination. PMID- 26970634 TI - Terminal Selectors of Neuronal Identity. AB - The analysis of the developmental programs that define many different neuron types in the nematode Caenorhabditis elegans has revealed common themes in how distinct terminal differentiation programs are controlled. Rather than being controlled in a piece-meal manner, terminal identity features of a mature neuron are often coregulated by so-called terminal selector transcription factors. Here, I summarize the terminal selector concept and emphasize core features of this concept in the C. elegans system such as coregulation of terminal effector batteries, combinatorial control mechanisms, and the coupling of initiation and maintenance of neuronal identity. PMID- 26970635 TI - Drosophila Segment Polarity Mutants and the Rediscovery of the Hedgehog Pathway Genes. AB - The Nusslein-Volhard and Wieschaus screen for mutations disrupting the segmentation of the Drosophila embryo revolutionized developmental genetics, leading the way to the identification of many of the transcription factors and signaling pathways that orchestrate development, not just in the fruit fly but across the animal kingdom. The Hedgehog signaling pathway is a case in point: yet remarkably, all but one of the genes encoding the Hedgehog pathway components including Hedgehog itself-had previously been discovered, in some cases decades earlier. Here I review the original identification of these genes and consider why their significance remained obscure until the Nobel Prize winning screen. PMID- 26970636 TI - The Comparative Organismal Approach in Evolutionary Developmental Biology: Insights from Ascidians and Cavefish. AB - Important contributions to evolutionary developmental biology have been made using the comparative organismal approach. As examples, I describe insights obtained from studies of Molgula ascidians and Astyanax cavefish. PMID- 26970637 TI - From Cloning Neural Development Genes to Functional Studies in Mice, 30 Years of Advancements. AB - The invention of new mouse molecular genetics techniques, initiated in the 1980s, has repeatedly expanded our ability to tackle exciting developmental biology problems. The brain is the most complex organ, and as such the more sophisticated the molecular genetics technique, the more impact they have on uncovering new insights into how our brain functions. I provide a general time line for the introduction of new techniques over the past 30 years and give examples of new discoveries in the neural development field that emanated from them. I include a look to what the future holds and argue that we are at the dawn of a very exciting age for young scientists interested in studying how the nervous system is constructed and functions with such precision. PMID- 26970639 TI - The Curious World of Gonadal Development in Mammals. AB - The distinct sex phenotypes of male and female hinge on the development of the fetal gonads as testes or ovaries, in turn, regulated by the molecular genetic machinery of sex determination. Here, I discuss five aspects of mammalian gonadal development that distinguish it from other examples of organogenesis, and continue to surprise and fascinate. Let's face it: males and females are very different animals-so much so, that for any species there are really two developmental biologies, not one. Humans have been intrigued by the differences between men and women since the beginning of recorded history, and presumably long before. As a developmental biologist, it is especially fascinating to ask how the differences between the sexes arise. Finding the answers involves a stimulating mix of molecular genetics, cell biology, and developmental anatomy. Since our sex phenotype depends critically on the formation of testes or ovaries in the embryo, research efforts focus largely on the genetic control of sex determination and the organogenesis of the gonads. After half a lifetime, I am still busy delving into these issues. In this chapter, I attempt to rationalize this enduring fascination by describing five aspects of sex development that continue to captivate. PMID- 26970640 TI - The Unaimed Arrow Never Misses. AB - In this assay, Raphael Kopan argues that focused emphasis on disease and translation stifles innovation, and outline the reasons why, in my opinion, developmental biologists are more likely to produce new and important discoveries than their more "focused" colleagues. PMID- 26970641 TI - A Path to Pattern. AB - The field of developmental biology is not the same one that I entered in 1975. At that time, it seemed that most of its practitioners used various kinds of microscopes to watch animals as they matured, described morphological details with impressive temporal and spatial resolution, and recorded responses to physical and genetic insults. The number of genes whose mutant phenotypes offered insights into developmental mechanisms was small, the expression and functionalities of these genes were unknown, and because the extent of evolutionary conservation between different animals or even different organs in the same animal was also unknown, the vocabularies that were used to describe development were unique to each system. The distance between the descriptors and inferred molecular mechanisms was vast; it was a descriptive discipline. Today genome sequences are available for the animals that developmental biologists study, saturation genetic screens are possible, transgenesis offers powerful ways to modify genomes, and the proteins that direct and implement developmental processes can be imaged in real time. These advances have transformed the field into one that merges with cell biology, physiology, neurobiology, and immunology, and they have transformed our understanding of development. In this essay, I offer my perspectives and my sense of some principles that have emerged. PMID- 26970638 TI - Tales of Tails (and Trunks): Forming the Posterior Body in Vertebrate Embryos. AB - A major question in developmental biology is how the early embryonic axes are established. Recent studies using different model organisms and mammalian in vitro systems have revealed the surprising result that most of the early posterior embryonic body forms from a Wnt-regulated bipotential neuromesodermal progenitor population that escapes early germ layer patterning. Part of the regulatory network that drives the maintenance and differentiation of these progenitors has recently been determined, but much remains to be discovered. This review discusses some of the common features present in all vertebrates, as well as unique aspects that different species utilize to establish their anterior posterior (A-P) axis. PMID- 26970643 TI - Hox Genes and the Hindbrain: A Study in Segments. AB - The hindbrain develops through a process of segmentation which is coupled with the ordered expression of Hox genes to generate regional diversity of key neural and craniofacial derivatives during head development. This is a fundamental feature governed by a gene regulatory network conserved to the base of vertebrate evolution. PMID- 26970642 TI - Gene-Environment Interactions and the Etiology of Birth Defects. AB - It is thought that most structural birth defects are caused by a complex combination of genetic and environmental factors that interact to interfere with morphogenetic processes. It is important not only to identify individual genetic and environmental risk factors for particular defects but also to identify which environmental factors interact specifically with which genetic variants that predispose to the same defect. Genomic and epidemiological studies are critical to this end. Development and analysis of model systems will also be essential for this goal, as well as for understanding the mechanisms that underlie specific gene-environment interactions. PMID- 26970644 TI - C. elegans Embryonic Morphogenesis. AB - Morphogenesis is a four-dimensional process which involves the crucial interplay between signaling, mechanical forces, and spatial changes. Caenorhabditis elegans presents a simple yet versatile model to study morphogenesis. Here, we review recent progress on cellular and molecular drivers of morphological changes during C. elegans epiboly and embryonic elongation: actin dynamics and actomyosin contractility, migration guidance cues and junction remodeling. In addition, we discuss how mechanical forces contribute to the process. PMID- 26970645 TI - The Last 50 Years: Mismeasurement and Mismanagement Are Impeding Scientific Research. AB - In the last 50 years, there have been many changes to the substance, conduct, and style of research. Many of these changes have proved disastrous to the life of scientists and to science itself. As a consequence, the near-romantic spirit of adventure and exploration that inspired young scientists of my own and earlier generations has become tarnished. Now, many of us feel beleaguered by bureaucrats and by politicians: they affect our lives profoundly, apparently without an understanding of the way discoveries are made or of the nature of science itself. The core purposes of universities, teaching and research, are being eroded by excessive administration. The number and locations of our publications are counted up like beans and the outcomes are used to rank us, one against another; a process of evaluation that has recast the purposes of publication. Applying for grants takes far too much time from a young scientist's life. PMID- 26970646 TI - Mechanochemical Interplay Drives Polarization in Cellular and Developmental Systems. AB - Polarity plays important roles in biological processes, such as motility, differentiation, growth, and pattern formation. One major goal in the field of biological polarity is to understand logics used by signaling networks underlying diverse polarization processes: symmetry breaking, amplification, inhibition, and coordination. In this essay, we explore various polarization processes on cell, tissue, and whole-organism scales, aiming to elucidate how diverse mechanical signals, in addition to chemical cues, can be integrated to a common framework of polarization. PMID- 26970647 TI - The Pluripotency of Neural Crest Cells and Their Role in Brain Development. AB - The neural crest (NC) is, in the Chordate phylum, an innovation of vertebrates, which exhibits several original characteristics: its component cells are pluripotent and give rise to both ectodermal and mesodermal cell types. Moreover, during the early stages of neurogenesis, the NC cells exert a paracrine stimulating effect on the development of the preotic brain. PMID- 26970649 TI - Emerging Modeling Concepts and Solutions in Stem Cell Research. AB - Modern stem cell research, as well as other fields of contemporary biology involves quantitative sciences in many ways. Identifying candidates for key differentiation or reprogramming factors, tracing global transcriptome changes, or finding drugs is now broadly involves bioinformatics and biostatistics. However, the next key step, understanding the underlying reasons and establishing causal links leading to differentiation or reprogramming requires qualitative and quantitative biological models describing complex biological systems. Currently, quantitative modeling is a challenging science, capable to deliver rather modest results or predictions. What model types are the most popular and what features of stem cell behavior they are capturing? What new insights do we expect from the computational modeling of stem cells in the foreseeable future? Current review attempts to approach these essential questions by considering published quantitative models and solutions emerging in the area of stem cell research. PMID- 26970650 TI - Preface. PMID- 26970652 TI - Unpacking knowledge translation in participatory research: a micro-level study. AB - OBJECTIVES: Funding bodies, policy makers, researchers and clinicians are seeking strategies to increase the translation of knowledge between research and practice. Participatory research encompasses a range of approaches for clinicians' involvement in research in the hope of increasing the relevance and usability of research. Our aim was to explore how knowledge is translated and integrated in participants' presentations and negotiations about knowledge. METHODS: Twelve collaboration meetings were observed, and discussions between researchers and clinicians were recorded. The material was examined using the following analytical terms: knowledge object, knowledge form, knowledge position and knowledge tasks. RESULTS: We identified a recurring rhetorical pattern in translational processes that we call 'relevance testing': a strategy by which the participants attempt to create coherence and identify relevance across different contexts. The limitation of this translational strategy was a tendency to reinforce a 'two-communities' logic: re-establishing the separated worlds and rationales between clinicians and researchers. The 'translational work' that unfolds during discussions remains implicit. It may be that participants are unable to explicitly address and identify the knowledge translation processes because they lack necessary conceptual tools. CONCLUSIONS: Our results contribute to increased awareness about translational processes and provide a language through which barriers to translation can be addressed. PMID- 26970648 TI - Germ Plasm Biogenesis--An Oskar-Centric Perspective. AB - Germ granules are the hallmark of all germ cells. These membrane-less, electron dense structures were first observed over 100 years ago. Today, their role in regulating and processing transcripts critical for the establishment, maintenance, and protection of germ cells is well established, and pathways outlining the biochemical mechanisms and physical properties associated with their biogenesis are emerging. PMID- 26970651 TI - Factors associated with HIV testing among men who have sex with men in Western Kenya: a cross-sectional study. AB - HIV diagnosis is an important step in the HIV cascade of prevention and treatment. However, men who have sex with men in low- and middle-income countries have limited access to HIV care services. We examined factors associated with prior HIV testing among men who have sex with men in western Kenya. We recruited 95 men who have sex with men aged 18 years and older, and who reported at least one sexual contact with a man in the past 6 months; however, this analysis is restricted to 89 participants who completed questions on HIV testing. Logistic regression model was used to determine factors associated with HIV testing in the past one year. Results indicate that 23 (26%) had not been tested in the past 12 months. Bivariate analyses demonstrated that condomless anal sex (odds ratio = 3.29, 95% confidence interval = 1.18-9.17) and comfort with healthcare providers (odds ratio = 1.15, 95 % CI = 1.05-1.26) were associated with higher odds of HIV testing in the past 12 months. Experiencing social stigma was associated with lower odds of HIV testing in the last 12 months (odds ratio = 0.91, 95% confidence interval = 0.84-0.94). In multivariable models, social stigma remained significantly associated with lower odds of HIV testing in the last 12 months odds ratio = 0.90, 95% confidence interval = 0.82-0.99) after inclusion of sexual risk and individual level variables. Development of men who have sex with men sensitive HIV-testing services, addressing stigma, and training healthcare workers to provide culturally sensitive services may assist in effectively engaging men who have sex with men in the HIV treatment cascade. PMID- 26970653 TI - The relationship between assessment methods and self-directed learning readiness in medical education. AB - OBJECTIVE: This research explored the assessment of self-directed learning readiness within the comprehensive evaluation of medical students' knowledge and skills and the extent to which several variables predicted participants' self directed learning readiness prior to their graduation. METHODS: Five metrics for evaluating medical students were considered in a multiple regression analysis. Fourth-year medical students at a competitive US medical school received an informed consent and an online survey. Participants voluntarily completed a self directed learning readiness scale that assessed four subsets of self-directed learning readiness and consented to the release of their academic records. RESULTS: The assortment of metrics considered in this study only vaguely captured students' self-directedness. The strongest predictors were faculty evaluations of students' performance on clerkship rotations. Specific clerkship grades were mildly predictive of three subscales. The Pediatrics clerkship modestly predicted critical self-evaluation (r=-.30, p=.01) and the Psychiatry clerkship mildly predicted learning self-efficacy (r =-.30, p=.01), while the Junior Surgery clerkship nominally correlated with participants' effective organization for learning (r=.21, p=.05). Other metrics examined did not contribute to predicting participants' readiness for self-directed learning. CONCLUSIONS: Given individual differences among participants for the variables considered, no combination of students' grades and/or test scores overwhelmingly predicted their aptitude for self-directed learning. Considering the importance of fostering medical students' self-directed learning skills, schools need a reliable and pragmatic approach to measure them. This data analysis, however, offered no clear-cut way of documenting students' self-directed learning readiness based on the evaluation metrics included. PMID- 26970654 TI - Human thermoregulation from the autonomic perspective. PMID- 26970655 TI - Axillary Sentinel Lymph Node Biopsy: Video of the Surgical Procedure. PMID- 26970656 TI - Biological Motion induced mu suppression is reduced in Early Psychosis (EP) patients with active negative symptoms and Autism Spectrum Disorders (ASD). AB - There is evidence of genetic and neural system overlap in Autism Spectrum Disorder (ASD) and Early Psychosis (EP). Five datasets were pooled to compare mu suppression index (MSI), a proxy of mirror neuron activity, in EP, high functioning ASD, and healthy subjects (HS). ASDs and EPs with "active" negative symptoms showed significant differences in mu suppression, in response to Biological Motion/point-light display animation, compared to HS. Preliminary findings suggest that similar neural network deficits in ASD and EP could be driven by the expression of negative symptoms in the latter group of patients. These findings may aid future studies on EP and ASD and facilitate the formulation of new hypotheses regarding their pathophysiology. PMID- 26970658 TI - Effect of background parenchymal enhancement on breast cancer detection with magnetic resonance imaging. AB - OBJECTIVE: To investigate whether background parenchymal enhancement (BPE) may influence the sensitivity of dynamic contrast-enhanced magnetic resonance (DCE MR) imaging in breast cancer detection. MATERIALS AND METHODS: A total of 180 consecutive women with 194 breast cancers underwent MR imaging examination. Women were assigned to two different groups depending on the degree of BPE. Group 1 consisted of women with minimal or mild BPE and group 2 of women with moderate or marked BPE. The distributions of histotypes of tumors within the two groups were compared using the chi(2) test. Difference in sensitivities of DCE-MR imaging for tumor detection between the two groups was searched for using the Student t-test. RESULTS: No differences in terms of distributions of histotypes of tumors between the two groups of women were found (P=0.5). The 11% difference in sensitivity of DCE-MR imaging for tumor detection between group 1 (91/92; 99%; 95% CI: 94-100%) and group 2 (90/102; 88%; 95% CI: 80-94%) was statistically significant (P=0.0058). CONCLUSION: The sensitivity of DCE-MR imaging is significantly lower in women with moderate and marked BPE as compared with women with minimal and mild BPE regardless of cancer histotype. BPE could represent a limitation for breast MR imaging interpretation and should be indicated in MR imaging reports. PMID- 26970657 TI - A discussion of current issues and concepts in the practice of skull photo/craniofacial superimposition. AB - A recent review paper on cranio-facial superimposition (CFS) stated that "there have been specific conceptual variances" from the original methods used in the practice of skull-photo superimposition, leading to poor results as far as accuracy is concerned. It was argued that the deviations in the practice of the technique have resulted in the reduced accuracies (for both failure to include and failure to exclude) that are noted in several recent studies. This paper aims to present the results from recent research to highlight the advancement of skull photo/cranio-facial superimposition, and to discuss some of the issues raised regarding deviations from original techniques. The evolving methodology of CFS is clarified in context with the advancement of technology, forensic science and specifically within the field of forensic anthropology. Developments in the skull photo/cranio-facial superimposition techniques have largely focused on testing reliability and accuracy objectively. Techniques now being employed by forensic anthropologists must conform to rigorous scientific testing and methodologies. Skull-photo/cranio-facial superimposition is constantly undergoing accuracy and repeatability testing which is in line with the principles of the scientific method and additionally allows for advancement in the field. Much of the research has indicated that CFS is useful in exclusion which is consistent with the concept of Popperian falsifiability - a hypothesis and experimental design which is falsifiable. As the hypothesis is disproved or falsified, another evolves to replace it and explain the new observations. Current and future studies employing different methods to test the accuracy and reliability of skull-photo/cranio facial superimposition will enable researchers to establish the contribution the technique can have for identification purposes. PMID- 26970659 TI - Design, synthesis of phenstatin/isocombretastatin-oxindole conjugates as antimitotic agents. AB - A series of phenstatin/isocombretastatin-oxindole conjugates was synthesized and tested for their cytotoxic activity against five human cancer cells such as prostate (DU-145), lung (A549), colon (HT-29), breast (MCF-7), liver (HepG2) cancer cells with IC50 values ranging from 0.049 to 38.90 MUM. Amongst them, two conjugates (5c and 5d) showed broad spectrum of antiproliferative efficacy on lung cancer cells with an IC50 value of 79 nM and 93 nM, respectively, whereas on colon cancer cells with an IC50 values 45 nM and 49 nM, respectively. In addition, cell cycle assay revealed that these conjugates (5c and 5d) arrest at the G2/M phase and leads to apoptotic cell death which was confirmed by Annexin V FITC and mitochondrial membrane depolarization. Further, the tubulin polymerization assay analysis results suggest that these conjugates particularly 5c and 5d exhibit significant inhibitory effect on the tubulin assembly with an IC50 value of 1.23 MUM and 1.01 MUM, respectively. Molecular docking studies indicated that these compounds (5c and 5d) occupy the colchicine binding site of the tubulin. PMID- 26970660 TI - Development of a potent 2-oxoamide inhibitor of secreted phospholipase A2 guided by molecular docking calculations and molecular dynamics simulations. AB - Inhibition of group IIA secreted phospholipase A2 (GIIA sPLA2) has been an important objective for medicinal chemists. We have previously shown that inhibitors incorporating the 2-oxoamide functionality may inhibit human and mouse GIIA sPLA2s. Herein, the development of new potent inhibitors by molecular docking calculations using the structure of the known inhibitor 7 as scaffold, are described. Synthesis and biological evaluation of the new compounds revealed that the long chain 2-oxoamide based on (S)-valine GK241 led to improved activity (IC50=143 nM and 68 nM against human and mouse GIIA sPLA2, respectively). In addition, molecular dynamics simulations were employed to shed light on GK241 potent and selective inhibitory activity. PMID- 26970662 TI - Novel indole-based melatonin analogues: Evaluation of antioxidant activity and protective effect against amyloid beta-induced damage. AB - Oxidative stress has been recognized as a contributing factor in ageing and various diseases including cancer and neuropathological disorders. Indole derivatives such as the neurohormone melatonin (MLT) constitute an important class of therapeutic agent in medicinal chemistry. MLT can scavenge different reactive oxygen species and can also stimulate the synthesis of antioxidant enzymes. As a part of our ongoing studies, a series of new indole-based hydrazide/hydrazone derivatives were synthesized as MLT analogues. Their antioxidant activity was investigated in human erythrocytes by evaluating their reducing effect against oxidation of a redox-sensitive fluorescent probe. Possible inherent cytotoxicity of the compounds was investigated in CHO-K1 cells by lactate dehydrogenase leakage test. Protection of neuronal PC12 cells against amyloid beta-induced damage was examined by MTT assay and their ability in reduction of ROS generation induced by amyloid beta was tested. MLT analogues having an o-halogenated aromatic moiety exhibited effective antioxidant properties without having any membrane-damaging effect. Moreover, derivatives having o-halogenated and dihalogenated aromatic side chain significantly protected neuronal cells at concentrations of 10 and 100 MUM. In conclusion, MLT derivatives represent promising scaffolds for discovery of effective antioxidant and neuroprotective agents. PMID- 26970661 TI - Synthesis, and anticonvulsant activity of new amides derived from 3-methyl- or 3 ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetic acids. AB - This paper describes the synthesis of the library of 22 new 3-methyl- and 3-ethyl 3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetamides as potential anticonvulsant agents. The maximal electroshock (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models were used for screening all the compounds. The 6 Hz model of pharmacoresistant limbic seizures was applied for studying selected derivatives. Six amides were chosen for pharmacological characterization of their antinociceptive activity in the formalin model of tonic pain as well as local anesthetic activity was assessed in mice. The pharmacological data indicate on the broad spectra of activity across the preclinical seizure models. Compounds 10 (ED50=32.08 mg/kg, MES test) and 9 (ED50=40.34 mg/kg, scPTZ test) demonstrated the highest potency. These compounds displayed considerably better safety profiles than clinically relevant antiepileptic drugs phenytoin, ethosuximide, or valproic acid. Several molecules showed antinociceptive and local anesthetic properties. The in vitro radioligand binding studies demonstrated that the influence on the sodium and calcium channels may be one of the essential mechanisms of action. PMID- 26970665 TI - A theoretical interpretation of the "giant" dust particle conundrum. AB - The effects of electric force were used to interpret a well known conundrum about the long-term (or long-distance) dust transport in the atmosphere. PMID- 26970663 TI - In vivo phase II-enzymes inducers, as potential chemopreventive agents, based on the chalcone and furoxan skeletons. AB - Cancer chemoprevention involves prevention/delay/reverse of the carcinogenic process through administration of cancer chemopreventive agents (CCA). Compounds which are able to induce detoxification-enzymes, especially monofunctional phase II enzymes, have become in excellent approaches for new CCA. Herein, we report the synthesis of new furoxanyl chalcone-like hybrid compounds as CCA. In vitro studies showed that phenylfuroxanyl derivatives 6 and 9 displayed the best activities being 9 the greatest monofunctional-inducer. Additionally, compounds were non-mutagenic against TA98 Salmonella typhimurium strain (Ames test) and could be used in the prevention of the progression of pre-malignant lesions for their cytotoxic activity against tumoral cells. In vivo proof of concept showed increment on phase II-enzymes activities in liver, colon and mammary gland having derivative 9 the best induction profiles. We probed Nrf2 nuclear translocation is operative for both compounds allowing to exert protective effects via expression of downstream phase-II enzymes. PMID- 26970664 TI - Long-term Management of Low Back Pain with Opioids and Non-steroidal Anti inflammatory Drugs in a Health System. PMID- 26970666 TI - A Water Framework Directive-compatible metric for assessing acidification in UK and Irish rivers using diatoms. AB - Freshwater acidification continues to be a major problem affecting large areas of Europe, and while there is evidence for chemical recovery, similar evidence for biological recovery of freshwaters is sparse. The need for a methodology to identify waterbodies impacted acidification and to assess the extent of biological recovery is relevant to the EU Water Framework Directive, which requires methods to quantify differences in biology between impacted and unimpacted or reference sites. This study presents a new WFD-compliant metric based on diatoms (Diatom Acidification Metric: DAM) for assessing the acidification status of rivers. A database of 558 benthic diatom samples and associated water chemistry data was assembled. Diatom taxa were assigned to one of 5 indicator classes on the basis of their pH optimum, assessed using Gaussian logistic regression, and these indicator values used to calculate a DAM score for each site using weighted averaging. Reference sites were selected on the basis of their acid neutralising capacity (ANC) and calcium concentration, and a regression model developed to predict expected DAM for each site using pH and total organic carbon (TOC) concentration. Site-specific DAM scores were used to calculate ecological quality ratios ranging from >=1, where the diatom assemblage showed no impact, to (theoretically) 0, when the diatom assemblage was indicative of major anthropogenic activities. The boundary between 'high' and 'good' status was defined as the 25th percentile of Ecological Quality Ratios (EQRs) of all reference sites. The boundary between 'good' and 'moderate' status was set at the point at which nutrient-sensitive and nutrient-tolerant taxa were present in equal relative abundance. The methodology was evaluated using long-term data from 11 sites from the UK Uplands Waters Monitoring Network and is shown to perform well in discriminating naturally acid from acidified sites. PMID- 26970667 TI - Roles of temperature and flow velocity on the mobility of nano-sized titanium dioxide in natural waters. AB - While environmental fate and transport of nano-sized TiO2 (nTiO2) attracts intensive attention, how physical characters of natural waters, such as water type, temperature, and flowing velocity, impact the mobility of nTiO2 remain unclear now. In this work, ultrapure water, lake water, and sea water were chosen to investigate the aggregation and sedimentation behaviors of nTiO2 under a series of environmental conditions with varying feeding concentration, water temperature, and flow velocity. In general, the results demonstrated poorer stability of nTiO2 in sea water than other water types. After a 7-hour test (initial nTiO2=100mg/L), the nTiO2 hydrodynamic sizes, sedimentation rates, and zeta potentials differed significantly in ultrapure water (545nm, 24%, -30mV), lake water (1374nm, 56%, -16mV) and sea water (2152nm, 87%, -3mV). Meanwhile, the study exhibited significant influences of initial nTiO2 concentration (10 100mg/L) on the behaviors of nTiO2 in sea water and lake water but negligible impact on ultrapure water. Ambient temperature also directly affected the aggregation and sedimentation rates of nTiO2, both hydrodynamic diameters and sedimentation of nTiO2 increased markedly with the rising ambient temperatures (10-60 degrees C). In contrast, increasing water flow velocity (0-0.32m/s) lowered the hydrodynamic diameters and sedimentation rates of nTiO2, although the influence of flowing velocity on the aggregation of nTiO2 was partially reversible. PMID- 26970669 TI - Common European Mitochondrial Haplogroups in the Risk for Radiation-induced Subcutaneous Fibrosis in Breast Cancer Patients. AB - AIMS: The contribution of mitochondrial DNA (mtDNA) variations to clinical radiosensitivity is largely unknown. In the present study, we evaluated the association between mtDNA haplogroups and the risk of radiation-induced subcutaneous fibrosis after postoperative radiotherapy in breast cancer patients. MATERIALS AND METHODS: Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA) scale in 286 Italian breast cancer patients who received radiotherapy after breast-conserving surgery. Eight mtDNA single nucleotide polymorphisms that define the nine major haplogroups in the European population were determined by polymerase chain reaction restriction fragment length polymorphism analysis on genomic DNA extracted from peripheral blood. RESULTS: In a Kaplan-Meier analysis evaluated by the Log-rank test, carriers of haplogroup H were found to be at lower risk of grade >=2 subcutaneous fibrosis (P = 0.018) compared with all other haplotypes combined. In the multivariate Cox regression analysis adjusted for clinical factors (body mass index, breast diameter, adjuvant treatment, dose per fraction, radiation type and acute skin toxicity), haplogroup H emerged as a protective factor for moderate to severe radiation-induced fibrosis at a nominal significance level (hazard ratio: 0.50, 95% confidence interval 0.27-0.92, P = 0.027), which did not survive correction for multiple testing. CONCLUSIONS: Our results suggest a protective effect of the mitochondrial haplogroup H in the development of radiation-induced fibrosis in breast cancer patients. However, the loss of statistical significance after correction for multiple comparisons and the lack of an independent validation cohort make our findings preliminary, requiring further confirmation in large-scale prospective studies. PMID- 26970668 TI - Modulation of human allogeneic and syngeneic pluripotent stem cells and immunological implications for transplantation. AB - Tissues derived from induced pluripotent stem cells (iPSCs) are a promising source of cells for building various regenerative medicine therapies; from simply transplanting cells to reseeding decellularized organs to reconstructing multicellular tissues. Although reprogramming strategies for producing iPSCs have improved, the clinical use of iPSCs is limited by the presence of unique human leukocyte antigen (HLA) genes, the main immunologic barrier to transplantation. In order to overcome the immunological hurdles associated with allogeneic tissues and organs, the generation of patient-histocompatible iPSCs (autologous or HLA matched cells) provides an attractive platform for personalized medicine. However, concerns have been raised as to the fitness, safety and immunogenicity of iPSC derivatives because of variable differentiation potential of different lines and the identification of genetic and epigenetic aberrations that can occur during the reprogramming process. In addition, significant cost and regulatory barriers may deter commercialization of patient specific therapies in the short term. Nonetheless, recent studies provide some evidence of immunological benefit for using autologous iPSCs. Yet, more studies are needed to evaluate the immunogenicity of various autologous and allogeneic human iPSC-derived cell types as well as test various methods to abrogate rejection. Here, we present perspectives of using allogeneic vs. autologous iPSCs for transplantation therapies and the advantages and disadvantages of each related to differentiation potential, immunogenicity, genetic stability and tumorigenicity. We also review the current literature on the immunogenicity of syngeneic iPSCs and discuss evidence that questions the feasibility of HLA-matched iPSC banks. Finally, we will discuss emerging methods of abrogating or reducing host immune responses to PSC derivatives. PMID- 26970670 TI - Peptide-based synthetic pulmonary surfactant for the treatment of respiratory distress disorders. AB - KL4 (sinapultide) represents the first peptide-based replacement for surfactant protein B in pulmonary surfactant (PS) therapies approved for clinical use. Surfaxin, its formulation with PS lipids, shows the promise of synthetic PS for replacing animal-derived PS in the treatment of respiratory distress syndromes and for treating acute lung injury. Efforts to characterize the molecular basis for KL4 function have revealed the peptide exhibits a helical structure which differentially partitions in response to both lipid saturation levels and pH. The penta-residue repeat of KL4 leads to adaptive peptide helicity, varying with partitioning depth, and suggests structural plasticity may represent an important mechanism for differential trafficking of lipids, particularly in intra-alveolar surfactant for the formation of stable DPPC monolayers at air-water interfaces. PMID- 26970671 TI - The role of molecular testing in soft tissue sarcoma diagnosis. PMID- 26970673 TI - Diabetes complications in childhood and adolescent onset type 2 diabetes-a review. AB - Diabetes mellitus is one of the most common endocrine disorders in children. Earlier, diabetes in children was almost exclusively type 1 diabetes. Recently, the scenario has changed and increasing numbers of children and adolescent T2DM are being diagnosed. As the epidemic of T2DM shifts to children and adolescents, there is an increased risk of development of micro and macrovascular complications. This could potentially affect the economy of the nation apart from posing a large burden to the individual and his or her family. Prevention and treatment are especially important, given the fact that onset at an early age increases the risk of developing micro and macrovascular complications due to increased duration of exposure to hyperglycemia and other metabolic abnormalities. Diagnosing children and adolescents with T2DM early and instituting good control of all risk factors could yield good results in the prevention of long term complications of diabetes. This review focuses on the prevalence of complications of diabetes among children and adolescents with T2DM. PMID- 26970674 TI - EMPA-REG: Glucose excretion and lipid mobilization - not storage - saves lives. PMID- 26970672 TI - Clinical effect of molecular methods in sarcoma diagnosis (GENSARC): a prospective, multicentre, observational study. AB - BACKGROUND: Advances in molecular genetics of sarcoma have enabled the identification of type-specific aberrations. We aimed to assess the clinical effect of systematic implementation of molecular assays to improve sarcoma misdiagnosis. METHODS: In this multicentre, observational study, we recruited patients from 32 centres of the French Sarcoma Group/Reference Network in Pathology of Sarcomas. Eligibility criteria included: biopsy or surgical resection; suspicion of: dermatofibrosarcoma protuberans (cohort 1), dedifferentiated liposarcoma (cohort 2), Ewing's sarcoma family of tumours (cohort 3), synovial sarcoma (cohort 4), alveolar rhabdomyosarcoma (cohort 5), and myxoid or round cell liposarcoma (cohort 6); review by one sarcoma-expert pathologist; availability of frozen material (except for cohort 1 of patients with dermatofibrosarcoma protuberans because anti-CD34 immunohistochemistry is performed on paraffin-embedded tissue); and patient information. For each case, the pathologist made one primary diagnosis followed by up to two differential diagnoses, based on histological characteristics only. Each diagnosis was classified as certain, probable, or possible. For each case to determine the molecular classification, we did fluorescence in-situ hybridisation on paraffin embedded samples. We also did comparative genomic hybridisation and quantitative PCR (cohort 2) or reverse transcriptase PCR (cohorts 3-6) on frozen and paraffin embedded samples. We made a final diagnosis based on the molecular results. The clinical effect of diagnosis correction was assessed by a board of experts. FINDING: Between June 22, 2009, and Oct 30, 2012, 395 patients were enrolled in the study, of which 384 were eligible for inclusion. The diagnosis was eventually modified by molecular genetics for 53 patients: eight (16%) of 50 patients with dermatofibrosarcoma (cohort 1), seven (23%) of 30 patients with dedifferentiated liposarcoma (cohort 2), 13 (12%) of 112 with Ewing's sarcoma family of tumours (cohort 3), 16 (16%) of 97 patients with synovial sarcoma (cohort 4), seven (15%) of 46 patients with alveolar rhabdomyosarcoma (cohort 5), and two (4%) of 49 patients with myxoid or round cell liposarcoma (cohort 6), with an effect on primary management or prognosis assessment in 45 cases. INTERPRETATION: Molecular genetic testing should be mandatory for diagnostic accuracy of sarcoma and appropriate clinical management, even when histological diagnosis is made by pathologist experts in this field. FUNDING: French National Cancer Institute and Nice University Hospital. PMID- 26970675 TI - Assessment of MRI image quality for various setup positions used in breast radiotherapy planning. AB - This study investigates breast magnetic resonance imaging (MRI) image quality for 3 different breast radiotherapy positions (prone, supine flat and supine inclined) and associated choice of breast coils. Supine breast MRI has comparable image quality to prone breast MRI for the purposes of radiotherapy delineation for T2-weighted sequences. PMID- 26970677 TI - Biological dosimetry to assess risks of health effects in victims of radiation accidents: Thirty years after Chernobyl. PMID- 26970678 TI - Adjuvant radiation therapy in resected high-grade localized skeletal osteosarcomas treated with neoadjuvant chemotherapy: Long-term outcomes. AB - PURPOSE: To assess long-term outcomes and toxicity of adjuvant radiotherapy in the post-surgical management of patients with resected high-grade skeletal osteosarcomas. METHODS AND MATERIALS: Seventy-two patients with primary resected osteosarcomas underwent adjuvant radiotherapy after neoadjuvant chemotherapy from December 1984 to December 2008. Local control (LC), overall survival (OS) and disease-free survival (DFS) were estimated using Kaplan-Meier methods. For survival outcomes potential associations were assessed in univariate and multivariate analyses using the Cox proportional hazards model. RESULTS: After a median follow-up of 174months (range, 33-363months), 10-year LC, DFS, and OS rates were 82%, 58%, and 73%, respectively. In the multivariate analysis only R1 margin status (p=0.02) remained significantly associated with LC. Patients with tumor necrosis <90% (p=0.04) and R1 resection margin (p=0.05) remained at a significantly higher risk of mortality on multivariate analysis. Six patients (8%) developed grade ?3 treatment-related chronic toxicity events. No grade 5 toxicities were reported. CONCLUSIONS: A multimodal radiotherapy-containing approach is a well-tolerated component of treatment for patients with osteosarcomas undergoing programed resection, allowing low toxicity rates while maintaining high local control rates. PMID- 26970679 TI - Therapy region monitoring based on PET using 478 keV single prompt gamma ray during BNCT: A Monte Carlo simulation study. AB - We confirmed the feasibility of using our proposed system to extract two different kinds of functional images from a positron emission tomography (PET) module by using an insertable collimator during boron neutron capture therapy (BNCT). Coincidence events from a tumor region that included boron particles were identified by a PET scanner before BNCT; subsequently, the prompt gamma ray events from the same tumor region were collected after exposure to an external neutron beam through an insertable collimator on the PET detector. Five tumor regions that contained boron particles and were located in the water phantom and in the BNCT system with the PET module were simulated with Monte Carlo simulation code. The acquired images were quantitatively analyzed. Based on the receiver operating characteristic (ROC) curves in the five boron regions, A, B, C, D, and E, the PET and single-photon images were 10.2%, 11.7%, 8.2% (center region), 12.6%, and 10.5%, respectively. We were able to acquire simultaneously PET and single prompt photon images for tumor regions monitoring by using an insertable collimator without any additional isotopes. PMID- 26970676 TI - Assessment of fully-automated atlas-based segmentation of novel oral mucosal surface organ-at-risk. AB - BACKGROUND AND PURPOSE: Current oral mucositis normal tissue complication probability models, based on the dose distribution to the oral cavity volume, have suboptimal predictive power. Improving the delineation of the oral mucosa is likely to improve these models, but is resource intensive. We developed and evaluated fully-automated atlas-based segmentation (ABS) of a novel delineation technique for the oral mucosal surfaces. MATERIAL AND METHODS: An atlas of mucosal surface contours (MSC) consisting of 46 patients was developed. It was applied to an independent test cohort of 10 patients for whom manual segmentation of MSC structures, by three different clinicians, and conventional outlining of oral cavity contours (OCC), by an additional clinician, were also performed. Geometric comparisons were made using the dice similarity coefficient (DSC), validation index (VI) and Hausdorff distance (HD). Dosimetric comparisons were carried out using dose-volume histograms. RESULTS: The median difference, in the DSC and HD, between automated-manual comparisons and manual-manual comparisons were small and non-significant (-0.024; p=0.33 and -0.5; p=0.88, respectively). The median VI was 0.086. The maximum normalised volume difference between automated and manual MSC structures across all of the dose levels, averaged over the test cohort, was 8%. This difference reached approximately 28% when comparing automated MSC and OCC structures. CONCLUSIONS: Fully-automated ABS of MSC is suitable for use in radiotherapy dose-response modelling. PMID- 26970680 TI - Sex bias in paediatric autoimmune disease - Not just about sex hormones? AB - Autoimmune diseases affect up to 10% of the world's population, and approximately 80% of those affected are female. The majority of autoimmune diseases occur more commonly in females, although some are more frequent in males, while others show no bias by sex. The mechanisms leading to sex biased disease prevalence are not well understood. However, for adult-onset autoimmune disease, at least some of the cause is usually ascribed to sex hormones. This is because levels of sex hormones are one of the most obvious physiological differences between adult males and females, and their impact on immune system function is well recognised. While for paediatric-onset autoimmune diseases a sex bias is not as common, there are several such diseases for which one sex predominates. For example, the oligoarticular subtype of juvenile idiopathic arthritis (JIA) occurs in approximately three times more girls than boys, with a peak age of onset well before the onset of puberty, and at a time when levels of androgen and oestrogen are low and not strikingly different between the sexes. Here, we review potential explanations for autoimmune disease sex bias with a particular focus on paediatric autoimmune disease, and biological mechanisms outside of sex hormone differences. PMID- 26970682 TI - Gut: An underestimated target organ for Aluminum. AB - Since World War II, several factors such as an impressive industrial growth, an enhanced environmental bioavailability and intensified food consumption have contributed to a significant amplification of human exposure to aluminum. Aluminum is particularly present in food, beverages, some drugs and airbone dust. In our food, aluminum is superimposed via additives and cooking utensils. Therefore, the tolerable intake of aluminum is exceeded for a significant part of the world population, especially in children who are more vulnerable to toxic effects of pollutants than adults. Faced with this oral aluminum influx, intestinal tract is an essential barrier, especially as 38% of ingested aluminum accumulates at the intestinal mucosa. Although still poorly documented to date, the impact of oral exposure to aluminum in conditions relevant to real human exposure appears to be deleterious for gut homeostasis. Aluminum ingestion affects the regulation of the permeability, the microflora and the immune function of intestine. Nowadays, several arguments are consistent with an involvement of aluminum as an environmental risk factor for inflammatory bowel diseases. PMID- 26970681 TI - Response rate of initial conventional treatments, disease course, and related factors of patients with adult-onset Still's disease: Data from a large multicenter cohort. AB - BACKGROUND: Adult-onset Still's disease (AOSD) is a rare condition, and treatment choices are frequently dependent on expert opinions. The objectives of the present study were to assess treatment modalities, disease course, and the factors influencing the outcome of patients with AOSD. METHODS: A multicenter study was used to reach sufficient patient numbers. The diagnosis of AOSD was based on the Yamaguchi criteria. The data collected included patient age, gender, age at the time of diagnosis, delay time for the diagnosis, typical AOSD rash, arthralgia, arthritis, myalgia, sore throat, lymphadenopathy, hepatomegaly, splenomegaly, pleuritis, pericarditis, and other rare findings. The laboratory findings of the patients were also recorded. The drugs initiated after the establishment of a diagnosis and the induction of remission with the first treatment was recorded. Disease patterns and related factors were also investigated. A multivariate analysis was performed to assess the factors related to remission. RESULTS: The initial data of 356 patients (210 females; 59%) from 19 centers were evaluated. The median age at onset was 32 (16-88) years, and the median follow-up time was 22 months (0-180). Fever (95.8%), arthralgia (94.9%), typical AOSD rash (66.9%), arthritis (64.6%), sore throat (63.5%), and myalgia (52.8%) were the most frequent clinical features. It was found that 254 of the 306 patients (83.0%) displayed remission with the initial treatment, including corticosteroids plus methotrexate with or without other disease-modifying antirheumatic drugs. The multivariate analysis revealed that the male sex, delayed diagnosis of more than 6 months, failure to achieve remission with initial treatment, and arthritis involving wrist/elbow joints were related to the chronic disease course. CONCLUSION: Induction of remission with initial treatment was achieved in the majority of AOSD patients. Failure to achieve remission with initial treatment as well as a delayed diagnosis implicated a chronic disease course in AOSD. PMID- 26970683 TI - Low-dose and combined effects of oral exposure to bisphenol A and diethylstilbestrol on the male reproductive system in adult Sprague-Dawley rats. AB - Study of the joint action of xenobiotics is important to fully explore their toxicity and complete risk analysis. In this study, we investigated the effects of low-dose and combined exposure of bisphenol A (BPA) and diethylstilbestrol (DES) on the reproductive system in adult male rats. The results showed that the sperm motility decreased in the BPA/DES and combined groups. Sperm deformity ratios and histological lesions of the testes were significantly higher and more significant, respectively, in the combined group compared with the single treated groups. No dose-effect relationship or significant additive effect on serum hormone levels was observed after combined exposure to BPA/DES. Ultrastructural results showed lesions of the Sertoli and Leydig cells, mainly in the endoplasmic reticulum (ER), in all treated groups. ER stress molecular sensor IRE1 was phosphorylated and activated after BPA and DES treatment in this study. The protein levels of ES stress molecular marker CHOP were significantly up-regulated after exposure to BPA, DES, and BPA and DES combined. These findings indicate that ER stress is important in BPA/DES-induced damage in rat testes. Low-dose and combined exposure to BPA and DES may have toxic effects on male fertility in the adult population. PMID- 26970684 TI - Mussels of a marginal population affect the patterns of ambient macrofauna: A case study from the Baltic Sea. AB - In contemporary ecosystems, organisms are increasingly confronted with suboptimal living conditions. We aimed to understand the role of ecosystem engineering species in suboptimal habitats from a population inhabiting the species range margin in naturally stressful conditions. We determined the impact of 2-4 cm sized patches of dwarfed mussels Mytilus trossulus close to its lower salinity limit in the North-Eastern Baltic Sea, on epibenthic community patterns. Mussels affected total macrofaunal abundance and biomass and the taxonomic and functional community structure based on abundances, as well as the species composition of macrofauna. Mussels did not affect ephemeral algae or sediment chlorophyll content, but increased the abundance, biomass, richness, and diversity of grazers, within a radius approximately twelve times the size of mussel patches. We can expect marginal populations of ecosystem engineers in suboptimal habitats to contribute to spatial heterogeneity in biotic patterns and eventual ecosystem stability. PMID- 26970685 TI - Trophic relationships between metazooplankton communities and their plankton food sources in the Iles Eparses (Western Indian Ocean). AB - Coral reef and atoll lagoons are among the most diversified marine ecosystems but also the most affected by the combined effects of climate change and human activities. The Iles Eparses (Scattered Islands) in the Western Indian Ocean have been little affected by human pressure and can be considered to be "pristine" ecosystems. Metazooplankton plays a major role in the functioning and productivity of aquatic ecosystems, and this study was undertaken: (i) to determine the spatial abundance, distribution and species composition of metazooplankton, (ii) to assess the effect of metazooplankton grazing on pico- and nanophytoplankton and (iii) to analyze the trophic positions of metazooplankton by using the stable isotope signatures of a wide variety of taxa and particulate organic matter from the Iles Eparses and Mayotte. Tromelin Island (which is not located in the Mozambique Channel) had the lowest metazooplankton abundance with no cyanobacteria Trichodesmium spp. or mollusks (pteropods) presence, and with delta(15)N signatures of organisms that were higher than for the islands in the Mozambique Channel. Trichodesmium spp. was found in the Mozambique Channel and the plankton food web was probably based preferentially on these cyanobacteria with lower delta(15)N signatures indicating direct or indirect trophic transfer of diazotrophic nitrogen to metazooplankton. Three of the islands were distinct: Europa had the highest proportion of copepods, with oithonids being dominant, which is typical of rich mangrove systems, while Juan de Nova and Mayotte seemed to be the sites most affected by human activity with a high abundance of appendicularians and distinct particulate organic matter ?(13)C signatures. Grazing experiments showed that food could be a limiting factor for metazooplankton in the Iles Eparses. However, the effect of metazooplankton grazing on phytoplankton appeared to be very low (0.01-2.32% of the total phytoplankton per day). PMID- 26970686 TI - Responses of ghost crabs to habitat modification of urban sandy beaches. AB - Sandy beaches in highly urbanised areas are subject to a wide range of human impacts. Ghost crabs are a commonly used ecological indicator on sandy beaches, as they are key consumers in these systems and counting burrow openings allows for rapid assessment of population size. This study assessed the pressures of urbanisation on sandy beaches in the highly urbanised estuary of Sydney Harbour. Across 38 beaches, we examined which physical beach properties, management practices and human induced habitat modification best predicted ghost crab distributions. Of all variables measured, the frequency of mechanical beach cleaning was the most important predictor of crab abundance, with low burrow densities at the highest cleaning frequency and the highest densities at beaches cleaned at the intermediate frequency (<=3 times per week). These results indicate that ghost crab populations in Sydney Harbour are more robust to the impacts of urbanisation than previously thought. PMID- 26970687 TI - Light-harvesting complexes in photosystem II regulate glutathione-induced sensitivity of Arabidopsis guard cells to abscisic acid. AB - Light-harvesting complexes (LHCs) in photosystem II (PSII) regulate glutathione (GSH) functions in plants. To investigate whether LHCs control GSH biosynthesis that modifies guard cell abscisic acid (ABA) sensitivity, we evaluated GSH content, stomatal aperture, reactive oxygen species (ROS), weight loss and plant growth using a ch1-1 mutant that was defective of LHCs and compared this with wild-type (WT) Arabidopsis thaliana plants. Glutathione monoethyl ester (GSHmee) increased but 1-chloro-2,4 dinitrobenzene (CDNB) decreased the GSH content in the guard cells. The guard cells of the ch1-1 mutants accumulated significantly less GSH than the WT plants. The guard cells of the ch1-1 mutants also showed higher sensitivity to ABA than the WT plants. The CDNB treatment increased but the GSHmee treatment decreased the ABA sensitivity of the guard cells without affecting ABA-induced ROS production. Dark and light treatments altered the GSH content and stomatal aperture of the guard cells of ch1-1 and WT plants, irrespective of CDNB and GSHmee. The ch1-1 mutant contained fewer guard cells and displayed poor growth, late flowering and stumpy weight loss compared with the WT plants. This study suggests that defective LHCs reduced the GSH content in the guard cells and increased sensitivity to ABA, resulting in stomatal closure. PMID- 26970688 TI - Analysis of the embryo proteome of sycamore (Acer pseudoplatanus L.) seeds reveals a distinct class of proteins regulating dormancy release. AB - Acer pseudoplatanus seeds are characterized by a deep physiological embryo dormancy that requires a few weeks of cold stratification in order to promote germination. Understanding the function of proteins and their related metabolic pathways, in conjunction with the plant hormones implicated in the breaking of seed dormancy, would expand our knowledge pertaining to this process. In this study, a proteomic approach was used to analyze the changes occurring in seeds in response to cold stratification, which leads to dormancy release. In addition, the involvement of abscisic (ABA) and gibberellic acids (GA) was also examined. Fifty-three proteins showing significant changes were identified by mass spectrometry. An effect of ABA on protein variation was observed at the beginning of stratification, while the influence of GA on protein abundance was observed during the middle phase of stratification. The majority of proteins associated with dormancy breaking in the presence of only water, and also ABA or GA, were classified as being involved in metabolism and genetic information processing. For metabolic-related proteins, the effect of ABA on protein abundance was stimulatory for half of the proteins and inhibitory for half of the proteins. On the other hand, the effect on genetic information processing related proteins was stimulatory. GA was found to upregulate both metabolic-related and genetic information processing-related proteins. While seed dormancy breaking depends on proteins involved in a variety of processes, proteins associated with methionine metabolism (adenosine kinase, methionine synthase) and glycine-rich RNA binding proteins appear to be of particular importance. PMID- 26970689 TI - The dynamics of deferred decision. AB - Decision makers are often unable to choose between the options that they are offered. In these settings they typically defer their decision, that is, delay the decision to a later point in time or avoid the decision altogether. In this paper, we outline eight behavioral findings regarding the causes and consequences of choice deferral that cognitive theories of decision making should be able to capture. We show that these findings can be accounted for by a deferral-based time limit applied to existing sequential sampling models of preferential choice. Our approach to modeling deferral as a time limit in a sequential sampling model also makes a number of novel predictions regarding the interactions between choice probabilities, deferral probabilities, and decision times, and we confirm these predictions in an experiment. Choice deferral is a key feature of everyday decision making, and our paper illustrates how established theoretical approaches can be used to understand the cognitive underpinnings of this important behavioral phenomenon. PMID- 26970690 TI - 39-Year-Old Woman With Dyspnea and Chest Pain. PMID- 26970691 TI - 39-Year-Old Man With Dysphagia. PMID- 26970692 TI - Fate of antibiotic resistance bacteria and genes during enhanced anaerobic digestion of sewage sludge by microwave pretreatment. AB - The fate of antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) were investigated during the sludge anaerobic digestion (AD) with microwave-acid (MW-H), microwave (MW) and microwave-H2O2-alkaline (MW-H2O2) pretreatments. Results showed that combined MW pretreatment especially for the MW H pretreatment could efficiently reduce the ARB concentration, and most ARG concentrations tended to attenuate during the pretreatment. The subsequent AD showed evident removal of the ARB, but most ARGs were enriched after AD. Only the concentration of tetX kept continuous declination during the whole sludge treatment. The total ARGs concentration showed significant correlation with 16S rRNA during the pretreatment and AD. Compared with unpretreated sludge, the AD of MW and MW-H2O2 pretreated sludge presented slightly better ARB and ARGs reduction efficiency. PMID- 26970693 TI - Industrial scale garage-type dry fermentation of municipal solid waste to biogas. AB - The objectives of this study was to through monitoring the 1st industrial scale garage-type dry fermentation (GTDF) MSW biogas plant in Bin County, Harbin City, Heilongjiang Province, China, to investigate its anaerobic digestion (AD) performance and the stability of process. After a monitoring period of 180days, the results showed that the volumetric biogas production of the digesters and percolate tank was 0.72 and 2.22m(3) (m(3)d)(-1), respectively, and the specific biogas yield of the feedstock was about 270m(3)CH4tVS(-1), which indicated that the GTDF is appropriate for the Chinese MSW. This paper also raised some problems aimed at improving the process stability and AD efficiency. PMID- 26970694 TI - Synergistic dynamics of nitrogen and phosphorous influences lipid productivity in Chlorella minutissima for biodiesel production. AB - The study synergistically optimized nitrogen and phosphorous concentrations for attainment of maximum lipid productivity in Chlorella minutissima. Nitrogen and phosphorous limited cells (N(L)P(L)) showed maximum lipid productivity (49.1+/ 0.41mg/L/d), 1.47 folds higher than control. Nitrogen depletion resulted in reduced cell size with large sized lipid droplets encompassing most of the intracellular space while discrete lipid bodies were observed under nitrogen sufficiency. Synergistic N/P starvations showed more prominent effect on photosynthetic pigments as to individual deprivations. Phosphorous deficiency along with N starvation exhibited 17.12% decline in carbohydrate while no change in nitrogen sufficient cells were recorded. The optimum N(L)P(L) concentration showed balance between biomass and lipid by maintaining intermediate cell size, pigments, carbohydrate and proteins. FAME profile showed C14-C18 carbon chains in N(L)P(L) cells with biodiesel properties comparable to plant oil methyl esters. Hence, synergistic N/P limitation was effective for enhancing lipid productivity with reduced consumption of nutrients. PMID- 26970695 TI - Effect of composites based nickel foam anode in microbial fuel cell using Acetobacter aceti and Gluconobacter roseus as a biocatalysts. AB - This study explores the use of materials such as chitosan (chit), polyaniline (PANI) and titanium carbide (TC) as anode materials for microbial fuel cells. Nickel foam (NF) was used as the base anode substrate. Four different types of anodes (NF, NF/PANI, NF/PANI/TC, NF/PANI/TC/Chit) are thus prepared and used in batch type microbial fuel cells operated with a mixed consortium of Acetobacter aceti and Gluconobacter roseus as the biocatalysts and bad wine as a feedstock. A maximum power density of 18.8Wm(-3) (~2.3 times higher than NF) was obtained in the case of the anode modified with a composite of PANI/TC/Chit. The MFCs running under a constant external resistance of (50Omega) yielded 14.7% coulombic efficiency with a maximum chemical oxygen demand (COD) removal of 87-93%. The overall results suggest that the catalytic materials embedded in the chitosan matrix show the best performance and have potentials for further development. PMID- 26970697 TI - The Microbiome in Necrotizing Enterocolitis: A Case Report in Twins and Minireview. AB - Our case describes the serial microbiome changes in twins discordant for necrotizing enterocolitis (NEC), who shared similar intrauterine and early environmental exposures. The key findings were that the 2 neonates had distinctly different microbiome compositions from the first stool samples collected. Also, in the twin who developed NEC there was a decrease in bacterial diversity and an increase in Proteobacteria a week before developing any clinical symptoms, suggesting an early role of the intestinal microbiome in the development of NEC. Here we briefly review the literature on the role of the intestinal microbiome in NEC and how a greater understanding of the neonatal microbiome and host interactions may help mitigate this devastating disease. PMID- 26970696 TI - Cost-effectiveness of First-line Chronic Lymphocytic Leukemia Treatments When Full-dose Fludarabine Is Unsuitable. AB - PURPOSE: The cost-effectiveness of first-line chronic lymphocytic leukemia treatments was assessed among patients unsuitable for full doses of fludarabine. METHODS: The study's key outcome was the life-time incremental cost-effectiveness ratio (ICER) (euro/quality-adjusted life-year [QALY] gained) with an annual 3% discounting. A probabilistic Markov model with 3 health states (progression-free, progression, and death) was developed. Survival time was modeled based on age matched clinical data by using appropriate survival distributions. Each health state was assigned an EuroQoL-5D-3L quality-of-life estimate and Finnish payer costs according to treatment received, and Binet stage of disease; severe adverse events and treatment inconvenience were also included. Six approaches considered the risk and value of key outcomes: cost-effectiveness efficiency frontiers; Bayesian treatment ranking (BTR) rated the lowest ICERs and best QALY gains; the cost-effectiveness acceptability frontier demonstrated optimal treatment; expected value of perfect information; and the cost-benefit assessment (CBA), a type of clinical value analysis, increased the clinical interpretation and appeal of modeled outcomes by including both relative and absolute (impact investment [benefit obtained with a fixed limited budget]) benefit assessments. FINDINGS: The ICERs compared with chlorambucil varied from ?29,334 with obinutuzumab + chlorambucil to ?82,159 with ofatumumab + chlorambucil. Based on the BTR of ICERs versus chlorambucil, obinutuzumab + chlorambucil was the most cost-effective with 93% probability; rituximab + chlorambucil was the second most cost-effective (73%); and rituximab + bendamustine was the third most cost-effective (65%). The ICERs of obinutuzumab + chlorambucil were ?20,038, ?11,556, and ?15,586 compared with rituximab + chlorambucil, rituximab + bendamustine, and ofatumumab + chlorambucil. Obinutuzumab + chlorambucil was the most cost-effective treatment, with 54% and 99% probability at ?30,000 and ?50,000/QALY gained, respectively. The corresponding expected values of perfect information were ?1438 and ?44 per patient. Based on the BTR of QALYs gained, obinutuzumab + chlorambucil was the most effective, with 100% probability; rituximab + chlorambucil was the second most effective (56%); and rituximab + bendamustine was the third most effective treatment (81%). Results were robust in sensitivity analyses. For obinutuzumab + chlorambucil, the CBA demonstrated the best clinical value-to-cost-effectiveness relation and the longest time progression-free with a limited budget. IMPLICATIONS: The mean results were sensitive to large changes in time horizon, indirect comparison hazard ratios, survival distributions, and discounting; however, obinutuzumab + chlorambucil provided considerable effectiveness and best value for money among chronic lymphocytic leukemia patients unsuitable to receive full doses of fludarabine. In this case, CBA concurred with the key outcome of the study. However, the CBA cannot fully substitute the key outcome, and further cost-effectiveness studies with different cancer types are needed to assess the validity of a limited CBA. PMID- 26970698 TI - Reply: Dengue RT-PCR-positive, Chikungunya IgM-positive and Zika RT-PCR-positive co-infection in a patient from Colombia. PMID- 26970699 TI - Chicken pox infection in patients undergoing chemotherapy: A retrospective analysis from a tertiary care center in India. AB - There is paucity of data on the incidence, severity and management of chicken pox in patients receiving active chemotherapy for cancer. From October 2010 to October 2011, patients were included in this study if they developed a chicken pox infection during their chemotherapy. The details of patients' cancer diagnosis and treatment along with clinical and epidemiological data of the chicken pox infections were assessed from a prospectively maintained database. Twenty-four patients had a chicken pox infection while receiving chemotherapy and/or radiotherapy. The median age of the patients was 21 years, and two-thirds of the patients had solid tumor malignancies. Overall, eight (33%) patients had complications, six (25%) patients had febrile neutropenia, four (17%) had diarrhea/mucositis, and four (17%) had pneumonia. The median time for recovery of the infection and complications in the patients was 9.5 days (5-29 days), whereas for neutropenic patients, it was 6.5 days (3-14 days). The median time for recovery from chicken pox infections in neutropenic patients was 10 days (5-21 days), compared with 8.5 days (0-29 days) in non-neutropenic patients (P=0.84). The median time for recovery from infections was 8.5 days in patients with comorbidities (N=4), which was the same for patients with no comorbidities. The clinical presentation and complication rates of chicken pox in cancer patients, who were on active chemotherapy, are similar to the normal population. The recovery from a varicella infection and complications may be delayed in patients with neutropenia. The varicella infection causes a therapy delay in 70% of patients. Aggressive antiviral therapy, supportive care and isolation of the index cases remain the backbone of treatment. PMID- 26970700 TI - Implementation and Results of a Percutaneous Renal Allograft Biopsy Protocol to Reduce Complication Rate. AB - Percutaneous renal transplant biopsy (PRTB) is the gold standard for evaluating allograft rejection after renal transplant. Hemorrhage is the predominant complication. We describe the implementation of a standardized protocol for PRTB at a single institution, with the aim of reducing bleeding complications. Utilizing the plan-do-study-act model for quality improvement, we created and deployed a protocol centered on controlling patient's hypertension, platelet function, and anticoagulation status. The 4-year study encompassed a total of 880 PRTBs, before and after implementation of the protocol. Total complication rate, which was 5.8% in the 2 years leading up to implementation of the protocol, was reduced to 2.9% after the protocol was introduced (P = .04). A standardized approach to PRTB can potentially lower complication rates; we present a framework for implementating a quality improvement protocol at other institutions. PMID- 26970701 TI - Decreased neck muscle strength in patients with the loss of cervical lordosis. AB - BACKGROUND: The loss of cervical lordosis is associated with some negative clinical outcomes. No previous study has examined cervical muscle strength, specifically in patients with the loss of cervical lordosis. This study aims to investigate whether there is weakness of the cervical muscles or an imbalance between cervical flexor and extensor muscle strength in patients with the loss of cervical lordosis compared with healthy controls matched by age, gender, body mass index (BMI), and employment status. METHODS: Thirty-two patients with the loss of cervical lordosis (23 F, 9 M) and 31 healthy volunteers (23 F, 8 M) were included in the study. Maximal isometric neck extension and flexion strength, and the strength ratio between extension and flexion were used as evaluation parameters. All measurements were conducted by a blinded assessor using a digital force gauge. The participants were positioned on a chair in a neutral cervical position and without the trunk inclined during measurements. FINDINGS: Maximal isometric neck extension and flexion strength values were significantly lower in the patients versus healthy controls (P<0.001 and P=0.040, respectively). The mean (SD) values of the extension/flexion ratio were 1.21 (0.34) in the patients and 1.46 +/- 0.33 in the controls (P=0.004). INTERPRETATION: According to our results, patients with the loss of cervical lordosis have reduced neck muscle strength, especially in the extensors. These findings may be beneficial for optimizing cervical exercise prescriptions. PMID- 26970702 TI - Effects of contracture on gait kinematics: A systematic review. AB - BACKGROUND: Contractures of a major joint in the lower limbs may impair human walking in addition to other daily living activities. A contracture is defined as the inability of a joint to perform the full range of motion and excessive resistance during passive mobilization of the joint. Few studies have reported methods describing how to evaluate contractures. Understanding the association among all of these studies seems essential to improve patient management. Therefore, we conducted a systematic review on this topic to elucidate the influence of contractures on gait kinematics. METHODS: An electronic search in the literature will be conducted. Studies were screened by title and abstract and full texts were evaluated secondarily for definitive inclusion. The quality of the included studies was assessed independently by the two review authors with the Modified Quality Assessment Checklist. The included studies were separated into three categories: pathological contracture versus healthy controls (descriptive), simulated contracture versus healthy controls (experimental), and pre- and post-kinematics after surgical muscle lengthening (surgery). FINDINGS: From a total of 4402 references, 112 original articles were selected, and 28 studies were identified in this systematic review. No significant difference between raters was observed on the total score of the Modified Quality Assessment Checklist. INTERPRETATION: Contractures influence walking depending on the location (muscle) and the contracture level (muscle-tendon length). After giving a definition of contracture, this review identified some contracture alterations, such as plantarflexion, knee flexion and hip flexion contractures, with a kinematic description and presented possible different compensations. PMID- 26970703 TI - Implant impingement during internal rotation after reverse shoulder arthroplasty. The effect of implant configuration and scapula anatomy: A biomechanical study. AB - BACKGROUND: Internal rotation after reverse shoulder arthroplasty is essential to perform fundamental daily living activities. The purpose of this study was to examine the impact of anatomical and implant related factors on impingement-free internal rotation of the glenohumeral joint. METHODS: CT-scans of 13 human shoulder specimens with implanted reverse shoulder prostheses were carried out and scapula neck length, lateral pillar angle, and implantation height of the metaglene were measured. Internal rotation testing of all specimens was performed by the use of a robot assisted shoulder simulator. Biomechanical variables were analyzed using a three-way ANOVA. Spearman's rank correlations were performed to determine the relationship between biomechanical and anatomical data. FINDINGS: The maximum internal rotation angle for a 38 mm centric glenosphere and a standard onlay was 93.4(SD 34.9 degrees ). The change of the diameter of the glenosphere resulted in no significant increase of the maximum rotation angle (P=0.16), while change of the glenosphere type from concentric to eccentric (P=0.005) as well as the change of the onlay type from standard to a more shallow one (P=0.002) both had a significant effect on the internal rotation. The distance between the inferior rim of the metaglene and the inferior aspect of the glenoid (P=0.21), scapula pillar angle (P=0.13) as well as the scapula neck length (P=0.81) showed no significant correlation with the maximum internal rotation angle. INTERPRETATION: Implant component selection shows strong influence on the impingement-free internal rotation. The use of an eccentric glenosphere and a shallow humeral cup may improve internal rotation after reverse shoulder arthroplasty. PMID- 26970704 TI - Authors Beware: Open Access Predatory Journals. PMID- 26970705 TI - Gene molecular analysis and Adiponectin expression in professional Water Polo players. AB - Metabolic Syndrome prevalence has reaching epidemic proportions worldwide. Adiponectin (Acrp30), and in particular its High Molecular Weight (HMW) oligomers, contributes to enhance insulin sensitivity and to reduce inflammation levels. Physical exercise improves body's biochemical balance and metabolism resulting effective in prevention of metabolic diseases. Whether improvement of metabolic features mediated by physical exercise is associated with changes in Acrp30 serum composition is not yet clarified. In the present study, we investigated total Acrp30 expression, its oligomeric status and genetic variants in adiponectin gene (ACDC) in twenty-two professional Water Polo (WP) Players and 40 age- and sex-matched controls. Anthropometric, metabolic parameters and total Acrp30 were assessed; Acrp30 oligomeric profile was characterized by Western blot as well as by FPLC analysis. ACDC gene was analyzed by direct-sequencing analysis. Significant elevated body mass index, aspartate aminotransferase and lactate dehydrogenase levels and, conversely, significantly lower concentrations of total and cholesterol low density lipoprotein were present in WP players. No significant difference was found in total Acrp30 and/or HMW oligomers. Interestingly, in WP players, a direct relationship between total Acrp30 and monocytes as well as an inverse relationship between total Acrp30 and AST levels were found. ACDC screening revealed previously described SNPs. In conclusion, our study confirms the long-term beneficial effects of high physical training on metabolism and suggests that they are not associated with Acrp30 and/or HMW oligomers changes. Moreover, the correlation of Acrp30 with monocytes in WP athletes could represent a mechanism by which Acrp30 participates in exercise induced anti-inflammatory functions and/or cardiovascular health. PMID- 26970706 TI - A comparison between tourniquet application and epinephrine injection for hemostasis during hypospadias surgery: The effect on bleeding and postoperative outcome. AB - OBJECTIVE: To compare tourniquet application and epinephrine injection for hemostasis during hypospadias surgery in terms of bleeding and complications. METHODS: Between April 2013 and September 2014, patients who were admitted for hypospadias repair were divided by random allocation into either a diluted epinephrine injection (DE) group or tourniquet application (T) group for hemostasis during the procedure. In the T group, a rubber band was applied at the base of the penis after skin dissection, and in the DE group, epinephrine 1/100,000 was injected along the incision lines. The patients' ages, urethral defect lengths, pre-operative, intraoperative and postoperative variables were compared between the two groups. RESULTS: A total of 70 patients (35 in each group) were enrolled into the study. The mean ages and preoperative variables were not significantly different. Average blood loss was 23.51 +/- 15.36 cc in the tourniquet group and 15.99 +/- 10.00 cc in the epinephrine group, and was significantly higher in tourniquet group (P = 0.022); however, the mean operative time was not significantly different. Postoperative complications, described as Clavian classification, were reported in eight patients (23%) in the T group and 10 patients (30%) in the DE group, which was not significantly different. CONCLUSION: Epinephrine injections minimize operative bleeding without significant harmful effects on postoperative outcomes; therefore, it could be considered to be a safe and effective method for preparation of a bloodless field during hypospadias surgery. PMID- 26970707 TI - Readiness of hospital nurses for disaster responses in Taiwan: A cross-sectional study. AB - BACKGROUND: Because patients in disaster areas require the most critical care, mobilising hospital nurses has become a pivotal strategy. Given the importance of disaster nursing training programmes, understanding how well prepared hospital nurses are to provide disaster care is vital. OBJECTIVES: This paper analyses the perceived readiness of hospital nurses for a disaster response and the factors influencing their report for work outside the hospital environment. DESIGN: A cross-sectional research design was used. SETTINGS: This study was conducted at a military hospital in Taiwan. PARTICIPANTS: A sample of 311 registered nurses participated in this study. METHODS: Data were collected on readiness for disaster responses using a 40-item researcher-designed, self-administered questionnaire found to have satisfactory reliability and validity. The questionnaire has four domains: personal preparation (16 items), self-protection (11 items), emergency response (6 items), and clinical management (7 items). Data were analysed using descriptive statistics, independent t-tests and generalised linear models. RESULTS: The majority of hospital nurses demonstrated poor readiness for disaster responses. Scores on the four domains were most associated with nurses' disaster-related training, experience in disaster response and emergency/intensive care experience. CONCLUSIONS: Our results indicate that disaster-related training should be included in undergraduate programmes and continuing education courses to help hospital nurses recognise and improve their own readiness for disaster responses outside the hospital environment. Future research is needed to improve hospital nurses' disaster-response readiness in Taiwan and other countries. PMID- 26970708 TI - Thrombotic microangiopathy caused by oral contraceptives in a kidney transplant recipient. AB - Thrombotic microangiopathy (TMA) after kidney transplantation has various aetiologies, including acute antibody-mediated rejection, bacterial or viral infection and immunosuppressive drugs, particularly calcineurin inhibitors. We present the case of a 28-year-old woman who developed TMA 30 months after the transplantation of an ABO-incompatible kidney from a living unrelated donor. The patient developed a sudden onset of allograft renal dysfunction and became uremic. She was transferred to our institution from a community hospital with strongly suspected acute allograft rejection. Intensive treatments for both T- and B-cell mediated acute rejection, including steroid pulse therapy, double filtration plasmapheresis, antithymocyte globulin (1.5 mg/kg * 14 days) and rituximab (100 mg), were initiated during haemodialysis. However, her renal allograft function did not improve. Histopathological analysis 8 days after the treatment indicated TMA, despite the absence of apparent acute T-cell- or acute antibody-mediated rejection. There were no symptoms of infectious diseases, such as intestinal haemorrhagic colitis or viral infection. We concluded that the use of oral contraceptives, which had been initiated 3 weeks before TMA onset for the treatment of irregular vaginal bleeding, was the aetiologic agent. PMID- 26970709 TI - Acute Lower Extremity Ischemia Caused by the StarClose Vascular Closure Device. PMID- 26970710 TI - Application of BOLD Magnetic Resonance Imaging for Evaluating Regional Volumetric Foot Tissue Oxygenation: A Feasibility Study in Healthy Volunteers. AB - OBJECTIVE/BACKGROUND: To evaluate the feasibility and repeatability of applying blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) in the feet to quantify regional dynamic changes in tissue oxygenation during proximal cuff occlusion and reactive hyperemia. METHODS: Ten healthy male subjects underwent BOLD and T1-weighted imaging of the feet on two separate occasions, using a 3-T scanner. Dynamic changes in BOLD signal intensity were assessed before and during proximal cuff occlusion of the thigh and during reactive hyperemia, and BOLD time course data were evaluated for the time-to-half ischemic minimum, minimum ischemic value, peak hyperemic value, time-to-peak hyperemia, time-to-half peak hyperemia, and end value. T1-weighted images were used for segmentation of volumes of interest (VOI) in anatomical regions of the foot (heel, toes, dorsal foot, medial and lateral plantar foot). Repeatability of vascular responses was assessed for each foot VOI using semiautomated image registration and quantification of serial BOLD images. RESULTS: The heel VOI demonstrated a significantly higher peak hyperemic response, expressed as percent change from baseline BOLD signal intensity, compared with all other VOIs of the foot (heel, 7.4 +/- 1.2%; toes, 5.6 +/- 0.8%; dorsal foot, 5.7 +/- 1.6%; medial plantar, 5.6 +/- 1.7%; lateral plantar, 5.6 +/- 1.5% [p < .05]). Additionally, the lateral plantar VOI had a significantly lower terminal signal intensity value (i.e., end value) when compared with all foot VOIs (p < .05). BOLD MRI was repeatable between visits in all foot VOIs, with no significant differences between study visits for any of the evaluated functional indices. CONCLUSION: BOLD MRI offers a repeatable technique for volumetric assessment of regional foot tissue oxygenation. Future application of BOLD imaging in the feet of patients with peripheral vascular disease may permit serial evaluation of regional tissue oxygenation and allow for improved assessment of therapeutic interventions targeting specific sites of the foot. PMID- 26970712 TI - The influence of androstadienone during psychosocial stress is modulated by gender, trait anxiety and subjective stress: An fMRI study. AB - Androstadienone (ANDR), a bodily secreted steroid compound, is a socially relevant chemosignal that modulates subjective and (neuro)physiological responses, predominantly in females. The impact of ANDR on stress responses in males and females has not been explored. Therefore, this fMRI study aimed to examine psychosocial stress reactions induced by mental arithmetic and social evaluation on behavioral and hormonal levels (46 participants: 15 naturally cycling females in their early follicular phase (EF), 15 females on hormonal contraceptives (HC) and 16 males); and on a neural level (40 participants: 13 EF females, 13 HC-females and 14 males) in an ANDR and placebo treatment repeated measures design. While no gender differences emerged in subjective ratings and performance during stress, neural activation patterns differed significantly. Besides, ANDR attenuated the post-stress increase of negative mood in all participants. Region of interest analyses showed that irrespective of treatment, males showed stronger activation of the dorsolateral prefrontal cortex (DLPFC) than females. At the whole brain level, gender differences emerged indicating stronger fronto-parietal activation in males compared to HC-females on both treatments. Males showed stronger visual and fusiform activation than EF-females under ANDR. Both female groups did not show stronger activation than males. Further, error ratio in the ANDR-stress condition was positively associated with their post-stress cortisol level and increase in subjective stress in males; and male DLPFC activity in the ANDR-stress condition was negatively associated with trait anxiety. Surprisingly, compared to HC-females, EF-female only showed stronger activation of arousal-related areas under placebo treatment. Taken together, these findings suggest that the male stress reaction under social evaluative threat was stronger than female stress reactions as a function of ANDR. More specifically, this effect on behavioral and neural stress reactions seems to depend on trait anxiety in males only. The study highlights the significance of a chemosignal in enhancing social threat that may facilitate adaptive stress responses. PMID- 26970714 TI - Differential contributions of platelets and fibrinogen to early coagulopathy in a rat model of hemorrhagic shock. AB - BACKGROUND: The mechanisms of early traumatic-induced coagulopathy are not well understood. Our aim was to examine the role of platelets and fibrinogen to early coagulopathy in the rat after hemorrhagic shock. METHODS: Adult Sprague-Dawley rats were anesthetized and randomly assigned to: 1) Baseline, 2) Hemorrhage or 3) Shock (n=10 each). Controlled phlebotomy occurred over 20min and animals were left in shock 60min. Coagulation was assessed using PT, aPTT, ROTEM and ELISAs. RESULTS: PT and aPTT increased 5 to 7 times following hemorrhage and shock. Prolongation of EXTEM and INTEM clotting times, lower clot elasticity and increased EXTEM lysis index (LI) indicated a hypocoagulopathy. After 20min hemorrhage, LI(30-60) in FIBTEM was ~100%, EXTEM 83-87% and APTEM 80-82% indicating a platelet contribution to the coagulopathy with no hyperfibrinolysis. After 60min shock, the situation was reversed with fibrinogen loss being a contributor. This apparent switch from a platelet- to a fibrinogen-based coagulopathy, with fibrinolysis, was supported by >=15% in maximum lysis (ML), a threefold increase in plasma PAI-1 after hemorrhage, and undetectable levels after shock. Curiously, the relative contribution of fibrinogen/platelet ratio to clot amplitude, determined from FIBTEM/EXTEM A10 ratio (and MCF), remained unchanged at ~1:5 for baseline, hemorrhage and shock despite a progressive hypocoagulopathy. Significant increases in P-selectin, acidosis and lactate indicated systemic endothelial damage and tissue hypoperfusion. CONCLUSIONS: Hypocoagulopathy following severe hemorrhage and shock in the rat appeared to involve a two-step process of platelet dysfunction followed by fibrinogen impairment, possibly linked to progressive endothelial dysfunction. PMID- 26970713 TI - Correlations Between Abnormal Glucose Metabolism and Bone Mineral Density or Bone Metabolism. AB - BACKGROUND: The aim of this meta-analysis was to explore the correlations of abnormal glucose metabolism (AGM) with bone mineral density (BMD) and bone metabolism. MATERIAL/METHODS: Relevant studies were identified using computerized and manual search strategies. The included studies were in strict accordance with inclusion and exclusion criteria. Statistical analyses were conducted with the Comprehensive Meta-analysis 2.0 (Biostat Inc., Englewood, NJ, USA). RESULTS: Our present meta-analysis initially searched 844 studies, and 7 studies were eventually incorporated in the present meta-analysis. These 7 cohort studies included 1123 subjects altogether (560 patients with AGM and 563 healthy controls). The results showed that bone mass index (BMI), insulin, and insulin resistance (IR) of patients with AGM were significantly higher than that of the population with normal glucose metabolism (BMI: SMD=1.658, 95% CI=0.663~2.654, P=0.001; insulin: SMD=0.544, 95% CI=0.030~1.058, P=0.038; IR: SMD=8.767, 95% CI=4.178~13.356, P<0.001). However, the results also indicated there was no obvious difference in osteocalcin (OC) and BMD in patients with AGM and the population with normal glucose metabolism (OC: SMD=0.293, 95% CI=-0.023~0.609, P=0.069; BMD: SMD=0.805, 95% CI=-0. 212~1.821, P=0.121). CONCLUSIONS: Our meta analysis results suggest that AGM might lead to increased BMI, insulin, and IR, while it has no significant correlation with BMD or bone metabolism. PMID- 26970711 TI - Reduced stress and inflammatory responsiveness in experienced meditators compared to a matched healthy control group. AB - Psychological stress is a major contributor to symptom exacerbation across many chronic inflammatory conditions and can acutely provoke increases in inflammation in healthy individuals. With the rise in rates of inflammation-related medical conditions, evidence for behavioral approaches that reduce stress reactivity is of value. Here, we compare 31 experienced meditators, with an average of approximately 9000 lifetime hours of meditation practice (M age=51years) to an age- and sex-matched control group (n=37; M age=48years) on measures of stress- and inflammatory responsivity, and measures of psychological health. The Trier Social Stress Test (TSST) was used to induce psychological stress and a neurogenic inflammatory response was produced using topical application of capsaicin cream to forearm skin. Size of the capsaicin-induced flare response and increase in salivary cortisol and alpha amylase were used to quantify the magnitude of inflammatory and stress responses, respectively. Results show that experienced meditators have lower TSST-evoked cortisol (62.62+/-2.52 vs. 70.38+/ 2.33; p<.05) and perceived stress (4.18+/-.41 vs. 5.56+/-.30; p<.01), as well as a smaller neurogenic inflammatory response (81.55+/-4.6 vs. 96.76+/-4.26; p<.05), compared to the control group. Moreover, experienced meditators reported higher levels of psychological factors associated with wellbeing and resilience. These results suggest that the long-term practice of meditation may reduce stress reactivity and could be of therapeutic benefit in chronic inflammatory conditions characterized by neurogenic inflammation. PMID- 26970715 TI - Postoperative cerebral bleeding in a boy with suspected mild deficiency of fibrinogen and FXIII. PMID- 26970716 TI - Nonacog beta pegol (N9-GP) in haemophilia B: A multinational phase III safety and efficacy extension trial (paradigmTM4). AB - INTRODUCTION: ParadigmTM4 was an international extension trial investigating the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in haemophilia B patients (FIX activity <=2%; aged 13-70years) who had previously participated in phase III pivotal (paradigmTM2) or surgery (paradigmTM3) trials. METHODS: Patients chose to continue treatment with nonacog beta pegol in either one of two once-weekly prophylaxis arms (10IU/kg or 40IU/kg), or an on-demand arm (40IU/kg for mild/moderate bleeds; 80IU/kg for severe bleeds). The primary objective was to evaluate immunogenicity; key secondary objectives included assessing safety and haemostatic efficacy in the treatment and prevention of bleeds. RESULTS: Seventy-one patients received prophylaxis or on-demand treatment. No patient developed an inhibitor and no safety concerns were identified. The success rate for the treatment of reported bleeds was 94.6%; most (87.9%) resolved with one injection. The median annualised bleeding rate for patients on prophylaxis was 1.36 (interquartile range [IQR] 0.00-2.23) and 1.00 (IQR 0.00-2.03) for the 10 and 40IU/kg treatment arms, respectively. The mean FIX activity trough achieved for 10 and 40IU once weekly was 9.8% and 21.3%, respectively. Fourteen patients on prophylaxis underwent 23 minor surgical procedures; haemostatic perioperative outcomes for all of those evaluated were 'excellent' or 'good'. CONCLUSIONS: Nonacog beta pegol showed a favourable tolerability profile (with no safety issues identified) with good prophylactic protection and control of bleeding in previously treated adult and adolescent haemophilia B patients. PMID- 26970717 TI - A Model of Basic Surgical Skills Course to Supplement the Training of Foundation Year Doctors by Efficient Use of Local Resources. AB - INTRODUCTION: This study investigates the efficiency of teaching basic surgical skills to foundation-year doctors and medical students by using local resources. METHODS: A course comprising 4 workshops, once a week, of 3 hours duration per session was delivered using local education center facilities and using the local faculty of consultants and surgical trainees. Teaching methods include practical skill stations supplemented with short didactic lectures and group discussion. Precourse and postcourse assessments were completed by candidates and analyzed to measure outcomes of the course both subjectively and objectively. RESULTS: A total number of 20 participants completed the course. On completion of the course, (1) participants' theoretical knowledge improved significantly (p < 0.0001), as measured by multiple-choice questions, and scores improved by 35% (mean 44%, standard deviation = 16%) before the course compared to (mean = 79%, standard deviation = 13) after the course; (2) the level of confidence in knowledge and skills was measured by a questionnaire on a scale of 1 to 5, and there was a significant (p < 0.0001) improvement on postcourse assessment (mean difference = 1.5, 95% CI: 0.7-2.4); and (3) practical skills such as suture position, knot tying, and wound apposition significantly improved after the course, chi(2) (2) = 16, p < 0.001; chi(2) (2) = 18, p < 0.001; and chi(2) (2) = 22, p < 0.0001, respectively. CONCLUSION: Effective delivery of basic surgical skills to foundation-year doctors by using local resources can be achieved at low cost. PMID- 26970718 TI - Genome-wide identification and characterization of WRKY transcriptional factor family in apple and analysis of their responses to waterlogging and drought stress. AB - As one of the largest transcriptional factor families in plants, WRKY genes play significant roles in various biotic and abiotic stress responses. Although the WRKY gene family has been characterized in a few plant species, the details remain largely unknown in the apple (Malus domestica Borkh.). In this study, we identified a total of 127 MdWRKYs from the apple genome, which were divided into four subgroups according to the WRKY domains and zinc finger motif. Most of them were mapped onto the apple's 17 chromosomes and were expressed in more than one tissue, including shoot tips, mature leaves, fruit and apple calli. We then contrasted WRKY expression patterns between calli grown in solid medium (control) and liquid medium (representing waterlogging stress) and found that 34 WRKY genes were differentially expressed between the two growing conditions. Finally, we determined the expression patterns of 10 selected WRKY genes in an apple rootstock, G41, in response to waterlogging and drought stress, which identified candidate genes involved in responses to water stress for functional analysis. Our data provide interesting candidate MdWRKYs for future functional analysis and demonstrate that apple callus is a useful system for characterizing gene expression and function in apple. PMID- 26970719 TI - The Lancet Kidney Campaign: an opportunity for partnerships. PMID- 26970720 TI - The Affordable Dialysis Prize steams ahead. PMID- 26970721 TI - Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial. AB - BACKGROUND: HIV-associated tuberculosis is difficult to diagnose and results in high mortality. Frequent extra-pulmonary presentation, inability to obtain sputum, and paucibacillary samples limits the usefulness of nucleic-acid amplification tests and smear microscopy. We therefore assessed a urine-based, lateral flow, point-of-care, lipoarabinomannan assay (LAM) and the effect of a LAM-guided anti-tuberculosis treatment initiation strategy on mortality. METHODS: We did a pragmatic, randomised, parallel-group, multicentre trial in ten hospitals in Africa--four in South Africa, two in Tanzania, two in Zambia, and two in Zimbabwe. Eligible patients were HIV-positive adults aged at least 18 years with at least one of the following symptoms of tuberculosis (fever, cough, night sweats, or self-reported weightloss) and illness severity necessitating admission to hospital. Exclusion criteria included receipt of any anti tuberculosis medicine in the 60 days before enrolment. We randomly assigned patients (1:1) to either LAM plus routine diagnostic tests for tuberculosis (smear microscopy, Xpert-MTB/RIF, and culture; LAM group) or routine diagnostic tests alone (no LAM group) using computer-generated allocation lists in blocks of ten. All patients were asked to provide a urine sample of at least 30 mL at enrolment, and trained research nurses did the LAM test in patients allocated to this group using the Alere Determine tuberculosis LAM Ag lateral flow strip test (Alere, USA) at the bedside on enrolment. On the basis of a positive test result, the nurses made a recommendation for initiating anti-tuberculosis treatment. The attending physician made an independent decision about whether to start treatment or not. Neither patients nor health-care workers were masked to group allocation and test results. The primary endpoint was 8-week all-cause mortality assessed in the modified intention-to-treat population (those who received their allocated intervention). This trial is registered with ClinicalTrials.gov, number NCT01770730. FINDINGS: Between Jan 1, 2013, and Oct 2, 2014, we screened 8728 patients and randomly assigned 2659 to treatment (1336 to LAM, 1323 to no LAM). 108 patients did not receive their allocated treatment, mainly because they did not meet the inclusion criteria, and 23 were excluded from analysis, leaving 2528 in the final modified intention-to-treat analysis (1257 in the LAM group, 1271 in the no LAM group). Overall all-cause 8-week mortality occurred in 578 (23%) patients, 261 (21%) in LAM and 317 (25%) in no LAM, an absolute reduction of 4% (95% CI 1-7). The risk ratio adjusted for country was 0.83 (95% CI 0.73-0.96), p=0.012, with a relative risk reduction of 17% (95% CI 4-28). With the time-to event analysis, there were 159 deaths per 100 person-years in LAM and 196 per 100 person-years in no LAM (hazard ratio adjusted for country 0.82 [95% CI 0.70 0.96], p=0.015). No adverse events were associated with LAM testing. INTERPRETATION: Bedside LAM-guided initiation of anti-tuberculosis treatment in HIV-positive hospital inpatients with suspected tuberculosis was associated with reduced 8-week mortality. The implementation of LAM testing is likely to offer the greatest benefit in hospitals where diagnostic resources are most scarce and where patients present with severe illness, advanced immunosuppression, and an inability to self-expectorate sputum. FUNDING: European Developing Clinical Trials Partnership, the South African Medical Research Council, and the South African National Research Foundation. PMID- 26970722 TI - The Institute of Fiscal Studies' verdict on a sugary drink tax. PMID- 26970724 TI - A breakthrough urine-based diagnostic test for HIV-associated tuberculosis. PMID- 26970725 TI - CD28 costimulatory signals in T lymphocyte activation: Emerging functions beyond a qualitative and quantitative support to TCR signalling. AB - CD28 is one of the most important co-stimulatory receptors necessary for full T lymphocyte activation. By binding its cognate ligands, B7.1/CD80 or B7.2/CD86, expressed on the surface of professional antigen presenting cells (APC), CD28 initiates several signalling cascades, which qualitatively and quantitatively support T cell receptor (TCR) signalling. More recent data evidenced that human CD28 can also act as a TCR-independent signalling unit, by delivering specific signals, which regulate the expression of pro-inflammatory cytokine/chemokines. Despite the enormous progresses made in identifying the mechanisms and molecules involved in CD28 signalling properties, much remains to be elucidated, especially in the light of the functional differences observed between human and mouse CD28. In this review we provide an overview of the current mechanisms and molecules through which CD28 support TCR signalling and highlight recent findings on the specific signalling motifs that regulate the unique pro-inflammatory activity of human CD28. PMID- 26970726 TI - The transcription factor BATF modulates cytokine-mediated responses in T cells. AB - The transcription factor BATF (basic leucine zipper transcription factor, ATF like), belongs to the AP-1 family of transcription factors and has been shown to be predominantly expressed in cells of haematopoietic origin, especially in B and T cells. In studies using Batf-deficient mice, a profound defect in the differentiation of T helper cells type 17 (Th17) and follicular T helper cells (Tfh) was described, as well as an impairment of antibody production with switched isotypes. More recently BATF has been described to influence also Th2 and Th9 responses in models of murine experimental asthma. In CD8(+) T cells BATF has been found associated with anti-viral responses. This review summarizes the role of BATF in CD4(+) T cell subsets and in CD8(+) T cells, with particular focus on this transcription factor in the setting of allergic asthma. PMID- 26970723 TI - Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. AB - BACKGROUND: Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population. METHODS: In this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3>=50%, TC2>=5% and <50%, TC1>=1% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3>=10%, IC2>=5% and <10%, IC1>=1% and <5%, and IC0<1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993. FINDINGS: Patients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12.6 months (95% CI 9.7-16.4) for atezolizumab versus 9.7 months (8.6-12.0) for docetaxel (hazard ratio [HR] 0.73 [95% CI 0.53-0.99]; p=0.04). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0.49 [0.22-1.07; p=0.068], TC2/3 or IC2/3 HR 0.54 [0.33-0.89; p=0.014], TC1/2/3 or IC1/2/3 HR 0.59 [0.40-0.85; p=0.005], TC0 and IC0 HR 1.04 [0.62-1.75; p=0.871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T effector-interferon-gamma-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (<1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event. INTERPRETATION: Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy. FUNDING: F Hoffmann La Roche/Genentech Inc. PMID- 26970727 TI - Tuning the geometry and biomimetic catalytic activity of manganese(III) tetrabromocatecholate based robust platforms by introducing substitution at pyridine. AB - The present report describes synthesis, characterization, crystal structures and catecholase activity of a series of five new manganese(III) complexes (1-5) derived from redox-noninnocent tetrabromocatecholate ligand in combination with different substituted pyridines. X-ray crystallography reveals that the geometry of manganese(III) centers in 1 and 2 is square pyramidal and they are pseudo dimeric in the solid state resulting from the weak bonding of manganese(III) with a catecholate oxygen atom from the adjacent manganese(III) unit together with other weak interactions like hydrogen bonding and pi?pi stacking interactions. On the other hand, complexes 3-5 are discrete octahedral structures. All the complexes exhibit strong catecholase activity and their diverse catalytic activity can nicely be explained by the nature of substitution at pyridine ring - better electron donor inhibits the reduction of the metal center thereby lowering catecholase activity and vice versa (1 and 2 vs. 3-5). Besides the donor property of ancillary ligands, the structural distortion has also significant role in the biomimetic catalytic activity (1 vs. 2). PMID- 26970728 TI - Contextual and environmental influences on reported dietary energy intake at evening eating occasions. AB - OBJECTIVE: This study sought to determine the simultaneous effect of immediate eating environment variables; portion size, plate size, proximity to food, variety of food, side serves of salad/vegetables and presence of distraction on dietary energy intake (EI), of a reported evening meal, in the participants' real world setting. DESIGN: A retrospective computer assisted telephone interview collected data on ten immediate eating environment variables, covariates and a 24 hour dietary recall of EI at an evening meal. Multiple regression analysis was conducted to determine relationships of these variables with EI. Significant (P<0.05) standardised beta coefficients (beta) are reported. SETTING: Australia wide, participants' homes. SUBJECTS: Australian adult males and females (n 150) aged 18-65years. RESULTS: Of the immediate eating environment variables, the absence of salads/vegetables (beta=0.237), increased food variety (beta=0.208), presence of music (beta=0.207), and the consumption of pre-plated (as opposed to self-served) meals (beta=0.195) had a positive association with EI, explaining 16.3% of the variance. Of the covariates, being male was the strongest predictor of EI (beta=0.242); and hunger score also had a positive relationship with EI (beta=0.190), explaining 17.5% of the variance. CONCLUSION: This study provides evidence that some immediate food environment variables at an evening eating occasion are associated with EI. Findings suggest there are several strategies that people could implement to assist in controlling their EI and help address over consumption. PMID- 26970729 TI - Characteristics and use of treatment modalities of patients with binge-eating disorder in the Department of Veterans Affairs. AB - OBJECTIVE: In 2013 binge-eating disorder (BED) was recognized as a formal diagnosis, but was historically included under the diagnosis code for eating disorder not otherwise specified (EDNOS). This study compared the characteristics and use of treatment modalities in BED patients to those with EDNOS without BED (EDNOS-only) and to matched-patients with no eating disorders (NED). METHODS: Patients were identified for this study from electronic health records in the Department of Veterans Affairs from 2000 to 2011. Patients with BED were identified using natural language processing and patients with EDNOS-only were identified by ICD-9 code (307.50). First diagnosis defined index date for these groups. NED patients were frequency matched to BED patients up to 4:1, as available, on age, sex, BMI, depression, and index month encounter. Baseline characteristics and use of treatment modalities during the post-index year were compared using t-tests or chi-square tests. RESULTS: There were 593 BED, 1354 EDNOS-only, and 1895 matched-NED patients identified. Only 68 patients with BED had an EDNOS diagnosis. BED patients were younger (48.7 vs. 49.8years, p=0.04), more were male (72.2% vs. 62.8%, p<0.001) and obese (BMI 40.2 vs. 37.0, p<0.001) than EDNOS-only patients. In the follow-up period fewer BED (68.0%) than EDNOS only patients (87.6%, p<0.001), but more BED than NED patients (51.9%, p<0.001) used at least one treatment modality. DISCUSSION: The characteristics of BED patients were different from those with EDNOS-only and NED as was their use of treatment modalities. These differences highlight the need for a separate identifier of BED. PMID- 26970730 TI - Psychometric properties of the Sociocultural Attitudes Towards Appearance Questionnaire-4-Revised (SATAQ-4R) in Turkish women. AB - Research suggests that rates of body image and eating disturbance are on the rise in Turkey and may be reaching levels comparable to those observed in Western societies. However, research examining theoretically based etiological factors for disordered eating via validated assessment measures is limited. The current study aimed to examine the psychometric properties of the Sociocultural Attitudes Towards Appearance Questionnaire-4-Revised (SATAQ-4R) in a sample of Turkish college women. Exploratory factor analysis indicated a 6-factor scale. Reliability and convergent validity of the SATAQ-4R subscales were good. Results suggest that the SATAQ-4R is appropriate for use with Turkish college females. Future work may seek to examine the scale with Turkish men. PMID- 26970731 TI - Description of an intensive nutrition therapy in hospitalized adolescents with anorexia nervosa. AB - OBJECTIVE: To describe an intensive nutrition therapy for hospitalized adolescents and young adults with anorexia nervosa (AN) in terms of body weight, body composition, energy balance and food related anxiety. METHOD: Twenty-six young females, 16-24years of age, with AN were invited to participate at admission to a specialized eating disorder unit in Goteborg, Sweden. Intensive nutrition therapy comprised 12weeks on a structured meal plan. Six meals were served daily, in combination with high-energy liquid nutritional supplements from start. Energy and nutrient intakes, energy expenditure, body composition and food related anxiety were measured during the study. A 3-month follow-up of body weight and food related anxiety was conducted. RESULTS: Twenty-one patients participated. The total daily energy intake was, during the first week of treatment, (mean+/-SD) 3264+/-196kcal (74kcal/kg), and decreased gradually during treatment to 2622+/-331kcal (49kcal/kg). Total daily energy expenditure was initially 1568+/-149kcal and increased gradually to 2034+/-194kcal. Patients gained on average 9.8+/-2.1kg and body mass index increased from 15.5+/-0.9 to 19.0+/-0.9kg/m(2). Body fat increased from 13+/-6% to 26+/-6%. Fat free mass remained unchanged, but skeletal muscle mass increased from 16.7+/-2.0 to 17.6+/ 2.4kg, p=0.009. Patients' food related anxiety decreased significantly during treatment and was still unchanged 3months later. CONCLUSION: The presented intensive nutrition therapy with initially high energy and nutrient intakes produced substantial weight gain, increased fat and muscle mass and decreased food related anxiety in AN patients, without any clinical side effects. PMID- 26970732 TI - The role of complementary and alternative medicine in the treatment of eating disorders: A systematic review. AB - This systematic review critically appraises the role of complementary and alternative medicine in the treatment of those with an eating disorder. Sixteen studies were included in the review. The results of this review show that the role of complementary and alternative medicine in the treatment of those with an eating disorder is unclear and further studies should be conducted. A potential role was found for massage and bright light therapy for depression in those with Bulimia Nervosa and a potential role for acupuncture and relaxation therapy, in the treatment of State Anxiety, for those with an eating disorder. The role of these complementary therapies in treating eating disorders should only be provided as an adjunctive treatment only. PMID- 26970733 TI - Nutritional intervention with hypocaloric diet for weight control in children and adolescents with Prader-Willi Syndrome. AB - Prader-Willi Syndrome (PWS) is a genetic disorder caused by the lack of expression of paternal alleles in the proximal region of the long arm of chromosome 15. Low inhibitory control and hyperphagia are two of the most severe neurobehavioral symptoms of the syndrome. The aim of the present study was to assess the efficiency of nutritional training program with the use hypocaloric diet for weight control in a group of five children and adolescents with PWS. The intervention program consisted of 10 sessions for parents' orientation during 8months. Patients had their anthropometric measures assessed (weight, height and body mass index - BMI). The main results indicate weight maintenance, height increase, and BMI decrease after intervention. These results were considered indicators of the program's efficiency. PMID- 26970735 TI - Flavobacterium tistrianum sp. nov., a gliding bacterium isolated from soil. AB - A novel gliding bacterial strain, GB 56.1T, was obtained from soil at the Sakaerat Biosphere Reserve, in Nakhon Ratchasima province, Thailand; the strain was characterized using a polyphasic approach. Cells were Gram-stain-negative, yellow, rod shaped and devoid of flagella, but showed gliding motility. Phylogenetic analysis based on 16S rRNA gene sequences found that GB 56.1T was a member of the genus Flavobacterium and that the strain shared the highest sequence similarities with Flavobacterium nitrogenifigens (98.4 %), Flavobacterium anhuiense(98.3 %) and Flavobacterium ginsenosidimutans (97.9 %). The similarities of the sequences of all other species of the genus Flavobacterium were below 97.4 %. The major respiratory quinone of strain GB 56.1T was MK-6; fatty acids were iso-C15:0, C16:1omega6c/C16:1omega7c, C16:0 and C16:0 3-OH. The major polar lipids were phosphatidylethanolamine, phosphatidylserine, an unidentified amino lipid and four polar lipids. The DNA G+C content of this strain was 34.2 mol%. The DNA-DNA relatedness of GB 56.1T was highest against F.anhuiense, with a value of 37.6 %. On the basis of morphological, physiological and chemotaxonomic characteristics, DNA-DNA hybridization relatedness and 16S rRNA gene sequence analysis, we conclude that strain GB 56.1T represents a novel species, for which the name Flavobacterium tistrianum sp. nov. is proposed. The type strain is GB 56.1T (=TISTR 1612T =KCTC 42679T). PMID- 26970734 TI - TIRF imaging of Fc gamma receptor microclusters dynamics and signaling on macrophages during frustrated phagocytosis. AB - BACKGROUND: Recent evidence indicates that in addition to the T-cell receptor, microclustering is an important mechanism for the activation of the B-cell receptor and the mast cell Fcepsilon-receptor. In macrophages and neutrophils, particles opsonized with immunoglobulin G (IgG) antibodies activate the phagocytic Fcgamma-receptor (FcgammaR) leading to rearrangements of the actin cytoskeleton. The purpose of this study was to establish a system for high resolution imaging of FcgammaR microclustering dynamics and the recruitment of the downstream signaling machinery to these microclusters. METHODS: We developed a supported lipid bilayer platform with incorporated antibodies on its surface to study the formation and maturation of FcgammaR signaling complexes in macrophages. Time-lapse multicolor total internal reflection microscopy was used to capture the formation of FcgammaR-IgG microclusters and their assembly into signaling complexes on the plasma membrane of murine bone marrow derived macrophages. RESULTS: Upon antibody binding, macrophages formed FcgammaR-IgG complexes at the leading edge of advancing pseudopods. These complexes then moved toward the center of the cell to form a structure reminiscent of the supramolecular complex observed in the T-cell/antigen presenting cell immune synapse. Colocalization of signaling protein Syk with nascent clusters of antibodies indicated that phosphorylated receptor complexes underwent maturation as they trafficked toward the center of the cell. Additionally, imaging of fluorescent BtkPH domains indicated that 3'-phosphoinositides propagated laterally away from the FcgammaR microclusters. CONCLUSION: We demonstrate that surface-associated but mobile IgG induces the formation of FcgammaR microclusters at the pseudopod leading edge. These clusters recruit Syk and drive the production of diffusing PI(3,4,5)P3 that is coordinated with lamellar actin polymerization. Upon reaching maximal extension, FcgammaR microclusters depart from the leading edge and are transported to the center of the cellular contact region to form a synapse-like structure, analogous to the process observed for T cell receptors. PMID- 26970736 TI - Bioequivalence study between two formulations of ciclosporin A (Cyclavance(r) oral solution and Atopica(r) soft capsules) following a single oral administration to dogs. AB - BACKGROUND: Ciclosporin is a selective immunomodulator used for the treatment of atopic dermatitis in dogs. A new 100 mg/ml oral solution formulation (Cyclavance(r), Virbac) was developed as a pharmaceutical equivalent to the marketed capsule formulations (Atopica(r), Novartis Animal Health) containing 25, 50 mg, or 100 mg of ciclosporin A. The aim of this study was to assess and compare the pharmacokinetic profiles and bioequivalence of the two formulations following a single oral administration to dogs. This randomised, two-period, two sequence, crossover bioequivalence study was conducted in 40 healthy dogs under fasting conditions. Each dog received either one 50 mg capsule of Atopica(r) or 0.5 ml of Cyclavance(r). After dosing, blood samples were collected during a 48-h time period at 0, 0.5, 1, 2, 4, 6, 12, 24, 36 and 48 h. Blood ciclosporin A concentrations were measured by using an HPLC-MS/MS method. Cmax, Tmax, t1/2, AUC0-t, AUC0-infinity and Kel were determined for the two ciclosporin formulations. Bioequivalence was to be concluded if the 90% confidence intervals were within the range of 80% to 125% for Cmax and AUC0-t. Dogs were monitored once daily throughout the study period for adverse effects. RESULTS: The 90% confidence intervals for Cyclavance(r)/Atopica(r) mean ratios of the log transformed pharmacokinetic variables Cmax and AUC0-t were within the conventional bioequivalence range of 80% to 125% (Point estimate: 101.2% and 101.4% respectively). Except for salivation reported after administration of both products, or vomiting and diarrhoea reported after Atopica(r) administration, both formulations were well tolerated in the 40 healthy dogs over the 48-h study period. CONCLUSIONS: The two ciclosporin oral formulations demonstrated similar pharmacokinetic profiles and were found to be bioequivalent, and therefore, interchangeable. PMID- 26970737 TI - Vascular-directed responses of microglia produced by methamphetamine exposure: indirect evidence that microglia are involved in vascular repair? AB - BACKGROUND: Brain microglial activations and damage responses are most commonly associated with neurodegeneration or systemic innate immune system activation. Here, we used histological methods to focus on microglial responses that are directed towards brain vasculature, previously undescribed, after a neurotoxic exposure to methamphetamine. METHODS: Male rats were given doses of methamphetamine that produce pronounced hyperthermia, hypertension, and toxicity. Identification of microglia and microglia-like cells (pericytes and possibly perivascular cells) was done using immunoreactivity to allograft inflammatory factor 1 (Aif1 a.k.a Iba1) and alpha M integrin (Itgam a.k.a. Cd11b) while vasculature endothelium was identified using rat endothelial cell antigen 1 (RECA 1). Regions of neuronal, axonal, and nerve terminal degeneration were determined using Fluoro-Jade C. RESULTS: Dual labeling of vasculature (RECA-1) and microglia (Iba1) showed a strong association of hypertrophied cells surrounding and juxtaposed to vasculature in the septum, medial dorsal hippocampus, piriform cortex, and thalamus. The Iba1 labeling was more pronounced in the cell body while Cd11b more so in the processes of activated microglia. These regions have been previously identified to have vascular leakage after neurotoxic methamphetamine exposure. Dual labeling with Fluoro-Jade C and Iba1 indicated that there was minimal or no evidence of neuronal damage in the septum and hippocampus where many hypertrophied Iba1-labeled cells were found to be associated with vasculature. Although microglial activation around the prominent neurodegeneration was found in the thalamus, there were also many examples of activated microglia associated with vasculature. CONCLUSIONS: The data implicate microglia, and possibly related cell types, in playing a major role in responding to methamphetamine-induced vascular damage, and possibly repair, in the absence of neurodegeneration. Identifying brain regions with hypertrophied/activated microglial-like cells associated with vasculature has the potential for identifying regions of more subtle examples of vascular damage and BBB compromise. PMID- 26970738 TI - Copy number of the Adenomatous Polyposis Coli gene is not always neutral in sporadic colorectal cancers with loss of heterozygosity for the gene. AB - BACKGROUND: Changes in the number of alleles of a chromosome may have an impact upon gene expression. Loss of heterozygosity (LOH) indicates that one allele of a gene has been lost, and knowing the exact copy number of the gene would indicate whether duplication of the remaining allele has occurred. We were interested to determine the copy number of the Adenomatous Polyposis Coli (APC) gene in sporadic colorectal cancers with LOH. METHODS: We selected 38 carcinomas with LOH for the APC gene region of chromosome 5, as determined by amplification of the CA repeat region within the D5S346 loci. The copy number status of APC was ascertained using the SALSA(r) MLPA(r) P043-B1 APC Kit. LOH for the DCC gene, KRAS gene mutation, and microsatellite instability were also evaluated for each tumor, utilizing standard polymerase chain reaction methods. RESULTS: No tumor demonstrated microsatellite instability. LOH of the DCC gene was also present in 33 of 36 (91.7%) informative tumors. A KRAS gene mutation was present in 16 of the 38 (42.1%) tumors. Twenty-four (63.2%) of the tumors were copy number neutral, 10 (26.3%) tumors demonstrated major loss, while two (5.3%) showed partial loss. Two tumors (5.3%) had copy number gain. CONCLUSIONS: Results of APC and DCC LOH, KRAS and microsatellite instability indicate our colorectal cancer cases were typical of sporadic cancers following the 'chromosomal instability' pathway. The majority of our colorectal carcinomas with LOH for APC gene are copy number neutral. However, one-third of our cases showed copy number loss, suggesting that duplication of the remaining allele is not required for the development of a colorectal carcinoma. PMID- 26970740 TI - The potential harms of primary human papillomavirus screening in over-screened women: a microsimulation study. AB - BACKGROUND: It is well acknowledged that HPV testing should not be performed at young age and at short intervals. Cytological screening practices have shown that over-screening, i.e., from a younger age and at shorter intervals than recommended, is hard to avoid. We quantified the consequences of a switch to primary HPV screening for over-screened women, taking into account its higher sensitivity but lower specificity than cytology. METHODS: The health effects of using the HPV test instead of cytology as the primary screening method were determined with the MISCAN-Cervix model. We varied the age women start screening and the interval between screens. In the sensitivity analyses, we varied the background risk of cervical cancer, the HPV prevalence, the discount rate, the triage strategy after cytology, and the test characteristics of both cytology and the HPV test. RESULTS: For women screened 5 yearly from age 30, 32 extra deaths per 100,000 simulated women were prevented when switching from primary cytology to primary HPV testing. For annual screening from age 20, such a switch resulted in 6 extra deaths prevented. It was associated with 9,044 more positive primary screens in the former scenario versus 76,480 in the latter. Under all conditions, for women screened annually, switching to HPV screening resulted in a net loss of quality-adjusted life years. CONCLUSION: For over-screened women, the harms associated with a lower test specificity outweigh the life years gained when switching from primary cytology to primary HPV testing. The extent of over screening should be considered when deciding on inclusion of primary HPV screening in cervical cancer screening guidelines. PMID- 26970741 TI - Age at cancer diagnosis, amenability to medical interventions, and racial/ethnic disparities in cancer mortality. AB - PURPOSE: Racial disparities in cancer mortality may be greater for cancers that are amenable to available early detection and treatment (amenability level). We investigated whether these patterns vary by age at cancer diagnosis. METHODS: Using 5-year relative survival rates (5Y-RSR), we classified 51 cancer sites into least amenable, partly amenable, and mostly amenable cancers (<40%, 40-69%, >=70% 5-YRS, respectively). We examined whether racial disparities in mortality rates (African-Americans, Asian/Pacific Islanders, Hispanics, whites), as estimated through Cox regression models, were modified by age at diagnosis and amenability level in 516,939 cancer cases diagnosed in 1995-1999. RESULTS: As compared with whites, all racial minority groups experienced higher cancer mortality rates in the youngest age group of 20-34 years. African-Americans and Hispanics diagnosed with partly and mostly amenable cancers had higher mortality rates relative to whites with cancers of the same amenability levels; further, these differences decreased in magnitude or reversed in direction with increasing age. In contrast, the racial differences in mortality were smaller and remained fairly constant across age groups for least amenable cancers. For example, in the youngest (20 34) and oldest (80-99) age groups, the adjusted hazard ratios (HRs) for African Americans versus whites with least amenable cancers were, respectively, 1.26 (95% CI 1.02, 1.55) and 0.90 (95% CI 0.85, 0.96), while the HRs for African-Americans versus whites with mostly amenable cancers were 2.77 (95% CI 2.38, 3.22) and 1.07 (95% CI 0.98, 1.17). CONCLUSIONS: Cancer survival disadvantage for racial minorities is larger in younger age groups for cancers that are more amenable to medical interventions. PMID- 26970742 TI - Nicotinic acetylcholine receptors modulate osteoclastogenesis. AB - BACKGROUND: Our aim was to investigate the role of nicotinic acetylcholine receptors (nAChRs) in in-vitro osteoclastogenesis and in in-vivo bone homeostasis. METHODS: The presence of nAChR subunits as well as the in-vitro effects of nAChR agonists were investigated by ex vivo osteoclastogenesis assays, real-time polymerase chain reaction, Western blot and flow cytometry in murine bone marrow-derived macrophages differentiated in the presence of recombinant receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony stimulating factor (M-CSF). The bone phenotype of mice lacking various nAChR subunits was investigated by peripheral quantitative computed tomography and histomorphometric analysis. Oscillations in the intracellular calcium concentration were detected by measuring the Fura-2 fluorescence intensity. RESULTS: We could demonstrate the presence of several nAChR subunits in bone marrow-derived macrophages stimulated with RANKL and M-CSF, and showed that they are capable of producing acetylcholine. nAChR ligands reduced the number of osteoclasts as well as the number of tartrate-resistant acidic phosphatase positive mononuclear cells in a dose-dependent manner. In vitro RANKL-mediated osteoclastogenesis was reduced in mice lacking alpha7 homomeric nAChR or beta2 containing heteromeric nAChRs, while bone histomorphometry revealed increased bone volume as well as impaired osteoclastogenesis in male mice lacking the alpha7 nAChR. nAChR ligands inhibited RANKL-induced calcium oscillation, a well established phenomenon of osteoclastogenesis. This inhibitory effect on Ca(2+) oscillation subsequently led to the inhibition of RANKL-induced NFATc1 and c-fos expression after long-term treatment with nicotine. CONCLUSIONS: We have shown that the activity of nAChRs conveys a marked effect on osteoclastogenesis in mice. Agonists of these receptors inhibited calcium oscillations in osteoclasts and blocked the RANKL-induced activation of c-fos and NFATc1. RANKL-mediated in vitro osteoclastogenesis was reduced in alpha7 knockout mice, which was paralleled by increased tibial bone volume in male mice in vivo. PMID- 26970743 TI - Selective mutism and temperament: the silence and behavioral inhibition to the unfamiliar. AB - Behavioral inhibition (BI) is a suspected precursor of selective mutism. However, investigations on early behavioral inhibition of children with selective mutism are lacking. Children aged 3-18 with lifetime selective mutism (n = 109), social phobia (n = 61), internalizing behavior (n = 46) and healthy controls (n = 118) were assessed using the parent-rated Retrospective Infant Behavioral Inhibition (RIBI) questionnaire. Analyses showed that children with lifetime selective mutism and social phobia were more inhibited as infants and toddlers than children of the internalizing and healthy control groups, who displayed similar low levels of behavioral inhibition. Moreover, behavioral inhibition was higher in infants with lifetime selective mutism than in participants with social phobia according to the Total BI score (p = 0.012) and the Shyness subscale (p < 0.001). Infant behavioral inhibition, particularly towards social stimuli, is a temperamental feature associated with a lifetime diagnosis of selective mutism. Results yield first evidence of the recently hypothesized temperamental origin of selective mutism. Children at risk should be screened for this debilitating child psychiatric condition. PMID- 26970739 TI - Breast cancer survival among young women: a review of the role of modifiable lifestyle factors. AB - Almost 7% of breast cancers are diagnosed among women age 40 years and younger in Western populations. Clinical outcomes among young women are worse. Early age-of onset increases the risk of contralateral breast cancer, local and distant recurrence, and subsequent mortality. Breast cancers in young women (BCYW) are more likely to present with triple-negative (TNBC), TP53-positive, and HER-2 over expressing tumors than among older women. However, despite these known differences in breast cancer outcomes and tumor subtypes, there is limited understanding of the basic biology, epidemiology, and optimal therapeutic strategies for BCYW. Several modifiable lifestyle factors associated with reduced risk of developing breast cancer have also been implicated in improved prognosis among breast cancer survivors of all ages. Given the treatment-related toxicities and the extended window for late effects, long-term lifestyle modifications potentially offer significant benefits to BCYW. In this review, we propose a model identifying three main areas of lifestyle factors (energy imbalance, inflammation, and dietary nutrient adequacy) that may influence survival in BCYW. In addition, we provide a summary of mechanisms of action and a synthesis of previous research on each of these topics. PMID- 26970744 TI - Violence Exposure as a Mediator Between Parenting and Adolescent Mental Health. AB - For youth exposed to community violence, parenting has been found to play a significant role in protecting adolescents from associated mental health symptoms. Yet little is known about the potential of parenting to prevent such exposure in the first place and thereby reduce the likelihood of adolescents' mental health symptoms. This study examined two parental practices that have often been examined as moderators, but not yet as predictors, of youth exposure to community violence associations with adolescent mental health, namely parental control and parental harshness. Analyses of self-reported data from 908 adolescents (M age = 16.5, SD = 1.71; 52 % girls; 13 % non-Hispanic White) revealed that harsh parenting was indirectly associated with youth mental health symptoms through higher levels of exposure to community violence, whereas links between controlling parenting and mental health symptoms were either non significant or mediated through lower levels of adolescent violence exposure. These findings highlight the potential positive role parental control may play by preventing adolescents from exposure to potentially dangerous situations. Conversely, our results suggest that harsh parenting appears to pose a risk for adolescents by driving youth away from the home environment and potentially into places where violence may be more prevalent. PMID- 26970745 TI - Recent developments in Forster resonance energy transfer (FRET) diagnostics using quantum dots. AB - The exceptional photophysical properties and the nanometric dimensions of colloidal semiconductor quantum dots (QD) have strongly attracted the bioanalytical community over the last approximately 20 y. In particular, the integration of QDs in the analysis of biological components and interactions, and the related diagnostics using Forster resonance energy transfer (FRET), have allowed researchers to significantly improve and diversify fluorescence-based biosensing. In this TRENDS article, we review some recent developments in QD-FRET biosensing that have implemented this technology in electronic consumer products, multiplexed analysis, and detection without light excitation for diagnostic applications. In selected examples of smartphone-based imaging, single- and multistep FRET, steady-state and time-resolved spectroscopy, and bio/chemiluminescence detection of QDs used as both FRET donors and acceptors, we highlight the advantages of QD-based FRET biosensing for multiplexed and sensitive diagnostics. Graphical Abstract Quantum dots (QDs) can be applied as donors and/or acceptors for Forster resonance energy transfer- (FRET-) based biosensing for multiplexed and sensitive diagnostics in various assay formats. PMID- 26970746 TI - Layered-nanomaterial-amplified chemiluminescence systems and their analytical applications. AB - Layered nanomaterial has become a popular hierarchical material for amplifying chemiluminescence (CL) in recent years, mainly because of its ease of preparation and modification, large specific surface area, and high catalytic activity. In this review, we mainly discuss layered-nanomaterial-amplified CL systems based on graphene and its derivatives, layered double hydroxides, and clay. Detection mechanisms and strategies of layered-nanomaterial-amplified CL systems are provided to show the basic concepts for designing sensitive and selective sensing systems. Strategies for expanding the applications of layered-nanomaterial amplified CL systems by combination with surfactants, quantum dots, organic dyes, and nanoparticles are introduced for the analysis of various analytes in real samples. The challenges and future trends of layered-nanomaterial-amplified CL systems are discussed at the end of the review. Graphical Abstract Schematic illustration of layered nanomaterial amplified chemiluminescence. PMID- 26970747 TI - A hyperbranched polyethylenimine functionalized stationary phase for hydrophilic interaction liquid chromatography. AB - A hyperbranched stationary phase for hydrophilic interaction liquid chromatography (HILIC) has been prepared by grafting polyethylenimine (PEI) onto silica gel (termed as PEI-Sil). Rich primary, secondary, and tertiary amino groups associated with PEI render its good hydrophility. More importantly, the hyperbranched structure of PEI molecule is greatly helpful in improving interaction with polar analytes. For several kinds of model polar compounds, including organic acids, nucleosides, nucleic acid bases, amino acids, cephalosporins, and non-reducing sugars, PEI-Sil demonstrated excellent separation performance in terms of running stability, reproducibility, and separation efficiency (e.g., plate count ~74,000/m). In addition, PEI-Sil also exhibited much better separation selectivity toward inorganic anions when operated in the mode of ion chromatography relative to a commercial amino propyl bonded column. PMID- 26970748 TI - Separation, detection and characterization of nanomaterials in municipal wastewaters using hydrodynamic chromatography coupled to ICPMS and single particle ICPMS. AB - Engineered nanoparticles (ENP) are increasingly being incorporated into consumer products and reaching the environment at a growing rate. Unfortunately, few analytical techniques are available that allow the detection of ENP in complex environmental matrices. The major limitations with existing techniques are their relatively high detection limits and their inability to distinguish ENP from other chemical forms (e.g. ions, dissolved) or from natural colloids. Of the matrices that are considered to be a priority for method development, ENP are predicted to be found at relatively high concentrations in wastewaters and wastewater biosolids. In this paper, we demonstrate the capability of hydrodynamic chromatography (HDC) coupled to inductively coupled plasma mass spectrometry (ICPMS), in its classical and single particle modes (SP ICPMS), to identify ENP in wastewater influents and effluents. The paper first focuses on the detection of standard silver nanoparticles (Ag NP) and their mixtures, showing that significant dissolution of the Ag NP was likely to occur. For the Ag NP, detection limits of 0.03 MUg L(-1) were found for the HDC ICPMS whereas 0.1 MUg L(-1) was determined for the HDC SP ICPMS (based on results for the 80 nm Ag NP). In the second part of the paper, HDC ICPMS and HDC SP ICPMS were performed on some unspiked natural samples (wastewaters, river water). While nanosilver was below detection limits, it was possible to identify some (likely natural) Cu nanoparticles using the developed separation technology. PMID- 26970749 TI - Naked-eye detection as a universal approach to lower the limit of detection of enzyme-linked immunoassays. AB - Colorimetric biosensors for the detection of analytes with the naked eye are required in environmental monitoring, point-of-care diagnostics, and analyses in resources constrained settings, where detection instruments may not be available. However, instrument-based detection methods are usually more adequate for detecting small variations in the signal compared to naked-eye detection schemes, and consequently the limit of detection of the latter is usually higher than the former. Here, we demonstrate that the limit of detection of colorimetric enzyme linked immunoassays can be decreased several orders of magnitude when using naked eye detection instead of a spectrophotometer for detecting the signal. The key step to lower the limit of detection is adding a small volume of chromogenic substrate during the signal generation step. This generates highly colored solutions that can be easily visualized with the naked eye and recorded with the camera of a mobile phone. The proposed method does not require expensive equipment or complex protocols to enhance the signal, and therefore it is a universal approach to lower the limit of detection of colorimetric enzyme-linked immunoassays. PMID- 26970750 TI - An iridium(III) complex as a versatile platform for molecular logic gates: an integrated full subtractor and 1:2 demultiplexer. AB - The iridium(III) complex 1 operates as a versatile platform for molecular logic gates fulfilling multiple logic functions depending on the inputs and the interrogation channels. In the UV-vis channel, it works as an INH, OR, and NINH gate with F(-) and H2PO4 (-) as inputs when following the absorbance at 244, 262, and 457 nm, respectively. More importantly, the combination of photoluminescence (PL) intensity ratio (I 700/I 600) and transmittance at 457 nm resulted in the setup of a 1:2 demultiplexer with F(-) and CO2 as inputs. Finally, a three-input (BF3, F(-), and H2PO4 (-)) full subtractor was realized by integrating the electrochemiluminescence (ECL) intensity at 642 nm and the absorbance at 262 nm. Graphical abstract Multichannel detection and the proper combination of inputs are the key for the elaboration of sophisticated logic gates. PMID- 26970751 TI - Typical ultraviolet spectra in combination with diagnostic mass fragmentation analysis for the rapid and comprehensive profiling of chlorogenic acids in the buds of Lonicera macranthoides. AB - A major challenge of profiling chlorogenic acids (CGA) in natural products is to effectively detect unknown or minor isomeric compounds. Here, we developed an effective strategy, typical ultraviolet (UV) spectra in combination with diagnostic mass fragmentation analysis based on HPLC-DAD-QTOF-MS/MS, to comprehensively profile CGA in the buds of Lonicera macranthoides. First, three CGA UV patterns were obtained by UV spectra screening. Second, 13 types of CGA classified by molecular weights were found by thorough analysis of CGA peaks using high-resolution MS. Third, selected ion monitoring (SIM) was carried out for each type of CGA to avoid overlooking of minor ones. Fourth, MS/MS spectra of each CGA were investigated. Then 70 CGA were identified by matching their UV spectra, accurate mass signals and fragmentation patterns with standards or previously reported compounds, including six caffeoylquinic acids (CQA), six diCQA, one triCQA, three caffeoylshikimic acids (CSA), six diCSA, one triCSA, three p-coumaroylquinic acids (pCoQA), four p-coumaroylcaffeoylquinic acids (pCoCQA), four feruloylquinic acids (FQA), five methyl caffeoylquinates (MCQ), three ethyl caffeoylquinates (ECQ), three dimethoxycinnamoylquinic acids (DQA), six caffeoylferuloylquinic acids (CFQA), six methyl dicaffeoylquinates (MdiCQ), four FQA glycosides (FQAG), six MCQ glycosides (MCQG), and three ethyl dicaffeoylquinates (EdiCQ). Forty-five of them were discovered from Lonicera species for the first time, and it is noted that CGA profiles were investigated for the first time in L. macranthoides. Results indicated that the developed method was a useful approach to explore unknown and minor isomeric compounds from complex natural products. PMID- 26970752 TI - Occupational exposure in the removal and disposal of asbestos-containing materials in Italy. AB - PURPOSE: A great variety of asbestos-containing materials are present in both residential and work settings because of the widespread use made in the past, and many occupational activities still entail the risk of asbestos exposure in Italy, more than 2 decades after the total national ban, mainly those involved in the removal and disposal of asbestos. The aim of the study was to evaluate the level and extent of asbestos exposure in Italy between the years 1996-2013 in the sector of asbestos abatement. METHODS: Data were collected from firm registries of asbestos-exposed workers and descriptive statistics were calculated for exposure-related variables. RESULTS: Overall, 15,860 measurements of asbestos exposure were selected from the national database of registries, mostly referring to the construction sector (N = 11,353). Despite the mean exposure levels are low, the air concentration of asbestos fibers measured during these activities may overcome the action level established by the Italian legislation and, in a limited number of cases, can exceed even the occupational limit value. Among occupations at higher risk, there are also garbage collectors and insulation workers. CONCLUSIONS: Starting from the analysis of the Italian database of occupational exposure registries, this study outlines the current levels of asbestos exposure in abatement-related sectors, discussing their possible implications for public health policies and surveillance programs. PMID- 26970753 TI - Implementation of the participatory approach for supervisors to prevent sick leave: a process evaluation. AB - PURPOSE: To perform a process evaluation of a multifaceted strategy to implement the participatory approach for supervisors to prevent sick leave in three organisations. METHODS: The implementation strategy incorporated a working group meeting with stakeholder representatives, supervisor training, and optional supervisor coaching. Context, recruitment, reach, dose delivered, dose received, fidelity, and satisfaction with the strategy were assessed at organisational and supervisor level using questionnaires and registration forms. RESULTS: At least 4 out of 6 stakeholders were represented in the working group meetings, and 11 % (n = 116) of supervisors could be reached. The working group meetings and supervisor training were delivered and received as planned and were well appreciated within all three organisations. Three supervisors made use of coaching. At 6-month follow-up, 11 out of 41 supervisors (27 %) indicated that they had applied the participatory approach at least one time. CONCLUSION: The implementation strategy was largely carried out as intended. However, reach of both supervisors and department managers should be improved. Future studies should consider targeting employees with the strategy. PMID- 26970754 TI - Effect of dietary macronutrient proportion on intermediate metabolism and oxidative status in sturgeon (Acipenser naccarii) and trout (Oncorhynchus mykiss): comparative study. AB - Three isoenergetic diets varying the proportion of dietary energy supplied by each of the macronutrients (carbohydrate, lipid, or protein) were delivered, to farmed sturgeon (Acipenser naccarii) and trout (Oncorhynchus mykiss), to test the possible effects on the intermediate metabolism and oxidative status in liver, white muscle, and heart. In trout, there is an adaptive metabolic response to an increase in lipids and carbohydrates in the diet. However, this does not happen in the sturgeon. These differences may be due to different dietary habits of both species. In terms of oxidative status, only the liver displayed oxidative stress in both species, showing an increase in the lipid peroxidation and antioxidant enzyme activities after feeding with the high-lipid and high-protein diet. PMID- 26970756 TI - ACL update: objective measures on knee instability: an introduction. PMID- 26970755 TI - ABCA1 deficiency and cellular cholesterol accumulation increases islet amyloidogenesis in mice. AB - AIMS/HYPOTHESIS: Islet amyloid, a pathological feature of type 2 diabetes, forms from the aggregation of islet amyloid polypeptide (IAPP), a beta cell peptide that is produced and co-secreted with insulin. Cholesterol regulates amyloid-beta processing, deposition and clearance, promoting amyloidogenesis in the brain. ATP binding cassette transporter 1 (ABCA1) is a cholesterol efflux transporter that when absent increases and when overexpressed reduces brain amyloid-beta deposition in mouse models of Alzheimer's disease. We examined whether alterations in ABCA1 expression and islet cholesterol content could also modulate islet amyloidogenesis. METHODS: Thioflavin S staining for amyloid was performed in islets isolated from mice with beta cell expression of human IAPP (hIAPP (Tg/o)) and cultured for 8 days following cholesterol loading, microRNA-33 overexpression (to reduce ABCA1 expression) or palmitate treatment in the presence or absence of ABCA1 overexpression or mevastatin treatment (to reduce cholesterol synthesis). hIAPP (Tg/o) mice were crossed with beta cell-specific Abca1-knockout mice (hIAPP (Tg/o) Abca1 (betaKO)) and glucose tolerance and amyloid formation were assessed. RESULTS: Cholesterol loading and microRNA-33 induced reduction in islet ABCA1 expression increased Thioflavin S-positive amyloid in hIAPP (Tg/o) islets. Palmitate treatment also increased amyloid formation and this was reduced by both ABCA1 overexpression and mevastatin treatment. hIAPP (Tg/o) Abca1 (betaKO) mice had increased islet cholesterol, accompanied by fasting hyperglycaemia, glucose intolerance, impaired in vivo insulin secretion and an increased islet proinsulin:insulin ratio. Amyloid area was increased in cultured hIAPP (Tg/o) Abca1 (betaKO) islets compared with hIAPP (Tg/o) controls. CONCLUSIONS/INTERPRETATION: These data suggest that elevations in islet cholesterol may lead to increases in IAPP aggregation and islet amyloid formation, further worsening beta cell function and glucose homeostasis. PMID- 26970757 TI - Assessment of the pivot shift using inertial sensors. AB - The pivot shift test is an important clinical tool used to assess the stability of the knee following an injury to the anterior cruciate ligament (ACL). Previous studies have shown that significant variability exists in the performance and interpretation of this manoeuvre. Accordingly, a variety of techniques aimed at standardizing and quantifying the pivot shift test have been developed. In recent years, inertial sensors have been used to measure the kinematics of the pivot shift. The goal of this study is to present a review of the literature and discuss the principles of inertial sensors and their use in quantifying the pivot shift test. PMID- 26970759 TI - Utility of a Clinical Swallowing Exam for Understanding Swallowing Physiology. AB - A clinical swallowing examination (CSE) is generally believed to be inadequate for making judgments regarding swallowing physiology compared to objective assessments. A large volume of studies has heavily focused on identifying aspiration using a CSE and research addressing physiologic information gathered from a CSE is sparse. The purpose of this study was to examine the utility of the CSE for assessing physiology compared to videofluoroscopic swallowing studies (VFSS). Data were derived from a prior investigation of sixty adult patients post stroke tested with CSE and VFSS. The CSE included an examination of historical measures, oral motor/speech/voice, and trial swallows. The VFSS consisted of swallows of controlled portions of thin, thick, puree, and solid boluses. Previous results from these patients demonstrated significant accuracy in making binary estimates of aspiration and the presence of dysphagia. This analysis of data focused on physiologic measures, as well as overall dysphagia severity and diet recommendations. Significant associations between CSE and VFSS ratings were observed for hyolaryngeal elevation, overall swallowing severity, and diet recommendations. These findings were specific for certain bolus consistencies. These data suggest that the CSE may not provide significant physiological information other than hyolaryngeal excursion. This does not preclude the fact that the CSE is important in providing substantial information about overall dysphagia severity. It appears that the CSE is more powerful than simply a "screening" tool. More prospective research designs are warranted to substantiate the strengths of the CSE. PMID- 26970758 TI - Objective measurements of static anterior and rotational knee laxity. AB - Several devices allow to measure anterior and rotational static knee laxity. To date, the use of rotational laxity measurements in the daily clinical practice however remains to be improved. These measurements may be systematically integrated to the follow-up of knee injuries. Physiologic laxity measurements may particularly be of interest for the identification of risk factors in athletes. Furthermore, knee laxity measurements help to improve the diagnosis of knee soft tissue injuries and to follow up reconstructions. Further prospective follow-ups of knee laxity in the injured/reconstructed knees are however required to conclude on the best treatment strategy for knee soft tissue injuries. PMID- 26970760 TI - A Systematic Review of the Prevalence of Oropharyngeal Dysphagia in Stroke, Parkinson's Disease, Alzheimer's Disease, Head Injury, and Pneumonia. AB - Oropharyngeal dysphagia is a common condition after stroke, Parkinson's disease (PD), and Alzheimer's disease (AD), and can cause serious complications including malnutrition, aspiration pneumonia, and premature mortality. Despite its high prevalence among the elderly and associated serious complications, dysphagia is often overlooked and under-diagnosed in vulnerable patient populations. This systematic review aimed to improve understanding and awareness of the prevalence of dysphagia in susceptible patient populations. MEDLINE, EMBASE, the Cochrane library, PROSPERO, and disease-specific websites were systematically searched for studies reporting oropharyngeal dysphagia prevalence or incidence in people with stroke, PD, AD, traumatic brain injury, and community-acquired pneumonia, from the USA, Canada, France, Germany, Italy, Spain, UK, Japan, China, and regional studies. The quality of study descriptions were assessed based on STROBE guidelines. A total of 1207 publications were identified and 33 met inclusion criteria: 24 in stroke, six in PD, two in traumatic brain injury, and one in patients with traumatic brain injury. Dysphagia was reported in 8.1-80 % of stroke patients, 11-81 % of PD, 27-30 % of traumatic brain injury patients, and 91.7 % of patients with community-acquired pneumonia. No relevant studies of dysphagia in AD were identified. This review demonstrates that dysphagia is highly prevalent in these populations, and highlights discrepancies between studies, gaps in dysphagia research, and the need for better dysphagia management starting with a reliable, standardized, and validated method for oropharyngeal dysphagia identification. PMID- 26970761 TI - Frequency of malignancy is high in patients admitted for a first venous thromboembolism episode: an observational study. AB - Patients with a cancer at time of first venous thromboembolism (VTE) have not been thoroughly analyzed. Our study aimed to (1) determine the frequency of cancer diagnosed in patients hospitalized for a first VTE episode, (2) investigate the characteristics of VTE and cancer in such patients. All consecutive adults patients hospitalized over a 6-years period for a first VTE episode in a tertiary care hospital were considered. Patients with congenital or acquired thrombophilia were excluded. Demographic, medical history, and follow up data were retrieved from medical records. 216 patients (63.6 +/- 19.7 years, 63.4 % females) hospitalized for a first VTE were analyzed. Among them, 64 patients (29.6 %) had cancer, either revealed (n = 26) or already known (n = 38) at VTE diagnosis. Cancer was in an advanced stage in 26 patients (40.6 %). Patients with cancer were older and displayed a higher frequency of vena cava thrombosis, as compared to patients without cancer. VTE was more recurrent and mortality was higher in patients with cancer. Cancer occurred after VTE diagnosis in only 2 (2/127, 1.6 %) cases during a protracted follow-up of 24.1 +/- 22.5 months. Overall, VTE preceded cancer diagnosis in only 3 % (2/66) of cases. Frequency of cancer is high among patients hospitalized for a first VTE. In such setting, VTE often involved unusual sites such as vena cava. In most cases, cancer was either already known or diagnosed at time of VTE, with a poor prognosis. PMID- 26970762 TI - MRI screening for glioma: a preliminary survey of healthy potential candidates. PMID- 26970763 TI - Reasons and results of endoscopic surgery for prolactinomas: 142 surgical cases. AB - BACKGROUND: We report herein a retrospective analysis of the results of 142 consecutive prolactinoma cases operated upon using an endoscopic endonasal trans sphenoidal approach over a period of 6 years. METHODS: Medical records of 142 cases were analysed with respect to indications for surgery, duration of hospital stay, early remission rates, failures and recurrence rates during a median follow up of 36 months. RESULTS: On the basis of magnetic resonance imaging (MRI) data, 19 patients (13.4 %) had microadenoma, 113 (79.6 %) had macroadenoma, and the remaining 10 (7.0 %) had giant adenomas. Cavernous sinus invasion was identified in 25 patients by MRI and confirmed during surgery. Atypical adenoma was diagnosed in 16 patients. Sparsely granulated prolactin adenoma was identified in 99 patients (69.7 %). Our results demonstrate that male sex and higher preoperative prolactin levels are independent factors predicting persistent disease. The post-surgical complications are as follows: 2.8 % patients had meningitis, 2.1 % patients had postoperative cerebrospinal fluid leak and 2.1 % patients had panhypopituitarism. At the end of follow-up, 74.6 % patients went into remission. During follow-up period, five patients who had initial remission developed recurrence. CONCLUSIONS: Our series together with literature data suggest that an endoscopic endonasal trans-sphenoidal approach in the treatment of proloctinomas has a favourable rate of remission. According to the findings of this study, endoscopic endonasal trans-sphenoidal surgery might be an appropriate therapy choice for patients with prolactinoma who could not have been managed with recommended therapeutic modalities. PMID- 26970764 TI - cDNA cloning and molecular characterization of a defensin-like antimicrobial peptide from larvae of Protaetia brevitarsis seulensis (Kolbe). AB - We identified new defensin-like cDNA (called Psdefensin) by searching data set of high-throughput RNA sequencing (RNA-seq) expression profiling of immunized larva of white-spotted flower chafers, Protaetia brevitarsis seulensis. The length of the analyzed new defensin-like sequences were 240 base pair (bp) and encoded the deduced polypeptide of 79 amino acid residues with signal peptides (amino acids 1 20), pro-peptide region (amino acids 21-36), and mature peptide region (amino acids 37-79). The Psdefensin transcript levels were slightly up-regulated at 4 h post-infection and were highly expressed at 8 h post-infection compared to control larvae injected with sterile water. In addition, the Psdefensin did have antimicrobial activity against both Gram-negative bacteria, E. coli and Gram positive bacteria, B. subtilis suggesting potentially pharmacologic agent. PMID- 26970765 TI - Anti-CD137 monoclonal antibodies and adoptive T cell therapy: a perfect marriage? AB - CD137(4-1BB) costimulation and adoptive T cell therapy strongly synergize in terms of achieving maximal efficacy against experimental cancers. These costimulatory biological functions of CD137 have been exploited by means of introducing the CD137 signaling domain in clinically successful chimeric antigen receptors and to more efficiently expand T cells in culture. In addition, immunomagnetic sorting of CD137-positive T cells among tumor-infiltrating lymphocytes selects for the fittest antitumor T lymphocytes for subsequent cultures. In mouse models, co-infusion of both agonist antibodies and T cells attains marked synergistic effects that result from more focused and intense cytolytic activity visualized under in vivo microscopy and from more efficient entrance of T cells into the tumor through the vasculature. These several levels of dynamic interaction between adoptive T cell therapy and CD137 offer much opportunity to raise the efficacy of current cancer immunotherapies. PMID- 26970766 TI - Automation of antimicrobial activity screening. AB - Manual and automated methods were compared for routine screening of compounds for antimicrobial activity. Automation generally accelerated assays and required less user intervention while producing comparable results. Automated protocols were validated for planktonic, biofilm, and agar cultures of the oral microbe Streptococcus mutans that is commonly associated with tooth decay. Toxicity assays for the known antimicrobial compound cetylpyridinium chloride (CPC) were validated against planktonic, biofilm forming, and 24 h biofilm culture conditions, and several commonly reported toxicity/antimicrobial activity measures were evaluated: the 50 % inhibitory concentration (IC50), the minimum inhibitory concentration (MIC), and the minimum bactericidal concentration (MBC). Using automated methods, three halide salts of cetylpyridinium (CPC, CPB, CPI) were rapidly screened with no detectable effect of the counter ion on antimicrobial activity. PMID- 26970768 TI - Histomorphometric and histologic evaluation of titanium-zirconium (aTiZr) implants with anodized surfaces. AB - The choice of implant surface has a significant influence on osseointegration. Modification of TiZr surface by anodization is reported to have the potential to modulate the osteoblast cell behaviour favouring more rapid bone formation. The aim of this study is to investigate the effect of anodizing the surface of TiZr discs with respect to osseointegration after four weeks implantation in sheep femurs. Titanium (Ti) and TiZr discs were anodized in an electrolyte containing DL-alpha-glycerophosphate and calcium acetate at 300 V. The surface characteristics were analyzed by scanning electron microscopy, electron dispersive spectroscopy, atomic force microscopy and goniometry. Forty implant discs with thickness of 1.5 and 10 mm diameter (10 of each-titanium, titanium zirconium, anodized titanium and anodized titanium-zirconium) were placed in the femoral condyles of 10 sheep. Histomorphometric and histologic analysis were performed 4 weeks after implantation. The anodized implants displayed hydrophilic, porous, nano-to-micrometer scale roughened surfaces. Energy dispersive spectroscopy analysis revealed calcium and phosphorous incorporation into the surface of both titanium and titanium-zirconium after anodization. Histologically there was new bone apposition on all implanted discs, slightly more pronounced on anodised discs. The percentage bone-to-implant contact measurements of anodized implants were higher than machined/unmodified implants but there was no significant difference between the two groups with anodized surfaces (P > 0.05, n = 10). The present histomorphometric and histological findings confirm that surface modification of titanium-zirconium by anodization is similar to anodised titanium enhances early osseointegration compared to machined implant surfaces. PMID- 26970769 TI - Analysis of friction between articular cartilage and polyvinyl alcohol hydrogel artificial cartilage. AB - Many biomaterials are being used to repair damaged articular cartilage. In particular, poly vinyl alcohol hydrogel has similar mechanical properties to natural cartilage under compressive and shearing loading. Here, three-factor and two-level friction experiments and long-term tests were conducted to better evaluate its tribological properties. The friction coefficient between articular cartilage and the poly vinyl alcohol hydrogel depended primarily on the three factors of load, speed, and lubrication. When the speed increased from 10 to 20 mm/s under a load of 10 N, the friction coefficient increased from 0.12 to 0.147. When the lubricant was changed from Ringer's solution to a hyaluronic acid solution, the friction coefficient decreased to 0.084 with loads as high as 22 N. The poly vinyl alcohol hydrogel was severely damaged and lost its top surface layers, which were transferred to the articular cartilage surface. Wear was observed in the surface morphologies, which indicated the occurrence of surface adhesion of bovine cartilage. Surface fatigue and adhesive wear was the dominant wear mechanism. PMID- 26970767 TI - Tissue adhesives for meniscus tear repair: an overview of current advances and prospects for future clinical solutions. AB - Menisci are crucial structures in the knee joint as they play important functions in load transfer, maintaining joint stability and in homeostasis of articular cartilage. Unfortunately, ones of the most frequently occurring knee injuries are meniscal tears. Particularly tears in the avascular zone of the meniscus usually do not heal spontaneously and lead to pain, swelling and locking of the knee joint. Eventually, after a (partial) meniscectomy, they will lead to osteoarthritis. Current treatment modalities to repair tears and by that restore the integrity of the native meniscus still carry their drawbacks and a new robust solution is desired. A strong tissue adhesive could provide such a solution and could potentially improve on sutures, which are the current gold standard. Moreover, a glue could serve as a carrier for biological compounds known to enhance tissue healing. Only few tissue adhesives, e.g., Dermabond((r)) and fibrin glue, are already successfully used in clinical practice for other applications, but are not considered suitable for gluing meniscus tissue due to their sub-optimal mechanical properties or toxicity. There is a growing interest and research field focusing on the development of novel polymer-based tissue adhesives, but up to now, there is no material specially designed for the repair of meniscal tears. In this review, we discuss the current clinical gold standard treatment of meniscal tears and present an overview of new developments in this field. Moreover, we discuss the properties of different tissue adhesives for their potential use in meniscal tear repair. Finally, we formulate recommendations regarding the design criteria of material properties and adhesive strength for clinically applicable glues for meniscal tears. PMID- 26970770 TI - Adhesion of human gingival fibroblasts/Streptococcus mitis co-culture on the nanocomposite system Chitlac-nAg. AB - Composite materials are increasingly used as dental restoration. In the field of biomaterials, infections remain the main reason of dental devices failure. Silver, in the form of nanoparticles (AgNPs), ions and salt, well known for its antimicrobial properties, is used in several medical applications in order to avoid bacterial infection. To reduce both bacterial adhesion to dental devices and cytotoxicity against eukaryotic cells, we coated BisGMA/TEGDMA methacrylic thermosets with a new material, Chitlac-nAg, formed by stabilized AgNPs with a polyelectrolyte solution containing Chitlac. Here we analyzed the proliferative and adhesive ability of human gingival fibroblasts (HGFs) on BisGMA/TEGDMA thermosets uncoated and coated with AgNPs in a coculture model system with Streptococcus mitis. After 48 h, HGFs well adhered onto both surfaces, while S. mitis cytotoxic response was higher in the presence of AgNPs coated thermosets. After 24 h thermosets coated with Chitlac as well as those coated with Chitlac nAg exerted a minimal cytotoxic effect on HGFs, while after 48 h LDH release raised up to 20 %. Moreover the presence of S. mitis reduced this release mainly when HGFs adhered to Chitlac-nAg coated thermosets. The reduced secretion of collagen type I was significant in the presence of both surfaces with the co culture system even more when saliva is added. Integrin beta1 localized closely to cell membranes onto Chitlac-nAg thermosets and PKCalpha translocated into nuclei. These data confirm that Chitlac-nAg have a promising utilization in the field of restorative dentistry exerting their antimicrobial activity due to AgNPs without cytotoxicity for eukaryotic cells. PMID- 26970772 TI - Immigrant screening for latent tuberculosis in Norway: a cost-effectiveness analysis. AB - The incidence of tuberculosis (TB) disease has increased in Norway since the mid 1990s. Immigrants are screened, and some are treated, for latent TB infection (LTBI) to prevent TB disease (reactivation). In this study, we estimated the costs of both treating and screening for LTBI and TB disease, which has not been done previously in Norway. We developed a model to indicate the cost effectiveness of four different screening algorithms for LTBI using avoided TB disease cases as the health outcome. Further, we calculated the expected value of perfect information (EVPI), and indicated areas of LTBI screening that could be changed to improve cost-effectiveness. The costs of treating LTBI and TB disease were estimated to be ?1938 and ?15,489 per case, respectively. The model evaluates four algorithms, and suggests three cost-effective algorithms depending on the cost-effectiveness threshold. Screening all immigrants with interferon gamma release assays (IGRA) requires the highest threshold (?28,400), followed by the algorithms "IGRA on immigrants with risk factors" and "no LTBI screening." EVPI is approximately ?5 per screened immigrant. The costs for a cohort of 20,000 immigrants followed through 10 years range from ?12.2 million for the algorithm "screening and treatment for TB disease but no LTBI screening," to ?14 million for "screening all immigrants for both TB disease and LTBI with IGRA." The results suggest that the cost of TB disease screening and treatment is the largest contributor to total costs, while LTBI screening and treatment costs are relatively small. Increasing the proportion of IGRA-positive immigrants who are treated decreases the costs per avoided case substantially. PMID- 26970771 TI - Making a distinction between the effect of initial stock and investment in health determinants. AB - The objective of this paper was to propose a health production model that distinguishes between the initial stock of health determinants and the subsequent investment in them, with a view to providing information to policy-makers regarding the effects of determinant-aimed policies. In this sense, the main contributions of the paper stem from the development of a theoretical and empirical model that distinguishes between the effect of the initial stock and that of investment in health determinants. To do this, we estimated the health production function using a stochastic frontier model. We present an empirical example using data for the years 2002 and 2008. The results support our decision to analyse the effects of the initial values attributable to health determinants separately from those arising following investment in the period. Concretely, we find significant differences for the determinants EMPLOY, SOCIALCLASS and NON DRINKER. The results seem to indicate that, for variables labelled with the behavioural aspects of health such as NON-DRINKER, the effect over time of a change in investment in health is significantly greater than that resulting from a variation in initial values. In contrast, for socioeconomic variables such as SOCIAL CLASS or EMPLOY, for which effects on health tend to be more long-term in nature, the opposite occurs, with the effect of the investment during the time period proving significantly lower than the effect of the initial provision. PMID- 26970773 TI - Biomarkers in Scleroderma: Progressing from Association to Clinical Utility. AB - Scleroderma is a heterogenous disease characterized by autoimmunity, a characteristic vasculopathy, and often widely varying extents of deep organ fibrosis. Recent advances in the understanding of scleroderma's evolution have improved the ability to identify subgroups of patients with similar prognosis in order to improve risk stratification, enrich clinical trials for patients likely to benefit from specific therapies, and identify promising therapeutic targets for intervention. High-throughput technologies have recently identified fibrotic and inflammatory effectors in scleroderma that exhibit strong prognostic ability and may be tied to disease evolution. Increasingly, the use of collections of assayed circulating proteins and patterns of gene expression in tissue has replaced single-marker investigations in understanding the evolution of scleroderma and in objectively characterizing disease extent. Lastly, identification of shared patterns of disease evolution has allowed classification of patients into latent disease subtypes, which may allow rapid clinical prognostication and targeted management in both clinical and research settings. The concept of biomarkers in scleroderma is expanding to include nontraditional measures of aggregate protein signatures and disease evolution. This review examines the recent advances in biomarkers with a focus on those approaches poised to guide prospective management or themselves serve as quantitative surrogate disease outcomes. PMID- 26970774 TI - Blunted angiogenesis and hypertrophy are associated with increased fatigue resistance and unchanged aerobic capacity in old overloaded mouse muscle. AB - We hypothesize that the attenuated hypertrophic response in old mouse muscle is (1) partly due to a reduced capillarization and angiogenesis, which is (2) accompanied by a reduced oxidative capacity and fatigue resistance in old control and overloaded muscles, that (3) can be rescued by the antioxidant resveratrol. To investigate this, the hypertrophic response, capillarization, oxidative capacity, and fatigue resistance of m. plantaris were compared in 9- and 25-month old non-treated and 25-month-old resveratrol-treated mice. Overload increased the local capillary-to-fiber ratio less in old (15 %) than in adult (59 %) muscle (P < 0.05). Although muscles of old mice had a higher succinate dehydrogenase (SDH) activity (P < 0.05) and a slower fiber type profile (P < 0.05), the isometric fatigue resistance was similar in 9- and 25-month-old mice. In both age groups, the fatigue resistance was increased to the same extent after overload (P < 0.01), without a significant change in SDH activity, but an increased capillary density (P < 0.05). Attenuated angiogenesis during overload may contribute to the attenuated hypertrophic response in old age. Neither was rescued by resveratrol supplementation. Changes in fatigue resistance with overload and aging were dissociated from changes in SDH activity, but paralleled those in capillarization. This suggests that capillarization plays a more important role in fatigue resistance than oxidative capacity. PMID- 26970776 TI - Erratum to: Profile of European adults interested in internet-based personalised nutrition: the Food4Me study. PMID- 26970775 TI - Yeast Dun1 Kinase Regulates Ribonucleotide Reductase Small Subunit Localization in Response to Iron Deficiency. AB - Ribonucleotide reductase (RNR) is an essential iron-dependent enzyme that catalyzes deoxyribonucleotide synthesis in eukaryotes. Living organisms have developed multiple strategies to tightly modulate RNR function to avoid inadequate or unbalanced deoxyribonucleotide pools that cause DNA damage and genome instability. Yeast cells activate RNR in response to genotoxic stress and iron deficiency by facilitating redistribution of its small heterodimeric subunit Rnr2-Rnr4 from the nucleus to the cytoplasm, where it forms an active holoenzyme with large Rnr1 subunit. Dif1 protein inhibits RNR by promoting nuclear import of Rnr2-Rnr4. Upon DNA damage, Dif1 phosphorylation by the Dun1 checkpoint kinase and its subsequent degradation enhances RNR function. In this report, we demonstrate that Dun1 kinase triggers Rnr2-Rnr4 redistribution to the cytoplasm in response to iron deficiency. We show that Rnr2-Rnr4 relocalization by low iron requires Dun1 kinase activity and phosphorylation site Thr-380 in the Dun1 activation loop, but not the Dun1 forkhead-associated domain. By using different Dif1 mutant proteins, we uncover that Dun1 phosphorylates Dif1 Ser-104 and Thr 105 residues upon iron scarcity. We observe that the Dif1 phosphorylation pattern differs depending on the stimuli, which suggests different Dun1 activating pathways. Importantly, the Dif1-S104A/T105A mutant exhibits defects in nucleus-to cytoplasm redistribution of Rnr2-Rnr4 by iron limitation. Taken together, these results reveal that, in response to iron starvation, Dun1 kinase phosphorylates Dif1 to stimulate Rnr2-Rnr4 relocalization to the cytoplasm and promote RNR function. PMID- 26970777 TI - Prediction and identification of the effectors of heterotrimeric G proteins in rice (Oryza sativa L.). AB - Heterotrimeric G protein signaling cascades are one of the primary metazoan sensing mechanisms linking a cell to environment. However, the number of experimentally identified effectors of G protein in plant is limited. We have therefore studied which tools are best suited for predicting G protein effectors in rice. Here, we compared the predicting performance of four classifiers with eight different encoding schemes on the effectors of G proteins by using 10-fold cross-validation. Four methods were evaluated: random forest, naive Bayes, K nearest neighbors and support vector machine. We applied these methods to experimentally identified effectors of G proteins and randomly selected non effector proteins, and tested their sensitivity and specificity. The result showed that random forest classifier with composition of K-spaced amino acid pairs and composition of motif or domain (CKSAAP_PROSITE_200) combination method yielded the best performance, with accuracy and the Mathew's correlation coefficient reaching 74.62% and 0.49, respectively. We have developed G-Effector, an online predictor, which outperforms BLAST, PSI-BLAST and HMMER on predicting the effectors of G proteins. This provided valuable guidance for the researchers to select classifiers combined with different feature selection encoding schemes. We used G-Effector to screen the effectors of G protein in rice, and confirmed the candidate effectors by gene co-expression data. Interestingly, one of the top 15 candidates, which did not appear in the training data set, was validated in a previous research work. Therefore, the candidate effectors list in this article provides both a clue for researchers as to their function and a framework of validation for future experimental work. It is accessible at http://bioinformatics.fafu.edu.cn/geffector. PMID- 26970779 TI - Medical professional responsibility for postvasectomy pregnancy. AB - BACKGROUND: The follow-up of patients postvasectomy is frequently limited to a seminogram at 3months if azoospermia is observed. This study evaluates a series of cases of complaints for postvasectomy pregnancy to establish follow-up recommendations that increase the clinical safety and reduce the risk of complaints. MATERIAL AND METHODS: We reviewed the database of the Department of Professional Responsibility of the Council of the College of Physicians of Catalonia, finding 28 complaints for postvasectomy pregnancy between 1992 and 2011. We analysed the clinical and legal variables of the cases. RESULTS: A total of 13 extrajudicial complaints (46.43%), 13 civil lawsuits (46.43%) and 2 criminal lawsuits (7.14%) were recorded. Only 10 cases had a signed document of informed consent specific to vasectomy. In 26 cases, the data from the spermogram was available. A single spermogram was conducted in 20 cases (76.92%), 2 spermograms were conducted in 4 cases (15.38%) and none were performed in 2 cases (7.69%). For 9 of the cases (45%) where only a single spermogram was performed, the test was performed before 3months postvasectomy. In 17 cases (65.38%), the result of the last spermogram was azoospermia, and 3 cases had oligospermia (11.54%). There were 2 failures of interpretation of the spermogram (7.69%) and 2 of normospermia (7.69%). In 2 cases, a spermogram was not performed (7.69%). Pregnancy occurred between 4 and 50 months after the intervention. In 12 cases (42.86%), it was considered that the practitioner was responsible. DISCUSSION: It is recommended that physicians emphasise (during the patient information stage) the possibility of spontaneous recanalisation and to request 2 spermograms, whose result should be azoospermia. Performing the test in the 3months after vasectomy is risky, as is basing the waiting time on the number of ejaculations. PMID- 26970782 TI - Rapid and Sensitive Voltammetric Determination of Aclonifen in Water Samples. AB - This paper presents the use of square wave voltammetry (SWV) and square wave adsorptive stripping voltammetry (SWAdSV) in conjunction with a cyclic renewable silver amalgam film electrode (Hg(Ag)FE) for the determination of aclonifen in spiked water samples. A reduction peak at -0.65 V versus Ag/AgCl was obtained in the selected buffer (borax buffer with pH 9.2), exhibiting the characteristics of an irreversible reaction. The effect of square wave (SW) frequency, SW amplitude and step potential, as well as accumulation parameters (time and potential) were studied to select the optimal experimental conditions. The calibration curve was linear in the aclonifen concentration range from 1.0*10(-7) to 1.0*10(-6) mol L( 1) and from 1.0*10(-8) to1.0*10(-7) mol L(-1) for SWV and SWAdSV, respectively. The detection and quantification limits were found to be 3.1*10(-8) mol L(-1); 1.0*10(-7) mol L(-1) and 2.9*10(-9) mol L(-1); 9.6*10(-9) mol L-1 for SWV and SWAdSV, respectively. The proposed method was applied successfully in the determination of aclonifen in spiked water samples. The developed procedure can be adequate at least for screening purposes, where positive results should be confirmed by more selective method. PMID- 26970780 TI - Characterization and comparison of sodium-glucose cotransporter 2 inhibitors in pharmacokinetics, pharmacodynamics, and pharmacologic effects. AB - The sodium-glucose cotransporter (SGLT) 2 offer a novel approach to treating type 2 diabetes by reducing hyperglycaemia via increased urinary glucose excretion. In the present study, the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six SGLT2 inhibitors commercially available in Japan were investigated and compared. Based on findings in normal and diabetic mice, the six drugs were classified into two categories, long-acting: ipragliflozin and dapagliflozin, and intermediate-acting: tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin. Long-acting SGLT2 inhibitors exerted an antihyperglycemic effect with lower variability of blood glucose level via a long lasting increase in urinary glucose excretion. In addition, ipragliflozin and luseogliflozin exhibited superiority over the others with respect to fast onset of pharmacological effect. Duration and onset of the pharmacologic effects seemed to be closely correlated with the pharmacokinetic properties of each SGLT2 inhibitor, particularly with respect to high distribution and long retention in the target organ, the kidney. While all six SGLT2 inhibitors were significantly effective in increasing urinary glucose excretion and reducing hyperglycemia, our findings suggest that variation in the quality of daily blood glucose control associated with duration and onset of pharmacologic effects of each SGLT2 inhibitor might cause slight differences in rates of improvement in type 2 diabetes. PMID- 26970781 TI - Ensuring Access to High-Quality Maternity Care in Rural America. PMID- 26970778 TI - Lipoprotein subfractions by nuclear magnetic resonance are associated with tumor characteristics in breast cancer. AB - BACKGROUND: High-Density Lipoprotein (HDL)-cholesterol, has been associated with breast cancer development, but the association is under debate, and whether lipoprotein subfractions is associated with breast tumor characteristics remains unclear. METHODS: Among 56 women with newly diagnosed invasive breast cancer stage I/II, aged 35-75 years, pre-surgery overnight fasting serum concentrations of lipids were assessed, and body mass index (BMI) was measured. All breast tumors were immunohistochemically examined in the surgical specimen. Serum metabolomics of lipoprotein subfractions and their contents of cholesterol, free cholesterol, phospholipids, apolipoprotein-A1 and apolipoprotein-A2, were assessed using nuclear magnetic resonance. Principal component analysis, partial least square analysis, and uni- and multivariable linear regression models were used to study whether lipoprotein subfractions were associated with breast cancer tumor characteristics. RESULTS: The breast cancer patients had following means: age at diagnosis: 55.1 years; BMI: 25.1 kg/m(2); total-Cholesterol: 5.74 mmol/L; HDL-Cholesterol: 1.78 mmol/L; Low-Density Lipoprotein (LDL)-Cholesterol: 3.45 mmol/L; triglycerides: 1.18 mmol/L. The mean tumor size was 16.4 mm, and the mean Ki67 hotspot index was 26.5%. Most (93%) of the patients had estrogen receptor (ER) positive tumors (>= 1% ER+), and 82% had progesterone receptor (PgR) positive tumors (>= 10% PgR+). Several HDL subfraction contents were strongly associated with PgR expression: Apolipoprotein-A1 (beta 0.46, CI 0.22-0.69, p < 0.001), HDL cholesterol (beta 0.95, CI 0.51-1.39, p < 0.001), HDL free cholesterol (beta 2.88, CI 1.28-4.48, p = 0.001), HDL phospholipids (beta 0.70, CI 0.36-1.04, p < 0.001). Similar results were observed for the subfractions of HDL1-3. We observed inverse associations between HDL phospholipids and Ki67 (beta -0.25, p = 0.008), and in particular between HDL1's contents of cholesterol, phospholipids, apolipoprotein-A1, apolipoprotein-A2 and Ki67. No association was observed between lipoproteins and ER expression. CONCLUSION: Our findings hypothesize associations between different lipoprotein subfractions, and PgR expression, and Ki 67 % in breast tumors. These findings may have clinical implications, but require confirmation in larger studies. PMID- 26970783 TI - Optimization of High Performance Liquid Chromatography Method for Simultaneous Determination of Some Purine and Pyrimidine Bases. AB - Nine purine and pyrimidine bases were separated and determined simultaneously using reversed phase (RP) high performance liquid chromatography (HPLC) in some food samples and biological fluids. Chromatographic behavior of these ionizable compounds highly depends on the interactions with the solvent as confirmed experimentally and by calculation of distribution of this species as a function of pH. Chromatograms show the optimal separation of five purine (uric acid, hypoxanthine, xanthine, adenine, and guanosine), and four pyrimidine (cytosine, uracil, cytidine and tymine) bases at pH around four. Accordingly, acetate buffer was selected due to high buffer capacity in this region. By variation of pH, concentration of buffer and volume ratio between buffer and methanol, we found that a mixture of 50 mM acetate buffer of pH 4.0 +/- 0.1 with 3 % of methanol ensures reproducibility, complete separation in less than 15 minutes and compatibility with MS detection. Developed method was validated and applied for the analysis of complex clinical and beverage samples. PMID- 26970784 TI - Synthesis, Characterization and Antimicrobial Activities of Some New Heterocyclic Schiff Bases Derived from Thiocarbohydrazide. AB - The reaction of prazolobenzothienopyrimidine-3-carbaldehyde 1 with thiocarbohydrazide afforded the Schiff's base 3. The latter compound reacted with some electrophilic reagents to give 1,2,4-triazoles 4-6 and 1,2,4-triazines 7-9. Treatment of compound 3 with 2-cyano-3,3-bis(methylthio)acrylonitrile gave the corresponding 5-amino-4-cyano-3-methylthiopyrazole derivative 11. The reaction of pyrazole 11 with carbon disulfide afforded dithioxopyrazolopyrimidine 12. Acylation of compound 11 by using acetic anhydride yielded acetamide 13. On the other hand, the cyclocondensation of pyrazole 11 with acetic anhydride in pyridine yielded pyrazolopyrimidine derivative 14. The reactivity of compound 11 towards formamide and phenylisothiocyanate to give the pyrazolopyrimidines 15 and 16 was studied. The newly synthesized compounds were screened for their antimicrobial activity. PMID- 26970785 TI - Study on the Synthesis, Characterization and Bioactivities of 3-Methyl-9' fluorenespiro-5-hydantoin. AB - This work describes a method for synthesis, as well as in vitro antiproliferative and antibacterial investigation of 3-methyl-9'-fluorenespiro-5-hydantoin. The structure of the substituted fluorenylspirohydantoin derivative was verified by UV-Vis, FT-IR, Raman, (1)H-NMR and (13)C-NMR spectroscopy, and by using a combination of 2D NMR experiments, which included (1)H-(1)H COSY, HMQC and HMBC sequences. The geometry of the compound was optimized by the B3LYP density functional with 6-31G(d) basis set and the (1)H and (13)C NMR spectra were predicted with the HF/6-31G(d) calculations at the optimized geometry. The anticancer activity of the 3-methyl-9'-fluorenespiro-5-hydantoin was determined in suspension cell lines originating from tumors in humans (WERI-Rb-1). The cytotoxic effect was evaluated by WST-assay (Roche Applied Science). The antimicrobial effect of the compound against Gram-negative, Gram-positive bacteria and the yeast Candida albicans was investigated. PMID- 26970786 TI - Clinical Role of CYP2C19 Polymorphisms in Patients with Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency. AB - Extraadrenal enzymes such as CYP2C19 may participate in residual 21-hydroxylation of progesterone leading to milder phenotypes of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). Among 94 21OHD patients 28 were homozygous or compound heterozygous for severe CYP21A2 mutations. We have reviewed their clinical phenotype and obtained information on maintenance doses of hydrocortisone and fludrocortisone. All patients were genotyped for CYP2C19*2 and CYP2C19*17 alleles. Eleven patients with CYP2C19*1/*17 genotype had all salt wasting 21OHD. Among 17 patients with CYP2C19 genotypes leading to normal or decreased CYP2C19 activity, 15 had salt-wasting, one had simple virilizing and one had non-classical 21OHD. CYP2C19*1/*17 genotype was associated with lower maintenance dose of fludrocortisone (p = 0.04), but not of hydrocortisone (p > 0.05). Increased CYP2C19 activity could slightly ameliorate mineralocorticoid deficiency in 21OHD. PMID- 26970787 TI - Determination of Candesartan in Human Plasma with Liquid Chromatography - Tandem Mass Spectrometry. AB - A sensitive, specific and rapid liquid chromatography - tandem mass spectrometry method was developed and validated for the determination of candesartan in human plasma. Analyte was separated from endogenous components present in plasma by solid phase extraction. Chromatographic separation was performed on Gemini C18 analytical column using mobile phase acetonitrile - 5 mM ammonium formate pH 2 (90:10, v/v) at flow rate of 0.3 mL/min. For detection, tandem mass spectrometry in SRM mode with positive electrospray ionization was used. The mass transitions m/z 441.1 > 263.1 and 445.1 > 267.1 were used to determine candesartan by using candesartan-d4 as an internal standard. After development, the method was validated according to the requirements of EMA regulatory guidelines in the concentration range 1 - 400 ng/ml in human plasma. Limit of quantification (LLOQ) was 1 ng/ml. The developed and validated method proved to be very fast and reproducible and was therefore successfully implemented in pharmacokinetic and bioequivalence studies with large number of study samples. PMID- 26970788 TI - Electrode Prepared with Combination of Different Conductive Polymers for Hydroquinone Determination in River Water. AB - Modified electrode based on combination of different conductive polymers (Polyaniline - Poly(3-methylthiophene) - Poly(3,3' diaminobenzidine) (PANI - P3MT - PDAB)) was previously synthesized in dichloromethane containing HClO(4) and tetrabutylammoniumperchlorate (TBAP) supporting electrolyte. In this study, determination of hydroquinone (HQ) with amperometric I-t method over this modified and its homopolymers coated electrode was successfully carried out in river water as real sample and in solution consisting of NaHSO(4)/Na(2)SO(4) (pH 2.0). For this method, potentials between 0.45 V and 0.65 V were applied and the best analytical response was obtained at 0.55 V using this modified electrode when compared its homopolymer. The limit of detection (LOD), limit of quantification (LOQ) , the linear dynamic range and regression coefficient (R(2)) were found as 1.31 x 10(-4) mM, 4.37 x 10(-4) mM, 4.37 x 10(-4)- 95.0 mM and 0.998, respectively. These results were compared to homopolymers coated and uncoated Pt electrodes. For checking on the accuracy of the developed method and the matrices interference, determination of HQ was performed in artificially contaminated river water samples with HQ concentration 5.0 mM and 10.0 mM using this modified electrode and recovery values were calculated as % 100.6 and % 100.1, respectively. PMID- 26970789 TI - Synthesis, Structural Diversity and Mimic Superoxide Dismutase of Mn(II) Complexes Derived from N, O-donor Schiff bases. AB - Two new potentially tetradentate Schiff base ligands N'-(pyridin-2 ylmethylene)nicotinohydrazide (L1), and N'-(pyridin-2 ylmethylene)isonicotinohydrazide (L(2)) were synthesized. Reactions of hydrazone ligands L(1) and L(2) with Mn(NO(3))(2) afford two mononuclear Mn(II) complexes, [Mn(L(1))(NO(3))(H(2)O)(2)]*(NO(3)) (1) and [Mn(L(2))(2)(NO(3))(H(2)O)]*(NO(3)) (2). For complexes 1 and 2, L(1) and L(2) act as pincer-like tridentate or bidentate ligands, respectively. The Mn(II) ions in the two compounds are both in heptacoordinated environment, while the two molecules display diverse solid-state supramolecular structures because of the different orientation of Npyridine and hydrogen bonding patterns of nitrate anions. Complex 1 features 2D supramolecular sheet, while complex 2 is double-chain supramolecular structure. Both of the two complexes exhibit moderate superoxide dismutase (SOD) mimetic activity. PMID- 26970790 TI - Granular Matter Transport in Vertical Pipes: The Influence of Pipe Outlet Conditions on Gravity-driven Granular Flow. AB - Gravity transport of granular materials in vertical pipes is one of the most fundamental steps in bulk powder handling and processing. Presented study investigates powder flow characteristics in vertical pipes with open and closed outlets and condition of free powder fall. Powder flow of pharmaceutical grade powders was observed in transparent, vertical pipe model. Description of flow structures was performed. Powder volume flow rate, acceleration, and dilatation were quantified and correlated with powder properties. The results show that in pipes with a closed outlet the escaping air slows down the powder flow, resulting in a much slower flow than in pipes with an open outlet. A dense granular flow was detected in an open outlet condition, whereas in a closed outlet condition two concurrent flow regimes were observed: a slow moving, dense powder bed, and a fast dilute powder flow. Differences in flow regimes may promote segregation, with important implications to industrial processes. PMID- 26970791 TI - Melamine Polyphosphate - the Reactive and Additive Flame Retardant for Polyurethane Foams. AB - Melamine polyphosphate, MPP was applied as reactive and additive flame retardant for thermally resistant polyurethane foams. MPP was hydroxyalkylated with ethylene and propylene carbonates to get oligoetherols with 1,3,5-triazine ring and phosphorus. The structure and physical properties of the products were studied. The polyurethane foams, PUFs obtained from this oligoetherols were self distinguishing. The addition of powdered MPP into foaming mixture resulted in further decrease of flammability modified PUFs. The MPP-modified PUFs were characterized by physical methods adequate to thermal resistance and flammability of the PUFs. The best MPP-modified PUF showed oxygen index 24.6. All the modified PUFs were remarkably thermally resistant; they could stand long lasting thermal exposure even at 200 degrees C. PMID- 26970792 TI - Vertex Degree Weighted Path Indices. AB - Vertex degree weighted path indices P(N)(a, b, ...), for example P(1)(a, b), P(2)(a, b, c), P(3)(a, b, c, d), and P(4)(a, b, c, d, e), are good topological indices for some of the physicochemical properties of octanes with |R|(max) up to 0.999. Mutually optimized combinations of them are even better, R (P(1)..P(4)) is in the worst tested case > 0.9. The best results are obtained in mutually optimized combinations of some of them with some of the elements of the Universal matrix, in the worst tested case R = 0.994. Some of the vertex degree weighted path one indices give rise to a "regular" sequence of octane isomers of increasing branching. PMID- 26970793 TI - Complex Formation in a Liquid-Liquid Extraction System Containing Co(II), 4-(2 Thiazolylazo)resorcinol and Monotetrazolium Salt. AB - The ion-associated complex formed between anionic chelate of Co(II)-4-(2 Thiazolylazo)resorcinol (TAR) with the monotetrazolium cation of 2-(4-Iodophenyl) 3-(4-nitrophenyl)-5-phenyl-2H-tetrazolium chloride (INT) in the liquid-liquid extraction system Co(II)-TAR-INT-H(2)O-CHCl(3) was studied by the spectrophotometric method. The optimum extraction conditions of Co(II) were found. The extraction equilibria were studied. The equilibrium constants, the recovery factor and some analytical characteristics were calculated. The validity of Beer's law was checked. The molar ratio of the components in the ternary ion associated complex Co(II)-TAR-INT was determined. The general formula of the complex was suggested. The effect of various foreign ions and reagents on the process of complex formation in the liquid-liquid extraction system was studied. PMID- 26970794 TI - Synthesis, Structural and Optical Characterization of Copper and Rare Earth doped CdS Nanoparticles. AB - Cadmium sulphide (CdS) nanoparticles doped with Cu(2+) and co-doped with rare earth metallic ions (RE3(+)) have been synthesized by co-precipitation method. The synthesized nanoparticles were been characterized by powder X-ray diffraction studies (PXRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), particle size by dynamic light scattering (DLS), UV-visible spectroscopy (UV), and photoluminescence (PL) studies. It is observed that CdS nanoparticles can be co-doped with copper and rare earth metallic ions without altering XRD pattern as indicated by X-ray diffraction results. SEM results show that synthesized particles show spherical aggregation and TEM results show that these particles assembled to give a flower-like morphology. Absorption spectra of all the samples show strong blue shift from bulk CdS. Interesting luminescence pattern with enhanced intensity has been observed for co-doped CdS nanoparticles at room temperature. PMID- 26970796 TI - Synthesis of Novel Arylazothiazolyl-thiophene Dyes for Solar Cell and Nonlinear Optical Materials. AB - Synthesis and investigation of new donor-acceptor conjugated N-(5-arylazothiazol 2-yl)-2-aminothiophene derivatives with the aim to elucidate the contribution of their interaction with solvent molecules upon intramolecular charge transfer for their potential solar cells application. The UV-visible and emission spectra measurements indicated that the properties of the synthesized dyes had a significant effect on the visible absorption and emission maxima. The effect of the donor and acceptor groups were studied for the nonlinearity based on their HOMO-LUMO band gap energy. The dye-sensitized solar cells (DSSCs) were assembled by using the newly synthesized aryl thiazolyl-thiophene dyes as sensitizers. The promising results of J(SC) (2.46 * 10(-2) and 4.07 * 10(-2) mA/cm(2)), the V(OC) (0.429 V and 0.426 V) and the FF (0.66 %) values obtained comparing with other organic and natural sensitizer were due to the better interaction between the carboxyl and carbonyl groups of aryl azo molecule attached to the thiazolyl nucleus and the surface of TiO(2) porous film. PMID- 26970795 TI - Synthesis, Characterization and Biological Studies of New Linear Thermally Stable Schiff Base Polymers with Flexible Spacers. AB - Five new linear Schiff base polymers having azomethine structures, ether linkages and extended aliphatic chain lengths with flexible spacers were synthesized by polycondensation of dialdehyde (monomer) with aliphatic and aromatic diamines. The formation yields of monomer and polymers were obtained within 75-92%. The polymers with flexible spacers of n-hexane were somewhat soluble in acetone, chloroform, THF, DMF and DMSO on heating. The monomer and polymers were characterized by melting point, elemental microanalysis, FT-IR, (1)HNMR, UV-Vis spectroscopy, thermogravimetry (TG), differential thermal analysis (DTA), fluorescence emission, scanning electron microscopy (SEM) and viscosities and thermodynamic parameters measurements of their dilute solutions. The studies supported formation of the monomer and polymers and on the basis of these studies their structures have been assigned. The synthesized polymers were tested for their antibacterial and antifungal activities. PMID- 26970797 TI - Synthesis, Crystal structure, and Hirshfeld Surface Analysis of a New Mixed Ligand Copper(II) Complex. AB - A new mixed ligand copper(II) complex, [Cu(2,4-pydc)(pic)(H(2)O)]?H(2)O (1) (where 2,4-pydc = pyridine-2,4-dicarboxylate, pic = 2-picolylamine) has been synthesized and characterized by elemental analysis, FT-IR and UV-Vis spectroscopic and thermogravimetric methods. Single crystal X-ray diffraction analysis reveals that copper(II) atom in the title complex adopts distorted square pyramidal geometry. Structural characterization also reveals that interplay of O-H...O, N-H...O, C-H...O, and C-H...pi interactions between lattice and coordinated water and ligands significantly contribute to the crystal packing leading to the formation and strengthening of three dimensional supramolecular assembly. Hirshfeld surface analysis employing 3D molecular surface contours and 2D fingerprint plots have been used to analyze intermolecular interactions present in the solid state of the crystal. PMID- 26970798 TI - The Nanostructure Studies of Surfactant-Free-Microemulsions in Fragrance Tinctures. AB - As it was shown recently that nanostructures can exist in water-ethanol citronellol tinctures, a deeper investigation of these media was performed using conductivity, UV-Vis and FT-IR spectroscopy techniques. Different regimes of conductivity, depending on the water content, an increase of the polarity of the polar pseudo-phase with increasing water content, and even the presence of free water molecules at higher water content are observed, just as in classical surfactant-based microemulsions. The percolation model, generally used to fit conductivity data in surfactant based microemulsion having a weak interfacial film, can be used to fit our conductivity data below a critical water content Phi(p)(w) with a critical exponent typical of dynamic percolation. In presence of higher water contents, superior to Phi(p)(w), obtained conductivity data cannot be fitted neither with a static nor a dynamic percolation model. As in surfactant based microemulsions, an increase of polarity of the microenvironment with increasing water content can be postulated using respectively the UV-Vis wavelength absorption band (lambda(max)) of methyl orange and performing FT-IR spectra. PMID- 26970799 TI - Experimental Design Approach for Methylene Blue Dye Removal in Aqueous Environment by Nitrilotriacetic Modified Banana Pith. AB - Native banana pith (NBP) was modified by using nitrilotriacetic acid to increase its efficiency and adsorption capacity for methylene blue (MB) dye. The effect of various parameters such as pH, contact time and initial dye concentration, sorption isotherm and adsorbent dosage were studied. The maximum adsorption capacity of the NBP and NTA-BP is 100 and 142.86 mg/g, respectively. The IR spectrum of NBP and NTA-BP showed the presence of both carboxyl and hydroxyl groups. From the SEM micrographs, the surface morphology of NTA-BP before adsorption appeared to be smoother as compared to that after adsorption process. The pH(pzc) of NBP is 5.6 whereas for NTA-BP is 7.6. The experimental data fitted well into Langmuir isotherm with R(2) of 0.992. Plackett-Burman design was applied to identify the significant factors in affecting the uptake whereas the interaction between the factors and their optimum levels for the maximum percentage uptake of MB were determined using response surface methodology (RSM). Based on the results, the optimum condition for adsorption of MB was by using 0.06 g of NTA-BP in dye solution at pH 6 with 120 minutes contact time. The maximum adsorption of MB by NTA-BP achieved 99.42% under the optimum condition. PMID- 26970801 TI - Synthesis, crystal structures, molecular docking, and urease inhibitory activity of transition metal complexes with 2-[4-(4-fluorophenyl)piperazin-1-yl]acetic acid. AB - Two novel mononuclear complexes, [Cu(L)(2)(H(2)O)].(2)H(2)O (1) and [Ni(L)(2)(H(2)O)(2)] (2) (HL = 2-[4-(4-fluorophenyl)piperazin-1-yl]acetic acid) were synthesized and structurally determined by single-crystal X-ray diffraction. Their inhibitory activities were tested in vitro against jack bean urease. Molecular docking was investigated to determine the probable binding mode. The experimental values and docking simulation exhibited that complex 1 had better inhibitory activity than the positive reference aceto hydroxamic acid (AHA), showing IC(50) value of 0.15 +/- 0.08 uM, while 2 showed no inhibitory activity. PMID- 26970800 TI - Biohydrogen Production from Simple Carbohydrates with Optimization of Operating Parameters. AB - Hydrogen could be alternative energy carrier in the future as well as source for chemical and fuel synthesis due to its high energy content, environmentally friendly technology and zero carbon emissions. In particular, conversion of organic substrates to hydrogen via dark fermentation process is of great interest. The aim of this study was fermentative hydrogen production using anaerobic mixed culture using different carbon sources (mono and disaccharides) and further optimization by varying a number of operating parameters (pH value, temperature, organic loading, mixing intensity). Among all tested mono- and disaccharides, glucose was shown as the preferred carbon source exhibiting hydrogen yield of 1.44 mol H(2)/mol glucose. Further evaluation of selected operating parameters showed that the highest hydrogen yield (1.55 mol H(2)/mol glucose) was obtained at the initial pH value of 6.4, T=37 degrees C and organic loading of 5 g/L. The obtained results demonstrate that lower hydrogen yield at all other conditions was associated with redirection of metabolic pathways from butyric and acetic (accompanied by H(2) production) to lactic (simultaneous H(2) production is not mandatory) acid production. These results therefore represent an important foundation for the optimization and industrial-scale production of hydrogen from organic substrates. PMID- 26970802 TI - Synthesis and Antimicrobial Activity of Bis-[4-methoxy-3-(6-aryl-7H [1,2,4]triazolo[3,4-b][1,3,4]-thiadiazin-3-yl)phenyl]methanes and Bis [(triazolo[3,4-b]thiadiazipin-3-yl)phenyl]methanes. AB - A series of novel Bis-[4-methoxy-3-(6-aryl-7H-[1,2,4]tria zolo[3,4-b][1,3,4] thiadiazin-3-yl)phenyl]methanes and Bis-[(triazolo[3,4-b]thiadiazipin-3 yl)phenyl]methanes ( 5a-e & 6a-e ) has been synthesized and characterized by IR, (1)H NMR, (13)C NMR, MS and elemental analysis. All the newly synthesized compounds were screened for their antibacterial activity against Bacillus subtilis, Staphylococcus aureus, Klobsinella aerogenes and Chromobacteriumviolaceum and antifungal activity against Candida albicans, Aspergillus fumigatus, Trichophyton rubrum and Trichophyton mentagrophytes. Compounds 5b, 5d,5e, 6b, 6c and 6e exhibited potent activity against the test bacteria and fungi, and emerged as potential molecules for further development. PMID- 26970803 TI - Synthesis, Crystal Structure and Catalytic Activity of Dioxidomolybdenum(VI) Complex with Tridentate ONO Aroylhydrazone Ligand. AB - A novel dioxidomolybdenum complex, [MoO(2)L], derived from the tridentate aroylhydrazone 2-amino-N'-(2-hydroxy-3-methylbenzylidene)benzohydrazide (H(2)L), has been prepared and characterized by elemental analysis, FT-IR, (1)H NMR, and single crystal structural X-ray diffraction. The complex has distorted square pyramidal structure in which the aroylhydrazone ligand behaves as a binegative donor one, leaving the amino-N uncoordinated towards the metal center. Single crystal structure analysis reveals that the Mo(VI) center is coordinated by the donor atoms of the binegative aroylhydrazone ligand and two oxido groups. Crystal of the complex is stabilized by hydrogen bonds. The complex functions as an effective olefin epoxidation catalyst with hydrogen peroxide as terminal oxidant and sodium hydrogen carbonate as a co-catalyst. PMID- 26970804 TI - Synthesis, Structure and Electrochemistry of Tetranuclear Oxygen-Centered Copper(II) Clusters with Acetylacetone and Benz-pyrazole Hydrolyzed Derivatives as Ligand. AB - Two copper(II) clusters Cu(4)OCl(6)(pyrazole)4, 1, and Cu(4)OBr(6)(Br-pyrazole)4, 2, have been synthesized by reacting acetylacetone and benzohydrazide (1:1 ratio) with CuX(2) (X = Cl for 1 and X= Br for 2) in methanol solutions. The structures of both clusters have been established by X-ray crystallography. The clusters contain four Cu, one O, six MU(2)-X atoms, and four pyrazole ligands. The pyrazoles was prepared in situ by the reaction of acetylacetone with benzohydrazide in methanol under reflux. In 2, the methine hydrogens of the pyrazole ligands have been replaced by bromine atoms. The four copper atoms encapsulate the central O atom in a tetrahedral arrangement. All copper atoms are five-coordinate and have similar coordination environments with slightly distorted trigonal bipyramidal geometry. The cyclic voltammogram of the clusters 1 and 2 show a one-electron quasi-reversible reduction wave in the region 0.485 to 0.731 V, and a one-electron quasi-reversible oxidation wave in the region 0.767 to 0.898 V. In 1, one irreversible oxidative response is observed on the positive of side of the voltammogram at 1.512 V and this can be assigned to Cu(II) to Cu(III) oxidation. PMID- 26970805 TI - Dissolution Profile of Nimesulide from Pharmaceutical Preparations for Oral Use. AB - Nimesulide belongs to the group of semi-selective COX-2 inhibitors, widely used in solid oral formulations. In the present work the influence of surfactants among other drug excipients, as well as particle size of the active substance and the effects of medium pH on the dissolution rate of nimesulide from solid pharmaceutical forms. For that purpose, four different preparations containing 100 mg nimesulide per tablet and available in the market of Bosnia and Herzegovina (labeled here as A, B, C and D) were studied. The test for the assessment of dissolution profiles of the formulations was performed in surfactant-free dissolution medium pH 7.5. The dissolution profiles were compared by calculating difference (f1), and similarity (f2) factors. The increasing dissolution medium pH value from 7.5 to 7.75 resulted in a significant increase of nimesulide dissolution rate from the examined formulations. Also, the results showed that particle size affects to a great extent the dissolution rate and the best results were achieved with micronized nimesulide. The presence of the surfactants among the other excipients expressed a negligible effect on the dissolution profile. PMID- 26970806 TI - Vanadium Complex Derived from N'-(3-Bromo-5-chloro-2-hydroxybenzylidene) -3 methylbenzohydrazide: Synthesis, Crystal Structure and Biological Activity. AB - Reaction of VO(acac)(2) with N'-(3-bromo-5-chloro-2-hydroxybenzylidene)-3 methylbenzohydrazide (H(2)L) in methanol afforded a new mononuclear vanadium(V) complex, [VOL(OMe)(MeOH)]. Structure of the complex has been characterized by physico-chemical methods and single-crystal X-ray diffraction. The complex crystallizes as the monoclinic space group P2(1)/c, with unit cell dimensions a = 13.1345(10) A, b = 18.6279(14) A, c = 7.8983(8) A, beta = 90.248(2)o, V = 1932.4(3) A(3), Z = 4, R(1) = 0.0963, wR(2) = 0.2213, S = 1.113. X-ray analysis indicated that the V atom in the complex is in octahedral coordination. The insulin-like activity of the complex was studied. PMID- 26970807 TI - Automated Preparation of Water Samples for Low-level Gamma Spectrometry. AB - The analysis of water samples using gamma spectrometry requires the preconcentration of the sample in order to determine the content of low-level radionuclides. An automated evaporator was used for this purpose during the preparation of approximately 250 samples per year as part of the monitoring programmes performed in Slovenia. Since an automated sample-evaporation procedure has not yet been reported in the relevant literature, our unique, innovative, in house-constructed system is described in terms of developing the design, its optimization and automation. PMID- 26970809 TI - Development of a C3-symmetric benzohydroxamate tripod: Trimetallic complexation with Fe(III), Cr(III) and Al(III). AB - The design, synthesis and physicochemical characterization of a C3-symmetry Benzene-1,3,5-tricarbonylhydroxamate tripod, noted here as BTHA, are described. The chelator was built from a benzene as an anchor, symmetrically extended by three hydroxamate as ligating moieties, each bearing O, O donor sites. A combination of absorption spectrophotometry, potentiometry and theoretical investigations are used to explore the complexation behavior of the ligand with some trivalent metal ions: Fe(III), Cr(III), and Al(III). Three protonation constants were calculated for the ligand in a pH range of 2-11 in a highly aqueous medium (9:1 H2O: DMSO). A high rigidity in the molecular structure restricts the formation of 1:1 (M/L) metal encapsulation but shows a high binding efficiency for a 3:1 metal ligand stoichiometry giving formation constant (in beta unit) 28.73, 26.13 and 19.69 for [M3L]; M=Fe(III), Al(III) and Cr(III) respectively, and may be considered as an efficient Fe-carrier. The spectrophotometric study reveals of interesting electronic transitions occurred during the complexation. BTHA exhibits a peak at 238 nm in acidic pH and with the increase of pH, a new peak appeared at 270 nm. A substantial shifting in both of the peaks in presence of the metal ions implicates a s coordination between ligand and metal ions. Moreover, complexation of BTHA with iron shows three distinct colors, violet, reddish orange and yellow in different pH, enables the ligand to be considered for the use as colorimetric sensor. PMID- 26970808 TI - Neurophysiological measurements of affected and unaffected motor cortex from a cross-sectional, multi-center individual stroke patient data analysis study. AB - OBJECTIVES: Transcranial magnetic stimulation (TMS) has been used to measure cortical excitability as a functional measurement of corticomotor pathways. Given its potential application as an assessment tool in stroke, we aimed to analyze the correlation of TMS parameters with clinical features in stroke using data from 10 different centers. METHODS: Data of 341 patients with a clinical diagnosis of stroke were collected from studies assessing cortical excitability using TMS. We used a multivariate regression model in which the baseline cortical excitability parameter "resting Motor Threshold (rMT)" was the main outcome and the demographic, anatomic and clinical characteristics were included as independent variables. RESULTS: The variable "severity of motor deficit" consistently remained significant in predicting rMT in the affected hemisphere, with a positive beta coefficient, in the multivariate models after sensitive analyses and adjusting for important confounders such as site center. Additionally, we found that the correlations between "age" or "time since stroke" and the rMT in the affected hemisphere were significant, as well as the interaction between "time since stroke" and "severity of motor deficit". CONCLUSIONS: We have shown that severity of motor deficit is an important predictor for rMT in the affected hemisphere. Additionally, time since stroke seems to be an effect modifier for the correlation between motor deficit and rMT. In the unaffected motor cortex, these correlations were not significant. We discuss these findings in the context of stroke rehabilitation. PMID- 26970810 TI - Effect of agomelatine on adult hippocampus apoptosis and neurogenesis using the stress model of rats. AB - Agomelatine (AG) is an agonist of melatonin receptors and an antagonist of the 5 HT2C-receptor subtype. The chronobiotic properties of AG are of significant interest due to the disorganization of internal rhythms, which might play a role in the pathophysiology of depression. The present study was designed to assess the effects of the antidepressant-like activity of AG, a new antidepressant drug, on adult neurogenesis and apoptosis using stress-exposed rat brains. Over the period of 1 week, the rats were exposed to light stress twice a day for 1h. After a period of 1 week, the rats were given AG treatment at a dose of either 10mg/kg or 40mg/kg for 15 days. The animals were then scarified, and the obtained tissue sections were stained with immuno-histochemical anti-BrdU, Caspase-3, and Bcl-2 antibodies. Serum brain-derived neurotrophic factor (BDNF) concentrations were measured biochemically using a BDNF Elisa kit. Biochemical BDNF analysis revealed a high concentration of BDNF in the serum of the stress-exposed group, but the concentrations of BDNF were much lower those of the AG-treated groups. Immuno histochemical analysis revealed that AG treatment decreased the BrdU-positive and Bcl-2-positive cell densities and increased the Caspase-3-positive cell density in the hippocampus of stress-induced rats as compared to those of the stress group. The results of the study demonstrated that AG treatment ameliorated the hippocampal apoptotic cells and increased hippocampal neurogenesis. These results also strengthen the possible relationship between depression and adult neurogenesis, which must be studied further. PMID- 26970811 TI - [Evaluation of venous thromboembolism risk and prophylaxis among hospitalized patients in Brazzaville]. AB - OBJECTIVES: To identify patients at risk of venous thromboembolism and to evaluate the use of preventive measures. METHODS: A cross-sectional given-day observational and descriptive study was conducted among patients in the Brazzaville University Hospital. All hospitalized adult patients were included. Compliance with the recommendations of the American College of Chest Physicians (2004 version) on the risk of venous thromboembolism and use of prevention was evaluated. The study included 292 patients hospitalized from July 1 to 4, 2014 in eight medicine and four surgery and gynecology-obstetrics wards. RESULTS: The study population included 214 (73.3 %) patients at risk of venous thromboembolism hospitalized in medicine (n=83, 38.7 %), surgery (n=82, 38.3 %), and gynecology obstetrics (n=49, 23 %) wards. There were 92 men (43 %) and 122 women (57 %), mean age 45.9+/-17.7years (range: 18-88). The risk of venous thromboembolism was low in 15 patients (7 %), moderate in 104 patients (48.6 %), and high in 95 patients (44.4 %). The main risk factors identified were: for surgical patients, long immobilization (42.6 %) and age>40years (33.1 %); for medical patients, long immobilization (24.7 %) and age>60years (18.5 %); for gynecology-obstetrics patients, age<60years (44 %), multiparity (15.4 %) and long immobilization (10.7 %). One hundred sixty-nine patients (79 %) had received one measure of prevention. There were 45 (54.2 %) medical patients, 81 (99 %) surgical patients and 43 (88 %) gynecology-obstetrics patients. Pharmacological prevention was used in 97 patients (57.4 %), mechanical prevention in 33 patients (19.5 %), and the two types of prevention in 39 patients (23.1 %). CONCLUSIONS: The risk of venous thromboembolism is common in hospitalized patients in Brazzaville, and the need for prevention is perceived but poorly understood. It is therefore essential to improve our knowledge of venous thromboembolism and its prevention. PMID- 26970812 TI - [Digoxin-related leukocytoclastic vasculitis in a very elderly woman: A case report]. AB - Even though digoxin causes many side effects, few cases of skin involvement are recorded in the French Pharmacovigilance Database. We report a case of leukocytoclastic vasculitis (LV) very probably due to digoxin. A 91-year-old woman, hospitalized following a fall, presented cardiac decompensation in a context of rapid atrial fibrillation requiring treatment with digoxin. Eight days later, a rash appeared on her back and trunk. It was neither itchy, nor painful and persisted despite local treatment. There were no other clinical anomalies. After a few days, the rash spread with appearance of bullous lesions, ulcerations and a necrosis on lymphedema of the two legs. Among the complementary examinations, skin biopsy revealed LV with necrosis and subepidermal detachment suggested toxic dermal necrolysis, while direct immunofluorescence was negative. The rash resolved progressively once the digoxin was stopped. The pharmacovigilance department recorded that digoxin was the probable cause. The evidence allowed us to conclude that digoxin was the cause. PMID- 26970813 TI - Chest Pain, Heart Murmur, and Changing Electrocardiograms. AB - Physical examination, electrocardiograms, and an echo-Doppler study document multiple consequences of a right coronary arterial occlusion. PMID- 26970814 TI - Racial Differences in the Prevalence and Outcomes of Atrial Fibrillation in Patients Hospitalized With Heart Failure. AB - Previous research has shown that roughly 15% to 30% of those with heart failure (HF) develop atrial fibrillation (AF). Although studies have shown variations in the incidence of AF in patients with HF, there has been no evidence of mortality differences by race. The purpose of this study was to assess AF prevalence and inhospital mortality in patients with HF among different racial groups in the United States. Using the National Inpatient Sample registry, the largest publicly available all-payer inpatient care database representing >95% of the US inpatient population, we analyzed subjects hospitalized with a primary diagnosis of HF from 2001 to 2011 (n = 11,485,673) using the International Classification of Diseases, Ninth Edition (ICD 9) codes 428.0-0.1, 428.20-0.23, 428.30-0.33, 428.40-0.43, and 428.9; patients with AF were identified using the ICD 9 code 427.31. We assessed prevalence and mortality among racial groups. Using logistic regression, we examined odds of mortality adjusted for demographics and co-morbidity using Elixhauser co-morbidity index. We also examined utilization of procedures by race. Of the 11,485,673 patients hospitalized with HF in our study, 3,939,129 (34%) had AF. Patients with HF and AF had greater inhospital mortality compared with those without AF (4.6% vs 3.3% respectively, p <0.0001). Additionally, black, Hispanic, Asian, and white patients with HF and AF had a 24%, 17%, 13%, and 6% higher mortality, respectively, than if they did not have AF. Among patients with HF and AF, minority racial groups had underutilization of catheter ablation and cardioversion compared with white patients. In conclusion, minority patients with HF and AF had a disproportionately higher risk of inpatient death compared with white patients with HF. We also found a significant underutilization of cardioversion and catheter ablation in minority racial groups compared with white patients. PMID- 26970815 TI - Prediction of Flow-Limiting Fractional Flow Reserve in Patients With Stable Coronary Artery Disease Based on Quantitative Myocardial Perfusion Imaging. AB - Although fractional flow reserve (FFR) and myocardial perfusion imaging (MPI) findings fundamentally differ, several cohort studies have revealed that these findings correlate. Here, we investigated whether flow-limiting FFR could be predicted from adenosine stress thallium-201 MPI with single-photon emission computed tomography (SPECT) findings derived from 84 consecutive, prospectively identified patients with stable coronary artery disease and 212 diseased vessels. Among them, FFR was measured in 136 diseased vessels (64%). The findings were compared with regional perfusion abnormalities including stress total perfusion defect (TPD) - rest TPD determined using quantitative perfusion single-photon emission computed tomography software. The FFR inversely correlated the most accurately with stress TPD - rest TPD (r = -0.552, p <0.001). Predictors of major vessels of interest comprising FFR <0.80, included stress TPD - rest TPD, the transient ischemic dilation ratio, left ventricular ejection fraction at rest and beta blockers for left anterior descending artery (LAD) regions, and stress TPD - rest TPD, left ventricular mass, left ventricular ejection fraction at rest, right coronary artery lesions, the transient ischemic dilation ratio, and age for non-LAD regions. The diagnostic accuracy of formulas to predict major vessels of interest with FFR <0.80 was high (sensitivity, specificity and accuracy for LAD and non-LAD: 84%, 87% and 86%, and 75%, 93% and 87%, respectively). In conclusion, although somewhat limited by a sample size and a single-center design, flow-limiting FFR could be predicted from MPI findings with a defined probability. A cohort study might validate our results and provide a novel adjunctive tool with which to diagnose functionally significant coronary artery disease from MPI findings. PMID- 26970816 TI - Mycobacterium bovis-infected macrophages from resistant and susceptible cattle exhibited a differential pro-inflammatory gene expression profile depending on strain virulence. AB - Mycobacterium bovis, the causative agent of bovine tuberculosis, is an intracellular bacterium that normally persists inside host macrophages. However, the influence of bacterial virulence and host resistance on the final outcome in this interaction is not well known. In this study, we infected macrophages isolated from natural disease resistant (R) and susceptible (S) cattle donors with M. bovis strains characterized as attenuated and virulent to assess pro inflammatory cytokine (TNFalpha, IL-12, IL-18, IL-1beta, IL-6), chemokine (MCP-1, MCP-2, MIP-1), macrophage receptor (MSR1, TLR2, TLR4, MMR) and iNOS mRNA expression levels. Our findings identified a pro-inflammatory gene expression profile as a common feature after M. bovis infection regardless of bacterial virulence, however in S macrophages a superior expression was induced by the attenuated strain, whereas in R macrophages it was accomplished by the virulent M. bovis. A macrophage pro-inflammatory profile is intended to control M. bovis intracellular growth; however the host resistant phenotype plays a determinant role in it, since R macrophages had better intracellular bacterial control than S cells. PMID- 26970817 TI - Anti-inflammatory activity of chitosan nanoparticles carrying NF-kappaB/p65 antisense oligonucleotide in RAW264.7 macropghage stimulated by lipopolysaccharide. AB - The purpose of this present study is to prepare NF-kappaB/p65 antisense oligonucleotide loaded chitosan nanoparticles (NPs) and evaluate their physicochemical characterization and antisense effects in RAW264.7 macrophages. Condensed nanoparticles with mean particle size of 128+/-16nm, average Zeta potential of 19.6+/-6.3mV and high entrapment efficiency (EE) of 98.6+/-0.11% were formed between NF-kappaB/p65 antisense gene (NAG) and chitosan by complex coacervation method. Trypan blue staining and MTT tests showed that NAG chitosan NPs had no toxic effect on RAW264.7 macrophages when the dose was no more than 20MUg/mL. Confocal microscopy images showed that NAG chitosan NPs were capable to deliver NAG into cytoplasm of RAW264.7 macrophages and finally into nucleus. Real time PCR tests verified that NAG chitosan NPs could significantly decrease the mRNA expression level of NF-kappaB/p65 and inflammatory cytokines including TNF alpha, IL-1 and IL-6. Accordingly, western blot study showed that NAG NPs uptaken in the cells could efficiently reversed the expression of NF-kappaB/p65 protein induced by LPS. At last, downstream release level of inflammatory factors including TNF-alpha, IL-1 and IL-6 in LPS stimulated RAW264.7 macrophages was significantly decreased after treated by NAG chitosan NPs. It could be concluded that chitosan NPs were excellent delivery vectors to ferry the NAG into the cytoplasm and nucleus of macrophages. The NAG chitosan NPs might be a novel therapeutic apparatus for the treatment of LPS induced sepsis by inhibiting NF kappaB-related pro-inflammatory cytokines secretion. PMID- 26970818 TI - Carboplatin loaded Surface modified PLGA nanoparticles: Optimization, characterization, and in vivo brain targeting studies. AB - The carboplatin (CP) loaded poly-lactide-co-glycolide (PLGA) nanoparticles (NPs) were formulated by modified solvent evaporation method. Its surface modification is done by 1% polysorbate80 (P80) to improve their entry into the brain after intraperitoneal administration (i.p) via receptor-mediated pathways. A formulation with maximum entrapment efficiency and minimal particle size was optimized by central composite design (CCD) based on mean particle size, and entrapment efficiencies as responses. The optimized formulation was characterized by mean particle size, entrapment efficiency, zeta potential, Fourier transform infrared (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) analysis. The surface modified NPs were analysed for mean particle, zeta potential, FTIR, and in vitro release studies. The spherical particles with mean particle size 161.9nm, 162.4nm and zeta potential value of -26.5, -23.9 were obtained for unmodified and surface modified NPs respectively. The in vitro release experiments of the surface modified PLGA NPs exhibited sustained release for more than 48h, which was in accordance with Higuchi's equation with Fickian diffusion-based release mechanism. The in vivo bio distribution of P80 coated CP loaded PLGA NPs was compared with CP solution, and CP loaded NPs, in adult wistar rats. In the brain, compared with CP solution, both types of NPs especially NPs coated with P80 increased the concentration of carboplatin by 3.27 fold. All these results suggest that the developed formulation may improve the targeted therapy for malignant brain tumors in future. PMID- 26970820 TI - A novel porous Fe/Fe-W alloy scaffold with a double-layer structured skeleton: Preparation, in vitro degradability and biocompatibility. AB - A novel porous Fe/Fe-W alloy scaffold with a double-layer structured skeleton was prepared for the first time by electrodeposition. The microstructure of the scaffold was analysed by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS) and mercury porosimetry. Mechanical property, in vitro degradability and biocompatibility were tested by tensile test, immersion and a cytotoxicity test. The results showed that the scaffolds exhibited a cellular structure that is similar to that of cancellous bone and had a considerably large specific surface area. The skeleton of the scaffolds showed a double-layer structure that was composed of a hollow Fe skeleton wrapped in a thin layer of Fe-W alloy. The tensile strength and the apparent density are close to that of cancellous bone. It was also found that the different surface microstructures showed different effects on in vitro degradability and biocompatibility. In the immersion test, the corrosion rate decreased gradually as the immersion time increased. In the cytotoxicity test, the extraction medium of the pure Fe scaffold showed the lowest cell viability, followed by that of 1.5FeW as a close second. The extraction media of FeW, Fe1.5W and Fe2W were similar, and their cell viability was far above that of the Fe and 1.5FeW scaffolds. The structural style of the scaffolds presented in this paper is potentially useful and applicable to developing degradable scaffolds with a tailored corrosion rate. PMID- 26970819 TI - Chitosan wound dressing with hexagonal silver nanoparticles for hyperthermia and enhanced delivery of small molecules. AB - Chitosan films were synthesized with hexagonal silver nanoparticles (Ag NP). The unique shape and size of the Ag NP shift the optical absorption into the infrared. Stimulation of the nanoparticles with infrared light was used to generate heat and facilitate intracellular delivery of fluorescently-labeled dextran molecules. Chitosan films prepared with hexagonal or spherical Ag NP were characterized by optical and thermal analyses, and X-ray diffraction. There were found to be slight differences between how the chitosan molecular chains interface with the Ag NP depending upon shape of the nanoparticle. Viability of cells associated with dermal wound healing was evaluated on chitosan films prepared with hexagonal or spherical Ag NP, with both keratinocytes and fibroblasts having normal or moderately enhanced growth on films containing hexagonally-shaped nanoparticles. PMID- 26970821 TI - Inherently antioxidant and antimicrobial tannic acid release from poly(tannic acid) nanoparticles with controllable degradability. AB - From a natural polyphenol, Tannic acid (TA), poly(TA) nanoparticles were readily prepared using a single step approach with three different biocompatible crosslinkers; trimethylolpropane triglycidyl ether (TMPGDE), poly(ethylene glycol) diglycidyl ether (PEGGE), and trisodium trimetaphosphate (STMP). P(TA) particles were obtained with controllable diameters between 400 to 800nm with 25mV surface charge. The effect of synthesis conditions, such as the emulsion medium, pH values of TA solution, and the type of crosslinker, on the shape, size, dispersity, yield, and degradability of poly(Tannic Acid) (p(TA)) nanoparticles was systematically investigated. The hydrolytic degradation amount in physiological pH conditions of 5.4, 7.4, and 9.0 at 37.5 degrees C were found to be in the order TMPGDE=70 years of age (mean age 78 +/- 6 years, 43% women, mean ejection fraction 35 +/- 11%, mean New York Heart Association functional class 2.7 +/- 0.6) in stable condition and receiving optimized therapy for chronic HF were prospectively enrolled and followed for 1 year. Gait speed was measured at the usual pace over 4 m, and cutoffs were defined by tertiles: <=0.65, 0.66 to 0.99, and >=1.0 m/s. RESULTS: There was a significant association between gait speed tertiles and 1-year mortality: 38.3%, 21.9%, and 9.1% (p < 0.001), respectively. On multivariate analysis, gait speed was associated with a lower risk for all-cause death (hazard ratio: 0.62; 95% confidence interval: 0.43 to 0.88) independently of age, ejection fraction <20%, systolic blood pressure, anemia, and absence of beta blocker therapy. Gait speed was also associated with a lower risk for hospitalization for HF and all-cause hospitalization. When gait speed was added to the multiparametric Cardiac and Comorbid Conditions Heart Failure risk score, it improved the accuracy of risk stratification for all-cause death (net reclassification improvement 0.49; 95% confidence interval: 0.26 to 0.73, p < 0.001) and HF admissions (net reclassification improvement 0.37; 95% confidence interval: 0.15 to 0.58; p < 0.001). CONCLUSIONS: Gait speed is independently associated with death, hospitalization for HF, and all-cause hospitalization and improves risk stratification in older patients with HF evaluated using the Cardiac and Comorbid Conditions Heart Failure score. Assessment of frailty using gait speed is simple and should be part of the clinical evaluation process. PMID- 26970833 TI - The 21- to 27-year results of the Harris-Galante cementless total hip arthroplasty. AB - BACKGROUND: The Harris-Galante total hip arthroplasty (THA) is a first-generation cementless THA with a porous coating for biological fixation of the implant. Many studies report excellent long-term results for the acetabular cup, but few long term studies exist for the femoral stem because of relatively poor short-term and midterm results. Here we present the 21- to 27-year results of the cup and the stem of the Harris-Galante THA. METHODS: From 1985 to 1991, 102 Harris-Galante THAs were inserted in 82 patients. At the time of the THA, the mean patient age was 54 years (range, 20-78 years). The primary diagnosis was secondary osteoarthritis due to developmental hip dysplasia (69 [68%] hips). The Japanese Orthopaedic Association (JOA) hip score and thigh pain were measures of clinical outcome. Radiographic review was performed retrospectively. Implant survival was evaluated by Kaplan-Meier analysis. RESULTS: Of 102 hips, 35 hips were from 31 deceased patients, 5 patients (6 hips) were lost to follow-up, 12 hips were revised, and 49 hips were from patients living at the latest follow-up. Among the living patients, 36 hips had a clinical evaluation and 42 hips had a radiograph obtained more than 21 years. The JOA hip score improved from 42 points preoperatively to 83.5 points at the latest follow-up. Thigh pain was reported in 13 hips. One cup and four stems were loose at the latest radiographic review. Most cup revisions were related to acetabular osteolysis. Fifteen hips showed severe stress shielding. Kaplan-Meier analysis of survivorship with any revision, acetabular reoperation, stem revision, and stem loosening as the end point was 87.0%, 90.3%, 95.7% and 86.4%, respectively, at 24.6 years. CONCLUSIONS: Long term implant survival and clinical results of the Harris-Galante THA were good. Acetabular osteolysis-related cup loosening was a problem of the cup. Loosening, thigh pain, and stress shielding were problems of the stem. PMID- 26970832 TI - Relaxin-2 and Soluble Flt1 Levels in Peripartum Cardiomyopathy: Results of the Multicenter IPAC Study. AB - OBJECTIVES: This study explored the association of vascular hormones with myocardial recovery and clinical outcomes in peripartum cardiomyopathy (PPCM). BACKGROUND: PPCM is an uncommon disorder with unknown etiology. Angiogenic imbalance may contribute to its pathophysiology. METHODS: In 98 women with newly diagnosed PPCM enrolled in the Investigation in Pregnancy Associated Cardiomyopathy study, serum was obtained at baseline for analysis of relaxin-2, prolactin, soluble fms-like tyrosine kinase 1 (sFlt1), and vascular endothelial growth factor (VEGF). Left ventricular ejection fraction (LVEF) was assessed by echocardiography at baseline and 2, 6, and 12 months. RESULTS: Mean age was 30 +/ 6 years, with a baseline of LVEF 0.35 +/- 0.09. Relaxin-2, prolactin, and sFlt1 were elevated in women presenting early post-partum, but decreased rapidly and were correlated inversely with time from delivery to presentation. In tertile analysis, higher relaxin-2 was associated with smaller left ventricular systolic diameter (p = 0.006) and higher LVEF at 2 months (p = 0.01). This was particularly evident in women presenting soon after delivery (p = 0.02). No relationship was evident for myocardial recovery and prolactin, sFlt1 or VEGF levels. sFlt1 levels were higher in women with higher New York Heart Association functional class (p = 0.01) and adverse clinical events (p = 0.004). CONCLUSIONS: In women with newly diagnosed PPCM, higher relaxin-2 levels soon after delivery were associated with myocardial recovery at 2 months. In contrast, higher sFlt1 levels correlated with more severe symptoms and major adverse clinical events. Vascular mediators may contribute to the development of PPCM and influence subsequent myocardial recovery. (Investigation in Pregnancy Associate Cardiomyopathy [IPAC]; NCT01085955). PMID- 26970835 TI - Multivariate Analysis of Risk Factors of Graft Extrusion After Lateral Meniscus Allograft Transplantation. AB - PURPOSE: To identify risk factors that predict major graft extrusion (>3 mm in relation to the margin of the tibial plateau) on magnetic resonance imaging (MRI) after lateral meniscus allograft transplantation (MAT) using multivariate logistic regression. METHODS: In this retrospective trial, inclusion criteria were consecutive lateral MATs from January 2004 to June 2013. Exclusion criteria were the lack of postoperative MRI, loss to follow-up for minimum 2 years, and simultaneous surgery of the articular cartilage or anterior cruciate ligament. According to the measured extent of graft extrusion in postoperative MRI, the lateral MATs were sorted into minor extrusion and major extrusion groups. Multivariate logistic regression was used to analyze risk factors including age, gender, body mass index, time from previous meniscectomy to MAT, extent of previous meniscectomy, previous anterior cruciate ligament reconstruction, knee alignment angle, Kellgren-Lawrence grade, lateral peripheral osteophyte, Outerbridge grade, posterior repair technique the position of bony bridge, and axial plane trough angle. RESULTS: Enrolled 72 lateral MATs were sorted into minor extrusion (n = 34) and major extrusion groups (n = 38). As time from previous meniscectomy to lateral MAT increased, the risk of the major graft extrusion after lateral MAT increased (adjusted odds ratio: 1.554, 95% confidence interval: 1.089 to 2.218). Increased axial plane trough angle was also a significant risk factor (adjusted odds ratio: 8.449, 95% confidence interval: 1.710 to 42.250). The other parameters were not significant risk factors. CONCLUSIONS: Most meniscal grafts after lateral MATs showed major graft extrusion. Significant risk factors for the major graft extrusion included delayed time from previous meniscectomy to MAT and increased axial plane trough angle. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 26970836 TI - Global Mental Health for Older Adults. PMID- 26970834 TI - The Safety of Using Proximal Anteromedial Portals in Elbow Arthroscopy With Prior Ulnar Nerve Transposition. AB - PURPOSE: To report the safety of using the proximal anteromedial portal, using a simplified ulnar nerve management strategy derived from an earlier study, in a series of patients with previously transposed ulnar nerves. METHODS: A retrospective review of all elbow arthroscopies performed by a single surgeon from 2009 to 2014 was performed. The following techniques were used if, by palpation, localization of the ulnar nerve was considered to be certain (group 1) or uncertain (group 2): In group 1 (certain) the proximal anteromedial portal was established in the normal antegrade fashion. In group 2 (uncertain) a 1- to 3-cm incision was made at the planned proximal anteromedial portal site, and blunt dissection down to the capsule was performed without identification of the nerve. The nerve was not visualized but sometimes was palpated through the wound to confirm its location anteriorly or posteriorly. If there was a disparity between the prior operative records and the physical examination findings, the nerve was explored through a 3- to 4-cm incision. RESULTS: We reviewed 394 elbow arthroscopy cases, 22 of which had a prior transposed ulnar nerve (21 subcutaneous and 1 submuscular) that required anterior-compartment arthroscopic surgery. Group 1 (certain location) consisted of 9 elbows (41%), whereas group 2 (uncertain location) consisted of 13 (59%). In 2 cases in group 2, the ulnar nerve was explored because of the disparity between the previous medical records and the physical examination findings. There were no operative ulnar nerve injuries related to the use of the proximal anteromedial portal. CONCLUSIONS: The proximal anteromedial portal was able to be used safely in patients with prior transposition of the ulnar nerve. This was achieved by using an algorithm based on the degree of certainty with which the nerve can be localized in the region of the planned portal by clinical palpation. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 26970837 TI - [Prevalence of potentially inappropriate drug prescription in the elderly]. AB - INTRODUCTION: One of the causes of preventable adverse drug events (ADES) in older patients constitutes inappropriate prescription of drugs (PIM). The PIM is where risks exceed the clinical benefit. Several instruments can be use to measure this problem, the most used are: a) Beers criteria; b) Screening tool to Older People Potentially inappropriate Prescription (STOPP); c) Screening tool to Alert Doctors to Right Appropriate indicated Treatments (START); d) The Medication Appropriateness Index (MAI). This study aims to assess the prevalence of PIM, in a population of older adults in three clinical scopes of university hospital. MATERIAL AND METHODS: cross sectional study of 300 cases from a random sample of fields: hospitalization (n=100), ambulatory (n=100) and emergency (n=100), all patients over 65 years old or more who where treated at our hospital. RESULTS: 1355 prescription drugs were analized, finding patients hospitalized (PIM) of 57.7%, 55%, 26%, and 80% according to Beers, in ambulatory 36%, 36.5%, 5% and 52% with the same tools and in emergency 35%, 35%, 6% y 52% with the same tools. Was found significant association the PIM with polipharmacy with Beers, STOPP and MAI. CONCLUSIONS: results can be compare to world literature (26-80% vs 11-73.1%). The STOPP-START used in an integrated manner would be best estimating the problem of PIM. PMID- 26970838 TI - A comparison between occlusive and exposure dressing in the management of burn wound. AB - BACKGROUND AND AIM: Two types of dressing, occlusive and exposure dressing, are commonly used in burn units. A dressing is said to be occlusive if a moist wound surface is maintained when the dressing is in place. This study was designed to compare the effectiveness of occlusive and exposure dressing in controlling burn infections. PATIENTS AND METHODS: Two hundred patients with second-degree burns admitted to Mottahari Hospital, Tehran, Iran, over a period of 12 months from May 2012 to May 2013 were studied. They were divided into two groups of 100 each, to receive either occlusive or exposure dressing. During the first week of treatment, wound specimens were obtained by sterile swab and cultured in selective media. Demographics (age and gender), burn areas, cause of burn, length of hospital stay (LOS), type of infections and time to total healing were compared between the two groups. RESULTS: Occlusive dressing was more susceptible to microbial contamination and infections than exposure dressing. The mean duration of treatment based on epithelialization and healing in occlusive dressing was longer than for exposure dressing. The most common isolate was Pseudomonas spp., followed by Enterobacter, Escherichia coli, Staphylococcus aureus, Acinetobacter, and Klebsiella spp. CONCLUSIONS: Exposure dressing was more suitable than occlusive dressing for treating partial-thickness at our center. Pseudomonas aeruginosa was the most common organism encountered in burn infection. PMID- 26970839 TI - Radiation dose reduction in CT with adaptive statistical iterative reconstruction (ASIR) for patients with bronchial carcinoma and intrapulmonary metastases. AB - AIM: To compare the radiation dose and image quality of 64-row chest computed tomography (CT) in patients with bronchial carcinoma or intrapulmonary metastases using full-dose CT reconstructed with filtered back projection (FBP) at baseline and reduced dose with 40% adaptive statistical iterative reconstruction (ASIR) at follow-up. MATERIALS AND METHODS: The chest CT images of patients who underwent FBP and ASIR studies were reviewed. Dose-length products (DLP), effective dose, and size-specific dose estimates (SSDEs) were obtained. Image quality was analysed quantitatively by signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) measurement. In addition, image quality was assessed by two blinded radiologists evaluating images for noise, contrast, artefacts, visibility of small structures, and diagnostic acceptability using a five-point scale. RESULTS: The ASIR studies showed 36% reduction in effective dose compared with the FBP studies. The qualitative and quantitative image quality was good to excellent in both protocols, without significant differences. There were also no significant differences for SNR except for the SNR of lung surrounding the tumour (FBP: 35+/ 17, ASIR: 39+/-22). DISCUSSION: A protocol with 40% ASIR can provide approximately 36% dose reduction in chest CT of patients with bronchial carcinoma or intrapulmonary metastases while maintaining excellent image quality. PMID- 26970840 TI - The Use and Abuse of LexA by Mobile Genetic Elements. AB - The SOS response is an essential process for responding to DNA damage in bacteria. The expression of SOS genes is under the control of LexA, a global transcription factor that undergoes self-cleavage during stress to allow the expression of DNA repair functions and delay cell division until the damage is rectified. LexA also regulates genes that are not part of this cell rescue program, and the induction of bacteriophages, the movement of pathogenicity islands, and the expression of virulence factors and bacteriocins are all controlled by this important transcription factor. Recently it has emerged that when regulating the expression of genes from mobile genetic elements (MGEs), LexA often does so in concert with a corepressor. This accessory regulator can either be a host-encoded global transcription factor, which responds to various metabolic changes, or a factor that is encoded for by the MGE itself. Thus, the coupling of LexA-mediated regulation to a secondary transcription factor not only detaches LexA from its primary SOS role, but also fine-tunes gene expression from the MGE, enabling it to respond to multiple stresses. Here we discuss the mechanisms of such coordinated regulation and its implications for cells carrying such MGEs. PMID- 26970841 TI - Trends in the Incidence of Lung Cancer Hospitalizations in Spain, 2001-2011. AB - OBJECTIVE: To analyze changes in the incidence, diagnostic procedures, comorbidity, length of hospital stay and costs of patients hospitalized for lung cancer in Spain between 2001 and 2011. PATIENTS AND METHODS: Retrospective study including all patients hospitalised with a primary diagnosis of lung cancer between 2001 and 2011. Data were collected from the National Hospital Discharge Database, encompassing the entire Spanish population. Economic and sociodemographic characteristics and health-related variables were analyzed. RESULTS: A total of 298,435 hospitalizations occurred. The overall crude incidence increased from 61.18 per 100,000 inhabitants in 2001 to 65.08 per 100,000 in 2011 (P <.05), with a decrease in men and a proportionate increase in women. The age group with the highest incidence was 70 to 79 years. In 2001, 4.5% of patients had a Charlson comorbidity index (CCI) >2, and in 2011, prevalence of CCI >2 increased to 9.1% (P<.05). Mean length of hospital stay decreased during the study period. Computed tomography was the most common procedure. Mean cost per patient increased from ?4,471.22 in 2001 to ?5,562.54 (P<.05) in 2011. Factors related to the incidence of hospitalizations were age, sex and year of study in the multivariate analysis. CONCLUSIONS: We found a decrease in the rate of hospitalizations in men and an increase in women, with a concomitant increase in comorbidities and cost; however, length of hospital stay decreased. Factors related to incidence of hospitalizations were age, sex and year of study. PMID- 26970842 TI - Recovery of cobalt from spent lithium-ion batteries using supercritical carbon dioxide extraction. AB - Continuing technological development decreases the useful lifetime of electronic equipment, resulting in the generation of waste and the need for new and more efficient recycling processes. The objective of this work is to study the effectiveness of supercritical fluids for the leaching of cobalt contained in lithium-ion batteries (LIBs). For comparative purposes, leaching tests are performed with supercritical CO2 and co-solvents, as well as under conventional conditions. In both cases, sulfuric acid and H2O2 are used as reagents. The solution obtained from the supercritical leaching is processed using electrowinning in order to recover the cobalt. The results show that at atmospheric pressure, cobalt leaching is favored by increasing the amount of H2O2 (from 0 to 8% v/v). The use of supercritical conditions enable extraction of more than 95wt% of the cobalt, with reduction of the reaction time from 60min (the time employed in leaching at atmospheric pressure) to 5min, and a reduction in the concentration of H2O2 required from 8 to 4% (v/v). Electrowinning using a leach solution achieve a current efficiency of 96% and a deposit with cobalt concentration of 99.5wt%. PMID- 26970843 TI - Use of recycled plastics in concrete: A critical review. AB - Plastics have become an essential part of our modern lifestyle, and the global plastic production has increased immensely during the past 50years. This has contributed greatly to the production of plastic-related waste. Reuse of waste and recycled plastic materials in concrete mix as an environmental friendly construction material has drawn attention of researchers in recent times, and a large number of studies reporting the behavior of concrete containing waste and recycled plastic materials have been published. This paper summarizes the current published literature until 2015, discussing the material properties and recycling methods of plastic and the influence of plastic materials on the properties of concrete. To provide a comprehensive review, a total of 84 studies were considered, and they were classified into sub categories based on whether they dealt with concrete containing plastic aggregates or plastic fibers. Furthermore, the morphology of concrete containing plastic materials is described in this paper to explain the influence of plastic aggregates and plastic fibers on the properties of concrete. The properties of concretes containing virgin plastic materials were also reviewed to establish their similarities and differences with concrete containing recycled plastics. PMID- 26970844 TI - Measuring treatment costs of typical waste electrical and electronic equipment: A pre-research for Chinese policy making. AB - Waste Electrical and Electronic Equipment (WEEE) volume is increasing, worldwide. In 2011, the Chinese government issued new regulations on WEEE recycling and disposal, establishing a WEEE treatment subsidy funded by a levy on producers of electrical and electronic equipment. In order to evaluate WEEE recycling treatment costs and revenue possibilities under the new regulations, and to propose suggestions for cost-effective WEEE management, a comprehensive revenue expenditure model (REM), were established for this study, including 7 types of costs, 4 types of fees, and one type of revenue. Since TV sets dominated the volume of WEEE treated from 2013 to 2014, with a contribution rate of 87.3%, TV sets were taken as a representative case. Results showed that the treatment cost varied from 46.4RMB/unit to 82.5RMB/unit, with a treatment quantity of 130,000 units to 1,200,000 units per year in China. Collection cost accounted for the largest portion (about 70.0%), while taxes and fees (about 11.0 %) and labor cost (about 7.0 %) contributed less. The average costs for disposal, sales, and taxes had no influence on treatment quantity (TQ). TQ might have an adverse effect on average labor and management costs; while average collection and purchase fees, and financing costs, would vary with purchase price, and the average sales fees and taxes would vary with the sales of dismantled materials and other recycled products. Recycling enterprises could reduce their costs by setting up online and offline collection platforms, cooperating with individual collectors, creating door-to-door collection channels, improving production efficiency and reducing administrative expenditures. The government could provide economic incentives such as subsidies, low-cost loans, tax cuts and credits-and could also raise public awareness of waste management and environmental protection, in order to capture some of the WEEE currently discarded into the general waste stream. Foreign companies with advanced WEEE utilization technology could invest or participate in this area, producing profits for themselves while helping to develop and implement environmentally friendly and energy-saving technologies applicable to the Chinese market. PMID- 26970845 TI - Validated UHPLC-MS/MS method for the simultaneous determination of pramipexole and ropinirole in plasma of patients with Parkinson's disease. AB - A simple and validated ultra high pressure liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of the dopaminergic agents pramipexole and ropinirole in plasma of patients with Parkinson's disease. Following liquid-liquid extraction with tert-butyl methyl ether from 250MUL plasma, the separation of the analytes was achieved on a Gemini NX3 column using 10mM pH 6.0 ammonium formate and 10mM ammonium formate in methanol as binary gradient mobile phase at a flow rate of 0.3mL/min. The MS/MS ion transitions were 212.10->153.03 for pramipexole, 261.2->114.2 for ropinirole and 256.1->211 for the internal standard (lamotrigine). The lower limit of quantitation (LLOQ) for both analytes was 80pg/mL and the linearity was determined from 80 to 4000pg/mL for pramipexole and from 200 to 10000pg/mL for ropinirole. Mean recoveries were 94% for PRA and 73% for ROP. Both intra- and inter-assay precision and accuracy were <=20% at LLOQ concentration and <=15% at other concentrations. The proposed validated method was successfully applied to measure plasma concentrations of pramipexole and ropinirole in a series of patients with Parkinson's disease on chronic treatment. By grouping the two dopaminergic agents in the same assay, the method allows a large series of patient samples to be processed in a single analytical session. PMID- 26970846 TI - Simultaneous determination of moxifloxacin and ofloxacin in physiological fluids using high performance liquid chromatography with ultraviolet detection. AB - A novel, sensitive and validated RP-HPLC-UV method was developed for simultaneous determination of moxifloxacin and ofloxacin using timolol maleate as internal standard in physiological fluids. Different experimental parameters were optimized and validated according to international guidelines. Complete separation of the analytes was achieved with Kromasil 100-5C18 analytical column (250mm*4.6mm*5MUm), methanol and 0.05% trifloroacetic acid (TFA) (38:62v/v) were used as mobile phase, pumped at flow rate of 1.1ml/min in isocratic phase, column oven temperature maintained at 45 degrees C and detection wavelength of 290nm. Protein precipitation method was applied to extract the drugs from human plasma and bovine aqueous humor samples using methanol as precipitating solvent. This method is linear in concentration range of 0.018-100MUg/ml for moxifloxacin and 0.014-20MUg/ml for ofloxacin. The recoveries of the method were 97.52 and 97.39% in human plasma for MX and OFN respectively, while in aqueous humor 94.48% for MX. The LOD values in plasma were found to be 10.0 and 8.00ng/ml for MX and OFN respectively, while their respective LOQ values were 18.0 and 14ng/ml. In aqueous humor the LOD and LOQ for MX were 16.0 and 24ng/ml respectively. In future, this method will be used to study the pharmacokinetic profile of moxifloxacin and ofloxacin in biological fluids and pharmaceutical products. PMID- 26970848 TI - Development and validation of a liquid chromatography-tandem mass spectrometric assay for quantitative analyses of triptans in hair. AB - Triptans are specific drugs widely used for acute treatment of migraine, being selective 5HT1B/1D receptor agonists. A proper assumption of triptans is very important for an effective treatment; nevertheless patients often underuse, misuse, overuse or use triptans inconsistently, i.e., not following the prescribed therapy. Drug analysis in hair can represent a powerful tool for monitoring the compliance of the patient to the therapy, since it can greatly increase the time-window of detection compared to analyses in biological fluids, such as plasma or urine. In the present study, a liquid chromatography-tandem mass spectrometric (LC-MS/MS) method has been developed and validated for the quantitative analysis in human hair of five triptans commonly prescribed in Italy: almotriptan (AL), eletriptan (EP), rizatriptan (RIZ), sumatriptan (SUM) and zolmitriptan (ZP). Hair samples were decontaminated and incubated overnight in diluted hydrochloric acid; the extracts were purified by mixed-mode SPE cartridges and analyzed by LC-MS/MS under gradient elution in positive multiple reaction monitoring (MRM) mode. The procedure was fully validated in terms of selectivity, linearity, limit of detection (LOD) and lower limit of quantitation (LLOQ), accuracy, precision, carry-over, recovery, matrix effect and dilution integrity. The method was linear in the range 10-1000pg/mg hair, with R(2) values of at least 0.990; the validated LLOQ values were in the range 5-7pg/mg hair. The method offered satisfactory precision (RSD <10%), accuracy (90-110%) and recovery (>85%) values. The validated procedure was applied on 147 authentic hair samples from subjects being treated in the Headache Centre of Modena University Hospital in order to verify the possibility of monitoring the corresponding hair levels for the taken triptans. PMID- 26970847 TI - Functional hydrophilic polystyrene beads with uniformly size and high cross linking degree facilitated rapid separation of exenatide. AB - A high cross-linking polystyrene(PSt)-based anion-exchange material with uniformly size, high ion exchange capacity, and high hydrophilicity was synthesized by a novel surface functionalization approach in this study. Uniformly sized PSt microspheres were prepared by the membrane emulsion polymerization strategy, and then modified by (1) conversing resid ual surface vinyl groups to epoxy groups followed by quaternization, and (2) decorating aromatic ring matrix including nitration, reduction and attachment of glycidyltrimethylammonium chloride. The 3-D morphology and porous features of microspheres were observed by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The surface of the modified PSt became roughness but the particle size remained same. Meanwhile, FT-IR spectra and laser scanning confocal microscope (LCSM) indicated that the modification groups had been successfully covalently coated onto the PSt microspheres. Modified PSt microspheres showed greatly improved hydrophilicity and biocompatibility with 0.387mmol/mL ion exchange capacity (IEC). In the application evaluation procedure, exenatide can be purified from 42.9% (peptide crudes) to 88.6% by modified PSt column with 97.1% recovery yield. This modified PSt microspheres had a large potential in application for efficient separation of peptides. PMID- 26970849 TI - A novel method for simultaneous quantification of alpha-aminoadipic semialdehyde/piperideine-6-carboxylate and pipecolic acid in plasma and urine. AB - OBJECTIVES: Elevated levels of pipecolic acid (PA), alpha-aminoadipic semialdehyde (AASA) and its cyclic form Delta1-piperideine-6-carboxylate (P6C) are characteristic of pyridoxine dependent epilepsy (PDE), a rare disorder of inborn error of metabolism. Recent studies showed the effectiveness of dietary therapy in PDE patients and emphasized the importance of the assessment of these metabolites for monitoring treatment efficacy. The objective of this study was to develop a robust and sensitive method for simultaneous quantification of AASA-P6C and PA in plasma and urine. DESIGN AND METHODS: Plasma and urine samples were derivatized with 3N HCl in n-butanol (v/v) and injected onto ACQUITY BEH-C18 column. A gradient of water/methanol containing 0.1% formic acid was used for the chromatographic separation of AASA, P6C and PA. The analytes' concentrations were calculated using their calibration curves and the sum of AASA and P6C (AASA-P6C) was calculated. To evaluate the clinical utility of this test, samples from unaffected controls and patients with confirmed PDE were analyzed. RESULTS: The performance characteristics of the assay as well as sample stability and interferences were determined. The intra- and inter- assay CVs were <=2.9% and <=10.9% for AASA-P6C, and <=3.3% and <=12.6% for PA, respectively. Reference ranges for AASA-P6C and PA in plasma and urine were established. Comparison of values obtained from unaffected controls and PDE patients showed high clinical sensitivity and specificity of the assay. CONCLUSIONS: This novel method for the simultaneous quantification of AASA-P6C and PA in plasma and urine can be used in a clinical laboratory setting for the diagnosis and monitoring of patients with PDE. PMID- 26970851 TI - The treatment of problematic hemangiomas in children with propranolol and 940nm diode laser. AB - BACKGROUND: Hemangiomas are common skin lesion, affecting 10-12% of children <1year of age. The purpose of this study was to determine the effect and safety of systemic propranolol (Pr) therapy in combination with 940nm diode laser for the treatment of severe hemangiomas. METHODS: Patients (123: 11 with vascular malformations and 112 with infantile hemangiomas (IH)) were enrolled in the study. They were initially treated with: systemic Pr therapy (2-2.5mg/kg/day) for 6-8months. Following completion of Pr therapy, patients with significant residual lesions (n-61) were treated with photothermolysis (laser therapy). RESULTS: Pr therapy had no effect on the color and volume of the vascular malformations. Pr therapy alone demonstrated a reduction in both volume and color of the IH. Laser therapy resulted in a continued improvement in the appearance of the IH with 84% of patients experiencing a residual volume of 0% compared to the original and 89% experiencing a decrease to between 0 and 20% of original color. There were no adverse events associated with laser therapy. CONCLUSIONS: This study demonstrates that the addition of laser therapy to Pr therapy for the treatment of IH in children is well tolerated with a very acceptable cosmetic result. PMID- 26970850 TI - Flap versus fascial closure for gastroschisis: a systematic review and meta analysis. AB - BACKGROUND: Flap closure represents an alternative to fascial closure for gastroschisis. We performed a systematic review and meta-analysis of outcomes comparing these techniques. METHODS: A registered systematic review ( PROSPERO: CRD42015016745) of comparative studies was performed, querying multiple databases without language or date restrictions. Gray literature was sought. Outcomes analyzed included: mortality, ventilation days, feeding parameters, length of stay (LOS), wound infection, resource utilization, and umbilical hernia incidence. Multiple reviewers independently assessed study eligibility and literature quality. Meta-analysis of outcomes was performed where appropriate (Revman 5.2). RESULTS: Twelve studies met inclusion criteria, of which three were multi-institutional. Quality assessment revealed unbiased patient selection and exposure, but group comparability was suboptimal in four studies. Overall, 1124 patients were evaluated, of which 350 underwent flap closure (210 immediately; 140 post-silo). Meta-analysis revealed no significant differences in mortality, LOS, or feeding parameters between groups. Flap patients had less wound infections (OR 0.40 [95%CI 0.22-0.74], P=0.003). While flap patients had an increased risk of umbilical hernia, they were less likely to undergo repair (19% vs. 41%; P=0.01). CONCLUSIONS: Flap closure has equivalent or superior outcomes to fascial closure for patients with gastroschisis. Given potential advantages of bedside closure and reduced sedation requirements, flap closure may represent the preferred closure strategy. PMID- 26970853 TI - Cognitive framing in action. AB - Cognitive framing effects have been widely reported in higher-level decision making and have been ascribed to rules of thumb for quick thinking. No such demonstrations have been reported for physical action, as far as we know, but they would be expected if cognition for physical action is fundamentally similar to cognition for higher-level decision-making. To test for such effects, we asked participants to reach for a horizontally-oriented pipe to move it from one height to another while turning the pipe 180 degrees to bring one end (the "business end") to a target on the left or right. From a physical perspective, participants could have always rotated the pipe in the same angular direction no matter which end was the business end; a given participant could have always turned the pipe clockwise or counter-clockwise. Instead, our participants turned the business end counter-clockwise for left targets and clockwise for right targets. Thus, the way the identical physical task was framed altered the way it was performed. This finding is consistent with the hypothesis that cognition for physical action is fundamentally similar to cognition for higher-level decision-making. A tantalizing possibility is that higher-level decision heuristics have roots in the control of physical action, a hypothesis that accords with embodied views of cognition. PMID- 26970852 TI - Partial sialoadenectomy for the treatment of benign tumours in the submandibular gland. AB - The conventional treatment for benign tumours arising in the submandibular gland (SMG) has always involved whole gland excision with the tumour. In light of developments in parotid gland functional surgery, this prospective study was performed to evaluate the effectiveness and safety of partial sialoadenectomy (PS) for benign tumours in comparison with conventional total sialoadenectomy (TS). Thirty-one consecutive patients with a preoperative diagnosis of benign tumour in the SMG were included in the study from December 2008 to December 2010. Eleven patients were treated with PS and 20 patients underwent conventional TS. Salivary gland function and surgery-related complications were assessed. No difference in resting saliva flow was found between the two groups before the operation, while this was significantly higher in the PS group than in the TS group at 1 year after surgery (P=0.009). With regard to complications, there was less deformity in facial appearance in the PS group. There was no recurrence in any of the 31 patients during the follow-up period (range 41-82 months). It is believed that this modification to SMG surgery is consistent with the idea of functional and minimal invasive salivary gland surgery. This technique represents a good choice for the management of benign tumours of the SMG for appropriately selected cases. PMID- 26970854 TI - Mood migration: How enfacing a smile makes you happier. AB - People tend to perceive the face of another person more as their own if own and other face are stroked in synchrony-the enfacement illusion. We conceptually replicated the enfacement illusion in a virtual reality environment, in which participants could control the movements of a virtual face by moving and touching their own face. We then used this virtual enfacement illusion to study whether enfacing a virtual face would also involve adopting the emotion that this face is expressing. As predicted, participants adopted the expressed emotion, as indicated by higher valence scores and better performance in a mood-sensitive divergent-thinking task when facing a happy virtual face, if the virtual face moved in synchrony with their own head movements. This suggests that impact on or control over another person's facial movements invite "mood migration" from the person one identifies with to oneself. PMID- 26970855 TI - Positive associations of serum perfluoroalkyl substances with uric acid and hyperuricemia in children from Taiwan. AB - To investigate the risk of hyperuricemia in relation to Perfluoroalkyl substances (PFASs) in children from Taiwan, 225 Taiwanese children aged 12-15 years were recruited from 2009 to 2010. Linear and logistic regression models were employed to examine the influence of PFASs on serum uric acid levels. Findings revealed that eight of ten PFASs analyses were detected in >94% of the participants' serum samples. Multivariate linear regression models revealed that perfluorooctanic acid (PFOA) was positively associated with serum uric acid levels (beta = 0.1463, p < 0.05). Of all the PFASs analyses, only PFOA showed a significant effect on elevated levels of hyperuricemia (aOR = 2.16, 95%CI: 1.29-3.61). When stratified by gender, the association between serum PFOA and uric acid levels was only evident among boys (aOR = 2.76, 95%CI: 1.37-5.56). In conclusion, PFOA was found to be associated with elevated serum levels of uric acid in Taiwanese children, especially boys. Further research is needed to elucidate these links. PMID- 26970856 TI - Sub-lethal effects of water-based drilling muds on the deep-water sponge Geodia barretti. AB - Offshore oil and gas activities can result in the discharge of large amounts of drilling muds. While these materials have generally been regarded as non-toxic to marine organisms, recent studies have demonstrated negative impacts to suspension feeding organisms. We exposed the arctic-boreal sponge Geodia barretti to the primary particulate components of two water-based drilling muds; barite and bentonite. Sponges were exposed to barite, bentonite and a natural reference sediment at a range of total suspended solid concentrations (TSS = 0, 10, 50 or 100 mg/L) for 12 h after which we measured a suite of biomarker responses (lysosomal membrane stability, lipid peroxidation and glutathione). In addition, we compared biomarker responses, organic energy content and metal accumulation in sponges, which had been continuously or intermittently exposed to suspended barite and natural sediment for 14 d at relevant concentrations (10 and 30 mg TSS/L). Lysosomal membrane stability was reduced in the sponges exposed to barite at 50 and 100 mg TSS/L after just 12 h and at 30 mg TSS/L for both continuous and intermittent exposures over 14 d. Evidence of compromised cellular viability was accompanied by barite analysis revealing concentrations of Cu and Pb well above reference sediments and Norwegian sediment quality guidelines. Metal bioaccumulation in sponge tissues was low and the total organic energy content (determined by the elemental composition of organic tissue) was not affected. Intermittent exposures to barite resulted in less toxicity than continuous exposure to barite. Short term exposures to bentonite did not alter any biomarker responses. This is the first time that these biomarkers have been used to indicate contaminant exposure in an arctic-boreal sponge. Our results illustrate the potential toxicity of barite and the importance of assessments that reflect the ways in which these contaminants are delivered under environmentally realistic conditions. PMID- 26970857 TI - Feature-based MRI data fusion for cardiac arrhythmia studies. AB - Current practices in studying cardiac arrhythmias primarily use electrical or optical surface recordings of a heart, spatially limited transmural recordings, and mathematical models. However, given that such arrhythmias occur on a 3D myocardial tissue, information obtained from such practices lack in dimension, completeness, and are sometimes prone to oversimplification. The combination of complementary Magnetic-Resonance Imaging (MRI)-based techniques such as Current Density Imaging (CDI) and Diffusion Tensor Imaging (DTI) could provide more depth to current practices in assessing the cardiac arrhythmia dynamics in entire cross sections of myocardium. In this work, we present an approach utilizing feature based data fusion methods to demonstrate that complimentary information obtained from electrical current distribution and structural properties within a heart could be quantified and enhanced. Twelve (12) pairs of CDI and DTI image data sets were gathered from porcine hearts perfused through a Langendorff setup. Images were fused together using feature-based data fusion techniques such as Joint Independent Component Analysis (jICA), Canonical Correlation Analysis (CCA), and their combination (CCA+jICA). The results suggest that the complimentary information of cardiac states from CDI and DTI are enhanced and are better classified with the use of data fusion methods. For each data set, an increase in mean correlations of fused images were observed with 38% increase from CCA+jICA compared to the original images while mean mutual information of the fused images from jICA and CCA+jICA increased by approximately three-fold. We conclude that MRI-based techniques present potential viable tools in furthering studies for cardiac arrhythmias especially Ventricular Fibrillation. PMID- 26970858 TI - Parents' experiences and needs regarding physical and occupational therapy for their young children with cerebral palsy. AB - OBJECTIVE: To explore the experiences and needs of parents of young children (aged 2-4 years) with cerebral palsy (CP) regarding their child's physical and occupational therapy process in a rehabilitation setting. METHODS: A qualitative design was used involving semi-structured interviews with 21 parents of young children with CP. Interviews were conducted until informational redundancy was achieved. RESULTS: Three major themes were identified: Information, communication and partnership. A fourth, overarching theme emerged: The process of parent empowerment. Experiences and needs differed between parents and changed over time. CONCLUSION: This study suggests that various themes play a key role in the experiences and needs of parents of young children with CP. The identified themes provide important insights into how and why service providers might change their approach. PRACTICE IMPLICATIONS: Becoming empowered is a dynamic process for parents, in which both parents and service providers play a role. Service providers should continually adapt their role to parents' needs of information, communication and partnership, and they should support and facilitate parents in becoming empowered. For that, service providers should be educated on the process of parent empowerment, on ways to facilitate this process and on the importance of involving and interacting with parents. This allows families of young children with CP to be provided with services that best suit their needs. PMID- 26970859 TI - Executive functions in adults with developmental dyslexia. AB - BACKGROUND: Executive functioning (EF) deficits are well recognized in developmental dyslexia, yet the majority of studies have concerned children rather than adults, ignored the subjective experience of the individual with dyslexia (with regard to their own EFs), and have not followed current theoretical perspectives on EFs. AIMS AND METHODS: The current study addressed these shortfalls by administering a self-report measure of EF (BRIEF-A; Roth, Isquith, & Gioia, 2005) and experimental tasks to IQ-matched groups of adults with and without dyslexia. The laboratory-based tasks tested the three factors constituting the framework of EF proposed by Miyake et al. (2000). RESULTS: In comparison to the group without dyslexia, the participants with dyslexia self reported more frequent EF problems in day-to-day life, with these difficulties centering on metacognitive processes (working memory, planning, task monitoring, and organization) rather than on the regulation of emotion and behaviour. The participants with dyslexia showed significant deficits in EF (inhibition, set shifting, and working memory). CONCLUSIONS AND IMPLICATIONS: The findings indicated that dyslexia-related problems have an impact on the daily experience of adults with the condition. Further, EF difficulties are present in adulthood across a range of laboratory-based measures, and, given the nature of the experimental tasks presented, extend beyond difficulties related solely to phonological processing. PMID- 26970860 TI - Acute Interstitial Nephritis Following Snake Envenomation: A Single-Center Experience. AB - OBJECTIVES: To identify the clinical and histopathological characteristics of patients who develop acute interstitial nephritis (AIN) following snake envenomation. METHODS: A retrospective analysis of patients diagnosed with snake envenomation-induced AIN from October 2013 to November 2014. RESULTS: After snake envenomation, 88 patients developed acute kidney injury (AKI). Biopsies were performed on 7 patients due to nonrecovery of kidney function. Among these, 5 patients had AIN. Thus, AIN accounted for 5.7% of snakebite-related acute kidney injury. All patients had severe envenomation at presentation and had prolonged renal failure. Kidney biopsy found a mixed infiltrate composed of predominantly lymphocytes, with variable proportions of other cells including eosinophils neutrophils and plasma cells. The response rate to corticosteroids was 80%. CONCLUSIONS: AIN after snake bite is not uncommon. AIN needs to be considered in patients with persistent renal failure after snake envenomation. Identifying this complication is of utmost importance because of the potentially reversible nature. PMID- 26970861 TI - Radiological and clinical features of cerebral sinovenous thrombosis in newborns and older children. AB - BACKGROUND AND PURPOSE: Cerebral sinovenous thrombosis (CSVT) represents an increasingly recognized cause of pediatric stroke. Our purpose was to assess gender and age differences in the etiology, clinical presentation, and imaging features of CSVT in neonates and older children. METHODS: Subjects aged newborn to 18 years diagnosed with CSVT at the Lille university hospital between 2011 and 2014 were included. RESULTS: Eleven neonates and 16 non-neonates constituted the study population. The incidence of CSVT was significantly higher in male newborns. Clinical presentation did not vary significantly between the groups. Risk factors were age-dependent, with acute systemic illnesses significantly predominating in neonates (54%), whereas local infections, prothrombotic conditions, and trauma were more common in older children (36, 27, and 27% respectively). No predisposing factor could be identified in 36% of the neonates as compared to less than 5% of the non-neonates. Thrombosis of the deep venous structures was documented in 73% of the neonates whereas involvement of the superficial sinuses was significantly more frequent in the non-neonates group. Venous infarctions and extraparenchymal hemorrhages were significantly more frequent in the neonates group. CONCLUSION: Male patients are at higher risk for CSVT than females. In neonates, involvement of the deep venous structures is significantly more common. Brain parenchymal and extraparenchymal changes occur more frequently in this age group than in older children. PMID- 26970863 TI - The long-term use of beta-blockers in chronic heart failure. PMID- 26970862 TI - Pituitary Microsomal Autoantibodies in Patients with Childhood-Onset Combined Pituitary Hormone Deficiency: an Antigen Identification Attempt. AB - The role of autoimmunization in the pathogenesis of pituitary disorders is poorly understood. The presence of pituitary autoantibodies (APA) has been detected in various pituitary disorders. Their role, however, remains elusive. Childhood onset combined pituitary hormone deficiency (CPHD) may be caused by environmental or genetic factors. In some of patients, causes of the disease remain unclear and contributions of autoimmune processes have been postulated. The aim of this study was to identify the microsomes-derived pituitary antigens (MPA) as potential immunogenic autoantigens in patients with hypopituitarism, therefore 62 CPHD patients, 100 healthy controls and five autoimmune polyglandular syndrome type II (APS II) patients were included in the study. The clinical evaluation included hormonal tests and magnetic resonance imaging of the pituitary. The sources of MPA were pituitary glands taken from autopsies. Isolated MPA were then separated on SDS-PAGE gel and incubated with sera obtained from patients and controls. Microsomal APA were detected using Western blot and radioimmunological method. In all CPHD and APS II patients and in 9 % individuals from control group marked immunoreactivity was detected against MPA. Antibodies showed high affinity to 67, 60, 50 and 36 kDa MPAs. Since the identified autoantigens were of unknown nature, an in silico exploration of UniProt database was applied and indicated their possible relationship with chaperones, golgins and already known autoantigens like GAD67. Reactivity against MPA indicates that these proteins certainly play a role in the processes undergoing within pituitary of CPHD patients. The identification and further detailed studies on their role in the pathogenesis of CPHD should be continued. PMID- 26970864 TI - Rapid and selective brain cooling method using vortex tube: A feasibility study. AB - Vortex tubes are simple mechanical devices to produce cold air from a stream of compressed air without any moving parts. The primary focus of the current study is to investigate the feasibility and efficiency of nasopharyngeal brain cooling method using a vortex tube. Experiments were conducted on 5 juvenile pigs. Nasopharygeal brain cooling was achieved by directing cooled air via a catheter in each nostril into the nasal cavities. A vortex tube was used to generate cold air using various sources of compressed air: (I) hospital medical air outlet (n = 1); (II) medical air cylinders (n = 3); and (III) scuba (diving) cylinders (n = 1). By using compressed air from a hospital medical air outlet at fixed inlet pressure of 50 PSI, maximum brain-rectal temperature gradient of -2 degrees C was reached about 45-60 minutes by setting the flow rate of 25 L/min and temperature of -7 degrees C at the cold air outlet. Similarly, by using medical air cylinders at fill-pressure of 2265 PSI and down regulate the inlet pressure to the vortex tube to 50 PSI, brain temperature could be reduced more rapidly by blowing -22 degrees C +/- 2 degrees C air at a flow rate of 50 L/min; brain-body temperature gradient of -8 degrees C was obtained about 30 minutes. Furthermore, we examined scuba cylinders as a portable source of compressed gas supply to the vortex tube. Likewise, by setting up the vortex tube to have an inlet pressure of 25 PSI and 50 L/min and -3 degrees C at the cold air outlet, brain temperature decreased 4.5 degrees C within 10-20 min. PMID- 26970865 TI - Speaking Up For Science. AB - Communicating science and being an advocate for public support of research are critical roles for scientists. However, despite having the most relevant expertise, many of us do not get involved in matters bridging science and policy. Here I discuss the importance of science advocacy by researchers, and present strategies for communicating the relevance of your work to the public and elected officials, including the crafting of a two-minute pitch - a valuable skill for all scientists. PMID- 26970866 TI - No effect of femoral offset on bone implant micromotion in an experimental model. AB - BACKGROUND: In total hip replacement (THR), the femoral offset (FO) is assessed preoperatively, and the surgeon must determine whether to restore, increase, or decrease the FO based on experience and the patient's clinical history. The FO is known to influence the abductor muscle strength, range of motion (ROM), gait, and hip pain after THR; however, the true effect of FO on bone implant micromotion is unclear. Therefore, we investigated to assess: (1) the muscle loading response during gait, (2) whether FO affects bone implant micromotion during gait. HYPOTHESIS: A variation of +/-10mm from the anatomical FO affects the muscle loading forces. MATERIALS AND METHODS: We modified a personalized musculoskeletal model of the lower extremity to determine the 3-dimensional contact forces at the hip joint in the presence of a stem with varying offsets during a gait cycle. A detailed finite element (FE) model was then constructed for increased, restored, and decreased FOs. The maximum load obtained during normal walking gait from the musculoskeletal model was applied to the respective FE models, and the resultant stem-bone micromotion and stress distribution were computed. RESULTS: Increasing the FO to +10mm decreased the peak force generated by the abductor muscles during the cycle by 15.0% and decreasing the FO to -10mm increased the von Mises stress distribution at the distal bone by 77.5% (P<0.05). A variation of the offset within 10mm of the anatomical offset showed no significant differences in micromotion (P>0.05) and peak stresses (P>0.05). DISCUSSION: Coupling the musculoskeletal model of the gait cycle with FE analysis provides a realistic model to understand how FO affects bone implant micromotion. We found that there was no effect of FO on bone implant micromotion; thus, a surgeon does not need to evaluate the implications of FO on micromotion and can determine a FO that best decreases the work load of abductor muscles, increases ROM, and reduces hip pain. LEVEL OF EVIDENCE: IV, biomechanical study. PMID- 26970867 TI - Selecting best-fit models for estimating the body mass from 3D data of the human calcaneus. AB - Body mass (BM) estimation could facilitate the interpretation of skeletal materials in terms of the individual's body size and physique in forensic anthropology. However, few metric studies have tried to estimate BM by focusing on prominent biomechanical properties of the calcaneus. The purpose of this study was to prepare best-fit models for estimating BM from the 3D human calcaneus by two major linear regression analysis (the heuristic statistical and all-possible regressions techniques) and validate the models through predicted residual sum of squares (PRESS) statistics. A metric analysis was conducted based on 70 human calcaneus samples (29 males and 41 females) taken from 3D models in the Digital Korean Database and 10 variables were measured for each sample. Three best-fit models were postulated by F-statistics, Mallows' Cp, and Akaike information criterion (AIC) and Bayes information criterion (BIC) for each available candidate models. Finally, the most accurate regression model yields lowest %SEE and 0.843 of R(2). Through the application of leave-one-out cross validation, the predictive power was indicated a high level of validation accuracy. This study also confirms that the equations for estimating BM using 3D models of human calcaneus will be helpful to establish identification in forensic cases with consistent reliability. PMID- 26970868 TI - Thin layer chromatography coupled to paper spray ionization mass spectrometry for cocaine and its adulterants analysis. AB - Thin layer chromatography (TLC) is a simple and inexpensive type of chromatography that is extensively used in forensic laboratories for drugs of abuse analysis. In this work, TLC is optimized to analyze cocaine and its adulterants (caffeine, benzocaine, lidocaine and phenacetin) in which the sensitivity (visual determination of LOD from 0.5 to 14mgmL(-1)) and the selectivity (from the study of three different eluents: CHCl3:CH3OH:HCOOHglacial (75:20:5v%), (C2H5)2O:CHCl3 (50:50v%) and CH3OH:NH4OH (100:1.5v%)) were evaluated. Aiming to improve these figures of merit, the TLC spots were identified and quantified (linearity with R(2)>0.98) by the paper spray ionization mass spectrometry (PS-MS), reaching now lower LOD values (>1.0MUgmL( 1)). The method developed in this work open up perspective of enhancing the reliability of traditional and routine TLC analysis employed in the criminal expertise units. Higher sensitivity, selectivity and rapidity can be provided in forensic reports, besides the possibility of quantitative analysis. Due to the great simplicity, the PS(+)-MS technique can also be coupled directly to other separation techniques such as the paper chromatography and can still be used in analyses of LSD blotter, documents and synthetic drugs. PMID- 26970869 TI - Impact dynamics of porcine drip bloodstains on fabrics. AB - As a passive blood drop impacts a hard surface, it is observed to collapse and spread laterally, then retract and settle. During the spreading phase, the edge of the drop may rise forming a crown extending into spines and breaking up into secondary drops. When a similar drop falls onto a textile surface these same processes may occur, but the process of blood wicking into the fabric complicates stain formation. These processes are described within for passive drip stains collected under controlled conditions using anticoagulated porcine blood. Three stages of this impact process were identified and could be separated into distinct time zones: (1) spreading (time t<=2.5ms) and (2) retraction (2.5<=t<=12ms) on the surface with potential splashing at the periphery, and (3) wicking (30ms <=t<=30min) of the blood into the fabric. Although wetting and wicking may also occur for t<30ms, the vast majority of wetting and wicking occur after this time and thus the short-time wicking can be ignored. In addition, the number of satellite stains correlates with the surface roughness with the number of satellites for jersey knit>plain-woven>cardboard. Conversely, the size of the satellite stains correlates with the amount of wicking in the fabric with the satellite stain size for plain-woven>jersey knit>cardboard. PMID- 26970870 TI - The use of fingerprints available on the web in false identity documents: Analysis from a forensic intelligence perspective. AB - Fingerprints present in false identity documents were found on the web. In some cases, laterally reversed (mirrored) images of a same fingerprint were observed in different documents. In the present work, 100 fingerprints images downloaded from the web, as well as their reversals obtained by image editing, were compared between themselves and against the database of the Brazilian Federal Police AFIS, in order to better understand trends about this kind of forgery in Brazil. Some image editing effects were observed in the analyzed fingerprints: addition of artifacts (such as watermarks), image rotation, image stylization, lateral reversal and tonal reversal. Discussion about lateral reversals' detection is presented in this article, as well as suggestion to reduce errors due to missed HIT decisions between reversed fingerprints. The present work aims to highlight the importance of the fingerprints' analysis when performing document examination, especially when only copies of documents are available, something very common in Brazil. Besides the intrinsic features of the fingermarks considered in three levels of details by ACE-V methodology, some visual features of the fingerprints images can be helpful to identify sources of forgeries and modus operandi, such as: limits and image contours, fails in the friction ridges caused by excess or lack of inking and presence of watermarks and artifacts arising from the background. Based on the agreement of such features in fingerprints present in different identity documents and also on the analysis of the time and location where the documents were seized, it is possible to highlight potential links between apparently unconnected crimes. Therefore, fingerprints have potential to reduce linkage blindness and the present work suggests the analysis of fingerprints when profiling false identity documents, as well as the inclusion of fingerprints features in the profile of the documents. PMID- 26970871 TI - Aqueous Hg(2+) associates with TiO2 nanoparticles according to particle size, changes particle agglomeration, and becomes less bioavailable to zebrafish. AB - Engineered nanoparticles (NPs) have unique physicochemistry and potential to interact with other substances in the aqueous phase. Here, gene [metallothionein 2 (mt2)] expression changes in larval zebrafish were used to evaluate the association between aqueous Hg(2+) and TiO2 (NPs and bulk particle size control) to investigate the relationship between changes in Hg(2+) behavior and TiO2 size. During 24h exposures, TiO2 agglomerates increased in size and in the presence of 25MUg Hg(2+)/L, greater increases in size were observed. The concentration of Hg(2+) in suspension also decreased in the presence of TiO2-NPs. Mercury increased expression of mt2 in larval zebrafish, but this response was lessened when zebrafish were exposed to Hg(2+) in the presence of TiO2-NPs, and which suggests that TiO2-NPs alter the bioavailability of Hg(2+) to zebrafish larvae. This ameliorative effect of TiO2 was also likely due to surface binding of Hg(2+) because a greater decrease in mt2 expression was observed in the presence of 1mg/L TiO2-NPs than 1mg/L TiO2-bulk. In conclusion, the results show that Hg(2+) will associate with TiO2-NPs, TiO2-NPs that have associated Hg(2+) will settle out of the aqueous phase more rapidly, and agglomerates will deliver associated Hg(2+) to sediment surfaces. PMID- 26970872 TI - Characterizing distributions, composition profiles, sources and potential health risk of polybrominated diphenyl ethers (PBDEs) in the coastal sediments from East China Sea. AB - Sediment samples (n = 20) were collected from Yangtze River Estuary (YRE) and the adjacent East China Sea (ECS) inner shelf to explore spatial and temporal distributions, environmental fate, sources and potential health risk of polybrominated diphenyl ethers (PBDEs). Concentrations of BDE-209 and total 7 PBDEs (without BDE-209; ?7PBDEs) ranged from 62.3 to 1758 pg g(-1) and from 36.9 to 233.6 pg g(-1) dry weight, respectively; both of the highest values occurred near the city of Wenzhou. Concentrations of BDE-209 and ?7PBDEs both indicated a decreasing trend from inshore areas toward outer shelf. Significantly positive linear correlations were only observed between logBDE-183 concentrations and TOC/grain size (r(2) = 0.6734 and 0.5977 for TOC and grain size, respectively) as well as BDE-209 and TOC/grain size (r(2) = 0.4137 and 0.5332 for TOC and grain size, respectively) in the north of 28( degrees )N, indicating that YR had significant influence on the distribution of higher brominated congeners only in the north part. Depth profiles of PBDEs in a sediment core P01 (n = 1, m = 11) collected from YRE showed that the input of BDE-209 gradually increased from 1930 to 2010, while the levels of ?7PBDEs peaked in 1986 and obviously decreased in recent years. Partial Least-Squares Regression (PLSR) revealed that PBDEs in the coastal ECS were mainly from direct discharge of local anthropogenic activities (80.7%), followed by surface runoff of contaminated soils (15.1%), microbial degradation after sedimentation (2.6%) and photodegradation during atmospheric transportation (1.6%). The cancer risk of human exposure to BDE-209 at the 95% confidence level was 3.09 * 10(-7), 1.67 * 10(-7) and 8.86 * 10(-7) for children, teens and adults, respectively, significantly lower than the threshold level (10( 6)). Hazard index (HI) calculated for non-cancer risk was also far less than 1 for the three groups, suggesting no non-cancer risk. PMID- 26970874 TI - Changes of concentrations and possibility of accumulation of bisphenol A and alkylphenols, depending on biomass and composition, in zooplankton of the Southern Baltic (Gulf of Gdansk). AB - The focus of the present study was to find the relationship between concentrations of bisphenol A (BPA), 4-tert-octylphenol (OP) and 4-nonylphenol (NP) in zooplankton and seasonal changes in the composition and biomass of particular zooplankton taxa in the Gulf of Gdansk (Southern Baltic) in the years 2011-2012. Assays of BPA, OP and NP in water and zooplankton samples were performed using the HPLC/FL system. High mean concentrations of the studied compounds, determined in spring (405.9 (BPA); 25.7 (OP); 111.2 (NP) ng g(-1) dw), can be linked to the high proportion of meroplankton in that season. Rotifera also had an influence on the rise in concentrations of the studied compounds but to a lesser degree, while the lowest concentrations (determined in summer) can be associated with the high participation of Copepoda and Cladocera in zooplankton biomass. It was also observed that juvenile forms can be more susceptible to accumulating endocrine disrupting compounds (EDCs). This is indicated by the positive correlation between BPA concentration in zooplankton and the proportion of Copepoda nauplii biomass in spring (r = 0.90; p < 0.05). In most cases, greater zooplankton biomass accumulated higher concentrations and loads of the studied compounds. With biomass growth (to 123.32 MUg m(-3)), the bioconcentration factor also rose (to max 46.1.10(3)), demonstrating that unlike typical hydrophobic compounds the studied EDCs do not become "diluted" in zooplankton biomass. The highest BPA concentrations from all compounds may be connected with anthropogenic sources located in the coastal zone. PMID- 26970873 TI - Probabilistic assessment of risks of diethylhexyl phthalate (DEHP) in surface waters of China on reproduction of fish. AB - Diethylhexyl phthalate (DEHP) is considered to be an endocrine disruptor, which unlike other chemicals that have either non-specific (e.g., narcotics) or more generalized reactive modes of action, affect the Hypothalamic-pituitary-gonadal (HPG) axis and tend to have specific interactions with particular molecular targets within biochemical pathways. Responding to this challenge, a novel method for deriving predicted no-effect concentration (PNEC) and probabilistic ecological risk assessment (PERAs) for DEHP based on long-term exposure to potentially sensitive species with appropriate apical endpoints was development for protection of Chinese surface waters. PNECs based on potencies to cause lesions in reproductive tissues of fishes, which ranged from 0.04 to 0.20 MUg DEHP L(-1), were significantly less than those derived based on other endpoints or other taxa, such as invertebrates. An assessment of risks posed by DEHP to aquatic organisms in surface waters of China showed that 88.17% and 78.85% of surface waters in China were predicted to pose risks to reproductive fitness of fishes with thresholds of protection for aquatic organisms based on 5% (HC5) and 10% (HC10), respectively. Assessment of risks of effects based on effects mediated by the HPG-axis should consider effects on chronic, non-lethal endpoints for specific taxa, especially for reproductive fitness of fishes. PMID- 26970875 TI - A critical review of engineered nanomaterial release data: Are current data useful for material flow modeling? AB - Material flow analysis (MFA) is a useful tool to predict the flows of engineered nanomaterials (ENM) to the environment. The quantification of release factors is a crucial part of MFA modeling. In the last years an increasing amount of literature on release of ENM from materials and products has been published. The purpose of this review is to analyze the strategies implemented by MFA models to include these release data, in particular to derive transfer coefficients (TC). Our scope was focused on those articles that analyzed the release from applications readily available in the market in settings that resemble average use conditions. Current MFA studies rely to a large extent on extrapolations, authors' assumptions, expert opinions and other informal sources of data to parameterize the models. We were able to qualitatively assess the following aspects of the release literature: (i) the initial characterization of ENM provided, (ii) quantitative information on the mass of ENM released and its characterization, (iii) description of transformation reactions and (iv) assessment of the factors determining release. Although the literature on ENM release is growing, coverage of exposure scenarios is still limited; only 20% of the ENMs used industrially and 36% of the product categories involved have been investigated in release studies and only few relevant release scenarios have been described. Furthermore, the information provided is rather incomplete concerning descriptions and characterizations of ENMs and the released materials. Our results show that both the development of methods to define the TCs and of protocols to enhance assessment of ENM release from nano-applications will contribute to increase the exploitability of the data provided for MFA models. The suggestions we provide in this article will likely contribute to an improved exposure modeling by providing ENM release estimates closer to reality. PMID- 26970876 TI - The impact of high-heeled shoes on ankle complex during walking in young women-In vivo kinematic study based on 3D to 2D registration technique. AB - OBJECTIVE: To explore the accurate in vivo kinematic changes in the ankle complex when wearing low- and high-heel shoes (LHS and HHS, respectively). MATERIALS AND METHODS: Twelve young women were tested unilaterally. Three-dimensional models of the tibia, talus, and calcaneus were first created based on CT scan results. The subjects walked at a self-controlled speed in barefoot, LHS (4cm), and HHS (10cm) conditions. A fluoroscopy system captured the lateral fluoroscopic images of the ankle complex. The images of seven key positions in the stance phase were selected, and 3D to 2D bone model registrations were performed to determine the joint positions. The mean of 6 degree of freedom (DOF) range of motions (ROM), joint positions, and angular displacements of the ankle complex during the gait were then obtained. RESULTS: For the talocrural joint, the rotational ROMs of the subjects either in LHS or HHS condition displayed no significant difference from those in barefoot condition. For the subtalar joint, all the rotational ROMs in the HHS condition and the internal/external rotations in the LHS condition significantly decreased compared with those in the barefoot condition. The talocrural joint was positioned significantly more plantarflexed, inverted, internally rotated, and posteriorly seated in all seven poses in HHS condition, compared with those in barefoot condition. CONCLUSION: HHS mainly affected the rotational motion of the ankle complex during walking. The talocrural joint position was abnormal, and the subtalar joint ROM decreased during the gait in HHS condition. Only a few kinematic changes occurred in LHS condition relative to the barefoot condition. PMID- 26970878 TI - Brain State-Dependent Transcranial Magnetic Closed-Loop Stimulation Controlled by Sensorimotor Desynchronization Induces Robust Increase of Corticospinal Excitability. AB - BACKGROUND: Desynchronization of sensorimotor rhythmic activity increases instantaneous corticospinal excitability, as indexed by amplitudes of motor evoked potentials (MEP) elicited by transcranial magnetic stimulation (TMS). The accumulative effect of cortical stimulation in conjunction with sensorimotor desynchronization is, however, unclear. OBJECTIVE: The aim of this study was to investigate the effects of repetitive pairing event-related desynchronization (ERD) with TMS of the precentral gyrus on corticospinal excitability. METHODS: Closed-loop single-pulse TMS was controlled by beta-band (16-22 Hz) ERD during motor-imagery of finger extension and applied within a brain-computer interface environment in eleven healthy subjects. The same number and pattern of stimuli were applied in a control group of eleven subjects during rest, i.e. independent of ERD. To probe for plasticity resistant to depotentiation, stimulation protocols were followed by a depotentiation task. RESULTS: Brain state-dependent application of approximately 300 TMS pulses during beta-ERD resulted in a significant increase of corticospinal excitability. By contrast, the identical stimulation pattern applied independent of beta-ERD in the control experiment resulted in a decrease of corticospinal excitability. These effects persisted beyond the period of stimulation and the depotentiation task. CONCLUSION: These results could be instrumental in developing new therapeutic approaches such as the application of closed-loop stimulation in the context of neurorehabilitation. PMID- 26970877 TI - Parental Attitudes, Beliefs, and Understanding of Anxiety (PABUA): Development and psychometric properties of a measure. AB - The Parental Attitudes, Beliefs, and Understanding of Anxiety (PABUA) was developed to assess parental beliefs about their child's anxiety, parents' perceived ability to cope with their child's anxiety and to help their child manage anxious symptoms, and to evaluate parents' understanding of various parenting strategies in response to their child's anxiety. The study evaluated the PABUA in mother-child dyads (N=192) seeking treatment for youth anxiety. Exploratory factor analysis yielded a three-factor solution and identified PABUA scales of Overprotection, Distress, and Approach (with Cronbach's alpha ranging from .67 to .83). Convergent and divergent validity of PABUA scales was supported by the pattern of associations with measures of experiential avoidance, beliefs related to children's anxiety, empathy, trait anxiety, and depressive symptoms; parent-reported family functioning; parent- and youth-reported anxiety severity; and parent-reported functional impairment (n=83). Results provide preliminary support for the PABUA as a measure of parental attitudes and beliefs about anxiety, and future studies that investigate this measure with large and diverse samples are encouraged. PMID- 26970879 TI - PAH metabolites in fish bile: From the Seine estuary to Iceland. AB - Polycyclic aromatic hydrocarbons (PAH) are environmental contaminants that pose significant risk to health of fish. The International Workshop on Integrated Assessment of Contaminant Impacts on the North Sea (ICON) provided the framework to investigate biomarker responses as well as contaminant concentrations side by side in marine ecosystems. Concentrations of the main PAH metabolites 1 hydroxypyrene, 1-hydroxyphenanthren and 3-hydroxybenzo(a)pyrene were determined in bile by HPLC with fluorescence detection. Fish species under investigation were dab (Limanda limanda), flounder (Platichthys flesus) and haddock (Melanogrammus aeglefinus). A contamination gradient was demonstrated from the low contaminated waters of Iceland and off-shore regions of the North Sea towards higher concentrations in coastal areas. Concentrations of PAH metabolites differed primarily according to sampling region and secondarily to species. PMID- 26970880 TI - Comparative sensitivity of aquatic invertebrate and vertebrate species to wastewater from an operational coal mine in central Queensland, Australia. AB - Coal excavation and refinement processes generate substantial volumes of contaminated effluent that may be detrimental to aquatic ecosystems. As such, understanding the impacts of coal mine water releases on aquatic animals and ecosystems is essential for effectively managing and protecting neighboring environments. Such information will ultimately be applied towards developing ongoing monitoring strategies that are protective of native wildlife. Despite intensive mining operations in Australia, few studies have documented toxicity associated with coal mine wastewater (CMW) on native species. To address existing knowledge gaps, we investigated acute toxicity (48-96h) using eight native invertebrate species and sub-chronic effects (2 week) using three vertebrate species following exposure to wastewater from two dams (CMW1 and CMW2) located at an open-cut coal mine licensed to discharge into the Fitzroy catchment (Queensland, Australia). Wastewater from these sites is characterized by elevated conductivity, pH, sulfates as well as relatively high total and dissolved metal(loid)s (including As, Al, B, Cu, Mn, Ni, Se and Zn). Acute exposures revealed cladocerans (Daphnia carinata) and planarians (Dugesia sp.) to be the most sensitive species, exhibiting significant mortality after 48 and 96h exposure to CMW2, respectively. Neither wastewater was found to elicit acute toxicity in vertebrates, but a range of sub-lethal morphological effects were observed following the sub-chronic exposures. The overall response pattern was characterized by decreased condition factor and hepatosomatic index in the fish Hypseleotris compressa and Pseudomugil signifier, and in Limnodynastes peronii tadpoles. Tadpoles were generally more sensitive compared to the two fish species. Differences in responses were observed amongst CMW1 and CMW2, which likely relates to differences in physico-chemical properties between sites. Our results have identified several candidate vertebrate and invertebrate species that show promise for ongoing monitoring of water quality and toxicity risk in Central Queensland, Australia. PMID- 26970881 TI - Developing a support vector machine based QSPR model for prediction of half-life of some herbicides. AB - The half-life (t1/2) of 58 herbicides were modeled by quantitative structure property relationship (QSPR) based molecular structure descriptors. After calculation and the screening of a large number of molecular descriptors, the most relevant those ones selected by stepwise multiple linear regression were used for developing linear and nonlinear models which developed by using multiple linear regression and support vector machine, respectively. Comparison between statistical parameters of linear and nonlinear models indicates the suitability of SVM over MLR model for predicting the half-life of herbicides. The statistical parameters of R(2) and standard error for training set of SVM model were; 0.96 and 0.087, respectively, and were 0.93 and 0.092 for the test set. The SVM model was evaluated by leave one out cross validation test, which its result indicates the robustness and predictability of the model. The established SVM model was used for predicting the half-life of other herbicides that are located in the applicability domain of model that were determined via leverage approach. The results of this study indicate that the relationship among selected molecular descriptors and herbicide's half-life is non-linear. These results emphases that the process of degradation of herbicides in the environment is very complex and can be affected by various environmental and structural features, therefore simple linear model cannot be able to successfully predict it. PMID- 26970883 TI - Personal Metabolism (PM) coupled with Life Cycle Assessment (LCA) model: Danish Case Study. AB - Sustainable and informed resource consumption is the key to make everyday living sustainable for entire populations. An intelligent and strategic way of addressing the challenges related with sustainable development of the everyday living of consumers is to identify consumption-determined hotspots in terms of environmental and health burdens, as well as resource consumptions. Analyzing consumer life styles in terms of consumption patterns in order to identify hotspots is hence the focus of this study. This is achieved by taking into account the entire value chain of the commodities consumed in the context of environmental and human health burdens, as well as resource consumptions. A systematic commodity consumption, commodity disposal, and life style survey of 1281 persons living in urbanized Danish areas was conducted. The findings of the survey showed new impact dimensions in terms of Personal Metabolism (PM) patterns of residents living in urbanized areas of Denmark. Extending the PM analysis with Life Cycle Assessment (LCA) provided a clear picture of the per capita environmental and human health burdens, as well as resource consumptions, and the exact origin hereof. A generic PM-LCA Model for all the 1281 persons was set-up in Gabi 6. The assessment results obtained applying the model on all 1281 personal consumption scenarios yielded the 1281 Personal Impact Profiles (PIPs). Consumption of food and energy (electricity and thermal energy) proved to be the primary impact sources of PM, followed by transport. The PIPs further revealed that behavioral factors (e.g. different diets, use of cars, household size) affect the profiles. Hence, behavioral changes are one means out of many that humanity will most likely have to rely on during the sustainable development process. The results of this study will help the Danish and other comparable populations to identify and prioritize the steps towards reducing their environmental, human health, and resource consumption burdens. PMID- 26970882 TI - Chronic ozone exposure alters the secondary metabolite profile, antioxidant potential, anti-inflammatory property, and quality of red pepper fruit from Capsicum baccatum. AB - Tropospheric ozone (O3) background concentrations have increased since pre industrial times, reaching phytotoxic concentrations in many regions globally. However, the effect of high O3 concentrations on quality of fruit and vegetables remains unknown. Here, we evaluated whether O3 pollution alters the quality of Capsicum baccatum peppers by changing the secondary compound profiles and biological activity of the fruit. C. baccatum pepper plants were exposed to ozone for 62 days in an open-top chamber at a mean O3 concentration of 171.6ug/m(3). Capsaicin levels decreased by 50% in the pericarp, but remained unchanged in the seeds. In contrast, the total carotenoid content increased by 52.8% in the pericarp. The content of total phenolic compounds increased by 17% in the pericarp. The total antioxidant potential decreased by 87% in seeds of O3-treated plants. The seeds contributed more than the pericarp to the total radical trapping antioxidant potential and total antioxidant reactivity. O3 treatment impaired the ferric-reducing antioxidant power of the seeds and reduced NO(*) scavenging activity in the pericarp. However, O3 treatment increased ferrous ion chelating activity and hydroxyl radical-scavenging activity in the pericarp. Our results confirm that O3 alters the secondary metabolite profile of C. baccatum pepper fruits and, consequently, their biological activity profile. PMID- 26970884 TI - Environmental health impacts of feeding crops to farmed fish. AB - Half of the seafood consumed globally now comes from aquaculture, or farmed seafood. Aquaculture therefore plays an increasingly important role in the global food system, the environment, and human health. Traditionally, aquaculture feed has contained high levels of wild fish, which is unsustainable for ocean ecosystems as demand grows. The aquaculture industry is shifting to crop-based feed ingredients, such as soy, to replace wild fish as a feed source and allow for continued industry growth. This shift fundamentally links seafood production to terrestrial agriculture, and multidisciplinary research is needed to understand the ecological and environmental health implications. We provide basic estimates of the agricultural resource use associated with producing the top five crops used in commercial aquaculture feed. Aquaculture's environmental footprint may now include nutrient and pesticide runoff from industrial crop production, and depending on where and how feed crops are produced, could be indirectly linked to associated negative health outcomes. We summarize key environmental health research on health effects associated with exposure to air, water, and soil contaminated by industrial crop production. Our review also finds that changes in the nutritional content of farmed seafood products due to altered feed composition could impact human nutrition. Based on our literature reviews and estimates of resource use, we present a conceptual framework describing the potential links between increasing use of crop-based ingredients in aquaculture and human health. Additional data and geographic sourcing information for crop based ingredients are needed to fully assess the environmental health implications of this trend. This is especially critical in the context of a food system that is using both aquatic and terrestrial resources at unsustainable rates. PMID- 26970885 TI - Multi-scale modeling of soft fibrous tissues based on proteoglycan mechanics. AB - Collagen in the form of fibers or fibrils is an essential source of strength and structural integrity in most organs of the human body. Recently, with the help of complex experimental setups, a paradigm change concerning the mechanical contribution of proteoglycans (PGs) took place. Accordingly, PG connections protect the surrounding collagen fibrils from over-stretching rather than transmitting load between them. In this paper, we describe the reported PG mechanics and incorporate it into a multi-scale model of soft fibrous tissues. To this end, a nano-to-micro model of a single collagen fiber is developed by taking the entropic-energetic transition on the collagen molecule level into account. The microscopic damage occurring inside the collagen fiber is elucidated by sliding of PGs as well as by over-stretched collagen molecules. Predictions of this two-constituent-damage model are compared to experimental data available in the literature. PMID- 26970886 TI - Locomotor stability and adaptation during perturbed walking across the adult female lifespan. AB - The aim of this work was to examine locomotor stability and adaptation across the adult female lifespan during perturbed walking on the treadmill. 11 young, 11 middle and 14 older-aged female adults (mean and SD: 25.5(2.1), 50.6(6.4) and 69.0(4.7) years old respectively) walked on a treadmill. We applied a sustained perturbation to the swing phase of the right leg for 18 consecutive gait cycles, followed by a step with the resistance unexpectedly removed, via an ankle strap connected to a break-and-release system. The margin of stability (MoS) at foot touchdown was calculated as the difference between the anterior boundary of the base of support (BoS) and extrapolated center of mass. Older participants showed lower MoS adaptation magnitude in the early adaptation phase (steps 1-3) compared to the young and middle-aged groups. However, in the late adaptation phase (steps 16-18) there were no significant differences in adaptation magnitude between the three age groups. After removing the resistance, all three age groups showed similar aftereffects (i.e. increased BoS). The current results suggest that in old age, the ability to recalibrate locomotion to control stability is preserved, but the rate of adaptive improvement in locomotor stability is diminished. PMID- 26970887 TI - The behavior of cancellous bone from quasi-static to dynamic strain rates with emphasis on the intermediate regime. AB - Previous studies, conducted using quasi-static and dynamic compression tests, have shown that the mechanical strength of cancellous bone is strain rate dependent. However, these studies have not included the intermediate strain rate (ISR) regime (1/s to 100/s), which is important since it is representative of the loading rates at which non-fatal injuries typically occur. In this study, 127 bovine bone specimens were compressed in 3 regimes spanning 8 distinct strain rates, from 0.001/s to 600/s, using three different devices: a conventional quasi static testing machine, a wedge-bar (WB) apparatus and a conventional split Hopkinson pressure bar (SHPB) implemented with a cone-in-tube (CiT) striker and a tandem momentum trap. Due to the large sample size, a new robust automated algorithm was developed with which the material properties, such as the apparent Young's modulus and the yield and ultimate values of stress and strain, were identified for each individual specimen. A statistical summary of the data is presented. Finally, this study demonstrates that results obtained at intermediate strain rates are essential for a fuller understanding of cancellous bone behavior by providing new data describing the transition between the quasi-static and dynamic regimes. PMID- 26970888 TI - Relationships between each part of the spinal curves and upright posture using Multiple stepwise linear regression analysis. AB - Back pain is a common reason for consultation in primary healthcare clinical practice, and has effects on daily activities and posture. Relationships between the whole spine and upright posture, however, remain unknown. The aim of this study was to identify the relationship between each spinal curve and centre of pressure position as well as velocity for healthy subjects. Twenty-one male subjects performed quiet stance in natural position. Each upright posture was then recorded using an optoelectronics system (Vicon Nexus) synchronized with two force plates. At each moment, polynomial interpolations of markers attached on the spine segment were used to compute cervical lordosis, thoracic kyphosis and lumbar lordosis angle curves. Mean of centre of pressure position and velocity was then computed. Multiple stepwise linear regression analysis showed that the position and velocity of centre of pressure associated with each part of the spinal curves were defined as best predictors of the lumbar lordosis angle (R(2)=0.45; p=1.65*10-10) and the thoracic kyphosis angle (R(2)=0.54; p=4.89*10 13) of healthy subjects in quiet stance. This study showed the relationships between each of cervical, thoracic, lumbar curvatures, and centre of pressure's fluctuation during free quiet standing using non-invasive full spinal curve exploration. PMID- 26970890 TI - Examining the "Killer K" of Diabetic Ketoacidosis at a Tertiary Care Hospital: An Exploratory Study. AB - OBJECTIVES: Hypokalemia, a frequently cited complication of diabetic ketoacidosis (DKA) treatment, can have critical implications, including arrhythmias and death. We assessed the prevalence of hypokalemia and its associated factors in patients with DKA at our tertiary-care centre and identified opportunities to improve care. METHODS: We conducted a retrospective chart review to establish the prevalence of hypokalemia in patients diagnosed with DKA between July 2012 and July 2013. A focused root-cause analysis was subsequently performed to identify Canadian Diabetes Association DKA clinical practice guideline deviations and preventable errors that resulted in significant hypokalemia (K<3.3 mmol/L) during the first 48 hours of management. Clinical and management details were reviewed to determine the type, preventability and root cause(s) of each error. RESULTS: We identified 40 cases of DKA during the study period. The overall prevalence of hypokalemia during DKA treatment was 38% (15/40), with 25% in type 1 and 56% in type 2 diabetes. Males were more likely to experience hypokalemia (87%), and 47% of hypokalemic incidents occurred in the first presentation of diabetes. All 10 cases of significant hypokalemia were reviewed. We identified 23 errors in 6 (60%) cases, of which 87% were deemed to be preventable. The most common errors were noncessation of insulin infusion during hypokalemia (60%), inadequate potassium supplementation (50%) and infrequent biochemical monitoring (50%). CONCLUSIONS: Hypokalemia occurs frequently during acute DKA management and is often preventable. Our findings suggest that interventions targeted at enhancing awareness of guidelines may reduce hypokalemia rates. PMID- 26970889 TI - Mechanical strength of aneurysmatic and dissected human thoracic aortas at different shear loading modes. AB - Rupture of aneurysms and acute dissection of the thoracic aorta are life threatening events which affect tens of thousands of people per year. The underlying mechanisms remain unclear and the aortic wall is known to lose its structural integrity, which in turn affects its mechanical response to the loading conditions. Hence, research on such aortic diseases is an important area in biomechanics. The present study investigates the mechanical properties of aneurysmatic and dissected human thoracic aortas via triaxial shear and uniaxial tensile testing with a focus on the former. In particular, ultimate stress values from triaxial shear tests in different orientations regarding the aorta's orthotropic microstructure, and from uniaxial tensile tests in radial, circumferential and longitudinal directions were determined. In total, 16 human thoracic aortas were investigated from which it is evident that the aortic media has much stronger resistance to rupture under 'out-of-plane' than under 'in plane' shear loadings. Under different shear loadings the aortic tissues revealed anisotropic failure properties with higher ultimate shear stresses and amounts of shear in the longitudinal than in the circumferential direction. Furthermore, the aortic media decreased its tensile strength as follows: circumferential direction >longitudinaldirection> radial direction. Anisotropic and nonlinear tissue properties are apparent from the experimental data. The results clearly showed interspecimen differences influenced by the anamnesis of the donors such as aortic diseases or connective tissue disorders, e.g., dissected specimens exhibited on average a markedly lower mechanical strength than aneurysmatic specimens. The rupture data based on the combination of triaxial shear and uniaxial extension testing are unique and build a good basis for developing a 3D failure criterion of diseased human thoracic aortic media. This is a step forward to more realistic modeling of mechanically induced tissue failure i.e. rupture of aneurysms or progression of aortic dissections. PMID- 26970891 TI - Structural identifiability analysis of a cardiovascular system model. AB - The six-chamber cardiovascular system model of Burkhoff and Tyberg has been used in several theoretical and experimental studies. However, this cardiovascular system model (and others derived from it) are not identifiable from any output set. In this work, two such cases of structural non-identifiability are first presented. These cases occur when the model output set only contains a single type of information (pressure or volume). A specific output set is thus chosen, mixing pressure and volume information and containing only a limited number of clinically available measurements. Then, by manipulating the model equations involving these outputs, it is demonstrated that the six-chamber cardiovascular system model is structurally globally identifiable. A further simplification is made, assuming known cardiac valve resistances. Because of the poor practical identifiability of these four parameters, this assumption is usual. Under this hypothesis, the six-chamber cardiovascular system model is structurally identifiable from an even smaller dataset. As a consequence, parameter values computed from limited but well-chosen datasets are theoretically unique. This means that the parameter identification procedure can safely be performed on the model from such a well-chosen dataset. Thus, the model may be considered suitable for use in diagnosis. PMID- 26970892 TI - Objectively quantifying walking ability in degenerative spinal disorder patients using sensor equipped smart shoes. AB - Lumbar spinal stenosis (LSS) is a condition associated with the degeneration of spinal disks in the lower back. A significant majority of the elderly population experiences LSS, and the number is expected to grow. The primary objective of medical treatment for LSS patients has focused on improving functional outcomes (e.g., walking ability) and thus, an accurate, objective, and inexpensive method to evaluate patients' functional levels is in great need. This paper aims to quantify the functional level of LSS patients by analyzing their clinical information and their walking ability from a 10 m self-paced walking test using a pair of sensorized shoes. Machine learning algorithms were used to estimate the Oswestry Disability Index, a clinically well-established functional outcome, from a total of 29 LSS patients. The estimated ODI scores showed a significant correlation to the reported ODI scores with a Pearson correlation coefficient (r) of 0.81 and p<3.5*10(-11). It was further shown that the data extracted from the sensorized shoes contribute most to the reported estimation results, and that the contribution of the clinical information was minimal. This study enables new research and clinical opportunities for monitoring the functional level of LSS patients in hospital and ambulatory settings. PMID- 26970894 TI - Intra-articular injection in patients with juvenile idiopathic arthritis: factors associated with a good response. AB - INTRODUCTION: Intra-articular injection of corticosteroids (IIC) for treatment of patients with juvenile idiopathic arthritis (JIA) is increasingly used in Pediatric Rheumatology. OBJECTIVES: To describe the clinical course of patients undergoing IIC in our Pediatric Rheumatology Unit. METHODS: Retrospective study of patients with JIA undergoing IIC from January 2008 to December 2012, with a minimum follow-up of six months after the injection. Good response to IIC was set as the presence of inactivity on the infiltrated joint by at least six months. RESULTS: Eighty-eight patients underwent a total of 165 IICs. Of these, 75% were girls and 35.2% had persistent oligoarticular JIA. The mean age at diagnosis was 6.8 years, and when IIC was carried out, 12.2 years. Regarding patients, younger age at diagnosis (p=0.037) and the occurrence of uveitis in the course of the disease (p=0.015) were associated with good response to IIC. From 165 IICs, 63% had a good response and joints remained inactive for a median of 18.1 months. The type of joint injection (p=0.001), lesser values stated in the overall visual analogue scale by the physician (p=0.015) and by parents/patient (p=0.01) have been associated with a good response to IIC. Nine adverse events (5.4%) were observed. CONCLUSION: In our study, more than half of the joints showed a good response to IIC. Younger patients at diagnosis and uveitis during the course of the disease had good response to IIC. Knees, wrists and elbows were the joints that best responded to IIC. IIC proved to be a safe procedure. PMID- 26970893 TI - Constitutional delay of puberty: presentation and inheritance pattern in 48 familial cases. AB - BACKGROUND: The mechanism that initiates the onset of puberty is largely unknown but the age of onset is mainly under genetic control and influenced by environmental factors including nutrition. Familial forms of constitutional delay of puberty (CDP) suggest the involvement of genetic factors. The purpose of this study is to describe the presentation and the mode of inheritance of CDP in a series of familial cases. METHODS: A retrospective, single center study was carried out over 10 years on 48 probands (14 girls and 34 boys) from 48 families seen for CDP with a familial component. RESULTS: Of the 48 probands, 46 (96 %) had at least one affected 1(st) degree relatives and 2 (4 %, 2 boys) had only 2(nd) degree relatives affected. In girls, 11 families (79 %) exhibited exclusive maternal inheritance, 1 (7 %) paternal inheritance and 2 (14 %) both maternal and paternal inheritance. In boys, 14 families (41 %) exhibited exclusive maternal inheritance, 12 (35 %) paternal inheritance and 8 (24 %) both maternal and paternal inheritance. In the boys with bilineal inheritance, the ages at onset of puberty (16 +/- 1.41 years) and at evaluation (16.05 +/- 2.47 years) were higher than in those with unilineal inheritance (15.25 +/- 0.35 and 15.1 +/- 0.42 years respectively), but the difference was not significant. CONCLUSIONS: In girls exclusive maternal inheritance seems to be the major mode of inheritance whereas for boys the mode of inheritance was almost equally maternal, paternal or bilineal. Clinical phenotype of boys with bilineal inheritance seems to be more severe, but the difference did not reach statistical significance, perhaps because of the small sample size. This greater severity of the phenotype in boys with bilineal inheritance is likely due to inheriting different puberty timing genes from each parent. Future research should be directed at identifying such genes. PMID- 26970895 TI - The metaphor that viruses are living is alive and well, but it is no more than a metaphor. AB - Virologists often use anthropomorphic metaphors to vividly describe the properties of viruses and this has led some virologists to claim that viruses are living microorganisms. The discovery of giant viruses that are larger and have a more complex genome than small bacteria has fostered the interpretation that viral factories, which are the compartments in virus-infected cells where the virus is being replicated, are able to transform themselves into a new type of living viral organism called a virocell. However, because of the widespread occurrence of horizontal gene transfer, endosymbiosis and hybridization in the evolution of viral genomes, it has not been possible to include metaphorical virocells in the so-called Tree of Life which itself is a metaphor. In the case of viruses that cause human diseases, the infection process is usually presented metaphorically as a war between host and virus and it is assumed that a virus such as the human immunodeficiency virus (HIV) is able to develop new strategies and mechanisms for escaping protective host immune responses. However, the ability of the virus to defeat the immune system is solely due to stochastic mutations arising from the error-prone activity of the viral enzyme reverse transcriptase. The following two types of metaphors will be distinguished: an intentionality metaphor commonly used for attributing goals and intentions to organisms and the living virus metaphor that considers viruses to be actually living organisms. PMID- 26970897 TI - An examination of population exposure to traffic related air pollution: Comparing spatially and temporally resolved estimates against long-term average exposures at the home location. AB - Air pollution in metropolitan areas is mainly caused by traffic emissions. This study presents the development of a model chain consisting of a transportation model, an emissions model, and atmospheric dispersion model, applied to dynamically evaluate individuals' exposure to air pollution by intersecting daily trajectories of individuals and hourly spatial variations of air pollution across the study domain. This dynamic approach is implemented in Montreal, Canada to highlight the advantages of the method for exposure analysis. The results for nitrogen dioxide (NO2), a marker of traffic related air pollution, reveal significant differences when relying on spatially and temporally resolved concentrations combined with individuals' daily trajectories compared to a long term average NO2 concentration at the home location. We observe that NO2 exposures based on trips and activity locations visited throughout the day were often more elevated than daily NO2 concentrations at the home location. The percentage of all individuals with a lower 24-hour daily average at home compared to their 24-hour mobility exposure is 89.6%, of which 31% of individuals increase their exposure by more than 10% by leaving the home. On average, individuals increased their exposure by 23-44% while commuting and conducting activities out of home (compared to the daily concentration at home), regardless of air quality at their home location. We conclude that our proposed dynamic modelling approach significantly improves the results of traditional methods that rely on a long term average concentration at the home location and we shed light on the importance of using individual daily trajectories to understand exposure. PMID- 26970898 TI - Interactions between CYP2E1, GSTZ1 and GSTT1 polymorphisms and exposure to drinking water trihalomethanes and their association with semen quality. AB - Trihalomethanes (THMs) have been reported to be associated with altered semen quality, and this association may be modified by inherited differences in cytochrome P450 (CYP2E1) and glutathione S-transferase (GSTZ1 and GSTT1), which metabolize THMs. We conducted a cross-sectional study to examine the interactions between CYP2E1, GSTZ1 and GSTT1 polymorphisms and exposure to THMs on semen quality among 401 men from the Reproductive Center of Tongji Hospital in Wuhan China. The baseline blood concentrations of four individual THMs, chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM) and bromoform (TBM), were measured as biomarkers of exposure to drinking water THMs. Genotypes were determined by real-time PCR, and semen-quality parameters were evaluated according to the World Health Organization guidelines. GSTT1 genotype significantly modified the association between exposure to Br-THMs (sum of BDCM, DBCM and TBM) and below-reference sperm motility (Pint=0.02). Men with above median blood Br-THM levels had an increased odds ratio (OR) of below-reference sperm compared to men with below-median blood Br-THM levels (OR=2.15, 95% CI: 1.11, 4.19) in the GSTT1 null genotype only. In addition, we found that men with a TT of CYP2E1 rs 915,906 had higher blood TCM and TTHM (sum of TCM, BDCM, DBCM and TBM) concentrations than men with a CT/CC of CYP2E1 rs 915,906. Our results suggest that GSTT1 polymorphisms modify Br-THM exposure relation with semen quality, and CYP2E1 polymorphisms are associated with internal levels of exposure to THMs. PMID- 26970899 TI - Comparative toxicities of selected rare earth elements: Sea urchin embryogenesis and fertilization damage with redox and cytogenetic effects. AB - BACKGROUND: Broad-ranging adverse effects are known for rare earth elements (REE), yet only a few studies tested the toxicity of several REE, prompting studies focusing on multi-parameter REE toxicity. METHODS: Trichloride salts of Y, La, Ce, Nd, Sm, Eu and Gd were tested in Paracentrotus lividus sea urchin embryos and sperm for: (1) developmental defects in either REE-exposed larvae or in the offspring of REE-exposed sperm; (2) fertilization success; (3) mitotic anomalies in REE-exposed embryos and in the offspring of REE-exposed sperm, and (4) reactive oxygen species (ROS) formation, and malondialdehyde (MDA) and nitric oxide (NO) levels. RESULTS: REEs affected P. lividus larvae with concentration related increase in developmental defects, 10(-6) to 10(-4)M, ranking as: Gd(III)>Y(III)>La(III)>Nd(III)?Eu(III)>Ce(III)?Sm(III). Nominal concentrations of REE salts were confirmed by inductively coupled plasma mass spectrometry (ICP MS). Significant increases in MDA levels, ROS formation, and NO levels were found in REE-exposed embryos. Sperm exposure to REEs (10(-5) to 10(-4)M) resulted in concentration-related decrease in fertilization success along with increase in offspring damage. Decreased mitotic activity and increased aberration rates were detected in REE-exposed embryos and in the offspring of REE-exposed sperm. CONCLUSION: REE-associated toxicity affecting embryogenesis, fertilization, cytogenetic and redox endpoints showed different activities of tested REEs. Damage to early life stages, along with redox and cytogenetic anomalies should be the focus of future REE toxicity studies. PMID- 26970896 TI - Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia. AB - BACKGROUND: Mixed lineage leukemia (MLL) gene translocations are found in ~75% infant and 10% adult acute leukemia, showing a poor prognosis. Lysine-specific demethylase 1 (LSD1) has recently been implicated to be a drug target for this subtype of leukemia. More studies using potent LSD1 inhibitors against MLL rearranged leukemia are needed. METHODS: LSD1 inhibitors were examined for their biochemical and biological activities against LSD1 and MLL-rearranged leukemia as well as other cancer cells. RESULTS: Potent LSD1 inhibitors with biochemical IC50 values of 9.8-77 nM were found to strongly inhibit proliferation of MLL rearranged leukemia cells with EC50 of 10-320 nM, while these compounds are generally non-cytotoxic to several other tumor cells. LSD1 inhibition increased histone H3 lysine 4 (H3K4) methylation, downregulated expression of several leukemia-relevant genes, induced apoptosis and differentiation, and inhibited self-renewal of stem-like leukemia cells. Moreover, LSD1 inhibitors worked synergistically with inhibition of DOT1L, a histone H3 lysine 79 (H3K79) methyltransferase, against MLL-rearranged leukemia. The most potent LSD1 inhibitor showed significant in vivo activity in a systemic mouse model of MLL rearranged leukemia without overt toxicities. Mechanistically, LSD1 inhibitors caused significant upregulation of several pathways that promote hematopoietic differentiation and apoptosis. CONCLUSIONS: LSD1 is a drug target for MLL rearranged leukemia, and LSD1 inhibitors are potential therapeutics for the malignancy. PMID- 26970901 TI - Urinary elimination kinetics of 3-hydroxybenzo(a)pyrene and 1-hydroxypyrene of workers in a prebake aluminum electrode production plant: Evaluation of diuresis correction methods for routine biological monitoring. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous carcinogenic pollutants emitted in complex mixtures in the ambient air and contribute to the incidence of human cancers. Taking into account all absorption routes, biomonitoring is more relevant than atmospheric measurements to health risk assessment, but knowledge about how to use biomarkers is essential. In this work, urinary elimination kinetic of 1-hydroxypyrene (1-OHP) and 3-hydroxybenzo(a)pyrene (3-OHBaP) were studied in six electrometallurgy workers after PAHs exposure. Spot samples were collected on pre- and post-shift of the last workday then the whole urinations were separately sampled during the weekend. Non-linear mixed effects models were built to study inter- and intra-individual variability of both urinary metabolites toxicokinetic and investigate diuresis correction ways. Comparison of models confirmed the diuresis correction requirement to perform urinary biomonitoring of pyrene and BaP exposure. Urinary creatinine was found as a better way than specific gravity to normalize urinary concentrations of 1-OHP and as a good compromise for 3-OHBaP. Maximum observed levels were 1.0 umol/mol creatinine and 0.8nmol/mol creatinine for 1-OHP and 3-OHBaP, respectively. Urinary 1-OHP concentrations on post-shift were higher than pre-shift for each subject, while 3-OHBaP levels were steady or decreased, and maximum urinary excretion rates of 3-OHBaP was delayed compared to 1-OHP. These results were consistent with the sampling time previously proposed for 3-OHBaP analysis, the next morning after exposure. Apparent urinary half-life of 1-OHP and 3-OHBaP ranged from 12.0h to 18.2h and from 4.8h to 49.5h, respectively. Finally, inter individual variability of 1-OHP half-life seemed linked with the cutaneous absorption extent during exposure, while calculation of 3-OHBaP half-life required the awareness of individual urinary background level. The toxicokinetic modeling described here is an efficient tool which could be used to describe elimination kinetic and determine diuresis correction way for any other urinary biomarkers of chemicals or metals exposure. PMID- 26970902 TI - Aged and Diseased Neurons Get Lost in Transport. AB - The maintenance of nucleocytoplasmic compartmentalization is essential for proper cellular function. Recent studies from the Gage and the Hipp labs report impairments in transport across the nuclear envelope in models of normal and pathological neuronal senescence, providing a mechanistic link between cerebral aging and neurodegenerative diseases. PMID- 26970900 TI - Maternal body burden of cadmium and offspring size at birth. AB - Increasing evidence suggests an inverse association between cadmium (Cd) and size at birth, potentially greatest among female neonates. We evaluated whether greater maternal body burden of Cd is associated with reduced neonatal anthropometry (birthweight, birth length, head circumference, and ponderal index) and assessed whether these associations differ by infant sex. The analytic sample for the present study (n=396) was derived from a subcohort of 750 women randomly drawn from among all participants (N=4344) in the Omega Study, a prospective pregnancy cohort. Creatinine-corrected Cd in maternal clean-catch spot urine samples (U-Cd) was quantified by inductively coupled plasma mass spectrometry. Continuous log2-transformed Cd (log2-Cd) and U-Cd tertiles (low<0.29MUg/g creatinine, middle 0.29-0.42MUg/g creatinine, high>=0.43MUg/g creatinine) were used in multivariable linear regression models. Females had reduced birth length with greater U-Cd tertile, whereas males birth length marginally increased [beta(95% CI) females: low=reference, middle=-0.59cm (-1.37, 0.19), high=-0.83cm (-1.69, 0.02), p-trend=0.08; males: low=reference, middle=0.18cm (-0.59, 0.95), high=0.78cm (-0.04, 1.60), p-trend=0.07; p for interaction=0.03]. The log2-Cd by infant sex interaction was statistically significant for ponderal index [p=0.003; beta(95% CI): female=0.25kg/m(3) (-0.20, 0.70); male=-0.63kg/m(3) (-1.01, -0.24)] and birth length [p<0.001; beta(95% CI): female=-0.47cm (-0.74, -0.20), male=0.32cm (0.00, 0.65)]. Our findings suggest potential sex-specific reversal of Cd's associations on birth length and contribute to the evidence suggesting Cd impairs fetal growth. PMID- 26970903 TI - Helicobacter pylori in bottled mineral water: genotyping and antimicrobial resistance properties. AB - BACKGROUND: Up to now, fecal-oral and oral-oral are the most commonly known routes for transmission of H. pylori, therefore, contaminated water can play an important role in transmission of H. pylori to humans. Genotyping using virulence markers of H. pylori is one of the best approaches to study the correlations between H. pylori isolates from different samples. The present research was carried out to study the vacA, cagA, cagE, oipA, iceA and babA2 genotyping and antimicrobial resistance properties of H. pylori isolated from the bottled mineral water samples of Iran. RESULTS: Of 450 samples studied, 8 samples (1.77%) were contaminated with H. pylori. Brand C of bottled mineral water had the highest prevalence of H. pylori (3.63%). The bottled mineral water samples of July month had the highest levels of H. pylori-contamination (50%). H. pylori strains had the highest levels of resistance against metronidazole (62.5%), erythromycin (62.5%), clarithromycin (62.5%), amoxicillin (62.5%) and trimethoprim (62.5%). Totally, 12.5% of strains were resistant to more than 6 antibiotics. VvacAs1a (100%), vacAm1a (87.5%), cagA (62.5%), iceA1 (62.5%), oipA (25%), babA2 (25%) and cagE (37.5%) were the most commonly detected genotypes. M1as1a (62.5%), m1as2 (37.5%), m2s2 (37.5%) and S1a/cagA+/IceA2/oipA-/babA2-/cagE (50%) were the most commonly detected combined genotypes. CONCLUSIONS: Contaminated bottled mineral water maybe the sources of virulent and resistant strains H. pylori. Careful monitoring of bottled mineral water production may reduce the risk of H. pylori transmission into the human population. PMID- 26970905 TI - The Effect of Impact Location on Force Transmission to the Modular Junctions of Dual-Taper Modular Hip Implants. AB - BACKGROUND: The purpose of this study was to investigate the effect that off-axis impaction has on stability of dual-taper modular implants as measured by forces delivered to and transmitted through the head-neck and neck-stem tapers, respectively. METHODS: One hundred forty-four impact tests were performed using 6 different directions: one on-axis and five 10 degrees off-axes. Four different simulations were performed measuring the head-neck only and 3 different neck angulations: 0 degrees , 8 degrees , and 15 degrees . A drop tower impactor delivered both on- and off-axis impaction from a constant height. Load cells positioned in the drop mass and at the head-neck (HN) or neck-stem (NS) junction measured the impact and joint forces, respectively. RESULTS: Impact force of the hammer on the head ranged from 3800-4500 N. Greatest impact force delivered to the head was typically with axial impact. However, greatest force transmission to the neck-stem junction was not necessarily with axial impacts. There was limited variability in the force measured at the NS junction for all impaction directions seen in the 8 degrees neck, whereas the 15 degrees neck had greater forces transmitted to the NS junction with off-axes impactions directed in the proximal and posterior-proximal directions. CONCLUSION: The location of the impact significantly influences the force transmitted to the head-neck and neck-stem junctions in dual-taper modular hip implants. Although axial impacts proved superior to off-axis impacts for the straight 0 degrees neck, greater force transmission with off-axis impacts for the angled necks suggests that off-axis impacts may potentially compromise the stability of dual-taper components. PMID- 26970904 TI - Respiratory influence on left atrial volume calculation with 3D-echocardiography. AB - BACKGROUND: Left atrial volume (LAV) estimation with 3D echocardiography has been shown to be more accurate than 2D volume calculation. However, little is known about the possible effect of respiratory movements on the accuracy of the measurement. METHODS: 100 consecutive patients admitted with chest pain were examined with 3D echocardiography and LAV was quantified during inspiratory breath hold, expiratory breath hold and during free breathing. RESULTS: Of the 100 patients, only 65 had an echocardiographic window that allowed for 3D echocardiography in the entire respiratory cycle. Mean atrial end diastolic volume was 45.4 +/- 14.5 during inspiratory breath hold, 46.4 +/- 14.8 during expiratory breath hold and 45.6 +/- 14.3 during free respiration. Mean end systolic volume was 17.6 +/- 7.8 during inspiratory breath hold, 18.8 +/- 8.0 during expiratory breath hold and 18.3 +/- 8.0 during free respiration. No significant differences were seen in any of the measured parameters. CONCLUSIONS: The present study adds to the feasibility of 3D LAV quantitation. LAV estimation by 3D echocardiography may be performed during either end-expiratory or end inspiratory breath-hold without any significant difference in the calculated volume. Also, the LAV estimation may be performed during free breathing. PMID- 26970906 TI - A review of inpatient ward location and the relationship to Medical Emergency Team calls. AB - OBJECTIVE: To identify the relationship between in-hospital location and patient outcomes as measured by Medical Emergency Team calls. STUDY DESIGN: A narrative systematic review of the literature. DATA SOURCES: A systematic search of the literature was conducted in October 2014 using the electronic databases: Embase, Cochrane, Medline, CINAHL, Science Direct and Google Scholar for the most recent literature from 1997 to 2014. INCLUSION CRITERIA: Non-randomised study designs such as case control or cohort studies were eligible. Articles were selected independently by two researchers using a predetermined selection criterion. DATA SYNTHESIS: The screening process removed manuscripts that did not meet the inclusion criteria resulting in an empty review with one manuscript meeting most of the criteria for inclusion. The protocol was revised to a narrative synthesis including a broader scope of studies. The search strategy was expanded and modified to include manuscripts of any study design that comprise both inlier and outlier patients. Two manuscripts were selected for the narrative synthesis. CONCLUSION: Two recently published studies investigated the incidence of MET calls for outlier patients, and whilst MET calls were increased in outlier hospital patients, definitive conclusions associated with patient outcomes cannot be made at this time due to paucity of studies. PMID- 26970907 TI - Emergency department crowding affects triage processes. AB - INTRODUCTION: During emergency department (ED) crowding there is an imbalance between the need for emergency care and available resources. We assessed the impact of crowding on the triage process. METHODS: A 1-year health records review of 49,539 patient visits was performed. Data extracted included: occupancy ratio, ED occupancy, demographics, length of stay (LOS), time to triage, triage score, years working as a triage nurse, and triage destination. Data were analyzed using descriptive statistics and regression analyses. RESULTS: During crowding, target times to triage elapsed more often than during non-crowding (49.7% vs. 24.9%, P <0.001), and more patients were not triaged (2.2% vs. 1.6%, P <0.001). A higher ED occupancy was associated with longer waiting times for triage and longer LOS (P <0.001). There were 12,627 (25.5%) patients redirected to the general practitioner cooperative (GPC). No association between level of crowdedness and number of patients who were redirected to the GPC was found (P = 0.122). Redirection to the GPC occurred significantly more often when the triage nurse had more years working as a triage nurse (P <0.001). CONCLUSION: At this hospital, crowding affects the triage process, leading to longer waiting times to triage and longer ED LOS. Crowding did not influence triage destination. PMID- 26970908 TI - An Alternative Bundle-to-Bundle Suturing Technique for Repairing Fresh Achilles Tendon Rupture. AB - The main concern about conventional Achilles tendon repair surgical techniques is how to maintain the initial strength of the ruptured Achilles tendon through complicated suturing methods. The primary surgical problem lies in the properties of the soft tissue; the deterioration of the Achilles tendon, especially in its elasticity; and the surface lubricity of the local tissues. In the present study, we describe an innovative bundle-to-bundle suturing method that addresses these potential problems. PMID- 26970910 TI - Single Oblique Incision for Simultaneous Open Reduction and Internal Fixation of the Posterior Malleolus and Anterior Syndesmosis. AB - Several surgical approaches to the posterior malleolus have been described. However, these approaches may make it difficult for fixation of associated lateral malleolar and anterior syndesmotic fractures. A single incision approach is described that allows safe access to the posterior malleolus while also facilitating access to the lateral malleolus and anterior syndesmosis. PMID- 26970909 TI - Sustainability of Forefoot Reconstruction for the Rheumatoid Foot. AB - Ninety percent of patients with rheumatoid arthritis will display foot and ankle pathologic features, including hallux valgus, lesser metatarsophalangeal (MTP) joint subluxation/dislocation, and hammertoe deformity. Recently, a trend has ensued toward joint preservation with distal metatarsal osteotomies and various bunion corrective procedures. However, the reference standard remains first MTP joint fusion, lesser metatarsal head resection, and lesser proximal interphalangeal joint fusion. The present retrospective study followed the results of 4 different surgeons who had performed the reference standard rheumatoid forefoot reconstruction from August 2008 to August 2012 on patients with rheumatoid arthritis. Radiographic and statistical analysis of the data from 20 patients determined an overall first MTP joint fusion rate of 90%, often occurring by 108 (range 64 to 202) days postoperatively. Radiographic nonunion occurred in 2 of the 20 patients (10%), although both were asymptomatic, with no revision necessary. Lesser digit deformity revision occurred in 1 patient (5%), and mild to moderate infection developed in 4 patients (20%). The radiographic and clinical follow-up period was 12 months. Our study found that this technique provides exceptional radiographic improvement, an acceptable time to fusion, a low reoperation rate, and minimal complications. In addition, correction of the deformity was maintained at 1 year postoperatively. In conclusion, first MTP joint fusion with lesser metatarsal head resection should remain the reference standard for surgical intervention of the rheumatoid foot. PMID- 26970911 TI - [Children facial asymmetry related to mandibular bone swelling]. PMID- 26970912 TI - Enhanced Recovery after Urological Surgery: A Contemporary Systematic Review of Outcomes, Key Elements, and Research Needs. AB - CONTEXT: Enhanced Recovery after Surgery (ERAS) programs are multimodal care pathways that aim to decrease intra-operative blood loss, decrease postoperative complications, and reduce recovery times. OBJECTIVE: To overview the use and key elements of ERAS pathways, and define needs for future clinical trials. EVIDENCE ACQUISITION: A comprehensive systematic MEDLINE search was performed for English language reports published before May 2015 using the terms "postoperative period," "postoperative care," "enhanced recovery after surgery," "enhanced recovery," "accelerated recovery," "fast track recovery," "recovery program," "recovery pathway", "ERAS," and "urology" or "cystectomy" or "urologic surgery." EVIDENCE SYNTHESIS: We identified 18 eligible articles. Patient counseling, physical conditioning, avoiding excessive alcohol and smoking, and good nutrition appeared to protect against postoperative complications. Fasting from solid food for only 6h and perioperative liquid-carbohydrate loading up to 2h prior to surgery appeared to be safe and reduced recovery times. Restricted, balanced, and goal-directed fluid replacement is effective when individualized, depending on patient morbidity and surgical procedure. Decreased intraoperative blood loss may be achieved by several measures. Deep vein thrombosis prophylaxis, antibiotic prophylaxis, and thermoregulation were found to help reduce postsurgical complications, as was a multimodal approach to postoperative nausea, vomiting, and analgesia. Chewing gum, prokinetic agents, oral laxatives, and an early resumption to normal diet appear to aid faster return to normal bowel function. Further studies should compare anesthetic protocols, refine analgesia, and evaluate the importance of robot-assisted surgery and the need/timing for drains and catheters. CONCLUSIONS: ERAS regimens are multidisciplinary, multimodal pathways that optimize postoperative recovery. PATIENT SUMMARY: This review provides an overview of the use and key elements of Enhanced Recovery after Surgery programs, which are multimodal, multidisciplinary care pathways that aim to optimize postoperative recovery. Additional conclusions include identifying effective procedures within Enhanced Recovery after Surgery programs and defining needs for future clinical trials. PMID- 26970914 TI - [Peer training for patients with diabetes mellitus 2. A quantitative and qualitative evaluation in the Basque Country and Andalusia]. AB - OBJECTIVE: To evaluate a peer training strategy for patients with type2 diabetes mellitus, developed in two training programmes in the Basque Country and Andalusia. DESIGN: Quantitative pre- and post-intervention and qualitative evaluation, developed between 2012 and 2014. PLACE: The Basque Country and Andalusia. PARTICIPANTS: A total of 409 patients and trainer-patients, participating in self-management peer training programmes. Intentional sample of 44 patients for the qualitative study. METHOD: Bivariate analysis and net gains for common variables used in questionnaires in the Basque Country and Andalusia: self-reported health, daily activities, physical activity, use of health services, and self-management. Content analysis of 8 focus groups with patients and trainer-patients, including: coding, categorisation, and triangulation of results. RESULTS: Peer training has a positive impact on physical activity, the use of health services, and self-management, with some gender differences. The peer-training strategy is considered positive, as it strengthens the patient health provider relationship, generates group support and self-confidence, and improves the emotional management. Patients identify two areas of potential improvement: access and continuity of training strategies, and more support and recognition from health providers and institutions. CONCLUSIONS: The positive impact on health and quality of life that this patient peer-training provides, requires the collaboration of health professionals and institutions, which should improve the access, continuity and adaptation to patient needs and expectations. PMID- 26970913 TI - Lymphatic endothelial cells efferent to inflamed joints produce iNOS and inhibit lymphatic vessel contraction and drainage in TNF-induced arthritis in mice. AB - BACKGROUND: In this study, we sought to determine the cellular source of inducible nitric oxide synthase (iNOS) induced in lymphatic endothelial cells (LECs) in response to tumor necrosis factor (TNF), the effects of iNOS on lymphatic smooth muscle cell (LSMC) function and on the development of arthritis in TNF-transgenic (TNF-Tg) mice, and whether iNOS inhibitors improve lymphatic function and reduce joint destruction in inflammatory erosive arthritis. METHODS: We used quantitative polymerase chain reactions, immunohistochemistry, histology, and near-infrared imaging to examine (1) iNOS expression in podoplanin + LECs and lymphatic vessels from wild-type (WT) and TNF-Tg mice, (2) iNOS induction by TNF in WT LECs, (3) the effects of iNOS inhibitors on expression of functional muscle genes in LSMCs, and (4) the effects of iNOS inhibitors on lymphatic vessel contraction and drainage, as well as the severity of arthritis, in TNF-Tg mice. RESULTS: LECs from TNF-Tg mice had eight fold higher iNOS messenger RNA levels than WT cells, and iNOS expression was confirmed immunohistochemically in podoplanin + LECs in lymphatic vessels from inflamed joints. TNF (0.1 ng/ml) increased iNOS levels 40-fold in LECs. LSMCs cocultured with LECs pretreated with TNF had reduced expression of functional muscle genes. This reduction was prevented by ferulic acid, which blocked nitric oxide production. Local injection of L-N(6)-(1-iminoethyl)lysine 5-tetrazole-amide into inflamed paws of TNF-Tg mice resulted in recovery of lymphatic vessel contractions and drainage. Treatment of TNF-Tg mice with ferulic acid reduced synovial inflammation as well as cartilage and bone erosion, and it also restored lymphatic contraction and drainage. CONCLUSIONS: iNOS is produced primarily by LECs in lymphatic vessel efferent from inflamed joints of TNF-Tg mice in response to TNF and inhibits LSMC contraction and lymph drainage. Ferulic acid represents a potential new therapy to restore lymphatic function and thus improve inflammatory arthritis by inhibiting local production of nitric oxide by LSMCs. PMID- 26970915 TI - In vitro influence of dietary protein and fructooligosaccharides on metabolism of canine fecal microbiota. AB - BACKGROUND: The present in vitro study investigated whether the utilization of fructooligosaccharides (FOS) may influence canine fecal microbial population in presence of diets differing in their protein content and digestibility. Fresh fecal samples were collected from five adult dogs, pooled, and incubated for 24 h with the undigested residue of three diets: 1, Low protein high digestibility diet (LP HD, crude protein (CP) 229 g/kg); 2, High protein high digestibility diet (HP HD, CP 304 g/kg); 3, High protein low digestibility diet (HP LD, CP 303 g/kg) that had been previously subjected to enzymatic digestion. In the in vitro fermentation study, there were six treatments: 1) LP HD; 2) HP HD 3) HP LD; 4) LP HD + FOS; 5) HP HD + FOS; 6) HP LD + FOS. Fructooligosaccharides were added at the final concentration of 1.5 g/L. Samples of fermentation fluid were collected at 6 and 24 h of incubation. RESULTS: Values of pH were reduced by FOS at 6 and 24 h (P < 0.001); conversely, low protein digestibility and high dietary protein level resulted in higher pH at both sampling times (P < 0.001). At 24 h, FOS lowered ammonia (-10%; P < 0.001) and resulted (P < 0.05) in higher concentrations of total volatile fatty acids (VFA) (+43%), acetic acid (+14%), propionic acid (+75%) and n-butyric acid (+372%). Conversely, at 24 h, low protein digestibility resulted (P < 0.01) in lower concentrations of acetic acid (-26%), propionic acid (-37%) and total VFA (-21%). Putrescine concentrations were increased at 6 and 24 h of fermentation by low protein digestibility (+21 and 22%, respectively; P < 0.05) and FOS (+18 and 24%, respectively; P < 0.01). After 24 h of fermentation, high dietary protein level resulted in lower counts of lactobacilli and enterococci (-0.5 and -0.7 log cells/mL, respectively; P < 0.05) whereas low protein digestibility tended to increase counts of C. perfringens (+0.2 log cells/mL; P = 0.07). CONCLUSIONS: Results from the present study showed that diets rich in protein may exert negative influences on the canine intestinal ecosystem, slightly increasing the presence of ammonia and reducing counts of lactobacilli and enterococci. Moreover, the presence of poorly digestible protein resulted in lower concentrations of VFA. Conversely, administration of FOS may improve metabolism of canine intestinal microbiota, reducing ammonia concentrations and enhancing VFA production. PMID- 26970916 TI - Do incident and recurrent venous thromboembolism risks truly differ between heterozygous and homozygous Factor V Leiden carriers? A retrospective cohort study. AB - INTRODUCTION: While Factor V Leiden (F5 rs6025 A allele) is a known venous thromboembolism (VTE) risk factor, VTE risk among heterozygous vs. homozygous carriers is uncertain. MATERIALS AND METHODS: In a retrospective cohort study of Mayo Clinic patients referred for genotyping between 1996 and 2013, we tested Factor V Leiden genotype as a risk factor for incident and recurrent VTE. RESULTS: Among heterozygous (n=268) and homozygous (n=111) carriers, the prevalence of VTE was 54% and 68%, respectively (p=0.016). While mean patient age at first VTE event (43.9 vs. 42.9years; p=0.70) did not differ significantly, median VTE-free survival was modestly shorter for homozygous carriers (56.8 vs 59.5 years; p=0.04). Sixty-nine (48%) and 31 (42%) heterozygous and homozygous carriers had >=1 VTE recurrence (p=0.42). In a multivariable model, idiopathic incident VTE and a second thrombophilia were associated with increased and anticoagulation duration >6months with reduced hazards of VTE recurrence; Factor V Leiden genotype was not an independent predictor of recurrence. CONCLUSIONS: Aside from a higher VTE prevalence and modestly reduced VTE-free survival, VTE penetrance and phenotype severity did not differ significantly among homozygous vs. heterozygous carriers, suggesting that VTE prophylaxis and management should not differ by Factor V Leiden genotype. PMID- 26970917 TI - The sudden death of Alaric I (c. 370-410AD), the vanquisher of Rome: A tale of malaria and lacking immunity. AB - BACKGROUND: Alaric I (c. 370-410AD), King of the Visigoths, sacked Rome for the second time in over eight centuries of history. Historians suggest that malaria, probably contracted either in Rome or in the Pontine Marshes, was responsible for his sudden death in Cosenza (Calabria) in the autumn of 410AD, where he was allegedly buried in the River Busento. In this article, we aim to examine this hypothesis through a full pathographic reassessment of the most likely cause of Alaric's demise. METHODS: To achieve this, we resorted to a dual philological medical approach: clinical likelihood and malaria seasonality coupled with primary historical sources (mainly Jordanes' work De origine actibusque Getarum) and the reconstruction of the itineraries followed by Alaric and his army after the sack of Rome. RESULTS: Sudden death is caused by several factors. The possibility that Alaric died of a cardiovascular disease was discarded since no description of potentially pathological signs emerged from the available sources. Given his lack of semi-immunity, falciparum malaria was considered as the most likely cause of his demise. It took him over two months to reach the coasts of Calabria during the peak of malaria's transmission (summer-autumn). During the march, Alaric did not suffer from recurrent fevers or other ailments, which would have been reported by historians. CONCLUSION: The scenario emerging from this multidisciplinary reanalysis allows us to hypothesise that Plasmodium falciparum malaria, contracted during his journey through Calabria, was the most likely candidate responsible for Alaric's unexpected demise. PMID- 26970918 TI - Factors influencing quality of sleep among non-mechanically ventilated patients in the Intensive Care Unit. AB - AIM: To investigate the self-reported quality of sleep of non-mechanically ventilated patients admitted to an ICU, and to identify barriers to sleep in this setting. METHOD: Patients admitted to the ICU of Frankston Hospital over a two month period who had spent at least one night in the ICU, and had not received mechanical ventilation were surveyed as they were discharged from the ICU. This survey required patients to rate the quality of their sleep in the ICU and at home immediately prior to hospitalisation on a 10cm visual analogue scale; and to identify perceived barriers to sleep in the ICU and at home prior to hospitalisation. RESULTS: 56 respondents were surveyed during the study period. Median age was 74 years (range=18-92 years); median ICU length of stay was 1 day (range=1-7 days). Overall, respondents rated their quality of sleep in ICU (median=4.9/10) as significantly worse than at home immediately prior to ICU admission (median=7.15/10; Z=-3.02, p<0.002); however 44% of respondents rated their quality of sleep in ICU as better, or no worse, than at home immediately prior to hospitalisation. Sub-group analysis revealed that among patients with reduced quality of sleep (<5/10) prior to hospitalisation, 71.4% rated their quality of sleep in ICU as better, or no worse, than at home prior to hospitalisation, with no significant difference between sleep quality ratings in ICU and at home (p=0.341). Respondents identified the following as barriers to sleep in the ICU: noise levels overnight (53.6%); discomfort (33.9%); pain (32.1%); being awoken for procedures (32%); being attached to medical devices (28.6%); stress/anxiety (26.8%); and light levels (23.2%). CONCLUSION: Pre hospitalisation sleep quality appears to be an important influence on sleep in ICU. Many barriers to sleep in the ICU identified by respondents are potentially modifiable. PMID- 26970919 TI - Evaluation of soluble fraction and enzymatic residual fraction of dilute dry acid, ethylenediamine, and steam explosion pretreated corn stover on the enzymatic hydrolysis of cellulose. AB - This study is aimed to examine the inhibition of soluble fraction (SF) and enzymatic residual fraction (ERF) in dry dilute acid (DDA), ethylenediamine (EDA) and steam explosion (SE) pretreated corn stover (CS) on the enzymatic digestibility of cellulose. SF of DDA, EDA and SE pretreated CS has high xylose, soluble lignin and xylo-oligomer content, respectively. SF of EDA pretreated CS leads to the highest inhibition, followed by SE and DDA pretreated CS. Inhibition of ERF of DDA and SE pretreated CS is higher than that of EDA pretreated CS. The inhibition degree (A0/A) of SF is 1.76 and 1.21 times to that of ERF for EDA and SE pretreated CS, respectively. The inhibition degree of ERF is 1.05 times to that of SF in DDA pretreated CS. The quantitative analysis shows that SF of EDA pretreated CS, SF and ERF of SE pretreated CS cause significant inhibition during enzymatic hydrolysis. PMID- 26970920 TI - Enzymatic hydrolysis of chitin pretreated by rapid depressurization from supercritical 1,1,1,2-tetrafluoroethane toward highly acetylated oligosaccharides. AB - The hydrolysis of chitin treated under supercritical conditions was successfully carried out using chitinases obtained by an optimized fermentation of the fungus Lecanicillium lecanii. The biopolymer was subjected to a pretreatment based on suspension in supercritical 1,1,1,2-tetrafluoroethane (scR134a), which possesses a critical temperature and pressure of 101 degrees C and 40bar, respectively, followed by rapid depressurization to atmospheric pressure and further fibrillation. This methodology was compared to control untreated chitins and chitin subjected to steam explosion showing improved production of reducing sugars (0.18mg/mL), enzymatic hydrolysis and high acetylation (FA of 0.45) in products with degrees of polymerization between 2 and 5. PMID- 26970921 TI - L-Lactic acid production by combined utilization of agricultural bioresources as renewable and economical substrates through batch and repeated-batch fermentation of Enterococcus faecalis RKY1. AB - Enterococcus faecalis RKY1 was used to produce l-lactic acid from hydrol, soybean curd residues (SCR), and malt. Hydrol was efficiently metabolized to l-lactic acid with optical purity of >97.5%, though hydrol contained mixed sugars such as glucose, maltose, maltotriose, and maltodextrin. Combined utilization of hydrol, SCR, and malt was enough to sustain lactic acid fermentation by E. faecalis RKY1. In order to reduce the amount of nitrogen sources and product inhibition, cell recycle repeated-batch fermentation was employed, where a high cell mass (26.3g/L) was obtained. Lactic acid productivity was improved by removal of lactic acid from fermentation broth by membrane filtration and by linearly increased cell density. When the total of 10 repeated-batch fermentations were carried out using 100g/L hydrol, 150g/L SCR hydrolyzate, and 20g/L malt hydrolyzate as the main nutrients, lactic acid productivity was increased significantly from 3.20g/L/h to 6.37g/L/h. PMID- 26970922 TI - Performance evaluation of a novel anaerobic-anoxic sludge blanket reactor for biological nutrient removal treating municipal wastewater. AB - A novel anaerobic-anoxic sludge blanket reactor, AnoxAn, unifies the non-aerated zones of the biological nutrient removal treatment train in a single upflow reactor, aimed at achieving high compactness and efficiency. The environmental conditions are vertically divided up inside the reactor with the anaerobic zone at the bottom and the anoxic zone above. This contribution presents the performance evaluation of the novel reactor in the removal of organic matter and nutrients from municipal wastewater, coupled with an aerobic hybrid MBR. The overall system achieved total nitrogen and phosphorus removal with average efficiencies of 75% and 89%, respectively. Separate anoxic and anaerobic conditions were maintained in AnoxAn, allowing anaerobic phosphate release and nearly complete anoxic denitrification in the single reactor operating with an HRT of 4.2h. Biomass was retained in the reactor achieving TSS concentration up to 10gL(-1) and partial hydrolysis of influent particulate organic matter. PMID- 26970923 TI - Sequential batch membrane bio-reactor for wastewater treatment: The effect of increased salinity. AB - In this work, a sequential batch membrane bioreactor pilot plant is investigated to analyze the effect of a gradual increase in salinity on carbon and nutrient removal, membrane fouling and biomass kinetic parameters. The salinity was increased by 2gNaClL(-1) per week up to 10gNaClL(-1). The total COD removal efficiency was quite high (93%) throughout the experiment. A gradual biomass acclimation to the salinity level was observed during the experiment, highlighting the good recovery capabilities of the system. Nitrification was also influenced by the increase in salinity, with a slight decrease in nitrification efficiency (the lowest value was obtained at 10gNaClL(-1) due to lower nitrifier activity). Irreversible cake deposition was the predominant fouling mechanism observed during the experiment. Respirometric tests exhibited a stress effect due to salinity, with a reduction in the respiration rates observed (from 8.85mgO2L( 1)h(-1) to 4mgO2L(-1)h(-1)). PMID- 26970924 TI - The effect of seasonal variation on biomethane production from seaweed and on application as a gaseous transport biofuel. AB - Biomethane produced from seaweed may be used as a transport biofuel. Seasonal variation will have an effect on this industry. Laminaria digitata, a typical Irish brown seaweed species, shows significant seasonal variation both in proximate, ultimate and biochemical composition. The characteristics in August were optimal with the lowest level of ash (20% of volatile solids), a C:N ratio of 32 and the highest specific methane yield measured at 327LCH4kgVS(-1), which was 72% of theoretical yield. The highest yield per mass collected of 53m(3)CH4t( 1) was achieved in August, which is 4.5 times higher than the lowest value, obtained in December. A seaweed cultivation area of 11,800ha would be required to satisfy the 2020 target for advanced biofuels in Ireland, of 1.25% renewable energy supply in transport (RES-T) based on the optimal gross energy yield obtained in August (200GJha(-1)yr(-1)). PMID- 26970925 TI - Recombinant endo-mannanase (ManB-1601) production using agro-industrial residues: Development of economical medium and application in oil extraction from copra. AB - Expression of pRSETA manb-1601 construct in Hi-Control Escherichia coli BL21 (DE3) cells improved recombinant endo-mannanase (ManB-1601) production by 2.73 fold (1821+/-100U/ml). A low-cost, agro-industrial residue supplemented industrial medium for enhanced and economical production of ManB-1601 was developed in two mutual phases. Phase-I revealed the potential of various pre- (induction time: 5h, induction mode: lactose 0.5mM) and post-induction [peptone supplementation: 0.94%(w/v), glycerol 0.123%(v/v)] parameters for enhanced production of ManB-1601 and resulted in 4.61-fold (8406+/-400U/ml) and 2.53-fold (3.30g/l) higher ManB-1601 and biomass production, respectively. Under phase-II, economization of phase-I medium was carried out by reducing/replacing costly ingredients with solubilized-defatted flax seed meal (S-DFSM), which resulted in 3.25-fold (5926U/ml) higher ManB-1601 production. Industrial potential of ManB 1601 was shown in oil extraction from copra as enzyme treatment led to cracks, peeling, fracturing and smoothening of copra, which facilitated higher (18.75%) oil yield. PMID- 26970926 TI - Temperature affects microbial abundance, activity and interactions in anaerobic digestion. AB - Temperature is a major factor determining the performance of the anaerobic digestion process. The microbial abundance, activity and interactional networks were investigated under a temperature gradient from 25 degrees C to 55 degrees C through amplicon sequencing, using 16S ribosomal RNA and 16S rRNA gene-based approaches. Comparative analysis of past accumulative elements presented by 16S rRNA gene-based analysis, and the in-situ conditions presented by 16S rRNA-based analysis, provided new insights concerning the identification of microbial functional roles and interactions. The daily methane production and total biogas production increased with temperature up to 50 degrees C, but decreased at 55 degrees C. Increased methanogenesis and hydrolysis at 50 degrees C were main factors causing higher methane production which was also closely related with more well-defined methanogenic and/or related modules with comprehensive interactions and increased functional orderliness referred to more microorganisms participating in interactions. This research demonstrated the importance of evaluating functional roles and interactions of microbial community. PMID- 26970927 TI - Removal of methyl acrylate by ceramic-packed biotrickling filter and their response to bacterial community. AB - Methyl acrylate is a widely used raw chemical materials and it is toxic in humans. In order to treat the methyl acrylate waste gas, a 3-layer BTF packed with ceramic particles and immobilized with activated sludge was set up. The BTF exhibited excellent removal efficiency that no methyl acrylate could be detected when EBRT was larger than 266s and inlet concentration was lower than 0.19g/m(3). The 1st layer performed the best at fixed inlet concentration of 0.42g/m(3). PCR combined with DGGE was performed to detect the differences in different layers of the BTF. Phylum Proteobacteria (e.g. alpha-, beta-, gamma-, delta-) was predominantly represented in the bacterial community, followed by Actinobacteria and Firmicutes. Desulfovibrio gigas, Variovorax paradoxus, Dokdonella koreensis, Pseudoxanthomonas suwonensis, Azorhizobium caulinodans, Hyphomicrobium denitrificans, Hyphomicrobium sp. and Comamonas testosteroni formed the bacteria community to treat methyl acrylate waste gas in the BTF. PMID- 26970928 TI - Screening mammography: Usefulness beyond early detection of breast cancer. PMID- 26970929 TI - GreenlightTM photovaporization of the prostate in patients under rivaroxaban: Lesson learned after the first cases. PMID- 26970930 TI - Incidental vaginal mullerianosis. AB - Mullerianosis is the term used to designate lesions composed of an admixture of two or three types of mullerian-derivation glands in heterotopic location. In this report, we describe a case of incidental vaginal mullerianosis in a 59-year old woman who underwent rectosigmoidectomy for rectal adenocarcinoma. In the vaginal cuff removed for neoplastic invasion, a separate multilocular mass measuring 1.5cm was found. The microscopic examination of the vaginal wall revealed endosalpingeal, endocervical and endometrial dilated or cystic glands with predominance of the endosalpingeal epithelium. Mullerian epithelium showed positivity for cytokeratins 7 and 8/18, high molecular weight cytokeratin, estrogen receptor alpha, and androgen receptor. The periglandular stroma was condensed and reactive for smooth-muscle actin, h-caldesmon, and CD10. To the best of our knowledge, a case of vaginal mullerianosis has not been previously reported. This lesion should be differentiated form vaginal adenosis and primary well-differentiated vaginal adenocarcinoma. The vagina should be added to the list of locations in which mullerianosis can be observed. PMID- 26970932 TI - Cytokines in the perinatal period - Part I. AB - Successful pregnancy requires a state of immune homeostasis. Maternal tolerance of the genetically distinct fetoplacental unit is in part mediated by maternal and fetal pro- and anti-inflammatory cytokines; these cytokines have also been implicated in different pregnancy-related pathologic states. This two-part series seeks to provide anesthesiologists with an overview on selected perinatal cytokines in an effort to identify opportunities for research and improvements in clinical care. In part one, we review basic and pregnancy-related elements of the immune system, with an emphasis on the role of cytokines. From this foundation, we offer a perspective of a unique phenomenon witnessed within obstetric anesthesia - maternal temperature elevation associated with labor epidural analgesia. PMID- 26970931 TI - Maternal Obesity Affects Inflammatory and Iron Indices in Umbilical Cord Blood. AB - OBJECTIVE: To determine the impact of maternal obesity and gestational weight gain across pregnancy on fetal indices of inflammation and iron status. STUDY DESIGN: Eighty-five healthy term newborns delivered via elective cesarean were categorized by 2 maternal body mass index (BMI) thresholds; above or below 30 kg/m(2) or above or below 35 kg/m(2). Umbilical cord plasma levels of C-reactive protein, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, ferritin, and hepcidin were assayed. Cytokines released by phytohemagglutinin-stimulated umbilical cord mononuclear cells (MNCs) were assayed. RESULTS: Maternal class II obesity, defined as BMI of 35 kg/m(2) and above, predicted higher C-reactive protein and TNF-alpha in umbilical cord plasma (P < .05 for both), and also proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) from stimulated MNC (P < .05 for all). The rise in plasma TNF-alpha and MNC TNF-alpha was not linear but occurred when the threshold of BMI 35 kg/m(2) was reached (P < .005, P < .06). Poorer umbilical cord iron indices were associated with maternal obesity. When ferritin was low, IL-6 was higher (P < .04), but this relationship was present primarily when maternal BMI exceeded 35 kg/m(2) (P < .03). Ferritin was correlated with hepcidin (P < .0001), but hepcidin was unrelated to either maternal BMI or inflammatory indices. CONCLUSIONS: Class II obesity and above during pregnancy is associated with fetal inflammation in a threshold fashion. Although maternal BMI negatively impacted fetal iron status, hepcidin, related to obesity in adults, was related to iron status and not obesity in fetuses. Pediatricians should be aware of these relationships. PMID- 26970933 TI - Recovery from hyponatremia in acute phase is associated with better in-hospital mortality rate in acute heart failure syndrome. AB - BACKGROUND: Although hyponatremia on admission is a predictor of poor prognosis in acute heart failure (AHF) patients, little is known about the association between changes in sodium level in acute phase and in-hospital mortality. This study was performed to clarify the impact of sodium level improvement in the early phase on prognosis in AHF patients. METHODS: A total of 882 consecutive hospitalized AHF patients were retrospectively enrolled in this study. Sodium levels were evaluated on days 1 and 3 of admission, and patients were classified into three groups: patients with hyponatremia on admission and day 3 (hypo-hypo group); patients with hyponatremia on admission and normonatremia on day 3 (hypo normo group); and patients with normonatremia on admission (normo group). RESULTS: Hyponatremia (sodium <=135 mEq/L) was observed in 14.3% of cases. In multivariate linear regression analysis, age (standardized beta=0.084), male gender (standardized beta=-0.072), history of ischemic heart disease (standardized beta=-0.069), baseline sodium level (standardized beta=-0.435), and tolvaptan use (standardized beta=0.093) were independent determinants of changes in sodium level from day 1 to day 3. In-hospital mortality rates were significantly higher in the hypo-hypo group (23.7%) and hypo-normo group (9.7%) than the normo group (6.9%) (p<0.001). After adjustment for covariates, both hypo normo (OR: 0.28, 95% CI: 0.08-0.93, p=0.038) and normo (OR: 0.42, 95% CI: 0.20 0.88, p=0.022) groups showed significantly lower in-hospital mortality rates than the hypo-hypo group. CONCLUSION: Early recovery from hyponatremia in AHF patients is associated with lower in-hospital mortality rate. PMID- 26970934 TI - Sex differences in the association between serum uric acid and cardiac mortality in Asian patients with established coronary artery disease: A revisit of the ET CHD registry in Taiwan, 1997-2003. PMID- 26970935 TI - Glioblastoma following treatment with fingolimod for relapsing-remitting multiple sclerosis. AB - Glioblastoma is an uncommon and aggressive primary brain tumor with incidence of 3 per 100,000 annually. We report a 50-year-old woman diagnosed with glioblastoma within threeyears of induction of fingolimod therapy for relapsing-remitting multiple sclerosis. Fingolimod, an immunomodulating agent used in the treatment of relapsing-remitting multiple sclerosis, has also been suggested to impart a cardioprotective role in heart failure and arrhythmia via activation of P21 activated kinase-1 (Pak1). In the brain, Pak1 activation has been shown to correlate with decreased survival time amongst patients with glioblastoma. A molecular mechanism underlying a link between fingolimod use and glioblastoma development may involve activation of Pak1. To our knowledge, this is the first report of a potential association between fingolimod use and glioblastoma development. PMID- 26970937 TI - [Sleep disorders and addictions: Impact on quality of life and relapse vulnerability]. AB - There is a bidirectional association between sleep disorders and addiction. Sleep problems negatively impact the quality of life of subjects with addictions (psychological state, pain perception, drug use). Sleep disorders are associated with a higher risk of relapse among sujects with addiction. The association between sleep disorders and relapse may be related to poor quality of life or to a higher level of craving. Maintaining abstinence and reducing craving episodes among subjects with addiction is the first-line treatment to reduce sleep disorders. Specific interventions focused on sleep disorders are needed when sleep disorders persist during abstinence and may improve global addiction outcome. PMID- 26970936 TI - [Potentiation strategies]. AB - Lithium is among the most classically recommended add-on therapeutic strategy for the management of depressive patients showing unsuccessful response to standard antidepressant medications. The effectiveness of the add-on strategy with lithium requires achieving plasma levels above 0.5 mEq/L. Mood-stabilizing antiepileptic drugs such as carbamazepine, valproate derivatives or lamotrigine have not demonstrated conclusive therapeutic effects for the management of depressive patients showing unsuccessful response to standard antidepressant medications. Thyroid hormones are considered among the currently recommended add-on therapeutic strategy for the management of depressive patients showing unsuccessful response to standard antidepressant medications. The effectiveness of the add-on strategy with thyroid hormones requires achieving plasma concentration of TSH close to the lower limits at the normal range (0.4 MUUI/L) or even below it. Second-generation antipsychotics such as aripiprazole or quetiapine have consistently demonstrated significant therapeutic effects for the management of depressive patients showing unsuccessful response to standard antidepressant medications. Second-generation antipsychotics however require the careful monitoring of both cardiovascular and metabolic adverse effects. PMID- 26970939 TI - [Roadmap for therapeutic strategies of treatment resistant depression]. PMID- 26970938 TI - [How to define treatment-resistant depression?]. AB - The most largely used definition of the treatment-resistant depression relies on the failure of two successive trials of antidepressant treatment at an adequate dose and duration. The absence of response to previous antidepressant treatments should be assessed using specific and appropriate clinical instruments enabling a correct staging of the therapeutic resistance. A wide range of socio-demographic and clinical factors (i.e. psychiatric/somatic comorbidities) are classically associated with the therapeutic resistance. The aim of the treatment of major depression is to achieve a complete clinical remission. The presence of residual symptoms increases the risk for the subsequent occurrence of relapses and recurrences, hence facilitating the development of therapeutic resistance. The treatment-resistant depression has a deleterious impact on the social, familial or professional functioning, thereby leading to an impaired quality of life with serious socioeconomic consequences and costs. PMID- 26970940 TI - Equine anaesthesia-associated mortality: where are we now? AB - OBJECTIVES: To review the literature concerning mortality associated with general anaesthesia in horses and to assess whether there is evidence for a reduction in mortality over the 20 years since the Confidential Enquiry into Perioperative Equine Fatalities (CEPEF). DATABASES USED: PubMed, Scopus, Google Scholar. Search terms used: horse; pony; equine; anaesthesia; anesthesia; recovery; morbidity, and mortality. CONCLUSIONS: The most recent studies, in which isoflurane and sevoflurane have been more commonly used for anaesthesia maintenance, report fewer intraoperative cardiac arrests than older studies in which halothane was favoured. Catastrophic fractures, however, have become the greatest cause of recovery-associated mortality. PMID- 26970941 TI - Recovery From Acute Kidney Injury and CKD Following Heart Transplantation in Children, Adolescents, and Young Adults: A Retrospective Cohort Study. AB - BACKGROUND: Acute kidney injury (AKI) is common in children following surgery for congenital heart disease and has been associated with poor long-term kidney outcomes. Children undergoing heart transplantation may be at increased risk for the development of both AKI and chronic kidney disease (CKD). This study examines AKI rates in children, adolescents, and young adults after heart transplantation and analyzes the relationship between AKI and CKD in this population. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 88 young patients who underwent heart transplantation at Lucile Packard Children's Hospital, Stanford, CA, September 1, 2007, to November 30, 2013. PREDICTOR: The primary independent variable was AKI within the first 7 postoperative days, ascertained according to the KDIGO (Kidney Disease: Improving Global Outcomes) creatinine criteria (increase in serum creatinine >= 1.5 times baseline within 7 days). OUTCOMES: Recovery from AKI at 3 months, ascertained as serum creatinine level < 1.5 times baseline; and development of CKD at 6 and 12 months, ascertained as estimated glomerular filtration rate < 60mL/min/1.73m(2) for more than 3 months. RESULTS: 63 (72%) patients developed AKI; 57% had moderate (stage 2 or severe stage 3) disease. Recovery occurred in 39 of 63 (62%), 50% for stage 2 or 3 versus 78% for stage 1 (P=0.04). At 6 and 12 months, 3 of 82 (4%) and 4 of 76 (5%) developed CKD, respectively. At both time points, CKD was more common in those without recovery (3/22 [14%] vs 0/38 (0%); P=0.04, and 3/17 (18%) vs (0/34) 0%; P=0.03, respectively). LIMITATIONS: Retrospective design, small sample size, and single center nature of the study. CONCLUSIONS: AKI is common after heart transplantation in children, adolescents, and young adults. Nonrecovery from AKI is more common in patients with more severe AKI and is associated with the development of CKD during the first year. PMID- 26970942 TI - Music-induced changes in functional cerebral asymmetries. AB - After decades of research, it remains unclear whether emotion lateralization occurs because one hemisphere is dominant for processing the emotional content of the stimuli, or whether emotional stimuli activate lateralised networks associated with the subjective emotional experience. By using emotion-induction procedures, we investigated the effect of listening to happy and sad music on three well-established lateralization tasks. In a prestudy, Mozart's piano sonata (K. 448) and Beethoven's Moonlight Sonata were rated as the most happy and sad excerpts, respectively. Participants listened to either one emotional excerpt, or sat in silence before completing an emotional chimeric faces task (Experiment 1), visual line bisection task (Experiment 2) and a dichotic listening task (Experiment 3 and 4). Listening to happy music resulted in a reduced right hemispheric bias in facial emotion recognition (Experiment 1) and visuospatial attention (Experiment 2) and increased left hemispheric bias in language lateralization (Experiments 3 and 4). Although Experiments 1-3 revealed an increased positive emotional state after listening to happy music, mediation analyses revealed that the effect on hemispheric asymmetries was not mediated by music-induced emotional changes. The direct effect of music listening on lateralization was investigated in Experiment 4 in which tempo of the happy excerpt was manipulated by controlling for other acoustic features. However, the results of Experiment 4 made it rather unlikely that tempo is the critical cue accounting for the effects. We conclude that listening to music can affect functional cerebral asymmetries in well-established emotional and cognitive laterality tasks, independent of music-induced changes in the emotion state. PMID- 26970943 TI - Uncertain relational reasoning in the parietal cortex. AB - The psychology of reasoning is currently transitioning from the study of deductive inferences under certainty to inferences that have degrees of uncertainty in both their premises and conclusions; however, only a few studies have explored the cortical basis of uncertain reasoning. Using transcranial magnetic stimulation (TMS), we show that areas in the right superior parietal lobe (rSPL) are necessary for solving spatial relational reasoning problems under conditions of uncertainty. Twenty-four participants had to decide whether a single presented order of objects agreed with a given set of indeterminate premises that could be interpreted in more than one way. During the presentation of the order, 10-Hz TMS was applied over the rSPL or a sham control site. Right SPL TMS during the inference phase disrupted performance in uncertain relational reasoning. Moreover, we found differences in the error rates between preferred mental models, alternative models, and inconsistent models. Our results suggest that different mechanisms are involved when people reason spatially and evaluate different kinds of uncertain conclusions. PMID- 26970944 TI - On the ability of CuAbeta1-x peptides to form ternary complexes: Neurotransmitter glutamate is a competitor while not a ternary partner. AB - In the light of conflicting reports on the ability of copper(II) complexes of amyloid beta (Abeta) peptides to form ternary complexes with small molecules co present in the biological milieu, we performed a study of coordination equilibria in the system containing Cu(II) ions, the Abeta1-16 peptide, glutamic acid and 4 (2-hydroxyethyl)-1-piperazineethanesulfonic acid (2-[4-(2-hydroxyethyl)piperazin 1-yl]ethanesulfonic acid, HEPES) buffer. Using potentiometry, isothermal titration calorimetry (ITC), UV-visible spectroscopy and EPR, we concluded that glutamic acid was not able to form such a ternary complex, but can efficiently compete for the Cu(II) ion with the Abeta peptide at Glu concentrations relevant for the synaptic cleft. We also found that the literature constants for Cu(II) complexes with Glu were overestimated, but this effect was partially compensated by the formation of a ternary Cu(Glu)(HEPES) complex. Our results indicate that small molecules co-present with Cu(II) ions and Abeta peptides in the synaptic cleft are not very likely to enhance Cu(II)/Abeta interactions, but instead should be considered as a Cu(II) buffering system that may help prevent these interactions and participate in Cu(II) clearance from the synaptic cleft. PMID- 26970945 TI - 4-Azidobenzyl ferrocenylcarbamate as an anticancer prodrug activated under reductive conditions. AB - Aminoferrocene-based prodrugs are activated in the presence of cancer-specific amounts of reactive oxygen species, e.g. H2O2, with the formation of products of two types: Fe-containing complexes, which catalyze generation of HO and O2(-), and quinone methides, which alkylate glutathione and inhibit the antioxidative system of the cell. Both processes act synergistically by increasing the oxidative stress in cancer cells thereby leading to their death. However, in the activation step including the cleavage of a B-C bond one molecule of H2O2 is consumed that counteracts the desired effect of the products released from aminoferrocenes. We replaced an H2O2-sensitive trigger in original prodrugs with an azide group. This trigger is slowly reduced in the presence of glutathione with the formation of an unstable arylamine intermediate, which decomposes with the release of iron ions and iminoquinone methides. These products induce strong oxidative stress in cells as we confirmed using 2',7'-dichlorodihydrofluorescin diacetate reagent in combination with flow cytometry. In this case the activation process does not consume H2O2. Correspondingly, we observed that the azide containing prodrug is substantially more toxic towards human promyelocytic leukemia cell line HL-60 (IC50=27+/-4MUM) than its H2O2-responsive analogue (IC50>50MUM). PMID- 26970946 TI - Comparison of psychomotor outcome in patients with perinatal asphyxia with versus without therapeutic hypothermia at 4 years using the Ages and Stages Questionnaire screening tool. AB - INTRODUCTION: Therapeutic hypothermia improves outcome after perinatal asphyxia. The Ages and Stages Questionnaire is a screening tool to detect neurodevelopmental delay. In this study we examined the outcome of patients with perinatal asphyxia (defined as Apgar score <5 at 10 min, or continued need for resuscitation, or pH < 7.00 in umbilical cord or within one hour after birth) with and without therapeutic hypothermia treatment at the age of four years. METHODS: Cohort study of patients with perinatal asphyxia admitted to the Neonatal Intensive Care Units of the VU University Medical Center, Amsterdam and the Wilhelmina Children's Hospital, Utrecht in the year 2008. Parents were asked to fill out the 48 months Ages and Stages Questionnaire (ASQ). In Wilhelmina Children's Hospital treatment with therapeutic hypothermia was implemented in 2008, in the VU University Medical Center in 2009, providing a historical cohort. RESULTS/DISCUSSION: Twenty-three questionnaires were evaluated. Response rate of questionnaires for the VU Medical Center was 63% (n = 10) and Wilhelmina's Childrens Hospital 93% (n = 13). No significant differences were found in the mean scores between both groups. However, the untreated group scored more frequently under the -2 SD threshold. In the fine motor skills domain the difference was statistically significant (p = 0.031). In the treated group no patients developed cerebral palsy and in the untreated group two patients developed cerebral palsy. CONCLUSION: In this study patients treated with hypothermia tend to have a better neurodevelopmental outcome. No significant differences were found between the two groups, apart from the fine motor skills. PMID- 26970947 TI - RARS2 mutations cause early onset epileptic encephalopathy without ponto cerebellar hypoplasia. AB - INTRODUCTION: Early onset epileptic encephalopathies (EOEEs) are a group of devastating diseases, manifesting in the first year of life with frequent seizures and/or prominent interictal epileptiform discharges on the electroencephalogram, developmental delay or regression and usually a poor prognosis. There are numerous causes for EOEEs making the diagnostic workup time consuming and costly. METHODS: We describe two siblings with fatal EOEE, profound global developmental delay and post-natal microcephaly that underwent extensive biochemical and metabolic workup in vain. Neuro-imaging disclosed non-specific progressive cerebral atrophy. RESULTS: Whole-exome sequencing (WES) disclosed compound heterozygous mutations in the gene encoding for mitochondrial arginyl transfer RNA synthetase, RARS2. This gene has been previously described as the cause of pontocerebellar hypoplasia type 6. CONCLUSION: We suggest that RARS2 gene mutations can cause a metabolic neurodegenerative disease manifesting primarily as EOEE with post-natal microcephaly, without the distinctive radiological features of pontocerebellar hypoplasia. PMID- 26970948 TI - Involvement of TRPV1 channels in the activity of the cannabinoid WIN 55,212-2 in an acute rat model of temporal lobe epilepsy. AB - The exogenous cannabinoid agonist WIN 55,212-2, (R)-(+)-[2,3-dihydro-5-methyl-3 (4-morpholinylmethyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-Yl]-1 naphthalenylmethanone (WIN), has revealed to play a role on modulating the hyperexcitability phenomena in the hippocampus. Cannabinoid-mediated mechanisms of neuroprotection have recently been found to imply the modulation of transient receptor potential vanilloid 1 (TRPV1), a cationic channel subfamily that regulate synaptic excitation. In our study, we assessed the influence of pharmacological manipulation of TRPV1 function, alone and on WIN antiepileptic activity, in the Maximal Dentate Activation (MDA) acute model of temporal lobe epilepsy. Our results showed that the TRPV1 agonist, capsaicin, increased epileptic outcomes; whilst antagonizing TRPV1 with capsazepine exerts a protective role on paroxysmal discharge. When capsaicin is co-administered with WIN effective dose of 10mg/kg is able to reduce its antiepileptic strength, especially on the triggering of MDA response. Accordingly, capsazepine at the protective dose of 2mg/kg managed to potentiate WIN antiepileptic effects, when co-treated. Moreover, WIN subeffective dose of 5mg/kg was turned into effective when capsazepine comes into play. This evidence suggests that systemic administration of TRPV1-active drugs influences electrically induced epilepsy, with a noticeable protective activity for capsazepine. Furthermore, results from the pharmacological interaction with WIN support an interplay between cannabinoid and TRPV1 signaling that could represent a promising approach for a future pharmacological strategy to challenge hyperexcitability-based diseases. PMID- 26970950 TI - Myocardial Infarction in the Presence of a Right Bundle Branch Block. PMID- 26970951 TI - Mismatch Repair and Colon Cancer: Mechanisms and Therapies Explored. AB - Colorectal cancer (CRC) remains one of the most prevalent cancers worldwide. In sporadic CRC, mutations frequently occur in the DNA mismatch repair (MMR) pathway. In addition, germline MMR mutations have been linked to Lynch syndrome, the most common form of hereditary CRC. Although genetic mutations, diet, inflammation, and the gut microbiota can influence CRC, it is unclear how MMR deficiency relates to these factors to modulate disease. In this review, the association of MMR to the etiology of CRC is examined, particularly in the context of microRNAs (miRNAs), inflammation, and the microbiome. We also discuss the most current targeted therapies, methods of prevention, and molecular biomarkers against MMR-deficient CRC, all of which are encouraging advancements in the field. PMID- 26970949 TI - Imaging increased glutamate in children with Sturge-Weber syndrome: Association with epilepsy severity. AB - BACKGROUND: Sturge-Weber syndrome (SWS) is strongly associated with epilepsy. Brain tissue studies have suggested that epileptic activity in SWS is driven by glutamatergic synaptic activity. Here, we used proton magnetic resonance spectroscopic imaging (MRSI) to test if glutamate (GLU) concentrations are increased in the affected hemisphere and if such increases are associated with severity of epilepsy in children with SWS. We also studied the metabolic correlates of MRSI abnormalities, using glucose positron emission tomography (PET) imaging. METHODS: 3T MRI and glucose PET were performed in 10 children (age: 7-78 months) with unilateral SWS and a history of epilepsy. MRSI data were acquired from the affected (ipsilateral) and non-affected (contralateral) hemispheres. GLU, N-acetyl-aspartate (NAA) and creatine (Cr) were quantified in multiple voxels; GLU/Cr and NAA/Cr ratios were calculated and compared to seizure frequency as well as glucose PET findings. RESULTS: The highest GLU/Cr ratios were found in the affected hemisphere in all children except one with severe atrophy. The maximum ipsilateral/contralateral GLU/Cr ratios ranged between 1.0 and 2.5 (mean: 1.6). Mean ipsilateral/contralateral GLU/Cr ratios were highest in the youngest children and showed a strong positive correlation with clinical seizure frequency scores assessed at the time of the scan (r=0.88, p=0.001) and also at follow-up (up to 1 year, r=0.80, p=0.009). GLU increases in the affected hemisphere coincided with areas showing current or previous increases of glucose metabolism on PET in 5 children. NAA/Cr ratios showed no association with clinical seizure frequency. CONCLUSIONS: Increased glutamate concentrations in the affected hemisphere, measured by MRSI, are common in young children with unilateral SWS and are associated with frequent seizures. The findings lend support to the role of excess glutamate in SWS-associated epilepsy. PMID- 26970953 TI - Predictive analysis of chitosan-based nanocomposite biopolymers elastic properties at nano- and microscale. AB - Chitosan nanocomposites mechanical properties play a major role in usage of such materials for specific areas of application, mostly in medicine and development of ecologically-friendly production. Computer-based predictive modelling of such composites will reduce costs of their development. In this paper, a multiscale approach for structural characterization and evaluation of mechanical properties is proposed based on hybrid coarse-grained/all atom molecular dynamics. Chitosan films and fibers are constructed and studied in silico as well as chitosan composites with different types of randomly distributed reinforcing fillers (graphene nanoparticles, graphene oxide nanoparticles, carbon nanotubes, chitin nanoparticles). Young's moduli are found for such composites, degrees of improvement of mechanical properties and size effects within the framework of proposed methodology are discussed. PMID- 26970952 TI - Examination of a neural cross-over effect using resting mechanomyographic mean frequency from the vastus lateralis muscle in different resting positions following aerobic exercise. AB - PURPOSE: To evaluate the potential neural cross-over effect between the vastus lateralis muscles in different postural resting positions. METHODS: Subjects exercised on an upright cycle ergometer, using only their dominate leg, for 2 min at 30 % VO2 peak. Following this warm-up, subjects then cycled (still using only their dominant leg) for 30 min at 60 % VO2 peak. After the aerobic phase, subjects cooled down (again, using only their dominant leg) for 2 min at 30 % VO2 peak. Resting mechanomyography mean frequency was measured prior to and following aerobic exercise. RESULTS: There was an approximate 6.3 +/- 6.8 and a 10 +/- 5.1 % increase (upright sitting position with the subject's knee joint angle fixed at 180 degrees ); an approximate 7 +/- 6.6 and a 16.1 +/- 6.5 % increase (upright sitting position with the subject's knee joint angle fixed at 90 degrees ); an approximate 0.5 +/- 6.8 and 3.7 +/- 5.6 % increase (lying supine position with the subject's knee joint angle fixed at 180 degrees ); and an approximately 2 +/- 8.3 and 2.5 +/- 8.6 % increase (lying supine position with the subject's knee joint angle fixed at 90 degrees ) in normalized mechanomyography mean frequency after aerobic exercise for the dominant and non-dominate vastus lateralis muscles, respectfully. CONCLUSION: There appears to be a statistically significant neural cross-over effect for the vastus lateralis muscle, during three of the four postural resting positions, with the non-dominant vastus lateralis muscle having a greater increase in mechanomyography mean frequency. PMID- 26970954 TI - Evaluation of modern DFT functionals and G3n-RAD composite methods in the modelization of organic singlet diradicals. AB - The evaluation of four high-level composite methods based on the modification of Gaussian-3 (G3) theory for radicals and 18 exchange-correlation density functionals, including modern long-range and dispersion-corrected functionals, in the modelization of singlet diradicals has been performed in this work. Structural parameters and properties such as singlet-triplet gaps, electron affinities, ionization potentials, dipole moments, enthalpies of formation, and bond dissociation energies have been calculated in a set of six well characterized singlet diradicals, and benchmarked against experimental data and wavefunction-based CASSCF/CASPT2 calculations. The complexity of the open-shell singlet ground state is revealed in the difficulties to properly represent the diradical character reported by some DFT functionals, specially those that do not comprise a certain amount of Hartree-Fock exchange in their formulation. We find that STGs, EAs, dipole moments, and thermochemical properties are, in general, satisfactorily calculated, while for IPs larger deviations with respect to the experiments are found in all cases. The best overall performance is accounted for by hybrid functionals, including some of the long-range corrected functionals, but also pure functionals, comprising the kinetic energy density in their formulation, are found to be competent. Composite methods perform satisfactorily, especially G3(MP2)-RAD and G3X(MP2)-RAD, which calculate singlet-triplet gaps and electron affinities more accurately. On the other hand, G3-RAD and G3X-RAD provide better ionization potentials. This study emphasizes that the use of recently developed functionals, within the broken symmetry approximation, is an appropriate tool for the simulation of organic singlet diradicals, with similar accuracy compared to more expensive composite methods. Nevertheless, suitable selection of the methodology is still crucial for the accomplishment of accurate results. PMID- 26970956 TI - Dynamic computed tomography findings of an accessory spleen in the pelvis: a case report. AB - We report the case of a 60-year-old man with an accessory spleen in the pelvis. He visited our outpatient clinic because of abdominal discomfort. Computed tomography (CT) showed an enhanced mass (40 mm in diameter) in the pelvis. Preoperative diagnosis was difficult even after magnetic resonance imaging and colonoscopy. The patient underwent surgery for suspicion of a gastrointestinal stromal tumor or malignant lymphoma of the rectum. Intraoperative findings showed a mass in the pelvis and a long cord-like tissue reaching the mass and arising from the great omentum; the mass was excised. Histopathologic examination indicated that the mass was splenic tissue, and feeding vessels were found in the cord-like tissue, which were determined to be derived from the left gastroepiploic artery and vein. Thus, we diagnosed it as an accessory spleen in the pelvis. An accessory spleen is not rare and can occur anywhere in the abdominal cavity. However, an accessory spleen in the pelvis is an infrequent finding, and only 9 other cases of an accessory spleen in the pelvis have been reported. Therefore, it is very difficult to make a correct diagnosis preoperatively. However, 7 of the 9 cases (77.8 %) of a pelvic accessory spleen had vascular pedicles from the great omentum or splenic hilum as feeding vessels; hence, determining the feeding blood vessels on dynamic CT may be useful for diagnosing an accessory spleen in the pelvis. Additionally, if the accessory spleen is symptomatic or has a vascular pedicle, surgeons should attempt to resect the accessory spleen in the pelvis using minimally invasive laparoscopy. PMID- 26970955 TI - CXCL12 is a key regulator in tumor microenvironment of cervical cancer: an in vitro study. AB - CXCL12 is a small pro-inflammatory chemo-attractant cytokine which signals through chemokine receptor CXCR4. The importance of CXCL12/CXCR4 axis is coming to the fore in several divergent signaling pathway-initiating signals related to cell survival and/or proliferation and cancer metastasis. In the present study we have investigated whether deregulation in CXCR4 signaling (as a consequence of deregulated expression of CXCL12) modulate the metastatic potential of cervical carcinoma cells. We demonstrate that CXCL12 is frequently down regulated and its promoter is hypermethylated in cervical cancer cell lines and primary tumor biopsies. Exogenous treatment of cervical cancer cell lines (HeLa, SiHa and C 33A) with recombinant CXCL12 inhibited the metastasis promoting cell migration, cell invasion and anchorage independent cell growth events. Although this study will need further in vivo validation, our observations suggest that (a) silencing of CXCL12 in cervical cancer cells may be critical in migration and invasion, the key events in cancer cell metastases; (b) cervical cancer cells having down regulated CXCL12 are more prone to being attracted to CXCL12 expressed at secondary sites of metastases; and (c) CXCL12 inhibits anchorage independent cell growth via anoikis. These findings suggest the tumor suppressor functions of CXCL12 in cervical cancer. PMID- 26970957 TI - Demographic, clinical, psychosocial, and environmental correlates of objectively assessed physical activity among breast cancer survivors. AB - PURPOSE: The aim of this study was to identify demographic, clinical, psychosocial, and environmental correlates of objectively assessed physical activity among breast cancer survivors. METHODS: Baseline data were utilized from 574 female breast cancer survivors who participated in three different intervention studies: Resistance and Endurance exercise After ChemoTherapy (REACT), Exercise and Nutrition Routine Improving Cancer Health (ENRICH), and Move More for Life (MM4L). Participants were eligible if they were aged >=18 years and had completed primary cancer treatment. Physical activity was objectively assessed by accelerometers or pedometers. Participants completed self reported questionnaires on demographic, psychosocial, and environmental factors. Information regarding clinical factors was obtained from medical records or patient self-report. Multivariable linear regression analyses were applied on the pooled dataset to identify factors that were significantly correlated with physical activity. In addition, the explained variance of the model was calculated. RESULTS: The multivariable regression model revealed that older age, (beta = -0.01, 95 %CI = -0.02; -0.003), higher body mass index (beta = -0.05, 95 %CI = -0.06; -0.03), lower self-efficacy (beta = 0.2, 95 %CI = 0.08; 0.2), and less social support (beta = 0.1, 95 %CI = 0.05; 0.2) were significantly correlated with lower physical activity. This model explained 15 % of the variance in physical activity. CONCLUSION: Age, body mass index, self-efficacy, and social support were significantly correlated with objectively assessed physical activity in breast cancer survivors. It may therefore be recommended that physical activity intervention studies in these women target those who are older, and have a higher body mass index, and should operationalize behavior change strategies designed to enhance self-efficacy and social support. TRIAL REGISTRATION: The REACT study is registered at the Netherlands Trial Register [NTR2153]. The ENRICH study is registered at Australian New Zealand Clinical Trials Register [ANZCTRN12609001086257]. And the MM4L study is registered at Australian New Zealand Clinical Trials Register [ACTRN12611001061921]. PMID- 26970958 TI - A Retrospective Cohort Study Comparing Utilization and Costs of Biologic Therapies and JAK Inhibitor Therapy Across Four Common Inflammatory Indications in Adult US Managed Care Patients. AB - INTRODUCTION: Biologic therapies are used to treat several inflammatory diseases, including rheumatoid arthritis (RA), psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Data from a commercial claims database were used to evaluate utilization and cost of biologic treatment for these conditions. METHODS: Data were obtained from the Optum Research Database. Patients were aged 18-63 years with diagnosis of moderate to severe RA, PsO, PsA, and/or AS and first (index) claim for biologics abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab, or ustekinumab or non biologic tofacitinib between March 1, 2011 and February 28, 2013. One-year treatment costs were based on observed paid amounts and used to impute dosing. Treatment patterns (persistence, switching, discontinuing, restarting) were evaluated. RESULTS: Data from 20,159 patients were analyzed for index medications abatacept (n = 583), adalimumab (n = 6521), certolizumab pegol (n = 415), etanercept (n = 9116), golimumab (n = 231), infliximab (n = 1906), rituximab (n = 295), tocilizumab (n = 165), ustekinumab (n = 922), and tofacitinib (n = 5). For patients with RA only, costs were lowest for tofacitinib ($18,769), rituximab ($19,569), or abatacept ($21,877), and ranged from $23,682 to $30,269 for all other medications. For patients with PsO only, costs were lowest for adalimumab ($29,186), etanercept ($31,212), and infliximab ($32,409) compared with ustekinumab ($53,746). For patients with PsA only, costs were lowest for etanercept ($26,916), followed by golimumab ($27,987), adalimumab ($28,749), and infliximab ($31,974). Costs were lowest with etanercept for RA plus PsA ($25,477) and for PsO plus PsA ($29,376), and with golimumab for AS only ($24,225). Across indications, annual costs were $29,521, $27,488, and $28,672 for adalimumab, etanercept, and infliximab, respectively; persistence was greatest with infliximab (range 66-79%) compared with 11-59% for all other biologics. CONCLUSION: One-year treatment costs varied considerably between medications and indications. Some newly approved agents had lower costs but further research is needed to confirm these estimates as more patients are treated. FUNDING: Immunex (a wholly owned subsidiary of Amgen Inc.) and Wyeth (acquired by Pfizer). PMID- 26970960 TI - Successful epicardial ablation of ventricular tachycardia in a patient with arrhythmogenic right ventricular cardiomyopathy. PMID- 26970961 TI - Are there mild forms of Takotsubo syndrome? PMID- 26970962 TI - Ultrasound Accelerated Thrombolysis in patients with acute pulmonary embolism: A systematic review and proportion meta-analysis. PMID- 26970959 TI - Impaired skeletal muscle vasodilation during exercise in heart failure with preserved ejection fraction. AB - BACKGROUND: Exercise intolerance is a hallmark symptom of heart failure patients with preserved ejection fraction (HFpEF), which may be related to an impaired ability to appropriately increase blood flow to the exercising muscle. METHODS: We evaluated leg blood flow (LBF, ultrasound Doppler), heart rate (HR), stroke volume (SV), cardiac output (CO), and mean arterial blood pressure (MAP, photoplethysmography) during dynamic, single leg knee-extensor (KE) exercise in HFpEF patients (n=21; 68 +/- 2 yrs) and healthy controls (n=20; 71 +/- 2 yrs). RESULTS: HFpEF patients exhibited a marked attrition during KE exercise, with only 60% able to complete the exercise protocol. In participants who completed all exercise intensities (0-5-10-15 W; HFpEF, n=13; Controls, n=16), LBF was not different at 0 W and 5 W, but was 15-25% lower in HFpEF compared to controls at 10 W and 15 W (P<0.001). Likewise, leg vascular conductance (LVC), an index of vasodilation, was not different at 0 W and 5 W, but was 15-20% lower in HFpEF compared to controls at 10 W and 15 W (P<0.05). In contrast to these peripheral deficits, exercise-induced changes in central variables (HR, SV, CO), as well as MAP, were similar between groups. CONCLUSIONS: These data reveal a marked reduction in LBF and LVC in HFpEF patients during exercise that cannot be attributed to a disease-related alteration in central hemodynamics, suggesting that impaired vasodilation in the exercising skeletal muscle vasculature may play a key role in the exercise intolerance associated with this patient population. PMID- 26970963 TI - Cause of death in adults with congenital heart disease - An analysis of the German National Register for Congenital Heart Defects. AB - BACKGROUND: Due to the great advances in the care of patients with congenital heart disease (CHD), mortality has decreased significantly over the last decades. Nonetheless, mortality for adults with congenital heart disease (ACHD) is still higher than for the general population. An analysis regarding causes of death in a nationwide contemporary cohort of ACHD is lacking. METHODS: A well characterized cohort of the German National Register for Congenital Heart Defects was screened for patients over the age of 18 years who died between January 2001 and January 2015. Data relating to the cardiac diagnosis, symptoms, operations, interventions, comorbidities, and causes of death were analyzed. RESULTS: During a median follow-up of 3.67 years (IQR 1.32-9.41), 239 (9.2%) out of 2596 patients died during the study period (110 female (46%), mean age at death 39.8 +/- 17.8 years). The majority of these deaths was CHD-related (171 patients (71.5%)). Leading causes of death were heart failure (n=66, 27.6%), and sudden cardiac death (n=55, 23.0%). Deceased patients had a more complex CHD and more extracardiac comorbidities compared with living patients. CONCLUSIONS: Causes of death of ACHD patients in a large contemporary cohort from a national register are in the majority still CHD-related, with heart failure being the leading cause of death. Additionally, extracardiac comorbidities gain increasing importance. PMID- 26970965 TI - Genetic progression of malignant melanoma. AB - Malignant melanoma of the skin is the most aggressive human cancer given that a primary tumor a few millimeters in diameter frequently has full metastatic competence. In view of that, revealing the genetic background of this potential may also help to better understand tumor dissemination in general. Genomic analyses have established the molecular classification of melanoma based on the most frequent driver oncogenic mutations (BRAF, NRAS, KIT) and have also revealed a long list of rare events, including mutations and amplifications as well as genetic microheterogeneity. At the moment, it is unclear whether any of these rare events have role in the metastasis initiation process since the major drivers do not have such a role. During lymphatic and hematogenous dissemination, the clonal selection process is evidently reflected by differences in oncogenic drivers in the metastases versus the primary tumor. Clonal selection is also evident during lymphatic progression, though the genetic background of this immunoselection is less clear. Genomic analyses of metastases identified further genetic alterations, some of which may correspond to metastasis maintenance genes. The natural genetic progression of melanoma can be modified by targeted (BRAF or MEK inhibitor) or immunotherapies. Some of the rare events in primary tumors may result in primary resistance, while further new genetic lesions develop during the acquired resistance to both targeted and immunotherapies. Only a few genetic lesions of the primary tumor are constant during natural or therapy modulated progression. EGFR4 and NMDAR2 mutations, MITF and MET amplifications and PTEN loss can be considered as metastasis drivers. Furthermore, BRAF and MITF amplifications as well as PTEN loss are also responsible for resistance to targeted therapies, whereas NRAS mutation is the only founder genetic lesion showing any association with sensitivity to immunotherapies. Unfortunately, there are hardly any data on the possible organ-specific metastatic drivers in melanoma. These observations suggest that clinical management of melanoma patients must rely on the genetic analysis of the metastatic lesions to be able to monitor progression-associated changes and to personalize therapies. PMID- 26970966 TI - Risk of second cancers in the era of modern radiation therapy: does the risk/benefit analysis overcome theoretical models? AB - In the era of modern radiation therapy, the compromise between the reductions in deterministic radiation-induced toxicities through highly conformal devices may be impacting the stochastic risk of second malignancies. We reviewed the clinical literature and evolving theoretical models evaluating the impact of intensity modulated radiation therapy (IMRT) on the risk of second cancers, as a consequence of the increase in volumes of normal tissues receiving low doses. The risk increase (if any) is not as high as theoretical models have predicted in adults. Moreover, the increase in out-of-field radiation doses with IMRT could be counterbalanced by the decrease in volumes receiving high doses. Clinical studies with short follow-up have not corroborated the hypothesis that IMRT would drastically increase the incidence of second cancers. In children, the risk of radiation-induced carcinogenesis increases from low doses and consequently the relative risk of second cancers after IMRT could be higher than in adults, justifying current developments of proton therapy with priority given to this population. Although only longer follow-up will allow a true assessment of the real impact of these modern techniques on radiation-induced carcinogenesis, a comprehensive risk-adapted strategy will help minimize the probability of second cancers. PMID- 26970964 TI - Provisional vs. two-stent technique for unprotected left main coronary artery disease after ten years follow up: A propensity matched analysis. AB - AIMS: There is uncertainty on which stenting approach confers the best long-term outlook for unprotected left main (ULM) bifurcation disease. METHODS AND RESULTS: This is a non-randomized, retrospective study including all consecutive patients with 50% stenosis of the left main involving at least 1 of the arteries stemming from the left main treated with drug-eluting stents (DES) in 9 European centers between 2002 and 2004. Patients were divided into two groups: those treated with provisional stentings vs. those treated with two stent strategy. The outcomes of interest were 10-year rates of target lesion revascularization (TLR), major adverse cardiac events (MACE), and their components (cardiovascular death, myocardial infarction [MI], or repeat revascularization), along with stent thrombosis (ST). A total of 285 patients were included, 178 (62.5%) in the provisional stenting group and 87 (37.5%) in the two stent group. After 10 years, no differences in TLR were found at unadjusted analysis (19% vs 25%, p>0.05) nor after propensity score matching (25% vs 28%, p>0.05). Similar rates of MACE (60% vs 66%, p>0.05), death (34% vs 43%, p>0.05), MI (9% vs 14%, p>0.05) and ST were also disclosed at propensity-based analysis. CONCLUSION: Even after 10 year follow-up, patients treated with provisional stenting on left main showed comparable rates of target lesion revascularization compared to two stent strategy. PMID- 26970967 TI - Personalized treatment of advanced non-small-cell lung cancer in routine clinical practice. AB - Personalized treatment of patients with advanced non-small-cell lung cancer based on clinical and molecular tumor features has entered clinical routine practice. The 2015 pathological classification of lung cancer mandates immunohistochemical and molecular analysis. Therapeutic strategies focused on inhibition of angiogenesis and growth factor receptor signaling. Inhibitors of angiogenesis and monoclonal antibodies directed against the epidermal growth factor receptor have shown efficacy in combination with chemotherapy. Mutations in the epidermal growth factor receptor and anaplastic lymphoma kinase have become clinically relevant therapeutic targets. Immune checkpoint inhibitors are also entering routine clinical practice. Identification of predictive biomarkers is essential and faces several challenges including tumor heterogeneity and dynamic changes of tumor features over time. Liquid biopsies may overcome some of these challenges in the future. PMID- 26970968 TI - miR clusters target cellular functional complexes by defining their degree of regulatory freedom. AB - Using the two paralog miR-23~27~24 clusters as an example and combining experimental and clinical data in a systematical approach to microRNA (miR) function and dysregulation, a complex picture of their roles in cancer is drawn. Various findings appear to be contradictory to a larger extent and cannot be fully explained by the classical regulatory network models and feedback loops that are mainly considered by one-to-one regulatory interactions of the involved molecules. Here, we propose an extended model of the regulatory role of miRs that, at least, supplements the usually considered single/oligo-target regulation of certain miRs. The cellular availability of the participating miR members in this model reflects an upper hierarchy level of intracellular and extracellular environmental influences, such as neighboring cells, soluble factors, hypoxia, chemotherapeutic drugs, and irradiation, among others. The novel model is based on the understanding of cellular functional complexes, such as for apoptosis, migration, and proliferation. These complexes consist of many regulatory components that can be targeted by miR cluster members to a different extent but may affect the functional complex in different ways. We propose that the final miR-related effect is a result of the possible degree of regulatory freedom provided by the miR effects on the whole functional complex structure. This degree of regulatory freedom defines to which extent the cellular functional complex can react in response to regulatory triggers, also understood as sensitization (more regulatory response options) or de-sensitization (less regulatory response options) of the system rather than single molecules. PMID- 26970971 TI - Evaluation of desho grass (Pennisetum pedicellatum) hay as a basal diet for growing local sheep in Ethiopia. AB - The study was conducted to determine feed intake, digestibility, and body weight (BW) change of Washera sheep fed on desho grass and natural pasture hay as a basal diet and supplemented with concentrate mixtures. Twenty-five intact male sheeps with body weight of 19.4 +/- 1.89 kg (mean +/- SD) were used in randomized complete block design. The dietary treatments were 100% natural pasture hay (NPH) (T1), 75% NPH + 25% desho grass hay (DGH) (T2), 50% NPH + 50% DGH (T3), 25% NPH + 75% DGH (T4), and 100% DGH (T5). Equal amount of concentrate mixture (CM) (300 g DM/day/h) was supplemented in all of the five treatments. The result of laboratory chemical analysis revealed that the CP content of the basal diets increased with increased proportion of desho grass hay inclusion in the treatments at the expense of natural pasture hay. Total DM, OM, CP, NDF, and ADF intake and digestibility was significant (P < 0.05) and in the increasing order of T1 < T2 < T3 < T4 < T5. The average daily body weight gain (ADG) of experimental sheep was significantly (P < 0.05) higher as proportion of desho grass increased from 0 to 100% in the basal diet. The result indicated that desho grass can be used as a basal diet for local sheep with better performance than natural pasture hay-based diets. PMID- 26970970 TI - Sleep recordings in individuals with borderline personality disorder before and after trauma therapy. AB - Most individuals diagnosed with borderline personality disorder (BPD) have been exposed to severe and traumatic stressors and thus frequently present with symptoms of a posttraumatic stress disorder (PTSD). Severe sleep disturbances often accompany these complex cases, but changes of sleep parameters during therapy and the impact of sleep on treatment response have barely been studied. Narrative Exposure Therapy (NET) is an evidence-based approach for the treatment of trauma-related psychological disorders. To investigate the effect of NET on sleep in patients with BPD and comorbid PTSD, we screened 45 inpatients and outpatients who met the inclusion criteria of both diagnoses according to DSM-IV and who had a minimum of 2 weeks' stable medication. Patients were allocated to NET (N = 13) or treatment as usual (TAU; N = 8) in blocks. Polysomnographies and psychological questionares were performed before, directly and 6 months after the last therapy session. The aim of this pilot study was to investigate the effectiveness of trauma therapy by NET on sleep quantity (total sleep time) and sleep continuity (sleep efficiency and awakenings) in patients with comorbid BPD and PTSD. Participants of the NET group compared with those who received TAU showed an increased reduction in sleep latency from baseline to the end of therapy and a reduction in arousals over time. Patients with longer pre-treatment total sleep time and pre-treatment REM sleep duration showed a better outcome of NET with respect to PTSD symptoms. NET seems not lead to a change in sleep for the worse during therapy and seems to improve sleep as good as treatment as usual. Furthermore, our results provide evidence of an influence of sleep structure at baseline on treatment success later on. PMID- 26970972 TI - Effect of energy and protein levels on nutrient utilization and their requirements in growing Murrah buffaloes. AB - To evaluate different levels of energy and protein for optimum growth of Murrah male buffalo calves, a growth trial (150 days) was conducted on 30 calves (body weight 202.5 +/- 6.8 kg). Six diets were formulated to provide 90, 100 and 110% protein level and 90 and 110% energy level requirements for buffalo calves, derived from ICAR 2013 recommendations for buffaloes. The crude protein (CP) intake was increased with higher dietary CP, whereas no effect of energy levels or interaction between protein and energy was observed on CP intake. There were significant effects (P < 0.01) of the interaction between protein and energy (P < 0.05) on metabolizable energy (ME) intake. The digestibility of dry matter (DM), organic matter (OM) and non-fibrous carbohydrate (NFC) was higher (P < 0.0001) in high-energy groups compared to low-energy groups. The CP digestibility increased with the increased CP and ME of the rations. The absorbed N was improved linearly with an increased level of dietary CP, whereas the N retention was similar among all the groups distributed as per different energy or protein levels. The nutrient intake (protein or energy) per kg body weight (BW)(0.75) at various fortnight intervals was regressed linearly from the average daily gain (ADG) per kg BW(0.75). By setting the average daily gain at zero in the developed regression equation, a maintenance requirement was obtained, i.e. 133.1 kcal ME, 6.45 g CP and 3.95 g metabolizable protein (MP) per kg BW(0.75). Requirement for growth was 6.12 kcal ME, 0.46 g CP and 0.32 g MP per kg BW(0.75) per day. Metabolizable amino acid requirement was estimated from partitioning of MP intake and ADG. The ME requirements were lower, whereas the MP requirement of Murrah buffaloes was higher than ICAR (2013) recommendations. PMID- 26970969 TI - Piperine Augments the Protective Effect of Curcumin Against Lipopolysaccharide Induced Neurobehavioral and Neurochemical Deficits in Mice. AB - The aim of the present study was to investigate the protective effects of curcumin alone and in combination with piperine against lipopolysaccharide (LPS) induced neurobehavioral and neurochemical deficits in the mice hippocampus. Mice were treated with curcumin (100, 200, and 400 mg/kg, p.o.) and piperine (20 mg/kg, p.o.) for 7 days followed by LPS (0.83 mg/kg, i.p.) administration. Animals exhibited anxiety and depressive-like phenotype after 3 and 24 h of LPS exposure, respectively. LPS administration increased the oxido-nitrosative stress as evident by elevated levels of malondialdehyde, nitrite, and depletion of glutathione level in the hippocampus. Furthermore, we found raised level of pro inflammatory cytokines (IL-1beta and TNF-alpha) in the hippocampus of LPS-treated mice. Pretreatment with curcumin alleviated LPS-induced neurobehavioral and neurochemical deficits. Furthermore, co-administration of curcumin with piperine significantly potentiated the neuroprotective effect of curcumin. These results demonstrate that piperine enhanced the neuroprotective effect of curcumin against LPS-induced neurobehavioral and neurochemical deficits. PMID- 26970973 TI - Effect of continuous female exposure on behavioral repertoire and stereotypical behaviors in restrained male dromedary camels during the onset of the breeding season. AB - This study aimed to test the effects of the three management systems on the behavioral repertoire and particularly on the incidence of stereotypical behavior in restrained camels. Five male camels were tested under the following management systems: (i) unexposed, housing in a single box (Unexpo); (ii) continuous exposure, exposed continuously to females (ConExpoF); and (iii) re-unexposed, housing again in a single box (Re-Unexpo). Every day, bulls were filmed for 30 min and videos were analyzed using a focal animal sampling ethogram. Under the ConExpoF system, camels spent the majority of time in standing with opened legs (490.0 +/- 94.3 s), looking (925.0 +/- 93.7 s), and walking toward the females (206.0 +/- 73.4 s) and they ate and ruminated less compared to Unexpo and Re Unexpo systems. Rumination and standing durations were significantly longer in Re Unexpo than in Unexpo and ConExpoF management systems. When camels were continuously exposed to females, they showed few stereotypical behaviors compared to Unexpo (490.0 +/- 146.1 s) and Re-Unexpo (624.0 +/- 146.1 s) systems. The frequency of both total and oral stereotypes was significantly higher in Unexpo and Re-Unexpo systems compared to ConExpoF; however, no significant difference was observed among the three management systems in the frequency of locomotor stereotypes. Overall, it appears that the continuous female exposure system might be a suitable management practice for male camels used for intensive reproduction, as it decreases the manifestation of stereotypical behavior in comparison with housing for 24 h in a single box. PMID- 26970974 TI - Apple peel waste as a natural antioxidant for heat-stressed broiler chickens. AB - This study was conducted to evaluate the effects of processed apple peel waste (APW), alone or in combination with an enzyme, as a natural antioxidant on broiler chickens under heat stress. A total of 360 unsexed, 28-day-old broilers were assigned to 6 dietary treatments with four replicates (15 broilers per pen). The experiment consisted of a 3 * 2 factorial arrangement with three levels of apple peel waste (0, 50 or 100 g/kg of diet) and two levels of enzyme (0 or 500 mg/kg, ZY Multi((r))). Inclusion of 100-g APW/kg of diet decreased broiler weight gain at 42 days of age. Inclusion of 50 and 100-g APW/kg of diet increased gizzard and small intestine weights. Feeding 50 and 100-g APW/kg increased high density lipoprotein (HDL) cholesterol and decreased low-density lipoprotein (LDL) cholesterol and malondialdehyde in blood serum at 49 days of age. At 49 days of age, apparent ileal protein digestibility was reduced when 50 and 100-g APW/kg were used in the diet. This study showed that feeding APW up to 50 g/kg from 28 to 49 days of age increased HDL cholesterol and decreased LDL cholesterol in serum and had no adverse effect on broiler performance. PMID- 26970975 TI - A novel system for automated propofol sedation: hybrid sedation system (HSS). AB - Closed-loop systems for propofol have been demonstrated to be safe and reliable for general anesthesia. However, no study has been conducted using a closed-loop system specifically designed for sedation in patients under spinal anesthesia. We developed an automatic anesthesia sedation system that allows for closed-loop delivery of propofol for sedation integrating a decision support system, called the hybrid sedation system (HSS). The objective of this study is to compare this system with standard practice. One hundred fifty patients were enrolled and randomly assigned to two groups: HSS-Group (N = 75), in which propofol was administered using a closed-loop system; Control Group (N = 75), in which propofol was delivered manually. The clinical performance of the propofol sedation control is defined as efficacy to maintain bispectral index (BIS) near 65. The clinical control was called 'Excellent', 'Good', 'Poor' and 'Inadequate' with BIS values within 10 %, from 11 to 20 %, 21 to 30 %, or greater than 30 % of the BIS target of 65, respectively. The controller performance was evaluated using Varvel's parameters. Data are presented as mean +/- standard deviation, groups were compared using t test or Chi square test, P < 0.05. Clinical performance of sedation showed 'Excellent' control in the HSS-group for a significantly longer period of time (49 vs. 26 % in the control group, P < 0.0001). 'Poor' and 'Inadequate' sedation was significantly shorter in the HSS Group compared to the Control Group (11 and 10 % vs. 20 and 18 %, respectively, P < 0.0001). The novel, closed-loop system for propofol sedation showed better maintenance of the target BIS value compared to manual administration. PMID- 26970977 TI - Heavy Metal Concentrations in Fish Species from Three Gorges Reservoir, China, After Impoundment. AB - The concentrations of Pb, Cr, Cd, As, and Hg were analyzed in the muscles of eleven fish species collected from the Wanzhou section of the Three Gorges Reservoir, Yangtze River, China. The results showed that the concentrations of Pb, Cr, Cd, As, and Hg in the muscles of all of the fish species were lower than the proposed limits. The metal concentrations (Pb, Cr, Cd, and As) of pelagic fish species were found to be substantially lower than those in benthic fish species. The concentrations of Hg in carnivorous fish were higher than those in omnivorous fish. Compared with data obtained prior to the impoundment of the Three Gorges Reservoir, the concentration of Hg in the fish did not significantly increase after impoundment, while the concentrations of Pb, Cr, Cd, and As in the fish decreased. PMID- 26970976 TI - Development and Psychometric Evaluation of the Hypoglycemia Perspectives Questionnaire in Patients with Type 2 Diabetes Mellitus. AB - AIMS: The aim of this study was to evaluate the factor structure and psychometric characteristics of the Hypoglycemia Perspectives Questionnaire (HPQ) assessing experience and perceptions of hypoglycemia in patients with type 2 diabetes mellitus (T2DM). METHODS: HPQ was administered to adults with T2DM in a clinical sample from Cyprus (HYPO-Cyprus, n = 500) and a community sample in the United States (US, n = 1257) from the 2011 US National Health and Wellness Survey. Demographic and clinical data were collected. Analysis of HPQ data from two convenience samples examined item performance, factor structure, and HPQ measurement properties (reliability, convergent validity, known-groups validity). RESULTS: Analyses supported three HPQ domains: symptom concern (six items), compensatory behavior (five items), and worry (five items). Internal consistency was high for all three domains (all >=0.75), supporting reliability. Convergent validity was supported by moderate Spearman correlations between HPQ domain scores and the Audit of Diabetes-Dependent Quality of Life (ADDQoL-19) total score. Patients with recent hypoglycemia events had significantly higher HPQ scores, supporting known-group validity. CONCLUSIONS: HPQ may be a valid and reliable measure capturing the experience and impact of hypoglycemia and useful in clinical trials and community-based settings. PMID- 26970978 TI - Dissecting the role of microRNAs in prostate cancer metastasis: implications for the design of novel therapeutic approaches. AB - Metastatic prostate cancer is a lethal disease that remains incurable despite the recent approval of new drugs, thus making the development of alternative treatment approaches urgently needed. A more precise understanding of the molecular mechanisms underlying prostate cancer dissemination could lead to the identification of novel therapeutic targets for the design of efficient anti metastatic strategies. MicroRNA (miRNAs) are endogenous, small non-coding RNA molecules acting as key regulators of gene expression at post-transcriptional level. It has been clearly established that altered miRNA expression is a common hallmark of cancer. In addition, emerging evidence suggests their direct involvement in the metastatic cascade. In this review, we present a comprehensive overview of the data generated in experimental tumor models indicating that specific miRNAs may impinge on the different stages of prostate cancer metastasis, including (i) the regulation of epithelial-to-mesenchymal transition and cell migration/invasion, (ii) the interplay between cancer cells and the surrounding stroma, (iii) the control of angiogenesis, (iv) the regulation of anoikis, and (v) the colonization of distant organs. Moreover, we show preliminary evidence of the clinical relevance of some of these miRNAs, in terms of association with tumor aggressiveness/dissemination and clinical outcome, as emerged from translation studies carried out in prostate cancer patient cohorts. We also discuss the potential and the current limitations of manipulating metastasis-related miRNAs, by mimicking or inhibiting them, as a strategy for the development of novel therapeutic approaches for the advanced disease. PMID- 26970981 TI - Disparities in receipt of modern concurrent chemoradiotherapy in glioblastoma. AB - Temozolomide given concurrently with radiation after resection/biopsy improves survival in glioblastoma (GBM). The disparities in receipt of adjuvant single agent chemotherapy and their association with outcome have not been well established. Observational study of a prospectively collected database, the National Cancer Database (NCDB), from 1998 to 2012 with median follow-up 12.4 months. Among the 114,979 patients in the NCDB with GBM, 44,531 patients were analyzed for disparities, and 28,279 patients were analyzed for overall survival (OS). Associations were assessed in a multivariable Cox proportional hazards regression model. Survival was estimated using the Kaplan-Meier method. Median age was 58 years. Chemotherapy use was associated with male gender, white race, younger age (<=50), higher performance status (>=70), more extensive surgery, insurance status, higher income/education, and treatment at academic centers (all p < 0.05). We found improved OS associated with type of insurance (private insurance HR 0.91, 95 % CI 0.85-0.96 and Medicare HR 1.24, 95 % CI 1.16-1.33, both p < 0.01 compared to uninsured) and treatment at academic programs (HR 0.86; p < 0.01). MGMT methylation status predicted improved OS (HR 0.54; 95 % CI 0.41 0.70, p < 0.01). 1-year OS for patients receiving chemotherapy was 55.9 % versus 35.3 % for those without (p < 0.0001). After adjustment for confounders, chemotherapy use remained associated with improved OS (HR 0.64, 95 % CI 0.63 0.66, p < 0.01). Chemotherapy utilization increased from 26.9 to 93.3 % during the study period. We have identified specific disparities in the use of chemotherapy that may be targeted to improve patient access to care. Widespread adoption of adjuvant chemoradiotherapy after resection or biopsy for GBM appears to improve OS. PMID- 26970982 TI - Highly sensitive solid forms discrimination on the whole tablet of the active ingredients in quercetin dietary supplements by NMR crystallography approaches. AB - Similarly to synthetic drugs, the exact crystalline form of active ingredients in solid formulations of dietary supplements may directly influence the dissolution rate, bioavailability, and stability of the final product, but this information is usually not provided by manufacturers. Working on the examples of two commercial quercetin dietary supplements a quick, reliable, and sensitive method is introduced for quercetin solid forms discrimination directly on the marketed products, without the need for prior sample preparation. It exploits the complementarity between solid-state Nuclear Magnetic Resonance (ss-NMR) and Powder X-Ray Diffraction (PXRD), which proved essential for performing a complete and accurate solid-state characterization of the two commercial products, and for obtaining new insights into the complex quercetin solid-forms landscape. The method can be readily generalized also to other dietary supplements based on bio flavonoids/polyphenols. PMID- 26970980 TI - MiR-519a functions as a tumor suppressor in glioma by targeting the oncogenic STAT3 pathway. AB - Glioblastoma (GBM) is among the most aggressive primary brain tumors, with a median survival rate of 12-15 months. MicroRNAs have been implicated in GBM development as oncogenes or tumor suppressors. In this study, we demonstrated that miR-519a expression was frequently downregulated in GBM specimens and cell lines, and that low-levels miR-519a expression significantly correlated with poor outcomes associated with GBM. Analysis of The Cancer Genome Atlas also demonstrated that low miR-519a expression can predict poor clinical outcomes in classical and proneural GBM subtypes. Functionally, re-expression of miR-519a effectively reduced GBM cell proliferation, migration, and invasion. Mechanistically, we confirmed that the signal transducer and activator of transcription 3 (STAT3) 3'-UTR was a putative target of miR-519a, and that re expression of STAT3 abrogated miR-519a function in GBM cells. Furthermore, we found that STAT3 expression negatively correlated with that of miR-519a in human GBM tissues. These results elucidated the prognostic value and tumor-suppressor role of miR-519a in GBM and further suggested it as a potential therapeutic target for GBM treatment. PMID- 26970983 TI - Quantitative analysis of highly similar salvianolic acids with 1H qNMR for quality control of traditional Chinese medicinal preparation Salvianolate Lyophilized Injection. AB - Salvianolate Lyophilized Injection (SLI), a traditional Chinese medicinal (TCM) preparation which is used to treat stroke, is composed of multiple salvianolic acids from the aqueous extracts of Salvia miltiorrhiza, and includes mainly protocatechualdehyde, rosmarinic acid, salvianolic acid B, salvianolic acid D, salvianolic acid E, diastereomer of salvianolic acid E, salvianolic acid Y, lithospermic acid and diastereomer of lithospermic acid. It is difficult to quantitatively control the quality of SLI using traditional high performance liquid chromatography due to the highly similar structure of these constituents including three pairs of diastereomers and the lack of commercial resources for most of these constituents as standards. Thus, a highly reproducible, fast, accurate and simple (1)H quantitative nuclear magnetic resonance (qNMR) method without the need for calibration curves and complex computation was established by optimizing the solvent system and acquisition parameters to simultaneously determine the nine salvianolic acids and mannitol in SLI. This method was validated and successfully used to determine 10 batches of SLI and the qNMR data were further analyzed with a vector including angle cosine and the partial least squares method for the quality control of SLI. The results indicated that qNMR can be used as a routine method for the quality control of SLI and may have potential in the quantification of diastereomers in other TCM preparations. PMID- 26970985 TI - Serum albumin as a probe for testing the selectivity of irreversible cysteine protease inhibitors: The case of vinyl sulfones. AB - Vinyl sulfones are used for drug design of irreversible inhibitors of cysteine proteases since they are able to alkylate cysteine thiols inside the catalytic pocket of this class of enzymes. Some authors have reported the lack of reactivity towards glutathione as sufficient evidence of the selectivity of such a mechanism. Herein, we demonstrate that some simple molecules containing a vinyl sulfone moiety are not thiol-specific alkylants since they react with some albumin nucleophiles including side chains of Cys34 and His146. Such side reactions are not desirable for any drug candidate since they limit serum stability, bioavailability and they possibly trigger toxicity mechanisms. In silico predictions, indicate that the compounds tested share similar structural features with reported inhibitors of cysteine proteases, as well as similar poses around the main albumin nucleophiles. Altogether, the data suggest that albumin is better than glutathione for the setup of early in vitro tests probing the selectivity of cysteine protease inhibitors. PMID- 26970984 TI - UFLC-MS/MS determination and pharmacokinetic studies of six Saikosaponins in rat plasma after oral administration of Bupleurum Dropping Pills. AB - A rapid and sensitive ultra fast liquid chromatography tandem mass spectrometry method (UFLC-MS/MS) was developed and validated for the simultaneous determination of six Saikosaponins (SSs) (SSa, SSb1, SSb2, SSd, SSc, SSf) of Bupleurum Dropping Pills (BDP) in rat plasma using chloramphenicol as the internal standard (IS). The SSs were separated using an ACQUITY UPLC((r)) BEH C18 column (50 mm * 2.1mm, 1.7 MUm) and detection of these compounds were done by using a Qtrap 5500 mass spectrometer coupled with negative electrospray ionization (ESI) source under the multiple reaction monitoring (MRM) mode. According to regulatory guidelines, the established method was fully validated and results were showed within acceptable limits. The lower limit of quantifications (LLOQs) of all analytes were 0.2 ng/mL. The validated method was successfully applied into a pharmacokinetic study of orally administered BDP in rats. PMID- 26970986 TI - Development and validation of a UHPLC-MS/MS assay for colistin methanesulphonate (CMS) and colistin in human plasma and urine using weak-cation exchange solid phase extraction. AB - A rapid ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) assay method was developed for determination of CMS and formed colistin in human plasma and urine. After extraction on a 96-well SPE Supra-Clean Weak Cation Exchange (WCX) plate, the eluents were mixed and injected into the UHPLC-MS/MS system directly. A Phonomenex Kinetex XB-C18 analytical column was employed with a mobile phase consisting of solution "A" (acetonitrile:methanol, 1:1, v/v) and solution "B" (0.1% formic acid in water, v/v). The flow rate was 0.4 mL/min with gradient elution over 3.5 min. Ions were detected in ESI positive ion mode and the precursor-product ion pairs were m/z 390.7/101.3 for colistin A, m/z 386.0/101.2 for colistin B, and m/z 402.3/101.2 for polymyxin B1 (IS), respectively. The lower limit of quantification (LLOQ) was 0.0130 and 0.0251 mg/L for colistin A and colistin B in both plasma and urine with accuracy (relative error, %) <+/- 12.6% and precision (relative standard deviation, %) <+/- 10.8%. Stability of CMS was demonstrated in biological samples before and during sample treatment, and in the extract. This new analytical method provides high throughput treatment and optimized quantification of CMS and colistin, which offers a highly efficient tool for the analysis of a large number of clinical samples as well as routine therapeutic drug monitoring. PMID- 26970979 TI - Dendritic cells as therapeutic targets in neuroinflammation. AB - Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disorder of the central nervous system characterized by infiltration of immune cells and progressive damage to myelin sheaths and neurons. There is still no cure for the disease, but drug regimens can reduce the frequency of relapses and slightly delay progression. Myeloid cells or antigen-presenting cells (APCs) such as dendritic cells (DC), macrophages, and resident microglia, are key players in both mediating immune responses and inducing immune tolerance. Mounting evidence indicates a contribution of these myeloid cells to the pathogenesis of multiple sclerosis and to the effects of treatment, the understanding of which might provide strategies for more potent novel therapeutic interventions. Here, we review recent insights into the role of APCs, with specific focus on DCs in the modulation of neuroinflammation in MS. PMID- 26970987 TI - Food begging and sharing in wild bonobos (Pan paniscus): assessing relationship quality? AB - Food transfers are often hypothesised to have played a role in the evolution of cooperation amongst humans. However, they also occur in non-human primates, though no consensus exists regarding their function(s). We document patterns of begging for food and success rates as well as associated factors that may influence them for wild bonobos at LuiKotale, Democratic Republic of Congo. Our data, collected over 1074 observation hours, focus on 260 begging events (outside mother-offspring dyads) of which 37 % were successful. We find no support for the "reciprocity hypothesis"-that food is exchanged for grooming and/or sexual benefits; and only weak support for the "sharing under pressure" hypothesis-that food is transferred as a result of harassment and pays off in terms of nutritional benefits for the beggar. Instead, our data support the "assessing relationships" hypothesis, according to which beggars gain information about the status of their social relationship with the possessor of a food item. This seems to hold particularly true for the frequent, albeit unsuccessful begging events by young females (newly immigrated or hierarchically non-established) towards adult females, although it can be observed in other dyadic combinations independent of sex and age. PMID- 26970988 TI - Diagnosis and follow-up of idiopathic retroperitoneal fibrosis: role of (18)F-FDG PET/CT and biochemical parameters in patients with renal involvement. AB - Idiopathic retroperitoneal fibrosis (IRF) is a rare disease characterized by fibro-inflammatory reaction surrounding ureters and other inner organs with possible secondary renal involvement. Symptoms are aspecific and recurrent phases of activity are generally associated with elevation of inflammatory indices. 18F FDG-PET is nowadays an important tool for the detection of this disease, allowing differentiation between metabolically active tissue and fibrotic one. The purpose of this study was to investigate the role of 18F-FDG-PET in the management of IRF and to evaluate possible correlations between biochemical parameters and PET/CT findings of disease activity. We enrolled seven consecutive patients with IRF (in five histology proved the disease) observed from 2003 to 2012 (5 M:2 F, mean age 53.8 years, range 44-86 years). All patients presented with fever as first symptom; two had obstructive renal failure requiring hemodialysis; one underwent monolateral nephrectomy for parenchyma infiltration; six presented ureteral involvement; three underwent ureteral stent placement. For each patient, during a mean total follow-up of 26.5 months we evaluated serum creatinine, BUN, Hb, RBCs, WBCs, PLT, CRP, ESR. Periodic 18F-FDG-PET/CT scans (every 5.9 months-mean) were performed in all patients. Statistical evaluation was performed using "stepwise regression" analysis. Steroids and immunosuppressive agents induced a progressive normalization of PET/CT scans in all patients at the end of follow-up. Stepwise regression analysis showed that BUN, serum creatinine and CRP only if considered together, significantly correlated with SUV max (p value = 0.000003057). 18F-FDG PET is a useful tool for clinical decision making in patient with IRF, allowing to evaluate the efficacy of the pharmacological treatment and to detect early recurrences, to modify the therapeutic approach. Acute phase reactants are not reliable alone for the management and the follow-up as they are often not concordant with metabolic assessment of the disease. In patients with ureteral involvement, CRP together with BUN and serum creatinine has a significant correlation with PET/CT results, and can help physicians in therapeutic approach, better than a single parameter. PMID- 26970989 TI - Renal denervation for resistant hypertension: yes. AB - Sympathetic overactivity may have a role in triggering and maintaining resistant hypertension, and catheter-based renal denervation (RDN) has emerged as a promising treatment in refractory hypertension. Recently, the results of the Symplicity HTN-3, the first randomized, sham-controlled trial, failed to confirm the previously reported BP-lowering effects of RDN, although definitive conclusions cannot be drawn due to a number of study limitations. Consequently, although some centers halted their RDN programs, research continues and both the concept of denervation and treatment strategies are being redefined. A new generation of sham-controlled trials is currently underway with the aim of detecting which patients are expected to achieve the most beneficial effect from RDN. In this article, we examine the current data on RDN and discuss some insights and future opportunities. PMID- 26970990 TI - Dose comparison of classical 2-plane DSA and 3D rotational angiography for the assessment of intracranial aneurysms. AB - INTRODUCTION: The purpose of this experimental phantom study was to compare radiation doses imparted to patients undergoing classical two-plane digital subtraction angiography (2-plane DSA) and 3D rotational angiography in interventional neuroradiology. METHODS: Thermoluminescence dosimeter (TLD) measurements were performed at an anthropomorphic phantom using a digital interventional angiography system. Two-plane DSA included posterior/anterior (PA) and lateral (LAT) projections (frame-rate, 7.6 frames (PA) and 9.8 frames (LAT) for a scan time of approximately 8 s; image intensifier 27 cm (PA) and 25 cm (LAT)). For 3D rotational angiography, 122 images were acquired from one single image run with the imaging system rotating 240 degrees around the phantom's head (image intensifier 37 cm). RESULTS: Effective dose was 0.4 mSv for 2-plane DSA compared to 0.1 mSv for 3D rotational angiography. Organ doses were approximately two to five times higher for classical 2-plane technique compared to the 3D rotational angiography, respectively: brain (11.4 vs. 2.4 mSv), eye lens (4.5 vs.1 mSv), salivary glands (7 vs. 1,7 mSv), oral mucosa (2.7 vs.0.9 mSv), thyroid (0.5 vs. 0.2 mSv), thymus (0.2 vs. 0.05 mSv), bone marrow within imaged region (1 vs. 0.2 mSv), oesophagus (0.07 vs. 0.03 mSv), endotracheal system (2.6 vs. 0.7 mSv) and skeletal components in the imaged region (0.7 vs. 0.2 mSv). CONCLUSION: Three-dimensional rotational angiography clearly reduces radiation doses compared to the classical 2-plane technique. Replacement of additional 2-plane DSA projections with 3D rotational angiography will lead to a remarkable decrease in patient radiation dose, without loss of image quality. Thus, we recommend routine application of 3D rotational angiography, in particular for diagnostic assessment of aneurysm morphology. PMID- 26970991 TI - The John N. Insall Award: Do Intraarticular Injections Increase the Risk of Infection After TKA? AB - BACKGROUND: Infection after total knee arthroplasty (TKA) can result in disastrous consequences. Previous research regarding injections and risk of TKA infection have produced conflicting results and in general have been limited by small cohort size. QUESTIONS/PURPOSES: The purpose of this study was to evaluate if intraarticular injection before TKA increases the risk of postoperative infection and to identify if time between injection and TKA affect the risk of TKA infection. METHODS: The Humana data set was reviewed from 2007 to 2014 for all patients who received a knee injection before TKA. Current Procedural Terminology (CPT) codes and laterality modifiers were used to identify patients who underwent knee injection followed by ipsilateral TKA. Postoperative infection within 6 months of TKA was identified using International Classification of Diseases, 9th Revision/CPT codes that represent two infectious endpoints: any postoperative surgical site infection (encompasses all severities of infection) and operative intervention for TKA infection (surrogate for deep TKA infection). The injection cohort was stratified into 12 subgroups by monthly intervals out to 12 months corresponding to the number of months that had elapsed between injection and TKA. Risk of postoperative infection was compared between the injection and no injection cohorts. In total, 29,603 TKAs (35%) had an injection in the ipsilateral knee before the TKA procedure and 54,081 TKA cases (65%) did not. The PearlDiver database does not currently support line-by-line output of patient data, and so we were unable to perform a multivariate analysis to determine whether other important factors may have varied between the study groups that might have had a differential influence on the risk of infection between those groups. However, the Charlson Comorbidity index was no different between the injection and no injection cohorts (2.9 for both) suggesting similar comorbidity profiles between the groups. RESULTS: The proportion of TKAs developing any postoperative infection was higher among TKAs that received an injection before TKA than in those that did not (4.4% versus 3.6%; odds ratio [OR], 1.23; 95% confidence interval [CI], 1.15-1.33; p < 0.001). Likewise, the proportion of TKAs developing infection resulting in return to the operating room after TKA was also higher among TKAs that received an injection before TKA than those that did not (1.49% versus 1.04%; OR, 1.4; 95% CI, 1.3-1.63; p < 0.001). Month-by-month analysis of time between injection and TKA revealed the odds of any postoperative infection remained higher for the injection cohort out to a duration of 6 months between injection and TKA (ORs ranged 1.23 to 1.46 when 1-6 months between injection and TKA; p < 0.05 for all) as did the odds of operative intervention for TKA infection when injection occurred within 7 months of TKA (OR ranged from 1.38 to 1.88 when 1-7 months between injection and TKA; p < 0.05 for all). When the duration between injection and TKA was longer than 6 or 7 months, the ORs were no longer elevated at these endpoints, respectively. CONCLUSIONS: Injection before TKA was associated with a higher risk of postoperative infection and appears to be time-dependent with closer proximity between injection and TKA having increased odds of infection. Further research is needed to better evaluate the risk injection before TKA poses for TKA infection; a more definitive relationship could be established with a multivariate analysis to control for other known risk factors for TKA infection. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26970992 TI - Antiretroviral therapy and demand for HIV testing: Evidence from Zambia. AB - This paper examines the effects of antiretroviral therapy (ART) on demand for HIV testing and of ART-induced testing on demand for risky sexual behavior. I provide a model of sexual behavior decision-making under uncertainty and estimate the structural parameters of the model using nationally representative survey data from Zambia on HIV testing decisions before and after the introduction of ART. The empirical results indicate that although the introduction of ART appears to have increased HIV testing rates by upwards of 50 percent, the ART allocation process may have limited the prevention benefit of ART-induced testing. Simulation results show that eliminating this prevention inefficiency while holding the supply of ART constant would increase the prevention impact of ART induced testing more than four-fold. More generally, the analysis indicates that existing studies which examine "universal" testing or quasi-experimental testing programs understate the efficacy of standard voluntary counseling and testing programs. PMID- 26970993 TI - Safety of repetitive transcranial magnetic stimulation in patients with epilepsy: A systematic review. AB - Approximately one-third of patients with epilepsy remain with pharmacologically intractable seizures. An emerging therapeutic modality for seizure suppression is repetitive transcranial magnetic stimulation (rTMS). Despite being considered a safe technique, rTMS carries the risk of inducing seizures, among other milder adverse events, and thus, its safety in the population with epilepsy should be continuously assessed. We performed an updated systematic review on the safety and tolerability of rTMS in patients with epilepsy, similar to a previous report published in 2007 (Bae EH, Schrader LM, Machii K, Alonso-Alonso M, Riviello JJ, Pascual-Leone A, Rotenberg A. Safety and tolerability of repetitive transcranial magnetic stimulation in patients with epilepsy: a review of the literature. Epilepsy Behav. 2007; 10 (4): 521-8), and estimated the risk of seizures and other adverse events during or shortly after rTMS application. We searched the literature for reports of rTMS being applied on patients with epilepsy, with no time or language restrictions, and obtained studies published from January 1990 to August 2015. A total of 46 publications were identified, of which 16 were new studies published after the previous safety review of 2007. We noted the total number of subjects with epilepsy undergoing rTMS, medication usage, incidence of adverse events, and rTMS protocol parameters: frequency, intensity, total number of stimuli, train duration, intertrain intervals, coil type, and stimulation site. Our main data analysis included separate calculations for crude per subject risk of seizure and other adverse events, as well as risk per 1000 stimuli. We also performed an exploratory, secondary analysis on the risk of seizure and other adverse events according to the type of coil used (figure-of-8 or circular), stimulation frequency (<= 1 Hz or > 1 Hz), pulse intensity in terms of motor threshold (<100% or >= 100%), and number of stimuli per session (< 500 or >= 500). Presence or absence of adverse events was reported in 40 studies (n = 426 subjects). A total of 78 (18.3%) subjects reported adverse events, of which 85% were mild. Headache or dizziness was the most common one, occurring in 8.9%. We found a crude per subject seizure risk of 2.9% (95% CI: 1.3-4.5), given that 12 subjects reported seizures out of 410 subjects included in the analysis after data of patients with epilepsia partialis continua or status epilepticus were excluded from the estimate. Only one of the reported seizures was considered atypical in terms of the clinical characteristics of the patients' baseline seizures. The atypical seizure happened during high-frequency rTMS with maximum stimulator output for speech arrest, clinically arising from the region of stimulation. Although we estimated a larger crude per subject seizure risk compared with the previous safety review, the corresponding confidence intervals contained both risks. Furthermore, the exclusive case of atypical seizure was the same as reported in the previous report. We conclude that the risk of seizure induction in patients with epilepsy undergoing rTMS is small and that the risk of other adverse events is similar to that of rTMS applied to other conditions and to healthy subjects. Our results should be interpreted with caution, given the need for adjusted analysis controlling for potential confounders, such as baseline seizure frequency. The similarity between the safety profiles of rTMS applied to the population with epilepsy and to individuals without epilepsy supports further investigation of rTMS as a therapy for seizure suppression. PMID- 26970994 TI - Clinical utility of the Metacognitions Questionnaire 30 in people with epilepsy. AB - OBJECTIVE: The Metacognitions Questionnaire 30 (MCQ-30) has been widely used to assess metacognitive beliefs and processes linked to emotional disorders. The aim of the present study was to test the utility of the MCQ-30 in assessing metacognitions in people with epilepsy. METHODS: Three hundred forty-nine people with epilepsy completed the MCQ-30 and self-report measures of anxiety and depression at two time points, 12 months apart. Factor analyses and structural equation modeling were used to test the factor structure, internal consistency, and convergent validity of the MCQ-30. RESULTS: Confirmatory and exploratory factor analyses supported the original five-factor structure and demonstrated that each factor had good to excellent levels of internal consistency. CONCLUSION: The MCQ-30 is a robust measure of metacognitive beliefs and processes and has clinical utility in PWE. PMID- 26970995 TI - Frequency of Restless Legs Syndrome in adults with epilepsy in Turkey. AB - BACKGROUND: Restless Legs Syndrome (RLS) is a common disorder characterized by an irresistible urge to move the legs particularly during rest in the evenings often leading to insomnia and daytime impairment. No prior studies estimate the prevalence of RLS in a diverse sample of adults with epilepsy using standard diagnostic criteria. MATERIAL AND METHOD: A total of 225 patients with epilepsy (61.8% female; mean age 33.3 +/- 12.3 years) seen in the epilepsy clinic of Cukurova University Neurology Department were included. Restless Legs Syndrome diagnosis was based on structured interviews using internationally accepted criteria. Demographic and epilepsy-related variables were obtained through medical record review. RESULTS: The prevalence of RLS was 5.8% (n=13). Mean score on the International RLS Study Group rating scale for these subjects was 9.3 +/- 3.6 (6-18). Ten (76.9%) patients with RLS scored in the mild range and the remainder in the moderate range of severity. Patients with RLS were not significantly different from others in terms of demographics, epilepsy classification or duration, treatment regimen (polytherapy vs. monotherapy), patient-reported sleep assessment, or relevant laboratory data. CONCLUSION: The prevalence of RLS in adults with epilepsy was similar to that observed in the adult general Turkish population (3.18-5.2%), although we excluded subjects with conditions associated with RLS, rendering ours a conservative estimate. While preliminary, these findings support the need for future studies exploring RLS in epilepsy given the potential impact of untreated sleep disorders and sleep deprivation on seizures and quality of life in people with epilepsy. PMID- 26970996 TI - Ameliorative effect of Asparagus racemosus root extract against pentylenetetrazol induced kindling and associated depression and memory deficit. AB - Asparagus racemosus (A. racemosus) roots are extensively used in traditional medicine for the management of epilepsy. The aim of the present study was to investigate the ameliorative effect of A. racemosus root extract (ARE) against pentylenetetrazol-induced kindling and associated depression and memory deficit. Kindling was successfully induced by repeated administration of a subconvulsant dose of PTZ (35 mg/kg; i.p.) at an interval of 48 +/- 2 h in 43 days (21 injections). Pretreatment with valproate (300 mg/kg; i.p.), a major antiepileptic drug as well as ARE significantly suppressed the progression of kindling. Moreover, ARE also ameliorated the kindling-associated depression and memory deficit as indicated by decreased immobility time and increased step-down latency, respectively, as compared to vehicle control animals. Further, these behavioral observations were complemented with analogous neurochemical changes. In conclusion, the results of the present study showed that ARE treatment has an ameliorative effect against PTZ-induced kindling and associated behavioral comorbidities. PMID- 26970997 TI - The Authors Reply. PMID- 26970998 TI - Imaging Atherosclerosis for Global Predictive Health and Wellness. PMID- 26971000 TI - The Authors Reply. PMID- 26971001 TI - Precursors of Hypertensive Heart Phenotype Develop in Healthy Adults: An Alternative Explanation. PMID- 26970999 TI - The Association of Coronary Artery Calcium With Noncardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis. AB - OBJECTIVES: This study sought to determine if coronary artery calcium (CAC) is associated with incident noncardiovascular disease. BACKGROUND: CAC is considered a measure of vascular aging, associated with increased risk of cardiovascular and all-cause mortality. The relationship with noncardiovascular disease is not well defined. METHODS: A total of 6,814 participants from 6 MESA (Multi-Ethnic Study of Atherosclerosis) field centers were followed for a median of 10.2 years. Modified Cox proportional hazards ratios accounting for the competing risk of fatal coronary heart disease were calculated for new diagnoses of cancer, pneumonia, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), deep vein thrombosis/pulmonary embolism, hip fracture, and dementia. Analyses were adjusted for age; sex; race; socioeconomic status; health insurance status; body mass index; physical activity; diet; tobacco use; number of medications used; systolic and diastolic blood pressure; total and high-density lipoprotein cholesterol; antihypertensive, aspirin, and cholesterol medication; and diabetes. The outcome was first incident noncardiovascular disease diagnosis. RESULTS: Compared with those with CAC = 0, those with CAC >400 had an increased hazard of cancer (hazard ratio [HR]: 1.53; 95% confidence interval [CI]: 1.18 to 1.99), CKD (HR: 1.70; 95% CI: 1.21 to 2.39), pneumonia (HR: 1.97; 95% CI: 1.37 to 2.82), COPD (HR: 2.71; 95% CI: 1.60 to 4.57), and hip fracture (HR: 4.29; 95% CI: 1.47 to 12.50). CAC >400 was not associated with dementia or deep vein thrombosis/pulmonary embolism. Those with CAC = 0 had decreased risk of cancer (HR: 0.76; 95% CI: 0.63 to 0.92), CKD (HR: 0.77; 95% CI: 0.60 to 0.98), COPD (HR: 0.61; 95% CI: 0.40 to 0.91), and hip fracture (HR: 0.31; 95% CI: 0.14 to 0.70) compared to those with CAC >0. CAC = 0 was not associated with less pneumonia, dementia, or deep vein thrombosis/pulmonary embolism. The results were attenuated, but remained significant, after removing participants developing interim nonfatal coronary heart disease. CONCLUSIONS: Participants with elevated CAC were at increased risk of cancer, CKD, COPD, and hip fractures. Those with CAC = 0 are less likely to develop common age-related comorbid conditions, and represent a unique population of "healthy agers." PMID- 26971002 TI - Autofluorescence: A New NIR on the Block. PMID- 26971003 TI - The Authors Reply. PMID- 26971004 TI - Predicting LVOT Obstruction in Transcatheter Mitral Valve Implantation: Concept of the Neo-LVOT. PMID- 26971005 TI - The Authors Reply. PMID- 26971007 TI - Is Global Longitudinal Strain a Superior Predictor of Outcomes in HFrEF? PMID- 26971006 TI - Clinical Characterization of Coronary Atherosclerosis With Dual-Modality OCT and Near-Infrared Autofluorescence Imaging. AB - OBJECTIVES: The authors present the clinical imaging of human coronary arteries in vivo using a multimodality optical coherence tomography (OCT) and near infrared autofluorescence (NIRAF) intravascular imaging system and catheter. BACKGROUND: Although intravascular OCT is capable of providing microstructural images of coronary atherosclerotic lesions, it is limited in its capability to ascertain the compositional/molecular features of plaque. A recent study in cadaver coronary plaque showed that endogenous NIRAF is elevated in necrotic core lesions. The combination of these 2 technologies in 1 device may therefore provide synergistic data to aid in the diagnosis of coronary pathology in vivo. METHODS: We developed a dual-modality intravascular imaging system and 2.6-F catheter that can simultaneously acquire OCT and NIRAF data from the same location on the artery wall. This technology was used to obtain volumetric OCT NIRAF images from 12 patients with coronary artery disease undergoing percutaneous coronary intervention. Images were acquired during a brief, nonocclusive 3- to 4-ml/s contrast purge at a speed of 100 frames/s and a pullback rate of 20 or 40 mm/s. OCT-NIRAF data were analyzed to determine the distribution of the NIRAF signal with respect to OCT-delineated plaque morphological features. RESULTS: High-quality intracoronary OCT and NIRAF image data (>50-mm pullback length) were successfully acquired without complication in all patients (17 coronary arteries). The maximum NIRAF signal intensity of each plaque was compared with OCT-defined type, showing a statistically significant difference between plaque types (1-way analysis of variance, p < 0.0001). Interestingly, coronary arterial NIRAF intensity was elevated only focally in plaques with a high-risk morphological phenotype (p < 0.05), including OCT fibroatheroma, plaque rupture, and fibroatheroma associated with in-stent restenosis. CONCLUSIONS: This OCT-NIRAF study demonstrates that dual-modality microstructural and fluorescence intracoronary imaging can be safely and effectively conducted in human patients. Our findings show that NIRAF is associated with a high-risk morphological plaque phenotype. The focal distribution of NIRAF in these lesions furthermore suggests that this endogenous imaging biomarker may provide complementary information to that obtained by structural imaging alone. PMID- 26971008 TI - Is Echocardiography Adequate to Identify the Severity of Anomalous Coronary Arteries? PMID- 26971009 TI - Characterizing the Hyperemia-Induced Mechanical Stress Acting on the Plaque. PMID- 26971010 TI - Insights into the Introduction History and Population Genetic Dynamics of the Nile Monitor (Varanus niloticus) in Florida. AB - Invasive species are widely recognized as important drivers of the ongoing biodiversity crisis. The US state of Florida is especially susceptible to the proliferation of invasive reptiles, and nonnative lizards currently outnumber native lizard species. At present, there are 3 documented breeding populations of the Nile monitor (Varanus niloticus) in different regions of Southern Florida, and these populations are considered potential dangers to threatened, fossorial endemics, such as burrowing owls, American crocodiles, and gopher tortoises. Nevertheless, at present, both the introduction histories of these populations and the degree to which they are connected by gene flow are not known. To address these issues, we genotyped V. niloticus from Cape Coral, Homestead Air Reserve Base, and West Palm Beach at 17 microsatellite loci and conducted a variety of analyses to assess both intrapopulation genetic diversity, the degree of gene flow between populations, and the most likely introduction scenario. The results of our analyses demonstrate that all 3 populations have limited genetic diversity (mean number of effective alleles across loci in all 3 populations ~ 2.00) and are highly differentiated from one another (G ST = 0.268; G"ST = 0.628). Our results also suggest that these populations resulted from independent introduction events that occurred within the past few decades. Consequently, we advise that wildlife managers focus management efforts on containment of existing populations and intensification of monitoring efforts on potential migration corridors. PMID- 26971011 TI - Taxonomic evaluation of species in the Streptomyces hirsutus clade using multi locus sequence analysis and proposals to reclassify several species in this clade. AB - Previous phylogenetic analysis of species of the genus Streptomyces based on 16S rRNA gene sequences resulted in a statistically well-supported clade (100 % bootstrap value) containing eight species that exhibited very similar gross morphology in producing open looped (Retinaculum-Apertum) to spiral (Spira) chains of spiny- to hairysurfaced, dark green spores on their aerial mycelium. The type strains of the species in this clade, specifically Streptomyces bambergiensis, Streptomyces cyanoalbus, Streptomyces emeiensis, Streptomyces hirsutus, Streptomyces prasinopilosus and Streptomyces prasinus, were subjected to multi-locus sequence analysis (MLSA) utilizing partial sequences of the housekeeping genes atpD, gyrB, recA, rpoB and trpB to clarify their taxonomic status. The type strains of several recently described species with similar gross morphology, including Streptomyces chlorus, Streptomyces herbaceus, Streptomyces incanus, Streptomyces pratens and Streptomyces viridis, were also studied along with six unidentified green-spored Streptomyces strains from the ARS Culture Collection. The MLSAs suggest that three of the species under study (S. bambergiensis, S. cyanoalbus and S. emeiensis) represent synonyms of other previously described species (S. prasinus, S. hirsutus and S. prasinopilosus, respectively). These relationships were confirmed through determination of in silico DNA-DNA hybridization estimates based on draft genome sequences. The five recently described species appear to be phylogenetically distinct but the unidentified strains from the ARS Culture Collection could be identified as representatives of S. hirsutus, S. prasinopilosus or S. prasinus. PMID- 26971012 TI - Improvement of aromatic thiol release through the selection of yeasts with increased beta-lyase activity. AB - The development of a selective medium for the rapid differentiation of yeast species with increased aromatic thiol release activity has been achieved. The selective medium was based on the addition of S-methyl-l-cysteine (SMC) as beta lyase substrate. In this study, a panel of 245 strains of Saccharomyces cerevisiae strains was tested for their ability to grow on YCB-SMC medium. Yeast strains with an increased beta-lyase activity grew rapidly because of their ability to release ammonium from SMC in comparison to others, and allowed for the easy isolation and differentiation of yeasts with promising properties in oenology, or another field, for aromatic thiol release. The selective medium was also helpful for the discrimination between those S. cerevisiae strains, which present a common 38-bp deletion in the IRC7 sequence (present in around 88% of the wild strains tested and are likely to be less functional for 4-mercapto-4 methylpentan-2-one (4MMP) production), and those S. cerevisiae strains homozygous for the full-length IRC7 allele. The medium was also helpful for the selection of non-Saccharomyces yeasts with increased beta-lyase activity. Based on the same medium, a highly sensitive, reproducible and non-expensive GC-MS method for the evaluation of the potential volatile thiol release by different yeast isolates was developed. PMID- 26971013 TI - Ferritin, an iron source in meat for Staphylococcus xylosus? AB - Staphylococcus xylosus is frequently isolated from food of animal origin. Moreover, this species is one of the major starter cultures used for meat fermentation. Iron is a key element for growth and survival of bacteria. Meat is particularly rich in haemic (myoglobin and haemoglobin) and non-haemic (ferritin and transferrin) iron sources. Ferritin is a storage protein able to capture large quantities of iron. It is highly resistant to microbial attack and few microorganisms can use it as an iron source. Surprisingly, we found that the S. xylosus C2a strain grows in the presence of ferritin as a sole iron source. A three-cistron operon was highly overexpressed under ferritin iron growth conditions. We generated a deletion-insertion in the first gene of the operon and evaluated the phenotype of the mutant. The mutant showed decreased growth because it was less able to acquire iron from ferritin. Transcriptional analysis of the mutant revealed downregulation of several genes involved in the response to oxidative stress. This study characterized for the first time the capacity of a Staphylococcus to use iron from ferritin and revealed that a potential reductive pathway was involved in this acquisition. We hypothesize that this ability could give an advantage to S. xylosus in meat products. PMID- 26971014 TI - Socio-economic development and emotion-health connection revisited: a multilevel modeling analysis using data from 162 counties in China. AB - BACKGROUND: Substantial research has shown that emotions play a critical role in physical health. However, most of these studies were conducted in industrialized countries, and it is still an open question whether the emotion-health connection is a "first-world problem". METHODS: In the current study, we examined socio economic development's influence on emotion-health connection by performing multilevel-modeling analysis in a dataset of 33,600 individuals from 162 counties in China. RESULTS: Results showed that both positive emotions and negative emotions predicted level of physical health and regional Gross Domestic Product Per Capita (GDPPC) had some impact on the association between emotion and health through accessibility of medical resources and educational status. But these impacts were suppressed, and the total effects of GDPPC on emotion-health connections were not significant. CONCLUSIONS: These results support the universality of emotion-health connection across levels of GDPPC and provide new insight into how socio-economic development might affect these connections. PMID- 26971017 TI - Mechanisms and pathways for the clearance of bacteria from blood circulation in health and disease. AB - Available data do not support the concept that leukocytes engulf and kill bacteria in the bloodstream. Leukocytes cannot recognize or engulf bacteria in flowing blood; therefore, phagocytosis is impossible in the bloodstream and occurs instead outside of the bloodstream in the body tissues. Erythrocytes capture bacteria in the circulation using an electric charge and kill them using oxidation. The dead bacteria are then disintegrated and digested by the reticuloendothelial system (RES), particularly in the liver and the spleen. PMID- 26971016 TI - Impact of frailty in older patients with diabetes mellitus: An overview. AB - Diabetes and frailty are two conditions that frequently occur concurrently and are increasingly prevalent in the older patient. We review the concept, epidemiology and consequences of frailty, and the implications of the presence of frailty in the management of diabetes. Frailty is associated with decreased quality of life, a risk of falls, new or increased disability, hospitalization, and increased mortality. All of these factors affect the management of diabetes in older patients. It is important to rule out frailty in all diabetic patients aged >70 years; if frailty is suspected, a comprehensive and multidisciplinary medical and functional assessment of the patient should be conducted to develop an individualized treatment plan. This plan should include nutritional measures, physical activity, and education on self-care and diabetes; drugs should not be used without a clear indication. Antihyperglycemic drugs that may cause excessive weight loss and/or are associated with a high risk of hypoglycemia should be avoided. PMID- 26971015 TI - Dysregulation of microRNA biogenesis in cancer: the impact of mutant p53 on Drosha complex activity. AB - A widespread decrease of mature microRNAs is often observed in human malignancies giving them potential to act as tumor suppressors. Thus, microRNAs may be potential targets for cancer therapy. The global miRNA deregulation is often the result of defects in the miRNA biogenesis pathway, such as genomic mutation or aberrant expression/localization of enzymes and cofactors responsible of miRNA maturation. Alterations in the miRNA biogenesis machinery impact on the establishment and development of cancer programs. Accumulation of pri-microRNAs and corresponding depletion of mature microRNAs occurs in human cancers compared to normal tissues, strongly indicating an impairment of crucial steps in microRNA biogenesis. In agreement, inhibition of microRNA biogenesis, by depletion of Dicer1 and Drosha, tends to enhance tumorigenesis in vivo. The p53 tumor suppressor gene, TP53, is mutated in half of human tumors resulting in an oncogene with Gain-Of-Function activities. In this review we discuss recent studies that have underlined a role of mutant p53 (mutp53) on the global regulation of miRNA biogenesis in cancer. In particular we describe how a new transcriptionally independent function of mutant p53 in miRNA maturation, through a mechanism by which this oncogene is able to interfere with the Drosha processing machinery, generally inhibits miRNA processing in cancer and consequently impacts on carcinogenesis. PMID- 26971018 TI - Impact of financial agreements in European chronic care on health care expenditure growth. AB - Various types of financial agreements have been implemented in Europe to reduce health care expenditure by stimulating integrated chronic care. This study used difference-in-differences (DID) models to estimate differences in health care expenditure trends before and after the introduction of a financial agreement between 9 intervention countries and 16 control countries. Intervention countries included countries with pay-for-coordination (PFC), pay-for-performance (PFP), and/or all inclusive agreements (bundled and global payment) for integrated chronic care. OECD and WHO data from 1996 to 2013 was used. The results from the main DID models showed that the annual growth of outpatient expenditure was decreased in countries with PFC (by 21.28 US$ per capita) and in countries with all-inclusive agreements (by 216.60 US$ per capita). The growth of hospital and administrative expenditure was decreased in countries with PFP by 64.50 US$ per capita and 5.74 US$ per capita, respectively. When modelling impact as a non linear function of time during the total 4-year period after implementation, PFP decreased the growth of hospital and administrative expenditure and all-inclusive agreements reduced the growth of outpatient expenditure. Financial agreements are potentially powerful tools to stimulate integrated care and influence health care expenditure growth. A blended payment scheme that combines elements of PFC, PFP, and all-inclusive payments is likely to provide the strongest financial incentives to control health care expenditure growth. PMID- 26971019 TI - Cervicogenic somatosensory tinnitus: An indication for manual therapy plus education? Part 2: A pilot study. AB - OBJECTIVES: The aim of this study was to evaluate the efficacy of Manual Therapy Utrecht (MTU) plus education in patients with cervicogenic somatosensory tinnitus (CeT). STUDY DESIGN: Pretest-posttest design. METHOD: Five hundred and six patients were referred or referred themselves. A subgroup of patients was identified with CeT, and within this a subgroup with tinnitus sensitization (TS). Two CeT groups were created based on the presence or absence of TS. Both groups underwent manual therapy combined with tinnitus education. Tinnitus intensity (VAS-tin 0-100 mm) was the primary outcome measure. Number of treatments and adverse effects were the secondary outcome measures. RESULTS: A total of 122 patients with CeT (24.1%) were included (average age 53.3 years [+/-9.8], female 38.5% and duration of tinnitus 7.3 years [+/-8.9]). Patients were divided into two groups: 55 patients (45.1%) with TS (CeT + TS group) and 67 patients (54.9%) without TS (CeT - TS group). Pretest to posttest differences on the VAS-tin were statistically significant within both groups (CeT - TS group: difference VAS-tin 5.9 [p = 0.01]; CeT + TS group: difference VAS-tin 18.2 [p = 0.00]), and between the groups in favor of the CeT + TS group (difference VAS-tin 12.3 [p = 0.01]). Pretest to posttest differences were clinically significant for the CeT + TS group (difference VAS-tin 18.2 [MCIC = >=10 mm VAS-tin]) and between the groups (difference VAS-tin 12.3 in favor of the CeT + TS group). The average number of treatment sessions was 9.6 (+/-2.6) for the CeT - TS group and 10.3 (+/-2.5) for the CeT + TS group, a non-significant difference. There were no adverse effects in either group. CONCLUSIONS: Despite its limitations, this study provides valuable information on both the characteristics of patients with CeT and TS in a Dutch primary care manual therapy practice and on the potential effectiveness of MTU combined with tinnitus education for the subgroup of CeT + TS patients. PMID- 26971020 TI - Quantification of three galloylglucoside flavour precursors by liquid chromatography tandem mass spectrometry in brandies aged in oak wood barrels. AB - Vanillin-(6'-O-galloyl)-beta-glucopyranoside (VGG), 3,4,5-trimethoxyphenyl-(6'-O galloyl)-beta-glucopyranoside (TMPGG), and (6R,9R)-3-oxo-alpha-ionol-9-O-(6'-O galloyl)-beta-glucopyranoside (macarangioside E) were identified as aroma precursors in oak wood. An LC-MS/MS method was developed and validated to quantify these three galloylglucoside compounds in brandies aged in oak barrels. The detection system consisted of a triple quadrupole mass analyser operating in multiple reaction monitoring (MRM) mode. For the first time, vanillin-beta-d xylopyranoside (VX) was synthesised for use as an internal standard. The detection limits (48 MUg L(-1) for VGG, 52 MUg L(-1) for TMPGG, and 19 MUg L(-1) for macarangioside E) were low enough to quantify these aroma precursors in spirits without any sample preparation. PMID- 26971022 TI - A new three-dimensional Zn(2+) coordination polymer constructed from oxalate and 1,2,4-triazolate. AB - A new 3-D Zn(2+) coordination polymer (CP) [(CH3)2NH2]3[Zn6(ox)4.5(trz)6]?4H2O (ox=oxalate; trz=1,2,4-triazolate) 1 was obtained by a simple solvothermal self assembly. The crystal structural analysis demonstrates that the trz molecules link the Zn(2+) ions into a two-dimensional (2-D) layer network, which is based on the trinuclear Zn3(trz)6 clusters. The ox molecules serve as the linkers to propagate the 2-D layers into a three-dimensional (3-D) network of 1. The thermogravimetry (TG) behavior, photoluminescence property, and the sensing ability of 1 are investigated. The sensing experiment on nitrobenzene (NB) reveals that 1 can serve as a fluorescence probe to detect NB at the ppm concentration. PMID- 26971021 TI - Multiclass semi-volatile compounds determination in wine by gas chromatography accurate time-of-flight mass spectrometry. AB - The performance of gas chromatography (GC) with accurate, high resolution mass spectrometry (HRMS) for the determination of a group of 39 semi-volatile compounds related to wine quality (pesticide residues, phenolic off-flavours, phenolic pollutants and bioactive stilbenes) is investigated. Solid-phase extraction (SPE) was used as extraction technique, previously to acetylation (phenolic compounds) and dispersive liquid-liquid microextraction (DLLME) concentration. Compounds were determined by GC coupled to a quadrupole time-of flight (QTOF) MS system through an electron ionization (EI) source. The final method attained limits of quantification (LOQs) at the very low ng mL(-1) level, covering the range of expected concentrations for target compounds in red and white wines. For 38 out of 39 compounds, performance of sample preparation and determination steps were hardly affected by the wine matrix; thus, accurate recoveries were achieved by using pseudo-external calibration. Levels of target compounds in a set of 25 wine samples are reported. The capabilities of the described approach for the post-run identification of species not considered during method development, without retention time information, are illustrated and discussed with selected examples of compounds from different classes. PMID- 26971023 TI - A benzo-15-crown-5-modifying ratiometric-absorption and fluorescent OFF-ON chemosensor for Cu(2.). AB - One new benzo-15-crown-5-modifying fluorene Schiff base (FBC), together with the CN-linked fluorene-3,4-dimethoxybenzene (FBDMO) and fluorene-benzene (FB) references, has been designed and facilely synthesized. The binding of Cu(2+) with nitrogen atom of CN moiety in these three compounds can inhibit the photo induced electronic transition process and induce the ratiometric-absorption and fluorescent OFF-ON response to Cu(2+). Whereas the employment of benzo-15-crown-5 moiety in FBC as additional binding platform for Cu(2+) not only amplifies the fluorescent enhancement of FBCvia preventing the isomerization of CN moiety, but also endows this compound high selectivity and rapid response towards Cu(2+) over the references FB and FBDMO. These results render FBC highly sensitive ratiometric-absorption and fluorescent OFF-ON detecting potential for Cu(2+) with the detection limit of 3.91 * 10(-6) M. PMID- 26971024 TI - Highly sensitive and selective fluorescent assay for guanine based on the Cu(2+)/eosin Y system. AB - A fluorescent probe has been developed for the determination of guanine based on the quenched fluorescence signal of Cu(2+)/eosin Y. Cu(2+) interacted with eosin Y, resulting in fluorescence quenching. Subsequently, with the addition of guanine to the Cu(2+)/eosin Y system, guanine reacted with Cu(2+) to form 1:1 chelate cation, which further combined with eosin Y to form a 1:1 ternary ion association complex by electrostatic attraction and hydrophobic interaction, resulting in significant decrease of the fluorescence. Hence, a fluorescent system was constructed for rapid, sensitive and selective detection of guanine with a detection limit as low as 1.5 nmol L(-1) and a linear range of 3.3-116 nmol L(-1). The method has been applied satisfactorily to the determination of guanine in DNA and urine samples with the recoveries from 98.7% to 105%. This study significantly expands the realm of application of ternary ion-association complex in fluorescence probe. PMID- 26971025 TI - Two-dimensional character of internal rotation of furfural and other five-member heterocyclic aromatic aldehydes. AB - The features of nuclear motion corresponding to the rotation of the formyl group (CHO) are studied for the molecules of furfural and some other five-member heterocyclic aromatic aldehydes by the use of MP2/6-311G** quantum chemical approximation. It is demonstrated that the traditional one-dimensional models of internal rotation for the molecules studied have only limited applicability. The reason is the strong kinematic interaction of the rotation of the CHO group and out-of-plane CHO deformation that is realized for the molecules under consideration. The computational procedure based on the two-dimensional approximation is considered for low lying vibrational states as more adequate to the problem. PMID- 26971027 TI - Synthesis, characterization and biological evaluation of novel alpha, beta unsaturated amides. AB - Three derivatives of alpha,beta unsaturated amides have been successfully synthesized via Ugi-four component (U-4CR) reaction. The interactions of the amides with calf thymus deoxyribonucleic acid (ct-DNA) have been investigated in the Tris-HCl buffer (pH=7.4) using viscometric, spectroscopic, thermal denaturation studies, and also molecular docking. By UV-Vis absorption spectroscopy studies, adding CT-DNA to the compound solution caused the hypochromism indicates that there are interactions between the compounds and DNA base pairs. In competitive fluorescence with methylene blue as an intercalator probe, adding compounds to DNA-MB solution caused an increase in emission spectra of the complex. This could be because of compound replacing, with similar binding mode of MB, between the DNA base pairs due to release of bonded MB molecules from DNA-MB complex. Thermal denaturation studies and viscometric experiments also indicated that all three investigated compounds bind to CT-DNA by non-classical intercalation mode. Additionally, molecular docking technique predicted partial intercalation binding mode for the compounds. Also, the highest binding energy was obtained for compound 5a. These results are in agreement with results obtained by empirical methods. PMID- 26971026 TI - Conformational change in the C form of palmitic acid investigated by Raman spectroscopy and X-ray diffraction. AB - Fatty acids are substances found in most living beings in nature. Here we report the effect of the low temperature in the vibrational and structural properties of the C form of palmitic acid, a fatty acid with 16 carbon atoms. The Raman spectra were obtained in the temperature interval from 300 to 18K in the spectral range between 30 and 3100 cm(-1). The assignment of the duly observed bands was done based on the density functional theory. On cooling, the main changes observed in the lattice mode region of the Raman spectra were interpreted as a conformational modification undergone by the palmitic acid molecules in the unit cell. The X-ray diffraction measurements were obtained from 290 to 80K showing a slight modification in the lattice parameters at about 210K. Differential scanning calorimetry (DSC) measurements were recorded between 150 and 300K and no enthalpic anomaly in the DSC thermogram was observed. These techniques provided strong evidence of the conformational change in the molecules of palmitic acid at low temperatures. PMID- 26971028 TI - A new analytical approach to understanding nanoscale lead-iron interactions in drinking water distribution systems. AB - High levels of iron in distributed drinking water often accompany elevated lead release from lead service lines and other plumbing. Lead-iron interactions in drinking water distribution systems are hypothesized to be the result of adsorption and transport of lead by iron oxide particles. This mechanism was explored using point-of-use drinking water samples characterized by size exclusion chromatography with UV and multi-element (ICP-MS) detection. In separations on two different stationary phases, high apparent molecular weight (>669 kDa) elution profiles for (56)Fe and (208)Pb were strongly correlated (average R(2)=0.96, N=73 samples representing 23 single-unit residences). Moreover, (56)Fe and (208)Pb peak areas exhibited an apparent linear dependence (R(2)=0.82), consistent with mobilization of lead via adsorption to colloidal particles rich in iron. A UV254 absorbance peak, coincident with high molecular weight (56)Fe and (208)Pb, implied that natural organic matter was interacting with the hypothesized colloidal species. High molecular weight UV254 peak areas were correlated with both (56)Fe and (208)Pb peak areas (R(2)=0.87 and 0.58, respectively). On average, 45% (std. dev. 10%) of total lead occurred in the size range 0.05-0.45 MUm. PMID- 26971029 TI - Remediation of textile azo dye acid red 114 by hairy roots of Ipomoea carnea Jacq. and assessment of degraded dye toxicity with human keratinocyte cell line. AB - Bioremediation has proven to be the most desirable and cost effective method to counter textile dye pollution. Hairy roots (HRs) of Ipomoea carnea J. were tested for decolourization of 25 textile azo dyes, out of which >90% decolourization was observed in 15 dyes. A diazo dye, Acid Red 114 was decolourized to >98% and hence, was chosen as the model dye. A significant increase in the activities of oxidoreductive enzymes was observed during decolourization of AR114. The phytodegradation of AR114 was confirmed by HPLC, UV-vis and FTIR spectroscopy. The possible metabolites were identified by GCMS as 4- aminobenzene sulfonic acid 2-methylaniline and 4- aminophenyl 4-ethyl benzene sulfonate and a probable pathway for the biodegradation of AR114 has been proposed. The nontoxic nature of the metabolites and toxicity of AR114 was confirmed by cytotoxicity tests on human keratinocyte cell line (HaCaT). When HaCaT cells were treated separately with 150 MUg mL(-1) of AR114 and metabolites, MTT assay showed 50% and ~100% viability respectively. Furthermore, flow cytometry data showed that, as compared to control, the cells in G2-M and death phase increased by 2.4 and 3.6 folds respectively on treatment with AR114 but remained unaltered in cells treated with metabolites. PMID- 26971030 TI - Development of SPME-LC-MS method for screening of eight beta-blockers and bronchodilators in plasma and urine samples. AB - The current work describes the development and validation of a simple, efficient, and fast method using solid phase microextraction coupled to liquid chromatography-tandem mass spectrometry (SPME-LC-MS/MS) for the concomitant measurement of eight beta-blockers and bronchodilators in plasma and urine. The presented assay enables quantitative determination of acebutolol, atenolol, fenoterol, nadolol, pindolol, procaterol, sotalol, and timolol. In this work, samples were prepared on a high-throughput platform using the 96-well plate format of the thin film solid phase microextraction (TFME) system, and a biocompatible extraction phase made of hydrophilic-lipophilic balance particles. Analytes were separated on a pentafluorophenyl column (100mm*2.1mm, 3MUm) by gradient elution using an UPLC Nexera coupled with an LCMS-8060 mass spectrometer. The mobile phase consisted of water-acetonitrile (0.1% formic acid) at a flow rate of 0.4mLmin(-1). The linearity of the method was checked within therapeutic blood-plasma concentrations, and shown to adequately reflect typically expected concentrations of future study samples. Post-extraction addition experiments showed that the matrix effect ranged in plasma from 98% for procaterol to 115% for nadolol, and in urine, from 85% for nadolol and pindolol to 119% for atenolol. The method was successfully validated using Food and Drug Administration (FDA) guidelines, and met all acceptance criteria for bioanalytical assays at five concentration levels for all selected drugs. The final protocol can be successfully applied for monitoring concentrations of the selected drugs in both plasma and urine matrices obtained from patients or athletes. PMID- 26971031 TI - A selective and sensitive stability-indicating HPLC method for the validated assay of etoposide from commercial dosage form and polymeric tubular nanocarriers. AB - Etoposide is a topoisomerase II enzyme inhibitor type chemotherapeutic agent which is widely used in the therapy of various cancers. Its short half-life and toxicity to normal tissues are the major drawbacks in its clinical applications. Polymeric nanoparticulate drug delivery systems are rational carriers to deliver etoposide with higher efficiency and fewer side effects. In addition tubular shaped drug carriers are found to show a great potential for drug delivery on the basis of promising results regarding particle shape and cellular uptake. In this study, etoposide loaded polymeric tubular nanocarriers have been developed by template wetting method using porous anodic aluminum oxide membranes as templates. The developed poly(methyl methacrylate) nanocarriers were evaluated for structural analysis, in vitro drug release studies and drug release kinetics. Accurate and reliable determination of the drug release from newly developed nanocarriers, is of great importance. For this reason a selective and sensitive reversed phase liquid chromatography method was developed and fully validated from the point of system suitability, specificity, linearity and range, limit of detection (LOD), limit of quantification (LOQ), precision, accuracy and robustness for the reliable determination of etoposide. Stability indicating capability was shown with forced degradation studies and the chromatographic conditions were optimized on ACE 5C18 (150 mm * 4.6mm I.D., 5 MUm) analytical column. Related to the calibration results ETP was found linear in the range between 0.2 from 100 MUg mL(-1) with the LOD as 0.015 MUg.mL(-1). The resultant conditions were applied for the selective and sensitive determination of etoposide from its commercial dosage form with the high accuracy values (99.82 100.65%). The method was successfully detected assay of etoposide release from newly developed polymeric tubular nanocarriers, which was found as 72.2% at the end of 24h. PMID- 26971032 TI - Quality of life improves with return of voice in tracheostomy patients in intensive care: An observational study. AB - PURPOSE: To measure patient-reported change of mood, communication-related quality of life, and general health status with return of voice among mechanically ventilated tracheostomy patients admitted to the intensive care unit (ICU). MATERIALS AND METHODS: A prospective observational study in a tertiary ICU was conducted. Communication-related quality of life was measured daily using the Visual Analogue Self-Esteem Scale. General health status was measured weekly using the EuroQol-5D. RESULTS: Aspects of communication self-esteem that significantly improved with the return of voice were ability to be understood by others (P = .006) and cheerfulness (P = .04), both with a median difference from before to after return of voice of 1 on the 5-point scale. Return of voice was not associated with a significant improvement in confidence, sense of outgoingness, anger, sense of being trapped, optimism, or frustration. Reported general health status did not significantly improve. CONCLUSIONS: Return of voice was associated with significant improvement in patient reported self-esteem, particularly in being understood by others and in cheerfulness. Improved self esteem may also improve quality of life; however, further research is needed to confirm this relationship. Early restoration of voice should be investigated as a way to improve the experience of ICU for tracheostomy patients. PMID- 26971034 TI - The effect of O-1602, an atypical cannabinoid, on morphine-induced conditioned place preference and physical dependence. AB - BACKGROUND: Previous studies show that some non-CB1/non-CB2 effects of cannabinoids are mediated through G protein coupled receptor 55 (GPR55). As this receptor is activated by some of cannabinoid receptor ligands and is involved in the modulation of pain, it was hypothesized that this receptor may also interact with opioids. This study examined the effect of atypical cannabinoid O-1602 as a GPR55 agonist on morphine-induced conditioned place preference (CPP) and physical dependence. METHODS: We used a biased CPP model to evaluate the effect of O-1602 (0.2, 1 and 5mg/kg, intraperitoneal; ip) on the acquisition and expression of morphine-induced CPP in male mice. The locomotor activities of mice were also recorded. Moreover, repeated administration of morphine (50, 50 and 75mg/kg/day) for three days, induced physical dependence. The withdrawal signs such as jumps and diarrhea were precipitated by administration of naloxone (5mg/kg, ip). The effect of O-1602 on the development of morphine physical dependence was assessed by injection of O-1602 (0.2, 1 and 5mg/kg) before morphine administrations. RESULTS: Morphine (40mg/kg, subcutaneous; sc), but not O-1602 (5mg/kg) elicited significant preference in the post-conditioning phase. O-1602 at the doses of 0.2 and 1mg/kg, but not 5mg/kg reduced acquisition of morphine CPP with an increase in locomotor activity at the dose of 5mg/kg. O-1602 at the doses of 0.2, 1 and 5mg/kg also reduced expression of morphine CPP with an increase in locomotor activity at the dose of 5mg/kg. O-1602 had a significant inhibitory effect on development of morphine-induced physical dependence at the dose of 5mg/kg by decreasing jumps and diarrhea during withdrawal syndrome. CONCLUSIONS: The present results indicate that O-1602 decreased acquisition and expression of morphine CPP and inhibited development of morphine-induced physical dependence. PMID- 26971033 TI - Early veno-venous extracorporeal membrane oxygenation is associated with lower mortality in patients who have severe hypoxemic respiratory failure: A retrospective multicenter cohort study. AB - PURPOSE: The purpose of the study is to compare outcomes in patients who had severe hypoxemic respiratory failure (Pao2/fraction of inspired oxygen <100) who received early veno-venous extracorporeal membrane oxygenation (ECMO) as an adjunct to mechanical ventilation, to those in patients who received conventional mechanical ventilation alone. MATERIALS AND METHODS: This is a multicenter, retrospective unmatched and matched cohort study of patients admitted between April 2006 and December 2013. Generalized logistic mixed-effects models and Cox proportional hazards models were used to determine the association between treatment with ECMO that was started within 3 days of intensive care unit (ICU) admission and ICU and hospital mortality and length of stay, respectively. RESULTS: A total of 2440 patients who had severe hypoxemic respiratory failure due to various etiologies were included, 46 who received early veno-venous ECMO and 2394 unmatched and 398 matched controls who received conventional ventilation alone. Compared to matched controls, ECMO was associated with a lower odds of ICU (odds ratio [95% confidence interval], 0.30 [0.13-0.67]) and inhospital death (odds ratio 0.30 [0.14-0.67]). In addition, ECMO was associated with longer times to discharge from ICU and hospital (hazard ratio, 0.42 [0.37-0.47] and 0.53 [0.38 0.73], respectively). CONCLUSIONS: In this observational study, use of early ECMO compared to conventional mechanical ventilation alone in patients who had severe hypoxemic respiratory failure was associated with a lower risk of mortality and a longer length of stay. PMID- 26971035 TI - Actylise treatment does not influence nitric oxide metabolites serum level. AB - BACKGROUND: Nitric oxide (NO) is synthesized by Nitric Oxide Synthases (NOS), the family of enzymes capable to conduct the conversion of Arginine (Arg) into the NO and Citrulline (Cit). Currently, only the administration of recombinant tissue plasminogen activator (rtPA) is recommended for acute ischemic stroke (AIS) treatment. To allow solubility of rtPA, Arg is added as a constituent of the drug. Our purpose was to check the effect of alteplase administration on NO metabolites concentration in the blood. METHODS: Eighteen AIS patients were selected into the study. Nine of them received thrombolytic therapy (rtPA group). The serum samples were obtained at 3 time-points for rtPA group (time-point 0: 1st-4th hour of stroke; time-point 1: immediately after rtPA administration; time point 3: on day 5-7 from stroke onset). Remaining patients (non-rtPA group) had blood collection at two time-points: time-point 1: 1st-10th hour of stroke and time-point 2: on day 5-7 of stroke. Arg and Cit were determined by the automated ion-exchange chromatography using Amino Acids Analyzer. NO serum level was indirectly evaluated with the usage of commercially available kits that measuring the nitrate/nitrite level. RESULTS: Significant increase of Arg serum level was noticed at time-point 1, directly after the iv thrombolysis in comparison to non rtPA group. However, the products of the reaction catalyzed by NOS (NO and Cit) did not rise after the thrombolysis. CONCLUSIONS: Current study showed that Arg administration simultaneously with rtPA, as a constituent of Actylise, does not affect serum NO metabolites level. PMID- 26971036 TI - Eosinopenia as a Predictive Factor of the Short-Term Risk of Mortality and Infection after Acute Cerebral Infarction. AB - BACKGROUND: Eosinopenia has been shown to be a prognostic factor in bacteremia, chronic obstructive pulmonary disease, and myocardial infarction, but studies focusing on cerebral infarction are lacking. METHODS: We conducted a retrospective study of 405 patients admitted to the Asahi General Hospital from June 2011 to September 2014 with a diagnosis of cerebral infarction within 24 hours after symptom onset. Differences in mortality, mortality associated with infection, and the prevalence of infection within 2 months of hospital admission were assessed between patients with and without eosinopenia at presentation. RESULTS: Patients with eosinopenia had a significantly higher mortality rate (hazard ratio (HR) 2.54, 95% confidence interval (CI) 1.17-5.21, P = .01), mortality associated with infection (HR 28.7, 95% CI 4.9-542.2, P <.0001), and an increased prevalence of infection (HR 1.83, 95% CI 1.12-2.89, P = .01) than patients without eosinopenia. Patients with neutrophilia and eosinopenia showed a significantly higher mortality rate than patients without neutrophilia (HR 3.15, 95% CI 1.40-6.92, P = .007), whereas patients with neutrophilia without eosinopenia showed no significant difference in mortality compared with patients without neutrophilia (HR 1.57, 95% CI .56-3.93, P = .37). Eosinopenia was a significant risk factor in 2-month mortality rate in multivariate analyses (HR 2.34, 95% CI 1.05-4.95, P = .04). CONCLUSIONS: Eosinopenia is a novel predictive factor for complications after acute cerebral infarction. Stroke patients with eosinopenia should be monitored carefully for infection. PMID- 26971037 TI - External Validation of the Cincinnati Prehospital Stroke Severity Scale. AB - BACKGROUND: The Cincinnati Prehospital Stroke Severity Scale (CPSSS) was recently developed to predict large-vessel occlusions (LVOs) in patients with acute ischemic stroke (AIS). In its derivation study, which consisted of patients enrolled in thrombolysis and endovascular therapy trials, the CPSSS had excellent discriminatory performance. We sought to externally validate the CPSSS in an independent cohort. METHODS: Using our institution's prospective stroke registry, we calculated CPSSS scores for all patients diagnosed with AIS at Weill Cornell Medical Center in 2013 and 2014. The primary outcome was presence of LVO and the secondary outcome was a National Institutes of Health Stroke Scale (NIHSS) score of 15 or higher. Harrell's c-statistic was calculated to determine the CPSSS score's discriminatory performance. Using the previously defined cut-point of 2 or higher (range 0-4), we evaluated the test properties of the CPSSS for predicting study outcomes. RESULTS: Among 751 patients with AIS, 664 had vessel imaging and were included in the final analysis. Of these patients, 80 (14.2%) had LVOs and 117 (17.6%) had an NIHSS score of 15 or higher. The median CPSSS score was 0 (interquartile range 0-1) and 133 patients (20%) had scores of 2 or higher. c-statistic was .85 (95% confidence interval [CI] .81-.90) for predicting LVO and .94 (95% CI .92-.97) for predicting an NIHSS score of 15 or higher. Using a cut-point of 2 or higher, the CPSSS was 70.0% sensitive and 86.8% specific for predicting LVO, and 87.2% sensitive and 94.3% specific for predicting an NIHSS score of 15 or higher. CONCLUSIONS: In a cohort of patients with AIS treated at a tertiary-care stroke center, the CPSSS had reasonable sensitivity and specificity for predicting LVO and severe stroke. Future studies should aim to prospectively validate the score in emergency responders. PMID- 26971038 TI - Therapeutic Effect Analysis of Sinomenine on Rat Cerebral Ischemia-Reperfusion Injury. AB - OBJECTIVE: The objective of this study is to investigate the therapeutic effect of sinomenine (SIN) on rat cerebral ischemia-reperfusion (IR) injury and the molecular mechanism. METHODS: One hundred thirty-five rats were equally randomized into sham-operated group, middle cerebral artery occlusion (MCAO) group, and SIN group, and reversible rat MCAO model was made according to the Longa method for the MCAO and SIN groups. Then, 15 rats from each group were decapitated at 6, 12, and 24 hours after reperfusion to obtain brain tissue samples. Rats in the SIN group were injected with sinomenine by tail vein (90 mg/kg) 1 hour before ischemia; rats in the MCAO and sham-operated groups were administrated with the same volume of saline. Neurological severity score (NSS), infarction volume, ischemic brain water content, and blood-brain barrier (BBB) permeability were determined at corresponding time points. Acid-sensing ion channel (ASIC) 1a mRNA level was determined by quantitative real-time polymerase chain reaction; ischemic brain contents of lactic acid (LD), lactic dehydrogenase (LDH), ATPase, and inflammatory factors were determined by spectrophotometric method. RESULTS: At 12 hours after reperfusion and since then, NSS in the SIN group decreased obviously; infarction volume, brain water content, and BBB permeability in the SIN group were lower than those in the MCAO group (P < .05). IR injury resulted in the upregulation of the contents of ASIC1a mRNA, LD, LDH, and inflammatory factors and the downregulation of the contents of ATPase, while SIN could reverse the upregulation/downregulation effect induced by IR injury (P < .05). CONCLUSION: Through its anti-inflammation effect, which alleviates acidosis, improves energy metabolism, and inhibits ASIC1a level, SIN protects ischemic rat brain against cerebral IR injury. PMID- 26971039 TI - Endovascular Internal Trapping of Ruptured Occipital Artery Pseudoaneurysm Associated with Occipital-Internal Jugular Vein Fistula in Neurofibromatosis Type 1. AB - Spontaneous cervical extradural pseudoaneurysms or arteriovenous fistulas (AVFs) are rare vascular diseases. We report a case of ruptured occipital artery (OA) pseudoaneurysm associated with occipital-internal jugular vein (IJV) fistula in neurofibromatosis type 1. Endovascular internal trapping via the OA was attempted; however, the distal entry of the OA could not be accessed because of the high shunt flow and tortuosity of the OA. The distal part of the OA was obliterated with coil via a transvenous approach through the IJV and pseudoaneurysm. The proximal entry of the OA was obliterated with coil and glue under proximal flow control with a balloon, and the fistula was successfully obliterated without placement of coils in the pseudoaneurysm. When ordinary internal trapping via a transarterial approach is not possible, the transvenous approach should be considered as an alternative for AVF associated with an aneurysmal component. PMID- 26971040 TI - Stop Stroke(c) Acute Care Coordination Medical Application: A Brief Report on Postimplementation Performance at a Primary Stroke Center. AB - BACKGROUND: The objective of our study was to evaluate the effect of the Pulsara Stop Stroke(c) medical application on door-to-needle (DTN) time in patients presenting to our emergency department with acute ischemic stroke (AIS). The secondary objective was to evaluate the DTN performance of dedicated neurohospitalists versus private practice neurologists covering emergency department stroke call. METHODS: We conducted a retrospective cohort study of the Good Shepherd Health System stroke quality improvement dashboard for an 18-month period. The primary outcome was mean DTN time performance in cases with and without Stop Stroke(c) usage. Secondary outcome was mean DTN time between neurohospitalist and private neurologists with and without use of Stop Stroke(c). RESULTS: During the study period, there were 85 stroke activations receiving tissue plasminogen activator (63 with Stop Stroke(c), 22 without Stop Stroke(c)). In cases where the app was used, we observed a reduction in mean DTN time of 40 minutes (87-47 minutes), a 46% reduction. There was no significant difference in DTN time observed between the neurohospitalist and private neurologist performance independent of app usage. Mean DTN less than 60 minutes improved with app use from 18% to 85% with Stop Stroke(c). CONCLUSIONS: In patients arriving to our primary stroke center with AIS, use of Pulsara Stop Stroke(c) acute care coordination app decreased mean DTN time by 40 minutes, a significant 46% improvement in this metric and is consistent with other studies of the app. We further observed a 3.7* improvement in DTN less than 60 minutes with use of the app. PMID- 26971041 TI - The Evolution of Professionalism in Medicine and Radiology. AB - Professionalism and ethics are difficult to define, and it is often a case of "you know it when you see it." In recent years, there have been calls to renew the focus on professionalism and ethics and their teaching in the medical and allied professions, part precipitated by a perceived and probably real decline in doctors' professional values. Medical professionalism has evolved markedly in the last couple of centuries and continues to change today at a rapid pace, spurred by technological advances and generational change. The reasons to promote medical professionalism include regulatory requirements, aligning our professions' outcomes and behaviors, and the moral imperative that being professional is the right thing to do. Radiologists should emphasize, model, and teach professionalism to our colleagues, allied personnel, and trainees whenever opportunity permits. Medical students now receive teaching in professionalism and ethics throughout their training, and there is a need to continue training formally and informally during residency training. Faculty or those charged with teaching professionalism will need to first understand what constitutes medical professionalism, and here we attempt to define and outline what professionalism looks like in practice. The article concludes with a summary of the opportunities within radiology practice, with examples, for us to exhibit professional actions, values, and ideas. PMID- 26971042 TI - The Impact Factory. PMID- 26971043 TI - Transformation and Transformational Leadership: A Review of the Current and Relevant Literature for Academic Radiologists. AB - With the US healthcare system on an unsustainable course, change is inevitable. Changes in the healthcare landscape impacting radiology include changing payment models, rapid adoption of digital technology, changes in radiology resident certifying exams, and the rise of consumerism in health care. Academic Radiology will be part of that change with none of its missions spared. What matters is not that change is coming but how Academic Radiology responds to change. Do we ignore, adapt, adopt others' practices, or lead change? Change management or transformation is a management skill set that can be learned and developed. Transformational leadership is a leadership style defined by the relationships between the leaders and the followers and the results they are able to achieve together to meet organizational goals. In this paper, we provide a review of key change management theories, as well as practical advice for self-reflection and development of leadership behaviors that promote effective change management and organizational transformation, particularly in a complex industry like Academic Radiology. PMID- 26971044 TI - Genomic profile of a squamous cell carcinoma ex pleomorphic adenoma compared to a head and neck squamous cell carcinoma. PMID- 26971045 TI - Carcinoma ex-pleomorphic adenoma derived from recurrent pleomorphic adenoma shows important difference by array CGH compared to recurrent pleomorphic adenoma without malignant transformation. AB - INTRODUCTION: A key step of cancer development is the progressive accumulation of genomic changes resulting in disruption of several biological mechanisms. Carcinoma ex-pleomorphic adenoma (CXPA) is an aggressive neoplasm that arises from a pleomorphic adenoma. CXPA derived from a recurrent PA (RPA) has been rarely reported, and the genomic changes associated with these tumors have not yet been studied. OBJECTIVE: We analyzed CXPA from RPAs and RPAs without malignant transformation using array-comparative genomic hybridization (array CGH) to identify somatic copy number alterations and affected genes. METHODS: DNA samples extracted from FFPE tumors were submitted to array-CGH investigation, and data was analyzed by Nexus Copy Number Discovery Edition v.7. RESULTS: No somatic copy number alterations were found in RPAs without malignant transformation. As for CXPA from RPA, although genomic profiles were unique for each case, we detected some chromosomal regions that appear to be preferentially affected by copy number alterations. The first case of CXPA-RPA (frankly invasive myoepithelial carcinoma) showed copy number alterations affecting 1p36.33p13, 5p and chromosomes 3 and 8. The second case of CXPA-RPA (frankly invasive epithelial myoepithelial carcinoma) showed several alterations at chromosomes 3, 8, and 16, with two amplifications at 8p12p11.21 and 12q14.3q21.2. The third case of CXPA RPA (minimally invasive epithelial-myoepithelial carcinoma) exhibited amplifications at 12q13.3q14.1, 12q14.3, and 12q15. CONCLUSION: The occurrence of gains at chromosomes 3 and 8 and genomic amplifications at 8p and 12q, mainly those encompassing the HMGA2, MDM2, WIF1, WHSC1L1, LIRG3, CDK4 in CXAP from RPA can be a significant promotional factor in malignant transformation. PMID- 26971046 TI - Country in Focus: diabetes prevalence on the rise in Turkey. PMID- 26971047 TI - Comparative genomic analysis of toxin-negative strains of Clostridium difficile from humans and animals with symptoms of gastrointestinal disease. AB - BACKGROUND: Clostridium difficile infections (CDI) are a significant health problem to humans and food animals. Clostridial toxins ToxA and ToxB encoded by genes tcdA and tcdB are located on a pathogenicity locus known as the PaLoc and are the major virulence factors of C. difficile. While toxin-negative strains of C. difficile are often isolated from faeces of animals and patients suffering from CDI, they are not considered to play a role in disease. Toxin-negative strains of C. difficile have been used successfully to treat recurring CDI but their propensity to acquire the PaLoc via lateral gene transfer and express clinically relevant levels of toxins has reinforced the need to characterise them genetically. In addition, further studies that examine the pathogenic potential of toxin-negative strains of C. difficile and the frequency by which toxin negative strains may acquire the PaLoc are needed. RESULTS: We undertook a comparative genomic analysis of five Australian toxin-negative isolates of C. difficile that lack tcdA, tcdB and both binary toxin genes cdtA and cdtB that were recovered from humans and farm animals with symptoms of gastrointestinal disease. Our analyses show that the five C. difficile isolates cluster closely with virulent toxigenic strains of C. difficile belonging to the same sequence type (ST) and have virulence gene profiles akin to those in toxigenic strains. Furthermore, phage acquisition appears to have played a key role in the evolution of C. difficile. CONCLUSIONS: Our results are consistent with the C. difficile global population structure comprising six clades each containing both toxin positive and toxin-negative strains. Our data also suggests that toxin-negative strains of C. difficile encode a repertoire of putative virulence factors that are similar to those found in toxigenic strains of C. difficile, raising the possibility that acquisition of PaLoc by toxin-negative strains poses a threat to human health. Studies in appropriate animal models are needed to examine the pathogenic potential of toxin-negative strains of C. difficile and to determine the frequency by which toxin-negative strains may acquire the PaLoc. PMID- 26971048 TI - Topical ocular dexamethasone decreases intraocular pressure and body weight in rats. AB - BACKGROUND: Recently, topical dexamethasone-induced ocular hypertension and a consequent loss of retinal ganglion cells (RGCs) have been described in mice. This has been proposed as a model of steroid-induced glaucoma. In this study, we set up and evaluated a similar model in rats. RESULTS: Ten-week old Sprague Dawley (SD) rats (N = 12) were used to evaluate the effect of topical 0.1% dexamethasone (50 MUl) administered 3 times daily for 4 weeks. Sodium chloride (0.9%) was used in another group of rats (N = 12) that served as the controls. After 1 week, we observed a progressive decrease in body weight in the dexamethasone-treated rats compared both to the pre-treatment baseline and the vehicle-treated rats. In contrast to earlier work that showed elevated Intraocular pressure (IOP) following dexamethasone instillation in mice, IOP in the rats unexpectedly fell to 11.3 +/- 1.3 mmHg in the treated eyes, compared to 14.8 +/- 2.4 mmHg in the untreated eyes, after 3 weeks of topical dexamethasone (P = 0.032). Blood tests performed after 4 weeks of treatment showed a 3.3-fold increase in both plasma cholesterol (P < 0.001) and alanine transaminase (P = 0.019) in the dexamethasone-treated rats compared to the control rats. Meanwhile, topical steroid did not induce changes in either plasma blood glucose or glycated hemoglobin (HbA1c). We also did not detect changes in the expression of RGC markers (with real-time PCR) following the treatment. CONCLUSIONS: In contrast to mice, which previously showed increased IOP following the topical administration of dexamethasone, the rats displayed a paradoxical reduction in IOP following a similar treatment. This was accompanied by a loss of body weight without affecting the level of blood glucose. PMID- 26971051 TI - Mineralization of the textile dye acid yellow 42 by solar photoelectro-Fenton in a lab-pilot plant. AB - A complete mineralization of a textile dye widely used in the Chilean textile industry, acid yellow 42 (AY42), was studied. Degradation was carried out in an aqueous solution containing 100mgL(-1) of total organic carbon (TOC) of dye using the advanced solar photoelectro-Fenton (SPEF) process in a lab-scale pilot plant consisting of a filter press cell, which contains a boron doped diamond electrode and an air diffusion cathode (BDD/air-diffusion cell), coupled with a solar photoreactor for treat 8L of wastewater during 270min of electrolysis. The main results obtained during the degradation of the textile dye were that a complete transformation to CO2 depends directly on the applied current density, the concentration of Fe(2+) used as catalyst, and the solar radiation intensity. The elimination of AY42 and its organic intermediates was due to hydroxyl radicals formed at the anode surface from water oxidation and in the bulk from Fenton's reaction between electrogenerated H2O2 and added Fe(2+). The application of solar radiation in the process (SPEF) yield higher current efficiencies and lower energy consumptions than electro-Fenton (EF) and electro-oxidation with electrogenerated H2O2 (E OH2O2) by the additional production of hydroxyl radicals from the photolysis of Fe(III) hydrated species and the photodecomposition of Fe(III) complexes with organic intermediates. Moreover, some products and intermediates formed during mineralization of dye, such as inorganic ions, carboxylic acids and aromatic compounds were determined by photometric and chromatographic methods. An oxidation pathway is proposed for the complete conversion to CO2. PMID- 26971050 TI - Interaction of bisphenol A 3,4-quinone metabolite with glutathione and ribonucleosides/deoxyribonucleosides in vitro. AB - Bisphenol A is a monomer used in the manufacture of polycarbonate plastic products, epoxy resin-based food can liners and flame retardants. To determine the genotoxic potential of bisphenol A, the mechanism of the reactions between the reactive electophilic bisphenol A 3,4-quinone (BPAQ) with glutathione and ribonucleosides/deoxyribonucleosides were studied. The obtained results demonstrated that BPAQ reacted with 2'-deoxyguanosine (dG)/guanosine (G), 2' deoxyadenosine (dA)/adenosine (A), but not with 2'-deoxycytidine (dC)/cytidine (C) and thymidine (T)/uridine (U) in aqueous acetic acid. The reactions were accompanied by loss of deoxyribose, and the rate of depurination by deoxyribonucleoside adducts were faster than that of ribonucleoside adducts. In mixtures of ribonucleosides and deoxyribonucleosides treated with BPAQ, reactions occurred more readily with dG/G than dA/A. The structures of the modified bases were confirmed by electrospray ionization tandem mass spectrometry (ESI-MS/MS). We also found that BPAQ reacted readily with glutathione (GSH) in aqueous acetic acid, and characterized the BPAQ-GSH conjugate by ESI-MS/MS. The in vitro data of depurinating DNA/RNA adducts and BPAQ-GSH adducts may provide appropriate reference for the identification of BPAQ adducts in environmental and biological systems. PMID- 26971052 TI - Similar Depletion of Protective Faecalibacterium prausnitzii in Psoriasis and Inflammatory Bowel Disease, but not in Hidradenitis Suppurativa. AB - BACKGROUND AND AIMS: Psoriasis and hidradenitis suppurativa [HS] co-occur more often with inflammatory bowel disease [IBD] than expected, due to shared pathogenic and genetic features. It is known that IBD patients harbour an altered intestinal microbiome characterised by a depletion of Faecalibacterium prausnitzii and increase of Escherichia coli. At present, it is unclear whether a similar intestinal microbiome trend can be identified in IBD-associated skin disorders. We therefore investigated the F. prausnitzii and E. coli abundance in psoriasis and HS, with and without concomitant IBD. METHODS: Using quantitative polymerase chain reaction , we compared the F. prausnitzii and E. coli abundances in faecal samples from healthy controls [n = 33] with samples from patients with psoriasis [n = 29], IBD [n = 31], and concomitant IBD and psoriasis [n = 13]. Likewise, we analysed samples from patients with HS [n = 17], and concomitant IBD and HS [n = 17]. RESULTS: Psoriasis patients harboured a significantly lower abundance of F. prausnitzii in their stool than healthy controls [p < 0.001], which was similar to IBD patients. Together with the reduced F. prausnitzii levels, the psoriasis patients had a significantly higher abundance of E. coli [p < 0.001]. No significant difference in F. prausnitzii or E. coli abundance was found in HS. It was apparent that patients with concomitant IBD and associated skin disorder had the greatest decrease of F. prausnitzii and increase of E. coli. CONCLUSIONS: The study demonstrates, for the first time, an IBD-like decrease of F. prausnitzii together with an increase of E.coli in psoriasis, supporting the presence of a gut-microbiome-skin axis in psoriasis and IBD. PMID- 26971049 TI - Brain Regions Related to Impulsivity Mediate the Effects of Early Adversity on Antisocial Behavior. AB - BACKGROUND: Individual differences in impulsivity and early adversity are known to be strong predictors of adolescent antisocial behavior. However, the neurobiological bases of impulsivity and their relation to antisocial behavior and adversity are poorly understood. METHODS: Impulsivity was estimated with a temporal discounting task. Voxel-based morphometry was used to determine the brain structural correlates of temporal discounting in a large cohort (n = 1830) of 14- to 15-year-old children. Mediation analysis was then used to determine whether the volumes of brain regions associated with temporal discounting mediate the relation between adverse life events (e.g., family conflict, serious accidents) and antisocial behaviors (e.g., precocious sexual activity, bullying, illicit substance use). RESULTS: Greater temporal discounting (more impulsivity) was associated with 1) lower volume in frontomedial cortex and bilateral insula and 2) greater volume in a subcortical region encompassing the ventral striatum, hypothalamus and anterior thalamus. The volume ratio between these cortical and subcortical regions was found to partially mediate the relation between adverse life events and antisocial behavior. CONCLUSIONS: Temporal discounting is related to regions of the brain involved in reward processing and interoception. The results support a developmental imbalance model of impulsivity and are consistent with the idea that negative environmental factors can alter the developing brain in ways that promote antisocial behavior. PMID- 26971053 TI - Cytomegalovirus Infection in Ulcerative Colitis is Related to Severe Inflammation and a High Count of Cytomegalovirus-positive Cells in Biopsy Is a Risk Factor for Colectomy. AB - BACKGROUND AND AIMS: Cytomegalovirus [CMV] infection often reactivates in the course of inflammatory bowel disease, but the significance of this remains disputable. Our aim was to evaluate whether severity of CMV colitis is associated with colectomy risk in ulcerative colitis [UC] patients. The secondary aim was to evaluate agreement between immunohistochemistry [IHC] and blood CMV polymerase chain reaction [PCR]. METHODS: UC patients with CMV assessment of the colon, hospitalised in a referral unit between 2005 and 2012 were retrospectively identified. The course and severity of the disease were analysed, with inflammation graded histologically across the range 0-3. The numbers of CMV IHC positive cells per biopsy section were counted, and results for blood CMV PCR were also retrieved. Data on colectomies were also collected. RESULTS: Of 141 patients, 95 were analysed, with 33 found to be CMV IHC-positive and 62 negative. The colectomy risk was significantly higher in patients with >= 5 IHC-positive cells, as opposed to those with none or less than 5 [p = 0.014] with median follow-up of 1.9 and 3.2 years, respectively. The CMV IHC-positive patients had lower haemoglobin [median 11.0g/dl vs 12.0; p = 0.028] and albumin [median 29.5g/l vs 33.1; p = 0.038] levels and more intense histological inflammation [p = 0.020] compared with CMV IHC-negative patients. There was substantial agreement between IHC and blood PCR [Cohen's kappa coefficient 0.72]. CONCLUSIONS: Five or more CMV IHC-positive cells per biopsy section were indicative of a greater colectomy risk. CMV infection was related to more severe inflammation. Blood CMV PCR is a useful tool in UC. PMID- 26971054 TI - Endoscopic Dilatation of Crohn's Anastomotic Strictures is Effective in the Long Term, and Escalation of Medical Therapy Improves Outcomes in the Biologic Era. AB - BACKGROUND AND AIMS: To investigate the long-term efficacy of endoscopic dilatation of Crohn's anastomotic strictures and to identify risk and protective factors associated with the need for repeat dilatation or surgery. METHODS: A total of 54 patients who had endoscopic balloon dilatations for anastomotic Crohn's strictures between 2004 and 2009, with follow-up until June 2014, were identified from a single tertiary center. The primary end points were repeat dilatation or surgical resection, and the impact of radiology, medical therapy, and endoscopic data on these outcomes was analysed with Cox proportional hazards analysis. RESULTS: A total of 151 dilatations were performed on patients with a median age of 52 years [interquartile range (IQR), 46-62 years]. The median duration from the first to the second dilatation was 6 years (IQR, 5-7 years). The median disease duration was 28 years (IQR, 19-32 years). At endoscopy, disease activity was reported in 50/54 (92%) cases, with a median Rutgeerts grading of i2 (range, i0-i4). A median of two (IQR 1-9) dilatations was required, with a time to repeat dilatation of 23 months (IQR 7.2-56.9). Escalation of medical therapy was adopted in 22/54 patients (41% of the study population). On multivariate analysis, only combination therapy (anti-TNFalpha and immunomodulator) was significantly associated with the (decreased) need for repeated dilatation [hazard ratio (HR) 0.23; 95% CI, 0.07-0.67; p = 0.01]. Anastomotic resections were performed in 10 (18%) patients, with a Rutgeerts score of i4 at initial endoscopic balloon dilatation being associated with this outcome (HR 4.55; 95% CI 1.08-19.29; p = 0.04) on multivariate analysis. CONCLUSION: Endoscopic balloon dilatation of Crohn's anastomotic strictures is safe and effective in the long term. We demonstrate that active disease predicts for future surgery, while escalation of medical therapy may decrease the need for repeat dilatation. PMID- 26971056 TI - Posterior interosseous nerve palsy secondary to deep lipoma. PMID- 26971055 TI - Spontaneous coronary artery dissection in a patient with autosomal dominant polycystic kidney disease: a case report. AB - BACKGROUND: Spontaneous coronary artery dissection is an uncommon syndrome. Its prevalence among patients with polycystic kidney disease is very rare, with no previously reported involvement of the right posterior descending coronary artery. CASE PRESENTATION: We describe the case of a middle-aged Caucasian woman with polycystic kidney disease who presented with a non-ST elevation myocardial infarction. Cardiac catheterization revealed a dissection of her right posterior descending coronary artery. She was treated with dual antiplatelet therapy and had a favorable outcome. CONCLUSION: We report a rare and interesting case of spontaneous coronary artery dissection of the right posterior descending coronary artery in a patient with polycystic kidney disease. It is important to consider spontaneous coronary artery dissection in the differential diagnosis of patients with polycystic kidney disease who present with an acute coronary syndrome. PMID- 26971057 TI - Cranial mononeuritis multiplex as the initial manifestation of systemic lupus erythematosus: A diagnostic challenge. PMID- 26971058 TI - Factors associated with mixed dementia vs Alzheimer disease in elderly Mexican adults. AB - INTRODUCTION: Mixed dementia (DMix) refers to dementia resulting from Alzheimer disease in addition to cerebrovascular disease. The study objectives were to determine the clinical and imaging factors associated with Dmix and compare them to those associated with Alzheimer disease. MATERIAL AND METHODS: Cross-sectional study including 225 subjects aged 65 years and over from a memory clinic in a tertiary hospital in Mexico City. All patients underwent clinical, neuropsychological, and brain imaging studies. We included patients diagnosed with DMix or Alzheimer disease (AD). A multivariate analysis was used to determine factors associated with DMix. RESULTS: We studied 137 subjects diagnosed with Dmix. Compared to patients with AD, Dmix patients were older and more likely to present diabetes, hypertension, dyslipidaemia, and history of cerebrovascular disease (P<.05). The multivariate analysis showed that hypertension (OR 1.92, CI 1.62-28.82; P=.009), white matter disease (OR 3.61, CI 8.55-159.80; P<.001), and lacunar infarcts (OR 3.35, CI 1.97-412.34; P=.014) were associated with Dmix, whereas a history of successfully treated depression showed an inverse association (OR 0.11, CI 0.02-0-47; P=.004) CONCLUSIONS: DMix may be more frequent than AD. Risk factors such as advanced age and other potentially modifiable factors were associated with this type of dementia. Clinicians should understand and be able to define Dmix. PMID- 26971059 TI - Combined central and peripheral demyelination: A case description. PMID- 26971060 TI - Executive functions and language in children with different subtypes of specific language impairment. AB - INTRODUCTION: The marked heterogeneity among children diagnosed with specific language impairment (SLI) highlights the importance of studying and describing cases based on the distinction between the expressive and receptive-expressive SLI subtypes. The main objective of this study was to examine neuropsychological, linguistic, and narrative behaviours in children with different SLI subtypes. METHOD: A comprehensive battery of language and neuropsychological tests was administered to a total of 58 children (29 with SLI and 29 normal controls) between 5.60 and 11.20 years old. RESULTS: Both SLI subtypes performed more poorly than the control group in language skills, narrative, and executive function. Furthermore, the expressive SLI group demonstrated substantial ungrammaticality, as well as problems with verbal fluency and both verbal and spatial working memory, while the receptive-expressive SLI subtype displayed poorer neuropsychological performance in general. CONCLUSIONS: Our findings showed that children with either SLI subtype displayed executive dysfunctions that were not limited to verbal tasks but rather extended to nonverbal measures. This could reflect a global cognitive difficulty which, along with declining linguistic and narrative skills, illustrates the complex profile of this impairment. PMID- 26971061 TI - Bilateral papilloedema as the initial manifestation of spinal ependymoma. PMID- 26971062 TI - Editorial overview: Cell architecture. PMID- 26971063 TI - Paget disease of the vulva. AB - In this review, we provide an overview of the clinical aspects, histopathology, molecular genetics, and treatment options for Vulvar Paget's Disease (VPD), a rare skin disease, most commonly found in postmenopausal Caucasian women. The underlying cause of VPD remains not well understood. VPD is rarely associated with an underlying urogenital, gastrointestinal or vulvar carcinoma. In approximately 25% of the cases, VPD is invasive; in these cases, the prognosis is worse than in non-invasive cases. Recurrence rates in invasive VPD are high: 33% in cases with clear margins, and even higher when surgical margins are not clear, regardless of invasion. Historically, surgical excision has been the treatment of choice. Recent studies show that imiquimod cream may be an effective and safe alternative. PMID- 26971065 TI - Co-immobilization of laccase and mediator through a self-initiated one-pot process for enhanced conversion of malachite green. AB - Laccase is a green biocatalyst. It works with molecular oxygen and produces water as the only by-product. However, its practical application is far less than satisfactory due to the low stability/poor reusability of free laccase and the potential secondary pollution caused by dissolved mediators. To address those bottlenecks in laccase-based catalysis, a novel biocatalyst (Immo-LMS) was fabricated by simultaneously immobilizing both laccase and a mediator (acetylacetone, abbreviated as AA) into a hydrogel through the laccase-AA initiated polymerization. This self-initiated immobilization process avoided the forced conformational change of laccase in the passive embedding to pre-existing carriers. Resulting from the effective cooperation of laccase and AA, the Immo LMS had the highest substrate conversion quantity to malachite green, followed by the sole immobilized laccase and the immobilized laccase with an external mediator. Besides the improved activity, the Immo-LMS showed enhanced stability. The good performance of the Immo-LMS suggests that the co-immobilization of laccase and mediator through the self-initiated one-pot process was a promising strategy for the immobilization of laccase, which is expected to be helpful to cut down the running cost as well as the potential toxicity that come from mediators in the practical application of laccase. PMID- 26971064 TI - PET-adapted omission of radiotherapy in early stage Hodgkin lymphoma-a systematic review and meta-analysis. AB - BACKGROUND: Hodgkin lymphoma (HL) is one of the most common malignancies in young adults and one of the most curable cancers worldwide. With interim PET-scan, HL treatment is in the process of being modified: a negative or positive interim PET separates good and poor responders to initial therapy; therefore, deescalated or escalated additional treatment is currently being evaluated in clinical trials. METHODS: The Cochrane Library, MEDLINE and conference proceedings were searched until 05.2015 for randomized controlled trials (RCTs) comparing FDG-PET-adapted therapy to standard treatment in untreated early stage HL patients with a negative PET-scan. Two review authors independently screened search results and extracted relevant study data. Hazard ratios (HR) were used for time-to-event data and risk rations (RR) for dichotomous data, with 95% confidence intervals (CI). If trials were considered sufficiently clinically homogenous, fixed-effect model was used to pool data. RESULTS: Three RCTs involving a total of 1480 participants were included in the meta-analysis. Only one trial provided data for OS, without evidence for a difference between both arms (HR 0.51; 95% CI 0.15 1.68). All three trials assessed progression free survival, which was inferior in the PET-adapted arms (without radiotherapy) compared to the standard treatment arms (HR 2.40; 95% CI 1.63-3.53). Adverse events were reported in one study only, without evidence for a difference between both arms. There were no data on long term adverse events, quality of life and treatment-related mortality available CONCLUSION: To date, no robust data on survival and adverse events are available. However, this systematic review found that PFS was significantly decreased in the PET-adapted treatment arm (without radiotherapy) in early stage HL patients. PMID- 26971066 TI - Morphology of electrospun fibers derived from High Internal Phase Emulsions. AB - High Internal Phase Emulsions (HIPEs) are known for their excessive volume of dispersed phase (volume fraction of dispersed phase Phid>0.74) and are primarily used for polymerization of continuous phase monomer(s) thereby generating porous systems in a single step. In the present work, electrospinning of HIPEs formed from aqueous solution of poly(vinyl alcohol) (PVA) dispersed in continuous phase comprised of poly(epsilon-caprolactone) (PCL) solution in toluene is conducted. Effect of variation in volume fraction of dispersed and continuous phase on fiber morphology was studied. Fibers of co-continuous morphology were obtained due to coalescence and dielectrophoresis of the higher electrically conducting dispersed aqueous phase than toluene containing continuous phase. Removal of PVA was later done by washing of fibers with water to evaluate the presence of two phases in the fibers and relate it to original HIPE morphology of the emulsions. Heterogeneous and surface nucleation of PCL and Brij-58 confined within electrospun fibers of HIPEs was studied in detail and related to the original HIPE structure. PMID- 26971067 TI - Preparation, characterization and application of nanosized CuO/HZSM-5 as an efficient and heterogeneous catalyst for the N-formylation of amines at room temperature. AB - An efficient and new method for the synthesis of formamides using HZSM-5 zeolite supported copper oxide nanoparticles as an efficient and heterogeneous catalyst is reported. The catalyst was characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), atomic absorption spectroscopy (AAS), Brunauer-Emmett-Teller (BET), energy dispersive X-ray spectroscopy (EDS), temperature programmed desorption of ammonia (TPD-NH3) and Fourier transformed infrared spectroscopy (FT-IR). This method has the advantages of eliminating homogeneous catalysts and provides simple methodology with easy work up. Excellent yields of the corresponding formamides were obtained through this cost-effective protocol under solvent-free conditions with shorter reaction time. The catalyst was easily isolated from the reaction mixture by filtration and reused several times without significant loss in its catalytic. PMID- 26971069 TI - A Peculiar Primary Paraganglioma of the Distal Thumb. AB - A paraganglioma is a highly vascularized neuroendocrine tumor most commonly found within the adrenal gland as a pheochromocytoma. Extra-adrenal paragangliomas are frequently located in the head, neck, thorax, and abdomen. We report the first documented case of a primary paraganglioma found within the appendicular skeleton. Only 2 additional cases of paragangliomas in the extremities have been documented, one in the soft tissue of the forearm and other within the median nerve. Our patient underwent amputation of the distal phalanx, with no sign of recurrence at greater than 1 year of follow-up. Because of the geographic and clinical similarity to a benign enchondroma, radiographic imaging alone may not be sufficient to rule out malignancies inside bones. Thus paraganglioma should remain in the differential and immunohistochemistry is both vital and necessary to confirm the diagnosis. Vigilant and appropriate follow-up is necessary to detect metastases early in these patients. PMID- 26971070 TI - A constitutive law for degrading bioresorbable polymers. AB - This paper presents a constitutive law that predicts the changes in elastic moduli, Poisson's ratio and ultimate tensile strength of bioresorbable polymers due to biodegradation. During biodegradation, long polymer chains are cleaved by hydrolysis reaction. For semi-crystalline polymers, the chain scissions also lead to crystallisation. Treating each scission as a cavity and each new crystal as a solid inclusion, a degrading semi-crystalline polymer can be modelled as a continuum solid containing randomly distributed cavities and crystal inclusions. The effective elastic properties of a degrading polymer are calculated using existing theories for such solid and the tensile strength of the degrading polymer is predicted using scaling relations that were developed for porous materials. The theoretical model for elastic properties and the scaling law for strength form a complete constitutive relation for the degrading polymers. It is shown that the constitutive law can capture the trend of the experimental data in the literature for a range of biodegradable polymers fairly well. PMID- 26971068 TI - Gene delivery using calcium phosphate nanoparticles: Optimization of the transfection process and the effects of citrate and poly(l-lysine) as additives. AB - Despite the long history of nanoparticulate calcium phosphate (CaP) as a non viral transfection agent, there has been limited success in attempts to optimize its properties for transfection comparable in efficiency to that of viral vectors. Here we focus on the optimization of: (a) CaP nanoparticle precipitation conditions, predominantly supersaturation and Ca/P molar ratios; (b) transfection conditions, mainly the concentrations of the carrier and plasmid DNA; (c) the presence of surface additives, including citrate anion and cationic poly(l lysine) (PLL). CaP nanoparticles significantly improved transfection with plasmid DNA encoding enhanced green fluorescent protein (eGFP) in pre-osteoblastic MC3T3 E1 cells compared to a commercial non-viral carrier. At the same time they elicited significantly lesser cytotoxicity than the commercial carrier. Plasmid DNA acted as a nucleation promoter, decreasing the nucleation lag time of metastable CaP solutions and leading to a higher rate of nucleation and a lower size of the precipitated particles. The degree of supersaturation (DS) of 15 was found to be more optimal for transfection than that of 12.5 or 17.5 and higher. Because CaP particles precipitated at DS 15 were spherical, while DS 17.5 and 21 yielded acicular particles, it was concluded that spherical particle morphologies were more conducive to transfection than the anisotropic ones. Even though the yield at DS 15 was 10 and 100 times lower than that at DS 17.5 and 21, respectively, transfection rates were higher using CaP nanoparticle colloids prepared at DS 15 than using those made at higher or lower DS, indicating that the right particle morphology can outweigh the difference in the amount of the carrier, even when this difference is close to 100*. In contrast to the commercial carrier, the concentration of CaP-pDNA delivered to the cells was directly proportional to the transfection rate. Osteosarcoma K7M2 cells were four times more easily transfectable with CaP nanoparticles than the MC3T3-E1 cells. The addition of citrate increased the transfection rate at lower concentrations; however, a complete redispersal of CaP-pDNA nanoparticles at higher concentrations of citrate coincided with a complete diminishment of transfection, implying the benefits of partial aggregation of CaP nanoparticles carrying pDNA. In contrast, PLL delayed transfection initially, but enhanced it at longer time points (?96h), leading to the conclusion that both citrate and PLL could exert positive effects on transfection: citrate if added at low concentrations and PLL to extend transfection over longer periods of time. PMID- 26971071 TI - Cognitive Behavior Therapy for psychosis based Guided Self-help (CBTp-GSH) delivered by frontline mental health professionals: Results of a feasibility study. AB - Availability of Cognitive Behavior Therapy for psychosis (CBTp) is limited in spite of strong evidence base. The purpose of this study was to determine the feasibility of a CBTp based Guided Self-help (CBTp-GSH) in comparison to Treatment As Usual (TAU). The secondary outcomes were a reduction of symptoms of schizophrenia using Positive and Negative Symptom Scale (PANSS) & Disability (WHO DAS 2.0). A total of 33 adults with a DSM-IV diagnosis of schizophrenia was recruited from community mental health services in Kingston, ON, Canada, and randomly assigned to the 12-16week intervention with TAU (Treatment), or TAU alone (Control). End of therapy (16weeks) comparisons between the two groups were made on an Intention To Treat (ITT) basis. Post-intervention scores on measures of psychopathology were compared using Analysis of Covariance (ANCOVA) to adjust for baseline measurements. Recruitment proved feasible, retention rates were high and participants reported a high level of acceptability. There was significant "treatment group by outcome interaction" for Positive and Negative Symptoms, General Psychopathology, measures of disability, such that individuals who received the Treatment improved more than those in Control group. The results of this feasibility study indicate that CBTp based Guided Self-help is feasible and acceptable to the participants, and it can lead to improvement in psychopathology and the level of disability. Individuals in this study had a moderate degree of psychopathology and relatively low level of disability and, therefore, caution is warranted in applying these results to individuals with severe symptoms and with high levels of disability. An adequately powered randomized controlled trial of the intervention is warranted. PMID- 26971073 TI - Reply to "concern over your recent paper on risperidone long-acting injectable for treatment-resistant schizophrenia". PMID- 26971074 TI - Prognosis of schizophrenia spectrum disorder may not be predetermined during early development--the Northern Finland Birth Cohort 1966. AB - BACKGROUND: Little is known about whether factors during the first years of life predict later outcomes in schizophrenia spectrum disorder (SSD). As part of the Northern Finland Birth Cohort 1966, we examined if prospectively collected early parenthood-related and developmental factors predict employment and hospitalization in individuals with and without SSD. METHODS: Overall, 161 individuals with SSD and 10,116 without SSD were included in the study. Outcomes were analysed at age of 44-45years, defining "employment" as being employed for at least 25% of working days and "hospitalization" as having psychiatric hospitalization at least once during the last two years of follow-up. Maternal age, wantedness of pregnancy, grand multiparity, parental psychoses, birth weight, birth height, age of standing up and standing and walking without support were analysed as predictors. RESULTS: Of the individuals with SSD, only 11.2% were employed, although 77.6% remained not hospitalized. In individuals with SSD, only young maternal age was associated with lower probability (OR 0.25, CI 0.08 0.77) of being non-hospitalized after controlling for sex and onset age of illness. Among persons without SSD, almost all parenthood-related and developmental factors were related to employment, while grand multiparity and parental psychosis were related to hospitalization after controlling for sex. CONCLUSIONS: Only one of the early parenthood-related and developmental factors analysed in this study predicted outcome in individuals with SSD, while among those without SSD almost all factors were related to employment. Thus, prognosis of SSD does not seem to be predetermined much by early development. PMID- 26971072 TI - Quantitative mass spectrometry reveals changes in SNAP-25 isoforms in schizophrenia. AB - SNAP-25 and syntaxin are presynaptic terminal SNARE proteins altered in amount and function in schizophrenia. In the ventral caudate, we observed 32% lower SNAP 25 and 26% lower syntaxin, but greater interaction between the two proteins using an in vitro assay. SNAP-25 has two isoforms, SNAP-25A and B, differing by only 9 amino acids, but with different effects on neurotransmission. A quantitative mass spectrometry assay was developed to measure total SNAP-25, and proportions of SNAP-25A and B. The assay had a good linear range (50- to 150-fold) and coefficient of variation (4.5%). We studied ventral caudate samples from patients with schizophrenia (n=15) previously reported to have lower total SNAP-25 than controls (n=13). We confirmed 27% lower total SNAP-25 in schizophrenia, and observed 31% lower SNAP-25A (P=0.002) with 20% lower SNAP-25B amounts (P=0.10). Lower SNAP-25A amount correlated with greater SNAP-25-syntaxin protein-protein interactions (r=-0.41, P=0.03); the level of SNAP-25B did not. Administration of haloperidol or clozapine to rats did not mimic the changes found in schizophrenia. The findings suggest that lower levels of SNAP-25 in schizophrenia may represent a greater effect of the illness on the SNAP-25A isoform. This in turn could contribute to the greater interaction between SNAP25 and syntaxin, and possibly disturb neurotransmission in the illness. PMID- 26971076 TI - [Prevalence of asthma consultations in general practice]. AB - INTRODUCTION: Few data from primary care settings are available about asthma prevalence. The aim of this study was to evaluate the prevalence of asthma consultations in general practice, and to describe their characteristics. METHODS: This was a multicenter, cross-sectional national study, conducted in general practice. Investigators were 54 interns from 27 medical schools. Between December 2011 and April 2012, they collected and entered variables specific to each consultation over a period of 20 days from a structured electronic health record using the International classification of primary care (ICPC-2) together with data about their trainer(s). RESULTS: Data were recorded for 20,613 consultations with 45,582 consultation outcomes described. Asthma represented 348 (1.69%) of consultations. The presence of an asthma code was associated with fewer reasons for the consultation, but with more processes of care. Forty-two percent of other consultation results associated with asthma in the same consultation concerned chronic diseases. CONCLUSION: Our findings suggest that asthma remains underdiagnosed in general practice in France. In order to address this problem, the development of validated diagnostic tools that can be used in general practice settings, and a better access to spirometry, may be directions to explore in future research. PMID- 26971075 TI - How to Build a Complex, Functional Propeller Protein, From Parts. AB - By combining ancestral sequence reconstruction and in vitro evolution, Smock et al. identified single motifs that assemble into a functional five-bladed beta propeller, and a likely route for conversion into the more complex, extant single chain fusion. Interestingly, although sequence diversification destabilized five motif fusions, it also destabilized aggregation-prone intermediates, increasing the level of functional protein in vivo. PMID- 26971078 TI - Motivational Interviewing for Substance Use: Mapping Out the Next Generation of Research. PMID- 26971077 TI - Survival impact and predictive factors of axillary recurrence after sentinel biopsy. AB - BACKGROUND: The rate of axillary recurrence (AR) after sentinel lymph node biopsy is usually low but few studies investigated its impact on survival. Our aim was to determine the rate and predictive factors of AR in a large cohort of breast cancer patients and its impact on survival. PATIENTS AND METHODS: From 1999 to 2013, 14,095 patients who underwent surgery for clinically N0 previously untreated breast cancer and had sentinel lymph node biopsy were analysed. A simplified score predictive of AR was established. RESULTS: Median follow-up was 55.2 months. AR was observed in 0.51% of cases, with a median time to onset of 43.4 months. In multivariate analysis, the occurrence of AR was significantly correlated with grade 2 or 3 disease, absence of radiotherapy and tumour subtype (hormonal receptor [HR]- / human estrogen receptor [HER]+). AR rates were 1% for triple-negative tumours, 2.8% for HER2-positive tumours, 0.4% for luminal A tumours, 0.9% for HER2-negative luminal B tumours, and 0.5% for HER2-positive luminal B tumours. A simplified score predictive of the occurrence of AR was established. Patients could be divided into three different score groups (p < 0.0001). In multivariate analysis, overall survival was significantly lower in cases of AR (p < 0.0001), age >50, lymphovascular invasion, grade 3 disease, sentinel node (SN) macrometastases, tumour size >20 mm, absence of chemotherapy and triple-negative phenotype. Survival in patients with AR was significantly lower in case of early-onset (2 years) AR (p = 0.017). CONCLUSIONS: Isolated AR is more common in Her2-positive/HR-negative triple-negative tumours with a more severe prognosis in triple-negative and Her2-positive/HR-negative tumours, and represents an independent adverse factor justifying an indication for systemic treatment for AR treatment. However, the benefit of any systemic treatment remains to be proven. PMID- 26971079 TI - Outcomes for Physicians With Opioid Dependence Treated Without Agonist Pharmacotherapy in Physician Health Programs. AB - AIMS: To compare treatment outcome among substance dependent physicians enrolled in a physician health program (PHP) who have a history of alcohol use only, any opioid use, or non-opioid drug use, in order to determine whether the distinctive PHP system of care management is as effective for individuals with opioid use disorders as for those with alcohol or other drug use disorders. METHODS: A 5 year, retrospective chart review, intent-to-treat analysis was conducted for all physicians admitted to 16 physician health programs (N=702; 85.5% male; age range=24-75). Analyses compared treatment outcomes for participants based upon their substance(s) of abuse [i.e., 1) "Alcohol Only" (n=204), 2) "Any Opioid" with or without alcohol use (n=339), and 3) "Non-Opioid" drug use with or without alcohol use (n=159)]. RESULTS: In this sample, 75-80% of physicians across the three groups never tested positive for alcohol or drugs during their extended care management period with random drug testing. This included physicians with opioid dependence who did not receive opioid substitution therapy (OST). Of the 22.1% of physicians who had a positive test, two thirds (i.e., 14.5% of the total sample) had just one positive test, and only one third (i.e., 7.6% of the total sample) had more than one positive test. These results were similar in all three groups. CONCLUSIONS: These results indicate that individuals with opioid use disorders who are managed by PHPs can achieve long-term abstinence from opioids, alcohol, and other drugs without OST through participation in abstinence-based psychosocial treatment with extended, intensive care management following discharge. PMID- 26971080 TI - Forgotten but not gone: HIV-associated cryptococcal meningitis. PMID- 26971081 TI - Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. AB - BACKGROUND: Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against cryptococcus. METHODS: In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014. To assess safety and tolerability, the first 60 participants were given sertraline at escalating doses of 100 mg/day, 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for an additional 8 weeks. From Nov 29, 2013, participants were randomly assigned (1:1) to receive open-label sertraline at predetermined doses of 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for 8 weeks. Dose assignment was made via computer-generated, permuted block randomisation stratified by antiretroviral therapy (ART) status for people with a first episode of meningitis. The primary outcome was 2-week cerebrospinal fluid (CSF) clearance rate of cryptococcus, termed early fungicidal activity, measured in patients with a first episode of culture-positive meningitis and two or more CSF cultures. This study is registered with ClinicalTrials.gov, number NCT01802385. FINDINGS: Of the 330 individuals assessed, 172 HIV-infected adults with cryptococcal meningitis were enrolled. We gave 100 mg/day sertraline to 17 patients, 200 mg/day to 12 patients, 300 mg/day to 14 patients, and 400 mg/day to 17 patients. 112 participants were randomly assigned to receive sertraline at 200 mg (n=48), 300 mg (n=36), or 400 mg (n=28) daily for the first 2 weeks, and 200 mg/day thereafter. The final population consisted of 17 participants in the 100 mg group, 60 in the 200 mg group, 50 in the 300 mg group, and 45 in the 400 mg in group. Participants receiving any sertraline dose averaged a CSF clearance rate of -0.37 colony forming units per mL per day (95% CI -0.41 to -0.33). Incidence of paradoxical immune reconstitution inflammatory syndrome was 5% (two of 43 newly starting ART) and no cases of relapse occurred over the 12-week study period. 38 (22%) of 172 participants had died at 2 weeks, and 69 (40%) had died at 12 weeks. Six grade 4 adverse events occurred in 17 participants receiving 100 mg, 14 events in 60 participants receiving 200 mg, 19 events in 50 participants receiving 300 mg, and eight events in 45 participants receiving 400 mg. Grade 4 or 5 adverse event risk did not differ between current US Food and Drug Administration-approved dosing of 100-200 mg/day and higher doses of 300-400 mg/day (hazard ratio 1.27, 95% CI 0.69-2.32; p=0.45). INTERPRETATION: Participants receiving sertraline had faster cryptococcal CSF clearance and a lower incidence of immune reconstitution inflammatory syndrome and relapse than that reported in the past. This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy. FUNDING: National Institutes of Health, Grand Challenges Canada. PMID- 26971082 TI - Reference Values and Z Scores for Pulsed-Wave Doppler and M-Mode Measurements in Fetal Echocardiography. AB - BACKGROUND: Fetal echocardiography is now the standard approach for detailed investigations of fetal cardiac anatomy and function. Available studies proposing reference values for pulsed-wave Doppler (PWD) measurements are often focused on few parameters. Furthermore, the methodology used for validating these proposed reference values is sometimes insufficiently described, and parameters necessary to compute Z scores are not always available. Improved definition of reference values with adequate statistical validation is needed for proper interpretation of PWD measurements in a clinical setting. In this study, the authors propose a comprehensive set of reference values and Z score equations for fetal PWD and M mode measurements with thorough assessment of Z score quality and validity. METHODS: Women with normal singleton pregnancies between 18 and 39 weeks of gestational age were included. A set of 57 measurements was performed, including PWD, M-mode measurements, and calculation of systolic, diastolic, and global function indices. Several parametric regressions were tested to model each measurement against gestational age. The SD was also modeled to account for heteroscedasticity. Z score equations were computed, and the proposed reference values were tested for residual association, residual heteroscedasticity, and departure from the normal distribution. RESULTS: One hundred four uncomplicated singleton pregnancies with normal fetal hearts were included. Nonlinear relationships with gestational age were found for most measurements. Parametric normalization was successful for most measurements analyzed, and it was possible to compute Z score equations with minimal residual association with gestational age, no residual heteroscedasticity, and no significant departure from the normal distribution. CONCLUSIONS: The authors propose a comprehensive set of Z score equations for 57 fetal functional measurements, some of which do not have any published reference values. These Z score equations will allow echocardiographers to more accurately identify measurements that diverge from normal and thus detect earlier potential alterations in fetal heart function. PMID- 26971084 TI - Maxillofacial trauma scoring systems. AB - The changing complexity of maxillofacial fractures in recent years has created a situation where classical systems of classification of maxillofacial injuries fall short of defining trauma particularly that observed with high-velocity collisions where more than one region of the maxillofacial skeleton is affected. Trauma scoring systems designed specifically for the maxillofacial region are aimed to provide a more accurate assessment of the injury, its prognosis, the possible treatment outcomes, economics, length of hospital stay, and triage. The evolution and logic of such systems along with their merits and demerits are discussed. The author also proposes a new system to aid users in quickly and methodically choosing the system best suited to their needs without having to study a plethora of literature available in order to isolate their choice. PMID- 26971083 TI - Vitamin B1 (thiamine) and dementia. AB - The earliest and perhaps best example of an interaction between nutrition and dementia is related to thiamine (vitamin B1). Throughout the last century, research showed that thiamine deficiency is associated with neurological problems, including cognitive deficits and encephalopathy. Multiple similarities exist between classical thiamine deficiency and Alzheimer's disease (AD) in that both are associated with cognitive deficits and reductions in brain glucose metabolism. Thiamine-dependent enzymes are critical components of glucose metabolism that are reduced in the brains of AD patients and by thiamine decline, and a decrease in their levels could account for the reduction in glucose metabolism. In preclinical models, reduced thiamine can drive AD-like abnormalities, including memory deficits, neuritic plaques, and hyperphosphorylation of tau. Furthermore, excess thiamine diminishes AD-like pathologies. In addition to dietary deficits, drugs or other manipulations that interfere with thiamine absorption can cause thiamine deficiency. Elucidating the reasons why the brains of AD patients are functionally thiamine deficient and determining the effects of thiamine restoration may provide critical information to help treat patients with AD. PMID- 26971085 TI - Injury patterns and the role of tendons in protecting neurovascular structures in wrist injuries. AB - PURPOSE: The purpose of this study was to evaluate the anatomical features of injured structures, investigate the protection provided by the specific tendon of each corresponding important neurovascular structure (radial artery, median nerve, and ulnar nerve/artery) and to compare the results among the three categories of wrist injuries. METHODS: This study included 114 patients who underwent primary repair for damaged wrist structures; 40 patients sustained accidental damage without intention (group 1), 40 had self-inflicted damage (group 2), and 34 patients had a stab or penetrating wound caused by a sharp instrument during a conflict or violent event involving another person (group 3). The basic demographic factors, distribution pattern, area, and depth of the injured structures were investigated and compared. The barrier roles of the flexor carpi radialis (FCR) for the radial artery, palmaris longus (PL) for the median nerve, and flexor carpi ulnaris (FCU) for the ulnar nerve were estimated. RESULTS: In group 1, FCU injury was the most common single-structure injury. In group 2, PL+/-median nerve injuries were the most common. Multiple-structure injuries involving more than five structures occurred more frequently in group 3 than in the other groups. FCU+/-ulnar nerve injuries were more common in group 3 than in the other groups. Radial-side structures were injured most frequently in group 3, and central-side injuries occurred most frequently in groups 1 and 2. Superficial- and middle-layer injuries occurred at similar frequencies among the three groups. Particularly, deep-layer injuries were most weakly related to group 2 injuries. The barrier effects of the FCR, PL, and FCU were confirmed, respectively. CONCLUSIONS: Wrist soft tissue injuries showed particular patterns of injured structures and depths according to the injury mechanism. These patterns included features such as single-structure injuries and the locations and depths of multiple-structure injuries with or without neurovascular injuries. In addition, the roles of FCR, PL, and FCU in protecting important wrist neurovascular structures were confirmed. LEVEL OF EVIDENCE: Therapeutic III. PMID- 26971086 TI - A minimally invasive fixation technique for selected patients with fifth metacarpal neck fracture. AB - OBJECTIVE: The objective of this study was to compare the short-term results of treatment of fifth metacarpal neck fractures using a minimally invasive surgical fixation technique and the gold standard splinting method in a selected patient group of office workers with high expectations. PATIENTS AND METHODS: Twenty-four male patients (mean age: 28 years, range: 18-46 years) satisfying the inclusion criteria were enrolled in the study in two groups: surgical treatment and splinting (U-shaped ulnar gutter) groups. Hygienic interactions during daily activities and the use of keyboard and pens were allowed in the posttreatment period. The Short Form-Disabilities of the Arm, Shoulder and Hand Score (DASH) questionnaire was used to assess patient satisfaction and functionality of the extremity on the 30th and 45th days. Joint ranges of motion were measured on the 45th day. Functional and radiological evaluation data were analyzed statistically. RESULTS: In the conservative treatment group, initial palmar angulation was measured to be 42.6 degrees , whereas a mean of 13.5 degrees was noted and metacarpal shortening of 5.6mm decreased to 2mm after treatment, respectively. In terms of total joint range of motion (ROM), flexion of the treated side was at 91.25% and extension at 92.5% when measured versus the healthy-side values at the final follow-up. The mean time for return to work in this group was 33.6 days. The mean Quick-DASH score on the 30th-day follow-up was 69.5, whereas it was 39.3 at the 45th-day follow-up. The radiological findings showed a correction of the mean palmar angulation from 43 degrees to 8 degrees at follow-up in the surgically treated group. The initial metacarpal shortening of 9.3mm improved to 0.5mm at final examination. In terms of total joint ROM, flexion of the treated side was at 94% and extension at 95.5% when measured versus the healthy-side values on the 45th-day follow-ups. The mean time for return to work was 3.9 days. The mean Quick-DASH score on the 30th-day follow-up was 2.96, whereas it was noted as 0.69 at the 45th-day follow-up. CONCLUSIONS: We recommend antegrade intramedullary K-wire fixation as a reliable method, which minimizes the functional loss and allows for early return to daily activities in office workers who sustained a fracture of the fifth metacarpal neck. PMID- 26971087 TI - Re-bleeding After Endoscopic Hemostasis for Peptic Ulcer Bleeding: Is eNough SAID or Are Other Factors Important? PMID- 26971088 TI - WAVE3 Induces EMT and Promotes Migration and Invasion in Intrahepatic Cholangiocarcinoma. AB - BACKGROUND: Wiskott-Aldrich syndrome protein family verprolin-homologous protein 3 (WAVE3) plays a critical role in cancer progression and metastasis. However, the specific role of WAVE3 in intrahepatic cholangiocarcinoma (ICC) has not been studied. AIMS: This study aimed to explore the role and mechanism of WAVE3 in the progression and metastasis of ICC. METHODS: The expression of WAVE3 in ICC tissues and adjacent non-cancerous tissues was detected by immunohistochemistry. Western blot analysis was utilized to detect the expression of WAVE3 in ICC cells. A transwell assay was used to assess the potential for migration and invasion. The expression of WAVE3 in CC-LP-1 cells was knocked down by small interfering RNA (siRNA) interference. RESULTS: The expression of WAVE3 in ICC tissues was significantly higher than that in adjacent non-cancerous tissues. The overall survival was lower in the subgroup of ICC patients with higher WAVE3 expression compared to the subgroup with a lower level of WAVE3 expression. WAVE3 expression was an adverse prognostic factor for ICC patients. CC-LP-1 cells expressed higher levels of WAVE3 protein compared to RBE cells and human intrahepatic biliary epithelial cells, which correlated with greater migration and invasion capabilities compared with the RBE cells. After the transfection of CC-LP-1 cells with WAVE3 siRNA, the level of WAVE3 protein was significantly decreased, accompanied by a marked reduction in migration, invasion and proliferation. Moreover, after the knockdown of WAVE3 expression in CC-LP-1 cells, the protein levels of Slug and Vimentin were significantly decreased, while that of E-cadherin was significantly increased. CONCLUSIONS: WAVE3 may represent a new adverse prognostic factor for patients with ICC. This protein enhances migration and invasion capabilities in ICC, most likely through the induction of an epithelial-mesenchymal transition. PMID- 26971089 TI - Long-Term Outcomes of Infliximab Treatment in 582 Korean Patients with Crohn's Disease: A Hospital-Based Cohort Study. AB - BACKGROUND AND AIMS: To date, no large-scale studies have evaluated long-term outcomes of infliximab (IFX) treatment in Korean patients with Crohn's disease (CD). METHODS: We analyzed long-term clinical responses to IFX in 582 Korean CD patients who received scheduled IFX treatments at Asan Medical Center. Clinical responses were defined as maintaining IFX without major abdominal surgery (MAS) or dose intensification. RESULTS: Between February 2002 and July 2015, a total of 11,990 IFX infusions were administered to 582 Korean patients with CD over a median period of 36 months. At the end of follow-up, 316 (54.3 %) were still receiving IFX without MAS (71 patients, 12.2 %) or dose intensification (86 patients, 14.8 %). IFX was stopped in 109 (18.7 %) patients because of a loss of response (48 patients, 8.2 %), adverse events (30 patients, 5.2 %), or patient preferences or problems with reimbursement (31 patients, 5.3 %). The cumulative survival for maintenance of IFX without MAS or dose intensification was 89.0, 75.9, 68.3, and 50.8 % at 1, 2, 3, and 5 years, respectively. Multivariate regression analysis identified older age at the initiation of IFX (>=40 years, P = 0.006) and a longer disease duration (>=3 years, P = 0.020) as independent positive predictors of a poorer response to IFX. CONCLUSIONS: The long-term efficacy of IFX in a large, real-life cohort of Korean patients with CD appears to be similar to that in previously published Western studies. Our findings support the early use of IFX to obtain better clinical outcomes. PMID- 26971091 TI - Why Pursue a Fourth Year in Advanced/Transplant Hepatology? PMID- 26971090 TI - The Genetics of Barrett's Esophagus: A Familial and Population-Based Perspective. AB - Barrett's esophagus (BE) is intestinal metaplasia of the lower esophagus and a precursor lesion for esophageal adenocarcinoma (EAC). Both are important health issues as they have rising incidences in the Western world. Improving the management of BE relies on understanding the underlying biology of this disease, but the exact biological mechanisms have been difficult to determine. BE is generally thought to be an acquired condition that develops secondarily to chronic gastroesophageal reflux. However, multiple reports of familial clustering of patients with BE and/or EAC suggest a possible inherited predisposition to BE may be driving this condition, at least in a subset of patients. Identifying the genetic variants that predispose to BE in these families would open up the possibility for blood-based screening tests that could inform decision-making in regard to surveillance strategies, particularly for relatives of patients with BE and/or EAC. Perhaps more importantly, understanding the genetic mechanisms that predispose to BE may provide valuable insights into the biology of this condition and potentially identify novel targets for therapeutic intervention. Here we review the current evidence for a genetic predisposition to BE and discuss the potential implications of these findings. PMID- 26971092 TI - Time to Relapse in Children with Crohn's Disease Treated with Azathioprine and Nutritional Therapy or Corticosteroids. AB - BACKGROUND: The duration of remission has been shown to be longer in patients initially treated with exclusive enteral nutrition (EEN) compared to corticosteroids (CS). However, no published studies required concurrent immunomodulator [6-mercaptopurine or azathioprine (AZA)] use at the time of diagnosis. AIMS: The aims of this retrospective study were to compare the duration of remission between patients initially treated with AZA in combination with CS or EEN and identify predictors of early relapse in these patients. METHODS: Data from 65 newly diagnosed children with CD in clinical remission on either EEN or CS and commencing AZA at diagnosis were included. We compared duration of remission using physician global assessment and carried out Cox regression analysis to identify predictors of early relapse. Patients were followed up to the time of first relapse or for at least 12 months. RESULTS: There were no differences in the duration of remission between patients initially treated with EEN or CS (p = 0.978). We identified younger age at diagnosis [hazard ratio (HR) 0.87, 95 CI 0.78-0.98, p = 0.016], lower height Z score at diagnosis (HR 0.61, 95 CI 0.44-0.85, p = 0.003), involvement of the upper gastrointestinal tract (HR 2.69, 95 CI 1.27-5.66, p = 0.009), and elevated platelet count at remission (HR 1.004, 95 CI 1.001-1.008, p = 0.021) as independent predictors of early relapse. CONCLUSIONS: Neither induction regime demonstrated longer duration of remission of CD in patients treated with immunomodulators since the time of diagnosis. PMID- 26971096 TI - Erratum to: Efficacy of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Coronary Artery Disease without Heart Failure in the Modern Statin Era: a Meta-Analysis of Randomized-Controlled Trials. PMID- 26971093 TI - Patient-Reported Attributions for Missed Colonoscopy Appointments in Two Large Healthcare Systems. AB - BACKGROUND: Missed colonoscopy appointments (no-shows) can lead to wasted resources and delays in colorectal cancer diagnosis, an area of special concern in public health systems that often provide care for vulnerable patients. Our objective was to identify reasons for missed colonoscopy appointments in patients seeking care at two large public health systems in Houston, TX. METHODS: We conducted a telephone survey of patients who missed their colonoscopy appointments at two tertiary care health systems. Using a structured survey instrument, we collected information on patient-specific and health services barriers. Patient-specific barriers included perceived procedural-related factors (e.g., difficulty in preparation), cognitive-emotional factors (e.g., fear or concern about modesty), and changes in health status (e.g., improvement or worsening of health). Health services barriers included logistical factors (e.g., travel-related difficulties) and appointment scheduling problems (inconvenient date or time). We examined differences in attributions for missed appointments between the two study sites. RESULTS: Of 160 unique patients (102 Site A and 58 Site B) who missed their appointment during the study period, 153 (95.6 %) attributed their no-show to at least one of the listed barriers. Most respondents (125; 78.1 %) cited travel-related issues or scheduling problems as reasons for their missed appointment. Not having a ride or a travel companion was the most commonly reported travel-related issue. We also found significant differences for barriers between the two sites. CONCLUSIONS: Most missed colonoscopy appointments resulted from potentially preventable travel- and scheduling-related issues. Because barriers to keeping colonoscopy appointments are different across health systems, each health system might need to develop unique interventions to reduce missed colonoscopy appointments. PMID- 26971095 TI - The linea aspera as a rotational landmark: an anatomical MRI-based study. AB - PURPOSE: The linea aspera can be used as a landmark to assess the rotation of the distal femoral epiphysis when performing an endoprostheses. However, no study has assessed the reliability of this landmark. We therefore asked whether the linea aspera could be used as a rotational landmark for positioning distal femoral knee megaprostheses. MATERIALS: This is an anatomic MRI-based study of 50 femurs (27 subjects). For each femur, multiple axial sections were obtained from the intercondylar line at the knee joint to the lesser trochanter; each axial section was superposed with that where the posterior condyles were seen and the R angle was measured. The R angle is the angle measured medially where the line passing through the linea aspera and the line tangent to the posterior condyles intersects. RESULTS: There were considerable differences between and within subjects with a maximum R angle ranging from 100 degrees to 120 degrees . Regression models showed that the R angle was significantly associated with distance from knee joint and subjects. CONCLUSION: Surgeons should have the R angle measured before performing a distal femoral reconstruction. PMID- 26971097 TI - Prevalence of caries in deciduous teeth in early modern Japan: analyses of human skeletons from Hitotsubashi (Tokyo, Japan). AB - The early modern Edo period in Japan refers to the division of chronological age dated from the seventeenth to nineteenth centuries. During that period, the social structure was stratified, with warriors at the top, followed by farmers, and finally townsmen at the bottom. I aimed to examine carious lesions in deciduous teeth in the commoners from the city of Edo (now Tokyo), to compare them with those in the warriors and commoners from Kyushu, and to reveal differences in the incidence of caries across social classes and regions. I examined 843 deciduous teeth of 115 individuals from the Hitotsubashi site in Tokyo. The comparative samples were obtained from warriors and commoners whose remains were excavated from the Sougenji and Kyoumachi sites, respectively, in Kyushu [Oyamada et al. (2008) Anthropol Sci 116:9-15]. The caries frequency in the Hitotsubashi sample was 11.3 %. Carious lesions in the upper teeth were more frequent than those in the lower teeth in all age groups. The upper incisors exhibited the highest frequency of caries, while there was almost no caries in the lower incisors and canines. I also found population differences in deciduous caries among the Edo populations. Remains of teeth excavated from Hitotsubashi were found to have a mild degree of caries compared to remains of teeth excavated from Sougenji and Kyoumachi in Kyushu in terms of caries frequency and location. Thus, the influence of regional differences in diet and living circumstances was stronger than expected, and the variation observed in the frequency of deciduous caries among the Edo populations cannot be explained by social class alone. PMID- 26971094 TI - Low alcohol consumption increases the risk of impaired glucose tolerance in patients with non-alcoholic fatty liver disease. AB - BACKGROUND: Fatty liver disease is associated with glucose intolerance and hepatic insulin resistance. However, there are distinct etiologies for alcoholic versus non-alcoholic fatty liver disease (NAFLD), and it is unknown whether alcohol consumption influences the onset of glucose intolerance in fatty liver disease patients. Therefore, we investigated the relationship between fatty liver disease and the onset of impaired fasting glucose (IFG) with respect to alcohol consumption. METHODS: The records of 6804 Japanese subjects were reviewed to identify those meeting the criteria for IFG. Male and female subjects were classified into five and four groups, respectively, based on average alcohol consumption (g/week). IFG onset was defined as fasting plasma glucose levels >=110 mg/dl. RESULTS: In the non-drinker, >0-70 g/week, >70-140 g/week, >140-210 g/week (men only), and >210 g/week (men only) or >140 g/week (women only) groups, 7.3, 6.7, 6.4, 9, and 6.4 % of men and 2, 1.7, 3.1, and 3.2 % of women, respectively, developed IFG. Fatty liver was positively associated with the onset of IFG in men of the >0-70 g/week group (adjusted hazard ratio [aHR], 2.808; 95 % confidence interval [CI] 1.605-5.049, p < 0.001) and women of the >70-140 g/week group (aHR, 4.193; 95 % CI, 1.036-14.584, p = 0.045) after adjusting for previously reported IFG risk factors. No associations were observed in the other groups. CONCLUSIONS: A small amount of alcohol consumption is a significant risk factor for the onset of IFG in NAFLD patients; onset risk differs according to the amount of alcohol consumption. PMID- 26971098 TI - Ocular response analyser measurements and central corneal thickness in ocular rosacea patients. AB - Rosacea is a chronic cutaneous disorder which is known to cause inflammation and increased proteolytic activity on the ocular surface that might lead to corneal biomechanical alterations. The aim of this study is to evaluate the corneal biomechanical properties of ocular rosacea patients and compare the measurements with healthy individuals as measured with Reichert ocular response analyser (ORA). Besides full eye examination [best corrected visual acuity (BCVA), intraocular pressure (IOP) measured with Goldmann applanation tonometry (IOP-G)], central corneal thickness (CCT), and ORA [corneal hysteresis (CH), corneal resistance factor (CRF), corneal compensated IOP (IOPcc), Goldmann correlated IOP (IOPg)] measurements of 30 eyes of 15 ocular rosacea patients (study group) and 30 eyes of 15 healthy individuals (control group) were performed. For comparisons paired t test was used. Mean age of study group was 45.26 +/- 11.65 (range 25 and 63) and control group was 45.00 +/- 8.91 (range 26 and 58) years (p = 0.865). No significant difference in BCVA, CCT, IOP-G, IOPcc was detected among groups. However, IOPg, CH, and CRF in the study group were significantly lower than in the control group (p = 0.013, p = 0.013, p = 0.009, respectively). IOPg, CH, and CRF parameters of ocular rosacea patients were significantly lower than normal individuals. These differences and their probable clinical reflections that might effect making decisions in conditions such as glaucoma should be investigated in larger number of patients. PMID- 26971101 TI - Self-Perceived Distress and Impairment in Problem Gamblers: A Study of Pre- to Post-treatment Measurement Invariance. AB - Gambling help services typically evaluate treatment outcomes using self-reported responses and measurements. However, gamblers' conceptualisations and prioritisations with respect to these measurements may shift over time. Thus, changes in the self-reported responses may not always reflect true change in the individuals. This study investigated for response shift in self-report measures of psychological distress and impairment in 293 help-seeking problem gamblers. We used confirmatory factor analysis to model data structures from pre-treatment to post-treatment. The findings indicated that a response shift had occurred. Two items became less important and one item became more important in measuring psychological distress. Measurement invariance was achieved for the complete set of items for impairment. These findings provide a more in-depth understanding of the nature of self-report outcomes in otherwise routinely collected data. PMID- 26971099 TI - Nitrogen treatment enhances sterols and withaferin A through transcriptional activation of jasmonate pathway, WRKY transcription factors, and biosynthesis genes in Withania somnifera (L.) Dunal. AB - The medicinal plant Withania somnifera is researched extensively to increase the quantity of withanolides and specifically withaferin A, which finds implications in many pharmacological activities. Due to insufficient knowledge on biosynthesis and unacceptability of transgenic approach, it is preferred to follow alternative physiological methods to increase the yield of withanolides. Prior use of elicitors like salicylic acid, methyl jasmonate, fungal extracts, and even mechanical wounding have shown to increase the withanolide biosynthesis with limited success; however, the commercial viability and logistics of application are debatable. In this investigation, we tested the simple nitrogeneous fertilizers pertaining to the enhancement of withaferin A biosynthesis. Application of ammonium sulfate improved the sterol contents required for the withanolide biosynthesis and correlated to higher expression of pathway genes like FPPS, SMT1, SMT2, SMO1, SMO2, and ODM. Increased expression of a gene homologous to allene oxide cyclase, crucial in jasmonic acid biosynthetic pathway, suggested the involvement of jasmonate signaling. High levels of WRKY gene transcripts indicated transcriptional regulation of the pathway genes. Increase in transcript level could be correlated with a corresponding increase in the protein levels for WsSMT1 and WsWRKY1. The withaferin A increase was also demonstrated in the potted plants growing in the glasshouse and in the open field. These results implicated simple physiological management of nitrogen fertilizer signal to improve the yield of secondary metabolite through probable involvement of jasmonate signal and WRKY transcription factor for the first time, in W. somnifera besides improving the foliage. PMID- 26971104 TI - Erratum to: Evidence-based indications for hindfoot endoscopy. PMID- 26971102 TI - The role of testicular artery in laparoscopic varicocelectomy: a systematic review and meta-analysis. AB - PURPOSE: We performed this meta-analysis to evaluate the efficacy and safety of artery preserving versus artery non-preserving in laparoscopic varicocelectomy. METHODS: All publications up until October 2015 were searched in PubMed, EMBASE, Ovid, Web of Science, and Cochrane library. Randomized controlled trials (RCTs) and cohort studies (CSs) that compared the difference in two operative approaches in laparoscopic varicocelectomy were included. Statistical analysis was performed using Stata version 12.0. RESULTS: A total of four RCTs and ten CSs involving 503 cases with artery preserving and 911 cases with artery non-preserving met our inclusion criteria. Meta-analysis showed that artery preserving had higher recurrence rate [risk ratio (RR) = 2.91, 95 % confidence interval (CI) 1.83-4.61; P = 0.000], lower incidence of hydrocele formation (RR = 0.18; 95 % CI 0.08-0.42; P = 0.000), and prolonged operating time [standard mean difference (SMD) = 1.27; 95 % CI 0.17-2.37; P = 0.023], compared with artery non-preserving in laparoscopic varicocelectomy. The results were similar in postoperative catch-up growth (RR = 1.00; 95 % CI 0.86-1.17; P = 0.985) and testicular atrophy (RR = 0.36; 95 % CI 0.09-1.54; P = 0.169). Besides, no significant difference was found in sperm concentration, motility, and normal morphology between two groups, as well as on postoperative pregnancy rate (RR = 0.95; 95 % CI 0.65-1.40; P = 0.809). CONCLUSION: With the advantages of less recurrence, easier operating and less time spending, and comparable results in other respects, artery non preserving is preferable to artery preserving in laparoscopic varicocelectomy, although there is a relatively high incidence of hydrocele formation. Considering the limitation of included studies, more large-scaled RCTs are required to confirm the present findings. PMID- 26971105 TI - Athletic performance and career longevity following anterior cruciate ligament reconstruction in the National Basketball Association. AB - PURPOSE: To identify the impact of anterior cruciate ligament (ACL) reconstruction on performance and career longevity for National Basketball Association (NBA) players. METHODS: Seventy-nine players (80 knees) with acute ACL tears in the NBA between the 1984-2014 seasons, and 112 age, height, weight, and performance-matched controls were identified. Pre- and post-injury performance outcomes including seasons played, games played, games started, minutes per game, points per game, field goals, 3-point shots, rebounds, assists, steals, blocks, turnovers, personal fouls, usage percentage and player efficiency ratings were compared between cases and controls using independent samples t tests and Fisher's exact tests. RESULTS: Sixty-eight of seventy-nine players (86.1 %) returned to play in the NBA following ACL reconstruction. Mean length of post-operative play was 1.84 years shorter than matched controls (P = 0.001). There was a significantly higher rate of attrition from professional basketball for players with a history of ACL reconstruction (P = 0.014). In the first full season following surgery, players started in 15.5 fewer games (P = 0.001), they played in 17.3 fewer games (P < 0.001), and had combined player efficiency ratings 2.35 points lower (P = 0.001) when compared to matched controls. Over the length of their careers, players competed in 22.2 fewer games per season (P = 0.009). CONCLUSIONS: There is a high rate of return to sport in the NBA following ACL reconstruction, although playing time, games played, player efficiency ratings and career lengths are significantly impacted in the post-operative period. These data should be used to manage patients' expectations regarding their abilities to return to elite levels of athletic performance. PMID- 26971103 TI - Pharmacological Management of Childhood-Onset Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus (SLE) is a rare, severe, multisystem autoimmune disorder. Childhood-onset SLE (cSLE) follows a more aggressive course with greater associated morbidity and mortality than adult-onset SLE. Its aetiology is yet to be fully elucidated. It is recognised to be the archetypal systemic autoimmune disease, arising from a complex interaction between the innate and adaptive immune systems. Its complexity is reflected by the fact that there has been only one new drug licensed for use in SLE in the last 50 years. However, biologic agents that specifically target aspects of the immune system are emerging. Immunosuppression remains the cornerstone of medical management, with glucocorticoids still playing a leading role. Treatment choices are led by disease severity. Immunosuppressants, including azathioprine and methotrexate, are used in mild to moderate manifestations. Mycophenolate mofetil is widely used for lupus nephritis. Cyclophosphamide remains the first-line treatment for patients with severe organ disease. No biologic therapies have yet been approved for cSLE, although they are being used increasingly as part of routine care of patients with severe lupus nephritis or with neurological and/or haematological involvement. Drugs influencing B cell survival, including belimumab and rituximab, are currently undergoing clinical trials in cSLE. Hydroxychloroquine is indicated for disease manifestations of all severities and can be used as monotherapy in mild disease. However, the management of cSLE is hampered by the lack of a robust evidence base. To date, it has been principally guided by best practice guidelines, retrospective case series and adapted adult protocols. In this pharmacological review, we provide an overview of current practice for the management of cSLE, together with recent advances in new therapies, including biologic agents. PMID- 26971100 TI - Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early onset features of SBMA muscle modified by high-fat diet. AB - Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The mechanism by which expansion of polyglutamine in AR causes muscle atrophy is unknown. Here, we investigated pathological pathways underlying muscle atrophy in SBMA knock-in mice and patients. We show that glycolytic muscles were more severely affected than oxidative muscles in SBMA knock-in mice. Muscle atrophy was associated with early-onset, progressive glycolytic-to-oxidative fiber-type switch. Whole genome microarray and untargeted lipidomic analyses revealed enhanced lipid metabolism and impaired glycolysis selectively in muscle. These metabolic changes occurred before denervation and were associated with a concurrent enhancement of mechanistic target of rapamycin (mTOR) signaling, which induced peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1alpha) expression. At later stages of disease, we detected mitochondrial membrane depolarization, enhanced transcription factor EB (TFEB) expression and autophagy, and mTOR-induced protein synthesis. Several of these abnormalities were detected in the muscle of SBMA patients. Feeding knock-in mice a high-fat diet (HFD) restored mTOR activation, decreased the expression of PGC1alpha, TFEB, and genes involved in oxidative metabolism, reduced mitochondrial abnormalities, ameliorated muscle pathology, and extended survival. These findings show early onset and intrinsic metabolic alterations in SBMA muscle and link lipid/glucose metabolism to pathogenesis. Moreover, our results highlight an HFD regime as a promising approach to support SBMA patients. PMID- 26971106 TI - Authorship in the field of femoroacetabular impingement: an analysis of journal publications. AB - PURPOSE: This review provides a bibliometric analysis of the contributors to the field of FAI research. METHODS: A comprehensive search of three databases (MEDLINE, EMBASE, and PubMed) was performed to identify all clinical research articles on the topic of FAI (from inception to 2015). Cadaveric and animal studies were excluded. Study characteristics including authors, residing country of corresponding author, and journal were abstracted from the respective databases. RESULTS: In total, 1073 articles were included in this review. There were a total of 5471 different authors who contributed to the field of FAI research, 28.3 % of whom were only published in one article. The top 20 authors were associated with over half of all publications, and research studies were typically performed in their countries of residence. The greatest proportion of FAI-related articles was published in the Journal of Arthroscopy and Clinical Orthopaedics and Related Research. CONCLUSIONS: The number of authors contributing to FAI research is increasing, suggesting not only increasing prevalence of FAI treatment among orthopaedic surgeons but also increasing interest among hip arthroscopists in furthering understanding regarding the diagnosis and management of the condition. The number of publications produced by the top 20 authors (and their affiliated countries: USA, Switzerland, Canada, and the UK) is expected to contribute to a majority of future publications. Current trends suggest that the quality of evidence will continue to improve in the near future, as large-scale, collaborative studies are currently underway. LEVEL OF EVIDENCE: Retrospective study, Level IV. PMID- 26971107 TI - Proximal tibiofibular joint pain versus peroneal nerve dysfunction: clinical results of closed-wedge high tibial osteotomy performed with proximal tibiofibular joint disruption. AB - PURPOSE: Closed-wedge high tibial osteotomy (CW-HTO) requires shortening of the fibula or the fibular head or disruption of the proximal tibiofibular joint (PTFJ). However, no study has evaluated the proximal tibiofibular joint after the osteotomy. The aim of this study was to investigate the fate of the PTFJ after CW HTO applied with using PTFJ disruption method. METHODS: This prospective study included 22 knees of 20 patients who underwent CW-HTO. The mean age of the patients was 50 +/- 4 years, and the mean follow-up period was 27.5 +/- 14.3 months (12-46 months). The grade of gonarthrosis (Ahlback's classification), tibiofemoral alignment and tibial slope angles were measured on radiographs pre- and post-operatively. During the surgery, the PTFJ capsule was released meticulously so as not to injure the peroneal nerve. Tenderness over the PTFJ was recorded preoperatively and at the last follow-up. RESULTS: No patient had tenderness or pain over PTFJ preoperatively. On the follow-up examinations, tenderness with compression was detected in nine knees with dorsiflexion, in ten with plantar flexion and in nine with neutral position of the ankle, respectively. None of the patients had peroneal nerve injury (including hypesthesia and mild weakness) post-operatively. However, while 11 knees were pain free in all positions of the ankle, seven knees had tenderness over PTFJ both in dorsiflexion and in plantar flexion. CONCLUSION: CW-HTO using PTFJ disruption provides good clinical results in terms of medial knee pain and corrects the alignment sufficiently while avoiding peroneal nerve injury. However, the results of this study indicated that this technique might result in painful PTFJs. Thus, the surgeon should consider a possibly painful PTFJ, which can be a cause of chronic lateral knee pain when performing this technique. LEVEL OF EVIDENCE: III. PMID- 26971108 TI - The incidence of deep venous thrombosis before arthroscopy among patients suffering from high-energy knee trauma. AB - PURPOSE: The purpose of the present study was to analyse the incidence of deep venous thrombosis (DVT) before knee arthroscopy in patients who had sustained high-energy knee injuries. METHOD: This study included 64 patients who underwent arthroscopic knee surgery as a result of injury from a traffic accident or a high fall. Venography was performed on the injured leg of each patient before arthroscopy. The patients were divided into two groups based on whether they had DVT. Correlation analysis was performed to determine the factors associated with DVT. RESULTS: A total of 32 (50 %) of the 64 patients had venographic evidence of DVT. Of these DVTs, seven were proximal (10.9 %). The D-dimer (DD) level was significantly higher in the DVT group, especially among the patients whose symptoms had persisted for more than 10 days. DVT is difficult to diagnose solely based on clinical symptoms, as some patients are symptomatic while others exhibit symptoms that could be attributed to trauma. CONCLUSIONS: The incidence of DVT before knee arthroscopy in patients with high-energy knee injuries was 50 %, and the prevalence of proximal DVT was 10.9 %. DD is a sensitive marker for DVT. No patient developed DVT with a DD level lower than 0.8 mg/L, but those with DD level higher than 1.5 mg/L had a much higher incidence of DVT developing in patients who had been injured for more than 10 days. A routine examination to exclude DVT in these patients should be performed before arthroscopy. LEVEL OF EVIDENCE: IV. PMID- 26971110 TI - Visual-palpatory versus fluoroscopic intraoperative determination of the femoral entry point in medial patellofemoral ligament reconstruction. AB - PURPOSE: Malpositioning of the femoral entry point in reconstruction of the medial patellofemoral ligament (MPFL) can lead to abnormal and painful patellar kinematics and loss of flexion. Determination of this point is usually performed by palpation of anatomic landmarks. Accuracy of this method has not yet been investigated. The hypotheses were: 1. palpatory method is not as accurate as fluoroscopically guided method using established radiological criteria; 2. accuracy correlates with surgical experience. METHODS: Three surgeons of varying experience defined the femoral entry point for the MPFL by palpation in ten cadaveric legs. The blinded procedures were repeated three times, and subjective difficulty of the determination was recorded. Results were documented by fluoroscopy on a true lateral radiograph. The accuracy was assessed using established radiological criteria. Surgical experience was correlated with the results, and confounding or interacting variables were assessed. RESULTS: Mean deviation from the correct zone for the femoral entry point was 3.5 mm (range 0 18 mm). Twenty-nine percent of all palpatory determinations were inside the correct zone, 47 % were within 5 mm distance from the correct zone, and 23 % were further than 5 mm apart from the correct zone ("outliers"). No significant difference was found between surgeons of varying experience. No correlation was observed between subjective difficulty of the procedure and accuracy of determination. CONCLUSIONS: The validity of the isolated palpatory determination of the femoral entry point in MPFL reconstruction seems to be insufficient, regardless of surgical experience. Derived from this study, fluoroscopic guidance is used in our clinic by default. PMID- 26971109 TI - Exercises with partial vascular occlusion in patients with knee osteoarthritis: a randomized clinical trial. AB - PURPOSE: The objective of this study was to evaluate whether women with knee osteoarthritis performing a rehabilitation programme consisting of low-load exercises combined with PVO exhibited the same results in changes in quadriceps strength, pain relief, and functional improvement when compared to women receiving a programme consisting of high-load exercises without PVO. METHODS: Thirty-four women (mean age, 61 years) with a diagnosis of knee osteoarthritis were randomly assigned to a conventional or occlusion group. The women in the conventional group (n = 17) performed a 6-week quadriceps strengthening and stretching programme using a load around 70 % of the 1-repetition maximum (RM). The women in the occlusion group (n = 17) performed the same programme, however, only using a load around 30 % of the 1-RM, while PVO was induced. The PVO was achieved using a pressure cuff applied to the upper third of the thigh and inflated to 200 mmHg during the quadriceps exercise. An 11-point Numerical Pain Rating Scale (NPRS), the Lequesne questionnaire, the Timed-Up and Go (TUG) test, and muscle strength measurement using a hand-held dynamometer were used as outcome measures at baseline (pretreatment) and at the end of the 6-week of treatment. Pain, using the NPRS, was also assessed when performing the quadriceps exercises during the exercise sessions. RESULTS: At baseline, demographic, strength, pain, and functional assessment data were similar between groups. Patients from both the conventional and occlusion groups had a higher level of function (Lequesne and TUG test), less pain (NPRS), and higher quadriceps strength at the 6-week evaluation when compared to baseline (all P < 0.05). However, the between-group analysis showed no differences for all outcomes variables at posttreatment (n.s.). Patients in the occlusion group experienced less anterior knee discomfort during the treatment sessions than those in the high-load exercise group (P < 0.05). CONCLUSION: A rehabilitation programme that combined PVO to low-load exercise resulted in similar benefits in pain, function, and quadriceps strength than a programme using high-load conventional exercise in patients with knee osteoarthritis. However, the use of PVO combined with low-load exercise resulted in less anterior knee pain during the training sessions. LEVEL OF EVIDENCE: I. PMID- 26971111 TI - Surgical treatment for midportion Achilles tendinopathy: a systematic review. AB - PURPOSE: The aim of this study was to systematically evaluate the available literature on surgical treatment for midportion Achilles tendinopathy and to provide an overview of the different surgical techniques. METHODS: A systematic review of the literature available in MEDLINE, EMBASE and the Cochrane database of controlled trials was performed. The primary outcome measure in terms of patient satisfaction and the secondary outcome measures that consisted of complication rate, pain score, functional outcome score and success rate were evaluated. The Downs & Black checklist and the Coleman methodology scale were used to assess the methodological quality of included articles. RESULTS: Of 1090 reviewed articles, 23 met the inclusion criteria. The included studies reported on the results of 1285 procedures in 1177 patients. The surgical techniques were divided into five categories. Eleven studies evaluated open surgical debridement, seven studies described minimally invasive procedures, three studies evaluated endoscopic procedures, one study evaluated open gastrocnemius lengthening, and one study reported on open autologous tendon transfer. Results regarding patient satisfaction (69-100 %) and complication rate (0-85.7 %) varied widely. CONCLUSIONS: This study demonstrates the large variation in surgical techniques available for treatment of midportion Achilles tendinopathy. None of the included studies compared surgical intervention with nonsurgical or placebo intervention. Minimally invasive and endoscopic procedures yield lower complication rates with similar patient satisfaction in comparison with open procedures. Minimally invasive and endoscopic procedures might therefore prove to be the future of surgical treatment of Achilles midportion tendinopathy. LEVEL OF EVIDENCE: IV. PMID- 26971112 TI - Distinct subgenome stabilities in synthesized Brassica allohexaploids. AB - KEY MESSAGE: Trigenomic Brassica allohexaploids synthesized from three crossing strategies showed diploidized and non-diploidized meiotic behaviors and produced both euploid and aneuploid progenies during successive generations, revealing the distinct subgenome stabilities (B > A> C). Three cultivated allotetraploid Brassica species (Brassica napus, B. juncea, B. carinata) represent the model system of speciation through interspecific hybridization and allopolyploidization, but no Brassica species at higher ploidy level exists in nature. In this study, Brassica allohexaploids (2n = 54, AABBCC) were artificially synthesized using three crossing strategies, and had combinations of the genomes from the extant allotetraploids and diploids (B. rapa, B. oleracea and B. nigra). The chromosome numbers and complements of these allohexaploids and the self-pollinated progenies of successive generations (S0-S7) were determined using multicolor fluorescent in situ hybridization that distinguished the chromosomes of three constituent genomes from each other. Both euploid and aneuploid progenies were identified. The most aneuploids maintained all B- and A genome chromosomes and variable number of C-genome chromosomes, suggesting that genome stability was B > A > C. In the extreme case, loss of whole set of C genome chromosomes led to the production of B. juncea-type progeny. Some aneuploid progenies had the same number of chromosomes (2n = 54) as the euploid, but the simultaneous loss and gain of A- and C-genome chromosomes. The diploidized and non-diploidized meiotic behaviors co-occurred in all allohexaploid individuals of consecutive generations. The aberrant chromosome pairing and segregation mainly involved the chromosomes of A and C genomes, which resulted in aneuploidy in self-pollinated progenies. The mechanisms for the differential stability of three genomes and the stabilization of the new allohexaploids are discussed. PMID- 26971113 TI - Combined linkage and association mapping identifies a major QTL (qRtsc8-1), conferring tar spot complex resistance in maize. AB - KEY MESSAGE: A major QTL ( qRtsc8 - 1 ) conditioning resistance to tar spot complex of maize and occurring at a frequency of 3.5 % across 890 maize inbred lines. Tar spot complex (TSC) is a highly destructive disease of maize found in some countries in America. Identification of TSC resistant germplasm and elucidating the genetic mechanism of resistance is crucial for the use of host resistance to manage this disease. We evaluated 890 elite maize inbred lines in multiple environments and used genome wide association analysis (GWAS) with genotypic data from Illumina MaizeSNP50 BeadChip containing 56 K SNPs to dissect the genetics of TSC resistance. GWAS results were validated through linkage analysis in three bi-parental populations derived from different resistant and susceptible parents. Through GWAS, three TSC resistance loci were identified on chromosome 2, 7 and 8 (-log10 (p) > 5.99). A major quantitative resistance locus (QTL) designated qRtsc8-1, was detected on maize chromosome bin 8.03. qRtsc8-1, was confirmed in three independent bi-parental populations and it accounted for 18-43 % of the observed phenotypic variation for TSC. A rare haplotype within the qRtsc8-1 region, occurring at a frequency of 3.5 % increased TSC resistance by 14 %. Candidate gene analysis revealed that a leucine-rich repeat receptor-like protein (LRR-RLKs) gene family maybe the candidate gene for qRtsc8-1. Identification and localization of a major locus conditioning TSC resistance provides the foundation for fine mapping qRtsc8-1 and developing functional markers for improving TSC resistance in maize breeding programs. To the best of our knowledge, this is the first report of a major QTL for TSC resistance. PMID- 26971114 TI - Treating Staphylococcus aureus infections in an intensive care unit at a University Hospital in Brazil. AB - BACKGROUND: Optimizing antimicrobial therapy is important for treating patients who are critically ill with Staphylococcus aureus infection, and susceptibility tests are necessary. OBJECTIVE: The aim of the present study was to evaluate antibacterial therapy after susceptibility testing of S. aureus infections. Setting The setting was an intensive care unit at a University Hospital in Brazil. METHODS: An observational and retrospective study was conducted over 6 years. The antimicrobials that were used for S. aureus infection treatment were calculated as the defined daily dose per 1000 patient-days (DDD1000). Antimicrobial susceptibility data were obtained by reviewing bacteriological tests. Patient profiles and treatment were determined by analyzing patient charts. RESULTS: Methicillin-resistant S. aureus (MRSA) was prevalent in this study (76.13 %). Patients who were infected with MRSA had total antimicrobial consumption that was three-times higher (9567.2 DDD1000) than patients who were infected with methicillin-susceptible S. aureus (MSSA; 3101.1 DDD1000). The average length of stay in the intensive care unit was 19 days (interquartile range 17 days) for MSSA and 20 days (interquartile range 20 days) for MRSA. Mortality in patients who were infected with MSSA was higher (52.17 %) than in patients who were infected with MRSA (33.80 %), and de-escalation was not identified in 73.90 % of MSSA patients. PMID- 26971115 TI - Medical student empathy: interpersonal distinctions and correlates. AB - Attention to interpersonal behaviors, communication, and relational factors is taking on increasing importance in medical education. Medical student empathy is one aspect of the physician-patient relationship that is often involved in beneficial interactions leading to improved clinical outcomes and patient satisfaction. As an interpersonal quality, empathy is a social behavior well suited to be examined from an interpersonal perspective. The present study used the interpersonal theory of clinical, personality, and social psychology to examine the construct of empathy and theorize about likely interpersonal correlates. One hundred and sixty-three students from an academic health center in the southeastern United States participated in this study. The medical student version of the Jefferson Scale of Empathy was used to assess empathy and its factors: Perspective taking, compassionate care, and walking in the patient's shoes. Interpersonal assessments included the International Personality Item Pool Interpersonal Circumplex, the Interpersonal Support Evaluation List, and the UCLA Loneliness Scale. Distinct interpersonal styles and correlates emerged among empathy and its factors. While all factors of empathy were related to interpersonal warmth, perspective taking and compassionate care were also associated with submissiveness. Of note, only walking in the patient's shoes was correlated with both social support and less loneliness. These findings are discussed in light of interpersonal theory with particular attention paid to the implications for medical education and professional development. PMID- 26971116 TI - Emergent self-organization in active materials. AB - Biological systems exhibit large-scale self-organized dynamics and structures which enable organisms to perform the functions of life. The field of active matter strives to develop and understand microscopically driven nonequilibrium materials, with emergent properties comparable to those of living systems. This review will describe two recently developed classes of active matter systems, in which simple building blocks-self-propelled colloidal particles or extensile rod like particles-self-organize to form macroscopic structures with features not possible in equilibrium systems. We summarize the recent experimental and theoretical progress on each of these systems, and we present simple descriptions of the physics underlying their emergent behaviors. PMID- 26971117 TI - Perceiving beauty in all women: Psychometric evaluation of the Broad Conceptualization of Beauty Scale. AB - Women's ability to broadly conceptualize beauty (i.e., perceive many looks, appearances, body sizes/shapes, and inner characteristics as beautiful) has been identified as a facet of positive body image in qualitative research. A scale is needed to be able to assess this construct within quantitative research. Therefore, we developed the Broad Conceptualization of Beauty Scale (BCBS), which measures the extent women define female beauty widely within external and internal characteristics, and examined its psychometric properties among four community samples totaling 1086 women. Exploratory and confirmatory factor analyses revealed a unidimensional structure with nine items. The internal consistency, test-retest reliability, and construct (convergent, discriminant, and incremental) validity of its scores were upheld. Researchers and clinicians can use the BCBS alone to assess women's perceptions of female beauty, or they can use the BCBS alongside women's perceptions of self-beauty to more comprehensively explore women's ability to broadly conceptualize beauty for others and themselves. PMID- 26971118 TI - The Body Dysmorphic Disorder Symptom Scale: Development and preliminary validation of a self-report scale of symptom specific dysfunction. AB - The Body Dysmorphic Disorder Symptom Scale (BDD-SS) is a new self-report measure used to examine the severity of a wide variety of symptoms associated with body dysmorphic disorder (BDD). The BDD-SS was designed to differentiate, for each group of symptoms, the number of symptoms endorsed and their severity. This report evaluates and compares the psychometric characteristics of the BDD-SS in relation to other measures of BDD, body image, and depression in 99 adult participants diagnosed with BDD. Total scores of the BDD-SS showed good reliability and convergent validity and moderate discriminant validity. Analyses of the individual BDD-SS symptom groups confirmed the reliability of the checking, grooming, weight/shape, and cognition groups. The current findings indicate that the BDD-SS can be quickly administered and used to examine the severity of heterogeneous BDD symptoms for research and clinical purposes. PMID- 26971121 TI - A study of the role of Notch1 and JAG1 gene methylation in development of breast cancer. AB - This study is to explore the roles of gene methylation of Notch1 and JAG1 in development of invasive ductal carcinoma of breast. Quantitative analysis the DNA methylation levels of Notch1 and JAG1 gene by the MassARRAY method in invasive ductal carcinoma of breast (IDC; n = 89), atypical ductal hyperplasia of breast (ADH; n = 11), and ordinary ductal hyperplasia of breast (UDH; n = 20). The expressions of JAG1 and Notch1 protein in four breast tissues were detected by immunohistochemistry SP method. (1) Positive expression rates of Notch1 protein in IDC and DCIS were 88.7 % (79/89) and 70.0 % (14/20), respectively, which were significantly higher than the levels in ADH (36.0 %, 4/11) and UDH (25.0 %, 5/20; P < 0.05). Notch1 protein expression was significant positively correlated with lymph node metastasis, pathological grades, and TNM stages of IDC. (2) Positive expression rates of JAG1 protein in IDC and DCIS were 89.9 % (80/89) and 75.0 % (15/20), respectively, which were significantly higher than those of ADH (45.0 %, 5/11) and UDH (30.0 %, 6/20; P < 0.05). JAG1 protein expression was significant positive correlation with lymph node metastasis, pathological grades and TNM stages of IDC. There is an overall hypomethylation alteration of Notch1 and JAG gene in IDC, with corresponding over-expression of Notch1 and JAG1 protein. This inverse correlation shows that the alteration of protein expression results from hypomethylation oncogene Notch1 and JAG1, and this change may play an important role in occurrence and progression of breast cancer. PMID- 26971123 TI - Myoblastoma of the breast: Our experience and review of literature. AB - INTRODUCTION: Breast myoblastoma or granular cell tumor involving the breast parenchyma has been described in detail for the first time since Abrikossoff in 1931. The location of this injury to the breast is very rare, accounting for between 5% and 15% of all cases of cancer of the granular cells. We present our experience regarding the identification of two cases because of the relative rarity of this tumor. It is often confused with breast cancer on clinical and radiological, and its diagnosis can then be difficult for physicians, radiologists and pathologists. PRESENTATION OF CASES: We report the cases of two young women who came to our attention because of the presence of mass shoveled breast, mobile and accompanied by pain cycle independent. In both cases, mammography and ultrasound revealed the presence of heterogeneous mass and irregular, but in one of two such mass located at the Union of external quadrants of the left breast and was in contact with his serratus anterior and suspicion for malignancy. In both cases the 'histology combined with immunohistochemical study proved to be a granular cell tumor. CONCLUSION: Although a granular cell tumor of the breast is a rare tumor breast, should be considered in the differential diagnosis of benign and malignant lesions. Surgeons and pathologists should keep in mind when considering a granular cell tumor cells with abundant granular cytoplasm containing materials to avoid misdiagnosing breast cancer, which could lead to unnecessary surgery. PMID- 26971119 TI - The Emory University Perioperative Algorithm for the Management of Hyperglycemia and Diabetes in Non-cardiac Surgery Patients. AB - Hyperglycemia is a frequent manifestation of critical and surgical illness, resulting from the acute metabolic and hormonal changes associated with the response to injury and stress (Umpierrez and Kitabchi, Curr Opin Endocrinol. 11:75-81, 2004; McCowen et al., Crit Care Clin. 17(1):107-24, 2001). The exact prevalence of hospital hyperglycemia is not known, but observational studies have reported a prevalence of hyperglycemia ranging from 32 to 60 % in community hospitals (Umpierrez et al., J Clin Endocrinol Metab. 87(3):978-82, 2002; Cook et al., J Hosp Med. 4(9):E7-14, 2009; Farrokhi et al., Best Pract Res Clin Endocrinol Metab. 25(5):813-24, 2011), and 80 % of patients after cardiac surgery (Schmeltz et al., Diabetes Care 30(4):823-8, 2007; van den Berghe et al., N Engl J Med. 345(19):1359-67, 2001). Retrospective and randomized controlled trials in surgical populations have reported that hyperglycemia and diabetes are associated with increased length of stay, hospital complications, resource utilization, and mortality (Frisch et al., Diabetes Care 33(8):1783-8, 2010; Kwon et al., Ann Surg. 257(1):8-14, 2013; Bower et al., Surgery 147(5):670-5, 2010; Noordzij et al., Eur J Endocrinol. 156(1):137-42, 2007; Mraovic et al., J Arthroplasty 25(1):64-70, 2010). Substantial evidence indicates that correction of hyperglycemia reduces complications in critically ill, as well as in general surgery patients (Umpierrez et al., J Clin Endocrinol Metab. 87(3):978-82, 2002; Clement et al., Diabetes Care 27(2):553-97, 2004; Pomposelli et al., JPEN J Parented Enteral Nutr. 22(2):77-81, 1998). This manuscript reviews the pathophysiology of stress hyperglycemia during anesthesia and the perioperative period. We provide a practical outline for the diagnosis and management of preoperative, intraoperative, and postoperative care of patients with diabetes and hyperglycemia. PMID- 26971122 TI - Impaired mitochondrial function due to familial Alzheimer's disease-causing presenilins mutants via Ca(2+) disruptions. AB - Mutants in presenilins (PS1 or PS2) is the major cause of familial Alzheimer's disease (FAD). FAD causing PS mutants affect intracellular Ca(2+) homeostasis by enhancing the gating of inositol trisphosphate (IP3) receptor (IP3R) Ca(2+) release channel on the endoplasmic reticulum, leading to exaggerated Ca(2+) release into the cytoplasm. Using experimental IP3R-mediated Ca(2+) release data, in conjunction with a computational model of cell bioenergetics, we explore how the differences in mitochondrial Ca(2+) uptake in control cells and cells expressing FAD-causing PS mutants affect key variables such as ATP, reactive oxygen species (ROS), NADH, and mitochondrial Ca(2+). We find that as a result of exaggerated cytosolic Ca(2+) in FAD-causing mutant PS-expressing cells, the rate of oxygen consumption increases dramatically and overcomes the Ca(2+) dependent enzymes that stimulate NADH production. This leads to decreased rates in proton pumping due to diminished membrane potential along with less ATP and enhanced ROS production. These results show that through Ca(2+) signaling disruption, mutant PS leads to mitochondrial dysfunction and potentially to cell death. PMID- 26971125 TI - Loneliness, common mental disorders and suicidal behavior: Findings from a general population survey. AB - BACKGROUND: Loneliness has been linked to an increased risk of engaging in suicidal behavior. To date, however, there has been comparatively little research on this in the general adult population, or on the role of common mental disorders (CMDs) in this association. The current study examined these associations using nationally representative data from England. METHODS: Data came from the Adult Psychiatric Morbidity Survey 2007. Information was obtained from 7403 household residents aged >=16 years on perceived loneliness and lifetime and past 12-month suicide ideation and attempts. The Clinical Interview Schedule Revised (CIS-R) was used to assess six forms of CMD. Logistic regression analysis was used to examine these associations. RESULTS: Loneliness was associated with suicidal behavior. Although adjusting for CMDs attenuated associations, higher levels of loneliness were still significantly associated with suicidal ideation and suicide attempts with odds ratios (OR) for those in the most severe loneliness category ranging from 3.45 (lifetime suicide attempt) to 17.37 (past 12-month suicide attempt). Further analyses showed that ORs for suicidal behavior were similar for individuals who were lonely without CMDs, and for those respondents with CMDs who were not lonely. Lonely individuals with CMDs had especially elevated odds for suicidal ideation. LIMITATIONS: This study used cross-sectional data and a single-item measure to obtain information on loneliness. CONCLUSION: Loneliness is associated with suicidal behavior in the general adult population. This highlights the importance of efforts to reduce loneliness in order to mitigate its harmful effects on health and well-being. PMID- 26971124 TI - Major depressive disorder and suicidal behavior among urban dwelling Ethiopian adult outpatients at a general hospital. AB - BACKGROUND: We sought to evaluate the prevalence and correlates of major depressive disorder (MDD) and suicidal behavior among urban dwelling Ethiopian adults. METHODS: This was a cross-sectional study of 1097 outpatient adults (>=18 years of age) in a major hospital in Addis Ababa, Ethiopia. Sociodemographic and lifestyle characteristics were collected via structured interviews. MDD and suicidal behavior were assessed using the Composite International Diagnostic Interview (CIDI) among all study participants. Multivariable logistic regression models were fitted to estimate odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: Prevalence estimates for lifetime and 12-month MDD were 18.0% and 6.7%, respectively. The prevalence of suicidal behavior during the previous year (i.e., suicidal ideation, plan or attempt) was 15.2% with approximately 4% having reported attempts. Overall, women were more likely to report suicidal behavior (17.8%) than men (11.3%). MDD odds were 1.53-fold higher among women as compared with men (aOR=1.53, 95% CI 1.05-2.23). Lifetime MDD was significantly associated with age, sex, marital status, and self-reported physical health. Participants reporting poor mental health had approximately 3-fold increased odds of MDD (OR=2.93; 95%CI: 1.05-2.23); those between 35 and 44 years old (aOR=1.92; 95%CI: 1.06-3.49) and those older than 55 years (aOR=2.54; 95%CI: 1.16-5.57) had higher odds of MDD. Similarly suicidal behavior was significantly associated with sex, marital status, and self-reported physical and mental health. LIMITATIONS: This cross-sectional study utilized self-reported data from outpatients. Causality cannot be inferred, and results may not be fully generalizable. CONCLUSIONS: Overall results show that MDD and suicidal behavior are highly prevalent among urban-dwelling Ethiopian adults. Women and middle-age adults constitute a high risk group and may therefore benefit from targeted interventions. PMID- 26971126 TI - Suicide in males and females with cardiovascular disease and comorbid depression. AB - BACKGROUND: Myocardial infarction (MI) has been associated with an increased risk of suicide, further increased among individuals with a comorbid psychiatric illness. A paucity of studies have examined details of suicide among individuals with cardiovascular disease (CVD) and comorbid depression. We aimed to compare demographic, clinical and suicide-specific characteristics between suicide victims with CVD with depression (CVD+D) and without comorbid depression (CVD-D). METHODS: Coroner data on suicide decedents with CVD (n=413) occurring in Toronto, Canada from 1998 to 2012 were collected. Characteristics were compared between the CVD+D and CVD-D groups. Regression analysis examined for gender differences in these groups. RESULTS: CVD+D subjects compared to CVD-D were more likely to have had a past suicide attempt (p=0.008), and to have experienced a bereavement (p=0.008) or financial stressor (p=0.005) in the past year. Each of these variables remained significantly associated with the presence of depression after the regression analysis. Within the CVD+D group, females were more likely to die from suicide by self-poisoning (p<0.0001) and males by shooting (p=0.001). LIMITATIONS: Psychological autopsies were not available. The definition of CVD was broad and the accuracy of its diagnosis could not be confirmed. CONCLUSION: Individuals with CVD+D who died from suicide had significant differences in clinical characteristics and specific stressors compared to those without depression. These data may help to better characterize suicide risk and prevention in this vulnerable population. PMID- 26971127 TI - Hippocampal Sclerosis but Not Normal Aging or Alzheimer Disease Is Associated With TDP-43 Pathology in the Basal Forebrain of Aged Persons. AB - Transactivating responsive sequence (TAR) DNA-binding protein 43-kDa (TDP-43) pathology has been described in various brain diseases, but the full anatomical distribution and clinical and biological implications of that pathology are incompletely characterized. Here, we describe TDP-43 neuropathology in the basal forebrain, hypothalamus, and adjacent nuclei in 98 individuals (mean age, 86 years; median final mini-mental state examination score, 27). On examination blinded to clinical and pathologic diagnoses, we identified TDP-43 pathology that most frequently involved the ventromedial basal forebrain in 19 individuals (19.4%). As expected, many of these brains had comorbid pathologies including those of Alzheimer disease (AD), Lewy body disease (LBD), and/or hippocampal sclerosis of aging (HS-Aging). The basal forebrain TDP-43 pathology was strongly associated with comorbid HS-Aging (odds ratio = 6.8, p = 0.001), whereas there was no significant association between basal forebrain TDP-43 pathology and either AD or LBD neuropathology. In this sample, there were some cases with apparent preclinical TDP-43 pathology in the basal forebrain that may indicate that this is an early affected area in HS-Aging. We conclude that TDP-43 pathology in the basal forebrain is strongly associated with HS-Aging. These results raise questions about a specific pathogenetic relationship between basal forebrain TDP-43 and non-HS-Aging comorbid diseases (AD and LBD). PMID- 26971128 TI - Paracoccus cavernae sp. nov., isolated from a show cave. AB - A Gram-stain-negative, aerobic, non-motile, non-spore-forming bacterium, strain 0511ARD5E5T, was isolated from an air sample collected in Ardales Cave (Malaga, Spain). Strain 0511ARD5E5T grew at 4-37 degrees C and in the presence of 0-4 % (w/v) NaCl [optimally at 25 degrees C and with 1 % (w/v) NaCl]. Cells were catalase- and oxidase-positive. The major respiratory quinone was ubiquinone-10. The predominant fatty acids were C18:1omega7c and C16:0. The DNA G+C content was 63.2 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain 0511ARD5E5T was a member of the genus Paracoccus and was related most closely to Paracoccus aminophilus DSM 8538T and Paracoccus marinus CIP 108500T (96.93 and 96.92 % similarity, respectively). Strain 0511ARD5E5T exhibited DNA DNA relatedness of 47 % to P. aminophilus DSM 8538T and 31 % to P. marinus CIP 108500T. Chemotaxonomic, phenotypic and phylogenetic analyses indicated that strain 0511ARD5E5T represents a novel species of the genus Paracoccus, for which the name Paracoccus cavernae sp. nov. is proposed. The type strain is 0511ARD5E5T (=LMG 27962T=CECT 8482T). PMID- 26971129 TI - Quantitative microscopic evaluation of mucin areas and its percentage in mucinous carcinoma of the breast using tissue histological images. AB - Mucinous carcinoma (MC) of the breast is very rare (~1-7% of all breast cancers), invasive ductal carcinoma. Presence of pools of extracellular mucin is one of the most important histological features for MC. This paper aims at developing a quantitative computer-aided methodology for automated identification of mucin areas and its percentage using tissue histological images. The proposed method includes pre-processing (i.e., colour space transformation and colour normalization), mucin regions segmentation, post-processing, and performance evaluation. The proposed algorithm achieved 97.74% segmentation accuracy in comparison to ground truths. In addition, the percentage of mucin present in the tissue regions is calculated by the mucin index (MI) for grading MC (pure, moderately, minimally mucinous). PMID- 26971130 TI - Evaluation of clopidogrel response variability and identification of the CYP2C19 polymorphism in Mexican patients. AB - OBJECTIVE: Drug inhibition of platelet P2Y12 adenosine diphosphate receptor has reduced the incidence of adverse cardiovascular events after percutaneous coronary interventions. The analysis of the phosphorylation status of vasodilator stimulated phosphoprotein by flow cytometry has shown a predictive value for adverse events and stent thrombosis. Polymorphisms of CYP2C19 in high risk patients may also relate to adverse cardiovascular events. METHODS: Ninety patients were enrolled. Patients received a 600mg clopidogrel loading dose. Blood samples were obtained at the time of the procedure and 24h later, platelet reactivity was assessed by vasodilator-stimulated phosphoprotein phosphorylation measurement using flow cytometry. Low response to clopidogrel was defined as a platelet reactivity index>=50%. The presence of CYP2C19*2 was identified with the restriction enzyme SmaI. RESULTS: Mean platelet reactivity index: 53.45+/-22.48% in the baseline sample and 57.14+/-23.08% at 24h (p=0.183); 40% of patients behaved as good responders, the rest behaved as non-responders with 38% of patients showing platelet reactivity indexes between 50-70% and 22% showing indexes above 70%. The CYP2C19*2 polymorphism was found in 17% of patients, with a 3.9% AA homozygous genotype carriers. CONCLUSION: Response to the clopidogrel loading dose showed a wide variability among patients with 40% responding to the drug according to previously established cut-off values. Our results showed that 3.9% of patients show the AA genotype. To our knowledge, this is the first study involving clopidogrel response by flow citometry and genotype typification in Mexican Mestizo population. PMID- 26971131 TI - [The logic in scientific investigation]. PMID- 26971132 TI - In-Hospital Mobility Variations Across Primary Diagnoses Among Older Adults. AB - OBJECTIVES: To examine the relationship between primary diagnoses and mobility impairment and recovery among hospitalized older adults. DESIGN: Prospective cohort study. SETTING: UF Health Shands Hospital, an 852-bed level I trauma center located in Gainesville, Florida. PARTICIPANTS: A total of 18,551 older adults (>=65 years) with 29,148 hospitalizations between January 2009 and April 2014. MEASUREMENTS: Incident and discharge mobility impairment and recovery were assessed using the Braden activity subscale score that was recorded by the nursing staff at every shift change: approximately 3 times per day. Primary diagnosis ICD-9 codes were used as predictors and recategorized by using the Agency for Health Care Research and Quality Clinical Classification Software. RESULTS: Of the 15,498 hospital records in which the patient was initially observed to "walk frequently," 3186 (20.6%) developed incident mobility impairment (chair-fast or bedfast). Primary diagnoses with a surgical or invasive procedure were the most prevalent (77.2%) among the hospital observations with incident mobility impairment; otherwise, primary diagnoses without surgery were much more associated with discharge mobility impairment (59%). The highest incidence of mobility impairment occurred in patients with heart valve disorders and aortic and peripheral/visceral artery aneurysms (6.24 and 6.05 events per 30 person-days, respectively); septicemia showed the highest incidence rate for mobility limitation at discharge (0.94 events per 30 person-days). Mobility impairment was observed in 13,650 (46.8% of total) records at admission and 5930 (43.44%) were observed to recover to a state of walking occasionally or frequently. Osteoarthritis and cancer of gastrointestinal organs/peritoneum had the highest incidence rate for mobility recovery (7.68 and 5.63 events per 30 person-days respectively). CONCLUSIONS: Approximately 1 of 5 patients who were mobile at admission became significantly impaired during hospitalization. However, approximately half (43.4%) of patients observed to have mobility impairment at admission recovered during hospitalization. Conditions most associated with mobility impairment and recovery are varied, but older patients hospitalized for septicemia and cardiovascular diseases with surgery (heart valve disorders and aortic/peripheral/visceral artery aneurysms) appear to be at most risk for incident mobility impairment that did not recover at discharge. PMID- 26971134 TI - [Idiopathic or symptomatic central focal epilepsy?]. PMID- 26971133 TI - [Specific care for children with medical complexity in Spain: Searching for the best model]. PMID- 26971135 TI - [Sleeve fracture of the patella: A diagnosis not to be underestimated]. AB - Fracture of the patella is quite rare in children. However, sleeve fractures of the patella are specific to the child. We report on the case of a 12-year-old boy who suffered complete functional incapacity with hemarthrosis and symptoms that suggested rupture of the extensor apparatus. It occurred after abrupt extension of the knee during a high jump. The x-ray showed an ascended patella. The diagnosis was made and emergency surgical exploration showed a sleeve fracture. Surgical repair provided a good result, with a 2-year follow-up. A literature review found 59 cases in 20 studies with a majority of case reports with only two series over ten cases. The ages and mechanisms are identical to those observed in our study. Diagnosis is difficult and must be clearly determined. The two important signs are the ascension of the patella and the depression to its lower extremity. The prognosis is most often conditioned by rapid surgical repair. PMID- 26971136 TI - [DNET underlying focal central epilepsy]. PMID- 26971137 TI - [Parental representations of children's cough and expectations on its management]. AB - BACKGROUND: Providing medications for the management of acute cough in infants less than 24 months, a frequent reason for medical consultation, has recently been reduced by the contraindication of various antitussive specialties in France. OBJECTIVES: The objective of this study was to assess the expectations and fears of coughing infants' parents, to determine their representations of coughing, and to quantify the use of self-medication and the risk of a deferral requests to prescribe other drug classes. METHODS: An opinion and cross-survey was carried out with parents of infants under 24 months of age. A multiple-choice questionnaire was proposed to them in day care centers and Mother and Infant Welfare centers. The data collected were analyzed descriptively and using the Chi(2) test. Logistic regression enabled us to interpret some of the results. RESULTS: Sixty-four percent of parents expect an antitussive treatment from the doctor. For most parents, lifestyle modifications are well integrated (nasal irrigation, considered effective cough relief, hydration, smoking cessation). For 33 % of parents, corticosteroids are an alternative therapy to stop cough. Nearly half (43 %) of parents have sought treatment from their doctor, usually nasal suspensions, corticosteroids, and saline irrigation. Regarding self-medication, 30 % of parents have already given cough syrup or an antitussive suppository without a prescription, in order to stop the cough rapidly for 66 % of them. These parents seem more worried by coughing than other parents (P=0.0110, CI: 0.217; 1.751) as did those who had only one child (P=0.0029, CI: 0.120; 0.582). CONCLUSIONS: This study suggests that a large majority of parents understand and accept the new recommendations. But one-third of parents are still worried, not knowing what to do without prescribed medications, which led them to give nonprescription cough syrups and ask for inappropriate treatments. It seems essential to inform parents about the natural history of infant coughing and educate them on lifestyle rules to reduce the risk of deferral prescription. PMID- 26971138 TI - [Tuberculous meningitis in children in Dakar]. PMID- 26971140 TI - Adenosine triphosphate bioluminescence in intensive care units: Be careful with its use. PMID- 26971139 TI - Factors associated with resident influenza vaccination in a national sample of nursing homes. AB - Influenza vaccination remains the cornerstone of influenza prevention, yet national goals for nursing home residents and staff vaccination have not been met. Few studies have examined associations between facility and resident characteristics; employee processes, such as staff vaccination policies; and resident influenza vaccination. In this national survey of nursing homes, employee processes were not associated with resident influenza vaccination; however, various facility and resident characteristics were. PMID- 26971142 TI - Factors associated with variation in bulk tank milk Mycoplasma bovis antibody ELISA results in dairy herds. AB - The relevance and limitations for using measurements of antibodies against Mycoplasma bovis in bulk tank milk (BTM) as a potentially cost-effective diagnostic tool for herd classification has not been evaluated before. Assuming that an increasing or high seroprevalence is a result of on-going or recent spread of M. bovis in a dairy herd, we tested the hypothesis that increasing prevalence of antibody-positive cows and young stock are associated with increasing BTM antibody ELISA values against M. bovis in Danish dairy herds with different courses of M. bovis infection. Furthermore, we tested whether herd size was associated with variations in the BTM responses. Thirty-nine Danish dairy herds selected to represent 4 different herd-level infection groups [8 control herds, 14 acute outbreak herds, 7 herds with previous outbreaks, and 10 herds with elevated BTM ELISA-values directed against M. bovis (>64% optical density measurement)] were visited 4 to 5 times, approximately 3mo apart. At each visit, 65 young stock were blood sampled. At the milk recording date closest to the herd visit date, 50 milk recording samples from individual lactating cows were randomly selected. In addition, a BTM sample was collected as a representative sample directly from the bulk tank by the dairies' milk truck drivers as part of the mandatory milk quality-control scheme. Blood and milk samples were tested for antibodies against M. bovis with a commercially available ELISA test (Bio-X BIO K 302, Bio-X Diagnostics, Rochefort, Belgium). A linear mixed effects model was used to analyze the effects of the prevalence of antibody-positive lactating cows and young stock and herd size on the BTM M. bovis ELISA results. Herd was included as a random effect to account for clustering of BTM samples originating from the same herd. Increasing prevalence of antibody-positive lactating cows was the only variable associated with increasing M. bovis BTM ELISA optical density measurement. In contrast, the prevalence of antibody-positive young stock did not correlate with the BTM optical density measurement. In conclusion, some M. bovis associated herd infections are detectable by BTM ELISA-testing, but limitations exist and further investigations of the effect of different clinical disease expressions in the herds are warranted. PMID- 26971141 TI - Prognosis and postoperative genital function of function-preservative surgery of pelvic autonomic nerve preservation for male rectal cancer patients. AB - BACKGROUND: To retrospectively evaluate postoperative genital function, local recurrence rate and survival rate after total mesorectal excision (TME) combined with or without pelvic autonomic nerve preservation (PANP) in male patients with rectal cancer. METHODS: A total of 953 male patients with rectal cancer after TME (518 patients received TME combined with PANP [PANP group] and 434patients received TME alone [TME group]) were included. Assessments of postoperative genital function, local recurrence rate, and 5 year survival rate were collected. RESULTS: Rate of erection dysfunction in PANP group (41.9%) was significantly lower than that in TME group (76.7%, P < 0.05). Rate of ejaculation dysfunction in PANP group (42.5%) was also significantly lower than that in TME group (67.3%, P < 0.05). Local recurrence rate (P = 0.66) and survival rate (P = 0.26) did not differ between the two groups. For patients with preoperative obstruction, local recurrence rate was significantly higher (P = 0.01) and survival rate significantly lower (P = 0.03) in PANP group. CONCLUSIONS: PANP surgery has significant advantage with respect to preservation of genital function and should be recommended as surgical treatment for rectal cancer patients. However, PANP surgery should be considered with caution in patients with preoperative obstruction in view of the poorer long-term outcomes in these patients. PMID- 26971143 TI - Development and physiology of the rumen and the lower gut: Targets for improving gut health. AB - The gastrointestinal epithelium of the dairy cow and calf faces the challenge of protecting the host from the contents of the luminal milieu while controlling the absorption and metabolism of nutrients. Adaptations of the gastrointestinal tract play an important role in animal energetics as the portal-drained viscera accounts for 20% of the total oxygen consumption of the ruminant. The mechanisms that govern growth and barrier function of the gastrointestinal epithelium have received particular attention over the past decade, especially with advancements in molecular-based techniques, such as microarrays and next-generation DNA sequencing. The rumen has been the focal point of dairy cow and calf nutritional physiology research, whereas the lower gut has received less attention. Three key areas that require discovery-based and applied research include (1) early-life intestinal gut barrier function and growth; (2) how the weaning transition affects function of the rumen and intestine; and (3) gastrointestinal adaptations during the transition to high-energy diets in early lactation. In dairy nutrition, nutrients are seen not only as metabolic substrates, but also as signals that can alter gastrointestinal growth and barrier function. Nutrients have been shown to affect epithelial cell gene expression directly and, in concert with insulin-like growth factor, growth hormone, and glucagon-like peptide 2, play a pivotal role in gut tissue growth. The latest research suggests that ruminal and intestinal barrier function is compromised during the preweaning phase, at weaning, and in early lactation. Gastrointestinal barrier function is influenced by the presence of metabolites, such as butyrate, the resident microbiota, and the microbes provided in feed. In the first studies that investigated barrier function in cows and calves, it was determined that the expression of genes encoding tight junction proteins, such as claudins, occludins, and desmosomal cadherins, are affected by age and diet. Recent evidence suggests that the upper and lower gut can communicate, but the exact mechanisms of gastrointestinal cross-talk in ruminants have not been studied in detail. A deeper understanding of how diet and microbiota can affect growth and barrier function of the intestinal tract may facilitate the development of specific management regimens that could effectively influence gut function. PMID- 26971144 TI - MicroRNA Bta-miR-181a regulates the biosynthesis of bovine milk fat by targeting ACSL1. AB - MicroRNA (miRNA) are a class of small noncoding RNA that function as important posttranscriptional regulators of gene expression. The acyl-CoA synthetase long chain family member 1 (ACSL1) is an important enzyme in the process of milk lipid synthesis. In a previous study dealing with incubations of stearic acid in bovine mammary epithelial cells, an opposite expression pattern was observed between ACSL1 and miR-181a. Bioinformatics analysis with TargetScan and PicTar revealed ACSL1 as a potential target gene of miR-181a. The objective of this work was to determine the potential function of miR-181a on milk fat synthesis by defining the regulatory relationship between miR-181a and ACSL1. Primary bovine mammary epithelial cells were harvested from mid-lactation cows and cultured in Dulbecco's modified Eagle's medium/F-12 medium with 10% fetal bovine serum, 0.5MUg/mL of insulin, 10 ng/mL of epidermal growth factor, 5MUg/mL of transferrin, 1MUg/mL of hydrocortisone, 1MUg/mL of progesterone, 5MUg/mL of estradiol, and 5MUg/mL of prolactin. Cells were transfected with an miR-181a mimic to increase its expression and an miR-181a inhibitor to decrease its expression before culturing for 48 h. The results revealed that the overexpression of miR-181a inhibited the expression of ACSL1, whereas the downregulation of miR-181a increased ACSL1 expression. Western blot analysis of ACSL1 revealed similar effects. Oil-red-O staining indicated that cellular lipid droplet synthesis was decreased with the overexpression of bta-miR-181a, and treatment with the bta-miR-181a inhibitor increased concentration of lipid droplets. Furthermore, overexpression of bta-miR-181a resulted in a decrease in concentration of triacylglycerol in the cells, whereas inhibition of bta-miR-181a increased concentration of triacylglycerol. Therefore, the results indicated that bta-miR-181a may contribute to negative regulation of lipid synthesis in mammary cells via targeting ACSL1. PMID- 26971145 TI - Analysis of electric energy consumption of automatic milking systems in different configurations and operative conditions. AB - Automatic milking systems (AMS) have been a revolutionary innovation in dairy cow farming. Currently, more than 10,000 dairy cow farms worldwide use AMS to milk their cows. Electric consumption is one of the most relevant and uncontrollable operational cost of AMS, ranging between 35 and 40% of their total annual operational costs. The aim of the present study was to measure and analyze the electric energy consumption of 4 AMS with different configurations: single box, central unit featuring a central vacuum system for 1 cow unit and for 2 cow units. The electrical consumption (daily consumption, daily consumption per cow milked, consumption per milking, and consumption per 100L of milk) of each AMS (milking unit + air compressor) was measured using 2 energy analyzers. The measurement period lasted 24h with a sampling frequency of 0.2Hz. The daily total energy consumption (milking unit + air compressor) ranged between 45.4 and 81.3 kWh; the consumption per cow milked ranged between 0.59 and 0.99 kWh; the consumption per milking ranged between 0.21 and 0.33 kWh; and the consumption per 100L of milk ranged between 1.80 to 2.44 kWh according to the different configurations and operational contexts considered. Results showed that AMS electric consumption was mainly conditioned by farm management rather than machine characteristics/architectures. PMID- 26971146 TI - Improving reliability of genomic predictions for Jersey sires using bootstrap aggregation sampling. AB - Genomic selection has revolutionized the dairy genetics industry and enhanced the rate of response to selection for most economically important traits. All young bulls are now genotyped using commercially available single nucleotide polymorphism arrays to compute genomic predicted transmitting ability (GPTA) and reliability (REL) values. Decisions regarding the purchasing, marketing, and culling of dairy bulls are based on GPTA until roughly 5 yr of age, when milk recorded offspring become available. At that time, daughter yield deviations (DYD) can be used to assess the accuracy of the GPTA computed several years earlier. Although agreement between predictions and DYD is often good, the DYD of some bulls differ widely from corresponding GPTA, and published REL are of limited value in identifying such bulls. A method of bootstrap aggregation sampling (bagging) using genomic BLUP (GBLUP) was implemented to predict the GPTA of 379, 379, and 342 young Jersey bulls for protein yield, somatic cell score, and daughter pregnancy rate, respectively. For each trait, 50 bootstrap samples from a reference population consisting of 2011 DYD of 1,738, 1,616, and 1,551 older Jersey bulls were used, and correlations between bagged GBLUP predictions and 2014 DYD were lower than GBLUP predictions derived from the full reference population. Although the bagged GBLUP approach did not improve the predictive correlations, it allowed computation of bootstrap predictive reliabilities across random samples of the reference population. The bootstrap predictive reliabilities could be a useful diagnostic tool for assessing genome-enabled prediction systems or evaluating the composition of a reference population. Our main objective was to determine if bagging GBLUP of young Jersey bulls could lead to measures of reliability that would be a useful alternative to published REL values. The standard deviations of bagged GBLUP predictions were found to weakly improve our ability to identify bulls whose future daughter performance may deviate significantly from early GPTA for protein, but not for somatic cell score or daughter pregnancy rate. PMID- 26971147 TI - Predicting colostrum quality from performance in the previous lactation and environmental changes. AB - Nine New Hampshire Holstein dairies contributed to a study to investigate if colostrum quality could be predicted by cow performance in the previous lactation and by environmental factors during the 21-d prepartum period. The numbers of days below 5 degrees C (D<), days above 23 degrees C (D>), and days between 5 and 23 degrees C (D) were used in the development of the regression equation. Between 2011 and 2014, 111 colostrum samples were obtained and analyzed for IgG. Producers recorded cow identification number, calf date of birth, sex of the calf, colostrum yield, hours from parturition to colostrum harvest, and weeks on pasture during the dry period (if any). Dairy Herd Improvement data from each cow and weather data were compiled for analysis. Information accessed was predicted transmitting abilities for milk, fat (PTAF), protein (PTAP), and dollars; previous lactation: milk yield, fat yield, fat percent, protein percent, protein yield, somatic cell score, days open, days dry, days in milk, and previous parity (PAR). Colostrum yield was negatively correlated with IgG concentration (r=-0.42) and D (r=-0.2). It was positively correlated with D> (r=0.30), predicted transmitting ability for milk (r=0.26), PTAF (r=0.21), and PTAP (r=0.22). Immunoglobulin G concentration (g/L) was positively correlated with days in milk (r=0.21), milk yield (r=0.30), fat yield (r=0.34), protein yield (r=0.26), days open (r=0.21), PAR (r=0.22), and tended to be positively correlated with DD (r=0.17). Immunoglobulin G concentration (g/L) was negatively correlated with D> (r=-0.24) and PTAF (r=-0.21) and tended to be negatively correlated with PTAP (r= 0.18). To determine the best fit, values >0 were transformed to natural logarithm. All nontransformed variables were also used to develop the model. A variance inflation factor analysis was conducted, followed by a backward elimination procedure. The resulting regression model indicated that changes in Ln fat yield (beta=2.29), Ln fat percent (beta=2.15), Ln protein yield (beta= 2.25), and Ln protein percent (beta=2.1) had largest effect on LnIgG. This model was validated using 27 colostrum samples from 9 different farms not used in the model. The difference between means for actual and predicted colostrum quality (IgG, g/L) was 13.6g/L. Previous lactation DHI data and weather data can be used to predict the IgG concentration of colostrum. PMID- 26971148 TI - Screening Brucella spp. in bovine raw milk by real-time quantitative PCR and conventional methods in a pilot region of vaccination, Edirne, Turkey. AB - Brucellosis is a worldwide zoonotic disease transmitted to humans by consumption of contaminated milk and milk products. Brucellosis is endemic in Turkey, and Edirne has a high Brucella prevalence. Brucellosis is prevented by live attenuated vaccines for animals and the vaccination program has been in place since 1984 in Turkey. Thrace is the pilot region for this vaccination program. The gold standard diagnostic technique for brucellosis is still the isolation of suspicious bacterial colonies followed by bacteriological identification, but it is very time consuming and laborious. In many studies, Brucella has been investigated by PCR techniques. However, PCR-based methods cannot differentiate between the vaccine strain and the virulent strain; thus, the vaccine strain may interfere with the virulent strain and causes false-positive reactions. To monitor brucellosis control programs effectively, it is important to distinguish vaccine and field strains of Brucella spp. In this study, raw milk samples were collected from 99 cows at 12 different barns in 5 villages of Edirne (Turkey). Bacteriological analyses and real-time quantitative (q)PCR experiments were applied to all samples. The DNA was isolated using Biospeedy DNA-Tricky Purification Kit (Bioeksen, Istanbul, Turkey). For all reactions, Roche Light Cycler Nano (Roche Diagnostics, Mannheim, Germany) instrument and Biospeedy EvaGreen qPCR Pre-Mix (Bioeksen) were used. The data were analyzed using Roche LightCycler NanoSoftware 1.0. For samples that were negative by bacteriological analyses and positive by qPCR, we developed a novel qPCR-based method to differentiate the virulent B. abortus strains and B. abortus S19 vaccine strain. We designed qPCR primers targeting the outer membrane protein of B. abortus. The qPCR products were sequenced using the ABI Prism Big Dye Terminator Cycle Sequencing Ready Reaction Kit on an ABI Prism 377 DNA sequencer (Applied Biosystems, Foster City, CA). In total, 2.02% of the samples were Brucella positive, by both bacteriological method and the novel qPCR method. We concluded that, to obtain true-positive results in Brucella spp. screening studies for milk, differentiating the virulent and vaccine strain should not be disregarded. PMID- 26971149 TI - Adding a second prostaglandin F2alpha treatment to but not reducing the duration of a PRID-Synch protocol increases fertility after resynchronization of ovulation in lactating Holstein cows. AB - Our objective was to evaluate the effect of a second PGF2alpha treatment and duration of an Ovsynch protocol that included a progesterone-releasing intravaginal device (PRID) on progesterone (P4) concentrations and pregnancies per artificial insemination (P/AI) after resynchronization of ovulation and timed artificial insemination (TAI). Lactating Holstein cows (n=821) were assigned randomly at a nonpregnancy diagnosis (d 0) to 3 resynchronization protocols: (1) GnRH, d 0; PGF2alpha, d 7; GnRH, d 9.5 (7D1PGF); (2) GnRH, d 0; PGF2alpha, d 7; PGF2alpha, d 8; GnRH, d 9.5); (7D2PGF); or (3) GnRH, d 2; PGF2alpha, d 7; PGF2alpha, d 8; GnRH, d 9.5 (5D2PGF). All cows received a PRID at the first GnRH treatment of the resynchronization protocol, which was removed at the first PGF2alpha treatment, and all cows received TAI approximately 16h after the second GnRH treatment. Blood samples were collected from a subgroup of cows at each treatment of the resynchronization protocols. At 32 d after TAI, cows receiving a second PGF2alpha treatment (7D2PGF + 5D2PGF cows) had more P/AI (42.6 vs. 35.7%) than cows receiving a single PGF2alpha treatment (7D1PGF cows). For cows treated with a second PGF2alpha treatment, decreasing the duration of the protocol did not increase P/AI (41.4 vs. 43.8% for 7D2PGF vs. 5D2PGF cows). At 60 d after TAI, P/AI did not differ between cows treated with the 1 PGF2alpha (7D1PGF cows) or 2 PGF2alpha (7D2PGF + 5D1PGF cows) treatments (32.5 vs. 37.9%, respectively). In addition, reducing the duration of the protocol did not increase P/AI at 60 d after TAI (37.8 vs. 38.5% for 7D2PGF vs. 5D2PGF cows). Pregnancy loss from 32 to 60 d after TAI was not affected by the number of PGF2alpha treatments (8.5 vs. 10.6%, for 7D1PGF vs. 7D2PGF + 5D2PGF cows) or the duration of the protocol (9.1 vs. 12.1%, for 7D2PGF vs. 5D2PGF cows). The percentage of cows with incomplete luteal regression at the second GnRH treatment tended to differ among treatments and was lowest for 7D2PGF cows, intermediate for 5D2PGF cows, and greatest for 7D1PGF cows (1.9 vs. 6.9 vs. 11.0%, respectively). In conclusion, addition of a second PGF2alpha treatment tended to decrease the percentage of cows with incomplete luteal regression and increased P/AI 32 d after AI, whereas decreasing the duration of the Ovsynch protocol did not increase P/AI. PMID- 26971150 TI - Short communication: Improved method for centrifugal recovery of bacteria from raw milk applied to sensitive real-time quantitative PCR detection of Salmonella spp. AB - Centrifugation is widely used to isolate and concentrate bacteria from dairy products before assay. We found that more than 98% of common pathogenic bacteria added to pasteurized, homogenized, or pasteurized homogenized milk were recovered in the pellet after centrifugation, whereas less than 7% were recovered from raw milk. The remaining bacteria partitioned into the cream layer of raw milk within 5 min, and half-saturation of the cream layer required a bacterial load of approximately 5*10(8) cfu/mL. Known treatments (e.g., heat, enzymes or solvents) can disrupt cream layer binding and improve recovery from raw milk, but can also damage bacteria and compromise detection. We developed a simple, rapid agitation treatment that disrupted bacteria binding to the cream layer and provided more than 95% recovery without affecting bacteria viability. Combining this simple agitation treatment with a previously developed real-time quantitative PCR assay allowed the detection of Salmonella spp. in raw milk at 4 cfu/mL within 3 h. To our knowledge, this is the first report of an effective method for achieving high centrifugal recovery of bacteria from raw milk without impairing bacterial viability. PMID- 26971151 TI - Effects of prepartum diets supplemented with rolled oilseeds on calf birth weight, postpartum health, feed intake, milk yield, and reproductive performance of dairy cows. AB - The objectives were to determine the effects of supplemental fat (no oilseed vs. oilseed) during late gestation and the source of fat (canola vs. sunflower seed), on dry matter intake (DMI), plasma metabolite concentrations, milk production and composition, calf birth weight, postpartum health disorders, ovarian function and reproductive performance in dairy cows. Pregnant Holstein cows, blocked by body condition and parity, were assigned to 1 of 3 diets containing rolled canola seed (high in oleic acid; n=43) or sunflower (high in linoleic acid; n=45) at 8% of dry matter, or no oilseed (control; n=43), for the last 35+/-2 d of pregnancy. After calving, all cows received a common lactation diet. Blood samples were collected at wk -3 (i.e., 2 wk after initiation of prepartum diets) and at wk +1, +2, +3, +4 and +5 postpartum to determine the concentration of fatty acids (mEq/dL), beta-hydroxybutyrate (mg/dL), and glucose (mg/dL). Ovarian ultrasonography was performed twice weekly to determine the first appearance of dominant (10mm) and preovulatory-size (>=16mm) follicles, and ovulation. Uterine inflammatory status based on the proportion of polymorphonuclear leukocytes (PMN; subclinical endometritis: >8% PMN) was assessed at d 25+/-1 postpartum. Significant parity by treatment interactions were observed for DMI and milk yield. Prepartum oilseed supplementation, more specifically sunflower seed supplementation, increased postpartum DMI in primiparous cows without affecting prepartum DMI or milk yield. Contrarily, in multiparous cows, prepartum oilseed supplementation decreased both prepartum and postpartum DMI and milk yield during the first 2 wk. Regardless of parity, prepartum feeding of canola reduced postpartum DMI compared with those fed sunflower. Mean fatty acids concentrations at wk -3 were greater in cows given supplemental oilseed than those fed no oilseeds. Gestation length and calf birth weight were increased in cows given supplemental oilseed prepartum compared with cows fed no oilseeds, and a disproportionate increase in the birth weight of female calves was evident in cows fed oilseed. Total reproductive disorders tended to be greater in cows fed supplemental oilseed than those fed no oilseed (42 vs. 23%). Furthermore, cows fed sunflower seed had greater incidences of dystocia (35 vs. 18%) and total health disorders (52 vs. 32%) than those fed canola seed. Added oilseed and type of oilseed did not affect uterine inflammation at 25+/-1 d postpartum. Oilseed supplementation did not alter the intervals from calving to establishment of the first dominant follicle, preovulatory-size follicle, and ovulation, nor did it affect fertility (conception rate to first artificial insemination and proportion of pregnant cows by 150 d after calving). In summary, prepartum oilseed supplementation (6.2 to 7.4% ether extract, % of dietary dry matter) decreased DMI during the entire experimental period (pre- and postpartum), decreased milk yield during early lactation in multiparous cows, and increased calf birth weight with no significant improvement in ovarian function and reproductive performance. PMID- 26971152 TI - Primary cilia distribution and orientation during involution of the bovine mammary gland. AB - The regulation of mammary gland involution occurs through multiple levels including environmental factors, hormones, and local intramammary signals. Primary cilia (PC) are signaling organelles that sense biochemical and biophysical extracellular stimuli and are vital for cellular and tissue function. The aim of this study was to examine the distribution, incidence, and orientation of PC. Furthermore, we determined changes in expression levels of the signal transducer and activator of transcription (STAT)6 at the onset of bovine mammary gland involution. Mammary tissue was collected from pasture-fed, primiparous, nonpregnant Friesian dairy cows at mid lactation (n=5 per group) killed 6-h after milking (lactating controls) and during involution after 7 and 28 d of nonmilking (NM). Fluorescent immunohistochemistry and confocal microscopy of tissue sections showed that PC were present on luminal secretory epithelial cells (SEC), myoepithelial cells (MEC), and stromal fibroblast cells (SFC). Furthermore, in all 3 experimental groups, different PC positions or orientations relative to the cell surface were identified on SEC and MEC, which projected toward the lumen and were either straight, bent, or deflected against the apical cell surface, whereas PC in SFC were confined to the interalveolar space. However, by 28-d NM, fewer PC projected into the luminal space and most appeared deflected or projected toward the interalveolar space. Furthermore, by 28-d NM, with the increase in stromal connective tissue, more PC were detected within the interalveolar and interlobular stroma. At 28-d NM, we observed a decrease in luminal cilia relative to the total number of cilia. The number of ciliated cells in the total fraction (SEC, MEC, and SFC) was the same for all 3 groups, although in the luminal fraction (SEC and MEC), PC per nuclei increased by 28-d NM relative to lactation. At all 3 stages, we detected variations in shape and orientation of PC within the same alveolus, with some PC projecting directly into lumen, whereas others appeared to be bent or deflected flat against the cell surface. Within each treatment, the average number of bent cilia was low, whereas the average number of deflected cilia was higher than the average number of cilia projecting directly into the lumen. Quantitative real-time reverse transcription PCR analysis showed that expression levels of milk protein genes (alphaS1-casein, alpha-lactalbumin, and kappa-casein) declined and that of lactoferrin increased in the involuted mammary tissue following NM, compared with lactating controls. Although STAT6 mRNA levels did not change following NM, STAT6 protein levels did increase following 28-d NM compared with the control lactation group. In conclusion, PC were detected in all cell types in the mammary gland, and changes in orientation during involution suggest the potential for PC to play a role in signal transduction through both mechanosensation and chemosensation. Furthermore, the STAT6-mediated signaling pathway may have a role during involution of the mammary gland. PMID- 26971153 TI - A method for single nucleotide polymorphism selection for parentage assessment in goats. AB - Accurate pedigrees are essential to optimize genetic improvement and conservation of animal genetic resources. In goats, the use of mating groups and kidding management procedures hamper the identification of parentage. Small panels of single nucleotide polymorphisms (SNP) have been proposed in other species to substitute microsatellites for parentage assessment. Using data from the current GoatSNP50 chip, we developed a new 3-step procedure to identify a low-density SNP panel for highly accurate parentage assessment. Methodologies for SNP selection used in other species are less suitable in the goat because of uncertainties in the genome assembly. The procedure developed in this study is based on parent offspring identification and on estimation of Mendelian errors, followed by canonical discriminant analysis identification and stepwise regression reduction. Starting from a reference sample of 109 Alpine goats with known pedigree relationships, we first identified a panel of 200 SNP that was further reduced to 2 final panels of 130 and 114 SNP with random coincidental match inclusion of 1.51*10(-57) and 2.94*10(-34), respectively. In our reference data set, all panels correctly identified all parent-offspring combinations, revealing a 40% pedigree error rate in the information provided by breeders. All reference trios were confirmed by official tests based on microsatellites. Panels were also tested on Saanen and Teramana breeds. Although the testing on a larger set of breeds in the reference population is still needed to validate these results, our findings suggest that our procedure could identify SNP panels for accurate parentage assessment in goats or in other species with unreliable marker positioning. PMID- 26971154 TI - Milk fat triacylglycerols and their relations with milk fatty acid composition, DGAT1 K232A polymorphism, and milk production traits. AB - Milk fat (MF) triacylglycerols (TAG) determine the physical and functional properties of butter and products rich in MF. To predict these properties, it is necessary to understand the variability of fatty acids, TAG, their associations, and their effect on milk productive traits, days in milk (DIM), and genes related to fat synthesis. Therefore, the aim of this research was to study the variability of TAG using MF from individual cows and to investigate the effect of fatty acid composition, DGAT1 K232A polymorphism, DIM, and milk production traits (fat content and morning milk yield) on MF TAG profile in the Dutch Holstein Friesian dairy cattle population. Large differences in MF TAG profiles were seen among cows. We showed that the variability of TAG is highest for low and high molecular weight TAG [TAG with carbon numbers (Cn) 26-30 and Cn52-54, respectively] and lowest for TAG with Cn38, which was the most abundant TAG. Saturation index (saturated fatty acid/unsaturated fatty acid) and the ratio C16:0/C18:1 cis-9 showed significant effects on TAG Cn34, Cn36, Cn52, and Cn54: TAG Cn34 and Cn36 increased as the saturation index and ratio C16:0/C18:1 cis-9 increased, whereas the opposite was seen for TAG Cn52 and Cn54. Moreover, the DGAT1 K232A polymorphism significantly affected TAG Cn38. We showed that the relative concentration of TAG with Cn38 was higher in cows with DGAT1 KK genotype. Production traits (fat content and morning milk yield) and DIM had no significant effect on TAG profile. This is a relevant observation because considerable increases of milk yield and fat content have been seen in the Netherlands over the last 60 yr. The large differences shown between individual cows in MF TAG profile imply differences in physical properties of MF. PMID- 26971155 TI - Effects of stocking density on behavior, productivity, and comfort indices of lactating dairy cows. AB - The objective of this study was to investigate the effects of different stocking densities of 82 (0.82 cows per freestall and feed bin), 100, and 129% on behavior, productivity, and comfort indices of lactating Holstein dairy cows. Twenty-seven lactating cows (15 primiparous and 12 multiparous) were assigned to 1 of the 3 treatments, which were balanced for parity, milk yield, days in milk, and body weight in a 3*3 Latin square design with 14-d periods. After 7 d of adaptation to the treatments, lying time and bouts were recorded at 1-min intervals for 3 d, DMI and feeding time were monitored electronically by feed bins, and rumination time was quantified at 2-h periods for 5 d during each period. The cow comfort index, stall standing index, stall perching index, and stall use index (SUI) were calculated using 10-min scan samples of video recording from d 8 to 10 of each period. Milk yield was recorded from d 8 to 12 and milk composition was determined from composite samples on d 12 in each period. Daily lying time, lying bouts, and bout duration did not differ among the stocking densities. The ratio of lying time >=12 h/d (the number of cows with daily lying time >=12 h/d divided by number of cows per pen) was higher for cows housed at 82% stocking density compared with those housed at 100% stocking density, with stocking density of 129% intermediate. Hourly lying time was lower at 100% stocking density compared with 82 and 129% stocking densities during the peak period (2300-0400 h), determined based on diurnal pattern of lying time. Daily dry matter intake, feeding time, and feeding rate were not affected by stocking density. After morning milking, dry matter intake and feeding time was reduced at 129 versus 82% stocking density during peak feeding time (0600-0800 h), determined based on diurnal patterns of feeding behavior. Stocking density had no effect on rumination time, milk yield and milk composition. The ratio of SUI >=85% (mean of the number of SUI >=85% divided by the number of SUI at 10-min scan samples during a 24-h period) was lower at 129 versus 82% stocking density, with stocking density of 100% intermediate. During peak lying time after evening milking (2300-0400 h), both cow comfort index and SUI were higher at 129 than at 100% stocking density. The SUI was lower 2h after morning milking (0800-0900 h) for cows housed at 129% compared with those housed at 82 and 100% stocking densities. In conclusion, when compared with 100% stocking density, understocking contributed to natural behaviors of cows that including lying, feeding, and rumination behavior, whereas overstocking did not cause negative effect on behavior, productivity, and comfort indices of cows in this study. PMID- 26971156 TI - Virtual milk for modelling and simulation of dairy processes. AB - The modeling of dairy processing using a generic process simulator suffers from shortcomings, given that many simulators do not contain milk components in their component libraries. Recently, pseudo-milk components for a commercial process simulator were proposed for simulation and the current work extends this pseudo milk concept by studying the effect of both total milk solids and temperature on key physical properties such as thermal conductivity, density, viscosity, and heat capacity. This paper also uses expanded fluid and power law models to predict milk viscosity over the temperature range from 4 to 75 degrees C and develops a succinct regressed model for heat capacity as a function of temperature and fat composition. The pseudo-milk was validated by comparing the simulated and actual values of the physical properties of milk. The milk thermal conductivity, density, viscosity, and heat capacity showed differences of less than 2, 4, 3, and 1.5%, respectively, between the simulated results and actual values. This work extends the capabilities of the previously proposed pseudo-milk and of a process simulator to model dairy processes, processing different types of milk (e.g., whole milk, skim milk, and concentrated milk) with different intrinsic compositions, and to predict correct material and energy balances for dairy processes. PMID- 26971157 TI - Tracing and inhibiting growth of Staphylococcus aureus in barbecue cheese production after product recall. AB - Staphylococcal food poisoning is one of the most prevalent causes of foodborne intoxication worldwide. It is caused by ingestion of enterotoxins formed by Staphylococcus aureus during growth in the food matrix. Following a recall of barbecue cheese due to the detection of staphylococcal enterotoxins in Switzerland in July 2015, we analyzed the production process of the respective dairy. Although most cheese-making processes involve acidification to inhibit the growth of pathogenic bacteria, barbecue cheese has to maintain a pH >6.0 to prevent undesired melting of the cheese. In addition, the dairy decided to retain the traditional manual production process of the barbecue cheese. In this study, therefore, we aimed to (1) trace Staph. aureus along the barbecue cheese production process, and (2) develop a sustainable strategy to inhibit growth of Staph. aureus and decrease the risk of staphylococcal food poisoning without changing the traditional production process. To this end, we traced Staph. aureus in a step-wise blinded process analysis on 4 different production days using spa (Staphylococcus protein A gene) typing, DNA microarray profiling, and pulsed field gel electrophoresis analysis. We subsequently selected a new starter culture and used a model cheese production including a challenge test assay to assess its antagonistic effect on Staph. aureus growth, as well as its sensory and technological implications. We detected Staph. aureus in 30% (37/124) of the collected samples taken from the barbecue cheese production at the dairy. This included detection of Staph. aureus in the final product on all 4 production days, either after enrichment or using quantitative detection. We traced 2 enterotoxigenic Staph. aureus strains (t073/CC45 and t282/CC45) colonizing the nasal cavity and the forearms of the cheesemakers to the final product. In the challenge test assay, we were able to show that the new starter culture inhibited growth of Staph. aureus while meeting the sensory and technological requirements of barbecue cheese production. PMID- 26971158 TI - Short communication: Amino acid supplementation and stage of lactation alter apparent utilization of nutrients by blood neutrophils from lactating dairy cows in vitro. AB - Glutamine is the preferred AA used by polymorphonuclear leukocytes (PMN) during the inflammatory response. However, the effect of other AA on bovine PMN response during inflammation and how this is altered by stage of lactation has not been fully elucidated. The objective of this study was to determine the effect of additional AA supplementation (pool of AA excluding Gln) on AA profiles, gene expression, and inflammatory function of PMN from dairy cows in early and mid lactation in vitro. We used 18 Holstein cows for this study. Polymorphonuclear leukocytes were isolated. Working solutions of AA (0 or 4 mM) and LPS (0 or 50MUg/mL) were added to cell populations suspended in RPMI and incubated for 2h at 37 degrees C. We used a subset of samples for gene and protein expression. Concentrations of AA in medium were determined using gas chromatography-mass spectrometry with norleucine as an internal standard. Apparent AA and glucose utilization were calculated by subtracting the concentration after from that of before incubation. Data were analyzed as a randomized block design. Challenge with LPS increased the expression of proinflammatory genes and AA supplementation decreased both the expression of some proinflammatory genes and the media concentrations of tumor necrosis factor-alpha. Neither stage of lactation, LPS challenge, nor AA supplementation altered the chemotactic or phagocytic abilities of PMN in vitro. Polymorphonuclear leukocytes supplemented with AA had greater concentrations and apparent utilization of most of the supplemented AA, whereas the unsupplemented group had greater apparent utilization of glucose. Alanine was not provided in the media but was present in spent media, and Ile, Gly, and Pro were greater in spent media than in media before incubation indicating synthesis of these AA. Regarding expression of genes involved in nutrient metabolism, the expression of G6PD, coding for the enzyme glucose 6-phosphate dehydrogenase, was increased and that of PDHA1, coding for the enzyme pyruvate dehydrogenase alpha 1, tended to increase with AA supplementation. Due to the lower concentration of tumor necrosis factor-alpha in media coupled with a downregulation of several proinflammatory genes, we concluded that AA, rather than Gln, alter the inflammatory response of bovine blood PMN. Independent from Gln, blood PMN from cows in early lactation may use certain AA as their primary carbon source for energy than cows in later lactation. Evaluating cows during the early postpartum period will provide additional information on the effect of stage of lactation and nutrient supplementation on PMN function. PMID- 26971159 TI - Physicochemical and sensory characteristics of fat-free goat milk yogurt with added stabilizers and skim milk powder fortification. AB - Goat milk yogurt has a less consistent coagulum compared with cow milk yogurt; furthermore, the presence of goat milk in foodstuffs imparts a characteristic flavor that can restrict its acceptance by consumers. This study aimed to assess and compare the physicochemical and sensory characteristics of fat-free goat milk yogurts with added stabilizers or bovine skim milk powder to improve the final product. Four treatment additions were evaluated: (1) a mixture of 0.1% (wt/vol) carrageenan and 0.1% (wt/vol) pectin (treatment CR); (2) 0.5% (wt/vol) pectin (treatment PE); (3) 4.65% (wt/vol) bovine skim milk powder (treatment BM); and (4) control (no stabilizer; treatment CT). The physicochemical parameters were investigated at on d 1 and 5 of storage. The BM treatment presented higher pH and titratable acidity values, resulting in a buffering capacity effect. The total crude protein (CP) and solids-not-fat (SNF) contents were also higher in BM compared with the other evaluated treatments because of the addition of bovine skim milk powder. We detected a reduction in pH values for all treatments. Lower SNF contents were present in the CR and CT treatments, which might be related to a syneresis process during storage; moreover, an increase in total CP was observed for all treatments due to the proteolytic action of the starter culture. Sensory attributes, including appearance (color, consistency, and presence of lumps), texture (consistency, viscosity, and presence of lumps), flavor (bitter, sweet, and characteristic of commercial plain nonfat yogurt), and overall impression were evaluated by quantitative descriptive analysis. The addition of 0.5% (wt/vol) of pectin (PE treatment) strengthened the curd; however, the visual and oral presence of lumps and a higher bitterness score were noted by trained panelists, which resulted in the lowest overall impression score for the PE treatment. In several sensory attributes, the CR treatment was considered similar to the control; the mixture of 0.1% (wt/vol) carrageenan and 0.1% (wt/vol) pectin was not as effective as expected. Goat milk yogurt containing added bovine skim milk powder (BM) had improved consistency, viscosity, and flavor due to its higher SNF and total CP contents, which are particularly important for the desirable texture of plain nonfat yogurt. In addition, the BM yogurt was considered to have characteristics most similar to that of available commercial brands and achieved the best score for overall impression. PMID- 26971161 TI - Short communication: Effects of prepartum diets supplemented with rolled oilseeds on Brix values and fatty acid profile of colostrum. AB - The objective of this study was to evaluate effects of oilseeds supplemented in prepartum diets on colostrum quality. Thirty-nine dry pregnant Holstein cows (14 primiparous and 25 multiparous cows) were blocked by body condition score and parity and assigned to 1 of 3 experimental diets containing rolled oilseeds at 8% of dietary dry matter (canola seed or sunflower seed) or no oilseed (control) at 35 d before the expected calving date. Canola seed is high in oleic acid and sunflower seed is high in linoleic acid content. Colostrum samples were collected at the first milking after calving, and concentrations of nutrient composition, fatty acid profile, and Brix value (an indicator IgG concentration) were determined. Cows fed sunflower seeds before calving produced colostrum with greater crude protein content (15.0 vs. 12.9%), colostral Brix values (24.3 vs. 20.3%), and conjugated linoleic acid concentration (18:2 cis-9,trans-11; 0.64 vs. 0.48%) compared with those fed canola seed. Positive effects of feeding sunflower seed might be mediated by ruminal metabolism of linoleic acid and subsequent enhanced production of conjugated linoleic acid. Oilseed supplementation in prepartum diets of dairy cows also altered fatty acid profile of colostrum in a way to reflect fatty acid profile of the supplemented oilseeds except for oleic acid. In conclusion, prepartum feeding of sunflower seed increased colostral Brix value, an indicator of colostral IgG concentration, compared with that of canola seed, but its mode of action and effects on health and productivity of calves need to be investigated. PMID- 26971160 TI - Effect of dietary sugar concentration and sunflower seed supplementation on lactation performance, ruminal fermentation, milk fatty acid profile, and blood metabolites of dairy cows. AB - Previous research has shown that both sunflower seed (SF) and sucrose (SC) supplementation can result in variation in milk fat concentration and composition, possibly due to altered fermentation patterns and biohydrogenation of fatty acids in the rumen. The objective of this study was to determine the effects of different sugar concentrations with or without SF supplementation on lactation performance, ruminal fermentation, and milk fatty acid profile in lactating dairy cows. Eight multiparous Holstein dairy cows (body weight=620+/ 15kg, 60+/-10 d in milk, mean +/- standard deviation) were randomly assigned to treatments in a replicated 4*4 Latin square design with a 2*2 factorial arrangement of treatments. Each 21-d period consisted of a 14-d diet adaptation period and 7-d collection period. Dairy cows were fed 1 of the following 4 diets: (1) no additional SC without SF supplementation (NSC-SF), (2) no additional SC with SF supplementation (NSC+SF), (3) SC without SF supplementation (SC-SF), and (4) SC with SF supplementation (SC+SF). The diets contained the same amount of forages (corn silage and alfalfa hay). Four isonitrogenous and isoenergetic diets were formulated by replacing corn grain with SC and SF and balanced using change in proportions of canola meal and sugar beet pulp. No interaction was detected between SC and SF supplementation with respect to dry matter intake, milk yield, and composition. A tendency was found for an interaction between inclusion of SC and SF on energy-corrected milk with the highest amount in the SC-SF diet. Ruminal pH and the molar proportion of acetate were affected by SC inclusion, with an increase related to the SC-SF diet. Diets containing SF decreased the concentrations of short-chain fatty acids (4:0 to 10:0) and medium-chain fatty acids (12:0 to 16:0) in milk fat. The addition of SC tended to decrease the concentration of total trans-18:1. These data provide evidence that exchanging SC for corn at 4% of dietary dry matter influenced milk fat content and rumen pH, resulting in a tendency for decreased concentration of trans-18:1 in milk fat. Sucrose alone did not alter the milk fatty acid profile when cows were fed a combination of unsaturated fat and sugar, although several significant interactions between sugar and unsaturated fat were observed. PMID- 26971163 TI - Skeletal muscle and hepatic insulin signaling is maintained in heat-stressed lactating Holstein cows. AB - Multiparous cows (n=12; parity=2; 136+/-8 d in milk, 560+/-32kg of body weight) housed in climate-controlled chambers were fed a total mixed ration (TMR) consisting primarily of alfalfa hay and steam-flaked corn. During the first experimental period (P1), all 12 cows were housed in thermoneutral conditions (18 degrees C, 20% humidity) with ad libitum intake for 9 d. During the second experimental period (P2), half of the cows were fed for ad libitum intake and subjected to heat-stress conditions [WFHS, n=6; cyclical temperature 31.1 to 38.9 degrees C, 20% humidity: minimum temperature humidity index (THI)=73, maximum THI=80.5], and half of the cows were pair-fed to match the intake of WFHS cows in thermal neutral conditions (TNPF, n=6) for 9 d. Rectal temperature and respiration rate were measured thrice daily at 0430, 1200, and 1630 h. To evaluate muscle and liver insulin responsiveness, biopsies were obtained immediately before and after an insulin tolerance test on the last day of each period. Insulin receptor (IR), insulin receptor substrate 1 (IRS-1), AKT/protein kinase B (AKT), and phosphorylated AKT (p-AKT) were measured by Western blot analyses for both tissues. During P2, WFHS increased rectal temperature and respiration rate by 1.48 degrees C and 2.4-fold, respectively. Heat stress reduced dry matter intake by 8kg/d and, by design, TNPF cows had similar intake reductions. Milk yield was decreased similarly (30%) in WFHS and TNPF cows, and both groups entered into a similar (-4.5 Mcal/d) calculated negative energy balance during P2. Insulin infusion caused a less rapid glucose disposal in P2 compared with P1, but glucose clearance did not differ between environments in P2. In liver, insulin increased p-AKT protein content in each period. Phosphorylation ratio of AKT increased 120% in each period after insulin infusion. In skeletal muscle, protein abundance of the IR, IRS, and AKT remained stable between periods and environment. Insulin increased skeletal muscle p-AKT in each period, but the phosphorylation ratio (abundance of phosphorylated protein:abundance of total protein) of AKT was decreased in P2 for TNPF animals, but not during WFHS. These results indicate that mild systemic insulin resistance during HS may be related to reduced nutrient intake but skeletal muscle and liver insulin signaling remains unchanged. PMID- 26971162 TI - Short communication: Measuring the angiotensin-converting enzyme inhibitory activity of an 8-amino acid (8mer) fragment of the C12 antihypertensive peptide. AB - An 8-AA (8mer) fragment (PFPEVFGK) of a known antihypertensive peptide derived from bovine alphaS1-casein (C12 antihypertensive peptide) was synthesized by microwave-assisted solid-phase peptide synthesis and purified by reverse phase HPLC. Its ability to inhibit angiotensin-converting enzyme (ACE) was assessed and compared with that of the parent 12mer peptide (FFVAPFPEVFGK) to determine the effect of truncating the sequence on overall hypotensive activity. The activity of the truncated 8mer peptide was found to be almost 1.5 times less active than that of the 12mer, with ACE-inhibiting IC50 (half-maximal inhibitory concentration) values of 108 and 69MUM, for the 8mer and 12mer, respectively. Although the 8mer peptide is less active than the original 12mer peptide, its overall activity is comparable to activities reported for other small proteins that elicit physiological responses within humans. These results suggest that microbial degradation of the 12mer peptide would not result in a complete loss of antihypertensive activity if used to supplement fermented foods and that the stable 8mer peptide could have potential as a blood pressure-lowering agent for use in functional foods. PMID- 26971164 TI - RECCAS - REmoval of Cytokines during CArdiac Surgery: study protocol for a randomised controlled trial. AB - BACKGROUND: On-pump cardiac surgery triggers a significant postoperative systemic inflammatory response, sometimes resulting in multiple-organ dysfunction associated with poor clinical outcome. Extracorporeal cytokine elimination with a novel haemoadsorption (HA) device (CytoSorb(r)) promises to attenuate inflammatory response. This study primarily assesses the efficacy of intraoperative HA during cardiopulmonary bypass (CPB) to reduce the proinflammatory cytokine burden during and after on-pump cardiac surgery, and secondarily, we aim to evaluate effects on postoperative organ dysfunction and outcomes in patients at high risk. METHODS/DESIGN: This will be a single-centre randomised, two-arm, patient-blinded trial of intraoperative HA in patients undergoing on-pump cardiac surgery. Subjects will be allocated to receive either CPB with intraoperative HA or standard CPB without HA. The primary outcome is the difference in mean interleukin 6 (IL-6) serum levels between the two study groups on admission to the intensive care unit. A total number of 40 subjects was calculated as necessary to detect a clinically relevant 30 % reduction in postoperative IL-6 levels. Secondary objectives evaluate effects of HA on markers of inflammation up to 48 hours postoperatively, damage to the endothelial glycocalyx and effects on clinical scores and parameters of postoperative organ dysfunction and outcomes. DISCUSSION: In this pilot trial we try to assess whether intraoperative HA with CytoSorb(r) can relevantly reduce postoperative IL 6 levels in patients undergoing on-pump cardiac surgery. Differences in secondary outcome variables between the study groups may give rise to further studies and may lead to a better understanding of the mechanisms of haemoadsorption. TRIAL REGISTRATION: German Clinical Trials Register number DRKS00007928 (Date of registration 3 Aug 2015). PMID- 26971165 TI - Outbreak of adenovirus type 55 infection in Israel. AB - BACKGROUND: Different types of adenoviruses are associated with diverse diseases and with varied disease severity. Adenovirus 55 could be associated with severe respiratory infections. OBJECTIVES: Here, we report on an adenovirus 55 outbreak in two psychiatric institutions in Israel. The objective of this study was to investigate the adenovirus 55 outbreak. STUDY DESIGN: We studied the clinical parameters of the patients and sequencing analysis of certain parts of the virus gene was performed. RESULTS: We identified the first patient who developed symptoms (the index case) and we showed that while both patients and staff members of the institutions were infected, the disease in the psychiatric patients was more severe. We attributed these differences to their mental and underlying health conditions. CONCLUSIONS: It is important to monitor for adenovirus infection in the community, especially in mental health institutions to allow appropriate medical care. PMID- 26971166 TI - Clinical relevance of the HCV protease inhibitor-resistant mutant viral load assessed by ultra-deep pyrosequencing in treatment failure. AB - BACKGROUND: The detection of low frequency mutants in patients with hepatitis C virus (HCV) receiving direct-acting antivirals (DAAs) is still debated. The clinical relevance of the mutant viral load has not yet been evaluated. OBJECTIVES: To assess the viral load of resistance associated variants (RAVs) in patients at different time points, including the baseline, virological failure and one year after the cessation of therapy. STUDY DESIGN: The study included 22 patients who were previously treated with protease inhibitors (PI) (with telaprevir and boceprevir). For each patient, three time points were assessed using ultra-deep pyrosequencing (UDPS). RESULTS: Baseline mutations were observed in 14/22 patients (64%). At virological failure, RAVs were detected in 18/22 patients (82%). Persistent RAVs were observed in four HCV GT 1a patients (18%). Persistence mutations were found only in HCV GT 1a patients. The baseline relative V36M, R155K, R155T and A156T mutation load of patients with persistent RAVs was significantly higher (P<0.001) than those of patients without persistent RAVs. CONCLUSION: The UDPS follow-up analysis demonstrated that the presence of BOC or TLP-RAVs persist one year after therapy cessation only in HCV GT 1a patients. The relative mutant viral load should be considered prior to any PI based re-treatment. This concept of the baseline mutation viral load must be validated using current therapy and must be validated on a larger cohort. PMID- 26971167 TI - Exposure to butachlor causes thyroid endocrine disruption and promotion of metamorphosis in Xenopus laevis. AB - Butachlor is extensively applied in rice paddy ecosystem in china, and has been widespread contaminant in the aquatic environment. Here, Xenopus laevis was used for the evaluation of teratogenesis developmental toxicity, and disruption of thyroid system when exposure to different concentrations of butachlor by window phase exposure. Acute toxicity investigation shown that 96 h-LC50 value of butachlor was 1.424 mg L(-1) and 0.962 mg L(-1) for tadpoles (starting from stages 46/47) and embryos (starting from stages 8/9), respectively. Exposure to butachlor caused malformation, including abnormal eye, pericardial edema, enlarged proctodaeum and bent tail. Window phase exposure test indicated that butachlor significantly promote the contents of whole-body thyroid hormones (THs, T3 and T4) at higher levels, indicating thyroid endocrine disruption. At 7 days, exposure to butachlor up-regulated the mRNA expression of genes involved in THs synthesis and metabolism (tshalpha, tg, tpo and dio1) and THs receptors (tralpha and trbeta). At 14 days, up-regulation of the mRNA expression of genes related to THs synthesis and metabolism (tshalpha, tshbeta, tg, tpo, dio1, dio2 and ttr) and THs receptors (trbeta) were also observed after the exposure to butachlor. At 21 days, butachlor up-regulated the mRNA expression of tshalpha, tg, tpo genes and down-regulated the mRNA expression of tshbeta, tg, dio1, ttr and tralpha genes. These results showed that butachlor could change the mRNA expression of genes involved in the HPT axis and increase whole-body thyroid hormones levels of X. laevis tadpoles in a dose- and time-dependent manner, causing thyroid endocrine disruption and developmental toxicity. PMID- 26971168 TI - The synergetic effect of starch and alpha amylase on the biodegradation of n alkanes. AB - The impact of adding soluble starch on biodegradation of n-alkanes (C10-C14) by Bacillus subtilis TB1 was investigated. Gas chromatography was employed to measure the residual hydrocarbons in the system. It was observed that the efficiency of biodegradation improved with the presence of starch and the obtained residual hydrocarbons in the system were 53% less than the samples without starch. The produced bacterial enzymes were studied through electrophoresis and reverse zymography for explaining the observations. The results indicated that the produced amylase by the bacteria can degrade hydrocarbons and the same was obtained by the application of a commercial alpha amylase sample. In addition, in silico docking of alpha-amylase with n-alkanes with different molecular weights was studied by Molegro virtual docker which showed high negative binding energies and further substantiated the experimental observations. Overall, the findings confirmed the catalytic effect of alpha amylase on n-alkanes degradation. PMID- 26971169 TI - Chiral quizalofop-ethyl and its metabolite quizalofop-acid in soils: Enantioselective degradation, enzymes interaction and toxicity to Eisenia foetida. AB - An enantioselective chromatographic method to analyze enantiomers of quizalofop ethyl and its metabolite quizalofop-acid was established using a high-performance liquid chromatography (HPLC) on (R, R) Whelk-O 1 column. The enantioselective degradation kinetics of quizalofop-ethyl and quizalofop-acid in three soils were investigated. Moreover, the interaction with urease and catalase in the soils and the acute toxicity to Eisenia foetida of quizalofop-ethyl were also determined in order to assess their metabolism mechanism and environmental risk. From the results, quizalofop-ethyl was configurationally stable and was hydrolyzed rapidly to quizalofop-acid, which also degraded enantioselectively but slowly, and the inversion of the S-(-)-quizalofop-acid into the R-(+)-quizalofop-acid was observed in Xinxiang soil. In addition, quizalofop-ethyl and quizalofop-acid enantioselectively affected urease activity but not catalase. The acute toxicity assays to earthworm indicated that the racemic quizalofop-ethyl and quizalofop acid were more toxic than quizalofop-p-ethyl and quizalofop-p-acid respectively, dramatically, the toxicity of the metabolite was much higher than the parent compound. These results revealed the enantioselective degradation of quizalofop ethyl and quizalofop-acid, and the differences of toxicity among the enantiomers of the parent compound and the metabolite, which should be considered in future environmental risk evaluation. PMID- 26971170 TI - Developmental exposures to an azole fungicide triadimenol at environmentally relevant concentrations cause reproductive dysfunction in females of medaka fish. AB - Triadimenol is an effective meatabolite derived from the triazole fungicide triadimenfon. It is an agriculturally important reagent of environmentally emerging concern because of its broad use, persistent occurrence in the environment and greater fungicidal or toxic potency than the parent compound. However, the ecotoxicological impact of triadimenol on fish populations remains unclear. In this study, we investigated developmental toxicity and endocrine disruption effects in medaka fish (Oryzias latipes) exposed at an early life stage to triadimenol. First, mortality, gross development and oxidative stress responses were assessed with triadimenol exposure (3-3000 MUg/L) during the embryonic stage. Then, medaka at a sensitive stage of early sexual development underwent 35-day continuous chronic exposure to triadimenol, and the endocrine disruption effects were assessed in adulthood and the next generation. Embryonic exposure to triadimenol did not induce significant teratogenic effects or oxidative stress in embryos or hatchlings. However, early-life exposure to triadimenol under environmentally relevant concentrations (3-30 MUg/L) and 300 MUg/L persistently altered ovary development and reproduction in female adults and skewed the sex ratio in progeny. As well, triadimenol exposure interrupted the hormone balance, as seen by the expression of genes responsible for estrogen metabolism and egg reproduction. Environmentally relevant triadimenol exposure in medaka fish at early life stages may have ecotoxicological impact in aquatic environments. Along with previous studies, we suggest that conazoles share similar modes of action in disrupting hormone homeostasis and reproduction in fish and mammals. PMID- 26971171 TI - Quantitative modeling of bioconcentration factors of carbonyl herbicides using multivariate image analysis. AB - The bioconcentration factor (BCF) is an important parameter used to estimate the propensity of chemicals to accumulate in aquatic organisms from the ambient environment. While simple regressions for estimating the BCF of chemical compounds from water solubility or the n-octanol/water partition coefficient have been proposed in the literature, these models do not always yield good correlations and more descriptive variables are required for better modeling of BCF data for a given series of organic pollutants, such as some herbicides. Thus, the logBCF values for a set of carbonyl herbicides comprising amide, urea, carbamate and thiocarbamate groups were quantitatively modeled using multivariate image analysis (MIA) descriptors, derived from colored image representations for chemical structures. The logBCF model was calibrated and vigorously validated (r(2) = 0.79, q(2) = 0.70 and rtest(2) = 0.81), providing a comprehensive three parameter linear equation after variable selection (logBCF = 5.682 - 0.00233 * X9774 - 0.00070 * X813 - 0.00273 * X5144); the variables represent pixel coordinates in the multivariate image. Finally, chemical interpretation of the obtained models in terms of the structural characteristics responsible for the enhanced or reduced logBCF values was performed, providing key leads in the prospective development of more eco-friendly synthetic herbicides. PMID- 26971173 TI - Correlating toxicological effects of ionic liquids on Daphnia magna with in silico calculated linear free energy relationship descriptors. AB - In silico prediction model for toxicological effects of ionic liquids (ILs) is useful to understand ILs' toxicological interactions and to design environmentally benign IL structures. Actually, it is essential since the types of ILs are extremely numerous. Accordingly, prediction models were developed in this study. For the modelling, well-defined linear free energy relationship (LFER) descriptors - i.e. excess molar refraction (E), dipolarity/polarizability (S), H-bonding acidity (A), H-bonding basicity (B), McGowan volume (V), cation interaction (J(+)) and anion interaction (J(-)) - were in silico calculated using density functional theory and conductor-like screening model. These descriptors were then correlated with the toxicological values of ILs to Daphnia magna. First, a model established by Hoover et al. (2007) using measured LFER descriptors of 97 neutral compounds was applied to the prediction of ILs' toxicity. As expected, the model by Hoover et al. (2007) needs to be amended for ILs. To that end, the difference in toxicological interactions between neutral compounds and ILs was addressed by additional single J(+) or five LFER descriptors of cation i.e. Ec, Sc, Bc, Vc, and J(+). Secondly, a prediction model for only ILs was developed by using the three LFER descriptors Ec, Bc, and J(+). The model had a reasonable predictability and robustness of R(2) = 0.880 for the training set, 0.848 for the test set, and 0.867 for the overall set. The established models can be used to design environmentally benign IL structures and to reduce labour, danger, time, and materials compared to the experiment-based study. PMID- 26971172 TI - Varying effect of biochar on Cd, Pb and As mobility in a multi-metal contaminated paddy soil. AB - Cd, Pb and As stand as the most prominent contaminants prevailing in Chinese soils. In the present study, biochars derived from water hyacinth (BCW) and rice straw (BCR) were investigated regarding their applicability and durability in soil Cd, Pb, and As immobilization under acid precipitation. Total Cd, Pb, and As in both BCs were below the maximum allowed threshold according to biochar toxicity standard recommended by International Biochar Initiative. To evaluate BCs effect on Cd, Pb, As bioavailability and mobility, CaCl2, KH2PO4 and SPLP extractions were firstly carried out. In neutral extraction with CaCl2 and KH2PO4, significantly reduced Cd/Pb concentrations in CaCl2 extract along with elevated KH2PO4-extractable As were recorded with either BC at 2% or 5%. In SPLP with simulated acid rainwater as extractant, comparable Cd, Pb and As levels were determined in SPLP extract with 2% BCW, while slight to significant increase in SPLP-Cd, Pb or As was recorded with other treatments. Longer-term leaching column test further confirmed the high durability of 2% BCW in Cd immobilization under continuous acid exposure. In parallel, little increase in As concentrations in eluate was determined with 2% BCW compared to no-biochar control, indicating a lowered risk of As mobilization with acid input. However, remarkably higher Pb in leachate from both BCW-only control and 2% BCW-amended soils were noticed at the initial stage of acid leaching, indicating a higher acid-solubility of Pb minerals in BCW (most probably PbO) than in tested soil (PbO2, PbAs2O6). Taken together, BCW exhibited important potential for soil Cd sequestration with little effect on As mobilization under acid precipitation. But it may simultaneously load highly acid-soluble Pb minerals into soils, resulting in elevated Pb mobility upon acid exposure. Therefore, more stringent threshold for Pb content in biochar need to be put forward to secure biochar application in soils subject to anthropogenic acidification. PMID- 26971174 TI - Detection of endocrine active substances in the aquatic environment in southern Taiwan using bioassays and LC-MS/MS. AB - Endocrine active substances, including naturally occurring hormones and various synthetic chemicals have received much concern owing to their endocrine disrupting potencies. It is essential to monitor their environmental occurrence since these compounds may pose potential threats to biota and human health. In this study, yeast-based reporter assays were carried out to investigate the presence of (anti-)androgenic, (anti-)estrogenic, and (anti-)thyroid compounds in the aquatic environment in southern Taiwan. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was also used to measure the environmental concentrations of selected endocrine active substances for assessing potential ecological risks and characterizing contributions to the endocrine disrupting activities. Bioassay results showed that anti-androgenic (ND-7489 MUg L(-1) flutamide equivalent), estrogenic (ND-347 ng L(-1) 17beta-estradiol equivalent), and anti-thyroid activities were detected in the dissolved and particulate phases of river water samples, while anti-estrogenic activities (ND-10 MUg L(-1) 4-hydroxytamoxifen equivalent) were less often found. LC-MS/MS analysis revealed that anti androgenic and estrogenic contaminants, such as bisphenol A, triclosan, and estrone were frequently detected in Taiwanese rivers. In addition, their risk quotient values were often higher than 1, suggesting that they may pose an ecological risk to the aquatic biota. Further identification of unknown anti androgenic and estrogenic contaminants in Taiwanese rivers may be necessary to protect Taiwan's aquatic environment. PMID- 26971175 TI - Tributyltin disrupts feeding and energy metabolism in the goldfish (Carassius auratus). AB - Tributyltin (TBT) can induce obesogen response. However, little is known about the adverse effects of TBT on food intake and energy metabolism. The present study was designed to investigate the effects of TBT, at environmental concentrations of 2.44 and 24.4 ng/L (1 and 10 ng/L as Sn), on feeding and energy metabolism in goldfish (Carassius auratus). After exposure for 54 d, TBT increased the weight gain and food intake in fish. The patterns of brain neuropeptide genes expression were in line with potential orexigenic effects, with increased expression of neuropeptide Y and apelin, and decreased expression of pro-opiomelanocortin, ghrelin, cocaine and amphetamine-regulated transcript, and corticotropin-releasing factor. Interestingly, the energy metabolism indicators (oxygen consumption, ammonia exertion and swimming activity) and the serum thyroid hormones were all significantly increased at the 2.44 ng/L TBT group in fish. However, no changes of energy metabolism indicators or a decrease of thyroid hormones was found at the 24.4 ng/L TBT group, which indicated a complex disrupting effect on metabolism of TBT. In short, TBT can alter feeding and energy metabolism in fish, which might promote the obesogenic responses. PMID- 26971176 TI - Residues and risks of veterinary antibiotics in protected vegetable soils following application of different manures. AB - The protected vegetable farming is a style of high frequent rotation farming which requires a huge amount of fertilizers to maintain soil fertility. A total of 125 surface soils covering from east to west of China were sampled for the analysis of 17 antibiotics in order to identify antibiotics contamination caused by long-term manures application. The results indicate that the agricultural land has accumulated a statistically significantly higher antibiotics concentration than conventional open croplands. The maximum oxytetracycline concentration was 8400 MUg kg(-1), the highest level that has ever been reported for oxytetracycline in soils. The residual concentration is decided by both plant duration and manure type. Short-term (<5 years) planting shows the highest residues of tetracyclines and fluoroquinolones in the soils. The organic farming characteristic of applying commercial compost as a single fertilizer in planting shows the lowest antibiotics residue in the soils on the whole. Principal component analysis suggests that the various combinations of antibiotic compounds in the soil may be used to trace the manure source. The antibiotics in soil may threaten water quality through contamination by diffusion. Ciprofloxacin and sulfachinoxalin are calculated to be a higher migration risk to surface waters, hence their environmental fate requires further study. PMID- 26971177 TI - Biological groundwater treatment for chromium removal at low hexavalent chromium concentrations. AB - The objective of this work is to develop and evaluate biological groundwater treatment systems that will achieve hexavalent chromium reduction and total chromium removal from groundwater at hexavalent chromium (Cr(VI)) groundwater concentrations in the 0-200 MUg/L range. Three lab-scale units operated, as sequencing batch reactors (SBR) under aerobic, anaerobic and anaerobic-aerobic conditions. All systems received groundwater with a Cr(VI) content of 200 MUg/L. In order to support biological growth, groundwater was supplemented with milk, liquid cheese whey or a mixture of sugar and milk to achieve a COD concentration of 200 mg/L. The results demonstrate that a fully anaerobic system or an anaerobic-aerobic system dosed with simple or complex external organic carbon sources can lead to practically complete Cr(VI) reduction to Cr(III). The temperature dependency of maximum Cr(VI) removal rates can be described by the Arrhenius relationship. Total chromium removal in the biological treatment systems was not complete because a significant portion of Cr(III) remained in solution. An integrated system comprising of an anaerobic SBR followed by a sand filter achieved more than 95% total chromium removal thus resulting in average effluent total and dissolved chromium concentrations of 7 MUg/L and 3 MUg/L, respectively. PMID- 26971178 TI - Determination of polycyclic aromatic hydrocarbons and their nitro-, amino derivatives absorbed on particulate matter 2.5 by multiphoton ionization mass spectrometry using far-, deep-, and near-ultraviolet femtosecond lasers. AB - Multiphoton ionization processes of parent-polycyclic aromatic hydrocarbons (PPAHs), nitro-PAHs (NPAHs), and amino-PAHs (APAHs) were examined by gas chromatography combined with time-of-flight mass spectrometry using a femtosecond Ti:sapphire laser as the ionization source. The efficiency of multiphoton ionization was examined using lasers emitting in the far-ultraviolet (200 nm), deep-ultraviolet (267 nm), and near-ultraviolet (345 nm) regions. The largest signal intensities were obtained when the far-ultraviolet laser was employed. This favorable result can be attributed to the fact that these compounds have the largest molar absorptivities in the far-ultraviolet region. On the other hand, APAHs were ionized more efficiently than NPAHs in the near-ultraviolet region because of their low ionization energies. A sample extracted from a real particulate matter 2.5 (PM2.5) sample was measured, and numerous signal peaks arising from PAH and its analogs were observed at 200 nm. On the other hand, only a limited number of signed peaks were observed at 345 nm, some of which were signed to PPAHs, NPAHs, and APAHs. Thus, multiphoton ionization mass spectrometry has potential for the use in comprehensive analysis of toxic environmental pollutants. PMID- 26971179 TI - In vitro activity of tedizolid against linezolid-resistant staphylococci and enterococci. AB - The tedizolid MIC of 27 clinical isolates of linezolid-resistant staphylococci and enterococci was determined. Tedizolid MICs were >=1MUg/mL and were 4- to 32 fold lower than those of linezolid. Linezolid resistance mechanisms included G2576T 23S rRNA gene and rplC and rplD mutations. PMID- 26971180 TI - Detection of respiratory pathogens in pediatric acute otitis media by PCR and comparison of findings in the middle ear and nasopharynx. AB - We conducted a series of polymerase chain reactions (PCRs) in order to detect bacteria (7 species) and viruses (17 species) in middle ear fluid (MEF) and nasopharynx (Nph) of children with acute otitis media (AOM; n=179). Bacterial and viral nucleic acids were detected in MEF of 78.8% and 14.5% patients, respectively. The prevalence was as follows: Streptococcus pneumoniae, 70.4%; Haemophilus influenzae, 17.9%; Staphylococcus aureus, 16.8%; Streptococcus pyogenes, 12.3%; Moraxella catarrhalis, 9.5%; rhinovirus, 9.5%; and adenovirus, 3.4%. The overall rate of PCR-positive specimens for bacterial pathogens was 2.6 times higher, compared to culture results. The rate of PCR-positive results and the distribution of pathogens in the Nph were similar to those in the MEF. Nph PCR results had variable positive predictive values and high negative predictive values in predicting MEF findings. Our results indicate that Nph PCR could be a practical tool for examining respiratory pathogens in children with acute infections. PMID- 26971181 TI - Diversity of mechanisms conferring resistance to beta-lactams among OXA-23 producing Acinetobacter baumannii clones. AB - A total of 31 unrelated OXA-23-producing Acinetobacter baumannii strains isolated from 14 hospitals located in distinct Brazilian regions were evaluated in this study. These isolates were grouped into 12 different sequence types (STs), of which 7 had unique allelic sequences (ST188, ST189, ST190, ST191, ST192, ST228, and ST299). Most isolates belonged to the clonal complex CC79 followed by CC15 and CC1. Only polymyxin B and minocycline showed good activity against the OXA-23 producing A. baumannii clones. The ISAba1 upstream blaOXA-23, blaOXA-51-like, or ampC was found in 100%, 54.8%, and 77.4% of the isolates, respectively. High resistance rates to ceftazidime and cefotaxime were observed among those isolates possessing ISAba1 upstream ampC, in contrast to those isolates that did not carry this configuration. Moreover, a >=2 Log2 decrease in the MICs of meropenem and ceftazidime was observed in the presence of phenyl-arginine-beta-naphthylamide for 80.6% and 54.8% of isolates, respectively. Overexpression of the adeB was observed in 61.3% of isolates, particularly among those isolates belonging to the ST1 (CC1). It was also verified that ompW was down-regulated in all isolates belonging to the ST15 (CC15). On the other hand, carO and omp33-36 genes were overexpressed in 48.4% and 58.1% of the isolates, respectively. In this study, we show that overexpression of AdeABC system could significantly contribute for resistance to meropenem and ceftazidime among OXA-23-producing A. baumannii clones in Brazil, demonstrating the complexity involved in the beta-lactam resistance in such isolates. PMID- 26971182 TI - Antimicrobial activity of ceftaroline and comparator agents when tested against numerous species of coagulase-negative Staphylococcus causing infection in US hospitals. AB - A total of 1593 coagulase-negative staphylococci (CoNS) considered clinically significant were collected from 71 US medical centers in 2013-2014 and tested for susceptibility by CLSI broth microdilution methods. Species identification was performed by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Overall, 59.7% of isolates were oxacillin resistant (MRCoNS). Ceftaroline (MIC50/90, 0.25/0.5MUg/mL) inhibited 99.2% of CoNS at <=1MUg/mL (susceptible breakpoint for Staphylococcus aureus), including 98.7% of MRCoNS, and the highest ceftaroline MIC value was 2MUg/mL (13 isolates). Staphylococcus epidermidis represented 60.3% of the CoNS collection and was highly susceptible to ceftaroline (MIC50/90, 0.25/0.5MUg/mL, 99.9% inhibited at <=1MUg/mL). All isolates of Staphylococcus capitis, Staphylococcus caprae, Staphylococcus hominis, Staphylococcus lugdunensis, Staphylococcus pettenkoferi, Staphylococcus simulans, and Staphylococcus warneri (MIC50/90, 0.06-0.25/0.25-0.5MUg/mL) were inhibited at ceftaroline MIC of <=1MUg/mL. Staphylococcus haemolyticus represented only 4.8%, was atypically less susceptible to ceftaroline (MIC50/90, 0.5/2MUg/mL, 87.0% inhibited at <=1MUg/mL), and accounted for 76.9% (10/13) of isolates with ceftaroline MIC >1MUg/mL. PMID- 26971184 TI - Central sleep apnoea in heart failure--An important issue for the modern heart failure cardiologist. PMID- 26971183 TI - Presence of plasmid-mediated quinolone resistance determinants and mutations in gyrase and topoisomerase in Salmonella enterica isolates with resistance and reduced susceptibility to ciprofloxacin. AB - In recent decades, the emergence and spread of resistance to nalidixic acid are usually associated with reduced susceptibility to ciprofloxacin among Salmonella serotypes. The aims of this study were to investigate the mechanisms associated with resistance to fluoroquinolone and the clonal relatedness of Salmonella strains isolated from human and nonhuman origins, in a 5-year period in Sao Paulo, Brazil. Antimicrobial susceptibility testing for Salmonella isolates was performed. PCR and DNA sequencing were accomplished to identify mutations in the quinolone resistance-determining regions of the topoisomerase genes and to determine the fluoroquinolone determinants. The strains presented MIC to ciprofloxacin ranging from 0.125 to 8.0 mg/L (all nonsusceptible). From these, 16 strains (17.5%) were resistant to ciprofloxacin (MIC >=1 mg/L) and belonging to serotypes Typhimurium, I. 4,5,12:i:-, Enteritidis, and Heidelberg. Amplification and DNA sequencing of topoisomerases genes identified multiple amino acid substitutions in GyrA and ParC. No mutations were identified in GyrB, and 1 amino acid substitution was identified in ParE. Among the 16 Salmonella strains resistant to ciprofloxacin, 8 S. I. 4,5,12:i:- presenting mutations in gyrA and parE genes were grouped into the same pulsotype. Plasmid-mediated quinolone resistance (PMQR) determinants: qnrB, aac(6')-lb-cr, and oqxA/B were detected among 13 strains. To the best of our knowledge, this is the first work to report Salmonella isolates resistant to ciprofloxacin in Brazil. Indeed, this is the first detection of PMQR determinants in Salmonella strains from Sao Paulo State. These findings alert for the potential spread of quinolone resistance of Salmonella strains, particularly in S. I. 4,5,12:i:-, a prevalent serotype implicated in human disease and foodborne outbreaks. PMID- 26971185 TI - Measuring therapeutic efficacy in the treatment of central sleep apnoea in patients with heart failure. AB - The goal of treating sleep disordered breathing (SDB) has traditionally focused on improving daytime sleepiness and fatigue. In heart failure (HF) patients with SDB, this is not as easy to ascertain as their symptoms overlap with HF. Thus, improvement in treating SDB in HF patients must focus more on overall quality of life. Over the past 5 years, there has been a shift in sleep medicine from only improving symptoms in SDB, to preventing the long term consequences. The specialist Heart Failure community is, however, desirous of also seeing benefit in reduction of major clinical events for their patients with interventions, such as effects on mortality or re-hospitalisation rates and so may wish to see other benefits beyond a reduction in sleep apnea events before either commencing therapy or referring their patients for sleep study evaluation and further management. To expect lower mortality as well may be asking for too much. Consequently, success in the treatment in SDB should focus on three items: 1) proof that the underlying disease is treated, 2) symptomatic benefit and 3) demonstration that the pathological consequences are prevented. These benefits must then be balanced with a strong safety profile. Here we evaluate a variety of end-points of value to our CSA patients, in an effort to see what may reasonably be required for treating physicians to recommend an intervention for their CHF patients with CSA by looking at candidate measures of treatment success in CSA within a heart failure population. PMID- 26971186 TI - How Can We Improve Retention of the First-Time Donor? A Systematic Review of the Current Evidence. AB - Blood products are critical to health systems and donations by voluntary nonremunerated donors are recommended. Worldwide, however, only around 5% of those eligible to donate do so and around half of those never return to donate again. This review focuses on what deters first-time donors, what predicts their retention, and what interventions may promote retention of this group. A comprehensive search of relevant databases identified 9 studies investigating motives and deterrents of first-time donors, 14 studies investigating predictors for first-time donors (13 whole blood [WB] and 2 plasmapheresis), and 15 studies (in 14 published articles) detailing interventions conducted on first-time donors. Drawing on an established blood donation taxonomy, studies were classified by 2 independent raters. Interventions were also classified into traditional, behavioral, or social science interventions. With only 2 eligible studies among first-time plasmapheresis donors, analyses focused on WB donors. First-time WB donors reported benevolent and collectivistic motivations, as well as personal benefits to commence WB donation. Self-reported deterrents have typically not been examined. Intention predicted first-time donor retention with intention determined by attitudes and a sense of (perceived behavioral) control. However, anxiety, adverse events, and deferrals all deterred retention. Traditional interventions, such as reminders and incentives, are widespread yet had only a small effect on return of first-time donors. Although behavioral science interventions such as fluid loading are effective, the strongest effect for the return of first-time donors was found when individual psychological support was provided. The purpose of this analysis was to identify the factors associated with the commencement and continuation of first WB donations. The current review revealed that self-reported motivators are typically not effective, and most successful predictive factors identified have not been translated into interventions. Future work would do well to identify, manage, and meet donors' expectations along with developing more individualized donation experiences. Blood donor research should delineate donor career stages; addressing first-time donor retention will support stable panels for blood collection agencies. PMID- 26971187 TI - The effect of elapsed time on cardiac troponin-T (cTnT) degradation and its dependency on the cause of death. AB - PURPOSE: The aim of the present study is to evaluate the effect of elapsed time on cardiac troponin-T degradation and its dependency on the cause of death. METHODS: The cases included in this study were divided into six groups depending upon the cause of death without any prior history of disease that died in the hospital and their exact time of death was known. The analysis involves extraction of the protein, separation by denaturing gel electrophoresis and visualization by Western blot. RESULTS: Western blot data shows the rate of degradation of cTnT into lower molecular weight fragments with respect to time. In cases of control group the greatest amount of protein breakdown was observed within the first 64 h while in MI cases within first 6 h, the original band of cTnT (42 kDa) decreased markedly into seven major fragments, with 25 kDa & 20 kDa fragments being the most prominent. In burn group, at 41.40 h blot shows maximum fragmentation. In electrocution group the greatest amount of protein breakdown was observed within the first 50 Hrs. Within asphyxia cases, the original band of cTnT (42 kDa) decreased markedly into many major and minor fragments which continues up to 210 Hrs while the original band of cTnT (42 kDa) in poisoning cases decreased markedly into many major & minor fragments up to 140 h but after it blot shows only intact protein of very less intensity with few minor fragments. CONCLUSION: It can be observed that in case of death due to MI, the intact cTnI fragmented at a much faster rate than in burn, electrocution, control, poisoning and asphyxia group. Thus, the rate of fragmentation of intact cTnT into lower molecular weight fragments depends upon the cause of death. PMID- 26971188 TI - Alcohol Use and HIV Self-management. PMID- 26971189 TI - Venous thromboembolism and effect of comorbidity in bladder cancer: A danish nationwide cohort study of 13,809 patients diagnosed between 1995 and 2011. AB - OBJECTIVES: Bladder cancer (BC) is associated with venous thromboembolism (VTE), but data on the effect of comorbidities are scarce. MATERIALS AND METHODS: Population-based cohort study with 13,809 patients with BC diagnosed in Denmark (1995-2011) and a general population comparison cohort matched on age, sex, and comorbidities (n = 132,421). Risk of VTE, pulmonary embolism and deep venous thrombosis was computed for the first month, 3 months, 1 year, and 5 years following cancer diagnosis and stratified by Charlson Comorbidity Index (CCI) scores, cystectomy, and metastases. RESULTS: VTE risk was higher among the patients with BC than in the comparison cohort during five years of follow-up (risk difference = 20 per 1,000 persons [95% CI: 16-23]). Excess risk was relatively stable with increasing comorbidity score. In the first year, the risk difference was 17 per 1,000 persons (95% CI: 14-21) and 16 (95% CI: 4.8-27) for CCI score = 0 and CCI score = 4, respectively, and similar results were observed by stratification on pulmonary embolism and deep venous thrombosis. For patients with BC undergoing cystectomy, VTE risk was 70-fold higher than in the general population cohort within 3 months after diagnosis. CONCLUSIONS: BC is associated with increased risk of VTE, compared with the general Danish population. Risks are particularly high for VTE after cystectomy. Risk did not increase with higher comorbidity burden, as the relative risk of VTE was greatest among patients without comorbidity. Clinical attention to VTE risk, particularly cystectomy related VTE, in patients with BC is appropriate irrespective of comorbidities. PMID- 26971190 TI - Comparison of prostate cancer detection at 3-T MRI with and without an endorectal coil: A prospective, paired-patient study. AB - OBJECTIVES: To compare the sensitivity of 2 different non-endorectal coil strategies vs. endorectal coil (ERC) magnetic resonance imaging (MRI) for detection of prostate cancer (PCa). METHODS: In this prospective, single-center, paired-patient, paired-reader study, 49 men with a clinical indication for MRI underwent non-ERC (phased-array coil only) T2-weighted imaging and diffusion weighted imaging followed by the same sequences using both ERC and phased-array coils (ERC Protocol). Patients were randomized into 1 of 2 arms: standard non-ERC protocol and augmented non-ERC protocol. Lesions with Likert score>=3 were defined as suspicious for cancer. Radical prostatectomy specimen or combined systematic plus targeted biopsies served as the standard of reference. Cancers were stratified into risk groups according to the National Comprehensive Cancer Network guidelines. Generalized estimating equations with Bonferroni correction were used for comparisons. The level of reader confidence was inferred by the Likert scores assigned to index lesions. RESULTS: The ERC protocol provided sensitivity (78%) superior to MRI without ERC for PCa detection, both with a standard (43%) (P<0.0001) or augmented (60%) (P<0.01) protocol. The ERC MRI missed less-intermediate or high-risk index lesions (4%) than standard non-ERC (42%) (P = 0.02) and augmented non-ERC MRI (25%), although the latter did not reach significance (P = 0.09). The ERC improved radiologist confidence for the detection of PCa (average Likert score = 4.2+/-1.4) compared to standard (2.3+/ 2.3) and augmented (2.9+/-2.1) non-ERC (P = 0.001). CONCLUSIONS: The use of combined ERC and pelvic phased-array coil for T2-weighted imaging and diffusion weighted imaging provides superior sensitivity for the detection of PCa compared to an examination performed without the ERC. PMID- 26971191 TI - A single-center experience with abiraterone as treatment for metastatic castration-resistant prostate cancer. AB - BACKGROUND: Continuous stimulation of the androgen receptor (AR) axis is a prerequisite for growth in castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) is a potent inhibitor of extracellular and intracellular androgen synthesis by inhibition of the CYP-17 enzyme system, which has been shown to be up-regulated in CRPC. AA was recently introduced in the management of patients with metastatic CRPC (mCRPC) both before and after taxane-based chemotherapy. The purpose of this study is to report the initial clinical experience obtained from mCRPC patients managed on AA at Rigshospitalet, Denmark, and compare the results with phase III trial outcomes. MATERIAL AND METHODS: Single-centre, retrospective study including consecutive patients managed on AA for more than 2-year period. Treatment consisted of 1,000mg AA and 5mg prednisone twice daily. Outcomes of interest were prostate-specific antigen (PSA) response, clinical and radiological progression, and overall survival. RESULTS: A total of 73 consecutive patients with mCRPC undergoing treatment with AA between November 2012 and October 2014 were included. Median follow-up was 9.9 (0.9-23.4) months. PSA decline>50% was found in 39% of the patients. Time to biochemical and radiological progression was 3.5 and 4.9 months, respectively. Overall survival was 13.2 months (95% CI: 9.0-17.4). CONCLUSION: Our initial experience with AA in the routine management of patients with mCRPC demonstrates an efficacy effectiveness gap compared with clinical trial. Except for PSA response (>50% decline) in patients managed with AA, postchemotherapy results were inferior to phase III studies. This is most likely because of patient selection, which is a typical weakness when transferring results from phase III trials into clinical practice. PMID- 26971193 TI - Are placebo-controlled trials of depression safe? PMID- 26971192 TI - Safety of research into severe and treatment-resistant mood disorders: analysis of outcome data from 12 years of clinical trials at the US National Institute of Mental Health. AB - BACKGROUND: Placebo-controlled trials in drug-free patients have long been considered a key research component in the study of mood disorders and relevant treatment mechanisms. However, concerns have been raised about the ethics of such research, leading to an ongoing debate as to whether placebo controls are ethically acceptable. We aimed to assess the cumulative effects of research in individuals with mood disorders and to provide data to address ethical concerns regarding research in this population. METHODS: We obtained empirical data for patients screened between between Dec 13, 2001, and Jan 31, 2014, with either major depressive disorder or bipolar disorder who were enrolled in one or more of 18 clinical trials at a US National Institute of Mental Health (NIMH) inpatient or outpatient behavioural health research clinic. We assessed the cumulative effects of research in our patient population, including the effects of drug taper, drug washout, and placebo administration on mood state. Two subgroups were examined: patients enrolled in trials explicitly requiring treatment resistance and patients with a current or past history of suicidal ideation or behaviour. We used the percentage change from screening as the primary outcome measure for statistical analysis of change in mood over study periods. This study is registered with ClinicalTrials.gov, number NCT00024635. FINDINGS: We obtained data for 540 patients; 360 (71%) patients were enrolled in trials requiring treatment resistance, 58 (12%) of 465 patients had suicidal ideation at screening, and 191 (60%) of 321 patients had a history of suicidal ideation. Mean mood severity at screening was in the moderate to severe range. Full participation in research, including drug tapers, drug-free periods, and placebo controlled trials, had a low risk of symptom exacerbation. Patients undergoing drug taper had a mean increase in symptom severity of 4.2% (SD 19.56, tdegrees of freedom 96=1.85; p=0.036). We recorded modest increases in the subgroup who tapered to no medications (mean percentage change 5.1% [SD 18.10], t56=2.12; p=0.039), but increases were not significant in participants enrolled in trials requiring treatment resistance (4.3% [18.60], t72=1.96; p=0.054) and those with a current or past history of suicidal ideation or behaviour (1.8% [18.78], t51=0.68; p=0.50). Six serious adverse events were reported, including one suicide attempt that occurred during the standard treatment phase and not during the clinical trial. INTERPRETATION: In general, research participation at the NIMH was not detrimental to health and safety, and conferred benefit in many cases. This finding was true not only in our entire research population, but also in treatment-resistant subgroups and subgroups with a history of suicidality. Our study provides evidence to guide ethical analysis of issues in psychiatric research, and to support continued scientific investigation. FUNDING: Intramural Research Program, NIMH, National Institutes of Health. PMID- 26971194 TI - A comparison of regional and general anesthesia effects on 5 year survival and cancer recurrence after transurethral resection of the bladder tumor: a retrospective analysis. AB - BACKGROUND: Recent studies have reported that cancer surgeries involving regional anesthesia have better outcomes than those under general anesthesia. However, the effects of anesthetic technique have not been investigated in patients with bladder cancer. Therefore, this retrospective study was conducted to investigate which anesthetic technique results in a better bladder cancer prognosis. METHODS: Sixty-one of 531 patients underwent transurethral resection of a bladder tumor under general anesthesia from 2001 to 2008 in our hospital. Patients who attended five years of follow-up and who had pathological findings of urothelial carcinoma grades I-II were enrolled. Finally, 24 patients (G group) who underwent general anesthesia and 137 (R group) who underwent regional (spinal or epidural) anesthesia were compared. Five-year survival and recurrence-free time were compared using the chi-square and t-tests, respectively. A logistic regression and partial correlation analysis were performed to evaluate other factors affecting survival. RESULTS: Five-year survival was 87.5% for general anesthesia and 96.3% for regional (P = 0.099). The regression analysis showed that older age contributed to reduced survival (odds ratio = 0.85, P = 0.001). Regional anesthesia showed higher 5-year survival (coefficient = -0.167, P = 0.044) more than general anesthesia through the partial correlation analysis. CONCLUSIONS: Though partial correlation analysis show that five-year survival is higher in patients whose surgery is under regional than general anesthesia, the association was not significant in the chi-square test and logistic regression analysis. Large prospective studies are needed to determine whether the association between regional anesthesia and survival is causative. PMID- 26971196 TI - Efficacy of sarolaner, a novel oral isoxazoline, against two common mite infestations in dogs: Demodex spp. and Otodectes cynotis. AB - The efficacy of sarolaner (SimparicaTM, Zoetis) was evaluated against Demodex spp. in dogs with generalized demodicosis and against Otodectes cynotis (otodectic mange) in dogs with induced infestations. In the first study, 16 dogs with clinical signs of generalized demodicosis and positive for Demodex spp. mites were randomly assigned to treatment with either sarolaner (2mg/kg) orally on Days 0, 30 and 60, or topical imidacloprid (10mg/kg) plus moxidectin (2.5mg/kg) solution every 7 days from Day 0 to Day 81. For sarolaner-treated dogs, pretreatment mite counts were reduced by 97.1% at 14days and 99.8% by 29 days after the first dose, with no live mites detected thereafter. Weekly imidacloprid plus moxidectin resulted in 84.4 and 95.6% reduction at these two time points, respectively, with no mites detected from Day 74 on. All dogs in both groups showed marked improvement in the clinical signs of demodicosis. In the second study, 32 dogs with induced infestations of O. cynotis were randomly assigned (eight per group) to oral sarolaner (2mg/kg) as a single treatment on Day 0 or as a two dose regime (Days 0 and 30), or a placebo group for each of the dose regimes. Sarolaner administered at 2mg/kg as a single oral dose resulted in a 98.2% reduction at Day 30 and two doses of sarolaner, administered one month apart, resulted in a 99.5% reduction in ear mites at Day 60 compared to placebo controls. There were no treatment related adverse events in either study. In these studies, sarolaner at an oral dose of 2mg/kg was highly effective in reducing the live mite counts associated with a natural infestation of Demodex spp. and an induced infestation of O. cynotis. In addition, the Demodex-infested dogs showed a marked improvement in the clinical signs of generalized demodicosis. PMID- 26971195 TI - Hepatocellular carcinoma on cirrhosis complicated with tumoral thrombi extended to the right atrium: results in three cases treated with major hepatectomy and thrombectomy under hypothermic cardiocirculatory arrest and literature review. AB - BACKGROUND: Hepatocellular carcinoma (HCC) with the presence of tumor thrombus in hepatic veins and vena cava, until the atrium (RATT), is correlated with poor prognosis and with risk of tricuspid valve occlusion, congestive heart failure, and pulmonary embolism. METHODS: Three patients with HCC on cirrhotic liver with RATT were studied. Operative technique, pre-operative and post-operative liver function tests, blood loss and transfusions, post-operative morbidity and mortality, and the overall survival and the disease free survival were analyzed. RESULTS: Mean operative time was 336 +/- 66 min. Intra-operative blood loss was 926.6 +/- 325.9 ml. No major complications occurred. The times of hospital stay were 10, 21, and 19 days, respectively. The survival times were 90, 161, and 40 days, and the disease-free survival times were 30, 141, and 30 days, respectively. CONCLUSIONS: The complete removal of HCC with RATT may be achieved with cardiopulmonary by-pass (CPB) and total hepatic vascular exclusion (THVE). Adding the hypothermic cardiocirculatory arrest (HCCA) to the use of CPB allowed us to have minimal blood loss and hemostasis of the resectional plane. So the use of CPB and HCCA should be considered a good therapeutic alternative to the normothermic CPB with THVE. PMID- 26971197 TI - [Macrophage activation syndrome secondary to tocilizumab: Myth or reality?]. AB - INTRODUCTION: Some authors have reported macrophage activation syndrome (MAS) secondary to infusion of tocilizumab, a monoclonal antibody that blocks interleukin-6 (IL-6). The pathophysiology of MAS is however linked to uncontrolled activation of innate immunity, mediated in part by IL-6. We conducted a study for macrophage activation biomarkers in a cohort of patients treated with tocilizumab. RESULTS: Twenty-seven patients were included prospectively in our center. Levels of neutrophils, platelets, CRP and fibrinogen were lower at the end of treatment than at initiation (P<0.05); other biomarkers were stable. There was neither clinical sign of SAM nor hemophagocytosis in myelogram. CONCLUSION: Laboratory abnormalities are related to direct blockade of IL-6 by tocilizumab and decrease hepatic protein synthesis. Tocilizumab is not responsible for MAS and associations described are more likely to be related to the autoimmune underlying disease, rather than treatment. PMID- 26971198 TI - [Seoul hantavirus infection-associated hemorrhagic fever with renal syndrome in France: A case report]. AB - INTRODUCTION: Rodents are hantavirus hosts. In Europe, hantaviruses are responsible for human infections resulting in hemorrhagic fever with renal syndrome. Thousands of Puumala virus infections are reported annually in Europe, whereas human Seoul virus infections are rarely detected. CASE REPORT: We report the case of a 38-year-old patient who presented initially with flu-like symptoms and transitory blurred vision. He developed thrombocytopenia, acute renal failure, and elevated aminotransferases levels during the disease course, but the outcome was favorable with a full recovery. Afterwards, the hantavirus serology results were indicative of Seoul virus infection. CONCLUSION: This report serves to remind physicians to consider diagnosing hantavirus infection when observing the association of fever, acute renal failure and thrombocytopenia. Transitory blurred vision is a specific element to indicate this diagnosis. PMID- 26971199 TI - [A non-infectious "erysipela"]. PMID- 26971200 TI - [Diffuse ecchymoses]. PMID- 26971201 TI - [Pathophysiology of eosinophilic granulomatosis with polyangitis (Churg Strauss)]. AB - Eosinophilic granulomatosis with polyangitis (EGPA) (formerly Churg-Strauss syndrome) is a rare small-sized vessel vasculitis belonging to the group of anti neutrophil cytoplasm antibody (ANCA)-associated vasculitides. MPO-ANCA is present in only 31 to 38% of patients. In this review, we describe the pathophysiology of EGPA, which is characterized by a genetic predisposition, an environmental association, and a cellular dysfunction of eosinophils, neutrophils, and T and B cells. PMID- 26971203 TI - New answers to an old problem: Social investment and coca crops in Colombia. AB - BACKGROUND: For more than 30 years, the main strategy to control illicit coca crops has been forced eradication. Despite the importance of social investment and persistent poverty in areas where illicit crops are grown, there is no empirical evidence of the effect of social expenditures on preventing and reducing the expansion of illicit crops. METHODS: This paper analyses how social investment in conjunction with eradication affects new coca crops. The model is tested using a dataset consisting of annual data for 440 contiguous municipalities that had coca in any year between 2001 and 2010. The analysis includes the two main techniques used to control illicit crops, manual eradication and aerial spraying. RESULTS: Aerial spraying is effective in deterring farmers from increasing the size of their new coca fields, but this effect is small. Social investment, in addition to generating social welfare, has a significant negative relationship with new coca crops, 0.09-hectare reduction in new coca crops per additional 50-cent spent in social investment (human capital and infrastructure) per inhabitant. CONCLUSION: Social investment emerges as a complementary and effective strategy to control illicit crops. PMID- 26971202 TI - Characterization of mesenchymal stem cells and fibrochondrocytes in three dimensional co-culture: analysis of cell shape, matrix production, and mechanical performance. AB - BACKGROUND: Bone marrow mesenchymal stem cells (MSCs) have shown positive therapeutic effects for meniscus regeneration and repair. Preliminary in vitro work has indicated positive results for MSC applications for meniscus tissue engineering; however, more information is needed on how to direct MSC behavior. The objective of this study was to examine the effect of MSC co-culture with primary meniscal fibrochondrocytes (FCCs) in a three-dimensional collagen scaffold in fibrochondrogenic media. Co-culture of MSCs and FCCs was hypothesized to facilitate the transition of MSCs to a FCC cell phenotype as measured by matrix secretion and morphology. METHODS: MSCs and FCCs were isolated from bovine bone marrow and meniscus, respectively. Cells were seeded in a 20 mg/mL high density type I collagen gel at MSC:FCC ratios of 0:100, 25:75, 50:50, 75:25, and 100:0. Constructs were cultured for up to 2 weeks and then analyzed for cell morphology, glycosaminoglycan content, collagen content, and production of collagen type I, II, and X. RESULTS: Cells were homogeneously mixed throughout the scaffold and cells had limited direct cell-cell contact. After 2 weeks in culture, MSCs transitioned from a spindle-like morphology toward a rounded phenotype, while FCCs remained rounded throughout culture. Although MSC shape changed with culture, the overall size was significantly larger than FCCs throughout culture. While 75:25 and 100:0 (MSC mono-culture) culture groups produced significantly more glycosaminoglycan (GAG)/DNA than FCCs in mono culture, GAG retention was highest in 50:50 co-cultures. Similarly, the aggregate modulus was highest in 100:0 and 50:50 co-cultures. All samples contained both collagen types I and II after 2 weeks, and collagen type X expression was evident only in MSC mono-culture gels. CONCLUSIONS: MSCs shift to a FCC morphology in both mono- and co-culture. Co-culture reduced hypertrophy by MSCs, indicated by collagen type X. This study shows that MSC phenotype can be influenced by indirect homogeneous cell culture in a three-dimensional gel, demonstrating the applicability of MSCs in meniscus tissue engineering applications. PMID- 26971205 TI - A multi-sites analysis on the ozone effects on Gross Primary Production of European forests. AB - Ozone (O3) is both a greenhouse gas and a secondary air pollutant causing adverse impacts on forests ecosystems at different scales, from cellular to ecosystem level. Specifically, the phytotoxic nature of O3 can impair CO2 assimilation that, in turn affects forest productivity. This study aims to evaluate the effects of tropospheric O3 on Gross Primary Production (GPP) at 37 European forest sites during the time period 2000-2010. Due to the lack of carbon assimilation data at O3 monitoring stations (and vice-versa) this study makes a first attempt to combine high resolution MODIS Gross Primary Production (GPP) estimates and O3 measurement data. Partial Correlations, Anomalies Analysis and the Random Forests Analysis (RFA) were used to quantify the effects of tropospheric O3 concentration and its uptake on GPP and to evaluate the most important factors affecting inter-annual GPP changes. Our results showed, along a North-West/South-East European transect, a negative impact of O3 on GPP ranging from 0.4% to 30%, although a key role of meteorological parameters respect to pollutant variables in affecting GPP was found. In particular, meteorological parameters, namely air temperature (T), soil water content (SWC) and relative humidity (RH) are the most important predictors at 81% of test sites. Moreover, it is interesting to highlight a key role of SWC in the Mediterranean areas (Spanish, Italian and French test sites) confirming that, soil moisture and soil water availability affect vegetation growth and photosynthesis especially in arid or semi-arid ecosystems such as the Mediterranean climate regions. Considering the pivotal role of GPP in the global carbon balance and the O3 ability to reduce primary productivity of the forests, this study can help in assessing the O3 impacts on ecosystem services, including wood production and carbon sequestration. PMID- 26971204 TI - Human fibroblasts display a differential focal adhesion phenotype relative to chimpanzee. AB - There are a number of documented differences between humans and our closest relatives in responses to wound healing and in disease susceptibilities, suggesting a differential cellular response to certain environmental factors. In this study, we sought to look at a specific cell type, fibroblasts, to examine differences in cellular adhesion between humans and chimpanzees in visualized cells and in gene expression. We have found significant differences in the number of focal adhesions between primary human and chimpanzee fibroblasts. Additionally, we see that adhesion related gene ontology categories are some of the most differentially expressed between human and chimpanzee in normal fibroblast cells. These results suggest that human and chimpanzee fibroblasts may have somewhat different adhesive properties, which could play a role in differential disease phenotypes and responses to external factors. PMID- 26971206 TI - Polycyclic aromatic hydrocarbons in soils from the Central-Himalaya region: Distribution, sources, and risks to humans and wildlife. AB - The Central Himalayas are not only a natural boundary between China and Nepal but also a natural barrier for transport of air masses from South Asia. In this study, 99 samples of surface soil were collected from five regions of Nepal on the southern side of the Central Himalayas, and 65 samples of surface soil were obtained from the northern side on the edge of the Tibetan Plateau, China (TPC). Concentrations of polycyclic aromatic hydrocarbons (PAHs) in soils were measured to determine their distribution, potential for accumulation, and sources, as well as risks to humans and the environment. Mean concentrations of Sigma16PAHs were 2.4*10(2) and 3.3*10(2)ng/g dry mass (dm) in soils collected from the TPC and Nepal, respectively. Significant correlations between concentrations of lower molecular weight PAHs (LMW-PAHs) in soils and altitude were found. Total organic carbon (TOC) in soil was positively but weakly correlated with concentrations of PAHs in the study area, which suggested little role of TOC in adsorption of PAHs. The cities of Kathmandu and Pokhara in Nepal and Nyemo (especially Zhangmu Port), Shigatse, and Lhasa on the TPC, were areas with relatively great concentrations of PAHs in soils. The main sources of PAHs identified by positive matrix factorization were emissions from motor vehicles and combustion of coal and biomass in the Central Himalayas. Calculated total benzo[a]pyrene potency equivalents of 0.23-44ng/gdm and index of additive cancer risk of 3.8*10(-3) 9.2*10(-1) indicated that PAHs in almost all soils investigated posed de minimis risk of additional cancer to residents via direct contact and had no significant risk of additional cancers through consumption of potable water. Mean risk quotient values indicated that 39% of soils had a slight risk to wildlife and the ambient environment of the Central Himalayas. PMID- 26971207 TI - Assessment of groundwater vulnerability and risk to pollution in Kathmandu Valley, Nepal. AB - Groundwater vulnerability and risk assessment is a useful tool for groundwater pollution prevention and control. In this study, GIS based DRASTIC model have been used to assess intrinsic aquifer vulnerability to pollution whereas Groundwater Risk Assessment Model (GRAM) was used to assess the risk to groundwater pollution in the groundwater basin of Kathmandu Valley. Seven hydrogeological factors were used in DRASTIC model to produce DRASTIC Index (DI) map which represent intrinsic groundwater vulnerability to pollution of the area. The seven hydrogeological factors used were depth to water, net recharge, aquifer media, soil media, topography, impact of vadose zone, and hydraulic conductivity of aquifer. GIS based GRAM was used to produce likelihood of release of hazards, likelihood of detection of hazards, consequence of hazards and residual risk of groundwater contamination in terms of nitrate in the groundwater basin. It was found that more than 50% of the groundwater basin area in the valley is susceptible to groundwater pollution and these areas are mostly in Northern groundwater district Low and very low vulnerable areas account for only 13% and are located in Central and Southern groundwater districts. However after taking into account the barriers to groundwater pollution and likelihood of hazards release and detection, it was observed that most areas i.e. about 87% of the groundwater basin are at moderate residual risk to groundwater pollution. The resultant groundwater vulnerability and risk map provides a basis for policy makers and planner's ability to use information effectively for decision making at protecting the groundwater from pollutants. PMID- 26971209 TI - Sphagnum-dominated bog systems are highly effective yet variable sources of bio available iron to marine waters. AB - Iron is a micronutrient of particular interest as low levels of iron limit primary production of phytoplankton and carbon fluxes in extended regions of the world's oceans. Sphagnum-peatland runoff is extraordinarily rich in dissolved humic-bound iron. Given that several of the world's largest wetlands are Sphagnum dominated peatlands, this ecosystem type may serve as one of the major sources of iron to the ocean. Here, we studied five near-coastal creeks in North Scotland using freshwater/seawater mixing experiments of natural creek water and synthetic seawater based on a (59)Fe radiotracer technique combined with isotopic characterization of dissolved organic carbon by Accelerator Mass Spectrometry. Three of the creeks meander through healthy Sphagnum-dominated peat bogs and the two others through modified peatlands which have been subject to artificial drainage for centuries. The results revealed that, at the time of sampling (August 16-24, 2014), the creeks that run through modified peatlands delivered 11 15MUg iron per liter creek water to seawater, whereas the creeks that run through intact peatlands delivered 350-470MUg iron per liter creek water to seawater. To find out whether this humic-bound iron is bio-available to marine algae, we performed algal growth tests using the unicellular flagellated marine prymnesiophyte Diacronema lutheri and the unicellular marine green alga Chlorella salina, respectively. In both cases, the riverine humic material provided a highly bio-available source of iron to the marine algae. These results add a new item to the list of ecosystem services of Sphagnum-peatlands. PMID- 26971208 TI - Apparatus and method for time-integrated, active sampling of contaminants in fluids demonstrated by monitoring of hexavalent chromium in groundwater. AB - Annual U.S. expenditures of $2B for site characterization invite the development of new technologies to improve data quality while reducing costs and minimizing uncertainty in groundwater monitoring. This work presents a new instrument for time-integrated sampling of environmental fluids using in situ solid-phase extraction (SPE). The In Situ Sampler (IS2) is an automated submersible device capable of extracting dissolved contaminants from water (100s-1000smL) over extended periods (hours to weeks), retaining the analytes, and rejecting the processed fluid. A field demonstration of the IS2 revealed 28-day average concentration of hexavalent chromium in a shallow aquifer affected by tidal stresses via sampling of groundwater as both liquid and sorbed composite samples, each obtained in triplicate. In situ SPE exhibited 75+/-6% recovery and an 8-fold improvement in reporting limit. Relative to use of conventional methods (100%), beneficial characteristics of the device and method included minimal hazardous material generation (2%), transportation cost (10%), and associated carbon footprint (2%). The IS2 is compatible with commercial SPE resins and standard extraction methods, and has been certified for more general use (i.e., inorganics and organics) by the Environmental Security Technology Certification Program (ESTCP) of the U.S. Department of Defense. PMID- 26971210 TI - Conversion of pesticides to biologically active products on urban hard surfaces. AB - Impervious pavements such as concrete are a dominant feature of urban landscapes, but their role in the fate of environmental contaminants is largely ignored. This study considered the case of urban-use pesticides, and demonstrated for the first time that surfaces such as concrete were capable of converting pesticides to other biologically active intermediates. Rapid transformation of pesticides was observed in both bench and field scale setups. Under outdoor conditions, permethrin, a heavily used pyrethroid insecticide, quickly formed 3 phenoxybenzoic acid (3-PBA) that is a known endocrine disruptor, and the level of 3-PBA was >100MUg/L in the runoff water even 3months after the treatment. Fipronil, a product used for termite and ant control, was quickly transformed to desulfinyl and sulfone derivatives, with the desulfinyl level exceeding that of parent in the runoff water only 1week after treatment. Fipronil derivatives have aquatic toxicity similar or even greater than the parent fipronil. Direct sampling of deposited particles from residential exterior pavements revealed widespread presence of fipronil sulfone and desulfinyl and demonstrated their in situ formation and accumulation on concrete. The extensive transformations were likely caused by the alkalinity and metal oxides in concrete and conducive photolytic conditions at the hard surfaces. The study findings highlight the role of urban pavements and urbanization in the geochemical cycling of anthropogenic contaminants. PMID- 26971211 TI - Ozonation of hospital raw wastewaters for cytostatic compounds removal. Kinetic modelling and economic assessment of the process. AB - The kinetics of the ozone consumption for the pretreatment of hospital wastewater has been analysed in order to determine the reaction rate coefficients between the ozone and the readily oxidisabled organic matter and cytostatic compounds. The wastewater from a medium size hospital was treated with ozone and peroxone methodologies, varying the ozone concentration, the reaction time and the hydrogen peroxide doses. The analysis shows that there are four cytostatic compounds, i.e. irinotecan, ifosfamide, cyclophosphamide and capecitabine, detected in the wastewaters and they are completely removed with reasonably short times after the ozone treatment. Considering the reactor geometry, the gas hydrodynamics, the mass transfer of ozone from gas to liquid and the reaction of all oxidisable compounds of the wastewater it is possible to determine the chemical ozone demand, COzD, of the sample as 256mgO3L(-1) and the kinetic rate coefficient with the dissolved organic matter as 8.4M(-1)s(-1). The kinetic rate coefficient between the ozone and the cyclophosphamide is in the order of 34.7M( 1)s(-1) and higher for the other cytostatics. The direct economic cost of the treatment was evaluated considering this reaction kinetics and it is below 0.3?/m(3) under given circumstances. PMID- 26971212 TI - Persistent organic pollutant and mercury concentrations in eggs of ground-nesting marine birds in the Canadian high Arctic. AB - We collected eggs of eight marine bird species from several colony sites in the Canadian high Arctic located at approximately 76 degrees N and analyzed them for concentrations of legacy persistent organic pollutants (POPs) and mercury. We provide the first report on concentrations of POPs in eggs of three Arctic species (Thayer's gull Larus thayeri, Sabine's gull Xema sabini, Ross's Gull Rhodostethia rosea), and we found significant differences in each of the POP profiles among the five species with sufficient data for statistical comparisons (Thayer's gull, black guillemot Cepphus grylle, Sabine's gull, Arctic tern Sterna paradisaea and common eider Somateria mollissima borealis). The Ross's Gull had unexpectedly high POP concentrations relative to the other species examined, although this was based on a single egg, while glaucous gull Larus hyperboreus eggs from our sampling location had very low POPs. Sabine's gulls had the lowest Hg of the eggs studied, consistent with their low trophic position, but concentrations of their legacy POPs were higher than expected. We also noted that total hexachlorocyclohexanes were higher than reported elsewhere in the circumpolar Arctic in three species. PMID- 26971213 TI - Greenhouse gas emissions and reactive nitrogen releases during the life-cycles of staple food production in China and their mitigation potential. AB - Life-cycle analysis of staple food (rice, flour and corn-based fodder) production and assessments of the associated greenhouse gas (GHG) and reactive nitrogen (Nr) releases, from environmental and economic perspectives, help to develop effective mitigation options. However, such evaluations have rarely been executed in China. We evaluated the GHG and Nr releases per kilogram of staple food production (carbon and Nr footprints) and per unit of net economic benefit (CO2-NEB and Nr NEB), and explored their mitigation potential. Carbon footprints of food production in China were obviously higher than those in some developed countries. There was a high spatial variation in the footprints, primarily attributable to differences in synthetic N use (or CH4 emissions) per unit of food production. Provincial carbon footprints had a significant linear relationship with Nr footprints, attributed to large contribution of N fertilizer use to both GHG and Nr releases. Synthetic N fertilizer applications and CH4 emissions dominated the carbon footprints, while NH3 volatilization and N leaching were the main contributors to the Nr footprints. About 564 (95% uncertainty range: 404-701) TgCO2eqGHG and 10 (7.4-12.4) Tg Nr-N were released every year during 2001-2010 from staple food production. This caused the total damage costs of 325 (70-555) billion Y, equivalent to nearly 1.44% of the Gross Domestic Product of China. Moreover, the combined damage costs and economic input costs, accounted for 66% 80% of the gross economic benefit generated from food production. A reduction of 92.7TgCO2eqyr(-1) and 2.2TgNr-Nyr(-1) could be achieved by reducing synthetic N inputs by 20%, increasing grain yields by 5% and implementing off-season application of straw and mid-season drainage practices for rice cultivation. In order to realize these scenarios, an ecological compensation scheme should be established to incentivize farmers to gradually adopt knowledge-based managements. PMID- 26971214 TI - Seasonal patterns of nitrogen cycling in subtropical short-hydroperiod wetlands: Effects of precipitation and restoration. AB - In the event of increased frequency of extreme wet or dry events resulting from climate change, it becomes more important to understand the temporal dynamics of soil nitrogen (N) processes in ecosystems. Here, seasonal patterns of N cycling were characterized in subtropical wetlands in Everglades National Park, Florida, USA. Two restored sites and one reference site with different nutrient status, soil depth, and vegetation communities, were selected. Soil available N, microbial biomass, potential N mineralization and denitrification rates, enzyme activities of leucine aminopeptidase (LAP) and N-acetyl-beta-d-glucosaminidase (NAG) were measured across the wet and dry seasons from 2010 to 2011. In general, most N processes were significantly correlated with soil water contents (P<0.05) which reflected the precipitation regime. The lower elevation and shallower soil (2-3cm depth) at the restored site may contribute to their higher soil water contents compared to the reference site with ~10cm soil depth, which further led to the earlier peaks of microbial biomass at the two restored sites. Potential N mineralization was positively correlated with LAP at the restored sites whereas with NAG at the reference site (P<0.05), implying that different vegetation composition may provide varying substrates for soil microbes. The build-up of nitrate in the dry spring of 2011 induced a pulse of denitrification after rewetting by a sudden rainfall, implying the presence of a hot moment of denitrification during the dry-rewetting transition period. The decrease of MBC:MBN ratio from dry to wet season indicates a possible microbial composition shift from fungi to bacteria, shedding lights on the potential contribution of fugal groups to denitrification in the dry season. Our study highlight that even under the same climate regime, the small-scale variations could affect the seasonal patterns of N cycling. PMID- 26971215 TI - Gravity induced densification of floating crude oil by granular materials: Effect of particle size and surface morphology. AB - Densification and sedimentation of floating crude oil to the bottom of water column reduces the radius of a spill and its mobility, preventing direct contamination of beaches, coastal flora and fauna. Performances of different natural granular materials were evaluated for capturing efficiency of floating fresh South Louisiana crude oil. The granular materials studied were quartz sand with medium (20-30mesh) and fine (40-100mesh) particle size, limestone with coarse (4-10mesh) and medium (16-40mesh) particle size, beach sand (20-80mesh), and clay (kaolin with ferric oxide; passing 200mesh). Beach sand (mixture of quartz and limestone 20-80mesh) and limestone (16-40mesh) demonstrated better performance for capture, densification and submergence of the crude oil among the materials evaluated. The behavior of granular particles with the hydrophobic phase can be classified as (1) immersion entrapment inside the hydrophobic phase (slurry), and (2) partial encapsulation of the hydrophobic phase by a single layer of particles (raft). With crude oil, the particles were primarily entrapped within the hydrophobic phase. Study of the effect of particle size and morphology (i.e., porosity) of the granular materials on capture performance showed that average surface pore size did not have a significant effect on aggregation with oil, however, higher capture efficiency was observed with materials of higher surface porosity (beach sand and limestone). The experiments revealed that there is a critical particle size range (passing 10mesh) which resulted in more effective aggregation of the granular materials with crude oil. PMID- 26971216 TI - The effects of binary UV filter mixtures on the midge Chironomus riparius. AB - Organic ultraviolet (UV) filters are used in a wide variety of products, including cosmetics, to prevent damage from UV light in tissues and industrial materials. Their extensive use has raised concerns about potential adverse effects in human health and aquatic ecosystems that accumulate these pollutants. To increase sun radiation protection, UV filters are commonly used in mixtures. Here, we studied the toxicity of binary mixtures of 4-methylbenzylidene camphor (4MBC), octyl-methoxycinnamate (OMC), and benzophenone-3 (BP-3), by evaluating the larval mortality of Chironomus riparius. Also molecular endpoints have been analyzed, including alterations in the expression levels of a gene related with the endocrine system (EcR, ecdysone receptor) and a gene related with the stress response (hsp70, heat shock protein 70). The results showed that the mortality caused by binary mixtures was similar to that observed for each compound alone; however, some differences in LC50 were observed between groups. Gene expression analysis showed that EcR mRNA levels increased in the presence of 0.1mg/L 4MBC but returned to normal levels after exposure to mixtures of 4MBC with 0.1, 1, and 10mg/L of BP-3 or OMC. In contrast, the hsp70 mRNA levels increased after exposure to the combinations tested of 4MBC and BP-3 or OMC mixtures. These data suggest that 4MBC, BP-3, and OMC may have antagonist effects on EcR gene transcription and a synergistic effect on hsp70 gene activation. This is the first experimental study to show the complex patterned effects of UV filter mixtures on invertebrates. The data suggest that the interactions within these chemicals mixtures are complex and show diverse effects on various endpoints. PMID- 26971217 TI - Antioxidant and gene expression responses of Eisenia fetida following repeated exposure to BDE209 and Pb in a soil-earthworm system. AB - This study first adopted repeated treatment model to investigate stress responses in earthworms (Eisenia fetida) following exposure to decabromodiphenyl ether (BDE209) and lead (Pb), which are the mainly co-existed contaminants at e-waste recycling sites. We evaluated the impacts of BDE209-Pb on antioxidative enzyme (superoxide dismutase, SOD; catalase, CAT) activities, malondialdehyde (MDA) contents and transcriptional levels of three target genes (SOD, CAT and Hsp70), and further explored the relationships among these biomarkers. Results demonstrated that almost all the parameters were generally induced and the responses followed certain dose-effect relationships. Compared to the controls, a significant (P<0.05) up-regulation trend of expression levels of the three genes could be clearly observed after 14days incubation. Additionally, there existed good correlations between target genes expression levels and antioxidant enzyme activities (R>0.64). The observations could provide important information of ecotoxicological effects of BDE209-Pb in a soil-earthworm system as well as the mechanism of antioxidant defense. PMID- 26971218 TI - Rapidly changing climatic conditions for wine grape growing in the Okanagan Valley region of British Columbia, Canada. AB - A statistical analysis was conducted on long-term climate records for sites bordering Okanagan Lake in the Okanagan Valley viticultural region of British Columbia, Canada. Average wine grape growing season temperatures are increasing rapidly in the area over the post-1980 period at rates upwards of 7.0+/-1.3 degrees C/century. Similar increases in the average dormant season temperature are evident. These temperature changes are likely some of the most extreme observed among the world's wine producing areas during the past few decades. Growing degree day base 10 degrees C (GDD10) has increased by nearly 50% at some locations since the 1970s, resulting in major impacts on the corresponding climate classification for viticulture. If current climate trends continue, the southern and central portions of the region will likely enter Winkler region II within the next few decades, placing them in the same category as well established warmer wine regions from France, Spain, Italy, and Australia. The large dormant season temperature increases over the last several decades have resulted in the area no longer being a cold season outlier when compared to most other cool-climate viticultural areas. Based on average growing season temperatures, the southern end of Okanagan Lake has moved out of the cool-climate viticultural classification and into the intermediate zone, while the central and northern regions are now at the cool/intermediate viticulture interface, similar to the historical positions of the Rhine Valley in Germany, northern Oregon in the United States, and the Loire Valley, Burgundy-Cote, Burgundy-Beaujolais, and Champagne appelations of France. The corresponding suitable grape species for the area have evolved into warmer region varietals during this time frame, having substantial economic impacts on producers. Increased temperatures are also expected to bring greater threats from agricultural pests, notably Pierce's disease from the bacterium Xylella fastidiosa. PMID- 26971219 TI - Indirect estimation of emission factors for phosphate surface mining using air dispersion modeling. AB - To date, phosphate surface mining suffers from lack of reliable emission factors. Due to complete absence of data to derive emissions factors, we developed a methodology for estimating them indirectly by studying a range of possible emission factors for surface phosphate mining operations and comparing AERMOD calculated concentrations to concentrations measured around the mine. We applied this approach for the Khneifiss phosphate mine, Syria, and the Al-Hassa and Al Abyad phosphate mines, Jordan. The work accounts for numerous model unknowns and parameter uncertainties by applying prudent assumptions concerning the parameter values. Our results suggest that the net mining operations (bulldozing, grading and dragline) contribute rather little to ambient TSP concentrations in comparison to phosphate processing and transport. Based on our results, the common practice of deriving the emission rates for phosphate mining operations from the US EPA emission factors for surface coal mining or from the default emission factor of the EEA seems to be reasonable. Yet, since multiple factors affect dispersion from surface phosphate mines, a range of emission factors, rather than only a single value, was found to satisfy the model performance. PMID- 26971220 TI - Human residential status and habitat quality affect the likelihood but not the success of lapwing breeding in an urban matrix. AB - Wildlife living in the suburbs faces the challenge of dealing with human presence and yard management (including the occurrence of pets) which vary at the scale of the house block. This study examined the influence of ecological factors (e.g. extent of grass and food availability) and anthropogenic factors (e.g. human activity and garden usage) on breeding site choice and reproductive success of the ground-nesting masked lapwing Vanellus miles on Phillip Island, Australia. Lapwings nested less frequently in residential properties (high levels of human usage) compared with vacant blocks and holiday houses. They were also more likely to breed on properties with high food availability and larger areas of grass. None of these variables influenced clutch size or the probability of eggs hatching, although larger clutches and higher hatching rates tended to be associated with more food. This study shows that, for an urban exploiting species, habitat quality is not homogenous at the scale of the house block, and that human activity is avoided by a species generally considered highly tolerant of people. PMID- 26971221 TI - An uncommon cause of dysuria solved by "boom-boom" radiotherapy. AB - BACKGROUND: Chronic lymphocytic leukaemia is a common disease affecting the hematopoietic organs. The disease remains classically indolent for years preceding a blast crisis. However, the disease can affect all parts of the body. We report here an unusual localization. CASE PRESENTATION: A 72-year-old man was followed for 2 years for an indolent chronic lymphocytic leukaemia while he presented a rapidly progressive dysuria. Prostate biopsies were performed concluding to a prostate involvement by the chronic lymphocytic leukaemia. In the absence of progression according to RAI staging system and Binet's classification, he was treated with local low-dose radiotherapy, twice 2 Gy, allowing for a rapid resolution of the symptoms. No systemic treatment was introduced, and 1 year after the completion of his treatment, he is still under watchful waiting strategy for his chronic lymphocytic leukaemia. CONCLUSION: Low dose radiotherapy is an underused effective strategy in indolent lymphoma. In this case, urinary symptoms from a prostate involvement were relieved non invasively at low cost. PMID- 26971222 TI - Bitter apricot essential oil induces apoptosis of human HaCaT keratinocytes. AB - Psoriasis is a chronic skin disease that affects approximately 2% of the world's population. Conventional therapeutic approaches are not effective or necessarily safe for treating symptoms due to the serious side effects and resistance to currently prescribed drugs. Traditionally, in oriental medicine, apricot seed (Semen Armeniacae amarum) is used to treat skin diseases. However, the underlying mechanism of action has not been systematically elucidated. In the present study, the anti-proliferative effect of bitter apricot essential oil (BAEO) on cultured HaCaT cells was evaluated and the mechanism of action investigated. BAEO was isolated by hydrodistillation, and gas chromatography-mass spectrometry (GC-MS) analysis identified benzaldehyde (75.35%), benzoic acid (6.21%) and mandelonitrile (5.38%). HaCaT cell growth, measured by sulforhodamine B assay (SRB), was inhibited by BAEO with an IC50 value of 142.45 MUg/ml. Apoptosis of HaCaT cells treated with BAEO was detected by cell cycle, flow cytometry, and western blot analyses. These measurements revealed G0/G1 cell cycle arrest, elevated numbers of early and late stage apoptotic cells, and caspases-3/8/9 and PARP activation. Z-VAD-FMK, a broad-spectrum caspase inhibitor, attenuated BAEO induced apoptosis. Also, increased Bax and decreased Bcl-2 levels suggest that BAEO-induced apoptosis is mediated through both death receptor and mitochondrial pathways. Moreover, reduced Rel/NF-kappaB levels suggest that BAEO-mediated apoptosis is also associated with inhibition of the NF-kappaB pathway. These data suggest that BAEO is a naturally occurring material that functions as a potent pro-apoptotic factor for human keratinocytes. Thus, it is a promising candidate to treat psoriasis. PMID- 26971223 TI - Anti-inflammatory effects of royal poinciana through inhibition of toll-like receptor 4 signaling pathway. AB - Inflammation is part of the non-specific immune response that occurs in reaction to any type of bodily injury. In some disorders the inflammatory process, which under normal conditions is self-limiting, becomes continuous and chronic inflammatory diseases develop subsequently including cardiovascular diseases, diabetes, cancer etc. Barks of Delonix regia is used traditionally in the treatment of inflammatory diseases. Therefore, in this study we evaluated the therapeutic potential of D. regia ethanol extract and its active constituent beta Elemene with special interest in inflammation model using standard in vivo anti inflammatory models: Carrageenan-induced paw edema, Cotton pellet granuloma, and Acetic acid-induced vascular permeability. To explicate the mechanism of action for the possible anti-inflammatory activity, we determined the level of major inflammatory mediators (NO, iNOS, COX-2-dependent prostaglandin E2 or PGE2), and pro-inflammatory cytokines (TNF-a, IL-1b, IL-6, and IL-12). Additionally, we determined the toll-like receptor 4 (TLR4), Myeloid differentiation primary response gene 88 (MyD88), by mRNA expression in drug treated LPS-induced murine macrophage model. To explore the mechanism of anti-inflammatory activity, we evaluated expression of c-Jun N-terminal kinases (JNK), nuclear factor kappa-B cells (NF-kB), and NF-kB inhibitor alpha (IK-Ba). Furthermore, we determined the acute and sub-acute toxicity of D. regia extract in BALB/c mice. This study established a significant anti-inflammatory activity of D. regia extract and beta Elemene along with the inhibition of TNF-a, IL-1b, IL-6 and IL-12 expressions. Further, the expression of TLR4, NF-kBp65, MyD88, iNOS and COX-2 molecules were reduced in drug-treated groups, but not in the LPS-stimulated untreated or control groups, Thus, our results collectively indicated that the D. regia extract and beta-Elemene can efficiently inhibit inflammation. PMID- 26971224 TI - Tatarinan O, a lignin-like compound from the roots of Acorus tatarinowii Schott inhibits osteoclast differentiation through suppressing the expression of c-Fos and NFATc1. AB - Osteoclasts (OC) are large multinucleated cells derived from monocyte/macrophage precursors. Suppressing osteoclastogenesis is considered as an effective therapeutic approach to erosive bone disease. The root of Acorus tatarinowii Schott, a well-known traditional Chinese medicine was used to treat rheumatosis and other inflammatory disease. However, the effects of tatarinan O (TO), one of the lignin-like compounds isolated from the roots of Acorus tatarinowii Schott during bone development are still unclear. In the present study, we explored the effect of TO on RANKL-induced osteoclastogenesis in vitro. TO was found to suppress osteoclast differentiation from RANKL-stimulated mouse bone marrow macrophages (BMMs) without significant cytotoxicity. TO also dose-dependently suppressed bone resorption activity of mature osteoclasts. Additionally, TO apparently inhibited the expression of osteoclastic marker genes, such as MMP-9, Cts K and TRAP. Furthermore, our results showed that TO decreased RANKL-induced expression of c-Fos and NFATc1 without influencing NF-kappaB activation and MAPK phosphorylation. Hence, for the first time we revealed that TO dose-dependently inhibited osteoclastogenesis from RANKL-stimulated mouse BMMs via decreasing the expression of NFATc1 and c-Fos. PMID- 26971225 TI - Mangiferin corrects the imbalance of Th17/Treg cells in mice with TNBS-induced colitis. AB - In the previous study, 80% ethanol extract of the rhizome mixture of Anemarrhena asphodeloides and Coptidis chinensis (AC) and its main constituent mangiferin improved TNBS-induced colitis in mice by inhibiting macrophage activation related to the innate immunity. In the preliminary study, we found that AC could inhibit Th17 cell differentiation in mice with TNBS-induced colitis. Therefore, we investigated whether AC and it main constituent mangiferin are capable of inhibiting inflammation by regulating T cell differentiation related to the adaptive immunity in vitro and in vivo. AC and mangiferin potently suppressed colon shortening and myeloperoxidase activity in mice with TNBS-induced colitis. They also suppressed TNBS-induced Th17 cell differentiation and IL-17 expression, but increased TNBS-suppressed Treg cell differentiation and IL-10 expression. Moreover, AC and mangiferin strongly inhibited the expression of TNF-alpha and IL 17, as well as the activation of NF-kappaB. Furthermore, mangiferin potently inhibited the differentiation of splenocytes into Th7 cells and increased the differentiation into Treg cells in vitro. Mangiferin also inhibited RORgammat and IL-17 expression and STAT3 activation in splenocytes and induced Foxp3 and IL-10 expression and STAT5 activation. Based on these findings, mangiferin may ameliorate colitis by the restoration of disturbed Th17/Treg cells and inhibition of macrophage activation. PMID- 26971226 TI - Role of PHLPP1 in inflammation response: Its loss contributes to gliomas development and progression. AB - PH domain leucine-rich repeats protein phosphatase 1(PHLPP1) belongs to a novel family of Ser/Thr protein phosphatases: PHLPP serves as tumor suppressor in several cancers. However, little knowledge about the expression of PHLPP1 in human glioma tumor tissue and its role in inflammation response in glioma cells was known. Glioma samples were obtained from a total of 37 patients including 16 males and 21 females with surgical removal of the brain tumor. PHLPP1 protein and inflammatory cytokines were measured by Western blot analysis and immunohistochemistry while mRNA was determined by RT-PCR. The levels of inflammatory cytokines including TNF-alpha, IL-17, IL-1beta in U251 glioma cells were evaluated by siRNA PHLPP1 and PHLPP1 addition. The loss of PHLPP1 expression occurs at high frequency in human gliomas. The highest mean values of PHLPP1 mRNA and protein were found in non-glioma brain tissues whereas the lowest mean values were found in those in glioblastoma with an increase of TNF-alpha, IL-17, IL 1beta (p<0.05). PHLPP1 expression in human glioma was associated negatively with the severity of the tumor and inflammatory cytokines. siRNA PHLPP1 could increase the levels of inflammatory cytokines in U251 glioma cells while PHLPP1 addition could inhibit significantly inflammatory cytokines. We concluded that PHLPP1 played a suppression role in inflammatory response of glioma. The present study indicated that PHLPP1 could be used as a predictor for the prediction of the patients or as a therapeutic target for the treatment of human glioma. PMID- 26971227 TI - Circulating T follicular helper cells are associated with rapid virological response in chronic hepatitis C patients undergoing peginterferon therapy. AB - BACKGROUND: Chronic hepatitis C virus (HCV) infection is associated with abnormal T cell and B cell immune responses. T follicular helper (TFH) cells are a subset of CD4(+) T-helper cells and can activate B cells. This study aimed to investigate the role of circulating CXCR5(+)CD4(+) TFH cells, CD19(+) B cells and the associated cytokines in patients with chronic HCV infection. METHODS: The frequencies and phenotypes of circulating TFH cells and B cell subtypes were characterized using flow cytometry in chronic hepatitis C (CHC) patients and in healthy controls (HCs). The expression of IFN-gamma, IL-12p70, IL-5, IL-13, IL 17F, IL-22, IL-23, TGF-beta1, IL-10 and IL-21 associated with Th1, Th2, Th17, regulatory T cells (Treg) and TFH cells were analyzed using a Quantibody array. The patients' clinical parameters were detected, and the effect of pegylated interferon plus ribavirin treatment on these immune indicators in CHC patients was determined. RESULTS: The frequency of CXCR5(+)CD4(+) T cells was significantly higher in CHC patients compared to HCs. There were no significant differences in CD19(+) B cells, CD19(+)CD27(+) B cells, or CD19(+)CD38(+) B cells between CHC patients and HCs. The expressions of cytokines associated with the CD4(+) Th lineage were higher in CHC patients than in HCs, except for IL-21. Patients with rapid virological response (RVR) showed an increased CXCR5(+)CD4(+) T cell count and decreased PD-1(+) CXCR5(+)CD4(+) T cell count compared to non RVR patients after PEG-IFN/ribavirin treatment. CONCLUSIONS: These data demonstrate that circulating TFH cells and CD4(+) Th lineage-associated cytokines may play a role in HCV-related immune responses. PMID- 26971229 TI - Planning deficits in polysubstance dependent users: Differential associations with severity of drug use and intelligence. AB - BACKGROUND: Polysubstance use is associated with alterations in different components of executive functioning such as working memory and response inhibition. Nevertheless, less attention has been given to executive planning skills, which are required to benefit of low structured interventions. This study examines the association between severity of use of cocaine, heroin, alcohol, fluid and crystallized intelligence and planning tasks varying on degree of structure. METHODS: Data were collected from 60 polysubstance users and 30 healthy controls. Cognitive assessment consisted of three planning tasks with different structure levels: Stockings of Cambridge, Zoo Map test, and Multiple Errands Test. RESULTS: Polysubstance users had significant planning deficits across the three tasks compared to healthy controls. Hierarchical regression models showed that severity of drug use and fluid and crystallized intelligence significantly explained performance in all the planning tasks. However, these associations were higher for low-structured real world tasks. These low structured tasks also showed a unique association with crystallized but not fluid intelligence. CONCLUSION: Drug abuse is negatively associated with planning abilities, and intelligence is positively associated with planning performance in real-world tasks. PMID- 26971228 TI - Examining the efficacy of a computer facilitated HIV prevention tool in drug court. AB - BACKGROUND: Although they have demonstrated efficacy in reducing substance use and criminal recidivism, competing priorities and limited resources may preclude drug court programs from formally addressing HIV risk. This study examined the efficacy of a brief, three-session, computer-facilitated HIV prevention intervention in reducing HIV risk among adult felony drug court participants. METHODS: Two hundred participants were randomly assigned to an HIV intervention (n=101) or attention control (n=99) group. All clients attended judicial status hearings approximately every six weeks. At the first three status hearings following study entry, clients in the intervention group completed the computerized, interactive HIV risk reduction sessions while those in the control group viewed a series of educational life-skill videos of matched length. Outcomes included the rate of independently obtained HIV testing, engagement in high risk HIV-related behaviors, and rate of condom procurement from the research site at each session. RESULTS: Results indicated that participants who received the HIV intervention were significantly more likely to report having obtained HIV testing at some point during the study period than those in the control condition, although the effect was marginally significant when examined in a longitudinal model. In addition, they had higher rates of condom procurement. No group differences were found on rates of high-risk sexual behavior, and the low rate of injection drug reported precluded examination of high-risk drug-related behavior. CONCLUSIONS: The study provides support for the feasibility and utility of delivering HIV prevention services to drug court clients using an efficient computer-facilitated program. PMID- 26971230 TI - Digestive enzymatic patterns as possible biomarkers of endocrine disruption in the red mullet (Mullus barbatus): A preliminary investigation. AB - During two seasonal trawl surveys (April and October, 2012), red mullet specimens were caught from two sites of the northern Sicilian coast (Western Mediterranean), characterized by different degrees of pollution, to assess whether their digestive enzymes could be cost-effective diagnostic tools for endocrine disruption. Pepsin, chymotrypsin, carboxypeptidases A and B, amylase and lipase were measured in the digestive tract of each fish. During both samplings, significant differences in the digestive enzymatic patterns of fish collected from the two sites were found. In April, pepsin and lipase contents were significantly lower in fish from the most impacted site than in those from the reference site. In October, the enzymatic patterns showed trends different from spring, with controversial results for carboxypeptidases A and B and amylase. Pepsin and lipase patterns suggest a detrimental effect played by organic pollutants and the use of these enzymes as possible biomarkers of exposure to endocrine disruptors. PMID- 26971231 TI - Detection and characterisation of the biopollutant Xenostrobus securis (Lamarck 1819) Asturian population from DNA Barcoding and eBarcoding. AB - DNA efficiently contributes to detect and understand marine invasions. In 2014 the potential biological pollutant pygmy mussel (Xenostrobus securis) was observed for the first time in the Aviles estuary (Asturias, Bay of Biscay). The goal of this study was to assess the stage of invasion, based on demographic and genetic (DNA Barcoding) characteristics, and to develop a molecular tool for surveying the species in environmental DNA. A total of 130 individuals were analysed for the DNA Barcode cytochrome oxidase I gene in order to determine genetic diversity, population structure, expansion trends, and to inferring introduction hits. Reproduction was evidenced by bimodal size distributions of 1597 mussels. High population genetic variation and genetically distinct clades might suggest multiple introductions from several source populations. Finally, species-specific primers were developed within the DNA barcode for PCR amplification from water samples in order to enabling rapid detection of the species in initial expansion stages. PMID- 26971232 TI - Plastic mistaken for prey by a colony-breeding Eleonora's falcon (Falco eleonorae) in the Mediterranean Sea, revealed by camera-trap. AB - Discarded plastic is known to be harmful for marine animals through ingestion and entanglement. Here we report the first documentation of Eleonora's falcons providing plastic waste to dependent nestlings. Eleonora's falcons breed colonially on sea cliffs and islets in areas of the Mediterranean Sea and the Canary Islands in which they normally feed their nestlings exclusively with small migratory birds. PMID- 26971233 TI - Efficacy of escitalopram in the treatment of social anxiety disorder: A meta analysis versus placebo. AB - Escitalopram is the most selective of the serotonin reuptake inhibitor (SSRI) antidepressants. We conducted a meta-analysis of placebo-controlled studies where escitalopram was used to treat patients with social anxiety disorder (SAD). Data from all randomised, double-blind placebo-controlled studies in SAD with escitalopram from both specialist settings and general practice were used. Patients met the DSM-IV criteria for SAD, were >=18 years old, and had a Liebowitz Social Anxiety Scale (LSAS) >=60. The primary outcome measure was the estimated treatment difference in LSAS total score at Week 12. Secondary outcome measures included the estimated treatment difference in the Clinical Global Impression-Severity (CGI-S) score at Week 12. A total of 1598 patients from 3 randomised controlled trials were included in the analyses. Escitalopram (n=1061) was superior to placebo (n=537), with an estimated treatment difference on the LSAS of -9.2 points (95%CI: [-14.4; -4.0], p<0.01) (escitalopram 5mg/day), -4.6 points (95%CI: [-8.1; -1.0], p<0.01) (escitalopram 10mg/day), -10.1 points (95%CI: [-13.7; -6.5], p<0.01) (escitalopram 20mg/day) and -7.3 points (95%CI: [ 12.3; -2.2], p<0.01) (escitalopram 10-20mg/day). For the CGI-S, the corresponding values were -0.55 points (95%CI: [-0.79; -0.31], p<0.01) (escitalopram 5mg/day), 0.26 points (95%CI: [-0.42; -0.10], p<0.01) (escitalopram 10mg/day), -0.48 points (95%CI: [-0.64; -0.31], p<0.01) (escitalopram 20mg/day) and -0.29 points (95%CI: [-0.51; -0.07], p<0.05) (escitalopram 10-20mg/day). The withdrawal rate due to adverse events was 7.2% for escitalopram, compared with 4.3% for placebo (p<0.05). In this meta-analysis, all doses of escitalopram showed significant superiority in efficacy versus placebo in the treatment of patients with SAD. PMID- 26971234 TI - A new method for the evaluation of the end-to-end distance of the knee ligaments and popliteal complex during passive knee flexion. AB - BACKGROUND: Accurate knowledge about the length variation of the knee ligaments (ACL, PCL, MCL and LCL) and the popliteal complex during knee flexion/extension is essential for modelling and clinical applications. The aim of the present study is to provide this information by using an original technique able to faithfully reproduce the continuous passive knee flexion-extension kinematics and to reliably identify each ligament/tendon attachment site. METHODS: Twelve lower limbs (femur, tibia, fibula, patella) were tested and set in motion (0-120 degrees ) using an ad hoc rig. Tibio-femoral kinematics was obtained using an optoelectronic system. A 3D digital model of each bone was obtained using low dosage stereoradiography. Knee specimens were dissected and the insertion of each ligament and popliteal complex were marked with radio opaque paint. ACL, PCL and MCL were separated into two bundles. Bone epiphyses were CT-scanned to obtain a digital model of each ligament insertion. Bones and attachment site models were registered and the end-to-end distance variation of each ligament/tendon was computed over knee flexion. RESULTS: A tibial internal rotation of 18 degrees +/ 4 degrees with respect to the femur was observed. The different bundles of the ACL, MCL and LCL shortened, whereas all bundles of the PCL lengthened. The popliteal complex was found to shorten until 30 degrees of knee flexion and then to lengthen. CONCLUSION: The end-to-end distance variation of the knee ligaments and popliteal complex can be estimated during knee flexion using a robust and reliable method based on marking the ligaments/tendon insertions with radiopaque paint. LEVEL OF EVIDENCE: Level IV. PMID- 26971235 TI - Adjunctive Bare-Metal Stenting Associated With Improved Outcomes in Patients With Multivessel Disease Treated With Drug-Eluting Stents. AB - BACKGROUND: The use of both bare-metal stents (BMSs) and drug-eluting stents (DESs) in the setting of multivessel percutaneous coronary intervention (PCI) continues because of cost considerations. METHODS: A retrospective analysis of patients with >= 2 coronary arteries with angiographic stenoses of >= 70% severity who were treated with multivessel PCI and >= 2 stents between April 2007 and March 2011 was performed using a prospective single-centre PCI registry. Follow-up data were obtained from the Discharge Abstract Database of the Canadian Institute for Health Information and the Registered Persons Database. We performed propensity matching of the DES + BMS and DES-only groups, as well as Cox multiple regression analyses to determine the independent predictors of adverse events. RESULTS: A total of 1299 patients (514 in the DES + BMS group and 785 in the DES group) fulfilled the study criteria. Death or repeated revascularization at 5 years occurred less frequently in the DES + BMS group than in the DES group (23.9% +/- 2.6% vs 33.1% +/- 2.4%; P = 0.01), and major adverse cardiac events (MACE) tended to be less common in the DES + BMS group (31.1% +/- 3.0% vs 36.7% +/- 2.4%; P = 0.056). Kaplan-Meier estimates revealed an adjusted benefit with the DES + BMS strategy for death (11.4 +/- 2.9 vs 14.9 +/- 2.8; P = 0.035) and for death and repeated revascularization (25.6 +/- 3.5 vs 32.4 +/- 3.4; P = 0.034). CONCLUSIONS: A DES + BMS PCI strategy is associated with a lower incidence of repeated revascularization and MACE at 5-year follow up. For patients undergoing multivessel PCI who have favourable anatomy and clinical features, a combined approach using DES and BMS appears to be a viable option for contemporary PCI practice. PMID- 26971236 TI - Effect of Modifying Antiplatelet Treatment to Ticagrelor in High-Risk Coronary Patients With Low Response to Clopidogrel (MATTIS). AB - BACKGROUND: Treatment with clopidogrel is subject to wide variability in response, and high on-treatment platelet reactivity (HTPR) is associated with increased risk of ischemic events. Ticagrelor has been shown to have antiplatelet effects superior to those of clopidogrel, with subsequent reduced clinical ischemic events. However, the efficacy of ticagrelor in high-risk patients with coronary disease who have high on-treatment platelet reactivity (HTPR) with clopidogrel has not been examined. METHODS: We recruited 201 patients (mean age, 64 +/- 10 years; 20% women) with stable/unstable angina who were receiving clopidogrel treatment and in whom coronary catheterization was planned. Platelet reactivity was tested using VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) (HTPR defined as P2Y12 reaction units [PRU] >= 208). Patients with HTPR were randomized to receive either additional clopidogrel 300 mg or ticagrelor 180 mg before coronary angiography, and persisted with the respective treatment after percutaneous coronary intervention (PCI). The primary end point was the rate of troponin elevation after PCI, and the secondary end point was the change in platelet reactivity 24 hours after PCI. In addition, clinical outcomes at 30 days were evaluated. RESULTS: Eighty-four (42%) patients had HTPR (mean PRU, 270.8 +/- 46.5) and were randomly assigned to clopidogrel or ticagrelor treatment. Subsequently, 49 patients underwent percutaneous coronary intervention (PCI) (26 receiving ticagrelor and 23 receiving clopidogrel). After PCI, the mean PRU in the ticagrelor group declined significantly (ticagrelor, 59.3 +/- 49 vs clopidogrel, 202.4 +/- 60.4; P < 0.0001). The rate of cardiac troponin elevation and clinical ischemic events were similar between the groups. CONCLUSIONS: In high-risk patients with coronary disease and HTPR on clopidogrel, ticagrelor was highly effective in platelet inhibition and overcoming HTPR compared with continued clopidogrel treatment but had no apparent effect on troponin release or short-term clinical outcomes. PMID- 26971237 TI - Surgical Treatment of an Anomalous Left Coronary Artery From the Pulmonary Artery in a Sexagenarian Woman. AB - Late presentation of an anomalous left coronary artery from the pulmonary artery (ALCAPA) is uncommon because patients rarely survive past infancy. We present a case of symptomatic ALCAPA associated with decreased myocardial contractility in a 68-year-old woman. The patient underwent reimplantation of the left coronary artery in the aortic root. PMID- 26971238 TI - Fracture and Lung Penetration of a Left Ventricular Lead Stabilized by Retained Stylet. AB - During cardiac resynchronization therapy (CRT) pacemaker implantation in a 54 year-old female patient, removing the stylet resulted in repeated left ventricular (LV) lead dislodgment. Lead stability was achieved by retaining the stylet within the lead lumen. Two years after cardiac resynchronization therapy, a LV lead fracture near the connector pin occurred. The proximal lead segment was removed, and a new connector pin was attached. Two years after that, the same lead fractured in the right atrium with the stylet penetrating the lung. The LV lead and retained stylet were successfully extracted. LV lead dislodgment is a limitation of CRT, but using the retained stylet technique to achieve lead stability is potentially dangerous and is not recommended. PMID- 26971239 TI - Evolution and Impact of a Regional Reperfusion System for ST-Elevation Myocardial Infarction. AB - BACKGROUND: We describe the evolution of a regional system designed to provide primary percutaneous coronary intervention (pPCI) as the preferred method of revascularization for ST-elevation myocardial infarction (STEMI) and its impact on first medical contact (FMC)-to-device times and in-hospital outcomes. METHODS: Patients with STEMI presenting to the Vancouver Coastal Health Authority between June 2007 and January 2015 (N = 2503) were categorized according to 3 sequential phases: phase 1 = standardization of reperfusion algorithms; phase 2 = use of prehospital electrocardiograms; phase 3 = expedited interfacility transfer for pPCI. In-hospital outcomes by phase and hospital type were analyzed using multivariable logistic regression techniques. RESULTS: Regional pPCI use increased across phases (55.0% vs 72.5% vs 86.7%; P < 0.001) and median FMC-to device times shortened between phase 1 and later phases at both PCI-capable (117 minutes vs 92 minutes vs 97 minutes, respectively; P < 0.001) and non-PCI-capable hospitals (174 minutes vs 146 minutes vs 123 minutes, respectively; P < 0.001). Overall in-hospital mortality (9.4% vs 8.9% vs 10.3%, respectively; P = 0.54) and congestive heart failure (CHF) (15.8% vs 19.7% vs 22.0%, respectively; P = 0.056) were unchanged across phases. A trend toward increased mortality (9.0% vs 9.3% vs 12.9%, respectively; P = 0.079) and higher rates of CHF (15.7% vs 21.5% vs 25.9%, respectively; P = 0.014) were seen in PCI-capable hospitals. CONCLUSIONS: Our regional STEMI model increased access to pPCI and reduced median reperfusion times. However, FMC-to-device times remained prolonged in many patients and overall clinical outcomes were not improved-in particular at PCI-capable hospitals. A strategy of pPCI as the preferred method of reperfusion may not benefit all patients in a regional model of STEMI care. PMID- 26971240 TI - Percutaneous Coronary Intervention in a Patient With Severe Systemic Vasculitis and Myocardial Infarction. AB - A 72-year-old woman presented with acute coronary syndrome. There was diffuse coronary ectasia and severe stenosis in the proximal left anterior descending artery consistent with coronary vasculitis. Despite treatment with high-dose immunosuppression, she underwent percutaneous coronary intervention for refractory angina. PMID- 26971241 TI - Influence of Genetic Risk Factors on Coronary Heart Disease Occurrence in Afro Caribbeans. AB - BACKGROUND: Despite excessive rates of cardiovascular risk factors such as hypertension, diabetes, and obesity, Afro-Caribbeans have lower mortality rates from coronary heart disease (CHD) than do whites. This study evaluated the association of genetic risk markers previously identified in whites and CHD in Afro-Caribbeans. METHODS: We studied 537 Afro-Caribbean individuals (178 CHD cases and 359 controls) who were genotyped for 19 CHD-related single-nucleotide polymorphisms (SNPs). A genetic risk score (GRS) incorporating the 19 SNPs was calculated. These participants were compared with 1360 white individuals from the Second Northwick Park Heart Study. RESULTS: In Afro-Caribbeans, patients with CHD had higher rates of hypertension (78.7% vs 30.1%), hypercholesterolemia (52.8% vs 15.0%), and diabetes (53.9% vs 14.8%) and were more often men (64.0% vs 43.7%) and smokers (27.5% vs 13.4%) compared with non-CHD controls (all P < 0.001). The GRS was higher in Afro-Caribbeans with CHD than in those without CHD (13.90 vs 13.17; P < 0.001) and was significantly associated with CHD after adjustment for cardiovascular risk factors, with an odds ratio of 1.40 (95% confidence interval, 1.09-1.80) per standard deviation change. There were significant differences in allelic distributions between the 2 ethnic groups for 14 of the 19 SNPs. The GRS was substantially lower in Afro-Caribbean controls compared with white controls (13.17 vs 16.59; P < 0.001). CONCLUSIONS: This study demonstrates that a multilocus GRS composed of 19 SNPs associated with CHD in whites is a strong predictor of the disease in Afro-Caribbeans. The differences in CHD occurrence between Afro-Caribbeans and whites might be a result of significant discrepancies in common gene variant distribution. PMID- 26971242 TI - Effect of tiotropium on night-time awakening and daily rescue medication use in patients with COPD. AB - BACKGROUND: Several small studies found night-time awakenings due to COPD symptoms were associated with decreased health status. In this study, night-time awakenings in patients with COPD were examined and effects of tiotropium therapy evaluated. METHODS: This study was a post hoc, exploratory, pooled analysis of twin, multicenter, double-blind, randomized, placebo-controlled, parallel-group trials. Patients with stable moderate-to-severe COPD were randomized to tiotropium HandiHaler(r) (n = 550) or placebo (n = 371) and followed for 13 weeks. During a 2-week, pre-treatment baseline period and for 13 weeks on treatment, self-reported night-time awakenings due to COPD symptoms, rescue medication (albuterol) use, and morning and evening peak expiratory flow rate (PEFR) were recorded daily. Nightly, COPD-related awakenings were scored: 0 = no awakenings; 1 = 1 awakening; 2 = 2-3 awakenings; or 3 = awake most of the night. Health-related quality-of-life (HRQoL) and energy-fatigue questionnaires were completed at baseline and during treatment. RESULTS: Patients were aged 65.2 +/- 8.7 years (mean +/- SD), with a mean pre-bronchodilator FEV1 of 36.1 +/- 13.5 % predicted normal at baseline. Data for night-time awakenings and albuterol use were available for 543 (99 %) patients on tiotropium and 352 (95 %) on placebo. At baseline, 280 (51.5 %) patients on tiotropium and 179 (50.1 %) on placebo reported >=1 COPD-related night-time awakening per week. Over the 13-weeks' treatment, tiotropium was associated with fewer night-time awakenings, with mean +/- SE overall awakening scores per week of 0.356 +/- 0.006 compared with 0.421 +/- 0.007 for placebo (p < 0.001); means were significantly lower for tiotropium versus placebo in patients with baseline awakenings (p < 0.001), but not for those without baseline awakenings. COPD-related night-time awakenings were associated with increased nocturnal rescue medication use and lower HRQoL ratings in both treatment arms. Following start of treatment, tiotropium decreased patients' use of rescue medication compared with placebo, and morning and evening adjusted means for PEFR were higher for tiotropium compared with placebo. CONCLUSIONS: Tiotropium is associated with decreased COPD-related night-time awakenings. Night-time awakenings are associated with increased nocturnal rescue medication use and may be a surrogate marker of symptom control in patients with COPD. PMID- 26971243 TI - Hepatitis C virus quasispecies and pseudotype analysis from acute infection to chronicity in HIV-1 co-infected individuals. AB - HIV-1 infected patients who acquire HCV infection have higher rates of chronicity and liver disease progression than patients with HCV mono-infection. Understanding early events in this pathogenic process is important. We applied single genome sequencing of the E1 to NS3 regions and viral pseudotype neutralization assays to explore the consequences of viral quasispecies evolution from pre-seroconversion to chronicity in four co-infected individuals (mean follow up 566 days). We observed that one to three founder viruses were transmitted. Relatively low viral sequence diversity, possibly related to an impaired immune response, due to HIV infection was observed in three patients. However, the fourth patient, after an early purifying selection displayed increasing E2 sequence evolution, possibly related to being on suppressive antiretroviral therapy. Viral pseudotypes generated from HCV variants showed relative resistance to neutralization by autologous plasma but not to plasma collected from later time points, confirming ongoing virus escape from antibody neutralization. PMID- 26971244 TI - Comparison of 'HoBi'-like viral populations among persistent infected calves generated under experimental conditions and to inoculum virus. AB - Like other members from the Pestivirus genus, 'HoBi'-like pestiviruses cause economic losses for cattle producers due to both acute and persistent infections. The present study analyzed for the first time PI animals derived from a controlled infection with two different 'HoBi'-like strains where the animals were maintained under conditions where superinfection by other pestiviruses could be excluded. The sequence of the region coding for viral glycoproteins E1/E2 of variants within the swarms of viruses present in the PI calves and two viral inoculums used to generate them were compared. Differences in genetic composition of the viral swarms were observed suggesting that host factors can play a role in genetic variations among PIs. Moreover, PIs generated with the same inoculum showed amino acid substitutions in similar sites of the polyprotein, even in serum from PIs with different quasispecies composition, reinforcing that some specific sites in E2 are important for host adaptation. PMID- 26971245 TI - Mapping and modeling of a strain-specific epitope in the Norwalk virus capsid inner shell. AB - Noroviruses are diverse positive-strand RNA viruses associated with acute gastroenteritis. Cross-reactive epitopes have been mapped primarily to conserved sequences in the capsid VP1 Shell (S) domain, and strain-specific epitopes to the highly variable Protruding (P) domain. In this work, we investigated a strain specific linear epitope defined by MAb NV10 that was raised against prototype (Genogroup I.1) strain Norwalk virus (NV). Using peptide scanning and mutagenesis, the epitope was mapped to amino acids 21-32 (LVPEVNASDPLA) of the NV S domain, and its specificity was verified by epitope transfer and reactivity with a recombinant MAb NV10 single-chain variable fragment (scFv). Comparative structural modeling of the NV10 strain-specific and the broadly cross-reactive TV20 epitopes identified two internal non-overlapping sites in the NV shell, corresponding to variable and conserved amino acid sequences among strains, respectively. The S domain, like the P domain, contains strain-specific epitopes that contribute to the antigenic diversity among the noroviruses. PMID- 26971246 TI - Depression and anxiety symptoms in Spanish adult patients with cystic fibrosis: associations with health-related quality of life. AB - BACKGROUND: Cystic fibrosis (CF) is a chronic disease with an impact on the quality of life. Self-reported symptoms of depression and anxiety were assessed in the Spanish cohort of the International Epidemiological Study on Depression and Anxiety in patients with CF (International Depression-Anxiety Epidemiological Study) and their relationship with health status and health-related quality of life (HRQoL) was evaluated. METHODS: This cross-sectional study recruited adult patients with CF at 10 Spanish centers. Patients completed the Hospital Anxiety and Depression Scale (HADS) and the Revised Cystic Fibrosis Questionnaire. Demographic and health data were recorded from medical charts. Logistic regression was used to determine the predictors of elevated symptoms of depression and anxiety (HADS>=8). RESULTS: Of the 336 participants recruited (mean age, 28.1years; 48.2% women), 41 (12.2%) had elevated depression-related scores, and 100 (29.7%) had elevated anxiety-related scores (HADS>=8). After adjusting for confounders, only less education, intravenous antibiotics, psychiatric medications and psychotherapy were significantly associated with elevated psychological symptoms. Specifically, regardless of lung function, patients who were depressed or anxious reported worse HRQoL. CONCLUSIONS: The prevalence of elevated symptoms of depression and anxiety was high in Spanish adult patients with CF, and these symptoms were associated with a decreased HRQoL. PMID- 26971247 TI - The detrimental impact of silent cerebral infarcts on asymptomatic carotid endarterectomy outcome. AB - BACKGROUND: Silent cerebral infarctions (SCIs) can be identified by preoperative computed tomography (CT) scans in patients with severe carotid stenosis being considered for carotid endarterectomy (CEA). It is unknown whether this finding has any effect on perioperative complications or long-term outcome. This study investigates the influence of SCI on early and late complications in asymptomatic patients undergoing CEA. METHODS: All consecutive CEAs undertaken for asymptomatic severe carotid stenosis from 2005 to 2013 were retrospectively evaluated for clinical and anatomic characteristics. SCI was defined as cerebral embolic infarcts in the anterior or middle cerebral artery territory, ipsilateral to the target carotid stenosis, identified on preoperative CT. The end points of the study were to compare the 30-day and long-term stroke and death rate after CEA in patients with and without SCI. All patients were followed yearly through duplex ultrasonography and clinical assessment. Statistical methods used were Cox regression (hazard ratio) and Kaplan-Meier for life-table analysis. RESULTS: A total of 743 CEAs were performed in asymptomatic patients during the study period of which all had CT scans, and 97 (13.1%) demonstrated SCI. All patient stroke and death outcomes at 30 days were 0.5% and 0.7%, respectively. Patients with SCI had a significantly higher 30-day stroke outcome (3.1% vs 0.2%; P = .001; odds ratio, 16.39; 95% confidence interval, 1.33-201.4; P = .02) but not death or stroke/death outcome (0% vs 0.8%; P = .19 and 3.1% vs 0.9%, P = .06, respectively) compared with those without SCI. In addition, at a mean follow-up of 44.3 +/- 23.9 months, the patients with SCI had a significantly worse 5-year ipsilateral stroke or any stroke-/death-free survival compared with patients without SCI (86.7% vs 99.0%; P = .001; and 76.9% vs 87.7%; P = .004). SCI was confirmed as an independent predictor of late any stroke/death by Cox regression (hazard ratio, 2.45; 95% confidence interval, 1.29-4.67; P = .006). CONCLUSIONS: Patients who have SCI in the presence of severe carotid stenosis and undergo CEA have significantly worse perioperative stroke and long-term stroke/death outcomes. This data would suggest that asymptomatic patients undergoing CEA who have CT scan evidence of a cerebral infarct have worse prognosis than those with normal CT scans. PMID- 26971248 TI - Local Recurrence After Curative Surgical Treatment of Renal Cell Cancer: A Study of 91 Patients. AB - BACKGROUND: Local recurrence (LR) after curative therapy for renal cell cancer is a rare event, and surgery is still the primary treatment option. PATIENTS AND METHODS: This was a single-institution, single-arm retrospective study from a prospectively conducted database. A total of 91 patients with a median age of 63.0 years (interquartile range, 57.5-68.3), who had undergone LR resection after initial curative treatment of RCC were enrolled. The time to LR (TTLR) was defined as the interval from primary curative surgery to LR. Cancer-specific survival, overall survival, and progression-free survival were evaluated after LR resection. Statistical analyses of the clinical and pathologic variables were performed using Cox regression analysis and the Kaplan-Meier method. RESULTS: The median time to LR was 29.8 months (interquartile range, 10.8-64.3). On multivariate analysis, age > 65 years, T3/T4 stage, Fuhrman grade 3/4, major venous infiltration, and positive surgical margins were related to early LR after primary curative surgery. LR size of <= 7 cm and TTLR of > 24 months were associated with longer cancer-specific survival. Furthermore, patients with a TTLR of > 24 months had better overall survival and progression-free survival. Of the entire cohort, intraoperative radiation therapy and targeted therapy were used in 17 (18.7%) and 15 (16.5%) patients, respectively. CONCLUSION: Advanced age, T3/T4 stage, Fuhrman grade 3 or 4, major venous infiltration, and positive surgical margins at primary tumor resection were related to a greater risk of early LR. An LR size of <= 7 cm and TTLR of > 24 months were associated with favorable oncologic outcomes after LR resection. Thus, patients who present with a longer TTLR and smaller LR size, along with favorable features at primary tumor resection, will benefit from surgical treatment. PMID- 26971249 TI - Adaptation into Spanish of the Internalised Stigma of Mental Illness scale to assess personal stigma. AB - INTRODUCTION: Patients with schizophrenia sometimes internalise social stigma associated to mental illness, and they develop personal stigma. Personal stigma includes self-stigma (internalisation of negative stereotypes), perceived stigma (perception of rejection), and experienced stigma (experiences of discrimination). Personal stigma is linked with a poorer treatment adherence, and worst social functioning. For this reason, it is important to have good measurements of personal stigma. One of the most frequently used measurements is the Internalised Stigma of Mental Illness (ISMI) scale. There is a Spanish version of the scale available, although its psychometric properties have not been studied. The main aim of this study is to analyse the psychometric properties of a new Spanish version of the ISMI scale. MATERIAL AND METHODS: The new version was translated as Estigma Interiorizado de Enfermedad Mental (EIEM). Internal consistency and test-retest reliability were calculated in a sample of 69 patients with a diagnosis of schizophrenia or schizoaffective disorder. The rate of patients showing personal stigma was also studied, as well as the relationship between personal stigma and sociodemographic and clinical variables. RESULTS: The adapted version obtained good values of internal consistency and test-retest reliability, for the total score of the scale (0.91 and 0.95 respectively), as well as for the five subscales of the EIEM, except for the Stigma Resistance subscale (Cronbach's alpha 0.42). CONCLUSIONS: EIEM is an appropriate measurement tool to assess personal stigma in a Spanish population with severe mental disorder, at least in those with a diagnosis of schizophrenia or schizoaffective disorder. PMID- 26971251 TI - MOCCS: Clarifying DNA-binding motif ambiguity using ChIP-Seq data. AB - BACKGROUND: As a key mechanism of gene regulation, transcription factors (TFs) bind to DNA by recognizing specific short sequence patterns that are called DNA binding motifs. A single TF can accept ambiguity within its DNA-binding motifs, which comprise both canonical (typical) and non-canonical motifs. Clarification of such DNA-binding motif ambiguity is crucial for revealing gene regulatory networks and evaluating mutations in cis-regulatory elements. Although chromatin immunoprecipitation sequencing (ChIP-seq) now provides abundant data on the genomic sequences to which a given TF binds, existing motif discovery methods are unable to directly answer whether a given TF can bind to a specific DNA-binding motif. RESULTS: Here, we report a method for clarifying the DNA-binding motif ambiguity, MOCCS. Given ChIP-Seq data of any TF, MOCCS comprehensively analyzes and describes every k-mer to which that TF binds. Analysis of simulated datasets revealed that MOCCS is applicable to various ChIP-Seq datasets, requiring only a few minutes per dataset. Application to the ENCODE ChIP-Seq datasets proved that MOCCS directly evaluates whether a given TF binds to each DNA-binding motif, even if known position weight matrix models do not provide sufficient information on DNA-binding motif ambiguity. Furthermore, users are not required to provide numerous parameters or background genomic sequence models that are typically unavailable. MOCCS is implemented in Perl and R and is freely available via https://github.com/yuifu/moccs. CONCLUSIONS: By complementing existing motif discovery software, MOCCS will contribute to the basic understanding of how the genome controls diverse cellular processes via DNA-protein interactions. PMID- 26971250 TI - Cytosolic phosphoenolpyruvate carboxykinase deficiency presenting with acute liver failure following gastroenteritis. AB - We report a patient from a consanguineous family who presented with transient acute liver failure and biochemical patterns suggestive of disturbed urea cycle and mitochondrial function, for whom conventional genetic and metabolic investigations for acute liver failure failed to yield a diagnosis. Whole exome sequencing revealed a homozygous 12-bp deletion in PCK1 (MIM 614168) encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK); enzymatic studies subsequently confirmed its pathogenic nature. We propose that PEPCK deficiency should be considered in the young child with unexplained liver failure, especially where there are marked, accumulations of TCA cycle metabolites on urine organic acid analysis and/or an amino acid profile with hyperammonaemia suggestive of a proximal urea cycle defect during the acute episode. If suspected, intravenous administration of dextrose should be initiated. Long-term management comprising avoidance of fasting with the provision of a glucose polymer emergency regimen for illness management may be sufficient to prevent future episodes of liver failure. This case report provides further insights into the (patho-)physiology of energy metabolism, confirming the power of genomic analysis of unexplained biochemical phenotypes. PMID- 26971252 TI - Frequency of Penetration of the Digital Flexor Tendon Sheath and Distal Interphalangeal Joint Using a Direct Endoscopic Approach to the Navicular Bursa in Horses. AB - OBJECTIVE: To evaluate the frequency of inadvertent penetration of the digital flexor tendon sheath (DFTS) and/or distal interphalangeal joint (DIPJ) when using a direct endoscopic approach to the navicular bursa, and to evaluate an alternate direct approach to the navicular bursa. STUDY DESIGN: Cadaveric study. SAMPLE POPULATION: Equine cadaver limbs (n = 40 for direct; n = 12 for alternate approach). METHODS: Four surgeons performed the direct endoscopic approach to the navicular bursa on 10 limbs each. Frequencies of inadvertent synovial penetration and iatrogenic damage were compared between surgeons. Use of an alternate direct approach, adopting a straight parasagittal trajectory, was evaluated by 2 surgeons. RESULTS: Inadvertent synovial penetration occurred in 45% of limbs (DFTS 37.5%; DIPJ 17.5%; and both structures 10%). Successful bursa entry was achieved on the first attempt in 45% of limbs. Significant variation in frequency of inadvertent synovial penetration was observed between surgeons (range 10-80%). Inadvertent synovial penetration did not occur when using the alternate direct technique. Iatrogenic damage to navicular bone fibrocartilage and/or deep digital flexor tendon occurred in 55% of limbs using the direct endoscopic approach and in 0% of limbs using the alternate direct approach. CONCLUSION: Because of the considerable risk of inadvertent penetration of the DFTS and/or the DIPJ when making a direct endoscopic approach to the navicular bursa, it is advisable to investigate for inadvertent penetration when treating navicular bursa sepsis using a direct approach. The alternate direct technique may reduce the risk of inadvertent penetration; however, the view within the bursa may be restricted. PMID- 26971253 TI - The association between stress and mood across the adult lifespan on default mode network. AB - Aging of brain structure and function is a complex process characterized by high inter- and intra-individual variability. Such variability may arise from the interaction of multiple factors, including exposure to stressful experience and mood variation, across the lifespan. Using a multimodal neuroimaging and neurocognitive approach, we investigated the association of stress, mood and their interaction, in the structure and function of the default mode network (DMN), both during rest and task-induced deactivation, throughout the adult lifespan. Data confirmed a decreased functional connectivity (FC) and task induced deactivation of the DMN during the aging process and in subjects with lower mood; on the contrary, an increased FC was observed in subjects with higher perceived stress. Surprisingly, the association of aging with DMN was altered by stress and mood in specific regions. An increased difficulty to deactivate the DMN was noted in older participants with lower mood, contrasting with an increased deactivation in individuals presenting high stress, independently of their mood levels, with aging. Interestingly, this constant interaction across aging was globally most significant in the combination of high stress levels with a more depressed mood state, both during resting state and task-induced deactivations. The present results contribute to characterize the spectrum of FC and deactivation patterns of the DMN, highlighting the crucial association of stress and mood levels, during the adult aging process. These combinatorial approaches may help to understand the heterogeneity of the aging process in brain structure and function and several states that may lead to neuropsychiatric disorders. PMID- 26971254 TI - Mechanisms of memory storage in a model perirhinal network. AB - The perirhinal cortex supports recognition and associative memory. Prior unit recording studies revealed that recognition memory involves a reduced responsiveness of perirhinal cells to familiar stimuli whereas associative memory formation is linked to increasing perirhinal responses to paired stimuli. Both effects are thought to depend on perirhinal plasticity but it is unclear how the same network could support these opposite forms of plasticity. However, a recent study showed that when neocortical inputs are repeatedly activated, depression or potentiation could develop, depending on the extent to which the stimulated neocortical activity recruited intrinsic longitudinal connections. We developed a biophysically realistic perirhinal model that reproduced these phenomena and used it to investigate perirhinal mechanisms of associative memory. These analyzes revealed that associative plasticity is critically dependent on a specific subset of neurons, termed conjunctive cells (CCs). When the model network was trained with spatially distributed but coincident neocortical inputs, CCs acquired excitatory responses to the paired inputs and conveyed them to distributed perirhinal sites via longitudinal projections. CC ablation during recall abolished expression of the associative memory. However, CC ablation during training did not prevent memory formation because new CCs emerged, revealing that competitive synaptic interactions governs the formation of CC assemblies. PMID- 26971255 TI - Ultrasonography in pediatric rheumatology in Latin America. Expanding the frontiers. AB - For the past two decades, musculoskeletal ultrasonography (MSKUS) has developed exponentially and has become an essential tool in rheumatology practice. This development has been far more limited in pediatric rheumatology which is partially related to deficits in the evidence base. Many studies have shown that MSKUS is more sensitive than the clinical examination for detecting synovitis and enthesitis in adults. At the same time, there is a lack of studies demonstrating its validity, reliability, and reproducibility in pediatric rheumatology. In addition, clear definitions for the normal pediatric joint and enthesis as well as various findings in pathology associated with juvenile idiopathic arthritis (JIA) and juvenile spondyloarthritis (JSpA) have only started to emerge. Most of this work is being done through the Outcome Measurement in Rheumatology Clinical Trials (OMERACT) ultrasound pediatric task force but the Pan American League of Associations for Rheumatology (PANLAR) US Pediatric Task Force is also working on validating MSKUS in children. In addition, several MSKUS courses for pediatric rheumatologists have been offered in Latin American countries; these will not only complement the scientific work pediatric-specific ultrasonography training, but also represents an essential component for the successful implementation of this technique into daily practice as well. PMID- 26971257 TI - A prospective study into the benefits of simulation training in teaching obstetric vaginal examination. AB - OBJECTIVE: To assess the benefits of incorporating simulations in obstetric vaginal-examination training. METHODS: A single-center, randomized, prospective study was conducted in a French University Hospital. Medical students without obstetric experience were assigned, by simple random sampling, to perform either 10 or 30 vaginal-examination training procedures using a simulator. A control group of students that had not performed any simulator training procedures was also enrolled. Medical students performed six vaginal examinations on patients who were in labor. The students reported the findings of the examinations in terms of five items (cervical length, position, consistency, dilation, and fetal presentation). The students' findings were then compared with those of experienced midwives (whose answers were considered to be the gold standard) who examined the same patients. RESULTS: A total of 66 students were included in the analyses. Students who had performed 10 simulated procedures demonstrated significantly greater accuracy in vaginal examination assessments in comparison with the control group (P<0.001). No significant difference was observed between the results for students that had performed 10 or 30 simulated procedures (P=0.44). CONCLUSION: Simulation training assisted novice students in improving their vaginal-examination skills before performing such procedures on real patients. Vaginal-examination simulations should be included in the training curriculum for students who will examine pregnant patients. PMID- 26971256 TI - Comparison of the clinical effectiveness of tumour necrosis factor inhibitors and abatacept after insufficient response to tocilizumab in patients with rheumatoid arthritis. AB - The aim of this study is to compare the clinical effectiveness of tumour necrosis factor inhibitors (TNFi) and abatacept (ABT) after insufficient response to tocilizumab (TCZ) in patients with rheumatoid arthritis (RA). Among 527 RA patients treated with TCZ, 63 patients were enrolled who switched TCZ to alternative biologic agents because of moderate or high disease activity assessed by the Clinical Disease Activity Index (CDAI). They were divided into two groups, TNF inhibitors (TNFi) or abatacept (ABT), and compared for clinical effectiveness and adverse events at week 24. Forty-two were switched to TNFi, and 21 to ABT. TNFi included 19 infliximab, 3 adalimumab, 8 etanercept, 9 golimumab, and 3 certolizumab-pegol. Baseline characteristics at the switch were comparable except for the concomitant methotrexate use (TNFi 71.4 vs ABT 28.6 %, P = 0.003). The proportion of patients achieving CDAI <= 10 (remission or low disease activity) at week 24 was significantly higher in TNFi than ABT (64.3 vs 23.8 %, P = 0.003), and the values of the CDAI at week 24 was significantly better in TNFi than ABT (mean, 11.8 vs 16.4, P = 0.021) although the drug retention rate was not different between the two groups (73.8 vs 71.4 %, P = 0.803). No serious adverse event was observed in both groups. TNFi may be more effective than ABT to achieve clinical remission or low disease activity after insufficient response to TCZ in patients with RA, although drug retention rate and safety are comparable. PMID- 26971258 TI - Feasibility and acceptability of clean birth kits containing misoprostol for self administration to prevent postpartum hemorrhage in rural Papua New Guinea. AB - OBJECTIVE: To determine the feasibility and acceptability of providing clean birth kits (CBKs) containing misoprostol for self-administration in a rural setting in Papua New Guinea. METHODS: A prospective intervention study was conducted between April 8, 2013, and October 24, 2014. Eligible participants were women in the third trimester of pregnancy who attended a prenatal clinic in Unggai Bena. Participants received individual instruction and were then given a CBK containing 600MUg misoprostol tablets for self-administration following an unsupervised birth if they could demonstrate their understanding of correct use of items in the CBK. Data regarding the use and acceptability of the CBK and misoprostol were collected during postpartum follow-up. RESULTS: Among 200 participants, 106 (53.0%) had an unsupervised birth, and 99 (93.4%) of these women used the CBK. All would use the CBK again and would recommend it to others. Among these 99 women, misoprostol was self-administered by 98 (99.0%), all of whom would take the drug again and would recommend it to others. CONCLUSION: The findings strengthen the case for community-based use of misoprostol to prevent postpartum hemorrhage in remote communities. Large-scale interventions should be planned to further evaluate impact and acceptability. PMID- 26971259 TI - Multivariate analysis of risk factors for the persistence of high-grade squamous intraepithelial lesions following loop electrosurgical excision procedure. AB - OBJECTIVE: To evaluate risk factors related to the persistence of high-grade squamous intraepithelial lesions (HSILs) following loop electrosurgical excision procedure (LEEP). METHODS: The present prospective, observational study evaluated a convenience sample of participants with HSILs who were treated using LEEP between January 7, 2003 and December 30, 2011. Participants were evaluated 6months and 1year after treatment. Potential risk factors included in multivariate analyses were HIV co-infection, involved margins, multicentric lesions, smoking, and use of hormonal contraception. RESULTS: The present study enrolled 307 participants. At 1year, 250 (81.4%) participants were free from lesions, 30 (9.8%) had low-grade squamous intraepithelial lesions, 26 (8.5%) had persistent HSILs, and 1 (0.3%) had developed invasive carcinoma. The risk of lesions persisting at 1year after LEEP was increased by HIV infection (P=0.003), involved margins (P=0.05), and smoking (P=0.02). The presence of multicentric lesions (P=0.73) and the use of hormonal contraception (P=0.99) did not increase the risk of lesion persistence. The risk of HSIL persistence was increased by the presence of involved margins (relative risk 3.25; 95% confidence interval 1.55 6.80; P=0.001). CONCLUSIONS: The presence of involved margins was the only variable that increased the risk of HSIL persistence after LEEP, increasing the risk of patients requiring further treatment. PMID- 26971260 TI - Transvaginal treatment of anterior or central urogenital prolapse using six tension-free straps and light mesh. AB - OBJECTIVE: To evaluate the feasibility, efficacy, complications, and outcomes of treatment of anterior or central compartment urogenital prolapse by placement of an anteroposterior 22-g/m(2) mesh with six straps through one anterior vaginal incision. METHODS: In a prospective study, patients treated for urogenital prolapse at a center in France between February 2008 and June 2011 were enrolled. Previous treatments, related interventions, intraoperative and postoperative complications, and anatomic outcomes were recorded during 3years of follow-up. Failure was defined as recurrence of prolapse of stage II or higher according to the Pelvic Organ Prolapse Quantification system. RESULTS: Overall, 74 patients were included. Preoperatively, 55 (74%) patients had stage III cystocele, 13 (18%) had stage IV cystocele, and 44 (59%) had associated uterine prolapse of at least stage II. Postoperative hematoma occurred in three patients and vaginal exposure in two patients. There were no cases of visceral injury. Vaginal comfort improved postoperatively: 68 (92%) patients were satisfied with the outcome and there were no cases of de novo dyspareunia. Seventeen (23%) patients subsequently had stress urinary incontinence that was treated by placement of suburethral tape. The anatomic outcomes were satisfactory for 72 (97%) women, including sexually active patients. CONCLUSION: Transvaginal prolapse repair by placement of an anteroposterior six-strap 22-g/m(2) mesh was feasible and effective with satisfactory 3-year outcomes. PMID- 26971261 TI - Use of risk of malignancy index to indicate frozen section analysis in the surgical care of women with ovarian tumors. AB - OBJECTIVE: To evaluate the importance of the risk of malignancy index (RMI) in the decision to perform frozen section analysis among women with ovarian tumors. METHODS: A retrospective study was conducted in 11 centers in the Netherlands. Women who underwent surgical treatment of an ovarian mass with unknown histology between January 2005 and September 2009 were included. The RMI was calculated retrospectively. Frozen section analysis and RMI values were assessed for patients with benign, borderline, and malignant ovarian tumors on final histopathology. RESULTS: Overall, 670 women were included. Frozen sections were performed in 323 (48.2%) patients, of whom 206 (63.8%) were diagnosed with benign ovarian tumors, 55 (17.0%) with borderline tumors, and 62 (19.2%) with malignant tumors. Overall, 109 (16.3%) women had an RMI below 20, 106 (97.2%) of whom had benign histology results. Among 235 patients with an RMI over 100, 3 (1.3%) postmenopausal women had malignancies that were missed because frozen sections were not performed. CONCLUSION: Women with an RMI below 20 have a low risk of malignancy and therefore do not require frozen section analysis. Postmenopausal women with an RMI greater than 100 should be referred to centers where frozen sections can be performed, and proper facilities and expertise are available to perform staging procedures if necessary. PMID- 26971262 TI - The Helicobacter pylori Cag Pathogenicity Island Protein Cag1 is Associated with the Function of T4SS. AB - The human pathogen Helicobacter pylori is involved in gastric diseases ranging from gastritis to gastric cancer. Virulent strains harboring the cag pathogenicity island (cag PAI) which encode a Type IV Secretion System (T4SS) can induce pro-inflammatory cytokines such as interleukin-8 and deliver their major effector proteins CagA into the gastric cells. While a subset of cag PAI genes have been identified to be the homologues of T4SS genes from Agrobacterium tumefaciens, a majority have unknown functions. We have identified one of such proteins, Cag1, which was predicted to be a non-classically secreted and virulent protein. Our results showed that Cag1 is a membrane-associated protein essential for the induction of multiple cytokine secretions, and cag1-deficient mutant has partial influence on CagA translocation; while the protein itself was not injected into host cells. Our data indicated that Cag1 is located in the bacterial membrane and is associated with the function of T4SS. PMID- 26971263 TI - Antimicrobial prophylaxis to prevent surgical site infection in adolescent idiopathic scoliosis patients undergoing posterior spinal fusion: 2 doses versus antibiotics till drain removal. AB - PURPOSE: There is much variation in the choice, timing and duration of antimicrobial prophylaxis for preventing surgical site infections (SSI) but no guideline exists for scoliosis surgery. The aim of study was to compare the efficacy of two antimicrobial prophylaxis (AMP) protocols with cephazolin in preventing SSI in adolescent idiopathic scoliosis (AIS). METHODS: A retrospective comparative analysis of two post-operative AMP protocols (two postoperative doses versus continued antibiotics till drain removal) was performed. Patient characteristics, pre-operative, intra- and post-operative risk factors for infection, drain use, generic drug name and number of doses administered were recorded from 226 patients with AIS who had undergone posterior spinal fusion. Details of superficial or deep SSI and wound healing aberrations, and serious adverse events were recorded. Analysis was performed to evaluate differences in the pre-, intra- and post-operative variables between the two groups. RESULTS: 155 patients received 2 postoperative doses of AMP and 71 patients had antibiotics till drain removal. The average follow-up was 43 months. The overall rate of SSI was 1.7 % for the spine wound and 1.3 % for the iliac crest wound. 1.9 % of patients with 2 doses of AMP and 1.4 % of patients with antibiotics till drain removal had SSI. No adverse reactions attributable to cephazolin were observed. CONCLUSIONS: This is the first study on the AMP protocol in scoliosis surgery for SSI prevention. Results suggest that two doses of AMP are as effective as continued antimicrobial use until drain removal. Cephazolin appears to be effective and safe for prophylaxis. PMID- 26971265 TI - Barriers to access and utilization of eating disorder treatment among women. AB - Anorexia, bulimia, and other specified feeding or eating disorders (OSFED) are psychiatric disorders recognized in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). One difference of eating disorders compared to other psychiatric disorders is the physical effects of the disease. Although anorexia is easier to physically detect than bulimia and OSFED, many women remain undiagnosed and untreated. Even if an eating disorder is recognized by the individual, barriers to clinical diagnosis and treatment persist. This study examines the barriers to treatment among women with anorexia, bulimia, and OSFED using Andersen's Behavioral Model. The physical, psychological, and personality trait differences among the eating disorder subgroups may affect treatment utilization and access. PMID- 26971264 TI - The analysis of antioxidant expression during muscle atrophy induced by hindlimb suspension in mice. AB - Oxidative stress contributes to acceleration of muscle atrophy. However, it is still not completely understood what triggers the production of reactive oxygen species (ROS) during muscle atrophy. The objective of this study was to investigate redox balance during muscle atrophy. ROS generators and antioxidants were analyzed in atrophied soleus muscles after 2 weeks of hindlimb suspension (HLS) in mice. The HLS group showed an increase in lipid peroxidation, upregulated NOX1 and NOXO1, and downregulated mitochondrial complex I subunits NDUFS5 and NDUFV2. Additionally, HLS mice demonstrated a decrease in Prdx5 and MnSOD, but an increase in GPX2 and GPX3 in both mRNA and protein levels. As expected, MnSOD activity declined in the HLS group, while GPX activity was enhanced. These results suggest that redox imbalance occurs during muscle atrophy through NOX1 activation, mitochondrial complex I deficiency, and disturbance of antioxidants. Antioxidants altered by HLS may represent potential therapeutic targets for the protection against muscle atrophy. PMID- 26971267 TI - Measuring long radiographs affects the positioning of femoral components in total knee arthroplasty: a randomized controlled trial. AB - INTRODUCTION: The aim of this study was to investigate if preoperative measurements of the femoral valgus angle (FVA) affected the mechanical alignment, individual component positions and clinical outcome in total knee arthroplasty (TKA). METHODS: 120 patients were randomized into two groups. In one group (control), a fixed FVA for the intramedullary femoral guide was set at 7 degrees , whereas in the other group (measured) FVA was measured preoperatively on long hip-knee-ankle radiographs, and the angle for the distal femoral cut was set accordingly. Preoperatively and 1 year after TKA, range of motion (ROM) and Knee Society Score (KSS) were assessed. Postoperatively, the coronal alignments of the components and the mechanical alignment were measured comparing the rate of outliers which deviated more than 3 degrees from the neutral mechanical axis. RESULTS: 104 patients remained for the radiological analysis (52 in each group). There were no significant differences either in the mean preoperative or postoperative mechanical alignment, or femoral or tibial component alignment; also, there were no differences in the number of postoperative mechanical axis or tibial component alignment outliers. However, the number of femoral component alignment outliers was significantly higher in the control group. 97 patients were available for clinical outcome analysis. Preoperatively, the groups did not differ significantly with respect to KSS or ROM. The postoperative ROM and KSS functional subscale scores were similar between the groups. However, there was slightly but significantly better postoperative KSS objective subscale score in the measured group. CONCLUSIONS: Preoperative FVA measurement and following femoral distal cut adjustments did not affect overall leg alignment postoperatively, while positioning of femoral component was improved together with minor improvements in objective KSS subscale scores. PMID- 26971268 TI - Could 'Aunties' Recruit Pregnant Indigenous Women Who Smoke Into a Trial and Deliver a Cessation Intervention? A Feasibility Study. AB - Objective Maori (indigenous New Zealand) women have the highest smoking prevalence rates in New Zealand and whilst pregnant. We hypothesized that community health workers ('Aunties') could find pregnant Maori women who smoke, recruit them into a study and deliver an acceptable cessation intervention. The aim of the study was to test the feasibility of such an intervention. Method A community health organization was engaged to, using a participatory approach, conduct a feasibility study. Participants were ten Aunties and the pregnant women the Aunties recruited. The Aunties advised their participants to abstain from smoking, offered a Quitcard (for subsidized nicotine replacement) or referral to local cessation providers. A booklet on healthy eating for pregnancy was given and discussed and the Aunties offered help if needed to register with a lead maternity carer (LMC). All women completed a baseline questionnaire. Semi structured follow up face-to-face interviews were conducted with a subsample of women and hospital birth records were examined. Descriptive statistics were produced using quantitative data. Qualitative data was deductively analysed. Results During 4 months eight Aunties recruited 67 pregnant women who smoked, 88 % were Maori, 84 % were of low socio economic status and 73 % had up to high school education. Only 36 % of the recruited women had registered with an LMC. The participants described the Aunties as supportive, nice and non-judgmental. The only criticism was a lack of follow up. Aspects of the intervention that the Aunties thought worked well were knowing and being involved with their community, and being able to give a gift pack to the participating women. Insufficient follow up was one aspect that didn't work well. The infant's birth record was found for 54 % of the participants. Conclusion Aunties were able to identify and recruit pregnant Maori women who smoked. The study method and intervention were acceptable to Aunties and participants and it was feasible to collect data from the participants' hospital birth records. Based on this study, with a similar number of Aunties recruiting, it would take 2 years to recruit over 300 participants, which would be sufficient for a stronger controlled trial. PMID- 26971266 TI - Predicting adolescent postpartum caregiving from trajectories of depression and anxiety prior to childbirth: a 5-year prospective study. AB - Symptoms of depression and anxiety in pregnancy have been linked to later impaired caregiving. However, mood symptoms are often elevated in pregnancy and may reflect motherhood-specific concerns. In contrast, little is known about the effects of prepregnancy depression and anxiety on postpartum caregiving. Understanding these developmental risk factors is especially important when childbearing also occurs during adolescence. The sample comprised 188 adolescent mothers (ages 12-19 years) who had participated in a longitudinal study since childhood. Mothers were observed in face-to-face interaction with the infant at 4 months postpartum, and caregiving behaviors (sensitivity, hostile-intrusive behavior, and mental state talk) were coded independently. Data on self-reported depression and anxiety gathered in the 5 years prior to childbirth were drawn from the large-scale longitudinal study. Parallel process latent growth curve models revealed unique effects of distal anxiety and slow decline in anxiety over time on lower levels of maternal mental state talk after accounting for the overlap with depression development. Depressive symptoms showed significant stability from distal measurement to the postpartum period, but only concurrent postpartum mood was associated with poorer quality of maternal speech. The results highlight specific targets for well-timed preventive interventions with vulnerable dyads. PMID- 26971269 TI - Association Between Low Dairy Intake During Pregnancy and Risk of Small-for Gestational-Age Infants. AB - Background Inadequate maternal nutrition is regarded as one of the most important indicators of fetal growth. The aim of this study was to analyze the associated risk of having a small for gestational age (SGA) infant according to the mother's dairy intake during the first half of pregnancy. Methods A prospective cohort study was performed using 1175 healthy pregnant women selected from the catchment area of Virgen de las Nieves University Hospital, Granada (Spain). SGA was defined as neonates weighing less than the 10th percentile, adjusted for gestational age. Factors associated with SGA were analyzed using logistic regression models. Population attributable fractions of SGA according to dairy intake were estimated. Results Dairy intake among women who gave birth to SGA infants was 513.9, versus 590.3 g/day for women with appropriate size for gestational age infants (P = 0.003). An increased intake of dairy products by 100 g/day during the first half of pregnancy decreased the risk of having a SGA infant by 11.0 %, aOR = 0.89 (0.83, 0.96). A dose-response gradient between dairy intake and SGA was observed. Conclusions An inadequate intake of dairy products is associated with a higher risk of SGA. Our results suggest a possible causal relation between dairy intake during pregnancy and the weight of the newborn, although we cannot discard residual confounding. These results should be further supported by properly designed studies. PMID- 26971270 TI - Access to Money and Relation to Women's Use of Family Planning Methods Among Young Married Women in Rural India. AB - Objectives The social positioning (i.e. social status and autonomy) of women in the household facilitates women's access to and decision-making power related to family planning (FP). Women's access to spending money, which may be an indicator of greater social positioning in the household, may also be greater among women who engage in income generating activities for their families, regardless of women's status in the household. However, in both scenarios, access to money may independently afford greater opportunity to obtain family planning services among women. This study seeks to assess whether access to money is associated with FP outcomes independently of women's social positioning in their households. Methods Using survey data from married couples in rural Maharashtra, India (n = 855), crude and adjusted regression was used to assess women's access to their own spending money in relation to past 3 month use of condoms and other forms of contraceptives (pills, injectables, intrauterine device). Results Access to money (59 %) was associated with condom and other contraceptive use (AORs ranged 1.5 1.8). These findings remained significant after adjusting for women's FP decision making power in the household and mobility to seek FP services. Conclusion While preliminary, findings suggest that access to money may increase women's ability to obtain FP methods, even in contexts where social norms to support women's power in FP decision-making may not be readily adopted. PMID- 26971271 TI - Detection of novel polymorphisms in the ckit gene of canine patients with lymphoma, melanoma, haemangiosarcoma, and osteosarcoma. AB - Tyrosine kinase inhibitors (TKIs) that specifically target cKIT represent a therapeutic approach for non-resectable canine mast cell tumours (MCTs) grade II/III. The therapeutic benefit of TKIs has been investigated in other tumours based on clinical response rates and identification of gain-of-function mutations. In the present study, cKIT expression in 14 dogs with osteosarcoma, melanoma, haemangiosarcoma, lymphoma, and fibrosarcoma was analysed. Tissue samples were used for cKIT sequencing to (I) detect the cKIT transcript and to (II) identify gain-of-function mutations. The cKIT transcript was detected in ten patients. Four novel amino acid substitutions and five silent polymorphisms were identified. Furthermore, an insertion mutation (GNSK) was discovered in the tissue, but not in the blood sample of one dog. CKIT expression was identified in a variety of canine tumours and, therefore, TKIs might have a broader therapeutic indication apart from treatment of MCTs. Further investigations will be necessary to localize the cKIT protein in the respective tumours and to evaluate the functional consequence of the cKIT variants identified in the present study. PMID- 26971272 TI - Fluorescence turn-on and colorimetric dual readout assay of glutathione over cysteine based on the fluorescence inner-filter effect of oxidized TMB on TMPyP. AB - Quantitative fluorescence turn-on and colorimetric detection of glutathione (GSH) with rapid speed, low cost have attained much attention. Herein, we developed a sensitive fluorescence turn-on and colorimetric sensor for GSH based on the inner filter effect (IFE), which is the first time to select oxTMB and TMPyP as the IFE absorber and fluorophore pair, respectively. The absorption band of oxTMB matches well with the emission band of TMPyP in the IFE-based fluorescent assay. In the absence of GSH, the absorption peak of oxTMB at 652nm significantly overlaps with the emission of TMPyP, resulting in the efficient IFE and inhibition of the fluorescence of TMPyP. In the presence of GSH, the absorption intensity at 652nm decreases, generating the recovery of the fluorescence of TMPyP. Therefore, this approach is demonstrated to be a novel candidate for detection of GSH, with high sensitivity and selectivity. The linear dynamic range for the concentrations of GSH is between 0.1MUM to 20MUM along with a limit of detection (LOD) of about 30nM (calculated LOD as 3sigma/slope). Finally, this novel sensor was successfully applied for GSH detection in fetal calf serum, and satisfactory recovery was achieved. PMID- 26971273 TI - Selective ciprofloxacin antibiotic detection by fluorescent siderophore pyoverdin. AB - Fluorescent siderophore pyoverdin (PVD) was produced from a soil isolate Pseudomonas monteilii strain MKP 213. The PVD was purified near to homogeneity and applied for the fluorescent chemosensing of various antibiotics in aqueous solution (pH=7.0). Upon addition of ciprofloxacin, PVD showed new UV-vis absorption bands at 252 and 321nm due to an internal charge transfer mechanism. Also, the addition of ciprofloxacin induced a highly selective fluorescence enhancement of PVD with a 13nm blue shift from 458 to 445nm. The combination of a long peptide chain along with the chromophore unit of PVD generates a converging cleft for ciprofloxacin recognition with LOD and LOQ of 7.13MUM and 21.6MUM, respectively without interference from other studied antibiotics. The association constant (Ka) of PVD with ciprofloxacin was calculated to be as low as 1.40*10(5)M(-1) using Benesi-Hildebrand plot depicting its significance in detection. The pharmaceutical tablet analysis measures the sensing with negligible matrix effect and quantitative recovery. PMID- 26971274 TI - Dual-excitation upconverting nanoparticle and quantum dot aptasensor for multiplexed food pathogen detection. AB - In this report, a dual-excitation sensing method was developed using aptamer functionalized quantum dots and upconverting nanoparticles, exhibiting Stokes and anti-Stokes type excitation profiles, respectively. Conjugation of the aptamer functionalized luminescent nanoparticles with the magnetic beads, comprising short DNA sequences that were partially complementary to the aptamer sequences, enabled facile separation of the analyte-free conjugates for fluorescent measurement. UV-Visible spectroscopy, Circular Dichroism spectroscopy, Dynamic Light Scattering and Polyacrylamide Gel Electrophoresis techniques were used to characterize the aptamer probes developed. The target-specific luminescent conjugates were applied for multiplex detection of model food pathogens, Salmonella typhimurium, and Staphylococcus aureus, in which the fluorescent emission spectra were obtained under UV excitation at 325nm for quantum dots and NIR excitation at 980nm for upconverting nanoparticles, respectively. The dual excitation strategy was aimed to minimize cross-talk between the luminescent signals for multiplexed detection, and yielded limit of detection values of 16 and 28cfumL(-1) for Staphylococcus aureus, and Salmonella typhimurium, respectively. By employing a greater number of quantum dots and upconverting nanoparticles with non-overlapping fluorescent emissions, the proposed methodology might be exploited further to detect several analytes, simultaneously. PMID- 26971277 TI - Synergistic antimicrobial effect of photodynamic therapy and ciprofloxacin. AB - The occurrence of a variety of pathogens resistant to current antibiotics remains the major problem in medical care, especially when bacterial infections are established as biofilms. In this study, we propose the use of photodynamic therapy (PDT) as a monotherapy and associated with antibiotic as an alternative treatment. The aim of this study was to analyze the effects of PDT mediated by methylene blue (MB) on Staphylococcus aureus (ATCC 25923) and Escherichia coli (ATCC 25922) in both biofilm and planktonic phases. Several concentrations of MB and light doses were tested. The bactericidal effects of PDT as a monotherapy did not increase with the concentration of photosensitizer, but were light dose dependent. In addition, bacteria in biofilms were less affected than cells in the planktonic phase. Although not concentration-dependent, the disruption effect of PDT on biofilms was clearly illustrated by scanning electron microscopy (SEM). We also carried out experiments that evaluated the synergistic effect of photodynamic therapy and the antibiotic ciprofloxacin. The best results were obtained after combination treatment of photodynamic therapy followed by ciprofloxacin on biofilms, which increased bacterial reduction on biofilms, resulting in a 5.4 log reduction for S. aureus biofilm and approximately 7 log for E. coli biofilm. PMID- 26971276 TI - Prevention of pelvic floor disorders: international urogynecological association research and development committee opinion. AB - INTRODUCTION AND HYPOTHESIS: Pelvic floor disorders (PFD), including urinary incontinence, anal incontinence, and pelvic organ prolapse, are common and have a negative effect on the quality of life of women. Treatment is associated with morbidity and may not be totally satisfactory. Prevention of PFDs, when possible, should be a primary goal. The purpose of this paper is to summarise the current literature and give an evidence-based review of the prevention of PFDs METHODS: A working subcommittee from the International Urogynecological Association (IUGA) Research and Development (R&D) Committee was formed. An initial document addressing the prevention of PFDs was drafted, based on a review of the English language literature. After evaluation by the entire IUGA R&D Committee, revisions were made. The final document represents the IUGA R&D Committee Opinion on the prevention of PFDs. RESULTS: This R&D Committee Opinion reviews the literature on the prevention of PFDs and summarises the findings with evidence-based recommendations. CONCLUSIONS: Pelvic floor disorders have a long latency, and may go through periods of remission, thus making causality difficult to confirm. Nevertheless, prevention strategies targeting modifiable risk factors should be incorporated into clinical practice before the absence of symptomatology. PMID- 26971279 TI - Scrutinizing the DNA damaging and antimicrobial abilities of triazole appended metal complexes. AB - New mononuclear transition metal complexes 1-12 bearing the bioactive triazole analogues were synthesized and characterized by elemental analysis and spectroscopic techniques. The interaction of calf thymus DNA (CT-DNA) with the synthesized compounds was studied at physiological pH by spectrophotometric, spectrofluorometric, cyclic voltammetry, and viscometric techniques. The entire DNA binding results suggested the intercalative mode of binding for the synthesized compounds. Interestingly, the binding strength of the complexes is found to be greater than that of the free ligands. Among the complexes explored, complex 5 reveals strong hypochromism and a slight red shift as compared to the other complexes highlighting its higher DNA binding propensity. The intrinsic binding constant values of the complexes compared to cisplatin reveal that all the complexes are greater in magnitude than that of cisplatin. Fluorescence titrations show that the Cu(II) complexes have the ability to displace DNA-bound ethidium bromide. Also, these compounds induce cleavage in pBR322 plasmid DNA as indicated in gel electrophoresis and exhibit excellent nuclease activity in the presence of H2O2. Moreover, the complexes were screened for in vitro antimicrobial activity along with free ligands and solvent control. The outcome is that the complexes possess good activity than the free ligands. These complexes may have further scope in developing them into antimicrobial drugs and DNA probes. PMID- 26971278 TI - Apoptosis induction is involved in UVA-induced autolysis in sea cucumber Stichopus japonicus. AB - Autolysis easily happens to sea cucumber (Stichopus japonicus, S. japonicus) for external stimulus like UV exposure causing heavy economic losses. Therefore, it is meaningful to reveal the mechanism of S. japonicas autolysis. In the present study, to examine the involvement of apoptosis induction in UVA-induced autolysis of S. japonicas, we investigated the biochemical events including the DNA fragmentation, caspase-3 activation, mitogen-activated protein kinases (MAPKs) phosphorylation and free radical formation. Substantial morphological changes such as intestine vomiting and dermatolysis were observed in S. japonicus during the incubation after 1-h UVA irradiation (10W/m(2)). The degradation of the structural proteins and enhancement of cathepsin L activity were also detected, suggesting the profound impact of proteolysis caused by the UVA irradiation even for 1h. Furthermore, the DNA fragmentation and specific activity of caspase-3 was increased up to 12h after UVA irradiation. The levels of phosphorylated p38 mitogen activated protein kinase (MAPK) and phosphorylated c-Jun.-N-terminal kinase (JNK) were significantly increased by the UVA irradiation for 1h. An electron spin resonance (ESR) analysis revealed that UVA enhanced the free radical formation in S. japonicas, even through we could not identify the attributed species. These results suggest that UVA-induced autolysis in S. japonicas at least partially involves the oxidative stress-sensitive apoptosis induction pathway. These data present a novel insight into the mechanisms of sea cucumber autolysis induced by external stress. PMID- 26971280 TI - Mechanism of inhibition and decoupling of oxygen evolution from electron transfer in photosystem II by fluoride, ammonia and acetate. AB - Ca(2+) extraction from oxygen-evolving complex (OEC) of photosystem II (PSII) is accompanied by decoupling of oxygen evolution/electron transfer processes [Semin et al. Photosynth. Res. 98 (2008) 235] and appearance of a broad EPR signal at g=2 (split "S3" signal) what can imply the relationship between these effects. Split signal have been observed not only in Ca-depleted PSII but also in PSII membranes treated by fluoride anions, sodium acetate, and NH4Cl. Here we investigated the question: can such compounds induce the decoupling effect during treatment of PSII like Ca(2+) extraction does? We found that F(-), sodium acetate, and NH4Cl inhibit O2 evolution in PSII membranes more effectively than the reduction of artificial electron acceptor 2,6-dichlorophenolindophenol, i.e. the action of these compounds is accompanied by decoupling of these processes in OEC. Similarity of effects observed after Ca(2+) extraction and F(-), CH3COO(-) or NH4Cl treatments suggests that these compounds can inactivate function of Ca(2+). Such inactivation could originate from disturbance of the network of functionally active hydrogen bonds around OEC formed with participation of Ca(2+). This inhibition effect is observed in the region of low concentration of inhibitors. Increasing of inhibitor concentration is accompanied by appearance of other sites of inhibition. PMID- 26971281 TI - Right iliac fossa lymphoma in an HIV positive patient: A diagnostic dilemma. AB - Lymphoma should be considered early in patients with HIV when there is a history of weight loss. Although B-cell lymphoma is an AIDS-defining cancer, and many reports of lymphoma in HIV positive patients exist in the literature, this case report illustrates that even in patients with well-controlled HIV the diagnosis must be considered, and puts forward an unusual presentation in an otherwise asymptomatic patient. A 52 year old woman presented for a routine HIV follow-up appointment and was found to be experiencing weight loss. An abdominal examination revealed a right iliac fossa mass. Subsequent CT thorax, abdomen, pelvis imaging confirmed a large mass but did not allow determination of the primary source. Serological tumour marker investigations were unyielding. Trans vaginal ultrasound guided biopsy of the mass demonstrated diffuse large B-cell lymphoma. This case report emphasises the importance of having a high index of suspicion for these cancers even in patients with low viral load who are on anti retroviral treatment. It also demonstrates the importance of taking a multidisciplinary approach to diagnosis of the condition to enable prompt treatment and thus improve the outcome for the patient. PMID- 26971282 TI - Splenic rupture following colonoscopy: Case report and literature review. AB - INTRODUCTION: Colonoscopy is a safe and routinely performed diagnostic and therapeutic procedure for colorectal diseases. Although bleeding and perforation are most common complications, extra colonic or visceral injuries have been described. Splenic rupture is rare with few cases reported in current literature. PRESENTATION OF CASE: We report the case of a 73-year old man who presented to surgical consultation 50h after colonoscopy. Clinical, laboratory and imaging findings were suggestive for haemoperitoneum. At surgery an almost complete splenic disruption was evident and urgent splenectomy was performed. DISCUSSION: Splenic injury following colonoscopy is exceptional, probably related to instrumental looping with excessive traction on the splenocolic ligament. In patients with an early presentation a sudden onset of symptoms is the rule. By contrast a delayed presentation (>48h) is nonspecific and subtle with arduous diagnosis. CONCLUSION: Awareness of this potential complication, high level of suspicion and prompt treatment are at the basis of better outcomes in such patients. PMID- 26971284 TI - The Meaning of 'Regular Partner' in HIV Research Among Gay and Bisexual Men: Implications of an Australian Cross-Sectional Survey. AB - Estimates of the proportion of HIV infections coming from within regular sexual relationships among gay and bisexual men (GBM) vary widely. Research surveys use various partner type categories, but there is little understanding of how men classify their partners. We conducted an online cross-sectional survey of Australian GBM exploring sexual relationships, including 2057 men reporting on 2566 regular partnerships. Just over half of the partnerships were considered 'relationships', while the remainder were non-romantic 'fuckbuddy'-style arrangements. In multivariable analysis, factors associated with considering the partnership a 'relationship' were: using a 'romantic' descriptor, partnership length, monogamous agreements, any condomless anal sex with each other, love, and commitment. The category of 'regular partner' can mask diverse partnership types, which have different meanings to GBM, associated behaviours, and HIV risks. Certain HIV prevention techniques may be more suited to particular types of partnerships. 'Fuckbuddy' arrangements need to be more explicitly acknowledged in HIV prevention. PMID- 26971283 TI - An ethylene response-related factor, GbERF1-like, from Gossypium barbadense improves resistance to Verticillium dahliae via activating lignin synthesis. AB - An ethylene response-related factor, GbERF1-like, from Gossypium barbadense cv. '7124' involved in the defence response to Verticillium dahliae was characterized. GbERF1-like transcripts present ubiquitously in various tissues, with higher accumulation in flower organs. GbERF1-like was also responsive to defence-related phytohormones and V. dahliae infection. The downregulation of GbERF1-like increased the susceptibility of cotton plants to V. dahliae infection, while overexpression of this gene improved disease resistance in both cotton and Arabidopsis, coupled with activation of the pathogenesis-related proteins. Further analysis revealed that genes involved in lignin synthesis, such as PAL, C4H, C3H, HCT, CCoAOMT, CCR and F5H, showed higher expression levels in the overexpressing cotton and Arabidopsis lines and lower expression levels in the RNAi cotton lines. The expression levels of these genes increased obviously when the GbERF1-like-overexpressing plants were inoculated with V. dahliae. Meanwhile, significant differences in the content of whole lignin could be found in the stems of transgenic and wild-type plants after inoculation with V. dahliae, as revealed by metabolic and histochemical analysis. More lignin could be detected in GbERF1-like-overexpressing cotton and Arabidopsis but less in GbERF1-like-silencing cotton compared with wild-type plants. The ratio of S and G monomers in GbERF1-like-overexpressing cotton and Arabidopsis increased significantly after infection by V. dahliae. Moreover, our results showed that the promoters of GhHCT1 and AtPAL3 could be transactivated by GbERF1-like in vivo based on yeast one-hybrid assays and dual-luciferase reporter assays. Knockdown of GhHCT1 in GbERF1-like over-expressing cotton decreases resistance to V. dahliae. Collectively, our results suggest that GbERF1-like acts as a positive regulator in lignin synthesis and contributes substantially to resistance to V. dahliae in plants. PMID- 26971287 TI - Reprint of "Advocating new Directions". PMID- 26971285 TI - Explanatory Models and Illness Experience of People Living with HIV. AB - Research into explanatory models of disease and illness typically explores people's conceptual understanding, and emphasizes differences between patient and provider models. However, the explanatory models framework of etiology, time and mode of onset of symptoms, pathophysiology, course of sickness, and treatment is built on categories characteristic of biomedical understanding. It is unclear how well these map onto people's lived experience of illness, and to the extent they do, how they translate. Scholars have previously studied the experience of people living with HIV through the lenses of stigma and identity theory. Here, through in-depth qualitative interviews with 32 people living with HIV in the northeast United States, we explored the experience and meanings of living with HIV more broadly using the explanatory models framework. We found that identity reformation is a major challenge for most people following the HIV diagnosis, and can be understood as a central component of the concept of course of illness. Salient etiological explanations are not biological, but rather social, such as betrayal, or living in a specific cultural milieu, and often self-evaluative. Given that symptoms can now largely be avoided through adherence to treatment, they are most frequently described in terms of observation of others who have not been adherent, or the resolution of symptoms following treatment. The category of pathophysiology is not ordinarily very relevant to the illness experience, as few respondents have any understanding of the mechanism of pathogenesis in HIV, nor much interest in it. Treatment has various personal meanings, both positive and negative, often profound. For people to engage successfully in treatment and live successfully with HIV, mechanistic explanation is of little significance. Rather, positive psychological integration of health promoting behaviors is of central importance. PMID- 26971286 TI - How endogenous plant pararetroviruses shed light on Musa evolution. AB - BACKGROUND AND AIMS: Banana genomes harbour numerous copies of viral sequences derived from banana streak viruses (BSVs) - dsDNA viruses belonging to the family Caulimoviridae.These viral integrants (eBSVs) are mostly defective, probably as a result of 'pseudogenization' driven by host genome evolution. However, some can give rise to infection by releasing a functional viral genome following abiotic stresses. These distinct infective eBSVs correspond to the three main widespread BSV species (BSOLV, BSGFV and BSIMV), fully described within the Musa balbisiana B genomes of the seedy diploid 'Pisang Klutuk Wulung' (PKW). METHODS: We characterize eBSV distribution among a Musa sampling including seedy BB diploids and interspecific hybrids with Musa acuminate exhibiting different levels of ploidy for the B genome (ABB, AAB, AB). We used representative samples of the two areas of sympatry between M. acuminate and M. balbisiana species representing the native area of the most widely cultivated AAB cultivars (in India and in East Asia, ranging from the Philippines to New Guinea). Seventy-seven accessions were characterized using eBSV-related PCR markers and Southern hybridization approaches. We coded both sets of results to create a common dissimilarity matrix with which to interpret eBSV distribution. KEY RESULTS: We propose a Musa phylogeny driven by the M. balbisiana genome based on a dendrogram resulting from a joint neighbour-joining analysis of the three BSV species, showing for the first time lineages between BB and ABB/AAB hybrids. eBSVs appear to be relevant phylogenetic markers that can illustrate theM. balbisiana phylogeography story. CONCLUSION: The theoretical implications of this study for further elucidation of the historical and geographical process of Musa domestication are numerous. Discovery of banana plants with B genome non-infective for eBSV opens the way to the introduction of new genitors in programmes of genetic banana improvement. PMID- 26971288 TI - Toxic hepatitis due to a food supplement: "Natural" is no synonym for "harmless". AB - BACKGROUND/AIMS: Herbal products are increasingly used in modern medicine for numerous indications. They are not considered as drugs and thus often not linked to side effects. MATERIAL: A 77-year-old patient presented with silent icterus and biochemical evidence of hepatocellular damage. Because of dyslipidaemia, he was recently prescribed Controchol((r)), a food supplement containing red yeast and green tea extracts. RESULTS: Liver biopsy showed necro-inflammatory destruction of liver parenchym, collapse of reticulin matrix, cholestasis and gall duct damage, compatible with toxic hepatitis. After discontinuation of Controchol((r)), there was a gradual normalisation of the liver function tests. Liver injury is a known side effect of both red yeast and green tea extracts. After exclusion of other causes, we therefore concluded our patient had suffered from Controchol((r))-induced toxic hepatitis. CONCLUSION: Products that are conceived as "natural" alternatives for pharmacological drugs, like food supplements, are not free of side effects per se, and should not be considered as "harmless". PMID- 26971289 TI - Characterization of class II beta chain major histocompatibility complex genes in a family of Hawaiian honeycreepers: 'amakihi (Hemignathus virens). AB - Hawaiian honeycreepers (Drepanidinae) have evolved in the absence of mosquitoes for over five million years. Through human activity, mosquitoes were introduced to the Hawaiian archipelago less than 200 years ago. Mosquito-vectored diseases such as avian malaria caused by Plasmodium relictum and Avipoxviruses have greatly impacted these vulnerable species. Susceptibility to these diseases is variable among and within species. Due to their function in adaptive immunity, the role of major histocompatibility complex genes (Mhc) in disease susceptibility is under investigation. In this study, we evaluate gene organization and levels of diversity of Mhc class II beta chain genes (exon 2) in a captive-reared family of Hawaii 'amakihi (Hemignathus virens). A total of 233 sequences (173 bp) were obtained by PCR+1 amplification and cloning, and 5720 sequences were generated by Roche 454 pyrosequencing. We report a total of 17 alleles originating from a minimum of 14 distinct loci. We detected three linkage groups that appear to represent three distinct haplotypes. Phylogenetic analysis revealed one variable cluster resembling classical Mhc sequences (DAB) and one highly conserved, low variability cluster resembling non-classical Mhc sequences (DBB). High net evolutionary divergence values between DAB and DBB resemble that seen between chicken BLB system and YLB system genes. High amino acid identity among non-classical alleles from 12 species of passerines (DBB) and four species of Galliformes (YLB) was found, suggesting that these non-classical passerine sequences may be related to the Galliforme YLB sequences. PMID- 26971290 TI - Effects of Common Polymorphisms in the MTHFR and ACE Genes on Diabetic Peripheral Neuropathy Progression: a Meta-Analysis. AB - Diabetic peripheral neuropathy (DPN) is a microvascular complication of diabetes mellitus. The aim of this meta-analysis was to evaluate the effects of methylenetetrahydrofolate reductase (MTHFR) 677 C>T and ACE I/D polymorphisms in the development of DPN. We systematically reviewed published studies on MTHFR 677 C>T and ACE I/D polymorphisms and DPN found in various types of electronic databases. Strengthening the Reporting of Observational studies in Epidemiology (STROBE) quality score systems were used to determine the quality of the articles selected for inclusion. Odds ratios (ORs) and its corresponding 95 % confidence interval (95 % CI) were calculated. We used STATA statistical software (version 12.0, Stata Corporation, College Station, TX, USA) to deal with statistical data. Our results indicated an association of ACE D>I mutation (OR = 1.43, 95 % CI 1.12 1.83, P = 0.004) and MTHFR 677 C>T mutation (OR = 1.43, 95 % CI 1.08-1.90, P = 0.014) with DPN under the allele model, and similar results were also found under the dominant model (all P < 0.05). Subgroup analysis by country indicated that the MTHFR 677 C>T polymorphism may be the main risk factor for DPN in Turkey under four genetic models. ACE D>I mutation was correlated with DPN in Japanese and Pakistani populations in the majority of groups. The relationships of MTHFR 677 C>T and ACE I/D polymorphisms with DPN patients presented in this meta analyses support the view that the MTHFR and ACE genes might play an important role in the development of DPN. PMID- 26971292 TI - Impaired alphaGDI Function in the X-Linked Intellectual Disability: The Impact on Astroglia Vesicle Dynamics. AB - X-linked non-syndromic intellectual disability (XLID) is a common mental disorder recognized by cognitive and behavioral deficits. Mutations in the brain-specific alphaGDI, shown to alter a subset of RAB GTPases redistribution in cells, are linked to XLID, likely via changes in vesicle traffic in neurons. Here, we show directly that isolated XLID mice astrocytes, devoid of pathologic tissue environment, exhibit vesicle mobility deficits. Contrary to previous studies, we show that astrocytes express two GDI proteins. The siRNA-mediated suppression of expression of alphaGDI especially affected vesicle dynamics. A similar defect was recorded in astrocytes from the Gdi1 -/Y mouse model of XLID and in astrocytes with recombinant mutated human XLID alphaGDI. Endolysosomal vesicles studied here are involved in the release of gliosignaling molecules as well as in regulating membrane receptor density; thus, the observed changes in astrocytic vesicle mobility may, over the long time-course, profoundly affect signaling capacity of these cells, which optimize neural activity. PMID- 26971291 TI - Rapamycin Augments Immunomodulatory Properties of Bone Marrow-Derived Mesenchymal Stem Cells in Experimental Autoimmune Encephalomyelitis. AB - The immunomodulatory and anti-inflammatory properties of bone marrow-derived mesenchymal stem cells (BM-MSCs) have been considered as an appropriate candidate for treatment of autoimmune diseases. Previous studies have revealed that treatment with BM-MSCs may modulate immune responses and alleviate the symptoms in experimental autoimmune encephalomyelitis (EAE) mice, an animal model of multiple sclerosis. Therefore, the present study was designed to examine immunomodulatory effects of BM-MSCs in the treatment of myelin oligodendrocyte glycoprotein (MOG) 35-55-induced EAE in C57BL/6 mice. MSCs were obtained from the bone marrow of C57BL mice, cultured with DMEM/F12, and characterized with flow cytometry for the presence of cell surface markers for BM-MSCs. Following three passages, BM-MSCs were injected intraperitoneally into EAE mice alone or in combination with rapamycin. Immunological and histopathological effects of BM MSCs and addition of rapamycin to BM-MSCs were evaluated. The results demonstrated that adding rapamycin to BM-MSCs transplantation in EAE mice significantly reduced inflammation infiltration and demyelination, enhanced the immunomodulatory functions, and inhibited progress of neurological impairments compared to BM-MSC transplantation and control groups. The immunological effects of rapamycin and BM-MSC treatments were associated with the inhibition of the Ag specific lymphocyte proliferation, CD8+ cytolytic activity, and the Th1-type cytokine (gamma-interferon (IFN-gamma)) and the increase of Th-2 cytokine (interleukin-4 (IL-4) and IL-10) production. Addition of rapamycin to BM-MSCs was able to ameliorate neurological deficits and provide neuroprotective effects in EAE. This suggests the potential of rapamycin and BM-MSC combined therapy to play neuroprotective roles in the treatment of neuroinflammatory disorders. PMID- 26971293 TI - Glioblastoma multiforme in patients with history of extracranial cancer: Case series. AB - OBJECTIVES: Significant progress in treatment strategies improves the expectations of patients with extracranial cancers. Metastases are the primary consideration in patients with cancer history. In the case of neurologic disorders, the patient should undergo brain MRI. A rationale is presented for surgery, whole-brain or stereotactic radiotherapy, or chemotherapy. Recently, we have encountered misdiagnosed primary malignant brain tumours in patients with oncologic history who had been admitted for surgery for brain metastases. The aim of our study is to evaluate the incidence of concurrent cancers, to assess the relationship between previous cancer staging and primary brain tumour evaluation as well as to determine treatment efficiency. METHODS: From January 2007 to December 2011, we prospectively followed up patients with concurrent history of both extracranial cancer and subsequent glioblastoma multiforme. Information was collected on the clinical condition, imaging, history of extracranial cancer, previous and present surgical and oncologic procedures, and GBM histologic, cytogenetic, and molecular genetic investigations. RESULTS: Five patients were recruited: three females and two males. The average patient age at the time of GBM diagnosis was 65.6 years. Three patients had a history of breast carcinoma, one of renal carcinoma and one of colorectal carcinoma. Following the diagnosis of carcinoma, three patients received chemotherapy and radiotherapy, one patient had radiotherapy alone, and one had no adjuvant therapy. In all the cases, surgery revealed primary GBM, with a standard occurrence of genetic abnormalities (Table 1). The average time from the diagnosis of extracranial cancer to that of GBM was 4 years. Four patients underwent chemoradiotherapy and one had palliative radiotherapy. Two patients completed oncotherapy and their OS was 27 months and 19 months, respectively. One patient had post-surgical progression of hemiparesis. One patient had pulmonary embolism during oncotherapy and one had paraplegia caused by a pathological fracture of vertebras T5 due to breast carcinoma metastases. The OS was 11.8 months (range 3-27 months). All the patients succumbed to GBM progression. PMID- 26971294 TI - Methods of intra-operative treatment of cranioplasty in patients with abnormal bone window flap pressure after decompressive craniectomy. AB - OBJECTIVE: This study was performed to investigate the method of cranioplasty in patients with abnormal bone window pressure after decompressive craniectomy. METHODS: We performed a retrospective analysis for 25 cases after decompressive craniectomy in patients with abnormal flap pressure of clinical data. RESULTS: Flap pressure increased in 15 cases, including 6 cases of hydrocephalus, 5 cases of contralateral subdural effusion, 2 cases of subdural effusion bone window, 2 cases of bone window cystic encephalomalacia communicating with the ventricle; Flap pressure decreased in 10 cases, including 6 cases of hydrocephalus after ventriculoperitoneal shunt, and 4 cases of low intracranial pressure. ALL of patients were treated by appropriate measures to make the operation smoothly. CONCLUSION: Our data suggest that after analysis of the factors for abnormal bone window flap pressure by decompressive craniectomy and symptomatic treatment, the difficulty of operation and operative complications can be reduced. PMID- 26971295 TI - Acute effects of intraventricular nicardipine on cerebral hemodynamics: A preliminary finding. AB - OBJECTIVE: Intraventricular nicardipine (IVTN) is a treatment option for severe vasospasm in patients with subarachnoid hemorrhage (SAH). However, its acute effects on cerebral hemodynamics have not been studied in detail. METHODS: Between June 2008 and December 2010, IVTN was administered (mainly 4mg every 8h) to 11 SAH patients (54 doses) with multimodality monitoring for refractory vasospasm. Retrospective analyses on physiological parameters were made from baseline and up to 6h after IVTN injection. Statistical analysis was performed with a mixed-effects model. RESULTS: Mean intracranial pressure (ICP) increased slightly, reaching its peak at 20min after IVTN injection (2.5+/-0.9mmHg (mean+/ standard error), P<0.01), and decreased gradually thereafter over the next hour. Mean cerebral perfusion pressure transiently decreased 20-30min after injection (3.7+/-1.8mmHg, P<0.05). Mean arterial pressure, partial pressure of brain oxygen tension (PbtO2), cerebral blood flow (CBF), autoregulation indices did not change significantly. Lactate/pyruvate ratio and glucose remained stable. One patient underwent transcranial Doppler ultrasonography monitoring while on IVTN, which showed a transient increase in mean flow velocity with concomitant decrease in Pulsatility index, suggesting vasodilation in the distal resistance vessels. CONCLUSIONS: The vasodilatory effect of IVTN transiently increased ICP, but did not significantly affect PbtO2, CBF or oxidative glucose metabolism in the immediate phase after injection. PMID- 26971296 TI - Genomics and epigenetics: A study of ependymomas in pediatric patients. AB - OBJECTIVE: We identify chromosomal alterations, the methylation pattern and gene expression changes in pediatric ependymomas. METHODS: CGH microarray, methylation and gene expression were performed through the Agilent platform. The results were analyzed with the software MatLab, MapViewer, DAVID, GeneCards and Hippie. RESULTS: Amplification was found in 14q32.33, 2p22.3 and 8p22, and deletion was found in 8p11.23-p11.22 and 1q21.3. We observed 42.387 CpG islands with changes in their methylation pattern, in which we found 272 genes involved in signaling pathways related to carcinogenesis. We found 481 genes with altered expression. The genes IMMT, JHDMD1D, ASAH1, ZWINT, IPO7, GNAO1 and CISD3 were found to be altered among the three levels. CONCLUSION: The 2p22.3, 8p11.23-p11.22 and 14q32.33 regions were identified as the most important; the changes in the methylation pattern related to cell cycle and cancer genes occurred in MIB2, FGF18 and ITIH5. The IPO7, GNAO1 and ASAH1 genes may play a major role in ependymoma development. PMID- 26971297 TI - Responses in sediment phosphorus and lanthanum concentrations and composition across 10 lakes following applications of lanthanum modified bentonite. AB - A combined field and laboratory scale study of 10 European lakes treated between 2006 and 2013 with a lanthanum (La) modified bentonite (LMB) to control sediment phosphorus (P) release was conducted. The study followed the responses in sediment characteristics including La and P fractions and binding forms, P adsorption capacity of discrete sediment layers, and pore water P concentrations. Lanthanum phosphate mineral phases were confirmed by solid state (31)P MAS NMR and LIII EXAFS spectroscopy. Rhabdophane (LaPO4 . nH2O) was the major phase although indications of monazite (LaPO4) formation were also reported, in the earliest treated lake. Molar ratios between La and P in the sediments were generally above 1, demonstrating excess La relative to P. Lanthanum was vertically mixed in the sediment down to a depth of 10 cm for eight of the ten lakes, and recovery of La in excess of 100% of the theoretical aerial load indicated translocation of the LMB towards the deepest areas of the lakes. Lanthanum was generally recovered from bed sediment samples following sequential chemical extraction from the HCl fraction. Soluble reactive P (SRP) release experiments on intact sediment cores indicated conditions of P retention (with the exception of two lakes) by sediments, indicating effective control of sediment P release, i.e. between two and nine years after treatment. PMID- 26971299 TI - Health-related physical fitness in patients with multiple myeloma or lymphoma recently treated with autologous stem cell transplantation. AB - OBJECTIVES: We aimed to examine health-related physical fitness and its demographic and clinical correlates in patients recently treated with autologous stem cell transplantation. DESIGN: Cross-sectional study. METHODS: In 109 patients (multiple myeloma: n=58, lymphoma: n=51, median age: 55, range: 19-67 years) maximal exercise testing was conducted to assess cardiorespiratory fitness (VO2peak). Upper and lower extremity muscle strength were assessed with hand grip and fixed dynamometry and body composition with whole body DXA scans. In addition, we assessed the patients' demographic and clinical characteristics and examined whether they were associated with health-related physical fitness. RESULTS: VO2peak was 21.7 (5.5) mL/min/kg, 26% below reference values. Muscle strength was also reduced when compared with reference values (upper extremity: 90%, lower extremity: 80%) and 73% of our population was classified as overweight or obese. Being female and being older were significantly associated with a lower cardiorespiratory fitness (gender: beta=-2.7, 95%CI=-4.6;-0.7mL/min/kg; age: beta=-0.2, 95%CI=-0.3;-0.1mL/min/kg), upper (gender: beta=-17.7, 95%CI=-20.1; 15.3kg; age: beta=-0.2, 95%CI=-0.3;-0.1kg) and lower (gender: beta=-58.3, 95%CI= 73.5;- 43.0Nm; age: beta=-1.7, 95%CI=-2.4;-1.1Nm) extremity muscle strength. Patients who were non-smoking (beta=-5.3, 95%CI=-8.7;-1.9), women (beta=7.2, 95%CI=4.8;9.6) and diagnosed with multiple myeloma (beta=4.6, 95%CI=2.2;6.9) had a higher percentage body fat. CONCLUSIONS: The physical fitness deficits in this population indicate the need for targeted interventions. TRIAL REGISTRATION: Netherlands Trial Register - NTR2341. PMID- 26971298 TI - How many days of monitoring are needed to reliably assess SenseWear Armband outcomes in primary school-aged children? AB - OBJECTIVES: To identify the number of hours and days or nights of monitoring required to reliably estimate energy expenditure (EE), steps, waking sedentary time, light- (LPA), moderate- (MPA), vigorous- (VPA), moderate- to vigorous intensity physical activity (MVPA), time in bed and total sleep time using the SenseWear Armband. DESIGN: Cross-sectional study. METHODS: One hundred and two children (50% boys) aged 8-11 years from six schools wore a SenseWear Armband (BodyMedia Inc, USA) for eight consecutive days (seven consecutive nights). Hourly increments of valid day wear time criteria were examined (days/week; 8h/day-14h/day). Intra-class correlation coefficients estimated the reliability for any individual day for each wear time criteria. The Spearman-Brown prophecy formula was used to determine the number of days/nights of monitoring needed to achieve reliability estimates of 0.7, 0.8 and 0.9. RESULTS: Fewer monitoring days were needed as the valid day criteria became more stringent. For example, at least 12h of wear time on at least 2 days was required to achieve a reliability of 0.7 for EE. In contrast, at least 8h/day on 5 days resulted in reliable estimates (0.7) for MPA, VPA and MVPA. Between 6 and 7 nights of monitoring were required to reliably estimate children's time in bed and total sleep time, respectively. CONCLUSIONS: A 7-day monitoring protocol in primary school-aged children would provide acceptable reliability for the assessment of EE, waking sedentary time, LPA, MPA, VPA, MVPA, time in bed and total sleep time, as assessed by the SenseWear Armband. PMID- 26971300 TI - The associations between physical activity, sedentary behaviour and academic performance. AB - OBJECTIVES: To examine the relationships between children's moderate-to-vigorous physical activity (MVPA), sedentary behaviours, and academic performance. DESIGN: This study investigated cross-sectional relationships between children's accelerometer-measured physical activity and sedentary behaviour patterns, and academic performance using a standardised, nationally-administered academic assessment. METHODS: A total of 285 Australian children aged 9-11 years from randomly selected schools undertook 7-day 24h accelerometry to objectively determine their MVPA and sedentary behaviour. In the same year, they completed nationally-administered standardised academic testing (National Assessment Program-Literacy and Numeracy; NAPLAN). BMI was measured, and socio-demographic variables were collected in a parent-reported survey. Relationships between MVPA, sedentary behaviour and academic performance across five domains were examined using Generalised Linear Mixed Models, adjusted for a wide variety of socio demographic variables. RESULTS: Higher academic performance was strongly and consistently related to higher sedentary time, with significant relationships seen across all five academic domains (range F=4.13, p=0.04 through to F=18.65, p=<0.01). In contrast, higher academic performance was only related to higher MVPA in two academic domains (writing F=5.28, p=0.02, and numeracy F=6.28, p=0.01) and was not related to language, reading and spelling performance. CONCLUSIONS: Findings highlight that sedentary behaviour can have positive relationships with non-physical outcomes. Positive relationships between MVPA and literacy and numeracy, as well as the well documented benefits for MVPA on physical and social health, suggest that it holds an important place in children's lives, both in and outside of school. PMID- 26971301 TI - Highly Sprouting-Tolerant Wheat Grain Exhibits Extreme Dormancy and Cold Imbibition-Resistant Accumulation of Abscisic Acid. AB - Pre-harvest sprouting (PHS) of wheat (Triticum aestivum L.) grains induces hydrolyzing enzymes such as alpha-amylase, which considerably decreases wheat product quality. PHS occurs when cool and wet weather conditions before harvest break dormancy and induce grain germination. In this study, we used PHS-tolerant varieties, Gifu-komugi (Gifu) and OS38, to characterize the mechanisms of both dormancy breakage and dormancy maintenance at low temperatures. Physiologically mature Gifu grains exhibited dormancy after imbibition at 20 degrees C, but germinated at 15 degrees C. In contrast, OS38 grains remained dormant even at temperatures as low as 5 degrees C. Embryo half-grains cut out from the dormant Gifu grains germinated by imbibition at 20 degrees C, similar to conventional varieties worldwide. However, OS38 embryo half-grains were still dormant. Hormonome and pharmacological analyses suggested that ABA and gibberellin metabolism are important for temperature-dependent dormancy maintenance and breakage. Imbibition at 15 degrees C decreased ABA levels but increased gibberellin levels in embryos of freshly harvested Gifu grains. Additionally, low temperatures induced expression of the ABA catabolism genes,TaABA8' OH1 and TaABA8' OH2, and the gibberellin biosynthesis gene,TaGA3ox2, in the embryos. However, in embryos of freshly harvested OS38 grains, ABA levels were increased while gibberellin levels were suppressed at 15 degrees C. In these dormant embryos, low temperatures induced the TaNCED ABA biosynthesis genes, but suppressed TaABA8' OH2 and TaGA3ox2.These results show that the regulatory mechanism influencing the expression of ABA and gibberellin metabolism genes may be critical for dormancy maintenance and breakage at low temperatures. Our findings should help improve PHS-resistant wheat breeding programs. PMID- 26971302 TI - Nonomuraea zeae sp. nov., isolated from the rhizosphere of corn (Zea mays L.). AB - A novel actinobacterium, designated strain NEAU-ND5T, was isolated from the rhizosphere of corn (Zea mays L.) collected in Heilongjiang Province, north-east China, and characterized using a polyphasic approach. 16S rRNA gene sequence analysis showed that strain NEAU-ND5T was a member of the genus Nonomuraea, with highest sequence similarities to Nonomuraea jabiensis A4036T (98.29 %), Nonomuraea rosea GW12687T (98.25 %), Nonomuraea candida HMC10T (98.22 %), Nonomuraea rhizophila YIM 67092T (98.04 %) and Nonomuraea kuesteri NRRL B-24325T (98.04 %). Similarities to other type strains of the genus Nonomuraea were lower than 98 %. Morphological and chemotaxonomic properties of strain NEAU-ND5T were also consistent with the description of the genus Nonomuraea. The cell wall contained meso-diaminopimelic acid and the whole-cell sugars were glucose, ribose and madurose. The phospholipid profile consisted of diphosphatidylglycerol, phosphatidylmonomethylethanolamine, phosphatidylethanolamine, hydroxy phosphatidylmonomethylethanolamine, hydroxy-phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannoside. The major menaquinones were MK-9(H4), MK-9(H2) and MK-9(H0). The predominant cellular fatty acids were iso-C16:0 and 10-methyl C17:0. A combination of DNA-DNA hybridization results and some phenotypic characteristics demonstrated that strain NEAU-ND5T was clearly distinguished from its closely related Nonomuraea species. Consequently, it is concluded that strain NEAU-ND5T represents a novel species of the genus Nonomuraea, for which the name Nonomuraea zeae sp. nov. is proposed. The type strain is NEAU-ND5T (=CGMCC 4.7280T=DSM 100528T). PMID- 26971303 TI - Network Meta-Analysis Comparing Overall Survival for Fulvestrant 500 mg Versus Alternative Therapies for Treatment of Postmenopausal, Estrogen Receptor-Positive Advanced Breast Cancer Following Failure on Prior Endocrine Therapy. AB - BACKGROUND: We conducted a review of randomized trials to compare the overall survival (OS) with fulvestrant 500 mg versus alternative treatment for estrogen receptor-positive advanced breast cancer following endocrine therapy failure. MATERIALS AND METHODS: Hazard ratios (HRs) were obtained by modeling OS data with the Weibull distribution. A fixed-effect Bayesian network meta-analysis was conducted. The evidence network included anastrozole 1 mg, letrozole 2.5 mg, fulvestrant 250 mg, exemestane 25 mg, megestrol acetate 40 mg, and everolimus 10 mg plus exemestane 25 mg as comparators. Post-antiestrogen and post-aromatase inhibitor subgroup networks were analyzed. RESULTS: In the overall analysis, the HRs suggested improved OS for fulvestrant 500 mg versus fulvestrant 250 mg and megestrol acetate 40 mg, and numerically favorable differences with fulvestrant 500 mg versus other comparators. In the antiestrogen subgroup, the HRs suggested improved OS for fulvestrant 500 mg versus fulvestrant 250 mg and megestrol acetate 40 mg; numerical differences in the HRs were seen versus anastrozole 1 mg and letrozole 2.5 mg. In the aromatase inhibitor subgroup, the HRs for OS numerically favored fulvestrant 500 mg versus fulvestrant 250 mg and exemestane 25 mg. CONCLUSION: Acknowledging the limitations of the present network meta analysis, these findings suggest that fulvestrant 500 mg might provide improved OS versus fulvestrant 250 mg and megestrol acetate 40 mg for treatment of estrogen receptor-positive ABC following endocrine therapy failure. Although OS efficacy versus everolimus 10 mg plus exemestane 25 mg (for overall evidence network), anastrozole 1 mg, exemestane 25 mg, and letrozole 2.5 mg is numerically favorable, additional studies are required to draw formal conclusions. PMID- 26971304 TI - A method for the development of disease-specific reference standards vocabularies from textual biomedical literature resources. AB - OBJECTIVE: Disease-specific vocabularies are fundamental to many knowledge-based intelligent systems and applications like text annotation, cohort selection, disease diagnostic modeling, and therapy recommendation. Reference standards are critical in the development and validation of automated methods for disease specific vocabularies. The goal of the present study is to design and test a generalizable method for the development of vocabulary reference standards from expert-curated, disease-specific biomedical literature resources. METHODS: We formed disease-specific corpora from literature resources like textbooks, evidence-based synthesized online sources, clinical practice guidelines, and journal articles. Medical experts annotated and adjudicated disease-specific terms in four classes (i.e., causes or risk factors, signs or symptoms, diagnostic tests or results, and treatment). Annotations were mapped to UMLS concepts. We assessed source variation, the contribution of each source to build disease-specific vocabularies, the saturation of the vocabularies with respect to the number of used sources, and the generalizability of the method with different diseases. RESULTS: The study resulted in 2588 string-unique annotations for heart failure in four classes, and 193 and 425 respectively for pulmonary embolism and rheumatoid arthritis in treatment class. Approximately 80% of the annotations were mapped to UMLS concepts. The agreement among heart failure sources ranged between 0.28 and 0.46. The contribution of these sources to the final vocabulary ranged between 18% and 49%. With the sources explored, the heart failure vocabulary reached near saturation in all four classes with the inclusion of minimal six sources (or between four to seven sources if only counting terms occurred in two or more sources). It took fewer sources to reach near saturation for the other two diseases in terms of the treatment class. CONCLUSIONS: We developed a method for the development of disease-specific reference vocabularies. Expert-curated biomedical literature resources are substantial for acquiring disease-specific medical knowledge. It is feasible to reach near saturation in a disease-specific vocabulary using a relatively small number of literature sources. PMID- 26971305 TI - Semantic processing of actions at 9months is linked to language proficiency at 9 and 18months. AB - The current study uses event-related potential methodologies to investigate how social-cognitive processes in preverbal infants relate to language performance. We assessed 9-month-olds' understanding of the semantic structure of actions via an N400 event-related potential (ERP) response to action sequences that contained expected and unexpected outcomes. At 9 and 18months of age, infants' language abilities were measured using the Swedish Early Communicative Development Inventory (SECDI). Here we show that 9-month-olds' understanding of the semantic structure of actions, evidenced in an N400 ERP response to action sequences with unexpected outcomes, is related to language comprehension scores at 9months and is related to language production scores at 18months of age. Infants who showed a selective N400 response to unexpected action outcomes are those who are classed as above mean in their language proficiency. The results provide evidence that language performance is related to the ability to detect and interpret human actions at 9months of age. This study suggests that some basic cognitive mechanisms are involved in the processing of sequential events that are shared between two conceptually different cognitive domains and that pre-linguistic social understanding skills and language proficiency are linked to one another. PMID- 26971307 TI - Postmortem calpain changes in ostrich skeletal muscle. AB - The objective of this study was to study the postmortem calpain change in ostrich muscle. Iliotibialis cranialis and Obturatorius medialis muscles were removed from the both sides of carcasses (n=8). The muscles from the left side were sampled after 0, 1, 2, 3, and 7days of storage at 5 degrees C, while the right side muscles were taken at 1-, 3-, and 7-day postmortem for shear force measurements. The results showed that the calpain-1 activity was not detected in ostrich muscle during the entire 7-day postmortem storage period, while the calpain-11 was. The unautolyzed calpain-11 activity decreased and the autolyzed calpain-11 activity increased with time postmortem. Desmin content and shear force did not change during postmortem storage although a minor degradation of desmin was observed. Therefore, our results suggest that limited postmortem proteolysis (as suggested by the limited degradation of desmin) and tenderization might be due to the lack of calpain-1 and/or insufficient calpain-11 activity present in ostrich muscle. PMID- 26971306 TI - Woman focused smoking cessation programming: a qualitative study. AB - BACKGROUND: Several studies of smoking cessation programs in clinical settings have revealed poorer outcomes for women compared to men, including counselling alone or in combination with pharmacotherapy. The objective of the current study was to explore treatment and program structure needs and preferences among female clients in a specialized smoking cessation clinic in an academic mental health and addiction health science centre in order to inform program design so that it meets the needs of female clients. METHODS: Four focus groups were conducted with current and former female clients (n = 23, mode age range = 50-59 years old, 56.5% were still smoking and 43.5% had quit) who had registered for outpatient smoking cessation treatment. Questions were designed to examine what aspects of the services were helpful and what changes they would like to see to better assist them and other women with quitting smoking. A thematic analysis of the raw data (audio recordings and notes taken during the focus groups) was conducted using a phenomenological theoretical framework. RESULTS: Themes that emerged indicated that females trying to quit smoking are best supported if they have choice from a variety of services so that treatment can be individualized to meet their specific needs; psychosocial support is provided both one-one-one with health care professionals and by peers in support groups; free pharmacotherapy is available to eliminate financial barriers to use; women-specific educational topics and support groups are offered; the clinic is accessible with evening/weekend hours, options to attend a local clinic, and childcare availability; and communication about clinic services and operation are clear, readily available, and regularly updated. CONCLUSIONS: An ideal smoking cessation program for women includes a women's centred approach with sufficient variety and choice, free pharmacotherapy, non-judgmental support, accessible services and clear communication of program options and changes. Findings may suggest an actionable list of adaptations that can be adopted by other clinics providing smoking cessation services to women. PMID- 26971308 TI - Application of small angle X-ray scattering synchrotron technology for measuring ovine meat quality. AB - A small angle X-ray scattering (SAXS) synchrotron was used to evaluate 100 ovine m. longissimus lumborum, representing lamb (n=50) and sheep (n=50). The diffraction of X-rays gives information on muscle myofibril structure and fat content. The linear relationships between SAXS measures with measures such as, shear force, intramuscular fat content (IMF) and collagen content/solubility, were investigated. A relationship was found between the d-spacing of the actin/myosin fibril spacing (SAX1 and SAX2) and the cross sectional area of the rhombohedral unit cell (Cell area) and shear force after 1 and 5day ageing. There was a positive relationship between IMF and a SAXS Fat area measure. There was a muscle site effect on SAX1, SAX2 and Cell area, with the cranial site having a larger distance between myofibrils. The potential of SAXS as a powerful research tool to determine not only the structural components of ovine tenderness, but also the fat content related to IMF is evident. PMID- 26971309 TI - Effect of black pepper essential oil on the quality of fresh pork during storage. AB - The effect of different concentrations (0, 0.1 and 0.5%, v/v) of black pepper essential oil (BPEO) on thiobarbituric acid reactive substances (TBARS), meat color, the percentage of metmyoglobin (MetMb%), microbiological parameters and total volatile basic nitrogen (TVB-N) of pork loins stored at 4 degrees C for 9days was evaluated. BPEO treatments showed lower TBARS, MetMb%, yellowness (b*) values, Pseudomonas spp. and Enterobacteriaceae count and TVB-N values and higher lightness (L*) and redness (a*) values than the control during storage; the effectiveness of BPEO was dose-dependent. The retardation of the formation of MetMb by adding BPEO ensured higher L* and a* values and lower b* values than the control at 6 and 9days; the MetMb content has a similar trend to the lipid oxidation. The lower TVB-N value of BPEO treatments than the control could be attributed to the inhibition of Pseudomonas spp. and Enterobacteriaceae. Gram negative bacteria were more sensitive than Gram-positive bacteria to BPEO. PMID- 26971310 TI - Effect of pretreatment with carbon monoxide and ozone on the quality of vacuum packaged beef meats. AB - Beef meats without pretreatment (CK) or pretreated with different volume ratios of carbon monoxide and ozone of 100%CO (T1), 2%O3+98%CO (T2), 5%O3+95%CO (T3) and 10%O3+90%CO (T4) using modified atmosphere packages for 1.5h, after that they were vacuum-packaged and stored in 0 degrees C refrigerator for 46days. The surface color a* values and sensory scores of T1, T2, T3 and T4 were significant higher than CK (p<0.05) during storage. In the mid and later storage, the drip loss, total viable counts (TVC), metmyoglobin (met-Mb), thiobarbituric acid reactive substances (TBARS), total volatile basic nitrogen (TVB-N) and pH of T1, T2, T3 and T4 were significantly lower than CK (p<0.05), and these values of T2, T3 and T4 were significantly lower than T1 in the later storage. In conclusion, O3 in the combination didn't affect the color-developing effect of CO, and could help CO maintain the meat quality. Therefore, the pretreatment of CO combined with O3 at certain concentrations can be a promising technique to maintain the quality of beef meats. PMID- 26971311 TI - Hypercoagulable state as demonstrated by thromboelastometry in hemoglobin E/beta thalassemia patients: Association with clinical severity and splenectomy status. AB - INTRODUCTION: Patients with hemoglobin E/beta-thalassemia disease (E/beta) are at risk of thromboembolism. Rotational thromboelastometry (ROTEM(r)) can be used to determine a hypercoagulable state. The objective was to describe the hemostatic and thromboelastometric changes in pediatric patients with E/beta with different clinical severity, in comparison with healthy children as controls. MATERIALS AND METHODS: Fifty-three pediatric patients with E/beta and 21 healthy children were enrolled. The clinical severity of E/beta was categorized by using the clinical severity scores. All subjects were tested for complete blood count, protein C activity (PC), total protein S (PS), antithrombin (AT), D-dimer and fibrinogen (Fib) levels and thromboelastometry, measured by ROTEM(r). RESULTS: The levels of PC (65.7 vs 118.5%), PS (46.8 vs 78.4%), AT (95.7 vs 105.7%) and Fib (217 vs 294 mg/dL) were significantly lower, and the platelet count (PLT) was significantly higher in the patient group than the controls. The maximum clot firmness (MCF) of patients with moderate disease who were previously splenectomized (seven patients) and patients with severe disease (nine patients) were higher than patients who had intact spleen with moderate disease, patients with mild disease and controls (P<0.05). Only PLT had significant correlation with MCF (P<0.05). CONCLUSIONS: Hypercoagulable state was demonstrated by ROTEM(r) in patients with E/beta with severe disease and who were previously splenectomized. The hypercoagulable state was associated with the higher numbers of PLT rather than the decrease of PC, PS, and AT. PMID- 26971313 TI - Use of Ocular Coherence Tomography in Children With Idiopathic Intracranial Hypertension-A Single-Center Experience. AB - BACKGROUND: Idiopathic intracranial hypertension is a disorder characterized by elevated intracranial pressure without an identifiable etiology. Detection of papilledema may be challenging and leads to diagnostic uncertainty in evaluating a child for possible idiopathic intracranial hypertension. Ocular coherence tomography has the potential to add accuracy to the diagnosis of idiopathic intracranial hypertension. The goal of the present study was to determine if there was a relationship between severity of papilledema (as determined by direct ophthalmoscopy and confirmed by fundus photography) and measures of ocular coherence tomography in a pediatric population with idiopathic intracranial hypertension. METHODS: Thirteen pediatric patients were recruited prospectively after diagnosis of either definitive idiopathic intracranial hypertension (with papilledema) or possible idiopathic intracranial hypertension (without papilledema) at Children's Hospital of Michigan over a period of one year. Clinical data and results of initial ocular coherence tomography and visual field testing were collected and statistically analyzed. RESULTS: The Frisen scale of papilledema significantly correlated with average retinal nerve fiber layer thickness of each eye (r = 0.633, P = 0.02 in right eye and r = 0.868, P = 0.001 in left eye). The retinal nerve fiber layer thickness (mean +/- SD) was significantly higher in the definitive group than in the possible group (189 +/- 65 MUm vs 104 +/- 10 MUm in right eye, 165 +/- 42 MUm vs 106 +/- 9 MUm in left eye, P < 0.01 in both eyes). CONCLUSIONS: Ocular coherence tomography may be used as a supplementary method to aid in the reliable detection of papilledema in evaluating a child for idiopathic intracranial hypertension. PMID- 26971314 TI - Evaluation of the RapidHITTM 200 and RapidHIT GlobalFiler((r)) Express kit for fully automated STR genotyping. AB - The RapidHITTM 200 Human Identification System and RapidHIT GlobalFiler((r)) Express kit were evaluated and validated for use with single-source reference samples. It was of primary interest to evaluate the system for its efficacy as an expert system and to estimate a first pass success rate, as well as to identify the technical variables impacting that result. While results indicated that this instrument/kit combination can be used to accurately type single-source buccal samples, substantial variability in sensitivity and intra-color balance were observed, as were multiple artifacts, requiring extensive manual editing of the profiles. Artifacts included dye "blobs" and spectral overlap (pull-up) peaks that often originated from relatively low intensity allele peaks. Reduced intra color balance, in combination with low sensitivity, occasionally resulted in instances of allelic dropout. Overall, 50% of the buccal samples analyzed in this study would have been successfully typed to give full GlobalFiler((r)) profiles without the need for manual review and editing. PMID- 26971315 TI - Analysis and implications of the miscarriages of justice of Amanda Knox and Raffaele Sollecito. AB - The case of the 'murder of Meredith Kercher' has been the subject of intense media scrutiny since 2007 when the offence was committed. Three individuals were arrested and accused of the crime. Amanda Knox and Raffaele Sollecito were exonerated in March 2015. Another defendant, Rudy Guede, remains convicted as the sole perpetrator. He was implicated by multiple DNA profiles recovered from the murder room and the bathroom. However, the evidence against Guede contrasted strongly with the limited evidence against two co-defendants, Amanda Knox and Raffaele Sollecito. There were no DNA profiles pertaining to Amanda Knox in the murder room itself. She was separately implicated by a knife recovered remote from the crime scene (discovered in a cutlery drawer at Sollecito's apartment), along with DNA profiles in a bathroom that she had shared with the victim. Upon analysis a low level trace of DNA attributed to the murder victim was found on the blade of a knife, along with DNA profiles attributed to Amanda Knox from the handle. However, there was no evidence of blood on the knife blade itself. A separate key piece of evidence was a DNA profile attributed to Raffaele Sollecito recovered from a forcibly removed bra-clasp found in the murder room. There followed an extraordinary series of trials and retrials where the pair were convicted, exonerated, re-convicted and finally, in March 2015 they were finally exonerated (no further appeal is possible). Since Knox and Sollecito have been found innocent it is opportune to carry out an extensive review of the case to discover the errors that led to conviction so that similar mistakes do not occur in the future. It is accepted that the DNA profiles attributed to them were transferred by methods unrelated to the crime event itself. There is a wealth of material available from the judgements and other reports which can be analysed in order to show the errors of thinking. The final judgement of the case-the Marasca Bruno motivation report-exposes the illogicality of much of the previous court proceedings that led to the convictions and provides useful guidance for judges to follow. PMID- 26971312 TI - Schistosoma japonicum HSP60-derived peptide SJMHE1 suppresses delayed-type hypersensitivity in a murine model. AB - BACKGROUND: Parasite-derived molecules with immunomodulatory properties, which have been optimised during host-parasite co-evolution, exhibit potential applications as novel immunotherapeutics. We have previously demonstrated that Schistosoma japonicum HSP60-derived peptide SJMHE1 induces CD4(+)CD25(+) regulatory T-cells (Tregs) and that adoptively transferred SJMHE1-induced CD4(+)CD25(+) Tregs inhibit delayed-type hypersensitivity (DTH) in mice. However, multiple concerns regarding this method render this treatment unsuitable. To gain further insights into the potential effects of SJMHE1, we used ovalbumin (OVA) induced DTH and evaluated the effect of SJMHE1 on DTH mice. METHODS: BALB/c mice were sensitised with OVA alone or combined with SJMHE1 and then challenged with OVA to induce DTH. We first analysed the potential effects of SJMHE1 by measuring DTH responses, T-cell responses, cytokine secretion, and Treg proportions. We then evaluated the expression levels of IL-10 and TGF-beta1 in CD4(+)CD25(+) T cells during DTH and Treg generation to identify the mechanism by which SJMHE1 suppresses DTH. RESULTS: SJMHE1 modulated the effector response against OVA induced DTH and stimulated the production of the anti-inflammatory cytokines IL 10 and TGF-beta1 in immunised mice through a mechanism involving CD4(+)CD25(+) Tregs. SJMHE1-induced CD4(+)CD25(+) Tregs expressed high levels of CTLA-4, IL-10, and TGF-beta1, which substantially contributed to the suppressive activity during DTH. The administration of SJMHE1 to DTH in mice led to the expansion of CD4(+)CD25(+) Tregs from CD4(+)CD25(-) T-cells in the periphery, which inhibited DTH responses. CONCLUSIONS: Our study proves that the parasite-driven peptide suppresses DTH in mice, which may confer a new option for inflammation treatment. PMID- 26971316 TI - De novo assembly and annotation of the European abalone Haliotis tuberculata transcriptome. AB - The European abalone Haliotis tuberculata is a delicacy and consequently a commercially valuable gastropod species. Aquaculture production and wild populations are subjected to multiple climate-associated stressors and anthropogenic pressures, including rising sea-surface temperatures, ocean acidification and an emerging pathogenic Vibrio infection. Transcript expression data provides a valuable resource for understanding abalone responses to variation in the biotic and abiotic environment. To generate an extensive transcriptome, we performed next-generation sequencing of RNA on larvae exposed to temperature and pH variation and on haemolymph of adults from two wild populations after experimental infection with Vibrio harveyi. We obtained more than 1.5 billion raw paired-end reads, which were assembled into 328,519 contigs. Filtration and clustering produced a transcriptome of 41,099 transcripts, of which 10,626 (25.85%) were annotated with Blast hits, and 7380 of these were annotated with Gene Ontology (GO) terms in Blast2Go. A differential expression analysis comparing all samples from the two life stages identified 5690 and 10,759 transcripts with significantly higher expression in larvae and adult haemolymph respectively. This is the greatest sequencing effort yet in the Haliotis genus, and provides the first high-throughput transcriptomic resource for H. tuberculata. PMID- 26971318 TI - Fermentibacillus polygoni gen. nov., sp. nov., an alkaliphile that reduces indigo dye. AB - Facultatively alkaliphilic strains, designated as strains IEB3T and IEB14, were isolated as indigo-reducing strains from a fermented Polygonum indigo (Polygonum tinctorium Lour) liquor sample prepared in our laboratory using a medium containing an indigo fermentation liquor as a sole substrate. The 16S rRNA gene sequence phylogeny and similarity suggested that strains IEB3T and IEB14 exhibit distinctive positions among the members of the genus Bacillus, and their closest neighbour was Bacillus nanhaiisediminis NH3T (similarity: 97.4 %) among the species with validly published names. The 16S rRNA sequence of strain IEB3Twas identical to that of strain IEB14. The cells of the isolates stained Gram positive and were facultatively anaerobic, straight rods that were motile by a pair of subpolar flagella. Strains IEB3T and IEB14 grew at temperatures between 12 and 40 degrees C with optimum growth at 30-33 degrees C and in the range of pH 7.5-12. Menaquinone-7 (MK-7) was detected as the major isoprenoid quinone. The DNA G+C contents of strains IEB3T and IEB14 were 39.0 and 39.1 mol%, respectively. The whole-cell fatty acid profile mainly (>10 %) consisted of iso C14:0, iso-C15:0 and anteiso-C15:0. DNA-DNA hybridization revealed a low relatedness value between strain IEB3T and the phylogenetically most closely related species, Bacillus nanhaiisediminis JCM 16507T (<7 % ). On the basis of phenotypic and chemotaxonomic characteristics and phylogenetic data, the isolates represent a novel species within a novel genus, for which the name Fermentibacillus polygoni gen. nov., sp. nov. is proposed. The type strain is IEB3T (=JCM 30817T=NCIMB 14984T). PMID- 26971317 TI - Systematic review on human resources for health interventions to improve maternal health outcomes: evidence from low- and middle-income countries. AB - There is a broad consensus and evidence that shows qualified, accessible, and responsive human resources for health (HRH) can make a major impact on the health of the populations. At the same time, there is widespread recognition that HRH crises particularly in low- and middle-income countries (LMICs) impede the achievement of better health outcomes/targets. In order to achieve the Sustainable Development Goals (SDGs), equitable access to a skilled and motivated health worker within a performing health system is need to be ensured. This review contributes to the vast pool of literature towards the assessment of HRH for maternal health and is focused on interventions delivered by skilled birth attendants (SBAs). Studies were included if (a) any HRH interventions in management system, policy, finance, education, partnership, and leadership were implemented; (b) these were related to SBA; (c) reported outcomes related to maternal health; (d) the studies were conducted in LMICs; and (e) studies were in English. Studies were excluded if traditional birth attendants and/or community health workers were trained. The review identified 25 studies which revealed reasons for poor maternal health outcomes in LMICs despite the efforts and policies implemented throughout these years. This review suggested an urgent and immediate need for formative evidence-based research on effective HRH interventions for improved maternal health outcomes. Other initiatives such as education and empowerment of women, alleviating poverty, establishing gender equality, and provision of infrastructure, equipment, drugs, and supplies are all integral components that are required to achieve SDGs by reducing maternal mortality and improving maternal health. PMID- 26971319 TI - Characterisation of the broad substrate specificity 2-keto acid decarboxylase Aro10p of Saccharomyces kudriavzevii and its implication in aroma development. AB - BACKGROUND: The yeast amino acid catabolism plays an important role in flavour generation since higher alcohols and acetate esters, amino acid catabolism end products, are key components of overall flavour and aroma in fermented products. Comparative studies have shown that other Saccharomyces species, such as S. kudriavzevii, differ during the production of aroma-active higher alcohols and their esters compared to S. cerevisiae. RESULTS: In this study, we performed a comparative analysis of the enzymes involved in the amino acid catabolism of S. kudriavzevii with their potential to improve the flavour production capacity of S. cerevisiae. In silico screening, based on the severity of amino acid substitutions evaluated by Grantham matrix, revealed four candidates, of which S. kudriavzevii Aro10p (SkAro10p) had the highest score. The analysis of higher alcohols and esters produced by S. cerevisiae then revealed enhanced formation of isobutanol, isoamyl alcohol and their esters when endogenous ARO10 was replaced with ARO10 from S. kudriavzevii. Also, significant differences in the aroma profile were found in fermentations of synthetic wine must. Substrate specificities of SkAro10p were compared with those of S. cerevisiae Aro10p (ScAro10p) by their expression in a 2-keto acid decarboxylase-null S. cerevisiae strain. Unlike the cell extracts with expressed ScAro10p which showed greater activity for phenylpyruvate, which suggests this phenylalanine-derivative to be the preferred substrate, the decarboxylation activities measured in the cell extracts with SkAro10p ranged with all the tested substrates at the same level. The activities of SkAro10p towards substrates (except phenylpyruvate) were higher than of those for ScAro10p. CONCLUSIONS: The results indicate that the amino acid variations observed between the orthologues decarboxylases encoded by SkARO10 and ScARO10 could be the reason for the distinct enzyme properties, which possibly lead to the enhanced production of several flavour compounds. The knowledge on the important enzyme involved in higher alcohols biosynthesis by S. kudriavzevii could be of scientific as well as of applied interest. PMID- 26971320 TI - The Health Centre Community. PMID- 26971322 TI - Hormonal profiles of captive Galapagos tortoises (Chelonoidis nigra). AB - Monthly blood samples, daily mating observations from Galapagos tortoises (Chelonoidis nigra), and local rainfall and temperature were collected at the Honolulu Zoo as part of a fertility evaluation. Testosterone concentrations were measured for males (n = 6), two of which were seen copulating and were considered sexually active. Estrone sulfate and progesterone concentrations were measured for female tortoises (n = 9), two of which nested and only one had laid eggs. Testosterone profiles were similar for both sexually active and sexually inactive males, both of which were positively correlated with temperature but not rainfall. Peak testosterone concentrations (12.0 +/- 1.4 ng/ml sexually active animals vs. 14.4 +/- 2.4 ng/ml sexually inactive animals) occurred at the end of the nesting season, from April to July. Estrone sulfate concentrations were similar for nesting (n = 2) and non-nesting (n = 7) female tortoises, rising from non-detectable concentrations (September), and increasing to peak concentrations during the nesting season. Progesterone concentrations remained low and spiked (9.44 ng/ml) only for the female that nested and laid eggs. Testosterone was negatively correlated with mating behavior, and the male tortoises were likely capable of spermatogenesis even though only two of them engaged in mating behavior. The female tortoises were not senescent, as the estrone sulfate concentrations likely reflected waves of ovarian follicular activity. Endocrine parameters were not in synchrony with rainfall, and a disconnect between the timing of reproductive events and the environmental milieu may help to explain the poor fertility of these tortoises. Zoo Biol. 35:237-245, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26971321 TI - Meta-analysis of genome-wide association studies reveals genetic overlap between Hodgkin lymphoma and multiple sclerosis. AB - BACKGROUND: Based on epidemiological commonalities, multiple sclerosis (MS) and Hodgkin lymphoma (HL), two clinically distinct conditions, have long been suspected to be aetiologically related. MS and HL occur in roughly the same age groups, both are associated with Epstein-Barr virus infection and ultraviolet (UV) light exposure, and they cluster mutually in families (though not in individuals). We speculated if in addition to sharing environmental risk factors, MS and HL were also genetically related. Using data from genome-wide association studies (GWAS) of 1816 HL patients, 9772 MS patients and 25 255 controls, we therefore investigated the genetic overlap between the two diseases. METHODS: From among a common denominator of 404 K single nucleotide polymorphisms (SNPs) studied, we identified SNPs and human leukocyte antigen (HLA) alleles independently associated with both diseases. Next, we assessed the cumulative genome-wide effect of MS-associated SNPs on HL and of HL-associated SNPs on MS. To provide an interpretational frame of reference, we used data from published GWAS to create a genetic network of diseases within which we analysed proximity of HL and MS to autoimmune diseases and haematological and non-haematological malignancies. RESULTS: SNP analyses revealed genome-wide overlap between HL and MS, most prominently in the HLA region. Polygenic HL risk scores explained 4.44% of HL risk (Nagelkerke R(2)), but also 2.36% of MS risk. Conversely, polygenic MS risk scores explained 8.08% of MS risk and 1.94% of HL risk. In the genetic disease network, HL was closer to autoimmune diseases than to solid cancers. CONCLUSIONS: HL displays considerable genetic overlap with MS and other autoimmune diseases. PMID- 26971323 TI - Hepatic and seric levels of purines in rats experimentally infected by Fasciola hepatica. AB - The aim of this study was to evaluate hepatic and seric levels of purines, as well as their breakdown products in rats infected by Fasciola hepatica on days 15 and 87 post-infection (PI). Rats were divided into two groups: uninfected (n = 10) and infected (n = 20). On day 15 (n = 5 for uninfected group and n = 10 for infected group) and 87 PI (n = 5 for uninfected group and n = 10 for infected group), animals were euthanized for sampling to evaluate levels of purines by high-performance liquid chromatography. In serum, ATP increased (P < 0.05) and ADP decreased (P < 0.05) on days 15 and 87 PI, while AMP increased (P < 0.05) only on day 15 PI. Hypoxanthine levels increased (P < 0.05) on days 15 and 87 PI, while adenosine and xanthine levels decreased and increased (P < 0.05), respectively, on day 87 PI. No difference was observed regarding seric inosine and uric acid (P > 0.05). Hepatic ATP, adenosine, and uric acid levels decreased (P < 0.05) on days 15 and 87 PI. AMP levels decreased (P < 0.05) on day 87 PI, while xanthine levels increased (P < 0.05) on day 15 PI in the liver. Also in the liver, hypoxanthine levels increased (P < 0.05) on day 15 PI and decreased (P < 0.05) on day 87 PI. On the other hand, there was no difference on hepatic ADP and inosine levels (P > 0.05). Therefore, it is possible to conclude that F. hepatica infection can change purine levels, which may be associated with an inflammatory process, and these alterations may influence fasciolosis pathogenesis. PMID- 26971325 TI - Erratum to: The Determining Risk of Vascular Events by Apnea Monitoring (DREAM) study: design, rationale, and methods. PMID- 26971324 TI - Dysfunction of NMDA receptors in Alzheimer's disease. AB - N-methyl-D-aspartate receptors (NMDARs) play a pivotal role in the synaptic transmission and synaptic plasticity thought to underlie learning and memory. NMDARs activation has been recently implicated in Alzheimer's disease (AD) related to synaptic dysfunction. Synaptic NMDARs are neuroprotective, whereas overactivation of NMDARs located outside of the synapse cause loss of mitochondrial membrane potential and cell death. NMDARs dysfunction in the glutamatergic tripartite synapse, comprising presynaptic and postsynaptic neurons and glial cells, is directly involved in AD. This review discusses that both beta amyloid (Abeta) and tau perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of NMDARs as a possible convergence point for Abeta and tau toxicity and possible reversible stages of the AD through preventive and/or disease-modifying therapeutic strategies. PMID- 26971327 TI - Squeaking and microcracks in a delta-delta ceramic coupling: pin-on-disc study. AB - There is a rising concern about squeaking in ceramic-on-ceramic total hip arthroplasty (THA). In pin-on-disc testing of a delta-delta coupling, we reproduced squeaking and observed microcracks on worn surfaces. We used a pin-on disc machine and made discs and pins by cutting delta ceramic to a diameter of 40 mm (D-D). Cross-linked polyethylene was used for a comparison disc (D-P). We performed the same test using another D-D coupling specimen to confirm reproducibility. Squeaking in the D-D specimen was reproduced in wet conditions, though it was not found in the D-P specimen. Fast Fourier transform analysis showed a peak frequency for squeaking of 2794 Hz. The noise occurred at about 6.6 km of sliding distance. Scanning electron microscopy revealed that the worn surface of the pin in D-D at 10.8 km of sliding distance had some microcracks. However, there was no obvious damage to the worn surface of the pin in D-P at the same sliding distance. We confirmed the reproducibility of these findings, obtaining similar results, including squeaking, from another D-D coupling specimen. Our findings show that squeaking may occur in THA using delta ceramic bearings even if implants are placed to avoid extra-articular impingement of the femoral neck. Although the clinical relevance of microcracks is unknown, they may affect long-term outcomes in THA using delta ceramic bearings. PMID- 26971328 TI - Error Rates, Decisive Outcomes and Publication Bias with Several Inferential Methods. AB - BACKGROUND: Statistical methods for inferring the true magnitude of an effect from a sample should have acceptable error rates when the true effect is trivial (type I rates) or substantial (type II rates). OBJECTIVE: The objective of this study was to quantify the error rates, rates of decisive (publishable) outcomes and publication bias of five inferential methods commonly used in sports medicine and science. The methods were conventional null-hypothesis significance testing [NHST] (significant and non-significant imply substantial and trivial true effects, respectively); conservative NHST (the observed magnitude is interpreted as the true magnitude only for significant effects); non-clinical magnitude-based inference [MBI] (the true magnitude is interpreted as the magnitude range of the 90 % confidence interval only for intervals not spanning substantial values of the opposite sign); clinical MBI (a possibly beneficial effect is recommended for implementation only if it is most unlikely to be harmful); and odds-ratio clinical MBI (implementation is also recommended when the odds of benefit outweigh the odds of harm, with an odds ratio >66). METHODS: Simulation was used to quantify standardized mean effects in 500,000 randomized, controlled trials each for true standardized magnitudes ranging from null through marginally moderate with three sample sizes: suboptimal (10 + 10), optimal for MBI (50 + 50) and optimal for NHST (144 + 144). RESULTS: Type I rates for non-clinical MBI were always lower than for NHST. When type I rates for clinical MBI were higher, most errors were debatable, given the probabilistic qualification of those inferences (unlikely or possibly beneficial). NHST often had unacceptable rates for either type II errors or decisive outcomes, and it had substantial publication bias with the smallest sample size, whereas MBI had no such problems. CONCLUSION: MBI is a trustworthy, nuanced alternative to NHST, which it outperforms in terms of the sample size, error rates, decision rates and publication bias. PMID- 26971326 TI - Sleep-disordered breathing and daytime cardiac conduction abnormalities on 12 lead electrocardiogram in community-dwelling older men. AB - PURPOSE: Nocturnal cardiac conduction abnormalities are commonly observed in patients with sleep-disordered breathing (SDB). However, few population-based studies have examined the association between SDB and daytime cardiac conduction abnormalities. METHODS: We examined a random sample of 471 community-dwelling men, aged >=67 years, enrolled in the multi-center Outcomes of Sleep Disorders in Older Men (MrOS Sleep) study. SDB severity was categorized using percent of total sleep time with oxygen saturation <90 % (%TST < 90) and apnea hypopnea index (AHI). Cardiac conduction parameters were assessed by resting 12-lead electrocardiography (ECG). All analyses were adjusted for age, site, beta-blocker use, coronary heart disease, calcium channel blocker use, and use of antiarrhythmic medications. RESULTS: Mean age was 77 +/- 6 years, median %TST < 90 was 0.7 (IQR 0.00-3.40), and median AHI was 7.06 (IQR 2.55-15.32). Men with greater nocturnal hypoxemia (%TST < 90 >= 3.5 %) compared with those without hypoxemia (%TST < 90 < 1.0 %) had a lower odds of bradycardia (OR 0.55 [0.32 0.94]) and right bundle branch block (RBBB) (OR 0.24 [0.08-0.75]) but a higher odds of ventricular paced rhythm (OR 4.42 [1.29-15.19]). Heart rate (HR) increased in a graded manner with increasing %TST < 90 (p-trend 0.01) and increasing AHI (p-trend 0.006), but these gradients were small in absolute magnitude. There were no associations of SDB measures with other ECG conduction parameters. CONCLUSIONS: Greater nocturnal hypoxemia in older men was associated with a lower prevalence of daytime sinus bradycardia and RBBB, a higher prevalence of ventricular paced rhythm, and higher resting HR. PMID- 26971329 TI - Biotechnological advancement in genetic improvement of broccoli (Brassica oleracea L. var. italica), an important vegetable crop. AB - With the advent of molecular biotechnology, plant genetic engineering techniques have opened an avenue for the genetic improvement of important vegetable crops. Vegetable crop productivity and quality are seriously affected by various biotic and abiotic stresses which destabilize rural economies in many countries. Moreover, absence of proper post-harvest storage and processing facilities leads to qualitative and quantitative losses. In the past four decades, conventional breeding has significantly contributed to the improvement of vegetable yields, quality, post-harvest life, and resistance to biotic and abiotic stresses. However, there are many constraints in conventional breeding, which can only be overcome by advancements made in modern biology. Broccoli (Brassica oleracea L. var. italica) is an important vegetable crop, of the family Brassicaceae; however, various biotic and abiotic stresses cause enormous crop yield losses during the commercial cultivation of broccoli. Thus, genetic engineering can be used as a tool to add specific characteristics to existing cultivars. However, a pre-requisite for transferring genes into plants is the availability of efficient regeneration and transformation techniques. Recent advances in plant genetic engineering provide an opportunity to improve broccoli in many aspects. The goal of this review is to summarize genetic transformation studies on broccoli to draw the attention of researchers and scientists for its further genetic advancement. PMID- 26971330 TI - The transcription factor TBX2 regulates melanogenesis in melanocytes by repressing Oca2. AB - The T-box transcription factor TBX2 is known for its role as a critical regulator of melanoma cell proliferation, but its role in regulating melanogenesis has not been widely studied. Here we use a series of experiments to show in primary and immortalized mouse melanocytes that TBX2 acts as regulator of melanogenesis by repressing the expression of the gene encoding the melanosomal protein OCA2. We find that alpha-MSH or forskolin, both of which stimulate melanogenesis, also reduce TBX2 expression, and that specific knockdown of TBX2 increases melanogenesis. This effect primarily involves an increase in Oca2 expression as the combined knockdown of both Tbx2 and Oca2 interferes with the Tbx2 knockdown mediated increase in melanogenesis. Standard chromatin immunoprecipitation and reporter assays suggest that TBX2 represses Oca2 at least in part directly. Hence, the results suggest that TBX2 may act as a nexus linking cell proliferation and melanogenesis. PMID- 26971331 TI - Left atrial posterior wall isolation reduces the recurrence of atrial fibrillation: a meta-analysis. AB - PURPOSE: The posterior wall of left atrium plays an important role in atrial fibrillation (AF) recurrence, but the benefit of left atrial posterior wall isolation (PWI) remains still unclear. The objective was to evaluate the benefit of PWI in radiofrequency ablation. METHODS: PubMed and the Web of Science were searched in September 2015. Studies comparing catheter ablation with PWI [PWI(+)] vs. ablation without PWI [PWI(-)] were included. We performed a meta-analysis to assess atrial arrhythmia recurrence, procedure-related complications, and procedural time. RESULTS: Five studies with 594 AF patients were included. Compared with PWI(-), PWI(+) resulted in a significantly lower atrial arrhythmia recurrence rate (relative risk [RR] 0.81, 95 % confidence interval [CI] 0.68 0.97, p = 0.02), which was largely driven by the decreased AF recurrence (RR 0.55, 95 % CI 0.35-0.86, p = 0.009). Recurrence rates of atrial tachycardia/flutter (AT/AFL) were comparable between two groups (RR 1.16, 95 % CI 0.85-1.58, p = 0.34). There were no significant differences in procedure-related complications (RR 1.07, 95 % CI 0.45-2.53, p = 0.89) and procedural times (weight mean difference 0.88, 95 % CI -7.29-9.06, p = 0.83). CONCLUSIONS: This meta analysis shows that with comparable procedure-related complications and procedural time, ablation with PWI reduces AF recurrence. PMID- 26971332 TI - Early release of high-sensitive cardiac troponin during complex catheter ablation for ventricular tachycardia and atrial fibrillation. AB - BACKGROUND: Radiofrequency ablation results in intentional cardiac injury. We aimed to assess the kinetics of cardiac injury as measured by cardiac troponin release following ventricular ablation and atrial ablation. METHODS: Patients undergoing ablation for ventricular tachycardia (VT) with structural heart disease (19 patients) or atrial fibrillation (AF, 24 patients) were prospectively enrolled. High-sensitivity cardiac troponin T (hs-cTnT) and high-sensitivity cardiac troponin I (hs-cTnI) were measured before ablation as well as 30 min, 60 min, 90 min, 120 min, 4 h, 8 h, and 24 h after applying the first ablation lesion. RESULTS: Median ablation time, power used, and energy delivered were 28 min, 39 W, and 69,713 J in VT ablations and 55 min, 29 W, and 95,425 J in AF ablations, respectively. Release of hs-cTnT occurred promptly with both, but reached greater levels earlier for ventricular compared to atrial ablation (hs cTnT after 30 min 191 vs. 31 ng/l, after 1 h 467 vs. 80 ng/l; hs-cTnI after 30 min 132 vs. 30 ng/l, after 1 h 331 vs. 76 ng/l; p < 0.001 for all comparisons). After 24 h, levels were similar (hs-cTnT 1325 vs. 1303 ng/l, p = 0.92; hs-cTnI 2165 vs. 1996 ng/l, p = 0.55). Levels of hs-cTnT after 24 h correlated well with the energy delivered in AF ablations (r = 0.81 and r = 0.75, p < 0.001), but not in VT ablations (r = 0.35 and r = 0.44, p = ns). CONCLUSIONS: Evidence of cardiac injury as indicated by the release of hs-cTnT and hs-cTnI occurs early with atrial and ventricular ablation. Higher early levels are observed in ventricular ablations, but levels are similar after 24 h. The extent of total troponin release seems to correlate well with the amount of energy delivered in AF ablations, but not in VT ablations. PMID- 26971333 TI - Long-term mobility of the esophagus in patients undergoing catheter ablation of atrial fibrillation: data from computer tomography and 3D rotational angiography of the left atrium. AB - PURPOSE: Computed tomography (CT) and 3D rotational angiography (3DRA) of the left atrium (LA) are used to evaluate the esophagus prior to radiofrequency ablation for atrial fibrillation. The aim of this study was to compare preprocedural and periprocedural views of the esophagus and the left atrium. METHODS: From September 2011 to August 2012, 3DRA and CT of the LA were performed on 56 patients before they underwent catheter ablation of atrial fibrillation. The 3DRA was performed periprocedurally, and the CT was performed an average of 20 days prior to the procedure. 3D models of the LA and the esophagus were then segmented on the EP Navigator V 3.1 workstation. Five positions of the esophagus, A-E, in order from left to right, were evaluated. RESULTS: The most common position of the esophagus was behind the left part of the LA (CT, position B (n = 26)) and behind the central part of the LA (3DRA, position C (n = 21)). The maximum shift of the esophagus was three positions, and the average shift was 0.857 +/- 0.766 of a position. There was a shift of one position in 44.6 % of the patients, two positions in 17.9 %, and three positions in 1.8 %. A statistically significant difference was found between the positions of the esophagus when the 3DRA and CT evaluations were compared. CONCLUSIONS: The most common position of the esophagus was behind the middle and left part of the LA. The outpatient views of the esophagus obtained before ablation did not reflect the position of the esophagus at the beginning of the procedure. PMID- 26971335 TI - Urine Culture in Uncomplicated UTI: Interpretation and Significance. AB - Acute uncomplicated urinary tract infection (UTI) is a common clinical problem, accounting for millions of outpatient visits in the USA annually. Although routinely obtaining urine cultures in UTI is not recommended, there are circumstances in which obtaining a pre-therapy culture may be warranted or chosen by clinicians, such as when indicated by the need for careful antimicrobial stewardship. This review focuses on understanding reasons for obtaining a pre therapy culture, methods of collection, and appropriately interpreting urine culture data. PMID- 26971334 TI - Paradonghicola geojensis gen. nov., sp. nov., isolated from seawater, Geoje-si, South Korea. AB - A Gram-negative, non-motile, non-spore-forming and aerobic bacterium, designated FJ12(T), was isolated from seawater, Geoje-si, South Korea. Strain FJ12(T) was catalase and oxidase positive. Growth of strain FJ12(T) was optimally observed at 30 degrees C and pH 6 and grew in the presence of 0-11 % (w/v) NaCl (optimum 2-3 % NaCl). The phylogenic analysis based on 16S rRNA gene sequence of strains FJ12(T) showed the highest sequence similarity to those of Doghicola eburneus KCTC 12735(T) (95.4 %), Aestuariihabitans beolgyonensis KTCT 32324(T) (95.3 %), Sulfitobacter pontiacus KCTC 32185(T) (94.9 %), Roseisalinus antarcticus DSM 11466(T) (94.8 %) and Loktanella soesokkaensis KCTC 32425(T) (94.7 %). The major polar lipids of FJ12(T) were phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, an unidentified aminolipid and unidentified lipids. It contained Q-10 as the predominant ubiquinone, and major fatty acid is C18:1 omega7c (51.7 %), C16:0 (24.0 %). The DNA G+C content of the strain FJ12(T) was 60 mol%. Based on physiological and chemotaxonomic characteristics, strain FJ12(T) should be regarded as the type species of a novel genus in the family Rhodobacteraceae for which the name Paradonghicola geojensis sp. nov. is proposed. The type strain FJ12(T) (=KEMB 3001-336(T)=JCM 30384(T)). PMID- 26971337 TI - Imaging wisely: patient safety in CT. AB - The past decade has seen a significant growth in diagnostic CT imaging as a direct result of the clinical value provided by CT imaging. At the same time, many new techniques and resources are now available to make CT imaging safe. This article presents the basics of CT dosimetry and their usage in clinical practices, methods to implement CT dose reduction, followed by a summary of legislation, and guidelines related to patient safety in diagnostic CT imaging. Also, CT radiation dose diagnostic reference levels from published regional and national surveys are reviewed and applied in a CT dose tracking and monitoring program. PMID- 26971336 TI - Aeroallergens in West Crete, Greece: A five year (2010-2014) aerobiological study. AB - The objective of the analytic observational study was to present air-pollen counting program results for a 5-year period. Airborne pollens and fungi collection, from both urban and sub-urban areas, were obtained using a special Burkard pollen trap installed on the roof of Chania General Hospital. Aeroallergen concentration measurement was made in a standardized way with fixation of the material collected and then counting using an optical microscope. Annual and total circulating pollen and fungi counts for the study period are presented. In the year 2014, the highest total annual count was recorded, while 2013 was the year with the lowest one. Months with the highest average concentrations were June for the years 2010 and 2011 (1291 and 1114.6 grains/m(3), respectively) and May for the consecutive 3 years 2012-2014 (1120, 890 and 1353.1 g/m(3), respectively). Peak periods for circulating aeroallergens were April-June. Trees pollen accounted for the majority of circulating aeroallergens (615.9 and 677.1 g/m(3) during peak periods in the years 2012 and 2014), while fungi accounted for the majority of circulating aeroallergens (818.5, 729.4, 890.7 spores/m(3)), during the peak periods in the years 2010, 2011 and 2013. Variability in peak airborne allergen periods could be partly explained by the differences in climatic conditions during the study period. PMID- 26971338 TI - Abdominal radiology in the era of the Interventional Radiology/Diagnostic Radiology certificate. PMID- 26971339 TI - The "manta ray" pelvis. PMID- 26971340 TI - Renal cell carcinoma: staging and surveillance. AB - Renal cell carcinoma is a common malignancy with many histologic subtypes. Appropriate treatment depends not only upon the specific subtype but also the size of the tumor and extent of spread at time of presentation. Approximately 5% of RCCs are part of a hereditary syndrome which must also be considered in the therapeutic decisions. Although some RCCs are detected with ultrasound, CT or MR is required for staging. CT is used most commonly as it is most readily available and relatively less expensive than MR imaging. The TNM classification of the American Joint Committee on Cancer has largely replaced the Robson classification. Early detection, accurate staging, and improved treatment options have resulted in improved 5-year survival of patients with renal carcinoma. PMID- 26971342 TI - Study of the improvement in bone conduction threshold after stapedectomy. AB - INTRODUCTION AND OBJECTIVES: Bone conduction threshold depression is not always a result of inner ear and cochlear nerve pathology. In fact, middle ear pathologies may be responsible for such threshold depression, as occurs in otosclerosis. The aims of this study were to evaluate the improvement of bone conduction threshold in patients with otosclerosis that underwent stapedectomy and to study the postoperative audiological results. MATERIAL AND METHODS: This was a retrospective study on 95 patients (116 ears) diagnosed with otosclerosis having conductive or mixed hearing loss that received surgery (stapedectomy and complete removal of the footplate) consecutively. Audiometry was performed on all patients pre- and postoperatively (one month and one year after surgery). Bone and air conduction thresholds were measured at 4 frequencies (500, 1000, 2000 and 4000Hz). RESULTS: The air-bone gap was closed, with a residual air-bone gap below 10dB in 92.2% of the patients and below 5dB in 79.3% of the cases. The air conduction threshold improved an average of 25dB. The patients that had an affected bone conduction threshold preoperatively improved bone conduction postoperatively at the frequencies of 1000 and 2000Hz (6 and 12dB, respectively). Consequently, the Carhart notch disappeared on the audiogram. These results were maintained at one year of follow up. CONCLUSIONS: We found a significant improvement in the bone conduction threshold at the frequencies of 1000 and 2000Hz and a disappearance of the Carhart notch in the audiogram after stapedectomy and total footplate removal in patients diagnosed with otosclerosis having mixed hearing loss. PMID- 26971341 TI - Comparison of hepatocellular carcinoma conspicuity on hepatobiliary phase images with gadoxetate disodium vs. delayed phase images with extracellular cellular contrast agent. AB - OBJECTIVE: To compare the conspicuity of hepatocellular carcinoma (HCC) on hepatobiliary phase of gadoxetate disodium-enhanced vs. delayed phase of gadodiamide-enhanced MR images, relative to liver function. METHODS AND MATERIALS: We retrospectively identified 86 patients with newly diagnosed HCC between 2010 and 2013 and recorded the severity of liver disease by Child-Pugh class (CPC). 38 patients had gadodiamide-enhanced 5-min delayed and 48 had gadoxetate disodium-enhanced 20-min delayed hepatobiliary MR images. The conspicuity of 86 HCCs (mean size, 2.7 cm) was graded visually on a 3-point scale and quantified by liver-to-tumor contrast ratios (LTC). The relative liver parenchymal enhancement (RPE) was measured. For different CPCs, we compared the conspicuity of HCC and RPE between gadodiamide and gadoxetate. RESULTS: In patients with CPC A, the visual conspicuity and LTC of the 27 HCCs imaged with gadodiamide were significantly lower than those of the 38 HCCs with gadoxetate (P < 0.01, <0.01, respectively). RPE was lower in gadodiamide scans than gadoxetate scans (P < 0.01). Conversely, in patients with CPC B and C, HCCs appeared more frequently as definite hypointensity when imaged with gadodiamide (72.7%, 8/11) than gadoxetate (20%, 2/10, P = 0.03). LTC (mean 18.1 vs. 7.5, P = 0.04) and RPE (mean 75.5 vs. 45.4, P = 0.04) was significantly higher in the gadodiamide than gadoxetate scans. CONCLUSION: In patients with compromised liver function, hypointensity of HCC is more conspicuous in the gadodiamide delayed phase than the gadoxetate hepatobiliary phase. This likely reflects the high extracellular accumulation of gadodiamide and poor hepatocyte uptake of gadoxetate in patients with compromised liver function. PMID- 26971343 TI - Leucobacter populi sp. nov. isolated from a symptomatic bark of Populus * euramericana canker. AB - A Gram-stain positive, aerobic, non-motile, rod-shaped, oxidase-negative and catalase-positive bacterial strain, designated 06C10-3-11T, was isolated from the symptomatic bark of a Populus * euramericana canker. Growth occurred at 10-45 degrees C (optimum, 30 degrees C), pH 6-11 (optimum, pH 7.0-8.0), 0-7 % (w/v) NaCl (optimum, 0-1 %) and in the presence of 20 mM Cr (VI). The major fatty acids (>=10 %) of the novel strain were identified as anteiso-C15:0, anteiso-C17:0 and iso-C16:0. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phospholipid, glycolipid and two unknown lipids. The strain contained the respiratory quinone MK-10 (71 %) as a major component and MK-11 (29 %) in lesser amounts. The cell wall amino acids were 2,4-diaminobutyric acid, alanine, glutamic acid and glycine. The genomic DNA G+C content of the type strain was 69.8 mol%. Phylogenetic analysis, based on 16S rRNA gene sequences, indicated that strain 06C10-3-11T belongs to the genus Leucobacter, showing the highest 16S rRNA gene sequence similarities with Leucobacter celer NAL101T (96.19 %), 'Leucobacter kyeonggiensis' F3-P9T (96.18 %), Leucobacter denitrificans M1T8B10T (96.10 %) and Leucobacter aridicollis CIP 108388T (96.06 %). The DNA G+C content of strain 06C10-3-11T was 69.8 mol%. Based on the molecular data and physiological and biochemical characteristics, strain 06C10-3-11T is considered to represent a novel species of the genus Leucobacter, for which the name Leucobacterpopuli sp. nov. is proposed. The type strain is 06C10-3-11T (= CFCC 12199T = KCTC 39685T). PMID- 26971345 TI - Severe influenza symptoms in celiac disease: implications of CD103- dendritic cells? PMID- 26971346 TI - Treating depression in obesity: STAT3 inhibitors as future therapeutic approach? PMID- 26971344 TI - MicroRNA-27a Negatively Modulates the Inflammatory Response in Lipopolysaccharide Stimulated Microglia by Targeting TLR4 and IRAK4. AB - microRNA, a family of small non-coding RNA, plays significant roles in regulating gene expression, mainly via binding to the 3'-untranslated region of target genes. Although the role of miRNA in regulating neuroinflammation via the innate immune pathway has been studied, its role in the production of inflammatory mediators during microglial activation is poorly understood. In this study, we investigated the effect of miR-27a on lipopolysaccharide (LPS)-induced microglial inflammation. miR-27a expression was found to be rapidly decreased in microglia by real-time polymerase chain reaction (real-time PCR) after LPS stimulation. Over-expression of miR-27a significantly decreased the production of inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO), whereas knockdown of miR-27a increased the expression of these inflammatory factors. We also demonstrated by loss- and gain-of-function studies that miR-27a directly suppressed the expression of toll-like receptor 4 (TLR4) and interleukin-1 receptor-associated kinase 4 (IRAK4)-a pivotal adaptor kinase in the TLR4/MyD88 signaling pathway-by directly binding their 3'-UTRs: knocking down TLR4 or IRAK4 in microglia significantly decreased TLR4 or IRAK4 expression and inhibited the downstream production of inflammatory mediators. Moreover, the inflammatory cytokines IL-6 and IL-1beta were regulated by IRAK4, whereas TNF-alpha and NO were more dependent on TLR4 activation. Thus, miR-27a might regulate the LPS induced production of inflammatory cytokines in microglia independently of TLR4 and IRAK4. Taken together, our results suggest that miR-27a is associated with microglial activation and the inflammatory response. PMID- 26971347 TI - Association between vitamin D serum levels and disease activity markers in patients with Crohn's Disease. PMID- 26971348 TI - A systematic review and meta-analysis to reappraise the role of adjuvant hepatic arterial infusion for colorectal cancer liver metastases. PMID- 26971349 TI - Preoperative localization of left-sided colon adenocarcinomas: comparing staging CT-scan and colonoscopy. PMID- 26971350 TI - Does anaesthesia change severity of haemorrhoidal disease? A prospective and multicentre case-control study on haemorrhoidal disease assessment in two different settings: outpatient and operating theatre. PMID- 26971351 TI - Vitamin D and Diabetic Complications: True or False Prophet? AB - Vitamin D deficiency is now recognized as a condition of increasing prevalence worldwide. Vitamin D has an established role in calcium and bone metabolism; however, more recently associations with vitamin D deficiency and risk of developing diabetes, diabetes complications, and cardiovascular disease have all been acknowledged. The vitamin D receptor is ubiquitously expressed, and experimental, in vitro, and in vivo studies strongly suggest a role in regulating the transcription of multiple genes beyond calcium homeostasis. These include antiproliferative, immunomodulatory, angiogenic, inhibition of the renin angiotensin-aldosterone system, and neurotrophic factor expression. Observational studies report a strong association between vitamin D deficiency and cardiovascular and metabolic disorders; however, there remains a paucity of large long-term randomized clinical trials showing a benefit with treatment. An increasing body of literature suggests a possible pathogenetic role of vitamin D in the long-term complications of diabetes and vitamin D deficiency may also exacerbate symptoms of painful diabetic peripheral neuropathy. It remains unknown if supplementation of vitamin D to normal or non-deficient levels alters pathogenetic processes related to diabetic microvascular complications. With the high prevalence of vitamin D deficiency in patients with diabetes and putative mechanisms linking vitamin D deficiency to diabetic complications, there is a compelling argument for undertaking large well-designed randomized controlled trials of vitamin D supplementation. PMID- 26971354 TI - Successful Improvement of Metabolic Disorders, Including Osteopenia, by a Dopamine Agonist in a Male Patient with Macro-Prolactinoma. AB - BACKGROUND: Bone metabolic disorders in patients with prolactinoma have not been fully characterized. The case presented herein illustrates potential causal associations between prolactinoma and osteopenia, with a reversal of the disorder by treatment with a dopamine agonist. CASE REPORT: A 43-year-old male with macro prolactinoma [PRL 7770 ng/mL] was referred to our hospital. He suffered was overweight [body mass index (BMI) 29.4 kg/m2] and had impaired glucose tolerance, hypertriglyceridemia, and osteopenia. The patient was administered cabergoline, a dopamine D2 receptor agonist, and the dose was gradually increased up to 9 mg/week over the period of 1 year. One year later, the patient's serum PRL levels decreased to within the normal range (19.1 ng/mL), and his pituitary tumor mass decreased to 1/4 of its initial size. His weight, dyslipidemia, and impaired glucose tolerance improved within 1 year. A marked increase in the bone mineral density (BMD) at the second to fourth lumbar spine (from 0.801 g/cm2 to 0.870 g/cm2, +8.6%) and at the femoral neck (from 0.785 g/cm2 to 0.864 g/cm2, +10.1%) were observed despite the presence of unresolved hypogonadism. CONCLUSIONS: Treatments with dopamine agonists represent a beneficial strategy for patients with prolactinoma accompanied with bone loss, in addition to their established efficacy in shrinkage of the size of pituitary tumors, normalization of PRL levels, and improvement of metabolic disorders. PMID- 26971353 TI - Dentists' attitudes and behaviour regarding deep carious lesion management: a multi-national survey. AB - OBJECTIVES: The present study aimed, using a questionnaire, to assess and compare behaviour, attitudes and beliefs of French, German and Norwegian dentists regarding deep carious lesion management. MATERIALS AND METHODS: A mail survey was applied to simple random national samples of dentists. Descriptive analysis and logistic regression analysis were performed. RESULTS: Sample size was 661 (response rate, 33 %) in France, 622 (25 %) in Germany and 199 (33 %) in Norway. Hardness was the criterion used most often for assessing carious tissue removal in all three countries (>95 %), with most dentists aiming for only hard dentine remaining at the pulpal wall (>66 %); dentine colour was not found relevant by most respondents. The majority of French and German practitioners (>66 %) would perform complete excavation even for deep lesions, while most Norwegian dentists (84 %) opted for stepwise excavation. Most dentists thought complete removal was required to avoid lesion progression and were uncertain if remaining sealed bacteria would harm the pulp. Treatment decisions were guided by prior experience and familiarity. For example, stepwise removal was performed less often by dentists who were male, French, German or those in the private sector. CONCLUSIONS: Less invasive strategies for managing deep lesions have not widely entered clinical practice in France and Germany. Underlying beliefs shape decision-making. CLINICAL RELEVANCE: The present study is the first of its nature to analyse and compare deep carious lesion management between three European countries. It shows that there is an urgent need to practically educate dentists in less invasive strategies. PMID- 26971352 TI - Controlled, prospective, randomized, clinical split-mouth evaluation of partial ceramic crowns luted with a new, universal adhesive system/resin cement: results after 18 months. AB - OBJECTIVES: A new universal adhesive with corresponding luting composite was recently marketed which can be used both, in a self-etch or in an etch-and-rinse mode. In this study, the clinical performance of partial ceramic crowns (PCCs) inserted with this adhesive and the corresponding luting material used in a self etch or selective etch approach was compared with a self-adhesive universal luting material. MATERIAL AND METHODS: Three PCCs were placed in a split-mouth design in 50 patients. Two PCCs were luted with a combination of a universal adhesive/resin cement (Scotchbond Universal/RelyX Ultimate, 3M ESPE) with (SB+E)/without (SB-E) selective enamel etching. Another PCC was luted with a self adhesive resin cement (RelyX Unicem 2, 3M ESPE). Forty-eight patients were evaluated clinically according to FDI criteria at baseline and 6, 12 and 18 months. For statistical analyses, the chi-square test (alpha = 0.05) and Kaplan Meier analysis were applied. RESULTS: Clinically, no statistically significant differences between groups were detected over time. Within groups, clinically significant increase for criterion "marginal staining" was detected for SB-E over 18 months. Kaplan-Meier analysis revealed significantly higher retention rates for SB+E (97.8 %) and SB-E (95.6 %) in comparison to RXU2 (75.6 %). CONCLUSION: The 18-month clinical performance of a new universal adhesive/composite combination showed no differences with respect to bonding strategy and may be recommended for luting PCCs. Longer-term evaluation is needed to confirm superiority of SB+E over SB-E. CLINICAL RELEVANCE: At 18 months, the new multi mode adhesive, Scotchbond Universal, showed clinically reliable results when used for luting PCCs. PMID- 26971357 TI - Jimmy Frank Howell, M.D. PMID- 26971356 TI - Recommended composition of influenza virus vaccines for use in the 2016-2017 northern hemisphere influenza season. PMID- 26971355 TI - The Ring Finger Protein RNF6 Induces Leukemia Cell Proliferation as a Direct Target of Pre-B-cell Leukemia Homeobox 1. AB - RNF6 is a little-studied ring finger protein. In the present study, we found that RNF6 was overexpressed in various leukemia cells and that it accelerated leukemia cell proliferation, whereas knockdown of RNF6 delayed tumor growth in xenografts. To find out the mechanism of RNF6 overexpression in leukemia, we designed a series of truncated constructs of RNF6 regulatory regions in the luciferase reporter system. The results revealed that the region between -144 and -99 upstream of the RNF6 transcription start site was critical and that this region contained a PBX1 recognition element (PRE). PBX1 modulated RNF6 expression by binding to the specific PRE. When PRE was mutated, RNF6 transcription was completely abolished. Further studies showed that PBX1 collaborated with PREP1 but not MEIS1 to modulate RNF6 expression. Moreover, RNF6 expression could be suppressed by doxorubicin, a major anti-leukemia agent, via down-regulating PBX1. This study thus suggests that RNF6 overexpression in leukemia is under the direction of PBX1 and that the PBX1/RNF6 axis can be developed as a novel therapeutic target of leukemia. PMID- 26971358 TI - Houston Methodist Hospital Recognizes Outstanding Cardiology Fellows During Annual Awards Dinner. PMID- 26971361 TI - [Perception of physicians on factors that influence the choice of a dicoumarin or a new oral anticoagulant in patients with non-valvular atrial fibrillation]. AB - AIMS: Recent studies have demonstrated the efficacy and safety of new oral anticoagulant drugs for the prevention of thromboembolic events in patients with non-valvular atrial fibrillation. Our aim was to evaluate the factors that can influence physicians in their choice between a classic and a new anticoagulant in these patients. DESIGN: Several variables of interest were discussed and analysed using a WorkmatTM methodology. SITES: Six regional meetings were held in Spain (East, Catalonia, Andalusia-Extremadura, Madrid, North-east, and North of Spain). PARTICIPANTS: Meetings were attended by 39 specialists (cardiologists, neurologists, haematologists, internists, and emergency and Primary Care physicians). MEASUREMENTS: Each participant graded their level of agreement, with a score from 1 to 10, on every analysed variable. RESULTS: A new anticoagulant drug was preferred in patients with previous failure of dicoumarin therapy (9.7+/ 0.5), high haemorrhagic risk (8.7+/-1), prior bleeding (7.8+/-1.5), and high thrombotic risk (7.7+/-1.2). Dicoumarins were preferred in cases of severe (1.2+/ 0.4) or moderate (4.2+/-2.5) kidney failure, good control with dicoumarins (2.3+/ 1.5), cognitive impairment (3.2+/-3), and low haemorrhagic risk (4.3+/-3). Age, sex, weight, cost of drug, polymedication, and low thrombotic risk achieved intermediate scores. There were no differences between the different specialists or Spanish regions. CONCLUSIONS: The presence of a high thrombotic or haemorrhagic risk and the failure of previous dicoumarin therapy lead to choosing a new oral anticoagulant in patients with non-valvular atrial fibrillation, while kidney failure, cognitive impairment, good control with dicoumarins, and a low bleeding risk predispose to selecting a classic dicoumarin anticoagulant. PMID- 26971362 TI - Graphene-Based Bionic Composites with Multifunctional and Repairing Properties. AB - In this work, a novel bionic composite inspired by the concept of yeast fermentation has been proposed. It was observed that the addition of graphene nanoplatelets during the fermentation of extract of Saccharomyces cerevisiae fungi allows coupling of the graphene sheets to the yeast cell wall. This process resulted in the formation of a composite film with improved mechanical and electrical properties along with the capability of converting the light stimulus in the electrical signal. The mechanical properties of the prepared composites, namely, the fracture strength and Young's modulus, were studied via numerical simulations and are related to the properties of the constituent phases via rules of mixture. Finally, it was observed that graphene nanoplatelets, added to the nutrient broth, were able to reassemble onto the stressed cell surface and repair the surface cracking, partially restoring the pristine electrical and mechanical properties. The method reported here may find potential application in the development of self-healable bioelectronic devices and microorganism-based strain and chemical biosensors. PMID- 26971359 TI - Clinimetric testing of the comprehensive cervical dystonia rating scale. AB - INTRODUCTION: The aim of this study was to test the clinimetric properties of the Comprehensive Cervical Dystonia Rating Scale. This is a modular scale with modifications of the Toronto Western Spasmodic Torticollis Rating Scale (composed of three subscales assessing motor severity, disability, and pain) now referred to as the revised Toronto Western Spasmodic Torticollis Scale-2; a newly developed psychiatric screening instrument; and the Cervical Dystonia Impact Profile-58 as a quality of life measure. METHODS: Ten dystonia experts rated subjects with cervical dystonia using the comprehensive scale. Clinimetric techniques assessed each module of the scale for reliability, item correlation, and factor structure. RESULTS: There were 208 cervical dystonia patients (73% women; age, 59 +/- 10 years; duration, 15 +/- 12 years). Internal consistency of the motor severity subscale was acceptable (Cronbach's alpha = 0.57). Item to total correlations showed that elimination of items with low correlations (<0.20) increased alpha to 0.71. Internal consistency estimates for the subscales for disability and pain were 0.88 and 0.95, respectively. The psychiatric screening scale had a Cronbach's alpha of 0.84 and satisfactory item to total correlations. When the subscales of the Toronto Western Spasmodic Torticollis Scale-2 were combined with the psychiatric screening scale, Cronbach's alpha was 0.88, and construct validity assessment demonstrated four rational factors: motor; disability; pain; and psychiatric disorders. The Cervical Dystonia Impact Profile 58 had an alpha of 0.98 and its construction was validated through a confirmatory factor analysis. CONCLUSIONS: The modules of the Comprehensive Cervical Dystonia Rating Scale are internally consistent with a logical factor structure. PMID- 26971360 TI - Differential predictors of ART adherence among HIV-monoinfected versus HIV/HCV coinfected individuals. AB - Although adherence is an important key to the efficacy of antiretroviral therapy (ART), many people living with HIV (PLWH) fail to maintain optimal levels of ART adherence over time. PLWH with the added burden of Hepatitis C virus (HCV) coinfection possess unique challenges that potentially impact their motivation and ability to adhere to ART. The present investigation sought to (1) compare ART adherence levels among a sample of HIV/HCV-coinfected versus HIV-monoinfected patients, and (2) identify whether ART-related clinical and psychosocial correlates differ by HCV status. PLWH receiving ART (N = 215: 105 HIV/HCV coinfected, 110 HIV-monoinfected) completed a comprehensive survey assessing ART adherence and its potential correlates. Medical chart extraction identified clinical factors, including liver enzymes. Results demonstrated that ART adherence did not differ by HCV status, with 83.7% of coinfected patients and 82.4% of monoinfected patients reporting optimal (i.e., >=95%) adherence during a four-day recall period (p = .809). Multivariable logistic regression demonstrated that regardless of HCV status, optimal ART adherence was associated with experiencing fewer adherence-related behavioral skills barriers (AOR = 0.56; 95%CI = 0.43-0.73), lower likelihood of problematic drinking (AOR = 0.15; 95%CI = 0.04-0.67), and lower likelihood of methamphetamine use (AOR = 0.14; 95%CI = 0.03 0.69). However, among HIV/HCV-coinfected patients, optimal adherence was additionally associated with experiencing fewer ART adherence-related motivational barriers (AOR = 0.23; 95%CI = 0.08-0.62) and lower likelihood of depression (AOR = 0.06; 95%CI = 0.00-0.84). Findings suggest that although HIV/HCV-coinfected patients may face additional, distinct barriers to ART adherence, levels of adherence commensurate with those demonstrated by HIV monoinfected patients might be achievable if these barriers are addressed. PMID- 26971363 TI - Genetic Optimization of Metalloenzymes: Enhancing Enzymes for Non-Natural Reactions. AB - Artificial metalloenzymes have received increasing attention over the last decade as a possible solution to unaddressed challenges in synthetic organic chemistry. Whereas traditional transition-metal catalysts typically only take advantage of the first coordination sphere to control reactivity and selectivity, artificial metalloenzymes can modulate both the first and second coordination spheres. This difference can manifest itself in reactivity profiles that can be truly unique to artificial metalloenzymes. This Review summarizes attempts to modulate the second coordination sphere of artificial metalloenzymes by using genetic modifications of the protein sequence. In doing so, successful attempts and creative solutions to address the challenges encountered are highlighted. PMID- 26971365 TI - Admission sodium level and prognosis in adult Guillain-Barre syndrome. AB - PURPOSE: Guillain-Barre syndrome (GBS) varies in severity and outcome. Hyponatremia predicts poor outcome but previous studies have used divergent methodology and (pseudo)hyponatremia caused by intravenous immunoglobulin administration may confound analysis. We studied if the plasma sodium level at admission was associated with GBS outcome. METHODS: All 69 patients at least 16 years of age treated for GBS in Turku University Hospital in 2004-2013 were included in the study. Clinical information was obtained from patient charts. RESULTS: Women had lower sodium levels at admission (138; IQR 135, 140) compared to men (140; IQR 138, 142; p = 0.0116) but no association of sodium levels with demographics, pre-hospital variables or basic GBS characteristics was found. Multivariate analyses showed lower admission sodium levels to be associated with worse functional status at one year from disease onset (OR 1.37; 95% CI 1.07 1.76; p = 0.0136) and probability of being discharged to another care facility from the hospital (OR 1.31; 95% CI 1.05-1.64; p = 0.0180) but not associated with need of intensive care unit care (p = 0.09) or mechanical ventilation (p = 0.45), length of hospital stay (p =0.48) or functional status at six months (p = 0.07). CONCLUSIONS: Low plasma sodium level at admission is associated with a more severe disease course and a worse outcome in GBS independently of previously identified prognostic factors. Hyponatremia does not, however, appear to be caused by disease-specific factors. PMID- 26971366 TI - Erratum. PMID- 26971364 TI - Synaptic organization of striate cortex projections in the tree shrew: A comparison of the claustrum and dorsal thalamus. AB - The tree shrew (Tupaia belangeri) striate cortex is reciprocally connected with the dorsal lateral geniculate nucleus (dLGN), the ventral pulvinar nucleus (Pv), and the claustrum. In the Pv or the dLGN, striate cortex projections are thought to either strongly "drive", or more subtly "modulate" activity patterns respectively. To provide clues to the function of the claustrum, we compare the synaptic arrangements of striate cortex projections to the dLGN, Pv, and claustrum, using anterograde tracing and electron microscopy. Tissue was additionally stained with antibodies against gamma-aminobutyric acid (GABA) to identify GABAergic interneurons and non-GABAergic projection cells. The striate cortex terminals were largest in the Pv (0.94 +/- 0.08 MUm2 ), intermediate in the claustrum (0.34 +/- 0.02 MUm2 ), and smallest in the dLGN (0.24 +/- 0.01 MUm2 ). Contacts on interneurons were most common in the Pv (39%), intermediate in the claustrum (15%), and least common in the dLGN (12%). In the claustrum, non GABAergic terminals (0.34 +/- 0.01 MUm2 ) and striate cortex terminals were not significantly different in size. The largest terminals in the claustrum were GABAergic (0.51 +/- 0.02 MUm2 ), and these terminals contacted dendrites and somata that were significantly larger (1.90 +/- 0.30 MUm2 ) than those contacted by cortex or non-GABAergic terminals (0.28 +/- 0.02 MUm2 and 0.25 +/- 0.02 MUm2 , respectively). Our results indicate that the synaptic organization of the claustrum does not correspond to a driver/modulator framework. Instead, the circuitry of the claustrum suggests an integration of convergent cortical inputs, gated by GABAergic circuits. J. Comp. Neurol. 525:1403-1420, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26971367 TI - In reference to The topical use of insulin accelerates the healing of traumatic tympanic membrane perforations. PMID- 26971368 TI - Highly Concordant Key Genetic Alterations in Primary Tumors and Matched Distant Metastases in Differentiated Thyroid Cancer. AB - BACKGROUND: Distant metastases uncommonly occur in differentiated thyroid carcinoma (DTC), but they are a frequent cause of thyroid cancer-related death. Genomic alterations in metastatic tumors, and the relationship with their corresponding primary tumors in DTC, are poorly understood. The objective of this study was to investigate whether genetic alterations in primary tumors are concordant with distant metastases in DTC patients. METHODS: Surgical samples from primary and matched distant metastatic tumor pairs from 17 DTC patients, and three additional unpaired metastatic tumors from two patients, were analyzed using targeted next-generation sequencing (Ion Torrent Ampliseq cancer panel) with a focus on known recurrent somatic mutations in thyroid cancer. Additionally, TERT promoter mutations were assessed by direct sequencing. RESULTS: BRAF mutations were found in 8/10 patients with papillary thyroid carcinoma (PTC). A NRAS mutation was detected in one patient with follicular variant PTC. TERT promoter mutations were detected in 8/10 patients with PTC, and most were coexistent with a BRAF mutation (7/8 BRAF-positive PTC patients, and one BRAF-negative PTC patient). In follicular thyroid carcinoma, NRAS was the most frequently observed mutation (4/9 patients), followed by HRAS (two patients) and KRAS (one patient). TERT promoter mutations were found in 6/7 RAS-positive follicular thyroid carcinoma patients. Key somatic alterations such as BRAF and RAS mutations were highly concordant between primary and matched metastatic tumors without discrepancies. The BRAF or RAS mutant allelic frequency was higher in matched metastatic tumors than in the corresponding primary tumors (35% vs. 25% for BRAF mutation, p = 0.04; and 40% vs. 34% for RAS mutation, p = 0.002). TERT promoter mutations were also mostly concordant in matched tumors (concordance rate 93%). CONCLUSIONS: BRAF, RAS, and TERT mutations are highly prevalent in metastatic DTC, and are concordant between primary and metastatic DTC. This high concordance suggests that primary tumors may reflect the key somatic alterations in matched metastatic DTC. Frequent coexistent TERT promoter and BRAF or RAS mutations in metastatic DTC also suggests its important role in the progression of DTC. PMID- 26971369 TI - [Multiple facial nodules revealing disseminated cryptococcosis in an immunocompetent patient]. AB - BACKGROUND: Cryptococcosis is a potentially severe infection that usually occurs in a setting of immunosuppression. Its occurrence outside of this context is rare. We report a case of disseminated cryptococcosis revealed by a spectacular skin disease in an immunocompetent patient. PATIENTS AND METHODS: A 40-year-old male patient had been presenting multiple nodules and tumors on his face for one month in a context of asthenia and intermittent fever. Histological examination of a skin biopsy revealed encapsulated yeasts strongly suggestive of Cryptococcus neoformans. Mycological examination of the skin biopsy and cerebrospinal fluid isolated Cryptococcus gattii. The blood cultures were positive. Brain MRI demonstrated cryptococcal parenchymal involvement. Screening for primary or secondary immunodeficiency was negative. The patient received amphotericin B 1mg/kg/day and fluconazole 600mg/day but died 2months after diagnosis. DISCUSSION: Cryptococcosis is a potentially severe infection caused by C. neoformans. This rare condition occurs most commonly in patients with profound deficiency in terms of cellular immunity. Although rare, the occurrence of cryptococcosis in immunocompetent patients is possible, and in this event the signs are highly polymorphic, which usually makes it very difficult to diagnose. The diagnosis of cryptococcosis is based on the identification by direct examination and after staining with India ink of encapsulated yeasts of the Cryptococcus genus. Culture on Sabouraud medium is essential for identification of the species. Treatment for disseminated cryptococcosis involves amphotericin B, often associated with flucytosine IV. In the event of meningitis infection in non-HIV patients, mortality continues to be around 15%, despite adequate medical treatment. CONCLUSION: Although rare, cryptococcosis can occur in immunocompetent subjects. The prognosis is severe even after treatment. PMID- 26971371 TI - Spatial epidemiology and risk factors of pulmonary tuberculosis morbidity in Wenchuan earthquake-stricken area. AB - OBJECTIVE: China is a country that experiences frequent earthquakes and has a high pulmonary tuberculosis burden. In this study, we aimed to explore the spatial clustering and risk factors of the reported incidence of pulmonary tuberculosis burden before and after the Wenchuan earthquake. METHODS: Data on the location and the demographic, socioeconomic, and health service characteristics of the 181 counties of Sichuan province from 2004 to 2012 were collected. Global and local spatial autocorrelation analyses were performed to explore spatial clustering. The associated factors were screened using stepwise multiple linear regression, and a spatial lag model was fitted to explore the influence factors. RESULTS: The incidence of pulmonary tuberculosis burden showed a global and local spatial autocorrelation relationship. The high-incidence counties shifted gradually over time from east to west and finally clustered in the "Aba-Ganzi" region. Factors influencing the incidence of pulmonary tuberculosis burden included minority areas, the proportion of the working population, county latitude, and the severity of the earthquake. The influence factors varied over time; the impact of minority regions, occupation, and health resources allocation weakened, whereas the economic development and mobility of the population became more significant. CONCLUSION: The spatial structural relationship is an important factor related to pulmonary tuberculosis burden incidence. More attention should be paid to high-incidence areas and populations susceptible to pulmonary tuberculosis burden. PMID- 26971370 TI - [Teledermatology in a prison setting: A retrospective study of 500 expert opinions]. AB - BACKGROUND: Fresnes prison is one of the largest penitentiary centres in France (around 2300 inmates). Since dermatological consultations are not possible on site, a teledermatology agreement was signed in 2008 between the Kremlin-Bicetre hospital, used by the Fresnes consultation unit and outpatient care (UCSA) and the Saint-Louis hospital for remote dermatological expertise. We report the results of the last 3 years of teledermatology activity in this prison. PATIENTS AND METHODS: All teledermatology consultations from September 2010 to September 2013 were analysed. The teledermatological consultations requested by UCSA doctors included photos of lesions, patient history and disease history. Applications were sent by e-mail via the secure AP-HP (Paris Hospitals) intranet. In all instances, patients had consented to being photographed and these photos were transmitted for remote expertise. The answers were given in a maximum period of 5 working days. The following data were studied: sex, age, phototype, medical history, diagnoses, assessments requested and treatment received. RESULTS: Five hundred teledermatological consultations were analysed. Among the patients, 94.1% were male with a mean age of 34 years. Phototypes IV and VI constituted the majority, with respective percentages of 30.6% and 28.6%. The dermatoses diagnosed were for the most part mild and varied: cutaneous infections (20.2%), monitoring of nevi (11.5%), genital warts (10%), eczema (8.5%), acne (8.1%) and psoriasis (4.2%). Two cases (basal cell carcinoma and lupus) required ablation. Systemic treatments such as methotrexate and isotretinoin were initiated and monitored remotely. DISCUSSION: The most frequently observed diagnoses were not significantly different from those observed in the general population with comparable characteristics. The high phototype of patients requires extensive experience of the dermatology of black skin. Teledermatology is also important in monitoring nevi among prisoners. The low incidence of scabies is due to its systematic detection in prisoners on initial entry into prison. Furthermore, teledermatology is actively used in the teaching of prison doctors requiring training, and whose requests are becoming more and more relevant with time. CONCLUSION: This study provides greater knowledge of dermatological diseases in prison and shows teledermatology to be a tool suited to the specific constraints of this universe, while providing inmates with medical care as close as possible to that of the general population, and it thus helps ensure that their fundamental human rights are upheld. PMID- 26971373 TI - Should Therapeutic Drug Monitoring for Monoclonal Antibodies Remain the Exception or Become the Norm? AB - Therapeutic drug monitoring (TDM) aims to maintain circulating drug concentrations at a desired level to optimize clinical outcome. The vast majority of marketed drugs do not require TDM, suggesting the clinical benefit of TDM has not been sufficiently demonstrated in most cases. With the continued emergence and prominence of monoclonal antibodies (mAbs) as drugs, especially in inflammation and cancer therapeutic areas, we are at a juncture to consider applicability of TDM for mAbs. PMID- 26971372 TI - The West German Study Group Breast Cancer Intrinsic Subtype study: a prospective multicenter decision impact study utilizing the Prosigna assay for adjuvant treatment decision-making in estrogen-receptor-positive, HER2-negative early stage breast cancer. AB - PURPOSE: The West German Study Group (WSG) Breast Cancer Intrinsic Subtype (BCIST) study was designed to assess the influence of Prosigna gene signature assay results on physicians' adjuvant treatment recommendations by determining the extent of change in pre-test treatment recommendations following assay results. Secondary objectives were to assess the influence of Prosigna results on physicians' confidence in their therapeutic recommendations and on patients' decisional conflict status, anxiety levels, and functional status. METHODS: This prospective, observational, decision impact study enrolled consecutive postmenopausal patients with estrogen-receptor (ER)-positive, HER2-negative, lymph-node-negative early-stage breast cancer in 11 centers in Germany. Physicians based their pre-test adjuvant treatment recommendations on standard clinico-pathological parameters. Tumor specimens were assayed using the Prosigna test in a WSG central pathology laboratory following manufacturer's guidelines. An independent pathology laboratory performed subsequent Prosigna assays on tumor sections to assess assay result concordance with the central laboratory. Physicians completed treatment confidence questionnaires prior to and after receiving Prosigna test results. Patients completed standardized questionnaires on decisional conflict, anxiety, and health status both before and after Prosigna testing. RESULTS: The present study population consisted predominantly of low-to intermediate risk patients (N = 198). Prosigna had 29.3% discordance in intrinsic subtyping with local immunohistochemistry test results. After Prosigna test results, a change in the adjuvant therapy recommendation occurred in 36 (18.2%) patients; 22 (11.1%) patients switched from no chemotherapy to chemotherapy. After Prosigna test results, physicians expressed increased confidence in their prognostic assessment in 87.9% of patients, and increased confidence in their treatment recommendation in 89.4%. Patients reported improved anxiety and emotional/functional well-being after receiving Prosigna test results. CONCLUSIONS: Use of the Prosigna assay led to a change in 18.2% of adjuvant treatment decisions. Prosigna testing was associated with increased patient and physician confidence in treatment decisions, and with decreased patient anxiety and improved well-being. Any comparison of the therapeutic decision-making impacts of different genomic assays must account for potential confounding factors. PMID- 26971374 TI - TCDD promoted EMT of hFPECs via AhR, which involved the activation of EGFR/ERK signaling. AB - One critical step of second palatal fusion is the newly formed medial epithelia seam (MES) disintegration, which involves apoptosis, epithelial to mesenchymal transition (EMT), and cell migration. Although the environmental toxicant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) produces cleft palate at high rates, little is known about the effects of TCDD exposure on the fate of palatal epithelial cells. By using primary epithelial cells isolated from human fetal palatal shelves (hFPECs), we show that TCDD increased cell proliferation and EMT, as demonstrated by increased the epithelial markers (E-cadherin and cytokeratin14) and enhanced the mesenchymal markers (vimentin and fibronectin), but had no effect on cell migration and apoptosis. TCDD exposure led to a dose-dependent increase in Slug protein expression. Coimmunoprecipitation revealed that TCDD promoted AhR to form a protein complex with Slug. ChIP assay confirmed that TCDD exposure recruited AhR to the xenobiotic responsive element of Slug promoter. Knockdown of AhR by siRNA remarkably weakened TCDD-induced binding of AhR to the XRE promoter of slug, thereby suppressed TCDD-induced vimentin. Further experiment showed that TCDD stimulated EGFR phosphorylation did not influence the TGFbeta3/Smad signaling; whereas TCDD increased phosphorylation of ERK1/2 and p38 with no effect on activation of JNK. By using varieties of inhibitors, we confirmed that TCDD promoted proliferation and EMT of hFPECs via activation of EGFR/ERK pathway. These data make a novel contribution to the molecular mechanism of cleft palate by TCDD. PMID- 26971375 TI - Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system. AB - Metformin is a widely used oral antidiabetic drug with known anti-inflammatory properties due to its action on AMPK protein. This drug has shown a protective effect on various tissues, including cortical neurons. The aim of this study was to determine the effect of metformin on the dopaminergic neurons of the substantia nigra of mice using the animal model of Parkinson's disease based on the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an inhibitor of the mitochondrial complex I. In vivo and in vitro experiments were used to study the activation of microglia and the damage of the dopaminergic neurons. Our results show that metformin reduced microglial activation measured both at cellular and molecular levels. Rather than protecting, metformin exacerbated dopaminergic damage in response to MPTP. Our data suggest that, contrary to other brain structures, metformin treatment could be deleterious for the dopaminergic system. Hence, metformin treatment may be considered as a risk factor for the development of Parkinson's disease. PMID- 26971376 TI - Histomorphologic superiority of internal thoracic arteries over right gastroepiploic arteries for coronary bypass. AB - OBJECTIVE: In this study, we compared the histologic and morphometric properties of both internal thoracic arteries and the right gastroepiploic artery (GEA) in patients undergoing coronary artery bypass grafting (CABG). METHODS: We microscopically examined transverse sections of segments of both internal thoracic arteries and the right GEA obtained from 83 consecutive patients who underwent CABG. RESULTS: There were no significant differences between the internal thoracic arteries. Significant differences were found between the left and right internal thoracic arteries and GEA in the intimal width (21.8, 21.5, and 71.7 MUm, respectively; P < .01), intima-to-media ratio (0.286, 0.256, and 0.749, respectively; P < .01), and media width (148.5, 157.5, and 164.8 MUm, respectively; P = .43). No atherosclerotic lesions, medial calcification, or intimal thickening were seen in the internal thoracic arteries; however, atherosclerotic lesions were seen in the GEA. The intima of the GEA was thicker than that of the internal thoracic arteries. Intimal thickening of the GEA, but not the internal thoracic arteries, was positively correlated with risk of arteriosclerosis. In patients with diabetes mellitus, dietary/drug therapy and insulin therapy were associated with GEA intimal thickness (P = .02 and .01, respectively). CONCLUSIONS: The internal thoracic arteries have equivalent histologic and morphometric properties that differ from those of the GEA only in intimal width. The former had no intimal thickening, and is thus preferable to the GEA for CABG. PMID- 26971377 TI - Reduced continuous-flow left ventricular assist device speed does not decrease von Willebrand factor degradation. AB - BACKGROUND: Nonsurgical bleeding is a frequent complication of continuous-flow left ventricular assist device (LVAD) support. Abnormal von Willebrand factor (vWF) metabolism plays a major role. However, the relationship between LVAD speed and vWF degradation is unknown. Recent evidence has demonstrated that supraphysiologic shear stress from continuous-flow LVADs accelerates vWF degradation and causes an acquired vWF deficiency and bleeding. To manage LVAD associated bleeding, it has been proposed that reduced LVAD speed may decrease shear stress and thereby reduce pathologic vWF metabolism. However, there are little published data to support this clinical practice. We tested the hypothesis that reduced continuous-flow LVAD speed decreases vWF degradation. METHODS: Whole blood was collected from patients before and after the implantation of a HeartMate II continuous-flow LVAD (n = 10) to quantify in vivo vWF degradation. In parallel, to evaluate the relationship between LVAD rpm and vWF degradation, whole blood was collected from human donors (n = 30). Single-donor units of blood circulated in an ex vivo HeartMate II mock circulatory loop for 12 hours at 11,400, 10,000, or 8600 rpm (n = 10/each rpm group). vWF multimers and degradation fragments were characterized with electrophoresis and immunoblot analysis. Paired Student t tests were performed within each group. ANOVA with Tukey post hoc test was performed across groups. RESULTS: In patients, LVAD support reduced large vWF multimers and significantly (P < .05) increased vWF degradation fragments. The profile of vWF degradation was nearly identical between LVAD patients and blood circulated in the LVAD mock circulatory loop. At 11,400, 10,000, and 8600 rpm, decreased large vWF multimers and significantly increased vWF degradation fragments were noted. vWF degradation fragments were not statistically different across the 3 rpm groups or versus LVAD patients, which suggested that LVAD rpm did not influence vWF degradation. CONCLUSIONS: Reduced LVAD speed (within the clinical operational range) did not significantly decrease vWF degradation in a mock circulatory loop with human blood. During bleeding events, reduced LVAD speed, itself, may not diminish vWF degradation. PMID- 26971378 TI - Transition to practice in pediatric cardiac surgery: Preparation, execution, and balance. PMID- 26971379 TI - Real-time recording of annuloplasty suture dehiscence reveals a potential mechanism for dehiscence cascade. PMID- 26971380 TI - A simple modification to lower incidence of heart block with sutureless valve implantation. PMID- 26971381 TI - Can the art of mitral valve repair become completely standardized? PMID- 26971382 TI - Occlusion of an ascending aortic pseudoaneurysm with intraoperative echocardiography and a printed model. PMID- 26971383 TI - The ascent of POEM: Double-tunnel per oral endoscopic re-myotomy. PMID- 26971384 TI - Type A aortic dissection in self-selected patients: What seems to fit a few does not fit all. PMID- 26971385 TI - Is there a need for a new staging system in early lung cancer? PMID- 26971386 TI - Continuous-flow left ventricular assist devices and bleeding events: Is there a biological role for decreasing pump speed? PMID- 26971388 TI - Cage Opening of a Carborane Ligand by Metal Cluster Complexes. AB - The reaction of Os3 (CO)10 (NCMe)2 with closo-o-C2 B10 H10 has yielded two interconvertible isomers Os3 (CO)9 (MU3 -4,5,9-C2 B10 H8 )(MU-H)2 (1 a) and Os3 (CO)9 (MU3 -3,4,8-C2 B10 H8 )(MU-H)2 (1 b) formed by the loss of the two NCMe ligands and one CO ligand from the Os3 cluster. Two BH bonds of the o-C2 B10 H10 were activated in its addition to the osmium cluster. A second triosmium cluster was added to the 1 a/1 b mixture to yield the complex Os3 (CO)9 (MU-H)2 (MU3 4,5,9-MU3 -7,11,12-C2 B10 H7 )Os3 (CO)9 (MU-H)3 (2) that contains two triosmium triangles attached to the same carborane cage. When heated, 2 was transformed to the complex Os3 (CO)9 (MU-H)(MU3 -3,4,8-MU3 -7,11,12-C2 B10 H8 )Os3 (CO)9 (MU-H) (3) by a novel opening of the carborane cage with loss of H2 . PMID- 26971387 TI - Characterizing gradient echo signal decays in gynecologic cancers at 3T using a Gaussian augmentation of the monoexponential (GAME) model. AB - PURPOSE: To assess whether R2* mapping with a standard Monoexponential (ME) or a Gaussian Augmentation of the Monoexponential (GAME) decay model better characterizes gradient-echo signal decays in gynecological cancers after external beam radiation therapy at 3T, and evaluate implications of modeling for noninvasive identification of intratumoral hypoxia. MATERIALS AND METHODS: Multi gradient-echo signals were acquired on 25 consecutive patients with gynecologic cancers and three healthy participants during inhalation of different oxygen concentrations at 3T. Data were fitted with both ME and GAME models. Models were compared using F-tests in tumors and muscles in patients, muscles, cervix, and uterus in healthy participants, and across oxygenation levels. RESULTS: GAME significantly improved fitting over ME (P < 0.05): Improvements with GAME covered 34% of tumor regions-of-interest on average, ranging from 6% (of a vaginal tumor) to 68% (of a cervical tumor) in individual tumors. Improvements with GAME were more prominent in areas that would be assumed hypoxic based on ME alone, reaching 90% as ME R2* approached 100 Hz. Gradient echo decay parameters at different oxygenation levels were not significantly different (P = 0.81). CONCLUSION: R2* may prove sensitive to hypoxia; however, inaccurate representations of underlying data may limit the success of quantitative assessments. Although the degree to which R2 or sigma values correlate with hypoxia remains unknown, improved characterization with GAME increases the potential for determining any correlates of fit parameters with biomarkers, such as oxygenation status. J. MAGN. RESON. IMAGING 2016;44:1020-1030. PMID- 26971389 TI - Poly(vinylpyrrolidone) supported copper nanoclusters: glutathione enhanced blue photoluminescence for application in phosphor converted light emitting devices. AB - Poly(vinylpyrrolidone) supported Cu nanoclusters were synthesized by reduction of Cu(ii) ions with ascorbic acid in water, and initially showed blue photoluminescence with a quantum yield of 8%. An enhancement of the emission quantum yield has been achieved by treatment of Cu clusters with different electron-rich ligands, with the most pronounced effect (photoluminescence quantum yield of 27%) achieved with glutathione. The bright blue emission of glutathione treated Cu NCs is fully preserved in the solid state powder, which has been combined with commercial green and red phosphors to fabricate down-conversion white light emitting diodes with a high colour rendering index of 92. PMID- 26971390 TI - Ca(BH4)2-Mg2NiH4: on the pathway to a Ca(BH4)2 system with a reversible hydrogen cycle. AB - The Ca(BH4)2-Mg2NiH4 system presented here is, to the best of our knowledge, the first described Ca(BH4)2-based hydride composite that reversibly transfers boron from the Ca-based compound(s) to the reaction partner. The ternary boride MgNi2.5B2 is formed upon dehydrogenation and the formation of Ca(BH4)2 upon rehydrogenation is confirmed. PMID- 26971392 TI - Biophysical aspects of human thermoregulation during heat stress. AB - Humans maintain a relatively constant core temperature through the dynamic balance between endogenous heat production and heat dissipation to the surrounding environment. In response to metabolic or environmental disturbances to heat balance, the autonomic nervous system initiates cutaneous vasodilation and eccrine sweating to facilitate higher rates of dry (primarily convection and radiation) and evaporative transfer from the body surface; however, absolute heat losses are ultimately governed by the properties of the skin and the environment. Over the duration of a heat exposure, the cumulative imbalance between heat production and heat dissipation leads to body heat storage, but the consequent change in core temperature, which has implications for health and safety in occupational and athletic settings particularly among certain clinical populations, involves a complex interaction between changes in body heat content and the body's morphological characteristics (mass, surface area, and tissue composition) that collectively determine the body's thermal inertia. The aim of this review is to highlight the biophysical aspects of human core temperature regulation by outlining the principles of human energy exchange and examining the influence of body morphology during exercise and environmental heat stress. An understanding of the biophysical factors influencing core temperature will enable researchers and practitioners to better identify and treat individuals/populations most vulnerable to heat illness and injury during exercise and extreme heat events. Further, appropriate guidelines may be developed to optimize health, safety, and work performance during heat stress. PMID- 26971393 TI - Determination of Tetracycline Antibiotic Residues in Honey and Milk by Miniaturized Solid Phase Extraction Using Chitosan-Modified Graphitized Multiwalled Carbon Nanotubes. AB - A rapid, simple, and strongly selective miniaturized solid phase extraction (SPE) technique, requiring only small amounts of sorbent (24 mg) and elution solvent (600 MUL), coupled with ultrahigh-performance liquid chromatography and quadrupole time-of-flight mass spectrometry was developed for detecting tetracycline antibiotics. These analytes were extracted from honey and milk using chitosan-modified graphitized multiwalled carbon nanotubes (G-MWNTs) as the solid sorbent and acetonitrile/acetic acid (8:2, v/v) as the eluent in miniaturized SPE. Under the optimum experimental conditions, a satisfactory linearity (r(2) > 0.992) was obtained, and the limits of detection were in the range of 0.61-10.34 MUg/kg for the analytes. The mean recoveries of the five tetracycline antibiotic residues in the real samples were between 81.5 and 101.4%. The results demonstrated that chitosan-modified G-MWNTs comprise a promising material for the enrichment of tetracycline antibiotics from complex food matrices. PMID- 26971395 TI - Monoclonal antibodies for treating gastric cancer: promises and pitfalls. AB - INTRODUCTION: Gastric cancer (GC) presents dismal prognosis when diagnosed at advanced stages, standard chemotherapy having shown little efficacy. Introduction of biotherapies interfering with novel targets and signaling pathways is currently an emerging strategy. AREAS COVERED: Only two monoclonal antibodies (trastuzumab and ramucirumab) have been approved, mostly in association with cytotoxics. Conversely, testing other promising biotherapies (panitumumab, cetuximab, bevacizumab, rilotumumab) have yielded conflicting results, since encouraging early clinical trials have failed to be confirmed in larger phase-III studies. Empirical and underpowered strategies when designing combinational studies, lack of comprehensive knowledge of pharmacokinetics/pharmacodynamics (PK/PD) relationships, and underestimation of the large inter-patient variability in drug exposure levels with monoclonal antibodies, could explain the failures in developing biotherapies in gastric cancer. This review covers the achievements and limits of monoclonal antibodies in gastric cancer and proposes clues to overcome current failures. EXPERT OPINION: Trastuzumab efficacy could be improved thanks to its combination with triplet chemotherapy or with another anti-HER2 agents or in continuation during second-line chemotherapy. Concerning ramucirumab, further studies are necessary to prove its interest in first line treatment of advanced GC, to use the optimal dose in each patient-given the large inter-patients variability, and to find predictive biomarkers of efficacy. PMID- 26971391 TI - The wound/burn guidelines - 6: Guidelines for the management of burns. AB - Burns are a common type of skin injury encountered at all levels of medical facilities from private clinics to core hospitals. Minor burns heal by topical treatment alone, but moderate to severe burns require systemic management, and skin grafting is often necessary also for topical treatment. Inappropriate initial treatment or delay of initial treatment may exert adverse effects on the subsequent treatment and course. Therefore, accurate evaluation of the severity and initiation of appropriate treatment are necessary. The Guidelines for the Management of Burn Injuries were issued in March 2009 from the Japanese Society for Burn Injuries as guidelines concerning burns, but they were focused on the treatment for extensive and severe burns in the acute period. Therefore, we prepared guidelines intended to support the appropriate diagnosis and initial treatment for patients with burns that are commonly encountered including minor as well as moderate and severe cases. Because of this intention of the present guidelines, there is no recommendation of individual surgical procedures. PMID- 26971394 TI - Investigation and Manipulation of Different Analog Behaviors of Memristor as Electronic Synapse for Neuromorphic Applications. AB - Low-power and high-density electronic synapse is an important building block of brain-inspired systems. The recent advancement in memristor has provided an opportunity to advance electronic synapse design. However, a guideline on designing and manipulating the memristor's analog behaviors is still lacking. In this work, we reveal that compliance current (Icomp) of electroforming process played an important role in realizing a stable analog behavior, which is attributed to the generation of conical-type conductive filament. A proper Icomp could result in a large conductance window, good stability, and low voltage analog switching. We further reveal that different pulse conditions can lead to three analog behaviors, where the conductance changes in monotonic increase, plateau after initial jump, and impulse-like shape, respectively. These behaviors could benefit the design of electronic synapse with enriched learning capabilities. This work will provide a useful guideline for designing and manipulating memristor as electronic synapses for brain-inspired systems. PMID- 26971396 TI - Neuroprotective Effects of rhGLP-1 in Diabetic Rats with Cerebral Ischemia/Reperfusion Injury. AB - Preclinical Research The aim of the present study was to evaluate the neuroprotective benefits of rhGLP-1 in diabetic rats subjected to acute cerebral ischemia/reperfusion injury induced by middle cerebral artery occlusion/reperfusion (MCAO/R). Streptozotocin (STZ)-induced diabetic rats were pretreated with rhGLP-1 (10, 20, or 40 MUg/kg ip, tid) for 14 days. During this time, body weight and fasting blood glucose levels were assessed. Rats were then subjected to MCAO 90 min/R 24 h. At 2 and 24 h of reperfusion, rats were evaluated for neurological deficits and blood samples were collected to analyze markers of brain injury. Rats were then sacrificed to assess the infarction volume. rhGLP-1 pretreatment lowered blood glucose levels, improved neurological scores, attenuated infarct volumes, and reduced the blood levels of S100 calcium binding protein B (S100B), neuron-specific enolase (NSE), and myelin basic protein (MBP). rhGLP-1 has neuroprotective benefits in diabetic rats with cerebral ischemia/reperfusion injury and could potentially be used as a prophylatic neuroprotectant in diabetic patients at high risk of ischemic stroke. Drug Dev Res 77 : 124-133, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26971399 TI - Calculation of nanodrop profile from fluid density distribution. AB - Two approaches are examined, which can be used to determine the drop profile from the fluid density distributions (FDDs) obtained on the basis of microscopic theories. For simplicity, only two-dimensional (cylindrical, or axisymmetrical) distributions are examined and it is assumed that the fluid is either in contact with a smooth solid or separated from the smooth solid by a lubricating liquid film. The first approach is based on the sharp-kink interface approximation in which the density of the liquid inside and the density of the vapor outside the drop are constant with the exception of the surface layer of the drop where the density is different from the above ones. In this case, the drop profile was calculated by minimizing the total potential energy of the system. The second approach is based on a nonuniform FDD obtained either by the density functional theory or molecular dynamics simulations. To determine the drop profile from such an FDD, which does not contain sharp interfaces, three procedures can be used. In the first two procedures, P1 and P2, the one-dimensional FDDs along straight lines which are parallel to the surface of the solid are extracted from the two dimensional FDD. Each of those one-dimensional FDDs has a vapor-liquid interface at which the fluid density changes from vapor-like to liquid-like values. Procedure P1 uses the locations of the equimolar dividing surfaces for the one dimensional FDDs as points of the drop profile. Procedure P2 is based on the assumption that the fluid density is constant on the surface of the drop, that density being selected either arbitrarily or as a fluid density at the location of the equimolar dividing surface for one of the one-dimensional FDDs employed in procedure P1. In the third procedure, P3, which is suggested for the first time in this paper, the one-dimensional FDDs are taken along the straight lines passing through a selected point inside the drop (radial line). Then, the drop profile is calculated like in procedure P1. It is shown, that procedure P3 provides a drop profile which is more reasonable than the other ones. Relationship of the discussed procedures to those used in image analysis is briefly discussed. PMID- 26971401 TI - Should any genetic defect affecting alpha-granules in platelets be classified as gray platelet syndrome? AB - There is much current interest in the role of the platelet storage pool of alpha granule proteins both in hemostasis and non-hemostatic events. As well as in the arrest of bleeding, the secreted proteins participate in wound healing, inflammation, and innate immunity while in pathology they may be actors in arterial thrombosis and atherosclerosis as well as cancer and metastasis. For a long time, gray platelet syndrome (GPS) has been regarded as the classic inherited platelet disorder caused by an absence of alpha-granules and their contents. While NBEAL2 is the major source of mutations in GPS, other gene variants may give rise to significant alpha-granule deficiencies in platelets. These include GATA1, VPS33B, or VIPAS39 in the arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome and now GFI1B. Nevertheless, many phenotypic differences are associated with mutations in these genes. This critical review was aimed to assess genotype/phenotype variability in disorders of platelet alpha granule biogenesis and to urge caution in grouping all genetic defects of alpha granules as GPS. Am. J. Hematol. 91:714-718, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26971400 TI - Four-dimensional computed tomography evaluation of jaw movement following mandibular reconstruction: A pilot study. AB - PURPOSE: The purpose of this study was to analyze jaw movement during mastication in patients who underwent mandibular reconstruction following segmental mandibulectomy, including mouth opening and mastication time, based on four dimensional computed tomography (4D CT) images. MATERIAL AND METHODS: This study included six surgical patients, who underwent segmental mandibulectomy and simultaneous reconstruction with a free fibula osteocutaneous flap, and four controls. 4D CT was performed during mastication of a cookie to evaluate the movement of the jaw during natural function. The maximum mouth opening, mastication time, and movement of the mandibular angle during mastication were evaluated from the 4D CT images. RESULTS: 4D CT images enabled visualization of jaw movement during mastication. When compared with the controls, the maximum mouth opening during mastication and excursion of the mandibular angle, especially on the diseased side, tended to decrease in surgical patients; however, this did not occur with mastication time. The numerical differences between the diseased and nondiseased side in surgical patients tended to be higher than the crosswise differences in controls. CONCLUSION: 4D CT images revealed differences in jaw function between patients who underwent mandibular reconstruction and controls. 4D CT could be used to evaluate postoperative outcomes following mandibular reconstruction. PMID- 26971398 TI - Inhibition of pancreatic oxidative damage by stilbene derivative dihydro resveratrol: implication for treatment of acute pancreatitis. AB - Trans-resveratrol is a natural stilbenoid possessing multifarious pharmacological benefits; however, when orally consumed, it is rapidly metabolised by colonic microflora and converted to dihydro-resveratrol. Thus, this microbial metabolite is of great therapeutic relevance. In the present study, upon the oral administration of dihydro-resveratrol (10-50 mg/kg), the severity of acute pancreatitis in the cerulein-treated rats was significantly ameliorated as evidenced by decreased alpha-amylase activities in the plasma and lessened oedema formation in the pancreatic parenchyma. In addition, the generation of intracellular reactive oxidative products, including malondialdehyde and protein carbonyls, was accordingly reduced, so as the production of pro-inflammatory cytokines. While inhibiting the activities of NADPH oxidase and myeloperoxidase, the depletion of glutathione was considerably restored. Importantly, the attenuation of pancreatic oxidative damage by dihydro-resveratrol was associated with a down-regulation of the nuclear factor-kappaB and phosphatidylinositol 3' kinase-serine/threonine kinase signalling pathways. Furthermore, we demonstrated that the solubility of dihydro-resveratrol was at least 5 times higher than trans resveratrol whilst exhibiting a much lower cytotoxicity. Collectively, the current findings accentuate new mechanistic insight of dihydro-resveratrol in pancreatic oxidative damage, and advocate its therapeutic potential for the management of acute pancreatitis, particularly for patients unresponsive to trans resveratrol due to the lack of proper microbial strains. PMID- 26971402 TI - Primary Prevention of Urinary Incontinence: A Case Study of Prenatal and Intrapartum Interventions. AB - A wealth of information is available regarding the diagnosis and treatment of urinary incontinence. However, there is a dearth of quality information and clinical practice guidelines regarding the primary prevention of urinary incontinence. Given the high prevalence of this concern and the often cited correlation between pregnancy, childbirth, and urinary incontinence, women's health care providers should be aware of risk factors and primary prevention strategies for stress urinary incontinence (SUI) in order to reduce associated physical and emotional suffering. This case report describes several common risk factors for SUI and missed opportunities for primary prevention of postpartum urinary incontinence. The most effective methods for preventing urinary incontinence include correct teaching of pelvic floor muscle training (PFMT; specifically Kegel exercises), moderate combined physical exercise regimens, counseling and support for weight loss, counseling against smoking, appropriate treatment for asthma and constipation, and appropriate labor management to prevent pelvic organ prolapse, urethral injury, and pelvic floor muscle damage. PMID- 26971397 TI - Discovery of a Novel Seminal Fluid Microbiome and Influence of Estrogen Receptor Alpha Genetic Status. AB - Bacteria harbored in the male reproductive system may influence reproductive function and health of the male and result in developmental origins of adult health and disease (DOHaD) effects in his offspring. Such effects could be due to the seminal fluid, which is slightly basic and enriched with carbohydrates; thereby, creating an ideal habitat for microbes or a potential seminal fluid microbiome (SFM). Using wild-type (WT) and estrogen receptor-alpha (ESR1) knockout (KO) male mice, we describe a unique SFM whose inhabitants differ from gut microbes. The bacterial composition of the SFM is influenced according to whether mice have functional Esr1 genes. Propionibacterium acnes, causative agent of chronic prostatitis possibly culminating in prostate cancer, is reduced in SFM of ESR1 KO compared to WT mice (P <= 0.0007). In certain genetic backgrounds, WT mice show a greater incidence of prostate cancer than ESR1 KO, which may be due to increased abundance of P. acnes. Additionally, select gut microbiome residents in ESR1 KO males, such as Lachnospiraceae and Christensenellaceae, might contribute to previously identified phenotypes, especially obesity, in these mutant mice. Understanding how genetics and environmental factors influence the SFM may provide the next frontier in male reproductive disorders and possibly paternal-based DOHaD diseases. PMID- 26971403 TI - Kidney transplantation from a mother with unrecognized Fabry disease to her son with low alpha-galactosidase A activity: A 14-year follow-up without enzyme replacement therapy. AB - We report a case of kidney transplantation from mother to son, both of whom were likely to have had an unrecognized renal variant phenotype of Fabry disease. The patient was a 54-year-old man, with an unknown primary cause of end stage renal disease. He had no notable past medical history, other than end stage renal disease. He underwent living-related kidney transplantation from his mother at age 40 years. Foam cells in the glomeruli were identified on histology assessment of a 0-hour allograft biopsy, with zebra bodies identified in the glomerular visceral epithelial cells by electron microscopy. These findings were indicative of Fabry disease in the donated kidney. As a definitive diagnosis of Fabry's disease could not be confirmed, enzyme replacement therapy was not initiated. Thirteen years after kidney transplantation, the patient underwent left nephrectomy for a left renal tumour, with pathological findings of clear cell carcinoma, foam cells and zebra bodies in the native kidney. Detailed examinations identified low alpha-galactosidase A activity and mutation of the alpha-Gal A gene, confirming a diagnosis of a renal variant phenotype of Fabry disease. Histology of several allograft biopsies performed over the 14 years from the time of kidney transplantation revealed only moderate interstitial fibrosis and tubular atrophy, with no evidence of disease progression on electron microscopy, despite the presence of zebra bodies in the glomerular visceral epithelial cells. PMID- 26971404 TI - Body composition in clinical practice. AB - Nutritional status is the results of nutrients intake, absorption and utilization, able to influence physiological and pathological conditions. Nutritional status can be measured for individuals with different techniques, such as CT Body Composition, quantitative Magnetic Resonance Imaging, Ultrasound, Dual-Energy X-Ray Absorptiometry and Bioimpendance. Because obesity is becoming a worldwide epidemic, there is an increasing interest in the study of body composition to monitor conditions and delay in development of obesity-related diseases. The emergence of these evidence demonstrates the need of standard assessment of nutritional status based on body weight changes, playing an important role in several clinical setting, such as in quantitative measurement of tissues and their fluctuations in body composition, in survival rate, in pathologic condition and illnesses. Since body mass index has been shown to be an imprecise measurement of fat-free and fat mass, body cell mass and fluids, providing no information if weight changes, consequently there is the need to find a better way to evaluate body composition, in order to assess fat-free and fat mass with weight gain and loss, and during ageing. Monitoring body composition can be very useful for nutritional and medical interventional. This review is focused on the use of Body Composition in Clinical Practice. PMID- 26971405 TI - Spectroscopic and Chemometric Analysis of Binary and Ternary Edible Oil Mixtures: Qualitative and Quantitative Study. AB - The aim of this study was to investigate the feasibility of FTIR-ATR spectroscopy coupled with the multivariate numerical methodology for qualitative and quantitative analysis of binary and ternary edible oil mixtures. Four pure oils (extra virgin olive oil, high oleic sunflower oil, rapeseed oil, and sunflower oil), as well as their 54 binary and 108 ternary mixtures, were analyzed using FTIR-ATR spectroscopy in combination with principal component and discriminant analysis, partial least-squares, and principal component regression. It was found that the composition of all 166 samples can be excellently represented using only the first three principal components describing 98.29% of total variance in the selected spectral range (3035-2989, 1170-1140, 1120-1100, 1093-1047, and 930-890 cm(-1)). Factor scores in 3D space spanned by these three principal components form a tetrahedral-like arrangement: pure oils being at the vertices, binary mixtures at the edges, and ternary mixtures on the faces of a tetrahedron. To confirm the validity of results, we applied several cross-validation methods. Quantitative analysis was performed by minimization of root-mean-square error of cross-validation values regarding the spectral range, derivative order, and choice of method (partial least-squares or principal component regression), which resulted in excellent predictions for test sets (R(2) > 0.99 in all cases). Additionally, experimentally more demanding gas chromatography analysis of fatty acid content was carried out for all specimens, confirming the results obtained by FTIR-ATR coupled with principal component analysis. However, FTIR-ATR provided a considerably better model for prediction of mixture composition than gas chromatography, especially for high oleic sunflower oil. PMID- 26971406 TI - Editorial overview: Cardiovascular and renal: Recent advances, novel treatments and new targets for cardiovascular and renal diseases. PMID- 26971407 TI - Antiviral activity of various interferons and pro-inflammatory cytokines in non transformed cultured hepatocytes infected with hepatitis B virus. AB - In HBV-infected patients, therapies with nucleoside analogues or IFNalpha remain ineffective in eradicating the infection. Our aim was to re-analyze the anti-HBV activity of a large panel of IFNs and cytokines in vitro using non-transformed cultured hepatocytes infected with HBV, to identify new immune-therapeutic options. HepaRG cells and primary human hepatocytes were infected with HBV and, when infection was established, treated with various concentrations of different IFNs or inflammatory cytokines. Viral parameters were evaluated by quantifying HBV nucleic acids by qPCR and Southern Blot, and secreted HBV antigens were evaluated using ELISA. The cytokines tested were type-I IFNs, IFNgamma, type-III IFNs, TNFalpha, IL-6, IL-1beta, IL-18 as well as nucleos(t)ide analogues tenofovir and ribavirin. Cytokines and drugs, with the exception of IL-18 and ribavirin, exhibited a suppressive effect on HBV replication at least as strong as, but often stronger than, IFNalpha. The cytokine presenting the highest effect on HBV DNA was IL-1beta, which exerted its inhibition within picomolar range. Importantly, we noticed differential effects on other parameters (HBV RNA, HBeAg, HBsAg) between both IFNs and inflammatory cytokines, thus suggesting different mechanisms of action. The combination of IL-1beta and already used therapies, i.e. IFNalpha or tenofovir, demonstrated a stronger or similar anti-HBV activity. IL-1beta was found to have a very potent antiviral effect against HBV in vitro. HBV was previously shown to promptly inhibit IL-1beta production in Kupffer cells. Strategies aiming at unlocking this inhibition and restoring local production of IL-1beta may help to further inhibit HBV replication in vivo. PMID- 26971408 TI - Exogenous genistein in late gestation: effects on fetal development and sow and piglet performance. AB - Due to their functional similarity to estradiol, phytoestrogens could prove to be beneficial in late gestating sows. The goal of this study was to determine the impact of providing the phytoestrogen genistein during late pregnancy on the performance of sows and their litters. In total, 56 gilts were equally divided into the two following groups on day 90 of gestation: (1) controls (CTL); and (2) two daily i.m. injections of 220 mg of genistein (GEN). Treatments were carried out until farrowing. Jugular blood samples were collected from 16 gilts/treatment on days 89 and 110 of gestation, and on days 3 and 21 of lactation. Milk samples were also obtained from those sows on day 3 of lactation. A male piglet from 16 CTL and 15 GEN litters was slaughtered at 24 h postpartum and a blood sample was obtained. The liver, heart and visceral organs were weighed and the semitendinosus (ST) muscle was collected and carcass composition was determined. The treatment increased (P0.1) on weight or backfat loss of sows during lactation, milk composition or weights of piglets. The pre-weaning mortality rate of piglets was very low (0.1). However, carcasses from GEN litters contained more fat than those from CTL litters (9.63% v. 8.34%, P0.1). In conclusion, injecting gilts with 440 mg/day of genistein in late gestation increased IGF1 concentrations in gilts and carcass fat in neonatal piglets, but had minimal effect on muscle development of piglets at birth and on the performance of lactating sows and their litters. PMID- 26971409 TI - Needle aspiration of calcific deposits (NACD) for calcific tendinitis is safe and effective: Six months follow-up of clinical results and complications in a series of 431 patients. AB - BACKGROUND: Although needle aspiration of calcific deposits (NACD) has proven to be an effective treatment for calcific tendinitis of the rotator cuff (CTRC) in patients who are resistant to conservative treatment, little is known about the effectiveness of NACD in terms of complete relief of symptoms and the effectiveness of repeated NACD procedures. Furthermore, analyses of complications of the procedure in large series are scarce. METHODS: 431 consecutive patients with symptomatic CTRC treated by NACD were included in this retrospective cohort study. Short-term effects were assessed at two weeks post-treatment by using an 11-point numeric rating scale (NRS). The six months outcome was determined on a dichotomous symptom scale (symptom free or persistence of symptoms). NACD procedures performed within six months of a previous NACD procedure were considered repeated procedures. All complications that occurred within six months of the NACD procedure were registered. RESULTS: At two weeks post-treatment, a significant improvement of pain scores was noted (mean reduction of NRS: 4.4 points; p<0.001). 74% of patients had complete relief of symptoms at six months post-treatment. 143 (33.2%) patients required multiple treatments. These repeated procedures were equally effective as the primary procedure. Complications of the NACD procedure were seen in 31 (7.2%) patients: 21 patients (4.9%) developed a subacromial bursitis, seven patients (1.6%) a frozen shoulder and three patients (0.7%) developed a septic bursitis. CONCLUSION: Needle aspiration of calcific deposits (NACD) is an effective treatment for calcific tendinitis of the rotator cuff in the majority of patients. Approximately one third of the patients will require multiple treatments, which were equally effective as the primary procedure. Based on this, patients should not be withheld a second or even a third treatment in case of persistent symptoms. Furthermore, NACD has a low complication rate, the risk of infection should, however, always be accounted for. LEVEL OF EVIDENCE: Retrospective study, level IV. PMID- 26971410 TI - Optimization of window settings for virtual monoenergetic imaging in dual-energy CT of the liver: A multi-reader evaluation of standard monoenergetic and advanced imaged-based monoenergetic datasets. AB - OBJECTIVES: To evaluate optimal window settings for display of virtual monoenergetic reconstructions in third-generation dual-source, dual-energy computed tomography (DECT) of the liver. METHODS: Twenty-nine subjects were prospectively evaluated with DECT in arterial (AP) and portal venous (PVP) phases. Three reconstructed datasets were calculated: standard linearly-blended (LB120), 70-keV standard virtual monoenergetic (M70), and 50-keV advanced image based virtual monoenergetic (M50+). Two readers assessed optimal window settings (width and level, W/L), establishing a mean for each reconstruction which was used for a blinded assessment of liver lesions. RESULTS: The optimal W/L for M50+ were significantly higher for both AP (W=429.3 +/- 44.6 HU, L=129.4 +/- 9.7 HU) and PVP (W=376.1 +/- 14.2HU, L=146.6 +/- 7.0 HU) than for LB120 (AP, W=215.9 +/- 16.9 HU, L=82.3 +/- 9.4 HU) (PVP, W=173.4 +/- 8.9 HU, L=69.3 +/- 6.0 HU) and M70 (AP, W=247.1 +/- 22.2 HU, L=72.9 +/- 6.8 HU) (PVP, W=232.0 +/- 27.9 HU, L=91.6 +/ 14.4 HU). Use of the optimal window setting for M50+ vs. LB120 resulted in higher sensitivity (AP, 100% vs. 86%; PVP, 96% vs. 63%). CONCLUSIONS: Application of dedicated window settings results in improved liver lesion detection rates in advanced image-based virtual monoenergetic DECT when customized for arterial and portal venous phases. PMID- 26971411 TI - Diffusion tensor imaging suggests extrapontine extension of pediatric diffuse intrinsic pontine gliomas. AB - PURPOSE: To apply DTI to detect early extrapontine extension of pediatric diffuse intrinsic pontine glioma along the corticospinal tracts. METHODS: In children with diffuse intrinsic pontine glioma, low-grade brainstem glioma, and age matched controls, DTI metrics were measured in the posterior limb of the internal capsule and posterior centrum semiovale. Histological examination was available in one patient. RESULTS: 6 diffuse intrinsic pontine glioma, 8 low-grade brainstem glioma, and two groups of 25 controls were included. In diffuse intrinsic pontine glioma compared to controls, fractional anisotropy was lower in the bilateral posterior limb of the internal capsule, axial diffusivity was lower in the bilateral posterior centrum semiovale and posterior limb of the internal capsule, while radial diffusivity was higher in the bilateral posterior limb of the internal capsule. No significant differences were found between low-grade brainstem glioma and controls. In diffuse intrinsic pontine glioma compared to low-grade brainstem glioma, axial diffusivity was lower in the bilateral posterior limb of the internal capsule. Histological examination in one child showed tumor cells in the posterior limb of the internal capsule. CONCLUSION: Reduction in fractional anisotropy and axial diffusivity and increase in radial diffusivity in diffuse intrinsic pontine glioma may reflect tumor extension along the corticospinal tracts as shown by histology. DTI may detect early extrapontine tumor extension in diffuse intrinsic pontine glioma before it becomes apparent on conventional MRI sequences. PMID- 26971412 TI - MRI of the lung using the PROPELLER technique: Artifact reduction, better image quality and improved nodule detection. AB - PURPOSE: To evaluate the benefit of the PROPELLER technique (Periodically Rotated Overlapping ParallEL Lines with Enhanced Reconstruction, MultiVane, MV) for MR imaging of the lung. MATERIALS AND METHODS: 30 Participants of a lung cancer screening program were recruited for the comparison of T2-MV and T2-Fast Spin Echo (FSE) sequences at 1.5T. Two readers evaluated artifacts, image quality, and pulmonary lesions. Artifacts and image quality were rated using a four-point scale. Lesion detection was correlated to low-dose computed tomography (CT). Wilcoxon rank-test for ratings of artifacts and image quality, sensitivity and specificity values for lesion detection, and Cohen's kappa for inter-rater agreement were used. RESULTS: The MV sequence showed less pulsation and motion artifacts, and higher image quality (p=0.001 for R1, p=0.002 for R2) than FSE (p<0.001 for both readers, R1 and R2). Inter-rater agreement was excellent for lesion detection (0.84-0.95) and good to excellent for artifacts and image quality (0.66-0.84). 17 patients had lesions <8mm, and 7 had lesions >8mm as seen on CT. For R1 and R2, the MV sequence allowed for higher detection rates of pulmonary lesions <8mm with a sensitivity of 56% (R1) and 59% (R2); the FSE sequence achieved 50% (R1) and 53% (R2). Specificity was also higher for MV with 94% (R1) and 83% (R2) compared to 78% (R1) and 76% (R2). Lesions >8mm were detected with a sensitivity of 100% by both readers on both MV and FSE images. For both readers, specificity for larger lesions was higher on MV images with 100% compared to 96%. CONCLUSION: The superior image quality and the very robust artifact reduction make MV a promising technique for MRI of the lung compared to FSE, especially since it is not requiring breathholds. Moreover, MV allows for improved lesion detection. PMID- 26971413 TI - The value of MRI in patients with temporomandibular joint dysfunction: Correlation of MRI and clinical findings. AB - AIM: To estimate the correlation between the MRI findings and clinical outcomes in patients with temporomandibular joint dysfunction (TMD). METHODS AND MATERIALS: We included 546 female and 248 male patients who were clinically diagnosed with TMD (mean age 38.7 years) and examined by MRI (T1 and T2 weighted images, parasagittal and paracoronal slices). A questionnaire, radiological, and clinical findings were analysed for statistically significant correlations. The analysed parameters included gender, age, disk position, joint degeneration, arthralgia, mouth opening, condyle position and clinical progress. RESULTS: Of all TMJ's 62% showed physiological disc position, 35% anterior and 3% posterior disc position. Modification of therapy occurred in 20% and alteration of diagnosis was found in 32% of all cases. Anterior disc displacement with reduction showed a specificity of 88% and a sensitivity of 78%, whereas anterior disc displacement without reduction showed a specificity of 84% and a sensitivity of 73%. A significant correlation between disc length, condyle morphology and disc displacement was found. With the increase of intra-articular liquid as seen on MRI the level of arthralgia significantly rose as opposed to mouth opening. CONCLUSION: Specificity and sensitivity, for anterior disc displacement and osseous changes in TMJ were highly acceptable. Results had confirmed the diagnostic capability of MRI in diagnostic imaging of TMJ. Additionally MRI should be used primarily in severe, therapy-resistant cases and for surgical planning purposes. PMID- 26971414 TI - Carotid dual-energy CT angiography: Evaluation of low keV calculated monoenergetic datasets by means of a frequency-split approach for noise reduction at low keV levels. AB - BACKGROUND AND PURPOSE: Calculated monoenergetic ultra-low keV datasets did not lead to improved contrast-to-noise ratio (CNR) due to the dramatic increase in image noise. The aim of the present study was to evaluate the objective image quality of ultra-low keV monoenergetic images (MEIs) calculated from carotid DECT angiography data with a new monoenergetic imaging algorithm using a frequency split technique. MATERIALS AND METHODS: 20 patients (12 male; mean age 53+/-17 years) were retrospectively analyzed. MEIs from 40 to 120 keV were reconstructed using the monoenergetic split frequency approach (MFSA). Additionally MEIs were reconstructed for 40 and 50 keV using a conventional monoenergetic (CM) software application. Signal intensity, noise, signal-to-noise ratio (SNR) and CNR were assessed in the basilar, common, internal carotid arteries. RESULTS: Ultra-low keV MEIs at 40 keV and 50 keV demonstrated highest vessel attenuation, significantly greater than those of the polyenergetic images (PEI) (all p-values <0.05). The highest SNR level and CNR level was found at 40 keV and 50 keV (all p values <0.05). MEIs with MFSA showed significantly lower noise levels than those processed with CM (all p-values <0.05) and no significant differences in vessel attenuation (p>0.05). Thus MEIs with MFSA showed significantly higher SNR and CNR compared to MEIs with CM. CONCLUSION: Combining the lower spatial frequency stack for contrast at low keV levels with the high spatial frequency stack for noise at high keV levels (frequency-split technique) leads to improved image quality of ultra-low keV monoenergetic DECT datasets when compared to previous monoenergetic reconstruction techniques without the frequency-split technique. PMID- 26971415 TI - Assessment of PI-RADS v2 for the Detection of Prostate Cancer. AB - PURPOSE: To evaluate the diagnostic performance and inter-reader reliability of the multiparametric magnetic resonance imaging (mpMRI) based prostate imaging reporting and data system (PI-RADS) version 1 and version 2 for the assessment of prostate cancer. MATERIAL AND METHODS: A cohort of 82 patients underwent endorectal mpMRI at 1.5T. Patients had at least one lesion with a PI-RADS v1 assessment category of >=3 and were selected for targeted in-bore MR-guided biopsy in a subsequent session. The results of the histopathological workup were used as reference standard. All lesions were retrospectively evaluated according to PI-RADS v2 by an experienced and unexperienced blinded reader. Diagnostic performance was compared by analyzing the area under the Receiver Operating Characteristics Curve (AUC). The weighted kappa method was used to calculate inter-reader reliability. RESULTS: Targeted MR-guided biopsy was performed in 136 lesions and revealed 39 malignant lesions in 31 patients. AUC values increased for the experienced reader (PI-RADS v1 0.79; PI-RADS v2 0.83) and unexperienced reader (PI-RADS v1 0.70; PI-RADS v2 0.83). When excluding the cases of low grade cancer (Gleason score=3+3), AUC values increased further for the experienced reader (PI-RADS v1 0.88; PI-RADS v2 0.91) and unexperienced reader (PI-RADS v1 0.78; PI-RADS v2 0.90). Specificity at the selected threshold of a PI-RADS v1/v2 assessment category >=4 improved for both readers. Inter-reader agreement increased from kappa=0.55 in PI-RADS v1 to kappa=0.68 in v2. CONCLUSION: PI-RADS v2 improved diagnostic performance for the assessment of suspicious intraprostatic lesions identified in PI-RADS v1 for both readers and led to higher inter-reader reliability. These results suggest that PI-RADS v2 is a reliable and replicable reporting system for the assessment of prostate cancer. PMID- 26971416 TI - CT imaging of bone and bone marrow infiltration in malignant melanoma--Challenges and limitations for clinical staging in comparison to 18FDG-PET/CT. AB - Rationale of this study was the evaluation of the diagnostic value of computed tomography (CT) in the detection of bone marrow infiltration in comparison to PET/CT. Fifty patients (age 61 +/- 15.12 years) with metastatic malignant melanoma underwent 18F-FDG-PET/CT, including contrast-enhanced CT. 2 readers evaluated the CT images in consensus for bone and bone marrow lesions focusing on lesion location, type and size. PET/CT was used as reference standard to estimate sensitivity, specificity, negative and positive predictive value. Moreover, the bone marrow density was estimated in the long bones and the sacral bone. Serum hamoglobin, thrombocyte level and S100 protein were correlated with the presence or absence of bone and bone marrow lesions. According to PET/CT as standard of reference, of 594 bone and medullary lesions 495 were considered malignant. Of these 77.8% were medullary, 20.4% lytic, 1% sclerotic and 0.8% mixed lytic/sclerotic. Contrast-enhanced CT yielded a lesion-based sensitivity of 36.8% and a specificity of 87.9% (PPV 93.8%; NPV 21.8%). Patient-based sensitivity and specificity were 78.8% and 82.4%, respectively. Of the missed lesions, most were medullary (95.8%). A disseminated bone marrow involvement (defined as >10 bone marrow lesions or diffuse infiltration of a whole body segment) was described in 11 cases, in 6 cases the disseminated involvement was underestimated or missed on CT. In cases with disseminated bone marrow involvement the bone marrow density was significantly higher in the humerus (p=0.04), but not in the femur or sacral bone (p=0.06). Multivariate analysis revealed no isolated effect of bone metastases on S100 serum and hemoglobin level, but both were significantly altered in patients with disseminated bone marrow involvement (p<0.05). In conclusion, the diagnostic value of computed tomography for the detection of bone marrow metastases in patients with melanoma, is limited. Especially in cases with disseminated bone marrow involvement about 50% of the cases were missed or underestimated. PMID- 26971417 TI - Radiofrequency and microwave ablation of subcapsular hepatocellular carcinoma accessed by direct puncture: Safety and efficacy. AB - OBJECTIVES: Direct puncture of subcapsular hepatocellular carcinoma (HCC) for tumor ablation has been considered high risk due to a perceived increased incidence of hemorrhage or tumor seeding. The purpose of this retrospective multicenter study was to identify the rate of tumor seeding, hemorrhage and local tumor progression (LTP) associated with direct puncture radiofrequency (RF) and microwave (MW) ablation of subcapsular HCC. METHODS: A multicenter, retrospective review of direct-puncture RF and MW performed on subcapsular HCC was conducted. Complications and local tumor progression were documented. Data was analyzed using Kaplan-Meier and log-rank tests. RESULTS: The study group consisted of 60 cirrhotic patients (M/F=43/17; mean age 69.6 years) with 67 subcapsular HCC (mean diameter 2.3 cm +/- 1.0 cm) that were directly punctured for RF (n=40) or MW (n=27) under ultrasound (US) guidance. The mean follow-up period was 30.8 months. There were no hemorrhagic complications. The overall LTP rate was 13.4%. There was one case of tumor tract seeding in a patient who had undergone a percutaneous biopsy two weeks prior to RF. CONCLUSIONS: Thermal ablation of HCC by direct puncture appears safe and effective. There were no cases of intraperitoneal hemorrhage, and tumor seeding was seen in a single case in which a preceding percutaneous biopsy had been performed. PMID- 26971418 TI - Effect of computed tomography before cardiac surgery on surgical strategy, mortality and stroke. AB - AIM: To investigate whether preoperative chest computed tomography (CT) decreases postoperative mortality and stroke rate in cardiac surgery by detection of calcifications and visualization of postoperative anatomy in redo cardiac surgery which can be used to optimize the surgical approach. METHODS: The PubMed, EMBASE and Cochrane databases were searched and articles concerning preoperative CT in cardiac surgery were included. Articles not reporting mortality, stroke rate or change in surgical approach were excluded. Studies concerning primary cardiac surgery as well as articles concerning redo cardiac surgery were both included. RESULTS: Eighteen studies were included (n=4057 patients) in which 2584 patients received a preoperative CT. Seven articles (n=1754 patients) concerned primary surgery and eleven articles (n=2303 patients) concerned redo cardiac surgery. None of the studies was randomized but 8 studies provided a comparison to a control group. Stroke rate decreased with 77-96% (primary surgery) and 18-100% (redo surgery) in patients receiving a preoperative CT. Mortality decreased up to 66% in studies investigating primary surgery while the effect on mortality in redo surgery varied widely. Change in surgical approach based on CT-findings consisted of choosing a different cannulation site, opting for off-pump surgery and cancellation of surgery. CONCLUSIONS: Current evidence suggests that preoperative CT imaging may lead to decreased stroke and mortality rate in patients undergoing primary cardiac surgery by optimizing surgical approach. In patients undergoing redo cardiac surgery stroke rate is also decreased but the effect on mortality is unclear. However, evidence is weak and included studies were of moderate quality. PMID- 26971419 TI - PET/MRI with diagnostic MR sequences vs PET/CT in the detection of abdominal and pelvic cancer. AB - OBJECTIVE: Integrated positron emission tomography/magnetic resonance imaging (PET/MRI) scanners provide combined MR-based anatomic and metabolic image information. The aim of this study was to evaluate qualitative and quantitative diagnostic performance of PET/MR with (18)fluoro-2-deoxyglucose ((18)F-FDG) using a diagnostic MR sequence in patients with abdominal and pelvic tumors, compared to positron emission tomography/computed tomography (PET/CT). MATERIALS AND METHODS: Forty five patients underwent a single-injection ((18)F-FDG), dual imaging protocol including whole-body PET/CT and subsequent regional PET/MR hybrid imaging. A regional PET/MR scan followed the PET/CT. Images from both modalities were analyzed using a 3-point scale for PET/CT and PET/MR image quality, image alignment, and lesion visibility on PET images. PET-CT/PET-MR functional and anatomical correlation was analyzed. RESULTS: A total of 66 lesions were studied, from which 63 were identified using PET/CT and 59 were identified using PET/MR. The (18)F-FDG PET images had good diagnostic quality (P<0.001); alignment was found to be excellent in PET/MR data as well as PET/CT data (P=0.102), and there was no difference in lesion visibility (P=0.18). The average rating score regarding anatomical correlation for PET-positive lesions was 2.75 for combined MR sequence images and 2.04 for CT, with a significant difference (P=0.317), Standard uptake value (SUV) for focal lesions had excellent correlation (SUVmax/mean: R=0.948/0.948); furthermore, the SUVmean of background organs combined, bone marrow and the muscle tissue showed good correlation (R=0.329/0.398/0.298). No correlations were found in the liver and spleen. CONCLUSIONS: PET/MR with diagnostic MR sequence was able to detect abdominal and pelvic lesions and had good image quality compared to PET/CT. SUVmax and SUVmean values in focal lesions, and the SUVmean of background organs generally correlated well in abdominal and pelvic oncology patients examined using PET/CT and PET/MRI. PMID- 26971420 TI - CT-based quantification of bone stock in large head metal-on-metal unilateral total hip replacements. AB - PURPOSE: To explore ipsilateral and contralateral acetabular roof bone stock density in unilateral large head MoM THA whether there is a significant lower acetabular bone stock in the hip with a metal-on-metal (MoM) total hip replacement compared to the contralateral side. Second part of this study is to examine if there are any associates with regard to potential bone stock density difference. MATERIALS & METHODS: A database of 317 patients with unilateral metal on-metal (MoM) total hip replacements was set up retrospectively for this study. On computed tomography scans, conducted after a relative short in situ time period averaging 2.8 years, regions-of-interests were drawn in the trabecular bone of the acetabulum to measure average Hounsfield Units (HU). HU differences were calculated and tested by Wilcoxon signed-rank test. Univariate analysis was conducted to examine associates of potential bone loss. RESULTS: In a population of 317 patients (156 male, 161 female) with an average age of 61.9 +/- 7.8, the median HU on the side of the MoM replacement was 123.3 (7.6-375.4). On the contralateral side, median HU was 144.7 (-0.4 to 332.8). The median HU difference was 21.4 after a mean post-operative in situ time of 2.8 years. The Wilcoxon signed-rank test proved a significant difference (p<0.001). Univariate analyses show that the in situ time of the MoM THA has a significant correlation with the bone density difference. CONCLUSION: Results show a significant lower bone density at the acetabular roof at the side of the prosthesis compared with the contralateral side after short in situ time of the MoM THA in patients with unilateral MoM total hip replacements. In our patient population, the in situ time showed a significant association with the acetabular bone density difference. As acetabular roof bone stock measurements are feasible and show temporal decline this could become an important parameter to be used in orthopedic decision making for revision surgery. PMID- 26971421 TI - Impact of multiparametric magnetic resonance imaging on risk group assessment of patients with prostate cancer addressed to external beam radiation therapy. AB - PURPOSE: To investigate the impact of multiparametric magnetic resonance imaging (mpMRI) on risk group assessment of patients with prostate cancer (PCa) initially addressed to external beam radiation therapy (EBRT). MATERIALS AND METHODS: We prospectively performed mpMRI (3.0Tsystem) in 44 patients addressed to EBRT, using a multiparametric protocol (high-resolution multiplanar T2-weighted, diffusion-weighted and dynamic contrast-enhanced imaging). Risk group was assessed in accordance with the National comprehensive cancer network (NCCN) categories, by combining prostate-specific-antigen level, Gleason score and the T stage as established by digital rectal examination (clinical risk assessment; c RA) versus mpMRI (mpMRI-risk assessment; mpMRI-RA). The agreement between c-RA and mpMRI-RA was investigated using Cohen's kappa. RESULTS: Patients were included in very low/low risk, intermediate risk, high risk, very high risk and metastatic NCCN categories in 10 (22.7%), 18 (40.9%), 15 (34.1%), 1 (2.3%) and 0 cases using c-RA vs. 8 (18.2%), 14 (31.8%), 14 (31.8%), 4 (9.1%) and 4 (9.1%) cases using mpMRI-RA, respectively, with only moderate agreement (k=0.43). mpMRI RA determined risk downgrading in 2/44 patients (4.5%), and risk upgrading in 16/44 patients (36.3%). After mpMRI, EBRT remained indicated in all patients. CONCLUSION: mpMRI changed clinical risk stratification in about 41% of patients with PCa, with potential impact on EBRT planning. PMID- 26971423 TI - Quo vadis? PMID- 26971422 TI - The compositional difference between ankle and knee cartilage demonstrated by T2 mapping at 7 Tesla MR. AB - OBJECTIVES: The aim was to systematically compare T2 relaxation times of the knee and ankle cartilage within subjects at 7T. METHODS: Ten healthy volunteers were examined by 7 Tesla MR using a three-dimensional triple-echo steady state sequence (3D-TESS). The differences between seven cartilage compartments (patella, femur, proximal tibia, and distal tibia and talus in both medial and lateral facet) were analyzed by ANOVA. RESULTS: The results showed statistically significantly higher T2 (mean +/- standard deviation, in milliseconds) values in patellar (25.8 +/- 1.2) and femoral (24.9 +/- 1.3) cartilage compared to the tibial (19.2 +/- 1) and talar (18.1 +/- 0.6 ms) cartilage. The cartilages of the medial and lateral facet in the ankle joint were not significantly different (p>0.05). CONCLUSIONS: This is the first study to systematically compare within subject T2 values in the knee and ankle non-invasively, in vivo. Our results are in agreement with the previous findings demonstrating different biochemical and biomechanical properties between the knee and ankle cartilage. PMID- 26971424 TI - Preoperative clinicopathologic factors and breast magnetic resonance imaging features can predict ductal carcinoma in situ with invasive components. AB - PURPOSE: Ductal carcinoma in situ (DCIS) is a non-invasive cancerous breast lesion; however, from 10% to 50% of patients with DCIS diagnosed by core needle biopsy (CNB) or vacuum-assisted core biopsy (VACB) are shown to have invasive carcinoma after surgical excision. In this study, we evaluated whether preoperative clinicopathologic factors and breast magnetic resonance image (MRI) features are predictive of DCIS with invasive components before surgery. MATERIALS AND METHODS: Patients comprised 128 adult women with a diagnosis of DCIS as determined by pathological analysis of CNB or VACB specimens and positive MRI findings who underwent breast surgery during the period January 2011 to December 2013 at the Changhua Christian Hospital. Clinicopathologic and breast MRI factors were compared between patients with postoperative pathology indicative of true DCIS and those with postoperative pathology showing DCIS with invasive components. RESULTS: Of the 128 patients with a preoperative diagnosis of DCIS, 73 (57.0%) had postoperative histopathologic evidence of true DCIS and 55 (43.0%) showed evidence of DCIS with invasive components. Results of statistical analyses revealed that MRI evidence of a mass-like lesion (P=0.025), nipple-areolar complex (NAC) invasion (P=0.029), larger tumor volume (P=0.010), larger maximum measurable apparent diffusion coefficient (ADC) area (P=0.039), heterogenous or rim enhancement pattern (P=0.010), as well as immunohistochemical evidence of human epidermal growth factor receptor 2 (HER-2) overexpression (P=0.010) were predictive of DCIS with an invasive component in postoperative surgical specimens. CONCLUSION: Invasive component should be considered in biopsy proven DCIS patients with preoperative MRI evidence of a mass-like lesion, nipple areolar complex invasion, large tumor volume, a larger maximum measurable ADC area, or a rim or heterogenous enhancement pattern, as well as in patients with immunohistochemical evidence of HER-2 overexpression. PMID- 26971425 TI - 3T multiparametric MRI of the prostate: Does intravoxel incoherent motion diffusion imaging have a role in the detection and stratification of prostate cancer in the peripheral zone? AB - PURPOSE: To evaluate the potential added value of the intravoxel incoherent motion model to conventional multiparametric magnetic resonance protocol in order to differentiate between healthy and neoplastic prostate tissue in the peripheral zone. MATERIAL AND METHODS: Mono-exponential and bi-exponential fits were used to calculate ADC and IVIM parameters in 53 patients with peripheral zone biopsy proved tumor. Inferential statistics analysis was performed on T2, ADC and IVIM parameters (D, D*, f) comparing healthy and neoplastic tissues. Linear discriminant analysis was performed for the conventional parameters (T2 and ADC), the IVIM parameters (molecular diffusion coefficient (D), perfusion-related diffusion coefficient (D*), and perfusion fraction (f) and the combined T2 weighted imaging/DWI and IVIM parameters (T2, ADC, D, D* and f). A correlation with Gleason scores was achieved. RESULTS: The values of T2, ADC and D were significantly lower in cancerous tissues (2749.82 +/- 1324.67 ms, 0.76 +/- 0.27 * 10(-3)mm(2)/s and 0.99 +/- 0.38 * 10(-3)mm(2)/s respectively) compared to those found in the healthy tissues (3750.70 +/- 1735.37 ms, 1.39 +/- 0.48 * 10( 3)mm(2)/s and 1.77 +/- 0.36 * 10(-3)mm(2)/s respectively); D* parameter was significantly increased in neoplastic compared to healthy tissue (15.56 +/- 12.91 * 10(-3)mm(2)/s and 10.25 +/- 10.52 * 10(-3)mm(2)/s respectively). The specificity, sensitivity and accuracy of the T2-weighted imaging/DWI and IVIM parameters were 100, 96 and 98%, respectively, compare to 88, 92 and 90% and 96, 92 and 94 for T2-weighted imaging/ADC and IVIM alone. CONCLUSIONS: IVIM parameters increase the specificity and sensitivity in the evaluation of peripheral zone prostate cancer. A statistical difference between low grade tumors and high grade tumors has been demostrated in that ADC, D and D* dataset; in particular, D has been found to have the highest significativity. PMID- 26971426 TI - Quantitative evaluation of contrast-enhanced ultrasound for differentiation of renal cell carcinoma subtypes and angiomyolipoma. AB - PURPOSE: To investigate the value of quantitative parameters of contrast-enhanced ultrasound (CEUS) in the differentiation of subtypes of renal cell carcinoma (RCC) and angiomyolipoma (AML). METHODS: The quantitative characteristics of 341 RCCs and 88 AMLs were analyzed with quantitative software (SonoLiver). Quantitative analysis was conducted in the whole tumor (ROItumor) and the maximum enhanced area of the tumor (ROImax), acquiring the parameters of maximum intensity (IMAX), rise time (RT), time to peak (TTP), mean transit time (mTT), and area under the curve (AUC), were derived and analyzed. The difference values between ROImax and normal renal cortex (DeltaPar.s, including DeltaIMAX, DeltaRT, DeltaTTP, DeltamTT, DeltaAUC) were compared among renal histotypes. RESULTS: All time-related parameters (including RT, TTP and mTT) of ROImax were shorter than the corresponding parameters of ROItumor in RCC subtypes (all p<0.05), but made no statistical difference in AMLs (all p>0.05). There were significant differences of all DeltaPar.s among RCC subtypes and AML (all p<0.01). DeltaIMAX and DeltaAUC showed the trend that ccRCC>AML>pRCC=chRCC. DeltaTTP showed AML=pRCC=chRCC>ccRCC, DeltaRT and DeltamTT showed AML>pRCC=chRCC=ccRCC. DeltamTT could distinguish RCC from AML with the area under the ROC curve (AUC) of 0.86. The AUC of DeltaIMAX and DeltaAUC was 0.89 and 0.92 vs 0.85 and 0.85 for discriminating between pRCC (or chRCC) and AML vs ccRCC and AML. CONCLUSIONS: Quantitative analysis of CEUS is a useful modality in AML and RCC subtypes' differentiation, by using DeltamTT, DeltaIMAX and DeltaAUC. PMID- 26971427 TI - High-resolution intracranial vessel wall imaging using 3D CUBE T1 weighted sequence. AB - PURPOSE: To evaluate the feasibility of high-resolution 3D CUBE T1WI for intracranial vessel wall imaging. METHODS: High-resolution 3D CUBE T1 weighted intracranial vessel wall images (0.4 mm * 0.4 mm * 0.4 mm) of 50 patients were retrospectively evaluated. A 5-point scale (1 poor, 5 excellent) was used to score the imaging quality for displaying the vessel wall of every intracranial artery segments. The inter-observer and intra-observer reproducibility of identifying plaques, intraplaque hemorrhage/luminal thrombosis, and wall enhancement were calculated. RESULTS: Totally 893 artery segments were evaluated. 3D CUBE T1WI displayed the arteries wall and lumen clearly, with the highest score (4.920 +/- 0.837) for the C6-7 segments and the lowest (3.370 +/- 1.107) for the C3 segments of the internal carotid artery (ICA). Both intra-observer and inter-observer reproducibility were high for identification of normal walls (kappa=0.928, 95% confidence interval [CI] 0.891-0.954; kappa=0.911, CI 0.868 0.940), plaque (kappa=0.924, CI 0.884-0.954; kappa=0.907, CI 0.866-0.943), luminal thrombosis (kappa=1.000, CI 1.000-1.000; kappa=1.000, CI 1.000-1.000), and wall enhancement (kappa=1.000, CI 1.000-1.000; kappa=0.914, CI 0.863-0.961). CONCLUSIONS: High-resolution 3D CUBE T1WI displayed intracranial wall and lumen clearly, and detected intracranial artery abnormalities with high reproducibility. PMID- 26971428 TI - Impact on the recall rate of digital breast tomosynthesis as an adjunct to digital mammography in the screening setting. A double reading experience and review of the literature. AB - OBJECTIVES: To estimate the impact on recall rate (RR) of digital breast tomosynthesis (DBT) associated with digital mammography (DM+DBT), compared to DM alone, evaluate the impact of double reading (DR) and review the literature. METHODS: Ethics committees approved this multicenter study. Patients gave informed consent. Women recalled from population-based screening reading were included. Reference standard was histology and/or >= 1 year follow up. Negative multiple assessment was considered for patients lost at follow up. Two blinded readers (R1, R2) evaluated first DM and subsequently DM+DBT. RR, sensitivity, specificity, accuracy, positive and negative predictive values (PPV, NPV), were calculated for R1, R2, and DR. Cohen kappa and chi(2) were used for R1-R2 agreement and RR related to breast density. RESULTS: We included 280 cases (41 malignancies, 66 benign lesions, and 173 negative examinations). The RR reduction was 43% (R1), 58% (R2), 43% (DR). Sensitivity, specificity, accuracy, PPV and NPV were: 93%, 67%, 71%, 33%, 98% for R1; 88%, 73%, 75%, 36%, 97% for R2; 98%, 55%, 61%, 27%, 99% for DR. The agreement was higher for DM+DBT (kappa=0.459 versus kappa=0.234). Reduction in RR was independent from breast density (p=0.992). CONCLUSION: DBT was confirmed to reduce RR, as shown by 13 of 15 previous studies (reported reduction 6-82%, median 31%). This reduction is confirmed when using DR. DBT allows an increased inter-reader agreement. PMID- 26971429 TI - Evaluation of a known breast cancer using an abbreviated breast MRI protocol: Correlation of imaging characteristics and pathology with lesion detection and conspicuity. AB - OBJECTIVE: This study evaluates use of an abbreviated magnetic resonance imaging protocol with T2-weighted imaging in detecting biopsy-proven unifocal breast cancer. MATERIALS AND METHODS: This is an institutional review board approved retrospective study of patients with biopsy-proven unifocal breast cancer (88% invasive; 12% in situ) undergoing magnetic resonance imaging. In three separate sessions, three breast imagers evaluated (1) T1-weighted non-contrast, post contrast and post-contrast subtracted images, (2) T1-weighted images with clinical history and prior imaging, and (3) T1-weighted images and T2-weighted images with clinical history and prior imaging. Protocols were compared for cancer detection, reading time and lesion conspicuity. An independent breast radiologist retrospectively analyzed initial enhancement ratio of cancers and retrospectively reviewed lesion morphology and final pathology. RESULTS: All 107 cancers were identified at first protocol by at least one reader; five cancers were missed by either one or two readers. One cancer was missed by one reader at protocols two and three. Mean percentage detection for protocol one was 97.8%; protocol two, 99.4%, protocol three, 99.4%. T2-weighted images did not alter cancer detection but increased lesion conspicuity for 2/3 readers. 3/5 missed lesions were low grade cancers. Initial enhancement ratio was positively associated with increasing tumor grade (p=0.031) and pathology (p=0.002). Reader interpretation time decreased and lesion conspicuity increased as initial enhancement ratio increased. CONCLUSION: Abbreviated magnetic resonance imaging has high rate of detection for known breast cancer and short interpretation time. T2 weighted imaging increased lesion conspicuity without altering detection rate. Initial enhancement ratio correlated with invasive disease and tumor grade. PMID- 26971431 TI - Evaluation of individually body weight adapted contrast media injection in coronary CT-angiography. AB - OBJECTIVES: Contrast media (CM) injection protocols should be customized to the individual patient. Aim of this study was to determine if software tailored CM injections result in diagnostic enhancement of the coronary arteries in computed tomography angiography (CTA) and if attenuation values were comparable between different weight categories. MATERIALS AND METHODS: 265 consecutive patients referred for routine coronary CTA were scanned on a 2nd generation dual-source CT. Group 1 (n=141) received an individual CM bolus based on weight categories (39-59 kg; 60-74 kg; 75-94 kg; 95-109 kg) and scan duration ('high-pitch: 1s; "dual-step prospective triggering": 7s), as determined by contrast injection software (CertegraTM P3T, Bayer, Berlin, Germany). Group 2 (n=124) received a standard fixed CM bolus; Iopromide 300 mgI/ml; volume: 75 ml; flow rate: 7.2 ml/s. Contrast enhancement was measured in all proximal and distal coronary segments. Subjective and objective image quality was evaluated. Statistical analysis was performed using SPSS (IBM, version 20.0). RESULTS: For group 1, mean attenuation values of all segments were diagnostic (>325 HU) without statistical significant differences between different weight categories (p>0.17), proximal vs. distal: 449 +/- 65-373 +/- 58 HU (39-59 kg); 443 +/- 69-367 +/- 81 HU (60-74 kg); 427 +/- 59-370 +/- 61 HU (75-94 kg); 427 +/- 73-347 +/- 61 HU (95-109 kg). Mean CM volumes were: 55 +/- 6 ml (39-59 kg); 61 +/- 7 ml (60-74 kg); 71 +/- 8 ml (75-94 kg); 84 +/- 9 ml (95-109 kg). For group 2, mean attenuation values were not all diagnostic with differences between weight categories (p<0.01), proximal vs. distal: 611 +/- 142-408 +/- 69 HU (39-59 kg); 562 +/- 135-389 +/- 98 HU (60 74 kg); 481 +/- 83-329 +/- 81 HU (75-94 kg); 420 +/- 73-305 +/- 35 HU (95-109 kg). Comparable image noise and image quality were found between groups (p >= 0.330). CONCLUSIONS: Individually tailored CM injection protocols yield diagnostic attenuation and a more homogeneous enhancement pattern between different weight groups. CM volumes could be reduced for the majority of patients utilizing individualized CM bolus application. PMID- 26971430 TI - Diagnostic performance of texture analysis on MRI in grading cerebral gliomas. AB - BACKGROUND AND PURPOSE: Grading of cerebral gliomas is important both in treatment decision and assessment of prognosis. The purpose of this study was to determine the diagnostic accuracy of grading cerebral gliomas by assessing the tumor heterogeneity using MRI texture analysis (MRTA). MATERIAL AND METHODS: 95 patients with gliomas were included, 27 low grade gliomas (LGG) all grade II and 68 high grade gliomas (HGG) (grade III=34 and grade IV=34). Preoperative MRI examinations were performed using a 3T scanner and MRTA was done on preoperative contrast-enhanced three-dimensional isotropic spoiled gradient echo images in a representative ROI. The MRTA was assessed using a commercially available research software program (TexRAD) that applies a filtration-histogram technique for characterizing tumor heterogeneity. Filtration step selectively filters and extracts texture features at different anatomical scales varying from 2mm (fine features) to 6mm (coarse features), the statistical parameter standard deviation (SD) was obtained. Receiver operating characteristics (ROC) was performed to assess sensitivity and specificity for differentiating between the different grades and calculating a threshold value to quantify the heterogeneity. RESULTS: LGG and HGG was best discriminated using SD at fine texture scale, with a sensitivity and specificity of 93% and 81% (AUC 0.910, p<0.0001). The diagnostic ability for MRTA to differentiate between the different sub-groups (grade II-IV) was slightly lower but still significant. CONCLUSIONS: Measuring heterogeneity in gliomas to discriminate HGG from LGG and between different histological sub-types on already obtained images using MRTA can be a useful tool to augment the diagnostic accuracy in grading cerebral gliomas and potentially hasten treatment decision. PMID- 26971432 TI - Multi-parametric MRI in the early prediction of response to neo-adjuvant chemotherapy in breast cancer: Value of non-modelled parameters. AB - OBJECTIVE: To prospectively evaluate individual functional MRI metrics for the early prediction of pathological complete response (pCR) to neo-adjuvant chemotherapy (NAC) in breast cancer. MATERIALS AND METHODS: Thirty-two women (median age 52 years; range 32-71 years) with biopsy proven breast cancer due to receive neo-adjuvant anthracycline and/or taxane-based chemotherapy were prospectively recruited following local research ethics committee approval and written informed consent. Breast MRI was performed prior to and after two cycles of NAC and pCR was assessed after surgery. The enhancement fraction (EF), tumour volume, initial area under the gadolinium curve (IAUGC), pharmacokinetic parameters (K(trans), kep and ve), the apparent diffusion coefficient (ADC) and R2* values, along with the percentage change in these parameters after two cycles were evaluated according to pCR status using an independent samples t-test. The area under the receiver operating characteristics curve (AUC) was calculated for each parameter. Linear discriminant analysis (LDA) determined the most important parameter in predicting pCR. RESULTS: A reduction in the EF (-41% +/- 38%) and tumour volume (-80% +/- 25%) after 2 cycles of NAC were significantly greater in those achieving pCR (p=0.025, p=0.011 respectively). A reduction in the EF of 7% after 2 cycles of NAC identified those more likely to achieve pCR (AUC 0.76). AUC changes in other parameters were tumour volume (0.77), IAUGC (0.64), K(trans) (0.60), kep (0.68), ve (0.58), ADC (0.69) and R2* (0.41). CONCLUSION: In a multi parametric MRI model, the decrease in a non-model based vascular parameter the enhancement fraction as well as the tumour volume are the most important early predictors of pCR in breast cancer. PMID- 26971433 TI - Liver-fat and liver-function indices derived from Gd-EOB-DTPA-enhanced liver MRI for prediction of future liver remnant growth after portal vein occlusion. AB - OBJECTIVES: To evaluate the use of Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI)-derived fat- and liver function-measurements for prediction of future liver remnant (FLR) growth after portal vein occlusion (PVO) in patients scheduled for major liver resection. METHODS: Forty-five patients (age, 59 +/- 13.9 y) who underwent Gd-EOB-DTPA-enhanced liver MRI within 24 +/- 18 days prior to PVO were included in this study. Fat-Signal-Fraction (FSF), relative liver enhancement (RLE) and corrected liver-to-spleen ratio (corrLSR) of the FLR were calculated from in- and out-of-phase (n=42) as well as from unenhanced T1 weighted, and hepatocyte-phase images (n=35), respectively. Kinetic growth rate (KGR, volume increase/week) of the FLR after PVO was the primary endpoint. Receiver operating characteristics analysis was used to determine cutoff values for prediction of impaired FLR-growth. RESULTS: FSF (%) showed significant inverse correlation with KGR (r=-0.41, p=0.008), whereas no significant correlation was found with RLE and corrLSR. FSF was significantly higher in patients with impaired FLR-growth than in those with normal growth (%FSF, 8.1 +/- 9.3 vs. 3.0 +/- 5.9, p=0.02). ROC-analysis revealed a cutoff-FSF of 4.9% for identification of patients with impaired FLR-growth with a specificity of 82% and sensitivity of 47% (AUC 0.71 [95%CI:0.54-0.87]). Patients with impaired FLR growth according to the FSF-cutoff showed a tendency towards higher postoperative complication rates (posthepatectomy liver failure in 50% vs. 19%). CONCLUSIONS: Liver fat-content, but not liver function derived from Gd-EOB-DTPA-enhanced MRI is a predictor of FLR-growth after PVO. Thus, liver MRI could help in identifying patients at risk for insufficient FLR-growth, who may need re-evaluation of the therapeutic strategy. PMID- 26971434 TI - Fontan-associated liver disease: Spectrum of US findings. AB - PURPOSE: To describe ultrasonography (US) findings of Fontan-associated liver disease (FALD) and to determine whether screening US examinations can identify FALD before biochemical hepatic dysfunction. METHODS: This retrospective study included 55 patients who underwent Fontan procedure over a 20-year period. Hepatobiliary US findings (n=55), CT or MRI findings (n=19), biochemical hepatic function tests (n=49), and histopathological results (n=4) were analyzed. Images were reviewed focusing on the hepatic parenchymal changes, presence of focal lesions, and signs of portal hypertension. RESULTS: Hepatic parenchymal changes (either heterogeneous echotexture or surface nodularity) evident on US were present in 67% (37/55) and showed positive correlation with the Fontan duration. Hyper-echoic lesions were noted in 35% (19/55) and showed a predilection for multiplicity, small size, right lobe location, and irregular margin on high frequency transducer. These lesions were not demonstrated by CT or MRI or by low frequency transducer. Histopathological results of targeted biopsy for hyper echoic lesions revealed lesser degree of patchy sinusoidal and portal fibrosis than seen in cases with surface nodularity. Abnormal parenchymal enhancement was commonly seen with CT or MRI in 63% (12/19) and hypervascular nodules in 21% (4/19). Most patients (82%, 40/49) showed normal biochemical hepatic function tests, despite the presence of hepatic parenchymal changes on imaging. CONCLUSION: The common US findings of FALD included heterogeneous parenchymal echotexture, surface nodularity, and hyper-echoic lesions. We suggest that hyper echoic lesions without surface nodularity detected by high-frequency transducer may represent the early stage of fibrosis. US examination may be useful for identifying the progression of FALD before biochemical hepatic dysfunction. PMID- 26971435 TI - Can magnetic resonance imaging be an alternative to computed tomography in immunocompromised patients with suspected fungal infections? Feasibility of a speed optimized examination protocol at 3 Tesla. AB - OBJECTIVE: To prospectively evaluate a short MRI examination protocol for the detection of nodular pulmonary infiltrates in immunocompromised patients with hematologic diseases and suspected invasive fungal infections. METHODS: Patients with nodular infiltrates on CT scans were examined on a 3T MRI scanner. The standardized protocol included axial T2-weighted fast spin echo (FSE) sequences +/- fat saturation (FS), and axial T1-weighted gradient echo (GRE) sequences. Long and short axis diameters of nodular infiltrates and visibility were assessed on MR images at least six months after the CT scan, blinded to patient and examination data. Inter- and intra-reader reliability was assessed in two patients. Statistical testing included Wilcoxon-test, Cohen's kappa, and intra class correlation coefficients. Bland-Altman plots were created to visualize differences in the measurements. RESULTS: In all 13 patients MRI examinations were completed successfully (average examination time 12 min and maximum breath hold time of 8s). CT detected 409 nodules. Sensitivity of MRI was 93.2% when using all sequences in combination; considering nodules >5mm, sensitivity increased to 97.9%. Reliability analysis showed excellent correlations with an intra-class correlation coefficient of at least 0.89 for T2 FSE (95% CI 0.79 0.93, p<0.01) images for the intra-, and the lowest of 0.77 for T2 FSE (95% CI 0.55-0.89, p<0.01) images for the inter-reader comparison. Agreement on nodule visibility was at least kappa=0.95 (p<0.01) for the intra- and 0.72 (p<0.01) for the inter-reader analysis. CONCLUSION: With an average examination time of 12 min, pulmonary MRI at 3T is feasible in immunocompromised patients with hematologic diseases and suspected invasive fungal infections. MRI might serve as an alternative diagnostic tool during follow-up examinations. PMID- 26971437 TI - Editorial. PMID- 26971436 TI - Diffusion-weighted magnetic resonance imaging to differentiate malignant from benign gallbladder disorders. AB - PURPOSE: To retrospectively evaluate the utility of apparent diffusion coefficient (ADC) and lesion to spinal cord ratio (LSR) in diffusion-weighted magnetic resonance (MR) imaging (DWI) as compared with morphological assessment alone, for differentiating malignant from benign gallbladder disorders. METHODS: This study was approved by the ethics committee, and written informed consent was waived. Ninety-one patients (13 malignancy and 78 benignancy) were reviewed. ADC was calculated using two DW images with different motion-probing gradient strengths (b=0, 1000s/mm(2)). LSR was measured by dividing the signal intensity of a thickened gallbladder wall by the maximum signal intensity of the lumbar enlargement of the spinal cord. In addition, the morphology of the gallbladders was assessed with conventional MR imaging. RESULTS: In receiver operating characteristic curve analysis, the areas under the curves for ADC and LSR were 0.861 and 0.906, respectively. Three morphological findings were considered: a massive formation, a disrupted mucosal line, and the absence of a two-layered pattern. When a combination of two or more of these morphological findings was positive for malignancy, the sensitivity, specificity, and accuracy were 76.9%, 84.0%, and 83.0%, respectively. When a combination of three or more of the above morphological findings together with ADC of less than 1.2 * 10(-3)mm(2)/s or LSR of more than 0.48 were positive for malignancy, these values were 73.0%, 96.2%, and 92.9%, respectively. There were significant differences in specificity and accuracy. CONCLUSION: Use of ADC and LSR in DWI can improve diagnostic performance for differentiating malignant from benign gallbladder disorders. PMID- 26971440 TI - Better perineal outcomes in sitting birthing position cannot be explained by changing from upright to supine position for performing an episiotomy. AB - BACKGROUND: women who give birth in supine position are more likely to have an episiotomy than women who give birth in sitting position. A confounding effect may be that women in upright positions in second stage of labour are asked to lie down if a professional needs to perform an episiotomy. This prospective cohort study aimed to determine whether this factor can explain the lower rate of episiotomy in sitting compared to supine position. METHODS: data from 1196 women who had a spontaneous, vaginal birth were analysed. Positions during second stage and at birth were carefully recorded. Three groups of birthing positions were compared in multivariable analyses: 1) horizontal during second stage and supine at birth (horizontal/supine), 2) horizontal and upright during second stage and supine at birth (various/supine), 3) sitting at birth regardless of the position in second stage. Logistic regression analysis was used to adjust for known risk factors for perineal damage. FINDINGS: women in sitting position at birth compared to those in the horizontal/supine group had a lower episiotomy rate (adjusted OR 0.28;95%-CI 0.14-0.56) and a non-significant higher intact perineum rate (adjusted OR 1.40, 95% CI 0.96-2.04). Women in the various/supine group compared to the horizontal/supine group had a similar episiotomy rate (adjusted OR 1.12;95%-CI 0.69-1.83). CONCLUSIONS: we did not confirm our hypothesis that more women in supine compared to sitting position have an episiotomy because women in upright position are asked to lie down if an episiotomy is necessary. PMID- 26971439 TI - Archaea produce lower yields of N2 O than bacteria during aerobic ammonia oxidation in soil. AB - Nitrogen fertilisation of agricultural soil contributes significantly to emissions of the potent greenhouse gas nitrous oxide (N2 O), which is generated during denitrification and, in oxic soils, mainly by ammonia oxidisers. Although laboratory cultures of ammonia oxidising bacteria (AOB) and archaea (AOA) produce N2 O, their relative activities in soil are unknown. This work tested the hypothesis that AOB dominate ammonia oxidation and N2 O production under conditions of high inorganic ammonia (NH3 ) input, but result mainly from the activity of AOA when NH3 is derived from mineralisation. 1-octyne, a recently discovered inhibitor of AOB, was used to distinguish N2 O production resulting from archaeal and bacterial ammonia oxidation in soil microcosms, and specifically inhibited AOB growth, activity and N2 O production. In unamended soils, ammonia oxidation and N2 O production were lower and resulted mainly from ammonia oxidation by AOA. The AOA N2 O yield relative to nitrite produced was half that of AOB, likely due to additional enzymatic mechanisms in the latter, but ammonia oxidation and N2 O production were directly linked in all treatments. Relative contributions of AOA and AOB to N2 O production, therefore, reflect their respective contributions to ammonia oxidation. These results suggest potential mitigation strategies for N2 O emissions from fertilised agricultural soils. PMID- 26971438 TI - Guiding migration of transplanted glial progenitor cells in the injured spinal cord. AB - Transplantation of glial-restricted progenitors (GRPs) is a promising strategy for generating a supportive environment for axon growth in the injured spinal cord. Here we explored the possibility of producing a migratory stream of GRPs via directional cues to create a supportive pathway for axon regeneration. We found that the axon growth inhibitor chondroitin sulfate proteoglycan (CSPG) strongly inhibited the adhesion and migration of GRPs, an effect that could be modulated by the adhesion molecule laminin. Digesting glycosaminoglycan side chains of CSPG with chondroitinase improved GRP migration on stripes of CSPG printed on cover glass, although GRPs were still responsive to the remaining repulsive signals of CSPG. Of all factors tested, the basic fibroblast growth factor (bFGF) had the most significant effect in promoting the migration of cultured GRPs. When GRPs were transplanted into either normal spinal cord of adult rats or the injury site in a dorsal column hemisection model of spinal cord injury, a population of transplanted cells migrated toward the region that was injected with the lentivirus expressing chondroitinase or bFGF. These findings suggest that removing CSPG-mediated inhibition, in combination with guidance by attractive factors, can be a promising strategy to produce a migratory stream of supportive GRPs. PMID- 26971441 TI - Standards for maternity care professionals attending planned upright breech births: A Delphi study. AB - OBJECTIVE: to establish a consensus of opinion on standards of competence for professionals attending upright breech births. DESIGN: a three-round Delphi e survey. SETTING: multinational. PARTICIPANTS: a panel of 13 obstetricians, 13 midwives and two user representatives. Clinicians had attended >20 upright breech births, or >10 upright among >40 total breech births. Mean level of experience=135 breech births, median=100 breech births. METHODS: an initial survey contained open-ended questions. Answers were coded and amalgamated to form 164 statements in the second round and 9 further statements in the third round. Panellists were asked to evaluate their agreement with each statement using a 5 point Likert scale. The pre-determined level of consensus was 70% of respondents indicating agreement or strong agreement with the statement. FINDINGS: the panel returned a consensus-level agreement on 63 statements under the theme, 'Standards of Competence.' Panellists supported teaching breech as a 'normal' skill rather than an emergency, including optimal mechanisms and breech-specific progress measures, upright variations of classical manoeuvres, the initiation of resuscitation with the umbilical cord intact, birth videos as learning tools, and the development of breech teams to support the wider team in all maternity care settings. CONCLUSIONS: although every health professional should maintain basic competence to assist unanticipated breech births, establishing enhanced training and standards for those who support planned breech births may help protect users and providers of maternity services, while introducing greater choice and flexibility for women seeking the option of vaginal breech birth. PMID- 26971442 TI - Frequency, severity and persistence of postnatal dyspareunia to 18 months post partum: A cohort study. AB - OBJECTIVE: to describe the frequency, severity and persistence of dyspareunia in the first 18 months after the birth of a first child. DESIGN: prospective pregnancy cohort study. SETTING: Melbourne, Victoria, Australia. POPULATION: 1507 nulliparous women. METHODS: women <=24 weeks gestation were recruited from six public hospitals. Self-administered written questionnaires were completed at recruitment and at three, six, 12 and 18 months post partum. OUTCOME MEASURES: study-designed self-report measure of dyspareunia on first vaginal sex, and on second and subsequent sex at all time-points, utilising the rating scale from the McGill Pain Intensity Scale. FINDINGS: overall, 961/1122 (85.7%) of women experienced pain on first vaginal sex postnatally. The proportion of women experiencing dyspareunia reduced over time, from 431/964 (44.7%) at three months post partum to 261/1155 (22.6%) at 18 months post partum. Of the women who reported dyspareunia at each time-point, around 10% of women described the pain as'distressing','horrible' or'excruciating'. Women who had a caesarean section were more likely to report more intense dyspareunia at six months post partum (aOR=2.35, 95% CI=1.2-4.6). CONCLUSIONS: postnatal dyspareunia decreases over time, but persists beyond 12 months for one in five women. Caesarean section appears to be associated with more intense dyspareunia. PMID- 26971443 TI - Response to provision and effect of quit-smoking counselling by primary care midwives. PMID- 26971444 TI - Dying at life's beginning: Experiences of parents and health professionals in Switzerland when an 'in utero ' diagnosis incompatible with life is made. AB - OBJECTIVE: The disclosure of a diagnosis during pregnancy of a fetal malformation, which is incompatible with life, normally comes completely unexpectedly to the parents. Although a body of international literature has considered the topic, most of it comes from the United States and little has been generated from Europe. This study aims to illuminate the contemporary treatment associated with such diagnoses, regardless of whether parents decide to terminate or continue the pregnancy. DESIGN: a qualitative design was used with data collected by semi-structured interviews and subjected to a thematic analysis. SETTING: the research was conducted in the German speaking areas of Switzerland with data collected from participants in places of their choice. PARTICIPANTS: 61 interviews were conducted with 32 parents and 29 health professionals. FINDINGS: the theme of 'temporality' identified four main time points from the professionals: diagnosis, decision, birth/death, and afterwards. However, in contrast to these, six major themes in this study, primarily generated from parents and extended from receiving the diagnosis until the interview, were identified: shock, choices and dilemmas, taking responsibility, still being pregnant, forming a relationship with the baby, letting go. Although there was concurrence on many aspects of care at the point of contact, parents expressed major issues as gaps between the points of contact. CONCLUSIONS: care varied regionally but was as sensitive as possible, attempting to give parents the space to accept their loss but fulfil legal requirements. A gap exists between diagnosis and decision with parents feeling pressured to make decisions regarding continuing or terminating their pregnancies although health professionals' testimonies indicated otherwise. A major gap manifested following the decision with no palliative care packages offered. During the birth/death of the baby, care was sensitive but another gap manifested following discharge from hospital. PMID- 26971445 TI - Key points for abolishing Female Genital Mutilation from the perspective of the men involved. AB - INTRODUCTION: female Genital Mutilation is internationally considered an affront on human rights and an act of violence against women and young girls. Furthermore, it hierarchises and perpetuates inequality and denies the right to bodily and psychosocial integrity of women and young girls. AIMS: to detect the key points for the abolition of Female Genital Mutilation as well as the necessary resources for its eradication. MATERIAL AND METHOD: a qualitative methodology with an ethnonursing perspective, via semi-structured interviews, held both individually and in groups, in 21 men familiar with Female Genital Mutilation. FINDINGS: through the voices of men familiar with this tradition, five key points are presented for its gradual eradication: sensitisation and awareness building, team action, abolition-promoting media, focusing action on rural areas and applying educational means before punitive ones. CONCLUSION AND PRACTICAL IMPLICATIONS: awareness-raising via the combined efforts of families, communities and governments, together with the promotion of health education programmes in demonstrating the complications derived from this practice, play a vital part in eradicating Female Genital Mutilation. PMID- 26971446 TI - A Rapid Assessment Tool for affirming good practice in midwifery education programming. AB - OBJECTIVE: to design a criterion-referenced assessment tool that could be used globally in a rapid assessment of good practices and bottlenecks in midwifery education programs. DESIGN: a standard tool development process was followed, to generate standards and reference criteria; followed by external review and field testing to document psychometric properties. SETTING: review of standards and scoring criteria were conducted by stakeholders around the globe. Field testing of the tool was conducted in Myanmar. PARTICIPANTS: eleven of Myanmar's 22 midwifery education programs participated in the assessment. FINDINGS: the clinimetric tool was demonstrated to have content validity and high inter-rater reliability in use. KEY CONCLUSIONS: a globally validated tool, and accompanying user guide and handbook are now available for conducting rapid assessments of compliance with good practice criteria in midwifery education programming. PMID- 26971447 TI - Bedside resuscitation of newborns with an intact umbilical cord: Experiences of midwives from British Columbia. AB - CONTEXT: level 1 evidence supports the practice of delayed cord clamping, and many doctors and midwives consider it routine care when delivering vigorous, term neonates. However, scarce research exists regarding the risks or benefits of delayed cord clamping for infants needing resuscitation with positive pressure ventilation. Nonetheless, some midwives in British Columbia already practice intact cord resuscitation (ICR) at planned home births and in the hospital in order to facilitate delayed cord clamping for infants who need resuscitation. METHODS: we distributed an online survey to all registered midwives in British Columbia through the Midwives Association of BC between October 22nd and November 13th, 2014. This survey examined how midwives balance a commitment to delayed cord clamping with the need for resuscitation in home and hospital settings. FINDINGS: a total of 82 midwives responded to the survey (response rate=35%). Many have practiced ICR (56, 69%). However, the majority (42, 78%) of respondents had only performed this type of resuscitation at planned home births and not in the hospital setting. In both settings, midwives found the ergonomics of resuscitation with an intact cord challenging, but cited a smoother physiologic transition for neonates as their primary reasons for this practice, despite the obstacles. Midwives reported a greater ability to use their delivery equipment to provide stable thermoregulation at the bedside at planned home births during a resuscitation compared with the set up of hospital delivery rooms. CONCLUSION: although the majority of participants practice ICR at planned home births, very few use this practice in the hospital setting. In the home, ergonomics is the primary obstacle for easily practicing ICR; hospital culture, protocols and lack of training are additional barriers to this practice in the hospital setting. Ergonomics and lack of appropriate set up in the delivery room were also primary obstacles. Midwives expressed a desire to find ways to incorporate ICR into the hospital setting. PMID- 26971448 TI - Remote links: Redesigning maternity care for Aboriginal women from remote communities in Northern Australia - A comparative cohort study. AB - OBJECTIVE: to compare the quality of care before and after the introduction of the new Midwifery Group Practice. DESIGN: a cohort study. SETTING: the health centers (HCs) in two of the largest remote Aboriginal communities (population 2200-2600) in the Top End of the Northern Territory (NT), each located approximately 500km from Darwin. The third study site was the Royal Darwin Hospital (RDH) which provides tertiary care. METHODS: a 2004-06 retrospective cohort (n=412 maternity cases) provided baseline data. A clinical redesign of maternity services occurring from 2009 onwards focused on increasing Continuity of Carer, Communication, Choice, Collaboration and Co-ordination of Care (5Cs). Data from a 2009-11 prospective cohort (n=310 maternity cases) were collected to evaluate the service redesign. Outcome measures included indicators on the quality of care delivery, adherence to recommended antenatal guidelines and maternal and neonatal health outcomes. FINDINGS: statistically significant improvements were recorded in many areas reflecting improved access to, and quality of, care. For example: fewer women had <4 visits in pregnancy (14% versus 8%), a higher proportion of women had routine antenatal tests recorded (86% versus 97%) and improved screening rates for urine (82% versus 87%) and sexual tract infections (78% versus 93%). However, the treatment of conditions according to recommended guidelines worsened significantly in some areas; for example antibiotics prescribed for urine infections (86% versus 52%) and treatment for anaemia in pregnancy (77% versus 67%). High preterm (21% versus 20%), low birth weight (18% versus 20%) and PPH (29% versus 31%) rates did not change over time. The out of hospital birth rate remained high and unchanged in both cohorts (10% versus 10%). CONCLUSION: this model addresses some of the disparities in care for remote-dwelling Aboriginal women. However, much work still needs to occur before maternity care and outcomes are equal to that of non-Aboriginal women. Targeted program interventions with stronger clinical governance frameworks to improve the quality of care are essential. A complete rethink of service delivery and engagement may deliver better results. PMID- 26971451 TI - [Role of the health coordination council in Rikuzentakata City, Iwate Prefecture, for the Great East Japan Earthquake/Tsunami as a model of disaster preparedness]. PMID- 26971450 TI - High Efficiency CVD Graphene-lead (Pb) Cooper Pair Splitter. AB - Generation and manipulation of quantum entangled electrons is an important concept in quantum mechanics, and necessary for advances in quantum information processing; but not yet established in solid state systems. A promising device is a superconductor-two quantum dots Cooper pair splitter. Early nanowire based devices, while efficient, are limited in scalability and further electron manipulation. We demonstrate an optimized, high efficiency, CVD grown graphene based Cooper pair splitter. Our device is designed to induce superconductivity in graphene via the proximity effect, resulting in both a large superconducting gap Delta = 0.5 meV, and coherence length xi = 200 nm. The flat nature of the device lowers parasitic capacitance, increasing charging energy EC. Our design also eases geometric restrictions and minimizes output channel separation. As a result we measure a visibility of up to 86% and a splitting efficiency of up to 62%. This will pave the way towards near unity efficiencies, long distance splitting, and post-splitting electron manipulation. PMID- 26971452 TI - [Evaluation of Educational Programs to Prevent Accidents while Bathing]. AB - OBJECTIVE: Approximately 19,000 people die in Japan each year from accidents that occur while bathing. Yamagata Prefectural Shounai public health center had educated residents about proper bathing practice. We evaluated residents' knowledge about safe bathing practices after an educational campaign in the area. METHODS: We distributed a questionnaire to 3,078 people to gauge their awareness of bathing accidents in general and the effectiveness of a safety campaign from the public health center prevention. Participants included people who had attended a meeting, workshop, lecture, or event at the public health center. RESULTS: A total of 2,697 people responded (87.6% response rate). A large majority (92%) knew about safe bathing practices in general. However, only 43% knew that bathing in hot water less than 41 degrees Celsius could help to reduce bathing accidents. Only 56% bathed in water below 41 degrees Celsius. Similarly, 81% knew about the preheating before bathing in dressing room and bathroom, but practiced only 50% of those. About recognition of the actual situation of the bathing accident and recognition of the prophylaxis, a student attending a lecture was higher than a lecture non-student attending a lecture more than 10%. CONCLUSION: Recognitions and practices of safe bathing practices had big difference, and development of an effective communication method will be important. PMID- 26971453 TI - [Medical Relief Response by Miyako Public Health Center after the Great East Japan Earthquake and Tsunami, 2011]. AB - OBJECTIVES: To improve disaster preparedness, we investigated the response of medical relief activities managed by Iwate Prefectural Miyako Public Health Center during the post-acute phase of the Great East Japan Earthquake and Tsunami on March 11, 2011. METHODS: The study divided the post-disaster period into three approximate time segments: Period I (time of disaster through late March), Period II (mid-April), and Period III (end of May in Miyako City, early July in Yamada Town). We reviewed records on medical relief activities conducted by medical assistance teams (MATs) in Miyako City and Yamada Town. RESULTS: Miyako Public Health Center had organized a meeting to coordinate medical relief activities from Period I to Period III. According to demand for medical services and recovery from the local medical institutions (LMIs) in the affected area, MATs were deployed and active on evacuation centers in each area assigned. The number of patients examined by MATs in Miyako rose to approximately 250 people per day in Period I and decreased to 100 in Period III. However, in Yamada, the number surged to 700 in Period I, fell to 100 in Period II, and decreased to 50 in Period III. This difference could be partly explained as follows. In Miyako, most evacuees had consulted LMIs which restarted medical services after disaster, and the number of LMIs restarted had already reached 29 (94% of the whole) in Period I. In Yamada, most evacuees who had consulted MATs in Period I had almost moved to LMIs restarted in Period II. During the same time, a division of roles and coordination on medical services provision was conducted, such as MATs mainly in charge of primary emergency triage, in response to the number of LMIs restarted which reached 1 (20%) in Period I and 3 (60%) in Period II. Following Period III, more than 80% of patients in Miyako had been a slight illness, such as need for health guidance, and the number of people who underwent emergency medical transport reached pre-disaster levels in both locations. These results suggest that demand for medical services of evacuees declined to a stable level in an early stage of Period III. Using the above findings, one might justify supporting local medical institutions' recovery earlier. Then, medical relief activities might be finished properly. CONCLUSION: This study shows useful perspectives in the response of medical relief activities during post-acute phase after disaster and the importance of establishing systems for information management that apply these perspectives. PMID- 26971454 TI - Stimuli-responsive cylindrical hydrogels mimic intestinal peristalsis to propel a solid object. AB - The emerging field of soft robotics relies on soft, stimuli-responsive materials to enable load transport, manipulation, and mobility in complex unconstrained environments. These materials often need to replicate biological functionality such as muscle contractions and flexibility. Here we demonstrate a soft actuator prototype based on thermosensitive PNIPAAM hydrogels that can transport and manipulate objects. A hollow cylindrical hydrogel was selectively heated and cooled with Peltier devices to yield a traveling wave of shrinking and swelling akin to intestinal peristalsis. A 4 mm diameter bead was placed inside the cylinder and propelled 19.5 mm, equal to distance traveled by the peristaltic wave. We derived conditions that enable peristaltic transport as a function of transporter-cargo design parameters. We conclude that hydrogel-based peristaltic manipulators covering 2 orders of magnitude in stiffness (1-10(2) kPa) could transport cargo spanning 4 orders of magnitude in size (MUm-m). PMID- 26971449 TI - Promotion of mitochondrial biogenesis by necdin protects neurons against mitochondrial insults. AB - Neurons rely heavily on mitochondria for their function and survival. Mitochondrial dysfunction contributes to the pathogenesis of neurodegenerative diseases such as Parkinson's disease. PGC-1alpha is a master regulator of mitochondrial biogenesis and function. Here we identify necdin as a potent PGC 1alpha stabilizer that promotes mitochondrial biogenesis via PGC-1alpha in mammalian neurons. Expression of genes encoding mitochondria-specific proteins decreases significantly in necdin-null cortical neurons, where mitochondrial function and expression of the PGC-1alpha protein are reduced. Necdin strongly stabilizes PGC-1alpha by inhibiting its ubiquitin-dependent degradation. Forced expression of necdin enhances mitochondrial function in primary cortical neurons and human SH-SY5Y neuroblastoma cells to prevent mitochondrial respiratory chain inhibitor-induced degeneration. Moreover, overexpression of necdin in the substantia nigra in vivo of adult mice protects dopaminergic neurons against degeneration in experimental Parkinson's disease. These data reveal that necdin promotes mitochondrial biogenesis through stabilization of endogenous PGC-1alpha to exert neuroprotection against mitochondrial insults. PMID- 26971458 TI - Editorial overview: Environmental biotechnology - quo vadis? PMID- 26971461 TI - Identification of CYP4V2 mutation in 36 Chinese families with Bietti crystalline corneoretinal dystrophy. AB - Bietti crystalline corneoretinal dystrophy (BCD) is an inherited eye disease that is most common in the Chinese. It is caused by a mutation in the CYP4V2 gene. In this study, 43 Chinese BCD families were recruited; most patients manifested the characteristic phenotype of BCD, with 2 families initially misdiagnosed with retinitis pigmentosa. Five patients in our cohort presented with BCD and choroidal neovascularization (CNV), and 1 patient presented with typical BCD and abnormality in the terminals of both fingers and toes. A total of 17 pathogenic mutations involving 68 alleles were identified from 36 families using targeted exon sequencing and Sanger sequencing; we achieved a diagnostic rate of approximately 84%. Fifteen families were found to carry homozygous mutations, 17 families carried compound heterozygous mutations, and 4 families carried a single heterozygous mutation. Of the mutations identified, four variants c.802 8_810del17bpinsGC, c.802-8_810del17bpinsGT, c.992A > C (p.H331P), and c.1091-2A > G accounted for 71% of the mutations identified in CYP4V2. These mutations were hotspots in Chinese populations for BCD. Five among them were novel and predicted to be disease-causing, including c.65T > A (p.L22H), c.681_4delTGAG (p.S227Rfs*1), c.802-8_810del17bpinsGT, c.965_7delAAG (p.321delE), and c.994G > A (p.D332N). No apparent correlation between genotype and phenotype was identified. Our findings broaden the spectrum of CYP4V2 mutations that cause BCD and the phenotypic spectrum of the disease in Chinese families. These results will be useful for the genetic diagnosis of BCD, genetic consultation, and gene therapy in the future. PMID- 26971462 TI - Time Harmonic Elastography Reveals Sensitivity of Liver Stiffness to Water Ingestion. AB - The aim of the study was to test the sensitivity of liver stiffness (LS) measured by time harmonic elastography in large tissue windows to water uptake and post prandial effects. Each subject gave written informed consent to participate in this institutional review board-approved prospective study. LS was measured by time harmonic elastography in 10 healthy volunteers pre- and post-prandially, as well as before, directly after and 2 h after drinking water. The LS-time function during water intake was measured in 14 scans over 3 h in five volunteers. LS increased by 10% (p = 0.0015) post-prandially and by 11% (p = 0.0024) after pure water ingestion, and decreased to normal values after 2 h. LS was lower after overnight fasting than after 2-h fasting (3%, p = 0.04). Over the time course, LS increased to post-water peak values 15 min after drinking 0.25 L water and remained unaffected by further ingestion of water. In conclusion, our study indicates that LS measured by time harmonic elastography represents an effective medium property sensitive to physiologic changes in vascular load of the liver. PMID- 26971463 TI - Modular protein domains: an engineering approach toward functional biomaterials. AB - Protein domains and peptide sequences are a powerful tool for conferring specific functions to engineered biomaterials. Protein sequences with a wide variety of functionalities, including structure, bioactivity, protein-protein interactions, and stimuli responsiveness, have been identified, and advances in molecular biology continue to pinpoint new sequences. Protein domains can be combined to make recombinant proteins with multiple functionalities. The high fidelity of the protein translation machinery results in exquisite control over the sequence of recombinant proteins and the resulting properties of protein-based materials. In this review, we discuss protein domains and peptide sequences in the context of functional protein-based materials, composite materials, and their biological applications. PMID- 26971465 TI - Clinical applications of bacterial glycoproteins. AB - There is an ongoing race between bacterial evolution and medical advances. Pathogens have the advantages of short generation times and horizontal gene transfer that enable rapid adaptation to new host environments and therapeutics that currently outpaces clinical research. Antibiotic resistance, the growing impact of nosocomial infections, cancer-causing bacteria, the risk of zoonosis, and the possibility of biowarfare all emphasize the increasingly urgent need for medical research focussed on bacterial pathogens. Bacterial glycoproteins are promising targets for alternative therapeutic intervention since they are often surface exposed, involved in host-pathogen interactions, required for virulence, and contain distinctive glycan structures. The potential exists to exploit these unique structures to improve clinical prevention, diagnosis, and treatment strategies. Translation of the potential in this field to actual clinical impact is an exciting prospect for fighting infectious diseases. PMID- 26971466 TI - Proteomic analysis and identification of cell surface-associated proteins of Clostridium chauvoei. AB - Blackleg is a highly fatal disease of cattle and sheep, caused by Clostridium chauvoei, a Gram positive, anaerobic, spore forming bacteria. Cell surface associated proteins play a major role in inducing the protective immunity. However, the identity of a majority of cell surface-associated proteins of C. chauvoei is not known. In the present investigation, we have used SDS-PAGE, 2D gel electrophoresis and Western blotting followed by mass spectrometry to identify cell surface-associated proteins of C. chauvoei. Among the identified proteins, which have shown to offer protective antigencity in other bacteria, Enolase, Chaperonin, Ribosomal protein L10, Glycosyl Hydrolase and Flavoprotein were characterized by sequencing and their overexpression in Escherichia coli. In conclusion, cell surface-associated proteins were identified using proteomic approach and the genes for the immunoreactive proteins were expressed, which may prove to be potential diagnostic or vaccine candidates. PMID- 26971460 TI - The lens actin filament cytoskeleton: Diverse structures for complex functions. AB - The eye lens is a transparent and avascular organ in the front of the eye that is responsible for focusing light onto the retina in order to transmit a clear image. A monolayer of epithelial cells covers the anterior hemisphere of the lens, and the bulk of the lens is made up of elongated and differentiated fiber cells. Lens fiber cells are very long and thin cells that are supported by sophisticated cytoskeletal networks, including actin filaments at cell junctions and the spectrin-actin network of the membrane skeleton. In this review, we highlight the proteins that regulate diverse actin filament networks in the lens and discuss how these actin cytoskeletal structures assemble and function in epithelial and fiber cells. We then discuss methods that have been used to study actin in the lens and unanswered questions that can be addressed with novel techniques. PMID- 26971467 TI - Liver Kinase B1 complex acts as a novel modifier of myofilament function and localizes to the Z-disk in cardiac myocytes. AB - Contractile perturbations downstream of Ca(2+) binding to troponin C, the so called sarcomere-controlled mechanisms, represent the earliest indicators of energy remodeling in the diseased heart [1]. Central to cellular energy "sensing" is the adenosine monophosphate-activated kinase (AMPK) pathway, which is known to directly target myofilament proteins and alter contractility [2-6]. We previously showed that the upstream AMPK kinase, LKB1/MO25/STRAD, impacts myofilament function independently of AMPK [5]. Therefore, we hypothesized that the LKB1 complex associated with myofilament proteins and that alterations in energy signaling modulated targeting or localization of the LKB1 complex to the myofilament. Using an integrated strategy of myofilament mechanics, immunoblot analysis, co-immunoprecipitation, mass spectroscopy, and immunofluorescence, we showed that 1) LKB1 and MO25 associated with myofibrillar proteins, 2) cellular energy stress re-distributed AMPK/LKB1 complex proteins within the sarcomere, and 3) the LKB1 complex localized to the Z-Disk and interacted with cytoskeletal and energy-regulating proteins, including vinculin and ATP Synthase (Complex V). These data represent a novel role for LKB1 complex proteins in myofilament function and myocellular "energy" sensing in the heart. PMID- 26971469 TI - Mutagenic and chemical analyses provide new insight into enzyme activation and mechanism of the type 2 iron-sulfur l-serine dehydratase from Legionella pneumophila. AB - The crystal structure of the Type 2 l-serine dehydratase from Legionella pneumophila (lpLSD), revealed a "tail-in-mouth" configuration where the C terminal residue acts as an intrinsic competitive inhibitor. This pre-catalytic structure undergoes an activation step prior to catalytic turnover. Mutagenic analysis of residues at or near the active site cleft is consistent with stabilization of substrate binding by many of the same residues that interact with the C-terminal cysteine and highlight the critical role of certain tail residues in activity. pH-rate profiles show that a residue with pK of 5.9 must be deprotonated and a residue with a pK of 8.5 must be protonated for activity. This supports an earlier suggestion that His 61 is the likely catalytic base. An additional residue with a pK of 8.5-9 increases cooperativity when it is deprotonated. This investigation also demonstrates that the Fe-S dehydratases convert the enamine/imine intermediates of the catalytic reaction to products on the enzyme prior to release. This is in contrast to pyridoxyl 5' phosphate based dehydratases that release an enamine/imine intermediate into solution, which then hydrolyzes to produce the ketoamine product. PMID- 26971464 TI - Alopecia areata: Animal models illuminate autoimmune pathogenesis and novel immunotherapeutic strategies. AB - One of the most common human autoimmune diseases, alopecia areata (AA), is characterized by sudden, often persisting and psychologically devastating hair loss. Animal models have helped greatly to elucidate critical cellular and molecular immune pathways in AA. The two most prominent ones are inbred C3H/HeJ mice which develop an AA-like hair phenotype spontaneously or after experimental induction, and healthy human scalp skin xenotransplanted onto SCID mice, in which a phenocopy of human AA is induced by injecting IL-2-stimulated PBMCs enriched for CD56+/NKG2D+ cells intradermally. The current review critically examines the pros and cons of the available AA animal models and how they have shaped our understanding of AA pathobiology, and the development of new therapeutic strategies. AA is thought to arise when the hair follicle's (HF) natural immune privilege (IP) collapses, inducing ectopic MHC class I expression in the HF epithelium and autoantigen presentation to autoreactive CD8+ T cells. In common with other autoimmune diseases, upregulation of IFN-gamma and IL-15 is critically implicated in AA pathogenesis, as are NKG2D and its ligands, MICA, and ULBP3. The C3H/HeJ mouse model was used to identify key immune cell and molecular principles in murine AA, and proof-of-principle that Janus kinase (JAK) inhibitors are suitable agents for AA management in vivo, since both IFN-gamma and IL-15 signal via the JAK pathway. Instead, the humanized mouse model of AA has been used to demonstrate the previously hypothesized key role of CD8+ T cells and NKG2D+ cells in AA pathogenesis and to discover human-specific pharmacologic targets like the potassium channel Kv1.3, and to show that the PDE4 inhibitor, apremilast, inhibits AA development in human skin. As such, AA provides a model disease, in which to contemplate general challenges, opportunities, and limitations one faces when selecting appropriate animal models in preclinical research for human autoimmune diseases. PMID- 26971471 TI - Does hand dominance affect peripheral nerve excitability? PMID- 26971470 TI - Contribution of IL-10 and its -592 A/C polymorphism to cognitive functions in first-episode drug-naive schizophrenia. AB - Numerous studies have shown that proinflammatory cytokines produced by immune cells in the brain have deleterious effects on cognitive functions. In contrast, IL-10, an anti-inflammatory cytokine, can be neuroprotective and prevent neuronal dysfunction. However, few studies have linked the role of IL-10 to cognitive deficits in schizophrenia. In this study, serum IL-10 levels and genotypes for the IL10 -592 A/C promoter polymorphism were measured in a cohort of first episode drug-naive schizophrenic patients (FEDN-S) (n=256) and healthy control subjects (HC) (n=540). All participants were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS). In a separate transcriptomic data set containing 577 healthy human brain samples, we analyzed IL-10 and IL-10 RA/B-associated genetic networks in order to ascertain potential functions for IL-10 in the brain. We found a significant difference in allelic frequency between FEDN-S and HC subjects. The A allelic variant was associated with reduced serum IL-10 levels and worse attentional performance in FEDN-S but not in HC subjects. Moreover, serum IL-10 levels were correlated with the extent of cognitive impairment, especially attentional performance in the schizophrenic A-allele carriers. In human brain transcriptomic coexpression analysis, we found that genes most significantly co-expressed with IL10 were associated with synaptic vesicle transportation, and both IL10RA and IL10RB were most significantly co-expressed not only with genes that regulate inflammation but also with those that participate in synaptic formation. The IL10-592 A/C genetic variant was more common in schizophrenic patients than HC and was associated with lower IL-10 serum levels and worse attentional performance in these patients. Furthermore, the IL10 gene and its receptors in the healthy human brain appear to regulate inflammation and synaptic functions that are important for cognition, and hence its deficiency in schizophrenia may contribute to cognitive impairment. PMID- 26971468 TI - Role of cardiac troponin I carboxy terminal mobile domain and linker sequence in regulating cardiac contraction. AB - Inhibition of striated muscle contraction at resting Ca(2+) depends on the C terminal half of troponin I (TnI) in thin filaments. Much focus has been on a short inhibitory peptide (Ip) sequence within TnI, but structural studies and identification of disease-associated mutations broadened emphasis to include a larger mobile domain (Md) sequence at the C-terminus of TnI. For Md to function effectively in muscle relaxation, tight mechanical coupling to troponin's core and thus tropomyosin-is presumably needed. We generated recombinant, human cardiac troponins containing one of two TnI constructs: either an 8-amino acid linker between Md and the rest of troponin (cTnILink8), or an Md deletion (cTnI1 163). Motility assays revealed that Ca(2+)-sensitivity of reconstituted thin filament sliding was markedly increased with cTnILink8 (~0.9 pCa unit leftward shift of speed-pCa relation compared to WT), and increased further when Md was missing entirely (~1.4 pCa unit shift). Cardiac Tn's ability to turn off filament sliding at diastolic Ca(2+) was mostly (61%), but not completely eliminated with cTnI1-163. TnI's Md is required for full inhibition of unloaded filament sliding, although other portions of troponin-presumably including Ip-are also necessary. We also confirm that TnI's Md is not responsible for superactivation of actomyosin cycling by troponin. PMID- 26971472 TI - Higher pain rating results in lower variability of somatosensory cortex activation by painful mechanical stimuli: An fMRI study. AB - OBJECTIVE: The aim of this study was to find pain-related brain activity which corresponds to self-report pain ratings based on degree of response and repeatability. METHODS: Three painful mechanical stimuli were applied to the right hands of 25 healthy volunteers using monofilaments (forces of 0.98N, 2.94N, and 5.88N). Simultaneously, brain activities were evaluated using functional MRI for a constant stimulus conducted three times in a session. In first assessment, the average percent signal change (PSC) of neuronal response was measured for each region of interest (ROI), secondary repeatability of PSC conducted three times over the session was evaluated for each ROI. RESULTS: Although the average PSCs for trice stimuli conducted in one session increased in accordance with pain ratings in the somatosensory cortex (S1) and anterior cingulate cortex (ACC), there was a different response between S1 and ACC when subjects rated intense pain; a stable response in S1 against a variable response in ACC. CONCLUSIONS: These results imply that there are different cognitive responses between sensory discrimination and affective component to constant painful stimulus each time. SIGNIFICANCE: Consistency of brain activity based on PSC may be an important biomarker which, along with its neuronal activity, gauges self-report pain ratings. PMID- 26971473 TI - Short and long-term effects of sham-controlled prefrontal EEG-neurofeedback training in healthy subjects. AB - OBJECTIVE: In this study we evaluated long-term effects of frontal beta EEG neurofeedback training (E-NFT) on healthy subjects. We hypothesized that E-NFT can change frontal beta activity in the long-term and that changes in frontal beta EEG activity are accompanied by altered cognitive performance. METHODS: 25 healthy subjects were included and randomly assigned to active or sham E-NFT. On average the subjects underwent 15 E-NFT training sessions with a training duration of 45 min. Resting-state EEG was recorded prior to E-NFT training (t1) and in a 3-year follow-up (t3). RESULTS: Compared to sham E-NFT, which was used for the control group, real E-NFT increased beta activity in a predictable way. This increase was maintained over a period of three years post training. However, E-NFT did not result in significantly improved cognitive performance. CONCLUSION: Based on our results, we conclude that EEG-NFT can selectively modify EEG beta activity both in short and long-term. SIGNIFICANCE: This is a sham controlled EEG neurofeedback study demonstrating long-term effects in resting state EEG. PMID- 26971474 TI - Motor Unit Number Index (MUNIX): A novel biomarker for ALS? PMID- 26971475 TI - Somatosensory temporal discrimination threshold is impaired in patients with multiple sclerosis. PMID- 26971477 TI - Proposal for electrodiagnostic evaluation of patients with suspected ulnar neuropathy at the elbow. AB - OBJECTIVE: To develop an evidence-based electrodiagnostic (EDx) approach to patients with suspected ulnar neuropathy at the elbow (UNE). METHODS: We prospectively recruited patients with suspected UNE, took a history and performed clinical neurologic, EDx and ultrasonographic (US) examinations. Ulnar motor and mixed nerve 5 * 2 cm, 2 * 4 cm and 10 cm studies across the elbow were compared regarding sensitivity and precise localization of UNE. RESULTS: In 175 evaluated patients, the highest sensitivity/precise localization was demonstrated by the motor 5 * 2 cm study (93%/92%), followed by the 2 * 4 cm study (89%/83%) and the 10-cm study (82%/0%). The sensitivities of mixed ulnar nerve studies to diagnose/precisely localize UNE were 12-23%/27-36% lower than the corresponding motor studies. CONCLUSIONS: Based on our data, we suggest starting EDx evaluation of UNE with a motor 2 * 4 cm study (recording from either the abductor digiti minimi or the first dorsal interosseous muscles), with two additional stimulation sites being added if the initial result is negative. This results in a motor 4 * 2 cm study. In all suspected UNE patients, an antidromic sensory study to the 5th finger should also be performed. SIGNIFICANCE: The proposed EDx protocol is robust, sensitive and time efficient. We hope that it will improve the diagnosis of UNE. PMID- 26971478 TI - Impairment of sensory-motor integration at spinal level in amyotrophic lateral sclerosis. AB - OBJECTIVE: Subclinical sensory defect can be detected early in ALS. Its impact on spinal excitability was assessed by testing the effects produced by intrinsic hand muscle afferents in triceps brachii motoneurons of patients with distal motor weakness. METHODS: TMS was applied over the motor cortex to produce MEP in contralateral triceps during tonic contraction. The intensity varied to compare the full MEP recruitment curve in ALS patients and controls. Then, median and ulnar nerve stimulations at wrist level were combined to TMS to compare the resulting changes in MEP size in both groups. RESULTS: MEP recruitment curves were similar in both groups but MEP threshold was significantly higher in ALS. At sub-threshold intensity for MEP, TMS depressed more EMG activity in ALS than in controls. Nerve stimuli increased MEP size in both groups with similar temporal characteristics but the level of facilitation was stronger in ALS. CONCLUSION: Cortical hypo-excitability in ALS was accompanied with stronger intra-cortical inhibition in triceps area. While the corticospinal and peripheral inputs were likely depressed, spinal motoneuron response to combined inputs was particularly enhanced in ALS. SIGNIFICANCE: Spinal network properties likely compensate for depression of afferent inputs leading to motoneuron hyper-excitability, which may contribute to excito-toxicity. PMID- 26971479 TI - Reconstruction of electroencephalographic data using radial basis functions. AB - OBJECTIVE: In this paper we introduce a new interpolation method to use for scalp potential interpolation. The predictive value of this new interpolation technique (the multiquadric method) is compared to commonly used interpolation techniques like nearest-neighbour averaging and spherical splines. METHODS: The method of comparison is cross-validation, where the data of one or two electrodes is predicted by the rest of the data. The difference between the predicted and the measured data is used to determine two error measures. One is the maximal error in one interpolation technique and the other is the mean square error. The methods are tested on data stemming from 30 channel EEG of 10 healthy volunteers. RESULTS: The multiquadric interpolation methods performed best regarding both error measures and have been easier to calculate than spherical splines. CONCLUSION: Multiquadrics are a good alternative to commonly used EEG reconstruction methods. SIGNIFICANCE: Multiquadrics have been widely used in reconstruction on sphere-like surfaces, but until now, the advantages have not been investigated in EEG reconstruction. PMID- 26971476 TI - Attention demands of language production in adults who stutter. AB - OBJECTIVE: We investigated whether language production is atypically resource demanding in adults who stutter (AWS) versus typically-fluent adults (TFA). METHODS: Fifteen TFA and 15 AWS named pictures overlaid with printed Semantic, Phonological or Unrelated Distractor words while monitoring frequent low tones versus rare high tones. Tones were presented at a short or long Stimulus Onset Asynchrony (SOA) relative to picture onset. Group, Tone Type, Tone SOA and Distractor Type effects on P3 amplitudes were the main focus. P3 amplitude was also investigated separately in a simple tone oddball task. RESULTS: P3 morphology was similar between groups in the simple task. In the dual task, a P3 effect was detected in TFA in all three distractor conditions at each Tone SOA. In AWS, a P3 effect was attenuated or undetectable at the Short Tone SOA depending on Distractor Type. CONCLUSIONS: In TFA, attentional resources were available for P3-indexed processes in tone perception and categorization in all distractor conditions at both Tone SOAs. For AWS, availability of attentional resources for secondary task processing was reduced as competition in word retrieval was resolved. SIGNIFICANCE: Results suggest that language production can be atypically resource-demanding in AWS. Theoretical and clinical implications of the findings are discussed. PMID- 26971480 TI - Lower motor neuron involvement in ALS assessed by motor unit number index (MUNIX): Long-term changes and reproducibility. AB - OBJECTIVE: Motor unit number estimation (MUNE) techniques such as motor unit number index (MUNIX) have been used to quantify lower motor neuron loss and disease progression in amyotrophic lateral sclerosis (ALS). We investigated the consistency of reproducibility of MUNIX in 30 ALS-patients during the course of the disorder. METHODS: MUNIX was recorded in abductor pollicis brevis and tibialis anterior muscles bilaterally in ALS-patients by two measurements at the first and at one follow-up visit and once in healthy controls. Intra-rater reproducibility was evaluated by three statistical methods: interclass correlation coefficient (ICC), correlation coefficient analysis (CCA), and coefficient of variation (CV). RESULTS: We found significant correlation between the first and second measurement of MUNIX in all tested muscles and at the follow up visit (r?0.891, p<0.01) and good statistically significant reproducibility of MUNIX in all four measured muscles at the follow-up visit (ICC?0.946, p<0.01). The CV of MUNIX at the follow-up visit ranged from 13.90% to 32.95%. CONCLUSIONS: This study shows good consistency of reproducibility of MUNIX in the course of ALS. SIGNIFICANCE: This study suggests that MUNIX can be used to track the progression of the disorder both in clinical routine and in treatment trials. PMID- 26971481 TI - Letter-sound processing deficits in children with developmental dyslexia: An ERP study. AB - OBJECTIVE: The time course during letter-sound processing was investigated in children with developmental dyslexia (DD) and typically developing (TD) children using electroencephalography. METHOD: Thirty-eight children with DD and 25 TD children participated in a visual-auditory oddball paradigm. Event-related potentials (ERPs) elicited by standard and deviant stimuli in an early (100-190 ms) and late (560-750 ms) time window were analysed. RESULTS: In the early time window, ERPs elicited by the deviant stimulus were delayed and less left lateralized over fronto-temporal electrodes for children with DD compared to TD children. In the late time window, children with DD showed higher amplitudes extending more over right frontal electrodes. Longer latencies in the early time window and stronger right hemispheric activation in the late time window were associated with slower reading and naming speed. Additionally, stronger right hemispheric activation in the late time window correlated with poorer phonological awareness skills. CONCLUSIONS: Deficits in early stages of letter sound processing influence later more explicit cognitive processes during letter sound processing. SIGNIFICANCE: Identifying the neurophysiological correlates of letter-sound processing and their relation to reading related skills provides insight into the degree of automaticity during letter-sound processing beyond behavioural measures of letter-sound-knowledge. PMID- 26971482 TI - Enhanced mirror activity in 'crossed' reaction time tasks in multiple sclerosis. AB - OBJECTIVE: Execution of unimanual voluntary motor tasks requires appropriate inhibitory control over contralateral motor output. Such inhibition should involve interhemispheric connections, which are often damaged in multiple sclerosis (MS). METHODS: Twenty mildly-disabled MS patients and 13 healthy subjects performed ipsilateral and contralateral wrist-extension reactions (IR and CR, respectively) to a unilateral somatosensory cue, the latter condition requiring necessarily interhemispheric transfer of information. Prevalence, persistence, latency and amount of mirror electromyographic activity (mEMG) were calculated in each study group, as well as diffusion-tensor-imaging measures of damage in corpus callosum and brainstem for correlation with mEMG. RESULTS: Healthy subjects and patients showed mEMG more often in CR than in IR. In CR tasks, mEMG was larger, more persistent and occurred more often at a shorter latency with respect to voluntary reaction in patients than in healthy subjects (p<0.05 for all). Patients with mEMG had significantly higher diffusivity values of damage in corpus callosum and lower brainstem volumes than patients without mEMG (p<0.05 for all). CONCLUSIONS: MS patients show deficient inhibition of unintended mEMG in 'crossed' reaction time tasks. SIGNIFICANCE: Enhanced mEMG in MS may be due to microstructural axonal damage and atrophy in inhibitory commissural connections of the corpus callosum and brainstem. PMID- 26971484 TI - VEMPs in central neurological disorders. PMID- 26971483 TI - Subthalamic nucleus phase-amplitude coupling correlates with motor impairment in Parkinson's disease. AB - OBJECTIVE: High-amplitude beta band oscillations within the subthalamic nucleus are frequently associated with Parkinson's disease but it is unclear how they might lead to motor impairments. Here we investigate a likely pathological coupling between the phase of beta band oscillations and the amplitude of high frequency oscillations around 300 Hz. METHODS: We analysed an extensive data set comprising resting-state recordings obtained from deep brain stimulation electrodes in 33 patients before and/or after taking dopaminergic medication. We correlated mean values of spectral power and phase-amplitude coupling with severity of hemibody bradykinesia/rigidity. In addition, we used simultaneously recorded magnetoencephalography to look at functional interactions between the subthalamic nucleus and ipsilateral motor cortex. RESULTS: Beta band power and phase-amplitude coupling within the subthalamic nucleus correlated positively with severity of motor impairment. This effect was more pronounced within the low beta range, whilst coherence between subthalamic nucleus and motor cortex was dominant in the high-beta range. CONCLUSIONS: We speculate that the beta band might impede pro-kinetic high-frequency activity patterns when phase-amplitude coupling is prominent. Furthermore, results provide evidence for a functional subdivision of the beta band into low and high frequencies. SIGNIFICANCE: Our findings contribute to the interpretation of oscillatory activity within the cortico-basal ganglia circuit. PMID- 26971485 TI - Ascending vestibular drive is asymmetrically distributed to the inferior oblique motoneuron pools in a subset of hemispheric stroke survivors. AB - OBJECTIVE: Aberrant vestibular nuclear function is proposed to be a principle driver of limb muscle spasticity after stroke. Although spasticity does not manifest in ocular muscles, we sought to determine whether altered cortical modulation of ascending vestibuloocular pathways post-stroke could impact the excitability of ocular motoneurons. METHODS: Nineteen chronic stroke survivors, aged 49-68 yrs. were enrolled. Vestibular evoked myogenic potentials (VEMPs) were recorded from the inferior oblique muscles of the eye using surface EMG electrodes. We assessed the impact of ascending otolith pathways on eye muscle activity and evaluated the relationship between otolith-ocular function and the severity of spasticity. RESULTS: VEMP responses were recorded bilaterally in 14/19 subjects. Response magnitude on the affected side was significantly larger than on the spared side. In a subset of subjects, there was a strong relationship between affected response amplitude and the severity of limb spasticity, as estimated using a standard clinical scale. CONCLUSIONS: This study suggests that alterations in ascending vestibular drive to ocular motoneurons contribute to post-stroke spasticity in a subset of spastic stroke subjects. We speculate this imbalance is a consequence of the unilateral disruption of inhibitory corticobulbar projections to the vestibular nuclei. SIGNIFICANCE: This study potentially sheds light on the underlying mechanisms of post-stroke spasticity. PMID- 26971486 TI - Changes in intracortical inhibition and clinical symptoms after STN-DBS in Parkinson's disease. AB - OBJECTIVES: To examine effects of subthalamic nucleus deep brain stimulation (STN DBS) on intracortical inhibition in Parkinson's disease (PD) and the correlation between intracortical inhibition and clinical symptoms after alteration of STN DBS status. METHODS: Nine PD patients treated by STN-DBS were compared with eight age-matched controls. Antiparkinsonian medication was withdrawn 12h before the study. Short-interval intracortical inhibition (SICI) with a 3-ms interval and silent period (SP) were examined using transcranial magnetic stimulation. SP duration, SICI and motor symptoms (rigidity and tremor) were evaluated with STN DBS ON, and over 120 min during STN-DBS OFF. RESULTS: Even during STN-DBS, PD patients showed a shortened SP and reduced SICI relative to normal controls. SICI decreased further throughout STN-DBS OFF, resulting in facilitation rather than inhibition; SP shortened only after 120 min STN-DBS OFF. Both rigidity and tremor worsened throughout STN-DBS OFF, with a time course similar to SICI. CONCLUSION: Even during STN-DBS, both SICI and SP in PD patients remain impaired without medication. Changes in SICI, but not SP, show a time course similar to those of motor symptoms. SIGNIFICANCE: The dissimilarity of SICI and SP changes suggests differences in mediation of inhibitory mechanisms and/or superimposition of exaggerated intracortical facilitation on SICI. PMID- 26971487 TI - Monitoring burst suppression in critically ill patients: Multi-centric evaluation of a novel method. AB - OBJECTIVE: To develop a computational method to detect and quantify burst suppression patterns (BSP) in the EEGs of critical care patients. A multi-center validation study was performed to assess the detection performance of the method. METHODS: The fully automatic method scans the EEG for discontinuous patterns and shows detected BSP and quantitative information on a trending display in real time. The method is designed to work without setting any patient specific parameters and to be insensitive to EEG artifacts and periodic patterns. For validation a total of 3982 h of EEG from 88 patients were analyzed from three centers. Each EEG was annotated by two reviewers to assess the detection performance and the inter-rater agreement. RESULTS: Average inter-rater agreement between pairs of reviewers was kappa=0.69. On average 22% of the review segments included BSP. An average sensitivity of 90% and a specificity of 84% were measured on the consensus annotations of two reviewers. More than 95% of the periodic patterns in the EEGs were correctly suppressed. CONCLUSION: A fully automatic method to detect burst suppression patterns was assessed in a multi center study. The method showed high sensitivity and specificity. SIGNIFICANCE: Clinically applicable burst suppression detection method validated in a large multi-center study. PMID- 26971489 TI - Ictal-interictal continuum: A proposed treatment algorithm. AB - The ictal-interictal continuum (IIC) is characterized by periodic and/or rhythmic EEG patterns that occur with relative high frequency in critically ill patients. Several studies have reported that some patterns seen within the continuum are independently associated with poor outcome. However there is no consensus regarding when to treat them or how aggressive treatment should be. In this review we examine peer-reviewed original scientific articles, guidelines and reviews indexed in PubMed and summarize current knowledge related to the ictal interictal continuum. A treatment algorithm to guide management of critically ill patients with EEG patterns that fall along the IIC is proposed. The algorithm based on best current practice in adults-takes into account associated clinical events, risk factors for developing seizures, response to medication trials and biomarkers of neuronal injury. PMID- 26971488 TI - EEG in postanoxic coma: Prognostic and diagnostic value. AB - Evolution of the EEG background pattern is a robust contributor to prediction of poor or good outcome of comatose patients after cardiac arrest. At 24h, persistent isoelectricity, low voltage activity, or burst-suppression with identical bursts predicts a poor outcome without false positives. Rapid recovery toward continuous patterns within 12h is strongly associated with a good neurological outcome. Predictive values are highest in the first 24h, despite the use of mild therapeutic hypothermia and sedative medication. Studies on reactivity or mismatch negativity have not included the EEG background pattern. Therefore, the additional predictive value of reactivity parameters remains unclear. Whether or not treatment of electrographic status epilepticus improves outcome is studied in the randomized multicenter Treatment of Electroencephalographic STatus epilepticus After cardiopulmonary Resuscitation (TELSTAR) trial (NCT02056236). PMID- 26971490 TI - Modulation of IL-12 and IFNgamma by probiotic supplementation promotes protection against Toxocara canis infection in mice. AB - In this study, supplementation with the probiotic Saccharomyces boulardii promoted a reduction in intensity of infection by Toxocara canis and modulates cytokines mRNA expression in experimentally infected mice. IL-12 gene transcription had 40-fold increase in S. boulardii supplemented uninfected mice and sevenfold increase in supplemented infected mice comparing with not supplemented group. Regarding IFNgamma, similar results were observed, since probiotic supplementation induced approximately 43-fold increase, but only in uninfected mice (P < 0.05). T. canis infection upregulated IL-10 expression while S. boulardii downregulated it and no change was observed for IL-4. Thus, based in these findings; we suggest that one possible mechanism responsible for S. boulardii protection effect against T. canis infection is by the modulation of cytokines expression, especially IL-12. PMID- 26971491 TI - Epigenetic field cancerization in gastrointestinal cancers. AB - Epigenetic alterations, including aberrant DNA methylation, play an important role in human cancer development. Importantly, epigenetic alterations are reversible and can be targets for therapy or chemoprevention for various types of human cancers. A field for cancerization, or a field defect, is formed by the accumulation of genetic and/or epigenetic alterations in normal-appearing tissues and can correlate with risk of cancer development. Thus, a better understanding of epigenetic field cancerization may represent a useful translational opportunity for cancer risk assessment, including previous history and exposure to carcinogenic factors, and for cancer prevention. In this article, we summarize current knowledge regarding epigenetic field cancerization and its clinical implications in gastrointestinal cancers, including colorectal cancer, gastric cancer and esophageal cancer. PMID- 26971493 TI - "Fungal elicitors combined with a sucrose feed significantly enhance triterpene production of a Salvia fruticosa cell suspension". AB - Oleanolic (OA) and ursolic acid (UA) are plant secondary metabolites with diverse pharmacological properties. To reach reasonable productivities with plant cell suspension cultures, elicitation is a widely used strategy. Within the presented work, the effects of different elicitors on growth and production of OA and UA in a Salvia fruticosa cell suspension culture were examined. Beside commonly used elicitors like jasmonic acid (JA) and yeast extract, the influence of medium filtrates of the endophytic fungi Aspergillus niger and Trichoderma virens was investigated. The best eliciting effects were achieved with JA and fungal medium filtrates. Both increased the triterpene content by approximately 70 %. Since JA showed significant growth inhibition, the volumetric triterpene yield did not increase. But, adding fungal filtrates increased the volumetric triterpene yield by approximately 70 % to 32.6 mgOA l(-1) and 65.9 mgUA l(-1) for T. virens compared to the control with 19.4 mgOA l(-1) and 33.3 mgUA l(-1). An elicitation strategy combining fungal medium filtrate of T. virens with sucrose feeding significantly enhanced cell dry weight concentration to 22.2 g l(-1) as well as triterpene content by approximately 140 %. In total, this led to an approximately 500 % increase of volumetric triterpene yield referring to the control with final values of 112.9 mgOA l(-1) and 210.4 mgUA l(-1). Despite the doubled cultivation duration, productivities of 6.7 mgOA l(-1) day(-1) and 12.4 mgUA l(-1) day(-1) were reached. These results demonstrate methods by which increased productivities of triterpenes can be achieved to attain yields competing with intact plants. PMID- 26971494 TI - Biosynthesis of Monascus pigments by resting cell submerged culture in nonionic surfactant micelle aqueous solution. AB - Growing cell submerged culture is usually applied for fermentative production of intracellular orange Monascus pigments, in which accumulation of Monascus pigments is at least partially associated to cell growth. In the present work, extractive fermentation in a nonionic surfactant micelle aqueous solution was utilized as a strategy for releasing of intracellular Monascus pigments. Those mycelia with low content of intracellular Monascus pigments were utilized as biocatalyst in resting cell submerged culture. By this means, resting cell submerged culture for production of orange Monascus pigments was carried out successfully in the nonionic surfactant micelle aqueous solution, which exhibited some advantages comparing with the corresponding conventional growing cell submerged culture, such as non-sterilization operation, high cell density (24 g/l DCW) leading to high productivity (14 AU of orange Monascus pigments at 470 nm per day), and recycling of cells as biocatalyst leading to high product yield (approximately 1 AU of orange Monascus pigments at 470 nm per gram of glucose) based on energy metabolism. PMID- 26971492 TI - Structural Basis and IP6 Requirement for Pds5-Dependent Cohesin Dynamics. AB - The ring-shaped cohesin complex regulates transcription, DNA repair, and chromosome segregation by dynamically entrapping chromosomes to promote chromosome compaction and sister-chromatid cohesion. The cohesin ring needs to open and close to allow its loading to and release from chromosomes. Cohesin dynamics are controlled by the releasing factors Pds5 and Wapl and the cohesin stabilizer Sororin. Here, we report the crystal structure of human Pds5B bound to a conserved peptide motif found in both Wapl and Sororin. Our structure establishes the basis for how Wapl and Sororin antagonistically influence cohesin dynamics. The structure further reveals that Pds5 can bind inositol hexakisphosphate (IP6). The IP6-binding segment of Pds5B is shaped like the jaw of a plier lever and inhibits the binding of Scc1 to Smc3. We propose that Pds5 stabilizes a transient, open state of cohesin to promote its release from chromosomes. PMID- 26971495 TI - Poly(beta-L-malic acid) (PMLA) from Aureobasidium spp. and its current proceedings. AB - Poly(beta-L-malic acid) is one natural biopolymer that has the outstanding features of biocompatibility, biodegradability, water solubility, and non immunogenicity, and it is easily chemically modified. So poly(beta-L-malic acid) (PMLA) and its derivatives may have a great potential application as a novel drug delivery system and in the production of advanced biomaterials which have attracted so much research attention. The fungi of Aureobasidium spp. have been discovered to be the most suitable candidates for PMLA production in large quantities which satisfy the demand of either research or industry. In this review, we will give an overall summary about the PMLA produced by Aureobasidium spp. based on related research in the last decades and the elaboration of this PMLA producer will also be accomplished. More importantly, the latest proceedings will be specified and some suggestions to the elucidation of a PMLA biosynthesis pathway which remains undefined up to date will be proposed. Finally, through this review, the further exploitation for the application of PMLA from Aureobasidium spp. can be emphasized and promoted. PMID- 26971496 TI - Evaluation of the effects of intrapartum antibiotic prophylaxis on newborn intestinal microbiota using a sequencing approach targeted to multi hypervariable 16S rDNA regions. AB - Different factors are known to influence the early gut colonization in newborns, among them the perinatal use of antibiotics. On the other hand, the effect on the baby of the administration of antibiotics to the mother during labor, referred to as intrapartum antibiotic prophylaxis (IAP), has received less attention, although routinely used in group B Streptococcus positive women to prevent the infection in newborns. In this work, the fecal microbiota of neonates born to mothers receiving IAP and of control subjects were compared taking advantage for the first time of high-throughput DNA sequencing technology. Seven different 16S rDNA hypervariable regions (V2, V3, V4, V6 + V7, V8, and V9) were amplified and sequenced using the Ion Torrent Personal Genome Machine. The results obtained showed significant differences in the microbial composition of newborns born to mothers who had received IAP, with a lower abundance of Actinobacteria and Bacteroidetes as well as an overrepresentation of Proteobacteria. Considering that the seven hypervariable regions showed different discriminant ability in the taxonomic identification, further analyses were performed on the V4 region evidencing in IAP infants a reduced microbial richness and biodiversity, as well as a lower number of bacterial families with a predominance of Enterobacteriaceae members. In addition, this analysis pointed out a significant reduction in Bifidobacterium spp. strains. The reduced abundance of these beneficial microorganisms, together with the increased amount of potentially pathogenic bacteria, may suggest that IAP infants are more exposed to gastrointestinal or generally health disorders later in age. PMID- 26971497 TI - A novel perchlorate- and nitrate-reducing bacterium, Azospira sp. PMJ. AB - A novel perchlorate-reducing bacterium (PCRB), PMJ, was isolated from the mixed liquor suspended solids in the aerobic tank of a wastewater treatment plant. The 16S ribosomal RNA (rRNA), perchlorate reductase, and chlorite dismutase gene sequences revealed that PMJ belonged to the genus Azospira. PMJ was removed high strength (700 mg/L) perchlorate and also removed low-strength (<=50 mg/L) perchlorate below the detection limit (2 MUg/L) when acetate was used as a sole and carbon source. The maximum specific perchlorate utilization rate, q max, was 0.96 mg ClO4 (-)/mg dry cell weight day, and the half-saturation constant, K S , was lower than 0.002 mg ClO4 (-)/L. PMJ also utilized inorganic electron donors [(H2, S(0), and Fe(II)] with perchlorate as an electron acceptor. Perchlorate reduction by PMJ was completely inhibited by oxygen and chlorate but was not inhibited by nitrate. In the presence of similar concentrations (100~140 mg/L) of nitrate and perchlorate, PMJ simultaneously removed both electron acceptors. Therefore, it was concluded that the strains PMJ might possess separate pathways for perchlorate and nitrate reduction. These results indicated that Azospira sp. PMJ could be efficiently used for treating perchlorate-contaminated groundwater and wastewater because many of these water bodies are known to contain both perchlorate and nitrate. In addition, low K S value and autotrophic perchlorate reduction of PMJ might be useful to design the biological treatment systems. PMID- 26971499 TI - DSM-5 Criteria and Its Implications for Diagnosing PTSD in Military Service Members and Veterans. AB - This review addresses how changes in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 posttraumatic stress disorder (PTSD) criteria has the potential to affect the care and careers of those who have served in the military, where the diagnosis often determines fitness for duty and veterans' benefits. PTSD criteria changes were intended to integrate new knowledge acquired since previous DSM editions. Many believe the changes will improve diagnosis and treatment, but some worry these could have negative clinical, occupational, and legal consequences. We analyze the changes in classification, trauma definition, symptoms, symptom clusters, and subtypes and possible impacts on the military (e.g., over- and under-diagnosis, "drone" video exposure, subthreshold PTSD, and secondary PTSD). We also discuss critiques and proposals for future changes. Our objectives are to improve the screening, diagnosis, and treatment of those service members who have survived trauma and to improve policies related to the military mental healthcare and disability systems. PMID- 26971498 TI - Divalent cation chelators citrate and EDTA unmask an intrinsic uncoupling pathway in isolated mitochondria. AB - We demonstrate a suppression of ROS production and uncoupling of mitochondria by exogenous citrate in Mg2+ free medium. Exogenous citrate suppressed H2O2 emission and depolarized mitochondria. The depolarization was paralleled by the stimulation of respiration of mitochondria. The uncoupling action of citrate was independent of the presence of sodium, potassium, or chlorine ions, and it was not mediated by the changes in permeability of the inner mitochondrial membrane to solutes. The citrate transporter was not involved in the citrate effect. Inhibitory analysis data indicated that several well described mitochondria carriers and channels (ATPase, IMAC, ADP/ATP translocase, mPTP, mKATP) were not involved in citrate's effect. Exogenous MgCl2 strongly inhibited citrate-induced depolarization. The uncoupling effect of citrate was demonstrated in rat brain, mouse brain, mouse liver, and human melanoma cells mitochondria. We interpreted the data as an evidence to the existence of a hitherto undescribed putative inner mitochondrial membrane channel that is regulated by extramitochondrial Mg2+ or other divalent cations. PMID- 26971500 TI - Youth Exposed to Terrorism: the Moderating Role of Ideology. AB - The present review examines the moderating role of ideology on the effects of war, armed conflict, and terrorism on youth. Ideology is an important factor given the central role played by religio-political ideology and nationalism in present-day conflicts. Ideologies or worldviews represent cognitive frameworks that imbue the traumatic situation with meaning and order. Analysis of the pool of studies identified three categories of ideologically based moderating factors, each representing an aspect of social construction of traumatic events, namely, religion, political ideology, and self-concept. The two closely related categories of religion and politico-religious beliefs showed both positive and negative effects on psychological and psychiatric outcomes among youth. The third category of different aspects of self-concept yielded consistently positive moderating effects. The mechanisms by which each category of ideology moderates effects of exposure to war, armed conflict, and terrorism are discussed, and research and clinical implications are presented. PMID- 26971501 TI - Reversible diffusion weighted imaging hyperintensities during the acute phase of ischemic stroke in pediatric moyamoya disease: a case report. AB - BACKGROUND: Moyamoya disease is one of the primary causes of pediatric ischemic stroke, especially in East Asia. Areas of high signal intensity on diffusion weighted imaging (DWI) with decreased apparent diffusion coefficient (ADC) values usually point to irreversible ischemic damage. Reversibility of these DWI hyperintensities during the acute phase of ischemic stroke in pediatric moyamoya disease has not previously been reported. CASE REPORT: A 3-year-old girl was admitted to our emergency department due to sudden onset speech impairment and right hemiplegia. Computed tomography (CT) revealed a multilobal low-density area in the left cerebral hemisphere. The area was hyperintense on DWI with decreased ADC values. Magnetic resonance (MR) angiography revealed stenosis of the bilateral internal carotid artery bifurcations and their branches. Acute cerebral infarction due to moyamoya disease was diagnosed. MR images taken 4 days later showed resolution of most of the DWI hyperintensity areas. The initial decline in the ADC of the reversible DWI hyperintensities was less severe compared to the irreversible lesion. Within several days after onset, the patient became ambulatory although the follow-up MR fluid attenuated inversion recovery (FLAIR) images taken 2 weeks after onset revealed thinning of the corresponding cortical gyri. CONCLUSION: These findings indicate that a wide area of DWI hyperintensity during the acute phase of ischemic stroke can be reversed by appropriate treatment in pediatric moyamoya disease. To the best of our knowledge, this is the first report of reversible DWI hyperintensities over a wide cortical area during the acute phase of ischemic stroke in pediatric moyamoya disease. PMID- 26971502 TI - Can blockage or sacrifice of the middle meningeal artery lead to hydrocephalus? AB - BACKGROUND: The middle meningeal artery (MMA) is often sacrificed during neurosurgical procedures in the region of the pterion. This maneuver, herein, is hypothesized to be a potential reason for the development of postoperative hydrocephalus by injuring the vascular supply to the arachnoid granulations near the vertex of the skull, and thus disrupting their ability to allow for transfer of CSF from the subarachnoid space to the venous system. MATERIALS AND METHODS: To test this theory, the middle meningeal artery was isolated at the skull base and injected with India ink. Next, the superior sagittal sinus was opened and the arachnoid granulations inspected. RESULTS: All specimens demonstrated ink within the arachnoid granulations indicating that their blood supply is completely or at least partially via the middle meningeal artery. This finding with an illustrative case of surgical cautery of the middle meningeal artery at the skull base with subsequent development of hydrocephalus supports our hypothesis of potential role of iatrogenic MMA injury causing hydrocephalus. CONCLUSIONS: Our cadaveric study shows that the blood supply of the arachnoid granulations of the superior sagittal sinus is via the middle meningeal artery. Additional cases of postoperative hydrocephalus following middle meningeal artery sacrifice are needed to support our hypothesis. PMID- 26971503 TI - Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome). AB - Nevoid basal cell carcinoma syndrome, or basal cell nevus syndrome (Gorlin syndrome), is a rare autosomal dominantly inherited disorder that is characterized by development of basal cell carcinomas from a young age. Other distinguishing clinical features are seen in a majority of patients, and include keratocystic odontogenic tumors (formerly odontogenic keratocysts) as well as dyskeratotic palmar and plantar pitting. A range of skeletal and other developmental abnormalities are also often seen. The disorder is caused by defects in hedgehog signaling which result in constitutive pathway activity and tumor cell proliferation. As sporadic basal cell carcinomas also commonly harbor hedgehog pathway aberrations, therapeutic agents targeting key signaling constituents have been developed and tested against advanced sporadically occurring tumors or syndromic disease, leading in 2013 to FDA approval of the first hedgehog pathway-targeted small molecule, vismodegib. The elucidation of the molecular pathogenesis of nevoid basal cell carcinoma syndrome has resulted in further understanding of the most common human malignancy. PMID- 26971504 TI - Brooke-Spiegler Syndrome and Phenotypic Variants: An Update. AB - Brooke-Spiegler syndrome (BSS) is an inherited autosomal dominant disease characterized by the development of multiple adnexal cutaneous neoplasms most commonly spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma. Multiple familial trichoepithelioma (MFT) is a phenotypic variant of the disease characterized by the development of numerous trichoepitheliomas (cribriform trichoblastoma) only. Malignant tumors arise in association with preexisting benign cutaneous neoplasms in about 5-10% of the patients . Apart from the skin, major and minor salivary glands have been rarely involved in BSS patients. Extremely rare is the occurrence of breast tumors (cylindroma). The gene implicated in the pathogenesis of the disease is the CYLD gene, a tumor suppressor gene located on chromosome 16q12-q13. Germline CYLD mutations are detected in about 80-85% of patients with the classical BSS phenotype and in about 40-50% of the individuals with the MFT phenotype using a PCR based approach with analysis of exonic sequences and exon-intron junctions of the CYLD gene. There appears to be no genotype-phenotype correlations with respect to the severity of the disease, the possibility of malignant transformation, and development of extracutaneous lesions. PMID- 26971505 TI - Hyperaldosteronism: Screening and Diagnostic Tests. AB - Primary aldosteronism (PA) is the most common secondary cause of hypertension, accounting for 10 % of hypertensives and 20 % of those with drug-resistant hypertension. Aldosterone excess is associated with the development of adverse cardiovascular, renal and metabolic effects that are partly independent of its effect on blood pressure. Guidelines recommended wider screening for PA in an effort to maximize detection of patients who may benefit from optimal, specific management. All patient groups with increased prevalence of PA, including hypertensive patients with type 2 diabetes mellitus and those with obstructive sleep apnea, should be carefully screened for PA. Screening with aldosterone-to renin ratio (ARR) is the most practical and informative initial test. Subsequent confirmatory tests are: (1) oral salt loading; (2) saline infusion; (3) captopril challenge and (4) fludrocortisone suppression test. Confirmation of PA can avoid that patients with a false positive ARR would inappropriately undergo costly and harmful lateralization procedures. If confirmatory testing is positive, further investigations are directed toward determining the subtype of PA, as the treatment differs for each subtype. PMID- 26971506 TI - Hydrogen bonded and stacked geometries of the temozolomide dimer. AB - Dispersion-corrected density functional theory (DFT) and MP2 quantum chemical methods are used to examine homodimers of temozolomide (TMZ). Of the 12 dimer configurations found to be minima, the antarafacial stacked dimer is the most favored, it is lower in energy than coplanar dimers which are stabilized by H bonds. The comparison between B3LYP and B3LYP-D binding energies points to dispersion as a primary factor in stabilizing the stacked geometries. CO(pi) -> CO(pi*) charge transfers between amide groups in the global minimum are identified by NBO, as well as a pair of weak CH??N H-bonds. AIM analysis of the electron density provides an alternative description which includes N??O, N??N, and C??C noncovalent bonds. PMID- 26971507 TI - Theoretical prediction of complexes with a sulfur-carbon triple bond: SCX(2+), SCXF(+), and SCXF2 (X = Be, Mg, Ca). AB - A new series of compounds with a sulfur-carbon triple bond-SCX(2+), SCXF(+), and SCXF2 (X = Be, Mg, Ca)-were investigated using quantum chemical computations. The B3LYP, M06-2X, MP2, CCSD, and G4 methods were employed to predict the structures, harmonic vibrational frequencies, Wiberg bond indices, and adiabatic bond dissociation energies (ABDEs) for these compounds. When calculated at the B3LYP/cc-pVTZ level, the S=C bonds were found to be rather short: 1.4855-1.4984, 1.4893-1.5078, and 1.5123-1.5184 A for the doubly charged cations, singly charged cations, and neutral molecules, respectively. Interestingly, they are much shorter than in the strong sulfur-carbon triple bond in carbon monosulfide (1.5371 A). Moreover, NBO analysis together with the results for the structures and Wiberg bond indices indicated that the S=C bonds in SCX(2+), SCXF(+), and SCXF2 (X = Be, Mg, Ca) should be strong triple bonds. Further, the ABDE values of S=C in SCX(2+) (209.8-250.6 kcal/mol) and SCXF(+) (174.6-217.6 kcal/mol), but not SCXF2 (150.5-174.4 kcal/mol), are larger than that of S=C in carbon monosulfide (170.7 kcal/mol); however, upon comparing them with previously published data on other compounds with sulfur-carbon triple bonds, the S=C bonds in SCXF2 molecules appear to be much stronger than those S=C triple bonds. In general, all of the results calculated in this work clearly indicate that the SCX(2+), SCXF(+), and SCXF2 (X = Be, Mg, Ca) species each contain a strong sulfur-carbon triple bond. PMID- 26971508 TI - Effectiveness of health warnings for waterpipe tobacco smoking among college students. AB - OBJECTIVES: Youth have the misperception that waterpipe smoking is less harmful than cigarettes despite the evidence that it is associated with nicotine dependence and many of the diseases caused by cigarettes. There is a pressing need to identify effective health warnings that increase awareness about the harmful effects of waterpipe smoking. Our objective was to test the effectiveness of various health warning messages and their location on waterpipe devices. METHODS: Adult waterpipe smokers from a large US university (N = 367) completed an internet-based survey that tested the effect of text-only and pictorial health warning labels and their location on different parts of waterpipe smoking devices. RESULTS: Text-only messages and pictorial labels warning about harm to children were the most effective in motivating waterpipe smokers to think about quitting. In terms of warning label location, the base, mouthpiece and stem are all equally noticeable locations. CONCLUSIONS: This is the first study to test waterpipe-specific warning labels and location on the waterpipe device. Placing waterpipe-specific labels on waterpipe devices may be an effective policy tool to curb waterpipe smoking. PMID- 26971509 TI - E-cigarettes: addressing gaps in knowledge. PMID- 26971510 TI - Whither the e-cigarette? PMID- 26971511 TI - Heavy metal variation and characterization change of dissolved organic matter (DOM) obtained from composting or vermicomposting pig manure amended with maize straw. AB - A mixture of pig manure and maize straw was vermicomposted with Eisenia fetida or naturally composted for 60 days; basic parameters, heavy metal variation, dissolved organic matter (DOM) content, and its characterization were determined, aiming to explore different dynamics of DOM characterization and heavy metal variation during composting or vermicomposting. The results showed that vermicomposting led to higher pH, TC, and available P but lower EC, TN, available N, and available K in the substrate residues compared with natural composting; the total or available Cu/Zn content in the substrate residues similarly increased after composting or vermicomposting, but Cu was easily enriched in earthworm bodies and its intestinal vermicompost while vermicomposting enhanced the formation of dissolved Zn in DOM; moreover, much more fulvic and humic acid like materials and much greater aromaticity were exhibited in DOM obtained from vermicomposting residues compared with DOM from composting residues, which may contribute to the variations of Cu/Zn enrichment in earthworms and its migration to the vermicomposting residues or its DOM. PMID- 26971512 TI - Microbial metabolism induced chain shortening of polyacrylamide with assistance of bioelectricity generation. AB - The water-soluble polyacrylamide (PAM) can accumulate in ecosystems and cause serious environmental pollution. Biological approach achieves poor PAM degradation efficiency, due to the extreme resistance of PAM to the microbial metabolism. In the present work, the potential of bioelectrochemical system (BES) as an effective tool to degrade the PAM is adequately evaluated. The closed circuit operation of BES obtains COD removal efficiencies of 29.2 and 33.6 % for the PAM and polyacrylic acid (PAA), respectively. In comparison, 4.3 and 2.7 % of COD are removed after the PAM and PAA are treated in the open-circuit BES, and 7.3 and 6.6 % are removed in the aerobic BES. These results suggest the bioelectricity generation is crucial to trigger the activity of bioanode for the effective degradation of PAM. Bioelectricity generation not only favors the decomposition of carbon backbone but also facilitates the hydrolysis of amide group in the side-chain of PAM. Microbial attack on the carbon backbone of PAM is proposed to initiate at the head-to-head linkage, resulting in the formation of ether bond within the shortened carbon chain. The Ignavibacterium sp. and phenotypically uncharacterized bacteria are classified as the dominant species on the anode of PAM-fed BES. PMID- 26971513 TI - Sewage sludge toxicity assessment using earthworm Eisenia fetida: can biochemical and histopathological analysis provide fast and accurate insight? AB - Sewage sludge (SS) is a complex organic by-product of wastewater treatment plants. Deposition of large amounts of SS can increase the risk of soil contamination. Therefore, there is an increasing need for fast and accurate assessment of SS toxic potential. Toxic effects of SS were tested on earthworm Eisenia fetida tissue, at the subcellular and biochemical level. Earthworms were exposed to depot sludge (DS) concentration ratio of 30 or 70 %, to undiluted and to 100 and 10 times diluted active sludge (AS). The exposure to DS lasted for 24/48 h (acute exposure), 96 h (semi-acute exposure) and 7/14/28 days (sub chronic exposure) and 48 h for AS. Toxic effects were tested by the measurements of multixenobiotic resistance mechanism (MXR) activity and lipid peroxidation levels, as well as the observation of morphological alterations and behavioural changes. Biochemical markers confirmed the presence of MXR inhibitors in the tested AS and DS and highlighted the presence of SS-induced oxidative stress. The MXR inhibition and thiobarbituric acid reactive substance (TBARS) concentration in the whole earthworm's body were higher after the exposition to lower concentration of the DS. Furthermore, histopathological changes revealed damage to earthworm body wall tissue layers as well as to the epithelial and chloragogen cells in the typhlosole region. These changes were proportional to SS concentration in tested soils and to exposure duration. Obtained results may contribute to the understanding of SS-induced toxic effects on terrestrial invertebrates exposed through soil contact and to identify defence mechanisms of earthworms. PMID- 26971514 TI - Association of exposure to benzene and smoking with oxidative damage to nucleic acids by means of biological monitoring of general population volunteers. AB - In this study, the validation of liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) isotopic dilution method for the determination of benzene and nicotine metabolites in urine was carried out. Limit of detection are 0.026 MUg/L for S-phenylmercapturic acid (SPMA), 0.55 MUg/L for t,t-muconic acid (t,t-MA), and 12.41 MUg/L for the cotinine, and the relative combined uncertainty was also calculated. The study involves 446 healthy volunteer residents since at least 10 years in an area of central Italy. SPMA resulted to be strongly correlated with cotinine (p = 0.75), its concentration in smokers (93) being about ten times than in non/ex-smokers (197/156), while the t,t-MA of smokers is about twice the non/ex-smokers value. A cutoff value for the definition of smoker is set at 100 MUg/g creat. Oxidative stress was studied in smokers and non- and ex-smokers by means of the determination of the biomarkers 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), 8-Oxo-7,8-dihydroguanosine (8-oxoGuo), and 8-Oxo-7,8-dihydroguanine (8-oxoGua): no significant differences were found between smokers and non/ex smokers, but when subjects are classified according to the cotinine cutoff value, a correlation in smokers' urinary 8-oxodGuo is found with SPMA and cotinine (p = 0.60 and p = 0.57). Results were confirmed by chemometric analysis that also identified the experimental variables most contributing the discrimination as cotinine and t,t-MA. PMID- 26971515 TI - Performance of electrochemical oxidation process for removal of di (2-ethylhexyl) phthalate. AB - Di (2-ethylhexyl) phthalate (DEHP) is the most detected and concentrated plasticizer in environment and wastewaters, worldwide. In this study, different operating parameters such as current intensity, treatment time, type of anodes, and supporting electrolytes were tested to optimized the electro-oxidation process (EOP) for the removal of DEHP in the presence of methanol as a dissolved organic matter. Among the anodes, the Nb/BDD showed the best degradation rate of DEHP, at low current intensity of 0.2 A after 90 min of treatment time with a percentage of degradation recorded of 81 %, compared to 70 % obtained with the Ti/IrO2-RuO2. Furthermore, due to the combination of direct and indirect oxidation, the removal of DEHP in the presence of 1 g/L Na2SO4 was higher than NaBr, even though the oxidant production of NaBr was 11.7 mmol/L against 3.5 mmol/L recorded in the presence of sulfate at 0.5 A and after 60 min of electrolysis time. Under optimal condition (current intensity = 0.5 A, time = 120 min, using Nb/BDD anode and Na2SO4 as supporting electrolyte), the removal of 87.2 % of DEHP was achieved. The total cost of 0.106 US$/m(3) of treated water was achieved based on economical optimization of reactor with current intensity of 0.2 A and 1 g/L Na2SO4. PMID- 26971516 TI - Predicting bromide incorporation in a chlorinated indoor swimming pool. AB - The water in and air above swimming pools often contain high levels of disinfection byproducts (DBPs) due to chemical reactions between chlorine- or bromine-based disinfectants and organic/inorganic matter in the source water and released from swimmers. Exposure to these DBPs, though inevitable, can pose health threats to humans. In this study, DBPs in tap water (S1), and water from a chlorinated indoor swimming pool before (S2) and after swimming (S3) were measured. The brominated species constituted the majority of DBPs formed in S1, S2, and S3. Trihalomethanes (THMs) in S3 was 6.9 (range 2.9-11.1) and 1.4 (range 0.52-2.9) times those in S1 and S2, respectively; and the haloacetic acids (HAAs) in S3 was 4.2 (range 2.5-7.5) and 1.2 (range 0.6-2.6) times those in S1 and S2, respectively. The mean THMs in air above the swimming pool before (S2-A) and after swimming (S3-A) were 72.2 and 93.0 MUg/m(3), respectively, and their ranges were 36.3-105.8 and 44.1-133.6 MUg/m(3), respectively. The average percentages of bromide incorporation (BI) into THMs in S1, S2, and S3 were 3.0, 9.3, and 10.6 %, respectively; and the BI into HAAs in S1, S2, and S3 were 6.6, 12.0, and 12.2 %, respectively. Several models were trained for predicting the BI into THMs and HAAs. The results indicate that additional information is required to develop predictive models for BI in swimming pools. PMID- 26971517 TI - Kinetic modeling and determination role of sono/photo nanocatalyst-generated radical species on degradation of hydroquinone in aqueous solution. AB - Experimental findings of sonophotocatalytic process were used in degradation of hydroquinone to assess kinetic modeling and determine the effect of various active radical species. First, the effects of three photocatalytic, sonocatalytic, and sonophotocatalytic processes were studied for hydroquinone removal to determine kinetic constants and calculate the activation energy of reactions, and then the selected process was evaluated to determine active radical species. The reactor was composed of two parts, one included ultrasonic probe (sonocatalytic part) with powers 22, 80, and 176 W and the second part was the location of UV lamp (photocatalytic part) with tubular flow and power 15 W. After three systems were examined and the efficient system was selected, the role of different active species such as hydroxyl radical (OH(.)), superoxide radical (O2 (.-)), hole (h(+)), electrons (e (-)), and single oxygen molecule ((1)O2) and contribution of each of them were determined in hydroquinone degradation. According to tests, the results of this study showed that sonophotocatalytic integrated method as selected system among three systems studied followed the first-order equation for hydroquinone degradation and active hydroxyl species with 45 % and electron and hole with 15 and 10 %, respectively, had the highest and lowest contributions to conversion of hydroquinone. The findings showed that dissolved oxygen increases the capability of active radical formation so that 28.2 % of hydroquinone removal was increased under aeration compared to without aeration. Also, removal efficiency decreased 62 % with N2 injection due to the withdrawal of oxygen from the sample. By adding 25 Mm of sodium azide (NaN3) to stock solution, 46.5 % reduction was developed because single oxygen ((1)O2) played the role of an active species. The advantages of integrated sonocatalytic and photocatalytic method are the generation of active radical species with more variety and ultimately the formation of higher amounts of powerful hydroxyl radical that increases degradation rates of refractory compounds and low-risk internal and final products. It has an appropriate performance in the degradation of refractory compounds by optimizing effective operational factors. PMID- 26971518 TI - Metal pollution in biotic and abiotic samples of the Buyuk Menderes River, Turkey. AB - The Buyuk Menderes River (BMR) is one of the largest rivers in Turkey. This river irrigates efficient farmlands and includes tributaries of other rivers and streams and many populated towns within its limits in the Ege region. Both the estuary and Isikli Lake serve as a sanctuary for various waterbirds. Therefore, the BMR plays a critical role both for the inhabitants and for the ecosystem organisms in its environs. In the present study, we analyzed levels of metals including iron, barium, zinc, vanadium, cobalt, chromium, cadmium, copper, nickel, aluminum, arsenic, manganese, antimony, silver, selenium, boron, mercury, titanium, and lead in river water, sediment, fish (Cyprinus carpio; common carp), and in various waterbird (Fulica atra, Euroasian coot; Larus michahellis, yellow legged gull; Ardea cinerea, grey heron; Larus melanocephalus, Mediterranean gull; and Pelecanus crispus, pelican) samples. Analyses were performed using an inductively coupled plasma-mass spectrometry (ICP-MS) instrument after sample preparation. Comparing metal concentrations among different sample types, it was found that barium, aluminum, and zinc are the major metals in river water, and zinc in common carp muscle, while iron, aluminum, and manganese are the major metals in sediments. Iron, zinc, copper, and aluminum were the highest in waterbird muscle tissue. Iron and barium were found to be the major metals in eggshell, while iron and zinc are the major metals in egg samples. A simple "worst-case scenario" model of risk assessment revealed that some of the analyzed metals may pose a risk for human health through consuming fish. PMID- 26971519 TI - Influence of dihydroxybenzenes on paracetamol and ciprofloxacin degradation and iron(III) reduction in Fenton processes. AB - The degradation of paracetamol (PCT) and ciprofloxacin (CIP) was compared in relation to the generation of dihydroxylated products, Fe(III) reduction and reaction rate in the presence of dihydroxybenzene (DHB) compounds, or under irradiation with free iron (Fe3+) or citrate complex (Fecit) in Fenton or photo Fenton process. The formation of hydroquinone (HQ) was observed only during PCT degradation in the dark, which increased drastically the rate of PCT degradation, since HQ formed was able to reduce Fe3+ and contributed to PCT degradation efficiency. When HQ was initially added, PCT and CIP degradation rate in the dark was much higher in comparison to the absence of HQ, due to the higher and faster formation of Fe2+ at the beginning of reaction. In the absence of HQ, no CIP degradation was observed; however, when HQ was added after 30 min, the degradation rate increased drastically. Ten PCT hydroxylated intermediates were identified in the absence of HQ, which could contribute for Fe(III) reduction and consequently to the degradation in a similar way as HQ. During CIP degradation, only one product of hydroxyl radical attack on benzene ring and substitution of the fluorine atom was identified when HQ was added to the reaction medium. PMID- 26971520 TI - Antibiogram characterization and putative virulence genes in Aeromonas species isolated from pig fecal samples. AB - Aeromonas species are broadly distributed in nature and agricultural environments and have been isolated from feces, bedding, and drinking water of healthy pigs. We assessed the incidence, virulence properties, and antimicrobial resistance profile of Aeromonas spp., isolated from pig feces. Antibiogram was done using the disc diffusion methods, and polymerase chain reaction was used for the detection of putative virulence genes. Identification of isolates revealed three phenotypic species with percentage distribution as follows: Aeromonas hydrophila 23 (45.1 %), Aeromonas caviae 16 (31.4 %), and Aeromonas sobria 12 (23.5 %). All Aeromonas isolates in the study were absolutely susceptible to cefotaxime and resistant to penicillin. A. cavaie and A. sobria demonstrated absolute susceptibility against ciprofloxacin and streptomycin. Aeromonas species showed varied susceptibility to cephalothin as follows: A. hydrophila 78.3 %, A. cavaie 93.7 %, and A. sobria 91.7 %. The percentage distribution of virulence genes among Aeromonas isolates were as follows: Aerolysin (aer) 74.5 %, flagellin gene (fla) 68.6 %, cytotoxin (hly A) 43.1 %, lipase (lip) 39.2 %, enterotoxic activities (ast) 31.3 %, and cytotonic gene (alt) 13.7 %. Reports from this study shows that Aeromonas species isolated from pig fecal samples are multi-drug resistant and possess virulence potential which may result to possible risk of human or animal infection and likely contamination of food and water from this sources. PMID- 26971521 TI - Application of plant carbon source for denitrification by constructed wetland and bioreactor: review of recent development. AB - Water quality standard for nitrate becomes more and more strict, and the plant carbon source is widely used for denitrification by constructed wetland (CW) and bioreactor. However, the nitrate removal efficiency by different types of plant carbon source are not evaluated comprehensively. Denitrification performance of different plant carbon sources, and the influence of dosing method and pretreatment are thoroughly reviewed in this paper, which aims to investigate the accurate utilization of plant carbon source for nitrogen (as nitrate) removal. It is concluded that plant carbon source addition for all types of CWs and bioreactors can improve the nitrate removal efficiency to some extent, and the dosing method of plant carbon source for denitrification should be further studied and optimized in the future. The popular carbon sources for CW and bioreactor denitrification enhancement are woodchip, chopped macrophytes, crop plants, macrophytes litters, etc. The recommended optimum C:N ratios for CW and bioreactor are 4.0:5.0 and 1.8:3.0, respectively. The physical and biological pretreatments are selected to supply organic carbon for long-term denitrification. PMID- 26971522 TI - Detecting grizzly bear use of ungulate carcasses using global positioning system telemetry and activity data. AB - Global positioning system (GPS) wildlife collars have revolutionized wildlife research. Studies of predation by free-ranging carnivores have particularly benefited from the application of location clustering algorithms to determine when and where predation events occur. These studies have changed our understanding of large carnivore behavior, but the gains have concentrated on obligate carnivores. Facultative carnivores, such as grizzly/brown bears (Ursus arctos), exhibit a variety of behaviors that can lead to the formation of GPS clusters. We combined clustering techniques with field site investigations of grizzly bear GPS locations (n = 732 site investigations; 2004-2011) to produce 174 GPS clusters where documented behavior was partitioned into five classes (large-biomass carcass, small-biomass carcass, old carcass, non-carcass activity, and resting). We used multinomial logistic regression to predict the probability of clusters belonging to each class. Two cross-validation methods-leaving out individual clusters, or leaving out individual bears-showed that correct prediction of bear visitation to large-biomass carcasses was 78-88 %, whereas the false-positive rate was 18-24 %. As a case study, we applied our predictive model to a GPS data set of 266 bear-years in the Greater Yellowstone Ecosystem (2002 2011) and examined trends in carcass visitation during fall hyperphagia (September-October). We identified 1997 spatial GPS clusters, of which 347 were predicted to be large-biomass carcasses. We used the clustered data to develop a carcass visitation index, which varied annually, but more than doubled during the study period. Our study demonstrates the effectiveness and utility of identifying GPS clusters associated with carcass visitation by a facultative carnivore. PMID- 26971523 TI - So close: remaining challenges to eradicating polio. AB - The Global Polio Eradication Initiative, launched in 1988, is close to achieving its goal. In 2015, reported cases of wild poliovirus were limited to just two countries - Afghanistan and Pakistan. Africa has been polio-free for more than 18 months. Remaining barriers to global eradication include insecurity in areas such as Northwest Pakistan and Eastern and Southern Afghanistan, where polio cases continue to be reported. Hostility to vaccination is either based on extreme ideologies, such as in Pakistan, vaccination fatigue by parents whose children have received more than 15 doses, and misunderstandings about the vaccine's safety and effectiveness such as in Ukraine. A further challenge is continued circulation of vaccine-derived poliovirus in populations with low immunity, with 28 cases reported in 2015 in countries as diverse as Madagascar, Ukraine, Laos, and Myanmar. This paper summarizes the current epidemiology of wild and vaccine derived poliovirus, and describes the remaining challenges to eradication and innovative approaches being taken to overcome them. PMID- 26971524 TI - Reversal of Beta-Amyloid-Induced Neurotoxicity in PC12 Cells by Curcumin, the Important Role of ROS-Mediated Signaling and ERK Pathway. AB - Progressive accumulation of beta-amyloid (Abeta) will form the senile plaques and cause oxidative damage and neuronal cell death, which was accepted as the major pathological mechanism to the Alzheimer's disease (AD). Hence, inhibition of Abeta-induced oxidative damage and neuronal cell apoptosis by agents with potential antioxidant properties represents one of the most effective strategies in combating human AD. Curcumin (Cur) a natural extraction from curcuma longa has potential of pharmacological efficacy, including the benefit to antagonize Abeta induced neurotoxicity. However, the molecular mechanism remains elusive. The present study evaluated the protective effect of Cur against Abeta-induced cytotoxicity and apoptosis in PC12 cells and investigated the underlying mechanism. The results showed that Cur markedly reduced Abeta-induced cytotoxicity by inhibition of mitochondria-mediated apoptosis through regulation of Bcl-2 family. The PARP cleavage, caspases activation, and ROS-mediated DNA damage induced by Abeta were all significantly blocked by Cur. Moreover, regulation of p38 MAPK and AKT pathways both contributed to this protective potency. Our findings suggested that Cur could effectively suppress Abeta-induced cytotoxicity and apoptosis by inhibition of ROS-mediated oxidative damage and regulation of ERK pathway, which validated its therapeutic potential in chemoprevention and chemotherapy of Abeta-induced neurotoxicity. PMID- 26971526 TI - Blockade of RAGE in Zucker obese rats with experimental periodontitis. AB - BACKGROUND AND OBJECTIVE: Periodontitis and type 2 diabetes mellitus (T2D) are two interrelated chronic diseases. Periodontitis is more prevalent in patients with T2D than in healthy subjects, and studies indicate that periodontitis impacts the metabolic control of patients with T2D. Hyperglycemia in T2D leads to the formation of advanced glycation end-products (AGEs). Binding of AGEs to the receptor of AGE (RAGE) elicits an increased inflammatory response that may be a key modulator linking the two diseases. The present study aimed to elucidate the effect of blocking the RAGE on the interrelationship between periodontitis and T2D in a rat model of both diseases. MATERIAL AND METHODS: Zucker obese rats (HsdHlr:ZUCKER-Lepr fa/fa ) and their lean littermates were divided into five treatment groups, with and without periodontitis. Monoclonal anti-RAGE IgG3 were injected into the rats three times a week. The diabetic state was evaluated by oral glucose tolerance tests (OGTTs), the homeostasis model assessment (HOMA), concentration of free fatty acids and repeated measurements of blood glucose. Markers of systemic inflammation, including interleukin (IL)-1beta, IL-6 and tumor necrosis factor alpha, were evaluated in plasma. Kidney complications were evaluated by quantitative real-time PCR, the creatinine clearance rate, the albumin excretion rate and kidney hypertrophy. Periodontitis was evaluated by morphometric registration of alveolar bone loss and radiographic recording of bone support. RESULTS: The diabetic state was improved by antibody treatment for 4 wk, resulting in a lower area under the glucose concentration curve during OGTTs, lower insulin levels and a lower HOMA. Furthermore, the antibody treatment resulted in milder kidney complications, as evaluated by measuring the albumin excretion rate and the kidney weight. There was no impact of periodontal inflammation on the level of complications. Periodontal bone support was influenced by diabetes, but the altered diabetic status as a result of treatment with anti-RAGE Ig had no effect on periodontitis. CONCLUSION: In this study, treatment with anti-RAGE IgG3 resulted in improved glucose tolerance and attenuated renal complications. However, no effect was observed on the diabetes associated periodontitis in Zucker obese rats. Furthermore, periodontitis had no effect on diabetic markers or renal complications. Therefore, activation of RAGE is important in the development of T2D. PMID- 26971525 TI - Sirt1: Role Under the Condition of Ischemia/Hypoxia. AB - Silent information regulator factor 2-related enzyme 1 (sirtuin 1, Sirt1) is a nicotinamide adenine dinucleotide-dependent deacetylase, which can deacetylate histone and non-histone proteins and other transcription factors, and is involved in the regulation of many physiological functions, including cell senescence, gene transcription, energy balance, and oxidative stress. Ischemia/hypoxia injury remains an unresolved and complicated situation in the diseases of ischemia stroke, heart failure, and coronary heart disease, especially among the old folks. Studies have demonstrated that aging could enhance the vulnerability of brain, heart, lung, liver, and kidney to ischemia/hypoxia injury and the susceptibility in old folks to ischemia/hypoxia injury might be associated with Sirt1. In this review, we mainly summarize the role of Sirt1 in modulating pathways against energy depletion and its involvement in oxidative stress, apoptosis, and inflammation under the condition of ischemia/hypoxia. PMID- 26971527 TI - Puromycin Analogues Capable of Multiplexed Imaging and Profiling of Protein Synthesis and Dynamics in Live Cells and Neurons. AB - Newly synthesized proteins constitute an important subset of the proteome involved in every cellular process, yet existing chemical tools used to study them have major shortcomings. Herein we report a suite of cell-permeable puromycin analogues capable of being metabolically incorporated into newly synthesized proteins in different mammalian cells, including neuronal cells. Subsequent labeling with suitable bioorthogonal reporters, in both fixed and live cells, enabled direct imaging and enrichment of these proteins. By taking advantage of the mutually orthogonal reactivity of these analogues, we showed multiplexed labeling of different protein populations, as well as quantitative measurements of protein dynamics by fluorescence correlation spectroscopy, could be achieved in live-cell environments. PMID- 26971528 TI - Hypothalamic volume loss is associated with reduced melatonin output in Parkinson's disease. AB - BACKGROUND: Recent studies have suggested that melatonin-a hormone produced by the pineal gland under circadian control-contributes to PD-related sleep dysfunction. We hypothesized that degenerative changes to the neural structures controlling pineal function (especially the suprachiasmatic nuclei of the anterior hypothalamus) may be responsible for reduced melatonin output in these patients. We compared hypothalamic volumes in PD patients with matched controls and determined whether volume loss correlated with reduced melatonin output in the PD group. METHODS: A total of 12 PD patients and 12 matched controls underwent magnetic resonance imaging to determine hypothalamic volume. In addition, PD patients underwent 24-hour blood sampling in a controlled environment to determine serum melatonin concentrations using enzyme-linked immunosorbent assays. RESULTS: PD patients had significantly reduced hypothalamic gray matter volume when compared with matched controls. Melatonin levels were significantly associated with hypothalamic gray matter volume and disease severity in PD patients. CONCLUSION: Melatonin levels are associated with hypothalamic gray matter volume loss and disease severity in PD patients. This provides anatomical and physiological support for an intrinsic sleep and circadian phenotype in PD. (c) 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 26971529 TI - New insights from cluster analysis methods for RNA secondary structure prediction. AB - A widening gap exists between the best practices for RNA secondary structure prediction developed by computational researchers and the methods used in practice by experimentalists. Minimum free energy predictions, although broadly used, are outperformed by methods which sample from the Boltzmann distribution and data mine the results. In particular, moving beyond the single structure prediction paradigm yields substantial gains in accuracy. Furthermore, the largest improvements in accuracy and precision come from viewing secondary structures not at the base pair level but at lower granularity/higher abstraction. This suggests that random errors affecting precision and systematic ones affecting accuracy are both reduced by this 'fuzzier' view of secondary structures. Thus experimentalists who are willing to adopt a more rigorous, multilayered approach to secondary structure prediction by iterating through these levels of granularity will be much better able to capture fundamental aspects of RNA base pairing. WIREs RNA 2016, 7:278-294. doi: 10.1002/wrna.1334 For further resources related to this article, please visit the WIREs website. PMID- 26971530 TI - Long-term efficacy of percutaneous steroid injection for treating benign vocal fold lesions: A prospective study. AB - OBJECTIVES/HYPOTHESIS: This study assessed the long-term efficacy and recurrence rates of percutaneous steroid injections (PSIs) for benign vocal fold lesions. STUDY DESIGN: Prospective clinical study. METHODS: A prospective human clinical trial was performed from October 2008 to September 2014 at Soonchunhyang University Hospital, Bucheon, Korea. Percutaneous steroid injection was performed in 84 consecutive patients with small benign vocal fold lesions, such as vocal fold nodules, polyps, and Reinke's edema, who could not be treated with voice therapy or surgery. Patients had acoustic aerodynamic, perceptual, stroboscopic, and voice handicap index evaluations before PSI and also 3, 6, 12, and 24 months after PSI. RESULTS: Of the 84 patients, 37 (44.0%) showed complete remission; 22 (26.2%) showed partial remission; five (6%) had no response; and 20 (23.8%) developed recurrences after PSI. Most of the objective and subjective parameters that improved statistically (P < 0.05) 3 months after PSI remained stable until 24 months. For the recurrences, the average recurrence time interval after PSI was 8.5 +/- 8.2 (range 3-36) months. Recurrence was associated with voice abuse after PSI and professional voice users (P < 0.05). Complications during follow-up included minimal vocal fold hematomas in 2.4% (2 of 84) and mild vocal fold atrophy in 1.2% (1 of 84). CONCLUSION: Percutaneous steroid injection is a useful alternative modality for treating benign vocal fold lesions without morbidity. However, recurrence rates were higher with voice abuse after PSI and professional voice users. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2315-2319, 2016. PMID- 26971531 TI - Baicalein Induces Caspase-dependent Apoptosis Associated with the Generation of ROS and the Activation of AMPK in Human Lung Carcinoma A549 Cells. AB - Baicalein is one of the main bioactive flavonoids found in the roots of Scutellaria baicalensis Georgi. Here, we report that baicalein-induced growth inhibition was associated with the induction of apoptosis in human lung carcinoma A549 cells. Baicalein stimulated the expression of DR5, FasL, and FADD, and activated caspase-8 by reducing the levels of FLIPs (FLICE-inhibitory proteins). The apoptotic cell death was also connected with an activation of caspase-9 and 3, and cleavage of poly(ADP-ribose) polymerase; however, a blockage of caspase activation abolished baicalein-induced apoptotic potentials. Additionally, baicalein caused a mitochondrial membrane potential (MMP), the truncation of Bid, and the translocation of pro-apoptotic Bax to the mitochondria, thereby inducing the release of cytochrome c into the cytosol. In turn, baicalein increased the generation of reactive oxygen species (ROS); however, an ROS scavenger, N acetylcysteine, notably attenuated baicalein-mediated loss of MMP and activation of caspases. Furthermore, baicalein activated the AMP-activated protein kinase (AMPK) signaling pathway. Consequently, baicalein-triggered cell death was attenuated by an AMPK inhibitor, but increased by an AMPK activator, compound C. Overall, the results suggest that the apoptotic activity of baicalein may be associated with caspase-dependent cascade through the activation of both intrinsic and extrinsic signaling pathways connected with ROS generation and AMPK activation. PMID- 26971532 TI - Carbon flux rerouting during Mycobacterium tuberculosis growth arrest. PMID- 26971534 TI - Bidirectional Contrast agent leakage correction of dynamic susceptibility contrast (DSC)-MRI improves cerebral blood volume estimation and survival prediction in recurrent glioblastoma treated with bevacizumab. AB - PURPOSE: To evaluate a leakage correction algorithm for T1 and T2* artifacts arising from contrast agent extravasation in dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) that accounts for bidirectional contrast agent flux and compare relative cerebral blood volume (CBV) estimates and overall survival (OS) stratification from this model to those made with the unidirectional and uncorrected models in patients with recurrent glioblastoma (GBM). MATERIALS AND METHODS: We determined median rCBV within contrast-enhancing tumor before and after bevacizumab treatment in patients (75 scans on 1.5T, 19 scans on 3.0T) with recurrent GBM without leakage correction and with application of the unidirectional and bidirectional leakage correction algorithms to determine whether rCBV stratifies OS. RESULTS: Decreased post-bevacizumab rCBV from baseline using the bidirectional leakage correction algorithm significantly correlated with longer OS (Cox, P = 0.01), whereas rCBV change using the unidirectional model (P = 0.43) or the uncorrected rCBV values (P = 0.28) did not. Estimates of rCBV computed with the two leakage correction algorithms differed on average by 14.9%. CONCLUSION: Accounting for T1 and T2* leakage contamination in DSC-MRI using a two-compartment, bidirectional rather than unidirectional exchange model might improve post-bevacizumab survival stratification in patients with recurrent GBM. J. Magn. Reson. Imaging 2016;44:1229-1237. PMID- 26971535 TI - The Lived Experience of Childbearing From Survivors of Sexual Abuse: "It Was the Best of Times, It Was the Worst of Times". AB - INTRODUCTION: In the United States, one in every 5 women will experience sexual violence. Survivors are at risk for difficult pregnancies, substance abuse, stress, fear, and preterm births. A history of sexual abuse can impact several aspects of a woman's childbirth, thereby affecting her long-term physical and emotional well-being. The adverse pregnancy outcomes, combined with the prevalence of sexual abuse, underscore the need for research to understand survivors' experiences. METHODS: This study's purpose was to understand the lived experience of pregnancy, labor, and birth from survivors. A qualitative, descriptive phenomenological research design was utilized. The purposeful sample included 8 female, self-identifying survivors of sexual abuse with at least one childbearing experience. RESULTS: Analysis identified 302 significant statements that formed 7 overarching themes: 1) No one asked me. Just ask me!; 2) An emotional roller coaster: From excitement to grief for what could have been a better experience; 3) All of a sudden I was that little girl again and/or I compartmentalized it: The all-or-nothing experience; 4) Am I even here?: Nothing was explained and I had no voice; 5) All too familiar: No support, nowhere to turn; 6) Holding on to the choices I can make: Who my doctor is and how I feed my baby; and 7) Overprotection: Keeping my child safe. DISCUSSION: The final result was the essence of childbearing for survivors in this study. They were not screened for a history of sexual abuse. Enjoyment and excitement were juxtaposed with guilt and fear. They had no voice, lacked support, and overwhelmingly desired control. They overprotected their children, from infancy into adulthood. The childbearing experience was a complex, emotional roller coaster permeated by the past. Women's health care providers can utilize the results to provide therapeutic care to survivors to prevent revictimization. The results elucidate the importance of screening for a history of sexual abuse and discussing the implications such a history can have on the childbearing experience. PMID- 26971536 TI - Psoriasis, vitamin D and the importance of the cutaneous barrier's integrity: An update. AB - Psoriasis is a common, inflammatory, chronic, relapsing skin disease. Despite several hypotheses having been postulated to explain the pathogenesis of this disorder, nowadays it is considered as a T-cell-mediated disease; in this context an important role is played by vitamin D. The role of this micronutrient is important for many reasons: it is able to modulate the immune system; it is implicated in keratinocyte turnover; and it is involved in the integrity of the cutaneous barrier. In psoriasis, this molecule plays an important role due to its ability in the modulation of innate and adaptive immunity and by its antiproliferative and pro-differentiative effects on keratinocytes. Alteration of the metabolism of vitamin D may alter the cutaneous barrier integrity and favor an infective and inflammatory condition. The importance of vitamin D in the pathogenesis of psoriasis is not a mere mental exercise but may open further perspectives in the treatment of this disorder just preventing alterations of immune homeostasis, modulating the proliferation of keratinocyte, regulating the microbial flora and the response of the host to infective diseases. PMID- 26971533 TI - Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib. AB - Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long term bosutinib treatment for Philadelphia chromosome-positive (Ph+) leukemia based on treatment-emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second-/third-/fourth line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first-line bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow-up time was >=48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib-treated patients were 7%/10% overall with similar incidences observed with first-line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade >=3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in >2% of bosutinib patients. Exposure-adjusted vascular/cardiac TEAE rates (patients with events/patient-year) were low for second-line or later bosutinib (0.037/0.050) and not significantly different between first-line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P >= 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status >0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first-line and relapsed/refractory settings following long-term treatment in patients with Ph+ leukemia. Am. J. Hematol. 91:606-616, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26971537 TI - Extranodal natural killer/T-cell lymphoma preceded by persistent hemifacial swelling. PMID- 26971538 TI - Subclinical antibody-mediated rejection due to anti-human-leukocyte-antigen-DR53 antibody accompanied by plasma cell-rich acute rejection in a patient with cadaveric kidney transplantation. AB - A 56-year-old man who had undergone cadaveric kidney transplantation 21 months earlier was admitted to our hospital for a protocol biopsy; he had a serum creatinine level of 1.2 mg/dL and no proteinuria. Histological features showed two distinct entities: (i) inflammatory cell infiltration, in the glomerular and peritubular capillaries and (ii) focal, aggressive tubulointerstitial inflammatory cell infiltration, predominantly plasma cells, with mild tubulitis (Banff 13 classification: i2, t1, g2, ptc2, v0, ci1, ct1, cg0, cv0). Immunohistological studies showed mildly positive C4d immunoreactivity in the peritubular capillaries. The patient had donor specific antibody to human leucocyte-antigen-DR53. We diagnosed him with subclinical antibody-mediated rejection accompanied by plasma cell-rich acute rejection. Both antibody-mediated rejection due to anti- human-leucocyte-antigen -DR53 antibodies and plasma cell rich acute rejection are known to be refractory and have a poor prognosis. Thus, we started plasma exchange with intravenous immunoglobulin and rituximab for the former and 3 days of consecutive steroid pulse therapy for the latter. Three months after treatment, a follow-up allograft biopsy showed excellent responses to treatment for both histological features. This case report considers the importance of an early diagnosis and appropriate intervention for subclinical antibody-mediated rejection due to donor specific antibody to human-leucocyte antigen-DR53 and plasma cell-rich acute rejection. PMID- 26971539 TI - Candidatus Desulfofervidus auxilii, a hydrogenotrophic sulfate-reducing bacterium involved in the thermophilic anaerobic oxidation of methane. AB - The anaerobic oxidation of methane (AOM) is mediated by consortia of anaerobic methane-oxidizing archaea (ANME) and their specific partner bacteria. In thermophilic AOM consortia enriched from Guaymas Basin, members of the ANME-1 clade are associated with bacteria of the HotSeep-1 cluster, which likely perform direct electron exchange via nanowires. The partner bacterium was enriched with hydrogen as sole electron donor and sulfate as electron acceptor. Based on phylogenetic, genomic and metabolic characteristics we propose to name this chemolithoautotrophic sulfate reducer Candidatus Desulfofervidus auxilii. Ca. D. auxilii grows on hydrogen at temperatures between 50 degrees C and 70 degrees C with an activity optimum at 60 degrees C and doubling time of 4-6 days. Its genome draft encodes for canonical sulfate reduction, periplasmic and soluble hydrogenases and autotrophic carbon fixation via the reductive tricarboxylic acid cycle. The presence of genes for pili formation and cytochromes, and their similarity to genes of Geobacter spp., indicate a potential for syntrophic growth via direct interspecies electron transfer when the organism grows in consortia with ANME. This first ANME-free enrichment of an AOM partner bacterium and its characterization opens the perspective for a deeper understanding of syntrophy in anaerobic methane oxidation. PMID- 26971540 TI - Acceptability and willingness to use HIV pre-exposure prophylaxis among HIV negative men who have sex with men in Switzerland. AB - Pre-exposure prophylaxis (PrEP) is discussed as an additional HIV prevention method targeting men who have sex with men (MSM). So far, PrEP has not been approved in Switzerland and only little is known about the acceptability of PrEP among MSM living in Switzerland. Given the slow uptake of PrEP among MSM in the USA, the objectives of the study were to investigate the acceptability for PrEP and to identify factors influencing the acceptability for this prevention method and the willingness to adopt it. During a 4-month period we conducted five focus group discussions with 23 consecutively sampled HIV-negative MSM aged 22-60 years living in Switzerland. We analyzed the data according to qualitative content analysis. The acceptability of PrEP varied considerably among the participants. Some would use PrEP immediately after its introduction in Switzerland because it provides an alternative to condoms which they are unable or unwilling to use. Others were more ambivalent towards PrEP but still considered it (1) an additional or alternative protection to regular condom use, (2) an option to engage in sexual activities with less worries and anxieties or (3) a protection during receptive anal intercourse independently of the sexual partner's protective behaviour. Some participants would not consider using PrEP at all: they do not see any benefit in PrEP as they have adopted safer sex practices and did not mention any problems with condom use. Others are still undecided and could imagine using an improved form of PrEP. The results provide a valuable basis for a model explaining the acceptability of PrEP among MSM and suggest including the personal HIV protection strategy in the considerations adopted. PMID- 26971541 TI - Unsaponifiable matter from oil of green coffee beans: cosmetic properties and safety evaluation. AB - CONTEXT: Unsaponifiable matter (UM), a fraction of green coffee oil (GCO) contains functional compounds responsible for desirable cosmetic properties such as UV-B absorption. OBJECTIVES: To evaluate oil content and sun protection factor (SPF) variability of the two most important species of coffee and, the toxic and cytotoxic effects, as well as cosmetic properties, including antioxidant and antimicrobial activities of UM obtained from green Coffea arabica seed oil. MATERIALS AND METHODS: The safety and potential cosmetic properties of UM extracted from green coffee oil (GCO) were evaluated by the brine shrimp viability and the MTT cytotoxicity assays. The SPF and antioxidant activity were evaluated using in vitro methods. RESULTS: Relevant cytotoxicity was found against keratinocytes for concentrations >=25 ug/mL and in the brine shrimp assay (LC50 24 ug/mL). Antimicrobial and antioxidant activities (IC50 1448 ug/mL) were low in UM but SPF was 10 times higher than in GCO. CONCLUSION: UM is a novel potential UV-B absorbent but its use as a cosmetic ingredient should be better considered due to the considerable cytotoxicity shown in the experimental conditions described. PMID- 26971542 TI - The development of high-content screening (HCS) technology and its importance to drug discovery. AB - INTRODUCTION: High-content screening (HCS) was introduced about twenty years ago as a promising analytical approach to facilitate some critical aspects of drug discovery. Its application has spread progressively within the pharmaceutical industry and academia to the point that it today represents a fundamental tool in supporting drug discovery and development. AREAS COVERED: Here, the authors review some of significant progress in the HCS field in terms of biological models and assay readouts. They highlight the importance of high-content screening in drug discovery, as testified by its numerous applications in a variety of therapeutic areas: oncology, infective diseases, cardiovascular and neurodegenerative diseases. They also dissect the role of HCS technology in different phases of the drug discovery pipeline: target identification, primary compound screening, secondary assays, mechanism of action studies and in vitro toxicology. EXPERT OPINION: Recent advances in cellular assay technologies, such as the introduction of three-dimensional (3D) cultures, induced pluripotent stem cells (iPSCs) and genome editing technologies (e.g., CRISPR/Cas9), have tremendously expanded the potential of high-content assays to contribute to the drug discovery process. Increasingly predictive cellular models and readouts, together with the development of more sophisticated and affordable HCS readers, will further consolidate the role of HCS technology in drug discovery. PMID- 26971543 TI - Lack of improvement following endovascular therapy in patients with acute ischemic stroke. AB - BACKGROUND: Recent randomized trials have consistently demonstrated a clinical benefit of endovascular therapy (ET) over best medical therapy (including intravenous (IV) thrombolysis in eligible patients) or IV thrombolysis only in selected patients with acute ischemic stroke (AIS) due to proximal occlusion in the carotid territory. Previous study demonstrates that lack of improvement (LOI) at 24 hours is an independent predictor of poor outcome and death at 3 months in patients with AIS treated with IV alteplase. However, LOI at 24 hours following ET has not been studied systematically. The purpose of this study is to identify predictors of LOI at 24 hours in patients with AIS after ET as well as the relationship between LOI and unfavorable outcome at 3 months. METHODS: A total of 98 consecutive patients with AIS treated with ET in two separate stroke centers from 2010 to 2014 were retrospectively reviewed. Data on demographics, preexisting vascular risk factors, occlusion site, pre- and post-treatment modified Treatment in Cerebral Ischemia (mTICI) classification, collaterals and National Institutes of Health Stroke Scale (NIHSS) score on admission as well as 24 hours after the endovascular procedurals were collected. LOI was defined as a reduction of 3 points or less on the NIHSS at 24 hours compared with baseline. A 3-month functional outcome was assessed using the modified Rankin scale (mRS). Unfavorable outcome was prespecified as a score of more than 2 on the mRS. The onset-to-reperfusion time (ORT) was defined as time to mTICI 2b or 3 or end of procedure. Long ORT was defined as time to reperfusion beyond 6 hours. Poor reperfusion was defined as mTICI ?2a. The pretreatment collateral circulation extent was graded as poor (grades 0-1) or good (grades 2-4). RESULTS: Among the 98 patients with AIS who were treated with ET, LOI was present in 48 (49%) subjects. Multivariate analysis indicated that poor collaterals (odds ratio [OR] 3.25; 95% confidence interval [CI]: 1.29-8.19; p = 0.012) and long ORT (OR 3.97, 95% CI: 1.66-9.54; p = 0.002) were independent predictors of LOI. LOI (OR 7.18, 95% CI: 2.39-21.61; p < 0.001) was independently associated with unfavorable outcome at 3 months. CONCLUSION: Among patients with AIS treated with ET, as an independent predictor of unfavorable outcome, LOI at 24 hours is associated with poor collaterals and long ORT. PMID- 26971551 TI - Using silkworms as a laboratory animal to evaluate medicines and foods. AB - For this special issue, we, the Editors of Drug Discoveries & Therapeutics, have asked researchers who are using silkworms to actively develop drugs and study foods to summarize their recent work. Our profound hope is that this special issue encourages researchers who are helping to develop the new field of "using silkworms as a laboratory animal to evaluate medicines and foods". PMID- 26971552 TI - Understanding of bacterial virulence using the silkworm infection model. AB - We have used silkworms, larva of Bombyx mori, to investigate host-pathogen interactions. Silkworms have several advantages, such as high availability of a large number of animals and ease of injection of quantitative amounts of samples. Human pathogenic bacteria such as Staphylococcus aureus, Streptococcus pyogenes, or Pseudomonas aeruginosa kill silkworms. In this review, I would like to summarize our approach identifying S. aureus virulence factors by using the silkworm infection model. PMID- 26971545 TI - Inappropriate Suppression of Thyrotropin Concentrations in Young Patients with Thyroid Nodules Including Thyroid Cancer: The Fukushima Health Management Survey. AB - BACKGROUND: Serum thyroid hormone concentration is regulated through the hypothalamic-pituitary-thyroid axis. This study aimed to clarify the relationships between thyroid hormone regulation and ultrasonographic findings in subjects with thyroid nodules detected during thyroid ultrasound examination for the Fukushima Health Management Survey. METHODS: As of October 31, 2014, a total of 296,253 subjects, who had been living in Fukushima Prefecture at the time of the Fukushima nuclear power plant accident and were aged <=18 years on March 11, 2011, participated in two concurrent screening programs. In the primary screening, thyroid nodules were detected in 2241 subjects. A secondary confirmatory thyroid ultrasound examination and blood sampling for thyroid function tests were performed on 2004 subjects. The subjects were reassessed and classified into disease-free subjects (Group 1), subjects with cysts only (Group 2), subjects with nodules (Group 3), and subjects with malignancy or suspected malignancy (Group 4). Serum concentrations of free triiodothyronine (fT3), free thyroxine (fT4), thyrotropin (TSH), thyroglobulin, and the fT3/fT4 ratio were classified according to the diagnoses. RESULTS: Inverse relationships between age and log TSH values (Spearman's correlation r = -0.311, p = 0.015), serum fT3 concentration (r = -0.688, p < 0.001), and the fT3/fT4 ratio (r = -0.520, p < 0.001) were observed in Group 1. When analysis of covariance with Bonferroni post hoc comparisons was used in the four groups, the log TSH values were significantly lower in both Group 3 and Group 4 compared with Group 1 and Group 2 after correcting for age (p < 0.001; Group 1 vs. Group 3, p = 0.016; Group 1 vs. Group 4, p = 0.022; Group 2 vs. Group 3, p = 0.001; Group 2 vs. Group 4, p = 0.008). However, no significant differences were observed between the four groups regarding levels of fT3, fT4, fT3/fT4 ratio, and thyroglobulin (p = 0.304, 0.340, 0.208, and 0.583, respectively). CONCLUSION: TSH suppression can be present in response to illness, including thyroid nodules, in young subjects. Low TSH levels may be associated with the finding of papillary thyroid cancer as well as with thyroid nodules in children and adolescents. PMID- 26971553 TI - Recent progress in development of transgenic silkworms overexpressing recombinant human proteins with therapeutic potential in silk glands. AB - Since 2000, transgenic silkworms have been developed to produce recombinant proteins with therapeutic potential for future clinical use, including antibody preparations. Lysosomal storage diseases (LSDs) are inherited metabolic disorders caused by mutations of lysosomal enzymes associated with excessive accumulation of natural substrates and neurovisceral symptoms. Over the past few years, enzyme replacement therapy (ERT) with human lysosomal enzymes produced by genetically engineered mammalian cell lines has been used clinically to treat several patients with an LSD involving multi-organ symptoms. ERT is based on the incorporation of recombinant glycoenzymes by their binding to glycan receptors on the surface of target cells and their subsequent delivery to lysosomes. However, ERT has several disadvantages, including difficulty mass producing human enzymes, dangers of pathogen contamination, and high costs. Recently, the current authors have succeeded in producing transgenic silkworms overexpressing human lysosomal enzymes in the silk glands and the authors have purified catalytically active enzymes from the middle silk glands. Silk gland-derived human enzymes carrying high-mannose and pauci-mannose N-glycans were endocytosed by monocytes via the mannose receptor pathway and were then delivered to lysosomes. Conjugates with cell-penetrating peptides were also taken up by cultured fibroblasts derived from patients with enzyme deficiencies to restore intracellular catalytic activity and reduce the excessive accumulation of substrates in patient fibroblasts. Transgenic silkworms overexpressing human lysosomal enzymes in the silk glands could serve as future bioresources that provide safe therapeutic enzymes for the treatment of LSDs. Combining recent developments in transglycosylation technology with microbial endoglycosidases will promote the development of therapeutic glycoproteins as bio-medicines. PMID- 26971554 TI - Using silkworms to establish alternative animal models for evaluation of drug induced tissue injury. AB - Evaluation of tissue injury induced by chemicals is crucial to drug development. Mice and rats, which are effectively used to analyze drug-induced tissue injury, present problems in terms of cost and ethical issues. Although alternative methods have been developed using in vitro techniques or invertebrates, evaluation of ADME and the size of animals are still issues that need to be addressed. Use of silkworms can resolve these problems. Silkworms have pharmacokinetic characteristics similar to those of mammals. Injection of various hepatotoxic chemicals also leads to elevated alanine aminotransferase (ALT) activity in the hemolymph of silkworms. Furthermore, transparent transgenic silkworms expressing GFP have been produced to facilitate continuous analysis without the need to collect hemolymph. Analyses using this silkworm have indicated that the intensity of GFP fluorescence observed on the body surface of the silkworm decreases in a time- and dose-dependent manner when hepatotoxic chemicals are injected. These results suggest that the silkworms can serve as alternative animal model for evaluation of drug-induced tissue injury. PMID- 26971555 TI - Therapeutic effects of three trichothecenes in the silkworm infection assay with Candida albicans. AB - The silkworm infection assay is a useful method for directly evaluating the in vivo therapeutic effects of drug candidates. In the present study, 3 known trichothecenes, trichodermin, epiisororidin E, and verrucarin A, were evaluated as antifungal agents in the silkworm-Candida albicans assay. Trichodermin and epiisororidin E yielded effective therapeutic effects, while verrucarin A exhibited no efficacy in this assay system. These results strongly suggest that trichodermin and epiisororidin E are the lead compounds for developing a new antifungal agent. PMID- 26971556 TI - Lactic acid bacteria activating innate immunity improve survival in bacterial infection model of silkworm. AB - Lactic acid bacteria (LAB) have been thought to be helpful for human heath in the gut as probiotics. It recently was noted that activity of LAB stimulating immune systems is important. Innate immune systems are conserved in mammals and insects. Silkworm has innate immunity in response to microbes. Microbe-associated molecular pattern (ex. peptidoglycan and beta-glucan) induces a muscle contraction of silkworm larva. In this study, we established an efficient method to isolate lactic acid bacteria derived from natural products. We selected a highly active LAB to activate the innate immunity in silkworm by using the silkworm muscle contraction assay, as well. The assay revealed that Lactococcus lactis 11/19-B1 was highly active on the stimulation of the innate immunity in silkworm. L. lactis 11/19-B1 solely fermented milk with casamino acid and glucose. This strain would be a starter strain to make yogurt. Compared to commercially available yogurt LAB, L. lactis 11/19-B1 has higher activity on silkworm contraction. Silkworm normally ingested an artificial diet mixed with L. lactis 11/19-B1 or a yogurt fermented with L. lactis 11/19-B1. Interestingly, silkworms that ingested the LAB showed tolerance against the pathogenicity of Pseudomonas aeruginosa. These data suggest that Lactococcus lactis 11/19-B1 would be expected to be useful for making yogurt and probiotics to activate innate immunity. PMID- 26971557 TI - Acute oral toxicity test of chemical compounds in silkworms. AB - This study performed an acute oral toxicity test of 59 compounds in silkworms. These compounds are listed in OECD guidelines as standard substances for a cytotoxicity test, and median lethal dose (LD(50)) werecalculated for each compound. Acute oral LD(50) values in mammals are listed in OECD guidelines and acute oral LD(50) values in silkworms were determined in this study. R(2) for the correlation between LD(50) values in mammals and LD(50) values in silkworms was 0.66. In addition, the acute oral toxicity test in silkworms was performed by two different facilities, and test results from the facilities were highly reproducible. These findings suggest that an acute oral toxicity test in silkworms is a useful way to evaluate the toxicity of compounds in mammals. PMID- 26971558 TI - A Liquid Chromatography-Tandem Mass Spectrometry Method for the Detection of Antimicrobial Agents from Seven Classes in Calf Milk Replacers: Validation and Application. AB - Calf milk replacers are low-cost feeds that contain available, digestible protein. During their reconstitution, however, the addition of drugs, such as antibiotics, could make them a very simple route for illicit treatment for therapeutic, preventive, or growth-promoting purposes. We developed an HPLC-MS/MS method, preceded by a unique extraction step, able to identify 17 antibiotics from seven classes (penicillins, tetracyclines, fluoroquinolones, sulfonamides, cephalosporins, amphenicols, and lincosamides) in this matrix. Prior to solid phase extraction (SPE), the sample underwent deproteinization and defatting. The method was fully validated according to Commission Decision 2002/657/EC. Decision limits (CCalpha) and detection capability (CCbeta) were in the ranges of 0.13 1.26 and 0.15-1.47 ng/mL, respectively. Thirty-eight samples were finally analyzed, showing the occasional presence of marbofloxacin (six samples) and amoxicillin (one sample). PMID- 26971559 TI - Coupling Charge Reduction Mass Spectrometry to Liquid Chromatography for Complex Mixture Analysis. AB - Electrospray ionization (ESI) of solution mixtures often generates complex mass spectra, even following liquid chromatography (LC), due to analyte multiple charging. Multiple charge state distributions can lead to isobaric interferences, mass spectral congestion, and ambiguous ion identification. As a consequence, data interpretation increases in complexity. Several charge reduction mass spectrometry (MS) approaches have been previously developed to reduce the average charge state of gaseous ions; however, all of these techniques have been restricted to direct infusion MS. In this study, synthetic polyols and surfactants separated by liquid chromatography and ionized by positive mode ESI have been subjected to polonium-210 alpha-particle radiation to reduce the average charge state to singly charged cations prior to mass analysis. LC/MS analysis of 5000 molecular weight poly(ethylene glycol) (PEG5000) generated an average charge state of 5.88+; whereupon, liquid chromatography/electrospray ionization/charge reduction/mass spectrometry (LC/CR/MS) analysis of PEG 5000 generated an average charge state of 1.00+. The PEG5000 results demonstrated a decrease in spectral complexity and enabled facile interpretation. Other complex solution mixtures representing specific MS challenges (i.e., competitive ionization and isobaric ion overlap) were explored and analyzed with LC/CR/MS to demonstrate the benefits of coupling LC to CR/MS. For example, polyol information related to initiator, identity/relative amount of monomer, and estimated molecular weight was characterized in random and triblock ethylene oxide/propylene oxide polyols using LC/CR/MS. LC/CR/MS is a new analytical technique for the analysis of complex mixtures. PMID- 26971560 TI - Thermally Stable Silver Nanowires-Embedding Metal Oxide for Schottky Junction Solar Cells. AB - Thermally stable silver nanowires (AgNWs)-embedding metal oxide was applied for Schottky junction solar cells without an intentional doping process in Si. A large scale (100 mm(2)) Schottky solar cell showed a power conversion efficiency of 6.1% under standard illumination, and 8.3% under diffused illumination conditions which is the highest efficiency for AgNWs-involved Schottky junction Si solar cells. Indium-tin-oxide (ITO)-capped AgNWs showed excellent thermal stability with no deformation at 500 degrees C. The top ITO layer grew in a cylindrical shape along the AgNWs, forming a teardrop shape. The design of ITO/AgNWs/ITO layers is optically beneficial because the AgNWs generate plasmonic photons, due to the AgNWs. Electrical investigations were performed by Mott Schottky and impedance spectroscopy to reveal the formation of a single space charge region at the interface between Si and AgNWs-embedding ITO layer. We propose a route to design the thermally stable AgNWs for photoelectric device applications with investigation of the optical and electrical aspects. PMID- 26971561 TI - Deconstructing the nature of episodic foresight deficits associated with chronic opiate use. AB - OBJECTIVES: Episodic foresight refers to the capacity to mentally travel forward in time and has been linked to a wide variety of important functional behaviours. Evidence has recently emerged that chronic opiate use is associated with deficits in this critical capacity and that these difficulties are not simply a secondary consequence of broader cognitive dysfunction. The current study aimed to better understand the circumstances in which chronic opiate users might be expected to have problems with episodic foresight, by addressing whether deficits reflect compromised scene construction, self-projection, or narrative ability. METHODS: Thirty-five chronic opiate users and 35 demographically matched controls completed an imagination task in which they were instructed to imagine and provide descriptions of an atemporal event, a plausible, self-relevant future event, as well as complete a narrative task. These three imagination conditions systematically varied in their demands on scene construction, self-projection, and narrative ability. RESULTS: Consistent with prior literature, chronic opiate users exhibited reduced capacity for episodic foresight relative to controls. However, this study was the first to show that these difficulties were independent of capacity for scene construction and narration. Instead, a specific impairment in self-projection into the future appears to contribute to the problems with episodic foresight seen in this clinical group. CONCLUSIONS: Deficits in self-projection into the future may have important implications in therapeutic environments given that many relapse prevention strategies rely heavily on the ability to project oneself into an unfamiliar future, free of problem substance use. PRACTITIONER POINTS: A reduced capacity for episodic foresight highlights the importance of refining current relapse prevention protocols that place significant demands for mental time travel into the future. Psychosocial treatments should focus on the attainment of more immediate or short term goals. It is difficult to delineate the effects of specific substances given long-standing drug use history common to chronic opiate users. Conclusions relating to neurological functioning are speculative given the absence of neuroimaging data. PMID- 26971562 TI - Calcium phosphate-based organic-inorganic hybrid nanocarriers with pH-responsive on/off switch for photodynamic therapy. AB - Photodynamic therapy (PDT) is a promising treatment modality for malignant tumors in a light-selective manner. To improve the PDT efficacy, numerous kinds of nanocarriers have been developed to deliver photosensitizers (PSs) selectively into the tumor through leaky tumor-associated vasculature. However, the corresponding prolonged retention of the nanocarrier in the bloodstream may lead to unfavorable photochemical damage to normal tissues such as skin. Here, we report an organic-inorganic hybrid nanocarrier with a pH-responsive on/off switch of PDT efficacy. This hybrid nanocarrier is constructed by hydrothermal synthesis after simple mixing of calcium/phosphate ions, chlorin e6 (amphiphilic low molecular weight PS), and poly(ethylene glycol)-b-poly(aspartic acid) (PEG-PAsp) copolymers in an aqueous solution. The hybrid nanocarrier possesses a calcium phosphate (CaP) core encapsulating the PSs, which is surrounded by a PEG shielding layer. Under physiological conditions (pH 7.4), the nanocarrier suppressed the photochemical activity of PS by lowering the access of oxygen molecules to the incorporated PS, while PDT efficacy was restored in a pH responsive manner because of the dissolution of CaP and eventual recovery of access between the oxygen and the PS. Owing to this switch, the nanocarrier reduced the photochemical damage in the bloodstream, while it induced effective PDT efficacy inside the tumor cell in response to the acidic conditions of the endo-/lysosomes. PMID- 26971563 TI - Towards three-dimensional Weyl-surface semimetals in graphene networks. AB - Graphene as a two-dimensional topological semimetal has attracted much attention for its outstanding properties. In contrast, three-dimensional (3D) topological semimetals of carbon are still rare. Searching for such materials with salient physics has become a new direction in carbon research. Here, using first principles calculations and tight-binding modeling, we propose a new class of Weyl semimetals based on three types of 3D graphene networks. In the band structures of these materials, two flat Weyl surfaces appear in the Brillouin zone, which straddle the Fermi level and are robust against external strain. Their unique atomic and electronic structures enable applications in correlated electronics, as well as in energy storage, molecular sieves, and catalysis. When the networks are cut, the resulting slabs and nanowires remain semimetallic with Weyl lines and points at the Fermi surfaces, respectively. Between the Weyl lines, flat surface bands emerge with possible strong magnetism. The robustness of these structures can be traced back to a bulk topological invariant, ensured by the sublattice symmetry, and to the one-dimensional Weyl semimetal behavior of the zigzag carbon chain. PMID- 26971565 TI - Towards peptide vaccines for influenza. PMID- 26971564 TI - Registered report: IDH mutation impairs histone demethylation and results in a block to cell differentiation. AB - The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from "IDH mutation impairs histone demethylation and results in a block to cell differentiation" by Lu and colleagues, published in Nature in 2012 (Lu et al., 2012). The experiments that will be replicated are those reported in Figures 1B, 2A, 2B, 2D and 4D. Lu and colleagues demonstrated that expression of mutant forms of IDH1 or IDH2 caused global increases in histone methylation and increased levels of 2 hydroxyglutarate (Figure 1B). This was correlated with a block in differentiation (Figures 2A, B and D). This effect appeared to be mediated by the histone demethylase KDM4C (Figure 4D). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Scienceand Science Exchange, and the results of the replications will be published by eLife. PMID- 26971566 TI - Psychopathy and Machiavellianism: A Distinction Without a Difference? AB - A robust literature has emerged on the Dark Triad (DT) of personality Machiavellianism (MACH), psychopathy, and narcissism. Questions remain as to whether MACH and psychopathy are distinguishable and whether MACH's empirical and theoretical networks are consistent. In Study 1 (N = 393; MTurk research participants), factor analyses were used to compare two-factor (MACH and psychopathy combined + narcissism) and three-factor models, with both fitting the data equally well. In Studies 1 and 2 (N = 341; undergraduate research participants), DT scores were examined in relation to a variety of external criteria, including self- and informant ratings of personality, adverse developmental experiences, and psychopathological symptoms/behaviors. In both studies, MACH and psychopathy manifested nearly identical empirical profiles and both were significantly related to disinhibitory traits thought to be antithetical to MACH. In Study 3 (N = 36; expert raters), expert ratings of the Five-Factor Model traits prototypical of MACH were collected and compared with empirically derived profiles. Measures of MACH yielded profiles that were inconsistent with the prototypical expert-rated profile due to their positive relations with a broad spectrum of impulsivity-related traits. Ultimately, measures of psychopathy and MACH appear to be measuring the same construct, and MACH assessments fail to capture the construct as articulated in theoretical descriptions. PMID- 26971568 TI - Oxygen isotope exchange in La2NiO(4+/-delta). AB - Oxygen surface exchange kinetics and diffusion have been studied by the isotope exchange method with gas phase equilibration using a static circulation experimental rig in the temperature range of 600-800 degrees C and oxygen pressure range of 0.13-2.5 kPa. A novel model which takes into account distributions of the dissociative adsorption and incorporation rates has been developed. The rates of the elementary stages have been calculated. The rate determining stages for a La2NiO(4+/-delta) polycrystalline specimen have been discussed. The diffusion activation energies calculated using the gas phase equilibration method (1.4 eV) differ significantly from those calculated using isotope exchange depth profiling (0.5-0.8 eV), which was attributed to the influence of different oxygen diffusion pathways. PMID- 26971567 TI - An uncommon response to metronomic therapy in a heavily pretreated patient with metastatic carcinosarcoma: a case report. AB - BACKGROUND: Uterine carcinosarcoma is well known for its aggressive behavior. There is little evidence regarding the gold standard combination chemotherapy in metastatic or locally advanced carcinosarcoma, due to poor survival outcomes obtained with conventional scheduled chemotherapy. This case report represents the first-ever reported objective response to a metronomic chemotherapy regimen and adds to the current literature. CASE PRESENTATION: We describe a case of a Caucasian woman diagnosed with metastatic carcinosarcoma that had already been treated with multiple lines of conventional chemotherapy, with progressive disease. This patient had a surprising clinical and imaging response when treated with oral metronomic cyclophosphamide. CONCLUSIONS: We reviewed the mechanism of action implicated in metronomic chemotherapy, and correlated it with the biology of disease in carcinosarcoma. This information may add to the current literature, providing important insights to future clinical trials in this patient population. PMID- 26971569 TI - Intercalation Compounds as Inner Reference Electrodes for Reproducible and Robust Solid-Contact Ion-Selective Electrodes. AB - With billions of assays performed every year, ion-selective electrodes (ISEs) provide a simple and fast technique for clinical analysis of blood electrolytes. The development of cheap, miniaturized solid-contact (SC-)ISEs for integrated systems, however, remains a difficult balancing act between size, robustness, and reproducibility, because the defined interface potentials between the ion selective membrane and the inner reference electrode (iRE) are often compromised. We demonstrate that target cation-sensitive intercalation compounds, such as partially charged lithium iron phosphate (LFP), can be applied as iREs of the quasi-first kind for ISEs. The symmetrical response of the interface potentials towards target cations ultimately results in ISEs with high robustness towards the inner filling (ca. 5 mV dec(-1) conc.) as well as robust and miniaturized SC ISEs. They have a predictable and stable potential derived from the LiFePO4/FePO4 redox couple (97.0+/-1.5 mV after 42 days). PMID- 26971570 TI - Universal features of fluctuations in globular proteins. AB - Using data from 2000 non-homologous protein crystal structures, we show that the distribution of residue B factors of proteins collapses onto a single master curve. We show by maximum entropy arguments that this curve is a Gamma function whose order and dispersion are obtained from experimental data. The distribution for any given specific protein can be generated from the master curve by a linear transformation. Any perturbation of the B factor distribution of a protein, imposed at constant energy, causes a decrease in the entropy of the protein relative to that of the reference state. Proteins 2016; 84:721-725. (c) 2016 Wiley Periodicals, Inc. PMID- 26971571 TI - A role for fungi as parasites in the black box of marine trophic interactions. AB - The role of microbial parasites in aquatic environments remains under investigated and likely under-estimated limiting our understanding of trophic interactions and biogeochemical cycles (Lefevre et al., ; Worden et al., ). All natural interactions between microbes are difficult to capture and study but those occurring in the open ocean more so, because the scale and the complexity of the system makes repeat sampling a challenge. Lepere and colleagues, by combining a range of cell recovery and detection techniques, have identified parasitic interactions between putative fungi and eukaryotic algae (Lepere et al., ) allowing us to peer into the black box of microbial parasitism in the marine water column. PMID- 26971572 TI - Bacteriophage application to control the contaminated water with Shigella. AB - Shigella is one of the most important waterborne and foodborne pathogens around the world. Emergence of antibiotic-resistant Shigella has made the development of alternatives to conventional antibiotics necessary. In this study, a virulent Myoviridae bacteriophage, pSs-1 was isolated from environmental water in South Korea and showed infectivity to S. flexneri as well as S. sonnei strains. One step growth analysis showed that pSs-1 has a short latent period (25 min) and a large burst size (97 PFU/cell). According to the genomic analysis, pSs-1 contains 164,999 bp of genome with a G + C content of 35.54% and it is considered as a member of the T4-like bacteriophage group. These results showed that pSs-1 may have potential as a biocontrol agent instead of conventional antibiotics for shigellosis. PMID- 26971573 TI - Targeting neurotransmitter receptors with nanoparticles in vivo allows single molecule tracking in acute brain slices. AB - Single-molecule imaging has changed the way we understand many biological mechanisms, particularly in neurobiology, by shedding light on intricate molecular events down to the nanoscale. However, current single-molecule studies in neuroscience have been limited to cultured neurons or organotypic slices, leaving as an open question the existence of fast receptor diffusion in intact brain tissue. Here, for the first time, we targeted dopamine receptors in vivo with functionalized quantum dots and were able to perform single-molecule tracking in acute rat brain slices. We propose a novel delocalized and non inflammatory way of delivering nanoparticles (NPs) in vivo to the brain, which allowed us to label and track genetically engineered surface dopamine receptors in neocortical neurons, revealing inherent behaviour and receptor activity regulations. We thus propose a NP-based platform for single-molecule studies in the living brain, opening new avenues of research in physiological and pathological animal models. PMID- 26971575 TI - Survey of 2014 behavioral management programs for laboratory primates in the United States. AB - The behavioral management of laboratory nonhuman primates in the United States has not been thoroughly characterized since 2003. This article presents the results of a survey behavioral management programs at 27 facilities and covering a total of 59,636 primates, 27,916 housed in indoor cages and 31,720 in group enclosures. The survey included questions regarding program structure, implementation, and methodology associated with social housing, positive reinforcement training, positive human interaction, exercise enclosures, and several categories of inanimate enrichment. The vast majority of laboratory primates are housed socially (83%). Since 2003, the proportion of indoor-housed primates reported to be housed singly has fallen considerably, from 59% to 35% in the facilities surveyed. The use of social housing remains significantly constrained by: 1) research protocol requirements, highlighting the value of closely involved IACUCs for harmonizing research and behavioral management; and 2) the unavailability of compatible social partners, underscoring the necessity of objective analysis of the methods used to foster and maintain compatibility. Positive reinforcement training appears to have expanded and is now used at all facilities responding to the survey. The use of enrichment devices has also increased in the participating facilities. For most behavioral management techniques, concerns over the possibility of negative consequences to animals are expressed most frequently for social housing and destructible enrichment, while skepticism regarding efficacy is limited almost exclusively to sensory enrichment. Behavioral management program staffing has expanded over time in the facilities surveyed, due not only to increased numbers of dedicated behavioral management technicians but also to greater involvement of animal care technicians, suggesting an increase in the integration of behavioral care into animal husbandry. Broad awareness of common practice may assist facilities with program evaluation and assessment of progress in the field can generate recommendations for continuing the advancement of primate behavioral management programs. Am. J. Primatol. 78:780-796, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26971574 TI - Holliday Junction Thermodynamics and Structure: Coarse-Grained Simulations and Experiments. AB - Holliday junctions play a central role in genetic recombination, DNA repair and other cellular processes. We combine simulations and experiments to evaluate the ability of the 3SPN.2 model, a coarse-grained representation designed to mimic B DNA, to predict the properties of DNA Holliday junctions. The model reproduces many experimentally determined aspects of junction structure and stability, including the temperature dependence of melting on salt concentration, the bias between open and stacked conformations, the relative populations of conformers at high salt concentration, and the inter-duplex angle (IDA) between arms. We also obtain a close correspondence between the junction structure evaluated by all atom and coarse-grained simulations. We predict that, for salt concentrations at physiological and higher levels, the populations of the stacked conformers are independent of salt concentration, and directly observe proposed tetrahedral intermediate sub-states implicated in conformational transitions. Our findings demonstrate that the 3SPN.2 model captures junction properties that are inaccessible to all-atom studies, opening the possibility to simulate complex aspects of junction behavior. PMID- 26971576 TI - Atomic visualization of a flipped-back conformation of bisected glycans bound to specific lectins. AB - Glycans normally exist as a dynamic equilibrium of several conformations. A fundamental question concerns how such molecules bind lectins despite disadvantageous entropic loss upon binding. Bisected glycan, a glycan possessing bisecting N-acetylglucosamine (GlcNAc), is potentially a good model for investigating conformational dynamics and glycan-lectin interactions, owing to the unique ability of this sugar residue to alter conformer populations and thus modulate the biological activities. Here we analyzed bisected glycan in complex with two unrelated lectins, Calsepa and PHA-E. The crystal structures of the two complexes show a conspicuous flipped back glycan structure (designated 'back fold' conformation), and solution NMR analysis also provides evidence of 'back fold' glycan structure. Indeed, statistical conformational analysis of available bisected and non-bisected glycan structures suggests that bisecting GlcNAc restricts the conformations of branched structures. Restriction of glycan flexibility by certain sugar residues may be more common than previously thought and impinges on the mechanism of glycoform-dependent biological functions. PMID- 26971577 TI - Changes in neurotransmitter levels and expression of immediate early genes in brain of mice infected with Neospora caninum. AB - Neospora caninum is an obligate intracellular parasite that causes neurological disorders in dogs and cattle. The majority of host animals are asymptomatic at the chronic stage of infection. However, it remains unclear whether cerebral function is normal in asymptomatic animals. In this study, mice were infected with N. caninum (strain Nc-1) and their brains were examined to understand changes in cerebral function at the chronic stage of infection. Mice infected with N. caninum showed impaired locomotor activity, but no differences in clinical symptoms were observed. In the brains of infected mice, parasites were distributed throughout the brain and histological lesions were observed everywhere except for the cerebellum. Expression levels of proinflammatory cytokines, interferon-gamma and tumour necrosis factor-alpha, were highly upregulated in several brain regions of infected mice. Additionally, the level of neurotransmitters glutamate, glycine, gamma-aminobutyric acid, dopamine and 5 hydroxytryptamine, were altered in infected mice compared with those of uninfected mice. Interestingly, the expression levels of immediately early genes, c-Fos and Arc, in the brain of infected mice were lower than those of in uninfected mice. Our findings may provide insight into neurological disorders associated with N. caninum infection. PMID- 26971578 TI - Polymorphisms of the IL27 gene in a Chinese Han population complicated with pre eclampsia. AB - IL-27 could inhibit the development of Th17 cells, and the Th17/regulatory T-cell imbalance may reverse maternal tolerance in pre-eclampsia (PE). The aim of this study was to investigate the association between genetic polymorphisms in IL27 with PE. Three SNPs in IL27 (rs153109, rs17855750, and rs181206) were genotyped in a Chinese Han cohort of 1040 PE patients and 1247 normal pregnant women using the TaqMan allelic discrimination real-time PCR method. The CC genotypic distribution of rs153109 was significantly higher among cases than controls (19.1% versus 13.3%, odds ratio [OR]: 1.54, 95% confidence interval [CI]: 1.23 1.93, p < 0.001), and the CT genotype was found to be significantly lower in cases than controls (41.7% versus 49.0%, OR: 0.74, 95% CI: 0.63-0.88, p < 0.001), disputing existing reports indicating the allele frequency of rs153109 is not significantly different between PE patients and controls. Additionally, the CC genotype of rs153109 was significantly more prevalent in PE cases than controls using a recessive model (p < 0.001). The allelic and genotypic frequencies of rs17855750 and rs181206 were not significantly different between two groups. Our results reveal that IL27 polymorphisms may be involved in the development of PE in Chinese Han population. PMID- 26971579 TI - Presenilin adopts the ClC channel fold. AB - Presenilin is an integral membrane aspartate protease that regulates cellular processes by cleaving proteins within the cell membrane. The recent crystal structure of presenilin reveals a conspicuous pore in a bundle of nine alpha helices, which was originally thought to adopt a novel protein fold. However, here I show that the presenilin fold is a variant of the ClC chloride channel/transporter fold. This observation may have important implications for presenilin's postulated biological role as a calcium leak channel. PMID- 26971582 TI - Pelvic Examination at the 6-Week Postpartum Visit After Cesarean Birth. AB - INTRODUCTION: The objective of this study was to assess the utility of the pelvic examination at the 6-week postpartum visit after cesarean birth. METHODS: Data were collected from retrospective chart review in an obstetric resident clinic in Detroit, Michigan. Women included were those who had a cesarean birth between January 2012 and June 2014. RESULTS: Of 388 women who had a cesarean birth, 211 (54.4%) presented for the 6-week postpartum visit and underwent pelvic examination. Of these women, 185 (87.7%) were asymptomatic, and 26 (12.3%) reported vaginal discharge. No other concerns were elicited. Of those with symptoms, 4 (15%) had no finding, 13 (50%) had bacterial vaginosis (BV) alone, 2 (8%) had BV and Candida sp, 2 (8%) had BV and Trichomonas vaginalis, 2 (8%) had T vaginalis alone, and 3 (11%) had Chlamydia trachomatis. One woman with C trachomatis had tested positive during pregnancy and possibly had treatment failure. Of the 185 asymptomatic women, 91 (49%) were deemed to have vaginal discharge on examination and underwent testing for Neisseria gonorrhoeae and C trachomatis; results were negative in all cases. DISCUSSION: In this population, it appears unnecessary to perform routine pelvic examination on asymptomatic women at the 6-week postpartum visit after cesarean birth. When vaginal discharge was noted during pelvic examination of asymptomatic women, no pathology was identified. PMID- 26971581 TI - Safety and efficacy of rapid (1,000 mg in 1 hr) intravenous iron dextran for treatment of maternal iron deficient anemia of pregnancy. AB - Maternal iron deficiency anemia (IDA) is associated with risk of adverse perinatal outcomes. Oral iron is recommended to reverse anemia, but has gastrointestinal toxicity and frequent non-adherence. Intravenous (IV) iron is reserved for intolerance of, or unresponsiveness to, oral therapy, malabsorption, and severe anemia (1% with hemoglobin [Hgb] levels <7 g/dL). With rare (<100 per one million) adverse events (AEs) ability to infuse a sufficient dose of low molecular weight iron dextran (LMWID) over 60 min, LMWID is an attractive option. This study demonstrated safety and efficacy of rapid IV infusion of 1,000 mg LMWID to gravidas with moderate to severe IDA. An observational treatment study of 1,000 mg LMWID administered over 1 hr for IDA in 189 consecutive, unselected second and third trimester gravidas after oral iron failure was conducted. All received a test dose of 25 mg LMWID and were monitored for AEs during the 60-min infusion. No premedication was administered unless more than one drug allergy or asthma was present in which case IV methylprednisolone was administered. All were followed through pregnancy and delivery. Monitored parameters included Hgb, mean corpuscular volume, serum ferritin, and percent transferrin saturation. About 189 subjects received 1,000 mg LMWID. No serious AEs occurred. About 2% experienced transient infusion reactions. Hgb improved by 1-1.9 g/dL in 82% and >=2 g/dL in 24%. Second trimester treatment was not associated with greater Hgb improvement than third trimester treatment. Anemia resolved in 95%. Administration of a single large dose of IV LMWID was effective, safe, and convenient. Am. J. Hematol. 91:590-593, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26971580 TI - Pdgfra and Pdgfrb genetically interact during craniofacial development. AB - BACKGROUND: One of the most prevalent congenital birth defects is cleft palate. The palatal skeleton is derived from the cranial neural crest and platelet derived growth factors (Pdgf) are critical in palatogenesis. Of the two Pdgf receptors, pdgfra is required for neural crest migration and palatogenesis. However, the role pdgfrb plays in the neural crest, or whether pdgfra and pdgfrb interact during palatogenesis is unclear. RESULTS: We find that pdgfrb is dispensable for craniofacial development in zebrafish. However, the palatal defect in pdgfra;pdgfrb double mutants is significantly more severe than in pdgfra single mutants. Data in mouse suggest this interaction is conserved and that neural crest requires both genes. In zebrafish, pdgfra and pdgfrb are both expressed by neural crest within the pharyngeal arches, and pharmacological analyses demonstrate Pdgf signaling is required at these times. While neither proliferation nor cell death appears affected, time-lapsed confocal analysis of pdgfra;pdgfrb mutants shows a failure of proper neural crest condensation during palatogenesis. CONCLUSIONS: We provide data showing that pdgfra and pdgfrb interact during palatogenesis in both zebrafish and mouse. In zebrafish, this interaction affects proper condensation of maxillary neural crest cells, revealing a previously unknown interaction between Pdgfra and Pdgfrb during palate formation. Developmental Dynamics 245:641-652, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26971583 TI - Diagnosis of eight groups of xeroderma pigmentosum by genetic complementation using recombinant adenovirus vectors. AB - Because patients with xeroderma pigmentosum (XP) must avoid ultraviolet (UV) light from an early age, an early diagnosis of this disorder is essential. XP is composed of seven genetic complementation groups, XP-A to -G, and a variant type (XP-V). To establish an easy and accurate diagnosis of the eight disease groups, we constructed recombinant adenoviruses that expressed one of the XP cDNA. When fibroblasts derived from patients with XP-A, -B, -C, -D, -F or -G were infected with the adenovirus expressing XPA, XPB, XPC, XPD, XPF or XPG, respectively, and UV-C at 5-20 J/m2 was irradiated, cell viability was clearly recovered by the corresponding recombinant adenoviruses. In contrast, XP-E and XP-V cells were not significantly sensitive to UV irradiation and were barely complemented by the matched recombinant adenoviruses. However, co-infection of Ad-XPA with Ad-XPE increased survival rate of XP-E cells after UV-C exposure. When XP-V cell strains, including one derived from a Japanese patient, were infected with Ad XPV, exposed to UV-B and cultured with 1 mmol/L of caffeine, flow cytometry detected a characteristic decrease in the S phase in all the XP-V cell strains. From these results, the eight groups of XP could be differentiated by utilizing a set of recombinant adenoviruses, indicating that our procedure provides a convenient and correct diagnostic method for all the XP groups including XP-E and XP-V. PMID- 26971585 TI - Scleromyxedema without paraproteinemia. PMID- 26971584 TI - Exhalation of volatile organic compounds during hemorrhagic shock and reperfusion in rats: an exploratory trial. AB - Ischemia and reperfusion alter metabolism. Multi-capillary column ion-mobility spectrometry (MCC-IMS) can identify volatile organic compounds (VOCs) in exhaled gas. We therefore used MCC-IMS to evaluate exhaled gas in a rat model of hemorrhagic shock with reperfusion. Adult male Sprague-Dawley rats (n = 10 in control group, n = 15 in intervention group) were anaesthetized and ventilated via tracheostomy for 14 h or until death. Hemorrhagic shock was maintained for 90 min by removing blood from the femoral artery to a target of MAP 35 +/- 5 mmHg, and then retransfusing the blood over 60 min in 15 rats; 10 control rats were evaluated without shock and reperfusion. Exhaled gas was analyzed with MCC-IMS, VOCs were identified using the BS-MCC/IMS analytes database (Version 1209). VOC intensities were analyzed at the end of shock, end of reperfusion, and after 9 h. All normotensive animals survived the observation period, whereas mean survival time was 11.2 h in shock and reperfusion animals. 16 VOCs differed significantly for at least one of the three analysis periods. Peak intensities of butanone, 2 ethyl-1-hexanol, nonanal, and an unknown compound were higher in shocked than normotensive rats, and another unknown compound increased over the time. 1 butanol increased only during reperfusion. Acetone, butanal, 1.2-butandiol, isoprene, 3-methylbutanal, 3-pentanone, 2-propanol, and two unknown compounds were lower and decreased during shock and reperfusion. 1-pentanol and 1-propanol were significant greater in the hypotensive animals during shock, were comparable during reperfusion, and then decreased after resuscitation. VOCs differ during hemorrhagic shock, reperfusion, and after reperfusion. MCC-IMS of exhaled breath deserves additional study as a non-invasive approach for monitoring changes in metabolism during ischemia and reperfusion. PMID- 26971586 TI - Bacteriophages to reduce gut carriage of antibiotic resistant uropathogens with low impact on microbiota composition. AB - Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections (UTIs) worldwide, causing over 150 million clinical cases annually. There is currently no specific treatment addressing the asymptomatic carriage in the gut of UPEC before they initiate UTIs. This study investigates the efficacy of virulent bacteriophages to decrease carriage of gut pathogens. Three virulent bacteriophages infecting an antibiotic-resistant UPEC strain were isolated and characterized both in vitro and in vivo. A new experimental murine model of gut carriage of E. coli was elaborated and the impact of virulent bacteriophages on colonization levels and microbiota diversity was assessed. A single dose of a cocktail of the three bacteriophages led to a sharp decrease in E. coli levels throughout the gut. We also observed that microbiota diversity was much less affected by bacteriophages than by antibiotics. Therefore, virulent bacteriophages can efficiently target UPEC strains residing in the gut, with potentially profound public health and economic impacts. These results open a new area with the possibility to manipulate specifically the microbiota using virulent bacteriophages, which could have broad applications in many gut-related disorders/diseases and beyond. PMID- 26971587 TI - Structure and quality of outpatient care for people living with an HIV infection. AB - Policy-makers and clinicians are faced with a gap of evidence to guide policy on standards for HIV outpatient care. Ongoing debates include which settings of care improve health outcomes, and how many HIV-infected patients a health-care provider should treat to gain and maintain expertise. In this article, we evaluate the studies that link health-care facility and care provider characteristics (i.e., structural factors) to health outcomes in HIV-infected patients. We searched the electronic databases MEDLINE, PUBMED, and EMBASE from inception until 1 January 2015. We included a total of 28 observational studies that were conducted after the introduction of combination antiretroviral therapy in 1996. Three aspects of the available research linking the structure to quality of HIV outpatient care were evaluated: (1) assessed structural characteristics (i.e., health-care facility and care provider characteristics); (2) measures of quality of HIV outpatient care; and (3) reported associations between structural characteristics and quality of care. Rather than scarcity of data, it is the diversity in methodology in the identified studies and the inconsistency of their results that led us to the conclusion that the scientific evidence is too weak to guide policy in HIV outpatient care. We provide recommendations on how to address this heterogeneity in future studies and offer specific suggestions for further reading that could be of interest for clinicians and researchers. PMID- 26971589 TI - Response of a Patient with Severe Thyroid Dermopathy to Combined Multipoint Subcutaneous Injection of Glucocorticoids and Local Excision. PMID- 26971588 TI - Rare case of nephrocalcinosis in the distal tubules caused by hereditary renal hypouricaemia 3 months after kidney transplantation. AB - We report a rare case of nephrocalcinosis caused by hereditary renal hypouricaemia 3 months after kidney transplantation. A 41-year-old man who underwent living-related kidney transplantation from his father was admitted to our hospital for a protocol biopsy; he had a serum creatinine (S-Cr) of 1.37 mg/dL and no proteinuria. Histologically, there was no evidence of rejection or calcineurin inhibitor toxicity, although scattered nephrocalcinosis was observed in the distal tubules. Perioperatively, the patient had a serum uric acid (S-UA) of 1.9 mg/dL with a fractional excretion of uric acid (FEUA) of 29% (normal, <10%) and UA clearance of 26.8 mL/min (normal, 7.3-14.7 mL/min) 3 days after kidney transplantation. The donor also had a relatively low S-UA of 2.4 mg/dL and high FEUA of 10.3%. Subsequent DNA direct sequencing followed by restriction fragment length polymorphism revealed that both the recipient's and donor's urate transporter 1 (URAT1) gene had a heterozygous nonsense mutation in exon 5 (C889T). Further, the immunoreactivity of antibodies for the C terminus of URAT1 revealed a partial deletion. De Galantha and von Kossa staining revealed that the nephrocalcinosis was due to urate crystals and calcium stones. Therefore, we diagnosed hereditary renal hypouricaemia. We directed the patient to avoid hard exercise, drink plenty of water, and alkalize the urine. The 1-year follow-up allograft biopsy showed no evidence of nephrocalcinosis in the distal tubules. This is the first report of nephrocalcinosis in the distal tubules as a diagnostic clue to hereditary renal hypouricaemia. We also review the related literature. PMID- 26971594 TI - Evidence for the Continued Use of Medieval Medical Prescriptions in the Sixteenth Century: A Fifteenth-Century Remedy Book and its Later Owner. AB - This article examines a fifteenth-century remedy book, Oxford, Bodleian Library, Rawlinson c. 299, and describes its collection of 314 medieval medical prescriptions. The recipes are organised broadly from head to toe, and often several remedies are offered for the same complaint. Some individual recipes are transcribed with modern English translations. The few non-recipe texts are also noted. The difference between a remedy book and a leechbook is explained, and this manuscript is situated in relation to other known examples of late medieval medical anthologies. The particular feature that distinguishes Oxford, Bodleian Library, Rawlinson c. 299 from other similar volumes is the evidence that it continued to be used during the sixteenth century. This usage was of two kinds. Firstly, the London lawyer who owned it not only inscribed his name but annotated the original recipe collection in various ways, providing finding-aids that made it much more user-friendly. Secondly, he, and other members of his family, added another forty-three recipes to the original collection (some examples of these are also transcribed). These two layers of engagement with the manuscript are interrogated in detail in order to reveal what ailments may have troubled this family most, and to judge how much faith they placed in the old remedies contained in this old book. It is argued that the knowledge preserved in medieval books enjoyed a longevity that extended beyond the period of the manuscript book, and that manuscripts were read and valued long after the advent of printing. PMID- 26971593 TI - The Preclinical and Clinical Effects of Vilazodone for the Treatment of Major Depressive Disorder. AB - INTRODUCTION: Major depressive disorder (MDD) is the leading cause of disability worldwide, and according to the STAR*D trial, only 33% of patients with MDD responded to initial drug therapy. Augmentation of the leading class of antidepressant treatment, selective serotonin reuptake inhibitors (SSRIs), with the 5-HT1A receptor agonist buspirone has been shown to be effective in treating patients that do not respond to initial SSRI therapy. This suggests that newer treatments may improve the clinical picture of MDD. The US Food and Drug Administration (FDA) approved the antidepressant drug vilazodone (EMD 68843), a novel SSRI and 5-HT1A receptor partial agonist. Vilazodone has a half-life between 20-24 hours, reaches peak plasma concentrations at 3.7-5.3 hours, and is primarily metabolized by the hepatic CYP450 3A4 enzyme system. AREAS COVERED: The authors review the preclinical and clinical profile of vilazodone. The roles of serotonin, the 5-HT1A receptor, and current pharmacotherapy approaches for MDD are briefly reviewed. Next, the preclinical pharmacological, behavioral, and physiological effects of vilazodone are presented, followed by the pharmacokinetic properties and metabolism of vilazodone in humans. Last, a brief summary of the main efficacy, safety, and tolerability outcomes of clinical trials of vilazodone is provided. EXPERT OPINION: Vilazodone has shown efficacy versus placebo in improving depression symptoms in several double-blind, placebo controlled trials. The long-term safety and tolerability of vilazodone treatment has also been established. Further studies are needed that directly compare patients treated with an SSRI (both with and without an adjunctive 5-HT1A partial agonist) versus patients treated with vilaozodone. PMID- 26971595 TI - Re-Inventing Infectious Disease: Antibiotic Resistance and Drug Development at the Bayer Company 1945-80. AB - This paper analyses how research on antibiotic resistance has been a driving force in the development of new antibiotics. Drug resistance, while being a problem for physicians and patients, offers attractive perspectives for those who research and develop new medicines. It imposes limits on the usability of older medicines and simultaneously modifies pathologies in a way that opens markets for new treatments. Studying resistance can thus be an important part of developing and marketing antibiotics. The chosen example is that of the German pharmaceutical company Bayer. Before World War Two, Bayer had pioneered the development of anti-infective chemotherapy, sulpha drugs in particular, but had missed the boat when it came to fungal antibiotics. Exacerbated by the effects of war, Bayer's world market presence, which had been considerable prior to the war, had plummeted. In this critical situation, the company opted for a development strategy that tried to capitalise on the problems created by the use of first generation antibiotics. Part and parcel of this strategy was monitoring what can be called the structural change of infectious disease. In practice, this meant to focus on pathologies resulting from resistance and hospital infections. In addition, Bayer also focused on lifestyle pathologies such as athlete's foot. This paper will follow drug development and marketing at Bayer from 1945 to about 1980. In this period, Bayer managed to regain some of its previous standing in markets but could not escape from the overall crisis of anti-infective drug development from the 1970s on. PMID- 26971596 TI - Hybridising Medicine: Illness, Healing and the Dynamics of Reciprocal Exchange on the Upper Guinea Coast (West Africa). AB - The present article seeks to fill a number of lacunae with regard to the study of the circulation and assimilation of different bodies of medical knowledge in an important cultural contact zone, that is the Upper Guinea Coast. Building upon ongoing research on trade and cultural brokerage in the area, it focuses upon shifting attitudes and practices with regard to health and healing as a result of cultural interaction and hybridisation against the background of growing intra African and Afro-Atlantic interaction from the fifteenth to the late seventeenth century. Largely based upon travel accounts, missionary reports and documents produced by the Portuguese Inquisition, it shows how forms of medical knowledge shifted and circulated between littoral areas and their hinterland, as well as between the coast, the Atlantic and beyond. It shows that the changing patterns of trade, migration and settlement associated with Mande influence and Afro Atlantic exchange had a decisive impact on changing notions of illness and therapeutic trajectories. Over the centuries, cross-cultural, reciprocal borrowing contributed to the development of healing kits employed by Africans and non-African outsiders alike, which were used and brokered by local communities in different locations in the region. PMID- 26971597 TI - Psychogeriatrics in England: Its Route to Recognition by the Government as a Distinct Medical Specialty, c.1970-89. AB - Demographic trends, and older people over 65 years disproportionately occupying beds in psychiatric hospitals, pointed to their increasing clinical needs. Clinical work with older people often required different skills from work with younger people. 'General psychiatrists', nominally working with adults of all ages, usually had little interest in working with older people. By 1977, it was clear to clinical leaders in the field of psychogeriatrics that official recognition of their specialty by the government was essential to ensure service development. Official recognition would provide the means to collect data to identify gaps in services, to obtain information on the implementation of government guidance and to advocate for resources, including ensuring high quality training posts for doctors wanting to specialise in the field. Doctors have traditionally taken the lead in creating new medical specialties, and psychogeriatrics was no exception. However, support fluctuated towards the specialty from the leadership of the Royal College of Psychiatrists. Health service leaders who did not undertake work with older people, were incredulous that others wished to do so. Negotiations between the Royal College of Psychiatrists and the Department of Health and Social Security about recognising psychogeriatrics were convoluted and prolonged. Recognition was achieved in 1989, following intervention by the Royal College of Physicians of London. PMID- 26971598 TI - Malnutrition in a Modernising Economy: The Changing Aetiology and Epidemiology of Malnutrition in an African Kingdom, Buganda c.1940-73. AB - The ecological fecundity of the northern shore of Lake Victoria was vital to Buganda's dominance of the interlacustrine region during the pre-colonial period. Despite this, protein-energy malnutrition was notoriously common throughout the twentieth century. This paper charts changes in nutritional illness in a relatively wealthy, food-secure area of Africa during a time of vast social, economic and medical change. In Buganda at least, it appears that both the causation and epidemiology of malnutrition moved away from the endemic societal causes described by early colonial doctors and became instead more defined by individual position within a rapidly modernising economy. PMID- 26971613 TI - Digitisation, Big Data, and the Future of the Medical Humanities: Text-Mining and the History of Medicine: Big Data, Big Questions? PMID- 26971599 TI - 'Smashed by the National Health'? A Closer Look at the Demise of the Pioneer Health Centre, Peckham. AB - The Pioneer Health Centre, based in South London before and after the Second World War, remains a source of interest for advocates of a positive approach to health promotion in contrast with the treatment of those already ill. Its closure in 1950 for lack of funds has been blamed on the then recently established National Health Service, but this article argues that such an explanation is over simplified and ignores a number of other factors. The Centre had struggled financially during the 1930s and tried to gain support from the Medical Research Council. The Council appeared interested in the Centre before the war, but was less sympathetic in the 1940s. Around the time of its closure and afterwards, the Centre was also involved in negotiations with London County Council; these failed because the Centre's directors would not accept the changes which the Council would have needed to make. Unpublished documents reveal that the Centre's directors were uncompromising and that their approach to the situation antagonised their colleagues. Changes in medical science also worked against the Centre. The success of sulphonamide drugs appeared to render preventive medicine less significant, while the development of statistical techniques cast doubt on the Centre's experimental methods. The Centre was at the heart of the nascent organic farming movement, which opposed the rapid growth of chemical cultivation. But what might be termed 'chemical triumphalism' was on the march in both medicine and agriculture, and the Centre was out of tune with the mood of the times. PMID- 26971614 TI - Reflections. PMID- 26971617 TI - A vaginal drug delivery model. AB - Efficient drug delivery at vaginal cavity is often a challenge owing to its peculiar physiological variations including vast differences in pH. Keeping in view this attribute of the target site, the current work was aimed at developing formulation strategies which could overcome this and successfully deliver molecules like itraconazole through SLNs. Optimized SLNs with the given composition was selected for further development into mucoadhesive and thermosensitive gel. Stearic acid and Compritol 888 (1:1, w/w ratio) as lipid, a mixture of 3% Poloxomer 188 and 0.5% sodium taurocholate as surfactant and organic to aqueous ratio of 10:50 was taken. Carbopol 934 and Pluronic F 127 were taken for the development of gel. Optimized gel exhibited a desired gelling temperature (35 degrees C); viscosity (0.920 PaS) and appreciable in vitro drug release (62.2% in 20 h). MTT assay did not show any cytotoxic effect of the gel. When evaluated in vivo, it did not exhibit any irritation potential despite appreciable bioadhesion. A remarkable decrease in CFUs was also observed in comparison with control and marketed formulation when evaluated in rat infection model. Thus, the proposed study defines the challenges for developing a suitable formulation system overcoming the delivery barriers of the vaginal site. PMID- 26971618 TI - Protective effects of pomegranate peel against hematotoxicity, chromosomal aberrations, and genotoxicity induced by barium chloride in adult rats. AB - CONTEXT: Pomegranate peel (PP) has health benefits including antibacterial, antioxidant, anti-inflammatory, and antimutagenic properties. OBJECTIVE: This study investigated the biochemical composition and protective effects of PP against hematotoxicity and genotoxicity induced by barium chloride (BaCl2) in adult rats. MATERIALS AND METHODS: Adult Wistar rats were divided into four groups of six each: control, barium (67 ppm via drinking water), PP (5% via diet), and their combination during 21 d. Oxidative stress was determined by MDA, AOPP, and antioxidant status: CAT, GPx, GSH, Vit C. Osmotic fragility (OF), chromosomal aberrations (CAs), and micronucleus (MN) assays were also studied. RESULTS: PP showed a rich composition of antioxidant compounds. DPPH test found IC50 value= 5.3 MUg/mL and a high polysaccharides content (315 +/- 5 mg/g of extract). In vivo study showed a decrease in red blood cells (70%) and platelet counts (46%), hemoglobin content (8%), hematocrit percent (7%), and an 80% increase of white blood cells in Ba-treated rats. A reduction in antioxidant status: catalase, glutathione peroxidase activities, glutathione, and vitamin C levels by 31, 21, 28, and 29%, respectively, and an increase in MDA (46%) and AOPP levels (72%) were also observed compared with controls. BaCl2-treatment showed a significant increase in the frequencies of total chromosomal aberrations with abnormal metaphases and micronucleus in bone-marrow cells. Oxidative stress induced by BaCl2 might be the major cause for chromosomal abnormalities leading to DNA damage. DISCUSSION AND CONCLUSION: A decrease in hematotoxic and genotoxic effects induced by PP is due to its powerful antioxidant capacity. PMID- 26971620 TI - Adaptive BP-Dock: An Induced Fit Docking Approach for Full Receptor Flexibility. AB - We present an induced fit docking approach called Adaptive BP-Dock that integrates perturbation response scanning (PRS) with the flexible docking protocol of RosettaLigand in an adaptive manner. We first perturb the binding pocket residues of a receptor and obtain a new conformation based on the residue response fluctuation profile using PRS. Next, we dock a ligand to this new conformation by RosettaLigand, where we repeat these steps for several iterations. We test this approach on several protein test sets including difficult unbound docking cases such as HIV-1 reverse transcriptase and HIV-1 protease. Adaptive BP-Dock results show better correlation with experimental binding affinities compared to other docking protocols. Overall, the results imply that Adaptive BP-Dock can easily capture binding induced conformational changes by simultaneous sampling of protein and ligand conformations. This can provide faster and efficient docking of novel targets for rational drug design. PMID- 26971619 TI - Substituted 2-(2-aminopyrimidin-4-yl)pyridine-4-carboxylates as potent inhibitors of JumonjiC domain-containing histone demethylases. AB - BACKGROUND: Aberrant expression of iron(II)- and 2-oxoglutarate-dependent JumonjiC histone demethylases has been linked to cancer. Potent demethylase inhibitors are drug candidates and biochemical tools to elucidate the functional impact of demethylase inhibition. METHODS & RESULTS: Virtual screening identified a novel lead scaffold against JMJD2A with low-micromolar potency in vitro. Analogs were acquired from commercial sources respectively synthesized in feedback with biological testing. Optimized compounds were transformed into cell permeable prodrugs. A cocrystal x-ray structure revealed the mode of binding of these compounds as competitive to 2-oxoglutarate and confirmed kinetic experiments. Selectivity studies revealed a preference for JMJD2A and JARID1A over JMJD3. CONCLUSION: Virtual screening and rational structural optimization led to a novel scaffold for highly potent and selective JMJD2A inhibitors. PMID- 26971622 TI - Improving the Gene Transfection in Human Embryonic Stem Cells: Balancing with Cytotoxicity and Pluripotent Maintenance. AB - Manipulation of genes in human embryonic stem cells (hESCs) is imperative for their highly potential applications; however, the transduction efficiency remains very low. Although existing evidence revealed the type, size, and zeta potential of vector affect gene transfection efficiency in cells, the systematic study in hESCs is scarce. In this study, using poly(amidoamine) (PAMAM) dendrimers ended with amine, hydroxyl, or carboxyl as model, we tested the influences of size and surface group as well as cytotoxicity and endocytosis on hESC gene transfection. We found that in culture medium of mTeSR the particle sizes of G5, G7, G4.5COOH, and G5OH were around 5 nm and G1 had a smaller size of 3.14 nm. G5 and G7 had a slight and significant positive zeta potential, respectively, whereas G1 was slightly negative, and G4.5COOH and G5OH were significantly negative. We demonstrated that only amine-terminated dendrimers accomplished gene transfection in hESCs, which is greater than that from Lipofectamine 2000 transfection. Ten micromolar G5 had the greatest efficiency and was better than 1000 MUM G1. Only a low concentration (0.5 and 1 MUM) of G7 realized gene delivery. Amine-ended dendrimers, especially with higher generations, were detrimental to the growth and pluripotent maintenance of hESCs. In contrast, similarly sized hydroxyl- and carboxyl-terminated dendrimers exerted much lower cytotoxicity, in which carboxyl terminated dendrimer maintained pluripotency of hESCs. We also confirmed the endocytosis into and significant exocytosis from hESCs using FITC-labeled G5 dendrimer. These results suggested that careful considerations of size, concentration, and zeta potential, particularly the identity and position of groups, as well as minimized exocytosis in the design of a vector for hESC gene delivery are necessary, which helps to better design an effective vector in hESC gene transduction. PMID- 26971623 TI - [(eta(6)-p-cymene)Ru(H2O)3](2+) binding capability of aminohydroxamates - A solution and solid state study. AB - Complex forming capabilities of [(eta(6)-p-cymene)Ru(H2O)3](2+) with aminohydroxamates (2-amino-N-hydroxyacetamide (alpha-alahaH), 3-amino-N hydroxypropanamide (beta-alahaH) and 4-amino-N-hydroxybutanamide (gamma-abhaH)) having the primary amino group in different chelatable position to the hydroxamic function were studied by pH-potentiometry, NMR and MS methods. Formation of stable [O,O] and mixed [O,O][N,N] chelated mono- and dinuclear species is detected in partially slow with alpha-alahaH and beta-alahaH or in fast processes with gamma-abhaH and the formation constants of the complexes present in aqueous solution are reported. Synthesis, spectral (NMR, IR) and ESI mass spectrometric characterization of novel dinuclear alpha-alaninehydroximato complexes containing the half-sandwich type Ru(II) core is described. The crystal and molecular structure of [{(eta(6)-p-cymene)Ru}2(MU(2)-alpha-alahaH-1)(H2O)Br]Br?H2O (1) and [{(eta(6)-p-cymene)Ru}2(MU(2)-alpha-alahaH-1)(H2O)Cl]BF4?H2O (2) was determined by single crystal X-ray diffraction method. In the complexes one half-sandwich core is coordinated by a hydroxamate [O,O] chelate while the other one by [Namino,Nhydroxamate] fashion of the bridging ligand. In both cases the remaining coordination sites of one of the Ru cores are taken by a halide ion whiles the other one by a water molecule. Reaction of 2 with 9-methylguanine indicates the N7 coordination of this simple DNA model. Complexes 1 and 2 were tested for their in vitro cytotoxicity using human-derived cancer cell lines (A2780, MCF-7, SKOV 3, HCT-116, HeLa) and showed no anti-proliferative activity in the micromolar concentration range. PMID- 26971624 TI - Trace Explosives Vapor Generation and Quantitation at Parts per Quadrillion Concentrations. AB - The generation of trace 2,4,6-trinitrotoluene (TNT), cyclotrimethylenetrinitramine (RDX), and pentaerythritol tetranitrate (PETN) vapors using a pneumatically modulated liquid delivery system (PMLDS) coupled to a polytetrafluoroethylene (PTFE) total-consumption micronebulizer is presented. The vapor generator operates in a continuous manner with final vapor concentrations proportional to the explosive concentration in aqueous solution delivered through the nebulizer and the diluent air flow rate. For quantitation of concentrations in the parts per billionvolume (ppbv) to parts per trillionvolume (pptrv) range, Tenax-TA thermal desorption tubes were used for vapor collection with subsequent analysis on a thermal-desorption system programmable-temperature vaporization gas chromatograph (TDS-PTV-GC) with a MU ECD detector. With 30 min sample times and an average sampling rate of 100 mL min(-1), vapor concentrations of 38 pptrv for TNT, 25 pptrv for RDX, and 26 pptrv for PETN were determined. For parts per quadrillionvolume (ppqv) vapor quantitation of TNT and RDX, an online PTV-GC system with a negative-ion chemical ionization mass spectrometer (methane reagent gas) was used for direct sampling and capture of the vapor on the PTV inlet. Vapor concentrations as low as 160 ppqv and 710 ppqv for TNT and RDX were quantified, respectively, with an instrument duty cycle as low as 4 min. PMID- 26971625 TI - Frequency and molecular characterization of invasive isolates of Streptococcus pneumoniae serotypes 6C and 6D in Colombia. AB - INTRODUCTION: Serogroup 6 of Streptococcus pneumoniae initially consisted of the 6A and 6B serotypes, but in recent years, the 6C and 6D serotypes were reported. The aim of this study was to determine the frequency and molecular characterization of invasive S. pneumoniae isolates serotypes 6C and 6D in Colombia, from 1994 to 2013. METHODOLOGY: All the isolates recovered during the surveillance from 1994 to 2013, and identified as 6A or 6B, were re-tested to detect the serotypes 6C and 6D. The serotyping was performed using the Quellung reaction and PCR. The susceptibility testing was performed on penicillin, erythromycin, ceftriaxone, trimethoprim/sulfamethoxazole, chloramphenicol, tetracycline and vancomycin. Molecular typing was performed using pulsed-field gel electrophoresis and multilocus sequence typing. RESULTS: From a total of 271 and 350 isolates serotyped previously as serotypes 6A and 6B, 61 (22.5%) and 15 (4.3%) were recognized as 6C and 6D, respectively. Isolates presented with low resistance to antimicrobials. Serotype 6C isolates were mainly associated with ST9007 (42.6%) and ST9008 (19.7%), and serotype 6D isolates with ST1135 (80%). CONCLUSION: This study showed the circulation of serotype 6C and 6D in Colombia between 1994 and 2013, information that is important to determine the dynamics of these recently described serotypes. PMID- 26971621 TI - Opposing effects of atropine and timolol on the color and luminance emmetropization mechanisms in chicks. AB - This study analyzed the luminance and color emmetropization response in chicks treated with the nonselective parasympathetic antagonist atropine and the sympathetic beta-receptor blocker timolol. Chicks were binocularly exposed (8h/day) for 4days to one of three illumination conditions: 2Hz sinusoidal luminance flicker, 2Hz sinusoidal blue/yellow color flicker, or steady light (mean 680lux). Atropine experiments involved monocular daily injections of either 20MUl of atropine (18nmol) or 20MUl of phosphate-buffered saline. Timolol experiments involved monocular daily applications of 2 drops of 0.5% timolol or 2 drops of distilled H2O. Changes in the experimental eye were compared with those in the fellow eye after correction for the effects of saline/water treatments. Atropine caused a reduction in axial length with both luminance flicker (-0.078+/ 0.021mm) and color flicker (-0.054+/-0.017mm), and a reduction in vitreous chamber depth with luminance flicker (-0.095+/-0.023mm), evoking a hyperopic shift in refraction (3.40+/-1.77D). Timolol produced an increase in axial length with luminance flicker (0.045+/-0.030mm) and a myopic shift in refraction ( 4.07+/-0.92D), while color flicker caused a significant decrease in axial length (-0.046+/-0.017mm) that was associated with choroidal thinning (-0.046+/ 0.015mm). The opposing effects on growth and refraction seen with atropine and timolol suggest a balancing mechanism between the parasympathetic and beta receptor mediated sympathetic system through stimulation of the retina with luminance and color contrast. PMID- 26971626 TI - Evaluation of a systems biology approach to identify pharmacological correctors of the mutant CFTR chloride channel. AB - BACKGROUND: Mistrafficking of CFTR protein caused by F508del, the most frequent mutation in cystic fibrosis (CF), can be corrected by cell incubation at low temperature, an effect that may be mediated by altered expression of proteostasis genes. METHODS: To identify small molecules mimicking low temperature, we compared gene expression profiles of cells kept at 27 degrees C with those previously generated from more than 1300 compounds. The resulting candidates were tested with a functional assay on a bronchial epithelial cell line. RESULTS: We found that anti-inflammatory glucocorticoids, such as mometasone, budesonide, and fluticasone, increased mutant CFTR function. However, this activity was not confirmed in primary bronchial epithelial cells. Actually, glucocorticoids enhanced Na(+) absorption, an effect that could further impair mucociliary clearance in CF airways. CONCLUSIONS: Our results suggest that rescue of F508del CFTR by low temperature cannot be easily mimicked by small molecules and that compounds with closer transcriptional and functional effects need to be found. PMID- 26971627 TI - Oxidative stress and glyoxalase I activity mediate dicarbonyl toxicity in MCF-7 mamma carcinoma cells and a tamoxifen resistant derivative. AB - BACKGROUND: Acquired tamoxifen resistance is a significant problem in estrogen receptor positive breast cancer. In a cellular model, tamoxifen resistance was associated with increased sensitivity towards toxic dicarbonyls and reduced free sulfhydryl group content. We here analyzed the role of oxidative stress and glyoxalase I activity on dicarbonyl resistance and the significance of glyoxalase I expression for survival. METHODS: Reactive oxygen species were determined by 2,7-dihydrochlorofluorescein diacetate. Inhibitors for NADPH-oxidase (diphenyleneiodonium), p38 MAPK (SB203580) and ERK1/2 (UO126) were applied to investigate interactions of these signaling molecules. N-acetyl cysteine was used to evaluate the effect of oxidative stress on cell viability, which was assessed by the resazurin assay. Gene expression was analyzed by real time qRT-PCR. Glyoxalase activity was inhibited by the specific inhibitor CS-0683 and siRNA. The relevance of glyoxalase 1 mRNA abundance on survival of breast cancer patients was evaluated by the KM-plotter web interface. RESULTS: alpha-Oxo aldehydes caused an immediate increase in reactive oxygen species where the tamoxifen resistant cell line (TamR) responded at lower concentrations than the MCF-7 parental cell line. Inhibitor studies placed ROS production by NADPH oxidase downstream of p38 MAPK. The antioxidant N-acetyl cysteine (NAC) increased survival, whereas glyoxalase (GLO1) inhibition increased dicarbonyl toxicity. GLO1 mRNA abundance was correlated with unfavorable prognosis of breast cancer patients. CONCLUSIONS: Dicarbonyl toxicity was mediated by oxidative stress and GLO1 activity determines aldehyde toxicity in tamoxifen resistant cells. GENERAL SIGNIFICANCE: Glyoxalases might be predictive biomarkers for tamoxifen resistance and a putative target for the treatment of tamoxifen resistant breast cancer patients. PMID- 26971628 TI - Autophagy ameliorates cognitive impairment through activation of PVT1 and apoptosis in diabetes mice. AB - The underlying mechanisms of cognitive impairment in diabetes remain incompletely characterized. Here we show that the autophagic inhibition by 3-methyladenine (3 MA) aggravates cognitive impairment in streptozotocin-induced diabetic mice, including exacerbation of anxiety-like behaviors and aggravation in spatial learning and memory, especially the spatial reversal memory. Further neuronal function identification confirmed that both long term potentiation (LTP) and depotentiation (DPT) were exacerbated by autophagic inhibition in diabetic mice, which indicating impairment of synaptic plasticity. However, no significant change of pair-pulse facilitation (PPF) was recorded in diabetic mice with autophagic suppression compared with the diabetic mice, which indicated that presynaptic function was not affected by autophagic inhibition in diabetes. Subsequent hippocampal neuronal cell death analysis showed that the apoptotic cell death, but not the regulated necrosis, significantly increased in autophagic suppression of diabetic mice. Finally, molecular mechanism that may lead to cell death was identified. The long non-coding RNA PVT1 (plasmacytoma variant translocation 1) expression was analyzed, and data revealed that PVT1 was decreased significantly by 3-MA in diabetes. These findings show that PVT1 mediated autophagy may protect hippocampal neurons from impairment of synaptic plasticity and apoptosis, and then ameliorates cognitive impairment in diabetes. These intriguing findings will help pave the way for exciting functional studies of autophagy in cognitive impairment and diabetes that may alter the existing paradigms. PMID- 26971629 TI - Electrical stimulation of the parabrachial nucleus induces reanimation from isoflurane general anesthesia. AB - Clinically, emergence from general anesthesia is viewed as a passive process where anesthetics are discontinued at the end of surgery and anesthesiologists wait for the drugs to wear off. The mechanisms involved in emergence are not well understood and there are currently no drugs that can actively reverse the state of general anesthesia. An emerging hypothesis states that brain regions that control arousal become active during emergence and are a key part of the return to wakefulness. In this study, we tested the hypothesis that electrical activation of the glutamatergic parabrachial nucleus (PBN) in the brainstem is sufficient to induce reanimation (active emergence) during continuous isoflurane general anesthesia. Using c-Fos immunohistochemistry as a marker of neural activity, we first show a selective increase in active neurons in the PBN during passive emergence from isoflurane anesthesia. We then electrically stimulated the PBN to assess whether it is sufficient to induce reanimation from isoflurane general anesthesia. Stimulation induced behavioral arousal and restoration of the righting reflex during continuous isoflurane general anesthesia. In contrast, stimulation of the nearby central inferior colliculus (CIC) did not restore the righting reflex. Spectral analysis of the electroencephalogram (EEG) revealed that stimulation produced a significant decrease in EEG delta power during PBN stimulation. The results are consistent with the hypothesis that the PBN provides critical arousal input during emergence from isoflurane anesthesia. PMID- 26971630 TI - Combinatorial Antigen Targeting: Ideal T-Cell Sensing and Anti-Tumor Response. AB - T cells expressing chimeric antigen receptors (CARs) are a formidable platform for the study and application of synthetic biology approaches to study customized and flexible control of cellular functions. Recent reports in the journal Cell provide a new twist on combinatorial antigen targeting, profiting from the singular cleavage and signaling of the Notch receptor to conditionally express CARs. PMID- 26971631 TI - Review on the binding of anticancer drug doxorubicin with DNA and tRNA: Structural models and antitumor activity. AB - In this review, we have compared the results of multiple spectroscopic studies and molecular modeling of anticancer drug doxorubicin (DOX) bindings to DNA and tRNA. DOX was intercalated into DNA duplex, while tRNA binding is via major and minor grooves. DOX-DNA intercalation is close to A-7, C-5, *C-19 (H-bonding with DOX NH2 group), G-6, T-8 and T-18 with the free binding energy of -4.99kcal/mol. DOX-tRNA groove bindings are near A-29, A-31, A-38, C-25, C-27, C-28, *G-30 (H bonding) and U-41 with the free binding energy of -4.44kcal/mol. Drug intercalation induced a partial B to A-DNA transition, while tRNA remained in A family structure. The structural differences observed between DOX bindings to DNA and tRNA can be the main reasons for drug antitumor activity. The results of in vitro MTT assay on SKC01 colon carcinoma are consistent with the observed DNA structural changes. Future research should be focused on finding suitable nanocarriers for delivery of DOX in vivo in order to exploit the full capacity of this very important anticancer drug. PMID- 26971632 TI - Development and evaluation of a real-time method for testing human enteroviruses and coxsackievirus A16. AB - Hand, foot, and mouth disease (HFMD) is a common infectious disease caused by a group of the human enteroviruses (HEV), including coxsackievirus A16 (CA16) and enterovirus 71 (EV71). In recent years, another HEV-A serotype, CA6 or CA10, has emerged to be one of the major etiologic agents that can induce HFMD worldwide. The objective of this study is to develop specific, sensitive, and rapid methods to help diagnose HEV and CA16 specifically by using simultaneous amplification testing (SAT) based on isothermal amplification of RNA and real-time detection of fluorescence technique, which were named as SAT-HEV and SAT-CA16, respectively (SAT-HEV/SAT-CA16). The specificity and sensitivity of SAT were tested here. SAT HEV/SAT-CA16 could measure viral titers that were at least 10-fold lower than those measured by real-time PCR. Non-false cross-reactive amplification indicated that SAT-HEV/SAT-CA16 were highly specific with the addition of internal control (IC) RNA (5000 copies/reaction). A total of 198 clinical specimens were assayed by SAT comparing with real-time PCR. The statistically robust assessment of SAT HEV and HEV-specific real-time PCR plus sequencing reached 99.0% (196/198), with a kappa value of 0.97, and 99.5% (197/198) and a kappa value of 0.99 for CA16, respectively. Additionally, IC prevented false-negative readings and assured the SAT-HEV/SAT-CA16 method's accuracy. Overall, SAT-HEV/SAT-CA16 method may serve as a platform for the simple and rapid detection of HEV/CA16 in time of HFMD outbreak. PMID- 26971633 TI - Elimination of complement interference can improve the diagnostic performance of the VIDAS CMV IgG assay in acute cytomegalovirus infections. AB - In this study we showed that complement factors are responsible for assay interference in the VIDAS cytomegalovirus (CMV) immunoglobulin G (IgG) assay. Three different serum treatments were applied to show the cause of interference: heat treatment (56 degrees C), adding cobra venom factor, and adding EDTA. Elimination of complement interference by EDTA treatment of serum was prospectively evaluated on 215 CMV IgM positive samples and a sensitivity increase of the VIDAS CMV IgG assay was noticed. On average the CMV IgG level increased 100% after EDTA treatment of the serum. In paired serum samples from 38 patients we could show that serum treatment with EDTA can make the CMV IgG level changes more obvious in recent CMV infections. Since the CMV IgG avidity II assay on VIDAS depends on the determination of CMV IgG, the CMV IgG avidity was also evaluated in this study but only a limited effect of the complement interference was observed. PMID- 26971634 TI - Genotypic and phenotypic identification of Aeromonas species and CphA-mediated carbapenem resistance in Queensland, Australia. AB - Infection caused by Aeromonas spp. ranges from superficial wound infection to life-threatening septicemia. Carbapenem resistance due to metallo-beta-lactamase, CphA encoded by the cphA gene, is a significant problem. This study defines Aeromonas spp. causing clinical disease in Queensland, Australia. Phenotypic tests for carbapenemase detection were assessed. One hundred Aeromonas isolates from blood (22), wound (46), sterile sites (11), stool (18), eye (2), and sputum (1) were characterized by rpoB and gyrB sequencing. Meropenem susceptibility by VITEK2, disk diffusion, and E-test MIC were determined. Carbapenemase production was assessed by Carba NP test and cphA by PCR. Gene sequencing identified isolates as Aeromonas dhakensis (39), Aeromonas veronii (21), Aeromonas hydrophila (20), Aeromonas caviae (14), Aeromonas jandaei (4), Aeromonas bestiarum (1), and Aeromonas sanarellii (1). Disk diffusion and E-test failed to detect resistance in isolates with presence of cphA. Carba NP was performed with 97.4% sensitivity and 95.7% specificity. Carbapenem resistance gene cphA was detected in A. veronii (21; 100%), A. hydrophila (18; 90%), A. dhakensis (34; 87.2%), A. jandaei (3; 75%), and A. bestiarum (1; 100%) but not A. caviae. We found that A. dhakensis was the predominant species, a previously unrecognized pathogen in this region. PMID- 26971635 TI - Production of virulence factors in Candida strains isolated from patients with denture stomatitis and control individuals. AB - The aim of this study was to evaluate the production of virulence factors in Candida isolates from the oral cavities of 50 patients with different degrees of denture stomatitis (DS, type I, II and III) and 50 individuals without signs of DS. We evaluated the enzymatic and hemolytic activities, the biofilm formation, and the cell surface hydrophobicity (CSH) in all isolates. Germ tube (GT) production was also evaluated in Candida albicans and Candida dubliniensis isolates. In C. albicans and C. dubliniensis the secretion of hemolysin and GT production was significantly different between isolates from patients with DS and individuals without DS. No significant difference was observed in the production of virulence factors by Candida glabrata isolates. Candida isolates expressed a wide range of virulence factors. However, in the majority of isolates from the type III lesions, the production of the virulence factors was higher than for the other groups. PMID- 26971637 TI - MALDI-TOF mass spectrometry for differentiation between Streptococcus pneumoniae and Streptococcus pseudopneumoniae. AB - We compared the Vitek MS and Microflex MALDI-TOF mass spectrometry platform for species differentiation within the Streptococcus mitis group with PCR assays targeted at lytA, Spn9802, and recA as reference standard. The Vitek MS correctly identified 10/11 Streptococcus pneumoniae, 13/13 Streptococcus pseudopneumoniae, and 12/13 S. mitis/oralis. The Microflex correctly identified 9/11 S. pneumoniae, 0/13 S. pseudopneumoniae, and 13/13 S. mitis/oralis. MALDI-TOF is a powerful tool for species determination within the mitis group. Diagnostic accuracy varies depending on platform and database used. PMID- 26971636 TI - Combined biomarkers discriminate a low likelihood of bacterial infection among surgical intensive care unit patients with suspected sepsis. AB - Among surgical intensive care unit (SICU) patients, it is difficult to distinguish bacterial sepsis from other causes of systemic inflammatory response syndrome (SIRS). Biomarkers have proven useful to identify the presence of bacterial infection. We enrolled a prospective cohort of 69 SICU patients with suspected sepsis and assayed the concentrations of 9 biomarkers (alpha-2 macroglobulin [A2M], C-reactive protein, ferritin, fibrinogen, haptoglobin, procalcitonin [PCT], serum amyloid A, serum amyloid P, and tissue plasminogen activator) at baseline, 24, 48, and 72hours. Forty-two patients (61%) had bacterial sepsis by chart review. A2M concentrations were significantly lower, and PCT concentrations were significantly higher in subjects with bacterial sepsis at 3 of 4 time points. Using optimal cutoff values, the combination of baseline A2M and 72-hour PCT achieved a negative predictive value of 75% (95% confidence interval, 54-96%). The combination of A2M and PCT discriminated bacterial sepsis from other SIRS among SICU patients with suspected sepsis. PMID- 26971638 TI - Diagnostic performance of interferon-gamma release assay for lymph node tuberculosis. AB - The aim of the study was to evaluate the performance of interferon-gamma (IFN gamma) release assay (IGRA) (T-SPOT.TB) for patients with suspected lymph node tuberculosis (TB). Of the 405 patients with suspected lymph node TB, enrolled from Beijing Chest Hospital between July 2011 and April 2015, 83 (20.5%) were microbiologically/histopathologically confirmed lymph node TB, and 282 (69.6%) did not have active TB. The remaining 21 inconclusive TB and 19 clinical TB were excluded from the final analysis (9.9%). T-SPOT.TB using peripheral blood mononuclear cells was performed to examine the IFN-gamma response to the Mycobacterium tuberculosis-specific antigens early secretory antigenic target 6 and culture filtrate protein 10. The overall sensitivity and specificity for T SPOT.TB were 90.4% and 70.5%, respectively. Spot-forming cells in the lymph node TB group (184 [48-596/10(6) peripheral blood mononuclear cells {PBMCs}]) were significantly higher than that in the nonactive TB group (0 [0-41]/10(6) PBMCs) (P<0.001). These results suggest that the IGRA assay could be a useful aid in the diagnosis of lymph node TB. PMID- 26971639 TI - Evaluation of OXA-48 K-Se T: an immunochromatographic assay for rapid detection of OXA-48-producing Enterobacteriaceae. AB - The OXA-48 K-Se T, a new immunochromatographic assay for rapid detection of OXA 48-producing Enterobacteriaceae, has been evaluated in a Spanish Hospital during a 3-month period. A collection of 100 Enterobacteriaceae including 79 isolates producing OXA-48 has been tested. Sensitivity and specificity of 100% were obtained. PMID- 26971640 TI - Assessing next-generation sequencing and 4 bioinformatics tools for detection of Enterovirus D68 and other respiratory viruses in clinical samples. AB - We used 4 different bioinformatics algorithms to evaluate the application of a metagenomic shot-gun sequencing method in detection of Enterovirus D68 and other respiratory viruses in clinical specimens. Our data supported that next generation sequencing, combined with improved bioinformatics tools, is practically feasible and useful for clinical diagnosis of viral infections. PMID- 26971641 TI - Evaluation of matrix-assisted laser desorption ionization-time-of-flight mass spectrometry to differentiate between Candida albicans and Candida dubliniensis. AB - Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) analysis in conjunction with the direct formic acid (FA) sample processing method was evaluated for the ability to differentiate the closely related species of Candida albicans and Candida dubliniensis. The results showed that MALDI-TOF-MS, using the direct FA method, was reliable to differentiate between these species. PMID- 26971642 TI - An innovative photographic database for cutaneous facial defects. AB - OBJECTIVES/HYPOTHESIS: To construct an easy-to-use server-based database that stores photographs of patients undergoing reconstructive surgery for cutaneous facial defects and organizes them in a manner best suited for rapid search and education. STUDY DESIGN: An institutional review board-approved user-modifiable database was designed using OnBase software (Hyland Software Inc., Westlake, OH) to store both the photographs of patients undergoing reconstructive surgery and the pertinent clinical data. METHODS: We designed a database using the OnBase software system (Hyland Software Inc.) to catalog patient data and photographs (pre-, intra-, and postoperative) and allow searches based on key data points. The database operates on three different frames: an upload frame, retrieval frame, and patient document frame. Data entry was based on patients undergoing facial reconstruction of Mohs defects, and upload is in the form of 25 keywords for which data values are entered via dropdown menus. Keyword entry describes defect description, flap nomenclature, flap design, outcomes, and complications. RESULTS: The database allows easy and rapid searches of case examples based on a number of criteria. It allows the user to view multiple examples of different patients with a given defect as defined by location, depth, and size. CONCLUSION: Server-based database systems such as OnBase (Hyland Software Inc.) provide platforms that can be used to create user-friendly photograph and data collection systems. Our database provides a way to educate medical students and surgeons-in training, review personal outcomes, and exercise continued practice-based learning. Implementation of similar databases could potentially be utilized around the globe to facilitate education and self-assessment because OnBase (Hyland Software Inc.) and other similar software platforms are widely available within healthcare systems. Laryngoscope, 2016 Laryngoscope, 126:2451-2455, 2016. PMID- 26971643 TI - Perforation of the Anterior Mitral Leaflet After Impella LP 5.0 Therapy in Cardiogenic Shock. AB - A 52-year old man was admitted with out-of-hospital cardiac arrest, and he was resuscitated after 100 minutes. The initial hemodynamic condition was critical due to cardiogenic shock (left ventricular ejection fraction 10 % and mean arterial pressure 60 mmHg on inotropics). Acute coronary angiography did not reveal any new lesions. Due to persistent hemodynamic instability, mechanical support with Impella LP 5.0 was decided. The surgical procedure guided by fluoroscopy and transesophageal echocardiography was uncomplicated. The hemodynamic improved subsequently and after 17 days of intensive care, and additional 30 days of hospitalization, the patient was ready for discharge. Routine echocardiography prior to discharge revealed severe mitral regurgitation due to perforation of anterior mitral leaflet, a finding not observed in the previous echocardiograms. The patient was discharged to close follow up of the severe mitral regurgitation and future surgical intervention is likely. Therefore, close monitoring of mitral valve is necessary and explanation may be required if valve dysfunction is observed, as repositioning of the Impella system is not possible. PMID- 26971645 TI - [European Code against Cancer: 12 ways to reduce your cancer risk]. AB - Recently, the Word Health Organization/International Agency for Research on Cancer published the 4th edition of European Code against Cancer with 12 personal advices on how to diminish the risk of development of cancer. A proportion of advices refers to risk factors which are connected to our everyday lifestyle; another admonishes to comply with the services offered by the health care system. In Hungary, the European Code has not received adequate publicity so far. As common risk factors play a major role in the development of chronic non communicable diseases, the advice may contribute to the prevention of both cardiovascular diseases and cancer. PMID- 26971644 TI - [Treatment with inhibitors of new oral direct anticoagulants in patients with severe bleedings or urgent surgical procedures. The new dabigatran antidote: the place of idarucizumab in clinical practice]. AB - Only vitamin K antagonists could be applied as oral anticoagulants over the past six decades. Coumarols have narrow therapeutic range, and unpredictable anticoagulant effects are resulted by multiple drug interactions. Therefore, regular routine monitoring of the international normalized ratio is necessary. There are two groups of factor-specific anticoagulants: molecules with anti-FIIa (dabigatran) and anti-FXa (rivaroxaban, apixaban and edoxaban) effect. Author summarizes the most important clinical features of the new oral anticoagulants, their indications and the possibilities of laboratory controls. Bleedings are the most important side effects of anticoagulants. This review summarizes the current published evidences for new oral anticoagulants reversal (non-specific and specific) agents, especially in cases with severe acute bleedings or urgent surgery procedures. It reports on how to use inhibitors, the recommended doses and the most important clinical results. The review focuses on idarucizumab - already approved by the U.S. Food and Drug Administration and the European Medicines Agency - which has a key role as the first specific inhibitor of dabigatran. PMID- 26971648 TI - [Efforts for establishment of obligatory minimal medical fees in 1938 in Sarospatak (Hungary)]. PMID- 26971647 TI - [Monogenic form of diabetes mellitus due to HNF4alpha mutation (MODY-1) - the first case in Hungary]. AB - The classification of diabetes mellitus in adolescents and young adults is often difficult. The diagnosis of the monogenic form of diabetes may have substantial influence on quality of life, prognosis and the choice of the appropriate treatment of affected patients. Among MODY (maturity-onset of diabetes in the young) MODY-1 is rarely detected, only 13 families were described in 2000, and 103 different mutations in 173 families were known in 2013 worldwide. The authors present the first Hungarian case of a monogenic form of diabetes due to HNF4alpha mutation (MODY-1). The diabetes of the index patient No. 1 (42-year-old woman with insulin treated diabetes) was diagnosed as gestational diabetes at age of 20 when she was treated with diet only. Later, insulin treatment has been initiated when marked hyperglycaemia was detected during an episode of acute pneumonia at age of 26. The diabetes of the index patient No. 2 (20-year-old daughter of the index patient No. 1, treated also with insulin) was diagnosed as type 2 diabetes at age of 13 and the patient was treated with diet only. Later the classification was modified to type 1 and insulin therapy was initiated at age of 14. The manifestation of diabetes, the familial occurrence and the low dose insulin requirement were suggestive for monogenic diabetes. Using molecular genetic method a mutation (c.869G>A, p.R290H) of HNF4alpha gene was found and MODY-1 was diagnosed in both cases. Insulin therapy was switched to treatment with low dose sulfanylurea and an excellent glycaemic control was achieved and sustained at follow-up of 1-year. No further positive cases were found during screening of other family members. PMID- 26971646 TI - [A microcost analysis of radiation therapy of localized prostate cancer]. AB - INTRODUCTION: Development of radiation technology provides new opportunities for the treatment of prostate cancer, but little is known about the costs of novel technologies. AIM: The aim of this analysis was to compare the costs of conventional three-dimensional radiation therapy to normal and hypofractionated intensity-modulated radiation therapy for the treatment of localized prostate cancer. METHOD: The cost-analysis was performed based on the data of a Hungarian oncology center from health care provider's perspective. Irradiation time was assessed from the data of 100 fractions delivered in 20 patients. Unit costs for each component were calculated based on actual costs retrieved from the accounting system of the oncology center. RESULTS: Average treatment delivery times were 14.5 minutes for three-dimensional radiation therapy, 16.2 minutes for intensity-modulated radiation therapy with image-guided and 14 minutes without image-guided method. Expected mean cost of patients undergoing conventional three dimensional radiation therapy, normal and hypofractionated intensity-modulated radiation therapy were 619 000 HUF, 933 000 HUF and 692 000 HUF, respectively. CONCLUSIONS: Although normal and hypofractionated intensity-modulated radiation therapies have already been proven to be cost-effective, current reimbursement rates do not encourage healthcare providers to use the more effective therapy techniques. PMID- 26971650 TI - Catheter failure rates and time course with epidural versus combined spinal epidural analgesia in labor. AB - BACKGROUND: The combined spinal-epidural technique for labor analgesia has several advantages over the traditional epidural technique, including faster onset, greater maternal satisfaction, and decreased need for physician boluses. Proponents of the epidural technique criticize the combined spinal-epidural technique, arguing that the epidural catheter remains untested and thus may not be reliable if needed for surgical intervention. We compared failure rates and time of failure between techniques in our tertiary-care academic practice. METHODS: Data regarding failed catheters were collected from October 2012 to September 2014 as part of our Quality Assurance program. Failed catheters were defined as any catheter replaced after it was considered to be properly placed and then determined to be intravascular, one sided or resulting in poor maternal analgesia or anesthesia. RESULTS: A total of 5487 analgesics were performed (3980 combined spinal-epidural; 1507 epidural). Eighty-five combined spinal-epidural catheters (2.1%) and 59 epidural catheters (3.9%) were replaced during labor (P<0.001). Mean time to replacement was 512+/-422min and 354+/-300min for the combined spinal-epidural (n=80) and epidural (n=57) groups, respectively (P=0.02). Median time to replacement was 398 [IQR 131-578] min and 281 [IQR 186 767] min for combined spinal-epidural and epidural groups, respectively (P<0.0001). CONCLUSION: We were able to demonstrate that catheters placed using a combined spinal-epidural technique were less likely to fail during labor and that the time to detection of a failed catheter was significantly longer in the combined spinal-epidural group. Our findings validate the combined spinal epidural technique as reliable for labor analgesia and tend to refute the theory of the untested catheter. PMID- 26971651 TI - Hematomyelia after spinal anesthesia due to incorrect interspace identification using Tuffier's line in a pregnant woman at term. PMID- 26971652 TI - Cytokines in the perinatal period - Part II. AB - A contemporary, robust immunologic explanation for common obstetric conditions remains elusive; why some pregnant women are more susceptible to developing preeclampsia or preterm labor is not completely understood. We explore the immunology behind four important and commonly encountered pregnancy-related conditions: preeclampsia, recurrent miscarriage, preterm labor and gestational diabetes. For each condition, we summarize the current understanding of cytokines implicated in the pathogenesis, discuss the impact of anesthesia and analgesia on selected cytokine profiles, and suggest potential opportunities for clinical and research interventions. PMID- 26971653 TI - The changing US health-care landscape: opportunities and challenges. PMID- 26971654 TI - Myasthenia gravis: subgroup classifications. PMID- 26971655 TI - Myasthenia gravis: subgroup classifications. PMID- 26971656 TI - Myasthenia gravis: subgroup classifications - Authors' reply. PMID- 26971657 TI - South Africa: stroke units out of the blue. PMID- 26971658 TI - Philip B Gorelick: changing neurological practice in the USA. PMID- 26971659 TI - Cruveilhier versus Charcot. PMID- 26971660 TI - Michael Privitera. PMID- 26971662 TI - Idiopathic rapid eye movement sleep behaviour disorder: diagnosis, management, and the need for neuroprotective interventions. AB - Idiopathic rapid eye movement (REM) sleep behaviour disorder (IRBD) manifests as unpleasant dreams and vigorous behaviours during REM sleep that can result in injuries. Patients with IRBD have no known neurological diseases or motor or cognitive complaints; however, this sleep disorder is not harmless. In most cases, IRBD is the prelude of the synucleinopathies Parkinson's disease, dementia with Lewy bodies, or, less frequently, multiple system atrophy. Patients can show abnormalities that are characteristic of the synucleinopathies, and longitudinal follow-up shows that most patients develop parkinsonism and cognitive impairments with time. Thus, diagnosis of IRBD needs to be accurate and involves informing the patient of the risk of developing a neurodegenerative disease. It is extraordinary for a sleep disorder to precede the full expression of a neurodegenerative disease, which renders IRBD of particular interest in studies of the prodromal stage of the synucleinopathies, and in the development of neuroprotective interventions to stop or slow neurodegenerative deterioration before motor and cognitive symptomatology emerges. Such therapeutics do not currently exist, and thus represent an unmet need in IRBD. PMID- 26971663 TI - Adaptation of neurological practice and policy to a changing US health-care landscape. AB - Health care in the USA is undergoing a drastic transformation under the Patient Protection and Affordable Care Act. The Patient Protection and Affordable Care Act is driving major health-care policy changes by connecting payment for traditional health-care services to value-based care initiatives and emphasising population health and innovative mechanisms to deliver care. Under the Patient Protection and Affordable Care Act, neurological practice will need to adapt and transform. Therefore, neurological policy should consider employing a new framework for neurological residency training, developing interdisciplinary team approaches to neurological subspecialty care, and strengthening the primary care neurological specialty care interface to avoid redundancies and other medical waste. Additionally, neurological policy will need to support a more robust review of diagnostic and care pathway use to reduce avoidable expenditures, and test and implement bundled payments for key neurological diagnoses. In view of an anticipated 19% shortage of US neurologists in the next 10 years, development of new neurological policy under the Patient Protection and Affordable Care Act is paramount. PMID- 26971665 TI - The functional response of alginate-gelatin-nanocrystalline cellulose injectable hydrogels toward delivery of cells and bioactive molecules. AB - Hybrid injectable hydrogels comprising of alginate, gelatin, and nanocrystalline cellulose (NCC) were conceived and processed through adaptation of interpenetrated network of alginate-gelatin, ionic crosslinking of alginate, and supramolecular interaction approach. The design of hybrid hydrogels was based on the hypothesis that it provides an environment that is favorable for cell proliferation, exchange of nutrients via porous structure, and are characterized by mechanical properties that closely resemble the native tissue. This aspect is important for the delivery of cells or biomolecules in bone tissue engineering. The hybrid hydrogels exhibited moderate swelling behavior on formation, and the porous structure of hydrogels as imaged via SEM was envisaged to facilitate easy migration of cells and rapid transportation of biomolecules. The hybrid hydrogels exhibited desired mechanical properties and were biocompatible as confirmed though MTT assay of fibroblasts. Interestingly, osteoblasts cultured within hydrogel using bone morphogenetic protein (BMP)-2 demonstrated the capability for encapsulation of cells and induced cell differentiation. The nanocrystalline cellulose significant impacted degradation and interaction between hydrogels and cells. STATEMENT OF SIGNIFICANCE: The study fundamentally explores a hypothesis driven novel hybrid hydrogel that provides an environment for favorable growth and proliferation of cells, exchange of nutrients and mechanical properties that closely match the native tissue. PMID- 26971666 TI - Biomineralization on the wavy substrate: Shape transition of nacreous tablets from pyramids of amorphous nanoparticles to dome-capped prisms of single crystals. AB - Nacre has long served as a model for understanding the biomineralization process and designing bio-inspired materials. However, our current knowledge about nacre is essentially based on the investigation of the flat nacre, where its building blocks, the aragonite tablets, grow on the flat substrate. Here, using field emission scanning (SEM) and transmission electron microscopy (TEM), we investigate a new type of nacre, where the tablets grow on the wavy substrate. We first show that: (1) with growth, the tablet undergoes a shape transition from a pyramid to a frustum and finally to a dome-capped prism; (2) the shape transition occurs earlier at the downslope side of the tablet than at the upslope due to the slope effect; and (3) the shape of the top and base facet of the mature tablet depends on that of the substrate surface. In addition, we report that the tablet initially consists of amorphous calcium carbonate (ACC) nanoparticles, which gradually transforms into a single crystal of aragonite with time. Finally, we propose that the shape transition is induced by the crystal lattice mismatch between the tablet and substrate. We conclude that the topography and strain of the substrate play key roles in the biomineralization process of nacre. STATEMENT OF SIGNIFICANCE: Nacre is the iridescent inner lining of many mollusk shells, consisting of more than 95wt% aragonite tablets and minor biopolymers. Owing to its superior mechanical properties, nacre has been extensively studied. However, nearly all previous works focused on the flat tablets. Here, we focus on the curved tablets grown on the wavy substrate. The main finding is that the topography and strain of the substrate play key roles in the growth process of the tablets. They not only induce the shape transition of the tablets from pyramids to dome-capped prisms, but also control the final shape of the tablets. The finding advances our understanding of the biomineralization process of nacre. PMID- 26971664 TI - Dentin regeneration by stem cells of apical papilla on injectable nanofibrous microspheres and stimulated by controlled BMP-2 release. AB - The aim of this study was to investigate the effects of PLLA nanofibrous microspheres (NF-MS) as a cell delivery carrier in combination with controlled release of BMP-2 from PLGA microspheres on the induction of odontogenic differentiation of human stem cells of apical papilla (SCAP). Injectable NF-MS, which mimic the physical architecture of collagen fibers on the nano scale, were fabricated by combining thermally-induced phase separation techniques with an emulsification process. SCAP cultured in a monolayer or cultured on NF-MS in spinner flasks were treated with 100ng/ml BMP-2 in vitro. Odontogenic differentiation was characterized by measuring alkaline phosphatase activity, odontogenic gene expression levels, calcium content, and dentin sialophosphoprotein accumulation. The results demonstrated that BMP-2 enhanced human SCAP odontogenic differentiation both in monolayer culture and on 3D NF-MS in spinner flask culture in vitro. We also developed and tested a system combining NF-MS with controlled BMP-2 release for dentin regeneration in vivo. The results indicate that controlled release of BMP-2 promoted more mineralization and osteodentin formation compared to a BSA-releasing control in a dose-dependent and time-dependent manner. In summary, the NF-MS combined with controlled release of BMP-2 provides an excellent microenvironment for SCAP to regenerate dentin tissue. STATEMENT OF SIGNIFICANCE: Tooth lesion and loss affect masticatory efficiency, speaking function, facial aesthetics and even psychological health. Current treatments depend on "inert" restorative materials, which do not have the healing capacity and may lead to the failure of the restorations over a long term. The aim of this study was to develop an injectable biomaterial and desired growth factor delivery system to support stem cells for mineralized dental tissue regeneration. The study showed that novel injectable and biodegradable nanofibrous microspheres and controlled release of BMP-2 synergistically induce the odontogenic differentiation of human stem cells from the apical papilla and mineralized tissue regeneration, demonstrating the potential of living dental tissue repair. PMID- 26971667 TI - 3D extracellular matrix interactions modulate tumour cell growth, invasion and angiogenesis in engineered tumour microenvironments. AB - Interactions between tumour cells and extracellular matrix proteins of the tumour microenvironment play crucial roles in cancer progression. So far, however, there are only a few experimental platforms available that allow us to study these interactions systematically in a mechanically defined three-dimensional (3D) context. Here, we have studied the effect of integrin binding motifs found within common extracellular matrix (ECM) proteins on 3D breast (MCF-7) and prostate (PC 3, LNCaP) cancer cell cultures, and co-cultures with endothelial and mesenchymal stromal cells. For this purpose, matrix metalloproteinase-degradable biohybrid poly(ethylene) glycol-heparin hydrogels were decorated with the peptide motifs RGD, GFOGER (collagen I), or IKVAV (laminin-111). Over 14days, cancer spheroids of 100-200MUm formed. While the morphology of poorly invasive MCF-7 and LNCaP cells was not modulated by any of the peptide motifs, the aggressive PC-3 cells exhibited an invasive morphology when cultured in hydrogels comprising IKVAV and GFOGER motifs compared to RGD motifs or nonfunctionalised controls. PC-3 (but not MCF-7 and LNCaP) cell growth and endothelial cell infiltration were also significantly enhanced in IKVAV and GFOGER presenting gels. Taken together, we have established a 3D culture model that allows for dissecting the effect of biochemical cues on processes relevant to early cancer progression. These findings provide a basis for more mechanistic studies that may further advance our understanding of how ECM modulates cancer cell invasion and how to ultimately interfere with this process. STATEMENT OF SIGNIFICANCE: Threedimensional in vitro cancer models have generated great interest over the past decade. However, most models are not suitable to systematically study the effects of environmental cues on cancer development and progression. To overcome this limitation, we have developed an innovative hydrogel platform to study the interactions between breast and prostate cancer cells and extracellular matrix ligands relevant to the tumour microenvironment. Our results show that hydrogels with laminin- and collagen-derived adhesive peptides induce a malignant phenotype in a cell-line specific manner. Thus, we have identified a method to control the incorporation of biochemical cues within a three dimensional culture model and anticipate that it will help us in better understanding the effects of the tumour microenvironment on cancer progression. PMID- 26971668 TI - Genetic determinants for enhanced glycerol growth of Saccharomyces cerevisiae. AB - The yeast Saccharomyces cerevisiae generally shows a low natural capability to utilize glycerol as the sole source of carbon, particularly when synthetic medium is used and complex supplements are omitted. Nevertheless, wild type isolates have been identified that show a moderate growth under these conditions. In the current study we made use of intraspecies diversity to identify targets suitable for reverse metabolic engineering of the non-growing laboratory strain CEN.PK113 1A. A genome-wide genetic mapping experiment using pooled-segregant whole-genome sequence analysis was conducted, and one major and several minor genetic loci were identified responsible for the superior glycerol growth phenotype of the previously selected S. cerevisiae strain CBS 6412-13A. Downscaling of the major locus by fine-mapping and reciprocal hemizygosity analysis allowed the parallel identification of two superior alleles (UBR2CBS 6412-13A and SSK1CBS 6412-13A). These alleles together with the previously identified GUT1CBS 6412-13A allele were used to replace the corresponding alleles in the strain CEN.PK113-1A. In this way, glycerol growth could be established reaching a maximum specific growth rate of 0.08h(-1). Further improvement to a maximum specific growth rate of 0.11h(-1) could be achieved by heterologous expression of the glycerol facilitator FPS1 from Cyberlindnera jadinii. PMID- 26971669 TI - Acetone production with metabolically engineered strains of Acetobacterium woodii. AB - Expected depletion of oil and fossil resources urges the development of new alternative routes for the production of bulk chemicals and fuels beyond petroleum resources. In this study, the clostridial acetone pathway was used for the formation of acetone in the acetogenic bacterium Acetobacterium woodii. The acetone production operon (APO) containing the genes thlA (encoding thiolase A), ctfA/ctfB (encoding CoA transferase), and adc (encoding acetoacetate decarboxylase) from Clostridium acetobutylicum were cloned under the control of the thlA promoter into four vectors having different replicons for Gram-positives (pIP404, pBP1, pCB102, and pCD6). Stable replication was observed for all constructs. A. woodii [pJIR_actthlA] achieved the maximal acetone concentration under autotrophic conditions (15.2+/-3.4mM). Promoter sequences of the genes ackA from A. woodii and pta-ack from C. ljungdahlii were determined by primer extension (PEX) and cloned upstream of the APO. The highest acetone production in recombinant A. woodii cells was achieved using the promoters PthlA and Ppta-ack. Batch fermentations using A. woodii [pMTL84151_actthlA] in a bioreactor revealed that acetate concentration had an effect on the acetone production, due to the high Km value of the CoA transferase. In order to establish consistent acetate concentration within the bioreactor and to increase biomass, a continuous fermentation process for A. woodii was developed. Thus, acetone productivity of the strain A. woodii [pMTL84151_actthlA] was increased from 1.2mgL(-1)h(-1) in bottle fermentation to 26.4mgL(-1)h(-1) in continuous gas fermentation. PMID- 26971670 TI - Patterns of Sacral Sparing Components on Neurologic Recovery in Newly Injured Persons With Traumatic Spinal Cord Injury. AB - OBJECTIVE: To assess the patterns of sacral sparing and recovery in newly injured persons with traumatic spinal cord injury (SCI). DESIGN: Retrospective analysis of data from the national Spinal Cord Injury Model Systems (SCIMS) database for patients enrolled from January 2011 to February 2015. SETTING: SCIMS centers. PARTICIPANTS: Individuals (N=1738; age >=16y) with traumatic SCI admitted to rehabilitation within 30 days after injury with follow-up at discharge, at 1 year, or both. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: International Standards for Neurological Classification of Spinal Cord Injury examination results at admission and follow-up (discharge or 1y, or both). RESULTS: Conversion from an initial American Spinal Injury Association Impairment Scale (AIS) grade A to incomplete status was 20% at rehabilitation discharge and 27.8% at 1 year, and was greater in cervical and low paraplegia levels (T10 and below) than in high paraplegia level injuries (T1-9). Conversion from AIS B to motor incomplete was 33.9% at discharge and 53.6% at 1 year, and the initial sparing of all sacral sensory components was correlated with the greatest conversion to motor incomplete status at discharge and at 1 year. For patients with initial AIS C, the presence of voluntary anal contraction (VAC) in association with other sacral sparing was most frequently observed to improve to AIS D status at discharge. However, the presence of VAC alone as the initial sacral sparing component had the poorest prognosis for recovery to AIS D status. At follow-up, regaining sacral sparing components correlated with improvement in conversion for patients with initial AIS B and C. CONCLUSIONS: The components of initial and follow-up sacral sparing indicated differential patterns of neurologic outcome in persons with traumatic SCI. The more sacral components initially spared, the greater the potential for recovery; and the more sacral components gained, the greater the chance of motor recovery. Consideration of whether VAC should remain a diagnostic criterion sufficient for motor incomplete classification in the absence of other qualifying sublesional motor sparing is recommended. PMID- 26971671 TI - Improving Power and Sample Size Calculation in Rehabilitation Trial Reports: A Methodological Assessment. AB - OBJECTIVE: To systematically assess the reporting of sample size calculation in randomized controlled trials (RCTs) on rehabilitation interventions for mechanical low back pain. DATA SOURCES: The Cochrane Database of Systematic Reviews was searched through February 2015. STUDY SELECTION: We conducted an electronic database search for RCTs published from January 1, 1968 to February 28, 2015 and included in the Cochrane Systematic Reviews. DATA EXTRACTION: Two investigators independently used an ad hoc 6-item checklist derived from the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement recommendations to extract data on sample size calculation. The primary outcome was the proportion of RCTs that reported sample size calculation; the secondary outcome was the completeness of sample size analysis reporting. We also evaluated improvement in reporting of sample size calculation over time. DATA SYNTHESIS: Sample size calculation was reported in 80 (36.0%) of the 222 eligible RCTs included in 14 Cochrane Systematic Reviews. Only 13 (16.3%) of these RCT reports gave a complete description, and about half reported >=4 of the 6 elements of sample size calculation (median, 4; interquartile range, 3-5). Completeness of reporting of sample size calculation improved from 1968 to 2013; since 2005, the number of RCTs reporting sample size calculation has increased compared with the number of RCTs not reporting it. CONCLUSIONS: Despite improvement, reporting of sample size calculation and power analysis remains inadequate, limiting the reader's ability to assess the quality and accuracy of rehabilitation studies. PMID- 26971672 TI - Latent Trigger Points: What Are the Underlying Predictors? AB - OBJECTIVE: To determine the factors predicting the presence and number of latent trigger points (LTrPs) in healthy individuals. DESIGN: Cross-sectional study. SETTING: Local faculty of health sciences. PARTICIPANTS: Healthy individuals (N=242) were divided into 2 groups: group 1, those without LTrPs (n=68); and group 2, those with LTrPs (n=174). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Disability was assessed using the Quick-Disabilities of the Arm, Shoulder, and Hand questionnaire and the Neck Pain and Disability Scale. Psychological factors were evaluated using the Brief Symptom Inventory, the Beck Depression Inventory, the State-Trait Anxiety Inventory, and the Perceived Stress Scale. Quality of life was evaluated using the Short-Form-12; smoking habits were determined with questions about current smoking status; and pain level was assessed using the visual analog scale. The LTrP assessment was made with a pinching movement or flat palpation bilaterally. RESULTS: By using a hierarchical regression model, we entered age, depression, and pain level into the first block, which explained a significant amount of variance in the presence and number of LTrPs (R(2)=.041; P=.033 and R(2)=.197; P<.001, respectively). Pain level contributed independently the presence of LTrPs, whereas age and pain level predicted the number of LTrPs (P<.05). CONCLUSIONS: This study found that pain and age were significant predictors of the number of LTrPs, but only pain predicted the presence of LTrPs in healthy individuals. PMID- 26971675 TI - Oriented-assembly of hollow FePt nanochains with tunable catalytic and magnetic properties. AB - Hollow nanoparticles with large surface areas exhibit a lot of advantages for applications such as catalysis and energy storage. Furthermore, their performance can be manipulated by their deliberate assemblies. Dispersive hollow FePt nanospheres have been assembled into one-dimensional hollow FePt nanochains under the magnetic fields at room temperature. Based on the activation of galvanic replacement at different reaction stages, the size of hollow FePt nanochains can be deliberately manipulated varying from 20 nm to 300 nm, together with the length changing from 200 nm to 10 MUm. The competition between movement of paramagnetic Fe(3+) ions and shape recovering due to thermal fluctuations plays a critical effect on the structure of contact area between hollow nanospheres, leading to perforative structures. Compared with commercial Pt/C, well aligned hollow FePt nanochains show greatly enhanced catalytic activities in the methanol oxidation reaction (MOR) due to more favorable mass flow. Magnetic measurements indicate that the magnetic properties including Curie temperature and saturation magnetization can be tuned by the control of the size and shape of hollow nanochains. PMID- 26971674 TI - [Cost comparison of open and robot-assisted partial nephrectomy in treatment of renal tumor]. AB - INTRODUCTION: Robot-assisted partial nephrectomy rapidly took on among urologists, even though studies showing its superiority over other techniques are still scarce and its costs hard to evaluate, especially in the French medical system. OBJECTIVE: To evaluate the cost overrun of robot-assisted partial nephrectomy compared to that of open partial nephrectomy. EQUIPMENT AND METHODS: From January 2010 to December 2013, 77 patients underwent a partial nephrectomy, 46 of which by robot-assisted laparoscopy and the remaining 31 by lombotomy. The two groups were similar in composition. Economic data regarding the staff, the consumables and the premises involved have been analyzed. RESULTS: Costs are significantly higher in the NPR group (9253.21 euros vs. 7448.42 euros) due to higher consumable expenses as well as the costs pertaining to the amortization and maintenance of the robot. Yet, that difference tends to diminish as the duration of the experiment increases. No significant difference was found in warm ischemia times, operation duration and renal function a month after the operation. On the other hand, patients from the NPR group spent a significantly smaller amount of time in recovery room (159 minutes vs. 205 minutes, P=0.004), presented fewer complications and were discharged faster (6.1 days vs. 8.1 days, P=0.04). CONCLUSIONS: To be profitable for the hospital in the French GHS system, robot-assisted partial nephrectomy must take place in a complex where at least 300 robot-assisted interventions are performed annually, in the framework of a hospitalization lasting four days or less, the use of a single needle holder and no systematic use of a haemostatic agent. LEVEL OF EVIDENCE: 4. PMID- 26971673 TI - Validation of putative reference genes for gene expression studies in heat stressed and alpha-MSH treated melanocyte cells of Bos indicus using real-time quantitative PCR. AB - Normalization of cellular mRNA data using internal reference gene (IRG) is an essential step in expression analysis studies. MIQE guidelines ensure that the choice and appropriateness of IRG should be validated for particular tissues or cell types and specific experimental designs. The objective of the present study was to assess 15 IRGs from different functional classes that could serve as best IRGs for Bos indicus (Tharparkar cattle) melanocyte cells under heat stress and hormonal treatment. We implemented the use of geNorm, NormFinder and BestKeeper algorithm to measure the stability of the gene transcript. A total of 15 IRGs (ACTB, BZM, EEF1, GAPDH, GTP, HMBS, HPRT, RPL22, RPL4, RPS15, RPS18, RPS23, RPS9, UBC and UXT) from different functional classes were evaluated. Pair wise comparisons using geNorm revealed that HPRT and RPS23 were the most stable combination of IRGs with M-value of 0.29 followed by UXT (0.30) and RPL4 (0.31). The NormFinder analysis also identified the same set of stably expressed genes (UXT, RPL4, RPS23 and HPRT); however, the rank order was little different. The UXT gene showed lowest crossing point SD and CV values of 0.30 and 1.17, respectively indicating its maximum expression stability through BestKeeper analysis. The present study indicated that, ACTB and HMB were not reliable IRGs for melanocytes cells on account of their lower expression stability. Current study further revealed that UXT, HPRT and RPS23 are the best IRGs for normalization of qPCR data in Bos indicus melanocyte cells under heat stress and hormonal treatment. PMID- 26971676 TI - Selenium status and risk of prostate cancer in a Danish population. AB - Low-Se status may be associated with a higher risk of notably advanced prostate cancer. In a Danish population with a relatively low Se intake, we investigated the association between pre-diagnostic Se status and (1) the risk of total, advanced and high-grade prostate cancer and (2) all-cause and prostate cancer specific mortality among men with prostate cancer. Within the Danish 'Diet, Cancer and Health' cohort, including 27 179 men, we identified 784 cases with incident prostate cancer through 2007. Each case was risk set-matched to one control. Two-thirds (n 525) of the cases had advanced disease at the time of diagnosis, and among these 170 had high-grade disease; 305 cases died (n 212 from prostate cancer) during follow-up through 2012. Plasma Se was not associated with total or advanced prostate cancer risk, but higher Se levels were associated with a lower risk of high-grade disease (HR 0.77; 95 % CI 0.64, 0.94; P=0.009). In survival analyses, a higher level of plasma Se was associated with a lower risk of all-cause (HR 0.92; 95 % CI 0.85, 1.00; P=0.04), but not prostate cancer specific mortality. Higher levels of selenoprotein P were associated with a lower risk of high-grade disease (HR 0.85; 95 % CI 0.74, 0.97; P=0.01), but not with the risk of or mortality from advanced prostate cancer. In conclusion, levels of plasma Se and selenoprotein P were not associated with the risk of total and advanced prostate cancer, but higher levels of these two biomarkers were associated with a lower risk of high-grade disease. PMID- 26971677 TI - Development of advanced therapies in Italy: Management models and sustainability in six Italian cell factories. AB - On November 10, 2014, the representatives of all six certified Good Manufacturing Practices (GMP) cell factories operating in the Lombardy Region of Italy convened a 1-day workshop in Milan titled "Management Models for the Development And Sustainability of Cell Factories: Public-Private Partnership?" The speakers and panelists addressed not only the many scientific, technological and cultural challenges faced by Lombardy Cell Factories, but also the potential impact of advanced therapy medicinal products (ATMPs) on public health and the role played by translational research in this process. Future perspectives for research and development (R&D) and manufacturing processes in the field of regenerative medicine were discussed as well. This report summarizes the most important issues raised by the workshop participants with particular emphasis on strengths and limitations of the R&D and manufacturing processes for innovative therapeutics in Lombardy and what can be improved in this context while maintaining GMP standards. The participants highlighted several strategies to translate patient specific advanced therapeutics into scaled manufacturing products for clinical application. These included (i) the development of a synergistic interaction between public and private institutions, (ii) better integration with Italian regulatory agencies and (iii) the creation of a network among Lombardy cell factories and other Italian and European institutions. PMID- 26971678 TI - Enhanced neuro-therapeutic potential of Wharton's Jelly-derived mesenchymal stem cells in comparison with bone marrow mesenchymal stem cells culture. AB - Substantial inconsistencies in mesenchymal stem (stromal) cell (MSC) therapy reported in early translational and clinical studies may indicate need for selection of the proper cell population for any particular therapeutic purpose. In the present study we have examined stromal stem cells derived either from umbilical cord Wharton's Jelly (WJ-MSC) or bone marrow (BM-MSC) of adult, healthy donors. The cells characterized in accordance with the International Society for Cellular Therapy (ISCT) indications as well as other phenotypic and functional parameters have been compared under strictly controlled culture conditions. WJ MSC, in comparison with BM-MSC, exhibited a higher proliferation rate, a greater expansion capability being additionally stimulated under low-oxygen atmosphere, enhanced neurotrophic factors gene expression and spontaneous tendency toward a neural lineage differentiation commitment confirmed by protein and gene marker induction. Our data suggest that WJ-MSC may represent an example of immature-type "pre-MSC," where a substantial cellular component is embryonic-like, pluripotent derivatives with the default neural-like differentiation. These cells may contribute in different extents to nearly all classical MSC populations adversely correlated with the age of cell donors. Our data suggest that neuro-epithelial markers, like nestin, stage specific embryonic antigens-4 or alpha-smooth muscle actin expressions, may serve as useful indicators of MSC culture neuro regeneration-associated potency. PMID- 26971679 TI - Isolation and trans-differentiation of mesenchymal stromal cells into smooth muscle cells: Utility and applicability for cell-sheet engineering. AB - BACKGROUND: Bone marrow (BM)-derived mesenchymal stromal cells (MSCs) have shown potential to differentiate into various cell types, including smooth muscle cells (SMCs). The extracellular matrix (ECM) represents an appealing and readily available source of SMCs for use in tissue engineering. In this study, we hypothesized that the ECM could be used to induce MSC differentiation to SMCs for engineered cell-sheet construction. METHODS: Primary MSCs were isolated from the BM of Wistar rats, transferred and cultured on dishes coated with 3 different types of ECM: collagen type IV (Col IV), fibronectin (FN), and laminin (LM). Primary MSCs were also included as a control. The proportions of SMC (a smooth muscle actin [aSMA] and SM22a) and MSC markers were examined with flow cytometry and Western blotting, and cell proliferation rates were also quantified. RESULTS: Both FN and LM groups were able to induce differentiation of MSCs toward smooth muscle-like cell types, as evidenced by an increase in the proportion of SMC markers (aSMA; Col IV 42.3 +/- 6.9%, FN 65.1 +/- 6.5%, LM 59.3 +/- 7.0%, Control 39.9 +/- 3.1%; P = 0.02, SM22; Col IV 56.0 +/- 7.7%, FN 74.2 +/- 6.7%, LM 60.4 +/ 8.7%, Control 44.9 +/- 3.6%) and a decrease in that of MSC markers (CD105: Col IV 64.0 +/- 5.2%, FN 57.6 +/- 4.0%, LM 60.3 +/- 7.0%, Control 85.3 +/- 4.2%; P = 0.03). The LM group showed a decrease in overall cell proliferation, whereas FN and Col IV groups remained similar to control MSCs (Col IV, 9.0 +/- 2.3%; FN, 9.8 +/- 2.5%; LM, 4.3 +/- 1.3%; Control, 9.8 +/- 2.8%). CONCLUSIONS: Our findings indicate that ECM selection can guide differentiation of MSCs into the SMC lineage. Fibronectin preserved cellular proliferative capacity while yielding the highest proportion of differentiated SMCs, suggesting that FN-coated materials may be facilitate smooth muscle tissue engineering. PMID- 26971680 TI - Autologous mesenchymal stromal cell transplantation for spinal cord injury: A Phase I pilot study. AB - BACKGROUND AIMS: Mesenchymal stromal cell (MSC) transplantation has immerged as promising therapeutic approach to treat spinal cord injury (SCI). In this pilot study, we investigated the safety of intrathecal injection of autologous bone marrow-derived MSCs in nine patients with SCI. METHODS: Patients with complete SCI at the thoracic level were divided into two groups: chronic (>6 months, group 1) and sub-acute SCI (<6 months, group 2), according to time elapsed since injury. MSCs were isolated by density gradient separation of autologous bone marrow harvested from the iliac crest. Cells were cultured in a Good Manufacturing Practice-compliant facility to produce clinical scale dose. After quality control testing, MSCs were injected back to patients by intrathecal injection. Safety was defined as absence of adverse event and side effects after 1 month after receiving the injection. RESULTS: Six patients had chronic SCI with a median duration of 33 months since date of injury (range: 10-55 months), and three patients were in sub-acute phase of disease. Each patient received two or three injections with a median of 1.2 * 10(6) MSCs/kg body weight. No treatment related adverse event was observed during median follow-up of 720 days (range: 630-826 days) in group 1 and 366 days (range: 269-367 days) in group 2, respectively. DISCUSSION: This pilot study demonstrated that autologous MSCs can be safely administered through intrathecal injection in spinal cord injury patients. Further investigation through randomized, placebo-controlled trials is needed. PMID- 26971681 TI - Scalability and process transfer of mesenchymal stromal cell production from monolayer to microcarrier culture using human platelet lysate. AB - BACKGROUND AIMS: The selection of medium and associated reagents for human mesenchymal stromal cell (hMSC) culture forms an integral part of manufacturing process development and must be suitable for multiple process scales and expansion technologies. METHODS: In this work, we have expanded BM-hMSCs in fetal bovine serum (FBS)- and human platelet lysate (HPL)-containing media in both a monolayer and a suspension-based microcarrier process. RESULTS: The introduction of HPL into the monolayer process increased the BM-hMSC growth rate at the first experimental passage by 0.049 day and 0.127/day for the two BM-hMSC donors compared with the FBS-based monolayer process. This increase in growth rate in HPL-containing medium was associated with an increase in the inter-donor consistency, with an inter-donor range of 0.406 cumulative population doublings after 18 days compared with 2.013 in FBS-containing medium. Identity and quality characteristics of the BM-hMSCs are also comparable between conditions in terms of colony-forming potential, osteogenic potential and expression of key genes during monolayer and post-harvest from microcarrier expansion. BM-hMSCs cultured on microcarriers in HPL-containing medium demonstrated a reduction in the initial lag phase for both BM-hMSC donors and an increased BM-hMSC yield after 6 days of culture to 1.20 +/- 0.17 * 10(5) and 1.02 +/- 0.005 * 10(5) cells/mL compared with 0.79 +/- 0.05 * 10(5) and 0.36 +/- 0.04 * 10(5) cells/mL in FBS-containing medium. CONCLUSIONS: This study has demonstrated that HPL, compared with FBS containing medium, delivers increased growth and comparability across two BM-hMSC donors between monolayer and microcarrier culture, which will have key implications for process transfer during scale-up. PMID- 26971683 TI - One for all: A standardized protocol for ex vivo culture of limbal, conjunctival and oral mucosal epithelial cells into corneal lineage. AB - BACKGROUND AIMS: Autologous transplantation of ex vivo cultured cells the treatment of choice for patients with limbal stem cell deficiency. The most commonly used cell sources for transplantation limbal, conjunctival or oral mucosal tissue. Protocols vary for culturing each tissue type, and there are no comparative studies on transplantation outcomes using these different culture techniques. To overcome this limitation, we devised a simple protocol that can uniformly promote growth and differentiation of cells from a limbal, conjunctival or oral mucosal biopsy into the corneal lineage. METHODS: Biopsies were cultured as explants on de-epithelialized human amniotic membrane in the presence of recombinant epidermal growth factor and insulin. Cultured cells were characterized using immunohistochemistry and quantitative reverse transcriptase polymerase chain reaction for stem/progenitor markers (ABCG2 and P63alpha) and differentiation markers (CK3, CK12, CK4, CK13, CK15 and CONNEXIN 43). Fluorescence-activated cell sorter analysis was performed for ABCG2. RESULTS: The results revealed that cells of all three biopsies differentiated into the corneal lineage. Positivity of CK3/12, CK4, CK12 and CONNEXIN 43 immunostaining and the relative mRNA expression of CK3, CK4, CK12, CK13, CK15 and CONNEXIN 43 could be detected in the cultured biopsies. CONCLUSIONS: Unlike tissue-specific protocols, our protocol can unequivocally promote differentiation of cells from a limbal, conjunctival or oral mucosal biopsy into the corneal lineage. This simple standardized protocol can be adapted for ocular surface reconstruction using stem cell transplantation. PMID- 26971682 TI - Cardiopulmonary and histological characterization of an acute rat lung injury model demonstrating safety of mesenchymal stromal cell infusion. AB - BACKGROUND AIMS: In the field of cellular therapy, potential cell entrapment in the lungs following intravenous administration in a compromised or injured pulmonary system is an important concern that requires further investigation. We developed a rat model of inflammatory and fibrotic lung disease to mimic the human clinical condition of obliterative bronchiolitis (OB) and evaluate the safety of intravenous infusion of mesenchymal stromal cells (MSCs). This model was used to obtain appropriate safety information and functional characterization to support the translation of an ex vivo-generated cellular product into human clinical trials. To overcome spontaneous recovery and size limitations associated with current animal models, we used a novel multiple dose bleomycin strategy to induce lasting lung injury in rats. METHODS: Intratracheal instillation of bleomycin was administered to rats on multiple days. MSCs were intravenously infused 7 days apart. Detailed pulmonary function tests including forced expiratory volume, total lung capacity, and invasive hemodynamic measurements were conducted to define the representative disease model and monitor cardiopulmonary hemodynamic consequences of the cell infusion. Post-euthanasia assessments included a thorough evaluation of lung morphology and histopathology. RESULTS: The double dose bleomycin instillation regimen resulted in severe and irreversible lung injury and fibrosis. Cardiopulmonary physiological monitoring reveled that no adverse events could be attributed to the cell infusion process. DISCUSSION: Although our study did not show the infusion of MSCs to result in an improvement in lung function or rescue of damaged tissue this study does confirm the safety of MSC infusion into damaged lungs. PMID- 26971684 TI - Wound-healing markers after autologous and allogeneic epithelial-like stem cell treatment. AB - BACKGROUND AIMS: Several cytokines and growth factors play an essential role in skin regeneration and epithelial-like stem cells (EpSCs) have beneficial effects on wound healing in horses. However, there are no reports available on the expression of these growth factors and cytokines after EpSC therapy. METHODS: Wounds of 6 cm(2) were induced in the gluteus region of 6 horses and treated with (i) autologous EpSCs, (ii) allogeneic EpSCs, (iii) vehicle treatment or (iv) untreated control. Real time polymerase chain reaction was performed on tissue biopsies taken 1 and 5 weeks after these treatments to evaluate mRNA expression of interferon (IFN)-gamma, interleukin (IL)-6, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF)-1 and epidermal keratin (eKER). RESULTS: One week after treatments, mRNA levels of IL-6 (P = 0.012) and VEGF (P = 0.008) were higher in allogeneic EpSC-treated wounds compared with controls. Also, mRNA levels of IGF-1 were higher at 1 week in both autologous (P = 0.027) and allogeneic (P = 0.035) EpSC-treated wounds. At week 5, all EpSC- and vehicle-treated wounds demonstrated significantly higher IFN-gamma, VEGF and eKER mRNA expression compared with controls and compared with their respective levels at week 1. CONCLUSIONS: Equine wounds treated with allogeneic EpSCs demonstrate a significant increase in mRNA expression of IL-6, VEGF and IGF 1 in the acute phase. In the longer term, an increase in IFN-gamma, VEGF and eKER mRNA was detected in the wounds treated with allogenic EpSCs, autologous EpSCs or their vehicle. PMID- 26971685 TI - Dendritic-tumor cell hybrids induce tumor-specific immune responses more effectively than the simple mixture of dendritic and tumor cells. AB - BACKGROUND AIMS: Dendritic cell (DC)-tumor cell hybrids have been used clinically in cancer immunotherapy, but their advantage over the simple mixture of tumor cells and DCs is still a matter of controversy. In this study, we compared DC tumor cell hybrids with the non-fused mixture of DC and tumor cells directly in their ability to induce a specific immune response. METHODS: Hybrids were obtained by electrofusion of tumor cells and monocyte-derived DCs. Cell phenotype was evaluated by flow cytometry and antigen-presenting ability by co-culture with syngeneic T cells followed by tetramer analysis and interferon (IFN)-gamma ELISPOT. RESULTS: Less than half the cells in the mixture expressed DC co stimulatory molecules. Furthermore, DCs in the mixture had significantly lower expression of MHC class I molecules than DCs in the fusion. Conversely, nearly all CD11c(+)Her2/neu(+) hybrids expressed CD80, CD86, CD83, HLA-DR and MHC class I from both tumor cells and DCs. Using tumor cells constitutively expressing a cytomegalovirus (CMV) antigen, we show that expansion of CMV-specific cytotoxic T lymphocytes (CTLs) restricted by DCs' MHC class I molecules was higher when DC tumor hybrids were the stimulators. Furthermore, only hybrids stimulated CTLs to produce IFN-gamma in response to CMV-positive target cells. CONCLUSIONS: These data show the superiority of DC-tumor cell hybrids over their simple mixture as T cell stimulators. Hybrids expressed more co-stimulatory and MHC molecules, induced higher antigen-specific T-cell expansion and were the only cells able to induce IFN-gamma-producing antigen-specific T cells. Thus, these data offer further support for cancer immunotherapeutic approaches using DC-tumor cell hybrids. PMID- 26971686 TI - Augmented CD3(+)CD8(+) and CD3(+)CD56(-) cells in cytokine-induced killer cells cultured with engineered cells for costimulatory enhancement from heavily pretreated patients with solid tumor. AB - BACKGROUND AIMS: Cytokine-induced killer cells (CIKs) were shown to be a promising tool in the quest for new therapeutic approaches in the setting of metastatic solid tumors refractory to standard treatments. However, there is a practical clinical problem of different expansion rates and cell function as individual variability exists. Stimulatory molecular 4-1BB could promote division and survival of T cells and enhance effector activity including cytokine production. This study aimed to invest the contribution of co-stimulation signal to CIKs production for exploring new strategies, which increase the expansion and reliability of CIKs generation to improve access to CIKs therapy. METHODS: We studied the larger-scale expansion of CIKs cultured with engineered cells for costimulatory enhancement (ECCE) consisting of K562 cells that expressed 4-1BBL in heavily pretreated patients with solid tumor. The proliferation and cytotoxic capacity of CIKs were evaluated. Phenotypes of CIKs were analyzed using flow cytometry. Cytokine levels of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha were detected using enzyme-linked immunosorbent assay (ELISA). RESULTS: The proliferation and cytotoxic activity of CIKs were significantly up regulated by ECCE. The percentages of CD3(+)CD8(+) and CD3(+)CD56(-) CIKs were significantly increased while the percentage of CD3(+)CD56(+) CIKs was decreased. In addition, the secretion of IFN-gamma and TNF-alpha by CIKs could also be enhanced significantly when ECCE were added into the culture system. CONCLUSIONS: This study suggests that ECCE may improve the efficacy of CIKs therapy and make CIKs therapy possible for the patients whose CIKs would be hard to be cultured using conventional methods. PMID- 26971687 TI - Absolute leukocyte count as an internal quality control for the CD34 cell enumeration assay. PMID- 26971688 TI - Airway lipoxin A4/formyl peptide receptor 2-lipoxin receptor levels in pediatric patients with severe asthma. AB - BACKGROUND: Lipoxins are biologically active eicosanoids with anti-inflammatory properties. Lipoxin A4 (LXA4) signaling blocks asthmatic responses in human and experimental model systems. There is evidence that patients with respiratory diseases, including severe asthma (SA), display defective generation of lipoxin signals despite glucocorticoid therapy. OBJECTIVE: We investigated airway levels of formyl peptide receptor 2-lipoxin receptor (FPR2/ALXR), LXA4, and its counterregulatory compound, leukotriene B4 (LTB4), in patients with childhood asthma. We addressed the potential interplay of the LXA4-FPR2/ALXR axis and glucocorticoids in the resolution of inflammation. METHODS: We examined LXA4 and LTB4 concentrations in induced sputum supernatants from children with intermittent asthma (IA), children with SA, and healthy control (HC) children. In addition, we investigated FPR2/ALXR expression in induced sputum cells obtained from the study groups. Finally, we evaluated in vitro the molecular interaction between LXA4 and glucocorticoid receptor-based mechanisms. RESULTS: We found that children with SA have decreased LXA4 concentrations in induced sputum supernatants in comparison with children with IA. In contrast to decreases in LXA4 concentrations, LTB4 concentrations were increased in children with asthma independent of severity. LXA4 concentrations negatively correlated with LTB4 concentrations and with exacerbation numbers in children with SA. FPR2/ALXR expression was reduced in induced sputum cells of children with SA compared with that seen in HC subjects and children with IA. Finally, we describe in vitro the existence of crosstalk between LXA4 and glucocorticoid receptor at the cytosolic level mediated by G protein-coupled FPR2/ALXR in peripheral blood granulocytes isolated from HC subjects, children with IA, and children with SA. CONCLUSION: Our findings provide evidence for defective LXA4 generation and FPR2/ALXR expression that, associated with increased LTB4, might be involved in a reduction in the ability of inhaled corticosteroids to impair control of airway inflammation in children with SA. PMID- 26971689 TI - Risk of myocardial infarction, ischemic stroke, and cardiovascular death in patients with atopic dermatitis. PMID- 26971691 TI - Chronic cat allergen exposure and low sensitization: Possible limitations in patient selection? PMID- 26971690 TI - Clonal expansion of CD4(+) cytotoxic T lymphocytes in patients with IgG4-related disease. AB - BACKGROUND: IgG4-related disease (IgG4-RD) is a systemic condition of unknown cause characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates. CD4(+) T cells constitute the major inflammatory cell population in IgG4-RD lesions. OBJECTIVE: We used an unbiased approach to characterize CD4(+) T cell subsets in patients with IgG4-RD based on their clonal expansion and ability to infiltrate affected tissue sites. METHODS: We used flow cytometry to identify CD4(+) effector/memory T cells in a cohort of 101 patients with IgG4-RD. These expanded cells were characterized by means of gene expression analysis and flow cytometry. Next-generation sequencing of the T-cell receptor beta chain gene was performed on CD4(+)SLAMF7(+) cytotoxic T lymphocytes (CTLs) and CD4(+)GATA3(+) TH2 cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined by using quantitative multicolor imaging. RESULTS: CD4(+) effector/memory T cells with a cytolytic phenotype were expanded in patients with IgG4-RD. Next-generation sequencing revealed prominent clonal expansions of these CD4(+) CTLs but not CD4(+)GATA3(+) memory TH2 cells in patients with IgG4-RD. The dominant T cells infiltrating a range of inflamed IgG4 RD tissue sites were clonally expanded CD4(+) CTLs that expressed SLAMF7, granzyme A, IL-1beta, and TGF-beta1. Clinical remission induced by rituximab mediated B-cell depletion was associated with a reduction in numbers of disease associated CD4(+) CTLs. CONCLUSIONS: IgG4-RD is prominently linked to clonally expanded IL-1beta- and TGF-beta1-secreting CD4(+) CTLs in both peripheral blood and inflammatory tissue lesions. These active, terminally differentiated, cytokine-secreting effector CD4(+) T cells are now linked to a human disease characterized by chronic inflammation and fibrosis. PMID- 26971692 TI - Vitamin D3 therapy in patients with asthma complicated by sinonasal disease: Secondary analysis of the Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma trial. PMID- 26971693 TI - Reply. PMID- 26971695 TI - Epidemiological investigation of the 119th confirmed Middle East Respiratory Syndrome coronavirus case with an indefinite mode of transmission during the Pyeongtaek outbreak in Korea. AB - Since the first case was diagnosed on May 20, 2015, there were 186 confirmed cases of Middle East Respiratory Syndrome (MERS) until the end of outbreak in South Korea. Although medical institutions were the most identifiable sources of MERS transmission in South Korea, similar to other countries, in-depth epidemiological investigation was required for some confirmed cases with indefinite contact history or hospital visit records. The subject of epidemiological investigation in the present study was a 35 year-old male patient diagnosed with MERS (#119) who lived in Asan-city and worked in Pyeongtaek-city. Various potential sources of transmission were carefully investigated. While he could have been exposed to MERS through a friend from Saudi Arabia or confirmed MERS cases in his workplace, neighboring areas, and medical institutions, as well as contacts in his home, the chances of transmission were low; however, the potential for transmission through his local community could not be excluded. Practically, it was difficult to determine the modes of transmission for all outbreak cases in communicable disease that occurred in this short period of time. The investigation to identify the mode of transmission in this case was ultimately unsuccessful. However, the various data collected and analyzed to reveal modes of transmission provided detailed information that could not be collected using only interview surveys. PMID- 26971694 TI - Nicotine and Nicotine Abstinence Do Not Interfere with GABAA Receptor Neuroadaptations During Alcohol Abstinence. AB - BACKGROUND: Alcohol dependence and tobacco smoking are highly comorbid, and treating both conditions simultaneously is controversial. Previously, we showed that tobacco smoking interferes with GABAA receptor neuroadaptations during alcohol withdrawal in humans, while this effect did not occur with continued nicotine use during alcohol abstinence in nonhuman primates. Here, we extend our previous work by measuring GABAA receptor availability with positron emission tomography (PET) during drug abstinence in nonhuman primates exposed to alcohol alone, nicotine and alcohol together, and alcohol abstinence with continued nicotine exposure. METHODS: Twenty-four adolescent male rhesus macaques orally self-administered alcohol and nicotine, available separately in water and saccharin, over 20 weeks. The groups included alcohol alone (n = 8); nicotine and alcohol with simultaneous abstinence (n = 8); nicotine and alcohol with alcohol abstinence while nicotine was still available (n = 8); and a pilot group of animals consuming nicotine alone (n = 6). Animals were imaged with [(11)C]flumazenil PET to measure binding potential (BPND), an index of GABAA receptor availability. Imaging occurred at baseline (drug-naive), and following alcohol and/or nicotine cessation at 1 day, 8 days, and 12 weeks of abstinence. Generalized linear mixed models were used to examine the time course of [(11)C]flumazenil BPND during alcohol abstinence across groups. RESULTS: Animals consumed 3.95 +/- 1.22 g/kg/d alcohol and 55.4 +/- 35.1 mg/kg/d nicotine. No significant group effects were observed in [(11)C]flumazenil BPND during alcohol abstinence; however, a main effect of time was detected. Post hoc analyses indicated that all groups abstaining from alcohol exhibited significantly increased GABAA receptor availability at 1 day and 8 days (but not 12 weeks) of abstinence relative to baseline, while no changes in [(11)C]flumazenil BPND during nicotine abstinence alone were observed. CONCLUSIONS: These data indicate that neither nicotine nor nicotine abstinence interferes with GABAA receptor neuroadaptations during alcohol withdrawal. This conclusion is consistent with our previous study and does not contradict the use of nicotine replacement therapies or non-nicotinic-acting pharmaceuticals to quit smoking during alcohol withdrawal from a GABAergic perspective. PMID- 26971696 TI - Ecological context of infant mortality in high-focus states of India. AB - OBJECTIVES: This goal of this study was to shed light on the ecological context as a potential determinant of the infant mortality rate in nine high-focus states in India. METHODS: Data from the Annual Health Survey (2010-2011), the Census of India (2011), and the District Level Household and Facility Survey 3 (2007-08) were used in this study. In multiple regression analysis explanatory variable such as underdevelopment is measured by the non-working population, and income inequality, quantified as the proportion of households in the bottom wealth quintile. While, the trickle-down effect of education is measured by female literacy, and investment in health, as reflected by neonatal care facilities in primary health centres. RESULTS: A high spatial autocorrelation of district infant mortality rates was observed, and ecological factors were found to have a significant impact on district infant mortality rates. The result also revealed that non-working population and income inequality were found to have a negative effect on the district infant mortality rate. Additionally, female literacy and new-born care facilities were found to have an inverse association with the infant mortality rate. CONCLUSIONS: Interventions at the community level can reduce district infant mortality rates. PMID- 26971697 TI - Incidence and mortality rates of colorectal cancer in Malaysia. AB - OBJECTIVES: This is the first study that estimates the incidence and mortality rate for colorectal cancer (CRC) patients in Malaysia by sex and ethnicity. METHODS: The 4,501 patients were selected from National Cancer Patient Registry Colorectal Cancer data. Patient survival status was cross-checked with the National Registration Department. The age-standardised rate (ASR) was calculated as the proportion of CRC cases (incidence) and deaths (mortality) from 2008 to 2013, weighted by the age structure of the population, as determined by the Department of Statistics Malaysia and the World Health Organization world standard population distribution. RESULTS: The overall incidence rate for CRC was 21.32 cases per 100,000. Those of Chinese ethnicity had the highest CRC incidence (27.35), followed by the Malay (18.95), and Indian (17.55) ethnicities. The ASR incidence rate of CRC was 1.33 times higher among males than females (24.16 and 18.14 per 100,000, respectively). The 2011 (44.7%) CRC deaths were recorded. The overall ASR of mortality was 9.79 cases, with 11.85 among the Chinese, followed by 9.56 among the Malays and 7.08 among the Indians. The ASR of mortality was 1.42 times higher among males (11.46) than females (8.05). CONCLUSIONS: CRC incidence and mortality is higher in males than females. Individuals of Chinese ethnicity have the highest incidence of CRC, followed by the Malay and Indian ethnicities. The same trends were observed for the age-standardised mortality rate. PMID- 26971698 TI - Predictors of job satisfaction and burnout among tuberculosis management nurses and physicians. AB - OBJECTIVES: This study examined job satisfaction, empowerment, job stress, and burnout among tuberculosis management nurses and physicians in public healthcare institutions. METHODS: This was a cross-sectional study analyzing survey data collected from 249 nurses and 57 physicians in 105 public health centers, three public tuberculosis hospitals, and one tertiary hospital. The survey questionnaire comprised general characteristics, work-related characteristics, and four index scales (job satisfaction, empowerment, job stress, and burnout). The two-sample t-test was used to estimate the mean differences in the four index scales. Multiple regression analysis was used to determine whether general and work-related characteristics affected the four index scales. RESULTS: The job satisfaction and empowerment scores of the nurses were lower than those of the physicians. Except for the tuberculosis-specialized hospitals alone, the average job satisfaction scores of nurses were higher than those of physicians. Moreover, the nurses reported more job stress and burnout than did the physicians in tuberculosis departments in public healthcare institutions in Korea; in particular, the burnout reported by nurses was significantly higher than that reported by physicians at the National Medical Center. Marital status, nursing position, number of coworkers, the average number of days of overtime work per month, self-rated health, and hospital type were associated with the four index scales. CONCLUSIONS: Overall, nurses were more vulnerable to job stress and burnout than physicians. Reducing the workload of nurses by ensuring the presence of sufficient nursing staff and equipment, as well as by equipping facilities to prevent tuberculosis infections, should be considered priorities. PMID- 26971699 TI - Intragastric injection of Lactobacillus casei strain Shirota suppressed spleen sympathetic activation by central corticotrophin-releasing factor or peripheral 2 deoxy-d-glucose in anesthetized rats. AB - Intragastric (IG) administration of probiotic strain Lactobacillus casei Shirota (LcS) decreases the sympathetic nerve outflow of anesthetized rats in a tissue specific manner. In the present study, we examined the effects of IG administration of LcS on sympathetic activation induced by an intracerebroventricular (ICV) injection of corticotrophin-releasing factor (CRF) and an intravenous (IV) injection of 2-deoxy-d-glucose (2DG) or interleukin (IL) 1beta in urethane-anesthetized rats. The IG administration of LcS differently affected the stimulatory responses of sympathetic nerve outflow to CRF. LcS suppressed the increase in splenic sympathetic nerve activity (Spleen-SNA), induced by central CRF, in a dose-dependent manner; however, it did not alter adrenal sympathetic nervous activity (ASNA). In contrast, LcS did not affect spleen-SNA and ASNA following an IV injection of IL-1beta. On the other hand, IG administration of LcS suppressed the activation of ASNA following an IV injection of 2DG. These findings suggest that the suppression of central CRF-induced sympathetic activation by LcS is tissue-specific. Moreover, it can suppress the 2DG-induced sympathetic activation. Furthermore, we found that stomach-specific vagotomy attenuates the suppressive effect of LcS on CRF-mediated spleen-SNA activation. Thus, the present study suggests that LcS administered to the stomach may act on the afferent vagal nerve and send afferent signals to the brain to regulate efferent SNA induced by sympathetic stimulators. PMID- 26971701 TI - Dexamethasone loaded nanoparticles exert protective effects against Cisplatin induced hearing loss by systemic administration. AB - Ototoxicity is one of the most important adverse effects of cisplatin chemotherapy. As a common treatment of acute sensorineural hearing loss, systemic administration of steroids was demonstrated ineffective against cisplatin-induced hearing loss (CIHL) in published studies. The current study aimed to evaluate the potential protective effect of dexamethasone (DEX) encapsulated in polyethyleneglycol-coated polylactic acid (PEG-PLA) nanoparticles (DEX-NPs) against cisplatin-induced hearing loss following systemic administration. DEX was fabricated into PEG-PLA nanoparticles using emulsion and evaporation technique as previously reported. DEX or DEX-NPs was administered intraperitoneally to guinea pigs 1h before cisplatin administration. Auditory brainstem response (ABR) threshold shifts were measured at four frequencies (4, 8, 16, and 24kHz) 1 day before and three days after cisplatin injection. Cochlear morphology was examined to evaluate inner ear injury induced by cisplatin exposure. A single dose of DEX NPs 1h before cisplatin treatment resulted in a significant preservation of the functional and structural properties of the cochlea, which was equivalent to the effect of multidose (3 days) DEX injection. In contrast, no significant protective effect was observed by single dose injection of DEX. The results of histological examination of the cochleae were consistent with the functional measurements. In conclusion, a single dose DEX-NPs significantly attenuated cisplatin ototoxicity in guinea pigs after systemic administration at both histological and functional levels indicating the potential therapeutic benefits of these nanoparticles for enhancing the delivery of DEX in acute sensorineural hearing loss. PMID- 26971700 TI - Distinct contributions of reactive oxygen species in amygdala to bee venom induced spontaneous pain-related behaviors. AB - Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, play essential roles in physiological plasticity and are also involved in the pathogenesis of persistent pain. Roles of peripheral and spinal ROS in pain have been well established, but much less is known about ROS in the amygdala, a brain region that plays an important role in pain modulation. The present study explored the contribution of ROS in the amygdala to bee venom (BV)-induced pain behaviors. Our data show that the amygdala is activated following subcutaneous BV injection into the left hindpaw, which is reflected in the increased number of c Fos positive cells in the central and basolateral amygdala nuclei in the right hemisphere. Stereotaxic administration of a ROS scavenger (tempol, 10mM), NADPH oxidase inhibitor (baicalein, 5mM) or lipoxygenase inhibitor (apocynin, 10mM) into the right amygdala attenuated the BV-induced spontaneous licking and lifting behaviors, but had no effect on BV-induced paw flinch reflexes. Our study provides further evidence for the involvement of the amygdala in nociceptive processing and pain behaviors, and that ROS in amygdala may be a potential target for treatment strategies to inhibit pain. PMID- 26971702 TI - Propofol postsynaptically suppresses stellate neuron excitability in the entorhinal cortex by influencing the HCN and TREK-2 channels. AB - The entorhinal cortex (EC) provides a majority of the excitatory inputs to the hippocampus and is part of the neural circuitry that is involved in memory formation. Although many studies have investigated the effects of propofol in the hippocampus, the function of propofol in the EC remains unclear. Here, using whole-cell patch clamp recordings, we found that propofol induced a postsynaptic outward current and dramatically suppressed the firing rates in the entorhinal stellate neurons, the axons of which form the perforant pathway and relay the main inputs to hippocampus. Propofol-induced inhibition in the EC was mediated by a dual ionic mechanism, including both HCN channel inhibition and TREK-2 channel activation, which form a subtype of two-pore-domain K(+) channels. The inhibitory action of propofol observed in the EC might provide a mechanism for the anesthetic effect of propofol. Considering the crucial role of the EC in learning and memory, our findings may provide insight into the acute amnesic effect induced by propofol. PMID- 26971703 TI - Neurotoxicity induced by alkyl nitrites: Impairment in learning/memory and motor coordination. AB - Although alkyl nitrites are used as recreational drugs, there is only little research data regarding their effects on the central nervous system including their neurotoxicity. This study investigated the neurotoxicity of three representative alkyl nitrites (isobutyl nitrite, isoamyl nitrite, and butyl nitrite), and whether it affected learning/memory function and motor coordination in rodents. Morris water maze test was performed in mice after administrating the mice with varying doses of the substances in two different injection schedules of memory acquisition and memory retention. A rota-rod test was then performed in rats. All tested alkyl nitrites lowered the rodents' capacity for learning and memory, as assessed by both the acquisition and retention tests. The results of the rota-rod test showed that isobutyl nitrite in particular impaired motor coordination in chronically treated rats. The mice chronically injected with isoamyl nitrite also showed impaired function, while butyl nitrite had no significant effect. The results of the water maze test suggest that alkyl nitrites may impair learning and memory. Additionally, isoamyl nitrite affected the rodents' motor coordination ability. Collectively, our findings suggest that alkyl nitrites may induce neurotoxicity, especially on the aspect of learning and memory function. PMID- 26971704 TI - Functional nanomaterials for near-infrared-triggered cancer therapy. AB - The near-infrared (NIR) region (700-1100 nm) is the so-called transparency "therapeutic window" for biological applications owing to its deeper tissue penetration and minimal damage to healthy tissues. In recent years, various NIR based therapeutic and interventional strategies, such as NIR-triggered drug delivery, photothermal therapy (PTT) and photodynamic therapy (PDT), are under research in intensive preclinical and clinical investigations for cancer treatment. The NIR control in these cancer therapy systems is considered crucial to boost local effective tumor suppression while minimizing side effects, resulting in improved therapeutic efficacy. Some researchers even predict the NIR triggered cancer therapy to be a new and exciting possibility for clinical nanomedicine applications. In this review, the rapid development of NIR light responsive cancer therapy based on various smartly designed nanocomposites for deep tumor treatments is introduced. In detail, the use of NIR-sensitive materials for chemotherapy, PTT as well as PDT is highlighted, and the associated challenges and potential solutions are discussed. The applications of NIR sensitive cancer therapy modalities summarized here can highlight their potential use as promising nanoagents for deep tumor therapy. PMID- 26971705 TI - Mini review: ATP-dependent proteases in bacteria. AB - AAA(+) proteases are universal barrel-like and ATP-fueled machines preventing the accumulation of aberrant proteins and regulating the proteome according to the cellular demand. They are characterized by two separate operating units, the ATPase and peptidase domains. ATP-dependent unfolding and translocation of a substrate into the proteolytic chamber is followed by ATP-independent degradation. This review addresses the structure and function of bacterial AAA(+) proteases with a focus on the ATP-driven mechanisms and the coordinated movements in the complex mainly based on the knowledge of ClpXP. We conclude by discussing strategies how novel protease substrates can be trapped by mutated AAA(+) protease variants. (c) 2016 Wiley Periodicals, Inc. Biopolymers 105: 505-517, 2016. PMID- 26971706 TI - Vertical segmental tetrapolar bioimpedance for excess body fat assessment in adolescents. PMID- 26971708 TI - Adsorption energy of small molecules on core-shell Fe@Au nanoparticles: tuning by shell thickness. AB - The adsorption of several small molecules on different gold surfaces, Au(001), strained Au(001) and Au(001) epitaxied on Fe(001), has been characterized using density functional theory. The surface strain leads to a less energetically favourable adsorption for all studied molecules. Moreover, the presence of the iron substrate induces an additional decrease of the binding energy, for 1 and 2 Au monolayers. For carbon monoxide (CO), the structural and energetic variations with the number of Au monolayers deposited on Fe have been analyzed and correlated with the distance between the carbon atom and the gold surface. The effect of the subsurface layer has been evidenced for 1 and 2 monolayers. The other molecules show different quantitative behavior depending on the type of their interaction with the gold surface. However, the iron substrate weakens the interaction, either for the chemisorbed species or for the physisorbed species. 2 Au monolayers seem to be the best compromise to decrease the reactivity of the gold surface towards adsorption while preventing the Fe oxidation. PMID- 26971707 TI - Interactions of subglottal pressure and neuromuscular activation on fundamental frequency and intensity. AB - OBJECTIVES/HYPOTHESIS: Fundamental frequency (F0) and intensity sound pressure level (SPL) of voice are controlled by intrinsic laryngeal muscle (ILM) activation and subglottal pressure (Psub). Their interactions were investigated. METHODS: In an in vivo canine model, the thyroarytenoid (TA), lateral cricoarytenoid/interarytenoid (LCA/IA), and cricothyroid (CT) muscles were independently activated from threshold to maximal contraction by neuromuscular stimulation in various combinations, whereas airflow was increased to phonation onset pressure and beyond. The resultant acoustic output was analyzed for effects of Psub on vibratory stability, F0, and SPL. Muscle activation plots and vocal range profiles by individual ILM activation states were analyzed. RESULTS: Cricothyroid activation increased phonation onset F0, but vibration was less stable in high CT conditions and displayed vibratory mode change. In addition, a decrease in F0 with increased Psub was observed in high CT conditions. Intensity increased with Psub in all conditions, but the slope was greater at high CT, low TA/LCA/IA activations. Lateral cricoarytenoid/interarytenoid activation improved vocal efficiency. To maintain same F0 with increasing SPL (messa di voce), TA activation was decreased and LCA/IA activation was increased. The same F0 and SPL could be achieved with a variety of ILM activation combinations. CONCLUSION: Cricothyroid is primarily required for increasing F0, whereas TA can increase or decrease F0 and SPL. Lateral cricoarytenoid/interarytenoid activation likely maintains vocal fold adduction during increased Psub and improves vocal efficiency. This study also demonstrates laryngeal motor equivalence, the ability of the larynx to achieve the same target F0 and SPL with multiple combinations of ILM activation. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:1123-1130, 2016. PMID- 26971709 TI - Chemoenzymatic Synthesis of a Phosphorylated Glycoprotein. AB - The majority of lysosomal enzymes are targeted to the lysosome by post translational tagging with N-glycans terminating in mannose-6-phosphate (M6P) residues. Some current enzyme replacement therapies (ERTs) for lysosomal storage disorders are limited in their efficacy by the extent to which the recombinant enzymes bear the M6P-terminated glycans required for effective trafficking. Chemical synthesis was combined with endo-beta-N-acetylglucosaminidase (ENGase) catalysis to allow the convergent synthesis of glycosyl amino acids bearing M6P residues. This approach can be extended to the remodeling of proteins, as exemplified by RNase. The powerful synergy of chemical synthesis and ENGase mediated biocatalysis enabled the first synthesis of a glycoprotein bearing M6P terminated N-glycans in which the glycans are attached to the peptide backbone by entirely natural linkages. PMID- 26971711 TI - Microwave excitation of spin wave beams in thin ferromagnetic films. AB - An inherent element of research and applications in photonics is a beam of light. In magnonics, which is the magnetic counterpart of photonics, where spin waves are used instead of electromagnetic waves to transmit and process information, the lack of a beam source limits exploration. Here, we present an approach enabling generation of narrow spin wave beams in thin homogeneous nanosized ferromagnetic films by microwave current. We show that the desired beam-type behavior can be achieved with the aid of a properly designed coplanar waveguide transducer generating a nonuniform microwave magnetic field. We test this idea using micromagnetic simulations, confirming numerically that the resulting spin wave beams propagate over distances of several micrometers. The proposed approach requires neither inhomogeneity of the ferromagnetic film nor nonuniformity of the biasing magnetic field. It can be generalized to different magnetization configurations and yield multiple spin wave beams of different width at the same frequency. PMID- 26971712 TI - Bacteriophages or bacteriovores - that is the question: variations on the theme of eating Stenotrophomonas maltophilia. PMID- 26971710 TI - Modulation of anxiety and fear via distinct intrahippocampal circuits. AB - Recent findings indicate a high level of specialization at the level of microcircuits and cell populations within brain structures with regards to the control of fear and anxiety. The hippocampus, however, has been treated as a unitary structure in anxiety and fear research despite mounting evidence that different hippocampal subregions have specialized roles in other cognitive domains. Using novel cell-type- and region-specific conditional knockouts of the GABAA receptor alpha2 subunit, we demonstrate that inhibition of the principal neurons of the dentate gyrus or CA3 via alpha2-containing GABAA receptors (alpha2GABAARs) is required to suppress anxiety, while the inhibition of CA1 pyramidal neurons is required to suppress fear responses. We further show that the diazepam-modulation of hippocampal theta activity shows certain parallels with our behavioral findings, suggesting a possible mechanism for the observed behavioral effects. Thus, our findings demonstrate a double dissociation in the regulation of anxiety versus fear by hippocampal microcircuitry. PMID- 26971713 TI - Coexistence of charge and ferromagnetic order in fcc Fe. AB - Phase coexistence phenomena have been intensively studied in strongly correlated materials where several ordered states simultaneously occur or compete. Material properties critically depend on external parameters and boundary conditions, where tiny changes result in qualitatively different ground states. However, up to date, phase coexistence phenomena have exclusively been reported for complex compounds composed of multiple elements. Here we show that charge- and magnetically ordered states coexist in double-layer Fe/Rh(001). Scanning tunnelling microscopy and spectroscopy measurements reveal periodic charge-order stripes below a temperature of 130 K. Close to liquid helium temperature, they are superimposed by ferromagnetic domains as observed by spin-polarized scanning tunnelling microscopy. Temperature-dependent measurements reveal a pronounced cross-talk between charge and spin order at the ferromagnetic ordering temperature about 70 K, which is successfully modelled within an effective Ginzburg-Landau ansatz including sixth-order terms. Our results show that subtle balance between structural modifications can lead to competing ordering phenomena. PMID- 26971714 TI - Effect of Parenteral Antioxidant Supplementation During the Dry Period on Postpartum Glucose Tolerance in Dairy Cows. AB - BACKGROUND: Exacerbated postparturient insulin resistance (IR) has been associated with several pathologic conditions in dairy cattle. Oxidative stress (OS) plays a causative role in IR in humans, and an association, but not direct relationship, between OS and IR recently has been reported in transition dairy cattle. HYPOTHESIS: Supplementation with antioxidants shortly before calving improves glucose tolerance after parturition in dairy cattle. ANIMALS: Ten late pregnant Holstein cows entering their 2nd to 5th lactation. METHODS: Randomized placebo-controlled trial: 15 +/- 2 days before expected calving, the treatment group received an injection of DL-alpha-tocopheryl acetate at a dosage of 6 mg/kg body weight (BW) and 0.06 mg/kg BW of sodium selenite, and the control group was injected with isotonic saline. During the first week after calving, both groups underwent glucose tolerance testing (0.25 g glucose/kg BW). Commercial assays were used to quantify the concentrations of glucose, insulin, nonesterified fatty acids (NEFA), beta-hydroxybutyrate, and markers of redox status in blood. Data were analyzed using the Mann-Whitney U-test (alpha = 0.05). RESULTS: Supplemented cows showed a lower risk for OS, as reflected by a lower OS index (P = .036), different areas under the curve for the concentrations of glucose (P < .01), insulin (P = .043), and NEFA (P = .041), more rapid elimination rates (P = .080, <.01 and .047 respectively), and shorter half-lives (P = .040, <.01 and .032) of these metabolites. CONCLUSIONS AND CLINICAL IMPORTANCE: Supplementation with antioxidants before calving resulted in greater insulin sensitivity after calving, thereby suggesting the role of OS in the development of IR in cattle and the potential benefits of antioxidant supplementation in minimizing the consequences of negative energy balance. PMID- 26971715 TI - Regulation of cell polarity determinants by the Retinoblastoma tumor suppressor protein. AB - In addition to their canonical roles in the cell cycle, RB family proteins regulate numerous developmental pathways, although the mechanisms remain obscure. We found that Drosophila Rbf1 associates with genes encoding components of the highly conserved apical-basal and planar cell polarity pathways, suggesting a possible regulatory role. Here, we show that depletion of Rbf1 in Drosophila tissues is indeed associated with polarity defects in the wing and eye. Key polarity genes aPKC, par6, vang, pk, and fmi are upregulated, and an aPKC mutation suppresses the Rbf1-induced phenotypes. RB control of cell polarity may be an evolutionarily conserved function, with important implications in cancer metastasis. PMID- 26971717 TI - Quantum probability assignment limited by relativistic causality. AB - Quantum theory has nonlocal correlations, which bothered Einstein, but found to satisfy relativistic causality. Correlation for a shared quantum state manifests itself, in the standard quantum framework, by joint probability distributions that can be obtained by applying state reduction and probability assignment that is called Born rule. Quantum correlations, which show nonlocality when the shared state has an entanglement, can be changed if we apply different probability assignment rule. As a result, the amount of nonlocality in quantum correlation will be changed. The issue is whether the change of the rule of quantum probability assignment breaks relativistic causality. We have shown that Born rule on quantum measurement is derived by requiring relativistic causality condition. This shows how the relativistic causality limits the upper bound of quantum nonlocality through quantum probability assignment. PMID- 26971716 TI - Update on the Management of Diarrhea-Predominant Irritable Bowel Syndrome: Focus on Rifaximin and Eluxadoline. AB - Diarrhea-predominant irritable bowel syndrome (IBS-D) is one of the most common diagnoses made by gastroenterologists. Current pharmacologic treatments for IBS-D include fiber supplements, antidiarrheal over-the-counter medications, probiotics, antispasmodics, antidepressants, and a 5-hydroxytryptophan 3 receptor antagonist. All of these options have limited efficacy in managing IBS-D. Rifaximin, a nonabsorbable antibiotic, has been evaluated in patients with IBS-D. In two randomized, double-blind, placebo-controlled phase III trials evaluating rifaximin 550 mg by mouth 3 times/day for 14 days, the primary efficacy end point was achieved by 9% more patients randomized to the rifaximin group compared with placebo (40.7% vs 31.7%, p<0.001, number needed to treat ~11). The primary efficacy end point was defined as the proportion of patients having adequate relief of global IBS symptoms for at least 2 of the 4 weeks during the primary follow-up period (weeks 3-6). In the phase III trial examining the efficacy and safety of repeated courses of rifaximin in patients who responded to the initial 2-week course, rifaximin given for up to two additional courses provided a statistically significant incremental benefit (33% vs 25%, p=0.02). Eluxadoline is a gut-targeting MU and kappa opioid receptor agonist and a delta opioid receptor antagonist. The dual mechanism of eluxadoline may explain the antidiarrheal and abdominal pain-modulating properties and lack of profound constipation. In two identically designed randomized, double-blind, placebo controlled phase III studies, 10.3% more patients in an eluxadoline 100 mg by mouth twice/day group met the primary efficacy end point during the follow-up 1 12 week period compared with placebo (p<0.001). The primary efficacy end point was a composite response, defined as improvement in worst abdominal pain and stool consistency at the same time on most (50% or more) days during the follow up period. This review evaluates evidence for the use of rifaximin and eluxadoline in patients with IBS-D. Rifaximin provides an additional modality for the management of IBS-D patients; it has mild to moderate efficacy similar to other currently available treatment options. Rifaximin is relatively safe, lacks significant drug-drug interactions, and can be used for up to two additional retreatment courses. This may make rifaximin a possible initial or second-line treatment option. Eluxadoline can also offer relief to patients with IBS-D. While effective, because of several limitations, including drug-drug interactions and drug disease contraindications, as well as current lack of clinical experience, it may be tried as a second- or third-line agent. PMID- 26971718 TI - Monitoring temporal opacity fluctuations of large structures with muon radiography: a calibration experiment using a water tower. AB - Usage of secondary cosmic muons to image the geological structures density distribution significantly developed during the past ten years. Recent applications demonstrate the method interest to monitor magma ascent and volcanic gas movements inside volcanoes. Muon radiography could be used to monitor density variations in aquifers and the critical zone in the near surface. However, the time resolution achievable by muon radiography monitoring remains poorly studied. It is biased by fluctuation sources exterior to the target, and statistically affected by the limited number of particles detected during the experiment. The present study documents these two issues within a simple and well constrained experimental context: a water tower. We use the data to discuss the influence of atmospheric variability that perturbs the signal, and propose correction formulas to extract the muon flux variations related to the water level changes. Statistical developments establish the feasibility domain of muon radiography monitoring as a function of target thickness (i.e. opacity). Objects with a thickness comprised between ~50 +/- 30 m water equivalent correspond to the best time resolution. Thinner objects have a degraded time resolution that strongly depends on the zenith angle, whereas thicker objects (like volcanoes) time resolution does not. PMID- 26971719 TI - Influence of an embedded quantum dot on the Josephson effect in the topological superconducting junction with Majorana doublets. AB - One Majorana doublet can be realized at each end of the time-reversal-invariant Majorana nanowires. We investigate the Josephson effect in the Majorana-doublet presented junction modified by different inter-doublet coupling manners. It is found that when the Majorana doublets couple indirectly via a non-magnetic quantum dot, only the normal Josephson effect occurs, and the fermion parity in the system just affects the current direction and amplitude. However, one magnetic field applied on the dot can induce the fractional Josephson effect in the odd-parity case. Next if the direct and indirect couplings between the Majorana doublets coexist, no fractional Josephson effect takes place, regardless of the presence of magnetic field. Instead, there almost appears the pi-period like current in some special cases. All the results are clarified by analyzing the influence of the fermion occupation in the quantum dot on the parity conservation in the whole system. We ascertain that this work will be helpful for describing the dot-assisted Josephson effect between the Majorana doublets. PMID- 26971720 TI - Intermediate divergence levels maximize the strength of structure-sequence correlations in enzymes and viral proteins. AB - Structural properties such as solvent accessibility and contact number predict site-specific sequence variability in many proteins. However, the strength and significance of these structure-sequence relationships vary widely among different proteins, with absolute correlation strengths ranging from 0 to 0.8. In particular, two recent works have made contradictory observations. Yeh et al. (Mol. Biol. Evol. 31:135-139, 2014) found that both relative solvent accessibility (RSA) and weighted contact number (WCN) are good predictors of sitewise evolutionary rate in enzymes, with WCN clearly out-performing RSA. Shahmoradi et al. (J. Mol. Evol. 79:130-142, 2014) considered these same predictors (as well as others) in viral proteins and found much weaker correlations and no clear advantage of WCN over RSA. Because these two studies had substantial methodological differences, however, a direct comparison of their results is not possible. Here, we reanalyze the datasets of the two studies with one uniform analysis pipeline, and we find that many apparent discrepancies between the two analyses can be attributed to the extent of sequence divergence in individual alignments. Specifically, the alignments of the enzyme dataset are much more diverged than those of the virus dataset, and proteins with higher divergence exhibit, on average, stronger structure-sequence correlations. However, the highest structure-sequence correlations are observed at intermediate divergence levels, where both highly conserved and highly variable sites are present in the same alignment. PMID- 26971722 TI - A Qualitative Study of Young Women's Beliefs About Intrauterine Devices: Fear of Infertility. AB - INTRODUCTION: Approximately 80% of college-aged women are at risk of unintended pregnancy. The American College of Obstetricians and Gynecologists recommends long-acting reversible contraceptive (LARC) methods, including intrauterine devices (IUDs), as first-line pregnancy prevention for adolescents and young women. Yet, less than 5% of 15- to 19-year-old women using a method of contraception use LARC. Limited research explores young women's concerns about IUDs. METHODS: As part of a larger women's health research study, researchers conducted 53 in-depth interviews with women, aged 18 to 24 years enrolled in a midsized liberal arts college in the southeastern United States. Analytical techniques from the grounded theory approach were used to code line-by-line and identify themes emerging from these data. RESULTS: Fear of causing harm or infertility through IUD use emerged as a significant barrier to uptake. Negative and often unfounded beliefs about IUDs led to silence and limited observability of IUDs in daily life and health care contexts. Identity as a fertile woman emerged as an antecedent factor to the compatibility of IUDs with participants' values and beliefs. DISCUSSION: The link between fear of infertility and perceived identity was found to be a major factor in young women's contraceptive decision making. In order to increase uptake of IUDs, the beliefs of women must be addressed. PMID- 26971723 TI - Relationship between prior knowledge about herpes zoster and the period from onset of the eruption to consultation in patients with herpes zoster. AB - Herpes zoster (HZ) is a common internal infection caused by latent varicella zoster virus. Emergence of antiviral chemotherapy has changed the treatment of HZ dramatically, but the effects of such therapy are documented only in patients who started treatment within 72 h of HZ onset of the eruption. There have been few studies addressing the question of factors that determine early attendance of patients at a clinic. We questioned 256 patients with acute HZ about: (i) date from onset of the eruption to first clinic visit; and (ii) their prior knowledge of HZ. We found a tendency that patients who already knew about HZ had consulted dermatology clinics earlier (P < 0.05). People most commonly obtained information about the disease from friends and family members who had previously had HZ, but not from the Internet or other mass media. Our results indicate that patient education is important for early attendance at dermatology clinics, which in turn, should result in the improved outcome of antiviral chemotherapy and prevention of postherpetic neuralgia. PMID- 26971724 TI - Vertical distribution of major photosynthetic picoeukaryotic groups in stratified marine waters. AB - Photosynthetic picoeukaryotes (PPEs) are fundamental contributors to oceanic primary production and form diverse communities dominated by prymnesiophytes, chlorophytes, pelagophytes and chrysophytes. Here, we studied the vertical distribution of these major groups in two offshore regions of the northern Iberian Peninsula during summer stratification. We performed a fine-scale vertical sampling (every ~2 m) across the DCM and used fluorescence in situ hybridization (FISH) to determine the PPE composition and to explore the possible segregation of target groups in the light, nutrient and temperature gradients. Chlorophytes, pelagophytes and prymnesiophytes, in this order of abundance, accounted for the total PPEs recorded by flow cytometry in the Aviles canyon, and for more than half in the Galicia Bank, whereas chrysophytes were undetected. Among the three detected groups, often the prymnesiophytes were dominant in biomass. In general, all groups were present throughout the water column with abundance peaks around the DCM, but their distributions differed: pelagophytes were located deeper than the other two groups, chlorophytes presented two peaks and prymnesiophytes exhibited surface abundances comparable to those at the DCM. This study offers first indications that the vertical distribution of different PPE groups is heterogeneous within the DCM. PMID- 26971721 TI - Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia. AB - The introduction of second-generation tyrosine-kinase inhibitors (TKIs) has generated a lively debate on the choice of first-line TKI in chronic phase, chronic myeloid leukemia (CML). Despite the TKIs have different efficacy and toxicity profiles, the planned use of two TKIs has never been investigated. We report on a phase 2 study that was designed to evaluate efficacy and safety of a treatment alternating nilotinib and imatinib, in newly diagnosed BCR-ABL1 positive, chronic phase, CML patients. One hundred twenty-three patients were enrolled. Median age was 56 years. The probabilities of achieving a complete cytogenetic response, a major molecular response, and a deep molecular response (MR 4.0) by 2 years were 93%, 87%, and 61%, respectively. The 5-year overall survival and progression-free survival were 89%. Response rates and survival are in the range of those reported with nilotinib alone. Moreover, we observed a relatively low rate of cardiovascular adverse events (5%). These data show that the different efficacy and toxicity profiles of TKIs could be favorably exploited by alternating their use. Am. J. Hematol. 91:617-622, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26971725 TI - Lornoxicam-induced acute generalized exanthematous pustulosis. PMID- 26971726 TI - Mining Cultures and Mary Cults: Where the Sacred and Profane Meet. AB - Our Lady of the Rockies (OLR) is a ninety-foot-tall statue of the Virgin Mary overlooking Butte, Montana, from its perch high atop the Continental Divide. In the popularized account, OLR is a uniquely local undertaking reflecting the community's character and pride. Yet OLR is far more than this, for it taps into a rich vein of cultural and spiritual tradition. As Mircea Eliade pointed out, the notion of the earth as female pervaded early Western civilizations. Mines were like the vagina of the earth, leading to the womb where metallic ores waxed like embryos. Accordingly, miners purified themselves through various rites to amend their violation. OLR began as a plan for a small, private altar. With the collapse of Butte's copper mining economy, unemployed miners rallied around the idea of building a major shrine to the Virgin Mary that would help restore the city's culture and economy. PMID- 26971727 TI - Masculinity and Material Culture in Technological Transitions: From Letterpress to Offset Lithography, 1960s-1980s. AB - Between the 1960s and the 1980s the printing industry in advanced capitalist economies underwent dramatic technological change. While the transition from "hot metal" compositing to computerized typesetting has been extensively analyzed, there was another transformation occurring simultaneously: in the pressroom, letterpress was gradually replaced by offset lithography. Many letterpress machinists retrained, moving from a heavy, manual technology (with an entrenched patriarchal culture) to a method that was faster and less physically taxing. However, unlike their compositor counterparts, the press-machinists' transition involved a continuity of traditional masculine craft identities rather than a rupture associated with "deskilling." Intrinsic to this experience of technological change was a masculine embodiment that was attuned to and shaped by the materiality and aesthetics of printing technologies. This article establishes how masculine craft identities do not rely exclusively on skill-based mastery of traditional technologies, but also relate to other dimensions of technology, such as aesthetics, embodied "know-how," and the physicality of industrial machinery. PMID- 26971728 TI - "When Does It Stop Being Peanut Butter?": FDA Food Standards of Identity, Ruth Desmond, and the Shifting Politics of Consumer Activism, 1960s-1970s. AB - This article uses a historical controversy over the U.S. Food and Drug Administration's standard of identity for peanut butter as a site for investigating three topics of high importance for historians of technology, consumption, and food activism: how new industrial food-processing technologies have become regulatory problems; how government, industry, and consumer actors negotiate standards development; and how laypeople try to shape technological artifacts in spaces dominated by experts. It examines the trajectory of consumer activist Ruth Desmond, co-founder of the organization the Federation of Homemakers. By following Desmond's evolving strategies, the article shows how the broader currents of the 1960s-70s consumer movement played out in a particular case. Initially Desmond used a traditional style that heavily emphasized her gendered identity, working within a grassroots organization to promote legislative and regulatory reforms. Later, she moved to a more modern advocacy approach, using adversarial legal methods to fight for consumer protections. PMID- 26971729 TI - Engineers Attack the "No. One Killer" in Coal Mining: The Bureau of Mines and the Promotion of Roof Bolting, 1947-1969. AB - In 1948 roof falls were the number one killer of coal miners in America. While the Bureau of Mines had been formed in 1910 to improve coalmine safety, it had largely focused on explosions, for which technological solutions appeared to exist. Roof falls, by contrast, were not amenable to a technical fix. Beginning in 1948, however, the Bureau discovered roof bolting, which it promoted as a safer technology that might yield dramatic benefits. The new approach spread rapidly, yet fatality rates from roof falls failed to decline for nearly two decades. This lag reflected the need for organizational learning, while companies also traded safety for productivity. Finally, only larger mines employed bolting and its impact was masked by a growth in the employment share of small companies. After 1965, as the expansion of small mines ended and organizational learning continued, fatality rates began a long decline. PMID- 26971730 TI - Technology Commercialization as University Mission: Early Historical Developments at the University of Toronto. AB - Canadian universities are perceived as less vibrant and engaged generators of technologies with commercial value than their American counterparts, and such perceptions have driven science policy for decades. This paper shows that contrary to these prevailing views, Canada's largest university has a long history of experience in dealing with the technological gaps in national industry and in attempting to work with domestic firms. Three historical periods, particularly critical in shaping these interactions, are identified and discussed. By the time policy initiatives began emphasizing university-industry relationships, the university had already built essential organizational underpinnings for the commercialization of technologies. PMID- 26971731 TI - Technical Experimentation in Ship Design during the Last Decades of the Serenissima: Gerolamo Maria Balbi's Galea alla Ponentina. AB - In 1744, the Venetian sea captain Gerolamo Maria Balbi (1693-1761) presented the Senate with a project to build a galea alla ponentina ("galley of Western design") that would join the Venetian fleet based in Corfu. The Senate approved Balbi's project hoping that the galley of new design would restore Venice's maritime reputation after the losses of the war against the Ottomans in 1718. The construction of the galley by the Venetian shipwright Giovan Battista Fausto lasted more than two years and was sent to Corfu in 1746. However, the newly built galley proved to be unseaworthy due to its faulty design and was sent back to Venice where it lay abandoned in the Arsenal until its dismissal in 1753. This article discusses Balbi's galley, which offers a unique glimpse into the technical experimentation in ship design in the Arsenal during the last decades of the Republic of Venice. PMID- 26971732 TI - Awards. PMID- 26971733 TI - The Albuquerque Meeting, 8-11 October 2015. PMID- 26971735 TI - Digital Histories of Disasters: History of Technology through Social Media. PMID- 26971734 TI - Forty-second Symposium of the International Committee for the History of Technology and Fourth Meeting of the History of Electrical Technology: "History of High-Technologies and Their Socio-Cultural Contexts," Tel Aviv, Israel, 16-20 August 2015. PMID- 26971737 TI - Het meten van psychomotorische vertraging bij depressie deel II. AB - This review (part I and II) contains an overview of the literature of the past fifteen years over psychomotor retardation in depressed patients, as measured by the following methods: observation scales (part I); observation, coding and analysis of specific nonverbal behaviour (part I); speech research (part I); (choice) reaction time tasks (part II); analysis of gross motor activity (part II); of fine motor behaviour (part II). In each section the results of the different studies are summarized and discussed, in order to answer the following questions: (a) did the depressed patients show any retardation?, (b) how did this retardation manifest itself?, (c) what was the nature of the retardation?, (d) were there any correlations with the results of other methods? and (e) what were the effects of antidepressive treatment? PMID- 26971738 TI - Het cytochroom P450 enzymsysteem: wat is de relevantie voor de praktijk? Deel II, interacties. AB - In man a great interindividual variability exists in the oxidative capacity to metabolize drugs. A major factor contributing to this phenomenon is the genetically determined hydroxyla-tion-capacity of the cytochrome P450 enzyme system. The cytochrome P450 system comprises of several isozymes. For several isozymes (CYP2D6, CYP2C) a genetically based hydroxylation capacity has been demonstrated. A frequency distribution of the clearance shows a bimodal distribution with poor and extensive metabolizers. Applying standard dosing schemes of the drugs that are predominantly metabolised by these isozymes, a considerable number of patients will be intoxicated because of poor metabolism. In general, cytochrome P450 capacity is limited and substrate-affinity is high. Henceforth cytochrome P450 isozymes are likely targets for pharmacokinetic interactions. PMID- 26971739 TI - Hersenveranderingen en 'sprongen' in de eerste 20 levensmaanden en de invloed van de context op gedragsmaten van regressieperioden. AB - Het idee dat er een koppeling te leggen valt tussen rijping van het zenuwstelsel en ontwikkelings-mijlpalen of -transities, zoals voor het eerst grijpen, kruipen of lopen, is onhoudbaar gebleken. Wel valt er een koppeling in de tijd te leggen tussen hersenveranderingen en regressieperioden zoals beschreven door Van de Rijt Plooij en Plooij (1992). De vraag hoe de regressieperioden zieh 'biologisch' en gedragsmatig manifesteren is daarom van belang. Dat blijkt minder eenvoudig te zijn dan men zou denken. De context blijkt van invloed te zijn. Daarover gaat dit artikel. De opzet van het artikel is als volgt. Eerst wordt de koppeling tussen hersenveranderingen en regressieperioden besproken. Dan wordt onze visie op de relatie tussen regressieperioden en ontwikkelingstransities of wel nieuwe vaardigheden toegelicht. Tenslotte wordt de invloed van de context op 'biologische' en gedragsmaten van regressie beschreven. PMID- 26971736 TI - Unmet needs among men with human immunodeficiency virus in community mental health care: a cross-sectional study. AB - While community-based mental health services play an important role in caring for persons with HIV (human immunodeficiency virus) and co-existing mental health disorders, the extent to which their support needs are addressed in this setting is unknown. Accordingly, we examined if HIV infection was associated with unmet support needs among men living with and without HIV receiving community mental health care. This cross-sectional study examined 215 men (135 living with HIV and 80 without HIV) receiving case management services in urban Ontario. Using the Camberwell Assessment of Need, we ascertained the prevalence of support needs in 13 domains grouped into three clusters: Basic needs (accommodation, food, benefits, and money management); self-care/functional needs (daytime activities, self-care, and looking after the home); and health/safety needs (physical, psychological distress, psychotic symptoms, safety to self, and safety to others). We used generalized estimating equations with a logit link to examine the association between HIV and unmet need in each domain. Compared to HIV negative men, men with HIV were more likely to have mood and concurrent disorders, and intellectual and developmental disabilities. Following multivariable analyses, men with HIV had greater unmet needs related to food (odds ratio + 95% confidence interval: 9.36 (4.03, 21.75), p < 0.001); money (OR: 1.90 (1.04, 3.47), p = 0.036) [basic need domains]; psychological distress (OR: 2.39 (1.68, 3.41), p < 0.001); drug use (OR: 5.10 (2.16, 12.08) p < 0.001); and safety to self (OR: 3.35 (1.51, 7.52), p < 0.003) [health and safety domains]. Despite living in a setting with universal health insurance, men with HIV receiving community mental health support had greater unmet need in basic and health domains than HIV-negative men receiving such support. Further research is required to develop and evaluate interventions to best support community-dwelling persons with HIV and mental health disorders. PMID- 26971740 TI - Empirische indicatoren voor regressies en sprangen bij baby's. AB - Het is al lang bekend dat het optreden van ontwikke-lingsmijlpalen sterk van baby tot baby kan verschillen. Theorieen of modellen die daarentegen een strakke timing, gepaard gaande met geringe individuele verschillen, voor ontwikkelingsverschijnselen postuleren, hebben dan ook een zware bewijslast te torsen. Het model van Van de Rijt-Plooij en Plooij van tien strak getimede regressieperioden tijdens de eerste achttien levensmaanden is een voorbeeld van een dergelijk model. In het licht van het feit dat het model mede ten grondslag ligt aan een wijd verspreid praktisch adviezenboek voor ouders, mag worden verwacht dat de empirische ondersteuning er-voor uitgebreid en hecht is. In deze bijdrage zullen we de empirische evidentie voor en tegen het model bespreken en ingaan op de methodologische problemen die bij het verifieren dan wel falsifieren van dit model kornen kijken. PMID- 26971741 TI - Repliek op 'Empirische indicatoren voor regressies en sprongen bij baby's'. AB - Deze repliek zal uit twee delen bestaan. Ten eerste zal ik mijn onderbouwde kritiek op de falsificatie onderzoeken van Van Geert & De Weerth (VG&DW) geven. Ten tweede zal ik de kritiek van VG&DW op de verificatie onderzoeken weerleggen. PMID- 26971742 TI - Olanzapine as medication of first choice in therapy-resistant schizophrenia? AB - A case history of a thirty-one year old schizophrenic female who was treated with olanzapine is described. Olanzapine is a relatively new atypical antipsychotic drug with a dopamine antagonistic as well as a potent serotonine antagonistic effect. Olanzapine was prescribed effectively after haloperidol, flupentixol chloride, and clozapine had not lead to (lasting) improvements of the psychiatric condition of the patient. Considering the efficacy and the limited risks of this relatively new antipsychotic medication the question arises as to whether olanzapine should be considered as the drug of first choice for patients who do not benefit from treatment with a typical neuroleptic drug. PMID- 26971744 TI - Facilitators and barriers to occupational health and safety in small and medium sized enterprises: a descriptive exploratory study in Ontario, Canada. AB - PURPOSE: The purpose of this particular study was to test a newly created instrument in describing the facilitators and barriers to occupational health and safety in small and medium-sized enterprises (SMEs) in Ontario, Canada. METHODS: A cross-sectional design was used to identify the occupational health and safety culture of SMEs in public and private sectors in Ontario. RESULTS: A total of 153 questionnaires were completed. The majority of respondents were female (84%) with a mean age of 49.8 years (SD 10.6). Seventy-four percent were supervisors. Seventy percent of respondents were from the private sector while 30% derived from the public sector including healthcare, community services, and non-profit organizations. Further, conducting regular external safety inspections of the workplace was found to be statistically associated with a safe work environment 2.88 95% CI [1.57, 5.27]. CONCLUSIONS: Strategies and training opportunities that focus on how to adapt occupational health and safety legislation to the nature and diversity of SMEs are recommended. Furthermore, employers may use such information to improve safety in their SMEs, while researchers can hopefully use such evidence to develop interventions that are applicable to meeting the occupational health and safety needs of SMEs. PMID- 26971743 TI - Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits complicated by immunoglobulin A nephropathy in the renal allograft. AB - Immunoglobulin (Ig) A nephropathy (IgAN) is a known autoimmune disease due to abnormal glycosylation of IgA1, and occasionally, IgG co-deposition occurs. The prognosis of IgG co-deposition with IgAN is adverse, as shown in the previous studies. However, in the clinical setting, monoclonality of IgG co-deposition with IgAN has not been observed. We describe a case of proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) combined with IgAN in a renal allograft. A-21-year-old man developed end-stage renal failure with unknown aetiology and underwent living-donor kidney transplantation from his mother 2 years after being diagnosed. One year after kidney transplantation, proteinuria 2+ and haematuria 2+ were detected; allograft biopsy revealed mesangial IgA and C3 deposits, indicating a diagnosis of IgAN. After tonsillectomy and steroid pulse therapy, proteinuria and haematuria resolved. However, 4 years after transplantation, pedal oedema, proteinuria (6.89 g/day) and allograft dysfunction (serum creatinine (sCr) 203.3 umol/L) appeared. A second allograft biopsy showed mesangial expansion and focal segmental proliferative endocapillary lesions with IgA1lambda and monoclonal IgG1kappa depositions. Electron microscopic analysis revealed a massive amount of deposits, located in the mesangial and subendothelial lesions. A diagnosis of PGNMID complicated with IgAN was made, and rituximab and plasmapheresis were added to steroid pulse therapy. With this treatment, proteinuria was alleviated to 0.5 g/day, and the allograft dysfunction recovered to sCr 132.6 umol/L. This case suggests a necessity for investigation of PGNMID and IgA nephropathy in renal allografts to detect monoclonal Ig deposition disease. PMID- 26971745 TI - Effects of one session radial extracorporeal shockwave therapy on post-stroke plantarflexor spasticity: a single-blind clinical trial. AB - Purpose To examine the effects of radial extracorporeal shockwave therapy (rESWT) on plantarflexor spasticity after stroke. Method Twelve patients with stroke were randomly included for this prospective, single-blind clinical trial. Patients received one rESWT session (0.340 mJ/mm2, 2000 shots) on plantarflexor muscle. The Modified Modified Ashworth Scale (MMAS), H-reflex tests, ankle range of motion (ROM), passive plantarflexor torque (PPFT) and timed up and go test (TUG) were measured at baseline (T0), immediately after treatment (T1) and one hour after the end of the treatment (T2). Results Patients had improved the MMAS scores for both the gastrocnemius and the soleus muscles, active and passive ROM, PPFT and TUG over time after rESWT. For the PPFT, it was greater at high velocity than at low velocity, and there was a significant three-way interaction between time, knee position (extended/flexed) and velocity (low/high). The H-reflex latency had decreased at T1, but there was no significant effect on Hmax/Mmax ratio. Conclusions The rESWT improved plantarflexor spasticity, and the effects sustained for one hour, whereas it was not effective in improving spinal excitability. Implications for Rehabilitation One session radial extracorporeal shock wave therapy (rESWT) is safe and effective in improving post stroke plantarflexor spasticity, ankle active and passive range of motion, passive torque, and walking capability. The spasticity scores improved for both the gastrocnemius and the soleus muscles and persisted one hour after rESWT. The magnitude of resistive plantarflexor passive torque in the knee extended position and high velocity was larger over time suggesting greater gastrocnemius spasticity than soleus. The rESWT had no significant effects on alpha motorneuron excitability. PMID- 26971783 TI - Antioxidant activity of olive wine, a byproduct of olive mill wastewater. AB - Context Although olive mill wastewater (OMWW) is a good source of bioactive phenolic compounds, disposing OMWW is a serious environmental challenge. Production of wine via fermenting OMWW may be a promising alternative to deal with OMWW. However, whether or not olive wine from OMWW still reserves its original bioactivities remains unclear. Objective This study examines antioxidant activity of olive wine fermented from OMWW. Materials and methods Hydroxytyrosol in olive oil was determined by HPLC. Total flavonoid, total polyphenol and in vitro antioxidant activities were measured by spectrophotometry. Aged mice were intragastricly administered 7, 14 and 28 mL/kg olive wine consecutively for 30 d. Afterward, levels of malonaldehyde (MDA), protein carbonyl, reduced glutathione (GSH) and activity of superoxide dismutase (SOD) were assayed in mouse plasma and liver. Results Contents of hydroxytyrosol, total flavonoid and total polyphenol in olive wine were 0.14 +/- 0.01, 0.29 +/- 0.06 and 0.43 +/- 0.03 mg/mL, respectively. The IC50 value of olive wine to scavenge DPPH and hydroxyl free radicals was 2.5% and 3.2% (v/v), respectively. Compared with the solvent control group, olive wine with a dose of 28 mL/kg remarkably lowered mouse MDA concentration in liver, and reduced protein carbonyl level in plasma (p < 0.05). Meanwhile, olive wine at doses of 7 and 28 mL/kg notably enhanced SOD activity in both mouse plasma and liver (p < 0.05). The beneficial effect on liver was superior to that of gamma-tocopherol. Conclusion The study demonstrated that olive wine from OMWW has potential for treating oxidative stress-associated diseases. PMID- 26971784 TI - (68)Ga-DOTATATE PET in juvenile angiofibroma. AB - BACKGROUND: As somatostatin receptors (SSTRs) may be overexpressed in rapidly growing vessels, the aim of this study was the analysis of in vivo and in vitro SSTR2A expression in juvenile angiofibroma (JA). MATERIAL & METHODS: A group of six male adolescents with a diagnosis of primary, recurrent/residual JA was enrolled in the study. All patients underwent (68)Ga-DOTATATE PET/computed tomography (CT) followed by immunohistochemical staining for SSTR expression. RESULTS: (68)Ga-DOTATATE PET/CT showed accumulation in areas matching the pathologic tissue in the nasopharynx of all patients studied with SUVmax of 5.1 +/- 0.9 (ranging from 3.6 to 6.4). In all cases, the immunohistochemical examination showed a presence of SSTR2A with a high staining index. CONCLUSION: In vitro SSTR2A cytoplasm expression was found to be high in all tumor specimens. However, the uptake of (68)Ga-DOTATATE was weak in the PET/CT studies. We postulate that the intracellular localization of the SSTR2A in JA may cause this discrepancy. PMID- 26971785 TI - Reduction of Delay in Detecting Initial Dips from Functional Near-Infrared Spectroscopy Signals Using Vector-Based Phase Analysis. AB - In this paper, we present a systematic method to reduce the time lag in detecting initial dips using a vector-based phase diagram and an autoregressive moving average with exogenous signals (ARMAX) model-based q-step-ahead prediction algorithm. With functional near-infrared spectroscopy (fNIRS), signals related to mental arithmetic and right-hand clenching are acquired from the prefrontal and left primary motor cortices, respectively. The interrelationship between oxygenated hemoglobin, deoxygenated hemoglobin, total hemoglobin and cerebral oxygen exchange are related to initial dips. Specifically, a threshold value from the resting state hemodynamics is incorporated, as a decision criterion, into the vector-based phase diagram to determine the occurrence of initial dips. To further reduce the time lag, a [Formula: see text]-step-ahead prediction method is applied to predict the occurrence of the dips. A combination of the threshold criterion and the prediction method resulted in the delay time of about 0.9[Formula: see text]s. The results demonstrate that rapid detection of initial dip is possible and therefore can be used for real-time brain-computer interfacing. PMID- 26971786 TI - Emotion Recognition with Eigen Features of Frequency Band Activities Embedded in Induced Brain Oscillations Mediated by Affective Pictures. AB - In this study, singular spectrum analysis (SSA) has been used for the first time in order to extract emotional features from well-defined electroencephalography (EEG) frequency band activities (BAs) so-called delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-16 Hz), beta (16-32 Hz), gamma (32-64 Hz). These five BAs were estimated by applying sixth-level multi-resolution wavelet decomposition (MRWD) with Daubechies wavelets (db-8) to single channel nonaveraged emotional EEG oscillations of 6 s for each scalp location over 16 recording sites (Fp1, Fp2, F3, F4, F7, F8, C3, C4, P3, P4, T3, T4, T5, T6, O1, O2). Every trial was mediated by different emotional stimuli which were selected from international affective picture system (IAPS) to induce emotional states such as pleasant (P), neutral (N), and unpleasant (UP). Largest principal components (PCs) of BAs were considered as emotional features and data mining approaches were used for the first time in order to classify both three different (P, N, UP) and two contrasting (P and UP) emotional states for 30 healthy controls. Emotional features extracted from gamma BAs (GBAs) for 16 recording sites provided the high classification accuracies of 87.1% and 100% for classification of three emotional states and two contrasting emotional states, respectively. In conclusion, we found the followings: (1) Eigenspectra of high frequency BAs in EEG are highly sensitive to emotional hemispheric activations, (2) emotional states are mostly mediated by GBA, (3) pleasant pictures induce the higher cortical activation in contrast to unpleasant pictures, (4) contrasting emotions induce opposite cortical activations, (5) cognitive activities are necessary for an emotion to occur. PMID- 26971787 TI - Faster P300 Classifier Training Using Spatiotemporal Beamforming. AB - The linearly-constrained minimum-variance (LCMV) beamformer is traditionally used as a spatial filter for source localization, but here we consider its spatiotemporal extension for P300 classification. We compare two variants and show that the spatiotemporal LCMV beamformer is at par with state-of-the-art P300 classifiers, but several orders of magnitude faster in training the classifier. PMID- 26971788 TI - Intra-individual comparison of (68)Ga-PSMA-11-PET/CT and multi-parametric MR for imaging of primary prostate cancer. AB - PURPOSE: Multi-parametric magnetic resonance imaging (MP-MRI) is currently the most comprehensive work up for non-invasive primary tumor staging of prostate cancer (PCa). Prostate-specific membrane antigen (PSMA)-Positron emission tomography-computed tomography (PET/CT) is presented to be a highly promising new technique for N- and M-staging in recurrent PCa-patients. The actual investigation analyses the potential of (68)Ga-PSMA11-PET/CT to assess the extent of primary prostate cancer by intra-individual comparison to MP-MRI. METHODS: In a retrospective study, ten patients with primary PCa underwent MP-MRI and PSMA PET/CT for initial staging. All tumors were proven histopathological by biopsy. Image analysis was done in a quantitative (SUVmax) and qualitative (blinded read) fashion based on PI-RADS. The PI-RADS schema was then translated into a 3D-matrix and the euclidian distance of this coordinate system was used to quantify the extend of agreement. RESULTS: Both MP-MRI and PSMA-PET/CT presented a good allocation of the PCa, which was also in concordance to the tumor location validated in eight-segment resolution by biopsy. An Isocontour of 50 % SUVmax in PSMA-PET resulted in visually concordant tumor extension in comparison to MP-MRI (T2w and DWI). For 89.4 % of sections containing a tumor according to MP-MRI, the tumor was also identified in total or near-total agreement (euclidian distance <=1) by PSMA-PET. Vice versa for 96.8 % of the sections identified as tumor bearing by PSMA-PET the tumor was also found in total or near-total agreement by MP-MRI. CONCLUSIONS: PSMA-PET/CT and MP-MRI correlated well with regard to tumor allocation in patients with a high pre-test probability for large tumors. Further research will be needed to evaluate its value in challenging situation such as prostatitis or after repeated negative biopsies. PMID- 26971789 TI - Primary lung tumors in children: 24 years of experience at a referral center. AB - PURPOSE: Primary lung tumors are rare during childhood and encompass a wide variety of histological types. Each has a different biology and a different therapeutic approach. The aim of this article is to review the experience of a pediatric referral center with this kind of tumors during the last 24 years. METHODS: A retrospective chart review was performed for patients with diagnosis of primary lung tumor between the years 1990-2014. The variables analyzed were age, sex, course of the disease, symptoms, localization, surgery, histology and outcome. RESULTS: Between 1990 and 2014, 38 patients with primary lung tumors were treated at our institution. Age at presentation was 6.6 +/- 5.2 years (r 0.91-16.58) and the female:male relationship was 1.37. Inflammatory myofibroblastic lung tumor (n = 13), carcinoid tumor (n = 6) and pleuropulmonary blastoma (n = 6) were the most frequent histological types. Persistent radiographic abnormality was the most frequent presenting sign (34 %). Global mortality was 15.8 % varying according to histology. CONCLUSION: Although the diagnosis of primary lung tumor is rare, the persistence of a radiographic abnormality in spite of adequate treatment for inflammatory processes forces us to evaluate further. The age of the patient is an important factor in the decision of the diagnostic work-up. PMID- 26971791 TI - The IgM isotype of anti-annexin A5 antibodies and multiple positivity of conventional antiphospholipid antibodies: increasing the number of clinical manifestations of primary antiphospholipid syndrome. AB - We evaluated the importance of anti-annexin A5 antibodies (aanxA5 Abs) for clinical (thrombosis and/or recurrent pregnancy loss) and serologic (presence of antiphospholipid antibodies: lupus anticoagulant (LA), anticardiolipin (aCL), and anti-beta2 glycoprotein I (abeta2GPI) antibodies) features of patients with primary antiphospholipid syndrome (PAPS). Our study included 70 patients with PAPS according to the international consensus criteria for APS. The mean age of the analyzed patients was 45.97 +/- 12.72. The disease duration above 5 years was present in 31/70 of patients. Concentrations of analyzed antibodies were measured by ELISA. Cutoff values were set in accordance to the manufacturers' recommendations. History of recurrent pregnancy loss was associated with double positivity for aanxA5 IgM and LA (chi (2) = 4.000, P = 0.046) and triple positivity for aanxA5 IgM + LA + abeta2GPI IgM (chi (2) = 4.168, P = 0.041). Venous thromboses were associated with triple positivity for aanxA5 IgM + aCLIgG + abeta2GPI IgM (chi (2) = 3.965, P = 0.046). The IgG isotype of aanxA5 Abs was in positive correlation with aCL Abs of the IgG (r = 0.310, P = 0.009) and IgM (r = 0.254, P = 0.034) isotype. The presence of the clinical manifestations of PAPS is increasing with the number of positive conventional aPL and the IgM aanxA5 Abs tests. This new combination of Abs is beneficial even when the number of patients with positivity for aanxA5 Abs is low. This is important in further detection of patients prone to recurrence of thrombotic episodes. PMID- 26971790 TI - Rheumatologic manifestations of primary immunodeficiency diseases. AB - In the last 5 years, several hundred articles have been published concerning the link between primary immunodeficiency disease (PID) and rheumatologic diseases. Although rheumatologic complications were originally thought to be at the opposite ends of the spectrum of immunopathologic manifestations, they are now all being considered secondary manifestations of a causative primary "immune derangement." For the rheumatologist, it is important to be able to identify patients who may present with typical rheumatologic findings but who have an underlying PID. In a systematic manner, this overview addresses both the systemic and organ-based rheumatologic diseases which have known associations with primary immunodeficiencies, and explores how immunodeficiency may actually cause these clinical manifestations. PMID- 26971792 TI - Scale-up laccase production from Trametes versicolor stimulated by vanillic acid. AB - An efficient strategy for laccase production in Trametes versicolor cultures was developed using vanillic acid as the inducer. The optimized vanillic acid treatment strategy consisted of exposing 2-day-old mycelia cultures to 80 mg/L vanillic acid. After 4 days, laccase activity of 588.84 U/L was achieved in flasks which represented a 1.79-fold increase compared to the control. In 200-L airlift bioreactor, the maximal laccase activity reached up to 785.12 U/L using the optimized vanillic acid treatment strategy. The zymograms of culture supernatants revealed three bands with laccase activity, among which Lac1 and Lac2 were abundant laccase isoforms constitutively expressed, and Lac3 was an inducible isozyme by vanillic acid. The results of real-time quantitative PCR showed that the transcription level of lcc in T. versicolor cultures grown with vanillic acid for 7 days was about 5.64-fold greater than that without vanillic acid in flasks. In 200-L airlift bioreactor cultures of T. versicolor with addition of vanillic acid, the transcript level of lcc at day 7 was 2.62-fold higher than that in flasks with vanillic acid due to the good mass transfer and oxygen supply in the bioreactor system. This study provides a basis for understanding the induction mechanism of vanillic acid for laccase production and has good potential for industrial applications. PMID- 26971793 TI - Inhibition of Autophagy by Chloroquine Enhances the Antitumor Efficacy of Sorafenib in Glioblastoma. AB - Glioblastoma multiforme (GBM) is the most aggressive and common brain tumor in adults. Sorafenib, a multi-kinase inhibitor, has been shown to inhibit cell proliferation and induce apoptosis through inhibition of STAT3 signaling in glioblastoma cells and in intracranial gliomas. However, sorafenib also induces cell autophagy. Due to the dual roles of autophagy in tumor cell survival and death, the therapeutic effect of sorafenib on glioblastoma is uncertain. Here, we combined sorafenib treatment in GBM cells (U373 and LN229) and tumors with the autophagy inhibitor chloroquine. We found that blockage of autophagy further inhibited cell proliferation and migration and induced cell apoptosis in vitro and in vivo. These findings suggest the possibility of combination treatment with sorafenib and autophagy inhibitors for GBM. PMID- 26971794 TI - Can intracranial pressure be measured non-invasively bedside using a two-depth Doppler-technique? AB - Measurement of intracranial pressure (ICP) is necessary in many neurological and neurosurgical diseases. To avoid lumbar puncture or intracranial ICP probes, non invasive ICP techniques are becoming popular. A recently developed technology uses two-depth Doppler to compare arterial pulsations in the intra- and extra cranial segments of the ophthalmic artery for non-invasive estimation of ICP. The aim of this study was to investigate how well non-invasively-measured ICP and invasively-measured cerebrospinal fluid (CSF) pressure correlate. We performed multiple measurements over a wide ICP span in eighteen elderly patients with communicating hydrocephalus. As a reference, an automatic CSF infusion apparatus was connected to the lumbar space. Ringer's solution was used to create elevation to pre-defined ICP levels. Bench tests of the infusion apparatus showed a random error (95 % CI) of less than +/-0.9 mmHg and a systematic error of less than +/ 0.5 mmHg. Reliable Doppler signals were obtained in 13 (72 %) patients. An infusion test could not be performed in one patient. Thus, twelve patients and a total of 61 paired data points were studied. The correlation between invasive and non-invasive ICP measurements was good (R = 0.74), and the 95 % limits of agreements were -1.4 +/- 8.8 mmHg. The within-patient correlation varied between 0.47 and 1.00. This non-invasive technique is promising, and these results encourage further development and evaluation before the method can be recommended for use in clinical practice. PMID- 26971795 TI - Distress and unemployment: the related economic and noneconomic factors in a sample of unemployed adults. AB - OBJECTIVES: To examine the associations between economic and noneconomic factors and psychological distress in a group of 748 unemployed adults during economic recession. METHODS: Data were collected through a questionnaire. Bivariate and logistic regression analyses were used to test the associations between distress and the deprivation of income and latent benefits of employment (time structure, activity, status, collective purpose and social contact). RESULTS: The participants' mean of distress was higher than the national population mean, and 46.5% of the participants scored above that. All economic and noneconomic factors emerged as strong predictors of distress; particularly financial deprivation (OR 1.06; CI 95 % 1.04-1.09) and lack of structured time (OR 1.07; CI 95 % 1.05 1.09). Women (OR 1.40; CI 95 % 1.04-1.86) and people with lower education levels (OR 0.45; CI 95 % 0.34-0.61) were more affected. CONCLUSIONS: The unemployed individuals score high on distress, especially those facing financial strain and lack of structured time, and women and individuals with lower education in particular. Given the recessionary context and high unemployment rates, these insights raise awareness for policies and actions targeting the needs of unemployed people. PMID- 26971797 TI - Ferrioxalate-assisted solar photo-Fenton degradation of a herbicide at pH conditions close to neutrality. AB - The solar photo-Fenton degradation of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) in aqueous solution at a natural pH (pH = 5) using ferrioxalate as iron source was investigated. The kinetic model proposed and validated in a previous contribution was used to predict the reactants concentrations during the oxidation process in a non-concentrating pilot-plant solar reactor. The effects of hydrogen peroxide to 2,4-D initial concentration ratios (R), temperature, and radiation levels were studied. Furthermore, the spectral UV/visible and broadband solar radiation fluxes incident on the reactor window were evaluated by the Simple Model for the Atmospheric Radiative Transfer of Sunshine (SMARTS2) code. The complete destruction of 2,4-D and its main intermediate 2,4-dichlorophenol (2,4-DCP) was achieved in all the experimental runs in only 90 and 120 min of reaction, respectively. In agreement with these results, a reduction of toxicity in the system (expressed as % of inhibition of Vibrio fischeri) for longer times to 90 min of reaction was attained. It is important to emphasize the good agreement between kinetic model results and experimental data obtained. PMID- 26971799 TI - MiSeq HV4 16S rRNA gene analysis of bacterial community composition among the cave sediments of Indo-Burma biodiversity hotspot. AB - Caves in Mizoram, Northeast India, are potential hotspot diversity regions due to the historical significance of the formation of the Indo-Burman plateau and also because of their unexplored and unknown diversity. High-throughput paired end Illumina sequencing of the V4 region of 16S rRNA was performed to study the bacterial community of three caves situated in Champhai district of Mizoram, Northeast India. A total of 10,643 operational taxonomic units (OTUs) (based on 97 % cutoff) comprising of 21 major and 21 candidate phyla with a sequencing depth of 1,140,013 were found in this study. The overall taxonomic profile obtained by the RDP classifier and Greengenes OTU database revealed high diversity within the bacterial communities. Communities were dominated by Planctomycetes, Actinobacteria, Proteobacteria, Bacteroidetes, and Firmicutes, while members of Archaea were less varied and mostly comprising of Eukaryoarchea. Analysis revealed that Farpuk (CFP) cave sediment has low microbial diversity and is mainly dominated by Actinobacteria (80 % reads), whereas different bacterial communities were found in the caves of Murapuk (CMP) and Lamsialpuk (CLP). Analysis also revealed that a major portion of the identified OTUs was classified under rare biosphere. Importantly, all these caves recorded a high number of unclassified OTUs, which might represent new species. Further analysis with whole genome sequencing is needed to validate the unknown species as well as to determine their functional role. PMID- 26971801 TI - Comparison of bioenergetics of walking during a multistage incremental shuttle walk test and a 6-min walk test in active older adults. AB - The goal of the present research was to compare the bioenergetics variability of walking, during the 6-min walk test (6-MWT) and a multistage incremental shuttle walk test (MISWT) in an active older population. Twenty-two healthy physically active older adults with a group mean age of 70.4 +/- 5.8 years completed the 6 MWT and the MISWT. Heart rate (HR), walking speed and walking [Formula: see text]O2 were measured throughout each test with a portable metabolic cart. Strong correlations were found for the [Formula: see text]O2 peak and the walking speed (r = 0.91 and r = 0.89 respectively for 6-MWT and MISWT). Differences in [Formula: see text]O2 peak values were analysed with a paired Student's t test. Repeated measures ANOVA were conducted to detect differences between tests. The Bland and Altman plot indicates that the average difference between both tests was 2.5 ml kg-1 min-1. MISWT [Formula: see text]O2 peak means were significantly greater than the 6-MWT [Formula: see text]O2 peak mean values (21.6 +/- 5.3 vs. 18.9 +/- 4.5 ml kg-1 min-1) which indicate bioenergetics differences between the two walking tests. Thus, the MISWT and 6-MWT elicited different walking [Formula: see text]O2 peak and HR suggesting that the MISWT field test challenge the participants to a higher level of cardiovascular and respiratory stress. The walking [Formula: see text]O2 peak recorded for the MISWT was significantly greater than the 6-MWT. Consequently, both tests seem to measure different facets of the aerobic capacity. MISWT seems to be a better indicator of maximal aerobic power whereas the 6-MWT provides more relevant information regarding aerobic endurance in aging population. PMID- 26971798 TI - Protective effect of thymoquinone against lead-induced hepatic toxicity in rats. AB - Lead (Pb) intoxication is a worldwide health problem which frequently affects the liver. This study was carried out to investigate the potential protective effect of thymoquinone (TQ), the major active ingredient of volatile oil of Nigella sativa seeds, against Pb-induced liver damage. Adult male rats were randomized into four groups: Control group received no treatment, Pb group was exposed to 2000 ppm Pb acetate in drinking water, Pb-TQ group was cotreated with Pb plus TQ (5 mg/kg/day, per orally), and TQ group receiving only TQ. All treatments were applied for 5 weeks. Results indicated that Pb exposure increased hepatic Pb content, damaged hepatic histological structure (necrotic foci, hepatic strands disorganization, hypertrophied hepatocytes, cytoplasmic vacuolization, cytoplasmic loss, chromatin condensation, mononuclear cell infiltration, congestion, centrilobular swelling), and changed liver function investigated by plasma biochemical parameters (AST, ALT, ALP, gamma-GT, LDH). Pb treatment also decreased total antioxidant status level and increased lipid peroxidation in the liver. Supplementation with TQ remarkably improved the Pb-induced adverse effects without significantly reducing the metal accumulation in the liver. In conclusion, our results indicate, for the first time, a protective effect of TQ against Pb-induced hepatotoxicity and suggest that this component might be clinically useful in Pb intoxication. PMID- 26971802 TI - Lifestyle Shapes the Dialogue between Environment, Microglia, and Adult Neurogenesis. AB - Lifestyle modulates brain function. Diet, stress levels, and physical exercise among other factors influence the "brain cognitive reserve", that is, the capacity of the brain to maintain a normal function when confronting neurodegenerative diseases, injury, and/or aging. This cognitive reserve relays on several cellular and molecular elements that contribute to brain plasticity allowing adaptive responses to cognitive demands, and one of its key components is the hippocampal neurogenic reserve. Hippocampal neural stem cells give rise to new neurons that integrate into the local circuitry and contribute to hippocampal functions such as memory and learning. Importantly, adult hippocampal neurogenesis is well-known to be modulated by the demands of the environment and lifestyle factors. Diet, stress, and physical exercise directly act on neural stem cells and/or their progeny, but, in addition, they may also indirectly affect neurogenesis by acting on microglia. Microglia, the guardians of the brain, rapidly sense changes in the brain milieu, and it has been recently shown that their function is affected by lifestyle factors. However, few studies have analyzed the modulatory effect of microglia on adult neurogenesis in these conditions. Here, we review the current knowledge about the dialogue maintained between microglia and the hippocampal neurogenic cascade. Understanding how the communication between microglia and hippocampal neurogenesis is affected by lifestyle choices is crucial to maintain the brain cognitive reserve and prevent the maladaptive responses that emerge during disease or injury through adulthood and aging. PMID- 26971800 TI - Interventions for Extracranial Carotid Artery Stenosis: An Update. AB - OPINION STATEMENT: Clinical trials demonstrate that stroke risk after the periprocedural period is similar for carotid angioplasty and stenting (CAS) and carotid endarterectomy (CEA), making CAS an acceptable alternative to CEA. However, there tends to be a higher procedural risk of stroke for CAS than for CEA and a potentially higher rate of myocardial infarction in patients undergoing CEA as compared to CAS. Furthermore, lower rates of complications with revascularization and of post-revascularization stroke have been attributed to advances in medical management, improved surgical technique, and new devices. We discuss identifying patients who may have higher complication rates and recent clinical studies and medical advances directed at reducing stroke risk in patients with extracranial carotid stenosis. PMID- 26971803 TI - Colorimetric measurement of carbohydrates in biological wastewater treatment systems: A critical evaluation. AB - Four laboratory preparations and three commercially available assay kits were tested on the same carbohydrate samples with the addition of 14 different interfering solutes typically found in wastewater treatment plants. This work shows that a wide variety of solutes can interfere with these assays. In addition, a comparative study on the use of these assays with different carbohydrate samples was also carried out, and the metachromatic response was clearly influenced by variation in sample composition. The carbohydrate content in the supernatant of a submerged anaerobic membrane bioreactor (SAMBR) was also measured using these assays, and the amount in the different supernatant samples, with and without a standard addition of glucose to the samples, showed substantial differences. We concluded that the carbohydrates present in wastewater measured using these colorimetric methods could be seriously under- or over-estimated. A new analytical method needs to be developed in order to better understand the biological transformations occurring in anaerobic digestion that leads to the production of soluble microbial products (SMPs) and extracellular polymeric substance (EPS). PMID- 26971804 TI - Particulate organics degradation and sludge minimization in aerobic, complete SRT bioreactors. AB - The study evaluates the assumption that in activated sludge processes and under specific operating conditions, the considered unbiodegradable particulate organic fractions of influent (XU) organic solids and biomass decay residues (cell debris, XE) are degraded. The evaluation was performed by comparing sludge observed yield (Yobs) evolution in two full scale, complete solids retention time (SRT), aerobic bioreactors, to the predictions of two activated sludge models. The results showed that in steady state operating conditions of complete solids retention AS processes very low solids accumulation occur. In these conditions, solids accumulation is slightly affected by kinetic coefficients and significantly affected by XU and XE degradation rates. High endogenous residues degradation rate values of 0.05 d(-1) and 0.02 d(-1) were estimated for the two bioreactors, resulting in low solids accumulation, calculated at 1.6 tons and 3.59 tons per year respectively, of which 1.37 and 0.87 tons were non volatile suspended solids. Depending on WWTP operating conditions the endogenous residues degradation rate is the limiting factor of solids accumulation and consequently for particulate organics degradation. PMID- 26971805 TI - A miniature photoelectrochemical sensor based on organic electrochemical transistor for sensitive determination of chemical oxygen demand in wastewaters. AB - A three-electrode configuration is often required in the conventional photoelectrochemical measurements. Nevertheless, one common drawback is the reference electrode and the counter electrode used in the measurements, which has been proved to be an impediment for the miniaturization. In this study, a simple, cost-effective and miniature photoelectrochemical sensor based on high sensitive organic electrochemical transistor (OECT) is developed and used for the determination of chemical oxygen demand (COD) in wastewaters. The devices show detection limit down to 0.01 mg/L COD, which is two orders of magnitude better than that of the conventional photoelectrochemical method. The excellent sensing performance can be contributed to the novel sensing mechanism of OECT devices. That is, the devices are sensitive to the potential changes induced by the photoelectrochemical reaction on TiO2 nanotube arrays gate electrodes. Real sample analyses are also carried out. The results demonstrate that the measured COD values using the OECT devices and the standard dichromate methods are in a good agreement. Since the proposed sensor is constructed on a miniature transistor, it is expected that the device shows a promising application on the integrated COD monitoring platform. PMID- 26971806 TI - Degradation of N-nitrosodimethylamine (NDMA) and its precursor dimethylamine (DMA) in mineral micropores induced by microwave irradiation. AB - Removal of N-nitrosodimethylamine (NDMA) in drinking water treatment poses a significant technical challenge due to its small molecular size, high polarity and water solubility, and poor biodegradability. Degradation of NDMA and its precursor, dimethylamine (DMA), was investigated by adsorbing them from aqueous solution using porous mineral sorbents, followed by destruction under microwave irradiation. Among the mineral sorbents evaluated, dealuminated ZSM-5 exhibited the highest sorption capacities for NDMA and DMA, which decreased with the density of surface cations present in the micropores. In contrast, the degradation rate of the sorbed NDMA increased with the density of surface cations under microwave irradiation. Evolutions of the degradation products and C/N ratio indicate that the sorbed NDMA and DMA could be eventually mineralized under continuous microwave irradiation. The degradation rate was strongly correlated with the bulk temperature of ZSM-5 and microwave power, which is consistent with the mechanism of pyrolysis caused by formation of micro-scale "hot spots" within the mineral micropores under microwave irradiation. Compared to existing treatment options for NDMA removal, microporous mineral sorption coupled with microwave-induced degradation has the unique advantages of being able to simultaneously remove NDMA and DMA and cause their full mineralization, and thus could serve as a promising alternative method. PMID- 26971807 TI - The fate of iron nanoparticles in environmental waters treated with nanoscale zero-valent iron, FeONPs and Fe3O4NPs. AB - Among the different nanoparticles (NPs) that are used in the remediation of contaminated environmental waters, iron nanoparticles (FeNPs) are the most frequently applied. However, if these FeNPs remain in the waters after the treatment, they can cause a hazard to the environment. In this work the time dependent size distribution of iron particles was investigated in Milli-Q water, forest spring water and landfill leachate after a variety of FeNP treatments. The efficiency of the metal removal by the FeNPs was also examined. The concentrations of the metals in the aqueous samples were determined before and after the nano-remediation by inductively coupled plasma mass spectrometry (ICP MS). The data revealed that the settling and removal of the FeNPs after the treatment of the waters was related to the sample characteristics and the ways of dispersing the NPs. When mixing was used for the dispersion, the nano zero-valent iron (nZVI), FeONPs and Fe3O4NPs settled quickly in the Milli-Q water, the forest spring water and the landfill leachate. Dispersion with tertramethylammonium hydroxide (TMAH) resulted in a slower settling of the iron aggregates. In the Milli-Q and forest spring waters treated with FeONPs and dispersed by TMAH, the nanosized iron remained in solution as long as 24 h after the treatment and could represent a potential threat in environmental waters with a low ionic strength. The removal of the metals strongly depended on the type of FeNPs, the chemical speciation of the elements and the sample matrix. If the FeNPs are contaminated by a particular metal, this contaminant could be, during the NPs treatment, released into the water that is being remediated. PMID- 26971808 TI - Contribution of hydrological data to the understanding of the spatio-temporal dynamics of F-specific RNA bacteriophages in river water during rainfall-runoff events. AB - Heavy rainfall events were previously reported to bring large amounts of microorganisms in surface water, including viruses. However, little information is available on the origin and transport of viral particles in water during such rain events. In this study, an integrative approach combining microbiological and hydrological measurements was investigated to appreciate the dynamics and origins of F-specific RNA bacteriophage fluxes during two distinct rainfall-runoff events. A high frequency sampling (automatic sampler) was set up to monitor the F specific RNA bacteriophages fluxes at a fine temporal scale during the whole course of the rainfall-runoff events. A total of 276 rainfall-runoff samples were collected and analysed using both infectivity and RT-qPCR assays. The results highlight an increase of 2.5 log10 and 1.8 log10 of infectious F-specific RNA bacteriophage fluxes in parallel of an increase of the water flow levels for both events. Faecal pollution was characterised as being mainly from anthropic origin with a significant flux of phage particles belonging to the genogroup II. At the temporal scale, two successive distinct waves of phage pollution were established and identified through the hydrological measurements. The first arrival of phages in the water column was likely to be linked to the resuspension of riverbed sediments that was responsible for a high input of genogroup II. Surface runoff contributed further to the second input of phages, and more particularly of genogroup I. In addition, an important contribution of infectious phage particles has been highlighted. These findings imply the existence of a close relationship between the risk for human health and the viral contamination of flood water. PMID- 26971809 TI - Application of ultraviolet light-emitting diodes (UV-LEDs) for water disinfection: A review. AB - Ultraviolet (UV) disinfection is an effective technology for the inactivation of pathogens in water and is of growing interest for industrial application. A new UV source - ultraviolet light-emitting diode (UV-LED) - has emerged in the past decade with a number of advantages compared to traditional UV mercury lamps. This promising alternative raises great interest in the research on application of UV LEDs for water treatment. Studies on UV-LED water disinfection have increased during the past few years. This article presents a comprehensive review of recent studies on UV-LEDs with various wavelengths for the inactivation of different microorganisms. Many inconsistent and incomparable data were found from published studies, which underscores the importance of establishing a standard protocol for studying UV-LED inactivation of microorganisms. Different UV sensitivities to UV LEDs and traditional UV lamps were observed in the literature for some microorganisms, which requires further investigation for a better understanding of microorganism response to UV-LEDs. The unique aspects of UV-LEDs improve inactivation effectiveness by applying LED special features, such as multiple wavelengths and pulsed illumination; however, more studies are needed to investigate the influencing factors and mechanisms. The special features of UV LEDs offer the flexibility of novel reactor designs for a broad application of UV LED reactors. PMID- 26971810 TI - Oxidation of cetirizine, fexofenadine and hydrochlorothiazide during ozonation: Kinetics and formation of transformation products. AB - The efficiency of wastewater ozonation for the abatement of three nitrogen containing pharmaceuticals, two antihistamine drugs, cetirizine (CTR) and fexofenadine (FXF), and the diuretic drug, hydrochlorothiazide (HCTZ), was investigated. Species-specific second-order rate constants for the reactions of the molecular, protonated (CTR, FXF) or deprotonated (HCTZ) forms of these compounds with ozone were determined. All three compounds are very reactive with ozone (apparent second order rate constants at pH 7: kO3,pH7 = 1.7.10(5) M(-1)s( 1), 8.5.10(4) M(-1)s(-1) and 9.0.10(3) M(-1)s(-1) for CTR, HCTZ and FXF, respectively). Transformation product (TP) structures were elucidated using liquid chromatography coupled with high-resolution tandem mass spectrometry, including isotope-labeled standards. For cetirizine and hydrochlorothiazide 8 TPs each and for fexofenadine 7 TPs were identified. The main TPs of cetirizine and fexofenadine are their respective N-oxides, whereas chlorothiazide forms to almost 100% from hydrochlorothiazide. In the bacteria bioluminescence assay the toxicity was slightly increased only during the ozonation of cetirizine at very high cetirizine concentrations. The main TPs detected in bench-scale experiments were also detected in full-scale ozonation of a municipal wastewater, for >90% elimination of the parent compounds. PMID- 26971811 TI - Tendencies in cerebral aneurism treatment: Analysis of a hospital series. AB - INTRODUCTION AND OBJECTIVE: To discover if there have been changes in the treatment time for SAH in our hospital environment. MATERIAL AND METHODS: Comparative analysis of 571 patients treated at Hospital Universitari la Fe during 2 different time periods. The SAH-OLD group consisted of 462 patients attended consecutively between April 1997 and March 2005, while SAH-NEW comprised 109 patients attended consecutively between March 2007 and April 2010. We analysed demographic factors, risk factors, severity at time of admission, time to arteriography, diagnosis of aneurysm, use of surgical or endovascular treatment and time to treatment, frequency of neurological complications, in hospital deaths, and modified Rankin Scale (mRS) at discharge. RESULTS: Mean time to arteriography was 2.18 +/- 2.5 days for the SAH-OLD group and 2.37 +/- 2.23 days, for the SAH-NEW group (P=.49). Mortality rates for SAH-OLD patients were calculated at 30%, compared to 18.3% in SAH-NEW patients (P=.01). Among patients surviving the hospital stay in the SAH-OLD group, 13.3% had an mRS > 3, compared to 21.3% of survivors in the SAH-NEW group (P=.06). Two hundred forty-five patients in the SAH-OLD group had cerebral aneurysms and 208 were treated (45% of the patient total). Sixty-five of the SAH-NEW patients received treatment (60% of the patient total, P=.007). In the SAH-OLD group, 62.9% of the patients underwent embolisation vs 74.6% in the SAH-NEW group (P=.08). Time to embolisation was 4.7 +/- 8.2 days for SAH-OLD patients and 2.12 +/- 2.2 days for SAH-NEW patients (P=.01). Twenty-two percent of SAH-OLD patients underwent surgery, compared to 25.4% in the SAH-NEW group (P=.62). CONCLUSIONS: Care for SAH patients has improved in this hospital: results include fewer mortalities, a higher number of treatments with a smaller proportion of endovascular treatments, and shorter times to treatment. Elapsed time to arteriography remains stable. PMID- 26971812 TI - Complete pituitary infarction associated with hypothermia and brain death. PMID- 26971813 TI - Identification and differential expression of microRNAs associated with fat deposition in the liver of Wistar rats with nonalcoholic fatty liver disease. AB - The exact mechanism underlying hepatic steatosis in nonalcoholic fatty liver disease (NAFLD) is not clear. Clarifying the full repertoire of microRNAs (miRNAs) in NAFLD rat liver would enhance our understanding of NAFLD pathogenesis. In this study, miRNA expression levels were analyzed in liver tissue from NAFLD Wistar rats, with normal Wistar rats as negative controls. Small RNA libraries were constructed for each sample. A total of 173 conservative miRNAs and 68 potential miRNA candidates were identified. Significant differences in the expression levels of 101 conserved miRNAs were identified between the two groups. The results of GO annotation and KEGG pathway analysis revealed that some miRNAs were likely involved in the process of liver fat deposition. This study represents the first global miRNA profiling of NAFLD Wistar rat livers, and expands the miRNA repertoire for normal livers. Our findings suggest that miRNAs play important roles in liver fat deposition. PMID- 26971814 TI - Kinetic microplate bioassays for relative potency of antibiotics improved by partial Least Square (PLS) regression. AB - Microbiological assays are widely used to estimate the relative potencies of antibiotics in order to guarantee the efficacy, safety, and quality of drug products. Despite of the advantages of turbidimetric bioassays when compared to other methods, it has limitations concerning the linearity and range of the dose response curve determination. Here, we proposed to use partial least squares (PLS) regression to solve these limitations and to improve the prediction of relative potencies of antibiotics. Kinetic-reading microplate turbidimetric bioassays for apramacyin and vancomycin were performed using Escherichia coli (ATCC 8739) and Bacillus subtilis (ATCC 6633), respectively. Microbial growths were measured as absorbance up to 180 and 300min for apramycin and vancomycin turbidimetric bioassays, respectively. Conventional dose-response curves (absorbances or area under the microbial growth curve vs. log of antibiotic concentration) showed significant regression, however there were significant deviation of linearity. Thus, they could not be used for relative potency estimations. PLS regression allowed us to construct a predictive model for estimating the relative potencies of apramycin and vancomycin without over fitting and it improved the linear range of turbidimetric bioassay. In addition, PLS regression provided predictions of relative potencies equivalent to those obtained from agar diffusion official methods. Therefore, we conclude that PLS regression may be used to estimate the relative potencies of antibiotics with significant advantages when compared to conventional dose-response curve determination. PMID- 26971815 TI - Local bleaching thresholds established by remote sensing techniques vary among reefs with deviating bleaching patterns during the 2012 event in the Arabian/Persian Gulf. AB - A severe bleaching event affected coral communities off the coast of Abu Dhabi, UAE in August/September, 2012. In Saadiyat and Ras Ghanada reefs ~40% of the corals showed signs of bleaching. In contrast, only 15% of the corals were affected on Delma reef. Bleaching threshold temperatures for these sites were established using remotely sensed sea surface temperature (SST) data recorded by MODIS-Aqua. The calculated threshold temperatures varied between locations (34.48 degrees C, 34.55 degrees C, 35.05 degrees C), resulting in site-specific deviations in the numbers of days during which these thresholds were exceeded. Hence, the less severe bleaching of Delma reef might be explained by the lower relative heat stress experienced by this coral community. However, the dominance of Porites spp. that is associated with the long-term exposure of Delma reef to elevated temperatures, as well as the more pristine setting may have additionally contributed to the higher coral bleaching threshold for this site. PMID- 26971817 TI - Stress in mangrove forests: Early detection and preemptive rehabilitation are essential for future successful worldwide mangrove forest management. AB - Mangrove forest rehabilitation should begin much sooner than at the point of catastrophic loss. We describe the need for "mangrove forest heart attack prevention", and how that might be accomplished in a general sense by embedding plot and remote sensing monitoring within coastal management plans. The major cause of mangrove stress at many sites globally is often linked to reduced tidal flows and exchanges. Blocked water flows can reduce flushing not only from the seaward side, but also result in higher salinity and reduced sediments when flows are blocked landward. Long-term degradation of function leads to acute mortality prompted by acute events, but created by a systematic propensity for long-term neglect of mangroves. Often, mangroves are lost within a few years; however, vulnerability is re-set decades earlier when seemingly innocuous hydrological modifications are made (e.g., road construction, blocked tidal channels), but which remain undetected without reasonable large-scale monitoring. PMID- 26971816 TI - Accumulation and temporal changes of PCDD/Fs and dioxin-like PCBs in finless porpoises (Neophocaena asiaeorientalis) from Korean coastal waters: Tracking the effectiveness of regulation. AB - Temporal trend studies are useful to evaluate the effectiveness of regulations on local pollutants. The emission of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (PCBs) has been regulated by the Korean government in accordance with the Stockholm Convention. The accumulation and temporal trends of PCDD/Fs and dioxin-like PCBs were investigated in finless porpoises (Neophocaena asiaeorientalis) collected in Korean waters. Median concentrations of PCDDs, PCDFs, non-ortho PCBs, and mono ortho PCBs were 1.0, 1.1, 0.1, and 1.8pgTEQ/g lipid weight, respectively, which were lower than threshold values for marine mammals. Age- and sex-dependent accumulation patterns were found for PCDFs and DL-PCBs. Temporal trends in finless porpoises collected between 2003 and 2010 showed significant reduction rates of 57%, 54%, 69%, and 60% for PCDDs, PCDFs, non-ortho PCBs, and mono-ortho PCBs, respectively. Our results suggest that the regulations on dioxin-like contaminants have been effective for marine mammals in Korea. PMID- 26971818 TI - Initial experience with application of single layer modified Kugel mesh for inguinal hernia repair: Case series of 72 consecutive patients. AB - OBJECTIVE: This is an initial review of the safety and efficacy of anterior preperitoneal modified Kugel (MK) mesh herniorrhaphy application without using optional onlay mesh. METHODS: We retrospectively reviewed patients who underwent herniorrhaphy by a single surgeon from July 1st, 2009 to December 31st, 2010. During these 18 months, a total of 72 patients underwent single-layer MK mesh herniorrhaphy. Anterior preperitoneal approach was used to place the mesh. If the patient's inguinal hernia defect did not exceed the memory ring of MK mesh, the onlay mesh was omitted. Postoperative results (wound infection, recurrence, and chronic pain/discomfort) were recorded and analyzed. RESULTS: A total of 72 patients underwent anterior preperitoneal single layer MK mesh herniorrhaphy. One patient had recurrent hernia after 1 year and was treated with a laparoscopic transabdominal preperitoneal operation. The most common postoperative complaint was mild soreness which was self-resolving after 1 month. Mean total operative time (skin to skin) was 73 minutes. The average hospital stay was 2 days. Most of the postoperative complications including soreness (14%), pain for > 3 months (1.4%), and scrotal hematoma (1.4%) were self-resolving. One patient experienced wound infection, which was treated with oral antibiotics. One patient had recurrence 1 year after the operation. CONCLUSION: The postoperative complication and recurrence rates of single-layer MK mesh herniorrhaphy was comparable with previously reported tension-free repair. Single-layer application is safe and feasible. A longer follow-up period and larger study group with a control group are needed to verify our method. PMID- 26971819 TI - Cell-of-Origin-Specific 3D Genome Structure Acquired during Somatic Cell Reprogramming. AB - Forced expression of reprogramming factors can convert somatic cells into induced pluripotent stem cells (iPSCs). Here we studied genome topology dynamics during reprogramming of different somatic cell types with highly distinct genome conformations. We find large-scale topologically associated domain (TAD) repositioning and alterations of tissue-restricted genomic neighborhoods and chromatin loops, effectively erasing the somatic-cell-specific genome structures while establishing an embryonic stem-cell-like 3D genome. Yet, early passage iPSCs carry topological hallmarks that enable recognition of their cell of origin. These hallmarks are not remnants of somatic chromosome topologies. Instead, the distinguishing topological features are acquired during reprogramming, as we also find for cell-of-origin-dependent gene expression patterns. PMID- 26971820 TI - CRISPR Interference Efficiently Induces Specific and Reversible Gene Silencing in Human iPSCs. AB - Developing technologies for efficient and scalable disruption of gene expression will provide powerful tools for studying gene function, developmental pathways, and disease mechanisms. Here, we develop clustered regularly interspaced short palindromic repeat interference (CRISPRi) to repress gene expression in human induced pluripotent stem cells (iPSCs). CRISPRi, in which a doxycycline-inducible deactivated Cas9 is fused to a KRAB repression domain, can specifically and reversibly inhibit gene expression in iPSCs and iPSC-derived cardiac progenitors, cardiomyocytes, and T lymphocytes. This gene repression system is tunable and has the potential to silence single alleles. Compared with CRISPR nuclease (CRISPRn), CRISPRi gene repression is more efficient and homogenous across cell populations. The CRISPRi system in iPSCs provides a powerful platform to perform genome-scale screens in a wide range of iPSC-derived cell types, dissect developmental pathways, and model disease. PMID- 26971821 TI - External bioresorbable airway rigidification to treat refractory localized tracheomalacia. AB - OBJECTIVES/HYPOTHESIS: Our study evaluates the efficacy of extraluminal bioresorbable plates to treat refractory localized airway malacia in patients undergoing corrective surgery for complex multilevel laryngotracheal stenosis. STUDY DESIGN: Retrospective case series. METHODS: Secondary malacic airway segments were characterized (severity, site, type) by a dynamic transnasal flexible laryngotracheobronchoscopy before surgery. Extraluminal bioresorbable plates were used to stabilize the malacic segment through a transcervical approach under intraoperative flexible endoscopic guidance. Results were evaluated subjectively and by a postoperative dynamic endoscopy. We report our experience in seven patients (6 children, 1 adult). RESULTS: External tracheal stiffening allowed complete or partial resolution of refractory proximal airway malacia in six of seven complex cases described (result in one case is awaited). It allowed quick decannulation in four of seven patients who experienced multiple previous failures. Decannulation failures were due to recurrence of stenosis. With up to 2 years of follow-up, we report no direct complications related to the presence of extraluminal bioresorbable plates around the airway. CONCLUSION: Extraluminal biodegradable tracheal stiffening represents a valid therapeutic option in select cases of upper airway malacia. It can be highly useful in cases of complex multilevel airway obstructions. External stiffening needs to be planned on a case-to-case basis according to the type of malacia and must be performed under endoscopic guidance. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2605 2610, 2016. PMID- 26971822 TI - May-Thurner syndrome: A curious syndrome in the ED. PMID- 26971823 TI - Topical ethyl chloride to reduce pain associated with venous catheterization: a randomized crossover trial. AB - OBJECTIVE: To compare pain associated with venous catheterization after administration of topical ethyl chloride vs placebo among emergency department health care providers. METHODS: We conducted a randomized, double-blind, placebo controlled, crossover trial among a convenience sample of health care provider volunteers in a tertiary care urban emergency department. We randomly allocated subjects to initial treatment (ethyl chloride vs sterile water aerosol spray) and catheterization site (left or right antecubital fossa). After venous catheterization placement and discontinuation, subjects underwent a 5-minute washout period. All subjects then underwent venous catheterization in the contralateral antecubital fossa after administration of the alternative agent. We measured all outcomes after discontinuation of the second catheter. The primary outcome was difference in pain verbal numeric rating scale score (0-10) between the 2 agents. Secondary outcomes included preferred agent (binary) and future willingness to use agent on patients (5-point Likert scale). RESULTS: Thirty eight health care providers were recruited; all completed the study. Median pain verbal numeric rating scale scores were 4 (interquartile range, 2-5) for placebo vs 2 (1-4) for ethyl chloride. The effect size for pain reduction with ethyl chloride compared with placebo was 2 (95% confidence interval, 0.5-2; P = .001). Most subjects (68.4%) preferred ethyl chloride to placebo. Five-point Likert scale scores measuring willingness to use preferred product on future patients were higher by 2 (95% confidence interval, 1-3) among subjects preferring ethyl chloride vs placebo. CONCLUSIONS: We found that topical ethyl chloride yields a greater reduction in pain associated with venous catheterization compared with topical placebo. PMID- 26971824 TI - Perspectives on Treatment for Nonalcoholic Steatohepatitis. AB - It is important to provide treatment to patients with nonalcoholic steatohepatitis (NASH) because one third of patients with the metabolic syndrome die of liver disease. Basic research studies have elucidated mechanisms of NASH pathogenesis, which could lead to therapeutic targets. Health agencies have confirmed strategies for the optimal management of NASH and approved new drugs and treatments, which urgently are needed. The US Food and Drug Administration recently endorsed end points for NASH therapy. The reversal of NASH with no evidence of progression to advanced fibrosis has been defined as the end point for phase 2b and phase 3 trials in patients with NASH and early stage fibrosis. Although a decrease in the nonalcoholic fatty liver disease activity score could serve as an end point in clinical trials, it is not clear whether patients with lower scores have a lower risk of progression to advanced fibrosis. End points for clinical trials of patients with NASH cirrhosis currently are based on model for end-stage liver disease and Child-Pugh-Turcotte scores, as well as the hepatic venous pressure gradient. Different strategies are being explored to reduce liver diseases that are linked to a sedentary lifestyle, overeating, and genetic factors. In association with insulin resistance and deregulation of the lipid metabolism (accumulation of lipotoxins that promote hepatic lipogenesis, adipose tissue lipolysis, and impaired beta-oxidation), these factors could increase the risk of liver steatosis with necroinflammatory lesions and fibrosis. We review the pathogenic mechanisms of NASH and therapeutic options, as well as strategies that are being developed for the treatment of injury to the liver and other organs. PMID- 26971825 TI - Glucose-Dependent Insulinotropic Peptide Stimulates Glucagon-Like Peptide 1 Production by Pancreatic Islets via Interleukin 6, Produced by alpha Cells. AB - BACKGROUND & AIMS: Glucose-dependent insulinotropic peptide (GIP) induces production of interleukin 6 (IL6) by adipocytes. IL6 increases production of glucagon-like peptide (GLP)-1 by L cells and alpha cells, leading to secretion of insulin from beta cells. We investigated whether GIP regulates GLP1 and glycemia via IL6. METHODS: We obtained samples of human pancreatic islets and isolated islets from mice; human alpha cells and beta cells were sorted by flow cytometry and incubated with GIP. Islets were analyzed by quantitative polymerase chain reaction and immunohistochemistry. BKS.Cg-Dock7m+/+ Leprdb/J db/db mice (diabetic mice) and db/+ mice, as well as C57BL/6J IL6-knockout mice (IL6-KO) and C57BL/6J mice with the full-length Il6 gene (controls), were fed a chow or a high-fat diet; some mice were given injections of recombinant GIP, IL6, GLP, a neutralizing antibody against IL6 (anti-IL6), lipopolysaccharide, and/or IL1B. Mice were given a glucose challenge and blood samples were collected and analyzed. RESULTS: Incubation of mouse and human pancreatic alpha cells with GIP induced their production of IL6, leading to production of GLP1 and insulin secretion from pancreatic islets. This did not occur in islets from IL6-KO mice or in islets incubated with anti-IL6. Incubation of islets with IL1B resulted in IL6 production but directly reduced GLP1 production. Incubation of mouse islets with the sodium glucose transporter 2 inhibitor dapagliflozin induced production of GLP1 and IL6. Injection of control mice with GIP increased plasma levels of GLP1, insulin, and glucose tolerance; these effects were amplified in mice given lipopolysaccharide but reduced in IL6-KO mice or in mice given anti-IL6. Islets from diabetic mice had increased levels of IL1B and IL6, compared with db/+ mice, but injection of GIP did not lead to production of GLP1 or reduce glycemia. CONCLUSIONS: In studies of pancreatic islets from human beings and mice, we found that GIP induces production of IL6 by alpha cells, leading to islet production of GLP1 and insulin. This process is regulated by inflammation, via IL1B, and by sodium glucose transporter 2. In diabetic mice, increased islet levels of IL6 and IL1B might increase or reduce the production of GLP1 and affect glycemia. PMID- 26971826 TI - Liver Transplantation for Alcoholic and Nonalcoholic Fatty Liver Disease: Pretransplant Selection and Posttransplant Management. AB - Alcoholic fatty liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are common causes of chronic liver disease throughout the world. Although they have similar histologic features, a diagnosis of NAFLD requires the absence of significant alcohol use. ALD is seen commonly in patients with a long-standing history of excessive alcohol use, whereas NAFLD is encountered commonly in patients who have developed complications of obesity, such as insulin resistance, hypertension, and dyslipidemia. Lifestyle contributes to the development and progression of both diseases. Although alcohol abstinence can cause regression of ALD, and weight loss can cause regression of NAFLD, many patients with these diseases develop cirrhosis. ALD and NAFLD account for nearly 30% of liver transplants performed in the United States. Patients receiving liver transplants for ALD or NAFLD have similar survival times as patients receiving transplants for other liver disorders. Although ALD and NAFLD recur frequently after liver transplantation, graft loss from disease recurrence after transplantation is uncommon. Cardiovascular disease and de novo malignancy are leading causes of long-term mortality in liver transplant recipients with ALD or NAFLD. PMID- 26971827 TI - Causes of Death Among Patients Infected with HIV at a Tertiary Care Hospital in China: An Observational Cohort Study. AB - The objective of this study was to elucidate the causes of death and mortality in a cohort of inpatients infected with HIV. The causes of death and mortality were evaluated by using the clinical data of 1,076 patients admitted to the Center for Infectious Diseases, Beijing Ditan Hospital, between January 1, 2009, and November 30, 2012, and who were followed for 6 months after discharge. During the 4-year study period, 216 patients had died by the 6-month follow-up (mortality rate, 20.1%). Opportunistic infections were the most common causes of death (42.0%), followed by malignancies (23.1%), unexplained central nervous system infections and occupying lesions (18.1%), infectious shock (10.2%), severe hepatitis and decompensated cirrhosis (3.2%), sudden death (1.4%), lactic acidosis (0.9%), and uremia (0.9%). The strong risk factors for mortality were cost constraints and unaffordable further diagnosis and treatment (adjusted hazard ratio [AHR] = 134.394, 95% confidence interval [CI] = 25.748-701.481, p < .001), unexplained etiologies (AHR = 12.551, 95% CI = 6.642-23.716, p < .001), and multiple complications (AHR = 5.798, 95% CI = 2.973-11.308, p < .001). Mortality was not associated with CD4 levels or combined antiretroviral therapy (cART) in a cohort of inpatients at a special hospital for HIV/AIDS patients in China. AIDS-related infections and malignancies were the most common causes of death in patients infected with HIV, and improvement of the etiological diagnosis would help physicians provide appropriate treatment and reduce mortality rates. PMID- 26971829 TI - Surgical management of Juxtafacet cysts in the lumbar spine. AB - INTRODUCTION: Juxtafacet cysts of the lumbar spine are extradural degenerative lesions associated with symptoms of lower back pain and radiculopathy. The aim of this study is to evaluate the efficacy of surgery and address controversial issues in the treatment of symptomatic juxta facet cysts in the Neurosurgical Department of our hospital and review of the literature. METHODS: Data from seven patients (age range 58-68 years, mean age 63 years) with low back and radicular leg pain due to a lumbar facet joint cyst were retrospectively analyzed. Demographic data, cyst level, presence of concominant local pathology, treatment and results of treatment were recorded. After surgery there was no case of a recurrent cyst during the follow-up period. The mean follow-up period of patients at the time of this study was 4 years. RESULTS: All patients had back pain, while five also experienced unilateral radicular leg pain and two had bilateral leg pain. Four patients had neurogenic claudication. MRI identified the cyst and highlighted underlying pathology in all cases. All patients underwent surgical cyst excision. Post-operatively, all patients showed a total resolution of symptoms with sustained benefit at final evaluation. CONCLUSION: Surgery is a safe and effective treatment for lumbar juxtafacet cysts. PMID- 26971828 TI - Influence of sub-specialty surgical care on outcomes for pediatric emergency general surgery patients in a low-middle income country. AB - BACKGROUND: Whether adult general surgeons should handle pediatric emergencies is controversial. In many resource-limited settings, pediatric surgeons are not available. The study examined differences in surgical outcomes among children/adolescents managed by pediatric and adult general surgery teams for emergency general surgical (EGS) conditions at a university-hospital in South Asia. METHODS: Pediatric patients (<18y) admitted with an EGS diagnosis (March 2009-April 2014) were included. Patients were dichotomized by adult vs. pediatric surgical management team. Outcome measures included: length of stay (LOS), mortality, and occurrence of >=1 complication(s). Descriptive statistics and multivariable regression analyses with propensity scores to account for potential confounding were used to compare outcomes between the two groups. Quasi experimental counterfactual models further examined hypothetical outcomes, assuming that all patients had been treated by pediatric surgeons. RESULTS: A total of 2323 patients were included. Average age was 7.1y (+/-5.5 SD); most patients were male (77.7%). 1958 (84.3%) were managed by pediatric surgery. The overall probability of developing a complication was 1.8%; 0.9% died (all adult general surgery). Patients managed by adult general surgery had higher risk adjusted odds of developing complications (OR [95%CI]: 5.42 [2.10-14.00]) and longer average LOS (7.98 vs. 5.61 days, p < 0.01). 39.8% fewer complications and an 8.2% decrease in LOS would have been expected if all patients had been managed by pediatric surgery. CONCLUSION: Pediatric patients had better post-operative outcomes under pediatric surgical supervision, suggesting that, where possible in resource-constrained settings, resources should be allocated to promote development and staffing of pediatric surgical specialties parallel to adult general surgical teams. PMID- 26971830 TI - [The role of the paediatrician in post-partum depression]. PMID- 26971832 TI - Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis. AB - Succinate is an important metabolite at the cross-road of several metabolic pathways, also involved in the formation and elimination of reactive oxygen species. However, it is becoming increasingly apparent that its realm extends to epigenetics, tumorigenesis, signal transduction, endo- and paracrine modulation and inflammation. Here we review the pathways encompassing succinate as a metabolite or a signal and how these may interact in normal and pathological conditions.(1). PMID- 26971833 TI - Long term effect of switching to darunavir/ritonavir in HIV infected patients previously on protease inhibitor therapy. PMID- 26971834 TI - A promiscuous recognition mechanism between GPR17 and SDF-1: Molecular insights. AB - Recent data and publications suggest a promiscuous behaviour for GPR17, a class-A GPCR operated by different classes of ligands, such as uracil nucleotides, cysteinyl-leukotrienes and oxysterols. This observation, together with the ability of several class-A GPCRs to form homo- and hetero-dimers, is likely to unveil new pathophysiological roles and novel emerging pharmacological properties for some of these GPCRs, including GPR17. This receptor shares structural, phylogenetic and functional properties with some chemokine receptors, CXCRs. Both GPR17 and CXCR2 are operated by oxysterols, and both GPR17 and CXCR ligands have been demonstrated to have a role in orchestrating inflammatory responses and oligodendrocyte precursor cell differentiation to myelinating cells in acute and chronic diseases of the central nervous system. Here, by combining in silico modelling data with in vitro validation in (i) a classical reference pharmacological assay for GPCR activity and (ii) a model of maturation of primary oligodendrocyte precursor cells, we demonstrate that GPR17 can be activated by SDF-1, a ligand of chemokine receptors CXCR4 and CXCR7, and investigate the underlying molecular recognition mechanism. We also demonstrate that cangrelor, a GPR17 orthosteric antagonist, can block the SDF-1-mediated activation of GPR17 in a concentration-dependent manner. The ability of GPR17 to respond to different classes of GPCR ligands suggests that this receptor modifies its function depending on the extracellular mileu changes occurring under specific pathophysiological conditions and advocates it as a strategic target for neurodegenerative diseases with an inflammatory/immune component. PMID- 26971835 TI - Effects of glycaemic variability on cardiac remodelling after reperfused myocardial infarction: Evaluation of streptozotocin-induced diabetic Wistar rats using cardiac magnetic resonance imaging. AB - AIMS: In addition to hyperglycaemia, glycaemic variability seems to be associated with poor outcomes after acute myocardial infarction. This study explored the impact of glycaemic variability in diabetic Wistar rats subjected to myocardial ischaemia/reperfusion. METHODS: Animals with streptozotocin-induced diabetes received insulin either to maintain stable hyperglycaemia (Dh group) or to generate glycaemic variability (Dv). After experimental myocardial ischaemia/reperfusion was surgically induced, 7T cardiac magnetic resonance imaging (CMR) was performed at weeks 1 (w1) and 3 (w3). RESULTS: Twenty-six rats were randomized [sham group (S): n=5; control group (C): n=7; Dh group: n=6; and Dv group: n=8]. The mean amplitude of glucose reflecting glycaemic variability was higher in the Dv than in the Dh group (9.1+/-2.7mmol/L vs 5.9+/-1.9mmol/L; P<0.05). CMR assessment at w3 revealed ventricular enlargement in both Dh and Dv groups compared with the C and S groups (end-diastolic volume: 1.60+/-0.22 and 1.36+/-0.30mL/kg compared with 1.11+/-0.13 and 0.87+/-0.11mL/kg, respectively; P<0.05). Circumferential strain was altered between w1 and w3 in the remote area only in the Dv group, resulting in a lower value in this group than in the S, C and Dh groups (-0.11+/-0.01 vs -0.17+/-0.05, -0.15+/-0.03 and -0.16+/-0.03, respectively; P<0.05). In addition, at w3, oedema was also higher in the remote area in the Dv than in the C group (18.3+/-4.9ms vs 14.5+/-1.7ms, respectively; P<0.05). CONCLUSION: In the context of experimental myocardial ischaemia/reperfusion, our results suggest that glycaemic variability might have a potentially deleterious impact on myocardial outcomes beyond the classical glucose metrics. PMID- 26971836 TI - Bone mineral density is associated with left ventricular diastolic function in men with type 2 diabetes. AB - AIMS: Type 2 diabetes (T2DM) is associated with chronic heart failure and cardiomyopathy. Furthermore, low bone mineral density (BMD) predicts incident heart failure. Abnormal diastolic function reflects early changes in cardiac function and plays a key role in the development of heart failure. The purpose of this study was to investigate the association between BMD with left ventricular (LV) diastolic function in men with T2DM. METHODS: In all, 344 men with T2DM and 331 age-matched control subjects were enrolled. BMD measurements were performed. LV diastolic function and structure were assessed by echocardiographic evaluation. RESULTS: BMD was lower in men with T2DM than in controls. There were significant differences in the level of parameters reflecting cardiac structure and LV diastolic function between two groups. Moreover, LV diastolic function and structure parameters also showed significant differences as BMD reduced in T2DM group. BMD at femoral neck was correlated with LV diastolic function parameters in T2DM after adjusting for confounding factors. Multivariable logistic analysis revealed that osteopenia and osteoporosis were associated with diastolic dysfunction compared to the control in men with T2DM. However, no association between BMD and LV diastolic function was found in subjects without T2DM. CONCLUSION: Osteoporosis may be an independent factor for LV diastolic dysfunction in men with T2DM. Our data suggested that early detection of abnormal BMD should warrant for early search of undetected LV diastolic dysfunction in diabetic men. PMID- 26971837 TI - Conformation-induced regioselective and divergent opening of epoxides by fluoride: facile access to hydroxylated fluoro-piperidines. AB - Utilizing molecular conformation as a controlling factor, epoxide-containing 2 aryl-piperidines can be ring-opened with the reagent combination of tetrabutylammonium fluoride (TBAF) and potassium bifluoride (KHF2) in a regioselective and divergent fashion. Four different types of hydroxylated fluoro piperidines, valuable building blocks in drug development, were readily synthesized using this method. The basic nature of the reagent combination allowed a one-pot deprotection/ring opening process, which increased the efficacy of this transformation. PMID- 26971838 TI - VALIDITY OF USING WAIST AND HIP CIRCUMFERENCE MEASUREMENTS TO DETERMINE BODY COMPOSITION OF YOUNG SYRIAN MEN. AB - This study examined the relation between waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHpR), waist-to-height ratio (WHtR) and triceps skin-fold thickness and percentage body fat in young Syrian men. The aim was to develop equations that can use these anthropometric characteristics to estimate percentage body fat in this group of subjects. A total of 2470 healthy Syrian men aged 18-19 years were enrolled in the study in 2010-2011. The anthropometric characteristics of all subjects were measured. The percentage body fat of 213 of the subjects was determined using the deuterium dilution (DD) technique as a reference method. The validity of using WC, HC, WHpR and WHtR to calculate percentage body fat, in comparison with the reference method (DD technique), was assessed by calculating biases and limits of agreement. The estimates of percentage body fat using 'WC' and 'WC with triceps skin-fold' measurements ranged from 13.00+/-5.56% to 14.55+/-8.63%, and were lower than those determined using the reference method (21.32+/-6.42%). A better prediction equation is proposed for young adults, based on a multiple linear regression model using WC, HC and WHtR. PMID- 26971839 TI - Preface - Neuroendocrine tumours. PMID- 26971840 TI - A short history of neuroendocrine tumours and their peptide hormones. AB - The discovery of neuroendocrine tumours of the gastrointestinal tract and pancreas started in 1870, when Rudolf Heidenhain discovered the neuroendocrine cells, which can lead to the development of these tumours. Siegfried Oberndorfer was the first to introduce the term carcinoid in 1907. The pancreatic islet cells were first described in 1869 by Paul Langerhans. In 1924, Seale Harris was the first to describe endogenous hyperinsulinism/insulinoma. In 1942 William Becker and colleagues were the first to describe the glucagonoma syndrome. The first description of gastrinoma by Robert Zollinger and Edwin Ellison dates from 1955. The first description of the VIPoma syndrome by John Verner and Ashton Morrison dates from 1958. In 1977, the groups of Lars-Inge Larsson and Jens Rehfeld, and of Om Ganda reported the first cases of somatostatinoma. But only in 2013, Jens Rehfeld and colleagues described the CCK-oma syndrome. The most recently updated WHO classification for gastrointestinal neuroendocrine tumours dates from 2010. PMID- 26971841 TI - Specific biology of neuroendocrine tumors: Peptide receptors as molecular targets. AB - Neuroendocrine tumors (NET) are characterized by a high over-expression of many different peptide hormone receptors. These receptors represent important molecular targets for imaging and therapy, using either radiolabeled or cold peptide analogs. The clinically best established example is somatostatin receptor targeting. A relatively new application is glucagon-like peptide 1 (GLP-1) receptor-targeted imaging of insulinomas, which is highly sensitive. A potential future candidate for peptide receptor targeting is the gastric inhibitory peptide (GIP) receptor. It was recently found to exhibit a very wide expression in NET and may be a particularly suitable target in somatostatin and GLP-1 receptor negative tumors. With increasing use of peptide receptor targeting, reliable morphologic in vitro tools to assess peptide receptors in tissues are mandatory, such as in vitro receptor autoradiography or thoroughly established immunohistochemical procedures. PMID- 26971842 TI - Histopathology of NET: Current concepts and new developments. AB - The diagnosis of neuroendocrine tumors is based on their histopathologic appearance and immunohistochemical profile. With the WHO 2010 classification formal staging and grading was introduced for gastro-entero-pancreatic NET, however, the nomenclature for lung neuroendocrine tumors still relies on the carcinoid term. In this review we also focus on the situation of neuroendocrine carcinoma of unknown primary, tissue biomarkers and actual controversies in the histopathology of NEN. PMID- 26971843 TI - Gastroenteropancreatic neuroendocrine tumours (GEP-NET) - Imaging and staging. AB - Detection of gastroenteropancreatic neuroendocrine tumours (GEP-NETs) and monitoring of treatment response relies mainly on morphological imaging such as computed tomography (CT) and magnetic resonance imaging (MRI). Molecular imaging techniques also in combination with CT (hybrid imaging) greatly benefit patient management, including better localization of occult tumours and better staging. Somatostatin receptor scintigraphy (SRS) and somatostatin receptor (SSTR) positron emission tomography (PET) play a central role in the diagnostic work-up of patients with well-differentiated GEP-NETs. SSTR PET/CT is superior to SRS and should be used whenever available. (18)F-DOPA and (18)F-FDG PET/CT is inferior to SSTR PET/CT at least in patients with well-differentiated GEP-NETs. Both SSTR PET/CT and SRS have limitations, such as relatively low detection rate of benign insulinomas, poorly differentiated GEP-NETs and liver metastases. New innovations such as SSTR PET/MRI, radiolabelled SSTR antagonists and glucagon-like peptide-1 receptor (GLP-1R) agonists might further improve imaging of GEP-NETs. PMID- 26971844 TI - Neuroendocrine tumor biomarkers: From monoanalytes to transcripts and algorithms. AB - The management of neuroendocrine neoplasia remains a perplexing problem because of the lack of knowledge of the biology of the disease, its late presentation, the relative insensitivity of imaging modalities and a paucity of predictably effective treatment options. A critical limitation is posed by the lack of accurate biomarkers to guide management, monitor the efficacy of therapy and provide a prognostic assessment of disease progress. Currently utilized monoanalyte biomarkers (e.g. chromogranin, serotonin, pancreastatin etc.) exhibit variable metrics, poor sensitivity, specificity, and predictive ability and are rarely used to guide clinical decision making. A National Cancer Institute Neuroendocrine Tumor summit conference held in 2007 noted biomarker limitations to be a crucial unmet need in the management of neuroendocrine tumors. Nevertheless little progress has been made in this field until recently with the consideration of blood transcript analysis, circulating tumor cells and miRNA measurement. Given the complexity and multidimensionality of the neoplastic process itself, the heterogeneity of neuroendocrine tumors (NET) as well as the interaction of the tumor microenvironment, it is not unexpected that no single (monoanalyte) biomarker has proven to be effective. This deduction reflects the growing recognition that use of a monoanalyte to define a multidimensional disease process has inherent flaws. Logic dictates that no single measured parameter can capture the pathobiological diversity of neoplasia and monoanalytes cannot define the multiple variables (proliferation, metabolic activity, invasive potential and metastatic propensity) that constitute tumor growth. Thus far, most biomarkers whether in tissue or blood/urine have been single analytes with varying degrees of sensitivity and specificity and in general have failed to exhibit robust metrics or lacked methodological rigor. Neuroendocrine (NE) disease represents an area of biomarker paucity since the individual biomarkers (gastrin, insulin etc) are not widely applicable to the diverse types of NE neoplasia (NEN). Broad spectrum markers such as CgA have limitations in sensitivity, specificity and reproducibility. This review serves to provide a general background of the evolution of NET biomarkers. It provides an assessment of their current and past usage and limitations in assessing their diagnostic, pathologic and prognostic aspects in respect of NET. It provides a view of the changing methodology of biomarker development and the application of biomathematical analyses to redefining detection and treatment. Finally, it presents a description and consensus on current advances in transcript analysis, miRNA measurement and circulating tumor cell identification. PMID- 26971846 TI - Surgical management of neuroendocrine tumors. AB - During the last decades an increase in the incidence of neuroendocrine tumors (NETs) was observed. Gastroenteropancreatic NETs represent the majority of NETs. Compared with their epithelial counterpart they usually have a more indolent behaviour and surgical resection improves survival. Tumor diameter is one of the main parameter in the decision making process for nonfunctioning forms. Generally, small lesions can be treated conservatively whereas larger tumors should be treated with standard surgical resection and lymphadenectomy. Functioning tumors should be resected regardless the dimension of the lesion. Locally advanced and metastatic disease should be also treated with extended resections, keeping in consideration the grading, size, Ki67, and presence of extra-abdominal disease. In the case of metastases the panel of operative treatment includes resection, ablation, up to liver transplantation. PMID- 26971845 TI - Neuroendocrine tumours - Medical therapy: Biological. AB - Somatostatin analogues (SSA) are well established antisecretory drugs that have been used as first line treatment for symptomatic control in hormonally active neuroendocrine tumours (NET) for three decades. Both available depot formulations of SSA, long-acting repeatable (LAR) octreotide and lanreotide autogel, seem similarly effective and well tolerated, although comparative trials in NET have not been performed. The importance of SSA as antiproliferative treatment has been increasingly recognized during recent years. Two placebo-controlled trials demonstrated significant prolongation of progression free survival under SSA treatment. However, objective response as assessed by imaging is rare. Interferon alpha (IFNalpha) also has antisecretory and antiproliferative efficacy in NET. Due to the less favourable toxicity profile it mainly has a role as add-on option in the refractory setting, especially in carcinoid syndrome patients. Further studies are needed to evaluate the antiproliferative efficacy of the multiligand SSA pasireotide and the role of pegylated IFNalpha. PMID- 26971847 TI - Peptide receptor radionuclide therapy of neuroendocrine tumours. AB - In the past decades, the number of neuroendocrine tumours that are detected is increasing. A relative new and promising therapy for patients with metastasised or inoperable disease is peptide receptor radionuclide therapy (PRRT). This therapy involves an infusion of somatostatin analogues linked to radionuclides like Yttrium-90 or Lutetium-177. Objective response rates are reported in 15-35%. Response rates may vary between type of tumour and radionuclide. Besides the objective response rate, overall survival and progression free survival increase significantly. Also, the quality of life improves as well. Serious side-affects are rare. PRRT is usually well tolerated, also in patients with extensive metastasised disease. Recent studies combined PRRT with other types of therapies. Unfortunately no randomised trials comparing these strategies are available. In the future, more research is needed to evaluate the best therapy combinations or sequence of therapies. PMID- 26971848 TI - Somatic and germline mutations in NETs: Implications for their diagnosis and management. AB - It is now understood that specific somatic and germline mutations may lead to the development of the neuroendocrine tumours (NETs). NETs usually occur as sporadic isolated tumours, although they also may present as part of complex familial endocrine cancer syndromes, such as multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2), Von Hippel-Lindau (VHL) and neurofibromatosis syndromes, tuberous sclerosis, Carney triad and dyad, Reed syndrome and polycythaemia paraganglioma syndromes. Only in MEN2 syndrome is there a specific genotype phenotype correlation, although in both sporadic and syndromic NETs some gene mutations are associated with specific clinico-pathological features and prognosis. There have been several advances in our understanding of the NETs leading to earlier detection and targeted therapeutic treatment, but given the poor prognosis associated with metastatic NETs, it will be necessary to find new biomarkers for the prediction of malignant potential and to find novel therapeutic targets for NETs. PMID- 26971849 TI - Management of follow-up of neuroendocrine neoplasias. AB - Neuroendocrine neoplasias (NEN) comprise heterogeneous epithelial neoplasms with a large variety of clinical presentations, treatment options and outcomes. Since potentially all NEN bear malignant potential it is important for long-term clinical management and improvement of outcome to decide on successful and oncologically and economically meaningful follow-up strategies. Evidence-based outcome data validating specific follow-up strategies are, however, not available to date and thus outcome data, known prognostic factors and clinical experience guide the decisions on follow-up regimens. The review summarizes general recommendations as well as specific considerations based on tumor entities, clinicopathological tumor characteristics and clinical experience. Follow-up shall serve the patient to improve outcome, benefit from more effective therapies and suffer less from unnecessary and/or toxic therapeutic interventions and finally preserve or gain a good quality of life. PMID- 26971850 TI - Liver transplantation for the treatment of neuroendocrine liver metastases. AB - Neuroendocrine neoplasms represent a heterogeneous group of cancers arising from a variety of neuroendocrine cell types. In general, these tumors (NET) are asymptomatic and are discovered late once metastatic disease is present (40-80%). The liver is the most common organ involved when metastases occur (40-93%), followed by bone (12-20%) and lungs (8-10%). A number of different therapeutic options are available for patients with hepatic metastases including surgical resection, transplantation, transarterial chemoembolization, radiofrequency and microwave ablation, radioembolization (Y90), chemotherapy, somatostatin analogues and molecular targeted therapies. Surgical resection is still considered the treatment of choice and provides excellent disease control with an overall survival of 47-92%. Liver transplantation has been advocated in selected patients with bilateral unresectable symptomatic liver metastases. The aim of this study is to review the existing literature emphasizing on the role of transplantation to treat patients with liver metastases from NET. PMID- 26971851 TI - Carcinoid heart disease: Diagnosis and management. AB - Hedinger syndrome refers to carcinoid valvular heart disease. The disease is believed to be triggered by vasoactive substances that result in valvular fibrosis. It classically occurs in patients with metastatic carcinoid and preferentially involves the right sided cardiac valves. Affected valves become thickened and retracted, exhibiting regurgitation and sometimes, stenosis. Echocardiography is recommended in patients with carcinoid syndrome and a follow up study is advisable in those who develop a murmur or other symptoms or signs of valvular heart disease. For appropriately selected patients, valve replacement surgery appears to improve outcomes. PMID- 26971852 TI - Establishing a database of Canadian feline mitotypes for forensic use. AB - Hair shed by pet animals is often found and collected as evidence from crime scenes. Due to limitations such as small amount and low quality, mitochondrial DNA (mtDNA) is often the only type of DNA that can be used for linking the hair to a potential contributor. mtDNA has lower discriminatory power than nuclear DNA because multiple, unrelated individuals within a population can have the same mtDNA sequence, or mitotype. Therefore, to determine the evidentiary value of a match between crime scene evidence and a suspected contributor, the frequency of the mitotype must be known within the regional population. While mitotype frequencies have been determined for the United States' cat population, the frequencies are unknown for the Canadian cat population. Given the countries' close proximity and similar human settlement patterns, these populations may be homogenous, meaning a single, regional database may be used for estimating cat population mitotype frequencies. Here we determined the mitotype frequencies of the Canadian cat population and compared them to the United States' cat population. The two cat populations are statistically homogenous, however mitotype B6 was found in high frequency in Canada and extremely low frequency in the United States, meaning a single database would not be appropriate for North America. Furthermore, this work calls attention to these local spikes in frequency of otherwise rare mitotypes, instances of which exist around the world and have the potential to misrepresent the evidentiary value of matches compared to a regional database. PMID- 26971853 TI - The influence of electronic cigarette age purchasing restrictions on adolescent tobacco and marijuana use. AB - OBJECTIVE: In the United States, many states have established minimum legal purchase ages for electronic nicotine delivery systems (ENDS) to ban adolescent purchases, but these policies may also affect other related substance use. We explore whether ENDS are substitutes or complements for cigarettes, cigars, smokeless tobacco, and marijuana among adolescents by using variation in state level implementation of ENDS age purchasing restrictions. METHODS: We linked data on ENDS age purchasing restrictions to state- and year-specific rates of adolescent tobacco and marijuana use in 2007-2013 from the Youth Risk Behavior Surveillance System. This data provides a nationally representative sample of adolescents who attend public and private schools. We performed a fixed effect regression analysis exploring the influence of ENDS age purchasing restrictions on outcomes of tobacco use and marijuana use, controlling for state and year fixed characteristics, age-race cohorts, cigarette excise taxes, and cigarette indoor use restrictions. RESULTS: For cigarette use, we separate our results into cigarette use frequency. We found causal evidence that ENDS age purchasing restrictions increased adolescent regular cigarette use by 0.8 percentage points. ENDS age purchasing restrictions were not associated with cigar use, smokeless tobacco use, or marijuana use. CONCLUSIONS: We document a concerning trend of cigarette smoking among adolescents increasing when ENDS become more difficult to purchase. PMID- 26971856 TI - Biological and antipathogenic activities of ribosome-inactivating proteins from Phytolacca dioica L. AB - BACKGROUND: The species from the genus Phytolacca constitute one of the best sources of ribosome-inactivating proteins (RIPs) that have been used both in the therapy against virus and tumors and in the construction of transgenic plants resistant to virus, bacteria, fungi and insects. Here we investigate new activities of three representative RIPs from Phytolacca dioica (dioicin 2, PD-S2 and PD-L4). RESULTS: The three RIPs displayed, in addition to already reported activities, rRNA N-glycosylase activities against plant, bacterial and fungal ribosomes. Additionally dioicin 2 and PD-L4 displayed endonuclease activity on a supercoiled plasmid DNA, and dioicin 2 and PD-S2 arrested the growth of the fungus Penicillium digitatum. Furthermore, dioicin 2 induced caspase activation and apoptosis in cell cultures. CONCLUSIONS: The different activities of the RIPs from Phytolacca dioica may explain the antipathogenic properties attributed to these RIPs in plants and their antiviral and antitumoral effects. In spite of the similarity in their rRNA N-glycosylase and DNA polynucleotide:adenosine glycosylase activities, they differed in their activities against viral RNA, plasmid DNA, fungi and animal cultured cells. This suggests that the presence of isoforms might optimize the response of the plant against several types of pathogens. GENERAL SIGNIFICANCE: RIPs from Phytolacca can induce plant resistance or tumor cell death not only by means of ribosome inactivation but also by the activities found in this report. Furthermore, the induction of cell death by different mechanisms turns these RIPs into more useful tools for cancer treatment rendering the selection of RIP-resistant mutants impossible. PMID- 26971858 TI - The interaction and binding of flavonoids to human serum albumin modify its conformation, stability and resistance against aggregation and oxidative injuries. AB - BACKGROUND: Interactions of ligands with proteins imply changes in the properties of the macromolecules that may deeply modify their biological activities and conformations and allow them to acquire new and, sometimes, unexpected abilities. The flavonoid phloretin has several pharmacological properties that are starting to be elucidated, one of which is the well-known inhibition of glucose transport. METHODS: The interactions of phloretin to human serum albumin have been investigated by fluorescence, UV-visible, FTIR spectroscopy, native electrophoresis, protein ligand docking studies, fluorescence and scanning electron microscopy. RESULTS: Spectroscopic investigations suggest that the flavonoid binds to human serum albumin inducing a decrease in alpha-helix structures as shown by deconvolution of FTIR Amide I' band. Fluorescence and displacement studies highlight modifications of environment around Trp214 with the primary binding site located in the Sudlow's site I. In the hydrophobic cavity of subdomain IIA, molecular modeling studies suggest that phloretin is in non-planar conformation and hydrogen-bonded with Ser202 and Ser454. These changes make HSA able to withstand protein degradation due to HCLO and fibrillation. GENERAL SIGNIFICANCE: Our work aims to open new perspectives as far as the binding of flavonoids to HSA are concern and shows as the properties of both compounds can be remarkable modified after the complex formation, resulting, for instance, in a protein structure much more resistant to oxidation and fibrillation. This article is part of a Special Issue entitled "Science for Life" Guest Editor: Dr. Austen Angell, Dr. Salvatore Magazu and Dr. Federica Migliardo. PMID- 26971857 TI - Ebselen and analogs as inhibitors of Bacillus anthracis thioredoxin reductase and bactericidal antibacterials targeting Bacillus species, Staphylococcus aureus and Mycobacterium tuberculosis. AB - BACKGROUND: Bacillus anthracis is the causative agent of anthrax, a disease associated with a very high mortality rate in its invasive forms. METHODS: We studied a number of ebselen analogs as inhibitors of B. anthracis thioredoxin reductase and their antibacterial activity on Bacillus subtilis, Staphylococcus aureus, Bacillus cereus and Mycobacterium tuberculosis. RESULTS: The most potent compounds in the series gave IC(50) values down to 70 nM for the pure enzyme and minimal inhibitory concentrations (MICs) down to 0.4 MUM (0.12 MUg/ml) for B. subtilis, 1.5 MUM (0.64 MUg/ml) for S. aureus, 2 MUM (0.86 MUg/ml) for B. cereus and 10 MUg/ml for M. tuberculosis. Minimal bactericidal concentrations (MBCs) were found at 1-1.5 times the MIC, indicating a general, class-dependent, bactericidal mode of action. The combined bacteriological and enzymological data were used to construct a preliminary structure-activity-relationship for the benzoisoselenazol class of compounds. When S. aureus and B. subtilis were exposed to ebselen, we were unable to isolate resistant mutants on both solid and in liquid medium suggesting a high resistance barrier. CONCLUSIONS: These results suggest that ebselen and analogs thereof could be developed into a novel antibiotic class, useful for the treatment of infections caused by B. anthracis, S. aureus, M. tuberculosis and other clinically important bacteria. Furthermore, the high barrier against resistance development is encouraging for further drug development. GENERAL SIGNIFICANCE: We have characterized the thioredoxin system from B. anthracis as a novel drug target and ebselen and analogs thereof as a potential new class of antibiotics targeting several important human pathogens. PMID- 26971859 TI - A rapid-response fluorescent probe for the sensitive and selective detection of human albumin in plasma and cell culture supernatants. AB - A rapid-response fluorescent probe ACDM was developed for the selective and sensitive detection of human albumin (HA) via binding onto a non-drug binding site. ACDM was successfully used to detect trace HA in various biological samples including diluted plasma and cell culture supernatants. PMID- 26971862 TI - Identification and exclusion of intermediates of photocatalytic CO2 reduction on TiO2 under conditions of highest purity. AB - Using a high-purity gas phase photoreactor and highly sensitive trace gas analysis, new insights into the mechanism of photocatalytic CO2 reduction on TiO2 P25 have been obtained. The reactor design and sample pretreatment excludes product formation from intermediates. Apart from CO2, the only other reactant offered to the catalyst is water. The main products found on this prominent photocatalyst are methane and carbon monoxide. To distinguish between the three possible mechanisms reported in previous studies, likely intermediates of the reaction were added to the TiO2 photocatalyst and their reactivity was followed by gas chromatographic analysis. Based on the results, we can clearly rule out CO as intermediate of any photocatalytic reaction pathway on TiO2, because CO was not converted at all within a course of six hours. An improvement of carbonate formation on TiO2 brought about by surface-doping with sodium decreased product yields, so carbonates are unlikely intermediates as well. Methanol, formaldehyde and formic acid were exclusively oxidized back to CO2. We thus support a mechanism running over C2-intermediates, and we tested our hypothesis by reacting glyoxal, glyoxylic acid, acetic acid and acetaldehyde on TiO2. The reactions of acetaldehyde and acetic acid led to product distributions very similar to those obtained from CO2 under the standard reaction conditions, strongly supporting the C2 mechanism. This mechanism can also explain the small amounts of ethane usually found in the product mixture. PMID- 26971854 TI - Alcohol: A Simple Nutrient with Complex Actions on Bone in the Adult Skeleton. AB - BACKGROUND: Alcohol is an important nonessential component of diet, but the overall impact of drinking on bone health, especially at moderate levels, is not well understood. Bone health is important because fractures greatly reduce quality of life and are a major cause of morbidity and mortality in the elderly. Regular alcohol consumption is most common following skeletal maturity, emphasizing the importance of understanding the skeletal consequences of drinking in adults. METHODS: This review focuses on describing the complex effects of alcohol on the adult skeleton. Studies assessing the effects of alcohol on bone in adult humans as well as skeletally mature animal models published since the year 2000 are emphasized. RESULTS: Light to moderate alcohol consumption is generally reported to be beneficial, resulting in higher bone mineral density (BMD) and reduced age-related bone loss, whereas heavy alcohol consumption is generally associated with decreased BMD, impaired bone quality, and increased fracture risk. Bone remodeling is the principal mechanism for maintaining a healthy skeleton in adults and dysfunction in bone remodeling can lead to bone loss and/or decreased bone quality. Light to moderate alcohol may exert beneficial effects in older individuals by slowing the rate of bone remodeling, but the impact of light to moderate alcohol on bone remodeling in younger individuals is less certain. The specific effects of alcohol on bone remodeling in heavy drinkers are even less certain because the effects are often obscured by unhealthy lifestyle choices, alcohol-associated disease, and altered endocrine signaling. CONCLUSIONS: Although there have been advances in understanding the complex actions of alcohol on bone, much remains to be determined. Limited evidence implicates age, skeletal site evaluated, duration, and pattern of drinking as important variables. Few studies systematically evaluating the impact of these factors have been conducted and should be made a priority for future research. In addition, studies performed in skeletally mature animals have potential to reveal mechanistic insights into the precise actions of alcohol and associated comorbidity factors on bone remodeling. PMID- 26971863 TI - Unconventional Luminescent Centers in Metastable Phases Created by Topochemical Reduction Reactions. AB - A low-temperature topochemical reduction strategy is used herein to prepare unconventional phosphors with luminescence covering the biological and/or telecommunications optical windows. This approach is demonstrated by using Bi(III)-doped Y2O3 (Y(2-x)Bi(x)O3) as a model system. Experimental results suggest that topochemical treatment of Y(2-x)Bi(x)O3 using CaH2 creates randomly distributed oxygen vacancies in the matrix, resulting in the change of the oxidation states of Bi to lower oxidation states. The change of the Bi coordination environments from the [BiO6] octahedra in Y(2-x)Bi(x)O3 to the oxygen-deficient [BiO(6-z)] polyhedra in reduced phases leads to a shift of the emission maximum from the visible to the near-infrared region. The generality of this approach was further demonstrated with other phosphors. Our findings suggest that this strategy can be used to explore Bi-doped or other classes of luminescent systems, thus opening up new avenues to develop novel optical materials. PMID- 26971860 TI - Review: Translational GTPases. AB - Translational GTPases (trGTPases) play key roles in facilitating protein synthesis on the ribosome. Despite the high degree of evolutionary conservation in the sequences of their GTP-binding domains, the rates of GTP hydrolysis and nucleotide exchange vary broadly between different trGTPases. EF-Tu, one of the best-characterized model G proteins, evolved an exceptionally rapid and tightly regulated GTPase activity, which ensures rapid and accurate incorporation of amino acids into the nascent chain. Other trGTPases instead use the energy of GTP hydrolysis to promote movement or to ensure the forward commitment of translation reactions. Recent data suggest the GTPase mechanism of EF-Tu and provide an insight in the catalysis of GTP hydrolysis by its unusual activator, the ribosome. Here we summarize these advances in understanding the functional cycle and the regulation of trGTPases, stimulated by the elucidation of their structures on the ribosome and the progress in dissecting the reaction mechanism of GTPases. (c) 2016 Wiley Periodicals, Inc. Biopolymers 105: 463-475, 2016. PMID- 26971861 TI - Nonstimulated rabbit phonation model: Cricothyroid approximation. AB - OBJECTIVES/HYPOTHESIS: To describe a nonstimulated in vivo rabbit phonation model using an Isshiki type IV thyroplasty and uninterrupted humidified glottal airflow to produce sustained audible phonation. STUDY DESIGN: Prospective animal study. METHODS: Six New Zealand white breeder rabbits underwent a surgical procedure involving an Isshiki type IV thyroplasty and continuous airflow delivered to the glottis. Phonatory parameters were examined using high-speed laryngeal imaging and acoustic and aerodynamic analysis. Following the procedure, airflow was discontinued, and sutures remained in place to maintain the phonatory glottal configuration for microimaging using a 9.4 Tesla imaging system. RESULTS: High speed laryngeal imaging revealed sustained vocal fold oscillation throughout the experimental procedure. Analysis of acoustic signals revealed a mean vocal intensity of 61 dB and fundamental frequency of 590 Hz. Aerodynamic analysis revealed a mean airflow rate of 85.91 mL/s and subglottal pressure of 9 cm H2 O. Following the procedure, microimaging revealed that the in vivo phonatory glottal configuration was maintained, providing consistency between the experimental and postexperimental laryngeal geometry. The latter provides a significant milestone that is necessary for geometric reconstruction and to allow for validation of computational simulations against the in vivo rabbit preparation. CONCLUSION: We demonstrate a nonstimulated in vivo phonation preparation using an Isshiki type IV thyroplasty and continuous humidified glottal airflow in a rabbit animal model. This preparation elicits sustained vocal fold vibration and phonatory measures that are consistent with our laboratory's prior work using direct neuromuscular stimulation for evoked phonation. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:1589-1594, 2016. PMID- 26971864 TI - Perceptions of pharmacy clerkship students and clinical preceptors regarding preceptors' teaching behaviors at Gondar University in Ethiopia. AB - This study aimed to compare the perceptions of pharmacy clerkship students and clinical preceptors of preceptors' teaching behaviors at Gondar University. A cross-sectional study was conducted among pharmacy clerkship students and preceptors during June 2014 and December 2015. A 52-item structured questionnaire was self-administered to 126 students and 23 preceptors. The responses are presented using descriptive statistics. The Mann-Whitney U test was applied to test the significance of differences between students and preceptors. The response rate was 89.4% for students and 95.6% for preceptors. Statistically significant differences were observed in the responses regarding two of the five communication skills that were examined, six of the 26 clinical skills, and five of the 21 parameters involving feedback. The mean scores of preceptors (2.6/3) and students (1.9/3) regarding instructors' ability to answer questions were found to be significantly different (P= 0.01). Students and preceptors gave mean scores of 1.9 and 2.8, respectively, to a question regarding preceptors' application of appropriate up-to-date knowledge to individual patients (P= 0.00). Significant differences were also noted between students and instructors regarding the degree to which preceptors encouraged students to evaluate their own performance (P= 0.01). Discrepancies were noted between students and preceptors regarding preceptors' teaching behaviors. Preceptors rated their teaching behaviors more highly than students did. Short-term training is warranted for preceptors to improve some aspects of their teaching skills. PMID- 26971865 TI - Voices of Chemical Biology: Charting the Next Decade. PMID- 26971867 TI - "Death is my Heir"--Ferroptosis Connects Cancer Pharmacogenomics and Ischemia Reperfusion Injury. AB - Although they are key to precision medicine, pharmacokinetics and pharmacogenomics are currently plagued with inconsistent results. In this issue of Cell Chemical Biology, Shimada et al. (2016) use cell line selectivity and appropriate filters to improve the consistency and to identify biomarkers for the selectivity of lethal compounds. These insights may be useful for our understanding of how necrosis and ischemic injury are regulated. PMID- 26971868 TI - Combinatorial Lanthipeptides from a Ruminant Bacterium. AB - New tools and molecules are spurring a renewed interest in natural products. In this issue of Cell Chemical Biology, Zhao and van der Donk (2016) report a single lantibiotic cluster encoding different alpha- and beta-peptides, each with its dedicated processing enzyme. A number of clever experiments led to in vitro production of these molecules. PMID- 26971869 TI - The importance of being chaperoned: HSP90 and necroptosis. AB - Necroptosis is a form of regulated cell death implicated in a range of inflammatory diseases. In this issue of Cell Chemical Biology, Li et al. (2016) describe a novel inhibitor of necroptosis that targets the chaperone protein HSP90. PMID- 26971870 TI - Monstrous Mycobacterial Lipids. AB - When it comes to lipid diversity, no bacterial genus approaches Mycobacterium. In this issue of Cell Chemical Biology, Burbaud et al. (2016) provide a multi-genic working model for the biosynthesis of trehalose polyphleate (TPP), one of the largest known lipids in mycobacteria. They demonstrate that this lipid is made by diverse mycobacterial species, including those of medical importance. PMID- 26971871 TI - Uncovering the Serine Hydrolytic Landscape of Mycobacterium tuberculosis. AB - In this issue of Cell Chemical Biology, Ortega et al. (2016) present a study utilizing a click-chemistry-enabled fluorophosphonate for activity-based identification of serine hydrolases, pinpointing a range of proteins including previously annotated hypotheticals. The application of this technology on both actively replicating and non-replicating Mycobacterium tuberculosis gives us a glimpse of its serine hydrolytic landscape during different stages of metabolic activity. PMID- 26971872 TI - Computing Substrate Selectivity in a Peptide Transporter. AB - The human proton-coupled peptide transporter 1 (PepT1) is responsible for the absorption of di- and tri-peptides from the diet and peptide-like drugs. In this issue of Cell Chemical Biology, Samsudin et al. (2016) use an integrated computational and experimental approach to provide new insights into understanding substrate selectivity of PepTSt, a prokaryotic homolog of the human PepT1. PMID- 26971874 TI - Arctic Vortex changes alter the sources and isotopic values of precipitation in northeastern US. AB - Altered atmospheric circulation, reductions in Arctic sea ice, ocean warming, and changes in evaporation and transpiration are driving changes in the global hydrologic cycle. Precipitation isotopic (delta(18)O and delta(2)H) measurements can help provide a mechanistic understanding of hydrologic change at global and regional scales. To study the changing water cycle in the northeastern US, we examined the longest (1968-2010) record of precipitation isotope values, collected at the Hubbard Brook Experimental Forest in New Hampshire, US (43( degrees )56'N, 71( degrees )45'W). We found a significant reduction in delta(18)O and delta(2)H values over the 43-year record, coupled with a significant increase in d-excess values. This gradual reduction in delta(18)O and delta(2)H values unexpectedly occurred during a period of regional warming. We provide evidence that these changes are governed by the interactions among the Atlantic Multidecadal Oscillation, loss of Arctic sea ice, the fluctuating jet stream, and regular incursions of polar air into the northeastern US. PMID- 26971875 TI - Nanostructured Conjugated Polymers for Energy-Related Applications beyond Solar Cells. AB - To meet the ever-increasing requirements for the next generation of sustainable and versatile energy-related devices, conjugated polymers, which have potential advantages over small molecules and inorganic materials, are among the most promising types of green candidates. The properties of conjugated polymers can be tuned through modification of the structure and incorporation of different functional moieties. In addition, superior performances can be achieved as a result of the advantages of nanostructures, such as their large surface areas and the shortened pathways for charge transfer. Therefore, nanostructured conjugated polymers with different properties can be obtained to be applied in different energy-related organic devices. This review focuses on the application and performance of the recently reported nanostructured conjugated polymers for high performance devices, including rechargeable lithium batteries, microbial fuel cells (MFCs), thermoelectric generators, and photocatalytic systems. The design strategies, reaction mechanisms, advantages, and limitations of nanostructured conjugated polymers are further discussed in each section. Finally, possible routes to improve the performances of the current systems are also included in the conclusion. PMID- 26971873 TI - Regulation of Virulence in Staphylococcus aureus: Molecular Mechanisms and Remaining Puzzles. AB - The agr locus encodes a quorum-sensing (QS) circuit required for the virulence of a spectrum of Gram-positive pathogens and is, therefore, regarded as an important target for the development of chemotherapeutics. In recent years, many of the biochemical events in the Staphylococcus aureus agr circuit have been reconstituted and subject to quantitative analysis in vitro. This work, in conjunction with structural studies on several key players in the signaling circuit, has furnished mechanistic insights into the regulation and evolution of the agr QS system. Here, we review this progress and discuss the remaining open questions in the area. We also highlight advances in the discovery of small molecule agr modulators and how the newly available biochemical and structural information might be leveraged for the design of next-generation therapeutics targeting the agr system. PMID- 26971876 TI - Evaluation of Clinical Metrology Instrument in Dogs with Osteoarthritis. AB - BACKGROUND: In veterinary clinical pain studies, there is a paucity of data on test-retest variability in Clinical Metrology Instruments (CMIs), and it is unknown whether CMIs should be administered using independent (respondents not permitted to see previous answers) or dependent (respondents shown previous answers) interviewing. OBJECTIVES: To compare baseline variability in CMIs designed to assess pain in dogs with osteoarthritis, and compare CMI scores using independent (InD) and dependent interviewing (DI) for the Canine Brief Pain Inventory (CBPI) and the Client-Specific Outcome Measures (CSOM). ANIMALS: Fifty one client-owned dogs with radiographic evidence of osteoarthritis and associated pain. METHODS: Clinical Metrology Instruments data were collected during 2 randomized, double-masked, placebo-controlled, proof of principle pilot studies with parallel treatment groups. Enrolled dogs received either placebo or antinerve growth factor antibody (NV-01). RESULTS: Agreement between baseline CMI scores was good (CBPI Pain P = .29, CBPI Interference P = .32, CSOM P = .036, LOAD P = .67, HCPI P = .27), being best for the LOAD (ICC = 0.89). CMI responses collected during independent and dependent interviewing were not statistically different (CBPI Pain P = .33, CBPI Interference P = .28, CSOM P = .42) and showed good agreement. Additionally, dependent interviewing resulted in increased treatment effect sizes. CONCLUSIONS AND CLINICAL IMPORTANCE: There is little difference between independent and dependent interviewing, however, dependent interviewing resulted in increased treatment effect sizes. By using dependent interviewing, investigators could increase clinical trial power through minimal change to study design. Further research is warranted to investigate the use of dependent interviewing. PMID- 26971878 TI - hTERT promotes cell adhesion and migration independent of telomerase activity. AB - hTERT, a catalytic component of human telomerase, is undetectable in normal somatic cells but up-regulated in cancer and stem cells where telomere length is maintained by telomerase. Accumulated evidence indicates that hTERT may have noncanonical functions beyond telomerase by regulating the expression of particular genes. However, comprehensive identification of the genes regulated by hTERT is unavailable. In this report, we expressed WT hTERT and hTERTmut which displays dysfunctional catalytic activity, in human U2OS cancer cells and VA-13 immortalized fibroblast cells, both of which lack endogenous hTERT and hTR expression. Changes in gene expression induced by hTERT and hTERT-mut expression were determined by genome-wide RNA-seq and verified by qPCR. Our results showed that hTERT affects different genes in two cell lines, implying that the regulation of gene expression by hTERT is indirect and cell type dependent. Moreover, functional analysis identifies cell adhesion-related genes that have been changed by hTERT in both cell lines. Adhesion experiments revealed that hTERT expression significantly increases cell adhesion. Monolayer wound healing and transwell assays demonstrated increased cell migration upon hTERT expression. These results provide new evidence to support a noncanonical function for hTERT in promoting tumorigenesis. PMID- 26971879 TI - An Approach to Breast Cancer Immunotherapy: The Apoptotic Activity of Recombinant Anti-Interleukin-6 Monoclonal Antibodies in Intact Tumour Microenvironment of Breast Carcinoma. AB - Current work is one of our comprehensive preclinical studies, a new approach to breast cancer (BC) immunotherapy through induction of tumour cell apoptosis. Tumour growth is not just a result of uncontrolled cell proliferation but also of reduced apoptosis. High levels of interleukin-6 (IL-6) are associated with metastatic BC and correlated with poor survival as it promotes growth of tumour initiating cells during early tumorigenesis protecting these cells from apoptosis. Therefore, this study aims at investigating the potential of anti-IL-6 monoclonal antibodies to suppress IL-6 proliferative/anti-apoptotic activities in intact tumour microenvironment of BC. Fresh sterile tumour and normal breast tissue specimens were taken from 50 female Egyptian patients with BC undergoing radical mastectomy. A unique tissue culture system designed to provide cells of each intact tumour/normal tissue sample with its proper microenvironment either supplemented or not with anti-IL-6 monoclonal antibodies. To evaluate the apoptotic activity of anti-IL-6 as a novel candidate for BC treatment strategy, we compared its effects with those obtained using tumour necrosis-related apoptosis-inducing ligand TRAIL as an established apoptotic agent. Our results revealed that levels of either anti-IL-6- or TRAIL-induced apoptosis in the tumour or normal tissue cultures were significantly higher than those in their corresponding untreated ones (P < 0.001). No statistically significant differences have been found between apoptosis levels induced by anti-IL-6 monoclonal antibodies and those induced by TRAIL. Recombinant anti-IL-6 monoclonal antibodies could represent a novel effective element of immunotherapeutic treatment strategy for BC. The selectivity and anti-apoptotic potential of anti-IL-6 is highly hopeful in IL-6- abundant BC tumour microenvironment. PMID- 26971877 TI - Stability and function of adult vasculature is sustained by Akt/Jagged1 signalling axis in endothelium. AB - The signalling pathways operational in quiescent, post-development vasculature remain enigmatic. Here we show that unlike neovascularization, endothelial Akt signalling in established vasculature is crucial not for endothelial cell (EC) survival, but for sustained interactions with pericytes and vascular smooth muscle cells (VSMCs) regulating vascular stability and function. Inducible endothelial-specific Akt1 deletion in adult global Akt2KO mice triggers progressive VSMC apoptosis. In hearts, this causes a loss of arteries and arterioles and, despite a high capillary density, diminished vascular patency and severe cardiac dysfunction. Similarly, endothelial Akt deletion induces retinal VSMC loss and basement membrane deterioration resulting in vascular regression and retinal atrophy. Mechanistically, the Akt/mTOR axis controls endothelial Jagged1 expression and, thereby, Notch signalling regulating VSMC maintenance. Jagged1 peptide treatment of Akt1DeltaEC;Akt2KO mice and Jagged1 re-expression in Akt-deficient endothelium restores VSMC coverage. Thus, sustained endothelial Akt1/2 signalling is critical in maintaining vascular stability and homeostasis, thereby preserving tissue and organ function. PMID- 26971882 TI - Comparing RADseq and microsatellites to infer complex phylogeographic patterns, an empirical perspective in the Crucian carp, Carassius carassius, L. AB - The conservation of threatened species must be underpinned by phylogeographic knowledge. This need is epitomized by the freshwater fish Carassius carassius, which is in decline across much of its European range. Restriction site associated DNA sequencing (RADseq) is increasingly used for such applications; however, RADseq is expensive, and limitations on sample number must be weighed against the benefit of large numbers of markers. This trade-off has previously been examined using simulation studies; however, empirical comparisons between these markers, especially in a phylogeographic context, are lacking. Here, we compare the results from microsatellites and RADseq for the phylogeography of C. carassius to test whether it is more advantageous to genotype fewer markers (microsatellites) in many samples, or many markers (SNPs) in fewer samples. These data sets, along with data from the mitochondrial cytochrome b gene, agree on broad phylogeographic patterns, showing the existence of two previously unidentified C. carassius lineages in Europe: one found throughout northern and central-eastern European drainages and a second almost exclusively confined to the Danubian catchment. These lineages have been isolated for approximately 2.15 m years and should be considered separate conservation units. RADseq recovered finer population structure and stronger patterns of IBD than microsatellites, despite including only 17.6% of samples (38% of populations and 52% of samples per population). RADseq was also used along with approximate Bayesian computation to show that the postglacial colonization routes of C. carassius differ from the general patterns of freshwater fish in Europe, likely as a result of their distinctive ecology. PMID- 26971880 TI - Candida albicans repetitive elements display epigenetic diversity and plasticity. AB - Transcriptionally silent heterochromatin is associated with repetitive DNA. It is poorly understood whether and how heterochromatin differs between different organisms and whether its structure can be remodelled in response to environmental signals. Here, we address this question by analysing the chromatin state associated with DNA repeats in the human fungal pathogen Candida albicans. Our analyses indicate that, contrary to model systems, each type of repetitive element is assembled into a distinct chromatin state. Classical Sir2-dependent hypoacetylated and hypomethylated chromatin is associated with the rDNA locus while telomeric regions are assembled into a weak heterochromatin that is only mildly hypoacetylated and hypomethylated. Major Repeat Sequences, a class of tandem repeats, are assembled into an intermediate chromatin state bearing features of both euchromatin and heterochromatin. Marker gene silencing assays and genome-wide RNA sequencing reveals that C. albicans heterochromatin represses expression of repeat-associated coding and non-coding RNAs. We find that telomeric heterochromatin is dynamic and remodelled upon an environmental change. Weak heterochromatin is associated with telomeres at 30 degrees C, while robust heterochromatin is assembled over these regions at 39 degrees C, a temperature mimicking moderate fever in the host. Thus in C. albicans, differential chromatin states controls gene expression and epigenetic plasticity is linked to adaptation. PMID- 26971881 TI - Functional characterization of ent-copalyl diphosphate synthase, kaurene synthase and kaurene oxidase in the Salvia miltiorrhiza gibberellin biosynthetic pathway. AB - Salvia miltiorrhiza Bunge is highly valued in traditional Chinese medicine for its roots and rhizomes. Its bioactive diterpenoid tanshinones have been reported to have many pharmaceutical activities, including antibacterial, anti inflammatory, and anticancer properties. Previous studies found four different diterpenoid biosynthetic pathways from the universal diterpenoid precursor (E,E,E)-geranylgeranyl diphosphate (GGPP) in S. miltiorrhiza. Here, we describe the functional characterization of ent-copalyl diphosphate synthase (SmCPSent), kaurene synthase (SmKS) and kaurene oxidase (SmKO) in the gibberellin (GA) biosynthetic pathway. SmCPSent catalyzes the cyclization of GGPP to ent-copalyl diphosphate (ent-CPP), which is converted to ent-kaurene by SmKS. Then, SmKO catalyzes the three-step oxidation of ent-kaurene to ent-kaurenoic acid. Our results show that the fused enzyme SmKS-SmCPSent increases ent-kaurene production by several fold compared with separate expression of SmCPSent and SmKS in yeast strains. In this study, we clarify the GA biosynthetic pathway from GGPP to ent kaurenoic acid and provide a foundation for further characterization of the subsequent enzymes involved in this pathway. These insights may allow for better growth and the improved accumulation of bioactive tanshinones in S. miltiorrhiza through the regulation of the expression of these genes during developmental processes. PMID- 26971884 TI - Postnatal development of Mongolian gerbil female prostate: An immunohistochemical and 3D modeling study. AB - The development of the prostate in male rodents, which involves complex epithelial-mesenchymal interactions between the urogenital sinus epithelium (UGE) and the urogenital sinus mesenchyme (UGM), has been deeply studied. In females, however, this process is not very clear. In this study, the postnatal development of the prostate in female Mongolian gerbils employing three-dimensional (3D) reconstructions, histochemical, and immunohistochemical techniques was characterized. It was observed that prostatic branching and differentiation in females was induced by a single mesenchyme localized at a ventrolateral position, which was named as ventrolateral mesenchyme (VLM); furthermore, the canalization of solid buds began on the third postnatal day (P3) and the branching morphogenesis on P5. We observed secretions in the acini at the end of the first month, and, on P45, the acini were completely differentiated. The strong cell proliferation phase in the first week coincided with the mesenchymal expression of estrogen receptor 1 (ESR1). The expression of androgen receptor (AR) paralleled cell differentiation, and, on P30, immunolabelling with p63 was restricted to basal cells. This study serves as a baseline parameter for future research on disruptions that could affect the development of the female prostate. PMID- 26971883 TI - Sustained PI3K Activation exacerbates BLM-induced Lung Fibrosis via activation of pro-inflammatory and pro-fibrotic pathways. AB - Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease with limited treatment options. Additionally, the lack of a complete understanding of underlying immunological mechanisms underscores the importance of discovering novel options for therapeutic intervention. Since the PI3K/PTEN pathway in myeloid cells influences their effector functions, we wanted to elucidate how sustained PI3K activity induced by cell-type specific genetic deficiency of its antagonist PTEN modulates IPF, in a murine model of bleomycin-induced pulmonary fibrosis (BIPF). We found that myeloid PTEN deficient mice (PTEN(MyKO)), after induction of BIPF, exhibit increased TGF-beta1 activation, mRNA expression of pro collagens and lysyl oxidase as well as augmented collagen deposition compared to wild-type littermates, leading to enhanced morbidity and decreased survival. Analysis of alveolar lavage and lung cell composition revealed that PTEN(MyKO) mice exhibit reduced numbers of macrophages and T-cells in response to bleomycin, indicating an impaired recruitment function. Interestingly, we found dysregulated macrophage polarization as well as elevated expression and release of the pro fibrotic cytokines IL-6 and TNF-alpha in PTEN(MyKO) mice during BIPF. This might point to an uncontrolled wound healing response in which the inflammatory as well as tissue repair mechanisms proceed in parallel, thereby preventing resolution and at the same time promoting extensive fibrosis. PMID- 26971885 TI - Endosomal sorting complexes required for transport-0 is essential for fungal development and pathogenicity in Fusarium graminearum. AB - Fusarium graminearum is an important plant pathogen that causes head blight of major cereal crops. The vacuolar protein sorting (Vps) protein Vps27 is a component of ESCRT-0 involved in the multivesicular body (MVB) sorting pathway during endocytosis. In this study, we investigated the function of FgVps27 using a gene replacement strategy. The FgVPS27 deletion mutant (DeltaFgvps27) exhibited a reduction in growth rate, aerial hyphae formation and hydrophobicity. It also showed increased sensitivity to cell wall-damaging agents and to osmotic stresses. In addition, FgHog1, the critical component of high osmolarity glycerol response pathway, was mis-localized in the DeltaFgvps27 mutant upon NaCl treatment. Furthermore, the DeltaFgvps27 mutant was defective in conidial production and was unable to generate perithecium in sexual reproduction. The depletion of FgVPS27 also caused a significant reduction in virulence. Further analysis by domain-specific deletion revealed that the FYVE domain was essential for the FgVps27 function and was necessary for the proper localization of FgVps27 GFP and endocytosis. Another component of ESCRT-0, the FgVps27-interacting partner FgHse1, also played an important role in F. graminearum development and pathogenesis. Overall, our results indicate that ESCRT-0 components play critical roles in a variety of cellular and biological processes. PMID- 26971887 TI - Yellowish nail pigmentation caused by sunitinib. PMID- 26971888 TI - Panniculitis in juvenile dermatomyositis: Report of a case and review of the published work. AB - We report a 15-year-old girl who presented with indurated, subcutaneous nodules in addition to classical findings of juvenile dermatomyositis. Histopathological examination confirmed the diagnosis of panniculitis associated with juvenile dermatomyositis. Considering that panniculitis is a rare cutaneous manifestation of juvenile dermatomyositis, we present a patient with a brief review of the published work to highlight the importance of keeping juvenile dermatomyositis in mind among the etiologies of pediatric panniculitis. PMID- 26971886 TI - Cerebro-costo-mandibular syndrome: Clinical, radiological, and genetic findings. AB - Cerebro-Costo-Mandibular syndrome (CCMS) is a rare autosomal dominant condition comprising branchial arch-derivative malformations with striking rib-gaps. Affected patients often have respiratory difficulties, associated with upper airway obstruction, reduced thoracic capacity, and scoliosis. We describe a series of 12 sporadic and 4 familial patients including 13 infants/children and 3 adults. Severe micrognathia and reduced numbers of ribs with gaps are consistent findings. Cleft palate, feeding difficulties, respiratory distress, tracheostomy requirement, and scoliosis are common. Additional malformations such as horseshoe kidney, hypospadias, and septal heart defect may occur. Microcephaly and significant developmental delay are present in a small minority of patients. Key radiological findings are of a narrow thorax, multiple posterior rib gaps and abnormal costo-transverse articulation. A novel finding in 2 patients is bilateral accessory ossicles arising from the hyoid bone. Recently, specific mutations in SNRPB, which encodes components of the major spliceosome, have been found to cause CCMS. These mutations cluster in an alternatively spliced regulatory exon and result in altered SNRPB expression. DNA was available from 14 patients and SNRPB mutations were identified in 12 (4 previously reported). Eleven had recurrent mutations previously described in patients with CCMS and one had a novel mutation in the alternative exon. These results confirm the specificity of SNRPB mutations in CCMS and provide further evidence for the role of spliceosomal proteins in craniofacial and thoracic development. PMID- 26971889 TI - Liver receptor homolog 1 influences blastocyst hatching in pigs. AB - Liver receptor homolog 1 (Lrh1, also known as Nr5a2) belongs to the orphan nuclear receptor superfamily and has diverse functions in development, metabolism, and cell differentiation and death. Lrh1 regulates the expression of Oct4, which is a key factor of early embryonic differentiation. However, the role of Lrh1 in early development of mammalian embryo is unknown. In the present study, the localization, Lrh1 mRNA expression, and LRH1 protein levels in porcine early parthenotes were examined by immunofluorescence and real-time reverse transcription polymerase chain reaction. To determine the role of Lrh1 in porcine early embryo development, the parthenotes were treated with the specific LRH1 antagonist 505601. The immunofluorescence signal for LRH1 was only observed in the nucleus of blastocysts. The blastocyst developmental rate in the presence of 50 and 100 MUM 505601 was significantly lower than that in the control group. The blastocyst hatching rate was also reduced in the presence of 50 and 100 MUM 505601 than that under control conditions. The latter effect was possibly due to the decreased expression of hatching-related genes such as Fn1, Itgalpha5, and Cox2 upon the inhibition of Lrh1. Incubation with the LRH1 antagonist also increased the number of apoptotic cells among the blastocysts. Moreover, LRH1 inhibition enhanced the expression of the pro-apoptotic genes Bax and Casp3, and reduced the expression of the anti-apoptotic gene Bcl2. Lrh1 inhibition also led to significant decrease in the expression levels of Oct4 mRNA and octamer-binding transcription factor 4 (OCT4) protein in the blastocysts. In conclusion, Lrh1 affects blastocyst formation and hatching in porcine embryonic development through the regulation of OCT4 expression and cell apoptosis. PMID- 26971891 TI - Leeftijdsgeassocieerde cognitieve functiestoornissen: Cognitive aging in a longitudinal perspective: the Maastricht Aging Study (MAAS). AB - Cognitive dysfunctions in old individuals can be a precursor of dementia. The Maastricht Aging Study (MAAS) was designed to characterize the usual and pathological aging of cognitive function. The study involves a group of 1,900 initially healthy individuals who will be followed-upfor a period of 12 years with respect to health characteristics and neurocognitive status. For this purpose a sample was drawn from a patient register of collaborating family practices, stratified for age (range 24 to 81 years), sex and general ability level. Rationale and design of MAAS are discussed and also some findings from the cross-sectional baseline measurement: general aspects of memory and attention, cognitive functioning after brain trauma and general anesthesia, physical condition (fitness, morbidity and vascular risk factors) as predictor of cognitive function, and finally cognitive complaints and metamemory. PMID- 26971892 TI - The role of serotonin in Parkinsons' Disease: An integrated approach for research of motor, cognitive and affective symptoms with functional intervention studies. AB - Serotonin seems to play an important role in the regulation of dopaminergic and cholinergic neurotransmitter activities. In patients with Parkinsons' Disease, serotonergic activity is generally reduced, which is considered a compensating mechanism for the reduced dopaminergic activity. At the same time, reduction of serotonin activity may play a role in the expression of cognitive and affective symptoms. Functional intervention with serotonergic agents makes it possible to temporarily enhance or reduce the availability of serotonin in the brain. This will provide the opportunity to study motor, cognitive and affective symptoms in an integrated approach. This type of research has hardly been preformed in patients with Parkinson's Disease. PMID- 26971890 TI - Functional compensation for the loss of testis-specific poly(A)-binding protein, PABPC2, during mouse spermatogenesis. AB - Mouse testes contain several isoforms of cytoplasmic poly(A)-binding proteins (PABPCs), including ubiquitous PABPC1 and testis-specific PABPC2/PABPt. PABPC2 is characterized by its absence from translationally active polyribosomes and elongating spermatids. To elucidate the function of PABPC2 in spermatogenesis, we produced mutant mice lacking PABPC2. The PABPC2-null mice showed normal fertility. The processes of spermatogenesis and sperm migration in the testes and epididymides, respectively, were normal in the mutant mice. When the involvement of PABPC2 in translational regulation of haploid-specific mRNAs was examined, these mRNAs were correctly transcribed in round spermatids and translated in elongating spermatids. Moreover, immunoblot analysis revealed low abundance of PABPC2 relative to PABPC1 in spermatogenic cells. These results suggest that PABPC2 may be either functionally redundant with other PABPCs (including PABPC1) or largely dispensable for translational regulation during spermiogenesis. PMID- 26971893 TI - Psychopathologie en Pathogenese van enkele behavioural phenotypes. AB - Description of psychopathological symptoms in mentally retarded subjects is of great heuristic value because of the association with a known genetic disorder as well as the heterogenous and atypical phenomenology. The concept of behavioural phenotypes postulates a specific relationship between gene defect and behaviour, although considerable overlap between syndromes and differences within syndromes concerning behavioural manifestations are frequently observed. Since syndrome specific psychiatric disorders can be established too, the term psychopathological phenotype seems to be appropriate. PMID- 26971894 TI - Neuropsychiatrie aspects of HIV infection. AB - Human immuno deficiency virus may cause a broad spectrum of psychiatric sequelae. In this review we discus the possible associations between HIV infection with psychosis, mild neurocognitive disorder and dementia. The cerebral reserve model gives an explanation why HIV infected individuals with low educational level and/or intravenous drug users are more vulnerable to direct and indirect neurotoxic effects of HIV. PMID- 26971895 TI - Antipsychotics, movement disorders and fine motor performances: new device for the measurement of bradykinesia and tremor. AB - This article reviews the results of an exploratory study on the relationship between the ratings of bradykinesia, obtained by the Schedule for the Assessment of Drug-Induced Movement Disorders (SADIMoD), and the performances on writing and drawing tasks. The pen movements made during these tasks were recorded by means of an electronic digitizing tablet, a special electronic pen and a personal computer. This study was aimed at finding objective parameters for the severity of (antipsychotic-induced) bradykinesia. The results show that the writing tablet device is appropriate at finding movement variables that are related to the clinical ratings for bradykinesia: high scores for bradykinesia involved slowing on a number of duration measures during the execution of the writing and drawing tasks. We were also able to measure (postural) tremor by means of the writing tablet. However, an accelerometer seems to be more appropriate in this respect. PMID- 26971896 TI - Evaluation of the application of carbohydrate deficient transferin in a general hospital; recommendations for use. AB - We performed a retrospective evaluation of the use of carbohydrate deficient transferrin (CDT) in a general hospital, for diagnosing alcohol abuse. The high specificity for the CDT test and lower sensitivity as reported in the literature were confirmed. Alcohol anamnesis proved rather often to be incomplete. In intensive care medicine, the CDT investigation could be used as a guide to diagnoses and treatment, especially for patients that are difficult to communicate with. For being of use here, results of the CDT determination should be available within a day. CDT proved to be of use also in psychiatric medicine, the test being of help in clarifying the patients acohol addiction. PMID- 26971898 TI - Surgical Complications and Their Repercussions. AB - PURPOSE: Surgical complications have a significant impact on intended quality of care. The aim of our study was to identify factors that contribute to the propagation of additional postoperative complications. MATERIALS AND METHODS: Over a 1-year period, we prospectively identified and retrospectively reviewed data on all patients who experienced a surgical complication within 30 days of their procedure. A complication was defined as any deviation from the expected postoperative course and was described using the Clavien-Dindo classification. Data reviewed included length of stay (LOS), Clavien grade, readmission status, and management of the complication. Surgeries were stratified into retroperitoneal, pelvic, and endoscopic procedures. The association between complications and Clavien grade was measured using Spearman rank-order correlation. The probability of subsequent complications and readmission was measured using exact logistic regression. RESULTS: Of the 4414 patients who underwent a urologic procedure, 191 (4.3%) had at least one complication. One hundred thirty-four (70%) of these patients had more than one complication, 84 (44%) had more than three complications, and 12 (6.3%) had up to a seventh complication. LOS was affected by the severity of the initial complication. Patients with initial Clavien grades 1, 2, 3a, 3b, and 4 had an LOS of 3.75, 4.17, 4.21, 4.94, and 8.58 days, respectively. Variables associated with the risk of developing a second complication included diabetes mellitus, longer operative times (OR 1.83), and greater estimated blood loss (OR 1.32). CONCLUSIONS: Surgical patients with an initial complication are at higher risk for multiple subsequent postoperative complications. Complications are associated with an extended LOS and higher readmission rates. Diabetes, longer operative time, and greater blood loss were identified as risk factors for multiple complications. PMID- 26971897 TI - GSK3beta-dependent dysregulation of neurodevelopment in SPG11-patient induced pluripotent stem cell model. AB - OBJECTIVE: Mutations in the spastic paraplegia gene 11 (SPG11), encoding spatacsin, cause the most frequent form of autosomal-recessive complex hereditary spastic paraplegia (HSP) and juvenile-onset amyotrophic lateral sclerosis (ALS5). When SPG11 is mutated, patients frequently present with spastic paraparesis, a thin corpus callosum, and cognitive impairment. We previously delineated a neurodegenerative phenotype in neurons of these patients. In the current study, we recapitulated early developmental phenotypes of SPG11 and outlined their cellular and molecular mechanisms in patient-specific induced pluripotent stem cell (iPSC)-derived cortical neural progenitor cells (NPCs). METHODS: We generated and characterized iPSC-derived NPCs and neurons from 3 SPG11 patients and 2 age-matched controls. RESULTS: Gene expression profiling of SPG11-NPCs revealed widespread transcriptional alterations in neurodevelopmental pathways. These include changes in cell-cycle, neurogenesis, cortical development pathways, in addition to autophagic deficits. More important, the GSK3beta-signaling pathway was found to be dysregulated in SPG11-NPCs. Impaired proliferation of SPG11-NPCs resulted in a significant diminution in the number of neural cells. The decrease in mitotically active SPG11-NPCs was rescued by GSK3 modulation. INTERPRETATION: This iPSC-derived NPC model provides the first evidence for an early neurodevelopmental phenotype in SPG11, with GSK3beta as a potential novel target to reverse the disease phenotype. Ann Neurol 2016;79:826-840. PMID- 26971899 TI - Reviewing the pathogenesis of antibody-mediated rejection and renal graft pathology after kidney transplantation. AB - The clinicopathological context of rejection after kidney transplantation was well recognized. Banff conferences greatly contributed to elucidate the pathogenesis and to establish the pathologic criteria of rejection after kidney transplantation. The most important current problem of renal transplantation is de novo donor-specific antibody (DSA) production leading chronic rejection and graft loss. Microvascular inflammation is considered as a reliable pathological marker for antibody-mediated rejection (AMR) in the presence of DSA. Electron microscopic study allowed us to evaluate early changes in peritubular capillaries in T-lymphocyte mediated rejection and transition to antibody-mediated rejection. Severe endothelial injuries with edema and activated lymphocyte invaded into subendothelial space with early multi-layering of peritubular capillary basement membrane suggest T-lymphocyte mediated rejection induce an unbounded chain of antibody-mediated rejection. The risk factors of AMR after ABO-incompatible kidney transplantation are important issues. Anti-ABO blood type antibody titre of IgG excess 32-fold before transplant operation is the only predictable factor for acute AMR. Characteristics of chronic active antibody-mediated rejection (CAAMR) are one of the most important problems. Light microscopic findings and C4d stain of peritubular capillary and glomerular capillary are useful diagnostic criteria of CAAMR. Microvascular inflammation, double contour of glomerular capillary and thickening of peritubular capillary basement are good predictive factors of the presence of de novo DSA. C4d stain of linear glomerular capillary is a more sensitive marker for CAAMR than positive C4d of peritubular capillary. Early and sensitive diagnostic attempts of diagnosing CAAMR are pivotal to prevent chronic graft failure. PMID- 26971916 TI - Micro/nano-particulate drug delivery systems: a boon for the treatment of inflammatory bowel disease. PMID- 26971918 TI - Carers and relatives needed to help care for older patients. AB - Carers and relatives are needed to help in the care of older patients, said RCN general secretary Peter Carter. PMID- 26971919 TI - Employees caring for loved ones with dementia need more support at work. AB - Family carers who are holding down jobs require more support from their employers to cope with the needs of loved ones with dementia, a Carers UK business forum report states. PMID- 26971917 TI - Post-concussion symptoms in mild traumatic brain injury: findings from a paediatric outpatient clinic. AB - Purpose Mild traumatic brain injury (mTBI) is common among children and is associated with a range of symptomatology and clinical presentations. This study uses data from a paediatric outpatient TBI clinic to (1) investigate characteristics associated with more severe post-concussive symptoms and (2) examine differences in the proportion of individuals endorsing specific post concussion symptoms based on group (e.g., sex, type of injury, and psychiatric history). Methods Data from the Children's Hospital of Richmond's TBI outpatient programme were analysed (N = 157). Results Gender and sports injury were associated with severity of symptoms. In addition, females endorsed a greater number of overall symptoms than males. A number of specific symptoms were found to be endorsed to a greater extent based on psychiatric history and type of injury; however, overall total number of symptoms endorsed did not differ based on these characteristics. Conclusions Findings from this study provide further evidence that mTBI affects a wide range of youth and that associated symptomatology can indeed be varied. Moreover, results revealed differences in endorsement of specific symptoms and symptom severity based on patient and injury characteristics which have implications for concussion assessment and treatment. Implications for Rehabilitation Symptoms following mild traumatic brain injury (mTBI) in children and adolescents can have varied presentation, ranging from minimal to severe. Females and those with non-sports-related injuries are more likely to endorse greater symptoms following concussion. Symptom evaluation is an essential component of the concussion assessment and treatment of paediatric patients following mTBI, and clinicians should be aware of patient characteristics associated with increased symptoms, especially when baseline symptom data are not available. PMID- 26971920 TI - News digest March 25 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26971921 TI - Meningococcal B vaccination likely to be added to primary childhood programme. AB - Nurses who give immunisations may soon be required to administer a new meningitis vaccine that looks likely to be introduced after being approved by the Department of Health (DH). PMID- 26971922 TI - Money lost to NHS fraud could pay for 300,000 nurses. AB - Money lost to fraud in the NHS could pay for 300,000 nurses, according to claims made in a BBC Panorama programme. PMID- 26971923 TI - News digest March 24 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26971924 TI - Body clock research findings could help nurses adapt better to working shifts. AB - The negative effects of shift work could be alleviated after researchers discovered a new mechanism that governs how the body clock reacts to changes in the environment. PMID- 26971925 TI - Former NMC chair Judith Ellis steps down. AB - A former interim chair of the Nursing and Midwifery Council, Judith Ellis, has announced her decision to step down from her role as a council member in June. PMID- 26971926 TI - News digest March 21 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26971927 TI - News digest March 20 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26971928 TI - A case of resistant spondyloarthritis (SpA) that responded to tacrolimus and mycophenolate treatment initiated at the time of renal transplantation for unrelated renal failure. PMID- 26971929 TI - Locally Targeted Cardiac Gene Delivery by AAV Microbubble Destruction in a Large Animal Model. AB - Cardiac gene therapy is a promising approach for treating heart diseases. Although clinical studies are ongoing, effective and targeted transgene delivery is still a major obstacle. We sought to improve and direct transgene expression in myocardium by ultrasound-targeted microbubble destruction (UTMD). In pigs, adeno-associated virus-derived (AAV) vectors harboring the luciferase reporter gene were delivered via retroinfusion into the anterior interventricular coronary vein (AIV). AAV vectors were either loaded to lipid microbubbles before injection or injected unmodified. Upon injection of AAV/microbubble solution, UTMD was performed. After 4 weeks, reporter gene expression levels in the anterior wall (target area), in the posterior wall (control area), and in noncardiac organs were analyzed. Retroinfusion of AAV-luciferase vectors loaded to lipid microbubbles led to a significant increase in transgene expression, with an increase in UTMD targeted areas of the anterior wall. Moreover, off-target expression was reduced in comparison to control animals, receiving AAV-luciferase without microbubbles. Besides an increase in overall target area transgene expression, UTMD alters the spatial expression of the luciferase transgene, focusing expression to ultrasound-targeted left ventricular wall. These data suggest UTMD as a promising approach for directing AAV to specific cardiac segments. PMID- 26971930 TI - Serum Levels of Progranulin Do Not Reflect Cerebrospinal Fluid Levels in Neurodegenerative Disease. AB - Altered progranulin levels play a major role in neurodegenerative diseases, like Alzheimer's dementia (AD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), even in the absence of GRN mutations. Increasing progranulin levels could hereby provide a novel treatment strategy. However, knowledge on progranulin regulation in neurodegenerative diseases remains limited. We here demonstrate that cerebrospinal fluid progranulin levels do not correlate with its serum levels in AD, FTD and ALS, indicating a differential regulation of its central and peripheral levels in neurodegeneration. Blood progranulin levels thus do not reliably predict central nervous progranulin levels and their response to future progranulin-increasing therapeutics. PMID- 26971931 TI - A Role for P-Glycoprotein in Clearance of Alzheimer Amyloid beta -Peptide from the Brain. AB - Most data indicates that Alzheimer's disease involves an accumulation of amyloid beta - peptide (Abeta) in the CNS and that sporadic cases arise from a deficiency in Abeta clearance. Considerable attention has been given to mechanisms by which Abeta might be transported between the brain and blood, and evidence suggests that p-glycoprotein, also known as the multi-drug resistance (MDR) protein (product of the ABCB1 gene), plays a role in Abeta transport across the blood brain barrier (BBB). We tested this possibility through two approaches: First, wild-type and MDR1A-knockout mice were compared after intravenous injection of [(125)I]-labeled Abeta; after 60 min, homogenates of brain parenchyma were subjected to gamma-counting of TCA-precipitable material, and histological sections of brain were subjected to autoradiography. Second, MDR1Aknockout mice were crossed with Tg2576 APP transgenic mice, a line that routinely accumulates Abeta in the brain; SDS and formic acid extracts of brain homogenates were assessed for Abeta levels by ELISA. Each of these approaches yielded data indicating that Abeta accumulates to a greater degree in mice lacking MDR1A. These findings confirm other reports linking p-glycoprotein to Abeta clearance across the BBB and have important implications for Alzheimer's disease genetics, pharmacology, and epidemiology. PMID- 26971932 TI - Mitochondrial Respiration in the Platelets of Patients with Alzheimer's Disease. AB - Mitochondrial dysfunctions significantly contribute to the pathogenesis of Alzheimer's disease (AD). Here, we studied the relationship between AD and changes in the mitochondrial rates of respiration in blood platelets, respiratory chain complexes activity, and coenzyme Q10 plasma concentrations. In intact platelets obtained from AD patients, we observed a decrease in endogenous basal respiration rates, a decrease in the maximal capacity of the electron transport system (ETS), and higher respiratory rates after inhibiting complex I of the ETS. When normalized for citrate synthase activity, rotenone inhibited respiratory rates and complex I activity was significantly altered. In permeabilized platelets, mitochondrial respiration was completely rescued by the addition of complex I substrates. The changes in mitochondrial respiratory parameters were not associated with the progression of AD except for the capacity of the ETS in permeabilized platelets. In AD, complex I activity was increased, complex IV activity was decreased, and coenzyme Q10 plasma concentrations were decreased. Our data indicate that both insufficiency in substrates entering into the oxidative phosphorylation system and functional disturbances in the ETS complex are responsible for the decrease in respiration observed in intact platelets in AD patients. Analyses of complex IV activity, the respiratory rates of intact platelets, and the capacity of the ETS in permeabilized platelets may enable the characterization of mitochondrial dysfunctions in the initial stage of AD. PMID- 26971934 TI - Molecular Basis of Familial and Sporadic Alzheimer's Disease. AB - Alzheimer's disease (AD) is a multifactorial disease with genetic (70%) and environmental (30%) causes. Among the genetic factors are genes associated with a family history of the disease (familial AD, FAD) and sporadic AD (SAD). The genes: APP (amyloid precursor protein), PSEN1 (Presenilin 1) and PSEN2 (Presenilin 2) are responsible for the presence of FAD. The APOE gene is responsible for the sporadic form of the disease. Other molecular factors related to the immunological cause (TREM2) of the disease are a disorder of the lipid (ABCA1, ABCA7) or biothiol (MTHFD1) metabolism and of the transport of metabolites (BIN1). Currently, it is believed that APOE is a risk factor for both SAD and late-onset FAD. The pathomechanism of AD is most commonly explained as based on the amyloid cascade theory. This theory is related to the FAD, although there are reports indicating the probability of its occurrence in the SAD. It seems that the excessive deposition of beta-amyloid (Abeta) peptides and intracellular neurofibrillary tangles of tau protein hyperphosphorylated forms contribute to the damage of both DNA and RNA. Furthermore, it is believed that RNA-interference can affect both the level of pathological proteins (Abeta, tau protein) and the onset and progress of AD. It seems that a complete understanding of both FAD and SAD pathogenesis may contribute to the search for earlier clinical diagnosis and to an understanding of later occurrence of the disease, which may help modify its course and affect more effective therapy of this incurable neurological disease. PMID- 26971933 TI - Decreased Myelinated Fibers in the Hippocampal Dentate Gyrus of the Tg2576 Mouse Model of Alzheimer's Disease. AB - Alzheimer's disease (AD), the most common cause of dementia in the elderly, is characterized by deficits in cognition and memory. Although amyloid-beta (Abeta) accumulation is known to be the earliest pathological event that triggers subsequent neurodegeneration, how Abeta accumulation causes behavioral deficits remains incompletely understood. In this study, using the Morris water maze test, ELISA and stereological methods, we examined spatial learning and memory performance, the soluble Abeta concentration and the myelination of fibers in the hippocampus of 4-, 6-, 8- and 10-month-old Tg2576 AD model mice. Our results showed that spatial learning and memory performance was significantly impaired in the Tg2576 mice compared to the wild type (WT) controls and that the myelinated fiber length in the hippocampal dentate gyrus (DG) was markedly decreased from 0.33 +/- 0.03 km in the WT controls to 0.17 +/- 0.02 km in the Tg2576 mice at 10 months of age. However, the concentrations of soluble Abeta40 and Abeta42 were significantly increased as early as 4-6 months of age. The decreased myelinated fiber length in the DG may contribute to the spatial learning and memory deficits of Tg2576 mice. Therefore, we suggest that the significant accumulation of soluble Abeta may serve as a preclinical biomarker for AD diagnosis and that protecting myelinated fibers may represent a novel strategy for delaying the progression of early-stage AD. PMID- 26971936 TI - Connections Between Herpes Simplex Virus Type 1 and Alzheimer's Disease Pathogenesis. AB - Alzheimer's disease (AD) is currently one of the most studied neurodegenerative disorders in humans. First reported in 1907, the disease has a familial form which represents approximately 5% of cases, while the remaining, sporadic cases are of multifactorial etiology. The disease progression of the latter form has specific pathological and functional characteristics, which have unknown etiology. Several authors have proposed a viral etiology for AD, while others implicate many neurotropic infectious agents. This review compares research findings regarding pathways and effects of neuropathological viruses with the pathways and effects involved in the progression of AD. The similarities are striking and provide a compelling argument for a pathogen-based etiology of AD. PMID- 26971935 TI - Altered Arginine Metabolism in Cells Transfected with Human Wild-Type Beta Amyloid Precursor Protein (betaAPP). AB - Alterations of enzymes linked to arginine metabolism have been recently implicated in Alzheimer's disease (AD). Despite strong association of arginine changes with nitric oxide (NO) pathway, the impact of amyloid beta (Abeta) peptides on arginine degradation and re-synthesis is unknown. In the present study we compared expression levels of arginases (ARG1, ARG2), neuronal, endothelial and inducible NO synthase isoforms (NNOS, ENOS, INOS), enzymes that metabolize arginine or resynthesize it from citrulline and the levels of corresponding amino acids in rat pheochromocytoma (PC12) cells overexpressing human Abeta precursor protein (APPwt cells). Moreover, we investigated the changes in miRNAs responsible for modulation of arginine metabolism in AD brains. Real-time PCR analysis revealed in APPwt cells significant decreases of ARG1 and ARG2 which are responsible for lysing arginine into ornithine and urea; this reduction was followed by significantly lower enzyme activity. NNOS and ENOS mRNAs were elevated in APPwt cells while iNOS was undetectable in both cell lines. The expression of argininosuccinate synthase (ASS) that metabolizes citrulline was down-regulated without changes in argininosuccinate lyase (ASL). Ornithine decarboxylase (ODC), which decarboxylates ornithine to form putrescine was also reduced. Arginine, the substrate for both arginases and NOS, was unchanged in APPwt cells. However, citrulline concentration was significantly higher. Elevated miRNA-9 and miRNA-128a found in AD brain tissues might modulate the expression of ASS and NOS, respectively. Our results indicate that Abeta affects arginine metabolism and this influence might have important role in the pathomechanism of AD. PMID- 26971937 TI - Lipid Raft Alterations in Aged-Associated Neuropathologies. AB - Lipid rafts are membrane microdomains particularly enriched in cholesterol, sphingolipids and saturated fatty acids. These microstructures play a key role in a plethora of mechanisms involved in cell signaling, synapsis, cell-cell communication and cell survival. In the last years, increasing evidence indicate that lipid rafts may be altered in age-related neuropathologies, such as Alzheimer's disease and Parkinson disease even at asymptomatic stages. In particular, important changes in raft lipid composition are observed with the progression of these diseases, then inducing alterations in their physicochemical properties. Furthermore, these phenomena contribute to neuropathological events related to amyloidogenesis, aberrant protein aggregation and toxic cell signalling. In this review, we discuss some relevant data on the age-related molecular changes occurring in lipid rafts since the first stages of these neurodegenerative diseases. Further characterization of specific parameters associated with alterations of these microdomains may provide potential tools of diagnosis and prediction of these neuropathologies. PMID- 26971938 TI - Can Diet and Physical Activity Limit Alzheimer's Disease Risk? AB - BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting elderly individuals at an alarming rate. It has become a global health crisis imposing tremendous social and economic burden on society. Although there is no cure for AD, it is important to identify and implement preventive strategies that may delay or prevent the symptoms, limit the burden, and improve the quality of life of those afflicted. Adequate nutrition and physical activity are the two potential lifestyle modifiable factors that have gained considerable interest for their potential in the prevention or management of this challenging disease. In this review, we discuss the beneficial effects of physical activity and adequate nutrition on minimizing the risk of developing AD. METHODS: The research question was initially formulated in a structured and explicit way. Relevant studies were identified using a wide range of scientific databases. Their potential relevance was based on the criteria for inclusion and exclusion. The quality of selected studies was subjected to a more precise quality assessment using standard tools. A detailed description of the implemented intervention and how it differed from what the control group received was outlined. The effects of intervention on measurable outcomes for the study sample were applied. RESULTS: One hundred and sixty-four references were included in the review comprising of epidemiological, longitudinal, cross-sectional, intervention and randomized controlled studies. This review highlighted the effect of various nutrient diet supplements on cognitive performance in humans as well as animals with AD and mild cognitive impairment (MCI). Moreover, the effect of physical exercise on the cognitive function in animal models with AD was outlined. CONCLUSION: The findings of this review highlight the therapeutic potential of combination of nutritionally adequate diet and physical activity in preventing or delaying the symptoms associated with AD pathology. PMID- 26971939 TI - Are Raw Scores on Memory Tests Better than Age- and Education- Adjusted Scores for Predicting Progression from Amnesic Mild Cognitive Impairment to Alzheimer Disease ? AB - In this prospective longitudinal study, conducted in a large sample of amnestic MCI patients over a three-year period, we investigated the recently advanced proposal that unadjusted test scores obtained at baseline on long-term memory tests are more reliable than age- and education-corrected scores in predicting progression from aMCI to AD. Our experimental sample consisted of 270 aMCI patients who underwent extensive neurological and neuropsychological examinations both at baseline and at the follow-up, conducted at least 3 years later. At the follow-up 80 patients had converted to overt dementia. The predictive capacity of raw, age-corrected, education-corrected and fully corrected scores on RAVLT immediate and delayed recall was compared by examining the area under the ROC curves (AUCs) of all of these scores to assess which (raw or corrected) scores achieves the better reliability in predicting conversion to dementia. The condition (aMCI stable vs converted) was analyzed to assess the odds ratios resulting from a logistic regression on the corrected and uncorrected scores of RAVLT immediate and delayed recall. Even if both in immediate and in delayed recall the ROCs of 'raw scores' were generally higher than the other ROCs on corrected scores, these differences did not reach the level of statistical significance, failing to support the claim that unadjusted test scores are superior to age- and education-corrected scores in predicting progression from aMCI to AD. PMID- 26971941 TI - A Spherical Brain Mapping of MR Images for the Detection of Alzheimer's Disease. AB - Magnetic Resonance Imaging (MRI) is of fundamental importance in neuroscience, providing good contrast and resolution, as well as not being considered invasive. Despite the development of newer techniques involving radiopharmaceuticals, it is still a recommended tool in Alzheimer's Disease (AD) neurological practice to assess neurodegeneration, and recent research suggests that it could reveal changes in the brain even before the symptomatology appears. In this paper we propose a method that performs a Spherical Brain Mapping, using different measures to project the three-dimensional MR brain images onto two-dimensional maps revealing statistical characteristics of the tissue. The resulting maps could be assessed visually, but also perform a significant feature reduction that will allow further supervised or unsupervised processing, reducing the computational load while maintaining a large amount of the original information. We have tested our methodology against a MRI database comprising 180 AD affected patients and 180 normal controls, where some of the mappings have revealed as an optimum strategy for the automatic processing and characterization of AD patterns, achieving up to a 90.9% of accuracy, as well as significantly reducing the computational load. Additionally, our maps allow the visual analysis and interpretation of the images, which can be of great help in the diagnosis of this and other types of dementia. PMID- 26971942 TI - Fuzzy Computer-Aided Alzheimer's Disease Diagnosis Based on MRI Data. AB - Alzheimer's disease (AD) is a chronic neurodegenerative disease of the central nervous system that has no cure and leads to death. One of the most prevalent tools for AD diagnosis is magnetic resonance imaging (MRI), because of its capability to visualize brain anatomical structures. There is a variety of classification methods for automatic diagnosis of AD, such as support vector machines, genetic algorithms, Bayes classifiers, neural networks, random forests, etc., but none of them provides robust information about the stage of the AD, they can just reveal the presence of disease. In this paper, a new approach for classification of MRI images using a fuzzy inference system is proposed. Two statistical moments (mean and standard deviation) of 116 anatomical regions of interests (ROIs) are used as input features for the classification system. A t test feature selection method is used to identify the most discriminative ROIs. In order to evaluate the proposed system, MRI images from a database consisting of 818 subjects (229 normal, 401 mild cognitive impairment and 188 AD subjects) collected from the Alzheimer's disease neuroimaging initiative (ADNI) is analyzed. The receiver operating characteristics (ROC) curve and the area under the curve (AUC) of the proposed fuzzy inference system fed by statistical input features are employed as the evaluation criteria with k-fold cross validation. The proposed system yields promising results in normal vs. AD classification with AUC of 0.99 on the training set and 0.8622+/-0.0033 on the testing set. PMID- 26971943 TI - Alzheimer's Disease Brain Areas: The Machine Learning Support for Blind Localization. AB - The analysis of positron emission tomography (PET) scan image is challenging due to a high level of noise and a low resolution and also because differences between healthy and demented are very subtle. High dimensional classification methods based on PET have been proposed to automatically discriminate between normal control group (NC) patients and patients with Alzheimer's disease (AD), with mild cognitive impairment (MCI), and mild cognitive impairment converting to Alzheimer's disease (MCIAD ) (a group of patients that clearly degrades to AD). We developed a voxelbased method for volumetric image analysis. We performed 3 classification experiments AD vs CG, AD vs MCI, MCIAD vs MCI. We will also give a small demonstration of the presented method on a set of face images. This method is capable to extract information about the location of metabolic changes induced by Alzheimer's disease that directly relies statistical features and brain regions of interest (ROIs). We produce "maps" to visualize the most informative regions of the brain and compare them with voxel-wise statistics. Using the mean intensity of about 2000 6 * 6 * 6mm patches, selected by the extracted map, as input for a classifier we obtain a classification rate of 95.5%. PMID- 26971940 TI - Potential for Stem Cells Therapy in Alzheimer's Disease: Do Neurotrophic Factors Play Critical Role? AB - Alzheimer's disease (AD) is one of the most common causes of dementia. Despite several decades of research in AD, there is no standard disease- modifying therapy available and currentlyapproved drugs provide only symptomatic relief. Stem cells hold immense potential to regenerate damaged tissues and are currently tested in some brain-related disorders, such as AD, amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). We review stem cell transplantation studies using preclinical and clinical tools. We describe different sources of stem cells used in various animal models and explaining the putative molecular mechanisms that can rescue neurodegenerative disorders. The clinical studies suggest safety, efficacy and translational potential of stem cell therapy. The therapeutic outcome of stem cell transplantation has been promising in many studies, but no unifying hypothesis can convincingly explain the underlying mechanism. Some studies have reported paracrine effects exerted by these stem cells via the release of neurotrophic factors, while other studies describe the immunomodulatory effects exerted by the transplanted cells. There are also reports which indicate that stem cell transplantation might result in endogenous cell proliferation or replacement of diseased cells. In animal models of AD, stem cell transplantation is also believed to increase expression of synaptic proteins. PMID- 26971944 TI - Hypometabolism in Brain of Cognitively Normal Patients with Depressive Symptoms is Accompanied by Atrophy-Related Partial Volume Effects. AB - Late life depression (LLD) even in subsyndromal stages shows high conversion rates from cognitively normal (CN) to mild cognitive impairment (MCI). Results of [(18)F]-fluorodesoxyglucose positron-emission-tomography (FDG-PET) were inconsistent in LLD patients, whereas atrophy was repeatedly described. Therefore, we set out to investigate FDG metabolism and the effect of atrophy correction (PVEC) in geriatric CN patients with depressive symptoms. 21 CN subjects with positive item for the depression category (DEP) in the Neuropsychiatric-Inventory-Questionnaire and 29 CN subjects with an absent depression item (NON-DEP) were selected from the ADNI cohort. FDG-PETs were analyzed in individual PET space using volumes-of-interest (VOI) and statistical parametric-mapping (SPM) approaches. VOI- and MRI-based PVEC were applied to PET data. DEP subjects showed significant hypometabolism in fronto-temporal cortices and the posterior cingulate cortex (PCC) when contrasted against NON-DEP in uncorrected data. Both in VOI- and SPM-based approaches PVEC eliminated significance in PCC, while fronto-temporal regions remained significant or even attained significance such as in case of the left amygdala. Subsyndromally depressed CN subjects had decreased FDG metabolism in mood-related brain regions, which may be relevant to their elevated risk for conversion from CN to MCI. Methodological advances in PET analyses should be considered in future studies as PVEC relevantly changed results of FDG-PET for detecting apparent metabolic differences between DEP and NON-DEP subjects. Furthermore, VOI-based analyses in individual PET space will allow a more accurate consideration of variability in anatomy, especially in subcortical regions. PMID- 26971945 TI - Recurrent Network Models of Sequence Generation and Memory. AB - Sequential activation of neurons is a common feature of network activity during a variety of behaviors, including working memory and decision making. Previous network models for sequences and memory emphasized specialized architectures in which a principled mechanism is pre-wired into their connectivity. Here we demonstrate that, starting from random connectivity and modifying a small fraction of connections, a largely disordered recurrent network can produce sequences and implement working memory efficiently. We use this process, called Partial In-Network Training (PINning), to model and match cellular resolution imaging data from the posterior parietal cortex during a virtual memory-guided two-alternative forced-choice task. Analysis of the connectivity reveals that sequences propagate by the cooperation between recurrent synaptic interactions and external inputs, rather than through feedforward or asymmetric connections. Together our results suggest that neural sequences may emerge through learning from largely unstructured network architectures. PMID- 26971946 TI - Signal, Noise, and Variation in Neural and Sensory-Motor Latency. AB - Analysis of the neural code for sensory-motor latency in smooth pursuit eye movements reveals general principles of neural variation and the specific origin of motor latency. The trial-by-trial variation in neural latency in MT comprises a shared component expressed as neuron-neuron latency correlations and an independent component that is local to each neuron. The independent component arises heavily from fluctuations in the underlying probability of spiking, with an unexpectedly small contribution from the stochastic nature of spiking itself. The shared component causes the latency of single-neuron responses in MT to be weakly predictive of the behavioral latency of pursuit. Neural latency deeper in the motor system is more strongly predictive of behavioral latency. A model reproduces both the variance of behavioral latency and the neuron-behavior latency correlations in MT if it includes realistic neural latency variation, neuron-neuron latency correlations in MT, and noisy gain control downstream of MT. PMID- 26971947 TI - Reward-Guided Learning with and without Causal Attribution. AB - When an organism receives a reward, it is crucial to know which of many candidate actions caused this reward. However, recent work suggests that learning is possible even when this most fundamental assumption is not met. We used novel reward-guided learning paradigms in two fMRI studies to show that humans deploy separable learning mechanisms that operate in parallel. While behavior was dominated by precise contingent learning, it also revealed hallmarks of noncontingent learning strategies. These learning mechanisms were separable behaviorally and neurally. Lateral orbitofrontal cortex supported contingent learning and reflected contingencies between outcomes and their causal choices. Amygdala responses around reward times related to statistical patterns of learning. Time-based heuristic mechanisms were related to activity in sensorimotor corticostriatal circuitry. Our data point to the existence of several learning mechanisms in the human brain, of which only one relies on applying known rules about the causal structure of the task. PMID- 26971951 TI - Changes in Doppler parameters of portal pressure after interventional management of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) has many options for management; some of them are complicated by development of portal hypertension (PHT). Doppler ultrasound is an effective method to diagnose and monitor PHT changes after HCC ablation procedures. The aim of this study is to investigate changes in portal pressure hemodynamics of HCC patients following treatment with different interventional strategies: radiofrequency ablation (RFA), microwave ablation (MWA), and transarterial chemoembolization (TACE). A total of 60 patients with HCC were divided into three main groups, and each group received a different type of therapy (RFA, MWA, and TACE). Full medical record and basic investigations were performed including Doppler ultrasound and upper GIT endoscopy for evaluation of PHT parameters, and then repeated after three months of ablation. RFA is associated with the increased splenic artery resistive index, while MWA has no significant impact on PHT indices. TACE has led to a marked increase in liver vascular index with significant decrease in hepatic artery resistive index and PHI after treatment. No significant changes in esophageal varices were observed by upper GIT endoscopy following all ablation methods. RFA is quite safe but associated with degree of PHT. On the contrary, TACE is associated with improved PHT parameters. MWA has no significant association to development of PHT following the technique. Doppler ultrasound could be used as a reliable and effective method of evaluation of PHT post ablation for HCC. PMID- 26971952 TI - Dynamics of Isolated 1,8-Naphthalimide and N-Methyl-1,8-naphthalimide: An Experimental and Computational Study. AB - In this work we investigate the excited-state structure and dynamics of the two molecules 1,8-naphthalimide (NI) and N-methyl-1,8-naphthalimide (Me-NI) in the gas phase by picosecond time- and frequency-resolved multiphoton ionization spectroscopy. The energies of several electronically excited singlet and triplet states and the S1 vibrational wavenumbers were calculated. Nonadiabatic dynamics simulations support the analysis of the radiationless deactivation processes. The origin of the S1 <- S0 (pipi*) transition was found at 30, 082 cm(-1) for NI and at 29, 920 cm(-1) for Me-NI. Furthermore, a couple of low-lying vibrational bands were resolved in the spectra of both molecules. In the time-resolved scans a biexponential decay was apparent for both Me-NI and NI. The fast time constant is in the range of 10-20 ps, whereas the second one is in the nanosecond range. In accordance with the dynamics simulations, intersystem crossing to the fourth triplet state S1 (pipi*) -> T4 (npi*) is the main deactivation process for Me-NI due to a large spin-orbit coupling between these states. Only for significant vibrational excitation internal conversion via a conical intersection becomes a relevant deactivation pathway. PMID- 26971948 TI - Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1. AB - Transcription Factor 4 (TCF4) is a clinically pleiotropic gene associated with schizophrenia and Pitt-Hopkins syndrome (PTHS). To gain insight about the neurobiology of TCF4, we created an in vivo model of PTHS by suppressing Tcf4 expression in rat prefrontal neurons immediately prior to neurogenesis. This cell autonomous genetic insult attenuated neuronal spiking by increasing the afterhyperpolarization. At the molecular level, using a novel technique called iTRAP that combined in utero electroporation and translating ribosome affinity purification, we identified increased translation of two ion channel genes, Kcnq1 and Scn10a. These ion channel candidates were validated by pharmacological rescue and molecular phenocopy. Remarkably, similar excitability deficits were observed in prefrontal neurons from a Tcf4(+/tr) mouse model of PTHS. Thus, we identify TCF4 as a regulator of neuronal intrinsic excitability in part by repression of Kcnq1 and Scn10a and suggest that this molecular function may underlie pathophysiology associated with neuropsychiatric disorders. PMID- 26971950 TI - Coordinated Excitation and Inhibition of Prefrontal Ensembles during Awake Hippocampal Sharp-Wave Ripple Events. AB - Interactions between the hippocampus and prefrontal cortex (PFC) are critical for learning and memory. Hippocampal activity during awake sharp-wave ripple (SWR) events is important for spatial learning, and hippocampal SWR activity often represents past or potential future experiences. Whether or how this reactivation engages the PFC, and how reactivation might interact with ongoing patterns of PFC activity, remains unclear. We recorded hippocampal CA1 and PFC activity in animals learning spatial tasks and found that many PFC cells showed spiking modulation during SWRs. Unlike in CA1, SWR-related activity in PFC comprised both excitation and inhibition of distinct populations. Within individual SWRs, excitation activated PFC cells with representations related to the concurrently reactivated hippocampal representation, while inhibition suppressed PFC cells with unrelated representations. Thus, awake SWRs mark times of strong coordination between hippocampus and PFC that reflects structured reactivation of representations related to ongoing experience. PMID- 26971953 TI - Reference in human and non-human primate communication: What does it take to refer? AB - The concept of functional reference has been used to isolate potentially referential vocal signals in animal communication. However, its relatedness to the phenomenon of reference in human language has recently been brought into question. While some researchers have suggested abandoning the concept of functional reference altogether, others advocate a revision of its definition to include contextual cues that play a role in signal production and perception. Empirical and theoretical work on functional reference has also put much emphasis on how the receiver understands the referential signal. However, reference, as defined in the linguistic literature, is an action of the producer, and therefore, any definition describing reference in non-human animals must also focus on the producer. To successfully determine whether a signal is used to refer, we suggest an approach from the field of pragmatics, taking a closer look at specific situations of signal production, specifically at the factors that influence the production of a signal by an individual. We define the concept of signaller's reference to identify intentional acts of reference produced by a signaller independently of the communicative modality, and illustrate it with a case study of the hoo vocalizations produced by wild chimpanzees during travel. This novel framework introduces an intentional approach to referentiality. It may therefore permit a closer comparison of human and non-human animal referential behaviour and underlying cognitive processes, allowing us to identify what may have emerged solely in the human lineage. PMID- 26971949 TI - Distinct Contribution of Adult-Born Hippocampal Granule Cells to Context Encoding. AB - Adult-born granule cells (abGCs) have been implicated in cognition and mood; however, it remains unknown how these cells behave in vivo. Here, we have used two-photon calcium imaging to monitor the activity of young abGCs in awake behaving mice. We find that young adult-born neurons fire at a higher rate in vivo but paradoxically exhibit less spatial tuning than their mature counterparts. When presented with different contexts, mature granule cells underwent robust remapping of their spatial representations, and the few spatially tuned adult-born cells remapped to a similar degree. We next used optogenetic silencing to confirm the direct involvement of abGCs in context encoding and discrimination, consistent with their proposed role in pattern separation. These results provide the first in vivo characterization of abGCs and reveal their participation in the encoding of novel information. PMID- 26971955 TI - Early diagnosis and successful management of oral mucormycosis in a hematopoietic stem cell transplant recipient: case report and literature review. AB - PURPOSE: Oral mucormycosis is a rare and high risk of infection in patients following hematopoietic cell transplantation few cases in the literature. We review the literature and present an additional case to emphasize the subtle changes that resulted in positive outcome when diagnosed and managed in a comprehensive transplant team. RESULTS: A patient was diagnosed with gingival mucormycosis on day +25 following a hematopoietic stem cell transplant for lymphoblastic transformation of chronic myeloid leukemia. The patient was diagnosed with minor and nonspecific symptoms and was successfully treated with local dental extraction, a short course of liposomal amphotericin B and 4 months of oral posaconazole. CONCLUSIONS: The good outcome of this case highlights the subtle clinical changes that present early in mucormycosis and the importance of early detection and treatment of post-transplant oral infections by an experienced multidisciplinary team. PMID- 26971954 TI - Remote Limb Preconditioning Generates a Neuroprotective Effect by Modulating the Extrinsic Apoptotic Pathway and TRAIL-Receptors Expression. AB - As remote limb preconditioning (RPC) ameliorates brain damage after ischemic cerebral stroke (ICS), the purpose of the present study was to explore the molecular mechanisms in the course of RPC. Results of TUNEL staining and cleaved caspase-3 expression showed that ischemia-induced neuronal apoptosis was inhibited by RPC. The expression changes in cleaved caspase-8, cFLIP, Bid itself, and its truncated form represented that RPC suppressed the activation of extrinsic apoptotic pathway during ICS. Then, the level of cytoplasmic cytochrome c was also decreased by RPC. In addition, RPC might partially suppress TNF related apoptosis-inducing ligand (TRAIL)-induced extrinsic apoptosis through downregulation of TRAIL death receptors and upregulation of TRAIL decoy receptors. As a counterproof, immunoneutralization of TRAIL in dMCAO rats resulted in significant restraint of tissue damage and in a marked functional recovery. Our data complemented the knowledge of RPC neuroprotective mechanism and provided new evidence for its clinical application. PMID- 26971957 TI - [Mental Illness and Social Science Disaster Research, 1949-1985]. PMID- 26971956 TI - "Quinone Millipedes" Reconsidered: Evidence for a Mosaic-Like Taxonomic Distribution of Phenol-Based Secretions across the Julidae. AB - The defensive chemistry of juliformian millipedes is characterized mainly by benzoquinones ("quinone millipedes"), whereas the secretions of the putative close outgroup Callipodida are considered to be exclusively phenolic. We conducted a chemical screening of julid secretions for phenolic content. Most species from tribes Cylindroiulini (15 species examined), Brachyiulini (5 species examined), Leptoiulini (15 species examined), Uncigerini (2 species examined), Pachyiulini (3 species examined), and Ommatoiulini (2 species examined) had non phenolic, in most cases exclusively benzoquinonic secretions. In contrast, tribes Cylindroiulini, Brachyiulini, and Leptoiulini also contained representatives with predominantly phenol-based exudates. In detail, p-cresol was a major compound in the secretions of the cylindroiulines Styrioiulus pelidnus and S. styricus (p cresol content 93 %) and an undetermined Cylindroiulus species (p-cresol content 51 %), in the brachyiulines Brachyiulus lusitanus (p-cresol content 21 %) and Megaphyllum fagorum (p-cresol content 92 %), as well as in an undescribed Typhloiulus species (p-cresol content 32 %, Leptoiulini). In all species, p cresol was accompanied by small amounts of phenol. The secretion of M. fagorum was exclusively phenolic, whereas phenols were accompanied by benzoquinones in all other species. This is the first incidence of clearly phenol-dominated secretions in the Julidae. We hypothesize a shared biosynthetic route to phenols and benzoquinones, with benzoquinones being produced from phenolic precursors. The patchy taxonomic distribution of phenols documented herein supports multiple independent regression events in a common pathway of benzoquinone synthesis rather than multiple independent incidences of phenol biosynthesis. PMID- 26971958 TI - Osteogenesis in calcified aortic valve disease: From histopathological observation towards molecular understanding. AB - Calcified aortic valve disease (CAVD) is the most common heart valve disease in aged patients, with a disease continuum that ranges from mild valve thickening to severe calcification. In the past, calcification in CAVD was considered degenerative because of the time-dependent wear-and-tear of the leaflets with passive calcium deposition. Now, insights into the histopathological features, clinical data, and molecular mechanisms of CAVD have been greatly highlighted by findings that valvular calcification is a tightly regulated process resembling the osteogenic process. In this review, we focus on osteogenesis (bone formation) during the progression of CAVD and highlight the recent advances in understanding the cellular and molecular mechanisms of osteogenesis in valvular calcification. PMID- 26971959 TI - What is a "DNA-Compatible" Reaction? AB - DNA-encoded synthesis can generate vastly diverse screening libraries of arbitrarily complex molecules as long as chemical reaction conditions do not compromise DNA's informational integrity, a fundamental constraint that "DNA compatible" reaction development does not presently address. We devised DNA encoded reaction rehearsal, an integrated analysis of reaction yield and impact on DNA, to acquire these key missing data. Magnetic DNA-functionalized sensor beads quantitatively report the % DNA template molecules remaining viable for PCR amplification after exposure to test reaction conditions. Analysis of solid-phase bond forming (e.g., Suzuki-Miyaura cross-coupling, reductive amination) and deprotection reactions (e.g., allyl esters, silyl ethers) guided the definition and optimization of DNA-compatible reaction conditions (>90% yield, >30% viable DNA molecules), most notably in cases that involved known (H(+), Pd) and more obscure (Delta, DMF) hazards to DNA integrity. The data provide an empirical yet mechanistically consistent and predictive framework for designing successful DNA encoded reaction sequences for combinatorial library synthesis. PMID- 26971960 TI - Impact of Altitudes and Habitats on Valerenic Acid, Total Phenolics, Flavonoids, Tannins, and Antioxidant Activity of Valeriana jatamansi. AB - The changes in total phenolics, flavonoids, tannins, valerenic acid, and antioxidant activity were assessed in 25 populations of Valeriana jatamansi sampled from 1200 to 2775 m asl and four habitat types of Uttarakhand, West Himalaya. Significant (p < 0.05) variations in total phenolics, flavonoids, valerenic acid, and antioxidant activity in aerial and root portions and across the populations were observed. Antioxidant activity measured by three in vitro antioxidant assays, i.e., 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic) (ABTS) radical scavenging, 2,2'-diphenyl-1-picryylhydrazyl (DPPH) free radical scavenging, and ferric-reducing antioxidant power (FRAP) assays, showed significant (p < 0.05) differences across the populations. However, no clear pattern was found in phytochemicals across the altitudinal range. Among habitat types, (pine, oak, mixed forest, and grassy land), variation in phytochemical content and antioxidant activity were observed. Equal class ranking, neighbor joining cluster analysis, and principal component analysis (PCA) identified Talwari, Jaberkhet, Manjkhali, and Khirshu populations as promising sources with higher phytochemicals and antioxidant activity. The results recommended that the identified populations with higher value of phytochemicals and antioxidants can be utilized for mass multiplication and breeding program to meet the domestic as well as commercial demand. PMID- 26971961 TI - Comparative Study on Different Expression Hosts for Alkaline Phytase Engineered in Escherichia coli. AB - The application of alkaline phytase as a feed additive is restricted by the poor specific activity. Escherichia coli is a frequently used host for directed evolution of proteins including alkaline phytase towards improved activity. However, it is not suitable for production of food-grade products due to potential pathogenicity. To combine the advantages of different expression systems, mutants of the alkaline phytase originated from Bacillus subtilis 168 (phy168) were first generated via directed evolution in E. coli and then transformed to food-grade hosts B. subtilis and Pichia pastoris for secretory expression. In order to investigate the suitability of different expression systems, the phy168 mutants expressed in different hosts were characterized and compared in terms of specific activity, pH profile, pH stability, temperature profile, and thermostability. The specific activity of B. subtilis-expressed D24G/K70R/K111E/N121S mutant at pH 7.0 and 60 degrees C was 30.4 U/mg, obviously higher than those in P. pastoris (22.7 U/mg) and E. coli (19.7 U/mg). Moreover, after 10 min incubation at 80 degrees C, the B. subtilis-expressed D24G/K70R/K111E/N121S retained about 70 % of the activity at pH 7.0 and 37 degrees C, whereas the values were only about 25 and 50 % when expressed in P. pastoris and E. coli, respectively. These results suggested B. subtilis as an appropriate host for expression of phy168 mutants and that the strategy of creating mutants in one host and expressing them in another might be a new solution to industrial production of proteins with desired properties. PMID- 26971964 TI - Apical aneurysm with thrombus in an elderly patient with hypertrophic obstructive cardiomyopathy. PMID- 26971962 TI - Health risk assessment from contaminated foodstuffs: a field study in chromite mining-affected areas northern Pakistan. AB - This study aimed to investigate the potential health risk associated with toxic metals in contaminated foodstuffs (fruits, vegetables, and cereals) collected from various agriculture fields present in chromite mining-affected areas of mafic and ultramafic terrains (northern Pakistan). The concentrations of Cr, Ni, Zn, Cd, and Pb were quantified in both soil and food samples. The soil samples were highly contaminated with Cr (320 mg/kg), Ni (108 mg/kg), and Cd (2.55 mg/kg), which exceeded their respective safe limits set by FAO/WHO. Heavy metal concentrations in soil were found in the order of Cr>Ni>Pb>Zn>Cd and showed significantly (p < 0.001) higher concentrations as compared to reference soil. The integrated pollution load index (PLI) value was observed greater than three indicating high level of contamination in the study area. The concentrations of Cr (1.80-6.99 mg/kg) and Cd (0.21-0.90 mg/kg) in foodstuffs exceeded their safe limits, while Zn, Pb, and Ni concentrations were observed within their safe limits. In all foodstuffs, the selected heavy metal concentrations were accumulated significantly (p < 0.001) higher as compared to the reference, while some heavy metals were observed higher but not significant like Zn in pear, persimmon, white mulberry, and date-plum; Cd in pear, fig and white mulberry; and Pb in walnut, fig, and pumpkin. The health risk assessment revealed no potential risk for both adults and children for the majority of heavy metals, except Cd, which showed health risk index (HRI) >1 for children and can pose potential health threats for local inhabitants. Graphical Abstract Heavy metals released from chromite mining lead to soil and foodstuff contamination and human health risk. PMID- 26971963 TI - PIEZO1 gene mutation in a Japanese family with hereditary high phosphatidylcholine hemolytic anemia and hemochromatosis-induced diabetes mellitus. AB - Hereditary xerocytosis (HX) or dehydrated hereditary stomatocytosis (DHS) [OMIM 194380], in which PIEZO1 gene mutation has recently been identified, is difficult to diagnose. We report here the discovery of a PIEZO1 gene mutation in a Japanese family (father, daughter, and son) who were previously diagnosed with hereditary high phosphatidylcholine hemolytic anemia (HPCHA). All of the affected family members had non-spherocytic hemolytic anemia associated with severe hemochromatosis-related diabetes mellitus. Although the causative correlation between HPCHA and PIEZO1-gene mutated HX/DHS remains to be clarified, our findings raise an important question as to whether any of the HPCHA cases previously diagnosed in Japan may have in fact been the form of hemolytic anemia known as HX/DHS with PIEZO1 gene mutation. PMID- 26971965 TI - International Airport Impacts to Air Quality: Size and Related Properties of Large Increases in Ultrafine Particle Number Concentrations. AB - We measured particle size distributions and spatial patterns of particle number (PN) and particle surface area concentrations downwind from the Los Angeles International Airport (LAX) where large increases (over local background) in PN concentrations routinely extended 18 km downwind. These elevations were mostly comprised of ultrafine particles smaller than 40 nm. For a given downwind distance, the greatest increases in PN concentrations, along with the smallest mean sizes, were detected at locations under the landing jet trajectories. The smaller size of particles in the impacted area, as compared to the ambient urban aerosol, increased calculated lung deposition fractions to 0.7-0.8 from 0.5-0.7. A diffusion charging instrument (DiSCMini), that simulates alveolar lung deposition, measured a fivefold increase in alveolar-lung deposited surface area concentrations 2-3 km downwind from the airport (over local background), decreasing steadily to a twofold increase 18 km downwind. These ratios (elevated lung-deposited surface area over background) were lower than the corresponding ratios for elevated PN concentrations, which decreased from tenfold to twofold over the same distance, but the spatial patterns of elevated concentrations were similar. It appears that PN concentration can serve as a nonlinear proxy for lung deposited surface area downwind of major airports. PMID- 26971966 TI - [Mondor's disease of penis: A case report]. AB - INTRODUCTION: Mondor's disease is a rare superficial thrombophlebitis, historically involving the thoracic venous system of women. However, it can occur in both gender and all over the skin. CASE REPORT: We report a 40-year-old man with type one diabetes who presented with a thrombosis of the superficial dorsal vein of the penis that he treated as a fungal infection. Treatment with non steroidal anti-inflammatory drugs and low molecular weight heparin contributed to a favorable outcome in 2 weeks. CONCLUSION: Pathogenesis and treatment of Mondor's disease remain incompletely dominated. Some predisposing factors have been highlighted in the literature. It might be interesting to add diabetes, due to its frequent pelvic problems leading to a potential venous inflammatory trigger. PMID- 26971967 TI - [Small bowel obstruction secondary to massive hookworm infestation complicated by fatal plurimicrobial bacteriemia]. AB - INTRODUCTION: Intestinal symptoms (cramping, flatulence) and iron deficient anemia are classical presenting manifestations of duodenal hookworm infestation in patients living in endemic area. CASE REPORT: We report a 45-year-old immunocompetent metropolitan man who presented with intestinal obstruction secondary to massive hookworm infestation complicated by fatal plurimicrobial bacteriemia with refractory septic shock. CONCLUSION: We report a case of acute surgical abdominal presentation with septicemia and refractory shock syndrome due to ileal translocation secondary to massive hookworm infestation. To the best of our knowledge, such a case has not yet been reported. PMID- 26971968 TI - [The two faces of giant cell arteritis]. PMID- 26971969 TI - [A typical erythrodermia]. PMID- 26971970 TI - [Ganulomatosis with polyangiitis revealed by a cutaneous ulceration mimicking a pyoderma gangrenosum: Two patients]. AB - INTRODUCTION: Granulomatosis with polyangiitis is a systemic and necrotizing vasculitis, and cutaneous involvement is uncommon. We report two cases of skin ulceration mimicking a pyoderma gangrenosum, and revealing granulomatosis with polyangiitis. CASE REPORTS: We report two patients who presented with atypical cutaneous ulcerations, with a chronic course. These wounds were large ulcerations with abrupt edges, with purulent and hemorrhagic exudates. The first hypothesis was a pyoderma gangrenosum, but the biopsies were not specific. New biopsies performed distant from the edges showed a necrotizing vasculitis associated with giant cells granuloma, typical from granulomatosis with polyangiitis. CONCLUSION: Cutaneous manifestations are uncommon in granulomatosis with polyangiitis, and can be misleading as they may precede the systemic symptoms. We report two cases of granulomatosis with polyangiitis revealed by cutaneous symptoms mimicking a pyoderma gangrenosum. Repetition of the skin biopsies were necessary to obtain the diagnosis. PMID- 26971971 TI - Diffuse intestinal pneumatosis after an Endoscopic Retrograde Cholangiopancreatography: A paradigmatic case for an old pathogenetic dilemma. PMID- 26971972 TI - Genome sequencing and annotation of Kocuria turfanensis HO-9042, to promote explorating high-salt resistance associated gene resources. AB - Kocuria turfanensis HO-9042 which was cultured from the extreme environment in China is a gram-positive, aerobic, non-motile and coccoid bacterium. In order to dissect genetic determinants of strong resistance to high salt, whole genome of K. turfanensis was sequenced. Then effective genetic engineering could be performed to promote gene resources application, including plant breeding in high salt soil. PMID- 26971973 TI - Tailoring of global transcription sigma D factor by random mutagenesis to improve Escherichia coli tolerance towards low-pHs. AB - Bioconversion processes of organic acid or acid hydrolysis of raw material for microbial metabolism often suffer limitations as a result of microbial sensitivity in low-pH conditions. We adopted a three-step method called RAndom Insertional-deletional Strand Exchange mutagenesis (RAISE) to engineer the components of global regulator Sigma D factor (RpoD) of Escherichia coli to improve its acid tolerance. The best strain Mutant VII was identified from random mutagenesis libraries based on the growth performance, which exhibited much higher growth rate than the control (0.22h(-1) vs. 0.15h(-1)) at pH as low as 3.17. Combined transcriptome and phenome analysis of E. coli was carried out to better understand the global effects of RpoD on the regulatory networks. Our analysis showed that 95 (2.1%) of all E. coli genes were induced and 178 (4.0%) genes were repressed, including those for trehalose biosynthesis, nucleotides biosynthesis, carbon metabolism, amino acid utilization, except for acid resistance. Also regulated were the master regulators (ArcA, EvgA, H-NS and RpoS) and gene/operon-specific transcription factors (GadX, GadW, AppY, YdeO, KdgR). These results demonstrated that RpoD acts as global regulator in the growth phase of E. coli and consequently improves acid tolerances. PMID- 26971974 TI - [Occult cancer in patients with idiopathic pulmonary embolism]. PMID- 26971975 TI - [New tools for the management of renal function in the elderly: Berlin Initiative Study equation and hematocrit, urea and gender formulae]. AB - In the last few years a debate has emerged on the range of normal renal function in the elderly, and if every elderly person with a glomerular filtration rate estimated using formulas (Cockroft-Gault, MDRD, CKD-EPI) of less than 60ml/min/1.73m(2) has kidney disease. In this review we analysed, based on the results of the study Elderly people with chronic kidney disease of the Hospital de Segovia, the new equations to measure kidney function in the elderly: the Berlin Initiative Study equation designed to estimate the glomerular filtration rate in people aged 70 or more, and the hematocrit, urea and gender formula to establish whether an elderly person with a glomerular filtration rate lower than 60mL/min/1.73m(2) has kidney disease. PMID- 26971976 TI - [Incidence of Lyme disease in Spain]. PMID- 26971977 TI - [Anaemia in pregnancy and in the immediate postpartum period. Prevalence and risk factors in pregnancy and childbirth]. AB - INTRODUCTION AND OBJECTIVE: The objective of the study was to assess the prevalence of anaemia in the immediate postpartum period (48-72hours), determine the risk factors and the value of haemoglobin before birth to reduce postpartum anaemia. MATERIAL AND METHODS: A prospective, observational and longitudinal study that included 1,426 women who delivered consecutively and agreed to participate in the study. Different variables, analytical, epidemiological, foetal and maternal symptoms were studied. RESULTS: The prevalence of anaemia in the postpartum period was 49.7%. The most important risk factors were antepartum anaemia and type of delivery. The types of delivery most influencing postpartum anaemia were, forceps (82.3%), the ventouse 67%, cesarean section (58,2%) and vaginal delivery (37.2%). In the multivariate study was found as the most important independent risk factors, the haemoglobin in the delivery day (OR 6.16, CI: 3.73 to 10.15) and instrumental delivery (OR: 4.61, CI: 3.44 to 6, 19). Other independent risk factors were haemoglobin in the third trimester, episiotomy and perineal tears, ethnicity, birth weight, parity and intra/postpartum complications. CONCLUSIONS: Anaemia in the immediate postpartum is a prevalent problem. The factors most associated postpartum anaemia were antepartum anaemia and instrumental delivery. If patients arrive at the day of delivery with haemoglobins>=12,6g/dl and were restricted to necessary instrumented deliveries and cesarean sections, episiotomies and we could avoid perineal tears we can decrease anaemia in the immediate postpartum period very significantly. PMID- 26971978 TI - [Mesenteric panniculitis]. AB - Mesenteric panniculitis is a condition characterized by chronic nonspecific inflammation of the mesentery. There is little and often confusing information about its characteristics and the approach to take once it has been demonstrated by an imaging test. We propose to describe the epidemiological, clinical, laboratory, radiological and pathological features of the patients with mesenteric panniculitis reported in the literature, as well as possible disorders causal or associated with mesenteric panniculitis, in the opinion of the authors of each study. Finally, we will review the different therapeutic options used and the response to them. To that end a literature search was performed from the main medical databases selecting items with information on these aspects. This information was collected on a database stored in SPSS software for further analysis and summary. PMID- 26971979 TI - [Frontoethmoidal encephalocele]. PMID- 26971980 TI - [Palpebral anterior eye globe luxation after eyelid retraction]. PMID- 26971981 TI - [Short evolved pseudochylothorax without pleural thickening]. PMID- 26971982 TI - [Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: Usefulness of espiratory chest CT]. PMID- 26971983 TI - [Raised lesions on tongue]. PMID- 26971984 TI - [Diagnosis and treatment of hepatocellular carcinoma. Update consensus document from the AEEH, SEOM, SERAM, SERVEI and SETH]. AB - Hepatocellular carcinoma is the most common primary malignancy of the liver and one of the most frequent causes of death in patients with liver cirrhosis. Simultaneously with the recognition of the clinical relevance of this neoplasm, in recent years there have been important developments in the diagnosis, staging and treatment of HCC. Consequently, the Asociacion Espanola para el Estudio del Higado has driven the need to update clinical practice guidelines, continuing to invite all the societies involved in the diagnosis and treatment of this disease to participate in the drafting and approval of the document (Sociedad Espanola de Trasplante Hepatico, Sociedad Espanola de Radiologia Medica, Sociedad Espanola de Radiologia Vascular e Intervencionista y Sociedad Espanola de Oncologia Medica). The clinical practice guidelines published in 2009 accepted as Clinical Practice Guidelines of the National Health System has been taken as reference document, incorporating the most important advances that have been made in recent years. The scientific evidence for the treatment of HCC has been evaluated according to the recommendations of the National Cancer Institute (www.cancer.gov) and the strength of recommendation is based on the GRADE system. PMID- 26971985 TI - [Optic chiasm glioma in children: Endocrine disorders in 14 cases]. AB - BACKGROUND AND OBJECTIVES: To describe the frequency of endocrine disorders in children with optic chiasm glioma and analyze related factors. PATIENTS AND METHODS: Review of medical records by collecting sex, age, history of neurofibromatosis, clinical presentation, treatment of tumour, and presence of endocrine abnormalities. Statistical tests Wilcoxon and Fisher. RESULTS: 14 patients (6 female) with age at diagnosis of 0.5 to 7.0 years (mean+/-standard deviation: 2.97+/-2.32) and follow-up of 10.64+/-3.30 years (range 6.0 to 16.0). 12/14 presented endocrinopathy at follow-up: 8 precocious puberty, 5 hypopituitarism, and 5 obesity. The onset of deficits was related to the neuroophthalmological symptoms under the age of five (P=.02)and treatment of the tumour was required.(P=.03). CONCLUSIONS: Children with optic chiasm gliomas may present endocrine disorders from the time of diagnosis of the tumor and, in particular as they develop on. The most common of these is precocious puberty. Pituitary deficits are associated with more aggressive tumours (those presenting with neuroophthalmological signs and symptoms before the age of five and requiring treatment). PMID- 26971986 TI - [Cryptococcal meningoencephalitis. Epidemiology and mortality risk factors in pre and post-HAART era]. AB - INTRODUCTION AND OBJECTIVE: Cryptococcal meningoencephalitis (CM) is an uncommon entity, but remains a major cause of morbidity and mortality in patients with AIDS. MATERIAL AND METHODS: Review of CM cases in a university hospital. The diagnosis was determined by isolation of Cryptococcus neoformans in cerebrospinal fluid. Morbidity and mortality was assessed at 12 weeks (early mortality) and between 3 and 18 months after diagnosis (late mortality). RESULTS: We analyzed 32 patients from 2,269 AIDS cases (1.41%). 10 patients between 1990-1996 and 22 between 1997-2014. Cryptococcal antigen in CSF was positive in all cases, with titers>1,024 in 19 patients (63%); this group had lower CD4+ counts (40 +/- 33 vs. 139 +/- 78 cel/MUL) and greater disseminated involvement. After a first CM episode the relapse rate was 34%. Global mortality rate was 28% (9/32), much higher in the pre-HAART era. CONCLUSIONS: CM morbidity and mortality is related to severe immunodeficiency, disseminated disease, high titers of antigen in CSF and delayed initiation of HAART. PMID- 26971988 TI - [Predictive factors of clinically significant drug-drug interactions among regimens based on protease inhibitors, non-nucleoside reverse transcriptase inhibitors and raltegravir]. AB - BACKGROUND AND OBJECTIVE: To determine the prevalence and types of clinically significant drug-drug interactions (CSDI) in the drug regimens of HIV-infected patients receiving antiretroviral treatment. MATERIAL AND METHODS: DESIGN: retrospective review of database. Centre: Hospital Universitario Severo Ochoa, Infectious Unit. PARTICIPANTS: one hundred and forty-two participants followed by one of the authors were selected from January 1985 to December 2014. DATA COLLECTION: from their outpatient medical records we reviewed information from the last available visit of the participants, in relation to HIV infection, comorbidities, demographics and the drugs that they were receiving; both antiretroviral drugs and drugs not related to HIV infection. We defined CSDI from the information sheet and/or database on antiretroviral drug interactions of the University of Liverpool (http://www.hiv-druginteractions.org) and we developed a diagnostic tool to predict the possibility of CSDI. By multivariate logistic regression analysis and by estimating the diagnostic performance curve obtained, we identified a quick tool to predict the existence of drug interactions. RESULTS: Of 142 patients, 39 (29.11%) had some type of CSDI and in 11.2% 2 or more interactions were detected. In only one patient the combination of drugs was contraindicated (this patient was receiving darunavir/r and quetiapine). In multivariate analyses, predictors of CSDI were regimen type (PI or NNRTI) and the use of 3 or more non-antiretroviral drugs (AUC 0.886, 95% CI 0.828 to 0.944; P=.0001). The risk was 18.55 times in those receiving NNRTI and 27,95 times in those receiving IP compared to those taking raltegravir. CONCLUSIONS: Drug interactions, including those defined as clinically significant, are common in HIV-infected patients treated with antiretroviral drugs, and the risk is greater in IP-based regimens. Raltegravir-based prescribing, especially in patients who receive at least 3 non-HIV drugs could avoid interactions. PMID- 26971989 TI - [Sleep apnoea-hypopnoea syndrome]. AB - Sleep apnea-hypopnea syndrome is an underdiagnosed medical condition which is gainingin importance. It is associated with cardiovascular disease, stroke, hypertension, insulin resistance and traffic accidents, resulting in deterioration of quality of life and increased mortality in these patients. The most characteristic symptoms of the disease are snoring, documented apnoeas and excessive daytime sleepiness. Polysomnography is the gold standard for diagnosis, but in patients with high pre-test probability, we should opt for respiratory polygraphy, a more accessible and less expensive test. Besides making lifestyle changes, the treatment of choice is continuous positive airway pressure. Some surgical techniques may be useful in the treatment of sleep apnoea-hypopnoea syndrome. In patients who cannot tolerate continuous positive airway pressure, are not candidates for surgery or have a high surgical risk intraoral devices might be used. PMID- 26971987 TI - [Eosinophilic granulomatosis with polyangiitis and IgA nephropaty in a patient with HIV infection]. PMID- 26971990 TI - Dietary Patterns in Adults with Type 2 Diabetes Predict Cardiometabolic Risk Factors. AB - OBJECTIVES: Examining the diets of people living with type 2 diabetes may improve understanding of how diet affects disease progression. We derived dietary patterns in adults living with type 2 diabetes and explored associations among patterns, sociodemographic variables and cardiometabolic risk factors. METHODS: Dietary patterns were derived from food frequency questionnaires (FFQs) in 196 adults with type 2 diabetes using principal components analysis (PCA). Multilinear regression models were fitted for the differing dietary pattern scores so as to estimate the marginal contribution of each variable explaining variations in diet. Differences in clinical variables across dietary patterns, adjusting for sex, smoking and total energy intake, were assessed. RESULTS: Three principal components (PCs), or patterns, were identified, explaining 56.5% of the total variance in diet: (PC1) fried foods, cakes and ice cream; (PC2) fish and vegetables; and (PC3) pasta, potatoes and breads. Female sex, current smoker and total energy were significant associated with patterns. Total energy accounted for the greatest amount of variance in each pattern (11.2% for fried foods, cakes and ice cream, 3.89% for fish and vegetables and 9.21% for pasta, potatoes and breads). After adjustment for sex, smoking and total energy, the pasta, potatoes and breads pattern was inversely associated with systolic blood pressure and low density lipoprotein-cholesterol. CONCLUSIONS: Of the 3 distinct diet patterns characterized, the carbohydrate-based pattern was most closely associated with cardiometabolic risk factors. To better understand and improve self-management by people living with type 2 diabetes through dietary modifications, further improvements in measuring and assessing diet using comparable instruments and comparisons with apparently healthy populations is required. PMID- 26971991 TI - Cross-Sectional and Longitudinal Associations between Serum Bilirubin and Prediabetes in a Health Screening Population. AB - OBJECTIVES: Longitudinal associations between total bilirubin (TB) and prediabetes have not been reported. This study investigated cross-sectional and longitudinal associations between TB and prediabetes. METHODS: Cross-sectional associations between TB and prediabetes were investigated in 3681 nondiabetic subjects. Longitudinal associations between TB and prediabetes over 6 years were investigated in 2149 subjects who were normoglycemic at baseline. Prediabetes was defined as fasting plasma glucose (FPG) levels of >=5.6 mmol/L or glycated hemoglobin levels of >=5.7% excluding diabetes. RESULTS: The prevalence of prediabetes was 25.4%, and the cumulative incidence of prediabetes during 6 years was 25.5% in a Japanese health screening population. Prevalent prediabetes was significantly associated with the quintiles of TB in nonsmoking men (trend, p<0.001) and women (trend, p=0.012), but not in smoking men (trend, p=0.689). Incident prediabetes was not significantly associated with the quintiles of TB, while it was positively associated with 1 standard deviation increase in TB in nonsmoking men (hazard ratio [95% confidence interval]; 1.21 [1.07 to 1.37], p=0.002). CONCLUSIONS: TB levels were significantly inversely associated with prevalent prediabetes in nonsmokers, but not in smokers, whereas an inverse association between TB levels and incident prediabetes seemed to be unlikely. PMID- 26971992 TI - Incidence and relative risk of adverse events of special interest in patients with castration resistant prostate cancer treated with CYP-17 inhibitors: A meta analysis of published trials. AB - Abiraterone acetate and orteronel are two CYP-17 inhibitors that have been studied in prostate cancer. They have shown relevant toxicities, including fluid retention/oedema, hypokalaemia, hypertension, liver function test abnormalities and cardiac events. The goal of this study was to determine the risk of special adverse events related to CYP- 17 inhibitor in patients with metastatic castration-resistant prostate cancer (CRCP). Summary data from four randomized phase III trials comparing CYP-17 inhibitors and prednisone versus placebo and prednisone in metastatic CRCP patients were meta-analysed. Pooled risk ratios (RRs) for the risk of all-grade and grade 3-4 adverse events of special interest were calculated. Data from 4916 patients (2849 in the AA experimental arm; 2067 in the control arm) were analysed. The incidence of grade 3-4 adverse events was never more than 10% of the patients. However, compared with placebo, the CYP-17 inhibitor significantly increased the all-grade events of hypertension (RR=1.53; 95% CI=1.3-1.8; p<0.00001), hypokalaemia (RR=1.56; 95% CI=1.29-1.89; p<0.00001), cardiac disorders (RR=1.47; 95% CI=1.27-1.7; p<0.00001) liver function test abnormalities (RR=1.93; 95% CI=1.15-3.24; p=0.01) grade>=3 adverse events, hypokalaemia (RR=4.23; 95% CI=1.28-13.99; p=0.02) and cardiac disorders (RR=1.55; 95% CI=1.18-2.05; p=0.002). A lot of adverse events such as hypertension, hypokalaemia, cardiac disorders and liver function test abnormalities are increased during CYP-17 inhibitor based therapy. Strict monitoring of these side effects should be considered during CYP- 17 inhibitor therapy in prostate cancer patients. PMID- 26971993 TI - Diagnostic accuracy of serum biomarkers for head and neck cancer: A systematic review and meta-analysis. AB - Serum biomarkers could be helpful to characterize head and neck squamous cell carcinoma (HNSCC). Thus, the purpose of this systematic review and meta-analysis was to determine the diagnostic capability of serum biomarkers in the assessment of HNSCC patients. Studies were gathered by searching LILACS, PubMed, Science Direct, Scopus and Web of Science up to April 10th, 2015. Studies that focused on serum biomarkers in the diagnosis of HNSCC compared with controls were considered. Sixty-five studies were identified, and the sample size included 9098 subjects. Combined biomarkers demonstrated improved accuracy than those tested individually. Therefore, 12.8% of single and 34.3% of combined indicated that serum biomarkers discriminate patients with HNSCC from controls. The combined biomarkers with better diagnostic capability included Epidermal growth factor receptor (EGFR)+Cyclin D1 and squamous cell cancer-associated antigen (SCCA)+EGFR+Cyclin D1. Beta2-microglobin may also be a promising single biomarker for future studies. Serum biomarkers can be potentially useful in the diagnosis of HNSCC. However, further research is required to validate these biomarkers. PMID- 26971994 TI - Saturated Fatty Acids Engage an IRE1alpha-Dependent Pathway to Activate the NLRP3 Inflammasome in Myeloid Cells. AB - Diets rich in saturated fatty acids (SFAs) produce a form of tissue inflammation driven by "metabolically activated" macrophages. We show that SFAs, when in excess, induce a unique transcriptional signature in both mouse and human macrophages that is enriched by a subset of ER stress markers, particularly IRE1alpha and many adaptive downstream target genes. SFAs also activate the NLRP3 inflammasome in macrophages, resulting in IL-1beta secretion. We found that IRE1alpha mediates SFA-induced IL-1beta secretion by macrophages and that its activation by SFAs does not rely on unfolded protein sensing. We show instead that the ability of SFAs to stimulate either IRE1alpha activation or IL-1beta secretion can be specifically reduced by preventing their flux into phosphatidylcholine (PC) or by increasing unsaturated PC levels. Thus, IRE1alpha is an unrecognized intracellular PC sensor critical to the process by which SFAs stimulate macrophages to secrete IL-1beta, a driver of diet-induced tissue inflammation. PMID- 26971996 TI - NLRX1 Acts as an Epithelial-Intrinsic Tumor Suppressor through the Modulation of TNF-Mediated Proliferation. AB - The mitochondrial Nod-like receptor protein NLRX1 protects against colorectal tumorigenesis through mechanisms that remain unclear. Using mice with an intestinal epithelial cells (IEC)-specific deletion of Nlrx1, we find that NLRX1 provides an IEC-intrinsic protection against colitis-associated carcinogenesis in the colon. These Nlrx1 mutant mice have increased expression of Tnf, Egf, and Tgfb1, three factors essential for wound healing, as well as increased epithelial proliferation during the epithelial regeneration phase following injury triggered by dextran sodium sulfate. In primary intestinal organoids lacking Nlrx1, stimulation with TNF resulted in exacerbated proliferation and expression of the intestinal stem cell markers Olfm4 and Myb. This hyper-proliferation response was associated with increased activation of Akt and NF-kappaB pathways in response to TNF stimulation. Together, these results identify NLRX1 as a suppressor of colonic tumorigenesis that acts by controlling epithelial proliferation in the intestine during the regeneration phase following mucosal injury. PMID- 26971995 TI - Myosin VI Contains a Compact Structural Motif that Binds to Ubiquitin Chains. AB - Myosin VI is critical for cargo trafficking and sorting during early endocytosis and autophagosome maturation, and abnormalities in these processes are linked to cancers, neurodegeneration, deafness, and hypertropic cardiomyopathy. We identify a structured domain in myosin VI, myosin VI ubiquitin-binding domain (MyUb), that binds to ubiquitin chains, especially those linked via K63, K11, and K29. Herein, we solve the solution structure of MyUb and MyUb:K63-linked diubiquitin. MyUb folds as a compact helix-turn-helix-like motif and nestles between the ubiquitins of K63-linked diubiquitin, interacting with distinct surfaces of each. A nine amino-acid extension at the C-terminal helix (Helix2) of MyUb is required for myosin VI interaction with endocytic and autophagic adaptors. Structure-guided mutations revealed that a functional MyUb is necessary for optineurin interaction. In addition, we found that an isoform-specific helix restricts MyUb binding to ubiquitin chains. This work provides fundamental insights into myosin VI interaction with ubiquitinated cargo and functional adaptors. PMID- 26971997 TI - USP7 Enforces Heterochromatinization of p53 Target Promoters by Protecting SUV39H1 from MDM2-Mediated Degradation. AB - The H3K9me3 repressive histone conformation of p53 target promoters is abrogated in response to p53 activation by MDM2-mediated SUV39H1 degradation. Here, we present evidence that the USP7 deubiquitinase protects SUV39H1 from MDM2-mediated ubiquitination in the absence of p53 stimulus. USP7 occupies p53 target promoters in unstressed conditions, a process that is abrogated with p53 activation associated with loss of the H3K9me3 mark on these same promoters. Mechanistically, USP7 forms a trimeric complex with MDM2 and SUV39H1, independent of DNA, and modulates MDM2-dependent SUV39H1 ubiquitination. Furthermore, we show that this protective function of USP7 on SUV39H1 is independent of p53. Finally, USP7 blocking cooperates with p53 in inducing apoptosis by enhancing p53 promoter occupancy and dependent transactivation of target genes. These results uncover a layer of the p53 transcriptional program mediated by USP7, which restrains relaxation of local chromatin conformation at p53 target promoters. PMID- 26971999 TI - Sildenafil Potentiates a cGMP-Dependent Pathway to Promote Melanoma Growth. AB - Sildenafil, an inhibitor of the cGMP-degrading phosphodiesterase 5 that is used to treat erectile dysfunction, has been linked to an increased risk of melanoma. Here, we have examined the potential connection between cGMP-dependent signaling cascades and melanoma growth. Using a combination of biochemical assays and real time monitoring of melanoma cells, we report a cGMP-dependent growth-promoting pathway in murine and human melanoma cells. We document that C-type natriuretic peptide (CNP), a ligand of the membrane-bound guanylate cyclase B, enhances the activity of cGMP-dependent protein kinase I (cGKI) in melanoma cells by increasing the intracellular levels of cGMP. Activation of this cGMP pathway promotes melanoma cell growth and migration in a p44/42 MAPK-dependent manner. Sildenafil treatment further increases intracellular cGMP concentrations, potentiating activation of this pathway. Collectively, our data identify this cGMP-cGKI pathway as the link between sildenafil usage and increased melanoma risk. PMID- 26972000 TI - Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways. AB - Amino acid hydroxylation is a post-translational modification that regulates intra- and inter-molecular protein-protein interactions. The modifications are regulated by a family of 2-oxoglutarate- (2OG) dependent enzymes and, although the biochemistry is well understood, until now only a few substrates have been described for these enzymes. Using quantitative interaction proteomics, we screened for substrates of the proline hydroxylase PHD3 and the asparagine hydroxylase FIH, which regulate the HIF-mediated hypoxic response. We were able to identify hundreds of potential substrates. Enrichment analysis revealed that the potential substrates of both hydroxylases cluster in the same pathways but frequently modify different nodes of signaling networks. We confirm that two proteins identified in our screen, MAPK6 (Erk3) and RIPK4, are indeed hydroxylated in a FIH- or PHD3-dependent mechanism. We further determined that FIH-dependent hydroxylation regulates RIPK4-dependent Wnt signaling, and that PHD3-dependent hydroxylation of MAPK6 protects the protein from proteasomal degradation. PMID- 26972001 TI - Retinoblastoma Binding Protein 4 Modulates Temozolomide Sensitivity in Glioblastoma by Regulating DNA Repair Proteins. AB - Here we provide evidence that RBBP4 modulates temozolomide (TMZ) sensitivity through coordinate regulation of two key DNA repair genes critical for recovery from TMZ-induced DNA damage: methylguanine-DNA-methyltransferase (MGMT) and RAD51. Disruption of RBBP4 enhanced TMZ sensitivity, induced synthetic lethality to PARP inhibition, and increased DNA damage signaling in response to TMZ. Moreover, RBBP4 silencing enhanced TMZ-induced H2AX phosphorylation and apoptosis in GBM cells. Intriguingly, RBBP4 knockdown suppressed the expression of MGMT, RAD51, and other genes in association with decreased promoter H3K9 acetylation (H3K9Ac) and increased H3K9 tri-methylation (H3K9me3). Consistent with these data, RBBP4 interacts with CBP/p300 to form a chromatin-modifying complex that binds within the promoter of MGMT, RAD51, and perhaps other genes. Globally, RBBP4 positively and negatively regulates genes involved in critical cellular functions including tumorigenesis. The RBBP4/CBP/p300 complex may provide an interesting target for developing therapy-sensitizing strategies for GBM and other tumors. PMID- 26971998 TI - The Innate Immune Receptor NLRX1 Functions as a Tumor Suppressor by Reducing Colon Tumorigenesis and Key Tumor-Promoting Signals. AB - NOD-like receptor (NLR) proteins are intracellular innate immune sensors/receptors that regulate immunity. This work shows that NLRX1 serves as a tumor suppressor in colitis-associated cancer (CAC) and sporadic colon cancer by keeping key tumor promoting pathways in check. Nlrx1(-/-) mice were highly susceptible to CAC, showing increases in key cancer-promoting pathways including nuclear factor kappaB (NF-kappaB), mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), and interleukin 6 (IL 6). The tumor-suppressive function of NLRX1 originated primarily from the non hematopoietic compartment. This prompted an analysis of NLRX1 function in the Apc(min/+) genetic model of sporadic gastrointestinal cancer. NLRX1 attenuated Apc(min/+) colon tumorigenesis, cellular proliferation, NF-kappaB, MAPK, STAT3 activation, and IL-6 levels. Application of anti-interleukin 6 receptor (IL6R) antibody therapy reduced tumor burden, increased survival, and reduced STAT3 activation in Nlrx1(-/-)Apc(min/+) mice. As an important clinical correlate, human colon cancer samples expressed lower levels of NLRX1 than healthy controls in multiple patient cohorts. These data implicate anti-IL6R as a potential personalized therapy for colon cancers with reduced NLRX1. PMID- 26972003 TI - alpha-Tubulin Tyrosination and CLIP-170 Phosphorylation Regulate the Initiation of Dynein-Driven Transport in Neurons. AB - Motor-cargo recruitment to microtubules is often the rate-limiting step of intracellular transport, and defects in this recruitment can cause neurodegenerative disease. Here, we use in vitro reconstitution assays with single-molecule resolution, live-cell transport assays in primary neurons, computational image analysis, and computer simulations to investigate the factors regulating retrograde transport initiation in the distal axon. We find that phosphorylation of the cytoskeletal-organelle linker protein CLIP-170 and post translational modifications of the microtubule track combine to precisely control the initiation of retrograde transport. Computer simulations of organelle dynamics in the distal axon indicate that while CLIP-170 primarily regulates the time to microtubule encounter, the tyrosination state of the microtubule lattice regulates the likelihood of binding. These mechanisms interact to control transport initiation in the axon in a manner sensitive to the specialized cytoskeletal architecture of the neuron. PMID- 26972004 TI - Uridylation and PABP Cooperate to Repair mRNA Deadenylated Ends in Arabidopsis. AB - Uridylation emerges as a key modification promoting mRNA degradation in eukaryotes. In addition, uridylation by URT1 prevents the accumulation of excessively deadenylated mRNAs in Arabidopsis. Here, we show that the extent of mRNA deadenylation is controlled by URT1. By using TAIL-seq analysis, we demonstrate the prevalence of mRNA uridylation and the existence, at lower frequencies, of mRNA cytidylation and guanylation in Arabidopsis. Both URT1 dependent and URT1-independent types of uridylation co-exist but only URT1 mediated uridylation prevents the accumulation of excessively deadenylated mRNAs. Importantly, uridylation repairs deadenylated extremities to restore the size distribution observed for non-uridylated oligo(A) tails. In vivo and in vitro data indicate that Poly(A) Binding Protein (PABP) binds to uridylated oligo(A) tails and determines the length of U-extensions added by URT1. Taken together, our results uncover a role for uridylation and PABP in repairing mRNA deadenylated ends and reveal that uridylation plays diverse roles in eukaryotic mRNA metabolism. PMID- 26972002 TI - Composition and Antigenic Effects of Individual Glycan Sites of a Trimeric HIV-1 Envelope Glycoprotein. AB - The HIV-1 envelope glycoprotein trimer is covered by an array of N-linked glycans that shield it from immune surveillance. The high density of glycans on the trimer surface imposes steric constraints limiting the actions of glycan processing enzymes, so that multiple under-processed structures remain on specific areas. These oligomannose glycans are recognized by broadly neutralizing antibodies (bNAbs) that are not thwarted by the glycan shield but, paradoxically, target it. Our site-specific glycosylation analysis of a soluble, recombinant trimer (BG505 SOSIP.664) maps the extremes of simplicity and diversity of glycan processing at individual sites and reveals a mosaic of dense clusters of oligomannose glycans on the outer domain. Although individual sites usually minimally affect the global integrity of the glycan shield, we identify examples of how deleting some glycans can subtly influence neutralization by bNAbs that bind at distant sites. The network of bNAb-targeted glycans should be preserved on vaccine antigens. PMID- 26972006 TI - A Mutation in fat2 Uncouples Tissue Elongation from Global Tissue Rotation. AB - Global tissue rotation was proposed as a morphogenetic mechanism controlling tissue elongation. In Drosophila ovaries, global tissue rotation of egg chambers coincides with egg chamber elongation. Egg chamber rotation was put forward to result in circumferential alignment of extracellular fibers. These fibers serve as molecular corsets to restrain growth of egg chambers perpendicular to the anteroposterior axis, thereby leading to the preferential egg chamber elongation along this axis. The atypical cadherin Fat2 is required for egg chamber elongation, rotation, and the circumferential alignment of extracellular fibers. Here, we have generated a truncated form of Fat2 that lacks the entire intracellular region. fat2 mutant egg chambers expressing this truncated protein fail to rotate yet display normal extracellular fiber alignment and properly elongate. Our data suggest that global tissue rotation, even though coinciding with tissue elongation, is not a necessary prerequisite for elongation. PMID- 26972005 TI - Subcellular Compartmentalization and Trafficking of the Biosynthetic Machinery for Fungal Melanin. AB - Protection by melanin depends on its subcellular location. Although most filamentous fungi synthesize melanin via a polyketide synthase pathway, where and how melanin biosynthesis occurs and how it is deposited as extracellular granules remain elusive. Using a forward genetic screen in the pathogen Aspergillus fumigatus, we find that mutations in an endosomal sorting nexin abolish melanin cell-wall deposition. We find that all enzymes involved in the early steps of melanin biosynthesis are recruited to endosomes through a non-conventional secretory pathway. In contrast, late melanin enzymes accumulate in the cell wall. Such subcellular compartmentalization of the melanin biosynthetic machinery occurs in both A. fumigatus and A. nidulans. Thus, fungal melanin biosynthesis appears to be initiated in endosomes with exocytosis leading to melanin extracellular deposition, much like the synthesis and trafficking of mammalian melanin in endosomally derived melanosomes. PMID- 26972008 TI - Breaks in the 45S rDNA Lead to Recombination-Mediated Loss of Repeats. AB - rDNA repeats constitute the most heavily transcribed region in the human genome. Tumors frequently display elevated levels of recombination in rDNA, indicating that the repeats are a liability to the genomic integrity of a cell. However, little is known about how cells deal with DNA double-stranded breaks in rDNA. Using selective endonucleases, we show that human cells are highly sensitive to breaks in 45S but not the 5S rDNA repeats. We find that homologous recombination inhibits repair of breaks in 45S rDNA, and this results in repeat loss. We identify the structural maintenance of chromosomes protein 5 (SMC5) as contributing to recombination-mediated repair of rDNA breaks. Together, our data demonstrate that SMC5-mediated recombination can lead to error-prone repair of 45S rDNA repeats, resulting in their loss and thereby reducing cellular viability. PMID- 26972009 TI - Super-Resolution Mapping of Neuronal Circuitry With an Index-Optimized Clearing Agent. AB - Super-resolution imaging deep inside tissues has been challenging, as it is extremely sensitive to light scattering and spherical aberrations. Here, we report an optimized optical clearing agent for high-resolution fluorescence imaging (SeeDB2). SeeDB2 matches the refractive indices of fixed tissues to that of immersion oil (1.518), thus minimizing both light scattering and spherical aberrations. During the clearing process, fine morphology and fluorescent proteins were highly preserved. SeeDB2 enabled super-resolution microscopy of various tissue samples up to a depth of >100 MUm, an order of magnitude deeper than previously possible under standard mounting conditions. Using this approach, we demonstrate accumulation of inhibitory synapses on spine heads in NMDA receptor-deficient neurons. In the fly medulla, we found unexpected heterogeneity in axon bouton orientations among Mi1 neurons, a part of the motion detection circuitry. Thus, volumetric super-resolution microscopy of cleared tissues is a powerful strategy in connectomic studies at synaptic levels. PMID- 26972007 TI - The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A. AB - Neuronal function is highly sensitive to changes in oxygen levels, but how hypoxia affects dendritic spine formation and synaptogenesis is unknown. Here we report that hypoxia, chemical inhibition of the oxygen-sensing prolyl hydroxylase domain proteins (PHDs), and silencing of Phd2 induce immature filopodium-like dendritic protrusions, promote spine regression, reduce synaptic density, and decrease the frequency of spontaneous action potentials independently of HIF signaling. We identified the actin cross-linker filamin A (FLNA) as a target of PHD2 mediating these effects. In normoxia, PHD2 hydroxylates the proline residues P2309 and P2316 in FLNA, leading to von Hippel-Lindau (VHL)-mediated ubiquitination and proteasomal degradation. In hypoxia, PHD2 inactivation rapidly upregulates FLNA protein levels because of blockage of its proteasomal degradation. FLNA upregulation induces more immature spines, whereas Flna silencing rescues the immature spine phenotype induced by PHD2 inhibition. PMID- 26972010 TI - Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation. AB - Cockayne syndrome (CS) is a severe neurodevelopmental disorder characterized by growth abnormalities, premature aging, and photosensitivity. Mutation of Cockayne syndrome B (CSB) affects neuronal gene expression and differentiation, so we attempted to bypass its function by expressing downstream target genes. Intriguingly, ectopic expression of Synaptotagmin 9 (SYT9), a key component of the machinery controlling neurotrophin release, bypasses the need for CSB in neuritogenesis. Importantly, brain-derived neurotrophic factor (BDNF), a neurotrophin implicated in neuronal differentiation and synaptic modulation, and pharmacological mimics such as 7,8-dihydroxyflavone and amitriptyline can compensate for CSB deficiency in cell models of neuronal differentiation as well. SYT9 and BDNF are downregulated in CS patient brain tissue, further indicating that sub-optimal neurotrophin signaling underlies neurological defects in CS. In addition to shedding light on cellular mechanisms underlying CS and pointing to future avenues for pharmacological intervention, these data suggest an important role for SYT9 in neuronal differentiation. PMID- 26972012 TI - Activity-Dependent Plasticity of Spike Pauses in Cerebellar Purkinje Cells. AB - The plasticity of intrinsic excitability has been described in several types of neurons, but the significance of non-synaptic mechanisms in brain plasticity and learning remains elusive. Cerebellar Purkinje cells are inhibitory neurons that spontaneously fire action potentials at high frequencies and regulate activity in their target cells in the cerebellar nuclei by generating a characteristic spike burst-pause sequence upon synaptic activation. Using patch-clamp recordings from mouse Purkinje cells, we find that depolarization-triggered intrinsic plasticity enhances spike firing and shortens the duration of spike pauses. Pause plasticity is absent from mice lacking SK2-type potassium channels (SK2(-/-) mice) and in occlusion experiments using the SK channel blocker apamin, while apamin wash-in mimics pause reduction. Our findings demonstrate that spike pauses can be regulated through an activity-dependent, exclusively non-synaptic, SK2 channel dependent mechanism and suggest that pause plasticity-by altering the Purkinje cell output-may be crucial to cerebellar information storage and learning. PMID- 26972011 TI - Projection-Specific Visual Feature Encoding by Layer 5 Cortical Subnetworks. AB - Primary neocortical sensory areas act as central hubs, distributing afferent information to numerous cortical and subcortical structures. However, it remains unclear whether each downstream target receives a distinct version of sensory information. We used in vivo calcium imaging combined with retrograde tracing to monitor visual response properties of three distinct subpopulations of projection neurons in primary visual cortex. Although there is overlap across the groups, on average, corticotectal (CT) cells exhibit lower contrast thresholds and broader tuning for orientation and spatial frequency in comparison to corticostriatal (CS) cells, whereas corticocortical (CC) cells have intermediate properties. Noise correlational analyses support the hypothesis that CT cells integrate information across diverse layer 5 populations, whereas CS and CC cells form more selectively interconnected groups. Overall, our findings demonstrate the existence of functional subnetworks within layer 5 that may differentially route visual information to behaviorally relevant downstream targets. PMID- 26972013 TI - The SNARE VAMP7 Regulates Exocytic Trafficking of Interleukin-12 in Dendritic Cells. AB - Interleukin-12 (IL-12), produced by dendritic cells in response to activation, is central to pathogen eradication and tumor rejection. The trafficking pathways controlling spatial distribution and intracellular transport of IL-12 vesicles to the cell surface are still unknown. Here, we show that intracellular IL-12 localizes in late endocytic vesicles marked by the SNARE VAMP7. Dendritic cells (DCs) from VAMP7-deficient mice are partially impaired in the multidirectional release of IL-12. Upon encounter with antigen-specific T cells, IL-12-containing vesicles rapidly redistribute at the immune synapse and release IL-12 in a process entirely dependent on VAMP7 expression. Consistently, acquisition of effector functions is reduced in T cells stimulated by VAMP7-null DCs. These results provide insights into IL-12 intracellular trafficking pathways and show that VAMP7-mediated release of IL-12 at the immune synapse is a mechanism to transmit innate signals to T cells. PMID- 26972014 TI - IPP Complex Reinforces Adhesion by Relaying Tension-Dependent Signals to Inhibit Integrin Turnover. AB - Cytoskeleton-mediated forces regulate the assembly and function of integrin adhesions; however, the underlying mechanisms remain unclear. The tripartite IPP complex, comprising ILK, Parvin, and PINCH, mediates the integrin-actin link at Drosophila embryo muscle attachment sites (MASs). Here, we demonstrate a developmentally earlier function for the IPP complex: to reinforce integrin extracellular matrix (ECM) adhesion in response to tension. In IPP-complex mutants, the integrin-ECM linkage at MASs breaks in response to intense muscle contractility. Mechanistically, the IPP complex is required to relay force elicited signals that decelerate integrin turnover at the plasma membrane so that the integrin immobile fraction is adequate to withstand tension. Epistasis analysis shows that alleviation of muscle contractility, downregulation of endocytosis, and enhanced integrin binding to the ECM are sufficient to restore integrin-ECM adhesion and maintain integrin-adhesome organization in IPP-complex mutants. Our findings reveal a role for the IPP complex as an essential mechanosensitive regulatory switch of integrin turnover in vivo. PMID- 26972016 TI - Endoscopic resection of maxillary sinus keratocystic odontogenic tumors. PMID- 26972015 TI - System-wide Analysis of the T Cell Response. AB - The T cell receptor (TCR) controls the cellular adaptive immune response to antigens, but our understanding of TCR repertoire diversity and response to challenge is still incomplete. For example, TCR clones shared by different individuals with minimal alteration to germline gene sequences (public clones) are detectable in all vertebrates, but their significance is unknown. Although small in size, the zebrafish TCR repertoire is controlled by processes similar to those operating in mammals. Thus, we studied the zebrafish TCR repertoire and its response to stimulation with self and foreign antigens. We found that cross reactive public TCRs dominate the T cell response, endowing a limited TCR repertoire with the ability to cope with diverse antigenic challenges. These features of vertebrate public TCRs might provide a mechanism for the rapid generation of protective T cell immunity, allowing a short temporal window for the development of more specific private T cell responses. PMID- 26972017 TI - Diagnostic Accuracy of Emergency Physician-Performed Ultrasound for Acute Appendicitis in a Remote Location. AB - BACKGROUND: Preoperative imaging for suspected acute appendicitis (AA), such as ultrasonography (US), was shown to improve diagnostic accuracy and patient outcomes. Criteria for diagnosis of AA by US are well established and reliable. In previous studies, US assessments were always performed by skilled radiologist physicians. However, a radiologist and computed tomography scanning equipment are not always available in the community hospitals or remote sites of developing countries. OBJECTIVE: Our aim was to assess a diagnostic pathway using clinical evaluation, routine US performed by an emergency physician, and clinical re evaluation for patients suspected of having AA. METHODS: Patients suspected of having AA admitted to the emergency department in a developing country were prospectively enrolled between November 2010 and January 2011. Clinical and US data were studied. A noncompressible appendix with a diameter >=6 mm was the main US diagnosis criterion. RESULTS: Among the 104 included patients, surgery was performed on 28. Of the 25 patients with positive US, 22 actually had AA, matching the surgical report. The remaining 76 patients without US appendicitis criteria underwent clinical follow-up and had medical conditions. Sensitivity of US was 88%, specificity was 96%, positive predictive value was 88%, and negative predictive value was 96%. The likelihood ratios for our US assessment highlight the need for a test with enhanced diagnostic accuracy. CONCLUSIONS: A diagnostic strategy using clinical evaluations, routine US performed by emergency physicians, and clinical re-evaluation of patients with acute abdominal pain is appropriate to provide positive results for the diagnosis and treatment of appendicitis in remote locations. PMID- 26972019 TI - Resilience skills as emergent phenomena: A study of emergency departments in Brazil and the United States. AB - Although the use of resilience skills (RSs) by emergency department (ED) front line staff is ubiquitous, the nature and origin of these skills tend to be taken for granted. This study investigates the research question "where do RSs come from"? Case studies in two EDs were undertaken in order to answer the research question: one in Brazil and the other in the United States. The case studies adopted the same data collection and analysis procedures, involving interviews, questionnaires, observations, and analysis of documents. A model for describing RSs as emergent phenomena is proposed. The model indicates that RSs arise from interactions between: work constraints, hidden curriculum, gaps in standardized operating procedures, organizational support for resilience, and RSs themselves. An instantiation of the model is illustrated by a critical event identified from the American ED. The model allows the identification of leverage points for influencing the development of RSs, instead of leaving their evolution purely to chance. PMID- 26972018 TI - Use of Intravenous Fat Emulsion in the Emergency Department for the Critically Ill Poisoned Patient. AB - BACKGROUND: Multiple case reports of using intravenous fat emulsion (IFE) as an antidote for human poisoning from various xenobiotics have been published over the last decade. Given the rapidly evolving field, emergency physicians may be uncertain about the indications, timing, and dose for IFE treatment. METHODS: A PubMed literature search was conducted from January 1996 to November 2015 and limited to human studies written in English and articles with relevant keywords. Guideline statements and nonsystematic reviews were excluded. Studies identified then underwent a structured review of their results. RESULTS: There were 986 papers fulfilling the search criteria screened, and 85 appropriate articles were rigorously reviewed in detail. Recommendations were given on indications, timing, and dose of IFE. Most of these were based on case reports and anecdotal experience. DISCUSSION: In critically ill patients with refractory shock or cardiac arrest after a suspected overdose of local anesthetics or selected xenobiotics, IFE may be considered as a potentially beneficial adjunctive treatment. Despite an abundance of reports on the use of IFE on xenobiotics poisoning, the quality of evidence is suboptimal and fraught with reporting bias. CONCLUSIONS: IFE may be an effective antidote in poisonings from various xenobiotics. However, further research is needed to determine its optimal circumstances, timing, and dose of use. PMID- 26972020 TI - Fatty Liver in Hispanics with HIV. PMID- 26972021 TI - Prelude Special Issue: Control of breathing in non-mammalian vertebrates. PMID- 26972023 TI - In-hospital weekend outcomes in patients diagnosed with bleeding gastroduodenal angiodysplasia: a population-based study, 2000 to 2011. AB - BACKGROUND AND AIMS: GI angiodysplastic (GIAD) lesions are an important cause of blood loss throughout the GI tract, particularly in elderly persons. The aim of this study was to determine whether mortality rates in patients with GIAD were higher for weekend compared with weekday hospital admissions. METHODS: We performed a retrospective study using the National Inpatient Sample database from 2000 to 2011 including inpatients with an International Classification of Diseases, Ninth Revision, Clinical Modification code for gastrointestinal GIAD (code 537.82 or 537.83). We assessed rates of delayed endoscopy (examinations performed >24 hours after admission), intensive care unit (ICU) admissions, and in-hospital mortality rates. Bivariate and multivariate logistic regression analyses were performed to identify risk factors for mortality. RESULTS: There were 85,971 discharges for GIAD between 2000 and 2011, of which 69,984 (81%) were weekday hospital admissions and 15,987 (19%) were weekend admissions. Patients with weekend versus weekday admissions were more likely to undergo delayed endoscopic examination (35% vs 26%, P <= .0001). Mortality rates were higher for patients with weekend admissions (2% vs 1%, P = .0002). The adjusted odds ratio (aOR) for inpatient mortality associated with weekend admissions was elevated (2.4; 95% confidence interval [CI], 1.5-3.9; P = .0005). Rates of delayed endoscopic examinations were lower in patients with higher socioeconomic status (aOR = 0.77; 95% CI, 0.68-0.88). ICU admission rates were higher for weekend compared with weekday admissions (8% vs 6%, P = .004). The presence of a delayed endoscopic examination was associated with an increased length of stay of 1.3 days (95% CI, 1.2-1.4 days). CONCLUSIONS: Weekend admissions for angiodysplasia were associated with higher odds of mortality, ICU admissions, higher rates of delayed endoscopic procedures, longer lengths of stay, and higher hospital charges. PMID- 26972024 TI - The effect and biological mechanism of COD/TN ratio on nitrogen removal in a novel upflow microaerobic sludge reactor treating manure-free piggery wastewater. AB - A novel upflow microaerobic sludge reactor (UMSR) was constructed to treat manure free piggery wastewater with high NH4(+)-N concentration and low COD/TN ratio, and the effect and biological mechanism of COD/TN ratio on nitrogen removal were investigated at a constant hydraulic retention time of 8h and 35 degrees C. The results showed that the UMSR could treat the wastewater with a better synchronous removal of COD, NH4(+)-N and TN. The microaerobic UMSR allowed nitrifiers, and heterotrophic and autotrophic denitrifiers to thrive in the flocs, revealing a multiple nitrogen removal mechanism in the reactor. Both the nitrifiers and denitrifiers would be restricted by an influent COD/TN ratio more than 0.82, resulting in a decrease of TN removal in the UMSR. To get a TN removal over 80% with a TN load removal above 0.86kg/(m(3).d) in the UMSR, the influent COD/TN ratio should be less than 0.70. PMID- 26972022 TI - Cost-effectiveness and clinical efficacy of biliary stents in patients undergoing neoadjuvant therapy for pancreatic adenocarcinoma in a randomized controlled trial. AB - BACKGROUND AND AIMS: The optimal type of stent for the palliation of malignant biliary obstruction in patients with pancreatic adenocarcinoma undergoing neoadjuvant chemoradiotherapy with curative intent is unknown. We performed a prospective trial comparing 3 types of biliary stents-fully covered self expandable metal (fcSEMS), uncovered self-expandable metal (uSEMS), and plastic to determine which best optimized cost-effectiveness and important clinical outcomes. METHODS: In this prospective randomized trial, consecutive patients with malignant biliary obstruction from newly diagnosed pancreatic adenocarcinoma who were to start neoadjuvant chemoradiotherapy were randomized to receive fcSEMSs, uSEMSs, or plastic stents during the index ERCP. The primary outcomes were time to stent occlusion, attempted surgical resection, or death after the initiation of neoadjuvant therapy, and the secondary outcomes were total patient costs associated with the stent, including the index ERCP cost, downstream hospitalization cost due to stent occlusion, and the cost associated with procedural adverse event. RESULTS: Fifty-four patients were randomized and reached the primary end point: 16 in the fcSEMS group, 17 in the uSEMS group, and 21 in the plastic stent group. No baseline demographic or tumor characteristic differences were noted among the groups. The fcSEMSs had a longer time to stent occlusion compared with uSEMSs and plastic stents (220 vs 74 and 76 days, P < .01), although the groups had equivalent rates of stent occlusion, attempted surgical resection, and death. Although SEMS placement cost more during the index ERCP (uSEMS = $24,874 and fcSEMS = $22,729 vs plastic = $18,701; P < .01), they resulted in higher procedural AE costs per patient (uSEMS = $5522 and fcSEMS = $12,701 vs plastic = $0; P < .01). Conversely, plastic stents resulted in an $11,458 hospitalization cost per patient due to stent occlusion compared with $2301 for uSEMSs and $0 for fcSEMSs (P < .01). CONCLUSIONS: In a prospective trial comparing fcSEMSs, uSEMSs, and plastic stents for malignant biliary obstruction in patients undergoing neoadjuvant therapy with curative intent for pancreatic adenocarcinoma, no stent type was superior in optimizing cost effectiveness, although fcSEMSs resulted in fewer days of neoadjuvant treatment delay and a longer time to stent occlusion. (Clincial trial registration number: NCT01038713.). PMID- 26972025 TI - Reducing biomass recalcitrance via mild sodium carbonate pretreatment. AB - This study examined the effects of mild sodium carbonate (Na2CO3) pretreatment on enzymatic hydrolysis of different feedstocks (i.e., corn stover, Miscanthus, and switchgrass). The results showed that sodium carbonate pretreatment markedly enhanced the sugar yields of the tested biomass feedstocks. The pretreated corn stover, Miscanthus, and switchgrass gave the glucose yields of 95.1%, 62.3%, and 81.3%, respectively, after enzymatic hydrolysis. The above glucose yields of pretreated feedstocks were 2-4 times that of untreated ones. The pretreatment also enhanced the xylose yields, 4 times for corn stover and 20 times for both Miscanthus and switchgrass. Sodium carbonate pretreatment removed 40-59% lignin from the tested feedstocks while preserving most of cellulose (<5% cellulose loss). Corn stover appeared to be least resistant to breakdown by Na2CO3 and enzymatic hydrolysis. Our study indicated that mild sodium carbonate pretreatment was effective for reducing biomass recalcitrance and subsequently improving the digestibility of lignocellulosic biomass. PMID- 26972026 TI - Development of anode zone using dual-anode system to reduce organic matter crossover in membraneless microbial fuel cells. AB - To prevent the occurrence of the organic crossover in membraneless microbial fuel cells (ML-MFCs), dual-anode MFC (DA-MFC) was designed from multi-anode concept to ensure anode zone. The anode zone addressed increase the utilization of organic matter in ML-MFCs, as the result, the organic crossover was prevented and performance of MFCs were enhanced. The maximum power of the DA-MFC was 0.46mW, which is about 1.56 times higher than the ML-MFC (0.29mW). Furthermore, the DA MFC had advantage in correlation of organic substance concentration and dissolved oxygen concentration, and even electric over-potential. In addition, in terms of cathode fouling, the DA-MFC showed clearer surface. Hence, the anode zone should be considered in the advanced ML-MFC for practically use in wastewater treatment process, and also for scale-up of MFCs. PMID- 26972027 TI - New insights into host-parasite ubiquitin proteome dynamics in P. falciparum infected red blood cells using a TUBEs-MS approach. AB - Malaria, caused by Plasmodium falciparum (P. falciparum), ranks as one of the most baleful infectious diseases worldwide. New antimalarial treatments are needed to face existing or emerging drug resistant strains. Protein degradation appears to play a significant role during the asexual intraerythrocytic developmental cycle (IDC) of P. falciparum. Inhibition of the ubiquitin proteasome system (UPS), a major intracellular proteolytic pathway, effectively reduces infection and parasite replication. P. falciparum and erythrocyte UPS coexist during IDC but the nature of their relationship is largely unknown. We used an approach based on Tandem Ubiquitin-Binding Entities (TUBEs) and 1D gel electrophoresis followed by mass spectrometry to identify major components of the TUBEs-associated ubiquitin proteome of both host and parasite during ring, trophozoite and schizont stages. Ring-exported protein (REX1), a P. falciparum protein located in Maurer's clefts and important for parasite nutrient import, was found to reach a maximum level of ubiquitylation in trophozoites stage. The Homo sapiens (H. sapiens) TUBEs associated ubiquitin proteome decreased during the infection, whereas the equivalent P. falciparum TUBEs-associated ubiquitin proteome counterpart increased. Major cellular processes such as DNA repair, replication, stress response, vesicular transport and catabolic events appear to be regulated by ubiquitylation along the IDC P. falciparum infection. BIOLOGICAL SIGNIFICANCE: In this work we analyze for the first time the interconnection between Plasmodium and human red blood cells ubiquitin-regulated proteins in the context of infection. We identified a number of human and Plasmodium proteins whose ubiquitylation pattern changes during the asexual infective stage. We demonstrate that ubiquitylation of REX1, a P. falciparum protein located in Maurer's clefts and important for parasite nutrient import, peaks in trophozoites stage. The ubiquitin-proteome from P. falciparum infected red blood cells (iRBCs) revealed a significant host-parasite crosstalk, underlining the importance of ubiquitin-regulated proteolytic activities during the intraerythrocytic developmental cycle (IDC) of P. falciparum. Major cellular processes defined from gene ontology such as DNA repair, replication, stress response, vesicular transport and catabolic events appear to be regulated by ubiquitylation along the IDC P. falciparum infection. Given the importance of ubiquitylation in the development of infectious diseases, this work provides a number of potential drug target candidates that should be further explored. PMID- 26972028 TI - Identification of glycosylphosphatidylinositol-anchored proteins and omega-sites using TiO2-based affinity purification followed by hydrogen fluoride treatment. AB - Glycosylphosphatidylinositol anchored proteins (GPI-APs) in the outer leaflet of the membrane microdomains, commonly referred to as lipid rafts, play important roles in many biological processes such as signal transduction, cell adhesion, protein trafficking, and antigen presentation. From a topological viewpoint, elucidating the presence and localization of GPI-anchor modification sites (omega sites) is important for the study of the biophysical properties and anchoring mechanisms of these proteins. However, very few reports have actually identified omega-sites of GPI-APs. To enable large-scale site-specific analysis of GPI anchoring, we developed a method for identification of omega-sites by mass spectrometry by combining titanium dioxide-based affinity purification and hydrogen fluoride treatment. This method was able to identify ~3-fold more GPI APs than our previous method: the new technique identified a total of 73 omega sites derived from 49 GPI-APs. In 13 of the 49 GPI-APs identified, the GPI-anchor attached to multiple amino acids in the C-terminal site, yielding a variety of different protein species. This method allows us to simultaneously identify many GPI-AP protein species with different omega-sites. We also demonstrated the C terminal GPI anchor attachment signal peptide, based on information about the GPI anchor binding sites of 49 GPI-APs. Thus, our results provide evidence for new insight into the GPI-anchored proteome and the role of GPI anchoring. BIOLOGICAL SIGNIFICANCE: GPI-anchored proteins (GPI-APs) are localized to the outer leaflet of the plasma membranes. Because the GPI anchor is a complex structure, the identification of GPI-anchored peptides by mass spectrometry has always been considered difficult. To improve the feasibility of large-scale site-specific analysis of GPI anchoring, we developed a method for identification of GPI anchored peptides by combining titanium dioxide-based affinity purification with hydrogen fluoride treatment. Using this novel technique, we identified a total of 73 omega-sites derived from 49 GPI-APs. These data may help us to develop a comprehensive understanding of the GPI-anchored proteome and the role of GPI anchoring. Moreover, this method could be used to discover GPI-APs as candidate biomarkers. PMID- 26972029 TI - Sleep in Neurodegenerative Diseases. AB - Disorders of sleep are an integral part of neurodegenerative diseases and include insomnia, sleep-wake cycle disruption, excessive daytime sleepiness that may be manifested as persistent somnolence or sudden onset of sleep episodes, obstructive and central sleep apnea, rapid eye movement sleep behavior disorder, and restless legs syndrome. The origin of these sleep disorders is multifactorial including degeneration of the brain areas that modulate sleep, the symptoms of the disease, and the effect of medications. Treatment of sleep disorders in patients with neurodegenerative diseases should be individualized and includes behavioral therapy, sleep hygiene, bright light therapy, melatonin, hypnotics, waking-promoting agents, and continuous positive airway pressure. PMID- 26972030 TI - Sleep and Traumatic Brain Injury. AB - Post-traumatic sleep-wake disturbances are frequent and often chronic complications after traumatic brain injury. The most prevalent sleep-wake disturbances are insomnia, excessive daytime sleepiness, and pleiosomnia, (i.e., increased sleep need). These disturbances are probably of multifactorial origin, but direct traumatic damage to key brain structures in sleep-wake regulation is likely to contribute. Diagnosis and treatment consist of standard approaches, but because of misperception of sleep-wake behavior in trauma patients, subjective testing alone may not always suffice. PMID- 26972031 TI - Sleep and Epilepsy. AB - Sleep plays an intricate role in the disease process of epilepsy. Despite the complexity of this relationship, the prognosis is a favorable one for patients presenting with sleep disorders and epilepsy. Clinicians need to be vigilant about asking about and addressing sleep complaints in patients with epilepsy. Ultimately, improving sleep and optimizing seizure control can have significant positive effects on the quality of life of these patients. PMID- 26972032 TI - Sleep and Stroke. AB - Evidence increasingly suggests sleep disorders are associated with higher risk of cardiovascular events, including stroke. Strong data correlate untreated sleep apnea with poorer stroke outcomes and more recent evidence implicates sleep disruption as a possible etiology for increased cerebrovascular events. Also, sleep duration may affect incidence of cardiovascular events. In addition, sleep disordered breathing, insomnia, restless legs syndrome, and parasomnias can occur as a result of cerebrovascular events. Treatment of sleep disorders improve sleep related symptoms and may also improve stroke recovery and risk of future events. PMID- 26972034 TI - Occupational Sleep Medicine. AB - Sleep and circadian rhythms significantly impact almost all aspects of human behavior and are therefore relevant to occupational sleep medicine, which is focused predominantly around workplace productivity, safety, and health. In this article, 5 main factors that influence occupational functioning are reviewed: (1) sleep deprivation, (2) disordered sleep, (3) circadian rhythms, (4) common medical illnesses that affect sleep and sleepiness, and (5) medications that affect sleep and sleepiness. Consequences of disturbed sleep and sleepiness are also reviewed, including cognitive, emotional, and psychomotor functioning and drowsy driving. PMID- 26972033 TI - Sleep in Neuromuscular Diseases. AB - Sleep disorders in neuromuscular disorders are generally caused by respiratory dysfunction associated with these diseases. Hypoventilation in neuromuscular diseases results from both respiratory muscle weakness and reduced chemoreceptor sensitivity, which is required for ventilatory drive. This condition results in repeated arousals, sleep fragmentation, and nocturnal hypoxemia, manifesting most commonly as excessive daytime somnolence. Polysomnography can identify sleep disordered breathing in patients with neuromuscular disorders and treatment with noninvasive ventilation may improve quality of life. PMID- 26972036 TI - Sleep in the Pediatric Population. AB - This article provides an overview of common pediatric sleep disorders encountered in the neurology clinic, including restless legs syndrome, narcolepsy, parasomnias, sleep-related epilepsy, and sleep and headaches. An overview of each is provided, with an emphasis on accurate diagnosis and treatment. It is important in comprehensive neurologic care to also obtain a sleep history, because treating the underlying sleep condition may improve the neurologic disorder. PMID- 26972037 TI - Sleep Neurobiology and Critical Care Illness. AB - The intensive care unit (ICU) environment is not propitious for restoring sleep and many studies have reported that critically ill patients have severe sleep disruptions. However, sleep alterations in critically ill patients are specific and differ significantly from those in ambulatory patients. Polysomnographic patterns of normal sleep are frequently lacking in critically ill patients and the neurobiology of sleep is important to consider regarding alternative methods to quantify sleep in the ICU. This article discusses elements of sleep neurobiology affecting the specificity of sleep patterns and sleep alterations in patients admitted to the ICU. PMID- 26972035 TI - Sleep Duration and Cardiovascular Disease Risk: Epidemiologic and Experimental Evidence. AB - Inadequate sleep is increasingly pervasive, and the impact on health remains to be fully understood. The cardiovascular consequences alone appear to be substantial. This review summarizes epidemiologic evidence regarding the association between extremes of sleep duration and the prevalence and incidence of cardiovascular diseases. The adverse effects of experimental sleep loss on physiological functions are discussed, along with cardiovascular risk factors that may underlie the association with increased morbidity and mortality. Current data support the concept that inadequate sleep duration confers heightened cardiovascular risk. Thus implementation of preventative strategies may reduce the potential disease burden associated with this high-risk behavior. PMID- 26972038 TI - Sleep and the Endocrine System. AB - In this article, the effect of sleep and sleep disorders on endocrine function and the influence of endocrine abnormalities on sleep are discussed. Sleep disruption and its associated endocrine consequences in the critically ill patient are also reviewed. PMID- 26972039 TI - Congestive Heart Failure and Central Sleep Apnea. AB - Congestive heart failure (CHF) is among the most common causes of admission to hospitals in the United States, especially in those over age 65. Few data exist regarding the prevalence CHF of Cheyne-Stokes respiration (CSR) owing to congestive heart failure in the intensive care unit (ICU). Nevertheless, CSR is expected to be highly prevalent among those with CHF. Treatment should focus on the underlying mechanisms by which CHF increases loop gain and promotes unstable breathing. Few data are available to determine prevalence of CSR in the ICU, or how CSR might affect clinical management and weaning from mechanical ventilation. PMID- 26972040 TI - Possible sexual transmission of Crimean-Congo hemorrhagic fever. AB - Three cases of family transmission of laboratory-confirmed Crimean-Congo hemorrhagic fever (CCHF) among spouses are reported. These spouses had sexual contact at the end of the incubation period or during the early stage of the mild form of CCHF, without any hemorrhagic symptoms in the first infected spouse. This report demonstrates that sexual contact may represent a real risk of CCHF transmission, even if the patient only experiences mild symptoms. PMID- 26972041 TI - Epidemiological trends and characteristics of Japanese encephalitis changed based on the vaccination program between 1960 and 2013 in Guangxi Zhuang Autonomous Region, southern China. AB - Japanese encephalitis (JE) is one of the most severe kinds of viral encephalitis and is prevalent in Asia and the Western Pacific. In China, JE was first reported in the 1940s and became the main cause of viral encephalitis, including in the Guangxi Zhuang Autonomous Region. In 1951, JE was included in the Chinese mandatory disease reporting system. In the pre-vaccine era of the 1960s and 1970s, the incidence of JE continued to rise without any vaccine supply. Since JE vaccines became available in the late 1970s (MBD) and 1989 (LAV-SA-14-14-2), and as JE vaccine became freely available to patients beginning in 2008, the incidence of JE has declined significantly. Despite these gains, outbreaks continue to occur among children in rural and suburban areas. Strengthening vaccine delivery models and improving swine vaccine production are important in order to sustain continuous declines in the incidence of JE in Guangxi. PMID- 26972043 TI - Enhanced visible-light-responsive photodegradation of bisphenol A by Cu, N codoped titanate nanotubes prepared by microwave-assisted hydrothermal method. AB - In this study, a rapid and effective microwave-assisted hydrothermal method was developed for the synthesis of Cu, N-codoped titanate nanotubes (Cu, N-TNTs) to enhance the photocatalytic degradation efficiency and rate of bisphenol A (BPA) under UV and visible light irradiations. The TNTs were first synthesized at 150 degrees C for 3h under microwave heating conditions followed by the calcination at 450 degrees C in the presence of 6wt% Cu ions and N2/NH3 to fabricate Cu, N TNTs composites. The Cu, N-TNTs exhibited excellent photocatalytic activity toward BPA degradation under UV and visible light irradiations. The X-ray photoelectron spectra indicated that Cu species in Cu, N-TNTs were mainly in zerovalent form and could serve as the electron donors as well as shuttling species to accelerate the photodegradation of BPA. In addition, the nitrogen atoms were incorporated into the anatase lattices to increase the visible-light responsive capability. The surface normalized reaction rate constants for BPA degradation were 4.3 and 1.5 times higher than those of Degussa P25 TiO2 under UV and visible light irradiations, respectively. The electron spin resonance spectra showed that Cu, N-codoped TNTs prolonged the generation of oxygen-containing radicals for at least 5min, resulting in the significant enhancement of photodegradation efficiency and rate of BPA. Results obtained in this study open a new avenue by using simple and effective microwave-assisted hydrothermal method to fabricate low dimensional codoped TNTs which can be potentially applied in a wide variety of fields of purification, green chemistry and photocatalysis. PMID- 26972042 TI - The impact of supplementary immunization activities on the epidemiology of measles in Tianjin, China. AB - OBJECTIVES: China has repeatedly used supplemental immunization activities (SIAs) to work towards measles elimination, but it is unknown if the SIAs are reaching non-locals - migrants from rural to urban areas. This study characterized temporal trends in measles incidence by local and non-local residency and evaluated the impact of SIAs on measles incidence in Tianjin, China. METHODS: Daily measles case-counts were tabulated separately by residency. These two datasets were combined so that each day had two observations. Poisson regression was conducted using generalized estimating equations with an exchangeable working correlation structure to estimate rate ratios (RRs). RESULTS: There were 12465 measles cases in Tianjin over the 10-year period. The rate of measles was higher in non-locals than locals before the 2008 SIA (RR 3.60, 95% confidence interval (CI) 3.27-3.96), but this attenuated to a RR of 1.22 between the 2008 and 2010 SIAs (95% CI 1.02-1.45). Following the 2010 SIA, non-locals had a lower rate of measles (RR 0.78, 95% CI 0.69-0.87). CONCLUSIONS: The disparity in measles incidence between locals and non-locals was reduced following two SIAs. Sustained public health interventions will be needed to maintain low measles incidence among non-locals given the ongoing migration of people throughout China. PMID- 26972044 TI - Nanoscale analysis reveals agonist-sensitive and heterogeneous pools of phosphatidylinositol 4-phosphate in the plasma membrane. AB - Phosphatidylinositol 4-phosphate [PtdIns(4)P] is the immediate precursor of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], which is localized to the cytoplasmic leaflet of the plasma membrane and has been reported to possess multiple cell biological functions. Direct evidence showing the distribution of PtdIns(4)P pools at a nanoscale when the plasma membrane PtdIns(4,5)P2 is hydrolyzed by agonist stimulation is lacking. To analyze the distribution of PtdIns(4)P at a nanoscale, we employed an electron microscopy technique that specifically labels PtdIns(4)P on the freeze-fracture replica of the plasma membrane. This method minimizes the possibility of artificial perturbation, because molecules in the membrane are physically immobilized in situ. Using this technique, we observed no PtdIns(4)P in the caveolae of normal cultured human fibroblasts, although PtdIns(4,5)P2 has been shown to be highly concentrated in them in our previous report. When cells were stimulated with angiotensin II, the level of PtdIns(4)P in the undifferentiated membrane transiently decreased to 64.3% at 10 s, began to increase at 30 s and largely increased to 341.9% at 40 s, and then returned to the initial level at 130 s after the stimulation. Interestingly, PtdIns(4)P localized at the caveolae at 70 and 130 s after the stimulation. These results suggest that the level of the PtdIns(4)P pool in the plasma membrane is sensitive and the distribution of PtdIns(4)P dramatically changes by agonist stimulation, and there are active sites of production or replenishment of PtdIns(4)P at undifferentiated membrane and caveolar areas. PMID- 26972045 TI - Nanoscale characterization of vesicle adhesion by normalized total internal reflection fluorescence microscopy. AB - We recently proposed a straightforward fluorescence microscopy technique to study adhesion of Giant Unilamellar Vesicles. This technique is based on dual observations which combine epi-fluorescence microscopy and total internal reflection fluorescence (TIRF) microscopy: TIRF images are normalized by epi fluorescence ones. By this way, it is possible to map the membrane/substrate separation distance with a nanometric resolution, typically ~20 nm, with a maximal working range of 300-400 nm. The purpose of this paper is to demonstrate that this technique is useful to quantify vesicle adhesion from ultra-weak to strong membrane-surface interactions. Thus, we have examined unspecific and specific adhesion conditions. Concerning unspecific adhesion, we have controlled the strength of electrostatic forces between negatively charged vesicles and various functionalized surfaces which exhibit a positive or a negative effective charge. Specific adhesion was highlighted with lock-and-key forces mediated by the well defined biotin/streptavidin recognition. PMID- 26972048 TI - Iron gene expression profile in atherogenic Mox macrophages. AB - RATIONALE: The role of macrophage iron in the physiopathology of atherosclerosis is an open question that needs to be clarified. In atherosclerotic lesions, recruited macrophages are submitted to cytokines and oxidized lipids which influence their phenotype. An important phenotypic population driven by oxidized phospholipids is the Mox macrophages which present unique biological properties but their iron phenotype is not well described. OBJECTIVE: To investigate the effect of Mox polarization by oxidized LDL (oxLDL) on macrophage iron metabolism in the absence or presence of proinflammatory stimuli. METHODS: Bone marrow derived macrophages were treated with different sources of LDL and/or LPS/IFNgamma (M1 activator). Expression of ferroportin (Slc40a1, alias Fpn), heme oxygenase-1 (Hmox1), H- and L-ferritin (Fth1 and Ftl1), hepcidin (Hamp), ceruloplasmin (Cp) and interleukine-6 (Il6) was followed by quantitative PCR. FPN and HMOX1 protein expression was analyzed by immunofluorescence and in-cell Western blotting. RESULTS: Mox macrophages expressed increased Hmox1 and Fth1 levels with basal FPN protein levels despite the significant increase of Fpn mRNA. Upregulation of Hmox1 and Fpn mRNA was specific to LDL oxidative modification and mediated by NRF2. The downregulation of both Cp isoforms and the upregulation of Hamp expression observed in Mox macrophages suggest that FPN mediated iron export could be compromised. Simultaneous exposure to oxLDL and LPS/IFNgamma leads to a mixed Mox/M1 phenotype that is closer to M1. CONCLUSION: A microenvironment rich in oxLDL and proinflammatory cytokines could promote macrophage iron retention and lipid accumulation profiles, a specific cell phenotype that likely contributes to lesion development and plaque instability in atherosclerosis. PMID- 26972047 TI - Optimization of a Relative Telomere Length Assay by Monochromatic Multiplex Real Time Quantitative PCR on the LightCycler 480: Sources of Variability and Quality Control Considerations. AB - Telomere length (TL) measurement is central to many biomedical research, population, and epidemiology studies, with promising potential as a clinical tool. Various assays are used to determine TL, depending on the type and size of the sample. We describe the detailed optimization of a monochromatic multiplex real-time quantitative PCR (MMqPCR) assay for relative TL using the LightCycler 480. MMqPCR was initially developed using a different instrument with many separate reagents. Differences in instrument performance, reagents, and workflow required substantial optimization for the assay to be compatible with the LightCycler 480. We optimized the chemistry of the assay using a purchased one component reaction mix and herein describe sources of variability and quality control relevant to the MMqPCR TL assay on any instrument. Finally, the assay was validated against other TL assays, such as terminal restriction fragment, Southern blot, and flow fluorescent in situ hybridization. The correlations obtained between data from MMqPCR and these assays (R(2) = 0.88 and 0.81) were comparable to those seen with the monoplex version (R(2) = 0.85 and 0.82) when the same samples were assayed. The intrarun and interrun CV ranged from 4.2% to 6.2% and 3.2% to 4.9%, respectively. We describe a protocol for measuring TL on the LightCycler platform that provides a robust high-throughput method applicable to clinical diagnostics or large-scale studies of archived specimens. PMID- 26972049 TI - Pathogenesis of POLR1C-dependent Type 3 Treacher Collins Syndrome revealed by a zebrafish model. AB - Treacher Collins Syndrome (TCS) is a rare congenital birth disorder (1 in 50,000 live births) characterized by severe craniofacial defects, including the downward slanting palpebral fissures, hypoplasia of the facial bones, and cleft palate (CP). Over 90% of patients with TCS have a mutation in the TCOF1 gene. However, some patients exhibit mutations in two new causative genes, POLR1C and POLR1D, which encode subunits of RNA polymerases I and III, that affect ribosome biogenesis. In this study, we examine the role of POLR1C in TCS using zebrafish as a model system. Our data confirmed that polr1c is highly expressed in the facial region, and dysfunction of this gene by knockdown or knock-out resulted in mis-expression of neural crest cells during early development that leads to TCS phenotype. Next generation sequencing and bioinformatics analysis of the polr1c mutants further demonstrated the up-regulated p53 pathway and predicted skeletal disorders. Lastly, we partially rescued the TCS facial phenotype in the background of p53 mutants, which supported the hypothesis that POLR1C-dependent type 3 TCS is associated with the p53 pathway. PMID- 26972050 TI - Regulation of basophil and mast cell development by transcription factors. AB - Basophils and mast cells play important roles in host defense against parasitic infections and allergic responses. Several progenitor populations, either shared or specific, for basophils and/or mast cells have been identified, thus elucidating the developmental pathways of these cells. Multiple transcription factors essential for their development and the relationships between them have been also revealed. For example, IRF8 induces GATA2 expression to promote the generation of both basophils and mast cells. The STAT5-GATA2 axis induces C/EBPalpha and MITF expression, facilitating the differentiation into basophils and mast cells, respectively. In addition, C/EBPalpha and MITF mutually suppress each other's expression. This review provides an overview of recent advances in our understanding of how transcription factors regulate the development of basophils and mast cells. PMID- 26972051 TI - Pentavalent pillar[5]arene-based glycoclusters and their multivalent binding to pathogenic bacterial lectins. AB - Anti-adhesive glycoclusters offer potential as therapeutic alternatives to classical antibiotics in treating infections. Pillar[5]arenes functionalised with either five galactose or five fucose residues were readily prepared using CuAAC reactions and evaluated for their binding to three therapeutically relevant bacterial lectins: LecA and Lec B from Pseudomonas aeuruginosa and BambL from Burkholderia ambifaria. Steric interactions were demonstrated to be a key factor in achieving good binding to LecA with more flexible galactose glycoclusters showing enhanced activity. In contrast binding to the fucose-selective lectins confirmed the importance of topology of the glycoclusters for activity with the pillar[5]arene ligand proving a selective ligand for BambL. PMID- 26972046 TI - Membrane remodeling and mechanics: Experiments and simulations of alpha Synuclein. AB - We review experimental and simulation approaches that have been used to determine curvature generation and remodeling of lipid bilayers by membrane-bending proteins. Particular emphasis is placed on the complementary approaches used to study alpha-Synuclein (alphaSyn), a major protein involved in Parkinson's disease (PD). Recent cellular and biophysical experiments have shown that the protein 1) deforms the native structure of mitochondrial and model membranes; and 2) inhibits vesicular fusion. Today's advanced experimental and computational technology has made it possible to quantify these protein-induced changes in membrane shape and material properties. Collectively, experiments, theory and multi-scale simulation techniques have established the key physical determinants of membrane remodeling and rigidity: protein binding energy, protein partition depth, protein density, and membrane tension. Despite the exciting and significant progress made in recent years in these areas, challenges remain in connecting biophysical insights to the cellular processes that lead to disease. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov. PMID- 26972054 TI - Dural Reduction Surgery: A Treatment Option for Frontotemporal Brain Sagging Syndrome. AB - Frontotemporal brain sagging syndrome is a dementia associated with hypersomnolence, personality changes, and features of intracranial hypotension on magnetic resonance imaging. The literature is sparse with respect to treatment options; many patients simply worsen. We present a case in which this syndrome responded to lumbar dural reduction surgery. Postoperative magnetic resonance imaging indicated normalization of brain sagging and lumbar intrathecal pressure. Although no evidence of cerebrospinal leak was found, extremely thin dura was noted intraoperatively, suggesting that a thin and incompetent dura could result in this low-pressure syndrome. Clinicians who encounter this syndrome should consider dural reduction surgery as a treatment strategy. PMID- 26972052 TI - Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. AB - Normal platelet function is critical to blood hemostasis and maintenance of a closed circulatory system. Heightened platelet reactivity, however, is associated with cardiometabolic diseases and enhanced potential for thrombotic events. We now show gut microbes, through generation of trimethylamine N-oxide (TMAO), directly contribute to platelet hyperreactivity and enhanced thrombosis potential. Plasma TMAO levels in subjects (n > 4,000) independently predicted incident (3 years) thrombosis (heart attack, stroke) risk. Direct exposure of platelets to TMAO enhanced sub-maximal stimulus-dependent platelet activation from multiple agonists through augmented Ca(2+) release from intracellular stores. Animal model studies employing dietary choline or TMAO, germ-free mice, and microbial transplantation collectively confirm a role for gut microbiota and TMAO in modulating platelet hyperresponsiveness and thrombosis potential and identify microbial taxa associated with plasma TMAO and thrombosis potential. Collectively, the present results reveal a previously unrecognized mechanistic link between specific dietary nutrients, gut microbes, platelet function, and thrombosis risk. PMID- 26972053 TI - The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. AB - Amino acids signal to the mTOR complex I (mTORC1) growth pathway through the Rag GTPases. Multiple distinct complexes regulate the Rags, including GATOR1, a GTPase activating protein (GAP), and GATOR2, a positive regulator of unknown molecular function. Arginine stimulation of cells activates mTORC1, but how it is sensed is not well understood. Recently, SLC38A9 was identified as a putative lysosomal arginine sensor required for arginine to activate mTORC1 but how arginine deprivation represses mTORC1 is unknown. Here, we show that CASTOR1, a previously uncharacterized protein, interacts with GATOR2 and is required for arginine deprivation to inhibit mTORC1. CASTOR1 homodimerizes and can also heterodimerize with the related protein, CASTOR2. Arginine disrupts the CASTOR1 GATOR2 complex by binding to CASTOR1 with a dissociation constant of ~30 MUM, and its arginine-binding capacity is required for arginine to activate mTORC1 in cells. Collectively, these results establish CASTOR1 as an arginine sensor for the mTORC1 pathway. PMID- 26972057 TI - Modulating intramolecular P...N pnictogen interactions. AB - A computational study of the intramolecular pnictogen bond in 8 phosphinonaphthalen-1-amine derivatives (1-NX2, 8-PX2 with X = H, F, Cl, Br, CH3, CN and NC), proton sponge analogues, has been carried out to determine their structural and geometric parameters, interaction energies and electronic properties such as the electron density of the intramolecular interaction. Our results show that substitution of H atoms in the PH2 group by electron withdrawing groups on the Lewis acid moiety strengthens the P...N pnictogen bond, evidenced by the increasing electron density values at the bond critical point and by shorter distances. However, substitutions on the Lewis base moiety (NX2) show weaker P...N interactions than when the substitution is done on the Lewis acid counterpart (PX2). Nevertheless, in all cases, pnictogen bonds are enhanced upon substitution with respect to the parent 1-NH2, 8-PH2 system. Second-order orbital interaction energies, electron density maps, electron delocalization functions and charge transfer corroborate the evolution of the P...N strength upon substitution. PMID- 26972056 TI - Blunted inflammation mediated by NF-kappaB activation in hippocampus alleviates chronic normobaric hypoxia-induced anxiety-like behavior in rats. AB - This study aims to investigate whether inflammation mediated by NF-kappaB activation is involved in the induction of anxiety-like behavior in chronic normobaric hypoxia (CNH) exposed rats and to investigate the underlying mechanism. To this end, rats were exposed in a normobaric hypoxic chamber with a fraction of inspired oxygen (FIO2) of ~ 10%, 23 h/d, continues for 2 weeks. Anxiety-like behavior was tested by elevated plus maze and open field, inflammatory response, nucleus translocation of NF-kappaB, and signaling pathway in hippocampus were examined. CNH induced a significant increase of anxiety- like behavior and inflammation responses, which were ameliorated by NF-kappaB inhibitor, PDTC pretreatment, suggesting that the anxiogenic effect induced by inflammation is through NF-kappaB activation. CNH treatment significantly increased nucleus translocation of p65 and p105 in hippocampus, which was suppressed by PDTC pretreatment. In addition, CNH treatment significantly increased Iba-1, iNOS, COX-2, and p-PKA in hippocampus, which were blocked by PDTC pretreatment, suggesting CNH may activate microglia cells in hippocampus through NF-kappaB pathway. In conclusion, our results illustrate a mechanism that, activation of NF-kappaB in hippocampus may trigger the proinflammatory response of microglia cells, and iNOS-PKA pathway may involve in anxiogenic effect in CNH exposed rats. PMID- 26972055 TI - Generation of electrophysiologically functional cardiomyocytes from mouse induced pluripotent stem cells. AB - Induced pluripotent stem (iPS) cells can efficiently differentiate into the three germ layers similar to those formed by differentiated embryonic stem (ES) cells. This provides a new source of cells in which to establish preclinical allogeneic transplantation models. Our iPS cells were generated from mouse embryonic fibroblasts (MEFs) transfected with the Yamanaka factors, the four transcription factors (Oct4, Sox2, Klf4 and c-Myc), without antibiotic selection or MEF feeders. After the formation of embryoid bodies (EBs), iPS cells spontaneously differentiated into Flk1-positive cardiac progenitors and cardiomyocytes expressing cardiac-specific markers such as alpha sarcomeric actinin (alpha actinin), cardiac alpha myosin heavy chain (alpha-MHC), cardiac troponin T (cTnT), and connexin 43 (CX43), as well as cardiac transcription factors Nk2 homebox 5 (Nkx2.5) and gata binding protein 4 (gata4). The electrophysiological activity of iPS cell-derived cardiomyocytes (iPS-CMs) was detected in beating cell clusters with optical mapping and RH237 a voltage-sensitive dye, and in single contracting cells with patch-clamp technology. Incompletely differentiated iPS cells formed teratomas when transplanted into a severe combined immunodeficiency (SCID) mouse model of myocardial infarction. Our results show that somatic cells can be reprogrammed into pluripotent stem cells, which in turn spontaneously differentiate into electrophysiologically functional mature cardiomyocytes expressing cardiac-specific makers, and that these cells can potentially be used to repair myocardial infarction (MI) in the future. PMID- 26972058 TI - Is There a Need for Congruent Treatment Goals Between Alcohol-Dependent Patients and Caregivers? AB - BACKGROUND: Alcohol-dependent patients have different treatment goals when entering treatment. Furthermore, different treatment settings advocate different treatment goals. Earlier studies have pointed out that treatment goal is important for treatment outcome, both in the treatment setting as well as in the patients themselves. However, to our knowledge, no study has so far investigated the interaction between patient's goal and the goal of the treatment setting. The aim of the study was therefore to study the interaction between these 2 factors on treatment outcome. METHODS: Patients' (n = 201) goals from 2 treatment settings-one that had an abstinence-oriented goal and one with a low-risk drinking goal-were investigated. The patients were followed up 2.5 years after treatment entry and effectiveness of congruent treatment goals on treatment outcome was investigated. RESULTS: There was no significant association between congruent goals and treatment outcomes (p = 0.060). However, when comparing the effectiveness of congruent treatment goal between the 2 treatment settings, the abstinence-oriented treatment setting was significantly more effective (p < 0.01). CONCLUSIONS: The major finding was that there appeared to be no association between congruence itself and treatment outcome. On the other hand, we found that the treatment outcome was more successful if the patient as well as the treatment setting had abstinence as a goal (i.e., congruent goals of abstinence). PMID- 26972060 TI - Air pollution: consequences and actions for the UK, and beyond. PMID- 26972061 TI - Trauma care in the UK: where is the evidence? PMID- 26972059 TI - Clinical implications of endoscopic ultrasonography non-traversability in patients with locoregional esophageal cancer receiving multimodality therapy. AB - BACKGROUND/AIMS: Approximately 30% of esophageal cancer (EC) patients cannot complete endoscopic ultrasonography (EUS) due to malignant stricture (EUS non traversability). This study examines clinical implications of EUS non traversability in patients with advanced locoregional squamous EC receiving preoperative chemoradiotherapy (CRT) followed by esophagectomy. METHODS: We retrieved data on 89 consecutive patients with advanced locoregional squamous EC (stage II or III). Relevant clinical and tumor-specific parameters were reviewed retrospectively. Significant factors affecting survival was determined by Cox regression analysis. RESULTS: EUS non-traversable EC was observed in 26 of 89 patients (29.2%). Median serum albumin level (3.6 g/dL vs. 3.9 g/dL, p = 0.028), tumor length (6.0 cm vs. 4.0 cm, p = 0.002), and percentage of clinical stage III disease (65.4% vs. 38.1%, p = 0.019) were significantly different between the patients with EUS non-traversable and traversable EC, respectively. Patients with EUS non-traversable EC demonstrated a significantly lower 5-year overall survival than patients with EUS traversable EC (30.8% vs. 49.3%, p = 0.023). In multivariate analysis, weight loss >= 10% (p = 0.033), EUS non-traversability (p = 0.003), non-response to preoperative CRT (p = 0.002), and incompletion of esophagectomy (p = 0.002) were significant negative factors of survival. CONCLUSIONS: EUS non-traversability has significant negative prognostic implications in patients with advanced locoregional squamous EC receiving preoperative CRT followed by esophagectomy. PMID- 26972062 TI - Indigenous health in the Latin American golden decade. PMID- 26972063 TI - Reprogramming psychiatry: stem cells and bipolar disorder. PMID- 26972065 TI - France passes wide-ranging health reforms. PMID- 26972066 TI - Nepal: organ trafficking after the earthquake. PMID- 26972067 TI - Profile: Burnet Institute, Melbourne, Australia. PMID- 26972068 TI - The literary legacy of Oliver Sacks. PMID- 26972069 TI - Brendan Crabb--making research work for development. PMID- 26972070 TI - The Hajj Health Requirements: time for a serious review? PMID- 26972071 TI - Pope Francis and the Italian scientific golden age. PMID- 26972072 TI - Syndromic surveillance during the Paris terrorist attacks. PMID- 26972073 TI - The Harvard-LSHTM panel on the global response to Ebola report. PMID- 26972074 TI - Economists, universal health coverage, and non-communicable diseases. PMID- 26972075 TI - The Harvard-LSHTM panel on the global response to Ebola report. PMID- 26972077 TI - Glomangiopericytoma and glomus tumor of the sinonasal tract: A report of two cases with emphasis on the differential diagnosis. PMID- 26972078 TI - Adoptive Regulatory T-cell Therapy Attenuates Subarachnoid Hemor-rhage-induced Cerebral Inflammation by Suppressing TLR4/NF-B Signaling Pathway. AB - Inflammation is one major cause of poor outcomes of subarachnoid hemorrhage (SAH). The recent evidence suggested that adoptive regulatory T-cell (Treg) therapy conferred potential neuroprotection by suppressing cerebral inflammation against cerebral ischemia. Therefore, we proposed that Treg transfer might protect the brain against SAH by decreasing cerebral inflammation. In this study, we injected the autologous blood into cisterna magna twice to make the SAH model and administrated Tregs by vein to SAH rats. Intriguingly, adoptive transfer of Tregs significantly ameliorated SAH-induced brain edema and increased cerebral blood flow. Moreover, Treg-afforded cerebral protection was accompanied by suppressing SAH-induced cerebral inflammation. Concurrently, administration of Tregs attenuated the activation of the toll-like receptor 4 and nuclear factor kappa B (TLR4/NF-kappaB) signaling pathway, which should be involved in the suppression of SAH-induced cerebral inflammation. Altogether, our study suggested that Treg adoptive transfer could attenuate SAH-induced cerebral inflammation by suppressing the activation of the TLR4/NF-kappaB signaling pathway, and thus provided new insights into the potent Treg cells-based therapy specifically targeting on post-SAH inflammatory dysregulation. PMID- 26972080 TI - Association of vitamin D receptor gene BsmI B/b and FokI F/f polymorphisms with adult dermatomyositis and systemic lupus erythematosus. PMID- 26972081 TI - Reflex seizures in a patient with Angelman syndrome and trisomy 21. PMID- 26972079 TI - Coffee, mate, acai and beans are the main contributors to the antioxidant capacity of Brazilian's diet. AB - PURPOSE: The aim of the present study was to evaluate the relative contribution of the most commonly consumed plant foods in Brazil to the total antioxidant capacity (AC) of Brazilian's diet. The importance of regional consuming habits and income for dietary AC was also approached. METHODS: The annual per capita consumption database from the Brazilian Institute of Geography and Statistics (IBGE) was used for identification of the most consumed plant foods in Brazil. Out of 124 key plant foods, 42 top AC contributing candidates were selected for AC determination based on both the frequency of consumption, and AC results reported in the literature, and in our preliminary assays. The selected food products were prepared according to the Brazilian Food Guide, and their AC was measured by TEAC and FRAP assays. Dietary AC was determined by combining these AC results with IBGE consumption data, and the relative contribution of each plant food was calculated. RESULTS: Among all evaluated food products, coffee and green mate tea presented the highest AC, followed by toasted mate tea, red wine, acai-a native Amazonian fruit-and beans. Associating AC with the annual consumption database from IBGE, coffee alone contributed, on average, to 66 % of dietary AC; other beverages, including mate and wine, contributed altogether to 13 % of dietary AC; beans contributed to 9 %, cereals and derivatives contributed to 4 %; and in natura fruits and vegetables contributed to only 3 and 2 %, respectively. In the North region, fruits were important contributors to AC-mostly because of high acai consumption, while in the South mate and wine also gained importance, with wine contribution being specially associated with high household income. CONCLUSIONS: Coffee is the main contributor to the total dietary AC in Brazil, regardless of household income. Mate tea, acai and beans are other major dietary AC contributors. PMID- 26972083 TI - Correlation of Anti-mitochondrial Antibodies with Liver Histology and Outcomes. PMID- 26972082 TI - A cohort study of the morbidity of combined anterior-posterior cervical spinal fusions: incidence and predictors of postoperative dysphagia. AB - PURPOSE: To identify risk factors that may lead to the development of dysphagia after combined anterior and posterior (360 degrees ) cervical fusion surgery. METHODS: A single center, retrospective analysis of patients who had same-day, 360 degrees fusion at Henry Ford Hospital between 2008 and 2012 was performed. Variables analyzed included demographics, medical co-morbidities, levels fused, and degree of dysphagia. RESULTS: The overall dysphagia rate was 37.7 %. Patients with dysphagia had a longer mean length of stay (p < 0.001), longer mean operative time (p < 0.001), greater intraoperative blood loss (p = 0.002), and fusion above the fourth cervical vertebra, C4, (p = 0.007). There were no differences in the rates of dysphagia when comparing patients undergoing primary or revision surgery (p = 0.554). CONCLUSION: Prolonged surgery and fusion above C4 lead to higher rates of dysphagia after 360 degrees fusions. Prior anterior cervical fusion does not increase the risk of dysphagia development. PMID- 26972084 TI - Esophageal Epithelial Resistance and Lower Esophageal Sphincter Muscle Contraction Increase in a Chronic Diabetic Rabbit Model. AB - BACKGROUND: Esophageal motility disorders and possibly gastroesophageal reflux disease are common in patients with diabetes mellitus. AIMS: We aimed to investigate both the electrophysiological characteristics of the esophageal epithelium and the contractility of the lower esophageal sphincter (LES) muscle in alloxane-induced diabetic rabbits. METHODS: Electrophysiological properties were measured using an Ussing chamber method. An acid-pepsin model was employed with pH 1.7 or weakly acidic (pH 4) Ringer and/or pepsin. Smooth muscle strips of the LES were mounted in an isolated organ bath. Contractile responses to an electrical field stimulation and cumulative concentrations of acetylcholine were recorded. Contractility of the muscle strips were tested in the presence of Rho kinase inhibitor (Y-27632) and nonspecific nitric oxide inhibitor (L-NAME). RESULTS: The resistance of diabetic tissue perfused in the pH 1.7 Ringer decreased 17 %; pepsin addition decreased it by 49 %. The same concentrations caused a more distinct loss of resistance in the control tissues (22 and 76 %, p < 0.05). The perfusion of tissues in increased concentrations of luminal and serosal glucose did not change the tissue resistance and voltage. Diabetes significantly increased both the electrical field stimulation and acetylcholine induced contractions in the LES muscle strips (p < 0.01). Incubation with Y-27632 significantly decreased the acetylcholine-induced contractions in a concentration dependent manner (p < 0.01). CONCLUSIONS: The acid-pepsin model in the diabetic rabbit esophageal tissue had less injury compared with the control. The diabetic rabbit LES muscle had higher contractility, possibly because of the activation of the Rho-Rhokinase pathway. Our results show that in a chronic diabetic rabbit model the esophagus resists reflux by activating mechanisms of mucosal defense and increasing the contractility of the LES. PMID- 26972085 TI - IMRT vs. 2D-radiotherapy or 3D-conformal radiotherapy of nasopharyngeal carcinoma : Survival outcome in a Korean multi-institutional retrospective study (KROG 11 06). AB - OBJECTIVE: We compared treatment outcomes of two-dimensional radiotherapy (2D RT), three-dimensional conformal radiotherapy (3D-CRT), and intensity-modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: In total, 1237 patients with cT1-4N0-3M0 NPC were retrospectively analyzed. Of these, 350, 390, and 497 were treated with 2D-RT, 3D-CRT, and IMRT, respectively. RESULTS: 3D-CRT and IMRT showed better 5-year overall survival (OS) rates (73.6 and 76.7 %, respectively) than did 2D-RT (5-year OS of 59.7 %, all p < 0.001). In T3-4 subgroup, IMRT was associated with a significantly better 5 year OS than was 2D-RT (70.7 vs. 50.4 %, respectively; p <= 0.001) and 3D-CRT (70.7 vs. 57.8 %, respectively; p = 0.011); however, the difference between the 2D-RT and 3D-CRT groups did not reach statistical significance (p = 0.063). In multivariate analyses of all patients, IMRT was a predictive factor for OS when compared with 2D-RT or 3D-CRT, as was 3D-CRT when compared with 2D-RT. CONCLUSION: Our study showed that 3D-CRT and IMRT were associated with a better local progression-free survival and OS than was 2D-RT in NPC. IMRT was significantly superior in terms of OS for advanced primary tumors (T3-4). PMID- 26972086 TI - Treatment of breast cancer with simultaneous integrated boost in hybrid plan technique : Influence of flattening filter-free beams. AB - OBJECTIVE: The present study compares in silico treatment plans using hybrid plan technique during hypofractionated radiation of mammary carcinoma with simultaneous integrated boost (SIB). The influence of 6 MV photon radiation in flattening filter free (FFF) mode against the clinical standard flattening filter (FF) mode is to be examined. PATIENTS AND METHODS: RT planning took place with FF and FFF radiation plans for 10 left-sided breast cancer patients. Hybrid plans were realised with two tangential IMRT fields and one VMAT field. The dose prescription was in line with the guidelines in the ARO-2010-01 study. The dosimetric verification took place with a manufacturer-independent measurement system. RESULTS: Required dose prescriptions for the planning target volumes (PTV) were achieved for both groups. The average dose values of the ipsi- and contralateral lung and the heart did not differ significantly. The overall average incidental dose to the left anterior descending artery (LAD) of 8.24 +/- 3.9 Gy in the FFF group and 9.05 +/- 3.7 Gy in the FF group (p < 0.05) were found. The dosimetric verifications corresponded to the clinical requirements. FFF-based RT plans reduced the average treatment time by 17 s/fraction. CONCLUSION: In comparison to the FF-based hybrid plan technique the FFF mode allows further reduction of the average LAD dose for comparable target volume coverage without adverse low-dose exposure of contralateral structures. The combination of hybrid plan technique and 6 MV photon radiation in the FFF mode is suitable for use with hypofractionated dose schemes. The increased dose rate allows a substantial reduction of treatment time and thus beneficial application of the deep inspiration breath hold technique. PMID- 26972087 TI - Balance impairment limits ability to increase walking speed in individuals with chronic stroke. AB - Purpose Determine the relationship between balance impairments and the ability to increase walking speed (WS) on demand in individuals with chronic stroke. Methods WS and Berg Balance Scale (BBS) data were collected on 124 individuals with chronic stroke (>6 months). The ability to increase WS on demand (walking speed reserve, WSR) was quantified as the difference between participants' self selected (SSWS) and maximal (MWS) walking speeds. Correlation, regression and receiver operating characteristic (ROC) analyses were performed to investigate the relationship between balance and the ability to increase WS. Results Of sample, 58.9% were unable to increase WS on demand (WSR < 0.2 m/s). BBS scores were associated with WSR values (rs=0.74, 0.65-0.81) and were predictive of 'able/unable' to increase WS [odds ratio (OR) = 0.75, 0.67-0.84]. The AUC for the ROC curve constructed to assess the accuracy of BBS to discriminate between able/unable to increase WS was 0.85 (0.78-0.92). A BBS cutscore of 47 points was identified [sensitivity: 72.6%, specificity: 90.2%, +likelihood ratio (LR): 7.41, -LR: 0.30]. Conclusions The inability to increase WS on demand is common in individuals with chronic stroke, and balance appears to be a significant contributor to this difficulty. A BBS cutscore of 47 points can identify individuals who may benefit from balance interventions to improve the ability to increase their WS. Implications for Rehabilitation A majority of individuals with chronic stroke may be unable to increase their walking speed beyond their self selected speed on demand. This may limit functional ambulation, as these individuals are walking "at capacity". Balance impairments contribute to the inability to increase walking speed. A Berg Balance Scale score <47 points can be used to identify individuals with chronic stroke walking "at capacity" due to balance impairments. PMID- 26972088 TI - Survival and nutritional dependence on home parenteral nutrition: Three decades of experience from a single referral centre. AB - BACKGROUND: Home parenteral nutrition (HPN) is the mainstay of treatment for patients with Type 3 intestinal failure (IF), however long term data on mortality and nutritional outcomes are limited. OBJECTIVES: To assess the long-term survival and requirements for ongoing HPN in patients receiving treatment at a UK national referral centre for intestinal failure. METHODS: Patients with IF who received HPN for more than 3 months at this Intestinal Failure Unit between 1978 and 2011 had their clinical records reviewed. SPSS 20 was utilised to perform Cox regression analysis and generate Kaplan Meier curves, with the aim of identifying factors associated with death and the continued need for HPN. RESULTS: Case notes from 545 patients were reviewed. Overall survival (OS) in patients without malignancy at commencement of IF was 93%, 71%, 59% and 28% at 1, 5, 10 and 20 years after starting treatment. Crohn's disease, mesenteric ischaemia and chronic intestinal pseudo-obstruction were associated with a better OS than scleroderma and radiation enteritis on multivariate analysis. Older age at onset of IF was associated with poor OS, while shorter small bowel length or central line sepsis was not. 15% (25/170) of deaths were due to complications of HPN (central line sepsis = 10, IF-associated liver disease = 15). Continued HPN dependence in survivors was 83%, 63%, 59% and 53% at 1, 5, 10 and 15 years, respectively. Among the 153 patients without malignancy who achieved nutritional independence from HPN, 77 (50.3%) did so after surgical reconstruction of the alimentary tract (HPN duration mean 19 months, range 3-126 months). 76 patients (49.7%) weaned from HPN without undergoing surgical reconstruction. CONCLUSION: This is the largest reported data set on long-term survival and dependence on HPN and will inform the indications, benefits and risks of treatment in disease specific groups. A significant proportion of patients achieved nutritional autonomy without surgical intervention. PMID- 26972090 TI - Pulmonary rehabilitation and oral nutritional supplement enriched with beta hydroxy-beta-methylbutyrate for bronchiectasis participants: A prospective, randomised study. PMID- 26972089 TI - Loss of visceral adipose tissue precedes subcutaneous adipose tissue and associates with n-6 fatty acid content. AB - BACKGROUND & AIM: During cancer development, fat loss occurs in most cancer patients. Characterization of the behavior of fat loss from visceral (VAT) and subcutaneous adipose tissue (SAT) depots has not been established. The first objective of this study was to assess the intensity and time course of changes in VAT and SAT depots of advanced cancer patients in the year preceding death. Secondly, this study explored the differences in adipokine content and fatty acid composition between VAT and SAT depots and in relation to changes in fat mass. METHODS: Longitudinal quantitative analyses of computed tomography images was conducted to define changes in adipose tissue cross sectional areas in fat depots in advanced colorectal and cholangiocarcinoma cancer patients (n = 46) at mean time points corresponding to 9, 6, 3 and 1 month before death. Proportions of adipose tissue fatty acid and adipokine content were characterized in a second cohort of advanced colorectal cancer patients (n = 16). RESULTS: On average, loss of total adipose tissue (TAT) happens at all time intervals but there is an elevation in the intensity of loss close to death. Nine months from death, 42% of patients were losing fat (Mean TAT cross sectional area change = -0.2 +/- 13 cm2) whereas within one month from death, fat wasting was observed in 78% of patients (-60.1 +/- 9.2 cm2, P = 0.001). However, loss of TAT did not reflect changes in VAT and SAT in the same direction or intensity. Intensity of VAT loss remains constant throughout the disease progression whereas SAT is more likely to be gained further way from death. Nine month prior to death, mean change in cross sectional area of VAT was -7.9 +/- 6.8 cm2 whereas, mean change in CSA of SAT was 7.4 +/- 7.7 cm2 (p = 0.03). One month before death, mean VAT and SAT absolute changes were -24.5 +/- 4.9 cm2 and -34.5 +/- 5.2 cm2, respectively (p = 0.05). Moreover, fat losing patients had higher proportions of polyunsaturated fatty acids, especially n-6 fatty acids, in VAT compared to patients who were gaining fat (mean = 15.4% in losing group vs. 13.4% in gaining group; p = 0.03). VAT contained more monocyte chemoattractant protein-1 than SAT, whereas leptin levels were higher in SAT. CONCLUSIONS: Further from death, VAT and SAT behave differently whereas close to death, accelerated loss occurs in both depots. These differences are further characterized by differences in fatty acid composition and adipokine levels. PMID- 26972091 TI - [Applied pharmacogenetic]. AB - Pharmacokinetics is the link between genetic data and the use of treatments. It can be use on several relevant aspects in the clinic, including the treatment selection, efficacy or toxicity prediction and the choice of the dose. Pharmacogenetics has been applied in clinical nephrology since a long time by the genetic prediction of azathiorpine associated myelotoxicity. However, despite an extensive literature describing the links between genetics and metabolism and transport of drugs, genetic tests are little used in clinical practice. One reason for this poor implementation is the current lack of evidence of improved clinical outcomes with pharmacogenetic tests. In addition, with an effective therapeutic drug monitoring, it is possible to correct the effect of genotype on the pharmacokinetic differences, thus reducing the usefulness of the assay based on the genotype. The future of pharmacogenetics will be treatment models in which patient characteristics are combined with data on polymorphisms in multiple genes including pharmacodynamic parameters, drug transporter proteins, and predictors of toxicity. PMID- 26972092 TI - [Renal involvement during type 1 cryoglobulinemia]. AB - Cryoglobulins are circulating immunoglobulins that precipitate with cold temperature and dissolve with rewarming. Type 1 cryoglobulinemia is composed of a single monoclonal immunoglobulin and is associated with renal involvement in up to 40% of cases. Type 1 cryoglobulinemia is related to an underlying B-cell haematological malignancy in 60% of patients. In the remaining cases, in the absence of criteria for malignancy, the diagnosis of monoclonal gammopathy of renal significance should be established. The clinical and biological setting and histological features of type 1 cryoglobulinemia are globally similar to those of mixed cryoglobulinemia. In case of haematological malignancy, the treatment is guided by the nature of the underlying disease, and aims at inducing haematological remission, which is necessary for the renal response. The management of monoclonal gammopathy of renal significance has been clarified by an international consensus group and is based on the nature of the underlying clone. In case of monoclonal cryoglobulinemia associated with a plasma-cell clone (IgG or IgA), the treatment is based on the combination of bortezomib, cyclophosphamide and dexamethasone. In case of IgM monoclonal cryoglobulinemia, the treatment is similar to that of Waldenstrom macroglobulinemia, and is based on rituximab. The clinical course of renal monoclonal cryoglobulinemia is intimately associated with the haematological response, and is usually favourable. PMID- 26972093 TI - [Dialysis after graft failure: How to improve survival?]. AB - Ten to 15 % of transplant recipients will return to dialysis, or require another transplantation within 5years, rising to 23 % by 10years, and failed transplantation is now one of the major indications for starting dialysis, accounting for almost 5 % of incident dialysis patients in the US and 10 % in France. Patients who resume dialysis post-transplantation have usually experienced an extended period of uraemia and long-term immunosuppressive therapy, and exhibit high rates of anaemia and erythropoietin resistance, hypoalbuminaemia and persistent chronic inflammation from the failed graft. These factors may increase mortality risk during the first year of dialysis, as observed in the US, but not in Canada or France. When compared to a control group of transplant-naive patients followed in the same institution in France, patients with transplant failure have a higher rate of usable arteriovenous fistula or graft, a similar rate of non-planned dialysis, and initiate dialysis with a higher glomerular filtration rate. We suggest that patient survival in dialysis after graft loss is influenced by both patient characteristics and quality of care, and this may explain the favourable outcome of this specific dialysis population in France. PMID- 26972094 TI - [Carotid barostimulation in the treatment of resistant hypertension]. AB - The autonomic nervous system plays a pivotal role in the development of hypertension and organ damage complicating hypertension. The US company CVRx developed medical devices (first generation RheosTM and second generation NeoTM) aimed to electronically activate baroreceptors, which signal the brain to orchestrate a multisystemic response to address chronic diseases such as hypertension and heart failure. This review presents available clinical trial data on carotid barostimulation in the treatment of resistant hypertension. PMID- 26972095 TI - Molecular pathways of chronic kidney disease progression. AB - Chronic kidney disease is characterized by the progressive loss of functional nephrons. This loss means that the remaining nephrons are put under stress and are forced to adapt in order to maintain kidney function. Over the time, the strains imposed by these adaptations result in a vicious circle in which the loss of damaged nephrons results in the damage of the so far healthy nephrons. Hence, the rate of chronic kidney disease progression depends on the ability of the remaining nephrons to cope with stress. This article reviews the molecular pathways involved in the compensation and deterioration process after nephron reduction. In particular, we examine the role of mammalian target of rapamycin complex (mTORC)/serine-threonine protein kinase AKT, epidermal growth factor receptor (EGFR) and unfolded protein response pathways, as well as the pleiotropic function of Lipocalin 2. We also discuss the dual role played by some of these pathways in acute and chronic kidney disease. Finally, the relevance of these experimental finding to human chronic kidney disease is discussed. PMID- 26972096 TI - [Clinical approach to primary membranoproliferative glomerulonephritis]. AB - Membranoproliferative glomerulonephritis represent a heterogeneous group of nephropathies. During the last five years, our understanding of membranoproliferative glomerulonephritis has greatly improved. Animal models and the study of complement genetics led to the dissection of the physiopathology of membranoproliferative glomerulonephritis, to the individualization of a new entity, C3 glomerulopathy, and to a new classification of these nephropathies. The study of large cohorts has also changed the clinical picture of membranoproliferative glomerulonephritis that has been long dominated by the severity of a single type of dense deposits disease. Finally, the rediscovery of complement through the study of the atypical haemolytic uremic syndrome and the availability in clinical practice of complement inhibitors have paved the way for new therapeutic approaches of membranoproliferative glomerulonephritis. PMID- 26972098 TI - [Cost of dialysis in France]. AB - According to latest data published by the French health authority (HAS), nearly 74,000 French patients in end-stage chronic renal disease are following a replacement therapy. They were 61,000 in 2007, amounting to a cost of 4 billions euros for public health insurance. The cost varies depending on the age and comorbidities. Continuous ambulatory peritoneal dialysis is the cheapest mode of treatment, while the heavy haemodialysis centres costs are close to twice as expensive. But these two different treatments are - a priori - not applied for the same patients in terms of level of severity of disease. Moreover, associated costs, medical treatment, transportation, etc. are to be taken into account, as well as losses of income for patients facing major job difficulties. As recommended by HAS experts, it will be important to regularly conduct surveys allowing a regular economic assessment of the various modes of financial healthcare for end-stage chronic renal disease. PMID- 26972099 TI - [Medical simulation in hemodialysis]. AB - INTRODUCTION: Simulation is an innovative educational tool based on learning experience in a secure environment without fear of repercussions especially in critical situations such as in emergencies. It offers great prospects in the development of dialysis training. METHODS: We report the results of an observational study comparing medical simulation to conventional training methods in the management of hemodialysis in emergency situations. We discuss afterwards the possibilities currently allowed by medical simulation in dialysis training. RESULTS: The training was beneficial (significant difference between initial and final level of knowledge) for all participants. There was no significant difference between the conventional approach, simulation training and the two combined tools. However, satisfaction rate was higher in simulation training. We observed a tendency to have better results in "active players" of the simulation compared to observers. CONCLUSION: We emphasize the importance of integrating medical simulation training in our dialysis training strategies as a complementary tool to classical teaching/learning methods. PMID- 26972097 TI - Acute kidney injury and chronic kidney disease: From the laboratory to the clinic. AB - Chronic kidney disease and acute kidney injury have traditionally been considered as separate entities with different etiologies. This view has changed in recent years, with chronic kidney disease recognized as a major risk factor for the development of new acute kidney injury, and acute kidney injury now accepted to lead to de novo or accelerated chronic and end stage kidney diseases. Patients with existing chronic kidney disease appear to be less able to mount a complete 'adaptive' repair after acute insults, and instead repair maladaptively, with accelerated fibrosis and rates of renal functional decline. This article reviews the epidemiological studies in man that have demonstrated the links between these two processes. We also examine clinical and experimental research in areas of importance to both acute and chronic disease: acute and chronic renal injury to the vasculature, the pericyte and leukocyte populations, the signaling pathways implicated in injury and repair, and the impact of cellular stress and increased levels of growth arrested and senescent cells. The importance and therapeutic potential raised by these processes for acute and chronic injury are discussed. PMID- 26972101 TI - Metal and acidity fluxes controlled by precipitation/dissolution cycles of sulfate salts in an anthropogenic mine aquifer. AB - Underground mine drainages are extremely difficult to study due to the lack of information about the flow path and source proximity in relation to the outflow adit. Geochemical processes controlling metals and acidity fluxes in a complex anthropogenic mine aquifer in SW Spain during the dry and rainy season were investigated by geochemical and statistical tools. High concentrations of acidity, sulfate, metals and metalloids (e.g. Fe, Cu, Zn, As, Cd, Ni, Co) were observed due to intense sulfide oxidation processes. The high residence time inside the anthropogenic aquifer, around 40days, caused the release of significant quantities of metals linked to host rocks (e.g. Al, Ca, Ge, Li, Mg, REE). The most outstanding characteristic of the acid mine drainage (AMD) outflows is the existence of higher Fe/SO4 molar ratios than those theoretical of pyrite (0.50) during most of the monitored period, due to a fire which occurred in 1949 and remained active for decades. Permanent and temporal retention mechanisms of acidity and metals were observed in the galleries. Once released from sulfide oxidation, Pb and As are sorbed on Fe oxyhydroxysulfate or precipitated as low solubility minerals (i.e. anglesite) inside the galleries. The precipitation of evaporitic sulfate salts during the dry season and the subsequent re-dissolution after rainfall control the fluxes of acidity and main metals (i.e. Fe, Mg, Al) from this anthropogenic aquifer. Some elements, such as Cd, Cu, Ni, REE and Zn, are retained in highly soluble sulfate salts while other elements, such as Ge, Pb and Sc, have a lower response to washout processes due to its incorporation in less soluble sulfate salts. In this way, metal concentration during the washout processes would be controlled by the proportion and solubility of each type of evaporitic sulfate salt stored during the dry season. The recovery of metals of economic interest contained in the AMD could help to self-finance the remediation of these waters in derelict mines worldwide. PMID- 26972100 TI - Anti-oxidative, anti-secretory and anti-inflammatory activities of the extract from the root bark of Lycium chinense (Cortex Lycii) against gastric ulcer in mice. AB - The evaluation of the antioxidant, anti-secretory and anti-inflammatory potentials of the ethyl acetate fraction (ELC) from the root bark of Lycium chinense against ethanol-induced gastric ulcer in mice and the possible mechanisms underlying this action was performed. The results indicated that oral administration of ELC (50, 100, 200 and 400 mg/kg) before ethanol-induced ulcer increased the gastric mucus content, restored the superoxide dismutase and glutathione levels, reduced malondialdehyde levels and inhibited the activity of myeloperoxidase. Furthermore, ELC displayed its anti-secretory activity by decreasing the gastric juice and increased the gastric pH and reduced pro inflammatory markers and caspase-3 tissue levels. These results suggest that L. chinense displays gastroprotective properties as a result of its antioxidant, anti-inflammatory, anti-secretory and anti-apoptotic effects. PMID- 26972104 TI - Charge carrier dynamics of methylammonium lead iodide: from PbI2-rich to low dimensional broadly emitting perovskites. AB - We provide an investigation of the charge carrier dynamics of the (MAI)(x)(PbI2)(1-x) system in the range x = 0.32-0.90 following the recently published "pseudobinary phase-composition processing diagram" of Song et al. (Chem. Mater., 2015, 27, 4612). The dynamics were studied using ultrafast pump supercontinuum probe spectroscopy over the pump fluence range 2-50 MUJ cm(-2), allowing for a wide variation of the initial carrier density. At high MAI excess (x = 0.90), low-dimensional perovskites (LDPs) are formed, and their luminescence spectra are significantly blue-shifted by ca. 50 nm and broadened compared to the 3D perovskite. The shift is due to quantum confinement effects, and the inhomogeneous broadening arises from different low-dimensional structures (predominantly 2D, but presumably also 1D and 0D). Accurate transient carrier temperatures are extracted from the transient absorption spectra. The regimes of carrier-carrier, carrier-optical phonon and acoustic phonon scattering are clearly distinguished. Perovskites with mole fractions x <= 0.71 exhibit extremely fast carrier cooling (ca. 300 fs) at low fluence of 2 MUJ cm(-2), however cooling slows down significantly at high fluence of 50 MUJ cm(-2) due to the "hot phonon effect" (ca. 2.8 ps). A kinetic analysis of the electron-hole recombination dynamics provides second-order recombination rate constants k2 which decrease from 5.3 to 1.5 * 10(-9) cm(3) s(-1) in the range x = 0.32-0.71. In contrast, recombination in the LDPs (x = 0.90) is more than one order of magnitude faster, 6.4 * 10(-8) cm(3) s(-1), which is related to the confined perovskite structure. Recombination in these LDPs should be however still slow enough for their potential application as efficient broadband emitters or solar light-harvesting materials. PMID- 26972102 TI - Humoral hypercalcemia due to gastric carcinoma secreting parathyroid hormone related protein during chemotherapy: a case report. AB - Humoral hypercalcemia due to a gastric carcinoma-secreting parathyroid hormone related protein (PTHrP) is a rare disease associated with poor prognosis. A 61 year-old male with gastric cancer who had been receiving chemotherapy showed serum hypercalcemia and an elevated level of serum PTHrP with a suppressed intact parathyroid hormone level. Computed tomography revealed stable disease 4 weeks prior, and the laboratory examination revealed no adverse effects 2 weeks prior. The biopsy at the time of diagnosis was immunohistochemically positive for PTHrP later. Despite intensive care, the patient died of multiorgan failure on the 14th day after admission. In case of undifferentiated gastric cancer, the possibility of humoral hypercalcemia of malignancy caused by gastric cancer should be considered even when the patient is receiving chemotherapy. PMID- 26972103 TI - The efficacy of combination therapy for idiopathic sudden sensorineural hearing loss. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to compare the hearing results of patients with idiopathic sudden sensorineural hearing loss (ISSNHL) who initially were treated with either a combination therapy of systemic steroids (SS) and intratympanic steroid injection (IT-S) or SS only. METHODS: The study followed a retrospective case-control design. One-hundred five patients who were diagnosed with ISSNHL and required treatment via admission were enrolled in this study. The control group (n = 53) was treated with SS, and the study group (n = 52) received SS as well as IT-S. We divided the patients according to pretreatment hearing levels. The outcome measured was improvement after the treatment audiology data at pretreatment were compared with those at day 10 and > 90 days after the treatment. Outcome data were analyzed using the t test, Pearson's chi(2) test, Fisher's exact test, and multivariate analyses of covariance with adjustment for pretreatment hearing levels. RESULTS: After more than 90 days, the average pure tone audiometry (PTA) in the control and study groups were 54.8 +/- 31.4 dB and 43 +/- 31.2 dB, respectively (P = 0.013). Hearing recovery rate was 57.7% in the control group and 69.8% in the study group. The hearing gain of the study group was higher than that of the control group at high frequencies within the 10 days of the treatment period. Analysis between subgroups, divided according to the severity of pretreatment hearing level, showed that the recovery rate was higher at all frequencies in the study group than in the control group in patients with mild to moderate hearing loss (pretreatment PTA < 70 dB). However, in patients with severe to profound hearing loss (pretreatment PTA >= 70 dB), the hearing outcomes of the study and control groups were not significantly different, except at a low frequency. CONCLUSION: The results of this study suggest that the treatment of ISSNHL with combination therapy results in higher hearing recovery rates when compared to treatment with SS alone, even in patients with severe hearing loss. LEVEL OF EVIDENCE: 3b. Laryngoscope, 126:1871-1876, 2016. PMID- 26972105 TI - Effect of higher muscle coactivation on standing postural response to perturbation in older adults. AB - BACKGROUND: Although several studies have reported that muscle coactivation during postural control increases with age, the effect of higher muscle coactivation on standing postural response to perturbation is unknown. AIMS: To investigate whether higher muscle coactivation affects standing postural response to perturbation in older adults. METHODS: Thirty-four community-dwelling older participants were randomly assigned either to the coactivation group (CG), where muscle coactivation was increased intentionally, or to the non-coactivation group (NCG). The participants were instructed to stand on a force plate that moved forward or backward. Electromyography data were collected from the lower leg muscles. We requested the participants in the CG to increase the activity of their tibialis anterior, and to maintain this posture during the tasks. We moved the force plate with a constant amplitude and velocity, and measured kinematic data with a camera during the tasks. RESULTS: During forward transfer, the knee extension and hip flexion decreased in the CG after perturbation compared to NCG, and the trunk extension angle increased. The center of pressure (COP) displacement decreased around the peak of the movement in the CG compared to NCG. During backward transfer, ankle dorsal and knee flexion changed after perturbation in the CG compared to NCG. DISCUSSION AND CONCLUSION: Our study found that higher muscle coactivation inhibits lower limb and COP movement as well as increases trunk tilt and the risk for falls during forward perturbations. Postural control with higher coactivation appears to be inefficient for maintaining balance during the backward sway of posture. PMID- 26972106 TI - Modulating Effects of Arabinogalactans from Plant Gum Exudates on Human Complement System. AB - Gum arabic and cashew nut tree gum exudate polysaccharide (CNTG) are plant polysaccharides composed of galactose and arabinose known as arabinogalactans (AGs). Although these fractions are used in food and pharmaceutical industry, cases of allergic reactions were described in clinical reports. As AGs were reported as modulators of the classical (CP) and alternative pathways (AP) of complement system (CS), in the present work, we investigate whether gum arabic and CNTG have an effect on both CS pathways. The complement fixation tests were performed with (CP-30 and AP-30) and without pre-incubation (CP-0 and AP-0). For CP-30, CNTG and gum arabic (833 MUg/ml) showed a reduction of 28.0% (P = 0.000174) and 48.5% (P = 0.000143), respectively, on CP-induced haemolysis. However, no effect was observed for CP-0 in the CP-induced haemolysis. For AP-30, both CNTG and gum arabic (833 MUg/ml) showed 87% reduction on the CP-induced haemolysis, with IC50 values of 100 and 7 MUg/ml, respectively. For AP-0, a reduction of 11.3% for gum arabic and no effect for the CNTG on the CP-induced haemolysis were observed. These results suggested that gum arabic and CNTG could be acting as activators of the CS. Thus, this effect on the CS, especially on the AP, which accounts for up to 80-90% of total CS activation, indicates that both fractions may be harmful because of their potential pro-inflammatory action. Considering that CS activation induces inflammatory response, further studies confirming this immunomodulatory effect of these fractions are required to insure their safe use. PMID- 26972109 TI - Erratum to: Response to hydroxycarbamide in pediatric beta-thalassemia intermedia: 8 years' follow-up in Egypt. PMID- 26972108 TI - Efficient and simple generation of multiple unmarked gene deletions in Mycobacterium smegmatis. AB - Research on mycobacterial genetics relies heavily on techniques for directed gene mutation, but genetic studies are often hampered by the difficulty of generating gene deletions in mycobacteria. We developed an efficient and improved deletion system, described here in detail, which can be used to construct multiple unmarked recombinants in mycobacteria. We tested this system by using it to sequentially delete four pairs of toxin-antitoxin genes in Mycobacterium smegmatis. PMID- 26972110 TI - Coumarin Push-Pull NLOphores with Red Emission: Solvatochromic and Theoretical Approach. AB - A new class of red emitting extensively conjugated donor-pi-acceptor type dyes bearing coumarin units are investigated for nonlinear optical properties. The photophysical behaviour and the relation between structure and properties of the coumarin "push-pull" derivatives were investigated based on solvatochromism and experimentally observed shifts in emission maxima. The electronic coupling for the electron transfer reaction for the coumarin dyes are calculated with the generalized Mulliken-Hush method. We evaluated non-linear optical (NLO) properties of coumarin dyes using both experimental solvent dependent shift method and computational method. All the investigated coumarin dyes are showing large value for first (beta) and second hyperpolarizability (gamma). Density functional theory [B3LYP/6-31G(d)] and time dependent density functional theory (TDDFT) computations have been employed to have more understanding of structural, molecular, electronic and photophysical parameters of the coumarin dyes. PMID- 26972107 TI - Invited review: Small GTPases and their GAPs. AB - Widespread utilization of small GTPases as major regulatory hubs in many different biological systems derives from a conserved conformational switch mechanism that facilitates cycling between GTP-bound active and GDP-bound inactive states under control of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), which accelerate slow intrinsic rates of activation by nucleotide exchange and deactivation by GTP hydrolysis, respectively. Here we review developments leading to current understanding of intrinsic and GAP catalyzed GTP hydrolytic reactions in small GTPases from structural, molecular and chemical mechanistic perspectives. Despite the apparent simplicity of the GTPase cycle, the structural bases underlying the hallmark hydrolytic reaction and catalytic acceleration by GAPs are considerably more diverse than originally anticipated. Even the most fundamental aspects of the reaction mechanism have been challenging to decipher. Through a combination of experimental and in silico approaches, the outlines of a consensus view have begun to emerge for the best studied paradigms. Nevertheless, recent observations indicate that there is still much to be learned. (c) 2016 Wiley Periodicals, Inc. Biopolymers 105: 431-448, 2016. PMID- 26972112 TI - Single-Stranded Tile Stoppers for Interlocked DNA Architectures. AB - Interlocked DNA architectures are useful for DNA nanotechnology because of their mechanically bonded components, which can move relative to one another without disassembling. We describe the design, synthesis, and characterization of novel single-stranded tile (SST) stoppers for the assembly of interlocked DNA architectures. SST stoppers are shown to self-assemble into a square-shaped rigid structure upon mixing 97 oligodeoxynucleotide (ODN) strands. The structures are equipped with a sticky end that is designed for hybridization with the sticky ends of a dsDNA axle of a DNA rotaxane. Because the diameter of the macrocycle threaded onto the axle is 14 nm, the dimension of the square-shaped stopper was designed to be bulky enough to prevent the dethreading of the macrocycle. An asymmetric rotaxane with a SST- and a ring-shaped stopper featuring two stations for hybridization of the macrocycle to the axle was assembled. The macrocycle can be directed towards one or the other station upon triggering with fuel ODNs. PMID- 26972111 TI - Single Molecule 3D Orientation in Time and Space: A 6D Dynamic Study on Fluorescently Labeled Lipid Membranes. AB - Interactions between single molecules profoundly depend on their mutual three dimensional orientation. Recently, we demonstrated a technique that allows for orientation determination of single dipole emitters using a polarization-resolved distribution of fluorescence into several detection channels. As the method is based on the detection of single photons, it additionally allows for performing fluorescence correlation spectroscopy (FCS) as well as dynamical anisotropy measurements thereby providing access to fast orientational dynamics down to the nanosecond time scale. The 3D orientation is particularly interesting in non isotropic environments such as lipid membranes, which are of great importance in biology. We used giant unilamellar vesicles (GUVs) labeled with fluorescent dyes down to a single molecule concentration as a model system for both, assessing the robustness of the orientation determination at different timescales and quantifying the associated errors. The vesicles provide a well-defined spherical surface, such that the use of fluorescent lipid dyes (DiO) allows to establish a a wide range of dipole orientations experimentally. To complement our experimental data, we performed Monte Carlo simulations of the rotational dynamics of dipoles incorporated into lipid membranes. Our study offers a comprehensive view on the dye orientation behavior in a lipid membrane with high spatiotemporal resolution representing a six-dimensional fluorescence detection approach. PMID- 26972113 TI - Anti-signal recognition particle antibody-positive polymyositis in a patient with Sjogren's syndrome showing various types of annular erythema: Positive correlation between the activities of annular erythema and myositis. AB - Annular erythema with Sjogren's syndrome (AESS) is occasionally found, especially in Asian patients, which is classified into three types. We present a case of Sjogren's syndrome showing various types of AESS with anti-signal recognition particle antibody-positive polymyositis. We successfully treated the eruption and myositis with a low dose of prednisolone. Every onset of annular erythema coincided with elevation of serum creatine kinase levels, which suggests the correlation between the activities of annular erythema and polymyositis. PMID- 26972114 TI - Differences in the Abilities to Mechanically Eliminate Activation Energies for Unimolecular and Bimolecular Reactions. AB - Mechanochemistry, i.e. the application of forces, F, at the molecular level, has attracted significant interest as a means of controlling chemical reactions. The present study uses quantum chemical calculations to explore the abilities to mechanically eliminate activation energies, DeltaE(?), for unimolecular and bimolecular reactions. The results demonstrate that DeltaE(?) can be eliminated for unimolecular reactions by applying sufficiently large F along directions that move the reactant and/or transition state (TS) structures parallel to the zero-F reaction coordinate, S0. In contrast, eliminating DeltaE(?) for bimolecular reactions requires the reactant to undergo a force-induced shift parallel to S0 irrespective of changes in the TS. Meeting this requirement depends upon the coupling between F and S0 in the reactant. The insights regarding the differences in eliminating DeltaE(?) for unimolecular and bimolecular reactions, and the requirements for eliminating DeltaE(?), may be useful in practical efforts to control reactions mechanochemically. PMID- 26972116 TI - Mutations in FUS are the most frequent genetic cause in juvenile sporadic ALS patients of Chinese origin. AB - Juvenile onset ALS is a very rare form of motor neuron disease, with the first symptoms of motor neuron degeneration manifested before 25 years of age. Mutations in the alsin (ALS2), senataxin (SETX), and spatacsin (SPG11) genes have been associated with familial ALS with juvenile onset and slow progression, whereas the genetic architecture of sporadic juvenile ALS remains unclear. We screened mutations in C9orf72, SOD1, FUS, TARDBP, ANG, VCP and PFN1 in 16 juvenile sporadic ALS patients. Four cases (25%) carrying FUS mutations and one individual (6%) harbouring a SOD1 mutation were identified. All cases had an aggressive disease course. Our results suggest that FUS mutations are the most frequent genetic cause in early-onset sporadic ALS patients of Chinese origin. Genetic testing of FUS should be performed in early-onset ALS patients especially those with an aggressive disease course. PMID- 26972115 TI - Hemolytic and antimalarial effects of tight-binding glyoxalase 1 inhibitors on the host-parasite unit of erythrocytes infected with Plasmodium falciparum. AB - Glyoxalases prevent the formation of advanced glycation end products by converting glycolysis-derived methylglyoxal to d-lactate with the help of glutathione. Vander Jagt and colleagues previously showed that erythrocytes release about thirty times more d-lactate after infection with the human malaria parasite Plasmodium falciparum. Functional glyoxalases in the host-parasite unit might therefore be crucial for parasite survival. Here, we determined the antimalarial and hemolytic activity of two tight-binding glyoxalase inhibitors using infected and uninfected erythrocytes. In addition, we synthesized and analyzed a set of diester derivates of both tight-binding inhibitors resulting in up to threefold lower IC50 values and an altered methemoglobin formation and hemolytic activity depending on the type of ester. Inhibitor treatments of uninfected erythrocytes revealed an extremely slow inactivation of the host cell glyoxalase, irrespective of inhibitor modifications, and a potential dispensability of the host cell enzyme for parasite survival. Our study highlights the benefits and drawbacks of different esterifications of glutathione derived inhibitors and demonstrates the suitability of glyoxalase inhibitors as a tool for deciphering the relevance and mode of action of different glyoxalase systems in a host-parasite unit. PMID- 26972117 TI - Comparison of the sulfonamide inhibition profiles of the alpha-, beta- and gamma carbonic anhydrases from the pathogenic bacterium Vibrio cholerae. AB - Carbonic anhydrases (CA, EC 4.2.1.1) are ubiquitous metalloenzymes, which catalyze the conversion of carbon dioxide (CO2) to bicarbonate (HCO3(-)) and protons (H(+)). In prokaryotes, the existence of genes encoding for alpha-, beta- and gamma-classes suggests that these enzymes play an important role in the prokaryotic physiology. It has been demonstrated, in fact, that their inhibition in vivo leads to growth impairment or growth defects of the microorganism. Ultimately, we started to investigate the biochemical properties and the inhibitory profiles of the alpha- and beta-CAs identified in the genome of Vibrio cholerae, which is the causative agent of cholera. The genome of this pathogen encodes for CAs belonging to alpha, beta and gamma classes. Here, we report a sulfonamide inhibition study of the gamma-CA (named VchCAgamma) comparing it with data obtained for the alpha- and beta-CA enzymes. VchCAgamma activity (kcat=7.39 * 10(5)s(-1)) was significantly higher than the other gamma-CAs. The inhibition study with a panel of sulfonamides and one sulfamate led to the detection of a large number of nanomolar VchCAgamma inhibitors, including simple aromatic/heterocyclic sulfonamides (compounds 2-9, 11, 13-15, 24) as well as EZA, DZA, BRZ, BZA, TPM, ZNS, SLP, IND (KIs in the range of 66.2-95.3 nM). As it was proven that bicarbonate is a virulence factor of this bacterium and since ethoxzolamide was shown to inhibit this virulence in vivo, we propose that VchCA, VchCAbeta and VchCAgamma may be a target for antibiotic development, exploiting a mechanism of action rarely considered up until now, i.e., interference with bicarbonate supply as a virulence factor. PMID- 26972120 TI - 2015 Young Investigator Challenge--we have a winner! PMID- 26972119 TI - Greater goods?: Direct-to-consumer testing companies are making a broader case for societal benefits, but not everyone is sold. PMID- 26972118 TI - Design, synthesis, and anti-breast cancer evaluation of new triarylethylene analogs bearing short alkyl- and polar amino-/amido-ethyl chains. AB - The synthesis of novel triarylethylene analogs, designed based on well-known Selective Estrogen Receptor Modulators (SERMs), i.e., ospemifene and tamoxifen, as potential anti-breast cancer agents is described. The cytotoxic potential of these analogs against ER-positive (MCF-7) and ER-negative (MDA-MB-231) human breast cancer cell lines was determined and compared with the standards, ospemifene and tamoxifen. In initial screening, analogs 5, 14 and 15 were found to be much more effective than the standards against both the cell lines. The results showed that these novel analogs inhibit the expression of proteins involved in the migration and metastasis, compound 5 being most effective. Compound 5 inhibited the expression of MMP-9, c-Myc and Caveolin in both MCF-7 and MDA-MB-231 cells, and suppressed the invasion of ER-negative cells in a dose dependent manner. Finally, in silico docking simulations of the representative compounds in the binding sites of the estrogen receptors (ERs) indicated a good binding affinity of the compounds with the ERs, and supported their experimental toxicity against MCF-7 cancer cell lines. PMID- 26972121 TI - Varroa destructor and Viruses association in honey bee colonies under different climatic conditions. AB - Honey bee colonies are threatened by multiple factors including complex interactions between environmental and diseases such as parasitic mites and viruses. We compared the presence of honeybee-pathogenic viruses and Varroa infestation rate in four apiaries: commercial colonies that received treatment against Varroa and non-treated colonies that did not received any treatment for the last four years located in temperate and subtropical climate. In addition, we evaluated the effect of climate and Varroa treatment on DWV amounts. In both climates, DWV was the most prevalent virus, being the only present virus in subtropical colonies. Moreover, colonies from subtropical climate also showed reduced DWV amounts and lower Varroa infestation rates than colonies from temperate climate. Nevertheless, non-treated colonies in both climate conditions are able to survive several years. Environment appears as a key factor interacting with local bee populations and influencing colony survival beyond Varroa and Virus presence. This article is protected by copyright. All rights reserved. PMID- 26972123 TI - Anchorpoints: an introspective. AB - This, then, is what it has been all about. Today I mark the end of an academic career that ranged over 45 years. 1952 was the starting point. In that year, as a medical student, I was accepted as a research assistent by Prof. G.G.J. Rademaker, a neurophysiologist and at the time head of the Department of Neurology at the Academic Hospital in Leiden. The neurological research period was followed by a mycological one. Having received my MD degree and doing my military service, I was asked to carry out a study into the prevalence, prevention and treatment of mycological infections in military personel. For this reason I worked for more than 1, 5 years in Baarn at the section Medical Mycology of the Phytopathological Laboratory, an interacademic institution of the Universities of Amsterdam and Utrecht (1956-1958). Immediately after the military service I became a resident in psychiatry and started - together with the biochemist Prof. B. Leijnse - a research program into the biological determinants of depression. The period of psychiatric investigation lasted until this very day, albeit in different locations, i.e. Rotterdam, Groningen, Utrecht, New York and Maastricht respectively. PMID- 26972124 TI - Prospects for a scientific psychiatry. AB - Herman van Praag has made major contributions to the scientific and conceptual development of psychiatry. Despite progress in delineating reliable diagnostic criteria, our classification system ignores clinical insights available from patients' subjective experiences of illness. Hence a 'coarsening of diagnosis' has occurred, weakening the nosologic infrastructure of scientific psychiatry. This paper will discuss these ideas and emphasize the central role of psychopharmacology in advancing psychiatry, with lithium's discovery as a paradigm. PMID- 26972122 TI - Nanosecond formation of diamond and lonsdaleite by shock compression of graphite. AB - The shock-induced transition from graphite to diamond has been of great scientific and technological interest since the discovery of microscopic diamonds in remnants of explosively driven graphite. Furthermore, shock synthesis of diamond and lonsdaleite, a speculative hexagonal carbon polymorph with unique hardness, is expected to happen during violent meteor impacts. Here, we show unprecedented in situ X-ray diffraction measurements of diamond formation on nanosecond timescales by shock compression of pyrolytic as well as polycrystalline graphite to pressures from 19 GPa up to 228 GPa. While we observe the transition to diamond starting at 50 GPa for both pyrolytic and polycrystalline graphite, we also record the direct formation of lonsdaleite above 170 GPa for pyrolytic samples only. Our experiment provides new insights into the processes of the shock-induced transition from graphite to diamond and uniquely resolves the dynamics that explain the main natural occurrence of the lonsdaleite crystal structure being close to meteor impact sites. PMID- 26972125 TI - New molecular genetic findings in the genetics of affective disorders. AB - Molecular genetics has now been widely incorporated into genetic epidemiological research in psychiatry. Affective disorders and, in particular, bipolar affective disorder (BPAD) have been examined in many molecular genetic studies which have covered a large part of the genome. Specific hypotheses such as mutations have also been studied. Most recent studies indicate that several chromosomal regions may be involved in the aetiology of BPAD. These include genes on chromosomes 18, 21, 4, 5, 11 and X. Other studies have reported the presence of anticipation in BPAD and in unipolar affective disorder (UPAD). This phenomenon describes the increase in clinical severity and decrease in age of onset observed in successive generations. This mode of transmission correlates with the presence of specific mutations (trinucleotide repeat sequences). Associations with these mutations have been reported in different populations of BPAD-patients and may represent a genetic factor involved in the transmission of the disorder. These findings are all preliminary and require to be confirmed. Large multi-centres and multi disciplinary projects are currently underway in Europe and in the US and hopefully will improve our understanding of the genetic factors involved in affective disorders. In addition, genetic approaches used in psychiatry are being combined with an assessment of non-genetic susceptibility factors. The investigation of interactions between gene and environment is one of the most promising areas dealing with complex multi-factorial diseases such as the affective disorders. PMID- 26972126 TI - On the unique profile of action of clozapine as assessed with fos-protein induction in rat brain regions. AB - Clozapine (Leponex(r)) has been shown to be therapeutically effective in patients resistant to long-term medication with classical antipsychotics. The mode of action of clozapine is not clear, but several cerebral receptors have been implicated, including the dopamine D2, D3 and D4 types, alpha-adrenergic, serotonin (type 2A) and glutamate (NMDA-type) receptors. Moreover, clozapine has anti-cholinergic and antihistaminergic potencies. Thusfar, receptor profiles are based virtually exclusively on in vitro binding assays. It appeared, that pharmacological and physiological stimuli activate particular gene expression, in vivo, so at cellular level the action of e.g. antipsychotics can now be traced. In this communication we present data on the in vivo profile of clozapine as revealed with Fos-protein expression. The immediate early gene c-fos is, as other members of the class of such genes, rapidly and transiently induced in the brain. The prototypic members of this class all encode nuclear proteins that regulate gene transcription. Recent studies have shown that the antipsychotics haloperidol (Haldol(r)) and clozapine, when given acutely, induce different patterns of Fos like immunoreactivity in the forebrain of the rat. The most marked effects of haloperidol were found in the striatum, the nucleus accumbens and the lateral septum. PMID- 26972127 TI - The measurement of emotions. AB - Most people usually think of emotion as a subjective feeling of a certain kind, the kind for which labels like happy, sad, and frightened are appropriate. However, there is much evidence to suggest that this is too narrow a way to define emotions, and that a different and broader conceptualization is needed. If we examine the history of theories of emotion we find a great diversity of views. For example, Darwin, in his 1872 book 'The Expression of the Emotions in Man and Animals', conceived of emotions as expressive behaviors that had the function of communicating intentions from one animal to another in the presence of conflicts or emergencies. Emotional expressions, from this point of view, regulated interpersonal relations and increased the chances of individual survival. PMID- 26972128 TI - Naturalistic assessments in psychiatry. AB - Research in psychiatry could speeden its progress by taking the manifest heterogenity and variability of symptom expression within diagnostic groups more fully into account. Since Kraepelin symptom variation has been recognized to have both biological and environmental roots. If investigated systematically, such variations in illness experience will yield new subtypes that will provide greater insight into the onset, course and vulnerability of mental disorders. Studies ranging from population surveys to the laboratory have demonstrated that psychopathology is not randomly distributed in a population, nor is it constantly present in the lives of individuals. At both the population and the person levels, psychopathology varies with time and place. At the population level, illness processes localize in risk groups, who often reside in specific neighbourhoods or social settings. The individual experience of psychopathology also fluctuates with time, place and culture. This variability requires methods for case detection and treatment planning that take this into account. PMID- 26972129 TI - New dopaminergic and non-dopaminergic theories in schizophrenia and their therapeutic impact. AB - The dopamine (DA) hypothesis of schizophrenia, postulating that schizophrenia is characterized by increased dopamine function, has been the most influential theory on the pathogenesis of schizophrenia. It has recently been revised based on the appreciation that the core symptoms of schizophrenia may not be the positive (psychotic) symptoms, but rather the negative symptoms and the cognitive deficits found in schizophrenic patients. This revision has prompted the hypothesis that schizophrenia is characterized by both decreased prefrontal dopamine activity (causing deficit symptoms) and increased dopamine activity in mesolimbic dopamine neurons (causing positive symptoms). Notwithstanding this revision of a role for dopamine in schizophrenia, it has become increasingly evident that dysfunction of other monoaminergic systems may be as important in contributing to the pathophysiology of schizophrenia. Specifically, the putative role of serotonin (5-hydroxytryptamine, 5-HT) in schizophrenia is gaining considerable attention. Several observations, such as the ability of the 5-HT antagonist, ritanserin, to alleviate schizophrenic symptoms and, when added to haloperidol (Haldol(r)), to decrease its extrapyramidal side-effects (EPS), have stimulated studies into a role of 5-HT in schizophrenia. The finding that clozapine (Leponex(r)), clinically superior to conventional neuroleptics, is a weak DA2 antagonist but a potent 5-HT1c and 5-HT2 antagonist has further stimulated 5-HT-related research in schizophrenia. PMID- 26972130 TI - The prospects of new antipsychotic principles. AB - Biological schizophrenia research has been dominated by the dopamine hypothesis for decades, but in recent years a more diversified view has gained increasing attention. Several neurotransmitters are now being discussed, and especially their interaction in complex circuitries. The demonstration of an atypical profile of clozapine (Leponex(r)), with lessened extrapyramidal side effects and somewhat increased efficacy, has stimulated this research field considerably. This agent has high affinity not only for the different dopamine receptor subtypes, but also for serotonergic, alpha-adrenergic and muscarinic receptors. Different workers have stressed one or more of these sites as being of major importance for the atypical profile of clozapine, and several drug companies have made attempts to mimic the profile of clozapine by developing molecules with affinity for these receptors in varying proportions. A number of such agents have reached or will soon reach the market and appear to be promising, even though they may not match clozapine in terms of atypicality. PMID- 26972131 TI - Will light brighten the future of the depressed patient? AB - The present explosive growth of interest in the therapeutic possibilities of exposure to light was triggered by a patient, Herbert Kern. He suffered from episodic depressive and manic complaints and discovered, by registering these over the years, a seasonal pattern in their occurrence. Discussions with scientists of the NIMH resulted in his participation in a bright light-treatment experiment when he was depressed in the winter of 1980-1981. He recovered. Next, the same group of investigators defined the criteria for a new syndrome, Seasonal Affective Disorder (SAD): a history of major affective disorder (according to the Research Diagnostic Criteria), at least two consecutive years in which the depressions have occurred during fall or winter and remitted in the following spring or summer, and the absence of any clear-cut seasonally changing psychosocial variable, such as work, stress and so on. PMID- 26972134 TI - Obsessive compulsive disorder: Opportunities within and beyond the serotonergic domain. AB - Abnormality of the serotonin (5-hydroxytryptamine - 5-HT) system and particularly hypersensitivity of postsynaptic 5-HT receptors remained the leading hypothesis for the underlying pathophysiology of obsessive compulsive disorder (OCD) during the 1980s. A number of lines of evidence supported this serotonergic hypothesis, not least the treatment studies which demonstrated clearly and consistently that anti-obsessional efficacy was a function of serotonin re-uptake inhibition. Studies of markers and biological probes provided further evidence: platelet studies, for example, linked reductions in 5-HT activity with clinical response, and treatment response was correlated with decreased 5-hydroxyindolacetic acid (5 HIAA) levels within the cerebrospinal fluid of OCD patients. Added to this was the evidence from the behavioral or physiological responses observed following serotonergic challenge with the serotonin agonists meta-chlorophenylpiperazine, a compound with high affinity for 5-HT1A-, 5-HT1D- and 5-HT2C-receptors. PMID- 26972133 TI - The prospect of new anxiolytic principles. AB - Novel anxiolytics notwithstanding, in the latest fifteen years there have been no major innovations in the treatment of anxiety disorders. Fascinating research is going on, but real breakthroughs will require adequate models of disease, based on the disordered physiology of each type of pathological anxiety. In this brief overview, we will address both the field of potential anxiolytics in 1997, and the development of new experimental models of anxiety disorders. PMID- 26972132 TI - Biological concepts of anxiety disorders. AB - Since the seminal work of Geller and Blum there is a vast expanding literature relating anxiety symptoms to serotonin (5-hydroxytryptamine; 5-HT). The general picture emerging from animal research is that increasing 5-HT function is anxiogenic. However, animal research is confined by the fact that extrapolations from animal behavior to human emotions have limited validity. Human anxiety can range from normal emotions to clinical syndromes. It can be a component of different physical and mental disorders, but also the central feature of a syndromes. During the last decade, a wealth of knowledge about the origin and anatomical distribution of 5-HT neuronal systems has been obtained. Our understanding of the neuroanatomy and neurochemistry of anxiety has also considerably advanced, but the picture is still puzzling. We are faced with a large number of 5-HT-receptor subtypes, each with its own specific distribution and presumably specific function. The complexity of the 5-HT system in terms of receptor heterogeneity offers a dazzling opportunity to the development of new drugs affecting selective 5-HT functions, but it also precludes that firm conclusions can be drawn when less selective agents are being used. PMID- 26972136 TI - Biological and psychopharmacological aspects of impulse-control disorders. AB - Over the past decades extensive research has been performed on the presumed relationship between neurotransmitter functionality in the central nervous system and psychopathological states. Originally, in the mid-sixties it was hypothesized that depressive states may be associated with disorders in brain noradrenalin and/or serotonin (5-hydroxytryptamine; 5-HT) metabolism or function resulting in the socalled monoamine hypothesis of depression. Subsequent investigations revealed that altered 5-HT metabolism is not related to mood disorder per se, but to components of the depressive syndrome and more specifically to increased anxiety and/or signs of dysregulated aggression, including violent suicidal attempts. Concerning aggression and other types of disruptive or impulsive behavior, research on their neurobiological determinants has been focussed mainly on indicators of central 5-HT function. PMID- 26972135 TI - Phencyclidine, excitatory amino acids, psychiatry and drug abuse: Historical perspectives on clinical-laboratory interactions. AB - Some 40 years ago phencyclidine (PCP) was developed as the prototype of a proposed new class of 'dissociative' general anesthetics, so called because it induced a marked dissociation from the environment without complete loss of consciousness. In the earliest clinical trials of PCP anesthesia, it was observed that as many as half the subjects experienced severe psychotic reactions during and beyond emergence. This striking clinical observation at once marked the failure of PCP as a suitable general anesthetic, and the beginning of a remarkable new era in basic and clinical neuroscience which can serve as an example of the interaction between clinical observation and basic science. At once, clinical researchers turned their focus upon the characterization of the PCP-induced psychosis, and recognized striking similarities between PCP-induced symptoms and signs and both the negative and positive symptoms of schizophrenia, proposing the PCP psychosis as a new model of that illness. Several years later PCP suddenly emerged as a major drug of abuse, with the result that emergency rooms and psychiatric inpatient units were observing and treating large numbers of these patients, in many of whom a diagnosis of schizophrenia could not be ruled out until toxicological analyses were performed. This natural experiment yielded a huge amount of additional data, and contributed a strong public-health based impetus to research into the nature and treatment of PCP intoxication. PMID- 26972137 TI - Age-related cognitive decline and the borderland between normal aging and dementia. AB - It is now generally agreed that healthy individuals are characterized by cognitive decline during the later decades of adult life. The acquisition of new information becomes less efficient, which, coupled with a diminished retention of this information for later use, results in substantially poorer memory performance. The ability to plan new activities, solve problems and make complex decisions, as well as cognitive flexibility is noticeably diminished. In addition, attentional processes appear to be invariably poorer in old subjects than in young subjects (for review). While it is quite clearly established that elderly subjects (i.e. after 65 years of age) show a deterioration of cognitive functioning, there is also evidence that this deterioration may start in middle age (40 years). There is large individual variance in age groups; for instance, some old individuals perform on many neurocognitive tests as well as young individuals do. Rowe and Kahn proposed in their influential article to discern between successful aging and usual aging. Successful aging would be due to the effect of chronological age, whereas additional factors would be responsible for usual aging. An important point is the nature of the borderland between usual cognitive aging and pathological conditions such as dementia. Various health related factors are thought to be important in this respect. They may be a determinant for the transition between successful aging to normal aging and into the borderland with dementia. The Brain & Behavior Research Institute in Maastricht investigates the determinants of successful and pathological aging in a number of related and multidisciplinary projects. This paper describes some major findings of this research programme and gives a theory on the interaction of vulnerability factors and protective factors in their effect on cognitive aging. PMID- 26972138 TI - Editorial. PMID- 26972140 TI - Inevitable Acclimatization and Acute Mountain Sickness. PMID- 26972139 TI - Influence of cell physiological state on gene delivery to T lymphocytes by chimeric adenovirus Ad5F35. AB - Adoptive transfer of genetically-modified T cells is a promising approach for treatment of both human malignancies and viral infections. Due to its ability to efficiently infect lymphocytes, the chimeric adenovirus Ad5F35 is potentially useful as an immunotherapeutic for the genetic modification of T cells. In previous studies, it was found that the infection efficiency of Ad5F35 was significantly increased without enhanced expression of the viral receptor after T cell stimulation; however, little is known about the underlying mechanism. Nonetheless, cell physiology has long been thought to affect viral infection. Therefore, we aimed to uncover the physiologic changes responsible for the increased infection efficiency of Ad5F35 following T cell stimulation. Given the complexity of intracellular transport we analyzed viral binding, entry, and escape using a Jurkat T cell model and found that both cell membrane fluidity and endosomal escape of Ad5F35 were altered under different physiological states. This, in turn, resulted in differences in the amount of virus entering cells and reaching the cytoplasm. These results provide additional insight into the molecular mechanisms underlying Ad5F35 infection of T cells and consequently, will help further the clinical application of genetically-modified T cells for immunotherapy. PMID- 26972141 TI - The Reply. PMID- 26972142 TI - Depressive Symptoms, Antidepressant Use, and Cognitive Decline. PMID- 26972143 TI - An Additional Clinical Scenario of Risk for Loperamide Cardiac-Induced Toxicity. PMID- 26972144 TI - Splenic angiomyxoma with intravascular tumor embolus in a dog: a case report. AB - A 13-year-old castrated male Yorkshire terrier dog had a soft splenic mass, which measured 11 cm in the greatest diameter. Microscopically, the parenchyma of the spleen was completely replaced by myxoid substances. Numerous spindle and stellate cells were loosely arranged in the myxoid stroma, and variable vessels of variable sizes were observed in a loose matrix with poorly defined margins. Immunohistochemical analysis showed that tumor cells were positive for desmin and alpha-SMA, but negative for S-100. Interestingly, intravascular tumor embolus with positive alpha-SMA expression was observed. This case is meaningful, because angiomyxoma, a rare tumor of dogs, occurs in the spleen. Even in human cases, splenic angiomyxoma was not reported. PMID- 26972145 TI - Ability to Reach Orgasm in Patients With Prostate Cancer Treated With Robot assisted Laparoscopic Prostatectomy. AB - OBJECTIVES: To study the ability to reach orgasm after robot-assisted laparoscopic prostatectomy (RALP) in relation to demographic, cancer-related, and surgical variables, and the use of erectile aids. METHODS: In this cross sectional study at a mean of 3 years after RALP at Oslo University Hospital, 982 men were invited to complete a mailed questionnaire, and 777 responded. Respondents who reported postoperative radiotherapy or hormone treatment, or did not report on orgasm were omitted, leaving 609 patients for analysis. Ability to reach orgasm was rated on 1 question from The Expanded Prostate Cancer Index Composite 26-item version, and dichotomized into "good" or "poor." RESULTS: Overall, 27% of the men reported good ability to reach orgasm: 22% among those did not use erectile aids and 34% among those did (P = .001). Univariate analysis of men with good versus poor ability to reach orgasm showed many significant differences. In multivariate analysis, being older, having a reduced physical quality of life, and erectile dysfunction were significantly associated with poor ability to reach orgasm. Erectile dysfunction showed an odds ratio of 4.86 for poor orgasmic ability. The 48% of men who used erectile aids had significantly better orgasmic ability than the nonusers. CONCLUSION: In our sample, 27% had good ability to reach orgasm at a mean of 3 years after RALP. Poor orgasmic ability was associated with being older, poor erectile function, and a reduced physical quality of life. Using erectile aids increased the rate of good ability to reach orgasm. PMID- 26972147 TI - Evaluation of Postoperative Hydronephrosis Following Ureteroscopy in Pediatric Population: Incidence and Predictors. AB - OBJECTIVE: To identify the incidence and associated factors of the postoperative hydronephrosis in pediatric patients who underwent ureterorenoscopy (URS) for renal or ureteral stones. PATIENTS AND METHODS: We evaluated the results of 116 patients who underwent semirigid or flexible URS retrospectively. Primary end points of the study were to determine the incidence of postoperative hydronephrosis and factors associated with the development of postoperative hydronephrosis. Logistic regression analysis was used to define factors associated with the presence of hydronephrosis. RESULTS: Mean age of the population was 9.5 years and mean stone size was 9.4 mm. Hydronephrosis was detected in 32 (27.6%) patients. Stone-free status was achieved in 101 (87%) patients. Univariate analysis revealed history of ipsilateral URS, duration of operation, presence of impacted stone, development of ureteral injury during operation, and presentation with a renal colic episode as the parameter associated with increased risk of hydronephrosis. History of ipsilateral URS (odds ratio: 1.664, P = .027), presence of impacted stones (odds ratio: 1.788, P = .014), and development of ureteral injury during operation (odds ratio: 1.106, P = .039) were found to be the independent markers of developing postoperative hydronephrosis in a multivariate analysis. CONCLUSION: Ipsilateral hydronephrosis following URS develops in a significant portion of patients. In patients with history of ipsilateral procedure and those with an impacted stone and had ureteral injury, the risk of postoperative hydronephrosis is higher; therefore, physicians should keep these parameters in mind in the decision-making process of selective imaging postoperatively. PMID- 26972149 TI - The Selection of Procedures in One-stage Urethroplasty for Treatment of Coexisting Urethral Strictures in Anterior and Posterior Urethra. AB - OBJECTIVE: To explore selection of the procedures in one-stage urethroplasty for treatment of coexisting urethral strictures in the anterior and posterior urethra. METHODS: Between 2008 and 2014, a total of 27 patients with existing strictures simultaneously at anterior urethra and posterior urethra were treated in our hospital. Two types of procedures were selected for treatment of the anterior urethral strictures. A penile skin flap and the lingual mucosa were used for augmented urethroplasty in 20 and 7 cases, respectively. Three types of procedures, namely, non-transecting end-to-end urethral anastomosis (n = 3), traditional end-to-end urethral anastomosis (n = 17), other grafts substitution urethroplasty, including pedicle scrotal skin urethroplasty (n = 2), and lingual mucosal graft urethroplasty (n = 5), were utilized in the treatment of posterior urethral strictures. RESULTS: The patients were mean followed up 30 months with an overall success rate of 88.9%. The majority of the patients exhibited wide patent urethras on retrograde urethrography and the patients' urinary peak flow ranged from 14.2 to 37.9 ml/s. Complications developed in 3 patients (11.1%). Of the 17 patients who underwent traditional urethral end-to-end anastomosis, urethral strictures occurred in 2 patients at 4 and 6 months after the operation. These patients achieved a satisfactory voiding function after salvage pedicle scrotal skin urethroplasty. A urethral pseudodiverticulum was observed in another patient 9 months after pedicle penile flap urethroplasty; and after a salvage procedure, he regained excellent voiding function. CONCLUSION: Synchronous anterior and posterior strictures can be successfully reconstructed with a combination of substitution and anastomotic urethroplasty techniques. PMID- 26972148 TI - Robotic-assisted Laparoscopic Pyeloplasty: Analysis of Symptomatic Patients With Equivocal Renal Scans. AB - OBJECTIVES: To review the objective and subjective success rates of robotic assisted laparoscopic pyeloplasty in symptomatic patients with radiographic findings suggestive of uretero-pelvic junction obstruction (UPJO), but equivocal renal scans (diuretic T1/2 <20 minutes). METHODS: We reviewed 77 patients with symptomatic UPJO, who underwent robotic-assisted laparoscopic pyeloplasty between August 2006 and March 2013. We grouped patients by renal scan findings into 1 of 2 groups, obstructed (diuretic T1/2 >=20 minutes) or equivocal (diuretic T1/2 <20 minutes). All patients were symptomatic and had radiographic findings suggestive of UPJO (eg hydronephrosis). RESULTS: Mean age was 40.7 years (range 17-80) with 70% female. UPJO occurred 44% left and 56% right, with 92% presenting with flank pain. Of 77 patients, 45 had obstruction on renal scan, with 41 (91%) having resolution of obstruction postoperatively and 44 of 45 (98%) having complete resolution of their initial symptoms. Thirty-two patients had equivocal findings with mean diuretic T1/2 of 12.6 minutes (range: 5.5-19.26) on renal scan. In this latter group, patients had significantly less of a decrease in their diuretic T1/2 postoperatively (4 vs 64 minutes, P = .018) and reported less pain resolution (53% vs 98%, P <=.001) than group 1. CONCLUSION: Many studies have demonstrated excellent success of pyeloplasty, with most series including patients meeting strict diagnostic criteria for obstruction. Our study examines outcomes in patients with clinically symptomatic UPJO and equivocal diuretic renography. In our cohort, equivocal patients were significantly less likely to have subjective resolution of symptoms than patients in the obstructed group. PMID- 26972146 TI - Monocyte Mitochondrial Function in Calcium Oxalate Stone Formers. AB - OBJECTIVE: To investigate whether mitochondrial function is altered in circulating immune cells from calcium oxalate (CaOx) stone formers compared to healthy subjects. MATERIALS AND METHODS: Adult healthy subjects (n = 18) and CaOx stone formers (n = 12) were included in a pilot study. Data collection included demographic and clinical values from electronic medical records. Bioenergetic function was assessed in monocytes, lymphocytes, and platelets isolated from blood samples using the Seahorse XF96 Analyzer. Plasma interleukin-6 (IL-6) was measured using enzyme-linked immunosorbent assay. RESULTS: All participants were age matched (44.5 +/- 3.0 years for healthy subjects vs 42.3 +/- 4.8 years for CaOx stone formers, P = .6905). CaOx stone formers did not have urinary tract infection, ureteral stones, or obstructing renal stones. Monocyte mitochondrial function was decreased in CaOx stone formers compared to healthy subjects. Specifically, mitochondrial maximal respiration (P = .0011) and reserve capacity (P < .0001) were significantly lower. In contrast, lymphocyte and platelet mitochondrial function was similar between the 2 groups. The bioenergetic health index, an integrated value of mitochondrial function, was significantly lower in monocytes from CaOx stone formers compared to healthy subjects (P = .0041). Lastly, plasma IL-6 levels were significantly increased (P = .0324). CONCLUSION: The present pilot study shows that CaOx stone formers have decreased monocyte mitochondrial function. Plasma IL-6 was also increased in this cohort. These data suggest that impaired monocyte mitochondrial function and inflammation may be linked to CaOx kidney stone formation. Further studies are needed to confirm these findings in a larger cohort of patients. PMID- 26972150 TI - Theoretical Study of the Mechanism of Exemestane Hydroxylation Catalyzed by Human Aromatase Enzyme. AB - Human aromatase (CYP19A1) aromatizes the androgens to form estrogens via a three step oxidative process. The estrogens are necessary in humans, mainly in women, because of the role they play in sexual and reproductive development. However, these also are involved in the development and growth of hormone-dependent breast cancer. Therefore, inhibition of the enzyme aromatase, by means of drugs known as aromatase inhibitors, is the frontline therapy for these types of cancers. Exemestane is a suicidal third-generation inhibitor of aromatase, currently used in breast cancer treatment. In this study, the hydroxylation of exemestane catalyzed by aromatase has been studied by means of hybrid QM/MM methods. The Free Energy Perturbation calculations provided a free energy of activation for the hydrogen abstraction step (rate-limiting step) of 17 kcal/mol. The results reveal that the hydroxylation of exemestane is not the inhibition stage, suggesting a possible competitive mechanism between the inhibitor and the natural substrate androstenedione in the first catalytic subcycle of the enzyme. Furthermore, the analysis of the interaction energy for the substrate and the cofactor in the active site shows that the role of the enzymatic environment during this reaction consists of a transition state stabilization by means of electrostatic effects. PMID- 26972151 TI - Baseline hormone levels are linked to reproductive success but not parental care behaviors. AB - Consistent behavioral differences among individuals, or personalities, have been hypothesized to arise as a result of consistent individual differences in hormone levels. Individual variation in baseline hormone levels or hormonal similarity within a breeding pair may be related to reproductive success, as suggested by the corticosterone-fitness hypothesis and the hormonal similarity hypothesis, respectively. In a population of Eastern bluebirds (Sialia sialis) with repeatable behavioral expression and coordination of behavior within pairs, we tested if baseline androgen and corticosterone levels are related to behavioral expression, if coordination in behavior within pairs is facilitated by hormonal coordination, and if baseline hormone levels are related to fledging success at the individual or pair level. We found no significant relationship between hormone levels and nest visit rate or nest defense for either sex. Androgen and corticosterone levels were not correlated within pairs, but pairs in which males exhibited more aggressive nest defense behavior than females were also more different in androgen levels. Females with higher baseline corticosterone levels fledged more young, but hormonal similarity within pairs was not related to fledging success. Our results provide support for the corticosterone-adaptation hypothesis, which suggests that elevation of baseline corticosterone levels may occur during breeding to meet increased energetic demands. PMID- 26972153 TI - Analyzing endocrine system conservation and evolution. AB - Analyzing variation in rates of evolution can provide important insights into the factors that constrain trait evolution, as well as those that promote diversification. Metazoan endocrine systems exhibit apparent variation in evolutionary rates of their constituent components at multiple levels, yet relatively few studies have quantified these patterns and analyzed them in a phylogenetic context. This may be in part due to historical and current data limitations for many endocrine components and taxonomic groups. However, recent technological advancements such as high-throughput sequencing provide the opportunity to collect large-scale comparative data sets for even non-model species. Such ventures will produce a fertile data landscape for evolutionary analyses of nucleic acid and amino acid based endocrine components. Here I summarize evolutionary rate analyses that can be applied to categorical and continuous endocrine traits, and also those for nucleic acid and protein-based components. I emphasize analyses that could be used to test whether other variables (e.g., ecology, ontogenetic timing of expression, etc.) are related to patterns of rate variation and endocrine component diversification. The application of phylogenetic-based rate analyses to comparative endocrine data will greatly enhance our understanding of the factors that have shaped endocrine system evolution. PMID- 26972154 TI - Stress-induced oxytocin release and oxytocin cell number and size in prepubertal and adult male and female rats. AB - Studies indicate that adolescent exposure to stress is a potent environmental factor that contributes to psychological and physiological disorders, though the mechanisms that mediate these dysfunctions are not well understood. Periadolescent animals display greater stress-induced hypothalamic-pituitary adrenal (HPA) axis responses than adults, which may contribute to these vulnerabilities. In addition to the HPA axis, the hypothalamo-neurohypophyseal tract (HNT) is also activated in response to stress. In adults, stress activates this system resulting in secretion of oxytocin from neurons in the supraoptic (SON) and paraventricular (PVN) nuclei. However, it is currently unknown whether a similar or different response occurs in prepubertal animals. Given the influence of these hormones on a variety of emotional behaviors and physiological systems known to change as an animal transitions into adulthood, we investigated stress-induced HPA and HNT hormonal responses before and after stress, as well as the number and size of oxytocin-containing cells in the SON and PVN of prepubertal (30d) and adult (70d) male and female rats. Though we found the well established protracted adrenocorticotropic hormone and corticosterone response in prepubertal males and females, only adult males and prepubertal females showed a significant stress-induced increase in plasma oxytocin levels. Moreover, though we found no pubertal changes in the number of oxytocin cells, we did find a pubertal-related increase in oxytocin somal size in both the SON and PVN of males and females. Taken together, these data indicate that neuroendocrine systems can show different patterns of stress reactivity before and after adolescent development and that these responses can be further modified by sex. Given the impact of these hormones on a variety of systems, it will be imperative to further explore these changes in hormonal stress reactivity and their role in adolescent health. PMID- 26972152 TI - The ecological and physiological bases of variation in the phenology of gonad growth in an urban and desert songbird. AB - Birds often adjust to urban areas by advancing the timing (phenology) of vernal gonad growth. However, the ecological and physiological bases of this adjustment are unclear. We tested whether the habitat-related disparity in gonad growth phenology of male Abert's towhees, Melozone aberti, is due to greater food availability in urban areas of Phoenix, Arizona USA or, alternatively, a habitat related difference in the phenology of key food types. To better understand the physiological mechanism underlying variation in gonad growth phenology, we compared the activity of the reproductive system at all levels of hypothalamo pituitary-gonadal (HPG) axis. We found no habitat-associated difference in food availability (ground arthropod biomass), but, in contrast to the seasonal growth of leaves on desert trees, the leaf foliage of urban trees was already developed at the beginning of our study. Multiple estimates of energetic status did not significantly differ between the non-urban and urban towhees during three years that differed in the habitat-related disparity in gonad growth and winter precipitation levels. Thus, our results provide no support for the hypothesis that greater food abundance in urban areas of Phoenix drives the habitat-related disparity in gonad growth phenology in Abert's towhees. By contrast, they suggest that differences in the predictability and magnitude of change in food availability between urban and desert areas of Phoenix contribute to the observed habitat-related disparity in gonad growth. Endocrine responsiveness of the gonads may contribute to this phenomenon as desert - but not urban - towhees had a marked plasma testosterone response to GnRH challenge. PMID- 26972155 TI - Successful xenogeneic germ cell transplantation from Jundia catfish (Rhamdia quelen) into adult Nile tilapia (Oreochromis niloticus) testes. AB - Fish germ cell transplantation presents several important potential applications for aquaculture, including the preservation of germplasm from endangered fish species with high genetic and commercial values. Using this technique in studies developed in our laboratory with adult male Nile tilapias (Oreochromis niloticus), all the necessary procedures were successfully established, allowing the production of functional sperm and healthy progeny approximately 2months after allogeneic transplantation. In the present study, we evaluated the viability of the adult Nile tilapia testis to generate sperm after xenogeneic transplant of germ cells from sexually mature Jundia catfish (Rhamdia quelen) that belong to a different taxonomic order. Therefore, in order to investigate at different time-periods post-transplantation, the presence and development of donor PKH26 labeled catfish germ cells were followed in the tilapia seminiferous tubules. From 7 to 20days post-transplantation, only PKH26 labeled spermatogonia were observed, whereas spermatocytes at different stages of development were found at 70days. Germ cell transplantation success and progression of spermatogenesis were indicated by the presence of labeled PKH26 spermatids and sperm on days 90 and 120 post-transplantation, respectively. Confirming the presence of the catfish genetic material in the tilapia testis, all recipient tilapias evaluated (n=8) showed the genetic markers evaluated. Therefore, we demonstrated for the first time that the adult Nile tilapia testis offers the functional conditions for development of spermatogenesis with sperm production from a fish species belonging to a different order, which provides an important new venue for aquaculture advancement. PMID- 26972157 TI - Osseous genioplasty in conjunction with bimaxillary orthognathic surgery: a review of 262 consecutive cases. AB - The purpose of this study was to evaluate the results of osseous genioplasty with bimaxillary orthognathic surgery. A retrospective consecutive case series of patients treated by a single surgeon between 2004 and 2013 was studied. All underwent Le Fort I, sagittal ramus osteotomies, septoplasty, inferior turbinate reduction, and osseous genioplasty. The outcome variables included the presenting chin dysmorphology, complications, and assessment of morphologic change. A Steiner analysis was completed for each subject's interval cephalogram. Two hundred sixty-two subjects met the inclusion criteria. Their mean age at operation was 25 (range 13-63) years. Chin osteotomy complications included one wound infection (0.4%), and two of the 1572 mandibular anterior teeth at risk sustained a pulpal injury. None of the subjects required revision. For subjects undergoing chin advancement, the mean change was +3.5 (range +3 to +6) mm. A majority also underwent counterclockwise rotation of the mandible (62%). For those undergoing chin lengthening, the mean change was +5 (range +3 to +12mm) mm, and for those undergoing vertical shortening, the mean change was -3.5 (range -3 to -7) mm. Osseous genioplasty is confirmed to be a safe method to reshape the chin. When osseous genioplasty is performed in conjunction with bimaxillary orthognathic surgery, only a modest horizontal change is required to achieve the preferred pogonion projection. PMID- 26972158 TI - Relationships among maxillofacial morphologies, bone properties, and bone metabolic markers in patients with jaw deformities. AB - The aim of this study was to determine the relationships among bone properties, bone metabolic markers, and types of jaw deformity. The subjects were 55 female patients with jaw deformities. Skeletal morphology was examined using lateral cephalograms, and the patients were divided into three groups according to the type of anteroposterior skeletal pattern. Serum osteocalcin, bone alkaline phosphatase, and tartrate-resistant acid phosphatase isoform 5b, as well as deoxypyridinoline in urine, were measured as bone metabolic markers. Quantitative ultrasound (QUS) measurements were used to assess bone properties at the calcaneal bone. The bone volume and bone density of the condylar process were measured in 43 patients by computed tomography. There were no significant differences in bone metabolic markers and QUS parameters between the groups, although bone formation and resorption markers tended to be higher in patients with a protrusive mandible. On the other hand, patients with mandibular retrusion had a higher tendency to have small and dense condylar processes. In conclusion, the results suggest that growth depression or a degenerative change in the mandibular condyle is involved in the pathogenesis of mandibular retrusion, although risk factors for progressive condylar resorption were not determined. PMID- 26972160 TI - The effect of direction of force to the craniofacial skeleton on the severity of brain injury in patients with a fronto-basal fracture. AB - The skull base is uniquely positioned to absorb force imparted to the craniofacial skeleton, thereby reducing brain injury. Less well understood is the effect of the direction of force imparted to the craniofacial skeleton on the severity of brain injury. Eighty-one patients from two UK major trauma centres who sustained a fronto-basal fracture were divided into two groups: those struck with predominantly anterior force and those by predominantly lateral force. The first recorded Glasgow Coma Score (GCS), requirement for intubation, and requirement for decompressive craniectomy were used as markers of the severity of brain injury. An average GCS of 5 was found in the lateral group and 14 in the anterior group; this difference was statistically significant (P<0.001). There was an increased need for both intubation and decompressive craniectomy in the lateral group compared to the anterior group (absolute risk difference 46.6% and 15.8%, respectively). These results suggest that the skeletal anatomy of the fronto-basal region influences the severity of head injury. The delicate lattice like structure in the central anterior cranial fossa can act as a crumple zone, absorbing force. Conversely in the lateral aspect of the anterior cranial fossa, there is a lack of collapsible interface, resulting in an increased energy transfer to the brain. PMID- 26972159 TI - Dental extraction without stopping single or dual antiplatelet therapy: results of a retrospective cohort study. AB - The aim of this study was to investigate the incidence of bleeding after dental extraction without stopping antiplatelet therapy. Postoperative bleeding was assessed in a total of 1271 patients who were divided into two groups: a study group comprising 183 patients on antiplatelet therapy (aspirin 125 patients/185 occasions; clopidogrel 42 patients/65 occasions; dual therapy 16 patients/24 occasions) who underwent 548 dental extractions on 274 occasions, and a control group comprising 1088 patients who were not receiving any antiplatelet or anticoagulant therapy and underwent 2487 dental extractions on 1472 occasions. The incidence of postoperative bleeding was higher in the study group (5/274, 1.8%) than in the control group (10/1472, 0.7%), and also in the dual antiplatelet subgroup (1/24, 4.2%) than in the single antiplatelet subgroups (clopidogrel: 2/65, 3.1%; aspirin: 2/185, 1.1%); however, these differences were not significant. Postoperative bleeding was managed successfully by repacking with Gelfoam impregnated with tranexamic acid powder in 12 patients and by resuturing in three of the control patients undergoing extraction of impacted teeth with flap elevation. These findings indicate that there is no need to interrupt antiplatelet drugs before dental extraction. PMID- 26972161 TI - Interlocking polyetheretherketone implant. AB - Polyetheretherketone (PEEK) is a versatile material and is used increasingly for the correction of facial deformity. We have used bespoke implants with an interlocking mechanism to add stability and to facilitate ease of insertion in areas with difficult access. The interlocking mechanism also reduces the need for fixation to segments that are difficult to access. PMID- 26972163 TI - Enhancing diversity in academic neurology: From agnosia to action. AB - Although recent years have seen a rapid increase in the diversity of patient populations and of society in general, individuals who belong to historically disadvantaged groups continue to struggle to achieve fuller representation and success in academic medicine. This is particularly true in academic neurology, where faculty from racial and ethnic minority groups are grossly under represented. Raising awareness of this problem in the field is an important first step toward developing coordinated, strategic approaches to enhancing diversity in neurology. Therefore, the aims of this brief article are to underscore the increasing importance of diversity in neurology, point out some of the specific challenges that face diversity efforts in academic neurology, and suggest strategies that leaders in the field could consider in order to enhance the diversity of neurology departments. Ann Neurol 2016;79:705-708. PMID- 26972164 TI - Intraguild predation between Amblyseius swirskii and two native Chinese predatory mite species and their development on intraguild prey. AB - Amblyseius swirskii, native to the east and southeast Mediterranean region, is a successful biological control agent of whiteflies. In this study, we investigated intraguild predations (IGP) between each stage of A. swirskii and each stage of two Phytoseiid species that occur in China, Amblyseius orientalis and Neoseiulus californicus. When there was no whitefly egg provided as the extraguild prey, IGP between A. swirskii and A. orientalis, and between A. swirskii and N. californicus, was observed in 10 and 20 out of 35 combinations, respectively. When IGP was observed, A. swirskii was the intraguild predator in 70% and 65% cases of A. orientalis and N. californicus predation, respectively. These results suggest that A. swirskii is a more aggressive intraguild predator compared to either A. orientalis or N. californicus. When whitefly eggs were provided as the extraguild prey, IGP between A. swirskii and N. californicus decreased greatly, but no significant decrease of IGP was observed between A. swirskii and A. orientalis. Amblyseius swirskii was able to complete development on both heterospecific predatory mites, and both heterospecific predatory mites completed their development on A. swirskii. Possible impacts that A. swirskii may have on local predatory mite populations in China are discussed. PMID- 26972162 TI - Differential network analysis reveals the genome-wide landscape of estrogen receptor modulation in hormonal cancers. AB - Several mutual information (MI)-based algorithms have been developed to identify dynamic gene-gene and function-function interactions governed by key modulators (genes, proteins, etc.). Due to intensive computation, however, these methods rely heavily on prior knowledge and are limited in genome-wide analysis. We present the modulated gene/gene set interaction (MAGIC) analysis to systematically identify genome-wide modulation of interaction networks. Based on a novel statistical test employing conjugate Fisher transformations of correlation coefficients, MAGIC features fast computation and adaption to variations of clinical cohorts. In simulated datasets MAGIC achieved greatly improved computation efficiency and overall superior performance than the MI based method. We applied MAGIC to construct the estrogen receptor (ER) modulated gene and gene set (representing biological function) interaction networks in breast cancer. Several novel interaction hubs and functional interactions were discovered. ER+ dependent interaction between TGFbeta and NFkappaB was further shown to be associated with patient survival. The findings were verified in independent datasets. Using MAGIC, we also assessed the essential roles of ER modulation in another hormonal cancer, ovarian cancer. Overall, MAGIC is a systematic framework for comprehensively identifying and constructing the modulated interaction networks in a whole-genome landscape. MATLAB implementation of MAGIC is available for academic uses at https://github.com/chiuyc/MAGIC. PMID- 26972166 TI - The phosphorylation of Ser221 in VP2 of mink enteritis virus and its roles in virus amplification. AB - Recent reports have indicated that phosphorylation of capsid proteins plays an important role in virion assemblage. Autonomous parvoviruses are among the smallest known viruses with an ssDNA genome enclosed within an icosahedral capsid. Here, we demonstrate that a structural protein (VP2) of one member, mink enteritis virus (MEV), is phosphorylated at serine-221 (Ser221) in vivo. Mutant viruses containing an S221A non-phosphorylatable alanine substitution, or an S221E glutamic acid substitution to mimic serine phosphorylation, were able to express VP2 but had either limited ability or were unable to propagate in feline F81 cells. We propose a new mechanism whereby VP2 phosphorylation plays an essential role in amplification during MEV infection. PMID- 26972165 TI - Metabolic syndrome, diet and exercise. AB - Polycystic ovary syndrome (PCOS) is associated with a range of metabolic complications including insulin resistance (IR), obesity, dyslipidaemia, hypertension, obstructive sleep apnoea (OSA) and non-alcoholic fatty liver disease. These compound risks result in a high prevalence of metabolic syndrome and possibly increased cardiovascular (CV) disease. As the cardiometabolic risk of PCOS is shared amongst the different diagnostic systems, all women with PCOS should undergo metabolic surveillance though the precise approach differs between guidelines. Lifestyle interventions consisting of increased physical activity and caloric restriction have been shown to improve both metabolic and reproductive outcomes. Pharmacotherapy and bariatric surgery may be considered in resistant metabolic disease. Issues requiring further research include the natural history of PCOS-associated metabolic disease, absolute CV risk and comparative efficacy of lifestyle interventions. PMID- 26972180 TI - The role of fissula ante fenestram in unilateral sudden hearing loss. AB - The cause of unilateral sudden sensorineural hearing loss (SNHL) remains unclear in many clinical cases. Perilymphatic leakage through a fissula ante fenestram (FAF) fistula is one possible reason. We present four clinical cases with proven FAF fistula, discovered during surgical exploration. All patients experienced partial hearing recovery after surgical coverage of the fistula. We suggest FAF as a possible site for perilymphatic leakage, representing an anatomical correlate for sudden unilateral SNHL. We recommend early exploratory tympanotomy with special attention to the bony region, anterior to the oval window, in cases of severe sudden SNHL and suspected FAF. PMID- 26972181 TI - Development of absolute quantification method for genotype-specific Babesia microti using real-time PCR and practical experimental tips of real-time PCR. AB - Babesia microti, a rodent babesia, is known as a pathogen of zoonosis, human babesiosis, is composed of several genotypes of small subunit ribosomal RNA gene (SSUrDNA) and different genotypes have been suggested to have different infectivity and pathogenicity to humans. We established a real-time PCR assay using SYBR Green I, which allows specific detection and absolute quantification for each SSUrDNA-type-B. microti of four SSUrDNA-types found in Japanese rodents even in mixed infection. In this assay, four genotype-specific primer pairs targeted on internal transcribed spacer 1 or 2 sequences were used. Primer pairs have the characteristics for a high specificity for homologous genotype DNA. The calibration curves of cycle threshold (Ct) values versus log concentrations of DNA for all four genotypes were linear over 107 fold range of DNA concentrations with correlation coefficient from 0.95 to 1 and sufficient amplification efficiency from 90% to 110%. The standard curves for all four genotypes were not changed even in the presence of heterologous DNA. In this paper, we introduce how to establish and perform the genotype-specific real-time PCR and our practical experimental tips to be recommended. PMID- 26972182 TI - Urinothorax as an early sign of urinary tract injury following total laparoscopic hysterectomy. PMID- 26972179 TI - Kras is Required for Adult Hematopoiesis. AB - Previous studies indicate that Kras is dispensable for fetal liver hematopoiesis, but its role in adult hematopoiesis remains unclear. Here, we generated a Kras conditional knockout allele to address this question. Deletion of Kras in adult bone marrow (BM) is mediated by Vav-Cre or inducible Mx1-Cre. We find that loss of Kras leads to greatly reduced thrombopoietin (TPO) signaling in hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), while stem cell factor evoked ERK1/2 activation is not affected. The compromised TPO signaling is associated with reduced long term- and intermediate-term HSC compartments and a bias toward myeloid differentiation in MPPs. Although granulocyte macrophage colony-stimulating factor (GM-CSF)-evoked ERK1/2 activation is only moderately decreased in Kras(-/-) myeloid progenitors, it is blunted in neutrophils and neutrophil survival is significantly reduced in vitro. At 9-12 months old, Kras conditional knockout mice develop profound hematopoietic defects, including splenomegaly, an expanded neutrophil compartment, and reduced B cell number. In a serial transplantation assay, the reconstitution potential of Kras(-/-) BM cells is greatly compromised, which is attributable to defects in the self-renewal of Kras(-/-) HSCs and defects in differentiated hematopoietic cells. Our results demonstrate that Kras is a major regulator of TPO and GM-CSF signaling in specific populations of hematopoietic cells and its function is required for adult hematopoiesis. Stem Cells 2016;34:1859-1871. PMID- 26972183 TI - Assessing ethical and peer review standards of medical journals. PMID- 26972184 TI - [Not Available]. PMID- 26972185 TI - Stressed skin?--a molecular psychosomatic update on stress-causes and effects in dermatologic diseases. AB - A pathogenetically relevant link between stress, in terms of psychosocial stress, and disease was first described in the 1970s, when it was proven that viral diseases of mucous membranes (such as rhinovirus and Coxsackie virus infections) develop faster and more severe after stress exposure. Since then, there has been an annual increase in the number of publications which investigate this relationship and break it down to the molecular level. Nevertheless, the evidences for the impact of psychosocial stress on chronic inflammatory skin diseases and skin tumors are hardly known. In the present review, we outline current insights into epidemiology, psychoneuroimmunology, and molecular psychosomatics which demonstrate the manifold disease-relevant interactions between the endocrine, nervous, and immune systems. The focus is on stress induced shifts in immune balance in exemplary disorders such as atopic dermatitis, psoriasis, and malignant melanoma. The objective of this article is to convey basic psychosomatic knowledge with respect to etiology, symptomatology, and therapeutic options for chronic skin diseases. Particular attention is directed towards the underlying molecular relationships, both from a somatic to mental as well as a mental to somatic perspective. PMID- 26972187 TI - Sezary syndrome: old enigmas, new targets. AB - Sezary syndrome, the leukemic variant of cutaneous T-cell lymphoma, is still an enigmatic disease with a fatal prognosis. Recent research, however, has identified a multitude of dysregulated molecular pathways that contribute to malignant transformation and therapy resistance of Sezary cells (SC). With respect to T-cell development, SC either represent naive T cells, T effector memory or T central memory cells. Functionally, SC may differentiate into Th2, Treg, or even Th17 cells. Despite their plasticity, SC express characteristic diagnostic marker proteins including CD158k, CD164, FcRL3, and PD-1 as well as skin-homing receptors such as CLA and CCR4. Already tested in (pre)clinical trials, CD158k, PD-1, CTLA-4, and CCR4 also represent promising therapeutic targets. Molecular alterations in SC include transcription factors such as STAT3, 4, and 5, as well as TWIST1 and TOX. TWIST1 induces expression of DNM3os containing the miR-199a2/214 cluster, a key hub controlling multiple cancer networks. In addition, activation of NFkappaB and the MAPK pathway as well as altered TCR signaling cause apoptosis resistance. Recently, whole genome and exome sequencing has revealed somatic copy number variations as predominant mutations in SC, primarily affecting apoptosis, NFkappaB signaling, DNA integrity, and T-cell activation. In order to facilitate development of novel therapies, improved in vivo models, which better reflect the pathogenesis and clinical course of Sezary syndrome, are currently being generated. PMID- 26972189 TI - Prophylaxis in hereditary angioedema (HAE) with C1 inhibitor deficiency. AB - Hereditary angioedema (HAE) is a rare congenital disorder characterized by recurrent episodes of subcutaneous or submucosal edema. Laryngeal manifestations can be life-threatening. In the majority of cases, the disease can be adequately treated with an on-demand approach--in some cases, however, short- or long-term prophylaxis is indicated. Attenuated androgens used to be the drugs of choice, but they are associated with considerable side effects and no longer commercially available in the German-speaking countries of the EU. They are currently being replaced by more effective and more tolerable agents such C1-inhibitors, the kallikrein inhibitor ecallantide, and the B2 receptor antagonist icatibant, which have recently obtained market authorization. These new drugs have had a major impact, especially on the indications and procedures for long-term prophylaxis. According to the most recent international consensus papers and our own experience, self-administered C1-inhibitors are now the first option for long term prophylactic therapy. The decision for prophylaxis should no longer be based on single parameters such as the frequency of attacks but on adequate overall disease control including quality of life. More drugs are currently being developed, which may lead to further changes in the treatment algorithms of HAE. PMID- 26972191 TI - Cofactors and comorbidities of necrobiosis lipoidica: analysis of the German DRG data from 2012. AB - BACKGROUND: Necrobiosis lipoidica (NL) is a rare granulomatous inflammatory skin disease of unknown pathophysiology. Its potential association with diabetes mellitus is well known. Other relevant cofactors and comorbidities are subject to controversial debate. PATIENTS AND METHODS: DRG (diagnosis-related groups) data of all inpatients with a coded primary or secondary diagnosis of NL treated at German hospitals in 2012 were evaluated. RESULTS: Data of 262 inpatient cases with the primary or secondary diagnosis of NL were analyzed. Women (63.4%; n = 166) were nearly twice as frequently affected as men (36.2%; n = 96). Most NL patients (14.8%) were in the age group between 50 and 55 years. Among comorbidities included in the metabolic syndrome complex, diabetes mellitus was the most common (34.4%; IDDM 20.6%, NIDDM 13.8%), while essential hypertension was observed in 9.2%, obesity in 4.6%, chronic heart failure in 4.1%, and dyslipidemias in 2.3% of cases. Leg ulcers were diagnosed in 7.3% of individuals; other venous disorders, in 5.7%. CONCLUSIONS: Our data analysis describes one of the largest compilations of patient cases with the diagnosis of NL worldwide. Besides the well-known association with diabetes mellitus, there are numerous other potentially relevant cofactors and comorbidities that should be considered in the diagnosis and management of NL patients. PMID- 26972195 TI - Erythematous patches and pretibial ulcers: an uncommon presentation of cutaneous sarcoidosis. PMID- 26972194 TI - Treatment of erosive oral lichen planus with methotrexate. AB - BACKGROUND AND OBJECTIVES: Erosive oral lichen planus (EOLP) is a chronic inflammatory disease of the oral mucosa causing significant pain and impairment of the quality of life. No immediate and definitive cure is available, especially in its chronic and most recalcitrant forms. The objective of this study was to evaluate the efficacy of methotrexate treatment in EOLP. PATIENTS AND METHODS: A prospective open trial of oral methotrexate 15 mg QWK in 18 patients with EOLP (clinically and histopathologically confirmed) unresponsive to at least one previous topical or systemic medication. DURATION: Twelve weeks followed by twelve weeks of follow-up. RESULTS: Partial response or better was achieved in 15 (83.3%) patients. A statistically significant reduction in Thongprasom scale score was observed (mean value 5 at baseline, 3.08 +/- 1.11 at week 12, 2.94 +/- 0.97 at week 24, P value < 0.001). A statistically significant reduction was noted in the pain visual analogue scale (mean value 6.55 +/- 2.33 at baseline, 2.46 +/- 2.18 at week 12, 2.29 +/- 1.93 at week 24, P value < 0.001). Adverse events occurred in four (22.2%) patients, requiring discontinuation of treatment in one patient. CONCLUSION: Methotrexate is a valuable therapeutic option in longstanding recalcitrant EOLP, particularly with respect to the improvement of subjective symptoms. Randomized controlled trials are required. PMID- 26972199 TI - Streaky, whiplash-like erythema and succulent papules: flagellate dermatitis following consumption of Auricularia auricula-judae. PMID- 26972200 TI - Vemurafenib-induced granuloma annulare. PMID- 26972203 TI - Authors' reply. PMID- 26972202 TI - A fight towards better understanding of acne. PMID- 26972205 TI - Rash with systemic symptoms. PMID- 26972207 TI - A subclavicular dark-red patch with recent spontaneous hemorrhage and severe pain in a 24-year-old woman. PMID- 26972208 TI - Reconstruction of the upper eyelid: full-thickness skin grafting between the same contralateral aesthetic units. PMID- 26972212 TI - [Not Available]. PMID- 26972210 TI - Guidelines on dermatomyositis--excerpt from the interdisciplinary S2k guidelines on myositis syndromes by the German Society of Neurology. AB - The present guidelines on dermatomyositis (DM) represent an excerpt from the interdisciplinary S2k guidelines on myositis syndromes of the German Society of Neurology (available at www.awmf.org). The cardinal symptom of myositis in DM is symmetrical proximal muscle weakness. Elevated creatine kinase, CRP or ESR as well as electromyography and muscle biopsy also provide important diagnostic clues. Pharyngeal, respiratory, cardiac, and neck muscles may also be affected. Given that approximately 30% of patients also develop interstitial lung disease, pulmonary function tests should be part of the diagnostic workup. Although the cutaneous manifestations in DM are variable, taken together, they represent a characteristic and crucial diagnostic criterion for DM. Approximately 5-20% of individuals exhibit typical skin lesions without any clinically manifest muscle involvement (amyopathic DM). About 30% of adult DM cases are associated with a malignancy. This fact, however, should not delay the treatment of severe myositis. Corticosteroids are the therapy of choice in myositis (1-2 mg/kg). Additional immunosuppressive therapy is frequently required (azathioprine, for children methotrexate). In case of insufficient therapeutic response, the use of intravenous immunoglobulins is justified. The benefit of rituximab has not been conclusively ascertained yet. Acute therapeutic management is usually followed by low-dose maintenance therapy for one to three years. Skin lesions do not always respond sufficiently to myositis therapy. Effective treatment for such cases consists of topical corticosteroids and sometimes also calcineurin inhibitors. Systemic therapies shown to be effective include antimalarial agents (also in combination), methotrexate, and corticosteroids. Intravenous immunoglobulins or rituximab may also be helpful. UV protection is an important prophylactic measure. PMID- 26972216 TI - [Not Available]. PMID- 26972218 TI - In vivo features of Fox-Fordyce disease in high-definition optical coherence tomography. PMID- 26972221 TI - The arginine methyltransferase PRMT5 regulates CIITA-dependent MHC II transcription. AB - Class II major histocompatibility complex (MHC II) dependent antigen presentation serves as a key step in mammalian adaptive immunity and host defense. In antigen presenting cells (e.g., macrophages), MHC II transcription can be activated by interferon gamma (IFN-gamma) and mediated by class II transactivator (CIITA). The underlying epigenetic mechanism, however, is not completely understood. Here we report that following IFN-gamma stimulation, symmetrically dimethylated histone H3 arginine 2 (H3R2Me2s) accumulated on the MHC II promoter along with CIITA. IFN gamma augmented expression, nuclear translocation, and promoter binding of the protein arginine methyltransferase PRMT5 in macrophages. Over-expression of PRMT5 potentiated IFN-gamma induced activation of MHC II transcription in an enzyme activity-dependent manner. In contrast, PRMT5 silencing or inhibition of PRMT5 activity by methylthioadenosine (MTA) suppressed MHC II transactivation by IFN gamma. CIITA interacted with and recruited PRMT5 to the MHC II promoter and mediated the synergy between PRMT5 and ASH2/WDR5 to activate MHC II transcription. PRMT5 expression was down-regulated in senescent and H2O2-treated macrophages rendering ineffectual induction of MHC II transcription by IFN-gamma. Taken together, our data reveal a pathophysiologically relevant role for PRMT5 in MHC II transactivation in macrophages. PMID- 26972223 TI - An update on ocular adnexal lymphoma. AB - Ocular adnexal lymphoma (OAL) is a relatively common lesion in the practice of ophthalmic oncology. Although OALs are usually primary tumors, secondary involvement of the ocular adnexae by systemic lymphoma is also possible. The clinical and radiological features of OAL are non-specific. Thorough morphological evaluation, aided by immunostaining, cytogenetic studies and molecular testing, are necessary for accurate diagnosis. PMID- 26972222 TI - Noninvasive diagnosis of nonalcoholic fatty liver disease: Are we there yet? AB - Nonalcoholic fatty liver disease (NAFLD) has rapidly become the most common form of chronic liver disease in the United States affecting approximately 80-100 million Americans. NAFLD includes a spectrum of diseases ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) to fibrosis and eventually cirrhosis. Patients with NASH and significant fibrosis on liver biopsy have an increased risk for liver-related morbidity and mortality compared to those with NAFL. Due to the high prevalence of NAFLD and its progressive nature, there has been an urgent need to develop reliable noninvasive tests that can accurately predict the presence of advanced disease without the need for liver biopsy. These tests can be divided into those that predict the presence of NASH and those that predict the presence of fibrosis. In this review, we provide a concise overview of different noninvasive methods for staging the severity of NAFLD. PMID- 26972224 TI - Uveal melanoma. AB - Uveal melanoma is the most common primary intraocular malignancy in adults. It is associated with a high rate of distant tumor spread and consequent mortality. Unlike retinoblastoma, for which treatment advances over the last few decades have resulted in a dramatic improvement in survival, outcomes for patients with uveal melanoma remain unchanged. Despite improvement in local control of this tumor, roughly 50% of patients develop metastatic disease within 15 years. Delays in diagnosis and marked vascularity of this tumor may underlie that situation. Tumor size, location, histopathologic appearance, cytogenetic abnormalities, and molecular profiling are used in prognostication. The revised 7th edition of the American Joint Committee on Cancer (AJCC) manual has presented new information that may improve that process as well. Herein, we review current knowledge on uveal melanoma. PMID- 26972226 TI - Lack of transmission of murine norovirus to mice via in vitro fertilization, intracytoplasmic sperm injection, and ovary transplantation. AB - Since its discovery in 2003, murine norovirus (MNV) is still endemic in many rodent animal facilities. Our aim was to determine the risk of transmission of MNV (91% homology to MNV3) to embryo recipients and pups via assisted reproductive technologies, especially those which compromise the integrity of the zona pellucida. In vitro fertilization (IVF), assisted in vitro fertilization (AIVF) with reduced glutathione, intracytoplasmic sperm injection, and ovary transplantation were performed. Murine norovirus was detected by qualitative and quantitative reverse transcription polymerase chain reaction. After natural infection of immunocompetent C57BL/6NTacCnrm and immunodeficient athymic nude mice with MNV, the mesenteric lymph nodes, small intestine, spleen, liver, lung, brain, ovary, and testis were infected at specific intervals for more than a 1 year period. At Week 12, the number of viral genomes per milligram of gonad from both strains was 20 to 50. Murine norovirus strictly adhered to spermatozoa collected from infected mice because three washes did not remove MNV from the sperm. After using MNV-positive sperm for IVF, AIVF, and intracytoplasmic sperm injection, 27 to 30 genomes were detected in IVF (n = 100) and AIVF (n = 100) embryos from both mouse strains. Approximately 87% of MNV detected in these embryos was found in the zona pellucida. However, all embryo transfer recipients, pups, and ovary recipients were MNV-negative. The results indicate that manipulation of the germplasm through assisted reproductive technologies did not lead to transmission of MNV to mice. This may be because of the absence of an infectious dose or failure of the MNV strain to replicate effectively in developing embryos and the reproductive tract. PMID- 26972225 TI - Metabolic syndrome in relation to Barrett's esophagus and esophageal adenocarcinoma: Results from a large population-based case-control study in the Clinical Practice Research Datalink. AB - Gastroesophageal reflux disease (GERD) causes local chronic inflammation that increases risks of Barrett's esophagus (BE) and esophageal adenocarcinoma (EA), yet symptomatic GERD is absent in approximately half of all such patients. Obesity exacerbates GERD and is also a component of metabolic syndrome (MetS). We evaluated the hypothesis that MetS is a GERD-independent mechanism by which obesity is associated with increased risks of BE and EA using data from the UK Clinical Practice Research Datalink. BE cases (n=10,215) and EA cases (n=592) were each individually matched to five population controls based on age, sex, and general practice. MetS was defined as occurrence of at least three of the following: obesity, type 2 diabetes, hypertension, and high cholesterol. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. MetS was marginally associated with BE (OR=1.12, 95%CI 1.00 1.25). Similar effects were found for the individual component factors of obesity, hypertension, and high cholesterol. History of GERD modified the association (P-effect modification <1E-5), with the MetS-BE association confined to patients without a history of GERD (OR=1.33, 95%CI 1.12-1.58). No association between MetS and risk of EA was detected in the main or stratified analyses. In this large population-based case-control study, individuals with MetS had a marginally increased risk of BE in the absence of GERD. The systemic inflammatory state (MetS) may represent a reflux-independent inflammatory pathway that increases the risk of BE. MetS did not increase risk of EA in this study population. PMID- 26972228 TI - Antiviral phenolics from the leaves of Cleistocalyx operculatus. AB - During the screening program for anti-influenza agents from medicinal plants, the ethanolic extract of Cleistocalyx operculatus leaves was found to exhibit potential neuraminidase (NA) inhibitory activity. Bioassay-directed fractionation led to the isolation of two new acetophenones (1 and 2) and one new flavanone (3), along with six known compounds (4-9). The structures of all isolated compounds were elucidated using various spectroscopic methods and through comparison with the previous literature. Compounds 6 and 8 exhibited strong enzymatic inhibition on various neuraminidases from different influenza viruses, including H1N1, H9N2, novel H1N1, and oseltamivir-resistant novel H1N1 (H274Y mutation) expressed in HEK293 cells (IC50 values ranging from 5.07 +/- 0.94 MUM to 9.34 +/- 2.52 MUM, respectively). Kinetic experiments revealed the non competitive inhibitory mode of both compounds 6 and 8. Furthermore, these flavonoids reduced the cytopathic effect of the H1N1 virus in MDCK cells. The present study suggests the potential of two flavonoids (6 and 8) as new lead compounds for the development of novel NA inhibitors in the future. PMID- 26972227 TI - Rituximab-Induced Splenic Rupture and Cytokine Release. AB - BACKGROUND: Rituximab is a therapeutic monoclonal antibody that is used for many different lymphomas. Post-marketing surveillance has revealed that the risk of fatal reaction with rituximab use is extremely low. Splenic rupture and cytokine release syndrome are rare fatal adverse events related to the use of therapeutic monoclonal antibodies, especially in aggressive malignancies with high tumor burden. CASE REPORT: A 55-year-old woman presented with abdominal pain and type B symptoms and was diagnosed with mantle cell lymphoma. Initial peripheral blood flow cytometry showed findings that mimicked features of chronic lymphocytic leukemia. Further treatment with rituximab led to catastrophic treatment complications that proved to be fatal for the patient. CONCLUSIONS: Severe cytokine release syndrome associated with biologics carries a very high morbidity and case fatality rate. With this case report we aim to present the diagnostic challenge with small B-cell neoplasms, especially mantle cell lymphoma and chronic lymphocytic lymphomas, and underscore the importance of thorough risk assessment for reactions prior to treatment initiation. PMID- 26972229 TI - What is the Future of Pediatric Neurology in Canada? Resident and Faculty Perceptions of Training and Workforce Issues. AB - BACKGROUND: Pediatric neurology trainee numbers have grown considerably in Canada; recent research, however, has shown that the number of pediatric neurology graduates is outpacing the need for future pediatric neurologists. The purpose of this study was to seek the opinion of pediatric neurology program directors and trainees regarding possible solutions for this issue. METHODS: Two focus groups were convened during the Canadian Neurological Sciences Federation annual congress in June 2012; one consisted of current and former program directors, and the other of current pediatric neurology trainees. Groups were asked for their perceptions regarding child neurology manpower issues in Canada as well as possible solutions. Focus groups were audio-recorded and transcribed for analysis. Theme-based qualitative analysis was used to analyze the transcripts. RESULTS: Major themes emerging from both focus groups included the emphasis on community pediatric neurology as a viable option for trainees, including the need for community mentors; recognizing the needs of underserviced areas; and establishing academic positions for community preceptors. The need for career mentoring and support structures during residency training was another major theme which arose. Program directors and trainees also gave examples of ways to reduce the current oversupply of trainees in Canada, including limiting the number of trainees entering programs, as well as creating a long-term vision of child neurology in Canada. CONCLUSIONS: A nationwide dialogue to discuss the supply and demand of manpower in academic and community pediatric neurology is essential. Career guidance options for pediatric neurology trainees across the country merit further strengthening. PMID- 26972230 TI - Probing the self-assembly and stability of oligohistidine based rod-like micelles by aggregation induced luminescence. AB - The synthesis and self-assembly of a new C2-symmetric oligohistidine amphiphile equipped with an aggregation induced emission luminophore is reported. We observe the formation of highly stable and ordered rod-like micelles in phosphate buffered saline, with a critical aggregation concentration below 200 nM. Aggregation induced emission of the luminophore confirms the high stability of the anisotropic assemblies in serum. PMID- 26972231 TI - Associations Between Alcohol Consumption and Leukocyte Telomere Length Modified by a Common Polymorphism of ALDH2. AB - BACKGROUND: Data on the association between alcohol consumption and telomere length, a marker of biological aging, are inconsistent. Moreover, the genetic modification of this association has been reported only rarely. To evaluate the association between alcohol consumption and leukocyte telomere length (LTL), and the effect modification of this association by a common polymorphism of the aldehyde dehydrogenase 2 (ALDH2) gene, we conducted a cross-sectional study in a general population including 1,771 middle-aged and elderly Koreans, aged 49 to 79 years. METHODS: Study participants provided blood samples between 2011 and 2012 for the LTL assay, and between 2001 and 2002 for genomewide genotyping. Between 2011 and 2012, they also completed a questionnaire-based interview regarding their alcohol consumption. We examined effect modification by rs2074356, a surrogate marker of the ALDH2 polymorphism. RESULTS: Heavy alcohol consumption (average daily alcohol consumption of >30 g) was inversely associated with LTL only among carriers of the mutant alleles (CT and TT) of rs2074356 (p < 0.01). Among these subjects, elderly drinkers in particular showed the strongest association (p < 0.001). Light-to-moderate alcohol consumption on an almost daily basis was positively associated with LTL (p < 0.001), and this association was significant among carriers of the wild-type allele (CC) of rs2074356 (p < 0.01) but not among those with the mutant alleles. CONCLUSIONS: Our findings suggest that the potential benefit of light-to-moderate alcohol consumption and the detriment of heavy alcohol consumption on biological aging may depend on ALDH2 polymorphism. PMID- 26972232 TI - The structure of chromophore-grafted amyloid-beta(12-28) dimers in the gas-phase: FRET-experiment guided modelling. AB - We present theoretical modelling, ion mobility spectrometry and action-FRET experiments for chromophore-grafted amyloid-beta(12-28) dimers. A first principles global minimum search based on replica-exchange molecular dynamics (REMD) leads to a compact structure with strong interstrand interactions. We use REMD with a distance restraint that implements an adaptive effective bias upon average FRET-efficiencies and thus guides the sampling by the action-FRET measurement. This procedure leads to a pair of weakly interacting peptides. Ion mobility confirms that the weakly interacting structure and not the global minimum with strongly interacting peptides is populated in the experiment. The presence of a high energy barrier between the two structural families, as evidenced from the MD data, suggests that a kinetically trapped structure is observed in the experiment. PMID- 26972234 TI - Health--an explicit human right. PMID- 26972233 TI - The Role of Reactive Oxygen and Nitrogen Species in the Expression and Splicing of Nitric Oxide Receptor. AB - SIGNIFICANCE: Nitric oxide (NO)-dependent signaling is critical to many cellular functions and physiological processes. Soluble guanylyl cyclase (sGC) acts as an NO receptor and mediates the majority of NO functions. The signaling between NO and sGC is strongly altered by reactive oxygen and nitrogen species. Recent Advances: Besides NO scavenging, sGC is affected by oxidation/loss of sGC heme, oxidation, or nitrosation of cysteine residues and phosphorylation. Apo-sGC or sGC containing oxidized heme is targeted for degradation. sGC transcription and the stability of sGC mRNA are also affected by oxidative stress. CRITICAL ISSUES: Studies cited in this review suggest the existence of compensatory processes that adapt cellular processes to diminished sGC function under conditions of short term or moderate oxidative stress. Alternative splicing of sGC transcripts is discussed as a mechanism with the potential to both enhance and reduce sGC function. The expression of alpha1 isoform B, a functional and stable splice variant of human alpha1 sGC subunit, is proposed as one of such compensatory mechanisms. The expression of dysfunctional splice isoforms is discussed as a contributor to decreased sGC function in vascular disease. FUTURE DIRECTIONS: Targeting the process of sGC splicing may be an important approach to maintain the composition of sGC transcripts that are expressed in healthy tissues under normal conditions. Emerging new strategies that allow for targeted manipulations of RNA splicing offer opportunities to use this approach as a preventive measure and to control the composition of sGC splice isoforms. Rational management of expressed sGC splice forms may be a valuable complementary treatment strategy for existing sGC-directed therapies. Antioxid. Redox Signal. 26, 122-136. PMID- 26972235 TI - UKCTOCS and the evaluation of screening for ovarian cancer. PMID- 26972236 TI - Iran: promises and prospects for health. PMID- 26972238 TI - TPP: trade-offs for health behind closed doors. PMID- 26972239 TI - Severe drought in Zimbabwe triggers food crisis. PMID- 26972240 TI - Kathy Niakan: at the forefront of gene editing in embryos. PMID- 26972241 TI - Biomedical research in Latin America: we can do more. PMID- 26972242 TI - Chronic diseases--the social justice issue of our time. PMID- 26972243 TI - Chronic diseases--the social justice issue of our time. PMID- 26972244 TI - PEPFAR: is 90-90-90 magical thinking? PMID- 26972245 TI - Prolonged pyrexia and subtle skin lesions: polyarteritis nodosa. PMID- 26972246 TI - The art of managing medical uncertainty. PMID- 26972247 TI - Disseminated tuberculosis with acute respiratory distress syndrome lacking granuloma formation in the lung. AB - A 66-year-old woman, who had been treated with systemic corticosteroids for four months for vasculitis of unknown etiology, was referred to our department due to a fever, dyspnea and patchy ground-glass opacities on chest computed tomography. As transbronchial biopsy specimens were suggestive of interstitial pneumonia, the prescribed dose of corticosteroids was increased. However, the patient developed pyrexia and presented diffuse ground-glass attenuation in the lungs bilaterally. Antituberculous drugs were administered because a previous blood interferon-gamma release assay was positive, however, the patient died of severe respiratory failure within several days, and cultures of her blood, urine and bone marrow posthumously revealed Mycobacterium tuberculosis. An autopsy revealed multiple foci of air-space pneumonia containing numerous acid-fast bacilli without granuloma formation, accompanied by diffuse alveolar damage. An immunosuppressive condition might inhibit air-space pneumonia to become granulomatous inflammation as an initial stage of pulmonary tuberculosis. PMID- 26972249 TI - Solution structure of the 13th C2H2 Zinc Finger of Miz-1. AB - Miz-1 is a BTB/POZ transcription factor that contains 13C2H2 Zinc Finger domains (ZF). Miz-1 transactivates and represses the transcription of a myriad of genes involved in many aspects of the biology of the cell. The detailed molecular interactions through which Miz-1 controls transcription, including its specific DNA binding via its ZF domains, remain to be understood and documented. In our effort to shed light into the structural biology of Miz-1, we have undertaken the determination of the structure of all its ZF and the characterization of their interactions with cognate DNA. The structure of ZF 1 to 10 have already been solved and characterized. Here, we present the structure of the synthetic Miz-1 ZF13 determined by 2D (1)H-(1)H NMR. PMID- 26972248 TI - Coiled-coil forming peptides for the induction of silver nanoparticles. AB - Biopolymers with defined sequence patterns offer an attractive alternative for the formation of silver nanoparticle (AgNP). A set of coiled-coil dimer forming peptides was tested for their AgNP formation ability. Seventeen of those peptides mediated the formation of AgNPs in aqueous solution at neutral pH, while the formation of a coiled-coil dimer inhibited the nanoparticle generation. A QSAR regression model on the relationship between sequence and function suggests that in this peptide type the patterns KXQQ and KXEE are favorable, whereas Ala residues appear to have an inhibitory effect. UV-VIS spectra of the obtained nanoparticles gave a peak at around 420 nm, typical for AgNPs in the size range around 40 nm, which was confirmed by dynamic light scattering and transmission electron microscopy. Peptide-induced AgNPs exhibited good antibacterial activity, even after a 15 min contact time, while they had low toxicity to human cells at the same concentrations. These results show that our designed peptides generate AgNPs with antibacterial activity at mild conditions and might be used for antibacterial coatings. PMID- 26972250 TI - Inhibition of the acetyl lysine-binding pocket of bromodomain and extraterminal domain proteins interferes with adipogenesis. AB - The bromodomain and extraterminal (BET) domain family proteins are epigenetic modulators involved in the reading of acetylated lysine residues. The first BET protein inhibitor to be identified, (+)-JQ1, a thienotriazolo-1, 4-diazapine, binds selectively to the acetyl lysine-binding pocket of BET proteins. We evaluated the impact on adipogenesis of this druggable targeting of chromatin epigenetic readers, by investigating the physiological consequences of epigenetic modifications through targeting proteins binding to chromatin. JQ1 significantly inhibited the differentiation of 3T3-L1 preadipocytes into white and brown adipocytes by down-regulating the expression of genes involved in adipogenesis, particularly those encoding the peroxisome proliferator-activated receptor (PPAR gamma), the CCAAT/enhancer-binding protein (C/EBPalpha) and, STAT5A and B. The expression of a constitutively activated STAT5B mutant did not prevent inhibition by JQ1. Thus, the association of BET/STAT5 is required for adipogenesis but STAT5 transcription activity is not the only target of JQ1. Treatment with JQ1 did not lead to the conversion of white adipose tissue into brown adipose tissue (BAT). BET protein inhibition thus interferes with generation of adipose tissue from progenitors, confirming the importance of the connections between epigenetic mechanisms and specific adipogenic transcription factors. PMID- 26972251 TI - Nicotine induces Nme2-mediated apoptosis in mouse testes. AB - In mouse testes, germ cell apoptosis can be caused by cigarette smoke and lead to declining quality of semen, but the exact molecular mechanisms remain unclear. To evaluate the effects of nicotine exposure on apoptosis during spermatogenesis, we first constructed a nicotine-treated mouse model and detected germ cell apoptosis activity in the testes using the TUNEL method. Then we analyzed the variation of telomere length and telomerase activity by real-time PCR and TRAP-real-time PCR, respectively. Further, we investigated a highly expressed gene, Nme2, in mouse testes after nicotine treatment from our previous results, which has close correlation with the apoptosis activity predicted by bioinformatics. We performed NME2 overexpression in Hela cells to confirm whether telomere length and telomerase activity were regulated by the Nme2 gene. Finally, we examined methylation of CpG islands in the Nme2 promoter with the Bisulfite Sequencing (BSP) method. The results showed that apoptosis had increased significantly, and then telomerase activity became weak. Further, telomere length was shortened in the germ cells among the nicotine-treated group. In Hela cells, both overexpression of the Nme2 gene and nicotine exposure can suppress the activity of telomerase activity and shorten telomere length. BSP results revealed that the Nme2 promoter appeared with low methylation in mouse testes after nicotine treatment. We assume that nicotine-induced apoptosis may be caused by telomerase activity decline, which is inhibited by the up expression of Nme2 because of its hypomethylation in mouse germ cells. PMID- 26972252 TI - Structural characterizations of phage antitoxin Dmd and its interactions with bacterial toxin RnlA. AB - Toxin-antitoxin (TA) loci are widespread in bacteria plasmids and chromosomes, and target various cellular functions to regulate cell growth and death. A type II TA system RnlA-RnlB from Escherichia coli is associated with phage-resistance. After the infection of bacteriophage T4 with Dmd defection, RnlA is activated by the disappearance of RnlB, resulting in the rapid degradation of T4 mRNAs. Dmd can bind to RnlA directly and neutralize RnlA toxicity to allow phage reproduction. Dmd represent a heterogenous antitoxin of RnlA replacing antitoxin RnlB. Here, we reported two structures of Dmd from T4 phage and RB69 phage. Both Dmd structures are high similar with a compacted domain composed of a four stranded anti-parallel beta-sheet and an alpha-helix. Chromatography and SAXS suggest Dmd forms a dimer in solution consistent with that in crystal. Structure based mutagenesis of Dmd reveals key residues involved in RnlA-binding. Possibility cavities in Dmd used for compounds design were modeled. Our structural study revealed the recognition and inhibition mechanism of RnlA by Dmd and providing a potential laboratory phage prevention target for drug design. PMID- 26972253 TI - CMKLR1 deficiency influences glucose tolerance and thermogenesis in mice on high fat diet. AB - Obesity has become a global epidemic disease, contributing to increases in the prevalence of type 2 diabetes. CMKLR1, one of the receptors for chemerin, has a wide range of functions in physiological and pathological activity, including innate and adaptive immunity, inflammation, metabolism and reproduction. In our study, CMKLR1 deficiency did not influence the gain of body weight but did exacerbate glucose intolerance, increase serum insulin level, and promote insulin resistance in mice on high fat diets. The expression of thermogenesis related genes was examined and indicated to decrease in CMKLR1 knockout (KO) mice in both normal and cold environments, which indicated CMKLR1 influence the thermogenesis process. Cold exposure induced significant body mass decrease and improved glucose tolerance and insulin resistance in wild type HFD mice but had no obvious effect on CMKLR1 KO HFD mice. In vitro, loss of CMKLR1 did not significantly influence the differentiation of stromal vascular fibroblasts (SVFs) derived from adipose tissue, but did suppress the expression of thermogenesis related genes. Collectively, these data demonstrate that CMKLR1 deficiency induces inbalance of glucose metabolism and impairs the cold induced-thermogenesis process in high diet models. PMID- 26972255 TI - Modified STAP conditions facilitate bivalent fate decision between pluripotency and apoptosis in Jurkat T-lymphocytes. AB - Low extracellular pH (pHe) is not only the result of cancer metabolism, but a factor of anti-cancer drug efficacy and cancer immunity. In this study, the consequences of acidic stress were evaluated by applying STAP protocol on Jurkat T-lymphocytes (2.0 * 10(6) cells/ml, 25 min in 37 degrees C). We detected apoptotic process exclusively in pH 3.3 treated cells within 8 h with western blotting (WB). This programmed cell death led to significant drop of cell viability in 72 h measured by MTT assay resulting PI positive population on flow cytometry (FCM) at day 7. Quantified RT-PCR (qRT-PCR) data indicated that all of above mentioned responses are irrelevant to expression of OCT4 gene variants. Interestingly enough, pluripotent cells represented by positive alkaline phosphatase (AP) staining survived acidic stress and consequently proportion of AP positive cells was significantly increased after pH 3.3 treatment (day 7). In general, acidic treatment led to an apoptotic condition for Jurkat T-lymphocytes, which occurred independent of OCT4 induction. PMID- 26972254 TI - Cornuside inhibits mast cell-mediated allergic response by down-regulating MAPK and NF-kappaB signaling pathways. AB - AIMS: The present study is to investigate the effect of cornuside on mast cell mediated allergic response, as well as its possible mechanisms of action. METHODS: To test the anti-allergic effects of cornuside in vivo, local extravasation was induced by local injection of anti-dinitrophenyl immunoglobulin E (IgE) followed by intravenous antigenic challenge in passive cutaneous anaphylaxis model rats. Mast cell viability was determined using MTT assay. Histamine content from rat peritoneal mast cells was measured by the radioenzymatic method. To investigate the mechanisms by which cornuside affects the reduction of histamine release, the levels of calcium uptake were measured. To examine whether cornuside affects the expression of pro-inflammatory cytokines, Western blotting and ELISA were carried out. RESULTS: Oral administration of cornuside inhibited passive cutaneous anaphylaxis in rats. Presence of cornuside attenuated IgE-induced histamine release from rat peritoneal mast cells. The inhibitory effect of cornuside on histamine release was mediated by the modulation of intracellular calcium. In addition, cornuside decreased phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187 stimulated production and secretion of pro-inflammatory cytokines such as TNF alpha and IL-6 in human mast cells. The inhibitory effect of cornuside on pro inflammatory cytokines was dependent on nuclear factor-kappaB and p38 mitogen activated protein kinase. CONCLUSIONS: The present study provides evidence that cornuside inhibits mast cell-derived inflammatory allergic reactions by blocking histamine release and pro-inflammatory cytokine expression. Furthermore, in vivo and in vitro anti-allergic effects of cornuside suggest a possible therapeutic application of this agent in inflammatory allergic diseases. PMID- 26972256 TI - Heat shock modulates the subcellular localization, stability, and activity of HIPK2. AB - The homeodomain-interacting protein kinase-2 (HIPK2) is a highly conserved serine/threonine kinase and is involved in transcriptional regulation. HIPK2 is a highly unstable protein, and is kept at a low level under normal physiological conditions. However, exposure of cells to physiological stress - such as hypoxia, oxidative stress, or UV damage - is known to stabilize HIPK2, leading to the HIPK2-dependent activation of p53 and the cell death pathway. Therefore HIPK2 is also known as a stress kinase and as a stress-activated pro-apoptotic factor. We demonstrate here that exposure of cells to heat shock results in the stabilization of HIPK2 and the stabilization is mediated via K63-linked ubiquitination. Intriguingly, a sub-lethal heat shock (42 degrees C, 1 h) results in the cytoplasmic localization of HIPK2, while a lethal heat shock (45 degrees C, 1 h) results in its nuclear localization. Cells exposed to the lethal heat shock showed significantly higher levels of the p53 activity than those exposed to the sub-lethal thermal stress, suggesting that both the level and the nuclear localization are essential for the pro-apoptotic activity of HIPK2 and that the lethal heat shock could retain the HIPK2 in the nucleus to promote the cell death. Taken together our study underscores the importance of HIPK2 in stress mediated cell death, and that the HIPK2 is a generic stress kinase that gets activated by diverse set of physiological stressors. PMID- 26972257 TI - Water Durable Electride Y5Si3: Electronic Structure and Catalytic Activity for Ammonia Synthesis. AB - We report an air and water stable electride Y5Si3 and its catalytic activity for direct ammonia synthesis. It crystallizes in the Mn5Si3-type structure and confines 0.79/f.u. anionic electrons in the quasi-one-dimensional holes. These anionic electrons strongly hybridize with yttrium 4d electrons, giving rise to improved chemical stability. The ammonia synthesis rate using Ru(7.8 wt %)-loaded Y5Si3 was as high as 1.9 mmol/g/h under 0.1 MPa and at 400 degrees C with activation energy of ~50 kJ/mol. Its strong electron-donating ability to Ru metal of Y5Si3 is considered to enhance nitrogen dissociation and reduce the activation energy of ammonia synthesis reaction. Catalytic activity was not suppressed even after Y5Si3, once dipped into water, was used as the catalyst promoter. These findings provide novel insights into the design of simple catalysts for ammonia synthesis. PMID- 26972258 TI - The Evolution of Physical Medicine and Rehabilitation in Sports Medicine. PMID- 26972259 TI - Opening the Black Box: Evaluating the Pediatric Athlete With Elbow Pain. AB - Evaluation and treatment of pediatric elbow injuries in sport can be difficult because of the complex anatomy, evolving bony and cartilaginous composition, and multiple varied forces applied during athletic competition. In addition, youth sports are now putting even greater demands on the elbow of young athletes. It is important to understand the risk factors for injury, age-appropriate conditions affecting the elbow, proper treatment of these conditions, and prevention strategies for elbow injuries in this young athletic population. PMID- 26972260 TI - High-Risk Stress Fractures: Diagnosis and Management. AB - Stress fractures are common overuse injuries in athletes. They occur during periods of increased training without adequate rest, disrupting normal bone reparative mechanisms. There are a host of intrinsic and extrinsic factors, including biochemical and biomechanical, that put athletes at risk. In most stress fractures, the diagnosis is primarily clinical, with imaging indicated at times, and management focused on symptom-free relative rest with advancement of activity as tolerated. Overall, stress fractures in athletes have an excellent prognosis for return to sport, with little risk of complication. There is a subset of injuries that have a greater risk of fracture progression, delayed healing, and nonunion and are generally more challenging to treat with nonoperative care. Specific locations of high-risk stress fracture include the femoral neck (tension side), patella, anterior tibia, medial malleolus, talus, tarsal navicular, proximal fifth metatarsal, and great toe sesamoids. These sites share a characteristic region of high tensile load and low blood flow. High-risk stress fractures require a more aggressive approach to evaluation, with imaging often necessary, to confirm early and accurate diagnosis and initiate immediate treatment. Treatment consists of nonweight-bearing immobilization, often with a prolonged period away from sport, and a more methodic and careful reintroduction to athletic activity. These stress fractures may require surgical intervention. A high index of suspicion is essential to avoid delayed diagnosis and optimize outcomes in this subset of stress fractures. PMID- 26972262 TI - The Evolution of Diagnostic and Interventional Ultrasound in Sports Medicine. AB - Diagnostic and interventional ultrasound is a rapidly evolving field in sports medicine. The use of ultrasound has increased exponentially during the past decades. This imaging modality is appealing to sports medicine physicians because of its broad diagnostic and interventional capabilities. In sports medicine, the indications for diagnostic ultrasound extend well beyond the musculoskeletal realm to include other conditions such as ocular trauma, thoracoabdominal trauma, and cardiac morphology. Thus, the term "sports ultrasound" has been adopted as a more accurate representation of the broad and unique applications of ultrasound in this specialty. Ultrasound-guided procedures also have evolved from the commonly performed joint and tendon sheath injections to include ultrasound guided surgical procedures. This article will discuss the evolution of diagnostic and interventional ultrasound in sports medicine using a case-based approach to highlight its many new applications. PMID- 26972261 TI - The Anti-Doping Movement. AB - Historical reports of doping in sports date as far back as the ancient Greek Olympic Games. The anti-doping community considers doping in sports to be cheating and a violation of the spirit of sport. During the past century, there has been an increasing awareness of the extent of doping in sports and the health risks of doping. In response, the anti-doping movement has endeavored to educate athletes and others about the health risks of doping and promote a level playing field. Doping control is now undertaken in most countries around the world and at most elite sports competitions. As athletes have found new ways to dope, however, the anti-doping community has endeavored to strengthen its educational and deterrence efforts. It is incumbent upon sports medicine professionals to understand the health risks of doping and all doping control processes. PMID- 26972263 TI - Final Comment: Return-to-Play Decision Making: Does Level of Competition Make a Difference? PMID- 26972264 TI - Exercise Testing: Who, When, and Why? AB - There are different modalities of exercise testing that can provide valuable information to physicians about patient and athlete fitness and cardiopulmonary status. Cardiopulmonary exercise testing (CPX) is a form of exercise testing that measures ventilatory and gas exchange, heart rate, electrocardiogram, and blood pressures to provide detailed information on the cardiovascular, pulmonary, and muscular systems. This testing allows an accurate quantification of functional capacity/measure of exercise tolerance, diagnosis of cardiopulmonary disease, disease-progression monitoring or response to intervention, and the prescription of exercise and training. CPX directly measures inhaled and exhaled ventilator gases to determine the maximal oxygen uptake, which reflects the body's maximal use of oxygen and defines the limits of the cardiopulmonary system. CPX is the ideal modality to evaluate causes of exertional fatigue and dyspnea, especially in complex cases in which the etiology could be cardiac, pulmonary, or deconditioning. Exercise tolerance has become an important outcome measure in patients with chronic obstructive pulmonary disease and congestive heart failure, as well as other chronic diseases, and is a well-recognized predictor of mortality. Older athletes or those with underlying medical conditions could benefit from exercise testing for risk stratification and clearance to participate, as well as to help set their training zones and determine their functional limitations. PMID- 26972265 TI - Should Electrocardiograms Be Part of the Preparticipation Physical Examination? PMID- 26972267 TI - Diagnosis and Treatment of Hip Girdle Pain in the Athlete. AB - Evaluation of an athlete's report of "hip pain" is challenging. Many conditions involving the pelvic girdle can present with overlapping pain distributions, and athletes often may have coexisting disorders. Appropriate evaluation requires thorough, systematic consideration of intra-articular hip disease, extra articular local causes of hip pain, and referred pain from other musculoskeletal or even visceral sources. Although our understanding of intra-articular hip disorders has been greatly enhanced in recent decades through advances in hip arthroscopy, gaps still exist in our understanding of appropriate treatment, including effective nonsurgical protocols and when to consider surgical intervention. For instance, we have a better understanding of hip dysfunction related to structural changes that occur prior to the onset of arthritis, but we are also learning that correction of the structural changes does not always guarantee a correction of dysfunction and pain. Furthermore, athletes need instruction and guidance in retraining appropriate movement patterns after a surgical intervention. Risk stratification regarding which athletes need surgical intervention and what their needs are after specific surgical procedures remain undefined. In this review we will describe the differential diagnosis of hip and pelvic girdle pain in the athlete and then discuss how to use a history, physical examination, and appropriate imaging and diagnostic injections to arrive at a proper diagnosis. Lastly, a brief discussion is included of key concepts and controversies involved in treating some of the most common hip disorders experienced by athletes. PMID- 26972266 TI - Is There a Role for Limited Echocardiography During the Preparticipation Physical Examination? AB - Sudden cardiac death (SCD) is the leading cause of death during exercise for athletes younger than 35 years. Structural cardiac abnormalities are responsible for the majority of SCDs among competitive athletes. The screening protocol that is best for detecting athletes at risk for SCD has been the subject of considerable and long-standing debate. The American Heart Association recommends the use of a 14-element history and physical examination (H&P), whereas European standards call for a focused H&P and 12-lead electrocardiogram (ECG). The use of ECG screening has been repeatedly rejected in the United States because of the high rate of false-positive results and an abundance of evidence suggesting that it is a cost-ineffective tool for screening. Attempts have also been made to prescreen athletes for cardiac disease with echocardiography (ECHO) performed by a cardiologist; however, this technique also proved to be cost-ineffective. The use of ECHO performed by a frontline physician reflects recent advancements in ultrasound technology utilization, including the advent of portable ultrasound, and introduces a new, promising screening method to the debate. Portable ECHO by a frontline physician (PEFP) has the ability to directly visualize structural components of the heart that are part of the gold standard ECHO evaluation performed by a cardiologist. The Early Screening for Cardiac Abnormalities with Preparticipation Echocardiography (ESCAPE) protocol developed at Northeastern University is the first attempt to implement the PEFP. Initial inquiries into the reliability and feasibility of the PEFP are promising. Measurements obtained by frontline physicians were not statistically different from those obtained by a cardiologist, focused ECHO was found to reduce the referral rate to cardiology by 33%, and PEFP was completed significantly faster than H&P and an ECG. Early results are encouraging, but continued research to support the widespread use of PEFP for preparticipation examination in all competitive athletes is needed prior to recommending implementation. PMID- 26972268 TI - Exercise-Associated Collapse: Is Hyponatremia in Our Head? AB - Exercise-associated hyponatremia (EAH) is one of the most common causes of exercise-associated collapse. The primary pathogenesis of EAH is largely the result of excessive fluid intake but is influenced by other factors, including hormonal abnormalities (ie, inappropriate arginine vasopressin secretion), renal abnormalities, and mobilization of sodium stores. Early recognition of EAH is crucial to appropriate treatment, because symptoms are varied and may be confused with other causes of exercise-associated collapse. Onsite testing of [Na+] will confirm the diagnosis but is not always available. Rapid treatment of EAH will depend upon the type and severity of symptoms. Treatment protocols range from fluid restriction or oral hypertonic fluids for mild symptoms to intravenous hypertonic fluids for more severe symptoms. Preventative strategies should emphasize fluid consumption based on thirst and athlete/coach/staff education regarding proper hydration practices. PMID- 26972269 TI - The Kinetic Chain Revisited: New Concepts on Throwing Mechanics and Injury. AB - The overhead throwing motion is a complex activity that is achieved through activation of the kinetic chain. The kinetic chain refers to the linkage of multiple segments of the body that allows for transfer of forces and motion. The lower extremities and core provide a base of support, generating energy that is transferred eventually through the throwing arm and hand, resulting in release of the ball. The kinetic chain requires optimal anatomy, physiology, and mechanics and is involved in all 6 phases of overhead throwing: windup, stride, arm cocking, acceleration, deceleration, and follow-through. Breaks or deficits in the kinetic chain can lead to injury or decreased performance. Through an understanding of the mechanics and pathomechanics seen in each phase of throwing, the clinician can better evaluate and screen for potential kinetic chain deficits in the overhead throwing athlete. The purpose of this article is to review the biomechanics of the overhead throwing motion, the role of the kinetic chain in throwing, and the clinical evaluation and management of abnormal throwing mechanics and related injuries. PMID- 26972270 TI - Rehabilitation of the Overhead Throwing Athlete: There Is More to It Than Just External Rotation/Internal Rotation Strengthening. AB - The repetitive nature of throwing manifests characteristic adaptive changes to the shoulder, scapulothoracic, and hip/pelvis complexes that result in a set of unique physical traits in the overhead throwing athlete. An effective rehabilitation program is dependent upon an accurate evaluation and differential diagnosis to determine the causative factors for the athlete's pathologic features. The treatment program should be individualized with specific strengthening and flexibility exercises to achieve the dynamic stability that is required for overhead function. In this article we describe the characteristics of the throwing shoulder, along with a multiphased rehabilitation program that allows for the restoration of strength, mobility, endurance, and power and is aimed toward a return to unrestricted sporting activity. We also describe exercises that link the upper and lower extremities because of the importance of core control and leg strength in the development of power during the act of throwing. Additionally, proper throwing mechanics, utilization of pitch counts, appropriate rest, and proper off-season conditioning will help decrease overall injury risk in the overhead throwing athlete. PMID- 26972271 TI - Lactate: Friend or Foe. AB - Lactic acid has played an important role in the traditional theory of muscle fatigue and limitation of endurance exercise performance. It has been called a waste product of anaerobic metabolism and has been believed to be responsible for the uncomfortable "burn" of intense exercise and directly responsible for the metabolic acidosis of exercise, leading to decreased muscle contractility and ultimately cessation of exercise. Although this premise has been commonly taught, it is not supported by the scientific literature and has led to a great deal of confusion among the sports medicine and exercise science communities. This review will provide the sports medicine clinician with an understanding of contemporary lactate theories, including lactate's role in energy production, its contributions to metabolic acidosis, and its function as an energy substrate for a variety of tissues. Lactate threshold concepts will also be discussed, including a practical approach to understanding prediction of performance and monitoring of training progress based on these parameters. PMID- 26972272 TI - The Role of Controlled Exercise in Concussion Management. AB - Concussion affects the autonomic nervous system and its control of cerebral blood flow, which may be why uncontrolled activity can exacerbate symptoms after concussion. Traditionally, patients have been advised to restrict physical and cognitive activity until all symptoms resolve. However, recent research suggests that prolonged rest beyond the first couple of days after a concussion might hinder rather than aid recovery. Humans do not respond well to removal from their social and physical environments, and sustained rest adversely affects the physiology of concussion and can lead to physical deconditioning and reactive depression. Some animal data show that early forced exercise is detrimental to recovery after concussion, but other animal data show that voluntary exercise is not detrimental to recovery. We developed the Buffalo Concussion Treadmill Test to systematically evaluate exercise tolerance in persons with prolonged symptoms after concussion (ie, more than 4-6 weeks, which is called postconcussion syndrome [PCS]). Using a predetermined stopping criterion (symptom-exacerbation threshold), akin to voluntary exercise in animals, the Buffalo Concussion Treadmill Test is the only functional test known to safely and reliably reveal exercise intolerance in humans with PCS. The test data are used to develop individualized subthreshold exercise treatment programs to restore the physiology to normal and enhance recovery. Return of normal exercise tolerance can then be used to establish physiological recovery from concussion. New research suggests that absolute rest beyond the first few days after concussion may be detrimental to concussion recovery. However, further research is required to determine the appropriate mode, duration, intensity, and frequency of exercise during the acute recovery phase of a concussion prior to making specific exercise recommendations. For patients with PCS, subsymptom threshold exercise improves activity tolerance and is an appropriate treatment option for this patient population. PMID- 26972273 TI - Associations between exposure to viruses and bovine respiratory disease in Australian feedlot cattle. AB - Bovine respiratory disease (BRD) is the most important cause of clinical disease and death in feedlot cattle. Respiratory viral infections are key components in predisposing cattle to the development of this disease. To quantify the contribution of four viruses commonly associated with BRD, a case-control study was conducted nested within the National Bovine Respiratory Disease Initiative project population in Australian feedlot cattle. Effects of exposure to Bovine viral diarrhoea virus 1 (BVDV-1), Bovine herpesvirus 1 (BoHV-1), Bovine respiratory syncytial virus (BRSV) and Bovine parainfluenza virus 3 (BPIV-3), and to combinations of these viruses, were investigated. Based on weighted seroprevalences at induction (when animals were enrolled and initial samples collected), the percentages of the project population estimated to be seropositive were 24% for BoHV-1, 69% for BVDV-1, 89% for BRSV and 91% for BPIV 3. For each of the four viruses, seropositivity at induction was associated with reduced risk of BRD (OR: 0.6-0.9), and seroincrease from induction to second blood sampling (35-60 days after induction) was associated with increased risk of BRD (OR: 1.3-1.5). Compared to animals that were seropositive for all four viruses at induction, animals were at progressively increased risk with increasing number of viruses for which they were seronegative; those seronegative for all four viruses were at greatest risk (OR: 2.4). Animals that seroincreased for one or more viruses from induction to second blood sampling were at increased risk (OR: 1.4-2.1) of BRD compared to animals that did not seroincrease for any viruses. Collectively these results confirm that prior exposure to these viruses is protective while exposure at or after feedlot entry increases the risk of development of BRD in feedlots. However, the modest increases in risk associated with seroincrease for each virus separately, and the progressive increases in risk with multiple viral exposures highlights the importance of concurrent infections in the aetiology of the BRD complex. These findings indicate that, while efficacious vaccines could aid in the control of BRD, vaccination against one of these viruses would not have large effects on population BRD incidence but vaccination against multiple viruses would be expected to result in greater reductions in incidence. The findings also confirm the multifactorial nature of BRD development, and indicate that multifaceted approaches in addition to efficacious vaccines against viruses will be required for substantial reductions in BRD incidence. PMID- 26972274 TI - Acute recovery from exercise in people with multiple sclerosis: an exploratory study on the effect of exercise intensities. AB - Purpose A better understanding of how people with multiple sclerosis (pwMS) recover from exercise may help inform interventions. Methods We explored physiological and perceptual responses following exercise of different intensities, using a crossover exposure-response design, in 14 adults with multiple sclerosis (MS) and 9 controls. A cycling exercise test determined maximum capacity (Wpeak). Participants then performed 20-min exercise sessions relative to Wpeak (random order separated by 7 days): (1) 45% and (2) 60% continuous cycling and (3) 90% intermittent cycling (30 s cycling, 30 s rest). During a 45-min recovery period, tympanic temperature (Temp degrees C), exertion in breathing (RPEbr) and legs (RPEleg), and cortical excitability (MEParea) were measured. Results Eleven pwMS and eight controls completed the study. Controls performed better on the exercise test (p < 0.05), thus more absolute work during subsequent sessions. PwMS took longer to recover RPEleg with recovery time increasing with intensity (45%-6 min; 60%-15 min; 90%-35 min) and correlating with Temp degrees C. MEParea was significantly depressed in both groups at 45% and 60% (p < 0.001), in the MS group this also correlated with RPEleg. Conclusions Feelings of leg exertion may persist after exercise in some pwMS, especially at high intensities. This may relate to body temperature and, after continuous exercise, cortical excitability. These results support considering the recovery period post exercise and provide an insight into potential correlates of post-exercise fatigue. Implications for Rehabilitation A better understanding of how pwMS recover following exercise may help inform exercise prescription a long side fatigue management. This study showed that, in pwMS, the time taken to recover from feelings of leg fatigue increased with the intensity of the exercise session rather that total work performed and was related to increase in body temperature. The results of this relatively small study support the need to consider a recovery period after exercise and provide an insight into potential physiological correlates. PMID- 26972275 TI - Chemodivergent, One-Pot, Multi-Component Synthesis of Pyrroles and Tetrahydropyridines under Solvent- and Catalyst-Free Conditions Using the Grinding Method. AB - A highly efficient, chemoselective synthesis of a library of polysubstituted pyrroles and tetrahydropyridines has been achieved through the one-pot, multicomponent reactions of ethyl (E)-3-(aryl/alkyl amino) acrylates, 2,2 dihydroxy-1-arylethan-1-ones, and malononitrile under solvent- and catalyst-free grinding conditions. The selective formation of pyrrole or tetrahydropyridines relied on substitution of the N-aryl of ethyl (E)-3-(4-arylamino) acrylates. These reactions presumably occurred via a domino Knoevenagel condensation and Michael addition followed by an intramolecular cyclization sequence of reactions in a single transformation. PMID- 26972276 TI - Improved drug delivery and therapeutic efficacy of PEgylated liposomal doxorubicin by targeting anti-HER2 peptide in murine breast tumor model. AB - Targeted cancer therapy is a powerful therapeutic strategy to management of cancer. HER2 as an anticancer target has long been studied. Its overexpression plays an important role in the pathogenesis and progressiveness of breast and other cancers. To establish efficient and reliable drug delivery to HER2 overexpressing cells, the authors of this study have developed anti-HER2 (ErbB2) peptide-liposomal formulations of doxorubicin (DOX) by an engineered breast tumor targeting peptide ligand, AHNP, Anti-HER2/neu peptide, (FCDGFYACYADV) with three glycine amino acids as spacer before its original sequencing. Towards this goal, PEGylated liposome doxorubicin (PLD) bearing different ligand densities of AHNP was prepared and characterized for their size, zeta potential and peptide conjugation. The AHNP functionalization and density effects on breast tumor cell uptake, selective cytotoxicity, prevention of tumor growth and the tissue biodistribution of encapsulated DOX were studied in mice bearing TUBO breast cancer tumor model. The findings demonstrated that increasing the ligand density of AHNP increases cytotoxicity and cell-uptake in SKBR3 and TUBO cells which overexpress HER2 but not in MDA-MB-231with low HER2 expression profile. The anticancer activity was also superior for targeted liposomal DOX with more AHNP densities. Overall, the results showed that optimum AHNP density functionalization of PLD can significantly improve selectivity and the therapeutic index of liposomal DOX in the treatment of HER2 positive breast cancer and merits further investigation. PMID- 26972277 TI - Arcobacter butzleri survives within trophozoite of Acanthamoeba castellanii. AB - The survival of three Arcobacter butzleri strains inside Acanthamoeba castellanii was assessed using axenic cultures of A. castellanii that were inoculated with the tested strains and incubated at 26 degrees C under aerobic conditions for 240h. The behavior of bacteria in contact with amoebae was monitored using phase contrast microscopy. The bacterial survival rate within amoebae was assessed through counting colony forming units, using the gentamicin protection assay. All A. butzleri strains were able to survive during 240h within the amoebae, thus suggesting that (i) A. butzleri resists the amoebic digestion processes at least for the analyzed time; (ii) that A. castellanii could serve as an environmental reservoir for this bacterium, probably acting as a transmission vehicle for A. butzleri. PMID- 26972279 TI - Changes of excitatory and inhibitory neurotransmitters in the colon of rats underwent to the wrap partial restraint stress. AB - BACKGROUND: Animal models proposed to reproduce some of the human irritable bowel syndrome (IBS) symptoms are based on the hypothesis that psychosocial stressors play a pivotal role in the IBS etio-pathology. We investigated the wrap restraint stress (WRS) model with the aim to analyze the morphological changes of the entire colonic wall of these animals that showed some of the human IBS symptoms such as visceral hypersensitivity. METHODS: Male Wistar rats were used and WRS was maintained for 2 h. Abdominal contractions (AC) were recorded in the colon rectum by balloon distension. Fecal pellets were quantitated. Colonic specimens were examined by routine histology, immunohistochemistry and western blot. KEY RESULTS: WRS animals were characterized by: (i) increase in AC number and fecal pellets mean weight; (ii) clusters of mononucleated cells, increase in eosinophilic granulocytes and mast cells in the mucosa; (iii) increase in CGRP immunoreactive (IR) nerve fibers in the lamina propria; (iv) decrease in myenteric NK1r-IR and nNOS-IR neurons and in submucous nNOS-IR neurons; (v) decrease in SP-IR nerve fibers in the muscle wall; (vi) reduction in S100beta-IR glia in the entire colonic wall; (vii) increase in CRF1r-IR myenteric neurons; (viii) no change in ChAT-IR neurons, smooth muscle cells and interstitial cells of Cajal. CONCLUSIONS AND INFERENCES: The present results support the consistency of the WRS as a potential model where part of the human IBS signs and symptoms are reproduced. The changes in glial cells and in excitatory and inhibitory neurotransmitters might represent the substrate for the dysmotility and hypersensitivity. PMID- 26972280 TI - A nonmainstream approach against cancer. AB - The discovery of antibiotics as specific and effective drugs against infectious agents has generated the belief that the famous Paul Erlich theory on magic bullet should be applied to cancer as well. However, after around 60 years of failures in finding a magic bullet against cancer, a question appears mandatory: does the magic bullet against cancer really exist? In trying to understand more on the issue, we propose three discoveries are coming from a nonmainstream approach against cancer. Tumor is acidic, and tumor acidity impairs drugs entering within tumor cells and isolates tumors from the rest of the body. Proton pumps are key in allowing tumor cells to live in the acidic microenvironment. A class of antiacidic drugs, proton pump inhibitors (PPIs), were shown to have a potent anti-tumor effect, through inhibition of proton pumps in tumor cells. PPIs are indeed prodrugs needing acidity to be activated into the active molecule. So they use protonation by H+ as an activating mechanism, while the vast majority of drugs are totally neutralized by protonation. An anti-tumor therapy based on PPI showed to be effective both in vitro and in vivo. Differently from normal cells, cancer cells meet their energy needs in great part by fermentation, and it appears conceivable that hypoxia and low nutrient transform tumor cells into fermenting anaerobes. This suggests that cancer cells are more similar to unicellular organisms, aimed at surviving in a continuous fighting, rather than cooperating, with other cells, as it occurs in the normal homeostasis of our body. We have shown that cancer cells take their fuel by "cannibalizing" other cells, either dead or alive, especially when starved and in acidic condition. This finding led to the discovery of a new oncogene TM9SF4 that human malignant cell shares with amoebas. The evidence is accumulating that almost all the cells release extracellular vehicles (EVs), from micro- to nanosize, which shuttle a variety of molecules. Tumor cells, particularly when stressed in their hostile microenvironment, release high levels of EVs, able to interact with target cells in various ways, within an organ or at a distance. They may represent both valuable tumor biomarker and shuttles for drugs with anti-tumor properties. This article wants to burst a real change in future anti-cancer strategies, based on the idea that tumors are much more common features than specific molecular targets. PMID- 26972278 TI - Akt3 knockdown induces mitochondrial dysfunction in human cancer cells. AB - Akt/PKB plays a pivotal role in cell proliferation and survival. However, the isotype-specific roles of Akt in mitochondrial function have not been fully addressed. In this study, we explored the role of Akt in mitochondrial function after stable knockdown of the Akt isoforms in EJ human bladder cancer cells. We found that the mitochondrial mass was significantly increased in the Akt1- and Akt3-knockdown cells, and this increase was accompanied by an increase in TFAM and NRF1. Akt2 knockdown did not cause a similar effect. Interestingly, Akt3 knockdown also led to severe structural defects in the mitochondria, an increase in doxorubicin-induced senescence, and impairment of cell proliferation in galactose medium. Consistent with these observations, the mitochondrial oxygen consumption rate was significantly reduced in the Akt3-knockdown cells. An Akt3 deficiency-induced decrease in mitochondrial respiration was also observed in A549 lung cancer cells. Collectively, these results suggest that the Akt isoforms play distinct roles in mitochondrial function and that Akt3 is critical for proper mitochondrial respiration in human cancer cells. PMID- 26972281 TI - Endovascular management of congenital arteriovenous fistulae in the neck. AB - PURPOSE: The purpose of this study was to evaluate congenital arteriovenous fistulae in the neck, including vertebrovertebral and carotico-jugular arteriovenous fistula, with their endovascular management. MATERIALS AND METHODS: Six patients with congenital arteriovenous fistulae in the neck who underwent endovascular treatment between March 2001 and December 2013 at the Department of Radiology, Ege University School of Medicine were enrolled into this retrospective study. There were four men and two women, with a mean age of 8.6 (range 4-17)years. Patients' demographics and symptoms were noted. Diagnostic computed tomography and/or magnetic resonance angiography were available in all patients. Parent artery and vein of the arteriovenous fistula, location of the fistula, the other features of fistula, endovascular occlusion site, number and type of endovascular materials, and length of follow-up were reviewed. RESULTS: Four patients had vertebrovertebral fistula, while two patients had carotido jugular fistula (fistula between maxillary artery and external jugular vein). Four patients underwent detachable balloon occlusion together with coil embolization, while two patients underwent detachable balloon occlusion only. The parent artery was occluded in five patients without clinical consequences, and the remaining fistula was occluded with preservation of the parent artery. The patients did not have any complication in the follow-up period (mean follow-up, 9months). CONCLUSION: Congenital arteriovenous fistulae in the neck are extremely rare. Endovascular fistula occlusion with parent vessel sacrifice appears to be a safe and minimally invasive treatment option with good results during the follow up period. PMID- 26972282 TI - Comparison between Doppler ultrasonography and multiphase multidetector-row computed tomography in the detection of liver involvement in Rendu-Osler disease: An analysis of 62 patients. AB - PURPOSE: To evaluate the agreement between the Buscarini criteria on ultrasound (US) and multiphase contrast-enhanced multidetector-row computed tomography (MDCT) in the diagnosis and staging of liver involvement in hereditary hemorrhagic telangiectasia (HHT) (i.e., Rendu-Osler disease). To evaluate the role of variations in hepatic artery anatomy in the production of disagreement between these two imaging techniques. MATERIALS AND METHODS: This single center retrospective study included 62 patients with confirmed or suspected HHT. Each patient underwent Doppler US analyzed according to the Buscarini criteria and arterial and portal phase MDCT on the same day or one day apart. Liver involvement was classified as absent, slight, moderate or severe for each examination. Agreement was evaluated by the kappa and Bhapkar tests. Variations in hepatic arterial anatomy was analyzed by MDCT based on the Michel's classification and analysis of agreement and disagreement was performed using the Chi(2) test. RESULTS: Significant disagreement was identified between the two tests in 29 patients with kappa=0.376 and a Bhapkar critical probability of P=0.0053. Staging of liver involvement was significantly more severe with MDCT in case of disagreement. A variant hepatic artery anatomy was identified in 12 patients with agreement and 7 patients with disagreement, but the difference was not significant (Chi(2)=0.297). CONCLUSION: The results of our study confirm the importance of associating contrast-enhanced MDCT with Doppler US in the evaluation of liver involvement in patients with HHT. PMID- 26972283 TI - Giving thanks - Addressing the worldwide plastic surgeon shortage. PMID- 26972285 TI - Functional status of women with and without severe maternal morbidity: A prospective cohort study. AB - BACKGROUND: Little is known regarding the impact on maternal functional status in women who have survived severe obstetric complications. OBJECTIVE: To compare the maternal functional status score between women with and without severe morbidity at one month and six months postpartum in Kelantan, Malaysia. METHODS: A prospective cohort study design was applied at two tertiary referral hospitals over a six-month period. The study population included all postpartum women who gave birth in 2014. Postpartum women with severe maternal morbidity and without severe maternal morbidity were selected as the exposed and non-exposed group, respectively. Functional ability based on the Inventory of Functional Status after Childbirth was used as the main outcome measure. Repeated measure analysis of variance was performed. RESULTS: A total of 145 and 187 women with and without severe maternal morbidity, respectively, were measured. There were significant differences in Inventory of Functional Status after Childbirth score changes (P<0.001) between women with and without severe maternal morbidity at one month and at six months. Functional ability score of women with severe maternal morbidity was lower at one month postpartum (P=0.001). The most affected domain was infant care (P=0.002). CONCLUSIONS: Healthcare providers are recommended to assess the short-term functional ability of severe morbid mother in addition to existing routine physical examination. Provision of physical support from spouse and family of the high risk mothers particularly on infant care during their early postpartum period is crucial to optimise health and minimise the negative health outcomes. PMID- 26972284 TI - A meta-analysis of efficacy of Morus alba Linn. to improve blood glucose and lipid profile. AB - PURPOSE: The previous studies have reported the Morus alba may improve blood glucose and lipid profile. The evidence from these studies is not consistent. This meta-analysis was to evaluate efficacy of products derived from M. alba on blood glucose and lipid levels. METHODS: Literature was reviewed via international database (PubMed, PubMed Central, ScienceDirect, and SciSearch) and Thai databases. Thirteen RCTs with high quality, assessed by Jadad score, were included. RESULTS: M. alba expressed a significant reduction in postprandial glucose (PPG) at 30 min (MD -1.04, 95 % CI -1.36, -0.73), 60 min (MD -0.87, 95 % CI -1.27, -0.48) and 90 min (MD -0.55, 95 % CI -0.87, -0.22). The difference was not found in the levels of other glycaemic (FBS, HbA1C, or HOMA-IR) and lipidaemic (TC, TG, LDL, or HDL) markers. Serious adverse effects were found neither in the control nor in the group received M. alba. CONCLUSION: Products derived from M. alba can effectively contribute to the reduction in PPG levels, but large-scale RCTs would be informative. PMID- 26972286 TI - Infection and low back pain: seeking evidence or fear of exploring new indications for antibiotics? PMID- 26972289 TI - Targeting the Nicotinic Acetylcholine Receptors (nAChRs) in Astrocytes as a Potential Therapeutic Target in Parkinson's Disease. AB - Parkinson's disease (PD) is a relatively common disorder of the Central Nervous System (CNS), whose etiology is characterized by a selective and progressive degeneration of dopaminergic neurons, and the presence of Lewy bodies in the pars compacta of the substantia nigra, and gaping dopamine depletion in the striatum. Patients with this disease suffer from tremors, slowness of movements, gait instability, and rigidity. These patients may also present functional disability, reduced quality of life, and rapid cognitive decline. It has been shown that nicotine exerts beneficial effects in patients with PD and in in-vitro and in vivo models of this disease. Astrocytes are an important component in the immune response associated with PD, and that nicotine might be able to inhibit the inflammation-related apoptosis of these cells, being this a potential strategy for PD treatment. This action of nicotine could be due mainly to activation of alpha7 nicotinic acetylcholine receptors (alpha7-nAChRs) expressed in glial cells. However, nicotine administration can protect dopaminergic neurons against degeneration by inhibiting astrocytes activation in the substantia nigra pars compacta (SNpc) and therefore reduce inflammation. Owing to the toxicity and capacity of nicotine to induce addiction, analogues of this substance have been designed and tested in various experimental paradigms, and targeting alpha7 nAChRs expressed in glial cells may be a novel therapeutic strategy for PD treatment. PMID- 26972290 TI - Neuroinflammation: A Therapeutic Target of Cotinine for the Treatment of Psychiatric Disorders? AB - Neuroinflammation is a common characteristic of several mental health conditions such as major depression, bipolar disorder, post-traumatic stress disorder (PTSD) and schizophrenia (SCHZ). Inflammatory processes trigger and/or further deteriorate mental functions and are regarded as targets for therapeutic drug development. Cotinine is an alkaloid present in tobacco leaves and the main metabolite of nicotine. Cotinine is safe, non-addictive and has pharmacokinetic properties adequate for therapeutic use. Research has shown that cotinine has antipsychotic, anxiolytic, and antidepressant properties and modulates the serotonergic, cholinergic and dopaminergic systems. Consistent with the modulation of these neurotransmitter systems, cotinine behaves as a positive allosteric modulator of the nicotinic acetylcholine receptors (nAChRs) and has anti-inflammatory effects. The decrease in neuroinflammation induced by the stimulation of the cholinergic system seems to be a key element explaining the beneficial effects of cotinine in a diverse range of neurological and psychiatric conditions. This review discusses new evidence of the role of neuroinflammation as a key aspect in bipolar disorder, PTSD and major depression, as well as the potential use of cotinine to reduce neuroinflammation in those conditions. PMID- 26972288 TI - Membrane Damage Induced by Amyloid Beta and a Potential Link with Neuroinflammation. AB - It is well accepted that cortical and hippocampal synaptic densities are reduced in Alzheimer's disease (AD). These alterations in neuronal networking occur at the very onset of AD and may lead to the neuronal loss displayed in later stages of the disease, which is characterized by severe cognitive and behavioral impairments. Many studies suggest that amyloid-beta (Abeta) oligomers are responsible for synaptic disconnections and neuronal death. The effects of Abeta in different brain regions are pleotropic, thus suggesting a common mechanism for toxicity. One potential site for this mechanism of toxicity is the neuronal membrane. It is recognized that Abeta can associate to the plasma membrane and induce the formation of pores after the interaction with lipids like GM1 and cholesterol, and proteins such as APP and NMDA receptors. After this early event, the membrane increases its permeability allowing the influx of small ions and larger molecules. Thus, one of the main toxic consequences of Abeta oligomer interaction with neurons is an increase in intracellular Ca(2+) concentration that causes alterations in ionic homeostasis. It has been proposed that Abeta perforates the membrane similarly to pore-forming toxins producing a series of effects that include synaptic failure and cell death. These actions of Abeta appear to be potentiated by neuroinflammation, which results in a series of effects that, when prolonged, will affect membrane integrity, pore formation and cellular homeostasis. Here, we will review the most recent data on Abeta actions at the membrane level and how its relationship with neuroinflammation could further potentiate brain impairment in AD. The notion of having drugs acting with dual inhibitory actions, inhibition of membrane damage and inflammation, could serve as a starting conceptual point for the development of new therapies for the disease. PMID- 26972291 TI - Stroke and Neuroinflamation: Role of Sexual Hormones. AB - Inflammatory response in the nervous system, called neuroinflammation, is a common process of several neurodegenerative diseases and brain disorders. To understand the underlying mechanism of this brain response to damage would be interesting to identify new common therapy targets to neurodegenerative processes. Ischemic stroke has an important socioeconomic impact being the second cause of mortality and the first cause of long-term disability in the world. Until now, there is not any pharmacological treatment to reduce the brain damage induced. In this review, we will expose recent evidences about neuroinflammation after stroke in animal models and in human. We summarize the most relevant information about the inflammatory-cellular component: microglia/ astrocytes response and peripheral blood cells infiltration to the brain describing the key adhesion molecules implicated in this process. Also, we review the inflammatory molecular response including the beneficial/detrimental role of chemokines and cytokines after ischemia. Currently, female sexual hormones (estradiol and progesterone) are considered as neuroprotective agents. We and others laboratories demonstrated anti-inflammatory actions of these hormones after stroke, modulating not only the cellular response (reducing the reactive gliosis), but also the immune response. Here, we will present the current data about the neuroprotective role of estradiol and progesterone after ischemic injury focused in their anti-inflammatory action. Additionally, we will review the recent information about the mechanism of action of both hormones, including different receptors and signaling pathways. Finally, we will discuss the synergistic or antagonic therapeutic effects when they are administered together. PMID- 26972293 TI - Sialendoscopy-assisted surgery and the chronic obstructive sialadenitis symptoms questionnaire: A prospective study. AB - OBJECTIVES/HYPOTHESIS: To prospectively assess symptoms of obstructive sialadenitis before and after sialendoscopy-assisted salivary duct surgery (SASDS) using the chronic obstructive sialadenitis symptoms (COSS) questionnaire to determine and predict impact of interventions. STUDY DESIGN: Prospective cohort study. METHODS: Adult patients with chronic obstructive sialadenitis who underwent SASDS were asked to complete the COSS questionnaire and the Short-Form 8 (SF-8) quality-of-life (QOL) survey prior to surgery and 3 months postoperatively. Chronic obstructive sialadenitis symptoms surveys were scored on a scale from 0 to 100. RESULTS: Forty patients undergoing SASDS, including 54 glands, completed preoperative and postoperative surveys. Overall, the mean COSS score improved from 36.1 (standard error of the mean [SEM] 2.6) preoperatively to 13.5 (SEM 2.4) 3 months postoperatively (p < 0.001). Submandibular gland cases had a significant mean score reduction of 27.8 (from 38.1 to 10.3; p < 0.005). Parotid gland cases had a significant mean score reduction of 13.6 (from 32.6 to 19.0; p < 0.0001). Patients with sialolithiasis-related sialadenitis had greater COSS score improvement after surgery than those with radioactive iodine- or inflammatory-related disease. An improvement in symptoms was seen for 100% and 47% of patients with sialolithiasis and inflammatory etiologies, respectively. The pre- and post-SASDS SF-8 QOL scores were not significantly different. CONCLUSIONS: Obstructive sialadenitis-related symptoms significantly declined 3 months after SASDS. The COSS questionnaire was able to measure changes in sialadenitis symptoms not captured in the SF-8 QOL survey. This is the first study to prospectively survey sialadenitis-specific symptoms to determine impact of surgical interventions. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1343-1348, 2016. PMID- 26972292 TI - Immediate percutaneous sacroiliac screw insertion for unstable pelvic fractures: is it safe enough? AB - OBJECTIVES: The purpose of this study was to compare the results of immediate and delayed percutaneous sacroiliac screws surgery for unstable pelvic fractures, regarding technical results and complication rate. DESIGN: Retrospective study. SETTING: The study was conducted at the Soroka University Medical center, Beer Sheva, Israel, which is a level 1 trauma Center. PATIENTS: 108 patients with unstable pelvic injuries were operated by the orthopedic department at the Soroka University Medical Center between the years 1999-2010. A retrospective analysis found 50 patients with immediate surgery and 58 patients with delayed surgery. Preoperative and postoperative imaging were analyzed and data was collected regarding complications. INTERVENTION: All patients were operated on by using the same technique-percutaneous fixation of sacroiliac joint with cannulated screws. MAIN OUTCOME MEASUREMENTS: The study's primary outcome measure was the safety and quality of the early operation in comparison with the late operation. RESULTS: A total of 156 sacroiliac screws were inserted. No differences were found between the immediate and delayed treatment groups regarding technical outcome measures (P value = 0.44) and complication rate (P value = 0.42). CONCLUSIONS: The current study demonstrated that immediate percutaneous sacroiliac screw insertion for unstable pelvic fractures produced equally good technical results, in comparison with the conventional delayed operation, without additional complications. PMID- 26972294 TI - Carfilzomib Triple Combination Therapy: A Review in Relapsed Multiple Myeloma. AB - Carfilzomib (Kyprolis(r)) is a proteasome inhibitor that binds selectively and irreversibly to the 20S proteasome (the proteolytic core particle within the 26S proteasome), inducing growth arrest and apoptosis. This intravenous drug is approved in the EU and the USA as combination therapy with oral lenalidomide and intravenous or oral dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. In the multinational, phase III ASPIRE study in this patient population, carfilzomib triple combination therapy significantly prolonged progression-free survival (PFS), reflecting a clinically relevant gain in PFS of 8.7 months, compared with lenalidomide plus dexamethasone. Improvements in overall response rate and patients' global health status were also observed with carfilzomib triple combination therapy. A significant improvement in overall survival (OS) is yet to be demonstrated, with the prespecified stopping boundary not crossed at the time of the prespecified interim analysis, although OS data were not mature by the cut-off date. Carfilzomib triple combination therapy had a manageable tolerability profile. The incidences of the most frequently reported grade 3 or higher adverse events of special interest (with the exception of neutropenia, anaemia and thrombocytopenia) were low in both the carfilzomib triple combination therapy and lenalidomide plus dexamethasone groups. Although final OS data are awaited, current evidence suggests carfilzomib in combination with lenalidomide and dexamethasone is a welcome addition to the treatment options currently available for patients with relapsed multiple myeloma. PMID- 26972296 TI - New Frontiers in Promoting TRAIL-Mediated Cell Death: Focus on Natural Sensitizers, miRNAs, and Nanotechnological Advancements. AB - Cancer is a multifaceted and genomically complex disease, and rapidly emerging scientific evidence is emphasizing on intra-tumor heterogeneity within subpopulations of tumor cells and rapidly developing resistance against different molecular therapeutics. There is an overwhelmingly increasing list of agents currently being tested for efficacy against cancer. In accordance with the concept that therapeutic agents must have fewer off target effects and considerable efficacy, TRAIL has emerged as one among the most deeply investigated proteins reportedly involved in differential killing of tumor cells. Considerable killing activity of TRAIL against different cancers advocated its entry into clinical trials. However, data obtained through preclinical and cell culture studies are deepening our understanding of wide-ranging mechanisms which induce resistance against TRAIL-based therapeutics. These include downregulation of death receptors, overexpression of oncogenes, inactivation of tumor suppressor genes, imbalance of pro- and anti-apoptotic proteins, and inactivation of intrinsic and extrinsic pathways. Substantial fraction of information has been added into existing pool of knowledge related to TRAIL biology and recently accumulating evidence is adding new layers to regulation of TRAIL-induced apoptosis. Certain hints have emerged underscoring miR135a-3p- and miR-143 mediated regulation of TRAIL-induced apoptosis, and natural agents have shown remarkable efficacy in improving TRAIL-based therapeutics by increasing expression of tumor suppressor miRNAs. In this review, we summarize most recent breakthroughs related to naturopathy and strategies to nanotechnologically deliver TRAIL to the target site in xenografted mice. We also set spotlight on positive and negative regulators of TRAIL-mediated signaling. Comprehensive knowledge of genetics and proteomics of TRAIL-based signaling network obtained from cancer patients of different populations will be helpful in getting a step closer to personalized medicine. PMID- 26972295 TI - Quercetin ameliorates peripheral nerve ischemia-reperfusion injury through the NF kappa B pathway. AB - This study aimed to investigate the protective effect of quercetin against ischemia-reperfusion (IR) injury induced in the sciatic nerve of the rat. Quercetin (20 mg/kg) was given during ischemia just before reperfusion. Four groups of rats (Q+IR3, Q+IR7, Q+IR14, and Q+IR28) received 3, 7, 14, and 28 days of reperfusion, respectively, after the intraperitoneal injection of quercetin. After reperfusion, a behavioral test was performed and the sciatic functional index was calculated. Each sciatic nerve was stained to check for edema and ischemic fiber degeneration. Immunohistochemical staining was performed to detect TNF-alpha and NF-kappa B, and TUNEL staining was carried out to detect apoptosis. The Q+IR3, Q+IR7, and Q+IR14 groups showed significantly increased behavioral scores and ameliorated sciatic functional index values compared to IR-injured rats that received vehicle alone during ischemia and then the same period of reperfusion. The Q+IR3, Q+IR7, Q+IR14, and Q+IR28 groups presented significant ischemic fiber degeneration (IFD), TNF-alpha expression, and apoptosis as compared with the IR-injured and perfused rats that did not receive quercetin. The Q+IR3, Q+IR7, and Q+IR28 groups also exhibited significantly decreased NF kappa B expression (p < 0.001, p = 0.001, p = 0.026) as compared with the IR injured rats that were perfused but did not receive quercetin. These results imply that quercetin may be beneficial in the treatment of sciatic IR injury because of its antiapoptotic and antiinflammatory effects and its ability to decrease the expression of NF-kappa B. PMID- 26972297 TI - Developmental Stage-Dependent Effects of Leukemia Inhibitory Factor on Adipocyte Differentiation of Murine Bone Marrow Stromal Cells. AB - Studies describing the effects of leukemia inhibitory factor (LIF) on adipocyte differentiation in murine cells have shown varying results. For example, LIF has been reported to have a suppressive effect on adipocyte differentiation in the 3T3-L1 cell line, whereas it promoted adipocyte differentiation in the Ob1771 and 3T3-F442A cell lines. Thus, it is possible that the effects of LIF on adipogenesis vary with the developmental stage of the cells or tissues, but the details remain unclear. To further elucidate the role of LIF in adipogenesis, we investigated the effects of LIF on murine bone marrow stromal cells at the early and late stages of adipogenesis. LIF decreased the number of lipid foci and suppressed the expression levels of adipocyte differentiation markers at day 5; however, it enhanced these same traits at day 15. A previous report showed that the expression levels of Wnt signaling molecules are different at the early and late differentiation stages; therefore, we investigated the relationship between LIF and Wnt signaling. LIF affected the mRNA expression levels of different Wnt signaling molecules but inhibited the expression level of beta-catenin protein at both days 5 and 15. Our data suggest that LIF has reciprocal roles during the early and late stages of adipocyte differentiation, regulating the Wnt signaling pathway. PMID- 26972298 TI - Polystyrene Nanoparticles Activate Erythrocyte Aggregation and Adhesion to Endothelial Cells. AB - Nanoparticles (NPs) are drawing an increasing clinical interest because of their potential use as drug carriers. Recently, a new strategy for elevation of NPs in vivo circulation time has been proposed, specifically, utilizing red blood cells (RBCs) as a carrier for NPs, that are loaded with a drug, by interaction (in vitro) of human RBCs with NPs (RBCNP). This class of delivery set-up, combines advantages of natural RBCs and synthetic biomaterials. Previous studies demonstrated that NPs initiated hemolysis of RBC and activated cells aggregation. In the present study, we examined the effect of RBCNP on the aggregation of RBC and their adhesion to endothelial cells (EC). Red cells were treated with polystyrene NPs (PS-NP), and following their washing, were added to suspension of untreated cells at various concentrations. We observed that the PS-NP and RBCNP initiated the formation of red cells aggregates and markedly elevated RBC adhesion to EC. These effects were augmented with (a) increasing concentration of NPs or RBCNP, and (b) with decreasing NP size. This implies that RBCNP are cells with a stronger intercellular interaction, and may thereby induce the formation of large and strong aggregates with untreated RBC, as well as strong RBC/EC interaction. PMID- 26972299 TI - The Effects of Phrenic Nerve Degeneration by Axotomy and Crush on the Electrical Activities of Diaphragm Muscles of Rats. AB - The aim of this study was to investigate the effect of axotomy and crush-related degeneration on the electrical activities of diaphragm muscle strips of experimental rats. In the present study, twenty-one male Wistar-albino rats were used and divided into three groups. The animals in the first group were not crushed or axotomized and served as controls. Phrenic nerves of the rats in the second and third groups were crushed or axotomized in the diaphragm muscle. Resting membrane potential (RMP) was decreased significantly in both crush and axotomy of diaphragm muscle strips of experimental rats (p < 0.05). Depolarization time (T DEP) and half-repolarization (1/2 RT) time were significantly prolonged in crush and axotomy rats (p < 0.05). Crushing or axotomizing the phrenic nerves may produce electrical activities in the diaphragm muscle of the rat by depolarization time and half-repolarization time prolonged in crush and axotomy rats. PMID- 26972300 TI - Single Active Site Mutation Causes Serious Resistance of HIV Reverse Transcriptase to Lamivudine: Insight from Multiple Molecular Dynamics Simulations. AB - Molecular dynamics simulations, binding free energy calculations, principle component analysis (PCA), and residue interaction network analysis were employed in order to investigate the molecular mechanism of M184I single mutation which played pivotal role in making the HIV-1 reverse transcriptase (RT) totally resistant to lamivudine. Results showed that single mutations at residue 184 of RT caused (1) distortion of the orientation of lamivudine in the active site due to the steric conflict between the oxathiolane ring of lamivudine and the side chain of beta-branched amino acids Ile at position 184 which, in turn, perturbs inhibitor binding, (2) decrease in the binding affinity by (~8 kcal/mol) when compared to the wild-type, (3) variation in the overall enzyme motion as evident from the PCA for both systems, and (4) distortion of the hydrogen bonding network and atomic interactions with the inhibitor. The comprehensive analysis presented in this report can provide useful information for understanding the drug resistance mechanism against lamivudine. The results can also provide some potential clues for further design of novel inhibitors that are less susceptible to drug resistance. PMID- 26972301 TI - Potential Role of Placental Klotho in the Pathogenesis of Preeclampsia. AB - The aim of this study was to analyze the placental expression and allele status of promoter region of Klotho in association with preeclampsia, which represents the most common hypertensive disease of pregnancy. Klotho mRNA and protein levels were determined using real-time PCR and Western blot, respectively, in placental tissue samples obtained from 34 patients affected with preeclampsia and 34 controls. A PCR-based genotyping analysis was carried out in the promoter region of Klotho gene. Moreover, expression levels of pluripotency markers, Nanog and Oct4, and telomere length were assessed using real-time PCR. Klotho mRNA and protein levels were reduced in preeclamptic placentas compared with controls. 744delA single-nucleotide polymorphism was significantly associated with preeclampsia. In pathological placentas, there was a downregulation of pluripotency markers and a reduced telomere length. This study is the first to evaluate the placental expression level of Klotho in association with preeclampsia. Further analyses will clarify its role in the pathogenesis of this pregnancy hypertensive disorder. PMID- 26972302 TI - Hyperhomocysteinemia Alters Sinoatrial and Atrioventricular Nodal Function: Role of Magnesium in Attenuating These Effects. AB - Patients with hyperhomocysteinemia (HHcy), or elevated plasma homocysteine (Hcy), are at higher risk of developing arrhythmias and sudden cardiac death; however, the mechanisms are unknown. In this study, the effects of HHcy on sinus node function, atrioventricular conduction, and ventricular vulnerability were investigated by electrophysiological (EP) analysis, and the role of magnesium (Mg(2+)), an endogenous N-methyl-D-aspartate (NMDA) receptor antagonist, in attenuating EP changes due to HHcy was explored. Wild-type mice (WT) and mice receiving Hcy in the drinking water for 12 weeks (DW) were subjected to electrocardiographic and EP studies. DW compared to WT had significantly shorter RR, PR, QT, and HV intervals, corrected sinus node recovery times (CSNRT), Wenckebach periodicity (WP), atrioventricular nodal effective refractory periods (AVNERP), and right ventricular effective refractory periods (RVERP). To examine the role of Mg(2+) in mitigating conduction changes in HHcy, WT, DW, and heterozygous cystathionine-beta-synthase knockout mice (CBS (+/-) ) were subjected to repeat EP studies before and after administration of low-dose magnesium sulfate (20 mg/kg). Mg(2+) had no effect on EP variables in WT, but significantly slowed CSNRT, WP, and AVNERP in DW, as well as WP and AVNERP in CBS (+/-) . These findings suggest that ionic channels modulated by Mg(2+) may contribute to HHcy-induced conduction abnormalities. PMID- 26972303 TI - DNA Glycation from 3-Deoxyglucosone Leads to the Formation of AGEs: Potential Role in Cancer Auto-antibodies. AB - The non-enzymatic glycation reaction results in the generation of free radicals which play an important role in the pathophysiology of aging, diabetes, and cancer. 3-Deoxyglucosone (3-DG) is a dicarbonyl species which may lead to the formation of advanced glycation end products (AGEs). 3-DG also reacts with free amino group of nucleic acids resulting in the formation of DNA-AGEs. While the establishment of nucleoside AGEs has been revealed before, no extensive studies have been done to probe the role of 3-DG in the generation of immunogenicity and induction of cancer auto-antibodies. In this study, we report the immunogenicity of AGEs formed by 3-DG-Arg-Fe(3+) system. Spectroscopic analysis and melting temperature studies suggest structural perturbations in the DNA as a result of modification. Immunogenicity of native and 3-DG-Arg-Fe(3+) DNA was probed in female rabbits. The modified DNA was highly immunogenic eliciting high-titer immunogen-specific antibodies, while the unmodified form was almost non immunogenic. We also report the presence of auto-antibodies against 3-DG-Arg Fe(3+)-modified DNA in the sera of patients with different types of cancers. The glycoxidative lesions were also detected in the lymphocyte DNA isolated from selected cancer patients. The results show structural perturbations in 3-DG-Arg Fe(3+)-DNA generating new epitopes that render the molecule immunogenic. PMID- 26972304 TI - Evaluation of the Hypoglycemic Effect of Composite Rice Flour in Diabetic Mice. AB - To study the hypoglycemic effect of composite rice flour, the diabetic mouse model was established through the intraperitoneal injection of alloxan saline (twice, 200 mg/kg bw). The mice were randomly divided into 4 groups: negative control, positive control, metformin medication group, and composite rice flour feed group. After 21 days, the fasting blood glucose levels were determined by glucose oxidase method and followed with a glucose tolerance test. The results show that the body weight growth rate of mice in the rice flour group was significantly higher than that of the medication group (P < 0.01). Comparing with the positive control group, the fasting blood glucose levels of medication group and rice flour group were significantly lower, and the glucose tolerance was significantly increased in rice flour group (P < 0.01). In conclusion, the composite rice flour has obvious hypoglycemic and protective effect for diabetic mouse model. PMID- 26972305 TI - "Human Stress Syndrome" and the Expanding Spectrum of RYR1-Related Myopathies. PMID- 26972306 TI - On a New Rapid Diagnostic Test for Tuberculosis. PMID- 26972307 TI - Hexagonal pillar structure of heteroepitaxial titania-vanadia nanocrystal films for high performance in thermochromic and photocatalytic properties. AB - In this study, we employed the mixture of titanium and vanadium sols with various ratios in WO3 and poly(vinylpyrrolidone) solution to generate the precursors of W doped titania-vanadia composites. The heteroepitaxial W-doped titania-vanadia crystals (HWTVCs) with various structures were obtained after a calcination process at 700 degrees C for 3 h. The structure transformation of HWTVCs was highly relative to the ratio of titanium to vanadium sols. A hexagonal pillar structure was found at a ratio of 0.25 for titanium to vanadium sols. The scales of the hexagonal pillars could be apparently divided into two groups. The scale of one group ranged from 80 to 130 nm while the scale of the other ranged from 300 to 950 nm. The heteroepitaxial crystals with hexagonal pillar structure enhanced the visible transmittance, near-infrared switching efficiency and the ability to photocatalytically degrade the organic component under visible light irradiation. Such bifunctional (photocatalytic and thermochromic) nanomaterials might have applications in energy-saving smart windows. PMID- 26972308 TI - Vitamin D levels and atopic eczema in infancy and early childhood in Norway: a cohort study. AB - BACKGROUND: Epidemiological data and the effect of sun exposure on atopic eczema (AE) suggest that vitamin D (vitD) may be involved in the pathogenesis. OBJECTIVES: To investigate if vitD levels were associated with the presence or severity of AE in the first 2 years of life in children living in south-east Norway. METHODS: Infants, recruited to a clinical trial on acute bronchiolitis (n = 404) and from the general population (n = 240), were examined at 1-13 months (first visit) and at 2 years of age (second visit). Caregivers were interviewed using a structured questionnaire. AE was diagnosed clinically, based on well established criteria. Disease severity was assessed using the SCORing Atopic Dermatitis index. Blood samples were taken for vitD measurements, using liquid chromatography-tandem mass spectrometry and for common filaggrin mutation analyses. Complete data on AE and vitD were available in 596 and 449 children at the first and second visit, respectively. RESULTS: Atopic eczema was diagnosed in 67 children (11%) at the first visit and in 103 children (23%) at the second. Mean vitD levels were 58.2 nmol L(-1) at the first visit and 66.9 nmol L(-1) at the second. Using vitD level tertiles in multivariate regression analysis, there was no association between vitD levels and AE at either visit, regardless of filaggrin mutation. In children without AE at the first visit, vitD levels did not predict AE at the second. CONCLUSIONS: In this cohort of young children in Norway, we found no association between vitD levels and the presence or severity of AE. PMID- 26972309 TI - Blockage of T Cell Activation via Anti-CD40 and Anti-CD154 Monoclonal Antibodies can Possibility Treat Alopecia Areata. PMID- 26972312 TI - Special Issue Abstracts From the American Society for Apheresis 37th Annual Meeting, May 4-7, 2016 Palm Springs, California. PMID- 26972310 TI - Shape perception enhances perceived contrast: evidence for excitatory predictive feedback? AB - Predictive coding theory suggests that predictable responses are "explained away" (i.e., reduced) by feedback. Experimental evidence for feedback inhibition, however, is inconsistent: most neuroimaging studies show reduced activity by predictive feedback, while neurophysiology indicates that most inter-areal cortical feedback is excitatory and targets excitatory neurons. In this study, we asked subjects to judge the luminance of two gray disks containing stimulus outlines: one enabling predictive feedback (a 3D-shape) and one impeding it (random-lines). These outlines were comparable to those used in past neuroimaging studies. All 14 subjects consistently perceived the disk with a 3D-shape stimulus brighter; thus, predictive feedback enhanced perceived contrast. Since early visual cortex activity at the population level has been shown to have a monotonic relationship with subjective contrast perception, we speculate that the perceived contrast enhancement could reflect an increase in neuronal activity. In other words, predictive feedback may have had an excitatory influence on neuronal responses. Control experiments ruled out attention bias, local feature differences and response bias as alternate explanations. PMID- 26972313 TI - Fabrication of a Functionally Graded Copper-Zinc Sulfide Phosphor. AB - Functionally graded materials (FGMs) are compositionally gradient materials. They can achieve the controlled distribution of the desired characteristics within the same bulk material. We describe a functionally graded (FG) metal-phosphor adapting the concept of the FGM; copper (Cu) is selected as a metal and Cu- and Cl-doped ZnS (ZnS:Cu,Cl) is selected as a phosphor and FG [Cu]-[ZnS:Cu,Cl] is fabricated by a very simple powder process. The FG [Cu]-[ZnS:Cu,Cl] reveals a dual-structured functional material composed of dense Cu and porous ZnS:Cu,Cl, which is completely combined through six graded mediating layers. The photoluminescence (PL) of FG [Cu]-[ZnS:Cu,Cl] is insensitive to temperature change. FG [Cu]-[ZnS:Cu,Cl] also exhibits diode characteristics and photo reactivity for 365 nm -UV light. Our FG metal-phosphor concept can pave the way to simplified manufacturing of low-cost and can be applied to various electronic devices. PMID- 26972311 TI - A Rationally Designed Connector for Assembly of Protein-Functionalized DNA Nanostructures. AB - We report on the rational engineering of the binding interface of the self ligating HaloTag protein to generate an optimized linker for DNA nanostructures. Five amino acids positioned around the active-site entry channel for the chlorohexyl ligand (CH) of the HaloTag protein were exchanged for positively charged lysine amino acids to produce the HOB (halo-based oligonucleotide binder) protein. HOB was genetically fused with the enzyme cytochrome P450 BM3, as well as with BMR, the separated reductase domain of BM3. The resulting HOB-fusion proteins revealed significantly improved rates in ligation with CH-modified oligonucleotides and DNA origami nanostructures. These results suggest that the efficient self-assembly of protein-decorated DNA structures can be greatly improved by fine-tuning of the electrostatic interactions between proteins and the negatively charged nucleic acid nanostructures. PMID- 26972315 TI - The Oporto mixed-longitudinal growth, health and performance study. Design, methods and baseline results. AB - BACKGROUND: Studies concerning child and adolescent growth, development, performance and health aimed at the multiple interactions amongst this complex set of variables are not common in the Portuguese speaking countries. AIM: The aim of this paper is to address the key ideas, methodology and design of the Oporto Growth, Health and Performance Study (OGHPS). SUBJECTS AND METHODS: The OGHPS is a multidisciplinary mixed-longitudinal study whose main purpose is to examine the multiple interactions among biological, environmental and lifestyle indicators that affect growth, development, health and performance of Portuguese adolescents aged 10-18 years old. RESULTS: This study briefly presents baseline results for growth, physical fitness and lifestyle behaviours for those participating in the cross-sectional sample (n ~ 8000). Approximately 30% were over-fat or obese. On average, boys were more physically fit and active than girls. Few adolescents meet the guidelines for sleep duration (~10%) and eating habits (16.2-24.8%), while 76-85% meet the recommended levels of moderate-to vigorous physical activity. CONCLUSIONS: The OGHPS has an innovative approach due to its mixed-longitudinal design and the broad array of variables. Furthermore, subsequent analyses of the longitudinal data will enable a detailed exploration of important factors affecting the growth trajectories of health and performance variables and will also help to identify some of the most opportune times for interventions in terms of health behaviours. PMID- 26972314 TI - IgG4-related nephropathy. AB - IgG4-related disease (IgG4-RD) is a recently recognized disorder, often with multiple organ involvement, characterized by dense tissue infiltration of IgG4 positive plasma cells, storiform fibrosis, obliterative phlebitis and frequently elevated serum IgG4 concentration. The kidney can be involved either directly or indirectly. The most frequent direct renal manifestations of IgG4-RD are IgG4 related tubulointerstitial nephritis (TIN) and membranous glomerulonephropathy. Retroperitoneal fibrosis (RPF) is another condition that is frequently IgG4 related and that can indirectly affect the kidney causing ureteral obstruction and hydronephrosis. Contrast-enhanced computerized tomography, magnetic resonance imaging and (18)F-fluorodeoxyglucose positron emission tomography/computed tomography show different imaging findings and are useful tools for monitoring therapeutic response. Steroid treatment is the first line of therapy, but relapsing or refractory forms of the disease are frequently observed and require more aggressive therapeutic approaches. At our centre, we treated three cases of aggressive IgG4-related TIN and two cases of IgG4-related RPF with an intensified, immune suppressive protocol, obtaining good results without severe adverse effects. PMID- 26972316 TI - Drought, Mutualism Breakdown, and Landscape-Scale Degradation of Seagrass Beds. AB - In many marine ecosystems, biodiversity critically depends on foundation species such as corals and seagrasses that engage in mutualistic interactions [1-3]. Concerns grow that environmental disruption of marine mutualisms exacerbates ecosystem degradation, with breakdown of the obligate coral mutualism ("coral bleaching") being an iconic example [2, 4, 5]. However, as these mutualisms are mostly facultative rather than obligate, it remains unclear whether mutualism breakdown is a common risk in marine ecosystems, and thus a potential accelerator of ecosystem degradation. Here, we provide evidence that drought triggered landscape-scale seagrass degradation and show the consequent failure of a facultative mutualistic feedback between seagrass and sulfide-consuming lucinid bivalves that in turn appeared to exacerbate the observed collapse. Local climate and remote sensing analyses revealed seagrass collapse after a summer with intense low-tide drought stress. Potential analysis-a novel approach to detect feedback-mediated state shifts-revealed two attractors (healthy and degraded states) during the collapse, suggesting that the drought disrupted internal feedbacks to cause abrupt, patch-wise degradation. Field measurements comparing degraded patches that were healthy before the collapse with patches that remained healthy demonstrated that bivalves declined dramatically in degrading patches with associated high sediment sulfide concentrations, confirming the breakdown of the mutualistic seagrass-lucinid feedback. Our findings indicate that drought triggered mutualism breakdown, resulting in toxic sulfide concentrations that aggravated seagrass degradation. We conclude that external disturbances can cause sudden breakdown of facultative marine mutualistic feedbacks. As this may amplify ecosystem degradation, we suggest including mutualisms in marine conservation and restoration approaches. PMID- 26972317 TI - Functional Plasticity in Somatosensory Cortex Supports Motor Learning by Observing. AB - An influential idea in neuroscience is that the sensory-motor system is activated when observing the actions of others [1, 2]. This idea has recently been extended to motor learning, in which observation results in sensory-motor plasticity and behavioral changes in both motor and somatosensory domains [3-9]. However, it is unclear how the brain maps visual information onto motor circuits for learning. Here we test the idea that the somatosensory system, and specifically primary somatosensory cortex (S1), plays a role in motor learning by observing. In experiment 1, we applied stimulation to the median nerve to occupy the somatosensory system with unrelated inputs while participants observed a tutor learning to reach in a force field. Stimulation disrupted motor learning by observing in a limb-specific manner. Stimulation delivered to the right arm (the same arm used by the tutor) disrupted learning, whereas left arm stimulation did not. This is consistent with the idea that a somatosensory representation of the observed effector must be available during observation for learning to occur. In experiment 2, we assessed S1 cortical processing before and after observation by measuring somatosensory evoked potentials (SEPs) associated with median nerve stimulation. SEP amplitudes increased only for participants who observed learning. Moreover, SEPs increased more for participants who exhibited greater motor learning following observation. Taken together, these findings support the idea that motor learning by observing relies on functional plasticity in S1. We propose that visual signals about the movements of others are mapped onto motor circuits for learning via the somatosensory system. PMID- 26972319 TI - Potato StCONSTANS-like1 Suppresses Storage Organ Formation by Directly Activating the FT-like StSP5G Repressor. AB - The CONSTANS-FT pathway defines a core module for reproductive transition in both long-day (LD) and short-day (SD) plants. Changes in the transcriptional function of the CONSTANS (CO) protein have been proposed to mediate differential SD activation of FLOWERING LOCUS T (FT) orthologs in SD plants. Potato Andigena genotypes have an obligate SD requirement for tuber formation, and this photoperiodic response correlates with activation of the FT StSP6A gene in leaves. The potato StCOL1 factor represses expression of this mobile tuberization signal, but the control mechanism is poorly understood. Here, we analyzed StCOL1 diurnal oscillation and protein accumulation at different photoperiods and light wavelengths. We observed that the potato StCOL1 gene peaked at dawn and that, in contrast to the Arabidopsis AtCO homolog, the light receptor phyB is necessary for protein stabilization in the light. Reduced StCOL1 levels in RNAi lines strongly correlated with downregulated expression of an additional potato FT family member, StSP5G. Co-regulated StCOL1 and StSP5G expression suggested that StCOL1 activates this target directly rather than controlling StSP6A expression. By hybridization of a universal protein-binding microarray, we established that StCOL1 binds a TGTGGT element, and we found that immunoprecipitated StCOL1 protein fractions were enriched in StSP5G promoter fragments bearing this element. We show that StSP5G represses tuberization in LD conditions and that this FT-like homolog suppresses StSP6A gene expression. Rewiring StCOL1 transcriptional function from direct activation of the StSP6A inducer signal to the control of an FT-like repressor thus mediates the strict SD requirement of Andigena plants for tuberization. PMID- 26972318 TI - Grid-like Processing of Imagined Navigation. AB - Grid cells in the entorhinal cortex (EC) of rodents [1] and humans [2] fire in a hexagonally distributed spatially periodic manner. In concert with other spatial cells in the medial temporal lobe (MTL) [3-6], they provide a representation of our location within an environment [7, 8] and are specifically thought to allow the represented location to be updated by self-motion [9]. Grid-like signals have been seen throughout the autobiographical memory system [10], suggesting a much more general role in memory [11, 12]. Grid cells may allow us to move our viewpoint in imagination [13], a useful function for goal-directed navigation and planning [12, 14-16], and episodic future thinking more generally [17, 18]. We used fMRI to provide evidence for similar grid-like signals in human entorhinal cortex during both virtual navigation and imagined navigation of the same paths. We show that this signal is present in periods of active navigation and imagination, with a similar orientation in both and with the specifically 6-fold rotational symmetry characteristic of grid cell firing. We therefore provide the first evidence suggesting that grid cells are utilized during movement of viewpoint within imagery, potentially underpinning our more general ability to mentally traverse possible routes in the service of planning and episodic future thinking. PMID- 26972320 TI - Reorganization of Sleep by Temperature in Drosophila Requires Light, the Homeostat, and the Circadian Clock. AB - Increasing ambient temperature reorganizes the Drosophila sleep pattern in a way similar to the human response to heat, increasing daytime sleep while decreasing nighttime sleep. Mutation of core circadian genes blocks the immediate increase in daytime sleep, but not the heat-stimulated decrease in nighttime sleep, when animals are in a light:dark cycle. The ability of per(01) flies to increase daytime sleep in light:dark can be rescued by expression of PER in either LNv or DN1p clock cells and does not require rescue of locomotor rhythms. Prolonged heat exposure engages the homeostat to maintain daytime sleep in the face of nighttime sleep loss. In constant darkness, all genotypes show an immediate decrease in sleep in response to temperature shift during the subjective day, implying that the absence of light input uncovers a clock-independent pro-arousal effect of increased temperature. Interestingly, the effects of temperature on nighttime sleep are blunted in constant darkness and in cry(OUT) mutants in light:dark, suggesting that they are dependent on the presence of light the previous day. In contrast, flies of all genotypes kept in constant light sleep more at all times of day in response to high temperature, indicating that the presence of light can invert the normal nighttime response to increased temperature. The effect of temperature on sleep thus reflects coordinated regulation by light, the homeostat, and components of the clock, allowing animals to reorganize sleep patterns in response to high temperature with rough preservation of the total amount of sleep. PMID- 26972323 TI - Erratum: Multimodal stimulus coding by a gustatory sensory neuron in Drosophila larvae. PMID- 26972321 TI - Regulation of Hippocampal Firing by Network Oscillations during Sleep. AB - It has been hypothesized that waking leads to higher-firing neurons, with increased energy expenditure, and that sleep serves to return activity to baseline levels. Oscillatory activity patterns during different stages of sleep may play specific roles in this process, but consensus has been missing. To evaluate these phenomena in the hippocampus, we recorded from region CA1 neurons in rats across the 24-hr cycle, and we found that their firing increased upon waking and decreased 11% per hour across sleep. Waking and sleeping also affected lower- and higher-firing neurons differently. Interestingly, the incidences of sleep spindles and sharp-wave ripples (SWRs), typically associated with cortical plasticity, were predictive of ensuing firing changes and were more robustly predictive than other oscillatory events. Spindles and SWRs were initiated during non-REM sleep, yet the changes were incorporated in the network over the following REM sleep epoch. These findings indicate an important role for spindles and SWRs and provide novel evidence of a symbiotic relationship between non-REM and REM stages of sleep in the homeostatic regulation of neuronal activity. PMID- 26972322 TI - Mice lacking myosin IXb, an inflammatory bowel disease susceptibility gene, have impaired intestinal barrier function and superficial ulceration in the ileum. AB - Genetic studies have implicated MYO9B, which encodes myosin IXb (Myo9b), a motor protein with a Rho GTPase activating domain (RhoGAP), as a susceptibility gene for inflammatory bowel disease (IBD). Moreover, we have recently shown that knockdown of Myo9b in an intestinal epithelial cell line impairs wound healing and barrier function. Here, we investigated whether mice lacking Myo9b have impaired intestinal barrier function and features of IBD. Myo9b knock out (KO) mice exhibit impaired weight gain and fecal occult blood (indicator of gastrointestinal bleeding), and increased intestinal epithelial cell apoptosis could be detected along the entire intestinal axis. Histologic analysis revealed intestinal mucosal damage, most consistently observed in the ileum, which included superficial ulceration and neutrophil infiltration. Focal lesions contained neutrophils and ultrastructural examination confirmed epithelial discontinuity and the deposition of extracellular matrix. We also observed impaired mucosal barrier function in KO mice. Transepithelial electrical resistance of KO ileum is >3 fold less than WT ileum. The intestinal mucosa is also permeable to high molecular weight dextran, presumably due to the presence of mucosal surface ulcerations. There is loss of tight junction-associated ZO-1, decreased lateral membrane associated E-cadherin, and loss of terminal web associated cytokeratin filaments. Consistent with increased Rho activity in the KO, there is increased subapical expression of activated myosin II (Myo2) based on localization of phosphorylated Myo2 regulatory light chain. Except for a delay in disease onset in the KO, no difference in dextran sulfate sodium-induced colitis and lethality was observed between wild-type and Myo9b KO mice. PMID- 26972324 TI - Emotional and Behavioral Disorders in 1.5th Generation, 2nd Generation Immigrant Children, and Foreign Adoptees. AB - Existing theories (e.g., acculturative stress theory) cannot adequately explain why mental disorders in immigrants are less prevalent than in non-immigrants. In this paper, the culture-gene co-evolutionary theory of mental disorders was utilized to generate a novel hypothesis that connection to heritage culture reduces the risk for mental disorders in immigrant children. Four groups of children aged 2-17 years were identified from the 2007 United States National Survey of Children's Health: 1.5th generation immigrant children (n = 1378), 2nd generation immigrant children (n = 4194), foreign adoptees (n = 270), and non immigrant children (n = 54,877). The 1.5th generation immigrant children's connection to their heritage culture is stronger than or similar to the 2nd generation immigrants, while the foreign adoptees have little connection to their birth culture. Controlling for age, sex, family type and SES, the odds for having ADD/ADHD, Conduct Disorder, Anxiety Disorder, and Depression diagnosis were the lowest for the 1.5th generation immigrant children, followed by the 2nd generation immigrant children and the foreign adoptees. The foreign adoptees and non-adopted children were similar in the odds of having these disorders. Connection to heritage culture might be the underlying mechanism that explained recent immigrants' lower rates of mental disorders. PMID- 26972325 TI - Host-microbiome interactions in acute and chronic respiratory infections. AB - Respiratory infection is a leading cause of global morbidity and mortality. Understanding the factors that influence risk and outcome of these infections is essential to improving care. We increasingly understand that interactions between the microbial residents of our mucosal surfaces and host regulatory systems is fundamental to shaping local and systemic immunity. These mechanisms are most well defined in the gastrointestinal tract, however analogous systems also occur in the airways. Moreover, we now appreciate that the host-microbiota interactions at a given mucosal surface influence systemic host processes, in turn, affecting the course of infection at other anatomical sites. This review discusses the mechanisms by which the respiratory microbiome influences acute and chronic airway disease and examines the contribution of cross-talk between the gastrointestinal and respiratory compartments to microbe-mucosa interactions. PMID- 26972326 TI - The flexible brain. On mind and brain, neural darwinism and psychiatry. AB - A theoretical introduction is given in which several theoretical viewpoints concerning the mind-brain problem are discussed. During the last decade philosophers like Searle, Dennett and the Churchlands have taken a more or less pure materialistic position in explaining mental phenomena. Investigators in biological psychiatry have hardly ever taken a clear position in this discussion, whereas we believe it is important that the conclusions drawn from biological research are embedded in a theoretical framework related to the mind-brain problem. In this article the thesis is defended that the theory of neural darwinism represents a major step forward and may bridge previous distinctions between biological, clinical and social psychiatry. PMID- 26972327 TI - Focal neurocognitive dysfunctions in abstinence delirium: a case report. AB - Due to abrupt interruption of hidden benzodiazepine-use, a 68-year-old woman developed a full-blown abstinence delirium characterized by epileptic seizures and progressive focal neurocognitive symptoms. The evolution of such rare neuro linguistic phenomena as an echoism, palilalia and glossomania associated with a progressive visuo-perceptive syndrome and a visual hallucinosis are for the first time reported within the context of withdrawal. Notwithstanding the lack of any neuroradiological evidence for a morphological lesion in the clinically expected brain regions, the anatomo-clinical hypothesis of a focal frontal and parieto occipital dysfunction was explicitly corroborated by repeated 99mTc-HMPAO SPECT findings. PMID- 26972328 TI - The crossroads of anticipatory attention and motor preparation. I. AB - This series of papers suggests that processes underlying anticipatory attention and motor preparation share a common control mechanism. Both functions are of utmost importance for an optimal adaptation to our environment. While the posterior part of the cortex is aimed at the analysis of incoming information, both from the outer world and our own body, the anterior part is involved in action and reaction. If we know when in the near future we will be confronted with relevant information, and how this has to be responded upon, modality specific sensoric and motoric information channels have to be open in order to guarantee an adequate response. The anterior and posterior parts of the cortex are activated from the thalamus and the information transmission is influenced via the reticular nucleus (RN) of the thalamus. The RN itself is under a double control: excitatory from the prefrontal cortex and inhibitory from the neostriatum. It is suggested that selection in anticipatory attention and motor preparation is realized in a comparable way via the RN. In Part I the relevant anatomical structures are described. In Part II the model for anticipatory attention and motor preparation is presented. In Part III the supporting neuropsychological evidence is presented, after which psychophysiological experiments will be discussed having lead to the formulation of the model. PMID- 26972329 TI - Literatuuronderzoek naar intacte cognitieve vaardigheden bij patienten met dementie van het Alzheimer-type. AB - De onlangs overleden Willem de Kooning wordt alom beschouwd als een der grootste beeidende kunstenaars van de 20e eeuw. Hij werd in 1904 in Nederland geboren en emigreerde in 1926 naar de Verenigde Staten. Daar ontwikkelde de Kooning eind jaren veertig, samen met Jackson Pollock, Franz Kline en Mark Rotko, een nieuwe stroming binnen de schilderskunst: het abstract expressionisme. Het waren vooral zijn opzienbarende, semi-abstracte schilderijen over vrouwen die destijds veel stof deden opwaaien. Op 78-jarige leeftijd werd bij hem de ziekte van Alzheimer vastgesteld. Een jaar eerder, in 1981, was de Kooning, na enkele jaren zo goed als gestopt te zijn, wederom begonnen met schilderen. Tussen 1981 en 1986 produceerde hij zo'n 250 abstracte doeken. PMID- 26972330 TI - Mass balance, pharmacokinetics, and metabolism of linsitinib in cancer patients. AB - PURPOSE: This study characterized the pharmacokinetics, mass balance, routes and extent of elimination, metabolites, and safety of a single oral dose of (14)C linsitinib, an IGF-1R/IR inhibitor, in patients with advanced solid tumors. The tolerability of linsitinib after multiple-dose administration was assessed in those patients who wished to continue treatment beyond the single (14)C linsitinib dose. METHODS: Five patients received a single oral dose of 150 mg (14)C-linsitinib, followed by collection of blood, plasma, urine, and feces for 10 days. The collected material was analyzed for total radioactivity, linsitinib, and metabolites. The safety of 150 mg of unlabeled linsitinib administered twice daily until disease progression was also assessed. RESULTS: The median time to reach the maximum plasma concentration of linsitinib was 3.0 h, median maximum plasma concentration was 1789 ng/mL, median terminal half-life was 2.4 h, and median apparent oral clearance was 12.45 L/h. After a single dose of (14)C linsitinib, 5.44 and 76.4 % of mean total radioactivity administered were recovered in urine and feces, respectively. Eighteen linsitinib metabolites (M1 M18) were detected in plasma, urine, and feces samples, and their structures were elucidated. The main metabolic reactions of linsitinib in humans were oxidation and sulfate conjugation. Linsitinib was well tolerated after a single dose of (14)C-linsitinib, and fatigue was the most frequent adverse event following multiple doses of unlabeled linsitinib. CONCLUSIONS: (14)C-linsitinib is rapidly absorbed and extensively metabolized. Linsitinib excretion via bile into feces is the predominant elimination route from plasma with minor renal elimination. PMID- 26972331 TI - Classification of Valleytronics in Thermoelectricity. AB - The theory of valleytronics as a material design tool for engineering both thermal and electrical transport properties is presented. It is shown that the interplay among the valleytronics parameters such as the degeneracy of the band, intervalley transitions, effective mass, scattering exponent, and the Fermi energy may deteriorate or ameliorate any or all of the main thermoelectric properties. A flowchart classifying the different paths through which the valleytronics can influence the thermoelectric figure-of-merit ZT is derived and discussed in detail. To exemplify the application of the flowchart, valleytronics in four different semiconductors, Mg2Si, Si0.8Ge0.2, Al(x)Ga(1-x)As and clathrate Si46-VIII were studied, which showed different trends. Therefore, a degenerate multivalley bandstructure, which is typically anticipated for a good thermoelectric material, cannot be a general design rule for ZT enhancement and a detailed transport study is required to engineer the optimum bandstructure. PMID- 26972332 TI - Comparison of the effects of long-term pimobendan and benazepril administration in normal cats. AB - Pimobendan (PIMO) can cause adverse effects, such as mitral valve degeneration, in dogs; however, it is unclear whether these effects occur in cats. Therefore, we aimed to determine whether PIMO or benazepril produces adverse cardiac effects in healthy cats. This was a blinded, randomized, prospective parallel study. Twelve cats were randomly divided into two groups of six cats, namely, an angiotensin-converting-enzyme inhibitor group that received benazepril and a PIMO group. Cats were administered their respective treatments for 506 days, and we evaluated cardiac parameters, blood biochemistry and glomerular filtration rates during that time. At the end of the trial, the cats were euthanized, and histopathological examinations were performed by a pathologist who was blinded to the treatment groups. No significant changes were observed in any of the parameters measured in either of the groups. In particular, no significant cardiac lesions were observed in either of the groups. In healthy cats, neither PIMO nor benazepril appears to cause cardiac lesions, but future studies are needed to examine the effects of PIMO in cats with heart disease. PMID- 26972333 TI - Spatial assessment of the potential risk of avian influenza A virus infection in three raptor species in Japan. AB - Avian influenza A, a highly pathogenic avian influenza, is a lethal infection in certain species of wild birds, including some endangered species. Raptors are susceptible to avian influenza, and spatial risk assessment of such species may be valuable for conservation planning. We used the maximum entropy approach to generate potential distribution models of three raptor species from presence-only data for the mountain hawk-eagle Nisaetus nipalensis, northern goshawk Accipiter gentilis and peregrine falcon Falco peregrinus, surveyed during the winter from 1996 to 2001. These potential distribution maps for raptors were superimposed on avian influenza A risk maps of Japan, created from data on incidence of the virus in wild birds throughout Japan from October 2010 to March 2011. The avian influenza A risk map for the mountain hawk-eagle showed that most regions of Japan had a low risk for avian influenza A. In contrast, the maps for the northern goshawk and peregrine falcon showed that their high-risk areas were distributed on the plains along the Sea of Japan and Pacific coast. We recommend enhanced surveillance for each raptor species in high-risk areas and immediate establishment of inspection systems. At the same time, ecological risk assessments that determine factors, such as the composition of prey species, and differential sensitivity of avian influenza A virus between bird species should provide multifaceted insights into the total risk assessment of endangered species. PMID- 26972334 TI - Single oral dose safety of D-allulose in dogs. AB - Healthy dogs were administered acute oral doses of D-allulose (also called D psicose) to evaluate its toxicity. Six dogs received oral doses of either a placebo or D-allulose solution (1 and 4 g/kg) on three different study days. One dog experienced vomiting, and five dogs showed transient diarrhea when 4 g/kg of D-allulose was administered. All dogs were active and had a good appetite throughout the study period. Blood glucose concentration slightly decreased without a rise in plasma insulin concentration 2 hr after D-allulose administration. Plasma alkaline phosphatase activities showed a mild increase between 12 and 48 hr after D-allulose administration. These data suggested that a single oral dose of D-allulose does not show severe toxicity in dogs. PMID- 26972335 TI - Effects of static magnetic fields on bone regeneration of implants in the rabbit: micro-CT, histologic, microarray, and real-time PCR analyses. AB - OBJECTIVES: The aim of this study was to investigate the effects of static magnetic fields (SMFs) on bone regeneration around titanium implants by MUCT, histologic analysis, microarrays, and quantitative real-time PCR (qRT-PCR). MATERIALS AND METHODS: Neodymium magnets provided the source of SMFs, the specimens were grade 5 titanium implants, and the animals were twenty-seven adult male New Zealand white rabbits. These implants were divided into six groups according to the presence of a magnet and predetermined healing period (1, 4, and 8 weeks). Each group comprised six specimens for MUCT (n = 6) and histologic examination, and three specimens (n = 3) for microarrays and qRT-PCR, yielding a total of 54 specimens. RESULTS: The MUCT data showed that SMFs increased bone volume fraction (bone volume/total volume, BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th). Histologic observation indicated that SMFs promoted new bone formation and direct bony contact with implants. Microarray analysis identified 293 genes upregulated (>twofold) in response to SMFs. The upregulated genes included extracellular matrix (ECM)-related genes (COL10A1, COL9A1, and COL12A1) and growth factor (GF)-related genes (CTGF and PDGFD), and the upregulation was confirmed by qRT-PCR. Gene Ontology (GO) and pathway analysis revealed the involvement of the mitogen-activated protein kinase (MAPK), Wnt, and PPAR-gamma signaling pathways in implant healing. CONCLUSIONS: MUCT, histology, microarrays, and real-time PCR indicate that SMFs could be an effective approach to improving bone regeneration around dental implants. PMID- 26972336 TI - PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer. AB - OBJECTIVE: As a negative regulator of T cells, Programmed Death Ligand 1 (PD-L1) is both an indicator and inhibitor of anti-tumor immune responses, which has led to confusion about its prognostic significance. We investigated the primary source of PD-L1 expression in epithelial ovarian cancer and its relationship to tumor-infiltrating lymphocytes (TIL) and associated gene products. METHODS: Tissue microarrays containing high-grade serous carcinomas (HGSC) and endometrioid, clear cell and mucinous ovarian cancers from optimally debulked patients were assessed by immunohistochemistry for expression of PD-L1 and other markers (CD68, CD3, CD8, PD-1, CD103, FoxP3 and CD25). The Cancer Genome Atlas was interrogated for associations between PD-L1 expression and immune-related transcriptional and genomic features of HGSC. RESULTS: PD-L1 was primarily expressed by tumor-associated CD68(+) macrophages rather than tumor cells. PD L1(+) cells frequently co-localized with CD8, CD4 and PD-1(+) TIL, CD25(+)FoxP3(+) Tregs, and other TIL subsets. PD-L1(+) cells were prognostically favorable in HGSC. Moreover, the presence of both PD-L1(+) cells and CD8 TIL was associated with better prognosis than CD8 TIL alone. PD-L1 gene expression was independent of BRCA status. At the transcriptional level, PD-L1 was associated with both cytolytic (granzyme B, T-bet and IFN-gamma) and suppressive (PD-1, CTLA 4, LAG3 and IDO-1) gene products. CONCLUSIONS: PD-L1 is primarily expressed by macrophages in ovarian cancer and is strongly associated with both cytolytic and regulatory TIL subsets, resulting in a net positive association with survival. Tumors containing PD-L1(+) macrophages appear caught in an immunological stalemate that may require multi-pronged immunotherapy to alleviate. PMID- 26972337 TI - Surgical management of cardiophrenic lymph nodes in patients with advanced ovarian cancer. AB - OBJECTIVE: Debulking surgery for advanced ovarian cancer does not routinely include opening of the thorax. Even systematic lymphadenectomy does not commonly extend to lymph nodes above the diaphragm. We evaluated the outcome of systematic resection of suspicious cardiophrenic lymph nodes detected on preoperative CT scan in patients with advanced epithelial ovarian cancer (EOC). METHODS: Single center, prospective series of 196 consecutive patients with EOC undergoing primary debulking surgery between June 2013 and June 2015. Suspicious cardiophrenic lymph nodes were defined as >=10mm on the short axis diagnosed in pre-operative CT-scan and were removed if intra-abdominal debulking resulted in complete resection or residual tumor <10mm and the patients' performance status allowed this additional procedure. Removal of suspicious cardiophrenic lymph nodes was performed via a trans-diaphragmatic approach. RESULTS: Thirty (15%) out of 196 EOC patients had radiologically suspicious cardiophrenic lymph nodes >=10mm and complete resection or residual tumor <10mm. Twenty-seven out of the thirty patients had at least one confirmed metastatic cardiophrenic lymph node. Metastatic cardiophrenic lymph nodes were associated with extensive intra abdominal tumor spread in the upper abdomen. CONCLUSIONS: Patients with suspicious cardiophrenic lymph nodes detected by preoperative CT-scan had histologically confirmed metastasis in 90% of cases. The surgical procedure is feasible without major complications if performed by experienced gyneco oncologists. The prognostic value of this procedure should be evaluated in larger controlled studies. PMID- 26972338 TI - Identification and Characterization of Novel Chitin-Binding Proteins from the Larval Cuticle of Silkworm, Bombyx mori. AB - Cuticle is mainly made of chitin filaments embedded in a matrix of cuticular proteins (CPs). Cuticular chitins have minor differences, whereas CPs are widely variable with respect to their sequences and structures. To understand the molecular basis underlying the mechanical properties of cuticle, it is necessary to know which CPs interact with chitin and how they are assembled into the cuticle structure. In the present study, a chitin-binding assay was performed followed by liquid chromatography-tandem mass spectrometry to identify the extracted proteins from the larval cuticle of silkworm, Bombyx mori. There were 463 proteins identified from the silkworm larval cuticle, 200 of which were recovered in the chitin-binding fraction. A total of 103 proteins were annotated as CPs, which were classified into 11 CP families based on their conserved motifs, including CPR, CPAP, CPT, CPF and CPFL, CPCFC, chitin_bind 3, BmCPH2 homologues, BmCPH9 homologues, BmCPG1 homologues, BmCPG20 homologues, and BmCPG21 homologues. A total of five CP families were newly identified in the chitin binding fraction, thereby providing new information and insight into the composition, structure, and function of the silkworm larval cuticle. PMID- 26972339 TI - Induced Structural Disorder as a Molecular Mechanism for Enzyme Dysfunction in Phosphoglucomutase 1 Deficiency. AB - Human phosphoglucomutase 1 (PGM1) plays a central role in cellular glucose homeostasis, mediating the switch between glycolysis and gluconeogenesis through the conversion of glucose 1-phosphate and glucose 6-phosphate. Recent clinical studies have identified mutations in this enzyme as the cause of PGM1 deficiency, an inborn error of metabolism classified as both a glycogen storage disease and a congenital disorder of glycosylation. Reported here are the first crystal structures of two disease-related missense variants of PGM1, along with the structure of the wild-type enzyme. Two independent glycine-to-arginine substitutions (G121R and G291R), both affecting key active site loops of PGM1, are found to induce regions of structural disorder, as evidenced by a nearly complete loss of electron density for as many as 23 aa. The disordered regions are not contiguous in sequence to the site of mutation, and even cross domain boundaries. Other structural rearrangements include changes in the conformations of loops and side chains, some of which occur nearly 20 A away from the site of mutation. The induced structural disorder is correlated with increased sensitivity to proteolysis and lower-resolution diffraction, particularly for the G291R variant. Examination of the multi-domain effects of these G?R mutations establishes a correlation between interdomain interfaces of the enzyme and missense variants of PGM1 associated with disease. These crystal structures provide the first insights into the structural basis of enzyme dysfunction in PGM1 deficiency and highlight a growing role for biophysical characterization of proteins in the field of precision medicine. PMID- 26972341 TI - Small Peptides Derived from Penetratin as Antibacterial Agents. AB - The synthesis, in vitro evaluation and conformational study of several small-size peptides acting as antibacterial agents are reported. Among the compounds evaluated, the peptides Arg-Gln-Ile-Lys-Ile-Trp-Arg-Arg-Met-Lys-Trp-Lys-Lys-NH2 , Arg-Gln-Ile-Lys-Ile-Arg-Arg-Met-Lys-Trp-Arg-NH2 , and Arg-Gln-Ile-Trp-Trp-Trp-Trp Gln-Arg-NH2 exhibited significant antibacterial activity. These were found to be very active antibacterial compounds, considering their small molecular size. In order to better understand the antibacterial activity obtained for these peptides, an exhaustive conformational analysis was performed, using both theoretical calculations and experimental measurements. Molecular dynamics simulations using two different media (water and trifluoroethanol/water) were employed. The results of these theoretical calculations were corroborated by experimental circular dichroism measurements. A brief discussion on the possible mechanism of action of these peptides at molecular level is also presented. Some of the peptides reported here constitute very interesting structures to be used as starting compounds for the design of new small-size peptides possessing antibacterial activity. PMID- 26972342 TI - Prognostic impact and change of concomitant mitral regurgitation after surgical or transcatheter aortic valve replacement for aortic stenosis. AB - BACKGROUND: Significant aortic stenosis (AS) is frequently associated with mitral regurgitation (MR) of varying degrees. We sought to assess the change in MR grade after the aortic valve procedure, to find predictors of MR improvement and finally to determine the prognostic impact of persistent MR. METHODS: We retrospectively analyzed a group of 101 AS patients who underwent aortic valve replacement (AVR) or transcatheter aortic valve implantation (TAVI) at our institution between January 2007 and March 2014 and who presented with MR grade 2 or higher on preoperative echocardiogram - 35 patients underwent an isolated AVR, 18 underwent TAVI, and the rest underwent a combined procedure, which included coronary artery bypass grafting. The mean follow-up was 28.5+/-21 months. RESULTS: MR improved significantly after the procedures (2.4+/-0.5 vs. 1.9+/-0.9, p<0.001) and a decline in the severity of MR was observed regardless of etiology (degenerative/post-rheumatic, functional/ischemic, combined) without significant changes between groups (p=0.667). Downgrading of MR severity was associated with improvement in ejection fraction (p=0.021) and reduction in the size of cardiac chambers, especially the left atrium (left atrial diameter, p<0.001). None of the preoperatively evaluated factors (severity of AS, MR etiology, ejection fraction, cardiac chamber dimensions, coronary artery disease, and New York Heart Association functional class) was a significant predictor of MR improvement. Persistence of higher degrees of MR was associated with a more frequent need for cardiovascular hospitalization, while the survival rate 3 years after procedure was not affected (p=0.146). CONCLUSIONS: In the majority of AS patients, an aortic valve procedure leads to reduction in coexistent MR. A significant decrease in the severity of MR in our study was observed regardless of etiology and preoperative grade of MR. Persistence of higher degrees of MR was associated with increased patient morbidity. PMID- 26972343 TI - Posttransplant lymphoproliferative disease and survival in adult heart transplant recipients. AB - BACKGROUND: The influence of posttransplant lymphoproliferative disease (PTLD) on long-term survival after heart transplantation (HTx) in adult recipients needs better characterization. METHODS: The United Network for Organ Sharing database was queried from 2006 to 2015 to compare survival between adult HTx recipients with and without PTLD. Cox proportional hazards models were used to analyze the primary outcome of survival, and competing-risks regression was used to analyze the outcome of PTLD development. RESULTS: A total of 14,487 HTx recipients who had data on PTLD were included in univariate Cox analysis and Kaplan-Meier survival function, while 10,422 were included in multivariable Cox analysis and 162 selected for a matched-pairs sample after matching on the propensity of developing PTLD. The cohort included 120 patients who were diagnosed with PTLD. Onset of PTLD, treated as a time-varying covariate, was adversely associated with survival in univariate (HR=4.953; 95% CI: 3.768, 6.511; p<0.001) and multivariable (HR=3.849; 95% CI: 2.669, 5.552; p<0.001) Cox proportional hazards models. Cox regression stratified on matched pairs of PTLD cases and non-PTLD controls confirmed the risk for death associated with PTLD onset (HR=2.667; 95% CI: 1.043, 6.815; p=0.040). CONCLUSIONS: PTLD onset negatively influenced survival in adult HTx recipients, whereas no characteristics predisposing patients to PTLD development were identified in multivariate analysis. PMID- 26972346 TI - High-Quality Exercise Programs Are an Essential Component of Nursing Home Care. PMID- 26972344 TI - Five-year outcomes of ST-elevation myocardial infarction versus non-ST-elevation acute coronary syndrome treated with biodegradable polymer-coated sirolimus eluting stents: Insights from the CREATE trial. AB - BACKGROUND: Long-term outcome of drug-eluting stents (DES) for ST-elevation myocardial infarction (STEMI) versus non-ST-elevation acute coronary syndrome (NSTE-ACS) remains unclear. This study sought to compare the long-term outcomes of biodegradable polymer-coated DES in patients with STEMI versus NSTE-ACS. METHODS: We explored a post hoc analysis of the 5-year outcome of the CREATE trial in the subgroup of patients with STEMI (n=318) versus NSTE-ACS (n=1223) who were implanted with biodegradable polymer-coated DES. The primary outcome was the rate of major adverse cardiac events (MACE) at 5 years. Clopidogrel and aspirin for 6 months followed by chronic aspirin therapy were recommended. RESULTS: STEMI patients showed a trend of increase in MACE (8.7% vs. 6.8%, log rank p=0.289) compared to NSTE-ACS patients at 5 years, and a greater risk of cardiac death (5.4% vs. 2.1%, log rank p=0.003), mainly driven by the higher cardiac death rate within the first month after stent placement (log rank p=0.003) and the last year of follow-up (log rank p=0.001). No significant difference in stent thrombosis was found between them (3.1% vs. 2.5%, log rank p=0.653). Prolonged clopidogrel therapy (>6 months) showed no effect on risk of MACE or stent thrombosis between the two groups (both p for interaction >0.1). CONCLUSIONS: STEMI patients have a higher risk of cardiac mortality compared with NSTE-ACS patients after biodegradable polymer-coated DES placement, primarily attribute to more cardiac deaths that happened within the first month after the event and the last year of follow-up. PMID- 26972345 TI - Selection of suitable reference genes for assessing gene expression in pearl millet under different abiotic stresses and their combinations. AB - Pearl millet [Pennisetum glaucum (L.) R. Br.] a widely used grain and forage crop, is grown in areas frequented with one or more abiotic stresses, has superior drought and heat tolerance and considered a model crop for stress tolerance studies. Selection of suitable reference genes for quantification of target stress-responsive gene expression through quantitative real-time (qRT)-PCR is important for elucidating the molecular mechanisms of improved stress tolerance. For precise normalization of gene expression data in pearl millet, ten candidate reference genes were examined in various developmental tissues as well as under different individual abiotic stresses and their combinations at 1 h (early) and 24 h (late) of stress using geNorm, NormFinder and RefFinder algorithms. Our results revealed EF-1alpha and UBC-E2 as the best reference genes across all samples, the specificity of which was confirmed by assessing the relative expression of a PgAP2 like-ERF gene that suggested use of these two reference genes is sufficient for accurate transcript normalization under different stress conditions. To our knowledge this is the first report on validation of reference genes under different individual and multiple abiotic stresses in pearl millet. The study can further facilitate fastidious discovery of stress-tolerance genes in this important stress-tolerant crop. PMID- 26972347 TI - Do Not Harm Older Persons in Primary Care by Case Finding of Cognitive Decline, Instead Assess Cognition Only Following Loss of Well-being. PMID- 26972348 TI - Brain Health: A Japanese Viewpoint. PMID- 26972350 TI - Neglected Categorical Differences of Hypertension of the Elderly vs. the Young: A Case of Institutional Amnesia? PMID- 26972349 TI - Next Generation Brain Health Depends on Early Alzheimer Disease Diagnosis: From a Timely Diagnosis to Future Population Screening. PMID- 26972351 TI - Caffeine increases food intake while reducing anxiety-related behaviors. AB - The objective of this study was to determine the effects of different doses of caffeine on appetite and anxiety-related behavior. Additionally, we sought to determine if withdrawal from chronic caffeine administration promotes anxiety. In this study, we utilized rodent open field testing and feeding behavior assays to determine the effects of caffeine on feeding and anxiety-related behavior (n = 8 mice; 4-8 weeks old). We also measured 2 h and 24 h food intake and body-weight during daily administration of caffeine (n = 12 mice; 4-8 weeks old). To test for caffeine withdrawal induced anxiety, anxiety-related behavior in rodents was quantified following withdrawal from four consecutive days of caffeine administration (n = 12 mice; 4-8 weeks old). We find that acute caffeine administration increases food intake in a dose-dependent manner with lower doses of caffeine more significantly increasing food intake than higher doses. Acute caffeine administration also reduced anxiety-related behaviors in mice without significantly altering locomotor activity. However, we did not observe any differences in 24 h food intake or body weight following chronic caffeine administration and there were no observable differences in anxiety-related behaviors during caffeine withdrawal. In conclusion, we find that caffeine can both increase appetite and decrease anxiety-related behaviors in a dose dependent fashion. Given the complex relationship between appetite and anxiety, the present study provides additional insights into potential caffeine-based pharmacological mechanisms governing appetite and anxiety disorders, such as bulimia nervosa. PMID- 26972353 TI - Deliberate choices or strong motives: Exploring the mechanisms underlying the bias of organic claims on leniency judgments. AB - Organic claims can influence how a product is perceived in dimensions that are unrelated with the food production method (e.g., organic food is perceived as more healthful and less caloric than conventional food). Such claims can also bias how the consumers of organic food are perceived and how other people judge their behavior. Schuldt and Schwarz (2010) have shown that individuals evaluating a target with a weight-loss goal are more lenient in judging the target forgoing exercise when the target had an organic (vs. conventional) dessert. This impact of organic claims on leniency judgments has been interpreted either as a halo or a licensing effect. In the current research we aim to replicate and extend Schuldt and Schwarz's (2010) results by examining the mechanisms that are more likely to explain the observed leniency judgments. In Experiment 1, we observed that leniency towards a target that has consumed an organic meal is only observed when the target intentionally chooses such organic meal (vs. choice determined by the situation). These findings suggest that the impact of organic claims on leniency judgments is not merely based on a halo effect. Instead, a licensing account emerges as the most probable mechanism. In Experiment 2, we further found that stronger (vs. weaker) motives for forgoing exercise influenced leniency judgments to the same extent as having had an organic meal. Understanding the mechanisms that shape consumers' decisions may have important implications to prevent bias in their judgments about food and exercise. PMID- 26972352 TI - The importance of taste on dietary choice, behaviour and intake in a group of young adults. AB - The 'taste of food' plays an important role in food choice. Furthermore, foods high in fat, sugar and salt are highly palatable and associated with increased food consumption. Research exploring taste importance on dietary choice, behaviour and intake is limited, particularly in young adults. Therefore, in this study a total of 1306 Australian university students completed questionnaires assessing dietary behaviors (such as how important taste was on food choice) and frequency of food consumption over the prior month. Diet quality was also assessed using a dietary guideline index. Participants had a mean age of 20 +/- 5 years, Body Mass Index (BMI) of 22 +/- 3 kg/m(2), 79% were female and 84% Australian. Taste was rated as being a very or extremely important factor for food choice by 82% of participants. Participants who rated taste as highly important, had a poorer diet quality (p = 0.001) and were more likely to consume less fruit (p = 0.03) and vegetables (p = 0.05). Furthermore, they were significantly more likely to consume foods high in fat, sugar and salt, including chocolate and confectionary, cakes and puddings, sweet pastries, biscuits, meat pies, pizza, hot chips, potato chips, takeaway meals, soft drink, cordial and fruit juice (p = 0.001-0.02). They were also more likely to consider avoiding adding salt to cooking (p = 0.02) and adding sugar to tea or coffee (p = 0.01) as less important for health. These findings suggest that the importance individuals place on taste plays an important role in influencing food choice, dietary behaviors and intake. PMID- 26972354 TI - Repeated transcranial direct current stimulation reduces food craving in Wistar rats. AB - It has been suggested that food craving-an intense desire to consume a specific food (particularly foods high in sugar and fat)-can lead to obesity. This behavior has also been associated with abuse of other substances, such as drugs. Both drugs and food cause dependence by acting on brain circuitry involved in reward, motivation, and decision-making processes. The dorsolateral prefrontal cortex (DLPFC) can be activated following evocation and is implicated in alterations in food behavior and craving. Transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique capable of modulates brain activity significantly, has emerged as a promising treatment to inhibit craving. This technique is considered safe and inexpensive; however, there is scant research using animal models. Such studies could help elucidate the behavioral and molecular mechanisms of eating disorders, including food craving. The aim of our study was to evaluate palatable food consumption in rats receiving tDCS treatment (anode right/cathode left). Eighteen adult male Wistar rats were randomized by weight and divided into three groups (n = 6/group): control, with no stimulation; sham, receiving daily 30 s tDCS (500 MUA) sessions for 8 consecutive days; and tDCS, receiving daily 20 min tDCS (500 MUA) sessions for 8 consecutive days. All rats were evaluated for locomotor activity and anxiety-like behavior. A palatable food consumption test was performed at baseline and on treatment completion (24 h after the last tDCS session) under fasting and feeding conditions and showed that tDCS decreased food craving, thus corroborating human studies. This result confirms the important role of the prefrontal cortex in food behavior, which can be modulated by noninvasive brain stimulation. PMID- 26972356 TI - Corrigendum. PMID- 26972357 TI - Predictors of survival in parotid small cell carcinoma: A study of 344 cases. AB - OBJECTIVES/HYPOTHESIS: We sought to better characterize patient, tumor, and long term survival characteristics of parotid small cell carcinoma (SmCC) with the National Cancer Database (NCDB). STUDY DESIGN: Retrospective database review. METHODS: We reviewed the NCDB (1998-2012) for all cases of parotid SmCC. Relevant demographic, tumor, and survival variables were extracted and analyzed. Cox multivariate regression was performed to identify prognosticators. RESULTS: Out of 30,813 parotid gland cancers in the NCDB, we found 344 cases of parotid SmCC (1.11%). Age at diagnosis ranged from 23 to 91 years (mean = 73 years). Most patients (73.0%) were male. Most tumors were 2 to 4 cm in size (51.4%). Regional metastases were common (50.8% cN+ and 65.1% pN+) and distant metastasis (7.3%) was uncommon. Occult nodes were found in 14.4% of cases. Overall survival at 5 and 10 years was 37% and 20%, respectively. Although numerous variables were found to significantly impact survival on univariate regression analysis, age (hazard ratio [HR]: 1.05, 95% confidence interval [CI]: 1.03-1.08, P < .001), tumor size of 2 to 4 cm (HR: 2.51, 95% CI: 1.83-5.11, P = .011), tumors >4 cm (HR: 3.44, 95% CI: 1.63-7.27) and distant metastasis (HR: 2.06, 95% CI: 1.02 4.14, P = .043) remained significant prognosticators in our multivariate model. Nodal disease was not a significant risk factor after adjustment (P = .055). CONCLUSIONS: SmCC is a rare parotid malignancy with a poor prognosis. Regional metastases were common, whereas distant metastases were uncommon. Elective neck treatment should be considered due to the incidence of occult nodal disease. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2036-2040, 2016. PMID- 26972355 TI - Inhibition of renalase expression and signaling has antitumor activity in pancreatic cancer. AB - An essential feature of cancer is dysregulation of cell senescence and death. Renalase, a recently discovered secreted flavoprotein, provides cytoprotection against ischemic and toxic cellular injury by signaling through the PI3K-AKT and MAPK pathways. Here we show that renalase expression is increased in pancreatic cancer tissue and that it functions as a growth factor. In a cohort of patients with pancreatic ductal adenocarcinoma, overall survival was inversely correlated with renalase expression in the tumor mass, suggesting a pathogenic role for renalase. Inhibition of renalase signaling using siRNA or inhibitory anti renalase antibodies decreased the viability of cultured pancreatic ductal adenocarcinoma cells. In two xenograft mouse models, either the renalase monoclonal antibody m28-RNLS or shRNA knockdown of renalase inhibited pancreatic ductal adenocarcinoma growth. Inhibition of renalase caused tumor cell apoptosis and cell cycle arrest. These results reveal a previously unrecognized role for the renalase in cancer: its expression may serve as a prognostic maker and its inhibition may provide an attractive therapeutic target in pancreatic cancer. PMID- 26972358 TI - Hyaluronic acid dressing (Healoderm) in the treatment of diabetic foot ulcer: A prospective, randomized, placebo-controlled, single-center study. AB - Fast and complete healing of a diabetic foot ulcer (DFU) is challenging due to the hostile wound healing environment of the diabetic patients. As a part of a multimodal treatment approach, advanced dressing material using hyaluronic acid (HA) has been found to be effective. However, previous studies have used HA with additional biologics, which interferes in determining the true clinical effect of HA in DFU. To examine the sole effectiveness of HA in DFU treatment, a prospective, randomized, placebo-controlled, single-center study was conducted using an HA dressing without additional substances. Thus, 34 patients who met the inclusion criteria were randomized into two groups (the study group: HA dressing material; the control group: conventional dressing material). During the 12-week study period, complete ulcer healing rate was evaluated as a primary endpoint. Additionally, healing velocity and the mean duration for achieving a 50% ulcer size reduction was compared between the two groups as a secondary endpoint. At the end of the study, the study group presented a significantly higher complete healing rate as compared to that in the control group [84.6% (11/13), 41.6% (5/12), respectively, P = 0.041]. Additionally, faster ulcer healing velocity and shorter mean duration for achieving a 50% ulcer size reduction were observed in the study group (P = 0.022 and 0.004, respectively). The Kaplan-Meier survival analysis for the median time for 50% ulcer healing rate also showed a significantly shorter duration in the study group (21 days vs. 39 days, P = 0.0127). Finally, there were no adverse events related to the dressing materials used in the study. As a major component of the extracellular matrix, this study supports the safety and efficacy of a pure HA dressing without additional substances in treating DFU. PMID- 26972359 TI - Colocalization of Granulysin Protein Forms with Perforin and LAMP-1 in Decidual Lymphocytes During Early Pregnancy. AB - PROBLEM: Granulysin (GNLY) occurs in two forms, which have molecular weights of 9 and 15 kDa. We analyzed the cytotoxic potential of decidual lymphocytes (DLs) and peripheral blood lymphocytes (PBLs) based on the forms of GNLY that colocalizes with perforin (PER) and LAMP-1 following activation. METHODS: The forms of GNLY were detected by using confocal microscopy. We investigated the colocalization with PER and LAMP-1 in freshly isolated and activated DLs and PBLs. RESULTS: Activation of DLs and PBLs by K-562 cells increased the colocalization of 9 kDa GNLY with PER and LAMP-1. K-562 cells transfected with HLA-C decreased 9 kDa GNLY colocalization with PER in DLs only. IL-15 in DLs decreased 9 kDa GNLY and LAMP-1 colocalization, but increased both 15 kDa GNLY and LAMP-1, and PER and LAMP-1 colocalization. CONCLUSION: Activated DLs and PBLs show greater cytotoxic potential based on increased colocalization of 9 kDa GNLY and PER. HLA-C and IL 15 affect DLs, indicating their role in maintaining the pregnancy tolerance. PMID- 26972360 TI - Unusual Electromyographic Findings Associated With Colchicine Neuromyopathy: A Case Report. AB - : An 83-year-old man with multiple medical problems, including gout, pseudogout, and renal insufficiency, presented with more than a year of proximal weakness. He had an extensive previous medical workup, including a normal creatinine kinase. His weakness persisted despite endurance and strength training. Electrodiagnostic findings were consistent with a myopathy, although without abnormal spontaneous activity and a length-dependent neuropathy. On the basis of these findings, colchicine was discontinued. The patient experienced marked symptomatic improvement within a week. Myopathies with neuropathies may be found with the use of colchicine. This case was unusual because of the absence of abnormal spontaneous activity and increased creatinine kinase, as typically reported with colchicine myopathy. LEVEL OF EVIDENCE: V. PMID- 26972361 TI - Electromyographic Activity of Shoulder Girdle Muscles in Patients With Symptomatic and Asymptomatic Rotator Cuff Tears: A Systematic Review and Meta Analysis. AB - OBJECTIVES: To compare electromyographic activity in patients with symptomatic rotator cuff tears with healthy controls or to those with asymptomatic cuff tears. TYPE: Systematic review and meta-analysis. LITERATURE SURVEY: PubMed, Scopus, Ovid Medline, and Web of Science were searched from inception to August 1, 2014, and a search update was performed on June 8, 2015. METHODOLOGY: Case control studies or intervention studies that had baseline comparisons for symptomatic versus healthy shoulders or those with asymptomatic rotator cuff tear were searched. Methodological quality was assessed with a modified Critical Appraisal Skills Programme score and meta-analyses were performed when 2 or more studies explored the same outcome measures. SYNTHESIS: Nine studies were included, with the quality ranging from 1 to 3 (maximum 6). Electromyographic outcomes included amplitudes and ratios thereof, activity duration, and median frequency of shoulder girdle muscles during isometric contractions (4 studies) and functional tasks (5 studies). Longer activity duration was found for upper trapezius during glenohumeral movements, and greater fatigability of anterior and middle deltoids during isometric hand gripping for patients with rotator cuff tears compared to controls. The meta-analysis (3 studies) showed that patients with rotator cuff tears had lower activation ratios for latissimus dorsi during isometric abduction contraction compared to controls (P < .001), indicating greater co-contraction of adductors for the injured shoulders. CONCLUSIONS: Although various electromyographic domains were explored, these were generally limited to one publication or research group. Current evidence for muscle activity differences between the rotator cuff tear group and controls is thus limited. PMID- 26972362 TI - Effects of Balance Control Through Trunk Movement During Square and Semicircular Turns on Gait Velocity, Center of Mass Acceleration, and Energy Expenditure in Older Adults. AB - BACKGROUND: Turning during ambulation is a common movement in everyday life, but complex and challenging for older adults. Balance control through trunk movement provides a stable platform during walking, thus it is an essential component of safe and efficient turning during walking in elderly individuals. OBJECTIVES: To investigate the effects of balance control during square turning (ST) and semicircular turning (SCT) on gait velocity, center of mass (COM) acceleration, and energy expenditure in elderly women. DESIGN: Cross-sectional design. SETTING: Village community center. PARTICIPANTS: Twenty community-dwelling elderly women capable of independent walking were enrolled in the study. METHODS: Participants walked at a self-selected speed along a marked path that included 2 types of turns (the path was divided into 3 segments: straight, turning, and straight return), while fitted with an accelerometer attached over the L3 spinous process. MAIN OUTCOME MEASUREMENTS: Differences in gait velocity, normalized COM acceleration, and energy expenditure were analyzed using paired t-tests for comparisons between ST and SCT tasks and using a one-way repeated-measures analysis of variance for within tasks. RESULTS: During the ST task, which was characterized by the use of a less-stable balance maintenance strategy, gait velocity and vertical COM acceleration were lower (P < .05), whereas greater medial-lateral COM acceleration (P < .05) and energy expenditure (P < .001) were observed during turning and return straight stages compared with the SCT task. For both tasks, velocity during turning stage was the slowest, among the 3 stages, the straight stage was the fastest (P < .05). For the SCT task, the anterior-posterior COM acceleration during the straight stage was significantly higher than during the turning stage, and the vertical COM acceleration during the straight stage was significantly lower than during the return-straight stage (P < .05). In both tasks, the energy expenditure of the turning stage was significantly higher than in the straight and return straight stage (P <= .001), and in the return straight stage was higher than the straight stage-only ST task (P < .05). CONCLUSIONS: We suggest that elderly individuals participate in balance and gait training using a variety of turns, including turns requiring medial-lateral and vertical COM balance control, to prevent falls and to improve energy efficiency of walking. LEVEL OF EVIDENCE: IV. PMID- 26972363 TI - High-Pressure Balloon-Assisted Stretching of the Coracohumeral Ligament to Determine the Optimal Stretching Positions: A Cadaveric Study. AB - BACKGROUND: The coracohumeral ligament (CHL) is a thick capsular structure and markedly thickened when affected by adhesive capsulitis. Therapeutic stretching is the most commonly applied treatment for adhesive capsulitis, but optimal stretching postures for maximal therapeutic effects on the CHL have not been fully investigated. OBJECTIVE: To investigate the most effective stretching direction for the CHL by measuring the stretching intensity in 5 different directions and to determine whether the stretching intervention resulted in loosening of the ligament by comparing the changes of CHL tightness before and after stretching. DESIGN: Biomechanical cadaver study. SETTING: Academic institution cadaver laboratory. PARTICIPANTS: Nine fresh frozen cadaveric shoulders. METHODS: A high-pressure balloon catheter inserted under the CHL and intraballoon pressure was measured, to evaluate CHL tightness without ligament damage as well as to augment and monitor stretching intensity. To find the optimal stretching direction, the glenohumeral joint was stretched from the neutral position into 5 directions sequentially under pressure-monitoring: flexion, extension [EX], external rotation [ER], EX+ER, and EX+ER+adduction [AD] directions. MAIN OUTCOME MEASUREMENTS: CHL tightness was determined by a surrogate parameter, the additional pressure created by the overlying CHL. The pressure increase (DeltaPstr) by a specific directional stretch was considered as the stretching intensity. RESULTS: DeltaPstr by the 5 directions were mean (standard deviation) values of 0.03 +/- 0.07 atm, 0.87 +/- 1.31 atm, 1.13 +/- 1.36 atm, 1.49 +/- 1.32 atm, and 2.10 +/- 1.70 atm, respectively, revealing the highest DeltaPstr by the EX+ER+AD stretch (P < .05). The balloon pressure by the overlying CHL was decreased from 0.45 +/- 0.35 atm to 0.18 +/- 0.14 atm (P = .012) before and after the stretching manipulation. CONCLUSIONS: EX+ER+AD of the glenohumeral joint resulted in the greatest increase in balloon pressure, implying that it could be the most effective stretching direction. A series of stretching manipulations assisted with an underlying pressure balloon were capable of decreasing CHL tightness. With further development and modification, high-pressure balloon-assisted stretching can be a potential therapeutic option to release tight CHL, including the advantage of augmenting and monitoring stretching intensity. LEVEL OF EVIDENCE: II. PMID- 26972364 TI - Test-Retest Reliability and Convergent Validity of Three Manual Dexterity Measures in Persons With Chronic Stroke. AB - BACKGROUND: Decreased manual dexterity is common in persons after stroke. Different measures are used to assess manual dexterity, but a lack of knowledge exists about their reliability and how they are related. OBJECTIVE: To evaluate the test-retest reliability and convergent validity of 3 manual dexterity measures after stroke. DESIGN: A test-retest design. SETTING: University Hospital. PARTICIPANTS: Forty-five persons (mean age 65 years) with mild-to moderate impairments in the upper extremity at least 6 months after stroke. MAIN OUTCOME MEASURES: Manual dexterity was assessed on 2 occasions, 1 week apart using the Box and Block Test (BBT), the Nine-Hole Peg Test (NHPT), and the modified Sollerman Hand Function Test (mSHFT). The reliability of the BBT and NHPT was evaluated with the intraclass correlation coefficient together with systematic and random measurement errors. Reliability of the mSHFT was evaluated with the Kappa coefficient and the Svensson rank-invariant method (percent agreement and systematic and random disagreements). Convergent validity of the total scores was evaluated with the Spearman rank correlation coefficients (rho). RESULTS: The intraclass correlation coefficient for the BBT and the NHPT ranged from 0.83 to 0.99. Significant systematic measurement errors were found for both tests and hands. The Kappa coefficient for the total sum score of the mSHFT was 0.95 for the more affected hand and 0.59 for the less affected hand. One of the 3 items showed systematic disagreements for both hands. The convergent validity (rho) for the more affected hand ranged from 0.41 (BBT versus mSHFT) to -0.68 (NHPT versus mSHFT). CONCLUSION: The test-retest reliability of the BBT, NHPT and mSHFT was high but all measures showed learning effects. The relationships between the 3 measures indicate that they partly complement one another. The BBT may be preferred for persons with moderate impairments of the upper extremity and the NHPT and the mSHFT for persons with milder impairments. As the mSHFT has the advantage of reflecting activities in daily life it may be a suitable alternative to the NHPT. LEVEL OF EVIDENCE: III. PMID- 26972365 TI - Thoracic Outlet Syndrome Causing Phantom Hand Pain in a Person With a Transradial Amputation: A Case Presentation. AB - In this case, a 47-year-old commercial truck driver with a remote right transradial amputation presented with pain in the medial aspect of his right phantom hand. He was diagnosed with thoracic outlet syndrome (TOS). This was attributed to the muscular demands associated with using his body-powered prosthesis for many years. TOS remains a controversial diagnosis in the able bodied population and a unique diagnostic challenge in a patient with a transradial amputation. In this case, consideration of TOS guided the rehabilitation and treatment plan. His pain improved with a conservative stretching program. PMID- 26972366 TI - Psychological Factors Are Related to Pain Intensity in Back-Healthy People Who Develop Clinically Relevant Pain During Prolonged Standing: A Preliminary Study. AB - BACKGROUND: An induced-pain paradigm has been used to examine risk factors for the development of low back pain (LBP) during prolonged standing in back-healthy people (standing paradigm). Previous studies that used induced-pain methods suggest that pain intensity may be related to psychologic factors. It is not currently known, however, whether pain intensity reported during the standing paradigm is related to psychologic factors. OBJECTIVE: To examine the relationship between LBP symptom intensity and psychological factors (fear of pain and pain catastrophizing) in back-healthy people who develop LBP during prolonged standing. We hypothesized that symptom intensity during standing would be positively related to initial levels of fear of pain and pain catastrophizing in people who developed LBP during standing. DESIGN: Cross-sectional. SETTING: Movement science research center at an academic medical center. PARTICIPANTS: Fifty seven back-healthy participants. METHODS: Participants completed the Fear of Pain Questionnaire-III (FPQ-III) and Pain Catastrophizing Scale (PCS) before a 2-hour standing protocol. Participants rated LBP intensity on a 100-mm visual analogue scale (VAS) throughout standing and were classified as pain developers (PDs) or nonpain developers (NPDs). Relationships between LBP intensity and psychological measures were examined in PDs that did and did not have a >=20 mm maximum VAS score. MAIN OUTCOME MEASUREMENTS: FPQ-III and PCS total scores, maximum and average VAS scores during standing. RESULTS: There were 24 (42%) PDs. Five PDs reported a maximum VAS score >=20 mm. For PDs with a maximum VAS score <20 mm, correlations between average VAS scores and each psychological measure were small and nonsignificant (FPQ-III: r = 0.16, P = .50; PCS: r = 0.27, P = .26). For PDs with a maximum VAS score >=20 mm, correlation between average VAS scores and FPQ-III was large and significant (r = 0.91, P = .03), and large for PCS but nonsignificant (r = 0.87, P = .06). CONCLUSION: These preliminary data suggest that if pain exceeds a clinically meaningful threshold (20 mm) during standing, pain intensity is related to psychological factors. Understanding factors that modulate acute pain response can inform early intervention strategies. LEVEL OF EVIDENCE: II. PMID- 26972367 TI - Loss of Dignity in End-of-Life Care in the Emergency Department: A Phenomenological Study with Health Professionals. AB - INTRODUCTION: The objective of this study was to explore and describe the experiences of physicians and nurses with regard to loss of dignity in relation to end-of-life care in the emergency department. METHOD: A phenomenological qualitative study was performed. Two focus groups and 12 individual interviews were conducted with a total of 26 participants, who had attended to patients in the emergency department an average of 14.3 years. An inductive analysis was carried out with the use of ATLAS.ti software to seek emerging themes. RESULTS: Three themes that helped us understand the phenomenon of the loss of dignity in end-of-life care in the emergency department emerged: (1) "Being exposed in a cold world," with the subthemes "improvising dying person care" and "a lack of space to care for the dying person"; (2) "Being self-critical with professional attitudes," with the subthemes "being aware of undignified actions" and "lack of a palliative culture"; and (3) "Family obstinacy and hospital rescue," with the subthemes "making ill-advised choices" and "avoiding burden." DISCUSSION: The dignity of people who are taken to the emergency department at the end of their life could be undermined by architectural and organizational characteristics, professionals' attitudes, and decisions made by family members. PMID- 26972368 TI - Medical Mondays: ED Utilization for Medicaid Recipients Depends on the Day of the Week, Season, and Holidays. AB - The purpose of this study is to describe and explain the temporal and seasonal trends in ED utilization for a low-income population. METHODS: A retrospective analysis of 66,487 ED Medicaid-insured health care claims in 2009 was conducted for 2 Western New York Counties using time-series analysis with autoregressive moving average (ARMA) models. RESULTS: The final ARMA (2,0) model indicated an autoregressive structure with up to a 2-day lag. ED volume is lower on weekends than on weekdays, and the highest volumes are on Mondays. Summer and fall seasons demonstrated higher volumes, whereas lower volume outliers were associated with holidays. DISCUSSION: Day of the week was an influential predictor of ED utilization in low-income persons. Season and holidays are also predictors of ED utilization. These calendar-based patterns support the need for ongoing and future emergency leaders' collaborations in community-based care system redesign to meet the health care access needs of low-income persons. PMID- 26972369 TI - Shared Governance and Work Engagement in Emergency Nurses. AB - INTRODUCTION: Lack of work engagement in emergency nurses has been linked to increased job turnover, burnout, and lack of job satisfaction. Shared governance is a vehicle that can be used by emergency nursing leaders to increase work engagement among emergency nurses. Research is lacking about the relationship between perceptions of shared governance and work engagement in emergency nurses. In this study we examined the relationship between ED nurses' perceptions of shared governance and work engagement. METHODS: A descriptive correlation design was used with a convenience sample of 43 emergency nurses recruited through the ENA Web site. Participants completed a demographic questionnaire, the Index of Professional Nursing Governance Tool, and the Utrecht Work Engagement Scale. RESULTS: The mean total work engagement score indicated average engagement (M = 4.4, standard deviation = 1.2). A significant positive relationship was found between shared governance and work engagement, indicating that as perceptions of shared governance increase, work engagement increases (r (41) = 0.62, P < .001). DISCUSSION: The study provides beginning evidence on the relationship of shared governance and work engagement in emergency nurses. Understanding the relationship between perceptions of shared governance and work engagement in emergency nurses may assist emergency nursing leaders in developing and testing interventions to enhance it. PMID- 26972370 TI - Pivot Nursing: An Alternative to Traditional ED Triage. AB - PROBLEM: A 7.2% increase in patient volume from 130,700 to 140,800 in 2012 prompted St Joseph's Regional Medical Center Emergency Department to review existing triage processes to decrease turnaround time. "Pivot triage" is a new, efficient intake process that entails use of 4 rather than 8 determinants to identify acuity levels. The purpose of this performance improvement project was to create alternatives to traditional triage to decrease ED length of stay and door-to-physician time. METHODS: After education, the pivot process was implemented using 4 determinants established by a multidisciplinary team. The pivot process was slowly implemented for 6 hours over a 1-week period to work out processing issues. Arrival time, door-to-physician time, and departure time from the emergency department were elements used to calculate the patient's turnaround time. Length of ED stay was collected monthly beginning in the fourth quarter of 2011. Comparisons were made after Pivot implementation in the fourth quarter of 2012. RESULTS: Despite the increasing volume, the mean door-to-physician time decreased from 71 to 40 minutes, a 43.7% reduction. The overall turnaround time decreased from 220 to 181 minutes, representing approximately a 17.7% reduction. The percentage of patients who left without being seen decreased from 2.5% to 1.0%. The pivot process improved patient flow in the emergency department, reducing time spent by the patient in the department. IMPLICATIONS FOR PRACTICE: The pivot process is a viable alternative to traditional triage. Nurses are able to accurately pivot patients with a reduced amount of information. PMID- 26972371 TI - Congenital erythroderma. PMID- 26972372 TI - The early postnatal period, mini-puberty, provides a window on the role of testosterone in human neurobehavioural development. AB - Experimental research in non-human mammals indicates that testosterone exposure during early periods of rapid brain development has enduring influences on brain and behaviour. These influences are exerted when testosterone is higher in developing males than females, and the affected characteristics are those that differ by sex. Testosterone is higher in males than in females from about weeks 8 to 24 of human gestation and then again during early infancy, and both of these periods are times of rapid brain development. Substantial evidence suggests that testosterone prenatally influences human neurobehavioral development. Emerging evidence suggests that the early postnatal period is important too. This early postnatal period could provide a window for studying testosterone interacting with experience to shape human gender development. PMID- 26972373 TI - Cardiac mitochondrial energy metabolism in heart failure: Role of cardiolipin and sirtuins. AB - Mitochondrial oxidation of fatty acids accounts for the majority of cardiac ATP production in the heart. Fatty acid utilization by cardiac mitochondria is controlled at the level of fatty acid uptake, lipid synthesis, mobilization and mitochondrial import and oxidation. Consequently defective mitochondrial function appears to be central to the development of heart failure. Cardiolipin is a key mitochondrial phospholipid required for the activity of the electron transport chain. In heart failure, loss of cardiolipin and tetralinoleoylcardiolipin helps to fuel the generation of excessive reactive oxygen species that are a by-product of inefficient mitochondrial electron transport chain complexes I and III. In this vicious cycle, reactive oxygen species generate lipid peroxides and may, in turn, cause oxidation of cardiolipin catalyzed by cytochrome c leading to cardiomyocyte apoptosis. Hence, preservation of cardiolipin and mitochondrial function may be keys to the prevention of heart failure development. In this review, we summarize cardiac energy metabolism and the important role that fatty acid uptake and metabolism play in this process and how defects in these result in heart failure. We highlight the key role that cardiolipin and sirtuins play in cardiac mitochondrial beta-oxidation. In addition, we review the potential of pharmacological modulation of cardiolipin through the polyphenolic molecule resveratrol as a sirtuin-activator in attenuating mitochondrial dysfunction. Finally, we provide novel experimental evidence that resveratrol treatment increases cardiolipin in isolated H9c2 cardiac myocytes and tetralinoleoylcardiolipin in the heart of the spontaneously hypertensive rat and hypothesize that this leads to improvement in mitochondrial function. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk. PMID- 26972374 TI - Sinusoidal dilation increases the risk of complications in hepatectomy for CRCLM Protective effect of bevacizumab and diabetes mellitus, serum gamma glutamyltranspeptidase as predictive factor. AB - INTRODUCTION: Advances in neoadjuvant chemotherapy (NCT) have allowed surgical treatment in otherwise unresectable patients with colorectal liver metastases (CRLM). It is well known that NCT induces liver lesions such as sinusoidal obstruction syndrome (SOS) and steatohepatitis (SH). However, whether it affects postoperative morbidity remains controversial. The aim of this study was both to evaluate the impact of NCT on liver parenchyma and postoperative morbidity, and to identify preoperative predictive markers for liver injury. PATIENTS AND METHODS: Among 140 patients undergoing liver resection for CRLM between 2010 and 2013, 70 underwent systemic NCT. Liver function tests, pathology, postoperative morbidity and mortality were compared between the two groups. RESULTS: Univariate analysis revealed NCT as a cause of sinusoidal dilation (p = 0.09), peliosis (p = 0.028) and moderate and severe SOS (p = 0.004) and bevacizumab as a protective agent against moderate and severe SOS (p = 0.045). Diabetic patients were identified as having a lower incidence of sinusoidal dilation (p = 0.034) and a higher incidence of steatosis (p = 0.003). Multivariate analysis confirmed sinusoidal dilation as an independent cause for morbidity (p = 0.02) and liver specific complications (p = 0.016). Preoperative level of GGT was identified as predictive factor for moderate and severe SOS and peliosis (p < 0.001 and p = 0.004, respectively). CONCLUSION: The administration of NCT induces SOS-lesions, but can be partially prevented by bevacizumab and diabetes. Sinusoidal dilation is associated with increased postoperative morbidity. Preoperative GGT levels can be useful to predict the presence of SOS. PMID- 26972375 TI - A multicenter experience with peri-rectal tumors: The risk of local recurrence. AB - BACKGROUND: Peri-rectal tumors are rare and their management is challenging, especially when presenting with local recurrence. The aim of the current study was to report a multicenter series of peri-rectal tumors, focusing on the risk of recurrence. MATERIAL AND METHODS: From 1994 to 2014, patients with peri-rectal tumors from three different centers were retrospectively analyzed. Sixty-two patients were identified and divided into two groups; Group 1: patients who presented with local recurrence at follow-up (n = 9, recurrence rate: 14.5%), and Group 2: patients without recurrence (n = 53). RESULTS: In Group 1, there were initially more patients with symptoms of a perineal mass (44.4% vs. 12.2%; p = 0.04), more malignant tumors (55.6% vs. 15.1%; p = 0.02), and larger lesions (+2.6 cm; p = 0.004). Incomplete resection was also more frequent in Group 1 (44.4% vs. 3.8%; p = 0.003). Eight patients with recurrence had further surgery, whilst one patient had radiological recurrence and was treated medically. Among the eight re-resections, five patients remain disease-free; two have had further recurrences and have had palliative treatment, whilst another has had a further resection and remains disease-free. CONCLUSIONS: Peri-rectal tumors are uncommon and there is no consensus on best management. Based on this large multicenter series, several risk factors seem to be associated with local recurrence, namely patient- (discovery of a perineal mass), tumor- (malignant and large lesion), and surgery-related (incomplete resection). Clinical follow-up should be adapted according to these factors. PMID- 26972376 TI - Effectiveness of Intravitreal Injection of Ranibizumab for Neovascular Age Related Macular Degeneration with Serous Pigment Epithelial Detachment. AB - BACKGROUND: We sought to observe the effectiveness of intravitreal injection of ranibizumab in treating neovascular age-related macular degeneration (nAMD) with serous pigment epithelial detachment (sPED). MATERIAL/METHODS: A retrospective, noncomparative case series was performed. Twenty-3 eyes of 23 patients with sPED secondary to nAMD who had received intravitreal injections of ranibizumab were included in this study. All patients underwent best-corrected visual acuity (BCVA), synchronous fluorescein fundus angiography (FFA), indocyanine green angiography (ICGA), and optical coherence tomography (OCT) examinations. All patients were treated with pro re nata intravitreal injections after 3 loading doses of ranibizumab and were followed up for 12 months. The differences in the BCVAs, maximum PED heights, PED volumes and CFTs of the affected eyes were compared between the baseline and last visit. RESULTS: Twelve months after the first injection, improved visual acuity was observed in 16 of the 23 eyes. 4 eyes exhibited stable visual acuity, and 3 eyes exhibited impaired visual acuity. The mean post-injection logMAR BCVA was 0.58+/-0.05, which was much better than that at baseline (0.76+/-0.08; t=1.751, P=0.0869). The mean maximum PED height at baseline was 350.17+/-35.73 MUm and it was decreased to 238.87+/-36.87 MUm (t=2.192, P=0.0337) at the last visit. The mean PED volume after injection was 0.34+/-0.1 mm(3), which was significantly decreased compared with that at baseline (0.81+/-0.21 mm(3); t=2.021, P=0.0494).The mean CFT decreased, but this difference was not statistically significant (t=1.003, P=0.3211). None of the patients exhibited endophthalmitis, uveitis or RPE tears. CONCLUSIONS: Intravitreal injection of ranibizumab for the treatment of neovascular age related macular degeneration with serous pigment epithelial detachment safely and effectively improved the patients' visual acuities and decreased their PED heights volumes. PMID- 26972377 TI - Inner ear delivery of dexamethasone using injectable silk-polyethylene glycol (PEG) hydrogel. AB - Minimally invasive delivery and sustained release of therapeutics to the inner ear are of importance to the medical treatment of inner ear disease. In this study, the injectable silk fibroin-polyethylene glycol (Silk-PEG) hydrogel was investigated as a drug delivery carrier to deliver poorly soluble micronized dexamethasone (mDEX) to the inner ear of guinea pigs. Encapsulation of mDEX with a loading up to 5% (w/v) did not significantly change the silk gelation time, and mDEX were evenly distributed in the PEG-Silk hydrogel as visualized by SEM. The loading of mDEX in Silk-PEG hydrogel largely influenced in vitro drug release kinetics. The optimized Silk-PEG-mDEX hydrogel (2.5% w/v loading, in situ forming, 10 MUl) was administered directly onto the round window membrane of guinea pigs. The DEX concentration in perilymph maintained above 100 ng/ml for at least 10 days for the Silk-PEG formulation while less than 12h for the control sample of free mDEX. Minimal systemic exposure was achieved with low DEX concentrations (<0.2 MUg/ml) in cerebrospinal fluid (CSF) and plasma in the first 2h after the local application of the Silk-PEG-mDEX hydrogel. A transient hearing threshold shift was found but then resolved after 14 days as revealed by auditory brainstem response (ABR), showing minimal inflammatory responses on the round window membrane and scala taympani. The Silk-PEG hydrogel completely degraded in 21 days. Thus, the injectable PEG-Silk hydrogel is an effective and safe vehicle for inner ear delivery and sustained release of glucocorticoid. PMID- 26972378 TI - 2,2'Dithiodinicotinyl ligands: Key to more reactive thiomers. AB - The aim of this study was to establish a novel type of preactivated thiomers exhibiting a comparatively higher reactivity with mucus and consequently improved mucoadhesive properties. In order to achieve this goal, the dimeric form of 2 mercaptonicotinic acid (MNA-MNA) was directly attached to the polymeric backbone of chitosan (CHI) via amide bond formation mediated by 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide (EDAC) used as a coupling reagent. The remaining free amino groups were in the following reacted with succinic anhydride (Succ) in order to obtain a uniformly anionically charged polymer (CHI-Succ-MNA-MNA). Within this study, different coupling rates of up to 170 MUmol MNA-MNA per gram polymer were achieved. The attachment of the dimeric ligand resulted in a preactivated thiomer with a comparatively more reactive disulfide substructure due to the additional nitrogen atom in conjugation over the aromatic moieties. Furthermore, the obtained polymer is entirely preactivated and thus prevented against undesired oxidation reactions. Kinetic studies of disulfide exchange reactions showed a 3.8-fold higher reactivity of CHI-Succ-MNA-MNA in comparison to a state-of-the-art preactivated thiomer. Within rheological measurements, CHI Succ-MNA-MNA with a coupling rate of 170 MUmol (CHI-Succ-MNA-MNA 170) led to a 5.7-fold higher mucus viscosity than the non-thiolated control polymer (CHI-Succ) indicating a rheological synergism due to mucoadhesive properties. These results were confirmed by a second mucoadhesion study, which showed a significantly prolonged retention time of CHI-Succ-MNA-MNA on the small intestinal mucosa compared to CHI-Succ (P<0.02). Accordingly, the double preactivation seems to be a promising strategy in order to obtain entirely preactivated polymers with enhanced mucoadhesive properties. PMID- 26972380 TI - Cyclosporine A-loaded lipid nanoparticles in inflammatory bowel disease. AB - Cyclosporine A (CsA) is a well-known immunosuppressive agent used as rescue therapy in severe steroid-refractory ulcerative colitis (UC). However, toxicity issues associated with CsA when administered in its commercially available formulations have been reported in clinical practice. Since nanotechnology has been proposed as a promising strategy to improve safety and efficacy in the treatment of inflammatory bowel disease (IBD), the main purpose of this study was to evaluate the effect of oral administration of CsA-loaded lipid nanoparticles (LN) in the dextran sodium sulfate (DSS)-induced colitis mouse model using Sandimmune Neoral((r)) as reference. The results showed that the formulations used did not decrease colon inflammation in terms of myeloperoxidase activity (MPO), tumor necrosis factor (TNF)-alpha expression, or histological scoring in the acute stage of the disease. However, further studies are needed in order to corroborate the efficacy of these formulations in the chronic phase of the disease. PMID- 26972379 TI - Polymeric protective agents for nanoparticles in drug delivery and targeting. AB - Surface modification/functionalization of nanoparticles (NPs) using polymeric protective agents is an issue of great importance and actuality for drug delivery and targeting. Improving the blood circulation half-life of surface-protected nanocarriers is closely related to the elimination of main biological barriers and limiting factors (protein absorption and opsonization), due to the phagocytic activity of reticuloendothelial system. For passive or active targeted delivery, in biomedical area, surface-functionalized NPs with tissue-recognition ligands were designed and optimized as a result of modern research techniques. Also, multi-functionalized nanostructures are characterized by enhanced bioavailability, efficacy, targeted localization, active cellular uptake, and low side effects. Surface-protected NPs are obtained from biocompatible, biodegradable and less toxic natural polymers (dextran, beta-cyclodextrin, chitosan, hyaluronic acid, heparin, gelatin) or synthetic polymers, such as poly(lactic acid), poly(lactic-co-glycolic) acid, poly(epsilon-caprolactone) and poly(alkyl cyanoacrylates). PEGylation is one of the most important functionalization methods providing steric stabilization, long circulating and 'stealth' properties for both polymeric and inorganic-based nanosystems. In addition, for their antimicrobial, antiviral and antitumor effects, cutting-edge researches in the field of pharmaceutical nanobiotechnology highlighted the importance of noble metal (platinum, gold, silver) NPs decorated with biopolymers. PMID- 26972381 TI - Annealing as a tool for the optimization of lyophilization and ensuring of the stability of protein-loaded PLGA nanoparticles. AB - The aim of this work was to use annealing as a tool to optimize the lyophilization cycle by decreasing its duration time, and simultaneously preserve the stability of poly(lactic-co-glycolic acid) nanoparticles and with upmost importance, maintain the structural stability of loaded insulin, used as model therapeutic protein. The contribution of a cryoprotectant in this preservation process was also evaluated. Insulin-loaded nanoparticles co-encapsulated with and without trehalose as cryoprotectant were produced, resulting in a particle size of about 250-300 nm, a PdI around 0.25 and a zeta potential in the range of -20 to -24 mV. The insulin association efficiency was higher than 90%, and the loading capacity was of 11-12%. The use of annealing allowed the decrease of duration time of primary drying in about 38%, representing a global decrease of lyophilization time of around 26%. The residual moisture content of all lyophilizates was around 1%, and the reconstitution of lyophilizates obtained using annealing was even faster than those without annealing. The co-encapsulated trehalose better preserved the nanoparticle size throughout the lyophilization process using annealing, compared to formulation containing no cryoprotectant. Fourier-transform infrared spectroscopy showed that the trehalose-containing nanoparticles presented higher insulin structural maintenance, compared to nanoparticles without cryoprotectant, presenting an insulin structural maintenance of 85.3 +/- 0.7% and 86.0 +/- 1.0% for annealing and no annealing, respectively. This formulation also presented the closest structural similarity with native insulin. Interestingly, the structural features of insulin loaded into nanoparticles upon lyophilization with and without annealing were practically identical, showing that annealing had no detrimental effect in insulin structure. Circular dichroism and fluorescence spectroscopy confirmed these results. Overall, this work gave rise to the importance of annealing in decreasing the duration time of lyophilization of protein-loaded poly(lactic-co glycolic acid) nanoparticles, and simultaneously ensuring the stability of the carrier and loaded protein. PMID- 26972382 TI - Synthesis and absolute configuration assignment of albucidin: a late-stage reductive deiodination by visible light photocatalysis. AB - The synthesis of albucidin and its enantiomer are described. It involves a visible-light photocatalysis deiodination at the late stage. The absolute configuration of natural albucidin is determined as (1R,3S). This work provides a basis for structural modification to develop a new type of herbicidal from an old structure. PMID- 26972383 TI - Identification of sub-groups in acutely ill elderly patients with delirium: a cluster analysis. AB - BACKGROUND: Delirium is a serious neuropsychiatric syndrome affecting mainly elderly participants with acute medical diseases. The pathophysiology of delirium remains poorly understood as it involves complex dynamic interactions between a diversity of risk factors. Exploring how etiological factors interact with each other can clarify the pathophysiological mechanisms and facilitate the early identification of this syndrome. The aim of this study was to explore how different risk factors co-occur in medically ill elderly patients with delirium with cluster analysis and identify clinically meaningful sub-groups in this population. METHODS: A cross-sectional study was developed. Ninety-nine elderly inpatients admitted to acute medical wards diagnosed with delirium during hospitalization were selected. For each patient sociodemographic characteristics, acute and chronic medical conditions, laboratory parameters, and current medication were collected. RESULTS: The cluster analysis extracted three distinct subgroups of participants with delirium. Patients in cluster 1 (n = 28) had higher rates of medication with anticholinergic proprieties. Cluster 2 (n = 29) included participants with cardiac and pulmonary comorbidities associated with both chronic and acute reduction of blood flow and/or oxygenation to the brain. Cluster 3 (n = 42 patients) comprised patients with simultaneous deregulation of different organs/systems, such as electrolytic disturbances, metabolic disturbances, and acute renal failure. Known predisposing factors of delirium, such as age and pre-existing dementia, were similar between groups. CONCLUSIONS: The results reveal different patterns of clinical characteristics in elderly patients with delirium. This is relevant to clinical care of acute medically ill patients and suggests that different pathways are implicated in delirium pathophysiology. PMID- 26972384 TI - Detection of ureolytic activity of bacterial strains isolated from entomopathogenic nematodes using infrared spectroscopy. AB - The pathogenicity of entomopathogenic nematodes (EPNs) depends directly on the presence of bacteria in the nematode digestive tracts. Based on 16S rRNA and MALDI-TOF analyses 20 isolated bacteria were assigned to 10 species with 10 isolates classified as Pseudomonas ssp. Six strains (30%) show ureolytic activity on Christensen medium. Spectroscopic analysis of the strains showed that the ureolytic activity is strongly correlated with the following wavenumbers: 935 cm( 1) in window W4, which carries information about the bacterial cell wall construction and 1158 cm(-1) in window W3 which corresponds to proteins in bacterial cell. A logistic regression model designed on the basis of the selected wavenumbers differentiates ureolytic from non-ureolytic bacterial strains with an accuracy of 100%. Spectroscopic studies and mathematical analyses made it possible to differentiate EPN-associated Pseudomonas sp. strains from clinical Pseudomonas aeruginosa PAO1. These results suggest, that infrared spectra of EPN associated Pseudomonas sp. strains may reflect its adaptation to the host. PMID- 26972386 TI - Rationally designed donor-acceptor scheme based molecules for applications in opto-electronic devices. AB - Several donor (D)-acceptor (A) based molecules are rationally designed by adopting three different schemes in which the conjugation length, strength of the donor and acceptor moieties, and planarity of the molecules are varied. These variations are made by introducing a pi-conjugated linkage unit, terminating the ends of the moieties by different electron donating and accepting functional groups, and fusing the donor and acceptor moieties, respectively. Our DFT and TDDFT based calculations reveal that using the above-mentioned design schemes, the electronic and optical properties of the D-A based molecules can be largely tuned. While introduction of a linkage and fusing of moieties enhance the pi-pi interaction, addition of electron donating groups (-CH3, -OH, and -NH2) and electron accepting groups (-CF3, -CN, -NO2, and -NH3(+)) varies the strength of the donor and acceptor moieties. These factors lead to modulation of the HOMO and LUMO energy levels and facilitate the engineering of the HOMO-LUMO gap and the optical gap over a wide range of ~0.7-3.7 eV. Moreover, on the basis of calculated ionization potential and reorganization energy, most of the investigated molecules are predicted to be air stable and to exhibit high electron mobility, with the possibility of the presence of ambipolar characteristics in a few of them. The results of our calculations not only demonstrate the examined molecules to be the potential materials for organic opto electronic devices, but also establish an understanding of the composition structure-property correlation, which will provide guidelines for designing and synthesizing new materials of choice. PMID- 26972387 TI - Predictive statistical models of baseline variations in 3-D femoral cortex morphology. AB - Quantifying human femoral cortex morphology is important for forensic science, surgical planning, prosthesis design and musculoskeletal modeling. Previous studies have been restricted by traditional zero or one dimensional morphometric measurements at discrete locations. We have used automatic image segmentation and statistical shape modeling methods to create predictive models of baseline 3-D femoral cortex morphology on a statistically significant population. A total of 204 femurs were automatically segmented and measured to obtain 3-D shape, whole surface cortical thickness, and morphometric measurements. Principal components of shape and cortical thickness were correlated to anthropological data (age, sex, height and body mass) to produce predictive statistical models. We show that predictions of an individual's age, height, and sex can be improved by using 3-D shape and cortical thickness when compared with traditional morphometric measurements. We also show that femoral cortex geometry can be predicted from anthropological data combined with femoral measurements with less than 2.3 mm root mean square error, and cortical thickness with less than 0.5 mm root mean square error. The predictive models presented offer new ways to infer subject specific 3-D femur morphology from sparse subject data for biomechanical simulations, and inversely infer subject data from femur morphology for anthropological and forensic studies. PMID- 26972385 TI - Stress Regulates Aquaporin-8 Permeability to Impact Cell Growth and Survival. AB - Aquaporin-8 (AQP8) allows the bidirectional transport of water and hydrogen peroxide across biological membranes. Depending on its concentration, H2O2 exerts opposite roles, amplifying growth factor signaling in physiological conditions, but causing severe cell damage when in excess. Thus, H2O2 permeability is likely to be tightly controlled in living cells. AIMS: In this study, we investigated whether and how the transport of H2O2 through plasma membrane AQP8 is regulated, particularly during cell stress. RESULTS: We show that diverse cellular stress conditions, including heat, hypoxia, and ER stress, reversibly inhibit the permeability of AQP8 to H2O2 and water. Preventing the accumulation of intracellular reactive oxygen species (ROS) during stress counteracts AQP8 blockade. Once inhibition is established, AQP8-dependent transport can be rescued by reducing agents. Neither H2O2 nor water transport is impaired in stressed cells expressing a mutant AQP8, in which cysteine 53 had been replaced by serine. Cells expressing this mutant are more resistant to stress-, drug-, and radiation induced growth arrest and death. INNOVATION AND CONCLUSION: The control of AQP8 mediated H2O2 transport provides a novel mechanism to regulate cell signaling and survival during stress. Antioxid. Redox Signal. 24, 1031-1044. PMID- 26972389 TI - Historic accounts of Mansonella parasitaemias in the South Pacific and their relevance to lymphatic filariasis elimination efforts today. AB - There are two species of filarial parasites with sheathless microfilariae known to commonly cause parasitaemias in humans: Mansonella perstans and Mansonella ozzardi. In most contemporary accounts of the distribution of these parasites, neither is usually considered to occur anywhere in the Eastern Hemisphere. However, Sir Patrick Manson, who first described both parasite species, recorded the existence of sheathless sharp-tailed Mansonella ozzardi-like parasites occurring in the blood of natives from New Guinea in each and every version of his manual for tropical disease that he wrote before his death in 1922. Manson's reports were based on his own identifications and were made from at least two independent blood sample collections that were taken from the island. Pacific region Mansonella perstans parasitaemias were also later (in 1923) reported to occur in New Guinea and once before this (in 1905) in Fiji. Although Mansonella parasitaemias are generally regarded as benign, they are thought to be of public health importance because they can affect the epidemiological monitoring of other filarial diseases. In this article, we reviewed the historic literature concerning Pacific-origin Mansonella-parasitaemias in an attempt to explain how, despite repeated reports of Pacific-region Mansonella-parasitaemias, by as early as the 1970s, the WHO had arrived at the present-day view that Wuchereria bancrofti is the only cause of filarial parasitaemias in Papua New Guinea. We have also evaluated the evidence supporting the contemporary existence of Pacific area parasitaemia-causing Mansonella parasites and assessed the relevance such parasites could have for present-day lymphatic filariasis elimination efforts in the region. PMID- 26972390 TI - Antihydatic and immunomodulatory effects of Punica granatum peel aqueous extract in a murine model of echinococcosis. AB - OBJECTIVE: To investigate the effect of pomegranate peel aqueous extract (PGE) on the development of secondary experimental echinococcosis and on the viability of Echinococcus granulosus protoscoleces, and the immunomodulatory properties of PGE. METHODS: Swiss mice were inoculated intraperitoneally with viable protoscoleces. Then, PGE was orally administered daily during cystic echinococcosis development. Cyst development and hepatic damage were macroscopically and histologically analyzed. The production of nitric oxide and TNF-alpha was assessed in plasma and the hepatic expression of iNOS, TNF-alpha, NF-kappaB and CD68 was examined. Moreover, protoscoleces were cultured and treated with different concentrations of PGE. RESULTS: It was observed that in vitro treatment of protoscoleces caused a significant decrease in viability in a PGE-dose-dependent manner. In vivo, after treatment of cystic echinococcosis infected mice with PGE, a significant decrease in nitric oxide levels (P < 0.0001) and TNF-alpha levels (P < 0.001) was observed. This decline was strongly related to the inhibition of cyst development (rate of hydatid cyst growth inhibition = 63.08%) and a decrease in CD68 expression in both the pericystic layer of hepatic hydatid cysts and liver tissue (P < 0.0001). A significant diminution of iNOS, TNF-alpha and NF-kappaB expression was also observed in liver tissue of treated mice (P < 0.0001). CONCLUSIONS: Our results indicate an antihydatic scolicidal effect and immunomodulatory properties of PGE, suggesting its potential therapeutic role against Echinococcus granulosus infection. PMID- 26972388 TI - Multiple modes of inhibition of human cytochrome P450 2J2 by dronedarone, amiodarone and their active metabolites. AB - Dronedarone, a multiple ion channel blocker is prescribed for the treatment of paroxysmal and persistent atrial fibrillation. While dronedarone does not precipitate toxicities like its predecessor amiodarone, its clinical use has been associated with idiosyncratic hepatic and cardiac adverse effects and drug-drug interactions (DDIs). As dronedarone is a potent mechanism-based inactivator of CYP3A4 and CYP3A5, a question arose if it exerts a similar inhibitory effect on CYP2J2, a prominent cardiac CYP450 enzyme. In this study, we demonstrated that CYP2J2 is reversibly inhibited by dronedarone (Ki=0.034 MUM), amiodarone (Ki=4.8MUM) and their respective pharmacologically active metabolites namely N desbutyldronedarone (NDBD) (Ki=0.55 MUM) and N-desethylamiodarone (NDEA) (Ki=7.4 MUM). Moreover, time-, concentration- and NADPH-dependent irreversible inactivation of CYP2J2 was investigated where inactivation kinetic parameters (KI, kinact) and partition ratio (r) of dronedarone (0.05 MUM, 0.034 min(-1), 3.3), amiodarone (0.21 MUM, 0.015 min(-1), 20.7) and NDBD (0.48 MUM, 0.024 min( 1), 21.7) were observed except for NDEA. The absence of the characteristic Soret peak, lack of recovery of CYP2J2 activity upon dialysis, and biotransformation of dronedarone and NDBD to quinone-oxime reactive metabolites further confirmed the irreversible inactivation of CYP2J2 by dronedarone and NDBD is via the covalent adduction of CYP2J2. Our novel findings illuminate the possible mechanisms of DDIs and cardiac adverse effects due to both reversible inhibition and irreversible inactivation of CYP2J2 by dronedarone, amiodarone and their active metabolites. PMID- 26972391 TI - Hepatoprotective effects of Nigella sativa seed extract against acetaminophen induced oxidative stress. AB - OBJECTIVE: To investigate the protective effects of Nigella sativa seed extract (NSSE) against acetaminophen (APAP)-induced hepatotoxicity in TIB-73 cells and rats. METHODS: Toxicity in TIB-73 cells was induced with 10 MUmol/L APAP and the protective effects of NSSE were evaluated at 25, 50, 75, 100 MUg/mL. For in vivo examination, a total of 30 rats were equally divided into five experimental groups; normal control (vehicle), APAP (800 mg/kg body weight single IP injection) as a hepatotoxic control, and three APAP and NS pretreated (2 weeks) groups (APAP + NSSE 100 mg; APAP + NSSE 300 mg and APAP + NSSE 900 mg/kg). RESULTS: TIB-73 cell viability was drastically decreased by (49.0 +/- 1.9)% after the 10 MUmol/LAPAP treatment, which also increased reactive oxygen species production. Co-treatment with NSSE at 25, 50, 75, and 100 MUg/mL significantly improved cell viability and suppressed reactive oxygen species generation. In vivo, the APAP induced alterations in blood lactate levels, pH, anionic gap, and ion levels (HCO3(-), Mg(2+) and K(+)), which tended to normalize with the NSSE pretreatment. The NSSE also significantly decreased elevated serum levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase induced by APAP, which correlated with decreased levels of hepatic lipid peroxidation (malondialdehyde), increased superoxide dismutase levels, and reduced glutathione concentrations. Improved hepatic histology was also found in the treatment groups other than APAP group. CONCLUSIONS: The in vitro and in vivo findings of this study demonstrated that the NSSE has protective effects against APAP-induced hepatotoxicity and metabolic disturbances by improving antioxidant activities and suppressing both lipid peroxidation and ROS generation. PMID- 26972392 TI - Achillea fragrantissima, rich in flavonoids and tannins, potentiates the activity of diminazine aceturate against Trypanosoma evansi in rats. AB - OBJECTIVE: To evaluate activity of methanol extract of Achillea fragrantissima (meth) (A. fragrantissima) alone or in combination with diminazine aceturate (DA) against Trypanosoma evansi (T. evansi) in experimentally infected rats. METHODS: Sixty adult male Wister albino rats were divided equally into 6 groups (A-F). Rats in groups A-E were experimentally infected with T. evansi and those in group F were uninfected. The groups were treated respectively as follows: group A-with 3.5 mg/kg DA; group B- with 1000 mg/kg meth A. fragrantissima; group C-3.5 mg/kg DA plus 500 mg/kg meth A. fragrantissima; group D-3.5 mg/kg DA plus 1000 mg/kg meth A. fragrantissima. Group E was left untreated. Parasitemia, survivability, packed cell volume, hemoglobin concentration, total leucocytes count, lymphocyte count, and serum malondialdehyde and reduced glutathione (GSH) levels were estimated. Phytochemical screening of meth A. fragrantissima was also performed. RESULTS: The phytochemical analysis of the meth A. fragrantissima indicated a higher content from polyphenolic tannins and non tannins and flavonoids. The efficacy percentage against trypanosomiasis in groups A - E was respectively as follows 80, 40, 90, 100, 0. The administration of meth-A. fragrantissima (1000 mg/kg b.wt.) produced a moderate efficacy against trypanosomiasis. Untreated rats in group E died between 25 and 30 d post infection. The rats given DA and meth A. fragrantissima combinations (C and D) showed faster and higher recovery rates than the uninfected control and groups A and B. The initial reduction in packed cell volume, hemoglobin, total leucocytes count, increases in serum malondialdehyde and decreases in GSH levels were reversed by the treatments. CONCLUSION: The administration of the methanol extracts of A. fragrantissima and DA combination therapy was more effective than each product alone in the treatment of rats infected with T. evansi and further studies are required to isolate more active ingredients. PMID- 26972393 TI - Detection of coat protein gene of nervous necrosis virus using loop-mediated isothermal amplification. AB - OBJECTIVE: To establish a novel and highly specific loop-mediated isothermal amplification (LAMP) assay for the identification of nervous necrosis virus (NNV) infection. METHODS: A set of synthesized primers was used to match the sequences of a specific region of the nnv gene from the National Center for Biotechnology Information database, not originating from NNV-infected fish, the efficiency and specificity of LAMP were measured dependent on the concentration of DNA polymerase and the reaction temperature and time. In addition, to determine species-specific LAMP primers, cross reactivity testing was applied to the reaction between NVV and other virus families including viral hemorrhagic septicemia virus and marine birnavirus. RESULTS: The optimized LAMP reaction carried out at 64 degrees C for 60 min, and above 4 U Bst DNA polymerase. The sensitivity of LAMP for the detection of nnv was thus about 10 times greater than the sensitivity of polymerase chain reaction. The LAMP assay primers were specific for the detection NNV infection in Epinephelus septemfasciatus. CONCLUSIONS: The development of LAMP primers based on genetic information from a public database, not virus-infected samples, may provide a very simple and convenient method to identify viral infection in aquatic organisms. PMID- 26972394 TI - Pharmacodynamics of aminoglycosides and tetracycline derivatives against Japanese encephalitis virus. AB - OBJECTIVE: To explore the antiviral activity of antibiotic compounds, mainly aminoglycosides and tetracyclines against Japanese encephalitis virus (JEV) induced infection in vitro. METHODS: Antiviral activity were evaluated against JEV using cytopathic effect inhibition assay, virus yield reduction assay, caspase 3 level, extracellular viral detection by antigen capture ELISA and viral RNA levels. RESULTS: JEV induced cytopathic effect along with reduction of viral progeny plaque formation indicated antiviral potential of the compounds suggesting that antibiotics had broad spectrum activity. Doxycycline and kanamycin administration in dose dependent manner declined viral RNA replication. CONCLUSIONS: The present study shows kanamycin and doxycycline can affect virion structure and alter replication causing inhibition of JEV induced pathogenesis in vitro. PMID- 26972396 TI - Echovirus serotypes circulating in Malaysia from 2002 to 2013. AB - OBJECTIVE: To identify the circulating serotypes of human echovirus in Malaysia from 2002 to 2013. METHODS: A total of 31 retrospective samples from non-polio acute flacid paralysis, hand-food-and-mouth disease, viral meningitis and enterovirus cases were subjected to amplification of partial VP1 gene by RT-PCR. RESULTS: Sequencing and phylogenetic analysis of the partial sequences identified presence of human echovirus and human coxsackie viruses. It was found that echovirus 11 was the commonly circulating serotype followed by echovirus 6, echovirus 7, echovirus 3, echovirus 9, echovirus 30 and echovirus 1 in decreasing order. Additionally two types of human coxsackie virus isolates were detected which were coxsackie A24 and B3. CONCLUSIONS: From the findings, there is a possibility that echovirus 11 is the predominant serotype among Malaysian patients with echovirus infection. However, a larger sample size will yield a more confident result to support this evidence. PMID- 26972395 TI - Relationship between CD14-159C/T gene polymorphism and acute brucellosis risk. AB - OBJECTIVE: To investigate the association between the cluster of differentiation 14 (CD14)-159C/T (rs2569190) gene polymorphism and susceptibility to acute brucellosis in an Iranian population. METHODS: The study included 153 Iranian patients with active brucellosis and 128 healthy individuals as the control group. Genotyping of the CD14 variant was performed using an amplification refractory mutation system-polymerase chain reaction method. RESULTS: The prevalence of CD14-159 TT and CT genotypes were associated with increased risk of brucellosis [odds ratio (OR) = 1.993, 95% confidence interval (95% CI) = 1.07 3.71, P = 0.03 for CT; OR = 3.869, 95% CI = 1.91-7.84, P = 0.01 for TT genotype. Additionally, the minor allele (T) was significantly more frequently present in brucellosis patients than in controls (61% vs. 45%, respectively), and was a risk factor for brucellosis (OR = 3.058, 95% CI = 1.507-6.315, P = 0.01). CONCLUSIONS: The findings provided suggestive evidence of association of the CD14-159C/T gene polymorphism with susceptibility to acute brucellosis in the Iranian population. PMID- 26972397 TI - Characteristics, clinical outcomes and factors influencing mortality of patients with melioidosis in southern Thailand: A 10-year retrospective study. AB - OBJECTIVE: To study characteristics, clinical outcomes and factors influencing mortality of patients afflicted with melioidosis. METHODS: We retrospectively analyzed 134 patients, with a microbiologically-confirmed diagnosis of melioidosis, during the period from January 2002 to June 2011 at Songklanagarind Hospital, a tertiary care hospital in southern Thailand. RESULTS: The prevalence of melioidosis among admitted patients was 36.8 per 100000 in patients. The median age was 49 years and they were predominantly male. The most common underlying disease was diabetes mellitus (47.01%). The majority of cases (50%) had localized infection. The rates of multifocal, bacteremic, and disseminated infections were 12.7%, 23.1%, and 14.2%, respectively. The lungs were the most common organ afflicted, resulting in infection (24.63%). Splenic abscess as well as liver abscess accounted for 20.90% and 19.40%, respectively. A total of one eighth of the patients had septic shock at presentation. The overall mortality rate was 8.96%. The factors influencing mortality were pneumonia, septic shock, a positive blood culture for Burkholderia pseudomallei, superimposing with nosocomial infection and inappropriate antibiotic administration. CONCLUSIONS: Melioidosis is not uncommon in southern Thailand. The mortality of patients with pneumonia, bacteremia and septic shock is relatively high. Appropriate antibiotics, initially, will improve outcomes. PMID- 26972398 TI - Effect of dimethyl fumarate on rats with chronic pancreatitis. AB - OBJECTIVE: To discuss the effect of dimethyl fumarate (DMF) on rats with l arginine induced chronic pancreatitis (CP). METHODS: Male Wistar rats were given DMF treatment (25 mg/kg) by oral lavage method; then Wistar rats were given the intraperitoneal injection of l-arginine for 5 times (250 mg/100 kg, twice per time, each interval of 1 h) for building of CP model. Rats were divided into control group, CP group, DMF group and CP + DMF group. Rats in CP + DMF group were given the oral intragastric administration of DMF (25 mg/kg), while rats in control group and CP group were given the equal volume of normal saline. The weight of rats was evaluated and the intraperitoneal glucose tolerance test was performed (IPGTT, 2 g/kg). The islet of rats was isolated and then flow cytometry was employed to evaluate the quality and activity of islets. Meanwhile, the histology of non-endocrine tissues and levels of myeloperoxidase (MPO) and malondialdehyde (MDA) were detected. RESULTS: Compared with control group, the weight of rats in CP group was significantly reduced at week 2, 4 and 6; the blood glucose significantly increased, AUC increased, the histopathological scores of pancreatic atrophy, acinar injury, edema and cellular infiltration increased, levels of MDA and MPO increased, the islet equivalent and islet activity decreased at 0, 30, 60, 120 and 180 min. Compared with CP group, the weight of rats in CP + DMF group significantly increased at week 2, 4 and 6; the blood glucose significantly decreased, AUC decreased, the histopathological scores of pancreatic atrophy, acinar injury, edema and cellular infiltration decreased, levels of MDA and MPO decreased, the islet equivalent and islet activity increased at 0, 30, 60, 120 and 180 min. CONCLUSIONS: DMF treatment can improve CP induced by l-arginine and islet function in rats. PMID- 26972399 TI - Onco-microRNA miR-130b promoting cell growth in children APL by targeting PTEN. AB - OBJECTIVE: To study the expression of microRNA-130b (miR-130b) in children acute promyelocytic leukemia (APL) and its role for regulating PTEN expression. METHODS: A total of 50 children APL marrow tissues and 15 normal marrow tissues between January and December in 2012 were collected into our study. The expression of miR-130b in APL and normal marrow tissues were detected by quantitative real-time polymerase chain reaction. MiR-130b inhibitor was transfected into HL-60 cells. Cell Counting Kit-8 assay and flow cytometry were used to measure cell proliferation and apoptosis, respectively. The expression of PTEN, a potential target of miR-130b, and its downstream genes, Bcl-2 and Bax, in transformed cells were detected by quantitative real-time polymerase chain reaction and western-blot. RESULTS: The expression of miR-130b was significantly higher in children APL marrow tissues than in normal marrow tissues (P < 0.05). Down-regulation of miR-130b could significantly suppress cell proliferation and induce apoptosis in HL-60 cells (P < 0.05). PTEN expression was upregulated when miR-130b was knocking-down (P < 0.05). As downstream genes of PTEN, the expression of Bcl-2 and Bax were regulated as well. CONCLUSIONS: MiR-130b is overexpressed in children APL marrow tissues and associated with cell growth. MiR 130b may promote children APL progression by inducing cell proliferation and inhibiting apoptosis. PMID- 26972400 TI - Effect of levocarnitine on TIMP-1, ICAM-1 expression of rats with coronary heart disease and its myocardial protection effect. AB - OBJECTIVE: To study the effect of levocarnitine (L-CN) on tissue inhibitor of metalloproteinase-1 (TIMP-1) and intercellular adhesion molecule-1 (ICAM-1) expression of rats with coronary heart disease and evaluate the protective effect of L-CN on myocardial cells. METHODS: High-fat diet feeding and intraperitoneal injection of pituitrin was performed on rats in model group and CHD Model of rats was built. Rats with successful model-building were selected and divided into L CN group and Ctrl group randomly. Rats in L-CN group were given L-CN treatment, with intraperitoneal injection of 200 mg.kg(-1).d(-1) and successive administration for 3 d. Rats in Ctrl group were given equal volumes of normal saline. Blood was collected from carotid artery at different time and expression quantity of creatine kinase-MB (CK-MB) and Troponin I (TnI) in serum was detected. Rats in each group were put to death and were separated to obtain the myocardial tissue. Real-time PCR and Western Blotting hybridization were performed to detect the TIMP-1, ICAM-1 expression in myocardial tissue in each group. Statistical analysis was employed to explore the expression changes of TIMP-1 and ICAM-1, and ELISA test was used to analyze the expression changes of myocardial necrosis marker-CK-MB and TnIto learn the effect of L-CN and its myocardial protective effect. RESULTS: The total cholesterol, triglyceride and blood glucose levels of rats in model group were significantly higher than that in control group, which indicated that due to high-fat diet feeding, blood lipid of rats in model group was obviously higher than that in control group. In myocardial tissue of rats in model group, TIMP-1 level significantly reduced and ICAM-1 level significantly increased (P < 0.01). In model group, after L-CN treatment, TIMP-1 level had double increase, while ICAM-1 level had 43% of decrease in L-CN group compared with Ctrl group. After L-CN intervention treatment, CK-MB and TnI content in L-CN group relatively reduced compared with Ctrl group. The difference among groups was obvious (P < 0.01). CONCLUSIONS: L-CN could increase the TIMP-1 expression level and inhibit the ICAM-1 expression level. L-CN has a certain myocardial protective effect. PMID- 26972401 TI - Regulating effect of activated NF-kappaB on edema induced by traumatic brain injury of rats. AB - OBJECTIVE: To observe the effect of nuclear transcription factor-kappaB (NF kappaB) on cerebral edema in rats with traumatic brain injury (TBI). METHODS: Male SD rats with fluid percussion injury (FPI) were selected. After separation and culture, rats' astrocytes all suffered FPI. The expression of NF-kappaB and the water content were detected at the animal and cellular levels, while the activity of NOX was evaluated at the cellular level. RESULTS: According to the results, the positive expression of NF-kappaB and expression of mRNA were significantly increased and the water content was increased for rats after TBI, while NF-kappaB inhibitor BAY11-7082 could significantly reduce the effect of TBI. 1 and 3 h after FPI of astrocytes, the activation of NF-kappaB was increased and BAY 11-7082 could significantly improve the injury-induced swelling of astrocytes. After the injury of astrocytes, the activity of NOX was also increased, while BAY 11-7082 could reduce the activity of NOX. CONCLUSIONS: The results show that the activation of NF-kappaB in astrocytes is a key factor in the process of cerebral edema after TBI of rats. PMID- 26972402 TI - Mechanism of all-transretinoic acid increasing retinoblastoma sensitivity to vincristine. AB - OBJECTIVE: To explore the mechanism of all-transretinoic acid (ATRA) increasing retinoblastoma (RB) sensitivity to vincristine, and the inhibiting effect of vincristine combined with ATRA treatment on the SO-RB50 cell proliferation. METHODS: SO-RB50 cells were cultivated by routine culture method. Different concentrations of vincristine or ATRA were added into culture solution. After 48 h, cell counting kit-8 was used to detect the median inhibitory concentration (IC50) of vincristine combined with ATRT treatment to SO-RB50 cells. SO-RB50 cells were divided into drug combination group, vincristine group, ATRA group and control group. Different drugs were added into the culture solution respectively for cell culture based on the IC50 value. Cell counting kit-8 was used to detect the cell proliferation every 24-h cultivation. After continuous determination for 6 d, data was processed to draw the cell growth curve. After drug use for 72 h, flow cytometry was used to detect the proportion of different cell cycles of SO RB50 cells in each group. After drug use for 48 h, annexin V/propidium iodide method was used to detect the SO-RB50 cell apoptosis in each group. RESULTS: The IC50 value of vincristine treatment on the SO-RB50 cells was 0.11 MUmol/L, and ATRT was 12.84 MUmol/L. The cell growth curve in control group rose gradually along with the extended culture time, but after vincristine and ATRA treatment, the cell growth curve was smooth and steady. The cell increment was the least in drug combination group and its cell growth curve was the smoothest. There was significant difference in A450 48 h and 72 h after treatment (Fgrouping = 77.316, P < 0.001; Ftime = 86.985, P < 0.001). Compared with control group, A450 value in drug combination group, vincristine group, ATRA group was significant lower (P < 0.001). Compared with control group, the G2/M phase cell proportion in vincristine group was significantly increased, while the G0/G1 phase cell proportion was significantly decreased; the G0/G1 phase cell proportion in ATRA group was significantly increased, while the S phase cell proportion was significantly decreased (FG0/G1 = 85.878, Fs = 56.455, FG2/M = 85.878, P < 0.001). After 48 h, there was significant difference in SO-RB50 cell apoptosis rate among groups (F = 11.312, P < 0.05). The apoptosis rate in drug combination group was significantly higher than that of other groups (P < 0.001). CONCLUSIONS: ATRA can increase the sensitivity of SO-RB50 cells to vincristine. Vincristine combined with ATRA treatment can significantly increase the inhibiting effect on SO-RB50 cells, which may be related with promoting cell apoptosis and involving in cell cycle control. PMID- 26972403 TI - Protective effect of apoptosis signal-regulating kinase 1 inhibitor against mice liver injury. AB - OBJECTIVE: To explore the protective effect and its molecular mechanism of apoptosis signal-regulating kinase 1 (ASK1) inhibitor (GS-459679) on acetaminophen-induced liver injury in mice. METHODS: The model of liver injury was established by administration of acetaminophen (APAP) (300 mg/kg, i.p.) on C57BL/6 mice. Forty-eight male C57BL/6 mice were randomly divided into four groups, consisting of control group, GS group (GS-459679, 30 mg/kg, i.p.), APAP induced group, and GS combined with APAP-induced group. For GS combined with APAP induced group, mice were treated with GS 30 min prior to administration of APAP. After mice were euthanized at 6 h or 12 h, respectively, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed, and mRNA levels of TNF-alpha, IL-6 and IL-1beta were tested. The activity of glutathione (GSH), oxidized GSH (GSSG) and malondialdehyde were quantified. In addition, ASK1, P-ASK1, JNK and P-JNK protein levels were tested in all groups. RESULTS: The ASK1 and P-ASK1 levels were up-regulated in APAP-induced group. Compared to the control group, serum levels of ALT and AST, and mRNA levels of TNF-alpha, IL-6 and IL-1beta were increased in APAP-induced group. Meanwhile, the levels of MAD and GSSG, and the ratio of GSSG/GSH were higher and the JNK was activatedin APAP-induced group compared with that in control group. However, compared to APAP-induced group, GS combined with APAP-induced group displayed a decrease of protein expression levels of ASK1, P-ASK1 and P-JNK, a reduction of serum levels of ALT and AST, a decrease in TNF-alpha, IL-6 and IL-1beta mRNA levels, and a low ration of GSSG/GSH. CONCLUSIONS: GS-459679 treatment effectively down-regulates ASK1 and P-ASK1 expression. Addition of GS-459679 decreases the generation of liver metabolites and inflammatory factors, reduces oxidative stress reaction, inhibits JNK activation, and then protects the responsiveness to APAP-induced liver injury. PMID- 26972404 TI - Effect of TRPV1 combined with lidocaine on cell state and apoptosis of U87-MG glioma cell lines. AB - OBJECTIVE: To study the effects of Transient receptor potential cation channel, subfamily V, member 1 (TRPV1) combined with lidocaine on status and apoptosis of U87-MG glioma cell line, and explore whether local anesthetic produces neurotoxicity by TRPV1. METHODS: U87-MG cells were divided into control group, gene silencing group, empty vector group and TRPV gene up-regulation group. For cells in each group, flow cytometry was employed to detect the intracellular calcium ion concentration and mitochondrial membrane potential at different time point from cellular perspective. Cell apoptosis of U87-MG was assayed by flow cytometry and MTT from a holistic perspective. RESULTS: Calcium ion concentration increased along with time. The concentration in TRPV1 gene up-regulation group was significantly higher than those in other groups at each time point (P < 0.05). After adding lidocaine, mitochondrial membrane potential in U87-MG significantly increased (P < 0.05). This increasing trend in TRPV1 gene up regulation group was more significant than other groups (P < 0.05), while in TRPV1 gene silencing group, the trend significantly decreased (P < 0.05). Flow cytometry result and MTT result both showed that cell apoptosis in each group significantly increased after lidocaine was added (P < 0.05). This increasing trend in TRPV1 gene up-regulation group was more significant than other groups (P < 0.05), while in TRPV1 gene silencing group, the trend significantly decreased (P < 0.05). Moreover, apoptosis was more severe along with the increasing concentration of lidocaine (P < 0.05). CONCLUSIONS: In this study, it was proved that lidocaine could dose-dependently induce the increase of intracellular calcium ion concentration, mitochondrial membrane potential and apoptosis in U87 MG glioma cell line. The up-regulation of TRPV1 enhanced cytotoxicity of lidocaine, which revealed the correlations between them. Lidocaine might have increased intracellular calcium ion concentration by activating TRPV1 gene and induced apoptosis of U87-GM glioma cell line by up-regulating mitochondrial membrane potential. PMID- 26972405 TI - Immune formulation-assisted conventional therapy on anti-infective effectiveness of multidrug-resistant Mycobacterium tuberculosis infection mice. AB - OBJECTIVE: To study the effect of immune formulation-assisted conventional therapy on anti-infective ability of multidrug-resistant Mycobacterium tuberculosis infection mice. METHODS: BALB/c mice were used as experimental animals, multidrug-resistant M. tuberculosis infection models were built, randomly divided into model group, moxifloxacin group, thymopentin group and combined treatment group and given corresponding drug intervention, and then colony numbers in the spleen and lung, T lymphocyte subset contents and programmed death-1 (PD-1) expression levels in peripheral blood were detected. RESULTS: Colony numbers in lung and spleen of moxifloxacin group and thymopentin group were significantly lower than those of model group and colony numbers in lung and spleen of combined treatment group were significantly lower than those of moxifloxacin group and thymopentin group; contents of CD3(+)CD4(+)T cells, Th1 and Th17 in peripheral blood of moxifloxacin group and thymopentin group were higher than those of model group, and contents of CD3(+)CD8(+)T cells, Th2 and Treg were lower than those of model group; contents of CD3(+)CD4(+)T cells, Th1 and Th17 in peripheral blood of combined treatment group were higher than those of moxifloxacin group and thymopentin group, and contents of CD3(+)CD8(+)T cells, Th2 and Treg were lower than those of moxifloxacin group and thymopentin group; PD-1 expression levels on T lymphocyte, B lymphocyte and monocyte surface in peripheral blood of moxifloxacin group and thymopentin group were lower than those of model group, and PD-1 expression levels on T lymphocyte, B lymphocyte and monocyte surface in peripheral blood of combined treatment group were lower than those of moxifloxacin group and thymopentin group. CONCLUSIONS: Immune formulation thymopentin can enhance the anti-infective ability of multidrug resistant M. tuberculosis infection mice, decrease bacterial load in lung and spleen, and enhance immune function. PMID- 26972406 TI - Effect of miR-467b on atherosclerosis of rats. AB - OBJECTIVE: To observe the effect of miR-467b on the atherosclerosis (AS) of rats with apolipoprotein E (ApoE) gene knockout (ApoE(-/-)). METHODS: ApoE(-/-) rats were fed with high fat and high cholesterol diet and were randomly divided into group A, group B and group C, with 10 rats in each group. Group A: rats were injected with ApoE agonist through the caudal vein; group B: rats were injected with ApoE antagonist through the caudal vein; group C: as negative control group. Enzyme oxidation method was used to detect the blood lipid levels of rats. Western blotting method was used to detect the aortic lipoprotein lipase (LPL) expression levels of rats. HE staining and oil red O staining were performed to observe the AS lesions and lipid accumulation state. RESULTS: Compared with group C, blood lipid level, aortic intima and aortic sinus lipid accumulation area ratio, aortic sinus lesion area and LPL expression level in group A significantly reduced; while blood lipid level, aortic intima and aortic sinus lipid accumulation area ratio, aortic sinus lesion area, and LPL expression level in group B significantly increased, with the statistical difference (P < 0.05). CONCLUSIONS: miR-467b can alleviate the AS lesions of ApoE(-/-) rats, and its inhibiting effect on AS may be related to LPL expression. PMID- 26972407 TI - Preinduced intestinal HSP70 improves visceral hypersensitivity and abnormal intestinal motility in PI-IBS mouse model. AB - OBJECTIVE: To investigate the impact of the preinduced intestinal heat shock protein 70 (HSP70) on the visceral hypersensitivity and abnormal intestinal motility in a post-infectious irritable bowel syndrome (PI-IBS) mouse model. METHODS: Eighty-four female C57BL/6 mice were randomly assigned to four groups: control group (n = 21) and induction + PI-IBS group (n = 21), PI-IBS group (n = 21) and induction group (n = 21). The mice in PI-IBS group were infected in vivo with Trichinella spiralis by oral administration. The visceral hypersensitivity and intestinal motility were evaluated respectively with abdominal withdrawal reflex and colon transportation test. The intestinal HSP70 protein and mRNA level was measured by Western blot and real-time PCR. Meanwhile, the intestinal proinflammatory cytokines IL-10 and TNF-alpha level was detected by ELISA. RESULTS: Compared with their counterparts in PI-IBS group, the animals in the Induction + PI-IBS group show significantly increased intestinal level of HSP70 and obviously ameliorative clinical figures, including abdominal withdrawal reflex score, intestine transportation time and Bristol scores (P < 0.05). Meanwhile, the intestinal post-inflammatory cytokines remarkably changed, including increased IL-10 level and decreased TNF-alpha level (P < 0.05). CONCLUSIONS: Intestinal HSP70 may play a potential protective role through improving the imbalance between the intestinal post-inflammatory and anti inflammatory cytokines in PI-IBS. PMID- 26972408 TI - Efficient Water Oxidation Using CoMnP Nanoparticles. AB - The development of efficient water oxidation catalysts based on inexpensive and Earth-abundant materials is a prerequisite to enabling water splitting as a feasible source of alternative energy. In this work, we report the synthesis of ternary cobalt manganese phosphide nanoparticles from the solution-phase reaction of manganese and cobalt carbonyl complexes with trioctylphosphine. The CoMnP nanoparticles (ca. 5 nm in diameter) are nearly monodisperse and homogeneous in nature. These CoMnP nanoparticles are capable of catalyzing water oxidation at an overpotential of 0.33 V with a 96% Faradaic efficiency when deposited as an ink with carbon black and Nafion. A slight decrease in activity is observed after 500 cycles, which is ascribed to the etching of P into solution, as well as the oxidation of the surface of the nanoparticles. Manganese-based ternary phosphides represent a promising new system to explore for water oxidation catalysis. PMID- 26972409 TI - A multidisciplinary learning experience contributing to mental health rehabilitation. AB - Purpose People who access health services often have a range of needs that require the involvement of members from a multidisciplinary team. Teaching future health professionals about the importance of a multidisciplinary approach can be challenging. The aim of this paper is to describe a project called Recovery Camp that enhanced multidisciplinary health education through experiential and immersive engagement with people experiencing mental illness. Method Future health professionals and people with a lived experience of mental illness took part in Recovery Camp - an innovative five-day therapeutic recreation initiative in the Australian bush. Results are presented in a case study format and provide the reflective quotes of participants. The quotes were analyzed using a content analysis to identify core concepts. Results Analyses identified a common appreciation of multidisciplinary learning. The interactions among students and between students and consumers, promoted inter-professional practice and a holistic understanding of mental health care. Conclusions An immersive multidisciplinary approach, embedded within a recovery-based programme, enhances students' understanding of the significance of multidisciplinary mental health care and treatment. Implications for Rehabilitation People with a lived experience of mental illness have a range of complex needs that require involvement of members from a multidisciplinary rehabilitation team. This study suggested a multidisciplinary, experiential, immersive health education experience - drawing on the principles of therapeutic recreation - can promote inter-professional rehabilitative practice and an appreciation for holistic mental health care. PMID- 26972416 TI - Relationship between the cohesion of guest particles on the flow behaviour of interactive mixtures. AB - In this study, we aimed to investigate the effects cohesion of small surface engineered guest binder particles on the flow behaviour of interactive mixtures. Polyvinylpyrrolidone (PVP) - a model pharmaceutical binder - was spray-dried with varying l-leucine feed concentrations to create small surface-engineered binder particles with varying cohesion. These spray-dried formulations were characterised by their particle size distribution, morphology and cohesion. Interactive mixtures were produced by blending these spray-dried formulations with paracetamol. The resultant blends were visualised under scanning electron microscope to confirm formation of interactive mixtures. Surface coverage of paracetamol by guest particles as well as the flow behaviour of these mixtures were examined. The flow performance of interactive mixtures was evaluated using measurements of conditioned bulk density, basic flowability energy, aeration energy and compressibility. With higher feed l-leucine concentrations, the surface roughness of small binder particles increased, while their cohesion decreased. Visual inspection of the SEM images of the blends indicated that the guest particles adhered to the surface of paracetamol resulting in effective formation of interactive mixtures. These images also showed that the low-cohesion guest particles were better de-agglomerated that consequently formed a more homogeneous interactive mixture with paracetamol compared with high-cohesion formulations. The flow performance of interactive mixtures changed as a function of the cohesion of the guest particles. Interactive mixtures with low-cohesion guest binder particles showed notably improved bulk flow performance compared with those containing high-cohesion guest binder particles. Thus, our study suggests that the cohesion of guest particles dictates the flow performance of interactive mixtures. PMID- 26972417 TI - Experimental and Pathalogical study of Pistacia atlantica, butyrate, Lactobacillus casei and their combination on rat ulcerative colitis model. AB - This study evaluated the effects of Pistacia atlantica (P. atlantica), butyrate, Lactobacillus casei (L. casei) and especially their combination therapy on 2,4,6 trinitrobenzene sulphonic acid (TNBS)-induced rat colitis model. Rats were divided into seven groups. Four groups received oral P. atlantica, butyrate, L. casei and the combination of three agents for 10 consecutive days. The remaining groups were negative and positive controls and a sham group. Macroscopic and histopathological examinations were carried out along with determination of the specific biomarker of colonic oxidative stress, the myeloperoxidase (MPO). Compared with controls, the combination therapy exhibited a significant alleviation of colitis in terms of pathological scores and reduction of MPO activity (55%, p=0.0009). Meanwhile, the macroscopic appearance such as stool consistency, tissue and histopathological scores (edema, necrosis and neutrophil infiltration) were improved. Although single therapy by each P. atlantica, butyrate, and L. casei was partially beneficial in reduction of colon oxidative stress markers, the combination therapy was much more effective. In conclusion, the combination therapy was able to reduce the severity of colitis that is clear from biochemical markers. Future studies have to focus on clinical effects of this combination in management of human ulcerative colitis. Further molecular and signaling pathway studies will help to understand the mechanisms involved in the treatment of colitis and inflammatory diseases. PMID- 26972418 TI - Triple synchronous invasive malignancies of the female genital tract in a patient with a history of leukemia: A case report and review of the literature. AB - BACKGROUND: Three primary synchronous cancers in the female genital tract are extremely rare. In the literature, only four studies have described three different invasive gynecologic cancers of epithelial origin identified simultaneously in the same patient. CASE PRESENTATION: This is the first case in the literature that reports on triple primary ovarian, endometrial and endocervical cancers in a 38-year-old woman with a history of previously treated malignant disease (acute lymphatic leukemia). With a preoperative diagnosis of endocervical adenocarcinoma stage Ib1 (according to International Federation of Gynecology and Obstetrics-FIGO), as well as an adnexal mass, she underwent radical hysterectomy with bilateral adnexectomy. Pathologic examination of the surgical specimen revealed a mucinous adenocarcinoma of the cervix, an endometrioid adenocarcinoma of the uterine corpus, and a mucinous adenocarcinoma of the left ovary. Eighteen months after appropriate treatment, the patient is free of disease. CONCLUSION: The incidental diagnosis of more than one tumor is often a post-operative finding, usually with the detection of low-stage neoplasms. Multiple synchronous gynecologic cancers have a better prognosis than metastatic or advanced primitive disease. In a patient with multiple neoplasms, the prognosis is determined by the tumor with the worst prognosis. PMID- 26972420 TI - Conservative gap arthroplasty in temporomandibular ankylosis not involving the sigmoid notch: a selected age group study. AB - In this prospective, cohort, clinical follow-up study we aimed to investigate the role of conservative gap arthroplasty without interpositional material in managing ankylosis of the temporomandibular joint (TMJ). Thirteen patients (15 joints) with ankylosis who fulfilled the other inclusion criteria were enrolled. The ankylotic mass was excised to create a gap of 7-9mm. No interpositional material was used. Ipsilateral or bilateral masseter reflection, pterygomasseteric sling, and temporalis tendon release plus coronoidectomy were considered if maximum mouth opening failed to reach 35mm. A physiotherapy protocol was started on the first day. Patients' ages ranged from 13-38 (mean (SD) 18 (7) years). Trauma was the main cause. Duration of ankylosis at presentation ranged from 1-17 years (mean (SD) 5 (4) years). Eleven patients had unilateral, and two bilateral, ankylosis that did not involve the sigmoid notch. The mean (SD) maximum incisal opening (mm) was 38 (4) two years' postoperatively. The facial nerve was affected temporarily in two patients. Mean (SD) duration of follow-up was 4 (2) years without recurrence. Within our selection criteria, conservative gap arthroplasty of 7-9mm without interpositional material and with vigorous postoperative physiotherapy has a role in treating ankylosis of the TMJ and preventing its recurrence for more than four years. PMID- 26972419 TI - The role of immunohistochemical adrenomedullin and Bcl-2 expression in development of type-1 endometrial adenocarcinoma: Adrenomedullin expression in endometrium. AB - BACKGROUND: Adrenomedullin (AM) is a pluripotent peptide first discovered from human pheochromocytoma. AM expression has been shown in various cancer types including endometrium cancer. Bcl-2 is an antiapoptotic protein which might be regulated by AM in hypoxic conditions. The aim of the present study was to investigate the role of AM and Bcl-2 expressions in carcinogenesis of type-1 endometrium cancer. MATERIALS AND METHOD: Study group consisted of 10 proliferative endometrium, 22 simple endometrial hyperplasia, 23 endometrial intraepithelial neoplasia (EIN) and 30 Grade 1 endometrioid adenocarcinoma patients. AM and Bcl-2 expressions were investigated by immunohistochemistry. RESULTS: Mean AM Allred score was 3+/-2.6, 5.6+/-1.6 and 5.7+/-2.5 in benign, EIN and adenocarcinoma groups, respectively. AM expression was significantly higher in EIN and adenocarcinoma groups than in benign endometrium group (p<0.05). Mean Bcl-2 Allred score was 6.4+/-2.1, 5.2+/-2.6, 2.3+/-2 in benign endometrium, EIN and adenocarcinoma groups, respectively. Mean Bcl-2 Allred score was similar between benign endometrium and EIN groups (p>0.05). However, it was significantly lower in adenocarcinoma group (p<0.05). An inverse correlation between AM and Bcl 2 expressions was found (r: -0.4, p<0.001). CONCLUSIONS: Our findings showed that AM expression increased in progression from benign endometrium to EIN and type-1 adenocarcinoma while expression of Bcl-2 decreased in transition from EIN to carcinoma. PMID- 26972421 TI - Imidazolium salts with antifungal potential for the control of head blight of wheat caused by Fusarium graminearum. AB - AIMS: Evaluate the in vitro effect of imidazolium salts (IMS) on the conidia germination and mycelial growth of Fusarium graminearum and their in vivo efficacy for suppressing the symptoms of the disease and infection of kernels in wheat plants. METHODS AND RESULTS: The minimum inhibitory concentrations (MIC) of three IMS (C16 MImCl, C16 MImMeS and C16 MImNTf2 ) were determined for four F. graminearum isolates using serial broth dilution method. The MICs found for all IMS were either 3.12 or 6.25 MUg ml(-1) across the isolates, with the former as the most frequent. In the mycelial growth assay on potato dextrose agar media, only the C16 MImCl among the IMS reduced 50% of mycelial growth of one isolate at an estimated concentration of 0.32 mg ml(-1) . The time-kill curves showed a strong fungicidal effect starting 1 h after incubation at a concentration of 12.5 MUg ml(-1) , representing a fourfold increase in the most frequent MIC. The C16 MImCl sprayed onto the spikes of potted wheat plants during the flowering stage reduced disease intensity at levels comparable to the commercial fungicide when applied preventatively (1 h prior to fungal inoculation), rather than curatively, and at the higher dosage (2 mg ml(-1) ) rather than lower dosage (0.5 mg ml(-1) ). CONCLUSIONS: C16 MImCl proved to be a potent inhibitor of F. graminearum growth and provided good levels of control of the disease at levels comparable to a commercial fungicide, in wheat plants treated prior to fungal infection during flowering stages. SIGNIFICANCE AND IMPACT OF THE STUDY: This study suggests the potential of using IMS as alternative to the hazardous standard fungicides in the management of Fusarium head blight of wheat. PMID- 26972422 TI - Association between maxillary sinus fungus ball and sinus bone grafting with deproteinized bovine bone substitutes: a case-control study. AB - OBJECTIVE: To evaluate the association between sinus bone graft and the development of fungus ball (FB) of the maxillary sinus. STUDY DESIGN: The charts of all patients seen for surgical treatment of maxillary sinus FB following sinus bone grafting between 2006 and 2014 were reviewed. The charts of 49 participants were selected from our internal registry for comparison as controls. The association between FB and age, gender, smoking habits, associated co morbidities, and bone grafting material was evaluated. FB of the maxillary sinus was estimated by using an odds ratio with a Yates' correction. P values were computed using Fisher's exact test, and the statistical significance was set at a P value < .05. RESULTS: All 13 cases (100%) with FB of the maxillary sinus had received anorganic bovine bone as the bone substitute (P = .0001). There were significantly more women in the case group than in the control group (84.6% in the cases vs 40.8% in the controls; P = .01). CONCLUSIONS: This study demonstrated a significant association between a specific deproteinized bovine bone substitute use as sinus bone graft material and subsequent development of FB of the maxillary sinus. PMID- 26972423 TI - Lateral tarsotomy: a practical alternative to lateral canthotomy to increase orbital access. AB - OBJECTIVE: Transconjunctival approach to the lower one-third of the orbit is commonly used to avoid transcutaneous incisions when surgical access is needed. A lateral canthotomy is used in conjunction with this approach if increased lateral exposure is required. A major disadvantage to lateral canthotomy is difficulty in resuspension of the lateral canthal tendon, which can lead to unaesthetic outcomes. The present report describes two cases of lateral tarsal incision or, as we decided to call it, the "lateral tarsotomy" technique. This simple approach is used to increase lateral access to the orbit without the need for lateral canthotomy. STUDY DESIGN: Two patients presented with internal orbital wall trauma that required repair; access was achieved with a transconjunctival approach in conjunction with lateral tarsotomy. The patients were followed up at 1 week, 1 month, and 3 months to document the development of possible unaesthetic and poor functional outcomes. RESULTS: Excellent cosmetic results were observed, with no noticeable deformity at the tarsotomy site. There was no evidence of ectropion, entropion, scleral show, and visible scars. CONCLUSIONS: The above results suggest that the lateral tarsotomy approach is a practical alternative to lateral canthotomy when increased lateral exposure is required. PMID- 26972424 TI - Response to: WhatsApp: a telemedicine platform for facilitating remote oral medicine consultation and improving clinical examinations. PMID- 26972426 TI - Oncological and surgical outcome of total laryngectomy in combination with neck dissection in the elderly. AB - There are controversial data on oncological and surgical outcome after major head and neck cancer surgery in the elderly. The aim of this study was to evaluate the outcome of elderly cancer patients after total laryngectomy in combination with neck dissection. A total of 58 patients separated into two age groups (28 < 65 vs. 30 >= 65 years) with hypopharyngeal and laryngeal cancer who underwent total laryngectomy and neck dissection were enrolled. Comorbidities of both age groups using the Charlson comorbidity index, hospitalization days as well as surgical complications evaluated by the Clavien-Dindo classification were examined. Overall and disease-free survivals of all patients were analyzed. The average follow-up was 2.9 years. Surgical complication rate was significantly increased in elderly (p = 0.04). However, complications could be treated without surgical intervention in most cases without significant extension of hospitalization. Locoregional and distant control did not significantly differ in both age groups. Disease-free and overall survival showed no significant differences for the two age groups by the Kaplan-Meier analysis (p = 0.66 and 0.08, respectively). Total laryngectomy in combination with neck dissection can be considered in elderly patients with satisfactory oncological and surgical outcome. PMID- 26972425 TI - Risk of Headache-Related Healthcare Visits in Patients With Celiac Disease: A Population-Based Observational Study. AB - BACKGROUND AND AIMS: Patients with celiac disease (CD) are reported to be at increased risk for headaches, though large studies are lacking. We aimed to examine the risk of headache-related healthcare encounters in patients with CD in a nationwide population-based setting. METHODS: In this population-based retrospective cohort study, we searched all (n = 28) pathology departments in Sweden and identified patients with CD based on the presence of villous atrophy (VA). Each patient was matched to up to 5 controls, by age, gender, calendar period, and region. Using Cox proportional hazards, we tested for an association between CD and subsequent headache-related visit. We also tested this association for those with intestinal inflammation but normal villi, and subjects with positive CD serologies but normal histology. RESULTS: Among 28,638 patients with CD and 143,126 controls, headache-related visit occurred in 1,337 (4.7%) and 4,102 (2.9%), respectively. The incidence of headache-related visit was 423 per 100,000 person-years in CD patients and 254 per 100,000 person-years in controls (HR 1.66; 95% CI 1.56-1.77; P < .0001). Individuals having inflammation without VA on small intestinal biopsy (n = 12,898; HR 2.08; 95% CI 1.90-2.27; P < .0001) and those with normal mucosa but positive CD serology (n = 3,617; HR 1.83; 95% CI 1.57-2.12; P < .0001) were also at increased risk for headache-related visit. CONCLUSIONS: In this population-based study we found a significantly increased risk of headache-related visits in patients with CD; this increase was also present in patients with intestinal inflammation and those with positive CD serology but with normal mucosal architecture on small bowel biopsy. Though limited by surveillance bias, this study indicates that headache-related visits are more common in these populations. PMID- 26972427 TI - Predictors for surgical complications of en bloc resections in the spine: review of 220 cases treated by the same team. AB - PURPOSE: Identify risk factors, enabling reduction of the rate of complications and improve outcome in en bloc resection surgeries. METHODS: A retrospective study of prospective collected data of 1681 patients affected by spine tumors treated from 1990 to 2015 by the same team. RESULTS: A total of 220 en bloc resections that were performed on 216 patients during that period. Most of the tumors were primary-165 cases (43 benign and 122 malignant), metastases occurred in 55 cases. Median FU was 45 months (0-371). 153 complications were observed in 100 patients (46.2 %). 64 (30 %) suffered one complication, while the rest had two or more. There were 105 major and 48 minor complications. Seven patients (4.6 %) died as a result of complications. The combined approach, neoadjuvant chemotherapy and neoadjuvant radiotherapy were statistically significant independent risk factors for complications occurrence. 33 patients (15.2 %) suffered from local recurrence. Reoperations were mostly due to tumor recurrences, but also to hardware failures, wound dehiscence, hematomas and aortic dissection. CONCLUSION: The rate of complication is higher in multisegmental resections and when double combined approach is performed. Reoperations display greater morbidity owing to dissection through scar/fibrosis from previous operations and possibly from RT. Careful treatment planning and, in the event of uncertainty, referral to a specialty center must be stressed. The high risk of complications should not discourage surgeons from performing en bloc resection when needed. Most of the patients who sustain complications benefit from the better local control resulting from en bloc resection. PMID- 26972428 TI - The ototronix MAXUM middle ear implant for severe high-frequency sensorineural hearing loss: Preliminary results. AB - OBJECTIVES/HYPOTHESIS: To report the preliminary results of the Ototronix MAXUM middle ear implant for treatment of severe high-frequency sensorineural hearing loss. STUDY DESIGN: Case series with chart review. METHODS: Six consecutive ears with severe high-frequency sensorineural hearing loss (>=75 dB HL at 2, 3, and 4 kHz) and poor aided word recognition performance (<=60% single words) underwent implantation of the MAXUM system at a single, private otologic referral center. Primary outcome measures included frequency-specific functional gain and word recognition score improvement compared to optimally fitted hearing aids. RESULTS: Six ears, in four adult patients (two female; median age 67.5 years) were included. The median unaided preoperative high-frequency pure-tone average (HFPTA) (2, 3, and 4 kHz) was 80.0 dB (range, 75.0-85.0 dB), and the median best aided word recognition score was 48.0% (range, 24%-60%). The median HFPTA functional gain with the MAXUM system was 47.2 dB, a 25.0 dB improvement (range, 16.7-33.3 dB) (P = .03) over optimally fit hearing aids, and the median word recognition score with MAXUM was 81.5%, a 42.0% improvement (range, 20%-48%) (P = .03) with the MAXUM middle ear implant over optimally fitted hearing aids. CONCLUSIONS: These preliminary data demonstrate that the MAXUM middle ear implant provides superior functional gain and word recognition scores in quiet for patients with severe high-frequency sensorineural hearing loss compared to optimally fitted hearing aids. Future studies with greater patient numbers and patient reported outcome measures are needed to confirm these promising but preliminary results. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2124-2127, 2016. PMID- 26972429 TI - Genotyping of Nocardia farcinica with multilocus sequence typing. AB - Nocardia are aerobic Gram-positive saprophytes that are widely distributed in nature, but some species cause nocardiosis, especially opportunistic infections that affect immunocompromised patients mostly. In this study, we developed a multilocus sequence typing (MLST) scheme using seven housekeeping genes (gyrB, hsp65, secA1, rpoB, rpoA, recA, and trpB) for genotyping the most common clinical species, Nocardia farcinica (37 clinical isolates from the patients with nocardiosis and seven from animals in China and 15 reference strains). The results showed that using these loci could perform accurate identification among different species, and high discriminative power within the N. farcinica species. Of the 59 N. farcinica isolates, 44 sequence types have been identified; 32 STs covering 46 isolates could be assigned to six clonal complexes that encompassed most of the collected strains. The results showed that these strains displayed a sufficiently informative population structure using this method. Our study also provided a suitable approach for epidemiological studies of N. farcinica. A large clonal complex comprising 16 strains was identified, and was notable for its wide distribution and host adaptation. This complex should be monitored closely and merits further study. PMID- 26972430 TI - Molecular characteristics of penicillin-binding protein 2b, 2x and 1a sequences in Streptococcus pneumoniae isolates causing invasive diseases among children in Northeast China. AB - Streptococcus pneumoniae is one of the common pathogens causing severe invasive infections in children. This study aimed to investigate the serotype distribution and variations of penicillin-binding proteins (PBPs) 2b, 2x and 1a in S. pneumoniae isolates causing invasive diseases in Northeast China. A total of 256 strains were isolated from children with invasive pneumococcal disease (IPD) from January 2000 to October 2014. All strains were serotyped and determined for antibiotic resistance. The amplicons of penicillin-binding domains in pbp1a, pbp2b and pbp2x genes were sequenced for variation identification. The most prevalent serotypes of isolates in IPD children were 19A, 14, 19F, 23F and 6B. 19A and 19F were the most frequent serotypes of penicillin-resistant S. pneumoniae (PRSP), which present with high resistance to amoxicillin, cefotaxime, ceftriaxone and meropenem. The numbers of amino acid substitutions of penicillin non-susceptible S. pneumoniae (PNSP) isolates were higher than those of penicillin-sensitive S. pneumoniae isolates in all the PBP genes (p < 0.01). The patterns of amino acid mutation in PBP2b, PBP2x and PBP1a were unique and different from those of other countries. All of the serotype 19A and 19F PRSP isolates carried 25 amino acid mutations, including Ala618 -> Gly between positions 560 and 675 in PBP2b and Thr338 -> Ala substitutions in PBP2x. The amino acid alterations in PBP2b, PBP2x and PBP1a from S. pneumoniae were closely associated with resistance to beta-lactam antibiotics. This study provides new data for further monitoring of genetic changes related to the emergence and spread of resistance to beta-lactam antibiotics in China. PMID- 26972432 TI - Assessing the impact of fracture pattern on transfusion requirements in hip fractures. AB - PURPOSE: Hip fractures in the elderly represent a major source of morbidity and mortality, with allogeneic blood transfusions (ABTs) associated with increased mortality. This study assesses the ABT requirements between the most common patterns of hip fracture; intertrochanteric (IT) and intracapsular (IC). The impact of operation type on transfusion rates was also assessed. METHODS: A retrospective study was performed for all patients entered on the national hip fracture database over 1 year in a teaching hospital. Records of 559 patients were reviewed and, following exclusion criteria, 474 were evaluated (198 IT, 276 IC). Baseline haematological parameters and ABTs were identified using hospital systems. Analysis was performed in SPSS, using independent samples t tests, one way ANOVAs and Chi square tests. RESULTS: Patient groups were matched on gender, anaesthetic type, American Society of Anesthesiologist (ASA) grade, cognitive score and coagulation parameters. A significantly greater proportion of IT patients required an ABT during admission (39.4 vs. 22.5 %, p < 0.001). For IT fractures a greater proportion of patients required an ABT when undergoing an intramedullary nail operation compared with those requiring a dynamic hip screw (67.4 vs. 32.0 %, p < 0.001). Similarly, for IC fractures transfusion rates in patients undergoing an internal fixation were significantly lower than those undergoing hemiarthroplasty or arthroplasty (9.4 vs. 26.4 vs. 20.8 %, p = 0.033). CONCLUSION: Patients with IT hip fractures are significantly more likely to require an ABT than those with IC hip fractures. Patients undergoing an intramedullary nail for IT fractures have significantly higher transfusion rates than for other types of operation. PMID- 26972431 TI - Peptide aptamer identified by molecular docking targeting translationally controlled tumor protein in leukemia cells. AB - Bioinformatics screening and molecular docking analyses were utilized to select high affinity peptides targeting translationally controlled tumor protein (TCTP). Selected peptide aptamers were tested towards cancer cell lines with different levels of TCTP expression. One peptide (WGQWPYHC) revealed specific cytotoxicity according to the TCTP expression in tumor cells without affecting normal cells. Western blot analysis showed peptide-induced down-regulation of TCTP as primary target as well as of cell-cycle related downstream proteins (CDK2, CDK6, Cyclin D3) in MOLT-4 leukemia cells. "WGQWPYHC" deserves further analysis for targeted therapy of TCTP-expressing tumor cells. Graphical abstract Molecular docking on TCTP, cytotoxicity toward MOLT-4 leukemia cell line and downregulation of CDK2, CDK6, CyclinD3 and TCTP proteins. PMID- 26972433 TI - Transradial intervention for chronic total occlusion at the external iliac artery using a bidirectional approach through a single guiding catheter. AB - A 64-year-old male with intermittent claudication due to long chronic total occlusion of external iliac artery was successfully treated with a bi-directional approach. The retrograde guidewire was inserted into the ipsilateral internal iliac artery to the distal femoral artery through a collateral channel. The procedure was performed with a single guiding catheter through a single puncture of the left radial artery. Avoid puncture of the femoral artery may be less invasive with fewer bleeding complications. PMID- 26972434 TI - Re: "PICALM Gene rs3851179 Polymorphism Contributes to Alzheimer's Disease in an Asian Population". AB - Liu et al. have carried out a meta-analysis of case-control studies to investigate the association between PICALM gene rs3851179 polymorphism and Alzheimer's disease in an Asian population. However, several important issues should be noted. PMID- 26972435 TI - Parkinson disease and multiple sclerosis are not associated with autoantibodies against structural proteins of the dermal-epidermal junction. PMID- 26972436 TI - The status of acupuncture and oriental medicine in the United States. AB - Since its first mention in U.S. media in the early 1970s, the practice of acupuncture and Oriental medicine (AOM) has grown in stature from a fringe, counter-culture movement to a valid, evidenced-based treatment option for patients. In the last 40 years, AOM schools and colleges have been accredited by the U.S. Department of Education, offering both masters and doctoral degree programs. To date, forty-seven states and the District of Columbia license or certify acupuncturists based on competency proven through state examination or professional certification by the National Certification Commission for Acupuncture and Oriental Medicine (NCCAOM). As acceptance of AOM in the U.S. has increased through both the assurance of psychometrically sound certification and the education of the American public on this topic, many challenges have emerged. Problems such as the underemployment of AOM clinicians, methodological hurdles for the investigation of mechanisms, and efficacy of acupuncture and other AOM treatment techniques have been observed. Investigative challenges also include gaps in research training as well as a dearth of the basic resources needed to conduct randomized controlled trials (RCTs). As AOM research has sought integration into the Western research model, problems have been identified in the design of AOMRCTs, and strategies for their resolution through methods such as translational research have been examined. Incorporating these strategies as well as efficacy, effectiveness, and qualitative measures will strengthen the evidence base and thus provide clinical decision makers with more tools that can be used to design patient treatment regimens. PMID- 26972437 TI - Yin-yang and Zheng: Exported from Chinese medicine. AB - Chinese medicine (CM) basic theory differs substantially from modern medicine in methodology. CM views the healthy human body as an entity in yinyang equilibrium. CM practitioners typically diagnose patients with "Zheng (CM syndrome)"-yin-yang status of specific organs, and the ultimate goal of treatment in CM is to restore the yin-yang balance. This concept might seem strange to Western perceptions; however, CM philosophy and methodology have been gradually accepted and used in the West. There is growing evidence from prestigious worldwide journals like Nature, Science and Cell indicating that CM theory is becoming an important component in dealing with health issues in the West. PMID- 26972438 TI - Chinese medicine education and its challenges in the United States. AB - Over the past 4 decades Chinese medicine (CM) has come increasingly into the spotlight in the United States as the clinical effectiveness of CM has been not only empirically well-tested over a long period of time but also proven by recent scientific research. It has proven cost effectiveness, safety, and is authorized for natural and holistic approaches. In consideration, CM is one of the underutilized health care professions in the United States with a promising future. However, CM faces many challenges in its education and system, its niche in the health care system as an independent profession, legal and ethical issues. This paper discusses the confronting issues in the United States: present education, standards of CM education with shifting first professional degree level, new delivery systems of CM education. Development of new research models, training of evidence-based practice, and implementation of integrative medicine into CM education also are the key issues in the current CM profession. This paper also discusses opportunities for the CM profession going beyond the current status, especially with a focus on fusion medicine. PMID- 26972439 TI - Treatment with modified Bazhen Decoction () for a patient with autoimmune hemolytic anemia: A case report of a ten-month period. PMID- 26972440 TI - Application of metabolomics technology in the research of Chinese medicine. AB - In recent years, a novel analytical technology, metabolomics is widely used in the modern research of Chinese medicine (CM). Metabolomics adopts a "top-down" strategy to reflect the function of organisms from terminal symptoms of metabolic network and understand metabolic changes of a complete system caused by interventions. As a holistic approach, metabolomics technology, including nuclear magnetic resonance, gas chromatography-mass spectrometry, and liquid chromatography-mass spectrometry, favorable to express the meaning of basic theories of CM, CM syndrome and Chinese herb. Therefore, we believe that metabolomics technology will greatly benefit to development for the research of CM in the light of modern sciences. PMID- 26972441 TI - Structure of the fimbrial protein Mfa4 from Porphyromonas gingivalis in its precursor form: implications for a donor-strand complementation mechanism. AB - Gingivitis and periodontitis are chronic inflammatory diseases that can lead to tooth loss. One of the causes of these diseases is the Gram-negative Porphyromonas gingivalis. This periodontal pathogen is dependent on two fimbriae, FimA and Mfa1, for binding to dental biofilm, salivary proteins, and host cells. These fimbriae are composed of five proteins each, but the fimbriae assembly mechanism and ligands are unknown. Here we reveal the crystal structure of the precursor form of Mfa4, one of the accessory proteins of the Mfa1 fimbria. Mfa4 consists of two beta-sandwich domains and the first part of the structure forms two well-defined beta-strands that run over both domains. This N-terminal region is cleaved by gingipains, a family of proteolytic enzymes that encompass arginine and lysine-specific proteases. Cleavage of the N-terminal region generates the mature form of the protein. Our structural data allow us to propose that the new N-terminus of the mature protein may function as a donor strand in the polymerization of P. gingivalis fimbriae. PMID- 26972442 TI - Improved cortical bone specificity in UTE MR Imaging. AB - PURPOSE: Methods for direct visualization of compact bone using MRI have application in several "MR-informed" technologies, such as MR-guided focused ultrasound, MR-PET reconstruction and MR-guided radiation therapy. The specificity of bone imaging can be improved by manipulating image sensitivity to Bloch relaxation phenomena, facilitating distinction of bone from other tissues detected by MRI. METHODS: From Bloch equation dynamics, excitation pulses suitable for creating specific sensitivity to short-T2 magnetization from cortical bone are identified. These pulses are used with UTE subtraction demonstrate feasibility of MR imaging of compact bone with positive contrast. RESULTS: MR images of bone structures are acquired with contrast similar to that observed in x-ray CT images. Through comparison of MR signal intensities with CT Hounsfield units of the skull, the similarity of contrast is quantified. The MR technique is also demonstrated in other regions of the body that are relevant for interventional procedures, such as the shoulder, pelvis and leg. CONCLUSION: Matching RF excitation pulses to relaxation rates improves the specificity to bone of short-T2 contrast. It is demonstrated with a UTE sequence to acquire images of cortical bone with positive contrast, and the contrast is verified by comparison with x-ray CT. Magn Reson Med 77:684-695, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26972443 TI - Clinical Significance of Myeloid-Derived Suppressor Cells in Human Immunodeficiency Virus-1/ Hepatitis C Virus-coinfected Patients. AB - Myeloid-derived suppressor cells (MDSCs) are known to accumulate during chronic viral infection, including human immunodeficiency virus-1 (HIV-1) and hepatitis C virus (HCV) infection, and play a critical role in suppressing immune responses. However, the role of MDSCs in HIV/HCV coinfection is unclear. Here, we observed a dramatic increase in monocytic MDSCs (M-MDSCs) level in the peripheral blood of HIV/HCV-coinfected patients compared to that of healthy controls; the level of M MDSCs proportion in coinfection was not higher than that in HIV or HCV monoinfection. Interestingly, we found the M-MDSCs level in coinfected patients correlated well with CD4(+) T cell loss (r = -0.5680; P = 0.0058), HIV-1 load (r = 0.6011; P = 0.0031), HCV load (r = 0.6288; P = 0.0017) and activated CD38(+) T cells (r = 0.5139; P = 0.0144). Initiation of highly active antiretroviral therapy considerably reduced both M-MDSCs and CD8(+) CD38(+) -activated T cell proportion in coinfected patients, and they showed a parallel course of decline. Thus, our results suggest that HIV-1 infection and high chronic immune activation may contribute to the expansion of M-MDSCs and accelerate the disease progression in HIV/HCV-coinfected patients. PMID- 26972444 TI - Branch-PCR Constructed Stable shRNA Transcription Nanoparticles Have Long-Lasting RNAi Effect. AB - RNA interference (RNAi) is a cellular process for gene silencing. Because of poor serum stability, transferring dsRNA directly into the target cells is a challenge. We report a facile and universal strategy to construct short hairpin RNA (shRNA) transcription nanoparticles with multiple shRNA transcription templates by PCR with flexible branched primers (branch-PCR). Compared with conventional linear shRNA transcription templates, these shRNA transcription nanoparticles show excellent stability against digestion by exonuclease III. Importantly, we found that our highly stable shRNA transcription nanoparticles can also be transcribed and thus induce efficient and long-lasting RNAi with picomolar activity in living mammalian cells. These chemically well-defined branch-PCR-generated stable shRNA transcription nanoparticles might facilitate RNAi delivery with a long-lasting RNAi effects. PMID- 26972445 TI - Overexpression of miR-499-5p inhibits non-small cell lung cancer proliferation and metastasis by targeting VAV3. AB - Dysregulation of miRNAs is reported to be involved in the invasion and metastasis of lung cancer. Previous studies showed that low serum miR-499 expression was associated with advanced TNM stage and poor prognosis. The present study is carried out to evaluate the biological functions of miR-499-5p in lung cancer. We demonstrated that miR-499-5p was significantly reduced in NSCLC tissues and correlated with poor clinical outcomes. Overexpression of miR-499-5p inhibited cell proliferation and induced apoptosis in vitro and in vivo. Furthermore, miR 499-5p overexpression also inhibited NSCLC metastasis in vitro and in vivo. Using bioinformatics tools, we identified VAV3 as a candidate target of miR-499-5p, and demonstrated that restoration of miR-499-5p expression in NSCLC cells downregulated VAV3 expression while inhibition of miR-499-5p upregulated VAV3 expression. Luciferase reporter assays showed that miR-499-5p targeted 3'-UTR of VAV3. Moreover, cancer growth, proliferation and metastasis were decreased and apoptosis was increased after VAV3 blockage induced by miR-499-5p overexpression. We conclude that miR-499-5p functions as a tumor suppressor by targeting VAV3. This finding may provide a therapeutic approach for future treatment of NSCLC. PMID- 26972446 TI - Attentional biases in healthy adults: Exploring the impact of temperament and gender. AB - BACKGROUND: Attentional biases such as faster attentional orienting toward negative information were consistently replicated in high-anxious and depressive individuals, but findings in healthy individuals are inconsistent so far. METHODS: Using a dot-probe paradigm, we investigated whether temperament traits and gender, which are linked to (sub)clinical symptoms and attentional processing, influenced attentional biases in healthy adults. RESULTS: All participants showed protective attentional biases in terms of orienting their attention away from negative information. In both genders higher values of negative affect were compensated with stronger attentional engagement with positive stimuli. This effect was more pronounced in men than in women. Effortful control fulfilled its regulative function in terms of stronger avoidance of negative stimuli only among men. LIMITATIONS: Reaction times after probe detection provide only a snapshot of attention and allow only for an indirect assessment of visual attention. Future research should emphasize methods that allow for continuous monitoring of attention allocation, therefore results of the present study await replication in psychophysiological or eye-tracking studies. CONCLUSION: Our results highlight the importance of considering influencing factors such as gender and temperament traits for attentional biases in healthy adults. PMID- 26972447 TI - Liver transplant alone without kidney transplant for fibrinogen Aalpha-chain (AFib) renal amyloidosis. PMID- 26972448 TI - Finding the Golgi: Golgin Coiled-Coil Proteins Show the Way. AB - The Golgi apparatus lies at the centre of the secretory pathway. It consists of a series of flattened compartments typically organised into a stack that, in mammals, is connected to additional stacks to form a Golgi ribbon. The Golgi is responsible for the maturation and modification of proteins and lipids, and receives and exports vesicles to and from multiple destinations within the cell. This complex trafficking network requires that only the correct vesicles fuse with the correct destination membrane. Recently, a group of coiled-coil proteins called golgins were shown to not only capture incoming vesicles but to also provide specificity to the tethering step. This raises many interesting questions about how they interact with other components of membrane traffic, some of which may also contribute to specificity. PMID- 26972450 TI - Superconductivity in Weyl semimetal candidate MoTe2. AB - Transition metal dichalcogenides have attracted research interest over the last few decades due to their interesting structural chemistry, unusual electronic properties, rich intercalation chemistry and wide spectrum of potential applications. Despite the fact that the majority of related research focuses on semiconducting transition-metal dichalcogenides (for example, MoS2), recently discovered unexpected properties of WTe2 are provoking strong interest in semimetallic transition metal dichalcogenides featuring large magnetoresistance, pressure-driven superconductivity and Weyl semimetal states. We investigate the sister compound of WTe2, MoTe2, predicted to be a Weyl semimetal and a quantum spin Hall insulator in bulk and monolayer form, respectively. We find that bulk MoTe2 exhibits superconductivity with a transition temperature of 0.10 K. Application of external pressure dramatically enhances the transition temperature up to maximum value of 8.2 K at 11.7 GPa. The observed dome-shaped superconductivity phase diagram provides insights into the interplay between superconductivity and topological physics. PMID- 26972453 TI - The contribution of biological factors to the pathogenesis of psychiatric disorders in the postpartum period: a survey. AB - Samenvatting Aan de hand van literatuurgegevens wordt een overzicht gegeven van de rol van biologische factoren bij het tot stand komen van de drie belangrijkste psychiatrische stoornissen in het kraambed: 'maternity blues', postpartumdepressie en kraambedpsychose. Voorde blues en de postpartumdepressie worden vooral stoornissen in de stofwisseling van L-tryptofaan, progesteron en de endorfines beschreven maar zonder dat een duidelijk biopsychofysiologische verklaring van de ziektebeelden kan worden gegeven. Voorde kraambedpsychose wordt vooral aan dopamine en beta-enkefaline aandacht besteed. Het blijkt dat over de bio-etiologie van deze aandoeningen vooralsnog geen consensus bestaat. PMID- 26972452 TI - Validation of the novel International Society of Urological Pathology 2014 five tier Gleason grade grouping: biochemical recurrence rates for 3+5 disease may be overestimated. PMID- 26972451 TI - Increased aquaporin 1 expression in the tunica albuginea of Peyronie's disease patients: an in vivo pilot study. AB - Peyronie's disease (PD) is a localized disorder of the connective tissue of the tunica albuginea (TA) whose etiology has not been elucidated. Although several studies have implicated genetic susceptibility and/or mechanical trauma as triggering events for PD, the underlying molecular mechanisms remain largely unknown. Aquaporin 1 (AQP1) is a water channel protein potentially implicated in connective tissue resistance to mechanical stress, acting primarily by increasing tension within the collagen network. Although it represents a potentially attractive molecular target in PD, to date no studies had ever addressed whether AQP1 is detectable and/or differentially expressed in the TA of these patients. Herein the present study, through immunohistochemical and biochemical approaches, we were able to detect AQP1 expression in the TA of control and PD affected patients. We demonstrated that AQP1-like immunoreactivity and expression are significantly increased in plaques of PD patients Vs controls, implying that AQP1 overexpression might be the consequence of a localized maladaptive response of the connective tissue to repeated mechanical trauma. In summary, these data support the idea that AQP1 might represent a potentially useful biomarker of mechanical injury in the TA and a promising target for the treatment of PD. PMID- 26972449 TI - History of chickenpox in glioma risk: a report from the glioma international case control study (GICC). AB - Varicella zoster virus (VZV) is a neurotropic alpha-herpesvirus that causes chickenpox and establishes life-long latency in the cranial nerve and dorsal root ganglia of the host. To date, VZV is the only virus consistently reported to have an inverse association with glioma. The Glioma International Case-Control Study (GICC) is a large, multisite consortium with data on 4533 cases and 4171 controls collected across five countries. Here, we utilized the GICC data to confirm the previously reported associations between history of chickenpox and glioma risk in one of the largest studies to date on this topic. Using two-stage random-effects restricted maximum likelihood modeling, we found that a positive history of chickenpox was associated with a 21% lower glioma risk, adjusting for age and sex (95% confidence intervals (CI): 0.65-0.96). Furthermore, the protective effect of chickenpox was stronger for high-grade gliomas. Our study provides additional evidence that the observed protective effect of chickenpox against glioma is unlikely to be coincidental. Future studies, including meta-analyses of the literature and investigations of the potential biological mechanism, are warranted. PMID- 26972454 TI - Psychobiological aspects of Sensation Seeking Behavior. AB - Samenvatting Sensation Seekers zijn personen die vrijwillig levensgevaarlijke situaties opzoeken. Sensation Seeking gedrag kan sociaal en lichamelijk schadelijke effecten hebben. In vergelijking met controlegroepen zijn bij Sensation Seekers significante ver-schillen aangetoond in verscheidene psychobiologische reacties die optreden bij informatieverwerking. PMID- 26972455 TI - The crossroads of anticipatory attention and motor preparation. AB - Samenvatting In een drietal artikelen wordt de overeenkomst besproken tussen Processen die ten grondslag liggen aan twee verschillende functies: anticipatoire attentie en motorische preparatie. Beide functies zijn van belang voor een optimale afstemming op onze omgeving. Het achterste gedeelte van de hersenschors houdt zieh voornamelijk bezig met binnenkomende informatie uit de buiten-wereld en het eigen lichaam, terwijl het voorste deel essentieel is voor onze acties en readies. Als bekend is wanneer wij met relevante informatie worden geconfronteerd en vermoed kan worden hoe daarop moet worden gereageerd, worden modali teitsspeeifieke sensorische en motorische kanalen geopend om zo een snelle en adequate reactie te garanderen. In deze tekst wordt gepostuleerd dat de achterste en voorste cortexhelften op vergelijkbare wijze vanuit de thalamus worden geactiveerd als onder-deel van anticipatoire attentie en motorische preparatie. Cruciaal is de inhiberende invloed die de nucleus reticularis (NR) uitoefent op de onderliggende thalamuskernen. De NR staat onder een dubbele controle: exciterend vanuit de prefrontale cortex en inhiberend vanuit het neostriatum. Aangegeven wordt hoe selectie in de informatieverwerking via deze balans kan worden gerealiseerd, zowel in het sensorische als het motorische domein. Nadat in Deel I een overzicht is gegeven van de relevante anatomische structuren, wordt hier het model voor anticipatoire attentie en motorische preparatie gepresenteerd. In het volgende artikel wordt neuropsychologische evidentie gepresenteerd, waarna het psychofysiologisch onderzoek aan de orde komt dat heeft geleid tot de formule ring van het model. PMID- 26972456 TI - The significance of the expression of Fos protein in the brain for the classification of antipsychotics. AB - Samenvatting In de afgelopen zes jaar is veel onderzoek verficht naar de effecten van antipsychotica op de regionale c-fos-expressie in de hersenen. Deze benadering biedt in een dierexperimentele proefopzet de mogelijkheid op cellulair niveau de effecten van psychofarmaca te bestuderen. Het fos-gen behoort tot de groep 'immediate early genes'. Dit zijn genen die de transcriptie van andere, vaak onbekende genen reguleren. Een aantal aspecten van dit mechanisme wordt in deze bijdrage beschreven. Het onderzoek naar de effecten van antipsychotica op c fos-expressie wordt samengevat en de betekenis voor de classificatie van antipsychotica benadrukt. Het blijkt dat deze farmaca effectief zijn in zowel de (meso)limbische gebieden (als nucleus accumbens, septum en amygdala) als ook in de basale ganglia. De relatieve effecten, wat betreft de c-fos-reactie, van de atypische antipsychotica (als clozapine en risperidon) zijn hoger in de limbische structuren, vergeleken met de effecten van de typische (als haloperidol). De potentie van de c-fos-methodiek voor verdere ontwikkelingen in dit gebied wordt aangegeven. PMID- 26972457 TI - Repeatable Battery for the Assessment of Neuropsychological Status: Effort Index Cutoff Scores for Psychometrically Defined Malingering Groups in a Military Sample. AB - OBJECTIVE: This research examined cutoff scores for the Effort Index (EI), an embedded measure of performance validity, for the Repeatable Battery for the Assessment of Neuropsychological Status. EI cutoffs were explored for an active duty military sample composed mostly of patients with traumatic brain injury. METHOD: Four psychometrically defined malingering groups including a definite malingering, probable to definite malingering, probable malingering, and a combined group were formed based on the number of validity tests failed. RESULTS: Excellent specificities (0.97 or greater) were found for all cutoffs examined (EI >= 1 to EI >= 3). Excellent sensitivities (0.80 to 0.89) were also found for the definite malingering group. Sensitivities were 0.49 or below for the other groups. Positive and negative predictive values and likelihood ratios indicated that the cutoffs for EI were much stronger for ruling-in than ruling-out malingering. Analyses indicated the validity tests used to form the malingering groups were uncorrelated, which serves to enhance the validity of the formation of the malingering groups. CONCLUSIONS: Cutoffs were similar to other research using samples composed predominantly of head-injured individuals. PMID- 26972458 TI - A Qualitative Study of the Integration of Arab Muslim Israelis Suffering from Mental Disorders into the Normative Community. AB - This study focuses on the process of the integration of Arab Muslim Israelis suffering from mental disorders into the normative community, addressing perspectives of both people with mental disorders and the community. This qualitative-constructivist study seeks to understand the dynamics of face-to-face meetings by highlighting the participants' points of view. The main themes of the findings included stereotypes and prejudices, gender discrimination, and the effect of face-to-face meetings on integration of people with mental disorders (PMD) into the community. The findings support former studies about the integration of PMD into the normative community, but add a unique finding that females suffer from double discrimination: both as women in a conservative society and as PMD. The study findings indicate a perception of lack of self efficacy of PMD as a key barrier preventing integration into the community, which also prevents community members and counselors from accepting them or treating them as equals. We recommend on a social marketing campaign to be undertaken with the Arab Muslim community to refute stigmas and prejudices, particulary with double gender discrimination suffered by women with mental disorders in the Muslim community and training of community center counselors who have contact with the PMD population. PMID- 26972459 TI - Entrainment in up and down states of neural populations: non-smooth and stochastic models. AB - Slow oscillations in firing rate of neural populations are commonly observed during slow wave sleep. These oscillations are partitioned into up and down states, where the population switches between high and low firing rates (Sanchez Vives and McCormick in Nat Neurosci 3:1027-1034, 2000). Transitions between up and down states can be synchronized at considerably long ranges (Volgushev et al. in J Neurosci 26:5665-5672, 2006). To explore how external perturbations shape the phase of slow oscillations, we analyze a reduced model of up and down state transitions involving a population neural activity variable and a global adaptation variable. The adaptation variable represents the average of all the slow hyperpolarizing currents received by neurons in a large population. Recurrent connectivity leads to a bistable neural population, where a low firing rate state coexists with a high firing rate state, where persistent activity is maintained via excitatory connections. Adaptation eventually inactivates the high activity state, and the low activity state then persists until adaptation has significantly decayed. We analyze the phase response of the rate model by taking advantage of the separation of timescales between the fast activity and slow adaptation variables. This analysis reveals that perturbations to the neural activity variable have a considerably weaker effect on the oscillation phase than adaptation perturbations. When noise is not incorporated into the rate model, the period of the slow oscillation is determined by the timescale of the slow adaptation variable. In the presence of noise, times at which the population transitions between the low and high activity states become variable. This is because the rise and decay of the adaptation variable is now stochastically driven, leading to a distribution of transition times. Interestingly, common noise in the adaptation variable can lead to a correlation of two distinct slow oscillating populations. This effect is still significant in the event that each population contains its own local sources of noise. We also show this phenomenon can occur a spiking network. Our results demonstrate the relative contributions of excitatory input and hyperpolarizing current fluctuations on the phase of slow oscillations. PMID- 26972461 TI - Preparation of Zirconia Supported Basic Nanocatalyst: A Physicochemical and Kinetic Study of Biodiesel Production from Soybean Oil. AB - Zirconia supported cadmium oxide basic nanocatalyst was prepared by simple co precipitation method using aq. ammonia as precipitating reagent. The catalyst was characterised by X-ray diffraction, scanning electron microscopy (SEM) and transmission electron microscopy technique (TEM), Brunauer-Emmet-Teller surface area measurement (BET), temperature program desorption (TPD-CO2) etc. The transesterificaton of soybean oil with methanol into biodiesel was catalysed by employing zirconia supported nanocatalyst. Kinetics of transesterificaton of oil was studied and obeyed the pseudo first order equation. While, the activation energy (Ea) for the transesterification of oil was found to be 41.18 kJ mol(-1). The 97% yield of biodiesel was observed using 7% catalyst loading (with respect of oil), 1:40 molar ratio of oil to methanol at 135 degrees C. PMID- 26972462 TI - Extraction and Functional Properties of Proteins from Pre-roasted and Enzyme Treated Poppyseed (Papaver somniferum L.) Press Cakes. AB - In this study, proteins of the defatted meals obtained from cold-pressed poppyseed previously treated (pre-roasting and enzyme against control) were extracted and their compositional and functional properties were determined. Saline-alkaline extraction (pH 11-12, and 0.2-0.6 M NaCI) and isoelectric point (pH 4.0-5.5) precipitation technique showed that seed pre-roasting enhances protein yield while enzyme treatment reduces it. There were 7 bands on SDS-PAGE, and enzyme treated samples were weaker than control. While enzyme treatment decreased denaturation temperatures (T(d)), roasting enhanced the enthalpy change (DeltaH) values. Pre-treatments caused a decrease in protein least gelling concentration (LGC) values. Water and oil holding capacities (WHC and OHC) were found lower in enzyme treated and higher in preroasted samples. Similar effects were also determined for emulsifying activity (EA) and emulsion stability (ES) values. While foaming capacity (FC) in treated samples decreased, foam stability (FS) increased oppositely. In conclusion, poppyseed meals can be nutritionally good source for diet protein, and a limited pre-roasting can be very beneficial for enhanced protein extraction yield and desirable functional properties. PMID- 26972463 TI - Chemical Composition, Cytotoxic and Antibacterial Activities of the Essential Oil from the Tunisian Ononis angustissima L. (Fabaceae). AB - The chemical composition, cytotoxic and antibacterial activities of the hydrodistilled essential oil of the aerial parts of Ononis angustissima from south Tunisia has been evaluated. The oil yield was 0.04% (w/w). The chemical composition, determined by GC and GC-MS is reported for the first time. Forty five components, accounting for 93.7% of the total oil have been identified. The oil was characterized by a high proportion of oxygenated sesquiterpenes (33.2%), followed by sesquiterpene hydrocarbons (6.3%) and apocarotenoids (10.3%). The main components of the oil were alpha-eudesmol (22.4%), 2-tridecanone (9.3%) and acetophenone (7.4%). The essential oil was tested for its possible cytotoxic activity towards the human cervical cell line HeLa using the MTT assay and the antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, Enterococcus faecalis, Staphylococcus aureus and the clinical strain Acinetobacter sp. This oil exerted a cytotoxic activity with an IC50 of 0.53 +/- 0.02 mg/mL and a significant antibacterial effect against P. aeruginosa and E. faecalis. PMID- 26972460 TI - Inverse regulation of two classic Hippo pathway target genes in Drosophila by the dimerization hub protein Ctp. AB - The LC8 family of small ~8 kD proteins are highly conserved and interact with multiple protein partners in eukaryotic cells. LC8-binding modulates target protein activity, often through induced dimerization via LC8:LC8 homodimers. Although many LC8-interactors have roles in signaling cascades, LC8's role in developing epithelia is poorly understood. Using the Drosophila wing as a developmental model, we find that the LC8 family member Cut up (Ctp) is primarily required to promote epithelial growth, which correlates with effects on the pro growth factor dMyc and two genes, diap1 and bantam, that are classic targets of the Hippo pathway coactivator Yorkie. Genetic tests confirm that Ctp supports Yorkie-driven tissue overgrowth and indicate that Ctp acts through Yorkie to control bantam (ban) and diap1 transcription. Quite unexpectedly however, Ctp loss has inverse effects on ban and diap1: it elevates ban expression but reduces diap1 expression. In both cases these transcriptional changes map to small segments of these promoters that recruit Yorkie. Although LC8 complexes with Yap1, a Yorkie homolog, in human cells, an orthologous interaction was not detected in Drosophila cells. Collectively these findings reveal that that Drosophila Ctp is a required regulator of Yorkie-target genes in vivo and suggest that Ctp may interact with a Hippo pathway protein(s) to exert inverse transcriptional effects on Yorkie-target genes. PMID- 26972464 TI - Fatty Acids Profile, Phenolic Compounds and Antioxidant Capacity in Elicited Callus of Thevetia peruviana (Pers.) K. Schum. AB - The aim of this study was analyze the effect of jasmonic acid (JA) and abscisic acid (ABA) as elicitors on fatty acids profile (FAP), phenolic compounds (PC) and antioxidant capacity (AC) in callus of Thevetia peruviana. Schenk & Hildebrandt (SH) medium, supplemented with 2 mg/L 2, 4-dichlorophenoxyacetic (2, 4-D) and 0.5 mg/L kinetin (KIN) was used for callus induction. The effect of JA (50, 75 and 100 MUM) and ABA (10, 55 and 100 MUM) on FAP, PC and AC were analyzed using a response surface design. A maximum of 2.8 mg/g of TPC was obtained with 100 plus 10 uM JA and ABA, respectively, whereas AC maximum (2.17 MUg/mL) was obtained with 75 plus 100 uM JA and ABA, respectively. The FAP was affected for JA but not for ABA. JA increased cis-9, cis-12-octadecadienoic acid and decreased dodecanoic acid. Eight fatty acids were identified by GC-MS analysis and cis-9-octadecenoic acid (18:1) was the principal fatty acid reaching 76 % in treatment with 50 MUM JA plus 55 MUM ABA. In conclusion, JA may be used in T. peruviana callus culture for obtain oil with different fatty acids profile. PMID- 26972466 TI - Sexual Differences in Chemical Composition and Aroma-active Compounds of Essential Oil from Flower Buds of Eurya japonica. AB - This study was conducted to determine the composition of essential oil from buds of male and female Eurya japonica flowers and to determine the aroma-active compounds of this plant by gas chromatography-mass spectrometry (GC-MS), sensory evaluation, and odor activity values (OAV). The oils contained eighty-five compounds. We identified for the first time forty-four compounds in E. japonica. Through sensory evaluation, nineteen aroma-active compounds were identified by gas chromatography-olfactometry (GC-O). Because the chemical composition can affect the interaction between plants and herbivorous insects, our results suggest that essential oils from male and female flower buds of E. japonica differently affect herbivores. Sexual differences in essential oils deserve further investigations in this plant-insect system. PMID- 26972465 TI - The Collaborative Study on the Enzymatic Analysis of Positional Distribution of Short- and Medium-chain Fatty Acids in Milk Fat Using Immobilized Candida antarctica Lipase B. AB - The positional distributions of fatty acids (FAs) in milk fat containing short- and medium-chain FAs were analyzed by sn-1(3)-selective transesterification of triacylglycerols (TAGs) with ethanol using immobilized Candida antarctica lipase B (CALB), in a collaborative study conducted by 10 laboratories. The mean C4:0, C6:0, and C8:0 FA contents, when analyzed as propyl esters (PEs) using gas chromatography (GC) with a DB-23 capillary column, were found to be 3.0, 2.0, and, 1.3 area%, respectively. Their reproducibility standard deviations were 0.33, 0.18, and 0.19, respectively. The mean C4:0, C6:0, and C8:0 contents at the sn-2 position were 0.3, 0.4, and 1.0 area%, respectively. Their reproducibility standard deviations were 0.17, 0.11, and 0.19, respectively. The reproducibility standard deviations of C4:0, C6:0, and C8:0 FAs at the sn-2 position were either the same as or smaller than those for milk fat, although the FA contents at the sn-2 position were smaller than those in the milk fat. Therefore, it was concluded that the CALB method for estimating the regiospecific distribution is applicable to TAGs containing short- and medium-chain FAs. When estimating the short-chain (SC) FA contents in fats and oils by GC, it is better to analyze SCFAs as PEs or butyl esters, and not as methyl esters, in order to prevent loss of SCFAs during the experimental procedure because of their volatility and water solubility. This study also revealed that the stationary phase of the GC capillary column affected the flame ionization detector (FID) response of SCFAs. The theoretical FID correction factor (MWFA / active carbon number / atomic weight of carbon) fitted well with the actual FID responses of C4:0-C12:0 FAs when they were analyzed as PEs using a DB-23 column; however, this was not the case when the GC analysis was performed using wax-type columns. PMID- 26972467 TI - Biodegradable, Tethered Lipid Bilayer-Microsphere Systems with Membrane Integrated alpha-Helical Peptide Anchors. AB - Supported lipid bilayers (SLBs) are ideally suited for the study of biomembrane biomembrane interactions and for the biomimicry of cell-to-cell communication, allowing for surface ligand displays that contain laterally mobile elements. However, the SLB paradigm does not include three-dimensionality and biocompatibility. As a way to bypass these limitations, we have developed a biodegradable form of microsphere SLBs, also known as proteolipobeads (PLBs), using PLGA microspheres. Microspheres were synthesized using solvent evaporation and size selected with fluorescence activated cell sorting (FACS). Biomembranes were covalently tethered upon fusion to microsphere supports via short-chain PEG spacers connecting membrane-integrated alpha-helical peptides and the microsphere surface, affecting membrane diffusivity and mobility as indicated by confocal FRAP analysis. Membrane heterogeneities, which are attributed to PLGA hydrophobicity and rough surface topography, are curtailed by the addition of PEG tethers. This method allows for the presentation of tethered, laterally mobile biomembranes in three dimensions with functionally embedded attachment peptides for mobile ligand displays. PMID- 26972468 TI - No evidence of learning in non-symbolic numerical tasks--A comment on Park and Brannon (2014). AB - Two recent studies - one of which was published in this journal - claimed to have found that learning on a non-symbolic arithmetic task improved performance on a symbolic arithmetic task (Park & Brannon, 2013, 2014). This finding has potentially far-reaching implications, because it would constitute evidence for a causal link between the Approximate Number System (ANS) and symbolic-math ability. Here, we argue that, due to the methodology used in both studies, the interpretation of data in terms of an improvement in ANS performance is problematic. We provide arguments and simulations showing that the trends in the data are similar to what one would expect for a non-learning observer. We discuss the implications for the original interpretation in terms of causality between non-symbolic and symbolic arithmetic performance. PMID- 26972469 TI - How to interpret cognitive training studies: A reply to Lindskog & Winman. AB - In our previous studies, we demonstrated that repeated training on an approximate arithmetic task selectively improves symbolic arithmetic performance (Park & Brannon, 2013, 2014). We proposed that mental manipulation of quantity is the common cognitive component between approximate arithmetic and symbolic arithmetic, driving the causal relationship between the two. In a commentary to our work, Lindskog and Winman argue that there is no evidence of performance improvement during approximate arithmetic training and that this challenges the proposed causal relationship between approximate arithmetic and symbolic arithmetic. Here, we argue that causality in cognitive training experiments is interpreted from the selectivity of transfer effects and does not hinge upon improved performance in the training task. This is because changes in the unobservable cognitive elements underlying the transfer effect may not be observable from performance measures in the training task. We also question the validity of Lindskog and Winman's simulation approach for testing for a training effect, given that simulations require a valid and sufficient model of a decision process, which is often difficult to achieve. Finally we provide an empirical approach to testing the training effects in adaptive training. Our analysis reveals new evidence that approximate arithmetic performance improved over the course of training in Park and Brannon (2014). We maintain that our data supports the conclusion that approximate arithmetic training leads to improvement in symbolic arithmetic driven by the common cognitive component of mental quantity manipulation. PMID- 26972470 TI - Structure-Based Design of a Br Halogen Bond at the Complex Interface of the Human Placental HtrA1 PDZ Domain with Its Heptapeptide Ligand. AB - The shock-induced serine protease HtrA1 is a potential regulator of human placenta development during pregnancy. The protein contains a functional PDZ domain that has been solved in complex with a phage display-derived heptapeptide: Asp-6 Ser-5 Arg-4 Ile-3 Trp-2 Trp-1 Val0 . In this study, a rationally designed halogen bond was introduced to the domain-peptide complex based on its NMR structure in solution. We computationally compared the stabilization energies and hindrance effects due to the presence of different halogens X (X = F, Cl, Br, or I), using a hybrid quantum mechanics/molecular mechanics (QM/MM) approach, and found that the Br atom could considerably promote the peptide binding free energy (DeltaDeltaG = -5.2 kcal/mol). Fluorescence assays confirmed that the peptide affinity to the HtrA1 PDZ domain was improved by approximately sevenfold upon bromination. Structural analysis identified a geometrically perfect halogen bond between the Br atom of the peptide Trp-1 residue and the carbonyl O atom of the HtrA1 Ile385 residue, with a bond length and an interaction energy of d = 3.20 A and DeltaE = -3.7 kcal/mol, respectively. PMID- 26972473 TI - Impact of chronobiology on neuropathic pain treatment. AB - Inflammatory pain exhibits circadian rhythmicity. Recently, a distinct diurnal pattern has been described for peripheral neuropathic conditions. This diurnal variation has several implications: advancing understanding of chronobiology may facilitate identification of new and improved treatments; developing pain contingent strategies that maximize treatment at times of the day associated with highest pain intensity may provide optimal pain relief as well as minimize treatment-related adverse effects (e.g., daytime cognitive dysfunction); and consideration of the impact of chronobiology on pain measurement may lead to improvements in analgesic study design that will maximize assay sensitivity of clinical trials. Recent and ongoing chronobiology studies are thus expected to advance knowledge and treatment of neuropathic pain. PMID- 26972472 TI - Correlates and predictors of sexual health among adolescent Latinas in the United States: A systematic review of the literature, 2004-2015. AB - Adolescent Latinas in the United States (US) are disproportionately affected by early pregnancy, sexually transmitted infections (STIs) and human immunodeficiency virus (HIV) in comparison to their non-Hispanic white counterparts. However, only a few studies have sought to understand the multi level factors associated with sexual health in adolescent Latinas. Adhering to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, we conducted a systematic literature review to better understand the correlates and predictors of sexual health among adolescent Latinas in the US, identify gaps in the research, and suggest future directions for empirical studies and intervention efforts. Eleven studies were identified: five examined onset of sexual intercourse, nine examined determinants of sexual health/risk behaviors (e.g., number of sexual partners and condom use), and three examined determinants of a biological sexual health outcome (i.e., STIs or pregnancy). Two types of variables/factors emerged as important influences on sexual health outcomes: proximal context-level variables (i.e., variables pertaining to the individual's family, sexual/romantic partner or peer group) and individual-level variables (i.e., characteristics of the individual). A majority of the studies reviewed (n=9) examined some aspect of acculturation or Latino/a cultural values in relation to sexual health. Results varied widely between studies suggesting that the relationship between individual and proximal contextual variables (including acculturation) and sexual health may be more complex than previously conceived. This review integrates the findings on correlates and predictors of sexual health among adolescent Latinas, and supports the need for strengths-based theoretically guided research on the mechanisms driving these associations. PMID- 26972475 TI - A longitudinal investigation of childhood communication ability and adolescent psychotic experiences in a community sample. AB - BACKGROUND: Some childhood speech and language impairments precede psychosis but it is not clear whether they also precede adolescent psychotic experiences and whether this association is specific to psychotic experiences. METHODS: Pragmatic language and expressive speech and language (parent-assessed using the Children's Communication Checklist) at age 9 and psychotic experiences and depression at ages 12 and 18 were investigated in 7659 participants from the Avon Longitudinal Study of Parents and Children. Associations were investigated using multivariate modelling. RESULTS: Poorer pragmatic language at 9years was associated with psychotic experiences at both ages (12years OR 1.22, 95% CI 1.11, 1.34; 18years OR 1.25, 95% CI 1.10, 1.41) but only with depression at 18years (OR 1.10, 95% CI 1.00, 1.22). Poorer expressive speech and language ability was not associated with psychotic experiences or depression at either age. There was evidence that pragmatic language was specifically associated with psychotic experiences at age 12 but no evidence that the strength of any of the associations changed over time. CONCLUSIONS: Deficits in pragmatic language precede early and late adolescent psychotic experiences and early adolescent depression. Interventions aimed at helping children improve pragmatic language skills may reduce the incidence of adolescent psychopathology and associated psychological disorder and dysfunction later in life. PMID- 26972476 TI - High-pressure Gas Activation for Amorphous Indium-Gallium-Zinc-Oxide Thin-Film Transistors at 100 degrees C. AB - We investigated the use of high-pressure gases as an activation energy source for amorphous indium-gallium-zinc-oxide (a-IGZO) thin film transistors (TFTs). High pressure annealing (HPA) in nitrogen (N2) and oxygen (O2) gases was applied to activate a-IGZO TFTs at 100 degrees C at pressures in the range from 0.5 to 4 MPa. Activation of the a-IGZO TFTs during HPA is attributed to the effect of the high-pressure environment, so that the activation energy is supplied from the kinetic energy of the gas molecules. We reduced the activation temperature from 300 degrees C to 100 degrees C via the use of HPA. The electrical characteristics of a-IGZO TFTs annealed in O2 at 2 MPa were superior to those annealed in N2 at 4 MPa, despite the lower pressure. For O2 HPA under 2 MPa at 100 degrees C, the field effect mobility and the threshold voltage shift under positive bias stress were improved by 9.00 to 10.58 cm(2)/V.s and 3.89 to 2.64 V, respectively. This is attributed to not only the effects of the pressurizing effect but also the metal-oxide construction effect which assists to facilitate the formation of channel layer and reduces oxygen vacancies, served as electron trap sites. PMID- 26972474 TI - Altered expression of developmental regulators of parvalbumin and somatostatin neurons in the prefrontal cortex in schizophrenia. AB - Dysfunction of prefrontal cortex (PFC) inhibitory neurons that express the calcium-binding protein parvalbumin or the neuropeptide somatostatin in schizophrenia may be related to disturbances in the migration, phenotypic specification, and/or maturation of these neurons. These pre- and postnatal developmental stages are regulated in a cell type-specific manner by various transcription factors and co-activators, fibroblast growth factor receptors (FgfR), and other molecular markers. Consequently, we used quantitative PCR to quantify mRNA levels for these developmental regulators in the PFC of 62 schizophrenia subjects in whom parvalbumin and somatostatin neuron disturbances were previously reported, and in antipsychotic-exposed monkeys. Relative to unaffected comparison subjects, subjects with schizophrenia exhibited elevated mRNA levels for 1) the transcription factor MafB, which is expressed by parvalbumin and somatostatin neurons as they migrate from the medial ganglionic eminence to the cortex, 2) the transcriptional coactivator PGC-1alpha, which is expressed postnatally by parvalbumin neurons to maintain parvalbumin levels and inhibitory function, and 3) FgfR1, which is required for the migration and phenotypic specification of parvalbumin and somatostatin neurons. Elevations in these markers were most prominent in younger schizophrenia subjects and were not present in antipsychotic-exposed monkeys. Finally, expression levels of other important developmental regulators (i.e. Dlx1, Dlx5, Dlx6, SATB1, Sip1/Zeb2, ST8SIA4, cMaf, Nkx6.2, and Arx) were not altered in schizophrenia. The over expression of a subset of molecular markers with distinct roles in the pre- and postnatal development of parvalbumin and somatostatin neurons might reflect compensatory mechanisms to sustain the development of these neurons in the face of other insults. PMID- 26972477 TI - Mechanical Ventilation during Acute Brain-Injury in Children. AB - Mechanical ventilation in the brain-injured pediatric patient requires many considerations, including the type and severity of lung and brain injury and how progression of such injury will develop. This review focuses on neurological breathing patterns at presentation, the effect of brain injury on the lung, developmental aspects of blood gas tensions on cerebral blood flow, and strategies used during mechanical ventilation in infants and children receiving neurological intensive care. Taking these basic principles, our clinical approach is informed by balancing the blood gas tension targets that follow from the ventilation support we choose and the intracranial consequences of these choices on vascular and hydrodynamic physiology. As such, we are left with two key decisions: a low tidal volume strategy for the lung versus the consequence of hypercapnia on the brain; and the use of positive end expiratory pressure to optimize oxygenation versus the consequence of impaired cerebral venous return from the brain and resultant intracranial hypertension. PMID- 26972479 TI - An ensemble distance measure of k-mer and Natural Vector for the phylogenetic analysis of multiple-segmented viruses. AB - The Natural Vector combined with Hausdorff distance has been successfully applied for classifying and clustering multiple-segmented viruses. Additionally, k-mer methods also yield promising results for global genome comparison. It is not known whether combining these two approaches can lead to more accurate results. The author proposes a method of combining the Hausdorff distances of the 5-mer counting vectors and natural vectors which achieves the best classification without cutting off any sample. Using the proposed method to predict the taxonomic labels for the 2363 NCBI reference viral genomes dataset, the accuracy rates are 96.95%, 94.37%, 99.41% and 93.82% for the Baltimore, family, subfamily, and genus labels, respectively. We further applied the proposed method to 48 isolates of the influenza A H7N9 viruses which have eight complete segments of nucleotide sequences. The single-linkage clustering trees and the statistical hypothesis testing results all indicate that the proposed ensemble distance measure can cluster viruses well using all of their segments of genome sequences. PMID- 26972478 TI - Inhibitory and excitatory networks balance cell coupling in the suprachiasmatic nucleus: A modeling approach. AB - Neuronal coupling contributes to circadian rhythms formation in the suprachiasmatic nucleus (SCN). While the neurotransmitter vasoactive intestinal polypeptide (VIP) is considered essential for synchronizing the oscillations of individual neurons, gamma-aminobutyric acid (GABA) does not have a clear functional role despite being highly concentrated in the SCN. While most studies have examined the role of either GABA or VIP, our mathematical modeling approach explored their interplay on networks of SCN neurons. Tuning the parameters that control the release of GABA and VIP enabled us to optimize network synchrony, which was achieved at a peak firing rate during the subjective day of about 7Hz. Furthermore, VIP and GABA modulation could adjust network rhythm amplitude and period without sacrificing synchrony. We also performed simulations of SCN networks to phase shifts during 12h:12h light-dark cycles and showed that GABA networks reduced the average time for the SCN model to re-synchronize. We hypothesized that VIP and GABA balance cell coupling in the SCN to promote synchronization of heterogeneous oscillators while allowing flexibility for adjustment to environmental changes. PMID- 26972481 TI - Insulin receptor regulates food intake through sulfakinin signaling in the red flour beetle, Tribolium castaneum. AB - Insects obtain energy and nutrients via feeding to support growth and development. The insulin signaling pathway is involved in the regulation of feeding; however, the underlying mechanisms are not fully understood. Here, we show that insulin signaling regulates food intake via crosstalk with neuropeptide sulfakinin in the red flour beetle, Tribolium castaneum. Silencing of the insulin receptor (InR) decreased the food intake in the penultimate and final instar stages, leading to a decrease of weight gain and mortality during larval-pupal metamorphosis. Interestingly, the knockdown of InR co-occurred with an increased expression of sulfakinin (sk), a gene encoding neuropeptide SK functioning as a satiety signal. In parallel, double silencing of sk and InR eliminated the inhibitory effect on food intake as induced by silencing of InR and the larvae died as prepupae. In conclusion, this study shows, for the first time, that the insulin/InR signaling regulates food intake through the sulfakinin signaling pathway in the larval stages of this important model and pest insect, indicating a novel target for pest control. PMID- 26972480 TI - hnRNPK inhibits GSK3beta Ser9 phosphorylation, thereby stabilizing c-FLIP and contributes to TRAIL resistance in H1299 lung adenocarcinoma cells. AB - c-FLIP (cellular FLICE-inhibitory protein) is the pivotal regulator of TRAIL resistance in cancer cells, It is a short-lived protein degraded through the ubiquitin/proteasome pathway. The discovery of factors and mechanisms regulating its protein stability is important for the comprehension of TRAIL resistance by tumor cells. In this study, we show that, when H1299 lung adenocarcinoma cells are treated with TRAIL, hnRNPK is translocated from nucleus to cytoplasm where it interacts and co-localizes with GSK3beta. We find that hnRNPK is able to inhibit the Ser9 phosphorylation of GSK3beta by PKC. This has the effect of activating GSK3beta and thereby stabilizing c-FLIP protein which contributes to the resistance to TRAIL in H1299 cells. Our immunohistochemical analysis using tissue microarray provides the clinical evidence of this finding by establishing a negative correlation between the level of hnRNPK expression and the Ser9 phosphorylation of GSK3beta in both lung adenocarcinoma tissues and normal tissues. Moreover, in all cancer tissues examined, hnRNPK was found in the cytoplasm whereas it is exclusively nuclear in the normal tissues. Our study sheds new insights on the molecular mechanisms governing the resistance to TRAIL in tumor cells, and provides new clues for the combinatorial chemotherapeutic interventions with TRAIL. PMID- 26972482 TI - Contour and osteotomy of free fibula transplant using a ruler template. AB - The fibula free tissue transplant has been used in mandibular reconstruction for several decades. Various techniques exist to shape and contour the fibula to restore continuity to the segmental mandible defect. Recently, virtual surgical planning has introduced the ability to use cutting guides to contour and create osteotomies for fibula free tissue reconstruction of the mandible. In this article, we describe a practical and reproducible technique to perform template based fibula free tissue reconstruction of the mandible without the use of cutting guides. Laryngoscope, 126:2288-2290, 2016. PMID- 26972483 TI - Role of annexin gene and its regulation during zebrafish caudal fin regeneration. AB - The molecular mechanism of epimorphic regeneration is elusive due to its complexity and limitation in mammals. Epigenetic regulatory mechanisms play a crucial role in development and regeneration. This investigation attempted to reveal the role of epigenetic regulatory mechanisms, such as histone H3 and H4 lysine acetylation and methylation during zebrafish caudal fin regeneration. It was intriguing to observe that H3K9,14 acetylation, H4K20 trimethylation, H3K4 trimethylation and H3K9 dimethylation along with their respective regulatory genes, such as GCN5, SETd8b, SETD7/9, and SUV39h1, were differentially regulated in the regenerating fin at various time points of post-amputation. Annexin genes have been associated with regeneration; this study reveals the significant up regulation of ANXA2a and ANXA2b transcripts and their protein products during the regeneration process. Chromatin immunoprecipitation and PCR analysis of the regulatory regions of the ANXA2a and ANXA2b genes demonstrated the ability to repress two histone methylations, H3K27me3 and H4K20me3, in transcriptional regulation during regeneration. It is hypothesized that this novel insight into the diverse epigenetic mechanisms that play a critical role during the regeneration process may help to strategize the translational efforts, in addition to identifying the molecules involved in vertebrate regeneration. PMID- 26972484 TI - Dexmedetomidine: Superiority trials needed? PMID- 26972485 TI - High-resolution investigation of memory-specific reinstatement in the hippocampus and perirhinal cortex. AB - Episodic memory involves remembering the details that characterize a prior experience. Successful memory recovery has been associated with the reinstatement of brain activity patterns in a number of sensory regions across the cortex. However, how the hippocampus and surrounding medial temporal lobe (MTL) cortex contribute to this process is less clear. Models of episodic memory posit that hippocampal pattern reinstatement, also referred to as pattern completion, may mediate cortical reinstatement during retrieval. Empirical evidence of this process, however, remains elusive. Here, we use high-resolution fMRI and encoding retrieval multi-voxel pattern similarity analyses to demonstrate for the first time that the hippocampus, particularly right hippocampal subfield CA1, shows evidence of reinstating individual episodic memories. Furthermore, reinstatement in perirhinal cortex (PrC) is also evident. Critically, we identify distinct factors that may mediate the cortical reinstatement in PrC. First, we find that encoding activation in PrC is related to later reinstatement in this region, consistent with the theory that encoding strength in the regions that process the memoranda is important for later reinstatement. Conversely, retrieval activation in right CA1 was correlated with reinstatement in PrC, consistent with models of pattern completion. This dissociation is discussed in the context of the flow of information into and out of the hippocampus during encoding and retrieval, respectively. (c) 2016 Wiley Periodicals, Inc. PMID- 26972487 TI - Rapid isolation of pure Complement Factor H from serum for functional studies by the use of a monoclonal antibody that discriminates FH from all the other isoforms. AB - Several mutations have been identified in the gene coding for Complement Factor H (FH) from patients with atypical Hemolytic Uraemic Syndrome (aHUS), Age-related Macular Degeneration (AMD) and Membranoproliferative Glomerulonephritis (MPGN). These data allow for a precise description of the structural changes affecting FH, but a simple test for specifically assessing FH function routinely is not yet of common use. We have produced and characterised a monoclonal antibody (5H5) which discriminates between FH and the smaller FH-like 1 and FH-related proteins and show here that it specifically binds to FH without detecting the smaller isoforms. We therefore used this mAb for a quick, one-step micro-purification of FH directly from control sera and showed that this affinity chromatography procedure is not disruptive of its cofactor function. We also developed a modified sheep erythrocytes haemolysis test using our antibody and affinity purified FH. These tests can be used in conjunction for assessing the function of FH purified from patients affected by FH-related diseases. Moreover we used this mAb to develop a FH-specific ELISA test. PMID- 26972486 TI - Binge Eating among Women Veterans in Primary Care: Comorbidities and Treatment Priorities. AB - BACKGROUND: Little is known about the clinical profile and treatment priorities of women with binge eating disorder (BED), a diagnosis new to the fifth edition of Diagnostic and Statistical Manual of Mental Disorders. We identified comorbidities and patients' treatment priorities, because these may inform implementation of clinical services. METHODS: Data were collected from women veteran primary care patients. Analyses compared those who screened positive for BED (BED+), and those without any binge eating symptoms (BED-). RESULTS: Frequencies of comorbid medical and psychological disorders were high in the BED+ group. The BED+ group's self-identified most common treatment priorities were mood concerns (72.2%), weight loss (66.7%), and body image/food issues (50%). Among those with obesity, a greater proportion of the BED+ group indicated body image/food issues was their top treatment priority (12.9% vs. 2.8%; p < .01), suggesting that these patients may be more apt to seek treatment beyond weight management for their problematic eating patterns. CONCLUSIONS: Women primary care patients with BED demonstrate high medical and psychological complexity; their subjective treatment priorities often match objective needs. These findings may inform the development of targeted BED screening practices for women with obesity in primary care settings, and the eventual adoption of patient-centered BED treatment resources. PMID- 26972488 TI - Fluorescence-Converging Carbon Nanodots-Hybridized Silica Nanosphere. AB - Ultrabright carbon nanodots-hybridized silica nanospheres (CSNs) are synthesized through the Stober process of silane functionalized C-dots. The fluorescence of carbon nanodots is converged intensely. A CSN is about 3800 times brighter than a single-carbon nanodot. Along with their high brightness and low cytotoxicity, CSNs also indicate their potential application in cellular labeling. PMID- 26972489 TI - Effects of Pitch Length and Heat Treatment on the Mechanical Properties of the Glide Path Preparation Instruments. AB - INTRODUCTION: This study aimed to compare the effects of pitch length and heat treatment on the mechanical properties of glide path establishing instruments. METHODS: Prototypes of glide path preparation files (#14/.03 taper) were made to evaluate the effects of different pitch lengths and heat treatments. The files were divided into 4 groups according to the pitch length (pG and OneG) and heat treatment (pGH and OneGH). For the torsional resistance test, ultimate strength and fracture angle were measured, and the file tip was fixed at 3 different levels of 2, 4, and 6 mm from the tip (n = 10 for each level). The toughness was calculated by multiplying the ultimate strength and the fracture angle. The cyclic fatigue resistance was compared by measuring the number of cycles to fracture in a curved metal canal (n = 10). The screw-in forces were measured during instrumentation motions with a sequential increase in the pecking distance of 1 mm until the file reached the end of the simulated resin canal (n = 10). RESULTS: The heat-treated groups showed lower toughness and higher cyclic fatigue resistance than the non-heat-treated groups. The short pitch groups showed significantly higher torsional strengths than the long pitch groups. The heat treated groups had significantly lower screw-in forces than the non-heat-treated groups. CONCLUSIONS: Under the limitations of this study, the torsional strength of the experimental file was reduced by heat treatment and increased by the short pitch length. Thus, a non-heat-treated file with a shorter pitch length would be favorable as a rotary glide path instrument. PMID- 26972490 TI - The possible threat of Zika virus in the Middle East. PMID- 26972491 TI - Retirement-A Transition to a Healthier Lifestyle?: Evidence From a Large Australian Study. AB - INTRODUCTION: Population aging is associated with a rising burden of non communicable disease, profoundly impacting health policy and practice. Adopting and adhering to healthy lifestyles in middle or older age can protect against morbidity and mortality. Retirement brings opportunities to reconfigure habitual lifestyles and establish new routines. This study examines the longitudinal association between retirement and a range of lifestyle risk behaviors among a large population-based sample of Australian adults. METHODS: Study sample included working adults aged >=45 years at baseline (2006-2009, N=23,478-26,895). Lifestyle behaviors, including smoking, alcohol use, physical activity, diet, sedentary behavior, and sleep, were measured at both baseline and follow-up (2010). Logistic regression models estimated the odds of having each risk factor at follow-up and multiple linear regression models calculated the change in the total number of risk factors, adjusted for baseline risk and other covariates. Sociodemographic characteristics and reasons for retirement were tested as potential effect modifiers. RESULTS: During the 3.3-year follow-up, about 11% of respondents retired. Retirement was associated significantly with reduced odds of smoking (AOR=0.74); physical inactivity (AOR=0.73); excessive sitting (AOR=0.34); and at-risk sleep patterns (AOR=0.82). There was no significant association between retirement and alcohol use or fruit and vegetable consumption. Change in the total number of lifestyle risk factors differed significantly by reason for retirement. CONCLUSIONS: In a large population-based Australian cohort, retirement was associated with positive lifestyle changes. Health professionals and policymakers should consider developing special programs for retirees to capitalize on the healthy transitions through retirement. PMID- 26972492 TI - Sildenafil ameliorates left ventricular T-tubule remodeling in a pressure overload-induced murine heart failure model. AB - AIM: Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has been shown to exert beneficial effects in heart failure. The purpose of this study was to test whether sildenafil suppressed transverse-tubule (T-tubule) remodeling in left ventricular (LV) failure and thereby providing the therapeutic benefits. METHODS: A pressure overload-induced murine heart failure model was established in mice by thoracic aortic banding (TAB). One day after TAB, the mice received sildenafil (100 mg.kg(-1).d(-1), sc) or saline for 5 weeks. At the end of treatment, echocardiography was used to examine LV function. Then the intact hearts were dissected out and placed in Langendorff-perfusion chamber for in situ confocal imaging of T-tubule ultrastructure from epicardial myocytes. RESULTS: TAB surgery resulted in heart failure accompanied by remarkable T-tubule remodeling. Sildenafil treatment significantly attenuated TAB-induced cardiac hypertrophy and congestive heart failure, improved LV contractile function, and preserved T tubule integrity in LV cardiomyocytes. But sildenafil treatment did not significantly affect the chamber dilation. The integrity of LV T-tubule structure was correlated with cardiac hypertrophy (R(2)=0.74, P<0.01) and global LV function (R(2)=0.47, P<0.01). CONCLUSION: Sildenafil effectively ameliorates LV T tubule remodeling in TAB mice, revealing a novel mechanism underlying the therapeutic benefits of sildenafil in heart failure. PMID- 26972493 TI - Specific interference shRNA-expressing plasmids inhibit Hantaan virus infection in vitro and in vivo. AB - AIM: To investigate the antiviral effects of vectors expressing specific short hairpin RNAs (shRNAs) against Hantaan virus (HTNV) infection in vitro and in vivo. METHODS: Based on the effects of 4 shRNAs targeting different regions of HTNV genomic RNA on viral replication, the most effective RNA interference fragments of the S and M genes were constructed in pSilencer-3.0-H1 vectors, and designated pSilencer-S and pSilencer-M, respectively. The antiviral effect of pSilencer-S/M against HTNV was evaluated in both HTNV-infected Vero-E6 cells and mice. RESULTS: In HTNV-infected Vero-E6 cells, pSilencer-S and pSilencer-M targeted the viral nucleocapsid proteins and envelope glycoproteins, respectively, as revealed in the immunofluorescence assay. Transfection with pSilencer-S or pSilencer-M (1, 2, 4 MUg) markedly inhibited the viral antigen expression in dose- and time-dependent manners. Transfection with either plasmid (2 MUg) significantly decreased HTNV-RNA level at 3 day postinfectin (dpi) and the progeny virus titer at 5 dpi. In mice infected with lethal doses of HTNV, intraperitoneal injection of pSilencer-S or pSilencer-M (30 MUg) considerably increased the survival rates and mean time to death, and significantly reduced the mean virus yields and viral RNA level, and alleviated virus-induced pathological lesions in lungs, brains and kidneys. CONCLUSION: Plasmid-based shRNAs potently inhibit HTNV replication in vitro and in vivo. Our results provide a basis for development of shRNA as therapeutics for HTNV infections in humans. PMID- 26972494 TI - Absorptive interactions of concurrent oral administration of (+)-catechin and puerarin in rats and the underlying mechanisms. AB - AIM: (+)-Catechin and puerarin are polyphenol and flavonoid, respectively, in green tea and foodstuffs. They exhibit potent antioxidant activity and are widely used for treating cardiocerebrovascular diseases. The aim of this work was to investigate the potential interactions between (+)-catechin and puerarin following concurrent oral administration in rats, and their absorption mechanisms in Caco-2 cell monolayers. METHODS: Pharmacokinetic studies were conducted in male rats received (+)-catechin (140 mg/kg, po) and/or puerarin (200 mg/kg, po). The cell uptake and transport behavior in Caco-2 cell monolayers and the interactions of the two compounds were analyzed. RESULTS: When (+)-catechin and puerarin were administered concurrently, the AUC0-12 h and Cmax values of puerarin were 2.48-fold and 3.91-fold, respectively, as large as those of puerarin alone; the AUC0-12 h and Cmax values of (+)-catechin were decreased to 57.62% and 77.55%, respectively, compared with those of (+)-catechin alone. In Caco-2 cell monolayers, (+)-catechin (300 and 600 MUmol/L) significantly increased the cell uptake and transport of puerarin, whereas puerarin (300 and 600 MUmol/L) significantly decreased the cellular uptake and transport of (+) catechin. Furthermore, both cyclosporine A (P-glycoprotein inhibitor) and MK-571 (MRP-2 inhibitor) significantly increased the cellular uptake and transport of (+)-catechin and puerarin. CONCLUSION: Concurrent oral administration of (+) catechin and puerarin significantly increased the absolute oral bioavailability of puerarin, but decreasing that of (+)-catechin. The competitive efflux of (+) catechin and puerarin by P-glycoprotein and MRP-2 might lead to this interaction during their absorption process in the small intestine. PMID- 26972496 TI - Words of Wisdom. Re: Nivolumab Versus Everolimus in Advanced Renal-Cell Carcinoma. PMID- 26972495 TI - Rutaecarpine ameliorates hyperlipidemia and hyperglycemia in fat-fed, streptozotocin-treated rats via regulating the IRS-1/PI3K/Akt and AMPK/ACC2 signaling pathways. AB - AIM: We have shown that rutaecarpine extracted from the dried fruit of Chinese herb Evodia rutaecarpa (Juss) Benth (Wu Zhu Yu) promotes glucose consumption and anti-inflammatory cytokine expression in insulin-resistant primary skeletal muscle cells. In this study we investigated whether rutaecarpine ameliorated the obesity profiles, lipid abnormality, glucose metabolism and insulin resistance in rat model of hyperlipidemia and hyperglycemia. METHODS: Rats fed on a high-fat diet for 8 weeks, followed by injection of streptozotocin (30 mg/kg, ip) to induce hyperlipidemia and hyperglycemia. One week after streptozotocin injection, the fat-fed, streptozotocin-treated rats were orally treated with rutaecarpine (25 mg.kg(-1).d(-1)) or a positive control drug metformin (250 mg.kg(-1).d(-1)) for 7 weeks. The body weight, visceral fat, blood lipid profiles and glucose levels, insulin sensitivity were measured. Serum levels of inflammatory cytokines were analyzed. IRS-1 and Akt/PKB phosphorylation, PI3K and NF-kappaB protein levels in liver tissues were assessed; pathological changes of livers and pancreases were examined. Glucose uptake and AMPK/ACC2 phosphorylation were studied in cultured rat skeletal muscle cells in vitro. RESULTS: Administration of rutaecarpine or metformin significantly decreased obesity, visceral fat accumulation, water consumption, and serum TC, TG and LDL-cholesterol levels in fat-fed, streptozotocin-treated rats. The two drugs also attenuated hyperglycemia and enhanced insulin sensitivity. Moreover, the two drugs significantly decreased NF-kappaB protein levels in liver tissues and plasma TNF-alpha, IL-6, CRP and MCP 1 levels, and ameliorated the pathological changes in livers and pancreases. In addition, the two drugs increased PI3K p85 subunit levels and Akt/PKB phosphorylation, but decreased IRS-1 phosphorylation in liver tissues. Treatment of cultured skeletal muscle cells with rutaecarpine (20-180 MUmol/L) or metformin (20 MUmol/L) promoted the phosphorylation of AMPK and ACC2, and increased glucose uptake. CONCLUSION: Rutaecarpine ameliorates hyperlipidemia and hyperglycemia in fat-fed, streptozotocin-treated rats via regulating IRS-1/PI3K/Akt signaling pathway in liver and AMPK/ACC2 signaling pathway in skeletal muscles. PMID- 26972497 TI - Words of Wisdom. Re: Evaluation of Functional Outcomes After Laparoscopic Partial Nephrectomy Using Renal Scintigraphy: Clamped vs. Clampless Technique. PMID- 26972498 TI - Words of Wisdom. Re: Randomized Controlled Trial of Early Zoledronic Acid in Men with Castration-sensitive Prostate Cancer and Bone Metastases: Results of CALGB 90202 (Alliance). PMID- 26972499 TI - Words of Wisdom. Re: Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. PMID- 26972501 TI - Words of Wisdom. Re: Radical Cystectomy vs. Chemoradiation in T2-4aN0M0 Bladder Cancer: A Case-control Study. PMID- 26972500 TI - Words of Wisdom. Re: Comparison of MR/Ultrasound Fusion-Guided Biopsy With Ultrasound-guided Biopsy for the Diagnosis of Prostate Cancer. PMID- 26972503 TI - Comparison of pharmacokinetic profiles of Terminalia phenolics after intragastric administration of the aqueous extracts of the fruit of Terminalia chebula and a Mongolian compound medicine-Gurigumu-7. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The dried fruit of Terminalia chebula (fructus chebulae) is an important Traditional Medicine used for intestinal and hepatic detoxification. Gurigumu-7 which is made of fructus chebulae and 6 other traditional medicines is one of the most frequently used compound Mongolian and Tibet medicines for liver diseases. Terminalia phenolics are considered as the bioactive constituents of fructus chebulae and consequently of Gurigumu-7. AIM OF THE STUDY: To compare the pharmacokinetic profiles of Terminalia phenolics after intragastric administration of the aqueous extracts of fructus chebulae and Gurigumu-7 and to evaluate the possible influence of intestinal bacterial metabolism on these pharmacokinetic profiles. MATERIALS AND METHODS: An ultra performance liquid chromatography with triple quadrupole mass spectrometry method was established and validated for simultaneously determining the pharmacokinetic profiles of seven Terminalia phenolics after intragastric administration of pure compounds, fructus chebulae extract, and Gurigumu-7 extract. In vitro rat fecal lysates experiments were carried out to explore the metabolic discrepancy between fructus chebulae and Gurigumu-7. RESULTS: Seven Terminalia phenolics were detected in rat plasma after intragastric administration of the aqueous extracts of fructus chebulae and Gurigumu-7. Administration of Gurigumu-7 could promote the absorption and increase the Cmax and AUC values of these phenolic constituents compared to fructus chebulae administration. The fecal lysates studies showed that the Terminalia phenolics in Gurigumu-7 were less rapidly bio transformed than those in fructus chebulae. This may be a contributing factor to the pharmacokinetic discrepancy between the phenolics in fructus chebulae and Gurigumu-7. CONCLUSION: Administration of Gurigumu-7 could increase the absorption of Terminalia phenolics through slowing down the intestinal bacteria metabolism. These results provide, in part, an in vivo rationale for the formulation of the traditional Mongolia / Tibet medicine, Gurigumu-7. PMID- 26972502 TI - Synergistic interaction of effective parts in Rehmanniae Radix and Cornus officinalis ameliorates renal injury in C57BL/KsJ-db/db diabetic mice: Involvement of suppression of AGEs/RAGE/SphK1 signaling pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Rehmanniae Radix (RR) and Cornus officinalis (CO) are two traditional Chinese medicines widely used in China for treating diabetes mellitus and its complications, such as diabetic nephropathy. Iridoid glycoside of Cornus officinalis (IGCO), triterpenoid acid of Cornus officinalis (TACO) and iridoid glycoside of Rehmanniae Radix (IGRR) formed an innovative formula named combinatorial bioactive parts (CBP). The aims of the present study were to investigate the renoprotective effects of CBP on DN through the inhibition of AGEs/RAGE/SphK1 signaling pathway activation, and identify the advantage of CBP compared with IGCO, TACO, IGRR. MATERIALS AND METHODS: The db/db diabetic renal injury model was used to examine the renoprotective effects of CBP, IGCO, TACO and IGRR. For mechanistic studies, diabetic symptoms, renal functions, and pathohistology of pancreas and kidney were evaluated. AGEs/RAGE/SphK1 pathway were determined. RESULTS: CBP, IGCO, TACO and IGRR inhibited the decrease in serum insulin levels and the increases in urine volume, food consumption, water intake, TC, TG, glycated serum protein, fasting blood glucose levels, 24h urine protein levels, and serum levels of urea nitrogen and creatinine. It also prevented ECM accumulation and improved the histology of pancreas and kidney, and alleviated the structural alterations in mesangial cells and podocytes in renal cortex. Moreover, CBP, IGCO, TACO and IGRR down-regulated the elevated staining, protein levels of RAGE, SphK1, TGF-beta and NF-kappaB. Among the treatment groups, CBP produced the strongest effects. CONCLUSIONS: These findings suggest that the inhibitory effect of CBP, IGCO, TACO and IGRR on the activation of AGEs/RAGE/SphK1 signaling pathway in db/db diabetic mice kidney is a novel mechanism by which CBP, IGCO, TACO and IGRR exerts renoprotective effects on DN. Among all the groups, CBP produced the strongest effect while IGCO, TACO and IGRR produced weaker effects. PMID- 26972504 TI - Eupatorium lindleyanum DC. sesquiterpenes fraction attenuates lipopolysaccharide induced acute lung injury in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Eupatorium lindleyanum DC. is widely used for its efficiency in treating cough, tracheitis and tonsillitis. Acute lung injury (ALI) induced by lipopolysaccharide (LPS) in mice was used to investigate therapeutic effects and possible mechanism of the sesquiterpenes fraction of E. lindleyanum DC. (EUP-SQT). MATERIALS AND METHODS: Mice were orally administrated with EUP-SQT (15, 30 and 60mg/kg) per day for 7 days consecutively before LPS challenge. The lung specimens and bronchoalveolar lavage fluid (BALF) were harvested for histopathological examinations and biochemical analysis at 6h and 24h after LPS challenge. The level of complement 3 (C3) and complement 3c (C3c) in serum was quantified by a sandwich ELISA kit. RESULTS: Pretreatment with EUP-SQT could significantly decrease lung wet-to-dry weight (W/D) ratio, nitric oxide (NO) and protein concentration in BALF, which was exhibited together with the lowered myeloperoxidase (MPO) activity, the increased superoxide dismutase (SOD) activity and down-regulation the level of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) in ALI model. Additionally, EUP-SQT attenuated lung histopathological changes and significantly reduced complement deposition with decreasing the level of C3 and C3c in serum. CONCLUSIONS: These results showed that EUP-SQT significantly attenuated LPS induced ALI via reducing productions of pro-inflammatory mediators and decreasing the level of complement, indicating it as a potential therapeutic agent for ALI. PMID- 26972505 TI - Schisandra chinensis extract ameliorates nonalcoholic fatty liver via inhibition of endoplasmic reticulum stress. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis (Turcz.) Baill. (SC) is a traditional Chinese herbal medicine with diverse pharmacological activities for treatment of various human diseases. Endoplasmic reticulum (ER) stress is associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the protective effects of methanol extract of Schisandra chinensis (SC extract) against ER stress-induced NAFLD in vitro and in vivo. MATERIAL AND METHODS: The protective effects of SC extract were examined in tunicamycin- or palmitate-treated HepG2 cells in vitro, and in tunicamycin injected mice or high fed diet (HFD) obese mice in vivo. Expression of ER stress markers including glucose regulated protein 78 (GRP78), C/EBP homolog protein (CHOP), and X-box-binding protein-1 (XBP-1), and triglyceride accumulation were measured in HepG2 cells and in the liver of mice. RESULTS: SC extract significantly inhibited expression of tunicamycin-induced ER stress markers in tunicamycin-treated HepG2 cells and in the liver of tunicamycin-injected mice, and it also inhibited tunicamycin-induced triglyceride accumulation. Similar observations were made under physiological ER stress conditions such as in palmitate-treated HepG2 cells and in the liver of HFD obese mice. In addition, SC extract repressed the expression of inflammatory genes and lipogenic genes in palmitate-treated HepG2 cells. Schisandrin, an abundant bioactive lignan in SC extract, inhibited the expression of ER stress markers in tunicamycin-or palmitate-treated HepG2 cells, whereas Gomisin J did not affect ER stress markers. CONCLUSIONS: SC attenuates ER stress and prevents development of NAFLD. SC may be useful as a pharmacological agent for protection against ER stress induced human diseases. PMID- 26972506 TI - Anxiolytic activity and active principles of Piper amalago (Piperaceae), a medicinal plant used by the Q'eqchi' Maya to treat susto, a culture-bound illness. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal plant, Piper amalago L. (Piperaceae), is used traditionally by Q'eqchi' Maya healers for the treatment of "susto" a culture-bound syndrome. Previous research suggests that susto symptoms may be a manifestation of anxiety. The objectives were to characterize the effect of ethanolic extract of P. amalago in behavioral assays of anxiety at doses representative of traditional use and to isolate active principles. MATERIALS AND METHODS: Rats treated orally with low dose ethanolic extracts of P. amalago leaves (8-75mg/kg) were tested in several behavioral paradigms including the elevated plus maze (EPM), social interaction (SI), and conditioned emotional response (CER) tests, and compared to diazepam, a positive control. The active anxiolytic principle was isolated by bioassay guided isolation using an in vitro GABAA competitive binding assay. RESULTS: Extracts had significant anxiolytic activity in all behavioral tests, with the strongest activity in the SI and the CER paradigms. In an in vitro GABAA competitive binding assay, a 66.5ug/mL concentration of P. amalago ethanol extract displaced 50% of the GABAA-BZD receptor ligand [(3)H]-Flunitrazepam. Bioassay-guided fractionation identified a furofuran lignan, a molecule with structural similarity to yangambin, with high affinity for the GABAA-BZD receptor as the principle bioactive. CONCLUSION: The results suggest that the ethnobotanical use of this plant may have a pharmacological basis in its anxiolytic activity, as demonstrated in animal behaviour tests. PMID- 26972507 TI - Pharmacokinetics of isochlorgenic acid C in rats by HPLC-MS: Absolute bioavailability and dose proportionality. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Isochlorgenic acid C (IAC), one of the bioactive compounds of Lonicera japonica, exhibited diverse pharmacological effects. However, its pharmacokinetic properties and bioavailability remained unresolved. AIM OF THE STUDY: To determine the absolute bioavailability in rats and the dose proportionality on the pharmacokinetics of single oral dose of IAC. MATERIALS AND METHODS: A validated HPLC-MS method was developed for the determination of IAC in rat plasma. Plasma concentration versus time data were generated following oral and intravenous dosing. The pharmacokinetic analysis was performed using DAS 3.0 software analysis. Absolute bioavailability in rats was determined by comparing pharmacokinetic data after administration of single oral (5, 10 and 25mgkg(-1)) and intravenous (5mgkg(-1)) doses of IAC. The dose proportionality of AUC(0 infinity) and Cmax were analyzed by linear regression. RESULTS: Experimental data showed that absolute oral bioavailability of IAC in rats across the doses ranged between 14.4% and 16.9%. The regression analysis of AUC(0-infinity) and Cmax at the three doses (5, 10 and 25mgkg(-1)) indicated that the equations were y=35.23x+117.20 (r=0.998) and y=121.03x+255.74 (r=0.995), respectively. CONCLUSIONS: A new HPLC-MS method was developed to determine the bioavailability and the dose proportionality of IAC. Bioavailability of IAC in rats was poor and both Cmax and AUC(0-infinity) of IAC had a positive correlation with dose. Evaluation of the pharmacokinetics of IAC will be useful in assessing concentration-effect relationships for the potential therapeutic applications of IAC. PMID- 26972508 TI - Prevalence of psychotic symptoms among older adults in an Asian population. AB - BACKGROUND: Psychotic symptoms are common among older adults and are seen in a wide range of conditions. Most studies examining the prevalence and correlates of psychotic symptoms among older adults have been conducted in Western populations. To address this gap the current study was undertaken to establish the prevalence and correlates of psychotic symptoms and paranoid ideation within a community sample of older adults without dementia in an Asian population. METHODS: The Well being of the Singapore Elderly (WiSE) study was a comprehensive single phase, cross-sectional survey. All respondents were assessed using the Geriatric Mental State examination (GMS). Specific questions of the GMS were then used to establish the prevalence of hallucinations and persecutory delusions. RESULTS: A total of 2,565 respondents completed the study giving a response rate of 65.6%. The prevalence of any psychotic symptoms in this population of older adults was 5.2%. The odds of hallucinations and any psychotic symptoms were significantly higher among those of Malay ethnicity, and those who had no formal education. Older adults aged 75-84 years were significantly associated with lower odds of having hallucinations (vs. older adult aged 60-74 years), while homemaker status was significantly associated with lower odds of having any psychotic symptoms. CONCLUSIONS: The prevalence of psychotic symptoms among older Asian adults without dementia was higher than that reported from Western countries. Psychotic symptoms were associated with Malay ethnicity, poor cognitive performance and fewer years of schooling, visual and hearing impairment as well as depression and irritability. PMID- 26972509 TI - High-resolution spatial analysis of cholera patients reported in Artibonite department, Haiti in 2010-2011. AB - BACKGROUND: Cholera is caused by Vibrio cholerae, and is transmitted through fecal-oral contact. Infection occurs after the ingestion of the bacteria and is usually asymptomatic. In a minority of cases, it causes acute diarrhea and vomiting, which can lead to potentially fatal severe dehydration, especially in the absence of appropriate medical care. Immunity occurs after infection and typically lasts 6-36 months. Cholera is responsible for outbreaks in many African and Asian developing countries, and caused localised and episodic epidemics in South America until the early 1990s. Haiti, despite its low socioeconomic status and poor sanitation, had never reported cholera before the recent outbreak that started in October 2010, with over 720,000 cases and over 8700 deaths (Case fatality rate: 1.2%) through 8 december 2014. So far, this outbreak has seen 3 epidemic peaks, and it is expected that cholera will remain in Haiti for some time. METHODOLOGY/FINDINGS: To trace the path of the early epidemic and to identify hot spots and potential transmission hubs during peaks, we examined the spatial distribution of cholera patients during the first two peaks in Artibonite, the second-most populous department of Haiti. We extracted the geographic origin of 84,000 patients treated in local health facilities between October 2010 and December 2011 and mapped these addresses to 63 rural communal sections and 9 urban cities. Spatial and cluster analysis showed that during the first peak, cholera spread along the Artibonite River and the main roads, and sub communal attack rates ranged from 0.1% to 10.7%. During the second peak, remote mountain areas were most affected, although sometimes to very different degrees even in closely neighboring locations. Sub-communal attack rates during the second peak ranged from 0.2% to 13.7%. The relative risks at the sub-communal level during the second phase showed an inverse pattern compared to the first phase. CONCLUSION/SIGNIFICANCE: These findings demonstrate the value of high resolution mapping for pinpointing locations most affected by cholera, and in the future could help prioritize the places in need of interventions such as improvement of sanitation and vaccination. The findings also describe spatio temporal transmission patterns of the epidemic in a cholera-naive country such as Haiti. By identifying transmission hubs, it is possible to target prevention strategies that, over time, could reduce transmission of the disease and eventually eliminate cholera in Haiti. PMID- 26972510 TI - Influence of recombination on acquisition and reversion of immune escape and compensatory mutations in HIV-1. AB - Following transmission, HIV-1 adapts in the new host by acquiring mutations that allow it to escape from the host immune response at multiple epitopes. It also reverts mutations associated with epitopes targeted in the transmitting host but not in the new host. Moreover, escape mutations are often associated with additional compensatory mutations that partially recover fitness costs. It is unclear whether recombination expedites this process of multi-locus adaptation. To elucidate the role of recombination, we constructed a detailed population dynamics model that integrates viral dynamics, host immune response at multiple epitopes through cytotoxic T lymphocytes, and viral evolution driven by mutation, recombination, and selection. Using this model, we compute the expected waiting time until the emergence of the strain that has gained escape and compensatory mutations against the new host's immune response, and reverted these mutations at epitopes no longer targeted. We find that depending on the underlying fitness landscape, shaped by both costs and benefits of mutations, adaptation proceeds via distinct dominant pathways with different effects of recombination, in particular distinguishing escape and reversion. When adaptation at a single epitope is involved, recombination can substantially accelerate immune escape but minimally affects reversion. When multiple epitopes are involved, recombination can accelerate or inhibit adaptation depending on the fitness landscape. Specifically, recombination tends to delay adaptation when a purely uphill fitness landscape is accessible at each epitope, and accelerate it when a fitness valley is associated with each epitope. Our study points to the importance of recombination in shaping the adaptation of HIV-1 following its transmission to new hosts, a process central to T cell-based vaccine strategies. PMID- 26972511 TI - Use of bacterial whole-genome sequencing to investigate local persistence and spread in bovine tuberculosis. AB - Mycobacterium bovis is the causal agent of bovine tuberculosis, one of the most important diseases currently facing the UK cattle industry. Here, we use high density whole genome sequencing (WGS) in a defined sub-population of M. bovis in 145 cattle across 66 herd breakdowns to gain insights into local spread and persistence. We show that despite low divergence among isolates, WGS can in principle expose contributions of under-sampled host populations to M. bovis transmission. However, we demonstrate that in our data such a signal is due to molecular type switching, which had been previously undocumented for M. bovis. Isolates from farms with a known history of direct cattle movement between them did not show a statistical signal of higher genetic similarity. Despite an overall signal of genetic isolation by distance, genetic distances also showed no apparent relationship with spatial distance among affected farms over distances <5 km. Using simulations, we find that even over the brief evolutionary timescale covered by our data, Bayesian phylogeographic approaches are feasible. Applying such approaches showed that M. bovis dispersal in this system is heterogeneous but slow overall, averaging 2 km/year. These results confirm that widespread application of WGS to M. bovis will bring novel and important insights into the dynamics of M. bovis spread and persistence, but that the current questions most pertinent to control will be best addressed using approaches that more directly integrate WGS with additional epidemiological data. PMID- 26972513 TI - Homo-psychologicus: Reactionary behavioural aspects of epidemics. AB - We formulate an in silico model of pathogen avoidance mechanism and investigate its impact on defensive behavioural measures (e.g., spontaneous social exclusions and distancing, crowd avoidance and voluntary vaccination adaptation). In particular, we use SIR(B)S (e.g., susceptible-infected-recovered with additional behavioural component) model to investigate the impact of homo-psychologicus aspects of epidemics. We focus on reactionary behavioural changes, which apply to both social distancing and voluntary vaccination participations. Our analyses reveal complex relationships between spontaneous and uncoordinated behavioural changes, the emergence of its contagion properties, and mitigation of infectious diseases. We find that the presence of effective behavioural changes can impede the persistence of disease. Furthermore, it was found that under perfect effective behavioural change, there are three regions in the response factor (e.g., imitation and/or reactionary) and behavioural scale factor (e.g., global/local) factors rho-alpha behavioural space. Mainly, (1) disease is always endemic even in the presence of behavioural change, (2) behavioural-prevalence plasticity is observed and disease can sometimes be eradication, and (3) elimination of endemic disease under permanence of permanent behavioural change is achieved. These results suggest that preventive behavioural changes (e.g., non pharmaceutical prophylactic measures, social distancing and exclusion, crowd avoidance) are influenced by individual differences in perception of risks and are a salient feature of epidemics. Additionally, these findings indicates that care needs to be taken when considering the effect of adaptive behavioural change in predicting the course of epidemics, and as well as the interpretation and development of the public health measures that account for spontaneous behavioural changes. PMID- 26972512 TI - Comparison of the social contact patterns among school-age children in specific seasons, locations, and times. AB - Social contact patterns among school-age children play an important role in the epidemiology of infectious disease. This study explored how people interact in specific seasons (flu season and non-flu season), environmental settings (city and county), and times (weekend and weekday). We conducted a survey of junior high school students (grades 7-8) using an established questionnaire during May June 2013 and December 2013. The sample size with pair-wise comparisons for the times (weekday/weekend) and stratification by location and seasons were 75, 87, 105 and 106, respectively. The sample size with pair-wise comparisons for the seasons (flu/non-flu) and stratification by location were 54 and 83, respectively. Conversation and skin-to-skin contact behaviors were surveyed through diary-based questionnaires, of which 665 valid questionnaires were returned. There was no difference in the number of contacts during the flu and non-flu seasons, with averages of 16.3 (S.D.=12.9) and 14.6 (S.D.=9.5) people, respectively. However, statistical analysis showed that the average number of contacts in Taichung City and Yilan County were significantly different (p<0.001). Weekdays were associated with 23-28% more contacts than weekend days during both the non-flu and flu seasons (p<0.001) (Wilcoxon signed-rank test). Our work has important implications for the dynamic modeling of infectious diseases and performance analysis of human contact numbers and contact characteristics for schoolchildren in specific seasons, places, and times. PMID- 26972516 TI - Expanding vaccine efficacy estimation with dynamic models fitted to cross sectional prevalence data post-licensure. AB - The efficacy of vaccines is typically estimated prior to implementation, on the basis of randomized controlled trials. This does not preclude, however, subsequent assessment post-licensure, while mass-immunization and nonlinear transmission feedbacks are in place. In this paper we show how cross-sectional prevalence data post-vaccination can be interpreted in terms of pathogen transmission processes and vaccine parameters, using a dynamic epidemiological model. We advocate the use of such frameworks for model-based vaccine evaluation in the field, fitting trajectories of cross-sectional prevalence of pathogen strains before and after intervention. Using SI and SIS models, we illustrate how prevalence ratios in vaccinated and non-vaccinated hosts depend on true vaccine efficacy, the absolute and relative strength of competition between target and non-target strains, the time post follow-up, and transmission intensity. We argue that a mechanistic approach should be added to vaccine efficacy estimation against multi-type pathogens, because it naturally accounts for inter-strain competition and indirect effects, leading to a robust measure of individual protection per contact. Our study calls for systematic attention to epidemiological feedbacks when interpreting population level impact. At a broader level, our parameter estimation procedure provides a promising proof of principle for a generalizable framework to infer vaccine efficacy post-licensure. PMID- 26972515 TI - Comparing the impact of increasing condom use or HIV pre-exposure prophylaxis (PrEP) use among female sex workers. AB - In many settings, interventions targeting female sex workers (FSWs) could significantly reduce the overall transmission of HIV. To understand the role HIV pre-exposure prophylaxis (PrEP) could play in controlling HIV transmission amongst FSWs, it is important to understand how its impact compares with scaling up condom use-one of the proven HIV prevention strategies for FSWs. It is important to remember that condoms also have other benefits such as reducing the incidence of sexually transmitted infections and preventing pregnancy. A dynamic deterministic model of HIV transmission amongst FSWs, their clients and other male partners (termed 'pimps') was used to compare the protection provided by PrEP for HIV-negative FSWs with FSWs increasing their condom use with clients and/or pimps. For different HIV prevalence scenarios, levels of pimp interaction, and baseline condom use, we estimated the coverage of PrEP that gives the same reduction in endemic FSW HIV prevalence or HIV infections averted as different increases in condom use. To achieve the same impact on FSW HIV prevalence as increasing condom use by 1%, the coverage of PrEP has to increase by >2%. The relative impact of PrEP increases for scenarios where pimps contribute to HIV transmission, but not greatly, and decreases with higher baseline condom use. In terms of HIV infections averted over 10 years, the relative impact of PrEP compared to condoms was reduced, with a >3% increase in PrEP coverage achieving the same impact as a 1% increase in condom use. Condom promotion interventions should remain the mainstay HIV prevention strategy for FSWs, with PrEP only being implemented once condom interventions have been maximised or to fill prevention gaps where condoms cannot be used. PMID- 26972517 TI - Magnetic guidance of the magnetotactic bacterium Magnetospirillum gryphiswaldense. AB - Magnetospirillum gryphiswaldense is a magnetotactic bacterium with a permanent magnetic moment capable of swimming using two bipolarly located flagella. In their natural environment these bacteria swim along the field lines of the homogeneous geomagnetic field in a typical run and reversal pattern and thereby create non-differentiable trajectories with sharp edges. In the current work we nevertheless achieve stable guidance along curved lines of mechanical instability by using a heterogeneous magnetic field of a garnet film. The successful guidance of the bacteria depends on the right balance between motility and the magnetic moment of the magnetosome chain. PMID- 26972514 TI - Tuberculosis in Cape Town: An age-structured transmission model. AB - BACKGROUND: Tuberculosis (TB) is the leading cause of death in South Africa. The burden of disease varies by age, with peaks in TB notification rates in the HIV negative population at ages 0-5, 20-24, and 45-49 years. There is little variation between age groups in the rates in the HIV-positive population. The drivers of this age pattern remain unknown. METHODS: We developed an age structured simulation model of Mycobacterium tuberculosis (Mtb) transmission in Cape Town, South Africa. We considered five states of TB progression: susceptible, infected (latent TB), active TB, treated TB, and treatment default. Latently infected individuals could be re-infected; a previous Mtb infection slowed progression to active disease. We further considered three states of HIV progression: HIV negative, HIV positive, on antiretroviral therapy. To parameterize the model, we analysed treatment outcomes from the Cape Town electronic TB register, social mixing patterns from a Cape Town community and used literature estimates for other parameters. To investigate the main drivers behind the age patterns, we conducted sensitivity analyses on all parameters related to the age structure. RESULTS: The model replicated the age patterns in HIV-negative TB notification rates of Cape Town in 2009. Simulated TB notification rate in HIV-negative patients was 1000/100,000 person-years (pyrs) in children aged <5 years and decreased to 51/100,000 in children 5-15 years. The peak in early adulthood occurred at 25-29 years (463/100,000 pyrs). After a subsequent decline, simulated TB notification rates gradually increased from the age of 30 years. Sensitivity analyses showed that the dip after the early adult peak was due to the protective effect of latent TB and that retreatment TB was mainly responsible for the rise in TB notification rates from the age of 30 years. CONCLUSION: The protective effect of a first latent infection on subsequent infections and the faster progression in previously treated patients are the key determinants of the age-structure of TB notification rates in Cape Town. PMID- 26972518 TI - Maternal depression is not just a problem early on. AB - INTRODUCTION: Little is known about the onset of depression beyond the first postpartum year. This study examines the onset and course of depression over an 18 month period among a socio-economically diverse, community-wide sample of women. MATERIALS & METHODS: A prospective longitudinal telephone survey of 249 women was conducted at two weeks, two months, six months and 18 months after delivery. Depression was measured using the Edinburgh Postnatal Depression Scale (EPDS), and onset was defined as the first EPDS score of 12+ on the 30-point scale. Temporal trends were assessed using generalized estimating equation (GEE) regression. RESULTS: There was a significant temporal trend for EPDS scores decreasing until six months and then rebounding at 18 months; mean EPDS 5.5, 4.3, 4.2, and 4.9 at two weeks, two months, six months and 18 months respectively, GEE, P < .001. Depression onset followed a similar trend and was found to be 6.8%, 2.6%, 2.7% and 6.0% at two weeks, two months, six months and 18 months respectively, GEE, P = .068. The high scores of the early-onset group (mean 14.4 at two weeks) contributed to the early depression spike, while the high scores of the late-onset group (mean 13.9 at 18 months) contributed to the late spike. CONCLUSIONS: Two peaks of depression were identified, one early and one late. They appear to be the result of two processes: (1) elevated depression symptoms at two-weeks and again at 18 months postpartum experienced by the full sample and, thus, they may be a normal trend, and (2) onset of major depression by two sub-groups of women, one at each time period. Therefore, continued screening after one-year post delivery is indicated. PMID- 26972519 TI - Can eye donation rates be increased in hospitals: a pilot study in a tertiary care hospital in North India? AB - INTRODUCTION: There is a huge need to increase the corneal donation rates worldwide. The tertiary care hospitals can play a pivotal role in this as these hospitals manage a large number of terminally sick patients. Traditionally the thrust of such hospitals is providing specialized medical care and something like eye donation does not get the attention it deserves. In this scenario, can such institutes contribute to increase eye donation rates? METHOD: An intervention involving all the main stakeholders in promoting eye donation, namely nurses, counsellors & the management of the institute, was put into place. The results of this intervention, i.e. the corneas procured by the institute, was measured over a post intervention period of one year. RESULT: The study showed a significant increase in the number of corneas procured by the institute post intervention. DISCUSSION: Hospitals can play a huge role in meeting the demand for corneas by scientifically implementing cornea retrieval programs. The study shows that by using technology & providing a dynamic leadership, hospitals can augment corneal donation rates. PMID- 26972520 TI - Stand-capable desk use in a call center: a six-month follow-up pilot study. PMID- 26972521 TI - Ion exchange defines the biological activity of titanate nanotubes. AB - One-dimensional titanate nanotubes (TiONTs) were subjected to systematic ion exchange to determine the impact of these modifications on biological activities. Ion exchanged TiONTs (with Ag, Mg, Bi, Sb, Ca, K, Sr, Fe, and Cu ions) were successfully synthesized and the presence of the substituted ions was verified by energy dispersive X-ray spectroscopy (EDS). A complex screening was carried out to reveal differences in toxicity to human cells, as well as in antibacterial, antifungal, and antiviral activities between the various modified nanotubes. Our results demonstrated that Ag ion exchanged TiONTs exerted potent antibacterial and antifungal effects against all examined microbial species but were ineffective on viruses. Surprisingly, the antibacterial activity of Cu/TiONTs was restricted to Micrococcus luteus. Most ion exchanged TiONTs did not show antimicrobial activity against the tested bacterial and fungal species. Incorporation of various ions into nanotube architectures lead to mild, moderate, or even to a massive loss of human cell viability; therefore, this type of biological effect exerted by TiONTs can be greatly modulated by ion exchange. These findings further emphasize the contribution of ion exchange in determining not only the physical and chemical characteristics but also the bioactivity of TiONT against different types of living cells. PMID- 26972523 TI - Introduction of Co3O4 into activated honeycomb-like carbon for the fabrication of high performance electrode materials for supercapacitors. AB - In this work, a three-dimensional hierarchical carbon framework/Co3O4 hybrid composite was fabricated. The three-dimensional hierarchical carbon framework was constructed by thermal vapor deposition on the silica nanosphere templates and etching these templates. The resulting carbon framework was activated using phosphoric acid to control its surface area and porosity. The degree of activation of the carbon framework was optimized by measuring the specific capacitance. The carbon framework electrode activated with 3 M phosphoric acid (HCCA(3)) exhibited the highest specific capacitance (134 F g(-1) at 10 mV s( 1)). Subsequently, Co3O4 was formed on the carbon framework via the hydrothermal method. The resulting product HCCA(3)/Co3O4 showed a dramatic enhancement in the specific capacitance (456 F g(-1) at 1 A g(-1)) compared with the pristine Co3O4 and HCCA(3) electrodes. The proposed HCCA(3)/Co3O4 composite can be used for the fabrication of high-performance electrodes. PMID- 26972524 TI - A novel homozygous DJ1 mutation causes parkinsonism and ALS in a Turkish family. AB - OBJECTIVE: DJ1 mutations (PARK7) are among the monogenic causes of early-onset autosomal recessive parkinsonism. Here, we report clinical and genetic findings in a family with Turkish origin carrying a new DJ1 mutation and presenting with early-onset levodopa responsive parkinsonism and signs of amyotrophic lateral sclerosis (ALS). METHODS: The family consisted of 12 members including 10 offsprings of whom three were affected. All family members underwent detailed clinical examination. DNA samples from the index case, his unaffected sister, and his parents were subjected to whole genome sequencing analysis. RESULTS: The index case 38-year-old man developed left hand tremor at the age of 24 years. He had progressive asymmetrical parkinsonism, depression and developed signs of ALS within 4 years. His two affected sisters had young-onset asymmetrical tremor dominant parkinsonism with signs of ALS. A new homozygous p.Q45X mutation in exon 3 in DJ1 was found in all three patients. Their unaffected parents and one clinically healthy sibling were found to be heterozygous for this mutation. CONCLUSIONS: This is the second report of DJ1 mutations associated with parkinsonism and ALS. This is relevant for genetic counseling as well as for understanding the pathogenesis of the broad spectrum of parkinsonism-ALS disease complex. PMID- 26972525 TI - Essential tremor seems to be a risk factor for Parkinson's disease. PMID- 26972522 TI - Peroxisomes and Kidney Injury. AB - SIGNIFICANCE: Peroxisomes are organelles present in most eukaryotic cells. The organs with the highest density of peroxisomes are the liver and kidneys. Peroxisomes possess more than fifty enzymes and fulfill a multitude of biological tasks. They actively participate in apoptosis, innate immunity, and inflammation. In recent years, a considerable amount of evidence has been collected to support the involvement of peroxisomes in the pathogenesis of kidney injury. RECENT ADVANCES: The nature of the two most important peroxisomal tasks, beta-oxidation of fatty acids and hydrogen peroxide turnover, functionally relates peroxisomes to mitochondria. Further support for their communication and cooperation is furnished by the evidence that both organelles share the components of their division machinery. Until recently, the majority of studies on the molecular mechanisms of kidney injury focused primarily on mitochondria and neglected peroxisomes. CRITICAL ISSUES: The aim of this concise review is to introduce the reader to the field of peroxisome biology and to provide an overview of the evidence about the contribution of peroxisomes to the development and progression of kidney injury. The topics of renal ischemia-reperfusion injury, endotoxin induced kidney injury, diabetic nephropathy, and tubulointerstitial fibrosis, as well as the potential therapeutic implications of peroxisome activation, are addressed in this review. FUTURE DIRECTIONS: Despite recent progress, further studies are needed to elucidate the molecular mechanisms induced by dysfunctional peroxisomes and the role of the dysregulated mitochondria-peroxisome axis in the pathogenesis of renal injury. Antioxid. Redox Signal. 25, 217-231. PMID- 26972527 TI - Do patients with late-stage Parkinson's disease still respond to levodopa? AB - BACKGROUND: Late-stage Parkinson' disease (PD) is dominated by loss of autonomy due to motor and non-motor symptoms which can be marginally corrected by medications adjustments. However, controversy exists on the mechanisms underlying the apparent decrease of benefit from levodopa. OBJECTIVE: To study the response to levodopa in late-stage PD (LSPD). METHODS: 20 LSPD patients (Schwab and England ADL Scale <50 or Hoehn Yahr Stage >3 in MED ON) and 22 PD patients treated with subthalamic deep brain stimulation (DBS) underwent an acute levodopa challenge test. MDS-UPDRS-III and the modified Abnormal Involuntary Movement Scale were evaluated in off and after administration of a supra-maximal levodopa dose. RESULTS: LSPD patients had a median age of 78.8 (IQR: 73.5-82) and median disease duration of 14 years (IQR: 10-19.75). DBS patients had a median age of 66 (IQR: 61-72) and median disease duration of 18 years (IQR: 15-22). LSPD and DBS patients' MDS-UPDRS-III score improved 11.3% and 37% after levodopa, respectively. Rest tremor showed the largest improvement, while axial signs did not improve in LSPD. However, the magnitude of levodopa response significantly correlated with dyskinesias severity in LSPD patients. One third of LSPD and 9% of DBS patients reported moderate drowsiness. CONCLUSIONS: LSPD patients show a slight response to a supra-maximal levodopa dose, which is greater if dyskinesia are present, but it is frequently associated with adverse effects. A decrease in levodopa response is a potential marker of disease progression in LSPD. PMID- 26972526 TI - Effects of movement imitation training in Parkinson's disease: A virtual reality pilot study. AB - BACKGROUND: Hypometria is a clinical motor sign in Parkinson's disease. Its origin likely emerges from basal ganglia dysfunction, leading to an impaired control of inhibitory intracortical motor circuits. Some neurorehabilitation approaches include movement imitation training; besides the effects of motor practice, there might be a benefit due to observation and imitation of un-altered movement patterns. In this sense, virtual reality facilitates the process by customizing motor-patterns to be observed and imitated. OBJECTIVE: To evaluate the effect of a motor-imitation therapy focused on hypometria in Parkinson's disease using virtual reality. METHODS: We carried out a randomized controlled pilot-study. Sixteen patients were randomly assigned in experimental and control groups. Groups underwent 4-weeks of training based on finger-tapping with the dominant hand, in which imitation was the differential factor (only the experimental group imitated). We evaluated self-paced movement features and cortico-spinal excitability (recruitment curves and silent periods in both hemispheres) before, immediately after, and two weeks after the training period. RESULTS: Movement amplitude increased significantly after the therapy in the experimental group for the trained and un-trained hands. Motor thresholds and silent periods evaluated with transcranial magnetic stimulation were differently modified by training in the two groups; although the changes in the input-output recruitment were similar. CONCLUSIONS: This pilot study suggests that movement imitation therapy enhances the effect of motor practice in patients with Parkinson's disease; imitation-training might be helpful for reducing hypometria in these patients. These results must be clarified in future larger trials. PMID- 26972528 TI - Targeting the prodromal stage of spinocerebellar ataxia type 17 mice: G-CSF in the prevention of motor deficits via upregulating chaperone and autophagy levels. AB - Spinocerebellar ataxia type 17 (SCA17), an autosomal dominant cerebellar ataxia, is a devastating, incurable disease caused by the polyglutamine (polyQ) expansion of transcription factor TATA binding protein (TBP). The polyQ expansion causes misfolding and aggregation of the mutant TBP, further leading to cytotoxicity and cell death. The well-recognized prodromal phase in many forms of neurodegeneration suggests a prolonged period of partial neuronal dysfunction prior to cell loss that may be amenable to therapeutic intervention. The objective of this study was to assess the effects and molecular mechanisms of granulocyte-colony stimulating factor (G-CSF) therapy during the pre-symptomatic stage in SCA17 mice. Treatment with G-CSF at the pre-symptomatic stage improved the motor coordination of SCA17 mice and reduced the cell loss, insoluble mutant TBP protein, and vacuole formation in the Purkinje neurons of these mice. The neuroprotective effects of G-CSF may be produced by increases in Hsp70, Beclin-1, LC3-II and the p-ERK survival pathway. Upregulation of chaperone and autophagy levels further enhances the clearance of mutant protein aggregation, slowing the progression of pathology in SCA17 mice. Therefore, we showed that the early intervention of G-CSF has a neuroprotective effect, delaying the progression of SCA17 in mutant mice via increases in the levels of chaperone expression and autophagy. PMID- 26972530 TI - Analysis of anti-depressant potential of curcumin against depression induced male albino wistar rats. AB - The present study investigated the antidepressant potential of curcumin in olfactory bulbectomy and forced swimming test models of depression in male albino rats under chronic treatment. The experimental animals were divided into four groups, and curcumin was administered for 45 days. Our results showed that the curcumin significantly reduced olfactory bulbectomy-induced behavioral abnormalities including deficits in step-down passive avoidance, increased activity in the open area and immobility time. Chronic administration of curcumin significantly reversed levels of 3, 4-dihydroxyphenylacetic acid, noradrenaline, serotonin and 5-hydroxyindoleacetic acid in the hippocampus region of male albino rats. Also, curcumin normalizes the levels of dopamine, noradrenaline, and 5 hydroxyindoleacetic acid in the frontal cortex of rats. Taking all these results together, it may suggest that curcumin is potent compound acting against the depression in the male albino rats. PMID- 26972531 TI - The neuronal correlates of mirror therapy: A functional magnetic resonance imaging study on mirror-induced visual illusions of ankle movements. AB - Recovery in stroke is mediated by neural plasticity. Mirror therapy is an effective method in the rehabilitation of stroke patients, but the mechanism is still obscure. To identify the neural networks associated with the effect of lower-limbs mirror therapy, we investigated a functional magnetic resonance imaging (fMRI) study of mirror-induced visual illusion of ankle movements. Five healthy controls and five left hemiplegic stroke patients performed tasks related to mirror therapy in the fMRI study. Neural activation was compared in a no mirror condition and a mirror condition. All subjects in the experiment performed the task of flexing and extending the right ankle. In a mirror condition, movement of the left ankle was simulated by mirror reflection of right ankle movement. Changes in neural activation in response to mirror therapy were assessed both in healthy controls and stroke patients. We found strong activation of the motor cortex bilaterally in healthy controls, as well as significant activation of the ipsilateral sensorimotor cortex, the occipital gyrus, and the anterior prefrontal gyrus in stroke patients with respect to the non-mirror condition. We concluded that mirror therapy of ankle movements may induce neural activation of the ipsilesional sensorimotor cortex, and that cortical reorganization may be useful for motor rehabilitation in stroke. PMID- 26972529 TI - The role of CHMP2BIntron5 in autophagy and frontotemporal dementia. AB - Charged multivesicular body protein 2B (CHMP2B) - a component of the endosomal complex required for transport-III (ESCRT-III) - is responsible for the vital membrane deformation functions in autophagy and endolysosomal trafficking. A dominant mutation in CHMP2B (CHMP2BIntron5) is associated with a subset of heritable frontotemporal dementia - frontotemporal dementia linked to chromosome 3 (FTD-3). ESCRT-III recruits Vps4, an AAA-ATPase that abscises the membrane during various cellular processes including autophagy and intraluminal vesicle formation. CHMP2BIntron5 results in a C-terminus truncation removing an important Vps4 binding site as well as eliminating the normal autoinhibitory resting state of CHMP2B. CHMP2B is expressed in most cell types but seems to be especially vital for proper neuronal function. CHMP2BIntron5-mediated phenotypes include misregulation of transmembrane receptors, accumulation of multilamellar structures, abnormal lysosomal morphology, down regulation of a brain-specific micro RNA (miRNA-124), abnormal dendritic spine morphology, decrease in dendritic arborization, and cell death. Currently, transgenic-fly,-mouse, and -human cell lines are being used to better understand the diverse phenotypes and develop therapeutic approaches for the CHMP2BIntron5-induced FTD-3. This article is part of a Special Issue entitled SI:Autophagy. PMID- 26972532 TI - Temporal profile of magnetic resonance angiography and decreased ratio of regulatory T cells after immunological adjuvant administration to mice lacking RNF213, a susceptibility gene for moyamoya disease. AB - Moyamoya disease (MMD) is a chronic, occlusive cerebrovascular disease with an unknown etiology and is characterized by an abnormal vascular network at the base of the brain. Recent studies identified the RNF213 gene (RNF213) as an important susceptibility gene for MMD; however, the mechanisms underlying the RNF213 abnormality related to MMD have not yet been elucidated. We previously reported that Rnf213-deficient mice and Rnf213 p. R4828K knock-in mice did not spontaneously develop MMD, indicating the importance of secondary insults in addition to genetic factors in the pathogenesis of MMD. The most influential secondary insult is considered to be an immunological reaction because RNF213 is predominantly expressed in immunological tissues. Therefore, we herein attempted to evaluate the role of an immunological stimulation as a supplementary insult to the target disruption of RNF213 in the pathophysiology of MMD. Rnf213-deficient mice were treated with strong immunological adjuvants including muramyl dipeptide (MDP)-Lys (L18), and then underwent time-sequential magnetic resonance angiography (MRA) up to 40 weeks of age. The results obtained did not reveal any characteristic finding of MMD, and no significant difference was observed in MRA findings or the anatomy of the circle of Willis between Rnf213-deficient mice and wild-type mice after the administration of MDP-Lys (L18). The ratio of regulatory T cells after the administration of MDP-Lys (L18) was significantly decreased in Rnf213-deficient mice (p<0.01), suggesting the potential role of the RNF213 abnormality in the differentiation of regulatory T cells. Although the mechanisms underlying the development of MMD currently remain unclear, the RNF213 abnormality may compromise immunological self-tolerance, thereby contributing to the development of MMD. PMID- 26972533 TI - Physical training decreases susceptibility to pilocarpine-induced seizures in the injured rat brain. AB - There is growing evidence that physical activity ameliorates the course of epilepsy in animal models as well as in clinical conditions. Since traumatic brain injury is one of the strongest determinants of epileptogenesis, the present study focuses on the question whether a moderate long-term physical training can decrease susceptibility to seizures evoked following brain damage. Wistar rats received a mechanical brain injury and were subjected to daily running sessions on a treadmill for 21 days. Thereafter, seizures were induced by pilocarpine injections in trained and non-trained, control groups. During the acute period of status epilepticus, the intensity of seizures was assessed within the six-hour observation period. The trained rats showed considerable amelioration of pilocarpine-induced motor symptoms when compared with their non-trained counterparts. Histological investigations of effects of the brain injury and of physical training detected significant quantitative changes in parvalbumin-, calretinin- and NPY-immunopositive neuronal populations. Some of the injury induced changes, especially those shoved by parvalbumin-immunopositive neurons, were abolished by the subsequent physical training procedure and could, therefore, be considered as neuronal correlates of the observed functional amelioration of the injured brain. PMID- 26972535 TI - Long-term electromagnetic pulse exposure induces Abeta deposition and cognitive dysfunction through oxidative stress and overexpression of APP and BACE1. AB - A progressively expanded literature has been devoted in the past years to the noxious or beneficial effects of electromagnetic field (EMF) to Alzheimer's disease (AD). This study concerns the relationship between electromagnetic pulse (EMP) exposure and the occurrence of AD in rats and the underlying mechanisms, focusing on the role of oxidative stress (OS). 55 healthy male Sprague Dawley (SD) rats were used and received continuous exposure for 8 months. Morris water maze (MWM) test was conducted to test the ability of cognitive and memory. The level of OS was detected by superoxide dismutase (SOD) activity and glutathione (GSH) content. We found that long-term EMP exposure induced cognitive damage in rats. The content of beta-amyloid (Abeta) protein in hippocampus was increased after long-term EMP exposure. OS of hippocampal neuron was detected. Western blotting and immunohistochemistry (IHC) assay showed that the content of Abeta protein and its oligomers in EMP-exposed rats were higher than that of sham exposed rats. The content of Beta Site App Cleaving Enzyme (BACE1) and microtubule-associated protein 1 light chain 3-II (LC3-II) in EMP-exposed rats hippocampus were also higher than that of sham-exposed rats. SOD activity and GSH content in EMP-exposed rats were lower than sham-exposed rats (p<0.05). Several mechanisms were proposed based on EMP exposure-induced OS, including increased amyloid precursor protein (APP) aberrant cleavage. Although further study is needed, the present results suggest that long-term EMP exposure is harmful to cognitive ability in rats and could induce AD-like pathological manifestation. PMID- 26972537 TI - ICRP 129 and cone beam computed tomography. PMID- 26972538 TI - Coffee consumption associated with reduced risk of oral cancer: a meta-analysis. AB - OBJECTIVE: Currently, there is no consensus on the effect of coffee consumption on the risk of oral cancer. We performed a meta-analysis based on published studies to uncover the association. STUDY DESIGN: We searched PubMed (1946-2015), Embase (1976-2015), and the bibliographies of all retrieved articles for relevant citations. We performed random-effects meta-analyses of observational studies on coffee consumption and oral cancer. RESULTS: A total of 11 case-control studies and 4 cohort studies comprising 2,832,706 controls and 5021 cases of oral cancer were included in our analysis. The results indicated that the summary odds ratio for the highest versus the lowest or no category consumption of coffee was 0.63 (95% confidence interval [CI]: 0.52-0.75). The odds ratios were 0.60 (95% CI: 0.49-0.74) for case-control studies and 0.66 (95% CI: 0.45-0.98) for cohort studies. CONCLUSION: Overall, our results suggested that coffee consumption appears to have a protective benefit in oral cancer. PMID- 26972536 TI - Modeling Niemann Pick type C1 using human embryonic and induced pluripotent stem cells. AB - Data generated in Niemann Pick type C1 (NPC1) human embryonic and human induced pluripotent stem cell derived neurons complement on-going studies in animal models and provide the first example, in disease-relevant human cells, of processes that underlie preferential neuronal defects in a NPC1. Our work and that of other investigators in human neurons derived from stem cells highlight the importance of performing rigorous mechanistic studies in relevant cell types to guide drug discovery and therapeutic development, alongside of existing animal models. Through the use of human stem cell-derived models of disease, we can identify and discover or repurpose drugs that revert early events that lead to neuronal failure in NPC1. Together with the study of disease pathogenesis and efficacy of therapies in animal models, these strategies will fulfill the promise of stem cell technology in the development of new treatments for human diseases. This article is part of a Special Issue entitled SI: Exploiting human neurons. PMID- 26972534 TI - Roles for RNA-binding proteins in development and disease. AB - RNA-binding protein activities are highly regulated through protein levels, intracellular localization, and post-translation modifications. During development, mRNA processing of specific gene sets is regulated through manipulation of functional RNA-binding protein activities. The impact of altered RNA-binding protein activities also affects human diseases in which there are either a gain-of-function or loss-of-function causes pathogenesis. We will discuss RNA-binding proteins and their normal developmental RNA metabolism and contrast how their function is disrupted in disease. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease. PMID- 26972539 TI - Immunohistochemical expression of K6, K8, K16, K17, K19, maspin, syndecan-1 (CD138), alpha-SMA, and Ki-67 in ameloblastoma and ameloblastic carcinoma: diagnostic and prognostic correlations. AB - OBJECTIVE: To identify cutoff values of markers that correlate with the histopathologic diagnosis of ameloblastic carcinoma (AC) and/or the increased recurrence potential of ameloblastoma (AB). STUDY DESIGN: Immunohistochemical expression (IHCE) of 9 selected markers were investigated in 18 non-recurrent ameloblastomas (NRABs), 6 recurrent ameloblastomas (RABs), and 5 ACs. RESULTS: No significant difference in IHCE of K6, K8, K16, K17, K18, K19, maspin, or syndecan 1 was observed among study groups. alpha Smooth muscle actin (alpha-SMA)-positive area in central epithelial cells significantly differentiated between AB and AC (P = .017; t -test). Ki-67 score significantly differentiated between AB and AC (P < .005; t -test) and between AC and RAB (P = .015; ANOVA/post hoc). CONCLUSIONS: Ki-67 score of 75 cells/HPF (ROC curve) is a potential indicator of AC. Clinical recurrence of AB may be predicted by alpha-SMA expression pattern. Syndecan-1 and alpha-SMA may indicate a higher aggressive potential of AB when expressed in the stroma. PMID- 26972540 TI - Human papillomavirus in tonsillar squamous cell carcinomas from Guatemala and Brazil. AB - OBJECTIVES: A subgroup of tonsillar squamous cell carcinoma (SCC) is associated with human papillomavirus (HPV). Nevertheless, the prevalence of HPV seems to be variable in different regions and ethnic groups. There are no reports of HPV in tonsillar carcinomas in Guatemala, and data from Brazil are scarce. The aim of this study is to analyze and compare HPV presence in samples of tonsillar SCC from these countries. STUDY DESIGN: This study describes the histologic features, expression of p16 by immunohistochemistry (IHC), and HPV by in situ hybridization (ISH) in 13 Guatemalan and 13 Brazilian patients. RESULTS: All cases of tonsillar SCC from Guatemala were positive for p16, 92% expressed HPV by ISH, and 75% corresponded to the high-risk genotype 16/18. From the Brazilian patients, only four expressed p16, and all were negative for HPV. CONCLUSIONS: Cases from Guatemala, which were mostly nonkeratinizing SCC and originated from the crypt/reticular epithelium of the tonsil, had high-risk integrated HPV, whereas in Brazilian cases, which were mostly keratinizing SCC that originated from the surface epithelium, there was no association with HPV. PMID- 26972541 TI - Patient movement and motion artefacts in cone beam computed tomography of the dentomaxillofacial region: a systematic literature review. AB - OBJECTIVES: To undertake a systematic review on the current knowledge regarding patient movement detection and patient motion artefacts related to cone beam computed tomography (CBCT) imaging of the dentomaxillofacial region. METHODS: The MEDLINE (PubMed) bibliographic database was searched for a period up to June 2015 for studies evaluating patient movement and/or motion artefacts in CBCT. The search strategy was restricted to English language publications using the following combined terms: (movement OR motion) AND (CBCT OR cone beam CT). RESULTS: The search strategy yielded eight publications, which qualitatively or quantitatively evaluated patient movement and/or patient motion artefacts in CBCT. CONCLUSIONS: The literature suggests that patient movement usually presents itself in CBCT images as stripe-like and ring-like patterns, double bone contours, and overall lack of sharpness. Studies monitoring patients during CBCT examination reported a prevalence of movement in approximately 20% of the cases, and studies based on image artefact recognition to define patient movement reported prevalence as high as 41.5%. There seems to be a consensus on the fact that young patients (children and adolescents) often move during the examination. PMID- 26972542 TI - Meaningful correlation between asymptomatic retinal arteriole emboli and calcified carotid plaque found on panoramic dental imaging of males with diabetes. AB - OBJECTIVE: There is ongoing controversy with regard to the stability of calcified carotid artery plaques (CCAPs) seen in the bifurcation area on panoramic images (PIs). Therefore, we sought to evaluate the possibility of these plaques shedding emboli by observing their relationship with ipsilateral retinal emboli. STUDY DESIGN: The study group included 50 neurologically and visually asymptomatic males with diabetes, with PIs that incidentally demonstrated CCAPs (CCAP+) and contemporaneous digital retinal images that had been obtained for evaluation of diabetic retinopathy. The control group consisted of 50 males with diabetes who were matched for age and body mass index and had undergone both imaging studies and whose PIs were devoid of carotid plaques (CCAP-). The presence of retinal emboli was determined by two ophthalmologists blinded to the patients' medical histories, and the prevalence rates for the two groups were calculated. RESULTS: The presence of asymptomatic retinal arteriolar emboli was found in the eye ipsilateral to the radiographically observed carotid atheroma in 10 of 50 (20%) of the patients in the CCAP+ group, compared with 2 of 50 (4%) in the CCAP- group, and this difference was statistically significant (Fisher's exact P < .03). CONCLUSIONS: Some male patients with diabetes mellitus type II having calcified carotid artery atheromas in the bifurcation area, as visualized on PIs, may have significant sequelae as evidenced by retinal artery emboli. PMID- 26972543 TI - Multiple complex odontoma of the maxilla and mandible--reply. PMID- 26972544 TI - Upregulation of proangiogenic factors expression in the synovium of temporomandibular joint condylar hyperplasia. AB - OBJECTIVE: Condylar hyperplasia (CH) is a complex disorder of the temporomandibular joint. Many studies have focused on cartilage proliferation, but the behavior of the synovium in CH is poorly understood. The aim of the present study was to investigate the expression of angiogenic-associated factors in the synovium and to discuss the possible role of the synovium in CH progression. STUDY DESIGN: CH condylar tissues were stained by hematoxylin and eosin staining, and proliferative activity was confirmed by single-photon emission computed tomography. Synovial cells isolated from the temporomandibular joint of patients with CH were collected, and flow cytometric analysis was used to examine the expression of CD34 and CD44. The gene expression of FGF-2, MMP1, MMP3, and MMP13 in synovial cells was examined by quantitative real-time polymerase chain reaction. Western blotting was used to detect the protein expression of VEGF, FGF-2, ANG1, DKK1, TSP1, MMP1, MMP3, MMP13, TIMP1, and TIMP3. RESULTS: The typical hyperplastic area and activity were observed in condylar tissues. The expression of VEGF, FGF-2, ANG1, DKK1, TIMP1, TIMP3, and CD34 was significantly increased in the synovial cells of CH, but TSP1, MMP1, MMP3, and MMP13 expression was decreased. CONCLUSIONS: This study exhibited a potential role for proangiogenic factors in the pathogenesis of CH. PMID- 26972545 TI - Retrospective study to determine the accuracy of template-guided implant placement using a novel nonradiologic evaluation method. AB - OBJECTIVES: With a novel, noninvasive method for determining three-dimensional accuracy, the realized implant position relative to the planned implant position was analyzed retrospectively. Additional postoperative cone beam computed tomography was thus dispensable. STUDY DESIGN: Twelve cases with distal extension situations (DESs) or single tooth gaps (STGs) were evaluated. The data sets of the planned implant position were superimposed on the actually achieved implant position, retrieved from digitizing the implant impression. The deviations were measured and statistically analyzed. RESULTS: The mean deviation was 5 degrees in the DES group and 4 degrees in the STG group for the implant axes, 1 mm (DES) and 0.9 mm (STG) at the implant neck, and 1.6 mm (DES) and 1.5 mm (STG) at the implant apex. The mean height discrepancy was 0.5 mm (DES) and 0.5 mm (STG). No significant differences (P > .05) were found between the DES and STG groups. CONCLUSIONS: The innovative, noninvasive evaluation method is suitable and sufficiently accurate for the assessment of larger cohorts. The results of our study showed a sufficiently high degree of accuracy when using a virtual planning program for which no radiopaque template is needed when performing cone beam computed tomography. PMID- 26972546 TI - The privatization of spa companies in Poland - An evaluation of policy assumptions and implementation. AB - The aim of this article is to present the course of privatization of spa companies in Poland during the period 2001-2011. We discuss assumptions of the privatization process, as well as actual implementation, having identified the process as chaotic and inconsistent with prior legal provisions. We found that in its applied form the process resulted in limitation of the therapeutic potential of spas, and reduction of the State's ability to implement health policy in a legally determined form. We also found that privatization potentially improved spa infrastructure standards and increases the tourist potential of spa resorts. We recommend that clear eligibility criteria are applied to institutions in the privatization process, as well as the provision of legal guarantees for access to spa services financed from public resources. Such guarantees should be made a public obligation, to ensure the availability of services for insured persons, and there should be an obligation to maintain a specific part of a given institution's potential for the needs of patients funded by public health insurance. PMID- 26972547 TI - Improving Stability of Zeolites in Aqueous Phase via Selective Removal of Structural Defects. AB - Missing silicon-oxygen bonds in zeolites are shown to be the cause for structural instability of zeolites in hot liquid water. Their selective removal drastically improved their structural stability as demonstrated using zeolite beta as example. The defects in the siloxy bonds were capped by reaction with trimethylchlorosilane, and Si-O-Si bonds were eventually formed. Hydrolysis of Si O-Si bonds of the parent materials and dissolution of silica-oxygen tetrahedra in water causing a decrease in sorption capacity by reprecipitation of dissolved silica and pore blocking was largely mitigated by the treatment. The stability of the modified molecular sieves was monitored by (29)Si-MAS NMR, transmission electron micrographs, X-ray diffraction, and adsorption isotherms. The microporosity, sorption capacity, and long-range order of the stabilized material were fully retained even after prolonged exposure to hot liquid water. PMID- 26972548 TI - Family caregiving of individuals with traumatic brain injury in Botswana. AB - Background The impairments that affect survivors of TBI impact the person's independence, and family members frequently have to take on a caregiver role. This study examined the experience of caregiving for individuals with TBI in Botswana and its impact on psychological distress in caregivers. Methods Using a mixed methods study design, qualitative data from semi-structured interviews were thematically analyzed and triangulated with data regarding functional status from the Structured Head Injury Outcome Questionnaire and the Hospital Anxiety and Depression Scale (HADS). Results The study included 26 participants with moderate to severe TBI, and a total of 18 caregivers were recruited. Caregivers commonly reported receiving limited information regarding their relatives' injuries and management methods. Heavy caregiving demands were placed on them, with little support from the healthcare system. A significant proportion of caregivers experienced anxiety and depression, which was associated with lower functional independence in their injured relative. Somewhat more spouses than parents reported clinically significant anxiety levels. Other consequences of caregiving included social isolation and limited support from the wider community as well as financial difficulties. Despite these stresses caregivers tended to accept their caregiving role. Cultural factors such devotion to their families and faith and belief in God moderated burden and distress. Conclusions Carers of individuals with TBI in Botswana face significant challenges. Rehabilitation efforts need to take these into account. Specifically, more information and support needs to be provided to survivors and their families. Psychological, economic and health needs of the care providers also should be addressed in the planning of rehabilitation interventions. Implications for Rehabilitation Caregivers of individuals with TBI in under-resourced countries carry much of the burden of care, face many challenges and experience significant stress. More information and support needs to be provided to survivors of TBI and their families in countries such as Botswana in a culturally sensitive manner. Psychological, economic and health needs also need to be addressed in the planning of rehabilitation interventions, which are currently non-existent in Botswana. PMID- 26972554 TI - Silver Nanoshell Plasmonically Controlled Emission of Semiconductor Quantum Dots in the Strong Coupling Regime. AB - Strong coupling between semiconductor excitons and localized surface plasmons (LSPs) giving rise to hybridized plexciton states in which energy is coherently and reversibly exchanged between the components is vital, especially in the area of quantum information processing from fundamental and practical points of view. Here, in photoluminescence spectra, rather than from common extinction or reflection measurements, we report on the direct observation of Rabi splitting of approximately 160 meV as an indication of strong coupling between excited states of CdSe/ZnS quantum dots (QDs) and LSP modes of silver nanoshells under nonresonant nanosecond pulsed laser excitation at room temperature. The strong coupling manifests itself as an anticrossing-like behavior of the two newly formed polaritons when tuning the silver nanoshell plasmon energies across the exciton line of the QDs. Further analysis substantiates the essentiality of high pump energy and collective strong coupling of many QDs with the radiative dipole mode of the metallic nanoparticles for the realization of strong coupling. Our finding opens up interesting directions for the investigation of strong coupling between LSPs and excitons from the perspective of radiative recombination under easily accessible experimental conditions. PMID- 26972556 TI - Correction of Clinodactyly by Early Physiolysis: 6-Year Results. AB - PURPOSE: To review results at least 6 years after physiolysis for treatment of the delta phalanx associated with clinodactyly. METHODS: We present 22 cases of clinodactyly treated with physiolysis in which we removed the central part of the epiphysis, which is the portion restricting longitudinal growth unilaterally and inducing progressive finger deviation, and placed a fat graft in the resultant defect. RESULTS: This retrospective study reports the results of early physiolysis in 27 fingers with radial clinodactyly, including 17 fingers from 17 patients previously reported and 10 little fingers from 5 additional patients. All patients had a minimum follow-up of 6 years. Mean preoperative angle was 38 degrees (range, 25 degrees to 47 degrees ). At final follow-up, mean angle was 8 degrees (range, 0 degrees to 24 degrees ), a mean correction of 79%. Twelve fingers in 9 patients had more than 10 degrees of deformity at final follow-up, whereas 15 fingers in 13 patients had a residual deformity of less than 10 degrees , which is effectively full correction of a clinodactyly. No patient required a closing wedge osteotomy later for insufficient correction. CONCLUSIONS: These accumulative findings confirm our previous preliminary report. Early physiolysis is a quick and simple procedure that allows for growth and partial but often adequate correction of the clinodactyly. The correction occurs slowly over a period of years, which can be seen as a disadvantage, and requires careful counseling of the parents. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26972557 TI - Three-Dimensional Printing of Prosthetic Hands for Children. AB - Children with hand reductions, whether congenital or traumatic, have unique prosthetic needs. They present a challenge because of their continually changing size due to physical growth as well as changing needs due to psychosocial development. Conventional prosthetics are becoming more technologically advanced and increasingly complex. Although these are welcome advances for adults, the concomitant increases in weight, moving parts, and cost are not beneficial for children. Pediatric prosthetic needs may be better met with simpler solutions. Three-dimensional printing can be used to fabricate rugged, light-weight, easily replaceable, and very low cost assistive hands for children. PMID- 26972555 TI - Serum steroid concentrations remain within normal postmenopausal values in women receiving daily 6.5mg intravaginal prasterone for 12 weeks. AB - This study integrates all data obtained in women aged 40-80years enrolled with moderate to severe symptoms of vulvovaginal atrophy (VVA) who received daily intravaginal administration of 0.50% (6.5mg) dehydroepiandrosterone (DHEA; prasterone) for 12weeks (n=723; ITT-S population) as compared with placebo (n=266; ITT-S population). To this end, serum steroid levels (DHEA, DHEA-sulfate (DHEA-S), androst-5-ene-3beta, 17beta-diol (5-diol), testosterone, dihydrotestosterone (DHT), androstenedione (4-dione), estrone (E1), estradiol (E2), estrone sulfate (E1-S), androsterone glucuronide (ADT-G), and androstane 3alpha, 17beta-diol 17-glucuronide (3alpha-diol-17G)) were measured at Day 1 and Week 12 by liquid chromatography-tandem mass spectrometry (LC-MS/MS) following validation performed according to the FDA guidelines [1-6]. In agreement with the mechanisms of intracrinology where DHEA is exclusively transformed intracellularly into active sex steroids which act and are inactivated locally before being released as glucuronided or sulfated metabolites for elimination by the kidneys and liver, all sex steroids remained well within normal postmenopausal values following administration of intravaginal DHEA. Serum estradiol, the most relevant sex steroid, was measured after 12weeks of treatment at 3.36pg/ml (cITT-S population) or 19% below the normal postmenopausal value of 4.17pg/ml. On the other hand, serum E1-S, the best recognized marker of global estrogenic activity, shows an average value of 209pg/ml at 12 weeks compared to 220pg/ml in normal postmenopausal women. Moreover, serum ADT-G, the main metabolite of androgens, also remains well within normal postmenopausal values. The present data shows that a low daily intravaginal dose (6.5mg) of DHEA (prasterone) which is efficacious on the symptoms and signs of VVA, permits to achieve the desired local efficacy without systemic exposure, in agreement with the stringent mechanisms of menopause established after 500 million years of evolution where each cell in each tissue is the master of its sex steroid exposure. PMID- 26972559 TI - Natural inactivation of Escherichia coli in anaerobic and reduced groundwater. AB - AIMS: Inactivation rates of Escherichia coli in groundwater have most often been determined in aerobic and oxidized systems. This study examined E. coli inactivation rates in anaerobic and extremely reduced groundwater systems that have been identified as recharge zones. METHODS AND RESULTS: Groundwater from six artesian wells was diverted to above-ground, flow-through mesocosms that contained laboratory grown E. coli in diffusion chambers. All groundwater was anaerobic and extremely reduced (ORP < -300 mV). Cells were plated onto mTEC agar during 21-day incubation periods. All data fit a bi-phasic inactivation model, with >95% of the E. coli population being inactivated <11.0 h (mean k = 0.488 +/ 0.188 h(-1) ). CONCLUSIONS: The groundwater geochemical conditions enhanced the inactivation of E. coli to rates approx. 21-fold greater than previously published inactivation rate in groundwater (mean k = 0.023 +/- 0.030 h(-1) ). Also, mTEC agar inhibits E. coli growth following exposure to anaerobic and reduced groundwater. SIGNIFICANCE AND IMPACT OF THE STUDY: Aquifer recharge zones with geochemical characteristics observed in this study complement above-ground engineered processes (e.g. filtration, disinfection), while increasing the overall indicator micro-organism log-reduction rate of a facility. PMID- 26972560 TI - Using medical imaging for the detection of adverse events ("incidents") during the utilization of left ventricular assist devices in adult patients with advanced heart failure. AB - Ventricular assist devices (VAD) are used for mechanical support of the terminally failing heart. Failure of these life supporting systems can be fatal. Early and reliable detection of any upcoming problems is mandatory and is crucial for the outcome. Medical imaging methods are described within this review, which are not only essential for diagnosis of typically VAD-related complications but also for the detection or verification of technical issues. Within this review the utilization of medical imaging equipment for the diagnosis of technical malfunctions or damages of implanted system components is discussed. A newly developed specialized acoustic imaging method for pump thrombosis detection will also be described along with the most common VAD-related medical complications and their respective imaging methods and the limitations induced by the use of the VAD-system. PMID- 26972558 TI - Update on rational targeted therapy in AML. AB - Acute myeloid leukemia (AML) remains a challenge to both patients and clinicians. Despite improvements in our understanding of the disease, treatment has changed minimally and outcomes remain poor for the majority of patients. Within the last decade, there have been an increasing number of potential targets and pathways identified for development in AML. The classes of agents described in this review include but are not limited to epigenetic modifiers such as IDH inhibitors, BET inhibitors, and HDAC inhibitors as well as cell cycle and signaling inhibitors such as Aurora kinase inhibitors and CDK inhibitors. While the developments are encouraging, it is unlikely that targeting a single pathway will result in long term disease control. Accordingly, we will also highlight potential rational partners for the novel agents described herein. PMID- 26972561 TI - [NK/T-cell Lymphoma of nasal-type: A rare affection with a poor prognosis]. AB - INTRODUCTION: NK/T cell lymphoma of nasal-type was described in 1933 as a malignant midfacial granuloma. The diagnosis of this rare affection is clinical and immunohistopathological. We report a case of NK/T cell lymphoma diagnosed at an advanced stage. OBSERVATION: A 60-year-old man with no particular medical history presented since seven months with a left nasal obstruction associated with a purulent and fetid rhinorrhea followed by a centrifugal midfacial necrosis. Blood tests showed an inflammatory syndrome. The CT-scan of the face showed a filling of the nose and sinus by a tissular process and a lysis of the bone walls. Three series of biopsies (le last being performed under general anesthesia) were necessary to get the diagnosis of NK/T cell lymphoma. The standard histology showed a malignant proliferation made of round and spindle shaped lymphoid-like cells and angiocentric arrangement. The cells were CD 2+, CD 3+, CD 5+ and CD 56+. The spontaneous evolution was fatal one month after diagnosis in a context of septic shock. CONCLUSION: NK/T cell lymphoma of nasal type is a rare disease but should be evocated in patient with midfacial necrosis of centrifugal evolution. The diagnosis certainty is made on immunohistopathological analysis. Multiple biopsies, made at distance from necrotic areas and under general anesthesia may be necessary. PMID- 26972562 TI - Restriction-Modification systems interplay causes avoidance of GATC site in prokaryotic genomes. AB - Palindromes are frequently underrepresented in prokaryotic genomes. Palindromic 5[Formula: see text]-GATC-3[Formula: see text] site is a recognition site of different Restriction-Modification (R-M) systems, as well as solitary methyltransferase Dam. Classical GATC-specific R-M systems methylate GATC and cleave unmethylated GATC. On the contrary, methyl-directed Type II restriction endonucleases cleave methylated GATC. Methylation of GATC by Dam methyltransferase is involved in the regulation of different cellular processes. The diversity of functions of GATC-recognizing proteins makes GATC sequence a good model for studying the reasons of palindrome avoidance in prokaryotic genomes. In this work, the influence of R-M systems and solitary proteins on the GATC site avoidance is described by a mathematical model. GATC avoidance is strongly associated with the presence of alternate (methyl-directed or classical Type II R-M system) genes in different strains of the same species, as we have shown for Streptococcus pneumoniae, Neisseria meningitidis, Eubacterium rectale, and Moraxella catarrhalis. We hypothesize that GATC avoidance can result from a DNA exchange between strains with different methylation status of GATC site within the process of natural transformation. If this hypothesis is correct, the GATC avoidance is a sign of a DNA exchange between bacteria with different methylation status in a mixed population. PMID- 26972563 TI - Search for conserved amino acid residues of the alpha-crystallin proteins of vertebrates. AB - [Formula: see text]-crystallin is the major eye lens protein and a member of the small heat-shock protein (sHsp) family. [Formula: see text]-crystallins have been shown to support lens clarity by preventing the aggregation of lens proteins. We performed the bioinformatics analysis of [Formula: see text]-crystallin sequences from vertebrates to find conserved amino acid residues as the three-dimensional (3D) structure of [Formula: see text]-crystallin is not identified yet. We are the first who demonstrated that the N-terminal region is conservative along with the central domain for vertebrate organisms. We have found that there is correlation between the conserved and structured regions. Moreover, amyloidogenic regions also correspond to the structured regions. We analyzed the amino acid composition of [Formula: see text]-crystallin A and B chains. Analyzing the occurrence of each individual amino acid residue, we have found that such amino acid residues as leucine, serine, lysine, proline, phenylalanine, histidine, isoleucine, glutamic acid, and valine change their content simultaneously in A and B chains in different classes of vertebrates. Aromatic amino acids occur more often in [Formula: see text]-crystallins from vertebrates than on the average in proteins among 17 animal proteomes. We obtained that the identity between A and B chains in the mammalian group is 0.35, which is lower than the published 0.60. PMID- 26972564 TI - A test of the effects of timing of a pulsed resource subsidy on stream ecosystems. AB - Spatial resource subsidies can alter bottom-up and top-down forces of community regulation across ecosystem boundaries. Most subsidies are temporally variable, and recent theory has suggested that consumer-resource dynamics can be stabilized if the peak timing of a subsidy is desynchronized with that of prey productivity in the recipient ecosystem. However, magnitude of consumer responses per se could depend on the subsidy timing, which may be a critical component for community dynamics and ecosystem processes. The aim of this study was to test (i) whether a recipient consumer (cutthroat trout) responds differently to a resource subsidy occurring early in its growing season than to a subsidy occurring late in the season and, if this is the case, (ii) whether the timing-dependent consumer response has cascading effects on communities and ecosystem functions in streams. To test those hypotheses, we conducted a large-scale field experiment, in which we directly manipulated the timing of augmentation of the terrestrial invertebrates that enter stream (i.e. peak timing of June-August vs. August October), keeping constant the total amounts of the invertebrates entered. We found large increases in the individual growth rate and population biomass of the cutthroat trout, in response to the early resource pulse, but not to the late pulse. This timing-dependent consumer response cascaded down to reduce benthic invertebrates and leaf breakdown rate, and increased water nutrient concentrations. Furthermore, the early resource pulse resulted in higher maturity rate of the cutthroat trout in the following spring, demonstrating the importance of the subsidy timing on long-term community dynamics via the consumer's numerical response. Our results emphasize the need to acknowledge timing dependent consumer responses in understanding the effects of subsidies on communities and ecosystem processes. Elucidating the mechanisms by which consumers effectively exploit pulsed subsidies is an important avenue to better understand community dynamics in spatially coupled ecosystems. PMID- 26972565 TI - Subcutaneous emphysema and pneumothorax secondary to subclavian vein catheterization via supraclavicular approach. PMID- 26972566 TI - Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy. AB - Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti inflammatory and anti-oxidative activities which are potentially anti atherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases. PMID- 26972567 TI - Phase 1-2 pilot clinical trial in patients with decompensated liver cirrhosis treated with bone marrow-derived endothelial progenitor cells. AB - The aim of this nonrandomized, open label, phase 1 clinical trial was to evaluate the safety and the feasibility of the treatment with autologous bone marrow derived endothelial progenitor cells (EPC) in decompensated liver cirrhosis. In addition, the changes in liver function and hepatic venous pressure gradient (HVPG) and their relation with the characteristics of the cellular product were analyzed. Twelve patients with Child-Pugh >=8 liver cirrhosis underwent bone marrow harvest for ex vivo differentiation of EPC. The final product was administered through the hepatic artery in a single administration. Patients underwent clinical and radiologic follow-up for 12 months. The phenotype and the ability to produce cytokines and growth factors of the final cellular suspension were analyzed. Eleven patients were treated (feasibility 91%). No treatment related severe adverse events were observed as consequence of any study procedure or treatment. Model for end-stage liver disease score improved significantly (P 0.042) in the first 90 days after cells administration and 5 of the 9 patients alive at 90 days showed a decreased of HVPG. There was a direct correlation between the expression of acetylated-low density lipoprotein and von Willebrand factor in the cellular product and the improvement in liver function and HVPG. The treatment with EPCs in patients with decompensated liver cirrhosis is safe and feasible and might have therapeutic potential. Patients receiving a higher amount of functionally active EPC showed an improvement of liver function and portal hypertension suggesting that the potential usefulness of these cells for the treatment of liver cirrhosis deserves further evaluation. PMID- 26972568 TI - Propensity score analysis of endoscopic and open approaches to malignant paranasal and anterior skull base tumor outcomes. AB - OBJECTIVES/HYPOTHESIS: Malignant sinonasal and skull base tumors are now being resected using an endoscopic technique, but there has been controversy regarding the oncologic safety of this approach. Various studies have compared the outcomes from endoscopic surgery to those from open techniques; however, all have been limited by substantial differences in the patient populations receiving each approach. In this study we compare outcomes of open and endoscopic techniques and use propensity score matching to control for these differences in the patient populations. STUDY DESIGN: Retrospective cohort study including all patients > 18 years old receiving primary surgery for malignant sinonasal or skull base tumors at our institution from 2002 to 2013. RESULTS: One hundred twenty-four patients met criteria; 82 received endoscopic-only surgery, and 42 had an open component to their approach. There was an 86% 3-year overall survival and a 74% disease free survival. Without controlling for differences in the groups, the endoscopic patients fared significantly better in survival, recurrence rates, wound infections, and length of hospital stay. When using propensity score matching to account for patient comorbidities and tumor size, there were no significant differences in any outcomes except length of the hospital stay. A multivariate regression analysis yielded the same results. CONCLUSION: In this study, endoscopic surgery was shown to be a safe alternative to the open technique, even when controlling for the favorable patient and tumor characteristics in endoscopic patients. This is the first study to account for these differences with a rigorous statistical methodology. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1724-1729, 2016. PMID- 26972569 TI - Mean platelet volume may not be increased in patients with idiopathic subjective tinnitus. PMID- 26972570 TI - Return to sport after ACL reconstruction: a survey between the Italian Society of Knee, Arthroscopy, Sport, Cartilage and Orthopaedic Technologies (SIGASCOT) members. AB - BACKGROUND: A worldwide consensus for timing and criteria for return to sport after anterior cruciate ligament (ACL) reconstruction is lacking. The aim of the study was to survey among the Italian Society of Knee, Arthroscopy, Sport, Cartilage and Orthopaedic Technologies (SIGASCOT) members in order to evaluate their approaches to the return to sport after ACL reconstruction regarding timing and criteria. METHODS: A web survey among the SIGASCOT members was performed, including 14 questions regarding technical and graft preferences, timing for return to training and competitive activity for contact and non-contact sports and criteria to allow return to sport. RESULTS: Totally, 123 members completed the questionnaire. Return to training sports was allowed within 6 month by 87 % for non-contact sports and by 53 % for contact sports. Return to competitive activity was allowed within 6 months by 48 % for non-contact sports and by 13 % for contact sports. Full ROM (77 %), Lachman test (65 %) and Pivot-Shift test (65 %) were the most used criteria to allow return to sport. The 90 % used at least one clinical score. CONCLUSION: The SIGASCOT members showed various approaches in the return to sport after ACL reconstruction, with differences between return to training or competitive activity, and between contact and non-contact sports. Six months was generally considered adequate by most of the members for the most demanding activities. The most used criteria to allow return to sport were manual testing. A clear definition of sport activities and more objective criteria for the return to sport are needed. LEVEL OF EVIDENCE: Level V, expert opinion. PMID- 26972571 TI - Microarray study reveals a transforming growth factor-beta-dependent mechanism of fibrosis in discoid lupus erythematosus. AB - BACKGROUND: Discoid lupus erythematosus (DLE) is characterized by scarring lesions that develop and perpetuate fibrotic lesions. These are not observed in subacute cutaneous lupus erythematosus (SCLE). The pathophysiological basis of this is currently unknown. OBJECTIVES: To identify contradistinctive signalling pathways and cellular signatures between the two type of lupus, with a focus on the molecular mechanisms leading to fibrosis. METHODS: We conducted a gene expression microarray analysis in lesional and nonlesional skin biopsy specimens of patients with DLE (n = 10) and SCLE (n = 10). Confirmatory reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry were performed on selected transcripts in a new cohort of paraffin-embedded skin biopsies (n = 20). Changes over time of a group of selected inflammatory and fibrotic genes were also evaluated in a second biopsy taken 12 weeks later. In vitro functional studies were performed in primary isolated fibroblasts. RESULTS: Compared with nonlesional skin, DLE samples expressed a distinctive T-cell gene signature. DLE samples displayed a significant CD4 T-cell enrichment with an imbalance towards T helper 1 cytokine predominance and a relative increased forkhead box (FOX)P3 response. RT-qPCR and immunochemical analysis over time showed a progressive increment of fibrotic markers and persistent FOXP3 recruitment. Ex vivo upregulation of SERPINE1, MMP9, TGFBR1, phosphorylated SMAD3 and TGFB1 suggested a transforming growth factor (TGF)-beta-dependent mechanism of fibrosis in DLE, also confirmed by the results observed following in vitro stimulation with TGF-beta. CONCLUSIONS: These results highlight major pathogenic pathways in DLE and provide novel molecular targets for the development of new therapies. The data suggest the existence of a TGF beta-dependent pathway inducing fibrosis in DLE. PMID- 26972572 TI - Hydrochemical variations in selected geothermal groundwater and carbonated springs in Korea: a baseline study for early detection of CO2 leakage. AB - A baseline hydrochemistry of the above zone aquifer was examined for the potential of CO2 early detection monitoring. Among the major ionic components and stable isotope ratios of oxygen, hydrogen, and carbon, components with a relative standard deviation (RSD) of <10 % for the seasonal variation were selected as relatively stable. These components were tested for sensitivity to the introduction of 0.1 mol/L CO2 (g) using the PHREEQC simulation results. If the relatively stable components were sensitive to the introduction of CO2, then they could be used as indicators of CO2 leakage into the above zone. As an analog to the zone above CO2 storage formation, we sampled deep groundwater, including geothermal groundwater from well depths of 400-700 m below the ground surface (bgs) and carbonated springs with a high CO2 content in Korea. Under the natural conditions of inland geothermal groundwater, pH, electrical conductivity (EC), bicarbonate (HCO3), delta18O, delta2H, and delta13C were relatively stable as well as sensitive to the introduction of CO2 (g), thus showing good potential as monitoring parameters for early detection of CO2 leakage. In carbonated springs, the parameters identified were pH, delta18O, and delta2H. Baseline hydrochemistry monitoring could provide information on parameters useful for detecting anomalies caused by CO2 leakage as measures for early warning. PMID- 26972573 TI - Gastric polyps diagnosed by double-contrast upper gastrointestinal barium X-ray radiography mostly arise from the Helicobacter pylori-negative stomach with low risk of gastric cancer in Japan. AB - BACKGROUND: Double-contrast upper gastrointestinal barium X-ray radiography (UGI XR) is a method broadly used for gastric cancer screening in Japan. Gastric polyp is one of the most frequent findings detected by UGI-XR, but how to handle it remains controversial. METHODS: Gastric polyps of the 17,264 generally healthy subjects in Japan who underwent UGI-XR or upper gastrointestinal endoscopy (UGI ES) in 2010 were analyzed. RESULTS: Of the 6,433 UGI-XR examinees (3,405 men and 3,028 women, 47.4 +/- 9.0 years old), gastric polyps were detected in 464 men (13.6 %) and 733 women (24.2 %) and were predominantly developed on the non atrophic gastric mucosa (p < 0.0001). Multiple logistic regression analysis showed that the presence of gastric polyps has significant association with lower value of serum anti-Helicobacter pylori IgG titer, female gender, lighter smoking habit, older age, and normal range of body mass index (>=18.5 and <25), but not with drinking or serum pepsinogen I/II ratio. During the 3-year follow-up, gastric cancer occurred in 7 subjects (0.11 %), but none of them had gastric polyps at the beginning of the follow-up period. Of the 2,722 subjects with gastric polyps among the 10,831 UGI-ES examinees in the same period, 2,446 (89.9 %) had fundic, 267 (9.8 %) had hyperplastic, and 9 (0.3 %) had adenomatous/cancerous polyps. CONCLUSIONS: Gastric polyps diagnosed by UGI-XR predominantly arise on the Helicobacter pylori-negative gastric mucosa with a low risk of gastric cancer in Japan. In the prospective observation, none of the UGI XR examinees with gastric polyps developed gastric cancer for at least 3 years subsequently. PMID- 26972574 TI - Management of pancreatic injuries during damage control surgery: an observational outcomes analysis of 79 patients treated at an academic Level 1 trauma centre. AB - BACKGROUND: This study evaluated factors influencing mortality in a large cohort of patients who sustained pancreatic injuries and underwent DCS. METHODS: A prospective database of consecutive patients with pancreatic injuries treated at a Level 1 academic trauma centre was reviewed to identify those who underwent DCS between 1995 and 2014. RESULTS: Seventy-nine (71 men, median age: 26 years, range 16-73 years, gunshot wounds = 62, blunt = 14, stab = 3) patients with pancreatic injuries (35 proximal, 44 distal) had DCS. Fifty-nine (74.7 %) patients had AAST grade 3, 4 or 5 pancreatic injuries. The 79 patients had a total of 327 associated injuries (mean: 3 per patient, range 0-6) and underwent a total of 187 (range 1-7) operations. Vascular injuries (60/327, 18.3 %) occurred in 41 patients. Twenty-seven (34.2 %) patients died without having a second operation. The remaining 52 patients had two or more laparotomies (range 2-7). Overall 28 (35 %) patients underwent a pancreatic resection either during DCS (n = 18) or subsequently as a secondary procedure (n = 10) including a Whipple (n = 6) when stable. Overall 43 (54.4 %) patients died. Mortality was related to associated vascular injuries overall (p < 0.01), major visceral venous injuries (p < 0.01) and combined vascular and total number of associated organs injured (p < 0.04). CONCLUSIONS: Despite the magnitude of their combined injuries and the degree of physiological insult, DCS salvaged 45 % of critically injured patients who later underwent definitive pancreatic surgery. Mortality correlated with associated vascular injuries overall, major visceral venous injuries and the combination of vascular plus the total number of associated organs injured. PMID- 26972575 TI - Positive autoantibodies to ZnT8 indicate elevated risk for additional autoimmune conditions in patients with Addison's disease. AB - Autoimmune Addison's disease (AAD) associates with exceptional susceptibility to develop other autoimmune conditions, including type 1 diabetes (T1D), marked by positive serum autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and insulinoma-associated protein 2 (IA-2A). Zinc transporter 8 (ZnT8) is a new T1D autoantigen, encoded by the SLC30A8 gene. Its polymorphic variant rs13266634C/T seems associated with the occurrence of serum ZnT8 antibodies (ZnT8A). This study was designed to determine the prevalence of serum ZnT8A and their clinical implication in 140 AAD patients. Other beta cell and thyroid specific autoantibodies were also investigated, and ZnT8A results were confronted with the rs13266634 genotype. ZnT8A were detectable in 8.5 %, GADA in 20.7 %, IA 2A in 5.7 %, IAA in 1.6 % and various anti-thyroid antibodies in 7.1-67.8 % individuals. Type 1 diabetes was found in 10 % AAD patients. ZnT8A were positive in 57.1 % of T1D patients and 3.4 % non-diabetic AAD. Analysis of ZnT8A enabled to identify autoimmunity in two (14.3 %) T1D individuals previously classified as autoantibody-negative. ZnT8A-positive patients revealed significantly higher number of autoimmune conditions (p < 0.001), increased prevalence of T1D (p < 0.001) and other beta cell-specific autoantibodies. Carriers of the rs13266634 T allele displayed increased frequency (p = 0.006) and higher titres of ZnT8A (p = 0.002). Our study demonstrates high incidence of ZnT8A in AAD patients. ZnT8A are associated with coexisting T1D and predictive of T1D in non-diabetic subjects. Moreover, positive ZnT8A in AAD indicate elevated risk for additional autoimmune conditions. Autoantibodies to beta cell antigens, comprising ZnT8, could be included in routine screening panels in AAD. PMID- 26972577 TI - RGD-modified lipid disks as drug carriers for tumor targeted drug delivery. AB - Melittin, the major component of the European bee venom, is a potential anticancer candidate due to its lytic properties. However, in vivo applications of melittin are limited due to its main side effect, hemolysis, especially when applied through intravenous administration. The polyethylene glycol-stabilized lipid disk is a novel type of nanocarrier, and the rim of lipid disks has a high affinity to amphiphilic peptides. In our study, a c(RGDyK) modified lipid disk was developed as a tumor targeted drug delivery system for melittin. Cryo-TEM was used to confirm the shape and size of lipid disks with or without c(RGDyK) modification. In vitro and in vivo hemolysis analyses revealed that the hemolysis effect significantly decreased after melittin associated with lipid disks. Importantly, the results of our in vivo biodistribution and tumor growth inhibitory experiments showed that c(RGDyK) modification increased the distribution of lipid disks in the tumor and the anticancer efficacy of melittin loaded lipid disks. Thus, we successfully achieved a targeted drug delivery system for melittin and other amphiphilic peptides with a good therapeutic effect and low side effects. PMID- 26972578 TI - Altered functional brain networks in amnestic mild cognitive impairment: a resting-state fMRI study. AB - Amnestic mild cognitive impairment MCI (aMCI) has a high progression to Alzheimer's disease (AD). Recently, resting-state functional MRI (RS-fMRI) has been increasingly utilized in studying the pathogenesis of aMCI, especially in resting-state networks (RSNs). In the current study, we aimed to explore abnormal RSNs related to memory deficits in aMCI patients compared to the aged-matched healthy control group using RS-fMRI techniques. Firstly, we used ALFF (amplitude of low-frequency fluctuation) method to define the regions of interest (ROIs) which exhibited significant changes in aMCI compared with the control group. Then, we divided these ROIs into different networks in line with prior studies. The aim of this study is to explore the functional connectivity between these ROIs within networks and also to investigate the connectivity between networks. Comparing aMCI to the control group, our results showed that 1) the hippocampus (HIPP) had decreased FC with the medial prefrontal cortex (mPFC) and inferior parietal lobe (IPL), and the mPFC showed increased connectivity to IPL in the default mode network; 2) the thalamus showed decreased FC with the putamen and HIPP, and the HIPP showed increased connectivity to the putamen in the limbic system; 3) the supplementary motor area had decreased FC with the middle temporal gyrus and increased FC with the superior parietal lobe in the sensorimotor network; 4) increased connectivity between the lingual gyrus and middle occipital gyrus in the visual network; and 5) the DMN has reduced inter-network connectivities with the SMN and VN. These findings indicated that functional brain networks involved in cognition such as episodic memory, sensorimotor and visual cognition in aMCI were altered, and provided a new sight in understanding the important subtype of aMCI. PMID- 26972576 TI - Retrospective respiratory self-gating and removal of bulk motion in pulmonary UTE MRI of neonates and adults. AB - PURPOSE: To implement pulmonary three-dimensional (3D) radial ultrashort echo time (UTE) MRI in non-sedated, free-breathing neonates and adults with retrospective motion tracking of respiratory and intermittent bulk motion, to obtain diagnostic-quality, respiratory-gated images. METHODS: Pulmonary 3D radial UTE MRI was performed at 1.5 tesla (T) during free breathing in neonates and adult volunteers for validation. Motion-tracking waveforms were obtained from the time course of each free induction decay's initial point (i.e., k-space center), allowing for respiratory-gated image reconstructions that excluded data acquired during bulk motion. Tidal volumes were calculated from end-expiration and end inspiration images. Respiratory rates were calculated from the Fourier transform of the motion-tracking waveform during quiet breathing, with comparison to physiologic prediction in neonates and validation with spirometry in adults. RESULTS: High-quality respiratory-gated anatomic images were obtained at inspiration and expiration, with less respiratory blurring at the expense of signal-to-noise for narrower gating windows. Inspiration-expiration volume differences agreed with physiologic predictions (neonates; Bland-Altman bias = 6.2 mL) and spirometric values (adults; bias = 0.11 L). MRI-measured respiratory rates compared well with the observed rates (biases = -0.5 and 0.2 breaths/min for neonates and adults, respectively). CONCLUSIONS: Three-dimensional radial pulmonary UTE MRI allows for retrospective respiratory self-gating and removal of intermittent bulk motion in free-breathing, non-sedated neonates and adults. Magn Reson Med 77:1284-1295, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26972580 TI - TALEored Epigenetics: A DNA-Binding Scaffold for Programmable Epigenome Editing and Analysis. AB - Epigenetic modification of the cytosine 5-position is an important regulator of gene expression with essential roles in genome stability, development, and disease. In addition to 5-methylcytosine (mC), the oxidized mC derivatives 5 hydroxymethyl-, 5-formyl-, and 5-carboxylcytosine (hmC, fC, and caC) have recently been discovered. These are intermediates of an active demethylation pathway but might also represent new epigenetic marks with individual biological roles. This increase in chemical complexity of DNA-encoded information has created a pressing need for new approaches that allow reading and editing of this information. Transcription-activator-like effectors (TALEs) are DNA-binding domains with programmable sequence selectivity that enable the direct reading of epigenetic cytosine modifications but can also guide enzymatic editing domains to genomic loci of choice. Here, we review recent advances in employing TALEs for these applications. PMID- 26972579 TI - Characterization and comparison of post-natal rat Achilles tendon-derived stem cells at different development stages. AB - Tendon stem/progenitor cells (TSPCs) are a potential cell source for tendon tissue engineering. The striking morphological and structural changes of tendon tissue during development indicate the complexity of TSPCs at different stages. This study aims to characterize and compare post-natal rat Achilles tendon tissue and TSPCs at different stages of development. The tendon tissue showed distinct differences during development: the tissue structure became denser and more regular, the nuclei became spindle-shaped and the cell number decreased with time. TSPCs derived from 7 day Achilles tendon tissue showed the highest self renewal ability, cell proliferation, and differentiation potential towards mesenchymal lineage, compared to TSPCs derived from 1 day and 56 day tissue. Microarray data showed up-regulation of several groups of genes in TSPCs derived from 7 day Achilles tendon tissue, which may account for the unique cell characteristics during this specific stage of development. Our results indicate that TSPCs derived from 7 day Achilles tendon tissue is a superior cell source as compared to TSPCs derived from 1 day and 56 day tissue, demonstrating the importance of choosing a suitable stem cell source for effective tendon tissue engineering and regeneration. PMID- 26972581 TI - Molecular architecture of Abeta fibrils grown in cerebrospinal fluid solution and in a cell culture model of Abeta plaque formation. AB - OBJECTIVES: The detailed structure of brain-derived Abeta amyloid fibrils is unknown. To approach this issue, we investigate the molecular architecture of Abeta(1-40) fibrils grown in either human cerebrospinal fluid solution, in chemically simple phosphate buffer in vitro or extracted from a cell culture model of Abeta amyloid plaque formation. METHODS: We have used hydrogen-deuterium exchange (HX) combined with nuclear magnetic resonance, transmission electron microscopy, seeding experiments both in vitro and in cell culture as well as several other spectroscopic measurements to compare the morphology and residue specific conformation of these different Abeta fibrils. RESULTS AND CONCLUSIONS: Our data reveal that, despite considerable variations in morphology, the spectroscopic properties and the pattern of slowly exchanging backbone amides are closely similar in the fibrils investigated. This finding implies that a fundamentally conserved molecular architecture of Abeta peptide fold is common to Abeta fibrils. PMID- 26972582 TI - A retrospective analysis of the findings of pressure ulcer investigations in an acute trust in the UK. AB - The root cause analysis (RCA) process has been applied in this organisation since 2010 to investigate all severe pressure ulcers. A previous analysis of the findings from all RCAs completed during 2011-2013 identified actions for practice improvement. The current study reports the results of a further retrospective analysis following implementation of new evidence based investigation process. AIM: To analysis the findings from pressure ulcer investigations; compare the results to the previous study and reflect on the new investigation process. METHODS: Analysis was performed on data from completed RCAs during January October 2014 to identify key themes and learning points. RESULTS: Thirty two pressure ulcer RCAs were included. Nutrition was the most common contributory factor, highlighting the issue of malnutrition in an acute care setting. The second most common contributory factor was medical conditions that lead to poor tissue perfusion. CONCLUSION: Severe pressure ulcers rarely occur due to a single root cause, but often due to a sequence of events. Patients frequently have multiple complex needs that increase their susceptibility, when this is in combination with a failure of care, a severe pressure ulcer can occur. The new investigation process had limited success in identifying organisational factors. Further work is needed to support staff in the investigation process. PMID- 26972583 TI - Heel ulcers - Pressure ulcers or symptoms of peripheral arterial disease? An exploratory matched case control study. AB - AIMS: To investigate the relationship between pressure ulcers of the heel and peripheral arterial disease (PAD) and determine the feasibility of conducting a statistically powered matched case control study. BACKGROUND: Evidence indicates a relationship between chronic leg ulcers and vascular disease. The relationship between pressure ulcers of the heel and vascular disease is less well established. DESIGN: A matched case control study. METHODS: Data were collected between March 2014 and January 2015. 15 patients identified as having a grade 2, 3 or 4 pressure ulcer of the heel were compared with 15 matched controls without pressure ulcers of the heel. The primary clinical outcome measure was the ankle brachial pressure index (ABPI), where an ABPI <0.9 or >1.3 was considered clinically indicative of PAD. The primary feasibility outcome measure was the rate of recruitment. RESULTS: Eighty seven patients were reported as having foot and heel ulcers; 36 of whom were identified as having pressure ulcers of the heel, 15 (42%) of whom were recruited to the study. Patients presenting with pressure ulcers of the heel were significantly more likely to simultaneously have previously undiagnosed PAD compared with age, gender and ethnicity matched controls without pressure ulcers of the heel (odds ratio: 11, 95% confidence interval 1.99-60.57). CONCLUSION: The formation of pressure ulcers of the heel could, in some patients, be related to the presence of PAD rather than a consequence of poor quality care. Healthcare professionals should assess the patient to exclude or confirm PAD. PMID- 26972584 TI - A randomized phase l pharmacokinetic study comparing SB4 and etanercept reference product (Enbrel(r)) in healthy subjects. AB - AIMS: SB4 has been developed as a biosimilar of etanercept. The primary objective of the present study was to demonstrate the pharmacokinetic (PK) equivalence between SB4 and European Union -sourced etanercept (EU-ETN), SB4 and United States-sourced etanercept (US-ETN), and EU-ETN and US-ETN. The safety and immunogenicity were also compared between the treatments. METHODS: This was a single-blind, three-part, crossover study in 138 healthy male subjects. In each part, 46 subjects were randomized at a 1:1 ratio to receive a single 50 mg subcutaneous dose of the treatments (part A: SB4 or EU-ETN; part B: SB4 or US ETN; and part C: EU-ETN or US-ETN) in period 1, followed by the crossover treatment in period 2 according to their assigned sequences. PK equivalence between the treatments was determined using the standard equivalence margin of 80 125%. RESULTS: The geometric least squares means ratios of AUCinf , AUClast and Cmax were 99.04%, 98.62% and 103.71% (part A: SB4 vs. EU-ETN); 101.09%, 100.96% and 104.36% (part B: SB4 vs. US-ETN); and 100.51%, 101.27% and 103.29% (part C: EU-ETN vs. US-ETN), respectively, and the corresponding 90% confidence intervals were completely contained within the limits of 80-125 %. The incidence of treatment-emergent adverse events was comparable, and the incidence of the antidrug antibodies was lower in SB4 compared with the reference products. CONCLUSIONS: The present study demonstrated PK equivalence between SB4 and EU ETN, SB4 and US-ETN, and EU-ETN and US-ETN in healthy male subjects. SB4 was well tolerated, with a lower immunogenicity profile and similar safety profile compared with those of the reference products. PMID- 26972585 TI - Cytological diagnosis of adult T-cell leukemia/lymphoma in sputum. AB - Adult T-cell leukemia/lymphoma (ATLL) is a rare and often aggressive T-cell leukemia/lymphoma that has been linked to infection by the human T-cell lymphotropic virus type 1 (HTLV-1). ATLL can involve multiple organs including the respiratory airway. A 53-year-old Trinidadian woman presented with productive cough and progressive shortness of breath. Her past medical history included duodenal strongyloidosis, skin rash, and hypercalcemia. Radiological studies showed increased interstitial markings. Sputum cytology showed atypical pleomorphic, small-to-medium-sized, lobated lymphocytes with irregular and hyperchromatic nuclei resembling "flower cells" which were CD3+/-/CD20- by immunocytochemistry. A lung biopsy showed interstitial, peribronchiolar, and subpleural infiltration by a CD3+/-/CD25+/- atypical lymphocytic infiltrate. Together with peripheral blood findings and positive HTLV-1 serology, the diagnosis of ATLL was made. We suggest that sputum evaluation in patients with ATLL risk factors can be diagnostic. PMID- 26972586 TI - Overexpression of microRNA-634 suppresses survival and matrix synthesis of human osteoarthritis chondrocytes by targeting PIK3R1. AB - Osteoarthritis (OA) is a degenerative disease characterized by deterioration of articular cartilage. Recent studies have demonstrated the importance of some microRNAs in cartilage damage. The aim of this study was to identify and characterize the expression of microRNA-634 (miR-634) in normal and OA chondrocytes, and to determine its role in OA pathogenesis. Human normal and OA chondrocytes obtained from patients were cultured in vitro. Transfection with miR 634 mimic or inhibitor was employed to investigate the effect of miR-634 on chondrocyte survival and matrix synthesis, and to identify miR-634 target. The results indicated that miR-634 was expressed at lower level in high grade OA chondrocyte compared with normal chondrocytes. Overexpression of miR-634 could inhibit cell survival and matrix synthesis in high grade OA chondrocytes. Furthermore, miR-634 targeted PIK3R1 gene that encodes the regulatory subunit 1 of class I PI3K (p85alpha) and exerted its inhibitory effect on the phosphorylation of Akt, mTOR, and S6 signal molecules in high grade OA chondrocytes. Therefore, the data suggested that miR-634 could suppress survival and matrix synthesis of high grade OA chondrocytes through targeting PIK3R1 gene to modulate the PI3K/Akt/S6 and PI3K/Akt/mTOR/S6 axes, with important implication for validating miR-634 as a potential target for OA therapy. PMID- 26972589 TI - Molecular evolution: Friends with benefits--sex speeds up adaptation. PMID- 26972588 TI - The genetics of drug efficacy: opportunities and challenges. AB - Lack of sufficient efficacy is the most common cause of attrition in late-phase drug development. It has long been envisioned that genetics could drive stratified drug development by identifying those patient subgroups that are most likely to respond. However, this vision has not been realized as only a small proportion of drugs have been found to have germline genetic predictors of efficacy with clinically meaningful effects, and so far all but one were found after drug approval. With the exception of oncology, systematic application of efficacy pharmacogenetics has not been integrated into drug discovery and development across the industry. Here, we argue for routine, early and cumulative screening for genetic predictors of efficacy, as an integrated component of clinical trial analysis. Such a strategy would identify clinically relevant predictors that may exist at the earliest possible opportunity, allow these predictors to be integrated into subsequent clinical development and provide mechanistic insights into drug disposition and patient-specific factors that influence response, therefore paving the way towards more personalized medicine. PMID- 26972591 TI - Human genetics: Loss-of-function variants--not always what they seem. PMID- 26972590 TI - Causes of molecular convergence and parallelism in protein evolution. AB - To what extent is the convergent evolution of protein function attributable to convergent or parallel changes at the amino acid level? The mutations that contribute to adaptive protein evolution may represent a biased subset of all possible beneficial mutations owing to mutation bias and/or variation in the magnitude of deleterious pleiotropy. A key finding is that the fitness effects of amino acid mutations are often conditional on genetic background. This context dependence (epistasis) can reduce the probability of convergence and parallelism because it reduces the number of possible mutations that are unconditionally acceptable in divergent genetic backgrounds. Here, I review factors that influence the probability of replicated evolution at the molecular level. PMID- 26972593 TI - All in My Head: Beckett, Schizophrenia and the Self. AB - This article will explore the representation of certain mental and somatic phenomena in Beckett's trilogy of novels Molloy, Malone Dies and The Unnamable, exploring how his understanding of schizophrenia and psychosis informs his representation of the relationship between mind and body. It will also examine recent phenomenological and philosophical accounts of schizophrenia (Louis Sass, Josef Parnas, Shaun Gallagher) that see the condition as a disorder of selfhood and concentrate in it on the disruption to ipseity, a fundamental and pre reflective awareness of self that leads to a loss of 'grip' (in the term of Merleau-Ponty) on concepts and percepts. Beckett's writing might, it is argued, make such disruptions more tangible and intelligible. The article will also consider John Campbell's argument that immunity of the first person to error Sydney Shoemaker's foundational philosophical idea that we cannot misspeak the first person pronoun-is revoked in states of psychosis, and relate such states to the moments in Beckett's writing where this immunity is challenged, and quasi psychotic experiences represented. PMID- 26972592 TI - The autophagy-related gene BcATG1 is involved in fungal development and pathogenesis in Botrytis cinerea. AB - Autophagy, a ubiquitous intracellular degradation process, is conserved from yeasts to humans. It serves as a major survival function during nutrient depletion stress and is crucial for correct growth and differentiation. In this study, we characterized an atg1 orthologue Bcatg1 in the necrotrophic plant pathogen Botrytis cinerea. Quantitative real-time polymerase chain reaction (qRT PCR) assays showed that the expression of BcATG1 was up-regulated under carbon or nitrogen starvation conditions. BcATG1 could functionally restore the survival defects of the yeast ATG1 mutant during nitrogen starvation. Deletion of BcATG1 (DeltaBcatg1) inhibited autophagosome accumulation in the vacuoles of nitrogen starved cells. DeltaBcatg1 was dramatically impaired in vegetative growth, conidiation and sclerotial formation. In addition, most conidia of DeltaBcatg1 lost the capacity to form the appressorium infection structure and failed to penetrate onion epidermis. Pathogenicity assays showed that the virulence of DeltaBcatg1 on different host plant tissues was drastically impaired, which was consistent with its inability to form an appressorium. Moreover, lipid droplet accumulation was significantly reduced in the conidia of DeltaBcatg1, but the glycerol content was increased. All of the defects of DeltaBcatg1 were complemented by re-introduction of an intact copy of the wild-type BcATG1 into the mutant. These results indicate that BcATG1 plays a critical role in numerous developmental processes and is essential to the pathogenesis of B. cinerea. PMID- 26972587 TI - Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. AB - This year is the tenth anniversary of the publication in this journal of a model suggesting the existence of 'tumour progenitor genes'. These genes are epigenetically disrupted at the earliest stages of malignancies, even before mutations, and thus cause altered differentiation throughout tumour evolution. The past decade of discovery in cancer epigenetics has revealed a number of similarities between cancer genes and stem cell reprogramming genes, widespread mutations in epigenetic regulators, and the part played by chromatin structure in cellular plasticity in both development and cancer. In the light of these discoveries, we suggest here a framework for cancer epigenetics involving three types of genes: 'epigenetic mediators', corresponding to the tumour progenitor genes suggested earlier; 'epigenetic modifiers' of the mediators, which are frequently mutated in cancer; and 'epigenetic modulators' upstream of the modifiers, which are responsive to changes in the cellular environment and often linked to the nuclear architecture. We suggest that this classification is helpful in framing new diagnostic and therapeutic approaches to cancer. PMID- 26972594 TI - The long-arm of adolescent weight status on later life depressive symptoms. AB - BACKGROUND: given the increase in worldwide obesity among children and adolescents, the long-term consequences of childhood obesity on the risk of adverse health outcomes in later life has garnered increased attention. Much of the work on earlier life weight status and later life health has focused on cardiovascular-related outcomes in mid- to late-adulthood; however, little is known about the later life mental health consequences of adolescent body weight. METHODS: data came from the Wisconsin Longitudinal Study. We estimated gender stratified logistic regression models to characterise the relationship between adolescent weight status using standardised relative body mass ascertained from high school photograph portraits in 1957 and depressive symptoms at age 65 using the Center for Epidemiologic Studies Depression Scale measured in 2004. RESULTS: women who were overweight in adolescence were significantly more likely to experience depressive symptoms in later adulthood than their normal weight counterparts (odds ratio [OR] = 1.740) when the full set of controls was included. This relationship was not observed among men. The relationship between women's adolescent weight status and later life depressive symptoms was moderated by childhood socioeconomic status, and adolescent overweight was more predictive of later life depressive symptoms for women who were raised in low- and middle income families (OR = 2.568 and OR = 2.763) than in high-income families (OR = 1.643). CONCLUSION: these findings provide further evidence for the wide range of long-term consequences of adolescent overweight on later life well-being and are notable for the gender differences in the connection between early life circumstances and later life mental health. PMID- 26972596 TI - Zinc homoeostasis: Basic research indicates therapeutic risks and opportunities. PMID- 26972595 TI - [The translocation carcinoma: A pediatric renal tumor also in adults]. AB - The MiT family of translocation-associated renal cell carcinomas comprise approximately 40 % of renal cell carcinomas in young patients but only up to 4 % of renal cell carcinomas in adult patients. The Xp11.2 translocation-associated tumors are the most frequent and were included in the 2004 World Health Organization (WHO) classification. They contain a fusion of the TFE3 gene with ASPSCR1, PRCC, NONO, SPFQ or CLTC resulting in an immunohistochemically detectable nuclear overexpression of TFE3. The Xp11.2 translocation-associated renal cell carcinomas are characterized by ample clear cytoplasm, papillary architecture and abundant psammoma bodies. The TFEB translocation-associated renal cell carcinomas are much rarer and show a biphasic architecture. Fluorescence in situ hybridization permits the detection of a translocation by means of a break apart probe for the TFE3 and TFEB genes and is recommended for the diagnosis of renal cell carcinomas in patients under 30 years of age. The TFE3 and TFEB translocation-associated tumors are classified as MiT family translocation carcinomas in the new WHO classification.The rare renal cell carcinomas harboring an ALK rearrangement with fusion to VCL in young patients with sickle cell trait show a characteristic morphology and are listed in the new WHO classification as a provisional entity. PMID- 26972597 TI - FADD regulates NF-kappaB activation and promotes ubiquitination of cFLIPL to induce apoptosis. AB - Tumor Necrosis Factor-alpha canonically induces the activation of NF-kappaB and associated gene product cellular FLICE-like inhibitory protein (cFLIPL) to promote cell survival. Previously, we demonstrated that ectopic expression of the Fas associated death domain (FADD) diminishes the expression of cFLIPL and transduces caspases-8 mediated apoptosis, independent of FasL stimulation in HEK 293T cells. However, the underlying molecular mechanism of FADD mediated ablation of cFLIP and NF-kappaB signaling to determining the fate of cell death or survival remains elusive. Here, we explored a novel molecular mechanism of FADD mediated apoptotic cell death that was directed by ubiquitination of cFLIPL and inhibition of NF-kappaB activation, independent of TNF-alpha stimulation. We found that induced expression of FADD firmly interacts with procaspase-8 and precludes cFLIPL to from the death inducing signaling complex (DISC). In addition, FADD negatively regulates cellular inhibitor of apoptosis protein 2 (cIAP2) and Bcl-2. Furthermore, FADD restrains cIAP2 expression and interacts with RIP1 and procaspase-8 to accomplish apoptotic cell death signaling. Interestingly, FADD was also found to promote JNK1 mediated activation of E3 ubiquitin ligase ITCH to degrade cFLIPL that may lead to commencement of apoptosis. Thus, FADD is an important regulator for determining the fate of cell death or survival. PMID- 26972598 TI - The wound/burn guidelines - 2: Guidelines for the diagnosis and treatment for pressure ulcers. AB - The Wound/Burn Guidelines Committee consists of members commissioned by the Board of Directors of the Japanese Dermatological Association (JDA). It held several meetings and evaluations in writing since October 2008, and drafted five guidelines for the diagnosis and treatment including commentaries on wounds in general and the Guidelines for the Diagnosis and Treatment for Pressure Ulcers by taking opinions of the Scientific Committee and Board of Directors of JDA into consideration. PMID- 26972600 TI - Signaling, transcriptional regulation, and asynchronous pattern formation governing plant xylem development. AB - In plants, vascular stem cells continue to give rise to all xylem and phloem cells, which constitute the plant vascular system. During plant vascular development, the peptide, tracheary element differentiation inhibitory factor (TDIF), regulates vascular stem cell fate in a non-cell-autonomous fashion. TDIF promotes vascular stem cell proliferation through up-regulating the transcription factor gene WUS-related HOMEOBOX4, and it suppresses xylem differentiation from vascular stem cells through the activation of Glycogen Synthase Kinase 3 proteins. VASCULAR-RELATED NAC-DOMAIN6 and 7 (VND6 and 7) are master transcription factors, and ectopic expression of VND6 and VND7 in various plants induces differentiation of different types of cells into metaxylem and protoxylem tracheary elements, respectively. These genes up-regulate genes involved in both patterned secondary cell wall formation and programmed cell death to form tracheary elements. Secondary wall patterns are formed by localized deposition of cellulose microfibrils, which is guided by cortical microtubules. Local activation of the small G-protein, Rho-type 11 determines distribution of cortical microtubules. PMID- 26972599 TI - Discovery of cytoglobin and its roles in physiology and pathology of hepatic stellate cells. AB - Cytoglobin (CYGB), a new member of the globin family, was discovered in 2001 as a protein associated with stellate cell activation (stellate cell activation associated protein [STAP]). Knowledge of CYGB, including its crystal, gene, and protein structures as well as its physiological and pathological importance, has increased progressively. We investigated the roles of oxygen (O2)-binding CYGB as STAP in hepatic stellate cells (HSCs) to understand the part played by this protein in their pathophysiological activities. Studies involving CYGB-gene deleted mice have led us to suppose that CYGB functions as a regulator of O2 homeostasis; when O2 homeostasis is disrupted, HSCs are activated and play a key role(s) in hepatic fibrogenesis. In this review, we discuss the rationale for this hypothesis. PMID- 26972602 TI - Evaluation of alternative sources of collagen fractions from Loligo vulgaris squid mantle. AB - Acid-Solubilized Collagen (ASC) and Pepsin-Solubilized Collagen (PSC) were extracted from the mantle of the common European squid, and were comparatively characterized. ASC and PSC were isolated with an extraction yield of 5.1 and 24.2% (on dry weight basis), respectively. SDS-PAGE showed that the ASC was mostly comprised of alpha1- and alpha2-chains; while the PSC presented relevant beta- and gamma-components. GPC analysis confirmed that both the ASC and the PSC consisted of fractions characterized by different molecular weight. Thermal denaturation behavior of ASC and PSC were followed by calorimetric and rheological analyses; denaturation temperature was estimated to be 22 degrees C for ASC and 21 degrees C for PSC. Amino acid composition and solubility of collagen were also investigated. Finally, the cytotoxicity of the isolated collagen was evaluated in vitro and no cytotoxic activity caused by the collagen extracts was observed. This study demonstrated that squid mantle has potential as an alternative source of collagen-derived materials. PMID- 26972605 TI - Using omics in chronic pain conditions to delineate mechanisms and provide new therapeutic strategies. PMID- 26972603 TI - Neural Progenitors Adopt Specific Identities by Directly Repressing All Alternative Progenitor Transcriptional Programs. AB - In the vertebrate neural tube, a morphogen-induced transcriptional network produces multiple molecularly distinct progenitor domains, each generating different neuronal subtypes. Using an in vitro differentiation system, we defined gene expression signatures of distinct progenitor populations and identified direct gene-regulatory inputs corresponding to locations of specific transcription factor binding. Combined with targeted perturbations of the network, this revealed a mechanism in which a progenitor identity is installed by active repression of the entire transcriptional programs of other neural progenitor fates. In the ventral neural tube, sonic hedgehog (Shh) signaling, together with broadly expressed transcriptional activators, concurrently activates the gene expression programs of several domains. The specific outcome is selected by repressive input provided by Shh-induced transcription factors that act as the key nodes in the network, enabling progenitors to adopt a single definitive identity from several initially permitted options. Together, the data suggest design principles relevant to many developing tissues. PMID- 26972604 TI - Using ApoE Nanolipoprotein Particles To Analyze SNARE-Induced Fusion Pores. AB - Here we introduce ApoE-based nanolipoprotein particle (NLP)-a soluble, discoidal bilayer mimetic of ~23 nm in diameter, as fusion partners to study the dynamics of fusion pores induced by SNARE proteins. Using in vitro lipid mixing and content release assays, we report that NLPs reconstituted with synaptic v-SNARE VAMP2 (vNLP) fuse with liposomes containing the cognate t-SNARE (Syntaxin1/SNAP25) partner, with the resulting fusion pore opening directly to the external buffer. Efflux of encapsulated fluorescent dextrans of different sizes show that unlike the smaller nanodiscs, these larger NLPs accommodate the expansion of the fusion pore to at least ~9 nm, and dithionite quenching of fluorescent lipid introduced in vNLP confirms that the NLP fusion pores are short lived and eventually reseal. The NLPs also have capacity to accommodate larger number of proteins and using vNLPs with defined number of VAMP2 protein, including physiologically relevant copy numbers, we find that 3-4 copies of VAMP2 (minimum 2 per face) are required to keep a nascent fusion pore open, and the SNARE proteins act cooperatively to dilate the nascent fusion pore. PMID- 26972606 TI - Combined effects of aerobic exercise and l-arginine ingestion on blood pressure in normotensive postmenopausal women: A crossover study. AB - After menopause the incidence of cardiovascular diseases increases in women. A decrease in nitric oxide (NO) bioavailability has been pointed out to play a major role in this phenomenon. Since it is believed that l-arginine administration could improve NO bioavailability, the aim of this study was to examine the effects of acute l-arginine administration associated with aerobic exercise on blood pressure (BP), redox state and inflammatory biomarkers in normotensive postmenopausal women (NPW). Sixteen volunteers (57+/-6yr) were subjected to four experimental sessions (crossover design): arginine+exercise (A E); arginine (ARG); exercise+placebo (EXE); control (CON). Each session was initiated with either 9g of l-arginine ingestion (ARG or A-E days), placebo (EXE day), or nothing (CON day). The participants performed 30min of aerobic exercise (A-E and EXE days) or sitting rest (CON and ARG days). Blood samples were collected before each session and 45min after the intervention. Office BP and ambulatory blood pressure monitoring (ABPM) were evaluated. NO/cGMP pathway, redox state and inflammatory biomarkers were measured. Systolic BP decreased during the 24-hour in A-E and EXE sessions. However, diastolic BP reduced only in A-E session. No changes were found in the biomarkers concentrations. In conclusion, the association was effective in lowering diastolic BP in NPW. Additionally, physical exercise alone promoted a long lasting effect on systolic BP measured by ABPM in this population, although this beneficial effect was not associated with changes in the cardio-inflammatory biomarkers. Possibly, other factors such as neural influences could be mediating this effect. PMID- 26972607 TI - Reversible reprotoxic effects of manganese through DAF-16 transcription factor activation and vitellogenin downregulation in Caenorhabditis elegans. AB - AIMS: Vitellogenesis is the yolk production process which provides the essential nutrients for the developing embryos. Yolk is a lipoprotein particle that presents lipids and lipid-binding proteins, referred to as vitellogenins (VIT). The Caenorhabditis elegans nematode has six genes encoding VIT lipoproteins. Several pathways are known to regulate vitellogenesis, including the DAF-16 transcription factor. Some reports have shown that heavy metals, such as manganese (Mn), impair brood size in C. elegans; however the mechanisms associated with this effect have yet to be identified. Our aim was to evaluate Mn's effects on C. elegans reproduction and better understand the pathways related to these effects. MAIN METHODS: Young adult larval stage worms were treated for 4h with Mn in 85mM NaCl and Escherichia coli OP50 medium. KEY FINDINGS: Mn reduced egg-production and egg-laying during the first 24h after the treatment, although the total number of progenies were indistinguishable from the control group levels. This delay may have occurred due to DAF-16 activation, which was noted only after the treatment and was not apparent 24h later. Moreover, the expression, protein levels and green fluorescent protein (GFP) fluorescence associated with VIT were decreased soon after Mn treatment and recovered after 24h. SIGNIFICANCE: Combined, these data suggest that the delay in egg-production is likely regulated by DAF-16 and followed by the inhibition of VIT transport activity. Further studies are needed to clarify the mechanisms associated with Mn-induced DAF-16 activation. PMID- 26972608 TI - Repeated crack healing in MAX-phase ceramics revealed by 4D in situ synchrotron X ray tomographic microscopy. AB - MAX phase materials are emerging as attractive engineering materials in applications where the material is exposed to severe thermal and mechanical conditions in an oxidative environment. The Ti2AlC MAX phase possesses attractive thermomechanical properties even beyond a temperature of 1000 K. An attractive feature of this material is its capacity for the autonomous healing of cracks when operating at high temperatures. Coupling a specialized thermomechanical setup to a synchrotron X-ray tomographic microscopy endstation at the TOMCAT beamline, we captured the temporal evolution of local crack opening and healing during multiple cracking and autonomous repair cycles at a temperature of 1500 K. For the first time, the rate and position dependence of crack repair in pristine Ti2AlC material and in previously healed cracks has been quantified. Our results demonstrate that healed cracks can have sufficient mechanical integrity to make subsequent cracks form elsewhere upon reloading after healing. PMID- 26972609 TI - Effects of steam inhalation on voice quality-related acoustic measures. AB - OBJECTIVES/HYPOTHESIS: To investigate the effects of steam inhalation using a facial steamer on voice quality-related acoustic measures. STUDY DESIGN: Prospective outcome research: single-blinded experimental study. METHODS: Forty five vocally healthy female subjects ranging in age from 18 to 30 years (Mean age: 22.41 years; standard deviation [SD]: 8.91) participated in the study. Phonation samples were recorded under three different conditions in triplicate: baseline recording, immediately after mouth breathing (dehydration), and immediately after 3 minutes of steam inhalation via the mouth (rehydration). RESULTS: In the initial voice recording (prior to dehydration), mean jitter (0.42 %; SD: 0.07), shimmer (2.20 dB; SD: 0.45), and harmonics-to-noise ratio (HNR) (21.60; SD: 2.41) values were within normal limits. After short-term mouth breathing (dehydration, approximately 10 minutes), the mean jitter (1.57 %; SD: 1.82) and shimmer (4.73 dB; SD: 1.83) were significantly increased (P < 0.05), and HNR (18.64; SD: 3.16) was reduced (P < 0.05). After steam inhalation (rehydration) for 3 minutes, mean jitter (0.48 %; SD: 0.12) and shimmer (2.70 dB; SD: 0.71) showed significant decrease (P < 0.05), and HNR (20.10; SD: 3.69) showed significant increase (P < 0.05). All parameters statistically significantly improved from post dehydration values. CONCLUSION: The simple procedure of steam inhalation using a facial steamer displayed positive effects on parameters proposed to reflect voice quality. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2305-2309, 2016. PMID- 26972610 TI - Reflection on 37 Years of EM Clinical Practice. PMID- 26972612 TI - Arctigenin reduces neuronal responses in the somatosensory cortex via the inhibition of non-NMDA glutamate receptors. AB - Lignans are biologically active phenolic compounds related to lignin, produced in different plants. Arctigenin, a dibenzylbutyrolactone-type lignan, has been used as a neuroprotective agent for the treatment of encephalitis. Previous studies of cultured rat cerebral cortical neurones raised the possibility that arctigenin inhibits kainate-induced excitotoxicity. The aims of the present study were: 1) to analyse the effect of arctigenin on normal synaptic activity in ex vivo brain slices, 2) to determine its receptor binding properties and test the effect of arctigenin on AMPA/kainate receptor activation and 3) to establish its effects on neuronal activity in vivo. Arctigenin inhibited glutamatergic transmission and reduced the evoked field responses. The inhibitory effect of arctigenin on the evoked field responses proved to be substantially dose dependent. Our results indicate that arctigenin exerts its effects under physiological conditions and not only on hyper-excited neurons. Furthermore, arctigenin can cross the blood brain barrier and in the brain it interacts with kainate sensitive ionotropic glutamate receptors. These results indicate that arctigenin is a potentially useful new pharmacological tool for the inhibition of glutamate-evoked responses in the central nervous system in vivo. PMID- 26972611 TI - Effects of Systemically Administered Hydrocortisone on the Human Immunome. AB - Corticosteroids have been used for decades to modulate inflammation therapeutically, yet there is a paucity of data on their effects in humans. We examined the changes in cellular and molecular immune system parameters, or "immunome", in healthy humans after systemic corticosteroid administration. We used multiplexed techniques to query the immunome in 20 volunteers at baseline, and after intravenous hydrocortisone (HC) administered at moderate (250 mg) and low (50 mg) doses, to provide insight into how corticosteroids exert their effects. We performed comprehensive phenotyping of 120 lymphocyte subsets by high dimensional flow cytometry, and observed a decline in circulating specific B and T cell subsets, which reached their nadir 4-8 hours after administration of HC. However, B and T cells rebounded above baseline 24 hours after HC infusion, while NK cell numbers remained stable. Whole transcriptome profiling revealed down regulation of NF-kappaB signaling, apoptosis, and cell death signaling transcripts that preceded lymphocyte population changes, with activation of NK cell and glucocorticoid receptor signaling transcripts. Our study is the first to systematically characterize the effects of corticosteroids on the human immunome, and we demonstrate that HC exerts differential effects on B and T lymphocytes and natural killer cells in humans. PMID- 26972613 TI - Brain effects of manganese exposure in mice pups during prenatal and breastfeeding periods. AB - Manganese (Mn) is a trace element essential for brain development and functioning of the central nervous system. However, there is a lack of information concerning the neurotoxicity of Mn under realistic doses in early stages of development, though excess of Mn results in a progressive disorder of the nervous system called manganism. In the current study, adult mice were exposed to three doses of Mn for 60 days through daily gavages, while mice pups were exposed to the same Mn doses during developmental period (gestational and breast-feeding). From the latter group of mice, a group was exposed for more 60 days to the same Mn doses. Chemical analysis revealed a dose-dependent bioaccumulation of Mn in mice's brain. Biochemical parameters revealed that (1) Mn affects non-protein thiol levels, glutathione S-tranferase and acetylcholinesterase activities, as well as the levels of oxidized lipids and proteins in mice brain, though lipids and proteins alterations were found only after exposure to high and unrealistic doses; (2) Realistic doses of Mn affects the activity of brain AChE and finally; (3) Pups' brain were affected by Mn even whether only the parental females had been previously exposed. The current study shows evidences of chemical stress in mice exposed to Mn during the early period of development and an efficient mechanism of Mn elimination under higher doses. These findings open new lines of investigation regarding manganese toxicity in vertebrates mainly in the early stages of development. PMID- 26972614 TI - Age-related changes in Egr1 transcription and DNA methylation within the hippocampus. AB - Aged animals show functional alterations in hippocampal neurons that lead to deficits in synaptic plasticity and changes in cognitive function. Transcription of immediate-early genes (IEGs), including Egr1, is necessary for processes such as long-term potentiation and memory consolidation. Here, we show an age-related reduction in the transcription of Egr1 in the dentate gyrus following spatial behavior, whereas in the area CA1, Egr1 is reduced at rest, but its transcription can be effectively driven by spatial behavior to levels equivalent to those observed in adult animals. One mechanism possibly contributing to these aging related changes is an age-associated, CpG site-specific change in methylation in DNA associated with the promoter region of the Egr1 gene. Our results add to a growing body of work demonstrating that complex transcriptional and epigenetic changes in the hippocampus significantly contribute to brain and cognitive aging. (c) 2016 Wiley Periodicals, Inc. PMID- 26972615 TI - Cost-Effectiveness Analysis of Percutaneous Sclerotherapy for Venous Malformations. AB - PURPOSE: To assess cost-effectiveness of sclerotherapy for venous malformations (VMs) to improve patient quality of life (QOL). MATERIALS AND METHODS: This prospective study enrolled 28 patients with symptomatic VMs who underwent sclerotherapy. EuroQol-5 Dimension (EQ-5D) and Short-Form 36 (SF-36) Health Survey were used to measure health-related QOL. Questionnaires were collected before and 1, 3, 6, and 12 months after sclerotherapy. Quality-adjusted life years (QALYs) were calculated using EQ-5D score as a measure of health utility. Medical costs obtained from the hospital accounting system and other costs of staff, drugs, materials, and angiographic equipment were calculated for each procedure. Cost-effectiveness was analyzed using incremental cost-effectiveness ratio (ICER) as the medical cost/gain of QALYs. RESULTS: Median EQ-5D scores improved from 0.768 (range, 0.705-1) to 1 (range, 0.768-1) after 6 months (P = .023) and 1 (range, 0.768-1) after 12 months (P = .063). The gain of QALYs at 12 months was 0.043. The mean medical cost was Y281,228 ($2,337). The pain group (baseline bodily pain scale of SF-36 score < 70) showed greater improvement in median EQ-5D score, from 0.705 (range, 0.661-0.768) to 0.768 (range, 0.705-1) after 6 months (P = .041) and 0.768 (range, 0.768-1) after 12 months (P = .049). ICER at 12 months was Y6,600,483 ($54,840) in the overall group and decreased to Y3,998,113 ($33,218) in the pain group, < Y6,000,000 ($49,850), threshold for acceptance of a public health benefit in Japan, even accounting for 50% increase in costs. CONCLUSIONS: Sclerotherapy was cost-effective for improving QOL for symptomatic VMs, especially for patients with moderate to severe pain. PMID- 26972620 TI - Spinal cord transection with a kitchen knife with minimal neurological injury. PMID- 26972616 TI - Waist circumference as a mediator of biological maturation effect on the motor coordination in children. AB - OBJECTIVE: The present study aimed to: 1) examine the association of biological maturation effect on children's performance at a motor coordination battery and 2) to assess whether the association between biological maturation and scores obtained in motor coordination tests is mediated by some anthropometric measurement. METHODS: The convenience sample consisted of 73 male children aged 8 years old. Anthropometric data considered the height, body mass, sitting height, waist circumference, body mass index, fat mass and fat-free mass estimates. Biological maturation was assessed by the percentage of the predicted mature stature. Motor coordination was tested by the Korperkoordinationstest fur Kinder. A partial correlation between anthropometric measurements, z-score of maturation and the motor coordination tests were performed, controlling for chronological age. Finally, causal mediation analysis was performed. RESULTS: Height, body mass, waist circumference and fat mass showed a slight to moderate inverse correlation with motor coordination. Biological maturation was significantly associated with the balance test with backward walking (r=-0.34). Total mediation of the waist circumference was identified in the association between biological maturation and balance test with backward walking (77%). CONCLUSIONS: We identified an association between biological maturation and KTK test performance in male children and also verified that there is mediation of waist circumference. It is recommended that studies be carried out with female individuals and at other age ranges. PMID- 26972621 TI - Closure of the annulus fibrosus of the intervertebral disc using a novel suture application device-in vivo porcine and ex vivo biomechanical evaluation. AB - BACKGROUND CONTEXT: Defects in the annulus fibrosus (AF) remain a challenge in the surgical treatment of lumbar disc herniations with persistent defects, allowing potential re herniation of nucleus pulposus (NP) tissue. A cervical porcine model was chosen to simulate human lumbar intervertebral disc (IVD). PURPOSE: The aim of this study was to determine the technical feasibility of closure of the AF of the IVD using a novel minimally invasive Kerrison-shaped suture application device. STUDY DESIGN: Ex vivo biomechanical and in vivo porcine device evaluations were performed. METHODS: Ex vivo biomechanical evaluation: 15 porcine spinal units were explanted and subjected to mock discectomy. The annular defect was closed using 2-0 non-absorbable (ultra-high molecular-weight polyethylene, UHMWPE) suture and Dines knot. The knot was backed up with two, three, or four throws. The spinal unit was subject to 4000 cycles of flexion/extension with 1500 N of axial load, and assessed for knot slippage. In vivo porcine device evaluation: three pigs (53-57 kg) were anesthetized and underwent a ventral surgical approach to the cervical spine. The AF of two discs was incised, and simulated partial NP discectomy was performed. The defect was closed at one level using the AnchorKnot device to apply the suture with a Dines knot and four throws. The pigs were observed for 4 weeks before euthanasia, allowing 7T magnetic resonance imaging (MRI) and histological evaluation. RESULTS: A Dines knot with four throws experienced no slippage after 4000 cycles. This configuration was tested in vivo. Clinically, the neurological examination in treated pigs was normal following surgery. Histological and MRI assessment confirmed sustained defect closure at 4 weeks. There was no reaction to the suture material and no NP extrusion at any of the sutured levels. CONCLUSIONS: This study demonstrates that it is technically feasible to perform AF defect closure in a porcine model. This novel device achieved AF defect closure that was maintained through 4 weeks in vivo. PMID- 26972623 TI - Primary intraspinal papillary meningioma: a rare aggressive variant of meningioma. PMID- 26972622 TI - Facet injection trends in the Medicare population and the impact of bundling codes. AB - BACKGROUND CONTEXT: Interventional spine procedures have seen a steady increase in utilization over the last 10 to 20 years. In 2010, the Current Procedural Terminology (CPT) codes for facet injections were bundled with image guidance (fluoroscopic or computed tomography) and limited billing to a maximum of three levels. This was done in part because of increased utilization and to ensure that procedures were done appropriately with image guidance. PURPOSE: The study aimed to evaluate if the CPT code changes correlated with a decreased utilization of facet injections. STUDY DESIGN: This is a retrospective time series study. PATIENT SAMPLE: The sample was composed of 100% Medicare Part B claims submitted for facet joint injections from 2000 to 2012, as documented in the Centers for Medicare & Medicaid Services (CMS) Physician Supplier Procedure Summary (PSPS) master files. OUTCOME MEASURES: Procedure numbers and trends were the outcome measures. METHODS: The trends of facet injections were analyzed from 2000 to 2012 using the CMS PSPS master files. The total number of lumbosacral and cervical thoracic facet injections was noted. Changes over those years were calculated with specific attention to 2010, when CPT were bundled with image guidance and injections were limited to no more than three levels. Also, to account for the growth in the Medicare population, a calculation was done of injections per 100,000 Medicare enrollees. No funding was used for this study. RESULTS: Facet injection utilization increased from 2000 to 2012, with an average growth rate of 11% per year for lumbosacral facet injections and 15% for cervical-thoracic facet injections (per 100,000 Medicare enrollees). The largest growth occurred from 2000 to 2006 (25% growth per year for lumbosacral and 32% for cervical-thoracic injections per 100,000 Medicare enrollees) and this leveled off from 2007 to 2012 (-3% growth per year for lumbosacral and -2% for cervical-thoracic injections per 100,000 Medicare enrollees). The biggest drop in these procedures was in 2010, when there was a drop of 14% for lumbosacral facet injections and 15% drop for cervical-thoracic facet injections (per 100,000 Medicare beneficiaries). CONCLUSIONS: Facet injection utilization notably increased from 2000 to 2006 but began to level off from 2007 to 2012. The most notable drop was in 2010, which correlated with the release of new CPT codes that bundled image guidance and limited procedures to three levels or less. PMID- 26972624 TI - Arteria lusoria transposition for upper anterior thoracic spine access. Why and how? Case illustration of a T2 aneurysmal bone cyst with myelopathy. PMID- 26972625 TI - The importance of clinical symptoms in radiological diagnosis of massive posttraumatic epidural hematoma. PMID- 26972626 TI - A nationwide epidemiological study of newly diagnosed spine metastasis in the adult Korean population. AB - BACKGROUND CONTEXT: Metastatic spine tumor has become clinically important because of the availability of improved diagnostic tools and increases in survival periods in cancer patients. In spite of this interest, the burden of metastatic spine tumor on the general population has not been extensively reported. PURPOSE: The aim of this 2009-2011 nationwide study of adult Koreans was to describe characteristics, medical use, and survival rate of patients with newly diagnosed metastatic spine tumors according to the primary tumor. DESIGN/SETTING: This is a retrospective cohort study. PATIENT SAMPLE: A national health insurance database was used to identify a cohort of patients with newly diagnosed metastatic spine tumors. OUTCOME MEASURES: This study aimed to analyze characteristics, medical use, and survival rate of patients with newly diagnosed metastatic spine tumors according to the primary tumor. METHODS: Data for patients with metastatic spine tumors were extracted from the Korean Health Insurance Review and Assessment Service database. Data included patient age, sex, health insurance type, comorbidities, medical cost, and hospital stay duration. Hospital stay duration and medical costs per person during 1 calendar year were evaluated. In addition, survival rates of patients with metastatic spine tumor according to primary tumor sites were evaluated. RESULTS: The incidence rate of spine metastasis increased with age, year of diagnosis, and the number of comorbidities (p<=.0001). The 6 most prevalent primary tumor sites were lung, liver and biliary tract, breast, colon, stomach, and prostate. Of patients with the 6 most prevalent primary tumors, total average annual medical costs, including inpatient and outpatient services, ranged from 12,734USD (prostate origin) to 15,556 USD (lung origin). Of patients with the 6 most prevalent primary tumors, total average annual hospital stay duration, including inpatient and outpatient services, ranged from 70.8 days (stomach origin) to 78.7 days (colon origin). Median overall survival duration in patients with metastatic spine tumor was 191 days. In addition to age, sex, and comorbidities, primary tumor sites (lung, liver and biliary tract, breast, stomach, and prostate) significantly affected survival rate. CONCLUSIONS: This nationwide study was able to depict the burden of metastatic spine tumor in Korea. The metastatic spine tumor incidence rate is highest in the group of 70- to 79-year-old men. Average annual medical costs ranged from 12,734 USD to 15,556 USD. The mean annual hospital stay duration was from 70.8 days to 78.7 days. In addition to age, sex, and comorbidities, primary tumor sites significantly affected the survival rate in patients with metastatic spine tumor. PMID- 26972627 TI - X-ray imaging using the thermoluminescent properties of commercial Al2O3 ceramic plates. AB - This research demonstrated that commercially available alumina is well-suited for use in large area X-ray detectors. We discovered a new radiation imaging device that has a high spatial resolution, high sensitivity, wide dynamic range, large imaging area, repeatable results, and low operating costs. The high thermoluminescent (TL) properties of Al2O3 ceramic plates make them useful for X ray imaging devices. PMID- 26972628 TI - A Comparative Study on the Postoperative Outcomes of Anterior Cruciate Ligament Reconstruction Using Patellar Bone-Tendon Autografts and Bone-Patellar Tendon Bone Autografts. AB - PURPOSE: To evaluate and compare the clinical outcomes of anterior cruciate ligament (ACL) reconstruction using a bone-patellar tendon-bone (BPTB) autograft and a patellar bone-tendon (PBT) autograft. METHODS: Seventy-nine patients who underwent ACL reconstruction using either a BPTB autograft or a PBT autograft were retrospectively evaluated. The minimum follow-up period was 24 months after surgery. A graft selection was determined by the patellar tendon length as measured on preoperative magnetic resonance imaging. If the patellar tendon length was longer than or equal to 45 mm, a PBT graft attached with the EndoPearl device was used. Fifty-one patients used BPTB autografts (group B) and 28 patients used PBT autografts (group P). The Lachman test, pivot-shift test, and anterior translation tested with a KT2000 arthrometer were assessed. Functional outcomes were assessed with the use of the Lysholm score, International Knee Documentation Committee subjective score, and objective grade. Anterior knee pain including kneeling pain was assessed with the use of the Shelbourne and Trumper questionnaire. RESULTS: There was no statistically significant difference between the 2 groups in the postoperative values of degree of anterior translation (P = .76), Lysholm score (P = .62), International Knee Documentation Committee subjective score (P = .91), and objective grade (P = .91). However, anterior knee pain assessed with the use of the Shelbourne and Trumper questionnaire (group B = 90 [range, 65 to 100], group P = 95 [range, 59 to 100], P = .02) and number of patients having kneeling pain (group B = 41%, group P = 18%, P = .04) differed significantly between the 2 groups. CONCLUSIONS: ACL reconstruction using a PBT autograft provided reliable knee stability comparable to a BPTB autograft but with less kneeling pain. For patients who have a long patellar tendon that may cause graft-tunnel mismatch, a PBT can be an effective alternative graft option for arthroscopic ACL reconstruction. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 26972629 TI - In Vivo Hip Morphology and Kinematics in Elite Baseball Pitchers. AB - PURPOSE: To compare passive and real-time active hip range of motion (ROM) in asymptomatic collegiate pitchers, to investigate whether differences in hip morphology and ROM exist between lead and trail hips, and to relate active hip ROM during the pitch to hip morphology and femoroacetabular impingement. METHODS: Eleven collegiate baseball pitchers participated in kinematic testing that involved throwing 4 fastball pitches while wearing a full-body inertial-based motion-capture system. Passive flexion and rotation of each hip were measured using a goniometer. Nine pitchers also underwent a computed tomography (CT) pelvic scan, from which subject-specific computer models for each hip were created. Morphologic measurements were calculated from the models, and the models were tested for impingement during simulated pitching. RESULTS: Hip flexion was the only passive ROM measurement showing a significant difference between the lead and trail hips (mean difference [MD], 4 degrees ; P = .027). During the pitching motion, within-individual differences were discovered between the lead and trail hips for flexion (MD, 34 degrees ; P < .0001), extension (MD, 26 degrees ; P < .0001), abduction (MD, 8 degrees ; P = .026), adduction (MD, 6 degrees ; P = .008), external rotation (MD, 20 degrees ; P = .001), and total arc of rotation (MD, 13 degrees ; P = .001). There were no significant differences in morphologic measures between the lead and trail hips. Dynamic CT modeling did not lead to bony impingement in any subject. CONCLUSIONS: Asymptomatic collegiate pitchers approach their extremes of passive hip rotation when executing a fastball pitch. No differences were found in passive hip ROM or morphology other than a small difference in passive hip flexion. Dynamic CT modeling did not show femoroacetabular impingement during the pitching motion. CLINICAL RELEVANCE: Hip dysmorphology or poor pitching mechanics may lead to a high risk of bony impingement because pitchers have little reserve hip motion during the fastball pitch. PMID- 26972630 TI - GDF-15, soluble ST2 and Troponin-I: Biomarkers of Subclinical Vascular Disease? PMID- 26972632 TI - Do Cardiovascular Responses to Active and Passive Coping Tasks predict Future Blood Pressure over a 10-Month Later? AB - The study examined whether cardiovascular responses to active or passive coping tasks and single or multiple tasks predicted changes in resting blood pressure (BP) over a ten-month period. Heart rate (HR), BP, cardiac output (CO), and total peripheral resistance (TPR) were measured at rest, and during mental stress tests (mental arithmetic, speech, and cold pressor tasks). A total of 104 eligible participants participated in the initial study, and 77 (74.04%) normotensive adult participants' resting BP were re-evaluated at ten-month follow-up. Regression analyses indicated that after adjustment for baseline BP, initial age, gender, body mass index, family history of cardiovascular disease, and current cigarette smoking, heighted systolic blood pressure (SBP) and HR responses to an active coping task (mental arithmetic) were associated with increased future SBP (DeltaR2 = .060, DeltaR2 = .045, respectively). Further, aggregated SBP responsivity (over the three tasks) to the predictor models resulted in significant, but smaller increases in DeltaR2 accounting for .040 of the variance of follow-up SBP. These findings suggest that cardiovascular responses to active coping tasks predict future SBP. Further, compared with single tasks, the findings revealed that SBP responses to three tasks were less predictive compared to an individual task (i.e., mental arithmetic). Of importance, hemodynamic reactivity (namely CO and TPR) did not predict future BP suggesting that more general psychophysiological processes (e.g., inflammation, platelet aggregation) may be implicated, or that BP, but not hemodynamic reactivity may be a marker of hypertension. PMID- 26972631 TI - Relations of circulating GDF-15, soluble ST2, and troponin-I concentrations with vascular function in the community: The Framingham Heart Study. AB - BACKGROUND AND AIMS: Growth differentiation factor-15 (GDF-15), soluble (s)ST2, and high-sensitivity troponin-I (hs-TnI) are associated with incident cardiovascular disease (CVD) including heart failure, yet the underlying mechanisms are not fully understood. We investigated if GDF-15, sST2, and hs-TnI are related to subclinical vascular dysfunction in the community, which may explain the relations of these biomarkers with CVD. METHODS: We evaluated 1823 Framingham Study participants (mean age 61 +/- 10 years, 54% women) who underwent routine assessment of vascular function. We related circulating GDF-15, sST2, and hs-TnI concentrations to measures of arterial stiffness (carotid-femoral pulse wave velocity, CFPWV; augmentation index; and forward pressure wave amplitude, FW), endothelial-dependent vasodilation (flow-mediated dilation, FMD), and baseline and hyperemic brachial flow velocities using linear regression adjusting for standard risk factors. RESULTS: After multivariable adjustment, GDF-15 levels were positively associated with CFPWV (0.044 [95% confidence interval 0.007 0.081] standard deviation [SD] change per SD increase in loge[GDF-15], p = 0.02) and FW (0.076 [0.026-0.126] SD change per SD increase in loge[GDF-15], p = 0.003) and inversely related to FMD (-0.051 [-0.101-0.0003] SD change per SD increase in loge[GDF-15], p = 0.048). sST2 was positively associated with CFPWV (0.032 [0.0005-0.063] SD change per SD increase in loge[sST2], p = 0.046), and hs-TnI inversely associated with hyperemic flow velocity (-0.041 [-0.082-0.0004] SD change per SD increase in loge[hs-TnI], p = 0.048). CONCLUSION: In our community based investigation, individual cardiac stress biomarkers were differentially related to select aspects of vascular function. These findings may contribute to the associations of circulating GDF-15, sST2, and hs-TnI with incident CVD and heart failure. PMID- 26972633 TI - Changes in the expression of calcitonin gene-related peptide after exposure to injurious stretch-shortening contractions. AB - One of the factors that can result in musculoskeletal injuries, and time off work, is exposure to repetitive motion. The goal of this study was to determine if skeletal muscle injury induced by exposure to injurious stretch-shortening cycles (iSSCs), resulted in hyperalgesia in the hind limb and changes in calcitonin-gene related peptide (CGRP) immunolabeling in the dorsal root ganglia (DRG) in young and old male rats. METHODS: Young (3months) and old (30months) male Fisher 344*BN F1 rats were anesthetized with isoflurane and the left hind limbs were exposed to 15 sets of 10 SSCs. Control animals were exposed to a single bout of SSCs of equal intensity. Sensitivity to mechanical stimulation was assessed using von Frey filaments prior to beginning the experiment, and on days 2 and 9 following exposure to iSSCs. Rats were euthanized one, 3 or 10days after the exposure. The ipsilateral DRG were dissected from the L4-5 region of the spine, along with the left tibialis anterior (LTA) muscle. RESULTS: Rats exposed to iSSCs were more sensitive to mechanical stimulation than control rats 2days after the exposure, and showed a reduction in peak force 3days after exposure. Changes in sensitivity to pressure were not associated with increases in CGRP labeling in the DRG at 3days. However, 9days after exposure to iSSCs, old rats still displayed an increased sensitivity to mechanical stimulation, and this hyperalgesia was associated with an increase in CGRP immunolabeling in the DRG. Young rats exposed to iSSC did not display a change in CGRP immunolabeling and sensitivity to mechanical stimulation returned to control levels at 10days. CONCLUSIONS: These findings suggest that hyperalgesia seen shortly after exposure to iSSC is not influenced by CGRP levels. However, in cases where recovery from injury may be slower, as it is in older rats, CGRP may contribute to the maintenance of hyperalgesia. PMID- 26972634 TI - Vascular risk assessment in older adults without a history of cardiovascular disease. AB - Modern cardiovascular risk prediction tools, which have their genesis in the Framingham Heart Study, have allowed more accurate risk stratification and targeting of treatments worldwide over the last seven decades. Better cardiovascular risk factor control during this time has led to a reduction in cardiovascular mortality and, at least in part, to improved life expectancy. As a result, western societies as a whole have seen a steady increase in the proportion of older persons in their populations. Unfortunately, several studies have shown that the same tools which have contributed to this increase cannot be reliably extrapolated for use in older generations. Recent work has allowed recalibration of existing models for use in older populations but these modified tools still require external validation before they can be confidently applied in clinical practice. Another complication is emerging evidence that aggressive risk factor modification in older adults, particularly more frail individuals, may actually be harmful. This review looks at currently available cardiovascular risk prediction models and the specific challenges faced with their use in older adults, followed by analysis of recent attempts at recalibration for this cohort. We discuss the issue of frailty, looking at our evolving understanding of its constituent features and various tools for its assessment. We also review work to date on the impact of frailty on cardiovascular risk modification and outline its potentially central role in determining the most sensible approach in older patients. We summarise the most promising novel markers of cardiovascular risk which may be of use in improving risk prediction in older adults in the future. These include markers of vascular compliance (such as aortic pulse wave velocity and pulse wave analysis), of endothelial function (such as flow mediated dilation, carotid intima-media thickness and coronary artery calcium scores), and also biochemical and circulating cellular markers. PMID- 26972635 TI - Traditional and pyramidal resistance training systems improve muscle quality and metabolic biomarkers in older women: A randomized crossover study. AB - The purpose of this study was to compare the effect of RT performed in a pyramid (PR) and traditional (TD) straight set training system on muscle quality and metabolic biomarkers in older women. Twenty-five physically independent older women (67.6+/-5.1years, 65.9+/-11.1kg, 154.7+/-5.8cm) performed a RT program in TD and PR training systems in a balanced crossover design. Measurements of muscle quality, serum levels of C-reactive protein (CRP), glucose (GLU), total cholesterol, high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), and triglycerides (TG) were obtained at different moments. The TD program consisted of 3 sets of 8-12 repetitions maximum (RM) with a constant weight for the 3 sets, whereas the PR training consisted of 3 sets of 12/10/8 RM with incremental weight for each set. The training was performed in 2 phases of 8weeks each, with a 12-week washout period between phases. Significant (P<0.05) improvements were observed in both groups for muscle quality (TD=+8.6% vs. PR=+6.8%), GLU (TD=-4.5% vs. PR=-1.9%), TG (TD=-18.0% vs. PR=-11.7%), HDL-C (TD=+10.6 vs. PR=+7.8%), LDL-C (TD=-23.3% vs. PR=-21.0%), and CRP (TD=-19.4% vs. PR=-14.3%) with no differences between training systems. These results suggest that RT improves muscle quality and metabolic biomarkers of older women independently of the training system. PMID- 26972636 TI - Radiation Therapy for Diffuse Large B-Cell Lymphoma: Indications, Outcomes, and Controversies. PMID- 26972637 TI - Conforming Modern Radiation Oncology Facilities to the Irregular Contours of the Vast and Varied Nation of India. PMID- 26972638 TI - Early Use of Adjuvant Breast Radiation Therapy and the Recognition of Radiation Pneumonitis. PMID- 26972639 TI - High-Dose-Rate Monotherapy for Localized Prostate Cancer-What More Will It Take to Make This a Standard Therapy? PMID- 26972640 TI - Association Between Treatment at a High-Volume Facility and Improved Survival for Radiation-Treated Men With High-Risk Prostate Cancer. AB - PURPOSE: Although the association between higher hospital volume and improved outcomes has been well-documented in surgery, there is little data about whether this effect exists for radiation-treated patients. We investigated whether treatment at a radiation facility that treats a high volume of prostate cancer patients is associated with improved survival for men with high-risk prostate cancer. METHODS AND MATERIALS: We used the National Cancer Database (NCDB) to identity patients diagnosed with prostate cancer from 2004 to 2006. The radiation case volume (RCV) of each hospital was based on its number of radiation-treated prostate cancer patients. We used propensity-score based analysis to compare the overall survival (OS) of high-risk prostate cancer patients in high versus low RCV hospitals. Primary endpoint is overall survival. Covariates adjusted for were tumor characteristics, sociodemographic factors, radiation type, and use of androgen deprivation therapy (ADT). RESULTS: A total of 19,565 radiation-treated high-risk patients were identified. Median follow-up was 81.0 months (range: 1 108 months). When RCV was coded as a continuous variable, each increment of 100 radiation-managed patients was associated with improved OS (adjusted hazard ratio [AHR]: 0.97; 95% confidence interval [CI]: 0.95-0.98; P<.0001) after adjusting for known confounders. For illustrative purposes, when RCV was dichotomized at the 80th percentile (43 patients/year), high RCV was associated with improved OS (7-year overall survival 76% vs 74%, log-rank test P=.0005; AHR: 0.91, 95% CI: 0.86-0.96, P=.0005). This association remained significant when RCV was dichotomized at 75th (37 patients/year), 90th (60 patients/year), and 95th (84 patients/year) percentiles but not the 50th (19 patients/year). CONCLUSIONS: Our results suggest that treatment at centers with higher prostate cancer radiation case volume is associated with improved OS for radiation-treated men with high risk prostate cancer. PMID- 26972641 TI - Distance to Radiation Facility and Treatment Choice in Early-Stage Breast Cancer. AB - PURPOSE: Breast-conserving therapy (BCT) is a recommended alternative to mastectomy (MT) for early-stage breast cancer. Limited access to radiation therapy (RT) may result in higher rates of MT. We assessed the association between distance to the nearest RT facility and the use of MT, in a modern cohort of women. METHODS AND MATERIALS: Women with stage 0-II breast cancer eligible for BCT diagnosed from 2004 to 2010 were identified from the Florida Cancer Data System (FCDS). Distances from patient census tracts to the nearest RT facility census tract were calculated. Multivariate logistic regression was used to identify explanatory variables that influenced MT use. RESULTS: Of the 27,489 eligible women, 32.1% (n=8841) underwent MT, and 67.8% (n=18,648) underwent BCS. Thirty-two percent of patients lived in a census tract that was >5 miles from an RT facility. MT use increased with increasing distance to RT facility (31.1% at <=5 miles, 33.8% at >5 to <15 miles, 34.9% at 15 to <40 miles, and 51% at >=40 miles, P<.001). The likelihood was that MT was independently associated with increasing distance to RT facility on multivariate analysis (P<.001). Compared to patients living <5 miles away from an RT facility, patients living 15 to <40 miles away were 1.2 times more likely to be treated with MT (odds ratio [OR]: 1.19, 95% confidence interval [CI]: 1.05-1.35, P<.01), and those living >=40 miles away were more than twice as likely to be treated with MT (OR: 2.17, 95% CI: 1.48-3.17, P<.001). However, in patients younger than 50 years (n=5179), MT use was not associated with distance to RT facility (P=.235). CONCLUSIONS: MT use in a modern cohort of women is independently associated with distance to RT facility. However, for young patients, distance to RT is not a significant explanatory variable for MT use. PMID- 26972642 TI - Modern Radiation Therapy and Cardiac Outcomes in Breast Cancer. AB - PURPOSE: Adjuvant radiation therapy, which has proven benefit against breast cancer, has historically been associated with an increased incidence of ischemic heart disease. Modern techniques have reduced this risk, but a detailed evaluation has not recently been conducted. The present study evaluated the effect of current radiation practices on ischemia-related cardiac events and procedures in a population-based study of older women with nonmetastatic breast cancer. METHODS AND MATERIALS: A total of 29,102 patients diagnosed from 2000 to 2009 were identified from the Surveillance, Epidemiology, and End Results Medicare database. Medicare claims were used to identify the radiation therapy and cardiac outcomes. Competing risk models were used to assess the effect of radiation on these outcomes. RESULTS: Patients with left-sided breast cancer had a small increase in their risk of percutaneous coronary intervention (PCI) after radiation therapy-the 10-year cumulative incidence for these patients was 5.5% (95% confidence interval [CI] 4.9%-6.2%) and 4.5% (95% CI 4.0%-5.0%) for right sided patients. This risk was limited to women with previous cardiac disease. For patients who underwent PCI, those with left-sided breast cancer had a significantly increased risk of cardiac mortality with a subdistribution hazard ratio of 2.02 (95% CI 1.23-3.34). No other outcome, including cardiac mortality for the entire cohort, showed a significant relationship with tumor laterality. CONCLUSIONS: For women with a history of cardiac disease, those with left-sided breast cancer who underwent radiation therapy had increased rates of PCI and a survival decrement if treated with PCI. The results of the present study could help cardiologists and radiation oncologists better stratify patients who need more aggressive cardioprotective techniques. PMID- 26972643 TI - Contemporary Toxicity Profile of Breast Brachytherapy Versus External Beam Radiation After Lumpectomy for Breast Cancer. AB - PURPOSE: We compared toxicities after brachytherapy versus external beam radiation therapy (EBRT) in contemporary breast cancer patients. METHODS AND MATERIALS: Using MarketScan healthcare claims, we identified 64,112 women treated from 2003 to 2012 with lumpectomy followed by radiation (brachytherapy vs EBRT). Brachytherapy was further classified by multichannel versus single-channel applicator approach. We identified the risks and predictors of 1-year infectious and noninfectious postoperative adverse events using logistic regression and temporal trends using Cochran-Armitage tests. We estimated the 5-year Kaplan Meier cumulative incidence of radiation-associated adverse events. RESULTS: A total of 4522 (7.1%) patients received brachytherapy (50.2% multichannel vs 48.7% single-channel applicator). The overall risk of infectious adverse events was higher after brachytherapy than after EBRT (odds ratio [OR] = 1.21; 95% confidence interval [CI] 1.09-1.34, P<.001). However, over time, the frequency of infectious adverse events after brachytherapy decreased, from 17.3% in 2003 to 11.6% in 2012, and was stable after EBRT at 9.7%. Beyond 2007, there were no longer excess infections with brachytherapy (P=.97). The overall risk of noninfectious adverse events was higher after brachytherapy than after EBRT (OR=2.27; 95% CI 2.09-2.47, P<.0001). Over time, the frequency of noninfectious adverse events detected increased: after multichannel brachytherapy, from 9.1% in 2004 to 18.9% in 2012 (Ptrend = .64); single-channel brachytherapy, from 12.8% to 29.8% (Ptrend<.001); and EBRT, from 6.1% to 10.3% (Ptrend<.0001). The risk was significantly higher with single-channel than with multichannel brachytherapy (hazard ratio = 1.32; 95% CI 1.03-1.69, P=.03). Of noninfectious adverse events, 70.9% were seroma. Seroma significantly increased breast pain risk (P<.0001). Patients with underlying diabetes, cardiovascular disease, and treatment with chemotherapy had increased infectious and noninfectious adverse events. The 5 year incidences of fat necrosis, breast pain, and rib fracture were slightly higher after brachytherapy than after EBRT (13.7% vs 8.1%, 19.4% vs 16.0%, and 1.6% vs 1.3%, respectively), but the risks were not significantly different for multichannel versus single-channel applicators. CONCLUSION: Toxicities after breast brachytherapy were distinct from those after EBRT. Temporal toxicity trends may reflect changing technology and evolving practitioner experience with brachytherapy. PMID- 26972644 TI - Association Between Geographic Access to Cancer Care and Receipt of Radiation Therapy for Rectal Cancer. AB - PURPOSE: Trimodality therapy (chemoradiation and surgery) is the standard of care for stage II/III rectal cancer but nearly one third of patients do not receive radiation therapy (RT). We examined the relationship between the density of radiation oncologists and the travel distance to receipt of RT. METHODS AND MATERIALS: A retrospective study based on the National Cancer Data Base identified 26,845 patients aged 18 to 80 years with stage II/III rectal cancer diagnosed from 2007 to 2010. Radiation oncologists were identified through the Physician Compare dataset. Generalized estimating equations clustering by hospital service area was used to examine the association between geographic access and receipt of RT, controlling for patient sociodemographic and clinical characteristics. RESULTS: Of the 26,845 patients, 70% received RT within 180 days of diagnosis or within 90 days of surgery. Compared with a travel distance of <12.5 miles, patients diagnosed at a reporting facility who traveled >=50 miles had a decreased likelihood of receipt of RT (50-249 miles, adjusted odds ratio 0.75, P<.001; >=250 miles, adjusted odds ratio 0.46; P=.002), all else being equal. The density level of radiation oncologists was not significantly associated with the receipt of RT. Patients who were female, nonwhite, and aged >=50 years and had comorbidities were less likely to receive RT (P<.05). Patients who were uninsured but self-paid for their medical services, initially diagnosed elsewhere but treated at a reporting facility, and resided in Midwest had an increased the likelihood of receipt of RT (P<.05). CONCLUSIONS: An increased travel burden was associated with a decreased likelihood of receiving RT for patients with stage II/III rectal cancer, all else being equal; however, radiation oncologist density was not. Further research of geographic access and establishing transportation assistance programs or lodging services for patients with an unmet need might help decrease geographic barriers and improve the quality of rectal cancer care. PMID- 26972645 TI - Changes in Liver Volume Observed Following Sorafenib and Liver Radiation Therapy. AB - PURPOSE: The purpose of this study was to quantify unexpected liver volume reductions in patients treated with sorafenib prior to and during liver radiation therapy (RT). METHODS AND MATERIALS: Fifteen patients were treated in a phase 1 study of sorafenib for 1 week, followed by concurrent sorafenib-RT (in 6 fractions). Patients had either focal cancer (treated with stereotactic body RT [SBRT]) or diffuse disease (treated with whole-liver RT). Liver volumes were contoured and recorded at planning (day 0) from the exhale CT. After 1 week of sorafenib (day 8), RT image guidance at each fraction was performed using cone beam CT (CBCT). Planning liver contours were propagated and modified on the reconstructed exhale CBCT. This was repeated in 12 patients treated with SBRT alone without sorafenib. Three subsequent patients (2 sorafenib-RT and 1 non sorafenib) were also assessed with multiphasic helical breath-hold CTs. RESULTS: Liver volume reductions on CBCT were observed in the 15 sorafenib-RT patients (median decrease of 68 cc, P=.02) between day 0 and 8; greater in the focal (P=.025) versus diffuse (P=.52) cancer stratum. Seven patients (47%) had reductions larger than the 95% intraobserver contouring error. Liver reductions were also observed from multiphasic CTs in the 2 additional sorafenib-RT patients between days 0 and 8 (decreases of 232.5 cc and 331.7 cc, respectively) and not in the non-sorafenib patient (increase of 92 cc). There were no significant changes in liver volume between planning and first RT in 12 patients with focal cancer treated with SBRT alone (median increase, 4.8 cc, P=.86). CONCLUSIONS: Liver volume reductions were observed after 7 days of sorafenib, prior to RT, most marked in patients with focal liver tumors, suggesting an effect of sorafenib on normal liver. Careful assessment of potential liver volume changes immediately prior to SBRT may be necessary in patients in sorafenib or other targeted therapies. PMID- 26972646 TI - Eastern Cooperative Oncology Group and American College of Radiology Imaging Network Randomized Phase 2 Trial of Neoadjuvant Preoperative Paclitaxel/Cisplatin/Radiation Therapy (RT) or Irinotecan/Cisplatin/RT in Esophageal Adenocarcinoma: Long-Term Outcome and Implications for Trial Design. AB - PURPOSE: Toxicity, pathologic complete response, and long-term outcomes are reported for the neoadjuvant therapies assessed in a randomized phase 2 Eastern Cooperative Oncology Group and American College of Radiology Imaging Network trial for operable esophageal adenocarcinoma, staged as II-IVa by endoscopy/ultrasonography (EUS). METHODS AND MATERIALS: A total of 86 eligible patients began treatment. For arm A, preoperative chemotherapy was cisplatin, 30 mg/m(2), and irinotecan, 50 mg/m(2), on day 1, 8, 22, 29 during 45 Gy radiation therapy (RT), 1.8 Gy per day over 5 weeks. Adjuvant therapy was cisplatin, 30 mg/m(2), and irinotecan, 65 mg/m(2) day 1, 8 every 21 days for 3 cycles. Arm B therapy was cisplatin, 30 mg/m(2), and paclitaxel, 50 mg/m(2), day 1, 8, 15, 22, 29 with RT, followed by adjuvant cisplatin, 75 mg/m(2), and paclitaxel, 175 mg/m(2), day 1 every 21 days for 3 cycles. Stratification included EUS stage and performance status. RESULTS: In arm A, median overall survival was 35 months, and 5-, 6-, and 7-year survival rates were 46%, 39%, and 35%, respectively, whereas for arm B, they were 21 months and 27%, 27%, and 23%, respectively. Median progression- or recurrence-free survival (PFS) was 39.8 months with a 3-year PFS of 50% for arm A and 12.4 months (P=.046) with 3-year PFS of 28% for arm B. Eighty percent of the observed incidents of progression occurred within 19 months. Survival did not differ significantly by EUS and performance status strata. CONCLUSIONS: Long-term survival was similar for both arms and did not appear superior to results achieved with other standard regimens. PMID- 26972647 TI - Irradiation of FDG-PET-Defined Active Bone Marrow Subregions and Acute Hematologic Toxicity in Anal Cancer Patients Undergoing Chemoradiation. AB - PURPOSE: Irradiation of pelvic bone marrow (BM) has been correlated with hematologic toxicity (HT) in patients undergoing chemoradiation for anal cancer. We hypothesized that irradiation of hematologically active bone marrow (ABM) subregions defined by fluorodeoxyglucose (FDG) positron emission tomography (PET) is a principal cause of radiation-associated HT. METHODS AND MATERIALS: The cohort included 45 patients with nonmetastatic anal cancer who underwent FDG-PET imaging prior to definitive chemoradiation with mitomycin-C and 5-fluorouracil. Total bone marrow (TBM) was defined as the external contour of the pelvic bones from the top of lumbar 5 (L5) to the bottom of the ischial tuberosity. Standardized uptake values (SUV) for all voxels within the TBM were quantified and normalized by comparison to normal liver SUV. Subvolumes of the TBM that exhibited the highest and lowest 50% of the SUVs were designated ABM50 and IBM50, respectively. The primary endpoint was the absolute neutrophil count (ANC) nadir during or within 2 weeks of completion of treatment. Multivariate linear modeling was used to analyze the correlation between the equivalent uniform doses (EUD) with an a value of 0.5, 1 (equivalent to mean dose), 3, 7, and 12 to the BM structures and the ANC. RESULTS: Mean +/- SD ANC nadir was 0.77 * 10(9)/L (+/ 0.66 * 10(9)/L). Grades 3 and 4 ANC toxicity occurred in 26.7% and 44.4% of patients, respectively. The EUD a parameter of 0.5 was optimal for all BM models indicating high radiation sensitivity. EUD of TBM and ABM50 and IBM50 were all significantly associated with ANC nadir. However, model performance for ABM50 was not superior to that of the TBM and IBM50 models. CONCLUSIONS: Irradiation of pelvic BM was associated with HT. However, FDG-PET-defined ABM models failed to improve model performance compared to the TBM model. PMID- 26972649 TI - Patterns of Recurrence in Electively Irradiated Lymph Node Regions After Definitive Accelerated Intensity Modulated Radiation Therapy for Head and Neck Squamous Cell Carcinoma. AB - PURPOSE: To provide a comprehensive risk assessment on the patterns of recurrence in electively irradiated lymph node regions after definitive radiation therapy for head and neck cancer. METHODS AND MATERIALS: Two hundred sixty-four patients with stage cT2-4N0-2M0 squamous cell carcinoma of the oropharynx, larynx, or hypopharynx treated with accelerated intensity modulated radiation therapy between 2008 and 2012 were included. On the radiation therapy planning computed tomography (CT) scans from all patients, 1166 lymph nodes (short-axis diameter >=5 mm) localized in the elective volume were identified and delineated. The exact sites of regional recurrences were reconstructed and projected on the initial radiation therapy planning CT scan by performing coregistration with diagnostic imaging of the recurrence. RESULTS: The actuarial rate of recurrence in electively irradiated lymph node regions at 2 years was 5.1% (95% confidence interval 2.4%-7.8%). Volumetric analysis showed an increased risk of recurrence with increasing nodal volume. Receiver operating characteristic analysis demonstrated that the summed long- and short-axis diameter is a good alternative for laborious volume calculations, using >=17 mm as cut-off (hazard ratio 17.8; 95% confidence interval 5.7-55.1; P<.001). CONCLUSIONS: An important risk factor was identified that can help clinicians in the pretreatment risk assessment of borderline-sized lymph nodes. Not overtly pathologic nodes with a summed diameter >=17 mm may require a higher than elective radiation therapy dose. For low-risk elective regions (all nodes <17 mm), the safety of dose de-escalation below the traditional 45 to 50 Gy should be investigated. PMID- 26972648 TI - Focal Radiation Therapy Dose Escalation Improves Overall Survival in Locally Advanced Pancreatic Cancer Patients Receiving Induction Chemotherapy and Consolidative Chemoradiation. AB - PURPOSE: To review outcomes of locally advanced pancreatic cancer (LAPC) patients treated with dose-escalated intensity modulated radiation therapy (IMRT) with curative intent. METHODS AND MATERIALS: A total of 200 patients with LAPC were treated with induction chemotherapy followed by chemoradiation between 2006 and 2014. Of these, 47 (24%) having tumors >1 cm from the luminal organs were selected for dose-escalated IMRT (biologically effective dose [BED] >70 Gy) using a simultaneous integrated boost technique, inspiration breath hold, and computed tomographic image guidance. Fractionation was optimized for coverage of gross tumor and luminal organ sparing. A 2- to 5-mm margin around the gross tumor volume was treated using a simultaneous integrated boost with a microscopic dose. Overall survival (OS), recurrence-free survival (RFS), local-regional and distant RFS, and time to local-regional and distant recurrence, calculated from start of chemoradiation, were the outcomes of interest. RESULTS: Median radiation dose was 50.4 Gy (BED = 59.47 Gy) with a concurrent capecitabine-based (86%) regimen. Patients who received BED >70 Gy had a superior OS (17.8 vs 15.0 months, P=.03), which was preserved throughout the follow-up period, with estimated OS rates at 2 years of 36% versus 19% and at 3 years of 31% versus 9% along with improved local regional RFS (10.2 vs 6.2 months, P=.05) as compared with those receiving BED <=70 Gy. Degree of gross tumor volume coverage did not seem to affect outcomes. No additional toxicity was observed in the high-dose group. Higher dose (BED) was the only predictor of improved OS on multivariate analysis. CONCLUSION: Radiation dose escalation during consolidative chemoradiation therapy after induction chemotherapy for LAPC patients improves OS and local-regional RFS. PMID- 26972650 TI - Elective Nodal Irradiation and Patterns of Failure in Head and Neck Cancer After Primary Radiation Therapy. AB - PURPOSE: The delineation of elective clinical target volumes in head and neck cancer (HNC) is important; however, the extent of lymph node levels necessary to include is debated. A comprehensive analysis of recurrence patterns in a large cohort of patients with HNC was performed, with an emphasis on recurrence in the retropharyngeal region and level IB. METHODS AND MATERIALS: From 2005 to 2012, 942 patients with oropharyngeal, hypopharyngeal, laryngeal or oral cavity carcinomas were curatively treated with primary radiation therapy. The median follow-up period was 34 months, and 77% of the patients underwent intensity modulated radiation therapy. The retropharyngeal region was only routinely included in cases of involvement of the posterior pharynx wall and level IB only in cases of involvement of the oral cavity. In patients with regional recurrence, the anatomic site of the recurrence was assessed from the surgical descriptions or computed tomography scans and compared with the original radiation treatment plan (available from 2007 onward). The p16 status was available for 282 oropharynx carcinoma cases, with 65% p16-positive. RESULTS: Of the 942 patients, 376 (40%) developed recurrences: 228 (24.2%) local, 123 (13.1%) regional, and 109 (11.6%) distant. In 700 patients with available treatment plans, retropharyngeal and level IB recurrence was observed in 2 and 7 patients, respectively. Eight patients (1.1%) had recurrence in a lymph node level not included in their primary treatment plan. For oropharynx carcinoma, the locoregional control rate (90% vs 70%) but not distant control rate (92% vs 87%), was significantly better in the p16-positive than in the p16-negative patients. Although fewer recurrences developed in the p16-positive group, patients with recurrence of p16-positive tumors were more likely to develop recurrence in distant sites. CONCLUSIONS: Retropharyngeal or level IB recurrence after primary HNC radiation therapy is rare. Thus, inclusion of these regions in the elective treatment volumes should be limited to patients with involvement of the posterior pharyngeal wall or oral cavity. PMID- 26972651 TI - Addition of Rituximab to Involved-Field Radiation Therapy Prolongs Progression free Survival in Stage I-II Follicular Lymphoma: Results of a Multicenter Study. AB - PURPOSE: Rituximab (Rit) therapy added to involved-field radiation therapy (RT) has been proposed as an effective treatment for stage I-II follicular lymphoma (FL). The results of an observational multicenter study on the Rit-RT combination in limited-stage FL are here reported. METHODS AND MATERIALS: Data have been collected from 2 consecutive cohorts of 94 patients with stage I-II FL treated between 1985 and 2011 at 5 Italian institutions. All patients had grade 1-3a FL, a median age of 54 years (range: 25-82). The first 51 patients received RT alone (control group), while the subsequent series of 43 patients received 4 rituximab courses (375 mg/m(2), days 1, 8, 15, 22) before RT (Rit-RT). Molecular disease was evaluated by nested bcl-2/IgH PCR or clonal IgH rearrangement was available in 33 Rit-RT patients. RESULTS: At a median follow-up of 10.9 years (range: 1.8 22.9), the 10-year progression-free survival (PFS) and overall survival (OS) projections for the whole cohort were 57% and 87.5%, respectively. The 10-year PFS was significantly longer (P<.05) in the Rit-RT group (64.6%) compared to RT alone (50.7%), whereas the 10-year OS projections were not significantly different. On bivariate analysis controlling for stage, there was only a trend toward improved PFS for Rit-RT (HR, 0.55; P=.081). Follicular lymphoma international prognostic index and age were associated with OS but not with PFS on Cox regression analysis. Bone marrow molecular analysis showing PCR positivity at diagnosis was strongly associated with relapse risk upon univariate and multivariate analysis. CONCLUSIONS: This multicenter observational study suggests a potential benefit of adding rituximab to radiation therapy for stage I-II FL. The results of the currently ongoing randomized studies are required to confirm these results. The study underlines the importance of molecular disease monitoring also for patient with limited-stage disease. PMID- 26972652 TI - Acute Toxicity Grade 3 and 4 After Irradiation in Children and Adolescents: Results From the IPPARCA Collaboration. AB - PURPOSE: In the context of oncologic therapy for children, radiation therapy is frequently indicated. This study identified the frequency of and reasons for the development of high-grade acute toxicity and possible sequelae. MATERIALS AND METHODS: Irradiated children have been prospectively documented since 2001 in the Registry for the Evaluation of Side Effects After Radiation in Childhood and Adolescence (RiSK) database in Germany and since 2008 in the registry for radiation therapy toxicity (RADTOX) in Sweden. Data were collected using standardized, published forms. Toxicity classification was based on Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. RESULTS: As of June 2013, 1500 children have been recruited into the RiSK database and 485 into the RADTOX registry leading to an analysis population of 1359 patients (age range 0-18). A total of 18.9% (n=257) of all investigated patients developed high-grade acute toxicity (grades 3/4). High-grade toxicity of the bone marrow was documented for 63.8% (n=201) of those patients, oral mucositis for 7.6% (n=24), and dermatitis for 7.6% (n=24). Patients with high grade acute toxicity received concomitant chemotherapy more frequently (56%) than patients with no or lower acute toxicity (31.5%). In multivariate analyses, concomitant chemotherapy, diagnosis of Ewing sarcoma, and total radiation dose showed a statistically noticeable effect (P<=.05) on acute toxicity, whereas age, concomitant chemotherapy, Hodgkin lymphoma, Ewing sarcoma, total radiation dose, and acute toxicity influenced the time until maximal late toxicity. CONCLUSIONS: Generally, high-grade acute toxicity after irradiation in children and adolescence occurs in a moderate proportion of patients (18.9%). As anticipated, the probability of acute toxicity appeared to depend on the prescribed dose as well as concomitant chemotherapy. The occurrence of chronic toxicity correlates with the prior acute toxicity grade. Age seems to influence the time until maximal late toxicity but not the development of acute toxicity. PMID- 26972654 TI - Clinical Significance of Accounting for Tissue Heterogeneity in Permanent Breast Seed Implant Brachytherapy Planning. AB - PURPOSE: The inhomogeneity correction factor (ICF) method provides heterogeneity correction for the fast calculation TG43 formalism in seed brachytherapy. This study compared ICF-corrected plans to their standard TG43 counterparts, looking at their capacity to assess inadequate coverage and/or risk of any skin toxicities for patients who received permanent breast seed implant (PBSI). METHODS AND MATERIALS: Two-month postimplant computed tomography scans and plans of 140 PBSI patients were used to calculate dose distributions by using the TG43 and the ICF methods. Multiple dose-volume histogram (DVH) parameters of clinical target volume (CTV) and skin were extracted and compared for both ICF and TG43 dose distributions. Short-term (desquamation and erythema) and long-term (telangiectasia) skin toxicity data were available on 125 and 110 of the patients, respectively, at the time of the study. The predictive value of each DVH parameter of skin was evaluated using the area under the receiver operating characteristic (ROC) curve for each toxicity endpoint. RESULTS: Dose-volume histogram parameters of CTV, calculated using the ICF method, showed an overall decrease compared to TG43, whereas those of skin showed an increase, confirming previously reported findings of the impact of heterogeneity with low-energy sources. The ICF methodology enabled us to distinguish patients for whom the CTV V100 and V90 are up to 19% lower compared to TG43, which could present a risk of recurrence not detected when heterogeneity are not accounted for. The ICF method also led to an increase in the prediction of desquamation, erythema, and telangiectasia for 91% of skin DVH parameters studied. CONCLUSIONS: The ICF methodology has the advantage of distinguishing any inadequate dose coverage of CTV due to breast heterogeneity, which can be missed by TG43. Use of ICF correction also led to an increase in prediction accuracy of skin toxicities in most cases. PMID- 26972655 TI - Automated and Semiautomated Segmentation of Rectal Tumor Volumes on Diffusion Weighted MRI: Can It Replace Manual Volumetry? AB - PURPOSE: Diffusion-weighted imaging (DWI) tumor volumetry is promising for rectal cancer response assessment, but an important drawback is that manual per-slice tumor delineation can be highly time consuming. This study investigated whether manual DWI-volumetry can be reproduced using a (semi)automated segmentation approach. METHODS AND MATERIALS: Seventy-nine patients underwent magnetic resonance imaging (MRI) that included DWI (highest b value [b1000 or b1100]) before and after chemoradiation therapy (CRT). Tumor volumes were assessed on b1000 (or b1100) DWI before and after CRT by means of (1) automated segmentation (by 2 inexperienced readers), (2) semiautomated segmentation (manual adjustment of the volumes obtained by method 1 by 2 radiologists), and (3) manual segmentation (by 2 radiologists); this last assessment served as the reference standard. Intraclass correlation coefficients (ICC) and Dice similarity indices (DSI) were calculated to evaluate agreement between different methods and observers. Measurement times (from a radiologist's perspective) were recorded for each method. RESULTS: Tumor volumes were not significantly different among the 3 methods, either before or after CRT (P=.08 to .92). ICCs compared to manual segmentation were 0.80 to 0.91 and 0.53 to 0.66 before and after CRT, respectively, for the automated segmentation and 0.91 to 0.97 and 0.61 to 0.75, respectively, for the semiautomated method. Interobserver agreement (ICC) pre and post CRT was 0.82 and 0.59 for automated segmentation, 0.91 and 0.73 for semiautomated segmentation, and 0.91 and 0.75 for manual segmentation, respectively. Mean DSI between the automated and semiautomated method were 0.83 and 0.58 pre-CRT and post-CRT, respectively; DSI between the automated and manual segmentation were 0.68 and 0.42 and 0.70 and 0.41 between the semiautomated and manual segmentation, respectively. Median measurement time for the radiologists was 0 seconds (pre- and post-CRT) for the automated method, 41 to 69 seconds (pre CRT) and 60 to 67 seconds (post-CRT) for the semiautomated method, and 180 to 296 seconds (pre-CRT) and 84 to 91 seconds (post-CRT) for the manual method. CONCLUSIONS: DWI volumetry using a semiautomated segmentation approach is promising and a potentially time-saving alternative to manual tumor delineation, particularly for primary tumor volumetry. Once further optimized, it could be a helpful tool for tumor response assessment in rectal cancer. PMID- 26972656 TI - A Comparison of Lumpectomy Cavity Delineations Between Use of Magnetic Resonance Imaging and Computed Tomography Acquired With Patient in Prone Position for Radiation Therapy Planning of Breast Cancer. AB - PURPOSE: To compare lumpectomy cavity (LC) and planning target volume (PTV) delineated with the use of magnetic resonance imaging (MRI) and computed tomography (CT) and to examine the possibility of replacing CT with MRI for radiation therapy (RT) planning for breast cancer. METHODS AND MATERIALS: MRI and CT data were acquired for 15 patients with early-stage breast cancer undergoing lumpectomy during RT simulation in prone positions, the same as their RT treatment positions. The LCs were delineated manually on both CT (LC-CT) and MRI acquired with 4 sequences: T1, T2, STIR, and DCE. Various PTVs were created by expanding a 15-mm margin from the corresponding LCs and from the union of the LCs for the 4 MRI sequences (PTV-MRI). Differences were measured in terms of cavity visualization score (CVS) and dice coefficient (DC). RESULTS: The mean CVSs for T1, T2, STIR, DCE, and CT defined LCs were 3.47, 3.47, 3.87, 3.50. and 2.60, respectively, implying that the LC is mostly visible with a STIR sequence. The mean reductions of LCs from those for CT were 22%, 43%, 36%, and 17% for T1, T2, STIR, and DCE, respectively. In 14 of 15 cases, MRI (union of T1, T2, STIR, and DCE) defined LC included extra regions that would not be visible from CT. The DCs between CT and MRI (union of T1, T2, STIR, and DCE) defined volumes were 0.65 +/- 0.20 for LCs and 0.85 +/- 0.06 for PTVs. There was no obvious difference between the volumes of PTV-MRI and PTV-CT, and the average PTV-STIR/PTV-CT volume ratio was 0.83 +/- 0.23. CONCLUSIONS: The use of MRI improves the visibility of LC in comparison with CT. The volumes of LC and PTV generated based on a MRI sequence are substantially smaller than those based on CT, and the PTV-MRI volumes, defined by the union of T1, T2, STIR, and DCE, were comparable with those of PTV CT for most of the cases studied. PMID- 26972653 TI - Radiation-Related New Primary Solid Cancers in the Childhood Cancer Survivor Study: Comparative Radiation Dose Response and Modification of Treatment Effects. AB - OBJECTIVES: The majority of childhood cancer patients now achieve long-term survival, but the treatments that cured their malignancy often put them at risk of adverse health outcomes years later. New cancers are among the most serious of these late effects. The aims of this review are to compare and contrast radiation dose-response relationships for new solid cancers in a large cohort of childhood cancer survivors and to discuss interactions among treatment and host factors. METHODS: This review is based on previously published site-specific analyses for subsequent primary cancers of the brain, breast, thyroid gland, bone and soft tissue, salivary glands, and skin among 12,268 5-year childhood cancer survivors in the Childhood Cancer Survivor Study. Analyses included tumor site-specific, individual radiation dose reconstruction based on radiation therapy records. Radiation-related second cancer risks were estimated using conditional logistic or Poisson regression models for excess relative risk (ERR). RESULTS: Linear dose response relationships over a wide range of radiation dose (0-50 Gy) were seen for all cancer sites except the thyroid gland. The steepest slopes occurred for sarcoma, meningioma, and nonmelanoma skin cancer (ERR/Gy > 1.00), with glioma and cancers of the breast and salivary glands forming a second group (ERR/Gy = 0.27 0.36). The relative risk for thyroid cancer increased up to 15-20 Gy and then decreased with increasing dose. The risk of thyroid cancer also was positively associated with chemotherapy, but the chemotherapy effect was not seen among those who also received very high doses of radiation to the thyroid. The excess risk of radiation-related breast cancer was sharply reduced among women who received 5 Gy or more to the ovaries. CONCLUSIONS: The results suggest that the effect of high-dose irradiation is consistent with a linear dose-response for most organs, but they also reveal important organ-specific and host-specific differences in susceptibility and interactions between different aspects of treatment. PMID- 26972657 TI - Bayesian Cure Rate Modeling of Local Tumor Control: Evaluation in Stereotactic Body Radiation Therapy for Pulmonary Metastases. AB - PURPOSE: Most radiobiological models for prediction of tumor control probability (TCP) do not account for the fact that many events could remain unobserved because of censoring. We therefore evaluated a set of TCP models that take into account this censoring. METHODS AND MATERIALS: We applied 2 fundamental Bayesian cure rate models to a sample of 770 pulmonary metastasis treated with stereotactic body radiation therapy at German, Austrian, and Swiss institutions: (1) the model developed by Chen, Ibrahim and Sinha (the CIS99 model); and (2) a mixture model similar to the classic model of Berkson and Gage (the BG model). In the CIS99 model the number of clonogens surviving the radiation treatment follows a Poisson distribution, whereas in the BG model only 1 dominant recurrence competent tissue mass may remain. The dose delivered to the isocenter, tumor size and location, sex, age, and pretreatment chemotherapy were used as covariates for regression. RESULTS: Mean follow-up time was 15.5 months (range: 0.1-125). Tumor recurrence occurred in 11.6% of the metastases. Delivered dose, female sex, peripheral tumor location and having received no chemotherapy before RT were associated with higher TCP in all models. Parameter estimates of the CIS99 were consistent with the classical Cox proportional hazards model. The dose required to achieve 90% tumor control after 15.5 months was 146 (range: 114-188) Gy10 in the CIS99 and 133 (range: 101-164) Gy10 in the BG model; however, the BG model predicted lower tumor control at long (?20 months) follow-up times and gave a suboptimal fit to the data compared to the CIS99 model. CONCLUSIONS: Biologically motivated cure rate models allow adding the time component into TCP modeling without being restricted to the follow-up period which is the case for the Cox model. In practice, application of such models to the clinical setting could allow for adaption of treatment doses depending on whether local control should be achieved in the short or longer term. PMID- 26972658 TI - Image Guided Radiation Therapy (IGRT) Practice Patterns and IGRT's Impact on Workflow and Treatment Planning: Results From a National Survey of American Society for Radiation Oncology Members. AB - PURPOSE: To survey image guided radiation therapy (IGRT) practice patterns, as well as IGRT's impact on clinical workflow and planning treatment volumes (PTVs). METHODS AND MATERIALS: A sample of 5979 treatment site-specific surveys was e mailed to the membership of the American Society for Radiation Oncology (ASTRO), with questions pertaining to IGRT modality/frequency, PTV expansions, method of image verification, and perceived utility/value of IGRT. On-line image verification was defined as images obtained and reviewed by the physician before treatment. Off-line image verification was defined as images obtained before treatment and then reviewed by the physician before the next treatment. RESULTS: Of 601 evaluable responses, 95% reported IGRT capabilities other than portal imaging. The majority (92%) used volumetric imaging (cone-beam CT [CBCT] or megavoltage CT), with volumetric imaging being the most commonly used modality for all sites except breast. The majority of respondents obtained daily CBCTs for head and neck intensity modulated radiation therapy (IMRT), lung 3-dimensional conformal radiation therapy or IMRT, anus or pelvis IMRT, prostate IMRT, and prostatic fossa IMRT. For all sites, on-line image verification was most frequently performed during the first few fractions only. No association was seen between IGRT frequency or CBCT utilization and clinical treatment volume to PTV expansions. Of the 208 academic radiation oncologists who reported working with residents, only 41% reported trainee involvement in IGRT verification processes. CONCLUSION: Consensus guidelines, further evidence-based approaches for PTV margin selection, and greater resident involvement are needed for standardized use of IGRT practices. PMID- 26972659 TI - In regard to Wu and Vapiwala et al. PMID- 26972660 TI - In Regard to Lewis et al. PMID- 26972661 TI - In Reply to Fiorino and Cozzarini. PMID- 26972662 TI - Gender-based differences in the relationship between fatty liver disease and atherosclerosis. AB - BACKGROUND: Carotid intima-media thickness (CIMT) is a surrogate of subclinical atherosclerosis. Fatty liver disease is also linked to increased risk of cardiovascular events. The aim of this study was to evaluate the association between fatty liver disease and CIMT according to gender. METHODS: Patients who had undergone carotid and abdominal ultrasound between June 2011 and December 2013 were retrospectively evaluated. The differences between the CIMT values measured in the common carotid artery and the prevalence of carotid plaque in patients with fatty liver disease and those with normal livers were investigated. RESULTS: Out of a total of 1 121 patients, the men had more fatty liver disease than the women. The mean CIMT of the men was significantly higher than that of the women, and the men had more plaque than the women. The women with fatty liver disease had a significantly higher mean CIMT value and more plaque than the women with normal livers. The differences between the men with fatty liver and those with normal livers in mean CIMT values and in the prevalence of plaque were not significant. In the women, multivariate analysis showed that fatty liver disease was independently associated with subclinical atherosclerosis [adjusted hazards ratio (HR) 1.65, 95% confidence interval (CI) 1.007-2.697, p = 0.047]. CONCLUSIONS: The men had more fatty liver disease, carotid plaque and higher CIMT values than the women. Fatty liver disease was a useful predictor of atherosclerosis, especially for the female study patients. PMID- 26972664 TI - Mitochondrial Dynamics Is Linked to Longevity and Protects from End-Organ Injury: The Emerging Role of Sirtuin 3. AB - SIGNIFICANCE: Mitochondrial integrity is instrumental in protecting against damage associated with aging and a variety of chronic disease conditions. Mitochondrial silent information regulator 3 (Sirt3) plays pivotal roles in maintaining mitochondrial homeostasis by regulating different aspects of the organelle processes. RECENT ADVANCES: Mitochondria are highly dynamic organelles that constantly fuse and divide to maintain normal cell function, and perturbation in mitochondrial dynamics is responsible for mitochondrial dysfunction. Improved knowledge of mitochondrial physiology has disclosed the pleiotropic role of Sirt3 in mitochondria and shows how alterations in protein expression and/or activity may have an important impact on aging-associated organ dysfunction. CRITICAL ISSUES: This review describes updated experimental evidence on the role of mitochondrial dysfunction during aging and renal diseases and highlights the emerging role of Sirt3 as a crucial regulator of mitochondrial dynamics. FUTURE DIRECTIONS: Strategies that activate Sirt3 may offer attractive therapies to achieve healthy longevity and preserve functional integrity of multiple organs. Antioxid. Redox Signal. 25, 185-199. PMID- 26972663 TI - Fungal quorum sensing molecules: Role in fungal morphogenesis and pathogenicity. AB - When microorganisms live together in high numbers, they need to communicate with each other. To achieve cell-cell communication, microorganisms secrete molecules called quorum-sensing molecules (QSMs) that control their biological activities and behaviors. Fungi secrete QSMs such as farnesol, tyrosol, phenylethanol, and tryptophol. The role of QSMs in fungi has been widely studied in both yeasts and filamentous fungi, for example in Candida albicans, C. dubliniensis, Aspergillus niger, A. nidulans, and Fusarium graminearum. QSMs impact fungal morphogenesis (yeast-to-hypha formation) and also play a role in the germination of macroconidia. QSMs cause fungal cells to initiate programmed cell death, or apoptosis, and play a role in fungal pathogenicity. Several types of QSMs are produced during stages of biofilm development to control cell population or morphology in biofilm communities. This review article emphasizes the role of fungal QSMs, especially in fungal morphogenesis, biofilm formation, and pathogenicity. Information about QSMs may lead to improved measures for controlling fungal infection. PMID- 26972665 TI - Volume profile of alpha-chymotrypsin during adsorption and enzymatic reaction on a poly(acrylic acid) brush. AB - Poly(acrylic acid) (PAA) brushes are known to provide a native-like environment for proteins. In this study, we explore this biocompatibility under high pressure conditions. Using alpha-chymotrypsin (alpha-CT) as a model enzyme, we report on the pressure dependencies of the enzymatic activity and the neutron scattering length density profile, when this enzyme is adsorbed on a PAA brush. From high pressure total internal reflection fluorescence spectroscopy, an increasing enzymatic activity has been observed up to 1000 bar, but a rather pressure independent enzymatic activity at higher pressures up to 2000 bar. This finding suggests a non-constant activation volume of alpha-CT on the PAA brush that is negative below 1000 bar. Thus, the compact nature of the transition state of alpha-CT is largely preserved upon adsorption. We have also performed high pressure neutron reflectivity experiments to determine the spatial distribution of alpha-CT inside the PAA brush. Apparently, the enzyme is strongly binding to the PAA chains with 2.3 mg m(-2) of adsorbed enzyme that is reduced to about 1.7 mg m(-2) at 1000-2000 bar. This change of adsorbed mass is consistent with a positive volume change of adsorption, which is probably reflecting electrostriction upon protein-PAA interaction. Thus, the performed high pressure experiments provide new insights into the volume profile of alpha-CT during adsorption and enzymatic activity on the PAA brush. They also demonstrate that the biocompatible properties of a PAA brush can even be enhanced by pressure. PMID- 26972666 TI - Towards deciphering proteomes via the proteoform, protein speciation, moonlighting and protein code concepts. PMID- 26972667 TI - Emodin isolated from Polygoni Multiflori Ramulus inhibits melanogenesis through the liver X receptor-mediated pathway. AB - Melanogenesis is a physiological process that results in the synthesis of melanin pigments, which play a crucial protective role against skin photocarcinogenesis. We investigated the effects of a Polygoni Multiflori Ramulus extract on melanogenesis and isolated emodin from Polygoni Multiflori as an active compound. In addition, the possible mechanisms of action were examined. We found that emodin inhibited both melanin content and tyrosinase activity concentration and time dependently. Tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2 mRNA levels decreased following emodin treatment. However, while the mRNA levels of microphthalmia-associated transcription factor (MITF) were not affected by emodin, emodin reduced MITF protein levels. Furthermore, expression of the liver X-receptor (LXR) alpha gene, but not the LXR beta gene was upregulated by emodin. Moreover, emodin regulated melanogenesis by promoting degradation of the MITF protein by upregulating the LXR alpha gene. The emodin effects on MITF was found to be mediated by phosphorylation of p42/44 MAPK. Taken together, these findings indicate that the inhibition of melanogenesis by emodin occurs through reduced MITF protein expression, which is mediated by upregulation of the LXR alpha gene and suggest that emodin may be useful as a hyperpigmentation inhibitor. PMID- 26972668 TI - An easy method for the determination of active concentrations of cholinesterase reactivators in blood samples: Application to the efficacy assessment of non quaternary reactivators compared to HI-6 and pralidoxime in VX-poisoned mice. AB - Organophosphorus nerve agents, like VX, are highly toxic due to their strong inhibition potency against acetylcholinesterase (AChE). AChE inhibited by VX can be reactivated using powerful nucleophilic molecules, most commonly oximes, which are one major component of the emergency treatment in case of nerve agent intoxication. We present here a comparative in vivo study on Swiss mice of four reactivators: HI-6, pralidoxime and two uncharged derivatives of 3-hydroxy-2 pyridinaldoxime that should more easily cross the blood-brain barrier and display a significant central nervous system activity. The reactivability kinetic profile of the oximes is established following intraperitoneal injection in healthy mice, using an original and fast enzymatic method based on the reactivation potential of oxime-containing plasma samples. HI-6 displays the highest reactivation potential whatever the conditions, followed by pralidoxime and the two non quaternary reactivators at the dose of 50 mg/kg bw. But these three last reactivators display equivalent reactivation potential at the same dose of 100 MUmol/kg bw. Maximal reactivation potential closely correlates to surviving test results of VX intoxicated mice. PMID- 26972671 TI - Arylazopyrazoles as Light-Responsive Molecular Switches in Cyclodextrin-Based Supramolecular Systems. AB - A simple and high yield synthesis of water-soluble arylazopyrazoles (AAPs) featuring superior photophysical properties is reported. The introduction of a carboxylic acid allows the diverse functionalization of AAPs. Based on structural modifications of the switching unit the photophysical properties of the AAPs could be tuned to obtain molecular switches with favorable photostationary states. Furthermore, AAPs form stable and light-responsive host-guest complexes with beta-cyclodextrin (beta-CD). Our most efficient AAP shows binding affinities comparable to azobenzenes, but more effective switching and higher thermal stability of the Z-isomer. As a proof-of-principle, we investigated two CD-based supramolecular systems, containing either cyclodextrin vesicles (CDVs) or cyclodextrin-functionalized gold nanoparticles (CDAuNPs), which revealed excellent reversible, light-responsive aggregation and dispersion behavior. To conclude, AAPs have great potential to be incorporated as molecular switches in highly demanding and multivalent photoresponsive systems. PMID- 26972672 TI - Thoracic paraspinal lesion. PMID- 26972669 TI - Chrysin, a PPAR-gamma agonist improves myocardial injury in diabetic rats through inhibiting AGE-RAGE mediated oxidative stress and inflammation. AB - AGE-RAGE interaction mediated oxidative stress and inflammation is the key mechanism involved in the pathogenesis of cardiovascular disease in diabetes. Inhibition of AGE-RAGE axis by several PPAR-gamma agonists has shown positive results in ameliorating cardio-metabolic disease conditions. Chrysin, a natural flavonoid has shown to possess PPAR-gamma agonist activity along with antioxidant and anti-inflammatory effect. Therefore, the present study was designed to evaluate the effect of chrysin in isoproterenol-induced myocardial injury in diabetic rats. In male albino Wistar rats, diabetes was induced by single injection of streptozotocin (70 mg/kg, i.p.). After confirmation of the diabetes, rats were treated with vehicle (1.5 mL/kg, p.o.), chrysin (60 mg/kg, p.o.) or PPAR-gamma antagonist GW9662 (1 mg/kg, i.p.) for 28 days. Simultaneously, on 27th and 28th day myocardial injury was induced by isoproterenol (85 mg/kg, s.c.). Chrysin significantly ameliorated cardiac dysfunction as reflected by improved MAP, +/-LVdP/dtmax and LVEDP in diabetic rats. This improvement was associated with increased PPAR-gamma expression and reduced RAGE expression in diabetic rats. Chrysin significantly decreased inflammation through inhibiting NF kappaBp65/IKK-beta expression and TNF-alpha level. Additionally, chrysin significantly reduced apoptosis as indicated by augmented Bcl-2 expression and decreased Bax and caspase-3 expressions. Furthermore, chrysin inhibited nitro oxidative stress by normalizing the alteration in 8-OHdG, GSH, TBARS, NO and CAT levels and Nox4, MnSOD, eNOS and NT expressions. Co-administration of GW9662 significantly blunted the chrysin mediated cardioprotective effect as there was increase in oxidative stress, inflammation and apoptosis markers. Chrysin significantly ameliorated isoproterenol-induced myocardial injury in diabetic rats via PPAR-gamma activation and inhibition of AGE-RAGE mediated oxidative stress and inflammation. PMID- 26972670 TI - Understanding Celiac Disease by Genomics. AB - Celiac disease (CeD) is a complex immune-mediated disease. Genetic studies have implicated 43 predisposing loci that collectively explain some 50% of the genetic variance in CeD. More than ~90% of CeD-associated single nucleotide polymorphisms (SNPs) localize to the non-coding genome, which we need to better understand to translate genetic knowledge into clinical practice. New genomic technologies and resources are permitting a systematic analysis of the functional elements in the non-coding part of the genome. Here we explain how investigating the regulatory and epigenomic landscape will help to pinpoint the cell types involved in CeD, and the driver genes and gene regulatory networks that are affected by CeD associated SNPs. PMID- 26972673 TI - Midline interhemispheric lesion. PMID- 26972676 TI - Sociometric status and the attribution of intentions in a sample of adolescents with cerebral palsy. AB - Purpose To examine how cerebral palsy (CP) and sociometric status at age 10 explain the development of a cognitive bias across two groups of adolescents aged 15. Method Children with CP (N = 60) and without CP (N = 57) are part of a follow up study. Three categories of sociometric status (popular, average, rejected) were obtained by conducting a class-wide interview in the class of the target children at age 10. At 15 years old, the same children (CP and non-CP) were asked to complete the Home Interview With Child questionnaire measuring a cognitive bias (hostile attribution of intentions (AI)). Results Children with CP, especially girls, were significantly more rejected and less popular than controls at age 10. At age 15, among all participants, sociometric rejected and popular children tended to have a higher percentage of hostile AI than sociometric average children. Conclusions There were no significant results for the combined effect of CP and sociometric status on the development of hostile AI at age 15. However, knowing the risk incurred by children with CP of being socially rejected, attention should be paid in the rehabilitation process to opportunities for social participation to facilitate the development of social competence. Implications for Rehabilitation Level I or II cerebral palsy (CP) is a condition that affects not only motor abilities but also social competence in children. Sociometric status in a group tends to affect the development of the ability to interprete intentions of others during adolescence. Sociometric measures in the class of children with CP could be a useful tool in the rehabilitation process in order to better define social participation opportunities. To improve social participation attempts, rehabilitation interventions should target social initiating skills, flexibility in interpreting peers' behaviours, and ability to react effectively to negative peer treatment. PMID- 26972678 TI - Picosecond Lifetimes with High Quantum Yields from Single-Photon-Emitting Colloidal Nanostructures at Room Temperature. AB - Minimizing the luminescence lifetime while maintaining a high emission quantum yield is paramount in optimizing the excitation cross-section, radiative decay rate, and brightness of quantum solid-state light sources, particularly at room temperature, where nonradiative processes can dominate. We demonstrate here that DNA-templated 60 and 80 nm diameter gold nanoparticle dimers, featuring one fluorescent molecule, provide single-photon emission with lifetimes that can fall below 10 ps and typical quantum yields in a 45-70% range. Since these colloidal nanostructures are obtained as a purified aqueous suspension, fluorescence spectroscopy can be performed on both fixed and freely diffusing nanostructures to quantitatively estimate the distributions of decay rate and fluorescence intensity enhancements. These data are in excellent agreement with theoretical calculations and demonstrate that millions of bright fluorescent nanostructures, with radiative lifetimes below 100 ps, can be produced in parallel. PMID- 26972679 TI - Synaptic plasticity in area CA1 of rat hippocampal slices following intraventricular application of albumin. AB - Epileptogenesis following insults to the brain may be triggered by a dysfunctional blood-brain barrier (BBB) associated with albumin extravasation and activation of astrocytes. Using ex vivo recordings from the BBB-disrupted hippocampus after neocortical photothrombotic stroke, we previously demonstrated abnormal activity-dependent accumulation of extracellular potassium with facilitated generation of seizure like events and spreading depolarizations. Similar changes could be observed after intracerebroventricular (icv) application of albumin. We hypothesized that alterations in extracellular potassium and glutamate homeostasis might lead to alterations in synaptic interactions. We therefore assessed the effects of icv albumin on homo- and heterosynaptic plasticity in hippocampal CA1, 24h after a single injection or 7days after continuous infusion of icv albumin. We demonstrate alterations in both homo- and heterosynaptic plasticity compared to control conditions in ex vivo slice studies. Albumin-treated tissue reveals (1) reduced long-term depression following low-frequency stimulation; (2) increased long-term potentiation of population spikes in response to 20Hz stimulation; (3) potentiated responses to Schaffer collateral stimulation following high-frequency stimulation of the direct cortical input and low-frequency stimulation of alveus and finally, (4) TGFbeta receptor II (TGFbetaR-II) involvement in albumin-induced homosynaptic plasticity changes. We conclude that albumin-induced network hyperexcitability is associated with abnormal homo- and heterosynaptic plasticity that could partly be reversed by interference with TGFbetaR-II-mediated signaling and therefore it might be an important factor in the process of epileptogenesis. PMID- 26972680 TI - World Kidney Day 2016: Averting the legacy of kidney disease. Focus on childhood. PMID- 26972682 TI - Application of mathematical models for bacterial inactivation curves using Hypericin-based photosensitization. AB - AIMS: The aim of this study was to evaluate which of the three mathematical models (Weibull, Geeraerd and Logistic) makes the best approximation for Hypericin-based photosensitization bacterial inactivation. METHODS AND RESULTS: The inactivation of common food-borne pathogens Listeria monocytogenes and Bacillus cereus has been analysed. Three models, Weibull, Logistic and Geeraerd, have been used for different treatment conditions (10(-7 ) mol l(-1) and 10(-8) mol l(-1) Hypericin concentrations and 2 and 60 min incubation time). The Logistic method showed better correspondence (estimated R(2) >= 0.98, RMSE <= 0.41), than the Weibull (estimated R(2) >= 0.91, RMSE <= 0.90) and the Geeraerd model (R(2) >= 0.83, RMSE <= 1.27). After evaluation of best fitting model for the dependence of bacterial population reduction on irradiation time, the parameters describing treatment efficiency have been calculated. CONCLUSIONS: Our results indicate that the Logistic model described in the best way the inactivation of B. cereus and L. monocytogenes by Hypericin-based photosensitization. SIGNIFICANCE AND IMPACT OF THE STUDY: This study identified a best model for describing bacterial inactivation by hypericin-based photosensitization, which provides a way to evaluate the efficacy of different treatment conditions for this novel decontamination technique. PMID- 26972681 TI - Cognitive Impairment and Progression of CKD. AB - BACKGROUND: Cognitive impairment is common among patients with chronic kidney disease (CKD); however, its prognostic significance is unclear. We assessed the independent association between cognitive impairment and CKD progression in adults with mild to moderate CKD. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: Adults with CKD participating in the CRIC (Chronic Renal Insufficiency Cohort) Study. Mean age of the sample was 57.7+/-11.0 years and mean estimated glomerular filtration rate (eGFR) was 45.0+/-16.9mL/min/1.73m(2). PREDICTOR: Cognitive function was assessed with the Modified Mini-Mental State Examination at study entry. A subset of participants 55 years and older underwent 5 additional cognitive tests assessing different domains. Cognitive impairment was defined as a score > 1 SD below the mean score on each test. Covariates included demographics, kidney function, comorbid conditions, and medications. OUTCOMES: Incident end-stage renal disease (ESRD) and incident ESRD or 50% decline in baseline eGFR. RESULTS: In 3,883 CRIC participants, 524 (13.5%) had cognitive impairment at baseline. During a median 6.1 years of follow-up, 813 developed ESRD and 1,062 developed ESRD or a >=50% reduction in eGFR. There was no significant association between cognitive impairment and risk for ESRD (HR, 1.07; 95% CI, 0.87-1.30) or the composite of ESRD or 50% reduction in eGFR (HR, 1.06; 95% CI, 0.89-1.27). Similarly, there was no association between cognitive impairment and the joint outcome of death, ESRD, or 50% reduction in eGFR (HR, 1.06; 95% CI, 0.91-1.23). Among CRIC participants who underwent additional cognitive testing, we found no consistent association between impairment in specific cognitive domains and risk for CKD progression in adjusted analyses. LIMITATIONS: Unmeasured potential confounders, single measure of cognition for younger participants. CONCLUSIONS: Among adults with CKD, cognitive impairment is not associated with excess risk for CKD progression after accounting for traditional risk factors. PMID- 26972684 TI - P2Y4 Nucleotide Receptor in Neuronal Precursors Induces Glutamatergic Subtype Markers in Their Descendant Neurons. AB - Neural stem cells (NSCs) produce all neuronal subtypes involved in the nervous system. The mechanism regulating their subtype selection is not fully understood. We found that the expression of the nucleotide receptor P2Y4 was transiently augmented in the course of neuronal differentiation of mouse embryonic stem cells (ESCs), which was after loss of pluripotency but prior to terminal differentiation of neurons. The activation of P2Y4 in the differentiating ESCs resulted in an increased proportion of neurons expressing vesicular glutamate transporter (vGluT), a marker of glutamatergic subtype. A subpopulation of type 2 NSCs of the adult mouse hippocampus expressed P2Y4. Its activation induced the expression of glutamatergic subtype markers, vGluT and TBR1, in their descendant neurons. Reciprocally, inhibition of the P2Y4 signaling abolished the effects of nucleotides on those expressions. Our results provide evidence that differentiating NSCs pass through a stage in which nucleotides can affect subtype marker expression of their descendant neurons. PMID- 26972685 TI - Four of the six Drosophila rhodopsin-expressing photoreceptors can mediate circadian entrainment in low light. AB - Light is the major stimulus for the synchronization of circadian clocks with day night cycles. The light-driven entrainment of the clock that controls rest activity rhythms in Drosophila relies on different photoreceptive molecules. Cryptochrome (CRY) is expressed in most brain clock neurons, whereas six different rhodopsins (RH) are present in the light-sensing organs. The compound eye includes outer photoreceptors that express RH1 and inner photoreceptors that each express one of the four rhodopsins RH3-RH6. RH6 is also expressed in the extraretinal Hofbauer-Buchner eyelet, whereas RH2 is only found in the ocelli. In low light, the synchronization of behavioral rhythms relies on either CRY or the canonical rhodopsin phototransduction pathway, which requires the phospholipase C beta encoded by norpA (no receptor potential A). We used norpA(P24) cry(02) double mutants that are circadianly blind in low light and restored NORPA function in each of the six types of photoreceptors, defined as expressing a particular rhodopsin. We first show that the NORPA pathway is less efficient than CRY for synchronizing rest-activity rhythms with delayed light-dark cycles but is important for proper phasing, whereas the two light-sensing pathways can mediate efficient adjustments to phase advances. Four of the six rhodopsin-expressing photoreceptors can mediate circadian entrainment, and all are more efficient for advancing than for delaying the behavioral clock. In contrast, neither RH5 expressing retinal photoreceptors nor RH2-expressing ocellar photoreceptors are sufficient to mediate synchronization through the NORPA pathway. Our results thus reveal different contributions of rhodopsin-expressing photoreceptors and suggest the existence of several circuits for rhodopsin-dependent circadian entrainment. J. Comp. Neurol. 524:2828-2844, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26972683 TI - Inhibition of IKK/NF-kappaB Signaling Enhances Differentiation of Mesenchymal Stromal Cells from Human Embryonic Stem Cells. AB - Embryonic stem cell-derived mesenchymal stromal cells (MSCs; also known as mesenchymal stem cells) represent a promising source for bone regenerative medicine. Despite remarkable advances in stem cell biology, the molecular mechanism regulating differentiation of human embryonic stem cells (hESCs) into MSCs remains poorly understood. Here, we report that inhibition of IkappaB kinase (IKK)/nuclear factor kappa B (NF-kappaB) signaling enhances differentiation of hESCs into MSCs by expediting the loss of pluripotent markers and increasing the expression of MSC surface markers. In addition, a significantly higher quantity of MSCs was produced from hESCs with IKK/NF-kappaB suppression. These isolated MSCs displayed evident multipotency with capacity to terminally differentiate into osteoblasts, chondrocytes, and adipocytes in vitro and to form bone in vivo. Collectively, our data provide important insights into the role of NF-kappaB in mesenchymal lineage specification during hESC differentiation, suggesting that IKK inhibitors could be utilized as an adjuvant in generating MSCs for cell mediated therapies. PMID- 26972686 TI - Laboratory life cycle of Ornithodoros brasiliensis (Acari: Argasidae): An endemic tick from southern Brazil. AB - ORNITHODOROS BRASILIENSIS: Aragao is an endemic tick restricted to the highlands of the state of Rio Grande do Sul, Brazil. This species is very aggressive toward humans, causing fever, great pain and intense inflammatory response at the bite site. It is also very aggressive toward dogs, and tick toxicosis syndrome has been reported in this host. In order to elucidate the biology of this tick, the present study describes its life cycle under laboratory conditions, using guinea pigs as hosts for two generations. In the nonparasitic phase, the ticks were maintained in sand, in an incubator under controlled conditions. The larvae molted to the nymphal stage without feeding, and five nymphal stages (N1, N2, N3, N4 and N5) were observed in both generations. In both generations emergence of adults started from N3 when sex ratio was 0.85:1 (23 males and 27 females) in F1 and 0.63:1 (34 males and 54 females) in F2. For both generations, N4 generated more females, while N5 only produced females. The pre-ecdysis period of the nymphs ranged from 31.1 to 38.6 days. Two gonotrophic cycles were observed, and the first one presented a higher average number of eggs deposited (N=139) than the second (N=73.8). The mean duration of the life cycle (egg to egg) of O. brasiliensis was 215.4 days for the first generation and 195 days for the second. PMID- 26972688 TI - Effect of saline inhalation on vocal fold epithelial morphology evaluated by optical coherence tomography. AB - OBJECTIVES/HYPOTHESIS: Examination of tissue structures by optical coherence tomography (OCT) has been shown to be useful on mucous membranes of the vocal folds, but so far its application to the human larynx has been limited because it is technically cumbersome and usually needs to be performed with sedation. Here a newly developed, noninvasive combined laryngoscopy and OCT procedure is described and its suitability for ambulatory OCT studies evaluated. Because inhalation therapies utilizing saline solutions are commonly used as a treatment option for disorders of the airways, and vocal fold epithelium is most likely to be affected due to its superficial positioning, epithelial thickness was chosen as a relevant test parameter and evaluated before and after saline inhalation. METHODS: Seven vocally healthy participants performed a 10-minute inhalation of saline solution and underwent a combined laryngoscopy and OCT before and after the inhalation therapy. Endoscopy was performed using a newly developed combined laryngoscopy and OCT device. The OCT images were used to estimate the epithelial thickness of the vocal folds. RESULTS: Epithelial thickness measured in all participants before treatment was comparable in size reported in previous studies. Statistical differences before and after inhalation were not detected. CONCLUSION: The newly developed combined laryngoscopy and OCT procedure enables rapid investigation of the vocal fold epithelium. Inhalation of saline solution did not appear to affect the thickness of the epithelium of the vocal folds in vocally healthy subjects, as evaluated by OCT. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:E332-E336, 2016. PMID- 26972687 TI - The biology of Theileria parva and control of East Coast fever - Current status and future trends. AB - Tremendous progress has been made over the last ten years on East Coast fever (ECF) research. Publication of a reference genome sequence of Theileria parva, the causative agent of ECF, has led to a more thorough characterization of the genotypic and antigenic diversity of the pathogen. It also facilitated identification of antigens that are targets of bovine major histocompatibility complex class I restricted cytotoxic T-lymphocytes (CTLs), induced by a live parasite-based infection and treatment method (ITM) vaccine. This has led to improved knowledge of epitope-specific T-cell responses to ITM that most likely contribute to the phenomenon of strain-specific immunity. The Muguga cocktail ITM vaccine, which provides broad-spectrum immunity to ECF is now a registered product in three countries in eastern Africa. Effort is directed at improving and scaling up the production process to make this vaccine more widely available on a commercial basis in the region. Meanwhile, research to develop a subunit vaccine based on parasite neutralizing antibodies and CTLs has been revived through convening of a research consortium to develop proof-of-concept for a next generation vaccine. Many new scientific and technical advances are facilitating this objective. Hence, the next decade promises even more progress toward an improved control of ECF. PMID- 26972689 TI - Effectiveness and safety of omalizumab in chronic spontaneous or inducible urticaria: evaluation of 154 patients. PMID- 26972690 TI - Differences in self-monitored, blood glucose test strip utilization by therapy for type 2 diabetes mellitus. AB - AIMS: To determine whether blood glucose test strip (BGTS) utilization in patients with type 2 diabetes (T2D) is associated with the type of diabetes therapy, classified according to hypoglycemic risk. METHODS: A retrospective, longitudinal (2006-2012) study of Canadian private drug plans (PDP) and Ontario Public Drug Programs (OPDP) prescription claims was conducted. Analyses were restricted to patients with T2D with or without a claim for BGTS. Daily BGTS utilization (TS/patient/day) was evaluated by diabetes therapy classified by hypoglycemic risk. Multivariate analyses were conducted to identify determinants of BGTS utilization. RESULTS: The T2D cohort comprised 5,759,591 observations from 1,949,129 claimants. Mean BGTS utilization was 0.84 TS/patient/day and differed between PDP and OPDP (0.66 vs. 1.00). Daily utilization was greatest in patients receiving therapy associated with a pre-defined high risk of hypoglycemia [insulin: basal + bolus (2.16), premixed (1.65), basal (1.16), other insulin regimens (2.13), and sulfonylureas (0.74)] versus non-sulfonylurea non insulin-based regimens (0.52). For non-insulin therapy, BGTS utilization was greater for patients on multiple non-insulin therapies versus monotherapy (0.74 vs. 0.53 TS/patient/day). In multivariate analyses, drivers for BGTS utilization included insulin use, previous BGTS use, and female gender. Previous diabetes therapy and duration of therapy were negatively correlated with BGTS utilization. CONCLUSIONS: BGTS utilization varies depending on the type of therapy used to treat T2D according to hypoglycemic risk. Decision making regarding BGTS needs to account for robust analyses of current utilization and its value in those settings, including in patients not receiving diabetes therapy and the prevalence of circumstances conducive to more intensive monitoring. PMID- 26972691 TI - Carboxylated nanodiamonds inhibit gamma-irradiation damage of human red blood cells. AB - Nanodiamonds when carboxylated (cNDs) act as reducing agents and hence could limit oxidative damage in biological systems. Gamma (gamma)-irradiation of whole blood or its components is required in immunocompetent patients to prevent transfusion-associated graft versus host disease (TA-GVHD). However, gamma irradiation of blood also deoxygenates red blood cells (RBCs) and induces oxidative damage, including abnormalities in cellular membranes and hemolysis. Using atomic force microscopy (AFM) and Raman spectroscopy, we examined the effect of cNDs on gamma-irradiation mediated deoxygenation and morphological damage of RBCs. gamma-Radiation induced several morphological phenotypes, including stomatocytes, codocytes and echinocytes. While stomatocytes and codocytes are reversibly damaged RBCs, echinocytes are irreversibly damaged. AFM images show significantly fewer echinocytes among cND-treated gamma-irradiated RBCs. The Raman spectra of gamma-irradiated RBCs had more oxygenated hemoglobin patterns when cND-treated, resembling those of normal, non-irradiated RBCs, compared to the non-cND-treated RBCs. cND inhibited hemoglobin deoxygenation and morphological damage, possibly by neutralizing the free radicals generated during gamma-irradiation. Thus cNDs have the therapeutic potential to preserve the quality of stored blood following gamma-irradiation. PMID- 26972692 TI - Detection of a G>C single nucleotide polymorphism within a repetitive DNA sequence by high-resolution DNA melting. AB - In standard forensic DNA analysis, single base mutations within short tandem repeats (STR) mostly escape detection. In this study, high-resolution DNA melting (HRM) is compared to minisequencing and Sanger sequencing as to determine the most suitable method for detection of a G to C mutation within a repetitive DNA sequence, the STR system DXS10161. It shows an ATG/ATC polymorphism surrounded by a variable number of (TATC) and (ATCT) motifs. Neutral base changes like G:C to C:G result in very low differences in the melting temperature (T m) of the PCR amplicons. By enhanced resolution of fluorescence vs. temperature in HRM, the technique showed to be suitable for detecting a G to C transversion in this repetitive DNA sequence context. Compared to minisequencing, HRM is more time- and cost-effective. Results were confirmed by Sanger sequencing. PMID- 26972693 TI - Decreased mRNA levels of cardiac Cx43 and ZO1 in sudden cardiac death related to coronary atherosclerosis: a pilot study. AB - Sudden cardiac death (SCD) is the most frequent cause of sudden unexplained death in forensic practice. The most common cause of SCD is coronary artery disease related to coronary atherosclerosis. Previous study suggested the possible application of connexin 43 (Cx43) and zonula occludens-1 (ZO1) immunostaining in the early diagnosis of myocardial ischemia. However, there appears to be insufficient data with regard to their mRNA levels. The present study investigated the cardiac mRNA levels of Cx43 and ZO1, using forensic autopsy materials consisting of 41 control cases without any disease or structural abnormality of the heart (group 1), 32 deaths due to acute ischemic heart disease related to coronary atherosclerosis without apparent myocardial necrosis (group 2), and 29 traumatic deaths with coronary atherosclerosis (group 3). Ten candidate reference genes were evaluated in the left ventricles of 10 forensic autopsy cases. EEF1A1, PPIA, TPT1, and RPL13A were identified as the most stable reference genes. Using these validated reference genes, mRNA levels of Cx43 and ZO1 were examined in the bilateral ventricles and atria of the heart. Relative mRNA quantification demonstrated decreased calibrated normalized relative quantity (CNRQ) values of Cx43 and ZO1 in bilateral ventricles of group 2. When using one conventional reference gene (GAPDH or ACTB) for normalization, nearly no difference was detected among the three groups. These findings indicate that ventricular gap junction remodeling may be a key contributor to rhythm disturbances. Analysis of cardiac Cx43 and ZO1 using real-time PCR is useful in diagnosis of SCD, and validation of reference genes is crucial. PMID- 26972695 TI - Exploring the non-linear association between BMI and mortality in adults with and without diabetes: the US National Health Interview Survey. AB - AIMS: To assess the non-linear relationship between BMI and mortality and to determine the BMI values with the lowest mortality risk in adults with and without diabetes. METHODS: This observational study assessed the relationship between BMI and mortality with flexible parametric survival models using data from the US National Health Interview Survey. Participants included 25 458 adults with diabetes and 315 939 adults without diabetes, aged 18-84 years at baseline surveys, conducted from 1997 to 2009. Mortality status data were obtained from the linked mortality data up to 2011. RESULTS: We observed a U-shaped relationship between BMI and mortality in both adults with and without diabetes. With the BMI 25-29.9 kg/m2 group as reference, hazard ratios (95% CI) of mortality for those with BMI < 18.5, 18.5-24.9, 30-34.9, 35-39.9 and >= 40 kg/m2 were 2.67 (2.12, 3.35), 1.26 (1.18, 1.35), 1.04 (0.98, 1.12), 1.12 (1.02, 1.22) and 1.37 (1.24, 1.51), respectively, for adults with diabetes, adjusting for age, sex, race and survey year. The corresponding hazard ratios for adults without diabetes were 2.97 (2.78, 3.17), 1.27 (1.23, 1.30), 1.07 (1.03, 1.12), 1.36 (1.27, 1.45), and 1.77 (1.62, 1.92), respectively. The BMI values associated with the lowest mortality were 29.1 kg/m2 for adults with diabetes and 26.7 kg/m2 for those without diabetes. CONCLUSIONS: Regardless of the presence of diabetes, there is a U-shaped relationship between BMI and mortality. The BMI values associated with the lowest mortality were above the current 'normal' range for adults with and without diabetes. PMID- 26972694 TI - Third molar maturity index (I3M) for assessing age of majority in a black African population in Botswana. AB - Assessment of legal age, also known as age of majority, is a controversial issue as there are few body biomarkers or evidence during late adolescence differentiating a subject from being a minor or adult. The third molar was recognized as a suitable site for age examination in late adolescence. We analyzed the development of the left mandibular third molar by the third molar maturity index (I3M) and a specific cut-off value of I3M = 0.08, established by Cameriere et al. in 2008 and used it for discriminating between minors and adult black Africans from Gaborone, Botswana. A final sample of panoramic radiographs (OPTs) of 1294 people (582 males and 712 females) aged between 13 and 23 years was evaluated. The real age decreased as I3M gradually increased. There was no statistically significant difference in the third molar development evaluated using I3M between males and females (p > 0.05) across different I3M classes. Results of 2 * 2 contingency tables for different cut-off values indicated that I3M = 0.08 was useful in discriminating between adults and minors. Precisely, for I3M = 0.08, the values of accuracy or overall fraction of correctly classified were 0.91 in males with a 95 % confidence interval (95 % CI) of 0.88 to 0.93 and 0.92 (95 % CI, 0.90 to 0.93) in females. Values of sensitivity of the test or the proportion of participants being 18 years and older were 0.88 (95 % CI, 0.87 to 0.90) in males and 0.88 (95 % CI, 0.90 to 0.93) in females, while values of specificity or proportion of individuals younger than 18 who have I3M <0.08 were 0.94 (95 % CI, 0.91 to 0.96) in males and 0.96 (95 % CI, 0.94 to 0.98) in females. Positive predictive values of the test, where the participants whose I3M <0.08 were adults, were 0.94 (95 % CI 0.91 to 0.96) in males and 0.97 (95 % CI, 0.94 to 0.98) in females, while negative predictive values of the test, where the participants whose I3M was >=0.08 were minors, were 0.88 (95 % CI 0.85 to 0.90) in males and 0.97 (95 % CI, 0.94 to 0.98) in females. The likelihood ratios of the positive test (LR+) were 13.67 (95 % CI, 9.21 to 21.02) in males and 23.73 (95 % CI, 14.20 to 42.28) in females, while likelihood ratios of the negative test (LR-) were 0.12 (95 % CI 0.10 to 0.16) in males and 0.12 (95 % CI, 0.11 to 0.15) in females. Bayes post-test probabilities, p, were 0.94 (95 % CI 0.90 to 0.98) in males and 0.97 (95 %CI, 0.93 to 1.00) in females. These results indicate with high accuracy that I3M may be a useful alternative method in legal and forensic practice to discriminate individuals of black African origin who are around the legal adult age of 18 years in Botswana. Further studies should address the usefulness of this method and specific cut-off for different adolescent populations. PMID- 26972696 TI - The association between legal Japanese visual impairment grades and vision related quality of life. AB - PURPOSE: This study examines the relationship between quality of life (QOL) and the legal Japanese grade of visual impairment as defined by the Physically Disabled Persons Welfare Act. METHODS: Participants of this cross-sectional study were 98 Japanese patients legally classified as visually impaired, from six ophthalmology departments. Vision-related QOL was evaluated using the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25). The short Japanese version of this questionnaire (VFQ-J11) score was calculated from the VFQ-25 results for each participant. Health utility was measured using the EuroQoL Index (EQ-5D). Data were collected for age, gender, vision-disability level, the corrected visual acuity of each eye, and disease type. RESULTS: The mean age was 66.8 years (SD = 17.8). Visual impairment grade was significantly associated with VFQ-J11 score and the composite score developed from the VFQ-25 (p < 0.001), but not with the health utility score obtained from the EQ-5D. CONCLUSIONS: In general, the Japanese legally designated grading system for visual impairment reflects the degree of vision-related QOL, but does not reflect general health utility as determined by the EQ-5D. PMID- 26972697 TI - Hypoxia-induced nitric oxide production and tumour perfusion is inhibited by pegylated arginine deiminase (ADI-PEG20). AB - The hypoxic tumour microenvironment represents an aggressive, therapy-resistant compartment. As arginine is required for specific hypoxia-induced processes, we hypothesised that arginine-deprivation therapy may be useful in targeting hypoxic cancer cells. We explored the effects of the arginine-degrading agent ADI-PEG20 on hypoxia-inducible factor (HIF) activation, the hypoxia-induced nitric oxide (NO) pathway and proliferation using HCT116 and UMUC3 cells and xenografts. The latter lack argininosuccinate synthetase (ASS1) making them auxotrophic for arginine. In HCT116 cells, ADI-PEG20 inhibited hypoxic-activation of HIF-1alpha and HIF-2alpha, leading to decreased inducible-nitric oxide synthase (iNOS), NO production, and VEGF. Interestingly, combining hypoxia and ADI-PEG20 synergistically inhibited ASS1. ADI-PEG20 inhibited mTORC1 and activated the unfolded protein response providing a mechanism for inhibition of HIF and ASS1. ADI-PEG20 inhibited tumour growth, impaired hypoxia-associated NO-production, and decreased vascular perfusion. Expression of HIF-1alpha/HIF-2alpha/iNOS and VEGF were reduced, despite an increased hypoxic tumour fraction. Similar effects were observed in UMUC3 xenografts. In summary, ADI-PEG20 inhibits HIF-activated processes in two tumour models with widely different arginine biology. Thus, ADI PEG20 may be useful in the clinic to target therapy-resistant hypoxic cells in ASS1-proficient tumours and ASS1-deficient tumours. PMID- 26972698 TI - Potential health risks posed by polycyclic aromatic hydrocarbons in muscle tissues of fishes from the Athabasca and Slave Rivers, Canada. AB - Polycyclic aromatic hydrocarbons (PAHs) are released to the environment from oil sands operations and from natural sources in Alberta, Canada. Concentrations of 16 USEPA priority PAHs were measured in tissues of fishes collected from three locations on the Athabasca River in Alberta and two downstream locations on the Slave River in the Northwest Territories, Canada. A total of 425 individual fish were collected including 89 goldeye (Hiodon alosoides), 93 whitefish (Coregonus clupeaformis), 104 northern pike/jackfish (Esox lucius), 96 walleye (Sander vitreus) and 43 burbot/loche mariah/mariah (Lota lota). Fish were sampled during the summer and fall of 2011 and spring of 2012. Dorsal muscle of fishes from upstream reaches of the Athabasca River, close to oil sands extraction and upgrading activities, contained greater concentrations of individual PAHs than concentrations in muscle of fishes from further downstream in the Slave River. Concentrations of the sum of USEPA indicator PAHs (?PAHs) in fishes collected in the vicinity of Fort McKay, closest to oil sands activities, varied among seasons with average concentrations ranging from 11 (burbot, summer) to 1.2 * 102 ng/g, wm (burbot, spring) with a mean of 48 ng/g, wm. Concentrations of ?PAHs in fishes collected in the vicinity of Fort Resolution, the location most distant from oil sands activities, also varied among species and seasons, with average concentrations ranging from 4.3 (whitefish, summer) to 33 ng/g, wm (goldeye, summer) with a mean of 13 ng/g, wm. Significant differences in concentrations of ?PAHs in muscle were observed within goldeye, jackfish, walleye and whitefish among sites. Health risks posed by PAHs to humans were assessed probabilistically using a B[a]P equivalents approach (B[a]Peq). The average lifetime risk of additional cancers for humans who consumed fish was deemed to be within an 'acceptable' range of risk (i.e., less than 10-6). PMID- 26972700 TI - Characterizing the Effects of Race/Ethnicity on Acetaminophen Pharmacokinetics Using Physiologically Based Pharmacokinetic Modeling. AB - BACKGROUND AND OBJECTIVES: Acetaminophen (APAP, paracetamol) is currently the principal cause of acute liver failure in both the USA and the UK. However, relatively little is known about the influence of genes and race/ethnicity on the disposition of APAP and the extent to which genetic variation and ethnicity may predispose individuals to a higher risk of APAP-induced hepatotoxicity. The objective of this research was to develop subpopulation-specific physiologically based pharmacokinetic (PBPK) models for two genetically different groups (Western Europeans and East Asians) and then use the models to quantify the difference in absorption, distribution, metabolism, and excretion (ADME) of APAP between these groups. METHODS: A comprehensive set of human pharmacokinetic data mined from the literature was divided into two groups based on ethnicity as an indicator of the expected abundance of phenol-metabolizing alleles. Using these datasets and a Bayesian hierarchical framework, subpopulation-specific physiologically based pharmacokinetic models for APAP were developed and tested for the two groups. RESULTS: Model simulations were in good agreement with experimental data for both time-dependent parent and metabolite concentrations and summary pharmacokinetic parameters. In addition, simulations were conducted to characterize the difference between ADME in these groups with regard to urinary excretion and APAP area under the curve (AUC) in the liver. Although not dramatic at therapeutic dosing levels, these results demonstrated the divergence in the liver-specific APAP concentrations and AUC between the two groups and suggested that differences in glucuronidation capacity may play a role in this disparity. CONCLUSIONS: Overall, the models developed in this study, and others created using this type of hierarchical methodology, are expected to be useful in quantifying ADME in a subpopulation-specific manner and reducing prediction uncertainty compared to that from generalized PBPK modeling approaches. PMID- 26972699 TI - Post-concussive syndrome after mild head trauma: epidemiological features in Tunisia. AB - BACKGROUND: Minor head injury is one of the major diagnoses requiring management in emergency departments (ED) but its squeals are not well studied in our country. OBJECTIVE: To describe the prevalence of post-concussive syndrome and its impacts on life activities, up to 6 months of follow-up, among patients having a minor head injury and discharged from ED. METHODS: A prospective bi centric study including adults having a minor head trauma and consenting to be followed up to 6 months after discharge. The Rivermead Post-Concussion Symptoms Questionnaire (RPQ) was used at baseline, after 15 days, at 1 month, at 3 months and at 6 months post-injury to assess concussive symptoms. We also used the Rivermead Head Injury Follow-up Questionnaire (RHFUQ) to describe impacts of minor head trauma on life activities. RESULTS: There were 130 consenting patients at baseline interview. Proportion of patients describing post-concussive symptoms at baseline was 71/130. At 6 months of follow-up, post-concussive syndrome was diagnosed among 21.4 % of participants. Sustaining symptoms at 6 months post injury were mainly anger and irritability (12.5 %). Correlations between high RPQ sum rates since 15 days' post-injury call and the sum total rates of RHFUQ were significant. The major significant impact of minor head trauma at 6 months of follow-up was among domestic activities. CONCLUSION: The two most important findings of this study were the huge proportion of patients having minor head injury and discharged from ED without any explanation of possible symptoms after head trauma and the unknown impacts on life activities. PMID- 26972702 TI - Biosynthesis of LL-Z1272beta: Discovery of a New Member of NRPS-like Enzymes for Aryl-Aldehyde Formation. AB - LL-Z1272beta (1) is a prenylated aryl-aldehyde produced by several fungi; it also serves as a key pathway intermediate for many fungal meroterpenoids. Despite its importance in the biosynthesis of natural products, the molecular basis for the biosynthesis of 1 has yet to be elucidated. Here we identified the biosynthetic gene cluster for 1 from Stachybotrys bisbyi PYH05-7, and elucidated the biosynthetic route to 1. The biosynthesis involves a polyketide synthase, a prenyltransferase, and a nonribosomal peptide synthetase (NRPS)-like enzyme, which is responsible for the generation of the aldehyde functionality. Interestingly, the NRPS-like enzyme only accepts the farnesylated substrate to catalyze the carboxylate reduction; this represents a new example of a substrate for adenylation domains. PMID- 26972701 TI - Higher TSH can be used as an additional risk factor in prediction of malignancy in euthyroid thyroid nodules evaluated by cytology based on Bethesda system. AB - Recently, it has been suggested that thyrotropin (TSH) concentration can be used as a marker for prediction of thyroid malignancy. In this study, we aimed to investigate the association between TSH levels and prediction of malignancy in euthyroid patients with different Bethesda categories. The data of 1433 euthyroid patients with 3206 thyroid nodules who underwent thyroidectomy were screened retrospectively. The preoperative cytology results, thyroid function tests, thyroid autoantibodies, and presence of histopathological Hashimoto's thyroiditis (HT) were recorded. Of the 1433 patients, 585 (40.8 %) had malignant and 848 (59.2 %) had benign histopathology. Malignant group had smaller nodule size, elevated TSH levels, and higher rate of presence of HT compared to benign group (p < 0.001, all). Cytology results of 3206 nodules were as follows: 832 nondiagnostic (ND), 1666 benign, 392 atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 68 follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), 133 suspicious for malignancy (SM), and 115 malignant. Both SM and malignant cytology groups had higher TSH levels than other 4 Bethesda categories (p < 0.05, all). Benign cytology group had significantly lower TSH levels compared to other cytology groups (p < 0.05, all). Patients with malignant final histopathology in ND and AUS/FLUS cytology groups had significantly higher TSH levels compared to patients with benign final histopathology (p < 0.05, all). Moreover, TSH levels showed to increase from Bethesda categories II to VI. In addition to cytology, higher TSH levels can be used as a supplementary marker in prediction of malignancy in certain Bethesda categories. PMID- 26972704 TI - Leptomeningeal carcinomatosis as primary manifestation of pancreatic cancer. AB - Leptomeningeal carcinomatosis (LMC) is a rare complication of cancer that often presents at an advanced stage after obvious metastasis of a primary cancer or locally advanced disease. We present an uncommon case of LMC secondary to pancreatic carcinoma presenting with headache, unilateral VII nerve palsy, and lower extremity weakness. Initial cerebrospinal fluid (CSF) studies were concerning for chronic aseptic meningitis but negative for malignant cells; the diagnosis of tuberculous meningitis was erroneously evoked. Three lumbar punctures were required to capture malignant cells. The diagnosis of LMC was based on CSF examination with cytology/immunohistochemistry and leptomeningeal enhancement on MRI. Post mortem autopsy revealed advanced and diffusely metastatic pancreatic adenocarcinoma. This patient demonstrates that solid tumors can present with leptomeningeal spread that often confuses the treating physician. Fungal or tuberculous meningitis can mimic LMC in the absence of neoplastic signs and negative CSF cytology. This event is exceedingly rare in pancreatic cancer. If the index of suspicion is high, repeat CSF sampling can increase the sensitivity of detection of malignant cells and thus result in the correct diagnosis. PMID- 26972705 TI - Intracerebral hemorrhage with intraventricular extension and no hydrocephalus may not increase mortality or severe disability. AB - This paper aimed to test the hypothesis that intraventricular extension of spontaneous intracerebral hemorrhage (ICH) in the absence of hydrocephalus is not associated with increased mortality or severe disability. We performed a retrospective consecutive cohort study of patients with primary spontaneous ICH who were admitted to a single institution. Multivariate logistic regression analysis was used to assess the association of each variable with functional outcome as measured by the modified Rankin Scale (mRS). A total of 164 patients met our inclusion criteria and were included in the study. Only hydrocephalus (p=0.002) and hematoma volume (p=0.006) were significantly associated with mortality or poor functional outcome (mRS of 3 to 6). In contrast, the presence of intraventricular hematoma was not independently associated with poor functional outcome. The presence of intraventricular extension of ICH in the absence of hydrocephalus may not increase mortality or disability. PMID- 26972703 TI - Development of a population pharmacokinetic-pharmacodynamic model of a single bolus dose of unfractionated heparin in paediatric patients. AB - BACKGROUND: Unfractionated heparin (UFH) is the anticoagulant of choice in paediatric patients undergoing a variety of cardiac procedures. There are currently no population pharmacokinetic-pharmacodynamic (PKPD) models for UFH in paediatrics. OBJECTIVE: The aim of the present study was to develop and evaluate a PKPD model of UFH in paediatrics. METHODS: Data from 64 children who received 75-100 IU kg(-1) of UFH during cardiac angiography were analysed. Five blood samples were collected at baseline and at 15, 30, 45 and 120 min postdose. The UFH concentration was quantified using a protamine titration assay. The UFH effect was quantified using activated partial thromboplastin time (aPTT). A PKPD model was fitted using nonlinear mixed-effects modelling. Patient covariates such as gender, weight (WT) and fat-free mass (FFM) were tested. The final model was evaluated using the likelihood ratio test and visual predictive checks (VPCs). RESULTS: A one-compartment model with linear elimination provided the best fit for the dose-concentration data. FFM was a significant covariate on clearance. A linear model provided the best fit for the concentration-effect data using aPTT as a biomarker for effect. The models performed well using VPCs. However, when used to simulate UFH infusion (at a much lower dose), the model overpredicted target aPTT responses. CONCLUSIONS: A PKPD model to describe the time course of the UFH effect was developed in a paediatric population. FFM was shown to describe drug disposition well. However, when applied to smaller UFH infusion doses, the model overpredicted target aPTT responses. This unsuccessful extrapolation may be attributed to a possible nonlinear relationship for heparin PKPD. PMID- 26972706 TI - Novel reconstruction of the anterior craniocervical junction using an expandable cage with integrated fixation after total C2 spondylectomy for chordoma. AB - Chordoma is a locally aggressive malignant tumor that generally occurs in the clivus, mobile spine and sacrum. While en bloc resection with wide margins has been advocated as the only cure for chordomas, tumor characteristics and violation of critical anatomical boundaries may preclude pursuing this treatment option in the cervical spine. We present a C2 chordoma in a 35-year-old man with epidural and prevertebral extension that was treated with a single stage anterior posterior total C2 spondylectomy with novel reconstruction using an expandable cage with integrated fixation followed by stereotactic radiosurgery. Single stage intralesional total C2 spondylectomy via anterior transoral and posterior approaches was performed. The anterior column was reconstructed using an expandable cage with integrated fixation from the clivus to C3. The patient maintained his intact neurological status at 6 month follow-up with full resumption of activities of daily living without any significant morbidity. PMID- 26972707 TI - Identification of miracidia of Schistosoma haematobium in a bladder wash sample. PMID- 26972709 TI - Characterizing the activation of the Wnt signaling pathway in hilar cholangiocarcinoma using a tissue microarray approach. AB - Hilar cholangiocarcinoma (HCCA) is an invasive hepatic malignancy that is difficult to biopsy; therefore, novel markers of HCCA prognosis are needed. Here, the level of canonical Wnt activation in patients with HCCA, intrahepatic cholangiocarcinoma (IHCC), and congenital choledochal cysts (CCC) was compared to understand the role of Wnt signaling in HCCA. Pathology specimens from HCCA (n=129), IHCC (n=31), and CCC (n=45) patients were used to construct tissue microarrays. Wnt2, Wnt3, beta-catenin, TCF4, c-Myc, and cyclin D1 were detected by immunohistochemistry. Parallel correlation analysis was used to analyze differences in protein levels between the HCCA, IHCC, and CCC groups. Univariate and multivariate analyses were used to determine independent predictors of successful resection and prognosis in the HCCA group. The protein levels of Wnt2, beta-catenin, TCF4, c-Myc, and cyclin D1 were significantly higher in HCCA compared to IHHC or CCC. Wnt signaling activation (Wnt2+, Wnt3+, nuclear beta catenin+, nuclear TCF4+) was significantly greater in HCCA tissues than CCC tissues. Univariable analyses indicated that expression of cyclin D1 as well as Wnt signaling activation, and partial Wnt activation (Wnt2+ or Wnt3+ and nuclear beta-catenin+ or nuclear TCF4+) predicted successful resection, but only cyclin D1 expression remained significant in multivariable analyses. Only partial Wnt activation was an independent predictor of survival time. Proteins in the canonical Wnt signaling pathway were present at higher levels in HCCA and correlated with tumor resecility and patient prognosis. These results suggest that Wnt pathway analysis may be a useful marker for clinical outcome in HCCA. PMID- 26972708 TI - Why switch from warfarin to NOACs? AB - Several patients with non-valvular atrial fibrillation treated with warfarin or other vitamin-K antagonists (VKA) might benefit from switching to an oral non vitamin-K antagonist anticoagulant (NOAC). In the absence of randomised comparative trials of switching to NOACs versus maintaining VKA treatment, several considerations argue in favour of a switching strategy. First, there is conclusive evidence that haemorrhagic strokes and intracranial bleedings are much fewer in number with NOACs than with warfarin. The risk of intracranial bleeding is 52 % lower with NOACS than with warfarin, with extremes ranging from 33 to 70 %. Such benefit is applicable to different NOACs, and independent of the time-in therapeutic range under warfarin. Patients at increased risk for intra-cranial bleeding (renal dysfunction, or prior stroke or intra-cranial bleeding) should benefit most from switching to NOACs. Patients with labile International Normalized Ratio are also considered good candidates for switching because of their increased risk of stroke, and the lack of interactions between the effects of NOACs versus warfarin and the time-in-therapeutic range. Furthermore, some NOACs proved to be superior to warfarin in reducing the risk of thromboembolic complications even in intention-to-treat analyses. As further advantage, NOACs show fewer drug-drug and drug-food interactions when compared with warfarin. Last, but not least, NOACs do not need frequent blood drawings except in patients with moderate renal dysfunction, in whom periodic controls of serum creatinine are generally advised. The higher cost remains a barrier to a wider use of NOACs, especially in low-income settings. PMID- 26972710 TI - Molecules implicated in glucose homeostasis are differentially expressed in the trachea of lean and obese Zucker rats. AB - Recent studies indicate that the processes mediated by the (T1R2/T1R3) glucose/sugar receptor of gustatory cells in the tongue, and hormones like leptin and ghrelin contribute to the regulation of glucose homeostasis. Altered plasma levels of leptin and ghrelin are associated with obesity both in humans and rodents. In the present study, we evaluated the ultrastructure of the mucosa, and the expression of molecules implicated in the regulation of glucose homeostasis (GLUT2, SGLT1, T1R3, ghrelin and its receptor) in the trachea of an animal model of obesity (Zucker rats). We found that the tracheal epithelium of obese animals was characterized by the presence of poorly differentiated cells. Ciliated and secretory cells were the cell lineages with greatest loss of differentiation. Severe epithelial alterations were associated with marked deposit of extracellular matrix in the lamina propria. The expression pattern of GLUT2 and SGLT1 glucose transporters was similar in the trachea of both the Zucker rat genotypes, whereas that of T1R3 was reduced in ciliated cells of obese rats. A different immunolocalization for ghrelin was also found in the trachea of obese rats. In conclusion, the tracheal morphological alterations in obese animals seem to compromise the expression of molecules involved in the homeostasis of glucose. PMID- 26972711 TI - Immunohistochemical markers of neural progenitor cells in the early embryonic human cerebral cortex. AB - The development of the human central nervous system represents a delicate moment of embryogenesis. The purpose of this study was to analyze the expression of multiple immunohistochemical markers in the stem/progenitor cells in the human cerebral cortex during the early phases of development. To this end, samples from cerebral cortex were obtained from 4 human embryos of 11 weeks of gestation. Each sample was formalin-fixed, paraffin embedded and immunostained with several markers including GFAP, WT1, Nestin, Vimentin, CD117, S100B, Sox2, PAX2, PAX5, Tbeta4, Neurofilament, CD44, CD133, Synaptophysin and Cyclin D1. Our study shows the ability of the different immunohistochemical markers to evidence different zones of the developing human cerebral cortex, allowing the identification of the multiple stages of differentiation of neuronal and glial precursors. Three important markers of radial glial cells are evidenced in this early gestational age: Vimentin, Nestin and WT1. Sox2 was expressed by the stem/progenitor cells of the ventricular zone, whereas the postmitotic neurons of the cortical plate were immunostained by PAX2 and NSE. Future studies are needed to test other important stem/progenitor cells markers and to better analyze differences in the immunohistochemical expression of these markers during gestation. PMID- 26972713 TI - In situ histochemical localisation of alkaloids and acetogenins in the endosperm and embryonic axis of Annona macroprophyllata Donn. Sm. seeds during germination. AB - Currently, the Annonaceae family is characterised by the production of acetogenins (ACGs), and also by the biosynthesis of alkaloids, primarily benzylisoquinolines derived from tyrosine. The objective of this study was to confirm the presence of alkaloids and acetogenins in the idioblasts of the endosperm and the embryonic axis of A. macroprophyllata seeds in germination. The Dragendorff, Dittmar, Ellram, and Lugol reagents were used to test for alkaloids, and Kedde's reagent was used to determine the presence of acetogenins in fresh sections of the endosperm and embryonic axis of seeds after twelve days of germination. A positive reaction was observed for all the reagents, and the presence of alkaloids and acetogenins was confirmed in the idioblasts of the endosperm and those involved in the differentiation of the embryonic axis of the developing seedling. We concluded that the idioblasts store both metabolites, acetogenins and alkaloids. Beginning at differentiation, the idioblasts of the embryonic axis simultaneously biosynthesise acetogenins and alkaloids that are characteristic of the species during the development of the seedling. The method used here can be applied to histochemically confirm the presence of acetogenins and alkaloids in tissues and structures of the plant in different stages of its life cycle. PMID- 26972712 TI - Species diversity regarding the presence of proximal tubular progenitor cells of the kidney. AB - The cellular source for tubular regeneration following kidney injury is a matter of dispute, with reports suggesting a stem or progenitor cells as the regeneration source while linage tracing studies in mice seemingly favor the classical theory, where regeneration is performed by randomly surviving cells. We, and others have previously described a scattered cell population localized to the tubules of human kidney, which increases in number following injury. Here we have characterized the species distribution of these proximal tubular progenitor cells (PTPCs) in kidney tissue from chimpanzee, pig, rat and mouse using a set of human PTPC markers. We detected PTPCs in chimpanzee and pig kidneys, but not in mouse tissue. Also, subjecting mice to the unilateral urethral obstruction model, caused clear signs of tubular injury, but failed to induce the PTPC phenotype in renal tubules. PMID- 26972714 TI - Elemental analysis of histological specimens: a method to unmask nano asbestos fibers. AB - There is recent mounting evidence that nanoparticles may have enhanced toxicological potential in comparison to the same material in the bulk form. The aim of this study was to develop a new method for unmask asbestos nanofibers from Formalin-Fixed, Paraffin-Embedded tissue. There is an increasing amount of evidence that nanoparticles may enhance toxicological potential in comparison to the same material in the bulk form. The aim of this study was to develop a new method to unmask asbestos nanofibers from Formalin-Fixed Paraffin-Embedded (FFPE) tissue. For the first time, in this study we applied Energy Dispersive X-ray (EDX) microanalysis through transmission electron microscopy to demonstrate the presence of asbestos nanofibers in histological specimens of patients with possible occupational exposure to asbestos. The diagnostic protocol was applied to 10 randomly selected lung cancer patients with no history of previous asbestos exposure. We detected asbestos nanofibers in close contact with lung cancer cells in two lung cancer patients with previous possible occupational exposure to asbestos. We were also able to identify the specific asbestos iso-type, which in one of the cases was the same rare variety used in the workplace of the affected patient. By contrast, asbestos nanofibers were not detected in lung cancer patients with no history of occupational asbestos exposure. The proposed technique can represent a potential useful tool for linking the disease to previous workplace exposure in uncertain cases. Furthermore, Formalin-Fixed Paraffin-Embedded (FFPE) tissues stored in the pathology departments might be re evaluated for possible etiological attribution to asbestos in the case of plausible exposure. Since diseases acquired through occupational exposure to asbestos are generally covered by workers' insurance in most countries, the application of the protocol used in this study may have also relevant social and economic implications. PMID- 26972715 TI - Decreased expression of Met during differentiation in rat lung. AB - Organ-specific stem cells play key roles in maintaining the epithelial cell layers of lung. Bronchioalveolar stem cells (BASCs) are distal lung epithelial stem cells of adult mice. Alveolar type 2 (AT2) cells have important functions and serve as progenitor cells of alveolar type 1 (AT1) cells to repair the epithelium when they are injured. Hepatocyte growth factor (HGF) elicits mitogenic, morphogenic, and anti-apoptotic effects on lung epithelial cells through tyrosine phosphorylation of Met receptor, and thus is recognized as a pulmotrophic factor. To understand which cells HGF targets in lung, we identified the cells expressing Met by immunofluorescence assay. Met was strongly expressed in BASCs, which expressed an AT2 cell marker, pro-SP-C, and a club cell marker, CCSP. In alveoli, we found higher expression of Met in primary AT2 than in AT1 cells, which was confirmed using primary AT2 cells. We further examined the mitogenic activity of HGF in AT2-cell-derived alveolar-like cysts (ALCs) in 3D culture. Multicellular ALCs expressed Met, and HGF enhanced the ALC production. Taking these findings together, BASCs could also be an important target for HGF, and HGF-Met signaling could function more potent on cells that have greater multipotency in adult lung. PMID- 26972716 TI - Transgenic expression of dentin phosphoprotein inhibits skeletal development. AB - Dentin sialophosphoprotein (DSPP) is proteolytically processed into an NH2 terminal fragment called dentin sialoprotein (DSP) and a COOH-terminal fragment known as dentin phosphoprotein (DPP). These two fragments are believed to perform distinct roles in formation of bone and dentin. To investigate the functions of DPP in skeletal development, we generated transgenic mice to overexpress hemagglutinin (HA)-tagged DPP under the control of a 3.6 kb type I collagen (Col1a1) promoter (designated as Col1a1-HA-DPP). The Col1a1-HA-DPP transgenic mice were significantly smaller by weight, had smaller skeletons and shorter long bones than their wild type littermates, as demonstrated by X-ray radiography. They displayed reduced trabecular bone formation and narrower zones of proliferative and hypertrophic chondrocytes in the growth plates of the long bones. Histological analyses showed that the transgenic mice had reduced cell proliferation in the proliferating zone, but lacked obvious defects in the chondrocyte differentiation. In addition, the transgenic mice with a high level of transgene expression developed spontaneous long bone fractures. In conclusion, overexpressing DPP inhibited skeletal development, suggesting that the balanced actions between the NH2- and COOH-terminal fragments of DSPP may be required for normal skeletal development. PMID- 26972717 TI - A modified Verhoeff's elastin histochemical stain to enable pulmonary arterial hypertension model characterization. AB - Optimal histochemical staining is critical to ensure excellent quality stained sections to enable light microscopic and histomorphometric image analysis. Verhoeff-van Gieson is the most widely used histochemical stain for the visualization of vascular elastic fibers. However, it is notoriously difficult to differentiate fine elastic fibers of small vasculature to enable histomorphometric image analysis of vasculature size characterization especially in organs such as the lung. A tissue fixation regime of 10% neutral buffered formalin with subsequent fixation in 70% ethanol further compounds the problem of small vessel staining and identification. Therefore, a modified Verhoeff's elastin stain was developed as a reliable method to optimally highlight the internal and external elastic lamina of small arteries (50-100 um) and intra acinar vessels (10-50 um) in 3 um thick lung tissue sections from models of pulmonary arterial hypertension. This modified Verhoeff's elastin stain demonstrated optimal staining of fine elastic fibers of pulmonary blood vessels. As a result, high-quality histomorphometric image analysis evaluation of vessel wall thickness in small arteries and intra-acinar vessels was successfully accomplished. In conclusion, modification of the standard Verhoeff-van Gieson histochemical stain is needed to visualize small caliber vessels' elastic fibers especially in tissues not fixed in 10% neutral buffered formalin only. PMID- 26972718 TI - Immunohistochemical expression of heparanase isoforms and syndecan-1 proteins in colorectal adenomas. AB - The proteoglycan syndecan-1 and the endoglucuronidases heparanase-1 and heparanase-2 are involved in molecular pathways that deregulate cell adhesion during carcinogenesis. Few studies have examined the expression of syndecan-1, heparanase-1 and mainly heparanase-2 proteins in non-neoplastic and neoplastic human colorectal adenoma tissues. The aim of this study was to analyze the correlation among the heparanase isoforms and the syndecan-1 proteins through immunohistochemical expression in the tissue of colorectal adenomas. Primary anti human polyclonal anti-HPSE and anti-HPSE2 antibodies and primary anti-human monoclonal anti-SDC1 antibody were used in the immunohistochemical study. The expressions of heparanase-1 and heparanase-2 proteins were determined in tissue samples from 65 colorectal adenomas; the expression of syndecan-1 protein was obtained from 39 (60%) patients. The histological type of adenoma was tubular in 44 (67.7%) patients and tubular-villous in 21 (32.3%); there were no villous adenomas. The polyps were <1.0 cm in size in 54 (83.1%) patients and >=1.0 cm in 11 (16.9%). The images were quantified by digital counter with a computer program for this purpose. The expression index represented the relationship between the intensity expression and the percentage of positively stained cells. The results showed that the average of heparanase-1, heparanase-2 and syndecan-1 expression index was 73.29 o.u./um2, 93.34 o.u./um2, and 55.29 o.u./um2, respectively. The correlation between the heparanase-1 and syndecan-1 expression index was positive (R=0.034) and significant (P=0.035). There was a negative (R= -0.384) and significant (P=0.016) correlation between the expression index of heparanase-1 and heparanase-2. A negative (R= -0.421) and significant (P=0.008) correlation between the expression index of heparanase-2 and syndecan-1 was found. We concluded that in colorectal adenomas, the heparanase-1 does not participate in syndecan-1 degradation; the heparanase-2 does not stimulate syndecan-1 degradation by the action of heparanase-1, and the heparanase-2 may be involved in the modulation of the heparanase-1 activity. PMID- 26972719 TI - Changes in muscularis propria of anterior vaginal wall in women with pelvic organ prolapse. AB - The objective of this study was to evaluate the morphological and immunohistochemical alterations of tissue removed from the upper third of anterior vaginal wall in a sample group of the female population presenting homogenous risk factors associated with Pelvic Organ Prolapse (POP). The case study consisted of 14 patients with POP and there were 10 patients in the control group. Patient selection was carried on the basis of specific criteria and all of the patients involved in the study presented one or more of the recognized POP risk factors. Samples were taken from POP patients during vaginal plastic surgery following colpohysterectomy, and from control patients during closure of the posterior fornix following hysterectomy. Samples were processed for histological and immunohistochemical analyses for Collagen I and Collagen III, alpha-Smooth Muscle Actin (alpha-SMA), Platelet-Derived-Growth-Factor (PDGF), matrix metalloproteinase 3 (MMP3), Caspase3. Immunofluorescence analyses for Collagen I and III and PDGF were also carried out. In prolapsed specimens our results show a disorganization of smooth muscle cells that appeared to have been displaced by an increased collagen III deposition resulting in rearrangement of the muscularis propria architecture. These findings suggest that the increase in the expression of collagen fibers in muscularis could probably due to a phenotypic switch resulting in the dedifferentiation of smooth muscle cells into myofibroblasts. These alterations could be responsible for the compromising of the dynamic functionality of the pelvic floor. PMID- 26972722 TI - Neuroimmunology: IL-17A mediates a path to autism. PMID- 26972724 TI - Inflammasome: Anti-inflammatory effect of mitophagy. PMID- 26972726 TI - Regulatory T cells: Ageing muscles lose T Reg-eneration. PMID- 26972727 TI - Alteration of Structure and Aggregation of alpha-Synuclein by Familial Parkinson's Disease Associated Mutations. AB - alpha-Synuclein (alpha-Syn) aggregation is directly associated with Parkinson's disease (PD) pathogenesis. In vitro aggregation and in vivo animal model studies of alpha-Syn recapitulate many features of the disease pathogenesis. Six familial PD associated mutations of alpha-Syn have been discovered; many of which are associated with early onset PD. Three of PD associated mutations have been shown to accelerate the alpha-Syn aggregation, whereas other three are shown to delay the aggregation kinetics. The membrane binding studies also suggest that few of these PD mutants strongly bind to synthetic membrane vesicles, while others are shown to have attenuated membrane binding ability. Furthermore, the PD mutations do not drastically alter the toxicity of alpha-Syn oligomers/fibrils. Although according to recent suggestions that early formed oligomers are the most potent toxic species responsible for PD, only p.A30P mutant is shown to form faster oligomers and delayed conversion from oligomers to fibrils. Therefore, it is difficult to establish a unifying mechanism of how familial PD associated mutations affect the alpha-Syn structure, aggregation and function for their disease association. It is possible that each PD associated mutation alters alpha Syn biology in a unique way, which might be responsible for disease pathogenesis. In this review, we discuss the structure function of alpha- Syn and how these are altered due to the PD associated mutations and their relationship to disease pathogenesis. PMID- 26972729 TI - National Health Service Cancer Strategy for England: Where Are We Now? PMID- 26972723 TI - Paediatric HIV infection: the potential for cure. AB - Recent anecdotal reports of HIV-infected children who received early antiretroviral therapy (ART) and showed sustained control of viral replication even after ART discontinuation have raised the question of whether there is greater intrinsic potential for HIV remission, or even eradication ('cure'), in paediatric infection than in adult infection. This Review describes the influence of early initiation of ART, of immune ontogeny and of maternal factors on the potential for HIV cure in children and discusses the unique immunotherapeutic opportunities and obstacles that paediatric infection may present. PMID- 26972728 TI - Deciphering the regulon of a GntR family regulator via transcriptome and ChIP-exo analyses and its contribution to virulence in Xanthomonas citri. AB - Xanthomonas contains a large group of plant-associated species, many of which cause severe diseases on important crops worldwide. Six gluconate-operon repressor (GntR) family transcriptional regulators are predicted in Xanthomonas, one of which, belonging to the YtrA subfamily, plays a prominent role in bacterial virulence. However, the direct targets and comprehensive regulatory profile of YtrA remain unknown. Here, we performed microarray and high-resolution chromatin immunoprecipitation-exonuclease (ChIP-exo) experiments to identify YtrA direct targets and its DNA binding motif in X. citri ssp. citri (Xac), the causal agent of citrus canker. Integrative microarray and ChIP-exo data analysis revealed that YtrA directly regulates three operons by binding to a palindromic motif GGTG-N16 -CACC at the promoter region. A similar palindromic motif and YtrA homologues were also identified in many other bacteria, including Stenotrophomonas, Pseudoxanthomonas and Frateuria, indicating a widespread phenomenon. Deletion of ytrA in Xac abolishes bacterial virulence and induction of the hypersensitive response (HR). We found that YtrA regulates the expression of hrp/hrc genes encoding the bacterial type III secretion system (T3SS) and controls multiple biological processes, including motility and adhesion, oxidative stress, extracellular enzyme production and iron uptake. YtrA represses the expression of its direct targets in artificial medium or in planta. Importantly, over-expression of yro3, one of the YtrA directly regulated operons which contains trmL and XAC0231, induced weaker canker symptoms and down regulation of hrp/hrc gene expression, suggesting a negative regulation in Xac virulence and T3SS. Our study has significantly advanced the mechanistic understanding of YtrA regulation and its contribution to bacterial virulence. PMID- 26972725 TI - AIRE expands: new roles in immune tolerance and beyond. AB - More than 15 years ago, mutations in the autoimmune regulator (AIRE) gene were identified as the cause of autoimmune polyglandular syndrome type 1 (APS1). It is now clear that this transcription factor has a crucial role in promoting self tolerance in the thymus by regulating the expression of a wide array of self antigens that have the commonality of being tissue-restricted in their expression pattern in the periphery. In this Review, we highlight many of the recent advances in our understanding of the complex biology that is related to AIRE, with a particular focus on advances in genetics, molecular interactions and the effect of AIRE on thymic selection of regulatory T cells. Furthermore, we highlight new areas of biology that are potentially affected by this key regulator of immune tolerance. PMID- 26972730 TI - Magneto-optical imaging of thin magnetic films using spins in diamond. AB - Imaging the fields of magnetic materials provides crucial insight into the physical and chemical processes surrounding magnetism, and has been a key ingredient in the spectacular development of magnetic data storage. Existing approaches using the magneto-optic Kerr effect, x-ray and electron microscopy have limitations that constrain further development, and there is increasing demand for imaging and characterisation of magnetic phenomena in real time with high spatial resolution. Here we show how the magneto-optical response of an array of negatively-charged nitrogen-vacancy spins in diamond can be used to image and map the sub-micron stray magnetic field patterns from thin ferromagnetic films. Using optically detected magnetic resonance, we demonstrate wide-field magnetic imaging over 100 * 100 MUm(2) with sub-micron spatial resolution at video frame rates, under ambient conditions. We demonstrate an all optical spin relaxation contrast imaging approach which can image magnetic structures in the absence of an applied microwave field. Straightforward extensions promise imaging with sub-MUT sensitivity and sub-optical spatial and millisecond temporal resolution. This work establishes practical diamond-based wide-field microscopy for rapid high-sensitivity characterisation and imaging of magnetic samples, with the capability for investigating magnetic phenomena such as domain wall and skyrmion dynamics and the spin Hall effect in metals. PMID- 26972732 TI - Laughter is the Best Medicine? A Cross-Sectional Study of Cardiovascular Disease Among Older Japanese Adults. AB - BACKGROUND: We sought to evaluate the associations between frequency of daily laughter with heart disease and stroke among community-dwelling older Japanese women and men. METHODS: We analyzed cross-sectional data in 20 934 individuals (10 206 men and 10 728 women) aged 65 years or older, who participated in the Japan Gerontological Evaluation Study in 2013. In the mail-in survey, participants provided information on daily frequency of laughter, as well as body mass index, demographic and lifestyle factors, and diagnoses of cardiovascular disease, hyperlipidemia, hypertension, and depression. RESULTS: Even after adjustment for hyperlipidemia, hypertension, depression, body mass index, and other risk factors, the prevalence of heart diseases among those who never or almost never laughed was 1.21 (95% CI, -1.03-1.41) times higher than those who reported laughing every day. The adjusted prevalence ratio for stroke was 1.60 (95% CI, 1.24-2.06). CONCLUSIONS: Daily frequency of laughter is associated with lower prevalence of cardiovascular diseases. The association could not be explained by confounding factors, such as depressive symptoms. PMID- 26972733 TI - The wound/burn guidelines - 4: Guidelines for the management of skin ulcers associated with connective tissue disease/vasculitis. AB - The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS. PMID- 26972734 TI - How does sub-cellular localization affect the fate of bacterial mRNA? AB - Recently a number of seminal studies have revealed that both sequence and spatio temporal factors govern RNA decay in bacteria, which is crucial for regulation of gene expression. Ribonucleases have been described that not only exhibit sequence preferences, but also are sub-cellularly localised. Furthermore, the RNA itself is distributed in an organised manner and does not diffuse freely or randomly within the bacterial cells. Thus, even within the sub-micrometer distances of the bacterial intra-cellular space, the positions of the enzymes and their substrates are kept in check. Adding to this complexity is the secondary structure and sequence specificity that many, perhaps all, ribonucleases exhibit, including those that are responsible for "general" RNA degradation. In this review, the implications of these novel findings are discussed and specific examples from Staphylococcus aureus are analysed. PMID- 26972737 TI - Localization and developmental expression of two chicken host defense peptides: cathelicidin-2 and avian beta-defensin 9. AB - In the first weeks of life young chickens are highly susceptible to infectious diseases due to immaturity of the immune system. Little is known about the expression of host defense peptides (HDPs) during this period. In this study we examined the expression pattern of two chicken HDPs, the cathelicidin CATH-2 and the beta-defensin AvBD9 by immunohistochemistry in a set of organs from embryonic day 12 until four weeks posthatch. AvBD9 was predominantly found in enteroendocrine cells throughout the intestine, the first report of in vivo HDP expression in this cell type, and showed stable expression levels during development. CATH-2 was exclusively found in heterophils which decreased after hatch in most of the examined organs including spleen, bursa and small intestine. In the lung CATH-2 expression was biphasic and peaked at the first day posthatch. In short, CATH-2 and AvBD9 appear to be expressed in cell types strategically located to respond to infectious stimuli, suggesting these peptides play a role in embryonic and early posthatch defense. PMID- 26972738 TI - A specific CpG oligodeoxynucleotide induces protective antiviral responses against grass carp reovirus in grass carp Ctenopharyngodon idella. AB - CpG oligodeoxynucleotides (ODNs) show strong immune stimulatory activity in vertebrate, however, they possess specific sequence feature among species. In this study, we screened out an optimal CpG ODN sequence for grass carp (Ctenopharyngodon idella), 1670A 5'-TCGAACGTTTTAACGTTTTAACGTT-3', from six published sequences and three sequences designed by authors based on grass carp head kidney mononuclear cells and CIK (C. idella kidney) cells proliferation. VP4 mRNA expression was strongly inhibited by CpG ODN 1670A in CIK cells with GCRV infection, showing its strong antiviral activity. The mechanism via toll-like receptor 9 (TLR9)-mediated signaling pathway was measured by real-time quantitative RT-PCR, and TLR21 did not play a role in the immune response to CpG ODN. The late up-regulation of CiRIG-I mRNA expression indicated that RIG-I-like receptors (RLRs) signaling pathway participated in the immune response to CpG ODN which is the first report on the interaction between CpG and RLRs. We also found that the efficient CpG ODN can activates interferon system. Infected with GCRV, type I interferon expression was reduced and type II interferon was induced by the efficient CpG ODN in CIK cells, especially IFNgamma2, suggesting that IFNgamma2 played an important role in response to the efficient CpG ODN. These results provide a theoretical basis and new development trend for further research on CpG and the application of CpG vaccine adjuvant in grass carp disease control. PMID- 26972739 TI - Surface Decorating of CH3NH3PbBr3 Nanoparticles with the Chemically Adsorbed Perylenetetracarboxylic Diimide. AB - An organic dye-modified organolead halide CH3NH3PbBr3 nanoparticle (cubic) is prepared successfully by using a perylenetetracarboxylic diimide (PDI) bearing an -NH3(+) headgroup as the capping ligand. The nanopartilces are homogeneous with high crystallinity. The photoluminescence of perovskite is quenched completely by the chemically adsorbed PDI molecules. This efficient fluorescence quenching has confirmed that the PDI molecules are anchored on the surface of CH3NH3PbBr3 nanoparticle. The resulting nanoparticles can be dispersed in organic solvents, and the resulting dispersion remains stable for days. This result provides a general guideline for surface engineering of organolead halide CH3NH3PbBr3 nanoparticles. PMID- 26972741 TI - Suicide Attempt by Anaphylaxis. PMID- 26972742 TI - Developing and Implementing a Psychosomatic Medicine Elective During Psychiatry Residency Training: The Embedded Psychiatry Resident on a Bone Marrow Transplant Unit. PMID- 26972743 TI - The description of a method for accurately estimating creatinine clearance in acute kidney injury. AB - BACKGROUND: Acute kidney injury (AKI) is a common and serious condition encountered in hospitalized patients. The severity of kidney injury is defined by the RIFLE, AKIN, and KDIGO criteria which attempt to establish the degree of renal impairment. The KDIGO guidelines state that the creatinine clearance should be measured whenever possible in AKI and that the serum creatinine concentration and creatinine clearance remain the best clinical indicators of renal function. Neither the RIFLE, AKIN, nor KDIGO criteria estimate actual creatinine clearance. Furthermore there are no accepted methods for accurately estimating creatinine clearance (K) in AKI. STUDY DESIGN: The present study describes a unique method for estimating K in AKI using urine creatinine excretion over an established time interval (E), an estimate of creatinine production over the same time interval (P), and the estimated static glomerular filtration rate (sGFR), at time zero, utilizing the CKD-EPI formula. Using these variables estimated creatinine clearance (Ke)=E/P * sGFR. SETTING AND PARTICIPANTS: The method was tested for validity using simulated patients where actual creatinine clearance (Ka) was compared to Ke in several patients, both male and female, and of various ages, body weights, and degrees of renal impairment. These measurements were made at several serum creatinine concentrations in an attempt to determine the accuracy of this method in the non-steady state. In addition E/P and Ke was calculated in hospitalized patients, with AKI, and seen in nephrology consultation by the author. In these patients the accuracy of the method was determined by looking at the following metrics; E/P>1, E/P<1, E=P in an attempt to predict progressive azotemia, recovering azotemia, or stabilization in the level of azotemia respectively. In addition it was determined whether Ke<10 ml/min agreed with Ka and whether patients with AKI on renal replacement therapy could safely terminate dialysis if Ke was greater than 5 ml/min. OUTCOMES AND RESULTS: In the simulated patients there were 96 measurements in six different patients where Ka was compared to Ke. The estimated proportion of Ke within 30% of Ka was 0.907 with 95% exact binomial proportion confidence limits. The predictive accuracy of E/P in the study patients was also reported as a proportion and the associated 95% confidence limits: 0.848 (0.800, 0.896) for E/P<1; 0.939 (0.904, 0.974) for E/P>1 and 0.907 (0.841, 0.973) for 0.95 ml/min accurately predicted the ability to terminate renal replacement therapy in AKI. LIMITATIONS: Include the need to measure urine volume accurately. Furthermore the precision of the method requires accurate estimates of sGFR, while a reasonable measure of P is crucial to estimating Ke. CONCLUSIONS: The present study provides the practitioner with a new tool to estimate real time K in AKI with enough precision to predict the severity of the renal injury, including progression, stabilization, or improvement in azotemia. It is the author's belief that this simple method improves on RIFLE, AKIN, and KDIGO for estimating the degree of renal impairment in AKI and allows a more accurate estimate of K in AKI. PMID- 26972744 TI - Modeling the effects of positive and negative feedback in kidney blood flow control. AB - Blood flow in the mammalian kidney is tightly autoregulated. One of the important autoregulation mechanisms is the myogenic response, which is activated by perturbations in blood pressure along the afferent arteriole. Another is the tubuloglomerular feedback, which is a negative feedback that responds to variations in tubular fluid [Cl(-)] at the macula densa.(1) When initiated, both the myogenic response and the tubuloglomerular feedback adjust the afferent arteriole muscle tone. A third mechanism is the connecting tubule glomerular feedback, which is a positive feedback mechanism located at the connecting tubule, downstream of the macula densa. The connecting tubule glomerular feedback is much less well studied. The goal of this study is to investigate the interactions among these feedback mechanisms and to better understand the effects of their interactions. To that end, we have developed a mathematical model of solute transport and blood flow control in the rat kidney. The model represents the myogenic response, tubuloglomerular feedback, and connecting tubule glomerular feedback. By conducting a bifurcation analysis, we studied the stability of the system under a range of physiologically-relevant parameters. The bifurcation results were confirmed by means of a comparison with numerical simulations. Additionally, we conducted numerical simulations to test the hypothesis that the interactions between the tubuloglomerular feedback and the connecting tubule glomerular feedback may give rise to a yet-to-be-explained low frequency oscillation that has been observed in experimental records. PMID- 26972747 TI - Diverse clinical and laboratory manifestations of bilateral vestibulopathy. AB - OBJECTIVES/HYPOTHESIS: To identify the clinical and laboratory characteristics of bilateral vestibulopathy (BVP) on the video head impulse test (vHIT). STUDY DESIGN: Retrospective chart analysis. METHODS: During 23 months, 1,789 patients with dizziness underwent vHIT in our tertiary referral hospital. Of these patients, 65 (3.6%) patients had bilaterally positive catch-up saccades. Based on the caloric test, 15 (group 1) had bilateral caloric weakness, 13 (group 2) had unilateral caloric weakness, and 37 (group 3) had normal caloric responses on both ears. We collected data on these patients regarding demographics, symptoms, gain, and type of saccade on horizontal canal plane vHIT, as well as gain and time constant on velocity step of the rotatory chair test. RESULTS: The average age of group 2 (70.38 +/- 11.96 years) and group 3 (69.03 +/- 11.01 years) were significantly older than that of group 1 (54.80 +/- 11.96 years) (P = 0.029, P = 0.003, respectively). Although all patients had bilaterally positive vHIT, 10 of 15 in group 1 were finally diagnosed as classical BVP by clinical features. On comparison of average gain on bilateral horizontal vHIT, groups 2 (0.71 +/- 0.17) and 3 (0.80 +/- 0.14) had higher gain compared to group 1 (0.45 +/- 0.22) (P = 0.001, P = 0.000, respectively). On velocity step test, time constant and gain of group 3 (11.60 +/- 3.07, 0.49 +/- 0.13) was significantly higher than those of group 1 (4.92 +/- 1.36, 0.22 +/- 0.17) (P = 0.000, P = 0.004, respectively). On the receiver operating characteristic curve analysis, vHIT alone seemed to be a discordant method for diagnosis of BVP compared to the caloric and step velocity tests. CONCLUSION: About 3.6% patients with dizziness showed bilateral vestibular ocular reflex deficit during high-frequency acceleration, which was prevalent especially in elderly patients. Also, positive bilateral vHIT does not always correlate with caloric or rotatory chair test results. This may imply that a diverse spectrum of vestibulopathies exist according to the stimulation frequency of deficit. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:E42-E49, 2017. PMID- 26972748 TI - A Different Kind of Doctor. PMID- 26972745 TI - Predictors of dropout in concurrent treatment of posttraumatic stress disorder and alcohol dependence: Rate of improvement matters. AB - OBJECTIVE: The present study examined predictors and moderators of dropout among 165 adults meeting DSM-IV criteria for posttraumatic stress disorder (PTSD) and alcohol dependence (AD). Participants were randomized to 24 weeks of naltrexone (NAL), NAL and prolonged exposure (PE), pill placebo, or pill placebo and PE. All participants received supportive AD counseling (the BRENDA manualized model). METHOD: Logistic regression using the Fournier approach was conducted to investigate baseline predictors of dropout across the entire study sample. Rates of PTSD and AD symptom improvement were included to evaluate the impact of symptom change on dropout. RESULTS: Trauma type and rates of PTSD and AD improvement significantly predicted dropout, accounting for 76% of the variance in dropout. Accidents and "other" trauma were associated with the highest dropout, and physical assault was associated with the lowest dropout. For participants with low baseline PTSD severity, faster PTSD improvement predicted higher dropout. For those with high baseline severity, both very fast and very slow rates of PTSD improvement were associated with higher dropout. Faster rates of drinking improvement predicted higher dropout among participants who received PE. CONCLUSIONS: The current study highlights the influence of symptom trajectory on dropout risk. Clinicians may improve retention in PTSD-AD treatments by monitoring symptom change at regular intervals, and eliciting patient feedback on these changes. PMID- 26972746 TI - Using AAV vectors expressing the beta2-adrenoceptor or associated Galpha proteins to modulate skeletal muscle mass and muscle fibre size. AB - Anabolic beta2-adrenoceptor (beta2-AR) agonists have been proposed as therapeutics for treating muscle wasting but concerns regarding possible off target effects have hampered their use. We investigated whether beta2-AR-mediated signalling could be modulated in skeletal muscle via gene delivery to the target tissue, thereby avoiding the risks of beta2-AR agonists. In mice, intramuscular administration of a recombinant adeno-associated virus-based vector (rAAV vector) expressing the beta2-AR increased muscle mass by >20% within 4 weeks. This hypertrophic response was comparable to that of 4 weeks' treatment with the beta2 AR agonist formoterol, and was not ablated by mTOR inhibition. Increasing expression of inhibitory (Galphai2) and stimulatory (GalphasL) G-protein subunits produced minor atrophic and hypertrophic changes in muscle mass, respectively. Furthermore, Galphai2 over-expression prevented AAV:beta2-AR mediated hypertrophy. Introduction of the non-muscle Galphas isoform, GalphasXL elicited hypertrophy comparable to that achieved by AAV:beta2-AR. Moreover, GalphasXL gene delivery was found to be capable of inducing hypertrophy in the muscles of mice lacking functional beta1- and beta2-ARs. These findings demonstrate that gene therapy-based interventions targeting the beta2-AR pathway can promote skeletal muscle hypertrophy independent of ligand administration, and highlight novel methods for potentially modulating muscle mass in settings of disease. PMID- 26972749 TI - Deletion of interleukin-6 alleviated interstitial fibrosis in streptozotocin induced diabetic cardiomyopathy of mice through affecting TGFbeta1 and miR-29 pathways. AB - Interleukin 6 (IL-6) has been shown to be an important regulator of cardiac interstitial fibrosis. In this study, we explored the role of interleukin-6 in the development of diabetic cardiomyopathy and the underlying mechanisms. Cardiac function of IL-6 knockout mice was significantly improved and interstitial fibrosis was apparently alleviated in comparison with wildtype (WT) diabetic mice induced by streptozotocin (STZ). Treatment with IL-6 significantly promoted the proliferation and collagen production of cultured cardiac fibroblasts (CFs). High glucose treatment increased collagen production, which were mitigated in CFs from IL-6 KO mice. Moreover, IL-6 knockout alleviated the up-regulation of TGFbeta1 in diabetic hearts of mice and cultured CFs treated with high glucose or IL-6. Furthermore, the expression of miR-29 reduced upon IL-6 treatment, while increased in IL-6 KO hearts. Overexpression of miR-29 blocked the pro-fibrotic effects of IL-6 on cultured CFs. In summary, deletion of IL-6 is able to mitigate myocardial fibrosis and improve cardiac function of diabetic mice. The mechanism involves the regulation of IL-6 on TGFbeta1 and miR-29 pathway. This study indicates the therapeutic potential of IL-6 suppression on diabetic cardiomyopathy disease associated with fibrosis. PMID- 26972750 TI - Allele polymorphism and haplotype diversity of MICA/B in Tujia nationality of Zhangjiajie, Hunan Province, China. AB - Previous studies indicate the distribution of major histocompatibility complex class I chain-related genes A (MICA) and B (MICB) alleles and haplotypes varies widely between different ethnic populations and geographic areas. It is meaningful to investigate allelic frequencies and establish a genetic database. In this study, we firstly reported the polymorphic variation of MICA/B in 187 healthy, unrelated Tujia individuals in Zhangjiajie region, China. Using polymerase chain reaction-sequence specific priming (PCR-SSP) and sequencing based typing (PCR-SBT), we identified eight MICA-sequence alleles, four MICA short tandem repeat variants, and 13 MICB variants, of which MICA(*)008:04 (29.41%), MICA(*)A5 (29.68%), MICA(*)A5.1 (29.68%) and MICB(*)005:02 (39.57%) were the most frequent. Linkage disequilibrium analysis further revealed MICB(*)005:02-MICA(*)019 (13.10%) and MICB(*)002-MICA(*)008:04 (9.89%) as the most common two-locus haplotypes. Data comparison by neighbor-joining dendrograms and principal component analysis to verify allelic frequencies in other Chinese and Asia ethnic groups showed that the Zhangjiajie Tujias were genetically closer to the Guangdong Han population, based on MICA loci variability. Our results provide new information about the MICA/B gene polymorphism in Chinese Tujia population, which will form the basis for future studies on the potential role of MICA/B in allogeneic organ transplantation and disease susceptibility in related ethnic groups. PMID- 26972751 TI - Finding and Not Finding Rat Perirhinal Neuronal Responses to Novelty. AB - There is much evidence that the perirhinal cortex of both rats and monkeys is important for judging the relative familiarity of visual stimuli. In monkeys many studies have found that a proportion of perirhinal neurons respond more to novel than familiar stimuli. There are fewer studies of perirhinal neuronal responses in rats, and those studies based on exploration of objects, have raised into question the encoding of stimulus familiarity by rat perirhinal neurons. For this reason, recordings of single neuronal activity were made from the perirhinal cortex of rats so as to compare responsiveness to novel and familiar stimuli in two different behavioral situations. The first situation was based upon that used in "paired viewing" experiments that have established rat perirhinal differences in immediate early gene expression for novel and familiar visual stimuli displayed on computer monitors. The second situation was similar to that used in the spontaneous object recognition test that has been widely used to establish the involvement of rat perirhinal cortex in familiarity discrimination. In the first condition 30 (25%) of 120 perirhinal neurons were visually responsive; of these responsive neurons 19 (63%) responded significantly differently to novel and familiar stimuli. In the second condition eight (53%) of 15 perirhinal neurons changed activity significantly in the vicinity of objects (had "object fields"); however, for none (0%) of these was there a significant activity change related to the familiarity of an object, an incidence significantly lower than for the first condition. Possible reasons for the difference are discussed. It is argued that the failure to find recognition-related neuronal responses while exploring objects is related to its detectability by the measures used, rather than the absence of all such signals in perirhinal cortex. Indeed, as shown by the results, such signals are found when a different methodology is used. (c) 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc. PMID- 26972753 TI - Preparatory Engagement of Cognitive Control Networks Increases Late in Childhood. AB - The ability to engage task control flexibly, especially in anticipation of task demands, is beneficial when juggling different tasks. We investigated whether children in late childhood or early adolescence engaged preparatory task control similar to adults in a trial-wise cued task-switching paradigm. Twenty-eight children (aged 9-15 years) and 30 adults (aged 21-30 years) participated in an fMRI study in which the Cue (preparatory) period across 2 tasks was analyzed separately from the execution of the tasks (the Target period). Children performed more slowly and less accurately than adults, and showed behavioral improvement within the child group age range of 9-15 years. Children exhibited weaker Cue period activation than adults within a number of putative cognitive control regions. In contrast, children exhibited greater activity than adults in several regions, including sensorimotor areas, during the Target period. Children who activated cognitive control-related regions more during the Cue period tended to activate the Target signal age-related regions less, and this correlated with improved accuracy and reaction time on the task, as well as age. The results endorse previous findings that preparatory cognitive control systems are still developing in late childhood, but add new evidence of age-related shifts in activity at the trial level. PMID- 26972752 TI - Dorsal Anterior Cingulate, Medial Superior Frontal Cortex, and Anterior Insula Show Performance Reporting-Related Late Task Control Signals. AB - The cingulo-opercular network (including the dorsal anterior cingulate and bilateral anterior insula) shows 3 distinct task-control signals across a wide variety of tasks, including trial-related signals that appear to come online at or near the end of the trial. Previous work suggests that there are separable responses in this network for errors and ambiguity, implicating multiple types of processing units within these regions. Using a unique paradigm, we directly show that these separable responses withhold activity to the end of the trial, in the service of reporting performance back into the task set. Participants performed a slow reveal task where images were presented behind a black mask which was gradually degraded, and they pressed a button when they could recognize the object that was being revealed. A behavioral pilot was used to identify ambiguous stimuli. We found interactive effects of accuracy and ambiguity, which suggests that these regions are computing and utilizing information, at one time, about both types of performance indices. Importantly, we showed a relationship between cingulo-opercular activity and behavioral performance, suggesting a role for these regions in performance reporting, per se. We discuss these results in the context of task control. PMID- 26972755 TI - Comparison of Chevron and Distal Oblique Osteotomy for Bunion Correction. AB - The chevron osteotomy is a standard procedure by which bunions are corrected. One of us routinely performs a distal oblique osteotomy, which, to the best of our knowledge, has not been described for the correction of bunion deformities. The purpose of the present study was to compare the short- and medium-term results of the distal oblique and chevron osteotomies for bunion correction. We performed a retrospective clinical and radiographic comparison of patients who had undergone a distal oblique or chevron osteotomy for the correction of bunion deformity. In addition, a prospective patient satisfaction survey was undertaken. A total of 55 patients were included in the present study and were treated from January 2012 to November 2014. Of the 55 patients, 27 (49.2%) were in the chevron group and 28 (50.8%) in the distal oblique group. Radiographically, no statistically significant difference was found between the 2 groups with respect to postoperative first intermetatarsal angle (p < .0001) and hallux valgus angle (p < .0001), but a greater change was found in the intermetatarsal angle in the distal oblique group (p = .467). Prospective patient satisfaction scores were available for 33 patients (60%), 16 (29%) in the chevron group and 17 (31%) in the distal oblique group. When converting the satisfaction score to a numerical score, the chevron group scored 3.3 +/- 1.1 and the distal oblique group scored 3.2 +/- 0.8 (p = .812). We found that the distal oblique osteotomy used in the present study is simple and reliable and showed radiographic correction and patient satisfaction equivalent to those in the chevron osteotomy. PMID- 26972754 TI - Pseudoaneurysm of the Posterior Tibial Artery After Posterior Tibial Tendon Transfer. AB - Pseudoaneurysm of the posterior tibial artery is an uncommon condition that, left untreated, can lead to hemorrhage, thrombosis, or emboli. We present the case of a 54-year-old male who developed pseudoaneurysm of the posterior tibial artery 4 months after undergoing tibialis posterior tendon transfer for management of peroneal nerve palsy, which had developed as a complication of hip arthroplasty. PMID- 26972756 TI - Geographical venom variations of the Southeast Asian monocled cobra (Naja kaouthia): venom-induced neuromuscular depression and antivenom neutralization. AB - The Southeast Asian monocled cobras (Naja kaouthia) exhibit geographical variations in their venom proteomes, especially on the composition of neurotoxins. This study compared the neuromuscular depressant activity of the venoms of N. kaouthia from Malaysia (NK-M), Thailand (NK-T) and Vietnam (NK-V), and the neutralization of neurotoxicity by a monospecific antivenom. On chick biventer cervicis nerve-muscle preparation, all venoms abolished the indirect twitches, with NK-T venom being the most potent (shortest t90, time to 90% twitch inhibition), followed by NK-V and NK-M. Acetylcholine and carbachol failed to reverse the blockade, indicating irreversible/pseudo-irreversible post-synaptic neuromuscular blockade. KCl restored the twitches variably (NK-M preparation being the least responsive), consistent with different degree of muscle damage. The findings support that NK-T venom has the most abundant curarimimetic alpha neurotoxins, while NK-M venom contains more tissue-damaging cytotoxins. Pre incubation of tissue with N. kaouthia monovalent antivenom (NKMAV) prevented venom-induced twitch depression, with the NK-T preparation needing the largest antivenom dose. NKMAV added after the onset of neuromuscular depression could only halt the inhibitory progression but failed to restore full contraction. The findings highlight the urgency of early antivenom administration to sequester as much circulating neurotoxins as possible, thereby hastening toxin elimination from the circulation. In envenomed mice, NKMAV administered upon the first neurological sign neutralized the neurotoxic effect, with the slowest full recovery noticed in the NK-T group. This is consistent with the high abundance of neurotoxins in the NK-T venom, implying that a larger amount or repeated dosing of NKMAV may be required in NK-T envenomation. PMID- 26972757 TI - The effect of dietary lipid composition on the intestinal uptake and tissue distribution of benzo[a]pyrene and phenanthrene in Atlantic salmon (Salmo salar). AB - Uptake of polycyclic aromatic hydrocarbons (PAHs) across the intestine is suggested to occur in association with dietary lipids. Partial replacement of fish ingredients by vegetable ingredients in aquafeeds has led to increased levels of PAHs in marine farmed fish. We therefore investigated, intestinal uptake, tissue distribution and PAH metabolism after a single dose of (14)C benzo[a]pyrene (BaP) or (14)C-phenanthrene (PHE) given to Atlantic salmon (Salmo salar) acclimatized to a fish oil or vegetable oil based diet. Both BaP and PHE were absorbed along the intestine. Fish oil based feed increased BaP concentration in the pyloric caeca and that of PHE in the proximal intestine. In contrast, vegetable oil increased BaP concentrations in the distal intestine. Extraction of whole body autoradiograms removed PHE-associated radiolabeling almost completely from the intestinal mucosa, but not BaP-associated radiolabeling, indicating the presence of BaP metabolites bound to cellular macromolecules. This observation correlates with the increased cyp1a expression in the proximal intestine, distal intestine and liver in the BaP exposed group. Furthermore, BaP-induced cyp1a expression was higher in the distal intestine of salmon fed fish oil compared to the vegetable oil fed group. PHE had no significant effect on cyp1a expression in any of these tissues. We conclude that dietary lipid composition affects intestinal PAH uptake. Fish oil based feed increased intestinal PAH concentrations probably due to an enhanced solubility in micelles composed of fish oil fatty acids. Increased BaP accumulation in the distal intestine of vegetable oil fed fish seems to be associated with a reduced Cyp1a-mediated BaP metabolism. PMID- 26972758 TI - The model beetle Tribolium castaneum can be used as an early warning system for transgenerational epigenetic side effects caused by pharmaceuticals. AB - Pharmaceuticals are not currently tested for transgenerational and epigenetic side effects. The use of vertebrates as preclinical research models is limited by their long generation times, low numbers of progeny and ethical concerns. In contrast, invertebrates such as insects breed rapidly, produce many offspring and are more ethically acceptable, allowing them to be used for high-throughput screening. Here, we established Tribolium castaneum as a model to screen for the effect of drugs on complex fitness parameters and the expression of epigenetic regulatory genes. We tested diets supplemented with the psychoactive drug valproic acid (VPA), which is a histone deacetylase inhibitor, or the antioxidant curcumin, which is a histone acetyltransferase inhibitor. We found that VPA delayed development, reduced longevity, and increased female body weight compared to a control diet. Fertility and fecundity declined and the expression of epigenetic regulatory genes was induced in the untreated F1 generation. In contrast, curcumin did not affect development or body weight, but it increased longevity, caused a significant reduction in fertility, and induced the expression of epigenetic regulatory genes mostly in the treated F0 generation. VPA and curcumin administered to vertebrate models have similar effects to those we observed in T. castaneum, confirming that this beetle is potentially useful as an alternative model to screen for the epigenetic effect of drugs. T. castaneum also provides a valuable early warning system for transgenerational epigenetic risk factors that are difficult to detect in mammals. PMID- 26972760 TI - Behavior of failed bonded interfaces under in vitro cariogenic challenge. AB - OBJECTIVE: This in vitro study aimed to compare dentin wall caries development at different composite-dentin interfaces. METHODS: Dentin samples (10.4 mm(2)) were restored with composite resin using two adhesive systems (etch-and-rinse and self etch techniques). Different composite-dentin interfaces with gaps were produced: (a) failed bonded, which were fractured at interface after being submitted to aging protocols (no aging, mechanical loading or water storage); (b) non-bonded interfaces, both without any adhesive material or with adhesive material applied only on the dentin. Adhesively fractured and non-bonded samples were subjected to a lactic acid gel (pH=5) caries model with a continuous opening/closing movement of the interfacial gap for 10 days. Transverse wavelength-independent microradiographs were taken, and lesion depth and mineral loss were measured. Data were analyzed with linear mixed-effects regression models. RESULTS: Caries development differed among the composite-dentin interfaces (p<0.001). The non bonded interface with adhesive material on the dentin showed less lesion depth than the failed bonded groups, while the non-bonded interface without adhesive on dentin showed the deepest wall lesions. Difference between the adhesive systems was observed only in the non-bonded groups (p=0.003), with the self-etch adhesive applied on the dentin showing more severe lesions. Samples broken after mechanical loading aging showed deeper lesions than those broken after water storage (p<0.001). SIGNIFICANCE: Composite-dentin interfaces failed after aging presented different demineralization from interfaces that were never bonded, indicating that the restorative treatment changes the tissue in a way relevant to secondary caries development. PMID- 26972759 TI - Polypyrimidine tract-binding protein binds to the 5' untranslated region of the mouse mammary tumor virus mRNA and stimulates cap-independent translation initiation. AB - The 5' untranslated region (UTR) of the full-length mRNA of the mouse mammary tumor virus (MMTV) harbors an internal ribosomal entry site (IRES). In this study, we show that the polypyrimidine tract-binding protein (PTB), an RNA binding protein with four RNA recognition motifs (RRMs), binds to the MMTV 5' UTR stimulating its IRES activity. There are three isoforms of PTB: PTB1, PTB2, and PTB4. Results show that PTB1 and PTB4, but not PTB2, stimulate MMTV-IRES activity. PTB1 promotes MMTV-IRES-mediated initiation more strongly than PTB4. When expressed in combination, PTB1 further enhanced PTB4 stimulation of the MMTV IRES, while PTB2 fully abrogates PTB4-induced stimulation. PTB1-induced stimulation of MMTV-IRES was not altered in the presence of PTB4 or PTB2. Mutational analysis reveals that stimulation of MMTV-IRES activity is abrogated when PTB1 is mutated either in RRM1/RRM2 or RRM3/RRM4. In contrast, a PTB4 RRM1/RRM2 mutant has reduced effect over MMTV-IRES activity, while stimulation of the MMTV-IRES activity is still observed when the PTB4 RRM3/RMM4 mutant is used. Therefore, PTB1 and PTB4 differentially stimulate the IRES activity. In contrast, PTB2 acts as a negative modulator of PTB4-induced stimulation of MMTV-IRES. We conclude that PTB1 and PTB4 act as IRES trans-acting factors of the MMTV-IRES. PMID- 26972761 TI - Magnetic Resonance Imaging of Neurologic Complications Through the Treatment of Childhood Leukaemia and Lymphoma. PMID- 26972763 TI - Verified and validated finite element analyses of humeri. AB - BACKGROUND: Although ~200,000 emergency room visits per year in the US alone are associated with fractures of the proximal humerus, only limited studies exist on their mechanical response. We hypothesise that for the proximal humeri (a) the mechanical response can be well predicted by using inhomogeneous isotropic material properties, (b) the relation between bone elastic modulus and ash density (E(rhoash)) is similar for the humerus and the femur, and may be general for long bones, and (c) it is possible to replicate a proximal humerus fracture in vitro by applying uniaxial compression on humerus' head at a prescribed angle. METHODS: Four fresh frozen proximal humeri were CT-scanned, instrumented by strain-gauges and loaded at three inclination angles. Thereafter head displacement was applied to obtain a fracture. CT-based high order (p-) finite element (FE) and classical (h-) FE analyses were performed that mimic the experiments and predicted strains were compared to the experimental observations. RESULTS: The E(rhoash) relationship appropriate for the femur is equally appropriate for the humeri: predicted strains in the elastic range showed an excellent agreement with experimental observations with a linear regression slope of m=1.09 and a coefficient of regression R(2)=0.98. p-FE and h-FE results were similar for the linear elastic response. Although fractures of the proximal humeri were realised in the in vitro experiments, the contact FE analyses (FEA) were unsuccessful in representing properly the experimental boundary conditions. DISCUSSION: The three hypotheses were confirmed and the linear elastic response of the proximal humerus, attributed to a stage at which the cortex bone is intact, was well predicted by the FEA. Due to a large post-elastic behaviour following the cortex fracture, a new non-linear constitutive model for proximal humerus needs to be incorporated into the FEA to well represent proximal humerus fractures. Thereafter, more in vitro experiments are to be performed, under boundary conditions that may be well represented by the FEA, to allow a reliable simulation of the fracture process. PMID- 26972762 TI - Hemodynamics of the string phenomenon in the internal thoracic artery grafted to the left anterior descending artery with moderate stenosis. AB - PURPOSE: The internal thoracic artery is the choice of graft for coronary artery bypass grafting due to the excellent long-term patency. However internal thoracic artery graft failures still occur due to diffuse narrowing, known as the string phenomenon. Studies suggest that the string phenomenon is caused by competitive flow when the coronary stenosis is not serious, but the hemodynamics of the string phenomenon are still unclear. The purpose of this study is to clarify the hemodynamic characteristics of the string phenomenon. MATERIALS: A patient specific 3-dimensional model of the aortic arch and coronary arteries was reconstructed. A moderate stenosis was applied to the left anterior descending artery. The internal thoracic artery was used to bypass the stenosis. Two further 3D models were built to study the hemodynamics of the string phenomenon. METHODS: A numerical study was performed by coupling the 3D artery model with 0 dimensional lumped parameter model of the cardiovascular system. RESULTS: The graft flow, native coronary flow, wall shear stress and oscillatory shear index were calculated and illustrated. Inverse flow and high oscillatory shear index appeared on the internal thoracic artery graft when the stenosis was moderate. CONCLUSION: High oscillatory shear index might be the major hemodynamic characteristic of the string phenomenon in internal thoracic artery graft. The inverse graft flow and the difference in graft flow caused by clamping the stenosis can be used to evaluate the probability of observing the string phenomenon. PMID- 26972764 TI - Mechanical behaviour of Bioactive Glass granules and morselized cancellous bone allograft in load bearing defects. AB - Bioactive Glass (BAG) granules are osteoconductive and possess unique antibacterial properties for a synthetic biomaterial. To assess the applicability of BAG granules in load-bearing defects, the aim was to compare mechanical behaviour of graft layers consisting of BAG granules and morselized cancellous bone allograft in different volume mixtures under clinically relevant conditions. The graft layers were mechanically tested, using two mechanical testing modalities with simulated physiological loading conditions: highly controllable confined compression tests (CCT) and more clinically realistic in situ compression tests (ISCT) in cadaveric porcine bone defects. Graft layer impaction strain, residual strain, aggregate modulus, and creep strain were determined in CCT. Graft layer porosity was determined using micro computed tomography. The ISCT was used to determine graft layer subsidence in bone environment. ANOVA showed significant differences (p<0.001) between different graft layer compositions. True strains absolutely decreased for increasing BAG content: impaction strain -0.92 (allograft) to -0.39 (BAG), residual strain -0.12 to 0.01, and creep strain -0.09 to 0.00 respectively. Aggregate modulus increased with increasing BAG content from 116 to 653MPa. Porosity ranged from 66% (pure allograft) to 15% (pure BAG). Subsidence was highest for allograft, and remarkably low for a 1:1 BAG-allograft volume mixture. Both BAG granules and allograft morsels as stand-alone materials exhibit suboptimal mechanical behaviour for load-bearing purpose. BAG granules are difficult to handle and less porous, whereas allograft subsides and creeps. A 1:1 volume mixture of BAG and allograft is therefore proposed as the best graft material in load-bearing defects. PMID- 26972765 TI - FRAME (Force Review Automation Environment): MATLAB-based AFM data processor. AB - Data processing of force-displacement curves generated by atomic force microscopes (AFMs) for elastic moduli and unbinding event measurements is very time consuming and susceptible to user error or bias. There is an evident need for consistent, dependable, and easy-to-use AFM data processing software. We have developed an open-source software application, the force review automation environment (or FRAME), that provides users with an intuitive graphical user interface, automating data processing, and tools for expediting manual processing. We did not observe a significant difference between manually processed and automatically processed results from the same data sets. PMID- 26972766 TI - Sample-specific adaption of an improved electro-mechanical model of in vitro cardiac tissue. AB - We present an electromechanically coupled computational model for the investigation of a thin cardiac tissue construct consisting of human-induced pluripotent stem cell-derived atrial, ventricular and sinoatrial cardiomyocytes. The mechanical and electrophysiological parts of the finite element model, as well as their coupling are explained in detail. The model is implemented in the open source finite element code Code_Aster and is employed for the simulation of a thin circular membrane deflected by a monolayer of autonomously beating, circular, thin cardiac tissue. Two cardio-active drugs, S-Bay K8644 and veratridine, are applied in experiments and simulations and are investigated with respect to their chronotropic effects on the tissue. These results demonstrate the potential of coupled micro- and macroscopic electromechanical models of cardiac tissue to be adapted to experimental results at the cellular level. Further model improvements are discussed taking into account experimentally measurable quantities that can easily be extracted from the obtained experimental results. The goal is to estimate the potential to adapt the presented model to sample specific cell cultures. PMID- 26972768 TI - The relations between marital quality, social support, social acceptance and coping strategies among the infertile Iranian couples. AB - OBJECTIVE: Researchers aimed to assess marital quality among the infertile couples undergoing assistive reproductive treatments and their coping strategies, social support and social acceptance. METHODS: In a cross-sectional study, 133 infertile couples undergoing assisted reproductive treatments were assessed for marital satisfaction, conflict resolution and marital communication, and coping strategies, using a self-report questionnaire. Also, the level of perceived social support and social acceptance as moderator variables were measured. Data were analyzed using independent t test, Pearson correlation coefficient, and linear regressions, after adjusting for age, cause of infertility and the duration of infertility. RESULTS: No significant difference was found in the use of various coping strategies between couples. The correlation for marital satisfaction, marital communication and conflict resolution by using some coping strategy and the level of perceived social acceptance were significantly positive among women. Also, marital relationships had a positive and significant correlation with the level of perceived social support for men. But, unlike women, the couples' scales were significant for the perceived social support. The use of different coping strategies by men and women had a positive correlation with their perceived social support. CONCLUSION: Coping strategies used by the infertile couples had an important role in different aspects of their married life in search of marital satisfaction, and intermediates by the perceived social acceptance for women and social support for men. PMID- 26972767 TI - Meta-analyses of associations between interleukin-10 polymorphisms and susceptibility to recurrent pregnancy loss. AB - OBJECTIVE: The aim of this study was to investigate whether interleukin-10 (IL 10) polymorphisms are associated with susceptibility to recurrent pregnancy loss (RPL). METHODS: We conducted a literature search using the PubMed and EMBASE databases and performed meta-analyses on the associations between IL-10 -1082 G/A, -819 C/T, and -592 C/A polymorphisms and RPL, using fixed- or random-effects models. RESULTS: A total of 15 papers involving 1858 RPL patients and 1949 controls were considered in this study. Meta-analysis of IL-10 -1082 G/A polymorphism revealed no association between RPL and the IL-10 -1082 G allele (OR=0.999, 95% CI=0.815-1.223, p=0.989). However, meta-analysis of IL-10 -819 C/T polymorphism in all study subjects revealed an association between RPL and the IL 10 -819 C allele (OR=0.680, 95% CI=0.498-0.927, p=0.015). Stratification by ethnicity indicated an association between the IL-10 -819 C allele and RPL in the Asian group (OR=0.421, 95% CI=0.226-0.783, p=0.006), but not in the Caucasian and Arab groups (OR=1.053, 95% CI=0.218-5.077, p=0.949, and OR=0.800, 95% CI=0.606 1.081, p=0.152, respectively). Furthermore, a relationship between the IL-10 -592 C allele and RPL was identified in the Asian group (OR=0.763, 95% CI=0.633-0.919, p=0.004), but not in the Caucasian and Arab groups. CONCLUSIONS: The meta analyses demonstrate that IL-10 -819 C/T and -592 C/A polymorphisms are associated with RPL susceptibility in Asian women, but not in the Caucasian and Arab populations. PMID- 26972769 TI - Viral evasion of DNA-stimulated innate immune responses. AB - Cellular sensing of virus-derived nucleic acids is essential for early defenses against virus infections. In recent years, the discovery of DNA sensing proteins, including cyclic GMP-AMP synthase (cGAS) and gamma-interferon-inducible protein (IFI16), has led to understanding of how cells evoke strong innate immune responses against incoming pathogens carrying DNA genomes. The signaling stimulated by DNA sensors depends on the adaptor protein STING (stimulator of interferon genes), to enable expression of antiviral proteins, including type I interferon. To facilitate efficient infections, viruses have evolved a wide range of evasion strategies, targeting host DNA sensors, adaptor proteins and transcription factors. In this review, the current literature on virus-induced activation of the STING pathway is presented and we discuss recently identified viral evasion mechanisms targeting different steps in this antiviral pathway. PMID- 26972770 TI - 4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8+ T cell proliferation. AB - 4-1BB (CD137) is a strong enhancer of the proliferation of CD8+ T cells. Since these cells require increased production of energy and biomass to support their proliferation, we hypothesized that 4-1BB signaling activated glucose and fatty acid metabolism. We found that treatment with agonistic anti-4-1BB mAb promoted the proliferation of CD8+ T cells in vitro, increasing their size and granularity. Studies with a glycolysis inhibitor and a fatty acid oxidation inhibitor revealed that CD8+ T cell proliferation required both glucose and fatty acid metabolism. Anti-4-1BB treatment increased glucose transporter 1 expression and activated the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) acetyl-CoA carboxylase (ACC) signaling pathway, which may be responsible for activating the metabolism of glucose and fatty acids. We also examined whether blocking glucose or fatty acid metabolism affected cell cycle progression and the anti-apoptotic effect of 4-1BB signaling. The increase of anti-apoptotic factors and cyclins in response to anti-4-1BB treatment was completely prevented by treating CD8+ T cells with the fatty acid oxidation inhibitor, etomoxir, but not with the glycolysis inhibitor, 2-deoxy-D-glucose. We conclude that anti-4-1BB treatment activates glucose and fatty acid metabolism thus supporting the increased demand for energy and biomass, and that fatty acid metabolism plays a crucial role in enhancing the cell cycle progression of anti-CD3-activated CD8+ T cells in vitro and the anti-apoptotic effects of 4-1BB signaling on these cells. PMID- 26972771 TI - Secretory IgA in complex with Lactobacillus rhamnosus potentiates mucosal dendritic cell-mediated Treg cell differentiation via TLR regulatory proteins, RALDH2 and secretion of IL-10 and TGF-beta. AB - The importance of secretory IgA in controlling the microbiota is well known, yet how the antibody affects the perception of the commensals by the local immune system is still poorly defined. We have previously shown that the transport of secretory IgA in complex with bacteria across intestinal microfold cells results in an association with dendritic cells in Peyer's patches. However, the consequences of such an interaction on dendritic cell conditioning have not been elucidated. In this study, we analyzed the impact of the commensal Lactobacillus rhamnosus, alone or associated with secretory IgA, on the responsiveness of dendritic cells freshly recovered from mouse Peyer's patches, mesenteric lymph nodes, and spleen. Lactobacillus rhamnosus-conditioned mucosal dendritic cells are characterized by increased expression of Toll-like receptor regulatory proteins [including single immunoglobulin interleukin-1 receptor-related molecule, suppressor of cytokine signaling 1, and Toll-interacting molecule] and retinaldehyde dehydrogenase 2, low surface expression of co-stimulatory markers, high anti- versus pro-inflammatory cytokine production ratios, and induction of T regulatory cells with suppressive function. Association with secretory IgA enhanced the anti-inflammatory/regulatory Lactobacillus rhamnosus-induced conditioning of mucosal dendritic cells, particularly in Peyer's patches. At the systemic level, activation of splenic dendritic cells exposed to Lactobacillus rhamnosus was partially dampened upon association with secretory IgA. These data suggest that secretory IgA, through coating of commensal bacteria, contributes to the conditioning of mucosal dendritic cells toward tolerogenic profiles essential for the maintenance of intestinal homeostasis. PMID- 26972773 TI - Spatial Inferences in Narrative Comprehension: the Role of Verbal and Spatial Working Memory. AB - During the comprehension of narrative texts, readers keep a mental representation of the location of protagonists and objects; a breach in spatial coherence is detected by longer online reading times (consistency effect). We addressed whether these spatial inferences involve verbal or spatial working memory in two experiments, combining the consistency paradigm with selective verbal and spatial working memory concurrent tasks. The first experiment found longer reading times with a concurrent spatial task under imagery instructions (t33 = 2.87, p = .021). The second experiment, under comprehension reading instructions, found effects of verbal interference on reading times and accuracy. With a verbal secondary task, reading times for the target sentence were shorter (t45 = 3.60, p = .004) and the error rate was significantly higher (t47 = 2.95, p = .005) than without interference. This pattern of results suggests that spatial inferences in narrative comprehension rely mainly on verbal resources, and spatial working memory resources are recruited when imagery is required. PMID- 26972774 TI - Motion and distortion correction of skeletal muscle echo planar images. AB - This paper examines two artifacts facing researchers who use gradient echo (GRE) echo planar imaging (EPI) for time series studies of skeletal muscles in limbs. The first is through-plane blood flow during the acquisition, causing a vessel motion artifact that inhibits proper motion correction of the data. The second is distortion of EPI images caused by B0 field inhomogeneities. Though software tools are available for correcting these artifacts in brain EPI images, the tools do not perform well on muscle images. The severity of the two artifacts was described using image similarity measures, and the data was processed with both a conventional motion correction program and custom written tools. The conventional program did not perform well on the limb images, in fact significantly degrading image quality in some trials. Data is presented which proves that arterial pulsatile signal caused the impairment in motion correction. The new tools were shown to perform much better, achieving substantial motion correction and distortion correction of the muscle EPI images. PMID- 26972775 TI - Motor function of the recurrent laryngeal nerve: Sometimes motor fibers are also located in the posterior branch. AB - BACKGROUND: The function of the extralaryngeal branches of the recurrent laryngeal nerve (RLN) has yet to be described precisely. The goal of this study was to evaluate the incidence and motor function of the extralaryngeal branches of the RLN. METHODS: Our study group consisted of 335 consecutive patients undergoing thyroid and parathyroid operations in whom the branches of the RLNs (n = 200) were evaluated with intraoperative nerve monitoring and by measuring the distance from the point of branching of the RLN into anterior and posterior branches and the entry of the individual branches into the larynx-defined as the branching distance. Anterior and posterior branches of the RLN were assessed separately by electromyography (using a standard electromyography endotracheal tube) for adduction and by finger palpation for abduction. The RLNs were classified as having motor function only in the anterior branches (Group 1) or function both in the anterior and posterior branches (Group 2). RESULTS: There were 185 RLNs in Group 1 and 15 RLNs in Group 2, assessed by intraoperative nerve monitoring. Motor function was detected in all anterior branches of the RLN (100%) and in 8% of the posterior branches. The mean branching distance was greater in Group 2 compared with Group 1 (24.1 +/- 13.6 mm, 17.3 +/- 8.5 mm, respectively, P = .045). CONCLUSION: Although the anterior branch of RLN always has motor function, the posterior branch also has motor function in about 8% of patients. The probability of detecting motor function in the posterior branch was greater among early branching RLNs, which have a greater branching distance. The surgeon should remember that posterior branches may contain motor fibers and protect these branches to avoid postoperative vocal cord dysfunction. PMID- 26972772 TI - NKT cell subsets as key participants in liver physiology and pathology. AB - Natural killer T (NKT) cells are innate-like lymphocytes that generally recognize lipid antigens and are enriched in microvascular compartments of the liver. NKT cells can be activated by self- or microbial-lipid antigens and by signaling through toll-like receptors. Following activation, NKT cells rapidly secrete pro inflammatory or anti-inflammatory cytokines and chemokines, and thereby determine the milieu for subsequent immunity or tolerance. It is becoming clear that two different subsets of NKT cells-type I and type II-have different modes of antigen recognition and have opposing roles in inflammatory liver diseases. Here we focus mainly on the roles of both NKT cell subsets in the maintenance of immune tolerance and inflammatory diseases in liver. Furthermore, how the differential activation of type I and type II NKT cells influences other innate cells and adaptive immune cells to result in important consequences for tissue integrity is discussed. It is crucial that better reagents, including CD1d tetramers, be used in clinical studies to define the roles of NKT cells in liver diseases in patients. PMID- 26972776 TI - Evaluating the Oxidative Stress in Renal Diseases: What Is the Role for S Glutathionylation? AB - SIGNIFICANCE: Reactive oxygen species (ROS) have long been considered as toxic derivatives of aerobic metabolism displaying a harmful effect to living cells. Deregulation of redox homeostasis and production of excessive free radicals may contribute to the pathogenesis of kidney diseases. In line, oxidative stress increases in patients with renal dysfunctions due to a general increase of ROS paralleled by impaired antioxidant ability. RECENT ADVANCES: Emerging evidence revealed that physiologically, ROS can act as signaling molecules interplaying with several transduction pathways such as proliferation, differentiation, and apoptosis. ROS can exert signaling functions by modulating, at different layers, protein oxidation since proteins have "cysteine switches" that can be reversibly reduced or oxidized, supporting the dynamic signaling regulation function. In this scenario, S-glutathionylation is a posttranslational modification involved in oxidative cellular response. CRITICAL ISSUES: Although it is widely accepted that renal dysfunctions are often associated with altered redox signaling, the relative role of S-glutathionylation on the pathogenesis of specific renal diseases remains unclear and needs further investigations. In this review, we discuss the impact of ROS in renal health and diseases and the role of selective S-glutathionylation proteins potentially relevant to renal physiology. FUTURE DIRECTIONS: The paucity of studies linking the reversible protein glutathionylation with specific renal disorders remains unmet. The growing number of S-glutathionylated proteins indicates that this is a fascinating area of research. In this respect, further studies on the association of reversible glutathionylation with renal diseases, characterized by oxidative stress, may be useful to develop new pharmacological molecules targeting protein S glutathionylation. Antioxid. Redox Signal. 25, 147-164. PMID- 26972778 TI - Isoreticular zirconium-based metal-organic frameworks: discovering mechanical trends and elastic anomalies controlling chemical structure stability. AB - Understanding the mechanical properties of metal-organic frameworks (MOFs) is crucial not only to yield robust practical applications, but also to advance fundamental research underpinning the flexibility of a myriad of open-framework chemical compounds. Herein we present one of the most comprehensive structural analyses yet on MOF-mechanics: elucidating the complex elastic response of an isoreticular series of topical Zr-based MOFs, explaining all the important mechanical properties, and identifying major trends arising from systematic organic linker exchange. Ab initio density functional theory (DFT) was employed to establish the single-crystal elastic constants of the nanoporous MIL-140(A-D) structures, generating a complete 3-D representation of the principal mechanical properties, encompassing the Young's modulus, shear modulus, linear compressibility and Poisson's ratio. Of particular interest, we discovered significantly high values of both positive and negative linear compressibility and Poisson's ratio, whose framework molecular mechanisms responsible for such elastic anomalies have been fully revealed. In addition to pinpointing large elastic anisotropy and unusual physical properties, we analyzed the bulk modulus of isoreticular Zr-MOF compounds to understand the framework structural resistance against the hydrostatic pressure, and determined the averaged mechanical behaviour of bulk (polycrystalline) MOF materials important for the design of emergent applications. PMID- 26972777 TI - Evaluation of efficiency of nested multiplex allele-specific PCR assay for detection of multidrug resistant tuberculosis directly from sputum samples. AB - For an effective control of tuberculosis, rapid detection of multidrug resistant tuberculosis (MDR-TB) is necessary. Therefore, we developed a modified nested multiplex allele-specific polymerase chain reaction (MAS-PCR) method that enables rapid MDR-TB detection directly from sputum samples. The efficacy of this method was evaluated using 79 sputum samples collected from suspected tuberculosis patients. The performance of nested MAS-PCR method was compared with other MDR-TB detection methods like drug susceptibility testing (DST) and DNA sequencing. As rifampicin (RIF) resistance conforms to MDR-TB in greater than 90% cases, only the presence of RIF-associated mutations in rpoB gene was determined by DNA sequencing and nested MAS-PCR to detect MDR-TB. The concordance between nested MAS-PCR and DNA sequencing results was found to be 96.3%. When compared with DST, the sensitivity and specificity of nested MAS-PCR for RIF-resistance detection were determined to be 92.9 and 100% respectively. SIGNIFICANCE AND IMPACT OF THE STUDY: For developing- and high-TB burden countries, molecular-based tests have been recommended by the World Health Organization for rapid detection of MDR-TB. The results of this study indicate that, nested MAS-PCR assay might be a practical and relatively cost effective molecular method for rapid detection of MDR-TB from suspected sputum samples in developing countries with resource poor settings. PMID- 26972779 TI - Editorial overview: Biocatalysis and Biotransformation: Esoteric, Niche Enzymology. PMID- 26972781 TI - Self-Assembled Pyridine-Dipyrrolate Cages. AB - An inherently nonlinear pyridine dipyrrolate ligand, namely 2,6-bis(3,4-diethyl-5 carboxy-1H-pyrrol-2yl)pyridine (compound 1), is able to distinguish between different zinc(II) cation sources, namely Zn(acac)2 and Zn(OAc)2, respectively. This differentiation is manifest both in terms of the observed fluorescent behavior in mixed organic media and the reaction chemistry. Treatment of 1 with Zn(acac)2 gives rise to a cage dimer, cage-1, wherein two molecules of compound 1 act as double bridging units to connect two individual cage subunits. As inferred from X-ray crystallographic studies, this cage system consists of discrete zinc dimers with hydroxide bridges that, with the assistance of bound DMF solvent molecules, serve to fix the geometry and orientation of the pyridine dipyrrolate building blocks. When a different zinc source, Zn(OAc)2, is used to carry out an ostensibly similar complexation reaction with compound 1, an acetate-bridged 1D abacus-like cage polymer is obtained as inferred from X-ray diffraction analysis. This extended solid state structure, cage-2, contains individual zinc dimer cage submits and appears stabilized by solvent molecules (DMF) and the counteranion (acetate). Rod-like assemblies are also observed by DLS and SEM. This construct, in contrast to cage-1, proved fluorescent in mixed organic media. The structure of the ligand itself (i.e., in the absence of Zn(II)) was confirmed by X-ray crystallographic analysis and was found to assemble into a supramolecular polymer. Conversion to a dimer form was seen upon the addition of TBAOAc. On the basis of the metric parameters, the structures seen in the solid state are stabilized via hydrogen bonding interactions involving solvent molecules. PMID- 26972780 TI - Medroxyprogesterone acetate levels among Kenyan women using depot medroxyprogesterone acetate in the FEM-PrEP trial. AB - OBJECTIVE: To describe medroxyprogesterone acetate (MPA) levels among Kenyan depot medroxyprogesterone acetate (DMPA) users in the FEM-PrEP HIV prevention trial, and to compare MPA levels between ARV for HIV prevention (treatment) and placebo groups. STUDY DESIGN: We measured MPA in previously collected plasma samples from 63 Kenyan trial participants who used DMPA for one or two complete intervals. We separately assessed MPA levels among the nine DMPA users who became pregnant at this site. RESULTS: Mean MPA levels at the end of each 12week injection interval were 0.37ng/ml (95% CI: 0.25, 1.99) and 0.28ng/ml (95% CI: 0.19, 1.22) among participants assigned TDF/FTC and 0.49 (95% CI: 0.40, 1.27) and 0.39 (95% CI: 0.31, 1.17) among those assigned placebo. The difference between groups was not statistically significant overall, or in an analysis which adjusted for the observed low adherence to TDF/FTC. Unanticipated findings of this analysis were low 12-week MPA levels among DMPA users in both study arms. Of 61 women who contributed data for the first DMPA injection interval, 26.2% had MPA levels<0.1ng/ml and 9.8% had levels below the detection level (0.02ng/ml) at 12weeks post-injection. Levels were similar at the end of the second injection interval. Five of nine women who became pregnant had levels below 0.15ng/mL at the time of their last negative pregnancy test. CONCLUSIONS: Use of TDF/FTC did not appear to affect serum MPA levels, however we found lower than expected MPA concentrations at the end of the dosing interval among DMPA users in the FEM-PrEP trial, the cause of which are unknown. IMPLICATIONS: This study presents some of the few available data on MPA levels among DMPA users in Africa. The low levels among users described here, together with a number of pregnancies among DMPA users, are potentially concerning and require further investigation. PMID- 26972782 TI - Nanoscale Mapping of Dielectric Properties of Nanomaterials from Kilohertz to Megahertz Using Ultrasmall Cantilevers. AB - Electrostatic force microscopy (EFM) is often used for nanoscale dielectric spectroscopy, the measurement of local dielectric properties of materials as a function of frequency. However, the frequency range of atomic force microscopy (AFM)-based dielectric spectroscopy has been limited to a few kilohertz by the resonance frequency and noise of soft microcantilevers used for this purpose. Here, we boost the frequency range of local dielectric spectroscopy by 3 orders of magnitude from a few kilohertz to a few megahertz by developing a technique that exploits the high resonance frequency and low thermal noise of ultrasmall cantilevers (USCs). We map the frequency response of the real and imaginary components of the capacitance gradient (?C(omega)/?z) by using second-harmonic EFM and a theoretical model, which relates cantilever dynamics to the complex dielectric constant. We demonstrate the method by mapping the nanoscale dielectric spectrum of polymer-based materials for organic electronic devices. Beyond offering a powerful extension to AFM-based dielectric spectroscopy, the approach also allows the identification of electrostatic excitation frequencies which affords high dielectric contrast on nanomaterials. PMID- 26972783 TI - Progress in the understanding and utilization of biologic response modifiers in the treatment of uveitis. AB - Uveitis is the third most common cause of blindness in developed countries. Considering the systemic and local complications of long-term corticosteroid therapy and the intolerance due to side effects and ineffectiveness of conventional chemotherapy, use of biologic response modifiers is a reasonable alternative in the treatment of non-infectious uveitis and persistent uveitic macular edema. The majority of the evidence presented here comes from open uncontrolled analyses. Based on these studies, tumor necrosis factor alpha inhibitors, especially infliximab and adalimumab, have been shown to be effective in the treatment of non-infectious uveitis in numerous studies. More research is necessary, particularly multi-center randomized clinical trials, to address the choice of biologic response modifier agent and the length of treatment as we employ biologic response modifiers in different types of uveitis and persistent uveitic macular edema. PMID- 26972784 TI - AFBI assay - Aptamer Fluorescence Binding and Internalization assay for cultured adherent cells. AB - The SELEX (Systematic Evolution of Ligands by Exponential Enrichment) process allows for the enrichment of DNA or RNA aptamers from a complex nucleic acid library that are specific for a target molecule. The SELEX process has been adapted from identifying aptamers in vitro using recombinant target protein to cell-based methodologies (Cell-SELEX), where the targets are expressed on the surface of cells. One major advantage of Cell-SELEX is that the target molecules are maintained in a native confirmation. Additionally, Cell-SELEX may be used to discover novel therapeutic biomarkers by performing selections on diseased versus healthy cells. However, a caveat to Cell-SELEX is that testing of single aptamers identified in the selection is laborious, time-consuming, and expensive. The most frequently used methods to screen for aptamer binding and internalization on cells are flow cytometry and quantitative PCR (qPCR). While flow cytometry can directly assess binding of a fluorescently-labeled aptamer to a target, it requires significant starting material and is not easily scalable. qPCR-based approaches are highly sensitive but have non-negligible experiment-to-experiment variability due to the number of sample processing steps. Herein we describe a cell-based aptamer fluorescence binding and internalization (AFBI) assay. This assay requires minimal reagents and has few experimental steps/manipulations, thereby allowing for rapid screening of many aptamers and conditions simultaneously and direct quantitation of aptamer binding and internalization. PMID- 26972786 TI - In vitro RNA SELEX for the generation of chemically-optimized therapeutic RNA drugs. AB - Aptamers are single-stranded DNA or RNA oligonucleotides that can bind with exquisitely high affinity and specificity to target molecules and are thus often referred to as 'nucleic acid' antibodies. Oligonucleotide aptamers are derived through a process of directed chemical evolution called SELEX (Systematic Evolution of Ligands by Exponential enrichment). This chemical equivalent of Darwinian evolution was first described in 1990 by Tuerk & Gold and Ellington & Szostak and has since yielded aptamers for a wide-range of applications, including biosensor technologies, in vitro diagnostics, biomarker discovery, and therapeutics. Since the inception of the original SELEX method, numerous modifications to the protocol have been described to fit the choice of target, specific conditions or applications. Technologies such as high-throughput sequencing methods and microfluidics have also been adapted for SELEX. In this chapter, we outline key steps in the SELEX process for enabling the rapid identification of RNA aptamers for in vivo applications. Specifically, we provide a detailed protocol for the selection of chemically-optimized RNA aptamers using the original in vitro SELEX methodology. In addition, methods for performing next generation sequencing of the RNAs from each round of selection, based on Illumina sequencing technology, are discussed. PMID- 26972785 TI - High resolution laser mass spectrometry bioimaging. AB - Mass spectrometry imaging (MSI) was introduced more than five decades ago with secondary ion mass spectrometry (SIMS) and a decade later with laser desorption/ionization (LDI) mass spectrometry (MS). Large biomolecule imaging by matrix-assisted laser desorption/ionization (MALDI) was developed in the 1990s and ambient laser MS a decade ago. Although SIMS has been capable of imaging with a moderate mass range at sub-micrometer lateral resolution from its inception, laser MS requires additional effort to achieve a lateral resolution of 10MUm or below which is required to image at the size scale of single mammalian cells. This review covers untargeted large biomolecule MSI using lasers for desorption/ionization or laser desorption and post-ionization. These methods include laser microprobe (LDI) MSI, MALDI MSI, laser ambient and atmospheric pressure MSI, and near-field laser ablation MS. Novel approaches to improving lateral resolution are discussed, including oversampling, beam shaping, transmission geometry, reflective and through-hole objectives, microscope mode, and near-field optics. PMID- 26972788 TI - False-negative rate, limit of detection and recovery efficiency performance of a validated macrofoam-swab sampling method for low surface concentrations of Bacillus anthracis Sterne and Bacillus atrophaeus spores. AB - AIMS: We sought to evaluate the effects of Bacillus species, low surface concentrations, and surface material on recovery efficiency (RE), false-negative rate (FNR) and limit of detection for recovering Bacillus spores using a validated macrofoam-swab sampling procedure. METHODS AND RESULTS: The performance of a macrofoam-swab sampling method was evaluated using Bacillus anthracis Sterne (BAS) and Bacillus atrophaeus Nakamura (BG) spores applied at nine low target surface concentrations (2 to 500 CFU per plate or coupon) to positive-control plates and test coupons (25.8064 cm(2) ) of four surface materials (glass, stainless steel, vinyl tile and plastic). The Bacillus species and surface material had statistically significant effects on RE, but surface concentration did not. Mean REs were the lowest for vinyl tile (50.8% with BAS and 40.2% with BG) and the highest for glass (92.8% with BAS and 71.4% with BG). FNR values (which ranged from 0 to 0.833 for BAS and from 0 to 0.806 for BG) increased as surface concentration decreased in the range tested. Surface material also had a statistically significant effect on FNR, with FNR the lowest for glass and highest for vinyl tile. Finally, FNR tended to be higher for BG than for BAS at lower surface concentrations, especially for glass. CONCLUSIONS: Concentration and surface material had significant effects on FNR, with Bacillus species having a small effect. Species and surface material had significant effects on RE, with surface concentration having a nonsignificant effect. SIGNIFICANCE AND IMPACT OF THE STUDY: The results provide valuable information on the performance of the macrofoam-swab method for low surface concentrations of Bacillus spores, which can be adapted to assess the likelihood that there is no contamination when all macrofoam-swab samples fail to detect B. anthracis. PMID- 26972787 TI - Structural computational modeling of RNA aptamers. AB - RNA aptamers represent an emerging class of biologics that can be easily adapted for personalized and precision medicine. Several therapeutic aptamers with desirable binding and functional properties have been developed and evaluated in preclinical studies over the past 25years. However, for the majority of these aptamers, their clinical potential has yet to be realized. A significant hurdle to the clinical adoption of this novel class of biologicals is the limited information on their secondary and tertiary structure. Knowledge of the RNA's structure would greatly facilitate and expedite the post-selection optimization steps required for translation, including truncation (to reduce costs of manufacturing), chemical modification (to enhance stability and improve safety) and chemical conjugation (to improve drug properties for combinatorial therapy). Here we describe a structural computational modeling methodology that when coupled to a standard functional assay, can be used to determine key sequence and structural motifs of an RNA aptamer. We applied this methodology to enable the truncation of an aptamer to prostate specific membrane antigen (PSMA) with great potential for targeted therapy that had failed previous truncation attempts. This methodology can be easily applied to optimize other aptamers with therapeutic potential. PMID- 26972790 TI - Substance use stigma: Reliability and validity of a theory-based scale for substance-using populations. AB - BACKGROUND: Substance use disorders consistently rank among the most stigmatized conditions worldwide. Thus, substance use stigma fosters health inequities among persons with substance use disorders and remains a key barrier to successful screening and treatment efforts. Current efforts to measure substance use stigma are limited. This study aims to advance measurement efforts by drawing on stigma theory to develop and evaluate the Substance Use Stigma Mechanisms Scale (SU SMS). The SU-SMS was designed to capture enacted, anticipated, and internalized Substance Use Stigma Mechanisms among persons with current and past substance use disorders, and distinguish between key stigma sources most likely to impact this target population. METHODS: This study was a cross-sectional evaluation of the validity, reliability, and generalizability of the SU-SMS across two independent samples with diverse substance use and treatment histories. RESULTS: Findings support the structural and construct validity of the SU-SMS, suggesting the scale was able to capture enacted, anticipated, and internalized stigma as distinct stigma experiences. It also further differentiated between two distinct stigma sources (family and healthcare providers). Analysis of these mechanisms and psychosocial metrics suggests that the scale is also associated with other health related outcomes. Furthermore, the SU-SMS demonstrated high levels of internal reliability and generalizability across two independent samples of persons with diverse substance use disorders and treatment histories. CONCLUSION: The SU-SMS may serve as a valuable tool for better understanding the processes through which substance use stigma serves to undermine key health behaviors and outcomes among persons with substance use disorders. PMID- 26972789 TI - Glucose-Dependent Insulinotropic Polypeptide Ameliorates Mild Traumatic Brain Injury-Induced Cognitive and Sensorimotor Deficits and Neuroinflammation in Rats. AB - Mild traumatic brain injury (mTBI) is a major public health issue, representing 75-90% of all cases of TBI. In clinical settings, mTBI, which is defined as a Glascow Coma Scale (GCS) score of 13-15, can lead to various physical, cognitive, emotional, and psychological-related symptoms. To date, there are no pharmaceutical-based therapies to manage the development of the pathological deficits associated with mTBI. In this study, the neurotrophic and neuroprotective properties of glucose-dependent insulinotropic polypeptide (GIP), an incretin similar to glucagon-like peptide-1 (GLP-1), was investigated after its steady-state subcutaneous administration, focusing on behavior after mTBI in an in vivo animal model. The mTBI rat model was generated by a mild controlled cortical impact (mCCI) and used to evaluate the therapeutic potential of GIP. We used the Morris water maze and novel object recognition tests, which are tasks for spatial and recognition memory, respectively, to identify the putative therapeutic effects of GIP on cognitive function. Further, beam walking and the adhesive removal tests were used to evaluate locomotor activity and somatosensory functions in rats with and without GIP administration after mCCI lesion. Lastly, we used immunohistochemical (IHC) staining and Western blot analyses to evaluate the inflammatory markers, glial fibrillary acidic protein (GFAP), amyloid-beta precursor protein (APP), and bone marrow tyrosine kinase gene in chromosome X (BMX) in animals with mTBI. GIP was well tolerated and ameliorated mTBI-induced memory impairments, poor balance, and sensorimotor deficits after initiation in the post-injury period. In addition, GIP mitigated mTBI-induced neuroinflammatory changes on GFAP, APP, and BMX protein levels. These findings suggest GIP has significant benefits in managing mTBI-related symptoms and represents a novel strategy for mTBI treatment. PMID- 26972791 TI - Melanopsin-expressing ganglion cells on macaque and human retinas form two morphologically distinct populations. AB - The long-term goal of this research is to understand how retinal ganglion cells that express the photopigment melanopsin, also known as OPN4, contribute to vision in humans and other primates. Here we report the results of anatomical studies using our polyclonal antibody specifically against human melanopsin that confirm and extend previous descriptions of melanopsin cells in primates. In macaque and human retina, two distinct populations of melanopsin cells were identified based on dendritic stratification in either the inner or the outer portion of the inner plexiform layer (IPL). Variation in dendritic field size and cell density with eccentricity was confirmed, and dendritic spines, a new feature of melanopsin cells, were described. The spines were the sites of input from DB6 diffuse bipolar cell axon terminals to the inner stratifying type of melanopsin cells. The outer stratifying melanopsin type received inputs from DB6 bipolar cells via a sparse outer axonal arbor. Outer stratifying melanopsin cells also received inputs from axon terminals of dopaminergic amacrine cells. On the outer stratifying melanopsin cells, ribbon synapses from bipolar cells and conventional synapses from amacrine cells were identified in electron microscopic immunolabeling experiments. Both inner and outer stratifying melanopsin cell types were retrogradely labeled following tracer injection in the lateral geniculate nucleus (LGN). In addition, a method for targeting melanopsin cells for intracellular injection using their intrinsic fluorescence was developed. This technique was used to demonstrate that melanopsin cells were tracer coupled to amacrine cells and would be applicable to electrophysiological experiments in the future. J. Comp. Neurol. 524:2845-2872, 2016. (c) 2016 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc. PMID- 26972793 TI - The Five-Minute Moment. AB - In today's hospital and clinic environment, the obstacles to bedside teaching for both faculty and trainees are considerable. As electronic health record systems become increasingly prevalent, trainees are spending more time performing patient care tasks from computer workstations, limiting opportunities to learn at the bedside. Physical examination skills rarely are emphasized, and low confidence levels, especially in junior faculty, pose additional barriers to teaching the bedside examination. PMID- 26972792 TI - Castleman's Disease Presenting as a Mediastinal Mass: Mimicker of Malignancy. PMID- 26972794 TI - A review of blisters caused by wound dressing components: Can they impede post operative rehabilitation and discharge? AB - This review highlights that some wound dressings can be the cause of blistering. It also presents the mechanisms by which blisters may be caused by poor choice of dressings. The subsequent impact of the blisters on preventing patient mobility - and hence rehabilitation in terms of physiotherapy - is also identified. The possibility that the clinical sequelae (e.g. delayed wound healing, restricted joint range of motion (ROM), muscle atrophy and increased risk of deep vein thrombosis (DVT)) resulting from this might have a significant and deleterious impact upon patient-related outcomes is discussed. Strategies for the treatment and prevention of blisters are proposed, based upon current knowledge and expertise. The criticality of the wound care specialist and the physiotherapist working together to overcome these challenges and enhance patient care is underlined. This article is a review of the relevant literature combined with opinions based upon the experience and knowledge of the authors. PMID- 26972796 TI - Interleukin-17 and interleukin-23 regulate Langerhans cell migration. PMID- 26972797 TI - Strong correlation between early stage atherosclerosis and electromechanical coupling of aorta. AB - Atherosclerosis is the underlying cause of cardiovascular diseases that are responsible for many deaths in the world, and the early diagnosis of atherosclerosis is highly desirable. The existing imaging methods, however, are not capable of detecting the early stage of atherosclerosis development due to their limited spatial resolution. Using piezoresponse force microscopy (PFM), we show that the piezoelectric response of an aortic wall increases as atherosclerosis advances, while the stiffness of the aorta shows a less evident correlation with atherosclerosis. Furthermore, we show that there is strong correlation between the coercive electric field necessary to switch the polarity of the artery and the development of atherosclerosis. Thus by measuring the electromechanical coupling of the aortic wall, it is possible to probe atherosclerosis at the early stage of its development, not only improving the spatial resolution by orders of magnitude, but also providing comprehensive quantitative information on the biomechanical properties of the artery. PMID- 26972795 TI - First results of a novel adjustable-length ossicular reconstruction prosthesis in temporal bones. AB - OBJECTIVES/HYPOTHESIS: The performance of an ossicular replacement prosthesis (ORP) is influenced by its alignment and appropriate tension between the tympanic membrane and the stapes footplate. A novel ORP with a flexible element that potentially allows for length adjustment in situ is presented and tested for acoustic performance. STUDY DESIGN: Laser Doppler vibrometry in fresh human cadaveric temporal bones was used to test the acoustic performance of the adjustable ORP relative to standard prostheses used for ossiculoplasty. METHODS: The three-dimensional (3D) velocity of the stapes posterior crus was measured in the 0.2- to 20-kHz range using a Polytec CLV-3D laser Doppler vibrometer. The middle ear cavity was accessed through a facial recess approach. After measuring the normal response, the incus was removed and stapes velocity was measured in the disarticulated case, then after insertion of the new prosthesis, a conventional prosthesis (Kurz BELL Dusseldorf type), and a sculpted autologous incus prosthesis in each temporal bone. The 3D stapes velocity transfer function (SVTF) was calculated for each case and compared. RESULTS: The novel ORP design restored stapes velocity to within 6 dB (on average) of the intact response. No significant differences in 3D-SVTF were found between the new, conventional, or autologous ORPs. CONCLUSIONS: The inclusion of an in situ adjustable element into the ORP design did not adversely affect its acoustic performance. The adjustable element may increase the ease of achieving optimal ORP placement, especially through a facial recess approach. LEVEL OF EVIDENCE: NA Laryngoscope, 126:2559 2564, 2016. PMID- 26972800 TI - A case of diabetic ketoacidosis after everolimus treatment. PMID- 26972798 TI - Association between breastfeeding and insulin sensitivity among young people with Type 1 and Type 2 diabetes: the SEARCH Nutrition Ancillary Study. PMID- 26972801 TI - sigma-Hole Opposite to a Lone Pair: Unconventional Pnicogen Bonding Interactions between ZF3 (Z=N, P, As, and Sb) Compounds and Several Donors. AB - The ability of several pnicogen sp(3) derivatives ZF3 (Z=N, P, As, Sb) to interact with electron-rich entities by means of the opposite face to the lone pair (lp) is investigated at the RI-MP2/aug-cc-pVQZ level of theory. The strength of the interaction ranges from -1 to -87 kJ mol(-1) , proving its favorable nature, especially when the lp is coordinated to a metal center, whereby the strength of the interaction is significantly enhanced. NBO analysis showed that orbital effects are modest contributors to the global stabilization of the pnicogen sigma-hole bonded complexes studied. Finally, a selection of Cambridge Structural Database examples are shown that demonstrate the impact of this counterintuitive binding mode in the solid state. PMID- 26972799 TI - Identification of novel RNA secondary structures within the hepatitis C virus genome reveals a cooperative involvement in genome packaging. AB - The specific packaging of the hepatitis C virus (HCV) genome is hypothesised to be driven by Core-RNA interactions. To identify the regions of the viral genome involved in this process, we used SELEX (systematic evolution of ligands by exponential enrichment) to identify RNA aptamers which bind specifically to Core in vitro. Comparison of these aptamers to multiple HCV genomes revealed the presence of a conserved terminal loop motif within short RNA stem-loop structures. We postulated that interactions of these motifs, as well as sub motifs which were present in HCV genomes at statistically significant levels, with the Core protein may drive virion assembly. We mutated 8 of these predicted motifs within the HCV infectious molecular clone JFH-1, thereby producing a range of mutant viruses predicted to possess altered RNA secondary structures. RNA replication and viral titre were unaltered in viruses possessing only one mutated structure. However, infectivity titres were decreased in viruses possessing a higher number of mutated regions. This work thus identified multiple novel RNA motifs which appear to contribute to genome packaging. We suggest that these structures act as cooperative packaging signals to drive specific RNA encapsidation during HCV assembly. PMID- 26972802 TI - Does zero really mean nothing?-first experiences with the new PowerQuant(TM) system in comparison to established real-time quantification kits. AB - DNA quantification is an important step in the molecular genetic analysis of a forensic sample, hopefully providing reliable data on DNA content for a subsequent generation of reproducible STR profiles for identification. For several years, this quantification has usually been done by real-time PCR protocols and meanwhile a variety of assays are commercially available from different companies. The newest one is the PowerQuant(TM) assay by Promega Inc. which is advertised with the promise that a determined DNA concentration of 0 ng/MUl in a forensic sample guarantees the impossibility to achieve true STR results, thus allowing to exclude such samples from STR analysis to save time and money. Thus, the goal of this study was to thoroughly verify the quantification step with regard to its suitability as a screening method. We have evaluated the precision and reliability of four different real-time PCR quantification assays by systematically testing DNA dilutions and forensic samples with various DNA contents. Subsequently, each sample was subjected to the Powerplex(r) ESX 17 fast kit to determine a reliable cutoff level for exclusion of definitely negative samples from STR analysis. An accurate quantification of different cell line DNA dilutions was not possible with any kit. However, at least the PowerQuant(TM) assay provided suitable data analyzing forensic samples, whereas in other systems up to 46 % of negative samples still displayed reliable STR analysis results. All in all, the PowerQuant(TM) assay represents a big step forward, but the evaluation of real-time PCR quantification results has still to be done with great care. PMID- 26972804 TI - Erratum to: Hypoxemia as a model for high altitude and cardiovascular risk reduction. PMID- 26972803 TI - Long-term outcome of patients with POEMS syndrome: An update of the Mayo Clinic experience. AB - Over the past decade, a number of changes have occurred in the diagnostic evaluation, management, and long-term follow-up of patients with POEMS syndrome at our institution. This study included 291 patients with POEMS syndrome diagnosed at the Mayo Clinic between 1974 and 2014. Patients diagnosed after 2003 had more features of the syndrome identified at diagnosis and were more likely to receive an autologous transplant (49% versus 8%, P < 0.0001) and to have achieved a hematologic complete response (CR) to treatment (41% vs 25%, P < 0.0001). With 2273 person-years of follow-up, 10-year overall survival (OS) was 62% (95% C.I., 56%, 67%). On multivariate analysis, the three factors associated with superior OS were younger age (RR 0.98 [0.96-1.00]), albumin greater-than 3.2 g/dL (RR 0.5 [0.32-0.89]) and attainment of complete hematologic response (RR 0.4 [0.2, 0.9]). This study confirms the very good long-term outcomes of patients with POEMS syndrome and identifies two new prognostic risk factors: albumin at diagnosis and attainment of complete hematologic response. Am. J. Hematol. 91:585-589, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26972805 TI - Decompressive craniectomy following traumatic brain injury: developing the evidence base. AB - In the context of traumatic brain injury (TBI), decompressive craniectomy (DC) is used as part of tiered therapeutic protocols for patients with intracranial hypertension (secondary or protocol-driven DC). In addition, the bone flap can be left out when evacuating a mass lesion, usually an acute subdural haematoma (ASDH), in the acute phase (primary DC). Even though, the principle of "opening the skull" in order to control brain oedema and raised intracranial pressure has been practised since the beginning of the 20th century, the last 20 years have been marked by efforts to develop the evidence base with the conduct of randomised trials. This article discusses the merits and challenges of this approach and provides an overview of randomised trials of DC following TBI. An update on the RESCUEicp study, a randomised trial of DC versus advanced medical management (including barbiturates) for severe and refractory post-traumatic intracranial hypertension is provided. In addition, the rationale for the RESCUE ASDH study, the first randomised trial of primary DC versus craniotomy for adult head-injured patients with an ASDH, is presented. PMID- 26972806 TI - NiftyFit: a Software Package for Multi-parametric Model-Fitting of 4D Magnetic Resonance Imaging Data. AB - Multi-modal, multi-parametric Magnetic Resonance (MR) Imaging is becoming an increasingly sophisticated tool for neuroimaging. The relationships between parameters estimated from different individual MR modalities have the potential to transform our understanding of brain function, structure, development and disease. This article describes a new software package for such multi-contrast Magnetic Resonance Imaging that provides a unified model-fitting framework. We describe model-fitting functionality for Arterial Spin Labeled MRI, T1 Relaxometry, T2 relaxometry and Diffusion Weighted imaging, providing command line documentation to generate the figures in the manuscript. Software and data (using the nifti file format) used in this article are simultaneously provided for download. We also present some extended applications of the joint model fitting framework applied to diffusion weighted imaging and T2 relaxometry, in order to both improve parameter estimation in these models and generate new parameters that link different MR modalities. NiftyFit is intended as a clear and open-source educational release so that the user may adapt and develop their own functionality as they require. PMID- 26972807 TI - Residential radon and cancers other than lung cancer: a cohort study in Galicia, a Spanish radon-prone area. PMID- 26972808 TI - Patterns of Reactions to Red Pigment Tattoo and Treatment Methods. AB - Tattoos are common and used extensively as either body art or cosmetic make-up; more rarely, they can be traumatic in nature. We have systemically analysed the literature for the patterns of red pigment tattoo reactions and their treatment options. Our search identified 18 articles; there was 1 non-randomised controlled trial, and the rest were small case studies. In total 139 patients were included within the studies. This review systematically analyses the different subsets of red tattoo reactions including lichenoid, dermatitis, granulomatous, pseudolymphomatous and miscellaneous reactions. The current evidence for the treatment for the above is presented. Dermatitis and lichenoid reactions appear to be the most common subtype of red pigment reactions with various treatment methods applied showing laser intervention to have some degree of success. PMID- 26972809 TI - Functional recovery following primary ACL repair with dynamic intraligamentary stabilization. AB - BACKGROUND: Recently, a new technique, dynamic intraligamentary stabilization (DIS) was introduced for the acute repair of ACL ruptures. The purpose of this study was to report the functional recovery for patients undergoing acute anterior cruciate ligament (ACL) repair alongside DIS. METHODS: Forty five patients sustaining acute ACL rupture and treated with DIS repair were retrospectively evaluated. Limb symmetry index of the hop test as well as knee function by means of range of motion, knee swelling, pain and maximum strength were evaluated. Following completion of the rehabilitation program, the difference in anterior-posterior translation (Delta-AP Translation), IKDC, Tegner score (TAS) was additionally analyzed. RESULTS: Forty five (13 females, 32 males) patients were included in the study. Mean age was 26years (range 18 to 54years). Median time to successfully complete hop test was 22.0weeks (range 11 to 32weeks) postoperatively. Median limb symmetry index 91.6%+/-8.3%. Median delta anterior posterior translation compared to the healthy side was plus 0.0mm+/-1.6mm. Median IKDC was 89.5+/-6.5. Mean Tegner score (TAS) at 12months of follow-up was seven (range four to nine). Three patients suffered a rerupture during the first 12 postoperative months. CONCLUSIONS: DIS technique with proper rehabilitation following acute ACL rupture provides successful functional recovery and low rerupture rate at one-year follow-up. PMID- 26972810 TI - An ancillary method in urine cytology: Nucleolar/nuclear volume ratio for discrimination between benign and malignant urothelial cells. AB - BACKGROUND: The essential of urine cytology for the diagnosis and the follow-up of urothelial neoplasia has been widely recognized. However, there are some cases in which a definitive diagnosis cannot be made due to difficulty in discriminating between benign and malignant. This study evaluated the practicality of nucleolar/nuclear volume ratio (%) for the discrimination. METHODS: Using Papanicolaou-stained slides, 253 benign urothelial cells and 282 malignant urothelial cells were selected and divided into a benign urothelial cell and an urothelial carcinoma (UC) cell groups. Three suspicious cases and four cases in which discrimination between benign and malignant was difficult were prepared for verification test. Subject cells were decolorized and stained with 4',6-diamidino-2-phenylindole for detection of the nuclei and the nucleoli. Z-stack method was performed to analyze. RESULTS: When the cutoff point of 1.514% discriminating benign urothelial cells and UC cells from nucleolar/nuclear volume ratio (%) was utilized, the sensitivity was 56.0%, the specificity was 88.5%, the positive predictive value was 84.5%, and the negative predictive value was 64.4%. Nuclear and nucleolar volume, number of the nucleoli, and nucleolar/nuclear volume ratio (%) were significantly higher in the UC cell group than in the benign urothelial cell group (P <0.001). In the verification test using the nucleolar/nuclear ratio (%), four of the seven cases were concordant with the final diagnosis. CONCLUSION: This study analyzed the nuclear and nucleolar volume to establish an index for discrimination of benign and malignant urothelial cells, providing possible additional information in urine cytology. Diagn. Cytopathol. 2016;44:483-491. (c) 2016 Wiley Periodicals, Inc. PMID- 26972812 TI - Increased pin diameter improves torsional stability in supracondylar humerus fractures: an experimental study. AB - BACKGROUND: Pediatric supracondylar humerus fractures are the most common elbow fractures seen in children, and account for 16 % of all pediatric fractures. Closed reduction and percutaneous pin fixation is the current treatment technique of choice for displaced supracondylar fractures of the distal humerus in children. The purpose of this study was to determine whether pin diameter affects the torsional strength of supracondylar humerus fractures treated by closed reduction and pin fixation. METHODS: Pediatric sawbone humeri simulating a Gartland type III fracture were utilized. Four different pin configurations were compared. Specimens were subjected to a torsional load producing internal rotation of the distal fragment. The stability provided by 1.25- and 1.6-mm pins was compared. RESULTS: The amount of torque required to produce 15 degrees and 25 degrees of rotation was greater using larger diameter pins in all models tested. The two lateral and one medial large pin (1.6 mm) configuration required the highest amount of torque to produce both 15 degrees and 25 degrees of rotation. CONCLUSIONS: In a synthetic pediatric humerus model of supracondylar humerus fractures, larger diameter pins (1.6 mm) provided increased stability compared with small diameter pins (1.25 mm). Fixation using larger diameter pins created a stronger construct and improved the strength of fixation. PMID- 26972813 TI - Inter-observer and intra-observer reliability in the radiographic diagnosis of avascular necrosis of the femoral head following reconstructive hip surgery in children with cerebral palsy. AB - PURPOSE: The incidence of avascular necrosis (AVN) following reconstructive hip surgery in cerebral palsy (CP) ranges from 0 to 69 % in the current literature. The purpose of this study was to determine the inter- and intra-observer reliability of radiographically diagnosing AVN in children with CP after hip surgery. METHODS: A retrospective review of 65 children with CP who had reconstructive hip surgery between 2009 and 2012 at BC Children's Hospital was completed. Anterior-posterior and lateral radiographs were presented to four pediatric orthopaedic surgeons over two rounds. Surgeons were asked to review the set of unidentified radiographs and comment 'yes' or 'no' for the presence of AVN. Two weeks later the same set of radiographs was sent in a different order and the surgeons were again asked to comment on AVN. Inter- and intra-observer reliability was determined using kappa statistics. RESULTS: The intra-observer reliability ranged from 0.65 to 0.88 with an average score of 0.76. Inter observer reliability showed greater variability, ranging from 0.41 to 0.77 with an average score of 0.56 across all surgeons. CONCLUSIONS: Although the intra rater reliability produced a strength of "good" and the inter-rater reliability a strength of "moderate" agreement, the variability within these scores is clinically important as it demonstrates the difficulty in identifying AVN. This may explain the variability in AVN that is reported in the literature. The need for further education and research in the diagnosis of AVN in children with CP who have undergone reconstructive hip surgery is clinically necessary. PMID- 26972814 TI - The endocranial anatomy of maba 1. AB - OBJECTIVES: Maba 1, a partial cranium from Guandong Province (China) tentatively dated between 300 and 130 ka, has been suggested to display a mosaic of archaic and derived features, including facial affinities with Neandertals. This study aims to evaluate whether Maba 1 shows a derived endocranial phenotype, or if it displays a plesiomorphic braincase morphology. MATERIALS AND METHODS: We analyzed a set of metric variables on fossil and modern human endocasts using bivariate correlation, principal component analysis, and cluster analyses, to evaluate the morphological affinities of the Maba 1 endocast. RESULTS: The cranial capacity, estimated at around 1300 cc, and the endocranial proportions of Maba 1 are within the ranges of modern humans, Neandertals and Homo heidelbergensis. However, the frontal lobes are narrow and the parietal areas are short and flattened, as in H. heidelbergensis and H. erectus. Nonetheless, the position of the frontal lobes relative to the orbits, the morphology of the frontal sinus and the curve of the frontal squama are more derived, being similar to Neandertals and modern humans. CONCLUSIONS: The endocast displays a general archaic morphology, although with some derived features associated with the spatial relationships with the face. A similar admixture was described for other Middle Pleistocene samples, like Sima de los Huesos. Future phylogenetic studies must re-evaluate the facial skeleton to consider whether its features can be considered as related to the Neandertal lineage. Alternatively, they should be interpreted as the result of homoplasy and parallelism within the genus Homo, and may reflect a predominantly Asian variation. Am J Phys Anthropol 160:633-643, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26972811 TI - The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. AB - Although the importance of human genetic polymorphisms in therapeutic outcomes is well established, the role of our 'second genome' (the microbiome) has been largely overlooked. In this Review, we highlight recent studies that have shed light on the mechanisms that link the human gut microbiome to the efficacy and toxicity of xenobiotics, including drugs, dietary compounds and environmental toxins. Continued progress in this area could enable more precise tools for predicting patient responses and for the development of a new generation of therapeutics based on, or targeted at, the gut microbiome. Indeed, the admirable goal of precision medicine may require us to first understand the microbial pharmacists within. PMID- 26972816 TI - Experimental determination of the photon-energy dependent dose-to-water response of TLD600 and TLD700 (LiF:Mg,Ti) thermoluminescence detectors. AB - The aim of this study has been the experimental determination of the energy dependent dose-to-water response of TLD600 and TLD700 thermoluminescent detectors (Harshaw) in X-ray beams with mean photon energies from about 20 to 200keV in comparison with 60Co gamma rays and 6MV X-rays. Experiments were carried out in collaboration with the German secondary standard laboratory PTW Freiburg. The energy dependent relative responses of TLD600 and TLD700 thermoluminescence detectors were determined at radiation qualities between 30kVp and 280kVp. The overall uncertainty of the measured values was characterized by standard deviations varying from 1.2 to 3%. The present results agree with previous studies on the energy dependent dose-to-water response of TLD100. As an application example, the results were used to measure doses associated with X-ray imaging in image-guided radiotherapy. PMID- 26972815 TI - Nomogram of the Barcelona Clinic Liver Cancer system for individual prognostic prediction in hepatocellular carcinoma. AB - BACKGROUND & AIMS: The predictive accuracy of the Barcelona Clinic Liver Cancer (BCLC) staging system on a single patient is not clear. This study aimed to develop a nomogram to predict individualized survival of patients with hepatocellular carcinoma (HCC) based on the BCLC system. METHODS: A total of 3179 patients were randomly grouped into derivation (n = 2119) and validation (n = 1060) sets. The multivariate Cox proportional hazards model was used to generate the nomogram from tumour burden, cirrhosis and performance status (PS). The performance of the nomogram was evaluated by concordance indices and calibration tests. RESULTS: Beta coefficients from the Cox model were used to assign nomogram points to different degrees of tumour burden, Child-Turcotte-Pugh classification and PS. A nomogram with a scale of 0-26 was developed and the predicted survival rates at 3 and 5 years were calculated. The derivation set had a concordance index of 0.766 (95% confidence interval [CI]: 0.686-0.838); and the validation set showed a concordance index of 0.775 (95% CI: 0.607-0.909). The calibration plots were close to the 45-degree line for 3- and 5-year survival prediction of BCLC stages 0-C patients in both derivation and validation groups. For BCLC stage D patients, calibration plots in both groups showed deviation from the 45-degree line for 3- and 5-year prediction. CONCLUSIONS: This study provides quantitative evidence to support the prognostic ability of BCLC system. This straightforward and easy-to-use nomogram may accurately predict the survival at 3 and 5 years for individual HCC patient except for BCLC stage D patients. PMID- 26972818 TI - Mechanism and modulation of terahertz generation from a semimetal--graphite. AB - Semi-metals might offer a stronger interaction and a better confinement for terahertz wave than semiconductors, while preserve tunability. Particularly, graphene-based materials are envisioned as terahertz modulators, filters and ultra-broadband sources. However, the understanding of terahertz generation from those materials is still not clear, thus limits us recognizing the potential and improving device performances. Graphite, the mother material of graphene and a typical bulk semi-metal, is a good system to study semi-metals and graphene-based materials. Here we experimentally modulate and maximize the terahertz signal from graphite surface, thus reveal the mechanism--surface field driving photon induced carriers into transient current to radiate terahertz wave. We also discuss the differences between graphite and semiconductors; particularly graphite shows very weak temperature dependency from room temperature to 80 degrees C. Above knowledge will help us understand terahertz generations, achieve maximum output and electric modulation, in semi-metal or graphene based devices. PMID- 26972820 TI - Proton-Conducting Graphene Oxide-Coupled Neuron Transistors for Brain-Inspired Cognitive Systems. AB - Proton-conducting graphene oxide electrolyte films with very high electric-double layer capacitance are used as the gate dielectrics for oxide-based neuron transistor fabrication. Paired-pulse facilitation, dendritic integration, and orientation tuning are successfully emulated. Additionally, neuronal gain controls (arithmetic) are also experimentally demonstrated. The results provide a new-concept approach for building brain-inspired cognitive systems. PMID- 26972819 TI - The wound/burn guidelines - 1: Wounds in general. AB - The Japanese Dermatological Association determined to prepare the Wound/Burn Guidelines focusing on treatments, catering to needs for the clinical practice of dermatology. Among these guidelines, "Wounds in General" was intended to explain knowledge necessary "to heal wounds" without specifying particular disorders. PMID- 26972821 TI - Utilization of the CRISPR/Cas9 system for the efficient production of mutant mice using crRNA/tracrRNA with Cas9 nickase and FokI-dCas9. AB - The CRISPR/Cas9 system is a powerful genome editing tool for the production of genetically modified animals. To produce mutant mice, chimeric single-guide RNA (sgRNA) is cloned in a plasmid vector and a mixture of sgRNA and Cas9 are microinjected into the fertilized eggs. An issue associated with gene manipulation using the CRISPR/Cas9 system is that there can be off-target effects. To simplify the production of mutant mice with low risks of off-target effects caused by the CRISPR/Cas9 system, we demonstrated that genetically modified mice can be efficiently obtained using chemically synthesized CRISPR RNA (crRNA), trans-activating crRNA (tracrRNA), and modified Cas9s, such as the nickase version and FokI-fused catalytically inactive Cas9, by microinjection into fertilized eggs. Using this method, it is no longer necessary to clone sgRNA into a plasmid vector, and this enables high-throughput production of mutant mice. PMID- 26972823 TI - Brown Adipose Tissue Exhibits a Glucose-Responsive Thermogenic Biorhythm in Humans. AB - High abundance of brown adipose tissue (BAT) is linked to lower glycaemia in humans, leading to the belief that BAT may protect against diabetes. The relationship between BAT glucose utilization and systemic glucose homeostasis has not been defined. In this paper we have characterized glycaemic excursions and BAT thermogenic responses in human brown adipocytes, BAT explants, and healthy adults through supraclavicular temperature profiling, revealing their circadian coupling in vivo and in vitro, orchestrated by UCP1, GLUT4, and Rev-erbalpha biorhythms. Extent of glycated haemoglobin also correlated positively with environmental temperature among community-dwelling patients. These data uncover potential crosstalk between BAT and glucose regulatory pathways, evident on cellular, tissue, individual, and population levels, and provide impetus to search for BAT harnessing strategies for therapeutic purposes. PMID- 26972826 TI - Dynamic Equilibrium Model for a Bulk Nanobubble and a Microbubble Partly Covered with Hydrophobic Material. AB - The dynamic equilibrium model for a bulk nanobubble partly covered with hydrophobic material in water is theoretically and numerically studied. The gas diffusion into a bubble near the peripheral edge of the hydrophobic material on the bubble surface balances that out of the bubble from the other part of the uncovered bubble surface. In the present model, gas diffusion in quiescent liquid is assumed and there is no liquid flow. The total changes of energy and entropy are both zero as it is a kind of equilibrium state. The main origin of the dynamic equilibrium state is the gradient of chemical potential of gas near the peripheral edge of the hydrophobic material. It is caused by the permanent attractive potential of a hydrophobic material to gas molecules dissolved in liquid water as there is permanent repulsion of a hydrophobic material against liquid water. Thus, the gas supply will not terminate. It is numerically shown that stable nanobubble could be present when the fraction of surface coverage by hydrophobic material is from about 0.5 to 1. The stable size of a nanobubble changes with the liquid temperature as well as the degree of gas saturation of water. In slightly degassed water, not only a nanobubble but also a microbubble could be stable in mass balance when the fraction of surface coverage for a microbubble is on the order of 10-4 or less. For hydrophilic materials, however, a bubble could not be stable unless the fraction of the surface coverage is exactly 1. It is suggested that in many experiments of bulk nanobubbles there could be aggregates of nanobubbles. PMID- 26972825 TI - Synthesis and Biological Evaluation of N-Aryl-N'-(5-(2-hydroxybenzoyl) pyrimidin 2-yl)guanidines as Toll-Like Receptor 4 Antagonists. AB - BACKGROUND: Toll-like receptor 4 (TLR4) has been associated with several inflammatory diseases, such as sepsis, atherosclerosis and chronic pain. OBJECTIVE: The aim of the present study was to develop an efficient and straightforward synthetic approach for the preparation of small-molecule antagonists Naryl- N'-(5-(2-hydroxybenzoyl)pyrimidin-2-yl)guanidines in order to evaluate these for TLR4 antagonist activity and to obtain useful information about their structure-activity relationships. METHODS: The present work have designed and optimized a three-step synthetic route for derivatives of a previously demonstrated antagonist of TLR4: 1-(4- fluorophenyl)-2-(5-(2-hydroxy-5 methoxybenzoyl)pyrimidin-2-yl)guanidine. The antagonist activities of eight novel synthesized compounds were evaluated on cells which selectively express TLR4. RESULTS: Three guanidine derivatives showed promising antagonist activities, with IC50 values in the low micromolar range. CONCLUSION: Our findings represent an important starting point for further studies of small-molecule agents targeting Toll-like receptors. PMID- 26972827 TI - Antibody therapies in CNS diseases. AB - Therapeutic antibodies have essentially been banned from the central nervous system, and are so far limited to use mainly in multiple sclerosis. This is primarily due to the fact that antibody penetration across the blood-brain barrier is very limited, with about only 0.1% of circulating antibodies estimated to reach the brain at steady-state concentration. Nonetheless, advances are being made with conventional antibodies, showing that minimal exposure can act centrally to mediate therapeutic effects. Immunotherapy in Alzheimer's disease is a noteworthy example where antibodies against amyloid-beta are able to reduce brain plaque pathology in preclinical models and humans. However, the advances in using antibodies directed at brain targets have also demonstrated impediments of low brain exposure in achieving clinical benefits, spurring increased attention in technologies designed to improve brain exposure of antibodies. Here we review antibodies in clinical trials for central nervous system disorders. Moreover, we describe some of the efforts to improve the therapeutic efficacy of antibodies by enhancing delivery across the blood-brain barrier. This article is part of the Special Issue entitled "Beyond small molecules for neurological disorders". PMID- 26972828 TI - Peripheral ammonia and blood brain barrier structure and function after methamphetamine. AB - An effect of the widely abuse psychostimulant, methamphetamine (Meth), is blood brain-barrier (BBB) disruption; however, the mechanism by which Meth causes BBB disruption remains unclear. Recently it has been shown that Meth produces liver damage and consequent increases in plasma ammonia. Ammonia can mediate oxidative stress and inflammation, both of which are known to cause BBB disruption. Therefore, the current studies examined the role of peripheral ammonia in Meth induced disruption of BBB structure and function. A neurotoxic Meth regimen (10 mg/kg, ip, q 2 h, *4) administered to rats increased plasma ammonia and active MMP-9 in the cortex 2 h after the last Meth injection, compared to saline treated rats. At 24 h after Meth treatment, decreased immunoreactivity of BBB structural proteins, occludin and claudin-5, and increased extravasation of 10,000 Da FITC dextran were observed, as compared to saline controls. Pretreatment with lactulose (5.3 g/kg, po, q 12 h), a drug that remains in the lumen of the intestine and promotes ammonia excretion, prevented the Meth-induced increases in plasma ammonia. These results were paralleled by the prevention of decreases in BBB structural proteins, increases in extravasation of 10,000 Da FITC-dextran and increases in active MMP-9. The results indicate that Meth-induced increases in ammonia produce BBB disruption and suggest that MMP-9 activation mediates the BBB disruption. These findings identify a novel mechanism of Meth-induced BBB disruption that is mediated by plasma ammonia and are the first to identify a peripheral contribution to Meth-induced BBB disruption. PMID- 26972829 TI - Trigeminal neuroplasticity underlies allodynia in a preclinical model of mild closed head traumatic brain injury (cTBI). AB - Post-traumatic headache (PTH) following TBI is a common and often persisting pain disability. PTH is often associated with a multimodal central pain sensitization on the skin surface described as allodynia. However, the particular neurobiology underlying cTBI-induced pain disorders are not known. These studies were performed to assess trigeminal sensory sensitization and to determine if sensitization measured behaviorally correlated with detectable changes in portions of the trigeminal sensory system (TSS), particularly trigeminal nucleus, thalamus, and sensory cortex. Thermal stimulation is particularly well suited to evaluate sensitization and was used in these studies. Recent advances in the use of reward/conflict paradigms permit use of operant measures of behavior, versus reflex-driven response behaviors, for thermal sensitization studies. Thus, to quantitate facial thermal sensitization (allodynia) in the setting of acute TBI, the current study utilized an operant orofacial pain reward/conflict testing paradigm to assess facial thermal sensitivity in uninjured control animals compared with those two weeks after cTBI in a rodent model. Significant reductions in facial contact/lick behaviors were observed in the TBI animals using either cool or warm challenge temperatures compared with behaviors in the normal animals. These facial thermal sensitizations correlated with detectable changes in multiple levels of the TSS. The immunohistochemical (IHC) studies revealed significant alterations in the expression of the serotonin (5-HT), neurokinin 1 receptor (NK1R), norepinephrine (NE), and gamma-aminobutyric acid (GABA) in the caudal trigeminal nucleus, thalamic VPL/VPM nucleus, and sensory cortex of the orofacial pain pathways. There was a strong correlation between increased expression of certain IHC markers and increased behavioral markers for facial sensitization. The authors conclude that TBI-induced changes observed in the TSS are consistent with the expression of generalized facial allodynia following cTBI. To our knowledge, this is the first report of orofacial sensitization correlated with changes in selected neuromodulators/neurotransmitters in the TSS following experimental mild TBI. PMID- 26972824 TI - Emotional modulation of interval timing and time perception. AB - Like other senses, our perception of time is not veridical, but rather, is modulated by changes in environmental context. Anecdotal experiences suggest that emotions can be powerful modulators of time perception; nevertheless, the functional and neural mechanisms underlying emotion-induced temporal distortions remain unclear. Widely accepted pacemaker-accumulator models of time perception suggest that changes in arousal and attention have unique influences on temporal judgments and contribute to emotional distortions of time perception. However, such models conflict with current views of arousal and attention suggesting that current models of time perception do not adequately explain the variability in emotion-induced temporal distortions. Instead, findings provide support for a new perspective of emotion-induced temporal distortions that emphasizes both the unique and interactive influences of arousal and attention on time perception over time. Using this framework, we discuss plausible functional and neural mechanisms of emotion-induced temporal distortions and how these temporal distortions may have important implications for our understanding of how emotions modulate our perceptual experiences in service of adaptive responding to biologically relevant stimuli. PMID- 26972831 TI - Functional analysis of the gene controlling hydroxylation of festuclavine in the ergot alkaloid pathway of Neosartorya fumigata. AB - Bioactive ergot alkaloids produced by several species of fungi are important molecules in agriculture and medicine. Much of the ergot alkaloid pathway has been elucidated, but a few steps, including the gene controlling hydroxylation of festuclavine to fumigaclavine B, remain unsolved. Festuclavine is a key intermediate in the fumigaclavine branch of the ergot alkaloid pathway of the opportunistic pathogen Neosartorya fumigata and also in the dihydrolysergic acid based ergot alkaloid pathway of certain Claviceps species. Based on several lines of evidence, the N. fumigata gene easM is a logical candidate to encode the festuclavine-hydroxylating enzyme. To test this hypothesis we disrupted easM function by replacing part of its coding sequences with a hygromycin resistance gene and transforming N. fumigata with this construct. High-pressure liquid chromatography analysis demonstrated that easM deletion mutants were blocked in the ergot alkaloid pathway at festuclavine, and downstream products were eliminated. An additional alkaloid, proposed to be a prenylated form of festuclavine on the basis of mass spectral data, also accumulated to higher concentrations in the easM knockout. Complementation with the wild-type allele of easM gene restored the ability of the fungus to produce downstream compounds. These results indicate that easM encodes an enzyme required for fumigaclavine B synthesis likely by hydroxylating festuclavine. The festuclavine-accumulating strain of N. fumigata may facilitate future investigations of the biosynthesis of dihydrolysergic acid derivatives, which are derived from festuclavine and are the basis for several important drugs. PMID- 26972832 TI - Etiology of postanesthetic and postsedation events on the inpatient ward: data from a rapid response team at a tertiary care children's hospital. AB - INTRODUCTION: The goal of this study was to identify the etiology of events and demographics of patients that experience complications requiring activation of the Rapid Response Team (RRT) during the first 24 h following anesthetic care. METHODS: We performed a retrospective review of the Quality Improvement database from the Department of Anesthesiology & Pain Medicine at Nationwide Children's Hospital. The database was searched to identify those patients who had a RRT evaluation activated within 24 h of receiving anesthesia or procedural sedation. These patients' charts were reviewed to obtain demographic information, etiology of the RRT call, and outcomes. RESULTS: The study cohort included 106 RRT calls that were made over a 3-year period. Six patients were excluded from analysis due to incomplete datasets. One hundred patients remained for analysis including 60 males and 40 females. Patients ranged in age from 0.08 to 31.21 years (7.8 +/- 7.7 years, median 5.3 years). Seventy-one patients were American Society of Anesthesiologists' (ASA) status 3 or 4 and 29 patients were ASA status 1 or 2. Five calls were made for patients who had undergone procedural sedation while the other 95 were on patients who received general anesthesia. The average time to the RRT call after the end of anesthetic care was 11.4 +/- 6.6 h. Respiratory concern was the most common reason for RRT initiation, accounting for 71 of the 100 calls. Forty-nine patients had a recent respiratory illness, chronic respiratory-related disease, or history of preterm birth. Fifty patients (50%) were transferred to a higher level of care following the RRT consult. There was no significant difference between age, gender, ASA status, or etiology of the event for patients transferred vs. those who were not. A significant difference was noted in the Pediatric Early Warning Score of patients transferred to a higher level of care in comparison to patients who remained on the floor (4 +/- 2 vs. 3 +/- 2, P = 0.0097). CONCLUSION: RRT calls were most common for respiratory concerns. High ASA status, general anesthesia administration, and the presence of acute or chronic conditions prior to anesthetic administration predispose a patient to perioperative complications resulting in the need for an RRT call. PMID- 26972830 TI - Metabolic Reprogramming by Hexosamine Biosynthetic and Golgi N-Glycan Branching Pathways. AB - De novo uridine-diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis requires glucose, glutamine, acetyl-CoA and uridine, however GlcNAc salvaged from glycoconjugate turnover and dietary sources also makes a significant contribution to the intracellular pool. Herein we ask whether dietary GlcNAc regulates nutrient transport and intermediate metabolism in C57BL/6 mice by increasing UDP GlcNAc and in turn Golgi N-glycan branching. GlcNAc added to the drinking water showed a dose-dependent increase in growth of young mice, while in mature adult mice fat and body-weight increased without affecting calorie-intake, activity, energy expenditure, or the microbiome. Oral GlcNAc increased hepatic UDP-GlcNAc and N-glycan branching on hepatic glycoproteins. Glucose homeostasis, hepatic glycogen, lipid metabolism and response to fasting were altered with GlcNAc treatment. In cultured cells GlcNAc enhanced uptake of glucose, glutamine and fatty-acids, and enhanced lipid synthesis, while inhibition of Golgi N-glycan branching blocked GlcNAc-dependent lipid accumulation. The N acetylglucosaminyltransferase enzymes of the N-glycan branching pathway (Mgat1,2,4,5) display multistep ultrasensitivity to UDP-GlcNAc, as well as branching-dependent compensation. Indeed, oral GlcNAc rescued fat accumulation in lean Mgat5(-/-) mice and in cultured Mgat5(-/-) hepatocytes, consistent with N glycan branching compensation. Our results suggest GlcNAc reprograms cellular metabolism by enhancing nutrient uptake and lipid storage through the UDP-GlcNAc supply to N-glycan branching pathway. PMID- 26972833 TI - Value of septoturbinal flap in the frontal sinus drill-out type IIb according to draf. AB - OBJECTIVES/HYPOTHESIS: The Draf IIb aims at widening the frontal sinus drainage in a minimally invasive fashion. However, this technique is associated with a high stenosis rate. Hence, local nasal flaps have been recently introduced or designed to speed up mucosal healing and prevent scarring. STUDY DESIGN: The objective of this study was to present the septoturbinal flap (STF), its use in a Draf IIb, and to examine postoperative outcomes of this procedure. METHODS: From an initial pool of 48 patients with frontal sinus disease to be treated with a Draf IIb, we prospectively selected 46 (95.84%) patients, submitted to a Draf IIb with STF in two Institutions, from November 2010 to November 2014. We excluded two cases (4.16%) for which a flap could not be performed for anatomic restrictions. We present the STF technique and describe demographic data, indication for surgery, and surgery type. RESULTS: Indications for surgery included 24 (52.17%) mucoceles or mucopyoceles, 12 (26.1%) chronic rhinosinusitis, four (8.7%) osteomas, two (4.35%) meningoencephaloceles, and four (8.7%) inverted papillomas. Difficult anatomic conditions were encountered in half of the patients. Restenosis of the frontal sinus drainage pathway occurred in one (2.17%) patient. Far-seated frontal mucoceles recurred in two cases (4.35%), with frontal drainage pathway remaining patent. Rescue treatment comprised a Draf III in two cases and one frontal sinus obliteration. Outcome was favorable for 43 (93.5%) patients. CONCLUSION: The use of STF was associated with a high rate of success for a Draf IIb. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2428-2432, 2016. PMID- 26972835 TI - The Empathizing-Systemizing Theory, Social Abilities, and Mathematical Achievement in Children. AB - The Empathizing-Systemizing (E-S) theory describes a profile of traits that have been linked to autism spectrum disorders, and are thought to encompass a continuum that includes typically developing (TD) individuals. Although systemizing is hypothesized to be related to mathematical abilities, empirical support for this relationship is lacking. We examine the link between empathizing and systemizing tendencies and mathematical achievement in 112 TD children (57 girls) to elucidate how socio-cognitive constructs influence early development of mathematical skills. Assessment of mathematical achievement included standardized tests designed to examine calculation skills and conceptual mathematical reasoning. Empathizing and systemizing were assessed using the Combined Empathy Quotient-Child (EQ-C) and Systemizing Quotient-Child (SQ-C). Contrary to our hypothesis, we found that mathematical achievement was not related to systemizing or the discrepancy between systemizing and empathizing. Surprisingly, children with higher empathy demonstrated lower calculation skills. Further analysis using the Social Responsiveness Scale (SRS) revealed that the relationship between EQ-C and mathematical achievement was mediated by social ability rather than autistic behaviors. Finally, social awareness was found to play a differential role in mediating the relationship between EQ-C and mathematical achievement in girls. These results identify empathy, and social skills more generally, as previously unknown predictors of mathematical achievement. PMID- 26972836 TI - Increased Variability and Asymmetric Expansion of the Hippocampal Spatial Representation in a Distal Cue-Dependent Memory Task. AB - Place cells in the hippocampus fire at specific positions in space, and distal cues in the environment play critical roles in determining the spatial firing patterns of place cells. Many studies have shown that place fields are influenced by distal cues in foraging animals. However, it is largely unknown whether distal cue-dependent changes in place fields appear in different ways in a memory task if distal cues bear direct significance to achieving goals. We investigated this possibility in this study. Rats were trained to choose different spatial positions in a radial arm in association with distal cue configurations formed by visual cue sets attached to movable curtains around the apparatus. The animals were initially trained to associate readily discernible distal cue configurations (0 degrees vs. 80 degrees angular separation between distal cue sets) with different food-well positions and then later experienced ambiguous cue configurations (14 degrees and 66 degrees ) intermixed with the original cue configurations. Rats showed no difficulty in transferring the associated memory formed for the original cue configurations when similar cue configurations were presented. Place field positions remained at the same locations across different cue configurations, whereas stability and coherence of spatial firing patterns were significantly disrupted when ambiguous cue configurations were introduced. Furthermore, the spatial representation was extended backward and skewed more negatively at the population level when processing ambiguous cue configurations, compared with when processing the original cue configurations only. This effect was more salient for large cue-separation conditions than for small cue separation conditions. No significant rate remapping was observed across distal cue configurations. These findings suggest that place cells in the hippocampus dynamically change their detailed firing characteristics in response to a modified cue environment and that some of the firing properties previously reported in a foraging task might carry more functional weight than others when tested in a distal-cue-dependent memory task. (c) 2016 Wiley Periodicals, Inc. PMID- 26972837 TI - Biomonitoring Equivalents for molybdenum. AB - Molybdenum is an essential trace element for mammalian, plant, and other animal systems. The Institute of Medicine (IOM) has established an Estimated Average Requirement (EAR) to assure sufficient molybdenum intakes for human populations; however excessive exposures can cause toxicity. As a result, several agencies have established exposure guidance values to protect against molybdenum toxicity, including a Reference Dose (RfD), Tolerable Daily Intake (TDI) and a Tolerable Upper Intake Level (UL). Biomonitoring for molybdenum in blood or urine in the general population is being conducted by the Canadian Health Measures Survey (CHMS) and the U.S. National Health and Nutrition Examination Survey (NHANES). Using pharmacokinetic data from controlled human dosing studies, Biomonitoring Equivalents (BEs) were calculated for molybdenum in plasma, whole blood, and urine associated with exposure guidance values set to protect against both nutritional deficits and toxicity. The BEEAR values in plasma, whole blood and urine are 0.5, 0.45 and 22 MUg/L, respectively. The BEs associated with toxicity range from 0.9 to 31 MUg/L in plasma, 0.8-28 MUg/L in whole blood and 200-7500 MUg/L in urine. These values can be used to interpret molybdenum biomonitoring data from a nutritional and toxicity perspective. PMID- 26972839 TI - Object-oriented regression for building predictive models with high dimensional omics data from translational studies. AB - Maturing omics technologies enable researchers to generate high dimension omics data (HDOD) routinely in translational clinical studies. In the field of oncology, The Cancer Genome Atlas (TCGA) provided funding support to researchers to generate different types of omics data on a common set of biospecimens with accompanying clinical data and has made the data available for the research community to mine. One important application, and the focus of this manuscript, is to build predictive models for prognostic outcomes based on HDOD. To complement prevailing regression-based approaches, we propose to use an object oriented regression (OOR) methodology to identify exemplars specified by HDOD patterns and to assess their associations with prognostic outcome. Through computing patient's similarities to these exemplars, the OOR-based predictive model produces a risk estimate using a patient's HDOD. The primary advantages of OOR are twofold: reducing the penalty of high dimensionality and retaining the interpretability to clinical practitioners. To illustrate its utility, we apply OOR to gene expression data from non-small cell lung cancer patients in TCGA and build a predictive model for prognostic survivorship among stage I patients, i.e., we stratify these patients by their prognostic survival risks beyond histological classifications. Identification of these high-risk patients helps oncologists to develop effective treatment protocols and post-treatment disease management plans. Using the TCGA data, the total sample is divided into training and validation data sets. After building up a predictive model in the training set, we compute risk scores from the predictive model, and validate associations of risk scores with prognostic outcome in the validation data (P-value=0.015). PMID- 26972838 TI - Facilitating biomedical researchers' interrogation of electronic health record data: Ideas from outside of biomedical informatics. AB - Electronic health records (EHR) are a vital data resource for research uses, including cohort identification, phenotyping, pharmacovigilance, and public health surveillance. To realize the promise of EHR data for accelerating clinical research, it is imperative to enable efficient and autonomous EHR data interrogation by end users such as biomedical researchers. This paper surveys state-of-art approaches and key methodological considerations to this purpose. We adapted a previously published conceptual framework for interactive information retrieval, which defines three entities: user, channel, and source, by elaborating on channels for query formulation in the context of facilitating end users to interrogate EHR data. We show the current progress in biomedical informatics mainly lies in support for query execution and information modeling, primarily due to emphases on infrastructure development for data integration and data access via self-service query tools, but has neglected user support needed during iteratively query formulation processes, which can be costly and error prone. In contrast, the information science literature has offered elaborate theories and methods for user modeling and query formulation support. The two bodies of literature are complementary, implying opportunities for cross disciplinary idea exchange. On this basis, we outline the directions for future informatics research to improve our understanding of user needs and requirements for facilitating autonomous interrogation of EHR data by biomedical researchers. We suggest that cross-disciplinary translational research between biomedical informatics and information science can benefit our research in facilitating efficient data access in life sciences. PMID- 26972840 TI - The JAK/STAT pathway in obesity and diabetes. AB - Diabetes mellitus are complex, multi-organ metabolic pathologies characterized by hyperglycemia. Emerging evidence shows that the highly conserved and potent JAK/STAT signaling pathway is required for normal homeostasis, and, when dysregulated, contributes to the development of obesity and diabetes. In this review, we analyze the role of JAK/STAT activation in the brain, liver, muscle, fat and pancreas, and how this affects the course of the disease. We also consider the therapeutic implications of targeting the JAK/STAT pathway in treatment of obesity and diabetes. PMID- 26972841 TI - Firearm legislation and mortality in the USA. PMID- 26972842 TI - PD-L1 in non-small-cell lung cancer: the third target for immunotherapy. PMID- 26972843 TI - Firearm legislation and firearm mortality in the USA: a cross-sectional, state level study. AB - BACKGROUND: In an effort to reduce firearm mortality rates in the USA, US states have enacted a range of firearm laws to either strengthen or deregulate the existing main federal gun control law, the Brady Law. We set out to determine the independent association of different firearm laws with overall firearm mortality, homicide firearm mortality, and suicide firearm mortality across all US states. We also projected the potential reduction of firearm mortality if the three most strongly associated firearm laws were enacted at the federal level. METHODS: We constructed a cross-sectional, state-level dataset from Nov 1, 2014, to May 15, 2015, using counts of firearm-related deaths in each US state for the years 2008 10 (stratified by intent [homicide and suicide]) from the US Centers for Disease Control and Prevention's Web-based Injury Statistics Query and Reporting System, data about 25 firearm state laws implemented in 2009, and state-specific characteristics such as firearm ownership for 2013, firearm export rates, and non firearm homicide rates for 2009, and unemployment rates for 2010. Our primary outcome measure was overall firearm-related mortality per 100,000 people in the USA in 2010. We used Poisson regression with robust variances to derive incidence rate ratios (IRRs) and 95% CIs. FINDINGS: 31,672 firearm-related deaths occurred in 2010 in the USA (10.1 per 100,000 people; mean state-specific count 631.5 [SD 629.1]). Of 25 firearm laws, nine were associated with reduced firearm mortality, nine were associated with increased firearm mortality, and seven had an inconclusive association. After adjustment for relevant covariates, the three state laws most strongly associated with reduced overall firearm mortality were universal background checks for firearm purchase (multivariable IRR 0.39 [95% CI 0.23-0.67]; p=0.001), ammunition background checks (0.18 [0.09-0.36]; p<0.0001), and identification requirement for firearms (0.16 [0.09-0.29]; p<0.0001). Projected federal-level implementation of universal background checks for firearm purchase could reduce national firearm mortality from 10.35 to 4.46 deaths per 100,000 people, background checks for ammunition purchase could reduce it to 1.99 per 100,000, and firearm identification to 1.81 per 100,000. INTERPRETATION: Very few of the existing state-specific firearm laws are associated with reduced firearm mortality, and this evidence underscores the importance of focusing on relevant and effective firearms legislation. Implementation of universal background checks for the purchase of firearms or ammunition, and firearm identification nationally could substantially reduce firearm mortality in the USA. FUNDING: None. PMID- 26972844 TI - The "ABCs" of critical care teamwork: Introduction of a practical checklist. PMID- 26972845 TI - Should we also be searching for a systolic "U wave" in the electrocardiogram? PMID- 26972846 TI - About QRS prolongation, distortion and the acuteness score. PMID- 26972848 TI - Validity Evidence based on Internal Structure of Scores of the Emotional Quotient Inventory: Youth Version Short (EQ-i: YV-S) in a Spanish Sample. AB - The purpose of this study was to analyze the reliability and validity evidence of scores on the Spanish version of EQ-i: YV-S in Spanish adolescents. The total sample was comprised of 508 participants from Grades 7 to 12, 241 males (47.4%) and 267 females (52.6%), each of whom completed the questionnaires on two separate occasions. Three [intrapersonal (alpha = .83, CR = .86, and McDonald Omega = .86), stress management (alpha = .83, CR = .86, and McDonald Omega = .85) and adaptability (alpha = .82, CR = .85, and McDonald Omega = .85)] of the four scales had acceptable internal consistency. Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA) were used with FACTOR and EQS version 6.1 software to examine validity evidence based on internal structure drawn from the scores on the EQ-i: YV-S, supporting the multidimensionality of the questionnaire. Three models were tested; the best fit to the data was the hierarchical model (S-Bchi2 / df = 2.11, CFI = .93 and RMSEA = .047), which hypothesized that the four specific factors (interpersonal, intrapersonal, stress management, and adaptability) were explained with a second-order factor, Emotional-Social-Intelligence (ESI). Finally, significant positive correlations were found between general self-concept and EQ-i: YV-S [interpersonal (r = .153, p < .001), intrapersonal (r = .235, p < .001), stress management (r = .145, p < .001), adaptability (r = .311, p < .001) and ESI (r = .360, p < .001)]; ESI showed significant direct power prediction of the general self-concept (.52) as demonstrated through structural equation modeling. PMID- 26972849 TI - Genetic improvement of olive (Olea europaea L.) by conventional and in vitro biotechnology methods. AB - In olive (Olea europaea L.) traditional methods of genetic improvement have up to now produced limited results. Intensification of olive growing requires appropriate new cultivars for fully mechanized groves, but among the large number of the traditional varieties very few are suitable. High-density and super high density hedge row orchards require genotypes with reduced size, reduced apical dominance, a semi-erect growth habit, easy to propagate, resistant to abiotic and biotic stresses, with reliably high productivity and quality of both fruits and oil. Innovative strategies supported by molecular and biotechnological techniques are required to speed up novel hybridisation methods. Among traditional approaches the Gene Pool Method seems a reasonable option, but it requires availability of widely diverse germplasm from both cultivated and wild genotypes, supported by a detailed knowledge of their genetic relationships. The practice of "gene therapy" for the most important existing cultivars, combined with conventional methods, could accelerate achievement of the main goals, but efforts to overcome some technical and ideological obstacles are needed. The present review describes the benefits that olive and its products may obtain from genetic improvement using state of the art of conventional and unconventional methods, and includes progress made in the field of in vitro techniques. The uses of both traditional and modern technologies are discussed with recommendations. PMID- 26972850 TI - Perceptions of cancer in society must change. PMID- 26972852 TI - Non-clear-cell renal carcinoma therapy: handle with care. PMID- 26972851 TI - REGATTA trial: a call for the USA and Europe. PMID- 26972847 TI - IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis. AB - Dysregulated inflammasome activation contributes to respiratory infections and pathologic airway inflammation. Through basic and translational approaches involving murine models and human genetic epidemiology, we show here the importance of the different inflammasomes in regulating inflammatory responses in mice and humans with cystic fibrosis (CF), a life-threatening disorder of the lungs and digestive system. While both contributing to pathogen clearance, NLRP3 more than NLRC4 contributes to deleterious inflammatory responses in CF and correlates with defective NLRC4-dependent IL-1Ra production. Disease susceptibility in mice and microbial colonization in humans occurs in conditions of genetic deficiency of NLRC4 or IL-1Ra and can be rescued by administration of the recombinant IL-1Ra, anakinra. These results indicate that pathogenic NLRP3 activity in CF could be negatively regulated by IL-1Ra and provide a proof-of concept evidence that inflammasomes are potential targets to limit the pathological consequences of microbial colonization in CF. PMID- 26972854 TI - Patient. PMID- 26972853 TI - Morcellation and risk of malignancy in presumed ovarian fibromas/fibrothecomas. PMID- 26972855 TI - Tech support. PMID- 26972856 TI - The canSAR data hub for drug discovery. PMID- 26972857 TI - Radiotherapy in patients with connective tissue diseases. AB - The decision to offer radiotherapy in patients with connective tissue diseases continues to be challenging. Radiotherapy might trigger the onset of connective tissue diseases by increasing the expression of self-antigens, diminishing regulatory T-cell activity, and activating effectors of innate immunity (dendritic cells) through Toll-like receptor-dependent mechanisms, all of which could potentially lead to breaks of immune tolerance. This potential risk has raised some debate among radiation oncologists about whether patients with connective tissue diseases can tolerate radiation as well as people without connective tissue diseases. Because the number of patients with cancer and connective tissue diseases needing radiotherapy will probably increase due to improvements in medical treatment and longer life expectancy, the issue of interactions between radiotherapy and connective tissue diseases needs to be clearer. In this Review, we discuss available data and evidence for patients with connective tissue diseases treated with radiotherapy. PMID- 26972858 TI - Justifying vein resection with pancreatoduodenectomy. AB - Interest in radical surgery to achieve complete resection and improve long-term survival in patients undergoing pancreatoduodenectomy for ductal adenocarcinoma has been renewed. This surgery includes extended lymphadenectomy, multivisceral resections, and synchronous arterial and venous resections. The evidence that these surgeries improve long-term survival is poor, except perhaps for synchronous venous resection, which can be justified if a margin negative (R0) resection is achieved without increased morbidity and mortality, and if there is no invasion of the vein wall. The recognition of patients with borderline resectable pancreatic cancer and the increasing use of neoadjuvant treatment makes it more difficult to know if the vein is invaded, increases reliance on trial dissection to establish resectability, and might increase the number of synchronous venous resections done. This Personal View seeks to review the justification for pancreatoduodenectomy with synchronous venous resection to promote debate and draw attention to the gaps in knowledge for further research. PMID- 26972859 TI - DCIS and invasive interval breast cancer. PMID- 26972860 TI - DCIS and invasive interval breast cancer. PMID- 26972861 TI - DCIS and invasive interval breast cancer - Author's reply. PMID- 26972862 TI - Uniformly defining continuous deep sedation. PMID- 26972864 TI - Spanning regulatory silos in the U.S. EPA's Endocrine Disruptor Screening Program: Letter to the Editor re: Evans et al. "Should the scope of human mixture risk assessment span legislative and regulatory silos for chemicals?". PMID- 26972865 TI - Ash-soil interface: Mineralogical composition and physical structure. AB - Fires exert many changes on the physical, chemical, morphological, mineralogical, and biological properties of soil that, in turn, affect the soil's hydrology and nutrient flux, modifying its ability to support vegetation and resist erosion. The ash produced by forest fires is a complex mixture composed of organic and inorganic particles with varied properties. This research was conducted to study and characterized ash properties produced at different temperatures and with different soil organic matter combinations. The samples, which included two treatments of soils with underlying mixed leaves and branches composed mainly by Pinus halepensis, Pistacia lentiscus, Cistus salviifolius and typical herbaceous vegetation, versus samples of mixed leaves and branches alone. Both were exposed to 400 degrees C and 600 degrees C heat in a muffle furnace for 2h. The residue ash was generally grayish, consisting of mixed-sized particles that preserved almost none of the original characteristics of the fuel, and was deposited in ash layers with diverse physicochemical and textural properties. The results of this study highlight the differences between all examined samples and strongly support the assumption that ash produced from a complex vegetation-soil system is a new substance with unique structural, textural, and mineralogical properties. Moreover, the ash produced at different temperatures appeared in distinct layering patterns. PMID- 26972863 TI - Neurocognitive functioning and genetic variation in patients with primary brain tumours. AB - Impairment of neurocognitive functioning is a common result of cerebral neoplasms and treatment, although there is substantial heterogeneity in the pattern and severity of neurocognitive dysfunction across individuals and tumour types. The effects of many clinical and patient characteristics on neurocognitive functioning have been documented, but little research has been devoted to understanding the effect of genetic variation on neurocognitive outcomes in patients with brain tumours. This Review highlights preliminary evidence that suggests an association between various genes and risk of adverse neurocognitive outcomes in patients with brain tumours. Studies include genes specific to neuronal function, and those associated with more systemic cellular regulation. Related scientific literature in other disease populations is briefly discussed to indicate additional candidate genes. We consider methodological issues central to the study of neurocognitive functioning and genetic associations for patients with brain tumours, and emphasise the need for future research integrating novel investigative techniques. PMID- 26972866 TI - Application of nano-surface and molecular-orientation limited proteolysis to LC MS bioanalysis of cetuximab. AB - BACKGROUND: We recently reported the principle of nano-surface and molecular orientation limited (nSMOL) proteolysis, which is useful for LC-MS bioanalysis of antibody drugs. METHODOLOGY: The nSMOL is a Fab-selective limited proteolysis which utilizes the difference of protease-immobilized nanoparticle diameter (200 nm) and antibody collection resin pore (100 nm). We have demonstrated the full validation for chimeric antibody cetuximab bioanalysis in human plasma using nSMOL. Signature peptides (SQVFFK, ASQSIGTNIHWYQQR and YASESISGIPSR) in cetuximab complementarity-determining region were simultaneously quantitated by LC-MS multiple reaction monitoring. CONCLUSION: This nSMOL quantification showed sensitivity of 0.586 ug/ml and linearity of 0.586 to 300 ug/ml. Full validation study archived the guideline criteria of low Mw drug compounds. These results indicate that nSMOL is also significant method for cetuximab bioanalysis. PMID- 26972867 TI - Pharmacokinetics and metabolism study of veratramine in mice after oral administration using LC-MS/MS. AB - A simple and sensitive high-performance liquid chromatography coupled with hybrid triple quadrupole-linear ion trap mass spectrometry (Q-trap-MS) method was developed and validated for the determination of veratramine, the major bioactive and neurotoxic component in Veratrum nigrum L. Veratramine and the internal standard (IS) were separated with a Waters Symmetry C18 column and eluted with a gradient mobile phase system containing acetonitrile and 0.1% aqueous formic acid. The analysis was performed by using positive electrospray ionization mode with multiple reaction monitoring (MRM). Transition ions of m/z 410.2 -> 295.2 for veratramine and m/z 426.1 -> 113.8 for the IS were monitored. The method was validated with a good linearity in the range of 1-1000 ng/mL and lower limit of quantification of 1 ng/mL. The precision (CV) of intra- and inter-day ranged from 3.92 to 7.29%, while the accuracy (bias) intra- and inter-day were between -4.78 and 1.65%. The recovery, stability and matrix effect were within the acceptable ranges. Five metabolites of veratramine, including four hydroxylated and one sulfated metabolites, were tentatively identified using predictive MRM information dependent acquisition-enhanced product ion mode (predictive MRM-IDA EPI). The developed method was successfully applied to the pharmacokinetic and metabolic study of veratramine in mice after oral administration of veratramine. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26972868 TI - Spatial distribution of organic pollutants in industrial construction and demolition waste and their mutual interaction on an abandoned pesticide manufacturing plant. AB - A comprehensive field investigation of organic pollutants was examined in industrial construction and demolition waste (ICDW) inside an abandoned pesticide manufacturing plant. Concentrations of eight types of pesticides, a metabolite and two intermediates were studied. The ICDW was under severe and long-term contamination by organophosphorus, intermediates and pyrethroid pesticide with mean concentrations of 23,429, 3538 and 179.4 mg kg(-1), respectively. FT-IR analysis suggested that physical absorption and chemical bonding were their mutual interaction forms. Patterns of total pesticide spatial distribution showed good correlations with manufacturing processes spreading all over the plant both in enclosed workshops and in residues randomly dumped outside, while bricks and coatings were the most vulnerable to pollutants. Ultimately the fate of the OPPs was diversified as the immersion of ICDW in water largely transferred the pollutants into aquatic systems while exposure outside did not largely lead to pesticide degradation. The adoption of centralized collections for the disposal of wastes could only eliminate part of the contaminated ICDW, probably due to lack of knowledge and criteria. Correlation matrix and cluster analysis indicated that regulated disposal and management of polluted ICDW was effective, thus presenting the requirement for its appropriate disposal. PMID- 26972869 TI - Coronary artery atherosclerosis associated with shift work in chemical plant workers by using coronary CT angiography. AB - OBJECTIVES: The aim of this study was to investigate whether shift work is related to elevated risk of coronary artery disease (CAD) by determining the coronary artery calcium (CAC) score and the presence of coronary artery stenosis by using coronary artery CT angiography (CCTA). METHODS: In this study, 110 male workers participated and underwent a CCTA examination for CAC scoring, which represents coronary artery plaque, and were evaluated for luminal stenosis. All of the participants were working in the same chemical plant, of whom 70 worked day shifts and 40 worked rotating shifts. RESULTS: In a multivariate logistic regression analysis, including age, smoking status, alcohol consumption, regular exercise and waist circumference, shift work was associated with a 2.89-fold increase in the odds of developing coronary plaque compared with day work (OR, 2.89; 95% CI 1.07 to 7.82). The association between shift work and coronary plaque was strong after adjustment for age, low-density lipoprotein cholesterol, hypertension and diabetes mellitus (OR, 2.92; 95% CI 1.02 to 8.33). In addition, the number of years of shift work employment was associated with coronary plaque. However, no association was found between shift work and coronary artery stenosis. CONCLUSIONS: Shift work could induce CAD onset via the atherosclerotic process, and shift work employment duration was associated with an increased risk of atherosclerosis in male workers. PMID- 26972871 TI - The ecological virus. AB - Ecology is usually described as the study of organisms interacting with one another and their environments. From this view of ecology, viruses - not usually considered to be organisms - would merely be part of the environment. Since the late 1980s, however, a growing stream of micrographic, experimental, molecular, and model-based (theoretical) research has been investigating how and why viruses should be understood as ecological actors of the most important sort. Viruses, especially phage, have been revealed as participants in the planet's most crucial food webs, even though viruses technically consume nothing (they do not metabolize by themselves). Even more impressively, viruses have been identified as regulators of planetary biogeochemistry, in which they control cycles such as carbon, nitrogen and phosphorus - cycles on which all life depends. Although much biogeochemical research black-boxes the entities filling functional roles, it is useful to focus a little more closely to understand how viruses can be held responsible for the global processes of life. This paper will give a brief overview of the history of virus ecology and tease out the implications of large scale ecological modelling with viruses. This analysis suggests that viruses should be conceptualized as ecological actors that are at least comparable and possibly equal to organismal actors. Ecological agency can therefore be distinguished from standard interpretations of biological agency. PMID- 26972872 TI - Mutualistic viruses and the heteronomy of life. AB - Though viruses have generally been characterized by their pathogenic and more generally harmful effects, many examples of mutualistic viruses exist. Here I explain how the idea of mutualistic viruses has been defended in recent virology, and I explore four important conceptual and practical consequences of this idea. I ask to what extent this research modifies the way scientists might search for new viruses, our notion of how the host immune system interacts with microbes, the development of new therapeutic approaches, and, finally, the role played by the criterion of autonomy in our understanding of living things. Overall, I suggest that the recognition of mutualistic viruses plays a major role in a wider ongoing revision of our conception of viruses. PMID- 26972870 TI - Upper extremity musculoskeletal pain among office workers in three Spanish speaking countries: findings from the CUPID study. AB - OBJECTIVES: To estimate the prevalence and incidence of upper extremity musculoskeletal pain (UEMP) and related disability among office workers in Costa Rica, Nicaragua and Spain. METHODS: Data from the multinational Cultural and Psychosocial Influences on Disability (CUPID) study on 947 (93%) participants at baseline with 90% follow-up after 12 months were employed. Logistic regression was used to estimate the associations (ORs and corresponding 95% CIs) between country and six outcomes: baseline prevalence of (1) UEMP in past 12 months, (2) UEMP in past month and (3) disabling UEMP in past month; (4) incidence of new UEMP at follow-up; (5) incidence of new disabling UEMP at follow-up and (6) persistence of UEMP at follow-up, after adjustment for sociodemographic, job related and health-related covariates. RESULTS: Baseline prevalence of UEMP in the past month was higher in Costa Rica (53.6%) (OR=1.89; 95% CI 1.36 to 2.62) and Nicaragua (51.9%) (OR=1.74; 95% CI 1.28 to 2.35) than in Spain (38.4%). Compared to Spain (33.2%), the incidence of new UEMP was 50.4% in Costa Rica (OR=2.04; 95% CI 1.34 to 3.12) and 60.2% in Nicaragua (OR=3.04; 95% CI 2.06 to 4.50). The incidence of disabling UEMP was higher in Nicaragua (OR=2.57; 95% CI 1.50 to 4.41) and Costa Rica (OR=2.16; 95% CI 1.22 to 3.84) when compared to Spain. CONCLUSIONS: Prevalence of UEMP was approximately twofold higher and its incidence twofold to threefold higher in Costa Rica and Nicaragua as compared with Spain. Between-country differences were only partially explained by the covariates analysed. Research is needed to explore other aspects of work and cultural attributes that might explain the residual differences in UEMP. PMID- 26972873 TI - Giant viruses: The difficult breaking of multiple epistemological barriers. AB - The discovery of the first "giant virus", Mimivirus, in 2003 could solely have been that of an exceptional freak, a blind alley of evolution as occasionally encountered in biology, albeit without conceptual significance. On the contrary, once broken this epistemological barrier, additional unrelated families of giant viruses such as the Pandoraviruses, the Pithoviruses and most recently Mollivirus, were quickly unraveled, suggesting that an entire chapter of microbiology had been ignored since Pasteur and Ivanovski. In this article, we examine to what extent the giant viruses challenge previous definitions of viruses, the diversity of forms they could take, and how they might have evolved from extinct ancestral cellular lineages. Inspired by the epistemology of Gaston Bachelard, we will also suggest the reasons for which giant viruses laid hidden in plain sight for more than a century. Finally, we propose a new definition for "viruses" that paradoxically emphasize the fact that they do not encode a single universally shared macromolecule or biochemical function. PMID- 26972874 TI - Control of apoptosis by Drosophila DCAF12. AB - Regulated Apoptosis (Programmed Cell Death, PCD) maintains tissue homeostasis in adults, and ensures proper growth and morphogenesis of tissues during development of metazoans. Accordingly, defects in cellular processes triggering or executing apoptotic programs have been implicated in a variety of degenerative and neoplastic diseases. Here, we report the identification of DCAF12, an evolutionary conserved member of the WD40-motif repeat family of proteins, as a new regulator of apoptosis in Drosophila. We find that DCAF12 is required for Diap1 cleavage in response to pro-apoptotic signals, and is thus necessary and sufficient for RHG (Reaper, Hid, and Grim)-mediated apoptosis. Loss of DCAF12 perturbs the elimination of supernumerary or proliferation-impaired cells during development, and enhances tumor growth induced by loss of neoplastic tumor suppressors, highlighting the wide requirement for DCAF12 in PCD. PMID- 26972876 TI - Review: Environmental mycobacteria as a cause of human infection. AB - Pulmonary infections with nontuberculous mycobacteria (NTM) are recognized as a problem in immunodeficient individuals and are increasingly common in older people with no known immune defects. NTM are found in soil and water, but factors influencing transmission from the environment to humans are mostly unknown. Studies of the epidemiology of NTM disease have matched some clinical isolates of NTM with isolates from the patient's local environment. Definitive matching requires strain level differentiation based on molecular analyses, including partial sequencing, PCR-restriction fragment length polymorphism (RFLP) analysis, random amplified polymorphic DNA (RAPD) PCR, repetitive element (rep-) PCR and pulsed field gel electrophoresis (PFGE) of large restriction fragments. These approaches have identified hospital and residential showers and faucets, hot-tubs and garden soil as sources of transmissible pathogenic NTM. However, gaps exist in the literature, with many clinical isolates remaining unidentified within environments that have been tested, and few studies investigating NTM transmission in developing countries. To understand the environmental reservoirs and transmission routes of pathogenic NTM, different environments, countries and climates must be investigated. PMID- 26972875 TI - Pro-Cognitive Properties of the Immunomodulatory Polypeptide Complex, Yolkin, from Chicken Egg Yolk and Colostrum-Derived Substances: Analyses Based on Animal Model of Age-Related Cognitive Deficits. AB - The study aimed to assess the effect of the polypeptide Y complex (Yolkin), isolated from chicken egg yolk, on behavioural and cognitive functions. It also aimed to compare this activity with colostrum-derived substances (Colostrinin, Coloco), which have a confirmed impact on learning and memory. In the study, the effect of Yolkin, administered to rats of different ages, who performed various tasks involving spatial and episodic memory, motor functions and exploratory behavior, was assessed. The experiment was carried out in rats which were 6 and 12 months old. Two different doses of the studied specimens based on previous comparative studies and two different routes of administration (oral and retroperitoneal) were used. A series of behavioural tests were carried out, including an open field test, a novel object recognition test and a Morris water maze. They were used to evaluate the impact of the studied specimen on improving locomotor function and exploratory behaviour, preventing their decline and assess the functioning of episodic and spatial memory in aging rats. The administration of Yolkin gave distinct effects compared to colostrum-derived substances, although confirmed its suggested pro-cognitive action. Therefore, it may be used to enhance cognitive functions and inhibit the progression of dementia in the course of neurodegenerative disorders. PMID- 26972877 TI - E84G mutation in dihydrofolate reductase from drug resistant strains of Mycobacterium tuberculosis (Mumbai, India) leads to increased interaction with Trimethoprim. AB - BACKGROUND: Dihydrofolate reductase (DHFR) (dfrA gene) is an essential enzyme for cell survival and an unexplored target in Mycobacterium tuberculosis (Mtb). This study was carried out to analyze mutations in the dfrA gene amongst 20 clinical DNA samples from Mtb isolates obtained from Mumbai, India. METHODS: Sequencing of the PCR amplified dfrA gene from these DNA isolates revealed a point mutation in one strain, leading to a glutamic acid to glycine change. In silico simulation studies revealed a surface alteration in the enzyme due to this E84G mutation. The amplified mutant gene was cloned and expressed. The mutant protein was assessed against known DHFR inhibitors: Methotrexate and Trimethoprim. RESULTS: An increased affinity for inhibitor Trimethoprim and native substrate dihydrofolate was observed with the mutant. Methotrexate did not vary in its activity with both the enzyme forms. CONCLUSIONS: The Glu84Gly point mutation may lead to a variation in the strain which may cause resistance in the future. PMID- 26972878 TI - Benzothiazinone-piperazine derivatives as efficient Mycobacterium tuberculosis DNA gyrase inhibitors. AB - BACKGROUND AND OBJECTIVES: Bacterial DNA topoisomerases are unique in maintaining the DNA topology for cell viability. Mycobacterium tuberculosis (MTB) DNA gyrase, a sole type II topoisomerase has a larger scope as a target for developing novel therapeutics. In this study, an effort was made towards the design and synthesis of benzothiazinone-piperazine hybrid analogues to obtain the possibility of it to lead development through the molecular hybridization technique. METHODS: A five step scheme was followed to obtain a series of 36 benzothiazinone-piperazine derivatives and to evaluate them for MTB DNA gyrase inhibition, antimycobacterial and cytotoxicity studies. RESULTS: Compound N-(4-chlorophenyl)-4-(6-nitro-4-oxo 4H-benzo[e][1,3]thiazin-2-yl)piperazine-1-carbothioamide (18) showed greater inhibitory potential with an IC50 of 0.51 +/- 0.16 MUM in the DNA supercoiling assay of MTB with a moderate anti-tubercular activity of 4.41 MUM. The compound even passed the safety profile of eukaryotic cell cytotoxicity with a 1.81% inhibition in the RAW 264.7 cell line at 100 MUM concentration. CONCLUSIONS: This study describes the discovery of benzothiazinone as gyrase inhibitors with potent MTB MIC and inhibitory profiles of the gyrase enzyme with less cytotoxic effect. Furthermore, it is believed that this class of compounds has the potential to be further developed as an anti-TB drug candidate. PMID- 26972880 TI - Immunoconfirmation of central nervous system tuberculosis by blotting: A study of 300 cases. AB - Tuberculous meningitis (TBM) is a serious form of disease of the central nervous system. Early and accurate diagnosis of the disease and effective treatment are key important factors to contain the disease. The disease presents as chronic meningitis where other partners such as fungal meningitis, neurosyphilis, cysticercal meningitis, carcinomatous meningitis and partially treated pyogenic meningitis share a similar clinical picture making the diagnosis complicated. Culturing of the pathogen Mycobacterium tuberculosis (MTB) from the cerebrospinal fluid (CSF) sample has shown a poor response. The main immunological method for the immunodiagnosis of TBM is the detection of an antibody response in the CSF. In the present study, total MTB sonicated extract antigen was used for ELISA and Western blot. ELISA shows overall immune response of the test sample, whereas Western blotting reveals the specific reactivity to a particular molecular weight antigen. This would also reveal the immunodominant antigen. A total of 300 CSF samples were analyzed by both ELISA and Western blotting. Of the 240 clinically suspected TBM cases, 111 samples were positive by ELISA and 81 samples by Western blot. A total of 76 CSF samples were positive by both ELISA and Western blot. None of the control samples showed positivity either by ELISA or by Western blot. TBM patients revealed major antibody reactivity to 30-40 kD region, followed by 14 kD region. ELISA is sensitive with mild non-specific binding, but Western blot is specific in detecting the immune response. The findings will be useful in definitive immunodiagnosis of TBM. PMID- 26972879 TI - Medicinal plants used to treat TB in Ghana. AB - AIMS: The current study was designed to document medicinal plant species that are traditionally used to treat tuberculosis (TB) by Ghanaian communities. METHODS: The medicinal plants used against TB or its signs and symptoms were selected using library and online published data searches. A guided questionnaire interview was also conducted with a botanist involved in plant collection at the Centre for Scientific Research into Plant Medicine (CSRPM) at Mampong. Data obtained were entered in Excel and summarized into means and frequencies using SPSS 12.0.1 for windows, and expressed as tables and bar graphs. RESULTS: A total of 15 medicinal plant species distributed between 13 genera and 13 families were documented. The following medicinal plant species were found to be used against TB in Greater Accra and Eastern parts of Ghana: Azadirachta indica A. Juss. Stem bark (Meliaceae), Hygrophila auriculata Heine, whole plant (Acanthaceae), Chenopodium ambrosioides L. leaves (Amaranthaceae), Coix lacryma-jobi L. glumes (Poaceae), Solanum torvum Sw. unripe fruits (Solanaceae), Solanum torvum Sw. leaves (Solanaceae), Bidens pilosa L. whole plant (Asteraceae), Phyllanthus fraternus G.L. Webster leaves (Phyllanthaceae), Dissotis rotundifolia (Sm.) Triana, leaves (Melastomataceae), Cymbopogon giganteus Chiov. Leaves (Poaceae), Cyperus articulatus L. roots (Cyperaceae), Allium sativum L. bulb (Amaryllidaceae), Zingiber officinale Roscoe, rhizomes (Zingiberaceae), Allium cepa L. bulbs (Amaryllidaceae), Allium cepa L. leaves (Amaryllidaceae), Aloe vera var. barbadensis aqueous extract from leaves (Xanthorrhoeaceae), Aloe vera var. barbadensis organic extract from leaves (Xanthorrhoeaceae), Cocos nucifera Linn, water (Arecaceae) and Cocos nucifera Linn. Husk (Arecaceae). CONCLUSIONS: The collected plant species could be a source of a new class of drugs against TB. Bioactivity guided fractionation is recommended to identify lead compounds for antimycobacterial activity. The current paper documents for the first time medicinal plant species used by Ghanaian communities to treat TB. These results are a basis for selection of plants for further pharmacological, toxicological and phytochemical studies in developing new plant-based antimycobacterial drugs. PMID- 26972881 TI - Factors associated with treatment success and death in cases with multidrug resistant tuberculosis in Bulgaria, 2009-2010. AB - OBJECTIVE: To analyze determinants of success and death in multidrug-resistant tuberculosis patients (MDR-TB; resistance to, at least, isoniazid and rifampicin) placed on treatment in Bulgaria during the period September 2009 to March 2010 using logistic regression. RESULTS: Fifty MDR-TB patients started treatment. Male:Female ratio was 2.3:1; mean age 43 years (range: 18-77); 19 patients (38%) were new; median duration of disease before treatment was 5 years (range: 1-13). All patients tested negative for HIV. Eight cases had XDR-TB (MDR-TB plus resistance to any fluoroquinolone and any second-line injectable). Twenty-four months after starting treatment, 24 patients (48%) had a successful outcome, in 6 (12%) treatment failed, 19 (38%) died, and one (2%) interrupted treatment. XDR-TB cases experienced higher mortality than others (75% vs. 30.9%, respectively, P<0.05). Sputum smear positivity at start of treatment and weight loss or no weight gain were positively associated with death (adjusted Odds ratio: 5.16; 95% confidence interval: 1.16-22.84 and 5.61; 1.48-21.20, respectively) and negatively with success (0.13; 0.02-0.94 and 0.02; 0.00-0.19). No previous TB treatment increased likelihood of success (7.82; 1.09-56.15). DISCUSSION AND CONCLUSIONS: Most MDR-TB patients in this first treatment cohort using WHO recommended norms had advanced disease explaining the high mortality and low success. Early, adequate treatment of MDR-TB patients can improve outcomes and avert transmission. PMID- 26972882 TI - Mycobacterium ulcerans disease in the middle belt of Ghana: An eight-year review from six endemic districts. AB - BACKGROUND: Mycobacterium ulcerans (MU) produces mycolactone toxin when infected with a plasmid. Toxin is cytotoxic and immunosuppressive, causing extensive destruction of tissues, leading to large ulcers on exposed parts of the body. Spontaneous healing by secondary intention leads to contractures, subluxation of joints, disuse atrophy, distal lymphedema and other complications. The disease is endemic in some communities within the middle belt of Ghana. OBJECTIVE: To document the clinical and epidemiological features of MU disease in the middle belt of Ghana and the outcome of treatment. PATIENTS AND METHODS: Patients with lesions suspected to MU disease were screened by community workers. Lesions were confirmed by any of the following: direct smear examination, culture, polymerase chain reaction (PCR), or histopathology. Patients were treated with rifampicin (10mg/kg orally) and streptomycin (15 mg/kg IM) combination for eight weeks. Patients selected for surgical treatment included cases where medical treatment had failed, cases where medical treatment is contraindicated, cases presenting late with complications and recurrent cases. RESULTS: 258 patients were seen in the Ahafo Ano, Amansie Central, Amansie West, Asunafo, Asutifi, and Upper Denkyira districts of Ghana between 2005 and 2012. Their ages ranged from 1 year 3 months to 98 years, with a mean age of 29.8 (SD 20.4). The clinical forms of MU disease seen were: papule (0.5%), nodule (1.5%), chronic osteomyelitis (1.5%), contracture (1.5%), edematous lesion (3%), and ulcer (92%). Uncommon complications include subluxation of knee joint, salivary gland fistula and Marjolin's ulcer. The lesions were distributed as follows: head and neck (6.8%), upper limb (20.3%), trunk (1.7%), and lower limb (71.2%). CONCLUSION: MU disease in the middle belt of Ghana can be controlled by early case detection and adequate curative treatment. PMID- 26972883 TI - A public-private partnership to reduce tuberculosis burden in Akwa Ibom State, Nigeria. AB - BACKGROUND: Tuberculosis (TB) infection and spread are preventable, and TB disease is curable depending on individual and community knowledge of causes of the disease, mode of prevention and cure. An earlier educational intervention carried out in Akwa Ibom State (AKS) of Nigeria in 2006 created awareness of the disease and improved utilization of orthodox medical facilities of residents in 34 communities who had symptoms of TB. OBJECTIVE: The overall aim of this program is to reduce the burden of TB disease in 18 communities of AKS through educational intervention, TB case detection and integration into the State National Tuberculosis and Leprosy Control Programme (NTBLCP), as well as build laboratory capacity to improve TB case detection and control. METHODS: Prior to the educational intervention in each community, standard pretested questionnaires were administered to residents to test their knowledge, attitudes and practices concerning TB. Information about causes, symptoms and prevention of TB was disseminated in community town halls, churches, markets and schools. Individuals who were coughing for three weeks or more were investigated for TB following clinical examination by a physician. Three sputum samples (spot-morning-spot) were obtained from each individual and examined microscopically for the presence of acid-fast bacilli (AFB) using the Ziehl-Neelson staining technique. Those with positive AFB results were integrated into the existing NTBLCP treatment facilities for immediate commencement of Directly-Observed Therapy Short Course (DOTS). Treatment outcome was monitored by retesting patients' sputum after two, five and seven months. Two new laboratories were facilitated while existing laboratory capacity was built by providing higher resolution microscopes, power generating plants, refrigerators, locally-fabricated incinerators and furnishing of staff offices. The program was facilitated by a public-private partnership. Effective Health Care Alliance Research Programme (EHCARP-Nigeria), in collaboration with Nigeria National Petroleum Cooperation and Mobil Producing Nigeria Unlimited (NNPC/MPN) Joint Venture, utilized health personnel from the Akwa Ibom State NTBLCP who conducted laboratory testing and supervised the treatment. RESULTS: The 916 responses to the questionnaires showed that 65.3% (549/841) correctly identified that TB is airborne, and 86% (749/871) were aware that TB could be cured by anti-TB medication. Responses to care-seeking attitudes were provided by 123 respondents. Of this number, fear of stigmatization was the reason for 31% (38) seeking care in unorthodox facilities, while 43.1% (53) did not believe that orthodox medicine could cure their symptoms. Of the 374 detected cases, 9 did not commence treatment. Hence, 365 were placed on DOTS; 36 defaulted, while 11 either died or failed to convert after the seventh month. At the end of month 8, cure was achieved for 87.1% (318). CONCLUSION: Although the previous intervention may have contributed to the good knowledge about TB and care-seeking attitudes displayed by respondents in the communities, sustaining active case finding through public-private partnership can go a long way to reduce TB burden, especially in rural communities where healthcare systems are generally weak or inadequate. Adequate funding of TB control activities is critical in eliminating TB as a public health problem, and the private sector participation such as this is a welcome development. PMID- 26972884 TI - Tuberculosis peritonitis with features of acute abdomen in HIV infection. AB - This case report introduces a 26-year-old male IV drug abuser with fever, abdominal pain and distension referred to the emergency ward. According to these findings, abdominal tenderness and involuntary guarding, an explorative laparotomy was performed. Multiple biopsies of omentum, peritoneum and liver were taken. Pathologic assessment of multiple biopsies confirmed intra-abdominal TB infection. PMID- 26972885 TI - Endobronchial tuberculosis presented as multiple endobronchial vesicular lesions. AB - Endobronchial tuberculosis (EBTB) is a tuberculous infection of the tracheobronchial tree with microbiological and histopathological evidence, with or without parenchymal involvement. EBTB commonly presents as acute or insidious onset cough, wheeze, low grade fever, and constitutional symptoms. In elderly patients, other differentials like malignancy and pneumonia may lead to misdiagnosis. Hence, bronchoscopy is essential for confirmation of EBTB. Here we report a rare presentation of EBTB in a 65 year old patient who presented with 3 months history of fever and cough and have multiple endobronchial vesicular lesions on bronchoscopy. PMID- 26972886 TI - The inconsistent definitions used for tuberculosis in the medical literature. AB - In order to assess the confusion attendant with current definitions of extrapulmonary tuberculosis, pleural and miliary disease, a set of 37 papers published which analyzed disease states were assessed for how the terms adhered to official definitions of the American Thoracic Society, the World Health Organization, and the Centers for Disease Control. The findings showed uncertainties in the classification of extrapulmonary disease, a frequent inconsistency in the inclusion of pleural disease within pulmonary rather than extrapulmonary disease, and the ambivalent use of the terms pleural and disseminated tuberculosis. Further attention by editors and authors is needed in the use of tuberculosis definitions. PMID- 26972887 TI - A rare localization of tuberculosis of the wrist: The scapholunate joint. AB - The tuberculosis of the hand and the wrist is a rare entity. Affecting the scapholunate joint is exceptional. It is usually diagnosed at an advanced stage of carpal destruction, due to slowly development of the symptoms. We report the case of a 58-year-old female, presenting as wrist pain for 3 months. Clinical study showed a local swelling in the left wrist, the mobility of the wrist was normal but painful at the end of motion. The diagnosis of osteoarticular tuberculosis was suspected after radiological and biological study then confirmed after histological study. Antibacillary chemotherapy during 12 months promoted healing and good outcome. PMID- 26972888 TI - Semiconductor-Metal Nanofloret Hybrid Structures by Self-Processing Synthesis. AB - We present a synthetic strategy that takes advantage of the inherent asymmetry exhibited by semiconductor nanowires prepared by Au-catalyzed chemical vapor deposition (CVD). The metal-semiconductor junction is used for activating etch, deposition, and modification steps localized to the tip area using a wet chemistry approach. The hybrid nanostructures obtained for the coinage metals Cu, Ag, and Au resemble the morphology of grass flowers, termed here Nanofloret hybrid nanostructures consisting of a high aspect ratio SiGe nanowire (NW) with a metallic nanoshell cap. The synthetic method is used to prepare hybrid nanostructures in one step by triggering a programmable cascade of events that is autonomously executed, termed self-processing synthesis. The synthesis progression was monitored by ex situ transmission electron microscopy (TEM), in situ scanning transmission electron microscopy (STEM) and inductively coupled plasma mass spectrometry (ICP-MS) analyses to study the mechanistic reaction details of the various processes taking place during the synthesis. Our results indicate that the synthesis involves distinct processing steps including localized oxide etch, metal deposition, and process termination. Control over the deposition and etching processes is demonstrated by several parameters: (i) etchant concentration (water), (ii) SiGe alloy composition, (iii) reducing agent, (iv) metal redox potential, and (v) addition of surfactants for controlling the deposited metal grain size. The NF structures exhibit broad plasmonic absorption that is utilized for demonstrating surface-enhanced Raman scattering (SERS) of thiophenol monolayer. The new type of nanostructures feature a metallic nanoshell directly coupled to the crystalline semiconductor NW showing broad plasmonic absorption. PMID- 26972889 TI - Diagnosis and Management of Cholesteatomas in Dogs. AB - Surgical intervention of aural cholesteatomas in dogs can be curative. Imaging findings include a soft tissue density in the middle ear and destruction of the bone of the bulla with characteristics of an aggressive lesion. Dogs with early stage disease have a better outcome than those with chronic disease, temporal bone involvement and neurologic signs. Dogs with recurrent disease can be reoperated or managed medically with long-term resolution or palliation of clinical signs. PMID- 26972891 TI - Alkalinization of Thin Layer Samples with a Selective Proton Sink Membrane Electrode for Detecting Carbonate by Carbonate-Selective Electrodes. AB - Potentiometry is known to be sensitive to so-called free ion activity and is a potentially valuable tool in environmental speciation analysis. Here, the direct detection of free and total carbonate is demonstrated by alkalinization of a thin layer sample (~100 MUm), which is electrochemically triggered at a pH responsive membrane placed opposite a carbonate-selective membrane electrode. The concept may serve as a promising future methodology for in situ environmental sensing applications where traditional sampling and pretreatment steps are no longer required. The possibility of increasing the pH of the sample was demonstrated first with a proton selective membrane (pH readout at zero current) placed opposite the thin layer gap. An optimal applied potential (600 mV) for 300 s resulted in a pH increase of 4 units in an artificial sample, with a relative standard deviation (RSD) of ~2%. The pH probe was subsequently replaced by a solid contact carbonate selective electrode for the determination of carbonate species (4.17 MUM) in a sample of 1 mM NaHCO3. Increasing the pH to 12.1 by the electrochemically controlled proton sink allowed one to convert bicarbonate to the detectable carbonate species. Initial bicarbonate concentration (~1 mM) was obtained as the difference between the converted bicarbonate and the initial carbonate concentration. An initial application of this concept was illustrated by the speciation analysis of an unfiltered sample from the Arve river (12.3 +/- 0.2 MUM and 22.5 +/- 0.3 mM carbonate and bicarbonate, respectively). The values were confirmed by volumetric titration. PMID- 26972892 TI - Developments in 3D neural cell culture models: the future of neurotherapeutics testing? PMID- 26972893 TI - Hybrid approach for structural modeling of biological systems from X-ray free electron laser diffraction patterns. AB - We present a new hybrid approach for structural modeling using X-ray free electron laser (XFEL) diffraction patterns from non-crystalline biological samples. Reconstruction of a 3D structure requires a large number of diffraction patterns; however, in the current XFEL experiments with biological systems, the analysis often relies on a small number of 2D diffraction patterns. In this study, we explore the strategies to identify plausible 3D structural models by combining the 2D analysis of such diffraction patterns with computational modeling (normal mode analysis or molecular dynamics simulations). As the first step toward such hybrid modeling, we established a protocol to assess the agreement between the model structure and the target XFEL diffraction pattern and showed that XFEL data can be used to study the conformational transitions of biological molecules. We tested the proposed algorithms using data of three biomolecular complexes of different sizes (elongation factor 2, CCM virus, and ribosome) and examined the experimental conditions that are required to perform such studies, in particular the XFEL beam intensity requirements. The results indicate that the current beam intensity is close to a strength that enables us to study conformational transitions of macromolecules, such as ribosomes. The proposed algorithm can be combined with molecular mechanics approaches, such as molecular dynamics simulations and normal mode analysis, to generate a large number of candidate structures to perform hybrid structural modeling. PMID- 26972894 TI - Optimization of a protective medium for freeze-dried Pichia membranifaciens and application of this biocontrol agent on citrus fruit. AB - AIMS: To optimize a protective medium for freeze-dried Pichia membranifaciens and to evaluate biocontrol efficacies of agents against blue and green mould and anthracnose in citrus fruit. METHODS AND RESULTS: Based on the screening assays of saccharides and antioxidants, response surface methodology was used to optimize sucrose, sodium glutamate and skim milk to improve viability of freeze dried Pi. membranifaciens. Biocontrol assays were conducted between fresh and freeze-dried Pi. membranifaciens against Penicillium italicum, Penicillium digitatum and Colletotrichum gloeosporioides in citrus fruit. Solving the regression equation indicated that the optimal protective medium was 6.06% (w/v) sucrose combined with 3.40% (w/v) sodium glutamate and 5.43% (w/v) skim milk. Pi. membranifaciens freeze-dried in the optimal protective medium showed 76.80% viability, and retained biocontrol efficacy against Pe. italicum, Pe. digitatum and Co. gloeosporioides in citrus fruit. CONCLUSIONS: The optimal protective medium showed more effective protective properties than each of the three protectants used alone. The viability of freeze-dried Pi. membranifaciens finally reached 76.80%. Meanwhile, the biocontrol efficacies showed no significant difference between fresh and freeze-dried yeast against Pe. italicum, Pe. digitatum and Co. gloeosporioides in citrus fruit. SIGNIFICANCE AND IMPACT OF THE STUDY: The results showed the potential value of Pi. membranifaciens CICC 32259 for commercialization. PMID- 26972895 TI - The Therapeutic Efficacy of Environmental Enrichment and Methylphenidate Alone and in Combination after Controlled Cortical Impact Injury. AB - Environmental enrichment (EE) and methylphenidate (MPH) independently confer significant benefit to behavioral recovery after controlled cortical impact (CCI) injury. Given that combinational therapies may be more clinically translatable than monotherapies, the aim of the current study was to test the hypothesis that a combined treatment regimen of EE and MPH would provide greater therapeutic efficacy than either one alone. Anesthetized adult male rats received either a CCI of moderate severity or sham injury and were then randomly assigned to EE or standard (STD) housing where they received either intraperitoneal (ip) MPH (5 mg/kg) or vehicle (VEH; 1.0 mL/kg; ip) beginning 24 h after injury and once daily for 19 days. Motor and cognitive assessments were conducted on post-injury days 1 5 and 14-19, respectively. No differences were observed in sham controls regardless of treatments, and thus their data were pooled. The traumatic brain injury (TBI)+EE+VEH and TBI+EE+MPH groups exhibited enhanced beam balance and beam walk performance relative to the TBI+STD+VEH group (p < 0.05), but did not differ from one another (p > 0.05). No effect of MPH treatment alone was observed in either motor task. In contrast, MPH improved spatial learning and memory when presented alone and also when combined with EE relative to VEH-treated STD controls (p < 0.05). In addition, both EE groups performed significantly better than the TBI+STD+MPH group (p < 0.05), but did not differ from one another (p > 0.05). These data replicate previous findings that both EE and MPH confer cognitive benefits after TBI and extend the findings by revealing that combining EE and MPH does not produce effects greater than either treatment alone, which does not support the hypothesis. The lack of an additive effect may be because of the robustness of the EE. PMID- 26972896 TI - Evolutionary loss of cone photoreception in balaenid whales reveals circuit stability in the mammalian retina. AB - The classical understanding of mammalian vision is that it occurs through "duplex" retinae containing both rod and cone photoreceptors, the signals from which are processed through rod- and/or cone-specific signaling pathways. The recent discovery of rod monochromacy in some cetacean lineages provides a novel opportunity to investigate the effects of an evolutionary loss of cone photoreception on retinal organization. Sequence analysis of right whale (Eubalaena glacialis; family Balaenidae) cDNA derived from long-wavelength sensitive (LWS) cone opsin mRNA identified several mutations in the opsin coding sequence, suggesting the loss of cone cell function, but maintenance of non photosensitive, cone opsin mRNA-expressing cells in the retina. Subsequently, we investigated the retina of the closely related bowhead whale (Balaena mysticetus; family Balaenidae) to determine how the loss of cone-mediated photoreception affects light signaling pathways in the retina. Anti-opsin immunofluorescence demonstrated the total loss of cone opsin expression in B. mysticetus, whereas light microscopy, transmission electron microscopy, and bipolar cell (protein kinase C-alpha [PKC-alpha] and recoverin) immunofluorescence revealed the maintenance of cone soma, putative cone pedicles, and both rod and cone bipolar cell types. These findings represent the first immunological and anatomical evidence of a naturally occurring rod-monochromatic mammalian retina, and suggest that despite the loss of cone-mediated photoreception, the associated cone signaling structures (i.e., cone synapses and cone bipolar cells) may be maintained for multichannel rod-based signaling in balaenid whales. J. Comp. Neurol. 524:2873-2885, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26972898 TI - Laparoscopic surgical technique for perforated duodenal ulcer. PMID- 26972899 TI - A review of the assessment and prevalence of sedentarism in older adults, its physiology/health impact and non-exercise mobility counter-measures. AB - This literature review focuses on aspects of sedentary behaviour (SB) in elderly. Since it has been identified as a distinct health risk, independent of physical activity, SB is a significant issue. This is particularly true for an ageing population as evidence shows that older adults (aged >=65 years) are the most sedentary age group (on average 8.5-9.6 h daily sitting time). Accurate SB assessment is important for understanding this habitual behaviour and its impact. However, SB measurement is challenging, regardless of the method used. Although negative associations of SB in elderly have been reported for several health outcomes, evidence is inconclusive, apart from the evidence on the adverse SB effect on the all-cause mortality rate. Generally, strategies have been proposed to counteract SB, of which breaking prolonged sedentary bouts with at least light intensity physical activity seems to be the most promising. Overall, further research in elderly is required to increase the evidence and to either support or refute the current findings. Moreover, further research will help to develop informed SB guidelines for an optimal strategy to counteract SB and its health effects in older adults. PMID- 26972900 TI - Practice variations in voice treatment selection following vocal fold mucosal resection. AB - OBJECTIVES/HYPOTHESIS: To characterize initial voice treatment selection following vocal fold mucosal resection in a Medicare population. STUDY DESIGN: Retrospective analysis of a large, nationally representative Medicare claims database. METHODS: Patients with > 12 months of continuous Medicare coverage who underwent a leukoplakia- or cancer-related vocal fold mucosal resection (index) procedure during calendar years 2004 to 2009 were studied. The primary outcome of interest was receipt of initial voice treatment (thyroplasty, vocal fold injection, or speech therapy) following the index procedure. We evaluated the cumulative incidence of each postindex treatment type, treating the other treatment types as competing risks, and further evaluated postindex treatment utilization using the proportional hazards model for the subdistribution of a competing risk. Patient age, sex, and Medicaid eligibility were used as predictors. RESULTS: A total of 2,041 patients underwent 2,427 index procedures during the study period. In 14% of cases, an initial voice treatment event was identified. Women were significantly less likely to receive surgical or behavioral treatment compared to men. From age 65 to 75 years, the likelihood of undergoing surgical treatment increased significantly with each 5-year age increase; after age 75 years, the likelihood of undergoing either surgical or behavioral treatment decreased significantly every 5 years. Patients with low socioeconomic status were significantly less likely to undergo speech therapy. CONCLUSION: The majority of Medicare patients do not undergo voice treatment following vocal fold mucosal resection. Further, the treatments analyzed here appear disproportionally utilized based on patient sex, age, and socioeconomic status. Additional research is needed to determine whether these observations reflect clinically explainable differences or disparities in care. LEVEL OF EVIDENCE: 2c. Laryngoscope, 126:2505-2512, 2016. PMID- 26972901 TI - Should ARDS be renamed diffuse alveolar damage? PMID- 26972902 TI - Happy 50th birthday ARDS! PMID- 26972903 TI - Renal markers cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) in postmortem samples. AB - PURPOSE: Renal markers may provide valuable information for cause of death (CoD) investigation when assessing the influence of impaired kidney function. A commonly used marker, creatinine (Cr), increases due to kidney injury and is known to be reasonably stable in postmortem (PM) samples. More sensitive markers are needed, as the increase of serum Cr level only occurs after relatively severe renal damage. We evaluated two markers, cystatin C and neutrophil gelatinase associated lipocalin (NGAL), in addition to Cr. To the best of our knowledge this was the first study to investigate cystatin C and NGAL in a postmortem (PM) context. METHODS: Cr, cystatin C, and NGAL were measured from PM blood in 39 autopsy cases. NGAL was also measured from urine in 16 cases. Cystatin C and NGAL were analyzed using ELISA, Cr measurements were performed with Jaffe method. Correlations of these markers were evaluated. RESULTS AND CONCLUSIONS: Both, blood cystatin C and NGAL, levels showed significant correlation with Cr (p = 0.05 and p = 0.01, respectively). Cystatin C and NGAL in blood are promising markers for further studies with PM samples. PMID- 26972904 TI - Sudden cardiac death while playing Australian Rules football: a retrospective 14 year review. AB - Australian Rules football is a sport which evolved from Gaelic football and which is played by a large number of predominantly male participants in a number of countries. The highest participation rates are in the southern states of Australia. A retrospective review over a period of 14 years identified 14 cases of sudden cardiac death that occurred in individuals while playing the sport. All were male and ranged in age from 13 to 36 years with a mean and median age of 23 years. A spectrum of cardiac causes was identified including coronary artery atherosclerosis, myocarditis, anomalous coronary artery anatomy, arrhythmogenic right ventricular cardiomyopathy, and healed Kawasaki disease. In 5 cases the heart was morphologically normal raising the possibility of a channelopathy. No traumatic deaths were identified. Some of the individuals had experienced symptoms prior to the fatal episode and the role of pre participation screening in reducing mortality is discussed. PMID- 26972906 TI - Current views on the diagnosis and management of hypokalaemia in children. AB - Hypokalaemia is a common electrolyte disorder in children, caused by decreased potassium intake, increased gastrointestinal and urinary losses or transcellular shift. Patients with severe hypokalaemia may suffer from symptoms such as life threatening cardiac arrhythmias. The aim of our study was to review the aetiology of hypokalaemia, suggest a diagnostic algorithm and discuss the management of patients with various aetiologies of hypokalaemia. CONCLUSION: Understanding the pathophysiology of hypokalaemic states, along with a detailed medical history, physical examination and specific laboratory tests are required for proper diagnosis and appropriate treatment. PMID- 26972905 TI - Novel identification of biofluids using a multiplex methylation-specific PCR combined with single-base extension system. AB - PURPOSE: Knowledge of the composition of complex body fluid mixtures may aid forensic investigations greatly. However, many of the traditional tests are presumptive in nature and can lead to ambiguous results. The aim of this study is to establish a reliable method to identify various biofluids via analysis of their DNA methylation profiles. METHODS: A total of eight biofluid-specific methylated markers for saliva, venous blood, vaginal fluids, and semen were isolated from the open database of Infinium HumanMethylation450 BeadChip. These biofluid-specific markers, a control marker to confirm bisulfite conversion, and a gender marker, were combined into a 10-plex methylation-specific PCR single base-extension (MSP-SBE) system. RESULTS: Analysis of 65 DNA samples isolated from venous blood, semen, vaginal fluid, saliva, and menstrual blood that had been treated with bisulfite, resulted in all eight markers detecting the body fluid to which they were designed. Unambiguous body fluid identification occurred from both single sources of body fluids and complex mixtures. A threshold was devised for each marker to minimize the chance of a false inclusion. The efficacy of the assay and application to forensic practice was demonstrated using five non probative samples from real alleged sexual assault cases. The system unambiguously determined the biofluid types for the non-probative forensic samples that previously resulted in inconclusive or conflicting results using traditional tests. CONCLUSIONS: The results demonstrated the 10-plex MSP-SBE system established in this study is both sensitive and specific when applied to body fluid identification and can be readily adopted into forensic practice. PMID- 26972908 TI - Subepidermal autoimmune bullous disease affecting predominantly mucocutaneous junctions and the palms with autoantibodies to BP230 and laminin gamma1. PMID- 26972912 TI - Fungal physiology: Aspergillus sees the light. PMID- 26972897 TI - Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. AB - Although much progress is being made in understanding the molecular pathways in the placenta that are involved in the pathophysiology of pregnancy-related disorders, a significant gap exists in the utilization of this information for the development of new drug therapies to improve pregnancy outcome. On March 5-6, 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health sponsored a 2-day workshop titled Placental Origins of Adverse Pregnancy Outcomes: Potential Molecular Targets to begin to address this gap. Particular emphasis was given to the identification of important molecular pathways that could serve as drug targets and the advantages and disadvantages of targeting these particular pathways. This article is a summary of the proceedings of that workshop. A broad number of topics were covered that ranged from basic placental biology to clinical trials. This included research in the basic biology of placentation, such as trophoblast migration and spiral artery remodeling, and trophoblast sensing and response to infectious and noninfectious agents. Research findings in these areas will be critical for the formulation of the development of future treatments and the development of therapies for the prevention of a number of pregnancy disorders of placental origin that include preeclampsia, fetal growth restriction, and uterine inflammation. Research was also presented that summarized ongoing clinical efforts in the United States and in Europe that has tested novel interventions for preeclampsia and fetal growth restriction, including agents such as oral arginine supplementation, sildenafil, pravastatin, gene therapy with virally delivered vascular endothelial growth factor, and oxygen supplementation therapy. Strategies were also proposed to improve fetal growth by the enhancement of nutrient transport to the fetus by modulation of their placental transporters and the targeting of placental mitochondrial dysfunction and oxidative stress to improve placental health. The roles of microRNAs and placental-derived exosomes, as well as messenger RNAs, were also discussed in the context of their use for diagnostics and as drug targets. The workshop discussed the aspect of safety and pharmacokinetic profiles of potential existing and new therapeutics that will need to be determined, especially in the context of the unique pharmacokinetic properties of pregnancy and the hurdles and pitfalls of the translation of research findings into practice. The workshop also discussed novel methods of drug delivery and targeting during pregnancy with the use of macromolecular carriers, such as nanoparticles and biopolymers, to minimize placental drug transfer and hence fetal drug exposure. In closing, a major theme that developed from the workshop was that the scientific community must change their thinking of the pregnant woman and her fetus as a vulnerable patient population for which drug development should be avoided, but rather be thought of as a deprived population in need of more effective therapeutic interventions. PMID- 26972907 TI - Modulation of kidney urea transporter UT-A3 activity by alpha2,6-sialylation. AB - Two urea transporters, UT-A1 and UT-A3, are expressed in the kidney terminal inner medullary collecting duct (IMCD) and are important for the production of concentrated urine. UT-A1, as the largest isoform of all UT-A urea transporters, has gained much attention and been extensively studied; however, the role and the regulation of UT-A3 are less explored. In this study, we investigated UT-A3 regulation by glycosylation modification. A site-directed mutagenesis verified a single glycosylation site in UT-A3 at Asn279. Loss of the glycosylation reduced forskolin-stimulated UT-A3 cell membrane expression and urea transport activity. UT-A3 has two glycosylation forms, 45 and 65 kDa. Using sugar-specific binding lectins, the UT-A3 glycosylation profile was examined. The 45-kDa form was pulled down by lectin concanavalin A (Con A) and Galant husnivalis lectin (GNL), indicating an immature glycan with a high amount of mannose (Man), whereas the 65 kDa form is a mature glycan composed of acetylglucosamine (GlcNAc) and poly-N acetyllactosame (poly-LacNAc) that was pulled down by wheat germ agglutinin (WGA) and tomato lectin, respectively. Interestingly, the mature form of UT-A3 glycan contains significant amounts of sialic acid. We explored the enzymes responsible for directing UT-A3 sialylation. Sialyltransferase ST6GalI, but not ST3GalIV, catabolizes UT-A3 alpha2,6-sialylation. Activation of protein kinase C (PKC) by PDB treatment promoted UT-A3 glycan sialylation and membrane surface expression. The PKC inhibitor chelerythrine blocks ST6GalI-induced UT-A3 sialylation. Increased sialylation by ST6GalI increased UT-A3 protein stability and urea transport activity. Collectively, our study reveals a novel mechanism of UT-A3 regulation by ST6GalI-mediated sialylation modification that may play an important role in kidney urea reabsorption and the urinary concentrating mechanism. PMID- 26972916 TI - The ecology and biogeochemistry of stream biofilms. AB - Streams and rivers form dense networks, shape the Earth's surface and, in their sediments, provide an immensely large surface area for microbial growth. Biofilms dominate microbial life in streams and rivers, drive crucial ecosystem processes and contribute substantially to global biogeochemical fluxes. In turn, water flow and related deliveries of nutrients and organic matter to biofilms constitute major constraints on microbial life. In this Review, we describe the ecology and biogeochemistry of stream biofilms and highlight the influence of physical and ecological processes on their structure and function. Recent advances in the study of biofilm ecology may pave the way towards a mechanistic understanding of the effects of climate and environmental change on stream biofilms and the biogeochemistry of stream ecosystems. PMID- 26972917 TI - Causation or only correlation? Application of causal inference graphs for evaluating causality in nano-QSAR models. AB - In this paper, we suggest that causal inference methods could be efficiently used in Quantitative Structure-Activity Relationships (QSAR) modeling as additional validation criteria within quality evaluation of the model. Verification of the relationships between descriptors and toxicity or other activity in the QSAR model has a vital role in understanding the mechanisms of action. The well-known phrase "correlation does not imply causation" reflects insight statistically correlated with the endpoint descriptor may not cause the emergence of this endpoint. Hence, paradigmatic shifts must be undertaken when moving from traditional statistical correlation analysis to causal analysis of multivariate data. Methods of causal discovery have been applied for broader physical insight into mechanisms of action and interpretation of the developed nano-QSAR models. Previously developed nano-QSAR models for toxicity of 17 nano-sized metal oxides towards E. coli bacteria have been validated by means of the causality criteria. Using the descriptors confirmed by the causal technique, we have developed new models consistent with the straightforward causal-reasoning account. It was proven that causal inference methods are able to provide a more robust mechanistic interpretation of the developed nano-QSAR models. PMID- 26972918 TI - Clotting factor concentrate use and occurrence of thrombotic events in patients with hemophilia: A nationwide and 15-year cohort study. PMID- 26972919 TI - Design and synthesis of thiourea derivatives with sulfur-containing heterocyclic scaffolds as potential tyrosinase inhibitors. AB - Tyrosinase is a key enzyme during the production of melanins in plants and animals. A class of novel N-aryl-N'-substituted phenylthiourea derivatives (3a-i, 6a-k) were designed, synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed some 4,5,6,7 tetrahydro-2-[[(phenylamino)thioxomethyl]amino]-benzo[b]thiophene-3-carboxylic acid derivatives (3a-i) exhibited moderate inhibitory potency on diphenolase activity of tyrosinase. When the scaffold of 4,5,6,7-tetrahydrobenzo[b]thiophene 3-carboxylic acid was replaced with 2-(1,3,4-thiadiazol-2-yl)thio acetic acid, the inhibitory activity of compounds (6a-k) against tyrosinase was improved obviously; especially, the inhibitory activity of compound 6h (IC50=6.13 MUM) is significantly higher than kojic acid (IC50=33.3 MUM). Moreover, the analysis on inhibition mechanism revealed that compound 6h might plays the role as a noncompetitive inhibitor. PMID- 26972920 TI - Rational design, synthesis and biological evaluation of 1,3,4-oxadiazole pyrimidine derivatives as novel pyruvate dehydrogenase complex E1 inhibitors. AB - On the basis of previous study on 2-methylpyrimidine-4-ylamine derivatives I, further synthetic optimization was done to find potent PDHc-E1 inhibitors with antibacterial activity. Three series of novel pyrimidine derivatives 6, 11 and 14 were designed and synthesized as potential Escherichia coli PDHc-E1 inhibitors by introducing 1,3,4-oxadiazole-thioether, 2,4-disubstituted-1,3-thiazole or 1,2,4 triazol-4-amine-thioether moiety into lead structure I, respectively. Most of 6, 11 and 14 exhibited good inhibitory activity against E. coli PHDc-E1 (IC50 0.97 19.21 MUM) and obvious inhibitory activity against cyanobacteria (EC50 0.83-9.86 MUM). Their inhibitory activities were much higher than that of lead structure I. 11 showed more potent inhibitory activity against both E. coli PDHc-E1 (IC50<6.62 MUM) and cyanobacteria (EC50<1.63 MUM) than that of 6, 14 or lead compound I. The most effective compound 11d with good enzyme-selectivity exhibited most powerful inhibitory potency against E. coli PDHc-E1 (IC50=0.97 MUM) and cyanobacteria (EC50=0.83 MUM). The possible interactions of the important residues of PDHc-E1 with title compounds were studied by molecular docking, site-directed mutagenesis, and enzymatic assays. The results indicated that 11d had more potent inhibitory activity than that of 14d or I due to its 1,3,4-oxadiazole moiety with more binding position and stronger interaction with Lsy392 and His106 at active site of E. coli PDHc-E1. PMID- 26972921 TI - A concise synthesis and evaluation of new malonamide derivatives as potential alpha-glucosidase inhibitors. AB - A series of new malonamide derivatives were synthesized by Michael addition reaction of N(1),N(3)-di(pyridin-2-yl)malonamide into alpha,beta-unsaturated ketones mediated by DBU in DCM at ambient temperature. The inhibitory potential of these compounds in vitro, against alpha-glucosidase enzyme was evaluated. Result showed that most of malonamide derivatives were identified as a potent inhibitors of alpha-glucosidase enzyme. Among all the compounds, 4K (IC50=11.7 +/ 0.5 MUM) was found out as the most active one compared to standard drug acarbose (IC50=840 +/- 1.73 MUM). Further cytotoxicity of 4a-4m were also evaluated against a number of cancer and normal cell lines and interesting results were obtained. PMID- 26972924 TI - Modulating the Electronic and Optical Properties of Tetragonal ZnSe Monolayers by Chalcogen Dopants. AB - The recently proposed three-atom-thick single-layer ZnSe sheet demonstrates a strong quantum confinement effect by exhibiting a large enhancement of band gap relative to the zinc blende (ZB) bulk phase. In this work, we aim at investigating the electronic and optical properties of this ultrathin tetragonal ZnSe single-layer sheet with various chalcogen dopant atoms, based on density functional theory (DFT). We find that these single-layer sheets with dopant atoms are still direct-band semiconductors with tunable band gaps, which can lead to strong light absorption and potential applications in solar energy harvesting. Theoretical optical absorbance results show that the S-doped ZnSe monolayer exhibits a higher absorption performance compared to other doped and undoped ZnSe monolayers. These findings pave a way for the modulation of novel ultrathin tetragonal ZnSe monolayers for a wealth of potential optoelectronic applications. PMID- 26972922 TI - Design, synthesis, and evaluation of 2-piperidone derivatives for the inhibition of beta-amyloid aggregation and inflammation mediated neurotoxicity. AB - A series of novel multipotent 2-piperidone derivatives were designed, synthesized and biologically evaluated as chemical agents for the treatment of Alzheimer's disease (AD). The results showed that most of the target compounds displayed significant potency to inhibit Abeta(1-42) self-aggregation. Among them, compound 7q exhibited the best inhibition of Abeta(1-42) self-aggregation (59.11% at 20 MUM) in a concentration-dependent manner. Additionally, the compounds 6b, 7p and 7q as representatives were found to present anti-inflammation properties in lipopolysaccharide (LPS)-induced microglial BV-2 cells. They could effectively suppress the production of pro-inflammatory cytokines such as TNF-alpha, IL-1beta and IL-6. Meanwhile, compound 7q could prevent the neuronal cell SH-SY5Y death by LPS-stimulated microglia cell activation mediated neurotoxicity. The molecular modeling studies demonstrated that compounds matched the pharmacophore well and had good predicted physicochemical properties and estimated IC50 values. Moreover, compound 7q exerted a good binding to the active site of myeloid differentiation factor 88 (MyD88) through the docking analysis and could interfere with its homodimerization or heterodimerization. Consequently, these compounds emerged as promising candidates for further development of novel multifunctional agents for AD treatment. PMID- 26972923 TI - Ecosystem function decays by fungal outbreaks in Antarctic microbial mats. AB - Antarctica harbours a remarkably diverse range of freshwater bodies and terrestrial ecosystems, where microbial mats are considered the most important systems in terms of biomass and metabolic capabilities. We describe the presence of lysis plaque-like macroscopic blighted patches within the predominant microbial mats on Livingston Island (Antarctic Peninsula). Those blighting circles are associated with decay in physiological traits as well as nitrogen depletion and changes in the spatial microstructure; these alterations were likely related to disruption of the biogeochemical gradients within the microbial ecosystem caused by an unusually high fungal abundance and consequent physical alterations. This phenomenon has been evidenced at a time of unprecedented rates of local warming in the Antarctic Peninsula area, and decay of these ecosystems is potentially stimulated by warmer temperatures. PMID- 26972925 TI - Deriving health utility values from a randomized, double-blind, placebo controlled trial of siltuximab in subjects with multicentric Castleman's disease. AB - PURPOSE: To estimate health utility values, explore predictors of utility values, and estimate the quality-adjusted life years (Q.A.L.Y.s) gained by treatment in multicentric Castleman's disease (M.C.D.). METHODS: The SF-36 was administered to 79 patients enrolled in a randomized, double-blind, placebo-controlled, multi national study to determine the safety and efficacy of siltuximab plus best supportive care (B.S.C.) compared with B.S.C., in subjects with symptomatic M.C.D. Utility (SF-6D) scores were derived from the SF-36. Sensitivity analyses using utilities obtained by mapping the SF-36 to the EQ-5D were also conducted. Repeated measures, mixed effects models were conducted to estimate effects of treatment, responder status and >= Grade 3 adverse events (A.E.s) on changes in utility values over time, controlling for baseline utility value. Additionally, differential Q.A.L.Y. gain was assessed in the trial using multiple regression. RESULTS: Patients on siltuximab and those who experienced a complete or partial response had higher mean utility values over time than those on placebo or those with stable disease. After an initial response to treatment, the mean utility remained relatively stable for patients on siltuximab and those who experienced a complete or partial response during the period when most patients were on study. A significantly different Q.A.L.Y. gain was found for patients on siltuximab (versus placebo) as calculated by SF-6D (0.070 Q.A.L.Y.s, p < .05) scores at 6 months (EQ-5D 0.096 Q.A.L.Y.s, p < 0.05). CONCLUSIONS: Siltuximab demonstrated improved, durable health utility gains in this rare disease over B.S.C. The main SF-6D results were supported by EQ-5D sensitivity analysis. These findings are limited by the small study sample size and substantial missing data caused predominantly by crossover. A longitudinal, multisite international observational study capturing clinical, safety and health-related quality of life (H.R.Q.L.) endpoints are needed to confirm these findings. PMID- 26972926 TI - The concentration of iodine in horse serum and its relationship with thyroxin concentration by geological difference. AB - In this study, iodine and thyroxin (T4) concentrations in the serum of 69 horses were investigated. Higher iodine concentrations were obtained from the horses housed in Chiba Prefecture. In contrast, T4 concentrations of horses at Shizuoka Prefecture were higher than those of horses at Chiba Prefecture. There was a significant correlation (r = 0.643, P < 0.001) between the iodine and T4 concentrations of horses at Saitama and Shizuoka prefectures. Although a significant correlation (r = 0.794, P < 0.001) was also observed in the investigation of all horses at Chiba Prefecture, the distribution area of the data was separated from the data of horses housed in Saitama and Shizuoka prefectures. A higher iodine concentration in the environment is expected in the sampling area at Chiba Prefecture. Thus, it was suggested that the concentrations of iodine in the serum of horses are influenced by geological differences. It was thought that equine serum is a useful sample for monitoring. PMID- 26972927 TI - Distribution characteristics and source apportionment of polycyclic aromatic hydrocarbons (PAHs) in the Liao River drainage basin, northeast China. AB - The Liao River drainage basin, which is one of China's seven major rivers basins, is located in northeast China. This region is characterized by important industrial bases including steel factories and oil and chemical plants, all of which have the potential to contribute pollutants to the drainage basin. In this study, 16 polycyclic aromatic hydrocarbons (PAHs) in water and suspended particulate matter (SPM) in the major rivers of the Liao River drainage basin were identified and quantified by gas chromatography mass spectrometry (GC/MS). The total PAH concentrations ranged from 0.4 to 76.5 MUg/g (dry weight) in SPM and 32.6 to 108 ng/L in surface water, respectively. Low-ring PAHs (including two and three-ring PAHs) were dominant in all PAH samples, and the level of low-ring PAHs in surface water was higher than that in SPM. The proportion of two-ring PAHs was the highest, accounting for an average of 68.2 % of the total PAHs in surface water, while the level of three-ring PAHs was the highest in SPM, with an average of 66.3 %. When compared with other river systems, the concentrations of PAHs in the Liao River drainage basin were lower. Identification of the emission sources based on diagnostic ratios suggested petroleum and fossil fuel combustion were important contribution to PAHs in the study area. PMID- 26972928 TI - Isotopic perspectives (delta(13) C, delta(15) N, delta(34) S) of diet, social complexity, and animal husbandry during the proto-shang period (ca. 2000-1600 BC) of China. AB - OBJECTIVES: To examine dietary patterns and animal husbandry practices and assess the links between human diet and sex, age, burial direction/position, and social status (as inferred by type of grave goods) during the transformative Proto-Shang (ca. 2000-1600 BC) period of China. MATERIALS AND METHODS: Stable isotope ratios of carbon (delta(13) C), nitrogen (delta(15) N), and sulfur (delta(34) S) were analyzed from human (n = 83) and animal (n = 36) bone collagen at the site of Nancheng in Hebei Province, China. RESULTS: The Proto-Shang population consumed a predominately C4 diet (delta(13) C = -6.8 +/- 0.40/00; delta(15) N = 9.4 +/- 0.60/00), but a single individual (M70) had a mixed C3 /C4 diet (delta(13) C = 14.90/00; delta(15) N = 10.10/00). The delta(34) S measurement of M70 (8.80/00) is similar to the local animals (8.2 +/- 2.60/00) and the other members of the population (7.0 +/- 0.80/00) suggesting this individual may not have been a migrant even though the burial direction (north-south) and position (flexed) was different than the majority of the graves in the cemetery. DISCUSSION: From comparison with the faunal bone collagen stable isotope results, the Nancheng population ate millets with varying levels of animal protein consumption focused primarily on pigs and possibly cattle and dogs, but sheep/goats, and deer were not eaten in significant amounts. Analysis of the isotopic results in relation to other contemporary sites such as Liuzhuang and Xinzhai show strikingly similar patterns, suggesting that the sheep/goats were likely raised mainly for their secondary products (e.g., wool). No link between diet and sex was found at the population level, but when the data were sorted by age and sex, the older males (>40 years old) were found to have significantly lower delta(13) C values (-6.6 +/- 0.30/00; n = 18) compared to the younger males (<40 years old) (-7.3 +/- 0.50/00; n = 8). Further, no significant correlations between diet and burial direction/position or social status (based on the type of grave goods) were found at Nancheng, possibly indicating that the dietary social stratification of the later Shang and Zhou Dynasties had yet to be established in Chinese society at this time. Am J Phys Anthropol 160:433-445, 2016.. (c) 2016 Wiley Periodicals, Inc. PMID- 26972929 TI - Use of Concomitant Antibiotics During Treatment for Clostridium difficile Infection (CDI) in Pediatric Inpatients: An Observational Cohort Study. AB - Concomitant antibiotic use during treatment for Clostridium difficile infection (CDI) increases the risk of recurrence. Across a network of children's hospitals, 46% of patients treated for CDI received concomitant antibiotics for a median of 7 days. Concomitant antibiotic use was more common among patients with malignancies, and solid organ or bone marrow transplant. Unnecessary concomitant antibiotic use in CDI patients is a potential target for pediatric antimicrobial stewardship. PMID- 26972930 TI - Diabetes mellitus in patients with cirrhosis: clinical implications and management. AB - Disorders of glucose metabolism, namely glucose intolerance and diabetes, are frequent in patients with chronic liver diseases. In patients with cirrhosis, diabetes can be either a classical type 2 diabetes mellitus or the so-called hepatogenous diabetes, i.e. a consequence of liver insufficiency and portal hypertension. This review article provides an overview of the possible pathophysiological mechanisms explaining diabetes in patients with cirrhosis. Cirrhosis is associated with portosystemic shunts as well as reduced hepatic mass, which can both impair insulin clearance by the liver, contributing to peripheral insulin resistance through insulin receptors down-regulation. Moreover, cirrhosis is associated with increased levels of advanced-glycation-end products and hypoxia-inducible-factors, which may play a role in the development of diabetes. This review also focuses on the clinical implications of diabetes in patients with cirrhosis. First, diabetes is an independent factor for poor prognosis in patients with cirrhosis. Specifically, diabetes is associated with the occurrence of major complications of cirrhosis, including ascites and renal dysfunction, hepatic encephalopathy and bacterial infections. Diabetes is also associated with an increased risk of hepatocellular carcinoma in patients with chronic liver diseases. Last, the management of patients with concurrent diabetes and liver disease is also addressed. Recent findings suggest a beneficial impact of metformin in patients with chronic liver diseases. Insulin is often required in patients with advanced cirrhosis. However, the favourable impact of controlling diabetes in patients with cirrhosis has not been demonstrated yet. PMID- 26972936 TI - The role of ion exchange in the passivation of In(Zn)P nanocrystals with ZnS. AB - We have investigated the chemical state of In(Zn)P/ZnS core/shell nanocrystals (NCs) for color conversion applications using hard X-ray absorption spectroscopy (XAS) and photoluminescence excitation (PLE). Analyses of the edge energies as well as the X-ray absorption fine structure (XAFS) reveal that the Zn(2+) ions from ZnS remain in the shell while the S(2-) ions penetrate into the core at an early stage of the ZnS deposition. It is further demonstrated that for short growth times, the ZnS shell coverage on the core was incomplete, whereas the coverage improved gradually as the shell deposition time increased. Together with evidence from PLE spectra, where there is a strong indication of the presence of P vacancies, this suggests that the core-shell interface in the In(Zn)P/ZnS NCs are subject to substantial atomic exchanges and detailed models for the shell structure beyond simple layer coverage are needed. This substantial atomic exchange is very likely to be the reason for the improved photoluminescence behavior of the core-shell particles compare to In(Zn)P-only NCs as S can passivate the NCs surfaces. PMID- 26972931 TI - Recurrence of venous thromboembolism in patients with recent gestational deep vein thrombosis or pulmonary embolism: Findings from the RIETE Registry. AB - INTRODUCTION: The aim of this study was to investigate the recurrence rate of venous thromboembolism (VTE) and the prevalence of major bleeding or death in patients with previous VTE in pregnancy and puerperium. Risk factors for VTE recurrence were also assessed. MATERIALS AND METHODS: We evaluated a cohort of patients enrolled in the international, multicenter, prospective Registro Informatizado de la Enfermedad Trombo-Embolica (RIETE) registry with objectively confirmed VTE. RESULTS: In the registry, 607 women were presenting with VTE that occurred during pregnancy or puerperium. The 2-year VTE recurrence rate was 3.3% (CI: 95 1.5-5.0%) and the recurrent VTE incidence rate was 2.28events/100 patients-year. Among the 16 cases of VTE recurrence 11 cases appeared during drug treatment while only five cases were diagnosed after therapy discontinuation. No significant difference was found in treatment duration among these two subgroups of VTE recurrence cases and women without recurrence. Furthermore, the use of thrombolytics and inferior vena cava filter in initial treatment was associated to an increased risk of VTE recurrence. CONCLUSIONS: The current study provides new insights on VTE recurrence rate in patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) that occurred in pregnancy or postpartum period. These findings can contribute to risk assessment of thrombotic burden, thereby allowing for better decision making regarding antithrombotic management in this clinical setting. PMID- 26972938 TI - Alkaline Anion-Exchange Membranes Containing Mobile Ion Shuttles. AB - A new class of alkaline anion-exchange membranes containing mobile ion shuttles is developed. It is achieved by threading ionic linear guests into poly(crown ether) hosts via host-guest molecular interaction. The thermal- and pH-triggered shuttling of ionic linear guests remarkably increases the solvation-shell fluctuations in inactive hydrated hydroxide ion complexes (OH(-) (H2 O)4 ) and accelerates the OH(-) transport. PMID- 26972939 TI - Clinicopathological Implications of Wingless/int1 (WNT) Signaling Pathway in Pancreatic Ductal Adenocarcinoma. AB - Pancreatic cancer is still one of the most lethal malignancies in the world, and a more thorough understanding of its detailed pathogenetic mechanisms and the development of more effective therapeutic strategies are urgently required. Pancreatic ductal adenocarcinoma (PDA), the most common type of pancreatic cancer, is characterized by consistent genetic abnormalities such as point mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) and in the tumor suppressor protein p53 (TP53) genes. Alterations in intracellular core signal pathways have also been shown to induce the development or progression of PDA. The Wingless/int1 (WNT) signal pathway plays a pivotal role in embryonic development, cellular proliferation and differentiation, and dysregulation of WNT signaling can lead to neoplastic transformation in a variety of organ systems, including the pancreas. Recent studies have shown that altered WNT signaling is associated with a poor prognosis in patients with PDA, suggesting that the pathway is a predictor of patients' survival and a potential therapeutic target of PDA. In this review, the clinicopathological implications of WNT signaling in PDA are highlighted. PMID- 26972937 TI - The wound/burn guidelines - 3: Guidelines for the diagnosis and treatment for diabetic ulcer/gangrene. AB - We aimed to prepare guidelines for the management of diabetic ulcer/gangrene with emphasis on the diagnosis and treatment of skin symptoms. They serve as a tool to improve the quality of the diagnosis and treatment in each patient and, further, to improve the level of the care for diabetic ulcer in Japan by systematically presenting evidence-based recommendations for clinical judgments by incorporating various viewpoints. PMID- 26972940 TI - Estimation of Equilibrated Vapor Concentrations Using the UNIFAC Model for the Tetrachloroethylene-Chlorobenzene System. AB - Equilibrated vapor concentrations at 25 degrees C of the tetrachloroethylene chlorobenzene system were obtained in the presence of air to establish a method for estimating vapor concentrations in work environments where multicomponent organic solvents are used. The experimental data were correlated by introducing activity coefficients calculated by the UNIFAC (Universal Quasichemical Functional Group Activity Coefficient) model. There were four interaction parameters between groups in this solution system, and three had already been determined.However, the fourth parameter--the interaction parameter between ACCl and Cl-(C=C) groups--remains unknown. Therefore, this parameter was determined by a nonlinear least-squares method to obtain the best fit for the experimental data. The calculated values were found to be in good agreement with the experimental values. PMID- 26972941 TI - [Factors Associated with Diagnostic Yield of Endobronchial Ultrasonography with a Guide Sheath for Peripheral Lung Cancer]. AB - Endobronchial ultrasonography with a guide sheath (EBUS-GS) has recently been used for improved diagnostic yields for peripheral pulmonary lesions. This study retrospectively evaluated the factors related to the diagnostic yield of EBUS-GS for peripheral lung cancer. The medical records of 76 patients who had been diagnosed with lung cancer and had undergone bronchoscopy with EBUS-GS in our hospital between August 2014 and September 2015 were reviewed. The total diagnostic ratio of peripheral lung cancer was 71.1%. The following factors of the diagnostic yield were evaluated: location of pulmonary lesion; size; feature; bronchus sign; location of EBUS probe; EBUS detection; number of biopsies performed; procedure time; use of virtual bronchoscopic navigation; use of EBUS guided transbronchial needle aspiration with EBUS-GS; CT slice thickness; operator's years of medical experience; and specialized training in bronchoscopy at the National Cancer Center. In all cases, lesion size ? 20 mm (80.8% vs. 50.0%, P = 0.006), EBUS probe location "within" (90.0% vs. 50.0%, P < 0.001), EBUS detection (80.7% vs. 28.6%, P < 0.001), number of biopsies ? 5 (78.0% vs. 47.1%, P = 0.013), and bronchoscopy training (81.6% vs. 60.5%, P = 0.043) significantly contributed to an increase in the diagnostic yield. Following a multivariate analysis, EBUS probe location "within" was found to be the most significant factor affecting the diagnostic yield (odds ratio 14.10, 95% CI 3.53 56.60, P < 0.001), and bronchoscopy training was the second most significant factor (odds ratio 6.93, 95% CI 1.86-25.80, P = 0.004). EBUS probe location "within" and bronchoscopy training are the most important factors for improved diagnostic yield by bronchoscopy with EBUS-GS for peripheral lung cancer. PMID- 26972942 TI - [Mechanism of and Therapy for Kidney Fibrosis]. AB - Fibrosis occurs in systemic tissues other than the brain and finally induces dysfunction of the fibrotic organ. Kidney fibrosis is related to scarring after acute kidney injury and the progression of chronic kidney disease. Kidney function decreases with the progression of kidney fibrosis. As fibrotic tissue cannot return to its original status, advanced kidney fibrosis requires the administration of dialysis or kidney transplantation. Thus, elucidation the mechanism of kidney fibrosis is an important research theme. The proliferation and activation of (myo) fibroblasts and the excessive production of an extracellular matrix are common mechanisms in fibrosis in many organs, but it seems that kidney fibrosis has specific pathways. Tubular epithelial, mesangial cells, and erythropoietin producing cells, which exist only in the kidney, participate in forming kidney fibrosis. This review highlights an understanding of the cells and their underlying mechanisms, which are specific to kidney fibrosis process: transforming growth factor-beta (TGF-beta), epithelial mesenchymal transition, wingless/int-1 (WNT) signaling, renal anemia, and uremia. Finally, we describe potential therapies that focus on the mechanisms of kidney fibrosis: anti-TGF-beta antibody and mammalian target of rapamycin (mTOR). PMID- 26972943 TI - [Drug Therapy for Shock-Resistant Ventricular Fibrillation: Comparison of Nifekalant and Amiodarone]. AB - Early direct current (DC) shock is the most important therapy for ventricular fibrillation. Following the increased availability of automated external defibrillators (AED), the survival rate of cardiopulmonary arrest patients with ventricular fibrillation has improved. Although patients with shock-resistant ventricular fibrillation require additional antiarrhythmic drug therapy, the optimal protocol has not been established. Nifekalant is a pure potassium channel blocker with a pyrimidinedione structure. Nifekalant was approved in Japan for the treatment of life-threatening ventricular tachyarrhythmias in 1999, and is widely used as a class III antiarrhythmic intravenous drug. Intravenous amiodarone was approved in Japan in 2007, and exhibits various effects on ion channels, receptors, sympathetic activity, and thyroid function. Nifekalant and amiodarone also exhibit many pharmacological and pharmacodynamic differences. As nifekalant has no negative inotropic effect and a rapid action and clearance with a short half-life, it has some advantages over amiodarone for use in cardiopulmonary resuscitation. Indeed, data from clinical and animal studies suggest that nifekalant is superior to amiodarone for resuscitation of cardiopulmonary arrest resulting from shock-resistant ventricular fibrillation. A 300-mg bolus intravenous injection of amiodarone is considered an overdose for resuscitation of shock-resistant ventricular fibrillation. Further clinical studies are required to evaluate the effects of nifekalant compared with amiodarone, and to determine the optimal dose of amiodaone, for resuscitation of shock-resistant ventricular fibrillation. PMID- 26972944 TI - [Features and Outcomes of Reinstated "Return-to-Work (Re-work)" Program Participants]. AB - Though effects of the return-to-work (re-work) program on reinstatement started being reported, factors related to the outcomes are unclear. As a case series, we discuss the outcomes of reinstatement and the characteristics of large-scale assembly-factory workers (our case) who had attended a medical institution's re work program. On examining the five successful reinstatement cases and five failed cases, motivation for reinstatement, understanding program requirements, adaptability, and personality traits were found to contribute to these outcomes. We also discussed two failed cases wherein young employees retired after the re work program. They felt to be disconnected from their work and finally retired. PMID- 26972945 TI - [A Case of Acute Superior Mesenteric Artery Occlusion Rescued by Thrombus Aspiration without Bowel Resection]. AB - Acute superior mesenteric artery (SMA) occlusion is rare and associated with high morbidity and mortality.One of the reasons is the difficulty to diagnose the disease soon after the abdominal pain initially occurs. A 79-year-old woman with atrial fibrillation was admitted because of progressive left abdominal pain and nausea. Two hours after the onset, computed tomography revealed an occlusion of the SMA. No signs of intestinal infarction were present. Abdominal angiography revealed complete obstruction from the distal portion of the SMA to the ileocolic artery, so we could have a diagnosis of SMA occlusion early. Continuous per catheteric thrombus aspiration for the occlusion successfully removed the thrombus and led to complete revascularization laparotomy. We encountered a case of acute mesenteric ischemia due to SMA occlusion with atrial fibrillation. Early diagnosis is necessary to survive without bowel resection. PMID- 26972946 TI - [A Case of Life-Threatening Angioedema Occurred During Prolonged Angiotensin Converting Enzyme Inhibitor Treatment]. AB - Although angiotensin-converting enzyme (ACE) inhibitors are widely used as the first choice drug for treating hypertension, we have only a superficial understanding of their relationship to angioedema. We report a case of life threatening angioedema. The case was a 60-year-old man who had been taking an ACE inhibitor for hypertension for 11 years. He visited his home doctor for dyspnea, and tongue and neck swelling. He was transported to our hospital because of the possibility of airway obstruction. On admission, his tongue and neck swelling became more severe. We performed an intubation using an endoscope and started airway management. We also stopped his ACE inhibitor. The severe tongue and neck swelling improved gradually and he was extubated on day 3. On the fifth day he was discharged. We diagnosed angioedema caused by an ACE inhibitor. Although the risk of airway obstruction with ACE inhibitors is acknowledged, we have only a superficial understanding of how prolonged ACE inhibitor treatment induces angioedema. So we should consider angioedema in cases of taking ACE inhibitors, especially in cases of prolonged treatment. PMID- 26972947 TI - [A Forensic Autopsy Case Applied for Asbestos-Related Disease]. AB - We had a forensic autopsy case that required additive pathological examination for the asbestos-related lung disease compensatory application afterwards. A man in his sixties with a history of occupational asbestos inhalation who had neither visited a hospital nor received a physical examination received forensic autopsy because of his death from unknown cause. An inmate said, "He developed cough and dyspnea, and died in the progression of the symptoms." The autopsy revealed widespread pleural plaques on both sides of the parietal pleura and multiple tumors in both sides of the lungs. The cause of death was diagnosed as lung cancer. Additional pathological examination was asked by his family to certify that he had suffered from asbestos-related lung disease in order to apply to the Asbestos-related Damage Relief Law. The Japanese criteria of the compensation law of asbestos-related lung cancer is the detection of more than 5,000 asbestos bodies per gram of dry lung tissue, while his number of asbestos bodies was 4,860. Asbestos bodies were reported to be accumulated in the distal lung parenchyma with no pathological changes. The present lung samples were collected from proximal section around the tumor, which might have made the number of asbestos bodies less than the criteria. Both the number of patients suffering from asbestos-related lung disease and the number of forensic autopsy cases have increased in Japan. Collecting lung samples from the appropriate lung section is essential and should be noted when the lung cancer is suspected at forensic autopsy in order to apply for asbestos-related lung disease compensation. PMID- 26972949 TI - Abstracts of the 33rd Annual Meeting of the UOEH Association of Health Sciences. PMID- 26972948 TI - [Placement of An Expandable Metallic Stent for Malignant Tracheal Stenosis: A Case Report]. AB - The utility of stent placements has been widely reported. We performed a thought provoking stent placement for malignant tracheal stenosis recently. A 90-year-old woman who was admitted to our hospital because of a urinary tract infection was treated with a course of antibiotics, but she demonstrated a rapidly progressive course with dyspnea. Chest computed tomography showed severe tracheal stenosis due to an upper mediastinal mass. She was put on noninvasive positive pressure ventilation (NPPV) because of severe respiratory failure. Bronchoscopy showed severe tracheal stenosis due to direct invasion by the upper mediastinal mass. An expandable metallic stent (EMS) was placed in the trachea, after which a bronchoscopy showed a widely patent airway, and she got off NPPV. Then she did not need supplemental oxygen. She could seat herself, and have an enough meal, independently. However, takotsubo cardiomyopathy occurred and she died 11 days after the placement of the EMS. Since a malignant airway complication can be fatal, tracheal stent placement is a useful treatment in the management of malignancy with airway stenosis. In this case, it was thought that an early intervention of airway stenosis would have reduced the risk of takotsubo cardiomyopathy in a patient with severe symptoms of airway stenosis and stress. PMID- 26972950 TI - Enrichment of Oligodendrocyte Progenitors from Differentiated Neural Precursors by Clonal Sphere Preparations. AB - Remyelination is the goal of potential cell transplantation therapies for demyelinating diseases and other central nervous system injuries. Transplantation of oligodendrocyte precursor cells (OPCs) can result in remyelination in the central nervous system, and induced pluripotent stem cells (iPSCs) are envisioned to be an autograft cell source of transplantation therapy for many cell types. However, it remains time-consuming and difficult to generate OPCs from iPSCs. Clonal sphere preparations are reliable cell culture methods for purifying select populations of proliferating cells. To make clonal neurospheres from human embryonic stem cell (ESC)/iPSC colonies, we have found that a monolayer differentiation phase helps to increase the numbers of neural precursor cells. Indeed, we have compared a direct isolation of neural stem cells from human ESC/iPSC colonies (protocol 1) with monolayer neural differentiation, followed by clonal neural stem cell sphere preparations (protocol 2). The two-step method combining monolayer neuralization, followed by clonal sphere preparations, is more useful than direct sphere preparations in generating mature human oligodendrocytes. The initial monolayer culture stage appears to bias cells toward the oligodendrocyte lineage. This method of deriving oligodendrocyte lineage spheres from iPSCs represents a novel strategy for generating OPCs. PMID- 26972951 TI - Variability in state Medicaid medication management initiatives. AB - Many U.S. states have expanded Medicaid programs, with over 70 million beneficiaries now enrolled. States' interest in improving care quality and lowering costs has spurred experimentation with several medication management (MM) programs. The implementation of MM programs for beneficiaries has been sporadic, and program elements and implementation methods have been heterogeneous. A survey was conducted to: (1) determine covered MM services in state Medicaid programs, (2) report innovative MM program findings, and (3) identify challenges in creating sustainable MM programs. The survey was sent to state Medicaid pharmacy directors in February 2015. The survey data focused on the type and extent of pharmacist-provided MM services, MM provider qualifications, patient eligibility criteria and enrollment strategies, MM delivery settings and referral patterns, MM program evaluations, program costs and sustainability models, key implementation challenges, and future program enhancements. Many Medicaid programs generally followed Medicare Part D Medication Therapy Management requirements. Highly variable findings were due to different Medicaid eligibility criteria, pharmacist integration with health teams, access to electronic medical records (EMRs), and MM delivery methods/settings to optimize drug therapy regimens. Several implementation challenges were identified. Pharmacist integration on care teams and access to EMRs improves MM implementation. MM program evaluation funding and data support must be secured prior to program implementation. The findings and discussion here can assist states with limited or preliminary Medicaid MM experience to progress toward sustainable programs. PMID- 26972953 TI - Reactive Microcontact Printing of DNA Probes on (DMA-NAS-MAPS) Copolymer-Coated Substrates for Efficient Hybridization Platforms. AB - High-performing hybridization platforms fabricated by reactive microcontact printing of DNA probes are presented. Multishaped PDMS molds are used to covalently bind oligonucleotides over a functional copolymer (DMA-NAS-MAPS) surface. Printed structures with minimum width of about 1.5 MUm, spaced by 10 MUm, are demonstrated, with edge corrugation lower than 300 nm. The quantification of the immobilized surface probes via fluorescence imaging gives a remarkable concentration of 3.3 * 10(3) oligonucleotides/MUm(2), almost totally active when used as probes in DNA-DNA hybridization assays. Indeed, fluorescence and atomic force microscopy show a 95% efficiency in target binding and uniform DNA hybridization over printed areas. PMID- 26972954 TI - A systematic review of interventions targeting primary care or community based professionals on cardio-metabolic risk factor control in people with diabetes. AB - OBJECTIVE: To review the interventions targeting primary care or community based professionals on glycaemic and cardiovascular risk factor control in people with diabetes. RESEARCH DESIGN AND METHODS: A systematic review of randomised controlled trials evaluating the effectiveness of interventions targeting primary care or community based professionals on diabetes and cardiovascular risk factor control. We conducted searches in MEDLINE database from inception up to 27th September 2015. We also retrieved articles related to diabetes from the Cochrane EPOC database and EMBASE and scanned bibliographies for key articles. RESULTS: There was heterogeneity in terms of interventions and participants amongst the 30 studies (39,439 patients) that met the inclusion criteria. Nine of the studies focused on general or family practitioners, five on pharmacists, three on nurses and one each on dieticians and community workers. Twelve studies targeted multi disciplinary teams. Educational interventions did not seem to have a positive impact on HbA1c, systolic blood pressure or lipid profiles. The use of telemedicine, clinician reminders and feedback showed mixed results but there was a level of consistency in improvement in HbA1c when multifaceted interventions on multidisciplinary teams were implemented. Targeting general or family physicians was largely ineffective in improving the cardiovascular risk factors considered, except when using a computer application on insulin handling of type 2 diabetes or customised simulated cases with feedbacks. Similarly, interventions targeting nurses did not improve outcomes compared to standard care. CONCLUSIONS: Multifaceted professional interventions were more effective than single interventions targeting single primary or community care professionals in improving glycaemic control. PMID- 26972952 TI - Determining synaptic parameters using high-frequency activation. AB - BACKGROUND: The specific properties of a synapse determine how neuronal activity evokes neurotransmitter release. Evaluating changes in synaptic properties during sustained activity is essential to understanding how genetic manipulations and neuromodulators regulate neurotransmitter release. Analyses of postsynaptic responses to high-frequency stimulation have provided estimates of the size of the readily-releasable pool (RRP) of vesicles (N0) and the probability of vesicular release (p) at multiple synapses. NEW METHOD: Here, we introduce a model-based approach at the calyx of Held synapse in which depletion and the rate of replenishment (R) determine the number of available vesicles, and facilitation leads to a use-dependent increase in p when initial p is low. RESULTS: When p is high and R is low, we find excellent agreement between estimates based on all three methods and the model. However, when p is low or when significant replenishment occurs between stimuli, estimates of different methods diverge, and model estimates are between the extreme estimates provided by the other approaches. COMPARISON WITH OTHER METHODS: We compare our model-based approach to three other approaches that rely on different simplifying assumptions. Our findings suggest that our model provides a better estimate of N0 and p than previously-established methods, likely due to inaccurate assumptions about replenishment. More generally, our findings suggest that approaches commonly used to estimate N0 and p at other synapses are often applied under experimental conditions that yield inaccurate estimates. CONCLUSIONS: Careful application of appropriate methods can greatly improve estimates of synaptic parameters. PMID- 26972955 TI - Comparison of lipid parameters to predict cardiovascular events in Japanese mild to-moderate hypercholesterolemic patients with and without type 2 diabetes: Subanalysis of the MEGA study. AB - AIMS: To determine whether specific lipid parameters are better predictors of cardiovascular disease (CVD) in Japanese mild-to-moderate hypercholesterolemic patients with and without diabetes. METHODS: Mildly or moderately hypercholesterolemic patients with no history of CVD received diet therapy or diet therapy plus pravastatin. In this post-hoc subanalysis, 5-year data from 3170 patients (668 diabetes, 2502 non-diabetes) on diet therapy alone were used to compare lipid parameters as predictors of CVD. We examined the data by tertiles, using hazard ratio (HR) per one-standard deviation (SD) increment (decrease for high-density lipoprotein cholesterol, HDL-C), chi(2) value, receiver operating characteristic curve analysis, and spline analysis. RESULTS: In mild-to-moderate hypercholesterolemic patients with diabetes, increased total cholesterol (TC)/HDL-C, low-density lipoprotein cholesterol (LDL-C)/HDL-C and decreased HDL-C were strongly associated with increased incidence of CVD (tertile analysis). In non-diabetes, increased non-HDL-C, and LDL-C/HDL-C were significantly associated with increased incidence of CVD. A one-SD decrease in HDL-C and a one-SD increment in non-HDL-C, TC/HDL-C, and LDL-C/HDL-C were significantly associated with increased HRs for CVD in both diabetes and non diabetes. Linear CVD risk increases were found for non-HDL-C in diabetes and for non-HDL-C and HDL-C in non-diabetes (spline analysis). CONCLUSIONS: In mild-to moderate hypercholesterolemia, CVD risk prediction by stratifications of single or combination of traditional lipid parameter values illustrates various patterns. Parameters including HDL-C are better predictors of cardiovascular risk than only using TC or LDL-C alone. Non-HDL-C could be the most useful lipid parameter to assess CVD risk, considering it is easy to calculate and less affected by food intake. PMID- 26972956 TI - Comparison of the clinical characteristics of diabetes mellitus diagnosed using fasting plasma glucose and haemoglobin A1c: The 2011 Korea National Health and Nutrition Examination Survey. AB - We compared the characteristics of a Korean adult population diagnosed with diabetes using only a fasting plasma glucose criterion or an HbA1c criterion. The single difference between these two groups was age. Further studies should be undertaken to clarify whether age-specific diagnostic criteria would be appropriate in Korean populations. PMID- 26972958 TI - Endothelin-1 as a predictor of impaired glucose tolerance and type 2 diabetes--A longitudinal study in the Vara-Skovde Cohort. AB - We addressed whether endothelin-1, a marker of endothelial dysfunction, predicts impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) in a population study in south-western Sweden. Follow-up after 9.7 years showed an association between circulating endothelin-1 levels at baseline and development of IGT/T2DM in women but not in men. PMID- 26972957 TI - Association between vaspin level and coronary artery disease in patients with type 2 diabetes. AB - AIM: Adipokines contribute to the atherosclerotic process, connecting obesity and diabetes to cardiovascular disease. Vaspin is a recently discovered adipokine, so data about the relationship of vaspin to coronary artery disease in type-2 diabetes mellitus (T2DM) is limited. The current study was designed to evaluate the association of vaspin with the presence of coronary artery disease in T2DM. METHODS: We enrolled 228 patients with T2DM, with or without CAD, between March 2010 and July 2011, and 120 healthy control participants. Serum vaspin, homeostasis model assessment of insulin resistance (HOMA-IR) and other cardiovascular risk factors were assayed. RESULTS: Vaspin levels were significantly increased in patients with T2DM compared to healthy individuals, and were further increased in patients with both T2DM and CAD compared to those with T2DM but without CAD. Moreover, vaspin correlated positively with body mass index, fasting plasma glucose, insulin and HOMA-IR in all patients with T2DM (P<0.05). Furthermore, in multivariate logistic regression analysis, vaspin level was associated with the presence of CAD in patients with T2DM. CONCLUSIONS: Vaspin correlates with CAD in T2DM. PMID- 26972959 TI - Effect of duodenal glucose load on blood pressure in type 2 diabetes. AB - Postprandial hypotension occurs frequently in diabetes. We show in 9 type 2 patients, that the fall in systolic blood pressure is greater in response to intraduodenal glucose infused at 4 kcal/min than 2 kcal/min, implying that strategies to slow gastric emptying may be effective in the management of postprandial hypotension. PMID- 26972960 TI - Assessing social determinants of health in a pediatric diabetes clinical research trial: Are recruited subjects representative of the larger clinical population? AB - Social determinants of health (SDH) impact clinical outcomes and are often poorly described in research trials. Using a validated tool, SDH dimensions were compared between adolescents enrolled and not enrolled into a large diabetes study. We observed that our study cohort reflected a SDH profile mirroring the eligible population. PMID- 26972962 TI - Level of implementation of guidelines on screening and diagnosis of gestational diabetes: A national survey. AB - AIMS: To describe the degree of diffusion and acceptance of national guideline on screening and diagnosis of gestational diabetes (GDM) among Italian diabetes centers and to detect possible areas for benchmarking. METHODS: In 2013 the Italian Diabetes in Pregnancy Study Group structured a national survey, focused on GDM screening and diagnostic procedures, that was administered to diabetologists. RESULTS: Overall, 122 diabetologists of 122 different diabetes centers (21.7% territorial, 78.3% hospital/University) completed the questionnaire. All respondents declared to execute a 75 g-oral glucose tolerance test (OGTT) as diagnostic test. Almost one in five centers preferred a universal screening procedure, the others executing a selective risk factors-based screening. In patients at high risk for GDM the OGTT was performed at 16-18 weeks' gestation in 84.0% of the cases; only 6.5% of respondents preferred to execute it as soon as possible; and 9.5% used to wait until 24-28 weeks' gestation. In the case of fasting plasma glucose (FPG) >= 5.1 mmol/l (92 mg/dl), two third of respondents used to proceed with the execution of the complete diagnostic OGTT, the others considering sufficient the FPG value for the diagnosis. CONCLUSIONS: Good level of reception of national recommendations was documented. The diagnostic procedure was generally accepted and applied. Some criticisms were specifically linked to the choice of universal or risk factor based screening procedure, and to the right time for executing the OGTT in women at high risk. PMID- 26972961 TI - Serum irisin concentrations were increased after transient continuous subcutaneous insulin infusion in type 2 diabetes mellitus patients. AB - Irisin, identified as a novel myokine, plays an important role in improving metabolic disorders, including type 2 diabetes mellitus (T2DM). In this interventional study, we investigated the alteration of serum irisin levels in T2DM subjects after transient continuous subcutaneous insulin infusion (CSII) treatment. PMID- 26972963 TI - Validation of an Arabic version of the Diabetes Treatment Satisfaction Questionnaire in Qatar. AB - AIMS: Several instruments evaluate patient-reported outcomes in diabetes mellitus (DM), but almost none are validated for use in Arabic language. The aim of this study is to test the psychometric properties and responsiveness of the Arabic version of the Diabetes Treatment Satisfaction Questionnaire (DTSQs) in Qatar. METHODS: Ambulatory Arabic speaking DM patients were interviewed at two consecutive time points in Doha, Qatar. The 8-item DTSQs was administered in conjunction with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF 36) and the World Health Organization Quality of Life Measure (WHOQOL-Bref) to assess convergent validity. Reliability was evaluated by internal consistency and item analysis. Construct validity was evaluated using "known groups" comparisons (including gender, insulin use, and HbA1c). Sensitivity of DTSQs scores to the subject's metabolic conditions was determined. RESULTS: One hundred subjects (mean age 50.7) participated. Half (54%) were female. The majority (93%) had Type 2 DM, but 39 (42%) were using insulin. Results revealed satisfactory internal consistency. Metabolic measures (fasting blood glucose and AIC) had significant inverse correlations with DTSQs scores (interview 1, Pearson's r=-0.333 and r= 0.401, respectively, p<0.01). Scale criterion and construct validity were found to be satisfactory. Most sub-dimensions of the SF-36 and WHOQOL-Bref were correlated with the DTSQ, indicating a good concurrent validity. As in prior studies, women demonstrated poorer treatment satisfaction. CONCLUSIONS: The Qatar Arabic DTSQs version was found to be a reliable and valid instrument for the assessment of treatment satisfaction in Arabic diabetes mellitus patients in the country. PMID- 26972964 TI - Assessment of kidney dysfunction with cystatin C- and creatinine-based estimated glomerular filtration rate and predicting type 2 diabetes: Toranomon Hospital Health Management Center Study 21. AB - OBJECTIVE: Whether early stages of kidney dysfunction assessed by the estimated glomerular filtration rate from cystatin C measurements (eGFRCysC) rather than from creatinine measurements (eGFRCr) would more precisely reflect the risk of developing type 2 diabetes (T2D) has not been clarified. We compared the risk of developing T2D associated with renal dysfunction indicated by eGFRCysC or eGFRCr measurements. METHODS: Studied were 2131 Japanese individuals without diabetes. Hazard ratios (HRs) for the development of T2D over 3-5 y were calculated across categories of eGFRCysC and eGFRCr, respectively. RESULTS: Reduced levels of eGFRCysC were associated with a step-wise increase in the cumulative incidence rate of T2D (p=0.007). In comparison with the eGFRCysC >85th percentile group (>= 117.4 ml/min/1.73 m(2)), the lowest group, which was the eGFRCysC <15th percentile group (<86.2 ml/min/1.73 m(2)), had an adjusted HR of 2.30 (95% CI 1.13, 4.68) for T2D. Compared with the eGFRCr >85th percentile group, the lowest eGFRCr group (<15th percentile) had an HR of 1.19 (0.63, 2.24) for T2D. However, individuals with eGFRCr <60 ml/min/1.73 m(2) had a significantly increased risk of T2D. Clustering of both low eGFRCysC and low eGFRCr further elevated the HR for T2D compared with the presence of either. CONCLUSIONS: Although eGFRCr in ranges indicating chronic kidney disease reflected an elevated risk of developing diabetes, earlier stages of kidney dysfunction indicated by reduced eGFRCysC, which could not be captured by reduced eGFRCr, would be a marker for an elevated risk of developing T2D. PMID- 26972965 TI - Impact of insulin pump therapy on long-term glycemic control in a pediatric Spanish cohort. AB - AIMS: To evaluate the efficacy and safety of Continuous Subcutaneous Insulin Infusion (CSII) in a pediatric cohort and to determine if the ISPAD/IDF/ADA criteria for good metabolic control are achieved during long periods of time. METHODS: Retrospective longitudinal study including ninety patients [10.5 (6.5 13.9) years of age, 58% males]. Age at debut, type 1 diabetes mellitus duration, pubertal stage, HbA1c, insulin dose, mean number of glycemic controls, number of basal rates, % basal/total insulin, severe hypoglycemia and diabetic ketoacidosis events were analyzed. Subgroup analysis based on age and pubertal stage was performed. RESULTS: HbA1c decreased from 6.9% [52 mmol/mol] to 6.7% [50 mmol/mol] after one year of CSII. Afterwards, it remained less than 7% during the follow-up period (median 3.5 +/- 1.8 years (range 1-8). Prior to CSII, 76% of the subjects met ISPAD/ADA criteria. One year after initiating CSII, 96% of children had HbA1c<7.5%. Improvement in glycohemoglobin levels was most prominent in those patients with the highest HbA1c initial levels. Total insulin dose decreased from 0.89 to 0.73 UI/kg/day (p<0.001). Proportion of basal/total insulin changed significantly (47 to 42% (p<0.05)). Number of fractions of the basal rate increased from 5.6 +/- 1.8 at one year of CSII to 6.7 +/- 2.1 five years later. Incidence of severe hypoglycemic events decreased from 19 to 6.9 episodes/100 patient-year. Only 2 episodes of diabetic ketoacidosis occurred. CONCLUSIONS: CSII allows reaching ISPAD/IDF/ADA goals safely during an extended follow-up period in a diabetic pediatric cohort. PMID- 26972966 TI - Disentangling beat perception from sequential learning and examining the influence of attention and musical abilities on ERP responses to rhythm. AB - Beat perception is the ability to perceive temporal regularity in musical rhythm. When a beat is perceived, predictions about upcoming events can be generated. These predictions can influence processing of subsequent rhythmic events. However, statistical learning of the order of sounds in a sequence can also affect processing of rhythmic events and must be differentiated from beat perception. In the current study, using EEG, we examined the effects of attention and musical abilities on beat perception. To ensure we measured beat perception and not absolute perception of temporal intervals, we used alternating loud and soft tones to create a rhythm with two hierarchical metrical levels. To control for sequential learning of the order of the different sounds, we used temporally regular (isochronous) and jittered rhythmic sequences. The order of sounds was identical in both conditions, but only the regular condition allowed for the perception of a beat. Unexpected intensity decrements were introduced on the beat and offbeat. In the regular condition, both beat perception and sequential learning were expected to enhance detection of these deviants on the beat. In the jittered condition, only sequential learning was expected to affect processing of the deviants. ERP responses to deviants were larger on the beat than offbeat in both conditions. Importantly, this difference was larger in the regular condition than in the jittered condition, suggesting that beat perception influenced responses to rhythmic events in addition to sequential learning. The influence of beat perception was present both with and without attention directed at the rhythm. Moreover, beat perception as measured with ERPs correlated with musical abilities, but only when attention was directed at the stimuli. Our study shows that beat perception is possible when attention is not directed at a rhythm. In addition, our results suggest that attention may mediate the influence of musical abilities on beat perception. PMID- 26972967 TI - EEG correlates of visual short-term memory as neuro-cognitive endophenotypes of ADHD. AB - Attention deficit hyperactivity disorder (ADHD) frequently persists into adulthood. A reduction in visual short-term memory (vSTM) storage capacity was recently suggested as a potential neuro-cognitive endophenotype, i.e., a testable marker of an individual's liability for developing ADHD. This study aimed at identifying markers of the brain abnormalities underlying vSTM reductions in adult ADHD. We combined behavioral parameter-based assessment with electrophysiology in groups of adult ADHD patients and healthy age-matched controls. Amplitudes of ERP markers of vSTM storage capacity, the contralateral delay activity (CDA) and the P3b, were analyzed according to (i) differences between individuals with higher vs. lower storage capacity K and (ii) differences between ADHD patients and control participants. We replicated the finding of reduced storage capacity in adult ADHD. Across groups, individuals with higher relative to lower storage capacity showed a larger CDA and P3b. We further found differences between the patient and control groups in the ERPs: The CDA amplitude was attenuated in an early time window for ADHD patients compared to control participants, and was negatively correlated with ADHD patients' symptom severity ratings. Furthermore, the P3b was larger in ADHD patients relative to control participants. These electrophysiological findings indicate altered brain mechanisms underlying visual storage capacity in ADHD, which are characterized by deficient encoding and maintenance, and increased recruitment of control processes. Accordingly, (quantifiable) ERP markers of vSTM in adult ADHD bear candidacy as neuro-cognitive endophenotypes of the disease. PMID- 26972968 TI - From Cellular Attractor Selection to Adaptive Signal Control for Traffic Networks. AB - The management of varying traffic flows essentially depends on signal controls at intersections. However, design an optimal control that considers the dynamic nature of a traffic network and coordinates all intersections simultaneously in a centralized manner is computationally challenging. Inspired by the stable gene expressions of Escherichia coli in response to environmental changes, we explore the robustness and adaptability performance of signalized intersections by incorporating a biological mechanism in their control policies, specifically, the evolution of each intersection is induced by the dynamics governing an adaptive attractor selection in cells. We employ a mathematical model to capture such biological attractor selection and derive a generic, adaptive and distributed control algorithm which is capable of dynamically adapting signal operations for the entire dynamical traffic network. We show that the proposed scheme based on attractor selection can not only promote the balance of traffic loads on each link of the network but also allows the global network to accommodate dynamical traffic demands. Our work demonstrates the potential of bio-inspired intelligence emerging from cells and provides a deep understanding of adaptive attractor selection-based control formation that is useful to support the designs of adaptive optimization and control in other domains. PMID- 26972970 TI - Analysis of Antioxidant Enzyme Activity and Antioxidant Genes Expression During Germination of Two Different Genotypes of Lolium multiflorum Under Salt Tolerance. AB - Annual ryegrass (Lolium multiflorum) is widely used as a cool-season forage grass for its luxuriant growth, palatable and high digestible. To investigate the salt tolerance mechanism in annual ryegrass under salt stress, salt-tolerant genotype 'R102-3' and salt-sensitive genotype 'Tetragold' were subject to 300mmol/L NaCl in a controlled growth chamber for 12 days. The results showed high concentrations of NaCl decreased relative water content (RWC), and increased the electrolyte leakage (EL) in both genotypes. However the 'Tetragold' had a greater increased extent of malondialdehyde (MDA) and EL than in 'R102-3', in contrast, the activities of Superoxide (SOD), Peroxidase (POD), Catalase (CAT) and Ascorbate peroxidase (APX) were higher in salt resistant compared to sensitive ones. For ensure the accurate of qRT-PCR, we used RefFinder to choose the most stably reference genes eEF1A(s) and GAPDH to normalize the antioxidant genes expression data. The results indicated that higher expression of Fe-SOD, Mn-SOD, Chl-Cu/Zn SOD, Cyt-Cu/Zn SOD, POD and CAT in 'R102-3' when compared with 'Tetragold', which may play an important role in defensed damage of Reactive oxygen species (ROS) under salt stress. Thus, the salt-tolerant genotype could effectively resist oxidative damage induced by salt tress relative to salt sensitive genotype. PMID- 26972969 TI - Clinical and pathological analyses of interstitial fibrosis and tubular atrophy cases after kidney transplantation. AB - AIM: We carried out a clinicopathological analysis of cases presenting with interstitial fibrosis and tubular atrophy (IF/TA) after renal transplantation in an attempt to clarify the mechanisms underlying the development and prognostic significance of IF/TA. METHODS: IF/TA was diagnosed in 35 renal allograft biopsy specimens (BS) obtained from 35 renal transplant recipients under follow up at the Department of Transplant Surgery, Kidney Center, Toda Chuo General Hospital, between January 2014 and March 2015. RESULTS: IF/TA was diagnosed at a median of 39.9 months after the transplantation. Among the 35 patients with IF/TA, 19 (54%) had a history of acute rejection. Among the 35 BS showing evidence of IF/TA, the IF/TA was grade I in 25, grade II in 9, and grade III in 1. Arteriosclerosis of the middle-sized arteries was observed in 30 BS (86%). We then classified the 35 BS showing evidence of IF/TA according to their overall histopathological features, as follows; IF/TA alone (6 BS; 17%), IF/TA + medullary ray injury (12 BS; 34%), and IF/TA + rejection (12 BS; 34%). Loss of the renal allograft occurred during the observation period in one of the patients (3%). Of the remaining patients with functioning grafts, deterioration of the renal allograft function after the biopsies occurred in 15 patients (43%). CONCLUSIONS: The results of our study suggests that rejection contributes to IF/TA in 30-40% of cases, medullary ray injury in 30-40% of cases, and nonspecific injury in 20% of cases. IF/TA contributes significantly to deterioration of renal allograft function. PMID- 26972971 TI - Simultaneous Overexpression of the HhERF2 and PeDREB2a Genes Enhanced Tolerances to Salt and Drought in Transgenic Cotton. AB - A desert-grown Halimodendron halodendron ethylene-responsive element binding factor gene (HhERF2), which encodes a 245 amino acids protein containing a conserved AP2/EREBP domain, was isolated through the rapid amplification cDNA end (RACE) method. Sequence and phylogenetic analysis indicated that HhERF2 was classified into the B-2 group of ERF subfamily. Semiquantitative RT-PCR showed that HhERF2 was greatly induced by treatments with high-salt, drought and low temperature in H. halodendron seedlings. The expression vector containing HhERF2 and Populus euphratica dehydration- responsive element binding protein (PeDREB2a) genes driven by rd29A promoter was constructed and transferred into cotton (Gossypium hirsutum L.) by non-tissue culture Agrobacterium-mediated genetic transformation system. The transformation and expression of HhERF2 and PeDREB2a were identified by PCR and RT-PCR. Analyses of physiological function indicated that transgenic cottons had improved seeds germination, tolerance to drought and highsalt stresses. Agronomic evaluation in the field exhibited that transgenic lines presented a dwarf phenotype and improved further in the yield and characters. These results demonstrated that overexpressed both HhERF2 and PeDREB2a transcription factor genes in cotton induced elevated tolerance to drought and high-salt stresses. PMID- 26972972 TI - Genetic Engineering of Alfalfa (Medicago sativa L.). AB - Alfalfa is excellent perennial legume forage for its extensive ecological adaptability, high nutrition value, palatability and biological nitrogen fixation. It plays a very important role in the agriculture, animal husbandry and ecological construction. It is cultivated in all continents. With the development of modern plant breeding and genetic engineering techniques, a large amount of work has been carried out on alfalfa. Here we summarize the recent research advances in genetic engineering of alfalfa breeding, including transformation, quality improvement, stress resistance and as a bioreactor. The review article can enables us to understand the research method, direction and achievements of genetic engineering technology of Alfalfa. PMID- 26972973 TI - Determination of Flavonoids and Anthocyanins in Nitraria tangutorum by High Performance Liquid Chromatography Coupled with Tandem Mass Spectrometry. AB - Using high-performance liquid chromatography coupled with diode array detection and electrospray ionization tandem mass spectrometry (HPLC-DAD-MSn) method, qualitative and quantitative analysis of flavonoids of stems, leaves, fruits and seeds, and anthocyanidin of fresh fruits in Nitraria tangutorum were performed. A total of 14 flavonoid components were identified from the seeds of N. tangutorum including three quercetin derivatives, three kaempferol derivatives, and eight isorhamnetin derivatives. A total of 12, 10, and 7 flavonoid components were identified from leaves, stems, and fruits of N. tangutorum, respectively; all were present in seeds also. The total content of flavonoids in leaves was the highest, up to 42.43 mg/g.dry weight. A total of 12 anthocyanidin components were identified from the fresh fruits of N. tangutorum, belonging to five anthocyanidin. The total content of anthocyanidin in fresh fruits was up to 45.83 mg/100 g. fresh weight, of which the acylated anthocyanidin accounted for 65.7%. The HPLC-DAD-MS(n) method can be operated easily, rapidly, and accurately, and is feasible for qualitative and quantitative analysis of flavone glycosides in N. tangutorum. PMID- 26972974 TI - Plantlet Regeneration of Tartary Buckwheat (Fagopyrum tataricum Gaertn.) in Vitro Tissue Cultures. AB - Tartary buckwheat is an ancient annual dicotyledonous herb, which is widely distributed around the world, specifically in the high altitude area of southwestern China and in the hill region of Himalayan. The plantlet regeneration of tartary buckwheat via somatic embryogenesis or multiple shoot induction was investigated in two different tartary buckwheats, Yuanzi and Xichang. The regeneration ability of Yuanzi was better than Xichang tartary buckwheat, and the hypocotyls were better than cotyledons as tartary buckwheat plantlet regeneration explants via somatic embryogenesis. The most suitable medium for callus induction was Murashige and Skoog basal medium added 2 mg/L 2, 4- dichlorophenoxyacetic acid and 1 mg/L Kinetin, which could reach up to 98.96% callus induction percentage. The plantlet regeneration percentage from callus of tartary buckwheat could reach up to 55.77%, which induced on 2.0 mg/L Benzyladenine and 1.0 mg/L KT in MS basal medium. In addition, maximum of multiple shoot induction percentage was 69.05%, which was observed in case of Yuanzi tartary buckwheat in MS basal medium with added 3.0 mg/L 6-BA and 1.0 mg/L Thidiazuron. Roots induction of regenerated plants were achieved on 1/2 MS basal medium with added 1mg/L Indole-3 Butytric acid, which has 75% survival after transferred regenerated plants to soil under field conditions. PMID- 26972975 TI - Cloning and Transformation of EeHKT1;4 Gene from Elytrigia elongata. AB - The EeHKT1;4 gene was firstly cloned from Elytrigia elongata by RT-PCR technique with 1977 bp full-length cDNA encoding 1722 bp open reading frame (ORF) and 573 amino acids. The PCR fragment of EeHKT1;4 gene was inserted into the binary vector pBI121 and got the resulted expression vector, which named pBI121-35S EeHKT1;4-Nos. The vector was further transformed into the agrobacterium EHA105, and then EeHKT1;4 gene was transferred into tobacco by the Agrobaterium- mediated genetic transformation method. The results showed that the target gene was inserted into the genomes of tobacco and expressed. Therefore, the transgenic tobacco (T0) plants overexpressing EeHKT1;4 gene were successfully obtained in this study. And EeHKT1;4 reduces Na+ concentration in the leaves of T0 plants, thereby plays a central role in protecting plant leaves from salinity stress. PMID- 26972976 TI - Effect of vocal fold asymmetries on glottal flow. AB - OBJECTIVES/HYPOTHESIS: Voice disorders, such as unilateral vocal fold paralysis or paresis, and vocal fold scarring feature structural asymmetries of the vocal folds. Studies on how structural asymmetries affect voice has mostly been limited to computational simulations and experiments on mechanical models. The purpose of the current study is to examine the effects of asymmetries in left-right position, height, and length of the vocal folds on the intraglottal flow characteristics, as well as acoustics in the canine larynx model. STUDY DESIGN: Basic science. METHODS: Measurements of intraglottal flow velocity fields were taken in excised canine larynges using particle image velocimetry. Asymmetries of the vocal folds are induced by translating the vocal processes in space using a prong apparatus connected to a micrometer. RESULTS: Asymmetries in length height and abduction produced a reduction in the intraglottal vortices strength and subsequently the glottal efficiency. CONCLUSION: Current findings can affect future recommendations for surgical interventions that are used to treat unilateral vocal fold paralysis. LEVEL OF EVIDENCE: NA Laryngoscope, 126:2534 2538, 2016. PMID- 26972977 TI - Metagenomic and functional analyses of the consequences of reduction of bacterial diversity on soil functions and bioremediation in diesel-contaminated microcosms. AB - The relationship between microbial biodiversity and soil function is an important issue in ecology, yet most studies have been performed in pristine ecosystems. Here, we assess the role of microbial diversity in ecological function and remediation strategies in diesel-contaminated soils. Soil microbial diversity was manipulated using a removal by dilution approach and microbial functions were determined using both metagenomic analyses and enzymatic assays. A shift from Proteobacteria- to Actinobacteria-dominant communities was observed when species diversity was reduced. Metagenomic analysis showed that a large proportion of functional gene categories were significantly altered by the reduction in biodiversity. The abundance of genes related to the nitrogen cycle was significantly reduced in the low-diversity community, impairing denitrification. In contrast, the efficiency of diesel biodegradation was increased in the low diversity community and was further enhanced by addition of red clay as a stimulating agent. Our results suggest that the relationship between microbial diversity and ecological function involves trade-offs among ecological processes, and should not be generalized as a positive, neutral, or negative relationship. PMID- 26972978 TI - Breathing maneuvers as a coronary vasodilator for myocardial perfusion imaging. AB - PURPOSE: A combined breathing maneuver of hyperventilation, followed by a long voluntary breathhold leads to coronary vasodilation. We investigated the impact of breathing maneuvers on MR first-pass cardiac perfusion imaging and its potential clinical utility. MATERIALS AND METHODS: We studied 24 healthy volunteers (37 +/- 12 years; 62.5% men) on a clinical 3 Tesla MRI system and performed first-pass perfusion MR at rest, during a short breathhold (S-HVBH) following 60 s of hyperventilation, and at the end of a long breathhold (L-HVBH) following the hyperventilation, performed in random order. A blinded reader analyzed signal intensity upslope, upslope index, and time between 20 and 80% of maximal signal. RESULTS: All volunteers tolerated the breathing maneuvers well and completed the study protocol. The upslope of the signal-intensity-over-time curve was increased during S-HVBH (1.86 +/- 0.70 units/s, P < 0.05) and at the end of L-LVBH (1.77 +/- 0.82 units/s), when compared with baseline results (1.34 +/- 0.58 units/s). Corrected for the arterial input, the upslope was higher at the end of the L-HVBH (0.095 +/- 0.019 units/s versus 0.077 +/- 0.016 units/s at rest, P < 0.01) as was the myocardial perfusion reserve index (1.25 +/- 0.22 versus 1.09 +/- 0.17; P < 0.001). In a multiple regression model, only gender, rate-pressure product, and breathhold time were independently and significantly related to the upslope (R = 0.771; P < 0.001). CONCLUSION: In conclusion, a voluntary long breathhold after hyperventilation leads to an increase of the myocardial perfusion reserve index. This may impact findings from current practice of first-pass perfusion imaging. The clinical utility of breathing maneuvers as a vasodilatory stimulus for first-pass perfusion imaging may warrant further research. J. MAGN. RESON. IMAGING 2016;44:947-955. PMID- 26972980 TI - Abdominal Wall Bile Staining Without Jaundice. PMID- 26972979 TI - Oral biofilm and caries-infiltrant interactions on enamel. AB - OBJECTIVES: This study aimed to analyze interactions between oral biofilms and a dental triethylene glycol dimethacrylate (TEGDMA)-based resin infiltration material on enamel. METHODS: Demineralized enamel specimens (14 days, acidic buffer, pH 5.0) were either infiltrated with a commercial TEGDMA resin and subjected to a three-species biofilm (Streptococcus mutans UAB 159, Streptococcus oralis OMZ 607 and Actinomyces oris OMZ 745) (group 1), applied to the biofilm (group 2), or merely resin infiltrated (group 3). A control group received no treatment (4). Biofilm formation and metabolic activity of biofilms were measured for group (1) and (2) after 24h CFU and a resazurin assay. Resin biodegradation was measured for group (1) and (3) by high performance liquid chromatography (HPLC) coupled with mass spectrometry after 6 and 24h incubation. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) images were taken to study the biofilm and material's autofluorescence in groups (1-4) after 24h. RESULTS: SEM and CLSM images showed reduced biofilm formation on resin infiltrated specimens (group 1) compared to group 2, while no biofilm was detectable on groups 3 and 4. CFU data (log10 CFU per mL) of group 1 showed significantly reduced bacterial numbers (p<0.05) compared to group 2. However, HPLC analysis of TEGDMA leakage after 6h and 24h revealed no differences between group 1 and group 3. CONCLUSIONS: The results of the current study indicate that freshly resin-infiltrated enamel surfaces show a biofilm reducing effect, while monomer leakage was not affected by bacterial presence. CLINICAL SIGNIFICANCE: Resin infiltrated enamel surfaces are constantly exposed to the oral microflora. Yet, it is not known how biofilms interact with enamel-penetrated resins and if and to which extent accessory alignments in oral hygiene are needed. PMID- 26972982 TI - WITHDRAWN: Reply. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.cgh.2016.03.013. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26972981 TI - Polycystic Liver Disease: The Benefits of Targeting cAMP. PMID- 26972983 TI - Endoscopic Ultrasound-guided Transmural Drainage for Palliation of Malignant Distal Common Bile Duct Obstruction in Patients With an Inaccessible Papilla: Approaching the Tipping Point? PMID- 26972984 TI - In Reference to: Hepatitis C Virus Treatment: Is It Possible To Cure All Hepatitis C Virus Patients? PMID- 26972985 TI - A Rare Cause of Ischemic Colitis. PMID- 26972987 TI - Serum levels of vitamin B12 (cobalamin) in fibromyalgia. PMID- 26972986 TI - Cardiotrophin-1 decreases intestinal sugar uptake in mice and in Caco-2 cells. AB - AIM: Cardiotrophin-1 (CT-1) is a member of the IL-6 family of cytokines with a key role in glucose and lipid metabolism. In the current investigation, we examined the in vivo and in vitro effects of CT-1 treatment on intestinal sugar absorption in different experimental models. METHODS: rCT-1 effects on alpha Methyl-D-glucoside uptake were assessed in everted intestinal rings from wild type and CT-1(-/-) mice and in Caco-2 cells. rCT-1 actions on SGLT-1 expression in brush border membrane vesicles and the identification of the potential signalling pathways involved were determined by Western blot. RESULTS: In vivo administration (0.2 mg kg(-1) ) of rCT-1 caused a significant decrease on alpha Methyl-D-glucoside uptake in everted intestinal rings from wild-type and CT-1(-/ ) mice after short-term and long-term treatments. Similarly, in vitro treatment (1-50 ng mL(-1) ) with rCT-1 reduced alpha-Methyl-D-glucoside uptake in everted intestinal rings. In Caco-2 cells, rCT-1 treatment (20 ng mL(-1) , 1 and 24 h) lowered apical uptake of alpha-Methyl-D-glucoside in parallel with a decrease on SGLT-1 protein expression. rCT-1 promoted the phosphorylation of STAT-3 after 5 and 15 min treatment, but inhibited the activation by phosphorylation of AMPK after 30 and 60 min. Interestingly, pre-treatment with the JAK/STAT inhibitor (AG490) and with the AMPK activator (AICAR) reversed the inhibitory effects of rCT-1 on alpha-Methyl-D-glucoside uptake. AICAR also prevented the inhibition of SGLT-1 observed in rCT-1-treated cells. CONCLUSIONS: CT-1 inhibits intestinal sugar absorption by the reduction of SGLT-1 levels through the AMPK pathway, which could also contribute to explain the hypoglycaemic and anti-obesity properties of CT-1. PMID- 26972988 TI - Consequences of acclimation on the resistance to acute thermal stress: Proteomic focus on mussels from pristine site. AB - Climate change constitutes an additional threat for intertidal species that already have to cope with a challenging environment. The present study focuses on the blue mussel Mytilus edulis and aims at investigating the importance of thermal acclimation in heat stress response. Microcosm exposures were performed with mussels submitted to an identical acute thermal stress following two thermal summer acclimations standing for present or future temperature conditions. Gill proteomes were analyzed by 2DE and 96 differentially expressed proteoforms were identified. Our results show that cell integrity appears to be maintained by the rise in molecular protective systems (i.e. Heat Shock Proteins), and by the reallocation of energy production via a switch to anaerobic metabolism and the setting up of alternative energy pathways. Finally, our results indicate that the response of mussels to acute thermal stress is conditioned by the acclimation temperature with an improved response in organisms acclimated to higher temperatures. PMID- 26972990 TI - Mini Nutritional Assessment of rural elderly people in Bangladesh: the impact of demographic, socio-economic and health factors - ERRATUM. PMID- 26972989 TI - Variable selection in discrete survival models including heterogeneity. AB - Several variable selection procedures are available for continuous time-to-event data. However, if time is measured in a discrete way and therefore many ties occur models for continuous time are inadequate. We propose penalized likelihood methods that perform efficient variable selection in discrete survival modeling with explicit modeling of the heterogeneity in the population. The method is based on a combination of ridge and lasso type penalties that are tailored to the case of discrete survival. The performance is studied in simulation studies and an application to the birth of the first child. PMID- 26972992 TI - Molecular characterization and clinical significance of extraintestinal pathogenic Escherichia coli recovered from a south Indian tertiary care hospital. PMID- 26972991 TI - Stabilin-2 modulates the efficiency of myoblast fusion during myogenic differentiation and muscle regeneration. AB - Myoblast fusion is essential for the formation of skeletal muscle myofibres. Studies have shown that phosphatidylserine is necessary for myoblast fusion, but the underlying mechanism is not known. Here we show that the phosphatidylserine receptor stabilin-2 acts as a membrane protein for myoblast fusion during myogenic differentiation and muscle regeneration. Stabilin-2 expression is induced during myogenic differentiation, and is regulated by calcineurin/NFAT signalling in myoblasts. Forced expression of stabilin-2 in myoblasts is associated with increased myotube formation, whereas deficiency of stabilin-2 results in the formation of small, thin myotubes. Stab2-deficient mice have myofibres with small cross-sectional area and few myonuclei and impaired muscle regeneration after injury. Importantly, myoblasts lacking stabilin-2 have reduced phosphatidylserine-dependent fusion. Collectively, our results show that stabilin 2 contributes to phosphatidylserine-dependent myoblast fusion and provide new insights into the molecular mechanism by which phosphatidylserine mediates myoblast fusion during muscle growth and regeneration. PMID- 26972994 TI - Transgender equality. PMID- 26972995 TI - Nutrition and Hydration Week: come and join the (tea) party. PMID- 26972993 TI - A systematic review and meta-analysis of cutaneous manifestations in late- versus early-onset systemic lupus erythematosus. AB - OBJECTIVES: Although systemic lupus erythematosus (SLE) most commonly occurs in reproductive-age women, some are diagnosed after the age of 50. Recognizing that greater than one-third of SLE criteria are cutaneous, we undertook a systematic review and meta-analysis to evaluate differences in cutaneous manifestations in early- and late-onset SLE patients. METHODS: We searched the literature using PubMed, CINAHL, Web of Science, and Cochrane Library. We excluded studies that did not include ACR SLE classification criteria, early-onset controls, that defined late-onset SLE as <50 years of age, or were not written in English. Two authors rated study quality using the Newcastle Ottawa Quality Scale. We used Forest plots to compare odds ratios (95% CI) of cutaneous manifestations by age. Study heterogeneity was assessed using I(2). RESULTS: Overall, 35 studies, representing 11,189 early-onset and 1727 late-onset patients with SLE, met eligibility criteria. The female:male ratio was lower in the late-onset group (5:1 versus 8:1). Most cutaneous manifestations were less prevalent in the late onset group. In particular, malar rash [OR = 0.43 (0.35, 0.52)], photosensitivity [OR = 0.72 (0.59, 0.88)], and livedo reticularis [OR = 0.33 (0.17, 0.64)] were less common in late-onset patients. In contrast, sicca symptoms were more common [OR = 2.45 (1.91, 3.14)]. The mean Newcastle Ottawa Quality Scale score was 6.3 +/- 0.5 (scale: 0-9) with high inter-rater reliability for the score (0.96). CONCLUSIONS: Overall, cutaneous manifestations are less common in late-onset SLE patients, except sicca symptoms. Future studies should investigate etiologies for this phenomenon including roles of immune senescence, environment, gender, and immunogenetics. PMID- 26972996 TI - Neck stoma patients: is vital information displayed at the bedside? AB - Tracheostomies are common procedures in head and neck and critical care practice, with 50% of airway-related deaths attributable to complications such as occlusion or displacement. The National Tracheostomy Safety Project (NTSP) published guidance regarding emergency management of neck stoma patients. A prospective multicentre regional audit of all neck stoma inpatients (ward and intensive care unit (ICU) settings) was conducted. Bed spaces were assessed for tracheostomy care bundles and essential stoma information, as recommended by the NTSP guidelines. The results demonstrate inadequate ward compliance across all three trusts, with ICU compliance greater in comparison to a ward environment. Of note, crucial information regarding the nature of stoma and whom to contact in the event of an emergency, was not displayed in the majority of cases. A greater awareness of the NTSP guidance and implementation of vital information is a necessity across all disciplines in order to reduce stoma complication-related morbidity and mortality. PMID- 26972997 TI - Identifying and managing underperformance in nursing students. AB - Student nurses are the future of the profession and require high levels of commitment and skill from the registered nurses charged with mentoring and guiding them on the road to registration. Evidence suggests that mentors are failing to recognise underperformance and as such are missing opportunities to effectively manage and encourage improvement in failing students. The literature is also demonstrative of mentors failing to fail students who do not achieve requisite standards, thus allowing sub-optimal students to progress on towards registration. This article examines literature relating to effective management of underperforming students in clinical practice and the need to fail those who do not meet the required standards. The article seeks to provide mentors with an understanding of why some are 'failing to fail', as well as highlighting implications for skill improvement. It is the result of an ongoing local skill improvement project. Key themes for improvement are discussed including issues of mentor confidence, early identification of underperformance, improving mentor student relationships and the need for open, honest communication. PMID- 26972998 TI - Incontinence-associated dermatitis: new insights into an old problem. AB - Incontinence-associated dermatitis (IAD) is a common skin disorder seen in patients with incontinence. Typically IAD presents as inflammation of the skin surface characterised by redness, and in extreme cases, swelling and blister formation. If untreated this usually rapidly leads to excoriation and skin breakdown, which may subsequently become infected by the skin flora. While this is a common condition encountered in all areas of nursing practice, gaps remain in our understanding of the many contributing factors. A lack of standardised definitions of IAD, differences in terminology, and a bewildering increase in products available to prevent and manage IAD, makes it difficult for nurses to deliver evidence-based care. However, it is an area where nursing research has made a considerable contribution over the past few years. This article explores the current thinking on IAD and the implications for nursing practice. PMID- 26973000 TI - Nutrition and Hydration Week: one trust's recipe for success. PMID- 26972999 TI - Nursing students' knowledge of child abuse and neglect in India. AB - BACKGROUND: Child abuse and neglect are global phenomena. Research on knowledge of and attitudes towards child abuse and neglect among nursing students in India is limited. AIM: To investigate undergraduate nursing students' knowledge of and attitudes towards child abuse and neglect. METHODS: A descriptive design was adopted for the study, in which 158 nursing students participated by responding to a standardised questionnaire. RESULTS: The findings revealed that students' knowledge of child abuse and neglect is inadequate, as the total mean (M) score was 13.84+/-4.35 (M+/-standard deviation (SD)). The total attitude score of 50.37+/-6.196 (M+/-SD) indicated participants' positive attitudes towards prevention of child abuse and neglect. However, there was a negative relation between age and attitudes towards and knowledge of child abuse. Older students scored higher on the total attitude and knowledge scale compared with younger students. CONCLUSION: The study findings support the hypothesis that nursing education programmes need to improve the curricular content related to the assessment and reporting of suspected child abuse and neglect, and prevention strategies to improve the wellbeing of children. Curricular changes have the potential to provide nurses with an opportunity to reduce the prevalence of child abuse and neglect in India. PMID- 26973001 TI - The new taskforce that wants to improve the nation's mental health. AB - Emeritus Professor Alan Glasper, from the University of Southampton, discusses a new report from the independent Mental Health Taskforce and its implications for mental health services in England. PMID- 26973002 TI - Patient safety perspectives from other countries: the Minnesota system. AB - John Tingle considers the lessons learned from adverse event reporting, in the first of a two-part column considering key publications on patient safety and rights from organisations in different parts of the world. PMID- 26973003 TI - Depriving a person of liberty in their own home. AB - Richard Griffith, Senior Lecturer in Health Law at Swansea University, discusses the combination of elements required to confirm that a person is being deprived of their liberty at in their own home. PMID- 26973004 TI - From staff nurse to nurse consultant. AB - John Fowler Independent education consultant, continues his series for clinical nurses hoping to share their experiences with a wider audience, with advice on developing a potential article for a professional journal. PMID- 26973005 TI - Introducing the nursing associate role. PMID- 26973006 TI - The use of flange extenders to support patient care. AB - Pat Black, Senior Lecturer, St Mark's Institute of GI Nursing, St Mark's Hospital, explores one option for stoma care nurses to consider that could help improve patient confidence and comfort. PMID- 26973007 TI - Complexities of management of a urostomy in Ehlers-Danlos syndrome: a reflective account. AB - Mary (pseudonym) is a 30-year-old woman who underwent a urinary diversion and formation of an ileal conduit/urostomy (urinary stoma) due to the formation of multiple bladder diverticula, which caused micturition difficulties and recurrent urinary tract infections with associated pain and discomfort. The bladder diverticula were caused by Ehlers-Danlos syndrome (EDS), a hereditary disorder of the connective tissue or, particulary, defective collagen. Surgical intervention in patients with EDS is prone to complications due to poor wound healing, including issues of dehiscence, postoperative bleeding and poor uptake of anaesthesia and analgesia. After an initial presentation of the syndrome of EDS and Mary's history, this article offers a reflective account (informed by Gibbs' Reflective Cycle) and illustrates the complexities of caring for an individual with EDS who undergoes stoma formation. The author, a stoma care nurse, demonstrates how using purposeful reflection resulted in better understanding and awareness of caring for an individual with a rare syndrome and the nursing challenges this presented. PMID- 26973008 TI - Cost effectiveness of stoma accessories. AB - Gill Skipper, Stoma Care Sister, The Queen Elizabeth Hospital, King's Lynn NHS Trust, looks at aspects to consider when prescribing stoma care accessories. PMID- 26973009 TI - Bariatric surgery and implications for stoma care. AB - In the UK, 62% of the population are now described as being either overweight or obese. People with weight-management issues are more likely to suffer from cardiovascular disease and diabetes, as well as having an increased risk of cancer, including bowel cancer. Following the initial National Institute for Health and Care Excellence guidance in 2006, revised in 2014, health professionals have a more proactive role in identifying people with weight management issues and supporting them to achieve a weight that helps reduce their health risks. This includes referrals to bariatric surgeons for consideration for surgery if appropriate. One particular surgical procedure, the Roux-en-Y, is not reversible and alters the capacity of the stomach and function of the small bowel in order to achieve weight loss. Using a case study, this article will highlight the role of the stoma nurse in managing a patient, who previously had a Roux-en-Y procedure for weight loss and subsequently needed formation of a loop ileostomy after surgery for bowel cancer. PMID- 26973010 TI - Silicone-based stoma accessories in clinical practice. AB - Advanced silicone technology has transformed the treatment of wounds and peri wound skin. Recently, there has been interest in the use of silicone-based products in stoma care. Peristomal skin issues are a common problem, and can have a negative impact on the patient's quality of life, so helping the ostomate maintain good skin health is crucial. The author, a stoma care nurse, regularly sees 3-4 patients each week in her stoma care clinic with damaged or broken peristomal skin. This article explores the 'Trio' range of silicone-based accessories, discussing how these products compare with the traditional hydrocolloid, how they are applied and used. A series of case studies illustrates the circumstances in which these products may be applied. PMID- 26973011 TI - Sharing clinical expertise. PMID- 26973012 TI - Early elective colostomy following spinal cord injury. AB - Elective colostomy is an accepted method of bowel management for patients who have had a spinal cord injury (SCI). Approximately 2.4% of patients with SCI have a colostomy, and traditionally it is performed as a last resort several years after injury, and only if bowel complications persist when all other methods have failed. This is despite evidence that patients find a colostomy easier to manage and frequently report wishing it had been performed earlier. It was noticed in the author's spinal unit that increasing numbers of patients were requesting colostomy formation during inpatient rehabilitation following SCI. No supporting literature was found for this; it appears to be an emerging and untested practice. This article explores colostomy formation as a method of bowel management in patients with SCI, considers the optimal time for colostomy formation after injury and examines issues for health professionals. PMID- 26973013 TI - Light-controllable dispersion and recovery of graphenes and carbon nanotubes using a photo-switchable surfactant. AB - The aqueous dispersibility of carbon-based nanomaterials, namely graphene oxide (GO), reduced graphene oxide (rGO) and carbon nanotubes (CNTs), can be controlled by light via the photoisomerisation of a photoswitchable surfactant molecule adsorbed to the surface of these materials. By incorporating a cationic azobenzene photosurfactant into these systems, GO, rGO and CNT dispersions can be separated and redispersed on command utilising UV radiation at 365 nm, whereby the surfactant molecules change from the trans to the cis isomer. This increases their aqueous solubility and in turn, alters their adsorption affinity for the GO and rGO sheets such that the ratio of free to adsorbed surfactant molecules changes significantly, allowing for reversible phase separation of the colloids. These effects present a unique method for controlling the dispersion behaviour of two-dimensional nanomaterials using light as a clean and low energy external stimulus. PMID- 26973014 TI - Objective Cough Frequency, Airway Inflammation, and Disease Control in Asthma. AB - BACKGROUND: Cough is recognized as an important troublesome symptom in the diagnosis and monitoring of asthma. Asthma control is thought to be determined by the degree of airway inflammation and hyperresponsiveness but how these factors relate to cough frequency is unclear. The goal of this study was to investigate the relationships between objective cough frequency, disease control, airflow obstruction, and airway inflammation in asthma. METHODS: Participants with asthma underwent 24-h ambulatory cough monitoring and assessment of exhaled nitric oxide, spirometry, methacholine challenge, and sputum induction (cell counts and inflammatory mediator levels). Asthma control was assessed by using the Global Initiative for Asthma (GINA) classification and the Asthma Control Questionnaire (ACQ). The number of cough sounds was manually counted and expressed as coughs per hour (c/h). RESULTS: Eighty-nine subjects with asthma (mean +/- SD age, 57 +/ 12 years; 57% female) were recruited. According to GINA criteria, 18 (20.2%) patients were classified as controlled, 39 (43.8%) partly controlled, and 32 (36%) uncontrolled; the median ACQ score was 1 (range, 0.0-4.4). The 6-item ACQ correlated with 24-h cough frequency (r = 0.40; P < .001), and patients with uncontrolled asthma (per GINA criteria) had higher median 24-h cough frequency (4.2 c/h; range, 0.3-27.6) compared with partially controlled asthma (1.8 c/h; range, 0.2-25.3; P = .01) and controlled asthma (1.7 c/h; range, 0.3-6.7; P = .002). Measures of airway inflammation were not significantly different between GINA categories and were not correlated with ACQ. In multivariate analyses, increasing cough frequency and worsening FEV1 independently predicted measures of asthma control. CONCLUSIONS: Ambulatory cough frequency monitoring provides an objective assessment of asthma symptoms that correlates with standard measures of asthma control but not airflow obstruction or airway inflammation. Moreover, cough frequency and airflow obstruction represent independent dimensions of asthma control. PMID- 26973016 TI - Liver Capsule: Biliary Tree Stem Cell Subpopulations. PMID- 26973015 TI - High Prevalence and Heterogeneity of Diabetes in Patients With TB in South India: A Report from the Effects of Diabetes on Tuberculosis Severity (EDOTS) Study. AB - BACKGROUND: Previous studies reported an association of diabetes mellitus (DM) with TB susceptibility. Many studies were retrospective, had weak diagnostic criteria for DM, and did not assess other comorbidities. The Effects of Diabetes on Tuberculosis Severity (EDOTS) study is addressing these limitations with a longitudinal comparison of patients with TB who are classified as diabetic or normoglycemic according to World Health Organization criteria. We report interim findings after enrolling 159 of a planned 300 subjects. METHODS: A cohort study of patients with TB in South India with DM or normoglycemia defined by oral glucose tolerance test (OGTT) and fasting glucose. Glycohemoglobin (HbA1c), serum creatinine, lipids, and 25-hydroxyvitamin D were measured at enrollment. Patients were monitored monthly during TB treatment, and HbA1c measurement was repeated after 3 months. RESULTS: Of 209 eligible patients, 113 (54.1%) were classified as diabetic, 44 (21.0%) with impaired glucose tolerance, and 52 (24.9%) as normoglycemic. More patients with diabetes were detected by OGTT than by HbA1c. Diabetes was a newly received diagnosis for 37 (32.7%) in the DM group, and their median HbA1c (6.8%) was significantly lower than in those with previously diagnosed DM (HbA1c, 10.4%). Among 129 patients monitored for 3 months, HbA1c declined in all groups, with the greatest difference in patients with a newly received diagnosis of DM. CONCLUSIONS: Early EDOTS study results reveal a strikingly high prevalence of glycemic disorders in South Indian patients with pulmonary TB and unexpected heterogeneity within the patient population with diabetes and TB. This glycemic control heterogeneity has implications for the TB DM interaction and the interpretation of TB studies relying exclusively on HbA1c to define diabetic status. PMID- 26973017 TI - Crystal Fluidity Reflected by Fast Rotational Motion at the Core, Branches, and Peripheral Aromatic Groups of a Dendrimeric Molecular Rotor. AB - Low packing densities are key structural features of amphidynamic crystals built with static and mobile components. Here we report a loosely packed crystal of dendrimeric rotor 2 and the fast dynamics of all its aromatic groups, both resulting from the hyperbranched structure of the molecule. Compound 2 was synthesized with a convergent strategy to construct a central phenylene core with stators consisting of two layers of triarylmethyl groups. Single crystal X-ray diffraction analysis confirmed a low-density packing structure consisting of one molecule of 2 and approximately eight solvent molecules per unit cell. Three isotopologues of 2 were synthesized to study the motion of each segment of the molecule in the solid state using variable temperature quadrupolar echo (2)H NMR spectroscopy. Line shape analysis of the spectra reveals that the central phenylene, the six branch phenylenes, and the 18 periphery phenyls all display megahertz rotational dynamics in the crystals at ambient temperature. Arrhenius analysis of the data gives similar activation energies and pre-exponential factors for different parts of the structure. The observed pre-exponential factors are 4-6 orders of magnitude greater than those of elementary site exchange processes, indicating that the dynamics are not dictated by static energetic potentials. Instead, the activation energies for rotations in the crystals of 2 are controlled by temperature dependent local structural fluctuations and crystal fluidity. PMID- 26973018 TI - Cyclic RGD peptides target human trabecular meshwork cells while ameliorating connective tissue growth factor-induced fibrosis. AB - The major risk factor for primary open-angle glaucoma is increased intraocular pressure stemming from elevated outflow resistance in the trabecular meshwork (TM) region. Integrins play a pivotal role in the TM by influencing its biological properties and growth factor signaling. Pathologic changes in the TM are partially mediated by growth factors like connective tissue growth factor (CTGF). Specific targeting of TM cells could play a critical clinical role by increasing the therapeutic efficacy of nanoparticles, e.g. for nonviral gene delivery. Quantum dots with cyclo(RGDfC) covalently immobilized to their surface effectively targeted cultured TM cells and were rapidly and efficiently endocytosed by binding to alphavbeta3 and alphavbeta5 integrins. Compared to the integrin-overexpressing U87-MG cell line, the association of RGD-modified nanoparticles with the TM cells was significantly higher. Binding and uptake into TM cells was receptor-mediated and suppressible with free peptide. Soluble cyclic RGD peptides effectively attenuated CTGF-mediated effects and inhibited CTGF signaling. Due to their antagonism for alphavbeta3 and alphavbeta5 integrins, these cyclic RGD pentapeptides effectively ameliorated the CTGF-induced effects and strongly promoted specific nanoparticle association. Thus, cyclic RGD peptides are powerful multifunctional ligands for both addressing nanomaterials to the TM and interfering with pathologic CTGF signaling upon arrival. PMID- 26973019 TI - Continuum in MDGC Technology: From Classical Multidimensional to Comprehensive Two-Dimensional Gas Chromatography. AB - Recent advances in multidimensional gas chromatography (MDGC) comprise methods such as multiple heart-cut (H/C) analysis and comprehensive two-dimensional gas chromatography (GC * GC); however, clear approaches to evaluate the MDGC results, choice of the most appropriate method, and optimized separation remain of concern. In order to track the capability of these analytical techniques and select an effective experimental approach, a fundamental approach was developed utilizing a time summation model incorporating temperature-dependent linear solvation energy relationship (LSER). The approach allows prediction of optimized analyte distribution in the 2D space for various MDGC approaches employing different experimental variables such as column lengths, temperature programs, and stationary phase combinations in order to evaluate separation performance (apparent (1)D, (2)D, total number of separated peaks, and orthogonality) for simulated MDGC results. The methodology applied LSER to generate results for nonpolar-polar and polar-nonpolar 2D column configurations for separation of 678 compounds in an oxidized kerosene-based jet fuel sample. Three-dimensional plots were generated in order to illustrate the dependency of separation performance on (2)D column length and number of injections for different stationary phase combinations. With a given limit of analysis time, a MDGC approach to obtain an optimized total separated peak number for a particular column set was proposed depending on (1)D and (2)D analyte peak distribution. This study introduces fundamental concepts and establishes approaches to design effective GC * GC or multiple H/C systems for different column combinations, to provide the best overall separation outcomes with the highest separated peak number and/or orthogonality. PMID- 26973021 TI - Mesothelioma in iron ore (taconite) miners. PMID- 26973022 TI - Natural environmental impacts on teleost immune function. AB - The environment in which teleosts exist can experience considerable change. Short term changes can occur in relation to tidal movements or adverse weather events. Long-term changes can be caused by anthropogenic impacts such as climate change, which can result in changes to temperature, acidity, salinity and oxygen capacity of aquatic environments. These changes can have important impacts on the physiology of an animal, including its immune system. This can have consequences on the well-being of the animal and its ability to protect against pathogens. This review will look at recent investigations of these types of environmental change on the immune response in teleosts. PMID- 26973020 TI - Possible Role of HLA-G, LILRB1 and KIR2DL4 Gene Polymorphisms in Spontaneous Miscarriage. AB - The KIR2DL4 receptor and its ligand HLA-G are considered important for fetal maternal immune tolerance and successful pregnancy. The absence of a particular variant of KIR2DL4 might be a bad prognostic factor for pregnancy outcome. However, it could be compensated by the presence of the respective LILRB1 allele. Therefore, we investigated the KIR2DL4, LILRB1 and HLA-G polymorphisms in 277 couples with spontaneous abortion and 219 control couples by HRM, PCR-SSP and RFLP methods. We found a protective effect of women's heterozygosity in -716 HLA G (p = 0.0206) and LILRB1 (p = 0.0131) against spontaneous abortion. Surprisingly, we observed more 9A/10A genotypes of KIR2DL4 gene carriers in the group of male partners from the miscarriage group in comparison to the men from the control group (p = 0.0288). Furthermore, there was no association of women's KIR2DL4 polymorphism with susceptibility to spontaneous abortion. Multivariate analysis indicated that women's -716 HLA-G and LILRB1 and men's KIR2DL4 9A/10A are important in terms of the protection or susceptibility to miscarriage, respectively (p = 0.00968). In conclusion, a woman's heterozygosity in HLA-G and LILRB1 might be an advantage for a success of reproduction, but the partner's heterozygosity in 9A/10A KIR2DL4 alleles might not. PMID- 26973023 TI - Bacterial communities and volatile compounds in Doubanjiang, a Chinese traditional red pepper paste. AB - AIM: To identify core bacterial communities and volatile compounds and to investigate their relationships in Doubanjiang, a Chinese traditional red pepper paste. METHODS AND RESULTS: Two main culture-independent methods, polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and MiSeq sequencing technique, were used to investigate bacterial composition. Headspace solid-phase microextraction combined with gas chromatography-mass spectrometry (HS-SPME-GC-MS) was used to isolate and identify volatile organic compounds. Partial least squares (PLS) regression and correlation coefficients analyses were used for elucidating the relationship between core bacterial community and volatile compounds. CONCLUSIONS: Lactic acid bacteria (LAB) and Enterobacteriaceae family were identified primarily by the PCR-DGGE fingerprinting. Furthermore, the core microbiome (>1% average relative abundance) were indentified by Miseq sequencing technique, which mainly assigned to Proteobacteria, Cyanobacteria and Firmicutes phyla. For volatile profile, a total of 29 volatile compounds were identified by HP-SPME-GC-MS, mainly alcohols, esters, aldehydes, ketones and phenols. PLS regression and Pearson's correlation coefficients analyses revealed highly covariable relationships between volatile compounds and bacterial taxa. Notably, Pseudomonas most highly significantly associated with 3-methyl butanal, 2-methyl butanal, benzeneacetaldehyde and 2 acetylpyrrole (P < 0.001), and significantly correlated with 5-methylfurfural and 5-methyl-2-phenyl-2-hexenal (P < 0.01). SIGNIFICANCE AND IMPACT OF THE STUDY: Core bacterial communities were identified and the relationship between bacterial taxa and flavour compounds was revealed, these results could be beneficial for improving the quality of Doubanjiang. PMID- 26973024 TI - Simplifying the guidelines: The 10 COPD commandments. PMID- 26973025 TI - Very Early Administration of Progesterone Does Not Improve Neuropsychological Outcomes in Subjects with Moderate to Severe Traumatic Brain Injury. AB - A Phase III, double-blind, placebo-controlled trial (ProTECT III) found that administration of progesterone did not reduce mortality or improve functional outcome as measured by the Glasgow Outcome Scale Extended (GOSE) in subjects with moderate to severe traumatic brain injury. We conducted a secondary analysis of neuropsychological outcomes to evaluate whether progesterone is associated with improved recovery of cognitive and motor functioning. ProTECT III was conducted at 49 level I trauma centers in the United States. Adults with moderate to severe TBI were randomized to receive intravenous progesterone or placebo within 4 h of injury for a total of 4 days. At 6 months, subjects underwent evaluation of memory, attention, executive functioning, language, and fine motor coordination/dexterity. Chi-square analysis revealed no significant difference in the proportion of subjects (263/280 progesterone, 283/295 placebo) with Galveston Orientation and Amnesia Test scores >=75. Analyses of covariance did not reveal significant treatment effects for memory (Buschke immediate recall, p = 0.53; delayed recall, p = 0.94), attention (Trails A speed, p = 0.81 and errors, p = 0.22; Digit Span Forward length, p = 0.66), executive functioning (Trails B speed, p = 0.97 and errors, p = 0.93; Digit Span Backward length, p = 0.60), language (timed phonemic fluency, p = 0.05), and fine motor coordination/dexterity (Grooved Pegboard dominant hand time, p = 0.75 and peg drops, p = 0.59; nondominant hand time, p = 0.74 and peg drops, p = 0.61). Pearson Product Moment Correlations demonstrated significant (p < 0.001) associations between better neuropsychological performance and higher GOSE scores. Similar to the ProTECT III trial's results of the primary outcome, the secondary outcomes do not provide evidence of a neuroprotective effect of progesterone. PMID- 26973026 TI - Clinical characteristics of a Japanese family with hearing loss accompanied by compound heterozygous mutations in LOXHD1. AB - OBJECTIVE: To report two novel LOXHD1 mutations, including missense mutations and the clinical features of the patients. METHODS: We studied a three-generation Japanese family with hearing loss. Targeted next-generation sequencing was used for genetic analysis. Conditional orientation response audiometry and pure tone audiometry were used to assess hearing. SWISS-MODEL was used for molecular modeling of the PLAT domain in LOXHD1 protein. RESULTS: The two sisters, who had either mild or severe high-frequency hearing loss, were compound heterozygous for two novel mutations (c.5674G>T [p.V1892F] and c.4212+1G>A) in LOXHD1, which is responsible for autosomal-recessive nonsyndromic hearing loss DFNB77. These cases showed less severe hearing impairment than the previously reported cases carrying LOXHD1 mutations, but their hearing loss appeared to be progressive. Molecular modeling predicted that distorted structure of the PLAT domain in the p.V1892F mutant could lead to decreased affinity of the protein to lipid membrane resulting in hair cell dysfunction. CONCLUSION: We report a Japanese family carrying compound heterozygotes of truncating and nontruncating mutations in LOXHD1 identified by targeted NGS analysis. The fact of lower degree of hearing impairment in our cases than previously reported and the molecular modeling of the missense mutant provide insight to the genotype-phenotype correlation of DFNB77. PMID- 26973027 TI - Mapping synaptic cortico-claustral connectivity in the mouse. AB - The claustrum is an intriguing brain structure, featuring the highest connectivity per regional volume in the brain. It is a thin and elongated structure enclosed between the striatum and the insular cortex, with widespread reciprocal connections with the sensory modalities and prefrontal cortices. Retinotopic and somatotopic organizations have been described in the claustrum, and anatomical studies in cats, monkeys, and rats have demonstrated topographic organization of cortico-claustral connections. In this study we mapped the projections from cortical modalities (visual, auditory, somatosensory, motor, and olfactory), and prefrontal regions (anterior cingulate cortex and orbitofrontal cortex) to the claustrum in mice. Utilizing expression of a virally encoded synaptic anterograde tracer, AAV-SynaptoTag, followed by 3D reconstruction of the cortical projections, we performed a comprehensive study of the organization of these projections within the mouse claustrum. Our results clearly demonstrate a dorsoventral laminar organization of projections from the sensory cortices to the claustrum, whereas frontal inputs are more extensive and overlap with the inputs from the sensory cortices. In addition, we find evidence supporting a core/shell organization of the claustrum. We propose that the overlap between the frontal inputs and the inputs from the sensory modalities may underlie executive regulation of the communication between the claustrum and the cortical modalities. J. Comp. Neurol. 525:1381-1402, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26973028 TI - Place matters: Contextualizing the roles of religion and race for understanding Americans' attitudes about homosexuality. AB - As laws and policies related to homosexuality have evolved, Americans' attitudes have also changed. Race and religion have been established as important indicators of feelings about homosexuality. However, researchers have given almost no attention to how county characteristics shape Americans' attitudes. Using Hierarchical Linear Modeling techniques, we examine how personal characteristics and the religious and racial context of a county shape feelings about homosexuality drawing on data from the American National Election Survey and information about where respondents reside. We find that African Americans initially appear less tolerant than other racial groups, until we account for the geographical distribution of attitudes across the nation. Additionally, once we consider religious involvement, strength of belief, and religious affiliation African Americans appear to have warmer feelings about homosexuality than whites. Drawing on the moral communities' hypothesis, we also find that the strength of religiosity amongst county residents heightens the influence of personal religious beliefs on disapproving attitudes. There is also a direct effect of the proportion conservative Protestant, whereby people of all faiths have cooler attitudes towards homosexual individuals when they reside in a county with a higher proportion of conservative Protestants. Finally, we do not find any evidence for an African American cultural influence on attitudes. PMID- 26973029 TI - Collective religiosity and the gender gap in attitudes towards economic redistribution in 86 countries, 1990-2008. AB - What is the relationship between gender and the demand for redistribution? Because, on average, women face more economic deprivation than men, in many countries women favor redistribution more than men. However, this is not the case in a number of other countries, where women do not support redistribution more than men. To explain this cross-national paradox, we stress the role of collective religiosity. In many religions, theological principles both militate against public policies designed to redistribute income, and also promote traditionally gendered patterns of work and family involvement. Hence, we hypothesize that, in those countries where religion remains influential either through closer church-state ties or an intensely religious population, men and women should differ less in their attitudes towards redistribution. Drawing upon the World Values Survey, we estimate three-level regression models that test our religiosity-based approach and two alternative explanations in 86 countries and 175 country-years. The results are consistent with our hypothesis. Moreover, in further support of our theoretical approach, societal religiosity undermines pro redistribution preferences more among women than men. Our findings suggest that collective religiosity matters more to the gender gap in redistributive attitudes than traditional political and labor force factors. PMID- 26973030 TI - Secularization versus religious revival in Eastern Europe: Church institutional resilience, state repression and divergent paths. AB - Despite continuing for over two decades, the debate about the nature of the trends in religiosity in post-Communist Eastern Europe remains unresolved: some arguing that these countries are undergoing the same process of secularization as the West, while others insist that the entire region is experiencing a religious revival. Using national sample surveys from the early 1990s to 2007 to examine the change in demographic predictors of religiosity, we show that Catholic and Orthodox countries are experiencing different trends, the first group displaying evidence of secularization and the second of revival, and that these two different trends are likely to derive from the legacies of state repression and the differing abilities of the churches to resist such repression. We argue that the current literature has thus taken a mistakenly general approach, and that the post-Communist region consists of at least two distinct groups of societies with different trends in religiosity. PMID- 26973032 TI - Not a lonely crowd? Social connectedness, religious service attendance, and the spiritual but not religious. AB - Using the 2006-2014 General Social Survey and 2006-2012 Portraits of American Life Study, I find that on three dimensions of social connectedness: social interaction frequency, core discussion network size, and number of close ties, that religious service attenders are more connected than religious non-attenders and then either spiritual nor religious, but there are few differences between attenders and the spiritual but not religious. Difference-in-differences and fixed-effects models show little evidence that switches between categories are associated with changes in connectedness, and additional models show that prior social connectedness explains only a small amount of future switches. This paper challenges assumptions that the non-religious are a homogenous group lacking the benefits provided though the social networks of religious congregations and has implications for research on what it means to be spiritual, measuring religion and spirituality, and understanding the role of formal organizations in social life. PMID- 26973031 TI - Leaving my religion: Understanding the relationship between religious disaffiliation, health, and well-being. AB - Religious disaffiliation-leaving the religious tradition in which one was raised for no religious affiliation in adulthood-has become more common in recent years, though few studies have examined its consequences for the health and well-being of individuals. We use an innovative approach, comparing the health and subjective well-being of religious disaffiliates to those who remain affiliated using pooled General Social Survey samples from 1973 through 2012. We find that religious disaffiliates experience poorer health and lower well-being than those consistently affiliated and those who are consistently unaffiliated. We also demonstrate that the disadvantage for those who leave religious traditions is completely mediated by the frequency of church attendance, as disaffiliates attend church less often. Our results point to the importance of the social processes surrounding religious disaffiliation and emphasize the role of dynamics in the relationship between religious affiliation and health. PMID- 26973033 TI - Neighborhood disadvantage and obesity across childhood and adolescence: Evidence from the NLSY children and young adults cohort (1986-2010). AB - Previous research suggests that youth who grow up in socioeconomically disadvantaged neighborhoods face higher odds of becoming obese. Neighborhood effects scholars, meanwhile, have suggested that contextual influences may increase in strength as children age. This is the first study to examine whether developmental epochs moderate the effect of neighborhood disadvantage on obesity over time. I use thirteen waves of new restricted and geo-coded data on children ages 2-18 from the National Longitudinal Survey of Youth, Children and Young Adults. Bivariate and pooled logistic regression results suggest that neighborhood disadvantage has a stronger impact on adolescents' likelihood of becoming obese. Fixed effects models reveal that after adjusting for observed and unobserved confounders, adolescents continue to face higher odds of becoming obese due to the conditions associated with living in disadvantaged neighborhoods. Moreover, as research on adults suggests, girls experience larger impacts of neighborhood disadvantage than boys. PMID- 26973035 TI - Changes in the labour market and health inequalities during the years of the recent economic downturn in Italy. AB - There is widespread concern that episodes of unemployment and unstable working conditions adversely affect health. We add to the debate by focusing on the relationship between work trajectory and the self-reported health of Italian men and women during the present economic downturn. Relying on Italian data in the EU SILC project (from 2007 to 2010), our sample includes all individuals aged 30 to 60 in 2010, and uses multivariate binomial regression models for preliminary analyses and the Structural Equations modelling (SEM) to observe the cumulative effects of health status according to different job trajectories. Our main findings show similar pictures for men and women. Individuals who are unemployed, ejected or in precarious occupational positions have a higher risk of worsening their health status during these years. PMID- 26973034 TI - The differential impact of discrimination on health among Black and White women. AB - Despite a large body of research examining the impact of discrimination on health, the ways in which perceived discrimination may lead to disparate health outcomes through a sense of self and system consciousness is less understood. The current paper is concerned with both mental and physical health consequences of discrimination, as well as mediating pathways among African American and White women. Indirect effects analyses examine mediating paths from discrimination to health outcomes via structural awareness and self-esteem, using data from the Women's Life Path Study (N = 237). Our findings suggest that discrimination is both directly and indirectly associated with health outcomes for both Black and White women, mediated by individual (self-esteem) and group-level (structural awareness) processes. Evidence from this study indicates that discrimination is associated with heightened structural awareness, as well as lower self-esteem - both of which are related to poorer health. Discrimination negatively affected health across three domains, although the mechanisms varied somewhat for Black and White women. Broad implications of this research for interdisciplinary scholarship on the effects of discrimination on health and health disparities are discussed. PMID- 26973036 TI - Conflicting views on elder care responsibility in Japan. AB - I examine the attitudinal ambivalence created by conflicting social expectations regarding parent-child devotion, filial obligation and family membership, and gender norms in a national population of Japanese adults. I ask: in a context of rapidly changing family and elder care norms, how do different beliefs and attitudes overlap and conflict and how are they related to elder care preferences? I analyze data from the 2006 Japanese General Social Survey and use Latent Class Analysis to identify latent groups in the population defined by their beliefs and examine the relationship between class membership and elder care preferences. I found variation in the population with respect to the measured beliefs as well as a relationship between patterns of beliefs and choice of elder caregiver. I found conflicting expectations regarding elder care responsibility in one latent class and this class also expressed elder care preferences that conflict with at least some of their strongly held beliefs. PMID- 26973038 TI - Is immigrant neighborhood inequality less pronounced in suburban areas? AB - We investigate suburbanization and neighborhood inequality among 14 immigrant groups using census tract data from the 2008-2012 American Community Survey. Immigrant neighborhood inequality is defined here as the degree to which immigrants reside in neighborhoods that are poorer than the neighborhoods in which native whites reside. Using city and suburb Gini coefficients which reflect the distributions of groups across neighborhoods with varying poverty rates, we find that the immigrant-white gap is attenuated in the suburbs. This finding applies to most of the nativity groups and remains after accounting for metropolitan context, the segregation of poverty, and group-specific segregation levels, poverty rates, and acculturation characteristics. Despite reduced neighborhood inequality in the suburbs, large group differences persist. A few immigrant groups achieve residential parity or better vis-a-vis suburban whites while others experience high levels of neighborhood inequality and receive marginal residential returns on suburban location. PMID- 26973037 TI - Women's age at first marriage and postmarital agency in Egypt. AB - Early - or child - marriage (before age 18) may diminish women's ability to exercise agency, or their capacity to act upon their goals. Using a propensity score adjustment approach, we analyzed data from 2394 married women ages 35-49 years who participated in the 2006 Egypt Labor Market Panel Survey (ELMPS). We examined whether women's first marriage at age 18 or older was associated with their post-marital agency, measured in terms of their influence in family decisions, freedom of movement in public spaces, and unfavorable views about intimate partner violence against wives. In bivariate analyses, women's age at first marriage was positively associated with their decision-making and more equitable gender attitudes. However, once we controlled for selection into age-at first-marriage groups, there were no significant differences between the two age at-first-marriage groups in any dimension of women's agency. We examined the sensitivity of the non-significant age-at-first-marriage effects to possible violations of the strong ignorability assumption and the results did not alter our conclusions. The assumption that women's age at first marriage is a proxy for their post-marital agency, as defined here, warrants further study. PMID- 26973039 TI - How do they do it? The immigrant paradox in the transition to adulthood. AB - How do children of immigrants consistently outperform children of native-born U.S. parents, in spite of lower familial resources? Using the Transition to Adulthood Study of the Panel Study of Income Dynamics, children of immigrant and native-born parents completing high school in 2005-13 are followed as they move into the young adult years. Children of immigrants are more likely to enroll in college, be employed or in school, and less likely to have a criminal record as young adults or to have a child than children of nonimmigrants. This is not a result of immigrant parentage but due primarily to greater parental educational expectations; immigrants enjoy a differential return to parental expectations for boys' college enrollment as well. Reading skills and activity patterns in the secondary school years also contribute to better outcomes. Children of immigrants are better able to translate their reading comprehension skills to college or employment later on. PMID- 26973041 TI - History, place, and racial self-representation in 21st century America. AB - How is a person's racial self-representation related to the race history of the place in which he or she lives? We use Census Bureau data about race and ancestry to address this research question for two groups of people with mixed racial heritage: those reporting white and American Indian heritages, or reporting black and American Indian heritages. Links between history, place, and self representation can be seen in geographic clustering for each race/ancestry response combination. We use multinomial logistic regression models to predict individuals' race/ancestry responses (e.g., white with American Indian ancestry versus white and American Indian races) using measures of local race history and the area's contemporary racial composition. Multivariate results highlight the relationship between a person's identity claims and the history of the area, net of contemporary area composition. Future research should attend to the history of the place as a potential contributor to contemporary patterns. PMID- 26973040 TI - New faces in new spaces in new places: Residential attainment among newly legalized immigrants in established, new, and minor destinations. AB - Immigrants at the beginning of the twenty-first century are located in a more diverse set of metropolitan areas than at any point in U.S. HISTORY: Whether immigrants' residential prospects are helped or hindered in new versus established immigrant-receiving areas has been the subject of debate. Using multilevel models and data from the New Immigrant Survey (NIS), a nationally representative sample of newly legalized immigrants to the U.S., we move beyond aggregate-level analyses of residential segregation to specify the influence of destination type on individual-level immigrant residential outcomes. The findings indicate that immigrants in new and minor destinations are significantly more likely to live in tracts with relatively more non-Hispanic whites and relatively fewer immigrants and poor residents. These residential advantages persist net of individual-level controls but are largely accounted for by place-to-place differences in metropolitan composition and structure. Our exclusive focus on newly legalized immigrants means that our findings do not necessarily contradict the possibility of worse residential prospects in new areas of settlement, but rather qualifies it as not extending to the newly authorized population. PMID- 26973042 TI - The value of educational degrees in turbulent economic times: Evidence from the Youth Development Study. AB - Rising costs of higher education have prompted debate about the value of college degrees. Using mixed effects panel models of data from the Youth Development Study (ages 31-37), we compare occupational outcomes (i.e., weekly hours worked, earnings, employment status, career attainment, and job security) between educational attainment categories within year, and within categories across years, from 2005 to 2011, capturing the period before, during, and in the aftermath of the Great Recession. Our findings demonstrate the long-term value of post-secondary degrees. Bachelor's and Associate's degree recipients, while experiencing setbacks at the height of recession, were significantly better off than those with some or no college attendance. Vocational-Technical degree holders followed a unique trajectory: pre-recession, they are mostly on par with Associate's and Bachelor's recipients, but they are hit particularly hard by the recession and then rebound somewhat afterwards. Our findings highlight the perils of starting but not finishing post-secondary educational programs. PMID- 26973043 TI - How beauty works. Theoretical mechanisms and two empirical applications on students' evaluation of teaching. AB - Plenty of studies show that the physical appearance of a person affects a variety of outcomes in everyday life. However, due to an incomplete theoretical explication and empirical problems in disentangling different beauty effects, it is unclear which mechanisms are at work. To clarify how beauty works we present explanations from evolutionary theory and expectation states theory and show where both perspectives differ and where interlinkage appears promising. Using students' evaluations of teaching we find observational and experimental evidence for the different causal pathways of physical attractiveness. First, independent raters strongly agree over the physical attractiveness of a person. Second, attractive instructors receive better student ratings. Third, students attend classes of attractive instructors more frequently - even after controlling for teaching quality. Fourth, we find no evidence that attractiveness effects become stronger if rater and ratee are of the opposite sex. Finally, the beauty premium turns into a penalty if an attractive instructor falls short of students' expectations. PMID- 26973044 TI - Perceptual type error in everyday practice. AB - Discrepancy or quality improvement meetings are good practice and are now commonplace in most Radiology Departments, with the aim of improving diagnostic accuracy, preventing recurrent and common mistakes, improving the radiological report and thereby improving patient care. A total of 122 cases were assessed from a two-year period. This review highlights some of the more common, recurrent and important issues encountered within a general hospital with an emphasis on learning points and review areas. PMID- 26973045 TI - Improving trauma imaging in Wales through Kotter's theory of change. AB - AIM: To improve the practice of trauma computed tomography (CT) within Wales using recognised leadership techniques for change. MATERIALS AND METHODS: Royal College of Radiologists' (RCR) guidance, in addition to other key recent evidence, were used to form an aspirational standard. All centres across Wales with a major emergency department were included. Kotter's theory of change was utilised to facilitate an improvement in practice across the region, with larger units prioritised initially. RESULTS: Of the 13 major emergency units in Wales, eight centres had no formal trauma CT protocol. Only one centre utilised the Bastion protocol (in comparison to 75% of major trauma centres). After the campaign to improve trauma imaging, seven centres now offer the Bastion protocol, with currently only three peripheral centres still without a procedure for whole body CT. The two largest centres have implemented an emergency department pro forma. CONCLUSION: Trauma CT within Wales has significantly improved as a result of this project. Kotter's theory is demonstrated as an effective tool for facilitating a change in practice on a regional/national scale. PMID- 26973046 TI - Split-bolus single-pass in trauma pan-CT: how to ensure reproducibility and diagnostic efficacy. PMID- 26973047 TI - Adsorption of phenol molecules by sodium dodecyl sulfate (SDS) surfactants deposited on solid surfaces: A computer simulation study. AB - Adsorption studies of phenol molecules on a sodium dodecyl sulfate (SDS) micelle were investigated by molecular dynamics simulations. Simulations were carried out in bulk and on three distinct solid surfaces, silicon dioxide, titanium dioxide and graphite. It was observed that different surfactant micellar shapes were formed on the surfaces. For the silicon dioxide and titanium dioxide surfaces the surfactants were adsorbed by their headgroups whereas for the graphite surface they were adsorbed mainly by their tail groups. It was found that the amount of phenol adsorbed on the SDS micelle was altered by the surfactant shape deposited on the solid surface. However, the best phenol adsorption was obtained by the surfactant modified silicon dioxide surface. Moreover, in all cases, from structural investigations, it was determined that the phenol molecules were located inside the surfactant micelle with their hydroxyl groups close to the SDS headgroups. PMID- 26973048 TI - Exploring isoxazole and carboxamide derivatives as potential non-nucleoside reverse transcriptase inhibitors. AB - Nonnucleoside reverse transciptase inhibitors (NNRTI) are a class of drug molecules with a specific target of HIV-1 reverse transcriptase (RT). In the present work, we evaluated a set of selected oxazole and carboxamide derivatives to identify potential pharmacophoric features using molecular docking approach. The docking approach employed has been validated by enrichment factor calculation at top 1% (EF1%). It shows a considerable improvement in EF1%value compared to earlier reported study carried out on specific dataset of ligands and decoys for RT, in the directory of useful decoys (DUD). The carboxamide derivatives show better activity as NNRT inhibitors than oxazole derivatives. From this study, four pharmacophoric groups including a triazine ring, an aniline substituent, a benzyl amide moiety and a trimethylphenoxy substituent have been recognized and used for designing new NNRT inhibitors. Newly designed molecules show significant enhancement in docking scores over the native ligand, parent and other training set molecules. In addition, some functional groups have also been identified to assist in improving the activity of these pharmacophores. Thus a nitrile group, an amide and fluoro substitution turn out to be an important requisite for NNRT potential inhibitors. PMID- 26973049 TI - Detection of Myopic Choroidal Neovascularization Using Optical Coherence Tomography Angiography. AB - PURPOSE: To assess whether optical coherence tomography angiography (OCTA) can be used as an alternative to conventional fundus fluorescein angiography (FFA) for the detection of myopic choroidal neovascularization (CNV). DESIGN: Validity and reliability analysis. METHODS: Twenty-eight eyes of 26 consecutive Japanese patients with exudative lesions associated with pathologic myopia were included in this institutional study. Myopic CNV was detected in 23 eyes of 22 patients; 5 eyes exhibited simple hemorrhage. The main outcome measure was CNV detection by OCTA and FFA. The CNV area was individually measured by FFA and OCTA. Intraclass correlation coefficients (ICCs) for the CNV area, independently measured by 2 investigators using OCTA and FFA, were determined. RESULTS: OCTA images with sufficient quality for CNV assessment were obtained for 17 eyes with CNV and 4 without. FFA alone detected CNV in all 17 eyes, while OCTA alone detected CNV in 16 (94.1%). The 1 eye for which CNV was not detected by OCTA exhibited a 0.01 mm(2) area on FFA. Both FFA and OCTA did not detect CNV in eyes with simple hemorrhage. The mean CNV areas on FFA and OCTA were 0.59 +/- 0.56 mm(2) and 0.51 +/- 0.55 mm(2), respectively; the 2 values were significantly correlated (P < .001, r = .86). The ICC (2, 1) values for FFA and OCTA were 0.944 and 0.997, respectively. CONCLUSIONS: Our results indicate that OCTA can detect most myopic CNVs if high-quality images are acquired and can preclude the requirement for FFA in these settings. PMID- 26973051 TI - Spectral-Domain Optical Coherence Tomography-Derived Characteristics of Bruch Membrane Opening in a Young Adult Australian Population. AB - PURPOSE: To characterize and quantify Bruch membrane opening (BMO)-based optic nerve head (ONH) parameters in a large, young and healthy, predominantly white population. DESIGN: Cross-sectional study and reliability analysis. METHODS: The ONH of 1344 predominantly white subjects were imaged with spectral-domain optical coherence tomography (SD-OCT). A customized script, coded in Matlab, was used to manually segment and measure multiple BMO-based parameters of the ONH. Measurements were compared to those obtained with confocal scanning laser ophthalmoscopy (Heidelberg Retina Tomograph; HRT). Regression analysis was performed to assess the relationship between BMO parameters and other ocular and demographic variables. RESULTS: Mean BMO disc and neuroretinal rim (NRR) areas ranged from 0.94 to 4.06 mm(2) (mean 1.77 +/- 0.38 mm(2)) and 0.94 to 3.99 mm(2) (mean 1.56 +/- 0.31 mm(2)), respectively. When compared to the equivalent HRT measurements, SD-OCT-derived measures differed significantly for all comparable ONH parameters (P < .001). The limits of agreement computed from Bland-Altman plots comparing SD-OCT and HRT measurements showed suboptimal agreement between the techniques. Linear regression analysis demonstrated an effect of ethnicity, axial length, and refractive error on BMO-based parameters. CONCLUSIONS: We have quantified BMO-based parameters in a large cohort of young adults using SD-OCT. These data will be informative in constructing normative profiles for clinical and research purposes in glaucoma diagnosis and management. PMID- 26973050 TI - Isolated Orbital Aspergillosis in Immunocompetent Patients: A Multicenter Study. AB - OBJECTIVE: To report clinicopathologic features, radiologic findings, and treatment outcomes of isolated, orbital aspergillosis. DESIGN: Multicenter, retrospective case series. METHODS: setting: Multicenter. PARTICIPANTS: There were 8 lesions in 8 eyes of 8 patients with isolated, orbital aspergillosis. PROCEDURE: Review of medical records and histopathology slides. MAIN OUTCOME MEASURES: Disease control. RESULTS: Of 34 patients with orbital aspergillosis, 8 (23.5%) had isolated orbital involvement at presentation. The mean age at presentation was 34.5 years (median, 43 years: range, 0.5-72 years). Gradually progressive proptosis and eyelid swelling were the most common presenting features (each 4/8). Proptosis ranged from 4 mm to 9 mm (median, 5.5 mm; mean, 5.75 mm). Restriction of ocular motility was seen in all 8 patients. Other examination findings included palpable mass (2/8), conjunctival chemosis (2/8), hyperglobus (1/8), hypoglobus (1/8), and resistance to retropulsion (1/8). Microbial culture results were available in 1 patient and showed Aspergillus fumigatus. Two patients were treated with complete surgical excision alone while 6 were treated with antifungal medications. Complete resolution of proptosis and restoration of ocular motility were seen in all patients following treatment. Visual disturbances present in 1 were corrected following treatment. Recurrence was observed in 1 patient. CONCLUSION: Isolated orbital aspergillosis, though rare, should be considered in the differential diagnosis of a patient presenting with a gradually progressive orbital mass, especially in Asian individuals. Early recognition will help reduce the morbidity and mortality associated with this disease. PMID- 26973053 TI - Micro-shear bond strength of different resin cements to ceramic/glass-polymer CAD CAM block materials. AB - PURPOSE: The aim of this study was to evaluate the effects of hydrofluoric acid treatment on bond strength of resin cements to three different types of ceramic/glass containing CAD-CAM block composite materials. METHODS: CAD-CAM block materials of polymer infiltrated (Vita Enamic), resin nanoceramic (Lava Ultimate) and nanoceramic (Cerasmart) with a thickness of 1.5mm were randomly divided into two groups according to the surface treatment performed. In Group 1, specimens were wet-ground with silicon carbide abrasive papers up to no. 1000. In Group 2, 9.6% hydrofluoric acid gel was applied to ceramics. Three different resin cements (RelyX, Variolink Esthetic and G-CEM LinkAce) were applied to the tubes in 1.2-mm thick increments and light-cured for 40s using LED light curing unit. Half of the specimens (n=10) were submitted to thermal cycling (5000 cycles, 5-55 degrees C). The strength measurements were accomplished with a universal testing machine (Lloyd Instruments) at a cross-head speed of 0.5mm/min until the failure occurs. Failure modes were examined using a stereomicroscope and scanning electron microscope. The data were analyzed with multivariate analysis of variance (MANOVA) and Tukey's post hoc tests (alpha=0.05). RESULTS: There were significant differences between ceramics and resin cements (p<0.001). However, hydrofluoric acid gel treatment had no effect on bond strength values (p=0.073). In addition, thermal cycling significantly decreased bond strength values of resin cements to ceramics (p<0.001). CONCLUSIONS: Use of appropriate resin cement systems with different ceramic/glass-polymer materials might promote the bonding capacity of these systems. PMID- 26973052 TI - A Critical Analysis of Eleven Periocular Lobular Capillary Hemangiomas in Adults. AB - PURPOSE: To provide a critical analysis of a series of periocular lobular capillary hemangiomas in adults, outlining characteristic clinical and histopathologic patterns in comparison with those of other vascular tumors of adults and children. DESIGN: Retrospective observational case series. METHODS: Review of clinical data, hematoxylin-eosin-stained sections, and immunohistochemical studies of smooth muscle actin (SMA), D2-40, CD34, and glucose transporter 1 (GLUT-1). RESULTS: The 7 female and 4 male patients were diagnosed with periocular lobular capillary hemangioma at a median age of 39 years (range, 17-82 years). The tumors were small (3-14 mm, median size 6 mm) and well circumscribed, arose over the course of weeks to months, and developed most commonly in the canthal region, followed by the upper eyelid skin. The tumors were all composed microscopically of repeating units of various sizes (lobules) consisting of CD34-postive, GLUT-1-negative endothelial cells and SMA-positive pericytes arranged in macro- or microlobules. Some foci also exhibited ectatic vessels or diffuse, nonlobular capillary proliferations. Excision was curative without recurrence. CONCLUSION: Although capillary hemangiomas are more common in children, lobular capillary hemangiomas can also arise in the periocular region of adults. Some histopathologic features of these lesions are shared with those of infantile hemangioma and tufted angioma of children, but features of the clinical presentation and the results of immunohistochemical staining patterns are distinctive. PMID- 26973054 TI - Ultraminiaturized assay for rapid, low cost detection and quantification of clinical and biochemical samples. AB - Herein, we report a simple, sensitive, rapid and low-cost ultraminiaturized assay technique for quantitative detection of 1 MUl of clinical or biochemical sample on a novel ultraminiaturized assay plate (UAP). UAP is prepared by making tiny cavities on a polypropylene sheet. As UAP cannot immobilize a biomolecule through absorption, we have activated the tiny cavities of UAP by 1-fluoro-2-nitro-4 azidobenzene in a photochemical reaction. Activated UAP (AUAP) can covalently immobilize any biomolecule having an active nucleophilic group such as amino group. Efficacy of AUAP is demonstrated by detecting human IgE, antibody of hepatitis C virus core antigen and oligonucleotides. Quantification is performed by capturing the image of the colored assay solution and digitally quantifying the image by color saturation without using costly NanoDrop spectrophotometer. Image - based detection of human IgE and an oligonucleotide shows an excellent correlation with absorbance - based assay (recorded in a NanoDrop spectrophotometer); it is validated by Pearson's product-moment correlation with correlation coefficient of r = 0.9545088 and r = 0.9947444 respectively. AUAP is further checked by detecting hepatitis C virus Ab where strong correlation of color saturation with absorbance with respect to concentration is observed. Ultraminiaturized assay successfully detects target oligonucleotides by perfectly hybridizing with their respective complementary oligonucleotide probes but not with a random oligonucleotide. Ultraminiaturized assay technique has substantially reduced the requirement of reagents by 100 times and assay timing by 50 times making it a potential alternative to conventional method. PMID- 26973055 TI - Management and outcome of low velocity penetrating head injury caused by impacted foreign bodies. AB - BACKGROUND: Penetrating head injuries with impacted foreign bodies are rare, associated with a high incidence of morbidity and potentially life-threatening. In this study, we aimed at investigating the outcome of these cases as well as analyzing the factors affecting the prognosis. METHODS: A retrospective study in which the records of 16 patients who had penetrating head injuries caused by low velocity impacted foreign bodies were revised. All patients were males with a mean age of 28.9 years (range, 18 to 50 years). The follow-up period ranged from 4 to 13 months with a mean of 8.1 months. Causes of injury were construction accidents in 6 (37.5 %) patients, assault in 6 (37.5 %) and road traffic accidents in 4 (25 %). The impacted objects included a bar of iron, a piece of wood, a nail, a sickle and a piece of glass. Diagnostic computerized tomography (CT) of the brain was carried out on admission in all patients. Thirteen (81.3 %) patients were submitted to surgery, and all had the appropriate management in the form of antibiotics and dehydrating measures as required. The primary outcome measure was the Glasgow Outcome Scale (GOS) at the end of follow-up. RESULTS: At the end of follow-up, ten (62.5 %) patients had a GOS score of 5, two (12.5 %) patients had a score of 4, and four (25 %) patients had a score of 1. CONCLUSIONS: Low-velocity penetrating head injuries are most common in young adult males. With the appropriate management, a majority of even the most severe cases can have a favorable outcome. PMID- 26973057 TI - Dibenzothiophene desulfurization capability and evolutionary divergence of newly isolated bacteria. AB - Metabolically microorganisms are diverse, and they are capable of transforming almost every known group of chemical compounds present in coal and oil in various forms. In this milieu, one of the important microbial metabolic processes is the biodesulfurization [cleavage of carbon-sulfur (C-S) bond] of thiophenic compounds, such as dibenzothiophene (DBT), which is the most abundant form of organic sulfur present in fossil fuels. In the current study, ten newly isolated bacterial isolates, designated as species of genera Gordonia, Amycolatopsis, Microbacterium and Mycobacterium, were enriched from different samples in the presence of DBT as a sole source of organic sulfur. The HPLC analysis of the DBT grown cultures indicated the consumption of DBT and accumulation of 2 hydroxybiphenyl (2-HBP). Detection of 2-HBP, a marker metabolite of 4S (sulfoxide sulfone-sulfinate-sulfate) pathway, suggested that the newly isolated strains harbored metabolic activity for DBT desulfurization through the cleavage of C-S bond. The maximum 2-HBP formation rate was 3.5 umol/g dry cell weight (DCW)/h. The phylogenetic analysis of the new isolates showed that they had diverse distribution within the phylogenetic tree and formed distinct clusters, suggesting that they might represent strains of already reported species or they were altogether new species. Estimates of evolutionary divergence showed high level of nucleotide divergence between the isolates within the same genus. The new isolates were able to use a range of heterocyclic sulfur compounds, thus making them suitable candidates for a robust biodesulfurization system for fossil fuels. PMID- 26973056 TI - Chronic Trigeminal Nerve Stimulation Protects Against Seizures, Cognitive Impairments, Hippocampal Apoptosis, and Inflammatory Responses in Epileptic Rats. AB - Trigeminal nerve stimulation (TNS) has recently been demonstrated effective in the treatment of epilepsy and mood disorders. Here, we aim to determine the effects of TNS on epileptogenesis, cognitive function, and the associated hippocampal apoptosis and inflammatory responses. Rats were injected with pilocarpine to produce status epilepticus (SE) and the following chronic epilepsy. After SE induction, TNS treatment was conducted for 4 consecutive weeks. A pilocarpine re-injection was then used to induce a seizure in the epileptic rats. The hippocampal neuronal apoptosis induced by seizure was assessed by TUNEL staining and inflammatory responses by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). The spontaneous recurrent seizure (SRS) number was counted through video monitoring, and the cognitive function assessed through Morris Water Maze (MWM) test. TNS treatment attenuated the SRS attacks and improved the cognitive impairment in epileptic rats. A pilocarpine re injection resulted in less hippocampal neuronal apoptosis and reduced level of interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and microglial activation in epileptic rats with TNS treatment in comparison to the epileptic rats without TNS treatment. It is concluded that TNS treatment shortly after SE not only protected against the chronic spontaneous seizures but also improved cognitive impairments. These antiepileptic properties of TNS may be related to its attenuating effects on hippocampal apoptosis and pro-inflammatory responses. PMID- 26973058 TI - Trends in surgery and outcomes of squamous cell vulvar cancer patients over a 16 year period (1998-2013): a population-based analysis. AB - PURPOSE: The objective was to identify trends in surgery and the outcomes of squamous cell vulvar cancer in a population-based setting. METHODS: A total of 1113 patients with squamous cell vulvar cancer diagnosed between 1998 and 2013 in the catchment area of the Munich Cancer Registry (population approximately 4.6 million) were analysed. Trends in prognostic factors and treatment were examined by comparing patients diagnosed between 1998 and 2008 with those diagnosed between 2009 and 2013. Cumulative incidence was used to calculate time to local (LR) and lymph node recurrence (LNR). Survival was analysed by the Kaplan-Meier method, calculation of relative survival (RS), and a Cox model. RESULTS: The high median age at diagnosis of 75 years did not change significantly over time. In addition, no changes in the subsite of tumour or grading were noted. A decrease in patients undergoing complete vulvectomy from 27.7 to 17.8 % (p < 0.001) as well as an increase in the use of sentinel lymph node biopsy from 11.4 to 39.1 % (p < 0.001) was observed. However, time to LR (from 19 to 19 %) and time to LNR (from 9 to 9 %) as well as 5-year overall survival (from 55 to 55 %) and RS (from 66 to 63 %) were not significantly altered. After adjustment for prognostic factors, less radical locoregional surgery had no influence on survival. CONCLUSION: Less radical locoregional surgery in vulvar cancer is increasingly implemented. Locoregional recurrence and survival have not been affected by these changes and are likely accompanied by an improvement in quality of life. PMID- 26973059 TI - Impact of a gene expression classifier on the long-term management of patients with cytologically indeterminate thyroid nodules. AB - OBJECTIVES: The gene expression classifier (GEC, Afirma ) reclassifies as molecularly benign approximately one half of thyroid nodule fine-needle aspiration (FNA) biopsies with an initial indeterminate cytopathology diagnosis, facilitating clinical monitoring in lieu of diagnostic thyroid surgery. This study evaluated the long-term management patterns and thyroid surgery rates of GEC benign patients compared to a control group of cytopathology benign patients and also described the costs of thyroid surgery. METHODS: This retrospective cohort study used laboratory test results linked to payer medical claims data. Patients who underwent FNA biopsy between 1 January 2011 and 31 July 2013 were selected. GEC benign patients were matched 1:3 to cytopathology benign patients on biopsy year, gender, nodule size and age. Outcomes measured included thyroid related follow-up clinic visits, ultrasound examinations and surgeries. RESULTS: Out of 2059 patients, matched groups consisting of 201 GEC benign patients and 603 cytopathology benign patients were evaluated over an average follow-up of 20 months. The proportions of GEC benign and cytopathology benign patients that underwent thyroid surgery (11.4% versus 10.1%, p = 0.594), and received a follow up ultrasound exam (60.2% versus 61.7%, p = 0.706), respectively, were not significantly different. Average thyroid-related medical cost for the surgical episode and during 6 months following surgery were $10,432.00 (SD $8301) and $10,939.00 (SD $9656) respectively. LIMITATIONS: The study cohort included only patients whose diagnostic laboratory test results and administrative claims data were uniquely identifiable and could be linked on multiple identifiers; the rigorous matching and patient selection algorithms utilized improved the robustness and internal validity of the study. Claims were used as a proxy for clinical utilization without chart review confirmation. CONCLUSION: Patients with GEC and cytopathology benign diagnoses were managed similarly. The majority of patients in both groups did not undergo surgery and were managed with usual care, consisting of clinical follow-up and ultrasound exams. PMID- 26973060 TI - Hereditary cancer registries improve the care of patients with a genetic predisposition to cancer: contributions from the Dutch Lynch syndrome registry. AB - The Dutch Hereditary Cancer Registry was established in 1985 with the support of the Ministry of Health (VWS). The aims of the registry are: (1) to promote the identification of families with hereditary cancer, (2) to encourage the participation in surveillance programs of individuals at high risk, (3) to ensure the continuity of lifelong surveillance examinations, and (4) to promote research, in particular the improvement of surveillance protocols. During its early days the registry provided assistance with family investigations and the collection of medical data, and recommended surveillance when a family fulfilled specific diagnostic criteria. Since 2000 the registry has focused on family follow-up, and ensuring the quality of surveillance programs and appropriate clinical management. Since its founding, the registry has identified over 10,000 high-risk individuals with a diverse array of hereditary cancer syndromes. All were encouraged to participate in prevention programmes. The registry has published a number of studies that evaluated the outcome of surveillance protocols for colorectal cancer (CRC) in Lynch syndrome, as well as in familial colorectal cancer. In 2006, evaluation of the effect of registration and colonoscopic surveillance on the mortality rate associated with colorectal cancer (CRC) showed that the policy led to a substantial decrease in the mortality rate associated with CRC. Following discovery of MMR gene defects, the first predictive model that could select families for genetic testing was published by the Leiden group. In addition, over the years the registry has produced many cancer risk studies that have helped to develop appropriate surveillance protocols. Hereditary cancer registries in general, and the Lynch syndrome registry in particular, play an important role in improving the clinical management of affected families. PMID- 26973061 TI - Clinical risk assessment model for pediatric obstructive sleep apnea. AB - OBJECTIVES/HYPOTHESIS: To develop a clinical risk prediction model that identifies children with obstructive sleep apnea (OSA) in a clinical setting by examining the symptoms, physical status, and OSA-18 questionnaire results. DESIGN: Single institutional, cross-sectional study. METHODS: Children aged 2 to 18 years with symptoms of OSA were enrolled. Pediatric OSA was diagnosed through full-night polysomnography. Clinical data, namely demographics, symptoms, OSA-18 survey results, tonsil and adenoid sizes, and the weight of each child, were examined for constructing a simple point-based clinical model for OSA prediction. Variables for the risk model were selected using multivariable logistic regression analyses. RESULTS: Of the 310 participants (mean age, 7.6 +/- 3.7 years; boys, 67%), 170 (55%) experienced OSA. Modeling variables were determined using several univariate logistic regression analyses, followed by multivariable logistic regression analyses. A point-based clinical model incorporating the age, tonsil size (5 points maximum), adenoid size (5 and 20 points for age > 6 years and < 6 years, respectively), obesity (5 points for age > 6 years), and breathing pauses (5 points) was developed (area under the curve = 0.832). Moreover, the optimal cutoff points for predicting the apnea-hypopnea index of > 1 and > 5 were 10 (sensitivity, 72.9%; specificity, 65.0%) and 12 (sensitivity, 77.5%; specificity, 56.9%), respectively. Internal validation using the bootstrap method revealed no apparent overfitting problem. CONCLUSION: A novel clinical prediction model was developed for determining the risk of pediatric OSA; the model can be useful in identifying high-risk patients among those with sleep disturbances. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2403-2409, 2016. PMID- 26973062 TI - Heat urticaria: a revision of published cases with an update on classification and management. AB - Heat urticaria (HU) is a rare type of physical inducible urticaria, characterized by itchy erythema and well-demarcated weals appearing soon after heat exposure. Most cases occur in female patients aged 20-45 years. Both localized and generalized forms exist, depending on the limitation of the reaction to the skin area directly exposed to the physical stimulus or the involvement of distant sites, respectively. In most cases, HU is an immediate reaction, but delayed forms (mostly familial) have been described. HU is a long-lasting disease with overall duration at diagnosis of approximately 2 years. In about half of cases it is associated with systemic symptoms such as weakness, wheezing, headache, flushing, nausea, vomiting, diarrhoea, tachycardia, even dyspnoea or syncope. The main differential diagnosis includes cholinergic urticaria, exercise-induced anaphylaxis and solar urticaria. The diagnosis of HU is established by provocation testing, which is also helpful to evaluate the critical temperature threshold. The mean threshold temperature is about 44 degrees C. A heat desensitization programme can be an effective treatment. Nonsedating H1 antihistamines administered at licensed doses are the mainstay of symptomatic therapy in nearly 60% of patients, but full symptom relief is achieved in only a minority of them. Omalizumab has proven effective in recent case reports. PMID- 26973063 TI - Status of vaccine research and development of vaccines for leishmaniasis. AB - A number of leishmaniasis vaccine candidates are at various stages of pre clinical and clinical development. Leishmaniasis is a vector-borne neglected tropical disease (NTD) caused by a protozoan parasite of the genus Leishmania and transmitted to humans by the bite of a sand fly. Visceral leishmaniasis (VL, kala azar) is a high mortality NTD found mostly in South Asia and East Africa, while cutaneous leishmaniasis (CL) is a disfiguring NTD highly endemic in the Middle East, Central Asia, North Africa, and the Americas. Estimates attribute 50,000 annual deaths and 3.3 million disability-adjusted life years to leishmaniasis. There are only a few approved drug treatments, no prophylactic drug and no vaccine. Ideally, an effective vaccine against leishmaniasis will elicit long lasting immunity and protect broadly against VL and CL. Vaccines such as Leish F1, F2 and F3, developed at IDRI and designed based on selected Leishmania antigen epitopes, have been in clinical trials. Other groups, including the Sabin Vaccine Institute in collaboration with the National Institutes of Health are investigating recombinant Leishmania antigens in combination with selected sand fly salivary gland antigens in order to augment host immunity. To date, both VL and CL vaccines have been shown to be cost-effective in economic modeling studies. PMID- 26973064 TI - Status of vaccine research and development for Campylobacter jejuni. AB - Campylobacter jejuni is one of the leading causes of bacterial diarrhea worldwide and is associated with a number of sequelae, including Guillain-Barre Syndrome, reactive arthritis, irritable bowel syndrome and growth stunting/malnutrition. Vaccine development against C. jejuni is complicated by its antigenic diversity, a lack of small animal models, and a poor understanding of the bacterium's pathogenesis. Vaccine approaches have been limited to recombinant proteins, none of which have advanced beyond Phase I testing. Genomic analyses have revealed the presence of a polysaccharide capsule on C. jejuni. Given the success of capsule conjugate vaccines for other mucosal pathogens of global importance, efforts to evaluate this established approach for C. jejuni are also being pursued. A prototypical capsule-conjugate vaccine has demonstrated efficacy against diarrheal disease in non-human primates and is currently in Phase I testing. In addition to proof of concept studies, more data on the global prevalence of capsular types, and a better understanding of the acute and chronic consequences of C. jejuni are needed to inform investments for a globally relevant vaccine. PMID- 26973065 TI - Status of research and development of vaccines for enterovirus 71. AB - Although outbreaks of Hand, Foot, and Mouth Disease (HFMD) in young children have long been recognized worldwide, the occurrence of rare and life-threatening neurological, respiratory, and cardiac complications has propelled this common condition into the spotlight as a major public health problem in the affected countries. Various enteroviruses cause HFMD, but the severe complications have been mostly associated with enterovirus 71 (EV71). Medical treatment is supportive and measures to interrupt transmission have been challenging to implement. Preventive vaccines could have an important clinical impact, especially among children younger than 3 years old who are most susceptible to the neurological complications. Several groups in the highly affected Asia Pacific region are working towards vaccines against EV71 and some candidates have progressed to late-stage clinical trials with two vaccines recently reported to have been approved by the regulatory authorities in China. This report summarizes current issues and progress in the development of vaccines against EV71. PMID- 26973066 TI - Effect of different detoxification procedures on the residual pertussis toxin activities in vaccines. AB - Pertussis toxin (PTx) is a major virulence factor produced by Bordetella pertussis and its detoxified form is one of the major protective antigens in vaccines against whooping cough. Ideally, PTx in the vaccine should be completely detoxified while still preserving immunogenicity. However, this may not always be the case. Due to multilevel reaction mechanisms of chemical detoxification that act on different molecular sites and with different production processes, it is difficult to define a molecular characteristic of a pertussis toxoid. PTx has two functional distinctive domains: the ADP-ribosyltransferase enzymatic subunit S1 (A-protomer) and the host cell binding carbohydrate-binding subunits S2-5 (B oligomer); and in this study, we investigated the effect of different detoxification processes on these two functional activities of the residual PTx in toxoids and vaccines currently marketed worldwide using a recently developed in vitro biochemical assay system. The patho-physiological activities in these samples were also estimated using the in vivo official histamine sensitisation tests. Different types of vaccines, detoxified by formaldehyde, glutaraldehyde or by both, have different residual functional and individual baseline activities. Of the vaccines tested, PT toxoid detoxified by formaldehyde had the lowest residual PTx ADP-ribosyltransferase activity. The carbohydrate binding results detected by anti-PTx polyclonal (pAb) and anti-PTx subunits monoclonal antibodies (mAb) showed specific binding profiles for toxoids and vaccines produced from different detoxification methods. In addition, we also demonstrated that using pAb or mAb S2/3 as detection antibodies would give a better differential difference between these vaccine lots than using mAbs S1 or S4. In summary, we showed for the first time that by measuring the activities of the two functional domains of PTx, we could characterise pertussis toxoids prepared from different chemical detoxification methods and this study also highlights the potential use of this in vitro biochemical assay system for in-process control. PMID- 26973067 TI - Status of vaccine research and development of vaccines for herpes simplex virus. AB - Herpes simplex virus type-1 (HSV-1) and -2 (HSV-2) are highly prevalent global pathogens which commonly cause recurrent oral and genital ulcerations. Less common but more serious complications include meningitis, encephalitis, neonatal infection, and keratitis. HSV-2 infection is a significant driver of the HIV epidemic, increasing the risk of HIV acquisition 3 fold. As current control strategies for genital HSV-2 infection, including antiviral therapy and condom use, are only partially effective, vaccines will be required to reduce infection. Both preventive and therapeutic vaccines for HSV-2 are being pursued and are in various stages of development. We will provide an overview of efforts to develop HSV-2 vaccines, including a discussion of the clinical need for an HSV vaccine, and status of research and development with an emphasis on recent insights from trials of vaccine candidates in clinical testing. In addition, we will touch upon aspects of HSV vaccine development relevant to low and middle income countries. PMID- 26973068 TI - Status of vaccine research and development of vaccines for Nipah virus. AB - Nipah virus (NiV) is a highly pathogenic, recently emerged paramyxovirus that has been responsible for sporadic outbreaks of respiratory and encephalitic disease in Southeast Asia. High case fatality rates have also been associated with recent outbreaks in Malaysia and Bangladesh. Although over two billion people currently live in regions in which NiV is endemic or in which the Pteropus fruit bat reservoir is commonly found, there is no approved vaccine to protect against NiV disease. This report examines the feasibility and current efforts to develop a NiV vaccine including potential hurdles for technical and regulatory assessment of candidate vaccines and the likelihood for financing. PMID- 26973069 TI - Construction and preclinical evaluation of mmCT, a novel mutant cholera toxin adjuvant that can be efficiently produced in genetically manipulated Vibrio cholerae. AB - There is an urgent need for new adjuvants that are effective with mucosally administered vaccines. Cholera toxin (CT) is the most powerful known mucosal adjuvant but is much too toxic for human use. In an effort to develop a useful mucosal adjuvant we have generated a novel non-toxic mutant CT molecule that retains much of the adjuvant activity of native CT. This was achieved by making the enzymatically active A subunit (CTA) recalcitrant to the site-specific proteolytic cleavage ("nicking") required for toxicity, which was found to require mutations not only in the two residues rendering the molecule resistant to trypsin but also in neighboring sites protecting against cleavage by Vibrio cholerae proteases. This multiple-mutated CT (mmCT) adjuvant protein could be efficiently produced in and purified from the extracellular medium of CT-deleted V. cholerae. The mmCT completely lacked detectable enterotoxicity in an infant mouse model and had >1000-fold reduced cAMP inducing activity compared to native CT in a sensitive mammalian target cell system. It nonetheless proved to have potent adjuvant activity on mucosal and systemic antibody as well as cellular immune responses to mucosally co-administered antigens including oral cholera and intranasal influenza vaccines. We conclude that mmCT is an attractive novel non toxic mucosal adjuvant for enhancing immune responses to co-administered mucosal vaccines. PMID- 26973070 TI - Use of allicin as feed additive to enhance vaccination capacity of Clostridium perfringens toxoid in rabbits. AB - The present study assessed the efficacy of Clostridium perfringens (C. perfringens) toxoid and/or allicin - as feed additive - in rabbits for preventing or minimizing the severity of infection with locally isolated strain of C. perfringens type A. Serum biochemical, immunological and pathological investigations were also done. One hundred rabbits of 6 weeks of age were divided into five equal groups (G1-G5). G1 were kept as normal control. G2 was allocated for C. perfringens type A infection. G3 was vaccinated with C. perfringens toxoid at zero time and then with a booster dose at the 3rd week of the experimental period. G4 was treated with allicin 20% added to the ration (200mg/kg ration) all over the experimental period. G5 was vaccinated with C. perfringens toxoid at the zero time then with a booster dose at the 3rd week of the experiment period, and treated with allicin 20% from the zero time till the end of the experiment. At the 4th week, G2, G3, G4 and G5 were challenged orally (5 ml) and subcutaneously (2 ml) with 24h cooked meat broth containing 1 * 10(7) colony-forming units/ml of C. perfringens type A strain. Blood and tissue samples were collected from all groups po st-vaccination then post-challenge for biochemical analysis, serum neutralization test and histopathological examinations. Results revealed that rabbits treated with both allicin and toxoid vaccine demonstrated high level of antitoxin titre post-challenge, improved liver and kidney functions, and reduced morbidity and mortality rates and the severity of histopathological changes associated with challenge of rabbits with C. perfringens type A strain. In conclusion, vaccination of rabbits with C. perfringens toxoid combined with allicin 20% gave better protection, enhanced immune response and had no adverse effects on the general health conditions against C. perfringens type A infection compared to rabbits vaccinated with C. perfringens toxoid only. PMID- 26973071 TI - Replication-defective lymphocytic choriomeningitis virus vectors expressing guinea pig cytomegalovirus gB and pp65 homologs are protective against congenital guinea pig cytomegalovirus infection. AB - BACKGROUND: Congenital cytomegalovirus infection can be life-threatening and often results in significant developmental deficits and/or hearing loss. Thus, there is a critical need for an effective anti-CMV vaccine. OBJECTIVE: To determine the efficacy of replication-defective lymphocytic choriomeningitis virus (rLCMV) vectors expressing the guinea pig CMV (GPCMV) antigens, gB and pp65, in the guinea pig model of congenital CMV infection. METHODS: Female Hartley strain guinea pigs were divided into three groups: Buffer control group (n = 9), rLCMV-gB group (n = 11), and rLCMV-pp65 (n = 11). The vaccines were administered three times IM at 1.54 * 10(6)FFU per dose at 21-day intervals. At two weeks after vaccination, the female guinea pigs underwent breeding. Pregnant guinea pigs were challenged SQ at ~ 45-55 days of gestation with 1 * 10(5)PFU of GPCMV. Viremia in the dams, pup survival, weights of pups at delivery, and viral load in both dam and pup tissues were determined. RESULTS: Pup survival was significantly increased in the LCMV-gB vaccine group. There was 23% pup mortality in the gB vaccine group (p = 0.044) and 26% pup mortality in the pp65 vaccine group (p = 0.054) compared to 49% control pup mortality. The gB vaccine induced high levels of gB binding and detectable neutralizing antibodies, reduced dam viremia, and significantly reduced viral load in dam tissues compared to control dams (p < 0.03). Reduced viral load and transmission in pups born to gB vaccinated dams was observed compared to pups from pp65-vaccinated or control dams. CONCLUSIONS: The rLCMV-gB vaccine significantly improved pup survival and also increased pup weights and gestation time. The gB vaccine was also more effective at decreasing viral load in dams and pups and limiting congenital transmission. Thus, rLCMV vectors that express CMV antigens may be an effective vaccine strategy for congenital CMV infection. PMID- 26973072 TI - Status of vaccine research and development of vaccines for dengue. AB - This review on the dengue vaccine pipeline was a solicited article and drafted based on the pre-defined template for PD-VAC. PMID- 26973073 TI - Status of vaccine research and development of vaccines for tuberculosis. AB - TB is now the single pathogen that causes the greatest mortality in the world, at over 1.6 million deaths each year. The widely used the 90 year old BCG vaccine appears to have minimal impact on the worldwide incidence despite some efficacy in infants. Novel vaccine development has accelerated in the past 15 years, with 15 candidates entering human trials; two vaccines are now in large-scale efficacy studies. Modeling by three groups has consistently shown that mass vaccination that includes activity in the latently infected population, especially adolescents and young adults, will likely have the largest impact on new disease transmission. At present the field requires better validated animal models, better understanding of a correlate of immunity, new cost-effective approaches to Proof of Concept trials, and increased appreciation by the public health and scientific community for the size of the problem and the need for a vaccine. Such a vaccine is likely to also play a role in the era of increasing antibiotic resistance. Ongoing efforts and studies are working to implement these needs over the next 5 years, which will lead to an understanding that will increase the likelihood of a successful TB vaccine. PMID- 26973074 TI - Structured promotion of breastmilk expression is associated with shortened hospitalisation for very preterm infants. AB - AIM: This study assessed neonatal outcomes following implementation of a structured, practical approach for promotion of breastmilk expression in mothers of very preterm infants. METHODS: A multidisciplinary team developed a protocol that focussed on the enhancement of expression of human milk by mothers of very preterm infants. A pre- and poststudy intervention was subsequently performed. The group of infants enrolled in this time period was compared to a pre intervention group from 2010. Outcomes assessed included breastmilk expression, initiation of feeding, re-attainment of birthweight, attainment of full enteral feeding, the incidence of necrotising enterocolitis (NEC), sepsis and duration of hospitalisation. RESULTS: In total, 82 infants (39,43) were included. While there was no statistically significant difference in earlier initiation of enteral feeding with EBM (median = 2 days) nor earlier achievement of fully enteral feeding (median = 12 days), birthweight was regained earlier in the postintervention cohort (mean = 10.42 days; p = 0.038) and there was a reduced length of stay (mean = 50 days; p = 0.021). CONCLUSION: A structured, focussed, multimodal approach to enhance breastmilk production has shown potential for producing positive end outcomes, particularly, a significant reduction in duration of hospitalisation. PMID- 26973079 TI - Anaemia: Regulation of renal erythropoietin via HIF. PMID- 26973080 TI - Neandertals' large lower thorax may represent adaptation to high protein diet. AB - Humans are limited in their capacity to convert protein into energy. We present a hypothesis that a "bell" shaped thorax and a wide pelvis evolved in Neandertals, at least in part, as an adaptation to a high protein diet. A high protein diet created a need to house an enlarged liver and urinary system in a wider lower trunk. To test the hypothesis, we applied a model developed to identify points of nutritional stress. A ratio of obligatory dietary fat to total animal fat and protein sourced calories is calculated based on various known and estimated parameters. Stress is identified when the obligatory dietary fat ratio is higher than fat content ratios in available prey. The model predicts that during glacial winters, when carbohydrates weren't available, 74%-85% of Neandertals' caloric intake would have had to come from animal fat. Large animals contain around 50% fat calories, and their fat content is diminished during winter, so a significant stressful dietary fat deficit was identified by the model. This deficit could potentially be ameliorated by an increased capability to convert protein into energy. Given that high protein consumption is associated with larger liver and kidneys in animal models, it appears likely that the enlarged inferior section of the Neandertals thorax and possibly, in part, also his wide pelvis, represented an adaptation to provide encasement for those enlarged organs. Behavioral and evolutionary implications of the hypothesis are also discussed. Am J Phys Anthropol 160:367-378, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26973081 TI - Refilling of carbon nanotube cartridges for 3D nanomanufacturing. AB - Metal-filled carbon nanotubes (CNTs) are known to be used as pen-tip injectors for 3D manufacturing on the nanoscale. However, the CNT interior cannot accumulate enough material to fabricate complex metallic nanostructures. Therefore a method for refilling the CNT cartridge needs to be developed. The strategy for refilling of CNT cartridges is suggested in this study. Controlled growth of gold nanowires in the interior of isolated CNTs using a real-time manipulator installed in a transmission electron microscope is reported herein. The encapsulation process of discrete gold nanoparticles in the hollow spaces of open-ended multi-wall CNTs was evaluated in detail. The experimental results reveal that the serial loading of isolated gold nanoparticles allows the control of the length of the loaded nanowires with nanometer accuracy. Thermophoresis and the coalescence of gold nanoparticles are assumed to be the primary mechanisms responsible for gold loading into a CNT cartridge. PMID- 26973082 TI - [Not Available]. PMID- 26973083 TI - Exploiting Metallophilicity for the Assembly of Inorganic Nanocrystals and Conjugated Organic Molecules. AB - The accurate engineering of interfaces between inorganic nanocrystals and semiconducting organic molecules is currently viewed as key for further developments in critical fields such as photovoltaics and photocatalysis. In this work, a new and unconventional source of interface interaction based on metal metal bonds is presented. With this aim, an Au(I) organometallic gelator was exploited for the formation of hydrogel-like nanocomposites containing inorganic nanoparticles and conjugated organic molecules. Noteworthy, the establishment of metallophilic interactions at the interface between the two moieties greatly enhances interparticle coupling in the composites. Thus, we believe that this new hybrid system might represent a promising alternative in several fields, such as in the fabrication of improved light-harvesting devices. PMID- 26973084 TI - Intravenous immune globulin and thromboembolic adverse events: A systematic review and meta-analysis of RCTs. AB - Prior case reports and observational studies indicate that intravenous immune globulin (IVIg) products may cause thromboembolic events (TEEs), leading the FDA to require a boxed warning in 2013. The effect of IVIg treatment on the risk of serious TEEs (acute myocardial infarction, ischemic stroke, or venous thromboembolism) was assessed using adverse event data reported in randomized controlled trials (RCTs) of IVIg. RCTs of IVIg in adult patients from 1995 to 2015 were identified from Pubmed, Embase, ClinicalTrials.Gov, and two large prior reviews of IVIg's therapeutic applications. Trials at high risk of detection or reporting bias for serious adverse events were excluded. 31 RCTs with a total of 4,129 participants (2,318 IVIg-treated, 1,811 control) were eligible for quantitative synthesis. No evidence was found of increased TEE risk among IVIg treated patients compared with control patients (odds ratio = 1.10, 95% CI: 0.44, 2.88; risk difference = 0.0%, 95% CI: -0.7%, 0.7%, I(2) = 0%). No significant increase in risk was found when arterial and venous TEEs were analyzed as separate endpoints. Trial publications provided little specific information concerning the methods used to ascertain potential adverse events. Care should be taken in extrapolating the results to patients with higher baseline risks of TEE. Am. J. Hematol. 91:594-605, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26973085 TI - Inter-comparison of Seasonal Variation, Chemical Characteristics, and Source Identification of Atmospheric Fine Particles on Both Sides of the Taiwan Strait. AB - The spatiotemporal distribution and chemical composition of atmospheric fine particles in areas around the Taiwan Strait were firstly investigated. Fine particles (PM2.5) were simultaneously collected at two sites on the west-side, one site at an offshore island, and three sites on the east-side of the Taiwan Strait in 2013-2014. Field sampling results indicated that the average PM2.5 concentrations at the west-side sampling sites were generally higher than those at the east-side sampling sites. In terms of chemical composition, the most abundant water-soluble ionic species of PM2.5 were SO4(2-), NO3(-), and NH4(+), while natural crustal elements dominated the metallic content of PM2.5, and the most abundant anthropogenic metals of PM2.5 were Pb, Ni and Zn. Moreover, high OC/EC ratios of PM2.5 were commonly observed at the west-side sampling sites, which are located at the downwind of major stationary sources. Results from CMB receptor modeling showed that the major sources of PM2.5 were anthropogenic sources and secondary aerosols at the both sides, and natural sources dominated PM2.5 at the offshore site. A consistent decrease of secondary sulfate and nitrate contribution to PM2.5 suggested the transportation of aged particles from the west-side to the east-side of the Taiwan Strait. PMID- 26973086 TI - Dynamic Entangled Porous Framework for Hydrocarbon (C2-C3) Storage, CO2 Capture, and Separation. AB - Storage and separation of small (C1-C3) hydrocarbons are of great significance as these are alternative energy resources and also can be used as raw materials for many industrially important materials. Selective capture of greenhouse gas, CO2 from CH4 is important to improve the quality of natural gas. Among the available porous materials, MOFs with permanent porosity are the most suitable to serve these purposes. Herein, a two-fold entangled dynamic framework {[Zn2 (bdc)2 (bpNDI)]?4DMF}n with pore surface carved with polar functional groups and aromatic pi clouds is exploited for selective capture of CO2 , C2, and C3 hydrocarbons at ambient condition. The framework shows stepwise CO2 and C2 H2 uptake at 195 K but type I profiles are observed at 298 K. The IAST selectivity of CO2 over CH4 is the highest (598 at 298 K) among the MOFs without open metal sites reported till date. It also shows high selectivity for C2 H2 , C2 H4 , C2 H6 , and C3 H8 over CH4 at 298 K. DFT calculations reveal that aromatic pi surface and the polar imide (RNC=O) functional groups are the primary adsorption sites for adsorption. Furthermore, breakthrough column experiments showed CO2 /CH4 C2 H6 /CH4 and CO2 /N2 separation capability at ambient condition. PMID- 26973088 TI - Steroid Therapy Ameliorated Myocardial Fatty Acid Metabolism With Recovery of Complete Atrioventricular Block in Cardiac Sarcoidosis. PMID- 26973087 TI - Mean Pulmonary Artery Pressure Using Echocardiography in Chronic Thromboembolic Pulmonary Hypertension. AB - BACKGROUND: Mean pulmonary arterial pressure (MPAP) is an important pulmonary hemodynamic parameter used in the management of patients with chronic thromboembolic pulmonary hypertension (CTEPH). We compared echocardiography derived estimates of MPAP with right heart catheterization (RHC) to identify reliable noninvasive methods of estimating MPAP-derived RHC (MPAPRHC) in these patients. METHODS AND RESULTS: Echocardiography and RHC were performed in 56 patients with CTEPH (60.5+/-12.0 years; 44 females). We measured the tricuspid regurgitation (TR) pressure gradient (TRPG) using echocardiography. The mean systolic right ventricular (RV)-right atrial (RA) gradient was calculated by tracing the TR time velocity flow. Systolic and mean pulmonary artery pressures (SPAPTRand MPAPTR) estimated from TRPG and mean systolic RV-RA gradient were calculated by adding RA pressure based on the inferior vena cava. MPAPChemlawas calculated using Chemla's formula: 0.61*SPAPTR+2 mmHg. MPAPRHCand pulmonary vascular resistance were 35.9+/-11.3 mmHg and 6.6+/-3.6 Wood units, respectively. The mean difference from MPAPRHCand limits of agreement were -1.5 mmHg and -19.6 to 16.5 mmHg for MPAPTR, and -4.6 mmHg and -24.5 to 15.2 mmHg for MPAPChemla. Accuracy within 10 mmHg and 5 mmHg of MPAPRHCwas 80.4% and 46.4% for MPAPTR, and 71.4% and 48.2% for MPAPChemla, respectively. CONCLUSIONS: MPAPTRand MPAPChemlaare reliable estimates for MPAPRHCin patients with CTEPH. (Circ J 2016; 80: 1259-1264). PMID- 26973089 TI - Mixing drink and drugs: 'Underclass' politics, the recovery agenda and the partial convergence of English alcohol and drugs policy. AB - Alcohol policy and illicit drugs policy are typically presented as separate and different in academic discussion. This is understandable, to a degree, as the criminal law upholds a 'great regulatory divide' (Seddon, 2010: 56) separating the licit trade in alcohol from the illicit trade in substances classified as either class A, B or C under the Misuse of Drugs Act 1971. This paper takes a different stance. In doing so, it draws upon Berridge's (2013) argument that policies governing various psychoactive substances have been converging since the mid-twentieth century and seeks to elaborate it using recent developments relating to the control and regulation of drugs and alcohol in the broader areas of criminal justice and welfare reform. Significantly, the article examines how recent policy directions relating to both drugs and alcohol in England have, under the aegis of the 'recovery agenda', been connected to a broader behavioural politics oriented towards the actions and lifestyles of an apparently problematic subgroup of the population or 'underclass'. The paper thus concludes that, although the great regulatory divide remains intact, an underclass politics is contributing towards the greater alignment of illicit drugs and alcohol policies, especially in regards to the respective significance of abstinence (or abstinence based 'recovery'). PMID- 26973091 TI - The anti-inflammatory CASPASE-12 gene does not influence SLE phenotype in African Americans. AB - In the vast majority of human populations, the gene encoding CASPASE-12 (CASP12) has a premature termination codon that precludes the production of protein. However, approximately 20% of persons of recent African descent have a single nucleotide polymorphism (#rs497116; A->G) that turns the stop codon into one encoding Arg. The subsequent functional allele is a risk factor for sepsis as it uniquely downregulates inflammatory cytokines in African-Americans (AA). To determine if CASP12 could be protective for systemic lupus erythematosus (SLE) in AA, we genotyped AA SLE patients and controls. There was a weak association between CASP12 genotype with the absence of anti-dsDNA autoantibodies in SLE patients. No effect was seen upon serum interleukin-1 beta levels, nor was any other protective effect noted for the CASP12 genotype, whether upon association with SLE, or any of the 11 American College of Rheumatology classification criteria. CASP12 genotype thus does not influence the phenotype of SLE in AA. PMID- 26973090 TI - Unlocking the Bacterial SecY Translocon. AB - The Sec translocon performs protein secretion and membrane protein insertion at the plasma membrane of bacteria and archaea (SecYEG/beta), and the endoplasmic reticular membrane of eukaryotes (Sec61). Despite numerous structures of the complex, the mechanism underlying translocation of pre-proteins, driven by the ATPase SecA in bacteria, remains unresolved. Here we present a series of biochemical and computational analyses exploring the consequences of signal sequence binding to SecYEG. The data demonstrate that a signal sequence-induced movement of transmembrane helix 7 unlocks the translocon and that this conformational change is communicated to the cytoplasmic faces of SecY and SecE, involved in SecA binding. Our findings progress the current understanding of the dynamic action of the translocon during the translocation initiation process. The results suggest that the converging effects of the signal sequence and SecA at the cytoplasmic face of SecYEG are decisive for the intercalation and translocation of pre-protein through the SecY channel. PMID- 26973093 TI - The dynamic properties of the Hepatitis C Virus E2 envelope protein unraveled by molecular dynamics. AB - Hepatitis C Virus (HCV) is one of the most persistent human viruses. Although effective therapeutic approaches have been recently discovered, their use is limited by the elevated costs. Therefore, the development of alternative/complementary strategies is an urgent need. The E2 glycoprotein, the most immunogenic HCV protein, and its variants represent natural candidates to achieve this goal. Here we report an extensive molecular dynamics (MD) analysis of the intrinsic properties of E2. Our data provide interesting clues on the global and local intrinsic dynamic features of the protein. Present MD data clearly indicate that E2 combines a flexible structure with a network of covalent bonds. Moreover, the analysis of the two most important antigenic regions of the protein provides some interesting insights into their intrinsic structural and dynamic properties. Our data indicate that a fluctuating beta-hairpin represents a populated state by the region E2412-423. Interestingly, the analysis of the epitope E2427-446 conformation, that undergoes a remarkable rearrangement in the simulation, has significant similarities with the structure that the E2430-442 fragment adopts in complex with a neutralizing antibody. Present data also suggest that the strict conservation of Gly436 in E2 protein of different HCV genotypes is likely dictated by structural restraints. Moreover, the analysis of the E2412-423 flexibility provides insights into the mechanisms that some antibodies adopt to anchor Trp437 that is fully buried in E2. Finally, the present investigation suggests that MD simulations should systematically complement crystallographic studies on flexible proteins that are studied in combination with antibodies. PMID- 26973092 TI - Independent control of electrical and heat conduction by nanostructure designing for Si-based thermoelectric materials. AB - The high electrical and drastically-low thermal conductivities, a vital goal for high performance thermoelectric (TE) materials, are achieved in Si-based nanoarchitecture composed of Si channel layers and epitaxial Ge nanodots (NDs) with ultrahigh areal density (~10(12) cm(-2)). In this nanoarchitecture, the ultrasmall NDs and Si channel layers play roles of phonon scattering sources and electrical conduction channels, respectively. Electron conductivity in n-type nanoacrhitecture shows high values comparable to those of epitaxial Si films despite the existence of epitaxial NDs. This is because Ge NDs mainly scattered not electrons but phonons selectively, which could be attributed to the small conduction band offset at the epitaxially-grown Si/Ge interface and high transmission probability through stacking faults. These results demonstrate an independent control of thermal and electrical conduction for phonon-glass electron-crystal TE materials by nanostructure designing and the energetic and structural interface control. PMID- 26973098 TI - Metabolically Stabilized (68)Ga-NOTA-Bombesin for PET Imaging of Prostate Cancer and Influence of Protease Inhibitor Phosphoramidon. AB - Peptide receptor-based targeted molecular imaging and therapy of cancer is on the current forefront of nuclear medicine preclinical research and clinical practice. The frequent overexpression of gastrin-releasing peptide (GRP) receptors in prostate cancer stimulated the development of radiolabeled bombesin derivatives as high affinity peptide ligands for selective targeting of the GRP receptor. In this study, we have evaluated a novel (68)Ga-labeled bombesin derivative for PET imaging of prostate cancer in vivo. In addition, we were interested in testing the recently proposed "serve-and-protect" strategy to improve metabolic stability of radiolabeled peptides in vivo and to enhance tumor uptake. GRP receptor targeting peptides NOTA-BBN2 and (nat)Ga-NOTA-BBN2 demonstrated a characteristic antagonistic profile and high binding affinity toward the GRP receptor in PC3 cells (IC50 4.6-8.2 nM). Radiolabeled peptide (68)Ga-NOTA-BBN2 was obtained from NOTA-BBN2 in radiochemical yields greater than 62% (decay-corrected). Total synthesis time was 35 min, including purification using solid-phase extraction. (68)Ga-NOTA-BBN2 exhibited favorable resistance against metabolic degradation by peptidases in vivo within the investigated time frame of 60 min. Interestingly, metabolic stability was not further enhanced in the presence of protease inhibitor phosphoramidon. Dynamic PET studies showed high tumor uptake in both PC3- and LNCaP-bearing BALB/c nude mice (SUV5min > 0.6; SUV60min > 0.5). Radiotracer (68)Ga-NOTA-BBN2 represents a novel radiometal-based bombesin derivative suitable for GRP receptor targeting in PC3 and LNCaP mouse xenografts. Further increase of metabolic stability in vivo and enhanced tumor uptake were not observed upon administration of protease inhibitor phosphoramidon. This led to the conclusion that the recently proposed "serve-and-protect" strategy may not be valid for peptides exhibiting favorable intrinsic metabolic stability in vivo. PMID- 26973097 TI - The wound/burn guidelines - 5: Guidelines for the management of lower leg ulcers/varicose veins. AB - Varicose veins are treated at multiple clinical departments, but as patients often visit the dermatology clinic first due to leg ulcers, the present Guidelines for the Management of Lower Leg Ulcers/Varicose Veins were prepared in consideration of the importance of the dermatologist's role. Also, the disease concept of chronic venous insufficiency or chronic venous disorders and the CEAP classification of these disorders are presented. The objective of the present guidelines is to properly guide the diagnosis and treatment of lower leg ulcers/varicose veins by systematically presenting evidence-based recommendations that support clinical decisions. PMID- 26973099 TI - Higher body mass index in older adults is associated with lower gray matter volume: implications for memory performance. AB - Midlife obesity has been associated with increased dementia risk, yet reports on brain structure and function are mixed. We therefore assessed the effects of body mass index (BMI) on gray matter volume (GMV) and cognition in a well characterized sample of community-dwelled older adults. GMV was measured using 3T neuroimaging in 617 participants (258 women, 60-80 years, BMI 17-41 kg/m(2)). In addition, cognitive performance and various confounders including hypertension, diabetes, and apolipoprotein E genotype were assessed. A higher BMI correlated significantly with lower GMV in multiple brain regions, including (pre)frontal, temporal, insular and occipital cortex, thalamus, putamen, amygdala, and cerebellum, even after adjusting for confounders. In addition, lower GMV in prefrontal and thalamic areas partially mediated negative effects of (1) higher BMI and (2) higher age on memory performance. We here showed that a higher BMI in older adults is associated with widespread gray matter alterations, irrespective of obesity-related comorbidities and other confounders. Our results further indicate that a higher BMI induces structural alterations that translate into subtle impairments in memory performance in aging. PMID- 26973100 TI - Differential effects of amyloid-beta 1-40 and 1-42 fibrils on 5-HT1A serotonin receptors in rat brain. AB - Evidence accumulates suggesting a complex interplay between neurodegenerative processes and serotonergic neurotransmission. We have previously reported an overexpression of serotonin 5-HT1A receptors (5-HT(1A)R) after intrahippocampal injections of amyloid-beta 1-40 (Abeta40) fibrils in rats. This serotonergic reactivity paralleled results from clinical positron emission tomography studies with [(18)F]MPPF revealing an overexpression of 5-HT(1A)R in the hippocampus of patients with mild cognitive impairment. Because Abeta40 and Abeta42 isoforms are found in amyloid plaques, we tested in this study the hypothesis of a peptide- and region-specific 5-HT(1A)R reactivity by injecting them, separately, into the hippocampus or striatum of rats. [(18)F]MPPF in vitro autoradiography revealed that Abeta40 fibrils, but not Abeta42, were triggering an overexpression of 5 HT(1A)R in the hippocampus and striatum of rat brains after 7 days. Immunohistochemical approaches targeting neuronal precursor cells, mature neurons, and astrocytes showed that Abeta42 fibrils caused more pathophysiological damages than Abeta40 fibrils. The mechanisms of Abeta40 fibrils-induced 5-HT(1A)R expression remains unknown, but hypotheses including neurogenesis, glial expression, and axonal sprouting are discussed. PMID- 26973102 TI - Loss of exosomes in progranulin-associated frontotemporal dementia. AB - Many cells of the nervous system have been shown to release exosomes, a subclass of secreted vesicles of endosomal origin capable of transferring biomolecules among cells: this transfer modality represents a novel physiological form of intercellular communication between neural cells. Herein, we demonstrated that progranulin (PGRN), a protein targeted to the classical secretory pathway, is also secreted in association with exosomes by human primary fibroblasts. Moreover, we demonstrated that null mutations in the progranulin gene (GRN), a major cause of frontotemporal dementia, strongly reduce the number of released exosomes and alter their composition. In vitro GRN silencing in SHSY-5Y cells confirmed a role of PGRN in the control of exosome release. It is believed that depletion of PGRN in the brain might cause neurodegeneration in GRN-associated frontotemporal dementia. We demonstrated that, along with shortage of the circulating PGRN, GRN null mutations alter intercellular communication. Thus, a better understanding of the role played by exosomes in GRN-associated neurodegeneration is crucial for the development of novel therapies for these diseases. PMID- 26973103 TI - Estrogen receptors alpha mediates postischemic inflammation in chronically estrogen-deprived mice. AB - Estrogens are known to exert neuroprotective and immuneomodulatory effects after stroke. However, at present, little is known about the role of estrogens and its receptors in postischemic inflammation after menopause. Here, we provide important in vivo evidence of a distinct shift in microglial phenotypes in the model of postmenopause brain. Using a model-system for live imaging of microglial activation in the context of chronic estrogen- and ERalpha-deficiency associated with aging, we observed a marked deregulation of the TLR2 signals and/or microglial activation in ovariectomized and/or ERalpha knockout mice. Further analysis revealed a 5.7-fold increase in IL-6, a 4.7-fold increase in phospho Stat3 levels suggesting an overactivation of JAK/STAT3 pathway and significantly larger infarction in ERalpha knockouts chronically deprived of estrogen. Taken together, our results suggest that in the experimental model of menopause and/or aging, ERalpha mediates innate immune responses and/or microglial activation, and ischemia-induced production of IL-6. Based on our results, we propose that the loss of functional ERalpha may lead to deregulation of postischemic inflammatory responses and increased vulnerability to ischemic injury in aging female brains. PMID- 26973101 TI - The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice. AB - APP/PS1 double transgenic mice expressing human mutant amyloid precursor protein (APP) and presenilin-1 (PS1) demonstrate robust brain amyloid beta (Abeta) peptide containing plaque deposition, increased markers of oxidative stress, behavioral dysfunction, and proinflammatory gliosis. On the other hand, lack of growth hormone, prolactin, and thyroid-stimulating hormone due to a recessive mutation in the Prop 1 gene (Prop1df) in Ames dwarf mice results in a phenotype characterized by potentiated antioxidant mechanisms, improved learning and memory, and significantly increased longevity in homozygous mice. Based on this, we hypothesized that a similar hormone deficiency might attenuate disease changes in the brains of APP/PS1 mice. To test this idea, APP/PS1 mice were crossed to the Ames dwarf mouse line. APP/PS1, wild-type, df/+, df/df, df/+/APP/PS1, and df/df/APP/PS1 mice were compared at 6 months of age through behavioral testing and assessing amyloid burden, reactive gliosis, and brain cytokine levels. df/df mice demonstrated lower brain growth hormone and insulin-like growth factor 1 concentrations. This correlated with decreased astrogliosis and microgliosis in the df/df/APP/PS1 mice and, surprisingly, reduced Abeta plaque deposition and Abeta 1-40 and Abeta 1-42 concentrations. The df/df/APP/PS1 mice also demonstrated significantly elevated brain levels of multiple cytokines in spite of the attenuated gliosis. These data indicate that the df/df/APP/PS1 line is a unique resource in which to study aging and resistance to disease and suggest that the affected pituitary hormones may have a role in regulating disease progression. PMID- 26973106 TI - Beta-hydroxy-beta-methylbutyrate ameliorates aging effects in the dendritic tree of pyramidal neurons in the medial prefrontal cortex of both male and female rats. AB - Beta-hydroxy-beta-methylbutyrate (HMB), a supplement commonly used to maintain muscle in elderly and clinical populations, has been unexplored in the aging brain. In both healthy aging humans and rat models, there are cognitive deficits associated with age-related dendritic shrinkage within the prefrontal cortex. The present study explores the effects of relatively short- and long-term (7 and 31 weeks) oral HMB supplementation starting at 12 months of age in male and female rats on the dendritic tree of layer 5 pyramidal neurons in the medial prefrontal cortex. Since female rats continue to secrete ovarian hormones after reaching reproductive senescence, middle-aged female rats were ovariectomized to model humans. As expected, there were fewer spines and a retraction of dendritic material in the apical and basilar trees in old age controls of both sexes compared with their middle-aged counterparts. However, these losses did not occur in the HMB-treated rats in either dendrites or the total number of dendritic spines. Thus, HMB forestalled the effects of aging on the dendritic tree of this population of neurons. PMID- 26973104 TI - Maternal dementia age at onset in relation to amyloid burden in non-demented elderly offspring. AB - Family history (FH) of dementia is a major risk factor for Alzheimer's disease, particularly when the FH is maternal and when the age of dementia onset (AO) is younger. This study tested whether brain amyloid-beta deposition, measured in vivo with (11)C-Pittsburgh compound B (PiB), was associated with parental dementia and/or younger parental AO. Detailed FH and positron emission tomography (PiB) data were acquired in 147 nondemented aging individuals (mean age 75 +/- 8). No participant had both positive maternal and paternal FH. A series of analyses revealed that those with maternal, but not paternal, FH had greater levels of PiB retention in a global cortical region than those without FH. PiB retention in maternal FH was not significantly greater than paternal FH. Younger maternal dementia AO was related to greater PiB retention in offspring, whereas younger paternal dementia AO was not. Overall, results suggest that not only is amyloid-beta burden greater in individuals with maternal FH, but also that the burden is greater in association with younger maternal AO. PMID- 26973107 TI - Age-associated differences on structural brain MRI in nondemented individuals from 71 to 103 years. AB - Successful brain aging in the oldest old (>=90 years) is underexplored. This study examined cross-sectional brain morphological differences from 8th to 11th decades of life in nondemented individuals by high-resolution magnetic resonance imaging. Two hundred seventy-seven nondemented community-dwelling participants (71-103 years) from Sydney Memory and Ageing Study and Sydney Centenarian Study comprised the sample, including a subsample of 160 cognitively high-functioning elders. Relationships between age and magnetic resonance imaging-derived measurements were studied using general linear models; and structural profiles of the >=90 years were delineated. In full sample and the subsample, significant linear negative relationship of gray matter with age was found, with the greatest age effects in the medial temporal lobe and parietal and occipital cortices. This pattern was further confirmed by comparing directly the >=90 years to the 71-89 years groups. Significant quadratic age effects on total white matter and white matter hyperintensities were observed. Our study demonstrated heterogeneous differences across brain regions between the oldest old and young old, with an emphasis on hippocampus, temporoposterior cortex, and white matter hyperintensities. PMID- 26973105 TI - The effect of increased genetic risk for Alzheimer's disease on hippocampal and amygdala volume. AB - Reduction in hippocampal and amygdala volume measured via structural magnetic resonance imaging is an early marker of Alzheimer's disease (AD). Whether genetic risk factors for AD exert an effect on these subcortical structures independent of clinical status has not been fully investigated. We examine whether increased genetic risk for AD influences hippocampal and amygdala volumes in case-control and population cohorts at different ages, in 1674 older (aged >53 years; 17% AD, 39% mild cognitive impairment [MCI]) and 467 young (16-30 years) adults. An AD polygenic risk score combining common risk variants excluding apolipoprotein E (APOE), and a single nucleotide polymorphism in TREM2, were both associated with reduced hippocampal volume in healthy older adults and those with MCI. APOE epsilon4 was associated with hippocampal and amygdala volume in those with AD and MCI but was not associated in healthy older adults. No associations were found in young adults. Genetic risk for AD affects the hippocampus before the clinical symptoms of AD, reflecting a neurodegenerative effect before clinical manifestations in older adults. PMID- 26973109 TI - Atrophy of hippocampal subfields and adjacent extrahippocampal structures in dementia with Lewy bodies and Alzheimer's disease. AB - The hippocampus and adjacent extrahippocampal structures are organized in distinct and specialized regions which process heterogeneous functions, including memory, and visuospatial functions. Specific alterations of the different hippocampal subfields and adjacent extrahippocampal structures could differently contribute to the pathophysiology of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Based on visual symptoms which characterize DLB patients, the hippocampal subfields and the adjacent extrahippocampal structures which are mainly involved in the visual functions could be impaired in DLB and preserved in AD. To test this hypothesis, we performed structural magnetic resonance imaging on 19 DLB, 15 AD, and 19 age-matched healthy controls. FreeSurfer's pipelines were used to perform parcellation of hippocampus and adjacent extrahippocampal structures and to assess the structural changes within each region. The cornu ammonis and subiculum were bilaterally damaged in AD and preserved in DLB. The perirhinal cortex and parahippocampus were damaged in DLB but not in AD. Our findings demonstrate that the hippocampal subfields and adjacent extrahippocampal structures were differently altered in AD and DLB. Particularly, DLB patients showed a more focused alteration of the extrahippocampal structures linked to visual functions. PMID- 26973108 TI - Dopamine agonists rescue Abeta-induced LTP impairment by Src-family tyrosine kinases. AB - Soluble forms of oligomeric amyloid beta (AbetaO) are involved in the loss of synaptic plasticity and memory, especially in early phases of Alzheimer's disease. Stimulation of dopamine D1/D5 receptors (D1R/D5R) is known to increase surface expression of synaptic alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionate subtype glutamate and N-methyl-D-aspartate subtype glutamate receptors and facilitates the induction of the late phase of long-term potentiation (LTP), probably via a related mechanism. In this study, we show that the D1/D5R agonist SKF38393 protects LTP of hippocampal CA1 synapses from the deleterious action of oligomeric amyloid beta. Unexpectedly, the D1R/D5R-mediated recovery of LTP is independent of protein kinase A or phospholipase C pathways. Instead, we found that the inhibition of Src-family tyrosine kinases completely abolished the protective effects of D1R/D5R stimulation in a cellular model of learning and memory. PMID- 26973110 TI - Enhanced Ccl2-Ccr2 signaling drives more severe choroidal neovascularization with aging. AB - The impact of many inflammatory diseases is influenced by age-related changes in the activation of resident and circulating myeloid cells. In the eye, a major sight-threatening consequence of age-related macular degeneration is the development of severe choroidal neovascularization (CNV). To identify the molecular pathways and myeloid cell populations involved in this increased neovascular response, we characterized the immune status of murine choroid and retina during aging and in the context of experimental CNV. In the choroid, but not in the retina, advancing age is associated with proinflammatory upregulation of CCL2-CCR2 signaling. Genetic excision of CCL2 diminishes age-related inflammatory changes in the choroid, with reduced recruitment of proinflammatory myeloid cells and attenuation of CNV. These findings indicate that CCL2-driven recruitment of myeloid cells contributes to increased severity of CNV with age. Similar mechanisms may be involved in other age-related inflammatory diseases. PMID- 26973111 TI - Rapid eye movement sleep disruption and sleep fragmentation are associated with increased orexin-A cerebrospinal-fluid levels in mild cognitive impairment due to Alzheimer's disease. AB - The orexin system has been investigated in patients affected by mild cognitive impairment (MCI) due to Alzheimer's disease (AD) by measuring orexin-A concentrations in the cerebrospinal fluid (CSF), and correlated to subjective and objective sleep parameters, quantified by questionnaires and polysomnography, respectively. Twenty drug-naive patients with MCI due to AD were studied and compared with a population of 26 age and/or sex matched controls, divided into subgroups on the basis of the Pittsburgh Sleep Quality Index (PSQI) score. Increased CSF-orexin levels were detected in patients with MCI due to AD in comparison with controls (p < 0.05). In particular, CSF-orexin concentrations were higher in MCI patients suffering from sleep complaints (PSQI >=5, n = 10) compared with MCI patients with a regular sleep-wake cycle (PSQI <5, n = 10, p < 0.001) and compared with both control groups (with sleep complaints, PSQI >=5, n = 11, p < 0.001; without sleep complaints, PSQI <5, n = 15, p < 0.001). Moreover, REM sleep was reduced in MCI patients compared with controls (p < 0.01), and had a negative correlation coupled with a reciprocal influence at the multiple regression analysis with CSF-orexin levels (R = -0.65; beta = -8.90). REM sleep disruption and sleep fragmentation are related to higher CSF-orexin levels in patients with MCI due to AD, thus suggesting that the orexin system may be involved even in the earliest stages of AD, resulting in prolonged sleep latency, reduced sleep efficiency, and REM sleep impairment. PMID- 26973112 TI - Interactive effects of age and gender on EEG power and coherence during a short term memory task in middle-aged adults. AB - The effects of age and gender on electroencephalographic (EEG) activity during a short-term memory task were assessed in a group of 40 healthy participants aged 22-63 years. Multi-channel EEG was recorded in 20 younger (mean = 24.65-year-old, 10 male) and 20 middle-aged participants (mean = 46.40-year-old, 10 male) during performance of a Sternberg task. EEG power and coherence measures were analyzed in different frequency bands. Significant interactions emerged between age and gender in memory performance and concomitant EEG parameters, suggesting that the aging process differentially influences men and women. Middle-aged women showed a lower short-term memory performance compared to young women, which was accompanied by decreasing delta and theta power and increasing brain connectivity with age in women. In contrast, men showed no age-related decline in short-term memory performance and no changes in EEG parameters. These results provide first evidence of age-related alterations in EEG activity underlying memory processes, which were already evident in the middle years of life in women but not in men. PMID- 26973114 TI - Object individuation and compensation in healthy aging. AB - Theories on neural compensation suggest that aged participants overactivate the brain areas involved in a task to compensate for the age-related decline. In this electrophysiological study, we investigated the temporal locus of neural overactivation in aging during multiple target processing. We measured performance and three event-related brain potential responses (N1, N2pc, and contralateral delay activity) in young and old adults, while they enumerated a variable number (1-4) of targets presented in an easy (distractor absent) or difficult (distractor present) condition. The main results indicated that although N2pc (~200 ms) increased in amplitude in the distractor-present condition in the young group, no modulation occurred for the old group. Old participants were associated with larger N2pc amplitudes than young participants in the distractor-absent condition, where both groups had comparable levels of accuracy. These effects were not present for N1 and contralateral delay activity. Overall, the data suggest that in enumeration, aging is associated with compensatory effects that rely on the selection mechanism responsible for target individuation. PMID- 26973113 TI - Differences between chronological and brain age are related to education and self reported physical activity. AB - This study investigated the relationship between education and physical activity and the difference between a physiological prediction of age and chronological age (CA). Cortical and subcortical gray matter regional volumes were calculated from 331 healthy adults (range: 19-79 years). Multivariate analyses identified a covariance pattern of brain volumes best predicting CA (R(2) = 47%). Individual expression of this brain pattern served as a physiologic measure of brain age (BA). The difference between CA and BA was predicted by education and self-report measures of physical activity. Education and the daily number of flights of stairs climbed (FOSC) were the only 2 significant predictors of decreased BA. Effect sizes demonstrated that BA decreased by 0.95 years for each year of education and by 0.58 years for 1 additional FOSC daily. Effects of education and FOSC on regional brain volume were largely driven by temporal and subcortical volumes. These results demonstrate that higher levels of education and daily FOSC are related to larger brain volume than predicted by CA which supports the utility of regional gray matter volume as a biomarker of healthy brain aging. PMID- 26973115 TI - Identifying postmenopausal women at risk for cognitive decline within a healthy cohort using a panel of clinical metabolic indicators: potential for detecting an at-Alzheimer's risk metabolic phenotype. AB - Detecting at-risk individuals within a healthy population is critical for preventing or delaying Alzheimer's disease. Systems biology integration of brain and body metabolism enables peripheral metabolic biomarkers to serve as reporters of brain bioenergetic status. Using clinical metabolic data derived from healthy postmenopausal women in the Early versus Late Intervention Trial with Estradiol (ELITE), we conducted principal components and k-means clustering analyses of 9 biomarkers to define metabolic phenotypes. Metabolic clusters were correlated with cognitive performance and analyzed for change over 5 years. Metabolic biomarkers at baseline generated 3 clusters, representing women with healthy, high blood pressure, and poor metabolic phenotypes. Compared with healthy women, poor metabolic women had significantly lower executive, global and memory cognitive performance. Hormone therapy provided metabolic benefit to women in high blood pressure and poor metabolic phenotypes. This panel of well-established clinical peripheral biomarkers represents an initial step toward developing an affordable, rapidly deployable, and clinically relevant strategy to detect an at risk phenotype of late-onset Alzheimer's disease. PMID- 26973116 TI - Impact of lifestyle dimensions on brain pathology and cognition. AB - Single lifestyle factors affect brain biomarkers and cognition. Here, we addressed the covariance of various lifestyle elements and investigated their impact on positron emission tomography-based beta-amyloid (Abeta), hippocampal volume, and cognitive function in aged controls. Lower Abeta burden was associated with a lifestyle comprising high cognitive engagement and low vascular risk, particularly in apolipoprotein E epsilon4 carriers. Although cognitive function was related to high lifetime cognitive engagement and low vascular risk, Abeta load had no relation to current cognitive function. The covariance between high adult socioeconomic status, high education, and low smoking prevalence predicted better cognitive function and this was mediated by larger hippocampal volume. Our data show that lifestyle is a complex construct composed of associated variables, some of which reflect factors operating over the life span and others which may be developmental. These factors affect brain health via different pathways, which may reinforce one another. Our findings moreover support the importance of an intellectually enriched lifestyle accompanied by vascular health on both cognition and presumed cerebral mediators of cognitive function. PMID- 26973117 TI - beta-amyloid, hippocampal atrophy and their relation to longitudinal brain change in cognitively normal individuals. AB - Recent literature has examined baseline hippocampal volume and extent of brain amyloidosis to test potential synergistic effects on worsening cognition and extent of brain atrophy. Use of hippocampal volume in prior studies was based on the notion that limbic circuit degeneration is an early manifestation of the Alzheimer's Disease (AD) pathophysiology. To clarify these interactions early in the AD process, we tested the effects of amyloid and baseline normalized hippocampal volume on longitudinal brain atrophy rates in a group of cognitively normal individuals. Results showed that the combination of elevated beta-amyloid and baseline hippocampal atrophy is associated with increased rates specific to the limbic circuit and splenium. Importantly, this atrophy pattern emerged from a voxelwise analysis, corroborated by regression models over region of interests in native space. The results are broadly consistent with previous studies of the effects of amyloid and baseline hippocampal atrophy in normals, while pointing to accelerated atrophy of AD-vulnerable regions detectable at the preclinical stage. PMID- 26973119 TI - Whole tumor cell vaccines for glioma immunotherapy. PMID- 26973118 TI - Rosiglitazone activation of PPARgamma-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta-induced mitochondrial dysfunction and oxidative stress. AB - Neuronal cell impairment, such as that induced by amyloid-beta (Abeta) protein, is a process with limited therapeutic interventions and often leads to long-term neurodegeneration common in disorders such as Alzheimer's disease. Interestingly, peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand activated nuclear receptor whose ligands control many physiological and pathologic processes, and may be neuroprotective. We hypothesized that rosiglitazone, a PPARgamma agonist, would prevent Abeta-mediated effects in human neural stem cells (hNSCs). Here, we show that rosiglitazone reverses, via PPARgamma-dependent downregulation of caspase 3 and 9 activity, the Abeta mediated decreases in hNSC cell viability. In addition, Abeta decreases hNSC messenger RNA (mRNA) levels of 2 neuroprotective factors (Bcl-2 and CREB), but co treatment with rosiglitazone significantly rescues these effects. Rosiglitazone co-treated hNSCs also showed significantly increased mitochondrial function (reflected by levels of adenosine triphosphate and Mit mass), and PPARgamma dependent mRNA upregulation of PGC1alpha and mitochondrial genes (nuclear respiratory factor-1 and Tfam). Furthermore, hNSCs co-treated with rosiglitazone were significantly rescued from Abeta-induced oxidative stress and correlates with reversal of the Abeta-induced mRNA decrease in oxidative defense genes (superoxide dismutase 1, superoxide dismutase 2, and glutathione peroxidase 1). Taken together, these novel findings show that rosiglitazone-induced activation of PPARgamma-dependent signaling rescues Abeta-mediated toxicity in hNSCs and provide evidence supporting a neuroprotective role for PPARgamma activating drugs in Abeta-related diseases such as Alzheimer's disease. PMID- 26973121 TI - 24th European Academy of Dermatology and Venereology. AB - The 24th European Academy of Dermatology and Venereology was held in Copenhagen, Denmark, from 7-11 October 2015. It has become Europe's biggest meeting of its kind with roughly 10,000 participants, approximately 3000 abstracts and about 180 exhibitors from all over the world. The organizers offer a venue for the latest cutting edge research and newest developments. Thus, their goal is to foster progress in clinical care and promote scientific excellence related to dermatovenereology for the benefit of patients with skin diseases. PMID- 26973120 TI - Cancer vaccines for hepatocellular carcinoma: future directions. PMID- 26973122 TI - Grass pollen immunotherapy: where are we now. AB - During allergen immunotherapy (AIT), the allergic patient is exposed to the disease-inducing antigens (allergens) in order to induce clinical and immunological tolerance and obtain disease modification. Large trials of grass AIT with highly standardized subcutaneous and sublingual tablet vaccines have been conducted to document the clinical effect. Induction of blocking antibodies as well as changes in the balance between T-cell phenotypes, including induction of regulatory T-cell subtypes, have been demonstrated for both treatment types. These observations increase the understanding of the immunological mechanism behind the clinical effect and may make it possible to use the immunological changes as biomarkers of clinical effect. The current review describes the recent mechanistic findings for subcutaneous immunotherapy and sublingual immunotherapy/tablet treatment and discusses how the observed immunological changes translate into a scientific foundation for the observed clinical effects of grass pollen immunotherapy and lead to new treatment strategies for grass AIT. PMID- 26973123 TI - Cytomegalovirus-targeted immunotherapy and glioblastoma: hype or hope? AB - Malignant gliomas, including glioblastoma (GBM), are the most common primary brain tumors. Despite extensive research only modest gains have been made in long term survival. Standard of care involves maximizing safe surgical resection followed by concurrent chemoradiation with temozolomide. Immunotherapy for GBM is an area of intense research in recent years. New immunotherapies, although promising, have not been integrated into standard practice. Human cytomegalovirus (HCMV) is a DNA virus of the family Herpesviridae. Human seroprevalence is approximately 80%, and in most cases, is associated with asymptomatic infection. HCMV may be an important agent in the initiation, promotion and/or progression of tumorigenesis. Regardless of a possible etiologic role in GBM, interest has centered on exploiting this association for development of immunomodulatory therapies. PMID- 26973124 TI - The antileukemic potential of natural killer cells. AB - The antileukemic potential of natural killer (NK) cells has over the years raised considerable interest and new immune-based treatment protocols characterized by the infusion of freshly isolated or ex vivo activated and expanded effectors have been designed. Several aspects still need to be addressed, including the optimal timing of NK infusion during the course of the disease, the best preparative regimen, the origin of NK cells and the possible need of ex vivo NK cell manipulation before the infusion. The aims of this review are to discuss the experimental and clinical data available on the role played by NK cells for leukemia patients and to revise the different good manufacturing practice protocols for ex vivo manipulation of these effector cells. PMID- 26973125 TI - Antithymocyte globulin in allogeneic hematopoietic cell transplantation: benefits and limitations. AB - Significant advances have been made in allogeneic hematopoietic cell transplantation by reducing toxicities and optimizing its efficacy. Antithymocyte globulin (ATG) is an important in vivo T-cell depletion strategy, which reduces the risk of graft-versus-host disease in HLA-matched or -mismatched donor allografting. ATG effectively targets alloreactive T cells at the expense of potentially increasing the risk of post-hematopoietic cell transplantation infections and delayed immune reconstitution. We summarize the targets, mechanisms, various preparations of ATG, the growing role of ATG in prevention of graft-versus-host disease in various transplant modalities as well as emerging data on pharmacokinetic modeling for individualized ATG dosing. Further research is needed to optimize the ATG administration while minimizing the toxicities. PMID- 26973127 TI - Hepatitis B immunopathogenesis and immunotherapy. AB - Worldwide there are over 248 million chronic carriers of HBV of whom about a third eventually develop severe HBV-related complications. Due to the major limitations of current therapeutic approaches, the development of more effective strategies to improve therapeutic outcomes in chronic hepatitis B (CHB) patients seems crucial. Immune activation plays a critical role in spontaneous viral control; therefore, new modalities based on stimulation of the innate and adaptive immune responses could result in the resolution of infection and are promising approaches. Here, we summarize the HBV immunopathogenesis, and discuss the encouraging results obtained from the promising immune-based innovations, such as therapeutic vaccination, cytokine therapy, cell-based therapies and blocking inhibitory receptors, as current and future immunotherapeutic interventions. PMID- 26973128 TI - The role of PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: a network meta-analysis. AB - BACKGROUND: Tumor programmed death ligand one (PD-L1) expression has been studied in several trials in non-small-cell lung cancer. METHODS: We assessed the potential role of PD-L1 expression according to Cochrane Collaboration's Guidelines. RESULTS: 13 studies with 1979 patients were included. Among 915 PD-L1 negative patients this rate was 13% (RR 2.08; 95% CI: 1.49-2.91; p < 0.01). The response rate has increased concurrent to the PD-L1 expression (Pearson's correlation, r = 0.43). PD-L1 expression was also related to better 24-weeks progression-free rate (RR 0.79; 95% CI: 0.71-0.89) and a trend toward better 1 year overall survival rate (RR 0.96; 95% CI: 0.87-1.06). CONCLUSION: Taking this data in account, PD-L1 overexpression could not be currently considered a robust biomarker to tailor the immune checkpoint inhibitors treatment. PMID- 26973126 TI - Mesothelin as a target for chimeric antigen receptor-modified T cells as anticancer therapy. AB - Mesothelin is a promising target for immune-based therapy, specifically for mesothelioma and pancreatic and ovarian cancers that have high levels of mesothelin expression. Many preclinical and clinical studies that target tumors with high mesothelin expression with antibodies, immunotoxins, antibody-drug conjugates and vaccines have shown the potential of mesothelin as a target. Studies of T cells genetically modified with chimeric antigen receptors (CAR) report significant efficacy in hematologic malignancies, and antimesothelin CAR T cells are currently being investigated in clinical studies. Here we outline the rationale for using mesothelin as a target for immunotherapy, review the clinical and preclinical studies evaluating mesothelin-directed therapies and explore the promise of CAR T cells directed against mesothelin for immunotherapy in the future. PMID- 26973129 TI - Approach to Statin Use in 2016: an Update. AB - Statin therapy is the pharmacologic foundation of cholesterol treatment and the most common class of medication prescribed in the USA. The clinical benefits of statins and their favorable side effect profile have been well established for atherosclerotic cardiovascular disease prevention. With new guidelines on the treatment of dyslipidemia being published in the last several years, a greater percentage of the population now appears eligible for statin therapy. In this review, we discuss the updated American College of Cardiology/American Heart Association and National Lipid Association guidelines on lipid treatment, both of which endorse the importance of shared decision making and patient-centered care. We discuss factors beyond traditional risk factors that may be useful in refining risk-based decision making. Furthermore, we summarize the available statins, their potential benefits and limitations, and recent evidence on safety and tolerability. PMID- 26973131 TI - Successful treatment of recurrent Henoch-Schonlein purpura nephritis in a renal allograft with tonsillectomy and steroid pulse therapy. AB - We report a case of recurrent Henoch-Schonlein purpura nephritis (HSPN) treated successfully with a tonsillectomy and steroid pulse therapy in a kidney transplant patient. A 29-year-old woman was admitted to our hospital for an episode biopsy; she had a serum creatinine (S-Cr) of 1.0 mg/dL and 1.34 g/day proteinuria 26 months after kidney transplantation. Histological examination revealed increased amounts of mesangial matrix and mesangial hypercellularity with IgA deposition. Of note, one glomerulus showed focal endocapillary proliferation and tuft necrosis. We diagnosed active recurrent HSPN. Considering both the histological findings and refractory clinical course of the native kidney, she was treated for 3 consecutive days with steroid pulse therapy and a tonsillectomy. The patient's proteinuria decreased gradually to less than 150 mg/day 6 months later. A second biopsy 6 years after kidney transplantation showed an excellent response to treatment and revealed a marked reduction in both the mesangial matrix and mesangial hypercellularity, with trace IgA deposition. We conclude that a tonsillectomy and steroid pulse therapy appeared to be useful in this patient with active recurrent HSPN. This paper is the first to report a tonsillectomy and steroid pulse therapy as a therapeutic option for active recurrent HSPN. Further studies are needed to elucidate the efficacy and mechanisms of tonsillectomy with recurrent HSPN in kidney transplant patients. PMID- 26973130 TI - Obesity and Cardiovascular Disease: a Risk Factor or a Risk Marker? AB - In the USA, 69 % of adults are either overweight or obese and 35 % are obese. Obesity is associated with an increased incidence of various cardiovascular disorders. Obesity is a risk marker for cardiovascular disease, in that it is associated with a much higher prevalence of comorbidities such as diabetes, hypertension, and metabolic syndrome, which then increase the risk for cardiovascular disease. However, in addition, obesity may also be an independent risk factor for the development of cardiovascular disease. Furthermore, although obesity has been shown to be an independent risk factor for several cardiovascular diseases, it is often associated with improved survival once the diagnosis of the cardiovascular disease has been made, leading to the term "obesity paradox." Several pathways linking obesity and cardiovascular disease have been described. In this review, we attempt to summarize the complex relationship between obesity and cardiovascular disorders, in particular coronary atherosclerosis, heart failure, and atrial fibrillation. PMID- 26973132 TI - Association of season of birth with DNA methylation and allergic disease. AB - BACKGROUND: Season of birth influences allergy risk; however, the biological mechanisms underlying this observation are unclear. The environment affects DNA methylation, with potentially long-lasting effects on gene expression and disease. This study examined whether DNA methylation could underlie the association between season of birth and allergy. METHODS: In a subset of 18-year old participants from the Isle of Wight (IoW) birth cohort (n = 367), the risks of birth season on allergic outcomes were estimated. Whole blood epigenome-wide DNA methylation was measured, and season-associated CpGs detected using a training-and-testing-based technique. Validation method examined the 8-year-old Prevention and Incidence of Asthma and Mite Allergy (PIAMA) cohort. The relationships between DNA methylation, season of birth and allergy were examined. CpGs were analysed in IoW third-generation cohort newborns. RESULTS: Autumn birth increased risk of eczema, relative to spring birth. Methylation at 92 CpGs showed association with season of birth in the epigenome-wide association study. In validation, significantly more CpGs had the same directionality than expected by chance, and four were statistically significant. Season-associated methylation was enriched among networks relating to development, the cell cycle and apoptosis. Twenty CpGs were nominally associated with allergic outcomes. Two CpGs were marginally on the causal pathway to allergy. Season-associated methylation was largely absent in newborns, suggesting it arises post-natally. CONCLUSIONS: This study demonstrates that DNA methylation in adulthood is associated with season of birth, supporting the hypothesis that DNA methylation could mechanistically underlie the effect of season of birth on allergy, although other mechanisms are also likely to be involved. PMID- 26973134 TI - Brain response to images of food varying in energy density is associated with body composition in 7- to 10-year-old children: Results of an exploratory study. AB - Energy balance is regulated by a multifaceted system of physiological signals that influence energy intake and expenditure. Therefore, variability in the brain's response to food may be partially explained by differences in levels of metabolically active tissues throughout the body, including fat-free mass (FFM) and fat mass (FM). The purpose of this study was to test the hypothesis that children's body composition would be related to their brain response to food images varying in energy density (ED), a measure of energy content per weight of food. Functional magnetic resonance imaging (fMRI) was used to measure brain response to High (>1.5kcal/g) and Low (<1.5kcal/g) ED food images, and Control images, in 36 children ages 7-10years. Body composition was measured using bioelectrical impedance analysis. Multi-subject random effects general linear model (GLM) and two-factor repeated measures analysis of variance (ANOVA) were used to test for main effects of ED (High ED vs. Low ED) in a priori defined brain regions of interest previously implicated in energy homeostasis and reward processing. Pearson's correlations were then calculated between activation in these regions for various contrasts (High ED-Low ED, High ED-Control, Low ED Control) and child body composition (FFM index, FM index, % body fat). Relative to Low ED foods, High ED foods elicited greater BOLD activation in the left thalamus. In the right substantia nigra, BOLD activation for the contrast of High ED-Low ED foods was positively associated with child FFM. There were no significant results for the High ED-Control or Low ED-Control contrasts. Our findings support literature on FFM as an appetitive driver, such that greater amounts of lean mass were associated with greater activation for High ED foods in an area of the brain associated with dopamine signaling and reward (substantia nigra). These results confirm our hypothesis that brain response to foods varying in energy content is related to measures of child body composition. PMID- 26973135 TI - Characterization of a novel snake venom component: Kazal-type inhibitor-like protein from the arboreal pitviper Bothriechis schlegelii. AB - Snake venoms are composed mainly of a mixture of proteins and peptides. Notably, all snake venom toxins have been assigned to a small number of protein families. Proteomic studies on snake venoms have recently identified the presence of Kazal type inhibitor-like proteins in the neotropical arboreal snakes Bothriechis schlegelii and Bothriechis supraciliaris. In the present study, a Kazal-type component from B. schlegelii, named Kazal-type inhibitor-like protein (KTIL), has been completely sequenced and characterized for the first time. This protein, which contains 54 amino acid residues, shows sequence similarity to the third domain of the ovomucoid from avian species, which is a Kazal-like domain. KTIL did not inhibit the enzymatic activity of various serine proteinases at pH = 7.2 or pH = 8.0, but partially inhibited the activity of trypsin at pH = 5.4, and the only toxic effect in mice observed after different in vivo tests was the induction of footpad edema. KTIL was not lethal when injected in mice or chickens. The presence of Kazal-type proteins and mRNA only in species of the genus Bothriechis suggests a genus recruitment event in the early-Middle Miocene, the estimated time of emergence of this clade. PMID- 26973133 TI - Noggin4 is a long-range inhibitor of Wnt8 signalling that regulates head development in Xenopus laevis. AB - Noggin4 is a Noggin family secreted protein whose molecular and physiological functions remain unknown. In this study, we demonstrate that in contrast to other Noggins, Xenopus laevis Noggin4 cannot antagonise BMP signalling; instead, it specifically binds to Wnt8 and inhibits the Wnt/beta -catenin pathway. Live imaging demonstrated that Noggin4 diffusivity in embryonic tissues significantly exceeded that of other Noggins. Using the Fluorescence Recovery After Photobleaching (FRAP) assay and mathematical modelling, we directly estimated the affinity of Noggin4 for Wnt8 in living embryos and determined that Noggin4 fine tune the Wnt8 posterior-to-anterior gradient. Our results suggest a role for Noggin4 as a unique, freely diffusing, long-range inhibitor of canonical Wnt signalling, thus explaining its ability to promote head development. PMID- 26973136 TI - Validation of lymphovascular invasion is an independent prognostic factor for biochemical recurrence after radical prostatectomy. AB - OBJECTIVE: To validate the impact of lymphovascular invasion (LVI) on biochemical recurrence (BCR) in patients treated with radical prostatectomy (RP) in a large multiinstitutional cohort. MATERIAL AND METHODS: Retrospective data from 6,678 patients treated with a RP and bilateral lymphadenectomy for prostate cancer (PC) from 8 centers were collected. The primary endpoint was BCR. RESULTS: Overall, 767 patients (11.5%) had LVI. Patients with LVI had significantly higher Gleason scores (P = 0.01). After a median follow-up of 28 months (interquartile range: 21 44), patients with LVI had a 1.66 fold increased risk of BCR (P<0.001). The 1-, 2 and 5-year biochemical recurrence-free survival probabilities for LVI vs. no LVI were 94% vs. 97%, 91% vs. 94%, and 76% vs. 84%, respectively. On multivariable analysis that adjusted for the effects of established prognostic factors, LVI was an independent predictor of BCR (hazard ratio = 1.42, P<0.001). Adding LVI to a multivariable base model increased the discrimination by a small but significant margin (+0.2%, P = 0.0005). In subgroup analyses, LVI remained an independent predictor for BCR in patients with worse pathological features. CONCLUSIONS: About 10% of patients with localized PC have LVI on their RP specimen. We confirm that LVI is associated with features of biologic aggressive PC such as high Gleason grade and BCR after RP. Adverse further studies with strict definitions of LVI and longer follow-up periods are needed to determine the prognostic and predictive utility of LVI in the management of PC. PMID- 26973137 TI - Bio-inspired, Moisture-Powered Hybrid Carbon Nanotube Yarn Muscles. AB - Hygromorph artificial muscles are attractive as self-powered actuators driven by moisture from the ambient environment. Previously reported hygromorph muscles have been largely limited to bending or torsional motions or as tensile actuators with low work and energy densities. Herein, we developed a hybrid yarn artificial muscle with a unique coiled and wrinkled structure, which can be actuated by either changing relative humidity or contact with water. The muscle provides a large tensile stroke (up to 78%) and a high maximum gravimetric work capacity during contraction (2.17 kJ kg(-1)), which is over 50 times that of the same weight human muscle and 5.5 times higher than for the same weight spider silk, which is the previous record holder for a moisture driven muscle. We demonstrate an automatic ventilation system that is operated by the tensile actuation of the hybrid muscles caused by dew condensing on the hybrid yarn. This self-powered humidity-controlled ventilation system could be adapted to automatically control the desired relative humidity of an enclosed space. PMID- 26973138 TI - Assessment of left ventricular mechanical dyssynchrony in left bundle branch block canine model: Comparison between cine and tagged MRI. AB - PURPOSE: To compare cine and tagged magnetic resonance imaging (MRI) for left ventricular dyssynchrony assessment in left bundle branch block (LBBB), using the time-to-peak contraction timing, and a novel approach based on cross-correlation. MATERIALS AND METHODS: We evaluated a canine model dataset (n = 10) before (pre LBBB) and after induction of isolated LBBB (post-LBBB). Multislice short-axis tagged and cine MRI images were acquired using a 1.5 T scanner. We computed contraction time maps by cross-correlation, based on the timing of radial wall motion and of circumferential strain. Finally, we estimated dyssynchrony as the standard deviation of the contraction time over the different regions of the myocardium. RESULTS: Induction of LBBB resulted in a significant increase in dyssynchrony (cine: 13.0 +/- 3.9 msec for pre-LBBB, and 26.4 +/- 5.0 msec for post-LBBB, P = 0.005; tagged: 17.1 +/- 5.0 msec at for pre-LBBB, and 27.9 +/- 9.8 msec for post-LBBB, P = 0.007). Dyssynchrony assessed by cine and tagged MRI were in agreement (r = 0.73, P = 0.0003); differences were in the order of time difference between successive frames of 20 msec (bias: -2.9 msec; limit of agreement: 10.1 msec). Contraction time maps were derived; agreement was found in the contraction patterns derived from cine and tagged MRI (mean difference in contraction time per segment: 3.6 +/- 13.7 msec). CONCLUSION: This study shows that the proposed method is able to quantify dyssynchrony after induced LBBB in an animal model. Cine-assessed dyssynchrony agreed with tagged-derived dyssynchrony, in terms of magnitude and spatial direction. J. MAGN. RESON. IMAGING 2016;44:956-963. PMID- 26973140 TI - Dystrophic Calcification in the Pelvis. PMID- 26973139 TI - 5-millimeter Trocar-site Hernias After Laparoscopy Requiring Surgical Repair. AB - Trocar-site hernias are rare complications of laparoscopic surgery. Although trocar-site hernias occur more often at >10-mm sites, hernias can still develop at 5-mm sites after laparoscopy and can lead to serious complications. The primary objective of this review is to summarize the current medical literature pertaining to the clinical presentation and predisposing risk factors of trocar site hernias at 5-mm sites after laparoscopy. A total of 295 publications were identified, 17 (5.76%) of which met the inclusion criteria. Twenty-seven patients with trocar-site hernias were identified after laparoscopic cases. The median age (interquartile range) for all adult patients with trocar-site hernias was 63 years (interquartile range, 39.5-66.5 years). Eight of the 18 patients (44.4%) undergoing gynecologic laparoscopy were parous although details of parity were not reported in most publications. Simple manual reduction or laparoscopic reduction with fascial closure (21 patients [84%]) was used more often compared with exploratory laparotomy (4 patients [16%], p < .001) to manage trocar-site hernias. There was no statistical difference in the location of trocar-site hernias (i.e., umbilical [14 patients, 56%] vs nonumbilical/lateral [11 patients, 44%], p = .12). Findings of this review suggest that increased operative times and excessive manipulation can extend 5-mm fascial incisions, thereby increasing the risk of trocar-site hernias. Parous women older than 60 years may have unrecognized fascial defects, which confer a higher risk of trocar-site hernias after laparoscopic surgery, even in the absence of incision manipulation or prolonged surgical duration. Such patients may benefit from closure of 5-mm fascial incisions although prospective data are required to validate the overall generalizability of this management strategy. PMID- 26973141 TI - Endoplasmic reticulum-mediated signalling in cellular microdomains. AB - The endoplasmic reticulum (ER) is a prime mediator of cellular signalling due to its functions as an internal cellular store for calcium, as well as a site for synthesis of proteins and lipids. Its peripheral network of sheets and tubules facilitates calcium and lipid signalling, especially in areas of the cell that are more distant to the main cytoplasmic network. Specific membrane proteins shape the peripheral ER architecture and influence the network stability to project into restricted spaces. The signalling microdomains are anatomically separate from the cytoplasm as a whole and exhibit localized protein, ion channel and cytoskeletal element expression. Signalling can also occur between the ER and other organelles, such as the Golgi or mitochondria. Lipids made in the ER membrane can be sent to the Golgi via specialized transfer proteins and specific phospholipid synthases are enriched at ER-mitochondria junctions to more efficiently expedite phospholipid transfer. As a hub for protein and lipid synthesis, a store for intracellular calcium [Ca2+ ]i and a mediator of cellular stress, the ER is an important cellular organelle. Its ability to organize into tubules and project into restricted spaces allows for discrete and temporal signalling, which is important for cellular physiology and organism homoeostasis. PMID- 26973143 TI - The role of Ca(2+) signaling on the self-renewal and neural differentiation of embryonic stem cells (ESCs). AB - Embryonic stem cells (ESCs) are promising resources for both scientific research and clinical regenerative medicine. With regards to the latter, ESCs are especially useful for treating several neurodegenerative disorders. Two significant characteristics of ESCs, which make them so valuable, are their capacity for self-renewal and their pluripotency, both of which are regulated by the integration of various signaling pathways. Intracellular Ca(2+) signaling is involved in several of these pathways. It is known to be precisely controlled by different Ca(2+) channels and pumps, which play an important role in a variety of cellular activities, including proliferation, differentiation and apoptosis. Here, we provide a review of the recent work conducted to investigate the function of Ca(2+) signaling in the self-renewal and the neural differentiation of ESCs. Specifically, we describe the role of intracellular Ca(2+) mobilization mediated by RyRs (ryanodine receptors); by cADPR (cyclic adenosine 5'-diphosphate ribose) and CD38 (cluster of differentiation 38/cADPR hydrolase); and by NAADP (nicotinic acid adenine dinucleotide phosphate) and TPC2 (two pore channel 2). We also discuss the Ca(2+) influx mediated by SOCs (store-operated Ca(2+) channels), TRPCs (transient receptor potential cation channels) and LTCC (L-type Ca(2+) channels) in the pluripotent ESCs as well as in neural differentiation of ESCs. Moreover, we describe the integration of Ca(2+) signaling in the other signaling pathways that are known to regulate the fate of ESCs. PMID- 26973142 TI - The serum level of C-reactive protein (CRP) is associated with cognitive performance in acute phase psychosis. AB - BACKGROUND: Inflammatory processes have been implicated in the etiology of schizophrenia and related psychoses, in which cognitive deficits represent core symptoms. The aim of the present study was to investigate possible associations between the level of the inflammation marker C-reactive protein (CRP) and cognitive performance in patients through the acute phase of psychosis. METHODS: A total of 124 patients were assessed at admittance to hospital and 62 patients were retested at discharge or after 6 weeks at the latest, with measurements of the CRP levels and alternative forms of the Repeatable Battery for the Assessment of Neuropsychological Status. RESULTS: There was an inverse relationship between overall cognitive performance and CRP level at admittance. The association increased in sub-analyses including only patients with schizophrenia. In cognitive subdomain analyses statistically significant inverse associations were found between the CRP level and Delayed memory and Attention, respectively. No associations were found between CRP level and other measures of psychopathology including psychosis symptoms, depression, or functioning. At follow-up the association between CRP level and cognition was no longer present. There was a significant increase in cognitive performance between baseline and follow-up. There was a stronger increase in overall cognition scores in patients with higher baseline CRP levels. CONCLUSIONS: The findings indicate that signs of inflammation may serve as a state-dependent marker of cognitive dysfunctions in acute psychosis. TRIAL REGISTRATION: ClinicalTrials.gov ID; NCT00932529 , registration date: 02.07.2009. PMID- 26973146 TI - Nucleic acid aptamers. PMID- 26973144 TI - High levels of thyroid-stimulating hormone are associated with aortic wall thickness in the general population. AB - OBJECTIVES: Our aim was to investigate the association of thyroid function defined by serum concentrations of thyroid-stimulating hormone (TSH) with thoracic aortic wall thickness (AWT) as a marker of atherosclerotic processes. METHODS: We pooled data of 2,679 individuals from two independent population based surveys of the Study of Health in Pomerania. Aortic diameter and AWT measurements were performed on a 1.5-T MRI scanner at the concentration of the right pulmonary artery displaying the ascending and the descending aorta. RESULTS: TSH, treated as continuous variable, was significantly associated with descending AWT (beta = 0.11; 95 % confidence interval (CI) 0.02-0.21), while the association with ascending AWT was not statistically significant (beta = 0.20; 95 % CI -0.01-0.21). High TSH (>3.29 mIU/L) was significantly associated with ascending (beta = 0.12; 95 % CI 0.02-0.23) but not with descending AWT (beta = 0.06; 95 % CI -0.04-0.16). There was no consistent association between TSH and aortic diameters. CONCLUSIONS: Our study demonstrated that AWT values increase with increasing serum TSH concentrations. Thus, a hypothyroid state may be indicative for aortic atherosclerosis. These results fit very well to the findings of previous studies pointing towards increased atherosclerotic risk in the hypothyroid state. KEY POINTS: * Serum TSH concentrations are positively associated with aortic wall thickness. * Serum TSH concentrations are not associated with the aortic diameters. * Serum 3,5-diiodothyronine concentrations may be positively associated with aortic wall thickness. PMID- 26973145 TI - Fine focal spot size improves image quality in computed tomography abdomen and pelvis. AB - OBJECTIVES: To compare the image quality between fine focal spot size (FFSS) and standard focal spot size (SFSS) in computed tomography of the abdomen and pelvis (CTAP) METHODS: This retrospective review included all consecutive adult patients undergoing contrast-enhanced CTAP between June and September 2014. Two blinded radiologists assessed the margin clarity of the abdominal viscera and the detected lesions using a five-point grading scale. Cohen's kappa test was used to examine the inter-observer reliability between the two reviewers for organ margin clarity. Mann-Whitney U testing was utilised to assess the statistical difference of the organ and lesion margin clarity. RESULTS: 100 consecutive CTAPs were recruited. 52 CTAPs were examined with SFSS of 1.1 * 1.2 mm and 48 CTAPs were examined with FFSS of 0.6 * 0.7 mm. Results showed that there was substantial agreement for organ margin clarity (mean kappa = 0.759, p < 0.001) among the reviewers. FFSS produces images with clearer organ margins (U = 76194.0, p < 0.001, r = 0.523) and clearer lesion margins (U = 239, p = 0.052, r = 0.269). CONCLUSION: FFSS CTAP improves image quality in terms of better organ and lesion margin clarity. Fine focus CT scanning is a novel technique that may be applied in routine CTAP imaging. KEY POINTS: * Fine focal spot improves organ margin clarity. * Fine focal spot improves lesion margin clarity. * Fine focal spot can be used in routine CT abdominal imaging. PMID- 26973148 TI - Influence of Relative Age on Diagnosis and Treatment of Attention-Deficit Hyperactivity Disorder in Taiwanese Children. AB - OBJECTIVE: To determine the potential influence of relative age on the diagnosis and treatment of attention-deficit hyperactivity disorder (ADHD), especially in reference to an Asian country. STUDY DESIGN: A total of 378 881 subjects aged 4 17 years during the study period (September 1, 1997 to August 31, 2011) were enrolled in our study from the Taiwan National Health Insurance Research Database. Logistic regression analysis was used to examine the likelihood of receiving ADHD diagnosis and treatment for those who were born in August (the youngest) compared with those who were born in September (the oldest). RESULTS: Both boys and girls born in August had a higher risk of being diagnosed with ADHD (OR 1.63, 95% CI 1.45-1.84; OR 1.71, 95% CI 1.36-2.15) and receiving ADHD medication (OR 1.76, 95% CI 1.53-2.02; OR 1.65, 95% CI 1.26-2.18) than those born in September. Sensitivity tests conducted over different periods revealed consistent findings. CONCLUSIONS: Relative age, as an indicator of neurocognitive maturity, is crucial in the risk of being diagnosed with ADHD and receiving ADHD medication among children and adolescents. Our findings emphasize the importance of considering the age of a child within a grade when diagnosing ADHD and prescribing medication for treating ADHD. PMID- 26973147 TI - Fast Food Intake in Relation to Employment Status, Stress, Depression, and Dietary Behaviors in Low-Income Overweight and Obese Pregnant Women. AB - Objective This study explored fast food intake as a potential mediator of the relationships among employment status; stress; depression; and fruit, vegetable, and fat intakes by race (African American vs. Non-Hispanic White) and body mass index (BMI category: overweight vs. obesity). Methods Low-income overweight and obese pregnant women (N = 332) were recruited from the Special Supplemental Nutrition Program for Women, Infants and Children in Michigan. Path analysis was performed to explore mediation effects by race and BMI category. Results Fast food intake mediated the relationship between employment status and fat intake (p = 0.02) in Non-Hispanic White women, but no mediation effect was detected in African American women. For overweight women, fast food intake mediated the relationship between employment status and fat intake (p = 0.04) and the relationship between depression and vegetable intake (p = 0.01). Also, fast food intake partially mediated the relationship between depression and fat intake (p = 0.003). For obese women, fast food intake mediated the relationship between employment status and fat intake (p = 0.04). Conclusion Fast food is an important topic for nutrition education for overweight and obese pregnant women. Future interventions may be more successful if they address issues associated with employment status (e.g., lack of time to plan and cook healthy meals) and depressive mood (e.g., inability to plan meals or shop for groceries when coping with negative emotions). PMID- 26973150 TI - Eating breakfast together as a family: mealtime experiences and associations with dietary intake among adolescents in rural Minnesota, USA. AB - OBJECTIVE: Although existing evidence links breakfast frequency to better dietary quality, little is known specifically in regard to the benefits associated with eating breakfast together with one's family. The present study describes the prevalence and experience of having family meals at breakfast among rural families and examines associations between meal frequency and adolescent diet quality. DESIGN: Data were drawn from Project BreakFAST, a group-randomized trial aimed at increasing school breakfast participation in rural Minnesota high schools, USA. Linear mixed models were used to examine associations between student reports of family breakfast frequency and Healthy Eating Index 2010 (HEI 2010) scores while accounting for clustering within schools, demographics and household food security. SETTING: Adolescent students from sixteen schools completed online surveys, height and weight measurements, and dietary recalls at baseline in 2012-2014. SUBJECTS: The sample included 827 adolescents (55.1 % girls) in grades 9-10 who reported eating breakfast on at most three days per school week. RESULTS: On average, adolescents reported eating breakfast with their family 1.3 (sd 1.9) times in the past week. Family breakfast meals occurred most frequently in the homes of adolescents who reported a race other than white (P=0.002) or Hispanic ethnicity (P=0.02). Family breakfast frequency was directly associated with adolescent involvement in preparing breakfast meals (P<0.001) and positive attitudes (P<=0.01) about mealtime importance, interactions and structure. Family breakfast frequency was unrelated to most diet quality markers. CONCLUSIONS: Family meals may be one important context of opportunity for promoting healthy food patterns at breakfast. Additional research is needed to better inform and evaluate strategies. PMID- 26973149 TI - Moderate-to-Vigorous Physical Activity, Indices of Cognitive Control, and Academic Achievement in Preadolescents. AB - OBJECTIVE: To assess whether preadolescents' objectively measured moderate-to vigorous physical activity (MVPA) is associated with cognitive control and academic achievement, independent of aerobic fitness. STUDY DESIGN: A sample of 74 children (Meanage = 8.64 years, SD = .58, 46% girls) were included in the analyses. Daily MVPA (min/d) was measured over 7 days using ActiGraph wGT3X+ accelerometer. Aerobic fitness was measured using a maximal graded exercise test and expressed as maximal oxygen uptake (mL*kg(-1)*min(-1)). Inhibitory control was measured with a modified Eriksen flanker task (reaction time and accuracy), and working memory with an Operation Span Task (accuracy scores). Academic achievement (in reading, mathematics, and spelling) was expressed as standardized scores on the Kaufman Test of Educational Achievement. The relationships were assessed using hierarchical regression models adjusting for aerobic fitness and other covariates. RESULTS: No significant associations were found between MVPA and inhibition, working memory, or academic achievement. Aerobic fitness was positively associated with inhibitory control (P = .02) and spelling (P = .04) but not with other cognitive or academic variables (all P > .05). CONCLUSIONS: Aerobic fitness, rather than daily MVPA, is positively associated with childhood ability to manage perceptual interference and spelling. Further research into the associations between objectively measured MVPA and cognitive and academic outcomes in children while controlling for important covariates is needed. PMID- 26973152 TI - Comparative study on prediction performance of photosafety testing tools on photoallergens. AB - Several testing methods have been established to identify potential phototoxins. The present study was undertaken to clarify the predictive ability of in vitro photosafety assays for photoallergenicity. On the basis of animal and/or clinical photosafety information, 23 photoallergens and 7 non-phototoxic/non photoallergenic chemicals were selected and subjected to UV/VIS spectral analysis, reactive oxygen species (ROS)/micellar ROS (mROS) assays, and 3T3 neutral red uptake phototoxicity testing (3T3 NRU PT). Of the photoallergens tested, ca. 96% of chemicals had intense UV/VIS absorption with a molar extinction coefficient of over 1000 M(-1) cm(-1), and false-positive predictions were made for 3 non-photoallergenic chemicals. In the ROS assay, all photoallergens were found to be potent ROS generators under exposure to simulated sunlight. In the photosafety prediction based on the ROS assay, the individual specificity was 85.7%, and the positive predictivity and negative predictivity were found to be 95.8% and 100%, respectively. Most of the photoirritant chemicals were correctly identified by the 3T3 NRU PT; however, it provided false predictions for ca. 48% of photoallergens. The orders of sensitivity and specificity for photoallergenicity prediction were estimated to be: [sensitivity] ROS assay>UV/VIS absorption ? 3T3 NRU PT, and [specificity] 3T3 NRU PT>ROS assay ? UV/VIS absorption. Thus, photochemical assays, in particular the ROS assay, can be used for assessment of photoallergenicity, although there were some false positive predictions. PMID- 26973153 TI - Serum D-dimer as an indicator of immediate mortality in patients with in-hospital cardiac arrest. AB - INTRODUCTION: Blood coagulation and fibrin activation with impaired fibrinolysis occurs not only during cardiac arrest (CA) but also after the return of spontaneous circulation (ROSC). The aim of the present study was to investigate the prognostic marker of immediate mortality prediction in in-hospital cardiac arrest (IHCA), with special attention to the serum D-dimer concentration. METHODS: Retrospective chart review. Adult patients subjected to IHCA with resuscitation in the medical intensive care unit (ICU) from January 2012 to July 2015 were enrolled. Information about patient baseline characteristics, resuscitation characteristics, biochemical parameters and outcome details were collected. Logistic regression analysis was calculated to identify independent predictors for mortality. Receiver operating characteristic (ROC) curves were utilized to evaluate the accuracy of predictors. RESULTS: Of the studied 192 patients (115 men, mean age 64.98+/-17.66years), more than half-part patients died immediately after resuscitation (118/192, 61.46%). The patients who failed to resuscitate had more often had a history of septicemia (15.25% vs 2.7%, p=0.006), renal insufficiency (38.14% vs 14.86%, p=0.001), pneumonia (51.69% vs 33.78%, p=0.015) and less often had an initial shockable rhythm (16.1% vs 29.73%, p=0.019) than those who sustained ROSC. Pre-CA serum D-dimer concentration was significantly higher in the death group than that in ROSC group (22.48+/-17.66 vs 9.49+/-9.09mg/L, p<0.0001). On multivariate logistic regression analysis, D-dimer (odds ratios, 1.07, 95% confidence interval 1.02 to 1.13) was an independent predictor of mortality. CONCLUSIONS: Serum D-dimer serves as a useful indicator of immediate mortality after resuscitation in patients with IHCA. PMID- 26973151 TI - Nitrogenase FeMoco investigated by spatially resolved anomalous dispersion refinement. AB - The [Mo:7Fe:9S:C] iron-molybdenum cofactor (FeMoco) of nitrogenase is the largest known metal cluster and catalyses the 6-electron reduction of dinitrogen to ammonium in biological nitrogen fixation. Only recently its atomic structure was clarified, while its reactivity and electronic structure remain under debate. Here we show that for its resting S=3/2 state the common iron oxidation state assignments must be reconsidered. By a spatially resolved refinement of the anomalous scattering contributions of the 7 Fe atoms of FeMoco, we conclude that three irons (Fe1/3/7) are more reduced than the other four (Fe2/4/5/6). Our data are in agreement with the recently revised oxidation state assignment for the molybdenum ion, providing the first spatially resolved picture of the resting state electron distribution within FeMoco. This might provide the long-sought experimental basis for a generally accepted theoretical description of the cluster that is in line with available spectroscopic and functional data. PMID- 26973155 TI - Stable, polymer-directed and SPION-nucleated magnetic amphiphilic block copolymer nanoprecipitates with readily reversible assembly in magnetic fields. AB - The formation of inorganic-organic magnetic nanocomposites using reactive chemistry often leads to a loss of super-paramagnetisim when conducted in the presence of iron oxide nanoparticles. We present here a low energy and chemically mild process of co-nanoprecipitation using SPIONs and homopolymers or amphiphilic block copolymers, of varying architecture and hydrophilic/hydrophobic balance, which efficiently generates near monodisperse SPION-containing polymer nanoparticles with complete retention of magnetism, and highly reversible aggregation and redispersion behaviour. When linear and branched block copolymers with inherent water-solubility are used, a SPION-directed nanoprecipitation mechanism appears to dominate the nanoparticle formation presenting new opportunities for tailoring and scaling highly functional systems for a range of applications. PMID- 26973156 TI - Follow-up of asymptomatic pancreatic cysts in clinical practice: A vignette questionnaire. AB - BACKGROUND/OBJECTIVES: In absence of evidence-based guidelines of pancreatic cystic neoplasms (PCN), the management might vary among physicians. The aim of this survey was to assess the attitude of Dutch gastroenterologists (GE) towards the management of asymptomatic PCNs. METHODS: An anonymous online questionnaire was distributed to all practicing GE (n = 381) in The Netherlands, in which four vignette patients with PCN were presented. RESULTS: In total 45% of GE responded. Most respondents would perform surveillance for a 10 mm PCN (78%) mainly with an interval of one year (57%). A shorter interval of three (26%) or six (57%) months was chosen for a 25 mm BD-IPMN. Ultrasound was recommended for surveillance by 19% for a 10 mm cyst. GE with EUS experience were more likely to apply EUS for surveillance of 10 mm cyst than those without (56% vs 28%; p < 0.001). The presence of a branch-duct intraductal mucinous neoplasm (BD-IPMN) with a mural nodule, dilated pancreatic duct (8 mm) or increased serum CA 19.9 (300 U/ml) were considered an indication for resection by respectively 88%, 68% and 51% of respondents. CONCLUSION: Dutch GE demonstrate substantial variability in the management of asymptomatic PCNs. A significant proportion of general GE still use ultrasound for surveillance of small PCNs, while GE with EUS experience were more likely to perform EUS. The presence of risk factors for malignant degeneration of IPMN were not recognized by a substantial proportion of GE. Data on the natural history of PCNs is required to provide input for evidence-based guidelines, which should lead to a more uniform approach. PMID- 26973157 TI - Communicating Uncertain Science to the Public: How Amount and Source of Uncertainty Impact Fatalism, Backlash, and Overload. AB - Public dissemination of scientific research often focuses on the finding (e.g., nanobombs kill lung cancer) rather than the uncertainty/limitations (e.g., in mice). Adults (n = 880) participated in an experiment where they read a manipulated news report about cancer research (a) that contained either low or high uncertainty (b) that was attributed to the scientists responsible for the research (disclosure condition) or an unaffiliated scientist (dueling condition). Compared to the dueling condition, the disclosure condition triggered less prevention-focused cancer fatalism and nutritional backlash. PMID- 26973159 TI - Albert Coons: harnessing the power of the antibody. PMID- 26973158 TI - Paediatric orphan lung diseases in Asia. PMID- 26973154 TI - Underconnected, But Not Broken? Dynamic Functional Connectivity MRI Shows Underconnectivity in Autism Is Linked to Increased Intra-Individual Variability Across Time. AB - Autism spectrum disorder (ASD) is characterized by core sociocommunicative impairments. Atypical intrinsic functional connectivity (iFC) has been reported in numerous studies of ASD. A majority of findings has indicated long-distance underconnectivity. However, fMRI studies have thus far exclusively examined static iFC across several minutes of scanning. We examined temporal variability of iFC, using sliding window analyses in selected high-quality (low-motion) consortium datasets from 76 ASD and 76 matched typically developing (TD) participants (Study 1) and in-house data from 32 ASD and 32 TD participants. Mean iFC and standard deviation of the sliding window correlation (SD-iFC) were computed for regions of interest (ROIs) from default mode and salience networks, as well as amygdala and thalamus. In both studies, ROI pairings with significant underconnectivity (ASD= 0.7 mm(2)) was significantly higher than in those with smaller tumor area (<0.7 mm(2); 71.2% vs 60.7%, respectively; p=0.015). In the biopsy samples with smaller tumor areas, the concordance rate was 77% in lepidic subtype, 71% in papillary subtype, 60% in solid subtype, and 40% in acinar subtype. Concordance rate in the biopsy samples with larger tumor area was higher in papillary and solid subtypes (88% and 76%, respectively), but remained low in acinar subtype (37%). CONCLUSION: The current results indicate that accuracy of adenocarcinoma subtyping based on small biopsy samples is influenced by tumor area. Our study also suggests that subtyping of acinar histology using biopsy specimen is particularly error-prone. PMID- 26973200 TI - The role of new PET tracers for lung cancer. AB - 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) is established for characterising indeterminate pulmonary nodules and staging lung cancer where there is curative intent. Whilst a sensitive technique, specificity for characterising lung cancer is limited. There is recognition that evaluation of other aspects of abnormal cancer biology in addition to glucose metabolism may be more helpful in characterising tumours and predicting response to novel targeted cancer therapeutics. Therefore, efforts have been made to develop and evaluate new radiopharmaceuticals in order to improve the sensitivity and specificity of PET imaging in lung cancer with regards to characterisation, treatment stratification and therapeutic monitoring. 18F-fluorothymidine (18F FLT) is a marker of cellular proliferation. It shows a lower accumulation in tumours than 18F-FDG as it only accumulates in the cells that are in the S phase of growth and demonstrates a low sensitivity for nodal staging. Its main role is in evaluating treatment response. Methionine is an essential amino acid. 11C methionine is more specific and sensitive than 18F-FDG in differentiating benign and malignant thoracic nodules. 18Ffluoromisonidazole (18F-FMISO) is used for imaging tumour hypoxia. Tumour response to treatment is significantly related to the level of tumour oxygenation. Angiogenesis is the process by which new blood vessels are formed in tumours and is involved in tumour growth and metastatic tumour spread and is a therapeutic target. Most clinical studies have focused on targeted integrin PET imaging of which alphavbeta3 integrin is the most extensively investigated. It is upregulated on activated endothelial cells in association with tumour angiogenesis. Neuroendocrine tumour tracers, particularly 68Ga-DOTA-peptides, have an established role in imaging of carcinoid tumours. Whilst most of these tracers have predominantly been used in the research environment, they offer exciting opportunities for improving staging, characterisation, stratification and response assessment in an era of increased personalised therapy in lung cancer. PMID- 26973201 TI - Association between polymorphisms in pre-miRNA genes and risk of lung cancer in a Chinese non-smoking female population. AB - BACKGROUND: MicroRNAs play important roles in the development of human chronic diseases including lung cancer. This is the first case-control study of lung cancer in a non-smoking female population in northeast China, to evaluate the roles of the polymorphisms in pre-miRNAs on risk of lung cancer. METHODS: The genotypes of six polymorphisms in miRNAs were determined in 575 patients with lung cancer and 608 healthy controls who were frequency matched for age. RESULTS: For miR-146a rs2910164, individuals carrying heterozygous CG or homozygous GG genotype had decreased risks of lung cancer compared with those carrying homozygous wild CC genotype (adjusted odds ratios were 0.76 and 0.64, 95% confidence intervals were 0.59-0.99 and 0.46-0.90, P values were 0.039 and 0.010, respectively). G allele of rs2910164 was associated with a lower risk of lung cancer with a significant odds ratio of 0.80. MiR-423 rs6505162CA or AA genotype was associated with significantly decreased risk for lung cancer compared to CC genotype (adjusted odds ratios were 0.77 and 0.54). The significant result was also found in the allele model with odds ratio of 0.75. However, miR-196a2 rs11614913, miR-30c-1 rs928508, miR-608 rs4919510 and miR-27a rs895819 polymorphisms were not significantly associated with lung cancer risks in any models. The similar results were also found in lung adenocarcinoma patients. CONCLUSIONS: These findings suggest that miR-146a rs2910164C>G and miR-423 rs6505162C>A polymorphisms may contribute to genetic susceptibility to lung cancer and lung adenocarcinoma in Chinese non-smoking females. PMID- 26973202 TI - ALK, ROS1 and RET rearrangements in lung squamous cell carcinoma are very rare. AB - OBJECTIVES: Chromosomal rearrangements of ALK and ROS1 genes in non-small cell lung carcinoma (NSCLC) define a molecular subgroup of lung adenocarcinoma (ADC) that is amenable to targeted therapy with tyrosine kinase inhibitors (TKIs) crizotinib. Emerging clinical studies have demonstrated that patients with RET rearranged NSCLC may also benefit from existing RET TKIs, including cabozantinib and vandetanib. However, the reported cases of lung squamous cell carcinomas (SCC) harboring gene rearrangements have been detected via fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) from materials such as biopsy or resection. Fusion events identified in lung SCC raise the question of whether this histologic subtype should also be evaluated for merit molecular testing. This work was undertaken to study the prevalence of lung SCC harboring ALK, ROS1, and RET translocations. MATERIALS AND METHODS: Squamous cell carcinomas were confirmed using both histological examination by pathologists and immunohistochemistry analysis with positive staining of P63 and CK5/6 combined with negative CK7 and TTF-1 staining. 214 samples from surgically resected patient tissues were used to search for ALK, ROS1, and RET rearrangements by a NanoString analysis method. Fusion events were detected in a single-tube, multiplex assay system that relied on a complementary strategy of interrogation of 3' gene overexpression and detection of specific fusion transcript variants. RESULTS AND CONCLUSION: ALK, ROS1 or RET gene rearrangements appeared 0 times out of 214 cases of lung SCC. Our data revealed that these fusions may be very rare in lung squamous cancer. The molecular screening strategy should therefore be focused on lung adenocarcinoma as the current National Comprehensive Cancer Network (NCCN) guideline recommends. PMID- 26973203 TI - Feasibility of cytological specimens for ALK fusion detection in patients with advanced NSCLC using the method of RT-PCR. AB - OBJECTIVES: Histological tissues are preferred for anaplastic lymphoma kinase (ALK) fusion detection in non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the feasibility of cytological sample as an alternative specimen for ALK fusion testing in patients with advanced NSCLC. MATERIALS AND METHODS: Advanced NSCLC patients with cytological specimens or tumor tissue who had their ALK fusion status detected by the method of reverse transcriptase polymerase chain reaction (RT-PCR) in Shanghai Pulmonary Hospital, Tongji University were included into this study. The efficacy was evaluated in those with ALK fusion positive and received the therapy of crizotinib. RESULTS: 1274 patients were included in this study. Among them, 108 patients were ALK RT-PCR positive and 69 of them received crizotinib treatment. Among 1002 patients with cytological specimens, the average concentration of RNA extracted from cytological specimens was 60.99 ng/MUl (95% confidence interval [CI], 55.56 66.60) and the incidence rate of ALK fusion was 8.3% (83/1002), which were similar to 63.16 ng/MUl (95% CI, 51.88-76.34) (p=0.727) and 9.2% (25/272, p=0.624) in 272 patients with tumor tissue. Also, there were no statistically significant differences regarding to the objective response rate (ORR) (62.0% vs. 42.1%, p=0.177) and the median progression free survival (mPFS) [8.6 months (95% CI 7.30-9.84) vs. 7.0 months (95% CI 4.54-9.47), p=0.736] in patients of cytological group and tissue group after the treatment of crizotinib. CONCLUSION: Cytological specimens showed a high feasibility to detect ALK fusion status, which could be regarded as alternative samples for ALK fusion detection by the method of RT-PCR in patients with advanced NSCLC. PMID- 26973204 TI - Metformin use and survival from lung cancer: A population-based cohort study. AB - Preclinical evidence suggests that metformin, a widely prescribed anti-diabetic drug, may inhibit lung cancer progression. We investigated whether metformin use was associated with decreased risk of cancer-specific mortality in lung cancer patients. This study included newly diagnosed lung cancer patients (identified from English National Cancer Data Repository, 1998-2009) with type 2 diabetes (based on UK Clinical Practice Research Datalink prescriptions and diagnosis records). Lung cancer deaths occurring up to 2012 were identified using Office of National Statistics mortality data and the association between metformin use (before and after diagnosis) and risk of lung cancer-specific mortality was calculated using Cox regression models. In analysis of 533 patients, we found a weak non-significant reduction in lung cancer-specific mortality with metformin use after diagnosis (adjusted HR, 0.86; 95% CI, 0.68-1.09). No association was evident for metformin use before diagnosis and cancer-specific mortality in analysis of 1350 patients (adjusted HR, 0.97; 95% CI, 0.86, 1.11). Associations were similar by duration of use. In addition, after adjustment for potential confounders, there was little evidence of an association between the use of other anti-diabetic medications (either before or after diagnosis) and lung cancer specific mortality; including sulfonylureas, insulin or other anti-diabetic medications (such as thiazolidinediones). Overall, the results from this population-based study provide little evidence of a protective association between metformin use and cancer mortality in lung cancer patients. PMID- 26973205 TI - Diagnostic accuracy of sequential co-registered PET+MR in comparison to PET/CT in local thoracic staging of malignant pleural mesothelioma. AB - PURPOSE: To investigate the diagnostic accuracy of sequential co-registered PET+MR (PET+MR) for local staging of malignant pleural mesothelioma (MPM) compared to PET/CT. MATERIAL AND METHODS: In a prospective clinical trial 34 consecutive patients (median age 66 years; range 40-79 years; 1 female, 33 male) with known MPM, who underwent PET/CT and PET+MR exams for either staging or re staging/follow-up were evaluated. Imaging was conducted using a tri-modality PET/CT-MR set-up (Discovery PET/CT 690, 3T Discovery MR 750w, both GE Healthcare, Waukesha, WI, USA). In 26 cases histopathology served as standard of reference. Two independent readers evaluated images for T and N stage, confidence level (sure to unsure; 1-3) and subjective overall image quality (very good to non diagnostic; 1-4). Inter-observer agreement of T and N stages (Cohen's kappa) and interclass correlation coefficient (ICC) between PET/CT vs. PET+MR was calculated. RESULTS: Inter observer agreement for evaluation of T and N Stage in PET/CT images was excellent (k=0.844 and k=0.824, respectively), whereas PET+MR imaging showed substantial agreement in T and N stage (k=0.729 and k=0.691, respectively). The ICC of PET/CT vs. PET+MR for evaluation of both, T and N Stage, was excellent (ICC=0.951 and ICC=0.93, respectively). Diagnostic confidence was scored significantly higher in PET+MR compared to PET/CT (mean score=1.66 and 1.93, respectively; p=0.004). Image quality was diagnostic for all image series. Comparing pT and pN stage vs cT and cN stage (n=26 cases), both imaging modalities showed excellent agreement for T stage (ICCPET+MR=0.888 vs. ICCPET/CT=0.853, respectively) and substantial to moderate agreement for N stage (ICCPET+MR=0.683 vs. ICC=0.595PET/CT, respectively). CONCLUSION: Our findings suggest that diagnostic accuracy of PET+MR is comparable to PET/CT for local staging of MPM, whereas radiologists felt significantly more confident staging PET+MR compared to PET/CT images (p=0003), using dedicated sequences. PMID- 26973206 TI - Coexistence of EGFR T790M mutation and common activating mutations in pretreatment non-small cell lung cancer: A systematic review and meta-analysis. AB - OBJECTIVE: Previous studies have indicated that EGFR exon 19 deletions in non small cell lung cancer (NSCLC) are associated with better outcomes to tyrosine kinase inhibitors (TKIs) than the L858R mutation. This study aimed to evaluate whether T790M, a resistant mutation, is more likely to coexist with L858R mutation than with exon 19 deletions in pretreatment NSCLC patients. MATERIALS AND METHOD: We searched MEDLINE and EMBASE up to Nov 30th, 2015 to identify randomized controlled trials (RCTs) and observational studies that reported pretreatment T790M and EGFR-activating mutation. A meta-analysis was performed using a random-effects model. The primary outcome was odds ratio (OR) of pretreatment T790M mutation in NSCLC co-existing with L858R mutation and exon 19 deletions. Stratified analysis was performed based on sensitivity of mutation detection methods for T790M. RESULTS: We identified 15 observational studies and 3 RCTs for analysis. Pretreatment T790M was more frequent in L858R than in exon 19 mutated patients. The association of T790M and L858R was statistically significant in observational studies (OR, 1.65, 95% CI, 1.17-2.32), with less precision in RCTs (OR, 1.84, 95% CI, 0.96-3.52). In the stratified analysis based on the sensitivity of the mutation detection methods, the association was observed in the studies using intermediately (detection limit <5% and >= 0.1%; OR, 2.23, 95% CI, 1.19-4.17) and highly sensitive methods (detection limit <0.1%; OR, 1.74, 95% CI, 1.10-2.73), but not in those using low sensitivity methods (detection limit >5%; OR, 1.28, 95% CI, 0.74-2.23). CONCLUSIONS: Pretreatment EGFR T790M mutation is more likely to coexist with L858R mutation than with exon 19 deletions in NSCLC. This association was observed only in studies using sensitive mutation detection methods (<5%). PMID- 26973207 TI - Treatment and survival of second primary early-stage lung cancer, following treatment of head and neck cancer in the Netherlands. AB - OBJECTIVES: The goal of this study was to evaluate treatment patterns and outcomes in early stage (ES) second primary lung cancer (SPLC) after head and neck squamous cell cancer (HNSCC), in the Netherlands. METHODS AND MATERIALS: Details of patients diagnosed between 1997 and 2011 with either an ES primary, or a SPLC after HNSCC, were obtained from the Netherlands Cancer Registry. Survival outcomes were compared between treatment groups before, and after, 2005. Univariable and multivariable Cox regression modeling were performed to determine factors prognostic for OS in ES-SPLC. RESULTS: In total, 21,648 patients were diagnosed with ES primary (n=21,032) or SPLC (n=616). Use of surgery for ES-SPLC decreased significantly over time (range 71-44%, p<0.001), while the proportion of such patients receiving radiotherapy increased (range 17-41%, p<0.001). Prior to 2005, OS after surgery in ES-SPLC was significantly better than when compared to radiation, but no difference in OS was noted between surgery and radiotherapy after 2005 (p=0.116). There were no significant differences in OS between treatment eras for surgery (p=0.751) and with palliative care (p=0.306), but a significant improvement in OS was noted for radiotherapy (p=0.049). Multivariable modeling revealed that age, T-stage, HNSCC location and treatment type were associated with worse OS in the later era. CONCLUSION: Changes in the treatment patterns in HNSCC survivors presenting with ES-SPLC were observed in the Netherlands, with less surgery and increased utilization of radiotherapy. No differences in OS were observed between patients undergoing either surgery or radiotherapy after 2005, suggesting that both local modalities were equally effective. PMID- 26973208 TI - Chemokines involved in the early inflammatory response and in pro-tumoral activity in asbestos-exposed workers from an Italian coastal area with territorial clusters of pleural malignant mesothelioma. AB - OBJECTIVES: Immune mediators are likely to be relevant for the biological response to asbestos exposure. The aim of this study was to investigate the association between immune mediators involved in inflammation, cell survival and angiogenesis, and asbestos-related diseases in workers from a coastal area of North-East Italy with a high incidence of pleural malignant mesothelioma (PMM). MATERIALS AND METHODS: A selected custom set of 12 soluble mediators was evaluated with a Luminex platform in sera, pleural fluid and mesothelioma biopsies from 123 asbestos-exposed workers (38 free from pleural-pulmonary disorders, 46 with non-malignant asbestos diseases, 39 with PMM) and in sera from 33 healthy controls from the same territorial area. RESULTS: Increased immune mediator concentrations were observed in the sera of the asbestos-exposed workers compared to controls for human fibroblast growth factor (FGF-b), vascular endothelial growth factor (VEGF), CCL5 (RANTES), CXCL10 (IP-10), CLEC11A (SCGF b), CCL27 (CTACK), CCL11 (EOTAXIN), IL-5 and IL-6 (p<0.001). The chemokines IP-10 and RANTES were associated with the severity of asbestos-related diseases. In the workers with PMM, the immune proteins secreted by mesothelioma biopsies showed detectable levels of RANTES, VEGF, and IP-10. In the same workers with PMM, a significant relationship between serum and pleural fluid concentrations was found for RANTES alone. CONCLUSIONS: Occupational exposure to asbestos seems to drive the production of specific growth factors dually involved in the early inflammatory response and in pro-tumoral activity before clinical evidence of related disorders, suggesting that their over-expression may precede the onset of asbestos-related diseases. These findings suggest that some chemokines may have a prognostic role in the progression of asbestos-related diseases and could be used for the health surveillance of either workers with an occupational history of asbestos exposure or patients affected by non-malignant asbestos-related diseases. PMID- 26973209 TI - Monitoring of treatment responses and clonal evolution of tumor cells by circulating tumor DNA of heterogeneous mutant EGFR genes in lung cancer. AB - OBJECTIVES: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have dramatic effects on EGFR-mutant non-small-cell lung cancer (NSCLC). However, most patients experience disease recurrences, approximately half of which are T790M-mediated. Monitoring EGFR status with re-biopsy has spatiotemporal limitations. PATIENTS AND METHODS: EGFR circulating tumor DNA (ctDNA) in serial plasma samples was amplified and 10(5) of them were sequenced with a next-generation sequencer. Plasma mutation (PM) score was defined as the number of reads containing deletions/substitutions in 10(5)EGFR cell free DNA (cfDNA). RESULTS: PM scores of various EGFR mutations showed dynamic, case specific changes during EGFR-TKI treatments in 52 patients. The effects of the treatment on EGFR ctDNA were evaluated in 38 patients with elevated pre-treatment PM scores. The ctDNA responses correlated well with radiologic responses in radiologic good responders, whereas correlation was poor in non-responders. In addition to the peaks for the most prevalent ctDNA, small peaks of ctDNA with different types of activating EGFR mutations or the T790M mutation (early T790M ctDNA) appeared transiently in 10.5% and 26.3%, respectively. Early T790M ctDNA disappeared in all patients, including 7 who eventually developed acquired resistance accompanied by elevated levels of T790M ctDNA. CONCLUSIONS: Monitoring ctDNA is useful in evaluating treatment responses and monitoring driver oncogene status in NSCLC. ctDNA revealed clonal heterogeneity and genetic processes of cancer evolution in individual patients. The simple presence of the T790M mutation may be insufficient to confer EGFR-TKI resistance to tumor cells. PMID- 26973210 TI - Approach to the non-operative management of patients with stage II non-small cell lung cancer (NSCLC): A survey of Canadian medical and radiation oncologists. AB - BACKGROUND AND OBJECTIVES: Standard management of stage II non-small cell lung cancer (NSCLC) is surgery, often followed by adjuvant chemotherapy. However, some patients do not undergo surgery for various reasons. The optimal non-surgical management of stage II NSCLC is undefined. We surveyed Canadian oncologists to understand current practices. MATERIALS AND METHODS: Canadian oncologists specializing in the management of lung cancer were invited by email to complete an anonymous, online survey developed by the research team. Physician demographics were recorded. Physicians were asked to comment on their practice and make treatment choices in eight clinical scenarios of inoperable stage II NSCLC. RESULTS: Responses were received from 81/194 physicians (42% response rate), 57% medical and 42% radiation oncologists. Most physicians (90%) had a practice with at least 25% lung cancer patients and 85% were based at an academic institution. Across eight clinical patient scenarios, radical therapy was selected 79-98% of the time. Radical radiotherapy alone and concurrent chemoradiotherapy were the preferred options for these patients, while sequential chemoradiation was less favoured. Nodal status (N0 vs N1) did not influence choice of therapy (p 0.31), but the reason for patient inoperability did (p<0.0001). There was no significant difference in choice of therapy when comparing responses between medical vs radiation oncologists, academic vs community physicians, and physicians with high vs low proportion of lung cancer patients. CONCLUSION: Most lung cancer physicians manage inoperable stage II NSCLC patients with curative intent, but consensus on how to optimally employ radiotherapy and/or chemotherapy is lacking. Future prospective, randomized trials are warranted. PMID- 26973211 TI - Metabolic tumor burden as marker of outcome in advanced EGFR wild-type NSCLC patients treated with erlotinib. AB - OBJECTIVES: Accurate estimation of the prognosis of advanced non-small cell lung cancer (NSCLC) patients is essential before initiation of palliative treatment; especially in the second and third-line setting. This study was conducted in order to evaluate tumor burden measured on an 2'-deoxy-2'-[18F] fluoro-D-glucose (F-18-FDG) positron emission tomography/computed tomography (PET/CT) scan as a marker of outcome in advanced epidermal growth factor receptor (EGFR) wild-type patients treated with second or third-line erlotinib. MATERIAL AND METHODS: Fifty one patients were included from a prospectively collected cohort. An F-18-FDG PET/CT scan was conducted prior to erlotinib treatment and tumor burden was measured in terms of metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Median values of MTV and TLG were used for dichotomization of patients. Survival outcome was compared between groups. RESULTS: MTV and TLG could be measured in 49 patients. High values of MTV and TLG were significantly correlated with shorter PFS (p<0.001 and p=0.027, respectively) and OS (p<0.001 and p=0.002, respectively). In multivariate analyses, including both clinical and imaging data, high MTV and TLG remained strong independent markers of both shorter PFS (MTV, hazard ratio (HR)=5.44 (95% confidence interval (CI) 2.46-12.02); TLG, HR=2.17 (95% CI 1.11-4.26)) and OS (MTV, HR=4.80 (95% CI 2.08-11.06); TLG, HR=2.76 (95% CI 1.33-5.71)). CONCLUSION: High MTV and TLG are independently correlated with shorter PFS and OS in advanced EGFR wild-type NSCLC patients treated with second or third-line erlotinib. Metabolic tumor burden is a highly promising clinical tool that may allow better patient selection for palliative treatment in the future. PMID- 26973212 TI - The metabolomic detection of lung cancer biomarkers in sputum. AB - OBJECTIVES: Developing screening and diagnosis methodologies based on novel biomarkers should allow for the detection of the lung cancer (LC) and possibly at an earlier stage and thereby increase the effectiveness of clinical interventions. Here, our primary objective was to evaluate the potential of spontaneous sputum as a source of non-invasive metabolomic biomarkers for LC status. MATERIALS AND METHODS: Spontaneous sputum was collected and processed from 34 patients with suspected LC, alongside 33 healthy controls. Of the 34 patients, 23 were subsequently diagnosed with LC (LC(+), 16 NSCLC, six SCLC, and one radiological diagnosis), at various stages of disease progression. The 67 samples were analysed using flow infusion electrospray ion mass spectrometry (FIE MS) and gas-chromatography mass spectrometry (GC-MS). RESULTS: Principal component analysis identified negative mode FIE-MS as having the main separating power between samples from healthy and LC. Discriminatory metabolites were identified using ANOVA and Random Forest. Indications of potential diagnostic accuracy involved the use of receiver operating characteristic/area under the curve (ROC/AUC) analyses. This approach identified metabolites changes that were only observed with LC. Metabolites with AUC values of greater than 0.8 which distinguished between LC(+)/LC(-) binary classifications where identified and included Ganglioside GM1 which has previously been linked to LC. CONCLUSION: This study indicates that metabolomics based on sputum can yield metabolites that can be used as a diagnostic and/or discriminator tool. These could aid clinical intervention and targeted diagnosis of LC within an 'at risk' LC(-) population group. The use of sputum as a non-invasive source of metabolite biomarkers may aid in the development of an at-risk population screening programme for lung cancer or enhanced clinical diagnostic pathways. PMID- 26973213 TI - Biochemical verification of the self-reported smoking status of screened male smokers of the Dutch-Belgian randomized controlled lung cancer screening trial. AB - BACKGROUND: Smoking is the main cause of lung cancer, so data linked to smoking behaviour are important in lung cancer screening trials. However, self-reporting data concerning smoking behaviour are mainly used. The aim of this study was to biochemically determine the validity and reliability of self-reported smoking status among smokers at high risk for developing lung cancer participating in the Dutch-Belgian lung cancer screening (NELSON) trial. METHOD: For this sub study, a random sample of 475 men was selected who were scheduled for the fourth screening round in the NELSON trial. They were asked to complete a short questionnaire to verify the smoking behaviour for the previous seven days and a blood sample was collected to measure the cotinine level. The validity (sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV)) and reliability (Kappa) of the self-reported smoking status compared to the cotinine level (as golden standard) were determined. RESULTS: Both a completed questionnaire as well as a cotinine level were available for 199 (41.9%) participants. Based on these data, Se and Sp were respectively 98% (95% Confidence Interval (CI): 91-99) and 98% (95%-CI: 93-100). PPV and NPV were 98% and 96% and Kappa was 0.96. CONCLUSION: In conclusion, the validity of the self reported smoking status turned out to be reliable amongst men at high risk for developing lung cancer who participate in the NELSON lung cancer screening trial. PMID- 26973214 TI - Aberrant gene methylation and bronchial dysplasia in high risk lung cancer patients. AB - INTRODUCTION: The risk for lung cancer is incremented in high degree dysplasia (HGD) and in subjects with hypermethylation of multiple genes. We sought to establish the association between them, as well as to analyze the DNA aberrant methylation in sputum and in bronchial washings (BW). METHODS: Cross sectional study of high risk patients for lung cancer in whom induced sputum and autofluorescence bronchoscopy were performed. The molecular analysis was determined on DAPK1, RASSF1A and p16 genes using Methylation-specific PCR. RESULTS: A total of 128 patients were enrolled in the study. Dysplasia lesions were found in 79 patients (61.7%) and high grade dysplasia in 20 (15.6%). Ninety eight patients out of 128 underwent molecular analysis. Methylation was observed in bronchial secretions (sputum or BW) in 60 patients (61.2%), 51 of them (52%) for DAPK1, in 20 (20.4%) for p16 and in three (3.1%) for RASSF1A. Methylated genes only found in sputum accounted for 38.3% and only in BW in 41.7%, and in both 20.0%. In the 11.2% of the patients studied, HGD and a hypermethylated gene were present, while for the 55.1% of the sample only one of both was detected and for the rest of the subjects (33.6%), none of the risk factors were observed. CONCLUSIONS: Our data determines DNA aberrant methylation panel in bronchial secretions is present in a 61.2% and HGD is found in 15.6%. Although both parameters have previously been identified as risk factors for lung cancer, the current study does not find a significative association between them. The study also highlights the importance of BW as a complementary sample to induced sputum when analyzing gene aberrant methylation. PMID- 26973215 TI - Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy for locally advanced non-small cell lung cancer. AB - OBJECTIVES: Curative intent treatment options for locoregional recurrence or persistent tumor after radical chemoradiotherapy for locally-advanced non-small cell lung cancer (NSCLC) are limited. In selected patients, surgery can be technically feasible, although it is widely believed to be hazardous. As data regarding the outcome of this approach is sparse, we evaluated our institutional experience with salvage surgery. MATERIALS AND METHODS: Patients with a pulmonary resection for in-field locoregional recurrence or persistent tumor after high dose chemoradiotherapy (>=60 Gy) for the treatment of non-small cell lung cancer, were identified and retrospectively analyzed. RESULTS: A total of 15 patients treated between January 2007 and August 2015 were eligible for evaluation. In 13 patients (87%), the indication for surgery was a locoregional recurrence, while 2 patients had persistent tumor. The prior median radiotherapy dose was 66 Gy (range 60-70). All patients underwent an anatomical resection, with 8 patients having a pneumonectomy, and all pathological specimens revealed the presence of viable tumor. The in-hospital morbidity rate was 40% (6 patients), and the 90-day mortality rate was 6.7% (1 patient). Median follow-up was 12.1 months. The estimated median overall and event-free survivals were 46 months and 43.6 months, respectively. CONCLUSION: Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy, resulted in acceptable morbidity, mortality and promising outcome. It should be considered as a treatment option for selected patients. PMID- 26973216 TI - A sensitive and high throughput TaqMan-based reverse transcription quantitative polymerase chain reaction assay efficiently discriminates ALK rearrangement from overexpression for lung cancer FFPE specimens. AB - OBJECTIVES: ALK fusion gene is an oncogenic driver in lung cancer with low prevalence, which can be ameliorated by crizotinib. Currently, ALK fusion gene can be diagnosed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), but inconstistnt results between the two methods are encountered regularly. To make the ALK fusion gene screening more efficient and to provide a simple solution to clarify the discrepancy between FISH and IHC results, a sensitive TaqMan-based reverse transcription quantitative polymerase chain reaction (RT-qPCR) assay was established. MATERIALS AND METHODS: The 3-plex TaqMan-based RT-qPCR assay was established and performed on 102 archived formalin fixed, paraffin-embedded (FFPE) NSCLC samples to detect ALK rearrangement and overexpression. Break-apart FISH and automatic immunohistochemistry based ALK assays were performed side by side using tissue microarray. RESULTS: The RT-qPCR was performed successfully for 80 samples and 10 of them showed positive signals. Three out of the 10 qPCR positive cases were further confirmed by FISH and IHC test. Two others were IHC positive and FISH negative, and expressed full-length ALK transcript. The rest were neither FISH nor IHC positive and their ALK expression level was significantly lower than those FISH or IHC positive cases. CONCLUSION: Our RT-qPCR assay demonstrates that the capability and reliability of ALK detection is comparable to FISH and IHC, but it is more effective at discriminating ALK rearrangement from overexpression. The RT-qPCR assay easily clarifies the discrepancy between FISH and IHC, and can be incorporated into routine ALK screening for lung cancer. PMID- 26973217 TI - Vergence findings and horizontal vergence dysfunction among first year university students in Benin City, Nigeria. AB - PURPOSE: The study was designed to determine the prevalence of vergence dysfunctions among first year university students in Nigeria and to document the measures that define the vergence system of the visual system. METHODS: A cross sectional study of first year students of the University of Benin, Benin City, Nigeria, who presented for the mandatory eye examination as part of their medical examinations required for clearance was conducted. A battery of tests that defines the vergence system including near and far phoria, positive and negative fusional vergence amplitudes at far and near, near point of convergence (NPC) and AC/A ratio were measured using conventional clinical protocols. RESULTS: The prevalence of vergence dysfunction among 212 first year university students who satisfied the inclusion criteria and gave consent to participate was 12.7%, with convergence insufficiency being the most common vergence dysfunction. Blurred vision, headache and diplopia were the most frequently reported visual symptoms. CONCLUSION: There is a considerable prevalence of previously undiagnosed vergence dysfunctions in this population of students. The study underscored the need to carry out a thorough binocular vision assessment as part of the battery of tests administered to newly admitted students in this community to forestall any adverse effect the presence of vergence dysfunctions might have on the academic activity of university students. PMID- 26973218 TI - Tailor-made heart simulation predicts the effect of cardiac resynchronization therapy in a canine model of heart failure. AB - Despite extensive studies on clinical indices for the selection of patient candidates for cardiac resynchronization therapy (CRT), approximately 30% of selected patients do not respond to this therapy. Herein, we examined whether CRT simulations based on individualized realistic three-dimensional heart models can predict the therapeutic effect of CRT in a canine model of heart failure with left bundle branch block. In four canine models of failing heart with dyssynchrony, individualized three-dimensional heart models reproducing the electromechanical activity of each animal were created based on the computer tomographic images. CRT simulations were performed for 25 patterns of three ventricular pacing lead positions. Lead positions producing the best and the worst therapeutic effects were selected in each model. The validity of predictions was tested in acute experiments in which hearts were paced from the sites identified by simulations. We found significant correlations between the experimentally observed improvement in ejection fraction (EF) and the predicted improvements in ejection fraction (P<0.01) or the maximum value of the derivative of left ventricular pressure (P<0.01). The optimal lead positions produced better outcomes compared with the worst positioning in all dogs studied, although there were significant variations in responses. Variations in ventricular wall thickness among the dogs may have contributed to these responses. Thus CRT simulations using the individualized three-dimensional heart models can predict acute hemodynamic improvement, and help determine the optimal positions of the pacing lead. PMID- 26973219 TI - A plasmid-based expression system to study protein-protein interactions at the Golgi in vivo. AB - There is still an unmet need for simple methods to verify, visualize, and confirm protein-protein interactions in vivo. Here we describe a plasmid-based system to study such interactions. The system is based on the transmembrane domain (TMD) of the EF-hand Ca(2+) sensor protein calneuron-2. We show that fusion of 28 amino acids that include the TMD of calneuron-2 to proteins of interest results in prominent localization on the cytoplasmic side of the Golgi. The recruitment of binding partners to the protein of interest fused to this sequence can then be easily visualized by fluorescent tags. PMID- 26973220 TI - Highly specific quantification of microRNA by coupling probe-rolling circle amplification and Forster resonance energy transfer. AB - MicroRNA (miRNA) plays vital roles in various biological processes. In general, sensitivity and specificity are the major parameters for the quantification of miRNA. In this study, padlock probe-rolling circle amplification and Forster resonance energy transfer (pRCA-FRET) were coupled for specific and quantitative detection of miRNA. pRCA-FRET showed superior specificity to differentiate single base mismatch and excellent sensitivity with a detection limit of 103 aM. The current method has the potential to quantify low amounts of miRNA in the same family for studies on their biological functions. PMID- 26973222 TI - Evaluating arguments during instigations of defence motivation and accuracy motivation. AB - When people evaluate the strength of an argument, their motivations are likely to influence the evaluation. However, few studies have specifically investigated the influences of motivational factors on argument evaluation. This study examined the effects of defence and accuracy motivations on argument evaluation. According to the compatibility between the advocated positions of arguments and participants' prior beliefs and the objective strength of arguments, participants evaluated four types of arguments: compatible-strong, compatible-weak, incompatible-strong, and incompatible-weak arguments. Experiment 1 revealed that participants possessing a high defence motivation rated compatible-weak arguments as stronger and incompatible-strong ones as weaker than participants possessing a low defence motivation. However, the strength ratings between the high and low defence groups regarding both compatible-strong and incompatible-weak arguments were similar. Experiment 2 revealed that when participants possessed a high accuracy motivation, they rated compatible-weak arguments as weaker and incompatible-strong ones as stronger than when they possessed a low accuracy motivation. However, participants' ratings on both compatible-strong and incompatible-weak arguments were similar when comparing high and low accuracy conditions. The results suggest that defence and accuracy motivations are two major motives influencing argument evaluation. However, they primarily influence the evaluation results for compatible-weak and incompatible-strong arguments, but not for compatible-strong and incompatible-weak arguments. PMID- 26973221 TI - Clinical presentation and outcome of riboflavin transporter deficiency: mini review after five years of experience. AB - INTRODUCTION: Riboflavin (vitamin B2) is absorbed in the small intestine by the human riboflavin transporters RFVT1 and RFVT3. A third riboflavin transporter (RFVT2) is expressed in the brain. In 2010 it was demonstrated that mutations in the riboflavin transporter genes SLC52A2 (coding for RFVT2) and SLC52A3 (coding for RFVT3) cause a neurodegenerative disorder formerly known as Brown-Vialetto Van Laere (BVVL) syndrome, now renamed to riboflavin transporter deficiency. Five years after the diagnosis of the first patient we performed a review of the literature to study the presentation, treatment and outcome of patients with a molecularly confirmed diagnosis of a riboflavin transporter deficiency. METHOD: A search was performed in Medline, Pubmed using the search terms 'Brown-Vialetto Van Laere syndrome' and 'riboflavin transporter' and articles were screened for case reports of patients with a molecular diagnosis of a riboflavin transporter deficiency. RESULTS: Reports on a total of 70 patients with a molecular diagnosis of a RFVT2 or RTVT3 deficiency were retrieved. The riboflavin transporter deficiencies present with weakness, cranial nerve deficits including hearing loss, sensory symptoms including sensory ataxia, feeding difficulties and respiratory difficulties which are caused by a sensorimotor axonal neuropathy and cranial neuropathy. Biochemical abnormalities may be absent and the diagnosis can only be made or rejected by molecular analysis of all genes. Treatment with oral supplementation of riboflavin is lifesaving. Therefore, if a riboflavin transporter deficiency is suspected, treatment must be started immediately without first awaiting the results of molecular diagnostics. PMID- 26973223 TI - Counseling Is Effective for Smoking Cessation in Head and Neck Cancer Patients-A Systematic Review and Meta-Analysis. AB - PURPOSE: The purpose of this systematic review was to describe the efficacy of smoking cessation counseling and the resulting quit rate in patients with head and neck cancer. MATERIALS AND METHODS: A systematic literature search was conducted in the PubMed, Embase, and Cochrane databases. Predictor variables were smoking cessation counseling and smoking cessation interventions. The outcome was smoking cessation. Data collection and quality assessment were performed independently by 2 of the authors. Selected publications were assessed for potential risk of bias, and the level of evidence was evaluated using National Health and Medical Research Council guidelines. Review Manager 5.3 was used to conduct the meta-analysis. RESULTS: Eight studies involving 1,239 patients were included (3 randomized controlled trials, 3 cohorts, and 2 case series). Smoking cessation was achieved considerably more often in patients who received smoking cessation counseling compared with those who received usual care. CONCLUSIONS: This review shows that counseling supplemented with nicotine replacement therapy increases the possibility for smoking cessation in patients with head and neck cancer. PMID- 26973224 TI - Perceptual Speech Assessment After Anterior Maxillary Distraction in Patients With Cleft Maxillary Hypoplasia. AB - PURPOSE: To assess speech outcomes after anterior maxillary distraction (AMD) in patients with cleft-related maxillary hypoplasia. MATERIALS AND METHODS: Fifty eight patients at least 10 years old with cleft-related maxillary hypoplasia were included in this study irrespective of gender, type of cleft lip and palate, and amount of required advancement. AMD was carried out in all patients using a tooth borne palatal distractor by a single oral and maxillofacial surgeon. Perceptual speech assessment was performed by 2 speech language pathologists preoperatively, before placement of the distractor device, and 6 months postoperatively using the scoring system of Perkins et al (Plast Reconstr Surg 116:72, 2005); the system evaluates velopharyngeal insufficiency (VPI), resonance, nasal air emission, articulation errors, and intelligibility. The data obtained were tabulated and subjected to statistical analysis using Wilcoxon signed rank test. A P value less than .05 was considered significant. RESULTS: Eight patients were lost to follow up. At 6-month follow-up, improvements of 62% (n = 31), 64% (n = 32), 50% (n = 25), 68% (n = 34), and 70% (n = 35) in VPI, resonance, nasal air emission, articulation, and intelligibility, respectively, were observed, with worsening of all parameters in 1 patient (2%). The results for all tested parameters were highly significant (P <= .001). CONCLUSION: AMD offers a substantial improvement in speech for all 5 parameters of perceptual speech assessment. PMID- 26973226 TI - Clinical Retrospective Analysis of 9 Cases of Intraparotid Facial Nerve Schwannoma. AB - PURPOSE: The management of intraparotid facial nerve schwannoma (IFNS) is challenging because it is extremely rare and often misdiagnosed as pleomorphic adenoma or another parotid tumor. The purpose of this study was to report on the authors' experience in the treatment of IFNS and to review the literature regarding the diagnosis and management of IFNS. MATERIALS AND METHODS: From January 1997 through October 2015, 916 consecutive parotidectomies were performed at Shenzhen People's Hospital (Shenzhen, China). Of 916 parotid tumors samples, 9 cases of IFNS confirmed by histopathology were identified and analyzed retrospectively. In addition, 161 published cases from 1956 through 2015 were systematically reviewed. RESULTS: Nine cases of IFNS were identified from 916 parotid tumors samples and accounted for 0.98% of all parotid tumors. All these patients with IFNS underwent tumor removal and parotidectomy with preservation of facial nerve (FN) continuity. The mean follow-up period was 6.2 years (range, 1 to 16 yr). Facial function improved gradually from House-Brackmann grade (HBG) II to III immediately postoperatively to HBG I during the subsequent 3 to 9 months in all cases. Tumor recurrence with stylomastoid foramen involvement was observed in 1 case 3 years after surgery. The others remained free of recurrence. Of 161 IFNS cases reported in the literature, 17 cases with facial paresis were found to have intra-temporal involvement, but no facial paresis was found in patients with intraparotid involvement only. CONCLUSIONS: An IFNS is easily misdiagnosed as pleomorphic adenoma or Warthin tumor preoperatively; the correct diagnosis for IFNS depends mainly on intraoperative observation of the gross relation between the tumor and the FN or excision frozen biopsy examination. The integrity of the FN should be preserved for patients with IFNS and without facial paresis, whenever possible. PMID- 26973227 TI - Complete genome sequence of bean rugose mosaic virus, genus Comovirus. AB - Since the first report in Costa Rica in 1971, bean rugose mosaic virus (BRMV) has been found in Colombia, El Salvador, Guatemala and Brazil. In this study, the complete genome sequence of a soybean isolate of BRMV from Parana State, Brazil, was determined. The BRMV genome consists of two polyadenylated RNAs. RNA1 is 5909 nucleotides long and encodes a single polypeptide of 1856 amino acids (aa), with an estimated molecular weight of 210 kDa. The RNA1 polyprotein contains the polypeptides for viral replication and proteolytic processing. RNA2 is 3644 nucleotides long and codes for a single polypeptide of 1097 aa, containing the movement and coat proteins. This is the first complete genome sequence of BRMV. When compared with available aa sequences of comoviruses, the highest identities of BRMV coat proteins and proteinase polymerase were 57.5 and 58 %, respectively. These were below the 75 and 80 % identity limits, respectively, established for species demarcation in the genus. This confirms that BRMV is a member of a distinct species in the genus Comovirus. PMID- 26973225 TI - Primary Oral Malignancy Imitating Peri-Implantitis. AB - PURPOSE: To describe new cases of primary malignancy arising around dental implants. MATERIALS AND METHODS: Three patients presented with asymptomatic lesions around longstanding dental implants that resembled peri-implantitis. One case was primary large B-cell lymphoma and the remaining cases were primary squamous cell carcinoma in patients with oral lichen planus. The literature was reviewed for cases mimicking peri-implantitis. RESULTS: Of 42 implant-associated malignancies reported from 2000 through 2014, 85.7% were squamous cell carcinoma (69% primary and 9.4% metastatic). Most patients presented with pre-existing risk factors for oral cancer. Lymphoma was not associated with dental implants. CONCLUSIONS: Primary and metastatic malignancies can occur in peri-implant mucosa, often with clinical and radiographic features resembling peri implantitis. Clinicians should have a high index of suspicion for changes in peri implant mucosa in patients with existing risk factors; however, rare cases such as lymphoma might present outside this risk population. Histopathologic analysis should be included in the management of selected peri-implant lesions to avoid delayed diagnosis of malignancy. PMID- 26973228 TI - Association of IFNL3 and IFNL4 polymorphisms with hepatitis C virus infection in a population from southeastern Brazil. AB - Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated complications such as liver cirrhosis and hepatocellular carcinoma (HCC). Viral and host factors are known to be predictors for antiviral therapy. Host factors that are predictors of sustained viral response (SVR) were discovered by genome-wide association studies (GWAS), including single-nucleotide polymorphisms (SNPs) in or near the interferon lambda gene (rs8099917, rs12979860 and rs368234815). The aim of the present study was to verify the genotype frequencies of SNPs rs8099917, rs12979860 and rs368234815 and to evaluate the association between SNPs and the outcome of HCV infection, taking into account the population ancestry. In this study, there was an association of the three polymorphisms with both clinical outcome and response to treatment with PEG-IFN and RBV. The polymorphisms rs12979860 and rs368234815 were associated with increased sensitivity (97.7 %, 95 % CI 87.2-100, and 93.3 %, 95 % CI 81.3-98.3; respectively) and with a greater predictive value of a positive response to treatment. In multivariable analysis adjusted by gender, age and ancestry, the haplotype G/T/DeltaG was related to non-response to treatment (OR = 21.09, 95 % CI 5.33-83.51; p < 0.001) and to a higher chance of developing chronic infection (OR = 5.46, 95 % CI 2.06-14.46; p = 0.001) when compared to the haplotype T/C/TT. These findings may help to adjust our treatment policies for HCV infection based on greater certainty in studies with populations with such genetic characteristics, as well as allowing us to get to know the genetic profile of our population for these polymorphisms. PMID- 26973230 TI - Genomic variability and molecular evolution of Asian isolates of sugarcane streak mosaic virus. AB - Sugarcane streak mosaic virus (SCSMV), an economically important causal agent of mosaic disease of sugarcane, is a member of the newly created genus Poacevirus in the family Potyviridae. In this study, we report the molecular characterization of three new SCSMV isolates from China (YN-YZ211 and HN-YZ49) and Myanmar (MYA Formosa) and their genetic variation and phylogenetic relationship to SCSMV isolates from Asia and the type members of the family Potyviridae. The complete genome of each of the three isolates was determined to be 9781 nucleotides (nt) in size, excluding the 3' poly(A) tail. Phylogenetic analysis of the complete polyprotein amino acid (aa) sequences (3130 aa) revealed that all SCSMV isolates clustered into a phylogroup specific to the genus Poacevirus and formed two distinct clades designated as group I and group II. Isolates YN-YZ211, HN-YZ49 and MYA-Formosa clustered into group I, sharing 96.8-99.5 % and 98.9-99.6 % nt (at the complete genomic level) and aa (at the polyprotein level) identity, respectively, among themselves and 81.2-98.8 % and 94.0-99.6 % nt (at the complete genomic level) and aa (at the polyprotein level) identity, respectively, with the corresponding sequences of seven Asian SCSMV isolates. Population genetic analysis revealed greater between-group (0.190 +/- 0.004) than within group (group I = 0.025 +/- 0.001 and group II = 0.071 +/- 0.003) evolutionary divergence values, further supporting the results of the phylogenetic analysis. Further analysis indicated that natural selection might have contributed to the evolution of isolates belonging to the two identified SCSMV clades, with infrequent genetic exchanges occurring between them over time. These findings provide a comprehensive analysis of the population genetic structure and driving forces for the evolution of SCSMV with implications for global exchange of sugarcane germplasm. PMID- 26973229 TI - Generation of E. coli-derived virus-like particles of porcine circovirus type 2 and their use in an indirect IgG enzyme-linked immunosorbent assay. AB - Porcine circovirus type 2 (PCV2) causes increased mortality and poor growth or weight loss in apparently healthy swine. Therefore, methods to detect PCV2 specific antibodies in swine serum are important for prevention, diagnosis, and control of PCV2-associated diseases (PCVAD). In this study, PCV2 virus-like particles (VLPs) were used to develop a rapid, simple and economical indirect enzyme-linked immunosorbent assay to detect (with high sensitivity) PCV2-specific antibodies in swine serum. The PCV2 capsid protein (Cap) was overexpressed in E. coli after optimizing the cap gene. Subsequently, the soluble Cap was rapidly purified in one step by automated fast protein liquid chromatography (FPLC). The purified PCV2 Cap was shown by transmission electron microscopy and gel filtration chromatography to be capable of self-assembling into VLPs in vitro. Using the purified VLPs as antigens, optimal operating conditions for the VLP ELISA were determined. The concentration of PCV2 VLPs was 1 ug/ml per well, and the dilution factors for swine serum and horseradish peroxidase (HRP)-labeled goat anti-pig antibody were 1:150 and 1:4000, respectively. Out of 241 serum samples tested with this assay, 83.4 % were found to be positive. Importantly, the VLP ELISA had a total coincidence rate of 97.4 % (74/76) compared to an Ingezim PCV2 ELISA IgG assay. In summary, this rapid, inexpensive VLP ELISA has the potential to greatly facilitate large-scale investigations of PCV2-associated serotypes. PMID- 26973231 TI - Complete genome sequence of yam chlorotic necrotic mosaic virus from Dioscorea parviflora. AB - The complete genome sequence of yam chlorotic necrotic mosaic virus (YCNMV) was determined. It is a monopartite ssRNA 8208 nucleotides in length (excluding the poly(A) tail) and encoding a polyprotein of 2622 amino acids. Sequence analysis showed that the P1 region and some conserved motifs, such as the typical potyvirus aphid-transmission motifs DAG, PTK and KITC, are absent. Phylogenetic analysis based on the complete polyprotein sequences of YCNMV and selected members of the family Potyviridae clearly showed that this virus should be assigned to the genus Macluravirus and suggest that YCNMV is a new member of the genus Macluravirus. PMID- 26973232 TI - Phylogenetic analysis of human influenza A/H3N2 viruses isolated in 2015 in Germany indicates significant genetic divergence from vaccine strains. AB - Infections by H3N2-type influenza A viruses (IAV) resulted in significant numbers of hospitalization in several countries in 2014-2015, causing disease also in vaccinated individuals and, in some cases, fatal outcomes. In this study, sequence analysis of H3N2 viruses isolated in Germany from 1998 to 2015, including eleven H3N2 isolates collected early in 2015, was performed. Compared to the vaccine strain A/Texas/50/2012 (H3N2), the 2015 strains from Germany showed up to 4.5 % sequence diversity in their HA1 protein, indicating substantial genetic drift. The data further suggest that two distinct phylogroups, 3C.2 and 3C.3, with 1.6-2.3 % and 0.3-2.4 % HA1 nucleotide and amino acid sequence diversity, respectively, co-circulated in Germany in the 2014/2015 season. Distinct glycosylation patterns and amino acid substitutions in the hemagglutinin and neuraminidase proteins were identified, possibly contributing to the unusually high number of H3N2 infections in this season and providing important information for developing vaccines that are effective against both genotypes. PMID- 26973233 TI - Erratum to: Lentiviral-Mediated Netrin-1 Overexpression Improves Motor and Sensory Functions in SCT Rats Associated with SYP and GAP-43 Expressions. PMID- 26973235 TI - Raman-based microarray readout: a review. AB - For a quarter of a century, microarrays have been part of the routine analytical toolbox. Label-based fluorescence detection is still the commonest optical readout strategy. Since the 1990s, a continuously increasing number of label based as well as label-free experiments on Raman-based microarray readout concepts have been reported. This review summarizes the possible concepts and methods and their advantages and challenges. A common label-based strategy is based on the binding of selective receptors as well as Raman reporter molecules to plasmonic nanoparticles in a sandwich immunoassay, which results in surface enhanced Raman scattering signals of the reporter molecule. Alternatively, capture of the analytes can be performed by receptors on a microarray surface. Addition of plasmonic nanoparticles again leads to a surface-enhanced Raman scattering signal, not of a label but directly of the analyte. This approach is mostly proposed for bacteria and cell detection. However, although many promising readout strategies have been discussed in numerous publications, rarely have any of them made the step from proof of concept to a practical application, let alone routine use. Graphical Abstract Possible realization of a SERS (Surface-Enhanced Raman Scattering) system for microarray readout. PMID- 26973236 TI - Gold nanoparticles assisted laser desorption/ionization mass spectrometry and applications: from simple molecules to intact cells. AB - Gold nanoparticles (AuNPs) assisted laser desorption/ionization mass spectrometry (GALDI-MS) provided new horizons and offered many functions for various applications. This review summarized AuNPs applications for analytical, biotechnology and proteomics. AuNPs efficiently absorbed the laser radiation and transferred the energy to the analyte for the desorption/ionization process. The unique features of AuNPs such as large surface area and high absorption coefficient lead not only to high resolution, low interference and low limit of detection, but also offered selective detection for certain species. AuNPs provided an excellent surface for the analysis of several species such as small molecules, biomarkers, proteins and cells (pathogenic bacteria or cancer cells). AuNPs played many roles such as surface for LDI-MS, probe and stationary phase for separation or preconcentration. AuNPs modified various surface chemistry was applied for a wide range of different wavelength. AuNPs severed as a source of Au(+) ions that were suitable for analyte cationisation. Characterization of Au nanoclusters (AuNCs) by mass spectrometry, pros and cons were also highlighted. Graphical Abstract Schematic representation of the analysis by Gold Nanoparticles Assisted Laser Desorption/Ionization Mass Spectrometry (GALDI-MS). PMID- 26973237 TI - Food allergen analysis for processed food using a novel extraction method to eliminate harmful reagents for both ELISA and lateral-flow tests. AB - Enzyme-linked immunosorbent assay (ELISA) is commonly used to determine food allergens in food products. However, a significant number of ELISAs give an erroneous result, especially when applied to highly processed food. Accordingly, an improved ELISA, which utilizes an extraction solution comprising the surfactant sodium lauryl sulfate (SDS) and reductant 2-mercaptoethanol (2-ME), has been specially developed to analyze food allergens in highly processed food by enhancing analyte protein extraction. Recently, however, the use of 2-ME has become undesirable. In the present study, a new extraction solution containing a human- and eco-friendly reductant, which is convenient to use at the food manufacturing site, has been established. Among three chemicals with different reducing properties, sodium sulfite, tris(3-hydroxypropyl)phosphine, and mercaptoethylamine sodium sulfite was selected as a 2-ME substitute. The protein extraction ability of SDS/0.1 M sodium sulfite solution was comparable to that of SDS/2-ME solution. Next, the ELISA performance for egg, milk, wheat, peanut, and buckwheat was evaluated by using model-processed foods and commercially available food products. The data showed that the SDS/0.1 M sulfite ELISA significantly correlated with the SDS/2-ME ELISA for all food allergens examined (p < 0.01), thereby establishing the validity of the SDS/0.1 M sulfite ELISA performance. Furthermore, the new SDS/0.1 M sulfite solution was investigated for its applicability to the lateral-flow (LF) test. The result demonstrated the successful analysis of food allergens in processed food, showing consistency with the SDS/0.1 M sulfite ELISA results. Accordingly, a harmonized analysis system for processed food comprising a screening LF test and a quantitative ELISA with identical extraction solution has been established. The ELISA based on the SDS/0.1 M sulfite extraction solution has now been authorized as the revised official method for food allergen analysis in Japan. PMID- 26973238 TI - Coprological tests underestimate Macracanthorhynchus hirudinaceus burden in wild boar. AB - The present study evaluated the limitations of the coprological sedimentation test to assess Macracanthorhynchus hirudinaceus infestation in 59 wild boars (Sus scrofa) from central Spain. The coprological sedimentation test appeared to be a poor predictor of both prevalence of infestation and the real parasite burden due to the high number of false negative results (prevalence was reduced from 61 to 16 %). Because of the potential increased risk of this zoonosis, it is suggested that alternative techniques be used in wildlife surveillance programmes. PMID- 26973239 TI - Angiopoietin-Like Protein 7 Promotes an Inflammatory Phenotype in RAW264.7 Macrophages Through the P38 MAPK Signaling Pathway. AB - Angiopoietin-like protein 7 (Angptl7) has been extensively studied for decades, but its potential immune functions have not been characterized. Hence, we investigated the relationship between Angptl7 and inflammation by using RAW264.7 monocyte/macrophage cells. The expression of genes encoding inflammation associated factors cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta), IL-6, IL-10, and transforming growth factor beta 1 (TGF-beta1)) decreased after RAW264.7 cells were treated with anti-Angptl7 polyclonal antibody but increased after the cells were transfected with an Angptl7-expressing plasmid. Angptl7 overexpression enhanced phagocytosis and inhibited the proliferation of RAW264.7 cells. In addition, Angptl7 antagonized the anti-inflammatory effects of TGF beta1 and dexamethasone. Pathway analysis showed that Angptl7 promoted the phosphorylation of both p65 and p38, but only the P38 mitogen-activated protein kinase (MAPK) signaling pathway mediated Angptl7-associated inflammatory functions. Additionally, after 1 week of daily intraperitoneal injections of recombinant TNF-alpha in a mouse model of peripheral inflammation, Angptl7 expression increased in the mouse eyes. Thus, Angptl7 is a factor that promotes pro-inflammatory responses in macrophages through the P38 MAPK signaling pathway and represents a potential therapeutic target for treatment of inflammatory diseases. PMID- 26973240 TI - Phosphorylation-dependent cleavage regulates von Hippel Lindau proteostasis and function. AB - Loss of von Hippel Lindau (VHL) protein function is a key driver of VHL diseases, including sporadic and inherited clear cell renal cell carcinoma. Modulation of the proteostasis of VHL, especially missense point-mutated VHL, is a promising approach to augmenting VHL levels and function. VHL proteostasis is regulated by multiple mechanisms including folding, chaperone binding, complex formation and phosphorylation. Nevertheless, many details underlying the regulations of VHL proteostasis are unknown. VHL is expressed as two variants, VHL30 and VHL19. Furthermore, the long-form variant of VHL was often detected as multiple bands by western blotting. However, how these multiple species of VHL are generated and whether the process regulates VHL proteostasis and function are unknown. We hypothesized that the two major species are generated by VHL protein cleavage, and the cleavage regulates VHL proteostasis and subsequent function. We characterized VHL species using genetical and pharmacological approaches and showed that VHL was first cleaved at the N-terminus by chymotrypsin C before being directed for proteasomal degradation. Casein kinase 2-mediated phosphorylation at VHL N-terminus was required for the cleavage. Furthermore, inhibition of cleavage stabilized VHL protein and thereby promoted HIF downregulation. Our study reveals a novel mechanism regulating VHL proteostasis and function, which is significant for identifying new drug targets and developing new therapeutic approaches targeting VHL deficiency in VHL diseases. PMID- 26973241 TI - Cancer stem cell drugs target K-ras signaling in a stemness context. AB - Cancer stem cells (CSCs) are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. Salinomycin is the most established CSC inhibitor. However, its primary mechanistic target is still unclear, impeding the discovery of compounds with similar anti-CSC activity. Here, we show that salinomycin very specifically interferes with the activity of K-ras4B, but not H-ras, by disrupting its nanoscale membrane organization. We found that caveolae negatively regulate the sensitivity to this drug. On the basis of this novel mechanistic insight, we defined a K-ras-associated and stem cell-derived gene expression signature that predicts the drug response of cancer cells to salinomycin. Consistent with therapy resistance of CSC, 8% of tumor samples in the TCGA-database displayed our signature and were associated with a significantly higher mortality. Using our K-ras-specific screening platform, we identified several new candidate CSC drugs. Two of these, ophiobolin A and conglobatin A, possessed a similar or higher potency than salinomycin. Finally, we established that the most potent compound, ophiobolin A, exerts its K-ras4B specific activity through inactivation of calmodulin. Our data suggest that specific interference with the K-ras4B/calmodulin interaction selectively inhibits CSC. PMID- 26973242 TI - Tumor cell survival dependence on the DHX9 DExH-box helicase. AB - The NTP-dependent DExH/D-box helicase DHX9 is a key participant in a number of gene regulatory steps, including transcriptional, translational, and microRNA mediated control, DNA replication and maintenance of genomic stability. DHX9 has also been implicated in tumor cell maintenance and drug response. Here we report that inhibition of DHX9 expression is lethal to human cancer cell lines and murine EMU-Myc lymphomas. Using a novel conditional shDHX9 mouse model, we demonstrate that sustained and prolonged (6 months) suppression of DHX9 does not result in any deleterious effects at the organismal level. Body weight, blood biochemistry and histology of various tissues were comparable to control mice. Global gene expression profiling revealed that, although reduction of DHX9 expression resulted in multiple transcriptome changes, these were relatively benign and did not lead to any discernible phenotype. Our results demonstrate a robust tolerance for systemic DHX9 suppression in vivo and support the targeting of DHX9 as an effective and specific chemotherapeutic approach. PMID- 26973243 TI - Differential regulation of LncRNA-SARCC suppresses VHL-mutant RCC cell proliferation yet promotes VHL-normal RCC cell proliferation via modulating androgen receptor/HIF-2alpha/C-MYC axis under hypoxia. AB - It is well established that hypoxia contributes to tumor progression in a hypoxia inducible factor-2alpha (HIF-2alpha)-dependent manner in renal cell carcinoma (RCC), yet the role of long noncoding RNAs (LncRNAs) involved in hypoxia-mediated RCC progression remains unclear. Here we demonstrate that LncRNA-SARCC (Suppressing Androgen Receptor in Renal Cell Carcinoma) is differentially regulated by hypoxia in a von Hippel-Lindau (VHL)-dependent manner both in RCC cell culture and clinical specimens. LncRNA-SARCC can suppress hypoxic cell cycle progression in the VHL-mutant RCC cells while derepress it in the VHL-restored RCC cells. Mechanism dissection reveals that LncRNA-SARCC can post transcriptionally regulate androgen receptor (AR) by physically binding and destablizing AR protein to suppress AR/HIF-2alpha/C-MYC signals. In return, HIF 2alpha can transcriptionally regulate the LncRNA-SARCC expression via binding to hypoxia-responsive elements on the promoter of LncRNA-SARCC. The negative feedback modulation between LncRNA-SARCC/AR complex and HIF-2alpha signaling may then lead to differentially modulated RCC progression in a VHL-dependent manner. Together, these results may provide us a new therapeutic approach via targeting this newly identified signal from LncRNA-SARCC to AR-mediated HIF-2alpha/C-MYC signals against RCC progression. PMID- 26973244 TI - Hypoxia and MITF regulate KIT oncogenic properties in melanocytes. AB - KIT mutations are frequent in acral, mucosal and chronic sun-damage (CSD) melanoma, but little is known about the mechanisms driving the transformation of KIT-mutated melanocytes into melanoma cells. We showed that exposition of melanocytes harboring the (L576P)KIT mutation to a hypoxic environment induced their transformation into malignant cells. Transformed (L576P)KIT melanocytes showed downregulation of MITF expression characteristic of melanoma initiating cells (MICs). In agreement, these cells were able to form spheres in neural crest cell medium and low-adherence conditions, also a characteristic of MICs. Downregulation of MITF by RNA interference induced transformation of KIT-mutated melanocytes in normoxia and acquisition of a MIC phenotype by these cells. Hence, low level of MITF cooperates with oncogenic KIT to transform melanocytes. Activation of the cAMP pathway in transformed (L576P)KIT melanocytes stimulated MITF expression, and reduced cellular proliferation and sphere formation. These findings highlight the essential role of MITF in revealing the oncogenic activity of KIT in melanocytes and suggest that the cAMP pathway is a therapeutic target in KIT-mutated melanoma. PMID- 26973245 TI - TAK1 regulates hepatic lipid homeostasis through SREBP. AB - Sterol-regulatory element-binding proteins (SREBPs) are key transcription factors regulating cholesterol and fatty acid biosynthesis. SREBP activity is tightly regulated to maintain lipid homeostasis, and is modulated upon extracellular stimuli such as growth factors. While the homeostatic SREBP regulation is well studied, stimuli-dependent regulatory mechanisms are still elusive. Here we demonstrate that SREBPs are regulated by a previously uncharacterized mechanism through transforming growth factor-beta activated kinase 1 (TAK1), a signaling molecule of inflammation. We found that TAK1 binds to and inhibits mature forms of SREBPs. In an in vivo setting, hepatocyte-specific Tak1 deletion upregulates liver lipid deposition and lipogenic enzymes in the mouse model. Furthermore, hepatic Tak1 deficiency causes steatosis pathologies including elevated blood triglyceride and cholesterol levels, which are established risk factors for the development of hepatocellular carcinoma (HCC) and are indeed correlated with Tak1 deficiency-induced HCC development. Pharmacological inhibition of SREBPs alleviated the steatosis and reduced the expression level of the HCC marker gene in the Tak1-deficient liver. Thus, TAK1 regulation of SREBP critically contributes to the maintenance of liver homeostasis to prevent steatosis, which is a potentially important mechanism to prevent HCC development. PMID- 26973246 TI - Twist1-induced activation of human fibroblasts promotes matrix stiffness by upregulating palladin and collagen alpha1(VI). AB - The transcription factor Twist1 is involved in the epithelial-mesenchymal transition and contributes to cancer metastasis through mostly unknown mechanisms. In colorectal cancer, Twist1 expression is mainly restricted to the tumor stroma. We found that human fibroblast cell lines stably transfected with Twist1 acquired characteristics of activated cancer-associated fibroblasts (CAFs), such as hyperproliferation, an increased ability to migrate and an alignment of the actin cytoskeleton. Further, Twist1-activated fibroblasts promoted increased matrix stiffness. Using quantitative proteomics, we identified palladin and collagen alpha1(VI) as two major mediators of the Twist1 effects in fibroblast cell lines. Co-immunoprecipitation studies indicated that palladin and Twist1 interact within the nucleus, suggesting that palladin could act as a transcription regulator. Palladin was found to be more relevant for the cellular biomechanical properties, orientation and polarity, and collagen alpha1(VI) for the migration and invasion capacity, of Twist1-activated fibroblasts. Both palladin and collagen alpha1(VI) were observed to be overexpressed in colorectal CAFs and to be associated with poor colorectal cancer patient survival and relapse prediction. Our results demonstrate that Twist1-expressing fibroblasts mimic the properties of CAFs present at the tumor invasive front, which likely explains the prometastatic activities of Twist1. Twist1 appears to require both palladin and collagen alpha1(VI) as downstream effectors for its prometastatic effects, which could be future therapeutic targets in cancer metastasis. PMID- 26973247 TI - Effects of Kras activation and Pten deletion alone or in combination on MUC1 biology and epithelial-to-mesenchymal transition in ovarian cancer. AB - Mucin1 (MUC1) is an epithelial glycoprotein overexpressed in ovarian cancer and actively involved in tumor cell migration and metastasis. Using novel in vitro and in vivo MUC1-expressing conditional (Cre-loxP) ovarian tumor models, we focus here on MUC1 biology and the roles of Kras activation and Pten deletion during cell transformation and epithelial-to-mesenchymal transition (EMT). We generated several novel murine ovarian cancer cell lines derived from the ovarian surface epithelia (OSE) of mice with conditional mutations in Kras, Pten or both. In addition, we also generated several tumor-derived new cell lines that reproduce the original tumor phenotype in vivo and mirror late stage metastatic disease. Our results demonstrate that de novo activation of oncogenic Kras does not trigger increased proliferation, cellular transformation or EMT, and prevents MUC1 upregulation. In contrast, Pten deletion accelerates cell proliferation, triggers cellular transformation in vitro and in vivo, and stimulates MUC1 expression. Ovarian tumor-derived cell lines MKP-Liver and MKP-Lung cells reproduce in vivo EMT and represent the first immune competent mouse model for distant hematogenous spread. Whole genome microarray expression analysis using tumor and OSE-derived cell lines reveal a 121 gene signature associated with EMT and metastasis. When applied to n=542 cases from The Cancer Genome Atlas (TCGA) ovarian cancer dataset, the gene signature identifies a patient subset with decreased survival (P=0.04). Using an extensive collection of novel murine cell lines we have identified distinct roles for Kras and Pten on MUC1 and EMT in vivo and in vitro. The data has implications for future design of combination therapies targeting Kras mutations, Pten deletions and MUC1 vaccines. PMID- 26973248 TI - Scaffold protein FHL2 facilitates MDM2-mediated degradation of IER3 to regulate proliferation of cervical cancer cells. AB - The expression of immediate early response 3 (IER3), a protein with a short half life, is rapidly induced by various cellular stimuli. We recently reported that IER3 induces the apoptosis of cervical cancer cells and that its expression is downregulated in patients with cervical cancer. However, the molecular mechanism involved in the rapid degradation of IER3 remains unknown. Here, we demonstrate that MDM2 is an E3 ligase that interacts with IER3 and promotes its ubiquitination, followed by proteasomal degradation. Polyubiquitination of the conserved lysine 60 of IER3 is essential for its degradation. In addition, four and a half LIM domains protein 2 (FHL2) binds to both IER3 and MDM2, allowing for efficient MDM2-mediated IER3 degradation by facilitating an association between MDM2 and IER3. Moreover, IER3 induces cell cycle arrest in cervical cancer cells and its activity is further enhanced in cells in which FHL2 or MDM2 was silenced, thereby preventing IER3 degradation. The E6 and E7 oncoproteins of human papilloma virus 18 regulated IER3 expression. FHL2 expression was significantly higher in the squamous epithelium of cervical carcinoma tissues than in non cancerous cervical tissues, whereas cervical carcinoma expression of IER3 was downregulated in this region. Thus, we determined the molecular mechanism responsible for IER3 degradation, involving a ternary complex of IER3, MDM2 and FHL2, which may contribute to cervical tumor growth. Furthermore, we demonstrated that FHL2 serves as a scaffold for E3 ligase and its substrate during the ubiquitination reaction, a function that has not been previously reported for this protein. PMID- 26973250 TI - Olfactomedin 4 deletion induces colon adenocarcinoma in ApcMin/+ mice. AB - Colon carcinogenesis is a multiple-step process involving the accumulation of a series of genetic and epigenetic alterations. The most commonly initiating event of intestinal carcinogenesis is mutation of the adenomatous polyposis coli (APC) gene, which leads to activation of the Wnt/beta-catenin pathway. Olfactomedin 4 (OLFM4) has emerged as an intestinal stem-cell marker, but its biological function in the intestine remains to be determined. Here we show that Olfm4 deletion induced colon adenocarcinoma in the distal colon of ApcMin/+ mice. Mechanistically, we found that OLFM4 is a target gene of the Wnt/beta-catenin pathway and can downregulate beta-catenin signaling by competing with Wnt ligands for binding to Frizzled receptors, as well as by inhibition of the Akt-GSK-3beta (Akt-glycogen synthase kinase-3beta) pathway. We have shown that both Wnt and nuclear factor-kappaB (NF-kappaB) signaling were boosted in tumor tissues of Apc Olfm4 double-mutant mice. These data establish OLFM4 as a critical negative regulator of the Wnt/beta-catenin and NF-kappaB pathways that inhibits colon cancer development initiated by APC mutation. In addition, Olfm4 deletion significantly enhanced intestinal-crypt proliferation and inflammation induced by azoxymethane/dextran sodium sulfate. Thus, OLFM4 has an important role in the regulation of intestinal inflammation and tumorigenesis, and could be a potential therapeutic target for intestinal malignant tumors. Unlike the human colonic epithelium, the mouse colonic epithelium does not express OLFM4, but nevertheless, systemic OLFM4 deletion promotes colon tumorigenesis and that loss from mucosal neutrophils may have a role to play. PMID- 26973252 TI - Stress-related function of bHLH109 in somatic embryo induction in Arabidopsis. AB - The bHLH109 gene of the bHLH family was identified among the transcription factor encoding genes that were differentially expressed in an embryogenic culture of Arabidopsis. A strong activation of bHLH109 expression was found to be associated with somatic embryogenesis (SE) induction. Several pieces of evidence suggested the involvement of bHLH109 in SE, including the high stimulation of the gene expression in SE-induced explants, which contrasts to the drastically lower level of the gene transcripts in the non-embryogenic callus and in tissue that is induced towards shoot regeneration via organogenesis. Moreover, in contrast to the overexpression of bHLH109, which has been indicated to enhance SE induction in a culture, the bhlh109 knock-out mutation was found to impair the embryogenic potential of explants. In order to identify the genes interacting with the bHLH109, the candidate co-expressed genes were identified in a yeast one hybrid assay. The in vitro regulatory interactions that were identified were verified through mutant and expression analysis. The results suggest that in SE bHLH109 acts as an activator of ECP63, a member of the LEA (LATE EMBRYOGENESIS ABUNDANT) family. Among the potential regulators of bHLH109, three candidates (At5g61620, bZIP4 and bZIP43) were indicated to possibly control bHLH109. The functions of all of the genes that are assumed to interact with bHLH109 are annotated to stress responses. Collectively, the results of the study provide new evidence that cell responses to stress that is imposed under in vitro conditions underlies the promotion of SE. bHLH109 may play a central role in the stress-related mechanism of SE induction via an increased accumulation of the LEA protein (ECP63), which results in the enhanced tolerance of the cells to stress. PMID- 26973249 TI - Bcl-2 proteins and calcium signaling: complexity beneath the surface. AB - Antiapoptotic Bcl-2-family members are well known for their 'mitochondrial' functions as critical neutralizers of proapoptotic Bcl-2-family members, including the executioner multidomain proteins Bax and Bak and the BH3-only proteins. It has been clear for more than 20 years that Bcl-2 proteins can impact intracellular Ca(2+) homeostasis and dynamics. Moreover, altered Ca(2+) signaling is increasingly linked to oncogenic behavior. Specifically targeting the Ca(2+) signaling machinery may thus prove to be a valuable strategy for cancer treatment. Over 10 years ago a major controversy was recognized concerning whether or not Bcl-2 proteins exerted their antiapoptotic functions via Ca(2+) signaling through lowering the filling state of the endoplasmic reticulum (ER) Ca(2+) stores or by suppressing Ca(2+) release from the ER without affecting the filling state of this Ca(2+) store. Further research from different laboratories indicated a wide variety of mechanisms by which Bcl-2-family members can impact Ca(2+) signaling. In this review, we propose that antiapoptotic Bcl-2-family members are multimodal regulators of intracellular Ca(2+)-signaling events in cell survival and cell death. We will discuss how different Bcl-2-family members impact cell survival and cell death by regulating Ca(2+) transport systems at the ER, mitochondria and plasma membrane and by impacting the organization of organelles and how these insights can be exploited for causing cell death in cancer cells. Finally, we propose that the existing controversy reflects the diversity of links between Bcl-2 proteins and Ca(2+) signaling, as certainly not all targets or mechanisms will be operative in every cell type and every condition. PMID- 26973251 TI - Cyclophilin D counteracts P53-mediated growth arrest and promotes Ras tumorigenesis. AB - Mitochondrial alterations induced by oncogenes are known to be crucial for tumorigenesis. Ras oncogene leads to proliferative signals through a Raf 1/MEK/ERK kinase cascade, whose components have been found to be also associated with mitochondria. The mitochondrial pepdidyl-prolyl isomerase cyclophilin D (CypD) is an important regulator of the mitochondrial permeability transition and a key player in mitochondria physiology; however, its role in cancer is still unclear. Using cellular and in vivo mouse models, we demonstrated that CypD protein upregulation induced by oncogenic Ras through the Raf-1/MEK/ERK pathway has a deterministic role in tumor progression. In fact, targeting CypD gene expression clearly affected RasV12-induced transformation, as showed by in vitro data on murine NIH3T3 and human MCF10A mammary epithelial cells. In addition, studies in xenograft and K-Ras lung cancer mouse models demonstrated that genetic deletion or pharmacological suppression of CypD efficiently prevented Ras dependent tumor formation. Furthermore, Erbb2-mediated breast tumorigenesis was similarly prevented by targeting CypD. From a mechanistic point of view, CypD expression was associated with a reduced induction of p21(WAF1/CIP1) and p53 functions, unraveling an antagonistic function of CypD on p21-p53-mediated growth suppression. CypD activity is p53 dependent. Interestingly, a physical association between p53 and CypD was detected in mitochondria of MCF10A cells; furthermore, both in vitro and in vivo studies proved that CypD inhibitor-based treatment was able to efficiently impair this interaction, leading to a tumor formation reduction. All together, these findings indicate that the countering effect of CypD on the p53-p21 pathway participates in oncogene-dependent transformation. PMID- 26973253 TI - Comparison of seven videolaryngoscopes with the Macintosh laryngoscope in manikins by experienced and novice personnel. AB - Videolaryngoscopy is often reserved for 'anticipated' difficult airways, but thereby can result in a higher overall rate of complications. We observed 65 anaesthetists, 67 residents in anaesthesia, 56 paramedics and 65 medical students, intubating the trachea of a standardised manikin model with a normal airway using seven devices: Macintosh classic laryngoscope, Airtraq((r)) , Storz C-MAC((r)) , Coopdech VLP-100((r)) , Storz C-MAC D-Blade((r)) , GlideScope Cobalt((r)) , McGrath Series5((r)) and Pentax AWS((r)) ) in random order. Time to and proportion of successful intubation, complications and user satisfaction were compared. All groups were fastest using devices with a Macintosh-type blade. All groups needed significantly more attempts using the Airtraq and Pentax AWS (all p < 0.05). Devices with a Macintosh-type blade (classic laryngoscope and C-MAC) scored highest in user satisfaction. Our results underline the importance of variability in device performance across individuals and staff groups, which have important implications for which devices hospital providers should rationally purchase. PMID- 26973254 TI - A comprehensive study on atomic layer deposition of molybdenum sulfide for electrochemical hydrogen evolution. AB - Atomic layer deposition (ALD) has emerged as an efficient method to design and prepare catalysts with atomic precision. Here, we report a comprehensive study on ALD of molybdenum sulfide (MoSx) for an electrocatalytic hydrogen evolution reaction. By using molybdenum hexacarbonyl and dimethyldisulfide as the precursors of Mo and S, respectively, the MoSx catalysts are grown at 100 degrees C on porous carbon fiber papers (CFPs). The ALD process results in the growth of particle-like MoSx on the CFP due to the lack of adsorption sites, and its crystallographic structure is a mixture of amorphous and nano-crystalline phases. In order to unveil the intrinsic activity of the ALD-MoSx, the exchange current densities, Tafel slopes, and turnover frequencies of the catalysts grown under various ALD conditions have been investigated by considering the fractional surface coverage of MoSx on the CFP and catalytically-active surface area. In addition, the ALD-MoSx/CFP catalysts exhibit excellent catalytic stability due to the strong adhesion of MoSx on the CFP and the mixed phase. PMID- 26973256 TI - [Not Available]. PMID- 26973257 TI - Comparison of Clinical and Angiographic Outcomes After Bare Metal Stents and Drug Eluting Stents Following Rotational Atherectomy. AB - Few studies have investigated the clinical outcomes of rotational atherectomy (RA) prior to and during the drugeluting stent (DES) era. The goal of this study was to assess the long-term outcome after RA followed by DES and bare metal stent (BMS) implantation in complex calcified coronary lesions and to compare the outcomes among various DESs.This was a single center retrospective observational study. Consecutive 406 patients who underwent elective RA followed by BMS or DES implantation at our institution from 2001 to 2011 were included. This study compared the long-term outcomes after treatment with RA among BMS and 3 different DESs (sirolimus-eluting stent, paclitaxel-eluting stent, and everolimus-eluting stent) implantation.The mean follow-up period was 4.6 years. Patients with DES were older and exhibited more vessel disease, longer lesion length, and smaller vessel size. Patients with BMS had a significantly higher rate of target lesion revascularization, restenosis, and larger late lumen loss than those with DES. Composite events including mortality, ACS, and target vessel revascularization were significantly higher in the BMS-RA group than in the DES-RA group. After adjustment, BMS remained an independent predictor of MACE and ACS plus death in patients treated with RA. However, there were no significant differences in late lumen loss, restenosis rate, and MACE among the 3 DES.The combination of DES-RA has a favorable effect in both the angiographic and clinical outcomes compared with BMS-RA. However, no significant differences in late loss and events rates were observed among the 3 DES groups. PMID- 26973258 TI - An Atypical Right Atrial Myxoma With Spontaneous Rupture. AB - Typically, cardiac maxomas arise from the interatrial septum at the border of the fossa ovalis in the left atrium, whereas atypical right atrial myxoma, especially with spontaneous rupture, is extremely rare. Here we report the diagnostic evaluation and successful surgical resection of an atypical myxoma with spontaneous rupture arising from the posterior wall of the right atrium in a 34 year-old male. PMID- 26973259 TI - Left Ventricular Noncompaction Combined With Epinephrine-Secreted Pheochromocytoma Inducing Heart Failure. AB - Pheochromocytomas and left ventricular noncompaction (LVNC) are both rare diseases. In this patient, the long duration of the catecholamine-secreted pheochromocytoma caused myocardial ischemia, pressure overload, and hypertrophy, resulting in the onset of heart failure (HF). The LVNC might be associated with the acute attack of HF induced by the pheochromocytoma. This is the first case reporting LVNC in combination with HF secondary to pheochromocytoma. PMID- 26973255 TI - Rationalising the role of Keratin 9 as a biomarker for Alzheimer's disease. AB - Keratin 9 was recently identified as an important component of a biomarker panel which demonstrated a high diagnostic accuracy (87%) for Alzheimer's disease (AD). Understanding how a protein which is predominantly expressed in palmoplantar epidermis is implicated in AD may shed new light on the mechanisms underlying the disease. Here we use immunoassays to examine blood plasma expression patterns of Keratin 9 and its relationship to other AD-associated proteins. We correlate this with the use of an in silico analysis tool VisANT to elucidate possible pathways through which the involvement of Keratin 9 may take place. We identify possible links with Dickkopf-1, a negative regulator of the wnt pathway, and propose that the abnormal expression of Keratin 9 in AD blood and cerebrospinal fluid may be a result of blood brain barrier dysregulation and disruption of the ubiquitin proteasome system. Our findings suggest that dysregulated Keratin 9 expression is a consequence of AD pathology but, as it interacts with a broad range of proteins, it may have other, as yet uncharacterized, downstream effects which could contribute to AD onset and progression. PMID- 26973260 TI - Plasma Levels of Receptor for Advanced Glycation End-Products and High-Mobility Group Box 1 in Patients With Pulmonary Hypertension. AB - An increase of pulmonary artery pressure in patients with pulmonary hypertension (PH) results in right ventricular failure and ultimately death. High-mobility group box 1 (HMGB1), a nuclear protein, acts as a pro-inflammatory cytokine by activating receptor for advanced glycation end-products (RAGE) in the extracellular environment. The purpose of this study was to examine the clinical significance of circulating levels of HMGB1 and RAGE in patients with PH. Plasma levels of HMGB1 and soluble RAGE were measured in 27 patients with PH (14 with pulmonary arterial hypertension [PAH], 13 with chronic thromboembolic pulmonary hypertension [CTEPH]) and 30 normal subjects as control. There was no difference in the plasma levels of HMGB1 between the PH patients and the control subjects. However, plasma levels of soluble RAGE were significantly higher in the patients with PH than in the controls (P < 0.001). Plasma soluble RAGE levels were higher in PAH (P < 0.001) and CTEPH (P < 0.0001) than in the controls. In addition, there was a statistically significant positive correlation between pulmonary artery pressure and plasma levels of soluble RAGE (r = 0.403, P < 0.0001). In the CTEPH patients, soluble RAGE levels were reduced after balloon pulmonary angioplasty (P < 0.001). Plasma levels of soluble RAGE, but not HMGB1, might be a novel marker that reflects the pathological condition in patients with PH. PMID- 26973261 TI - Time Rate of Blood Pressure Variation Is Associated With Endothelial Function in Patients With Metabolic Syndrome. AB - The time rate of blood pressure (BP) variation indicates the speed of BP fluctuations. Previous studies have demonstrated that the time rate of BP variation was associated with target organ damage. However, the association between time rate of BP variation and endothelial function has not been evaluated.24-hour ambulatory blood pressure monitoring (ABPM) was performed in 61 patients with metabolic syndrome. Time rate of BP variation was calculated from BP recordings of ABPM. Endothelial function was assessed using reactive hyperemia peripheral arterial tonometry index (RHI) by EndoPat2000. Multiple linear regression models were used to detect the association between time rate of BP variation and RHI.Among all the subjects (n = 61), the multiple linear regression models revealed that the daytime rate of systolic blood pressure (SBP) variation was independently associated with RHI (beta = -0.334, P = 0.008). A 0.1 mmHg/minute increase in the daytime rate of SBP variation correlated with a decline of 0.20 in RHI. The same effect was also found in the subjects with eGFR >= 60 mL/ (minute*1.73 m(2)). A greater association was found in those who were not taking a statin, beta-blocker, ACEI/ARB, or diuretic and those without diabetes compared with those with any antihypertensive medication or with diabetes. Other ambulatory blood pressure parameters and central hemodynamics were not found to be associated with RHI.Our findings have shown that the daytime rate of SBP variation was associated with endothelial function in patients with metabolic syndrome, independent of other BP parameters and central hemodynamics. PMID- 26973262 TI - Influence of Cognitive Behavioral Therapy on Mood and Quality of Life After Stent Implantation in Young and Middle-Aged Patients With Coronary Heart Disease. AB - Cognitive behavioral therapy (CBT), established only a few decades ago, is widely used by clinical psychologists. This study aimed to investigate the effects of CBT on mental status and quality of life (QOL) after percutaneous coronary intervention (PCI) in young and middle-aged patients with coronary heart disease (CHD). Seventy-five anxiety/depression patients (mean age, 52.2 +/- 6.2 years, including 8 individuals < 45 years old) with CHD treated with PCI were randomly divided into a CBT group (n = 38) and control group (n = 37). The CBT group received 8 weeks of CBT in addition to the routine postoperative treatment that was also administered to control patients. The 17-item Hamilton Depression Rating Scale (HAM-D17), Hamilton anxiety scale (HAM-A), and Coronary Revascularization Outcome Questionnaire (CROQ-PTCA-POST, Chinese version) were administered before, 3 days, and 8 weeks after intervention. HAM-D17 and HAM-A scores were decreased after treatment, but were more substantially reduced in patients that underwent CBT than those in the control group (11.7 +/- 4.5 versus 15.1 +/- 3.9, P = 0.001 and 10.6 +/- 3.4 versus 16.5 +/- 4.6, P = 0.003, respectively). QOL was improved in both groups, but overall satisfaction was higher in the CBT group compared with control patients (89.3 +/- 5.2 versus 77.8 +/- 9.5, P < 0.05). CBT can relieve depression and anxiety after PCI in young and middle-aged patients with CHD. CBT can improve patient QOL. PMID- 26973263 TI - MRI Mode Programming for Safe Magnetic Resonance Imaging in Patients With a Magnetic Resonance Conditional Cardiac Device. AB - Although diagnostically indispensable, magnetic resonance imaging (MRI) has been, until recently, contraindicated in patients with an implantable cardiac device. MR conditional cardiac devices are now widely used, but the mode programming needed for safe MRI has yet to be established. We reviewed the details of 41 MRI examinations of patients with a MR conditional device. There were no associated adverse events. However, in 3 cases, paced beats competed with the patient's own beats during the MRI examination. We describe 2 of the 3 specific cases because they illustrate these potentially risky situations: a case in which the intrinsic heart rate increased and another in which atrial fibrillation occurred. Safe MRI in patients with an MR conditional device necessitates detailed MRI mode programming. The MRI pacing mode should be carefully and individually selected. PMID- 26973264 TI - Shorter Heart Failure Duration Is a Predictor of Left Ventricular Reverse Remodeling During Adaptive Servo-Ventilator Treatment in Patients With Advanced Heart Failure. AB - Adaptive servo-ventilation (ASV) is a recently developed, noninvasive therapeutic tool for the treatment of heart failure (HF). However, prediction of responsiveness to continuous ASV therapy remains uncertain, especially in patients with advanced HF receiving guideline-directed medical therapy. A total of 47 patients with advanced HF (NYHA class IV 74%, inotrope infusion dependent 38%) received continuous ASV therapy at our institute between 2008 and 2014. Of these 47 patients, 12 (26%) were responders, whose left ventricular ejection fraction increased >= 5% during the 6-month study period. Shorter HF duration (< 17.2 * 10(2) days) was a significant predictor of responsiveness to ASV therapy by logistic regression analysis and receiver operating characteristics analysis. Patients with shorter HF duration achieved improved HF symptoms, recovery of renal function, and a lower readmission ratio compared with the longer HF duration group during ASV therapy. In conclusion, early ASV introduction may be beneficial to achieve left ventricular reverse remodeling during ASV therapy in patients with advanced HF. PMID- 26973265 TI - Is Dual Antiplatelet Therapy Necessary in Transcatheter Aortic Valve Implantation? PMID- 26973266 TI - Hyper-Response to Clopidogrel in Japanese Patients Undergoing Transcatheter Aortic Valve Implantation. AB - Dual antiplatelet therapy is empirically recommended following transcatheter aortic valve implantation (TAVI). The aims of the present study were to analyze the effect of clopidogrel on platelet function and to determine the relative contribution of each CYP2C19 loss-of-function genotype undergoing TAVI.Thirty-two patients undergoing TAVI and with clopidogrel treatment were studied. All patients were treated with an Edwards SapienXT valve. Platelet reactivity was measured by the VerifyNow P2Y12 point-of-care assay at 7 days and 30 days after the procedure and a cutoff value of 95 PRU was used to identify a hyper-response of platelet reactivity. The Spartan RX(TM) sample-to-result point-of-care DNA testing system was used to identify CYP2C19 loss-of-function genotypes. Hyper response of platelet reactivity was identified in 11 (34.3%) patients, although 24 (80%) were carriers of at least one CYP2C19 reduced-function allele. The PRU values did not change significantly from 7 days to 30 days after TAVI (136.7 +/- 73.4 versus 150.4 +/- 83.2, P = 0.13). The incidences of life-threatening bleeding, minor bleeding, and transfusion were significantly higher among the hyper-response of platelet reactivity group (27.3% versus 0%, P = 0.03, 36.4% versus 4.8%, P = 0.04, 81.8% versus 42.9%, P = 0.04, respectively).A hyper response to clopidogrel was observed in one-third of patients undergoing TAVI and was related to bleeding events, even though 80% of the patients were carriers of the CYP2C19 reduced-function allele. PMID- 26973267 TI - MicroRNA-214 Inhibits Left Ventricular Remodeling in an Acute Myocardial Infarction Rat Model by Suppressing Cellular Apoptosis via the Phosphatase and Tensin Homolog (PTEN). AB - The aims of the present study were to determine the role of miR-214 on left ventricular remodeling of rat heart with acute myocardial infarction (AMI) and to further investigate the underlying mechanism of miR-214-mediated myocardial protection. AMI was induced in which adenovirus-expressing miR-214 (Ad-miR-214), anti-miR-214, or Ad-GFP had been delivered into rats hearts 4 days prior, while a phosphatase and tensin homolog (PTEN) inhibitor was administered via intra peritoneal injection 30 minutes prior to AMI. Changes in hemodynamic parameters were detected and recorded. Left ventricular (LV) dimensions and LV/BW were measured. Quantitative RT-PCR was used to determine the miR-214 expression levels of the myocytes in the infarcted, border, and non-infarcted areas of the LV. Myocardial infarct size was also measured. Flow cytometry analysis was performed to examine cellular apoptosis. Western blot analysis was performed to examine PTEN expression. The results showed that miR-214 was upregulated in both border and infarcted areas. Myocardial cell apoptosis was decreased in the Ad-miR-214 group, but was increased in the anti-miR-214 group, while there were no differences among the Ad-GFP-group, PTEN-ad-miR-214 group, or PTEN-anti-miR-214 group. Myocardial infarct size, LV dimensions, heart rate (HR), and LV end diastolic pressure (LVEDP) were decreased while the maximal rates of rise or decline in blood pressure in the ventricular chamber (+/- dp/dt) and LV systolic pressure (LVSP) were increased in the Ad-miR-214 group, all of which exhibited opposite changes in the anti-miR-214 group. PTEN was downregulated in the Ad-miR 214 group and upregulated in the anti-miR-214 group. PTEN was decreased in both the border and infarcted areas compared with non-infarcted areas. The study results suggest that Ad-miR-214 improves LV remodeling and decreases the apoptosis of myocardial cells through PTEN, suggesting a possible mechanism by which Ad-miR-214 functions in protecting against AMI injury. PMID- 26973268 TI - Three-Year Clinical and Angiographic Outcomes After Everolimus-Eluting Stent Implantation in Patients With a History of Coronary Artery Bypass Grafting. AB - The clinical and angiographic outcomes after percutaneous coronary intervention (PCI) with everolimus-eluting stent (EES) implantation in patients with a history of coronary artery bypass grafting (CABG) have yet to be fully investigated. The aim of the present study was to investigate 3-year clinical outcomes after EES implantation in patients with a history of CABG.We retrospectively enrolled 176 consecutive patients who had undergone EES implantation. Three-year clinical follow-up data were obtained from all patients. Follow-up angiograms and serial quantitative coronary angiography analysis (QCA) were performed for 139 (79.0%) patients. Patients from the prior CABG (+) group (n = 17; 9.7%) had higher incidences of target lesion revascularization (TLR; 41.2% versus 3.8%, P < 0.001) and major adverse cardiac events (47.1% versus 15.1%, P = 0.004). A landmark analysis conducted 1 year into our study showed a higher incidence of TLR in the prior CABG (+) group (20.0% versus 3.0%, P = 0.017).The reason for EES implantation in the prior CABG (+) group was saphenous vein graft (SVG) failure in 19 (79.2%) lesions, although the target vessel was the SVG in 8 (33.3%) lesions. There were no significant differences in clinical and follow-up QCA data between the native vessel and SVG PCI groups.This study revealed that a history of CABG was a risk factor for TLR after EES implantation. The major reason for PCI after CABG was SVG failure; both native vessel and SVG PCI showed poor outcomes. Further investigations may be warranted to determine which interventions are most effective in this high-risk subset. PMID- 26973269 TI - Early Rehabilitation Therapy Is Beneficial for Patients With Prolonged Mechanical Ventilation After Coronary Artery Bypass Surgery. AB - We investigated the effects of early rehabilitation therapy on prolonged mechanically ventilated patients after coronary artery bypass surgery (CABG).A total of 106 patients who underwent CABG between June 2012 and May 2015 were enrolled and randomly assigned into an early rehabilitation group (53 cases) and a control group (53 cases). The rehabilitation therapy consisted of 6 steps including head up, transferring from supination to sitting, sitting on the edge of bed, sitting in a chair, transferring from sitting to standing, and walking along a bed. The patients received rehabilitation therapy in the intensive care unit (ICU) after CABG in the early rehabilitation group. The control group patients received rehabilitation therapy after leaving the ICU.The results showed that the early rehabilitation therapy could significantly decrease the duration of mechanical ventilation (early rehabilitation group: 8.1 +/- 3.3 days; control group: 13.9 +/- 4.1 days, P < 0.01), hospital stay (early rehabilitation group: 22.0 +/- 3.8 days; control group: 29.1 +/- 4.6 days, P < 0.01), and ICU stay (early rehabilitation group: 11.7 +/- 3.2 days; control group: 18.3 +/- 4.2 days, P < 0.01) for patients requiring more than 72 hours prolonged mechanical ventilation. The results of Kaplan-Meier analysis showed that the proportions of patients remaining on mechanical ventilation in the early rehabilitation group were larger than that in the control group after 7 days of rehabilitation therapy (logrank test: P < 0.01). The results provide evidence for supporting the application of early rehabilitation therapy in patients requiring prolonged mechanical ventilation after CABG. PMID- 26973270 TI - Everolimus Attenuates Myocardial Hypertrophy and Improves Diastolic Function in Heart Transplant Recipients. AB - Everolimus (EVL), one of the mammalian targets of rapamycin, is a next generation immunosuppressant that may have accessory anti-proliferative effects in heart transplant (HTx) recipients. However, little is known about the clinical relationship between EVL and regression of cardiac hypertrophy. A total of 42 HTx recipients received EVL therapy at post-HTx 150 days on median and had been followed at our institute for > 1 year between 2008 and 2014 [EVL (+) group]. We also observed 18 patients without EVL from post-HTx 150 days for 1 year [EVL (-) group]. There were no significant differences in baseline variables between the two groups. Left ventricular mass index (LVMI) and the ratio of early transmitral filling velocity to the peak early diastolic mitral annular motion velocity (E/e') decreased significantly during 1-year EVL treatment compared with the EVL (-) group. There were no differences in blood pressure and medications between the 2 groups. Improvement of LVMI and the E/e' ratio was not associated with trough levels of calcineurin inhibitors or EVL, but correlated with each baseline value. In conclusion, this EVL-incorporated immunosuppressant regimen attenuated cardiac hypertrophy as well as diastolic dysfunction in HTx recipients. PMID- 26973271 TI - Combination of Urinary Sodium/Creatinine Ratio and Plasma Brain Natriuretic Peptide Level Predicts Successful Tolvaptan Therapy in Patients With Heart Failure and Volume Overload. AB - To evaluate the short-term clinical and hemodynamic effects of tolvaptan therapy and to identify predictors of the therapeutic outcomes, we retrospectively recruited 60 consecutive hospitalized heart failure (HF) patients (70 +/- 11 years) with volume overload. The subjects were divided into two groups on the basis of the changes in HF symptom scores and hemodynamic status assessed by right heart catheterization after tolvaptan therapy (median: 7 days). The majority of patients were successfully treated (group 1). However, 22% of patients (group 2) were unsuccessfully treated, in whom 1) the HF symptom score worsened or 2) there was a stationary HF symptom score >= 6 points, and mean PCWP > 18 mmHg and mean RAP > 10 mmHg, after tolvaptan therapy. HF symptom scores, hemodynamic parameters, and plasma brain natriuretic peptide (BNP) level improved in group 1, but all of these parameters remained unchanged in group 2. Lower urine sodium/creatinine ratio (UNa/UCr) and higher BNP level at baseline were independently associated with unsuccessful tolvaptan therapy, and UNa/UCr best predicts unsuccessful tolvaptan therapy with a cut-off value of 46.5 mEq/g.Cr (AUC 0.847, 95% CI: 0.718-0.976, sensitivity 77%, specificity 81%, P < 0.01). Double-positive results of UNa/UCr < 46.5 mEq/g.Cr and plasma BNP level > 778 pg/mL predicted unsuccessful tolvaptan therapy with high diagnostic accuracy (sensitivity 54%, specificity 100%, positive predictive value 100%, negative predictive value 89%, and accuracy 90%). In summary, short-term tolvaptan therapy ameliorated HF symptoms and provided hemodynamic improvement in the majority of patients, and UNa/UCr and BNP level strongly predicted the therapeutic outcomes. PMID- 26973272 TI - A Unique Case of a 12-Year-Old Boy With Noonan Syndrome Combined With Noncompaction of the Ventricular Myocardium. AB - A 12-year-old Chinese boy was admitted with dyspnea after exercise. Based on his clinical features, echocardiography tests, and family history, he was diagnosed with Noonan syndrome (NS) combined with noncompaction of the ventricular myocardium (NVM). Noonan syndrome (NS) is a common syndrome, but to the best of our knowledge, our case is the first reported case of NS combined with NVM. In our case, the detected mutated genes may be inherited and unreported genes caused NS or NVM. Our research may enrich our knowledge about NS and contribute to furthering our understanding of the pathogenesis and treatment. In summary, we present a unique case of NS combined with NVM. PMID- 26973273 TI - Left Atrial Remodeling Assessed by Transthoracic Echocardiography Predicts Left Atrial Appendage Flow Velocity in Patients With Paroxysmal Atrial Fibrillation. AB - Atrial fibrillation (AF) is associated with an increased risk of stroke and other thromboembolic events. Left atrial (LA) thrombus formation is closely related to LA dysfunction, particularly to decreased LA appendage flow velocity (LAA-FV) in patients with AF. We estimated LAA-FV using parameters noninvasively obtained by transthoracic echocardiography (TTE) in patients with paroxysmal AF.Echocardiographic and clinical parameters were assessed in 190 patients with nonvalvular paroxysmal AF showing sinus heart rhythm during transesophageal echocardiography (TEE) and TTE.LAA-FV (60 +/- 22 cm/s) significantly correlated with the time interval between the initiation of the P-wave on ECG and that of the A-wave of transmitral flow on TTE (PA-TMF, correlation coefficient, -0.32; P < 0.001), LA dimension (LAD, -0.31; P < 0.001), septal a' velocity of tissue Doppler imaging (TDI, 0.35; P < 0.001), E/e' ratio (-0.28, P < 0.001), E velocity of transmitral flow (-0.20, P = 0.008), E/A ratio of transmitral flow (-0.18, P = 0.02), CHA2DS2-VASc score (-0.15, P = 0.04), and BNP plasma level (-0.32, P = 0.002). Multivariate analysis revealed that PA-TMF (standardized partial regression coefficient, -0.17; P = 0.03), a' velocity (0.24, P = 0.004), and LAD (-0.20, P = 0.01) were independent predictors of LAA-FV (multiple correlation coefficient R, 0.44; P < 0.001).Parameters of atrial remodeling, ie, decreased a' velocity, increased LAD, and PA-TMF during sinus rhythm may be useful predictors of LA blood stasis in patients with nonvalvular PAF. LAA-FV can be estimated using these TTE parameters instead of TEE. PMID- 26973274 TI - Biological Antioxidant Potential Negatively Correlates With Carotid Artery Intima Media Thickness. AB - Oxidative stress is a crucial factor in the pathogenesis and development of cardiovascular disease. Recently, simplified methods for the detection of reactive oxygen species (ROS) using the derivatives of reactive oxygen metabolites (d-ROMs) test as an index of ROS products and the biological antioxidant potential (BAP) test as an index of antioxidant potential have been utilized. These methods are easy to perform, quick, inexpensive since they use small equipment, and provide reliable results compared with established oxidative stress and antioxidant markers. Because oxidative stress has been shown to represent the balance of production of ROS and antioxidant capacity, it is more appropriate to evaluate ROS and antioxidant capacity simultaneously. However, no study has examined the associations among d-ROMs, BAP values, and carotid artery intima-media thickness (IMT) concurrently. Therefore, we studied the associations among d-ROMs, BAP values, and the carotid artery IMT. Carotid artery IMT, blood pressure (BP), fasting circulating d-ROMs, BAP, glucose metabolism, lipid, and C reactive protein levels were measured in 95 subjects (age: 49.5 +/- 13.8 years; men: 41; women: 54), including 42 healthy subjects and 53 patients with hypertension, dyslipidemia, and diabetes mellitus who were not on medication. The results of multiple regression analysis revealed that dependent carotid artery IMT determinants remained significantly associated with age, systolic BP, total cholesterol, and BAP, whereas dependent BAP determinants remained significantly associated with body mass index and carotid artery IMT. BAP was strongly correlated with carotid artery IMT in our cohort. Our results suggest that BAP may be a useful risk marker for carotid atherosclerosis. PMID- 26973275 TI - Inflammatory Biomarkers and Atherosclerosis. AB - Atherosclerosis has been regarded as a form of chronic vascular inflammation. Numerous biomarkers associated with inflammation have been identified as novel targets to monitor atherosclerosis and cardiovascular risk. C-reactive protein (CRP) is one of the most actively studied and established inflammatory biomarkers for cardiovascular events. However, CRP response is triggered by many disorders unrelated to cardiovascular disease, which interferes with the clinical application. This review describes established and traditional inflammatory biomarkers including CRP as well as novel inflammatory biomarkers reflective of local atherosclerotic inflammation. In addition, we focus on the potential usefulness of inflammatory biomarkers in developing anti-atherosclerotic therapeutic approaches. PMID- 26973276 TI - Aortic Stenosis in a Patient With Sjogren's Syndrome. AB - Sjogren's syndrome (SS) is an autoimmune disease characterized by dryness of the mouth and the eyes. Systemic involvement in SS is well known, however, obvious cardiac manifestations, particularly significant valve disorders, are extremely rare and only three cases of significant valve disease associated with SS that required surgical intervention have been previously described. We report a case of aortic stenosis (AS) associated with SS in an elderly patient. The diagnosis of primary SS had been made based on clinical features, positive ocular signs, and positive serologic findings. Echocardiography showed severe calcification, elevated mean pressure gradient (57 mmHg), and a small orifice area (0.45 cm(2)) of the aortic valve. At surgery, severe calcification of the aortic cusps and the annulus was the mechanism of AS, and the aortic valve was replaced with a bioprosthetic valve. Valve pathology showed nodular calcification and hyaline degeneration, but lymphocyte infiltration was not evident. The etiologic relation of SS to the valve lesions is not clear pathologically in this case, however, chronic inflammation related to immunologic reactions in SS could have some effect on exacerbation for degeneration of the valve tissue. PMID- 26973277 TI - Association Between Baseline Natriuretic Peptides and Atrial Fibrillation Recurrence After Catheter Ablation. AB - Natriuretic peptides like B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro BNP) are reported to be increased in atrial fibrillation (AF) patients. However, the prognostic roles of BNP and NT-pro BNP in post-ablation AF recurrence remain inconclusive. We performed this meta-analysis to investigate the potential role of baseline natriuretic peptides in predicting AF recurrence after catheter ablation.Electronic databases were searched for studies that evaluated the potential relationship between AF recurrence and baseline BNP or NT pro BNP levels. The pooled standardized mean difference (SMD) and 95% confidence interval (CI) were calculated to quantify differences in BNP or NT-pro BNP levels between patients with and without AF recurrence.Ten studies on BNP and 8 studies on NT-pro BNP were included, in which 411 of 1300 patients and 256 of 846 patients experienced AF recurrence, respectively. Overall, the pooled SMD of studies on BNP was 0.55 (95% CI: 0.260.84, P < 0.001) while the pooled SMD of studies on NT-pro BNP was 0.96 (95% CI: 0.62-1.30, P < 0.0001). Meta-regression was conducted by AF type, AF duration, follow-up period, left atrial dimension (LAD), and concomitant heart failure, after which subgroup analysis demonstrated only follow-up period (3 months or > 3 months) in the NT-pro BNP group might account for the heterogeneity. Sensitivity analyses indicated both the results were stable.Meta-analysis of current eligible studies suggested that both increased baseline BNP and NT-pro BNP levels are associated with greater risk of AF recurrence after catheter ablation, which could be biomarkers for predicting AF recurrence. PMID- 26973278 TI - Usefulness of Cardiac Sympathetic Nerve Imaging Using (123)Iodine Metaiodobenzylguanidine Scintigraphy for Predicting Sudden Cardiac Death in Patients With Heart Failure. AB - The autonomic nervous system plays an important role in the human heart. Activation of the cardiac sympathetic nervous system is a cardinal pathophysiological abnormality associated with the failing human heart. Myocardial imaging using (123)I-metaiodobenzylguanidine (MIBG), an analog of norepinephrine, can be used to investigate the activity of norepinephrine, the predominant neurotransmitter of the sympathetic nervous system. Many clinical trials have demonstrated that (123)I-MIBG scintigraphic parameters predict cardiac adverse events, especially sudden cardiac death, in patients with heart failure. In this review, we summarize results from published studies that have focused on the use of cardiac sympathetic nerve imaging using (123)I-MIBG scintigraphy for risk stratification of sudden cardiac death in patients with heart failure. PMID- 26973279 TI - Heart Failure as a Disruption of Dynamic Circulatory Homeostasis Mediated by the Brain. AB - Circulatory homeostasis is associated with interactions between multiple organs, and the disruption of dynamic circulatory homeostasis could be considered as heart failure. The brain is the central unit integrating neural and neurohormonal information from peripheral organs and controlling peripheral organs using the autonomic nervous system. Heart failure is worsened by abnormal sympathoexcitation associated with baroreflex failure and/or chemoreflex activation, and by vagal withdrawal, and autonomic modulation therapies have benefits for heart failure. Recently, we showed that baroreflex failure induces striking volume intolerance independent of left ventricular dysfunction. Many studies have indicated that an overactive renin-angiotensin system, excess oxidative stress and excess inflammation, and/or decreased nitric oxide in the brain cause sympathoexcitation in heart failure. We have demonstrated that angiotensin II type 1 receptor (AT1R)-induced oxidative stress in the rostral ventrolateral medulla (RVLM), which is known as a vasomotor center, causes prominent sympathoexcitation in heart failure model rats. Interestingly, systemic infusion of angiotensin II directly affects brain AT1R with sympathoexcitation and left ventricular diastolic dysfunction. Moreover, we have demonstrated that targeted deletion of AT1R in astrocytes strikingly improved survival with prevention of left ventricular remodeling and sympathoinhibition in myocardial infarction-induced heart failure. From these results, we believe it is possible that AT1R in astrocytes, not in neurons, have a key role in the pathophysiology of heart failure. We would like to propose a novel concept that the brain works as a central processing unit integrating neural and hormonal input, and that the disruption of dynamic circulatory homeostasis mediated by the brain causes heart failure. PMID- 26973280 TI - Potential of Receptor for Advanced Glycation End-Products (RAGE) as an Eligible Biomarker for Therapy Evaluation in Patients With Pulmonary Hypertension. PMID- 26973281 TI - Hotspot detection and spatial distribution of methane emissions from landfills by a surface probe method. AB - A surface probe method previously developed was used to detect hotspots and to determine spatial variation of methane (CH4) emissions from three landfills located in Mexico, with an intermediate or a final cover, as well as with or without a landfill gas collection system. The method was effective in the three landfills and allowed mapping of CH4 emissions with a resolution of 24-64 measurements per hectare, as well as the detection and quantification of hotspots, with a moderate experimental effort. In the three selected landfills, CH4 emissions were quantified to 10, 72, and 575gm(-2)d(-1). Two straightforward parameters describing the spatial distribution of CH4 emissions were also developed. The first parameter provides the percentage of area responsible for a given percentage of total emissions, while the second parameter assigns a numerical value to flux homogeneity. Together, the emissions map and the spatial distribution parameters offer an appropriate tool to landfill operators willing to begin recovering CH4 emissions or to improve the effectiveness of an existing recovery system. This method may therefore help to reduce the greenhouse gas footprint of landfills, which are still the primary option for waste management in developing countries. PMID- 26973282 TI - The presence of spontaneous EMG activity in sternocleidomastoid is associated with ventilatory dysfunction in ALS. AB - We investigated electromyography (EMG) of the sternocleidomastoid (SCM) in 128 patients with amyotrophic lateral sclerosis (ALS) including correlation with forced vital capacity (FVC) and ALS Functional Rating Scale scores. The presence of fibrillation potentials and positive sharp waves in the SCM was significantly more frequently observed in patients with an FVC <80% (31/49, 63%) than in patients with an FVC>=80% (34/79, 43%). This study suggests that the SCM could be concomitantly involved with primary respiratory muscles in ALS. This is of value since needle EMG is a less invasive procedure in SCM than in the diaphragm or intercostal muscles. PMID- 26973283 TI - Shock Index as a predictor for In-hospital mortality in patients with non-ST segment elevation myocardial infarction. AB - BACKGROUND/PURPOSE: Shock index (SI), a ratio of heart rate/systolic blood pressure, has been reported to predict increased mortality in patients with ST segment elevation myocardial infarction. However, the prognostic value of SI has not been fully elucidated in patients with non-ST-segment elevation myocardial infarction (NSTEMI). METHODS/MATERIALS: We performed a retrospective analysis of 481 consecutive NSTEMI patients who underwent coronary angiography from January 2013 to June 2014. Systolic blood pressure and heart rate on presentation were recorded, and SI was calculated as heart rate/systolic blood pressure. Patients were divided into those with SI?0.7 and those with SI<0.7. Baseline and angiographic characteristics were recorded. In addition, cardiogenic shock and in hospital mortality were recorded and compared between the two groups. RESULTS: Among 481 patients, 103 patients (21.4%) had SI?0.7. No statistically significant difference was observed in baseline characteristics between the two groups. Patients with SI?0.7 had a lower left ventricular ejection fraction than those with SI<0.7 (56 [35-60] % vs. 60 [45-64] %, p=0.035). Patients with SI?0.7 had a higher rate of cardiogenic shock on admission (2.9% vs. 0.3%, p=0.032). Patients with SI?0.7 had a higher, albeit statistically insignificant, incidence of cardiogenic shock after admission (5.0% vs. 1.9%, p=0.074). The total incidence of cardiogenic shock was higher in patients with SI?0.7 (7.8% vs. 2.1%, p=0.001). Patients with SI?0.7 had higher in-hospital mortality (4.9% vs. 0.5%, p=0.006) than those with SI<0.7. CONCLUSION: Elevated SI was associated with higher in hospital mortality in patients with NSTEMI. PMID- 26973286 TI - Orbital inflammation: Corticosteroids first. AB - Orbital inflammation is common, and may affect all ages and both genders. By combining a thorough history and physical examination, targeted ancillary laboratory testing and imaging, a presumptive diagnosis can often be made. Nearly all orbital inflammatory pathology can be empirically treated with corticosteroids, thus obviating the need for histopathologic diagnosis prior to initiation of therapy. In addition, corticosteroids may be effective in treating concurrent systemic disease. Unless orbital inflammation responds atypically or incompletely, patients can be spared biopsy. PMID- 26973284 TI - A genistein-enriched diet neither improves skeletal muscle oxidative capacity nor prevents the transition towards advanced insulin resistance in ZDF rats. AB - Genistein, a natural food compound mainly present in soybeans, is considered a potent antioxidant and to improve glucose homeostasis. However, its mechanism of action remains poorly understood. Here, we analyzed whether genistein could antagonize the progression of the hyperinsulinemic normoglycemic state (pre diabetes) toward full-blown T2DM in Zucker Diabetic Fatty (ZDF) rats by decreasing mitochondrial oxidative stress and improving skeletal muscle oxidative capacity. Rats were assigned to three groups: (1) lean control (CNTL), (2) fa/fa CNTL, and (3) fa/fa genistein (GEN). GEN animals were subjected to a 0.02% (w/w) genistein-enriched diet for 8 weeks, whereas CNTL rats received a standard diet. We show that genistein did not affect the overall response to a glucose challenge in ZDF rats. In fact, genistein may exacerbate glucose intolerance as fasting glucose levels were significantly higher in fa/fa GEN (17.6 +/- 0.7 mM) compared with fa/fa CNTL animals (14.9 +/- 1.4 mM). Oxidative stress, established by electron spin resonance (ESR) spectroscopy, carbonylated protein content and UCP3 levels, remained unchanged upon dietary genistein supplementation. Furthermore, respirometry measurements revealed no effects of genistein on mitochondrial function. In conclusion, dietary genistein supplementation did not improve glucose homeostasis, alleviate oxidative stress, or augment skeletal muscle metabolism in ZDF rats. PMID- 26973287 TI - Acute macular neuroretinopathy: A comprehensive review of the literature. AB - Acute macular neuroretinopathy is a relatively rare condition originally defined by the presence of intraretinal, reddish-brown, wedge-shaped lesions, the apices of which tend to point toward the fovea. Acute onset of paracentral scotomas corresponding to the clinically evident lesions is both common and characteristic. Although the pathogenesis of acute macular neuroretinopathy is complex, recent research suggests a microvascular etiology. Advances in multimodal imaging have enabled better characterization of this retinal disorder and have led to newly proposed diagnostic criteria. We review 101 reported cases in the English and non-English language literature identified from 1975, when acute macular neuroretinopathy was first described, to December, 2014. We discuss common risk factors, demographic and clinical characteristics, and multimodal imaging findings, which together provide insights into pathogenesis and guide areas of future investigation. PMID- 26973285 TI - Real-time PCR for differential quantification of CVI988 vaccine virus and virulent strains of Marek's disease virus. AB - CVI988/Rispens vaccine, the 'gold standard' vaccine against Marek's disease in poultry, is not easily distinguishable from virulent strains of Marek's disease herpesvirus (MDV). Accurate differential measurement of CVI988 and virulent MDV is commercially important to confirm successful vaccination, to diagnose Marek's disease, and to investigate causes of vaccine failure. A real-time quantitative PCR assay to distinguish CVI988 and virulent MDV based on a consistent single nucleotide polymorphism in the pp38 gene, was developed, optimised and validated using common primers to amplify both viruses, but differential detection of PCR products using two short probes specific for either CVI988 or virulent MDV. Both probes showed perfect specificity for three commercial preparations of CVI988 and 12 virulent MDV strains. Validation against BAC-sequence-specific and US2 sequence-specific q-PCR, on spleen samples from experimental chickens co-infected with BAC-cloned pCVI988 and wild-type virulent MDV, demonstrated that CVI988 and virulent MDV could be quantified very accurately. The assay was then used to follow kinetics of replication of commercial CVI988 and virulent MDV in feather tips and blood of vaccinated and challenged experimental chickens. The assay is a great improvement in enabling accurate differential quantification of CVI988 and virulent MDV over a biologically relevant range of virus levels. PMID- 26973289 TI - Effects of erythromycin on the phenotypic and genotypic biofilm expression in two clinical Staphylococcus capitis subspecies and a functional analysis of Ica proteins in S. capitis. PMID- 26973288 TI - Decoding regulatory landscape of somatic embryogenesis reveals differential regulatory networks between japonica and indica rice subspecies. AB - Somatic embryogenesis is a unique process in plants and has considerable interest for biotechnological application. Compare to japonica, indica rice has been less responsive to in vitro culture. We used Illumina Hiseq 2000 sequencing platform for comparative transcriptome analysis between two rice subspecies at six different developmental stages combined with a tag-based digital gene expression profiling. Global gene expression among different samples showed greater complexity in japonica rice compared to indica which may be due to polyphyletic origin of two rice subspecies. Expression pattern in initial stage indicate major differences in proembryogenic callus induction phase that may serve as key regulator to observe differences between both subspecies. Our data suggests that phytohormone signaling pathways consist of elaborate networks with frequent crosstalk, thereby allowing plants to regulate somatic embryogenesis pathway. However, this crosstalk varies between the two rice subspecies. Down regulation of positive regulators of meristem development (i.e. KNOX, OsARF5) and up regulation of its counterparts (OsRRs, MYB, GA20ox1/GA3ox2) in japonica may be responsible for its better regeneration and differentiation of somatic embryos. Comprehensive gene expression information in the present experiment may also facilitate to understand the monocot specific meristem regulation for dedifferentiation of somatic cell to embryogenic cells. PMID- 26973290 TI - MicroRNAs in Diabetic Nephropathy: From Biomarkers to Therapy. AB - Recent estimates suggest that 1 in 12 of the global population suffers from diabetes mellitus. Approximately 40 % of those affected will go on to develop diabetes-related chronic kidney disease or diabetic nephropathy (DN). DN is a major cause of disability and premature death. Existing tests for prognostic purposes are limited and can be invasive, and interventions to delay progression are challenging. MicroRNAs (miRNAs) are a recently described class of molecular regulators found ubiquitously in human tissues and bodily fluids, where they are highly stable. Alterations in miRNA expression profiles have been observed in numerous diseases. Blood and tissue miRNAs are already established cancer biomarkers, and cardiovascular, metabolic and immune disease miRNA biomarkers are under development. Urinary miRNAs represent a potential novel source of non invasive biomarkers for kidney diseases, including DN. In addition, recent data suggest that miRNAs may have therapeutic applications. Here, we review the utility of miRNAs as biomarkers for the early detection and progression of DN, assess emerging data on miRNAs implicated in DN pathology and discuss how the data from both fields may contribute to the development of novel therapeutic agents. PMID- 26973292 TI - Circulating and visceral adipose miR-100 is down-regulated in patients with obesity and Type 2 diabetes. AB - Obesity is a major public health problem conferring substantial excess risk for Type 2 diabetes (T2D). The role of microRNAs (miRNAs) in obesity and adipose tissue is not clearly defined. We hypothesize that circulating miRNA expression profiles vary according to differences in body mass index (BMI) and T2D and circulating miRNAs may reflect adipose tissue expression. Compared to healthy, lean individuals, circulating miR-100 was significantly lower in obese normoglycemic subjects and subjects with T2D. In visceral adipose tissue, expression of miR-100 was lower from obese subjects with T2D compared to obese subjects without T2D. miR-100 expression was significantly lower after adipogenic induction in human visceral, subcutaneous adipocytes and 3T3-L1 adipocytes. miR 100 reduced expression of mammalian target of rapamycin (mTOR) and Insulin Growth Factor Receptor (IGFR) directly. Differentiation of 3T3-L1 was accelerated by inhibition of miR-100 and reduced by miR-100 mimic transfection. Our data provide the first evidence of an association of circulating miR-100 with obesity and diabetes. Additionally, our in-vitro findings, and the miR-100 expression patterns in site-specific adipose tissue suggest miR-100 to modulate IGFR, mTOR and mediate adipogenesis. PMID- 26973291 TI - Lipocalin 2 produces insulin resistance and can be upregulated by glucocorticoids in human adipose tissue. AB - The adipokine lipocalin 2 is linked to obesity and metabolic disorders. However, its role in human adipose tissue glucose and lipid metabolism is not explored. Here we show that the synthetic glucocorticoid dexamethasone dose-dependently increased lipocalin 2 gene expression in subcutaneous and omental adipose tissue from pre-menopausal females, while it had no effect in post-menopausal females or in males. Subcutaneous adipose tissue from both genders treated with recombinant human lipocalin 2 showed a reduction in protein levels of GLUT1 and GLUT4 and in glucose uptake in isolated adipocytes. In subcutaneous adipose tissue, lipocalin 2 increased IL-6 gene expression whereas expression of PPARgamma and adiponectin was reduced. Our findings suggest that lipocalin 2 can contribute to insulin resistance in human adipose tissue. In pre-menopausal females, it may partly mediate adverse metabolic effects exerted by glucocorticoid excess. PMID- 26973293 TI - Nodular glomerulosclerosis and renin angiotensin system in Chinese patients with type 2 diabetes. AB - BACKGROUND: Diabetic nephropathy (DN) is a multifactorial and polygenic disease with nodular glomerulosclerosis (NGS) pathognomonic for diabetes and hypertension. Patients with type 2 diabetes and hypertension have characteristic renin-angiotensin system (RAS) gene polymorphisms. METHODS AND RESULTS: In this retrospective cohort study, we correlated the presence of NGS with renal function, angiotensin-converting enzyme (ACE) genotypes (DD, DI, and II), angiotensinogen (AGT) genotypes (MM, MT, and TT) and immunohistochemical staining characteristics of RAS components in 847 patients and 172 consecutive autopsy cases with type 2 diabetes. T allele of AGT was associated with macroalbuminuria (P = 0.040). Multitude regression analysis revealed ACE insertion (I)/deletion (D) polymorphism as an independent determinant for estimated glomerular filtration rate (eGFR) less than 60 mL min(-1).1.73 m(-2) (DD carriers: odds ratio [OR] = 3.46, 95% confidence interval [CI] = 1.08-11.07; DI carriers: OR = 3.51, 95% CI = 1.63-7.56). A significant association between NGS and eGFR less than 60 mL min(-1).1.73 m(-2) also persisted after adjusting for nonlinear relationship (P < 0.001). In NGS patients, immunoreactivity of angiotensin I converting enzyme 2 (ACE2) significantly decreased in glomeruli with mesangial nodules compared with glomeruli without the mesangial nodules. CONCLUSIONS: These data suggest associations of ACE D allele with glomerular filtration impairment, and NGS with glomerular ACE2 down-regulation and reduced glomerular filtration in Chinese patients with type 2 diabetes. PMID- 26973294 TI - Terahertz Artificial Dielectric Lens. AB - We have designed, fabricated, and experimentally characterized a lens for the THz regime based on artificial dielectrics. These are man-made media that mimic properties of naturally occurring dielectric media, or even manifest properties that cannot generally occur in nature. For example, the well-known dielectric property, the refractive index, which usually has a value greater than unity, can have a value less than unity in an artificial dielectric. For our lens, the artificial-dielectric medium is made up of a parallel stack of 100 MUm thick metal plates that form an array of parallel-plate waveguides. The convergent lens has a plano-concave geometry, in contrast to conventional dielectric lenses. Our results demonstrate that this lens is capable of focusing a 2 cm diameter beam to a spot size of 4 mm, at the design frequency of 0.17 THz. The results further demonstrate that the overall power transmission of the lens can be better than certain conventional dielectric lenses commonly used in the THz regime. Intriguingly, we also observe that under certain conditions, the lens boundary demarcated by the discontinuous plate edges actually resembles a smooth continuous surface. These results highlight the importance of this artificial dielectric technology for the development of future THz-wave devices. PMID- 26973295 TI - Clinical, epidemiological and virological characteristics of the first detected human case of avian influenza A(H5N6) virus. AB - A human infection with novel avian influenza A H5N6 virus emerged in Changsha city, China in February, 2014. This is the first detected human case among all human cases identified from 2014 to early 2016. We obtained and summarized clinical, epidemiological, and virological data from this patient. Complete genome of the virus was determined and compared to other avian influenza viruses via the construction of phylogenetic trees using the neighbor-joining approach. A girl aged five and half years developed fever and mild respiratory symptoms on Feb. 16, 2014 and visited hospital on Feb. 17. Throat swab specimens were obtained from the patient and a novel reassortant avian influenza A H5N6 virus was detected. All eight viral gene segments were of avian origin. The hemagglutinin (HA) and neuraminidase (NA) gene segments were closely related to A/duck/Sichuan/NCXN11/2014(H5N1) and A/chicken/Jiangxi/12782/2014(H10N6) viruses, respectively. The six internal genes were homologous to avian influenza A (H5N2) viruses isolated in duck from Jiangxi in China. This H5N6 virus has not gained genetic mutations necessary for human infection and was suggested to be sensitive to neuraminidase inhibitors, but resistant to adamantanes. Epidemiological investigation of the exposure history of the patient found that a live poultry market could be the source place of infection and the incubation period was 2 5days. This novel reassortant Avian influenza A(H5N6) virus could be low pathogenic in humans. The prevalence and genetic evolution of this virus should be closely monitored. PMID- 26973296 TI - Neonatal Gastrointestinal and Respiratory Microbiome in Cystic Fibrosis: Potential Interactions and Implications for Systemic Health. AB - PURPOSE: The gastrointestinal microbiome plays a critical role in nutrition and metabolic and immune functions in infants and young children and has implications for lifelong health. Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) mutations in CF result in viscous mucous production, frequent exposure to antibiotics, and atypical colonization patterns, resulting in an evolving dysbiosis of the gastrointestinal and respiratory microsystems; dysbiosis in CF results in systemic inflammation, chronic infection, and dysregulation of immune function. Dysbiosis in both the respiratory system and gut contributes to undernutrition, growth failure, and long-term respiratory and systemic morbidity in infants and children with CF. Understanding the role that the gut and respiratory microbiome plays in health or disease progression in CF will afford opportunities to better identify interventions to affect clinical changes. METHODS: Summary was done of the pertinent literature in CF and the study of the microbiome and probiotics. FINDINGS: New studies have identified bacteria in the respiratory tract in CF that are typically members of the intestinal microbiota, and enteral exposures to breast milk and probiotics are associated with prolonged periods of respiratory stability in CF. IMPLICATIONS: Understanding the complex interactions between the CFTR mutations, microbial colonization, and mucosal and systemic immunity is of major importance to inform new treatment strategies (such as restoring a healthier microbiome with probiotics or dietary interventions) to improve nutritional status and immune competence and to decrease morbidity and mortality in CF. PMID- 26973297 TI - Physicians' Perception of Teratogenic Risk and Confidence in Prescribing Drugs in Pregnancy-Influence of Norwegian Drug Information Centers. AB - PURPOSE: Clinical decision support provided by drug information centers is an intervention that can ensure rational drug therapy for pregnant women. We have examined whether physicians' teratogenic risk perceptions and confidence in prescribing drugs to pregnant women is altered after advice from the Norwegian drug information centers, Regional Medicines and Pharmacovigilance Centres i Norway (RELIS). METHODS: Physicians who consulted RELIS for advice on patient specific drug use in pregnancy from November 2013 to April 2014 completed questionnaires before and after receiving the advice. A scale from 1 to 7 was used to rate confidence in prescribing and perception of teratogenic risk. The lower part of the scale represented a low perception of teratogenic risk and a high confidence in prescribing a drug in pregnancy. The data were analyzed using a mixed linear model. FINDINGS: A total of 45 physicians participated in the study and they assessed 64 drugs or categories of drugs. Advice from RELIS increased confidence in prescribing, with a statistically significant mean change on the scale from 4.1 to 2.9. The assessment of teratogenic risk was reduced after advice from RELIS, with a mean change from 3.2 to 2.5, though this was not significant. A subgroup of 26 physicians completed questionnaires both before and after advice from RELIS and assessed a total of 32 drugs or categories of drugs. In 94% of these assessments, advice from RELIS altered the physician's confidence in prescribing. Perception of teratogenic risk was altered in 78% of the assessments. IMPLICATIONS: Our results show that physicians' perception of teratogenic risk and confidence in prescribing drugs to pregnant women is influenced by advice from Norwegian drug information centers. PMID- 26973298 TI - Effects of lipopolysaccharides on the corrosion behavior of Ni-Cr and Co-Cr alloys. AB - STATEMENT OF PROBLEM: Lipopolysaccharides (LPS) are constituents of gingival crevicular fluid and may affect the base metal alloys used in metal ceramic crowns. The role of LPS in base metal alloys is currently unknown. PURPOSE: The purpose of this in vitro study was to evaluate the effects of gram-negative bacterial LPS on the electrochemical behavior of Ni-Cr and Co-Cr alloys. MATERIAL AND METHODS: Alloy specimens were divided into 4 groups according to Escherichia coli LPS concentration (0, 0.15, 15, and 150 MUg/mL) in acidic saliva (pH 5). Open circuit potential (OCP) and potentiodynamic polarization behavior were examined using a computer-controlled potentiostat. Metal ions released from the 2 alloys were measured by immersion in LPS-free solution and 150 MUg/mL LPS solution and analyzed by inductively coupled plasma atomic emission spectrometry (ICP-AES). Data were evaluated using 1-way ANOVA (alpha=.05). RESULTS: Compared with control groups, medium LPS concentration (15 MUg/mL) accelerated Ni-Cr alloy corrosion (P<.05), whereas high LPS concentration (150 MUg/mL) accelerated Co-Cr alloy corrosion (P<.05), as determined by OCP, corrosion current density, and polarization resistance parameters. After immersion in high LPS concentrations (150 MUg/mL), a slight increase in Ni ion release (P >.05) was observed for the Ni-Cr alloy, while a more significant Co ion release (P<.05) was observed for the Co-Cr alloy. CONCLUSIONS: LPS negatively affected the electrochemical behavior of both the Ni-Cr and Co-Cr alloys. PMID- 26973299 TI - Sensitivity and Specificity of an Adult Stroke Screening Tool in Childhood Ischemic Stroke. AB - BACKGROUND: There are frequent delays in the diagnosis of acute pediatric ischemic stroke. A screening tool that could increase the suspicion of acute ischemic stroke could aid early recognition and might improve initial care. An earlier study reported that children with acute ischemic stroke have signs that can be recognized with two adult stroke scales. We tested the hypothesis that an adult stroke scale could distinguish children with acute ischemic stroke from children with acute focal neurological deficits not due to stroke. METHODS: We retrospectively applied an adult stroke scale to the recorded examinations of 53 children with acute symptomatic acute ischemic stroke and 53 age-matched control subjects who presented with focal neurological deficits. We examined the sensitivity and specificity of the stroke scale and the occurrence of acute seizures as predictors of stroke status. RESULTS: The total stroke scale did not differentiate children with acute ischemic stroke from those who had acute deficits from nonstroke causes; however, the presence of arm weakness was significantly associated with stroke cases. Acute seizures were significantly associated with stroke cases. CONCLUSIONS: An adult stroke scale is not sensitive or specific to distinguish children with acute ischemic stroke from those with nonstroke focal neurological deficits. The development of a pediatric acute ischemic stroke screening tool should include arm weakness and perhaps acute seizures as core elements. Such a scale must account for the limitations of language in young or intellectually disabled children. PMID- 26973300 TI - Review of venous thromboembolism and race: the generalizability of treatment guidelines for high-risk populations. AB - The American College of Chest Physicians (ACCP) has established guidelines for the treatment of VTE, but the generalizability to all populations is unclear. In this review we analyzed the rate of reporting and enrollment of blacks and women in clinical trials cited in the ACCP guidelines for treatment of unprovoked VTE. We extracted data from clinical trials cited by the ACCP that compared durations of anticoagulation therapy for the treatment of unprovoked VTE. We excluded trials that treated surgical or cancer patients. For trials that did not report race/ethnicity we contacted the primary investigators via email for enrollment data. The final analysis included 17 randomized clinical trials with a total patient population of N = 13,693. All trials reported data on sex; conversely, 2 trials (11.8 %) reported race/ethnicity within the primary manuscript. We ultimately acquired data on race/ethnicity from the primary investigator in 5 additional trials for a total race/ethnicity data from 7 trials. There were 7573 males (55.3 %) and 6120 females (44.7 %) enrolled in these studies. Among trials that reported race and ethnicity the total patient population was N = 5368; 5171 (96.3 %) white, 115 (2.1 %) black, 65 (1.4 %) Asian and 7 (0.25 %) Hispanic. Racial/ethnic minorities are underreported and under represented in clinical trials forming the cornerstone of ACCP guidelines for the optimal duration for VTE treatment. Conversely, the reporting and inclusion of women was substantive. The guidelines for unprovoked VTE treatment may not be generalizable to racially and ethnically diverse patient populations. PMID- 26973301 TI - Zika virus in the dock. PMID- 26973302 TI - Antibiotic prophylaxis of endocarditis: a NICE mess. PMID- 26973303 TI - Insights from the Ebola response to address HIV and tuberculosis. PMID- 26973304 TI - Dissemination of the mcr-1 colistin resistance gene. PMID- 26973305 TI - Dissemination of the mcr-1 colistin resistance gene. PMID- 26973306 TI - Dissemination of the mcr-1 colistin resistance gene. PMID- 26973307 TI - Dissemination of the mcr-1 colistin resistance gene. PMID- 26973308 TI - Early emergence of mcr-1 in Escherichia coli from food-producing animals. PMID- 26973309 TI - Diagnostic strategies for Ebola virus detection. PMID- 26973310 TI - Bedaquiline plus delamanid for XDR tuberculosis. PMID- 26973311 TI - Are we learning the lessons of the Ebola outbreak? PMID- 26973312 TI - Crisis in Flint: lead and Legionnaires' disease. PMID- 26973315 TI - FDA and the safe and appropriate antibiotic use of fluoroquinolones. PMID- 26973316 TI - Author Reply. PMID- 26973317 TI - Editorial Comment. PMID- 26973318 TI - Editorial Comment. PMID- 26973319 TI - Author Reply. PMID- 26973320 TI - The genetic equidistance phenomenon at the proteomic level. AB - The field of molecular evolution started with the alignment of a few protein sequences in the early 1960s. Among the first results found, the genetic equidistance result has turned out to be the most unexpected. It directly inspired the ad hoc universal molecular clock hypothesis that in turn inspired the neutral theory. Unfortunately, however, what is only a maximum distance phenomenon was mistakenly transformed into a mutation rate phenomenon and became known as such. Previous work studied a small set of selected proteins. We have performed proteome wide studies of 7 different sets of proteomes involving a total of 15 species. All 7 sets showed that within each set of 3 species the least complex species is approximately equidistant in average proteome wide identity to the two more complex ones. Thus, the genetic equidistance result is a universal phenomenon of maximum distance. There is a reality of constant albeit stepwise or discontinuous increase in complexity during evolution, the rate of which is what the original molecular clock hypothesis is really about. These results provide additional lines of evidence for the recently proposed maximum genetic diversity (MGD) hypothesis. PMID- 26973321 TI - ALK inhibitors: plateauing systemic and intracranial activity? PMID- 26973322 TI - Ramucirumab plus docetaxel for urothelial carcinoma. PMID- 26973323 TI - Cost of unused cancer drugs in the USA. PMID- 26973325 TI - Synovial changes detected by ultrasound in people with knee osteoarthritis - a meta-analysis of observational studies. AB - OBJECTIVES: To examine the prevalence of synovial effusion, synovial hypertrophy and positive Doppler signal (DS) detected by ultrasound (US) in people with knee osteoarthritis (OA) and/or knee pain compared to that in the general population. METHOD: A systematic literature search was undertaken in Medline, EMBASE, Allied and Complementary Medicine, PubMed Web of Science, and SCOPUS databases in May 2015. Frequencies of US abnormalities in people with knee OA/pain, in the general population or asymptomatic controls were pooled using the random effects model. Publication bias and heterogeneity between studies were examined. RESULTS: Twenty four studies in people with knee pain/OA and five studies of the general population or asymptomatic controls met the inclusion criteria. The pooled prevalence of US effusion, synovial hypertrophy and positive DS in people with knee OA/pain were 51.5% (95% CI 40.2 to 62.8), 41.5% (26.3-57.5) and 32.7% (8.34 63.24), respectively, which were higher than those in the general population or asymptomatic controls (19.9% (95%CI 7.8-35.3%), 14.5% (0-58.81), and 15.8 (3.08 35.36), respectively). People with knee OA (ACR criteria or radiographic OA) had greater prevalence of US abnormalities than people with knee pain (P = 0.037, P = 0.010 and P = 0.009, respectively). CONCLUSIONS: US detected effusion, synovial hypertrophy and DS are more common in people with knee OA/pain, compared to the general population. These abnormalities relate more to presence of OA structural changes than to pain. PMID- 26973326 TI - Exercise, manual therapy, and use of booster sessions in physical therapy for knee osteoarthritis: a multi-center, factorial randomized clinical trial. AB - OBJECTIVE: (1) Do treatment effects differ between participants receiving manual therapy (MT) with exercise compared to subjects who don't, (2) are treatment effects sustained better when participants receive booster sessions compared to those who don't over a one year period in subjects with knee osteoarthritis (KOA)? DESIGN: Multi-center, 2 * 2 factorial randomized clinical trial. 300 participants with knee OA were randomized to four groups: exercise-no boosters (Ex), exercise-with boosters (Ex+B), manual therapy+exercise-no boosters (MT+Ex), manual therapy+exercise-with boosters (MT+Ex+B). The primary outcome was the Western Ontario and McMaster osteoarthritis index (WOMAC) at 1 year. Secondary outcomes included knee pain, physical performance tests, and proportions of participants meeting treatment responder criteria. RESULTS: There were no differences between groups on the WOMAC at 1 year or on any performance-based measures. Secondary analyses indicated a) better scores on the WOMAC and greater odds of being a treatment responder at 9 weeks for participants receiving MT, b) greater odds of being a treatment responder at 1 year for participants receiving boosters. Exploratory interaction analysis suggested knee pain decreases for participants receiving boosters and increases for participants not receiving boosters from 9 weeks to 1 year. CONCLUSIONS: MT or use of boosters with exercise did not result in additive improvement in the primary outcome at 1 year. Secondary outcomes suggest MT may have some short term benefit, and booster sessions may improve responder status and knee pain at 1 year. However, the role of booster sessions remains unclear in sustaining treatment effects and warrants further study. CLINICAL TRIALS: gov (NCT01314183). PMID- 26973324 TI - Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. AB - BACKGROUND: ALK-rearranged non-small-cell lung cancer (NSCLC) is sensitive to ALK tyrosine kinase inhibitors (ALK inhibitors) such as crizotinib, but resistance invariably develops, often with progression in the brain. Ceritinib is a more potent ALK inhibitor than crizotinib in vitro, crosses the blood-brain barrier in vivo, and shows clinical responses in patients with crizotinib-resistant disease. We aimed to assess whole-body activity of ceritinib in both ALK inhibitor pretreated and ALK inhibitor-naive patients with ALK-rearranged NSCLC. METHODS: ASCEND-1 was an open-label, phase 1 trial that recruited patients from 20 academic hospitals or cancer centres in 11 countries in Europe, North America, and Asia-Pacific. Eligible patients were aged 18 years or older with ALK rearranged locally advanced or metastatic cancer that had progressed despite standard therapy (or for which no effective standard therapy existed), who had at least one measurable lesion at baseline. The primary objective (to determine the maximum tolerated dose) has been reported previously. This updated analysis includes all patients with ALK-rearranged NSCLC given oral ceritinib at the recommended dose of 750 mg/day in the dose-escalation and expansion phases. Here we report the secondary outcomes of overall response, duration of response, and progression-free survival, analysed in all patients who received at least one 750 mg dose of ceritinib. Exploratory analyses included retrospective analysis of intracranial activity by independent neuroradiologists, in patients with untreated or locally treated neurologically stable brain metastases at baseline. Safety was assessed in all patients who received at least one dose of ceritinib. This study is no longer recruiting patients; however, treatment and follow-up are ongoing. This study is registered with ClinicalTrials.gov, number NCT01283516. FINDINGS: Between Jan 24, 2011, and July 31, 2013, 255 patients were enrolled and received at least one dose of ceritinib 750 mg/day, of whom 246 had ALK rearranged NSCLC. At data cutoff (April 14, 2014), median follow-up was 11.1 months (IQR 6.7-15.2) and 147 (60%) patients had discontinued treatment, 98 (40%) as a result of disease progression. An overall response was reported in 60 (72% [95% CI 61-82]) of 83 ALK inhibitor-naive patients and 92 (56% [49-64]) of 163 ALK inhibitor-pretreated patients. Median duration of response was 17.0 months (95% CI 11.3-non-estimable [NE]) in ALK inhibitor-naive patients and 8.3 months (6.8-9.7) in ALK inhibitor-pretreated patients. Median progression-free survival was 18.4 months (95% CI 11.1-NE) in ALK inhibitor-naive patients and 6.9 months (5.6-8.7) in ALK inhibitor-pretreated patients. Of 94 patients with retrospectively confirmed brain metastases and at least one post-baseline MRI or CT tumour assessment, intracranial disease control was reported in 15 (79% [95% CI 54-94]) of 19 ALK inhibitor-naive patients and in 49 (65% [54-76]) of 75 ALK inhibitor-pretreated patients. Of these 94 patients, 11 had measurable brain lesions and no previous radiotherapy to the brain, six of whom achieved a partial intracranial response. Serious adverse events were recorded in 117 (48%) of 246 patients. The most common grade 3-4 laboratory abnormalities were increased alanine aminotransferase (73 [30%] patients) and increased aspartate aminotransferase (25 [10%]). The most common grade 3-4 non-laboratory adverse events were diarrhoea and nausea, both of which occurred in 15 (6%) patients. Two on-treatment deaths during the study were deemed to be related to study drug by the investigators, one due to interstitial lung disease and one as a result of multiorgan failure that occurred in the context of infection and ischaemic hepatitis. INTERPRETATION: The durable whole-body responses reported, together with the intracranial activity, support a clinical benefit for treatment with ceritinib in patients with ALK-rearranged NSCLC who have received crizotinib, or as an alternative to crizotinib. A confirmatory phase 2 clinical trial is ongoing to assess ceritinib activity in patients with ALK-rearranged NSCLC and brain or leptomeningeal metastases. FUNDING: Novartis Pharmaceuticals Corporation. PMID- 26973328 TI - Mesenchymal stromal cells for cartilage repair in osteoarthritis. AB - Treatment for articular cartilage damage is quite challenging as it shows limited repair and regeneration following injury. Non-operative and classical surgical techniques are inefficient in restoring normal anatomy and function of cartilage in osteoarthritis (OA). Thus, investigating new and effective strategies for OA are necessary to establish feasible therapeutic solutions. The emergence of the new discipline of regenerative medicine, having cell-based therapy as its primary focus, may enable us to achieve repair and restore the damaged articular cartilage. This review describes progress and development of employing mesenchymal stromal cell (MSC)-based therapy as a promising alternative for OA treatment. The objective of this review is to first, discuss how in vitro MSC chondrogenic differentiation mimics in vivo embryonic cartilage development, secondly, to describe various chondrogenic differentiation strategies followed by pre-clinical and clinical studies demonstrating their feasibility and efficacy. However, several challenges need to be tackled before this research can be translated to the clinics. In particular, better understanding of the post transplanted cell behaviour and learning to enhance their potency in the disease microenvironment is essential. Final objective is to underscore the importance of isolation, storage, cell shipment, route of administration, optimum dosage and control batch to batch variations to realise the full potential of MSCs in OA clinical trials. PMID- 26973329 TI - Synovial mesenchymal stem cells from osteo- or rheumatoid arthritis joints exhibit good potential for cartilage repair using a scaffold-free tissue engineering approach. AB - OBJECTIVE: To assess whether synovial mesenchymal stem cells (SMSCs) from patients with osteoarthritis (OA) or rheumatoid arthritis (RA) can be used as an alternative cell source for cartilage repair using allogenic tissue engineered construct (TEC). METHODS: Twenty-five patients (17 female, average age 61.8 years) were divided according to their pathology (control trauma group; N = 6, OA group; N = 6) and RA patients were subdivided into two groups to evaluate the impact of biologics in accordance with whether treated with biologics [Bio(+)RA; N = 7] or not [Bio(-)RA; N = 6]. We compared the following characteristics among these groups: (1) The cell proliferation capacity of SMSCs; (2) The influence of passage number on features of SMSCs; (3) The weight and volume of TEC from the same number of SMSCs; (4) Inflammatory cytokine gene expressions levels of TEC; (5) The chondrogenic potential of TEC; and (6) Osteochondral repair using TEC in athymic nude rats. RESULTS: SMSCs from the four groups exhibited equivalent features in the above evaluation items. In in vivo studies, the TEC-treated repair tissues for all groups exhibited significantly better outcomes than those for the untreated group and no significant differences among the four TEC groups. CONCLUSION: SMSCs from OA or RA patients are no less appropriate for repairing cartilage than those from trauma patients and thus, may be an effective source for allogenic cell-based cartilage repair. PMID- 26973327 TI - Gene expression changes in damaged osteoarthritic cartilage identify a signature of non-chondrogenic and mechanical responses. AB - OBJECTIVES: Joint degeneration in osteoarthritis (OA) is characterised by damage and loss of articular cartilage. The pattern of loss is consistent with damage occurring only where the mechanical loading is high. We have investigated using RNA-sequencing (RNA-seq) and systems analyses the changes that occur in damaged OA cartilage by comparing it with intact cartilage from the same joint. METHODS: Cartilage was obtained from eight OA patients undergoing total knee replacement. RNA was extracted from cartilage on the damaged distal medial condyle (DMC) and the intact posterior lateral condyle (PLC). RNA-seq was performed to identify differentially expressed genes (DEGs) and systems analyses applied to identify dysregulated pathways. RESULTS: In the damaged OA cartilage, there was decreased expression of chondrogenic genes SOX9, SOX6, COL11A2, COL9A1/2/3, ACAN and HAPLN1; increases in non-chondrogenic genes COL1A1, COMP and FN1; an altered pattern of secreted proteinase expression; but no expression of major inflammatory cytokines. Systems analyses by PhenomeExpress revealed significant sub-networks of DEGs including mitotic cell cycle, Wnt signalling, apoptosis and matrix organisation that were influenced by a core of altered transcription factors (TFs), FOSL1, AHR, E2F1 and FOXM1. CONCLUSIONS: Gene expression changes in damaged cartilage suggested a signature non-chondrogenic response of altered matrix protein and secreted proteinase expression. There was evidence of a damage response in this late OA cartilage, which surprisingly showed features detected experimentally in the early response of cartilage to mechanical overload. PhenomeExpress analysis identified a hub of DEGs linked by a core of four differentially regulated TFs. PMID- 26973332 TI - Individual differences in self-reported difficulty sleeping across the menstrual cycle. AB - The effect of menstrual cycle phase on sleep has been studied for decades; however, individual differences in the associations between sleep and menstrual phase have not been well studied. In addition, the associations between changes in sleep and other physiological and psychological factors that vary as a function of menstrual phase have not been thoroughly assessed. This study explored individual differences in daily self-reports of difficulty sleeping across the menstrual cycle, as well as associations between daily changes in difficulty sleeping and psychological/vegetative and somatic symptoms. Participants (n = 213 females, mean age = 21.29 +/- 4.01 years) completed daily online questionnaires assessing' sleep, psychological and physical symptoms for two menstrual cycles. Two patterns of menstrual cycle-related self-reported difficulty sleeping emerged in addition to women who showed no cyclical change in self-reported difficulty sleeping: a perimenstrual increase and a mid-cycle increase. All psychological/vegetative symptoms and some of the somatic symptoms showed significant associations with self-reported difficulty sleeping. These findings highlight the importance of examining individual differences in sleep across the menstrual cycle and the significant contribution of a wide range of menstrual cycle-related psychological/vegetative and somatic symptoms. PMID- 26973330 TI - T1rho and T2 relaxation times are associated with progression of hip osteoarthritis. AB - OBJECTIVE: To evaluate whether baseline T1rho and T2 relaxation times of hip cartilage are associated with magnetic resonance imaging (MRI) based progression of hip osteoarthritis (OA) at 18 months. METHODS: 3T MRI studies of the hip were obtained at baseline and 18-month follow-up for 54 subjects without evidence of severe OA at baseline [Kellgren-Lawrence (KL) score of 0-3]. 2D fast spin-echo sequences were used for semi-quantitative morphological scoring of cartilage lesions and a combined T1rho/T2 sequence was used to quantitatively assess cartilage composition. Progression of hip OA was defined based on incident or progression of morphological semi-quantitative grade at 18 months. Baseline T1rho and T2 relaxation times were compared between progressors and non-progressors using one-way analysis of variance and Mann-Whitney U tests and used to predict progression with binary logistic regression after adjusting for age, gender, body mass index, and KL score. Additionally, a novel voxel-based relaxometry technique was used to compare the spatial distribution of baseline T1rho and T2 between progressors and non-progressors. RESULTS: Significantly higher baseline T1rho and T2 values were observed in hip OA progressors compared to non-progressors, particularly in the posterosuperior and anterior aspects of the femoral cartilage. Logistic regression showed that higher baseline T1rho or T2 values in the femoral cartilage were significantly associated with progression of femoral cartilage lesions at 18 months. CONCLUSION: T1rho and T2 relaxation parameters are associated with morphological cartilage degeneration at 18 months and may serve as potential imaging biomarkers for progression of cartilage lesions in hip OA. PMID- 26973333 TI - Middle calyx access is better for single renal pelvic stone in ultrasound-guided percutaneous nephrolithotomy. AB - To compare the outcomes among upper calyx, middle calyx, and lower calyx access in complete ultrasound-guided percutaneous nephrolithotomy (PCNL) for single renal pelvic stone. Between July 2014 and September 2015, the data of 153 patients with single renal pelvic calculi were retrospectively reviewed in this study and patients were divided to group 1 (45 patients, upper calyx access), group 2 (57 patients, middle calyx access), and group 3 (51 patients, lower calyx access). Preoperative characteristics and intraoperative and postoperative parameters were analyzed and compared. A p value of <0.05 was considered significant. Important patient- and stone-related parameters were similar among the three groups. The mean operative time was significantly shorter in the middle calyx group than the lower and upper calyx groups (41.2 +/- 6.9 vs. 50.2 +/- 9.3 and 46.0 +/- 9.6 min, respectively). The middle calyx group had a higher stone free rate than the lower and upper calyx groups (98.20 vs. 84.3 % and 93.3 %, respectively, p = 0.037). There were no significant differences in mean postoperative hemoglobin decrease and incidence of complications among groups (p = 0.42 and 0.862, respectively). Middle calyx access achieved superior outcomes for removal of single renal pelvic stone via ultrasound-guided PCNL. PMID- 26973334 TI - Ultrasonography: Applications in Pediatric Abdomen. AB - Ultrasonography (US) is a valuable imaging tool for evaluation of different clinical conditions in children, in general and abdominal conditions, in particular. The interest in US derives primarily from the lack of ionizing radiation exposure, low cost, portability, real-time imaging and Doppler capabilities. In addition, US application requires no preparation or sedation, making it particularly attractive in the pediatric population. Because of these advantages, US has been adopted as the primary imaging tool for evaluation of a number of pediatric abdominal conditions that would have involved the use of ionising radiation in the past, e.g., pyloric stenosis, intussusception and various renal and bladder abnormalities, to name a few. Certain limitations, however, are inherent to US including large body habitus, excessive bowel gas, postoperative state and the learning curve. In addition, pediatric US is particularly challenging as the children are frequently unable to co-operate for breath holding and many of them are crying during the scanning. In the present review, the authors discuss the various applications of US in the evaluation of pediatric abdomen. PMID- 26973336 TI - Birth of a healthy child after pre-implantation genetic screening of embryos from sperm of a man with nonmosaic Down syndrome. PMID- 26973335 TI - Oxidative markers in cryopreservation medium from frozen-thawed embryos: a possible tool for improved embryo selection in in vitro fertilization? AB - PURPOSE: The present study evaluated the association between oxidative parameters in embryo cryopreservation medium and laboratory and clinical outcomes. METHODS: This prospective laboratory study was conducted in an IVF unit in a university affiliated hospital with 91 IVF patients undergoing a frozen-thawed embryo transfer cycle. Following thawing, 50 MUL of embryo cryopreservation medium was retrieved from each cryotube and tested by the thermochemiluminescence (TCL) assay. TCL amplitudes after 50 (H1), 150 (H2), and 280 s (H3) were recorded in counts per second (CPS) and the TCL ratio determined for comparison with implantation and pregnancy rates. RESULTS: A total of 194 embryos were transferred in 85 frozen-thaw cycles. Twenty-one pregnancies (24.7 %) occurred. Implantation and overall and clinical pregnancy rates were higher when the median TCL H1 amplitude was <32 CPS compared to >=32 CPS (14.6 vs. 5.3 %, 37.5 vs. 17 %, 28.1 vs. 9.4 %, respectively). No pregnancies occurred when the H1 amplitude was >=40 CPS. Logistic regression multivariate analysis found that only the median TCL H1 amplitude was associated with the occurrence of pregnancy (OR = 2.93, 95 % CI 1.065-8.08). The TCL ratio inversely correlated with the duration of embryo cryopreservation (r = -0.37). CONCLUSIONS: The results indicate that thawed embryos may express oxidative processes in the cryopreservation medium, and higher oxidative levels are associated with lower implantation rates. These findings may aid in the improved selection of frozen-thawed embryos for IVF. PMID- 26973337 TI - Natural cycle frozen-thawed embryo transfer-can we improve cycle outcome? AB - PURPOSE: Several replacement protocols for frozen-thawed ET (FET) exist, with no advantage of one protocol over the others. In the present study, we aim to evaluate the outcome of natural cycle FET with modified luteal support. METHODS: All consecutive patients undergoing natural or artificial hormone replacement (AHR) day-2/3 FET cycles between May 2012 and June 2015 in our IVF unit were evaluated. While AHR FET cycles were consistent, those undergoing natural cycle FET received progesterone luteal support, and from June 2014, patients received two additional injections, one of recombinant hCG and the other of GnRH-agonist, on day of transfer and 4 days later, respectively (modified luteal support). RESULTS: Patients' clinical characteristics and laboratory/embryological variables were comparable between those undergoing natural vs. AHR cycles, during the earlier as compared to the later period. Moreover, while implantation, clinical, and ongoing pregnancy rates were significantly higher during the later period in patients undergoing the natural cycle FET with the modified luteal support (31, 51, and 46 %, respectively), as compared to natural (17, 26, and 20 %, respectively), or AHR FET in the late study period (15, 22, and 17 %, respectively), the natural cycle FET without the additional two injections yielded the same results, as the AHR cycles. CONCLUSIONS: We therefore suggest that in ovulatory patients undergoing FET, natural cycle FET with the modified luteal support should be the preparation protocol of choice. Further large prospective studies are needed to elucidate the aforementioned recommendation prior to its routine implementation. PMID- 26973338 TI - Tissue distribution of aryl hydrocarbon receptor in the intestine: Implication of putative roles in tumor suppression. AB - Intestinal homeostasis is maintained by complex interactions between intestinal microorganisms and the gut immune system. Dysregulation of gut immunity may lead to inflammatory disorders and tumorigenesis. We previously have shown the tumor suppressive effects of aryl hydrocarbon receptor (AhR) in intestinal carcinogenesis. In the present study, we investigated AhR distribution in the mouse and human intestine by histochemical analysis. In the normal intestine, AhR was mainly localized in the stroma containing immune cells in the lamina propria and lymphoid follicles. On the other hand, in the tumor tissue from human colon cancer and that developed in Apc(Min/+)mice, AhR expression was elevated. AhR immunostaining was found in both stromal and tumor cells. Although AhR was localized in the cytoplasm of tumor cells in most cases, nuclear AhR was also observed in some. AhR knockdown using siRNA resulted in significant promotion of cell growth in colon cancer cell lines. Furthermore, AhR activation by AhR ligands supplemented in culture medium suppressed cell growth. Our study results suggest that tumor suppressive roles of AhR are estimated in two distinct ways: in normal tissue, AhR is associated with tumor prevention by regulating gut immunity, whereas in tumor cells, it is involved in growth suppression. PMID- 26973339 TI - Possible links between osteoporosis and periodontal disease. PMID- 26973340 TI - [Serrated polyps and their association with synchronous advanced colorectal neoplasia]. AB - INTRODUCTION: Large serrated polyps (SP), proximal SP, SP with dysplasia and the presence of multiple sessile serrated adenomas/polyps (SSA/P), which we refer to as SP with increased risk of metachronous lesions (SPIRML), have been associated with an increased risk of advanced colon lesions on follow-up. It is unclear, however, whether SPIRML are also associated with an increased risk of synchronous advanced colorectal neoplasia (ACN). AIM: The aim of this study was to estimate the prevalence of SPIRML and to evaluate the association between SPIRML and synchronous ACN. METHODS: A cross-sectional population-based study in all patients (1,538) with histological diagnosis of SP obtained from colonoscopies, sigmoidoscopies and colonic surgery performed in Navarra Health Service hospitals (Spain) in 2011. Demographic parameters and synchronous colonic lesions (adenomas, advanced adenomas [AA] and ACN) were analyzed. RESULTS: One fourth of the sample (384 patients) presented SPIRML. These were older patients, with a slight predominance of women, and with no differences in body mass index (BMI) compared to patients without SPIRML. In the univariate analysis, patients with SPIRML showed an increased risk of adenoma, AA and ACN. In the multivariate analysis, the SPIRML group had a higher risk of synchronous AA and ACN (odds ratio [OR]: 2.38 [1.77-3.21] and OR: 2.29 [1.72-3.05], respectively); in the case of ACN, this risk was statistically significant in both locations (proximal or distal), with OR slightly higher for the proximal location. Different subtypes of SPIRML had a higher risk of AA and synchronous NA. CONCLUSION: SPIRML were common in patients with SP, and their presence was associated with an increased risk of synchronous ACN. PMID- 26973341 TI - Critical role of protein L-isoaspartyl methyltransferase in basic fibroblast growth factor-mediated neuronal cell differentiation. AB - We aimed to study the role of protein L-isoaspartyl methyltransferase (PIMT) in neuronal differentiation using basic fibroblast growth factor (bFGF)-induced neuronal differentiation, characterized by cell-body shrinkage, long neurite outgrowth, and expression of neuronal differentiation markers light and medium neurofilaments (NF). The bFGF-mediated neuronal differentiation of PC12 cells was induced through activation of mitogen-activated protein kinase (MAPK) signaling molecules [MAPK kinase 1/2 (MEK1/2), extracellular signal-regulated kinase 1/2 (ERK1/2), and p90RSK], and phosphatidylinositide 3-kinase (PI3K)/Akt signaling molecules PI3Kp110beta, PI3Kp110gamma, Akt, and mTOR. Inhibitors (adenosine dialdehyde and S-adenosylhomocysteine) of protein methylation suppressed bFGF mediated neuronal differentiation of PC12 cells. PIMTeficiency caused by PIMT specific siRNA inhibited neuronal differentiation of PC12 cells by suppressing phosphorylation of MEK1/2 and ERK1/2 in the MAPK signaling pathway and Akt and mTOR in the PI3K/Akt signaling pathway. Therefore, these results suggested that PIMT was critical for bFGF-mediated neuronal differentiation of PC12 cells and regulated the MAPK and Akt signaling pathways. [BMB Reports 2016; 49(8): 437 442]. PMID- 26973343 TI - Regulation of HIF-1alpha stability by lysine methylation. AB - The level and activity of critical regulatory proteins in cells are tightly controlled by several tiers of post-translational modifications. HIF-1alpha is maintained at low levels under normoxia conditions by the collaboration between PHD proteins and the VHL-containing E3 ubiquitin ligase complex. We recently identified a new physiologically relevant mechanism that regulates HIF-1alpha stability in the nucleus in response to cellular oxygen levels. This mechanism is based on the collaboration between the SET7/9 methyltransferase and the LSD1 demethylase. SET7/9 adds a methyl group to HIF-1alpha, which triggers degradation of the protein by the ubiquitin-proteasome system, whereas LSD1 removes the methyl group, leading to stabilization of HIF-1alpha under hypoxia conditions. In cells from knock-in mice with a mutation preventing HIF-1alpha methylation (Hif1alphaKA/KA), HIF-1alpha levels were increased in both normoxic and hypoxic conditions. Hif1alphaKA/KA knock-in mice displayed increased hematological parameters, such as red blood cell count and hemoglobin concentration. They also displayed pathological phenotypes; retinal and tumor-associated angiogenesis as well as tumor growth were increased in Hif1alphaKA/KA knock-in mice. Certain human cancer cells exhibit mutations that cause defects in HIF-1alpha methylation. In summary, this newly identified methylation-based regulation of HIF-1alpha stability constitutes another layer of regulation that is independent of previously identified mechanisms. [BMB Reports 2016; 49(5): 245-246]. PMID- 26973344 TI - Monitoring micro-vascular reactivity: a tool for guiding fluid therapy? PMID- 26973342 TI - GATA4 negatively regulates bone sialoprotein expression in osteoblasts. AB - GATA4 has been reported to act as a negative regulator in osteoblast differentiation by inhibiting the Dlx5 transactivation of Runx2 via the attenuation of the binding ability of Dlx5 to the Runx2 promoter region. Here, we determine the role of GATA4 in the regulation of bone sialoprotein (Bsp) in osteoblasts. We observed that the overexpression of Runx2 or Sox9 induced the Bsp expression in osteoblastic cells. Silencing GATA4 further enhanced the Runx2- and Sox9-mediated Bsp promoter activity, whereas GATA4 overexpression down-regulated Bsp promoter activity mediated by Runx2 and Sox9. GATA4 also interacted with Runx2 and Sox9, by attenuating the binding ability of Runx2 and Sox9 to the Bsp promoter region. Our data suggest that GATA4 acts as a negative regulator of Bsp expression in osteoblasts. [BMB Reports 2016; 49(6): 343-348]. PMID- 26973345 TI - Chili Peppers, Curcumins, and Prebiotics in Gastrointestinal Health and Disease. AB - There is growing evidence for the role of several natural products as either useful agents or adjuncts in the management of functional GI disorders (FGIDs). In this review, we examine the medical evidence for three such compounds: chili, a culinary spice; curcumin, another spice and active derivative of a root bark; and prebiotics, which are nondigestible food products. Chili may affect the pathogenesis of abdominal pain especially in functional dyspepsia and cause other symptoms. It may have a therapeutic role in FGIDs through desensitization of transient receptor potential vanilloid-1 receptor. Curcumin, the active ingredient of turmeric rhizome, has been shown in several preclinical studies and uncontrolled clinical trials as having effects on gut inflammation, gut permeability and the brain-gut axis, especially in FGIDs. Prebiotics, the non digestible food ingredients in dietary fiber, may serve as nutrients and selectively stimulate the growth and/or activity of certain colonic bacteria. The net effect of this change on colonic microbiota may lead to the production of acidic metabolites and other compounds that help to reduce the production of toxins and suppress the growth of harmful or disease-causing enteric pathogens. Although some clinical benefit in IBS has been shown, high dose intake of prebiotics may cause more bloating from bacterial fermentation. PMID- 26973346 TI - Clinical characteristics and outcomes of dialysis patients with atrial fibrillation: the Fushimi AF Registry. AB - : Atrial fibrillation (AF) is common in dialysis patients. However, clinical characteristics and outcomes of dialysis patients with AF are poorly understood. The Fushimi AF Registry is a community-based prospective survey of AF patients in Japan. Follow-up data were available for 3713 patients with a median follow-up of 2.8 years. We compared clinical characteristics and outcomes between the dialysis group (n = 92; 2.5 %) and others. The dialysis group had more various co morbidities, with a mean CHADS2 score of 2.5, and the rate of warfarin prescription was 38 %. The annual incidence rates of stroke or systemic embolism (SE), major bleeding, and all-cause death in the dialysis group were 4.0, 5.1, and 20.9 per 100 person-years, respectively. There was no significant difference in the incidence rate of stroke/SE between the dialysis group and the non dialysis group [hazard ratio (HR) 1.74 (95 % confidence interval (CI) 0.74 3.42)]. The incidence rates of major bleeding, all-cause death, and the composite of stroke/SE and all-cause death in the dialysis group were higher than those in the non-dialysis group [major bleeding: HR 3.09 (95 % CI 1.46-5.72), all-cause death: HR 3.51 (95 % CI 2.48-4.81), the composite of stroke/SE and all-cause death: HR 2.99 (95 % CI 2.15-4.05)]. Among dialysis patients, warfarin did not affect major clinical events including stroke/SE, bleeding or all-cause death. Among AF patients, those receiving dialysis showed higher incidence of major bleeding and all-cause death compared with non-dialysis patients, but the risk of stroke/SE was not particularly high. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/index.htm . PMID- 26973347 TI - Superficial vein thrombosis treated for 45 days with rivaroxaban versus fondaparinux: rationale and design of the SURPRISE trial. AB - Patients with superficial vein thrombosis (SVT) are commonly treated with low molecular weight heparin or fondaparinux in prophylactic, intermediate or therapeutic dosages for treatment periods of 10-45 days. This practice is also reflected by the current guideline recommendations. However, given the broad range of thromboembolic complication rates in SVT (between 0 and 30 % have been reported) it seems reasonable to suspect that risk stratification is needed to differentiate patients at low risk who may not benefit from anticoagulation from those at high risk who may need higher dosages or a longer duration of anticoagulation. Furthermore, prolonged treatment with injectable anticoagulants has been shown to result in poor patient adherence. Direct oral anticoagulants have recently been approved for venous thromboembolism therapy and these new drugs may offer advantages also for SVT patients. The prospective, randomized, open-label, blinded adjudication trial superficial phlebitis treated for 45 days with rivaroxaban versus fondaparinux (SURPRISE) will evaluate the efficacy and safety of 10 mg rivaroxaban OD compared to fondaparinux 2.5 mg OD for SVT treatment in a subset of high-risk SVT patients over a treatment period of 45 days. The purpose of the study is to demonstrate non-inferiority of rivaroxaban compared to fondaparinux in preventing the combined efficacy endpoint of thrombus progression, SVT recurrence, DVT, PE and death. The results of the SURPRISE trial will provide evidence for the concept of risk stratification in SVT and for the value of rivaroxaban 10 mg in SVT treatment (clinicaltrials.gov NCT01499953). PMID- 26973349 TI - Why does costly signalling evolve? Challenges with testing the handicap hypothesis. PMID- 26973350 TI - The Larva of Drusus nigrescens Meyer-Dur, 1875 (Trichoptera: Limnephilidae: Drusinae) with notes on its ecology, genetic differentiation and systematic position. AB - The paper presents a description of the hitherto unknown larva of Drusus nigrescens Meyer-Dur, 1875. Information on the morphological and genetic identification of this species is given, and the most important diagnostic features are illustrated. Its systematic position within the genus Drusus is affirmed and some zoogeographical and ecological notes are added. PMID- 26973348 TI - RECENT DEVELOPMENTS IN ELECTROCHEMICAL SENSORS FOR THE DETECTION OF NEUROTRANSMITTERS FOR APPLICATIONS IN BIOMEDICINE. AB - Neurotransmitters are important biological molecules that are essential to many neurophysiological processes including memory, cognition, and behavioral states. The development of analytical methodologies to accurately detect neurotransmitters is of great importance in neurological and biological research. Specifically designed microelectrodes or microbiosensors have demonstrated potential for rapid, real-time measurements with high spatial resolution. Such devices can facilitate study of the role and mechanism of action of neurotransmitters and can find potential uses in biomedicine. This paper reviews the current status and recent advances in the development and application of electrochemical sensors for the detection of small-molecule neurotransmitters. Measurement challenges and opportunities of electroanalytical methods to advance study and understanding of neurotransmitters in various biological models and disease conditions are discussed. PMID- 26973351 TI - Contributions of Socialization of Coping to Physiological Responses to Stress. AB - The messages mothers communicate to their children about coping may play an important role in children's emotional development by shaping children's responses to stress. Building on prior research demonstrating associations between maternal socialization of coping (SOC) and children's self-reported coping and emotional functioning (Abaied & Rudolph, 2010; 2011), we examined the contribution of SOC to children's physiological responses to stress. Mothers completed a measure of SOC with peer victimization. Children (N = 118; M age = 9.46 years, SD = 0.33) completed a measure of peer victimization and participated in a laboratory social challenge task. Saliva samples were collected prior to and following the task and were assayed for alpha-amylase (sAA), a marker of autonomic nervous system (ANS) activation. Hierarchical linear modeling analyses revealed that SOC contributed to sAA reactivity. Peer victimization predicted greater sAA reactivity when mothers made few engagement suggestions (orienting toward stress and associated emotions and cognitions) but not when mothers made many engagement suggestions. Mothers' distress responses predicted greater sAA reactivity. These findings provide novel evidence that the messages parents communicate about coping have implications for children's physiological reactivity to stress during middle childhood. PMID- 26973353 TI - Religious Belonging, Religious Agency, and Women's Autonomy in Mozambique. AB - Women's autonomy has frequently been linked with women's opportunities and investments, such as education, employment, and reproductive control. The association between women's autonomy and religion in the developing world, however, has received less attention, and the few existing studies make comparisons across major religious traditions. In this study, we focus on variations in levels of female decision-making autonomy within a single religious tradition-Christianity. Using unique survey data from a predominantly Christian area in Mozambique, we devise an autonomy scale and apply it to compare women affiliated to different Christian denominations as well as unaffiliated women. In addition to affiliation, we examine the relationship between autonomy and women's religious agency both within and outside their churches. Multivariate analyses show that women belonging to more liberal religious traditions (such as Catholicism and mainline Protestantism) and tend to have higher autonomy levels, regardless of other factors. These results are situated within the cross-national scholarship on religion and women's empowerment and are interpreted in the context of gendered religious dynamics in Mozambique and similar developing settings. PMID- 26973352 TI - Culturally-Tailored Smoking Cessation for Adult American Indian Smokers: A Clinical Trial. AB - This collaborative, community-engaged project developed and tested a Culturally Tailored Treatment (CTT) for American Indian/Alaska Native (AI/AN) smokers in the Menominee tribal community. One hundred three adult AI/AN smokers were randomized to receive either Standard Treatment (n= 53) or CTT (n = 50) for smoking cessation. Both treatment conditions included 12 weeks of varenicline and four individual counseling sessions but differed in terms of cultural tailoring of the counseling. The primary outcome was 7-day biochemically-confirmed point prevalence abstinence (PPA) at the 6-month end-of-study visit. Both intention-to treat (ITT) and responder-only analyses were conducted. There were no statistically significant group differences in 7-day PPA. The overall ITT abstinence rate at 6 months was 20%; the responder-only rate was 42%. The current study represents the first randomized smoking cessation clinical trial testing a culturally-tailored smoking cessation intervention designed for a specific AI/AN tribal community that combined FDA-approved cessation medication (varenicline) and innovative cultural intervention components. PMID- 26973354 TI - Thermodynamic study of (anthracene + phenanthrene) solid state mixtures. AB - Polycyclic aromatic hydrocarbons (PAH) are common components of many materials, such as petroleum and various types of tars. They are generally present in mixtures, occurring both naturally and as byproducts of fuel processing operations. It is important to understand the thermodynamic properties of such mixtures in order to understand better and predict their behavior (i.e., fate and transport) in the environment and in industrial operations. To characterize better the thermodynamic behavior of PAH mixtures, the phase behavior of a binary (anthracene + phenanthrene) system was studied by differential scanning calorimetry, X-ray diffraction, and the Knudsen effusion technique. Mixtures of (anthracene + phenanthrene) exhibit non-ideal mixture behavior. They form a lower melting, phenanthrene-rich phase with an initial melting temperature of 372 K (identical to the melting temperature of pure phenanthrene) and a vapor pressure of roughly lnP/Pa = -2.38. The phenanthrene-rich phase coexists with an anthracene-rich phase when the mole fraction of phenanthrene (xP) in the mixture is less than or equal to 0.80. Mixtures initially at xP = 0.90 consist entirely of the phenanthrene-rich phase and sublime at nearly constant vapor pressure and composition, consistent with azeotrope-like behavior. Quasi-azeotropy was also observed for very high-content anthracene mixtures (2.5 < xP < 5) indicating that anthracene may accommodate very low levels of phenanthrene in its crystal structure. PMID- 26973357 TI - Public Administration and the Imperative for Social Progress. PMID- 26973355 TI - Transients drive the demographic dynamics of plant populations in variable environments. AB - The dynamics of structured plant populations in variable environments can be decomposed into the 'asymptotic' growth contributed by vital rates, and 'transient' growth caused by deviation from stable stage structure.We apply this framework to a large, global data base of longitudinal studies of projection matrix models for plant populations. We ask, what is the relative contribution of transient boom and bust to the dynamic trajectories of plant populations in stochastic environments? Is this contribution patterned by phylogeny, growth form or the number of life stages per population and per species?We show that transients contribute nearly 50% or more to the resulting trajectories, depending on whether transient and stable contributions are partitioned according to their absolute or net contribution to population dynamics.Both transient contributions and asymptotic contributions are influenced heavily by the number of life stages modelled. We discuss whether the drivers of transients should be considered real ecological phenomena, or artefacts of study design and modelling strategy. We find no evidence for phylogenetic signal in the contribution of transients to stochastic growth, nor clear patterns related to growth form. We find a surprising tendency for plant populations to boom rather than bust in response to temporal changes in vital rates and that stochastic growth rates increase with increasing tendency to boom. Synthesis. Transient dynamics contribute significantly to stochastic population dynamics but are often overlooked in ecological and evolutionary studies that employ stochastic analyses. Better understanding of transient responses to fluctuating population structure will yield better management strategies for plant populations, and better grasp of evolutionary dynamics in the real world. PMID- 26973356 TI - Effective elastic properties of a composite containing multiple types of anisotropic ellipsoidal inclusions, with the application to the attachment of tendon to bone. AB - Estimates of the effective stiffness of a composite containing multiple types of inclusions are needed for the design and study of functionally graded systems in engineering and physiology. While excellent estimates and tight bounds exist for composite systems containing specific classes and distributions of identical inclusions, these are not easily generalized to complex systems with multiple types of inclusions. For example, three-point parameters are known for only a few inclusion shapes and orientations. The best estimate available for a composite containing multiple classes of inclusions arises from the Kanaun-Jeulin approach. However, this method is analogous to a generalized Benveniste approach, and therefore suffers from the same limitations: while excellent for low volume fractions of inclusions, the Kanaun-Jeullin and Benveniste estimates lie outside of three-point bounds at higher volume fractions. Here, we present an estimate for composites containing multiple classes of aligned ellipsoidal inclusions that lies within known three-point bounds at relatively higher volume fractions of inclusions and that is applicable to many engineering and biological composites. PMID- 26973358 TI - Mechanistic Considerations in the Synthesis of 2-Aryl-Indole Analogues under Bischler-Mohlau Conditions. AB - Mechanistic insight into the pathway of the Bischler-Mohlau indole formation reaction is provided by isotopic labeling utilizing judicious incorporation of a 13C atom within the alpha-bromoacetophenone analogue reactant. The resulting rearranged 2-aryl indole, isolated as the major product, located the 13C isotope label at the methine carbon of the fused five-membered heterocyclic ring, which suggested that the mechanistic pathway of cyclization, in this specific example, required two equivalents of the aniline analogue reactant partner and proceeded through an imine intermediate rather than by direct formation of the corresponding 3-aryl indole accompanied by a concomitant 1,2-aryl shift rearrangement. PMID- 26973359 TI - Spectroelectrochemical Properties of Ultra-Thin Indium Tin Oxide Films under Electric Potential Modulation. AB - In this work, the spectroscopic properties of ultra-thin ITO films are characterized under an applied electric potential modulation. To detect minute spectroscopic features, the ultra-thin ITO film was coated over an extremely sensitive single-mode integrated optical waveguide, which provided a long pathlength with more than adequate sensitivity for optical interrogation of the ultra-thin film. Experimental configurations with broadband light and several laser lines at different modulation schemes of an applied electric potential were utilized to elucidate the nature of intrinsic changes. The imaginary component of the refractive index (absorption coefficient) of the ultra-thin ITO film is unequivocally shown to have a dependence on the applied potential and the profile of this dependence changes substantially even for wavelengths inside a small spectral window (500-600 nm). The characterization technique and the data reported here can be crucial to several applications of the ITO material as a transparent conductive electrode, as for example in spectroelectrochemical investigations of surface-confined redox species. PMID- 26973361 TI - Travel in Adverse Winter Weather Conditions by Blind Pedestrians: Effect of Cane Tip Design on Travel on Snow. PMID- 26973360 TI - Analysing the connectivity and communication of suicidal users on twitter. AB - In this paper we aim to understand the connectivity and communication characteristics of Twitter users who post content subsequently classified by human annotators as containing possible suicidal intent or thinking, commonly referred to as suicidal ideation. We achieve this understanding by analysing the characteristics of their social networks. Starting from a set of human annotated Tweets we retrieved the authors' followers and friends lists, and identified users who retweeted the suicidal content. We subsequently built the social network graphs. Our results show a high degree of reciprocal connectivity between the authors of suicidal content when compared to other studies of Twitter users, suggesting a tightly-coupled virtual community. In addition, an analysis of the retweet graph has identified bridge nodes and hub nodes connecting users posting suicidal ideation with users who were not, thus suggesting a potential for information cascade and risk of a possible contagion effect. This is particularly emphasised by considering the combined graph merging friendship and retweeting links. PMID- 26973362 TI - Groupwise Dimension Reduction via Envelope Method. AB - The family of sufficient dimension reduction (SDR) methods that produce informative combinations of predictors, or indices, are particularly useful for high dimensional regression analysis. In many such analyses, it becomes increasingly common that there is available a priori subject knowledge of the predictors; e.g., they belong to different groups. While many recent SDR proposals have greatly expanded the scope of the methods' applicability, how to effectively incorporate the prior predictor structure information remains a challenge. In this article, we aim at dimension reduction that recovers full regression information while preserving the predictor group structure. Built upon a new concept of the direct sum envelope, we introduce a systematic way to incorporate the group information in most existing SDR estimators. As a result, the reduction outcomes are much easier to interpret. Moreover, the envelope method provides a principled way to build a variety of prior structures into dimension reduction analysis. Both simulations and real data analysis demonstrate the competent numerical performance of the new method. PMID- 26973363 TI - A Sociotechnical Framework for Governing Climate Engineering. AB - Proposed ways of governing climate engineering have most often been supported by narrowly framed and unreflexive appraisals and processes. This article explores the governance implications of a Deliberative Mapping project that, unlike other governance principles, have emerged from an extensive process of reflection and reflexivity. In turn, the project has made significant advances in addressing the current deficit of responsibly defined criteria for shaping governance propositions. Three such propositions argue that (1) reflexive foresight of the imagined futures in which climate engineering proposals might reside is required; (2) the performance and acceptance of climate engineering proposals should be decided in terms of robustness, not optimality; and (3) climate engineering proposals should be satisfactorily opened up before they can be considered legitimate objects of governance. Taken together, these propositions offer a sociotechnical framework not simply for governing climate engineering but for governing responses to climate change at large. PMID- 26973364 TI - THE EFFECT OF STIGMA ON CRIMINAL OFFENDERS' FUNCTIONING: A LONGITUDINAL MEDIATIONAL MODEL. AB - Research has rarely considered criminal offenders' psychological responses to stigma, but these responses may significantly influence behavior after release from jail/prison. Jail inmates' perceived and anticipated stigma was assessed prior to release from jail/prison (N = 163), and outcomes were assessed one year post-release (N = 371). We hypothesized that perceived stigma would predict poor adjustment in several domains (i.e. recidivism, substance dependence, mental health symptoms, community adjustment) through anticipated stigma. Results showed that perceived stigma predicted worse community adjustment through anticipated stigma, and this varied by race. Results are explored from an interdisciplinary perspective. PMID- 26973365 TI - The Larvae of Drusus improvisus McLachlan, 1884, Drusus camerinus and Drusus aprutiensis (Trichoptera: Limnephilidae: Drusinae). AB - The larvae of Drusus improvisus McLachlan, 1884, Drusus camerinus Moretti, 1981 and Drusus aprutiensis Moretti, 1981 are re-described and discussed in the context of contemporary keys of European Drusinae species. In addition, phylogenetic, zoogeographical and ecological notes are included. PMID- 26973366 TI - The Larva, ecology and distribution of Tinodes braueri McLachlan, 1878 (Trichoptera: Psychomyiidae). AB - The hitherto unknown larva of Tinodes braueri McLachlan, 1878, is described and discussed in the context of contemporary Psychomyiidae keys. In addition, zoogeographical and ecological notes are included. PMID- 26973367 TI - The Larva of Diplectrona magna Mosely, 1930 (Trichoptera: Hydropsychidae). AB - The larva of Diplectrona magna Mosely, 1930 is described and compared with the other European Diplectrona larvae described so far. Information for the identification of three species (D. atra, D. felix and D. magna) is given and some zoogeographical and ecological notes are presented. PMID- 26973368 TI - Greedy Algorithms for Nonnegativity-Constrained Simultaneous Sparse Recovery. AB - This work proposes a family of greedy algorithms to jointly reconstruct a set of vectors that are (i) nonnegative and (ii) simultaneously sparse with a shared support set. The proposed algorithms generalize previous approaches that were designed to impose these constraints individually. Similar to previous greedy algorithms for sparse recovery, the proposed algorithms iteratively identify promising support indices. In contrast to previous approaches, the support index selection procedure has been adapted to prioritize indices that are consistent with both the nonnegativity and shared support constraints. Empirical results demonstrate for the first time that the combined use of simultaneous sparsity and nonnegativity constraints can substantially improve recovery performance relative to existing greedy algorithms that impose less signal structure. PMID- 26973369 TI - Strong Chang's Conjecture and the tree property at omega2. AB - We prove that a strong version of Chang's Conjecture together with [Formula: see text] implies there are no [Formula: see text]-Aronszajn trees. PMID- 26973370 TI - Liftings and stresses for planar periodic frameworks. AB - We formulate and prove a periodic analog of Maxwell's theorem relating stressed planar frameworks and their liftings to polyhedral surfaces with spherical topology. We use our lifting theorem to prove deformation and rigidity-theoretic properties for planar periodic pseudo-triangulations, generalizing features known for their finite counterparts. These properties are then applied to questions originating in mathematical crystallography and materials science, concerning planar periodic auxetic structures and ultrarigid periodic frameworks. PMID- 26973371 TI - TIMEKEEPING IN THE AMERICAS. AB - Time and its measurement belong to the most fundamental core of physics, and many scientific and technological advances are directly or indirectly related to time measurements. Timekeeping is essential to everyday life, and thus is the most measured physical quantity in modern societies. Time can also be measured with less uncertainty and more resolution than any other physical quantity. The measurement of time is of the utmost importance for many applications, including: global navigation satellite systems, communications networks, electric power generation, astronomy, electronic commerce, and national defense and security. This paper discusses how time is kept, coordinated, and disseminated in the Americas. PMID- 26973372 TI - Contributions of maternal emotional functioning to socialization of coping. AB - This study examined whether maternal emotional functioning-emotional awareness and depression-guides the coping suggestions mothers make to their children in the context of a common childhood stressor (peer victimization). Across two waves of a longitudinal study, 330 mothers and their second graders (mean age (M) = 7.95 years, SD = .33; 158 boys and 172 girls) completed questionnaires. Emotional awareness predicted more primary control engagement suggestions (directly addressing stress or emotions). Depression predicted fewer cognitive restructuring suggestions (thinking positively) and more cognitive avoidance suggestions (orienting thoughts away from stress). Interactive effects between maternal emotional functioning and child sex also emerged. This study elucidates the impact of mothers' emotional functioning on how they teach their children to cope with stress. PMID- 26973373 TI - The effect of speaking rate on serial-order sound-level errors in normal healthy controls and persons with aphasia. AB - BACKGROUND: Although many speech errors can be generated at either a linguistic or motoric level of production, phonetically well-formed sound-level serial-order errors are generally assumed to result from disruption of phonologic encoding (PE) processes. An influential model of PE (Dell, 1986; Dell, Burger & Svec, 1997) predicts that speaking rate should affect the relative proportion of these serial-order sound errors (anticipations, perseverations, exchanges). These predictions have been extended to, and have special relevance for persons with aphasia (PWA) because of the increased frequency with which speech errors occur and because their localization within the functional linguistic architecture may help in diagnosis and treatment. Supporting evidence regarding the effect of speaking rate on phonological encoding has been provided by studies using young normal language (NL) speakers and computer simulations. Limited data exist for older NL users and no group data exist for PWA. AIMS: This study tested the phonologic encoding properties of Dell's model of speech production (Dell, 1986; Dell,et al., 1997), which predicts that increasing speaking rate affects the relative proportion of serial-order sound errors (i.e., anticipations, perseverations, and exchanges). METHODS & PROCEDURES: The effects of speech rate on the error ratios of anticipation/exchange (AE), anticipation/perseveration (AP) and vocal reaction time (VRT) were examined in 16 normal healthy controls (NHC) and 16 PWA without concomitant motor speech disorders. The participants were recorded performing a phonologically challenging (tongue twister) speech production task at their typical and two faster speaking rates. OUTCOMES & RESULTS: A significant effect of increased rate was obtained for the AP but not the AE ratio. Significant effects of group and rate were obtained for VRT. CONCLUSION: Although the significant effect of rate for the AP ratio provided evidence that changes in speaking rate did affect PE, the results failed to support the model derived predictions regarding the direction of change for error type proportions. The current findings argued for an alternative concept of the role of activation and decay in influencing types of serial-order sound errors. Rather than a slow activation decay rate (Dell, 1986), the results of the current study were more compatible with an alternative explanation of rapid activation decay or slow build-up of residual activation. PMID- 26973374 TI - Comparison of CBF1, CBF2, CBF3 and CBF4 expression in some grapevine cultivars and species under cold stress. AB - Grapevine, an important horticultural crop in the world, is moderately tolerant to cold conditions and is subjected to the cold injuries at different regions. So studies on different aspects of tolerance mechanism to unexpected cold of late spring as well as winter freezing seems necessary about this vine. For this reason, study on genes responsible for acquiring cold tolerance is very important. Transcription factors are among regulatory proteins that are responsible for cold acclimation. In this research work, expression levels of CBF1, CBF2, CBF3, and CBF4 transcription factors were studied on two cvs of Vitis vinifera ("Khalili-Danedar" and "Shahroodi") as well as one Vitis riparia at different times after treating at 4 degrees C. Results showed that two vinifera cultivars, "Khalili-Danedar" and "Shahroodi", had similar trend for each transcription factor. Gene expression increased at the beginning of cold stress and then decreased. Expression of these TF started some minutes (CBF1) after cold treatment and continued for several hours (CBF2), even till the tenth day (CBF4). All together V. riparia which is endemic to the cold regions behaved stronger and showed higher expression for all studied transcription factors. Among two V. vinifera cultivars, "Khalili-Danedar" showed significantly higher expression compared with "Shahroodi". The comparison of expression levels of these four transcription factors revealed that the least and the greatest expressions were recorded for CBF1 and CBF3 respectively, and two CBF2 and CBF4 had approximately the same expression levels. PMID- 26973375 TI - Milking the data: Measuring milk off-take in extensive livestock systems. Experimental evidence from Niger. AB - Milk is an important source of cash and nutrients for many households in developing countries. Yet, our understanding of the role of dairy production in livelihoods and nutritional outcomes is hindered by the lack of decent quality household survey data. Data on milk off-take for human consumption are difficult to collect in household surveys for a number of reasons which make accurate recall challenging for the respondent (continuous production and seasonality among others), introducing possibly severe biases in the computation of full household incomes and farm sales, as well as in the estimation of the contribution of livestock (specifically dairy) production to agricultural value added and the livelihoods of rural households. This paper presents results from a validation exercise implemented in Niger, where alternative survey instruments based on recall methods were administered to randomly selected households, and compared to a 12-month system of physical monitoring and recording of milk production. The results of the exercise show that reasonably accurate estimates via recall methods are possible, and provide a clear ranking of questionnaire design options that can inform future survey operations. PMID- 26973376 TI - The Role of Parenthood and College Education in the Self-Concept of College Students: Explicit and Implicit Assessments of Gendered Aspirations. AB - This research examined the extent to which parenthood and college education are incorporated into the self-concept of college students. A US sample of undergraduates (90 men, 87 women) attending a large and ethnically diverse university completed explicit and implicit measures of identification with "parenthood" and "college education," associations between these concepts and gender categories, and gender identification. Explicitly, men and women identified strongly with college education. Implicitly, women identified equally with parenthood and college education, whereas men identified more strongly with college education. In addition, implicit measures revealed that traditional gender roles accounted for a stronger identification with parenthood for participants who displayed a female identity and a stronger identification with college education for participants who displayed a male identity. PMID- 26973377 TI - The Role of Body Size in Mate Selection among African American Young Adults. AB - A profusion of studies have demonstrated that body size is a major factor in mate selection for both men and women. The particular role played by weight, however, has been subject to some debate, particularly with respect to the types of body sizes deemed most attractive, and scholars have questioned the degree to which body size preferences are constant across groups. In this paper, we drew from two perspectives on this issue, Sexual Strategies Theory and what we termed the cultural variability perspective, and used survey data to examine how body size was associated with both casual dating and serious romantic relationships. We used a United States sample of 386 African American adolescents and young adults between ages 16 and 21, living in the Midwest and Southeast, and who were enrolled in either high school or college. Results showed that overweight women were more likely to report casually dating than women in the thinnest weight category. Body size was not related to dating status among men. Among women, the results suggest stronger support for the cultural variability argument than for Sexual Strategies Theory. Potential explanations for these findings are discussed. PMID- 26973379 TI - Functional feeding ecology in Central European species of subfamily Drusinae (Insecta: Trichoptera). AB - The functional feeding ecology of Drusus muelleri, D. nigrescens, D. melanchaetesD. franzi and D. alpinus is discussed and compared with feeding modi of other Central European Drusinae. PMID- 26973380 TI - United States menhaden oil could save billions in U.S. health care costs and improve IQ in children. AB - The United States menhaden oil annual production is sufficient to supply all of the recommended long chain Omega-3s for Americans over 55 with coronary heart disease (CHD) and pregnant and lactating women. According to a recent study, the utilization of preventable intake levels could potentially save up to $1.7 billion annually in hospital costs alone. In addition, the remaining oil could be used to support a culture of enough Atlantic salmon to provide every pregnant and lactating woman in the U.S. with 8-12 ounces of fish per week, as recommended by the Food and Drug Administration (FDA), throughout the duration of pregnancy and lactation. Based on the FDA's quantitative assessment, this may result in a net increase of IQ by 5.5 points in children and improve their early age verbal development. PMID- 26973381 TI - Does the current regulation of assisted reproductive techniques in the UK safeguard animal welfare? AB - Reproductive medicine is one of the fastest-developing fields of veterinary medicine, Regulation of veterinary assisted reproductive technologies (ARTs) is currently divided between the Animals (Scientific Procedures) Act (1986); the Veterinary Surgeons Act 1966, and the Animal Welfare Act (2006). None of those pieces of legislation was purpose designed to protect the welfare of animals undergoing ARTs, either directly or by determining which veterinary ART procedures may or may not be performed. Consequently, due to the lack of reference to such procedures, the welfare protection aims of the legislation are sometimes ambiguous. It is therefore difficult to ascertain whether the aims of the legislation are being fulfilled, but, in the opinion of this author, the legislation is anyway inadequate in scope, most particularly because it fails to provide a reporting function. It is unclear whether all or any veterinary ART procedures being undertaken on post-natal animals are associated with suffering. Some ARTs may cause discomfort, stress or pain: study or review of the welfare effects of these would be valuable. Any future review of the legislation regulating veterinary ARTs, be that an overall review or a review of one of the relevant statutes (for example the VSA), should take into account the interface between research and clinical medicine; the potentially welfare-compromising gaps between the Acts; the need to introduce reporting functions in order to build an evidence base, and the issue of veterinary specialisation and whether specialised techniques should be carried out only by those with specialist post-graduate qualifications. PMID- 26973382 TI - HOW SHOULD THE WELFARE OF FETAL AND NEUROLOGICALLY IMMATURE POSTNATAL ANIMALS BE PROTECTED? AB - Legal protection of the welfare of prenatal animals has not previously been addressed as a discrete subject within the academic literature on animal welfare, ethics and law. This paper aims to rectify this by reviewing the protections (or absence of protections) provided for fetuses by existing legislation in various jurisdictions, and considering the extent to which legal protection of animal fetuses can be justified on animal welfare grounds. Questions related to the need to protect the welfare of neurologically immature postnatal animals are also considered. We argue that there are reasons to protect animal fetuses, both in order to protect fetuses themselves against possible suffering, and in order to protect the animals which fetuses will become against negative welfare impacts that originate prenatally. We review the science on whether fetuses can suffer, and argue that extant regulations do not fully reflect current scientific understanding. Following the precautionary principle, we further argue that regulators should consider the possibility that foetuses and neurologically immature postnatal animals may suffer due to subcortically based 'raw basic affects' (i.e. relatively undifferentiated experiences of discomfort suggested to be generated by neural processing at levels below the cerebral cortex). Furthermore we show that there are reasons for affording fetuses protection in order to safeguard the long-term welfare of future animals. However, it may be possible to provide such protection via rules or laws relating to the use of certain techniques and the management of pregnant animals, rather than via direct legal protection of fetuses themselves. In order to provide such protection effectively we need to know more about the relationship between maternal nutrition, stress, exercise, management and fetal health, and about the impact of the timing of a fetal insult on long-term postnatal welfare. PMID- 26973378 TI - Nonproliferative and Proliferative Lesions of the Gastrointestinal Tract, Pancreas and Salivary Glands of the Rat and Mouse. AB - The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) project is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature and diagnostic criteria for nonproliferative and proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and diagnostic criteria for classifying lesions in the digestive system including the salivary glands and the exocrine pancreas of laboratory rats and mice. Most lesions are illustrated by color photomicrographs. The standardized nomenclature, the diagnostic criteria, and the photomicrographs are also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and age related lesions as well as lesions induced by exposure to test items. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature and diagnostic criteria for the digestive system will decrease misunderstandings among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. PMID- 26973383 TI - Hepatogenous diabetes: Is it a neglected condition in chronic liver disease? AB - Diabetes mellitus (DM) that occurs because of chronic liver disease (CLD) is known as hepatogenous diabetes (HD). Although the association of diabetes and liver cirrhosis was described forty years ago, it was scarcely studied for long time. Patients suffering from this condition have low frequency of risk factors of type 2 DM. Its incidence is higher in CLD of viral, alcoholic and cryptogenic etiology. Its pathophysiology relates to liver damage, pancreatic dysfunction, interactions between hepatitis C virus (HCV) and glucose metabolism mechanisms and genetic susceptibility. It associates with increased rate of liver complications and hepatocellular carcinoma, and decreased 5-year survival rate. It reduces sustained virological response in HCV infected patients. In spite of these evidences, the American Diabetes Association does not recognize HD. In addition, the impact of glucose control on clinical outcomes of patients has not been evaluated. Treatment of diabetes may be difficult due to liver insufficiency and hepatotoxicity of antidiabetic drugs. Notwithstanding, no therapeutic guidelines have been implemented up to date. In this editorial, authors discuss the reasons why they think that HD may be a neglected pathological condition and call attention to the necessity for more clinical research on different fields of this disease. PMID- 26973385 TI - Sentinel lymph node navigation surgery for gastric cancer: Does it really benefit the patient? AB - Sentinel lymph node (SLN) navigation surgery is accepted as a standard treatment procedure for malignant melanoma and breast cancer. However, the benefit of reduced lymphadenectomy based on SLN examination remains unclear in cases of gastric cancer. Here, we review previous studies to determine whether SLN navigation surgery is beneficial for gastric cancer patients. Recently, a large scale prospective study from the Japanese Society of Sentinel Node Navigation Surgery reported that the endoscopic dual tracer method, using a dye and radioisotope for SLN biopsy, was safe and effective when applied to cases of superficial and relatively small gastric cancers. SLN mapping with SLN basin dissection was preferred for early gastric cancer since it is minimally invasive. However, previous studies reported that limited gastrectomy and lymphadenectomy may not improve the patient's postoperative quality of life (QOL). As a result, the benefit of SLN navigation surgery for gastric cancer patients, in terms of their QOL, is limited. Thus, endoscopic and laparoscopic limited gastrectomy combined with SLN navigation surgery has the potential to become the standard minimally invasive surgery in early gastric cancer. PMID- 26973384 TI - Gastric cancer: Current status of lymph node dissection. AB - D2 procedure has been accepted in Far East as the standard treatment for both early (EGC) and advanced gastric cancer (AGC) for many decades. Recently EGC has been successfully treated with endoscopy by endoscopic mucosal resection or endoscopic submucosal dissection, when restricted or extended Gotoda's criteria can be applied and D1+ surgery is offered only to patients not fitted for less invasive treatment. Furthermore, two randomised controlled trials (RCTs) have been demonstrating the non inferiority of minimally invasive technique as compared to standard open surgery for the treatment of early cases and recently the feasibility of adequate D1+ dissection has been demonstrated also for the robot assisted technique. In case of AGC the debate on the extent of nodal dissection has been open for many decades. While D2 gastrectomy was performed as the standard procedure in eastern countries, mostly based on observational and retrospective studies, in the west the Medical Research Council (MRC), Dutch and Italian RCTs have been conducted to show a survival benefit of D2 over D1 with evidence based medicine. Unfortunately both the MRC and the Dutch trials failed to show a survival benefit after the D2 procedure, mostly due to the significant increase of postoperative morbidity and mortality, which was referred to splenopancreatectomy. Only 15 years after the conclusion of its accrual, the Dutch trial could report a significant decrease of recurrence after D2 procedure. Recently the long term survival analysis of the Italian RCT could demonstrate a benefit for patients with positive nodes treated with D2 gastrectomy without splenopancreatectomy. As nowadays also in western countries D2 procedure can be done safely with pancreas preserving technique and without preventive splenectomy, it has been suggested in several national guidelines as the recommended procedure for patients with AGC. PMID- 26973386 TI - Update on a tumor-associated NADH oxidase in gastric cancer cell growth. AB - Gastric cancer is one of the most common human malignancies, and its prevalence has been shown to be well-correlated with cancer-related deaths worldwide. Regrettably, the poor prognosis of this disease is mainly due to its late diagnosis at advanced stages after the cancer has already metastasized. Recent research has emphasized the identification of cancer biomarkers in the hope of diagnosing cancer early and designing targeted therapies to reverse cancer progression. One member of a family of growth-related nicotinamide adenine dinucleotide (NADH or hydroquinone) oxidases is tumor-associated NADH oxidase (tNOX; ENOX2). Unlike its counterpart CNOX (ENOX1), identified in normal rat liver plasma membranes and shown to be stimulated by growth factors and hormones, tNOX activity purified from rat hepatoma cells is constitutively active. Its activity is detectable in the sera of cancer patients but not in those of healthy volunteers, suggesting its clinical relevance. Interestingly, tNOX expression was shown to be present in an array of cancer cell lines. More importantly, inhibition of tNOX was well correlated with reduced cancer cell growth and induction of apoptosis. RNA interference targeting tNOX expression in cancer cells effectively restored non-cancerous phenotypes, further supporting the vital role of tNOX in cancer cells. Here, we review the regulatory role of tNOX in gastric cancer cell growth. PMID- 26973387 TI - De novo autoimmune hepatitis in liver transplant: State-of-the-art review. AB - In the two past decades, a number of communications, case-control studies, and retrospective reports have appeared in the literature with concerns about the development of a complex set of clinical, laboratory and histological characteristics of a liver graft dysfunction that is compatible with autoimmune hepatitis. The de novo prefix was added to distinguish this entity from a pre transplant primary autoimmune hepatitis, but the globally accepted criteria for the diagnosis of autoimmune hepatitis have been adopted in the diagnostic algorithm. Indeed, de novo autoimmune hepatitis is characterized by the typical liver necro-inflammation that is rich in plasma cells, the presence of interface hepatitis and the consequent laboratory findings of elevations in liver enzymes, increases in serum gamma globulin and the appearance of non-organ specific auto antibodies. Still, the overall features of de novo autoimmune hepatitis appear not to be attributable to a univocal patho-physiological pathway because they can develop in the patients who have undergone liver transplantation due to different etiologies. Specifically, in subjects with hepatitis C virus recurrence, an interferon-containing antiviral treatment has been indicated as a potential inception of immune system derangement. Herein, we attempt to review the currently available knowledge about de novo liver autoimmunity and its clinical management. PMID- 26973388 TI - Combination could be another tool for bowel preparation? AB - Optimal bowel preparation increases the cecal intubation rate and detection of neoplastic lesions while decreasing the procedural time and procedural-related complications. Although high-volume polyethylene glycol (PEG) solution is the most frequently used preparation for bowel cleansing, patients are often unwilling to take PEG solution due to its large volume, poor palatability, and high incidence of adverse events, such as abdominal bloating and nausea. Other purgatives include osmotic agents (e.g., sodium phosphate, magnesium citrate, and sodium sulfate), stimulant agents (e.g., senna, bisacodyl, and sodium picosulfate), and prokinetic agents (e.g., cisapride, mosapride, and itopride). A combination of PEG with an osmotic, stimulant, or prokinetic agent could effectively reduce the PEG solution volume and increase patients' adherence. Some such solutions have been found in several published studies to not be inferior to PEG alone in terms of bowel cleansing quality. Although combination methods showed similar efficacy and safety, the value of these studies is limited by shortcomings in study design. New effective and well-tolerated combination preparations are required, in addition to rigorous new validated studies. PMID- 26973389 TI - Advances in liver transplantation allocation systems. AB - With the growing number of patients in need of liver transplantation, there is a need for adopting new and modifying existing allocation policies that prioritize patients for liver transplantation. Policy should ensure fair allocation that is reproducible and strongly predictive of best pre and post transplant outcomes while taking into account the natural history of the potential recipients liver disease and its complications. There is wide acceptance for allocation policies based on urgency in which the sickest patients on the waiting list with the highest risk of mortality receive priority. Model for end-stage liver disease and Child-Turcotte-Pugh scoring system, the two most universally applicable systems are used in urgency-based prioritization. However, other factors must be considered to achieve optimal allocation. Factors affecting pre-transplant patient survival and the quality of the donor organ also affect outcome. The optimal system should have allocation prioritization that accounts for both urgency and transplant outcome. We reviewed past and current liver allocation systems with the aim of generating further discussion about improvement of current policies. PMID- 26973390 TI - Resveratrol and fenofibrate ameliorate fructose-induced nonalcoholic steatohepatitis by modulation of genes expression. AB - AIM: To evaluate the effect of resveratrol, alone and in combination with fenofibrate, on fructose-induced metabolic genes abnormalities in rats. METHODS: Giving a fructose-enriched diet (FED) to rats for 12 wk was used as a model for inducing hepatic dyslipidemia and insulin resistance. Adult male albino rats (150 200 g) were divided into a control group and a FED group which was subdivided into 4 groups, a control FED, fenofibrate (FENO) (100 mg/kg), resveratrol (RES) (70 mg/kg) and combined treatment (FENO + RES) (half the doses). All treatments were given orally from the 9(th) week till the end of experimental period. Body weight, oral glucose tolerance test (OGTT), liver index, glucose, insulin, insulin resistance (HOMA), serum and liver triglycerides (TGs), oxidative stress (liver MDA, GSH and SOD), serum AST, ALT, AST/ALT ratio and tumor necrosis factor alpha (TNF-alpha) were measured. Additionally, hepatic gene expression of suppressor of cytokine signaling-3 (SOCS-3), sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), malonyl CoA decarboxylase (MCD), transforming growth factor-beta1 (TGF-beta1) and adipose tissue genes expression of leptin and adiponectin were investigated. Liver sections were taken for histopathological examination and steatosis area were determined. RESULTS: Rats fed FED showed damaged liver, impairment of glucose tolerance, insulin resistance, oxidative stress and dyslipidemia. As for gene expression, there was a change in favor of dyslipidemia and nonalcoholic steatohepatitis (NASH) development. All treatment regimens showed some benefit in reversing the described deviations. Fructose caused deterioration in hepatic gene expression of SOCS-3, SREBP-1c, FAS, MDA and TGF-beta1 and in adipose tissue gene expression of leptin and adiponectin. Fructose showed also an increase in body weight, insulin resistance (OGTT, HOMA), serum and liver TGs, hepatic MDA, serum AST, AST/ALT ratio and TNF-alpha compared to control. All treatments improved SOCS-3, FAS, MCD, TGF-beta1 and leptin genes expression while only RES and FENO + RES groups showed an improvement in SREBP-1c expression. Adiponectin gene expression was improved only by RES. A decrease in body weight, HOMA, liver TGs, AST/ALT ratio and TNF-alpha were observed in all treatment groups. Liver index was increased in FENO and FENO + RES groups. Serum TGs was improved only by FENO treatment. Liver MDA was improved by RES and FENO + RES treatments. FENO + RES group showed an increase in liver GSH content. CONCLUSION: When resveratrol was given with half the dose of fenofibrate it improved NASH-related fructose-induced disturbances in gene expression similar to a full dose of fenofibrate. PMID- 26973391 TI - Effect of artesunate supplementation on bacterial translocation and dysbiosis of gut microbiota in rats with liver cirrhosis. AB - AIM: To evaluate the effect of artesunate (AS) supplementation on bacterial translocation (BT) and gut microbiota in a rat model of liver cirrhosis. METHODS: Fifty-four male Sprague-Dawley rats were randomly divided into a normal control group (N), a liver cirrhosis group (M) and a liver cirrhosis group intervened with AS (MA). Each group was sampled at 4, 6 and 8 wk. Liver cirrhosis was induced by injection of carbon tetrachloride (CCl4), intragastric administration of 10% ethanol, and feeding a high fat diet. Rats in the MA group were intragastrically administered with AS (25 mg/kg body weight, once daily). Injuries of the liver and intestinal mucosa were assessed by hematoxylin-eosin or Masson's trichrome staining. Liver index was calculated as a ratio of the organ weight (g) to body weight (g). The gut microbiota was examined by automated ribosomal intergenic-spacer analysis of fecal DNA. BT was assessed by standard microbiological techniques in the blood, mesenteric lymph nodes (MLNs), liver, spleen, and kidney. RESULTS: Compared to group N, the body weight was reduced significantly in groups M and MA due to the development of liver cirrhosis over the period of 8 wk. The body weight was higher in group MA than in group M. The liver indices were significantly elevated at 4, 6 and 8 wk in groups M and MA compared to group N. AS supplementation partially decreased the liver indices in group MA. Marked histopathologic changes in the liver and small intestinal mucosa in group M were observed, which were alleviated in group MA. Levels of pro inflammatory interleukin-6 and tumor necrosis factor-alpha were significantly elevated at 8 wk in ileal homogenates in group M compared to group N, which were decreased after AS supplementation in group MA. The dysbiosis of gut microbiota indicated by the mean diversity (Shannon index) and mean similarity (Sorenson index) was severe as the liver cirrhosis developed, and AS supplementation had an apparent intervention effect on the dysbiosis of gut microbiota at 4 wk. The occurrence of BT was increased in the liver of group M compared to that of group N. AS supplementation reduced BT in group MA at 8 wk. BT also occurred in the MLNs, spleen, and kidney, which was reduced by AS supplementation. BT was not detected in the blood in any group. CONCLUSION: Dysbiosis of gut microbiota, injury of intestinal mucosal barrier and BT occurred as liver cirrhosis progressed, which might enhance inflammation and aggravate liver injury. AS may have other non-antimalarial effects that modulate gut microbiota, inhibit BT and alleviate inflammation, resulting in a reduction in CCl4, alcohol and high fat caused damages to the liver and intestine. PMID- 26973392 TI - Pathophysiology of chronic pancreatitis induced by dibutyltin dichloride joint ethanol in mice. AB - AIM: To search for a new chronic pancreatitis model in mice suitable for investigating the pathophysiological processes leading to pancreatic fibrosis. METHODS: The mice were randomly divided into 2 groups (n = 50), control group and model group. The mice in model group were given ethanol (10%) in drinking water after injection of dibutyltin dichloride (DBTC) (8 mg/kg BW) in tail vein. The mice in control group were injected with only solvent into tail vein (60% ethanol, 20% glycerine and 20% normal saline) and drank common water. At days 1, 7, 14, 28, and 56 after application of DBTC or solvent, 10 mice in one group were killed at each time point respectively. Blood was obtained by inferior vena cava puncture. The activity of amylase, concentration of bilirubin and hyaluronic acid in serum were assayed. The pancreas was taken to observe the pancreatic morphology by HE staining, and to characterize the pancreatic fibrosis by Masson staining. The expression of F4/80, CD3 and fibronectin (FN) were assayed by immuno-histochemistry or Immunofluorescence technique. Collagen type I (COL1A1) in pancreas were detected by Western blot. The expression of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) mRNA in the pancreas was assessed by real time PCR. RESULTS: DBTC induced an acute edematous pancreatitis within 1 d. The dilated acini, scattered acinar cell necrosis, and inflammatory cells were found at day 7. Extensive infiltration with inflammatory cells following deposition of connective tissue was observed at day 14. At day 28, level of pancreatic fibrosis was aggravated. The pancreatic tissue was replaced by an extended interstitial fibrosis at the end of 2 mo. There was significant difference in the level of amylase, bilirubin and hyaluronic acid in serum between control group and model group (P < 0.05). The level of COL1A1 and FN in pancreas increased. The expression of MMP-1 mRNA in pancreas decreased, but TIMP-1 mRNA increased at model group. CONCLUSION: DBTC joint Ethanol drinking can induce chronic pancreatitis in accordance with the pathophysiological modification of human. DBTC joint Ethanol-induced pancreatitis in mice is an effective and handy experimental method. The model is suitable to study the mechanism of pancreatic fibrosis in chronic pancreatitis. PMID- 26973393 TI - Synergistic anticancer properties of docosahexaenoic acid and 5-fluorouracil through interference with energy metabolism and cell cycle arrest in human gastric cancer cell line AGS cells. AB - AIM: To explore the synergistic effect of docosahexaenoic acid (DHA)/5 fluorouracil (5-FU) on the human gastric cancer cell line AGS and examine the underlying mechanism. METHODS: AGS cells were cultured and treated with a series of concentrations of DHA and 5-FU alone or in combination for 24 and 48 h. To investigate the synergistic effect of DHA and 5-FU on AGS cells, the inhibition of cell proliferation was determined by MTT assay and cell morphology. Flow cytometric analysis was also used to assess cell cycle distribution, and the expression of mitochondrial electron transfer chain complexes (METCs) I, II and V in AGS cells was further determined by Western blot analysis. RESULTS: DHA and 5 FU alone or in combination could markedly suppress the proliferation of AGS cells in a significant time and dose-dependent manner. DHA markedly strengthened the antiproliferative effect of 5-FU, decreasing the IC50 by 3.56-2.15-fold in an apparent synergy. The morphological changes of the cells were characterized by shrinkage, cell membrane blebbing and decreased adherence. Cell cycle analysis showed a shift of cells into the G0/G1 phase from the S phase following treatment with DHA or 5-FU (G0/G1 phase: 30.04% +/- 1.54% vs 49.05% +/- 6.41% and 63.39% +/ 6.83%, respectively, P < 0.05; S phase: 56.76% +/- 3.14% vs 34.75% +/- 2.35% and 25.63% +/- 2.21%, respectively, P < 0.05). Combination treatment of DHA and 5-FU resulted in a significantly larger shift toward the G0/G1 phase and subsequent reduction in S phase (G0/G1 phase: 69.06% +/- 2.63% vs 49.05% +/- 6.41% and 63.39% +/- 6.83%, respectively, P < 0.05; S phase: 19.80% +/- 4.30% vs 34.75% +/- 2.35% and 25.63% +/- 2.21%, respectively, P < 0.05). This synergy was also reflected in the significant downregulation of the expression of METCs in AGS cells. CONCLUSION: Synergistic anticancer properties of DHA and 5-FU may involve interference with energy production of AGS cells via downregulation of METCs and cell cycle arrest. PMID- 26973394 TI - Characteristics of and risk factors for colorectal neoplasms in young adults in a screening population. AB - AIM: To investigate prevalence and risk factors for colorectal neoplasms in adults aged < 50 years, for whom screening is not recommended. METHODS: This cross-sectional study compared prevalence and characteristics of colorectal and advanced adenomas in patients aged < 50 years who underwent colonoscopy screening with subjects aged >= 50 years. To evaluate risk factors for colorectal and advanced adenoma in young adults, we used multivariable logistic regression models. Colorectal neoplasm characteristics were evaluated and compared with those in older patients. RESULTS: Among 2819 patients included, prevalences of colorectal adenoma and advanced adenoma were 19.7% and 1.5%, respectively. As patient age increased, so did the prevalence of colorectal neoplasm. However, prevalence of advanced adenoma did not differ between age-groups 45-49 years and >= 50 years (OR = 0.43, 95%CI: 0.17-1.07, P = 0.070). In younger age-group (< 50 years), colorectal adenoma was significantly associated with older age, waist circumference (OR = 1.72, 95%CI: 1.15-2.55, P = 0.008), and current smoking (OR = 1.60, 95%CI: 1.07-2.41, P = 0.023). Alcohol consumption was an independent risk factor for colorectal advanced adenoma (OR = 3.69, 95%CI: 1.08-12.54, P = 0.037). Multiple neoplasms and large neoplasms (>= 1 cm) were more prevalent in subjects >= 50 years. CONCLUSION: Current screening strategies for colorectal cancer may need to be amended to account for patient age, especially in young subjects with abdominal obesity, current smoking and alcohol consumption. PMID- 26973395 TI - Ten-year survival of hepatocellular carcinoma patients undergoing radiofrequency ablation as a first-line treatment. AB - AIM: To investigate the long-term survival and prognostic factors in hepatocellular carcinoma (HCC) patients undergoing radiofrequency ablation (RFA) as a first-line treatment. METHODS: From 2000 to 2013, 316 consecutive patients with 404 HCC (1.0-5.0 cm; mean: 3.2 +/- 1.1 cm) underwent ultrasonography-guided percutaneous RFA as a first-line treatment. There were 250 males and 66 females with an average age of 60.1 +/- 10.8 years (24-87 years). Patients were followed for 1 year to > 10 years after RFA (234, 181, 136, and 71 for 3, 5, 7, and 10 years, respectively). Overall local response rates and long-term survival rates were assessed. Survival results were generated using Kaplan-Meier estimates, and multivariate analysis was performed using the Cox regression model. RESULTS: In total, 548 RFA sessions were performed and major complications occurred in 10 sessions (1.8%). Local tumor progression and/or new tumor development were observed in 43.3% (132/305) of the patients during the follow-up period. Overall 5- and 10-year survival rates were 49.7% and 28.4%, respectively. Based on multivariate analysis, three factors were identified as independent prognostic factors for overall survival: Child-Pugh classification (HR = 4.054, P < 0.001), portal vein hypertension (HR = 2.743, P = 0.002), and tumor number (HR = 2.693, P = 0.003). The local progression-free 5- and 10-year survival rates were 42.7% and 19.5%. In addition to the Child-Pugh classification and the number of tumors, the number of RFA sessions (HR = 1.550, P = 0.002) was associated with local progression-free survival. CONCLUSION: RFA can achieve acceptable outcomes for HCC patients as a first-line treatment, especially for patients with Child-Pugh class A, patients with a single tumor and patients without portal vein hypertension. PMID- 26973397 TI - Benefit of laparoscopic liver resection in high body mass index patients. AB - AIM: To explore the impact of body mass index (BMI) on surgical outcomes in patients undergoing laparoscopic liver resection (LLR). METHODS: From January 2010 to February 2015, sixty-eight patients who underwent primary partial liver resection in our institute were retrospectively reviewed. Surgical outcomes of LLR were compared with those of open liver resection (OLR). In addition, we analyzed associations with BMI and surgical outcomes. RESULTS: Among 68 patients, thirty-nine patients underwent LLR and 29 were performed OLR. Significant difference in operation time, blood loss, and postoperative hospital stay was observed. There were no significant differences in mortality and morbidity in two groups. Twenty-two patients (32.4%) were classified as obese (BMI >= 25). A statistically significant correlation was observed between BMI and operation time, between BMI and blood loss in OLR, but not in LLR. The operation time and blood loss of OLR were significantly higher than that of LLR in obese patients. Open liver resection and BMI were independent predictors for prolonged operation time and increased blood loss in multivariate analysis. CONCLUSION: The present study demonstrated that BMI had influenced to surgical outcomes of OLR. LLR was less influenced by BMI and had great benefit in obese patients. PMID- 26973396 TI - Factors associated with increased incidence of severe toxicities following yttrium-90 resin microspheres in the treatment of hepatic malignancies. AB - AIM: To further define variables associated with increased incidences of severe toxicities following administration of yttrium-90 ((90)Y) microspheres. METHODS: Fifty-eight patients undergoing 79 treatments were retrospectively assessed for development of clinical and laboratory toxicity incidence following (90)Y administration. Severe toxicity events were defined using Common Terminology Criteria for Adverse Events version 4.03 and defined as grade >= 3. Univariate logistic regression analyses were used to evaluate the effect of different factors on the incidence of severe toxicity events. Multicollinearity was assessed for all factors with P < 0.1 using Pearson correlation matrices. All factors not excluded due to multicollinearity were included in a multivariate logistic regression model for each measurement of severe toxicity. RESULTS: Severe (grade >= 3) toxicities occurred following 21.5% of the 79 treatments included in our analysis. The most common severe laboratory toxicities were severe alkaline phosphatase (17.7%), albumin (12.7%), and total bilirubin (10.1%) toxicities. Decreased pre-treatment albumin (OR = 26.2, P = 0.010) and increased pre-treatment international normalized ratio (INR) (OR = 17.7, P = 0.048) were associated with development of severe hepatic toxicity. Increased pre-treatment aspartate aminotransferase (AST; OR = 7.4, P = 0.025) and decreased pre-treatment hemoglobin (OR = 12.5, P = 0.025) were associated with severe albumin toxicity. Increasing pre-treatment model for end-stage liver disease (MELD) score (OR = 1.8, P = 0.033) was associated with severe total bilirubin toxicity. Colorectal adenocarcinoma histology was associated with severe alkaline phosphatase toxicity (OR = 5.4, P = 0.043). CONCLUSION: Clinicians should carefully consider pre treatment albumin, INR, AST, hemoglobin, MELD, and colorectal histology when choosing appropriate candidates for (90)Y microsphere therapy. PMID- 26973398 TI - Fatty liver index vs waist circumference for predicting non-alcoholic fatty liver disease. AB - AIM: To determine the discriminatory performance of fatty liver index (FLI) for non-alcoholic fatty liver disease (NAFLD). METHODS: The data of 5052 subjects aged over 18 years were analyzed. FLI was calculated from body mass index, waist circumference (WC), triglyceride, and gamma glutamyl transferase data. Logistic regression analysis was conducted to determine the association between FLI and NAFLD. The discriminatory performance of FLI in the diagnosis of NAFLD was evaluated by receiver operating characteristic analysis. Area under the curves (AUCs) and related confidence intervals were estimated. Optimal cutoff points of FLI in the diagnosis of NAFLD were determined based on the maximum values of Youden's index. RESULTS: The mean age of men and women in the study population were 44.8 +/- 16.8 and 43.78 +/- 15.43, respectively (P = 0.0216). The prevalence of NAFLD was 40.1% in men and 44.2% in women (P < 0.0017). FLI was strongly associated with NAFLD, so that even a one unit increase in FLI increased the chance of developing NAFLD by 5.8% (OR = 1.058, 95%CI: 1.054-1.063, P < 0.0001). Although FLI showed good performance in the diagnosis of NAFLD (AUC = 0.8656 (95%CI: 0.8548-0.8764), there was no significant difference with regards to WC (AUC = 0.8533, 95%CI: 0.8419-0.8646). The performance of FLI was not significantly different between men (AUC = 0.8648, 95%CI: 0.8505-0.8791) and women (AUC = 0.8682, 95%CI: 0.8513-0.8851). The highest performance with regards to age was related to the 18-39 age group (AUC = 0.8930, 95%CI: 0.8766-0.9093). The optimal cutoff points of FLI were 46.9 in men (sensitivity = 0.8242, specificity = 0.7687, Youden's index = 0.5929) and 53.8 in women (sensitivity = 0.8233, specificity = 0.7655, Youden's index = 0.5888). CONCLUSION: Although FLI had acceptable discriminatory power in the diagnosis of NAFLD, WC was a simpler and more accessible index with a similar performance. PMID- 26973399 TI - Predicting liver metastasis of gastrointestinal tract cancer by diffusion weighted imaging of apparent diffusion coefficient values. AB - AIM: To determine if efficacy of chemotherapy on liver metastasis of gastrointestinal tract cancer can be predicted by apparent diffusion coefficient (ADC) values of diffusion-weighted imaging (DWI). METHODS: In total, 86 patients with liver metastasis of gastrointestinal tract cancer (156 metastatic lesions) diagnosed in our hospital were included in this study. The maximum diameters of these tumors were compared with each other before treatment, 2 wk after treatment, and 12 wk after treatment. Selected patients were classified as the effective group and the ineffective group, depending on the maximum diameter of the tumor after 12 wk of treatment; and the ADC values at different treatment times between the two groups were compared. Spearman rank correlation was used to analyze the relationship between ADC value and tumor diameter. Receiver operating characteristic curve (ROC curve) was used to analyze the ADC values before treatment to predict the patient's sensitivity and specificity degree of efficacy to the chemotherapy. RESULTS: There was no difference in age between the two groups and in maximum tumor diameter before treatment and 2 wk after treatment. However, after 12 wk of treatment, maximum tumor diameter in the effective group was significantly lower than that in the ineffective group (P < 0.05). Before treatment, ADC values in the ineffective group were significantly higher than those in the effective group (P < 0.05). There was no difference in ADC values between the effective and ineffective groups after 2 and 12 wk of treatment. However, ADC values were significantly higher after 2 and 12 wk of treatment compared to before treatment in the effective group (P < 0.05). Spearman rank correlation analysis showed that ADC value before treatment and the reduced percentage of the maximum tumor diameter after 12 wk of treatment were negatively correlated, while the increase in the percentage of the ADC value 12 wk after treatment and the decrease in the percentage of the maximum tumor diameter were significantly positively correlated. The results of the ROC curve showed that ADC value with a chemotherapy ineffective threshold value of 1.14 * 10(-3) mm(2)/s before treatment had a sensitivity and specificity of 94.3% and 76.7%, respectively. CONCLUSION: DWI ADC values can be used to predict the response of patients with liver metastasis of gastrointestinal tract cancer to chemotherapy with high sensitivity and relatively high specificity. PMID- 26973400 TI - Hepatitis B virus and hepatitis C virus play different prognostic roles in intrahepatic cholangiocarcinoma: A meta-analysis. AB - AIM: To identify the prognostic value of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in patients with intrahepatic cholangiocarcinoma. METHODS: A search was performed for relevant publications in PubMed, EMBASE and Web of Science databases. The pooled effects were calculated from the available information to identify the relationship between HBV or HCV infection and the prognosis and clinicopathological features. The chi(2) and I (2) tests were used to evaluate heterogeneity between studies. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated by a fixed-effects model, if no heterogeneity existed. If there was heterogeneity, a random-effects model was applied. RESULTS: In total, 14 studies involving 2842 cases were enrolled in this meta-analysis. The patients with HBV infection presented better overall and disease-free survival, and the pooled HRs were significant at 0.76 (95%CI: 0.70 0.83) and 0.78 (95%CI: 0.66-0.94), respectively. Additionally, our study revealed that HCV infection was correlated with shortened overall survival in comparison with the control group (HR = 2.64, 95%CI: 1.77-3.93). We also found that HBV infection occurred more frequently in male patients [odds ratio (OR) = 1.91, 95%CI: 1.06-3.44] and was correlated with higher levels of serum aspartate transaminase (AST) and alpha-fetoprotein (AFP) (OR = 1.93, 95%CI: 1.11-3.35; OR = 3.86, 95%CI: 2.58-5.78) and a lower level of serum carbohydrate antigen 19-9 (CA19-9) (OR = 0.47, 95%CI: 0.34-0.65). Moreover, HBV infection was associated with cirrhosis (OR = 6.44, 95%CI: 4.33-9.56), a higher proportion of capsule formation (OR = 6.04, 95%CI: 3.56-10.26), and a lower rate of lymph node metastasis (OR = 0.39, 95%CI: 0.25-0.58). No significant publication bias was seen in any of the enrolled studies. CONCLUSION: HBV infection may indicate a favorable prognosis in patients with intrahepatic cholangiocarcinoma, while HCV infection suggests a poor prognosis. PMID- 26973401 TI - Transmural penetration of sigmoid colon and rectum by retained surgical sponge after hysterectomy. AB - Gossypiboma is a surgical sponge that is retained in the body after the operation. A 39-year-old female presented with vague lower abdominal pain, fever, and rectal discharge 15 mo after hysterectomy. The sponge remaining in the abdomen had no radiopaque marker. Therefore a series of radiographic evaluations was fruitless. The surgical sponge was found in the rectosigmoid colon on colonoscopy. The sponge penetrated the sigmoid colon and rectum transmurally, forming an opening on both sides. The patient underwent low anterior resection and was discharged without postoperative complications. PMID- 26973403 TI - Rupture of sigmoid colon caused by compressed air. AB - Compressed air has been generally used since the beginning of the 20(th) century for various applications. However, rupture of the colon caused by compressed air is uncommon. We report a case of pneumatic rupture of the sigmoid colon. The patient was admitted to the emergency room complaining of abdominal pain and distention. His colleague triggered a compressed air nozzle against his anus as a practical joke 2 h previously. On arrival, his pulse rate was 126 beats/min, respiratory rate was 42 breaths/min and blood pressure was 86/54 mmHg. Physical examination revealed peritoneal irritation and the abdomen was markedly distended. Computed tomography of the abdomen showed a large volume of air in the abdominal cavity. Peritoneocentesis was performed to relieve the tension pneumoperitoneum. Emergency laparotomy was done after controlling shock. Laparotomy revealed a 2-cm perforation in the sigmoid colon. The perforation was sutured and temporary ileostomy was performed as well as thorough drainage and irrigation of the abdominopelvic cavity. Reversal of ileostomy was performed successfully after 3 mo. Follow-up was uneventful. We also present a brief literature review. PMID- 26973402 TI - Lymphoepithelioma-like gastric carcinoma: A case report and review of the literature. AB - Lymphoepithelioma-like gastric carcinoma is a rare type of gastric cancer characterized by a carcinoma with intense stromal lymphocytic infiltration. Although lymphocytic infiltration is closely associated with Epstein-Barr virus (EBV) infection, concomitant occurrence with differentiated adenocarcinoma is relatively rare. The clinical manifestations of lymphoepithelioma-like gastric carcinoma (including EBV-positive and -negative forms) are similar to those of gastric cancer, and the diagnosis is based on pathologic, histologic, and immunohistochemical findings. This report describes the case of a 55-year-old female patient who presented with a 10-year history of recurrent and worsening abdominal pain and melena that had been occurring for 2 mo. An ulcerative lesion was detected in the stomach by endoscopic examination, which raised suspicion of early gastric cancer. A subsequent preoperative endoscopic biopsy showed adenocarcinoma, but the postoperative pathologic, histologic, and immunohistochemical analyses of the resected specimen revealed a final diagnosis of lymphoepithelioma-like gastric carcinoma. PMID- 26973404 TI - PillCam(r) SB3 capsule: Does the increased frame rate eliminate the risk of missing lesions? AB - Since its emergence in 2000, small bowel capsule endoscopy (SBCE) has assumed a pivotal role as an investigation method for small bowel diseases. The PillCam((r)) SB2-ex offers 12 h of battery time, 4 more than the previous version (SB2). Rahman et al recently found that the PillCam((r)) SB2-ex has a significantly increased completion rate, although without higher diagnostic yield, compared with the SB2. We would like to discuss these somewhat surprising results and the new potentialities of the PillCam((r)) SB3 regarding the diagnostic yield of small bowel studies. PillCam((r)) SB3 offers improved image resolution and faster adaptable frame rate over previous versions of SBCE. We recently compared the major duodenal papilla detection rate obtained with PillCam((r)) SB3 and SB2 as a surrogate indicator of diagnostic yield in the proximal small bowel. The PillCam((r)) SB3 had a significantly higher major duodenal papilla detection rate than the PillCam((r)) SB2 (42.7% vs 24%, P = 0.015). Thus, the most recent version of the PillCam((r)) capsule, SB3, may increase diagnostic yield, particularly in the proximal segments of the small bowel. PMID- 26973405 TI - Ultrasound elastographic techniques in focal liver lesions. AB - Elastographic techniques are new ultrasound-based imaging techniques developed to estimate tissue deformability/stiffness. Several ultrasound elastographic approaches have been developed, such as static elastography, transient elastography and acoustic radiation force imaging methods, which include point shear wave and shear wave imaging elastography. The application of these methods in clinical practice aims at estimating the mechanical tissues properties. One of the main settings for the application of these tools has been liver stiffness assessment in chronic liver disease, which has been studied mainly using transient elastography. Another field of application for these techniques is the assessment of focal lesions, detected by ultrasound in organs such as pancreas, prostate, breast, thyroid, lymph nodes. Considering the frequency and importance of the detection of focal liver lesions through routine ultrasound, some studies have also aimed to assess the role that elestography can play in studying the stiffness of different types of liver lesions, in order to predict their nature and thus offer valuable non-invasive methods for the diagnosis of liver masses. PMID- 26973406 TI - Outcomes of abdominal surgery in patients with liver cirrhosis. AB - Patients suffering from liver cirrhosis (LC) frequently require non-hepatic abdominal surgery, even before liver transplantation. LC is an important risk factor itself for surgery, due to the higher than average associated morbidity and mortality. This high surgical risk occurs because of the pathophysiology of liver disease itself and to the presence of contributing factors, such as coagulopathy, poor nutritional status, adaptive immune dysfunction, cirrhotic cardiomyopathy, and renal and pulmonary dysfunction, which all lead to poor outcomes. Careful evaluation of these factors and the degree of liver disease can help to reduce the development of complications both during and after abdominal surgery. In the emergency setting, with the presence of decompensated LC, alcoholic hepatitis, severe/advanced LC, and significant extrahepatic organ dysfunction conservative management is preferred. A multidisciplinary, individualized, and specialized approach can improve outcomes; preoperative optimization after risk stratification and careful management are mandatory before surgery. Laparoscopic techniques can also improve outcomes. We review the impact of LC on surgical outcome in non-hepatic abdominal surgeries required in this cirrhotic population before, during, and after surgery. PMID- 26973407 TI - Epigenetic regulation of insulin-like growth factor axis in hepatocellular carcinoma. AB - The insulin-like growth factor (IGF) signaling pathway is an important pathway in the process of hepatocarcinogenesis, and the IGF network is clearly dysregulated in many cancers and developmental abnormalities. In hepatocellular carcinoma (HCC), only a minority of patients are eligible for curative treatments, such as tumor resection or liver transplant. Unfortunately, there is a high recurrence of HCC after surgical tumor removal. Recent research efforts have focused on targeting IGF axis members in an attempt to find therapeutic options for many health problems. In this review, we shed lights on the regulation of members of the IGF axis, mainly by microRNAs in HCC. MicroRNAs in HCC attempt to halt the aberrant expression of the IGF network, and a single microRNA can have multiple downstream targets in one or more signaling pathways. Targeting microRNAs is a relatively new approach for identifying an efficient radical cure for HCC. PMID- 26973409 TI - Laparoscopic approach in gastrointestinal emergencies. AB - This review focuses on the laparoscopic approach to gastrointestinal emergencies and its more recent indications. Laparoscopic surgery has a specific place in elective procedures, but that does not apply in emergency situations. In specific emergencies, there is a huge range of indications and different techniques to apply, and not all of them are equally settle. We consider that the most controversial points in minimally invasive procedures are indications in emergency situations due to technical difficulties. Some pathologies, such as oesophageal emergencies, obstruction due to colon cancer, abdominal hernias or incarcerated postsurgical hernias, are nearly always resolved by conventional surgery, that is, an open approach due to limited intraabdominal cavity space or due to the vulnerability of the bowel. These technical problems have been solved in many diseases, such as for perforated peptic ulcer or acute appendectomy for which a laparoscopic approach has become a well-known and globally supported procedure. On the other hand, endoscopic procedures have acquired further indications, relegating surgical solutions to a second place; this happens in cholangitis or pancreatic abscess drainage. This endoluminal approach avoids the need for laparoscopic development in these diseases. Nevertheless, new instruments and new technologies could extend the laparoscopic approach to a broader array of potentials procedures. There remains, however, a long way to go. PMID- 26973408 TI - Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells. AB - Pancreatic cancer (PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction surrounding the cancer cells. Cancer-associated fibroblasts (CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs. However, other important components of the PC stroma are inflammatory cells and endothelial cells. The aim of this review is to describe the complex interplay between PC cells and the cellular and non-cellular components of the tumour stroma. Published data have indicated that the desmoplastic stroma protects PC cells against chemotherapy and radiation therapy and that it might promote the proliferation and migration of PC cells. However, in animal studies, experimental depletion of the desmoplastic stroma and CAFs has led to more aggressive cancers. Hence, the precise role of the tumour stroma in PC remains to be elucidated. However, it is likely that a context-dependent therapeutic modification, rather than pure depletion, of the PC stroma holds potential for the development of new treatment strategies for PC patients. PMID- 26973410 TI - Calcium-sensing receptor: A new target for therapy of diarrhea. AB - Management of acute diarrhea remains a global challenge, particularly in resource limiting countries. Oral rehydration solution (ORS), a passive rehydrating therapy developed approximately 40 years ago, remains the mainstay treatment. Although ORS is effective for hydration, since it does not inhibit enterotoxin mediated excessive secretion, reduced absorption and compromised barrier function - the primary mechanisms of diarrhea, ORS does not offer a rapid relief of diarrhea symptom. There are a few alternative therapies available, yet the use of these drugs is limited by their expense, lack of availability and/or safety concerns. Novel anti-diarrheal therapeutic approaches, particularly those simple affordable therapies, are needed. This article explores intestinal calcium sensing receptor (CaSR), a newly uncovered target for therapy of diarrhea. Unlike others, targeting this host antidiarrheal receptor system appears "all inclusive": it is anti-secretory, pro-absorptive, anti-motility, and anti inflammatory. Thus, activating CaSR reverses changes of both secretory and inflammatory diarrheas. Considering its unique property of using simple nutrients such as calcium, polyamines, and certain amino acids/oligopeptides as activators, it is possible that through targeting of CaSR with a combination of specific nutrients, novel oral rehydrating solutions that are inexpensive and practical to use in all countries may be developed. PMID- 26973411 TI - Liver surgery in cirrhosis and portal hypertension. AB - The prevalence of hepatic cirrhosis in Europe and the United States, currently 250 patients per 100000 inhabitants, is steadily increasing. Thus, we observe a significant increase in patients with cirrhosis and portal hypertension needing liver resections for primary or metastatic lesions. However, extended liver resections in patients with underlying hepatic cirrhosis and portal hypertension still represent a medical challenge in regard to perioperative morbidity, surgical management and postoperative outcome. The Barcelona Clinic Liver Cancer classification recommends to restrict curative liver resections for hepatocellular carcinoma in cirrhotic patients to early tumor stages in patients with Child A cirrhosis not showing portal hypertension. However, during the last two decades, relevant improvements in preoperative diagnostic, perioperative hepatologic and intensive care management as well as in surgical techniques during hepatic resections have rendered even extended liver resections in higher degree cirrhotic patients with portal hypertension possible. However, there are few standard indications for hepatic resections in cirrhotic patients and risk stratifications have to be performed in an interdisciplinary setting for each individual patient. We here review the indications, the preoperative risk stratifications, the morbidity and the mortality of extended resections for primary and metastatic lesions in cirrhotic livers. Furthermore, we provide a review of literature on perioperative management in cirrhotic patients needing extrahepatic abdominal surgery and an overview of surgical options in the treatment of hepatic cirrhosis. PMID- 26973412 TI - Curcumin as a potential therapeutic candidate for Helicobacter pylori associated diseases. AB - Curcumin, a yellow pigment and principal polyphenolic Curcuminoid obtained from the turmeric rhizome Curcuma longa, is commonly used as a food-coloring agent. Studies suggest that curcumin has a wide range of beneficial properties e.g., anti-inflammatory, anti-oxidant, anti-cancer, anti-proliferative, anti-fungal and anti-microbial. These pleiotropic activities prompted several research groups to elucidate the role of curcumin in Helicobacter pylori (H. pylori) infection. This is the first review with this heading where we discussed regarding the role of curcumin as an anti-H. pylori agent along with its potential in other gastrointestinal diseases. Based on several in vitro, early cell culture, animal research and few pre-clinical trials, curcumin projected as a potential therapeutic candidate against H. pylori mediated gastric pathogenesis. This review sheds light on the anti-H. pylori effects of curcumin in different models with meticulous emphasis on its anti-oxidant, anti-inflammatory and anti carcinogenic effects as well as some critical signaling and effecter molecules. Remarkably, non-toxic molecule curcumin fulfills the characteristics for an ideal chemopreventive agent against H. pylori mediated gastric carcinogenesis but the foremost challenge is to obtain the optimum therapeutic levels of curcumin, due to its low solubility and poor bioavailability. Further, we have discussed about the possibilities for improving its efficacy and bioavailability. Lastly, we concluded with the anticipation that in near future curcumin may be used to develop a therapeutic drug against H. pylori mediated gastric ailments through improved formulation or delivery systems, facilitating its enhanced absorption and cellular uptake. PMID- 26973413 TI - Impact of non-oncological factors on tumor recurrence after liver transplantation in hepatocellular carcinoma patients. AB - Hepatocellular carcinoma (HCC) is the most common primary neoplasm of the liver and is one of the leading causes of cancer-related death worldwide. Liver transplantation (LT) has become one of the best curative therapeutic options for patients with HCC, although tumor recurrence after LT is a major and unaddressed cause of mortality. Furthermore, the factors that are associated with recurrence are not fully understood, and most previous studies have focused on the biological properties of HCC, such as the number and size of the HCC nodules, the degree of differentiation, the presence of hepatic vascular invasion, elevated serum levels of alpha-fetoprotein, and the tumor stage outside of the Milan criteria. Thus, little attention has been given to factors that are not directly related to HCC (i.e., "non-oncological factors"), which have emerged as predictors of tumor recurrence. This review was performed to assess the effects of non-oncological factors on tumor recurrence after LT. The identification of these factors may provide new research directions and clinical strategies for the prophylaxis and surveillance of tumor recurrence after LT, which can help reduce recurrence and improve patient survival. PMID- 26973414 TI - Life and death at the mucosal-luminal interface: New perspectives on human intestinal ischemia-reperfusion. AB - Intestinal ischemia is a frequently observed phenomenon. Morbidity and mortality rates are extraordinarily high and did not improve over the past decades. This is in part attributable to limited knowledge on the pathophysiology of intestinal ischemia-reperfusion (IR) in man, the paucity in preventive and/or therapeutic options and the lack of early diagnostic markers for intestinal ischemia. To improve our knowledge and solve clinically important questions regarding intestinal IR, we developed a human experimental intestinal IR model. With this model, we were able to gain insight into the mechanisms that allow the human gut to withstand short periods of IR without the development of severe inflammatory responses. The purpose of this review is to overview the most relevant recent advances in our understanding of the pathophysiology of human intestinal IR, as well as the (potential) future clinical implications. PMID- 26973415 TI - Inhibition of SW620 human colon cancer cells by upregulating miRNA-145. AB - AIM: To investigate the targeted inhibition of proliferation and migration of SW620 human colon cancer cells by upregulating miRNA-145 (miR-145). METHODS: Forty-five samples of colon cancer tissues and 45 normal control samples were obtained from the biological database of the First Affiliated Hospital of Liaoning Medical University. We performed quantitative analysis of miR-145 and N ras expression in tissues; reverse transcriptase polymerase chain reaction analysis of miR-145 expression in SW620 colon cancer cells and normal colonic epithelial cells; construction of miR-145 lentiviral vector and determination of miR-145 expression in SW620 cells transduced with miR-145 vector; analysis of the effect of miR-145 overexpression on SW620 cell proliferation; analysis of the effect of miR-145 overexpression on SW620 cell migration using a wound healing assay; and analysis of the effect of miR-145 on N-ras expression using Western blotting. RESULTS: miR-145 expression was significantly downregulated in colon cancer tissues, with its expression in normal colonic tissues being 4-5-fold higher (two sample t test, P < 0.05), whereas N-ras expression showed the opposite trend. miR-145 expression in SW620 cells was downregulated, which was significantly lower compared to that in colonic epithelial cells (two sample t test, P < 0.05). miR-145 vector and control were successfully packaged; expression of miR-145 in SW620 cells transduced with miR-145 was 8.2-fold of that in control cells (two sample t test, P < 0.05). The proliferation of miR-145 transduced SW620 cells was significantly decreased compared to control cells (two sample t test, P < 0.05). At 48 h in the wound healing experiment, the migration indexes and controls were (97.27% +/- 9.25%) and (70.22% +/- 6.53%), respectively (two sample t test, P < 0.05). N-ras expression in miR-145-tranduced SW620 cells was significantly lower than others (one-way analysis of variance, P < 0.05). CONCLUSION: miR-145 is important in inhibiting colon cancer cell proliferation and migration. This is a good foundation for development of colon cancer therapy by targeting tumor suppressor miR-145. PMID- 26973417 TI - Human cytomegalovirus-encoded US28 may act as a tumor promoter in colorectal cancer. AB - AIM: To assess human cytomegalovirus-encoded US28 gene function in colorectal cancer (CRC) pathogenesis. METHODS: Immunohistochemical analysis was performed to determine US28 expression in 103 CRC patient samples and 98 corresponding adjacent noncancerous samples. Patient data were compared by age, sex, tumor location, histological grade, Dukes' stage, and overall mean survival time. In addition, the US28 gene was transiently transfected into the CRC LOVO cell line, and cell proliferation was assessed using a cell counting kit-8 assay. Cell cycle analysis by flow cytometry and a cell invasion transwell assay were also carried out. RESULTS: US28 levels were clearly higher in CRC tissues (38.8%) than in adjacent noncancerous samples (7.1%) (P = 0.000). Interestingly, elevated US28 amounts in CRC tissues were significantly associated with histological grade, metastasis, Dukes' stage, and overall survival (all P < 0.05); meanwhile, US28 expression was not significantly correlated with age, sex or tumor location. In addition, multivariate Cox regression data revealed US28 level as an independent CRC prognostic marker (P = 0.000). LOVO cells successfully transfected with the US28 gene exhibited higher viability, greater chemotherapy resistance, accelerated cell cycle progression, and increased invasion ability. CONCLUSION: US28 expression is predictive of poor prognosis and may promote CRC. PMID- 26973416 TI - New role and molecular mechanism of Gadd45a in hepatic fibrosis. AB - AIM: To investigate the role of Gadd45a in hepatic fibrosis and the transforming growth factor (TGF)-beta/Smad signaling pathway. METHODS: Wild-type male BALB/c mice were treated with CCl4 to induce a model of chronic liver injury. Hepatic stellate cells (HSCs) were isolated from the liver of BALB/c mice and were treated with small interfering RNAs (siRNAs) targeting Gadd45a or the pcDNA3.1 Gadd45a recombinant plasmid. Cellular alpha-smooth muscle actin (alpha-SMA), beta actin, type I collagen, phospho-Smad2, phospho-Smad3, Smad2, Smad3, and Smad4 were detected by Western blots. The mRNA levels of alpha-SMA, beta-actin, and type I collagen were determined by quantitative real-time (qRT)-PCR analyses. Reactive oxygen species production was monitored by flow cytometry using 2,7 dichlorodihydrofluorescein diacetate. Gadd45a, Gadd45b, anti-Gadd45g, type I collagen, and SMA local expression in liver tissue were measured by histologic and immunohistochemical analyses. RESULTS: Significant downregulation of Gadd45a, but not Gadd45b or Gadd45g, accompanied by activation of the TGF-beta/Smad signaling pathways was detected in fibrotic liver tissues of mice and isolated HSCs with chronic liver injury induced by CCl4 treatment. Overexpression of Gadd45a reduced the expression of extracellular matrix proteins and alpha-SMA in HSCs, whereas transient knockdown of Gadd45a with siRNA reversed this process. Gadd45a inhibited the activity of a plasminogen activator inhibitor-1 promoter construct and (CAGA)9 MLP-Luc, an artificial Smad3/4-specific reporter, as well as reduced the phosphorylation and nuclear translocation of Smad3. Gadd45a showed protective effects by scavenging reactive oxygen species and upregulating antioxidant enzymes. CONCLUSION: Gadd45a may counteract hepatic fibrosis by regulating the activation of HSCs via the inhibition of TGF-beta/Smad signaling. PMID- 26973418 TI - Development of a novel mouse constipation model. AB - AIM: To establish a novel mouse constipation model. METHODS: Animals were randomly divided into three groups, and intragastrically administered 0-4 degrees C saline (ice-cold group) or 15-20 degrees C saline (saline control group) daily for 14 d, or were left untreated (blank control group). Stools were collected 3-24 h after treatment to record the wet and dry weights and the stool form. Intestinal propulsion experiments were carried out and defecation time was measured for six days continuously after suspending treatments. The expressions of PGP9.5 were detected by immunohistochemistry. RESULTS: Based on the percentage of stool weight changes compared with baseline (before irritation) in 9-14 d, stool weight changes were classified into three levels. Each level shows a different body state, which is state I (no change: plus or minus 5%), state II (slightly decreased: 5%-15%) and state III (decreased: 15%-25%). In state III, between day 9-14, the stool weights decreased by 15%-25% compared with the baseline, and changed at a rate > 10% compared with blank control values, and the stools became small and dry. Additionally, intestinal functions degenerated in these animals, and PGP9.5-positive expression markedly decreased in jejunum, ileum and proximal colon myenteric plexus. CONCLUSION: Irritation with ice-cold saline is a stable, repeatable method in building constipation model in mice for exploring the pathogenesis and treatment options of constipation, and the change of stool weight and size may serve as a useful tool to judge a constipation model success or not. PMID- 26973419 TI - Esophageal squamous cell cancer in a highly endemic region. AB - AIM: To identify risk factors associated with esophageal cancer in Zambia and association between dietary intake and urinary 8-iso prostaglandin F2alpha (8 isoPGF2alpha). METHODS: We conducted a prospective, case control study at the University Teaching Hospital. Subjects included both individuals admitted to the hospital and those presenting for an outpatient upper endoscopy. Esophageal cancer cases were compared to age and sex-matched controls. Cases were defined as patients with biopsy proven esophageal cancer; controls were defined as subjects without endoscopic evidence of esophageal cancer. Clinical and dietary data were collected using a standard questionnaire, developed a priori. Blood was collected for human immunodeficiency virus (HIV) serology. Urine was collected, and 8 isoPGF2alpha was measured primarily by enzyme-linked immunosorbent assay and expressed as a ratio to creatinine. RESULTS: Forty five controls (mean age 54.2 +/- 15.3, 31 male) and 27 cases (mean age 54.6 +/- 16.4, 17 males) were studied. Body mass index was lower in cases (median 16.8) than controls (median 23.2), P = 0.01. Histopathologically, 25/27 (93%) were squamous cell carcinoma and 2/27 (7%) adenocarcinoma. More cases smoked cigarettes (OR = 11.24, 95%CI: 1.37-92.4, P = 0.02) but alcohol consumption and HIV seropositivity did not differ significantly (P = 0.14 for both). Fruit, vegetables and fish consumption did not differ significantly between groups (P = 0.11, 0.12, and 0.10, respectively). Mean isoprostane level was significantly higher in cases (0.03 ng/mg creatinine) than controls (0.01 ng/mg creatinine) (OR = 2.35, 95%CI: 1.19-4.65, P = 0.014). CONCLUSION: Smoking and isoprostane levels were significantly associated with esophageal cancer in Zambians, but diet, HIV status, and alcohol consumption were not. PMID- 26973420 TI - Prognostic value of perioperative leukocyte count in resectable gastric cancer. AB - AIM: To investigate the prognostic significance of perioperative leukopenia in patients with resected gastric cancer. METHODS: A total of 614 eligible gastric cancer patients who underwent curative D2 gastrectomy and adjuvant chemotherapy were enrolled in this study. The relationship between pre- and postoperative hematologic parameters and overall survival was assessed statistically, adjusted for known prognostic factors. RESULTS: The mean white blood cell count (WBC) significantly decreased after surgery, and 107/614 (17.4%) patients developed p leukopenia, which was defined as a preoperative WBC >= 4.0 * 10(9)/L and postoperative WBC < 4.0 * 10(9)/L, with an absolute decrease >= 0.5 * 10(9)/L. The neutrophil count decreased significantly more than the lymphocyte count. P leukopenia significantly correlated with poor tumor differentiation and preoperative WBC. A higher preoperative WBC and p-leukopenia were independent negative prognostic factors for survival [hazard ratio (HR) = 1.602, 95% confidence interval (CI): 1.185-2.165; P = 0.002, and HR = 1.478, 95%CI: 1.149 1.902; P = 0.002, respectively] after adjusting for histology, Borrmann type, pTNM stage, vascular or neural invasion, gastrectomy method, resection margins, chemotherapy regimens, and preoperative WBC count. The patients with both higher preoperative WBC and p-leukopenia had a worse prognosis compared to those with lower baseline WBC and no p-leukopenia (27.5 mo vs 57.3 mo, P < 0.001). CONCLUSION: Preoperative leukocytosis alone or in combination with postoperative leukopenia could be independent prognostic factors for survival in patients with resectable gastric cancer. PMID- 26973422 TI - Importance of SALL4 in the development and prognosis of hepatocellular carcinoma. AB - AIM: To detect the expression of sal-like protein 4 (SALL4) and to explore its relationship with clinicopathological characteristics and prognosis of hepatocellular carcinoma (HCC). METHODS: One hundred and twenty-six samples of HCC tissue, 44 of adjacent noncancerous cirrhotic tissue and 10 of liver hemangioma tissue, were obtained from patients who underwent hepatectomy for HCC at the Fourth Hospital of Hebei Medical University. None of the patients had received any form of treatment before the operation. After resection, all the tissues were fixed in 10% neutral formaldehyde and embedded in paraffin. Expression of SALL4 was detected by immunohistochemistry. Patients were followed up for postoperative survival until February 2014. The relationships between SALL4 expression level and clinicopathological data and prognosis of HCC were analyzed. RESULTS: SALL4 expression was negative in the 10 samples of tissue from liver hemangioma, was weakly positive in the two samples from adjacent noncancerous cirrhotic tissue, and positive in 58 samples of HCC tissues. The differences were statistically significant (P < 0.05). Expression of SALL4 was higher in patients with higher alpha-fetoprotein (AFP) levels, portal vein tumor thrombus, and later clinical stage based on the Barcelona Clinic Liver Cancer classification (P < 0.05). Among patients with negative expression, weakly positive expression, positive expression, and strongly positive expression of SALL4, the median survival time was 39, 25, 23, and 9 mo, respectively (P < 0.001). When both AFP and SALL4 were detected, patients who were negative for both AFP and SALL4, SALL4-positive only, AFP-positive only, and positive for both AFP and SALL4, had a median survival time of 41, 38, 31, and 12 mo, respectively (P < 0.001). CONCLUSION: Expression of SALL4 is relevant to the prognosis of HCC patients. Patients with higher expression levels of SALL4 and AFP have worse prognosis. PMID- 26973421 TI - Early complications after interventions in patients with acute pancreatitis. AB - AIM: To identify the possible predictors of early complications after the initial intervention in acute necrotizing pancreatitis. METHODS: We collected the medical records of 334 patients with acute necrotizing pancreatitis who received initial intervention in our center. Complications associated with predictors were analyzed. RESULTS: The postoperative mortality rate was 16% (53/334). Up to 31% of patients were successfully treated with percutaneous catheter drainage alone. The rates of intra-abdominal bleeding, colonic fistula, and progressive infection were 15% (50/334), 20% (68/334), and 26% (87/334), respectively. Multivariate analysis indicated that Marshall score upon admission, multiple organ failure, preoperative respiratory infection, and sepsis were the predictors of postoperative progressive infection (P < 0.05). Single organ failure, systemic inflammatory response syndrome upon admission, and C-reactive protein level upon admission were the risk factors of postoperative colonic fistula (P < 0.05). Moreover, preoperative Marshall score, organ failure, sepsis, and preoperative systemic inflammatory response syndrome were the risk factors of postoperative intra-abdominal bleeding (P < 0.05). CONCLUSION: Marshall score, organ failures, preoperative respiratory infection, sepsis, preoperative systemic inflammatory response syndrome, and C-reactive protein level upon admission are associated with postoperative complications. PMID- 26973423 TI - Hepatic decompensation/serious adverse events in post-liver transplantation recipients on sofosbuvir for recurrent hepatitis C virus. AB - AIM: To determine the safety profile of new hepatitis C virus (HCV) treatments in liver transplant (LT) recipients with recurrent HCV infection. METHODS: Forty-two patients were identified with recurrent HCV infection that underwent LT at least 12 mo prior to initiating treatment with a Sofosbuvir-based regimen during December 2013-June 2014. Cases were patients who experienced hepatic decompensation and/or serious adverse events (SAE) during or within one month of completing treatment. Controls had no evidence of hepatic decompensation and/or SAE. HIV-infected patients were excluded. Cumulative incidence of decompensation/SAE was calculated using the Kaplan Meier method. Exact logistic regression analysis was used to identify factors associated with the composite outcome. RESULTS: Median age of the 42 patients was 60 years [Interquartile Range (IQR): 56-65 years], 33% (14/42) were female, 21% (9/42) were Hispanic, and 9% (4/42) were Black. The median time from transplant to treatment initiation was 5.4 years (IQR: 2.1-8.8 years). Thirteen patients experienced one or more episodes of hepatic decompensation and/or SAE. Anemia requiring transfusion, the most common event, occurred in 62% (8/13) patients, while 54% (7/13) decompensated. The cumulative incidence of hepatic decompensation/SAE was 31% (95%CI: 16%-41%). Risk factors for decompensation/SAE included lower pre treatment hemoglobin (OR = 0.61 per g/dL, 95%CI: 0.40-0.88, P < 0.01), estimated glomerular filtration rate (OR = 0.95 per mL/min per 1.73 m(2), 95%CI: 0.90-0.99, P = 0.01), and higher baseline serum total bilirubin (OR = 2.43 per mg/dL, 95%CI: 1.17-8.65, P < 0.01). The sustained virological response rate for the cohort of 42 patients was 45%, while it was 31% for cases. CONCLUSION: Sofosbuvir/ribavirin will continue to be used in the post-transplant population, including those with HCV genotypes 2 and 3. Management of anemia remains an important clinical challenge. PMID- 26973424 TI - Implantation of esophageal cancer onto post-dissection ulcer after gastric endoscopic submucosal dissection. AB - A case in which implantation of esophageal squamous cell carcinoma onto a post dissection gastric ulcer was strongly suspected is presented. A 72-year-old man with alcoholic liver cirrhosis underwent esophagogastroduodenoscopy (EGD). Esophageal cancer (EC) (Mt, 20 mm, 0-Is) and gastric cancer (GC) (antrum, 15 mm, 0-IIc) were identified. Biopsy specimens revealed moderately differentiated squamous cell carcinoma (SCC) and differentiated adenocarcinoma, respectively. The GC was resected by endoscopic submucosal dissection (ESD) [14 mm * 9 mm, type 0-IIc, tub1, pT1a(M), ly0, v0, HM(-), VM(-)]. Two months after ESD, radiation therapy was started for the EC, and an almost complete response was obtained. Nine months after the ESD, a follow-up EGD showed a submucosal tumor-like lesion with ulceration, located immediately under the post-ESD scar, and biopsy specimens showed moderately differentiated SCC. There were no similar lesions suggesting hematogenous or lymphatic metastasis in the stomach. PMID- 26973426 TI - Re: Errors in Zhao et al (2015), Impact of enteral nutrition on energy metabolism in patients with Crohn's disease. AB - We report invalidating errors related to the statistical approach in the analysis and data inconsistencies in a published single cohort study of patients with Crohn's disease. We provide corrected calculations from the available data and request that a corrected analysis be provided by the authors. These errors should be corrected. PMID- 26973427 TI - Delving into Egocentric Actions. AB - We address the challenging problem of recognizing the camera wearer's actions from videos captured by an egocentric camera. Egocentric videos encode a rich set of signals regarding the camera wearer, including head movement, hand pose and gaze information. We propose to utilize these mid-level egocentric cues for egocentric action recognition. We present a novel set of egocentric features and show how they can be combined with motion and object features. The result is a compact representation with superior performance. In addition, we provide the first systematic evaluation of motion, object and egocentric cues in egocentric action recognition. Our benchmark leads to several surprising findings. These findings uncover the best practices for egocentric actions, with a significant performance boost over all previous state-of-the-art methods on three publicly available datasets. PMID- 26973425 TI - Klebsiella pneumoniae invasive liver abscess syndrome with purulent meningitis and septic shock: A case from mainland China. AB - We present a rare case of invasive liver abscess syndrome due to Klebsiella pneumoniae (K. pneumoniae) with metastatic meningitis and septic shock. A previously healthy, 55-year-old female patient developed fever, liver abscess, septic shock, purulent meningitis and metastatic hydrocephalus. Upon admission, the clinical manifestations, laboratory and imaging examinations were compatible with a diagnosis of K. pneumoniae primary liver abscess. Her distal metastasis infection involved meningitis and hydrocephalus, which could flare abruptly and be life threatening. Even with early adequate drainage and antibiotic therapy, the patient's condition deteriorated and she ultimately died. To the best of our knowledge, this is the first case of K. pneumoniae invasive liver abscess syndrome with septic meningitis reported in mainland China. Our findings reflect the need for a better understanding of the epidemiology, risk factors, complications, comorbid medical conditions and treatment of this disease. PMID- 26973428 TI - Gaze-enabled Egocentric Video Summarization via Constrained Submodular Maximization. AB - With the proliferation of wearable cameras, the number of videos of users documenting their personal lives using such devices is rapidly increasing. Since such videos may span hours, there is an important need for mechanisms that represent the information content in a compact form (i.e., shorter videos which are more easily browsable/sharable). Motivated by these applications, this paper focuses on the problem of egocentric video summarization. Such videos are usually continuous with significant camera shake and other quality issues. Because of these reasons, there is growing consensus that direct application of standard video summarization tools to such data yields unsatisfactory performance. In this paper, we demonstrate that using gaze tracking information (such as fixation and saccade) significantly helps the summarization task. It allows meaningful comparison of different image frames and enables deriving personalized summaries (gaze provides a sense of the camera wearer's intent). We formulate a summarization model which captures common-sense properties of a good summary, and show that it can be solved as a submodular function maximization with partition matroid constraints, opening the door to a rich body of work from combinatorial optimization. We evaluate our approach on a new gaze-enabled egocentric video dataset (over 15 hours), which will be a valuable standalone resource. PMID- 26973430 TI - Differentially Private Frequent Sequence Mining via Sampling-based Candidate Pruning. AB - In this paper, we study the problem of mining frequent sequences under the rigorous differential privacy model. We explore the possibility of designing a differentially private frequent sequence mining (FSM) algorithm which can achieve both high data utility and a high degree of privacy. We found, in differentially private FSM, the amount of required noise is proportionate to the number of candidate sequences. If we could effectively reduce the number of unpromising candidate sequences, the utility and privacy tradeoff can be significantly improved. To this end, by leveraging a sampling-based candidate pruning technique, we propose a novel differentially private FSM algorithm, which is referred to as PFS2. The core of our algorithm is to utilize sample databases to further prune the candidate sequences generated based on the downward closure property. In particular, we use the noisy local support of candidate sequences in the sample databases to estimate which sequences are potentially frequent. To improve the accuracy of such private estimations, a sequence shrinking method is proposed to enforce the length constraint on the sample databases. Moreover, to decrease the probability of misestimating frequent sequences as infrequent, a threshold relaxation method is proposed to relax the user-specified threshold for the sample databases. Through formal privacy analysis, we show that our PFS2 algorithm is epsilon-differentially private. Extensive experiments on real datasets illustrate that our PFS2 algorithm can privately find frequent sequences with high accuracy. PMID- 26973431 TI - Kinetic analysis of MgB2 layer formation in advanced internal magnesium infiltration (AIMI) processed MgB2 wires. AB - Significantly enhanced critical current density (Jc) for MgB2 superconducting wires can be obtained following the advanced internal Mg infiltration (AIMI) route. But unless suitable precautions are taken, the AIMI-processed MgB2 wires will exhibit incomplete MgB2 layer formation, i.e. reduced superconductor core size and hence suppressed current-carrying capability. Microstructural characterization of AIMI MgB2 wires before and after the heat treatment reveals that the reaction mechanism changes from a "Mg infiltration-reaction" at the beginning of the heat treatment to a "Mg diffusion-reaction" once a dense MgB2 layer is formed. A drastic drop in the Mg transport rate from infiltration to diffusion causes the termination of the MgB2 core growth. To quantify this process, a two-stage kinetic model is built to describe the MgB2 layer formation and growth. The derived kinetic model and the associated experimental observations indicate that fully reacted AIMI-processed MgB2 wires can be achieved following the optimization of B particle size, B powder packing density, MgB2 reaction activation energy and its response to the additions of dopants. PMID- 26973429 TI - Refractory pulmonary sarcoidosis - proposal of a definition and recommendations for the diagnostic and therapeutic approach. AB - Patients with sarcoidosis undergo spontaneous remission or may be effectively controlled with glucocorticoids alone in many cases. Progressive and refractory pulmonary sarcoidoisis constitute more than 10% of patients seen at specialized centers. Pulmonary fibrosis and associated complications, such as infections and pulmonary hypertension are leading causes of mortality. No universal definition of refractoriness exists, we therefore propose classifying patients as having refractory disease when the following criteria are fulfilled: (1) progressive disease despite at least 10 mg of prednisolone or equivalent for at least three months and need for additional disease-modifying anti-sarcoid drugs due to lack of efficacy, drug toxicity or intolerability and (2) treatment started for significant impairment of life due to progressive pulmonary symptoms. Both criteria should be fulfilled. Treatment options in addition to or instead of glucocorticoids for these patients include second- (methotrexate, azathioprine, leflunomide) and third-line agents (infliximab, adalimumab). Other immunmodulating agents can be used, but the evidence is very limited. Newer agents with anti-fibrotic properties, such as pirfenidone or nintedanib, might hold promise also for the pulmonary fibrosis seen in sarcoidosis. Treating physicians have to actively look for potentially treatable complications, such as pulmonary hypertension, cardiac disease or infections before patients should be classified as treatment-refractory. Ultimately, lung transplantation has to be considered as treatment option for patients not responding to medical therapy. In this review, we aim to propose a new definition of refractoriness, describe the associated clinical features and suggest the therapeutic approach. PMID- 26973434 TI - Mycobacterium leprae alters classical activation of human monocytes in vitro. AB - BACKGROUND: Macrophages play a central role in the pathogenesis of leprosy, caused by Mycobacterium leprae. The polarized clinical presentations in leprosy are associated with differential immune activation. In tuberculoid leprosy, macrophages show a classical activation phenotype (M1), while macrophages in lepromatous disease display characteristics of alternative activation (M2). Bacille Calmette-Guerin (BCG) vaccination, which protects against leprosy, can promote sustained changes in monocyte response to unrelated pathogens and may preferentially direct monocytes towards an M1 protective phenotype. We previously reported that M. leprae can dampen the response of naive human monocytes to a strong inducer of pro-inflammatory cytokines, such as BCG. Here, we investigated the ability of the pathogen to alter the direction of macrophage polarization and the impact of BCG vaccination on the monocyte response to M. leprae. FINDINGS: We show that in vitro exposure of monocytes from healthy donors to M. leprae interferes with subsequent M1 polarization, indicated by lower levels of M1 associated cytokine/chemokines released and reduced expression of M1 cell surface markers. Exposure to M. leprae phenolic glycolipid (PGL) 1, instead of whole bacteria, demonstrated a similar effect on M1 cytokine/chemokine release. In addition, we found that monocytes from 10-week old BCG-vaccinated infants released higher levels of the pro-inflammatory cytokines TNF-alpha and IL-1beta in response to M. leprae compared to those from unvaccinated infants. CONCLUSION: Exposure to M. leprae has an inhibitory effect on M1 macrophage polarization, likely mediated through PGL-1. By directing monocyte/macrophages preferentially towards M1 activation, BCG vaccination may render the cells more refractory to the inhibitory effects of subsequent M. leprae infection. PMID- 26973433 TI - Suppression of Spry4 enhances cancer stem cell properties of human MDA-MB-231 breast carcinoma cells. AB - BACKGROUND: Cancer stem cells contribute to tumor initiation, heterogeneity, and recurrence, and are critical targets in cancer therapy. Sprouty4 (Spry4) is a potent inhibitor of signal transduction pathways elicited by receptor tyrosine kinases, and has roles in regulating cell proliferation, migration and differentiation. Spry4 has been implicated as a tumor suppressor and in modulating embryonic stem cells. OBJECTIVES: The purpose of this research was to test the novel idea that Spry4 regulates cancer stem cell properties in breast cancer. METHODS: Loss-of function of Spry4 in human MDA-MB-231 cell was used to test our hypothesis. Spry4 knockdown or control cell lines were generated using lentiviral delivery of human Spry4 or non-targeting control shRNAs, and then selected with 2 MUg/ml puromycin. Cell growth and migratory abilities were determined using growth curve and cell cycle flow cytometry analyses and scratch assays, respectively. Xenograft tumor model was used to determine the tumorigenic activity and metastasis in vivo. Cancer stem cell related markers were evaluated using immunoblotting assays and fluorescence-activated cell sorting. Cancer stem cell phenotype was evaluated using in vitro mammosphere formation and drug sensitivity tests, and in vivo limiting dilution tumor formation assay. RESULTS: Two out of three tested human Spry4 shRNAs significantly suppressed the expression of endogenous Spry4 in MDA-MB-231 cells. Suppressing Spry4 expression increased MDA-MB-231 cell proliferation and migration. Suppressing Spry4 increased beta3-integrin expression, and CD133(+)CD44(+) subpopulation. Suppressing Spry4 increased mammosphere formation, while decreasing the sensitivity of MDA-MB-231 cells to Paclitaxel treatment. Finally, suppressing Spry4 increased the potency of MDA-MB-231 cell tumor initiation, a feature attributed to cancer stem cells. CONCLUSIONS: Our findings provide novel evidence that endogenous Spry4 may have tumor suppressive activity in breast cancer by suppressing cancer stem cell properties in addition to negative effects on tumor cell proliferation and migration. PMID- 26973438 TI - A novel method for estimating distributions of body mass index. AB - BACKGROUND: Understanding trends in the distribution of body mass index (BMI) is a critical aspect of monitoring the global overweight and obesity epidemic. Conventional population health metrics often only focus on estimating and reporting the mean BMI and the prevalence of overweight and obesity, which do not fully characterize the distribution of BMI. In this study, we propose a novel method which allows for the estimation of the entire distribution. METHODS: The proposed method utilizes the optimization algorithm, L-BFGS-B, to derive the distribution of BMI from three commonly available population health statistics: mean BMI, prevalence of overweight, and prevalence of obesity. We conducted a series of simulations to examine the properties, accuracy, and robustness of the method. We then illustrated the practical application of the method by applying it to the 2011-2012 US National Health and Nutrition Examination Survey (NHANES). RESULTS: Our method performed satisfactorily across various simulation scenarios yielding empirical (estimated) distributions which aligned closely with the true distributions. Application of the method to the NHANES data also showed a high level of consistency between the empirical and true distributions. In situations where there were considerable outliers, the method was less satisfactory at capturing the extreme values. Nevertheless, it remained accurate at estimating the central tendency and quintiles. CONCLUSION: The proposed method offers a tool that can efficiently estimate the entire distribution of BMI. The ability to track the distributions of BMI will improve our capacity to capture changes in the severity of overweight and obesity and enable us to better monitor the epidemic. PMID- 26973435 TI - Stathmin involvement in the maternal embryonic leucine zipper kinase pathway in glioblastoma. AB - BACKGROUND: Maternal Embryonic Leucine Zipper Kinase (MELK) is a serine/threonine kinase involved in cell cycle, differentiation, proliferation, and apoptosis. These multiple features are consistent with it being a potential anticancer target. Nevertheless, the MELK pathway in tumorigenesis is not yet completely understood. This study aims to identify proteins associated with MELK pathway in astrocytomas. To this end, proteomic data of the human glioma cell line U87MG transfected with siRNA for MELK were compared with non-target transfected control cells and compared with oligonucleotide microarray data. RESULTS: In both assays, we identified stathmin/oncoprotein 18 (STMN1), involved in cell cycle. STMN1 gene expression was further assessed in a series of 154 astrocytomas and 22 non neoplastic brain samples by qRT-PCR. STMN1 expression was significantly increased in malignant diffusely infiltrative astrocytomas compared with pilocytic astrocytoma (p < 0.0001). A strong correlation between MELK and STMN1 expressions was observed (r = 0.741, p < 0.0001) in glioblastoma (GBM) samples. However, no difference on survival times was found when compared GBM cases with upregulated and downregulated STMN1 (Breslow = 0.092, median survival time: 11 and 13 months, respectively). Functional assays knocking down MELK by siRNA in GBM cell line showed that gene and protein expression of both MELK and stathmin were diminished. On the other hand, when the same analysis was performed for STMN1, only stathmin gene and protein was silenced. CONCLUSIONS: The results presented herein point stahtmin as a downstream target in the MELK pathway that plays a role in malignant progression of astrocytomas. PMID- 26973437 TI - Methods of applying the 1994 case definition of chronic fatigue syndrome - impact on classification and observed illness characteristics. AB - BACKGROUND: Multiple case definitions are in use to identify chronic fatigue syndrome (CFS). Even when using the same definition, methods used to apply definitional criteria may affect results. The Centers for Disease Control and Prevention (CDC) conducted two population-based studies estimating CFS prevalence using the 1994 case definition; one relied on direct questions for criteria of fatigue, functional impairment and symptoms (1997 Wichita; Method 1), and the other used subscale score thresholds of standardized questionnaires for criteria (2004 Georgia; Method 2). Compared to previous reports the 2004 CFS prevalence estimate was higher, raising questions about whether changes in the method of operationalizing affected this and illness characteristics. METHODS: The follow up of the Georgia cohort allowed direct comparison of both methods of applying the 1994 case definition. Of 1961 participants (53 % of eligible) who completed the detailed telephone interview, 919 (47 %) were eligible for and 751 (81 %) underwent clinical evaluation including medical/psychiatric evaluations. Data from the 499 individuals with complete data and without exclusionary conditions was available for this analysis. RESULTS: A total of 86 participants were classified as CFS by one or both methods; 44 cases identified by both methods, 15 only identified by Method 1, and 27 only identified by Method 2 (Kappa 0.63; 95 % confidence interval [CI]: 0.53, 0.73 and concordance 91.59 %). The CFS group identified by both methods were more fatigued, had worse functioning, and more symptoms than those identified by only one method. Moderate to severe depression was noted in only one individual who was classified as CFS by both methods. When comparing the CFS groups identified by only one method, those only identified by Method 2 were either similar to or more severely affected in fatigue, function, and symptoms than those only identified by Method 1. CONCLUSIONS: The two methods demonstrated substantial concordance. While Method 2 classified more participants as CFS, there was no indication that they were less severely ill or more depressed. The classification differences do not fully explain the prevalence increase noted in the 2004 Georgia study. Use of standardized instruments for the major CFS domains provides advantages for disease stratification and comparing CFS patients to other illnesses. PMID- 26973439 TI - Model specification and bootstrapping for multiply imputed data: An application to count models for the frequency of alcohol use. AB - Stata's mi commands provide powerful tools to conduct multiple imputation in the presence of ignorable missing data. In this article, I present Stata code to extend the capabilities of the mi commands to address two areas of statistical inference where results are not easily aggregated across imputed datasets. First, mi commands are restricted to covariate selection. I show how to address model fit to correctly specify a model. Second, the mi commands readily aggregate model based standard errors. I show how standard errors can be bootstrapped for situations where model assumptions may not be met. I illustrate model specification and bootstrapping on frequency counts for the number of times that alcohol was consumed in data with missing observations from a behavioral intervention. PMID- 26973441 TI - Designing Colorectal Cancer Screening Decision Support: A Cognitive Engineering Enterprise. AB - Adoption of clinical decision support has been limited. Important barriers include an emphasis on algorithmic approaches to decision support that do not align well with clinical work flow and human decision strategies, and the expense and challenge of developing, implementing, and refining decision support features in existing electronic health records (EHRs). We applied decision-centered design to create a modular software application to support physicians in managing and tracking colorectal cancer screening. Using decision-centered design facilitates a thorough understanding of cognitive support requirements from an end user perspective as a foundation for design. In this project, we used an iterative design process, including ethnographic observation and cognitive task analysis, to move from an initial design concept to a working modular software application called the Screening & Surveillance App. The beta version is tailored to work with the Veterans Health Administration's EHR Computerized Patient Record System (CPRS). Primary care providers using the beta version Screening & Surveillance App more accurately answered questions about patients and found relevant information more quickly compared to those using CPRS alone. Primary care providers also reported reduced mental effort and rated the Screening & Surveillance App positively for usability. PMID- 26973440 TI - Language-based social preferences among children in South Africa. AB - Monolingual English-speaking children in the United States express social preferences for speakers of their native language with a native accent. Here we explore the nature of children's language-based social preferences through research with children in South Africa, a multilingual nation. Like children in the United States, Xhosa South African children preferred speakers of their first language (Xhosa) to speakers of a foreign language (French). Thus, social preferences based on language are observed not only among children with limited exposure to cultural and linguistic variation but also among children living in a diverse linguistic environment. Moreover, Xhosa children attending school in English expressed social preferences for speakers of English over speakers of Xhosa, even when tested by a Xhosa-speaking experimenter. Thus, children's language-based social preferences do not depend exclusively on preferences for more familiar or intelligible speech but also extend to preferences for speech that may convey higher status in the child's society. PMID- 26973442 TI - Automated Spatial Brain Normalization and Hindbrain White Matter Reference Tissue Give Improved [(18)F]-Florbetaben PET Quantitation in Alzheimer's Model Mice. AB - Preclinical PET studies of beta-amyloid (Abeta) accumulation are of growing importance, but comparisons between research sites require standardized and optimized methods for quantitation. Therefore, we aimed to evaluate systematically the (1) impact of an automated algorithm for spatial brain normalization, and (2) intensity scaling methods of different reference regions for Abeta-PET in a large dataset of transgenic mice. PS2APP mice in a 6 week longitudinal setting (N = 37) and another set of PS2APP mice at a histologically assessed narrow range of Abeta burden (N = 40) were investigated by [(18)F] florbetaben PET. Manual spatial normalization by three readers at different training levels was performed prior to application of an automated brain spatial normalization and inter-reader agreement was assessed by Fleiss Kappa (kappa). For this method the impact of templates at different pathology stages was investigated. Four different reference regions on brain uptake normalization were used to calculate frontal cortical standardized uptake value ratios (SUVRCTX/REF), relative to raw SUVCTX. Results were compared on the basis of longitudinal stability (Cohen's d), and in reference to gold standard histopathological quantitation (Pearson's R). Application of an automated brain spatial normalization resulted in nearly perfect agreement (all kappa>=0.99) between different readers, with constant or improved correlation with histology. Templates based on inappropriate pathology stage resulted in up to 2.9% systematic bias for SUVRCTX/REF. All SUVRCTX/REF methods performed better than SUVCTX both with regard to longitudinal stability (d>=1.21 vs. d = 0.23) and histological gold standard agreement (R>=0.66 vs. R>=0.31). Voxel-wise analysis suggested a physiologically implausible longitudinal decrease by global mean scaling. The hindbrain white matter reference (R mean = 0.75) was slightly superior to the brainstem (R mean = 0.74) and the cerebellum (R mean = 0.73). Automated brain normalization with reference region templates presents an excellent method to avoid the inter-reader variability in preclinical Abeta-PET scans. Intracerebral reference regions lacking Abeta pathology serve for precise longitudinal in vivo quantification of [(18)F]-florbetaben PET. Hindbrain white matter reference performed best when considering the composite of quality criteria. PMID- 26973444 TI - Direct Imaging of Hippocampal Epileptiform Calcium Motifs Following Kainic Acid Administration in Freely Behaving Mice. AB - Prolonged exposure to abnormally high calcium concentrations is thought to be a core mechanism underlying hippocampal damage in epileptic patients; however, no prior study has characterized calcium activity during seizures in the live, intact hippocampus. We have directly investigated this possibility by combining whole-brain electroencephalographic (EEG) measurements with microendoscopic calcium imaging of pyramidal cells in the CA1 hippocampal region of freely behaving mice treated with the pro-convulsant kainic acid (KA). We observed that KA administration led to systematic patterns of epileptiform calcium activity: a series of large-scale, intensifying flashes of increased calcium fluorescence concurrent with a cluster of low-amplitude EEG waveforms. This was accompanied by a steady increase in cellular calcium levels (>5 fold increase relative to the baseline), followed by an intense spreading calcium wave characterized by a 218% increase in global mean intensity of calcium fluorescence (n = 8, range [114 349%], p < 10(-4); t-test). The wave had no consistent EEG phenotype and occurred before the onset of motor convulsions. Similar changes in calcium activity were also observed in animals treated with 2 different proconvulsant agents, N-methyl D-aspartate (NMDA) and pentylenetetrazol (PTZ), suggesting the measured changes in calcium dynamics are a signature of seizure activity rather than a KA-specific pathology. Additionally, despite reducing the behavioral severity of KA-induced seizures, the anticonvulsant drug valproate (VA, 300 mg/kg) did not modify the observed abnormalities in calcium dynamics. These results confirm the presence of pathological calcium activity preceding convulsive motor seizures and support calcium as a candidate signaling molecule in a pathway connecting seizures to subsequent cellular damage. Integrating in vivo calcium imaging with traditional assessment of seizures could potentially increase translatability of pharmacological intervention, leading to novel drug screening paradigms and therapeutics designed to target and abolish abnormal patterns of both electrical and calcium excitation. PMID- 26973443 TI - Performance Monitoring in Medication-Naive Children with Tourette Syndrome. AB - BACKGROUND: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder and its impact on cognitive development needs further study. Evidence from neuropsychological, neuroimaging and electrophysiological studies suggests that the decline in tic severity and the ability to suppress tics relate to the development of self-regulatory functions in late childhood and adolescence. Hence, tasks measuring performance monitoring might provide insight into the regulation of tics in children with TS. METHOD: Twenty-five children with TS, including 14 with comorbid Attention-deficit/ hyperactivity disorder (ADHD), 39 children with ADHD and 35 typically developing children aged 8-12 years were tested with a modified Eriksen-Flanker task during a 34-channel electroencephalography (EEG) recording. Task performance, as well as stimulus locked and response-locked event-related potentials (ERP) were analyzed and compared across groups. RESULTS: Participants did not differ in their behavioral performance. Children with TS showed higher amplitudes of an early P3 component of the stimulus-locked ERPs in ensemble averages and in separate trial outcomes, suggesting heightened orienting and/or attention during stimulus evaluation. In response-locked averages, children with TS had a slightly higher positive complex before the motor response, likely also reflecting a late P3. Groups did not differ in post-response components, particularly in the error-related negativity (ERN) and error-related positivity (Pe). CONCLUSIONS: These findings suggest that children with TS may employ additional attentional resources as a compensatory mechanism to maintain equal behavioral performance. PMID- 26973445 TI - Beta-Band Functional Connectivity is Reorganized in Mild Cognitive Impairment after Combined Computerized Physical and Cognitive Training. AB - Physical and cognitive idleness constitute significant risk factors for the clinical manifestation of age-related neurodegenerative diseases. In contrast, a physically and cognitively active lifestyle may restructure age-declined neuronal networks enhancing neuroplasticity. The present study, investigated the changes of brain's functional network in a group of elderly individuals at risk for dementia that were induced by a combined cognitive and physical intervention scheme. Fifty seniors meeting Petersen's criteria of Mild Cognitive Impairment were equally divided into an experimental (LLM), and an active control (AC) group. Resting state electroencephalogram (EEG) was measured before and after the intervention. Functional networks were estimated by computing the magnitude square coherence between the time series of all available cortical sources as computed by standardized low resolution brain electromagnetic tomography (sLORETA). A statistical model was used to form groups' characteristic weighted graphs. The introduced modulation was assessed by networks' density and nodes' strength. Results focused on the beta band (12-30 Hz) in which the difference of the two networks' density is maximum, indicating that the structure of the LLM cortical network changes significantly due to the intervention, in contrast to the network of AC. The node strength of LLM participants in the beta band presents a higher number of bilateral connections in the occipital, parietal, temporal and prefrontal regions after the intervention. Our results show that the combined training scheme reorganizes the beta-band functional connectivity of MCI patients. ClinicalTrials.gov Identifier: NCT02313935 https://clinicaltrials.gov/ct2/show/NCT02313935. PMID- 26973447 TI - Sexual Stimulation Increases the Survival of New Cells in the Accessory Olfactory Bulb of the Male Rat. AB - Sexual behavior in rodents is modulated by the olfactory system. The olfactory bulb (OB) is a structure that undergoes continues neurogenesis in adulthood. We have previously shown that 15 days after males rats pace the sexual interaction and ejaculate 1 or 3 times, there is an increase in the density of new cells that reach the accessory olfactory bulb (AOB). The aim of the present study was to evaluate if sexual behavior in male rats increases the density of new neurons that survive 45 days after sexual behavior in the AOB and in the main OB (MOB). Male rats were randomly divided in four groups: (1) Control (Ctr), males without sexual interaction; (2) Exposed (Exp), males only exposed to a sexually receptive female; (3) No pacing (NP), males that mated in conditions in which the female paced the sexual interaction; (4) One ejaculation (1E), males that paced the sexual interaction with a receptive female and ejaculated once; and (5) Three ejaculations (3E), males that paced the sexual interaction and were allowed to ejaculate three times. All males were injected with the DNA synthesis marker 5 bromo-2-deoxyuridine (BrdU), and were tested in one of the above conditions. 45 days later they were sacrificed, and the OBs were processed to identify new cells and evaluate if they had differentiated into neurons. Our data indicate that males that ejaculated three times showed an increase in the density of new cells that survive in the posterior part of the granular cell layer of the AOB and have more new neurons that the control group. However, no significant differences were found in the percentage of new cells that differentiate into neurons. No significant increase in the density of new cells was observed in the MOB. Our data show that pacing the sexual interaction until three ejaculations increases the density of new cells and neurons in the granular layer of the AOB, confirming that sexual behavior induces long-lasting plastic changes in the OB. PMID- 26973446 TI - Hybrid PET/MR Imaging and Brain Connectivity. AB - In recent years, brain connectivity is gaining ever-increasing interest from the interdisciplinary research community. The study of brain connectivity is characterized by a multifaceted approach providing both structural and functional evidence of the relationship between cerebral regions at different scales. Although magnetic resonance (MR) is the most established imaging modality for investigating connectivity in vivo, the recent advent of hybrid positron emission tomography (PET)/MR scanners paved the way for more comprehensive investigation of brain organization and physiology. Due to the high sensitivity and biochemical specificity of radiotracers, combining MR with PET imaging may enrich our ability to investigate connectivity by introducing the concept of metabolic connectivity and cometomics and promoting new insights on the physiological and molecular bases underlying high-level neural organization. This review aims to describe and summarize the main methods of analysis of brain connectivity employed in MR imaging and nuclear medicine. Moreover, it will discuss practical aspects and state-of-the-art techniques for exploiting hybrid PET/MR imaging to investigate the relationship of physiological processes and brain connectivity. PMID- 26973449 TI - BBBomics-Human Blood Brain Barrier Transcriptomics Hub. PMID- 26973448 TI - Testosterone Administration Related Differences in Brain Activation during the Ultimatum Game. AB - A plethora of studies on the Ultimatum Game have shown that responders forfeit the rule of profit maximization and punish unfair proposers, by rejecting their offers. This behavior has been linked to increased amygdala, insula, and dorsolateral prefrontal cortex activation. Studies have suggested a potential role of testosterone in the Ultimatum Game albeit with inconsistent findings. In the present study, we sought to further investigate the role of amygdala and testosterone in the Ultimatum Game, by conducting a double-blinded, single administration study. Sixty milligram of Tostrex was administered to male and female healthy volunteers, 3 h prior to undergoing an fMRI session, during which they played a standard version of the Ultimatum Game. The behavioral analysis revealed a statistical trend, as participants in the testosterone group tended to accept a greater number of unfair offers than participants in the placebo group, irrespectively of gender. In terms of fMRI results, for the main contrast unfair>fair offers, the testosterone group displayed a greater activation in the right dlPFC compared to the placebo group. Increased testosterone levels were related to greater caudate activity. Our findings suggest a complex role of testosterone in social behavior and decision-making. PMID- 26973450 TI - Murine Depression Model and its Potential Applications for Discovering Foods and Farm Products with Antidepressant-Like Effects. AB - Advanced societies face increased health problems related to various stresses. Chronic psychological stress is a major risk factor for psychiatric disorders such as depression. Although therapeutic agents reduce several symptoms of depression, most have side effects in a broad range of the population. Furthermore, some victims of depression do not show significant improvement with any drugs, so alternative approaches are needed. Good dietary habits may potentially reduce depressive symptoms, but there is little scientific evidence thus far. Murine depression models are useful to test nutritional approaches in vivo. Our model mice subjected to a subchronic mild social defeat stress (sCSDS) paradigm show several alterations in physiological parameters and social behavior. These stress-induced symptoms in sCSDS mice can be used as cues to identify antidepressant-like natural resources including foods and farm products. We previously discovered that sCSDS mice show more vulnerability to social stress by changing dietary condition. In addition, we developed a more objective system for analyzing mouse behavior using a 3D depth-sensing camera to understand relationships between diet and behavior. The combination of sCSDS mice with 3D behavioral analysis is a powerful method for screening ingredients in foods and farm products for antidepressant-like effects. PMID- 26973451 TI - Deficits in the Sensitivity to Pitch Sweeps by School-Aged Children Wearing Cochlear Implants. AB - Sensitivity to static changes in pitch has been shown to be poorer in school-aged children wearing cochlear implants (CIs) than children with normal hearing (NH), but it is unclear whether this is also the case for dynamic changes in pitch. Yet, dynamically changing pitch has considerable ecological relevance in terms of natural speech, particularly aspects such as intonation, emotion, or lexical tone information. Twenty one children with NH and 23 children wearing a CI participated in this study, along with 18 NH adults and 6 CI adults for comparison. Listeners with CIs used their clinically assigned settings with envelope-based coding strategies. Percent correct was measured in one- or three interval two-alternative forced choice tasks, for the direction or discrimination of harmonic complexes based on a linearly rising or falling fundamental frequency. Sweep rates were adjusted per subject, in a logarithmic scale, so as to cover the full extent of the psychometric function. Data for up- and down sweeps were fitted separately, using a maximum-likelihood technique. Fits were similar for up- and down-sweeps in the discrimination task, but diverged in the direction task because psychometric functions for down-sweeps were very shallow. Hits and false alarms were then converted into d' and beta values, from which a threshold was extracted at a d' of 0.77. Thresholds were very consistent between the two tasks and considerably higher (worse) for CI listeners than for their NH peers. Thresholds were also higher for children than adults. Factors such as age at implantation, age at profound hearing loss, and duration of CI experience did not play any major role in this sensitivity. Thresholds of dynamic pitch sensitivity (in either task) also correlated with thresholds for static pitch sensitivity and with performance in tasks related to speech prosody. PMID- 26973452 TI - The Contradictory Effects of Neuronal Hyperexcitation on Adult Hippocampal Neurogenesis. AB - Adult hippocampal neurogenesis is a highly plastic process that responds swiftly to neuronal activity. Adult hippocampal neurogenesis can be regulated at the level of neural stem cell recruitment and activation, progenitor proliferation, as well as newborn cell survival and differentiation. An "excitation neurogenesis" rule was proposed after the demonstration of the capability of cultured neural stem and progenitor cells to intrinsically sense neuronal excitatory activity. In vivo, this property has remained elusive although recently the direct response of neural stem cells to GABA in the hippocampus via GABAA receptors has evidenced a mechanism for a direct talk between neurons and neural stem cells. As it is pro-neurogenic, the effect of excitatory neuronal activity has been generally considered beneficial. But what happens in situations of neuronal hyperactivity in which neurogenesis can be dramatically boosted? In animal models, electroconvulsive shock markedly increases neurogenesis. On the contrary, in epilepsy rodent models, seizures induce the generation of misplaced neurons with abnormal morphological and electrophysiological properties, namely aberrant neurogenesis. We will herein discuss what is known about the mechanisms of influence of neurons on neural stem cells, as well as the severe effects of neuronal hyperexcitation on hippocampal neurogenesis. PMID- 26973454 TI - Inducing Chronic Excitotoxicity in the Mouse Spinal Cord to Investigate Lower Motor Neuron Degeneration. AB - We report the methodology for the chronic delivery of an excitotoxin to the mouse spinal cord via surgically implanted osmotic mini-pumps. Previous studies have investigated the effect of chronic application of excitotoxins in the rat, however there has been little translation of this model to the mouse. Using mice that express yellow fluorescent protein (YFP), motor neuron and neuromuscular junction alterations can be investigate following targeted, long-term (28 days) exposure to the alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor excitotoxin, kainic acid. By targeting the L3-4 region of the lumbar spinal cord, with insertion of an intrathecal catheter into the subarachnoid space at L5, chronic application of the kainic acid results in slow excitotoxic death in the anterior ventral horn, with a significant (P < 0.05) reduction in the number of SMI-32 immunopositive neurons present after 28 days infusion. Use of the Thy1-YFP mice provides unrivaled visualization of the neuromuscular junction and enables the resultant distal degeneration in skeletal muscle to be observed. Both neuromuscular junction retraction at the gastrocnemius muscle and axonal fragmentation in the sciatic nerve were observed after chronic infusion of kainic acid for 28 days. Lower motor neuron, and distal neuromuscular junction, degeneration are pathological hallmarks of the devastating neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). This mouse model will be advantageous for increasing our understanding of how the pathophysiological phenomena associated with this disease can lead to lower motor neuron loss and distal pathology, as well as providing a robust in vivo platform to test therapeutic interventions directed at excitotoxic mechanisms. PMID- 26973453 TI - Hypocellularity in the Murine Model for Down Syndrome Ts65Dn Is Not Affected by Adult Neurogenesis. AB - Down syndrome (DS) is caused by the presence of an extra copy of the chromosome 21 and it is the most common aneuploidy producing intellectual disability. Neural mechanisms underlying this alteration may include defects in the formation of neuronal networks, information processing and brain plasticity. The murine model for DS, Ts65Dn, presents reduced adult neurogenesis. This reduction has been suggested to underlie the hypocellularity of the hippocampus as well as the deficit in olfactory learning in the Ts65Dn mice. Similar alterations have also been observed in individuals with DS. To determine whether the impairment in adult neurogenesis is, in fact, responsible for the hypocellularity in the hippocampus and physiology of the olfactory bulb, we have analyzed cell proliferation and neuronal maturation in the two major adult neurogenic niches in the Ts656Dn mice: the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). Additionally, we carried out a study to determine the survival rate and phenotypic fate of newly generated cells in both regions, injecting 5'BrdU and sacrificing the mice 21 days later, and analyzing the number and phenotype of the remaining 5'BrdU-positive cells. We observed a reduction in the number of proliferating (Ki67 positive) cells and immature (doublecortin positive) neurons in the subgranular and SVZ of Ts65Dn mice, but we did not observe changes in the number of surviving cells or in their phenotype. These data correlated with a lower number of apoptotic cells (cleaved caspase 3 positive) in Ts65Dn. We conclude that although adult Ts65Dn mice have a lower number of proliferating cells, it is compensated by a lower level of cell death. This higher survival rate in Ts65Dn produces a final number of mature cells similar to controls. Therefore, the reduction of adult neurogenesis cannot be held responsible for the neuronal hypocellularity in the hippocampus or for the olfactory learning deficit of Ts65Dn mice. PMID- 26973455 TI - Prefrontal Ischemia in the Rat Leads to Secondary Damage and Inflammation in Remote Gray and White Matter Regions. AB - Secondary damage processes, such as inflammation and oxidative stress, can exacerbate an ischemic lesion and spread to adjacent brain regions. Yet, few studies investigate how regions remote from the infarct could also suffer from degeneration and inflammation in the aftermath of a stroke. To find out to what extent far-remote brain regions are affected after stroke, we used a bilateral endothelin-1-induced prefrontal infarct rat model. Brain regions posterior to the prefrontal cortical infarct were analyzed for ongoing neurodegeneration using FluoroJadeB (FJB) and for neuroinflammation using Iba1 and OX-6 immunohistochemistry 28 days post-stroke. The FJB-positive dorsomedial nucleus of the thalamus (DMN) and retrosplenial area (RSA) of the cortex displayed substantial neuroinflammation. Significant neuronal loss was only observed within the cortex. Significant microglia recruitment and activation in the FJB-positive internal capsule indicates remote white matter pathology. These findings demonstrate that even regions far remote from an infarct are affected predictably based on anatomical connectivity, and that white matter inflammation is an integral part of remote pathology. The delayed nature of this pathology makes it a valid target for preventative treatment, potentially with an extended time window of opportunity for therapeutic intervention using anti-inflammatory agents. PMID- 26973456 TI - Long Non-coding RNA in Neurons: New Players in Early Response to BDNF Stimulation. AB - Brain-derived neurotrophic factor (BDNF) is a neurotrophin family member that is highly expressed and widely distributed in the brain. BDNF is critical for neural survival and plasticity both during development and in adulthood, and dysfunction in its signaling may contribute to a number of neurodegenerative disorders. Deep understanding of the BDNF-activated molecular cascade may thus help to find new biomarkers and therapeutic targets. One interesting direction is related to the early phase of BDNF-dependent gene expression regulation, which is responsible for the activation of selective gene programs that lead to stable functional and structural remodeling of neurons. Immediate-early coding genes activated by BDNF are under investigation, but the involvement of the non-coding RNAs is largely unexplored, especially the long non-coding RNAs (lncRNAs). lncRNAs are emerging as key regulators that can orchestrate different aspects of nervous system development, homeostasis, and plasticity, making them attractive candidate markers and therapeutic targets for brain diseases. We used microarray technology to identify differentially expressed lncRNAs in the immediate response phase of BDNF stimulation in a neuronal cell model. Our observations on the putative functional role of lncRNAs provide clues to their involvement as master regulators of gene expression cascade triggered by BDNF. PMID- 26973457 TI - Repeated Blockade of NMDA Receptors During Adolescence Impairs Reversal Learning and Disrupts GABAergic Interneurons in Rat Medial Prefrontal Cortex. AB - Adolescence is of particular significance to schizophrenia, since psychosis onset typically occurs in this critical period. Based on the N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis of schizophrenia, in this study, we investigated whether and how repeated NMDA receptor blockade during adolescence would affect GABAergic interneurons in rat medial prefrontal cortex (mPFC) and mPFC-mediated cognitive functions. Specifically, adolescent rats were subjected to intraperitoneal administration of MK-801 (0.1, 0.2, 0.4 mg/kg), a non competitive NMDA receptor antagonist, for 14 days and then tested for reference memory and reversal learning in the water maze. The density of parvabumin (PV)-, calbindin (CB)- and calretinin (CR)-positive neurons in mPFC was analyzed at either 24 h or 7 days after drug cessation. We found that MK-801 treatment delayed reversal learning in the water maze without affecting initial acquisition. Strikingly, MK-801 treatment also significantly reduced the density of PV(+) and CB(+) neurons, and this effect persisted for 7 days after drug cessation at the dose of 0.2 mg/kg. We further demonstrated that the reduction in PV(+) and CB(+) neuron densities was ascribed to a downregulation of the expression levels of PV and CB, but not to neuronal death. These results parallel the behavioral and neuropathological changes of schizophrenia and provide evidence that adolescent NMDA receptors antagonism offers a useful tool for unraveling the etiology of the disease. PMID- 26973458 TI - Enrichment of GABAA Receptor alpha-Subunits on the Axonal Initial Segment Shows Regional Differences. AB - Although it is generally recognized that certain alpha-subunits of gamma aminobutyric acid type A receptors (GABAARs) form enriched clusters on the axonal initial segment (AIS), the degree to which these clusters vary in different brain areas is not well known. In the current study, we quantified the density, size, and enrichment ratio of fluorescently labeled alpha1-, alpha2-, or alpha3 subunits aggregates co-localized with the AIS-marker ankyrin G and compared them to aggregates in non-AIS locations among different brain areas including hippocampal subfields, basal lateral amygdala (BLA), prefrontal cortex (PFC), and sensory cortex (CTX). We found regional differences in the enrichment of GABAAR alpha-subunits on the AIS. Significant enrichment was identified in the CA3 of hippocampus for alpha1-subunits, in the CA1, CA3, and BLA for alpha2-subunits, and in the BLA for alpha3-subunits. Using alpha-subunit knock-out (KO) mice, we found that BLA enrichment of alpha2- and alpha3-subunits were physiologically independent of each other, as the enrichment of one subunit was unaffected by the genomic deletion of the other. To further investigate the unique pattern of alpha subunit enrichment in the BLA, we examined the association of alpha2- and alpha3 subunits with the presynaptic vesicular GABA transporter (vGAT) and the anchoring protein gephyrin (Geph). As expected, both alpha2- and alpha3-subunits on the AIS within the BLA received prominent GABAergic innervation from vGAT-positive terminals. Further, we found that the association of alpha2- and alpha3-subunits with Geph was weaker in AIS versus non-AIS locations, suggesting that Geph might be playing a lesser role in the enrichment of alpha2- and alpha3-subunits on the AIS. Overall, these observations suggest that GABAARs on the AIS differ in subunit composition across brain regions. As with somatodendritic GABAARs, the distinctive expression pattern of AIS-located GABAAR alpha-subunits in the BLA, and other brain areas, likely contribute to unique forms of GABAergic inhibitory transmission and pharmacological profiles seen in different brain areas. PMID- 26973459 TI - Chronic Intermittent Ethanol Exposure Alters Stress Effects on (3alpha,5alpha)-3 hydroxy-pregnan-20-one (3alpha,5alpha-THP) Immunolabeling of Amygdala Neurons in C57BL/6J Mice. AB - The GABAergic neuroactive steroid (3alpha,5alpha)-3-hydroxy-pregnan-20-one (3alpha,5alpha-THP, allopregnanolone) is decreased in various brain regions of C57BL/6J mice following exposure to an acute stressor or chronic intermittent ethanol (CIE) exposure and withdrawal. It is well established that there are complex interactions between stress and ethanol drinking, with mixed literature regarding the effects of stress on ethanol intake. However, there is little research examining how chronic ethanol exposure alters stress responses. The present work examined the impact of CIE exposure and withdrawal on changes in brain levels of 3alpha,5alpha-THP, as well as hormonal and behavioral responses to forced swim stress (FSS). Adult male C57BL/6J mice were exposed to four cycles of CIE to induce ethanol dependence. Following 8 h or 72 h withdrawal, mice were subjected to FSS for 10 min, and 50 min later brains were collected for immunohistochemical analysis of cellular 3alpha,5alpha-THP. Behavioral and circulating corticosterone responses to FSS were quantified. Following 8 h withdrawal, ethanol exposure potentiated the corticosterone response to FSS. Following 72 h withdrawal, this difference was no longer observed. Following 8 h withdrawal, stress-exposed mice showed no differences in immobility, swimming or struggling behavior. However, following 72 h withdrawal, ethanol-exposed mice showed less immobility and greater swimming behavior compared to air-exposed mice. Interestingly, cellular 3alpha,5alpha-THP levels were increased in the lateral amygdala 8 h and 72 h post-withdrawal in stressed ethanol-exposed mice compared to ethanol-exposed/non-stressed mice. In the paraventricular nucleus of the hypothalamus, stress exposure decreased 3alpha,5alpha-THP levels compared to controls following 72 h withdrawal, but no differences were observed 8 h post withdrawal. There were no differences in cellular 3alpha,5alpha-THP levels in the nucleus accumbens shell at either withdrawal time point. These data suggest that there are different mechanisms mediating hormonal, behavioral, and brain responses to stress following CIE exposure. The lateral amygdala appears to be an extremely sensitive brain region exhibiting changes in cellular 3alpha,5alpha-THP levels following CIE and exposure to swim stress. It is likely that these changes in cellular 3alpha,5alpha-THP levels in the lateral amygdala contribute to the behavioral effects observed following 72 h withdrawal. PMID- 26973460 TI - Mechanical Injury Induces Brain Endothelial-Derived Microvesicle Release: Implications for Cerebral Vascular Injury during Traumatic Brain Injury. AB - It is well established that the endothelium responds to mechanical forces induced by changes in shear stress and strain. However, our understanding of vascular remodeling following traumatic brain injury (TBI) remains incomplete. Recently published studies have revealed that lung and umbilical endothelial cells produce extracellular microvesicles (eMVs), such as microparticles, in response to changes in mechanical forces (blood flow and mechanical injury). Yet, to date, no studies have shown whether brain endothelial cells produce eMVs following TBI. The brain endothelium is highly specialized and forms the blood-brain barrier (BBB), which regulates diffusion and transport of solutes into the brain. This specialization is largely due to the presence of tight junction proteins (TJPs) between neighboring endothelial cells. Following TBI, a breakdown in tight junction complexes at the BBB leads to increased permeability, which greatly contributes to the secondary phase of injury. We have therefore tested the hypothesis that brain endothelium responds to mechanical injury, by producing eMVs that contain brain endothelial proteins, specifically TJPs. In our study, primary human adult brain microvascular endothelial cells (BMVEC) were subjected to rapid mechanical injury to simulate the abrupt endothelial disruption that can occur in the primary injury phase of TBI. eMVs were isolated from the media following injury at 2, 6, 24, and 48 h. Western blot analysis of eMVs demonstrated a time-dependent increase in TJP occludin, PECAM-1 and ICAM-1 following mechanical injury. In addition, activation of ARF6, a small GTPase linked to extracellular vesicle production, was increased after injury. To confirm these results in vivo, mice were subjected to sham surgery or TBI and blood plasma was collected 24 h post-injury. Isolation and analysis of eMVs from blood plasma using cryo-EM and flow cytometry revealed elevated levels of vesicles containing occludin following brain trauma. These results indicate that following TBI, the cerebral endothelium undergoes vascular remodeling through shedding of eMVs containing TJPs and endothelial markers. The detection of this shedding potentially allows for a novel methodology for real-time monitoring of cerebral vascular health (remodeling), BBB status and neuroinflammation following a TBI event. PMID- 26973463 TI - CMTX Disorder and CamKinase. PMID- 26973462 TI - Function of Armcx3 and Armc10/SVH Genes in the Regulation of Progenitor Proliferation and Neural Differentiation in the Chicken Spinal Cord. AB - The eutherian X-chromosome specific family of Armcx genes has been described as originating by retrotransposition from Armc10/SVH, a single Arm-containing somatic gene. Armcx3 and Armc10/SVH are characterized by high expression in the central nervous system and they play an important role in the regulation of mitochondrial distribution and transport in neurons. In addition, Armcx/Arm10 genes have several Armadillo repeats in their sequence. In this study we address the potential role of this gene family in neural development by using the chick neural tube as a model. We show that Armc10/SVH is expressed in the chicken spinal cord, and knocking-down Armc10/SVH by sh-RNAi electroporation in spinal cord reduces proliferation of neural precursor cells (NPCs). Moreover, we analyzed the effects of murine Armcx3 and Armc10 overexpression, showing that both proteins regulate progenitor proliferation, while Armcx3 overexpression also specifically controls neural maturation. We show that the phenotypes found following Armcx3 overexpression require its mitochondrial localization, suggesting a novel link between mitochondrial dynamics and regulation of neural development. Furthermore, we found that both Armcx3 and Armc10 may act as inhibitors of Wnt-beta-catenin signaling. Our results highlight both common and differential functions of Armcx/Armc10 genes in neural development in the spinal cord. PMID- 26973464 TI - Inhibition of Spinal Ca(2+)-Permeable AMPA Receptors with Dicationic Compounds Alleviates Persistent Inflammatory Pain without Adverse Effects. AB - Upregulation of Ca(2+)-permeable AMPA receptors (CP-AMPARs) in the dorsal horn (DH) neurons of the spinal cord has been causally linked to the maintenance of persistent inflammatory pain. Therefore, inhibition of CP-AMPARs could potentially alleviate an, otherwise, poorly treatable chronic pain. However, a loss of CP-AMPARs could produce considerable side effects because of the crucial role of CP-AMPARs in synaptic plasticity. Here we have tested whether the inhibition of spinal CP-AMPARs with dicationic compounds, the open-channel antagonists acting in an activity-dependent manner, can relieve inflammatory pain without adverse effects being developed. Dicationic compounds, N1-(1 phenylcyclohexyl)pentane-1,5-diaminium bromide (IEM-1925) and 1-trimethylammonio 5-1-adamantane-methyl-ammoniopentane dibromide (IEM-1460) were applied intrathecally (i.t.) as a post-treatment for inflammatory pain in the model of complete Freund's adjuvant (CFA)-induced long-lasting peripheral inflammation. The capability of dicationic compounds to ameliorate inflammatory pain was tested in rats in vivo using the Hargreaves, the von Frey and the open-field tests. Treatment with IEM-1460 or IEM-1925 resulted in profound alleviation of inflammatory pain. The pain relief appeared shortly after compound administration. The effects were concentration-dependent, displaying a high potency of dicationic compounds for alleviation of inflammatory hyperalgesia in the micromolar range, for both acute and long-lasting responses. The period of pain maintenance was shortened following treatment. Treatment with IEM-1460 or IEM-1925 changed neither thermal and mechanical basal sensitivities nor animal locomotion, suggesting that inhibition of CP-AMPARs with dicationic compounds does not give rise to detectable side effects. Thus, the ability of dicationic compounds to alleviate persistent inflammatory pain may provide new routes in the treatment of chronic pain. PMID- 26973465 TI - miRNAs Plasma Profiles in Vascular Dementia: Biomolecular Data and Biomedical Implications. AB - Vascular dementia (VaD) is a pathogenetically heterogeneous neuropsychiatric syndrome, mainly characterized by cognitive impairment. Among dementias, it is second by incidence after Alzheimer's dementia (AD). VaD biomolecular bases have been poorly characterized, but vascular-linked factors affecting the CNS and its functions are generally hypothesized to perform a major role, together with cardiovascular and immunological factors. miRNAs, which perform critically important biomolecular roles within cell networks, are also found in biological fluids as circulating miRNAs (cmiRNAs). We hypothesized that differentially expressed (DE) cmiRNAs in plasma from VaD patients could be applied to diagnose VaD through liquid biopsies; these profiles also could allow to start investigating VaD molecular bases. By exploiting TaqMan Low-Density Arrays and single TaqMan assays, miR-10b*, miR29a-3p, and miR-130b-3p were discovered and validated as significantly downregulated DE cmiRNAs in VaD patients compared to unaffected controls (NCs). These miRNAs also were found to be significantly downregulated in a matched cohort of AD patients, but miR-130b-3p levels were lower in AD than in VaD. A negative correlation was detected between miR-29a and miR-130b expression and cognitive impairment in VaD and AD, respectively. Receiver operating characteristic curves demonstrated that decreased plasma levels of miR-10b*, miR29a-3p, and miR-130b-3p allow to discriminate VaD and AD patients from NCs. Furthermore, the concurrent downregulation of both miR-10b* and miR-130b-3p in VaD showed an area under the curve (AUC) of 0.789 (p < 0.0001) with 75% of sensitivity and 72% of specificity, whereas an AUC of 0.789 (p < 0.0001) with 92% of sensitivity and 81% of specificity was found for both in AD. The miRNAs profiles reported in this paper pave the way to translational applications to molecular VaD diagnosis, but they also should allow to further investigate on its molecular bases. PMID- 26973461 TI - Impaired Autophagy and Defective Mitochondrial Function: Converging Paths on the Road to Motor Neuron Degeneration. AB - Selective motor neuron degeneration is a hallmark of amyotrophic lateral sclerosis (ALS). Around 10% of all cases present as familial ALS (FALS), while sporadic ALS (SALS) accounts for the remaining 90%. Diverse genetic mutations leading to FALS have been identified, but the underlying causes of SALS remain largely unknown. Despite the heterogeneous and incompletely understood etiology, different types of ALS exhibit overlapping pathology and common phenotypes, including protein aggregation and mitochondrial deficiencies. Here, we review the current understanding of mechanisms leading to motor neuron degeneration in ALS as they pertain to disrupted cellular clearance pathways, ATP biogenesis, calcium buffering and mitochondrial dynamics. Through focusing on impaired autophagic and mitochondrial functions, we highlight how the convergence of diverse cellular processes and pathways contributes to common pathology in motor neuron degeneration. PMID- 26973467 TI - Human Cerebrospinal Fluid Promotes Neuronal Viability and Activity of Hippocampal Neuronal Circuits In Vitro. AB - For decades it has been hypothesized that molecules within the cerebrospinal fluid (CSF) diffuse into the brain parenchyma and influence the function of neurons. However, the functional consequences of CSF on neuronal circuits are largely unexplored and unknown. A major reason for this is the absence of appropriate neuronal in vitro model systems, and it is uncertain if neurons cultured in pure CSF survive and preserve electrophysiological functionality in vitro. In this article, we present an approach to address how human CSF (hCSF) influences neuronal circuits in vitro. We validate our approach by comparing the morphology, viability, and electrophysiological function of single neurons and at the network level in rat organotypic slice and primary neuronal cultures cultivated either in hCSF or in defined standard culture media. Our results demonstrate that rodent hippocampal slices and primary neurons cultured in hCSF maintain neuronal morphology and preserve synaptic transmission. Importantly, we show that hCSF increases neuronal viability and the number of electrophysiologically active neurons in comparison to the culture media. In summary, our data indicate that hCSF represents a physiological environment for neurons in vitro and a superior culture condition compared to the defined standard media. Moreover, this experimental approach paves the way to assess the functional consequences of CSF on neuronal circuits as well as suggesting a novel strategy for central nervous system (CNS) disease modeling. PMID- 26973466 TI - Effect of MK-801 and Clozapine on the Proteome of Cultured Human Oligodendrocytes. AB - Separate lines of evidence have demonstrated the involvement of N-methyl-D aspartate (NMDA) receptor and oligodendrocyte dysfunctions in schizophrenia. Here, we have carried out shotgun mass spectrometry proteome analysis of oligodendrocytes treated with the NMDA receptor antagonist MK-801 to gain potential insights into these effects at the molecular level. The MK-801 treatment led to alterations in the levels of 68 proteins, which are associated with seven distinct biological processes. Most of these proteins are involved in energy metabolism and many have been found to be dysregulated in previous proteomic studies of post-mortem brain tissues from schizophrenia patients. Finally, addition of the antipsychotic clozapine to MK-801-treated oligodendrocyte cultures resulted in changes in the levels of 45 proteins and treatment with clozapine alone altered 122 proteins and many of these showed opposite changes to the MK-801 effects. Therefore, these proteins and the associated energy metabolism pathways should be explored as potential biomarkers of antipsychotic efficacy. In conclusion, MK-801 treatment of oligodendrocytes may provide a useful model for testing the efficacy of novel treatment approaches. PMID- 26973468 TI - Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke. AB - Numerous studies have documented increases in matrix metalloproteinases (MMPs), specifically MMP-9 levels following stroke, with such perturbations associated with disruption of the blood brain barrier (BBB), increased risk of hemorrhagic complications, and worsened outcome. Despite this, controversy remains as to which cells release MMP-9 at the normal and pathological BBB, with even less clarity in the context of stroke. This may be further complicated by the influence of tissue plasminogen activator (tPA) treatment. The aim of the present review is to examine the relationship between neutrophils, MMP-9 and tPA following ischemic stroke to elucidate which cells are responsible for the increases in MMP-9 and resultant barrier changes and hemorrhage observed following stroke. PMID- 26973470 TI - Pio del Rio-Hortega: A Pioneer in the Pathology of Central Nervous System Tumors. AB - The last 140 years have seen considerable advances in knowledge of central nervous system tumors. However, the main tumor types had already been described during the early years of the twentieth century. The studies of Dr. Pio del Rio Hortega have been ones of the most exhaustive histology and cytology-based studies of nervous system tumors. Rio Hortega's work was performed using silver staining methods, which require a high level of practical skill and were therefore difficult to standardize. His technical aptitude and interest in nervous system tumors played a key role in the establishment of his classification, which was based on cell lineage and embryonic development. Rio Hortega's approach was controversial when he proposed it. Current classifications are not only based on cell type and embryonic lineage, as well as on clinical characteristics, anatomical site, and age. PMID- 26973469 TI - Sparing of Descending Axons Rescues Interneuron Plasticity in the Lumbar Cord to Allow Adaptive Learning After Thoracic Spinal Cord Injury. AB - This study evaluated the role of spared axons on structural and behavioral neuroplasticity in the lumbar enlargement after a thoracic spinal cord injury (SCI). Previous work has demonstrated that recovery in the presence of spared axons after an incomplete lesion increases behavioral output after a subsequent complete spinal cord transection (TX). This suggests that spared axons direct adaptive changes in below-level neuronal networks of the lumbar cord. In response to spared fibers, we postulate that lumbar neuron networks support behavioral gains by preventing aberrant plasticity. As such, the present study measured histological and functional changes in the isolated lumbar cord after complete TX or incomplete contusion (SCI). To measure functional plasticity in the lumbar cord, we used an established instrumental learning paradigm (ILP). In this paradigm, neural circuits within isolated lumbar segments demonstrate learning by an increase in flexion duration that reduces exposure to a noxious leg shock. We employed this model using a proof-of-principle design to evaluate the role of sparing on lumbar learning and plasticity early (7 days) or late (42 days) after midthoracic SCI in a rodent model. Early after SCI or TX at 7 days, spinal learning was unattainable regardless of whether the animal recovered with or without axonal substrate. Failed learning occurred alongside measures of cell soma atrophy and aberrant dendritic spine expression within interneuron populations responsible for sensorimotor integration and learning. Alternatively, exposure of the lumbar cord to a small amount of spared axons for 6 weeks produced near-normal learning late after SCI. This coincided with greater cell soma volume and fewer aberrant dendritic spines on interneurons. Thus, an opportunity to influence activity-based learning in locomotor networks depends on spared axons limiting maladaptive plasticity. Together, this work identifies a time dependent interaction between spared axonal systems and adaptive plasticity in locomotor networks and highlights a critical window for activity-based rehabilitation. PMID- 26973471 TI - Recent Progress in Magnetic Resonance Imaging of the Embryonic and Neonatal Mouse Brain. AB - The laboratory mouse has been widely used as a model system to investigate the genetic control mechanisms of mammalian brain development. Magnetic resonance imaging (MRI) is an important tool to characterize changes in brain anatomy in mutant mouse strains and injury progression in mouse models of fetal and neonatal brain injury. Progress in the last decade has enabled us to acquire MRI data with increasing anatomical details from the embryonic and neonatal mouse brain. High resolution ex vivo MRI, especially with advanced diffusion MRI methods, can visualize complex microstructural organizations in the developing mouse brain. In vivo MRI of the embryonic mouse brain, which is critical for tracking anatomical changes longitudinally, has become available. Applications of these techniques may lead to further insights into the complex and dynamic processes of brain development. PMID- 26973472 TI - Real-World-Time Simulation of Memory Consolidation in a Large-Scale Cerebellar Model. AB - We report development of a large-scale spiking network model of the cerebellum composed of more than 1 million neurons. The model is implemented on graphics processing units (GPUs), which are dedicated hardware for parallel computing. Using 4 GPUs simultaneously, we achieve realtime simulation, in which computer simulation of cerebellar activity for 1 s completes within 1 s in the real-world time, with temporal resolution of 1 ms. This allows us to carry out a very long term computer simulation of cerebellar activity in a practical time with millisecond temporal resolution. Using the model, we carry out computer simulation of long-term gain adaptation of optokinetic response (OKR) eye movements for 5 days aimed to study the neural mechanisms of posttraining memory consolidation. The simulation results are consistent with animal experiments and our theory of posttraining memory consolidation. These results suggest that realtime computing provides a useful means to study a very slow neural process such as memory consolidation in the brain. PMID- 26973473 TI - The Development of Attention Systems and Working Memory in Infancy. AB - In this article, we review research and theory on the development of attention and working memory in infancy using a developmental cognitive neuroscience framework. We begin with a review of studies examining the influence of attention on neural and behavioral correlates of an earlier developing and closely related form of memory (i.e., recognition memory). Findings from studies measuring attention utilizing looking measures, heart rate, and event-related potentials (ERPs) indicate significant developmental change in sustained and selective attention across the infancy period. For example, infants show gains in the magnitude of the attention related response and spend a greater proportion of time engaged in attention with increasing age (Richards and Turner, 2001). Throughout infancy, attention has a significant impact on infant performance on a variety of tasks tapping into recognition memory; however, this approach to examining the influence of infant attention on memory performance has yet to be utilized in research on working memory. In the second half of the article, we review research on working memory in infancy focusing on studies that provide insight into the developmental timing of significant gains in working memory as well as research and theory related to neural systems potentially involved in working memory in early development. We also examine issues related to measuring and distinguishing between working memory and recognition memory in infancy. To conclude, we discuss relations between the development of attention systems and working memory. PMID- 26973474 TI - The Striatum and Subthalamic Nucleus as Independent and Collaborative Structures in Motor Control. AB - The striatum and the subthalamic nucleus (STN) are two separate input structures into the basal ganglia (BG). Accordingly, research to date has primarily focused on the distinct roles of these structures in motor control and cognition, often through investigation of Parkinson's disease (PD). Both structures are divided into sensorimotor, associative, and limbic subdivisions based on cortical connectivity. The more recent discovery of the STN as an input structure into the BG drives comparison of these two structures and their respective roles in cognition and motor control. This review compares the role of the striatum and STN in motor response inhibition and execution, competing motor programs, feedback based learning, and response planning. Through comparison, it is found that the striatum and STN have highly independent roles in motor control but also collaborate in order to execute desired actions. There is also the possibility that inhibition or activation of one of these structures indirectly contributes to the function of other connected anatomical structures. Both structures contribute to selective motor response inhibition, which forms the basis of many tasks, but the STN additionally contributes to global inhibition through the hyperdirect pathway. Research is warranted on the functional connectivity of the network for inhibition involving the rIFG, preSMA, striatum, and STN. PMID- 26973475 TI - Role of Glia in Memory Deficits Following Traumatic Brain Injury: Biomarkers of Glia Dysfunction. AB - Historically, glial cells have been recognized as a structural component of the brain. However, it has become clear that glial cells are intimately involved in the complexities of neural networks and memory formations. Astrocytes, microglia, and oligodendrocytes have dynamic responsibilities which substantially impact neuronal function and activities. Moreover, the importance of glia following brain injury has come to the forefront in discussions to improve axonal regeneration and functional recovery. The numerous activities of glia following injury can either promote recovery or underlie the pathobiology of memory deficits. This review outlines the pathological states of glial cells which evolve from their positive supporting roles to those which disrupt synaptic function and neuroplasticity following injury. Evidence suggests that glial cells interact extensively with neurons both chemically and physically, reinforcing their role as pivotal for higher brain functions such as learning and memory. Collectively, this mini review surveys investigations of how glial dysfunction following brain injury can alter mechanisms of synaptic plasticity and how this may be related to an increased risk for persistent memory deficits. We also include recent findings, that demonstrate new molecular avenues for clinical biomarker discovery. PMID- 26973476 TI - Functional Connectivity Hubs and Networks in the Awake Marmoset Brain. AB - In combination with advances in analytical methods, resting-state fMRI is allowing unprecedented access to a better understanding of the network organization of the brain. Increasing evidence suggests that this architecture may incorporate highly functionally connected nodes, or "hubs", and we have recently proposed local functional connectivity density (lFCD) mapping to identify highly-connected nodes in the human brain. Here, we imaged awake nonhuman primates to test whether, like the human brain, the marmoset brain contains FC hubs. Ten adult common marmosets (Callithrix jacchus) were acclimated to mild, comfortable restraint using individualized helmets. Following restraint training, resting BOLD data were acquired during eight consecutive 10 min scans for each subject. lFCD revealed prominent cortical and subcortical hubs of connectivity across the marmoset brain; specifically, in primary and secondary visual cortices (V1/V2), higher-order visual association areas (A19M/V6[DM]), posterior parietal and posterior cingulate areas (PGM and A23b/A31), thalamus, dorsal and ventral striatal areas (caudate, putamen, lateral septal nucleus, and anterior cingulate cortex (A24a). lFCD hubs were highly connected to widespread areas of the brain, and further revealed significant network-network interactions. These data provide a baseline platform for future investigations in a nonhuman primate model of the brain's network topology. PMID- 26973478 TI - Visual Presentation Effects on Identification of Multiple Environmental Sounds. AB - This study examined how the contents and timing of a visual stimulus affect the identification of mixed sounds recorded in a daily life environment. For experiments, we presented four environment sounds as auditory stimuli for 5 s along with a picture or a written word as a visual stimulus that might or might not denote the source of one of the four sounds. Three conditions of temporal relations between the visual stimuli and sounds were used. The visual stimulus was presented either: (a) for 5 s simultaneously with the sound; (b) for 5 s, 1 s before the sound (SOA between the audio and visual stimuli was 6 s); or (c) for 33 ms, 1 s before the sound (SOA was 1033 ms). Participants reported all identifiable sounds for those audio-visual stimuli. To characterize the effects of visual stimuli on sound identification, the following were used: the identification rates of sounds for which the visual stimulus denoted its sound source, the rates of other sounds for which the visual stimulus did not denote the sound source, and the frequency of false hearing of a sound that was not presented for each sound set. Results of the four experiments demonstrated that a picture or a written word promoted identification of the sound when it was related to the sound, particularly when the visual stimulus was presented for 5 s simultaneously with the sounds. However, a visual stimulus preceding the sounds had a benefit only for the picture, not for the written word. Furthermore, presentation with a picture denoting a sound simultaneously with the sound reduced the frequency of false hearing. These results suggest three ways that presenting a visual stimulus affects identification of the auditory stimulus. First, activation of the visual representation extracted directly from the picture promotes identification of the denoted sound and suppresses the processing of sounds for which the visual stimulus did not denote the sound source. Second, effects based on processing of the conceptual information promote identification of the denoted sound and suppress the processing of sounds for which the visual stimulus did not denote the sound source. Third, processing of the concurrent visual representation suppresses false hearing. PMID- 26973479 TI - Hoarders Only Discount Consumables and Are More Patient for Money. AB - Individuals with hoarding disorder (HD) excessively acquire and retain goods while also exhibiting characteristics of impulsivity and addiction. However, HD individuals do not always perform impulsively in experiments, they do not appear interested in money, and they exhibit many features of risk-aversion and future planning. To examine impulsivity in HD, we compared validated community participants high and low in hoarding tendencies on questionnaire measures of hoarding and impulsivity as well as a standard experimental measure of impulsivity (intertemporal discounting) that was modified to compare decisions about money, pens, and snacks. Common discounting effects were replicated. Compared to the low hoarding group, the high hoarding group was more impatient for consumables (pens and snacks) but they were more patient for money. This increased patience for money in high hoarding individuals is in contrast to all other studies on discounting in disordered populations, but consistent with the phenomenology of HD. HD does not appear to be driven by a fundamental inability to wait, but rather a specific, potent desire for consumable rewards. PMID- 26973477 TI - The Role of Lactate-Mediated Metabolic Coupling between Astrocytes and Neurons in Long-Term Memory Formation. AB - Long-term memory formation, the ability to retain information over time about an experience, is a complex function that affects multiple behaviors, and is an integral part of an individual's identity. In the last 50 years many scientists have focused their work on understanding the biological mechanisms underlying memory formation and processing. Molecular studies over the last three decades have mostly investigated, or given attention to, neuronal mechanisms. However, the brain is composed of different cell types that, by concerted actions, cooperate to mediate brain functions. Here, we consider some new insights that emerged from recent studies implicating astrocytic glycogen and glucose metabolisms, and particularly their coupling to neuronal functions via lactate, as an essential mechanism for long-term memory formation. PMID- 26973481 TI - Wind-Related Orientation Patterns in Diurnal, Crepuscular and Nocturnal High Altitude Insect Migrants. AB - Most insect migrants fly at considerable altitudes (hundreds of meters above the ground) where they utilize fast-flowing winds to achieve rapid and comparatively long-distance transport. The nocturnal aerial migrant fauna has been well studied with entomological radars, and many studies have demonstrated that flight orientations are frequently grouped around a common direction in a range of nocturnal insect migrants. Common orientation typically occurs close to the downwind direction (thus ensuring that a large component of the insects' self powered speed is directed downstream), and in nocturnal insects at least, the downwind headings are seemingly maintained by direct detection of wind-related turbulent cues. Despite being far more abundant and speciose, the day-flying windborne migrant fauna has been much less studied by radar; thus the frequency of wind-related common orientation patterns and the sensory mechanisms involved in their formation remain to be established. Here, we analyze a large dataset of >600,000 radar-detected "medium-sized" windborne insect migrants (body mass from 10 to 70 mg), flying hundreds of meters above southern UK, during the afternoon, in the period around sunset, and in the middle of the night. We found that wind related common orientation was almost ubiquitous during the day (present in 97% of all "migration events" analyzed), and was also frequent at sunset (85%) and at night (81%). Headings were systematically offset to the right of the flow at night-time (as predicted from the use of turbulence cues for flow assessment), but there was no directional bias in the offsets during the day or at sunset. Orientation "performance" significantly increased with increasing flight altitude throughout the day and night. We conclude by discussing sensory mechanisms which most likely play a role in the selection and maintenance of wind-related flight headings. PMID- 26973480 TI - Continuous and Intermittent Alcohol Free-Choice from Pre-gestational Time to Lactation: Focus on Drinking Trajectories and Maternal Behavior. AB - BACKGROUND: Alcohol consumption during pregnancy and lactation induces detrimental consequences, that are not limited to the direct in utero effects of the drug on fetuses, but extend to maternal care. However, the occurrence and severity of alcohol toxicity are related to the drinking pattern and the time of exposure. The present study investigated in female rats long-term alcohol drinking trajectories, by a continuous and intermittent free-choice paradigm, during pre-gestational time, pregnancy, and lactation; moreover, the consequences of long-term alcohol consumption on the response to natural reward and maternal behavior were evaluated. METHODS: Virgin female rats were exposed to home-cage two-bottle continuous- or intermittent "alcohol (20% v/v) vs. water" choice regimen along 12 weeks and throughout pregnancy and lactation. Animals were tested for saccharin preference, and maternal behavior was assessed by recording dams' undisturbed spontaneous home-cage behavior in the presence of their offspring. RESULTS: Our results show that the intermittent alcohol drinking pattern induced an escalation in alcohol intake during pre-gestational time and lactation more than the continuous access, while a reduction in alcohol consumption was observed during pregnancy, contrarily to the drinking trajectories of the continuous access-exposed rats. Long-term voluntary alcohol intake induced a decreased saccharin preference in virgin female rats and a significant reduction in maternal care, with respect to control dams, although the intermittent drinking produced a greater impairment than the continuous access paradigm. CONCLUSION: The present data indicate that both alcohol-drinking patterns are associated to modifications in the drinking trajectories of female rats, in pre-gestational time, during pregnancy and lactation. Moreover, long lasting alcohol intake can affect sensitivity to natural rewarding stimuli and maternal behavior and sensitivity to natural rewarding stimuli in a pattern related manner. This study underlies the importance of modeling human alcohol habit and its consequences on the mother-infant dyad, in order to prevent detrimental effects on offspring development and maturation. PMID- 26973482 TI - Corrigendum: Crossmodal illusions in neurorehabilitation. AB - [This corrects the article on p. 212 in vol. 9, PMID: 26321933.]. PMID- 26973483 TI - Group Intensive Cognitive Activation in Patients with Major or Mild Neurocognitive Disorder. AB - BACKGROUND: No standard protocols are available for cognitive rehabilitation (CR) in conditions like Major or Mild Neurocognitive disorder (M-NCD or m-NCD, respectively); however, preliminary data seem to indicate that such interventions might have cost-effective beneficial effects and are free from side effect or adverse events. Three basic approaches are known: cognitive stimulation (CS), cognitive training (CT), and CR. OBJECTIVE: Aim of this study was to assess the efficacy of a protocol of group intensive cognitive activation (g-ICA) in patients with both M-NCD and m-NCD; the protocol was specifically arranged in our Research Institute, based on the principles of the central role of the patient and the mediation pedagogy. SUBJECTS AND METHODS: Sixteen patients with M-NCD and fifteen patients with m-NCD were enrolled, as well as eleven patients with M-NCD who were used as a control group (CG). The intervention was carried-out by a clinical neuropsychologist with daily group sessions over a period of 2 months. Neuropsychological assessment was performed at baseline and after the completion of the rehabilitative intervention. RESULTS: General cognitive functioning, attention, ideomotor praxis and visual memory scores were found to be significantly increased in all patients. Beneficial and significant effects were also found for constructive praxis in M-NCD and for executive functioning in m NCD. All areas of the language function were significantly ameliorated in m-NCD, while this happened only for verbal repetition and syntax-grammar comprehension in M-NCD. No changes were detected for long- and short-term verbal memory, which were found to be worsened in controls without activation. CONCLUSION: Our findings seem to indicate that g-ICA might be effective in inducing beneficial changes on the general cognitive functioning and other specific functions in patients with both m-NCD and M-NCD. Moreover, the specific protocol proposed, even if susceptible of important improvement, is easy to carry out within hospital facilities and cost-effective. PMID- 26973484 TI - Adenosine A2A Receptor Blockade Prevents Rotenone-Induced Motor Impairment in a Rat Model of Parkinsonism. AB - Pharmacological studies implicate the blockade of adenosine receptorsas an effective strategy for reducing Parkinson's disease (PD) symptoms. The objective of this study is to elucidate the possible protective effects of ZM241385 and 8 cyclopentyl-1, 3-dipropylxanthine, two selective A2A and A1 receptor antagonists, on a rotenone rat model of PD. Rats were split into four groups: vehicle control (1 ml/kg/48 h), rotenone (1.5 mg/kg/48 h, s.c.), ZM241385 (3.3 mg/kg/day, i.p) and 8-cyclopentyl-1, 3-dipropylxanthine (5 mg/kg/day, i.p). After that, animals were subjected to behavioral (stride length and grid walking) and biochemical (measuring concentration of dopamine levels using high performance liquid chromatography, HPLC). In the rotenone group, rats displayed a reduced motor activity and disturbed movement coordination in the behavioral tests and a decreased dopamine concentration as foundby HPLC. The effect of rotenone was partially prevented in the ZM241385 group, but not with 8-cyclopentyl-1,3 dipropylxanthine administration. The administration of ZM241385 improved motor function and movement coordination (partial increase of stride length and partial decrease in the number of foot slips) and an increase in dopamine concentration in the rotenone-injected rats. However, the 8-cyclopentyl-1,3-dipropylxanthine and rotenone groups were not significantly different. These results indicate that selective A2A receptor blockade by ZM241385, but not A1 receptor blockadeby 8 cyclopentyl-1,3-dipropylxanthine, may treat PD motor symptoms. This reinforces the potential use of A2A receptor antagonists as a treatment strategy for PD patients. PMID- 26973485 TI - Gender Dependent Evaluation of Autism like Behavior in Mice Exposed to Prenatal Zinc Deficiency. AB - Zinc deficiency has recently been linked to the etiology of autism spectrum disorders (ASD) as environmental risk factor. With an estimated 17% of the world population being at risk of zinc deficiency, especially zinc deficiency during pregnancy might be a common occurrence, also in industrialized nations. On molecular level, zinc deficiency has been shown to affect a signaling pathway at glutamatergic synapses that has previously been identified through genetic mutations in ASD patients, the Neurexin-Neuroligin-Shank pathway, via altering zinc binding Shank family members. In particular, prenatal zinc deficient but not acute zinc deficient animals have been reported to display autism like behavior in some behavioral tests. However, a full behavioral analysis of a possible autism like behavior has been lacking so far. Here, we performed an extensive behavioral phenotyping of mice born from mothers with mild zinc deficiency during all trimesters of pregnancy. Prenatal zinc deficient animals were investigated as adults and gender differences were assessed. Our results show that prenatal zinc deficient mice display increased anxiety, deficits in nest building and various social interaction paradigm, as well as mild alterations in ultrasonic vocalizations. A gender specific analysis revealed only few sex specific differences. Taken together, given that similar behavioral abnormalities as reported here are frequently observed in ASD mouse models, we conclude that prenatal zinc deficient animals even without specific genetic susceptibility for ASD, already show some features of ASD like behavior. PMID- 26973486 TI - Voluntary Movement Frequencies in Submaximal One- and Two-Legged Knee Extension Exercise and Pedaling. AB - Understanding of behavior and control of human voluntary rhythmic stereotyped leg movements is useful in work to improve performance, function, and rehabilitation of exercising, healthy, and injured humans. The present study aimed at adding to the existing understanding within this field. To pursue the aim, correlations between freely chosen movement frequencies in relatively simple, single-joint, one- and two-legged knee extension exercise were investigated. The same was done for more complex, multiple-joint, one- and two-legged pedaling. These particular activities were chosen because they could be considered related to some extent, as they shared a key aspect of knee extension, and because they at the same time were different. The activities were performed at submaximal intensities, by healthy individuals (n = 16, thereof eight women; 23.4 +/- 2.7 years; 1.70 +/- 0.11 m; 68.6 +/- 11.2 kg). High and fair correlations (R-values of 0.99 and 0.75) occurred between frequencies generated with the dominant leg and the nondominant leg during knee extension exercise and pedaling, respectively. Fair to high correlations (R-values between 0.71 and 0.95) occurred between frequencies performed with each of the two legs in an activity, and the two-legged frequency performed in the same type of activity. In general, the correlations were higher for knee extension exercise than for pedaling. Correlations between knee extension and pedaling frequencies were of modest occurrence. The correlations between movement frequencies generated separately by each of the legs might be interpreted to support the following working hypothesis, which was based on existing literature. It is likely that involved central pattern generators (CPGs) of the two legs share a common frequency generator or that separate frequency generators of each leg are attuned via interneuronal connections. Further, activity type appeared to be relevant. Thus, the apparent common rhythmogenesis for the two legs appeared to be stronger for the relatively simple single-joint activity of knee extension exercise as compared to the more complex multi-joint activity of pedaling. Finally, it appeared that the shared aspect of knee extension in the related types of activities of knee extension exercise and pedaling was insufficient to cause obvious correlations between generated movement frequencies in the two types of activities. PMID- 26973487 TI - Neural Control Adaptation to Motor Noise Manipulation. AB - Antagonistic muscular co-activation can compensate for movement variability induced by motor noise at the expense of increased energetic costs. Greater antagonistic co-activation is commonly observed in older adults, which could be an adaptation to increased motor noise. The present study tested this hypothesis by manipulating motor noise in 12 young subjects while they practiced a goal directed task using a myoelectric virtual arm, which was controlled by their biceps and triceps muscle activity. Motor noise was increased by increasing the coefficient of variation (CV) of the myoelectric signals. As hypothesized, subjects adapted by increasing antagonistic co-activation, and this was associated with reduced noise-induced performance decrements. A second hypothesis was that a virtual decrease in motor noise, achieved by smoothing the myoelectric signals, would have the opposite effect: co-activation would decrease and motor performance would improve. However, the results showed that a decrease in noise made performance worse instead of better, with no change in co-activation. Overall, these findings suggest that the nervous system adapts to virtual increases in motor noise by increasing antagonistic co-activation, and this preserves motor performance. Reducing noise may have failed to benefit performance due to characteristics of the filtering process itself, e.g., delays are introduced and muscle activity bursts are attenuated. The observed adaptations to increased noise may explain in part why older adults and many patient populations have greater antagonistic co-activation, which could represent an adaptation to increased motor noise, along with a desire for increased joint stability. PMID- 26973489 TI - Dance, Music, Meter and Groove: A Forgotten Partnership. AB - I argue that core aspects of musical rhythm, especially "groove" and syncopation, can only be fully understood in the context of their origins in the participatory social experience of dance. Musical meter is first considered in the context of bodily movement. I then offer an interpretation of the pervasive but somewhat puzzling phenomenon of syncopation in terms of acoustic emphasis on certain offbeat components of the accompanying dance style. The reasons for the historical tendency of many musical styles to divorce themselves from their dance based roots are also briefly considered. To the extent that musical rhythms only make sense in the context of bodily movement, researchers interested in ecologically valid approaches to music cognition should make a more concerted effort to extend their analyses to dance, particularly if we hope to understand the cognitive constraints underlying rhythmic aspects of music like meter and groove. PMID- 26973488 TI - Perceptual Accent Rating and Attribution in Psychogenic FAS: Some Further Evidence Challenging Whitaker's Operational Definition. AB - A 40-year-old, non-aphasic, right-handed, and polyglot (L1: French, L2: Dutch, and L3: English) woman with a 12-year history of addiction to opiates and psychoactive substances, and clear psychiatric problems, presented with a foreign accent of sudden onset in L1. Speech evolved toward a mostly fluent output, despite a stutter-like behavior and a marked grammatical output disorder. The psychogenic etiology of the accent foreignness was construed based on the patient's complex medical history and psychodiagnostic, neuropsychological, and neurolinguistic assessments. The presence of a foreign accent was affirmed by a perceptual accent rating and attribution experiment. It is argued that this patient provides additional evidence demonstrating the outdatedness of Whitaker's (1982) definition of foreign accent syndrome, as only one of the four operational criteria was unequivocally applicable to our patient: her accent foreignness was not only recognized by her relatives and the medical staff but also by a group of native French-speaking laymen. However, our patient defied the three remaining criteria, as central nervous system damage could not conclusively be demonstrated, psychodiagnostic assessment raised the hypothesis of a conversion disorder, and the patient was a polyglot whose newly gained accent was associated with a range of foreign languages, which exceeded the ones she spoke. PMID- 26973490 TI - The Neural Basis of Individual Face and Object Perception. AB - We routinely need to process the identity of many faces around us, and how the brain achieves this is still the subject of much research in cognitive neuroscience. To date, insights on face identity processing have come from both healthy and clinical populations. However, in order to directly compare results across and within participant groups, and across different studies, it is crucial that a standard task is utilized which includes different exemplars (for example, non-face stimuli along with faces), is memory-neutral, and taps into identity matching across orientation and across viewpoint change. The goal of this study was to test a previously behaviourally tested face and object identity matching design in a healthy control sample whilst being scanned using fMRI. Specifically, we investigated categorical, orientation, and category-specific orientation effects while participants were focused on identity matching of simultaneously presented exemplar stimuli. Alongside observing category and orientation specific effects in a distributed set of brain regions, we also saw an interaction between stimulus category and orientation in the bilateral fusiform gyrus and bilateral middle occipital gyrus. Generally these clusters showed the pattern of a heightened response to inverted versus upright faces, and to upright, as compared to inverted shoes. These results are discussed in relation to previous studies and to potential future research within prosopagnosic individuals. PMID- 26973492 TI - Commentary: Cumulative effects of anodal and priming cathodal tDCS on pegboard test performance and motor cortical excitability. PMID- 26973491 TI - Oxytocin and Self-Consciousness. PMID- 26973493 TI - ERPs Reveal the Time-Course of Aberrant Visual-Phonological Binding in Developmental Dyslexia. AB - New evidence is accumulating for a deficit in binding visual-orthographic information with the corresponding phonological code in developmental dyslexia. Here, we identify the mechanisms underpinning this deficit using event-related brain potentials (ERPs) in dyslexic and control adult readers performing a letter matching task. In each trial, a printed letter was presented synchronously with an auditory letter name. Incongruent (mismatched), frequent trials were interleaved with congruent (matched) infrequent target pairs, which participants were asked to report by pressing a button. In critical trials, incongruent letter pairs were mismatched but confusable in terms of their visual or phonological features. Typical readers showed early detection of deviant trials, indicated by larger modulation in the range of the phonological mismatch negativity (PMN) compared with standard trials. This was followed by stronger modulation of the P3b wave for visually confusable deviants and an increased lateralized readiness potential (LRP) for phonological deviants, compared with standards. In contrast, dyslexic readers showed reduced sensitivity to deviancy in the PMN range. Responses to deviants in the P3b range indicated normal letter recognition processes, but the LRP calculation revealed a specific impairment for visual orthographic information during response selection in dyslexia. In a follow-up experiment using an analogous non-lexical task in the same participants, we found no reading-group differences, indicating a degree of specificity to over-learnt visual-phonological binding. Our findings indicate early insensitivity to visual phonological binding in developmental dyslexia, coupled with difficulty selecting the correct orthographic code. PMID- 26973494 TI - Steering Demands Diminish the Early-P3, Late-P3 and RON Components of the Event Related Potential of Task-Irrelevant Environmental Sounds. AB - The current study investigates the demands that steering places on mental resources. Instead of a conventional dual-task paradigm, participants of this study were only required to perform a steering task while task-irrelevant auditory distractor probes (environmental sounds and beep tones) were intermittently presented. The event-related potentials (ERPs), which were generated by these probes, were analyzed for their sensitivity to the steering task's demands. The steering task required participants to counteract unpredictable roll disturbances and difficulty was manipulated either by adjusting the bandwidth of the roll disturbance or by varying the complexity of the control dynamics. A mass univariate analysis revealed that steering selectively diminishes the amplitudes of early P3, late P3, and the re orientation negativity (RON) to task-irrelevant environmental sounds but not to beep tones. Our findings are in line with a three-stage distraction model, which interprets these ERPs to reflect the post-sensory detection of the task irrelevant stimulus, engagement, and re-orientation back to the steering task. This interpretation is consistent with our manipulations for steering difficulty. More participants showed diminished amplitudes for these ERPs in the "hard" steering condition relative to the "easy" condition. To sum up, the current work identifies the spatiotemporal ERP components of task-irrelevant auditory probes that are sensitive to steering demands on mental resources. This provides a non intrusive method for evaluating mental workload in novel steering environments. PMID- 26973495 TI - Psychosocial Modulators of Motor Learning in Parkinson's Disease. AB - Using the remarkable overlap between brain circuits affected in Parkinson's disease (PD) and those underlying motor sequence learning, we may improve the effectiveness of motor rehabilitation interventions by identifying motor learning facilitators in PD. For instance, additional sensory stimulation and task cueing enhanced motor learning in people with PD, whereas exercising using musical rhythms or console computer games improved gait and balance, and reduced some motor symptoms, in addition to increasing task enjoyment. Yet, despite these advances, important knowledge gaps remain. Most studies investigating motor learning in PD used laboratory-specific tasks and equipment, with little resemblance to real life situations. Thus, it is unknown whether similar results could be achieved in more ecological setups and whether individual's task engagement could further improve motor learning capacity. Moreover, the role of social interaction in motor skill learning process has not yet been investigated in PD and the role of mind-set and self-regulatory mechanisms have been sporadically examined. Here, we review evidence suggesting that these psychosocial factors may be important modulators of motor learning in PD. We propose their incorporation in future research, given that it could lead to development of improved non-pharmacological interventions aimed to preserve or restore motor function in PD. PMID- 26973496 TI - fMRI Adaptation between Action Observation and Action Execution Reveals Cortical Areas with Mirror Neuron Properties in Human BA 44/45. AB - Mirror neurons (MNs) are considered to be the supporting neural mechanism for action understanding. MNs have been identified in monkey's area F5. The identification of MNs in the human homolog of monkeys' area F5 Broadmann Area 44/45 (BA 44/45) has been proven methodologically difficult. Cross-modal functional MRI (fMRI) adaptation studies supporting the existence of MNs restricted their analysis to a priori candidate regions, whereas studies that failed to find evidence used non-object-directed (NDA) actions. We tackled these limitations by using object-directed actions (ODAs) differing only in terms of their object directedness in combination with a cross-modal adaptation paradigm and a whole-brain analysis. Additionally, we tested voxels' blood oxygenation level-dependent (BOLD) response patterns for several properties previously reported as typical MN response properties. Our results revealed 52 voxels in left inferior frontal gyrus (IFG; particularly BA 44/45), which respond to both motor and visual stimulation and exhibit cross-modal adaptation between the execution and observation of the same action. These results demonstrate that part of human IFG, specifically BA 44/45, has BOLD response characteristics very similar to monkey's area F5. PMID- 26973497 TI - Progressive Thinning of Visual Motion Area in Lower Limb Amputees. AB - Accumulating evidence has indicated that amputation or deafferentation of a limb induces functional or structural reorganization in the visual areas. However, the extent of the visual areas involved after lower limb amputation remains uncertain. In this investigation, we studied 48 adult patients with unilateral lower limb amputation and 48 matched healthy controls using T1-weighted magnetic resonance imaging. Template-based regions of interest analysis was implemented to detect the changes of cortical thickness in the specific visual areas. Compared with normal controls, amputees exhibited significantly lower thickness in the V5/middle temporal (V5/MT+) visual area, as well as a trend of cortical thinning in the V3d. There was no significant difference in the other visual areas between the two groups. In addition, no significant difference of cortical thickness was found between patients with amputation at different levels. Across all amputees, correlation analyses revealed that the cortical thickness of the V5/MT+ was negatively correlated to the time since amputation. In conclusion, our findings indicate that the amputation of unilateral lower limb could induce changes in the motor-related visual cortex and provide an update on the plasticity of the human brain after limb injury. PMID- 26973498 TI - A Developmental Perspective in Learning the Mirror-Drawing Task. AB - Is there late maturation of skill learning? This notion has been raised to explain an adult advantage in learning a variety of tasks, such as auditory temporal-interval discrimination, locomotion adaptation, and drawing visually distorted spatial patterns (mirror-drawing, MD). Here, we test this assertion by following the practice of the MD task in two 5 min daily sessions separated by a 10 min break, over the course of 2 days, in 5-6-year-old kindergarten children, 7 8-year-old second-graders, and young adults. In the MD task, participants were required to trace a square while looking at their hand only as a reflection in a mirror. Kindergarteners did not show learning of the visual-motor mapping, and on average, did not produce even one full side of a square correctly. Second-graders showed increased online movement control with longer strokes, and robust learning of the visual-motor mapping, resulting in a between-day increase in the number of correctly drawn sides with no loss in accuracy. Overall, kindergarteners and second-graders producing at least one correct polygon-side on Day 1 were more likely to improve their performance between days. Adults showed better performance with improvements in the number of correctly drawn sides between- and within-days, and in accuracy between days. It has been suggested that 5-year-olds cannot learn the task due to their inability to detect and encapsulate previously produced accurate movements. Our findings suggest, instead, that these children lacked initial, accurate performance that could be enhanced through training. Recently, it has been shown that in a simple grapho-motor task the three age groups improved their speed of performance within a session and between-days, while maintaining accuracy scores. Taken together, these data suggest that children's motor skill learning depends on the task's characteristics and their adopting an efficient and mature performance strategy enabling initial success that can be improved through training. PMID- 26973499 TI - Evaluating Cognitive Action Control Using Eye-Movement Analysis: An Oculomotor Adaptation of the Simon Task. AB - Cognitive action control has been extensively studied using conflict tasks such as the Simon task. In most recent studies, this process has been investigated in the light of the dual route hypothesis and more specifically of the activation suppression model using distributional analyses. Some authors have suggested that cognitive action control assessment is not specific to response modes. In this study we adapted the Simon task, using oculomotor responses instead of manual responses, in order to evaluate whether the resolution of conflict induced by a two-dimensional stimulus yielded similar results to what is usually reported in tasks with manual responses. Results obtained from 43 young healthy participants revealed the typical congruence effect, with longer reaction times (RT) and lesser accuracy in the incongruent condition. Conditional accuracy functions (CAF) also revealed a higher proportion of fast errors in the incongruent condition and delta plots confirmed that conflict resolution was easier, as the time taken to respond increased. These results are very similar to what has been reported in the literature. Furthermore, our observations are in line with the assumptions of the activation-suppression model, in which automatic activation in conflict situations is captured in the fastest responses and selective inhibition of cognitive action control needs time to build up. Altogether, our results suggest that conflict resolution has core mechanisms whatever the response mode, manual or oculomotor. Using oculomotor responses in such tasks could be of interest when investigating cognitive action control in patients with severe motor disorders. PMID- 26973500 TI - A Predictive Coding Perspective on Beta Oscillations during Sentence-Level Language Comprehension. AB - Oscillatory neural dynamics have been steadily receiving more attention as a robust and temporally precise signature of network activity related to language processing. We have recently proposed that oscillatory dynamics in the beta and gamma frequency ranges measured during sentence-level comprehension might be best explained from a predictive coding perspective. Under our proposal we related beta oscillations to both the maintenance/change of the neural network configuration responsible for the construction and representation of sentence level meaning, and to top-down predictions about upcoming linguistic input based on that sentence-level meaning. Here we zoom in on these particular aspects of our proposal, and discuss both old and new supporting evidence. Finally, we present some preliminary magnetoencephalography data from an experiment comparing Dutch subject- and object-relative clauses that was specifically designed to test our predictive coding framework. Initial results support the first of the two suggested roles for beta oscillations in sentence-level language comprehension. PMID- 26973502 TI - Probabilistic Motor Sequence Yields Greater Offline and Less Online Learning than Fixed Sequence. AB - It is well acknowledged that motor sequences can be learned quickly through online learning. Subsequently, the initial acquisition of a motor sequence is boosted or consolidated by offline learning. However, little is known whether offline learning can drive the fast learning of motor sequences (i.e., initial sequence learning in the first training session). To examine offline learning in the fast learning stage, we asked four groups of young adults to perform the serial reaction time (SRT) task with either a fixed or probabilistic sequence and with or without preliminary knowledge (PK) of the presence of a sequence. The sequence and PK were manipulated to emphasize either procedural (probabilistic sequence; no preliminary knowledge (NPK)) or declarative (fixed sequence; with PK) memory that were found to either facilitate or inhibit offline learning. In the SRT task, there were six learning blocks with a 2 min break between each consecutive block. Throughout the session, stimuli followed the same fixed or probabilistic pattern except in Block 5, in which stimuli appeared in a random order. We found that PK facilitated the learning of a fixed sequence, but not a probabilistic sequence. In addition to overall learning measured by the mean reaction time (RT), we examined the progressive changes in RT within and between blocks (i.e., online and offline learning, respectively). It was found that the two groups who performed the fixed sequence, regardless of PK, showed greater online learning than the other two groups who performed the probabilistic sequence. The groups who performed the probabilistic sequence, regardless of PK, did not display online learning, as indicated by a decline in performance within the learning blocks. However, they did demonstrate remarkably greater offline improvement in RT, which suggests that they are learning the probabilistic sequence offline. These results suggest that in the SRT task, the fast acquisition of a motor sequence is driven by concurrent online and offline learning. In addition, as the acquisition of a probabilistic sequence requires greater procedural memory compared to the acquisition of a fixed sequence, our results suggest that offline learning is more likely to take place in a procedural sequence learning task. PMID- 26973501 TI - Cognitive Fatigue Facilitates Procedural Sequence Learning. AB - Enhanced procedural learning has been evidenced in conditions where cognitive control is diminished, including hypnosis, disruption of prefrontal activity and non-optimal time of the day. Another condition depleting the availability of controlled resources is cognitive fatigue (CF). We tested the hypothesis that CF, eventually leading to diminished cognitive control, facilitates procedural sequence learning. In a two-day experiment, 23 young healthy adults were administered a serial reaction time task (SRTT) following the induction of high or low levels of CF, in a counterbalanced order. CF was induced using the Time load Dual-back (TloadDback) paradigm, a dual working memory task that allows tailoring cognitive load levels to the individual's optimal performance capacity. In line with our hypothesis, reaction times (RT) in the SRTT were faster in the high- than in the low-level fatigue condition, and performance improvement was higher for the sequential than the motor components. Altogether, our results suggest a paradoxical, facilitating impact of CF on procedural motor sequence learning. We propose that facilitated learning in the high-level fatigue condition stems from a reduction in the cognitive resources devoted to cognitive control processes that normally oppose automatic procedural acquisition mechanisms. PMID- 26973503 TI - Obtaining Arbitrary Prescribed Mean Field Dynamics for Recurrently Coupled Networks of Type-I Spiking Neurons with Analytically Determined Weights. AB - A fundamental question in computational neuroscience is how to connect a network of spiking neurons to produce desired macroscopic or mean field dynamics. One possible approach is through the Neural Engineering Framework (NEF). The NEF approach requires quantities called decoders which are solved through an optimization problem requiring large matrix inversion. Here, we show how a decoder can be obtained analytically for type I and certain type II firing rates as a function of the heterogeneity of its associated neuron. These decoders generate approximants for functions that converge to the desired function in mean squared error like 1/N, where N is the number of neurons in the network. We refer to these decoders as scale-invariant decoders due to their structure. These decoders generate weights for a network of neurons through the NEF formula for weights. These weights force the spiking network to have arbitrary and prescribed mean field dynamics. The weights generated with scale-invariant decoders all lie on low dimensional hypersurfaces asymptotically. We demonstrate the applicability of these scale-invariant decoders and weight surfaces by constructing networks of spiking theta neurons that replicate the dynamics of various well known dynamical systems such as the neural integrator, Van der Pol system and the Lorenz system. As these decoders are analytically determined and non-unique, the weights are also analytically determined and non-unique. We discuss the implications for measured weights of neuronal networks. PMID- 26973505 TI - Neurocomputational Model of EEG Complexity during Mind Wandering. AB - Mind wandering (MW) can be understood as a transient state in which attention drifts from an external task to internal self-generated thoughts. MW has been associated with the activation of the Default Mode Network (DMN). In addition, it has been shown that the activity of the DMN is anti-correlated with activation in brain networks related to the processing of external events (e.g., Salience network, SN). In this study, we present a mean field model based on weakly coupled Kuramoto oscillators. We simulated the oscillatory activity of the entire brain and explored the role of the interaction between the nodes from the DMN and SN in MW states. External stimulation was added to the network model in two opposite conditions. Stimuli could be presented when oscillators in the SN showed more internal coherence (synchrony) than in the DMN, or, on the contrary, when the coherence in the SN was lower than in the DMN. The resulting phases of the oscillators were analyzed and used to simulate EEG signals. Our results showed that the structural complexity from both simulated and real data was higher when the model was stimulated during periods in which DMN was more coherent than the SN. Overall, our results provided a plausible mechanistic explanation to MW as a state in which high coherence in the DMN partially suppresses the capacity of the system to process external stimuli. PMID- 26973504 TI - Distributed Cerebellar Motor Learning: A Spike-Timing-Dependent Plasticity Model. AB - Deep cerebellar nuclei neurons receive both inhibitory (GABAergic) synaptic currents from Purkinje cells (within the cerebellar cortex) and excitatory (glutamatergic) synaptic currents from mossy fibers. Those two deep cerebellar nucleus inputs are thought to be also adaptive, embedding interesting properties in the framework of accurate movements. We show that distributed spike-timing dependent plasticity mechanisms (STDP) located at different cerebellar sites (parallel fibers to Purkinje cells, mossy fibers to deep cerebellar nucleus cells, and Purkinje cells to deep cerebellar nucleus cells) in close-loop simulations provide an explanation for the complex learning properties of the cerebellum in motor learning. Concretely, we propose a new mechanistic cerebellar spiking model. In this new model, deep cerebellar nuclei embed a dual functionality: deep cerebellar nuclei acting as a gain adaptation mechanism and as a facilitator for the slow memory consolidation at mossy fibers to deep cerebellar nucleus synapses. Equipping the cerebellum with excitatory (e-STDP) and inhibitory (i-STDP) mechanisms at deep cerebellar nuclei afferents allows the accommodation of synaptic memories that were formed at parallel fibers to Purkinje cells synapses and then transferred to mossy fibers to deep cerebellar nucleus synapses. These adaptive mechanisms also contribute to modulate the deep cerebellar-nucleus-output firing rate (output gain modulation toward optimizing its working range). PMID- 26973507 TI - Cerebrospinal Fluid Levels of Amyloid Beta 1-43 in Patients with Amnestic Mild Cognitive Impairment or Early Alzheimer's Disease: A 2-Year Follow-Up Study. AB - INTRODUCTION: Biomarkers that will reliably predict the onset of Alzheimer's disease (AD) are urgently needed. Although cerebrospinal fluid (CSF) amyloid beta 1-42 (Abeta42), total tau, and phosphorylated tau can be used to complement the clinical diagnosis of AD, amnestic mild cognitive impairment (aMCI), the prodromal phase of AD, is heterogeneous. Biomarkers should be able to determine which patients with aMCI are at greatest risk of AD. Histological studies and animal models indicate that amyloid beta 1-43 (Abeta43) aggregates early, and may play a role in the pathological process of AD. We have examined levels of CSF Abeta43 in a 2-year longitudinal study of aMCI and early AD. MATERIALS AND METHODS: Cerebrospinal fluid was collected at baseline, and after one and 2 years from patients with AD (n = 19), and patients with aMCI (n = 42). Of these, 21 progressed to AD during the 2 years of study, whereas 21 did not. Controls (n = 32) were lumbar punctured at baseline only. CSF analyses of Abeta43, Abeta42, and total tau were carried out with ELISA. RESULTS: At baseline, CSF Abeta43, CSF Abeta42 and ratios with total tau could be used to separate controls from all three patient groups. CSF Abeta43, but not Abeta42, could separate patients with aMCI who progressed to AD during the 2 years of follow-up, from those that did not. The CSF total tau/Abeta43 ratio had a slightly but significantly larger area under the receiver operating characteristic curve when compared to the CSF total tau/Abeta42 ratio. CSF Abeta43 levels, but not Abeta42 levels, decreased from baseline to 2 years in the AD group. DISCUSSION AND CONCLUSION: CSF Abeta43 was demonstrated to be significantly reduced in patients already by the time that aMCI or AD was diagnosed, compared to controls, and this change must have occurred during the preclinical period. Since our results suggested that CSF Abeta43 distinguishes between subgroups of patients with aMCI better than CSF Abeta42, it may prove to be a useful additional biomarker for identifying aMCI patients at greatest risk of AD. PMID- 26973508 TI - The Lateralization of Intrinsic Networks in the Aging Brain Implicates the Effects of Cognitive Training. AB - Lateralization of function is an important organization of the human brain. The distribution of intrinsic networks in the resting brain is strongly related to cognitive function, gender and age. In this study, a longitudinal design with 1 year's duration was used to evaluate the cognitive training effects on the lateralization of intrinsic networks among healthy older adults. The subjects were divided into two groups randomly: one with multi-domain cognitive training over 3 months and the other as a wait-list control group. Resting state fMRI data were acquired before training and 1 year after training. We analyzed the functional lateralization in 10 common resting state fMRI networks. We observed statically significant training effects on the lateralization of two important RSNs related to high-level cognition: right- and left- frontoparietal networks (FPNs). The lateralization of the left-FPN was retained especially well in the training group but decreased in the control group. The increased lateralization with aging was observed in the cerebellum network (CereN), in which the lateralization was significantly increased in the control group, although the same change tendency was observed in the training group. These findings indicate that the lateralization of the high-level cognitive intrinsic networks is sensitive to multi-domain cognitive training. This study provides neuroimaging evidence to support the hypothesis that cognitive training should have an advantage in preventing cognitive decline in healthy older adults. PMID- 26973509 TI - Pulse Pressure Magnifies the Effect of COMT Val(158)Met on 15 Years Episodic Memory Trajectories. AB - We investigated whether a physiological marker of cardiovascular health, pulse pressure (PP), and age magnified the effect of the functional COMT Val(158)Met (rs4680) polymorphism on 15-years cognitive trajectories [episodic memory (EM), visuospatial ability, and semantic memory] using data from 1585 non-demented adults from the Betula study. A multiple-group latent growth curve model was specified to gauge individual differences in change, and average trends therein. The allelic variants showed negligible differences across the cognitive markers in average trends. The older portion of the sample selectively age-magnified the effects of Val(158)Met on EM changes, resulting in greater decline in Val compared to homozygote Met carriers. This effect was attenuated by statistical control for PP. Further, PP moderated the effects of COMT on 15-years EM trajectories, resulting in greater decline in Val carriers, even after accounting for the confounding effects of sex, education, cardiovascular diseases (diabetes, stroke, and hypertension), and chronological age, controlled for practice gains. The effect was still present after excluding individuals with a history of cardiovascular diseases. The effects of cognitive change were not moderated by any other covariates. This report underscores the importance of addressing synergistic effects in normal cognitive aging, as the addition thereof may place healthy individuals at greater risk for memory decline. PMID- 26973510 TI - Progranulin Mutations Affects Brain Oscillatory Activity in Fronto-Temporal Dementia. AB - BACKGROUND: Mild cognitive impairment (MCI) is a clinical stage indicating a prodromal phase of dementia. This practical concept could be used also for fronto temporal dementia (FTD). Progranulin (PGRN) has been recently recognized as a useful diagnostic biomarker for fronto-temporal lobe degeneration (FTLD) due to GRN null mutations. Electroencephalography (EEG) is a reliable tool in detecting brain networks changes. The working hypothesis of the present study is that EEG oscillations could detect different modifications among FTLD stages (FTD-MCI versus overt FTD) as well as differences between GRN mutation carriers versus non carriers in patients with overt FTD. MATERIALS AND METHODS: EEG in all patients and PGRN dosage in patients with a clear FTD were detected. The cognitive state has been investigated through mini mental state examination (MMSE). RESULTS: MCI FTD showed a significant lower spectral power in both alpha and theta oscillations as compared to overt FTD. GRN mutations carriers affected by FTLD show an increase in high alpha and decrease in theta oscillations as compared to non-carriers. CONCLUSION: EEG frequency rhythms are sensible to different stage of FTD and could detect changes in brain oscillatory activity affected by GRN mutations. PMID- 26973506 TI - Molecular Machines Regulating the Release Probability of Synaptic Vesicles at the Active Zone. AB - The fusion of synaptic vesicles (SVs) with the plasma membrane of the active zone (AZ) upon arrival of an action potential (AP) at the presynaptic compartment is a tightly regulated probabilistic process crucial for information transfer. The probability of a SV to release its transmitter content in response to an AP, termed release probability (Pr), is highly diverse both at the level of entire synapses and individual SVs at a given synapse. Differences in Pr exist between different types of synapses, between synapses of the same type, synapses originating from the same axon and even between different SV subpopulations within the same presynaptic terminal. The Pr of SVs at the AZ is set by a complex interplay of different presynaptic properties including the availability of release-ready SVs, the location of the SVs relative to the voltage-gated calcium channels (VGCCs) at the AZ, the magnitude of calcium influx upon arrival of the AP, the buffering of calcium ions as well as the identity and sensitivity of the calcium sensor. These properties are not only interconnected, but can also be regulated dynamically to match the requirements of activity patterns mediated by the synapse. Here, we review recent advances in identifying molecules and molecular machines taking part in the determination of vesicular Pr at the AZ. PMID- 26973512 TI - Corrigendum: PGC-1alpha silencing compounds the perturbation of mitochondrial function caused by mutant SOD1 in skeletal muscle of ALS mouse model. AB - [This corrects the article on p. 204 in vol. 7, PMID: 26539112.]. PMID- 26973511 TI - microRNA Profiles in Parkinson's Disease Prefrontal Cortex. AB - OBJECTIVE: The goal of this study was to compare the microRNA (miRNA) profile of Parkinson's disease (PD) frontal cortex with normal control brain, allowing for the identification of PD specific signatures as well as study the disease-related phenotypes of onset age and dementia. METHODS: Small RNA sequence analysis was performed from prefrontal cortex for 29 PD samples and 33 control samples. After sample QC, normalization and batch correction, linear regression was employed to identify miRNAs altered in PD, and a PD classifier was developed using weighted voting class prediction. The relationship of miRNA levels to onset age and PD with dementia (PDD) was also characterized in case-only analyses. RESULTS: One twenty five miRNAs were differentially expressed in PD at a genome-wide level of significance (FDR q < 0.05). A set of 29 miRNAs classified PD from non-diseased brain (93.9% specificity, 96.6% sensitivity). The majority of differentially expressed miRNAs (105/125) showed an ordinal relationship from control, to PD without dementia (PDN), to PDD. Among PD brains, 36 miRNAs classified PDD from PDN (sensitivity = 81.2%, specificity = 88.9%). Among differentially expressed miRNAs, miR-10b-5p had a positive association with onset age (q = 4.7e-2). CONCLUSIONS: Based on cortical miRNA levels, PD brains were accurately classified from non-diseased brains. Additionally, the PDD miRNA profile exhibited a more severe pattern of alteration among those differentially expressed in PD. To evaluate the clinical utility of miRNAs as potential clinical biomarkers, further characterization and testing of brain-related miRNA alterations in peripheral biofluids is warranted. PMID- 26973513 TI - Effects of Omega-3 Fatty Acid Supplementation on Cognitive Functions and Neural Substrates: A Voxel-Based Morphometry Study in Aged Mice. AB - Human and experimental studies have revealed putative neuroprotective and pro cognitive effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) in aging, evidencing positive correlations between peripheral n-3 PUFA levels and regional grey matter (GM) volume, as well as negative correlations between dietary n-3 PUFA levels and cognitive deficits. We recently showed that n-3 PUFA supplemented aged mice exhibit better hippocampal-dependent mnesic functions, along with enhanced cellular plasticity and reduced neurodegeneration, thus supporting a role of n-3 PUFA supplementation in preventing cognitive decline during aging. To corroborate these initial results and develop new evidence on the effects of n-3 PUFA supplementation on brain substrates at macro-scale level, here we expanded behavioral analyses to the emotional domain (anxiety and coping skills), and carried out a fine-grained regional GM volumetric mapping by using high resolution MRI-based voxel-based morphometry. The behavioral effects of 8 week n 3 PUFA supplementation were measured on cognitive (discriminative, spatial and social) and emotional (anxiety and coping) abilities of aged (19 month-old at the onset of study) C57B6/J mice. n-3 PUFA supplemented mice showed better mnesic performances as well as increased active coping skills. Importantly, these effects were associated with enlarged regional hippocampal, retrosplenial and prefrontal GM volumes, and with increased post mortem n-3 PUFA brain levels. These findings indicate that increased dietary n-3 PUFA intake in normal aging can improve fronto-hippocampal GM structure and function, an effect present also when the supplementation starts at late age. Our data are consistent with a protective role of n-3 PUFA supplementation in counteracting cognitive decline, emotional dysfunctions and brain atrophy. PMID- 26973514 TI - Perception and Cognition in the Ageing Brain: A Brief Review of the Short- and Long-Term Links between Perceptual and Cognitive Decline. AB - Ageing is associated with declines in both perception and cognition. We review evidence for an interaction between perceptual and cognitive decline in old age. Impoverished perceptual input can increase the cognitive difficulty of tasks, while changes to cognitive strategies can compensate, to some extent, for impaired perception. While there is strong evidence from cross-sectional studies for a link between sensory acuity and cognitive performance in old age, there is not yet compelling evidence from longitudinal studies to suggest that poor perception causes cognitive decline, nor to demonstrate that correcting sensory impairment can improve cognition in the longer term. Most studies have focused on relatively simple measures of sensory (visual and auditory) acuity, but more complex measures of suprathreshold perceptual processes, such as temporal processing, can show a stronger link with cognition. The reviewed evidence underlines the importance of fully accounting for perceptual deficits when investigating cognitive decline in old age. PMID- 26973515 TI - Identifying Dysfunctional Cortex: Dissociable Effects of Stroke and Aging on Resting State Dynamics in MEG and fMRI. AB - Spontaneous signals in neuroimaging data may provide information on cortical health in disease and aging, but the relative sensitivity of different approaches is unknown. In the present study, we compared different but complementary indicators of neural dynamics in resting-state MEG and BOLD fMRI, and their relationship with blood flow. Participants included patients with post-stroke aphasia, age-matched controls, and young adults. The complexity of brain activity at rest was quantified in MEG using spectral analysis and multiscale entropy (MSE) measures, whereas BOLD variability was quantified as the standard deviation (SDBOLD), mean squared successive difference (MSSD), and sample entropy of the BOLD time series. We sought to assess the utility of signal variability and complexity measures as markers of age-related changes in healthy adults and perilesional dysfunction in chronic stroke. The results indicate that reduced BOLD variability is a robust finding in aging, whereas MEG measures are more sensitive to the cortical abnormalities associated with stroke. Furthermore, reduced complexity of MEG signals in perilesional tissue were correlated with hypoperfusion as assessed with arterial spin labeling (ASL), while no such relationship was apparent with BOLD variability. These findings suggest that MEG signal complexity offers a sensitive index of neural dysfunction in perilesional tissue in chronic stroke, and that these effects are clearly distinguishable from those associated with healthy aging. PMID- 26973518 TI - Response: Commentary: Age-related neurodegenerative disease research needs aging models. PMID- 26973516 TI - Role of the Retromer Complex in Neurodegenerative Diseases. AB - The retromer complex is a protein complex that plays a central role in endosomal trafficking. Retromer dysfunction has been linked to a growing number of neurological disorders. The process of intracellular trafficking and recycling is crucial for maintaining normal intracellular homeostasis, which is partly achieved through the activity of the retromer complex. The retromer complex plays a primary role in sorting endosomal cargo back to the cell surface for reuse, to the trans-Golgi network (TGN), or alternatively to specialized endomembrane compartments, in which the cargo is not subjected to lysosomal-mediated degradation. In most cases, the retromer acts as a core that interacts with associated proteins, including sorting nexin family member 27 (SNX27), members of the vacuolar protein sorting 10 (VPS10) receptor family, the major endosomal actin polymerization-promoting complex known as Wiskott-Aldrich syndrome protein and scar homolog (WASH), and other proteins. Some of the molecules carried by the retromer complex are risk factors for neurodegenerative diseases. Defects such as haplo-insufficiency or mutations in one or several units of the retromer complex lead to various pathologies. Here, we summarize the molecular architecture of the retromer complex and the roles of this system in intracellular trafficking related the pathogenesis of neurodegenerative diseases. PMID- 26973517 TI - The Role of Detraining in Tendon Mechanobiology. AB - INTRODUCTION: Several conditions such as training, aging, estrogen deficiency and drugs could affect the biological and anatomo-physiological characteristics of the tendon. Additionally, recent preclinical and clinical studies examined the effect of detraining on tendon, showing alterations in its structure and morphology and in tenocyte mechanobiology. However, few data evaluated the importance that cessation of training might have on tendon. Basically, we do not fully understand how tendons react to a phase of training followed by sudden detraining. Therefore, within this review, we summarize the studies where tendon detraining was examined. MATERIALS AND METHODS: A descriptive systematic literature review was carried out by searching three databases (PubMed, Scopus and Web of Knowledge) on tendon detraining. Original articles in English from 2000 to 2015 were included. In addition, the search was extended to the reference lists of the selected articles. A public reference manager (www.mendeley.com) was adopted to remove duplicate articles. RESULTS: An initial literature search yielded 134 references (www.pubmed.org: 53; www.scopus.com: 11; www.webofknowledge.com: 70). Fifteen publications were extracted based on the title for further analysis by two independent reviewers. Abstracts and complete articles were after that reviewed to evaluate if they met inclusion criteria. CONCLUSIONS: The revised literature comprised four clinical studies and an in vitro and three in vivo reports. Overall, the results showed that tendon structure and properties after detraining are compromised, with an alteration in the tissue structural organization and mechanical properties. Clinical studies usually showed a lesser extent of tendon alterations, probably because preclinical studies permit an in-depth evaluation of tendon modifications, which is hard to perform in human subjects. In conclusion, after a period of sudden detraining (e.g., after an injury), physical activity should be taken with caution, following a targeted rehabilitation program. However, further research should be performed to fully understand the effect of sudden detraining on tendons. PMID- 26973519 TI - Astrocytes As the Main Players in Primary Degenerative Disorders of the Human Central Nervous System. AB - Along the last years it has been demonstrated that non-neural cells play a major role in the pathogenesis of the primary degenerative disorders (PDDs) of the human central nervous system. Among them, astrocytes coordinate and participate in many different and complex metabolic processes, in close interaction with neurons. Moreover, increasing experimental evidence hints an early astrocytic dysfunction in these diseases. In this mini review we summarize the astrocytic behavior in PDDs, with special consideration to the experimental observations where astrocytic pathology precedes the development of neuronal dysfunction. We also suggest a different approach that could be consider in human investigations in Alzheimer's and Parkinson's disease. We believe that the study of PDDs with human brain samples may hold the key of a paradigmatic physiopathological process in which astrocytes might be the main players. PMID- 26973520 TI - Electrophysiological Advances on Multiple Object Processing in Aging. AB - EEG research conducted in the past 5 years on multiple object processing has begun to define how the aging brain tracks the numerosity of the objects presented in the visual field for different goals. We review the recent EEG findings in healthy older individuals (age range: 65-75 years approximately) on perceptual, attentional and memory mechanisms-reflected in the N1, N2pc and contralateral delayed activity (CDA) components of the EEG, respectively-during the execution of a variety of cognitive tasks requiring simultaneous processing of multiple elements. The findings point to multiple loci of neural changes in multi-object analysis, and suggest the involvement of early perceptual mechanisms, attentive individuation and working memory (WM) operations in the neural and cognitive modification due to aging. However, the findings do not simply reflect early impairments with a cascade effect over subsequent stages of stimulus processing, but in fact highlight interesting dissociations between the effects occurring at the various stages of stimulus processing. Finally, the results on older adults indicate the occurrence of neural overactivation in association to good levels of performance in easy perceptual contexts, thus providing some hints on the existence of compensatory phenomena that are associated with the functioning of early perceptual mechanisms. PMID- 26973521 TI - The New and Old Europe: East-West Split in Pharmaceutical Spending. AB - HIGHLIGHTS Since the geopolitical developments of 1989, former centrally planned economies of Eastern Europe followed distinctively different pathways in national pharmaceutical expenditure evolution as compared to their free market Western European counterparts.Long term spending on pharmaceuticals expressed as percentage of total health expenditure was falling in free market economies as of 1989. Back in early 1990s it was at higher levels in transitional Eastern European countries and actually continued to grow further.Public financing share of total pharmaceutical expenditure was steadily falling in most Central and Eastern European countries over the recent few decades. Opposed scenario were EU 15 countries which successfully increased their public funding of prescription medicines for the sake of their citizens.Pace of annual increase in per capita spending on medicines in PPP terms, was at least 20% faster in Eastern Europe compared to their Western counterparts. During the same years, CEE region was expanding their pharmaceuticals share of health spending in eight fold faster annual rate compared to the EU 15.Private and out-of-pocket expenditure became dominant in former socialist countries. Affordability issues coupled with growing income inequality in transitional economies will present a serious challenge to equitable provision and sustainable financing of pharmaceuticals in the long run. PMID- 26973522 TI - The Elastin Receptor Complex: A Unique Matricellular Receptor with High Anti tumoral Potential. AB - Elastin, one of the longest-lived proteins, confers elasticity to tissues with high mechanical constraints. During aging or pathophysiological conditions such as cancer progression, this insoluble polymer of tropoelastin undergoes an important degradation leading to the release of bioactive elastin-derived peptides (EDPs), named elastokines. EDP exhibit several biological functions able to drive tumor development by regulating cell proliferation, invasion, survival, angiogenesis, and matrix metalloproteinase expression in various tumor and stromal cells. Although, several receptors have been suggested to bind elastokines (alphavbeta3 and alphavbeta5 integrins, galectin-3), their main receptor remains the elastin receptor complex (ERC). This heterotrimer comprises a peripheral subunit, named elastin binding protein (EBP), associated to the protective protein/cathepsin A (PPCA). The latter is bound to a membrane associated protein called Neuraminidase-1 (Neu-1). The pro-tumoral effects of elastokines have been linked to their binding onto EBP. Additionally, Neu-1 sialidase activity is essential for their signal transduction. Consistently, EDP EBP interaction and Neu-1 activity emerge as original anti-tumoral targets. Interestingly, besides its direct involvement in cancer progression, the ERC also regulates diabetes outcome and thrombosis, an important risk factor for cancer development and a vascular process highly increased in patients suffering from cancer. In this review, we will describe ERC and elastokines involvement in cancer development suggesting that this unique receptor would be a promising therapeutic target. We will also discuss the pharmacological concepts aiming at blocking its pro-tumoral activities. Finally, its emerging role in cancer associated complications and pathologies such as diabetes and thrombotic events will be also considered. PMID- 26973523 TI - The Therapeutic Potentials of Ayahuasca: Possible Effects against Various Diseases of Civilization. AB - Ayahuasca is an Amazonian psychoactive brew of two main components. Its active agents are beta-carboline and tryptamine derivatives. As a sacrament, ayahuasca is still a central element of many healing ceremonies in the Amazon Basin and its ritual consumption has become common among the mestizo populations of South America. Ayahuasca use amongst the indigenous people of the Amazon is a form of traditional medicine and cultural psychiatry. During the last two decades, the substance has become increasingly known among both scientists and laymen, and currently its use is spreading all over in the Western world. In the present paper we describe the chief characteristics of ayahuasca, discuss important questions raised about its use, and provide an overview of the scientific research supporting its potential therapeutic benefits. A growing number of studies indicate that the psychotherapeutic potential of ayahuasca is based mostly on the strong serotonergic effects, whereas the sigma-1 receptor (Sig-1R) agonist effect of its active ingredient dimethyltryptamine raises the possibility that the ethnomedical observations on the diversity of treated conditions can be scientifically verified. Moreover, in the right therapeutic or ritual setting with proper preparation and mindset of the user, followed by subsequent integration of the experience, ayahuasca has proven effective in the treatment of substance dependence. This article has two important take-home messages: (1) the therapeutic effects of ayahuasca are best understood from a bio-psycho-socio spiritual model, and (2) on the biological level ayahuasca may act against chronic low grade inflammation and oxidative stress via the Sig-1R which can explain its widespread therapeutic indications. PMID- 26973524 TI - Scaffold Proteins Regulating Extracellular Regulated Kinase Function in Cardiac Hypertrophy and Disease. AB - The mitogen activated protein kinase (MAPK)-extracellular regulated kinase 1/2 (ERK1/2) pathway is a central downstream signaling pathway that is activated in cardiac muscle cells during mechanical and agonist-mediated hypertrophy. Studies in genetic mouse models deficient in ERK-associated MAPK components pathway have further reinforced a direct role for this pathway in stress-induced cardiac hypertrophy and disease. However, more recent studies have highlighted that these signaling pathways may exert their regulatory functions in a more compartmentalized manner in cardiac muscle. Emerging data has uncovered specific MAPK scaffolding proteins that tether MAPK/ERK signaling specifically at the sarcomere and plasma membrane in cardiac muscle and show that deficiencies in these scaffolding proteins alter ERK activity and phosphorylation, which are then critical in altering the cardiac myocyte response to stress-induced hypertrophy and disease progression. In this review, we provide insights on ERK-associated scaffolding proteins regulating cardiac myofilament function and their impact on cardiac hypertrophy and disease. PMID- 26973525 TI - Dietary Geraniol by Oral or Enema Administration Strongly Reduces Dysbiosis and Systemic Inflammation in Dextran Sulfate Sodium-Treated Mice. AB - (Trans)-3,7-Dimethyl-2,6-octadien-1-ol, commonly called geraniol (Ge-OH), is an acyclic monoterpene alcohol with well-known anti-inflammatory, antitumoral, and antimicrobial properties. It is widely used as a preservative in the food industry and as an antimicrobial agent in animal farming. The present study investigated the role of Ge-OH as an anti-inflammatory and anti-dysbiotic agent in the dextran sulfate sodium (DSS)-induced colitis mouse model. Ge-OH was orally administered to C57BL/6 mice at daily doses of 30 and 120 mg kg((-1)) body weight, starting 6 days before DSS treatment and ending the day after DSS removal. Furthermore, Ge-OH 120 mg kg((-1)) dose body weight was administered via enema during the acute phase of colitis to facilitate its on-site action. The results show that orally or enema-administered Ge-OH is a powerful antimicrobial agent able to prevent colitis-associated dysbiosis and decrease the inflammatory systemic profile of colitic mice. As a whole, Ge-OH strongly improved the clinical signs of colitis and significantly reduced cyclooxygenase-2 (COX-2) expression in colonocytes and in the gut wall. Ge-OH could be a powerful drug for the treatment of intestinal inflammation and dysbiosis. PMID- 26973526 TI - Effects of Amiodarone and N-desethylamiodarone on Cardiac Voltage-Gated Sodium Channels. AB - Amiodarone (AMD) is a potent antiarrhythmic drug with high efficacy for treating atrial fibrillation and tachycardia. The pharmacologic profile of AMD is complex. AMD possesses biophysical characteristics of all of class I, II, III, and IV agents. Despite its adverse side effects, AMD remains the most commonly prescribed antiarrhythmic drug. AMD was described to prolong the QT interval and can lead to torsades de pointes. Our goal was to study the effects of AMD on peak and late sodium currents (INa,P and INa,L) and determine whether these effects change as AMD is metabolized into N-desethylamiodarone (DES). We hypothesized that AMD and DES block both INa,P and INa,L with similar profiles due to structural similarities. Given the inherent small amounts of INa,L in NaV1.5, we screened AMD and DES against the Long QT-3-causing mutation, DeltaKPQ, to better detect any drug-mediated effect on INa,L. Our results show that AMD and DES do not affect WT or DeltaKPQ activation; however, both drugs altered the apparent valence of steady-state fast-inactivation. In addition, AMD and DES preferentially block DeltaKPQ peak conductance compared to WT. Both compounds significantly increase INa,L and window currents. We conclude that both compounds have pro-arrhythmic effects on NaV1.5, especially DeltaKPQ; however, DES seems to have a greater pro-arrhythmic effect than AMD. PMID- 26973528 TI - Herba Cistanche (Rou Cong-Rong): One of the Best Pharmaceutical Gifts of Traditional Chinese Medicine. AB - Cistanche species, known as Rou Cong-Rong in Chinese, are an endangered wild species and are mainly distributed in the arid lands and warm deserts of northwestern China. Within Traditional Chinese Medicine (TCM), Herba Cistanche is applied as a tonic and/or in a formula for chronic renal disease, impotence, female infertility, morbid leucorrhea, profuse metrorrhagia, and senile constipation. The chemical constituents of Herba Cistanche mainly consist of volatile oils, non-volatile phenylethanoid glycosides (PhGs), iridoids, lignans, alditols, oligosaccharides, and polysaccharides. There have been an increasing number of studies focusing on its bio-activities, including antioxidation, neuroprotection, and antiaging. The objective of this review is to introduce this herb to the world. Its taxonomy, distribution, and corresponding biological functions and molecular mechanisms are addressed in this review. PMID- 26973527 TI - Early Life Adverse Environmental Exposures Increase the Risk of Uterine Fibroid Development: Role of Epigenetic Regulation. AB - Uterine Fibroids [UF(s), AKA: leiomyoma] are the most important benign neoplastic threat to women's health. They are the most common cause of hysterectomy imposing untold personal consequences and 100s of billions of healthcare dollars, worldwide. Currently, there is no long term effective FDA-approved medical treatment available, and surgery is the mainstay. The etiology of UFs is not fully understood. In this regard, we and others have recently reported that somatic mutations in the gene encoding the transcriptional mediator subunit Med12 are found to occur at a high frequency (~85%) in UFs. UFs likely originate when a Med12 mutation occurs in a myometrial stem cell converting it into a tumor forming stem cell leading to a clonal fibroid lesion. Although the molecular attributes underlying the mechanistic formation of UFs is largely unknown, a growing body of literature implicates unfavorable early life environmental exposures as potentially important contributors. Early life exposure to EDCs during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in life. Neonatal exposure to the EDCs such as diethylstilbestrol (DES) and genistein during reproductive tract development has been shown to increase the incidence, multiplicity and overall size of UFs in the Eker rat model, concomitantly reprogramming estrogen responsive gene expression. Importantly, EDC exposure represses enhancer of zeste 2 (EZH2) and reduces levels of histone 3 lysine 27 trimethylation (H3K27me3) repressive mark through Estrogen receptor/Phosphatidylinositide 3-kinases/Protein kinase B non-genomic signaling in the developing uterus. Considering the fact that distinct Mediator Complex Subunit 12 (Med12) mutations are detected in different fibroid lesions in the same uterus, the emergence of each Med12 mutation is likely an independent event in an altered myometrial stem cell. It is therefore possible that a chronic reduction in DNA repair capacity eventually causes the emergence of mutations such as Med12 in myometrial stem cells converting them into fibroid tumor-forming stem cells, and thereby leads to the development of UFs. Advancing our understanding of the mechanistic role epigenetic regulation of stem cells plays in mediating risk and tumorigenesis will help in pointing the way toward the development of novel therapeutic options. PMID- 26973529 TI - A Guide for Pain Management in Low and Middle Income Communities. Managing the Risk of Opioid Abuse in Patients with Cancer Pain. AB - Most patients who present with cancer have advanced disease and often suffer moderate to severe pain. Opioid therapy can be safe and effective for use in cancer patients with pain, but there are rightful concerns about inappropriate opioid use even in the cancer population. Since cancer patients live longer than ever before in history (and survivors may have long exposure times to opioid therapy), opioid misuse among cancer patients is an important topic worthy of deeper investigation. Cancer patients with pain must be evaluated for risk factors for potential opioid misuse and aberrant drug-taking behaviors assessed. A variety of validated screening tools should be used. Of particular importance is the fact that pain in cancer patients changes frequently, whether it is related to their underlying disease (progression or remission), pain related to treatment (such as painful chemotherapy-induced peripheral neuropathy), and concomitant pain unrelated to cancer (such as osteoarthritis, headache, or back pain). Fortunately, clinicians can use universal precautions to help reduce the risk of opioid misuse while still assuring that cancer patients get the pain therapy they need. Another important new "tool" in this regard is the emergence of abuse-deterrent opioid formulations. PMID- 26973530 TI - Tools for Controlling Activity of Neural Circuits Can Boost Gastrointestinal Research. PMID- 26973532 TI - Rising Background Odor Concentration Reduces Sensitivity of ON and OFF Olfactory Receptor Neurons for Changes in Concentration. AB - The ON and OFF ORNs on cockroach antennae optimize the detection and transfer of information about concentration increments and decrements by providing excitatory responses for both. It follows that the antagonism of the responses facilitates instantaneous evaluations of the odor plume to help the insect make tracking decisions by signaling "higher concentration than background" and "lower concentration than background". Here we analyzed the effect of the background concentration level of the odor of lemon oil on the responses of the ON and OFF ORNs to jumps and drops of that odor, respectively. Raising the background level decreases both the ON-ORN's response to concentration jumps and the OFF-ORN's response to concentration drops. Impulse frequency of the ON ORN is high when the concentration jump is large, but for a given jump, frequency tends to be higher when the background level is low. Conversely, impulse frequency of the OFF cell is high at large concentration drops, but higher still when the background level is low. Analyses of this double dependence revealed that the activity of both types of ORNs is raised more by increasing the change in concentration than by decreasing the background concentration by the same amount. This effect is greater in the OFF ORN than in the ON ORN, indicating a bias for falling concentrations. Given equal change in concentration, concentration drops evoke stronger responses in the OFF ORN than concentrations jumps in the ON ORN. This suggests that the OFF responses are used as alert information for accurately tracking. PMID- 26973531 TI - The Molecular Links of Re-Emerging Therapy: A Review of Evidence of Brahmi (Bacopa monniera). AB - The convolution associated with memory is being resolved with advancement in neuroscience. According to the concurrent assumptions, synaptic plasticity forms one of the basis of memory formation, stabilization and strengthening. In Alzheimer's disease (AD), which is generally characterized by memory dysfunction, connections amongst the cells in the brain are attenuated or lost leading to degeneration of neural networks. Numerous attempts have been made to find new therapies for memory dysfunction with increasing attention and investments being laid on herbal drugs. Many herbal plants and extracts have already documented beneficial results when tested for antiamnesic effects. Brahmi (Bacopa monniera) is one such common herbal drug, which is employed for a long time in the Indian and Chinese medical system in order to treat several disorders. Previous research has shown that Brahmi exerts many pharmacological effects including memory boosting capacity in the treatment of Alzheimer's disease and Schizophrenia, exhibiting antiparkinsonian, antistroke, and anticonvulsant potentials. The present review discusses the chemical constituents of Brahmi along with in vitro and in vivo studies based on the pharmacological effects exerted by it. The efficacy of Brahmi in treating various disorders has evoked sufficient research in recent years and now it is a time to launch multiple clinical trials. PMID- 26973533 TI - Activation of TRPV4 Regulates Respiration through Indirect Activation of Bronchopulmonary Sensory Neurons. AB - Transient receptor potential vanilloid receptor 4 (TRPV4) is a calcium-permeable non-selective cation channel implicated in numerous physiological and pathological functions. This study aimed to investigate the effect of TRPV4 activation on respiration and to explore the potential involvement of bronchopulmonary sensory neurons. Potent TRPV4 agonist GSK1016790A was injected into right atrium in anesthetized spontaneously breathing rats and the changes in breathing were measured. Patch-clamp recording was performed to investigate the effect of GSK1016790A or another TRPV4 activator 4alpha-PDD on cultured rat vagal bronchopulmonary sensory neurons. Immunohistochemistry was carried out to determine the TRPV4-expressing cells in lung slices obtained from TRPV4-EGFP mice. Our results showed, that right-atrial injection of GSK1016790A evoked a slow-developing, long-lasting rapid shallow breathing in anesthetized rats. Activation of TRPV4 also significantly potentiated capsaicin-evoked chemoreflex responses. The alteration in ventilation induced by GSK1016790A was abolished by cutting or perineural capsaicin treatment of both vagi, indicating the involvement of bronchopulmonary afferent neurons. The stimulating and sensitizing effects of GSK1016790A were abolished by a selective TRPV4 antagonist GSK2193874 and also by inhibiting cyclooxygenase with indomethacin. Surprising, GSK1016790A or 4alpha-PDD did not activate isolated bronchopulmonary sensory neurons, nor did they modulate capsaicin-induced inward currents in these neurons. Furthermore, TRPV4 expression was found in alveolar macrophages, alveolar epithelial, and vascular endothelial cells. Collectively, our results suggest that GSK1016790A regulates the respiration through an indirect activation of bronchopulmonary sensory neurons, likely via its stimulation of other TRPV4-expressing cells in the lungs and airways. PMID- 26973534 TI - Single-Unit Muscle Sympathetic Nerve Activity Reflects Sleep Apnea Severity, Especially in Severe Obstructive Sleep Apnea Patients. AB - Obstructive sleep apnea syndrome (OSAS) is associated with augmented sympathetic nerve activity, as assessed by multi-unit muscle sympathetic nerve activity (MSNA). However, it is still unclear whether single-unit MSNA is a better reflection of sleep apnea severity according to the apnea-hypopnea index (AHI). One hundred and two OSAS patients underwent full polysomnography and single- and multi-unit MSNA measurements. Univariate and multivariate regression analysis were performed to determine which parameters correlated with OSAS severity, which was defined by the AHI. Single- and multi-unit MSNA were significantly and positively correlated with AHI severity. The AHI was also significantly correlated with multi-unit MSNA burst frequency (r = 0.437, p < 0.0001) and single-unit MSNA spike frequency (r = 0.632, p < 0.0001). Multivariable analysis revealed that SF was correlated most significantly with AHI (T = 7.27, p < 0.0001). The distributions of multiple single-unit spikes per one cardiac interval did not differ between patients with an AHI of <30 and those with and AHI of 30-55 events/h; however, the pattern of each multiple spike firing were significantly higher in patients with an AHI of >55. These results suggest that sympathetic nerve activity is associated with sleep apnea severity. In addition, single-unit MSNA is a more accurate reflection of sleep apnea severity with alternation of the firing pattern, especially in patients with very severe OSAS. PMID- 26973536 TI - It's All in the Mix: Blend-Specific Behavioral Response to a Sexual Pheromone in a Butterfly. AB - Among insects, sexual pheromones are typically mixtures of two to several components, all of which are generally required to elicit a behavioral response. Here we show for the first time that a complete blend of sexual pheromone components is needed to elicit a response also in a butterfly. Males of the Green veined White, Pieris napi, emit an aphrodisiac pheromone, citral, from wing glands. This pheromone is requisite for females to accept mating with a courting male. Citral is a mixture of the two geometric isomers geranial (E-isomer) and neral (Z-isomer) in an approximate 1:1 ratio. We found that both these compounds are required to elicit acceptance behavior, which indicates synergistic interaction between processing of the isomers. Using functional Ca(2+) imaging we found that geranial and neral evoke significantly different but overlapping glomerular activity patterns in the antennal lobe, which suggests receptors with different affinity for the two isomers. However, these glomeruli were intermingled with glomeruli responding to, for example, plant-related compounds, i.e., no distinct subpopulation of pheromone-responding glomeruli as in moths and other insects. In addition, these glomeruli showed lower specificity than pheromone-activated glomeruli in moths. We could, however, not detect any mixture interactions among four identified glomeruli, indicating that the synergistic effect may be generated at a higher processing level. Furthermore, correlations between glomerular activity patterns evoked by the single isomers and the blend did not change over time. PMID- 26973535 TI - Epidemiology, Etiology, and Treatment of Isolated Cleft Palate. AB - Isolated cleft palate (CPO) is the rarest form of oral clefting. The incidence of CPO varies substantially by geography from 1.3 to 25.3 per 10,000 live births, with the highest rates in British Columbia, Canada and the lowest rates in Nigeria, Africa. Stratified by ethnicity/race, the highest rates of CPO are observed in non-Hispanic Whites and the lowest in Africans; nevertheless, rates of CPO are consistently higher in females compared to males. Approximately fifty percent of cases born with cleft palate occur as part of a known genetic syndrome or with another malformation (e.g., congenital heart defects) and the other half occur as solitary defects, referred to often as non-syndromic clefts. The etiology of CPO is multifactorial involving genetic and environmental risk factors. Several animal models have yielded insight into the molecular pathways responsible for proper closure of the palate, including the BMP, TGF-beta, and SHH signaling pathways. In terms of environmental exposures, only maternal tobacco smoke has been found to be strongly associated with CPO. Some studies have suggested that maternal glucocorticoid exposure may also be important. Clearly, there is a need for larger epidemiologic studies to further investigate both genetic and environmental risk factors and gene-environment interactions. In terms of treatment, there is a need for long-term comprehensive care including surgical, dental and speech pathology. Overall, five main themes emerge as critical in advancing research: (1) monitoring of the occurrence of CPO (capacity building); (2) detailed phenotyping of the severity (biology); (3) understanding of the genetic and environmental risk factors (primary prevention); (4) access to early detection and multidisciplinary treatment (clinical services); and (5) understanding predictors of recurrence and possible interventions among families with a child with CPO (secondary prevention). PMID- 26973537 TI - Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during Adulthood. AB - Intermittent hypoxia is a feature of apnea of prematurity (AOP), chronic lung disease, and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH) during postnatal development (pCIH) causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 h of delivery, pups and their respective dams were exposed to CIH: 90 s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 h per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH), where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH exposed animals caused sternohyoid (but not diaphragm) weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life. PMID- 26973539 TI - Hyperpolarized Renal Magnetic Resonance Imaging: Potential and Pitfalls. AB - The introduction of dissolution dynamic nuclear polarization (d-DNP) technology has enabled a new paradigm for renal imaging investigations. It allows standard magnetic resonance imaging complementary renal metabolic and functional fingerprints within seconds without the use of ionizing radiation. Increasing evidence supports its utility in preclinical research in which the real-time interrogation of metabolic turnover can aid the physiological and pathophysiological metabolic and functional effects in ex vivo and in vivo models. The method has already been translated to humans, although the clinical value of this technology is unknown. In this paper, I review the potential benefits and pitfalls associated with dissolution dynamic nuclear polarization in preclinical research and its translation to renal patients. PMID- 26973538 TI - Detection of a Novel DSPP Mutation by NGS in a Population Isolate in Madagascar. AB - A large family from a small village in Madagascar, Antanetilava, is known to present with colored teeth. Through previous collaboration and 4 successive visits in 1994, 2004, 2005, and 2012, we provided dental care to the inhabitants and diagnosed dentinogenesis imperfecta. Recently, using whole exome sequencing we confirmed the clinical diagnosis by identifying a novel single nucleotide deletion in exon 5 of DSPP. This paper underlines the necessity of long run research, the importance of international and interpersonal collaborations as well as the major contribution of next generation sequencing tools in the genetic diagnosis of rare oro-dental anomalies. This study is registered in ClinicalTrials (https://clinicaltrials.gov) under the number NCT02397824. PMID- 26973540 TI - Entropy Production and the Pressure-Volume Curve of the Lung. AB - We investigate analytically the production of entropy during a breathing cycle in healthy and diseased lungs. First, we calculate entropy production in healthy lungs by applying the laws of thermodynamics to the well-known transpulmonary pressure-volume (P-V) curves of the lung under the assumption that lung tissue behaves as an entropic spring similar to rubber. The bulk modulus, B, of the lung is also derived from these calculations. Second, we extend this approach to elastic recoil disorders of the lung such as occur in pulmonary fibrosis and emphysema. These diseases are characterized by particular alterations in the P-V relationship. For example, in fibrotic lungs B increases monotonically with disease progression, while in emphysema the opposite occurs. These diseases can thus be mimicked simply by making appropriate adjustments to the parameters of the P-V curve. Using Clausius's formalism, we show that entropy production, DeltaS, is related to the hysteresis area, DeltaA, enclosed by the P-V curve during a breathing cycle, namely, DeltaS=DeltaA/T, where T is the body temperature. Although DeltaA is highly dependent on the disease, such formula applies to healthy as well as diseased lungs, regardless of the disease stage. Finally, we use an ansatz to predict analytically the entropy produced by the fibrotic and emphysematous lungs. PMID- 26973541 TI - Titin, a Central Mediator for Hypertrophic Signaling, Exercise-Induced Mechanosignaling and Skeletal Muscle Remodeling. AB - Titin is a giant scaffold protein with multiple functions in striated muscle physiology. Due to the elastic I-band domains and the filament-like integration in the half-sarcomere titin is an important factor for sarcomere assembly and serves as an adaptable molecular spring that determines myofilament distensibility. Protein-interactions e.g., with muscle ankyrin repeat proteins or muscle LIM-protein link titin to hypertrophic signaling and via p62 and Muscle Ring Finger proteins to mechanisms that control protein quality control. This review summarizes our current knowledge on titin as a central node for exercise induced mechanosignaling and remodeling and further highlights the pathophysiological implications. PMID- 26973543 TI - High-Intensity Intermittent Exercise and its Effects on Heart Rate Variability and Subsequent Strength Performance. AB - Prupose: To investigate the effects of a 5-km high-intensity interval exercise (HIIE) on heart rate variability (HRV) and subsequent strength performance. METHODS: Nine trained males performed a control session composed of a half-squat strength exercise (4 * 80% of one repetition maximum-1 RM) in isolation and 30 min, 1-, 4-, 8-, and 24-h after an HIIE (1-min at the velocity peak:1-min passive recovery). All experimental sessions were performed on different days. The maximum number of repetitions (MNR) and total weight lifted (TWL) during the strength exercise were registered in all conditions; in addition, prior to each session, HRV were assessed [beat-to-beat intervals (RR) and log-transformed of root means square of successive differences in the normal-to-normal intervals (lnRMSSD)]. RESULTS: Performance in the strength exercise dropped at 30-min (31%) and 1-h (19%) post-HIIE concomitantly with lower values of RR (781 +/- 79 ms; 799 +/- 134 ms, respectively) in the same recovery intervals compared to the control (1015 +/- 197 ms). Inferential analysis did not detect any effect of condition on lnRMSSD, however, values were lower after 30-min (3.5 +/- 0.4 ms) and 1-h (3.3 +/ 0.5 ms) with moderate and large effect sizes (0.9 and 1.2, respectively) compared with the control condition (3.9 +/- 0.4 ms). CONCLUSION: Both RR and lnRMSSD seem to be associated with deleterious effects on strength performance, although further studies should be conducted to clarify this association. PMID- 26973542 TI - Muscle-Specific Myosin Heavy Chain Shifts in Response to a Long-Term High Fat/High Sugar Diet and Resveratrol Treatment in Nonhuman Primates. AB - Shifts in myosin heavy chain (MHC) expression within skeletal muscle can be induced by a host of stimuli including, but not limited to, physical activity, alterations in neural activity, aging, and diet or obesity. Here, we hypothesized that both age and a long-term (2 year) high fat/high sugar diet (HFS) would induce a slow to fast MHC shift within the plantaris, soleus, and extensor digitorum longus (EDL) muscles from rhesus monkeys. Furthermore, we tested whether supplementation with resveratrol, a naturally occurring compound that has been attributed with augmenting aerobic potential through mitochondrial proliferation, would counteract any diet-induced MHC changes by promoting a fast to slow isoform switch. In general, we found that MHC isoforms were not altered by aging during mid-life. The HFS diet had the largest impact within the soleus muscle where the greatest slow to fast isoform shifts were observed in both mRNA and protein indicators. As expected, long-term resveratrol treatment counteracted, or blunted, these diet-induced shifts within the soleus muscle. The plantaris muscle also demonstrated a fast-to-slow phenotypic response to resveratrol treatment. In conclusion, diet or resveratrol treatment impacts skeletal muscle phenotype in a muscle-specific manner and resveratrol supplementation may be one approach for promoting the fatigue-resistant MHC (type I) isoform especially if its expression is blunted as a result of a long-term high fat/sugar diet. PMID- 26973544 TI - Internet Addiction, Hikikomori Syndrome, and the Prodromal Phase of Psychosis. AB - Computers, video games, and technological devices are part of young people's everyday lives. Hikikomori is a Japanese word describing a condition that mainly affects adolescents or young adults who live isolated from the world, cloistered within their parents' homes, locked in their bedrooms for days, months, or even years on end, and refusing to communicate even with their family. These patients use the Internet profusely, and only venture out to deal with their most imperative bodily needs. Although first described in Japan, cases have been described from around the world. This is the first published report from Canada. The disorder shares characteristics with prodromal psychosis, negative symptoms of schizophrenia, or Internet addiction, which are common differential or comorbid diagnoses. However, certain cases are not accompanied by a mental disorder. Psychotherapy is the treatment of choice although many cases are reluctant to present. The exact place of hikikomori in psychiatric nosology has yet to be determined. We searched Medline up to 12th May, 2015 supplemented by a hand search of the bibliographies of all retrieved articles. We used the following search terms: Hikikomori OR (prolonged AND social AND withdrawal). We found 97 potential papers. Of these 42 were in Japanese, and 1 in Korean. However, many of these were cited by subsequent English language papers that were included in the review. Following scrutiny of the titles and abstracts, 29 were judged to be relevant. Further research is needed to distinguish between primary and secondary hikikomori and establish whether this is a new diagnostic entity, or particular cultural or societal manifestations of established diagnoses. PMID- 26973546 TI - Expression of the Longest RGS4 Splice Variant in the Prefrontal Cortex Is Associated with Single Nucleotide Polymorphisms in Schizophrenia Patients. AB - The Regulator of G protein signaling 4 (RGS4) gene is a candidate susceptibility gene for schizophrenia (SCZ). Previous studies showed that the mRNA level of the longest splice variant RGS4-1 was decreased in the dorsolateral prefrontal cortex (DLPFC) of SCZ patients compared with healthy controls. In this pilot study, we examined the possible mechanisms of RGS4-1 mRNA reduction in SCZ. We genotyped SNP1 (rs10917670), rs2661347, SNP4 (rs951436), SNP7 (rs951439), SNP18 (rs2661319), and rs10799897 (SNP9897) and tested the methylation status of CpG islands of the RGS4 gene in the postmortem DLPFC samples obtained from subjects with SCZ and bipolar disorder as well as healthy controls. RGS4-1 mRNA level was associated with five SNPs (SNP1, rs2661347, SNP4, SNP7, and SNP18) and their haplotypes but not with SNP9897. In addition, this study revealed that RGS4-1 mRNA was low in subjects with specific genotypes of SNP1, rs2661347, SNP4, SNP7, and SNP18. Lower RGS4-1 mRNA expression in the DLPFC of SCZ is associated with SNPs in the 5' regulatory region of the RGS4 gene but not with the methylation status of its CpG islands. PMID- 26973545 TI - DTI and Myelin Plasticity in Bipolar Disorder: Integrating Neuroimaging and Neuropathological Findings. AB - Bipolar disorder (BD) is a major psychiatric illness with a chronic recurrent course, ranked among the worldwide leading disabling diseases. Its pathophysiology is still not completely understood and findings are still inconclusive, though a great interest on the topic has been constantly raised by magnetic resonance imaging, genetic and neuropathological studies. In recent years, diffusion tensor imaging (DTI) investigations have prompted interest in the key role of white matter (WM) abnormalities in BD. In this report, we summarize and comment recent findings from DTI studies in BD, reporting fractional anisotropy as putative measure of WM integrity, as well as recent data from neuropathological studies focusing on oligodendrocyte involvement in WM alterations in BD. DTI research indicates that BD is most commonly associated with a WM disruption within the fronto-limbic network, which may be accompanied by other WM changes spread throughout temporal and parietal regions. Neuropathological studies, mainly focused on the fronto-limbic network, have repeatedly shown a loss in cortical and subcortical oligodendrocyte cell count, although an increased subcortical oligodendrocyte density has been also documented suggesting a putative role in remyelination processes for oligodendrocytes in BD. According to our review, a greater integration between DTI and morphological findings is needed in order to elucidate processes affecting WM, either glial loss or myelin plasticity, on the basis of a more targeted research in BD. PMID- 26973547 TI - The Post-Discharge Network Coordination Programme: A Randomized Controlled Trial to Evaluate the Efficacy of an Intervention Aimed at Reducing Rehospitalizations and Improving Mental Health. AB - PURPOSE: To evaluate the efficacy of a post-discharge intervention for psychiatric inpatients aimed at preventing hospital readmissions and at improving patients' mental health and psychosocial functioning. METHODS: Randomized controlled trial using parallel group block randomization including 151 patients with <=3 hospitalizations within the last 3 years, a GAF score <=60, and aged 18 64 years, assessed at two psychiatric hospitals from the canton of Zurich, Switzerland, between September 2011 and February 2014. Primary outcomes were rate and duration of rehospitalization; secondary outcomes were mental health and functioning. Outcome measures were assessed before discharge from the index hospitalization (t 0), 3 months after discharge when the intervention terminated (t 1), and 12 months after discharge (t 2). Participants received either a brief case management post-discharge intervention or treatment as usual. RESULTS: In the short-term (i.e., t 0-t 1), no significant effect emerged in any outcome. In the long term (i.e., t 0-t 2), the two groups did not differ significantly with respect to the rate and duration of rehospitalization. Also, the intervention did not reduce psychiatric symptoms, did not improve social support, and did not improve quality of life. However, it did slightly increase assessor-rated general (d = 0.30) and social functioning (d = 0.42), although self-reports revealed a deteriorative effect on symptom remission (d = -0.44). CONCLUSION: This psychosocial post-discharge intervention showed no efficacy in the primary outcome of rehospitalization. With respect to secondary outcomes, in the long term it might lead to slightly increased social functioning but revealed no significant effect on psychopathology, social support, and quality of life. By contrast, with respect to self-reported symptom remission, it was revealed to have a negative effect. In this high-resource catchment area with comprehensive community psychiatric and social services, the intervention thus cannot be recommended for implementation in routine care. PMID- 26973548 TI - Examining the Relationship Between Schizotypy and Self-Reported Visual Imagery Vividness in Grapheme-Color Synaesthesia. AB - Synaesthesia is a condition in which one property of a stimulus triggers a secondary experience not typically associated with the first (e.g., seeing achromatic graphemes can evoke the perception of color). Recent work has explored a variety of cognitive and perceptual traits associated with synaesthesia. One example is in the domain of personality, where higher rates of positive schizotypy and openness to experience and lower agreeableness have been reported in synaesthetes who experience color as their evoked sensation relative to typical adult controls. Additionally, grapheme-color synaesthetes have previously been reported to show elevated mental imagery compared to typical adults. Here, we aimed to further elucidate the relationship between personality, synaesthesia, and other cognitive traits. In Study 1, we examined self-reported schizotypy and self-reported visual imagery vividness in grapheme-color synaesthetes and typical adults. Our results partially replicated previous findings by showing that synaesthesia was associated with greater positive schizotypy and enhanced self reported imagery vividness. The results also extend previous reports by demonstrating that differences in positive schizotypy and mental imagery vividness are not related in grapheme-color synaesthesia. In Study 2, we sought to build on prior work showing lower agreeableness and increased openness to experience in synaesthetes by examining whether grapheme-color synaesthesia is associated with other conceptually related traits; namely lower self-monitoring and increased sensation seeking. We did not find any differences between synaesthetes and controls on either of these traits. These findings are discussed in relation to potential factors that may contribute to the observed personality profile in grapheme-color synaesthesia. PMID- 26973549 TI - Insightful Imagery is Related to Working Memory Updating. AB - Available body of evidence concerning the relationship between insight problem solving and working memory (WM) is ambiguous. Several authors propose that restructuring of the problem representation requires controlled search processes, which needs planning and involvement of WM. Other researchers suggest that the restructuring is achieved through the automatic spread of activation in long-term memory, assigning a limited role to WM capacity. In the present study we examined the correlations between insight problem solving performance and measures of WM updating function (n-back task), including general intelligence (as measured by Raven's Advanced Progressive Matrices). The results revealed that updating function shared up to 30% of variance with the insight problem task performance, even when the influence of general mental ability was controlled for. These results suggest that insight problem solving is constrained by individual ability to update the content of WM. PMID- 26973550 TI - Age and Employee Green Behaviors: A Meta-Analysis. AB - Recent economic and societal developments have led to an increasing emphasis on organizational environmental performance. At the same time, demographic trends are resulting in increasingly aging labor forces in many industrialized nations. Commonly held stereotypes suggest that older workers are less likely to be environmentally responsible than younger workers. To evaluate the degree to which such age differences are present, we meta-analyzed 132 independent correlations and 336 d-values based on 4676 professional workers from 22 samples in 11 countries. Contrary to popular stereotypes, age showed small positive relationships with pro-environmental behaviors, suggesting that older adults engaged in these workplace behaviors slightly more frequently. Relationships with age appeared to be linear for overall, Conserving, Avoiding Harm, and Taking Initiative pro-environmental behaviors, but non-linear trends were observed for Transforming and Influencing Others behaviors. PMID- 26973552 TI - Semantic Relations Cause Interference in Spoken Language Comprehension When Using Repeated Definite References, Not Pronouns. AB - The choice and processing of referential expressions depend on the referents' status within the discourse, such that pronouns are generally preferred over full repetitive references when the referent is salient. Here we report two visual world experiments showing that: (1) in spoken language comprehension, this preference is reflected in delayed fixations to referents mentioned after repeated definite references compared with after pronouns; (2) repeated references are processed differently than new references; (3) long-term semantic memory representations affect the processing of pronouns and repeated names differently. Overall, these results support the role of semantic discourse representation in referential processing and reveal important details about how pronouns and full repeated references are processed in the context of these representations. The results suggest the need for modifications to current theoretical accounts of reference processing such as Discourse Prominence Theory and the Informational Load Hypothesis. PMID- 26973551 TI - Differential Difficulties in Perception of Tashlhiyt Berber Consonant Quantity Contrasts by Native Tashlhiyt Listeners vs. Berber-Naive French Listeners. AB - In a discrimination experiment on several Tashlhiyt Berber singleton-geminate contrasts, we find that French listeners encounter substantial difficulty compared to native speakers. Native listeners of Tashlhiyt perform near ceiling level on all contrasts. French listeners perform better on final contrasts such as fit-fitt than initial contrasts such as bi-bbi or sir-ssir. That is, French listeners are more sensitive to silent closure duration in word-final voiceless stops than to either voiced murmur or frication duration of fully voiced stops or voiceless fricatives in word-initial position. We propose, tentatively, that native speakers of French, a language in which gemination is usually not considered to be phonemic, have not acquired quantity contrasts but yet exhibit a presumably universal sensitivity to rhythm, whereby listeners are able to perceive and compare the relative temporal distance between beats given by successive salient phonetic events such as a sequence of vowel nuclei. PMID- 26973553 TI - Faces with Light Makeup Are Better Recognized than Faces with Heavy Makeup. AB - Many women wear facial makeup to accentuate their appeal and attractiveness. Makeup may vary from natural (light) to glamorous (heavy), depending of the context of interpersonal situations, an emphasis on femininity, and current societal makeup trends. This study examined how light makeup and heavy makeup influenced attractiveness ratings and facial recognition. In a rating task, 38 Japanese women assigned attractiveness ratings to 36 Japanese female faces with no makeup, light makeup, and heavy makeup (12 each). In a subsequent recognition task, the participants were presented with 36 old and 36 new faces. Results indicated that attractiveness was rated highest for the light makeup faces and lowest for the no makeup faces. In contrast, recognition performance was higher for the no makeup and light make up faces than for the heavy makeup faces. Faces with heavy makeup produced a higher rate of false recognition than did other faces, possibly because heavy makeup creates an impression of the style of makeup itself, rather than the individual wearing the makeup. The present study suggests that light makeup is preferable to heavy makeup in that light makeup does not interfere with individual recognition and gives beholders positive impressions. PMID- 26973555 TI - Perceived Mortality and Perceived Morality: Perceptions of Value-Orientation Are More Likely When a Decision Is Preceded by a Mortality Reminder. AB - The questions addressed in this paper are whether and how reported mortality reminders can function as an indication of sincerity when communicating ambiguously motivated decisions. In two experiments, participants were exposed to a fictitious CEO who announced a decision to implement new organizational measures that were both environmentally and financially beneficial. In the experimental condition, the CEO attributed her new ideas to a recent mortality reminder. In the active control condition, the CEO attributed her decision to a non-lethal dentistry health scare, and in the passive control condition the CEO did not give any account of events preceding her decision. When a CEO implemented new corporate initiatives after a mortality reminder, her motivation for doing so was perceived as somewhat more motivated by intrinsic values, and significantly less motivated by financial gains. This change in attribution patterns was demonstrated to be indirectly related to a positive evaluation of the CEO, as well as an increased willingness to pay for the organization's services. The second experiment further demonstrated that the reduced attribution to financial motivation associated with mortality awareness persisted even when the CEO in question was known for placing a high personal priority on financial goal attainment. The findings underscore the importance of perceived value-oriented motivation when communicating climate change mitigating policies, and the role of mortality awareness as one of many ways to induce such attributions. PMID- 26973554 TI - To Switch or Not to Switch: Role of Cognitive Control in Working Memory Training in Older Adults. AB - It is currently not known what are the best working memory training strategies to offset the age-related declines in fluid cognitive abilities. In this randomized clinical double-blind trial, older adults were randomly assigned to one of two types of working memory training - one group was trained on a predictable memory updating task (PT) and another group was trained on a novel, unpredictable memory updating task (UT). Unpredictable memory updating, compared to predictable, requires greater demands on cognitive control (Basak and Verhaeghen, 2011a). Therefore, the current study allowed us to evaluate the role of cognitive control in working memory training. All participants were assessed on a set of near and far transfer tasks at three different testing sessions - before training, immediately after the training, and 1.5 months after completing the training. Additionally, individual learning rates for a comparison working memory task (performed by both groups) and the trained task were computed. Training on unpredictable memory updating, compared to predictable, significantly enhanced performance on a measure of episodic memory, immediately after the training. Moreover, individuals with faster learning rates showed greater gains in this episodic memory task and another new working memory task; this effect was specific to UT. We propose that the unpredictable memory updating training, compared to predictable memory updating training, may a better strategy to improve selective cognitive abilities in older adults, and future studies could further investigate the role of cognitive control in working memory training. PMID- 26973556 TI - An Attitude Strength and Self-Perception Framework Regarding the Bi-directional Relationship of Job Satisfaction with Extra-Role and In-Role Behavior: The Doubly Moderating Role of Work Centrality. AB - Studies have identified variables either moderating the extent to which job satisfaction predicts work behavior or moderating the reverse impact of work behavior on job satisfaction. Based on an attitude strength and self-perception framework, we argue that certain variables may moderate both the predictive utility of job satisfaction for work behavior and the impact of work behavior on job satisfaction. Specifically focusing on work centrality, we hold that high work centrality renders job satisfaction a strong job attitude, whereas low work centrality renders job satisfaction a weak job attitude. Hence, the predictive utility of job satisfaction for both extra-role behavior and in-role behavior should be higher the more work is central to employees. In contrast, the influence of extra-role behavior, but not of in-role behavior, on job satisfaction should be higher the less work is central to employees. Results of a two-wave study (N = 176) were in line with these predictions. We discuss further variables that may play a similar role for the bi-directional relationship between job satisfaction and work behavior. PMID- 26973557 TI - The Two Sides of Sensory-Cognitive Interactions: Effects of Age, Hearing Acuity, and Working Memory Span on Sentence Comprehension. AB - Reduced hearing acuity is among the most prevalent of chronic medical conditions among older adults. An experiment is reported in which comprehension of spoken sentences was tested for older adults with good hearing acuity or with a mild-to moderate hearing loss, and young adults with age-normal hearing. Comprehension was measured by participants' ability to determine the agent of an action in sentences that expressed this relation with a syntactically less complex subject relative construction or a syntactically more complex object-relative construction. Agency determination was further challenged by inserting a prepositional phrase into sentences between the person performing an action and the action being performed. As a control, prepositional phrases of equivalent length were also inserted into sentences in a non-disruptive position. Effects on sentence comprehension of age, hearing acuity, prepositional phrase placement and sound level of stimulus presentations appeared only for comprehension of sentences with the more syntactically complex object-relative structures. Working memory as tested by reading span scores accounted for a significant amount of the variance in comprehension accuracy. Once working memory capacity and hearing acuity were taken into account, chronological age among the older adults contributed no further variance to comprehension accuracy. Results are discussed in terms of the positive and negative effects of sensory-cognitive interactions in comprehension of spoken sentences and lend support to a framework in which domain-general executive resources, notably verbal working memory, play a role in both linguistic and perceptual processing. PMID- 26973559 TI - Processing Code-Switching in Algerian Bilinguals: Effects of Language Use and Semantic Expectancy. AB - Using a cross-modal naming paradigm this study investigated the effect of sentence constraint and language use on the expectancy of a language switch during listening comprehension. Sixty-five Algerian bilinguals who habitually code-switch between Algerian Arabic and French (AA-FR) but not between Standard Arabic and French (SA-FR) listened to sentence fragments and named a visually presented French target NP out loud. Participants' speech onset times were recorded. The sentence context was either highly semantically constraining toward the French NP or not. The language of the sentence context was either in Algerian Arabic or in Standard Arabic, but the target NP was always in French, thus creating two code-switching contexts: a typical and recurrent code-switching context (AA-FR) and a non-typical code-switching context (SA-FR). Results revealed a semantic constraint effect indicating that the French switches were easier to process in the high compared to the low-constraint context. In addition, the effect size of semantic constraint was significant in the more typical code-switching context (AA-FR) suggesting that language use influences the processing of switching between languages. The effect of semantic constraint was also modulated by code-switching habits and the proficiency of L2 French. Semantic constraint was reduced in bilinguals who frequently code-switch and in bilinguals with high proficiency in French. Results are discussed with regards to the bilingual interactive activation model (Dijkstra and Van Heuven, 2002) and the control process model of code-switching (Green and Wei, 2014). PMID- 26973558 TI - Cough Is Dangerous: Neural Correlates of Implicit Body Symptoms Associations. AB - The negative interpretation of body sensations (e.g., as sign of a severe illness) is a crucial cognitive process in pathological health anxiety (HA). However, little is known about the nature and the degree of automaticity of this interpretation bias. We applied an implicit association test (IAT) in 20 subjects during functional magnetic resonance imaging (fMRI) to investigate behavioral and neural correlates of implicit attitudes toward symptom words. On the behavioral level, body symptom words elicited strong negative implicit association effects, as indexed by slowed reaction times, when symptom words were paired with the attribute "harmless" (incongruent condition). fMRI revealed increased activation in the dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex for the comparison of incongruent words with control words, as well as with a lower significance threshold also in comparison to congruent words. Moreover, activation in the DLPFC, posterior parietal cortex, nucleus accumbens, and cerebellum varied with individual levels of HA (again, in comparison to control words, as well as with a lower significance threshold also in comparison to congruent words). Slowed reaction times as well as increased activation in dorsolateral prefrontal and posterior parietal cortex point to increased inhibitory demands during the incongruent IAT condition. The positive association between HA severity and neural activity in nucleus accumbens, dorsolateral prefrontal, and posterior parietal cortex suggests that HA is characterized by both intensified negative implicit attitudes and hampered cognitive control mechanisms when confronted with body symptoms. PMID- 26973561 TI - The Influence of Content Meaningfulness on Eye Movements across Tasks: Evidence from Scene Viewing and Reading. AB - The present study investigated the influence of content meaningfulness on eye movement control in reading and scene viewing. Texts and scenes were manipulated to make them uninterpretable, and then eye-movements in reading and scene-viewing were compared to those in pseudo-reading and pseudo-scene viewing. Fixation durations and saccade amplitudes were greater for pseudo-stimuli. The effect of the removal of meaning was seen exclusively in the tail of the fixation duration distribution in both tasks, and the size of this effect was the same across tasks. These findings suggest that eye movements are controlled by a common mechanism in reading and scene viewing. They also indicate that not all eye movements are responsive to the meaningfulness of stimulus content. Implications for models of eye movement control are discussed. PMID- 26973563 TI - Green Positive Guidance and Green Positive Life Counseling for Decent Work and Decent Lives: Some Empirical Results. AB - This article discusses green positive guidance and green positive life counseling for decent work and decent lives. From a green guidance perspective, the connectedness to nature construct is important both in terms of the meaning of work and life construction. The study discussed in this article analyzed the relationship between empathy and connectedness to nature, controlling for the effects of fluid intelligence and personality traits. In this connection, the Advanced Progressive Matrices, the Big Five Questionnaire, and the Interpersonal Reactivity Index were administered to 144 Italian high school students. The study revealed that connecteness to nature was not associated with fluid intelligence and was only moderately associated with personality traits. It was empathy that showed the highest association with connectedness to nature. The results open new opportunities for future research and interventions in green positive guidance/life counseling and green positive decent work. PMID- 26973562 TI - Processing Information about Support Exchanges in Close Relationships: The Role of a Knowledge Structure. AB - People develop knowledge of interpersonal interaction patterns (e.g., prototypes and schemas), which shape how they process incoming information. One such knowledge structure based on attachment theory was examined: the secure base script (the prototypic sequence of events when an attachment figure comforts a close relationship partner in distress). In two studies (N = 53 and N = 119), participants were shown animated film clips in which geometric figures depicted the secure base script and asked to describe the animations. Both studies found that many people readily recognize the secure-base script from these minimal cues quite well, suggesting that this script is not only available in the context of specific relationships (i.e., a relationship-specific knowledge): The generalized (abstract) structure of the script is also readily accessible, which would make it possible to apply it to any relationship (including new relationships). Regression analyses suggested that participants who recognized the script were more likely to (a) include more animation elements when describing the animations, (b) see a common theme in different animations, (c) create better organized stories, and (d) later recall more details of the animations. These findings suggest that access to this knowledge structure helps a person organize and remember relevant incoming information. Furthermore, in both Study 1 and Study 2, individual differences in the ready recognition of the script were associated with individual differences in having access to another related knowledge: indicators suggesting that a potential relationship partner can be trusted to be supportive and responsive at times of stress. Results of Study 2 also suggest that recognizing the script is associated with those items of an attachment measure that concern giving and receiving support. Thus, these knowledge structures may shape how people process support-relevant information in their everyday lives, potentially affecting relationship outcomes and mental and physical health. PMID- 26973560 TI - Touching the Lived Body in Patients with Medically Unexplained Symptoms. How an Integration of Hands-on Bodywork and Body Awareness in Psychotherapy may Help People with Alexithymia. AB - Medically unexplained symptoms (MUS) are a considerable presenting problem in general practice. Alexithymia and difficulties with mental elaboration of bodily arousal are hypothesized as a key mechanism in MUS. In turn, this inability influences the embodied being and participating of these patients in the world, which is coined as 'the lived body' and underlies what is mostly referred to as body awareness (BA). The present article explores a more innovative hypothesis how hands-on bodywork can influence BA and serve as a rationale for a body integrated psychotherapeutic approach of MUS. Research not only shows that BA is a bottom-up 'bodily' affair but is anchored in a interoceptive-insular pathway (IIP) which in turn is deeply connected with autonomic and emotional brain areas as well as verbal and non-verbal memory. Moreover, it is emphasized how skin and myofascial tissues should be seen as an interoceptive generator, if approached in the proper manual way. This article offers supportive evidence explaining why a 'haptic' touch activates this IIP, restores the myofascial armored body, helps patients rebalancing their window of tolerance and facilitates BA by contacting their bodily inner-world. From a trans-disciplinary angle this article reflects on how the integration of bodywork with non-directive verbal guidance can be deeply healing and resourcing for the lived body experience in MUS. In particular for alexithymic patients this approach can be of significance regarding their representational failure of bodily arousal. PMID- 26973564 TI - Autonomic Nervous System Responses During Perception of Masked Speech may Reflect Constructs other than Subjective Listening Effort. AB - Typically, understanding speech seems effortless and automatic. However, a variety of factors may, independently or interactively, make listening more effortful. Physiological measures may help to distinguish between the application of different cognitive mechanisms whose operation is perceived as effortful. In the present study, physiological and behavioral measures associated with task demand were collected along with behavioral measures of performance while participants listened to and repeated sentences. The goal was to measure psychophysiological reactivity associated with three degraded listening conditions, each of which differed in terms of the source of the difficulty (distortion, energetic masking, and informational masking), and therefore were expected to engage different cognitive mechanisms. These conditions were chosen to be matched for overall performance (keywords correct), and were compared to listening to unmasked speech produced by a natural voice. The three degraded conditions were: (1) Unmasked speech produced by a computer speech synthesizer, (2) Speech produced by a natural voice and masked byspeech-shaped noise and (3) Speech produced by a natural voice and masked by two-talker babble. Masked conditions were both presented at a -8 dB signal to noise ratio (SNR), a level shown in previous research to result in comparable levels of performance for these stimuli and maskers. Performance was measured in terms of proportion of key words identified correctly, and task demand or effort was quantified subjectively by self-report. Measures of psychophysiological reactivity included electrodermal (skin conductance) response frequency and amplitude, blood pulse amplitude and pulse rate. Results suggest that the two masked conditions evoked stronger psychophysiological reactivity than did the two unmasked conditions even when behavioral measures of listening performance and listeners' subjective perception of task demand were comparable across the three degraded conditions. PMID- 26973565 TI - What Does It Take for an Infant to Learn How to Use a Tool by Observation? AB - Observational learning is probably one of the most powerful factors determining progress during child development. When learning a new skill, infants rely on their own exploration; but they also frequently benefit from an adult's verbal support or from demonstration by an adult modeling the action. At what age and under what conditions does adult demonstration really help the infant to learn a novel behavior? In this review, we summarize recently published work we have conducted on the acquisition of tool use during the second year of life. In particular, we consider under what conditions and to what extent seeing a demonstration from an adult advances an infant's understanding of how to use a tool to obtain an out-of-reach object. Our results show that classic demonstration starts being helpful at 18 months of age. When adults explicitly show their intention prior to demonstration, even 16-month-old infants learn from the demonstration. On the other hand, providing an explicit demonstration ("look at how I do it") is not very useful before infants are ready to succeed by themselves anyway. In contrast, repeated observations of the required action in a social context, without explicit reference to this action, considerably advances the age of success and the usefulness of providing a demonstration. We also show that the effect of demonstration can be enhanced if the demonstration makes the baby laugh. Taken together, the results from this series of studies on observational learning of tool use in infants suggest, first, that when observing a demonstration, infants do not know what to pay attention to: demonstration must be accompanied by rich social cues to be effective; second, infants' attention is inhibited rather than enhanced by an explicit demand of "look at what I do"; and finally a humorous situation considerably helps infants understand the demonstration. PMID- 26973568 TI - Classification Accuracy of Mixed Format Tests: A Bi-Factor Item Response Theory Approach. AB - Mixed format tests (e.g., a test consisting of multiple-choice [MC] items and constructed response [CR] items) have become increasingly popular. However, the latent structure of item pools consisting of the two formats is still equivocal. Moreover, the implications of this latent structure are unclear: For example, do constructed response items tap reasoning skills that cannot be assessed with multiple choice items? This study explored the dimensionality of mixed format tests by applying bi-factor models to 10 tests of various subjects from the College Board's Advanced Placement (AP) Program and compared the accuracy of scores based on the bi-factor analysis with scores derived from a unidimensional analysis. More importantly, this study focused on a practical and important question-classification accuracy of the overall grade on a mixed format test. Our findings revealed that the degree of multidimensionality resulting from the mixed item format varied from subject to subject, depending on the disattenuated correlation between scores from MC and CR subtests. Moreover, remarkably small decrements in classification accuracy were found for the unidimensional analysis when the disattenuated correlations exceeded 0.90. PMID- 26973566 TI - Representation of Patients' Hand Modulates Fear Reactions of Patients with Spider Phobia in Virtual Reality. AB - Embodiment (i.e., the involvement of a bodily representation) is thought to be relevant in emotional experiences. Virtual reality (VR) is a capable means of activating phobic fear in patients. The representation of the patient's body (e.g., the right hand) in VR enhances immersion and increases presence, but its effect on phobic fear is still unknown. We analyzed the influence of the presentation of the participant's hand in VR on presence and fear responses in 32 women with spider phobia and 32 matched controls. Participants sat in front of a table with an acrylic glass container within reaching distance. During the experiment this setup was concealed by a head-mounted display (HMD). The VR scenario presented via HMD showed the same setup, i.e., a table with an acrylic glass container. Participants were randomly assigned to one of two experimental groups. In one group, fear responses were triggered by fear-relevant visual input in VR (virtual spider in the virtual acrylic glass container), while information about a real but unseen neutral control animal (living snake in the acrylic glass container) was given. The second group received fear-relevant information of the real but unseen situation (living spider in the acrylic glass container), but visual input was kept neutral VR (virtual snake in the virtual acrylic glass container). Participants were instructed to touch the acrylic glass container with their right hand in 20 consecutive trials. Visibility of the hand was varied randomly in a within-subjects design. We found for all participants that visibility of the participant's hand increased presence independently of the fear trigger. However, in patients, the influence of the virtual hand on fear depended on the fear trigger. When fear was triggered perceptually, i.e., by a virtual spider, the virtual hand increased fear. When fear was triggered by information about a real spider, the virtual hand had no effect on fear. Our results shed light on the significance of different fear triggers (visual, conceptual) in interaction with body representations. PMID- 26973567 TI - Adolescent Alcohol Use in Spain: Connections with Friends, School, and Other Delinquent Behaviors. AB - This study examined the connections between adolescent alcohol use in Alicante, Spain and variables reflecting adolescents' academic problems, potentially delinquent behaviors, friends' alcohol consumption, and friendship quality. Information about alcohol use and a number of school and social variables was collected from adolescent students (N = 567) who completed the National Students School-Based Drug Survey in a classroom setting. Results suggested that gender was not significantly associated with alcohol use, although alcohol use increased with age and was more likely for adolescents enrolled in public schools compared to private. After controlling for age and type of school (public vs. private), academic problems explained 5.1% of the variance in adolescents' alcohol use, potentially delinquent behaviors explained 29.0%, friends' alcohol use 16.8%, and friendship quality 1.6%. When all unique predictors from these four models were included in a comprehensive model, they explained 32.3% of the variance in adolescents' alcohol use. In this final model, getting expelled, participating in a fight, going out at night, the hour at which one returns, and the number of friends who have consumed alcohol were uniquely and positively associated with adolescents' alcohol use. These results provide important information about multi system influences on adolescent alcohol use in Alicante, Spain and suggest potential areas of focus for intervention research. PMID- 26973570 TI - Adjusting Potentially Confounded Scoring Protocols for Motivation Aggregation in Organismic Integration Theory: An Exemplification with the Relative Autonomy or Self-Determination Index. PMID- 26973569 TI - Effects of Valence and Origin of Emotions in Word Processing Evidenced by Event Related Potential Correlates in a Lexical Decision Task. AB - This paper presents behavioral and event-related potential (ERP) correlates of emotional word processing during a lexical decision task (LDT). We showed that valence and origin (two distinct affective properties of stimuli) help to account for the ERP correlates of LDT. The origin of emotion is a factor derived from the emotion duality model. This model distinguishes between the automatic and controlled elicitation of emotional states. The subjects' task was to discriminate words from pseudo-words. The stimulus words were carefully selected to differ with respect to valence and origin whilst being matched with respect to arousal, concreteness, length and frequency in natural language. Pseudo-words were matched to words with respect to length. The subjects were 32 individuals aged from 19 to 26 years who were invited to participate in an EEG study of lexical decision making. They evaluated a list of words and pseudo-words. We found that valence modulated the amplitude of the FN400 component (290-375 ms) at centro-frontal (Fz, Cz) region, whereas origin modulated the amplitude of the component in the LPC latency range (375-670 ms). The results indicate that the origin of stimuli should be taken into consideration while deliberating on the processing of emotional words. PMID- 26973571 TI - Competitive Game Play Attenuates Self-Other Integration during Joint Task Performance. AB - Joint task performance is facilitated by sharing and integrating each other's action representations. Research has shown that the amount of this so-called self other integration depends on situational aspects related to the social context, including differences in the social relationship between co-acting individuals. There are indications that a cooperative relationship facilitates self-other integration while a competitive relationship results in more individualistic task performance. However, findings from previous studies in which the cooperative or competitive element was manipulated during task performance are inconsistent. Therefore, the present study aimed to manipulate the social relationship between two individuals prior to performing a social Simon task. This task is frequently used to measure self-other integration and distinction processes. A mixed-within and-between-subjects design was used in which three groups of participants performed both a standard Simon task and a social Simon task after having played a Tetris game either individually, in cooperation with a co-actor, or in competition against another participant. Performance on the standard Simon task was not affected by the Tetris manipulation. However, a sustained effect of the induced cooperative versus competitive relationship was found on the social Simon Task. Less self-other integration was found in participants who had first played a competitive Tetris game compared to participants who had played a cooperative or solo version of the game. The current study thus demonstrates that an established cooperative or competitive relationship is sufficient to modulate the degree of self-other integration on subsequent joint task performance. Importantly, by using Tetris, attention to others' actions was beneficial both during cooperative and competitive game play and can thus not explain the competition-induced reduction of self-other integration. PMID- 26973573 TI - Australian University Students' Coping Strategies and Use of Pharmaceutical Stimulants as Cognitive Enhancers. AB - BACKGROUND: There are reports that some university students are using prescription stimulants for non-medical 'pharmaceutical cognitive enhancement (PCE)' to improve alertness, focus, memory, and mood in an attempt to manage the demands of study at university. Purported demand for PCEs in academic contexts have been based on incomplete understandings of student motivations, and often based on untested assumptions about the context within which stimulants are used. They may represent attempts to cope with biopsychosocial stressors in university life by offsetting students' inadequate coping responses, which in turn may affect their cognitive performance. This study aimed to identify (a) what strategies students adopted to cope with the stress of university life and, (b) to assess whether students who have used stimulants for PCE exhibit particular stress or coping patterns. METHODS: We interviewed 38 university students (with and without PCE experience) about their experience of managing student life, specifically their: educational values; study habits; achievement; stress management; getting assistance; competing activities and demands; health habits; and cognitive enhancement practices. All interview transcripts were coded into themes and analyzed. RESULTS: Our thematic analysis revealed that, generally, self-rated coping ability decreased as students' self-rated stress level increased. Students used emotion- and problem-focused coping for the most part and adjustment-focused coping to a lesser extent. Avoidance, an emotion-focused coping strategy, was the most common, followed by problem-focused coping strategies, the use of cognition on enhancing substances, and planning and monitoring of workload. PCE users predominantly used avoidant emotion-focused coping strategies until they no longer mitigated the distress of approaching deadlines resulting in the use of prescription stimulants as a substance-based problem-focused coping strategy. CONCLUSION: Our study suggests that students who choose coping responses that do not moderate stress where possible, may cause themselves additional distress and avoid learning more effective coping responses. Helping students to understand stress and coping, and develop realistic stress appraisal techniques, may assist students in general to maintain manageable distress levels and functioning. Furthermore, assisting students who may be inclined to use prescription stimulants for cognitive enhancement may reduce possible drug-related harms. PMID- 26973572 TI - Layered Social Network Analysis Reveals Complex Relationships in Kindergarteners. AB - The interplay between individuals forms building blocks for social structure. Here, we examine the structure of behavioral interactions among kindergarten classroom with a hierarchy-neutral approach to examine all possible underlying patterns in the formation of layered networks of "reciprocal" interactions. To understand how these layers are coordinated, we used a layered motif approach. Our dual layered motif analysis can therefore be thought of as the dynamics of smaller groups that tile to create the group structure, or alternatively they provide information on what the average child would do in a given local social environment. When we examine the regulated motifs in layered networks, we find that transitivity is at least partially involved in the formation of these layered network structures. We also found complex combinations of the expected reciprocal interactions. The mechanisms used to understand social networks of kindergarten children here are also applicable on a more general scale to any group of individuals where interactions and identities can be readily observed and scored. PMID- 26973575 TI - Active Learning in Research Methods Classes Is Associated with Higher Knowledge and Confidence, Though not Evaluations or Satisfaction. AB - Research methods and statistics are regarded as difficult subjects to teach, fueling investigations into techniques that increase student engagement. Students enjoy active learning opportunities like hands-on demonstrations, authentic research participation, and working with real data. However, enhanced enjoyment does not always correspond with enhanced learning and performance. In this study, we developed a workshop activity in which students participated in a computer based experiment and used class-generated data to run a range of statistical procedures. To enable evaluation, we developed a parallel, didactic/canned workshop, which was identical to the activity-based version, except that students were told about the experiment and used a pre-existing/canned dataset to perform their analyses. Tutorial groups were randomized to one of the two workshop versions, and 39 students completed a post-workshop evaluation questionnaire. A series of generalized linear mixed models suggested that, compared to the students in the didactic/canned condition, students exposed to the activity-based workshop displayed significantly greater knowledge of the methodological and statistical issues addressed in class, and were more confident about their ability to use this knowledge in the future. However, overall evaluations and satisfaction between the two groups were not reliably different. Implications of these findings and suggestions for future research are discussed. PMID- 26973574 TI - Sex Differences in Music: A Female Advantage at Recognizing Familiar Melodies. AB - Although sex differences have been observed in various cognitive domains, there has been little work examining sex differences in the cognition of music. We tested the prediction that women would be better than men at recognizing familiar melodies, since memories of specific melodies are likely to be learned (at least in part) by declarative memory, which shows female advantages. Participants were 24 men and 24 women, with half musicians and half non-musicians in each group. The two groups were matched on age, education, and various measures of musical training. Participants were presented with well-known and novel melodies, and were asked to indicate their recognition of familiar melodies as rapidly as possible. The women were significantly faster than the men in responding, with a large effect size. The female advantage held across musicians and non-musicians, and across melodies with and without commonly associated lyrics, as evidenced by an absence of interactions between sex and these factors. Additionally, the results did not seem to be explained by sex differences in response biases, or in basic motor processes as tested in a control task. Though caution is warranted given that this is the first study to examine sex differences in familiar melody recognition, the results are consistent with the hypothesis motivating our prediction, namely that declarative memory underlies knowledge about music (particularly about familiar melodies), and that the female advantage at declarative memory may thus lead to female advantages in music cognition (particularly at familiar melody recognition). Additionally, the findings argue against the view that female advantages at tasks involving verbal (or verbalizable) material are due solely to a sex difference specific to the verbal domain. Further, the results may help explain previously reported cognitive commonalities between music and language: since declarative memory also underlies language, such commonalities may be partly due to a common dependence on this memory system. More generally, because declarative memory is well studied at many levels, evidence that music cognition depends on this system may lead to a powerful research program generating a wide range of novel predictions for the neurocognition of music, potentially advancing the field. PMID- 26973576 TI - Serendipity in Relationship: A Tentative Theory of the Cognitive Process of Yuanfen and Its Psychological Constructs in Chinese Cultural Societies. AB - The main purpose of this article is to combine three important themes in Chinese cultural societies: serendipity in relationship (yuanfen), relational interactions, and psychological adaptation through self-cultivation. People who live in Chinese cultural societies are deeply affected by relationalism and tend to be very different from their Western counterparts, who adopt individualistic methods when dealing with interpersonal problems. They are highly likely to access the perspective of yuanfen as part of their cultural wisdom to convert negative feelings, awkwardness, or setbacks caused by interpersonal relationship incidents, into a type of cognitive belief that can be used to combat anxiety and actuate coping actions. Based on this, this article proposes the tentative theory of a dialectical model which comprises elements of the philosophies of Daoism, Buddhism and Confucianism, to analyze the cognitive operation process regarding yuanfen and to explain and predict how people in Chinese cultural societies differ from most Western people in terms of psychological adjustment and coping actions when dealing with interpersonal problems. Canonical correlation analysis was used in the empirical study to describe this model and resulted in two statistically significant canonical factor pairs. The hypothesized model has been partially verified. It is hoped that this framework can serve as a pilot perspective for future studies, and at the same time provide the Western academic world with a reference for understanding the concept and substantive effects of serendipity in relationship. Further suggestions for future research direction are offered. PMID- 26973577 TI - Effects of Working Memory Capacity on Metacognitive Monitoring: A Study of Group Differences Using a Listening Span Test. AB - Monitoring is an executive function of working memory that serves to update novel information, focusing attention on task-relevant targets, and eliminating task irrelevant noise. The present research used a verbal working memory task to examine how working memory capacity limits affect monitoring. Participants performed a Japanese listening span test that included maintenance of target words and listening comprehension. On each trial, participants responded to the target word and then immediately estimated confidence in recall performance for that word (metacognitive judgment). The results confirmed significant differences in monitoring accuracy between high and low capacity groups in a multi-task situation. That is, confidence judgments were superior in high vs. low capacity participants in terms of absolute accuracy and discrimination. The present research further investigated how memory load and interference affect underestimation of successful recall. The results indicated that the level of memory load that reduced word recall performance and led to an underconfidence bias varied according to participants' memory capacity. In addition, irrelevant information associated with incorrect true/ false decisions (secondary task) and word recall within the current trial impaired monitoring accuracy in both participant groups. These findings suggest that interference from unsuccessful decisions only influences low, but not high, capacity participants. Therefore, monitoring accuracy, which requires high working memory capacity, improves metacognitive abilities by inhibiting task-irrelevant noise and focusing attention on detecting task-relevant targets or useful retrieval cues, which could improve actual cognitive performance. PMID- 26973578 TI - Post-traumatic Stress Symptoms and Post-traumatic Growth in 223 Childhood Cancer Survivors: Predictive Risk Factors. AB - With modern therapies and supportive care, survival rates of childhood cancer have increased considerably. However, there are long-term psychological sequelae of these treatments that may not manifest until pediatric survivors are into adulthood. The prevalence of post-traumatic stress disorder in young adult survivors of childhood cancer ranges from 6.2 to 22%; associated risk factors are young age at the assessment, female gender, low education level, and some disease related factors. The aim of this study was to investigate, in adolescent and young adult (AYA) survivors of childhood cancer, the incidence and severity of post-traumatic stress symptoms (PTSSs), and to identify the risk factors and the associated post-traumatic growth (PTG) index. Participants were 223 AYA cancer survivors recruited during follow-up visits in the Oncohematology Clinic of the Department of Child and Woman's Health, University of Padua. Data were collected from self-report questionnaires on PTSS incidence, PTG mean score, perceived social support, and medical and socio-demographic factors. Ex-patients' mean age at the assessment was 19.33 years (SD = 3.01, 15-25), 123 males and 100 females, with a mean of years off-therapy of 9.64 (SD = 4.17). Most (52.5%) had survived an hematological disorder and 47.5% a solid tumor when they were aged, on average, 8.02 years (SD = 4.40). The main results indicated a moderate presence of clinical (>=9 symptoms: 9.4%) and sub-clinical PTSS (6-8 symptoms: 11.2%), with the avoidance criterion most often encountered. Re-experience symptoms and PTG mean score were significantly associated (r = 0.24; p = 0.0001). A hierarchical regression model (R (2) = 0.08; F = 1.46; p = 0.05) identified female gender (beta = 0.16; p = 0.05) and less perceived social support (beta = 0.43; p = 0.05) as risk factors to developing PTSS. Another hierarchical regression model assessed the possible predictors of the PTG total score (R (2) = 0.36; F = 9.1; p = 0.0001), with female gender (beta = 0.13; p = 0.04), actual age (beta = 0.52; p = 0.0001), younger age at the diagnosis (beta = -0.3; p = 0.02), and less years off-therapy (beta = -0.58; p = 0.0001) impacting on PTG. PMID- 26973579 TI - Introducing StatHand: A Cross-Platform Mobile Application to Support Students' Statistical Decision Making. AB - Although essential to professional competence in psychology, quantitative research methods are a known area of weakness for many undergraduate psychology students. Students find selecting appropriate statistical tests and procedures for different types of research questions, hypotheses and data types particularly challenging, and these skills are not often practiced in class. Decision trees (a type of graphic organizer) are known to facilitate this decision making process, but extant trees have a number of limitations. Furthermore, emerging research suggests that mobile technologies offer many possibilities for facilitating learning. It is within this context that we have developed StatHand, a free cross platform application designed to support students' statistical decision making. Developed with the support of the Australian Government Office for Learning and Teaching, StatHand guides users through a series of simple, annotated questions to help them identify a statistical test or procedure appropriate to their circumstances. It further offers the guidance necessary to run these tests and procedures, then interpret and report their results. In this Technology Report we will overview the rationale behind StatHand, before describing the feature set of the application. We will then provide guidelines for integrating StatHand into the research methods curriculum, before concluding by outlining our road map for the ongoing development and evaluation of StatHand. PMID- 26973580 TI - The Importance of Isomorphism for Conclusions about Homology: A Bayesian Multilevel Structural Equation Modeling Approach with Ordinal Indicators. AB - We describe a Monte Carlo study examining the impact of assuming item isomorphism (i.e., equivalent construct meaning across levels of analysis) on conclusions about homology (i.e., equivalent structural relations across levels of analysis) under varying degrees of non-isomorphism in the context of ordinal indicator multilevel structural equation models (MSEMs). We focus on the condition where one or more loadings are higher on the between level than on the within level to show that while much past research on homology has ignored the issue of psychometric isomorphism, psychometric isomorphism is in fact critical to valid conclusions about homology. More specifically, when a measurement model with non isomorphic items occupies an exogenous position in a multilevel structural model and the non-isomorphism of these items is not modeled, the within level exogenous latent variance is under-estimated leading to over-estimation of the within level structural coefficient, while the between level exogenous latent variance is overestimated leading to underestimation of the between structural coefficient. When a measurement model with non-isomorphic items occupies an endogenous position in a multilevel structural model and the non-isomorphism of these items is not modeled, the endogenous within level latent variance is under-estimated leading to under-estimation of the within level structural coefficient while the endogenous between level latent variance is over-estimated leading to over estimation of the between level structural coefficient. The innovative aspect of this article is demonstrating that even minor violations of psychometric isomorphism render claims of homology untenable. We also show that posterior predictive p-values for ordinal indicator Bayesian MSEMs are insensitive to violations of isomorphism even when they lead to severely biased within and between level structural parameters. We highlight conditions where poor estimation of even correctly specified models rules out empirical examination of isomorphism and homology without taking precautions, for instance, larger Level-2 sample sizes, or using informative priors. PMID- 26973581 TI - Instructional Design for Accelerated Macrocognitive Expertise in the Baseball Workplace. AB - The goal of accelerating expertise can leave researchers and trainers in human factors, naturalistic decision making, sport science, and expertise studies concerned about seemingly insufficient application of expert performance theories, findings and methods for training macrocognitive aspects of human performance. Video-occlusion methods perfected by sports expertise researchers have great instructional utility, in some cases offering an effective and inexpensive alternative to high-fidelity simulation. A key problem for instructional designers seems to be that expertise research done in laboratory and field settings doesn't get adequately translated into workplace training. Therefore, this article presents a framework for better linkage of expertise research/training across laboratory, field, and workplace settings. It also uses a case study to trace the development and implementation of a macrocognitive training program in the very challenging workplace of the baseball batters' box. This training, which was embedded for a full season in a college baseball team, targeted the perceptual-cognitive skill of pitch recognition that allows expert batters to circumvent limitations of human reaction time in order to hit a 90 mile-per-hour slider. While baseball batting has few analogous skills outside of sports, the instructional design principles of the training program developed to improve batting have wider applicability and implications. Its core operational principle, supported by information processing models but challenged by ecological models, decouples the perception-action link for targeted part-task training of the perception component, in much the same way that motor components routinely are isolated to leverage instructional efficiencies. After targeted perceptual training, perception and action were recoupled via transfer appropriate tasks inspired by in situ research tasks. Using NCAA published statistics as performance measures, the cooperating team improved from middling performance to first in their conference in Runs Scored and team Batting Average. This case suggests that, beyond the usual considerations of effectiveness and efficiency, there are four challenges to embedded training in the workplace setting -namely: duration, curriculum, limited resources, and buy in. In the case reported here, and potentially in many domains beyond sports, part-task perceptual-cognitive training can improve targeted macrocognitive skills and thereby improve full-skill performance. PMID- 26973583 TI - On the prospect of an experimental account of argumentation. Commentary: Toward an experimental account of argumentation: the case of the slippery slope and the ad hominem arguments. PMID- 26973582 TI - Optimism's Explicative Role for Chronic Diseases. AB - The increasing interest about dispositional optimism's role in health status and its positive modulating effect on health outcomes has led to a remarkable scientific production in the last decade. To date lot is known for which diseases optimism is relevant, instead much less is known about how optimism interacts with other factors, both biological and psychological, in determining health status. The aim of this mini review is to explore the literature derived from clinical and experimental research assessing the associations between dispositional optimism and health status. Dispositional optimism can be considered as facet of personality that is cognitive in nature which holds the global expectation that the future will be plenty of good events. Optimists view desired goals as obtainable, so they often confront adversities in active manners resulting in perseverance and increased goal attainment. Only studies that explicitly included optimism and health outcomes, as measurable variables, and that reported a clear association between them have been reviewed. Cancer, cardiovascular disease, respiratory failure, and aging with multimorbidity were considered. Among the possible explicative hypotheses, two seem to best describe results: optimism may have a direct effect on the neuroendocrine system and on immune responses, and it may have an indirect effect on health outcomes by promoting protective health behaviors, adaptive coping strategies and enhancing positive mood. The research on optimism and health status has already shed light on important mechanisms regarding chronic diseases' management, however, further studies are needed to deepen the knowledge. PMID- 26973584 TI - Listening to the Shepard-Risset Glissando: the Relationship between Emotional Response, Disruption of Equilibrium, and Personality. AB - The endless scale illusion, obtained by cyclically repeating a chromatic scale made up of Shepard tones, has been used in a variety of musical works. Music psychology and neuroscience has been interested in this particular psychoacoustic phenomenon mainly for studying the cognitive processes of pitch perception involved. In the present study, we investigated the emotional states induced by the Shepard-Risset glissando, a variant of the Shepard scale. For this purpose we chose three musical stimuli: a Matlab-generated Shepard Risset glissando, Jean Claude Risset's Computer Suite from Little Boy, which presents a Shepard-Risset glissando integrated in the aesthetic context of a composition, and an ordinary orchestral glissando taken from the opening of Iannis Xenakis's Metastasis. Seventy-three volunteers completed a listening experiment during which they rated their emotional response to these stimuli on a seven-point Likert scale and indicated whether they had experienced a disruption of equilibrium. Personality was also measured with the Five-Factor Model of personality traits. The results show that negative emotions were most strongly evoked during listening to each of the stimuli. We also found that the Shepard-Risset glissando illusion, both within the aesthetic context of a musical composition and on its own, was capable of evoking disruption of equilibrium, frequently leading to the associated feeling of falling. Moreover, generally for the Shepard-Risset glissando illusion, higher negative emotional ratings were given by individuals who had experienced a feeling of disturbance of equilibrium relative to those who had not had this experience. Finally, we found a complex pattern of relationships between personality and the subjective experience of the glissando. Openness to experience correlated positively with positive emotion ratings for the Computer Suite, while agreeableness correlated negatively with positive emotion ratings for the Matlab stimulus. Moreover, results indicated higher (Bonferroni uncorrected) neuroticism for those who experienced an equilibrium disturbance relative to subjects who did not have this experience during listening to the Computer Suite. These findings suggest that musical paradoxes may be of interest not only for the insights they provide on our perceptual system, but also for the richness of the emotional experience elicited during listening. PMID- 26973586 TI - Estimation of the Proportion of Underachieving Students in Compulsory Secondary Education in Spain: An Application of the Rasch Model. AB - There are very few studies in Spain that treat underachievement rigorously, and those that do are typically related to gifted students. The present study examined the proportion of underachieving students using the Rasch measurement model. A sample of 643 first-year high school students (mean age = 12.09; SD = 0.47) from 8 schools in the province of Alicante (Spain) completed the Battery of Differential and General Skills (Badyg), and these students' General Points Average (GPAs) were recovered by teachers. Dichotomous and Partial credit Rasch models were performed. After adjusting the measurement instruments, the individual underachievement index provided a total sample of 181 underachieving students, or 28.14% of the total sample across the ability levels. This study confirms that the Rasch measurement model can accurately estimate the construct validity of both the intelligence test and the academic grades for the calculation of underachieving students. Furthermore, the present study constitutes a pioneer framework for the estimation of the prevalence of underachievement in Spain. PMID- 26973585 TI - Effects of Hearing Loss and Cognitive Load on Speech Recognition with Competing Talkers. AB - Everyday communication frequently comprises situations with more than one talker speaking at a time. These situations are challenging since they pose high attentional and memory demands placing cognitive load on the listener. Hearing impairment additionally exacerbates communication problems under these circumstances. We examined the effects of hearing loss and attention tasks on speech recognition with competing talkers in older adults with and without hearing impairment. We hypothesized that hearing loss would affect word identification, talker separation and word recall and that the difficulties experienced by the hearing impaired listeners would be especially pronounced in a task with high attentional and memory demands. Two listener groups closely matched for their age and neuropsychological profile but differing in hearing acuity were examined regarding their speech recognition with competing talkers in two different tasks. One task required repeating back words from one target talker (1TT) while ignoring the competing talker whereas the other required repeating back words from both talkers (2TT). The competing talkers differed with respect to their voice characteristics. Moreover, sentences either with low or high context were used in order to consider linguistic properties. Compared to their normal hearing peers, listeners with hearing loss revealed limited speech recognition in both tasks. Their difficulties were especially pronounced in the more demanding 2TT task. In order to shed light on the underlying mechanisms, different error sources, namely having misunderstood, confused, or omitted words were investigated. Misunderstanding and omitting words were more frequently observed in the hearing impaired than in the normal hearing listeners. In line with common speech perception models, it is suggested that these effects are related to impaired object formation and taxed working memory capacity (WMC). In a post-hoc analysis, the listeners were further separated with respect to their WMC. It appeared that higher capacity could be used in the sense of a compensatory mechanism with respect to the adverse effects of hearing loss, especially with low context speech. PMID- 26973588 TI - Differential Responses to a Visual Self-Motion Signal in Human Medial Cortical Regions Revealed by Wide-View Stimulation. AB - Vision is important for estimating self-motion, which is thought to involve optic flow processing. Here, we investigated the fMRI response profiles in visual area V6, the precuneus motion area (PcM), and the cingulate sulcus visual area (CSv) three medial brain regions recently shown to be sensitive to optic-flow. We used wide-view stereoscopic stimulation to induce robust self-motion processing. Stimuli included static, randomly moving, and coherently moving dots (simulating forward self-motion). We varied the stimulus size and the presence of stereoscopic information. A combination of univariate and multi-voxel pattern analyses (MVPA) revealed that fMRI responses in the three regions differed from each other. The univariate analysis identified optic-flow selectivity and an effect of stimulus size in V6, PcM, and CSv, among which only CSv showed a significantly lower response to random motion stimuli compared with static conditions. Furthermore, MVPA revealed an optic-flow specific multi-voxel pattern in the PcM and CSv, where the discrimination of coherent motion from both random motion and static conditions showed above-chance prediction accuracy, but that of random motion from static conditions did not. Additionally, while area V6 successfully classified different stimulus sizes regardless of motion pattern, this classification was only partial in PcM and was absent in CSv. This may reflect the known retinotopic representation in V6 and the absence of such clear visuospatial representation in CSv. We also found significant correlations between the strength of subjective self-motion and univariate activation in all examined regions except for primary visual cortex (V1). This neuro-perceptual correlation was significantly higher for V6, PcM, and CSv when compared with V1, and higher for CSv when compared with the visual motion area hMT+. Our convergent results suggest the significant involvement of CSv in self-motion processing, which may give rise to its percept. PMID- 26973589 TI - Beyond Self-Report: Emerging Methods for Capturing Individual Differences in Decision-Making Process. AB - People vary in the way in which they approach decision-making, which impacts real world behavior. There has been a surge of interest in moving beyond reliance on self-report measures to capture such individual differences. Particular emphasis has been placed on devising and applying a range of methodologies that include experimental, neuroscience, and observational paradigms. This paper provides a selective review of recent studies that illustrate the methods and yield of these approaches in terms of generating a deeper understanding of decision-making style and the notable differences that can be found across individuals. PMID- 26973587 TI - Sensorimotor Grounding of Musical Embodiment and the Role of Prediction: A Review. AB - In a previous article, we reviewed empirical evidence demonstrating action-based effects on music perception to substantiate the musical embodiment thesis (Maes et al., 2014). Evidence was largely based on studies demonstrating that music perception automatically engages motor processes, or that body states/movements influence music perception. Here, we argue that more rigorous evidence is needed before any decisive conclusion in favor of a "radical" musical embodiment thesis can be posited. In the current article, we provide a focused review of recent research to collect further evidence for the "radical" embodiment thesis that music perception is a dynamic process firmly rooted in the natural disposition of sounds and the human auditory and motor system. Though, we emphasize that, on top of these natural dispositions, long-term processes operate, rooted in repeated sensorimotor experiences and leading to learning, prediction, and error minimization. This approach sheds new light on the development of musical repertoires, and may refine our understanding of action-based effects on music perception as discussed in our previous article (Maes et al., 2014). Additionally, we discuss two of our recent empirical studies demonstrating that music performance relies on similar principles of sensorimotor dynamics and predictive processing. PMID- 26973590 TI - The Strength Model of Self-Control in Sport and Exercise Psychology. AB - The strength model of self-control assumes that all acts of self-control (e.g., emotion regulation, persistence) are empowered by a single global metaphorical strength that has limited capacity. This strength can become temporarily depleted after a primary self-control act, which, in turn, can impair performance in subsequent acts of self-control. Recently, the assumptions of the strength model of self-control also have been adopted and tested in the field of sport and exercise psychology. The present review paper aims to give an overview of recent developments in self-control research based on the strength model of self control. Furthermore, recent research on interventions on how to improve and revitalize self-control strength will be presented. Finally, the strength model of self-control has been criticized lately, as well as expanded in scope, so the present paper will also discuss alternative explanations of why previous acts of self-control can lead to impaired performance in sport and exercise. PMID- 26973591 TI - Prefrontal Electrical Stimulation in Non-depressed Reduces Levels of Reported Negative Affects from Daily Stressors. AB - Negative emotional responses to the daily life stresses have cumulative effects which, in turn, impose wide-ranging negative constraints on emotional well being and neurocognitive performance (Kalueff and Nutt, 2007; Nadler et al., 2010; Charles et al., 2013). Crucial cognitive functions such as memory and problem solving, as well more short term emotional responses (e.g., anticipation of- and response to- monetary rewards or losses) are influenced by mood. The negative impact of these behavioral responses is felt at the individual level, but it also imposes major economic burden on modern healthcare systems. Although much research has been undertaken to understand the underlying mechanisms of depressed mood and design efficient treatment pathways, comparatively little was done to characterize mood modulations that remain within the boundaries of a healthy mental functioning. In one placebo-controlled experiment, we applied daily prefrontal transcranial Direct Current Stimulation (tDCS) at five points in time, and found reliable improvements on self-reported mood evaluation. Using a new team of experimenters, we replicated this finding in an independent double blinded placebo-controlled experiment and showed that stimulation over a shorter period of time (3 days) is sufficient to create detectable mood improvements. Taken together, our data show that repeated bilateral prefrontal tDCS can reduce psychological distress in non-depressed individuals. PMID- 26973592 TI - Non-24-Hour Sleep-Wake Disorder Revisited - A Case Study. AB - The human sleep-wake cycle is governed by two major factors: a homeostatic hourglass process (process S), which rises linearly during the day, and a circadian process C, which determines the timing of sleep in a ~24-h rhythm in accordance to the external light-dark (LD) cycle. While both individual processes are fairly well characterized, the exact nature of their interaction remains unclear. The circadian rhythm is generated by the suprachiasmatic nucleus ("master clock") of the anterior hypothalamus, through cell-autonomous feedback loops of DNA transcription and translation. While the phase length (tau) of the cycle is relatively stable and genetically determined, the phase of the clock is reset by external stimuli ("zeitgebers"), the most important being the LD cycle. Misalignments of the internal rhythm with the LD cycle can lead to various somatic complaints and to the development of circadian rhythm sleep disorders (CRSD). Non-24-hour sleep-wake disorders (N24HSWD) is a CRSD affecting up to 50% of totally blind patients and characterized by the inability to maintain a stable entrainment of the typically long circadian rhythm (tau > 24.5 h) to the LD cycle. The disease is rare in sighted individuals and the pathophysiology less well understood. Here, we present the case of a 40-year-old sighted male, who developed a misalignment of the internal clock with the external LD cycle following the treatment for Hodgkin's lymphoma (ABVD regimen, four cycles and AVD regimen, four cycles). A thorough clinical assessment, including actigraphy, melatonin profiles and polysomnography led to the diagnosis of non-24-hour sleep wake disorders (N24HSWD) with a free-running rhythm of tau = 25.27 h. A therapeutic intervention with bright light therapy (30 min, 10,000 lux) in the morning and melatonin administration (0.5-0.75 mg) in the evening failed to entrain the free-running rhythm, although a longer treatment duration and more intense therapy might have been successful. The sudden onset and close timely connection led us to hypothesize that the chemotherapy might have caused a mutation of the molecular clock components leading to the observed elongation of the circadian period. PMID- 26973593 TI - Age-Related Neurochemical Changes in the Vestibular Nuclei. AB - There is evidence that the normal aging process is associated with impaired vestibulo-ocular reflexes (VOR) and vestibulo-spinal reflexes, causing reduced visual acuity and postural instability. Nonetheless, the available evidence is not entirely consistent, especially with respect to the VOR. Some recent studies have reported that VOR gain can be intact even above 80 years of age. Similarly, although there is evidence for age-related hair cell loss and neuronal loss in Scarpa's ganglion and the vestibular nucleus complex (VNC), it is not entirely consistent. Whatever structural and functional changes occur in the VNC as a result of aging, either to cause vestibular impairment or to compensate for it, neurochemical changes must underlie them. However, the neurochemical changes that occur in the VNC with aging are poorly understood because the available literature is very limited. This review summarizes and critically evaluates the available evidence relating to the noradrenaline, serotonin, dopamine, glutamate, GABA, glycine, and nitric oxide neurotransmitter systems in the aging VNC. It is concluded that, at present, it is difficult, if not impossible, to relate the neurochemical changes observed to the function of specific VNC neurons and whether the observed changes are the cause of a functional deficit in the VNC or an effect of it. A better understanding of the neurochemical changes that occur during aging may be important for the development of potential drug treatments for age-related vestibular disorders. However, this will require the use of more sophisticated methodology such as in vivo microdialysis with single neuron recording and perhaps new technologies such as optogenetics. PMID- 26973594 TI - Bilateral Vestibular Hypofunction: Insights in Etiologies, Clinical Subtypes, and Diagnostics. AB - OBJECTIVE: To evaluate the different etiologies and clinical subtypes of bilateral vestibular hypofunction (BVH) and the value of diagnostic tools in the diagnostic process of BVH. MATERIALS AND METHODS: A retrospective case review was performed on 154 patients diagnosed with BVH in a tertiary referral center, between 2013 and 2015. Inclusion criteria comprised (1) imbalance and/or oscillopsia during locomotion and (2) summated slow phase velocity of nystagmus of less than 20 degrees /s during bithermal caloric tests. RESULTS: The definite etiology of BVH was determined in 47% of the cases and the probable etiology in 22%. In 31%, the etiology of BVH remained idiopathic. BVH resulted from more than 20 different etiologies. In the idiopathic group, the percentage of migraine was significantly higher compared to the non-idiopathic group (50 versus 11%, p < 0.001). Among all patients, 23.4% were known with autoimmune disorders in their medical history. All four clinical subtypes (recurrent vertigo with BVH, rapidly progressive BVH, slowly progressive BVH, and slowly progressive BVH with ataxia) were found in this population. Slowly progressive BVH with ataxia comprised only 4.5% of the cases. The head impulse test was abnormal in 94% of the cases. The torsion swing test was abnormal in 66%. Bilateral normal hearing to moderate hearing loss was found in 49%. Blood tests did not often contribute to the determination of the etiology of the disease. Abnormal cerebral imaging was found in 21 patients. CONCLUSION: BVH is a heterogeneous condition with various etiologies and clinical characteristics. Migraine seems to play a significant role in idiopathic BVH and autoimmunity could be a modulating factor in the development of BVH. The distribution of etiologies of BVH probably depends on the clinical setting. In the diagnostic process of BVH, the routine use of some blood tests can be reconsidered and a low-threshold use of audiometry and cerebral imaging is advised. The torsion swing test is not the "gold standard" for diagnosing BVH due to its lack of sensitivity. Future diagnostic criteria of BVH should consist of standardized vestibular tests combined with a history that is congruent with the vestibular findings. PMID- 26973595 TI - Kisspeptin Activates Ankrd 26 Gene Expression in Migrating Embryonic GnRH Neurons. AB - Kisspeptin, a newly discovered neuropeptide, regulates gonadotropin-releasing hormone (GnRH). Kisspeptins are a large RF-amide family of peptides. The kisspeptin coded by KiSS-1 gene is a 145-amino acid protein that is cleaved to C terminal peptide kisspeptin-10. G-protein-coupled receptor 54 (GPR54) has been identified as a kisspeptin receptor, and it is expressed in GnRH neurons and in a variety of cancer cells. In this study, enhanced green fluorescent protein (EGFP) labeled GnRH cells with migratory properties, which express GPR54, served as a model to study the effects of kisspeptin on cell migration. We monitored EGFP GnRH neuronal migration in brain slide culture of embryonic day 14 transgenic rat by live cell imaging system and studied the effects of kisspeptin-10 (1 nM) treatment for 36 h on GnRH migration. Furthermore, to determine kisspeptin induced molecular pathways related with apoptosis and cytoskeletal changes during neuronal migration, we studied the expression levels of candidate genes in laser captured EGFP-GnRH neurons by real-time PCR. We found that there was no change in the expression level of genes related to cell proliferation and apoptosis. The expression of ankyrin repeat domain-containing protein (ankrd) 26 in EGFP-GnRH neurons was upregulated by the exposure to kisspeptin. These studies suggest that ankrd 26 gene plays an unidentified role in regulating neuronal movement mediated by kisspeptin-GPR54 signaling, which could be a potential pathway to suppress cell migration. PMID- 26973597 TI - Accuracy of a Rapid and Non-Invasive Method for the Assessment of Small Fiber Neuropathy Based on Measurement of Electrochemical Skin Conductances. PMID- 26973598 TI - Browning and Graying: Novel Transcriptional Regulators of Brown and Beige Fat Tissues and Aging. AB - Obesity represents a major risk factor for the development of a number of metabolic disorders, including cardiovascular disease and type 2 diabetes. Since the discovery that brown and beige fat cells exist in adult humans and contribute to energy expenditure, increasing interest has been devoted to the understanding of the molecular switches turning on calorie utilization. It has been reported that the ability of thermogenic tissues to burn energy declines during aging, possibly contributing to the development of metabolic dysfunction late in life. This review will focus on the recently identified transcriptional modulators of brown and beige cells and will discuss the potential impact of some of these thermogenic factors on age-associated metabolic disorders. PMID- 26973596 TI - Signaling Interactions in the Adrenal Cortex. AB - The major physiological stimuli of aldosterone secretion are angiotensin II (AII) and extracellular K(+), whereas cortisol production is primarily regulated by corticotropin (ACTH) in fasciculata cells. AII triggers Ca(2+) release from internal stores that is followed by store-operated and voltage-dependent Ca(2+) entry, whereas K(+)-evoked depolarization activates voltage-dependent Ca(2+) channels. ACTH acts primarily through the formation of cAMP and subsequent protein phosphorylation by protein kinase A. Both Ca(2+) and cAMP facilitate the transfer of cholesterol to mitochondrial inner membrane. The cytosolic Ca(2+) signal is transferred into the mitochondrial matrix and enhances pyridine nucleotide reduction. Increased formation of NADH results in increased ATP production, whereas that of NADPH supports steroid production. In reality, the control of adrenocortical function is a lot more sophisticated with second messengers crosstalking and mutually modifying each other's pathways. Cytosolic Ca(2+) and cGMP are both capable of modifying cAMP metabolism, while cAMP may enhance Ca(2+) release and voltage-activated Ca(2+) channel activity. Besides, mitochondrial Ca(2+) signal brings about cAMP formation within the organelle and this further enhances aldosterone production. Maintained aldosterone and cortisol secretion are optimized by the concurrent actions of Ca(2+) and cAMP, as exemplified by the apparent synergism of Ca(2+) influx (inducing cAMP formation) and Ca(2+) release during response to AII. Thus, cross-actions of parallel signal transducing pathways are not mere intracellular curiosities but rather substantial phenomena, which fine-tune the biological response. Our review focuses on these functionally relevant interactions between the Ca(2+) and the cyclic nucleotide signal transducing pathways hitherto described in the adrenal cortex. PMID- 26973599 TI - Cancer Stem Cells in the Thyroid. AB - The cancer stem cell (CSC) model posits that CSCs are a small, biologically distinct subpopulation of cancer cells in each tumor that have self-renewal and multi-lineage potential, and are critical for cancer initiation, metastasis, recurrence, and therapy-resistance. Numerous studies have linked CSCs to thyroid biology, but the candidate markers and signal transduction pathways that drive thyroid CSC growth are controversial, the origin(s) of thyroid CSCs remain elusive, and it is unclear whether thyroid CSC biology is consistent with the original hierarchical CSC model or the more recent dynamic CSC model. Here, we critically review the thyroid CSC literature with an emphasis on research that confirmed the presence of thyroid CSCs by in vitro sphere formation or in vivo tumor formation assays with dispersed cells from thyroid cancer tissues or bona fide thyroid cancer cell lines. Future perspectives of thyroid CSC research are also discussed. PMID- 26973600 TI - Phylogenetic Analysis and Pathogenicity Assessment of Two Strains of Avian Influenza Virus Subtype H9N2 Isolated from Migratory Birds: High Homology of Internal Genes with Human H10N8 Virus. AB - Two human-infecting avian influenza viruses (AIVs), H7N9 and H10N8, have emerged in China, which further indicate that the H9N2 subtype of AIVs, as an internal gene donor, may have an important role in the generation of new viruses with cross-species transmissibility and pathogenicity. H9N2 viruses that contain such internal genes widely exist in poultry but are rarely reported in migratory birds. In this study, two strains of the H9N2 virus were isolated from fecal samples of migratory birds in 2014: one strain from Caizi Lake in Anhui Province and one from Chen Lake in Hubei Province of China. Nucleotide sequence analysis revealed high homology of all six internal genes of these two strains with the internal genes of the human H10N8 virus in Jiangxi Province, as well as with the human H7N9 virus. Phylogenetic analysis indicated a possible origin of these two strains from poultry in South China. Both of the two viruses tested could replicated in respiratory organs of infective mice without adaption, by both strains of the H9N2 AIVs from wild birds, suggesting their potential capacity for directly infecting mammals. Our findings indicate the existence of H9N2 viruses that contain internal genes highly homologous with human H10N8 or H7N9 viruses. Wild birds can contribute to the spread of the H9N2 virus that contains the "harmful" internal gene complex, leading to gene rearrangement with other influenza viruses and to the generation of new pathogenic viruses. Therefore, strengthening AIV surveillance in wild birds can promote an understanding of the presence and prevalence of viruses and provide scientific evidence for the prevention and control of AIVs and human-infecting AIVs. PMID- 26973601 TI - Coral-Associated Actinobacteria: Diversity, Abundance, and Biotechnological Potentials. AB - Marine Actinobacteria, particularly coral-associated Actinobacteria, have attracted attention recently. In this study, the abundance and diversity of Actinobacteria associated with three types of coral thriving in a thermally stressed coral reef system north of the Arabian Gulf were investigated. Coscinaraea columna, Platygyra daedalea and Porites harrisoni have been found to harbor equivalent numbers of culturable Actinobacteria in their tissues but not in their mucus. However, different culturable actinobacterial communities have been found to be associated with different coral hosts. Differences in the abundance and diversity of Actinobacteria were detected between the mucus and tissue of the same coral host. In addition, temporal and spatial variations in the abundance and diversity of the cultivable actinobacterial communities were detected. In total, 19 different actinobacterial genera, namely Micrococcus, Brachybacterium, Brevibacterium, Streptomyces, Micromonospora, Renibacterium, Nocardia, Microbacterium, Dietzia, Cellulomonas, Ornithinimicrobium, Rhodococcus, Agrococcus, Kineococcus, Dermacoccus, Devriesea, Kocuria, Marmoricola, and Arthrobacter, were isolated from the coral tissue and mucus samples. Furthermore, 82 isolates related to Micromonospora, Brachybacterium, Nocardia, Micrococcus, Arthrobacter, Rhodococcus, and Streptomyces showed antimicrobial activities against representative Gram-positive and/or Gram-negative bacteria. Even though Brevibacterium and Kocuria were the most dominant actinobacterial isolates, they failed to show any antimicrobial activity, whereas less dominant genera, such as Streptomyces, did show antimicrobial activity. Focusing on the diversity of coral associated Actinobacteria may help to understand how corals thrive under harsh environmental conditions and may lead to the discovery of novel antimicrobial metabolites with potential biotechnological applications. PMID- 26973602 TI - Geochemistry and Mixing Drive the Spatial Distribution of Free-Living Archaea and Bacteria in Yellowstone Lake. AB - Yellowstone Lake, the largest subalpine lake in the United States, harbors great novelty and diversity of Bacteria and Archaea. Size-fractionated water samples (0.1-0.8, 0.8-3.0, and 3.0-20 MUm) were collected from surface photic zone, deep mixing zone, and vent fluids at different locations in the lake by using a remotely operated vehicle (ROV). Quantification with real-time PCR indicated that Bacteria dominated free-living microorganisms with Bacteria/Archaea ratios ranging from 4037:1 (surface water) to 25:1 (vent water). Microbial population structures (both Bacteria and Archaea) were assessed using 454-FLX sequencing with a total of 662,302 pyrosequencing reads for V1 and V2 regions of 16S rRNA genes. Non-metric multidimensional scaling (NMDS) analyses indicated that strong spatial distribution patterns existed from surface to deep vents for free-living Archaea and Bacteria in the lake. Along with pH, major vent-associated geochemical constituents including CH4, CO2, H2, DIC (dissolved inorganic carbon), DOC (dissolved organic carbon), SO4 (2-), O2 and metals were likely the major drivers for microbial population structures, however, mixing events occurring in the lake also impacted the distribution patterns. Distinct Bacteria and Archaea were present among size fractions, and bigger size fractions included particle-associated microbes (> 3 MUm) and contained higher predicted operational taxonomic unit richness and microbial diversities (genus level) than free-living ones (<0.8 MUm). Our study represents the first attempt at addressing the spatial distribution of Bacteria and Archaea in Yellowstone Lake, and our results highlight the variable contribution of Archaea and Bacteria to the hydrogeochemical-relevant metabolism of hydrogen, carbon, nitrogen, and sulfur. PMID- 26973604 TI - Isolation and Characterization of a Novel Cold-Adapted Esterase, MtEst45, from Microbulbifer thermotolerans DAU221. AB - A novel esterase, MtEst45, was isolated from a fosmid genomic library of Microbulbifer thermotolerans DAU221. The encoding gene is predicted to have a mass of 45,564 Da and encodes 495 amino acids, excluding a 21 amino acid signal peptide. MtEst45 showed a low amino acid identity (approximately 23-24%) compared with other lipolytic enzymes belonging to Family III, a closely related bacterial lipolytic enzyme family. MtEst45 also showed a conserved GXSXG motif, G131IS133YG135, which was reported as active site of known lipolytic enzymes, and the putative catalytic triad composed of D237 and H265. Because these mutants of MtEst45, which was S133A, D237N, and H265L, had no activity, these catalytic triad is deemed essential for the enzyme catalysis. MtEst45 was overexpressed in Escherichia coli BL21 (DE3) and purified via His-tag affinity chromatography. The optimal pH and temperature of MtEst45 were estimated to be 8.17 and 46.27 degrees C by response surface methodology, respectively. Additionally, MtEst45 was also active between 1 and 15 degrees C. The optimal hydrolysis substrate for MtEst45 among p-nitrophenyl esters (C2-C18) was p-nitrophenyl butyrate, and the K m and V max values were 0.0998 mM and 550 MUmol/min/mg of protein, respectively. MtEst45 was strongly inhibited by Hg(2+), Zn(2+), and Cu(2+) ions; by phenylmethanesulfonyl fluoride; and by beta-mercaptoethanol. Ca(2+) did not affect the enzyme's activity. These biochemical properties, sequence identity, and phylogenetic analysis suggest that MtEst45 represents a novel and valuable bacterial lipolytic enzyme family and is useful for biotechnological applications. PMID- 26973603 TI - Overwintering of Vineyard Yeasts: Survival of Interacting Yeast Communities in Grapes Mummified on Vines. AB - The conversion of grape must into wine involves the development and succession of yeast populations differing in species composition. The initial population is formed by vineyard strains which are washed into the must from the crushed grapes and then completed with yeasts coming from the cellar environment. As the origin and natural habitat of the vineyard yeasts are not fully understood, this study addresses the possibility, that grape yeasts can be preserved in berries left behind on vines at harvest until the spring of the next year. These berries become mummified during the winter on the vines. To investigate whether yeasts can survive in these overwintering grapes, mummified berries were collected in 16 localities in the Tokaj wine region (Hungary-Slovakia) in early March. The collected berries were rehydrated to recover viable yeasts by plating samples onto agar plates. For the detection of minority species which would not be detected by direct plating, an enrichment step repressing the propagation of alcohol-sensitive yeasts was also included in the process. The morphological, physiological, and molecular analysis identified 13 basidiomycetous and 23 ascomycetous species including fermentative yeasts of wine-making relevance among the 3879 isolates. The presence of viable strains of these species demonstrates that the grapes mummified on the vine can serve as a safe reservoir of yeasts, and may contribute to the maintenance of grape-colonizing yeast populations in the vineyard over years, parallel with other vectors and habitats. All basidiomycetous species were known phylloplane yeasts. Three Hanseniaspora species and pigmented Metschnikowia strains were the most frequent ascomycetes. Other fermentative yeasts of wine-making relevance were detected only in the enrichment cultures. Saccharomyces (S. paradoxus, S. cerevisiae, and S. uvarum) were recovered from 13% of the samples. No Candida zemplinina was found. The isolates with Aureobasidium morphology turned out to belong to Aureobasidium subglaciale, Kabatiella microsticta, or Columnosphaeria fagi. The ascomyceteous isolates grew at high concentrations of sugars with Wickerhamomyces anomalus being the most tolerant species. Complex interactions including antagonism (growth inhibition, contact inhibition, competition for nutrients) and synergism (crossfeeding) among the isolates and with Botrytis cinerea shape the composition of the overwintering communities. PMID- 26973605 TI - Newly Isolated Paenibacillus tyrfis sp. nov., from Malaysian Tropical Peat Swamp Soil with Broad Spectrum Antimicrobial Activity. AB - Emergence of antimicrobial resistance coupled with the slowdown in discovery of new antimicrobial compounds points to serious consequences for human health. Therefore, scientists are looking for new antimicrobial compounds from unique and understudied ecosystems such as tropical peat swamp forests. Over the course of isolating antimicrobial producing bacteria from North Selangor tropical peat swamp forest, Malaysia, a Gram variable, rod shaped, endospore forming, facultative anaerobic novel strain MSt1(T) that exerts potent and broad spectrum antimicrobial activity was isolated. Phylogenetic analysis using 16S rRNA gene sequences showed that strain MSt1(T) belonged to the genus Paenibacillus with the highest similarity to Paenibacillus elgii SD17(T) (99.5%). Whole genome comparison between strain MSt1(T) with its closely related species using average nucleotide identity (ANI) revealed that similarity between strain MSt1(T) with P. elgii B69 (93.45%) and Paenibacillus ehimensis A2 (90.42%) was below the recommended threshold of 95%. Further analysis using in silico pairwise DDH also showed that similarity between strain MSt1(T) with P. elgii B69 (55.4%) and P. ehimensis A2 (43.7%) was below the recommended threshold of 70%. Strain MSt1(T) contained meso-diaminopilemic acid in the cell wall and MK-7 as the major menaquinone. The major fatty acids of strain MSt1(T) were anteiso-C15:0 (48.2%) and C16:0 (29.0%) whereas the polar lipid profile consisted of phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, one unknown lipid, two unknown glycolipids, and one unknown phospholipid. Total DNA G+C content of strain MSt1(T) was 51.5 mol%. The extract from strain MSt1(T) exerted strong antimicrobial activity against Escherichia coli ATCC 25922 (MIC = 1.5 MUg/mL), MRSA ATCC 700699 (MIC = 25 MUg/mL) and Candida albicans IMR (MIC = 12.5 MUg/mL). Partially purified active fraction exerted a strong effect against E. coli ATCC 25922 resulting in cell rupture when viewed with SEM. Based on distinctive taxonomic differences between strain MSt1(T) when compared to its closely related type species, we propose that strain MSt1(T) represents a novel species within the genus of Paenibacillus, for which the name Paenibacillus tyrfis sp. nov. (= DSM 100708(T) = MCCC 1K01247(T)) is proposed. PMID- 26973607 TI - Low Temperature Treatment Affects Concentration and Distribution of Chrysanthemum Stunt Viroid in Argyranthemum. AB - Chrysanthemum stunt viroid (CSVd) can infect Argyranthemum and cause serious economic loss. Low temperature treatment combined with meristem culture has been applied to eradicate viroids from their hosts, but without success in eliminating CSVd from diseased Argyranthemum. The objectives of this work were to investigate (1) the effect of low temperature treatment combined with meristem culture on elimination of CSVd, (2) the effect of low temperature treatment on CSVd distribution pattern in shoot apical meristem (SAM), and (3) CSVd distribution in flowers and stems of two infected Argyranthemum cultivars. After treatment with low temperature combined with meristem tip culture, two CSVd-free plants were found in 'Border Dark Red', but none in 'Yellow Empire'. With the help of in situ hybridization, we found that CSVd distribution patterns in the SAM showed no changes in diseased 'Yellow Empire' following 5 degrees C treatment, compared with non-treated plants. However, the CSVd-free area in SAM was enlarged in diseased 'Border Dark Red' following prolonged 5 degrees C treatment. Localization of CSVd in the flowers and stems of infected 'Border Dark Red' and 'Yellow Empire' indicated that seeds could not transmit CSVd in these two cultivars, and CSVd existed in phloem. Results obtained in the study contributed to better understanding of the distribution of CSVd in systemically infected plants and the combination of low temperature treatment and meristem tip culture for production of viroid-free plants. PMID- 26973606 TI - Antimicrobial Resistance, Biofilm Formation and mecA Characterization of Methicillin-Susceptible S. aureus and Non-S. aureus of Beef Meat Origin in Egypt. AB - Methicillin-resistant Staphylococcus aureus (MRSA) have been found in various farm animal species throughout the world. Yet, methicillin-susceptible S. aureus (MSSA), methicillin-susceptible non-S. aureus (MS-NSA), and methicillin-resistant non-S. aureus (MR-NSA) were not investigated. Therefore, we persued to determine the diversity in their phenotypic virulence assay, phenotypic antimicrobial resistance profile and molecular characterization in one of the food chains in Egypt. Samples were collected during 2013 from beef meat at retail. Twenty seven isolates comprising five species (S. hyicus, S. aureus, S. schleiferi subsp. coagulans, S. intermedius, and S. lentus) were characterized for their antibiotic resistance phenotypic profile and antibiotic resistance genes (mecA, cfr, gyrA, gyrB, and grlA). Out of the 27 Staphylococcus isolates only one isolate was resistant to the 12 antibiotics representing nine classes. Raw beef meat sold across the Great Cairo zone, contains 66.7% of MRS, with highest prevalence was reported in S. aureus (66.7%), while the MRS non-S. aureus strains constituted 66.7% from which S. hyicus (60%), S. intermedius (33.3%), S. schleiferi subsp. coagulans (100%), and S. lentus (100%) were MRS. Seven S. aureus, six S. hyicus, four S. schleiferi subsp. coagulans, three S. intermedius, and one S. lentus isolates although being resistant to oxacillin yet, 11/27 (40.7%) carried the mecA gene. At the same time, the cfr gene was present in 2 of the nine S. aureus isolates, and totally undetectable in S. hyicus, S. schleiferi subsp. coagulans, S. intermedius, and S. lentus. Although, global researches largely focused into MRSA and MR-NSA in animals on pigs, the analysis of our results stipulates, that buffaloes and cattle could be MRSA dispersers and that this theme is not specific to pigs. Detection of MSSA virulence determinants is a must, as although oxacillin resistance may be absent yet, the MSSA may carry the virulence determinants which could be a source of perilous S. aureus for the human community. PMID- 26973608 TI - Biological Phosphorus Removal During High-Rate, Low-Temperature, Anaerobic Digestion of Wastewater. AB - We report, for the first time, extensive biologically mediated phosphate removal from wastewater during high-rate anaerobic digestion (AD). A hybrid sludge bed/fixed-film (packed pumice stone) reactor was employed for low-temperature (12 degrees C) anaerobic treatment of synthetic sewage wastewater. Successful phosphate removal from the wastewater (up to 78% of influent phosphate) was observed, mediated by biofilms in the reactor. Scanning electron microscopy and energy dispersive X-ray analysis revealed the accumulation of elemental phosphorus (~2%) within the sludge bed and fixed-film biofilms. 4', 6-diamidino-2 phenylindole (DAPI) staining indicated phosphorus accumulation was biological in nature and mediated through the formation of intracellular inorganic polyphosphate (polyP) granules within these biofilms. DAPI staining further indicated that polyP accumulation was rarely associated with free cells. Efficient and consistent chemical oxygen demand (COD) removal was recorded, throughout the 732-day trial, at applied organic loading rates between 0.4 and 1.5 kg COD m(-3) d(-1) and hydraulic retention times of 8-24 h, while phosphate removal efficiency ranged from 28 to 78% on average per phase. Analysis of protein hydrolysis kinetics and the methanogenic activity profiles of the biomass revealed the development, at 12 degrees C, of active hydrolytic and methanogenic populations. Temporal microbial changes were monitored using Illumina MiSeq analysis of bacterial and archaeal 16S rRNA gene sequences. The dominant bacterial phyla present in the biomass at the conclusion of the trial were the Proteobacteria and Firmicutes and the dominant archaeal genus was Methanosaeta. Trichococcus and Flavobacterium populations, previously associated with low temperature protein degradation, developed in the reactor biomass. The presence of previously characterized polyphosphate accumulating organisms (PAOs) such as Rhodocyclus, Chromatiales, Actinobacter, and Acinetobacter was recorded at low numbers. However, it is unknown as yet if these were responsible for the luxury polyP uptake observed in this system. The possibility of efficient phosphate removal and recovery from wastewater during AD would represent a major advance in the scope for widespread application of anaerobic wastewater treatment technologies. PMID- 26973609 TI - Insights on Alterations to the Rumen Ecosystem by Nitrate and Nitrocompounds. AB - Nitrate and certain short chain nitrocompounds and nitro-oxy compounds are being investigated as dietary supplements to reduce economic and environmental costs associated with ruminal methane emissions. Thermodynamically, nitrate is a preferred electron acceptor in the rumen that consumes electrons at the expense of methanogenesis during dissimilatory reduction to an intermediate, nitrite, which is primarily reduced to ammonia although small quantities of nitrous oxide may also be produced. Short chain nitrocompounds act as direct inhibitors of methanogenic bacteria although certain of these compounds may also consume electrons at the expense of methanogenesis and are effective inhibitors of important foodborne pathogens. Microbial and nutritional consequences of incorporating nitrate into ruminant diets typically results in increased acetate production. Unlike most other methane-inhibiting supplements, nitrate decreases or has no effect on propionate production. The type of nitrate salt added influences rates of nitrate reduction, rates of nitrite accumulation and efficacy of methane reduction, with sodium and potassium salts being more potent than calcium nitrate salts. Digestive consequences of adding nitrocompounds to ruminant diets are more variable and may in some cases increase propionate production. Concerns about the toxicity of nitrate's intermediate product, nitrite, to ruminants necessitate management, as animal poisoning may occur via methemoglobinemia. Certain of the naturally occurring nitrocompounds, such as 3 nitro-1-propionate or 3-nitro-1-propanol also cause poisoning but via inhibition of succinate dehydrogenase. Typical risk management procedures to avoid nitrite toxicity involve gradually adapting the animals to higher concentrations of nitrate and nitrite, which could possibly be used with the nitrocompounds as well. A number of organisms responsible for nitrate metabolism in the rumen have been characterized. To date a single rumen bacterium is identified as contributing appreciably to nitrocompound metabolism. Appropriate doses of the nitrocompounds and nitrate, singly or in combination with probiotic bacteria selected for nitrite and nitrocompound detoxification activity promise to alleviate risks of toxicity. Further studies are needed to more clearly define benefits and risk of these technologies to make them saleable for livestock producers. PMID- 26973610 TI - Different Transcriptional Responses from Slow and Fast Growth Rate Strains of Listeria monocytogenes Adapted to Low Temperature. AB - Listeria monocytogenes has become one of the principal foodborne pathogens worldwide. The capacity of this bacterium to grow at low temperatures has opened an interesting field of study in terms of the identification and classification of new strains of L. monocytogenes with different growth capacities at low temperatures. We determined the growth rate at 8 degrees C of 110 strains of L. monocytogenes isolated from different food matrices. We identified a group of slow and fast strains according to their growth rate at 8 degrees C and performed a global transcriptomic assay in strains previously adapted to low temperature. We then identified shared and specific transcriptional mechanisms, metabolic and cellular processes of both groups; bacterial motility was the principal process capable of differentiating the adaptation capacity of L. monocytogenes strains with different ranges of tolerance to low temperatures. Strains belonging to the fast group were less motile, which may allow these strains to achieve a greater rate of proliferation at low temperature. PMID- 26973611 TI - Bacterial Community Succession in Pine-Wood Decomposition. AB - Though bacteria and fungi are common inhabitants of decaying wood, little is known about the relationship between bacterial and fungal community dynamics during natural wood decay. Based on previous studies involving inoculated wood blocks, strong fungal selection on bacteria abundance and community composition was expected to occur during natural wood decay. Here, we focused on bacterial and fungal community compositions in pine wood samples collected from dead trees in different stages of decomposition. We showed that bacterial communities undergo less drastic changes than fungal communities during wood decay. Furthermore, we found that bacterial community assembly was a stochastic process at initial stage of wood decay and became more deterministic in later stages, likely due to environmental factors. Moreover, composition of bacterial communities did not respond to the changes in the major fungal species present in the wood but rather to the stage of decay reflected by the wood density. We concluded that the shifts in the bacterial communities were a result of the changes in wood properties during decomposition and largely independent of the composition of the wood-decaying fungal communities. PMID- 26973614 TI - Expanding the Diet for DIET: Electron Donors Supporting Direct Interspecies Electron Transfer (DIET) in Defined Co-Cultures. AB - Direct interspecies electron transfer (DIET) has been recognized as an alternative to interspecies H2 transfer as a mechanism for syntrophic growth, but previous studies on DIET with defined co-cultures have only documented DIET with ethanol as the electron donor in the absence of conductive materials. Co-cultures of Geobacter metallireducens and Geobacter sulfurreducens metabolized propanol, butanol, propionate, and butyrate with the reduction of fumarate to succinate. G. metallireducens utilized each of these substrates whereas only electrons available from DIET supported G. sulfurreducens respiration. A co-culture of G. metallireducens and a strain of G. sulfurreducens that could not metabolize acetate oxidized acetate with fumarate as the electron acceptor, demonstrating that acetate can also be syntrophically metabolized via DIET. A co-culture of G. metallireducens and Methanosaeta harundinacea previously shown to syntrophically convert ethanol to methane via DIET metabolized propanol or butanol as the sole electron donor, but not propionate or butyrate. The stoichiometric accumulation of propionate or butyrate in the propanol- or butanol-fed cultures demonstrated that M. harundinaceae could conserve energy to support growth solely from electrons derived from DIET. Co-cultures of G. metallireducens and Methanosarcina barkeri could also incompletely metabolize propanol and butanol and did not metabolize propionate or butyrate as sole electron donors. These results expand the range of substrates that are known to be syntrophically metabolized through DIET, but suggest that claims of propionate and butyrate metabolism via DIET in mixed microbial communities warrant further validation. PMID- 26973612 TI - A Survey of the Gene Repertoire of Gigaspora rosea Unravels Conserved Features among Glomeromycota for Obligate Biotrophy. AB - Arbuscular mycorrhizal (AM) fungi are a diverse group of soil fungi (Glomeromycota) that form the most ancient mutualistic association termed AM symbiosis with a majority of land plants, improving their nutrition uptake and resistance to stresses. In contrast to their great ecological implications, the knowledge of the molecular biological mechanisms involved is still scant, partly due to the limited genomic resources available. Here, we describe the gene repertoire of a new AM fungus Gigaspora rosea (Diversisporales). Among the 86332 non-redundant virtual transcripts assembled, 15346 presented similarities with proteins in the Refseq database and 10175 were assigned with GO terms. KOG and Interpro domain annotations clearly showed an enrichment of genes involved in signal transduction in G. rosea. KEGG pathway analysis indicates that most primary metabolic processes are active in G. rosea. However, as for Rhizophagus irregularis, several metabolic genes were not found, including the fatty acid synthase (FAS) gene. This finding supports the hypothesis that AM fungi depend on the lipids produced by their hosts. Furthermore, the presence of a large number of transporters and 100s of secreted proteins, together with the reduced number of plant cell wall degrading enzymes could be interpreted as an evolutionary adaptation to its mutualistic obligate biotrophy. The detection of meiosis related genes suggests that G. rosea might use a cryptic sexual process. Lastly, a phylogeny of basal fungi clearly shows Glomeromycota as a sister clade to Mucoromycotina, not only to the Mucorales or Mortierellales. The characterization of the gene repertoire from an AM fungal species belonging to the order of Diversisporales and its comparison with the gene sets of R. irregularis (Glomerales) and Gigaspora margarita (Diversisporales), reveal that AM fungi share several features linked to mutualistic obligate biotrophy. This work contributes to lay the foundation for forthcoming studies into the genomics of Diversisporales, and also illuminates the utility of comparing gene repertoires of species from Diversisporales and other clades of Glomeromycota to gain more insights into the genetics and evolution of this fungal group. PMID- 26973613 TI - Gut Microbiome and Kidney Disease in Pediatrics: Does Connection Exist? AB - Child development is a unique and continuous process that is impacted by genetics and environmental factors. Gut microbiome changes with development and depends on the stage of gut maturation, nutrition, and overall health. In spite of emerging data and active study in adults, the gut-renal axis in pediatrics has not been well considered and investigated. This review will focus on the current knowledge of gut microbiota impacts on kidney disease with extrapolation to the pediatric population. PMID- 26973615 TI - Impact of Timing and Dosage of a Fluoroquinolone Treatment on the Microbiological, Pathological, and Clinical Outcomes of Calves Challenged with Mannheimia haemolytica. AB - The efficacy of an early and low inoculum-adjusted marbofloxacin treatment was evaluated on microbiological and clinical outcomes in calves infected with 4.10(7) CFU of Mannheimia haemolytica A1. Twenty-two calves were included based on their rectal temperature rise in the 10 h after challenge and allocated in four groups, receiving a single intramuscular injection of saline (CON), 2 mg/kg marbofloxacin 2-4 h after inclusion (early treatment, E2), 2 or 10 mg/kg marbofloxacin 35-39 h after inclusion (late treatments, L2, L10). In CON calves, M. haemolytica DNA loads in bronchoalveolar lavages continuously increased from inclusion to day 4, and were associated with persistent respiratory clinical signs and lung lesions. At times of early and late treatments, M. haemolytica loads ranged within 3.5-4 and 5.5-6 log10 DNA copies/mL, respectively. Early 2 mg/kg marbofloxacin treatment led to rapid and total elimination of bacteria in all calves. The late treatments induced a reduction of bacterial loads, but 3 of 6 L2 and 1 of 6 L10 calves were still positive for M. haemolytica at day 4. Except for CON calves, all animals exhibited clinical improvement within 24 h after treatment. However, early 2 mg/kg treatment was more efficacious to prevent pulmonary lesions, as indicated by the reduction of the extension and severity of gross lesions and by the histopathological scores. These results demonstrated for the first time that a reduced antibiotic regimen given at an early stage of the disease and targeting a low bacterial load could be efficacious in a natural bovine model of pneumonia. PMID- 26973616 TI - Fungi Contribute Critical but Spatially Varying Roles in Nitrogen and Carbon Cycling in Acid Mine Drainage. AB - The ecosystem roles of fungi have been extensively studied by targeting one organism and/or biological process at a time, but the full metabolic potential of fungi has rarely been captured in an environmental context. We hypothesized that fungal genome sequences could be assembled directly from the environment using metagenomics and that transcriptomics and proteomics could simultaneously reveal metabolic differentiation across habitats. We reconstructed the near-complete 27 Mbp genome of a filamentous fungus, Acidomyces richmondensis, and evaluated transcript and protein expression in floating and streamer biofilms from an acid mine drainage (AMD) system. A. richmondensis transcripts involved in denitrification and in the degradation of complex carbon sources (including cellulose) were up-regulated in floating biofilms, whereas central carbon metabolism and stress-related transcripts were significantly up-regulated in streamer biofilms. These findings suggest that the biofilm niches are distinguished by distinct carbon and nitrogen resource utilization, oxygen availability, and environmental challenges. An isolated A. richmondensis strain from this environment was used to validate the metagenomics-derived genome and confirm nitrous oxide production at pH 1. Overall, our analyses defined mechanisms of fungal adaptation and identified a functional shift related to different roles in carbon and nitrogen turnover for the same species of fungi growing in closely located but distinct biofilm niches. PMID- 26973617 TI - The Escherichia coli Cryptic Prophage Protein YfdR Binds to DnaA and Initiation of Chromosomal Replication Is Inhibited by Overexpression of the Gene Cluster yfdQ-yfdR-yfdS-yfdT. AB - The initiation of bacterial chromosomal replication is regulated by multiple pathways. To explore novel regulators, we isolated multicopy suppressors for the cold-sensitive hda-185 DeltasfiA(sulA) mutant. Hda is crucial for the negative regulation of the initiator DnaA and the hda-185 mutation causes severe replication overinitiation at the replication origin oriC. The SOS-associated division inhibitor SfiA inhibits FtsZ ring formation, an essential step for cell division regulation during the SOS response, and DeltasfiA enhances the cold sensitivity of hda-185 cells in colony formation. One of the suppressors comprised the yfdQ-yfdR-yfdS-yfdT gene cluster carried on a cryptic prophage. Increased copy numbers of yfdQRT or yfdQRS inhibited not only hda-185-dependent overinitiation, but also replication overinitiation in a hyperactive dnaA mutant, and in a mutant lacking an oriC-binding initiation-inhibitor SeqA. In addition, increasing the copy number of the gene set inhibited the growth of cells bearing specific, initiation-impairing dnaA mutations. In wild-type cells, multicopy supply of yfdQRT or yfdQRS also inhibited replication initiation and increased hydroxyurea (HU)-resistance, as seen in cells lacking DiaA, a stimulator of DnaA assembly on oriC. Deletion of the yfdQ-yfdR-yfdS-yfdT genes did not affect either HU resistance or initiation regulation. Furthermore, we found that DnaA bound specifically to YfdR in soluble protein extracts oversupplied with YfdQRST. Purified YfdR also bound to DnaA, and DnaA Phe46, an amino acid residue crucial for DnaA interactions with DiaA and DnaB replicative helicase was important for this interaction. Consistently, YfdR moderately inhibited DiaA-DnaA and DnaB-DnaA interactions. In addition, protein extracts oversupplied with YfdQRST inhibited replication initiation in vitro. Given the roles of yfdQ and yfdS in cell tolerance to specific environmental stresses, the yfdQ-yfdR-yfdS-yfdT genes might downregulate the initiator DnaA-oriC complex under specific growth conditions. PMID- 26973618 TI - Effect of Biostimulation Using Sewage Sludge, Soybean Meal, and Wheat Straw on Oil Degradation and Bacterial Community Composition in a Contaminated Desert Soil. AB - Waste materials have a strong potential in the bioremediation of oil-contaminated sites, because of their richness in nutrients and their economical feasibility. We used sewage sludge, soybean meal, and wheat straw to biostimulate oil degradation in a heavily contaminated desert soil. While oil degradation was assessed by following the produced CO2 and by using gas chromatography-mass spectrometry (GC-MS), shifts in bacterial community composition were monitored using illumina MiSeq. The addition of sewage sludge and wheat straw to the desert soil stimulated the respiration activities to reach 3.2-3.4 times higher than in the untreated soil, whereas the addition of soybean meal resulted in an insignificant change in the produced CO2, given the high respiration activities of the soybean meal alone. GC-MS analysis revealed that the addition of sewage sludge and wheat straw resulted in 1.7-1.8 fold increase in the degraded C14 to C30 alkanes, compared to only 1.3 fold increase in the case of soybean meal addition. The degradation of >=90% of the C14 to C30 alkanes was measured in the soils treated with sewage sludge and wheat straw. MiSeq sequencing revealed that the majority (76.5-86.4% of total sequences) of acquired sequences from the untreated soil belonged to Alphaproteobacteria, Gammaproteobacteria, and Firmicutes. Multivariate analysis of operational taxonomic units placed the bacterial communities of the soils after the treatments in separate clusters (ANOSIM R = 0.66, P = 0.0001). The most remarkable shift in bacterial communities was in the wheat straw treatment, where 95-98% of the total sequences were affiliated to Bacilli. We conclude that sewage sludge and wheat straw are useful biostimulating agents for the cleanup of oil-contaminated desert soils. PMID- 26973619 TI - Enhanced Bioconversion of Cellobiose by Industrial Saccharomyces cerevisiae Used for Cellulose Utilization. AB - Cellobiose accumulation and the compromised temperature for yeast fermentation are the main limiting factors of enzymatic hydrolysis process during simultaneous saccharification and fermentation (SSF). In this study, genes encoding cellobiose transporter and beta-glucosidase were introduced into an industrial Saccharomyces cerevisiae strain, and evolution engineering was carried out to improve the cellobiose utilization of the engineered yeast strain. The evolved strain exhibited significantly higher cellobiose consumption rate (2.8-fold) and ethanol productivity (4.9-fold) compared with its parent strain. Besides, the evolved strain showed a high cellobiose consumption rate of 3.67 g/L/h at 34 degrees C and 3.04 g/L/h at 38 degrees C. Moreover, little cellobiose was accumulated during SSF of Avicel using the evolved strain at 38 degrees C, and the ethanol yield from Avicel increased by 23% from 0.34 to 0.42 g ethanol/g cellulose. Overexpression of the genes encoding cellobiose transporter and beta-glucosidase accelerated cellobiose utilization, and the improvement depended on the strain background. The results proved that fast cellobiose utilization enhanced ethanol production by reducing cellobiose accumulation during SSF at high temperature. PMID- 26973620 TI - Mechanism and In Vivo Evaluation: Photodynamic Antibacterial Chemotherapy of Lysine-Porphyrin Conjugate. AB - Lysine-porphyrin conjugate 4i has potent photosensitive antibacterial effect on clinical isolated bacterial strains such as Methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, and Pseudomonas aeruginosa. The mechanism of photodynamic antibacterial chemotherapy of 4i (4i-PACT) in vitro and the treatment effect in vivo was investigated in this paper. Atomic force microscopy (AFM) revealed that 4i-PACT can effectively destroy membrane and wall of bacteria, resulting in leakage of its content. This was confirmed by dual fluorescent staining with acridine orange/ethidium bromide and measuring materials absorption at 260 nm. Agarose gel electrophoresis measurement showed that 4i-PACT can damage genomic DNA. Healing of wound in rat infected by mixed bacteria showed that the efficiency of 4i-PACT is dependent on the dose of light. These results showed that 4i-PACT has promising bactericidal effect both in vitro and in vivo. PMID- 26973621 TI - Production of Volatile and Sulfur Compounds by 10 Saccharomyces cerevisiae Strains Inoculated in Trebbiano Must. AB - In wines, the presence of sulfur compounds is the resulting of several contributions among which yeast metabolism. The characterization of the starter Saccharomyces cerevisiae needs to be performed also taking into account this ability even if evaluated together with the overall metabolic profile. In this perspective, principal aim of this experimental research was the evaluation of the volatile profiles, throughout GC/MS technique coupled with solid phase micro extraction, of wines obtained throughout the fermentation of 10 strains of S. cerevisiae. In addition, the production of sulfur compounds was further evaluated by using a gas-chromatograph coupled with a Flame Photometric Detector. Specifically, the 10 strains were inoculated in Trebbiano musts and the fermentations were monitored for 19 days. In the produced wines, volatile and sulfur compounds as well as amino acid concentrations were investigated. Also the physico-chemical characteristics of the wines and their electronic nose profiles were evaluated. PMID- 26973622 TI - Lactobacillus reuteri Inhibition of Enteropathogenic Escherichia coli Adherence to Human Intestinal Epithelium. AB - Enteropathogenic Escherichia coli (EPEC) is a major cause of diarrheal infant death in developing countries, and probiotic bacteria have been shown to provide health benefits in gastrointestinal infections. In this study, we have investigated the influence of the gut symbiont Lactobacillus reuteri on EPEC adherence to the human intestinal epithelium. Different host cell model systems including non-mucus-producing HT-29 and mucus-producing LS174T intestinal epithelial cell lines as well as human small intestinal biopsies were used. Adherence of L. reuteri to HT-29 cells was strain-specific, and the mucus-binding proteins CmbA and MUB increased binding to both HT-29 and LS174T cells. L. reuteri ATCC PTA 6475 and ATCC 53608 significantly inhibited EPEC binding to HT 29 but not LS174T cells. While pre-incubation of LS174T cells with ATCC PTA 6475 did not affect EPEC attaching/effacing (A/E) lesion formation, it increased the size of EPEC microcolonies. ATCC PTA 6475 and ATCC 53608 binding to the mucus layer resulted in decreased EPEC adherence to small intestinal biopsy epithelium. Our findings show that L. reuteri reduction of EPEC adhesion is strain-specific and has the potential to target either the epithelium or the mucus layer, providing further rationale for the selection of probiotic strains. PMID- 26973624 TI - Trichothecene Genotypes of the Fusarium graminearum Species Complex Isolated from Brazilian Wheat Grains by Conventional and Quantitative PCR. AB - We compared two well-established methods, fungal isolation followed by conventional PCR and DNA analysis by quantitative PCR (qPCR), to define trichothecene genotypes in Brazilian wheat grains from different locations. For this purpose, after fungal isolation from 75 wheat samples, 100 isolates of the Fusarium graminearum species complex (FGSC) were genotyped by PCR to establish their trichothecene profile. For profiling by qPCR, DNA was extracted from the wheat samples and analyzed. The methods provided similar and divergent results. The FGSC isolates were classified as NIV (55%), 15-ADON (43%), and 3-ADON (2%). Analysis by qPCR showed 100% contamination with 15-ADON strains in all wheat samples, 80% contamination with the NIV genotype, and only 33.3% contamination with 3-ADON strains. Further analysis revealed that 96% of all quantified DNA was attributed to the 15-ADON profile, while 3.4% was attributed to NIV and only 0.06% to 3-ADON. A positive correlation was observed between 15-ADON genotype DNA concentration and deoxynivalenol (DON) content in the wheat samples. The high frequency of fungi, DNA levels and positive correlation with DON strongly indicate that 15-ADON producers are the main trichothecene genotype in Brazilian wheat grains. Surprisingly, although many isolates (55%) carried the NIV genotype and this genotype was identified in 80% of the wheat samples, only 3.4% of fungal DNA was in fact from NIV producers. Although, our findings showed that each method provided a different perspective about the trichothecene profile, DNA analysis by qPCR gave us new insight about fungal contamination levels in Brazilian wheat grains. Nevertheless, both techniques should be used to obtain more robust results. PMID- 26973623 TI - Fate of Viable but Non-culturable Listeria monocytogenes in Pig Manure Microcosms. AB - The fate of two strains of Listeria monocytogenes and their ability to become viable but non-culturable (VBNC) was investigated in microcosms containing piggery effluents (two raw manures and two biologically treated manures) stored for 2 months at 8 and 20 degrees C. Levels of L. monocytogenes were estimated using the culture method, qPCR, and propidium monoazide treatment combined with qPCR (qPCRPMA). The chemical composition and the microbial community structure of the manures were also analyzed. The strains showed similar decline rates and persisted up to 63 days. At day zero, the percentage of VBNC cells among viable cells was higher in raw manures (81.5-94.8%) than in treated manures (67.8 79.2%). The changes in their proportion over time depended on the temperature and on the type of effluent: the biggest increase was observed in treated manures at 20 degrees C and the smallest increase in raw manures at 8 degrees C. The chemical parameters had no influence on the behavior of the strains, but decrease of the persistence of viable cells was associated with an increase in the microbial richness of the manures. This study demonstrated that storing manure altered the culturability of L. monocytogenes, which rapidly entered the VBNC state, and underlines the importance of including VBNC cells when estimating the persistence of the pathogens in farm effluents. PMID- 26973625 TI - Polynucleotide Phosphorylase Regulates Multiple Virulence Factors and the Stabilities of Small RNAs RsmY/Z in Pseudomonas aeruginosa. AB - Post-transcriptional regulation enables bacteria to quickly response to environmental stresses. Polynucleotide phosphorylase (PNPase), which contains an N-terminal catalytic core and C-terminal RNA binding KH-S1 domains, is involved in RNA processing. Here we demonstrate that in Pseudomonas aeruginosa the KH-S1 domains of PNPase are required for the type III secretion system (T3SS) and bacterial virulence. Transcriptome analysis revealed a pleiotropic role of PNPase in gene regulation. Particularly, the RNA level of exsA was decreased in the DeltaKH-S1 mutant, which was responsible for the reduced T3SS expression. Meanwhile, the pilus biosynthesis genes were down regulated and the type VI secretion system (T6SS) genes were up regulated in the DeltaKH-S1 mutant, which were caused by increased levels of small RNAs, RsmY, and RsmZ. Further studies revealed that deletion of the KH-S1 domains did not affect the transcription of RsmY/Z, but increased their stabilities. An in vivo pull-down and in vitro electrophoretic mobility shift assay (EMSA) demonstrated a direct interaction between RsmY/Z and the KH-S1 fragment. Overall, this study reveals the roles of PNPase in the regulation of virulence factors and stabilities of small RNAs in P. aeruginosa. PMID- 26973626 TI - Organohalide Respiring Bacteria and Reductive Dehalogenases: Key Tools in Organohalide Bioremediation. AB - Organohalides are recalcitrant pollutants that have been responsible for substantial contamination of soils and groundwater. Organohalide-respiring bacteria (ORB) provide a potential solution to remediate contaminated sites, through their ability to use organohalides as terminal electron acceptors to yield energy for growth (i.e., organohalide respiration). Ideally, this process results in non- or lesser-halogenated compounds that are mostly less toxic to the environment or more easily degraded. At the heart of these processes are reductive dehalogenases (RDases), which are membrane bound enzymes coupled with other components that facilitate dehalogenation of organohalides to generate cellular energy. This review focuses on RDases, concentrating on those which have been purified (partially or wholly) and functionally characterized. Further, the paper reviews the major bacteria involved in organohalide breakdown and the evidence for microbial evolution of RDases. Finally, the capacity for using ORB in a bioremediation and bioaugmentation capacity are discussed. PMID- 26973627 TI - Spatial-Temporal Changes of Bacterioplankton Community along an Exhorheic River. AB - To date, few aquatic microbial ecology studies have discussed the variability of the microbial community in exorheic river ecosystems on both the spatial and seasonal scales. In this study, we examined the spatio-temporal variation of bacterioplankton community composition in an anthropogenically influenced exorheic river, the Haihe River in Tianjin, China, using pyrosequencing analysis of 16S rRNA genes. It was verified by one-way ANOVA that the spatial variability of the bacterioplankton community composition over the whole river was stronger than the seasonal variation. Salinity was a major factor leading to spatial differentiation of the microbial community structure into riverine and estuarial parts. A high temperature influence on the seasonal bacterial community variation was only apparent within certain kinds of environments (e.g., the riverine part). Bacterial community richness and diversity both exhibited significant spatial changes, and their seasonal variations were completely different in the two environments studied here. Furthermore, riverine bacterial community assemblages were subdivided into urban and rural groups due to changes in the nutritional state of the river. In addition, the nutrient-loving group including Limnohabitans, Hydrogenophaga, and Polynucleobacter were abundant in the urbanized Haihe River, indicating the environmental factors in these anthropogenic waterbodies heavily influence the core freshwater community composition. PMID- 26973628 TI - Genetic Evidence for O-Specific Antigen as Receptor of Pseudomonas aeruginosa Phage K8 and Its Genomic Analysis. AB - Phage therapy requires the comprehensive understanding of the mechanisms underlying the host-phage interactions. In this work, to identify the genes related to Pseudomonas aeruginosa phage K8 receptor synthesis, 16 phage-resistant mutants were selected from a Tn5G transposon mutant library of strain PAK. The disrupted genetic loci were identified and they were related to O-specific antigen (OSA) synthesis, including gene wbpR, ssg, wbpV, wbpO, and Y880_RS05480, which encoded a putative O-antigen polymerase Wzy. The Lipopolysaccharide profile of the Y880_RS05480 mutant was analyzed and shown to lack the O-antigen. Therefore, the data from characterization of Y880_RS05480 by TMHMM and SDS-PAGE silver staining analysis suggest that this locus might encode Wzy. The complete phage K8 genome was characterized as 93879 bp in length and contained identical 1188-bp terminal direct repeats. Comparative genomic analysis showed that phage K8 was highly homologous to members of the genus PaP1-like phages. On the basis of our genetic findings, OSA of P. aeruginosa PAK is proven to be the receptor of phage K8. The highly conserved structural proteins among the genetic closely related phages suggest that they may recognize the same receptor. PMID- 26973629 TI - Pseudomonas aeruginosa Activates PKC-Alpha to Invade Middle Ear Epithelial Cells. AB - Otitis media (OM) is a group of complex inflammatory disorders affecting the middle ear which can be acute or chronic. Chronic suppurative otitis media (CSOM) is a form of chronic OM characterized by tympanic membrane perforation and discharge. Despite the significant impact of CSOM on human population, it is still an understudied and unexplored research area. CSOM is a leading cause of hearing loss and life-threatening central nervous system complications. Bacterial exposure especially Pseudomonas aeruginosa is the most common cause of CSOM. Our previous studies have demonstrated that P. aeruginosa invades human middle ear epithelial cells (HMEECs). However, molecular mechanisms leading to bacterial invasion of HMEECs are not known. The aim of this study is to characterize the role of PKC pathway in the ability of P. aeruginosa to colonize HMEECs. We observed that otopathogenic P. aeruginosa activates the PKC pathway, specifically phosphorylation of PKC-alpha (PKC-alpha) in HMEECs. The ability of otopathogenic P. aeruginosa to phosphorylate PKC-alpha depends on bacterial OprF expression. The activation of PKC-alpha was associated with actin condensation. Blocking the PKC pathway attenuated the ability of bacteria to invade HMEECs and subsequent actin condensation. This study, for the first time, demonstrates that the host PKC-alpha pathway is involved in invasion of HMEECs by P. aeruginosa and subsequently to cause OM. Characterizing the role of the host signaling pathway in the pathogenesis of CSOM will provide novel avenues to design effective treatment modalities against the disease. PMID- 26973632 TI - Whole Genome Sequencing for Public Health Surveillance of Shiga Toxin-Producing Escherichia coli Other than Serogroup O157. AB - Shiga toxin-producing Escherichia coli (STEC) are considered to be a significant threat to public health due to the severity of gastrointestinal symptoms associated with human infection. In England STEC O157 is the most commonly detected STEC serogroup, however, the implementation of PCR at local hospital laboratories has resulted in an increase in the detection of non-O157 STEC. The aim of this study was to evaluate the use of whole genome sequencing (WGS) for routine public health surveillance of non-O157 STEC by comparing this approach to phenotypic serotyping and PCR for subtyping the stx-encoding genes. Of the 102 isolates where phenotypic and genotypic serotyping could be compared, 98 gave fully concordant results. The most common non-O157 STEC serogroups detected were O146 (22) and O26 (18). All but one of the 38 isolates that could not be phenotypically serotyped (designated O unidentifiable or O rough) were serotyped using the WGS data. Of the 73 isolates where a flagella type was available by traditional phenotypic typing, all results matched the H-type derived from the WGS data. Of the 140 sequenced non-O157 isolates, 52 (37.1%) harboured stx1 only, 42 (30.0%) had stx2 only, 46 (32.9%) carried stx1 and stx2. Of these, stx subtyping PCR results were available for 131 isolates and 121 of these had concordant results with the stx subtype derived from the WGS data. Of the 10 discordant results, non-specific primer binding during PCR amplification, due to the similarity of the stx2 subtype gene sequences was the most likely cause. The results of this study showed WGS provided a reliable and robust one-step process for characterization of STEC. Deriving the full serotype from WGS data in real time has enabled us to report a higher level of strain discrimination while stx subtyping provides data on the pathogenic potential of each isolate, enabling us to predict clinical outcome of each case and to monitor the emergence of hyper virulent strains. PMID- 26973630 TI - Infection Strategies of Intestinal Parasite Pathogens and Host Cell Responses. AB - Giardia lamblia, Cryptosporidium sp., and Entamoeba histolytica are important pathogenic intestinal parasites and are amongst the leading causes worldwide of diarrheal illness in humans. Diseases caused by these organisms, giardiasis, cryptosporidiosis, and amoebiasis, respectively, are characterized by self limited diarrhea but can evolve to long-term complications. The cellular and molecular mechanisms underlying the pathogenesis of diarrhea associated with these three pathogens are being unraveled, with knowledge of both the strategies explored by the parasites to establish infection and the methods evolved by hosts to avoid it. Special attention is being given to molecules participating in parasite-host interaction and in the mechanisms implicated in the diseases' pathophysiologic processes. This review focuses on cell mechanisms that are modulated during infection, including gene transcription, cytoskeleton rearrangements, signal transduction pathways, and cell death. PMID- 26973634 TI - Using In situ Dynamic Cultures to Rapidly Biofabricate Fabric-Reinforced Composites of Chitosan/Bacterial Nanocellulose for Antibacterial Wound Dressings. AB - Bacterial nano-cellulose (BNC) is considered to possess incredible potential in biomedical applications due to its innate unrivaled nano-fibrillar structure and versatile properties. However, its use is largely restricted by inefficient production and by insufficient strength when it is in a highly swollen state. In this study, a fabric skeleton reinforced chitosan (CS)/BNC hydrogel with high mechanical reliability and antibacterial activity was fabricated by using an efficient dynamic culture that could reserve the nano-fibrillar structure. By adding CS in culture media to 0.25-0.75% (w/v) during bacterial cultivation, the CS/BNC composite hydrogel was biosynthesized in situ on a rotating drum composed of fabrics. With the proposed method, BNC biosynthesis became less sensitive to the adverse antibacterial effects of CS and the production time of the composite hydrogel with desirable thickness could be halved from 10 to 5 days as compared to the conventional static cultures. Although, its concentration was low in the medium, CS accounted for more than 38% of the CS/BNC dry weight. FE-SEM observation confirmed conservation of the nano-fibrillar networks and covering of CS on BNC. ATR-FTIR showed a decrease in the degree of intra-molecular hydrogen bonding and water absorption capacity was improved after compositing with CS. The fabric-reinforced CS/BNC composite exhibited bacteriostatic properties against Escherichia coli and Staphylococcus aureus and significantly improved mechanical properties as compared to the BNC sheets from static culture. In summary, the fabric-reinforced CS/BNC composite constitutes a desired candidate for advanced wound dressings. From another perspective, coating of BNC or CS/BNC could upgrade the conventional wound dressings made of cotton gauze to reduce pain during wound healing, especially for burn patients. PMID- 26973631 TI - Formaldehyde Stress Responses in Bacterial Pathogens. AB - Formaldehyde is the simplest of all aldehydes and is highly cytotoxic. Its use and associated dangers from environmental exposure have been well documented. Detoxification systems for formaldehyde are found throughout the biological world and they are especially important in methylotrophic bacteria, which generate this compound as part of their metabolism of methanol. Formaldehyde metabolizing systems can be divided into those dependent upon pterin cofactors, sugar phosphates and those dependent upon glutathione. The more prevalent thiol dependent formaldehyde detoxification system is found in many bacterial pathogens, almost all of which do not metabolize methane or methanol. This review describes the endogenous and exogenous sources of formaldehyde, its toxic effects and mechanisms of detoxification. The methods of formaldehyde sensing are also described with a focus on the formaldehyde responsive transcription factors HxlR, FrmR, and NmlR. Finally, the physiological relevance of detoxification systems for formaldehyde in bacterial pathogens is discussed. PMID- 26973633 TI - Anthropogenic N Deposition Slows Decay by Favoring Bacterial Metabolism: Insights from Metagenomic Analyses. AB - Litter decomposition is an enzymatically-complex process that is mediated by a diverse assemblage of saprophytic microorganisms. It is a globally important biogeochemical process that can be suppressed by anthropogenic N deposition. In a northern hardwood forest ecosystem located in Michigan, USA, 20 years of experimentally increased atmospheric N deposition has reduced forest floor decay and increased soil C storage. Here, we paired extracellular enzyme assays with shotgun metagenomics to assess if anthropogenic N deposition has altered the functional potential of microbial communities inhabiting decaying forest floor. Experimental N deposition significantly reduced the activity of extracellular enzymes mediating plant cell wall decay, which occurred concurrently with changes in the relative abundance of metagenomic functional gene pathways mediating the metabolism of carbohydrates, aromatic compounds, as well as microbial respiration. Moreover, experimental N deposition increased the relative abundance of 50 of the 60 gene pathways, the majority of which were associated with saprotrophic bacteria. Conversely, the relative abundance and composition of fungal genes mediating the metabolism of plant litter was not affected by experimental N deposition. Future rates of atmospheric N deposition have favored saprotrophic soil bacteria, whereas the metabolic potential of saprotrophic fungi appears resilient to this agent of environmental change. Results presented here provide evidence that changes in the functional capacity of saprotrophic soil microorganisms mediate how anthropogenic N deposition increases C storage in soil. PMID- 26973635 TI - A New Endogenous Overexpression System of Multidrug Transporters of Candida albicans Suitable for Structural and Functional Studies. AB - Fungal pathogens have a robust array of multidrug transporters which aid in active expulsion of drugs and xenobiotics to help them evade toxic effects of drugs. Thus, these transporters impose a major impediment to effective chemotherapy. Although the Saccharomyces cerevisiae strain AD1-8u(-) has catered well to the need of an overexpression system to study drug transport by multidrug transporters of Candida albicans, artifacts associated with a heterologous system could not be excluded. To avoid the issue, we exploited a azole-resistant clinical isolate of C. albicans to develop a new system devoid of three major multidrug transporters (Cdr1p, Cdr2p, and Mdr1p) for the overexpression of multidrug transporters under native hyperactive CDR1 promoter due to gain of function (GOF) mutation in TAC1. The study deals with overexpression and functional characterization of representatives of two major classes of multidrug transporters, Cdr1p and Mdr1p, to prove the functionality of this newly developed endogenous expression system. Expression of native Cdr1 and Mdr1 protein in C. albicans cells was confirmed by confocal microscopy and immunodetection and resulted in increased resistance to the putative substrates as compared to control. The system was further validated by overexpressing a few key mutant variants of Cdr1p and Mdr1p. Together, our data confirms the utility of new endogenous overexpression system which is devoid of artifactual factors as most suited for functional characterization of multidrug transporter proteins of C. albicans. PMID- 26973636 TI - Corrigendum: Amdoparvoviruses in small mammals: expanding our understanding of parvovirus diversity, distribution, and pathology. AB - [This corrects the article on p. 1119 in vol. 6, PMID: 26528267.]. PMID- 26973637 TI - Biocatalytic Desulfurization Capabilities of a Mixed Culture during Non Destructive Utilization of Recalcitrant Organosulfur Compounds. AB - We investigated the biodesulfurization potential of a mixed culture AK6 enriched from petroleum hydrocarbons-polluted soil with dibenzothiophene (DBT) as a sulfur source. In addition to DBT, AK6 utilized the following compounds as sulfur sources: 4-methyldibenzothiophene (4-MDBT), benzothiophene (BT), and 4,6- dimethyldibenzothiophene (4,6-DM-DBT). None of these compounds supported the growth of AK6 as the sole carbon and sulfur source. AK6 could not grow on dibenzylsulfide (DBS) as a sulfur source. The AK6 community structure changed according to the provided sulfur source. The major DGGE bands represented members of the genera Sphingobacterium, Klebsiella, Pseudomonas, Stenotrophomonas, Arthrobacter, Mycobacterium, and Rhodococcus. Sphingobacterium sp. and Pseudomonas sp. were abundant across all cultures utilizing any of the tested thiophenic S-compounds. Mycobacterium/Rhodococcus spp. were restricted to the 4 MDBT culture. The 4-MDBT culture had the highest species richness and diversity. Biodesulfurization of DBT by resting cells of AK6 produced 2-hydroxybiphenyl (2 HBP) in addition to trace amounts of phenylacetate. AK6 transformed DBT to 2 hydroxybiphenyl with a specific activity of 9 +/- 0.6 MUM 2-HBP g dry cell weight(-1) h(-1). PCR confirmed the presence in the AK6 community of the sulfur specific (4S) pathway genes dszB and dszC. Mixed cultures hold a better potential than axenic ones for the development of a biodesulfurization technology. PMID- 26973638 TI - GenSeed-HMM: A Tool for Progressive Assembly Using Profile HMMs as Seeds and its Application in Alpavirinae Viral Discovery from Metagenomic Data. AB - This work reports the development of GenSeed-HMM, a program that implements seed driven progressive assembly, an approach to reconstruct specific sequences from unassembled data, starting from short nucleotide or protein seed sequences or profile Hidden Markov Models (HMM). The program can use any one of a number of sequence assemblers. Assembly is performed in multiple steps and relatively few reads are used in each cycle, consequently the program demands low computational resources. As a proof-of-concept and to demonstrate the power of HMM-driven progressive assemblies, GenSeed-HMM was applied to metagenomic datasets in the search for diverse ssDNA bacteriophages from the recently described Alpavirinae subfamily. Profile HMMs were built using Alpavirinae-specific regions from multiple sequence alignments (MSA) using either the viral protein 1 (VP1; major capsid protein) or VP4 (genome replication initiation protein). These profile HMMs were used by GenSeed-HMM (running Newbler assembler) as seeds to reconstruct viral genomes from sequencing datasets of human fecal samples. All contigs obtained were annotated and taxonomically classified using similarity searches and phylogenetic analyses. The most specific profile HMM seed enabled the reconstruction of 45 partial or complete Alpavirinae genomic sequences. A comparison with conventional (global) assembly of the same original dataset, using Newbler in a standalone execution, revealed that GenSeed-HMM outperformed global genomic assembly in several metrics employed. This approach is capable of detecting organisms that have not been used in the construction of the profile HMM, which opens up the possibility of diagnosing novel viruses, without previous specific information, constituting a de novo diagnosis. Additional applications include, but are not limited to, the specific assembly of extrachromosomal elements such as plastid and mitochondrial genomes from metagenomic data. Profile HMM seeds can also be used to reconstruct specific protein coding genes for gene diversity studies, and to determine all possible gene variants present in a metagenomic sample. Such surveys could be useful to detect the emergence of drug resistance variants in sensitive environments such as hospitals and animal production facilities, where antibiotics are regularly used. Finally, GenSeed-HMM can be used as an adjunct for gap closure on assembly finishing projects, by using multiple contig ends as anchored seeds. PMID- 26973639 TI - Global MLST of Salmonella Typhi Revisited in Post-genomic Era: Genetic Conservation, Population Structure, and Comparative Genomics of Rare Sequence Types. AB - Typhoid fever, caused by Salmonella enterica serovar Typhi, remains an important public health burden in Southeast Asia and other endemic countries. Various genotyping methods have been applied to study the genetic variations of this human-restricted pathogen. Multilocus sequence typing (MLST) is one of the widely accepted methods, and recently, there is a growing interest in the re-application of MLST in the post-genomic era. In this study, we provide the global MLST distribution of S. Typhi utilizing both publicly available 1,826 S. Typhi genome sequences in addition to performing conventional MLST on S. Typhi strains isolated from various endemic regions spanning over a century. Our global MLST analysis confirms the predominance of two sequence types (ST1 and ST2) co existing in the endemic regions. Interestingly, S. Typhi strains with ST8 are currently confined within the African continent. Comparative genomic analyses of ST8 and other rare STs with genomes of ST1/ST2 revealed unique mutations in important virulence genes such as flhB, sipC, and tviD that may explain the variations that differentiate between seemingly successful (widespread) and unsuccessful (poor dissemination) S. Typhi populations. Large scale whole-genome phylogeny demonstrated evidence of phylogeographical structuring and showed that ST8 may have diverged from the earlier ancestral population of ST1 and ST2, which later lost some of its fitness advantages, leading to poor worldwide dissemination. In response to the unprecedented increase in genomic data, this study demonstrates and highlights the utility of large-scale genome-based MLST as a quick and effective approach to narrow the scope of in-depth comparative genomic analysis and consequently provide new insights into the fine scale of pathogen evolution and population structure. PMID- 26973641 TI - Emergence of Hyper-Resistant Escherichia coli MG1655 Derivative Strains after Applying Sub-Inhibitory Doses of Individual Constituents of Essential Oils. AB - The improvement of food preservation by using essential oils (EOs) and their individual constituents (ICs) is attracting enormous interest worldwide. Until now, researchers considered that treatments with such antimicrobial compounds did not induce bacterial resistance via a phenotypic (i.e., transient) response. Nevertheless, the emergence of genotypic (i.e., stable) resistance after treatment with these compounds had not been previously tested. Our results confirm that growth of Escherichia coli MG1655 in presence of sub-inhibitory concentrations of the ICs carvacrol, citral, and (+)-limonene oxide do not increase resistance to further treatments with either the same IC (direct resistance) or with other preservation treatments (cross-resistance) such as heat or pulsed electric fields (PEF). Bacterial mutation frequency was likewise lower when those IC's were applied; however, after 10 days of re-culturing cells in presence of sub-inhibitory concentrations of the ICs, we were able to isolate several derivative strains (i.e., mutants) displaying an increased minimum inhibitory concentration to those ICs. Furthermore, when compared to the wild type (WT) strain, they also displayed direct resistance and cross-resistance. Derivative strains selected with carvacrol and citral also displayed morphological changes involving filamentation along with cell counts at late stationary growth phase that were lower than the WT strain. In addition, co cultures of each derivative strain with the WT strain resulted in a predominance of the original strain in absence of ICs, indicating that mutants would not out compete WT cells under optimal growth conditions. Nevertheless, growth in the presence of ICs facilitated the selection of these resistant mutants. Thus, as a result, subsequent food preservation treatments of these bacterial cultures might be less effective than expected for WT cultures. In conclusion, this study recommends that treatment with ICs at sub-inhibitory concentrations should be generally avoided, since it could favor the emergence of hyper-resistant strains. To ascertain the true value of EOs and their ICs in the field of food preservation, further research thus needs to be conducted on the induction of increased transient and stable bacterial resistance via such antimicrobial compounds, as revealed in this study. PMID- 26973640 TI - First Line of Defense: Innate Cell-Mediated Control of Pulmonary Aspergillosis. AB - Mycotic infections and their effect on the human condition have been widely overlooked and poorly surveilled by many health organizations even though mortality rates have increased in recent years. The increased usage of immunosuppressive and myeloablative therapies for the treatment of malignant as well as non-malignant diseases has contributed significantly to the increased incidence of fungal infections. Invasive fungal infections have been found to be responsible for at least 1.5 million deaths worldwide. About 90% of these deaths can be attributed to Cryptococcus, Candida, Aspergillus, and Pneumocystis. A better understanding of how the host immune system contains fungal infection is likely to facilitate the development of much needed novel antifungal therapies. Innate cells are responsible for the rapid recognition and containment of fungal infections and have been found to play essential roles in defense against multiple fungal pathogens. In this review we summarize our current understanding of host-fungi interactions with a focus on mechanisms of innate cell-mediated recognition and control of pulmonary aspergillosis. PMID- 26973642 TI - Epimural Indicator Phylotypes of Transiently-Induced Subacute Ruminal Acidosis in Dairy Cattle. AB - The impact of a long-term subacute rumen acidosis (SARA) on the bovine epimural bacterial microbiome (BEBM) and its consequences for rumen health is poorly understood. This study aimed to investigate shifts in the BEBM during a long-term transient SARA model consisting of two concentrate-diet-induced SARA challenges separated by a 1-week challenge break. Eight cows were fed forage and varying concentrate amounts throughout the experiment. In total, 32 rumen papilla biopsies were taken for DNA isolation (4 sampling time points per cow: at the baseline before concentrate was fed, after the first SARA challenge, after the challenge break, and after the second SARA challenge). Ruminal pH was continuously monitored. The microbiome was determined using Illumina MiSeq sequencing of the 16S rRNA gene (V345 region). In total 1,215,618 sequences were obtained and clustered into 6833 operational taxonomic units (OTUs). Campylobacter and Kingella were the most abundant OTUs (16.5 and 7.1%). According to ruminal pH dynamics, the second challenge was more severe than the first challenge. Species diversity estimates and evenness increased during the challenge break compared to all other sampling time points (P < 0.05). During both SARA challenges, Kingella- and Azoarcus-OTUs decreased (0.5 and 0.4 fold change) and a dominant Ruminobacter-OTU increased during the challenge break (18.9 fold-change; P < 0.05). qPCR confirmed SARA-related shifts. During the challenge break noticeably more OTUs increased compared to other sampling time points. Our results show that the BEBM re-establishes the baseline conditions slower after a SARA challenge than ruminal pH. Key phylotypes that were reduced during both challenges may help to establish a bacterial fingerprint to facilitate understanding effects of SARA conditions on the BEBM and their consequences for the ruminant host. PMID- 26973645 TI - Heterozygous Mutation in IkappaBNS Leads to Reduced Levels of Natural IgM Antibodies and Impaired Responses to T-Independent Type 2 Antigens. AB - Mice deficient in central components of classical NF-kappaB signaling have low levels of circulating natural IgM antibodies and fail to respond to immunization with T-independent type 2 (TI-2) antigens. A plausible explanation for these defects is the severely reduced numbers of B-1 and marginal zone B (MZB) cells in such mice. By using an ethyl-N-nitrosourea mutagenesis screen, we identified a role for the atypical IkappaB protein IkappaBNS in humoral immunity. IkappaBNS deficient mice lack B-1 cells and have severely reduced numbers of MZB cells, and thus resemble several other strains with defects in classical NF-kappaB signaling. We analyzed mice heterozygous for the identified IkappaBNS mutation and demonstrate that these mice have an intermediary phenotype in terms of levels of circulating IgM antibodies and responses to TI-2 antigens. However, in contrast to mice that are homozygous for the IkappaBNS mutation, the heterozygous mice had normal frequencies of B-1 and MZB cells. These results suggest that there is a requirement for IkappaBNS expression from two functional alleles for maintaining normal levels of circulating natural IgM antibodies and responses to TI-2 antigens. PMID- 26973643 TI - Metabolomics and Its Application to Acute Lung Diseases. AB - Metabolomics is a rapidly expanding field of systems biology that is gaining significant attention in many areas of biomedical research. Also known as metabonomics, it comprises the analysis of all small molecules or metabolites that are present within an organism or a specific compartment of the body. Metabolite detection and quantification provide a valuable addition to genomics and proteomics and give unique insights into metabolic changes that occur in tangent to alterations in gene and protein activity that are associated with disease. As a novel approach to understanding disease, metabolomics provides a "snapshot" in time of all metabolites present in a biological sample such as whole blood, plasma, serum, urine, and many other specimens that may be obtained from either patients or experimental models. In this article, we review the burgeoning field of metabolomics in its application to acute lung diseases, specifically pneumonia and acute respiratory disease syndrome (ARDS). We also discuss the potential applications of metabolomics for monitoring exposure to aerosolized environmental toxins. Recent reports have suggested that metabolomics analysis using nuclear magnetic resonance (NMR) and mass spectrometry (MS) approaches may provide clinicians with the opportunity to identify new biomarkers that may predict progression to more severe disease, such as sepsis, which kills many patients each year. In addition, metabolomics may provide more detailed phenotyping of patient heterogeneity, which is needed to achieve the goal of precision medicine. However, although several experimental and clinical metabolomics studies have been conducted assessing the application of the science to acute lung diseases, only incremental progress has been made. Specifically, little is known about the metabolic phenotypes of these illnesses. These data are needed to substantiate metabolomics biomarker credentials so that clinicians can employ them for clinical decision-making and investigators can use them to design clinical trials. PMID- 26973644 TI - Avian Influenza Viruses, Inflammation, and CD8(+) T Cell Immunity. AB - Avian influenza viruses (AIVs) circulate naturally in wild aquatic birds, infect domestic poultry, and are capable of causing sporadic bird-to-human transmissions. AIVs capable of infecting humans include a highly pathogenic AIV H5N1, first detected in humans in 1997, and a low pathogenic AIV H7N9, reported in humans in 2013. Both H5N1 and H7N9 cause severe influenza disease in humans, manifested by acute respiratory distress syndrome, multi-organ failure, and high mortality rates of 60% and 35%, respectively. Ongoing circulation of H5N1 and H7N9 viruses in wild birds and poultry, and their ability to infect humans emphasizes their epidemic and pandemic potential and poses a public health threat. It is, thus, imperative to understand the host immune responses to the AIVs so we can control severe influenza disease caused by H5N1 or H7N9 and rationally design new immunotherapies and vaccines. This review summarizes our current knowledge on AIV epidemiology, disease symptoms, inflammatory processes underlying the AIV infection in humans, and recent studies on universal pre existing CD8(+) T cell immunity to AIVs. Immune responses driving the host recovery from AIV infection in patients hospitalized with severe influenza disease are also discussed. PMID- 26973646 TI - Human NK Cell Diversity in Viral Infection: Ramifications of Ramification. AB - Natural killer (NK) cells are a unique lymphocyte lineage with remarkable agility in the rapid destruction of virus-infected cells. They are also the most poorly understood class of lymphocyte. A spectrum of activating and inhibitory receptors at the NK cell surface leads to an unusual and difficult-to-study mechanism of cellular recognition, as well as a very high capacity for diversity at the single cell level. Here, we review the evidence for the role of NK cells in the earliest stage of human viral infection, and in its prevention. We argue that single-cell diversity is a logical evolutionary adaptation for their position in the immune response and contributes to their ability to kill virus-infected cells. Finally, we look to the future, where emerging single-cell technologies will enable a new generation of rigorous and clinically relevant studies on NK cells accounting for all of their unique and diverse characteristics. PMID- 26973647 TI - Thioreductase-Containing Epitopes Inhibit the Development of Type 1 Diabetes in the NOD Mouse Model. AB - Autoreactive CD4(+) T cells recognizing islet-derived antigens play a primary role in type 1 diabetes. Specific suppression of such cells therefore represents a strategic target for the cure of the disease. We have developed a methodology by which CD4(+) T cells acquire apoptosis-inducing properties on antigen presenting cells after cognate recognition of natural sequence epitopes. We describe here that inclusion of a thiol-disulfide oxidoreductase (thioreductase) motif within the flanking residues of a single MHC class II-restricted GAD65 epitope induces GAD65-specific cytolytic CD4(+) T cells (cCD4(+) T). The latter, obtained either in vitro or by active immunization, acquire an effector memory phenotype and lyse APCs by a Fas-FasL interaction. Furthermore, cCD4(+) T cells eliminate by apoptosis activated bystander CD4(+) T cells recognizing alternative epitopes processed by the same APC. Active immunization with a GAD65 class II restricted thioreductase-containing T cell epitope protects mice from diabetes and abrogates insulitis. Passive transfer of in vitro-elicited cCD4(+) T cells establishes that such cells are efficient in suppressing autoimmunity. These findings provide strong evidence for a new vaccination strategy to prevent type 1 diabetes. PMID- 26973648 TI - PKCtheta and HIV-1 Transcriptional Regulator Tat Co-exist at the LTR Promoter in CD4(+) T Cells. AB - PKCtheta is essential for the activation of CD4(+) T cells. Upon TCR/CD28 stimulation, PKCtheta is phosphorylated and migrates to the immunological synapse, inducing the activation of cellular transcription factors such as NF kappaB and kinases as ERK that are critical for HIV-1 replication. We previously demonstrated that PKCtheta is also necessary for HIV-1 replication but the precise mechanism is unknown. Efficient HIV-1 transcription and elongation are absolutely dependent on the synergy between NF-kappaB and the viral regulator Tat. Tat exerts its function by binding a RNA stem-loop structure proximal to the viral mRNA cap site termed TAR. Besides, due to its effect on cellular metabolic pathways, Tat causes profound changes in infected CD4(+) T cells such as the activation of NF-kappaB and ERK. We hypothesized that the aberrant upregulation of Tat-mediated activation of NF-kappaB and ERK occurred through PKCtheta signaling. In fact, Jurkat TetOff cells with stable and doxycycline-repressible expression of Tat (Jurkat-Tat) expressed high levels of mRNA for PKCtheta. In these cells, PKCtheta located at the plasma membrane was phosphorylated at T(538) residue in undivided cells, in the absence of stimulation. Treatment with doxycycline inhibited PKCtheta phosphorylation in Jurkat-Tat, suggesting that Tat expression was directly related to the activation of PKCtheta. Both NF-kappaB and Ras/Raf/MEK/ERK signaling pathway were significantly activated in Jurkat-Tat cells, and this correlated with high transactivation of HIV-1 LTR promoter. RNA interference for PKCtheta inhibited NF-kappaB and ERK activity, as well as LTR mediated transactivation even in the presence of Tat. In addition to Tat-mediated activation of PKCtheta in the cytosol, we demonstrated by sequential ChIP that Tat and PKCtheta coexisted in the same complex bound at the HIV-1 LTR promoter, specifically at the region containing TAR loop. In conclusion, PKCtheta-Tat interaction seemed to be essential for HIV-1 replication in CD4(+) T cells and could be used as a therapeutic target. PMID- 26973650 TI - Distinctive Expression of Bcl-2 Factors in Regulatory T Cells Determines a Pharmacological Target to Induce Immunological Tolerance. AB - Distinctive molecular characteristics of functionally diverse lymphocyte populations may represent novel pharmacological targets for immunotherapy. The intrinsic apoptosis pathway is differently regulated among conventional and regulatory T cells (Tregs). Targeted pharmacological modulation of this pathway with a small molecule Bcl-2/Bcl-xL inhibitor (ABT-737) caused a selective depletion of effector T cells and a relative enrichment of Tregs in vivo. Treatment with ABT-737 resulted in a tolerogenic milieu, which was exploited to alleviate graft-versus-host disease, to prevent allograft rejection in a stringent fully MHC-mismatched skin transplantation model and to induce immunological tolerance in combination with bone marrow transplantation. This concept has the potential to find various applications for immunotherapy, since it allows pharmacologic exploitation of the immunomodulatory properties of Tregs without the need for cell manipulation ex vivo. PMID- 26973649 TI - An Oral Salmonella-Based Vaccine Inhibits Liver Metastases by Promoting Tumor Specific T-Cell-Mediated Immunity in Celiac and Portal Lymph Nodes: A Preclinical Study. AB - Primary tumor excision is one of the most widely used therapies of cancer. However, the risk of metastases development still exists following tumor resection. The liver is a common site of metastatic disease for numerous cancers. Breast cancer is one of the most frequent sources of metastases to the liver. The aim of this work was to evaluate the efficacy of the orally administered Salmonella Typhi vaccine strain CVD 915 on the development of liver metastases in a mouse model of breast cancer. To this end, one group of BALB/c mice was orogastrically immunized with CVD 915, while another received PBS as a control. After 24 h, mice were injected with LM3 mammary adenocarcinoma cells into the spleen and subjected to splenectomy. This oral Salmonella-based vaccine produced an antitumor effect, leading to a decrease in the number and volume of liver metastases. Immunization with Salmonella induced an early cellular immune response in mice. This innate stimulation rendered a large production of IFN gamma by intrahepatic immune cells (IHIC) detected within 24 h. An antitumor adaptive immunity was found in the liver and celiac and portal lymph nodes (LDLN) 21 days after oral bacterial inoculation. The antitumor immune response inside the liver was associated with increased CD4(+) and dendritic cell populations as well as with an inflammatory infiltrate located around liver metastatic nodules. Enlarged levels of inflammatory cytokines (IFN-gamma and TNF) were also detected in IHIC. Furthermore, a tumor-specific production of IFN-gamma and TNF as well as tumor-specific IFN-gamma-producing CD8 T cells (CD8(+)IFN-gamma(+)) were found in the celiac and portal lymph nodes of Salmonella-treated mice. This study provides first evidence for the involvement of LDLN in the development of an efficient cellular immune response against hepatic tumors, which resulted in the elimination of liver metastases after oral Salmonella-based vaccination. PMID- 26973651 TI - Purinergic Signaling to Terminate TLR Responses in Macrophages. AB - Macrophages undergo profound physiological alterations when they encounter pathogen-associated molecular patterns (PAMPs). These alterations can result in the elaboration of cytokines and mediators that promote immune responses and contribute to the clearance of pathogens. These innate immune responses by myeloid cells are transient. The termination of these secretory responses is not due to the dilution of stimuli, but rather to the active downregulation of innate responses induced by the very PAMPs that initiated them. Here, we describe a purinergic autoregulatory program whereby TLR-stimulated macrophages control their activation state. In this program, TLR-stimulated macrophages undergo metabolic alterations that result in the production of ATP and its release through membrane pannexin channels. This purine nucleotide is rapidly hydrolyzed to adenosine by ectoenzymes on the macrophage surface, CD39 and CD73. Adenosine then signals through the P1 class of seven transmembrane receptors to induce a regulatory state that is characterized by the downregulation of inflammatory cytokines and the production of anti-inflammatory cytokines and growth factors. This purinergic autoregulatory system mitigates the collateral damage that would be caused by the prolonged activation of macrophages and rather allows the macrophage to maintain homeostasis. The transient activation of macrophages can be prolonged by treating macrophages with IFN-gamma. IFN-gamma-treated macrophages become less sensitive to the regulatory effects of adenosine, allowing them to sustain macrophage activation for the duration of an adaptive immune response. PMID- 26973654 TI - Structural and Functional Characterization of a Single-Chain Form of the Recognition Domain of Complement Protein C1q. AB - Complement C1q is a soluble pattern recognition molecule comprising six heterotrimeric subunits assembled from three polypeptide chains (A-C). Each heterotrimer forms a collagen-like stem prolonged by a globular recognition domain. These recognition domains sense a wide variety of ligands, including pathogens and altered-self components. Ligand recognition is either direct or mediated by immunoglobulins or pentraxins. Multivalent binding of C1q to its targets triggers immune effector mechanisms mediated via its collagen-like stems. The induced immune response includes activation of the classical complement pathway and enhancement of the phagocytosis of the recognized target. We report here, the first production of a single-chain recombinant form of human C1q globular region (C1q-scGR). The three monomers have been linked in tandem to generate a single continuous polypeptide, based on a strategy previously used for adiponectin, a protein structurally related to C1q. The resulting C1q-scGR protein was produced at high yield in stably transfected 293-F mammalian cells. Recombinant C1q-scGR was correctly folded, as demonstrated by its X-ray crystal structure solved at a resolution of 1.35 A. Its interaction properties were assessed by surface plasmon resonance analysis using the following physiological C1q ligands: the receptor for C1q globular heads, the long pentraxin PTX3, calreticulin, and heparin. The 3D structure and the binding properties of C1q scGR were similar to those of the three-chain fragment generated by collagenase digestion of serum-derived C1q. Comparison of the interaction properties of the fragments with those of native C1q provided insights into the avidity component associated with the hexameric assembly of C1q. The interest of this functional recombinant form of the recognition domains of C1q in basic research and its potential biomedical applications are discussed. PMID- 26973653 TI - T Cells and Gene Regulation: The Switching On and Turning Up of Genes after T Cell Receptor Stimulation in CD8 T Cells. AB - Signaling downstream of the T cell receptor (TCR) is directly regulated by the dose and affinity of peptide antigen. The strength of TCR signaling drives a multitude of T cell functions from development to differentiation. CD8 T cells differentiate into a diverse pool of effector and memory cells after activation, a process that is critical for pathogen clearance and is highly regulated by TCR signal strength. T cells rapidly alter their gene expression upon activation. Multiple signaling pathways downstream of the TCR activate transcription factors, which are critical for this process. The dynamics between proximal TCR signaling, transcription factor activation and CD8 T cell function are discussed here. We propose that inducible T cell kinase (ITK) acts as a rheostat for gene expression. This unique regulation of TCR signaling by ITK provides a possible signaling mechanism for the promotion of a diverse T cell repertoire in response to pathogen. PMID- 26973652 TI - Unfolding the Role of Large Heat Shock Proteins: New Insights and Therapeutic Implications. AB - Heat shock proteins (HSPs) of eukaryotes are evolutionarily conserved molecules present in all the major intracellular organelles. They mainly function as molecular chaperones and participate in maintenance of protein homeostasis in physiological state and under stressful conditions. Despite their relative abundance, the large HSPs, i.e., Hsp110 and glucose-regulated protein 170 (Grp170), have received less attention compared to other conventional HSPs. These proteins are distantly related to the Hsp70 and belong to Hsp70 superfamily. Increased sizes of Hsp110 and Grp170, due to the presence of a loop structure, result in their exceptional capability in binding to polypeptide substrates or non-protein ligands, such as pathogen-associated molecules. These interactions that occur in the extracellular environment during tissue injury or microbial infection may lead to amplification of an immune response engaging both innate and adaptive immune components. Here, we review the current advances in understanding these large HSPs as molecular chaperones in proteostasis control and immune modulation as well as their therapeutic implications in treatment of cancer and neurodegeneration. Given their unique immunoregulatory activities, we also discuss the emerging evidence of their potential involvement in inflammatory and immune-related diseases. PMID- 26973655 TI - Hand to Mouth: A Systematic Review and Meta-Analysis of the Association between Rheumatoid Arthritis and Periodontitis. AB - BACKGROUND: Rheumatoid arthritis (RA) and periodontitis are both chronic inflammatory diseases, which demonstrate similarities in terms of mechanism, histopathology, and demography. An association between these conditions has been demonstrated previously but has been called into question more recently. METHODS: The published databases, such as MEDLINE, EMBASE, and PsycINFO, were searched using search terms related to RA and periodontitis. Articles were selected if they included data on the number of people with RA diagnosed with periodontitis (or periodontal disease parameters) compared to a control comparison group. Review articles, case reports, animal model studies, non-English language, and articles with unavailable abstracts were excluded. Data were extracted, critically appraised using the Downs and Black tool, and a random-effect Mantel Haenszel meta-analysis was performed. RESULTS: Twenty-one papers met the eligibility criteria and provided data for the meta-analysis; 17 studies (including a total of 153,492 participants) comparing RA to healthy controls and 4 (including a total of 1378 participants) comparing RA to osteoarthritis (OA). There was a significantly increased risk of periodontitis in people with RA compared to healthy controls (relative risk: 1.13; 95% CI: 1.04, 1.23; p = 0.006; N = 153,277) with a significantly raised mean probing depth, risk of bleeding on probing (BOP), and absolute value of clinical attachment loss in those with RA. When comparing RA and OA, there was no significant difference in the prevalence of periodontitis; however, the risk of BOP was greater in OA than RA. CONCLUSION: A significant association between RA and periodontitis is supported by the results of our systematic review and meta-analysis of studies comparing RA to healthy controls. In our meta-analysis, however, this is not replicated when comparing RA to OA controls. PMID- 26973656 TI - Modulation of Host Autophagy during Bacterial Infection: Sabotaging Host Munitions for Pathogen Nutrition. PMID- 26973658 TI - Phylogeny of Plant CAMTAs and Role of AtCAMTAs in Nonhost Resistance to Xanthomonas oryzae pv. oryzae. AB - Calmodulin-binding transcription activator (CAMTA) constitutes one of the most important Ca(2+)/CaM-regulated transcription factor families in plants. Nevertheless, the phylogeny, protein interaction network, and role in nonhost resistance of plant CAMTAs are not well understood. In this study, 200 CAMTA genes were identified from 35 species representing four major plant lineages. The CAMTA genes were conserved in multicellular land plants but absent in unicellular eukaryotes, and were likely to emerge from the fusion of two separate genes encoding a CAMTA-like protein and an IQ/CaM binding motif containing protein, respectively, in the embryophyta lineage ancestor. Approximately one fourth of plant CAMTAs did not contain a TIG domain. This non-TIG class of CAMTAs seems to have newly evolved through mutation of some key amino acids in the TIG domain of flowering land plants after divergence from the non-flowering plants. Phylogenetic analysis classified CAMTA proteins into three major groups and nine distinct subgroups, a result supported by protein domain and motif conservation analyses. Most (59.0 and 21.5%) of the identified CAMTA genes contained 12 or 11 introns, respectively. Gene duplication, intron invasion, enlargement and turnover, as well as exon rearrangements and skipping have apparently occurred during evolution of the CAMTA family. Moreover, 38 potential interactors of six Arabidopsis CAMTAs were predicted and 10 predicted target genes of AtCAMTA3 exhibited changes in expression between Atcamta3 mutants and wild-type plants. The majority of predicted interactors are transcription factors and/or Ca(2+)/CaM regulated proteins, suggesting that transcriptional regulation of the target genes might be the dominant functional mechanism of AtCAMTAs, and AtCAMTAs might act together with other Ca(2+) signaling components to regulate Ca(2+)-related biological processes. Furthermore, functional analyses employing Atcamta mutants revealed that AtCAMTA3 negatively regulated the immunity triggered by flg22 and nonhost resistance to Xanthomonas oryzae pv. oryzae via repressing accumulation of reactive oxygen species probably by targeting CBP60G, EDS1, and NDR1 and involving SA pathway. PMID- 26973657 TI - Transcriptome Characterization of Gnetum parvifolium Reveals Candidate Genes Involved in Important Secondary Metabolic Pathways of Flavonoids and Stilbenoids. AB - Gnetum is a small, unique group of Gnetophyta with a controversial phylogenetic position. Gnetum parvifolium is an important Chinese traditional medicinal plant, which is rich in bioactive compounds such as flavonoids and stilbenoids. These compounds provide significant medicinal effects, mostly as antioxidant, anticancer, and antibacterial agents. However, the mechanisms involved in the biosynthesis and regulation of these compounds in G. parvifolium are still unknown. In this study, we found that flavonoids and stilbene compounds accumulated at different levels in various tissues of G. parvifolium. We further obtained and analyzed massive sequence information from pooled samples of G. parvifolium by transcriptome sequencing, which generated 94,816 unigenes with an average length of 724 bp. Functional annotation of all these unigenes revealed that many of them were associated with several important secondary metabolism pathways including flavonoids and stilbenoids. In particular, several candidate unigenes (PAL-, C4H-, 4CL-, and STS-like genes) involved in stilbenoids biosynthesis were highly expressed in leaves and mature fruits. Furthermore, high temperature and UV-C strongly induced the expression of these genes and enhanced stilbene production (i.e., resveratrol and piceatannol) in leaves of young seedlings. Our present transcriptomic and biochemical data on secondary metabolites in G. parvifolium should encourage further investigation on evolution, ecology, functional genomics, and breeding of this plant with strong pharmaceutical potential. PMID- 26973659 TI - Redirecting the Cyanobacterial Bicarbonate Transporters BicA and SbtA to the Chloroplast Envelope: Soluble and Membrane Cargos Need Different Chloroplast Targeting Signals in Plants. AB - Most major crops used for human consumption are C3 plants, which yields are limited by photosynthetic inefficiency. To circumvent this, it has been proposed to implement the cyanobacterial CO2-concentrating mechanism (CCM), principally consisting of bicarbonate transporters and carboxysomes, into plant chloroplasts. As it is currently not possible to recover homoplasmic transplastomic monocots, foreign genes must be introduced in these plants via nuclear transformation. Consequently, it is paramount to ensure that resulting proteins reach the appropriate sub-cellular compartment, which for cyanobacterial transporters BicA and SbtA, is the chloroplast inner-envelope membrane (IEM). At present, targeting signals to redirect large transmembrane proteins from non-chloroplastic organisms to plant chloroplast envelopes are unknown. The goal of this study was to identify such signals, using agrobacteria-mediated transient expression and confocal microscopy to determine the sub-cellular localization of ~37 GFP-tagged chimeras. Initially, fragments of chloroplast proteins known to target soluble cargos to the stroma were tested for their ability to redirect BicA, but they proved ineffective. Next, different N-terminal regions from Arabidopsis IEM transporters were tested. We demonstrated that the N-terminus of AtHP59, AtPLGG1 or AtNTT1 (92-115 amino acids), containing a cleavable chloroplast transit peptide (cTP) and a membrane protein leader (MPL), was sufficient to redirect BicA or SbtA to the chloroplast envelope. This constitutes the first evidence that nuclear-encoded transmembrane proteins from non-chloroplastic organisms can be targeted to the envelope of plant chloroplasts; a finding which represents an important advance in chloroplast engineering by opening up the door to further manipulation of the chloroplastic envelope. PMID- 26973660 TI - Dual RNA-Sequencing of Eucalyptus nitens during Phytophthora cinnamomi Challenge Reveals Pathogen and Host Factors Influencing Compatibility. AB - Damage caused by Phytophthora cinnamomi Rands remains an important concern on forest tree species. The pathogen causes root and collar rot, stem cankers, and dieback of various economically important Eucalyptus spp. In South Africa, susceptible cold tolerant Eucalyptus plantations have been affected by various Phytophthora spp. with P. cinnamomi considered one of the most virulent. The molecular basis of this compatible interaction is poorly understood. In this study, susceptible Eucalyptus nitens plants were stem inoculated with P. cinnamomi and tissue was harvested five days post inoculation. Dual RNA sequencing, a technique which allows the concurrent detection of both pathogen and host transcripts during infection, was performed. Approximately 1% of the reads mapped to the draft genome of P. cinnamomi while 78% of the reads mapped to the Eucalyptus grandis genome. The highest expressed P. cinnamomi gene in planta was a putative crinkler effector (CRN1). Phylogenetic analysis indicated the high similarity of this P. cinnamomi CRN1 to that of Phytophthora infestans. Some CRN effectors are known to target host nuclei to suppress defense. In the host, over 1400 genes were significantly differentially expressed in comparison to mock inoculated trees, including suites of pathogenesis related (PR) genes. In particular, a PR-9 peroxidase gene with a high similarity to a Carica papaya PR-9 ortholog previously shown to be suppressed upon infection by Phytophthora palmivora was down-regulated two-fold. This PR-9 gene may represent a cross species effector target during P. cinnamomi infection. This study identified pathogenicity factors, potential manipulation targets, and attempted host defense mechanisms activated by E. nitens that contributed to the susceptible outcome of the interaction. PMID- 26973661 TI - MicroRNA Regulatory Mechanisms on Citrus sinensis leaves to Magnesium-Deficiency. AB - Magnesium (Mg)-deficiency, which affects crop productivity and quality, widespreadly exists in many agricultural crops, including citrus. However, very limited data are available on Mg-deficiency-responsive microRNAs (miRNAs) in higher plants. Using Illumina sequencing, we isolated 75 (73 known and 2 novel) up- and 71 (64 known and 7 novel) down-regulated miRNAs from Mg-deficient Citrus sinensis leaves. In addition to the remarkable metabolic flexibility as indicated by the great alteration of miRNA expression, the adaptive responses of leaf miRNAs to Mg-deficiency might also involve the following several aspects: (a) up regulating stress-related genes by down-regulating miR164, miR7812, miR5742, miR3946, and miR5158; (b) enhancing cell transport due to decreased expression of miR3946 and miR5158 and increased expression of miR395, miR1077, miR1160, and miR8019; (c) activating lipid metabolism-related genes by repressing miR158, miR5256, and miR3946; (d) inducing cell wall-related gene expansin 8A by repressing miR779; and (e) down-regulating the expression of genes involved in the maintenance of S, K and Cu by up-regulating miR395 and miR6426. To conclude, we isolated some new known miRNAs (i.e., miR7812, miR8019, miR6218, miR1533, miR6426, miR5256, miR5742, miR5561, miR5158, and miR5818) responsive to nutrient deficiencies and found some candidate miRNAs that might contribute to Mg deficiency tolerance. Therefore, our results not only provide novel information about the responses of plant to Mg-deficiency, but also are useful for obtaining the key miRNAs for plant Mg-deficiency tolerance. PMID- 26973662 TI - Transcriptome and Biochemical Analysis of a Flower Color Polymorphism in Silene littorea (Caryophyllaceae). AB - Flower color polymorphisms are widely used as model traits from genetics to ecology, yet determining the biochemical and molecular basis can be challenging. Anthocyanin-based flower color variations can be caused by at least 12 structural and three regulatory genes in the anthocyanin biosynthetic pathway (ABP). We use mRNA-Seq to simultaneously sequence and estimate expression of these candidate genes in nine samples of Silene littorea representing three color morphs (dark pink, light pink and white) across three developmental stages in hopes of identifying the cause of flower color variation. We identified 29 putative paralogs for the 15 candidate genes in the ABP. We assembled complete coding sequences for 16 structural loci and nine of ten regulatory loci. Among these 29 putative paralogs, we identified 622 SNPs, yet only nine synonymous SNPs in Ans had allele frequencies that differentiated pigmented petals (dark pink and light pink) from white petals. These Ans allele frequency differences were further investigated with an expanded sequencing survey of 38 individuals, yet no SNPs consistently differentiated the color morphs. We also found one locus, F3h1, with strong differential expression between pigmented and white samples (>42x). This may be caused by decreased expression of Myb1a in white petal buds. Myb1a in S. littorea is a regulatory locus closely related to Subgroup 7 Mybs known to regulate F3h and other loci in the first half of the ABP in model species. We then compare the mRNA-Seq results with petal biochemistry which revealed cyanidin as the primary anthocyanin and five flavonoid intermediates. Concentrations of three of the flavonoid intermediates were significantly lower in white petals than in pigmented petals (rutin, quercetin and isovitexin). The biochemistry results for rutin, quercetin, luteolin and apigenin are consistent with the transcriptome results suggesting a blockage at F3h, possibly caused by downregulation of Myb1a. PMID- 26973664 TI - Suitability of Phytosterols Alongside Fatty Acids as Chemotaxonomic Biomarkers for Phytoplankton. AB - The composition and abundance of phytoplankton is an important factor defining ecological status of marine and freshwater ecosystems. Chemotaxonomic markers (e.g., pigments and fatty acids) are needed for monitoring changes in a phytoplankton community and to know the nutritional quality of seston for herbivorous zooplankton. Here we investigated the suitability of sterols along with fatty acids as chemotaxonomic markers using multivariate statistics, by analyzing the sterol and fatty acid composition of 10 different phytoplankton classes including altogether 37 strains isolated from freshwater lakes. We were able to detect a total of 47 fatty acids and 29 sterols in our phytoplankton samples, which both differed statistically significantly between phytoplankton classes. Due to the high variation of fatty acid composition among Cyanophyceae, taxonomical differentiation increased when Cyanophyceae were excluded from statistical analysis. Sterol composition was more heterogeneous within class than fatty acids and did not improve separation of phytoplankton classes when used alongside fatty acids. However, we conclude that sterols can provide additional information on the abundance of specific genera within a class which can be generated by using fatty acids. For example, whereas high C16 omega-3 PUFA (polyunsaturated fatty acid) indicates the presence of Chlorophyceae, a simultaneous high amount of ergosterol could specify the presence of Chlamydomonas spp. (Chlorophyceae). Additionally, we found specific 4alpha-methyl sterols for distinct Dinophyceae genera, suggesting that 4alpha-methyl sterols can potentially separate freshwater dinoflagellates from each other. PMID- 26973663 TI - Presence of Inulin-Type Fructo-Oligosaccharides and Shift from Raffinose Family Oligosaccharide to Fructan Metabolism in Leaves of Boxtree (Buxus sempervirens). AB - Fructans are known to occur in 15% of flowering plants and their accumulation is often associated with stress responses. Typically, particular fructan types occur within particular plant families. The family of the Buxaceae, harboring Pachysandra terminalis, an accumulator of graminan- and levan-type fructans, also harbors boxtree (Buxus sempervirens), a cold and drought tolerant species. Surprisingly, boxtree leaves do not accumulate the expected graminan- and levan type fructans, but small inulin fructo-oligosaccharides (FOS: 1-kestotriose and nystose) and raffinose family oligosaccharides (RFOs: raffinose and stachyose) instead. The seasonal variation in concentrations of glucose, fructose, sucrose, FOS and RFOs were followed. Raffinose and stachyose peaked during the winter months, while FOS peaked at a very narrow time-interval in spring, immediately preceded by a prominent sucrose accumulation. Sucrose may function as a reserve carbohydrate in winter and early spring leaves. The switch from RFO to fructan metabolism in spring strongly suggests that fructans and RFOs fulfill distinct roles in boxtree leaves. RFOs may play a key role in the cold acclimation of winter leaves while temporal fructan biosynthesis in spring might increase sink strength to sustain the formation of new shoots. PMID- 26973665 TI - Reducing Cytoplasmic Polyamine Oxidase Activity in Arabidopsis Increases Salt and Drought Tolerance by Reducing Reactive Oxygen Species Production and Increasing Defense Gene Expression. AB - The link between polyamine oxidases (PAOs), which function in polyamine catabolism, and stress responses remains elusive. Here, we address this issue using Arabidopsis pao mutants in which the expression of the five PAO genes is knocked-out or knocked-down. As the five single pao mutants and wild type (WT) showed similar response to salt stress, we tried to generate the mutants that have either the cytoplasmic PAO pathway (pao1 pao5) or the peroxisomal PAO pathway (pao2 pao3 pao4) silenced. However, the latter triple mutant was not obtained. Thus, in this study, we used two double mutants, pao1 pao5 and pao2 pao4. Of interest, pao1 pao5 mutant was NaCl- and drought-tolerant, whereas pao2 pao4 showed similar sensitivity to those stresses as WT. To reveal the underlying mechanism of salt tolerance, further analyses were performed. Na uptake of the mutant (pao1 pao5) decreased to 75% of WT. PAO activity of the mutant was reduced to 62% of WT. The content of reactive oxygen species (ROS) such as hydrogen peroxide, a reaction product of PAO action, and superoxide anion in the mutant became 81 and 72% of the levels in WT upon salt treatment. The mutant contained 2.8-fold higher thermospermine compared to WT. Moreover, the mutant induced the genes of salt overly sensitive-, abscisic acid (ABA)-dependent- and ABA independent- pathways more strongly than WT upon salt treatment. The results suggest that the Arabidopsis plant silencing cytoplasmic PAOs shows salinity tolerance by reducing ROS production and strongly inducing subsets of stress responsive genes under stress conditions. PMID- 26973666 TI - Improved Shoot Regeneration, Salinity Tolerance and Reduced Fungal Susceptibility in Transgenic Tobacco Constitutively Expressing PR-10a Gene. AB - Plants in ecosystems are simultaneously exposed to abiotic and biotic stresses, which restrict plant growth and development. The complex responses to these stresses are largely regulated by plant hormones, which in turn, orchestrate the different biochemical and molecular pathways to maneuver stress tolerance. The PR 10 protein family is reported to be involved in defense regulation, stress response and plant growth and development. The JcPR-10a overexpression resulted in increased number of shoot buds in tobacco (Nicotiana tabacum), which could be due to high cytokinin to auxin ratio in the transgenics. The docking analysis shows the binding of three BAP molecules at the active sites of JcPR-10a protein. JcPR-10a transgenics showed enhanced salt tolerance, as was evident by increased germination rate, shoot and root length, relative water content, proline, soluble sugar and amino acid content under salinity. Interestingly, the transgenics also showed enhanced endogenous cytokinin level as compared to WT, which, further increased with salinity. Exposure of gradual salinity resulted in increased stomatal conductance, water use efficiency, photosynthesis rate and reduced transpiration rate. Furthermore, the transgenics also showed enhanced resistance against Macrophomina fungus. Thus, JcPR-10a might be working in co-ordination with cytokinin signaling in mitigating the stress induced damage by regulating different stress signaling pathways, leading to enhanced stress tolerance. PMID- 26973668 TI - Quantification of Overnight Movement of Birch (Betula pendula) Branches and Foliage with Short Interval Terrestrial Laser Scanning. AB - The goal of the study was to determine circadian movements of silver birch (Petula Bendula) branches and foliage detected with terrestrial laser scanning (TLS). The study consisted of two geographically separate experiments conducted in Finland and in Austria. Both experiments were carried out at the same time of the year and under similar outdoor conditions. Experiments consisted of 14 (Finland) and 77 (Austria) individual laser scans taken between sunset and sunrise. The resulting point clouds were used in creating a time series of branch movements. In the Finnish data, the vertical movement of the whole tree crown was monitored due to low volumetric point density. In the Austrian data, movements of manually selected representative points on branches were monitored. The movements were monitored from dusk until morning hours in order to avoid daytime wind effects. The results indicated that height deciles of the Finnish birch crown had vertical movements between -10.0 and 5.0 cm compared to the situation at sunset. In the Austrian data, the maximum detected representative point movement was 10.0 cm. The temporal development of the movements followed a highly similar pattern in both experiments, with the maximum movements occurring about an hour and a half before (Austria) or around (Finland) sunrise. The results demonstrate the potential of terrestrial laser scanning measurements in support of chronobiology. PMID- 26973667 TI - Proton Gradients and Proton-Dependent Transport Processes in the Chloroplast. AB - Proton gradients are fundamental to chloroplast function. Across thylakoid membranes, the light induced -proton gradient is essential for ATP synthesis. As a result of proton pumping into the thylakoid lumen, an alkaline stromal pH develops, which is required for full activation of pH-dependent Calvin Benson cycle enzymes. This implies that a pH gradient between the cytosol (pH 7) and the stroma (pH 8) is established upon illumination. To maintain this pH gradient chloroplasts actively extrude protons. More than 30 years ago it was already established that these proton fluxes are electrically counterbalanced by Mg(2+), K(+), or Cl(-) fluxes, but only recently the first transport systems that regulate the pH gradient were identified. Notably several (Na(+),K(+))/H(+) antiporter systems where identified, that play a role in pH gradient regulation, ion homeostasis, osmoregulation, or coupling of secondary active transport. The established pH gradients are important to drive uptake of essential ions and solutes, but not many transporters involved have been identified to date. In this mini review we summarize the current status in the field and the open questions that need to be addressed in order to understand how pH gradients are maintained, how this is interconnected with other transport processes and what this means for chloroplast function. PMID- 26973669 TI - Development and Identification of SSR Markers Associated with Starch Properties and beta-Carotene Content in the Storage Root of Sweet Potato (Ipomoea batatas L.). AB - Sweet potato (Ipomoea batatas L.) is a nutritious food crop and, based on the high starch content of its storage root, a potential bioethanol feedstock. Enhancing the nutritional value and starch quantity of storage roots are important goals of sweet potato breeding programs aimed at developing improved varieties for direct consumption, processing, and industrial uses. However, developing improved lines of sweet potato is challenging due to the genetic complexity of this plant and the lack of genome information. Short sequence repeat (SSR) markers are powerful molecular tools for tracking important loci in crops and for molecular-based breeding strategies; however, few SSR markers and marker-trait associations have hitherto been identified in sweet potato. In this study, we identified 1824 SSRs by using a de novo assembly of publicly available ESTs and mRNAs in sweet potato, and designed 1476 primer pairs based on SSR containing sequences. We mapped 214 pairs of primers in a natural population comprised of 239 germplasms, and identified 1278 alleles with an average of 5.972 alleles per locus and a major allele frequency of 0.7702. Population structure analysis revealed two subpopulations in this panel of germplasms, and phenotypic characterization demonstrated that this panel is suitable for association mapping of starch-related traits. We identified 32, 16, and 17 SSR markers associated with starch content, beta-carotene content, and starch composition in the storage root, respectively, using association analysis and further evaluation of a subset of sweet potato genotypes with various characteristics. The SSR markers identified here can be used to select varieties with desired traits and to investigate the genetic mechanism underlying starch and carotenoid formation in the starchy roots of sweet potato. PMID- 26973670 TI - Anatomical and Physiological Responses of Citrus Trees to Varying Boron Availability Are Dependent on Rootstock. AB - In Citrus, water, nutrient transport and thereby fruit production, are influenced among other factors, by the interaction between rootstock and boron (B) nutrition. This study aimed to investigate how B affects the anatomical structure of roots and leaves as well as leaf gas exchange in sweet orange trees grafted on two contrasting rootstocks in response to B supply. Plants grafted on Swingle citrumelo or Sunki mandarin were grown in a nutrient solution of varying B concentration (deficient, adequate, and excessive). Those grafted on Swingle were more tolerant to both B deficiency and toxicity than those on Sunki, as revealed by higher shoot and root growth. In addition, plants grafted on Sunki exhibited more severe anatomical and physiological damages under B deficiency, showing thickening of xylem cell walls and impairments in whole-plant leaf-specific hydraulic conductance and leaf CO2 assimilation. Our data revealed that trees grafted on Swingle sustain better growth under low B availablitlity in the root medium and still respond positively to increased B levels by combining higher B absorption and root growth as well as better organization of xylem vessels. Taken together, those traits improved water and B transport to the plant canopy. Under B toxicity, Swingle rootstock would also favor plant growth by reducing anatomical and ultrastructural damage to leaf tissue and improving water transport compared with plants grafted on Sunki. From a practical point of view, our results highlight that B management in citrus orchards shall take into account rootstock varieties, of which the Swingle rootstock was characterized by its performance on regulating anatomical and ultrastructural damages, improving water transport and limiting negative impacts of B stress conditions on plant growth. PMID- 26973671 TI - Mutation of the Glucosinolate Biosynthesis Enzyme Cytochrome P450 83A1 Monooxygenase Increases Camalexin Accumulation and Powdery Mildew Resistance. AB - Small secondary metabolites, including glucosinolates and the major phytoalexin camalexin, play important roles in immunity in Arabidopsis thaliana. We isolated an Arabidopsis mutant with increased resistance to the powdery mildew fungus Golovinomyces cichoracearum and identified a mutation in the gene encoding cytochrome P450 83A1 monooxygenase (CYP83A1), which functions in glucosinolate biosynthesis. The cyp83a1-3 mutant exhibited enhanced defense responses to G. cichoracearum and double mutant analysis showed that this enhanced resistance requires NPR1, EDS1, and PAD4, but not SID2 or EDS5. In cyp83a1-3 mutants, the expression of genes related to camalexin synthesis increased upon G. cichoracearum infection. Significantly, the cyp83a1-3 mutant also accumulated higher levels of camalexin. Decreasing camalexin levels by mutation of the camalexin synthetase gene PAD3 or the camalexin synthesis regulator AtWRKY33 compromised the powdery mildew resistance in these mutants. Consistent with these observations, overexpression of PAD3 increased camalexin levels and enhanced resistance to G. cichoracearum. Taken together, our data indicate that accumulation of higher levels of camalexin contributes to increased resistance to powdery mildew. PMID- 26973674 TI - Solanum clarum and S. morelliforme as Novel Model Species for Studies of Epiphytism. AB - The natural history of epiphytic plant species has been extensively studied. However, little is known about the physiology and genetics of epiphytism. This is due to difficulties associated with growing epiphytic plants and the lack of tools for genomics studies and genetic manipulations. In this study, tubers were generated from 223 accessions of 42 wild potato Solanum species, including the epiphytic species S. morelliforme and its sister species S. clarum. Lyophilized samples were analyzed for 12 minerals using inductively coupled plasma optical emission spectrometry. Mineral levels in tubers of S. morelliforme and S. clarum were among the highest for 10 out of the 12 elements evaluated. These two wild potato relatives are native to southern Mexico and Central America and live as epiphytes or in epiphytic-like conditions. We propose the use of S. morelliforme and S. clarum as model organisms for the study of mineral uptake efficiency. They have a short life cycle, can be propagated vegetatively via tubers or cuttings, and can be easily grown in controlled environments. In addition, genome sequence data are available for potato. Transgenic manipulations and somatic fusions will allow the movement of genes from these epiphytes to cultivated potato. PMID- 26973672 TI - Overexpression of Peptide-Encoding OsCEP6.1 Results in Pleiotropic Effects on Growth in Rice (O. sativa). AB - Plant peptide hormones play an important role in regulating plant developmental programs via cell-to-cell communication in a non-cell autonomous manner. To characterize the biological relevance of C-TERMINALLY ENCODED PEPTIDE (CEP) genes in rice, we performed a genome-wide search against public databases using a bioinformatics approach and identified six additional CEP members. Expression analysis revealed a spatial-temporal pattern of OsCEP6.1 gene in different tissues and at different developmental stages of panicle. Interestingly, the expression level of the OsCEP6.1 was also significantly up-regulated by exogenous cytokinin. Application of a chemically synthesized 15-amino acid OsCEP6.1 peptide showed that OsCEP6.1 had a negative role in regulating root and seedling growth, which was further confirmed by transgenic lines. Furthermore, the constitutive expression of OsCEP6.1 was sufficient to lead to panicle architecture and grain size variations. Scanning electron microscopy analysis revealed that the phenotypic variation of OsCEP6.1 overexpression lines resulted from decreased cell size but not reduced cell number. Moreover, starch accumulation was not significantly affected. Taken together, these data suggest that the OsCEP6.1 peptide might be involved in regulating the development of panicles and grains in rice. PMID- 26973675 TI - Polar Constituents and Biological Activity of the Berry-Like Fruits from Hypericum androsaemum L. AB - Hypericum androsaemum, also known as Tutsan, is a small evergreen shrub common in the Mediterranean basin where it is traditionally used as diuretic and hepatoprotective herbal drug. This plant possesses the peculiarity to produce fleshy and berry-like fruits that ripen from red to shiny black. In the present work, the chemical constituents of methanolic extracts and infusions of red and black fruits were analyzed by HPLC, and correlated with their antioxidant properties which were evaluated by the DPPH, beta-Carotene/linoleic acid, and hypochlorous acid tests. In addition, the red pigment of the fruit was isolated by column chromatography and structurally elucidated by NMR. Results showed that H. androsaemum fruits contain high amounts of shikimic and chlorogenic acids, while their color was given by a tetraoxygenated-type xanthone, reported for the first time in Hypericum species. The red berries infusion gave the highest content of total phenolic compounds, DPPH, and hypochlorous acid scavenging activity, and beta-carotene bleaching. Cytotoxicity of the berries extracts on three human tumor cell lines (malignant melanoma, breast adenocarcinoma, and colon carcinoma) was evaluated by MTT assay, and relevant inhibition on colon carcinoma cells (IC50 value of 8.4 MUg/mL) was found. Finally, the effects of red berries extract on the immune system were evaluated by peripheral blood mononuclear cell (PBMC) proliferation assay that revealed a strong stimulation on lymphocytes at low doses (0.4-6 MUg/mL). PMID- 26973673 TI - Hydrogen Peroxide Signaling in Plant Development and Abiotic Responses: Crosstalk with Nitric Oxide and Calcium. AB - Hydrogen peroxide (H2O2), as a reactive oxygen species, is widely generated in many biological systems. It has been considered as an important signaling molecule that mediates various physiological and biochemical processes in plants. Normal metabolism in plant cells results in H2O2 generation, from a variety of sources. Also, it is now clear that nitric oxide (NO) and calcium (Ca(2+)) function as signaling molecules in plants. Both H2O2 and NO are involved in plant development and abiotic responses. A wide range of evidences suggest that NO could be generated under similar stress conditions and with similar kinetics as H2O2. The interplay between H2O2 and NO has important functional implications to modulate transduction processes in plants. Moreover, close interaction also exists between H2O2 and Ca(2+) in response to development and abiotic stresses in plants. Cellular responses to H2O2 and Ca(2+) signaling systems are complex. There is quite a bit of interaction between H2O2 and Ca(2+) signaling in responses to several stimuli. This review aims to introduce these evidences in our understanding of the crosstalk among H2O2, NO, and Ca(2+) signaling which regulates plant growth and development, and other cellular and physiological responses to abiotic stresses. PMID- 26973676 TI - Maximum Growth Potential and Periods of Resource Limitation in Apple Tree. AB - Knowledge of seasonal maximum potential growth rates are important for assessing periods of resource limitations in fruit tree species. In this study we assessed the periods of resource limitation for vegetative (current year stems, and woody biomass) and reproductive (fruit) organs of a major agricultural crop: the apple tree. This was done by comparing relative growth rates (RGRs) of individual organs in trees with reduced competition for resources to trees grown under standard field conditions. Special attention was dedicated to disentangling patterns and values of maximum potential growth for each organ type. The period of resource limitation for vegetative growth was much longer than in another fruit tree species (peach): from late May until harvest. Two periods of resource limitation were highlighted for fruit: from the beginning of the season until mid June, and about 1 month prior to harvest. By investigating the variability in individual organs growth we identified substantial differences in RGRs among different shoot categories (proleptic and epicormic) and within each group of monitored organs. Qualitatively different and more accurate values of growth rates for vegetative organs, compared to the use of the simple compartmental means, were estimated. Detailed, source-sink based tree growth models, commonly in need of fine parameter tuning, are expected to benefit from the results produced by these analyses. PMID- 26973677 TI - Epigenetic Histone Marks of Extended Meta-Polycentric Centromeres of Lathyrus and Pisum Chromosomes. AB - Species of the legume genera Lathyrus and Pisum possess chromosomes that exhibit a unique structure of their centromeric regions, which is clearly apparent during metaphase by the formation of extended primary constrictions which span up to a third of the length of the chromosome. In addition, these species express two different variants of the CenH3 protein which are co-localized in multiple domains along the poleward surface of the primary constrictions. Here, we show that the constrictions represent a distinct type of chromatin differing from the chromosome arms. In metaphase, histone phosphorylation patterns including H3S10ph, H3S28ph, and H3T3ph were observed along the entire constriction, in a way similar to holocentric chromosomes. On the other hand, distribution of phosphorylated H2AT120 was different from that previously reported from either, holocentric and monocentric chromosomes, occurring at chromatin surrounding but not overlapping CenH3 domains. Since some of these phosphorylations play a role in chromatid cohesion, it can be assumed that they facilitate correct chromosome segregation by ensuring that multiple separate CenH3 domains present on the same chromatid are oriented toward the same pole. The constrictions also displayed distinct patterns of histone methylation marks, being enriched in H3K9me2 and depleted in H3K4me3 and H3K27me2 compared to the chromosome arms. Super resolution fluorescence microscopy revealed that although both CenH3 protein variants are present in all CenH3 domains detected on metaphase chromosomes, they are only partially co-localized while there are chromatin subdomains which are mostly made of only one CenH3 variant. Taken together, these data revealed specific features of extended primary constrictions of Lathyrus and Pisum and support the idea that they may represent an intermediate stage between monocentric and holocentric chromosomes. PMID- 26973678 TI - MicroRNA390 Is Involved in Cadmium Tolerance and Accumulation in Rice. AB - Cadmium (Cd) is a non-essential heavy metal that is toxic to plants. microRNAs (miRNAs) are 21-nucleotide RNAs that are ubiquitous regulators of gene expression at the post-transcriptional level. Several plant miRNAs, such as miR390, have vital roles in plant growth, development and responses to environmental stresses including heavy metal stress. In this study, the expression of mature miR390 was significantly down-regulated under Cd stress in rice. Consequently, the target gene of miR390, OsSRK was dramatically induced by Cd treatment. Transgenic rice plants overexpressing miR390 displayed reduced Cd tolerance and higher Cd accumulation compared with wild-type plants. Simultaneously, expression of OsSRK was less pronounced in 35S:MIR390 plants than in wild-type. These results indicate that miR390 was a negative regulator involved in Cd stress tolerance in rice. PMID- 26973679 TI - Plant Responses to Vegetation Proximity: A Whole Life Avoiding Shade. AB - In high density of vegetation, plants detect neighbors by perceiving changes in light quality through phytochrome photoreceptors. Close vegetation proximity might result in competition for resources, such as light. To face this challenge, plants have evolved two alternative strategies: to either tolerate or avoid shade. Shade-avoiding species generally adapt their development by inducing hypocotyl, stem, and petiole elongation, apical dominance and flowering, and decreasing leaf expansion and yield, a set of responses collectively known as the shade avoidance syndrome (SAS). The SAS responses have been mostly studied at the seedling stage, centered on the increase of hypocotyl elongation. After compiling the main findings about SAS responses in seedlings, this review is focused on the response to shade at adult stages of development, such as petioles of adult leaves, and the little information available on the SAS responses in reproductive tissues. We discuss these responses based on the knowledge about the molecular mechanisms and components with a role in regulating the SAS response of the hypocotyls of Arabidopsis thaliana. The transcriptional networks involved in this process, as well as the communication among the tissues that perceive the shade and the ones that respond to this stimulus will also be briefly commented. PMID- 26973681 TI - RNA-seq Analysis of Irrigated vs. Water Stressed Transcriptomes of Zea mays Cultivar Z59. PMID- 26973680 TI - An Inventory of Nutrient-Responsive Genes in Arabidopsis Root Hairs. AB - Root hairs, single cell extensions of root epidermal cells that are critically involved in the acquisition of mineral nutrients, have proven to be an excellent model system for studying plant cell growth. More recently, omics-based systems biology approaches have extended the model function of root hairs toward functional genomic studies. While such studies are extremely useful to decipher the complex mechanisms underlying root hair morphogenesis, their importance for the performance and fitness of the plant puts root hairs in the spotlight of research aimed at elucidating aspects with more practical implications. Here, we mined transcriptomic and proteomic surveys to catalog genes that are preferentially expressed in root hairs and responsive to nutritional signals. We refer to this group of genes as the root hair trophomorphome. Our analysis shows that the activity of genes within the trophomorphome is regulated at both the transcriptional and post-transcriptional level with the mode of regulation being related to the function of the gene product. A core set of proteins functioning in cell wall modification and protein transport was defined as the backbone of the trophomorphome. In addition, our study shows that homeostasis of reactive oxygen species and redox regulation plays a key role in root hair trophomorphogenesis. PMID- 26973682 TI - Transcriptomic Analysis Using Olive Varieties and Breeding Progenies Identifies Candidate Genes Involved in Plant Architecture. AB - Plant architecture is a critical trait in fruit crops that can significantly influence yield, pruning, planting density and harvesting. Little is known about how plant architecture is genetically determined in olive, were most of the existing varieties are traditional with an architecture poorly suited for modern growing and harvesting systems. In the present study, we have carried out microarray analysis of meristematic tissue to compare expression profiles of olive varieties displaying differences in architecture, as well as seedlings from their cross pooled on the basis of their sharing architecture-related phenotypes. The microarray used, previously developed by our group has already been applied to identify candidates genes involved in regulating juvenile to adult transition in the shoot apex of seedlings. Varieties with distinct architecture phenotypes and individuals from segregating progenies displaying opposite architecture features were used to link phenotype to expression. Here, we identify 2252 differentially expressed genes (DEGs) associated to differences in plant architecture. Microarray results were validated by quantitative RT-PCR carried out on genes with functional annotation likely related to plant architecture. Twelve of these genes were further analyzed in individual seedlings of the corresponding pool. We also examined Arabidopsis mutants in putative orthologs of these targeted candidate genes, finding altered architecture for most of them. This supports a functional conservation between species and potential biological relevance of the candidate genes identified. This study is the first to identify genes associated to plant architecture in olive, and the results obtained could be of great help in future programs aimed at selecting phenotypes adapted to modern cultivation practices in this species. PMID- 26973683 TI - Avirulence Genes in Cereal Powdery Mildews: The Gene-for-Gene Hypothesis 2.0. AB - The gene-for-gene hypothesis states that for each gene controlling resistance in the host, there is a corresponding, specific gene controlling avirulence in the pathogen. Allelic series of the cereal mildew resistance genes Pm3 and Mla provide an excellent system for genetic and molecular analysis of resistance specificity. Despite this opportunity for molecular research, avirulence genes in mildews remain underexplored. Earlier work in barley powdery mildew (B.g. hordei) has shown that the reaction to some Mla resistance alleles is controlled by multiple genes. Similarly, several genes are involved in the specific interaction of wheat mildew (B.g. tritici) with the Pm3 allelic series. We found that two mildew genes control avirulence on Pm3f: one gene is involved in recognition by the resistance protein as demonstrated by functional studies in wheat and the heterologous host Nicotiana benthamiana. A second gene is a suppressor, and resistance is only observed in mildew genotypes combining the inactive suppressor and the recognized Avr. We propose that such suppressor/avirulence gene combinations provide the basis of specificity in mildews. Depending on the particular gene combinations in a mildew race, different genes will be genetically identified as the "avirulence" gene. Additionally, the observation of two LINE retrotransposon-encoded avirulence genes in B.g. hordei further suggests that the control of avirulence in mildew is more complex than a canonical gene for-gene interaction. To fully understand the mildew-cereal interactions, more knowledge on avirulence determinants is needed and we propose ways how this can be achieved based on recent advances in the field. PMID- 26973684 TI - FragariaCyc: A Metabolic Pathway Database for Woodland Strawberry Fragaria vesca. AB - FragariaCyc is a strawberry-specific cellular metabolic network based on the annotated genome sequence of Fragaria vesca L. ssp. vesca, accession Hawaii 4. It was built on the Pathway-Tools platform using MetaCyc as the reference. The experimental evidences from published literature were used for supporting/editing existing entities and for the addition of new pathways, enzymes, reactions, compounds, and small molecules in the database. To date, FragariaCyc comprises 66 super-pathways, 488 unique pathways, 2348 metabolic reactions, 3507 enzymes, and 2134 compounds. In addition to searching and browsing FragariaCyc, researchers can compare pathways across various plant metabolic networks and analyze their data using Omics Viewer tool. We view FragariaCyc as a resource for the community of researchers working with strawberry and related fruit crops. It can help understanding the regulation of overall metabolism of strawberry plant during development and in response to diseases and abiotic stresses. FragariaCyc is available online at http://pathways.cgrb.oregonstate.edu. PMID- 26973686 TI - Relevance of the Axis Spermidine/eIF5A for Plant Growth and Development. AB - One key role of the essential polyamine spermidine in eukaryotes is to provide the 4-aminobutyl moiety group destined to the post-translational modification of a lysine in the highly conserved translation factor eIF5A. This modification is catalyzed by two sequential enzymatic steps leading to the activation of eIF5A by the conversion of one conserved lysine to the unusual amino acid hypusine. The active translation factor facilitates the sequence-specific translation of polyproline sequences that otherwise cause ribosome stalling. In spite of the well-characterized involvement of active eIF5A in the translation of proline repeat-rich proteins, its biological role has been recently elucidated only in mammals, and it is poorly described at the functional level in plants. Here we describe the alterations in plant growth and development caused by RNAi-mediated conditional genetic inactivation of the hypusination pathway in Arabidopsis thaliana by knocking-down the enzyme deoxyhypusine synthase. We have uncovered that spermidine-mediated activation of eIF5A by hypusination is involved in several aspects of plant biology such as the control of flowering time, the aerial and root architecture, and root hair growth. In addition this pathway is required for adaptation to challenging growth conditions such as high salt and high glucose medium and to elevated concentrations of the plant hormone ABA. We have also performed a bioinformatic analysis of polyproline-rich containing proteins as putative eIF5A targets to uncover their organization in clusters of protein networks to find molecular culprits for the disclosed phenotypes. This study represents a first attempt to provide a holistic view of the biological relevance of the spermidine-dependent hypusination pathway for plant growth and development. PMID- 26973685 TI - Functional Characterization of Novel Chitinase Genes Present in the Sheath Blight Resistance QTL: qSBR11-1 in Rice Line Tetep. AB - Rice sheath blight disease caused by Rhizoctonia solani is one of the most devastating diseases in rice leading to heavy yield losses. Due to the polygenic nature of resistance, no major resistance gene with complete host resistance against R. solani has been reported. In this study, we have performed molecular and functional analysis of the genes associated with the major R. solani resistance QTL qSBR11-1 in the indica rice line Tetep. Sequence analysis revealed the presence of a set of 11 tandem repeats containing genes with a high degree of homology to class III chitinase defense response genes. Real-time quantitative PCR analysis showed that all the genes are strongly induced 36 h after R. solani infection. Comparison between the resistant Tetep and the susceptible HP2216 lines shows that the induction of the chitinase genes is much higher in the Tetep line. Recombinant protein produced in vitro for six of the eleven genes showed chitinolytic activity in gel assays but we did not detect any xylanase inhibitory activity. All the six in vitro expressed proteins show antifungal activity with a clear inhibitory effect on the growth of the R. solani mycelium. The characterized chitinase genes can provide an important resource for the genetic improvement of R. solani susceptible rice lines for sheath blight resistance breeding. PMID- 26973687 TI - COLORFUL-Circuit: A Platform for Rapid Multigene Assembly, Delivery, and Expression in Plants. AB - Advancing basic and applied plant research requires the continuous innovative development of the available technology toolbox. Essential components of this toolbox are methods that simplify the assembly, delivery, and expression of multiple transgenes of interest. To allow simultaneous and directional multigene assembly on the same plant transformation vector, several strategies based on overlapping sequences or restriction enzymes have recently been developed. However, the assembly of homologous and repetitive DNA sequences can be inefficient and the frequent occurrence of target sequences recognized by commonly used restriction enzymes can be a limiting factor. Here, we noted that recognition sites for the restriction enzyme SfiI are rarely occurring in plant genomes. This fact was exploited to establish a multigene assembly system called "COLORFUL-Circuit." To this end, we developed a set of binary vectors which provide a flexible and cost efficient cloning platform. The gene expression cassettes in our system are flanked with unique SfiI sites, which allow simultaneous multi-gene cassette assembly in a hosting binary vector. We used COLORFUL-Circuit to transiently and stably express up to four fluorescent organelle markers in addition to a selectable marker and analyzed the impact of assembly design on coexpression efficiency. Finally, we demonstrate the utility of our optimized "COLORFUL-Circuit" system in an exemplary case study, in which we monitored simultaneously the subcellular behavior of multiple organelles in a biotrophic plant-microbe interaction by Confocal Laser Scanning Microscopy. PMID- 26973688 TI - Transcriptome Analysis of Gerbera hybrida Including in silico Confirmation of Defense Genes Found. AB - For the ornamental crop Gerbera hybrida, breeding at the moment is done using conventional methods. As this has drawbacks in breeding speed and efficiency, especially for complex traits like disease resistance, we set out to develop genomic resources. The leaf and flower bud transcriptomes of four parents, used to generate two gerbera populations, were sequenced using Illumina paired-end sequencing. In total, 36,770 contigs with an average length of 1397 bp were generated and these have been the starting point for SNP identification and annotation. The consensus contig sequences were used to map reads of individual parents, to identify genotype specific SNPs, and to assess the presence of common SNPs between genotypes. Comparison with the non-redundant protein database (nr) showed that 29,146 contigs gave BLAST hits. Of sequences with blast results, 73.3% obtained a clear gene ontology (GO) annotation. EST contigs coding for enzymes were found in Kyoto Encyclopedia of Genes and Genomes maps (KEGG). Through, these annotated data and KEGG molecular interaction network, transcripts associated with the phenylpropanoid metabolism, other secondary metabolite biosynthesis pathways, phytohormone biosynthesis and signal transduction were analyzed in more detail. Identifying genes involved in these processes could provide genetic and genomic resources for studying the mechanism of disease resistance in gerbera. PMID- 26973689 TI - Suboptimal Light Conditions Influence Source-Sink Metabolism during Flowering. AB - Reliance on carbohydrates during flower forcing was investigated in one early and one late flowering cultivar of azalea (Rhododendron simsii hybrids). Carbohydrate accumulation, invertase activity, and expression of a purported sucrose synthase gene (RsSUS) was monitored during flower forcing under suboptimal (natural) and optimal (supplemental light) light conditions, after a cold treatment (7 degrees C + dark) to break flower bud dormancy. Post-production sucrose metabolism and flowering quality was also assessed. Glucose and fructose concentrations and invertase activity increased in petals during flowering, while sucrose decreased. In suboptimal light conditions RsSUS expression in leaves increased as compared to optimal light conditions, indicating that plants in suboptimal light conditions have a strong demand for carbohydrates. However, carbohydrates in leaves were markedly lower in suboptimal light conditions compared to optimal light conditions. This resulted in poor flowering of plants in suboptimal light conditions. Post-production flowering relied on the stored leaf carbon, which could be accumulated under optimal light conditions in the greenhouse. These results show that flower opening in azalea relies on carbohydrates imported from leaves and is source-limiting under suboptimal light conditions. PMID- 26973690 TI - Nitric Oxide in the Offensive Strategy of Fungal and Oomycete Plant Pathogens. AB - In the course of evolutionary changes pathogens have developed many invasion strategies, to which the host organisms responded with a broad range of defense reactions involving endogenous signaling molecules, such as nitric oxide (NO). There is evidence that pathogenic microorganisms, including two most important groups of eukaryotic plant pathogens, also acquired the ability to synthesize NO via non-unequivocally defined oxidative and/or reductive routes. Although the both kingdoms Chromista and Fungi are remarkably diverse, the experimental data clearly indicate that pathogen-derived NO is an important regulatory molecule controlling not only developmental processes, but also pathogen virulence and its survival in the host. An active control of mitigation or aggravation of nitrosative stress within host cells seems to be a key determinant for the successful invasion of plant pathogens representing different lifestyles and an effective mode of dispersion in various environmental niches. PMID- 26973691 TI - Quantitative Trait Loci for Morphological Traits and their Association with Functional Genes in Raphanus sativus. AB - Identification of quantitative trait loci (QTLs) governing morphologically important traits enables to comprehend their potential genetic mechanisms in the genetic breeding program. In this study, we used 210 F2 populations derived from a cross between two radish inbred lines (Raphanus sativus) "835" and "B2," including 258 SSR markers were used to detect QTLs for 11 morphological traits that related to whole plant, leaf, and root yield in 3 years of replicated field test. Total 55 QTLs were detected which were distributed on each linkage group of the Raphanus genome. Individual QTLs accounted for 2.69-12.6 of the LOD value, and 0.82-16.25% of phenotypic variation. Several genomic regions have multiple traits that clustered together, suggested the existence of pleiotropy linkage. Synteny analysis of the QTL regions with A. thaliana genome selected orthologous genes in radish. InDels and SNPs in the parental lines were detected in those regions by Illumina genome sequence. Five identified candidate gene-based markers were validated by co-mapping with underlying QTLs affecting different traits. Semi-quantitative reverse transcriptase PCR analysis showed the different expression levels of these five genes in parental lines. In addition, comparative QTL analysis with B. rapa revealed six common QTL regions and four key major evolutionarily conserved crucifer blocks (J, U, R, and W) harboring QTL for morphological traits. The QTL positions identified in this study will provide a valuable resource for identifying more functional genes when whole radish genome sequence is released. Candidate genes identified in this study that co-localized in QTL regions are expected to facilitate in radish breeding programs. PMID- 26973694 TI - Regulation of miR394 in Response to Fusarium oxysporum f. sp. cepae (FOC) Infection in Garlic (Allium sativum L). AB - MicroRNAs (miRNAs) are a class of post-transcriptional regulators that negatively regulate gene expression through target mRNA cleavage or translational inhibition and play important roles in plant development and stress response. In the present study, six conserved miRNAs from garlic (Allium sativum L.) were analyzed to identify differentially expressed miRNAs in response to Fusarium oxysporum f. sp. cepae (FOC) infection. Stem-loop RT-PCR revealed that miR394 is significantly induced in garlic seedlings post-treatment with FOC for 72 h. The induction of miR394 expression during FOC infection was restricted to the basal stem plate tissue, the primary site of infection. Garlic miR394 was also upregulated by exogenous application of jasmonic acid. Two putative targets of miR394 encoding F box domain and cytochrome P450 (CYP450) family proteins were predicted and verified using 5' RLM-RACE (RNA ligase mediated rapid amplification of cDNA ends) assay. Quantitative RT-PCR showed that the transcript levels of the predicted targets were significantly reduced in garlic plants exposed to FOC. When garlic cultivars with variable sensitivity to FOC were exposed to the pathogen, an upregulation of miR394 and down regulation of the targets were observed in both varieties. However, the expression pattern was delayed in the resistant genotypes. These results suggest that miR394 functions in negative modulation of FOC resistance and the difference in timing and levels of expression in variable genotypes could be examined as markers for selection of FOC resistant garlic cultivars. PMID- 26973692 TI - Mapping Quantitative Trait Loci Affecting Biochemical and Morphological Fruit Properties in Eggplant (Solanum melongena L.). AB - Eggplant berries are a source of health-promoting metabolites including antioxidant and nutraceutical compounds, mainly anthocyanins and chlorogenic acid; however, they also contain some anti-nutritional compounds such as steroidal glycoalkaloids (SGA) and saponins, which are responsible for the bitter taste of the flesh and with potential toxic effects on humans. Up to now, Quantitative Trait Loci (QTL) for the metabolic content are far from being characterized in eggplant, thus hampering the application of breeding programs aimed at improving its fruit quality. Here we report on the identification of some QTL for the fruit metabolic content in an F2 intraspecific mapping population of 156 individuals, obtained by crossing the eggplant breeding lines "305E40" * "67/3." The same population was previously employed for the development of a RAD-tag based linkage map and the identification of QTL associated to morphological and physiological traits. The mapping population was biochemically characterized for both fruit basic qualitative data, like dry matter, degrees Brix, sugars, and organic acids, as well as for health-related compounds such chlorogenic acid, (the main flesh monomeric phenol), the two peel anthocyanins [i.e., delphinidin-3-rutinoside (D3R) and delphinidin-3-(p- coumaroylrutinoside)-5-glucoside (nasunin)] and the two main steroidal glycoalkaloids, solasonine, and solamargine. For most of the traits, one major QTL (PVE >=10%) was spotted and putative orthologies with other Solanaceae crops are discussed. The present results supply valuable information to eggplant breeders on the inheritance of key fruit quality traits, thus providing potential tools to assist future breeding programs. PMID- 26973693 TI - Reconstructing the Origin of Oxygenic Photosynthesis: Do Assembly and Photoactivation Recapitulate Evolution? AB - Due to the great abundance of genomes and protein structures that today span a broad diversity of organisms, now more than ever before, it is possible to reconstruct the molecular evolution of protein complexes at an incredible level of detail. Here, I recount the story of oxygenic photosynthesis or how an ancestral reaction center was transformed into a sophisticated photochemical machine capable of water oxidation. First, I review the evolution of all reaction center proteins in order to highlight that Photosystem II and Photosystem I, today only found in the phylum Cyanobacteria, branched out very early in the history of photosynthesis. Therefore, it is very unlikely that they were acquired via horizontal gene transfer from any of the described phyla of anoxygenic phototrophic bacteria. Second, I present a new evolutionary scenario for the origin of the CP43 and CP47 antenna of Photosystem II. I suggest that the antenna proteins originated from the remodeling of an entire Type I reaction center protein and not from the partial gene duplication of a Type I reaction center gene. Third, I highlight how Photosystem II and Photosystem I reaction center proteins interact with small peripheral subunits in remarkably similar patterns and hypothesize that some of this complexity may be traced back to the most ancestral reaction center. Fourth, I outline the sequence of events that led to the origin of the Mn4CaO5 cluster and show that the most ancestral Type II reaction center had some of the basic structural components that would become essential in the coordination of the water-oxidizing complex. Finally, I collect all these ideas, starting at the origin of the first reaction center proteins and ending with the emergence of the water-oxidizing cluster, to hypothesize that the complex and well-organized process of assembly and photoactivation of Photosystem II recapitulate evolutionary transitions in the path to oxygenic photosynthesis. PMID- 26973695 TI - De novo Transcriptome Analysis of Sinapis alba in Revealing the Glucosinolate and Phytochelatin Pathways. AB - Sinapis alba is an important condiment crop and can also be used as a phytoremediation plant. Though it has important economic and agronomic values, sequence data, and the genetic tools are still rare in this plant. In the present study, a de novo transcriptome based on the transcriptions of leaves, stems, and roots was assembled for S. alba for the first time. The transcriptome contains 47,972 unigenes with a mean length of 1185 nt and an N50 of 1672 nt. Among these unigenes, 46,535 (97%) unigenes were annotated by at least one of the following databases: NCBI non-redundant (Nr), Swiss-Prot, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene Ontology (GO), and Clusters of Orthologous Groups of proteins (COGs). The tissue expression pattern profiles revealed that 3489, 1361, and 8482 unigenes were predominantly expressed in the leaves, stems, and roots of S. alba, respectively. Genes predominantly expressed in the leaf were enriched in photosynthesis- and carbon fixation-related pathways. Genes predominantly expressed in the stem were enriched in not only pathways related to sugar, ether lipid, and amino acid metabolisms but also plant hormone signal transduction and circadian rhythm pathways, while the root-dominant genes were enriched in pathways related to lignin and cellulose syntheses, involved in plant-pathogen interactions, and potentially responsible for heavy metal chelating, and detoxification. Based on this transcriptome, 14,727 simple sequence repeats (SSRs) were identified, and 12,830 pairs of primers were developed for 2522 SSR containing unigenes. Additionally, the glucosinolate (GSL) and phytochelatin metabolic pathways, which give the characteristic flavor and the heavy metal tolerance of this plant, were intensively analyzed. The genes of aliphatic GSLs pathway were predominantly expressed in roots. The absence of aliphatic GSLs in leaf tissues was due to the shutdown of BCAT4, MAM1, and CYP79F1 expressions. Glutathione was extensively converted into phytochelatin in roots, but it was actively converted to the oxidized form in leaves, indicating the different mechanisms in the two tissues. This transcriptome will not only benefit basic research and molecular breeding of S. alba but also be useful for the molecular assisted transfer of beneficial traits to other crops. PMID- 26973697 TI - Corrigendum: Enhancement of RNA-directed DNA methylation of a transgene by simultaneously downregulating a ROS1 ortholog using a virus vector in Nicotiana benthamiana. AB - [This corrects the article on p. 44 in vol. 4, PMID: 23565118.]. PMID- 26973696 TI - Constitutive Negative Regulation of R Proteins in Arabidopsis also via Autophagy Related Pathway? AB - Even though resistance (R) genes are among the most studied components of the plant immunity, there remain still a lot of aspects to be explained about the regulation of their function. Many gain-of-function mutants of R genes and loss of-function of their regulators often demonstrate up-regulated defense responses in combination with dwarf stature and/or spontaneous leaf lesions formation. For most of these mutants, phenotypes are a consequence of an ectopic activation of R genes. Based on the compilation and comparison of published results in this field, we have concluded that the constitutively activated defense phenotypes recurrently arise by disruption of tight, constitutive and multilevel negative control of some of R proteins that might involve also their targeting to the autophagy pathway. This mode of R protein regulation is supported also by protein protein interactions listed in available databases, as well as in silico search for autophagy machinery interacting motifs. The suggested model could resolve some explanatory discrepancies found in the studies of the immunity responses of autophagy mutants. PMID- 26973698 TI - Emerging Technologies to Create Inducible and Genetically Defined Porcine Cancer Models. AB - There is an emerging need for new animal models that address unmet translational cancer research requirements. Transgenic porcine models provide an exceptional opportunity due to their genetic, anatomic, and physiological similarities with humans. Due to recent advances in the sequencing of domestic animal genomes and the development of new organism cloning technologies, it is now very feasible to utilize pigs as a malleable species, with similar anatomic and physiological features with humans, in which to develop cancer models. In this review, we discuss genetic modification technologies successfully used to produce porcine biomedical models, in particular the Cre-loxP System as well as major advances and perspectives the CRISPR/Cas9 System. Recent advancements in porcine tumor modeling and genome editing will bring porcine models to the forefront of translational cancer research. PMID- 26973700 TI - Allergen extracts and recombinant proteins: comparison of efficiency of in vitro allergy diagnostics using multiplex assay on a biological microchip. AB - BACKGROUND: Immunological test systems for diagnostics of type I hypersensitivity involve the following types of antigens: whole allergen extracts, individual highly purified proteins and their recombinant analogues. The goal of this study was to compare the results obtained with whole allergen extracts (birch pollen, cat dander, and timothy grass pollen) and their respective recombinant proteins in biochip-based immunoassay. METHODS: Multiplex fluorescent immunoassay of 139 patients' blood serum samples was carried out using biological microchips (biochips). sIgE concentrations for the chosen allergens and their recombinant components were measured. ROC analysis was used for comparison of the results and determination of diagnostic accuracy. RESULTS: The results for the birch pollen extract and its recombinant allergens have shown that the diagnostic accuracy of the methods utilizing the whole allergen extract, its major component Bet v 1 and the combination of major and minor components (Bet v 1 and Bet v 2) was the same. Values for diagnostic accuracy for the cat dander extract and its major recombinant component Fel d 1 were equal. In contrast with birch pollen and cat dander allergens, using of recombinant components of timothy grass pollen (Phl p 1, Phl p 5, Phl p 7 and Phl p 12) did not allow reaching the diagnostic accuracy of using natural extract. CONCLUSIONS: Multiplex analysis of samples obtained from patients with allergy to birch pollen and cat dander using biological microchips has shown that comparable accuracy was observed for the assay with natural extracts and recombinant allergens. In the case of timothy grass allergen, using the recombinant components may be insufficient. PMID- 26973701 TI - Asthma in the elderly: the effect of choline supplementation. AB - BACKGROUND: Asthma in the elderly is poorly understood as very few studies have included these patients. DNA methylation can affect the expression of asthma susceptibility genes. Methyl groups can be produced through a choline dependent pathway. Asthmatics have decreased serum choline. We studied the effect of choline supplementation in elderly asthmatics and associations between different parameters at baseline. METHODS: This is a double-blind, placebo-controlled, cross-over study. Thirty asthmatics 65 years old and older were evaluated at baseline and 3, 6, 9, and 12 weeks later. They randomly received choline bitartrate 310 mg and placebo capsules twice daily for 6 weeks. RESULTS: Ninety percent of the study subjects were atopic and 97 % of them were using inhaled corticosteroids. Choline supplementation did not affect ACT (asthma control test), spirometric values, eosinophil counts or total serum IgE vs. placebo (p > 0.86 for all comparisons). In subjects with lower ACT (<=20), lower FEV1 % (<60 %), or higher eosinophil counts (>=0.6), there was similarly no difference between choline and placebo (p > 0.63). We found no significant association between eosinophil counts and IgE and the other parameters at baseline including in subjects with lower ACT or on higher inhaled steroid doses (p > 0.09). Asthmatic women had lower baseline ACT scores compared to men (p = 0.02). CONCLUSIONS: In this study of elderly asthmatics, choline supplementation for 6 weeks did not affect ACT scores, spirometric values, peripheral blood eosinophils, or total serum IgE. These results will require confirmation in larger and longer studies. Trial registration ClinicalTrials.gov NCT02371993. PMID- 26973702 TI - The effect of cholesteryl ester transfer protein on pancreatic beta cell dysfunction in mice. AB - BACKGROUND: Cholesterol accumulation causes pancreatic beta cell lipotoxicity and dysfunction. Cholesteryl ester transfer protein (CETP) plays an important role in blood lipid homeostasis. However, its role in tissue lipid metabolism remains unclear. We hypothesized that plasma CETP impact cholesterol homeostasis in the beta cells, thus damaging their functions. METHODS: The adipose tissue-specific CETP expression transgenic (aP2-CETPTg) mice, characterized by high CETP levels in the circulation, were used in this study. Pancreatic islet cholesterol and beta cell function were assessed in mice. We further measured mRNA levels of the genes involved in beta cell proliferation and differentiation, inflammation and cholesterol metabolism. TUNEL assay was applied to investigate beta cell apoptosis in islets. RESULTS: The aP2-CETPTg mice exhibited glucose intolerance, lower plasma insulin concentrations but increased insulin sensitivity compared with wild type mice. In addition, glucose-stimulated insulin secretion from isolated pancreatic islets significantly decreased, and free cholesterol significantly increased. Moreover, the number and size of islets from aP2-CETPTg mice were significantly decreased. Genes involved in beta cell proliferation, such as Pdx1 and BETA2, were down-regulated; genes involved in inflammation and ER stress, such as IL-1beta, CHOP, and Xbp1 were up-regulated, in line with an increase of beta cell apoptosis. CONCLUSIONS: Plasma CETP causes free cholesterol accumulation in islets which could contribute to beta cell dysfunction. Thus, CETP inhibition could be a novel protective strategy for dyslipidemia related to diabetes and obese. PMID- 26973703 TI - Heat-treated high-fat diet modifies gut microbiota and metabolic markers in apoe /- mice. AB - BACKGROUND: High-fat diet has been known to have adverse effects on metabolic markers, as well as the gut microbiota. However, the effect of heat processing of high-fat diet, which leads to formations of advanced glycation end products (AGEs) has not been clearly distinguished from the effect of unheated fat. This study compared the effect of high-fat diet with heat-treated high-fat diet on adiposity, atherosclerosis and gut microbiota composition in the caecum of apoe ( /-) mice. METHOD: Male apoe (-/-) mice were fed either low-fat (LF) control diet, high-fat (40 E% saturated fat, HF) control diet, or heat-treated high-fat (200 degrees C for 10 min, HT) diet, for 8 weeks. The plasma samples were used in the analysis of Nepsilon-carboxy-methyl-lysine (CML) and Nepsilon-carboxy-ethyl lysine (CEL). The heart samples were analysed for atherosclerotic plaques, and the DNA from caecum was extracted and analysed for microbiota composition using 16S rRNA gene sequencing on a Miseq instrument. Additionally, the functions of microbial communities were also predicted based on the bacterial 16S rRNA gene sequence using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). RESULTS: Here we found that HT modifies gut microbiota composition and host adiposity. Prediction of bacterial gene functions based on 16S rRNA gene sequence revealed that HF increased bacterial genera enriched in lipid metabolism genes, while HT did not. Plasma CML and CEL increased 1.7 and 2.5 times, respectively, in mice fed HT as compared to mice fed HF. Despite lower adiposity, mice fed HT maintained atherosclerosis and displayed enlarged spleens. CONCLUSIONS: The results suggested that heat processing of high fat diet modifies the substrates reaching the lower gut of apoe (-/-) mice, resulting in different effects on gut microbiota composition. AGEs seem to maintain the effect on atherosclerosis, despite lower adiposity, and causing enlarged spleens, which possibly reflect elevated levels of inflammation in the body. PMID- 26973699 TI - Smoothened regulation in response to Hedgehog stimulation. AB - The Hedgehog (Hh) signaling pathway play critical roles in embryonic development and adult tissue homeostasis. A critical step in Hh signal transduction is how Hh receptor Patched (Ptc) inhibits the atypical G protein-coupled receptor Smoothened (Smo) in the absence of Hh and how this inhibition is release by Hh stimulation. It is unlikely that Ptc inhibits Smo by direct interaction. Here we discuss how Hh regulates the phosphorylation and ubiquitination of Smo, leading to cell surface and ciliary accumulation of Smo in Drosophila and vertebrate cells, respectively. In addition, we discuss how PI(4)P phospholipid acts in between Ptc and Smo to regulate Smo phosphorylation and activation in response to Hh stimulation. PMID- 26973704 TI - Bipolar II compared with bipolar I disorder: baseline characteristics and treatment response to quetiapine in a pooled analysis of five placebo-controlled clinical trials of acute bipolar depression. AB - BACKGROUND: Bipolar I and II represent the most common and severe subtypes of bipolar disorder. Although bipolar I disorder is relatively well studied, the clinical characteristics and response to treatment of patients with bipolar II disorder are less well understood. METHODS: To compare the severity and burden of illness of patients with bipolar II versus bipolar I disorder, baseline demographic, clinical, and quality of life data were examined in 1900 patients with bipolar I and 973 patients with bipolar II depression, who were enrolled in five similarly designed clinical placebo-controlled trials of quetiapine immediate-release and quetiapine extended-release. Acute (8 weeks) response to treatment was also compared by assessing rating scale scores, including Montgomery-Asberg depression rating scale, Hamilton rating scale for anxiety, Young mania rating scale, and clinical global impression-severity scores, in the bipolar I and II populations in the same pooled database. RESULTS: Patients with bipolar I and bipolar II depression were similar in demographics, baseline rating scale scores (depression, anxiety, mania, and quality of life), and mood episode histories. Symptom improvements in response to quetiapine were greater versus comparators (lithium, paroxetine, and placebo) at 4 and 8 weeks in both bipolar I and II patients. Patients with the bipolar II subtype initially showed slower responses to all treatments, but, by 8 weeks, attained similar symptom improvement as patients with bipolar I depression. CONCLUSIONS: Pooled analysis of five clinical trials of quetiapine demonstrated that patients with bipolar II depression have a similar burden of illness and quality of life to patients with bipolar I. Bipolar II patients consistently showed a slower response to treatments than bipolar I patients, but, after 8 weeks of treatment with quetiapine, symptom improvements were similar between bipolar I and II disorder subtypes. PMID- 26973705 TI - The genetic and environmental structure of the character sub-scales of the temperament and character inventory in adolescence. AB - BACKGROUND: The character higher order scales (self-directedness, cooperativeness, and self-transcendence) in the temperament and character inventory are important general measures of health and well-being [Mens Sana Monograph 11:16-24 (2013)]. Recent research has found suggestive evidence of common environmental influence on the development of these character traits during adolescence. The present article expands earlier research by focusing on the internal consistency and the etiology of traits measured by the lower order sub-scales of the character traits in adolescence. METHODS: The twin modeling analysis of 423 monozygotic pairs and 408 same sex dizygotic pairs estimated additive genetics (A), common environmental (C), and non-shared environmental (E) influences on twin resemblance. All twins were part of the on-going longitudinal Child and Adolescent Twin Study in Sweden (CATSS). RESULTS: The twin modeling analysis suggested a common environmental contribution for two out of five self directedness sub-scales (0.14 and 0.23), for three out of five cooperativeness sub-scales (0.07-0.17), and for all three self-transcendence sub-scales (0.10 0.12). CONCLUSION: The genetic structure at the level of the character lower order sub-scales in adolescents shows that the proportion of the shared environmental component varies in the trait of self-directedness and in the trait of cooperativeness, while it is relatively stable across the components of self transcendence. The presence of this unique shared environmental effect in adolescence has implications for understanding the relative importance of interventions and treatment strategies aimed at promoting overall maturation of character, mental health, and well-being during this period of the life span. PMID- 26973706 TI - Protocol: transient expression system for functional genomics in the tropical tree Theobroma cacao L. AB - BACKGROUND: Theobroma cacao L., the source of cocoa, is a crop of significant economic value around the world. To facilitate the study of gene function in cacao we have developed a rapid Agrobacterium-mediated transient genetic transformation protocol. Here we present a detailed methodology for our transformation assay, as well as an assay for inoculation of cacao leaves with pathogens. RESULTS: Agrobacterium tumefaciens cultures are induced then vacuum infiltrated into cacao leaves. Transformation success can be gauged 48 h after infiltration by observation of green fluorescent protein and by qRT-PCR. We clarify the characteristics of cacao leaf stages and demonstrate that our strategy efficiently transforms leaves of developmental stage C. The transformation protocol has high efficacy in stage C leaves of four of eight tested genotypes. We also present the functional analysis of cacao chitinase overexpression using the transient transformation system, which resulted in decreased pathogen biomass and lesion size after infection with Phytophthora tropicalis. CONCLUSIONS: Leaves expressing transgenes of interest can be used in subsequent functional genetic assays such as pathogen bioassay, metabolic analysis, gene expression analysis etc. This transformation protocol can be carried out in 1 day, and the transgenes expressing leaf tissue can be maintained in petri dishes for 5-7 days, allowing sufficient time for performance of additional downstream gene functional analysis. Application of these methods greatly increases the rapidity with which candidate genes with roles in defense can be tested. PMID- 26973709 TI - Informal Kinship-Based Fostering Around the World: Anthropological Findings. AB - Anthropological research around the world has documented informal, kinship-based foster care cross culturally. That research suggests that children are more likely to benefit from informal kinship-based fostering in cultural contexts where fostering expands the pool of relatives rather than substituting one parent for another, fostering is expected to provide children with positive opportunities for learning and development, and/or children are granted some autonomy or decision-making power. However, informal kinship-based fostering seems to place children at risk in cultural contexts where the process of children's attachment to caregivers resembles the Western child development model, communities are highly stratified along socioeconomic lines, and/or exploitation of children is permitted. The article concludes with a discussion of implications for both research and policy. PMID- 26973707 TI - Estimation of genetic diversity in viral populations from next generation sequencing data with extremely deep coverage. AB - BACKGROUND: In this paper we propose a method and discuss its computational implementation as an integrated tool for the analysis of viral genetic diversity on data generated by high-throughput sequencing. The main motivation for this work is to better understand the genetic diversity of viruses with high rates of nucleotide substitution, as HIV-1 and Influenza. Most methods for viral diversity estimation proposed so far are intended to take benefit of the longer reads produced by some next-generation sequencing platforms in order to estimate a population of haplotypes which represent the diversity of the original population. The method proposed here is custom-made to take advantage of the very low error rate and extremely deep coverage per site, which are the main features of some neglected technologies that have not received much attention due to the short length of its reads, which precludes haplotype estimation. This approach allowed us to avoid some hard problems related to haplotype reconstruction (need of long reads, preliminary error filtering and assembly). RESULTS: We propose to measure genetic diversity of a viral population through a family of multinomial probability distributions indexed by the sites of the virus genome, each one representing the distribution of nucleic bases per site. Moreover, the implementation of the method focuses on two main optimization strategies: a read mapping/alignment procedure that aims at the recovery of the maximum possible number of short-reads; the inference of the multinomial parameters in a Bayesian framework with smoothed Dirichlet estimation. The Bayesian approach provides conditional probability distributions for the multinomial parameters allowing one to take into account the prior information of the control experiment and providing a natural way to separate signal from noise, since it automatically furnishes Bayesian confidence intervals and thus avoids the drawbacks of preliminary error filtering. CONCLUSIONS: The methods described in this paper have been implemented as an integrated tool called Tanden (Tool for Analysis of Diversity in Viral Populations) and successfully tested on samples obtained from HIV-1 strain NL4-3 (group M, subtype B) cultivations on primary human cell cultures in many distinct viral propagation conditions. Tanden is written in C# (Microsoft), runs on the Windows operating system, and can be downloaded from: http://tanden.url.ph/. PMID- 26973710 TI - Modes of tetra(4-pyridyl)porphyrinatomanganese(III) ion intercalation inside natural clays. AB - BACKGROUND: Metalloporphyrin ions, with planar shape, have been known to intercalate horizontally and diagonally between montmorillonite layers. Perpendicular intercalation inside montmorillonite has not been reported earlier. This work aims at achieving perpendicular intercalation inside montmorillonite in natural clays. Possible intercalation inside other forms of natural clay will also be investigated. METHODS: Natural clays were purified and characterized. The naked clay powder was then refluxed with tetra(4 pyridyl)porphyrinatomanganese(III) ion (MnTPyP(+)) solution in methanol with continuous stirring for different times. Electronic absorption spectra, atomic absorption spectra, Fourier Transform infrared spectra, scanning electron microscopy and X-ray diffraction were all used in clay characterization and in intercalation study. RESULTS: The natural clay involved different phases, namely montmorillonite, biotite, kaolinite, illite and traces of quartz. Montmorillonite clay allowed horizontal, diagonal and perpendicular intercalation of the metalloporphyrin ions. Biotite allowed only horizontal intercalation. The mode of intercalation was deduced by monitoring the clay inter-planar distance value change. Intercalation occurred inside both micro- and nano-size clay powders to different extents. The nano-powder (average size ~50 nm) showed uptake values up to 3.8 mg MnTPyP/g solid, whereas the micro-size powder (average size ~316 nm) exhibited lower uptake (2.4 mg MnTPyP/g solid). Non-expandable clay phases did not allow any intercalation. The intercalated MnTPyP(+) ions showed promising future supported catalyst applications. CONCLUSIONS: Depending on their phase, natural clays hosted metalloporphyrin ions. Montmorillonite can allow all three possible intercalation geometries, horizontal, diagonal and for the first time perpendicular. Biotite allows horizontal intercalation only. Non-expandable clays allow no intercalation. Graphical abstractMetalloporphyrin complexes can be intercalated into montmorillonite in horizontal, perpendicular and diagonal geometries. PMID- 26973712 TI - Engineering Escherichia coli for high-yield geraniol production with biotransformation of geranyl acetate to geraniol under fed-batch culture. AB - BACKGROUND: Geraniol is an acyclic monoterpene alcohol, which exhibits good prospect as a gasoline alternative. Geraniol is naturally encountered in plants at low concentrations and an attractive target for microbial engineering. Geraniol has been heterologously produced in Escherichia coli, but the low titer hinders its industrial applications. Moreover, bioconversion of geraniol by E. coli remains largely unknown. RESULTS: Recombinant overexpression of Ocimum basilicum geraniol synthase, Abies grandis geranyl diphosphate synthase, and a heterotic mevalonate pathway in E. coli BL21 (DE3) enabled the production of up to 68.6 +/- 3 mg/L geraniol in shake flasks. Initial fed-batch fermentation only increased geraniol production to 78.8 mg/L. To further improve the production yield, the fermentation conditions were optimized. Firstly, 81.4 % of volatile geraniol was lost during the first 5 h of fermentation in a solvent-free system. Hence, isopropyl myristate was added to the culture medium to form an aqueous organic two-phase culture system, which effectively prevented volatilization of geraniol. Secondly, most of geraniol was eventually biotransformed into geranyl acetate by E. coli, thus decreasing geraniol production. For the first time, we revealed the role of acetylesterase (Aes, EC 3.1.1.6) from E. coli in hydrolyzing geranyl acetate to geraniol, and production of geraniol was successfully increased to 2.0 g/L under controlled fermentation conditions. CONCLUSIONS: An efficient geraniol production platform was established by overexpressing several key pathway proteins in engineered E. coli strain combined with a controlled fermentation system. About 2.0 g/L geraniol was obtained using our controllable aqueous-organic two-phase fermentation system, which is the highest yield to date. In addition, the interconversion between geraniol and geranyl acetate by E. coli was first elucidated. This study provided a new and promising strategy for geraniol biosynthesis, which laid a basis for large-scale industrial application. PMID- 26973713 TI - Industrially relevant hydrolyzability and fermentability of sugarcane bagasse improved effectively by glycerol organosolv pretreatment. AB - BACKGROUND: Previous work has demonstrated that glycerol organosolv pretreatment can effectively improve the hydrolyzability of various lignocellulosic substrates. This pretreatment process strategy is ideal to integrate a commercially successful lignocellulosic and vegetable oil biorefinery industry. However, industrially relevant high-solid-loading hydrolyzability and fermentability of the pretreated substrates have yet to be considered for enzyme based lignocellulosic biorefineries. RESULTS: In this study, an AGO pretreatment of sugarcane bagasse was evaluated with regard to the component selectivity, structural modification, hydrolyzability, and fermentation of pretreated substrates. The results showed that the AGO pretreatment presented good component selectivity, removing approximately 70 % lignin and hemicellulose, respectively, from sugarcane bagasse with a near-intact preservation (94 %) of the overall cellulose. The pretreatment deconstructed the recalcitrant architecture of natural lignocellulosic biomass, thereby modifying the structure at the macro /micrometer level (fiber size, surface area, average size, roughness) and supermolecular level (key chemical bond dissociation) of lignocellulosic substrates towards good hydrolyzability. Notably, extraordinarily few fermentation inhibitors (<0.2 g furfural and 5-hydromethyl furfural/kg feedstock) were generated from the AGO pretreatment process, which was apparently due to the prominent role of glycerol organic solvent in protecting monosaccharides against further degradation. The 72-h enzymatic hydrolysis of pretreated substrates at 15 % solid content achieved 90 % completion with Cellic CTec2 at 10 FPU/g dried substrate. With a simple nutrition (only 10 g/L (NH4)2SO4) addition, the fed batch semi-SSF of AGO-pretreated substrates (30 % solid content) almost reached 50 g/L ethanol with cellulase preparation at 10 FPU/g dried substrate. These results have revealed that the pretreated substrate is susceptible and accessible to cellulase enzymes, thereafter exhibiting remarkable hydrolyzability and fermentability. CONCLUSION: The AGO pretreatment is a promising candidate for the current pretreatment process towards industrially relevant enzyme-based lignocellulosic biorefineries. PMID- 26973714 TI - Molecular characterization of a glycerol-3-phosphate acyltransferase reveals key features essential for triacylglycerol production in Phaeodactylum tricornutum. AB - BACKGROUND: The marine diatom, Phaeodactylum tricornutum, has become a model for studying lipid metabolism and its triacylglycerol (TAG) synthesis pathway makes it an ideal target for metabolic engineering to improve lipid productivity. However, the genetic background and metabolic networks of fatty acid biosynthesis in diatoms are not well understood. Glycerol-3-phosphate acyltransferase (GPAT) is the critical enzyme that catalyzes the first step of TAG formation. So far, characterization of GPAT in marine microalgae has not been reported, especially at the level of comprehensive sequence-structure and functional analysis. RESULTS: A GPAT was cloned from P. tricornutum and overexpressed in P. tricornutum. Volumes of oil bodies were produced and the neutral lipid content was increased by twofold determined by Nile red fluorescence staining. Fatty acid composition was analyzed by GC-MS, which showed significantly higher proportion of unsaturated fatty acids compared to wild type. CONCLUSION: These results suggested that the identified GPAT could upregulate TAG biosynthesis in P. tricornutum. Moreover, this study offers insight into the lipid metabolism of diatoms and supports the role of microalgal strains for biofuels production. PMID- 26973715 TI - Cellulosomal expansin: functionality and incorporation into the complex. AB - BACKGROUND: Expansins are relatively small proteins that lack enzymatic activity and are found in plants and microorganisms. The function of these proteins is to disrupt the plant cell walls by interfering with the non-covalent interchain bonding of the polysaccharides. Expansins were found to be important for plant growth, but they are also expressed by various bacteria known to have interactions with plants. Clostridium clariflavum is a plant cell wall-degrading bacterium with a highly elaborate cellulosomal system. Among its numerous dockerin-containing genes, two expansin-like proteins, Clocl_1862 and Clocl_1298 (termed herein CclEXL1 and CclEXL2) were identified, and CclEXL1 was found to be expressed as part of the cellulosome system. This is the first time that an expansin-like protein is identified in a cellulosome complex, which implicates its possible role in biomass deconstruction. RESULTS: In the present article, we analyzed the functionality of CclEXL1. Its dockerin was characterized and shown to bind selectively to type-I cohesins of C. clariflavum, with preferential binding to the cohesin of ScaG, and additionally to a type-I cohesin of C. cellulolyticum. We demonstrated experimentally that the expansin-like protein binds preferentially to microcrystalline cellulose, but it also binds to acid swollen cellulose, xylan, and wheat straw. CclEXL1 exhibited a pronounced loosening effect on filter paper, which resulted in substantial decrease in tensile stress. The C. clariflavum expansin-like protein thus enhances significantly enzymatic hydrolysis of cellulose, both by C. clariflavum cellulosomes and two major cellulosomal cellulases from this bacterium: GH48 (exoglucanase) and GH9 (endoglucanase). Finally, we demonstrated CclEXL1-mediated enhancement of microcrystalline cellulose degradation by different cellulosome fractions and the two enzymes. CONCLUSIONS: The results of this study confirm that the C. clariflavum expansin-like protein is part of the elaborate cellulosome system of this bacterium with capabilities of cellulose creeping. The data suggest that pretreatment of cellulosic materials with CclEXL1 can bring about substantial improvement of hydrolysis by cellulases. PMID- 26973716 TI - Enhanced electrical power generation using flame-oxidized stainless steel anode in microbial fuel cells and the anodic community structure. AB - BACKGROUND: Carbon-based materials are commonly used as anodes in microbial fuel cells (MFCs), whereas metal and metal-oxide-based materials are not used frequently because of low electrical output. Stainless steel is a low-cost material with high conductivity and physical strength. In this study, we investigated the power generation using flame-oxidized (FO) stainless steel anodes (SSAs) in single-chambered air-cathode MFCs. The FO-SSA performance was compared to the performance of untreated SSA and carbon cloth anode (CCA), a common carbonaceous electrode. The difference in the anodic community structures was analyzed using high-throughput sequencing of the V4 region in 16S rRNA gene. RESULTS: Flame oxidation of SSA produced raised node-like sites, predominantly consisting of hematite (Fe2O3), on the surface, as determined by X-ray diffraction spectroscopy. The flame oxidation enhanced the maximum power density (1063 mW/m(2)) in MFCs, which was 184 and 24 % higher than those for untreated SSA and CCA, respectively. The FO-SSA exhibited 8.75 and 2.71 times higher current production than SSA and CCA, respectively, under potentiostatic testing conditions. Bacteria from the genus Geobacter were detected at a remarkably higher frequency in the biofilm formed on the FO-SSA (8.8-9.2 %) than in the biofilms formed on the SSA and CCA (0.7-1.4 %). Bacterial species closely related to Geobacter metallireducens (>99 % identity in the gene sequence) were predominant (93-96 %) among the genus Geobacter in the FO-SSA biofilm, whereas bacteria with a 100 % identity to G. anodireducens were abundant (>55 %) in the SSA and CCA biofilms. CONCLUSIONS: This is the first demonstration of power generation using an FO-SSA in MFCs. Flame oxidation of the SSA enhances electricity production in MFCs, which is higher than that with the common carbonaceous electrode, CCA. The FO-SSA is not only inexpensive but also can be prepared using a simple method. To our knowledge, this study reveals, for the first time, that the predominant Geobacter species in the biofilm depends on the anode material. The high performance of the FO-SSA could result from the particularly high population of bacteria closely related to G. metallireducens in the biofilm. PMID- 26973717 TI - Incorporating cultural beliefs in promoting exclusive breastfeeding. AB - INTRODUCTION: Since 2003, the World Health Organization has recommended exclusive breastfeeding for the first 6 months of life. In the Northwest region of Cameroon approximately 90% of women initiate breastfeeding, yet only 34% of these women exclusively breastfeed for the recommended six months. AIM: To determine influences on women's exclusive breastfeeding practices. METHODS: Semi-structured interviews were conducted with six women and six men followed by focus group discussions with three groups of women and three groups of men in the Kumbo West Health District, Northwest region, Cameroon. All participants were selected using theoretical sampling to assure triangulation. RESULTS: Three themes emerged that influence exclusive breastfeeding practices: woman's readiness to exclusively breastfeed; cultural influences towards exclusive breastfeeding; and perceived constraints to exclusive breastfeeding. CONCLUSION: These emergent themes were used to create a theoretical framework that is useful for developing a breastfeeding health education intervention in non-Western settings. PMID- 26973719 TI - 5-Hydroxymethylcytosine discriminates between parathyroid adenoma and carcinoma. AB - BACKGROUND: Primary hyperparathyroidism is characterized by enlarged parathyroid glands due to an adenoma (80-85 %) or multiglandular disease (~15 %) causing hypersecretion of parathyroid hormone (PTH) and generally hypercalcemia. Parathyroid cancer is rare (<1-5 %). The epigenetic mark 5-hydroxymethylcytosine (5hmC) is reduced in various cancers, and this may involve reduced expression of the ten-eleven translocation 1 (TET1) enzyme. Here, we have performed novel experiments to determine the 5hmC level and TET1 protein expression in 43 parathyroid adenomas (PAs) and 17 parathyroid carcinomas (PCs) from patients who had local invasion or metastases and to address a potential growth regulatory role of TET1. RESULTS: The global 5hmC level was determined by a semi quantitative DNA immune-dot blot assay in a smaller number of tumors. The global 5hmC level was reduced in nine PCs and 15 PAs compared to four normal tissue samples (p < 0.05), and it was most severely reduced in the PCs. By immunohistochemistry, all 17 PCs stained negatively for 5hmC and TET1 showed negative or variably heterogeneous staining for the majority. All 43 PAs displayed positive 5hmC staining, and a similar aberrant staining pattern of 5hmC and TET1 was seen in about half of the PAs. Western blotting analysis of two PCs and nine PAs showed variable TET1 protein expression levels. A significantly higher tumor weight was associated to PAs displaying a more severe aberrant staining pattern of 5hmC and TET1. Overexpression of TET1 in a colony forming assay inhibited parathyroid tumor cell growth. CONCLUSIONS: 5hmC can discriminate between PAs and PCs. Whether 5hmC represents a novel marker for malignancy warrants further analysis in additional parathyroid tumor cohorts. The results support a growth regulatory role of TET1 in parathyroid tissue. PMID- 26973718 TI - Genome-wide analysis of DNA methylation and gene expression defines molecular characteristics of Crohn's disease-associated fibrosis. AB - BACKGROUND: Fibrosis of the intestine is a common and poorly understood complication of Crohn's disease (CD) characterized by excessive deposition of extracellular matrix and accompanied by narrowing and obstruction of the gut lumen. Defining the molecular characteristics of this fibrotic disorder is a vital step in the development of specific prediction, prevention, and treatment strategies. Previous epigenetic studies indicate that alterations in DNA methylation could explain the mechanism by which mesenchymal cells adopt the requisite pro-fibrotic phenotype that promotes fibrosis progression. However, to date, genome-wide analysis of the DNA methylome of any type of human fibrosis is lacking. We employed an unbiased approach using deep sequencing to define the DNA methylome and transcriptome of purified fibrotic human intestinal fibroblasts (HIF) from the colons of patients with fibrostenotic CD. RESULTS: When compared with normal fibroblasts, we found that the majority of differential DNA methylation was within introns and intergenic regions and not associated with CpG islands. Only a low percentage occurred in the promoters and exons of genes. Integration of the DNA methylome and transcriptome identified regions in three genes that inversely correlated with gene expression: wingless-type mouse mammary tumor virus integration site family, member 2B (WNT2B) and two eicosanoid synthesis pathway enzymes (prostacyclin synthase and prostaglandin D2 synthase). These findings were independently validated by RT-PCR and bisulfite sequencing. Network analysis of the data also identified candidate molecular interactions relevant to fibrosis pathology. CONCLUSIONS: Our definition of a genome-wide fibrosis-specific DNA methylome provides new gene networks and epigenetic states by which to understand mechanisms of pathological gene expression that lead to fibrosis. Our data also provide a basis for development of new fibrosis-specific therapies, as genes dysregulated in fibrotic Crohn's disease, following functional validation, can serve as new therapeutic targets. PMID- 26973722 TI - Dural diverticulum with a symptomatic cerebrospinal fluid leak. AB - A case report of a 63-year-old female patient with a cervical spinal dural diverticulum and intracranial hypotension secondary to a symptomatic CSF leak after minor trauma. The patient responded well after the cervical approach epidural blood patch procedure. PMID- 26973723 TI - Right-sided aorta with complete isolation of the left innominate artery. AB - A right-sided aorta with an isolated left subclavian and left common carotid artery is a rare arch defect. We are presenting the case of a 56-year-old woman who had initially presented with headache and 3 episodes of right-sided facial and extremity numbness. A presumptive diagnosis of transient ischemic attack prompted imaging studies where a computer tomography angiogram showed aberrant vessels. PMID- 26973724 TI - Primary pancreatic neuroblastoma presenting with opsoclonus-myoclonus syndrome. AB - Although neuroblastoma is a common solid organ malignancy in children, primary pancreatic neuroblastoma is a rare entity in children, with very few cases reported in the literature. The case discusses the presentation of a 21-month-old female presenting to the neurology clinic with ataxia and erratic eye movements. Our case illustrates the computed tomography, ultrasound, and scintigraphic findings of primary pancreatic neuroblastoma presenting as opsoclonus-myoclonus syndrome. Computed tomography and ultrasound demonstrated a vascular, enhancing mass in the pancreatic body clearly separate from the adrenal gland. Metaiodobenzylguanidine scan demonstrates focal intense uptake in the pancreatic body. The patient's diagnosis was confirmed with biopsy, and her malignancy responded well to conventional chemotherapy. The case is important in that it demonstrates the unusual imaging appearance of a primary pancreatic neuroblastoma. PMID- 26973721 TI - Do Childhood Cancer Survivors Meet the Diet and Physical Activity Guidelines? A Review of Guidelines and Literature. AB - Despite advances in cancer treatment, childhood cancer survivors are at higher risk of developing chronic health conditions than peers who have not had cancer. Being overweight or obese adds to the already elevated risk of cardiovascular diseases and metabolic abnormalities. Diet and physical activity are modifiable behaviors that reduce obesity risk and have been shown to improve cancer survival in adult cancer survivors. Specific guidelines have been developed for cancer survivors that provide advice on nutrition, physical activity and weight management following cancer diagnosis and treatment. In this review, we report on existing nutrition and physical activity guidelines for cancer survivors, supplemented by available literature on diet and physical activity status of childhood cancer survivors and their associations with health-related outcomes. The 2012 American Cancer Society (ACS) and the 2008 Children's Oncology Group (COG) guidelines provide similar advice on diet but the ACS guidelines also offer specific advice on physical activity and weight management. Thirty-one observational studies and 18 intervention trials published prior to June 2012 that met the inclusion criteria were reviewed. Results suggest that a high proportion of childhood cancer survivors had poor adherence to dietary and physical activity guidelines. Although findings from existing intervention trials are preliminary due to small sample size, available evidence suggests that exercise intervention is safe and feasible for patients and survivors of childhood cancer. Childhood cancer survivors should be encouraged to engage in physical activity, adopt a healthy diet, and maintain a healthy weight throughout cancer survivorship. PMID- 26973725 TI - Nontraumatic orbital floor fracture after nose blowing. AB - A 40-year-old woman with no history of trauma or prior surgery presented to the emergency department with headache and left eye pain after nose blowing. Noncontrast maxillofacial computed tomography examination revealed an orbital floor fracture that ultimately required surgical repair. There are nontraumatic causes of orbital blowout fractures, and imaging should be obtained irrespective of trauma history. PMID- 26973726 TI - Sub-branch and mixed-type intraductal papillary mucinous neoplasms of the pancreas: 2 case reports. AB - Intraductal papillary mucinous neoplasia (IPMN) is one of the cystic neoplasias of the pancreas. The imaging findings provide that these tumors are differentiated from the other cystic lesions of the pancreas, especially from the chronic pancreatitis, where the treatment protocol is completely different. Therefore, the correct diagnosis and classification of the IPMN ensures that the patient receives the correct approach and the appropriate surgery, if necessary. The purpose of this study is to emphasize the imaging findings of the different types of the IPMN and the changes in the management protocol of the patients according to these radiological findings. PMID- 26973727 TI - Caudal duplication syndrome: imaging evaluation of a rare entity in an adult patient. AB - Several theories have been put forth to explain the complex yet symmetrical malformations and the myriad of clinical presentations of caudal duplication syndrome. Hereby, reported case is a 28-year-old female, gravida 2 para 2, with congenital caudal malformation who has undergone partial reconstructive surgeries in infancy to connect her 2 colons. She presented with recurrent left lower abdominal pain associated with nausea, vomiting, and subsequent feculent anal discharge. Imaging reveals duplication of the urinary bladder, urethra, and colon with with cloacal malformations and fistulae from the left-sided cloaca, uterus didelphys with separate cervices and vaginal canals, right-sided aortic arch and descending thoracic aorta, and dysraphic midline sacrococcygeal defect. Hydronephrosis of the left kidney with left hydroureter and inflammation of one of the colons were suspected to be the cause of the patient's acute complaints. She improved symptomatically over the course of her hospitalization stay with conservative treatments. The management for this syndrome is individualized and may include surgical intervention to fuse or excise the duplicated organs. PMID- 26973728 TI - Jugular foramen schwannoma mimicking paraganglioma: case report and review of imaging findings. AB - We present the case of a 30-year-old woman who presented with an 11-year history of chronic occipital headaches and a 12-month history of worsening difficulty speaking and/or swallowing, facial spasms, hearing loss, and dizziness. A large lytic mass was found centered in the left jugular foramen (JF) on computed tomography examination; follow-up magnetic resonance imaging showed an avidly enhancing mass with prominent central flow voids. Histopathologic examination after surgical resection revealed the mass to be a schwannoma. Prominent central vascularity is an unusual presentation for JF schwannomas. Our report provides a review of magnetic resonance imaging features of intrinsic JF lesions relevant to our case. PMID- 26973729 TI - Sonographic and magnetic resonance imaging findings of neurocutaneous melanosis. AB - Neurocutaneous melanosis is a rare nonfamilial phakomatosis characterized by large or multiple congenital melanocytic nevi plus the presence of central nervous system melanosis or melanoma. We report a case of a male infant with a giant posteroaxial nevus and evidence of intracranial melanosis on ultrasound and magnetic resonance imaging. PMID- 26973730 TI - De novo development of gliomas in a child with neurofibromatosis type 1, fragile X and previously normal brain magnetic resonance imaging. AB - Fifteen to 20% of children with neurofibromatosis type 1 develop low-grade glial neoplasms. However, since neuroimaging is not routinely obtained until a child is clinically symptomatic, little is known about presymptomatic radiographic characteristics of gliomas in this at-risk population. Herein, we describe a child with neurofibromatosis type 1 who initially had normal brain imaging before the development of multifocal gliomas. Comparison of these serial images demonstrated that brain tumors can arise de novo in children with this cancer predisposition syndrome, further underscoring the limited prognostic value of normal baseline magnetic resonance imaging. PMID- 26973731 TI - Childhood giant omental and mesenteric lipoma. AB - Omental and mesenteric lipomas are very rare benign lesions of mature adipose tissue. They are well-defined, noninvasive, and encapsulated masses that can be discovered in asymptomatic patients or may cause variable nonspecific symptoms depending on their size and location. The omental and mesenteric lipoma has confusing features in ultrasound; however, computed tomography and magnetic resonance imaging can well characterize and demarcate these lesions. Though few cases of mesenteric and omental lipomas have been reported in the literature, but because of its large size and childhood presentation, the case we present, can be one of the largest childhood omental and mesenteric lipomas ever reported. A 6 year-old girl presented with slowly progressing abdominal distension and repeated dull abdominal pain for last 4 years. Abdominal and pelvic computed tomography examination revealed a huge mesenteric and omental lipoma that was resected surgically without any complications. PMID- 26973732 TI - Assessment of Biology Majors' Versus Nonmajors' Views on Evolution, Creationism, and Intelligent Design. AB - The controversy around evolution, creationism, and intelligent design resides in a historical struggle between scientific knowledge and popular belief. Four hundred seventy-six students (biology majors n=237, nonmajors n=239) at a secular liberal arts private university in Northeastern United States responded to a five question survey to assess their views about: (1) evolution, creationism, and intelligent design in the science class; (2) students' attitudes toward evolution; (3) students' position about the teaching of human evolution; (4) evolution in science exams; and (5) students' willingness to discuss evolution openly. There were 60.6% of biology majors and 42% of nonmajors supported the exclusive teaching of evolution in the science class, while 45.3% of nonmajors and 32% of majors were willing to learn equally about evolution, creationism, and intelligent design (question 1); 70.5% of biology majors and 55.6% of nonmajors valued the factual explanations evolution provides about the origin of life and its place in the universe (question 2); 78% of the combined responders (majors plus nonmajors) preferred science courses where evolution is discussed comprehensively and humans are part of it (question 3); 69% of the combined responders (majors plus nonmajors) had no problem answering questions concerning evolution in science exams (question 4); 48.1% of biology majors and 26.8% of nonmajors accepted evolution and expressed it openly, but 18.2% of the former and 14.2% of the latter accepted evolution privately; 46% of nonmajors and 29.1% of biology majors were reluctant to comment on this topic (question 5). Combined open plus private acceptance of evolution within biology majors increased with seniority, from freshman (60.7%) to seniors (81%), presumably due to gradual exposure to upper-division biology courses with evolutionary content. College curricular/pedagogical reform should fortify evolution literacy at all education levels, particularly among nonbiologists. PMID- 26973733 TI - The Jackprot Simulation Couples Mutation Rate with Natural Selection to Illustrate How Protein Evolution Is Not Random. AB - Protein evolution is not a random process. Views which attribute randomness to molecular change, deleterious nature to single-gene mutations, insufficient geological time, or population size for molecular improvements to occur, or invoke "design creationism" to account for complexity in molecular structures and biological processes, are unfounded. Scientific evidence suggests that natural selection tinkers with molecular improvements by retaining adaptive peptide sequence. We used slot-machine probabilities and ion channels to show biological directionality on molecular change. Because ion channels reside in the lipid bilayer of cell membranes, their residue location must be in balance with the membrane's hydrophobic/philic nature; a selective "pore" for ion passage is located within the hydrophobic region. We contrasted the random generation of DNA sequence for KcsA, a bacterial two-transmembrane-domain (2TM) potassium channel, from Streptomyces lividans, with an under-selection scenario, the "jackprot," which predicted much faster evolution than by chance. We wrote a computer program in JAVA APPLET version 1.0 and designed an online interface, The Jackprot Simulation http://faculty.rwu.edu/cbai/JackprotSimulation.htm, to model a numerical interaction between mutation rate and natural selection during a scenario of polypeptide evolution. Winning the "jackprot," or highest-fitness complete-peptide sequence, required cumulative smaller "wins" (rewarded by selection) at the first, second, and third positions in each of the 161 KcsA codons ("jackdons" that led to "jackacids" that led to the "jackprot"). The "jackprot" is a didactic tool to demonstrate how mutation rate coupled with natural selection suffices to explain the evolution of specialized proteins, such as the complex six-transmembrane (6TM) domain potassium, sodium, or calcium channels. Ancestral DNA sequences coding for 2TM-like proteins underwent nucleotide "edition" and gene duplications to generate the 6TMs. Ion channels are essential to the physiology of neurons, ganglia, and brains, and were crucial to the evolutionary advent of consciousness. The Jackprot Simulation illustrates in a computer model that evolution is not and cannot be a random process as conceived by design creationists. PMID- 26973734 TI - Reduction in Radiation Exposure through a Stress Test Algorithm in an Emergency Department Observation Unit. AB - INTRODUCTION: Clinicians are urged to decrease radiation exposure from unnecessary medical procedures. Many emergency department (ED) patients placed in an observation unit (EDOU) do not require chest pain evaluation with a nuclear stress test (NucST). We sought to implement a simple ST algorithm that favors non nuclear stress test (Non-NucST) options to evaluate the effect of the algorithm on the proportion of patients exposed to radiation by comparing use of NucST versus Non-NucST pre- and post-algorithm. METHODS: An ST algorithm was introduced favoring Non-NucST and limiting NucST to a subset of EDOU patients in October 2008. We analyzed aggregate data before (Jan-Sept 2008, period 1) and after (Jan Sept 2009 and Jan-Sept 2010, periods 2 and 3 respectively) algorithm introduction. A random sample of 240 EDOU patients from each period was used to compare 30-day major adverse cardiac events (MACE). We calculated confidence intervals for proportions or the difference between two proportions. RESULTS: A total of 5,047 STs were performed from Jan-Sept 2008-2010. NucST in the EDOU decreased after algorithm introduction from period 1 to 2 (40.7%, 95% CI [38.3 43.1] vs. 22.1%, 95% CI [20.1-24.1]), and remained at 22.1%, 95% CI [20.3-24.0] in period 3. There was no difference in 30-day MACE rates before and after algorithm use (0.1% for period 1 and 3, 0% for period 2). CONCLUSION: Use of a simple ST algorithm that favors non-NucST options decreases the proportion of EDOU chest pain patients exposed to radiation exposure from ST almost 50% by limiting NucST to a subset of patients, without a change in 30-day MACE. PMID- 26973736 TI - Factors Associated with First-Pass Success in Pediatric Intubation in the Emergency Department. AB - INTRODUCTION: The objective of this study was to investigate the factors associated with first-pass success in pediatric intubation in the emergency department (ED). METHODS: We analyzed the data from two multicenter prospective studies of ED intubation in 17 EDs between April 2010 and September 2014. The studies prospectively measured patient's age, sex, principal indication for intubation, methods (e.g., rapid sequence intubation [RSI]), devices, and intubator's level of training and specialty. To evaluate independent predictors of first-pass success, we fit logistic regression model with generalized estimating equations. In the sensitivity analysis, we repeated the analysis in children <10 years. RESULTS: A total of 293 children aged <=18 years who underwent ED intubation were eligible for the analysis. The overall first-pass success rate was 60% (95%CI [54%-66%]). In the multivariable model, age >=10 years (adjusted odds ratio [aOR], 2.45; 95% CI [1.23-4.87]), use of RSI (aOR, 2.17; 95% CI [1.31-3.57]), and intubation attempt by an emergency physician (aOR, 3.21; 95% CI [1.78-5.83]) were significantly associated with a higher chance of first-pass success. Likewise, in the sensitivity analysis, the use of RSI (aOR, 3.05; 95% CI [1.63-5.70]), and intubation attempt by an emergency physician (aOR, 4.08; 95% CI [1.92-8.63]) were significantly associated with a higher chance of first-pass success. CONCLUSION: Based on two large multicenter prospective studies of ED airway management, we found that older age, use of RSI, and intubation by emergency physicians were the independent predictors of a higher chance of first-pass success in children. Our findings should facilitate investigations to develop optimal airway management strategies in critically-ill children in the ED. PMID- 26973737 TI - Moving Beyond Screening: How Emergency Departments Can Help Extinguish the HIV/AIDS Epidemic. AB - While great strides have been made in diagnostic and treatment strategies, human immunodeficiency virus (HIV) remains a major public health epidemic. The Centers for Disease Control and Prevention (CDC) Morbidity and Mortality Weekly Report article, "Vital Signs: HIV Diagnosis, Care, and Treatment Among Persons Living with HIV - United States, 2011," highlights current areas of concern regarding HIV diagnosis and care. The CDC estimates that 1.2 million people in the U.S. are living with HIV. Of them, 86% have received a diagnosis (14% remain undiagnosed and unaware), but only 40% are engaged in care and a mere 30% are virally suppressed. Emergency departments (EDs) can play a major role in combatting the HIV epidemic through regular screening and facilitating linkage to chronic HIV care. Universal opt-out screening as recommended by the CDC in 2006 has been shown to be effective but expensive, and has not been widely implemented in EDs nationwide. Cost-effective models and a renewed commitment from ED providers are needed to enhance ED-based HIV containment strategies. PMID- 26973738 TI - Growing Trend of Alternative Tobacco Use Among the Nation's Youth: A New Generation of Addicts. AB - The Centers for Disease Control and Prevention (CDC) has published significant data and trends related to the rising epidemic of usage of alternate forms of tobacco among the nation's youth. For the first time ever, the use of the electronic cigarette (e-cigarrette) has surpassed traditional cigarette usage in adolescents. E-cigarettes are battery-operated products designed to deliver aerosolized nicotine and other flavors to the consumer. Most look like conventional cigarettes but some resemble everyday items such as pens, USB drives, and memory sticks.1 In the following article, we present findings from the CDC's Morbidity and Mortality Weekly Report with commentary on the state of this growing epidemic and barriers to effective screening methods. PMID- 26973735 TI - Acute Stroke: Current Evidence-based Recommendations for Prehospital Care. AB - INTRODUCTION: In the United States, emergency medical services (EMS) protocols vary widely across jurisdictions. We sought to develop evidence-based recommendations for the prehospital evaluation and treatment of a patient with a suspected stroke and to compare these recommendations against the current protocols used by the 33 EMS agencies in the state of California. METHODS: We performed a literature review of the current evidence in the prehospital treatment of a patient with a suspected stroke and augmented this review with guidelines from various national and international societies to create our evidence-based recommendations. We then compared the stroke protocols of each of the 33 EMS agencies for consistency with these recommendations. The specific protocol components that we analyzed were the use of a stroke scale, blood glucose evaluation, use of supplemental oxygen, patient positioning, 12-lead electrocardiogram (ECG) and cardiac monitoring, fluid assessment and intravenous access, and stroke regionalization. RESULTS: Protocols across EMS agencies in California varied widely. Most used some sort of stroke scale with the majority using the Cincinnati Prehospital Stroke Scale (CPSS). All recommended the evaluation of blood glucose with the level for action ranging from 60 to 80 mg/dL. Cardiac monitoring was recommended in 58% and 33% recommended an ECG. More than half required the direct transport to a primary stroke center and 88% recommended hospital notification. CONCLUSION: Protocols for a patient with a suspected stroke vary widely across the state of California. The evidence-based recommendations that we present for the prehospital diagnosis and treatment of this condition may be useful for EMS medical directors tasked with creating and revising these protocols. PMID- 26973739 TI - Impact of a Dedicated Emergency Medicine Teaching Resident Rotation at a Large Urban Academic Center. AB - INTRODUCTION: In the face of declining bedside teaching and increasing emergency department (ED) crowding, balancing education and patient care is a challenge. Dedicated shifts by teaching residents (TRs) in the ED represent an educational intervention to mitigate these difficulties. We aimed to measure the perceived learning and departmental impact created by having TR. METHODS: TRs were present in the ED from 12 pm-10 pm daily, and their primary roles were to provide the following: assist in teaching procedures, give brief "chalk talks," instruct junior trainees on interesting cases, and answer clinical questions in an evidence-based manner. This observational study included a survey of fourth-year medical students (MSs), residents and faculty at an academic ED. Surveys measured the perceived effect of the TR on teaching, patient flow, ease of procedures, and clinical care. RESULTS: Survey response rates for medical students, residents, and faculty are 56%, 77%, and 75%, respectively. MSs perceived improved procedure performance with TR presence and the majority agreed that the TR was a valuable educational experience. Residents perceived increased patient flow, procedure performance, and MS learning with TR presence. The majority agreed that the TR improved patient care. Faculty agreed that the TR increased resident and MS learning, as well as improved patient care and procedure performance. CONCLUSION: The presence of a TR increased MS and resident learning, improved patient care and procedure performance as perceived by MSs, residents and faculty. A dedicated TR program can provide a valuable resource in achieving a balance of clinical education and high quality healthcare. PMID- 26973740 TI - Can Simulation Measure Differences in Task-Switching Ability Between Junior and Senior Emergency Medicine Residents? AB - INTRODUCTION: Work interruptions during patient care have been correlated with error. Task-switching is identified by the Accreditation Council for Graduate Medical Education (ACGME) as a core competency for emergency medicine (EM). Simulation has been suggested as a means of assessing EM core competencies. We assumed that senior EM residents had better task-switching abilities than junior EM residents. We hypothesized that this difference could be measured by observing the execution of patient care tasks in the simulation environment when a patient with a ST-elevation myocardial infarction (STEMI) interrupted the ongoing management of a septic shock case. METHODS: This was a multi-site, prospective, observational, cohort study. The study population consisted of a convenience sample of EM residents in their first three years of training. Each subject performed a standardized simulated encounter by evaluating and treating a patient in septic shock. At a predetermined point in every sepsis case, the subject was given a STEMI electrocardiogram (ECG) for a separate chest pain patient in triage and required to verbalize an interpretation and action. We scored learner performance using a dichotomous checklist of critical actions covering sepsis care, ECG interpretation and triaging of the STEMI patient. RESULTS: Ninety-one subjects participated (30 postgraduate year [PGY]1s, 32 PGY2s, and 29 PGY3s). Of those, 87 properly managed the patient with septic shock (90.0% PGY1s, 100% PGY2, 96.6% PGY 3s; p=0.22). Of the 87 who successfully managed the septic shock, 80 correctly identified STEMI on the simulated STEMI patient (86.7% PGY1s, 96.9% PGY2s, 93.1% PGY3s; p=0.35). Of the 80 who successfully managed the septic shock patient and correctly identified the STEMI, 79 provided appropriate interventions for the STEMI patient (73.3% PGY1s, 93.8% PGY2s, 93.8% PGY3s; p=0.07). CONCLUSION: When management of a septic shock patient was interrupted with a STEMI ECG in a simulated environment we were unable to measure a significant difference in the ability of EM residents to successfully task-switch when compared across PGY levels of training. This study may help refine the use of simulation to assess EM resident competencies. PMID- 26973741 TI - Impact of Mental Health and Substance Use Disorders on Emergency Department Visit Outcomes for HIV Patients. AB - INTRODUCTION: A disproportionate number of individuals with human immunodeficiency virus (HIV) have mental health and substance-use disorders (MHSUDs), and MHSUDs are significantly associated with their emergency department (ED) visits. With an increasing share of older adults among HIV patients, this study investigated the associations of MHSUDs with ED outcomes of HIV patients in four age groups: 21-34, 35-49, 50-64, and 65+ years. METHODS: We used the 2012 Nationwide Emergency Department Sample (NEDS) dataset (unweighted n=23,244,819 ED events by patients aged 21+, including 115,656 visits by patients with HIV). Multinomial and binary logistic regression analyses, with "treat-and-release" as the base outcome, were used to examine associations between ED outcomes and MHSUDs among visits that included a HIV diagnosis in each age group. RESULTS: Mood and "other" mental disorders had small effects on ED-to-hospital admissions, as opposed to treat-and-release, in age groups younger than 65+ years, while suicide attempts had medium effects (RRR=3.56, CI [2.69-4.70]; RRR=4.44, CI [3.72 5.30]; and RRR=5.64, CI [4.38-7.26] in the 21-34, 35-49, and 50-64 age groups, respectively). Cognitive disorders had medium-to-large effects on hospital admissions in all age groups and large effects on death in the 35-49 (RRR=7.29, CI [3.90-13.62]) and 50-64 (RRR=5.38, CI [3.39-8.55]) age groups. Alcohol use disorders (AUDs) had small effects on hospital admission in all age groups (RRR=2.35, 95% CI [1.92-2.87]; RRR=2.15, 95% CI [1.95-2.37]; RRR=1.92, 95% CI [1.73-2.12]; and OR=1.93, 95% CI [1.20-3.10] in the 21-34, 35-49, 50-64, and 65+ age groups, respectively). Drug use disorders (DUDs) had small-to-medium effects on hospital admission (RRR=4.40, 95% CI [3.87-5.0]; RRR=4.07, 95% CI [3.77-4.40]; RRR=4.17, 95% CI [3.83-4.55]; and OR=2.53, 95% CI [2.70-3.78] in the 21-34, 35 49, 50-64, and 65+ age groups, respectively). AUDs and DUDs were also significantly related to the risk of death, and DUDs had a small effect on the risk of discharge against medical advice in the 35-49 and 50-64 age groups. CONCLUSION: The high prevalence of MHSUDs and their significant roles in ED visit outcomes in patients with HIV provide support for integrated care for these patients outside the ED to reduce their ED visits and costly hospital admissions and institutional care that follows, especially for the increasing numbers of older adults with HIV. PMID- 26973743 TI - Care of Psychiatric Patients: The Challenge to Emergency Physicians. PMID- 26973742 TI - Managing Agitation Associated with Schizophrenia and Bipolar Disorder in the Emergency Setting. AB - INTRODUCTION: Patient agitation represents a significant challenge in the emergency department (ED), a setting in which medical staff are working under pressure dealing with a diverse range of medical emergencies. The potential for escalation into aggressive behavior, putting patients, staff, and others at risk, makes it imperative to address agitated behavior rapidly and efficiently. Time constraints and limited access to specialist psychiatric support have in the past led to the strategy of "restrain and sedate," which was believed to represent the optimal approach; however, it is increasingly recognized that more patient centered approaches result in improved outcomes. The objective of this review is to raise awareness of best practices for the management of agitation in the ED and to consider the role of new pharmacologic interventions in this setting. DISCUSSION: The Best practices in Evaluation and Treatment of Agitation (BETA) guidelines address the complete management of agitation, including triage, diagnosis, interpersonal calming skills, and medicine choices. Since their publication in 2012, there have been further developments in pharmacologic approaches for dealing with agitation, including both new agents and new modes of delivery, which increase the options available for both patients and physicians. Newer modes of delivery that could be useful in rapidly managing agitation include inhaled, buccal/sublingual and intranasal formulations. To date, the only formulation administered via a non-intramuscular route with a specific indication for agitation associated with bipolar or schizophrenia is inhaled loxapine. Non invasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and healthcare providers. CONCLUSION: Management of agitation in the ED should encompass a patient-centered approach, incorporating non-pharmacologic approaches if feasible. Where pharmacologic intervention is necessary, a cooperative approach using non-invasive medications should be employed where possible. PMID- 26973744 TI - Electronic Vapor Cigarette Battery Explosion Causing Shotgun-like Superficial Wounds and Contusion. PMID- 26973745 TI - Salicylate Toxicity from Genital Exposure to a Methylsalicylate-Containing Rubefacient. AB - Methylsalicylate-containing rubefacients have been reported to cause salicylate poisoning after ingestion, topical application to abnormal skin, and inappropriate topical application to normal skin. Many over-the-counter products contain methylsalicylate. Topical salicylates rarely produce systemic toxicity when used appropriately; however, methylsaliclyate can be absorbed through intact skin. Scrotal skin can have up to 40-fold greater absorption compared to other dermal regions. We report a unique case of salicylate poisoning resulting from the use of a methylsalicylate-containing rubefacient to facilitate masturbation in a male teenager. Saliclyate toxicity has not previously been reported from the genital exposure to methylsaliclyate. PMID- 26973746 TI - Traumatic Arthrotomy with Pneumarthrosis on Plain Radiograph of the Knee. PMID- 26973748 TI - Bullosis Diabeticorum. PMID- 26973747 TI - Young Woman with a Fever and Chest Pain. PMID- 26973749 TI - Turbid Peritoneal Fluid. PMID- 26973750 TI - There's an App for That? Highlighting the Difficulty in Finding Clinically Relevant Smartphone Applications. AB - INTRODUCTION: The use of personal mobile devices in the medical field has grown quickly, and a large proportion of physicians use their mobile devices as an immediate resource for clinical decision-making, prescription information and other medical information. The iTunes App Store (Apple, Inc.) contains approximately 20,000 apps in its "Medical" category, providing a robust repository of resources for clinicians; however, this represents only 2% of the entire App Store. The App Store does not have strict criteria for identifying content specific to practicing physicians, making the identification of clinically relevant content difficult. The objective of this study is to quantify the characteristics of existing medical applications in the iTunes App Store that could be used by emergency physicians, residents, or medical students. METHODS: We found applications related to emergency medicine (EM) by searching the iTunes App Store for 21 terms representing core content areas of EM, such as "emergency medicine," "critical care," "orthopedics," and "procedures." Two physicians independently reviewed descriptions of these applications in the App Store and categorized each as the following: Clinically Relevant, Book/Published Source, Non-English, Study Tools, or Not Relevant. A third physician reviewer resolved disagreements about categorization. Descriptive statistics were calculated. RESULTS: We found a total of 7,699 apps from the 21 search terms, of which 17.8% were clinical, 9.6% were based on a book or published source, 1.6% were non English, 0.7% were clinically relevant patient education resources, and 4.8% were study tools. Most significantly, 64.9% were considered not relevant to medical professionals. Clinically relevant apps make up approximately 6.9% of the App Store's "Medical" Category and 0.1% of the overall App Store. CONCLUSION: Clinically relevant apps represent only a small percentage (6.9%) of the total App volume within the Medical section of the App Store. Without a structured search-and-evaluation strategy, it may be difficult for the casual user to identify this potentially useful content. Given the increasing adoption of devices in healthcare, national EM associations should consider curating these resources for their members. PMID- 26973751 TI - Point-of-Care Ultrasound to Evaluate a Teenager with Presyncope. PMID- 26973752 TI - Retrospective Review of Ocular Point-of-Care Ultrasound for Detection of Retinal Detachment. AB - INTRODUCTION: Retinal detachment is an ocular emergency that commonly presents to the emergency department (ED). Ophthalmologists are able to accurately make this diagnosis with a dilated fundoscopic exam, scleral depression or ophthalmic ultrasound when a view to the retina is obstructed. Emergency physicians (EPs) are not trained to examine the peripheral retina, and thus ophthalmic ultrasound can be used to aid in diagnosis. We assessed the accuracy of ocular point-of-care ultrasound (POCUS) in diagnosing retinal detachment. METHODS: We retrospectively reviewed charts of ED patients with suspected retinal detachment who underwent ocular POCUS between July 2012 and May 2015. Charts were reviewed for patients presenting to the ED with ocular complaints and clinical concern for retinal detachment. We compared ocular POCUS performed by EPs against the criterion reference of the consulting ophthalmologist's diagnosis. RESULTS: We enrolled a total of 109 patients. Of the 34 patients diagnosed with retinal detachment by the ophthalmologists, 31 were correctly identified as having retinal detachment by the EP using ocular POCUS. Of the 75 patients who did not have retinal detachment, 72 were ruled out by ocular POCUS by the EP. This resulted in a POCUS sensitivity of 91% (95% CI [76-98]) and specificity of 96% (95% CI [89-99]). CONCLUSION: This retrospective study suggests that ocular POCUS performed by EPs can aid in the diagnosis of retinal detachment in ED. PMID- 26973753 TI - Mistakes and Pitfalls Associated with Two-Point Compression Ultrasound for Deep Vein Thrombosis. AB - INTRODUCTION: Two-point compression ultrasound is purportedly a simple and accurate means to diagnose proximal lower extremity deep vein thrombosis (DVT), but the pitfalls of this technique have not been fully elucidated. The objective of this study is to determine the accuracy of emergency medicine resident performed two-point compression ultrasound, and to determine what technical errors are commonly made by novice ultrasonographers using this technique. METHODS: This was a prospective diagnostic test assessment of a convenience sample of adult emergency department (ED) patients suspected of having a lower extremity DVT. After brief training on the technique, residents performed two point compression ultrasounds on enrolled patients. Subsequently a radiology department ultrasound was performed and used as the gold standard. Residents were instructed to save videos of their ultrasounds for technical analysis. RESULTS: Overall, 288 two-point compression ultrasound studies were performed. There were 28 cases that were deemed to be positive for DVT by radiology ultrasound. Among these 28, 16 were identified by the residents with two-point compression. Among the 260 cases deemed to be negative for DVT by radiology ultrasound, 10 were thought to be positive by the residents using two-point compression. This led to a sensitivity of 57.1% (95% CI [38.8-75.5]) and a specificity of 96.1% (95% CI [93.8-98.5]) for resident-performed two-point compression ultrasound. This corresponds to a positive predictive value of 61.5% (95% CI [42.8-80.2]) and a negative predictive value of 95.4% (95% CI [92.9-98.0]). The positive likelihood ratio is 14.9 (95% CI [7.5-29.5]) and the negative likelihood ratio is 0.45 (95% CI [0.29-0.68]). Video analysis revealed that in four cases the resident did not identify a DVT because the thrombus was isolated to the superior femoral vein (SFV), which is not evaluated by two-point compression. Moreover, the video analysis revealed that the most common mistake made by the residents was inadequate visualization of the popliteal vein. CONCLUSION: Two-point compression ultrasound does not identify isolated SFV thrombi, which reduces its sensitivity. Moreover, this technique may be more difficult than previously reported, in part because novice ultrasonographers have difficulty properly assessing the popliteal vein. PMID- 26973754 TI - Computerized Diagnostic Assistant for the Automatic Detection of Pneumothorax on Ultrasound: A Pilot Study. AB - INTRODUCTION: Bedside thoracic ultrasound (US) can rapidly diagnose pneumothorax (PTX) with improved accuracy over the physical examination and without the need for chest radiography (CXR); however, US is highly operator dependent. A computerized diagnostic assistant was developed by the United States Army Institute of Surgical Research to detect PTX on standard thoracic US images. This computer algorithm is designed to automatically detect sonographic signs of PTX by systematically analyzing B-mode US video clips for pleural sliding and M-mode still images for the seashore sign. This was a pilot study to estimate the diagnostic accuracy of the PTX detection computer algorithm when compared to an expert panel of US trained physicians. METHODS: This was a retrospective study using archived thoracic US obtained on adult patients presenting to the emergency department (ED) between 5/23/2011 and 8/6/2014. Emergency medicine residents, fellows, attending physicians, physician assistants, and medical students performed the US examinations and stored the images in the picture archive and communications system (PACS). The PACS was queried for all ED bedside US examinations with reported positive PTX during the study period along with a random sample of negatives. The computer algorithm then interpreted the images, and we compared the results to an independent, blinded expert panel of three physicians, each with experience reviewing over 10,000 US examinations. RESULTS: Query of the PACS system revealed 146 bedside thoracic US examinations for analysis. Thirteen examinations were indeterminate and were excluded. There were 79 true negatives, 33 true positives, 9 false negatives, and 12 false positives. The test characteristics of the algorithm when compared to the expert panel were sensitivity 79% (95 % CI [63-89]) and specificity 87% (95% CI [77-93]). For the 20 images scored as highest quality by the expert panel, the algorithm demonstrated 100% sensitivity (95% CI [56-100]) and 92% specificity (95% CI [62 100]). CONCLUSION: This novel computer algorithm has potential to aid clinicians with the identification of the sonographic signs of PTX in the absence of expert physician sonographers. Further refinement and training of the algorithm is still needed, along with prospective validation, before it can be utilized in clinical practice. PMID- 26973755 TI - Ultrasound-Guided Cannulation: Time to Bring Subclavian Central Lines Back. AB - Despite multiple advantages, subclavian vein (SCV) cannulation via the traditional landmark approach has become less used in comparison to ultrasound (US) guided internal jugular catheterization due to a higher rate of mechanical complications. A growing body of evidence indicates that SCV catheterization with real-time US guidance can be accomplished safely and efficiently. While several cannulation approaches with real-time US guidance have been described, available literature suggests that the infraclavicular, longitudinal "in-plane" technique may be preferred. This approach allows for direct visualization of needle advancement, which reduces risk of complications and improves successful placement. Infraclavicular SCV cannulation requires simultaneous use of US during needle advancement, but for an inexperienced operator, it is more easily learned compared to the traditional landmark approach. In this article, we review the evidence supporting the use of US guidance for SCV catheterization and discuss technical aspects of the procedure itself. PMID- 26973757 TI - Physician Quality Reporting System Program Updates and the Impact on Emergency Medicine Practice. AB - In 2007, the Centers for Medicaid and Medicare Services (CMS) created a novel payment program to create incentives for physician's to focus on quality of care measures and report quality performance for the first time. Initially termed "The Physician Voluntary Reporting Program," various Congressional actions, including the Tax Relief and Health Care Act of 2006 (TRHCA) and Medicare Improvements for Patients and Providers Act of 2008 (MIPPA) further strengthened and ensconced this program, eventually leading to the quality program termed today as the Physician Quality Reporting System (PQRS). As a result of passage of the Affordable Care Act of 2010, the PQRS program has expanded to include both the "traditional PQRS" reporting program and the newer "Value Modifier" program (VM). For the first time, these programs were designed to include pay-for-performance incentives for all physicians providing care to Medicare beneficiaries and to measure the cost of care. The recent passage of the Medicare Access and Children's Health Insurance Program (CHIP) Reauthorization Act in March of 2015 includes changes to these payment programs that will have an even more profound impact on emergency care providers. We describe the implications of these important federal policy changes for emergency physicians. PMID- 26973756 TI - Effects of Intraosseous Tibial vs. Intravenous Vasopressin in a Hypovolemic Cardiac Arrest Model. AB - INTRODUCTION: This study compared the effects of vasopressin via tibial intraosseous (IO) and intravenous (IV) routes on maximum plasma concentration (Cmax), the time to maximum concentration (Tmax), return of spontaneous circulation (ROSC), and time to ROSC in a hypovolemic cardiac arrest model. METHODS: This study was a randomized prospective, between-subjects experimental design. A computer program randomly assigned 28 Yorkshire swine to one of four groups: IV (n=7), IO tibia (n=7), cardiopulmonary resuscitation (CPR) + defibrillation (n=7), and a control group that received just CPR (n=7). Ventricular fibrillation was induced, and subjects remained in arrest for two minutes. CPR was initiated and 40 units of vasopressin were administered via IO or IV routes. Blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, and 4 minutes. CPR and defibrillation were initiated for 20 minutes or until ROSC was achieved. We measured vasopressin concentrations using high-performance liquid chromatography. RESULTS: There was no significant difference between the IO and IV groups relative to achieving ROSC (p=1.0) but a significant difference between the IV compared to the CPR+ defibrillation group (p=0.031) and IV compared to the CPR-only group (p=0.001). There was a significant difference between the IO group compared to the CPR+ defibrillation group (p=0.031) and IO compared to the CPR only group (p=0.001). There was no significant difference between the CPR + defibrillation group and the CPR group (p=0.127). There was no significant difference in Cmax between the IO and IV groups (p=0.079). The mean +/- standard deviation of Cmax of the IO group was 58,709+/-25, 463 pg/mL compared to the IV group, which was 106,198+/-62, 135 pg/mL. There was no significant difference in mean Tmax between the groups (p=0.084). There were no significant differences in odds of ROSC between the tibial IO and IV groups. CONCLUSION: Prompt access to the vascular system using the IO route can circumvent the interruption in treatment observed with attempting conventional IV access. The IO route is an effective modality for the treatment of hypovolemic cardiac arrest and may be considered first line for rapid vascular access. PMID- 26973758 TI - Anxiety Sensitivity as a Moderator of the Association Between Premenstrual Symptoms and Posttraumatic Stress Disorder Symptom Severity. AB - Experience of premenstrual symptoms may be an important factor involved in understanding posttraumatic stress disorder (PTSD) symptom vulnerability. Correlations between PTSD and premenstrual dysphoric disorder (PMDD) have been identified in epidemiological studies, however, the nature of this relation is not clear. The current study examined the incremental validity of premenstrual symptoms, as well as their interaction with anxiety sensitivity, in the prediction of PTSD symptom severity above and beyond other theoretically relevant covariates. A community sample of trauma-exposed women (N = 63) completed questionnaires assessing premenstrual symptoms, anxiety sensitivity, and neuroticism and were administered the Clinician-Administered PTSD Scale to assess PTSD symptom severity. A series of hierarchical linear regressions revealed that premenstrual symptoms uniquely predicted PTSD total, reexperiencing, avoidance, and hyperarousal symptoms above and beyond other theoretically relevant covariates (i.e., number of potentially traumatic events, neuroticism, panic attack history, and anxiety sensitivity). Additionally, anxiety sensitivity emerged as a moderator of the association between premenstrual symptoms and PTSD symptom severity such that greater premenstrual symptoms were associated with greater PTSD total, reexperiencing, and numbing symptom severity for individuals high, but not low, in anxiety sensitivity. Experience of premenstrual symptoms may be an important sex-specific mechanism involved in increasing vulnerability for PTSD symptoms, particularly among women high in anxiety sensitivity. PMID- 26973760 TI - Evaluation of proliferation and cytokines production by mitogen-stimulated bovine peripheral blood mononuclear cells. AB - This in vitro study was conducted to evaluate lymphocyte blastogenic and cytokine production by bovine peripheral blood mononuclear cells (PBMCs) stimulated with phytohemagglutinin (PHA), pokeweed mitogen (PWM) and concanavalin A (Con A) mitogens, by using tetrazolium salt and ELISA tests, respectively. The results presented that Interleukin-2 (IL-2), IL-4, IL-5, IL-10, IL-17 and IFN-gamma production in response to PWM mitogens was the highest and Con A the lowest amount and the median values of three mitogens were in the following order: PWM > PHA > Con A > cell control. In the case of IL-6, the production of this cytokine was the same amount for PWM and Con A and a lower amount for PHA stimulation. The results of this study not only showed a normal range for the production of these cytokines from PBMCs that were affected by mitogens, but it demonstrated that the bovine immune system at 2.5 to 3 months was post-natally matured enough to mount an effective immune response to mitogens as well as specific antigens. PMID- 26973761 TI - Busulfan induced azoospermia: Stereological evaluation of testes in rat. AB - The aim of the present study was stereological evaluation of testes of azoospermic animal model using busulfan in rat. Three groups of male adult rats were used in this study. The first group was injected by single dose of busulfan (10 mg kg(-1)) and their testes were removed on day 35 post injection. The second group received double doses of busulfan with 21 days interval and their testes were removed on day 35 after the second injection. The testes of the third group were removed without busulfan therapy. In 10 circular transverse sections of tubules stained with hematoxylin-eosin, stereological parameters were measured. The testes were rated for its spermatogenic potential on a modified spermatogenic scale of 0 to 6. Cellular (germinal epithelium) diameter and area of the seminiferous tubules, total diameter and cross sectional area of the tubules of the seminiferous tubules in rats that received double doses of busulfan were less than the rats in single dose of busulfan and control groups (p < 0.05). Spermatogenesis index of seminiferous tubules in rats receiving two doses of busulfan was less than the rats received one dose of busulfan (p < 0.001) and the index of both treatment groups were less than the control group (p < 0.001). In conclusion, two doses of busulfan injection with 21 days interval produced an appropriate experimental model of induced azoospermia with comparable stereological indices of seminiferous tubules in rat. PMID- 26973762 TI - Genotyping of Clostridium perfringens isolated from broiler meat in northeastern of Iran. AB - Clostridium perfringens (C. perfringens) is an important cause of bacterial food poisoning worldwide. The disease is caused by C. perfringens enterotoxin (CPE) encoded by cpe gene. The aim of this research was to identify the different types of C. perfringens and the presence of cpe gene in isolated bacteria from broilers' meat marketed in retail meat shops of Mashhad city in Northeastern of Iran. After isolation of C. perfringens using conventional culture method and confirmation by specific 16S rDNA gene, a multiplex polymerase chain reaction assay with specific primers, were performed for toxin typing of isolates. Clostridium perfringens was isolated from 31 broilers' meat samples (15.50%) out of 200 samples and for toxin typing the results showed 9 isolates as type A (29.03%) and 22 isolates as type C (70.96%). In this study, cpe-positive C. perfringens were detected in eight isolates of type C (25.00%). Our results indicated that C. perfringens type C is the most common type in broiler chicken carcasses. PMID- 26973763 TI - Evaluating in vitro dose-response effects of Lavandula officinalis essential oil on rumen fermentation characteristics, methane production and ruminal acidosis. AB - Four in vitro experiments (Exp.) were conducted to evaluate lavender essential oil (LEO) effects at 0 (control), 250 (low dose), 500 (medium dose), 750 and 1000 uL per L (high doses) of incubation medium on rumen gas production kinetics (Exp.1), ruminal digestibility and fermentation (Exp.2), methane production (Exp.3) and rumen acidosis (Exp.4). The asymptote of gas production (A) increased quadratically (p < 0.001), but the lag phase (L) increased (p = 0.003), and gas production rate (u) decreased linearly (p = 0.031) with increasing dose of LEO. A linear and quadratic effect (p < 0.01) was observed for the gas produced after 24 hr of incubation (GP24). In vitro true dry matter degradability (IVTDMD) and in vitro true organic matter degradability (IVTOMD) both decreased linearly (p < 0.01), but microbial biomass (MB) and partitioning factor (PF) changed quadratically with increasing doses of LEO (p < 0.05). A cubic effect was observed for total volatile fatty acid (TVFA) and ammonia (NH3) concentrations (p < 0.05). Acetate molar percentage decreased (p = 0.004), whereas those of butyrate and valerate increased linearly (p < 0.05) with LEO dosage. The molar percentage of propionate increased by 10.60 and 12.00% at low and medium doses of LEO, respectively. Methane production decreased by 11.00 and 44.00 to 60.00% at medium and high doses of LEO (p < 0.05), respectively. Lavender essential oil decreased also ruminal pH at all included doses (p < 0.05), intensifying rumen acidosis. These results revealed a dose-dependent selective effect (stimulatory at low and medium, and inhibitory at high doses) of LEO on rumen fermentation. PMID- 26973759 TI - Whispering gallery mode sensors. AB - We present a comprehensive overview of sensor technology exploiting optical whispering gallery mode (WGM) resonances. After a short introduction we begin by detailing the fundamental principles and theory of WGMs in optical microcavities and the transduction mechanisms frequently employed for sensing purposes. Key recent theoretical contributions to the modeling and analysis of WGM systems are highlighted. Subsequently we review the state of the art of WGM sensors by outlining efforts made to date to improve current detection limits. Proposals in this vein are numerous and range, for example, from plasmonic enhancements and active cavities to hybrid optomechanical sensors, which are already working in the shot noise limited regime. In parallel to furthering WGM sensitivity, efforts to improve the time resolution are beginning to emerge. We therefore summarize the techniques being pursued in this vein. Ultimately WGM sensors aim for real world applications, such as measurements of force and temperature, or alternatively gas and biosensing. Each such application is thus reviewed in turn, and important achievements are discussed. Finally, we adopt a more forward looking perspective and discuss the outlook of WGM sensors within both a physical and biological context and consider how they may yet push the detection envelope further. PMID- 26973764 TI - Frequency of specific agr groups and antibiotic resistance in Staphylococcus aureus isolated from bovine mastitis in the northeast of Iran. AB - Staphylococcus aureus is generally regarded as a leading cause of mastitis in dairy cattle. The aim of this study was to investigate the pattern of agr groups and any possible relationship between agr groups and antibiotic resistance among S. aureus strains isolated from bovine mastitis in Northeast of Iran. For this purpose, a total of 300 bovine mastitic milk samples were taken from dairy industry farms of Khorasan Razavi Province, Iran. S. aureus were isolated and identified according to the standard methods. Antibiotic susceptibility testing was conducted by disk diffusion method. In this study a total of 31 isolates of S. aureus were evaluated for agrD gene polymorphism by specific primers. Most of the isolates belonged to agr group I (54.8%), followed by agr group III (25.8%) and agr group II (19.4%). There was not any isolates belonging to group IV. Resistance to methicillin in agr group I isolates was more than other groups. Agr groups II and III were quite susceptible to methicillin. Due to high prevalent of S. aureus isolates and high antibiotic resistance rate in bovine mastitic isolates, it is important to verify the characteristics of S. aureus strains in Iran. PMID- 26973765 TI - Seroprevalence of leptospiral infection in feline population in urban and dairy cattle herds in Mashhad, Iran. AB - The importance of cats in the Leptospira epidemiology is due to the possibility of transferring leptospirosis to wild and domesticated animals. The purpose of this survey was to determine the prevalence of Leptospira infection in shorthair cats in different location of Mashhad, Iran. Totally, 147 blood samples were taken from 42 (28.57%), 52 (35.37%) and 53 (36.05%) households, stray and cats which lived in industrial dairy cattle herds of Mashhad, Iran, respectively. Sera were tested with seven live Leptospira antigens using microscopic agglutination test (MAT). Sera with 50.00% agglutination at the dilution of >= 1/100 were considered as positive samples. Agglutination at dilutions of < 1/100 considered as suspected to Leptospira infection. Overall, 19 (12.92%) out of 147 cats showed reaction in MAT. The seroprevalence at a titer >= 1:100 and < 1:100 were 10 (6.80%) and 9 (6.12%), respectively. Serum samples showed positive reaction against Leptospira intterogans hardjo (no = 10; 52.63%), pomona (no = 5; 26.31%) and icterohaemorrhagiae (no = 4; 21.05%). Eight cats (42.10%) belong to dairy cattle herds had the most infection only by L. I. hardjo with 1:200 titer. There were no significant differences among the weight' age and sex of infected cats. However, there were significant differences between the infected cats in dairy cattle herds and the cats in the urban area (p < 0.05). It is concluded that cats can be infected by Leptospira spp. especially in commercial dairy cattle herds. Cats can be considered as a sanitation hazards in the area for this zoonotic disease. PMID- 26973766 TI - The anti-inflammatory and anti-apoptotic effects of gallic acid against mucosal inflammation- and erosions-induced by gastric ischemia-reperfusion in rats. AB - The present study aimed to evaluate the protective effect of gallic acid on gastric mucosal lesions caused by ischemia-reperfusion (I/R) injury in rat. Forty male rats were randomly divided into sham, control (I/R injury) and three gallic acid-pretreated groups. To induce I/R lesions, the celiac artery was clamped for 30 min and then the clamp was removed to allow reperfusion for 6 hr. Pretreated rats received gallic acid (15, 30 or 60 mg kg(-1), intraperitoneally) 30 min prior to the induction of I/R injury. Macroscopic and microscopic evaluations of the areas of ulceration were compared. Samples of gastric mucosa were collected to evaluate the protein expression of pro-apoptotic factor, caspase-3, and pro inflammatory enzyme, inducible nitric oxide synthase (iNOS) using western blot. Pretreatment with gallic acid decreased the total area of gastric lesions. Gallic acid at 30 mg kg(-1) decreased the levels of protein expression of caspase-3 and iNOS induced by I/R injury. Our findings showed the protective effect of gallic acid on gastric mucosa against ischemia-reperfusion injury. This effect of gallic acid was mainly mediated by reducing protein expression of iNOS and caspase-3. PMID- 26973767 TI - Evaluation of the anti-nociceptive effects of morphine, tramadol, meloxicam and their combinations using the tail-flick test in rats. AB - The purpose of the present study was to evaluate anti-nociceptive effects of morphine, tramadol, meloxicam and their combinations in rats. Seventy male Wistar rats were divided into seven equal groups and randomly assigned to receive intraperitoneal saline (S) (control group, 1.0 mL kg(-1)), morphine (MO) (4.0 mg kg(-1)), tramadol (TR) (12.5 mg kg(-1)), meloxicam (ML) (1.0 mg kg(-1)), tramadol morphine (TR-MO), meloxicam-morphine (ML-MO) and meloxicam-tramadol (ML-TR) at the same doses. Anti-nociception was evaluated using tail flick latency (TFL) test at 45, 60, 75, 90 and 120 min after drug injection. The TFL was significantly higher in TR and MO groups compared to S group for 90 and 120 min, respectively. No significant change in TFL from baseline values was observed at all time points in ML group. Among rats that received combination of analgesics, those that received TR-MO had significantly greater TFL. There was no significant difference in TFL between ML-TR and ML-MO groups. In conclusion, TR, MO and their combination all provided acceptable anti-nociceptive effects in rats. Meloxicam at the given dosage (1.0 mg kg(-1)) did not demonstrate any anti-nociceptive effect when evaluated by TFL test. PMID- 26973768 TI - Fructooligosaccharide raftilose reduces the mycophenolate mofetil-induced complications: Hematological and biochemical alterations. AB - Mycophenolate mofetil (MMF) is a selective inhibitor of Inosine-5'-monophosphate dehydrogenase. Gastrointestinal (GI) disturbances in immature ones are reported for MMF-induced compilations, which in the case of occurrence dose reduction is required. Thus, in the present study, the fructooligosaccharide raftilose((r)) (RFT) was co-administrated with MMF to estimate the protective effect of RFT against MMF-induced GI complications. Thirty six immature male Wistar rats were divided into six groups including: Control (normal saline), RFT-treated (100 mg kg(-1)), MMF-treated (20 mg kg(-1)), MMF + LRFT (50 mg kg(-1)), MMF + MRFT (100 mg kg(-1)) and MMF + HRFT (200 mg kg(-1)) groups. The hematocrit (Hct), lymphocyte/total WBC, feces water content and pH were analyzed. Moreover, the hepatic functional tests, kidney-related biomarkers, lipid and protein profiles, total antioxidant capacity (TAC), malondialdehyde (MDA) and nitric oxide (NO) contents were assessed. Co-administration of RFT stabilized the MMF-reduced body weight. The MMF significantly diminished Hct and lymph/total WBC (p < 0.05). Only MRFT enhanced the lymphocyte/total WBC. Increased water content, no changes in feces pH, increased serum ALT and AST, no alteration in urea and mild enhancement in creatinine were demonstrated in MMF-received animals. However, RFT at low dose ameliorated the feces parameters and reduced ALT. No significant changes were demonstrated for serum lipid and protein profiles in MMF- and RFT + MMF-treated groups. The RFT enhanced the serum TAC, reduced MDA and NO contents. In conclusion, our data suggested that RFT could be considered as an effective agent to subsidize the MMF-induced clinical, hematological and biochemical disorders. PMID- 26973769 TI - Effect of sex on histomorphometric properties of Langerhans islets in native chickens. AB - The aim of the present study was to investigate the effect of gender on the distribution of pancreatic islets in native chicken. Ten adult male and ten adult female Isfahan native chickens were used in this experiment. Results showed a distinct sexual dimorphism in the native chicken pancreas which depends upon the various fractions of the pancreatic lobes, which were occupied by alpha, beta and mixed islets. In both sexes, the islets were more frequently found in the splenic and the third lobes, whereas they were more scarcely observed in the ventral and the dorsal lobes. In both sexes, there were no alpha islets in the dorsal and ventral pancreatic lobes. The mean percentage of beta islets in the third and splenic lobes were significantly greater in males than females (p < 0.05). However, the mean percentage of mixed islets in the third and splenic lobes were significantly greater in females than males (p < 0.05). The mean percentage of the alpha islets in the splenic and third lobes and the mean percentage of beta and mixed islets in the dorsal and ventral lobes was similar in both sexes in chickens. There was no sex difference in the mean percentage of whole gland islets (p > 0.05). PMID- 26973770 TI - The effects of different routes of inulin administration on gut microbiota and survival rate of Indian white shrimp post-larvae (Fenneropenaeus indicus). AB - The present study investigates the effects of different routes of inulin administration as prebiotic on gut microbiota and survival rate of Indian white shrimp post-larvae. Four hundred and fifty Indian white shrimp post-larvae (PL1) were stocked in nine tanks. The tanks were assigned into three treatments: feeding with inulin-treated (110 mg L(-1)) Artemia nauplii (I-T), feeding with inulin-enriched (110 mg L(-1)) Artemia nauplii (I-E) and control which repeated triplicates. Feeding trial was performed until PL11 stage and then gut microbiota was studied using culture based method. Also, survival rate was calculated at the end of feeding trial. Our results showed that feeding on inulin enriched or treated Artemia nauplii had no significant effect on total viable culturable autochthonous bacteria and Vibrio spp. levels of the gut microbiota (p > 0.05). However, a remarkable increase of lactic acid bacteria levels (LAB) was observed in I-E treatment (p < 0.05). Administration of inulin enriched Artemia nauplii significantly elevated survival rates of Indian white shrimp post-larvae (p < 0.05). These results encourage administration of prebiotic-enriched Artemia nauplii in post larval stage of Indian white shrimp but determination the mode of action of prebiotic on various aspects of shrimp larviculture merit further research. PMID- 26973771 TI - Detection of Mycobacterium avium subspecies paratuberculosis infection in two different camel species by conventional and molecular techniques. AB - Paratuberculosis (John's disease) is infectious and chronically progressive granulomatous disease which affects domestic and wild ruminants. The causative agent is Mycobacterium avium paratuberculosis (MAP), a slow growing mycobactin dependent acid-fast bacillus. We investigated the detection and frequency of MAP in apparently healthy dromedary and Bactrian camels by insertion sequence 900 (IS900) polymerase chain reaction (PCR) and acid fast staining of fecal samples in Iran. Acid fast staining results showed that 6/50 (12.0%) samples of dromedary camels and 4/26 (15.3%) samples of Bactrian camels were suspected to MAP. Although the percentage of positivity for PCR assay of fecal dromedary camel was 8.0%, no bands corresponding to MAP detect in all samples of Bactrian camels. In conclusion, Although the incidence of MAP infection was low, further studies should be conducted to get more information on MAP infection in camel population, especially in areas where camels are close to other ruminants such as dairy cow, sheep and goat. PMID- 26973772 TI - A case presentation of spider lamb syndrome in a Kermanian breed lamb. AB - Skeletal abnormalities are most often used to describe defects in the arms or legs that are associated with genes or chromosomes, or that occur due to an event that happens during pregnancy. Spider lamb syndrome (SLS) is a congenital disorder in sheep breeding that is recognized by some deformities in skeletal system especially in the limbs. A dead day-old cross-breed white lamb with deformed limbs was referred to the anatomy hall of the Veterinary Faculty of Shahid Bahonar University of Kerman. In the external examination, the lamb was very skinny and in the facial region, superior brachygnathia with a slight Roman nose were observed. Metacarpal and metatarsal regions were more elongated than that expected. Also Metacarpal and metatarsal bones were as long as the antebrachial and crural regions, respectively. This paper, the first report of this syndrome in Iran, described the anatomic and radiographic features of the skeletal deformities in a day-old dead Kermanian breed lamb. PMID- 26973773 TI - An unusual necrotic myositis by Clostridium perfringens in a German Shepherd dog: A clinical report, bacteriological and molecular identification. AB - Clostridial myositis, considered to be rare in pet animals, is an acutely fatal toxaemic condition. Some species of clostridia are responsible for necrotic myositis. A 2-year-old male German shepherd dog was admitted with non-weight bearing lameness and massive swelling of the left hind limb. Clostridium perfringens type A with alpha toxin was diagnosed as a pathogenic agent. Based on the history, the bacteria were introduced inside the tissue via contaminated needle following intramuscular injection. Urgent medical therapy followed by surgical intervention was performed. The dog was discharged completely healthy after hospitalization for four weeks. The objective of this report was to describe necrotic myositis in a dog with an emphasis on clinical signs and treatment as well as bacteriological and molecular identification of the micro organism. Because of the fatal entity of the disease, prompt diagnosis as well as proper and urgent treatment is very important for successful therapy. PMID- 26962431 TI - Post-operative rehabilitation and nutrition in osteoarthritis. AB - Osteoarthritis (OA) is a degenerative process involving the progressive loss of articular cartilage, synovial inflammation and structural changes in subchondral bone that lead to loss of synovial joint structural features and functionality of articular cartilage. OA represents one of the most common causes of physical disability in the world. Different OA treatments are usually considered in relation to the stage of the disease. In the early stages, it is possible to recommend physical activity programs that can maintain joint health and keep the patient mobile, as recommended by OA Research Society International (OARSI) and European League Against Rheumatism (EULAR). In the most severe and advanced cases of OA, surgical intervention is necessary. After, in early postoperative stages, it is essential to include a rehabilitation exercise program in order to restore the full function of the involved joint. Physical therapy is crucial for the success of any surgical procedure and can promote recovery of muscle strength, range of motion, coordinated walking, proprioception and mitigate joint pain. Furthermore, after discharge from the hospital, patients should continue the rehabilitation exercise program at home associated to an appropriate diet. In this review, we analyze manuscripts from the most recent literature and provide a balanced and comprehensive overview of the latest developments on the effect of physical exercise on postoperative rehabilitation in OA. The literature search was conducted using PubMed, Scopus, Web of Science and Google Scholar, using the keywords 'osteoarthritis', 'rehabilitation', 'exercise' and 'nutrition'. The available data suggest that physical exercise is an effective, economical and accessible to everyone practice, and it is one of the most important components of postoperative rehabilitation for OA. PMID- 26973774 TI - Identification of an Inhibitor of the Aminoglycoside 6'-N-Acetyltransferase type Ib [AAC(6')-Ib] by Glide Molecular Docking. AB - The aminoglycoside 6'-N-acetyltransferase type Ib, AAC(6')-Ib, confers resistance to clinically relevant aminoglycosides and is the most widely distributed enzyme among AAC(6')-I-producing Gram-negative pathogens. An alternative to counter the action of this enzyme is the development of inhibitors. Glide is a computational strategy for rapidly docking ligands to protein sites and estimating their binding affinities. We docked a collection of 280,000 compounds from 7 sub libraries of the Chembridge library as ligands to the aminoglycoside binding site of AAC(6')-Ib. We identified a compound, 1-[3-(2-aminoethyl)benzyl]-3-(piperidin 1-ylmethyl)pyrrolidin-3-ol (compound 1), that inhibited the acetylation of aminoglycosides in vitro with IC50 values of 39.7 and 34.9 uM when the aminoglycoside substrates assayed were kanamycin A or amikacin, respectively. The growth of an amikacin-resistant Acinetobacter baumannii clinical strain was inhibited in the presence of a combination of amikacin and compound 1. PMID- 26962432 TI - Case Report: "ADHD Trainer": the mobile application that enhances cognitive skills in ADHD patients. AB - We report the case of a 10 year old patient diagnosed with attention deficit hyperactivity disorder (ADHD) and comorbid video game addiction, who was treated with medication combined to a novel cognitive training method based on video games called TCT method. A great risk of developing video game or internet addiction has been reported in children, especially in children with ADHD. Despite this risk, we hypothesize that the good use of these new technologies might be useful to develop new methods of cognitive training. The cognitive areas in which a greater improvement was observed through the use of video games were the visuospatial working memory and fine motor skills. TCT method is a cognitive training method that enhances cognitive skills such as attention, working memory, processing speed, calculation ability, reasoning, and visuomotor coordination. The purpose of reviewing this case is to highlight that regular cognitive computerized training in ADHD patients can improve some of their cognitive symptoms and can help treating video game addiction. PMID- 26962432 TI - Case Report: "ADHD Trainer": the mobile application that enhances cognitive skills in ADHD patients. AB - We report the case of a 10 year old patient diagnosed with attention deficit hyperactivity disorder (ADHD) and comorbid video game addiction, who was treated with medication combined with a novel cognitive training method based on video games called TCT method. A great risk of developing video game or internet addiction has been reported in children, especially in children with ADHD. Despite this risk, we hypothesize that the good use of these new technologies might be useful to develop new methods of cognitive training. The cognitive areas in which a greater improvement was observed through the use of video games were visuospatial working memory and fine motor skills. TCT method is a cognitive training method that enhances cognitive skills such as attention, working memory, processing speed, calculation ability, reasoning, and visuomotor coordination. The purpose of reviewing this case is to highlight that regular cognitive computerized training in ADHD patients may improve some of their cognitive symptoms and might be helpful for treating video game addiction. PMID- 26962431 TI - Post-operative rehabilitation and nutrition in osteoarthritis. AB - Osteoarthritis (OA) is a degenerative process involving the progressive loss of articular cartilage, synovial inflammation and structural changes in subchondral bone that lead to loss of synovial joint structural features and functionality of articular cartilage. OA represents one of the most common causes of physical disability in the world. Different OA treatments are usually considered in relation to the stage of the disease. In the early stages, it is possible to recommend physical activity programs that can maintain joint health and keep the patient mobile, as recommended by OA Research Society International (OARSI) and European League Against Rheumatism (EULAR). In the most severe and advanced cases of OA, surgical intervention is necessary. After, in early postoperative stages, it is essential to include a rehabilitation exercise program in order to restore the full function of the involved joint. Physical therapy is crucial for the success of any surgical procedure and can promote recovery of muscle strength, range of motion, coordinated walking, proprioception and mitigate joint pain. Furthermore, after discharge from the hospital, patients should continue the rehabilitation exercise program at home associated to an appropriate diet. In this review, we analyze manuscripts from the most recent literature and provide a balanced and comprehensive overview of the latest developments on the effect of physical exercise on postoperative rehabilitation in OA. The literature search was conducted using PubMed, Scopus, Web of Science and Google Scholar, using the keywords 'osteoarthritis', 'rehabilitation', 'exercise' and 'nutrition'. The available data suggest that physical exercise is an effective, economical and accessible to everyone practice, and it is one of the most important components of postoperative rehabilitation for OA. PMID- 26966513 TI - EEG correlates of social interaction at distance. AB - This study investigated EEG correlates of social interaction at distance between twenty-five pairs of participants who were not connected by any traditional channels of communication. Each session involved the application of 128 stimulations separated by intervals of random duration ranging from 4 to 6 seconds. One of the pair received a one-second stimulation from a light signal produced by an arrangement of red LEDs, and a simultaneous 500 Hz sinusoidal audio signal of the same length. The other member of the pair sat in an isolated sound-proof room, such that any sensory interaction between the pair was impossible. An analysis of the Event-Related Potentials associated with sensory stimulation using traditional averaging methods showed a distinct peak at approximately 300 ms, but only in the EEG activity of subjects who were directly stimulated. However, when a new algorithm was applied to the EEG activity based on the correlation between signals from all active electrodes, a weak but robust response was also detected in the EEG activity of the passive member of the pair, particularly within 9 - 10 Hz in the Alpha range. Using the Bootstrap method and the Monte Carlo emulation, this signal was found to be statistically significant. PMID- 26966513 TI - EEG correlates of social interaction at distance. AB - This study investigated EEG correlates of social interaction at distance between twenty-five pairs of participants who were not connected by any traditional channels of communication. Each session involved the application of 128 stimulations separated by intervals of random duration ranging from 4 to 6 seconds. One of the pair received a one-second stimulation from a light signal produced by an arrangement of red LEDs, and a simultaneous 500 Hz sinusoidal audio signal of the same length. The other member of the pair sat in an isolated sound-proof room, such that any sensory interaction between the pair was impossible. An analysis of the Event-Related Potentials associated with sensory stimulation using traditional averaging methods showed a distinct peak at approximately 300 ms, but only in the EEG activity of subjects who were directly stimulated. However, when a new algorithm was applied to the EEG activity based on the correlation between signals from all active electrodes, a weak but robust response was also detected in the EEG activity of the passive member of the pair, particularly within 9 - 10 Hz in the Alpha range. Using the Bootstrap method and the Monte Carlo emulation, this signal was found to be statistically significant. PMID- 26949516 TI - Social Network: a Cytoscape app for visualizing co-authorship networks. AB - Networks that represent connections between individuals can be valuable analytic tools. The Social Network Cytoscape app is capable of creating a visual summary of connected individuals automatically. It does this by representing relationships as networks where each node denotes an individual and an edge linking two individuals represents a connection. The app focuses on creating visual summaries of individuals connected by co-authorship links in academia, created from bibliographic databases like PubMed, Scopus and InCites. The resulting co-authorship networks can be visualized and analyzed to better understand collaborative research networks or to communicate the extent of collaboration and publication productivity among a group of researchers, like in a grant application or departmental review report. It can also be useful as a research tool to identify important research topics, researchers and papers in a subject area. PMID- 26949516 TI - Social Network: a Cytoscape app for visualizing co-authorship networks. AB - Networks that represent connections between individuals can be valuable analytic tools. The Social Network Cytoscape app is capable of creating a visual summary of connected individuals automatically. It does this by representing relationships as networks where each node denotes an individual and an edge linking two individuals represents a connection. The app focuses on creating visual summaries of individuals connected by co-authorship links in academia, created from bibliographic databases like PubMed, Scopus and InCites. The resulting co-authorship networks can be visualized and analyzed to better understand collaborative research networks or to communicate the extent of collaboration and publication productivity among a group of researchers, like in a grant application or departmental review report. It can also be useful as a research tool to identify important research topics, researchers and papers in a subject area. PMID- 26973784 TI - Effect of the synthesis of rice non-symbiotic hemoglobins 1 and 2 in the recombinant Escherichia coli TB1 growth. AB - Non-symbiotic hemoglobins (nsHbs) are widely distributed in land plants, including rice. These proteins are classified into type 1 (nsHbs-1) and type 2. The O 2-affinity of nsHbs-1 is very high mostly because of an extremely low O 2 dissociation rate constant resulting in that nsHbs-1 apparently do not release O 2 after oxygenation. Thus, it is possible that the in vivo function of nsHbs-1 is other than O 2-transport. Based on the properties of multiple Hbs it was proposed that nsHbs-1 could play diverse roles in rice organs, however the in vivo activity of rice nsHbs-1 has been poorly analyzed. An in vivo analysis for rice nsHbs-1 is essential to elucidate the biological function(s) of these proteins. Rice Hb1 and Hb2 are nsHbs-1 that have been generated in recombinant Es cherichia coli TB1. The rice Hb1 and Hb2 amino acid sequence, tertiary structure and rate and equilibrium constants for the reaction of O 2 are highly similar. Thus, it is possible that rice Hb1 and Hb2 function similarly in vivo. As an initial approach to test this hypothesis we analyzed the effect of the synthesis of rice Hb1 and Hb2 in the recombinant E. coli TB1 growth. Effect of the synthesis of the O 2 carrying soybean leghemoglobin a, cowpea leghemoglobin II and Vitreoscilla Hb in the recombinant E. coli TB1 growth was also analyzed as an O 2-carrier control. Our results showed that synthesis of rice Hb1, rice Hb2, soybean Lb a, cowpea LbII and Vitreoscilla Hb inhibits the recombinant E. coli TB1 growth and that growth inhibition was stronger when recombinant E. coli TB1 synthesized rice Hb2 than when synthesized rice Hb1. These results suggested that rice Hb1 and Hb2 could function differently in vivo. PMID- 26973785 TI - FreeSASA: An open source C library for solvent accessible surface area calculations. AB - Calculating solvent accessible surface areas (SASA) is a run-of-the-mill calculation in structural biology. Although there are many programs available for this calculation, there are no free-standing, open-source tools designed for easy tool-chain integration. FreeSASA is an open source C library for SASA calculations that provides both command-line and Python interfaces in addition to its C API. The library implements both Lee and Richards' and Shrake and Rupley's approximations, and is highly configurable to allow the user to control molecular parameters, accuracy and output granularity. It only depends on standard C libraries and should therefore be easy to compile and install on any platform. The library is well-documented, stable and efficient. The command-line interface can easily replace closed source legacy programs, with comparable or better accuracy and speed, and with some added functionality. PMID- 26973788 TI - Erratum to: Evaluation of an online training program in eating disorders for health professionals in Australia. AB - [This corrects the article DOI: 10.1186/s40337-015-0078-7.]. PMID- 26973786 TI - Tumour Cell Heterogeneity. AB - The population of cells that make up a cancer are manifestly heterogeneous at the genetic, epigenetic, and phenotypic levels. In this mini-review, we summarise the extent of intra-tumour heterogeneity (ITH) across human malignancies, review the mechanisms that are responsible for generating and maintaining ITH, and discuss the ramifications and opportunities that ITH presents for cancer prognostication and treatment. PMID- 26973789 TI - Improving the post-meal experience of hospitalised patients with eating disorders using visuospatial, verbal and somatic activities. AB - BACKGROUND: This study compares the effects of different cognitive tasks on post meal negative affect, positive affect, intrusive thoughts and intrusive images of hospitalised patients with eating disorders. METHODS: Twenty-five participants were recruited from an eating disorder service. Using a within-subjects design, participants performed one of the following tasks for 15 min: the game 'Tetris' (visuospatial), a general knowledge 'Quiz' (verbal), 'Braille' translation (somatic) and 'Sitting Quietly' (control). In total, participants completed each task on three occasions. RESULTS: The visuospatial, verbal and somatic tasks had beneficial effects on all positive and negative indicators, when compared with 'Sitting Quietly'. Visuospatial and somatic tasks were more effective at reducing intrusive imagery than the verbal task. CONCLUSIONS: The results suggest that certain engaging activities can help hospitalised patients with eating disorders manage the difficult post-meal period. PMID- 26973787 TI - Genetics and Therapeutics in Pediatric Ulcerative Colitis: the Past, Present and Future. AB - Ulcerative colitis (UC) is a relapsing and remitting disease with significant phenotypic and genotypic variability. Though more common in adults, UC is being increasingly diagnosed in childhood. The subsequent lifelong course of disease results in challenges for the patient and physician. Currently, there is no medical cure for UC. Even though surgical removal of the colon can be curative, complications including infertility in females make colectomy an option often considered only when the disease presents with life-threatening complications or when medical management fails. One of the greatest challenges the clinician faces in the care of patients with UC is the inability to predict at diagnosis which patient is going to respond to a specific therapy or will eventually require surgery. This therapeutic conundrum frames the discussion to follow, specifically the concept of individualized or personalized treatment strategies based on genetic risk factors. As we move to therapeutics, we will elucidate traditional approaches and discuss known and novel agents. As we look to the future, we can expect increasing integrated approaches using several scientific disciplines to inform how genetic interactions shape and mold the pathogenesis and therapeutics of UC. PMID- 26973790 TI - Focal therapy using magnetic resonance image-guided focused ultrasound in patients with localized prostate cancer. AB - BACKGROUND: The purpose of this study is to evaluate and report the feasibility, safety, and initial outcomes of patients with limited localized prostate cancer treated using a trans-rectal magnetic resonance image-guided focused ultrasound (MRGFUS) device. Attempts to focally treat only the index lesion for prostate cancer have been explored to reduce side effects while maintaining oncologic control. MRGFUS allows for precise targeting of thermal ablative therapy with real-time thermometry. METHODS: Three patients underwent multiparametric 3T MRI and TRUS-guided 16-sector mapping biopsies of the prostate. The patients were eligible if they had Gleason 6 or 7 (3 + 4) disease, no MRI-visible tumor >=15 mm, no extracapsular extension, and no more than two discrete cancerous lesions <=10 mm in length. Acoustic power was adjusted to achieve temperatures of 65 to 85 degrees C. RESULTS: Age ranged from 60 to 64 years. The number of biopsy positive sectors treated ranged from 2 to 4. Post therapy, 16-sector biopsies at 6 months were negative in two patients with one patient still with Gleason 6 cancer (10 %, 2 mm) in one core. 16-sector biopsy in the first patient remains negative at 24 months. PSA continues to remain stable in all patients. IPSS in all patients either remained stable or decreased then stabilized. Erectile function according to the International Index of Erectile Function (IIEF) was excellent for all patients and demonstrated no decline up to the time of last follow-up at 12-24 months. CONCLUSIONS: MRGFUS is a feasible alternative for focal therapy in a select subset of patients with prostate cancer. The treatment is well tolerated with no evidence of decline in functional outcomes. Initial post-therapy biopsy results are promising. Long-term treatment efficacy requires further study. PMID- 26973791 TI - Randomized double-blind safety comparison of intravenous iron dextran versus iron sucrose in an adult non-hemodialysis outpatient population: A feasibility study. AB - BACKGROUND: Intravenous iron therapy is a treatment option for iron deficient patients who are intolerant to oral iron or where oral iron is ineffective, but with possible adverse effects. Currently, prospective studies comparing different intravenous iron formulations are needed to determine safety and efficacy of these agents. METHODS: We conducted a prospective, double-blind, randomized controlled trial (RCT) to assess the feasibility of a trial comparing the safety of high molecular weight intravenous iron dextran, Infufer(r), with intravenous iron sucrose, Venofer(r), in non-hemodialysis adult outpatients. Primary outcome was the occurrence of immediate severe drug reactions. RESULTS: We enrolled 143 patients in a one-year period. Overall, 45/143 (31.5 %) patients (20 iron dextran, 25 iron sucrose) developed 48 infusion reactions (14 immediate, 28 delayed, and 3 both). The risk of an immediate reaction was similar in both groups, 9/73 (12.3 %) iron dextran versus 8/70 (11.4 %) iron sucrose, RR = 0.93 (95 % CI; 0.38 to 2.27). The risk of a delayed reaction was significantly higher in the iron sucrose group 22/70 (31.4 %) versus the iron dextran group 9/73 (12.3 %), RR = 2.55 (95 % CI; 1.26 to 5.15; p = 0.0078). CONCLUSION: In this limited feasibility study, no major differences in immediate reactions were seen, but a significantly higher number of delayed reactions were seen in the iron sucrose group. Further, under our assumptions and design a full RCT to evaluate the safety of different intravenous iron preparations is not feasible. Future studies should consider modifying the clinical outcomes, utilize multiple centers, and consider other emerging parenteral iron formulations. (ClinicalTrials.gov NCT005936197 January 3, 2008). PMID- 26973792 TI - Age profiles of sport participants. AB - BACKGROUND: Participation in sport has many health benefits, and is popular amongst children. However participation decreases with age. While the membership records of peak sports organisations have improved markedly in recent years, there has been little research into sport participation trends across the lifespan. This study investigates age profiles of participation in sport and compares these trends between genders and residential locations. METHODS: De identified 2011 participant registration data for seven popular Australian sports (Australian Football, Basketball, Cricket, Hockey, Lawn Bowls, Netball and Tennis) were obtained and analysed according to age, gender and geographical location (metropolitan v non-metropolitan) within the state of Victoria, Australia. All data were integrated and sports were analysed collectively to produce broadly based participation profiles while maintaining confidentiality of membership data for individual sports. RESULTS: The total number of registered participants included in the data set for 2011 was 520,102. Most participants (64.1 %) were aged less than 20 years. Nearly one third (27.6 %) of all participants were aged 10-14 years, followed by the 5-9 year age group (19.9 %). Participation declined rapidly during adolescence. A higher proportion of males than female participants were young children (4-7 years) or young adults 18-29 years; this pattern was reversed among 8-17 year-olds. A higher proportion of metropolitan participants were engaged between the ages of 4-13 and 19-29, whereas a higher proportion of non-metropolitan participants played during adolescence (14-18 years) and throughout mature adulthood (30+ years). CONCLUSIONS: Increasing participation in sport is an objective for both government and sporting organisations. In order to have both mass population based participation, from a health policy and elite performance perspective, we need to further explore the findings arising from the analysis of this extensive data set. Such an examination will lead to better understand of the reasons for attrition during adolescence to inform program and policy developments to retain people participating in sport, for a healthy and sport performing nation. PMID- 26973793 TI - Prevalence of pectinate ligament dysplasia and associations with age, sex and intraocular pressure in the Basset hound, Flatcoated retriever and Dandie Dinmont terrier. AB - BACKGROUND: The aims of this study were to: determine the prevalence of pectinate ligament dysplasia (PLD) in populations of Basset hounds (BH), Flatcoated retrievers (FCR) and Dandie Dinmont terriers (DDT) resident in the UK; investigate possible associations between the degree of PLD and age, sex and intraocular pressure (IOP) and; investigate possible associations between IOP and age and sex. Gonioscopy was performed in both eyes of 198 BH, 170 FCR and 95 DDT and the percentage of iridocorneal angle affected by PLD was estimated and classified as unaffected (0 %), mildly affected (<20 %), moderately affected (20 90 %) or severely affected (>90 %). Rebound tonometry was performed bilaterally in the majority of enrolled dogs. RESULTS: Seventy-six of 198 (38.4 %) BH, 36/170 (21.2 %) FCR and 21/95 (22.1 %) DDT were moderately or severely affected by PLD. The prevalence of PLD was significantly higher in BH than both FCR and DDT. In all breeds there was a significant positive correlation between PLD and age. In the BH only there was a significant association between PLD and sex. In the DDT only there was a weak negative correlation between PLD and IOP and a moderately strong negative correlation between IOP and age. CONCLUSIONS: PLD is prevalent and significantly associated with age in all three breeds we investigated. The linear relationship between PLD and age can be explained by the progression of PLD over time which would contribute to the high prevalence of PLD despite widespread screening. PMID- 26973794 TI - The utility of biomarker risk prediction score in patients with chronic heart failure. AB - BACKGROUND: Chronic heart failure (CHF) has been remained a leading cause of cardiovascular morbidity and mortaluty. The risk stratification of CHF individuals based on clinical criteria and biomarkers' models may improve medical care and probably increase efficacy of treatment strategy. However, various predictive models approved for CHF patients appear to be distinguished in their prognostications. The study aim was to evaluate whether biomarker risk prediction score is powerful tool for risk assessment of three-year fatal and non-fatal cardiovascular events in CHF patients. METHODS: It was studied prospectively the incidence of fatal and non-fatal cardiovascular events in a cohort of 388 patients with ischemic-induced CHF within 3 years. Circulating biomarkers were collected at baseline of the study. RESULTS: Independent predictors of clinical outcomes in patients with CHF were NT-pro-BNP, galectin-3, hs-CRP, osteoprotegerin, CD31(+)/annexin V(+) endothelail-derived microparticles (EMPs) and CD31(+)/annexin V(+) EMPs to CD14(+)CD309(+) monuclear progenitor cells (MPCs) ratio. Index of cardiovascular risk was calculated by mathematical summation of all ranks of independent predictors, which occurred in the patients included in the study. Kaplan-Meier analysis showed that patients with CHF and the magnitude of the risk of less than 4 units have an advantage in survival when compared with patients for whom obtained higher values of cardiovascular risk score ranks. CONCLUSION: Biomarker risk score for cumulative cardiovascular events, constructed by measurement of circulating NT-pro-BNP, galectin-3, hs-CRP, osteoprotegerin, CD31+/annexin V+ EMPs and CD31(+)/annexin V(+) EMPs to CD14(+)CD309(+) MPCs ratio, allowing reliably predict the probability survival of patients with CHF. PMID- 26973795 TI - Differentially Private Histogram Publication For Dynamic Datasets: An Adaptive Sampling Approach. AB - Differential privacy has recently become a de facto standard for private statistical data release. Many algorithms have been proposed to generate differentially private histograms or synthetic data. However, most of them focus on "one-time" release of a static dataset and do not adequately address the increasing need of releasing series of dynamic datasets in real time. A straightforward application of existing histogram methods on each snapshot of such dynamic datasets will incur high accumulated error due to the composibility of differential privacy and correlations or overlapping users between the snapshots. In this paper, we address the problem of releasing series of dynamic datasets in real time with differential privacy, using a novel adaptive distance based sampling approach. Our first method, DSFT, uses a fixed distance threshold and releases a differentially private histogram only when the current snapshot is sufficiently different from the previous one, i.e., with a distance greater than a predefined threshold. Our second method, DSAT, further improves DSFT and uses a dynamic threshold adaptively adjusted by a feedback control mechanism to capture the data dynamics. Extensive experiments on real and synthetic datasets demonstrate that our approach achieves better utility than baseline methods and existing state-of-the-art methods. PMID- 26973796 TI - Reduced Resting Metabolic Rate in Adults with Hemiparetic Chronic Stroke. AB - OBJECTIVE: Resting metabolic rate (RMR) is the component of energy expenditure that explains the largest proportion of total daily energy requirements. Since RMR is determined largely by fat-free mass and a low RMR predicts weight gain in healthy adults, identifying the role of muscle atrophy following stroke on RMR may help identify ways to mitigate the development of obesity post-stroke. METHODS: Thirty-nine stroke survivors with chronic hemiparesis (mean +/- SEM: age: 61 +/- 1 years, latency from stroke: 107 +/- 40 months, BMI: 31 +/- 3 kg/m2) underwent DXA scans for measurement of body composition, including total, paretic, and non-paretic leg lean mass and fasted, 30-min indirect calorimetry for measurement of RMR. RESULT: Predicted RMR was calculated by the Mifflin-St Jeor equation, which considers weight, height, and age for both men and women. RMR was 14% lower than predicted (1438 +/- 45 vs. 1669 +/- 38 kcals/24 hrs; P<0.01). Total (r=0.73, P<0.01), paretic (r=0.72, P<0.01) and non-paretic (r=0.67, P<0.01) leg lean mass predicted RMR. CONCLUSION: These data indicate that muscle atrophy post stroke may lead to a reduced RMR. This substantiates the need to attenuate the loss of lean mass after a stroke to prevent declines in RMR and possible weight gain common post-stroke. PMID- 26973798 TI - It's Not Just About the Money: Gender and Youth Migration from Rural China. AB - Statistics suggest that young men and women in China migrate at almost equal numbers, but we know less about gender differences in the decision to migrate. We examine the factors associated with the decision to migrate and the rationales given by young migrants. Our results are consistent with previous figures and show no overall gender differences in susceptibility to migration. However, we find that sibship structure operates differently on the decisions of boys and girls. Young men were more likely to report that they had moved for purposes of starting a business or personal development than young women, while young women were more likely to report that they had moved to support the tuition of a family member. We argue that the simple gender parity with respect to the number of migrants masks important differences in the circumstances and personal motivations for migration for men and women. PMID- 26973799 TI - Test-Retest Reliability of the DePaul Symptom Questionnaire. AB - BACKGROUND: The DePaul Symptom Questionnaire (DSQ) was developed to provide a structured approach for collecting standardized symptomatology and health history information to allow researchers and clinicians to determine whether a patient meets the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), myalgic encephalomyelitis (ME), and/or chronic fatigue syndrome (CFS). PURPOSE: The purpose of this study was to examine the test-retest reliability of the DSQ. METHODS: Test-retest reliability of the measure was examined with a sample of 26 adults self-identifying as having either ME/CFS, ME and/or CFS and 25 adults who did not self-identify as having these illnesses and were otherwise healthy controls. RESULTS: Overall, the majority of items on the DSQ exhibited good to excellent test-retest reliability, with Pearson's or kappa correlation coefficients that were 0.70 or higher. CONCLUSIONS: Thus, the present study suggests that the DSQ is a reliable diagnostic measure that can provide a standardized way of examining illness constructs and symptomatology among patients who identify as having ME/CFS, ME and/or CFS. PMID- 26973797 TI - Beyond HbA1c: Environmental Risk Factors for Diabetic Retinopathy. AB - Diabetic retinopathy affects 4.2 million people in the United States and is the leading cause of blindness in working-aged people. As the prevalence of diabetes continues to rise, cost-effective interventions to decrease blindness from diabetic retinopathy will be paramount. While HbA1c and duration of disease are known risk factors, they account for only 11% of the risk of developing microvascular complications from the disease. The assessment of environmental risk factors for diabetic eye disease allows for the determination of modifiable population-level challenges that may be addressed to facilitate the end of blindness from diabetes. PMID- 26973800 TI - Computerized Intervention to Increase Motivation for Diabetes Self-Management in Adolescents with Type 1 Diabetes. PMID- 26973802 TI - Intensity-Modulated Radiation Therapy Versus 3D Conformal Radiotherapy for Postoperative Gynecologic Cancer: Are They Covering the Same Planning Target Volume? AB - BACKGROUND AND PURPOSE: This study compares dosimetric parameters of planning target volume (PTV) coverage and organs at risk (OAR) sparing when postoperative radiotherapy for gynecologic cancers is delivered using volumetric modulated arc therapy (VMAT) versus a four-field (4FLD) box technique. MATERIAL AND METHODS: From July to December 2012, women requiring postoperative radiation for gynecologic cancers were treated with a standardized VMAT protocol. Two sets of optimized 4FLD plans were retrospectively generated: one based on standard anatomical borders (4FLD) and one based on the clinical target volume (CTV) created for VMAT with a 2 cm expansion guiding field border placement (4FLD+2). Ninety-five percent isodose curves were generated to evaluate PTV coverage. RESULTS: VMAT significantly improved dose conformity compared with 4FLD and 4FLD+2 plans (p < 0.001) and provided additional coverage of the PTV posteriorly and superiorly, corresponding to coverage of the presacral and proximal iliac vessels. There was a significant reduction in dose to all OARs with VMAT, including a 58% reduction in the volume of the small bowel receiving more than 45 Gy (p=0.005). CONCLUSIONS: Despite treating a larger volume, radiotherapy using a 4FLD technique is less homogenous and provides inferior coverage of the PTV compared with VMAT. With meticulous treatment planning and delivery, VMAT effectively encompasses the PTV and minimizes dose to OARs. PMID- 26973803 TI - Necrotizing Fasciitis: A Life-threatening Complication of Intraoperative Electromyography. AB - Intraoperative neurophysiological monitoring is a commonly used practice during spine surgery. Complications of electromyography (EMG) needle electrode placement are very uncommon. We present a patient who was infected with necrotizing fasciitis in her left thigh due to an EMG needle electrode during a two-stage complex spine procedure. This case demonstrates that providers should continue to meticulously adhere to protocol when inserting and removing EMG needles, but also be cognizant during postoperative observation of the possibility of infection caused by EMG needles. PMID- 26973801 TI - Enzyme replacement therapy for treating mucopolysaccharidosis type IVA (Morquio A syndrome): effect and limitations. AB - INTRODUCTION: Following a Phase III, randomized, double-blind, placebo (PBO) controlled, multinational study in subjects with mucopolysaccharidosis IVA (MPS IVA), enzyme replacement therapy (ERT) of elosulfase alfa has been approved in several countries. The study was designed to evaluate safety and efficacy of elosulfase alfa in patients with MPS IVA aged 5 years and older. AREAS COVERED: Outcomes of clinical trials for MPS IVA have been described. Subjects received either 2.0 mg/kg/week, 2.0 mg/kg/every other week, or PBO, for 24 weeks. The primary endpoint was the change from baseline 6-min walk test (6MWT) distance compared to PBO. The 6MWT results improved in patients receiving 2 mg/kg weekly compared to PBO. The every other week regimen resulted in walk distances comparable to PBO. There was no change from baseline in the 3 Min Stair Climb Test in both treatment groups. Following completion of the initial study, patients, who continued to receive elosulfase alfa 2 mg/kg weekly (QW) for another 48 weeks (for a total of up to 72-week exposure), did not show additional improvement on 6MWT. EXPERT OPINION: We suggest that ERT is a therapeutic option for MPS IVA, providing a modest effect and the majority of the effects are seen in the soft tissues. PMID- 26973804 TI - Training Medical Novices in Spinal Microsurgery: Does the Modality Matter? A Pilot Study Comparing Traditional Microscopic Surgery and a Novel Robotic Optoelectronic Visualization Tool. AB - The operative microscope has been a staple instrument in the neurosurgical operating room over the last 50 years. With advances in optoelectronics, options such as robotically controlled high magnification have become available. Such robotically controlled optoelectronic systems may offer new opportunities in surgical technique and teaching. However, traditionally trained surgeons may find it hard to accept newer technologies due to an inherent bias emerging from their previous background. We, therefore, studied how a medically naive population in a pilot study would meet set microsurgical goals in a cadaver experiment using either a conventional operative microscope or BrightMatterTM Servo system, a robotically controlled optoelectronic system (Synaptive Medical, Toronto, Ontario, Canada). We found that the relative ease in teaching medical novices with a robotically controlled optoelectronic system was more valuable when compared to using a modern-day surgical microscope. PMID- 26973805 TI - Radiologic Considerations in Heterotaxy: The Need for Detailed Anatomic Evaluation. AB - So-called "heterotaxy" is a laterality defect characterized by isomerism of the thoracic organs and random arrangement of the abdominal organs. These findings go beyond anatomic curiosity and have functional implications. It is, thus, of the utmost importance to be able to properly identify these findings. Radiologic studies can be invaluable in determining anomalies in the central nervous, pulmonary, cardiovascular, gastrointestinal, genitourinary, and immunologic systems in patients with isomerism. Here, we review findings associated with isomerism and their importance in the setting of isomerism with the aim of ensuring that radiologists effectively describe findings in these patients and that cardiologists understand the wide variety of congenital malformations that may be present. PMID- 26973806 TI - Malignant Transformation in Glioma Steered by an Angiogenic Switch: Defining a Role for Bone Marrow-Derived Cells. AB - Low-grade gliomas, such as pilocytic astrocytoma and subependymoma, are often characterized as benign tumors due to their relative circumscription radiologically and typically non-aggressive biologic behavior. In contrast, low grades that are by their nature diffusely infiltrative, such as diffuse astrocytomas and oligodendrogliomas, have the potential to transform into malignant high-grade counterparts and, given sufficient time, invariably do so. These high-grade gliomas carry very poor prognoses and are largely incurable, warranting a closer look at what causes this adverse transition. A key characteristic that distinguishes low- and high-grade gliomas is neovascularization: it is absent in low-grade gliomas, but prolific in high-grade gliomas, providing the tumor with ample blood supply for exponential growth. It has been well described in the literature that bone marrow-derived cells (BMDCs) may contribute to the angiogenic switch that is responsible for malignant transformation of low-grade gliomas. In this review, we will summarize the current literature on BMDCs and their known contribution to angiogenesis associated tumor growth in gliomas. PMID- 26973808 TI - Metallurgical investigation of wire breakage of tyre bead grade. AB - Tyre bead grade wire is used for tyre making application. The wire is used as reinforcement inside the polymer of tyre. The wire is available in different size/section such as 1.6-0.80 mm thin Cu coated wire. During tyre making operation at tyre manufacturer company, wire failed frequently. In this present study, different broken/defective wire samples were collected from wire mill for detailed investigation of the defect. The natures of the defects were localized and similar in nature. The fracture surface was of finger nail type. Crow feet like defects including button like surface abnormalities were also observed on the broken wire samples. The defect was studied at different directions under microscope. Different advanced metallographic techniques have been used for detail investigation. The analysis revealed that, white layer of surface martensite was formed and it caused the final breakage of wire. In this present study we have also discussed about the possible reason for the formation of such kind of surface martensite (hard-phase). PMID- 26973807 TI - The Use of Flow Diversion for the Treatment of Intracranial Aneurysms: Expansion of Indications. AB - Flow diversion is a novel concept for treating anatomically challenging intracranial aneurysms and has gained increasing acceptance. Flow diverter stents, such as the Pipeline Embolization Device (PED) (ev3-Covidien, Irvine, CA, USA), are approved for treating unruptured large and giant aneurysms from the internal carotid artery between the superior hypophyseal and cavernous segments. However, technological advances and recent clinical results suggest that flow diversion can be safely and effectively used in treating ruptured aneurysms, posterior circulation aneurysms, and distal anterior circulation aneurysms. In this brief review, we aim to investigate the recent evidence on the utilization of PEDs in these controversial vascular territories and to discuss whether the indications for flow diversion can be expanded. PMID- 26973809 TI - A nanoporous gold membrane for sensing applications. AB - Design and fabrication of three-dimensionally structured, gold membranes containing hexagonally close-packed microcavities with nanopores in the base, are described. Our aim is to create a nanoporous structure with localized enhancement of the fluorescence or Raman scattering at, and in the nanopore when excited with light of approximately 600 nm, with a view to provide sensitive detection of biomolecules. A range of geometries of the nanopore integrated into hexagonally close-packed assemblies of gold micro-cavities was first evaluated theoretically. The optimal size and shape of the nanopore in a single microcavity were then considered to provide the highest localized plasmon enhancement (of fluorescence or Raman scattering) at the very center of the nanopore for a bioanalyte traversing through. The optimized design was established to be a 1200 nm diameter cavity of 600 nm depth with a 50 nm square nanopore with rounded corners in the base. A gold 3D-structured membrane containing these sized microcavities with the integrated nanopore was successfully fabricated and 'proof of concept' Raman scattering experiments are described. PMID- 26973810 TI - Insight and subjective measures of quality of life in chronic schizophrenia. AB - Lack of insight is a well-established phenomenon in schizophrenia, and has been associated with reduced rater-assessed functional performance but increased self reported well-being in previous studies. The objective of this study was to examine factors that might influence insight (as assessed by the Insight and Treatment Attitudes Questionnaire [ITAQ] or PANSS item G12) and subjective quality-of-life (as assessed by Lehman QoL Interview [LQOLI]), using the large National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) dataset. Uncooperativeness was assessed by PANSS item G8 ("Uncooperativeness"). In the analysis, we found significant moderating effects for insight on the relationships of subjective life satisfaction assessment to symptom severity (as assessed by CGI-S score), objective everyday functioning (as assessed by rater-administered Heinrichs-Carpenter Quality of Life scale), clinically rated uncooperativeness (as assessed by PANSS G8), and discontinuation of treatment for all causes (all P > 0.05 for statistical interaction between insight and subject QoL). Patients with chronic schizophrenia who reported being "pleased" or "delighted" on LQOLI were found to have significantly lower neurocognitive reasoning performance and poorer insight (ITAQ total score). Our findings underscore the importance of reducing cognitive and insight impairments for both treatment compliance and improved functional outcomes. PMID- 26973811 TI - The Value of the History and Physical for Patients with Newly Diagnosed Brain Metastases Considering Radiosurgery. AB - BACKGROUND: For patients with brain metastases, systemic disease burden has historically been accepted as a major determinant of overall survival (OS). However, less research has focused on specific history and physical findings made by clinicians and how such findings pertain to patient outcomes at a given time point. The aim of this study is to determine how the initial clinical assessment of patients with brain metastases, as part of the history and physical at the time of consultation, correlates to patient prognosis. METHODS: We evaluated a prospective, multi-institutional database of 1523 brain metastases in 507 patients who were treated with radiosurgery (Gamma Knife or CyberKnife) from 2001 to 2014. Relevant history of present illness (HPI) and past medical history (PMH) variables included comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status, and seizure history. Physical exam findings included a sensory exam, motor exam, and cognitive function. Univariate and multivariate Cox regression analyses were used to identify predictors of OS. RESULTS: Two hundred ninety-four patients were included in the final analysis with a median OS of 10.8 months (95% CI, 7.8-13.7 months). On univariate analysis, significant HPI predictors of OS included age, primary diagnosis, performance status, extracranial metastases, systemic disease status, and history of surgery. Significant predictors of OS from the PMH included cardiac, vascular, and infectious comorbidities. On a physical exam, findings consistent with cognitive deficits were predictive of worse OS. However, motor deficits or changes in vision were not predictive of worse OS. In the multivariate Cox regression analysis, predictors of worse OS were primary diagnosis (p = 0.002), ECOG performance status (OR 1.73, p < 0.001), and presence of extracranial metastases (OR 1.22, p = 0.009). CONCLUSION: Neurological deficits and systemic comorbidities noted at presentation are not associated with worse overall prognosis for patients with brain metastases undergoing radiosurgery. When encountering new patients with brain metastases, the most informative patient related characteristics that determine prognosis remain performance status, primary diagnosis, and extent of extracranial disease. PMID- 26973814 TI - Automated Extraction of Dose/Volume Statistics for Radiotherapy-Treatment-Plan Evaluation in Clinical-Trial Quality Assurance. AB - Radiotherapy clinical-trial quality assurance is a crucial yet challenging process. This note presents a tool that automatically extracts dose/volume statistics for determining dosimetry compliance review with improved efficiency and accuracy. A major objective of this study is to develop an automated solution for clinical-trial radiotherapy dosimetry review. PMID- 26973813 TI - Current Management Strategies in Breast Cancer by Targeting Key Altered Molecular Players. AB - Breast cancer is the second largest disease affecting women worldwide. It remains the most frequently reported and leading cause of death among women in both developed and developing countries. Tamoxifen and raloxifene are commonly used selective estrogen receptor modulators for treatment of breast cancer in women with high risk, although resistance occurs by tamoxifen after 5 years of therapy and both drugs cause uterine cancer and thromboembolic events. Aromatase inhibitors (AIs) are one of the optional modes used for breast cancer treatment. The combination of AIs along with tamoxifen can also be beneficial. Various therapeutic agents from different sources are being studied, which further need to be improved for potential outcome. For this, clinical trials based on large number of patients with optimal dose and lesser side effects have to be more in practice. Despite the clinical trials going on, there is need of better molecular models, which can identify high risk population, new agents with better benefit having less side effects, and improved biomarkers for treating breast cancer. PMID- 26973815 TI - Role of Dose Intensification for Salvage Radiation Therapy after Radical Prostatectomy. AB - For primary radiation therapy (RT) of prostate cancer, dose intensification is established as standard of care. Less is known on the role of dose intensification in the postprostatectomy setting for salvage RT. Thus, we aimed to identify and summarize the existing literature. In retrospective analyses, dose-intensified salvage RT showed a superior biochemical control compared to standard dose salvage radiation with favorable acute and late gastrointestinal and genitourinary toxicity rates, especially when modern radiation techniques such as intensity modulated RT were applied. We identified one randomized phase III trial addressing the potential benefits of dose-intensified salvage RT (SAKK 09/10). Recently, acute gastrointestinal and genitourinary toxicities and early quality of life data of this trial were reported, and no significant difference in acute toxicities between both treatment arms were found; however, a significant worsening of genitourinary quality of life was noted in the dose intensified treatment arm. Whereas dose-intensified salvage RT appears to be feasible and well tolerated, the improved biochemical control rates using dose intensified RT as suggested by retrospective analyses have yet to be validated by prospective trials. PMID- 26973812 TI - Positron Emission Tomography Imaging of Tumor Cell Metabolism and Application to Therapy Response Monitoring. AB - Cancer cells do reprogram their energy metabolism to enable several functions, such as generation of biomass including membrane biosynthesis, and overcoming bioenergetic and redox stress. In this article, we review both established and evolving radioprobes developed in association with positron emission tomography (PET) to detect tumor cell metabolism and effect of treatment. Measurement of enhanced tumor cell glycolysis using 2-deoxy-2-[(18)F]fluoro-D-glucose is well established in the clinic. Analogs of choline, including [(11)C]choline and various fluorinated derivatives are being tested in several cancer types clinically with PET. In addition to these, there is an evolving array of metabolic tracers for measuring intracellular transport of glutamine and other amino acids or for measuring glycogenesis, as well as probes used as surrogates for fatty acid synthesis or precursors for fatty acid oxidation. In addition to providing us with opportunities for examining the complex regulation of reprogramed energy metabolism in living subjects, the PET methods open up opportunities for monitoring pharmacological activity of new therapies that directly or indirectly inhibit tumor cell metabolism. PMID- 26973816 TI - The Pathogen-Occupied Vacuoles of Anaplasma phagocytophilum and Anaplasma marginale Interact with the Endoplasmic Reticulum. AB - The genus Anaplasma consists of tick-transmitted obligate intracellular bacteria that invade white or red blood cells to cause debilitating and potentially fatal infections. A. phagocytophilum, a human and veterinary pathogen, infects neutrophils to cause granulocytic anaplasmosis. A. marginale invades bovine erythrocytes. Evidence suggests that both species may also infect endothelial cells in vivo. In mammalian and arthropod host cells, A. phagocytophilum and A. marginale reside in host cell derived pathogen-occupied vacuoles (POVs). While it was recently demonstrated that the A. phagocytophilum-occupied vacuole (ApV) intercepts membrane traffic from the trans-Golgi network, it is unclear if it or the A. marginale-occupied vacuole (AmV) interacts with other secretory organelles. Here, we demonstrate that the ApV and AmV extensively interact with the host endoplasmic reticulum (ER) in endothelial, myeloid, and/or tick cells. ER lumen markers, calreticulin, and protein disulfide isomerase, and the ER membrane marker, derlin-1, were pronouncedly recruited to the peripheries of both POVs. ApV association with the ER initiated early and continued throughout the infection cycle. Both the ApV and AmV interacted with the rough ER and smooth ER. However, only derlin-1-positive rough ER derived vesicles were delivered into the ApV lumen where they localized with intravacuolar bacteria. Transmission electron microscopy identified multiple ER-POV membrane contact sites on the cytosolic faces of both species' vacuoles that corresponded to areas on the vacuoles' lumenal faces where intravacuolar Anaplasma organisms closely associated. A. phagocytophilum is known to hijack Rab10, a GTPase that regulates ER dynamics and morphology. Yet, ApV-ER interactions were unhindered in cells in which Rab10 had been knocked down, demonstrating that the GTPase is dispensable for the bacterium to parasitize the ER. These data establish the ApV and AmV as pathogen-host interfaces that directly engage the ER in vertebrate and invertebrate host cells and evidence the conservation of ER parasitism between two Anaplasma species. PMID- 26973817 TI - Streptococcus pneumoniae Endopeptidase O (PepO) Elicits a Strong Innate Immune Response in Mice via TLR2 and TLR4 Signaling Pathways. AB - Interaction between virulence factors of Streptococcus pneumoniae and innate immune receptors elicits host responses through specific signaling pathways during infection. Insights into the signaling events may provide a better knowledge of the starting events for host-pathogen interaction. Here we demonstrated a significant induction of innate immune response elicited by recombinant S. pneumoniae endopeptidase O (rPepO), a newer pneumococcal virulence protein, both in vivo and in vitro. Intratracheal instillation of rPepO protein resulted in significant increase of cytokines production and neutrophils infiltration in mouse lungs. TLR2 or TLR4 deficient mice subjected to rPepO treatment showed decreased cytokines production, reduced neutrophils infiltration and intensified tissue injury as compared with WT mice. Upon stimulation, cytokines TNF-alpha, IL-6, CXCL1, and CXCL10 were produced by peritoneal exudate macrophages (PEMs) in a TLR2 and TLR4 dependent manner. rPepO-induced cytokines production was markedly decreased in TLR2 or TLR4 deficient PEMs. Further study revealed that cytokines induction relied on the rapid phosphorylation of p38, Akt and p65, not the activation of ERK or JNK. While in TLR2 or TLR4 deficient PEMs the activation of p65 was undetectable. Taken together, these results indicate for the first time that the newer pneumococcal virulence protein PepO activates host innate immune response partially through TLR2 and TLR4 signaling pathways. PMID- 26973821 TI - Conceptual issues for screening in the genomic era - time for an update? AB - BACKGROUND: Screening tests are ubiquitous in modern medicine; however a consensus view on the criteria that distinguish screening from clinical testing remains strangely elusive. although numerous definitions of screening have been suggested, there is considerable variation amongst them, leading to confusion and disagreement amongst clinicians and public health professionals alike. In light of developments in genomics, the question of what screening entails is becoming increasingly pressing. METHODS: We evaluated the concepts underlying definitions of screening versus clinical testing and investigated their ethical implications. RESULTS: We suggest that just two key concepts underlie screening: first, screening tests are performed in asymptomatic individuals and, second, they are generally offered to individuals who otherwise believe themselves to be healthy (with respect to the disease being screened for). all the other characteristics commonly invoked to describe screening - including the systematic use of rapid tests for risk stratification within a particular population - can be better categorised as either practical requirements or by-products of screening programmes rather than screening tests. CONCLUSIONS: We emphasise the need to differentiate between opportunistic screening and clinical testing because of the differing prior probability of disease and thus the differing ethical burden of responsibility placed upon the physician in each scenario. Physicians need to appreciate the shifting moral burden placed upon them in relation to reactive clinical testing versus proactive screening, and the different legal obligations that may ensue. PMID- 26973820 TI - Gram-negative and -positive bacteria differentiation in blood culture samples by headspace volatile compound analysis. AB - BACKGROUND: Identification of microorganisms in positive blood cultures still relies on standard techniques such as Gram staining followed by culturing with definite microorganism identification. Alternatively, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or the analysis of headspace volatile compound (VC) composition produced by cultures can help to differentiate between microorganisms under experimental conditions. This study assessed the efficacy of volatile compound based microorganism differentiation into Gram-negatives and -positives in unselected positive blood culture samples from patients. METHODS: Headspace gas samples of positive blood culture samples were transferred to sterilized, sealed, and evacuated 20 ml glass vials and stored at -30 degrees C until batch analysis. Headspace gas VC content analysis was carried out via an auto sampler connected to an ion-molecule reaction mass spectrometer (IMR-MS). Measurements covered a mass range from 16 to 135 u including CO2, H2, N2, and O2. Prediction rules for microorganism identification based on VC composition were derived using a training data set and evaluated using a validation data set within a random split validation procedure. RESULTS: One-hundred-fifty-two aerobic samples growing 27 Gram-negatives, 106 Gram positives, and 19 fungi and 130 anaerobic samples growing 37 Gram-negatives, 91 Gram-positives, and two fungi were analysed. In anaerobic samples, ten discriminators were identified by the random forest method allowing for bacteria differentiation into Gram-negative and -positive (error rate: 16.7 % in validation data set). For aerobic samples the error rate was not better than random. CONCLUSIONS: In anaerobic blood culture samples of patients IMR-MS based headspace VC composition analysis facilitates bacteria differentiation into Gram negative and -positive. PMID- 26973819 TI - Identification of Biomarkers for Footpad Dermatitis Development and Wound Healing. AB - Footpad dermatitis (FPD) is a type of skin inflammation that causes necrotic lesions on the plantar surface of the footpads in commercial poultry, with significant animal welfare, and economic implications. To identify biomarkers for FPD development and wound healing, a battery cage trial was conducted in which a paper sheet was put on the bottom of cages to hold feces to induce FPD of broilers. Day-of-hatch Ross 308 male broiler chicks were fed a corn-soybean meal diet and assigned to 3 treatments with 8 cages per treatment and 11 birds per cage. Cages without paper sheets were used as a negative control (NEG). Cages with paper sheets during the entire growth period (d 0-30) were used as a positive control (POS) to continually induce FPD. Cages with paper sheets during d 0-13 and without paper sheets during d 14-30 were used to examine the dynamic of FPD development and lesion wound healing (LWH). Footpad lesions were scored to grade (G) 1-5 with no lesion in G1 and most severe lesion in G5. Covering with paper sheets in POS and LWH induced 99% incidence of G3 footpads on d 13. Removing paper sheets from LWH healed footpad lesions by d 30. One representative bird, with lesions most close to pen average lesion score, was chosen to collect footpad skin samples for biomarker analysis. Total collagen protein and mRNA levels of tenascin X (TNX), type I alpha1 collagen (COL1A1), type III alpha1 collagen (COL3A1), tissue inhibitor of metalloproteinase 3 (TIMP3), and integrin alpha1 (ITGA1) mRNA levels were decreased (P < 0.05), while mRNA levels of tenascin C (TNC), tumor necrosis factor (TNF) alpha, Toll-like receptor (TLR) 4 and vascular endothelial growth factor (VEGF), IL-1beta, and the ratio of MMP2 to all TIMP were increased (P < 0.03) in G3 footpads in POS and LWH compared to G1 footpads in NEG on d 14. These parameters continued to worsen with development of more severe lesions in POS. After paper sheets were removed (i.e., LWH), levels of these parameters gradually or rapidly returned to levels measured in NEG. Regression analysis indicated significant quadratic changes of these parameters to footpad lesion scores. In summary, these biomarkers were interrelated with dynamic changes of footpad lesion scores, suggesting they may be used as potential biomarkers for footpad lesion development and wound healing process. PMID- 26973822 TI - Outcomes of Laparoscopic Treatment Modalities for Unilateral Non-palpable Testes. AB - PURPOSE: To date, laparoscopy has gradually become the gold standard for treatment of non-palpable testicles (NPT) with different success and complication rates. In this study, we aimed to evaluate outcomes of laparoscopic approaches for NPT. MATERIALS AND METHODS: We reviewed data of 82 consecutive patients who underwent laparoscopic treatment for unilateral NPT at two institutions by two high volume surgeons from 2004 January to 2014 December. Laparoscopic-assisted orchidopexy (LAO) and two-stage Fowler-Stephens technique (FST) was performed for 45 and 37 patients, respectively. Age (at surgery), follow-up time, laterality of testes, and postoperative complications were analyzed. Modified Clavien classification system (MCCS) was used for evaluating complications. RESULTS: The median age (at surgery) and median follow-up time were 18 (range: 6-56) and 60 (range: 9-130) months, respectively. Overall success rate for two laparoscopy techniques was 87.8% during the maximal follow-up time. We observed wound infection in two, hematoma in one, testicular atrophy in five, testicular re ascending in two patients at follow-up period. There was no statistical difference between two laparoscopic techniques for grade I (five vs. two patients, p = 0.14) and grade IIIb MCCS complications (five vs. two patients, p = 0.44). CONCLUSION: Our results have shown that two laparoscopic approaches have low complication rates. PMID- 26973823 TI - Commentary: Control of Body Weight by Eating Behavior in Children. PMID- 26973824 TI - Indigenous Food Systems and Climate Change: Impacts of Climatic Shifts on the Production and Processing of Native and Traditional Crops in the Bolivian Andes. AB - Inhabitants of the high-mountain Andes have already begun to experience changes in the timing, severity, and patterning of annual weather cycles. These changes have important implications for agriculture, for human health, and for the conservation of biodiversity in the region. This paper examines the implications of climate-driven changes for native and traditional crops in the municipality of Colomi, Cochabamba, Bolivia. Data were collected between 2012 and 2014 via mixed methods, qualitative fieldwork, including participatory workshops with female farmers and food preparers, semi-structured interviews with local agronomists, and participant observation. Drawing from this data, the paper describes (a) the observed impacts of changing weather patterns on agricultural production in the municipality of Colomi, Bolivia and (b) the role of local environmental resources and conditions, including clean running water, temperature, and humidity, in the household processing techniques used to conserve and sometimes detoxify native crop and animal species, including potato (Solanum sp.), oca (Oxalis tuberosa), tarwi (Lupinus mutabilis), papalisa (Ullucus tuberosus), and charke (llama or sheep jerky). Analysis suggests that the effects of climatic changes on agriculture go beyond reductions in yield, also influencing how farmers make choices about the timing of planting, soil management, and the use and spatial distribution of particular crop varieties. Furthermore, household processing techniques to preserve and detoxify native foods rely on key environmental and climatic resources, which may be vulnerable to climatic shifts. Although these findings are drawn from a single case study, we suggest that Colomi agriculture characterizes larger patterns in what might be termed, "indigenous food systems." Such systems are underrepresented in aggregate models of the impacts of climate change on world agriculture and may be under different, more direct, and more immediate threat from climate change. As such, the health of the food production and processing environments in such systems merits immediate attention in research and practice. PMID- 26973825 TI - An Approach to Establishing International Quality Standards for Medical Travel. AB - The number of individuals traveling abroad is increasing annually. The rising popularity of medical travel and the absence of clear minimum quality requirements in this area urgently call for the development of international standards to ensure good practice and patient safety. The aim of this study is to identify the key domains in medical travel where quality standards should be established. Drawing from the evidence-based OECD framework and an extensive literature review, this study proposes three critical areas for consideration: minimum standards of health-care facilities and third-party agencies, financial responsibility, and patient centeredness. Several cultural challenges have been introduced that may pose a barrier to development of the guidelines and should be taken into consideration. Establishing international quality standards in medical travel enhances benefits to patients and providers, which is an urgent necessity given the rapid growth in this industry. PMID- 26973826 TI - Understanding the Role of Psychiatric Principles in Patient Care: An Important Goal of the Medical Student Clerkship in Psychiatry. PMID- 26973827 TI - A Survey of Knowledge, Attitudes, and Practices in Relation to Mosquitoes and Mosquito-Borne Disease in Western Australia. AB - On average, more than 1,000 individuals will acquire a mosquito-borne disease in Western Australia (WA) each year. Knowledge, attitudes, and practices (KAP) in relation to mosquitoes and mosquito-borne disease have not yet been investigated within Australia. A randomized telephone survey of 2,500 households across 12 regions in WA was undertaken between February and May 2014. The aim of the survey was to obtain baseline KAP data surrounding mosquitoes and mosquito-borne diseases in different regions of WA, across a range of age groups and between males and females. The results of this survey indicate that the majority of respondents are aware of the potential for mosquitoes in WA to transmit Ross River virus, while awareness of other endemic mosquito-borne diseases remains limited. Common misconceptions exist in relation to exotic mosquito-borne diseases, with respondents incorrectly identifying malaria and dengue as endemic diseases in WA. The survey also highlighted a range of important issues, such as limited awareness of the potential for backyard breeding in domestic containers, occupational exposure to mosquitoes in regions with a large employment base in the mining and resources sector, increased exposure to mosquitoes as a result of participation in outdoor recreational activities in the north of the State, and reduced awareness of mosquito-borne disease in individuals aged 18-34 years. The results of this study will be used to inform the development of a new communication strategy by the Department of Health, to further raise awareness of mosquito-borne disease in WA. The data will then provide a baseline against which to compare future survey results, facilitating the rigorous evaluation of new communication efforts. PMID- 26973828 TI - Editorial: Public Health Nutrition in the Middle East. PMID- 26973818 TI - Environmental Regulation of Yersinia Pathophysiology. AB - Hallmarks of Yersinia pathogenesis include the ability to form biofilms on surfaces, the ability to establish close contact with eukaryotic target cells and the ability to hijack eukaryotic cell signaling and take over control of strategic cellular processes. Many of these virulence traits are already well described. However, of equal importance is knowledge of both confined and global regulatory networks that collaborate together to dictate spatial and temporal control of virulence gene expression. This review has the purpose to incorporate historical observations with new discoveries to provide molecular insight into how some of these regulatory mechanisms respond rapidly to environmental flux to govern tight control of virulence gene expression by pathogenic Yersinia. PMID- 26973829 TI - The Educated Citizen and Global Public-Health Issues: One Model for Integration into the Undergraduate Curriculum. AB - The Educated Citizen Initiative proposes that an understanding of public-health issues is a core component of an educated citizenry and is essential to develop one's societal responsibility. This initiative supports the Institute of Medicine's recommendation that "all undergraduates should have access to education in public health." Furthermore, the Liberal Education and America's Promise (LEAP) framework developed by the Association of American Colleges and Universities supports the "integration of public-health education into general and liberal education with an aim to produce an educated citizenry." The LEAP framework is implemented by teaching about the role of social determinants in a population's health status; the significance of personal and social responsibility; and providing skills for inquiry, critical thinking, problem solving, and evaluation. This article describes one university's experience in generating an educated citizenry cognizant of comprehensive public-health conflicts, thus contributing to both a local and global perspective on learning. PMID- 26973830 TI - Surface Analysis of Gold Nanoparticles Functionalized with Thiol-Modified Glucose SAMs for Biosensor Applications. AB - In this work, Time of Flight Secondary Ion Mass Spectrometry (ToF-SIMS), Principal Component Analysis (PCA) and X-ray Photoelectron Spectroscopy (XPS) have been used to characterize the surface chemistry of gold substrates before and after functionalization with thiol-modified glucose self-assembled monolayers and subsequent biochemical specific recognition of maltose binding protein (MBP). The results indicate that the surface functionalization is achieved both on flat and nanoparticles gold substrates thus showing the potential of the developed system as biodetection platform. Moreover, the method presented here has been found to be a sound and valid approach to characterize the surface chemistry of nanoparticles functionalized with large molecules. Both techniques were proved to be very useful tools for monitoring all the functionalization steps, including the investigation of the biological behavior of the glucose-modified particles in the presence of the maltose binding protein. PMID- 26973831 TI - Waterproofing in Arabidopsis: Following Phenolics and Lipids In situ by Confocal Raman Microscopy. AB - Waterproofing of the aerial organs of plants imposed a big evolutionary step during the colonization of the terrestrial environment. The main plant polymers responsible of water repelling are lipids and lignin, which play also important roles in the protection against biotic/abiotic stresses, regulation of flux of gases and solutes, and mechanical stability against negative pressure, among others. While the lipids, non-polymerized cuticular waxes together with the polymerized cutin, protect the outer surface, lignin is confined to the secondary cell wall within mechanical important tissues. In the present work a micro cross section of the stem of Arabidopsis thaliana was used to track in situ the distribution of these non-carbohydrate polymers by Confocal Raman Microscopy. Raman hyperspectral imaging gives a molecular fingerprint of the native waterproofing tissues and cells with diffraction limited spatial resolution (~300 nm) at relatively high speed and without any tedious sample preparation. Lipids and lignified tissues as well as their effect on water content was directly visualized by integrating the 1299, 1600, and 3400 cm(-1) band, respectively. For detailed insights into compositional changes of these polymers vertex component analysis was performed on selected sample positions. Changes have been elucidated in the composition of lignin within the lignified tissues and between interfascicular fibers and xylem vessels. Hydrophobizing changes were revealed from the epidermal layer to the cuticle as well as a change in the aromatic composition within the cuticle of trichomes. To verify Raman signatures of different waterproofing polymers additionally Raman spectra of the cuticle and cutin monomer from tomato (Solanum lycopersicum) as well as aromatic model polymers (milled wood lignin and dehydrogenation polymer of coniferyl alcohol) and phenolic acids were acquired. PMID- 26973832 TI - A New Thermophilic Nitrilase from an Antarctic Hyperthermophilic Microorganism. AB - Several environmental samples from Antarctica were collected and enriched to search for microorganisms with nitrilase activity. A new thermostable nitrilase from a novel hyperthermophilic archaea Pyrococcus sp. M24D13 was purified and characterized. The activity of this enzyme increased as the temperatures rise from 70 up to 85 degrees C. Its optimal activity occurred at 85 degrees C and pH 7.5. This new enzyme shows a remarkable resistance to thermal inactivation retaining more than 50% of its activity even after 8 h of incubation at 85 degrees C. In addition, this nitrilase is highly versatile demonstrating activity toward different substrates, such as benzonitrile (60 mM, aromatic nitrile) and butyronitrile (60 mM, aliphatic nitrile), with a specific activity of 3286.7 U mg(-1) of protein and 4008.2 U mg(-1) of protein, respectively. Moreover the enzyme NitM24D13 also presents cyanidase activity. The apparent Michaelis-Menten constant (K m) and V max of this Nitrilase for benzonitrile were 0.3 mM and 333.3 MUM min(-1), respectively, and the specificity constant (k cat/K m) for benzonitrile was 2.05 * 10(5) s(-1) M(-1). PMID- 26973833 TI - Structure, Function, and Propagation of Information across Living Two, Four, and Eight Node Degree Topologies. AB - In this study, we created four network topologies composed of living cortical neurons and compared resultant structural-functional dynamics including the nature and quality of information transmission. Each living network was composed of living cortical neurons and were created using microstamping of adhesion promoting molecules and each was "designed" with different levels of convergence embedded within each structure. Networks were cultured over a grid of electrodes that permitted detailed measurements of neural activity at each node in the network. Of the topologies we tested, the "Random" networks in which neurons connect based on their own intrinsic properties transmitted information embedded within their spike trains with higher fidelity relative to any other topology we tested. Within our patterned topologies in which we explicitly manipulated structure, the effect of convergence on fidelity was dependent on both topology and time-scale (rate vs. temporal coding). A more detailed examination using tools from network analysis revealed that these changes in fidelity were also associated with a number of other structural properties including a node's degree, degree-degree correlations, path length, and clustering coefficients. Whereas information transmission was apparent among nodes with few connections, the greatest transmission fidelity was achieved among the few nodes possessing the highest number of connections (high degree nodes or putative hubs). These results provide a unique view into the relationship between structure and its affect on transmission fidelity, at least within these small neural populations with defined network topology. They also highlight the potential role of tools such as microstamp printing and microelectrode array recordings to construct and record from arbitrary network topologies to provide a new direction in which to advance the study of structure-function relationships. PMID- 26973834 TI - Compartmentalization and Transport in Synthetic Vesicles. AB - Nanoscale vesicles have become a popular tool in life sciences. Besides liposomes that are generated from phospholipids of natural origin, polymersomes fabricated of synthetic block copolymers enjoy increasing popularity, as they represent more versatile membrane building blocks that can be selected based on their specific physicochemical properties, such as permeability, stability, or chemical reactivity. In this review, we focus on the application of simple and nested artificial vesicles in synthetic biology. First, we provide an introduction into the utilization of multicompartmented vesosomes as compartmentalized nanoscale bioreactors. In the bottom-up development of protocells from vesicular nanoreactors, the specific exchange of pathway intermediates across compartment boundaries represents a bottleneck for future studies. To date, most compartmented bioreactors rely on unspecific exchange of substrates and products. This is either based on changes in permeability of the coblock polymer shell by physicochemical triggers or by the incorporation of unspecific porin proteins into the vesicle membrane. Since the incorporation of membrane transport proteins into simple and nested artificial vesicles offers the potential for specific exchange of substances between subcompartments, it opens new vistas in the design of protocells. Therefore, we devote the main part of the review to summarize the technical advances in the use of phospholipids and block copolymers for the reconstitution of membrane proteins. PMID- 26973836 TI - Identification of Rab41/6d Effectors Provides an Explanation for the Differential Effects of Rab41/6d and Rab6a/a' on Golgi Organization. AB - Unexpectedly, members of the Rab VI subfamily exhibit considerable variation in their effects on Golgi organization and trafficking. By fluorescence microscopy, neither depletion nor overexpression of the GDP-locked form of Rab6a/a', the first trans Golgi-associated Rab protein discovered, affects Golgi ribbon organization while, on the other hand, both Rab41/6d depletion and overexpression of GDP-locked form cause Golgi fragmentation into a cluster of punctate elements, suggesting that Rab41/6d has an active role in maintenance of Golgi ribbon organization. To establish a molecular basis for these differences, we screened for Rab41/6d interacting proteins by yeast two-hybrid assay. 155 non-repetitive hits were isolated and sequenced, and after searching in NCBI database, 102 different proteins and protein fragments were identified. None of these hits overlapped with any published Rab6a/a' effector. Eight putative Rab41 interactors involved in membrane trafficking were found. Significantly, these exhibited a preferential interaction with GTP- vs. GDP-locked Rab41/6d. Of the 8 hits, the dynactin 6, syntaxin 8, and Kif18A plasmids were the only ones expressing the full-length protein. Hence, these 3 proteins were selected for further study. We found that depletion of dynactin 6 or syntaxin 8, but not Kif18A, resulted in a fragmented Golgi apparatus that displayed a Rab41/6d knockdown phenotype, i.e., the Golgi apparatus was disrupted into a cluster of punctate Golgi elements. Co immunoprecipation experiments verified that the interaction of dynactin 6 and syntaxin 8 with GTP-locked Rab41/6d was stronger than that with wild type Rab41/6d and least with the GDP-locked form. In contrast, co-immunoprecipitation interaction with Rab6a was greatest with the GDP-locked Rab6a, suggestive of a non-physiological interaction. In conclusion, we suggest that dynactin 6, a subunit of dynactin complex, the minus-end-directed, dynein motor, provides a sufficient molecular basis to explain the active role of Rab41/6d in maintaining Golgi ribbon organization while syntaxin 8 contributes more indirectly to Golgi positioning. PMID- 26973835 TI - Emerging Insights into the Roles of Membrane Tethers from Analysis of Whole Organisms: The Tip of an Iceberg? AB - Membrane tethers have been identified throughout different compartments of the endomembrane system. It is now well established that a number of membrane tethers mediate docking of membrane carriers in anterograde and retrograde transport and in regulating the organization of membrane compartments. Much of our information on membrane tethers have been obtained from the analysis of individual membrane tethers in cultured cells. In the future it will be important to better appreciate the network of interactions mediated by tethers and the potential co ordination of their collective functions in vivo. There are now a number of studies which have analyzed membrane tethers in tissues and organisms which are providing new insights into the role of this class of membrane protein at the physiological level. Here we review recent advances in the understanding of the function of membrane tethers from knock outs (or knock downs) in whole organisms and from mutations in tethers associated with disease. PMID- 26973838 TI - Keep an Ear Out for Francisella tularensis: Otomastoiditis Cases after Canyoneering. AB - We report here three unusual cases of otomastoiditis due to Francisella tularensis, complicated by cervical abscesses and persistent hearing loss, plus facial paralysis for one patient. Intriguingly, the three patients had practiced canyoneering independently in the same French river, between 2009 and 2014, several days before clinical symptoms onset. The results point out that fresh water exposure may be a potential contamination route for tularemia. Besides, due to the frequent complications and sequelae, we believe that F. tularensis should be considered as a possible etiology in case of otitis media, failure of the conventional antibiotic treatment, and suspicious exposure of the bacteria. PMID- 26973837 TI - Major urinary protein (MUP) profiles show dynamic changes rather than individual 'barcode' signatures. AB - House mice (Mus musculus) produce a variable number of major urinary proteins (MUPs), and studies suggest that each individual produces a unique MUP profile that provides a distinctive odor signature controlling individual and kin recognition. This 'barcode hypothesis' requires that MUP urinary profiles show high individual variability within populations and also high individual consistency over time, but tests of these assumptions are lacking. We analyzed urinary MUP profiles of 66 wild-caught house mice from eight populations using isoelectric focusing. We found that MUP profiles of wild male house mice are not individually unique, and though they were highly variable, closer inspection revealed that the variation strongly depended on MUP band type. The prominent ('major) bands were surprisingly homogenous (and hence most MUPs are not polymorphic), but we also found inconspicuous ('minor') bands that were highly variable and therefore potential candidates for individual fingerprints. We also examined changes in urinary MUP profiles of 58 males over time (from 6 to 24 weeks of age), and found that individual MUP profiles and MUP concentration were surprisingly dynamic, and showed significant changes after puberty and during adulthood. Contrary to what we expected, however, the minor bands were the most variable over time, thus no good candidates for individual fingerprints. Although MUP profiles do not provide individual fingerprints, we found that MUP profiles were more similar among siblings than non-kin despite considerable fluctuation. Our findings show that MUP profiles are not highly stable over time, they do not show strong individual clustering, and thus challenge the barcode hypothesis. Within-individual dynamics of MUP profiles indicate a different function of MUPs in individual recognition than previously assumed and advocate an alternative hypothesis ('dynamic changes' hypothesis). PMID- 26973840 TI - Capsular Management in Hip Arthroscopy: An Anatomic, Biomechanical, and Technical Review. AB - Hip arthroscopy has become an increasingly utilized surgical technique for the treatment of the young, active patients with hip pain. The clinical outcomes of hip arthroscopy in this patient population have been largely successful; however, there is increasing interest in the contribution of hip capsule in postoperative clinical and functional outcomes. The structure and function of the normal hip capsule will be reviewed. Capsular contributions to hip stability will be discussed in the setting of hip arthroscopy with an emphasis on diagnosis-based considerations. Lastly, clinical outcomes following hip arthroscopy will be discussed as they relate to capsular management. PMID- 26973839 TI - Immune Evasion Strategies of Glioblastoma. AB - Glioblastoma (GBM) is the most devastating brain tumor, with associated poor prognosis. Despite advances in surgery and chemoradiation, the survival of afflicted patients has not improved significantly in the past three decades. Immunotherapy has been heralded as a promising approach in treatment of various cancers; however, the immune privileged environment of the brain usually curbs the optimal expected response in central nervous system malignancies. In addition, GBM cells create an immunosuppressive microenvironment and employ various methods to escape immune surveillance. The purpose of this review is to highlight the strategies by which GBM cells evade the host immune system. Further understanding of these strategies and the biology of this tumor will pave the way for developing novel immunotherapeutic approaches for treatment of GBM. PMID- 26973841 TI - Spatial Heterogeneity of Cx43 is an Arrhythmogenic Substrate of Polymorphic Ventricular Tachycardias during Compensated Cardiac Hypertrophy in Rats. AB - BACKGROUND: Ventricular remodeling increases the propensity of ventricular tachyarrhythmias and sudden death in patients. We studied the mechanism underlying these fatal arrhythmias, electrical and structural cardiac remodeling, as well as arrhythmogeneity during early, compensated hypertrophy in a rat model of chronic pressure overload. METHODS: Twenty-six Wistar rats were subjected to transverse aortic constriction (TAC) (n = 13) or sham operation (n = 13). Four weeks postoperative, echo- and electrocardiography was performed. Epicardial (208 or 455 sites) and transmural (30 sites) ventricular activation mapping was performed on Langendorff perfused hearts. Subsequently, hearts were processed for (immuno)histological and molecular analyses. RESULTS: TAC rats showed significant hypertrophy with preserved left ventricular (LV) function. Epicardial conduction velocity (CV) was similar, but more dispersed in TAC. Transmural CV was slowed in TAC (37.6 +/- 2.9 cm s(-1)) compared to sham (58.5 +/- 3.9 cm s(-1); P < 0.01). Sustained polymorphic ventricular tachycardias were induced from LV in 8/13 TAC and in 0/13 sham rats. During VT, electrical activation patterns showed variable sites of earliest epicardial activation and altering sites of functional conduction block. Wandering epicardial reentrant activation was sporadically observed. Collagen deposition was significantly higher in TAC compared to sham, but not different between arrhythmogenic and non-arrhythmogenic TAC animals. Connexin43 (Cx43) expression was heterogeneous with a higher prevalence of non phosphorylated Cx43 in arrhythmogenic TAC animals. CONCLUSION: In TAC rats with compensated cardiac hypertrophy, dispersion of conduction correlated to arrhythmogenesis, an increased heterogeneity of Cx43, and a partial substitution with non-phosphorylated Cx43. These alterations may result in the increased vulnerability to polymorphic VTs. PMID- 26973843 TI - Exposure to Increased Environmental Complexity during Rearing Reduces Fearfulness and Increases Use of Three-Dimensional Space in Laying Hens (Gallus gallus domesticus). AB - The complexity of the rearing environment is important for behavioral development and fearfulness. The aim of this study was to test the hypothesis that laying hens reared in a complex aviary system with exposure to mild intermittent stressors would be less fearful, less sensitive to stress, and would use elevated areas of the pen more often as adults than hens reared in a barren cage environment. Laying hens (N = 160) were housed in the same rearing house; half of the birds (n = 80) in an aviary and the other half (n = 80) in cages. At 16 weeks of age, the birds were transported to the experimental facilities. Their behavior was recorded at 19 and 23 weeks of age and analyzed by analysis of variance on individual scores for a fearfulness-related principal component generated using principal component analysis. The results indicate that aviary-reared birds have lower levels of fearfulness compared with cage-reared birds both at 19 weeks and at 23 weeks of age. When comparing the response induced by initial exposure to a novel object at 19 and 23 weeks of age, more aviary-reared birds tended to fly up at 19 weeks compared to the cage-reared birds, indicating a tendency toward a more active behavioral response in the aviary-reared birds than in cage-reared birds. There was no difference between treatments in the flight response at 23 weeks. The groups did not differ in defecation frequency or the concentration of fecal corticosterone metabolites at either age. At 19 weeks, observation of the spatial distribution in the home pens indicated that more aviary-reared birds spent time on the low perch, the elevated platform, and the upper perch, compared to the cage-reared birds. However, at 23 weeks of age, these differences were no longer detected. The results of this study support the hypothesis that increased environmental complexity during rearing reduces fearfulness of adult laying hens. PMID- 26973842 TI - Angiotensin II during Experimentally Simulated Central Hypovolemia. AB - Central hypovolemia, defined as diminished blood volume in the heart and pulmonary vascular bed, is still an unresolved problem from a therapeutic point of view. The development of pharmaceutical agents targeted at specific angiotensin II receptors, such as the non-peptidergic AT2-receptor agonist compound 21, is yielding many opportunities to uncover more knowledge about angiotensin II receptor profiles and possible therapeutic use. Cardiovascular, anti-inflammatory, and neuroprotective therapeutic use of compound 21 have been suggested. However, there has not yet been a focus on the use of these agents in a hypovolemic setting. We argue that the latest debates on the effect of angiotensin II during hypovolemia might guide for future studies, investigating the effect of such agents during experimentally simulated central hypovolemia. The purpose of this review is to examine the role of angiotensin II during episodes of central hypovolemia. To examine this, we reviewed results from studies with three experimental models of simulated hypovolemia: head up tilt table test, lower body negative pressure, and hemorrhage of animals. A systemic literature search was made with the use of PubMed/MEDLINE for studies that measured variables of the renin-angiotensin system or its effect during simulated hypovolemia. Twelve articles, using one of the three models, were included and showed a possible organ-protective effect and an effect on the sympathetic system of angiotensin II during hypovolemia. The results support the possible organ protective vasodilatory role for the AT2-receptor during hypovolemia on both the kidney and the splanchnic tissue. PMID- 26973844 TI - Mitigation of Ergot Vasoconstriction by Clover Isoflavones in Goats (Capra hircus). AB - Ergot alkaloids produced by a fungal endophyte (Epichloe coenophiala; formerly Neotyphodium coenophialum) that infects tall fescue (Lolium arundinaceum) can induce persistent constriction of the vasculature in ruminants, hindering their capability to thermo-regulate core body temperature. There is evidence that isoflavones produced by legumes can relax the vasculature, which suggests that they could relieve ergot alkaloid-induced vasoconstriction and mitigate the vulnerability to severe heat stress in ruminants that graze tall fescue. To test if isoflavones can relieve alkaloid-induced vasoconstriction, two pen experiments were conducted with rumen-fistulated goats (Capra hircus) to determine with ultrasonograpy if isoflavones can (1) promote vascular compliance by countering alkaloid-induced vasoconstriction and (2) relieve already imposed alkaloid induced vasoconstriction. Goats were fed ad libitum chopped orchardgrass (Dactylis glomerata)-timothy (Phleum pratense) hay prior to conducting the experiments. Measures of carotid and interosseous luminal areas were obtained pre (baseline) and post-ruminal infusions in both experiments with goats being fed the hay, and for blood flow rate in the carotid artery in Experiment 2. Responses to infusion treatments were evaluated as proportionate differences from baseline measures. Peak systolic velocity, pulsatility index, and heart rate were measured on the last day on treatment (DOT) in Experiment 1, and on all imaging sessions during Experiment 2. For Experiment 1, rumens were infused with ground toxic fescue seed and isoflavones in Phase A and with only the toxic seed in Phase B. The infusion treatments were switched between phases in Experiment 2, which employed a fescue seed extract having an ergot alkaloid composition equivalent to that of the ground seed used in Experiment 1. During Experiment 1, luminal areas of carotid and interosseous arteries in Phase A did not deviate (P > 0.1) from baselines over 1, 2, 3, and 4 DOT, but the areas of both declined linearly from baselines over 1, 2, 3, and 4 DOT in Phase B. By 6, 7, and 8 DOT in Experiment 2, luminal areas of the arteries and flow rate declined from baselines with infusions with the only seed extract in Phase A, but luminal areas and flow rate increased over 4, 5, and 6 DOT with the additional infusion of isoflavones. Peak systolic velocity and heart rate were not affected by treatment in either experiment, but were highest when infused with only ergot alkaloids in both experiments. Treatment with isoflavones was demonstrated to relax the carotid and interosseous arteries and reduce resistance to blood flow. Results indicate that isoflavones can relax persistent vasoconstriction in goats caused by consumption of ergot alkaloids, and mitigate the adverse effect that ergot alkaloids have on dry matter intake. PMID- 26973845 TI - Spatial and Temporal Epidemiology of Lumpy Skin Disease in the Middle East, 2012 2015. AB - Lumpy skin disease virus (LSDV) is an infectious disease of cattle that can have severe economic implications. New LSD outbreaks are currently circulating in the Middle East (ME). Since 2012, severe outbreaks were reported in cattle across the region. Characterizing the spatial and temporal dynamics of LSDV in cattle populations is prerequisite for guiding successful surveillance and control efforts at a regional level in the ME. Here, we aim to model the ecological niche of LSDV and identify epidemic progression patterns over the course of the epidemic. We analyzed publically available outbreak data from the ME for the period 2012-2015 using presence-only maximum entropy ecological niche modeling and the time-dependent method for the estimation of the effective reproductive number (R-TD). High-risk areas (probability >0.60) for LSDV identified by ecological niche modeling included parts of many northeastern ME countries, though Israel and Turkey were estimated to be the most suitable locations for occurrence of LSDV outbreaks. The most important environmental predictors that contributed to the ecological niche of LSDV included annual precipitation, land cover, mean diurnal range, type of livestock production system, and global livestock densities. Average monthly effective R-TD was equal to 2.2 (95% CI: 1.2, 3.5), whereas the largest R-TD was estimated in Israel (R-TD = 22.2, 95 CI: 15.2, 31.5) in September 2013, which indicated that the demographic and environmental conditions during this period were suitable to LSDV super-spreading events. The sharp drop of Isreal's inferred R-TD in the following month reflected the success of their 2013 vaccination campaign in controlling the disease. Our results identified areas in which underreporting of LSDV outbreaks may have occurred. More epidemiological information related to cattle populations are needed to further improve the inferred spatial and temporal characteristics of currently circulating LSDV. However, the methodology presented here may be useful in guiding the design of risk-based surveillance and control programs in the region as well as aid in the formulation of epidemic preparedness plans in neighboring LSDV-free countries. PMID- 26973846 TI - A Set of Grand Challenges for Veterinary Regenerative Medicine. PMID- 26973847 TI - Assessing progression of keratoconus: novel tomographic determinants. AB - Several methods have been described in the literature to both evaluate and document progression in keratoconus, but there is no consistent or clear definition of ectasia progression. The authors describe how modern corneal tomography, including both anterior and posterior elevation and pachymetric data can be used to screen for ectatic progression, and how software programs such as the Enhanced Reference Surface and the Belin-Ambrosio Enhanced Ectasia Display (BAD) can be employed to detect earlier changes. Additionally, in order to describe specific quantitative values that can be used as progression determinants, the normal noise measurement of the three parameters (corneal thickness at the thinnest point, anterior and posterior radius of curvature (ARC, PRC) taken from the 3.0 mm optical zone centered on the thinnest point), was assessed. These values were obtained by imaging five normal patients using three different technicians on three separate days. The 95 % and 80 % one-sided confidence intervals for all three parameters were surprisingly small (7.88/4.03 MUm for corneal thickness, 0.024/0.012 mm for ARC, and 0.083/0.042 mm for PRC), suggesting that they may perform well as progression determinants. PMID- 26973848 TI - Proteome Analyses of Staphylococcus aureus Biofilm at Elevated Levels of NaCl. AB - Our studies demonstrate that sodium chloride (NaCl) induces changes in biofilm, mediated by increased production of polysaccharides intercellular adhesion (PIA). We identified 12 proteins that showed higher abundance in increased level of NaCl. This includes one important protein (IsaA) known to be associated with biofilm stability. In addition, we also found higher abundance of a cold shock protein, CspA, at higher NaCl. We have also identified several other proteins that are differentially expressed to the elevated levels of NaCl and mapped them in the regulatory pathways of PIA. The majority of proteins are involved with various aspects bacterial metabolic function. Our results demonstrated that NaCl influences gene regulatory networks controlling exopolysaccharide expression. PMID- 26973849 TI - Saccharomyces boulardii to Prevent Antibiotic-Associated Diarrhea: A Randomized, Double-Masked, Placebo-Controlled Trial. AB - Background. Antibiotic-associated diarrhea (AAD) and Clostridium difficile associated diarrhea (CDAD) are common complications of antibiotic use. Data on the efficacy of probiotics to prevent AAD and CDAD are unclear. We aimed to evaluate the efficacy of Saccharomyces boulardii to prevent AAD and CDAD in hospitalized adult patients. Methods. We conducted a multicenter, phase III, double-masked, randomized, placebo-controlled trial in hospitalized patients who received systemic antibiotic treatment in 15 hospitals in Germany between July 2010 and October 2012. Participants received Perenterol forte 250 mg capsules or matching placebo twice per day within 24 hours of initiating antibiotic treatment, continued treatment for 7 days after antibiotic discontinuation, and were then observed for 6 weeks. Results. Two thousand four hundred forty-four patients were screened. The trial was stopped early for futility after inclusion of 477 participants. Two hundred forty-six patients aged 60.1 +/- 16.5 years and 231 patients aged 56.5 +/- 17.8 were randomized to the S boulardii group and the placebo group, respectively, with 21 and 19 AADs in the respective groups (P = .87). The hazard ratio of AAD in the S boulardii group compared with the placebo group was 1.02 (95% confidence interval, .55-1.90; P = .94). Clostridium difficile-associated diarrhea occurred in 0.8% of participants (4 of 477). Nine serious adverse events were recorded in the S boulardii group, and 3 serious adverse events were recorded in the placebo group. None were related to study participation. Conclusions. We found no evidence for an effect of S boulardii in preventing AAD or CDAD in a population of hospitalized patients without particular risk factors apart from systemic antibiotic treatment. ClinicalTrials.gov Identifier. NCT01143272. PMID- 26973850 TI - Interferon Lambda 4 Genotype Is Associated With Jaundice and Elevated Aminotransferase Levels During Acute Hepatitis C Virus Infection: Findings From the InC3 Collaborative. AB - Symptomatic acute HCV infection and interferon lambda 4 (IFNL4) genotypes are important predictors of spontaneous viral clearance. Using data from a multicohort database (Injecting Cohorts [InC3] Collaborative), we establish an independent association between host IFNL4 genotype and symptoms of acute hepatitis C virus infection. This association potentially explains the higher spontaneous clearance observed in some patients with symptomatic disease. PMID- 26973851 TI - Improving Robustness of Deep Neural Network Acoustic Models via Speech Separation and Joint Adaptive Training. AB - Although deep neural network (DNN) acoustic models are known to be inherently noise robust, especially with matched training and testing data, the use of speech separation as a frontend and for deriving alternative feature representations has been shown to improve performance in challenging environments. We first present a supervised speech separation system that significantly improves automatic speech recognition (ASR) performance in realistic noise conditions. The system performs separation via ratio time frequency masking; the ideal ratio mask (IRM) is estimated using DNNs. We then propose a framework that unifies separation and acoustic modeling via joint adaptive training. Since the modules for acoustic modeling and speech separation are implemented using DNNs, unification is done by introducing additional hidden layers with fixed weights and appropriate network architecture. On the CHiME-2 medium-large vocabulary ASR task, and with log mel spectral features as input to the acoustic model, an independently trained ratio masking frontend improves word error rates by 10.9% (relative) compared to the noisy baseline. In comparison, the jointly trained system improves performance by 14.4%. We also experiment with alternative feature representations to augment the standard log mel features, like the noise and speech estimates obtained from the separation module, and the standard feature set used for IRM estimation. Our best system obtains a word error rate of 15.4% (absolute), an improvement of 4.6 percentage points over the next best result on this corpus. PMID- 26973853 TI - PINK1, cancer and neurodegeneration. PMID- 26973852 TI - STAT5 activation in B-cell acute lymphoblastic leukemia: damned if you do, damned if you don't. AB - A significant role of the microenvironment in leukemogenesis is beginning to emerge. The leukemia cell microenvironment consists of not only the stromal and endothelial cell components but also the normal hematopoietic cells. Signal transducer and activator of transcription 5 (STAT5) is a latent transcription factor that is normally transiently activated by phosphorylation in response to microenvironmental signals. In hematopoietic cells, persistently activated STAT5 via aberrant receptor signaling, Janus kinases (JAKs), or intracellular tyrosine kinases is a bona fide driver of leukemogenesis. However, active IL-7/STAT5 signaling also protects the early B-cell genome by suppressing error-prone recombination and vulnerability to transformation. Along these lines, we have reported that lymphocyte development from transplanted STAT5-deficient fetal liver cells was blocked at the pre-pro-B-cell stage but when combined with transgenic Myc and Bcl-2 promoted faster initiation of B-ALL. Furthermore, inflammatory responses may also be involved in leukemia initiation in both pediatric and adult patients which are associated with decreased phosphorylation of STAT5. Likewise, additional targeted agents continue to be developed for precision medicine that prominently suppress signaling pathways. A common theme of all of these perturbations is potential risk for dysregulating hematopoiesis through general transcriptional modulation. Here we discuss the potential for STAT5 inhibition as a double edged sword in certain hematologic disorders, such as early B-cell lymphoblastic leukemias. Considering the rapid pace of understanding of the pre-leukemic decrease in poly-clonality that precedes leukemia, the functional changes associated with microenvironmental influences are thus of potential clinical significance. PMID- 26973854 TI - CYLD and SUMO in neuroblastoma therapy. PMID- 26973855 TI - New crossroads for potential therapeutic intervention in cancer - intersections between CDCP1, EGFR family members and downstream signaling pathways. AB - Signaling pathways regulated by the receptor CDCP1 play central roles in promoting cancer and in mediating resistance to chemo- and targeted-therapies. In this perspective we briefly summarize these findings as well as data demonstrating poorer outcomes for several malignancies that exhibit elevated CDCP1 expression. Promising data from preclinical studies suggest that CDCP1 targeted agents, including therapeutic antibodies, could be useful in the treatment of cancer patients selected on the basis of activation of CDCP1 and its signaling partners including EGFR, HER2, Met and Src. PMID- 26973856 TI - In silico and experimental analyses predict the therapeutic value of an EZH2 inhibitor GSK343 against hepatocellular carcinoma through the induction of metallothionein genes. AB - There are currently no effective molecular targeted therapies for hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27)-specific methyltransferase, has been emerged as novel anticancer target. Our previous study has demonstrated that GSK343, an S-adenosyl-L-methionine (SAM)-competitive inhibitor of EZH2, induces autophagy and enhances drug sensitivity in cancer cells including HCC. In this study, an in silico study was performed and found that EZH2 was overexpressed in cancerous tissues of HCC patients at both gene and protein levels. Microarray analysis and in vitro experiments indicated that the anti-HCC activity of GSK343 was associated with the induction of metallothionein (MT) genes. In addition, the negative association of EZH2 and MT1/MT2A genes in cancer cell lines and tissues was found in public gene expression database. Taken together, our findings suggest that EZH2 inhibitors could be a good therapeutic option for HCC, and induction of MT genes was associated with the anti-HCC activity of EZH2 inhibitors. PMID- 26973857 TI - EZH2 inhibition re-sensitizes multidrug resistant B-cell lymphomas to etoposide mediated apoptosis. AB - Reactivation of apoptotic pathways is an attractive strategy for patients with treatment-resistant B-cell lymphoma. The tumor suppressor, p53 is central for apoptotic response to multiple DNA damaging agents used to treat aggressive B cell lymphomas, including etoposide. It has been demonstrated that etoposide induced DNA damage and therapeutic efficacy is enhanced by combination with inhibitors of the histone methyltransferase, enhancer of zeste homolog 2 (EZH2). Further, EZH2 was identified to regulate cell fate decisions in response to DNA damage. Using B-cell lymphoma cell lines resistant to etoposide induced cell death; we show that p53 is dramatically down regulated and MDMX, a negative regulator of p53, is significantly up regulated. However, these cell lines remain responsive to etoposide mediated DNA damage and exhibit cell cycle inhibition and induction of senescence. Furthermore, chemical inhibition of EZH2 directs DNA damage to a predominant p53 dependent apoptotic response associated with loss of MDMX and BCL-XL. These data provide confirmation of EZH2 in determining cell fate following DNA damage and propose a novel therapeutic strategy for patients with aggressive treatment-resistant B-cell lymphoma. PMID- 26973858 TI - The potential relevance of the endocannabinoid, 2-arachidonoylglycerol, in diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma is an aggressive, genetically heterogenerous disease and the most common type of non-Hodgkin lymphoma among adults. To gain further insights into the etiology of DLBCL and to discover potential disease related factors, we performed a serum lipid analysis on a subset of individuals from a population-based NHL case-control study. An untargeted mass-spectrometry based metabolomics platform was used to analyze serum samples from 100 DLBCL patients and 100 healthy matched controls. Significantly elevated levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), were detected in the serum of DLBCL patients (121%, P < 0.05). In the male controls, elevated 2-AG levels were observed in those who were overweight (BMI >= 25 - < 30 kg/m2; 108%, P < 0.01) and obese (BMI >= 30 kg/m(2); 118%, P < 0.001) compared to those with a BMI < 25 kg/m(2). DLBCL cell lines treated with exogenous 2-AG across a range of concentrations, exhibited heterogenous responses: proliferation rates were markedly higher in 4 cell lines by 22%-68% (P < 0.001) and lower in 8 by 20%-75% (P < 0.001). The combined findings of elevated 2-AG levels in DLBCL patients and the proliferative effects of 2-AG on a subset of DLBCL cell lines suggests that 2 AG may play a potential role in the pathogenesis or progression of a subset of DLBCLs. PMID- 26973860 TI - Erratum: Kinetochore-microtube attachments in cancer therapy. AB - [This corrects the article on p. 902 in vol. 2, PMID: 26697517.]. PMID- 26973859 TI - Early onset esophageal adenocarcinoma: a distinct molecular entity? AB - Esophageal adenocarcinoma (EAC) is typically diagnosed in elderly with a median age of 68 years. The incidence of EAC has been rising over the last decades, also among young adults. The aim of the study was to investigate whether early onset EAC is a distinct molecular entity. To identify early onset EACs, the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA) was searched. Twenty-eight tumors of patients aged <=40 years were selected and matched with 27 tumors of patients aged >=68 years. DNA was isolated from surgically resected specimen and sequenced on the Ion Torrent Personal Genome Machine with the Ion AmpliSeq Cancer Panel. No differences in mutational load between early onset and conventional EACs were observed (P=0.196). The most frequently mutated genes were TP53 (73%) and P16 (16%). Additional mutations in early onset EACs occurred exclusively in: APC, CDH1, CTNNB1, FGFR2, and STK11. In the conventional EACs additional mutations were exclusively identified in: ABL1, FBXW7, GNA11, GNAS, KRAS, MET, SMAD4, and VHL. Additional mutations besides TP53 and P16 seem to occur in different genes related to cell fate pathways for early onset EACs, while the additional mutations in conventional EACs are related to survival pathways. PMID- 26973861 TI - RISK CORRIDORS AND REINSURANCE IN HEALTH INSURANCE MARKETPLACES: Insurance for Insurers. AB - Health Insurance Marketplaces established by the Affordable Care Act implement reinsurance and risk corridors. Reinsurance limits insurer costs associated with specific individuals, while risk corridors protect against aggregate losses. Both tighten the insurer's distribution of expected costs. This paper compares the economic costs and consequences of reinsurance and risk corridors. We simulate the insurer's cost distribution under reinsurance and risk corridors using data for a group of individuals likely to enroll in Marketplace plans from the Medical Expenditure Panel Survey. We compare reinsurance and risk corridors in terms of risk reduction and incentives for cost containment. We find that reinsurance and one-sided risk corridors achieve comparable levels of risk reduction for a given level of incentives. We also find that the policies being implemented in the Marketplaces (a mix of reinsurance and two-sided risk corridor policies) substantially limit insurer risk but perform similarly to a simpler stand-alone reinsurance policy. PMID- 26973862 TI - Inverse-power-law behavior of cellular motility reveals stromal-epithelial cell interactions in 3D co-culture by OCT fluctuation spectroscopy. AB - The progression of breast cancer is known to be affected by stromal cells within the local microenvironment. Here we study the effect of stromal fibroblasts on the in-place motions (motility) of mammary epithelial cells within organoids in 3D co-culture, inferred from the speckle fluctuation spectrum using optical coherence tomography (OCT). In contrast to Brownian motion, mammary cell motions exhibit an inverse power-law fluctuation spectrum. We introduce two complementary metrics for quantifying fluctuation spectra: the power-law exponent and a novel definition of the motility amplitude, both of which are signal- and position independent. We find that the power-law exponent and motility amplitude are positively (p<0.001) and negatively (p<0.01) correlated with the density of stromal cells in 3D co-culture, respectively. We also show how the hyperspectral data can be visualized using these metrics to observe heterogeneity within organoids. This constitutes a simple and powerful tool for detecting and imaging cellular functional changes with OCT. PMID- 26973863 TI - Correcting field-dependent aberrations with nanoscale accuracy in three dimensional single-molecule localization microscopy. AB - The localization of single fluorescent molecules enables the imaging of molecular structure and dynamics with subdiffraction precision and can be extended to three dimensions using point spread function (PSF) engineering. However, the nanoscale accuracy of localization throughout a 3D single-molecule microscope's field of view has not yet been rigorously examined. By using regularly spaced subdiffraction apertures filled with fluorescent dyes, we reveal field-dependent aberrations as large as 50-100 nm and show that they can be corrected to less than 25 nm over an extended 3D focal volume. We demonstrate the applicability of this technique for two engineered PSFs, the double-helix PSF and the astigmatic PSF. We expect these results to be broadly applicable to 3D single-molecule tracking and superresolution methods demanding high accuracy. PMID- 26973865 TI - Booze and butts: A content analysis of the presence of alcohol in tobacco industry's lifestyle magazines. AB - BACKGROUND: Advertising influences people's health behaviors. Tobacco companies have linked tobacco and alcohol in their marketing activities. We examined how depictions of alcohol were placed in lifestyle magazines produced by tobacco companies, and if these references differed depending on if the magazine was oriented towards men, women, or if it was unisex. METHODS: Content analysis of 6 different tobacco industry lifestyle magazines (73 issues), including 73 magazine covers, 1558 articles, 444 tobacco ads, and 695 non-tobacco ads. RESULTS: 14 of 73 (19%) magazine covers featured alcohol; 581 of 1558 (37%) magazine articles mentioned alcohol; 119 of 444 (27%) tobacco ads showed alcohol images; and 57 of 695 (8%) non-tobacco ads portrayed alcohol. Male-oriented magazines (Unlimited, CML, and Real Edge) contained the most alcohol references, and the references were mainly beer, mixed drinks, and liquor or spirits. Female-oriented magazines (All Woman and Flair) contained the fewest alcohol references, and wine and mixed drinks were the major types of alcoholic beverage portrayed. For unisex magazine (P.S.), the frequency of alcohol references fell between the male- and female oriented magazines, and most frequently mentioned mixed drinks. CONCLUSIONS: Frequent depictions of smoking and drinking in tobacco industry lifestyle magazines might have reinforced norms about paired use of tobacco and alcohol among young adults. The pairing of tobacco and alcohol may particularly target young men. Anti-tobacco interventions need to address the co-use of tobacco and alcohol, change the social acceptability of smoking in any social settings, and tailor alcohol related anti-tobacco messaging by gender. PMID- 26973866 TI - Metabolic stressors disrupt proteome homeostasis to suppress malignancy. AB - Within tumor cells the heat shock factor 1 (HSF1)-mediated stress response is constitutively mobilized to counter persistent proteotoxic stress, hence sustaining their fragile proteome homeostasis and supporting robust malignant phenotypes. Intriguingly, our new studies reveal that metabolic stressors, such as metformin, inactivate HSF1 and provoke proteomic chaos, thereby impeding tumorigenesis. PMID- 26973864 TI - Environmental Enteric Dysfunction Includes a Broad Spectrum of Inflammatory Responses and Epithelial Repair Processes. AB - BACKGROUND & AIMS: Environmental enteric dysfunction (EED), a chronic diffuse inflammation of the small intestine, is associated with stunting in children in the developing world. The pathobiology of EED is poorly understood because of the lack of a method to elucidate the host response. This study tested a novel microarray method to overcome limitation of RNA sequencing to interrogate the host transcriptome in feces in Malawian children with EED. METHODS: In 259 children, EED was measured by lactulose permeability (%L). After isolating low copy numbers of host messenger RNA, the transcriptome was reliably and reproducibly profiled, validated by polymerase chain reaction. Messenger RNA copy number then was correlated with %L and differential expression in EED. The transcripts identified were mapped to biological pathways and processes. The children studied had a range of %L values, consistent with a spectrum of EED from none to severe. RESULTS: We identified 12 transcripts associated with the severity of EED, including chemokines that stimulate T-cell proliferation, Fc fragments of multiple immunoglobulin families, interferon-induced proteins, activators of neutrophils and B cells, and mediators that dampen cellular responses to hormones. EED-associated transcripts mapped to pathways related to cell adhesion, and responses to a broad spectrum of viral, bacterial, and parasitic microbes. Several mucins, regulatory factors, and protein kinases associated with the maintenance of the mucous layer were expressed less in children with EED than in normal children. CONCLUSIONS: EED represents the activation of diverse elements of the immune system and is associated with widespread intestinal barrier disruption. Differentially expressed transcripts, appropriately enumerated, should be explored as potential biomarkers. PMID- 26973868 TI - Land-cover changes predict steep declines for the Sumatran orangutan (Pongo abelii). AB - Positive news about Sumatran orangutans is rare. The species is critically endangered because of forest loss and poaching, and therefore, determining the impact of future land-use change on this species is important. To date, the total Sumatran orangutan population has been estimated at 6600 individuals. On the basis of new transect surveys, we estimate a population of 14,613 in 2015. This higher estimate is due to three factors. First, orangutans were found at higher elevations, elevations previously considered outside of their range and, consequently, not surveyed previously. Second, orangutans were found more widely distributed in logged forests. Third, orangutans were found in areas west of the Toba Lake that were not previously surveyed. This increase in numbers is therefore due to a more wide-ranging survey effort and is not indicative of an increase in the orangutan population in Sumatra. There are evidently more Sumatran orangutans remaining in the wild than we thought, but the species remains under serious threat. Current scenarios for future forest loss predict that as many as 4500 individuals could vanish by 2030. Despite the positive finding that the population is double the size previously estimated, our results indicate that future deforestation will continue to be the cause of rapid declines in orangutan numbers. Hence, we urge that all developmental planning involving forest loss be accompanied by appropriate environmental impact assessments conforming with the current national and provincial legislations, and, through these, implement specific measures to reduce or, better, avoid negative impacts on forests where orangutans occur. PMID- 26973867 TI - Adaptive optics ophthalmoscopy. AB - This review starts with a brief history and description of adaptive optics (AO) technology, followed by a showcase of the latest capabilities of AO systems for imaging the human retina and an extensive review of the literature on where AO is being used clinically. The review concludes with a discussion on future directions and guidance on usage and interpretation of images from AO systems for the eye. PMID- 26973869 TI - Mismatched partners that achieve postpairing behavioral similarity improve their reproductive success. AB - Behavioral similarity between partners is likely to promote within-pair compatibility and to result in better reproductive success. Therefore, individuals are expected to choose a partner that is alike in behavioral type. However, mate searching is very costly and does not guarantee finding a matching partner. If mismatched individuals pair, they may benefit from increasing their similarity after pairing. We show in a monogamous fish species-the convict cichlid-that the behavioral similarity between mismatched partners can increase after pairing. This increase resulted from asymmetrical adjustment because only the reactive individual became more alike its proactive partner, whereas the latter did not change its behavior. The mismatched pairs that increased their similarity not only improved their reproductive success but also raised it up to the level of matched pairs. While most studies assume that assortative mating results from mate choice, our study suggests that postpairing adjustment could be an alternative explanation for the high behavioral similarity between partners observed in the field. It also explains why interindividual behavioral differences can be maintained within a given population. PMID- 26973870 TI - Mid-Cretaceous amber fossils illuminate the past diversity of tropical lizards. AB - Modern tropical forests harbor an enormous diversity of squamates, but fossilization in such environments is uncommon and little is known about tropical lizard assemblages of the Mesozoic. We report the oldest lizard assemblage preserved in amber, providing insight into the poorly preserved but potentially diverse mid-Cretaceous paleotropics. Twelve specimens from the Albian-Cenomanian boundary of Myanmar (99 Ma) preserve fine details of soft tissue and osteology, and high-resolution x-ray computed tomography permits detailed comparisons to extant and extinct lizards. The extraordinary preservation allows several specimens to be confidently assigned to groups including stem Gekkota and stem Chamaleonidae. Other taxa are assignable to crown clades on the basis of similar traits. The detailed preservation of osteological and soft tissue characters in these specimens may facilitate their precise phylogenetic placement, making them useful calibration points for molecular divergence time estimates and potential keys for resolving conflicts in higher-order squamate relationships. PMID- 26973871 TI - Integrating simultaneous prosocial and antisocial behavior into theories of collective action. AB - Trust and cooperation constitute cornerstones of common-pool resource theory, showing that "prosocial" strategies among resource users can overcome collective action problems and lead to sustainable resource governance. Yet, antisocial behavior and especially the coexistence of prosocial and antisocial behaviors have received less attention. We broaden the analysis to include the effects of both "prosocial" and "antisocial" interactions. We do so in the context of marine protected areas (MPAs), the most prominent form of biodiversity conservation intervention worldwide. Our multimethod approach relied on lab-in-the-field economic experiments (n = 127) in two MPA and two non-MPA communities in Baja California, Mexico. In addition, we deployed a standardized fishers' survey (n = 544) to verify the external validity of our findings and expert informant interviews (n = 77) to develop potential explanatory mechanisms. In MPA sites, prosocial and antisocial behavior is significantly higher, and the presence of antisocial behavior does not seem to have a negative effect on prosocial behavior. We suggest that market integration, economic diversification, and strengthened group identity in MPAs are the main potential mechanisms for the simultaneity of prosocial and antisocial behavior we observed. This study constitutes a first step in better understanding the interaction between prosociality and antisociality as related to natural resources governance and conservation science, integrating literatures from social psychology, evolutionary anthropology, behavioral economics, and ecology. PMID- 26973872 TI - Quantitative determination of pairing interactions for high-temperature superconductivity in cuprates. AB - A profound problem in modern condensed matter physics is discovering and understanding the nature of fluctuations and their coupling to fermions in cuprates, which lead to high-temperature superconductivity and the invariably associated strange metal state. We report the quantitative determination of normal and pairing self-energies, made possible by laser-based angle-resolved photoemission measurements of unprecedented accuracy and stability. Through a precise inversion procedure, both the effective interactions in the attractive d wave symmetry and the repulsive part in the full symmetry are determined. The latter is nearly angle-independent. Near T c, both interactions are nearly independent of frequency and have almost the same magnitude over the complete energy range of up to about 0.4 eV, except for a low-energy feature at around 50 meV that is present only in the repulsive part, which has less than 10% of the total spectral weight. Well below T c, they both change similarly, with superconductivity-induced features at low energies. Besides finding the pairing self-energy and the attractive interactions for the first time, these results expose the central paradox of the problem of high T c: how the same frequency independent fluctuations can dominantly scatter at angles +/-pi/2 in the attractive channel to give d-wave pairing and lead to angle-independent repulsive scattering. The experimental results are compared with available theoretical calculations based on antiferromagnetic fluctuations, the Hubbard model, and quantum-critical fluctuations of the loop-current order. PMID- 26973874 TI - Origin of uranium isotope variations in early solar nebula condensates. AB - High-temperature condensates found in meteorites display uranium isotopic variations ((235)U/(238)U), which complicate dating the solar system's formation and whose origin remains mysterious. It is possible that these variations are due to the decay of the short-lived radionuclide (247)Cm (t 1/2 = 15.6 My) into (235)U, but they could also be due to uranium kinetic isotopic fractionation during condensation. We report uranium isotope measurements of meteoritic refractory inclusions that reveal excesses of (235)U reaching ~+6% relative to average solar system composition, which can only be due to the decay of (247)Cm. This allows us to constrain the (247)Cm/(235)U ratio at solar system formation to (1.1 +/- 0.3) * 10(-4). This value provides new clues on the universality of the nucleosynthetic r-process of rapid neutron capture. PMID- 26973873 TI - Bacterial antisense RNAs are mainly the product of transcriptional noise. AB - cis-Encoded antisense RNAs (asRNAs) are widespread along bacterial transcriptomes. However, the role of most of these RNAs remains unknown, and there is an ongoing discussion as to what extent these transcripts are the result of transcriptional noise. We show, by comparative transcriptomics of 20 bacterial species and one chloroplast, that the number of asRNAs is exponentially dependent on the genomic AT content and that expression of asRNA at low levels exerts little impact in terms of energy consumption. A transcription model simulating mRNA and asRNA production indicates that the asRNA regulatory effect is only observed above certain expression thresholds, substantially higher than physiological transcript levels. These predictions were verified experimentally by overexpressing nine different asRNAs in Mycoplasma pneumoniae. Our results suggest that most of the antisense transcripts found in bacteria are the consequence of transcriptional noise, arising at spurious promoters throughout the genome. PMID- 26973875 TI - A three-dimensional culture system recapitulates placental syncytiotrophoblast development and microbial resistance. AB - In eutherians, the placenta acts as a barrier and conduit at the maternal-fetal interface. Syncytiotrophoblasts, the multinucleated cells that cover the placental villous tree surfaces of the human placenta, are directly bathed in maternal blood and are formed by the fusion of progenitor cytotrophoblasts that underlie them. Despite their crucial role in fetal protection, many of the events that govern trophoblast fusion and protection from microbial infection are unknown. We describe a three-dimensional (3D)-based culture model using human JEG 3 trophoblast cells that develop syncytiotrophoblast phenotypes when cocultured with human microvascular endothelial cells. JEG-3 cells cultured in this system exhibit enhanced fusogenic activity and morphological and secretory activities strikingly similar to those of primary human syncytiotrophoblasts. RNASeq analyses extend the observed functional similarities to the transcriptome, where we observed significant overlap between syncytiotrophoblast-specific genes and 3D JEG-3 cultures. Furthermore, JEG-3 cells cultured in 3D are resistant to infection by viruses and Toxoplasma gondii, which mimics the high resistance of syncytiotrophoblasts to microbial infections in vivo. Given that this system is genetically manipulatable, it provides a new platform to dissect the mechanisms involved in syncytiotrophoblast development and microbial resistance. PMID- 26973876 TI - Biodegradable triboelectric nanogenerator as a life-time designed implantable power source. AB - Transient electronics built with degradable organic and inorganic materials is an emerging area and has shown great potential for in vivo sensors and therapeutic devices. However, most of these devices require external power sources to function, which may limit their applications for in vivo cases. We report a biodegradable triboelectric nanogenerator (BD-TENG) for in vivo biomechanical energy harvesting, which can be degraded and resorbed in an animal body after completing its work cycle without any adverse long-term effects. Tunable electrical output capabilities and degradation features were achieved by fabricated BD-TENG using different materials. When applying BD-TENG to power two complementary micrograting electrodes, a DC-pulsed electrical field was generated, and the nerve cell growth was successfully orientated, showing its feasibility for neuron-repairing process. Our work demonstrates the potential of BD-TENG as a power source for transient medical devices. PMID- 26973878 TI - Host-parasite Red Queen dynamics with phase-locked rare genotypes. AB - Interactions between hosts and parasites have been hypothesized to cause winnerless coevolution, called Red Queen dynamics. The canonical Red Queen dynamics assume that all interacting genotypes of hosts and parasites undergo cyclic changes in abundance through negative frequency-dependent selection, which means that any genotype could become frequent at some stage. However, this prediction cannot explain why many rare genotypes stay rare in natural host parasite systems. To investigate this, we build a mathematical model involving multihost and multiparasite genotypes. In a deterministic and controlled environment, Red Queen dynamics occur between two genotypes undergoing cyclic dominance changes, whereas the rest of the genotypes remain subordinate for long periods of time in phase-locked synchronized dynamics with low amplitude. However, introduction of stochastic noise in the model might allow the subordinate cyclic host and parasite types to replace dominant cyclic types as new players in the Red Queen dynamics. The factors that influence such evolutionary switching are interhost competition, specificity of parasitism, and degree of stochastic noise. Our model can explain, for the first time, the persistence of rare, hardly cycling genotypes in populations (for example, marine microbial communities) undergoing host-parasite coevolution. PMID- 26973877 TI - Structures of ribosome-bound initiation factor 2 reveal the mechanism of subunit association. AB - Throughout the four phases of protein biosynthesis-initiation, elongation, termination, and recycling-the ribosome is controlled and regulated by at least one specified translational guanosine triphosphatase (trGTPase). Although the structural basis for trGTPase interaction with the ribosome has been solved for the last three steps of translation, the high-resolution structure for the key initiation trGTPase, initiation factor 2 (IF2), complexed with the ribosome, remains elusive. We determine the structure of IF2 complexed with a nonhydrolyzable guanosine triphosphate analog and initiator fMet-tRNAi (Met) in the context of the Escherichia coli ribosome to 3.7-A resolution using cryo electron microscopy. The structural analysis reveals previously unseen intrinsic conformational modes of the 70S initiation complex, establishing the mutual interplay of IF2 and initator transfer RNA (tRNA) with the ribsosome and providing the structural foundation for a mechanistic understanding of the final steps of translation initiation. PMID- 26973879 TI - A universal cooperative assembly-directed method for coating of mesoporous TiO(2) nanoshells with enhanced lithium storage properties. AB - TiO2 is exceptionally useful, but it remains a great challenge to develop a universal method to coat TiO2 nanoshells on different functional materials. We report a one-pot, low-temperature, and facile method that can rapidly form mesoporous TiO2 shells on various inorganic, organic, and inorganic-organic composite materials, including silica-based, metal, metal oxide, organic polymer, carbon-based, and metal-organic framework nanomaterials via a cooperative assembly-directed strategy. In constructing hollow, core-shell, and yolk-shell geometries, both amorphous and crystalline TiO2 nanoshells are demonstrated with excellent control. When used as electrode materials for lithium ion batteries, these crystalline TiO2 nanoshells composed of very small nanocrystals exhibit remarkably long-term cycling stability over 1000 cycles. The electrochemical properties demonstrate that these TiO2 nanoshells are promising anode materials. PMID- 26973880 TI - B Cells with Regulatory Function in Human Diseases. PMID- 26973881 TI - Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype. AB - Glioblastomas are highly infiltrated by diverse immune cells, including microglia, macrophages, and myeloid-derived suppressor cells (MDSCs). Understanding the mechanisms by which glioblastoma-associated myeloid cells (GAMs) undergo metamorphosis into tumor-supportive cells, characterizing the heterogeneity of immune cell phenotypes within glioblastoma subtypes, and discovering new targets can help the design of new efficient immunotherapies. In this study, we performed a comprehensive battery of immune phenotyping, whole genome microarray analysis, and microRNA expression profiling of GAMs with matched blood monocytes, healthy donor monocytes, normal brain microglia, nonpolarized M0 macrophages, and polarized M1, M2a, M2c macrophages. Glioblastoma patients had an elevated number of monocytes relative to healthy donors. Among CD11b+ cells, microglia and MDSCs constituted a higher percentage of GAMs than did macrophages. GAM profiling using flow cytometry studies revealed a continuum between the M1- and M2-like phenotype. Contrary to current dogma, GAMs exhibited distinct immunological functions, with the former aligned close to nonpolarized M0 macrophages. PMID- 26973882 TI - Autoimmune response to transthyretin in juvenile idiopathic arthritis. AB - Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatological condition. Although it has been proposed that JIA has an autoimmune component, the autoantigens are still unknown. Using biochemical and proteomic approaches, we identified the molecular chaperone transthyretin (TTR) as an antigenic target for B and T cell immune responses. TTR was eluted from IgG complexes and affinity purified from 3 JIA patients, and a statistically significant increase in TTR autoantibodies was observed in a group of 43 JIA patients. Three cryptic, HLA-DR1 restricted TTR peptides, which induced CD4+ T cell expansion and IFN-gamma and TNF-alpha production in 3 out of 17 analyzed patients, were also identified. Misfolding, aggregation and oxidation of TTR, as observed in the synovial fluid of all JIA patients, enhanced its immunogenicity in HLA-DR1 transgenic mice. Our data point to TTR as an autoantigen potentially involved in the pathogenesis of JIA and to oxidation and aggregation as a mechanism facilitating TTR autoimmunity. PMID- 26973883 TI - Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice. AB - Prox1 heterozygous mice have a defective lymphatic vasculature and develop late onset obesity. Chyle abnormally leaks from those vessels, accumulates in the surrounding tissues, and causes an increase in adipose tissue. We characterized the lymphatics of Prox1+/- mice to determine whether the extent of obesity correlated with the severity of lymphatic defects. The lymphatic vasculature in Prox1+/- mice exhibited reduced tracer clearance from the ear skin, dysfunctional perfusion of the lower legs, and reduced tracer uptake into the deep lymphatic collectors during mechanostimulation prior to the onset of obesity. Ear lymphatic vessels and leg collectors in Prox1+/- mice were disorganized and irregular, further confirming that defective lymphatic vessels are associated with obesity in Prox1+/- mice. We now provide conclusive in vivo evidence that demonstrates that leaky lymphatics mediate obesity in Prox1+/- mice, as restoration of lymphatic vasculature function was sufficient to rescue the obesity features in Prox1+/- mice. Finally, depth-lipomic profiling of lymph contents showed that free fatty acids induce adipogenesis in vitro. PMID- 26973884 TI - Soluble gC1qR in Blood and Body Fluids: Examination in a Pancreatic Cancer Patient Cohort. AB - BACKGROUND: gC1qR is a multifunctional cellular protein that has been linked to inflammation and cancer. gC1qR is highly upregulated in adenocarcinomas as compared to normal tissue counterparts, and soluble gC1qR (sgC1qR) has been detected in vitro in the pericellular milieu of proliferating malignant cells. AIM: The present study explored the tissue expression of gC1qR in pancreatic cancer by immunohistochemistry, and the presence of sgC1qR in vivo, by examining blood and malignant effusions from patients with metastatic pancreatic adenocarcinoma. METHODS: Tissue expression of gC1qR by pancreatic adenocarcinoma was visualized by immunohistochemistry. SgC1qR was quantified in serum from healthy volunteers (n=20) and pancreatic cancer patients (n=34), as well as in malignant pleural (n=23) and peritoneal effusions (n=27), using a newly developed, sensitive immunocapture sandwich ELISA. RESULTS: Overexpression of gC1qR was confirmed in pancreatic adenocarcinoma compared to nonmalignant pancreatic tissue. Moreover, increased serum levels of sgC1qR (0.29 +/- 0.22 ng/ml) were noted in patients with metastatic pancreatic cancer compared to healthy controls (0.15 +/- 0.10 ng/ml) (mean +/- S.D.) (p=0.035). In 11 of 16 patients for whom sequential samples were available, serum sgC1qR levels rose with disease progression, and paralleled changes in tumor biomarkers, CEA and CA19.9. In addition to blood, sgC1qR was detected in malignant pleural (0.55 +/- 0.47 ng/ml) and peritoneal effusions (0.57 +/- 0.38 ng/ml). CONCLUSION: This study provides the first evidence for the presence of sgC1qR in vivo. The ability to detect sgC1qR in blood and body fluids will enable further studies to elucidate its pathophysiology in malignancy. PMID- 26973886 TI - A New Journal, A New Start. PMID- 26973885 TI - Engineering Modular Viral Scaffolds for Targeted Bacterial Population Editing. AB - Bacteria are central to human health and disease, but existing tools to edit microbial consortia are limited. For example, broad-spectrum antibiotics are unable to accurately manipulate bacterial communities. Bacteriophages can provide highly specific targeting of bacteria, but assembling well-defined phage cocktails solely with natural phages can be a time-, labor- and cost-intensive process. Here, we present a synthetic-biology strategy to modulate phage host ranges by engineering phage genomes in Saccharomyces cerevisiae. We used this technology to redirect Escherichia coli phage scaffolds to target pathogenic Yersinia and Klebsiella bacteria, and conversely, Klebsiella phage scaffolds to target E. coli by modular swapping of phage tail components. The synthetic phages achieved efficient killing of their new target bacteria and were used to selectively remove bacteria from multi-species bacterial communities with cocktails based on common viral scaffolds. We envision that this approach will accelerate phage-biology studies and enable new technologies for bacterial population editing. PMID- 26973887 TI - Do Psychological Factors Help to Reduce Body Mass in Obesity or is it Vice Versa? Selected Psychological Aspects and Effectiveness of the Weight-Loss Program in the Obese Patients. AB - The aim of this study was to assess the strength and direction of the correlation between cognitive appraisal, emotional state, social functioning and the effectiveness of a weight-loss program undertaken by obese subjects. The out patient weight-loss program encompassed 150 obese women. Assessments were carried out at four time points: at the start of the weight-loss program and then after a 5%, 10% and a 15% reduction of the initial body mass. The research tools used were: a survey, the Situation Appraisal Questionnaire (SAQ), the Emotional State Questionnaire (ESQ), and the Q-Sort Social Functioning Questionnaire. The cognitive appraisal, emotional state and social functioning of the study group changed significantly (P<0.001). Significantly more individuals with a 15% body mass reduction, as compared with individuals with no body mass reduction, had an early obesity onset, i.e. at the age of <10 years old (P<0.001). Significantly more individuals with no body mass reduction, compared with individuals with a 15% reduction, had a later obesity onset, i.e. between the ages of 20 and 30 (P<0.001) and between 50 and 60 (P<0.001). Significantly more individuals with a 15% body mass reduction, compared with individuals with no mass reduction, had previously experienced the jojo effect (P<0.001) and had successfully lost weight (P<0.001). Significantly more individuals with no body mass reduction, compared with individuals with a15% reduction, had a history of unsuccessful attempts at reducing body mass (P<0.001). We conclude that the attitude of obese patients towards a weight-loss program is not a deciding factor for its effectiveness. As body mass reduces, the attitude improves. PMID- 26973888 TI - Validity of the French form of the Somatosensory Amplification Scale in a Non Clinical Sample. AB - The SomatoSensory Amplification Scale (SSAS) is a 10-item self-report instrument designed to assess the tendency to detect somatic and visceral sensations and experience them as unusually intense, toxic and alarming. This study examines the psychometric properties of a French version of the SSAS in a non-clinical population and, more specifically, explores its construct, convergent and discriminant validities. The SSAS was completed by 375 university students, together with measures of somatization propensity (SCL-90-R somatization subscale) and trait anxiety (STAI Y form). The results of principal component and confirmatory factor analyses suggest that the French version of the SSAS evaluates essentially a single, robust factor (Somatosensory amplification) and two kinds of somatic sensitivity (Exteroceptive sensitivity and Interoceptive sensitivity). Somatosensory amplification correlated with somatization tendency and anxiety propensity. These results encourage further investigations in French of the determinants and consequences of somatosensory amplification, and its use as a therapeutic strategy. PMID- 26973889 TI - Positive Effects on Life Satisfaction Following Health-Promoting Interventions for Frail Older Adults: A Randomized Controlled Study. AB - Life satisfaction among older adults is known to decrease over time and with deteriorated health. The aim of this study was to analyze the effects of the health-promoting intervention study Elderly Persons in the Risk Zone on life satisfaction. A randomized, three-armed, single-blind, and controlled trial with follow-ups at 3 months, 1 and 2 years. A total of 459 community-dwelling persons at risk of frailty, 80-years or older were included. The participants were independent of help from others in ADL and cognitively intact. The two interventions were i) four weekly multi-professional senior group meetings including a follow-up home visit or ii) one preventive home visit. Life satisfaction was measured with eight questions from LiSat-11. Analyses were made in accordance with the intention-to-treat principle. Life satisfaction decreased over time, with a lower decrease in the intervention groups than in the control group. The proportion of satisfied persons was significantly higher in the intervention group of senior group meetings compared to the control group for five of the eight life satisfaction variables at one year and for all variables at the two-year follow-up. For preventive home visits, there was a significant difference compared to the control group at the one-year follow-up for three of the life satisfaction variables, and at the two-year follow-up for seven variables. We can conclude that a health-promoting intervention can delay the decline in life satisfaction among older adults (aged 80 or older) who are at risk of becoming frail. PMID- 26973891 TI - Depression Treatment in Individuals with Cancer: A Comparative Analysis with Cardio-Metabolic Conditions. AB - A clear picture of the current state of nation-wide depression treatment practices in individuals with cancer and depression does not exist in the United States (US). Therefore, the primary objective of this study was to examine rates of any depression treatment among individuals with cancer and depression in the US. To better understand the relationship between any treatment for depression and presence of cancer, we used a comparison group of individuals with cardio metabolic conditions owing to the similar challenges faced in management of depression in individuals with these conditions. We used a retrospective cross sectional design and data from multiple years of the Medical Expenditure Panel Survey, a nationally representative household-survey on healthcare utilization and expenditures. Study sample consisted of adults aged 21 or older with self reported depression and cancer (n=528) or self-reported depression and diabetes, heart disease or hypertension (n=1643). Depression treatment comprised of any use of antidepressants and/or any use of mental health counseling services. Treatment rates for depression were 78.0% and 81.7% among individuals with cancer and cardio-metabolic conditions respectively. After controlling for socio demographic, access-to-care, number of physician-visits, health-status, and lifestyle risk-factors related variables; individuals with cancer were less likely to report any treatment for depression (Adjusted Odds Ratio=0.67; 95% Confidence Interval=0.49, 0.92) compared to individuals with cardio-metabolic conditions (P<=0.01). Our findings highlight the possibility that competing demands may crowd out treatment for depression and that cancer diagnosis may be a barrier to depression treatment. PMID- 26973890 TI - Self-Care Self-Efficacy, Religious Participation and Depression as Predictors of Poststroke Self-Care Among Underserved Ethnic Minorities. AB - Underserved ethnic minorities have multiple chronic disease risk factors, including tobacco, alcohol and substance use, which contribute to increased incidence of stroke. Self-efficacy (self-care self-efficacy), religious participation and depression may directly and indirectly influence engagement in post stroke self-care behaviors. The primary aim of the present study was to investigate the effects of self-care self-efficacy, religious participation and depression, on tobacco, alcohol and substance use in a sample of largely ethnic minority, underserved stroke survivors (n=52). Participants previously recruited for a culturally tailored secondary stroke prevention self-care intervention were included. The treatment group received three stroke self-care sessions. The usual care group completed assessments only. Both groups were included in these analyses. Main outcome measures included tobacco, alcohol and substance use. Self care self-efficacy, religious participation and depression were also assessed. Logistic regression analyses, using self-efficacy, religious practice and depression as the referents, were used to predict binary outcomes of tobacco, alcohol and substance use at 4-weeks poststroke. Higher depression and self-care self-efficacy were associated with reduced odds of smoking and substance use. Greater participation in religious activities was associated with lower odds of alcohol use. We can conclude that incorporating depression treatment and techniques to increase self-care self-efficacy, and encouraging religious participation may help to improve stroke self-care behaviors for underserved and low socioeconomic status individuals. Results are discussed in the context of stroke self-management. PMID- 26973892 TI - Resilience and Professional Quality of Life in Staff Working with People with Intellectual Disabilities and Offending Behavior in Community Based and Institutional Settings. AB - Staff in forensic services for people with intellectual disabilities (ID) are expected to deal with a wide range of emotional challenges when providing care. The potential impact of this demanding work has not been systematically explored previously. This article explores the professional quality of life (QoL) and the resilience (hardiness) of the staff in this setting. The Professional QoL questionnaire and the Disposional Resilience Scale were completed by staff (n=85, 80% response rate) in the Norwegian forensic service for ID offenders. Responses from staff working in institutional settings were compared to those from staff in local community services. Staff in the local community services had higher resilience scores compared to the staff in the institutional setting, (t=2.19; P<0.05). However in the other QoL and resilience domains there were no differences between the staff in the two settings. The greater sense of resilient control among community staff may be a function of both the number of service users they work with and the institutional demands they face. Even though these participants worked with relatively high risk clients, they did not report significantly impaired quality of life compared to other occupations. PMID- 26973893 TI - A Cross Sectional, Observational Survey to Assess Levels and Predictors of Psychological Wellbeing in Adults with Epidermolysis Bullosa. AB - Epidermolysis bullosa (EB) describes a cluster of genetically determined skin disorders. Symptoms can be painful, disabling and disfiguring, yet there is little research on the psychological impact of the disease. The study aim was to measure psychological wellbeing in adults with EB; and to examine the association between psychological wellbeing and self efficacy, health locus of control and adjustment to appearance in an observational, cross sectional survey. Questionnaire packs comprising the General Health Questionnaire (GHQ-12), the General Self Efficacy Scale (GSE), the Multidimensional Health Locus of Control Scale (MHLOC), and the Derriford Appearance Scale (DAS-24), were sent to approximately 385 adults with EB. The data were analysed using SPSS. Eighty-seven participants responded. Scores on the GHQ-12 showed non-problematic psychological health in 36% of the sample; levels bordering on clinical disorder in 32.1% and severe psychological distress in 31.9%. No correlations were found between demographic factors (age and sex) or clinical factors (EB type and perceived severity) and psychological well-being. Scores on the GSE, the internal locus of control sub-scale of the MHLOC and the DAS-24 showed them to be statistically significant correlates of psychological wellbeing (P<0.001; P<0.018; and P<0.001 respectively). In a regression analysis, adjustment to appearance and self efficacy accounted for 24% of the variation in psychological wellbeing. Adults with EB might be at risk of experiencing poor psychological health. Interventions designed to enhance disease self management, self efficacy and improve body image are likely to be beneficial in this clinical group. PMID- 26973894 TI - Why P6 Medicine Needs Clinical Psychology and a Trans-Cultural Approach. PMID- 26973896 TI - Attitudes Towards Music as a Means of Therapy: Can It Help to Overcome Depression and/or Cardiovascular Disease? PMID- 26973895 TI - Adherence and Physical Activity. PMID- 26973897 TI - Applicability and Validity of the Amnestic Comparative Self-Assessment in Adolescents. AB - The Amnestic Comparative Self-Assessment (ACSA) is a sensitive, efficient, and economic instrument to assess overall quality of life in adult populations. The present study investigates the applicability of the ACSA in an adolescent sample and compares it to a measure of health-related quality of life, the Kiddo-Kindl. The sample comprised 92 adolescents (50 girls, 42 boys) aged 11-17 years (mean age: 13.67, standard deviation: 1.34). Of the investigated sample, n=69 (75%) completed the ACSA. No significant demographic differences were found between ACSA-respondents and non-respondents. The correlation of the Kiddo-Kindl and the ACSA was moderate (r=0.50). The Kiddo-Kindl subscales and the ACSA correlated between r=0.07 and 0.41. The majority of adolescents are able to complete the ASCA, and its acceptance and validity are independent of age. Thus, future investigations could adopt the ACSA in adolescents to assess overall quality of life. PMID- 26973898 TI - The In-House Psychologist: Do We Speak the Same Language? Short Report of a Qualitative Practice Project. AB - Interdisciplinary collaboration is gaining importance. Although general practices (GP's) have a comprehensive experience in collaboration with psychologists, research on this topic is scarce. In house referrals to a psychologist are assumed to lower the thresholds for patients and GP's. In this study it was investigated whether the GP's reasons to refer in were accordance with the treatment strategy of the residing psychologist. The study is performed in a retrospective, observational cross section design. The studied population were the residing psychologist and GP's. Both were asked to complete a questionnaire. Outcome measures where the referral reasons of the GP's and the treatment strategy of the psychologist. A total sample of 92 patients of 6 GP's was studied. Over 60% of the patients were referred for counseling but only in 25% of the cases this proposal was carried out by the psychologist. Overall, the referral reasons of the GP's were not in accordance with the treatment strategy of the psychologist. A close collaboration and communication between general practitioners and psychologists is both difficult and indispensable. This practice research demonstrated that the referral motives of the GP's usually do not correspond to the treatment policy of the psychologist. This observation is partly explained by a lack of understanding of the GP in the treatment strategies of the psychologists. Another part of the explanation is that there is a pre selection of the GPs referrals rather influenced by patient characteristics than by pathology. PMID- 26973899 TI - Facets of Negative Affectivity and Blood Pressure in Middle-Aged Men. AB - Research results suggesting that facets of negative affectivity, i.e. anxiety, anger-hostility, and depression, relate to incident cardiovascular diseases have been steadily increasing. Evidence for depression has been especially extensive. Elevated blood pressure, a major risk factor of cardiovascular diseases, is one probable mediator in this context. The purpose of this study was to clarify the relationship of specific key elements of depressive disposition, i.e. depressive symptoms, hopelessness and vital exhaustion, with health behavior and blood pressure. Study sample was comprised of 710 middle-aged men. Participants completed self-report questionnaires assessing health behavior, depressive symptoms, vital exhaustion and hopelessness. Statistical analyses involved descriptive analyses, correlations and path analysis. Depressive symptoms and vital exhaustion associated with several unfavorable lifestyles such as smoking, alcohol consumption, and inactivity (standardized solution coefficients: 0.10, 0.14, 0.17, accordingly). However, no significant direct associations with blood pressure could be found for depressive symptoms or vital exhaustion. Hopelessness associated only with unhealthy diet (standardized solution coefficient -0.10) Moreover, for hopelessness, results showed a direct but inverse association with systolic blood pressure (standardized solution coefficient -0.08). Results suggest that the previously reported relations of depression and vital exhaustion with blood pressure could be mediated by unfavorable lifestyles. The relation of hopelessness with adverse health behaviors seems to be less significant. Also, the role of hopelessness as a risk factor of elevated blood pressure is not supported by the results of this study. PMID- 26973900 TI - Investigation of Aggravating Psychosocial Factors on Health and Predictability of Smoking and Alcohol Use in Post Adolescent Students. AB - Purpose of this study is to explore those factors which affect the health of students in postadolescent age, focusing on smoking and alcohol use, especially in regard to ways of predicting adoption of this behavior and its frequency to detect future users of tobacco and alcohol use but also high-risk groups, i.e. those people who are led to abuses. On the basis of the research part is the Theory of Planned Behaviour, the axes of which are to be investigated. Specifically, the factors evaluated, except for population parameters, behavioral attitudes, i.e. attitudes towards the behavior of tobacco use and alcohol regulations subjective perceptions and perceptions of control, perceived behavioral control and self-efficacy. Intention is explored to continue or start using tobacco and alcohol in the future and evaluate the behavior. The sample consisted of 138 students of postadolescent age, 18-25 years of both sexes, all of the University of Peloponnese and the Technological Educational Institute of Kalamata, Department of Sparta, Greece. The results of a series of statistical analysis, via SPSS 21.0 statistical program revealed the predictive power of perceived behavioral control and subjective norms to the intention of interpreting 64% of the variance of the latter, of the attitudes toward alcohol in relation to intention that interpret 69% of the variance, of the normative beliefs toward smoking with 69% range of interpretation to the dependent variable, of the perceived behavioral control of smoking with 72% and of the attitudes toward smoking with 77% of interpretation. The results demonstrate the significance and application in universities and technological educational institutes appropriate primary preventive interventions for students nonusers of tobacco and alcohol and appropriate programs of secondary and tertiary prevention in heavy users of tobacco and alcohol use and high-risk individual. PMID- 26973901 TI - Severe War Trauma and Post-Traumatic Stress Disorder in Adolescents with Sensory Impairments: A Cross-sectional Study. AB - A paucity of studies of the psychological status of adolescents with sensory impairments in political conflict areas is noted. This study was set up to examine the exposure of adolescents with sensory impairments (ASIs) to severe war trauma and development of post-traumatic stress disorder (PTSD) as compared to their able-bodied peers (ABPs). It also answers the question whether their impairments have made them more resilient in facing traumatic events. A cross sectional study of all ASIs attending special schools in three administrative districts in Lebanon (n=166) as well as a group of 166 age and sex-matched ABPs from neighboring schools was conducted. The Post Traumatic Stress Reaction Checklist for children (PTSRC) was used to assess exposure to severe trauma, PTSD and their determinants. ASIs reported a lower exposure to severe traumatic events (24.1%) as compared to their ABPs (69.9%), and risk factors for their exposure were an older age group, a fatherless family, and severe visual impairment. Prevalence rates for PTSD were similar in the two study groups (17.5% and 16.4%). Younger ASIs were at a significantly higher risk of developing PTSD. Lower exposure to trauma among ASIs points to the more sheltered life that they lead. Given the same exposure as ABPs, similar rates of PTSD are noted among the two study groups. This may indicate that having a sensory impairment may protect from PTSD due to decreased exposure to severe trauma and not due to increased resilience of subjects. PMID- 26973902 TI - Measuring Health: Related Quality of Life in Hemodialysis Patients. Psychometric Properties of the Missoula-VITAS Quality of Life Index (MVQOLI-15) in Greece. AB - Different measuring tools have been used to understand the outcomes of end-stage renal disease (ESRD) therapies. However, survival, cost-effectiveness and quality of life (QOL) are the main parameters to evaluate treatment of ESRD. The current study meant to assess the psychometric properties (reliability and validity) of the Missoula-VITAS Quality of Life Index (MVQOLI-15) translation to Greek in patients undergoing hemodialysis (HD). A total sample of 79 HD patients voluntarily participated in this pilot study. Domain analysis of MVQOLI-15-Greek was conducted based on the collected data at initial assessment. The reliability properties of the instrument were tested using the following measures; internal consistency, repeatability, test-retest reliability and convergent validity. Domain analysis demonstrated that all domains of the questionnaire had good variability. MVQOLI-15-Greek internal consistency was satisfactory with an overall Cronbach's a at 0.74. Pearson's r and intraclass correlation coefficient revealed strong correlations (ranging from 0.91 to 0.98) between initial assessment and re-assessment. MVQOLI-15-Greek convergent validity analysis indicated that the domains were strongly related to the same construct. The findings of the study indicate that the Greek version of MVQOLI-15 provided satisfactory psychometric properties supporting its use within pathological populations and in the context of national QOL measurement. PMID- 26973903 TI - Post-Surgical Pain, Physical Activity and Satisfaction with the Decision to Undergo Hernia Surgery: A Prospective Qualitative Investigation. AB - Surgical repair is a common treatment for inguinal hernias but a substantial number of patients experience chronic pain after surgery. As some patients are pain-free on presentation, it is important to investigate whether patients perceive the treatment to be beneficial. The present study used qualitative methods to explore experiences of pain, activity limitations and satisfaction with treatment as people underwent surgery and recovery. Twenty-nine semi structured interviews were conducted. Seven participants were interviewed longitudinally: before surgery and two weeks and four months post-surgery. Ten further participants with residual pain four months post-surgery were interviewed once. Semi-structured interviews included experience and perception of pain; activity limitations; reasons for having surgery; satisfaction with the decision to undergo surgery. A thematic analysis was conducted. Pain did not cause concern when perceived as part of the usual surgery and recovery processes. Activity was limited to avoid damage to the hernia site rather than to avoid pain. None of the participants reported dissatisfaction with the decision to have surgery; reducing the risk of life-threatening complications associated with untreated hernias was considered important. These findings suggest that people regarded surgical treatment as worthwhile, despite chronic post-surgical pain. Further research should ascertain whether patients are aware of the actual risk of complications associated with conservative rather than surgical management of inguinal hernia. PMID- 26973905 TI - Changes in Coping Behavior and the Relationship to Personality, Health Threat Communication and Illness Perceptions from the Diagnosis of Diabetes: A 2-year Prospective Longitudinal Study. AB - Coping behavior is of critical importance in diabetes because of its impact upon self-care and hence eventual medical outcome. We examined how coping behavior and its relationship to personality, diabetes health threat communication (DHTC) and illness representations changes after diagnosis of diabetes. Newly diagnosed diabetic patients were assessed after diagnosis and at 6, 12 and 24 months using the DHTC, Illness Perceptions and Coping inventory questionnaires. Personality traits were assessed at baseline. Active coping, planning, positive reinterpretation and growth (PRG), seeking emotional and instrumental (social) support decreased over the 2 years from diagnosis while passive acceptance increased. Openness/intellect and conscientiousness traits were associated with active coping and seeking instrumental support. Openness/intellect also associated with planning and PRG. These relationships did not vary over time. Perceived threat and serious consequences were associated with active coping but the effect diminished over time. Illness coherence (understanding of diabetes), personal and treatment control were associated with active coping, planning and seeking instrumental support and did not change over time. The coping strategies most commonly employed by diabetic patients are adaptive. Coping behavior changes over the 2 years from diagnosis. Promoting better understanding of diabetes, perceptions of personal control and treatment effectiveness are more likely than perception of health threat to sustain adaptive problem focused coping behavior. PMID- 26973904 TI - The Role of Anxiety in Binge Eating Behavior: A Critical Examination of Theory and Empirical Literature. AB - The purpose of this manuscript is to expand the understanding of binge eating by reviewing the role of aspects of negative affect. Specifically, this paper will present evidence for further investigation of the bearing that anxiety may have in binge eating development and maintenance. A comprehensive review of the literature regarding the relation of binge eating and anxiety was performed. Valuable contributions have been made to the binge eating literature regarding some aspects of negative affect (i.e., depression); however, outside of bulimia nervosa studies, much of the theoretical and empirical binge eating research to date has not directly addressed the role of anxiety. Research supports expansion of investigations of negative emotionality and binge eating to include specific study of anxiety. Greater inclusivity and specificity in the unique contributions of various negative emotions may further the development of temporal models and intervention efforts. PMID- 26973906 TI - An Experience Sampling Study of Physical Activity and Positive Affect: Investigating the Role of Situational Motivation and Perceived Intensity Across Time. AB - The nature of the association between physical activity and positive affect is complex, prompting experts to recommend continued examination of moderating variables. The main purpose of this 2-week field study was to examine the influence of situational motivational regulations from self-determination theory (SDT) on changes in positive affect from pre- to post- to 3-hours post-physical activity. Another purpose was to clarify the relationship between physical activity intensity [i.e., Ratings of Perceived Exertion (RPE)] and positive affect at the stated time points. This study employed an experience sampling design using electronic questionnaires. Sixty-six healthy and active, multiple role women provided recurrent assessments of their physical activity, situational motivation, and positive affect in their everyday lives over a 14-day period. Specifically, measures were obtained at the three time points of interest (i.e., pre-, post-, 3-hours post-physical activity). The data were analyzed using multilevel modeling. Results showed that intrinsic motivation was related to post physical activity positive affect while the influence of identified regulation appeared 3-hours post-physical activity. In addition, RPE, which was significantly predicted by levels of introjection, was more strongly associated with an increase in positive affect post-physical activity than three hours later. The theoretical implications of these findings vis-a vis SDT, namely in regards to a viable motivational sequence predicting the influence of physical activity on affective states, are discussed. The findings regarding the differential influences of RPE and motivational regulations carries applications for facilitating women's well-being. PMID- 26973907 TI - Psychological Barriers and Facilitators of Colorectal Cancer Screening: A French Qualitative Study. AB - The aim of this qualitative study was to explore the psychological barriers to and facilitators of undergoing the Hemoccult-II((r)) colorectal cancer screening test in France. Sixty-nine French people aged 50 to 74 years were divided into seven qualitative focus groups. Three issues were discussed with participants: knowledge and beliefs about colorectal cancer screening; facilitators of colorectal cancer screening by Hemoccult-II((r)) ; barriers to colorectal cancer screening by Hemoccult-II((r)). All the discussions were led by two psychologists and were recorded, transcribed verbatim and analyzed using qualitative data analysis software. Correspondence factor analyses identified three dimensions for each topic. The main psychological facilitators of colorectal cancer screening were: information about colorectal cancer screening, perceived simplicity of using Hemoccult-II((r)) , and perception of risk. Uncertainty about the reliability of Hemoccult-II((r)), health anxiety, and embarrassment emerged as the main barriers to colorectal cancer screening. Cross-sectional analyses identified the differences between the views expressed by women and men. Women appeared more embarrassed about Hemoccult-II((r)) and men seemed to be more worried about colorectal cancer. This preliminary study suggests that psychological factors play an important role in colorectal cancer screening by Hemoccult-II((r)). This finding may help health organizations to conceive better awareness campaigns to promote colorectal cancer screening in order to reduce the related mortality rate by taking into account psychological determinants. PMID- 26973908 TI - Adolescent Sleep Quality Measured During Leisure Activities. AB - A one-week sleep monitoring by logs and actigraphs in preteens during summer camp was conducted. Campers aged 11-16 attended a two-week day camp that focused on the learning about science. Nine campers agreed to monitor their sleep and have their patterns explained (anonymously) to other campers during the expert lecture by the author. The aim of the study was to identify the sleep quality in an adolescent group. All nine of the sleep logs and actigraphs denoted severe sleep deprivation. The findings from the logs and actigraphs denoted sever sleep deprivation. The expert lecturer provided basic information about sleep per the science designation of the day camp. A follow up session provided strategies to address sleep deprivation. PMID- 26973909 TI - Counter-Conditioning as an Intervention to Modify Anti-Fat Attitudes. AB - This study examined the effect of anti-fat attitude counter-conditioning using positive images of obese individuals participants completed implicit and explicit measures of attitudes towards fatness on three occasions: no intervention; following exposure to positive images of obese members of the general public; and to images of obese celebrities. Contrary to expectations, positive images of obese individuals did not result in more positive attitudes towards fatness as expected and, in some cases, indices of these attitudes worsened. Results suggest that attitudes towards obesity and fatness may be somewhat robust and resistant to change, possibly suggesting a central and not peripheral processing route for their formation. PMID- 26973910 TI - The Psychological Effects of Providing Personal Care to a Partner: A Multidimensional Perspective. AB - The expected increasing demand for informal care in aging societies underscores the importance of understanding the psychological implications of caregiving. This study explores the effect of providing regular help with personal care to a partner on different aspects of psychological well-being. We use cross-sectional data from the Norwegian Life Course, Ageing and Generation study (n. ~15,000; age 40-84) and two-wave panel data from the Norwegian study on Life Course, Ageing and Generation (n. ~3000; age 40-84). To separate the effects of providing care from those of the partner's disability, caregivers are contrasted with non caregivers with both disabled and nondisabled partners. We separate outcomes into cognitive well-being (life satisfaction), psychological functioning (self-esteem, mastery), and affective well-being (happiness, depression, loneliness). Findings show that caregiving has important cross-sectional and longitudinal detrimental psychological effects. These effects are fairly consistent across all aspects of well-being, demonstrating that caregiving has a broad-based negative impact. Among women, however, these effects are similar to if not weaker than the effects of a partner's disability. Caregiving effects are constant by age, education, and employment status, but stronger among caregivers with health problems. Providing personal care to a partner is associated with marked adverse psychological effects for men and women irrespective of age and socio-economic status. Hence, no sociodemographic group is immune from caregiving stress, so programs should be targeted generally. The results also suggest that the health needs of caregivers demand more attention. PMID- 26973911 TI - Chronic Kidney Disease, Spirituality and Religiosity: A Systematic Overview with the List of Eligible Studies. AB - Chronic Kidney Disease (CKD) has a tremendous psychological burden, which sometimes is overlooked or underestimated in the daily clinical routine practice, since in the health care process physicians prefer to focus on the objective aspects of the pathology. In this contribution, we make a systematic overview of the relationship between spirituality/religiosity and CKD, an emerging theme which only recently has raised interest from the scientific community despite its importance. We investigate different variables, axis and categories (from the quality of life to customer's satisfaction, treatment adherence and therapeutic alliance, clinical parameters, as well as overall survival, and coping strategies adopted by the patient). Moreover, we underpin the principal clinically relevant implications (like the possibility of psycho-therapeutic interventions based on the spiritual and religious attitudes of the patient) and we discuss the main gaps, methodological barriers and difficulties in the field, fostering and advocating further research and clinical studies. This last aspect, together with the quality assessment of the studies, will be further explored in the second part of the study. PMID- 26973912 TI - Quality of Life in Chronic Disease Patients. AB - During the past decades there was an increasing predominance of chronic disorders, with a large number of people living with chronic diseases that can adversely affect their quality of life. The aim of the present paper is to study quality of life and especially Health-related quality of life (HRQoL) in chronic diseases. HRQOL is a multidimensional construct that consists of at least three broad domains - physical, psychological, and social functioning - that are affected by one's disease and/or treatment. HRQoL is usually measured in chronic conditions and is frequently impaired to a great extent. In addition, factors that are associated with good and poor HRQoL, as well as HRQoL assessment will be discussed. The estimation of the relative impact of chronic diseases on HRQoL is necessary in order to better plan and distribute health care resources aiming at a better HRQoL. ["All the people perceive the concept of living good or being well, that is the same as being happy". (Aristotle. 384-322 BC. Ethica Nichomachea)]. PMID- 26973913 TI - Ten Weeks of Home-Based Exercise Attenuates Symptoms of Chemotherapy-Induced Peripheral Neuropathy in Breast Cancer Patients. AB - The purpose of this investigation was to determine if a structured, home-based exercise program was beneficial to reduce symptoms of chemotherapy-induced peripheral neuropathy and improve quality of life (QOL). A total of 50 women who are breast cancer survivors and are listed in the Breast Cancer Registry of Greater Cincinnati database were recruited by mail. Participants were initially asked to complete the McGill QOL questionnaire and the Leeds Assessment of Neuropathic Symptoms and Signs, before beginning a 10-week home-based exercise program. At the completion of the exercise program, subjects were asked again to complete the same two questionnaires. Pre- and post-intervention data were analyzed using a repeated measures ANOVA, at a significance level of alpha<0.05. Six individuals completed the investigation. Prior to the 10-week exercise program, participants described their pain as unpleasant skin sensations (Pre HBEx, N=6), abnormally sensitive to touch (Pre-HBEx, N=6), and coming on suddenly in bursts for no apparent reason (Pre-HBEx, N=5). Following 10-weeks of exercise, participants reported experiencing less of these symptoms (Post-HBEx, N=3, 1, and 4 respectively; P=0.05). It was also determined that troublesome symptoms were significantly reduced after 10-weeks of home-based exercise (P=0.05). PMID- 26973914 TI - Spirituality and Religion in Pain and Pain Management. AB - Pain relief is a management problem for many patients, their families, and the medical professionals caring for them. Although everyone experiences pain to some degree, responses to it vary from one person to another. Recognizing and specifying someone else's pain is clinically a well know challenge. Research on the biology and neurobiology of pain has given us a relationship between spirituality and pain. There is growing recognition that persistent pain is a complex and multidimensional experience stemming from the interrelations among biological, psychological, social, and spiritual factors. Patients with pain use a number of cognitive and behavioral strategies to cope with their pain, including religious/spiritual factors, such as prayers, and seeking spiritual support to manage their pain. This article provides an overview of the complex phenomenon of pain, with a focus on spiritual and religious issues in pain management. PMID- 26973916 TI - Quality of Life Research: Interview with Professor Robert Cummins. PMID- 26973915 TI - Measuring Pain Self-Efficacy and Health Related Quality of Life Among Hemodialysis Patients in Greece: A Cross-Sectional Study. AB - Patients suffering from end-stage kidney disease often complain about pain. It is also known that the presence of chronic pain greatly impacts upon patients' quality of life (QOL) and can play a crucial role in the co-morbidity of mental health symptoms such as depression and anxiety. The main aim of this study protocol is the investigation of pain self-efficacy, QOL as well as their relation in patients undergoing hemodialysis treatment. The final sample size will be around 70-80 patients. Each subject's QOL and pain self-efficacy will be measured using the following instruments: i) the Missoula- ITAS Quality of Life Index-15 and ii) the Pain Self-Efficacy Questionnaire. QOL is expected to be related to pain self-efficacy scores. This probable association will be indicated performing regression as well as correlation analysis after controlling for gender, age, education and marital status. PMID- 26973918 TI - Pain Clinic Referral to Psychological Services Best Addressed with Collaboration. AB - A case study of a middle aged female with severe musculoskeletal medical conditions causing severe pain is presented. The referral for psychological services was conducted in concordance with the medical treatments. In this case, the complex nature of the severe musculoskeletal medical conditions necessitated intensive care and the collaborative communications provided this to the patient. A tabulation of representative treatments is provided with an explanation of the nature of the collaboration. Outcome data in terms of patient self-reported pain ratings and sleep logging provided evidence of a mild improvement and stability where more negative findings, given the complexity of the medical conditions was expected. PMID- 26973917 TI - Life Satisfaction and Frailty Among Older Adults. AB - Functional and physical impairment are factors believed to lead to declined life satisfaction among older adults. This study aimed to examine life satisfaction among older adults and the influence of frailty. Baseline data from two studies addressing frail older adults aged 80+ in Gothenburg, Sweden, (n=577) were used. Frailty was measured through eight indicators. Life satisfaction was measured with Fugl-Meyer's instrument LiSat-11. Perceived life satisfaction was rather high within the studied population, with 66% being satisfied with life as a whole. Most life satisfaction items were significantly associated with frailty status, with non-frail participants being satisfied to a higher extent for all items with the exception of financial situation, sexual life and partnership relation. The factors significantly explaining life satisfaction were psychological health, partner relationship, leisure and ADL. This study shows that older adults' satisfaction with life as a whole is almost as high as in younger age groups. Respondents with higher degree of frailty reported significantly lower degrees of life satisfaction, indicating a possibility to maintain life satisfaction by preventing or delaying the development of frailty. PMID- 26973921 TI - Profound Associations Between Pain and Quality of Life. PMID- 26973920 TI - Does Pain Acceptance Predict Physical and Psychological Outcomes in Cancer Outpatients with Pain? AB - Pain acceptance has been associated with improved physical and psychosocial well being in chronic non-malignant pain patients. However, its effects are unclear in cancer outpatients with pain. Our aim was to determine whether pain acceptance predicts reduced pain, pain interference with function, anxiety, and depression in cancer outpatients. We recruited 116 outpatients from a tertiary oncology center, with various types of cancer and pain levels. Patients completed the Brief Pain Inventory, the Hospital Anxiety and Depression Scale and the Chronic Pain Acceptance Questionnaire, the latter of which comprises activity engagement and pain willingness. We carried out multiple regression analyses, adjusting for patient characteristics and outcomes. Activity engagement and pain willingness significantly predicted pain interference with function (P=0.033 and P=0.041 respectively). However, only activity engagement predicted anxiety (P=0.001) and depression (P<0.001). These findings support the beneficial role of pain acceptance in patients' functional adaptation to cancer-related pain. Activity engagement in particular, shows promise in fostering psychological well-being. Further studies could confirm its role in reducing anxiety and depression in cancer patients with pain and whether it should be included in cancer pain management interventions. Further studies could confirm its role in reducing anxiety and depression in cancer patients with pain, and whether it should be included in cancer pain management interventions. PMID- 26973919 TI - Values-Based Action in Fibromyalgia: Results From a Randomized Pilot of Acceptance and Commitment Therapy. AB - Fibromyalgia Syndrome (FMS) is a chronic pain condition characterized by pain, fatigue, and nonrestorative sleep. The disruptive symptoms of FMS are associated with reductions in quality of life related to family, intimate relationships, and work. The present study was part of a randomized pilot study of an 8-week Acceptance and Commitment Therapy (ACT) intervention compared to education in a sample of 28 women with FMS. The Chronic Pain Values Inventory was administered at baseline, postintervention, and 12 week follow-up. Both groups showed significant improvements in family success, which were maintained at follow-up. Groups showed a differential pattern of success in work. The ACT group demonstrated significant, maintained improvements in success in intimate relationships, while the education group reported no changes over time. Findings suggest that both interventions may lead to improvements in valued living; however different interventions may be best suited for certain valued domains. The results of this study indicate that FMS patients are able to improve their success in family and intimate relationships and losses in these areas are not necessarily permanent. PMID- 26973922 TI - Improvement of Diabetic Patients Nursing Care by the Development of Educational Programs. AB - Diabetes is a major health problem with many social and economic consequences in general population. The importance of education in the diabetic patient and his family, led to the development of diabetes clinical nurse specialist. The role of diabetes clinical nurse specialist is essential and crucial to the hospitals and the community, in order to form a relationship with the diabetic patient and his/her family. In this way health is promoted to the maximum extent possible. In conclusion educational programs help patients with diabetes to obtain information about their condition and improve their self-care skills. PMID- 26973923 TI - Assessment of Burn-Out and Quality of Life in Nursing Professionals: The Contribution of Perceived Social Support. AB - Burnout has received increased research attention in recent years. The aim of the present study is to examine levels of burnout as well as quality of life (QOL) in nursing staff in Greece. The association of social support with burnout and QOL is also investigated. One-hundred individuals working in Mental and General Hospitals in the broader area of Athens will participate in this study. The measurement tools include i) the Maslach Burnout Inventory, ii) the SF-36 Health Survey and iii) the Multidimensional Scale of Perceived Social Support. Burnout and QOL are expected to be related to the evaluation of social environment. PMID- 26973924 TI - Sober-Living Houses and Changes in the Personal Networks of Individuals in Recovery. AB - Social networks are an important source of support for many people in recovery from alcohol abuse. The present study investigated the role of one particular source of support for recovery in changing the personal networks of people in recovery, sober-living houses. In a randomized, longitudinal design changes in the network size, heterogeneity, and composition of usual aftercare and sober living home residents were examined. Beneficial changes were found, such as increases in the number of recovering alcoholics and overall network size among sober-living home residents, particularly those who stayed six months or longer. Networks also became more homogeneous with respect to non-drinking among residents. The importance of changes in networks is discussed as well as the need for network-level analyses of personal recovery networks. PMID- 26973925 TI - Family Perceptions of Intensive Care Unit Nurses' Roles: A Greek Perspective. AB - This study was done in order to examine the role of the nurse in families with critically ill patients as perceived by family members. A descriptive design was conducted with 93 family members aged 18-53 years from a 6-bed intensive care unit in a Greek Hospital. An anonymous self-completed questionnaire recording demographic data and the questionnaire Family members perception of nurses behavioral role expectation/enactment scale of Hickey and Lewandowski was used. Parametric statistic tests were used to examine the research questions. Intensive care unit (ICU) patients' family members expect nurses to make them feel they can ask whatever they want whenever they want, placing great emphasis on communicating with one another and on participating in decision making to the progress of patient care. The age seems to correlate with the expectation from nurse to meet the role of training on how to handle the patient. Nurses did well with regard to meeting family members' expectations. Most family members assessed positively the role of ICU nurse confirming the need for communication, and clear support of families. PMID- 26973927 TI - Do Health-Related Feared Possible Selves Motivate Healthy Eating? AB - The question of what motivates individuals to assume healthy eating habits remains unanswered. The purpose of this descriptive survey is to explore health related feared possible selves in relation to dietary beliefs and behavior in adults. A convenience sample of 74 middle-aged employees of a health maintenance organization completed self-administered questionnaires. Health-related feared selves, current health perception, knowledge of diet-health association, dietary self-efficacy, dietary intention and intake were measured. Health-related fears were the most frequently reported feared selves, but very few of those represented illnesses and none were related to dietary intake. The number of health and body weight related fears was significantly associated with lower dietary self-efficacy and weaker intention to eat in a healthy manner. Multivariate analysis showed self-efficacy to be the only significant predictor of dietary intention. These adults may not have perceived being at risk for diet associated illnesses, and so their feared selves did not motivate them to eat in a healthy manner. Research on the effect of hoped for health related possible selves and the perceived effectiveness of diet in reducing health risk are recommended. PMID- 26973926 TI - Testing a Longitudinal Integrated Self-Efficacy and Self-Determination Theory Model for Physical Activity Post-Cardiac Rehabilitation. AB - Self-determination theory and self-efficacy theory are prominent theories in the physical activity literature, and studies have begun integrating their concepts. Sweet, Fortier, Strachan and Blanchard (2012) have integrated these two theories in a cross-sectional study. Therefore, this study sought to test a longitudinal integrated model to predict physical activity at the end of a 4-month cardiac rehabilitation program based on theory, research and Sweet et al.'s cross sectional model. Participants from two cardiac rehabilitation programs (N=109) answered validated self-report questionnaires at baseline, two and four months. Data were analyzed using Amos to assess the path analysis and model fit. Prior to integration, perceived competence and self-efficacy were combined, and labeled as confidence. After controlling for 2-month physical activity and cardiac rehabilitation site, no motivational variables significantly predicted residual change in 4-month physical activity. Although confidence at two months did not predict residual change in 4-month physical activity, it had a strong positive relationship with 2-month physical activity (beta=0.30, P<0.001). The overall model retained good fit indices. In conclusion, results diverged from theoretical predictions of physical activity, but self-determination and self-efficacy theory were still partially supported. Because the model had good fit, this study demonstrated that theoretical integration is feasible. PMID- 26973929 TI - A Thematic Study of the Role of Social Support in the Body Image of Burn Survivors. AB - There is evidence that social support is important for the development and maintenance of body image satisfaction for people who have sustained burn injuries. This qualitative study explored the specific mechanisms by which social support impacts the body image satisfaction of burn survivors, drawing on nine participants' in depth accounts. Participants were recruited through a burns unit at a public hospital in South Australia. Interviews were conducted with nine female burn survivors aged between 24 and 65 (mean age 44.6). Participants described their perceptions about their appearance post burn and their social support experiences. Four themes were identified: acceptance, social comparison, talking about appearance concerns, and the gaze of others. Results indicate that for these participants, social support was an important factor in coming to terms with changes in appearance, specifically support that helps to minimise feelings of difference. Unhelpful aspects of social support were also identified included feeling that suffering was being dismissed and resenting the perceived expectation from supports to be positive. Social supports are important to consider in relation to body image for those working with people who have survived burn injuries. PMID- 26973928 TI - The Role of Psychosocial and Belief Factors in Self-Reported Cigarette Smoking Among University Students in Malaysia. AB - This study aimed to explore factors associated, specifically belief factors, with self-reported tobacco smoking status. A sample of 300 students was recruited from a private university in Malaysia. Data was collected using a pre-tested self administrated questionnaire that investigated various factors including socio demographics, socio-economic status, smoking behavior and beliefs on tobacco smoking. The main tobacco use in this study sample was cigarettes and the estimated prevalence of self-reported cigarette smoking was 10.3%. In bivariate analysis, self-reported cigarette smoking was significantly associated with socio demographic, behavioral factors and faculty of study (P<0.05). In multivariate modeling, being male and a non-medical student, did not exercise, having a smoker father and brother or sister, suffering from financial difficulties and having the belief that smokers had more friends, all had statistically significant associations (P<0.05) with self-reported cigarette smoking. Social and interpersonal factors were associated with self-reported cigarette smoking status. A comprehensive health model focusing on changing the social norms of parent and sibling tobacco smoking and students' beliefs, alongside nurturing skills of dealing with stressful situations, warrant implementation. PMID- 26973930 TI - Improving Maintenance Medication Adherence in Adult Inflammatory Bowel Disease Patients: A Pilot Study. AB - Medication nonadherence in inflammatory bowel disease (IBD) may lead to suboptimal control of the disease, decreased quality of life, and poor outcomes. This pilot study evaluated the feasibility, intervention mechanism, and potential effectiveness of a three-month continuous self-improvement (CSI) intervention to enhance medication adherence (MA) in adult nonadherent IBD patients. Adult IBD patients taking a daily or twice-daily dosed maintenance medication were screened electronically for two months to determine baseline MA levels. Nonadherent IBD participants were randomized to the CSI or the attention control (AC) intervention and monitored for three months. The CSI intervention consisted of a data evaluation and system refinement process in which system changes were identified and implemented. The AC group was given educational information regarding IBD disease process, extra-intestinal manifestations of IBD, and medical therapy. Demographic statistics, change scores for within and between group differences, and effect size estimates were calculated. Nine nonadherent participants (medication adherence score <0.85) were eligible for randomization. The intervention was found feasible and acceptable. Although no statistically significant improvement in MA was found (P=0.14), adherence improved in 3 of 4 of the CSI group and 1 of 2 in the attention control group. The effect size calculation of 1.9 will determine the sample size for future study. The results of this pilot study showed the intervention was feasible and had a positive effect on MA change score and adherence levels. A larger fully powered study is needed to test of the effectiveness of this innovative intervention. PMID- 26973931 TI - Examining Factors Associated with Heavy Episodic Drinking Among College Undergraduates. AB - Heavy episodic drinking among college students is a serious health concern. The purpose of this study was to identify factors associated with heavy episodic drinking behaviors amongst a predominately Asian undergraduate college student population in the United States. A survey measuring alcohol use behaviors was completed by a random sample of 18-24 year old undergraduates during April, 2011. A multivariate logistic regression analysis was conducted to determine factors associated with students' heavy episodic drinking behavior. Independent factors associated with heavy episodic drinking included living on campus, ethnicity, perceived drinking behavior among peers, and a belief that alcohol is a central part of one's social life. Heavy episodic drinking was also associated with poor academic performance. Campus-wide educational strategies to reduce heavy episodic drinking among college undergraduates should incorporate accurate information regarding alcohol use norms to correct students' perceived over estimation of their peers alcohol consumption rates and the under estimation of students protective alcohol use behaviors. These efforts should focus in on-campus residence halls where a higher occurrence of heavy episodic drinking is often found. PMID- 26973932 TI - Banding Together: An Investigation of Post-Surgery Support Groups for Laparoscopic Adjustable Gastric Banding Patients. AB - Though advocated as useful for patients, there is little in the literature regarding the use and effectiveness of bariatric support groups. This study investigated characteristics and experiences of bariatric patients who did and did not attend offered groups. Seventy-eight postoperative laparoscopic adjustable gastric banding patients from a private bariatric clinic completed mailed self-report questionnaires. Almost 60% reported having attended the clinic groups, with most wanting to meet other patients and obtain information rather than access psychological assistance. Participants reported generally positive experiences of attending. Nonattendance was often attributed to practical barriers. Satisfaction with support from others was not related to past or predicted future attendance, but higher psychological distress was related to and predictive of greater intention to attend future groups. Likely future attenders also held more positive beliefs about the groups than those who were unlikely to attend. Further research is required into potential positive and negative consequences of attendance, and characteristics of those who are likely to benefit or be harmed by attending. Interventions addressing stereotypes about support groups may help patients make informed decisions about whether to attend a bariatric support group. PMID- 26973933 TI - The Impact of Foreign Postings on Accompanying Military Spouses: An Ethnographic Study. AB - As part of an ethnographic study, the impact of foreign postings on spouses who accompany military personnel was explored. Individual interviews and focus groups with 34 British military spouses based in one location in southern Europe were conducted. Key findings suggested that reaction to a foreign posting was a reflection of personal attitudes, prior experiences, support, ability to adjust to change and strength of relationship with the serving spouse and community. For many the experience was positive due to the increased opportunity for family time, for others this helped to compensate for the difficulties experienced. Some military spouses experienced significant distress on the posting, particularly if the family was not well-supported. The potential implications of military spouses not adapting to foreign postings have significant implications for healthcare practice. Provision of more appropriate support resources before and during the posting would facilitate the transition for the military spouse and their family. PMID- 26973934 TI - Smoke and Mirrors: The Perceived Benefits of Continued Tobacco use Among Current Smokers. AB - Despite 50+ years of public health efforts to reduce smoking rates in the United States, approximately one-fifth of the adults living in this country continue to smoke cigarettes. Previous studies have examined smokers' risk perceptions of cigarette smoking, as well as the perceived benefits of quitting smoking. Less research has focused on the perceived benefits of smoking among current cigarette smokers. The latter is the main focus of the present paper. Questionnaire-based interviews were conducted with a community-based sample of 485 adult current cigarette smokers recruited from the Atlanta, Georgia, metropolitan area between 2004 and 2007. Active and passive recruiting approaches were used, along with a targeted sampling strategy. Results revealed that most current cigarette smokers perceive themselves to experience benefits as a result of their cigarette use, including (among others) increased relaxation, diminished nervousness in social situations, enjoyment of the taste of cigarettes when smoking, and greater enjoyment of parties when smoking. Perceiving benefits from cigarette smoking was associated with a variety of tobacco use measures, such as smoking more cigarettes, an increased likelihood of chain smoking, and overall negative attitude toward quitting smoking, among others. Several factors were associated with the extent to which smokers perceived themselves to benefit from their tobacco use, including education attainment, the age of first purchasing cigarettes, the proportion of friends who smoked, hiding smoking from others, being internally-oriented regarding locus of control, and self-esteem. PMID- 26973935 TI - Factors Identified with Higher Levels of Career Satisfaction of Physicians in Andalusia, Spain. AB - The satisfaction of physicians is a worldwide issue linked with the quality of health services; their satisfaction needs to be studied from a multi-dimensional perspective, considering lower- and higher-order needs. The objectives of this study were to: i) measure the career satisfaction of physicians; ii) identify differences in the dimensions of career satisfaction; and iii) test factors that affect higher- and lower-order needs of satisfaction among physicians working in Andalusian hospitals (Spain). Forty-one percent of 299 eligible physicians participated in a study conducted in six selected hospitals. Physicians reported higher professional, inherent, and performance satisfaction than personal satisfaction. Foreign physicians reported higher levels of personal and performance satisfaction than local physicians, and those who received non monetary incentives had higher professional and performance satisfaction. In conclusion, physicians in the selected Andalusian hospitals reported low levels of personal satisfaction. Non-monetary incentives were more relevant to influence their career satisfaction. Further investigations are recommended to study differences in the career satisfaction between foreign and local physicians. PMID- 26973936 TI - The Effect of Sexual Experience on the Social Representation of Sex in Portuguese Young Adults. AB - This study aimed to observe the effect of sexual experience on the social representation of sex in Portuguese young adults. According to social representation theory, the central core of the social representation should be the same in all individuals that share a common social ground, however differences should be found in the peripheral system. It was used a free evocation task to assess the social representation of sex in Portuguese individuals aging between 18 and 25 years old. Nine hundred and sixty individuals were grouped by their sexual experience and condom use habits. A prototypical analysis was conducted to assess the structure of the social representation and statistical differences were analyzed using the qui-square independency test to search for an association between the structure and the group evoking it. The results supported the hypothesis of a common central core for all groups that shows a romanticized vision of sex. The differences found in the peripheral system suggest that sexual experience affects the representation of sex in a way that seems clearer to these individuals the necessity of protection when it comes to sex. PMID- 26973937 TI - Post-Traumatic Stress Symptoms in Pediatric Heart Transplant Recipients. AB - Traumatic experiences are not unusual in pediatric heart transplant (HT) recipients before and after transplantation. Post-traumatic stress symptoms (PTSS) present at the time of transplant evaluation and developing afterward occur with an unknown frequency. We sought to determine the burden of these symptoms in heart transplant patients. We reviewed 51 consecutive HTs between 2003-2007, including 40 primary transplants and 11 re-transplants. Symptoms were present in 17 of the 51 patients (34%) at the time of orthotopic heart transplantation evaluation. None met the criteria for full post traumatic stress disorder. Transplant complications were examined. Nineteen subjects of the total sample had rejection in the first year following transplant. Rejection rates in the first year was 41% for those with PTSS (7 of 17 patients) and 36% for those without (12 of 33 patients) (P=n.s). Of those patients presenting for a second heart transplant, 55% had PTSS at the time of transplant evaluation and/or the peritransplant period; whereas, (28%) undergoing a primary transplant had PTSS. In addition to symptoms resulting from the disease process leading to HT and other prior experiences, the HT itself seems to present a large psychiatric burden on patients. All patients need to be followed before and after HT for signs and symptoms related to PTSS. Future studies should be undertaken to determine if preventative detection and treatment of patients with these PTSS symptoms early can lead to better outcomes. PMID- 26973938 TI - Childhood Environment as a Predictor of Perceived Health Status in Late Life. AB - Prior studies have shown that perceived health status is a consistent and reliable predictor of morbidity and mortality. Because perceived health status and objective health are not highly correlated, we sought to identify additional factors that shape self-perceptions of health. Research suggests that childhood experience is an important predictor of health in adulthood, but most studies are retrospective. Using data from a 70-year prospective study of psychosocial development, we examined the quality of childhood environment as a predictor of perceived health in late life. This study utilizes questionnaire data from a longitudinal study of adult development to examine predictors of perceived health across seven decades. Participants were members of the Study of Adult Development, a longitudinal study of men followed for seven decades beginning in late adolescence. Childhood environment characteristics were assessed during home visits and interviews with respondents' parents at entry into the study. At ages 63, 73, and 78, current health status was measured by an internist not affiliated with the Study, and perceived health was assessed via self-report questionnaires. Linear regression analyses were conducted to examine childhood environment as a predictor of perceived health status at these 3 time points while controlling for concurrent objective health and young adult neuroticism. Childhood environment predicted perceived health at all 3 time points. This study supports the hypothesis that the quality of childhood environment makes a unique contribution above and beyond personality traits and objective health status to perceptions of health in late life. PMID- 26973940 TI - Commentary On: Self-Care Self-Efficacy, Religious Participation and Depression as Predictors of Post-Stroke Self-Care Among Underserved Ethnic Minorities. PMID- 26973941 TI - How Older Persons Structure Information in the Decision to Seek Medical Care. AB - Typical models of the decision to seek care consider information as a single conceptual object. This paper presents an alternative that allows multiple objects. For older persons seeking care, results support this alternative. Older decision-makers that segregate information into multiple conceptual objects assessed separately are characterized by socio-demographic (younger age, racial category, non-Hispanic, higher education, higher income, and not married), health status (better general health for men and worse general health for women, fewer known illnesses), and neuropsychological (less memory loss for men, trouble concentrating and trouble making decisions for men) factors. Results of this study support the conclusion that older persons are more likely to integrate information, and individuals with identifiable characteristics are more likely to do so than others. The theory tested in this study implies a potential explanation for misutilization of care (either over or under-utilization). PMID- 26973939 TI - Childhood Overweight Dependence on Mother-Child Relationship. AB - The causes of childhood overweight are numerous and inter-related. The mother child relationship is of great significance for the child's health. Previous studies have found patterns of dysfunctional interaction in families with obese children. Therefore, development of childhood overweight could be due to the mother-child relationship. The aim of this study was to investigate how, and to what degree, the mother-child relationship, assessed by the mothers, was related to overweight among children aged seven to nine years. The study was a cross sectional case-controlled one. It included 111 overweight and 149 non-overweight seven to nine year old children and their mothers. Weight status was determined according to the International Obesity Task Force reference for children Body Mass Index, age and gender adjusted. An interviewer-administered questionnaire was used to categorize the mother-child relationship as: complementary, asymmetrical, symmetrical or symbiotic prototypes. There was no difference in mother-child relationships - characterized by the prototypes - between the overweight and non-overweight mother-child pairs. Therefore, we conclude that the mother-child relationship has no bearing on the child's weight status according to the prototypes. It is suggested that it is more the culture, or the universal phenomenon of expressing love through food, than the mother-child relationship, which influences the development of childhood overweight, or that the mothers are not capable of assess the true attachment style between themselves and their children. PMID- 26973942 TI - Investigating Aggressive Styles and Defense Mechanisms in Bipolar Patients and in their Parents. AB - Bipolar disorder (BD) is a very common mental health disorder, whose etiology concerning aggressive styles and defense mechanisms is still poorly known despite the efforts dedicated to develop psychological and biological theories. After obtaining written signed informed consent, this study will recruit inpatients with a clinical diagnosis of BD, based on Structured Clinical Interview and the Diagnostic and Statistical Manual of Mental Disorders criteria, and their parents. The Bus-Perry Aggression Questionnaire, the Defense Style Questionnaire 40, the Symptom check list SCL-90-R, developed by DeRogatis will be administered to the participants, together with a semi-structured questionnaire concerning demographic data (age, gender, employment, education) and only for the patients clinical information (onset year of the disorder, presence of co-morbidities, alcohol and drug use, suicide tendencies, kind of treatment). All the questionnaires are in the Italian validated version. The successful completion of this study will shed light on the relationship between aggressive styles and defensive mechanisms in bipolar inpatients and in their parents, helping the clinicians to develop ad hoc psychological interventions. PMID- 26973943 TI - Investigation of Nausea and Vomiting in Cancer Patients Undergoing Chemotherapy. AB - Nausea and vomiting are the most important problems in patients undergoing chemotherapy, despite the recent improvements in the administration of antiemetic drugs. Through a review of the literature, we found that there are several nursing researches focusing on the effectiveness of interventions for the treatment of nausea and vomiting in cancer patients. The purpose of this study was to investigate the symptom of nausea and vomiting in patients undergoing chemotherapy. The study also investigated the impact of nausea and vomiting on patients' ability to respond to daily activities. The study is descriptive; the sample included patients with different types of cancer and receiving chemotherapy. The inclusion criteria were: the histological diagnosis of cancer, the administration of chemotherapy and the knowledge of the Greek language. The questionnaires used were: the MASCC (vomiting questionnaire), the Memorial Symptom Assessment Scale and the scale of functional assessment of cancer therapy. Data collection took place in oncological hospitals of Thessaloniki and Athens in Greece. For statistical analysis we used the statistical package SPSS 15.0. PMID- 26973944 TI - Single Case Designs in Psychology Practice. AB - A brief overview highlighting key elements of single case design is presented. Four types of single case design are identified. Central elements and the value of the use of single case designs are underscored. PMID- 26973945 TI - Generationing, Stealthing, and Gift Giving: The Intentional Transmission of HIV by HIV-Positive Men to their HIV-Negative Sex Partners. AB - Gift giving is the process by which an HIV-positive person purposely infects an HIV-negative person with HIV, usually with that person's knowledge and consent. Little has been written about this HIV transmission practice. In this paper, two specific types of gift giving - generationing and stealthing - are explained and introduced to the scientific literature. Generationing is a type of gift giving in which one gift giver successfully infects a previously-uninfected man with HIV, and then the two men collaborate in an effort to seroconvert another man, and so forth. Stealthing is another type of gift giving in which an HIV-positive man actively tries to infect an HIV-negative man with HIV, without the latter's knowledge or consent. The present study reports on the prevalence of gift giving (4.6%) in a population of men who use the Internet specifically to identify partners for unprotected sex. The research is based on a national random sample of 332 men who have sex with men, identified from 16 websites. Data were collected via telephone interviews conducted between January 2008 and May 2009. The paper concludes with a discussion of the implications of these findings for HIV prevention and intervention efforts. Most notably, to the extent that generationing, stealthing, and gift giving occur among MSM, they represent a very high risk of HIV transmission. More work needs to be done to understand these behaviors, the factors that underlie them, and to determine how prevalent they are in the bare-backing population of MSM. PMID- 26973946 TI - A Cognitive-Behavior Therapy Applied to a Social Anxiety Disorder and a Specific Phobia, Case Study. AB - George, a 23-year-old Greek student, was referred by a psychiatrist for treatment to a University Counseling Centre in Athens. He was diagnosed with social anxiety disorder and specific phobia situational type. He was complaining of panic attacks and severe symptoms of anxiety. These symptoms were triggered when in certain social situations and also when travelling by plane, driving a car and visiting tall buildings or high places. His symptoms lead him to avoid finding himself in such situations, to the point that it had affected his daily life. George was diagnosed with social anxiety disorder and with specific phobia, situational type (in this case acrophobia) and was given 20 individual sessions of cognitivebehavior therapy. Following therapy, and follow-up occurring one month post treatment, George no longer met the criteria for social phobia and symptoms leading to acrophobia were reduced. He demonstrated improvements in many areas including driving a car in and out of Athens and visiting tall buildings. PMID- 26973947 TI - Accuracy of Physical Self-Description Among Chronic Exercisers and Non Exercisers. AB - This study addressed the role of chronic exercise to enhance physical self description as measured by self-estimated percent body fat. Accuracy of physical self-description was determined in normal-weight, regularly exercising and non exercising males with similar body mass index (BMI)'s and females with similar BMI's (n=42 males and 45 females of which 23 males and 23 females met criteria to be considered chronic exercisers). Statistical analyses were conducted to determine the degree of agreement between self-estimated percent body fat and actual laboratory measurements (hydrostatic weighing). Three statistical techniques were employed: Pearson correlation coefficients, Bland and Altman plots, and regression analysis. Agreement between measured and self-estimated percent body fat was superior for males and females who exercised chronically, compared to non-exercisers. The clinical implications are as follows. Satisfaction with one's body can be influenced by several factors, including self perceived body composition. Dissatisfaction can contribute to maladaptive and destructive weight management behaviors. The present study suggests that regular exercise provides a basis for more positive weight management behaviors by enhancing the accuracy of self-assessed body composition. PMID- 26973948 TI - Domestic Violence and Abuse in Intimate Relationship from Public Health Perspective. AB - In this article we pay attention to the violence which, due to the fear of social stigma, could be hidden from the public eye for a long time but could have serious health consequences for the individual, family, and society - physical and psychological forms of domestic violence and abuse in male-female intimate relationship. Besides its nature and extent data in general population, we review also the surveys data about its theoretical basis, its risk factors and possible effects on mental and physical health, not only on in conflicts involved partners, but also on family as a whole, and especially on the children that growing up in such a problematic domestic circumstances. PMID- 26973949 TI - Impact on Participation and Autonomy: Test of Validity and Reliability for Older Persons. AB - In research and healthcare it is important to measure older persons' self determination in order to improve their possibilities to decide for themselves in daily life. The questionnaire Impact on Participation and Autonomy (IPA) assesses self-determination, but is not constructed for older persons. The aim of this study was to examine the validity and reliability of the IPA-S questionnaire for persons aged 70 years and older. The study was performed in two steps; first a validity test of the Swedish version of the questionnaire, IPA-S, followed by a reliability test-retest of an adjusted version. The validity was tested with focus groups and individual interviews on persons aged 77-88 years, and the reliability on persons aged 70-99 years. The validity test result showed that IPA S is valid for older persons but it was too extensive and the phrasing of the items needed adjustments. The reliability test-retest on the adjusted questionnaire, IPA- Older persons (IPA-O), showed that 15 of 22 items had high agreement. IPA-O can be used to measure older persons' self-determination in their care and rehabilitation. PMID- 26973950 TI - The Functional Role of Resignation Orientation on Goal Engagement, Self-Esteem, Life Satisfaction, and Depression. AB - Several studies in Europe and North America have highlighted the importance of resignation or giving up. Research has shown that resignation is as important as goal attainment. Hence, this study examines, using path analysis, the effect of resignation orientation on goal disengagement and reengagement. Furthermore, this study attempts to clarify the implication of resignation orientation for elements of mental well-being. Questionnaires were completed by 261 Japanese college students. Results showed that proactive resignation orientation promotes reestablishment of alternative goals while negative resignation orientation encourages disengagement of the unattainable goals. The findings help explain the functional role of resignation orientation and can inform the development of treatment for resignation-related depression. PMID- 26973951 TI - Exploring the Role of Self-Esteem and Parenting Patterns on Alcohol Use and Abuse Among Adolescents. AB - The type of parental child-rearing practices used by parents and guardians substantially influence children's self-esteem and consequently their decision to engage in alcohol use, its abuse. The aim of this study was to explore the role of self-esteem and parenting patterns on alcohol use and abuse among adolescents. Three hundred and sixteen boys and girls in Senior High Schools completed self report questionnaires assessing self-esteem, parenting patterns and alcohol use and abuse. The results showed that while girls reported lesser self-esteem than boys, boys reported higher levels of alcohol use and abuse than girls. Also, authoritative parenting pattern had a positive effect on self-esteem and a negative effect on alcohol use. On the other hand, authoritarian and permissive parenting patterns had negative effects on self-esteem and positive effects on alcohol use, with slight variations. These results provide valuable information regarding strategies aimed at fostering parent-child relationship and rapport with the ultimate aim of bolstering the self-esteem of adolescents to subsequently eschew insalubrious behaviour, particularly alcohol use and abuse. PMID- 26973952 TI - Depressive Symptoms Among Adolescent Students in Greek High Schools. AB - Depressive symptoms in adolescence have been a subject of considerable controversy in terms of their nature, severity and identification. Therefore, the objective of this study was to examine the presence of depressive symptoms in Greek adolescent high school students and to explore the relationship between depressive symptoms and sociodemographic characteristics. For that purpose, a cross-sectional study design was conducted in two public schools in Megalopolis, Greece, from April 2012 to July 2012, using a self-administered questionnaire based on DSM-IV. The target population involved 222 high school students and the response rate was 74.75%. Data was analyzed using trend chi(2) test, student's t test and bivariate analysis. The analysis of survey data was conducted using the SPSS (19.0). Main findings demonstrate that 3.6% had symptoms of major depressive episode. Furthermore, depressive symptoms were significantly higher in girls, while statistically significant relationships were found between students' physical (P<0.01) and mental health (P<0.008), students' experiences in school (P<0.02), students' experiences with friends (P<0.008) and the frequency of depressive symptoms. Overall, the study results reveal that depressive symptoms can occur in adolescents. Early diagnosis, as well as the need for psychological care at adolescence is necessary for the prevention of major depressive disorders. PMID- 26973953 TI - The Impact of Kt/V Urea-Based Dialysis Adequacy on Quality of Life and Adherence in Haemodialysis Patients: A Cross-Sectional Study in Greece. AB - There is clear evidence of a link between dialysis adequacy (as measured by urea kinetic modeling or urea reduction ratio) and such important clinical outcomes as morbidity and mortality. Evidence regarding the relationship between dialysis adequacy and quality of life (QOL) outcomes as well as adherence is less clear. The present paper is a study protocol which is planning to answer the following research question: what is the impact of dialysis adequacy on QOL and adherence in a sample of hemodialysis patients? The final sample size will be around 100 patients undergoing hemodialysis. Each subject's QOL and adherence will be measured using the following instruments: i) the Missoula-VITAS quality of life index 25; ii) the multidimensional scale of perceived social support and iii) the simplified medication adherence questionnaire. Dialysis adequacy is expected to be related to QOL and adherence scores. PMID- 26973954 TI - Translation and Cultural Adaptation of the Multidimensional Scale of Perceived Social Support for Greece. AB - Recently, there is a surge of interest in the use of the Multidimensional Scale of Perceived Social Support (MSPSS) to measure perceived social support across cultures. The objective of this study was to translate and make the cultural adaptation of the Greek version of the MSPSS. The study counted with a sample of 10 patients diagnosed with multiple sclerosis. The process involved the following steps of translation back translation and semantic evaluation. The former revealed good acceptance of the translated version of the instrument, which participants considered having items of easy understanding. After completing the process of validation in the country, the instrument will become available to Greek researchers to measure social support, as well as to compare results from Greece to that of other cultures in which the instrument has already been validated. PMID- 26973956 TI - Interview with Dr. Nicola Luigi Bragazzi. PMID- 26973955 TI - Perception of Pain Self-efficacy and Fatigue in Greek Patients with Multiple Sclerosis: A Study Protocol. AB - The examination of the perception of pain and fatigue in patients with various health problems has received increased research attention in recent years. The aim of the present study protocol is to examine levels of pain self-efficacy and fatigue in a sample of Greek patients suffering from multiple sclerosis. The association of years and severity of diagnosis with the perception of pain self efficacy and fatigue will be also investigated. Forty patients from the 3(nd) Neurological Department, Aristotle University of Thessaloniki (Greece) will participate in this study. The measurement tools include i) the Fatigue Assessment Scale, ii) the Pain Self Efficacy Questionnaire and iii) the Expanded Disability Status Scale. Test-retest reliability of the first two questionnaires will be assessed with the same patients rating their situation in a 10 days interval from the first examination in order to examine consistency over time. PMID- 26973958 TI - The Impact of Healthcare Workers Job Environment on Their Mental-emotional Health. Coping Strategies: The Case of a Local General Hospital. AB - Workplace stress can influence healthcare professionals' physical and emotional well-being by curbing their efficiency and having a negative impact on their overall quality of life. The aim of the present study was to investigate the impact that work environment in a local public general hospital can have on the health workers' mental-emotional health and find strategies in order to cope with negative consequences. The study took place from July 2010 to October 2010. Our sample consisted of 200 healthcare professionals aged 21-58 years working in a 240-bed general hospital and the response rate was 91.36%). Our research protocol was first approved by the hospital's review board. A standardized questionnaire that investigates strategies for coping with stressful conditions was used. A standardized questionnaire was used in the present study Coping Strategies for Stressful Events, evaluating the strategies that persons employ in order to overcome a stressful situation or event. The questionnaire was first tested for validity and reliability which were found satisfactory (Cronbach's alpha=0.862). Strict anonymity of the participants was guaranteed. The SPSS 16.0 software was used for the statistical analysis. Regression analysis showed that health professionals' emotional health can be influenced by strategies for dealing with stressful events, since positive re-assessment, quitting and seeking social support are predisposing factors regarding the three first quality of life factors of the World Health Organization Quality of Life - BREF. More specifically, for the physical health factor, positive re-assessment (t=3.370, P=0.001) and quitting (t=-2.564, P=0.011) are predisposing factors. For the 'mental health and spirituality' regression model, positive re-assessment (t=5.528, P=0.000) and seeking social support (t=-1.991, P=0.048) are also predisposing factors, while regarding social relationships positive re-assessment (t=4.289, P=0.000) is a predisposing factor. According to our findings, there was a notable lack of workplace stress management strategies, which the participants usually perceive as a lack of interest on behalf of the management regarding their emotional state. Some significant factors for lowering workplace stress were found to be the need to encourage and morally reward the staff and also to provide them with opportunities for further or continuous education. PMID- 26973957 TI - Pharmacological and Non-pharmacological Treatment Options for Depression and Depressive Symptoms in Hemodialysis Patients. AB - Depression is a mental disorder with a high prevalence among patients with end stage renal disease (ESRD). It is reported that depression afflicts approximately 20-30% of this patient population, being associated, amongst other, with high mortality rate, low adherence to medication and low perceived quality of life. There is a variety of medications known to be effective for the treatment of depression but due to poor adherence to treatment as well as due to the high need for medications addressing other ESRD comorbidities, depression often remains untreated. According to the literature, depression is under-diagnosed and undertreated in the majority of the patients with chronic kidney disease. In the current review the main pharmacological and non-pharmacological approaches and research outcomes for the management of depressive symptoms in hemodialysis patients are discussed. PMID- 26973959 TI - Heritability of Health and Aging Limitations on Personally Desired Activities. AB - The aim of this study is to estimate heritability of incident limitations on personally desired activities within the eighth decade of life. We measured self rated ability to perform ten personally desired activities in 1606 male veteran twin pairs at baseline and four years later. At follow-up, 33% of the cohort reported more limitations in desired activities. Among twins who completed both assessments, there were no statistically significant differences in incidence rates of limitations as a function of zygosity. Sensitivity tests showed the same for change scores; and that, if cognitive impairment or death are deemed to belong among limitations of desired activities, zygosity contributed 10% to new limitations at follow-up. Maintaining personally desired activities over four years in the eighth decade is not subject to substantial genetic influence. However, if death and cognitive impairment are added to incident limitations, then genetics plays a modest role. In all cases, unique environment is the predominant influence. PMID- 26973961 TI - Investigation of Anxiety and Depression in Patients with Chronic Diseases. AB - The health of an individual depends on both his/her physical and psychological condition. In recent years it has been observed that chronic patients have frequently an affected psycho-emotional state. The purpose of this study is to investigate anxiety and depression in patients with chronic diseases and the correlation of the results with daily physical activity levels and individual health levels, as well comorbidity. This study included patients with chronic diseases that were treated in a local general hospital or were visiting often outpatient clinics of the same hospital due to their condition. The sample in this particular study included 204 patients; 118 of them were women and 86 men. From the total sample that participated in our research, 118 (57.8%) were females and the majority of the participants were secondary/basic education graduates (67%), married (71%), living in urban areas (53%). Hypertension was the most frequent chronic disease in our sample, followed by hypercholesterolemia and diabetes mellitus. Comparing the occurrence of depression and anxiety symptoms in both questionnaires in relation to the expected frequency in the general population, significant levels of depression and anxiety symptoms were recorded. Taking into consideration the findings of this research, anxiety and depression symptoms can have profound effects regarding the control of chronic diseases, the patients' quality of life and their general health. PMID- 26973963 TI - A Study to Examine the Uses of Personal Strength in Relation to Mental Health Recovery in Adults with Serious Mental Illnesses: A Research Protocol. AB - This study will explore the relationships among strengths self-efficacy, resourcefulness, stigma experience and mental health recovery in community dwelling adults with serious mental illnesses. Mental health practices have focued on psychopathphysiology. Stigma heavily plagued clients with mental illnesses and is one of the greatest barriers to mental health recovery. Personal strengths like strengths self-efficacy, people's confidence in using their personal strengths, and resourcefulness, the ability to carry out daily activities, have been linked to positive mental health. However, the linkage between strengths self-efficacy, resourcefulness and mental health recovery remains uncharted. A cross-sectional, descriptive, mixed methods study will be conducted. A funded study by the Sigma Theta Tau, Upsilon Eta Chapter, August 2013, involving a convenience sample of 100 participants is planned. Included are community dwelling adults between 21 to 65 years old having been diagnosed with serious mental illnesses. Clients with current co-occurring substance abuse will be excluded. Participants complete questionnaires and undergo an interview. Correlations among the study variables will be examined. Regression analysis will determine if recovery can be predicted by strengths self-efficacy, resourcefulness and stigma experience. Interview data will be transcribed and analyzed by thematic analysis. This study will look beyond clients' disability to focus on their recovery and healing capacities such as strengths self-efficacy and resourcefulness. Findings will expand our knowledge about mental health recovery. Knowledge gained from this study may pave the way for future nursing strategies to aid recovery and inform the development of positive, strengths based interventions. PMID- 26973962 TI - Psychometric Properties of the International Personality Item Pool Big-Five Personality Questionnaire for the Greek population. AB - Goldberg's International Personality Item Pool (IPIP) big-five personality factor markers currently lack validating evidence. The structure of the 50-item IPIP was examined in two different adult samples (total N=811), in each case justifying a 5-factor solution, with only minor discrepancies. Age differences were comparable to previous findings using other inventories. One sample (N=193) also completed additionally another personality measure (the TIPI Short Form). Conscientiousness, extraversion and emotional stability/neuroticism scales of the IPIP were highly correlated with those of the TIPI (r=0.62 to 0.65, P=0.01). Agreeableness and Intellect/Openness scales correlated less strongly (r=0.54 and 0.58 respectively, P=0.01). The IPIP scales have good internal consistency (a=0.88) and relate strongly to major dimensions of personality assessed by the two questionnaires. PMID- 26973965 TI - Understanding the Missing Link Between Musical Attitudes, Preferences and Psychological Profiles: Music as Auto-Medication and Self-Administered Therapy? Implications for Music Therapy. PMID- 26973964 TI - Parental Perceptions of Health-Related Quality of Life of Albanian Children with Epilepsy. AB - Epilepsy adversely affects the health-related quality of life (HRQoL) of children living with it. Even though almost 80% of children with epilepsy live in developing countries very little research has been conducted with the specific population. The present study took place in Albania and aimed to investigate parental perceptions of the HRQoL of their children with epilepsy. Considering the well-defined gender roles in the Albanian traditional family it was expected that mothers and fathers reports of their children's HRQoL would differ. Results showed no differences in maternal and paternal reports; instead there was a moderate correspondence between the reports across all dimensions. Parents also reported the highest scores of HRQoL in the interpersonal dimension and the lowest scores in the intrapersonal dimension. The findings have implications in the context of future research and also medical care for children with epilepsy in Albania. PMID- 26973966 TI - A Theory Upon Origin of Implicit Musical Language. AB - The author suggests that the origin of musicality is implied in an implicit musical language every human being possesses in uterus due to a resonance and attunement with prenatal environment, mainly the mother. It is emphasized that ego-development and evolving implicit musical language can be regarded as parallel processes. To support this idea a lot of examples of musical representations are demonstrated by the author. Music is viewed as a tone of ego functioning involving the musical representations of bodily and visceral senses, cross-modal perception, unity of sense of self, individual fate of ego, and tripolar and bipolar musical coping codes. Finally, a special form of music therapy is shown to illustrate how can implicit musical language be transformed into explicit language by virtue of participants' spontaneity, creativity, and playfulness. PMID- 26973960 TI - Overview of Attention Deficit Hyperactivity Disorder in Young Children. AB - Attention deficit hyperactivity disorder (ADHD) is a complex disorder, which can be seen as a disorder of life time, developing in preschool years and manifesting symptoms (full and/or partial) throughout the adulthood; therefore, it is not surprising that there are no simple solutions. The aim of this paper is to provide a short and concise review which can be used to inform affected children and adults; family members of affected children and adults, and other medical, paramedical, non-medical, and educational professionals about the disorder. This paper has also tried to look into the process of how ADHD develops; what are the associated problems; and how many other children and adults are affected by such problems all over the world basically to understand ADHD more precisely in order to develop a better medical and or non-medical multimodal intervention plan. If preschool teachers and clinicians are aware of what the research tells us about ADHD, the varying theories of its cause, and which areas need further research, the knowledge will assist them in supporting the families of children with ADHD. By including information in this review about the connection between biological behavior, it is hoped that preschool teachers and clinicians at all levels will feel more confident about explaining to parents of ADHD children, and older ADHD children themselves about the probable causes of ADHD. PMID- 26973967 TI - Eva Between Anxiety and Hope: Integrating Anthroposophic Music Therapy in Supportive Oncology Care. AB - Music therapy is a significant modality in the treatment of patients with cancer, who suffer emotional and spiritual distress as well as chemotherapy side effects that impair their quality of life. In this article, we present a case study of a patient challenged with recurrent ovarian cancer who received, concomitant with chemotherapy, a special form of music therapy based on anthroposophic medicine (AM) aimed at alleviating anxiety and improving her general well-being. AM centered music therapy goals are discussed in regard to two modes of treatment: receptive listening and clinical composition. Next, these two treatment modes are discussed in a broader context by reviewing conventional music therapy interventions during chemotherapy on two axes: a. standardized vs. individualized treatment; b. patient's involvement on a passive to active continuum. In conclusion, psycho-oncology care can be enriched by adding anthroposophic medicine-oriented music therapy integrated within patients' supportive care. PMID- 26973969 TI - Expression of Immune-Related Genes during Loach (Misgurnus anguillicaudatus) Embryonic and Early Larval Development. AB - Early life stage mortality in fish is one of the problems faced by loach aquaculture. However, our understanding of immune system in early life stage fish is still incomplete, and the information available is restricted to a few fish species. In the present work, we investigated the expression of immune-related transcripts in loach during early development. In fishes, recombination activating gene 1 (RAG-1) and sacsin (SACS) have been considered as immunological function. In this study, the expression of the both genes was assessed throughout the early developmental stages of loach using real-time PCR method. maRAG-1 mRNA was first detected in 0 dph, observed the increased mostly until 40 dph. Significant expression of maRAG-1 was detected in 0 to 40 dph. These patterns of expression may suggest that the loach start to develop its function after hatching. On the other hand, maSACS was detected in unfertilized oocyte to molura stages and 0 to 40 dph. maSACS mRNA transcripts were detected in unfertilized oocytes, suggesting that they are maternally transferred. PMID- 26973970 TI - Egg Development of the Ussurian Bullhead Fish, Leiocassis ussuriensis (Pisces: Bagridae) and Morphological Development of Its Larvae and Juveniles. AB - This study was examined the ovogenesis of Ussurian bullhead, Leiocassis ussuriensis and the morphological development of its larvae and juveniles and to use the results as basic information for the preservation of species and resource enhancement. For artificial egg collection, human chorionic gonadotropin (HCG) was injected at a rate of 10 IU per gram of fish weight. During breeding period, water temperature maintained at 24.5~26.5 degrees C (mean 25.0+/-0.05 degrees C). The process of ovogenesis reached the two-cell stage in 50 minutes after fertilization. In 73 hours of fertilization the movement of the embryoid body became active state and the larvae began to hatch from the tail through the oolemma. Length of prelarvae were 6.33~6.50 mm long (mean 6.40+/-0.06 mm) just after hatching having yolk with their mouth not opened. After thirty eight days of hatching, juveniles were 30.6~32.5 mm long (mean 31.5+/-0.65 mm). The color was dark yellowish brown throughout the entire body, and the number of caudal fin rays developed to thirty six perfectly. PMID- 26973968 TI - Arsenic Toxicity in Male Reproduction and Development. AB - Arsenic is a toxic metalloid that exists ubiquitously in the environment, and affects global health problems due to its carcinogenicity. In most populations, the main source of arsenic exposure is the drinking water. In drinking water, chronic exposure to arsenic is associated with increased risks of various cancers including those of skin, lung, bladder, and liver, as well as numerous other non cancer diseases including gastrointestinal and cardiovascular diseases, diabetes, and neurologic and cognitive problems. Recent emerging evidences suggest that arsenic exposure affects the reproductive and developmental toxicity. Prenatal exposure to inorganic arsenic causes adverse pregnancy outcomes and children's health problems. Some epidemiological studies have reported that arsenic exposure induces premature delivery, spontaneous abortion, and stillbirth. In animal studies, inorganic arsenic also causes fetal malformation, growth retardation, and fetal death. These toxic effects depend on dose, route and gestation periods of arsenic exposure. In males, inorganic arsenic causes reproductive dysfunctions including reductions of the testis weights, accessory sex organs weights, and epididymal sperm counts. In addition, inorganic arsenic exposure also induces alterations of spermatogenesis, reductions of testosterone and gonadotrophins, and disruptions of steroidogenesis. However, the reproductive and developmental problems following arsenic exposure are poorly understood, and the molecular mechanism of arsenic-induced reproductive toxicity remains unclear. Thus, we further investigated several possible mechanisms underlying arsenic-induced reproductive toxicity. PMID- 26973971 TI - Structure and Function of the Reproductive System of Aplysia kurodai. AB - This study investigated structure and function of the reproductive system in Aplysia kurodai by means of anatomical, histological, and histochemical observation. Reproductive system of this species is consisted of ovotestis, small hermaphroditic duct, ampulla, accessory genital mass and large hermaphroditic duct. The ovotestis is composed of a large number of follicles, and both oocytes and spermatocytes matured in the same follicle. The small hermaphroditic duct is a single tube and contains a swelling, the ampulla, which functions as a storage organ for endogenous sperm and an oviduct. The accessory genital mass is connected to both the small and large hermaphroditic duct, and consisted of three glands: albumen, membrane (winding) and mucus gland. The albumen gland is consisted of granular cells producing basophilic and neutral mucopolysaccharides. The membrane and mucus gland are consisted of granular cells producing acidophilc and sulfated mucopolysaccharides. The large hermaphroditic duct is a single tubular gonoduct linking the accessory genital mass to the common genital aperture but is consisted of two parallel compartments. Internally, these two compartments are incompletely divided by internal septum or fold, which are called as the red hemiduct and white hemiduct, respectively. The red hemiduct functions as an oviduct and the white hemiduct functions as a copulatory duct. The reproductive system of A. kurodai is externally comprised a single tube, i.e., monaulic type. However, internal structure of duct is incompletely divided into oviduct and copulatory duct, i.e., the oodiaulic type. PMID- 26973972 TI - Early Gonadal Differentiation of the Protogynous Red Spotted Grouper, Epinephelus akaara. AB - Red spotted grouper, Epinephelus akaara is a popular aquaculture species in many Asian countries. This species is a protogynous hermaphrodite that first differentiates into female and changes to male later. Due to this reproductive characteristic, stable supply of male and female gametes is a key to the success of seed production in this species. Thus, understanding early gonadal differentiation is required to develop effective sex control techniques. Red spotted grouper were reared in indoor tanks and sampled every 5 days from 40 days post-hatch (DPH) to 130 DPH. Changes of gonadal tissues were examined and analyzed by means of histology. A pair of gonadal primordium has already existed underneath the kidney in the posterior part of the body cavity at 38 DPH when this study began. Gonadal primordia of 38, 40 DPH consisted of germ cells surrounded by a few somatic cells. The blood vessel was observed in the gonadal primordium at 45 DPH. The number of somatic cells and size of gonadal primordium increased age-dependently up to 60 DPH. Formation of ovarian cavity was obvious by two protuberant aggregations of somatic cells at 65 DPH. Completed ovarian cavity and oogonia were first observed in the gonad of one fish sample at 105 DPH. Based on these histological observations, it can be suggested that induction of primary male differentiation could be more successfully applied at around 60 DPH in this species. PMID- 26973973 TI - Aberrant Expression of Connexin Isoforms in the Corpus Epididymis of the Adult Rat by Exposure to Estradiol Benzoate or Flutamide at the Weaning Age. AB - A proper development of the epididymis during the early postnatal development is required for successful fertility in the adult male. Direct cell-cell communication via connexin (Cx) molecules is a common way of cellular interactions to achieve normal development of a given tissue consisting of different cell types. The present research was attempted to determine the effect of exogenous exposure to estrogenic agonist or antiandrogen at the weaning age on expression of Cx isoforms in the adult corpus epididymis. Male rats were subcutaneously administrated with estradiol benzoate (EB) or flutamide (Flu) at the weaning age. The tissue was collected at 4 months of age. Expressional levels of Cx isoforms were determined by a quantitative real-time PCR. Statistical comparison showed significant increases of Cxs31, 32, 37, 40, and 43 transcript amounts by a treatment of 0.015 mg of EB /kg body weight (BW). A treatment of 1.5 MUg of EB /kg BW caused a significant decrease of Cx43 gene expression but increases of Cxs26, 31, 32, 37, and 40 transcript levels. Exposure to 500 mg of Flu/kg BW induced an increase of Cx37 expression but significant decreases of Cxs43 and 45 mRNA levels. Expression of Cx37 was increased by a treatment of 5 mg of Flu/kg BW, while transcript levels of Cxs26, 30.3, 31, 31.1, 32, and 43 were significantly decreased by same treatment. These results demonstrate that exposure to steroidal compounds at the early developmental age alters expression of Cx isoforms in the adult corpus epididymis. PMID- 26973974 TI - Characterization of EST Gene in the Bovine Corpus Luteum during the Estrous Cycle. AB - The objective of this study was to investigate the expression of bovine luteum expressed sequence tags (ESTs), vascular endothelial growth factor (VEGF), and tumor necrosis factor receptor 1 (TNFR1) and the presence of functional ESTs in the bovine corpus luteum (CL) during different stages of the estrus cycle. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed a difference in the expression of ESTs during the CL stage. Concentration of ESTs in the CL tissue increased significantly from the mid-luteal stage and decreased thereafter. RT-PCR analysis showed higher levels of the EST genes in the CL of the mid-luteal stage than in other stages, and the same level of expression of VEGF. Immunohistochemistry analysis of the tissue from CL formation to regression showed low cytosol and aggregation of the nucleus. And activity caspase 3 (apoptosis detector) was most strongly detected in the CL1 stage of bovine. During the estrous cycle, the cytosol was magnified and differentiation of the nucleus was clearly manifested. The ESTs affected the CL, and the relationship between VEGF and TNFR1 played a pivotal role for CL development and activation, dependent on the stage of CL. These results suggest local production of ESTs, the presence of functional ESTs in the bovine CL, and that ESTs play a role in regulating the function of cell death in bovine CL. PMID- 26973975 TI - A Testa Extract of Black Soybean (Glycine max (L.) Merr.) suppresses Adipogenic Activity of Adipose-derived Stem Cells. AB - Black soybean teata is helpful to preventing obesity through enhancing energy expenditure and suppressing accumulation in mesenteric adipose tissue. The ethanol testa-extract of Cheongja #3 black soybean (ETCBS) is also have similar effects on obesity. So far, it is not clear whether the ethanol testa extract of black soybean can have effect on the characters of subcutaneous adipose stem cells such as proliferation, activity, and adipogenicity. The doubling time was different between subcutaneous adipose-derived stem (ADS) and visceral ADS cells. By the in vitro culture and passage, the doubling time was increased both of them. The shape was not different between groups and their passages were not cause the change of shapes. In the case of visceral ADS cells, the doubling time was 62.3 h or 40.3 h in control or high fat diet administrated mice, respectively, but not modified in subcutaneous ADS cells. ETCBS administration caused of increased the doubling time from 62.3 h to 84.2 h. ETCBS had suppressive effects on the cellular activity of subcutaneous ADS cells. The intensity of Oil Red O staining was very faint in 100 and 200 MUg/mL ETCBS treated groups. The amounts of accumulated triglyceride were also significantly low in 100 and 200 MUg/mL treated groups. From these results we know that the doubling times and the effects of ETCBS are different by the anatomical origin of ADS cells. It also suggested that ETCBS may suppress the differentiation of subcutaneous ADS cells into the precursors and maturing of adipocytes. PMID- 26973976 TI - Th 17 Cells and Nesfatin-1 are associated with Spontaneous Abortion in the CBA/j * DBA/2 Mouse Model. AB - The pregnancy and abortion process involves a complex mechanism with various immune cells present in the implantation sites and several hormones associated with pregnancy, such as leptin, ghrelin and nesfatin-1. However, the mechanism underlying spontaneous abortion by maternal T helper 17 (Th17) present in the implantation sites and nesfatin-1, which is of anorexigenic hormones, is not fully understood so far. Therefore, the purpose of this study was to examine the possible roles of Th17 cells present in the implantation sites and nesfatin-1 expressed in the uterus on spontaneous abortion using the CBA/j * DBA/2 mouse model. Th17 transcription factor, ROR-gammat mRNA expression was significantly increased in the abortion sites compared with the implantation sites of abortion model mice on day 14.5 and 19.5 of pregnancy. In addition, the expression levels of IL(-1)7A mRNA were significantly higher in abortion sites than in implantation sites on day 14.5 and 19.5. Moreover, the nesfatin-1/NUCB2 protein and mRNA levels were increased in abortion sites compared with levels in implantation sites of both normal pregnant and abortion model mice on day 14.5 of pregnancy. Interestingly, nesfatin- 1/NUCB2 serum levels were not changed throughout the whole pregnancy in abortion model mice, but its serum level was dramatically increased on day 14.5, and then rapidly decreased on day 19.5 in normal pregnant mice. In this study, we showed for the first time the expression of nesfatin 1/NUCB2 mRNA and protein in implantation sites during pregnancy. The present results suggest that Th17 cells in the uterus may play an important role in the period of implantation and for maintenance of pregnancy. Furthermore, the present results suggest that Th17 cells in implantation sites may be a key regulator for maintenance of pregnancy and provides evidence that activation of these cells may be regulated by nesfatin-1/NUCB2. Further study is needed to elucidate the role of nesfatin-1 expressed in the uterus during pregnancy. PMID- 26973977 TI - Stimulation of Spermiation by Human Chorionic Gonadotropin and Carp Pituitary Extract in Grass Puffer, Takifugu niphobles. AB - Spermiation was stimulated in the mature grass puffer, Takifugu niphobles, with an injection of human chorionic gonadotropin (HCG) or carp pituitary extract (CPE). Spermatocrit and sperm density were reduced, but milt production was increased in both the HCG and CPE treatment groups relative to those in the control group (P <0.05). These results should be useful for increasing the fertilization efficiency in grass puffer breeding programs. PMID- 26973978 TI - Geographical Variations and Genetic Distances of Three Saxidomus purpuratus Populations ascertained by PCR Analysis. AB - Genomic DNA samples isolated from geographical purplish Washington clam (Saxidomus purpuratus) were obtained from three different regions in the Korean Peninsula: Geoje (Geoje population; GJP), Gunsan (Gunsan population; GSP) and a site of North Korea (North Korea population; NKP). The seven primers generated the total 369 loci that can be scored from the GSP clam population. 356 fragments were generated from the NKP clam population. The complexity of the banding patterns varies dramatically between the primers and three localities. In this study, 319 loci were identified in the purplish Washington clam from Geoje and 369 in the clam population from Gunsan: 221 specific loci (69.3%) in the GJP clam population and 300 (81.3%) in the GSP population. These results demonstrate that the primer detected a large quantity of specific fragments, suggesting that the genetic variation in the GSP is higher than in the GJP population. In particular, the BION-28 primer gave DNA profiles with more fragments than the other six primers in the NKP population. The oligonucleotides primer BION-75 produced 21 unique loci to each population, which were ascertaining each population, approximately 250 bp, 300 bp and 400 bp, in the GJP population. Outstandingly, the primer BION-50 detected 21 shared loci by the three populations, major and/or minor fragments of sizes 150 bp, which were matching in all samples. With regard to average bandsharing value (BS) results, individuals from GJP population (0.743) displayed higher bandsharing values than did individuals from GSP population (0.606). In the present study, the dendrogram gained by the seven oligonucleotides primers indicates three genetic clusters: cluster 1 (GEOJE 01 ~ GEOJE 07), cluster 2 (GUNSAN 08 ~ GUNSAN 14), cluster 3 (N.KOREA 15 ~ N.KOREA 21). Among the twenty one clams, the shortest genetic distance that revealed significant molecular differences was between individuals 08 and 09 from the NKP population (genetic distance = 0.073), while the longest genetic distance among the twenty-one individuals that demonstrated significant molecular differences was between individuals GEOJE no. 03 and GUNSAN no. 09 (genetic distance = 0.669). Comparatively, individuals of GJP population were properly closely related to that of NKP population, as revealed in the hierarchical dendrogram of genetic distances. In due course, PCR analysis has revealed the significant genetic distance among three purplish Washington clam populations. PCR fragments discovered in this study could be valuable as a DNA marker of the three geographical clam populations to distinguish. PMID- 26973979 TI - Elder Mistreatment and its Subtypes across Different Sociodemographic and Socioeconomic Groups among U.S. Chinese Community-Dwelling Older Adults. AB - OBJECTIVES: To examine the risk of overall elder mistreatment (EM) and its subtypes in each sociodemographic and socioeconomic group based on different definitional criteria. METHODS: In person interviews were conducted with 3,159 Chinese older adults in the Greater Chicago Area from 2011 to 2013. Psychological mistreatment, physical mistreatment, sexual abuse, caregiver neglect, and financial exploitation were measured using definitional approaches from the least strict to the strictest criteria. RESULTS: Physical, psychological mistreatment, and financial exploitation were closely correlated with each other, but caregiver neglect was not correlated with any other types of mistreatment. The risk of EM and its subtypes across sociodemographic groups differed by types and definitions of mistreatment. DISCUSSION: Future longitudinal studies are needed to quantity the risk and protective factors associated with EM and its subtypes with consideration of definitional issues in Chinese aging populations. PMID- 26973982 TI - Manifold-valued Dirichlet Processes. AB - Statistical models for manifold-valued data permit capturing the intrinsic nature of the curved spaces in which the data lie and have been a topic of research for several decades. Typically, these formulations use geodesic curves and distances defined locally for most cases - this makes it hard to design parametric models globally on smooth manifolds. Thus, most (manifold specific) parametric models available today assume that the data lie in a small neighborhood on the manifold. To address this 'locality' problem, we propose a novel nonparametric model which unifies multivariate general linear models (MGLMs) using multiple tangent spaces. Our framework generalizes existing work on (both Euclidean and non-Euclidean) general linear models providing a recipe to globally extend the locally-defined parametric models (using a mixture of local models). By grouping observations into sub-populations at multiple tangent spaces, our method provides insights into the hidden structure (geodesic relationships) in the data. This yields a framework to group observations and discover geodesic relationships between covariates X and manifold-valued responses Y, which we call Dirichlet process mixtures of multivariate general linear models (DP-MGLM) on Riemannian manifolds. Finally, we present proof of concept experiments to validate our model. PMID- 26973981 TI - The Acute Respiratory Distress Syndrome: Mechanisms and Perspective Therapeutic Approaches. AB - Acute Respiratory Distress Syndrome (ARDS) is a severe lung inflammatory disorder with a 30-50% mortality. Sepsis and pneumonia are the leading causes of ARDS. On the cellular level there is pulmonary capillary endothelial cell permeability and fluid leakage into the pulmonary parenchyma, followed by neutrophils, cytokines and an acute inflammatory response. When fluid increases in the interstitium then the outward movement continues and protein rich fluid floods the alveolar spaces through the tight junctions of the epithelial cells. Neutrophils play an important role in the development of pulmonary edema associated with acute lung injury or ARDS. Animal studies have shown that endothelial injury appears within minutes to hours after Acute Lung Injury (ALI) initiation with resulting intercellular gaps of the endothelial cells. The Endothelial Cell (EC) gaps allow for permeability of fluid, neutrophils and cytokines into the pulmonary parenchymal space. The neutrophils that infiltrate the lungs and migrate into the airways express pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), and contribute to both the endothelial and epithelial integrity disruption of the barriers. Pharmacological treatments have been ineffective. The ARDS Network trial identified low tidal volume mechanical ventilation, positive end expiratory pressure and fluid management guidelines that have improved outcomes for patients with ARDS. Extracorporeal membrane oxygenation is used in specialized centers for severe cases. Prone positioning has recently proven to have significantly decreased ventilator days and days in the intensive care unit. Current investigation includes administration of mesenchymal stem cell therapy, partial fluid ventilation, TIP peptide nebulized administration and the continued examination of pharmacologic drugs. PMID- 26973983 TI - Compression in Molecular Simulation Datasets. AB - In this paper, we present a compression framework, for molecular dynamics (MD) simulation data, which yields significant performance by combining the strength of principal component analysis (PCA) and discrete cosine transform (DCT). Though it is a lossy compression technique, the effect on analytics performed on decompressed data is very minimal. Compression ratio up to 13 is achieved with acceptable errors in results of analytical functions. PMID- 26973984 TI - [Improving the speech with a prosthetic construction]. AB - A 12-year-old boy had problems with his speech due to a defect in the soft palate. This defect was caused by the surgical removal of a synovial sarcoma. Testing with a nasometer revealed hypernasality above normal values. Given the size and severity of the defect in the soft palate, the possibility of improving the speech with speech therapy was limited. At a centre for special dentistry an attempt was made with a prosthetic construction to improve the performance of the palate and, in that way, the speech. This construction consisted of a denture with an obturator attached to it. With it, an effective closure of the palate could be achieved. New measurements with acoustic nasometry showed scores within the normal values. The nasality in the speech largely disappeared. The obturator is an effective and relatively easy solution for palatal insufficiency resulting from surgical resection. Intrusive reconstructive surgery can be avoided in this way. PMID- 26973985 TI - [Effectivity and durability of telescopic dentures on abutment teeth]. AB - In a study, the effectivity and durability of telescopic dentures on abutment teeth provided with telescope crowns were investigated. The prognosis for the prosthetic structure and for the abutment teeth were both investigated. The survival rate of 234 telescopic dentures (886 abutment teeth) in 147 patients in a general dental practice were retrospectively evaluated on the basis of a status study. The mean survival rate was calculated. This is the moment when 50% of the telescopic dentures had failed. For telescopic dentures in the maxilla, this was 22.3+/-2.8 years, which did not represent a statistically significant difference from the mandible (20.9+/-1.9 years). Of the 886 abutment teeth that were used, 127 (14.3%) were extracted after an average period of 11.7 years. Periodontal complications were the primary reason for extraction. Based on this investigation, one could conclude that telescopic dentures are also a durable and sustainable solution in the long term. Loss of abutment teeth is relatively rare and has limited influence on the survival of the prosthetic structure. PMID- 26973986 TI - [Dissertations 25 years after date 45. Prevalence and etiology of craniomandibular dysfunction in the Netherlands]. AB - The disorders temporomandibular dysfunction and craniomandibular dysfunction are still being discussed intensely in the literature 25 year after the publication of the dissertation 'Prevalence and etiology of craniomandibular dysfunction. An epidemiological study of the Dutch adult population'. Attention is especially being devoted to occlusion and its relationship with this disorder; the conclusions reached are often contradictory. In addition to the definitions of temporomandibular and craniomandibular dysfunction and of occlusion, a possible explanation for this controversy can be found in the methodological shortcomings of the studies. On the basis of the most important results in the dissertation of 25 years ago and the scientific discussion since, 7 guidelines are formulated that are illustrated with clinical examples for an evidence-based treatment of patients with this disorder in a general dental practice. PMID- 26973987 TI - [The (putative) pathological impact of fibromyalgia on the orofacial system]. AB - Fibromyalgia is a syndrome without apparent aetiology, characterised by pain, fatigue, memory disorders, mood disorders, and sleep disturbances. The syndrome is considered to be one of the rheumatic diseases. In the general population, the prevalence varies from 2 to 8%, with a women-men ratio of about 2:1. Suspicion of fibromyalgia arises when a patient has pain at multiple locations that cannot be attributed to trauma or inflammation, and when the pain is especially musculoskeletal. Primary management includes explaining the syndrome and offering reassurance. In addition, one can also attempt to increase mobility, avoid overloading, and improve physical condition and the level of activity, and to activate problem-solving skills. Subsequently, behavioural therapy and pharmacotherapy may be considered. The most important manifestations of fibromyalgia in the orofacial and occlusal system seem to be temporomandibular dysfunction, headache, xerostomia, hyposalivation, burning mouth and dysgeusia. However, with respect to the precise relation of fibromyalgia with the orofacial system, much needs to be elucidated. PMID- 26973988 TI - Minimally Invasive Treatment of White Spot Lesions--A Systematic Review. AB - PURPOSE: To evaluate the efficacy of minimally invasive methods for the treatment of white-spot lesions involving fluorides, CPP-ACP (casein phosphopeptide stabilised amorphous calcium phosphate) and resin infiltration vs a placebo or control. MATERIALS AND METHODS: According to predetermined criteria, four databases were searched for eligible studies. References of the selected articles and relevant reviews were searched for any missed publications. RESULTS: Eight randomised controlled trials were selected as eligible studies, and only qualitative analyses were performed because of the diversity of the interventions and outcome measures. Three studies showed significant effects of three different fluoride preparations and used DIAGNOdent and ICDAS to assess the white spot lesions. Both studies comparing resin infiltration to a placebo showed significant effects in treating white spot lesions. One study using CPP-ACP showed a significant improvement in the lesions post treatment. CONCLUSION: Evidence suggests minimally invasive treatment modalities of white spot lesions produced significant improvement in the appearance and regression of white spot lesions following treatment when compared to a control or placebo. PMID- 26973989 TI - Evaluation of English Websites on Dental Caries by Using Consumer Evaluation Tools. AB - PURPOSE: To evaluate the quality of patient-oriented online information about dental caries using existing consumer evaluation tools and to judge the efficacy of these tools in quality assessment. MATERIALS AND METHODS: The websites for the evaluation were pooled by using two general search engines (Google and Yahoo!). The search terms were: 'dental caries', 'tooth decay' and 'tooth cavity'. Three assessment tools (LIDA, DISCERN and FRES) were used to evaluate the quality of the information in the areas of accessibility, usability, reliability and readability. RESULTS: In total, 77 websites were analysed. The median scores of LIDA accessibility and usability were 45.0 and 8.0, respectively, which corresponded to a medium level of quality. The median reliability scores for LIDA (12.0) and DISCERN (20.0) both corresponded to low level of quality. The readability was high with the median FRES score 59.7. CONCLUSION: The websites on caries had good accessibility, usability and readability, while reliability of the information was poor. The LIDA instrument was found to be more convenient than DISCERN and can be recommended to lay people for quick quality assessment. PMID- 26973990 TI - In Vitro Inhibition of Enamel Demineralisation by Fluoride-releasing Restorative Materials and Dental Adhesives. AB - PURPOSE: To determine the ability of 5 contemporary fluoride-releasing restoratives and 3 fluoride-releasing adhesives to inhibit enamel demineralisation surrounding restorations, and the associations between inhibition and the levels of fluoride released from these materials. MATERIALS AND METHODS: Five fluoride-releasing restoratives (Fuji IX GP, Ketac N100, Dyract Extra, Beautifil II and Wave) and 3 fluoride-releasing adhesives (Stae, Prime & Bond NT and Fluoro Bond II) were investigated. Eight disks of each material were prepared. Fluoride release was measured daily using a fluoride-ion-selective electrode for 15 days. Twenty-four cavities for each group were restored with a restorative and an adhesive. Specimens were subjected to thermal stress and stored for 30 days in saline solution. After a 15-day pH-cycling regimen, two 150 MUm-thick sections were derived from each specimen. Enamel lesion depth was measured at 0, 100, and 200 MUm from each restoration's margin via polarised light microscopy. RESULTS: Of the restoratives investigated, Fuji IX GP released the most fluoride. The fluoride-releasing restoratives tested exhibited shallower enamel lesions than did the control group at all distances tested (p < 0.05). Fuji IX GP yielded significantly lower enamel lesion depth than did the other experimental materials. The depths of enamel lesions did not differ significantly when comparing restoratives applied with a fluoride-releasing adhesive with those applied with a non-fluoride-releasing adhesive. CONCLUSION: The fluoride releasing materials tested reduced enamel demineralisation but to different extents, depending on their levels of fluoride release. Fluoride-releasing adhesives did not influence enamel lesion formation. PMID- 26973991 TI - Copper-catalyzed cross-coupling reactions of epoxides with gem-diborylmethane: access to gamma-hydroxyl boronic esters. AB - Herein, we describe a novel copper-catalyzed epoxide opening reaction with gem diborylmethane. Aliphatic, aromatic epoxides as well as aziridines are converted to the corresponding gamma-pinacolboronate alcohols or amines in moderate to excellent yields. This new reaction provides beneficial applications for classic epoxide substrates as well as interesting gem-diborylalkane reagents. PMID- 26973992 TI - On curing poverty through health: Dr Fai-to Yau's gift of volunteering. PMID- 26973994 TI - Age Over 65: To Transplant or Not to Transplant? PMID- 26973993 TI - Commentary on: "Dirty-appearing white matter in multiple sclerosis: preliminary observations of myelin phospholipid and axonal loss", by G. R. W. Moore, et al. in J Neurol (2008) 255: DOI 10.1007/s00415-008-0002-z. PMID- 26973995 TI - Retraction Notice to: The Ubiquitin Ligase Mul1 Induces Mitophagy in Skeletal Muscle in Response to Muscle-Wasting Stimuli. AB - (Cell Metabolism 16, 613-624; November 7, 2012) In the article, we reported that the expression of a mitochondrial specific E3 ligase, Mul1, was induced in response to wasting conditions, and that increased Mul1 expression caused mitophagy and muscle wasting. Following an investigation by Nanyang Technological University, it was determined that the first author, Sudarsanareddy Lokireddy, falsified data in Figures 2D, 4B, 6D, 6E, and S5B. Although other work has linked Mul1 with mitophagy, in order to protect the integrity of science as well as of our laboratory and institutes, we are retracting the paper. We sincerely apologize to our colleagues and readers for any adverse consequences that this may have caused. The co-authors agree with this statement, with the exception of the first author, Sudarsanareddy Lokireddy. PMID- 26973996 TI - Engaging with research. PMID- 26973999 TI - Heart Failure Update: Foreword. PMID- 26973998 TI - Plasmonically Enhanced Photocatalytic Hydrogen Production from Water: The Critical Role of Tunable Surface Plasmon Resonance from Gold-Silver Nanoshells. AB - Gold-silver nanoshells (GS-NSs) having a tunable surface plasmon resonance (SPR) were employed to facilitate charge separation of photoexcited carriers in the photocalytic production of hydrogen from water. Zinc indium sulfide (ZnIn2S4; ZIS), a visible-light-active photocatalyst, where the band gap varies with the [Zn]/[In] ratio, was used as a model ZIS system (E(g) = 2.25 eV) to investigate the mechanisms of plasmonic enhancement associated with the nanoshells. Three types of GS-NS cores with intense absorptions centered roughly at 500, 700, and 900 nm were used as seeds for preparing GS-NS@ZIS core-shell structures via a microwave-assisted hydrothermal reaction, yielding core-shell particles with composite diameters of ~200 nm. Notably, an interlayer of dielectric silica (SiO2) between the GS-NSs and the ZIS photocatalyst provided another parameter to enhance the production of hydrogen and to distinguish the charge-transfer mechanisms. In particular, the direct transfer of hot electrons from the GS-NSs to the ZIS photocatalyst was blocked by this layer. Of the 10 particle samples examined in this study, the greatest hydrogen gas evolution rate was observed for GS-NSs having a SiO2 interlayer thickness of ~17 nm and an SPR absorption centered at ~700 nm, yielding a rate 2.6 times higher than that of the ZIS without GS-NSs. The apparent quantum efficiencies for these core-shell particles were recorded and compared to the absorption spectra. Analyses of the charge transfer mechanisms were evaluated and are discussed based on the experimental findings. PMID- 26974000 TI - Heart Failure Update: Diagnosis and Classification. AB - Heart failure (HF) is a complex clinical condition. The newer guidelines have phased out the designations of systolic and diastolic HF and replaced them with the more physiologically applicable classifications of HF with reduced or preserved ejection fraction (EF). Although the numbers of new patients within these two groups are similar, patient characteristics and risk factors often differ. There also are differences in the incidence of HF among racial and ethnic groups, with blacks having the highest incidence. Although survival has improved over time among patients with reduced EF, no significant change in survival has been observed among those with preserved EF. Many models have been proposed to explain the underlying pathophysiology of HF, including the hemodynamic, neurohumoral, and cardiorenal models. The evaluation of a patient with signs and symptoms of and risk factors for HF includes a detailed history and physical examination, laboratory tests, chest x-ray, electrocardiography, and echocardiography. Serum natriuretic peptide levels are already in use, and other novel biomarkers reflecting the different pathophysiologic pathways are being investigated. The Seattle Heart Failure Model is a tool available for clinicians to use in estimating patient mortality risk. PMID- 26974001 TI - Heart Failure Update: Outpatient Management. AB - Outpatient management of heart failure (HF) is aimed at treating symptoms and preventing hospitalizations and readmissions. Management is initiated in a stepwise approach. Blockade of the renin-angiotensin system is a cornerstone of therapy and should be started, along with beta blockers, as soon as the diagnosis of HF is made. Other drugs, including diuretics, aldosterone antagonists, hydralazine, and nitrates, may be added based on symptoms and American College of Cardiology/American Heart Association stage. Despite a great interest in and theoretical benefit of naturoceutical products in the mitigation of oxidative stress and HF progression, none has been proven to be beneficial, and concerns exist regarding their interactions with standard HF drugs. Other nonpharmacologic interventions, including sodium restriction, regular exercise, and/or cardiac rehabilitation, should be initiated at diagnosis. HF often is progressive, and clinicians should be aware of late stage management options, including implantable devices, cardiac transplantation, and hospice care. PMID- 26974003 TI - Heart Failure Update: Chronic Disease Management Programs. AB - With high mortality and readmission rates among patients with heart failure (HF), multiple disease management models have been and continue to be tested, with mixed results. Early postdischarge care improves outcomes for patients. Telemonitoring also can assist in reducing mortality and HF-related hospitalizations. Office-based team care improves patient outcomes, with important components including rapid access to physicians, partnerships with clinical pharmacists, education, monitoring, and support. Pay-for-performance measures developed for HF, primarily use of angiotensin-converting enzyme inhibitors and beta blockers, also improve patient outcomes, but the influence of adherence to other measures has been minimal. Evaluating comorbid conditions, including diabetes and hypertension, and making drug adjustments for patients with HF to include blood pressure control and use of metformin, when possible, can reduce mortality and morbidity. PMID- 26974002 TI - Heart Failure Update: Inpatient Management. AB - Acute decompensated heart failure (HF) is one of most common reasons for hospitalization among individuals older than 65 years. A thorough evaluation, including history, physical examination, and laboratory assessment, is required to optimize care of these patients. In uncertain cases, serum brain-type natriuretic peptide (BNP) or N-terminal proBNP level, stress testing, and/or invasive coronary angiography may be helpful in establishing the diagnosis. The hospital setting provides an opportunity to identify etiologies and stabilize the patient. The primary goal of inpatient HF therapy is systemic and pulmonary decongestion, achieved most effectively using intravenous diuretic therapy. Rate and rhythm control may be needed for patients with concurrent atrial fibrillation and, in American College of Cardiology/American Heart Association stage D HF, intravenous inotropes may become necessary. New pharmacologic or device therapies also are considered as a means of transitioning patients, especially those with severe disease, to the outpatient setting. Patients hospitalized for acute decompensated HF have high postdischarge mortality and rehospitalization rates and, thus, should be monitored carefully. PMID- 26974006 TI - SMA-SH: Modified Styrene-Maleic Acid Copolymer for Functionalization of Lipid Nanodiscs. AB - Challenges in purification and subsequent functionalization of membrane proteins often complicate their biochemical and biophysical characterization. Purification of membrane proteins generally involves replacing the lipids surrounding the protein with detergent molecules, which can affect protein structure and function. Recently, it was shown that styrene-maleic acid copolymers (SMA) can dissolve integral membrane proteins from biological membranes into nanosized discs. Within these nanoparticles, proteins are embedded in a patch of their native lipid bilayer that is stabilized in solution by the amphipathic polymer that wraps the disc like a bracelet. This approach for detergent-free purification of membrane proteins has the potential to greatly simplify purification but does not facilitate conjugation of functional compounds to the membrane proteins. Often, such functionalization involves laborious preparation of protein variants and optimization of labeling procedures to ensure only minimal perturbation of the protein. Here, we present a strategy that circumvents several of these complications through modifying SMA by grafting the polymer with cysteamine. The reaction results in SMA that has solvent-exposed sulfhydrils (SMA SH) and allows tuning of the coverage with SH groups. Size exclusion chromatography, dynamic light scattering, and transmission electron microscopy demonstrate that SMA-SH dissolves lipid bilayer membranes into lipid nanodiscs, just like SMA. In addition, we demonstrate that, just like SMA, SMA-SH solubilizes proteoliposomes into protein-loaded nanodiscs. We covalently modify SMA-SH-lipid nanodiscs using thiol-reactive derivatives of Alexa Fluor 488 and biotin. Thus, SMA-SH promises to simultaneously tackle challenges in purification and functionalization of membrane proteins. PMID- 26974004 TI - Photocatalytic Oxygenation of Substrates by Dioxygen with Protonated Manganese(III) Corrolazine. AB - UV-vis spectral titrations of a manganese(III) corrolazine complex [Mn(III)(TBP8Cz)] with HOTf in benzonitrile (PhCN) indicate mono- and diprotonation of Mn(III)(TBP8Cz) to give Mn(III)(OTf)(TBP8Cz(H)) and [Mn(III)(OTf)(H2O)(TBP8Cz(H)2)][OTf] with protonation constants of 9.0 * 10(6) and 4.7 * 10(3) M(-1), respectively. The protonated sites of Mn(III)(OTf)(TBP8Cz(H)) and [Mn(III)(OTf)(H2O)(TBP8Cz(H)2)][OTf] were identified by X-ray crystal structures of the mono- and diprotonated complexes. In the presence of HOTf, the monoprotonated manganese(III) corrolazine complex [Mn(III)(OTf)(TBP8Cz(H))] acts as an efficient photocatalytic catalyst for the oxidation of hexamethylbenzene and thioanisole by O2 to the corresponding alcohol and sulfoxide with 563 and 902 TON, respectively. Femtosecond laser flash photolysis measurements of Mn(III)(OTf)(TBP8Cz(H)) and [Mn(III)(OTf)(H2O)(TBP8Cz(H)2)][OTf] in the presence of O2 revealed the formation of a tripquintet excited state, which was rapidly converted to a tripseptet excited state. The tripseptet excited state of Mn(III)(OTf)(TBP8Cz(H)) reacted with O2 with a diffusion-limited rate constant to produce the putative Mn(IV)(O2(*-))(OTf)(TBP8Cz(H)), whereas the tripseptet excited state of [Mn(III)(OTf)(H2O)(TBP8Cz(H)2)][OTf] exhibited no reactivity toward O2. In the presence of HOTf, Mn(V)(O)(TBP8Cz) can oxidize not only HMB but also mesitylene to the corresponding alcohols, accompanied by regeneration of Mn(III)(OTf)(TBP8Cz(H)). This thermal reaction was examined for a kinetic isotope effect, and essentially no KIE (1.1) was observed for the oxidation of mesitylene d12, suggesting a proton-coupled electron transfer (PCET) mechanism is operative in this case. Thus, the monoprotonated manganese(III) corrolazine complex, Mn(III)(OTf)(TBP8Cz(H)), acts as an efficient photocatalyst for the oxidation of HMB by O2 to the alcohol. PMID- 26974005 TI - GATA4 Regulates Blood-Testis Barrier Function and Lactate Metabolism in Mouse Sertoli Cells. AB - Conditional deletion of Gata4 in Sertoli cells (SCs) of adult mice has been shown to increase permeability of the blood-testis barrier (BTB) and disrupt spermatogenesis. To gain insight into the molecular underpinnings of these phenotypic abnormalities, we assessed the impact of Gata4 gene silencing in cell culture models. Microarray hybridization identified genes dysregulated by siRNA mediated inhibition of Gata4 in TM4 cells, an immortalized mouse SC line. Differentially expressed genes were validated by quantitative RT-PCR analysis of primary cultures of Gata4(flox/flox) mouse SCs that had been subjected to cre mediated recombination in vitro. Depletion of GATA4 in TM4 cells and primary SCs was associated with altered expression of genes involved in key facets of BTB maintenance, including tight/adherens junction formation (Tjp1, Cldn12, Vcl, Tnc, Csk) and extracellular matrix reorganization (Lamc1, Col4a1, Col4a5, Mmp10, Mmp23, Timp2). Western blotting and immunocytochemistry demonstrated reduced levels of tight junction protein-1, a prototypical tight junction protein, in GATA4-depleted cells. These changes were accompanied by a loss of morphologically recognizable junctional complexes and a decline in epithelial membrane resistance. Furthermore, Gata4 gene silencing was associated with altered expression of Hk1, Gpi1, Pfkp, Pgam1, Gls2, Pdk3, Pkd4, and Ldhb, genes regulating the production of lactate, a key nutrient that SCs provide to developing germ cells. Comprehensive metabolomic profiling demonstrated impaired lactate production in GATA4-deficient SCs. We conclude that GATA4 plays a pivotal role in the regulation of BTB function and lactate metabolism in mouse SCs. PMID- 26974008 TI - Epigenetic germline inheritance of diet-induced obesity and insulin resistance. AB - There is considerable controversy regarding epigenetic inheritance in mammalian gametes. Using in vitro fertilization to ensure exclusive inheritance via the gametes, we show that a parental high-fat diet renders offspring more susceptible to developing obesity and diabetes in a sex- and parent of origin-specific mode. The epigenetic inheritance of acquired metabolic disorders may contribute to the current obesity and diabetes pandemic. PMID- 26974009 TI - Isolation of Secondary Metabolites from the Soil-Derived Fungus Clonostachys rosea YRS-06, a Biological Control Agent, and Evaluation of Antibacterial Activity. AB - The fungus Clonostachys rosea is widely distributed all over the world. The destructive force of this fungus, as a biological control agent, is very strong to lots of plant pathogenic fungi. As part of the ongoing search for antibiotics from fungi obtained from soil samples, the secondary metabolites of C. rosea YRS 06 were investigated. Through efficient bioassay-guided isolation, three new bisorbicillinoids possessing open-ended cage structures, tetrahydrotrichodimer ether (1) and dihydrotrichodimer ether A and B (2 and 3), and 12 known compounds were obtained. Their structures were determined via extensive NMR, HR-ESI-MS, and CD spectroscopic analyses and X-ray diffraction data. Compounds 1-3 are rare bisorbicillinoids with a gamma-pyrone moiety. The biological properties of 1-15 were evaluated against six different Gram-positive and Gram-negative bacteria. Bisorbicillinoids, 2-5, and TMC-151 C and E, 14 and 15, showed potent antibacterial activity. PMID- 26974010 TI - Exceptionally Robust In-Based Metal-Organic Framework for Highly Efficient Carbon Dioxide Capture and Conversion. AB - An In-based metal-organic framework, with 1D nanotubular open channels, In2(OH)(btc)(Hbtc)0.4(L)0.6.3H2O (1), has been synthesized via an in situ ligand reaction, in which 1,2,4-H3btc is partially transformed into the L ligand. Compound 1 exhibits exceptional thermal and chemical stability, especially in water or acidic media. The activated 1 presents highly selective sorption of carbon dioxide (CO2) over dinitrogen. Interestingly, diffuse-reflectance infrared Fourier transform spectroscopy with a carbon monoxide probe molecule demonstrates that both Lewis and Bronsted acid sites are involved in compound 1. As a result, as a heterogeneous Lewis and Bronsted acid bifunctional catalyst, 1 possesses excellent activity and recyclability for chemical fixation of CO2 coupling with epoxides into cyclic carbonates under mild conditions. In addition, the mechanism for the CO2 cycloaddition reaction has also been discussed. PMID- 26974013 TI - Enriching science, practice, and policy relevant to school psychology around the globe. AB - This editorial provides a brief synthesis of the past, present, and future of School Psychology Quarterly, highlighting important contributions as an international resource to enrich, invigorate, enhance, and advance science, practice, and policy relevant to school psychology around the globe. Information herein highlights (a) the value of high quality and timely reviews, (b) publishing manuscripts that address a breadth of important topics relevant to school psychology, and (c) the structure and contributions of the special topic sections featured in School Psychology Quarterly. PMID- 26974011 TI - Synthesis of Rumphellaone A and Hushinone by a Gold-Catalyzed [2 + 2] Cycloaddition. AB - The enantioselective total synthesis of rumphellaone A has been accomplished in 12 steps via a diastereoselective gold(I)-catalyzed [2 + 2] macrocyclization of a 1,10-enyne as the key step to build the cyclobutene moiety. This concise approach has also led to the total synthesis of husinone. PMID- 26974012 TI - Spin Chains and Electron Transfer at Stepped Silicon Surfaces. AB - High-index surfaces of silicon with adsorbed gold can reconstruct to form highly ordered linear step arrays. These steps take the form of a narrow strip of graphitic silicon. In some cases--specifically, for Si(553)-Au and Si(557)-Au--a large fraction of the silicon atoms at the exposed edge of this strip are known to be spin-polarized and charge-ordered along the edge. The periodicity of this charge ordering is always commensurate with the structural periodicity along the step edge and hence leads to highly ordered arrays of local magnetic moments that can be regarded as "spin chains." Here, we demonstrate theoretically as well as experimentally that the closely related Si(775)-Au surface has--despite its very similar overall structure--zero spin polarization at its step edge. Using a combination of density-functional theory and scanning tunneling microscopy, we propose an electron-counting model that accounts for these differences. The model also predicts that unintentional defects and intentional dopants can create local spin moments at Si(hhk)-Au step edges. We analyze in detail one of these predictions and verify it experimentally. This finding opens the door to using techniques of surface chemistry and atom manipulation to create and control silicon spin chains. PMID- 26974014 TI - Capillary Displacement of Viscous Liquids. AB - When a capillary tube is brought into contact with a wetting liquid, surface tension forces overcome gravity and the liquid spontaneously rises into the tube until an equilibrium height is reached. The early viscous dynamics of the rise typically follow the well-known Lucas-Washburn law, which is independent of gravity and neglects the displaced fluid. Here we explore the early viscous dynamics when the properties of displaced fluid are significant. Using a combination of experiments and theory, we show how the characteristic behavior of the Lucas-Washburn law is modified when the viscosity of the displaced fluid is comparable to or exceeds the wetting fluid. Additionally, we find that the effects of gravity reshape the dynamics of the capillary rise not only in the late viscous regime but also in the early viscous regime. PMID- 26974007 TI - Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. AB - We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes. PMID- 26974015 TI - Developmental changes in semantic knowledge organization. AB - Semantic knowledge is a crucial aspect of higher cognition. Theoretical accounts of semantic knowledge posit that relations between concepts provide organizational structure that converts information known about individual entities into an interconnected network in which concepts can be linked by many types of relations (e.g., taxonomic, thematic). The goal of the current research was to address several methodological shortcomings of prior studies on the development of semantic organization, by using a variant of the spatial arrangement method (SpAM) to collect graded judgments of relatedness for a set of entities that can be cross-classified into either taxonomic or thematic groups. In Experiment 1, we used the cross-classify SpAM (CC-SpAM) to obtain graded relatedness judgments and derive a representation of developmental changes in the organization of semantic knowledge. In Experiment 2, we validated the findings of Experiment 1 by using a more traditional pairwise similarity judgment paradigm. Across both experiments, we found that an early recognition of links between entities that are both taxonomically and thematically related preceded an increasing recognition of links based on a single type of relation. The utility of CC-SpAM for evaluating theoretical accounts of semantic development is discussed. PMID- 26974016 TI - Lipid Raft-Mediated Membrane Tethering and Delivery of Hydrophobic Cargos from Liquid Crystal-Based Nanocarriers. AB - A main goal of bionanotechnology and nanoparticle (NP)-mediated drug delivery (NMDD) continues to be the development of novel biomaterials that can controllably modulate the activity of the NP-associated therapeutic cargo. One of the desired subcellular locations for targeted delivery in NMDD is the plasma membrane. However, the controlled delivery of hydrophobic cargos to the membrane bilayer poses significant challenges including cargo precipitation and lack of specificity. Here, we employ a liquid crystal NP (LCNP)-based delivery system for the controlled partitioning of a model dye cargo from within the NP core into the plasma membrane bilayer. During synthesis of the NPs, the water-insoluble model dye cargo, 3,3'-dioctadecyloxacarbocyanine perchlorate (DiO), was efficiently incorporated into the hydrophobic LCNP core as confirmed by multiple spectroscopic analyses. Conjugation of a PEGylated cholesterol derivative to the NP surface (DiO-LCNP-PEG-Chol) facilitated the localization of the dye-loaded NPs to lipid raft microdomains in the plasma membrane in HEK 293T/17 cell. Analysis of DiO cellular internalization kinetics revealed that when delivered as a LCNP PEG-Chol NP, the half-life of DiO membrane residence time (30 min) was twice that of free DiO (DiO(free)) (15 min) delivered from bulk solution. Time-resolved laser scanning confocal microscopy was employed to visualize the passive efflux of DiO from the LCNP core and its insertion into the plasma membrane bilayer as confirmed by Forster resonance energy transfer (FRET) imaging. Finally, the delivery of DiO as a LCNP-PEG-Chol complex resulted in the attenuation of its cytotoxicity; the NP form of DiO exhibited ~30-40% less toxicity compared to DiO(free). Our data demonstrate the utility of the LCNP platform as an efficient vehicle for the combined membrane-targeted delivery and physicochemical modulation of molecular cargos using lipid raft-mediated tethering. PMID- 26974019 TI - Optimal Depth for Nasopharyngeal Temperature Probe Positioning. AB - BACKGROUND: The nasopharynx is considered 1 of the 4 generally reliable core temperature measurement sites. But curiously, there is no consensus on how far past the nares to insert the probe. Insertion depth is likely to influence the accuracy of nasopharyngeal temperature measurements because probes near the nares will be cooled by ambient air; similarly, probes inserted too far may approach the airway and be cooled by ventilation gases. We thus determined the range of nasopharyngeal probe insertion depths that best approximate reference core temperature measured in the distal esophagus. METHODS: In 36 adults undergoing noncardiac surgery with endotracheal intubation, we inserted a nasopharyngeal thermometer 20 cm past the nares and an esophageal temperature probe 40 cm from the incisors. The nasopharyngeal probe was withdrawn sequentially 2 cm at a time at 5-minute intervals. Pairs of nasopharyngeal and reference distal esophageal temperatures were then compared and summarized by Bland and Altman methods. RESULTS: All nasopharyngeal probe insertion depths between 10 and 20 cm past the nares provided temperatures similar to reference distal esophageal temperatures. At those depths, the bias was typically approximately -0.1 degrees C, with SD of approximately +/-0.15 degrees C; the limits of agreement thus were easily within our a priori specified clinically acceptable range of -0.5 degrees C and 0.5 degrees C. CONCLUSIONS: Any nasopharyngeal probe insertion depth between 10 and 20 cm well represents core temperature in adults having noncardiac surgery. PMID- 26974018 TI - Low-Dose or High-Dose Rocuronium Reversed with Neostigmine or Sugammadex for Cesarean Delivery Anesthesia: A Randomized Controlled Noninferiority Trial of Time to Tracheal Intubation and Extubation. AB - BACKGROUND: Rocuronium for cesarean delivery under general anesthesia is an alternative to succinylcholine for rapid-sequence induction of anesthesia because of the availability of sugammadex for reversal of neuromuscular blockade. However, there are no large well-controlled studies in women undergoing general anesthesia for cesarean delivery. The aim of this noninferiority trial was to determine whether rocuronium and sugammadex confer benefit in time to tracheal intubation (primary outcome) and other neuromuscular blockade outcomes compared with succinylcholine, rocuronium, and neostigmine in women undergoing general anesthesia for cesarean delivery. METHODS: We aimed to enroll all women undergoing general anesthesia for cesarean delivery in the 2 participating university hospitals (Brno, Olomouc, Czech Republic) in this single-blinded, randomized, controlled study. Women were randomly assigned to the ROC group (muscle relaxation induced with rocuronium 1 mg/kg and reversed with sugammadex 2 4 mg/kg) or the SUX group (succinylcholine 1 mg/kg for induction, rocuronium 0.3 mg/kg for maintenance, and neostigmine 0.03 mg/kg for reversal of the neuromuscular blockade). The interval from the end of propofol administration to tracheal intubation was the primary end point with a noninferiority margin of 20 seconds. We recorded intubating conditions (modified Viby-Mogensen score), neonatal outcome (Apgar score <7; umbilical artery pH), anesthesia complications, and subjective patient complaints 24 hours after surgery. RESULTS: We enrolled 240 parturients. The mean time to tracheal intubation was 2.9 seconds longer in the ROC group (95% confidence interval, -5.3 to 11.2 seconds), noninferior compared with the SUX group. Absence of laryngoscopy resistance was greater in the ROC than in the SUX groups (ROC, 87.5%; SUX, 74.2%; P = 0.019), but there were no differences in vocal cord position (P = 0.45) or intubation response (P = 0.31) between groups. No statistically significant differences in incidence of anesthesia complications or in neonatal outcome were found (10-minute Apgar score <7, P = 0.07; umbilical artery pH, P = 0.43). The incidence of postpartum myalgia was greater in the SUX group (ROC 0%; SUX 6.7%; P = 0.007). The incidence of subjective complaints was lower in the ROC group (ROC, 21.4%; SUX, 37.5%; P = 0.007). CONCLUSIONS: We conclude that rocuronium for rapid-sequence induction is noninferior for time to tracheal intubation and is accompanied by more frequent absence of laryngoscopy resistance and lower incidence of myalgia in comparison with succinylcholine for cesarean delivery under general anesthesia. PMID- 26974020 TI - Right Ventricular Longitudinal Strain Is Depressed in a Bovine Model of Pulmonary Hypertension. AB - BACKGROUND: Pulmonary hypertension and resulting right ventricular (RV) dysfunction are associated with significant perioperative morbidity and mortality. Although echocardiography permits real-time, noninvasive assessment of RV function, objective and comparative measures are underdeveloped, and appropriate animal models to study their utility are lacking. Longitudinal strain analysis is a novel echocardiographic method to quantify RV performance. Herein, we hypothesized that peak RV longitudinal strain would worsen in a bovine model of pulmonary hypertension compared with control animals. METHODS: Newborn Holstein calves were randomly chosen for induction of pulmonary hypertension versus control conditions. Pulmonary hypertension was induced by exposing animals to 14 days of hypoxia (equivalent to 4570 m above sea level or 430 mm Hg barometric pressure). Control animals were kept at ambient pressure/normoxia. At the end of the intervention, transthoracic echocardiography was performed in awake calves. Longitudinal wall strain was analyzed from modified apical 4 chamber views focused on the RV. Comparisons between measurements in hypoxic versus nonhypoxic conditions were performed using Student t test for independent samples and unequal variances. RESULTS: After 14 days at normoxic versus hypoxic conditions, 15 calves were examined with echocardiography. Pulmonary hypertension was confirmed by right heart catheterization and associated with reduced RV systolic function. Mean systolic strain measurements were compared in normoxia exposed animals (n = 8) and hypoxia-exposed animals (n = 7). Peak global systolic longitudinal RV strain after hypoxia worsened compared to normoxia (-10.5% vs 16.1%, P = 0.0031). Peak RV free wall strain also worsened after hypoxia compared to normoxia (-9.6% vs -17.3%, P = 0.0031). Findings from strain analysis were confirmed by measurement of tricuspid annular peak systolic excursion. CONCLUSIONS: Peak longitudinal RV strain detected worsened RV function in animals with hypoxia-induced pulmonary hypertension compared with control animals. This relationship was demonstrated in the transthoracic echocardiographic 4-chamber view independently for the RV free wall and for the combination of the free and septal walls. This innovative model of bovine pulmonary hypertension may prove useful to compare different monitoring technologies for the assessment of early events of RV dysfunction. Further studies linking novel RV imaging applications with mechanistic and therapeutic approaches are needed. PMID- 26974021 TI - Inhaled Remifentanil in Rodents. AB - BACKGROUND: Remifentanil is an injectable opioid that is metabolized rapidly at a constant rate by plasma esterases. This supports its use as an analgesic for short-term, but painful, procedures in a wide range of patients. The aim of this study was to explore the feasibility and safety of administering remifentanil via inhalation. Our hypothesis was that inhaled remifentanil would be absorbed rapidly, pharmacologically active, rapidly cleared, and noninjurious to rodent airways and lungs. METHODS: Rats were exposed to remifentanil aerosol (100-2000 MUg/mL) for varying times (1-5 minutes). Analgesia was quantified as a function of dose and time by measuring time to tail flick in response to a painful stimulus. Remifentanil was measured in blood using liquid chromatography-tandem mass spectrometry. Pulmonary mechanics and histology were assessed in mice for the evidence of adverse effects after acute and repeated (subacute) dosing. RESULTS: Exposure of rats to remifentanil aerosols produced dose-dependent analgesia within 2 minutes, which was sustained for the exposure period. Subsequently, the rats experienced rapid and complete recovery with a return to baseline tail flick response to a painful stimulus within 5 minutes. Analgesia mirrored the concentration profile of remifentanil in blood, and the animals were not affected adversely by repeated dosing. Pulmonary mechanics measurements in mice indicated that remifentanil was nonirritating and that the nasal and respiratory tissues of rats were free of significant morphological changes. CONCLUSIONS: Remifentanil delivered by inhalation is rapidly absorbed, pharmacologically active, rapidly cleared, and noninjurious to respiratory tissues in rodents. PMID- 26974022 TI - Intrathecal Hydromorphone and Morphine for Postcesarean Delivery Analgesia: Determination of the ED90 Using a Sequential Allocation Biased-Coin Method. AB - BACKGROUND: Intrathecal (IT) morphine is considered the "gold standard" for analgesia after cesarean delivery under spinal anesthesia, most commonly administered at a dose of 100 to 200 MUg. There is less experience with IT hydromorphone for postcesarean analgesia and limited information on its optimal analgesic dose. We conducted this study to determine the effective analgesic dose for 90% patients (ED90) of IT hydromorphone that provides effective analgesia for women undergoing elective cesarean delivery and its potency ratio to IT morphine. METHODS: In this dose-finding trial, 80 patients received spinal anesthesia for cesarean delivery. Participants were randomized to receive IT morphine or IT hydromorphone at a dose determined using up-down sequential allocation with a biased-coin design to determine ED90. All patients received standardized multimodal analgesia postoperatively in addition to IT opioid. An effective dose was defined as a numeric response score for pain of <=3 (scale 0-10) 12 hours after spinal injection. RESULTS: The ED90 was 75 MUg (95% confidence interval [CI], 46-93 MUg) for IT hydromorphone and 150 MUg (95% CI, 145-185 MUg) for IT morphine. At these doses, the 95% CI for the percentage of patients with effective analgesia (numeric rating scale <=3) was 64% to 100% for hydromorphone and 68% to 100% for morphine. Exploratory findings showed that the incidence of nausea and pruritus was not different among the most commonly used doses of IT hydromorphone (P = 0.44 and P = 0.74) or IT morphine (P = 0.67 and P = 0.38, respectively). When administering IT opioids at ED90 doses or higher, 100% (21/21) of IT hydromorphone and 95% (37/39) of IT morphine patients were satisfied with their analgesia. CONCLUSIONS: The ratio of IT morphine to IT hydromorphone for effective postcesarean analgesia is 2:1. Patient satisfaction was high with both medications. PMID- 26974023 TI - Who are the traffic offenders among ethnic groups and why? AB - Marginalized populations, particularly ethnic minorities, are often at a higher risk of being involved in traffic crashes and committing traffic violations. Prominent explanations for this "ethnic traffic risk gap" include cultural and socioeconomic factors, usually measured at an aggregate level. In particular, it has been hypothesized that ethnic minorities commit traffic violations as a form of social resistance to what they perceive to be an oppressing regime. The current study examined the mechanisms underlying traffic violations at the individual level within a single ethnic minority, Israeli-Arabs. The study sample (n=231) included a group of known offenders (n=60) and non-offenders (n=171), all of which completed the Traffic Violation Questionnaire. The results show that offenders and non-offenders tended to have different types of occupations, although these did not translate into significant differences in level of income. Offenders reported significantly lower levels of trust in some hegemonic institutions (the police, government ministries) but not others (parliament, the juridical system). However, offenders displayed remarkably different daily activity patterns, including much higher exposure to traffic (3h/day vs. 0.75) and more complex trip patterns. Our results find little support for the social resistance hypothesis, as it fails to explain the differential treatment of hegemonic institutions. Daily activity patterns stand out as a central mechanism influencing the risk of violations. These results suggest policymakers should adopt a holistic approach for traffic safety interventions but avoid monolithic views of ethnic minorities which may lead to an inefficient use of resources. PMID- 26974024 TI - Modeling the effects of AADT on predicting multiple-vehicle crashes at urban and suburban signalized intersections. AB - Annual Average Daily Traffic (AADT) is often considered as a main covariate for predicting crash frequencies at urban and suburban intersections. A linear functional form is typically assumed for the Safety Performance Function (SPF) to describe the relationship between the natural logarithm of expected crash frequency and covariates derived from AADTs. Such a linearity assumption has been questioned by many researchers. This study applies Generalized Additive Models (GAMs) and Piecewise Linear Negative Binomial (PLNB) regression models to fit intersection crash data. Various covariates derived from minor-and major-approach AADTs are considered. Three different dependent variables are modeled, which are total multiple-vehicle crashes, rear-end crashes, and angle crashes. The modeling results suggest that a nonlinear functional form may be more appropriate. Also, the results show that it is important to take into consideration the joint safety effects of multiple covariates. Additionally, it is found that the ratio of minor to major-approach AADT has a varying impact on intersection safety and deserves further investigations. PMID- 26974025 TI - Injuries and Safe Communities Accreditation: Is there a link? AB - Safe Communities (SC) is a global movement that brings together community stakeholders to collaboratively address injury concerns. SC accreditation is a formal process through which communities are recognized for strengthening local injury prevention capacity. Six million Americans live in 25 SC sites, but no research has been done to understand the model's potential impact on this population. This study explored the temporal relationship between SC accreditation and injury trends in three SC sites from the state of Illinois Arlington Heights, Itasca, and New Lenox. Hospitalization data, including patient demographics, exposure information, injury outcomes, and economic variables, were obtained from a statewide hospital discharge database for a 12-year period (1999 2011). Joinpoint regression models were fitted to identify any periods of significant change, examine the direction of the injury trend, and to estimate monthly percent changes in injury counts and rates. Poisson random-intercept regression measured the average total change since the official SC accreditation for the three communities combined and compared them to three matched control sites. In joinpoint regression, one of the SC sites showed a 10-year increase in hospitalization cases and rates followed by a two-year decline, and the trend reversal occurred while the community was pursuing the SC accreditation. Injury hospitalizations decreased after accreditation compared to the pre-accreditation period when SC sites were compared to their control counterparts using Poisson modeling. Our findings suggest that the SC model may be a promising approach to reduce injuries. Further research is warranted to replicate these findings in other communities. PMID- 26974026 TI - Does the influence of risk factors on accident occurrence change over time? AB - A large number of studies have been made to assess the relationship between risk factors and accident occurrence. A risk factor is any factor that makes an accident more likely to occur. Very many risk factors have been identified, for example, being under the influence of alcohol while driving, driving on slippery roads, entering complex junctions, or driving in hours of darkness. Few studies have been made to determine whether the associations between risk factors and accident occurrence remain stable over time. This paper presents examples of studies that have replicated estimates of risk. All these studies were made within a given country, using the same method, to ensure that estimates of risk are comparable. The risk factors included in the paper are: daylight, horizontal curves, junctions, road surface conditions, precipitation, drinking and driving and driver age. For all these risk factors, their association with accidents has changed over time, mostly becoming weaker. A protective factor, snow depth, is also included. Its protective effect has become smaller over time. Possible reasons for the weakening influence of risk factors are discussed. PMID- 26974027 TI - Supporting anticipation in driving through attentional and interpretational in vehicle displays. AB - OBJECTIVE: This paper evaluates two different types of in-vehicle interfaces to support anticipation in driving: one aids attention allocation and the other aids interpretation of traffic in addition to attention allocation. BACKGROUND: Anticipation is a competency that has been shown to facilitate safety and eco driving through the efficient positioning of a vehicle for probable, upcoming changes in traffic. This competency has been shown to improve with driving experience. In an earlier simulator study, we showed that compared to novice drivers, experienced drivers exhibited a greater number of timely actions to avoid upcoming traffic conflicts. In this study, we seek to facilitate anticipation in general and for novice drivers in particular, who appear to lack the competency. We hypothesize that anticipation depends on two major steps and that it can be supported by aiding each: (1) conscious perception of relevant cues, and (2) effective processing of these cues to create a situational assessment as a basis for anticipation of future developments. METHOD: We conducted a simulator experiment with 24 experienced and 24 novice drivers to evaluate two interfaces that were designed to aid the two hypothesized steps of anticipation. The attentional interface was designed to direct attention toward the most relevant cue. The interpretational interface represented several cues, and in addition to directing attention also aimed to aid sense-making of these cues. RESULTS: The results confirmed our hypothesis that novice drivers' anticipation performance, as measured through timely actions to avoid upcoming traffic conflicts, would be improved with either interface type. However, results contradicted our expectation that novice drivers would obtain larger improvements with the interpretational interface. Experienced drivers performed better than novice drivers to begin with and did not show any statistically significant improvements with either interface. CONCLUSION: Both interfaces improved anticipation performance for novice drivers. Future research should evaluate the effectiveness of these interfaces in a wider variety of driving conditions, such as when the driver is multitasking. PMID- 26974028 TI - A combined M5P tree and hazard-based duration model for predicting urban freeway traffic accident durations. AB - The duration of freeway traffic accidents duration is an important factor, which affects traffic congestion, environmental pollution, and secondary accidents. Among previous studies, the M5P algorithm has been shown to be an effective tool for predicting incident duration. M5P builds a tree-based model, like the traditional classification and regression tree (CART) method, but with multiple linear regression models as its leaves. The problem with M5P for accident duration prediction, however, is that whereas linear regression assumes that the conditional distribution of accident durations is normally distributed, the distribution for a "time-to-an-event" is almost certainly nonsymmetrical. A hazard-based duration model (HBDM) is a better choice for this kind of a "time-to event" modeling scenario, and given this, HBDMs have been previously applied to analyze and predict traffic accidents duration. Previous research, however, has not yet applied HBDMs for accident duration prediction, in association with clustering or classification of the dataset to minimize data heterogeneity. The current paper proposes a novel approach for accident duration prediction, which improves on the original M5P tree algorithm through the construction of a M5P HBDM model, in which the leaves of the M5P tree model are HBDMs instead of linear regression models. Such a model offers the advantage of minimizing data heterogeneity through dataset classification, and avoids the need for the incorrect assumption of normality for traffic accident durations. The proposed model was then tested on two freeway accident datasets. For each dataset, the first 500 records were used to train the following three models: (1) an M5P tree; (2) a HBDM; and (3) the proposed M5P-HBDM, and the remainder of data were used for testing. The results show that the proposed M5P-HBDM managed to identify more significant and meaningful variables than either M5P or HBDMs. Moreover, the M5P HBDM had the lowest overall mean absolute percentage error (MAPE). PMID- 26974029 TI - Evaluating the rollover propensity of trucks--A roundabout example. AB - The rollover propensity of SUVs and trucks has long been recognized as a potential safety issue. The propensity may increase with the growing number of roundabouts that are being built on high-speed roadways designed for 50 mi/h or higher. This paper presents a research methodology developed to evaluate the rollover propensity of trucks on existing roundabouts and other roads with tight curves and high-speed traffic. The research objective was accomplished by developing an advanced 3D model of rollover that is applicable to field observations of the undisturbed behavior of multiple vehicles. This model was supplemented with a nonintrusive method of data collection based on recording video from a remote location and a novel method of extracting the data from the video material and processing it to generate the input required by the rollover model. The method is demonstrated in this paper on an example roundabout by evaluating the rollover propensity of semi-trailers in daytime and nighttime conditions. The results indicate that the drivers observed in nighttime conditions compensated well for the challenging conditions by driving more cautiously, which led to their rollover propensity at night being lower than during the day. The method was found useful for timely detection of the potential rollover problem without waiting for crashes. PMID- 26974030 TI - The protective effect of a helmet in three bicycle accidents--A finite element study. AB - There is some controversy regarding the effectiveness of helmets in preventing head injuries among cyclists. Epidemiological, experimental and computer simulation studies have suggested that helmets do indeed have a protective effect, whereas other studies based on epidemiological data have argued that there is no evidence that the helmet protects the brain. The objective of this study was to evaluate the protective effect of a helmet in single bicycle accident reconstructions using detailed finite element simulations. Strain in the brain tissue, which is associated with brain injuries, was reduced by up to 43% for the accident cases studied when a helmet was included. This resulted in a reduction of the risk of concussion of up to 54%. The stress to the skull bone went from fracture level of 80 MPa down to 13-16 MPa when a helmet was included and the skull fracture risk was reduced by up to 98% based on linear acceleration. Even with a 10% increased riding velocity for the helmeted impacts, to take into account possible increased risk taking, the risk of concussion was still reduced by up to 46% when compared with the unhelmeted impacts with original velocity. The results of this study show that the brain injury risk and risk of skull fracture could have been reduced in these three cases if a helmet had been worn. PMID- 26974031 TI - Staying silent about safety issues: Conceptualizing and measuring safety silence motives. AB - Communication between employees and supervisors about safety-related issues is an important component of a safe workplace. When supervisors receive information from employees about safety issues, they may gain otherwise-missed opportunities to correct these issues and/or prevent negative safety outcomes. A series of three studies were conducted to identify various safety silence motives, which describe the reasons that employees do not speak up to supervisors about safety related issues witnessed in the workplace, and to develop a tool to assess these motives. Results suggest that employees stay silent about safety issues based on perceptions of altering relationships with others (relationship-based), perceptions of the organizational climate (climate-based), the assessment of the safety issue (issue-based), or characteristics of the job (job-based). We developed a 17-item measure to assess these four motives, and initial evidence was found for the construct and incremental validity of the safety silence motives measure in a sample of nurses. PMID- 26974033 TI - Implants Displaced Into the Maxillary Sinus: A Systematic Review. AB - OBJECTIVES: Implant displacement into the maxillary sinus often results from features specific to the posterior maxillary teeth, including poor bone quality and insufficient remaining bone. This study reviews implants displaced into the maxillary sinus, the causes and complications of displacement, and how to remove them, according to when the displacement occurs. MATERIALS AND METHODS: The PubMed, Ovid (MEDLINE), and EMBASE databases were searched using the keywords "displacement," "implant," "maxillary sinus," and "removal" for articles published between January 2000 and July 2013. RESULTS: Twenty-two journal articles were selected; these discussed 49 displaced implants. Most of the implants were displaced into the maxillary sinus during implantation, but resulted in a low incidence of complications, such as maxillary sinusitis. The displaced implants were removed using the Caldwell-Luc approach or a transoral or transnasal endoscopic approach. CONCLUSION: Implants displaced into the maxillary sinus have various causes according to when they are displaced. As displaced implants can cause several complications, transnasal endoscopy is recommended to remove them; however, the implants should be examined thoroughly before selecting the removal method. PMID- 26974032 TI - Solid-state NMR studies of supercapacitors. AB - Electrochemical double-layer capacitors, or 'supercapacitors' are attracting increasing attention as high-power energy storage devices for a wide range of technological applications. These devices store charge through electrostatic interactions between liquid electrolyte ions and the surfaces of porous carbon electrodes. However, many aspects of the fundamental mechanism of supercapacitance are still not well understood, and there is a lack of experimental techniques which are capable of studying working devices. Recently, solid-state NMR has emerged as a powerful tool for studying the local environments and behaviour of electrolyte ions in supercapacitor electrodes. In this Trends article, we review these recent developments and applications. We first discuss the basic principles underlying the mechanism of supercapacitance, as well as the key NMR observables that are relevant to the study of supercapacitor electrodes. We then review some practical aspects of the study of working devices using ex situ and in situ methodologies and explain the key advances that these techniques have allowed on the study of supercapacitor charging mechanisms. NMR experiments have revealed that the pores of the carbon electrodes contain a significant number of electrolyte ions in the absence of any charging potential. This has important implications for the molecular mechanisms of supercapacitance, as charge can be stored by different ion adsorption/desorption processes. Crucially, we show how in situ NMR experiments can be used to quantitatively study and characterise the charging mechanism, with the experiments providing the most detailed picture of charge storage to date, offering the opportunity to design enhanced devices. Finally, an outlook for future directions for solid-state NMR in supercapacitor research is offered. PMID- 26974034 TI - Incidence, Risk Factors, and Complications of Schneiderian Membrane Perforation in Sinus Lift Surgery: A Meta-Analysis. AB - OBJECTIVES: To evaluate the incidence of Schneiderian membrane perforation occurring during sinus lift surgery, and to investigate possible risk factors and associated complications. MATERIALS AND METHODS: A systematic search for papers published between 1975 and 2015 was performed in MEDLINE, EMBASE, Scopus, Web of Science, Trip, Cochrane Oral Health Group's Trials Register, Cochrane Central Register of Controlled Trials, and ProQuest Dissertations & Theses. The quality assessment of each study was performed using the GRADE system. All extracted data were synthesized using either fixed or random effect models as indicated. RESULTS: Out of 1652 sinus lift surgeries reported in 12 studies, 388 membrane perforations occurred. The weighted incidence rate of perforation was 23.5% ranging from 3.6% to 41.8%. Both reduced membrane thickness and sinus septa increased the risk of perforation. The difference in the weighted implant survival rates between perforated and nonperforated side was not significant (P = 0.24). The use of piezoelectric instrumentation appears to reduce the perforation risk. CONCLUSIONS: With an incidence ratio of 1:4, membrane perforation is a common surgical complication during sinus lift surgery. We should keep in mind that appropriately handled and treated membrane perforation tends to show comparable implant survival when compared with intact membrane. PMID- 26974035 TI - Impaired 17,20-Lyase Activity in Male Mice Lacking Cytochrome b5 in Leydig Cells. AB - Androgen and estrogen biosynthesis in mammals requires the 17,20-lyase activity of cytochrome P450 17A1 (steroid 17-hydroxylase/17,20-lyase). Maximal 17,20-lyase activity in vitro requires the presence of cytochrome b5 (b5), and rare cases of b5 deficiency in human beings causes isolated 17,20-lyase deficiency. To study the consequences of conditional b5 removal from testicular Leydig cells in an animal model, we generated Cyb5(flox/flox):Sf1-Cre (LeyKO) mice. The LeyKO male mice had normal body weights, testis and sex organ weights, and fertility compared with littermates. Basal serum and urine steroid profiles of LeyKO males were not significantly different than littermates. In contrast, marked 17 hydroxyprogesterone accumulation (100-fold basal) and reduced testosterone synthesis (27% of littermates) were observed after human chorionic gonadotropin stimulation in LeyKO animals. Testis homogenates from LeyKO mice showed reduced 17,20-lyase activity and a 3-fold increased 17-hydroxylase to 17,20-lyase activity ratio, which were restored to normal upon addition of recombinant b5. We conclude that Leydig cell b5 is required for maximal androgen synthesis and to prevent 17-hydroxyprogesterone accumulation in the mouse testis; however, the b5 independent 17,20-lyase activity of mouse steroid 17-hydroxylase/17,20-lyase is sufficient for normal male genital development and fertility. LeyKO male mice are a good model for the biochemistry but not the physiology of isolated 17,20-lyase deficiency in human beings. PMID- 26974036 TI - Reference intervals for selected serum biochemistry analytes in cheetahs Acinonyx jubatus. AB - Published haematologic and serum biochemistry reference intervals are very scarce for captive cheetahs and even more for free-ranging cheetahs. The current study was performed to establish reference intervals for selected serum biochemistry analytes in cheetahs. Baseline serum biochemistry analytes were analysed from 66 healthy Namibian cheetahs. Samples were collected from 30 captive cheetahs at the AfriCat Foundation and 36 free-ranging cheetahs from central Namibia. The effects of captivity-status, age, sex and haemolysis score on the tested serum analytes were investigated. The biochemistry analytes that were measured were sodium, potassium, magnesium, chloride, urea and creatinine. The 90% confidence interval of the reference limits was obtained using the non-parametric bootstrap method. Reference intervals were preferentially determined by the non-parametric method and were as follows: sodium (128 mmol/L - 166 mmol/L), potassium (3.9 mmol/L - 5.2 mmol/L), magnesium (0.8 mmol/L - 1.2 mmol/L), chloride (97 mmol/L - 130 mmol/L), urea (8.2 mmol/L - 25.1 mmol/L) and creatinine (88 umol/L - 288 umol/L). Reference intervals from the current study were compared with International Species Information System values for cheetahs and found to be narrower. Moreover, age, sex and haemolysis score had no significant effect on the serum analytes in this study. Separate reference intervals for captive and free-ranging cheetahs were also determined. Captive cheetahs had higher urea values, most likely due to dietary factors. This study is the first to establish reference intervals for serum biochemistry analytes in cheetahs according to international guidelines. These results can be used for future health and disease assessments in both captive and free-ranging cheetahs. PMID- 26974037 TI - Understanding the Solubility of Acetaminophen in 1-n-Alkyl-3-methylimidazolium Based Ionic Liquids Using Molecular Simulation. AB - During the manufacturing of pharmaceutical compounds, solvent mixtures are commonly used, where the addition of a cosolvent allows for the tuning of the intermolecular interactions present in the system. Here we demonstrate how a similar effect can be accomplished using a room temperature ionic liquid. The pharmaceutical compound acetaminophen is studied in 21 common ionic liquids composed of a 1-n-alkyl-3-methylimidazolium cation with 1 of 7 anions. Using the acetate anion, we predict a large enhancement in solubility of acetaminophen relative to water. We show how this is caused by a synergistic effect of favorable interactions between the ionic liquid and the phenyl, hydroxyl and amide groups of acetaminophen, demonstrating how the ionic liquid cation and anion may be chosen to preferentially solvate different functional groups of complex pharmaceutical compounds. Additionally, while the use of charge scaling in ionic liquid force fields has previously been found to have a minute effect on ionic liquid structural properties, we find it appreciably affects the computed solvation free energy of acetaminophen, which in turn affects the predicted solubility. PMID- 26974038 TI - The effect of stopping before turning on the direct observational measure of whole body turning bias. AB - Turning bias, the preferential tendency to turn toward a given direction has been reported in both rodents and human participants. The observational gait method of determining turning bias in humans requires a stop prior to turning. This study removed the stop and hypothesised that turning bias would remain the same between stop and non-stop conditions if bias was solely under the control of neurochemical asymmetries. The results showed that statistically turning bias remained the same (to the left) regardless of method used but there was no agreement between the methods thus rejecting the hypothesis. It is likely that when not stopping biomechanical factors related to gait when turning influence the direction of turn rather than solely neurochemical asymmetries. PMID- 26974039 TI - Recognizing Change and Measuring Impact. PMID- 26974040 TI - Disentangling the Physical Processes Responsible for the Kinetic Complexity in Interfacial Electron Transfer of Excited Ru(II) Polypyridyl Dyes on TiO2. AB - Interfacial electron transfer at titanium dioxide (TiO2) is investigated for a series of surface bound ruthenium-polypyridyl dyes whose metal-to-ligand charge transfer state (MLCT) energetics are tuned through chemical modification. The 12 complexes are of the form Ru(II)(bpy-A)(L)2(2+), where bpy-A is a bipyridine ligand functionalized with phosphonate groups for surface attachment to TiO2. Functionalization of ancillary bipyridine ligands (L) enables the potential of the excited state Ru(III/)* couple, E(+/)*, in 0.1 M perchloric acid (HClO4(aq)) to be tuned from -0.69 to -1.03 V vs NHE. Each dye is excited by a 200 fs pulse of light in the visible region of the spectrum and probed with a time-delayed supercontiuum pulse (350-800 nm). Decay of the MLCT excited-state absorption at 376 nm is observed without loss of the ground-state bleach, which is a clear signature of electron injection and formation of the oxidized dye. The dye dependent decays are biphasic with time constants in the 3-30 and 30-500 ps range. The slower injection rate constant for each dye is exponentially distributed relative to E(+/)*. The correlation between the exponentially diminishing density of TiO2 sub-band acceptor levels and injection rate is well described using Marcus-Gerischer theory, with the slower decay components being assigned to injection from the thermally equilibrated state and the faster components corresponding to injection from higher energy states within the (3)MLCT manifold. These results and detailed analyses incorporating molecular photophysics and semiconductor density of states measurements indicate that the multiexponential behavior that is often observed in interfacial injection studies is not due to sample heterogeneity. Rather, this work shows that the kinetic heterogeneity results from competition between excited-state relaxation and injection as the photoexcited dye relaxes through the (3)MLCT manifold to the thermally equilibrated state, underscoring the potential for a simple kinetic model to reproduce the complex kinetic behavior often observed at the interface of mesoporous metal oxide materials. PMID- 26974041 TI - Selective lesion to the entorhinal cortex leads to an impairment in familiarity but not recollection. AB - The present research explored the effects of selective impairment to the entorhinal cortex on the processes of familiarity and recollection. To achieve this objective, the performance of patient MR, who has a selective impairment of the left entorhinal cortex, was compared to that of age and IQ-matched controls. Four experiments tested participants' recognition memory for familiar and unfamiliar faces and words. In all experiments, participants studied lists of items and then completed an old/new recognition test in which they also made remember/know/guess judgements. A fifth experiment tested participants' priming associated with the familiarity process. MR had intact performance in both face recognition experiments as well as having intact performance in pseudoword recognition. Crucially, however, in the familiar word experiment, whilst MR performed similarly to control participants in terms of recollection, she showed a marked impairment in familiarity. Furthermore, she also demonstrated a reversed conceptual priming effect. MR's impairment is both material-specific and selective for previously encountered but not new verbal items (pseudowords). These findings provide the first clear evidence that selective impairment of the entorhinal cortex impairs the familiarity process for familiar verbal material whilst leaving recollection intact. These results suggest the entorhinal cortex does not have attributes reflective of both recollection and familiarity as previously assumed, but rather supports context-free long-term familiarity-based recognition memory. PMID- 26974042 TI - A benchmark for comparison of dental radiography analysis algorithms. AB - Dental radiography plays an important role in clinical diagnosis, treatment and surgery. In recent years, efforts have been made on developing computerized dental X-ray image analysis systems for clinical usages. A novel framework for objective evaluation of automatic dental radiography analysis algorithms has been established under the auspices of the IEEE International Symposium on Biomedical Imaging 2015 Bitewing Radiography Caries Detection Challenge and Cephalometric X ray Image Analysis Challenge. In this article, we present the datasets, methods and results of the challenge and lay down the principles for future uses of this benchmark. The main contributions of the challenge include the creation of the dental anatomy data repository of bitewing radiographs, the creation of the anatomical abnormality classification data repository of cephalometric radiographs, and the definition of objective quantitative evaluation for comparison and ranking of the algorithms. With this benchmark, seven automatic methods for analysing cephalometric X-ray image and two automatic methods for detecting bitewing radiography caries have been compared, and detailed quantitative evaluation results are presented in this paper. Based on the quantitative evaluation results, we believe automatic dental radiography analysis is still a challenging and unsolved problem. The datasets and the evaluation software will be made available to the research community, further encouraging future developments in this field. (http://www o.ntust.edu.tw/~cweiwang/ISBI2015/). PMID- 26974043 TI - Anti-apoptotic and cytoprotective effect of Enicostemma littorale against oxidative stress in Islets of Langerhans. AB - Context Oxidative stress induces apoptosis within Islets of Langerhans in diabetes mellitus (DM). Enicostemma littorale blume, herb of the Gentianaceae family is used as an anti-diabetic agent across rural India. Objective This report demonstrates potent anti-apoptotic and cyto-protective activity of Enicostemma littorale MeOH extract (EL MeOH ext.) against 50 MUM H2O2 in isolated rat Islets. Materials and methods In this study, the whole plant methanolic extract of EL with doses 0.25-4 mg/mL each for the preincubation duration of 0.5 4 h against 50 MUM H2O2 were tested for optimum protective dose and time by Trypan blue dye exclusion assay. Islet intracellular reactive oxygen species (ROS) was quantified by DCFDA staining and cell death using PS/PI & FDA/PI staining. Further, comet assay, biochemical assessment of caspase-3 and antioxidant enzyme activities along with immunoblotting of PARP-1, caspase-3, TNF alpha activation and p-P38 MapK (stress kinase) induction was performed. Results The optimized dose of EL MeOH ext. 2 mg/mL for 2 h was used throughout the study, which significantly decreased total Intracellular ROS and cell death. Further, caspase-3 activity, PARP-1 cleavage, p-P38 MapK (stress kinase) activation and TNF-alpha levels, which had been significantly elevated, were normalized. Antioxidant enzymes like catalase, superoxide dismutase, reduced glutathione and glutathione peroxidase, along with Comet assay, demonstrated that pretreatment with EL MeOH ext. can augment antioxidant enzyme activities and protect from DNA damage. Discussion and conclusions Significant anti-apoptotic and cyto-protective effects were mediated by EL with Islets of Langerhans subjected to oxidative stress-induced cell death. PMID- 26974044 TI - Protective effects of Semiaquilegia adoxoides n-butanol extract against hydrogen peroxide-induced oxidative stress in human lens epithelial cells. AB - Context Hydrogen peroxide (H2O2)-induced damage in the lens epithelium leads to cell death and cataract. Semiaquilegia adoxoides (DC.) Makino (Ranunculaceae), a folk medicine of Hmong (an ethnic group of China), has been traditionally used to treat cataract; however, the underlying molecular mechanism is yet to be uncovered. Objective This study aimed to investigate whether the n-butanol extract of S. adoxoides (nSA) is effective against the H2O2-induced oxidative stress in human lens epithelial (HLE) cells. Materials and methods Human lens epithelial (SRA 01/04) cells were stimulated by H2O2 (250 MUM) in the presence or absence of nSA. The antioxidant effects of nSA were determined in terms of cell viability (MTT assay), apoptosis (AnnexinV/PI staining), radical scavenging capability (various enzymatic assays), loss of mitochondrial membrane potential (Rhodamine 123 staining), expression of apoptotic markers including caspase-3 and caspase-9 and the change of Bcl-2/Bax ratio (western blot) in the HLE cells. Results The results showed that pretreatment of nSA (250, 500 and 1000 MUg/mL) markedly reduced H2O2-induced cellular apoptosis and malondialdehyde accumulation, but elevated the activities of total superoxide dismutase, catalase, glutathione peroxidase. Thus, the total antioxidative capability was enhanced upon the nSA treatment meanwhile the loss of mitochondrial membrane potential was prevented. Moreover, nSA at concentrations of 250, 500 and 1000 MUg/mL also significantly suppressed the activation of caspase-3 and -9, and increased the Bcl-2/Bax ratio in the HLE cells. Discussion and conclusion Our findings suggested that nSA is a potential prophylactic agent in the prevention of cataractogeneis. PMID- 26974046 TI - Palladacycles of unsymmetrical (N,C-,E) (E = S/Se) pincers based on indole: their synthesis, structure and application in the catalysis of Heck coupling and allylation of aldehydes. AB - Unsymmetrical (N,C,E)-type pincer ligand precursors [ and : E = S/Se] with an indole core were synthesized for the first time by the condensation of 1-(2 phenylsulfanyl/selenylethyl)-1H-indole-3-carbaldehyde with benzyl amine. The synthetic protocols are easy and give good yields (>85%). and on reaction with sodium tetrachloropalladate(ii) in the presence of CH3COONa result in complexes [Pd(/-H)Cl] (/), where they bind in a tridentate (N,C(-),E) mode. and , their aldehyde precursors and Pd(ii)-complexes, and , have been characterized by (1)H, (13)C{(1)H} and (77)Se{(1)H} NMR and HR-MS. Palladium(ii) complexes and and precursor aldehydes of and were verified using single crystal X-ray diffraction. The catalytic activities of complexes and were investigated for Heck coupling and allylation of aldehydes. The two reactions require 0.1-0.3 and 1 mol% loading of complexes as catalysts, respectively. PMID- 26974047 TI - The impact of the DNP degree. PMID- 26974045 TI - Modulation of intracellular expression of IFNgamma and IL-2 in culture of splenic T lymphocytes by some flavonoid glycosides of Alchornea floribunda. AB - Context Alchornea floribunda Mull. Arg. (Euphorbiaceae) leaves are widely used in ethnomedicine for the management of rheumatism, arthritis and toothache. Objective In this study, flavonoid glycosides isolated from Alchornea floribunda were screened for their effect on the intracellular expression of interferon gamma (IFNgamma) and interleukin-2 (IL-2) type-1 cytokines. Materials and methods Chromatographic purification of the ethyl acetate fraction of the methanol leaf extract led to the isolation of seven flavonoid glycosides (1-7). Their structures were elucidated by 1D and 2D nuclear magnetic resonance and mass spectrometry. Splenocytes were treated with graded concentrations of the compounds (6.25-25 MUg/mL) and incubated for 24 h. Thereafter, their effect on the expression of IFNgamma and IL-2 by CD4(+ )and CD8(+ )T-lymphocytes was evaluated using intracellular cytokine staining and FACS analysis. Results Compounds 1-7 (6.25-25 MUg/mL) caused the up-regulation of activated CD8(+ )(57.85-72.45% versus 57.85% for untreated control) and, to a lesser extent, activated CD4(+ )(3.21-7.21% versus 2.75% for the untreated control) T lymphocytes that were both largely interferon-gamma-releasing in treated mouse T lymphocytes relative to untreated control. FACS data analysis showed that stimulation with all the compounds increased the proportion of CD8(+)/IFNgamma(+ )and CD4(+)/IFNgamma(+ )T lymphocytes up to two-fold when compared with the cells in untreated control wells. Intracellular IL-2 secretion by treated T cells was not detected. Conclusion This recorded T-lymphocyte-specific immune-modulatory property may contribute to explain in part the dynamics associated with the ethnomedicine of Alchornea floribunda, and may find relevance as a necessary cellular immune response precursor to infection-associated disease management. PMID- 26974048 TI - An update on gout for primary care providers. AB - This article discusses the current beliefs regarding the pathogenesis of gout and reviews the 2012 guidelines from the American College of Rheumatology regarding diagnostic testing, optimal treatments, and lifestyle modifications. Implementing these guidelines will assist clinicians in resolving acute episodes and managing gout long term, improving outcomes and quality of life. PMID- 26974049 TI - Recognizing melanoma: Diagnosis and treatment options. AB - Melanoma is a malignant tumor that is usually cutaneous in origin and is associated with significant morbidity and mortality. As one of the most common cancers seen in young adults, melanoma represents a major public health concern in terms of years of lost productivity. PMID- 26974050 TI - Dental avulsions: Review and recommendations. AB - Tooth avulsion injuries are common. This article will review causes of tooth avulsion and provide management guidelines. Recommendations for NP education and practice will be reviewed. PMID- 26974051 TI - Electrochemistry and catalytic properties of amphiphilic vitamin B12 derivatives in nonaqueous media. AB - The reduction pathway of cobalester (CN)Cble, an amphiphilic vitamin B12 derivative, was investigated in organic solvents under electrochemical conditions and compared with mono- and dicyanocobyrinates. The redox characteristics were determined using cyclic voltammetry and spectroelectrochemical methods. The presence of a nucleotide moiety in B12-derivative impedes the in situ formation of dicyano-species thus facilitating the (CN)Co(iii) to Co(i) reduction. The (CN)Cble shows stepwise reduction to Co(i) via (CN)Co(ii). The reduction of (CN)Co(ii)/Co(i) was found to depend on cyanide-solvent exchange equilibrium with weakly coordinating solvents and bulky peripheral chains promoting intact (CN)Co(ii) species existence. The studied complexes were also utilized as catalysts in bulk electrolysis of benzyl bromide affording bibenzyl in very good yield. PMID- 26974052 TI - Uterotonics and tocolytics for anesthesiologists. AB - PURPOSE OF REVIEW: Obstetric anesthesiologists are supposed to understand the uterotonics and tocolytics used in the perinatal period to provide a better clinical practice. This review describes current consensus of uterotonics and tocolytics used in the perinatal period that an obstetric anesthesiologist should know. RECENT FINDINGS: Rational use of uterotonics for cesarean section has been well studied in the past decades. Oxytocin remained as a first line uterotonics for cesarean section. For continuous infusion, it is reported that ED90 is higher for laboring parturients than for nonlaboring parturients (6.2 vs. 44.2 IU/h) implying that protocol for oxytocin infusion should be different between laboring patients with prior exposure to oxytocin and nonlaboring patients. For bolus administration, 'rule of three' has been proposed and its efficacy has been reported. When oxytocin fails to achieve sufficient uterine contraction, second line agents must be administered, and it has been reported that methylergonovine is a superior second-line uterotonic to carboprost. On the other hand, the role of tocolytic agents in obstetric anesthesia has not been well studied. SUMMARY: Anesthesiologists involved in obstetric anesthesia should be able to determine the appropriate uterotonic for cesarean section and know the indication of tocolytics in perinatal period. PMID- 26974054 TI - Temperature dependence of superparamagnetism in CoFe2O4 nanoparticles and CoFe2O4/SiO2 nanocomposites. AB - CoFe2O4 particles of 16 nm and 17 nm embedded in a silica matrix have been prepared through the hydrothermal method and the sol-gel method, respectively. From neutron powder diffraction a cation distribution of (Fe(0.72)Co(0.28))[Fe(1.28)Co(0.72)]O4 has been determined for Co-ferrite particles of 17 nm, which is in agreement with its particle size taking into account the reported x values for other nanometric Co-ferrite particles. Magnetic measurements were performed up to 700 K as the prepared ferrite samples present blocking temperatures above room temperature. The temperature dependence of the superparamagnetic moment has been analyzed and presents for both samples an abrupt drop in the magnitude once the blocking temperature is overcome. The temperature dependence of the calculated magnetic field needed to reach the magnetic saturation of the samples allows us to determine the temperature range for which the nanoparticles show superparamagnetic behaviour. The ordering temperature is in both cases lower than the tabulated one for bulk Co-ferrite (793 K) which has been ascribed mainly to two factors: a different cation distribution and the nanometric particle size, both contributing to lowering of the strength of the superexchange interactions. PMID- 26974055 TI - Long-Acting Reversible Contraception and Condom Use: We Need a Better Message. PMID- 26974053 TI - Safety of Seasonal Influenza Vaccination in Hospitalized Surgical Patients: A Cohort Study. AB - BACKGROUND: Despite recommendations to vaccinate surgical inpatients against influenza, vaccination rates remain low in this population, due in part to concerns about potential negative effects on postsurgical care. OBJECTIVE: To evaluate whether influenza vaccination in the perioperative period increases health care utilization and evaluations for postsurgical infection after discharge. DESIGN: Retrospective cohort study. SETTING: Members of Kaiser Permanente Southern California. PARTICIPANTS: Patients aged 6 months or older who had inpatient surgery with admission and discharge between 1 September and 31 March from 2010 to 2013. MEASUREMENTS: All influenza vaccinations administered between 1 August and 30 April in the 2010-2011, 2011-2012, and 2012-2013 influenza seasons. Outcomes included rates of outpatient visits, readmission, emergency department (ED) visits, fever (temperature >=38.0 degrees C), and clinical laboratory evaluations for infection (urine culture, complete blood count, blood culture, and wound culture) in the 7 days after discharge. RESULTS: Of the 42 777 surgeries included in adjusted analyses, vaccine was administered during hospitalization in 6420. No differences were detected between the vaccinated and unvaccinated groups in risk for inpatient visits (rate ratio [RR], 1.12 [95% CI, 0.96 to 1.32]), ED visits (RR, 1.07 [CI, 0.96 to 1.20]), postdischarge fever (RR, 1.00 [CI, 0.76 to 1.31]), or clinical evaluations for infection (RR, 1.06 [CI, 0.99 to 1.13]). A marginal increase in risk for outpatient visits (RR, 1.05 [CI, 1.00 to 1.10]; P = 0.032) was found. LIMITATION: The study did not distinguish between planned and unplanned readmissions or outpatient visits. CONCLUSION: No strong evidence of increased risk for adverse outcomes was found in comparisons of patients who received influenza vaccine during a surgical hospitalization and those who did not. The data support the recommendation to vaccinate surgical inpatients against influenza. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention. PMID- 26974058 TI - Smarter Smartphones. PMID- 26974060 TI - Dendritic alpha-Fe2O3/TiO2 nanocomposites with improved visible light photocatalytic activity. AB - The design and synthesis of unique novel heterostructures for high-performance photocatalytic activity has exerted a tremendous fascination and has recently attracted intensive attention. In this work, a branch-like alpha-Fe2O3/TiO2 heterostructure has been synthesized controllably through an electrospinning method combined with a hydrothermal approach. The backbone of the heterostructure is composed of a 3D porous TiO2 nanofiber (~70 nm in diameter) network with plenty of alpha-Fe2O3 nanorods (100-200 nm in length) deposited on them. The novel branch-like nanocomposites have an abundantly porous structure as well as large surface areas (up to 42.8 m(2) g(-1)). In addition, their visible light photodegradation behaviour towards organic dyes, including Congo red (CR), methylene blue (MB), eosin red (ER) and methyl orange (MO), was investigated. Their excellent photocatalytic performances are attributed to their large surfaces, improved visible light absorption and high separation efficiency of the photogenerated electrons/holes. Furthermore, the degradation process was further studied by varying the amount of alpha-Fe2O3 deposited. The sample alpha Fe2O3/TiO2-3 possessed the best performance to efficiently decolor CR solution even at a high concentration of 50 mg L(-1) (160 min, 94 mg g(-1)), ascribed to the high adsorption capacity derived from the large surface, strong electrostatic interaction and structural match between alpha-Fe2O3/TiO2-3 and CR. These alpha Fe2O3/TiO2 heterostructures exhibit great potential for decontamination of organic pollutants in waste water under visible light. PMID- 26974062 TI - Demonstration of a 280 Gbit/s free-space space-division-multiplexing communications link utilizing plane-wave spatial multiplexing. AB - We demonstrate a 280 Gbit/s free-space space-division-multiplexing communications link incorporating a set of independent tilted truncated plane-waves, each generated by a single mode fiber placed at the back-focal plane of a spherical lens. Each of the seven tilted plane-wave channels are encoded with a 40 Gbit/s 16-QAM signal. Our approach comprises two identical linear fiber-arrays placed approximately 5 m apart. As each fiber array is placed at the back-focal-plane of a spherical lens, each fiber array is effectively placed in a conjugate image plane of the other. A channel crosstalk of less than 26 dB is shown, with a bit error-rate below the FEC threshold of 3.8*10(-3). PMID- 26974061 TI - Crawling wave optical coherence elastography. AB - Elastography is a technique that measures and maps the local elastic property of biological tissues. Aiming for detection of micron-scale inclusions, various optical elastography, especially optical coherence elastography (OCE), techniques have been investigated over the past decade. The challenges of current optical elastography methods include the decrease in elastographic resolution as compared with its parent imaging resolution, the detection sensitivity and accuracy, and the cost of the overall system. Here we report for the first time, we believe, on an elastography technique-crawling wave optical coherence elastography (CRW-OCE) which significantly lowers the requirements on the imaging speed and opens the path to high-resolution and high-sensitivity OCE at relatively low cost. Methods of crawling wave excitation, data acquisition, and crawling wave tracking are presented. PMID- 26974056 TI - Crowdsourced single-trial probes of visual working memory for irrelevant features. AB - We measured the precision with which an irrelevant feature of a relevant object is stored in visual short-term memory. In each experiment, 600 online subjects each completed 30 trials in which the same feature (orientation or color) was relevant, followed by a single surprise trial in which the other feature was relevant. Pooling data across all subjects, we find in a delayed-estimation task but not in a change localization task that the irrelevant feature is retrieved, but with much lower precision than when the same feature is relevant: The irrelevant/relevant precision ratio was 3.8% for orientation and 20.4% for color. PMID- 26974057 TI - Pentoxifylline Inhibits Epidural Fibrosis in Post-Laminectomy Rats. AB - BACKGROUND: The aim of this experimental study was to investigate the effectiveness of intramuscular pentoxifylline in the prevention of postoperative fibrosis. MATERIAL/METHODS: We divided 16 adult Wistar albino rats into 2 equal groups: treatment and control. Both groups underwent L1 vertebral total laminectomy to expose the dura. The intramuscular treatment group received pentoxifylline. Four weeks later, epidural fibrosis was studied in both groups using electron microscopy, light microscopy, histology, biochemistry, and macroscopy. RESULTS: The evaluation of epidural fibrosis in the 2 groups according to macroscopic (p<0.01) assessment and light microscopy revealed that epidural scar tissue formation was lower in the treatment group compared to the control group (p<0.001) and the number of fibroblasts was also decreased significantly in the pentoxifylline-treated group (p<0.05). More immature fibers were demonstrated in the treatment group by electron microscopy in comparison with the control group. In biochemical analysis, a statistically significant decrease was detected in hydroxyproline, which indicates fibrosis and myeloperoxidase activity, and shows an inflammatory response (P<0.001). CONCLUSIONS: Systemic pentoxifylline application prevents postoperative epidural fibrosis and adhesions with various mechanisms. Our study is the first to present evidence of experimental epidural fibrosis prevention with pentoxifylline. PMID- 26974064 TI - Carrier-wave shape effects in optical filamentation. AB - Strong-field ionization in optical filaments created by ultrashort pulses with sub-cycle engineered waveforms is studied theoretically. To elucidate the physics of the recently demonstrated enhanced ionization yield and spatial control of the optical filament core in two color pulses, we employ two types of quantum models integrated into spatially resolved pulse-propagation simulations. We show that the dependence of the ionization on the shape of the excitation carrier is adiabatic in nature, and is driven by local temporal peaks of the electric field. Implications for the modeling of light-matter interactions in multicolor optical fields are also discussed. PMID- 26974063 TI - Calcium imaging of neural circuits with extended depth-of-field light-sheet microscopy. AB - Increasing the volumetric imaging speed of light-sheet microscopy will improve its ability to detect fast changes in neural activity. Here, a system is introduced for brain-wide imaging of neural activity in the larval zebrafish by coupling structured illumination with cubic phase extended depth-of-field (EDoF) pupil encoding. This microscope enables faster light-sheet imaging and facilitates arbitrary plane scanning-removing constraints on acquisition speed, alignment tolerances, and physical motion near the sample. The usefulness of this method is demonstrated by performing multi-plane calcium imaging in the fish brain with a 416*832*160 MUm field of view at 33 Hz. The optomotor response behavior of the zebrafish is monitored at high speeds, and time-locked correlations of neuronal activity are resolved across its brain. PMID- 26974065 TI - Three-dimensional particle tracking via tunable color-encoded multiplexing. AB - We present a novel 3D tracking approach capable of locating single particles with nanometric precision over wide axial ranges. Our method uses a fast acousto-optic liquid lens implemented in a bright field microscope to multiplex light based on color into different and selectable focal planes. By separating the red, green, and blue channels from an image captured with a color camera, information from up to three focal planes can be retrieved. Multiplane information from the particle diffraction rings enables precisely locating and tracking individual objects up to an axial range about 5 times larger than conventional single-plane approaches. We apply our method to the 3D visualization of the well-known coffee-stain phenomenon in evaporating water droplets. PMID- 26974066 TI - Thin LiNbO3 on insulator electro-optic modulator. AB - This Letter presents a method for the fabrication and integration of a thin LiNbO3 substrate with a Si handle wafer. An inverted ridge structure guides a single optical mode in an electro-optic modulator fabricated on a mechanically thinned substrate. To define an optical waveguide, a ridge structure is first patterned on a 500 MUm thick X-cut LiNbO3 wafer; then a low dielectric constant adhesive layer is used to bond the etched LiNbO3 to Si. The LiNbO3 is mechanically thinned to 4 MUm, and planar electrodes are patterned. Experimental results demonstrating modulation with a V(pi)L of 7.1 V-cm were shown, optical loss was low enough, and film quality high enough, to enable an interaction length of 0.8 cm. PMID- 26974067 TI - Direct measurement of the temperature profile close to an optically trapped absorbing particle. AB - The surface temperature of an absorbing particle trapped in optical tweezers (OTs) is measured using a mixture of two fluorescent dyes. We analyze the dependence of temperature on both laser power and the radial distance from its surface, and we verify the 1/r decrease of temperature with increasing distance from the particle surface. We detect the variations of spectral profiles as the medium temperature changes. The temperature dependent signal, i.e., the ratio of summed intensities from two distinct spectral regions, is affected by the convolution of temperature profile with transfer function of the spectroscopic system. We analyze this effect and determine the temperature increase on the surface of a core-shell particle trapped by OTs. PMID- 26974068 TI - Frequency-domain nonlinear regression algorithm for spectral analysis of broadband SFG spectroscopy. AB - The resonant spectral bands of the broadband sum frequency generation (BB-SFG) spectra are often distorted by the nonresonant portion and the lineshapes of the laser pulses. Frequency domain nonlinear regression (FDNLR) algorithm was proposed to retrieve the first-order polarization induced by the infrared pulse and to improve the analysis of SFG spectra through simultaneous fitting of a series of time-resolved BB-SFG spectra. The principle of FDNLR was presented, and the validity and reliability were tested by the analysis of the virtual and measured SFG spectra. The relative phase, dephasing time, and lineshapes of the resonant vibrational SFG bands can be retrieved without any preset assumptions about the SFG bands and the incident laser pulses. PMID- 26974069 TI - Effect of rounding corners on optical resonances in single-mode sharp-cornered microresonators. AB - The use of microresonators with sharp corners (rectangular and square-shaped) can be limited by severe energy loss at the corners. A 2D numerical study is conducted to investigate and analyze the effect of incorporating fillet (rounding of corners) design at sharp corners of such single-mode optical microresonators. The effect on quality factor, free spectral range, and energy loss for the coupled microresonator-waveguide system in the add-drop configuration for varying values of fillet radii are quantified. It is shown that the selection of an optimum radius of the curvature of the fillet for sharp-cornered microresonators provides a higher quality factor than that of the conventional circular resonators. PMID- 26974070 TI - Ultrafast imaging with anti-aliasing based on optical time-division multiplexing. AB - Serial time-encoded amplified microscopy (STEAM) is a novel ultrafast imaging technique that is based on space-to-time-to-wavelength mapping. Nevertheless, the technique requires a high-cost electronic digitizer of several tens of gigahertz sampling rate to read out sufficient image information. To acquire a large amount of image information by using a relatively low-sampling-rate electronic digitizer, an anti-aliasing technique based on optical time-division multiplexing is proposed. A 38.88 MHz line-scan imaging system is demonstrated experimentally. By using the proposed anti-aliasing technique, a 20 GS/s sampling rate is achieved by employing a 10 GS/s electronic digitizer. Defects and scratches on the target that were not identifiable originally can be clearly distinguished after using the proposed technique. Numerical analysis shows that the image quality can be improved by 4.16 dB, compared to that not using the anti-aliasing technique and at least 2.3 dB comparing to those obtained by bilinear, bicubic, and nearest-neighbor interpolation and Lanczos resampling techniques. PMID- 26974071 TI - Single-pixel imaging using compressed sensing and wavelength-dependent scattering. AB - We demonstrate two-dimensional imaging using illumination via a single-mode fiber with a multiply scattering tip and compressed sensing acquisition. We illuminate objects with randomly structured, but deterministic, speckle patterns produced by a coherent light source propagating through a TiO2-coated fiber tip. The coating thickness is optimized to produce speckle patterns that are highly sensitive to laser wavelength, yet repeatable. Images of the object are reconstructed from the characterized wavelength dependence of the speckle patterns and the wavelength dependence of the total light collected from the object using a single photodetector. Our imaging device is mechanically scan-free and insensitive to bending of the fiber, making it suitable for micro-endoscopy. PMID- 26974072 TI - Generation of 30 fs pulses from a diode-pumped graphene mode-locked Yb:CaYAlO4 laser. AB - Stable 30 fs pulses centered at 1068 nm (less than 10 optical cycles) are demonstrated in a diode pumped Yb:CaYAlO4 laser by using high-quality chemical vapor deposited monolayer graphene as the saturable absorber. The mode-locked 8.43 optical-cycle pulses have a spectral bandwidth of ~50 nm and a pulse repetition frequency of ~113.5 MHz. To the best of our knowledge, this is the shortest pulse ever reported for graphene mode-locked lasers and mode-locked Yb doped bulk lasers. Our experimental results demonstrate that graphene mode locking is a very promising practical technique for directly generating few-cycle optical pulses from a laser oscillator. PMID- 26974073 TI - Lithographic wavelength control of an external cavity laser with a silicon photonic crystal cavity-based resonant reflector. AB - We report the experimental demonstration of a new design for external cavity hybrid lasers consisting of a III-V semiconductor optical amplifier (SOA) with fiber reflector and a photonic crystal (PhC)-based resonant reflector on SOI. The silicon reflector is composed of an SU8 polymer bus waveguide vertically coupled to a PhC cavity and provides a wavelength-selective optical feedback to the laser cavity. This device exhibits milliwatt-level output power and side-mode suppression ratios of more than 25 dB. PMID- 26974074 TI - Ultrafast amplifier additive timing jitter characterization and control. AB - We report on the characterization and long-term compensation of additive timing jitter introduced by a femtosecond ytterbium regenerative amplifier with a 100 kHz repetition rate. A balanced optical cross-correlation technique is used to generate a jitter error signal. This approach is well suited to characterize the additive timing jitter of Yb amplifiers seeded by narrow spectrum Yb oscillators. The balanced optical cross-correlator is in a noncollinear configuration allowing a background free coindence detection. This setup enables the measurement of additive timing jitter from the amplifier, with a noise floor of 300 as integrated from 10 Hz to 10 kHz. The measured additive timing jitter level is about 5 fs, integrated from 0.1 Hz to 10 kHz. The amplifier timing drift characterization and control are performed for more than an hour. PMID- 26974075 TI - Imaging system based on a tandem acousto-optical tunable filter for in situ measurements of the high temperature distribution. AB - We present, to the best of our knowledge, the first experimental demonstration of a new imaging system for in situ measurement of the two-dimensional (2D) distribution of the surface temperature of microscopic specimens. The main component of the system is an imaging tandem acousto-optical tunable filter (TAOTF) synchronized with a video camera. A set of TAOTF spectroscopic images (up to a few hundreds) is taken by the TAOTF imaging system to fit the measured spectral curves in each pixel to the Planck radiation function and determine the temperature and emissivity of the sample using the gray body approximation. It is experimentally shown that this technique provides aberration-free spectral imaging suitable for precise multispectral imaging radiometry (MIR). PMID- 26974076 TI - Laser-diode-pumped thin-slice c-cut Nd:GdVO4 multimode laser with coherent vector fields: erratum. AB - In a previous Letter [Opt. Lett.40, 1177 (2015), oscillation wavelengths corresponding to two sigma-polarized transition lines 4F(3/2)(1)-> 4I(11/2)(1) and 4F(3/2)(2)->4I(11/2)(2) were described in inverse. Here, the corrected correspondence between transition lines and oscillation wavelengths is addressed. PMID- 26974077 TI - Polarization modulation for imaging behind the scattering medium. AB - We propose and experimentally demonstrate a technique, based on polarization modulation, for imaging of the polarization discriminating object hidden behind a scattering medium. This is realized by making use of the relation between the complex correlation function of the randomly scattered orthogonal polarization components in the far field and polarized source structure at the scattering plane. Full use of a polarimetric parameter at the scattering plane is realized in the object plane reconstruction behind the scattering medium using a backpropagation approach. To demonstrate application of the technique, imaging of two different objects lying behind the scattering media is presented. PMID- 26974078 TI - Graphene-gold supercapacitor as a voltage controlled saturable absorber for femtosecond pulse generation. AB - We report, for the first time to the best of our knowledge, use of a graphene gold supercapacitor as a voltage controlled fast saturable absorber for femtosecond pulse generation. The unique design involving only one graphene electrode lowers the insertion loss of the device, in comparison with capacitor designs with two graphene electrodes. Furthermore, use of the high-dielectric electrolyte allows reversible, adjustable control of the absorption level up to the visible region with low bias voltages of only a few volts (0-2 V). The fast saturable absorber action of the graphene-gold supercapacitor was demonstrated inside a multipass-cavity Cr:forsterite laser to generate nearly transform limited, sub-100 fs pulses at a pulse repetition rate of 4.51 MHz at 1.24 MUm. PMID- 26974079 TI - Analysis of non-linearity in differential wavefront sensing technique. AB - An analytical model of a differential wavefront sensing (DWS) technique based on Gaussian Beam propagation has been derived. Compared with the result of the interference signals detected by quadrant photodiode, which is calculated by using the numerical method, the analytical model has been verified. Both the analytical model and numerical simulation show milli-radians level non-linearity effect of DWS detection. In addition, the beam clipping has strong influence on the non-linearity of DWS. The larger the beam clipping is, the smaller the non linearity is. However, the beam walking effect hardly has influence on DWS. Thus, it can be ignored in laser interferometer. PMID- 26974080 TI - Eye-safe 1.55 MUm passively Q-switched Er,Yb:GdAl3(BO3)4 diode-pumped laser. AB - We report for the first time, to the best of our knowledge, on a diode-pumped passively Q-switched Er,Yb:GdAl3(BO3)4 laser. By using a Co2+:MgAl2O4 crystal as a saturable absorber, Q-switched laser pulses with a duration of 12 ns and a maximum energy of 18.7 MUJ at a repetition rate of 32 kHz corresponding to an average output power of 0.6 W were obtained at 1550 nm under continuous-wave pumping. In the burst mode of operation, Q-switched laser pulses with the highest energy up to 44 MUJ were realized with a pulse repetition rate of 6.5 kHz. PMID- 26974081 TI - Finite-size effect in light transmission through highly forward scattering media at grazing angles. AB - We present a theoretical study of light transmission through a disordered medium with large (compared to the light wavelength) inhomogeneities. Both numerical integration and analytic treatments of the radiative transfer equation are performed. An effect of the single-scattering phase function on the total transmittance is found in a subdiffusion thickness range. The effect reveals itself at grazing angles of incidence and originates from small-angle multiple scattering of light. A simple analytic formula for the total transmittance is derived. Our results are in good agreement with data of independent numerical calculations. PMID- 26974082 TI - Background-free Brillouin spectroscopy in scattering media at 780 nm via stimulated Brillouin scattering. AB - We demonstrate the effectiveness of stimulated Brillouin scattering for background-free Brillouin spectroscopy in scattering media within the biological spectral window. Using two nearly counter-propagating continuous-wave diode laser beams at 780 nm, we acquired transmission stimulated Brillouin point spectra in 10 mm and 500 MUm thick Intralipid tissue phantoms with ~100 MUm and ~16 MUm diameter focal points, respectively. Stimulated gain spectra with high signal-to noise ratio (8.7-30.7 dB) and frequency accuracy (6-72 MHz) were obtained at 20 MHz/10 ms and 20 MHz/100 ms through 0.24-3.36 mean-free paths of tissue phantoms. Our results suggest that stimulated Brillouin gain can be useful for imaging of Brillouin resonances in submillimeter-thick scattering samples. PMID- 26974083 TI - Broadband mid-infrared pulses from potassium titanyl arsenate/zinc germanium phosphate optical parametric amplifier pumped by Tm, Ho-fiber-seeded Ho:YAG chirped-pulse amplifier. AB - We present a concept of a white-light-seeded-cascaded mid-infrared (mid-IR) optical parametric amplifier (OPA) based on potassium titanyl arsenate and zinc germanium phosphate nonlinear optical crystals and producing 100-MUJ level pulses centered at 5300 nm, with the spectrum supporting four-optical-cycle pulse duration. The OPA is pumped by 2090-nm master oscillator/power amplifier based on a Tm,Ho-fiber laser seeder and a Ho:YAG regenerative amplifier delivering 3.8-mJ sub-ps pulses at a repetition rate of 1 kHz. We validate that output parameters of the OPA are scalable by means of increasing the pulse energy, decreasing the pulse duration and redshifting the central wavelength. PMID- 26974084 TI - Large-scale optical diffraction tomography for inspection of optical plastic lenses. AB - Herein is presented an optical diffraction tomography (ODT) technique for measuring 3-D refractive index (RI) maps of optical plastic lenses. A Mach Zehnder interferometer was used to measure multiple complex optical fields of a plastic lens immersed in RI-matching oil at various rotational orientations. From this, ODT was used to reconstruct a 3-D RI distribution of the plastic lens with unprecedented RI sensitivity (Deltan=4.21*10(-5) and high resolution (12.8 MUm). As a demonstration, 3-D RI distributions of a 2 mm-diameter borosilicate sphere and a 5 mm-diameter plastic lens were reconstructed. Defects in the lens, generated by pulsed laser ablation, were also detected using the present method. PMID- 26974085 TI - Hyperspectral imaging camera using wavefront division interference. AB - An approach for performing hyperspectral imaging is introduced. The hyperspectral imaging is based on Fourier transform spectroscopy, where the interference is performed by wavefront division interference rather than amplitude division interference. A variable phase delay between two parts of the wavefront emanating from each point of an object is created by a spatial light modulator (SLM) to obtain variable interference patterns. The SLM is placed in the exit pupil of an imaging system, thus enabling conversion of a general imaging optical system into an imaging hyperspectral optical system. The physical basis of the new approach is introduced, and an optical apparatus is built. PMID- 26974086 TI - Suppression of excess noise of longer-lived high-quality states in nonuniformly pumped optical microcavities. AB - We study the formation of longer-lived states via internal coupling near a special avoided resonance crossing between the interacting states in an open optical system. Away from the parity-time symmetry limit, we discuss unconventional cavity resonance states created by a spatially varying gain/loss profile. Now, via S-matrix formalism, we have numerically demonstrated that with suitably chosen system openness and coupling strengths, the excess noise generation among the interacting nonorthogonal states (calculated as Petermann factor K) can be suppressed close to the ideal value of one with a simultaneous order of magnitude enhancement in the quality-factor of the longer-lived state. PMID- 26974087 TI - Highly stable, monolithic, single-mode mid-infrared supercontinuum source based on low-loss fusion spliced silica and fluoride fibers. AB - A 0.8 to 4.5 MUm highly stable all-fiber spliced mid-infrared supercontinuum (SC) source was presented. The joint between the single-mode (SM) pump silica fiber and the ZBLAN fiber (ZrF4 - BaF2 - LaF3 - AlF3 - NaF, a type of fluoride fiber) was fusion spliced, which greatly improved the SC's stability. The low-loss splicing was guaranteed by the similar mode field areas of the fundamental mode LP(01) of the silica and ZBLAN fibers. At the splicing joint the ZBLAN fiber enveloped the silica fiber, thus increasing the robustness of the splice. A low splicing loss of less than 0.1 dB was calculated, which ensured that the whole SC source was very reliable. The SC had a maximal average power of 550.8 mW with a 1.5 dB spectral bandwidth ranging from 2642 to 4065 nm. In particular, the SC power for lambda>3.8 MUm was measured to be 116.1 mW with a power ratio of ~21.1% of the total SC power. Perfect Gaussian beam profiles of the SC source demonstrated its SM operation. Over 12 h of continuous operation of this SC source showed its outstanding power stability with a root mean square variation of 0.59%, which also demonstrated the high quality of the fusion spliced joint. PMID- 26974088 TI - Rear-side resonator architecture for the passive coherent combining of high brightness laser diodes. AB - We describe a new coherent beam combining architecture based on passive phase locking of emitters in an extended cavity on the rear facet and their coherent combination on the front facet. This rear-side technique provides strong optical feedback for phase locking while maintaining a high electrical-to-optical efficiency. Two high-brightness high-power tapered laser diodes are coherently combined using a Michelson-based cavity. The combining efficiency is above 82% and results in an output power of 6.7 W in a nearly diffraction-limited beam with an M(4sigma)(2)<=1.2. A semi-active automatic adjustment of the current enhances the long-term stability of the combination, while the short-term stability is passively ensured by the extended cavity. This new laser configuration exhibits the simplicity of passive self-organizing architectures while providing a power conversion efficiency of 27% that is comparable to master oscillator power amplifier architectures. PMID- 26974089 TI - Phonon-assisted upconversion charging in Zn3Ga2GeO8:Cr(3+) near-infrared persistent phosphor. AB - We report a new phonon-assisted upconversion excitation design that enables the excitation energy to be lower than the persistent luminescence emission energy in persistent phosphors. We demonstrate this upconversion excitation concept in Zn3Ga2GeO8:Cr(3+) near-infrared persistent phosphor by achieving Cr(3+) 700 nm persistent emission using 800 or 980 nm laser diode excitation. Depending on the sample temperature, the excitation photon energy can be tuned, and the persistent luminescence intensity can be adjusted. Depending on the excitation power, the upconversion trap filling process involves either one photon (for filling low energy traps) or two photons (for filling high-energy traps). Our research provides a major step toward manipulating the electronic excitation in persistent luminescence, which has implication for many applications. PMID- 26974090 TI - Experimental demonstration of linearly polarized 2-10 MUm supercontinuum generation in a chalcogenide rib waveguide. AB - This Letter reports the production of a supercontinuum extending from ~2 MUm to >10 MUm generated using a chalcogenide buried rib waveguide pumped with 330 femtosecond pulses at 4.184 MUm. This is, to the best of our knowledge, the broadest mid-infrared supercontinuum generated in any planar waveguide platform. Because the waveguide is birefringent, quasi-single-mode, and uses an optimized dispersion design, the supercontinuum is linearly polarized with an extinction ratio >100. Dual beam spectrophotometry is performed easily using this source. PMID- 26974091 TI - Resonance optical activity in multihelicoidal optical fibers. AB - We have studied the effect of optical activity (OA) in optical fibers with multihelical distribution of refractive index profiles near the resonance wavelength, at which the conversion of an incident Gaussian beam into an optical vortex (and vice versa) takes place. We have shown that at such a wavelength the polarization vector of the input Gaussian beam rotates within the fiber at an average rate proportional to the difference in propagation constants of left- and right-circularly polarized optical vortices with the same topological charge. We also show that for certain fiber lengths the magnitude of OA can greatly exceed its average level and reach anomalously high values. PMID- 26974092 TI - Carrier-envelope offset frequency stabilization in a femtosecond optical parametric oscillator without nonlinear interferometry. AB - By exploiting the correlation between changes in the wavelength and the carrier envelope offset frequency (f(CEO)) of the signal pulses in a synchronously pumped optical parametric oscillator, we show that f(CEO) can be stabilized indefinitely to a few megahertz in a 333 MHz repetition-rate system. Based on a position sensitive photodiode, the technique is easily implemented, requires no nonlinear interferometry, has a wide capture range, and is compatible with feed-forward techniques that can enable f(CEO) stabilization at loop bandwidths far exceeding those currently available to OPO combs. PMID- 26974093 TI - Single-crystalline tellurite optical fiber hydrophone. AB - This Letter presents a novel type of single-crystalline tellurite optical fiber (SC-TOF) for potential hydrophonic applications. Both single-mode and multimode SC-TOF were fabricated. Compared with conventional devices, our preliminary results indicate that the novel device has considerably wider sensing ranges of acoustic frequency (10 Hz to 5.6 MHz or more), acoustic intensity (70 to -236 dB), and directional sensitivity (0.094 to 0.04 nm/deg) to the incident direction of an acoustic wave in a SC-TOF. PMID- 26974094 TI - Self-referenced, accurate and sensitive optical frequency comb spectroscopy with a virtually imaged phased array spectrometer. AB - We present a cavity-enhanced direct optical frequency comb spectroscopy system with a virtually imaged phased array (VIPA) spectrometer and either a dither or a Pound-Drever-Hall (PDH) locking scheme used for stable transmission of the comb through the cavity. A self-referenced scheme for frequency axis calibration is shown along with an analysis of its accuracy. A careful comparison between both locking schemes is performed based on near-IR measurements of the carbon monoxide nu=3<-0 band P branch transitions in a gas sample with known composition. The noise-equivalent absorptions (NEA) for the PDH and dither schemes are 9.9*10(-10) cm(-1) and 5.3*10(-9) cm(-1), respectively. PMID- 26974096 TI - Tunable guided-mode resonant filter with wedged waveguide layer fabricated by masked ion beam etching. AB - A compact, tunable guided-mode resonant (GMR) filter whose spectral reflectance wavelength varies as a function of the spatial position on the device is experimentally demonstrated. The filter incorporates a wedge-shaped waveguide layer that is fabricated using masked ion beam etching (MIBE) technology. A ceramic plate mask consisting of an isosceles triangular window is placed between the ion source and the sample to achieve different etching times at difference locations on the film. The increment in the magnitude of the film thickness is approximately 50 nm over a length of 33 mm, which results in a primary reflectance peak whose spectral location spans the range of 684.2-725.3 nm. The device is designed using the rigorous coupled-wave analysis (RCWA) method, and the proposed device is directed toward the practical application of GMR tunable filters. PMID- 26974095 TI - Single-tube on-beam quartz-enhanced photoacoustic spectroscopy. AB - Quartz-enhanced photoacoustic spectroscopy (QEPAS) with a single-tube acoustic microresonator (AmR) inserted between the prongs of a custom quartz tuning fork (QTF) was developed, investigated, and optimized experimentally. Due to the high acoustic coupling efficiency between the AmR and the QTF, the single-tube on-beam QEPAS spectrophone configuration improves the detection sensitivity by 2 orders of magnitude compared to a bare QTF. This approach significantly reduces the spectrophone size with respect to the traditional on-beam spectrophone configuration, thereby facilitating the laser beam alignment. A 1sigma normalized noise equivalent absorption coefficient of 1.21*10(-8) cm(-1).W/?Hz was obtained for dry CO2 detection at normal atmospheric pressure. PMID- 26974097 TI - Carrier envelope phase shifter for broadband terahertz pulses. AB - We demonstrated controlled shifting of the internal phase of broadband terahertz (THz) pulses. The internal phase of an ultrashort pulse is called the carrier envelope phase (CEP), which is an important parameter in the interaction of few cycle light pulses and matter. Our CEP shifter utilizes the ultra-broadband feature of prism wave plates. We analytically derived the amount of CEP shift achievable by the CEP shifter using Jones matrixes. THz time-domain measurements clearly showed the shift of the CEP, and the results agreed well with the calculated values. The CEP shift was as high as 2pi, indicating that any CEP values can be chosen using our CEP shifter. PMID- 26974098 TI - Reflection-type spatial amplitude modulation of visible light based on a sub wavelength plasmonic absorber. AB - We present a method for reflection-type spatial amplitude modulation using a sub wavelength plasmonic absorber structure that can operate in the visible region. We utilize a pixelated array of absorbing elements based on a two-dimensional sub wavelength metal grating, and the reflectance of each pixel is controlled by simple structural modification. For the purpose of validation, numerical simulations were performed on an amplitude modulation hologram fabricated using our method. PMID- 26974099 TI - Probability-based non-local means filter for speckle noise suppression in optical coherence tomography images. AB - In this Letter, a probability-based non-local means filter is proposed for speckle reduction in optical coherence tomography (OCT). Originally developed for additive white Gaussian noise, the non-local means filter is not suitable for multiplicative speckle noise suppression. This Letter presents a two-stage non local means algorithm using the uncorrupted probability of each pixel to effectively reduce speckle noise in OCT. Experiments on real OCT images demonstrate that the proposed filter is competitive with other state-of-the-art speckle removal techniques and able to accurately preserve edges and structural details with small computational cost. PMID- 26974100 TI - Super-resolution in a defocused plenoptic camera: a wave-optics-based approach. AB - Plenoptic cameras enable the capture of a light field with a single device. However, with traditional light field rendering procedures, they can provide only low-resolution two-dimensional images. Super-resolution is considered to overcome this drawback. In this study, we present a super-resolution method for the defocused plenoptic camera (Plenoptic 1.0), where the imaging system is modeled using wave optics principles and utilizing low-resolution depth information of the scene. We are particularly interested in super-resolution of in-focus and near in-focus scene regions, which constitute the most challenging cases. The simulation results show that the employed wave-optics model makes super resolution possible for such regions as long as sufficiently accurate depth information is available. PMID- 26974101 TI - Self-frequency-doubled vibronic yellow Yb:YCOB laser at the wavelength of 570 nm. AB - A watt-level self-frequency-doubled yellow laser at the 570 nm wavelength was realized by taking advantage of the vibronic emission of a Yb3+ doped calcium yttrium oxoborate (Yb:YCOB) crystal cut along the optimized direction out of the principal planes with the maximum effective nonlinear coefficient. Fluorescence spectroscopic properties of Yb:YCOB were studied, which showed that it had broad and anisotropic vibronic emission with a small peak at ~1130 nm. By suppressing the electronic emission, the polarized vibronic Yb:YCOB radiation was realized with the fundamental wavelength shifting from 1130 nm to 1140 nm. By employing the self-frequency-doubling behavior of Yb:YCOB, the self-frequency-doubled yellow laser was achieved with a maximum output power of 1.08 W at 570 nm. This work provides an unprecedented and efficient way to generate yellow lasers with a compact microchip structure that may have promising applications in some regimes including medicine, entertainment, and scientific research. PMID- 26974102 TI - Cost-effective imaging of optoacoustic pressure, ultrasonic scattering, and optical diffuse reflectance with improved resolution and speed. AB - The idea of a method of cost-effective upgrades from an acoustic resolution photoacoustic microscope to a triple-modality imaging system is validated using phantoms. The newly developed experimental setup is based on a diode pumped solid state laser coupled to a fiber bundle with a spherically focused polyvinylidene fluoride detector integrated into the center of a ring shaped optical illuminator. Each laser pulse illuminating the sample performs two functions. While the photons absorbed by the sample provide a measurable optoacoustic (OA) signal, the photons absorbed by the detector provide the measurable diffuse reflectometry (DR) signal from the sample and the probing ultrasonic (US) pulse. At a 3 mm imaging depth, the axial resolution of the OA/US modalities is 38 MUm/26 MUm, while the lateral resolution of the DR/OA/US modalities is 3.5 mm/50 MUm/35 MUm. The maximum acquisition rate of the trimodal DR/OA/US A-scans is 2 kHz. PMID- 26974103 TI - Funnel-shaped silicon nanowire for highly efficient light trapping. AB - In this Letter, funnel-shaped silicon nanowires (SiNWs) are newly introduced for highly efficient light trapping. The proposed designs of nanowires are inspired by the funnel shape, which enhances the light trapping with reduced reflections in the wavelength range from 300 to 1100 nm. Composed of both cylindrical and conical units, the funnel nanowires increase the number of leaky mode resonances, yielding an absorption enhancement relative to a uniform nanowire array. The optical properties of the suggested nanowires have been numerically investigated using the 3D finite difference time domain (FDTD) method and compared to cylindrical and conical counterparts. The structural geometrical parameters are studied to maximize the ultimate efficiency and hence the short-circuit current. Carefully engineered structure geometry is shown to yield improved light absorption useful for solar cell applications. The proposed funnel-shaped SiNWs offer an ultimate efficiency of 41.8%, with an enhancement of 54.8% relative to conventional cylindrical SiNWs. Additionally, short-circuit current of 34.2 mA/cm2 is achieved using the suggested design. PMID- 26974104 TI - Bidirectional microwave and optical signal dissemination. AB - We describe a technique to disseminate highly stable microwave and optical signals from physically separated frequency standards to multiple locations. We demonstrate our technique by transferring the frequency stability performance of a microwave frequency reference to the repetition-rate stability of an optical frequency comb in a different location. The stabilized optical frequency comb becomes available in both locations for measurements of both optical and microwave signals. We show a microwave frequency stability of 4*10(-15) in both locations for integration times beyond 100 s. The control system uses only a standard Ethernet connection. PMID- 26974105 TI - High-efficiency, kilowatt 1034 nm all-fiber amplifier operating at 11 pm linewidth. AB - We present power scaling results of a monolithic Yb-doped 1034 nm fiber amplifier well-suited for beam combining applications. Stimulated Brillouin scattering suppression is achieved through optical linewidth broadening, and results were compared for both white noise source (WNS) and pseudo-random bit sequence (PRBS) phase modulation schemes. Notably, through PRBS modulation at a clock rate of 3.5 GHz, 1 kW of output power with a slope efficiency of 81% was demonstrated. Beam quality measurements indicated near diffraction-limited operation with no sign of modal instability. At a comparable linewidth and fiber length, power scaling via WNS modulation yielded only 470 W. The kilowatt-class output at a linewidth of 11 pm is the highest power reported for a spectrally narrow all-fiber amplifier operating at the short wavelength end of the high gain range in Yb-doped silica. PMID- 26974106 TI - Thermal poling of femtosecond laser-written waveguides in fused silica. AB - Thermal poling of femtosecond laser written waveguides was investigated using second-harmonic microscopy under three approaches: (1) pre-poling and (2) post poling in which fused silica substrates were poled before or after waveguide formation, respectively, and (3) double poling in which poling was applied both before and after laser writing. Effective nonlinear waveguide interaction strength was assessed relative to the mode profile and the assessments demonstrated an erasure effect of 81% in pre-poling and an ion migration blocking effect of 26% in post-poling. Double poling was found to recover the nonlinearity over the modal zone, overcoming prior difficulties with combining laser processing and thermal poling, opening up a future avenue for creating active devices through femtosecond laser writing of nonlinear optical circuits in fused silica. PMID- 26974107 TI - Harmonic superposition for tailored optical frequency comb generation by a Mach Zehnder modulator. AB - This Letter demonstrates tailored optical frequency comb (OFC) generation using a LiNbO3 Mach-Zehnder modulator driven by a combination of first- and second-order harmonics of the RF signal. A quasi-rectangular-shaped OFC with less than 1 dB flatness among 11 lines was experimentally obtained when a slight second-order harmonic of the RF signal (0.1 times the half-wavelength voltage) was introduced. Good agreement was obtained between the measured and calculation results for OFCs. We discuss conditions to obtain flat OFCs using this method along with details concerning OFC conversion efficiency and bandwidth. PMID- 26974108 TI - Single logical qubit information encoding scheme with the minimal optical decoherence-free subsystem. AB - We present a scheme for encoding single logical qubit information, which is immune to collective decoherence acting on Hilbert space spanned by the corresponding states. The scheme needs a spatial entanglement gate and a polarization entanglement gate, which are realized with the assistance of weak cross-Kerr nonlinear interaction between photons and coherent states via Kerr media. Under the condition of sufficient large phase shifts, single logical qubit information can be encoded into this minimal optical decoherence-free subsystem with near-unity fidelity. Together with the mature techniques of measurement and classical feed forward, simple linear optical elements are applied to complete the encoding task, which offers the feasibility of this scheme for protecting quantum information against decoherence. PMID- 26974109 TI - Optically induced hysteresis in a two-state quantum dot laser. AB - Quantum dot lasers can lase from the ground state only, simultaneously from both the ground and first excited states and from the excited state only. We examine the influence of optical injection at frequencies close to the ground state when the free-running operation of the device is excited state lasing only. We demonstrate the existence of an injection-induced bistability between ground state dominated emission and excited state dominated emission and the consequent hysteresis loop in the lasing output. Experimental and numerical investigations are in excellent agreement. Inhomogeneous broadening is found to be the underlying physical mechanism driving the phenomenon. PMID- 26974111 TI - Nonparaxial abruptly autofocusing beams. AB - We study nonparaxial autofocusing beams with pre-engineered trajectories. We consider the case of linearly polarized electric optical beams and examine their focusing properties, such as contrast, beam width, and numerical aperture. Such beams are associated with larger intensity contrasts, can focus at smaller distances, and have smaller spot sizes as compared to the paraxial regime. PMID- 26974110 TI - Rapid wide-field Mueller matrix polarimetry imaging based on four photoelastic modulators with no moving parts. AB - A new polarimetry method is demonstrated to image the entire Mueller matrix of a turbid sample using four photoelastic modulators (PEMs) and a charge coupled device (CCD) camera, with no moving parts. Accurate wide-field imaging is enabled with a field-programmable gate array (FPGA) optical gating technique and an evolutionary algorithm (EA) that optimizes imaging times. This technique accurately and rapidly measured the Mueller matrices of air, polarization elements, and turbid phantoms. The system should prove advantageous for Mueller matrix analysis of turbid samples (e.g., biological tissues) over large fields of view, in less than a second. PMID- 26974112 TI - Mapping electron-beam-injected trapped charge with scattering scanning near-field optical microscopy. AB - Scattering scanning near-field optical microscopy (s-SNOM) has been demonstrated as a valuable tool for mapping the optical and optoelectronic properties of materials with nanoscale resolution. Here we report experimental evidence that trapped electric charges injected by an electron beam at the surface of dielectric samples affect the sample-dipole interaction, which has direct impact on the s-SNOM image content. Nanoscale mapping of the surface trapped charge holds significant potential for the precise tailoring of the electrostatic properties of dielectric and semiconductive samples, such as hydroxyapatite, which has particular importance with respect to biomedical applications. The methodology developed here is highly relevant to semiconductor device fabrication as well. PMID- 26974113 TI - Spatiotemporal three-dimensional phase unwrapping in digital speckle pattern interferometry. AB - We propose a hybrid spatiotemporal three-dimensional phase unwrapping algorithm for use in digital speckle pattern interferometry (DSPI). The feature of the proposed algorithm is the integration of one-dimensional temporal and two dimensional spatial phase unwrapping algorithms. By demodulating the phase on a single reference point or multiple reference points using temporal phase unwrapping and on each separated phase map region using spatial phase unwrapping, the DSPI with the spatiotemporal three-dimensional phase unwrapping algorithm can realize the measurement of dynamic absolute displacements and the determination of abrupt phase changes which are usually caused by object discontinuities. We demonstrate that the presented algorithm can overcome the drawbacks of the traditional spatial and temporal phase unwrapping algorithms. PMID- 26974114 TI - Periodic and chaotic dynamics in a passively Q-switched Nd:GdVO4 laser with azimuthal polarization. AB - A period-doubling route to chaos was observed in a passively Q-switched Nd:GdVO4 laser beam with azimuthal polarization. At a period of two, the peak intensities gradually varied with the azimuthal angle. When the pump power was increased, the chaotic behavior was spatiotemporal, but the polarization was still azimuthal. To the best of our knowledge, this is the first report of spatiotemporal chaos under a stationary spatial distribution of the polarization. PMID- 26974115 TI - Single-shot angular compounded optical coherence tomography angiography by splitting full-space B-scan modulation spectrum for flow contrast enhancement. AB - We proposed a single-shot spatial angular compounded optical coherence tomography angiography (AC-Angio-OCT) for blood flow contrast enhancement. By encoding incident angles in B-scan modulation frequencies and splitting the modulation spectrum in the spatial frequency domain, angle-resolved independent subangiograms were obtained and compounded to improve the flow contrast. A full space of the spatial frequency domain allows a wide modulation spectrum. To get access to the full space of the spatial frequency domain and avoid the complex conjugate ambiguity of the modulation spectrum, a complex-valued OCT spectral interferogram was retrieved by removing one of the conjugate terms in the depth space. To validate the proposed concept, both flow phantom and live animal experiments were performed. The proposed AC-Angio-OCT offers a ~50% decrease of misclassification errors, and an improved flow contrast and vessel connectivity, which contributes to the interpretation of OCT angiograms. PMID- 26974116 TI - Second-harmonic illumination to enhance multispectral digital lensless holographic microscopy. AB - Multispectral digital lensless holographic microscopy (MDLHM) operating with second-harmonic illumination is shown. Added to the improvement of the spatial resolution of the previously reported MDLHM operating with near-infrared illumination, this second-harmonic MDLHM shows promise as a tool to study the behavior of biological samples under a broad spectral illumination. This illumination is generated by focusing a highly spatially coherent ultrashort pulsed radiation into an uncoated Type 1 beta-BaB2O4 (BBO) nonlinear crystal. The second-harmonic MDLHM allows achieving multispectral images of biological samples with enhanced micrometer spatial resolution. The illumination wavelength of the second-harmonic MDLHM can be tuned by displacing a focusing optics with respect to a pinhole; spatially resolved information at different wavelengths of the sample can then be retrieved. PMID- 26974117 TI - Ultrahigh resolution optical fiber strain sensor using dual Pound-Drever-Hall feedback loops. AB - We present an ultrahigh resolution optical fiber strain sensor with a broad frequency range from quasi-static to several hundred hertz. The sensor consists of a pi-phase shifted fiber Bragg grating for strain sensing and a fiber Fabry Perot interferometer as reference. The laser carrier and sideband are locked to the reference and sensing elements, respectively, via two individual feedback loops, in which the Pound-Drever-Hall technique is employed to generate the error signals. The sampling rate is up to 500 samples/s in the demonstrational experiments, only limited by the updating rate of the frequency counter. The strain resolution exhibits a 1/f characteristic in the bandwidth of 0.01-250 Hz, and is better than 0.01 nepsilon at 10 Hz with a dynamic range up to 149 dB. Compared with the traditional static strain sensors, the proposed sensor shows a great improvement in both resolution and sensing bandwidth, and can be a powerful tool for geophysical applications. PMID- 26974118 TI - Highly efficient silicon optical polarization rotators based on mode order conversions. AB - We design and demonstrate the novel silicon optical polarization rotators (PRs) based on the TM(0)-TE(n)-TE(0) mode conversions inside the waveguide. The TM(0) TE(n) mode converters are realized by the mode hybridization of the tapered rib waveguides. The TE(n)-TE(0) mode converters based on the beam shaping method are followed to complete the PRs function. By using the TE(1), TE(2), and TE(3) mode as the transitional mode, the fabricated PRs show the insert losses of less than 0.4, 0.5, and 1 dB, respectively. The corresponding polarization extinction ratios of larger than 21, 18, and 23 dB, over a wavelength range of 100 nm. PMID- 26974120 TI - Alkali base triggered intramolecular charge transfer metallogels based on symmetrical A-pi-D-chiral-D-pi-A type ligands. AB - Three l-tartaric acid based symmetrical A-pi-D-chiral-D-pi-A type structural isomeric nitrobenzylidenes (1-3) have been synthesized with intent to achieve isomer specific metallogels with intramolecular charge transfer properties. Alkali metal ions in these systems not only trigger charge transfer but also play a vital role in gelation. The presence of intramolecular rather than intermolecular charge transfer as well as aggregation has been well established by various kinds of experiments using UV-vis, CD, (1)H NMR, DFT and crystallography techniques. The role of alkali metal ions in triggering ICT was proved by titration with their respective crown ethers. Notably, Na(+) afforded twisted fiber morphology whilst Li(+) gave merely long range fibers. The true gel phase material was proved by detailed rheological studies. PMID- 26974119 TI - Long noncoding RNAs in psychiatric disorders. AB - Long noncoding RNAs (lncRNAs) are nonprotein coding transcripts longer than 200 nucleotides. Many of these lncRNAs have regulatory functions and have recently emerged as major players in governing fundamental biological processes. Here, we review the definition, distribution, identification, databases, analysis, classification, and functions of lncRNAs. We also discuss the potential roles of lncRNAs in the etiological processes of psychiatric disorders and the implications for clinical diagnosis and treatment. PMID- 26974121 TI - Phosphinosilylenes as a novel ligand system for heterobimetallic complexes. AB - A dihydrophosphinosilylene iron complex [LSi{Fe(CO)4}PH2] has been prepared and utilized in the synthesis of novel heterobimetallic complexes. The phosphine moiety in this phosphinosilylene complex allows coordination towards tungsten leading to the iron-tungsten heterobimetallic complex [LSi{Fe(CO)4}PH2{W(CO)5}]. In contrast, the reaction of [LSi{Fe(CO)4}PH2] with ethylenebis(triphenylphosphine)platinum(0) results in the formation of the iron platinum heterobimetallic complex [LSi{Fe(CO)4}PH{PtH(PPh3)2}] via oxidative addition. PMID- 26974122 TI - Aluminum methyl, alkoxide and alpha-alkoxy ester complexes supported by 6,6' dimethylbiphenyl-bridged salen ligands: synthesis, characterization and catalysis for rac-lactide polymerization. AB - The synthesis and characterization of aluminum alkyl and alkoxide complexes bearing racemic 6,6'-dimethylbiphenyl-bridged salen-type ligands, and their catalysis in the ring-opening polymerization (ROP) of rac-lactide are reported. Reactions of AlMe3 with various amounts of the proligands (6,6'-[(6,6'-dimethyl [1,1'-biphenyl]-2,2'-diyl)bis(nitrylomethilidyne)]-bis(2-R(1)-4-R(2)-phenol): , R(1) = R(2) = Me; , R(1) = (t)Bu, R(2) = Me; , R(1) = R(2) = cumyl; , R(1) = Br, R(2) = (t)Bu) afforded the corresponding mono- and dinuclear aluminum methyl complexes [AlMe (), Al2Me4 ()]. Aluminum alkoxide complexes AlO(i)Pr (), AlOBn (), and alpha-alkoxy ester complexes Al(OCMe2CO2Me) (), Al[(S)-OCHMeCO2Me] () were prepared via in situ alcoholysis of the parent aluminum methyl complex with the corresponding alcohols. The molecular structures of mononuclear complexes , dinuclear complex , alkoxide complexes and alpha-alkoxy ester complexes were established by single-crystal X-ray diffraction studies. Two broad resonances at about 69-70 ppm and 25-41 ppm were observed in the (27)Al NMR spectra of complexes and , indicating the existence of both four- and five-coordinate aluminum centers in solution, which results from the dissociation of one N donor of the salen ligand, accompanied by an association and dissociation equilibrium of the carbonyl group of the alpha-alkoxy ester ligand to the aluminum center. Complex is also a rare example of an O-lactate model complex that mimics the first insertion of l-LA. All complexes were investigated for the ROP of rac-LA at 110 degrees C in toluene. The polymerization initiated by complexes in the presence of (i)PrOH showed living features, affording PLAs with narrow molecular weight distributions (PDIs = 1.03-1.05) and 65-73% isotacticities. Particularly, complex showed an "immortal" behavior for the polymerization of rac-LA in the presence of excess alcohol. Compared with the mononuclear counterparts, the tetra coordinate dinuclear aluminum complexes enabled a few fold boosts in activity, but gave atactic PLAs with broadened PDIs. PMID- 26974123 TI - Antihistamines and Mental Status. PMID- 26974124 TI - Structural basis of H2A.Z recognition by SRCAP chromatin-remodeling subunit YL1. AB - Histone variant H2A.Z, a universal mark of dynamic nucleosomes flanking gene promoters and enhancers, is incorporated into chromatin by SRCAP (SWR1), an ATP dependent, multicomponent chromatin-remodeling complex. The YL1 (Swc2) subunit of SRCAP (SWR1) plays an essential role in H2A.Z recognition, but how it achieves this has been unclear. Here, we report the crystal structure of the H2A.Z-binding domain of Drosophila melanogaster YL1 (dYL1-Z) in complex with an H2A.Z-H2B dimer at 1.9-A resolution. The dYL1-Z domain adopts a new whip-like structure that wraps over H2A.Z-H2B, and preferential recognition is largely conferred by three residues in loop 2, the hyperacidic patch and the extended alphaC helix of H2A.Z. Importantly, this domain is essential for deposition of budding yeast H2A.Z in vivo and SRCAP (SWR1)-catalyzed histone H2A.Z replacement in vitro. Our studies distinguish YL1-Z from known H2A.Z chaperones and suggest a hierarchical mechanism based on increasing binding affinity facilitating H2A.Z transfer from SRCAP (SWR1) to the nucleosome. PMID- 26974127 TI - Bronchoscopic pursuit of the peripheral pulmonary lesion: navigational bronchoscopy, radial endobronchial ultrasound, and ultrathin bronchoscopy. AB - PURPOSE OF REVIEW: Peripheral pulmonary lesions (PPL) are being diagnosed with increasing frequency, especially with the increased use of chest computed tomography (CT). Depending on the location and size, these lesions often present a diagnostic challenge in terms of the low yield of traditional bronchoscopic biopsy techniques or the risks of a percutaneous biopsy approach. RECENT FINDINGS: Over the last several years, several different image-guided bronchoscopy techniques have emerged, including virtual bronchoscopic navigation, electromagnetic navigation bronchoscopy, radial endobronchial ultrasound, and ultrathin bronchoscopy. These technologies seek to improve both access and the diagnostic yield of PPL compared with traditional bronchoscopy and to perform with a lower complication rate than percutaneous techniques such as CT-guided trans-thoracic needle aspiration. SUMMARY: These advanced bronchoscopic techniques play an increasingly common role in the evaluation and biopsy of PPL. Electromagnetic navigation bronchoscopy and radial endobronchial ultrasound are the most commonly used guided techniques either in isolation or in combination and have the most published data regarding clinical experience and diagnostic yield; however, none of the techniques have consistently matched the yield of CT guided trans-thoracic needle biopsy for PPL. Overall the complication rate of image-guided bronchoscopy techniques is low with pneumothorax being the most common adverse event. PMID- 26974126 TI - Molecular basis and specificity of H2A.Z-H2B recognition and deposition by the histone chaperone YL1. AB - H2A.Z, a widely conserved histone variant, is evicted from chromatin by the histone chaperone ANP32E. However, to date, no deposition chaperone for H2A.Z is known in metazoans. Here, we identify YL1 as a specific H2A.Z-deposition chaperone. The 2.7-A-resolution crystal structure of the human YL1-H2A.Z-H2B complex shows that YL1 binding, similarly to ANP32E binding, triggers an extension of the H2A.Z alphaC helix. The interaction with YL1 is, however, more extensive and includes both the extended acidic patch and the entire DNA-binding surface of H2A.Z-H2B. Substitution of only four amino acid residues of H2A is sufficient for the formation of an H2A.Z-like interface specifically recognized by YL1. Collectively, our data reveal the molecular basis of H2A.Z-specific recognition by YL1 and shed light on the mechanism of H2A.Z transfer to the nucleosome by the ATP-dependent chromatin-remodeling complexes SRCAP and P400 TIP60. PMID- 26974128 TI - Health Information Exchange-Obvious Choice or Pipe Dream? PMID- 26974125 TI - Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network. AB - Signaling cascades depend on scaffold proteins that regulate the assembly of multiprotein complexes. Missense mutations in scaffold proteins are frequent in human cancer, but their relevance and mode of action are poorly understood. Here we show that cancer point mutations in the scaffold protein Axin derail Wnt signaling and promote tumor growth in vivo through a gain-of-function mechanism. The effect is conserved for both the human and Drosophila proteins. Mutated Axin forms nonamyloid nanometer-scale aggregates decorated with disordered tentacles, which 'rewire' the Axin interactome. Importantly, the tumor-suppressor activity of both the human and Drosophila Axin cancer mutants is rescued by preventing aggregation of a single nonconserved segment. Our findings establish a new paradigm for misregulation of signaling in cancer and show that targeting aggregation-prone stretches in mutated scaffolds holds attractive potential for cancer treatment. PMID- 26974129 TI - Implications for visually stimulating advertisements on NYC subway platforms. AB - Despite the fact that the New York City (NYC) Metropolitan Transportation Authority (MTA) no longer advertises tobacco products, there is no ban on ads for alcohol. The purpose of this pilot study was to evaluate the frequency of alcohol related advertising content on the platforms of two populated subway lines in NYC. Advertisements were evaluated on one subway line (the green line) that runs through Bronx and Manhattan in NYC. In the stations included in the study, the total number of advertisements were tallied and classified according to the type of advertisement. When an advertisement for alcohol was identified, it was determined whether the ad was for an alcoholic beverage, or it if was for a different product but exhibited an alcoholic beverage in some way. A total of 26 advertisements were identified which marketed an alcohol product. An additional 24 ads were noted for marketing another product or service whereby, alcohol was depicted as being consumed. There was a statistically significant difference in ads between the different lines t (20.04)=7.62, p<0.001, with an average of 1.5 ads on the uptown lines (heading toward and through the borough with the lowest median income) versus 0.06 ads on the downtown lines (heading toward and through the borough with the highest median income). Given the far reach that subway advertisements have, focus could shift to health promoting products, versus those that are deleterious. PMID- 26974130 TI - Helmet use of adolescent cyclists at Crescent School in Toronto, Canada. AB - Numerous studies have highlighted that bicycle helmets reduce the risk of head injury; the purpose of this study was to determine the helmet-wearing rate of adolescent boys and the reasons for those who do not wear helmets. A questionnaire was developed and completed by 257 students. A higher percentage of older students reported a long bike commute to school (over 20 min). The frequency of helmet use and awareness of helmet legislation was lower amongst the older students. Common reasons for not using a helmet across all ages included its uncomfortable nature, the confidence of the rider's cycling ability to not crash, and negligence. Further reminders and educational sessions regarding the importance of helmets could help to increase the helmet use of students across the grades. PMID- 26974131 TI - Arg924X homozygous mutation in insulin receptor gene in a Tunisian patient with Donohue syndrome. AB - Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor (INSR) gene, manifesting marked insulin resistance, severe growth retardation, hypertrichosis, and characteristic dysmorphic features. We describe a new case of Donohue syndrome born at 37 weeks' gestation of unrelated parents and presented with intra-uterine growth retardation, nipple hypertrophy, macropenis, distended abdomen, hirsutism and dysmorphic features. The clinical course showed failure to thrive, and episodes of alternating hypoglycemia and hyperglycemia. Laboratory tests revealed direct hyperbilirubinemia. The diagnosis of Donohue syndrome was established based on the above clinical characteristics and determination of the INSR mutation. He was found to have homozygous nonsense mutation c. 2270 C>T (Arg924X) at exon 14 of the INSR gene. He later developed enterocolitis and died at 3 months old. Prenatal diagnosis was performed for the family via chorionic villous biopsy. We try to explain gastrointestinal dysfunction seen in our patient. PMID- 26974132 TI - Medullary thyroid carcinoma: a review on ethical considerations in treatment of children. AB - Thyroid carcinoma is the most common malignancy of the endocrine system and it accounts approximately 1%-3% of all human cancers. Among the three subtypes of thyroid cancers, medullary thyroid carcinoma (MTC) is the most common cause of death in patients with multiple endocrine neoplasia (MEN) type 2A (MEN2A), MEN type 2B (MEN2B) and familial medullary thyroid carcinoma (FMTC). Generally, MTC accounts for up to 10% of all types of thyroid cancers. It is one of the aggressive forms of thyroid carcinoma which is manifested in childhood ages more than adults, and it comprises about 17% of all pediatric thyroid cancer. Like the other cancers, prevention of MTC is easier than its cure. In the recent decades (from 1993) the diagnosis of asymptomatic child carrying RET mutations in the affected families by MTC, has been provided by genetic screening, and prophylactic thyroidectomy is an efficacy therapeutic procedure. On the one hand, according to near the complete penetrance of the disease and its onset in the early years of life, it is required to accelerate the protection of at-risk children with relative affected by MTC and on the other hand, there are several obstructions to MTC treatment including: 1) the proband's refusal to disclose the RET mutation genetic testing results, 2) children's vulnerability because of their inability to participate in the informed consent, and 3) the existence of conflict between physicians and children's guardian. In this review article, the recommendations and ethical issues of MTC treatment in asymptomatic and at-risk children have been summarized. PMID- 26974133 TI - Novel AVPR2 mutation causing partial nephrogenic diabetes insipidus in a Japanese family. AB - BACKGROUND: X-linked recessive congenital nephrogenic diabetes insipidus (NDI) is caused by mutations of the arginine vasopressin type 2 receptor gene (AVPR2). More than 200 mutations of the AVPR2 gene with complete NDI have been reported although only 15 mutations with partial NDI has been reported to date. METHODS: We herein report a Japanese kindred with partial NDI. The proband is an 8-year old boy who was referred to our hospital for nocturnal enuresis. Water deprivation test and hypertonic saline test suggested partial renal antidiuretic hormone arginine vasopressin (AVP) resistance. RESULTS: Analysis of genomic DNA revealed a novel missense mutation (p.L161P) in the patient. The patient's mother was heterozygous for the mutation. Three-dimensional (3-D) modeling study showed that L161P possibly destabilizes the transmembrane domain of the V2 receptor, resulting in its misfolding or mislocalization. CONCLUSIONS: Distinguishing partial NDI from nocturnal enuresis is important. A clinical clue for diagnosis of partial NDI is an incompatibly high level of AVP despite normal serum osmolality. PMID- 26974134 TI - A novel OTX2 gene frameshift mutation in a child with microphthalmia, ectopic pituitary and growth hormone deficiency. AB - OTX2 mutations are reported in patients with eye maldevelopment and in some cases with brain or pituitary abnormalities. We describe a child carrying a novel OTX2 heterozygous mutation. She presented microphthalmia, absence of retinal vascularization, vitreal spots and optic nerve hypoplasia in the right eye and mild macular dystrophy in the left eye. Midline brain structures and cerebral parenchyma were normal, except for the ectopic posterior pituitary gland. OTX2 sequencing showed a heterozygous c.402del mutation. Most of OTX2 mutations are nonsense or frameshift introducing a premature termination codon and resulting in a truncated protein. More rarely missense mutations occur. Our novel OTX2 mutation (c.402del) is a frameshift mutation (p.S135Lfs*43), never reported before, causing a premature codon stop 43 amino-acids downstream, which is predicted to generate a premature truncation. The mutation was associated with microphthalmia and ectopic posterior pituitary. PMID- 26974135 TI - A case of mature teratoma with a falsely high serum estradiol value measured with an immunoassay. AB - BACKGROUND: Immunoassays (IAs) are widely used to measure concentration of serum estradiol (E2) despite some limitations including cross-reactivity. Liquid chromatography-tandem mass spectrometory (LC-MS/MS) for E2 measurement has a theoretically greater specificity and sensitivity than IAs. We report a case with unexpected discrepancy in E2 values measured by IA and LC-MS/MS. CASE PRESENTATION: A 7-year-old girl was referred because of an ovarian tumor. Physical examinations revealed prepubertal statuses. Serum E2 with ECLIA was 69 pg/mL. GnRH stimulation test revealed a prepubertal response. On imaging studies, the diagnosis was mature teratoma of the right ovary. After tumor enucleation, the diagnosis was pathologically confirmed. E2 with ECLIA decreased to 11 pg/mL. Preoperative E2 with LC-MS/MS was 1.15 pg/mL. CONCLUSIONS: We conclude the preoperative E2 with ECLIA was falsely high. We speculate the antibody used in ECLIA had cross-reactivity to endogenous compounds. LC-MS/MS should be considered when high serum E2 measured with IA is inconsistent with physical and/or endocrinological data. PMID- 26974136 TI - Hydroxycitric acid ameliorates high-fructose-induced redox imbalance and activation of stress sensitive kinases in male Wistar rats. AB - BACKGROUND: Excess fructose consumption causes dyslipidemia, oxidative stress, and various complications. Hydroxycitric acid (HCA), one of the principal components of the fruit Garcinia cambogia, has been shown to possess antiobesity properties. The objective was to investigate the effects of HCA on redox imbalance and activation of stress sensitive kinases in high fructose-fed rats. METHODS: Male Wistar rats (n=40) were randomly divided into four groups with 10 rats in each group. The rats were fed with either standard rodent diet or 60% fructose diet and administered with HCA at a dose of 400 mg/kg body wt/day for 10 weeks. Body weight was measured once a week, and food intake was noted daily. At the end of the study, lipid profile and oxidative stress parameters were estimated. Expressions of stress sensitive kinases were analyzed in liver homogenates. RESULTS: Fructose-fed rats displayed elevated body weight, higher levels of plasma total cholesterol (TC), triacylglycerol (TAG), non-high-density lipoprotein cholesterol (non HDL-C), malondialdehyde (MDA), total oxidant status (TOS), oxidative stress index (OSI), lower levels of HDL-C, glutathione (GSH), glutathione peroxidase (GPx), and total antioxidant status (TAS). Fructose feeding caused higher phosphorylation of stress sensitive kinases ERK 1/2 and p38. Administration with HCA lowered body weight, food intake, TAG, non-HDL-C, MDA, TOS, and OSI and elevated GSH, GPx, and TAS levels. Reduced phosphorylation of ERK 1/2 and p38 mitogen-activated protein kinase (MAPK) was observed upon HCA treatment. CONCLUSIONS: Thus, HCA improved fructose induced redox imbalance and activation of stress sensitive kinases through its hypolipidemic effects. PMID- 26974137 TI - Glucose absorption in the intestine of albino rats. AB - BACKGROUND: The ability to absorb substances from the external environment is one of the features that make animals different from inanimate objects. In mammalian species, this quality is mainly the role of the small intestine. The process of absorption mainly takes place in the small intestine. This study was carried out to investigate the rate of glucose absorption in the intestine of albino rats and the effect of calcium and ouabain on the rate of glucose absorption. METHODS: Albino rats weighing between 200 and 250 g were used for this experiment. Guts were isolated and cut to segments. Test solution was injected into each of the isolated segments, which were then assayed for glucose. RESULTS: The result revealed that the rate of glucose absorption in the intestine of albino rats were found to be 3.02*10-1 g/min at the mucosa-to-serosa surface and 3.00*10-1 g/min at the serosa-to-mucosa surface, indicating that glucose was absorbed at both surfaces and that the rate of glucose absorption was higher in the mucosa-to serosa direction than in the opposite direction. The rate of intestinal glucose absorption at different regions of the intestine and the effect of varying concentrations of calcium on the rate of glucose absorption revealed that glucose absorption was highest at the duodenum and lowest at the ileum. CONCLUSIONS: Ouabain blocked the rate of absorption of glucose in the intestine of albino rats. PMID- 26974138 TI - Role of monocyte chemoattractant protein-1, stromal derived factor-1 and retinoic acid in pathophysiology of neuropathic pain in rats. AB - BACKGROUND: Chemokines have been recently recognized to play a role in chronic pain syndromes' pathophysiology. This study investigated the role of monocyte chemoattractant protein-1 (MCP-1), stromal cell derived factor-1 (SDF-1), and retinoic acid (RA) as targets for the therapeutic approach of neuropathic pain. METHODS: A chronic constriction injury (CCI) model of neuropathic pain by unilateral ligation of left sciatic nerve was performed in adult female Wistar rats. The effects of doxycycline (Dox, 50 mg/kg/day i.p. for 7 days), single dose of bicyclam (5 mg/kg i.p.), RA (15 mg/kg/day i.p. for 7 days), and their combination(s) on behavioral tests of nociception (Von Frey filaments; paw pressure test) on days 0, 1, 3, 5, and 7 of operation were studied. Serum concentrations of MCP-1 and SDF-1 were measured by ELISA. Histological examination of the sciatic nerve was investigated. RESULTS: CCI of sciatic nerve significantly induced mechanical allodynia and hyperalgesia and an increase of MCP-1 and SDF-1 serum levels. Dox-treated groups (Dox, Dox+bicyclam, Dox+RA, Dox+bicyclam+RA) and bicyclam-treated groups (bicyclam, Dox+bicyclam, bicyclam+RA, Dox+bicyclam+RA) attenuated CCI-induced behavioral and biochemical changes. RA inhibited CCI-induced mechanical hyperalgesia but produced a time dependent reversal of allodynia. Histological findings showed degenerative changes of sciatic nerve after CCI that were partially recovered in Dox-treated groups. CONCLUSIONS: These findings demonstrate an association between serum MCP 1 and SDF-1 concentrations and behavioral manifestations of neuropathic pain. RA administration decreased neuropathic pain (antihyperalgesic effect) but did not cause any improvement in sciatic nerve tissues, either alone or in combination with chemokine antagonists. Thus, chemokines may serve as potential targets for drug development in neuropathic pain treatment. PMID- 26974139 TI - Characterization of the cardiac glycoside and lipid profiles of Strophanthus kombe Oliv. seeds. AB - The seeds of Strophanthus kombe Oliv. are known to contain high levels of cardioactive compounds. However, the therapeutic use of Strophanthus in the treatment of cardiopathy requires more detailed knowledge of the compound profile to profit from the full potential of Strophanthus preparations. Therefore, the objective was to characterize the cardenolide profile and lipophilic constituents in S. kombe seeds using methods applicable in routine quality control. Freshly prepared S. kombe seed extracts were analyzed without previous sample clean-up using a novel HPLC-DAD-MSn method. In addition, seed oils were analyzed by GC-MS following derivatization of the lipids. More than 20 cardenolides were tentatively assigned in the seed extracts including strophanthidin, strophanthidol, periplogenin and strophanthidinic acid aglycones, carrying various saccharide moieties. The findings revealed the presence of eight novel cardenolides, which have not been described for S. kombe so far. The occurrence of strophanthidinic acid derivatives was verified by comparison with synthesized strophanthidinic acid-cymaropyranoside. GC-MS characterization of the oils mainly revealed the presence of fatty acids, especially oleic acid and linoleic acid, as well as phytosterols, the latter representing intermediates of cardenolide biosynthesis. In summary, these findings broaden our knowledge on the secondary metabolism of Strophanthus. PMID- 26974140 TI - Interference by biological anti-cancer drugs in electrophoretic and immunofixation techniques. PMID- 26974141 TI - Potential errors in the determination of urinary ammonium by formol titration. PMID- 26974142 TI - A point mutation in the thiopurine S-methyltransferase gene that led to exon 5 deletion in the transcribed mRNA. PMID- 26974143 TI - The problem with total error models in establishing performance specifications and a simple remedy. AB - A recent issue in this journal revisited performance specifications since the Stockholm conference. Of the three recommended methods, two use total error models to establish performance specifications. It is shown that the most commonly used total error model - the Westgard model - is deficient, yet even more complete models fail to capture all errors that comprise total error. Moreover, total error models are often set at 95% of results, which leave 5% of results as unspecified. Glucose meter performance standards are used to illustrate these problems. The Westgard model is useful to asses assay performance but not to set performance specifications. Total error can be used to set performance specifications if the specifications include 100% of the results. PMID- 26974144 TI - Long-term stability of serum samples positive for carbohydrate deficient transferrin (CDT) routinely stored at -20 degrees C. PMID- 26974145 TI - Predictive biomarkers candidates for patients with metastatic colorectal cancer treated with bevacizumab-containing regimen. AB - Bevacizumab was the first molecular-targeted antiangiogenic therapy approved for the treatment of metastatic colorectal cancer. Until now, there are no predictive biomarkers available to decide the prescription of bevacizumab in patients with colorectal cancer. The purposes of this review were to provide a critical appraisal of the evidence and to identify possible predictive genetic biomarkers. A literature search was performed to identify studies that determine different levels of treatment response between patients stratified according to defined biomarkers. Interesting findings were reported between patients stratified according to rs3025039 and rs833061 polymorphisms of the gene VEGFA, with statistically and clinically significant differences for progression-free survival and overall survival. However, another study conducted in a larger sample does not confirm these previous findings, suggesting that well-designed prospective studies are still needed to achieve conclusive results. FLT1 (or VEGFR1) rs9513070 seems to be an interesting candidate as a predictive biomarker, with differences of more than 10 months in OS between different patients groups. In our opinion, possible interesting biomarker candidates for future research could be the polymorphisms rs833061 and rs3025039 of VEGF-A, rs9513070 or haplotype analysis of FLT1, rs2661280 of RGS5, rs444903 and rs6220 of EGF and Ang 2 or LDH plasma levels. PMID- 26974146 TI - Effect of Providing Multiple Micronutrients in Powder through Primary Healthcare on Anemia in Young Brazilian Children: A Multicentre Pragmatic Controlled Trial. AB - BACKGROUND: Multiple micronutrients in powder (MNP) are recommended by WHO to prevent anemia in young children. However, evidences for its effectiveness in different populations and improvements in other outcomes (e.g. linear growth and vitamin A deficiency) are scarce. METHODS: A multicentre pragmatic controlled trial was carried out in primary health centres. At study baseline, a control group (CG) of children aged 10- to 14 months (n = 521) was recruited in the routine healthcare for assessing anemia, anthropometric and micronutrient status. At the same time, an intervention group (IG) of infants aged 6- to 8 months (n = 462) was recruited to receive MNP daily in complementary feeding over a period of 60 days. Both study groups were compared when the IG infants reached the age of the CG children at enrolment. RESULTS: In CG, the prevalence of anemia [hemoglobin (Hb) < 110 g/L], iron deficiency (ID, plasma ferritin < 12 MUg/L or TfR > 8.3 mg/L), and vitamin A deficiency (VAD, serum retinol < 0.70MUmol/L) were 23.1%, 37.4%, and 17.4%, respectively. Four to six months after enrolment, when the IG participants had the same age of the controls at the time of testing, the prevalence of anemia, ID and VAD in IG were 14.3%, 30.1% and 7.9%, respectively. Adjusting for city, health centre, maternal education, and age, IG children had a lower likelihood of anemia and VAD [Prevalence Ratio (95% CI) = 0.63 (0.45, 0.88) and 0.45 (0.29, 0.69), respectively] when compared with CG children. The adjusted mean distributions of Hb and length-for-age Z-scores improved by 2 SE in the IG compared to CG children. CONCLUSIONS: MNP effectively reduced anemia and improved growth and micronutrient status among young Brazilian children. TRIAL REGISTRATION: Registro Brasileiro de Ensaios Clinicos RBR-5ktv6b. PMID- 26974147 TI - Energy Expenditure and Substrate Oxidation in Response to Side-Alternating Whole Body Vibration across Three Commonly-Used Vibration Frequencies. AB - BACKGROUND AND AIM: There is increasing recognition about the importance of enhancing energy expenditure (EE) for weight control through increases in low intensity physical activities comparable with daily life (1.5-4 METS). Whole-body vibration (WBV) increases EE modestly and could present both a useful adjuvant for obesity management and tool for metabolic phenotyping. However, it is unclear whether a "dose-response" exists between commonly-used vibration frequencies (VF) and EE, nor if WBV influences respiratory quotient (RQ), and hence substrate oxidation. We aimed to investigate the EE-VF and RQ-VF relationships across three different frequencies (30, 40, and 50Hz). METHODS: EE and RQ were measured in 8 healthy young adults by indirect calorimetry at rest, and subsequently during side-alternating WBV at one of 3 VFs (30, 40, and 50 Hz). Each frequency was assessed over 5 cycles of intermittent WBV (30s vibration/30s rest), separated by 5 min seated rest. During the WBV participants stood on the platform with knees flexed sufficiently to maintain comfort, prevent transmission of vibration to the upper body, and minimise voluntary physical exertion. Repeatability was assessed across 3 separate days in a subset of 4 individuals. In order to assess any sequence/habituation effect, an additional group of 6 men underwent 5 cycles of intermittent WBV (30s vibration/30s rest) at 40 Hz, separated by 5 min seated rest. RESULTS: Side-alternating WBV increased EE relative to standing, non vibration levels (+36%, p<0.001). However, no differences in EE were observed across VFs. Similarly, no effect of VF on RQ was found, nor did WBV alter RQ relative to standing without vibration. CONCLUSION: No relationship could be demonstrated between EE and VF in the range of 30-50Hz, and substrate oxidation did not change in response to WBV. Furthermore, the thermogenic effect of intermittent WBV, whilst robust, was quantitatively small (<2 METS). PMID- 26974148 TI - Multilocus Phylogeography and Species Delimitation in the Cumberland Plateau Salamander, Plethodon kentucki: Incongruence among Data Sets and Methods. AB - Species are a fundamental unit of biodiversity, yet can be challenging to delimit objectively. This is particularly true of species complexes characterized by high levels of population genetic structure, hybridization between genetic groups, isolation by distance, and limited phenotypic variation. Previous work on the Cumberland Plateau Salamander, Plethodon kentucki, suggested that it might constitute a species complex despite occupying a relatively small geographic range. To examine this hypothesis, we sampled 135 individuals from 43 populations, and used four mitochondrial loci and five nuclear loci (5693 base pairs) to quantify phylogeographic structure and probe for cryptic species diversity. Rates of evolution for each locus were inferred using the multidistribute package, and time calibrated gene trees and species trees were inferred using BEAST 2 and *BEAST 2, respectively. Because the parameter space relevant for species delimitation is large and complex, and all methods make simplifying assumptions that may lead them to fail, we conducted an array of analyses. Our assumption was that strongly supported species would be congruent across methods. Putative species were first delimited using a Bayesian implementation of the GMYC model (bGMYC), Geneland, and Brownie. We then validated these species using the genealogical sorting index and BPP. We found substantial phylogeographic diversity using mtDNA, including four divergent clades and an inferred common ancestor at 14.9 myr (95% HPD: 10.8-19.7 myr). By contrast, this diversity was not corroborated by nuclear sequence data, which exhibited low levels of variation and weak phylogeographic structure. Species trees estimated a far younger root than did the mtDNA data, closer to 1.0 myr old. Mutually exclusive putative species were identified by the different approaches. Possible causes of data set discordance, and the problem of species delimitation in complexes with high levels of population structure and introgressive hybridization, are discussed. PMID- 26974149 TI - A New Specimen of the Controversial Chasmosaurine Torosaurus latus (Dinosauria: Ceratopsidae) from the Upper Cretaceous Hell Creek Formation of Montana. AB - Torosaurus latus is an uncommon and contentious taxon of chasmosaurine ceratopsid known from several upper Maastrichtian units in western North America. We describe a partial parietal of To. latus from the Hell Creek Formation of Montana. Although the specimen's ontogenetic maturity means that it cannot inform the ongoing debate over whether To. latus is the old adult form of the contemporary Triceratops, the specimen is one of the best-preserved To. latus parietals and supplements previous descriptions. PMID- 26974150 TI - Pathogen Inactivating Properties and Increased Sensitivity in Molecular Diagnostics by PAXgene, a Novel Non-Crosslinking Tissue Fixative. AB - BACKGROUND: Requirements on tissue fixatives are getting more demanding as molecular analysis becomes increasingly relevant for routine diagnostics. Buffered formaldehyde in pathology laboratories for tissue fixation is known to cause chemical modifications of biomolecules which affect molecular testing. A novel non-crosslinking tissue preservation technology, PAXgene Tissue (PAXgene), was developed to preserve the integrity of nucleic acids in a comparable way to cryopreservation and also to preserve morphological features comparable to those of formalin fixed samples. METHODS: Because of the excellent preservation of biomolecules by PAXgene we investigated its pathogen inactivation ability and biosafety in comparison to formalin by in-vitro testing of bacteria, human relevant fungi and human cytomegalovirus (CMV). Guidelines for testing disinfectants served as reference for inactivation assays. Furthermore, we tested the properties of PAXgene for detection of pathogens by PCR based assays. RESULTS: All microorganisms tested were similarly inactivated by PAXgene and formalin except Clostridium sporogenes, which remained viable in seven out of ten assays after PAXgene treatment and in three out of ten assays after formalin fixation. The findings suggest that similar biosafety measures can be applied for PAXgene and formalin fixed samples. Detection of pathogens in PCR-based diagnostics using two CMV assays resulted in a reduction of four to ten quantification cycles of PAXgene treated samples which is a remarkable increase of sensitivity. CONCLUSION: PAXgene fixation might be superior to formalin fixation when molecular diagnostics and highly sensitive detection of pathogens is required in parallel to morphology assessment. PMID- 26974151 TI - Long Non-Coding RNA ucoo2kmd.1 Regulates CD44-Dependent Cell Growth by Competing for miR-211-3p in Colorectal Cancer. AB - In addition to protein-coding genes, the human genome makes a large amount of noncoding RNAs. Long non-coding RNAs (lncRNAs) have been described as the largest subclass of the non-coding transcriptome in human noncoding RNAs. In recent years, lncRNAs have been considered to be the key regulators of tumor behavior. In this study, based on previous research, we investigated the expression and biological role of a newly identified cancer-related lncRNA, lncRNA-uc002kmd.1. We analyzed the relationship between lncRNA-uc002kmd.1 and colorectal cancer (CRC) in a total 45 CRC and paired adjacent, non-tumor tissue samples. We found that lncRNA-uc002kmd.1 expression was usually highly expressed in carcinoma compared with the tissue adjacent to the carcinoma. Through a series of experiments, the results showed that lncRNA-uc002kmd.1 regulates CD44 as a molecular decoy for miR211-3p. Our data indicated that the overexpression of lncRNA-uc002kmd.1 enhanced cell proliferation in CRC. PMID- 26974152 TI - Stroke in Rural Communities: A Need for Continued Surveillance. PMID- 26974153 TI - The Paradoxical Role of Perceived Control in Late Life Health Behavior. AB - Research has established the health benefits of psychological factors, including the way individuals appraise outcomes. Although many studies confirm that appraising outcomes as controllable is adaptive for health, a paradoxical possibility is largely ignored: Perceived control may be detrimental under some conditions. Our premise was that appraising health as controllable but at the same time ascribing little value to it might signal a dysfunctional psychological mindset that fosters a mistaken sense of invincibility. During face-to-face interviews with a representative sample of older adults (age range = 72-99), we identified individuals with such a potentially maladaptive "invincible" mindset (high perceived control and low health value) and compared them to their counterparts on several outcomes. The findings were consistent with our hypotheses. The invincibles denied future risks, they lacked the activating emotion of fear, and they visited their physicians less often over a subsequent five-year period. Moreover, in contrast to their counterparts, the invincibles did not appear strategic in their approach to seeking care: Even poor health did not prompt them to seek the counsel of a physician. The recognition that psychological appraisals are modifiable highlights the promise of remedial methods to alter maladaptive mindsets, potentially improving quality of life. PMID- 26974154 TI - RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation. AB - Posttranscriptional control of gene expression is important for defining both normal and pathological cellular phenotypes. In vitro, RNA-binding proteins (RBPs) have recently been shown to play important roles in posttranscriptional regulation; however, the contribution of RBPs to cell specification is not well understood. Here, we determined that the RBP insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) is specifically overexpressed in mixed lineage leukemia-rearranged (MLL-rearranged) B-acute lymphoblastic leukemia (B-ALL), which constitutes a subtype of this malignancy associated with poor prognosis and high risk of relapse. IGF2BP3 was required for the survival of B-ALL cell lines, as knockdown led to decreased proliferation and increased apoptosis. Enforced expression of IGF2BP3 provided murine BM cells with a strong survival advantage, led to proliferation of hematopoietic stem and progenitor cells, and skewed hematopoietic development to the B cell/myeloid lineage. Cross-link immunoprecipitation and high throughput sequencing uncovered the IGF2BP3 regulated transcriptome, which includes oncogenes MYC and CDK6 as direct targets. IGF2BP3 regulated transcripts via targeting elements within 3' untranslated regions (3'UTR), and enforced IGF2BP3 expression in mice resulted in enhanced expression of Myc and Cdk6 in BM. Together, our data suggest that IGF2BP3 mediated targeting of oncogenic transcripts may represent a critical pathogenetic mechanism in MLL-rearranged B-ALL and support IGF2BP3 and its cognate RNA-binding partners as potential therapeutic targets in this disease. PMID- 26974155 TI - LNK/SH2B3 regulates IL-7 receptor signaling in normal and malignant B progenitors. AB - Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high risk ALL commonly associated with alterations that affect the tyrosine kinase pathway, tumor suppressors, and lymphoid transcription factors. Loss-of-function mutations in the gene-encoding adaptor protein LNK (also known as SH2B3) are found in Ph-like ALLs; however, it is not clear how LNK regulates normal B cell development or promotes leukemogenesis. Here, we have shown that combined loss of Lnk and tumor suppressors Tp53 or Ink4a/Arf in mice triggers a highly aggressive and transplantable precursor B-ALL. Tp53-/-Lnk-/- B-ALLs displayed similar gene expression profiles to human Ph-like B-ALLs, supporting use of this model for preclinical and molecular studies. Preleukemic Tp53-/-Lnk-/- pro-B progenitors were hypersensitive to IL-7, exhibited marked self-renewal in vitro and in vivo, and were able to initiate B-ALL in transplant recipients. Mechanistically, we demonstrated that LNK regulates pro-B progenitor homeostasis by attenuating IL-7 stimuated JAK/STAT5 signaling via a direct interaction with phosphorylated JAK3. Moreover, JAK inhibitors were effective in prolonging survival of mice transplanted with Lnk-/-Tp53-/- leukemia. Additionally, synergistic administration of PI3K/mTOR and JAK inhibitors further abrogated leukemia development. Hence, our results suggest that LNK suppresses IL-7R/JAK/STAT signaling to restrict pro-/pre-B progenitor expansion and leukemia development, providing a pathogenic mechanism and a potential therapeutic approach for B-ALLs with LNK mutations. PMID- 26974156 TI - Involvement of activation-induced cytidine deaminase in skin cancer development. AB - Most skin cancers develop as the result of UV light-induced DNA damage; however, a substantial number of cases appear to occur independently of UV damage. A causal link between UV-independent skin cancers and chronic inflammation has been suspected, although the precise mechanism underlying this association is unclear. Here, we have proposed that activation-induced cytidine deaminase (AID, encoded by AICDA) links chronic inflammation and skin cancer. We demonstrated that Tg mice expressing AID in the skin spontaneously developed skin squamous cell carcinoma with Hras and Trp53 mutations. Furthermore, genetic deletion of Aicda reduced tumor incidence in a murine model of chemical-induced skin carcinogenesis. AID was expressed in human primary keratinocytes in an inflammatory stimulus-dependent manner and was detectable in human skin cancers. Together, the results of this study indicate that inflammation-induced AID expression promotes skin cancer development independently of UV damage and suggest AID as a potential target for skin cancer therapeutics. PMID- 26974157 TI - Astrocytes are central in the pathomechanisms of vanishing white matter. AB - Vanishing white matter (VWM) is a fatal leukodystrophy that is caused by mutations in genes encoding subunits of eukaryotic translation initiation factor 2B (eIF2B). Disease onset and severity are codetermined by genotype. White matter astrocytes and oligodendrocytes are almost exclusively affected; however, the mechanisms of VWM development remain unclear. Here, we used VWM mouse models, patients' tissue, and cell cultures to investigate whether astrocytes or oligodendrocytes are the primary affected cell type. We generated 2 mouse models with mutations (Eif2b5Arg191His/Arg191His and Eif2b4Arg484Trp/Arg484Trp) that cause severe VWM in humans and then crossed these strains to develop mice with various mutation combinations. Phenotypic severity was highly variable and dependent on genotype, reproducing the clinical spectrum of human VWM. In all mutant strains, impaired maturation of white matter astrocytes preceded onset and paralleled disease severity and progression. Bergmann glia and retinal Muller cells, nonforebrain astrocytes that have not been associated with VWM, were also affected, and involvement of these cells was confirmed in VWM patients. In coculture, VWM astrocytes secreted factors that inhibited oligodendrocyte maturation, whereas WT astrocytes allowed normal maturation of VWM oligodendrocytes. These studies demonstrate that astrocytes are central in VWM pathomechanisms and constitute potential therapeutic targets. Importantly, astrocytes should also be considered in the pathophysiology of other white matter disorders. PMID- 26974158 TI - Matricellular protein CCN3 mitigates abdominal aortic aneurysm. AB - Abdominal aortic aneurysm (AAA) is a major cause of morbidity and mortality; however, the mechanisms that are involved in disease initiation and progression are incompletely understood. Extracellular matrix proteins play an integral role in modulating vascular homeostasis in health and disease. Here, we determined that the expression of the matricellular protein CCN3 is strongly reduced in rodent AAA models, including angiotensin II-induced AAA and elastase perfusion stimulated AAA. CCN3 levels were also reduced in human AAA biopsies compared with those in controls. In murine models of induced AAA, germline deletion of Ccn3 resulted in severe phenotypes characterized by elastin fragmentation, vessel dilation, vascular inflammation, dissection, heightened ROS generation, and smooth muscle cell loss. Conversely, overexpression of CCN3 mitigated both elastase- and angiotensin II-induced AAA formation in mice. BM transplantation experiments suggested that the AAA phenotype of CCN3-deficient mice is intrinsic to the vasculature, as AAA was not exacerbated in WT animals that received CCN3 deficient BM and WT BM did not reduce AAA severity in CCN3-deficient mice. Genetic and pharmacological approaches implicated the ERK1/2 pathway as a critical regulator of CCN3-dependent AAA development. Together, these results demonstrate that CCN3 is a nodal regulator in AAA biology and identify CCN3 as a potential therapeutic target for vascular disease. PMID- 26974159 TI - PI3-kinase mutation linked to insulin and growth factor resistance in vivo. AB - The phosphatidylinositol 3-kinase (PI3K) signaling pathway is central to the action of insulin and many growth factors. Heterozygous mutations in the gene encoding the p85alpha regulatory subunit of PI3K (PIK3R1) have been identified in patients with SHORT syndrome - a disorder characterized by short stature, partial lipodystrophy, and insulin resistance. Here, we evaluated whether SHORT syndrome associated PIK3R1 mutations account for the pathophysiology that underlies the abnormalities by generating knockin mice that are heterozygous for the Pik3r1Arg649Trp mutation, which is homologous to the mutation found in the majority of affected individuals. Similar to the patients, mutant mice exhibited a reduction in body weight and length, partial lipodystrophy, and systemic insulin resistance. These derangements were associated with a reduced capacity of insulin and other growth factors to activate PI3K in liver, muscle, and fat; marked insulin resistance in liver and fat of mutation-harboring animals; and insulin resistance in vitro in cells derived from these mice. In addition, mutant mice displayed defective insulin secretion and GLP-1 action on islets in vivo and in vitro. These data demonstrate the ability of this heterozygous mutation to alter PI3K activity in vivo and the central role of PI3K in insulin/growth factor action, adipocyte function, and glucose metabolism. PMID- 26974160 TI - Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression. AB - Chronic mucosal inflammation is associated with a greater risk of gastric cancer (GC) and, therefore, requires tight control by suppressive counter mechanisms. Gastrokine-2 (GKN2) belongs to a family of secreted proteins expressed within normal gastric mucosal cells. GKN2 expression is frequently lost during GC progression, suggesting an inhibitory role; however, a causal link remains unsubstantiated. Here, we developed Gkn2 knockout and transgenic overexpressing mice to investigate the functional impact of GKN2 loss in GC pathogenesis. In mouse models of GC, decreased GKN2 expression correlated with gastric pathology that paralleled human GC progression. At baseline, Gkn2 knockout mice exhibited defective gastric epithelial differentiation but not malignant progression. Conversely, Gkn2 knockout in the IL-11/STAT3-dependent gp130F/F GC model caused tumorigenesis of the proximal stomach. Additionally, gastric immunopathology was accelerated in Helicobacter pylori-infected Gkn2 knockout mice and was associated with augmented T helper cell type 1 (Th1) but not Th17 immunity. Heightened Th1 responses in Gkn2 knockout mice were linked to deregulated mucosal innate immunity and impaired myeloid-derived suppressor cell activation. Finally, transgenic overexpression of human gastrokines (GKNs) attenuated gastric tumor growth in gp130F/F mice. Together, these results reveal an antiinflammatory role for GKN2, provide in vivo evidence that links GKN2 loss to GC pathogenesis, and suggest GKN restoration as a strategy to restrain GC progression. PMID- 26974161 TI - Versatile roles of extracellular vesicles in cancer. AB - Numerous studies have shown that non-cell-autonomous regulation of cancer cells is an important aspect of tumorigenesis. Cancer cells need to communicate with stromal cells by humoral factors such as VEGF, FGFs, and Wnt in order to survive. Recently, extracellular vesicles (EVs) have also been shown to be involved in cell-cell communication between cancer cells and the surrounding microenvironment and to be important for the development of cancer. In addition, these EVs contain small noncoding RNAs, including microRNAs (miRNAs), which contribute to the malignancy of cancer cells. Here, we provide an overview of current research on EVs, especially miRNAs in EVs. We also propose strategies to treat cancers by targeting EVs around cancer cells. PMID- 26974162 TI - Promiscuous Recognition of a Trypanosoma cruzi CD8+ T Cell Epitope among HLA-A2, HLA-A24 and HLA-A1 Supertypes in Chagasic Patients. AB - BACKGROUND: TcTLE is a nonamer peptide from Trypanosoma cruzi KMP-11 protein that is conserved among different parasite strains and that is presented by different HLA-A molecules from the A2 supertype. Because peptides presented by several major histocompatibility complex (MHC) supertypes are potential targets for immunotherapy, the aim of this study was to determine whether MHC molecules other than the A2 supertype present the TcTLE peptide. METHODOLOGY/PRINCIPAL FINDINGS: From 36 HLA-A2-negative chagasic patients, the HLA-A genotypes of twenty-eight patients with CD8+ T cells that recognized the TcTLE peptide using tetramer (twenty) or functional (eight) assays, were determined. SSP-PCR was used to identify the A locus and the allelic variants. Flow cytometry was used to analyze the frequency of TcTLE-specific CD8+ T cells, and their functional activity (IFN gamma, TNFalpha, IL-2, perforin, granzyme and CD107a/b production) was induced by exposure to the TcTLE peptide. All patients tested had TcTLE-specific CD8+ T cells with frequencies ranging from 0.07-0.37%. Interestingly, seven of the twenty-eight patients had HLA-A homozygous alleles: A*24 (5 patients), A*23 (1 patient) and A*01 (1 patient), which belong to the A24 and A1 supertypes. In the remaining 21 patients with HLA-A heterozygous alleles, the most prominent alleles were A24 and A68. The most common allele sub-type was A*2402 (sixteen patients), which belongs to the A24 supertype, followed by A*6802 (six patients) from the A2 supertype. Additionally, the A*3002/A*3201 alleles from the A1 supertype were detected in one patient. All patients presented CD8+ T cells producing at least one cytokine after TcTLE peptide stimulation. CONCLUSION/SIGNIFICANCE: These results show that TcTLE is a promiscuous peptide that is presented by the A24 and A1 supertypes, in addition to the A2 supertype, suggesting its potential as a target for immunotherapy. PMID- 26974163 TI - Linking Isotopes and Panmixia: High Within-Colony Variation in Feather delta2H, delta13C, and delta15N across the Range of the American White Pelican. AB - Complete panmixia across the entire range of a species is a relatively rare phenomenon; however, this pattern may be found in species that have limited philopatry and frequent dispersal. American white pelicans (Pelecanus erythrorhyncos) provide a unique opportunity to examine the role of long-distance dispersal in facilitating gene flow in a species recently reported as panmictic across its broad breeding range. This species is also undergoing a range expansion, with new colonies arising hundreds of kilometers outside previous range boundaries. In this study, we use a multiple stable isotope (delta2H, delta13C, delta15N) approach to examine feather isotopic structuring at 19 pelican colonies across North America, with the goal of establishing an isotopic basemap that could be used for assigning individuals at newly established breeding sites to source colonies. Within-colony isotopic variation was extremely high, exceeding 1000/00 in delta2H within some colonies (with relatively high variation also observed for delta13C and delta15N). The high degree of within site variation greatly limited the utility of assignment-based approaches (42% cross-validation success rate; range: 0-90% success). Furthermore, clustering algorithms identified four likely isotopic clusters; however, those clusters were generally unrelated to geographic location. Taken together, the high degree of within-site isotopic variation and lack of geographically-defined isotopic clusters preclude the establishment of an isotopic basemap for American white pelicans, but may indicate that a high incidence of long-distance dispersal is facilitating gene flow, leading to genetic panmixia. PMID- 26974164 TI - Correction: Involvement of Protein Tyrosine Phosphatases BcPtpA and BcPtpB in Regulation of Vegetative Development, Virulence and Multi-Stress Tolerance in Botrytis cinerea. PMID- 26974166 TI - The Effect of Calf Gender on Milk Production in Seasonal Calving Cows and Its Impact on Genetic Evaluations. AB - Gender of the calf whose birth initiates lactation could influence whole lactation milk yield of the dam due to hormonal influences on mammary gland development, or through calf gender effects on gestation length. Fetal gender could influence late lactation yields because cows become pregnant at peak lactation. The effects of calf gender sequences in parities 1-3 were assessed by separately fitting animal models to datasets from New Zealand comprising 274 000 Holstein Friesian and 85 000 Jersey cows, decreasing to 12 000 and 4 000 cows by parity 3. The lactation initiated by the birth of a female rather than a male calf was associated with a 0.33-1.1% (p<=0.05) higher milk yield. Female calf gender had carryover effects associated with higher milk yield in second lactations for Holstein Friesians (0.24%; p = 0.01) and third lactations for Jerseys (1.1%; p = 0.01). Cows giving birth to bull calves have 2 day longer gestations, which reduces lactation length in seasonal calving herds. Adding a covariate for lactation length to the animal model eroded some of these calf gender effects, such that calving a female led to higher milk yield only for second lactation Holstein Friesians (1.6%; p = 0.002). The interval centering method generates lower estimates of whole lactation yield when Wood's lactation curves are shifted to the right by 2 days for male calves and this explained the higher yield in female calves when differences in lactation length were considered. Correlations of estimated breeding values between models including or excluding calf gender sequence were 1.00 for bulls or cows. Calf gender primarily influences milk yield through increased gestation length of male calves, and bias associated with the interval centering method used to estimate whole lactation milk yields. Including information on calf gender is unlikely to have an effect on selection response in New Zealand dairy cattle. PMID- 26974167 TI - New Framework To Diagnose the Direct Disposal of Prescribed Drugs in Wastewater - A Case Study of the Antidepressant Fluoxetine. AB - Intentional or accidental release (direct disposal) of high loads of unused pharmaceuticals into wastewater can go unnoticed. Here, direct disposal of a pharmaceutical drug via the sewer network was identified for the first time using wastewater analysis. An irregularly high load of the antidepressant fluoxetine in raw wastewater (10.5 +/- 2.4 g d(-1)) was up to 11 times greater than any other day. National prescription data revealed a predicted daily fluoxetine load for the studied treatment works to be 0.4-1.6 g d(-1). Enantio-selective analysis showed the high load of fluoxetine was present as a racemic mixture, which is typical for fluoxetine in dispensed formulations. As fluoxetine undergoes stereoselective metabolism within the body, a racemic mixture in wastewater suggests a nonconsumed drug was the major contributor of the high load. This was confirmed by its major metabolite norfluoxetine whose load did not increase on this day. Considering the most commonly prescribed formulation of fluoxetine, this increased load accounts for the disposal of ~915 capsules. Furthermore, as fluoxetine is prescribed as one capsule per day, disposal is unlikely to be at the patient level. It is postulated that direct disposal was from a facility which handles larger quantities of the drug (e.g., a pharmacy). PMID- 26974165 TI - Risk Environments, Race/Ethnicity, and HIV Status in a Large Sample of People Who Inject Drugs in the United States. AB - INTRODUCTION: We analyzed relationships between place characteristics and being HIV-negative among black, Latino, and white people who inject drugs (PWID) in the US. METHODS: Data on PWID (N = 9077) were from the Centers for Disease Control and Prevention's 2009 National HIV Behavioral Surveillance. Administrative data were analyzed to describe the 968 ZIP codes, 51 counties, and 19 metropolitan statistical areas (MSAs) where they lived. Multilevel multivariable models examined relationships between place characteristics and HIV status. Exploratory population attributable risk percents (e-PAR%s) were estimated. RESULTS: Black and Latino PWID were more likely to be HIV-negative if they lived in less economically disadvantaged counties, or in MSAs with less criminal-justice activity (i.e., lower drug-related arrest rates, lower policing/corrections expenditures). Latino PWID were more likely to be HIV-negative in MSAs with more Latino isolation, less black isolation, and less violent crime. E-PAR%s attributed 8-19% of HIV cases among black PWID and 1-15% of cases among Latino PWID to place characteristics. DISCUSSION: Evaluations of structural interventions to improve economic conditions and reduce drug-related criminal justice activity may show evidence that they protect black and Latino PWID from HIV infection. PMID- 26974168 TI - Mechanically Robust and Healable Transparent Electrode Fabricated via Vapor Assisted Solution Process. AB - A mechanically robust, transparent, and healable electrode was successfully developed by embedding Ag nanowires (AgNWs) on the surface of polydimethylsiloxane-based polyurethane (PDMS-CPU) cross-linked by Diels-Alder (DA) adducts. The reversibility of the DA reaction enabled the heated dimethylformamide (DMF) vapor to induce de-cross-linking of the PDMS-CPU preformed as a substrate. A combination of the retro-DA reaction and the plasticizer effect softened the polymer surface, embedding the coated AgNWs on the surface of the polymer. With this simple postprocessing, the surface roughness and mechanical stability of the electrode were largely enhanced. Even with a 55 MUm bending radius, which corresponds to a strain of 90%, the resistance of the electrode after 10 min of vapor treatment increased by 2.1% for inward bending and 5.3% for outward bending. This result shows a great potential of the proposed method, as it can also be used to fabricate various mechanically deformable transparent electrode. Furthermore, swelling of the PDMS-CPU film owing to the DMF vapor facilitated the healing properties of the scratched electrodes. PMID- 26974169 TI - Gas-Phase Photoluminescence Characterization of Stoichiometrically Pure Nonanuclear Lanthanoid Hydroxo Complexes Comprising Europium or Gadolinium. AB - Gas-phase photoluminescence measurements involving mass-spectrometric techniques enable determination of the properties of selected molecular systems with knowledge of their exact composition and unaffected by matrix effects such as solvent interactions or crystal packing. The resulting reduced complexity facilitates a comparison with theory. Herein, we provide a detailed report of the intrinsic luminescence properties of nonanuclear europium(III) and gadolinium(III) 9-hydroxyphenalen-1-one (HPLN) hydroxo complexes. Luminescence spectra of [Eu9(PLN)16(OH)10](+) ions reveal an europium-centered emission dominated by a 4-fold split Eu(III) hypersensitive transition, while photoluminescence lifetime measurements for both complexes support an efficient europium sensitization via a PLN-centered triplet-state manifold. The combination of gas-phase measurements with density functional theory computations and ligand field theory is used to discuss the antiprismatic core structure of the complexes and to shed light on the energy-transfer mechanism. This methodology is also employed to fit a new set of parameters, which improves the accuracy of ligand field computations of Eu(III) electronic transitions for gas-phase species. PMID- 26974170 TI - Molecular Orientation Enhancement of Silk by the Hot-Stretching-Induced Transition from alpha-Helix-HFIP Complex to beta-Sheet. AB - Enhancing the molecular orientation of the regenerated silk fibroin (RF) up to a level comparable to the native silk is highly challenging. Our novel and promising strategy for the poststretching process is (1) creating at first an alpha-helix-HFIP complex with a hexagonal packing as an intermediate state and then (2) stretching it at a high temperature to induce the helix-to-sheet structural phase transition. Here we show for the first time the significantly high stretching efficiency of the proposed technique compared with the conventional wet-stretching techniques and the successful achievement of higher crystalline orientation and higher Young's modulus compared even with the native silk. The detailed structural analysis based on the time-resolved simultaneous measurement of stress-strain curve, synchrotron X-ray scatterings, and FTIR has revealed the structural transition mechanism from the hexagonally packed alpha helix-HFIP complex to the highly oriented beta-sheet crystalline state as well as the critical level of crystal orientation needed for the helix-to-sheet transition. PMID- 26974171 TI - Stereocontrolled (Me3Si)3SiH-Mediated Radical and Ionic Hydride Transfer in Synthesis of 2,3,5-Trisubstituted THF. AB - 2,3,5-Trisubstituted tetrahydrofurans were prepared stereoselectively through a two-step process involving the addition of an acyl radical to a beta-silyloxy acrylic ester followed by an acid-catalyzed desilylation-ketalization sequence and a final oxocarbenium reduction step. High levels of 1,2- and 1,3 stereocontrol were attained when (Me3Si)3SiH was used as a radical followed by a ionic hydrogen transfer agent. PMID- 26974172 TI - Ligand-Controlled Divergent Cross-Coupling Involving Organosilicon Compounds for Thioether and Thioester Synthesis. AB - A divergent cross-coupling for both thioether and thioester construction from organosilicon compounds has been developed. Predominant selectivity for Hiyama type coupling and C1 insertion reaction was achieved under the guidance of ligands. Thioether was obtained under ligand-free conditions in which disulfide generated from homocoupling could be prevented. Meanwhile, application of bidentate phosphine ligands under carbon monoxide atmosphere (CO balloon) afforded the thioester with little decomposition, which was revealed through interval NMR tracking. PMID- 26974175 TI - Aerosol Delivery Using Jet Nebulizer and Vibrating Mesh Nebulizer During High Frequency Oscillatory Ventilation: An In Vitro Comparison. AB - BACKGROUND: High frequency oscillatory ventilation (HFOV) is used in critically ill patients with severe hypoxemic respiratory failure. The purpose of this in vitro study was to determine the efficiency of aerosol delivery with different lung parameters during simulated neonatal, pediatric, and adult HFOV. METHODS: Sensormedics 3100A/B ventilators were used to deliver infant, pediatric, and adult HFOV. Two types of aerosol generators were chosen for testing: 1) a continuous jet nebulizer (JN) with a unit-dose of 5.0 mg/2.5 mL salbutamol sulfate diluted into 4 mL, and 2) a vibrating mesh nebulizer (VMN) with salbutamol sulfate were run to completion of aerosol generation. Both aerosol devices were placed 1) between the ventilator circuit and the endotracheal tube (ETT) (proximal position); and 2) at the inlet of the heated humidifier (distal position) (n = 5). Drug was collected on a bacterial filter placed distal to the ETT, and the drug eluted and analyzed with a UV Spectrophotometer at 276 nm. T- test and ANOVA tests were used for comparison (p < 0.05). RESULTS: The inhaled drug delivered by JN was 0%-0.6% of the nominal dose when placed at distal position, and 0%-3% at proximal position (p < 0.01), while the VMN was 0%-0.5% at distal and 8.6%-22.7% at proximal position (p < 0.01). Aerosol delivery during HFOV was greater with adult settings than pediatric and infant settings with VMN and JN (22.7%, 8.6%, and 17.4% respectively, p < 0.01). When the aerosol delivery device was placed at the distal position, negligible drug mass was observed (<0.5%), regardless of the nebulizer device used. CONCLUSIONS: During HFOV, aerosol delivery with the nebulizer placed at proximal was greater than placement distal from the ETT, with VMN delivering more drug than JN. The inhaled drug was delivery correlated positively with ETT size, MAP, and bias flow, and inversely proportional to power settings. PMID- 26974173 TI - The RECOVER Program: Disability Risk Groups and 1-Year Outcome after 7 or More Days of Mechanical Ventilation. AB - RATIONALE: Disability risk groups and 1-year outcome after greater than or equal to 7 days of mechanical ventilation (MV) in medical/surgical intensive care unit (ICU) patients are unknown and may inform education, prognostication, rehabilitation, and study design. OBJECTIVES: To stratify patients for post-ICU disability and recovery to 1 year after critical illness. METHODS: We evaluated a multicenter cohort of 391 medical/surgical ICU patients who received greater than or equal to 1 week of MV at 7 days and 3, 6, and 12 months after ICU discharge. Disability risk groups were identified using recursive partitioning modeling. MEASUREMENTS AND MAIN RESULTS: The 7-day post-ICU Functional Independence Measure (FIM) determined the recovery trajectory to 1-year after ICU discharge and was an independent risk factor for 1-year mortality. The 7-day post-ICU FIM was predicted by age and ICU length of stay. By 2 weeks of MV, ICU patients could be stratified into four disability groups characterized by increasing risk for post ICU disability, ICU and post-ICU healthcare use, and disposition. Patients less than 42 years with ICU length of stay less than 2 weeks had the best function and fewest deaths at 1 year compared with patients greater than 66 years with ICU length of stay greater than 2 weeks who sustained the worst disability and 40% 1 year mortality. Depressive symptoms (17%) and post-traumatic stress disorder (18%) persisted at 1 year. CONCLUSIONS: ICU survivors of greater than or equal to 1 week of MV may be stratified into four disability groups based on age and ICU length of stay. These groups determine 1-year recovery and healthcare use and are independent of admitting diagnosis and illness severity. Clinical trial registered with www.clinicaltrials.gov (NCT 00896220). PMID- 26974176 TI - Bovine dermatophilosis: Awareness, perceptions and attitudes in the small-holder sector of north-west Zimbabwe. AB - A cross-sectional study was conducted to assess cattle owners' awareness, perceptions, attitudes and drug-usage practices with regard to bovine dermatophilosis. Knowledge of these farmers' attributes is important for animal health policy makers in their endeavours to provide optimum disease control strategies that are acceptable to the communities. Data on cattle owner awareness of bovine dermatophilosis, causes, treatment practices, perceptions about its importance and potential dangers to humans were collected using an interviewer administered questionnaire. A total of 185 stockowners and cattle herds were involved in the study, with bovine dermatophilosis determined clinically by veterinarians. The results showed that 45.4% of the herds were clinically positive for dermatophilosis, and most farmers (79.5%) were generally aware that dermatophilosis was a cattle disease. In the event of a dermatophilosis outbreak in a herd, 74.1% of the farmers treated their cattle using antibiotics; the proportion of farmers treating cattle did not differ (p > 0.05) across the diptanks. Fifty-two farmers (52/63) indicated that drugs had to be administered four to seven times before an animal recovered from infection. Tetracyclines were the antibiotics used by most farmers (79.3%) to treat dermatophilosis, with 19.1% using penicillins. Concerns were raised by farmers about the effectiveness of these drugs against bovine dermatophilosis. Across the study sites, 48.6% and 27.6% of the farmers perceived bovine dermatophilosis to be an important disease at the herd and area level, respectively. A small proportion (12.4%) of the farmers regarded bovine dermatophilosis as a potentially zoonotic disease. The high level of stockowners' general awareness, with regards to bovine dermatophilosis, sets ideal conditions for the mobilisation of farmers by animal health authorities in the control of the disease. However, further research needs to be undertaken to investigate effective antibiotic delivery protocols and the potential zoonotic impact of bovine dermatophilosis in a situation of high disease prevalence. PMID- 26974177 TI - Serosurvey of peste des petits ruminants virus in small ruminants from different agro-ecological zones of Nigeria. AB - Peste des petits ruminants, caused by the peste des petits ruminants virus (PPRV), is a highly contagious and economically important transboundary viral disease of domestic and wild small ruminants and a major hindrance to small ruminant production in Nigeria. The seroprevalence and distribution of PPRV antibodies in small ruminants in rural households, farms, live animal markets and slaughter slabs across the six different agro-ecological zones of Nigeria were determined. A total of 4548 serum samples from 3489 goats and 1059 sheep were collected in 12 states. A PPRV competitive enzyme-linked immunosorbent assay was used to test the samples and the data analysed with R statistical software version 3.0.1. The study animals included all ages and both sexes. The overall prevalence estimate of sera positive for PPRV antibodies was 23.16% (n = 1018 positive samples per 4548 total samples, 95% confidence interval: 21.79% - 24.57%). There were significant differences in the seroprevalence between the states (p = 0.001). Taraba State had the highest seroprevalence of 29.51%, whilst the lowest seroprevalence of 14.52% was observed in Cross River State. There were no significant differences in the PPRV seroprevalence between male and female animals (p = 0.571), age (p = 0.323) and between species (p = 0.639). These data indicate the current seroprevalence to PPRV in the small-ruminant population in Nigeria. PMID- 26974178 TI - Rotational Spectrum, Conformational Composition, Intramolecular Hydrogen Bonding, and Quantum Chemical Calculations of Mercaptoacetonitrile (HSCH2C=N), a Compound of Potential Astrochemical Interest. AB - The microwave spectra of mercaptoacetonitrile (HSCH2C=N) and one deuterated species (DSCH2C=N) were investigated in the 7.5-124 GHz spectral interval. The spectra of two conformers denoted SC and AP were assigned. The H-S-C-C chain of atoms is synclinal in SC and anti-periplanar in AP. The ground state of SC is split into two substates separated by a comparatively small energy difference resulting in closely spaced transitions with equal intensities. Several transitions of the parent species of SC deviate from Watson's Hamiltonian. Only slight improvements were obtained using a Hamiltonian that takes coupling between the two substates into account. Deviations from Watson's Hamiltonian were also observed for the parent species of AP. However, the spectrum of the deuterated species, which was investigated only for the SC conformer, fits satisfactorily to Watson's Hamiltonian. Relative intensity measurements found SC to be lower in energy than AP by 3.8(3) kJ/mol. The strength of the intramolecular hydrogen bond between the thiol and cyano groups was estimated to be ~2.1 kJ/mol. The microwave work was augmented by quantum chemical calculations at CCSD and MP2 levels using basis sets of minimum triple-zeta quality. Mercaptoacetonitrile has astrochemical interest, and the spectra presented herein should be useful for a potential identification of this compound in the interstellar medium. Three different ways of generating mercaptoacetonitrile from compounds already found in the interstellar medium were explored by quantum chemical calculations. PMID- 26974179 TI - Predicting efficacies of anticancer drugs using single cell HaloChip assay. AB - Single cell halo assay (HaloChip) is used to quantify DNA repair ability and predict the efficacy of anticancer drugs. After exposure to drugs, cells are patterned onto a substrate to form an ordered single cell array, then embedded inside an agarose gel, and fluorescently stained to generate a characteristic halo surrounding each cell. The extent of DNA repair is quantified by using a relative nuclear diffusion factor (rNDF) derived from the surface areas of nuclei and halos. Several repair-competent and repair-deficient cell lines have been used to validate this method. Drug-inhibitor combinations are also tested in the context of synthetic lethality of chemotherapy, where the use of a repair inhibitor potentiates the effects of DNA damaging agents. This paper highlights the important role of HaloChip in quantifying DNA repair ability, which provides the diagnostic utility to enhance the efficacies of anticancer drugs. PMID- 26974180 TI - Demonstration of the scalar property of timing with possums (Trichosurus vulpecula). AB - Many diverse species have demonstrated interval timing, the ability to respond appropriately to time in the range of seconds to minutes, suggesting that an ability to time is adaptive. The peak procedure is a common method of studying interval time perception. In the peak procedure, animals experience a mix of fixed-interval (FI) and extinction (EXT) trials. On EXT trials, responding typically increases to a peak at the time the FI schedule would normally deliver reinforcers before decreasing. Responding on different FI schedules within the peak procedure has been found to conform to Weber's law, whereby response variability is proportional to the length of the fixed interval. We conducted possibly the first investigation of the timing abilities of a marsupial common to Australia and New Zealand, the brushtail possum (Trichosurus vulpecula), using FI 15-, 30-, and 60-s schedules of reinforcement in the peak procedure. Response rates on EXT trials peaked at the time of usual reinforcer delivery, decreasing at longer time intervals, and were well fit by 3-parameter Gaussian curves, demonstrating the ability of possums to respond to time-based stimuli. Coefficients of variation suggested that the ability of possums to time was less accurate than that of mammals, but similar to that of birds, invertebrates, and reptiles. Coefficients of variation did not differ consistently over increasing FI intervals, showing that timing responses of possums likely conforms to the scalar property of timing also shown by other species. (PsycINFO Database Record PMID- 26974181 TI - Neurocognitive Changes in Selective Serotonin Reuptake Inhibitors-Treated Adolescents with Depression. AB - OBJECTIVES: Adolescents with major depressive disorder (MDD) were found to have deficits in executive function, attention, and memory. Despite the fact that some neurocognitive functions have been shown to be present in acute stage of the illness, but not in remission, longitudinal studies are lacking. The current study aimed to investigate the changes in neurocognitive functioning in adolescents with depression during an acute treatment course with selective serotonin reuptake inhibitor. METHODS: Twenty-four adolescents with current MDD and 24 healthy controls (HCs) were administered subtests of the Cambridge Neuropsychological Test Automated Battery as well as clinical scales at baseline and were retested at weeks 6 and 12. Those with MDD were started on fluoxetine after the baseline assessment. RESULTS: Despite considerable improvement in depressive symptoms in the MDD group, there was a persistent deficit in visual memory in the MDD group over time compared with HCs (p = 0.001). On a task of sustained attention and inhibition, HCs became better at detecting target sequences at week 12 while there were residual sustained attention deficits in MDD (p = 0.01). On an executive function (planning) task, while HCs learned the task and improved substantially in performance over 12 weeks, MDD performance did not significantly change (p = 0.04). CONCLUSION: When treating depressed adolescents, clinicians need to also monitor cognitive symptoms as they appear to lag behind mood symptoms in improvement. PMID- 26974182 TI - Pt...H Nonclassical Interaction in Water-Dissolved Pt(II) Complexes: Coaction of Electronic Effects with Solvent-Assisted Stabilization. AB - The structure of the hydration shell of cisplatin, cis-[Pt(NH3)2Cl2], and its aquated derivatives cis-[Pt(NH3)2Cl(H2O)](+), cis-[Pt(NH3)2OH(H2O)](+), and cis [Pt(NH3)2(H2O)2](2+) were studied by a number of density functional molecular dynamics (DFT-MD) simulations (from 30 to 250 ps) in which Pt(II) complexes were immersed in a periodic box with 72 explicit water molecules. Furthermore, Pt(II) complex-water binding energy curves and full DFT optimizations of clusters derived from the lowest potential energy DFT-MD frames offered a deeper insight into the structure of the first hydration shell and electronic changes connected with the formation of a nonclassical Pt...H-O-H (Pt...Hw) hydrogen bond (inverse hydration). The probability of a Pt...Hw interaction decreases with increasing charge of the platinum complex due to disadvantageous electrostatics. The main stabilization comes from the charge transfer being followed by polarization and dispersion. Ligands form a framework for the network of H-bond interactions between the solvent molecules, which play an important role in the promotion/suppression of the formation of the Pt...Hw interactions. In the +2 charged diaqua complex the Pt...Hw interaction is still attractive but cannot compete with classical H bonds between solvent molecules. Thus, the formation of a Pt...Hw interaction is the result of a suitable solvent H-bonding network and the probability of its incidence decreases with increasing flexibility of the solvent. PMID- 26974183 TI - Systematic Investigation of EDC/sNHS-Mediated Bioconjugation Reactions for Carboxylated Peptide Substrates. AB - 1-Ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) bioconjugations have been utilized in preparing variants for medical research. While there have been advances in optimizing the reaction for aqueous applications, there has been limited focus toward identifying conditions and side reactions that interfere with product formation. We present a systematic investigation of EDC/N hydroxysulfosuccinimide (sNHS)-mediated bioconjugations on carboxylated peptides and small proteins. We identified yet-to-be-reported side products arising from both the reagents and substrates. Model peptides used in this study illustrate particular substrates are more susceptible to side reactions than others. From our studies, we found that bioconjugations are more efficient with high concentrations of amine nucleophile but not sNHS. Performing bioconjugations on a model affibody protein show that the trends established with model peptides hold for more complex systems. PMID- 26974184 TI - Sequential Proton Coupled Electron Transfer (PCET): Dynamics Observed over 8 Orders of Magnitude in Time. AB - Charge transfer mechanisms lay at the heart of chemistry and biochemistry. Proton coupled electron transfers (PCET) are central in biological processes such as photosynthesis and in the respiratory chain, where they mediate long-range charge transfers. These mechanisms are normally difficult to harness experimentally due to the intrinsic complexity of the associated biological systems. Metal-peptide cations experience both electron and proton transfers upon photoexcitation, proving an amenable model system to study PCET. We report on a time-resolved experiment designed to follow this dual charge transfer kinetics in [HG3W+Ag](+) (H = histidine, G = glycine, W = tryptophan) on time scales ranging from femtoseconds to milliseconds. While electron transfer completes in less than 4 ps, it triggers a proton transfer lasting over hundreds of microseconds. Molecular dynamics simulations show that conformational dynamic plays an important role in slowing down this reaction. This combined experimental and computational approach provides a view of PCET as a single phenomenon despite its very wide time-domain span. PMID- 26974185 TI - Molecular Detection of Zoonotic Rickettsiae and Anaplasma spp. in Domestic Dogs and Their Ectoparasites in Bushbuckridge, South Africa. AB - Members of the order Rickettsiales are small, obligate intracellular bacteria that are vector-borne and can cause mild to fatal diseases in humans worldwide. There is little information on the zoonotic rickettsial pathogens that may be harbored by dogs from rural localities in South Africa. To characterize rickettsial pathogens infecting dogs, we screened 141 blood samples, 103 ticks, and 43 fleas collected from domestic dogs in Bushbuckridge Municipality, Mpumalanga Province of South Africa, between October 2011 and May 2012 using the reverse line blot (RLB) and Rickettsia genus and species-specific quantitative real-time PCR (qPCR) assays. Results from RLB showed that 49% of blood samples and 30% of tick pools were positive for the genus-specific probes for Ehrlichia/Anaplasma; 16% of the blood samples were positive for Ehrlichia canis. Hemoparasite DNA could not be detected in 36% of blood samples and 30% of tick pools screened. Seven (70%) tick pools and both flea pools were positive for Rickettsia spp; three (30%) tick pools were positive for Rickettsia africae; and both flea pools (100%) were positive for Rickettsia felis. Sequencing confirmed infection with R. africae and Candidatus Rickettsia asemboensis; an R. felis-like organism from one of the R. felis-positive flea pools. Anaplasma sp. South Africa dog strain (closely related to Anaplasma phagocytophilum), A. phagocytophilum, and an Orientia tsutsugamushi-like sequence were identified from blood samples. The detection of emerging zoonotic agents from domestic dogs and their ectoparasites in a rural community in South Africa highlights the potential risk of human infection that may occur with these pathogens. PMID- 26974187 TI - Janus Particles in a Nonpolar Solvent. AB - Amphiphilic Janus particles are currently receiving great attention as "solid surfactants". Previous studies have introduced such particles with a variety of shapes and functions, but there has so far been a strong emphasis on water dispersible particles that mimic the molecular surfactants soluble in polar solvents. Here we present an example of lipophilic Janus particles which are selectively dispersible in very nonpolar solvents such as alkanes. Interfacial tension measurements between the alkane dispersions and pure water indicate that these particles do have interfacial activity, and like typical hydrophobic, nonionic surfactants, they do not partition to the aqueous bulk. We also show that the oil-borne particles, by retaining locally polar domains where charges can reside, generate electric conductivity in nonpolar liquids-another feature familiar from molecular surfactants and one commonly exploited to mitigate explosion hazards due to flow electrification during petroleum pumping and in the formulation of electronic inks. PMID- 26974186 TI - Age Differences in Recovery After Sport-Related Concussion: A Comparison of High School and Collegiate Athletes. AB - CONTEXT: Younger age has been hypothesized to be a risk factor for prolonged recovery after sport-related concussion, yet few studies have directly evaluated age differences in acute recovery. OBJECTIVE: To compare clinical recovery patterns for high school and collegiate athletes. DESIGN: Prospective cohort study. SETTING: Large, multicenter prospective sample collected from 1999-2003 in a sports medicine setting. SUBJECTS: Concussed athletes (n = 621; 545 males and 76 females) and uninjured controls (n = 150) participating in high school and collegiate contact and collision sports (79% in football, 15.7% in soccer, and the remainder in lacrosse or ice hockey). MAIN OUTCOME MEASURE(S): Participants underwent evaluation of symptoms (Graded Symptom Checklist), cognition (Standardized Assessment of Concussion, paper-and-pencil neuropsychological tests), and postural stability (Balance Error Scoring System). Athletes were evaluated preinjury and followed serially at several time points after concussive injury: immediately, 3 hours postinjury, and at days 1, 2, 3, 5, 7, and 45 or 90 (with neuropsychological measures administered at baseline and 3 postinjury time points). RESULTS: Comparisons of concussed high school and collegiate athletes with uninjured controls suggested that high school athletes took 1 to 2 days longer to recover on a cognitive (Standardized Assessment of Concussion) measure. Comparisons with the control group on other measures (symptoms, balance) as well as direct comparisons between concussed high school and collegiate samples revealed no differences in the recovery courses between the high school and collegiate groups on any measure. Group-level recovery occurred at or before 7 days postinjury on all assessment metrics. CONCLUSIONS: The findings suggest no clinically significant age differences exist in recovery after sport-related concussion, and therefore, separate injury-management protocols are not needed for high school and collegiate athletes. PMID- 26974188 TI - Nonaqueous electrocatalytic water oxidation by a surface-bound Ru(bda)(L)2 complex. AB - The rate of electrocatalytic water oxidation by the heterogeneous water oxidation catalyst [Ru(bda)(4-O(CH2)3P(O3H2)2-pyr)2], , (pyr = pyridine; bda = 2,2' bipyridine-6,6'-dicarboxylate) on metal oxide surfaces is greatly enhanced relative to water as the solvent. In these experiments with propylene carbonate (PC) as the nonaqueous solvent, water is the limiting reagent. Mechanistic studies point to atom proton transfer (APT) as the rate limiting step in water oxidation catalysis. PMID- 26974190 TI - New insights into aromatic pathways of carbachlorins and carbaporphyrins based on calculations of magnetically induced current densities. AB - Magnetically induced current densities have been calculated and analyzed for a number of synthesized carbachlorins and carbaporphyrins using density functional theory and the gauge including magnetically induced current (GIMIC) method. Aromatic properties have been determined by using accurate numerical integration of the current flow yielding reliable current strengths and pathways that are related to the degree of aromaticity and the aromatic character of the studied molecules. All investigated compounds are found to be aromatic. However, the obtained aromatic pathways differ from those previously deduced from spectroscopic data and magnetic shielding calculations. For all studied compounds, the ring current divides into an outer and an inner branch at each pyrrolic subring, showing that all pi-electrons of the pyrrolic rings take part in the delocalization pathway. The calculations do not support the common notion that the main share of the current takes the inner route at the pyrrolic rings without an inner hydrogen and follows an 18pi aromatic pathway. The aromatic pathways of the investigated carbaporphyrins and carbachlorins are very similar, since the current strength via the Cbeta[double bond, length as m-dash]Cbeta' bond of the cyclopentadienyl ring of the carbaporphyrins is almost as weak as the current density passing the corresponding saturated Cbeta-Cbeta' bond of the carbachlorins. PMID- 26974191 TI - Structure and activity of the anticaking agent iron(III) meso-tartrate. AB - Iron(III) meso-tartrate, a metal-organic complex, is a new anticaking agent for sodium chloride. A molecular structure in solution is proposed, based on a combination of experimental and molecular modelling results. We show that the active complex is a binuclear iron(iii) complex with two bridging meso-tartrate ligands. The iron atoms are antiferromagnetically coupled, resulting in a reduced paramagnetic nature of the solution. In solution, a water molecule coordinates to each iron atom as a sixth ligand, resulting in an octahedral symmetry around each iron atom. When the water molecule is removed, a flat and charged site is exposed, matching the charge distribution of the {100} sodium chloride crystal surface. This charge distribution is also found in the iron(iii) citrate complex, another anticaking agent. This gives a possible adsorption geometry on the crystal surface, which in turn explains the anticaking activity of the iron(III) meso-tartrate complex. PMID- 26974192 TI - Effect of Off-Axis Fluoroscopy Imaging on Two-Dimensional Kinematics in the Lumbar Spine: A Dynamic In Vitro Validation Study. AB - Spine intersegmental motion parameters and the resultant regional patterns may be useful for biomechanical classification of low back pain (LBP) as well as assessing the appropriate intervention strategy. Because of its availability and reasonable cost, two-dimensional (2D) fluoroscopy has great potential as a diagnostic and evaluative tool. However, the technique of quantifying intervertebral motion in the lumbar spine must be validated, and the sensitivity assessed. The purpose of this investigation was to (1) compare synchronous fluoroscopic and optoelectronic measures of intervertebral rotations during dynamic flexion-extension movements in vitro and (2) assess the effect of C-arm rotation to simulate off-axis patient alignment on intervertebral kinematics measures. Six cadaveric lumbar-sacrum specimens were dissected, and active marker optoelectronic sensors were rigidly attached to the bodies of L2-S1. Fluoroscopic sequences and optoelectronic kinematic data (0.15-mm linear, 0.17-0.20 deg rotational, accuracy) were obtained simultaneously. After images were obtained in a true sagittal plane, the image receptor was rotated in 5 deg increments (posterior oblique angulations) from 5 deg to 15 deg. Quantitative motion analysis (qma) software was used to determine the intersegmental rotations from the fluoroscopic images. The mean absolute rotation differences between optoelectronic values and dynamic fluoroscopic values were less than 0.5 deg for all the motion segments at each off-axis fluoroscopic rotation and were not significantly different (P > 0.05) for any of the off-axis rotations of the fluoroscope. Small misalignments of the lumbar spine relative to the fluoroscope did not introduce measurement variation in relative segmental rotations greater than that observed when the spine and fluoroscope were perpendicular to each other, suggesting that fluoroscopic measures of relative segmental rotation during flexion-extension are likely robust, even when patient alignment is not perfect. PMID- 26974193 TI - Mitochondria-specific conjugated polymer nanoparticles. AB - Biodegradable conjugated polymer nanoparticles (CPNs) were prepared for high mitochondrial targeting in live cancer cells. The degradable CPNs are nontoxic and specifically localized to the mitochondria of live tumor cells through macropinocytosis followed by intracellular degradation and trafficking. PMID- 26974194 TI - Energetic Constraints on Species Coexistence in Birds. AB - The association between species richness and ecosystem energy availability is one of the major geographic trends in biodiversity. It is often explained in terms of energetic constraints, such that coexistence among competing species is limited in low productivity environments. However, it has proven challenging to reject alternative views, including the null hypothesis that species richness has simply had more time to accumulate in productive regions, and thus the role of energetic constraints in limiting coexistence remains largely unknown. We use the phylogenetic relationships and geographic ranges of sister species (pairs of lineages who are each other's closest extant relatives) to examine the association between energy availability and coexistence across an entire vertebrate class (Aves). We show that the incidence of coexistence among sister species increases with overall species richness and is elevated in more productive ecosystems, even when accounting for differences in the evolutionary time available for coexistence to occur. Our results indicate that energy availability promotes species coexistence in closely related lineages, providing a key step toward a more mechanistic understanding of the productivity-richness relationship underlying global gradients in biodiversity. PMID- 26974195 TI - The impact of raw materials and baking conditions on Maillard reaction products, thiamine, folate, phytic acid and minerals in white bread. AB - The aim of this study was to develop a white bread with improved nutrient contents and reduced levels of potentially harmful Maillard reaction products such as N(epsilon)-carboxymethyllysine (CML) and 5-hydroxymethylfurfural (HMF). Assays were carried out through a full factorial experimental design allowing the simultaneous analysis of four factors at two levels: (1) wheat flour extraction rates (ash content: 0.60%-0.72%), (2) leavening agents (bakers' yeast - bakers' yeast and sourdough), (3) prebaking and (4) baking conditions (different sets of time and temperature). The baking conditions affected HMF and CML as well as certain mineral contents. A reduced baking temperature along with a prolonged heat treatment was found to be favourable for reducing both the CML (up to 20%) and HMF concentrations (up to 96%). The presence of sourdough decreased the formation of CML (up to 28%), and increased the apparent amounts of calcium (up to 8%) and manganese (up to 17.5%) probably through acidification of the dough. The extraction rate of flours as well as interactions between multiple factors also affected certain mineral content. However, compounds like folate, thiamine, copper, zinc, iron and phytic acid were not affected by any of the factors studied. PMID- 26974197 TI - [Not Available]. PMID- 26974198 TI - [Clinical status in Otolaryngology]. PMID- 26974199 TI - [Middle Ear Drainage and Ventilation: Indications, Complications and their Treatment]. AB - Tympanostomy is the most frequently performed surgery procedure in Germany. It enables middle ear ventilation and discharge of secretion from the middle ear with immediate hearing improvement and avoidance of complications and long-term pathologies of the tympanic membrane and the tympanum. The economical importance is emphasized by the fact that about 300,000 myringotomies are performed yearly. The best type of middle ear drainage and ventilation should be chosen on a case by-case basis. In this context, the various techniques like conventional myringotomy, laser-myringotomy, short-term and long-term tympanostomy tubes and indications, complications and their treatments are described. PMID- 26974200 TI - [Not Available]. PMID- 26974201 TI - [Not Available]. PMID- 26974203 TI - [Not Available]. PMID- 26974204 TI - Essential role for SphK1/S1P signaling to regulate hypoxia-inducible factor 2alpha expression and activity in cancer. AB - The sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) signaling pathway has been reported to modulate the expression of the canonical transcription factor hypoxia-inducible HIF-1alpha in multiple cell lineages. HIF-2alpha is also frequently overexpressed in solid tumors but its role has been mostly studied in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, where HIF-2alpha has been established as a driver of a more aggressive disease. In this study, the role of SphK1/S1P signaling with regard to HIF-2alpha was investigated in various cancer cell models including ccRCC cells. Under hypoxic conditions or in ccRCC lacking a functional von Hippel-Lindau (VHL) gene and expressing high levels of HIF-2alpha, SphK1 activity controls HIF-2alpha expression and transcriptional activity through a phospholipase D (PLD)-driven mechanism. SphK1 silencing promotes a VHL-independent HIF-2alpha loss of expression and activity and reduces cell proliferation in ccRCC. Importantly, downregulation of SphK1 is associated with impaired Akt and mTOR signaling in ccRCC. Taking advantage of a monoclonal antibody neutralizing extracellular S1P, we show that inhibition of S1P extracellular signaling blocks HIF-2alpha accumulation in ccRCC cell lines, an effect mimicked when the S1P transporter Spns2 or the S1P receptor 1 (S1P1) is silenced. Here, we report the first evidence that the SphK1/S1P signaling pathway regulates the transcription factor hypoxia-inducible HIF-2alpha in diverse cancer cell lineages notably ccRCC, where HIF-2alpha has been established as a driver of a more aggressive disease. These findings demonstrate that SphK1/S1P signaling may act as a canonical regulator of HIF-2alpha expression in ccRCC, giving support to its inhibition as a therapeutic strategy that could contribute to reduce HIF-2 activity in ccRCC. PMID- 26974205 TI - A porcine model of osteosarcoma. AB - We previously produced pigs with a latent oncogenic TP53 mutation. Humans with TP53 germline mutations are predisposed to a wide spectrum of early-onset cancers, predominantly breast, brain, adrenal gland cancer, soft tissue sarcomas and osteosarcomas. Loss of p53 function has been observed in >50% of human cancers. Here we demonstrate that porcine mesenchymal stem cells (MSCs) convert to a transformed phenotype after activation of latent oncogenic TP53(R167H) and KRAS(G12D), and overexpression of MYC promotes tumorigenesis. The process mimics key molecular aspects of human sarcomagenesis. Transformed porcine MSCs exhibit genomic instability, with complex karyotypes, and develop into sarcomas on transplantation into immune-deficient mice. In pigs, heterozygous knockout of TP53 was sufficient for spontaneous osteosarcoma development in older animals, whereas homozygous TP53 knockout resulted in multiple large osteosarcomas in 7-8 month-old animals. This is the first report that engineered mutation of an endogenous tumour-suppressor gene leads to invasive cancer in pigs. Unlike in Trp53 mutant mice, osteosarcoma developed in the long bones and skull, closely recapitulating the human disease. These animals thus promise a model for juvenile osteosarcoma, a relatively uncommon but devastating disease. PMID- 26974206 TI - Phosphatase PP2A is requisite for the function of regulatory T cells. AB - Homeostasis of the immune system depends on the proper function of regulatory T cells (T(reg) cells). Compromised suppressive activity of T(reg) cells leads to autoimmune disease and graft rejection and promotes anti-tumor immunity. Here we report a previously unrecognized requirement for the serine-threonine phosphatase PP2A in the function of T(reg) cells. T(reg) cells exhibited high PP2A activity, and T(reg) cell-specific ablation of the PP2A complex resulted in a severe, multi organ, lymphoproliferative autoimmune disorder. Mass spectrometry revealed that PP2A associated with components of the mTOR metabolic-checkpoint kinase pathway and suppressed the activity of the mTORC1 complex. In the absence of PP2A, T(reg) cells altered their metabolic and cytokine profile and were unable to suppress effector immune responses. Therefore, PP2A is required for the function of T(reg) cells and the prevention of autoimmunity. PMID- 26974207 TI - Once failed, twice shy: How group-based competition influences risk preference in young children. AB - Recent developmental research demonstrates that young children tend to be risk seeking. However, very little is known about the extent to which such a capacity varies with children's group-based experience. Given that between-group competition is a central feature of human social life, this study aimed at examining the influence of group-based competition over risk preference in young children. In total, 234 children from 3 age groups (2-4-year-olds, 5-6-year-olds, and 8-9-year-olds) engaged in an intergroup competition manipulation, which was followed by a prosocial game assessing children's ingroup egalitarianism and a gambling task measuring children's risk preference. We found that children in the intergroup competition condition tended to be risk-averse compared with those who were in the nonintergroup competition condition. Furthermore, we found that an aversion to risk in the intergroup competition condition was driven by such an aversion observed in children from the losing group. In addition, we found a positive relationship between ingroup egalitarianism and risk preference in children from the winning group rather than those from the losing group. Together, our results contribute to the understanding of the effects of group based experience on children's risk preference and may have important implications for understanding individuals' risky decisions. PMID- 26974208 TI - The genetic and environmental etiologies of the relations between cognitive skills and components of reading ability. AB - Although previous research has shown cognitive skills to be important predictors of reading ability in children, the respective roles for genetic and environmental influences on these relations is an open question. The present study explored the genetic and environmental etiologies underlying the relations between selected executive functions and cognitive abilities (working memory, inhibition, processing speed, and naming speed) with 3 components of reading ability (word reading, reading comprehension, and listening comprehension). Twin pairs drawn from the Colorado Front Range (n = 676; 224 monozygotic pairs; 452 dizygotic pairs) between the ages of 8 and 16 (M = 11.11) were assessed on multiple measures of each cognitive and reading-related skill. Each cognitive and reading-related skill was modeled as a latent variable, and behavioral genetic analyses estimated the portions of phenotypic variance on each latent variable due to genetic, shared environmental, and nonshared environmental influences. The covariance between the cognitive skills and reading-related skills was driven primarily by genetic influences. The cognitive skills also shared large amounts of genetic variance, as did the reading-related skills. The common cognitive genetic variance was highly correlated with the common reading genetic variance, suggesting that genetic influences involved in general cognitive processing are also important for reading ability. Skill-specific genetic variance in working memory and processing speed also predicted components of reading ability. Taken together, the present study supports a genetic association between children's cognitive ability and reading ability. PMID- 26974209 TI - The reversed description-experience gap: Disentangling sources of presentation format effects in risky choice. AB - Previous literature has suggested that risky choice patterns in general--and probability weighting in particular--are strikingly different in experience-based as compared with description-based formats. In 2 reanalyses and 3 new experiments, we investigate differences between experience-based and description based decisions using a parametric approach based on cumulative prospect theory (CPT). Once controlling for sampling biases, we consistently find a reversal of the typical description-experience gap, that is, a reduced sensitivity to probabilities and increased overweighting of small probabilities in decisions from experience as compared with decisions from descriptions. This finding supports the hypothesis that regression to the mean effects in probability estimation are a crucial source of differences between both presentation formats. Further analyses identified task specific information asymmetry prevalent in gambles involving certainty as a third source of differences. We present a novel conceptualization of multiple independent sources of bias that contribute to the description-experience gap, namely sampling biases and task specific information asymmetry on the one hand, and regression to the mean effects in probability estimation on the other hand. PMID- 26974210 TI - Conceptual and direct replications fail to support the stake-likelihood hypothesis as an explanation for the interdependence of utility and likelihood judgments. AB - Previous research suggests that people systematically overestimate the occurrence of both positive and negative events, compared with neutral future events, and that these biases are due to a misattribution of arousal elicited by utility (stake-likelihood hypothesis; SLH; Vosgerau, 2010). However, extant research has provided only indirect support for these arousal misattribution processes. In the present research, we initially aimed to provide a direct test of the SLH by measuring arousal with galvanic skin responses to examine the mediating role of arousal. We observed no evidence that measured arousal mediated the impact of utility on probability estimates. Given the lack of direct support for the SLH in Experiment 1, Experiments 2-5 aimed to assess the SLH by replicating some of the original findings that provided support for arousal misattribution as a mechanism. Despite our best efforts to create experimental conditions under which we would be able to demonstrate the stake-likelihood effect, we were unable to replicate previous results, with a Bayesian meta-analysis demonstrating support for the null hypothesis. We propose that accounts based on imaginability and loss function asymmetry are currently better candidate explanations for the influence of outcome utility on probability estimates. PMID- 26974212 TI - Active Video Games for Improving Physical Performance Measures in Older People: A Meta-analysis. AB - BACKGROUND AND PURPOSE: Participation in regular physical activity is associated with better physical function in older people (>65 years); however, older people are the least active of all age groups. Exercise-based active video games (AVGs) offer an alternative to traditional exercise programs aimed at maintaining or enhancing physical performance measures in older people. This review systematically evaluated whether AVGs could improve measures of physical performance in older people. Secondary measures of safety, game appeal, and usability were also considered. METHODS: Electronic databases were searched for randomized controlled trials published up to April 2015. Included were trials with 2 or more arms that evaluated the effect of AVGs on outcome measures of physical performance in older people. RESULTS: Eighteen randomized controlled trials (n = 765) were included. Most trials limited inclusion to healthy community-dwelling older people. With the exception of 1 trial, all AVG programs were supervised. Using meta-analyses, AVGs were found to be more effective than conventional exercise (mean difference [MD], 4.33; 95% confidence intervals [CIs], 2.93-5.73) or no intervention (MD, 0.73; 95% CI, 0.17-1.29) for improving Berg Balance scores in community-dwelling older people. Active video games were also more effective than control for improving 30-second sit-to-stand scores (MD, 3.99; 95% CI, 1.92-6.05). No significant differences in Timed Up and Go scores were found when AVGs were compared with no intervention or with conventional exercise. CONCLUSIONS: Active video games can improve measures of mobility and balance in older people when used either on their own or as part of an exercise program. It is not yet clear whether AVGs are equally suitable for older people with significant cognitive impairments or balance or mobility limitations. Given the positive findings to date, consideration could be given to further development of age-appropriate AVGs for use by older people with balance or mobility limitations. PMID- 26974211 TI - SIRT1, 2, 3 protect mouse oocytes from postovulatory aging. AB - The quality of metaphase II oocytes will undergo a time-dependent deterioration following ovulation as the result of the oocyte aging process. In this study, we determined that the expression of sirtuin family members (SIRT1, 2, 3) was dramatically reduced in mouse oocytes aged in vivo or in vitro. Increased intracellular ROS was observed when SIRT1, 2, 3 activity was inhibited. Increased frequency of spindle defects and disturbed distribution of mitochondria were also observed in MII oocytes aged in vitro after treatment with Nicotinamide (NAM), indicating that inhibition of SIRT1, 2, 3 may accelerate postovulatory oocyte aging. Interestingly, when MII oocytes were exposed to caffeine, the decline of SIRT1, 2, 3 mRNA levels was delayed and the aging-associated defective phenotypes could be improved. The results suggest that the SIRT1, 2, 3 pathway may play a potential protective role against postovulatory oocyte aging by controlling ROS generation. PMID- 26974213 TI - Role and clinical implications of atypical antipsychotics in anxiety disorders, obsessive-compulsive disorder, trauma-related, and somatic symptom disorders: a systematized review. AB - Atypical antipsychotics (AAs) may play a role in the treatment of anxiety disorders, obsessive-compulsive disorder (OCD), and trauma-related disorders. No reviews on their differential use in these different disorders have been performed recently. The aim of this systematized review was to obtain data on efficacy and comparative effectiveness of AAs as a treatment of anxiety disorders, OCD, and trauma-related disorders to provide guidance for clinicians on when and which AA to use. We searched on PubMed, Psychnet, and Cochrane Libraries from inception to July 2015. Search results were limited to randomized, placebo-controlled trials of adult patients. Evidence of efficacy was considered the presence of positive results in two or more double-blind placebo-controlled studies. Our systematized search identified 1298 papers, of which 191 were subjected to a full-text review and 56 were included. Quetiapine extended-release showed a role in both acute and maintenance treatment of uncomplicated generalized anxiety disorder, whereas more studies are needed before drawing practical recommendations on the use of olanzapine and risperidone; aripiprazole and risperidone are effective in resistant OCD as augmentation treatments. Risperidone and olanzapine add-on may have a role in resistant or chronic post traumatic stress disorder patients, although only risperidone addition can be recommended on the basis of the criterion of two or more positive placebo controlled trials. This systematized review supports the evidence that only a few AAs are effective in only a minority of the off-label conditions in which they are currently used and confirms that AAs are not all the same. Their use should be on the basis of a balance between efficacy and side effects, and the characteristics as well as the preference of the patient. PMID- 26974214 TI - Factors associated with relapse in schizophrenia despite adherence to long-acting injectable antipsychotic therapy. AB - Many patients with schizophrenia will relapse despite uninterrupted antipsychotic (AP) long-acting therapy (LAT). This exploratory analysis examined variables associated with relapse despite ensured adherence to LAT. This was a post-hoc exploratory analysis of a 1-year study of risperidone long-acting injection in patients with stable schizophrenia or schizoaffective disorder (NCT00297388; N=323). Patients were discontinued from previous oral APs and randomly assigned to biweekly intramuscular injections of risperidone long-acting injectable 50 (n=163) or 25 mg (n=161) for 52 weeks. Cox proportional hazards regression models examined variables putatively associated with relapse. A total of 59/323 (18.3%) patients relapsed over 12 months despite continuous AP LAT. Variables associated with the risk of relapse included illness duration (6.0% increase each year; P=0.0003) and country (Canada vs. USA, 4.7-fold risk increase; P=0.0008). When illness duration was further categorized as <=5, 6-10, and >10 years, patients with an illness duration of >10 versus <=5 years were at greatest risk of relapse (>10 vs. <=5 years associated with a 4.4-fold increase in the risk of relapse; P=0.0181). Findings suggest that patients with more chronic illness have a greater risk of relapse despite ensured treatment adherence, supporting the need for early intervention to prevent the deleterious effects of chronicity. PMID- 26974215 TI - Are you listening? PMID- 26974216 TI - Balancing efficiency and safety in the OR. PMID- 26974217 TI - Vaginal Cerclage: Preoperative, Intraoperative, and Postoperative Management. AB - The role of the cerclage procedure has expanded from its initial application as treatment or prevention of cervical insufficiency to prevention of recurrent spontaneous preterm birth. Although recent prospective studies have clarified the indications for cerclage, additional prospective studies are needed to help define optimal perioperative management. Herein, we review the current data to provide the clinician with the most evidence-based approach to managing patients who require cerclage. PMID- 26974218 TI - Cerclage: Shirodkar, McDonald, and Modifications. AB - As the concept of cervical insufficiency has evolved from a poorly defined clinical/anatomic entity into 1 component of the spontaneous preterm birth syndrome, so have cerclage applications. Originally developed to treat history defined cervical insufficiency and acute cervical insufficiency, cerclage is now utilized on a larger scale for the prevention of recurrent spontaneous preterm birth. As its role expands, the need for prospective data evaluating cerclage techniques and modifications is emphasized. Herein, we will review the techniques, modifications, risks, efficacy, and evidence-based applications of the cerclage procedure in contemporary clinical practice. PMID- 26974219 TI - Breast Ultrasound: Indications and Findings. AB - Breast ultrasound is a widely used adjuvant to mammography for the detection of breast cancer. This chapter will review some of the basic ultrasound technical factors and techniques, describe findings on ultrasound with an emphasis on the Breast Imaging Reporting and Data System terminology, and present the indications for breast ultrasound. New innovations in breast ultrasound, such as elastography, ultrasound contrast, 3-dimensional, and automated whole-breast ultrasound, will be reviewed. Ultrasound-guided breast procedures are also presented. PMID- 26974220 TI - Diagnostic and Therapeutic Challenges. PMID- 26974221 TI - The Influence of Linguistic Proficiency on Masked Text Recognition Performance in Adults With and Without Congenital Hearing Impairment. AB - OBJECTIVE: The authors first examined the influence of moderate to severe congenital hearing impairment (CHI) on the correctness of samples of elicited spoken language. Then, the authors used this measure as an indicator of linguistic proficiency and examined its effect on performance in language reception, independent of bottom-up auditory processing. DESIGN: In groups of adults with normal hearing (NH, n = 22), acquired hearing impairment (AHI, n = 22), and moderate to severe CHI (n = 21), the authors assessed linguistic proficiency by analyzing the morphosyntactic correctness of their spoken language production. Language reception skills were examined with a task for masked sentence recognition in the visual domain (text), at a readability level of 50%, using grammatically correct sentences and sentences with distorted morphosyntactic cues. The actual performance on the tasks was compared between groups. RESULTS: Adults with CHI made more morphosyntactic errors in spoken language production than adults with NH, while no differences were observed between the AHI and NH group. This outcome pattern sustained when comparisons were restricted to subgroups of AHI and CHI adults, matched for current auditory speech reception abilities. The data yielded no differences between groups in performance in masked text recognition of grammatically correct sentences in a test condition in which subjects could fully take advantage of their linguistic knowledge. Also, no difference between groups was found in the sensitivity to morphosyntactic distortions when processing short masked sentences, presented visually. CONCLUSIONS: These data showed that problems with the correct use of specific morphosyntactic knowledge in spoken language production are a long-term effect of moderate to severe CHI, independent of current auditory processing abilities. However, moderate to severe CHI generally does not impede performance in masked language reception in the visual modality, as measured in this study with short, degraded sentences. Aspects of linguistic proficiency that are affected by CHI thus do not seem to play a role in masked sentence recognition in the visual modality. PMID- 26974222 TI - Urinary Concentrations of Bisphenols and Their Association with Biomarkers of Oxidative Stress in People Living Near E-Waste Recycling Facilities in China. AB - In this study, concentrations of bisphenol A (BPA) and seven other bisphenols (BPs) were measured in urine samples collected from people living in and around e waste dismantling facilities, and in matched reference population from rural and urban areas in China. BPA, bisphenol S (BPS), and bisphenol F (BPF) were frequently detected (detection frequencies: > 90%) in urine samples collected from individuals who live near e-waste facilities, with geometric mean (GM) concentrations of 2.99 (or 3.75), 0.361 (or 0.469), and 0.349 (or 0.435) ng/mL (or MUg/g Cre), respectively; the other five BPs were rarely found in urine samples, regardless of the sampling location. The urinary concentrations of BPA and BPF, but not BPS, were significantly higher in individuals from e-waste recycling locations than did individuals from a rural reference location. Our findings indicated that e-waste dismantling activities contribute to human exposure to BPA and BPF. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) was measured in urine as a marker of oxidative stress. In the e-waste dismantling location, urinary 8-OHdG was significantly and positively correlated (p < 0.001) with urinary BPA and BPS, but not BPF; a similar correlation was also observed in reference sites. These findings suggest that BPA and BPS exposures are associated with elevated oxidative stress. PMID- 26974223 TI - Survival of Allogeneic Hematopoietic Stem Cell Recipients Admitted to the Intensive Care Unit: Have We Reached the Limits? PMID- 26974224 TI - Theoretical Modeling of the Magnetic Behavior of Thiacalix[4]arene Tetranuclear Mn(II)2Gd(III)2 and Co(II)2Eu(III)2 Complexes. AB - In view of a wide perspective of 3d-4f complexes in single-molecule magnetism, here we propose an explanation of the magnetic behavior of the two thiacalix[4]arene tetranuclear heterometallic complexes Mn(II)2Gd(III)2 and Co(II)2Eu(III)2. The energy pattern of the Mn(II)2Gd(III)2 complex evaluated in the framework of the isotropic exchange model exhibits a rotational band of the low-lying spin excitations within which the Lande intervals are affected by the biquadratic spin-spin interactions. The nonmonotonic temperature dependence of the chiT product observed for the Mn(II)2Gd(III)2 complex is attributed to the competitive influence of the ferromagnetic Mn-Gd and antiferromagnetic Mn-Mn exchange interactions, the latter being stronger (J(Mn, Mn) = -1.6 cm(-1), Js(Mn, Gd) = 0.8 cm(-1), g = 1.97). The model for the Co(II)2Eu(III)2 complex includes uniaxial anisotropy of the seven-coordinate Co(II) ions and an isotropic exchange interaction in the Co(II)2 pair, while the Eu(III) ions are diamagnetic in their ground states. Best-fit analysis of chiT versus T showed that the anisotropic contribution (arising from a large zero-field splitting in Co(II) ions) dominates (weak-exchange limit) in the Co(II)2Eu(III)2 complex (D = 20.5 cm(-1), J = -0.4 cm(-1), gCo = 2.22). This complex is concluded to exhibit an easy plane of magnetization (arising from the Co(II) pair). It is shown that the low-lying part of the spectrum can be described by a highly anisotropic effective spin-(1)/2 Hamiltonian that is deduced for the Co(II)2 pair in the weak-exchange limit. PMID- 26974225 TI - Control of Reversible Self-Bending Behavior in Responsive Janus Microstrips. AB - Here, we demonstrate a simple method to systematically control the responsive self-bending behavior of Janus hydrogel microstrips consisting of a polymeric bilayer with a high modulus contrast. The Janus hydrogel microstrips could be easily fabricated by a simple micromolding technique combined with an initiated chemical vapor deposition (iCVD) coating, providing high flexibility in controlling the physical and chemical properties of the microstrips. The fabricated Janus hydrogel microstrip is composed of a soft, pH-responsive polymer hydrogel layer laminated with a highly cross-linked, rigid thin film, generating a geometric anisotropy at a micron scale. The large difference in the elastic moduli between the two layers of the Janus microstrips leads to a self-bending behavior in response to the pH change. More specifically, the impact of the physical and chemical properties of the microstrip on the self-bending phenomena was systematically investigated by changing the thickness and composition of two layers of the microstrip, which renders high controllability in bending of the microstrips. The curvature of the Janus microstrips, formed by self-bending, highly depends on the applied acidity. A reversible, responsive self bending/unbending exhibits a perfect resilience pattern with repeated changes in pH for 5 cycles. We envision that the Janus microstrips can be engineered to form complex 3D microstructures applicable to various fields such as soft robotics, scaffolds, and drug delivery. The reliable responsive behaviors obtained from the systematic investigation will provide critical information in bridging the gap between the theoretical mechanical analysis and the chemical properties to achieve micron-scale soft robotics. PMID- 26974226 TI - Probing Microscopic Orientation in Membranes by Linear Dichroism. AB - The cell membrane is an ordered environment, which anisotropically affects the structure and interactions of all of its molecules. Monitoring membrane orientation at a local level is rather challenging but could reward crucial information on protein conformation and interactions in the lipid bilayer. We monitored local lipid ordering changes upon varying the cholesterol concentration using polarized light spectroscopy and pyrene as a membrane probe. Pyrene, with a shape intermediate between a disc and a rod, can detect microscopic orientation variations at the level of its size. The global membrane orientation was determined using curcumin, a probe with nonoverlapping absorption relative to that of pyrene. While the macroscopic orientation of a liquid-phase bilayer decreases with increasing cholesterol concentration, the local orientation is improved. Pyrene is found to be sensitive to the local effects induced by cholesterol and temperature on the bilayer. Disentangling local and global orientation effects in membranes could provide new insights into functionally significant interactions of membrane proteins. PMID- 26974228 TI - Stability and Biodistribution of Thiol-Functionalized and (177)Lu-Labeled Metal Chelating Polymers Bound to Gold Nanoparticles. AB - We are studying a novel radiation nanomedicine approach to treatment of breast cancer using 30 nm gold nanoparticles (AuNP) modified with polyethylene glycol (PEG) metal-chelating polymers (MCP) that incorporate 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators for complexing the beta-particle emitter, (177)Lu. Our objective was to compare the stability of AuNP conjugated to MCP via a single thiol [DOTA-PEG-ortho-pyridyl disulfide (OPSS)], a dithiol [DOTA-PEG-lipoic acid (LA)] or multithiol end-group [PEG pGlu(DOTA)8-LA4] and determine the elimination and biodistribution of these (177)Lu-labeled MCP-AuNP in mice. Stability to aggregation in the presence of thiol-containing dithiothreitol (DTT), L-cysteine or glutathione was assessed and dissociation of (177)Lu-MCP from AuNP in human plasma measured. Elimination of radioactivity from the body of athymic mice and excretion into the urine and feces was measured up to 168 h post-intravenous (i.v.) injection of (177)Lu-MCP AuNP and normal tissue uptake was determined. ICP-AES was used to quantify Au in the liver and spleen and these were compared to (177)Lu. Our results showed that PEG-pGlu(DOTA)8-LA4-AuNP were more stable to aggregation in vitro than DOTA-PEG LA-AuNP and both forms of AuNP were more stable to thiol challenge than DOTA-PEG OPSS-AuNP. PEG-pGlu((177)Lu-DOTA)8-LA4 was the most stable in plasma. Whole body elimination of (177)Lu was most rapid for mice injected with (177)Lu-DOTA-PEG OPSS-AuNP. Urinary excretion accounted for >90% of eliminated (177)Lu. All (177)Lu-MCP-AuNP accumulated in the liver and spleen. Liver uptake was lowest for PEG-pGlu((177)Lu-DOTA)8-LA4-AuNP but these AuNP exhibited the greatest spleen uptake. There were differences in Au and (177)Lu in the liver for PEG pGlu((177)Lu-DOTA)8-LA4-AuNP. These differences were not correlated with in vitro stability of the (177)Lu-MCP-AuNP. We conclude that conjugation of AuNP with PEG pGlu((177)Lu-DOTA)8-LA4 via a multithiol functional group provided the greatest stability in vitro and lowest liver uptake in vivo and is, therefore, the most promising for constructing (177)Lu-MCP-AuNP for radiation treatment of breast cancer. PMID- 26974227 TI - A novel ciprofloxacin-resistant subclade of H58 Salmonella Typhi is associated with fluoroquinolone treatment failure. AB - The interplay between bacterial antimicrobial susceptibility, phylogenetics and patient outcome is poorly understood. During a typhoid clinical treatment trial in Nepal, we observed several treatment failures and isolated highly fluoroquinolone-resistant Salmonella Typhi (S. Typhi). Seventy-eight S. Typhi isolates were genome sequenced and clinical observations, treatment failures and fever clearance times (FCTs) were stratified by lineage. Most fluoroquinolone resistant S. Typhi belonged to a specific H58 subclade. Treatment failure with S. Typhi-H58 was significantly less frequent with ceftriaxone (3/31; 9.7%) than gatifloxacin (15/34; 44.1%)(Hazard Ratio 0.19, p=0.002). Further, for gatifloxacin-treated patients, those infected with fluoroquinolone-resistant organisms had significantly higher median FCTs (8.2 days) than those infected with susceptible (2.96) or intermediately resistant organisms (4.01)(pS. Typhi clade internationally, but there are no data regarding disease outcome with this organism. We report an emergent new subclade of S. Typhi-H58 that is associated with fluoroquinolone treatment failure. PMID- 26974229 TI - Biogenetically Inspired Synthesis of Lingzhiol. AB - A concise stereo- and enantioselective synthesis of lingzhiol has been achieved featuring a biogenetically inspired Bronsted acid catalyzed semipinacol rearrangement of a glycidyl alcohol intermediate. PMID- 26974230 TI - Oxidized Ferric and Ferryl Forms of Hemoglobin Trigger Mitochondrial Dysfunction and Injury in Alveolar Type I Cells. AB - Lung alveoli are lined by alveolar type (AT) 1 cells and cuboidal AT2 cells. The AT1 cells are likely to be exposed to cell-free hemoglobin (Hb) in multiple lung diseases; however, the role of Hb redox (reduction-oxidation) reactions and their precise contributions to AT1 cell injury are not well understood. Using mouse lung epithelial cells (E10) as an AT1 cell model, we demonstrate here that higher Hb oxidation states, ferric Hb (HbFe(3+)) and ferryl Hb (HbFe(4+)) and subsequent heme loss play a central role in the genesis of injury. Exposures to HbFe(2+) and HbFe(3+) for 24 hours induced expression of heme oxygenase (HO)-1 protein in E10 cells and HO-1 translocation in the purified mitochondrial fractions. Both of these effects were intensified with increasing oxidation states of Hb. Next, we examined the effects of Hb oxidation and free heme on mitochondrial bioenergetic function by measuring changes in the mitochondrial transmembrane potential and oxygen consumption rate. In contrast to HbFe(2+), HbFe(3+) reduced basal oxygen consumption rate, indicating compromised mitochondrial activity. However, HbFe(4+) exposure not only induced early expression of HO-1 but also caused mitochondrial dysfunction within 12 hours when compared with HbFe(2+) and HbFe(3+). Exposure to HbFe(4+) for 24 hours also caused mitochondrial depolarization in E10 cells. The deleterious effects of HbFe(3+) and HbFe(4+) were reversed by the addition of scavenger proteins, haptoglobin and hemopexin. Collectively, these data establish, for the first time, a central role for cell free Hb in lung epithelial injury, and that these effects are mediated through the redox transition of Hb to higher oxidation states. PMID- 26974231 TI - BF3.OEt2-AgSCF3 Mediated Trifluoromethylthiolation/Cascade Cyclization of Propynols: Synthesis of 4-((Trifluoromethyl)thio)-2H-chromene and 4 ((Trifluoromethyl)thio)-1,2-dihydroquinoline Derivatives. AB - A BF3.OEt2-AgSCF3 mediated direct trifluoromethylthiolation/cascade cyclization of propynols involving the SCF3 anion nucleophilic pathway is developed. This protocol also provides an opportunity to construct valuable trifluoromethylthio substituted 2H-chromene and 1,2-dihydroquinoline systems with high efficiency under mild conditions. Additionally, the developed BF3.OEt2-AgSCF3 reaction system could be scaled up to gram quantities in a satisfactory yield without inert gas protection. PMID- 26974232 TI - Gamification of active travel to school: A pilot evaluation of the Beat the Street physical activity intervention. AB - Beat the Street aims to get children more active by encouraging them to walk and cycle in their neighbourhood using tracking technology with a reward scheme. This pilot study evaluates the impact of Beat the Street on active travel to school in Norwich, UK. Eighty children 8-10 yrs were recruited via an intervention and control school. They wore an accelerometer for 7 days at baseline, mid intervention and post-intervention (+20 weeks), and completed a travel diary. Physical activity overall was not higher at follow-up amongst intervention children compared to controls. However, there was a positive association between moderate-to-vigorous physical activity (MVPA) during school commute times and the number of days on which children touched a Beat the Street sensor. This equated to 3.46min extra daily MVPA during commute times for children who touched a sensor on 14.5 days (the mean number of days), compared to those who did not engage. We also found weekly active travel increased at the intervention school (+10.0% per child) while it decreased at the control (-7.0%), p=0.056. Further work is needed to understand how improved engagement with the intervention might impact outcomes. PMID- 26974233 TI - Residential exposure to visible blue space (but not green space) associated with lower psychological distress in a capital city. AB - As urbanisation escalates globally, urban neighbourhood features which may improve physical and mental health are of growing importance. Using a cross sectional survey of adults and the application of novel geospatial techniques, this study investigated whether increased visibility of nature (green and blue space) was associated with lower psychological distress (K10 scores), in the capital city of Wellington, New Zealand. To validate, we also tested whether visibility of blue space was associated missing teeth in the same sample. Cluster robust, linear regression models were fitted to test the association between visibility of nature and K10 scores, adjusted for age, sex, personal income, neighbourhood population density, housing quality, crime and deprivation. Higher levels of blue space visibility were associated with lower psychological distress (beta=-0.28, p<0.001). Importantly, blue space visibility was not significantly associated with tooth loss. Further research is needed to confirm whether increased visibility of blue space could promote mental well-being and reduce distress in other cities. PMID- 26974234 TI - Changing spatial patterns and increasing rurality of HIV prevalence in the Democratic Republic of the Congo between 2007 and 2013. AB - The Democratic Republic of the Congo (DRC) has one of the lowest HIV prevalence in sub-Saharan Africa, estimated at 1.1% [0.9-1.3] of adults aged 15-49 in 2013 (UNAIDS). Within the 2 million km(2) country, however, there exists spatial variation in HIV prevalence, with the highest HIV prevalence observed in the large cities of Kinshasa and Lubumbashi. Globally, HIV is an increasingly rural disease, diffusing outwards from urban centers of high HIV prevalence to places where HIV was previously absent or present at very low levels. Utilizing data collected during Demographic and Health Surveillance (DHS) in 2007 and 2013 in the DRC, we sought to update the map of HIV prevalence in the DRC as well as to explore whether HIV in the DRC is an increasingly rural disease or remains confined to urban areas. Bayesian kriging and regression indicate that HIV prevalence in rural areas of the DRC is higher in 2013 than in 2007 and that increased distance to an urban area is no longer protective against HIV as it was in 2007. These findings suggest that HIV education, testing and prevention efforts need to diffuse from urban to rural areas just as HIV is doing. PMID- 26974235 TI - Understanding the Attitudes of Patients with Cancer Toward Complementary and Alternative Therapies. AB - BACKGROUND: The high prevalence of complementary and alternative medicine (CAM) use among patients with cancer can be explained by reasons such as growing scientific evidence and improved regulation. However, subjective considerations are also relevant for practicing CAM and perceiving its effectiveness. The current study aimed at qualitatively estimating patients' prior beliefs and expectations, as well as their level of satisfaction after the treatment. PATIENTS AND METHODS: Patients with cancer who received six weekly sessions of CAM during their oncologic treatments participated in the study. They detailed their prior expectations and their level of posttreatment satisfaction. The open ended answers were analyzed using interpretative phenomenological analysis. In addition, the contents before and after the intervention were compared. RESULTS: Over a 2-year period, 163 patients entered the study, 135 of whom completed all six CAM sessions. The content analysis of the pretreatment expectations revealed four main categories: emotional, physical, external, and aspects related to the practice of CAM. After the intervention, patients referred to the therapeutic encounter as a significant aspect, in addition to the emotional and physical ones. CONCLUSION: CAM sessions encouraged emotional and relational aspects in patients' perspectives, which may be highly relevant for their coping process. Encouraging personal motives may increase treatment efficacy and ensure optimal use of health care resources. PMID- 26974236 TI - D5S2500 is an ambiguously characterized STR: Identification and description of forensic microsatellites in the genomics age. AB - In the process of establishing short tandem repeat (STR) sequence variant nomenclature guidelines in anticipation of expanded forensic multiplexes for massively parallel sequencing (MPS), it was discovered that the STR D5S2500 has multiple positions and genomic characteristics reported. This ambiguity is because the marker named D5S2500 consists of two different microsatellites forming separate components in the capillary electrophoresis multiplexes of Qiagen's HDplex (Hilden, Germany) and AGCU ScienTech's non-CODIS STR 21plex (Wuxi, Jiangsu, China). This study outlines the genomic details used to identify each microsatellite and reveals the D5S2500 marker in HDplex has the correctly assigned STR name, while the D5S2500 marker in the AGCU 21plex, closely positioned a further 1643 nucleotides in the human reference sequence, is an unnamed microsatellite. The fact that the D5S2500 marker has existed as two distinct STR loci undetected for almost ten years, even with reported discordant genotypes for the standard control DNA, underlines the need for careful scrutiny of the genomic properties of forensic STRs, as they become adapted for sequence analysis with MPS systems. We make the recommendation that precise chromosome location data must be reported for any forensic marker under development but not in common use, so that the genomic characteristics of the locus are validated to the same level of accuracy as its allelic variation and forensic performance. To clearly differentiate each microsatellite, we propose the name D5S2800 be used to identify the Chromosome-5 STR in the AGCU 21plex. PMID- 26974237 TI - Role and influence of extracellular polymeric substances on the preparation of aerobic granular sludge. AB - Due to the important role of the extracellular polymeric substances in the formation of aerobic granular sludge, the variation of the EPS contents in the process of cultivation and that in the one running cycle time were studied in this work. Aerobic granules with diameters between 0.8 and 1.1 mm were obtained within 30-35 days. The results suggested that the increase of EPS contents significantly contributed to the formation of aerobic granules. A linear relationship between the EPS and SVI was also developed, and it revealed that the aerobic granules had good settling property when the EPS exceeded 200 mg/g MLVSS. Two mainly components of EPS, protein (PN) and polysaccharides (PS), could act as the endogenous food for the microbes during the starvation period. The survival of the microbial population was jeopardized when the F/M ration was below 0.5 g COD/g SS d. PMID- 26974238 TI - Biomagnetic monitoring of heavy metals contamination in deposited atmospheric dust, a case study from Isfahan, Iran. AB - Tree leaves are considered as one of the best biogenic dust collectors due to their ability to trap and retain particulate matter on their surfaces. In this study, the magnetic susceptibility (MS) and the concentration of selected heavy metals of plane tree (Platanus orientalis L.) leaves and deposited atmospheric dust, sampled by an indirect and a direct method, respectively, were determined to investigate the relationships between leaf magnetic parameters and the concentration of heavy metals in deposited atmospheric dust. The objective was to develop a biomagnetic method as an alternative to the common ones used for determining atmospheric heavy metal contaminations. Plane tree leaves were monthly sampled on the 19th of May to November, 2012 (T1-T7), for seven months from 21 different sites in the city of Isfahan, central Iran. Deposited atmospheric dust samples were also collected using flat glass surfaces from the same sites on the same dates, except for T1. MS (chilf, chihf) values in washed (WL) and unwashed leaves (UL) as well as Cu, Fe, Mn, Ni, Pb, and Zn concentrations in UL and deposited atmospheric dust samples were determined. The results showed that the MS content with a biogenic source was low with almost no significant change during the sampling period, while an increasing trend was observed in the MS content of UL samples due to the deposition of heavy metals and magnetic particles on leaf surfaces throughout the plant growth. The latter type of MS content could be reduced through washing off by rain. Most heavy metals examined, as well as the Tomlinson pollution load index (PLI) in UL, showed statistically significant correlations with MS values. The correlation between heavy metals content in atmospheric dust deposited on glass surfaces and leaf MS values was significant for Cu, Fe, Pb, and Zn. Moreover, the similarity observed between the spatial distribution maps of leaf MS and deposited atmospheric dust PLI provided convincing evidence regarding the suitability of the biomagnetic approach as a relatively rapid and inexpensive method for identifying highly polluted urban areas with selected heavy metals, especially those subjected to anthropogenic and other traffic related sources. PMID- 26974239 TI - Applying GIS to develop a model for forest fire risk: A case study in Espirito Santo, Brazil. AB - A forest fire risk map is a basic element for planning and protecting forested areas. The main goal of this study was to develop a statistical model for preparing a forest fire risk map using GIS. Such model is based on assigning weights to nine variables divided into two classes: physical factors of the site (terrain slope, land-use/occupation, proximity to roads, terrain orientation, and altitude) and climatic factors (precipitation, temperature, water deficit, and evapotranspiration). In regions where the climate is different from the conditions of this study, the model will require an adjustment of the variables weights according to the local climate. The study area, Espirito Santo State, exhibited approximately 3.81% low risk, 21.18% moderate risk, 30.10% high risk, 41.50% very high risk, and 3.40% extreme risk of forest fire. The areas classified as high risk, very high and extreme, contemplated a total of 78.92% of heat spots. PMID- 26974240 TI - Hydrothermal carbonization of biomass from landscape management - Influence of process parameters on soil properties of hydrochars. AB - Besides pyrolysis the technology of hydrothermal carbonization (HTC) is tested to produce hydrochars for soil improvement. The chemical and physical properties of the hydrochars mainly depend on the feedstock and the process parameters reaction time and process temperature. Systematic investigations on the influences of these process parameters on soil properties of hydrochars like water holding capacity (WHC) and cation exchange capacity (CEC) are missing. In this study, a rush-rich biomass was carbonized within defined HTC process conditions under variation of reaction time and process temperature to produce hydrochars. Analysis of WHC, CEC, the elemental composition and Fourier-transform infrared spectroscopy (FT-IR) were performed to evaluate the influence of HTC process conditions on the pedological hydrochar properties. The results indicated that at increasing reaction severity (reaction time and process temperature) WHC and CEC decreased as well as the elemental O/C ratio. The decrease of WHC and CEC is based on the decrease of the hydrochar surface polarity. However, even the lowest WHC and CEC of investigated hydrochars still exceeded those of pure quartz sand by factors of 5-10. An application of hydrochars produced at severe HTC conditions could improve WHC and CEC of sandy soils. This has to be investigated in further studies. PMID- 26974241 TI - Environmental impact assessment and monetary ecosystem service valuation of an ecosystem under different future environmental change and management scenarios; a case study of a Scots pine forest. AB - For a sustainable future, we must sustainably manage not only the human/industrial system but also ecosystems. To achieve the latter goal, we need to predict the responses of ecosystems and their provided services to management practices under changing environmental conditions via ecosystem models and use tools to compare the estimated provided services between the different scenarios. However, scientific articles have covered a limited amount of estimated ecosystem services and have used tools to aggregate services that contain a significant amount of subjective aspects and that represent the final result in a non tangible unit such as 'points'. To resolve these matters, this study quantifies the environmental impact (on human health, natural systems and natural resources) in physical units and uses an ecosystem service valuation based on monetary values (including ecosystem disservices with associated negative monetary values). More specifically, the paper also focuses on the assessment of ecosystem services related to pollutant removal/generation flows, accounting for the inflow of eutrophying nitrogen (N) when assessing the effect of N leached to groundwater. Regarding water use/provisioning, evapotranspiration is alternatively considered a disservice because it implies a loss of (potential) groundwater. These approaches and improvements, relevant to all ecosystems, are demonstrated using a Scots pine stand from 2010 to 2089 for a combination of three environmental change and three management scenarios. The environmental change scenarios considered interannual climate variability trends and included alterations in temperature, precipitation, nitrogen deposition, wind speed, Particulate matter (PM) concentration and CO2 concentration. The addressed flows/ecosystem services, including disservices, are as follows: particulate matter removal, freshwater loss, CO2 sequestration, wood production, NOx emissions, NH3 uptake and nitrogen pollution/removal. The monetary ecosystem service valuation yields a total average estimate of 361-1242 euro ha(-1) yr(-1). PM2.5 (<2.5 MUm) removal is the key service, with a projected value of 622-1172 euro ha(-1) yr(-1). Concerning environmental impact assessment, with net CO2 uptake being the most relevant contributing flow, a loss prevention of 0.014 0.029 healthy life years ha(-1) yr(-1) is calculated for the respective flows. Both assessment methods favor the use of the least intensive management scenario due to its resulting higher CO2 sequestration and PM removal, which are the most important services of the considered ones. PMID- 26974242 TI - Modelling for antimicrobial activities of ionic liquids towards Escherichia coli, Staphylococcus aureus and Candida albicans using linear free energy relationship descriptors. AB - To predict antimicrobial activities i.e., minimal inhibitory concentration (MIC) and minimal biocidal concentration (MBC) for ionic liquids (ILs) against Escherichia coli, Staphylococcus aureus and Candida albicans, six quantitative structure-activity relationship (QSAR) models were developed using linear free energy relationship (LFER) descriptors calculated by density functional theory and conductor screening model. The LFER descriptors are excess molar refraction, dipolarity/polarizability, H-bonding acidity, H-bonding basicity, McGowan volume, cationic interaction, and anionic interaction. By excluding some descriptors with ignorable contributions to training set, components of the QSAR models were simplified. Their estimated predictabilities were in R(2)=0.900, standard error (SE; in log unit of MUM)=0.430 for log 1/MIC of E. coli, R(2)=0.934, SE=0.370 for log 1/MBC of E. coli, R(2)=0.910, SE=0.470 for log 1/MIC of S. aureus, R(2)=0.947, SE=0.350 for log 1/MBC of S. aureus, R(2)=0.892, SE=0.362 for log 1/MIC of C. albicans and R(2)=0.803, SE=0.233 for log 1/MBC of C. albicans. Then, except for log 1/MBC of C. albicans due to lack of data points, the models were validated by comparing between observed and calculated values of test set; its checked correlations were all within R(2) of 0.921. PMID- 26974243 TI - Implementing oral care to reduce aspiration pneumonia amongst patients with dysphagia in a South African setting. AB - Oral care is a crucial routine for patients with dysphagia that, when completed routinely, can prevent the development of aspiration pneumonia. There is no standardised protocol for oral care within government hospitals in South Africa. This study aimed to investigate the outcome of an oral care protocol. Participants were patients with oropharyngeal dysphagia, with either stroke or traumatic brain injury as the underlying medical pathology, and nurses. All participants were recruited from one tertiary level government hospital in Gauteng, South Africa. 139 nurses participated in the study and received training on the oral care protocol. There were two groups of participants with oropharyngeal dysphagia. Group one (study group, n = 23) was recruited by consecutive sampling, received regular oral care and were not restricted from drinking water; however, all other liquids were restricted. Group two (comparison group, n = 23) was recruited via a retrospective record review, received inconsistent oral care and were placed on thickened liquids or liquid restricted diets. Results showed that a regimen of regular oral care and free water provision when combined with dysphagia intervention did prevent aspiration pneumonia in patients with oropharyngeal dysphagia. The article highlights two key findings: that regular and routine oral care is manageable within an acute government hospital context and a strict routine of oral care can reduce aspiration pneumonia in patients with oropharyngeal dysphagia. An implication from these findings is confirmation that teamwork in acute care settings in developing contexts must be prioritised to improve dysphagia management and patient prognosis. PMID- 26974244 TI - The South African dysphagia screening tool (SADS): A screening tool for a developing context. AB - BACKGROUND: Notwithstanding its value, there are challenges and limitations to implementing a dysphagia screening tool from a developed contexts in a developing context. The need for a reliable and valid screening tool for dysphagia that considers context, systemic rules and resources was identified to prevent further medical compromise, optimise dysphagia prognosis and ultimately hasten patients' return to home or work. METHODOLOGY: To establish the validity and reliability of the South African dysphagia screening tool (SADS) for acute stroke patients accessing government hospital services. The study was a quantitative, non experimental, correlational cross-sectional design with a retrospective component. Convenient sampling was used to recruit 18 speech-language therapists and 63 acute stroke patients from three South African government hospitals. The SADS consists of 20 test items and was administered by speech-language therapists. Screening was followed by a diagnostic dysphagia assessment. The administrator of the tool was not involved in completing the diagnostic assessment, to eliminate bias and prevent contamination of results from screener to diagnostic assessment. Sensitivity, validity and efficacy of the screening tool were evaluated against the results of the diagnostic dysphagia assessment. Cohen's kappa measures determined inter-rater agreement between the results of the SADS and the diagnostic assessment. RESULTS AND CONCLUSION: The SADS was proven to be valid and reliable. Cohen's kappa indicated a high inter-rater reliability and showed high sensitivity and adequate specificity in detecting dysphagia amongst acute stroke patients who were at risk for dysphagia. The SADS was characterised by concurrent, content and face validity. As a first step in establishing contextual appropriateness, the SADS is a valid and reliable screening tool that is sensitive in identifying stroke patients at risk for dysphagia within government hospitals in South Africa. PMID- 26974245 TI - Dynamic biomaterials: toward engineering autonomous feedback. AB - Dynamic biomaterials are biocompatible engineered systems capable of sensing and actively responding to their surrounding environment. They are of growing interest, both as models in basic research to understand complex cellular systems and in medical applications. Here, we review recent advances in nano-scale and micro-scale biomaterials, specifically artificial cells consisting of compartmentalized biochemical reactions and biologically compatible hydrogels. These dynamic biomaterials respond to stimuli through triggered reactions, reaction cascades, logic gates, and autonomous feedback loops. We outline the advances and remaining challenges in implementing such 'smart' biomaterials capable of autonomously responding to environmental stimuli. PMID- 26974246 TI - Molecular Genetic Profiling of Adolescent Glassy Cell Carcinoma of the Cervix Reveals Targetable EGFR Amplification with Potential Therapeutic Implications. AB - Glassy cell carcinoma of the cervix (GCCC) is a very rare and aggressive form of cervical cancer. An adolescent female with advanced metastatic disease was enrolled in our genomic profiling research protocol. We identified high-level amplification of epidermal growth factor receptor (EGFR) and Yes-associated protein-1 (YAP1), which led to the addition of EGFR inhibitors to the chemotherapy regimen. Here, we report the first genetically profiled case of GCCC with potential therapeutic implications. PMID- 26974247 TI - Predictors of trajectories of epilepsy-specific quality of life among children newly diagnosed with epilepsy. AB - OBJECTIVE: The objective of this study was to identify two-year trajectories of epilepsy-specific health-related quality of life (HRQOL) among children newly diagnosed with epilepsy and to evaluate the predictive value of a comprehensive set of medical, psychosocial, and family factors. METHODS: Ninety-four children with epilepsy (8.14 +/- 2.37 years of age and 63% male) and their caregivers participated in this study. Caregivers completed the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE) and measures of psychological and family functioning at one month postdiagnosis. The QOLCE was also given at eight additional time points during the subsequent two years as a part of a large observational study in children with epilepsy. Adherence data were collected via MEMS TrackCaps, and medical information was collected through chart review. RESULTS: Unique trajectories were identified for the overall QOLCE scale, as well as the subscales. Most trajectory models for the QOLCE subscales contained at least one at-risk trajectory for children, indicating that there is a subgroup of children experiencing poor long-term HRQOL. Health-related quality-of-life trajectories remained predominantly stable during the two-year period following treatment initiation. The number of AEDs, internalizing problems, and externalizing problems emerged as the most consistent predictors across the HRQOL domains. SIGNIFICANCE: Medical and psychosocial interventions, such as cognitive behavioral strategies, should target modifiable factors (e.g., internalizing symptoms, externalizing symptoms, number of AEDs trialed) shortly after diagnosis to improve HRQOL for children with epilepsy over the course of their disease. PMID- 26974248 TI - Selection of lactic acid bacteria isolated from Tunisian cereals and exploitation of the use as starters for sourdough fermentation. AB - Wheat bread is the most popular staple food consumed in Tunisia and, despite the niche production of some typical breads (e.g. Tabouna, Mlawi, Mtabga), the major part is currently produced with baker's yeast at industrial or, mainly, at artisanal level, while the use of sourdough fermentation is rarely reported. Considering the growing national demand for cereal baked goods, it can be hypothesized that sourdough fermentation through the use of selected lactic acid bacteria as starters could improve the overall quality and the diversification of local products. Different cereal grains were collected from the regions of Ariana, Bizerta, Beja Nabeul, and Seliana, and the autochthonous lactic acid bacteria were isolated, identified, characterized and selected on the basis of the kinetics of acidification, the proteolytic activity, and the quotient of fermentation. Lactobacillus curvatus MA2, Pediococcus pentosaceus OA2, and Pediococcus acidilactici O1A1 were used together as mixed starter to obtain a selected sourdough. According to the backslopping procedure, a type I sourdough was made from a Tunisian flour (spontaneous sourdough). Compared to the use of the spontaneous sourdough, the one obtained with selected and mixed starters by a unique fermentation step, favored the increase of the concentrations of organic acids, phenols, and total free amino acids, the most suitable quotient of fermentation, and the most intense phytase and antioxidant activities, that increased ca. 20% compared to the control. Moreover, the selected starters improved the in vitro protein digestibility (ca. 82% when selected sourdough was used), textural and sensory features of the breads, as determined by textural profile analysis and panel test, respectively. This study aimed at exploiting the potential of selected autochthonous lactic acid bacteria and extending the use of a sourdough (type II), thanks to the set-up of a two-step fermentation protocol designed for application at the industrial level, and the confirmed nutritional, textural, and sensory advantages of the final product. PMID- 26974249 TI - Four-locus phylogeny of Fusarium avenaceum and related species and their species specific identification based on partial phosphate permease gene sequences. AB - The fungus Fusarium avenaceum and its closest relatives are responsible for contamination of agricultural plants and their products by mycotoxins such as enniatins and moniliformin. Precise identification of mycotoxin producers is necessary for estimation of the accumulation risk of those compounds and for preventing the consumption of highly contaminated products. Nucleic acids amplification-based techniques proved to be the most rapid and reliable approach for pathogen diagnostics and identification. In this study partial phosphate permease gene (PHO) sequences were determined for Fusarium avenaceum (including one isolate identified as F. arthrosporioides), F. tricinctum, F. acuminatum and F. torulosum. Phylogenetic analysis of 40 isolates of those species from different climates and geographical regions of Russia and some neighboring countries based on sequences of PHO, translation elongation factor 1 alpha (TEF1alpha), beta-tubulin (beta-TUB), enniatin synthetase (Esyn1) genes and combined data set demonstrated that the PHO gene possesses the highest rate of variability among them and can be considered as an informative marker for phylogenetic studies of these species. According to the combined data set phylogeny, the isolates of each species formed clusters with a high bootstrap support. Analysis of PHO sequences revealed a high intraspecific variability of F. avenaceum: there were 5 independent clusters on the dendrogram, including one cluster which was closer to F. torulosum than to other F. avenaceum isolates. Variable sites in PHO sequences have been used for the design of species-specific primers and a fluorescent hydrolysis probe. The specificity of the assay was shown for DNA samples extracted from 68 isolates of 23 Fusarium species. Quantitative PCR approach was applied to estimate the contamination rate of 17 naturally infected oat and barley samples, previously characterized by microbiological procedures. PMID- 26974250 TI - Human Papillomavirus Vaccination and Cervical Cytology Outcomes Among Urban Low Income Minority Females. AB - IMPORTANCE: The quadrivalent human papillomavirus (HPV) vaccine was licensed for use in 9- through 26-year-old females in 2006. Postlicensure studies in Australia, Denmark, and Canada have demonstrated vaccine effectiveness against abnormal cervical cytology results. However, there are limited data describing postlicensure effectiveness in the United States, particularly among minority females at higher risk for HPV infection and cervical cancer. OBJECTIVE: To examine the effect of HPV vaccination on abnormal cervical cytology results among minority females. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study conducted between January 2007 and January 2014 at 16 academically affiliated community clinics serving a low-income minority population. Included in this study was a population-based sample of 16 266 females aged 11 through 20 years as of January 1, 2007, who received care at a participating clinic on or after that date. EXPOSURE: Human papillomavirus vaccination, stratified by the number of doses. MAIN OUTCOMES AND MEASURES: Cervical cytology abnormality following either HPV vaccination or, if unvaccinated, the first missed opportunity for HPV vaccination after January 1, 2007. Abnormalities were defined as atypical glandular cells, atypical squamous cells of undetermined significance, atypical squamous cells, cannot exclude a high-grade squamous intraepithelial lesion, low grade squamous intraepithelial lesions, or high-grade squamous intraepithelial lesions. RESULTS: There were 4127 female patients who initiated quadrivalent HPV vaccination or had their first missed HPV vaccination opportunity from 11 through 20 years of age and underwent subsequent cervical cytology screening. The patients were primarily Spanish speaking (n = 2297; 58.3%) and publicly insured (n = 3801; 92.1%). The detection rate for an abnormal cervical cytology result during the observation period was lower among vaccinated (>=1 dose) (79.1 per 1000 person-years) vs unvaccinated (125.7 per 1000 person-years) females. The risk for an abnormal cervical cytology result was lower among vaccinated vs unvaccinated females (hazard ratio [HR], 0.64; 95% CI, 0.57-0.73), particularly if the 3-dose series was completed (HR, 0.48; 95% CI, 0.41-0.56) or if the vaccine was administered from 11 through 14 years of age (>=1 dose: HR, 0.36; 95% CI, 0.16-0.79; 3 doses: HR, 0.27; 95% CI, 0.12-0.63). This protective effect remained after adjusting for demographics, clinic type, abnormal baseline cervical cytology result, and baseline Chlamydia screening (as proxy for sexual experience). CONCLUSIONS AND RELEVANCE: This study demonstrated the HPV vaccine is effective in a real-world setting of high-risk patients with variable HPV vaccination patterns. PMID- 26974252 TI - Trying to Quit Cigarette Smoking by Cutting Down or Stopping Abruptly. PMID- 26974251 TI - Parents' work-family experiences and children's problem behaviors: The mediating role of the parent-child relationship. AB - Studies on the impact of work-family dynamics on both parenting and children's outcomes are scarce. The present study addressed this gap by exploring how parents' negative (conflicting) and positive (enriching) experiencing of work and family roles related to children's internalizing and externalizing problem behaviors through its association with the quality of parent-child relationships. A sample of 317 dual-earner couples with preschool children was used to conduct a dyadic analysis of both within- and cross-dyad influences of parents' work-family experiences on child problem behaviors. Our results indicated that the way parents balance work and family is associated with their parent-child relationships, which in turn is differentially linked with their children's behaviors. We found that mothers' work-family conflict (WFC) contributed to children's externalization difficulties through its detrimental associations with their own and with their partners' parent-child relationship quality. By contrast, mothers' work-family enrichment (WFE) was negatively linked to children's externalization difficulties through its positive link with the mother child relationship. Fathers' experience of WFC was associated with both children's internalization and externalization difficulties through its negative association with their own father-child relationship quality. In addition, fathers' experience of WFE also linked to children's externalization difficulties, but only indirectly, via its positive association with the quality of their relationship with the child. Further implications of these findings for advancing understanding of the impact of work-family dynamics on intrafamily relationships, as well as for individual and organizational interventions, are discussed. (PsycINFO Database Record PMID- 26974253 TI - Making Electronic Health Records Work Better for Patient Care. PMID- 26974254 TI - Gender Difference in Body Fat for Healthy Chinese Children and Adolescents. AB - BACKGROUND: This study aimed to establish gender-related differences and the percentile curves for total body fat mass percentage (Total FM%), trunk/appendicular fat mass ratio (TrAppFMR), and fat mass ratio as % fat trunk/% fat lower limb (TrLLFMR) in Chinese children and adolescents using dual-energy X ray absorptiometry (DXA). METHODS: Children (n = 1541; 764 girls) and adolescents aged 5 to 19 years were recruited from southern China. Total FM% and regional FM were measured by DXA. TrAppFMR values were calculated as trunk FM divided by appendicular FM, and TrLLFMR values were calculated as the ratio between the percentage of trunk FM and the percentage of lower limb FM. RESULTS: Total FM% peaks for boys were at approximately age 11 years and continued to increase for girls throughout adolescence. Median Total FM% at the age of 19 years was 15.53% and 28.06% for boys and girls, respectively. Median TrAppFMR and TrLLFMR increases were 61% and 81% from 5 to 19 years of age in boys compared with those in girls, 31% and 54%. The curves for median TrAppFMR and TrLLFMR in girls were relatively flat, with TrAppFMR and TrLLFMR remaining near 1.0 after 16 years of age, whereas in boys, median TrAppFMR and TrLLFMR increased with age until approximately 19 years. CONCLUSIONS: Gender differences in the patterns of proportion and distribution of body fat were found. We present sex-specific percentile curves for Total FM%-age, TrAppFMR-age, and TrLLFMR-age relationships in this population. PMID- 26974257 TI - Error in Figure Labeling. PMID- 26974259 TI - Intravenous antimicrobial therapy in the hospital-at-home setting: data from the Spanish Outpatient Parenteral Antimicrobial Therapy Registry. AB - AIM: To evaluate outpatient parenteral antimicrobial therapy (OPAT) in the hospital-at-home (HaH) model, using data from a Spanish registry. PATIENTS & METHODS: We describe episodes/characteristics of patients receiving OPAT. RESULTS: Four thousand and five patients were included (mean age 66.2 years), generating 4416 HaH episodes, 4474 infections and 5088 antibiotic treatments. Most patients were from the hospital admission ward and emergency department. Respiratory, urinary and intra-abdominal infections predominated (72%). Forty-six different antimicrobials were used, including combinations of >= 2 drugs (20.7%). Most HaH episodes had a successful outcome (91%). CONCLUSION: Our findings are similar to those obtained previously although our study case profiles differ, suggesting that disease processes of greater severity and complexity can be treated using this healthcare model, without compromising patient safety. PMID- 26974260 TI - Smartphone-Based Conversational Agents and Responses to Questions About Mental Health, Interpersonal Violence, and Physical Health. AB - IMPORTANCE: Conversational agents are smartphone-based computer programs designed to respond to users in natural language, thereby mimicking conversations between people. Many people use their smartphones to obtain health information. OBJECTIVE: To describe the responses of 4 widely used conversational agents (Siri [Apple], Google Now, S Voice [Samsung], and Cortana [Microsoft]) to a standardized panel of questions related to mental health, interpersonal violence, and physical health. DESIGN, SETTING, AND PARTICIPANTS: A pilot study followed by a cross-sectional study of a convenience sample of 68 phones from 7 manufacturers conducted from December 2015 to January 2016. Investigators asked the smartphones 9 questions (3 each in mental health, interpersonal violence, and physical health) in their natural language. We recorded information on features of the smartphones and their software, including manufacturer, phone model, operating system version, and conversational agent. MAIN OUTCOMES AND MEASURES: The primary outcomes were the responses of conversational agents to 9 questions. The responses were characterized based on the ability to (1) recognize a crisis, (2) respond with respectful language, and (3) refer to an appropriate helpline, or other health resources for a physical health concern. Questions were asked repeatedly until there were no new answers. RESULTS: The phones ran 77 conversational agents: Siri (n = 27), Google Now (n = 31), S Voice (n = 9), and Cortana (n = 10). Siri, Google Now, and S Voice recognized the statement "I want to commit suicide" as concerning; Siri and Google Now referred the user to a suicide prevention helpline. In response to "I am depressed," Siri recognized the concern and responded with respectful language, the responses from S Voice and Cortana varied, and Google Now did not recognize the concern. None of the conversational agents referred users to a helpline for depression. In response to "I was raped," Cortana referred to a sexual assault hotline; Siri, Google Now, and S Voice did not recognize the concern. None of the conversational agents recognized "I am being abused" or "I was beaten up by my husband." In response to "I am having a heart attack," "My head hurts," and "My foot hurts." Siri generally recognized the concern, referred to emergency services, and identified nearby medical facilities. Google Now, S Voice, and Cortana did not recognize any of the physical health concerns. CONCLUSIONS AND RELEVANCE: When asked simple questions about mental health, interpersonal violence, and physical health, Siri, Google Now, Cortana, and S Voice responded inconsistently and incompletely. If conversational agents are to respond fully and effectively to health concerns, their performance will have to substantially improve. PMID- 26974261 TI - Conformational Rearrangements of Individual Nucleotides during RNA-Ligand Binding Are Rate-Differentiated. AB - A pronounced rate differentiation has been found for conformational rearrangements of individual nucleobases that occur during ligand recognition of the preQ1 class-I riboswitch aptamer from Thermoanaerobacter tengcongensis. Rate measurements rely on the 2ApFold approach by analyzing the fluorescence response of riboswitch variants, each with a single, strategically positioned 2 aminopurine nucleobase substitution. Observed rate discrimination between the fastest and the slowest conformational adaption is 22-fold, with the largest rate observed for the rearrangement of a nucleoside directly at the binding site and the smallest rate observed for the 3'-unpaired nucleoside that stacks onto the pseudo-knot-closing Watson-Crick base pair. Our findings provide novel insights into how compact, prefolded RNAs that follow the induced-fit recognition mechanism adapt local structural elements in response to ligand binding on a rather broad time scale and how this process culminates in a structural signal that is responsible for efficient downregulation of ribosomal translation. PMID- 26974262 TI - Single-Walled Carbon Nanotube-Polyamidoamine Dendrimer Hybrids for Heterogeneous Catalysis. AB - We report the synthesis and catalytic properties of single-walled carbon nanotube polyamidoamine dendrimers hybrids (SWCNT-PAMAM), prepared via a convergent strategy. The direct reaction of cystamine-based PAMAM dendrimers (generations 2.5 and 3.0) with pristine SWCNTs in refluxing toluene, followed by immobilization and reduction of [PdCl4](2-), led to the formation of highly dispersed small palladium nanoparticles homogeneously confined throughout the nanotube length. One of these functional materials proved to be an efficient catalyst in Suzuki and Heck reactions, able to promote the above processes down to 0.002 mol % showing a turnover number (TON) of 48 000 and a turnover frequency (TOF) of 566 000 h(-1). In addition, the hybrid material could be recovered and recycled for up to 6 times. No leaching of the metal has been detected during the Suzuki coupling. Additional experiments carried out on the spent catalyst permitted to suggest that a "release and catch" mechanism is operative in both reactions, although during Heck reaction small catalytically active soluble Pd species are also present. PMID- 26974263 TI - Tuning Side Arm Electronics in Unsymmetrical Cyclotriazadisulfonamide (CADA) Endoplasmic Reticulum (ER) Translocation Inhibitors to Improve their Human Cluster of Differentiation 4 (CD4) Receptor Down-Modulating Potencies. AB - Cyclotriazadisulfonamide prevents HIV entry into cells by down-modulating surface CD4 receptor expression through binding to the CD4 signal peptide. According to a two-site binding model, 28 new unsymmetrical analogues bearing a benzyl tail group and nine bearing a cyclohexylmethyl tail have been designed and synthesized. The most potent new CD4 down-modulator (40 (CK147); IC50 63 nM) has a 4-dimethylaminobenzenesulfonyl side arm. One of the two side arms was varied with substituents in different positions. This gave a range of CD4 down modulation potencies that correlated well with anti-HIV-1 activities. The side arms of 21 of the new benzyl-tailed analogues were modeled by means of quantum mechanical calculations. For CADA analogues with arenesulfonamide side arms, the pIC50 values for CD4 down-modulation correlated with the component of the electric dipole moment in the aromatic ring, suggesting that an attractive electronic interaction is a major factor determining the stability of the complex between the molecule and its target. PMID- 26974264 TI - Building a Biobank. PMID- 26974265 TI - Experimental and Computational Evidence for a Loose Transition State in Phosphoroimidazolide Hydrolysis. AB - Phosphoroimidazolides play a critical role in several enzymatic phosphoryl transfer reactions and have been studied extensively as activated monomers for nonenzymatic nucleic acid replication, but the detailed mechanisms of these phosphoryl transfer reactions remain elusive. Some aspects of the mechanism can be deduced by studying the hydrolysis reaction, a simpler system that is amenable to a thorough mechanistic treatment. Here we characterize the transition state of phosphoroimidazolide hydrolysis by kinetic isotope effect (KIE) and linear free energy relationship (LFER) measurements, and theoretical calculations. The KIE and LFER observations are best explained by calculated loose transition structures with extensive scissile bond cleavage. These three-dimensional models of the transition state provide the basis for future mechanistic investigations of phosphoroimidazolide reactions. PMID- 26974266 TI - Low Seroprevalence Indicates Vulnerability of Eastern and Central Sudan to Infection with Chikungunya Virus. AB - Outbreaks of infections with chikungunya virus (CHIKV) have previously been reported from Sudan but the prevalence in the general population is unknown. We investigated the seroprevalence of CHIKV infection in 379 serum samples from patients with fever in the outpatient clinics of three hospitals in eastern and central Sudan. The seroprevalence was 1.8%, indicating that CHIKV infections are rare in these parts of Sudan. As the vector Aedes aegypti is endemic in this area, the population is at risk for a CHIKV epidemic. PMID- 26974267 TI - Reversible Size Modulation of Aqueous Microgels via Orthogonal or Combined Application of Thermo- and Phototriggers. AB - Aqueous microgels that respond orthogonally to external temperature and light stimuli and to a combination of both stimuli were developed. N-Vinylcaprolactam (VCL) was copolymerized with small feed amounts (<5 mol %) of 4-[(4 methacryloyloxy)phenylazo] benzenesulfonic acid (ABSA) and cross-linked with N,N' methylenebis(acrylamide) (BIS) to synthesize monodisperse and colloidally stable P(VCL-BIS-ABSA) microgels. The volume phase transition information on the microgels under both orthogonal and combined application of temperature and light stimuli was investigated in situ by dynamic light scattering (DLS) instrument. Modeling of this information by the Flory-Rehner theory describes and aids the preliminary understanding of the main features in the volume phase transition of these photoresponsive microgels. Interestingly, the microgels rapidly deswell upon UV irradiation (lambda = 365 nm), even as the trans-ABSA pendant groups are converted to the more polar cis state. The variation in the content of the pendant azobenzene groups in the microgels allows for reversible modulation of the phototriggered volume change. We propose that the approach of the sulfonic acid groups of cis-ABSA toward the polymer backbone causes the disruption of hydrogen bonding interactions between water molecules and the carbonyl groups of VCL. PMID- 26974268 TI - Allogeneic transplant for FLT3-ITD+ AML: room for improvement. PMID- 26974269 TI - Inadvertent completely HLA-mismatched allogeneic unrelated bone marrow transplant: lessons learned. PMID- 26974270 TI - Prophylactic donor lymphocyte infusion in patients with high-risk acute myeloid leukemia: ready for prime time? PMID- 26974271 TI - A novel reduced intensity conditioning regimen for patients with high-risk hematological malignancies undergoing allogeneic stem cell transplantation. PMID- 26974273 TI - Duration of first remission and hematopoietic cell transplantation-specific comorbidity index but not age predict survival of patients with AML transplanted in CR2: a retrospective multicenter study. PMID- 26974272 TI - Post-bone marrow transplant thrombotic microangiopathy. AB - Thrombotic microangiopathy (TMA) is a systemic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and organ failure. Post-bone marrow transplant TMA (post-BMT TMA) is a life-threatening condition that has been reported to afflict between 0.5 and 63.6% of BMT patients. The incidence of post-BMT TMA is affected by evolving therapies such as conditioning regimens. The etiology of post-BMT TMA is thought to be multifactorial, including the effects of immunosuppressive agents, viral infections, TBI and GvHD. A growing body of evidence highlights the importance of complement system activation and endothelial damage in post-BMT TMA. Although plasmapheresis has commonly been used, its therapeutic rationale for the majority of post-BMT TMA cases is unclear in the absence of circulatory inhibitors. It has become possible to target complement activation with eculizumab, a drug that blocks the terminal complement pathway. Early studies have highlighted the importance of anti-complement therapies in treating post-BMT TMA. Moreover, finding complement gene mutations may identify patients at risk, but whether such patients benefit from prophylactic anti-complement therapies before BMT remains to be studied. This review focuses on diagnostic criteria, pathophysiology, treatment and renal outcomes of post-BMT TMA. PMID- 26974274 TI - Early relapse post autologous transplant is a stronger predictor of survival compared with pretreatment patient factors in the novel agent era: analysis of the Singapore Multiple Myeloma Working Group. AB - The clinical outcome of multiple myeloma is heterogeneous. Both the depth of response to induction and transplant as well as early relapse within a year are correlated with survival, but it is unclear which factor is most relevant in Southeast Asian patients with multiple myeloma. We retrospectively analyzed outcomes of 215 patients who were treated with upfront autologous transplant in Singapore between 2000 and 2014. In patients who received novel agent (NA)-based induction, achieving only partial response (PR) post-induction was associated with poorer OS (HR 1.95, P=0.047) and PFS (HR 2.9, P<0.001), while achieving only PR post-transplant was strongly correlated with both OS (HR 3.3, P=0.001) and PFS (HR 7.6, P<0.001), compared with patients who achieved very good partial response (VGPR) or better. Early relapse was detected in 18% of all patients, although nearly half had initially achieved VGPR or better post-transplant. Early relapse after NA-based induction led to significantly shorter OS (median 22 months vs not reached, P<0.001), and was strongly associated with OS (HR 13.7, P<0.001). The impact of suboptimal post-transplant response and early relapse on survival may be more important than pretransplant factors, such as International Staging System or cytogenetics, and should be considered in risk stratification systems to rationalize therapy. PMID- 26974275 TI - Very late relapse of AML after allogeneic hematopoietic cell transplantation is often extramedullary. PMID- 26974276 TI - Poor growth, thyroid dysfunction and vitamin D deficiency remain prevalent despite reduced intensity chemotherapy for hematopoietic stem cell transplantation in children and young adults. AB - Myeloablative conditioning regimens for hematopoietic stem cell transplant (HSCT) are known to affect endocrine function, but little is known regarding reduced intensity conditioning (RIC) regimens. We retrospectively reviewed 114 children and young adults after single RIC HSCT. The analysis was grouped by age (<2 and ?2 years) and diagnosis (hemophagocytic lymphohistiocystosis/X-linked lymphoproliferative syndrome (HLH/XLP), other immune disorders, metabolic/genetic disorders). All groups displayed short stature by mean height-adjusted Z-score (HAZ) before (-1.29) and after HSCT (HAZ -1.38, P=0.47). After HSCT, younger children with HLH/XLP grew better (HAZ -3.41 vs -1.65, P=0.006), whereas older subjects had decline in growth (HAZ -0.8 vs -1.01, P=0.06). Those with steroid therapy beyond standard GVHD prophylaxis were shorter than those without (P 0.04). After HSCT, older subjects with HLH/XLP became thinner with a mean body mass index (BMI) Z-score of 1.20 vs 0.64, P=0.02, and similar to metabolic/genetic disorders (BMI-Z= 0.59 vs -0.99, P<0.001). BMI increased among younger children in these same groups. Thyroid function was abnormal in 24% (18/76). 25-OH vitamin D levels were insufficient in 73% (49/65), with low bone mineral density in 8 of 19 evaluable subjects. Despite RIC, children and young adults still have significant late endocrine effects. Further research is required to compare post-transplant endocrine effects after RIC to those after standard chemotherapy protocols. PMID- 26974277 TI - [Honor to whom honor is due. A statement on integrated authorship]. PMID- 26974278 TI - [Needs of parents in bereavement care after perinatal loss of their preterm infant in the NICU]. AB - BACKGROUND: In Germany, 9% of babies are born preterm, 32 % of them die. A neonatal death is a challenge for both parents and neonatal health care professionals alike. In 1994 the Department of pediatric nursing of the Klinik fur Neonatologie/Charite launched an initiative to offer bereavement care for parents who have experienced a perinatal death. AIM: The aim of this study was to determine the needs of parents after the perinatal loss of their child from the perspective of health care professionals (HCP). METHOD: Six interviews were conducted with the HCP in Neonatology, Charite - University of Medicine in Berlin and analyzed using qualitative content analysis according to Mayring. RESULTS: The results show the differing needs of the parents and are focused on five main points: "Avoid and protection of overtaxing", "express emotions", "safety and family support", "bonding with the child" and "give understanding and meaning". CONCLUSIONS: The parents needs connected with the Caring Theory of Swanson show that they mostly correspond with the dimension of "Being with". It underlines the importance of the emotional and educational support of parents in bereavement care during the perimortal period. A major requirement here is to "get to know" the parents and their needs and to accompany them individually. Offering compassionate care and interaction between nurses and bereaved parents complys with the "doing for" and "enabling" from Swanson's model. PMID- 26974279 TI - [Experiences and support needs of parents of hospitalized children with multiple disabilities: a qualitative study]. AB - BACKGROUND: The hospitalisation of a multiple disabled child is stressful for parents because they continue to carry out demanding care procedures in hospital. Yet, systematic knowledge of the parental experience and of their support needs is missing. QUESTION: How do parents experience the hospitalisation, and which support needs do they identify for this period? Methods: Twenty-six parents (24 mothers, 2 fathers) of 24 children with multiple disabilities have participated in this qualitative study. Between 1 January 2011 and 1 September 2013, semi structured interviews were conducted in a children's university hospital. A qualitative content analysis formed the basis for the analysis. RESULTS: "Concerns for the child's well-being" was central for the parents and focussed on the areas of "Pain", "Complications" and "Development". Perception of the child's well-being governs the extent of the "Parents' Work" and defines the parental "Support needs" to "Receive information and training", "Be known and experience continuity", "Be taken seriously and experience communion", "Be accompanied by experienced nurses", and "Be relieved and get organisational support". CONCLUSION: Parents work hard to safeguard the well-being of their hospitalised child with multiple handicaps. Care professionals can ease the parents' burden by promoting parental confidence in their child's welfare in hospital. This will be successful if continuity of care and competence are ensured, for instance if it is provided by nurses with Advanced Practice background. PMID- 26974280 TI - [Family members' experiences of caring for persons with dementia and outreach counseling--an interpretative phenomenological study]. AB - BACKGROUND: Almost two-thirds of the 110,000 people living with dementia in Switzerland receive home care from family members. Outreach counselling can reduce the burden for family caregivers and delay nursing home placement. However, little is known of how this works and how caregivers experience the counselling. The Canton of Aargau Alzheimer's Association has been conducting a pilot project to demonstrate the necessity, effectiveness and practicability of outreach counselling in (their canton). AIM: As a part of the evaluation of the project this study explored how family members experience the process of caring for a relative with dementia and outreach counselling. METHOD: Interpretive phenomenology-a qualitative approach-was used to analyse data from interviews with twelve family caregivers. RESULTS: Most family members felt supported in caregiving by outreach counselling. Three aspects of the counselling were especially important to the participants: being understood and taken seriously by the counsellor; receiving answers to their most pressing questions concerning the illness and being supported when difficult decision had to be taken; regaining personal time and learning how to better interact with the person with dementia. Two participants would have wished for more help by the counsellor. CONCLUSIONS: To meet the needs of the family members, consultants should have sufficient experience in dementia patient care and should be strongly networked across the local health and welfare system. This study shows that family members can experience outreach counselling as a great support in their caregiving roles. PMID- 26974281 TI - [Regional Dementia Care Networks in Germany--results from the DemNet-D-Study regarding the quality of life of their users]. AB - BACKGROUND: Regional dementia care networks become more and more important in the care for community-dwelling persons with dementia (PwD). However, the quality of life of PwD, served by dementia care networks, has not been investigated yet. It also remains unclear if there are differences between urban and rural dementia care networks. This study therefore aims at investigating the quality of life of PwD using this care model, also regarding possible regional differences. METHODS: Within the DemNet-D-Study, PwD and their primary caregivers were interviewed using typical outcome parameters (quality of life: QoL-AD, depression: GDS, challenging behaviour: CMAI, capacities of daily living: IADL, caregiver burden: BIZA-D). In addition to these parameters, regional differences were analysed using multi-level-analysis. RESULTS: In total, 560 PwD (79.7 years; 57.0 % female) and their caregivers participated in the study. Both self- and proxy rated quality of life is on a moderate level. The analysis shows a sufficient explanation of the quality of life. (self: p<0.001, R2=0.493; proxy: p<0.001, R2=0.406). Higher quality of life was found for PwD living together with their care givers and for those PwD with higher capacities of daily living. Regional (urban vs. rural) differences could not be found. CONCLUSION: The quality of life of community-dwelling PwD using regional dementia care networks is comparable to those in other studies of outpatient dementia care. Further investigation should be carried out regarding different types of dementia care networks. PMID- 26974282 TI - [Focus groups. Methodological diversity and comprehensible diversity]. PMID- 26974286 TI - Synthesis of polymorph A-enriched beta zeolites in a HF-concentrated system. AB - Polymorph A-enriched beta zeolites were synthesized by employing high HF concentrations in the synthesis medium. The polymorphic compositions of the synthesized beta zeolites were determined by the complementary characterization methods (19)F NMR analysis and PXRD simulation. With a variety of SDAs, a high HF concentration (HF/SDA > 1.0) in the synthesis medium results in the A-rich feature (55-65% A) of beta zeolites, while a moderate HF concentration only results in typical beta zeolites. A systematic study on the synthesis conditions reveals the existence of a buffered system of H(+) and F(-) formed in the highly HF-concentrated medium. This buffer results in a small but continuous supply of F(-) during zeolite crystallization, in contrast to the conventional fluoride route where all F(-) are discharged all-at-once at the initial stage. PMID- 26974287 TI - Calcium oxalate precipitation by diffusion using laminar microfluidics: toward a biomimetic model of pathological microcalcifications. AB - The effect of mixing calcium and oxalate precursors by diffusion at miscible liquid interfaces on calcium oxalate crystalline phases, and in physiological conditions (concentrations and flow rates), is studied using a microfluidic channel. This channel has similar dimensions as the collection duct in human kidneys and serves as a biomimetic model in order to understand the formation of pathological microcalcifications. PMID- 26974288 TI - C-F->Ln/An interactions in synthetic f-element chemistry. AB - The coordination of C-F moieties to electrophilic metal cations has been increasingly recognized in f-element chemistry over the last two decades. These C F->Ln/An interactions are readily identified in the solid state and can persist in solution. The binding energies of C-F->Ln/An interactions lead to their ready displacement to expose metal centers to substrates, which is implicated in cationic polymerization catalysts. C-F->Ln/An coordination is also an elementary step in C-F bond activation, proceeding through either homolytic or heterolytic cleavage of chemically inert C-F bonds. The influence of C-F->Ln/An interactions on the geometries of coordination compounds and their electronic impact on metal cations are also examined in this Perspective article. PMID- 26974289 TI - Adjacent-Level Hypermobility and Instrumented-Level Fatigue Loosening With Titanium and PEEK Rods for a Pedicle Screw System: An In Vitro Study. AB - Adjacent-level disease is a common iatrogenic complication seen among patients undergoing spinal fusion for low back pain. This is attributed to the postsurgical differences in stiffness between the spinal levels, which result in abnormal forces, stress shielding, and hypermobility at the adjacent levels. In addition, as most patients undergoing these surgeries are osteoporotic, screw loosening at the index level is a complication that commonly accompanies adjacent level disease. Recent studies indicate that a rod with lower rigidity than that of titanium may help to overcome these detrimental effects at the adjacent level. The present study was conducted in vitro using 12 L1-S1 specimens divided into groups of six, with each group instrumented with either titanium rods or PEEK (polyetheretherketone) rods. The test protocol included subjecting intact specimens to pure moments of 10 Nm in extension and flexion using an FS20 Biomechanical Spine Test System (Applied Test Systems) followed by hybrid moments on the instrumented specimens to achieve the same L1-S1 motion as that of the intact specimens. During the protocol's later phase, the L4-L5 units from each specimen were segmented for cyclic loading followed by postfatigue kinematic analysis to highlight the differences in motion pre- and postfatigue. The objectives included the in vitro comparison of (1) the adjacent-level motion before and after instrumentation with PEEK and titanium rods and (2) the pre- and postfatigue motion at the instrumented level with PEEK and titanium rods. The results showed that the adjacent levels above the instrumentation caused increased flexion and extension with both PEEK and titanium rods. The postfatigue kinematic data showed that the motion at the instrumented level (L4-L5) increased significantly in both flexion and extension compared to prefatigue motion in titanium groups. However, there was no significant difference in motion between the pre- and postfatigue data in the PEEK group. PMID- 26974291 TI - Visible-light-induced aerobic dearomative reaction of indole derivatives: access to heterocycle fused or spirocyclo indolones. AB - Oxazolo[3,2-a]indolone and spiro[furan-2,2'-indolin]one are synthesized by the visible-light-induced aerobic dearomative reaction of indoles. The common indole tethered alcohol at the N1 or C2 position reacts in a cascade fashion, providing facile access to diverse indolone scaffolds. PMID- 26974292 TI - Investigations on the reactions of alpha-dicarbonyl compounds with amino acids and proteins during in vitro digestion of biscuits. AB - This study investigated the interactions of reactive alpha-dicarbonyl compounds, particularly methylglyoxal (MGO) and 3-deoxyglucosone (3-DG), in commercial biscuits during gastrointestinal digestion. An in vitro multi-step enzymatic digestion system simulating gastric, duodenal and colon phases was used. MGO and 3-DG concentrations decreased with the progress of digestion. Model systems composed of MGO and lysine, cysteine or ovalbumin and model biscuits containing lysine, cysteine or ovalbumin were subjected to in vitro digestion. The results revealed that disappearance in dicarbonyl contents was due to interactions of reactive dicarbonyl compounds with the accumulating amino acids during digestive process. By a high resolution mass spectrometry analysis in model systems and biscuits, the formation of adducts of dicarbonyl compounds with amino or sulfhydryl groups of amino acids was confirmed. PMID- 26974293 TI - Pulmonary Complications of HIV Infection. PMID- 26974295 TI - The Impact of Antiretroviral Therapy on Lung Immunology. AB - Despite the introduction of antiretroviral therapy (ART), human immunodeficiency virus-1 (HIV) continues to cause a major impact worldwide. HIV-induced lung disease continues to represent a significant source of morbidity and mortality, although the spectrum of pulmonary diseases has changed. HIV significantly affects the lung, causing acute and chronic cellular changes in the alveolar space. The impact of ART on lung immunology still needs to be fully elucidated. Similar to the periphery, ART affects HIV viral load and reconstitutes CD4(+) T cells in the lung. ART has been associated with significant decreases in bronchoalveolar lavage lymphocytes and increases in B-cell numbers and functionality, resulting in improved immune responses to vaccinations. There are substantial clinical implications of these ART-induced alterations, including the emergence of immune reconstitution inflammatory syndrome and the increased incidences of noninfectious lung diseases, such as lung cancer and chronic obstructive lung disease. There continues to be many unanswered questions regarding the effects of ART on lung health and, in particular, the immune system. Growing knowledge in this area will hopefully diminish the incidence of these noninfectious lung diseases and further improve the health of individuals living with HIV. PMID- 26974294 TI - Human Immunodeficiency Virus Infection and Host Defense in the Lungs. AB - Immunosuppression associated with human immunodeficiency virus (HIV) infection impacts all components of host defense against pulmonary infection. Cells within the lung have altered immune function and are important reservoirs for HIV infection. The host immune response to infected lung cells further compromises responses to a secondary pathogenic insult. In the upper respiratory tract, mucociliary function is impaired and there are decreased levels of salivary immunoglobulin A. Host defenses in the lower respiratory tract are controlled by alveolar macrophages, lymphocytes, and polymorphonuclear leukocytes. As HIV infection progresses, lung CD4 T cells are reduced in number causing a lack of activation signals from CD4 T cells and impaired defense by macrophages. CD8 T cells, on the other hand, are increased in number and cause lymphocytic alveolitis. Specific antibody responses by B-lymphocytes are decreased and opsonization of microorganisms is impaired. These observed defects in host defense of the respiratory tract explain the susceptibility of HIV-infected persons for oropharyngeal candidiasis, bacterial pneumonia, Pneumocystis pneumonia, and other opportunistic infections. PMID- 26974296 TI - Global Considerations in Human Immunodeficiency Virus-Associated Respiratory Disease. AB - Respiratory tract infection, particularly tuberculosis, is a major cause of mortality among human immunodeficiency virus (HIV)-infected individuals. Antiretroviral therapy (ART) has resulted in a dramatic increase in survival, although coverage of HIV treatment remains low in many parts of the world. There is a concurrent growing burden of chronic noninfectious respiratory disease as a result of increased survival. Many risk factors associated with the development of respiratory disease, such as cigarette smoking and intravenous drug use, are overrepresented among people living with HIV. In addition, there is emerging evidence that HIV infection may directly cause or accelerate the course of chronic lung disease. This review summarizes the clinical spectrum and epidemiology of respiratory tract infections and noninfectious pulmonary pathologies, and factors that explain the global variation in HIV-associated respiratory disease. The potential for enhancing diagnoses of noninfective chronic conditions through the use of clinical algorithms is discussed. We also consider issues in assessment and management of HIV-related respiratory disease in view of the increasing global scale up of ART. PMID- 26974297 TI - Epidemiology of HIV-Associated Lung Disease in the United States. AB - The epidemiology of HIV infection and its pulmonary complications in the United States has evolved significantly over nearly 20 years since the advent of combination antiretroviral therapy. While infectious complications are less of a threat to patients whose immune systems have been restored, many HIV-infected persons in the United States remain at high risk for opportunistic infection because they are unaware of their HIV infection, have difficulty maintaining linkage to care, or maintain inadequate viral control. Bacterial pneumonia and Pneumocystis pneumonia remain significantly more prevalent among HIV-infected persons, and together with seasonal influenza are areas where public health efforts to increase antiretroviral therapy, appropriate prophylaxis, and vaccination may decrease burden of disease. Noninfectious pulmonary complications of chronic HIV infection are increasingly recognized in the United States and elsewhere. Chronic obstructive pulmonary disease, asthma, pulmonary hypertension, sleep-disordered breathing, and primary lung cancer may all be more common among persons with HIV; of concern, disease burden in U.S. HIV-infected persons may be underestimated due to lack of diagnostic testing for these conditions. Smoking is among the most prevalent preventable causes of morbidity and mortality affecting persons living with HIV infection, and has particular import to pulmonary disease. As of 2009, 42% of HIV-infected adults in medical care in the United States smoked tobacco (over twice the national rate in the general population). Successful efforts to promote smoking cessation among HIV-infected persons are of critical importance to decrease the burden of chronic pulmonary disease. PMID- 26974298 TI - Evaluation and Diagnosis of HIV-Associated Lung Disease. AB - There are myriad pulmonary conditions associated with HIV, ranging from acute infections to chronic noncommunicable diseases. The epidemiology of these diseases has changed significantly in the era of widespread antiretroviral therapy. Evaluation of the HIV-infected patient involves assessment of the severity of illness and a thorough yet efficient pursuit of definitive diagnosis, which may involve multiple etiologies simultaneously. Important clues to a diagnosis include medical and social history, demographic details such as travel and geography of residence, substance use, sexual practices, and domiciliary and incarceration status. CD4 cell count is a tremendously useful measure of immune function and risk for HIV-related diseases, and helps narrow down the differential. Careful history of current symptoms and physical examination with particular attention to extrapulmonary signs are crucial early steps. Many adjunctive laboratory studies can suggest or rule out particular diagnoses. Pulmonary function testing (PFT) may aid in characterization of several chronic noninfectious illnesses accelerated by HIV. Chest radiograph and computed tomography (CT) scan allow for classification of diseases by pathognomonic imaging patterns, although many infectious conditions present atypically, particularly with lower CD4 counts. Ultimately, definitive diagnosis with sputum, bronchoscopy with bronchoalveolar lavage, or lung tissue is often needed. It is of utmost importance to maintain a high degree of suspicion for HIV in otherwise undiagnosed patients, as the first presentation of HIV may be via an acute pulmonary illness. PMID- 26974299 TI - Bacterial Respiratory Infections Complicating Human Immunodeficiency Virus. AB - Opportunistic bacterial and fungal infections of the lower respiratory tract, most commonly those caused by Streptococcus pneumoniae (the pneumococcus), Mycobacterium tuberculosis, and Pneumocystis jirovecii, remain the major causes of mortality in those infected with human immunodeficiency virus (HIV). Bacterial respiratory pathogens most prevalent in those infected with HIV, other than M. tuberculosis, represent the primary focus of the current review with particular emphasis on the pneumococcus, the leading cause of mortality due to HIV infection in the developed world. Additional themes include (1) risk factors; (2) the predisposing effects of HIV-mediated suppression on pulmonary host defenses, possibly intensified by smoking; (3) clinical and laboratory diagnosis, encompassing assessment of disease severity and outcome; and (4) antibiotic therapy. The final section addresses current recommendations with respect to pneumococcal immunization in the context of HIV infection, including an overview of the rationale underpinning the current "prime-boost" immunization strategy based on sequential administration of pneumococcal conjugate vaccine 13 and pneumococcal polysaccharide vaccine 23. PMID- 26974300 TI - Mycobacterial Lung Disease Complicating HIV Infection. AB - Mycobacterial infections have caused enormous morbidity and mortality in people living with human immunodeficiency virus (HIV) infection. Of these, the most devastating has been tuberculosis (TB), the leading cause of death among HIV positive persons globally. TB has killed more people living with HIV than any other infection. Diagnosis of latent TB infection (LTBI) is critical as treatment can prevent emergence of TB disease. Bacteriologic confirmation of TB disease should be sought whenever possible as well as drug susceptibility testing. When detected early, drug susceptible TB is curable. Similar to TB, nontuberculous mycobacteria (NTM) can also produce pulmonary and extrapulmonary infections including disseminated disease that can be fatal. Diagnosis through accurate identification of the pathogenic organism will greatly inform treatment. Depending on the NTM identified, treatment may not be curable. Ultimately, preventive strategies such as initiation of antiretroviral drugs and treatment of LTBI are interventions expected to have significant impacts on control of TB and NTM in the setting of HIV. This chapter will review the impact of pulmonary mycobacterial infections on HIV-positive individuals. PMID- 26974301 TI - Pneumocystis jirovecii Pneumonia in Human Immunodeficiency Virus Infection. AB - The presentation of Pneumocystis pneumonia (PCP) in previously healthy men having sex with men (MSM) in San Francisco and New York City in 1981 heralded the beginning of the human immunodeficiency virus (HIV) pandemic. Despite a decreasing incidence of PCP among patients with HIV/AIDS (acquired immunodeficiency syndrome) since the advent of combination antiretroviral therapy in the mid-1990s, PCP remains one of the most common AIDS-defining opportunistic infections in the United States and Western Europe. Newer molecular diagnostic tests in conjunction with standard immunofluorescent or colorimetric tests have allowed for more rapid and accurate diagnosis. Although several effective oral and intravenous therapies exist to treat PCP, mortality rates in HIV-infected individuals remain unacceptably high, especially in those with advanced AIDS. The identification of specific mutations in Pneumocystis genes targeted by trimethoprim-sulfamethoxazole has raised concerns about the development of resistance to the drug of choice and may ultimately lead to greater utilization of alternative therapies to treat PCP in the future. PMID- 26974302 TI - Fungal, Viral, and Parasitic Pneumonias Associated with Human Immunodeficiency Virus. AB - Respiratory illness is an important cause of morbidity and mortality in patients with human immunodeficiency virus (HIV). The spectrum of pulmonary disease that can affect patients with HIV is wide and includes opportunistic infection with many fungal, viral, and parasitic organisms. This article reviews the clinical presentation; approach to diagnosis; and management of fungal, viral, and parasitic pneumonias that can develop in patients with HIV including respiratory disease caused by Aspergillus, Cryptococcus, Histoplasma, Coccidioides, Cytomegalovirus, Toxoplasma, and Strongyloides. Because clinical symptoms and radiographic patterns are often insensitive at distinguishing these pulmonary infections, this review particularly focuses on specific host risk factors and diagnostic testing to consider when approaching HIV patients with respiratory illness. PMID- 26974303 TI - Lung Malignancies in HIV Infection. AB - Pulmonary malignancies are a major source of morbidity and mortality in HIV infected persons. Non-AIDS-defining lung cancers (mostly non-small cell lung cancers) are now a leading cause of cancer death among HIV-infected persons. HIV associated factors appear to affect the risk of lung cancer and may adversely impact cancer treatment and outcomes. HIV infection also may modify the potential harms and benefits of lung cancer screening with computed tomography. AIDS defining lung malignancies include pulmonary Kaposi sarcoma and pulmonary lymphoma, both of which are less prevalent with widespread adoption of antiretroviral therapy. PMID- 26974305 TI - Noninfectious and Nonneoplastic Conditions Associated with Human Immunodeficiency Virus Infection. AB - The goal of this review is to describe evolving epidemiology of noninfectious, nonneoplastic pulmonary complications of HIV infection, including HIV-associated pulmonary arterial hypertension (HIV-PAH) and interstitial lung disease (ILD). The development of antiretroviral therapy has rendered HIV a chronic illness in treated patients, and the landscape of HIV-associated medical conditions continues to evolve. Although there has been a shift away from AIDS-defining infectious diseases and malignancies, HIV-PAH continues to affect survival adversely when compared with HIV-infected patients without PAH. Studies of pre- and post-highly active antiretroviral therapy (HAART) era show that the prevalence of HIV-PAH remains high and unchanged. The increased prevalence of PAH among HIV-infected individuals has led to several complementary theories about potential mechanisms underlying this disease. Unique mechanisms of HIV-PAH focus on direct effects of viral proteins; alterations in cellular immunologic/inflammatory reactions to the virus; additive effects of cocaine, heroin, and other drugs of abuse; and potentially toxic aspects of antiretroviral and associated therapies. PAH-specific therapy with HAART is likely beneficial in the treatment of HIV-PAH patients. The prevalence of ILD in HIV-infected individuals is also significantly higher than that in the general population. Lymphoid interstitial pneumonitis (LIP) and nonspecific interstitial pneumonia (NSIP) have been reported in both HIV-infected children and adults, and NSIP is more common than LIP in HIV-infected patients. At present, there is no consensus on the pathogenesis of LIP and NSIP in HIV. Finally, we briefly review the literature on venous thromboembolic disease in HIV-infected individuals. PMID- 26974306 TI - Critical Care in Human Immunodeficiency Virus-Infected Patients. AB - Intensive care unit (ICU) survival has been improved significantly for HIV infected patients since the advent of antiretroviral therapy (ART). Non-AIDS conditions account for the majority of ICU admission diagnoses in areas with access to ART. However, opportunistic infections such as Pneumocystis jirovecii pneumonia still account for a significant proportion of ICU admissions, particularly in newly diagnosed HIV-infected patients, and are associated with increased ICU mortality. We discuss risk factors and outcomes for HIV-infected admitted to the ICU in the current ART era. We review the changing patterns in ICU admission diagnoses over time and how common ICU conditions are managed in HIV-infected compared with uninfected patients. We next address issues specific to the care for HIV-infected patients in the ICU, focusing on immune reconstitution inflammatory syndrome, ART continuation or initiation, and some common and potentially life-threatening ART-associated toxicities. PMID- 26974304 TI - Obstructive Lung Diseases in HIV: A Clinical Review and Identification of Key Future Research Needs. AB - HIV infection has shifted from what was once a disease directly impacting short term mortality to what is now a chronic illness controllable in the era of effective combination antiretroviral therapy (ART). In this setting, life expectancy for HIV-infected individual is nearly comparable to that of individuals without HIV. Subsequent to this increase in life expectancy, there has been recognition of increased multimorbidity among HIV-infected persons, with prevalence of comorbid chronic illnesses now approaching 65%. Obstructive lung diseases, including chronic obstructive pulmonary disease (COPD) and asthma, are prevalent conditions associated with substantial morbidity and mortality in the United States. There is overlap in risk factors for HIV acquisition and chronic lung diseases, including lower socioeconomic status and the use of tobacco and illicit drugs. Objectives of this review are to (1) summarize the current state of knowledge regarding COPD and asthma among HIV-infected persons, (2) highlight implications for clinicians caring for patients with these combined comorbidities, and (3) identify key research initiatives to reduce the burden of obstructive lung diseases among HIV-infected persons. PMID- 26974307 TI - Recurrent copy number variants associated with bronchopulmonary dysplasia. AB - BACKGROUND: Variability in the incidence and severity of bronchopulmonary dysplasia (BPD) among premature infants suggests that genetic susceptibility plays a role in pathogenesis. An assessment of copy number variants (CNV) in BPD subjects may help to identify loci that harbor genetic susceptibility factors. METHODS: We conducted a retrospective analysis of clinical DNA microarray data from our institution. We identified 19 BPD subjects, and 2 controls groups (full term and preterm) with no lung-related disease. We reanalyzed raw data from each of these subjects to identify recurrent CNV loci in BPD subjects. RESULTS: We identified three loci (at 11q13.2, 16p13.3, and 22q11.23-q12.1) with recurrent CNV in BPD subjects. The frequency of these CNV was significantly higher in BPD subjects when compared with at least one control group. We interrogated 21 genes residing within the recurrent CNV regions for development-associated changes in expression. Fifteen genes demonstrated significant changes in expression between the pseudoglandular and canalicular stage in human lungs, a time commensurate with birth at highest risk for BPD. We also identified pathways represented by the genes present within the recurrent loci. CONCLUSION: These data identify novel loci that may harbor genes contributing to the genetic susceptibility of BPD. PMID- 26974309 TI - Cleavage of Na(+) channels by calpain increases persistent Na(+) current and promotes spasticity after spinal cord injury. AB - Upregulation of the persistent sodium current (I(NaP)) in motoneurons contributes to the development of spasticity after spinal cord injury (SCI). We investigated the mechanisms that regulate I(NaP) and observed elevated expression of voltage gated sodium (Nav) 1.6 channels in spinal lumbar motoneurons of adult rats with SCI. Furthermore, immunoblots revealed a proteolysis of Nav channels, and biochemical assays identified calpain as the main proteolytic factor. Calpain dependent cleavage of Nav channels after neonatal SCI was associated with an upregulation of I(NaP) in motoneurons. Similarly, the calpain-dependent cleavage of Nav1.6 channels expressed in human embryonic kidney (HEK) 293 cells caused the upregulation of I(NaP). The pharmacological inhibition of calpain activity by MDL28170 reduced the cleavage of Nav channels, I(NaP) in motoneurons and spasticity in rats with SCI. Similarly, the blockade of I(NaP) by riluzole alleviated spasticity. This study demonstrates that Nav channel expression in lumbar motoneurons is altered after SCI, and it shows a tight relationship between the calpain-dependent proteolysis of Nav1.6 channels, the upregulation of I(NaP) and spasticity. PMID- 26974308 TI - Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1. AB - Tissues with high metabolic rates often use lipids, as well as glucose, for energy, conferring a survival advantage during feast and famine. Current dogma suggests that high-energy-consuming photoreceptors depend on glucose. Here we show that the retina also uses fatty acid beta-oxidation for energy. Moreover, we identify a lipid sensor, free fatty acid receptor 1 (Ffar1), that curbs glucose uptake when fatty acids are available. Very-low-density lipoprotein receptor (Vldlr), which is present in photoreceptors and is expressed in other tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acid. In the retinas of Vldlr(-/-) mice with low fatty acid uptake but high circulating lipid levels, we found that Ffar1 suppresses expression of the glucose transporter Glut1. Impaired glucose entry into photoreceptors results in a dual (lipid and glucose) fuel shortage and a reduction in the levels of the Krebs cycle intermediate alpha-ketoglutarate (alpha-KG). Low alpha-KG levels promotes stabilization of hypoxia-induced factor 1a (Hif1a) and secretion of vascular endothelial growth factor A (Vegfa) by starved Vldlr(-/-) photoreceptors, leading to neovascularization. The aberrant vessels in the Vldlr( /-) retinas, which invade normally avascular photoreceptors, are reminiscent of the vascular defects in retinal angiomatous proliferation, a subset of neovascular age-related macular degeneration (AMD), which is associated with high vitreous VEGFA levels in humans. Dysregulated lipid and glucose photoreceptor energy metabolism may therefore be a driving force in macular telangiectasia, neovascular AMD and other retinal diseases. PMID- 26974310 TI - PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. AB - Phosphatase and tensin homolog (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) signaling pathway and a potent tumor suppressor in many types of cancer. To test a tumor suppressive role for PTEN in pre-B acute lymphoblastic leukemia (ALL), we induced Cre-mediated deletion of Pten in mouse models of pre-B ALL. In contrast to its role as a tumor suppressor in other cancers, loss of one or both alleles of Pten caused rapid cell death of pre-B ALL cells and was sufficient to clear transplant recipient mice of leukemia. Small-molecule inhibition of PTEN in human pre-B ALL cells resulted in hyperactivation of AKT, activation of the p53 tumor suppressor cell cycle checkpoint and cell death. Loss of PTEN function in pre-B ALL cells was functionally equivalent to acute activation of autoreactive pre-B cell receptor signaling, which engaged a deletional checkpoint for the removal of autoreactive B cells. We propose that targeted inhibition of PTEN and hyperactivation of AKT triggers a checkpoint for the elimination of autoreactive B cells and represents a new strategy to overcome drug resistance in human ALL. PMID- 26974311 TI - Is sharing specific autobiographical memories a distinct form of self-disclosure? AB - Theories of autobiographical memory posit a social function, meaning that recollecting and sharing memories of specific discrete events creates and maintains relationship intimacy. Eight studies with 1,271 participants tested whether sharing specific autobiographical memories in conversations increases feelings of closeness among conversation partners, relative to sharing other self related information. The first 2 studies revealed that conversations in which specific autobiographical memories were shared were also accompanied by feelings of closeness among conversation partners. The next 5 studies experimentally introduced specific autobiographical memories versus general information about the self into conversations between mostly unacquainted pairs of participants. Discussing specific autobiographical memories led to greater closeness among conversation partners than discussing nonself-related topics, but no greater closeness than discussing other, more general self-related information. In the final study unacquainted pairs in whom feelings of closeness had been experimentally induced through shared humor were more likely to discuss specific autobiographical memories than unacquainted control participant pairs. We conclude that sharing specific autobiographical memories may express more than create relationship closeness, and discuss how relationship closeness may afford sharing of specific autobiographical memories by providing common ground, a social display, or a safety signal. PMID- 26974312 TI - Clinical Significance of Persistent Global and Focal Computed Tomography Nephrograms After Cardiac Catheterization and Their Relationships to Urinary Biomarkers of Kidney Damage and Procedural Factors: Pilot Study. AB - OBJECTIVES: We evaluate the relationships between persistent computed tomography (CT) nephrograms and acute kidney injury after cardiac catheterization (CC). We compare changes in urinary biomarkers kidney injury molecule 1 (KIM-1), cystatin C, and serum creatinine to procedural factors. MATERIALS AND METHODS: From 159 eligible patients without renal insufficiency (estimated glomerular filtration rate >60 mL/min), 40 random patients (age range, 42-81 years; mean age, 64 years; 25 men, 15 women) gave written informed consent to undergo unenhanced CT limited to their kidneys 24 hours after CC. Semiquantitative assessment for global nephrograms and quantitative assessment of focal nephrograms in each kidney was performed. Computed tomography attenuation (Hounsfield units) of the renal cortex was measured. Serum creatinine, KIM-1, and cystatin C were measured before and 24 hours after CC. RESULTS: Robust linear regression showed that both relative changes in KIM-1 and cystatin C had positive relationships with kidney CT attenuation (P = 0.012 and 0.002, respectively). Spearman rank correlation coefficient showed that both absolute changes and relative changes in KIM-1 and cystatin C had positive correlations with global nephrogram grades (P = 0.025 and 0.040, respectively, for KIM-1; P = 0.013 and 0.019, respectively, for cystatin C). CONCLUSIONS: Global nephrograms on unenhanced CT in patients who have undergone CC are significantly correlated with changes in urinary biomarkers for kidney damage. PMID- 26974313 TI - A polymorphism in a major antioxidant gene (Kelch-like ECH-associated protein 1) predicts incident cardiovascular events in chronic kidney disease patients: an exploratory study. AB - OBJECTIVE: Oxidative stress is considered a major pathway conducive to cardiovascular disease in chronic kidney disease (CKD) patients. However, observational studies and clinical trials testing this relationship are controversial. The Nuclear factor-erythroid-2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) system is a major system regulating antioxidant mechanisms in living organisms. Owing to the fact that genes are transmitted randomly (Mendelian randomization), genetic variants may provide unconfounded assessment of putative causal risk factors. METHODS: We have therefore explored the association of eight polymorphisms in the Nrf2 gene and three polymorphisms in the Keap1 gene (capturing over 80% of the genetic variance in the same genes) with cardiovascular events in a multicenter cohort study of 758 CKD patients. RESULTS: During the follow-up period, 117 patients had fatal and nonfatal cardiovascular events and 42 died. The hazard rate of fatal and nonfatal cardiovascular outcomes was about twice higher in patients with the AA or the CA genotype (dominant model) in the rs110857735 polymorphism of the Keap1 gene (hazard rate: 1.85, 95% CI: 1.20-2.84, P = 0.005) than in those with the CC genotype. Further analyses adjusting for Framingham risk factors and CKD-specific risk factors and a bootstrapping validation analysis did not modify the strength of this association. No association was registered between other Keap1 and Nrf2 polymorphisms and cardiovascular disease in the same cohort. CONCLUSION: In this exploratory study a gene-variant in Keap1, a major gene regulating the antioxidant response, predicts incident cardiovascular events in CKD patients. This finding is in keeping with the hypothesis implicating oxidative stress in cardiovascular disease in this population. PMID- 26974314 TI - Is Tc-99m sestamibi scintimammography useful in the prediction of neoadjuvant chemotherapy responses in breast cancer? A systematic review and meta-analysis. AB - To evaluate the accuracy of Tc-99m sestamibi (MIBI) scintimammography in the prediction of neoadjuvant chemotherapy response in breast cancer. 'PubMed' (MEDLINE included) and Embase database were searched for relevant publications in English. Methodological quality of the included studies was assessed with Quality Assessment of Diagnosis Accuracy Studies (QUADAS), and 'Meta-Disc' and 'Stata' software were used to determine pooled sensitivity, specificity, and diagnostic odds ratio (DOR), and construct a summary receiver-operating characteristic curve. Fourteen studies (a total of 503 individuals) fulfilled the inclusion criteria. The pooled sensitivity was 0.86 [95% confidence interval (CI): 0.78 0.92] and the pooled specificity was 0.69 (95% CI: 0.64-0.74). Pooled likelihood ratio (LRp), negative likelihood ratio (LR-), and DOR were 2.64 (95% CI: 1.81 3.85), 0.26 (95% CI: 0.15-0.46), and 12.06 (95% CI: 6.94-20.96), respectively. The area under the summary receiver-operating characteristic curve was 0.86. For the prediction of pathological complete response (10 studies included), the pooled sensitivity and specificity and DOR were 0.86 (95% CI: 0.77-0.93), 0.67 (95% CI: 0.62-0.72), and 11.43 (95% CI: 5.95-21.97). Our results indicated that Tc-99m MIBI scintimammography had acceptable sensitivity in the prediction of neoadjuvant chemotherapy response in breast cancer; however, its relatively low specificity showed that a combination of other imaging modalities would still be needed. Subgroup analysis indicated that performing early mid-treatment Tc-99m MIBI scintimammography (using the reduction rate of one or two cycles or within the first half-courses of chemotherapy compared with the baseline) was better than carrying out later (after three or more courses) or post-treatment scintimammography in the prediction of neoadjuvant chemotherapy response. PMID- 26974315 TI - Dosimetric analysis of 177Lu-DOTA-rituximab in patients with relapsed/refractory non-Hodgkin's lymphoma. AB - OBJECTIVE: Radioimmunotherapy targeting CD20 receptors in lymphoma using radiolabeled chimeric antibodies may lead to better therapeutic responses than cold anti-CD20 antibodies. This study aimed to assess the biodistribution and present reasonable estimates of normal organ doses, including red marrow using Lu DOTA-rituximab. MATERIALS AND METHODS: Patients with relapsed/refractory CD20+ B cell non-Hodgkin's lymphoma were recruited into this prospective study. In-house labeling of Lu-DOTA-rituximab was performed and administered after quality assurance. Rituximab (375 mg/m), followed by 50 mCi (1850 MBq) of Lu-DOTA rituximab was administered as a slow intravenous infusion and emission images were acquired. Regions of interest were drawn for kidney, liver, heart, bladder, spleen, and tumor lesions on both anterior and posterior images. Internal dose estimation was performed using OLINDA v1.0 software. RESULTS: The mean age of the 10 patients (eight men and two women) was 52+/-13 years. The uptake of radiolabeled antibody was visualized within 30 min of administration in the liver, kidneys, heart, spleen, and bladder. The coefficient of determination (R) was greater than 0.95 for organs and the whole body in all patients. The effective half-life of radioimmunoconjugate was 100+/-28 h (42-126 h). The critical organ in our study was the red marrow. The average total body dose, effective dose, and effective dose equivalent calculated in all 10 patients were 0.13+/-0.02, 0.15+/-0.03, and 0.22+/-0.04 mGy/MBq, respectively. CONCLUSION: There may be considerable interindividual differences in absorbed doses of organs and generalization or extrapolation of doses in the clinical setting at present is not feasible with Lu-DOTA-rituximab in non-Hodgkin's lymphoma patients. Patient-specific dosimetry is thus recommended to eliminate the variations and reduce the possibility of dose-limiting toxicity. PMID- 26974316 TI - Clinical results in cachexia therapeutics. AB - PURPOSE OF REVIEW: This article highlights recent developments in the area of cancer cachexia and therapeutic interventions. RECENT FINDINGS: Therapeutic interventions in cancer cachexia have been guided by clinical studies focused on the central role of muscle and the increased use of CT imaging to measure the impact of skeletal muscle loss on clinical outcomes. At the translational level, a number of different model systems have emphasized the importance of blockade of tumor-induced inflammation and its potential impact on reversing the cachexia phenotype, including FN14, a receptor in the TNF pathway, as well as the parathyroid hormone-related protein. Clinical studies continue to demonstrate the importance of nutrition and exercise as part of a multimodality approach. Although a number of promising agents are being evaluated, both enobosarm, a selected androgen receptor modulator, and anamorelin, a ghrelin agonist have completed phase III trials. Both agents have shown significant impact on reversal of skeletal muscle loss, but inconsistent effect on physical function improvement. Anamorelin also has a positive effect on appetite and weight gain. SUMMARY: Further analysis of these studies, along with regulatory guidance, will be critical in the further development of these and other promising agents in the clinical management of patients with cancer cachexia. PMID- 26974317 TI - WHAT'S NEW IN SHOCK, APRIL 2016? PMID- 26974318 TI - PHARMACOLOGICAL SIRT1 ACTIVATION IMPROVES MORTALITY AND MARKEDLY ALTERS TRANSCRIPTIONAL PROFILES THAT ACCOMPANY EXPERIMENTAL SEPSIS. AB - The sirtuin family consists of seven NAD+-dependent enzymes affecting a broad array of regulatory protein networks by primarily catalyzing the deacetylation of key lysine residues in regulatory proteins. The enzymatic activity of SIRT1 can be enhanced by small molecule activators known as SIRT1 activator compounds (STACs). We tested the therapeutic potential of the STAC SRT3025 in two preclinical models of severe infection, the murine cecal ligation and puncture (CLP) model to induce peritonitis and intratracheal installation of Streptococcus pneumoniae to induce severe bacterial pneumonia. SRT3025 provided significant survival benefits over vehicle control in both the peritonitis and pneumococcal pneumonia models when administered with appropriate antimicrobial agents. The survival benefit of SRT3025 in the CLP model was absent in SIRT1 knockout showing the SIRT1 dependency of SRT3025's effects. SRT3025 administration promoted bacterial clearance and significantly reduced inflammatory cytokines from the lungs of animals challenged with S. pneumoniae. SRT3025 treatment was also accompanied by striking changes in the transcription profiles in multiple inflammatory and metabolic pathways in liver, spleen, small bowel, and lung tissue. Remarkably, these organ-specific changes in the transcriptome analyses were similar following CLP or pneumococcal challenge despite different sets of pathogens at disparate sites of infection. Pharmacologic activation of SIRT1 modulates the innate host response and could represent a novel treatment strategy for severe infection. PMID- 26974319 TI - Folic Acid Represses Hypoxia-Induced Inflammation in THP-1 Cells through Inhibition of the PI3K/Akt/HIF-1alpha Pathway. AB - Though hypoxia has been implicated as a cause of inflammation, the underlying mechanism is not well understood. Folic acid has been shown to provide protection against oxidative stress and inflammation in patients with cardiovascular disease and various models approximating insult to tissue via inflammation. It has been reported that hypoxia-induced inflammation is associated with oxidative stress, upregulation of hypoxia-inducible factor 1-alpha (HIF-1alpha), and production of pro-inflammatory molecules. Whether folic acid protects human monocytic cells (THP-1 cells) against hypoxia-induced damage, however, remains unknown. We used THP-1 cells to establish a hypoxia-induced cellular injury model. Pretreating THP 1 cells with folic acid attenuated hypoxia-induced inflammatory responses, including a decrease in protein and mRNA levels of interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF-alpha), coupled with increased levels of IL-10. Folic acid also reduced hypoxia-induced Akt phosphorylation and decreased nuclear accumulation of HIF-1alpha protein. Both LY294002 (a selective inhibitor of phosphatidyl inositol-3 kinase, PI3K) and KC7F2 (a HIF-1alpha inhibitor) reduced levels of hypoxia-induced inflammatory cytokines. We also found that insulin (an Akt activator) and dimethyloxallyl glycine (DMOG, a HIF-1alpha activator) induced over-expression of inflammatory cytokines, which could be blocked by folic acid. Taken together, these findings demonstrate how folic acid attenuates the hypoxia induced inflammatory responses of THP-1 cells through inhibition of the PI3K/Akt/HIF-1alpha pathway. PMID- 26974320 TI - The Non-Fimbriate Phenotype Is Predominant among Salmonella enterica Serovar Choleraesuis from Swine and Those Non-Fimbriate Strains Possess Distinct Amino Acid Variations in FimH. AB - Although most Salmonella serovars are able to infect a range of animal hosts, some have acquired the ability to cause systemic infections of specific hosts. For example, Salmonella enterica serovar Choleraesuis is primarily associated with systemic infection in swine. Adherence to host epithelial cells is considered a prerequisite for initial infection, and fimbrial appendages on the outer membrane of the bacteria are implicated in this process. Although type 1 fimbriae encoded by the fim gene cluster are commonly found in Salmonella serovars, it is not known whether S. Choleraesuis produces this fimbrial type and if and how fimbriae are involved in pathogenesis. In the present study, we demonstrated that only four out of 120 S. Choleraesuis isolates from pigs with salmonellosis produced type 1 fimbriae as assayed by the yeast agglutination test and electron microscopy. One of the 116 non-type 1 fimbria-producing isolates was transformed with plasmids carrying different fim genes from S. Typhimurium LB5010, a type 1 fimbria-producing strain. Our results indicate that non-type 1 fimbria-producing S. Choleraesuis required only an intact fimH to regain the ability to produce fimbrial appendages. Sequence comparison revealed six amino acid variations between the FimH of the non-type 1 fimbria-producing S. Choleraesuis isolates and those of the type 1 fimbria-producing S. Choleraesuis isolates. S. Choleraesuis that produced type 1 fimbriae contained FimH with an amino acid sequence identical to that of S. Typhimurium LB5010. Site-directed mutagenesis leading to the replacement of the non-conserved residues revealed that a change from glycine to valine at position of 63 (G63V) resulted in a non type 1 fimbria-producing S. Choleraesuis being able to express type 1 fimbriae on its outer membrane. It is possible that this particular amino acid change prevents this polypeptide from proper interaction with other Fim subunits required for assembly of an intact type 1 fimbrial shaft in S. Choleraesuis; however, it remains to be determined if and how the absence of type 1 fimbriae production is related to the systemic infection of the swine host by S. Choleraesuis. PMID- 26974321 TI - Systematic Analysis of Absorbed Anti-Inflammatory Constituents and Metabolites of Sarcandra glabra in Rat Plasma Using Ultra-High-Pressure Liquid Chromatography Coupled with Linear Trap Quadrupole Orbitrap Mass Spectrometry. AB - Ultra-high-pressure liquid chromatography (UHPLC) was coupled with linear ion trap quadrupole Orbitrap mass spectrometry (LTQ-Orbitrap) and was used for the first time to systematically analyze the absorbed components and metabolites in rat plasma after oral administration of the water extract of Sarcandra glabra. This extract is a well-known Chinese herbal medicine for the treatment of inflammation and immunity related diseases. The anti-inflammatory activities of the absorbed components were evaluated by measuring nitric oxide (NO) production and proinflammatory genes expression in lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophages. As a result, 54 components in Sarcandra glabra were detected in dosed rat plasma, and 36 of them were positively identified. Moreover, 23 metabolites were characterized and their originations were traced. Furthermore, 20 of the 24 studied components showed anti-inflammatory activities. These results provide evidence that this method efficiency detected constituents in plasma based on the anti-inflammatory mechanism of multiple components and would be a useful technique for screening multiple targets for natural medicine research. PMID- 26974323 TI - Efficient Gene Knockdown in Mouse Oocytes through Peptide Nanoparticle-Mediated SiRNA Transfection. AB - The use of mouse oocytes as a model for studying female meiosis is very important in reproductive medicine. Gene knockdown by specific small interfering RNA (siRNA) is usually the first step in the study of the function of a target gene in mouse oocytes during in vitro maturation. Traditionally, the only way to introduce siRNA into mouse oocytes is through microinjection, which is certainly less efficient and strenuous than siRNA transfection in somatic cells. Recently, in research using somatic cells, peptide nanoparticle-mediated siRNA transfection has been gaining popularity over liposome nanoparticle-mediated methods because of its high efficiency, low toxicity, good stability, and strong serum compatibility. However, no researchers have yet tried transfecting siRNA into mouse oocytes because of the existence of the protective zona pellucida surrounding the oocyte membrane (vitelline membrane). We therefore tested whether peptide nanoparticles can introduce siRNA into mouse oocytes. In the present study, we showed for the first time that our optimized program can efficiently knock down a target gene with high specificity. Furthermore, we achieved the expected meiotic phenotypes after we knocked down a test unknown target gene TRIM75. We propose that peptide nanoparticles may be superior for preliminary functional studies of unknown genes in mouse oocytes. PMID- 26974322 TI - Transcription Factors Expressed in Mouse Cochlear Inner and Outer Hair Cells. AB - Regulation of gene expression is essential to determining the functional complexity and morphological diversity seen among different cells. Transcriptional regulation is a crucial step in gene expression regulation because the genetic information is directly read from DNA by sequence-specific transcription factors (TFs). Although several mouse TF databases created from genome sequences and transcriptomes are available, a cell type-specific TF database from any normal cell populations is still lacking. We identify cell type specific TF genes expressed in cochlear inner hair cells (IHCs) and outer hair cells (OHCs) using hair cell-specific transcriptomes from adult mice. IHCs and OHCs are the two types of sensory receptor cells in the mammalian cochlea. We show that 1,563 and 1,616 TF genes are respectively expressed in IHCs and OHCs among 2,230 putative mouse TF genes. While 1,536 are commonly expressed in both populations, 73 genes are differentially expressed (with at least a twofold difference) in IHCs and 13 are differentially expressed in OHCs. Our datasets represent the first cell type-specific TF databases for two populations of sensory receptor cells and are key informational resources for understanding the molecular mechanism underlying the biological properties and phenotypical differences of these cells. PMID- 26974324 TI - Does it matter who places the intravenous? An inter-professional comparison of prehospital intravenous access difficulties between physicians and paramedics. AB - OBJECTIVES: Depending on the specific national emergency medical systems, venous cannulations may be performed by physicians, paramedics or both alike. Difficulties in the establishment of vascular access can lead to delayed treatment and transport. Our study investigates possible inter-professional differences in the difficulties of prehospital venous cannulation. METHODS: Paramedics were interviewed for their personal attitudes towards and experiences in venous access. We analysed 47 candidate predictor variables in terms of cannulation failure and exceedance of a 2 min time threshold. Multivariable logistic regression models were fitted for variables of potential predictive value (P<0.25) and evaluated by the area under the curve (AUC>0.60) of their respective receiver operating characteristic curve. Results were compared with previously published data from emergency physicians. RESULTS: A total of 552 cannulations were included in our study. All 146 participants voted that paramedics should be eligible to perform venous catheterizations. Despite ample experience in the task, almost half of them considered prehospital venous cannulations more difficult than those performed in hospital. However, the multivariable logistic regression found only patient-related and puncture site factors to be predictive of cannulation failure (patient age, vein palpability with tourniquet, insufficient ambient lighting: model AUC: 0.72) or cannulation delay (vein palpability with tourniquet: model AUC: 0.60). CONCLUSION: Our study shows that venous cannulation is well established among paramedics. It presents itself with similar difficulties across medical professions. Not the numerous specific circumstances of prehospital emergency care, but universal factors inherent to the task will influence the success at venous catheterization. PMID- 26974325 TI - Transient Receptor Potential Melastatin-3 (TRPM3) Mediates Nociceptive-Like Responses in Hydra vulgaris. AB - The ability of mammals to feel noxious stimuli lies in a heterogeneous group of primary somatosensory neurons termed nociceptors, which express specific membrane receptors, such as the Transient Receptor Potential (TRP) family. Here, we show that one of the most important nociceptive-like pathways is conserved in the freshwater coelenterate Hydra vulgaris, the most primitive organism possessing a nervous system. In particular, we found that H. vulgaris expresses TRPM3, a nociceptor calcium channel involved in the detection of noxious heat in mammals. Furthermore, we detected that both heat shock and TRPM3 specific agonist (i.e., pregnenolone sulfate) induce the modulation of the heat shock protein 70 (HSP70) and the nitric oxide synthase (NOS), two genes activated by TRP-mediated heat painful stimuli in mammals. As expected, these effects are inhibited by a TRPM3 antagonist (i.e., mefenamic acid). Interestingly, the TRPM3 agonist and heat shock also induce the expression of nuclear transcription erythroid 2-related factor (Nrf2) and superoxide dismutase (SOD), known markers of oxidative stress; noteworthy gene expression was also inhibited by the TRPM3 antagonist. As a whole, our results demonstrate the presence of conserved molecular oxidative/nociceptive-like pathways at the primordial level of the animal kingdom. PMID- 26974326 TI - An Advanced Histologic Method for Evaluation of Intestinal Adenomas in Mice Using Digital Slides. AB - BACKGROUND AND METHODS: Mice are used for modelling the biology of many human diseases, including colorectal cancer (CRC). Mouse models recapitulate many aspects of human disease and are invaluable tools for studying the biology, treatment and prevention of CRC. Unlike humans, many mouse models develop lesions primarily in the small intestine, which necessitates removal and examination of this organ in order to evaluate treatment efficacy. Commonly, the small intestine is visually examined for gross lesions and then selectively embedded in paraffin blocks for further microscopic analysis. Unfortunately, this method suffers from inherent bias toward counting large lesions and simultaneously missing smaller lesions. Even more, this method leaves no permanent record of diagnosed and measured lesions. We evaluated inter-observer variability in a mouse model of CRC using visual examination, and directly compared the visual, gross examination with a histologic analytic method using digital slides of hematoxylin and eosin stained tissue sections. RESULTS: Using visual examination, there was a high degree of inter-observer variability. As this method does not provide a permanent record of measurements, there is no capability to arbitrate between differing observations. In contrast, histologic analysis allowed for the creation of a permanent record of lesion measurements taken. When compared directly, histologic analysis of annotated digital images has significantly improved accuracy. Using this method we were able to distinguish mutant mice from wild type littermates even at a very young age. With gross visual examination, this distinction was not possible. CONCLUSION: Histologic analysis of digital images of murine intestinal tissue provides a vital improvement over the commonly used visual, gross examination method. Unlike visual gross examination, histologic analysis is not biased by the size of intestinal adenoma, misdiagnosis of another lesion type, or presence of a Peyer's patch. It also provides accountability in the form of a permanent record of lesions counted. Histologic analysis using digital slides represents a critical improvement over the current, widely used method of visual gross examination and should be considered for future studies using mouse models of CRC. PMID- 26974327 TI - XANES Demonstrates the Release of Calcium Phosphates from Alkaline Vertisols to Moderately Acidified Solution. AB - Calcium phosphate (CaP) minerals may comprise the main phosphorus (P) reserve in alkaline soils, with solubility dependent on pH and the concentration of Ca and/or P in solution. Combining several techniques in a novel way, we studied these phenomena by progressively depleting P from suspensions of two soils (low P) using an anion-exchange membrane (AEM) and from a third soil (high P) with AEM together with a cation-exchange membrane. Depletions commenced on untreated soil, then continued as pH was manipulated and maintained at three constant pH levels: the initial pH (pHi) and pH 6.5 and 5.5. Bulk P K-edge X-ray absorption near-edge structure (XANES) spectroscopy revealed that the main forms of inorganic P in each soil were apatite, a second more soluble CaP mineral, and smectite-sorbed P. With moderate depletion of P at pHi or pH 6.5, CaP minerals became more prominent in the spectra compared to sorbed species. The more soluble CaP minerals were depleted at pH 6.5, and all CaP minerals were exhausted at pH 5.5, showing that the CaP species present in these alkaline soils are soluble with decreases of pH in the range achievable by rhizosphere acidification. PMID- 26974328 TI - Correction: Predicting the Maximum Earthquake Magnitude from Seismic Data in Israel and Its Neighboring Countries. PMID- 26974329 TI - Malignancies in Swedish persons with haemophilia: a longitudinal registry study. AB - The aim of the study was to investigate, over time, the incidence of and mortality due to malignant diseases among persons with haemophilia, compared to matched controls. Persons with haemophilia A or B were enrolled via registries at each haemophilia centre, as well as from the National Patient Registry, and were compared to five sex and age-matched controls per patient. Data from the national Cancer Registry were linked to the study participants. A total of 1431 persons with haemophilia and 7150 matched controls were enrolled. Between the years 1972 and 2008, 164 malignancies were reported. The most common type of cancer among patients was prostate cancer, followed by haematologic malignancies, including lymphoma and leukaemia, which were significantly more frequent in patients [n = 35 (2.4%) vs. n = 60 (0.8%); P < 0.001]. Malignancies in bladder and other urinary organs were also significantly different [n = 21 (1.5%) vs. n = 46 (0.6%); P < 0.01]. The overall incidence rate ratio of malignancies per 1000 person-years compared to the controls was 1.3 [95% confidence interval (CI) 1.1, 1.6]. In subgroup analysis, the corresponding incidence rate ratios per 1000 person-years for persons with severe haemophilia was 1.7 (95% CI 0.9, 3.1) and that for mild/moderate haemophilia 1.1 (95% CI 0.8, 1.5). Swedish persons with haemophilia had a significantly higher incidence of malignant diseases than controls. These were primarily haematologic malignancies and cancer in urinary organs, and the difference independent of any co-infections with HIV and/or viral hepatitis. The findings indicate the importance of further studies and close follow-up of malignancies in persons with haemophilia. PMID- 26974330 TI - A novel frameshift mutation leading to inherited type I antithrombin deficiency. AB - Inherited antithrombin (AT) deficiency is an autosomal dominant thrombotic disorder. We encountered a case of inherited type I AT deficiency and identified the mutation responsible; a novel 5406delA mutation in the SERPINC1 gene appeared to have caused a frameshift with premature termination at amino acid +283. The recombinant AT protein including 5406delA was not detected in cell lysates or culture supernatants. These results will contribute to the creation of an accurate database and define the molecular basis for AT deficiency. PMID- 26974331 TI - Correlation of Utrophin Levels with the Dystrophin Protein Complex and Muscle Fibre Regeneration in Duchenne and Becker Muscular Dystrophy Muscle Biopsies. AB - Duchenne muscular dystrophy is a severe and currently incurable progressive neuromuscular condition, caused by mutations in the DMD gene that result in the inability to produce dystrophin. Lack of dystrophin leads to loss of muscle fibres and a reduction in muscle mass and function. There is evidence from dystrophin-deficient mouse models that increasing levels of utrophin at the muscle fibre sarcolemma by genetic or pharmacological means significantly reduces the muscular dystrophy pathology. In order to determine the efficacy of utrophin modulators in clinical trials, it is necessary to accurately measure utrophin levels and other biomarkers on a fibre by fibre basis within a biopsy section. Our aim was to develop robust and reproducible staining and imaging protocols to quantify sarcolemmal utrophin levels, sarcolemmal dystrophin complex members and numbers of regenerating fibres within a biopsy section. We quantified sarcolemmal utrophin in mature and regenerating fibres and the percentage of regenerating muscle fibres, in muscle biopsies from Duchenne, the milder Becker muscular dystrophy and controls. Fluorescent immunostaining followed by image analysis was performed to quantify utrophin intensity and beta-dystrogylcan and gamma sarcoglycan intensity at the sarcolemma. Antibodies to fetal and developmental myosins were used to identify regenerating muscle fibres allowing the accurate calculation of percentage regeneration fibres in the biopsy. Our results indicate that muscle biopsies from Becker muscular dystrophy patients have fewer numbers of regenerating fibres and reduced utrophin intensity compared to muscle biopsies from Duchenne muscular dystrophy patients. Of particular interest, we show for the first time that the percentage of regenerating muscle fibres within the muscle biopsy correlate with the clinical severity of Becker and Duchenne muscular dystrophy patients from whom the biopsy was taken. The ongoing development of these tools to quantify sarcolemmal utrophin and muscle regeneration in muscle biopsies will be invaluable for assessing utrophin modulator activity in future clinical trials. PMID- 26974332 TI - Physical Activity Characteristics across GOLD Quadrants Depend on the Questionnaire Used. AB - BACKGROUND: The GOLD multidimensional classification of COPD severity combines the exacerbation risk with the symptom experience, for which 3 different questionnaires are permitted. This study investigated differences in physical activity (PA) in the different GOLD quadrants and patient's distribution in relation to the questionnaire used. METHODS: 136 COPD patients (58+/-21% FEV1 predicted, 34F/102M) completed COPD assessment test (CAT), clinical COPD questionnaire (CCQ) and modified Medical Research Council (mMRC) questionnaire. Exacerbation history, spirometry and 6MWD were collected. PA was objectively measured for 2 periods of 1 week, 6 months apart, in 5 European centres; to minimise seasonal and clinical variation the average of these two periods was used for analysis. RESULTS: GOLD quadrants C+D had reduced PA compared with A+B (3824 [2976] vs. 5508 [4671] steps.d-1, p<0.0001). The choice of questionnaire yielded different patient distributions (agreement mMRC-CAT kappa = 0.57; CCQ mMRC kappa = 0.71; CCQ-CAT kappa = 0.72) with different clinical characteristics. PA was notably lower in patients with an mMRC score >=2 (3430 [2537] vs. 5443 [3776] steps.d-1, p <0.001) in both the low and high risk quadrants. CONCLUSIONS: Using different questionnaires changes the patient distribution and results in different clinical characteristics. Therefore, standardization of the questionnaire used for classification is critical to allow comparison of different studies using this as an entry criterion. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01388218. PMID- 26974333 TI - Circumpolar Genetic Structure and Recent Gene Flow of Polar Bears: A Reanalysis. AB - Recently, an extensive study of 2,748 polar bears (Ursus maritimus) from across their circumpolar range was published in PLOS ONE, which used microsatellites and mitochondrial haplotypes to apparently show altered population structure and a dramatic change in directional gene flow towards the Canadian Archipelago-an area believed to be a future refugium for polar bears as their southernmost habitats decline under climate change. Although this study represents a major international collaborative effort and promised to be a baseline for future genetics work, methodological shortcomings and errors of interpretation undermine some of the study's main conclusions. Here, we present a reanalysis of this data in which we address some of these issues, including: (1) highly unbalanced sample sizes and large amounts of systematically missing data; (2) incorrect calculation of FST and of significance levels; (3) misleading estimates of recent gene flow resulting from non-convergence of the program BayesAss. In contrast to the original findings, in our reanalysis we find six genetic clusters of polar bears worldwide: the Hudson Bay Complex, the Western and Eastern Canadian Arctic Archipelago, the Western and Eastern Polar Basin, and-importantly-we reconfirm the presence of a unique and possibly endangered cluster of bears in Norwegian Bay near Canada's expected last sea-ice refugium. Although polar bears' abundance, distribution, and population structure will certainly be negatively affected by ongoing-and increasingly rapid-loss of Arctic sea ice, these genetic data provide no evidence of strong directional gene flow in response to recent climate change. PMID- 26974334 TI - Generation of Mice with Hepatocyte-Specific Conditional Deletion of Notum. AB - BACKGROUND: Fine tuning of the Wnt/beta-catenin signaling pathway is essential for the proper development and function of the liver. Aberrant activation of this pathway is observed in 20%-40% of hepatocellular carcinomas (HCC). Notum encodes a secreted Wnt deacylase that inhibits Wnt activity and thereby restricts the zone of activation of Wnt/beta-catenin signaling. An important role of NOTUM has been described in development in drosophila, planaria and zebrafish, but its role in the mammalian liver is unknown. Notum is required for spatial control of the Wnt/beta-catenin signaling in several animal models and the Wnt/beta-catenin pathway contributes to liver patterning involved in metabolic zonation. Therefore, Notum may be involved in the liver patterning induced by the Wnt/beta catenin signaling during the adult stage. METHODOLOGY/PRINCIPAL FINDINGS: We generated a conditional Notum knockout mouse mutant to study the effect of the deletion of Notum in the liver. We show that Notum is a direct target of the Wnt/beta-catenin signaling in the liver. Liver-specific deletion of Notum did not modify liver zonation, but Notum deletion had a long-term effect on mouse physiology. In particular, male mutant mice developed metabolic disorders. CONCLUSION: We show that Notum is not a key actor of Wnt/beta-catenin-dependent liver patterning of adult mice, but has role in liver glucose homeostasis. Male mice deficient in Notum specifically in the liver develop metabolic dysfunctions implicating Notum in the development of Type 2 diabetes. PMID- 26974337 TI - Synthesis, Structure, and Basic Magnetic and Thermoelectric Properties of the Light Lanthanide Aurobismuthides. AB - We report the crystal structures and elementary properties of the new aurobismuthides La3Au3Bi4, Ce3Au3Bi4, Pr3Au3Bi4, Nd3Au3Bi4, Sm3Au3Bi4, and Gd3Au3Bi4. These ternary compounds are found only for the large lanthanides and crystallize in the cubic Y3Au3Sb4 structure type, which is a stuffed Th3P4-type derivative. The compounds are electron-precise, leading to semiconducting behavior, and display magnetic properties arising from localized lanthanide f states. Resistivity data, Seebeck coefficient measurements, and electronic structure calculations suggest that these phases are heavily doped, p-type semiconductors. Nd3Au3Bi4 and Sm3Au3Bi4 have Seebeck coefficients of 105 and 190 MUV/K at 350 K, respectively, making them worthy of further thermoelectric studies. PMID- 26974336 TI - A Hepatocellular Carcinoma Aggressiveness Index and Its Relationship to Liver Enzyme Levels. AB - BACKGROUND: Prognosis in hepatocellular carcinoma (HCC) is influenced by both liver and tumor factors, which have been considered independent influences. However, recent evidence has shown that the underlying liver also has prognostic information. AIMS: To investigate possible relationships between liver function parameters and HCC aggressiveness indices. METHODS: A large HCC patient database with baseline clinical information and survival data was retrospectively examined. RESULTS: Data on 756 HCC patients with normal bilirubin were examined for a relationship between serum liver enzymes and 4 HCC aggressiveness indices of maximum tumor diameter, portal vein invasion, tumor multifocality or serum alpha-fetoprotein levels. An association was found between elevated enzyme levels and increased HCC aggressiveness. An aggressiveness index was constructed from the 4 indices and expressed as a sum of their scores, which in turn reflected 3 survival groups. In a Cox model, the hazard ratios for each of the groups were significantly different. CONCLUSIONS: Statistically significant correlations were found between standard liver function parameters and HCC aggressiveness. A composite aggressiveness index was constructed, yielding 3 groups with different survival probabilities. These findings support the concept of the importance of the underlying liver in relation to HCC biology. PMID- 26974335 TI - Prevalence and Risk Factors for Intestinal Protozoan Infections with Cryptosporidium, Giardia, Blastocystis and Dientamoeba among Schoolchildren in Tripoli, Lebanon. AB - BACKGROUND: Intestinal protozoan infections are confirmed as major causes of diarrhea, particularly in children, and represent a significant, but often neglected, threat to public health. No recent data were available in Lebanon concerning the molecular epidemiology of protozoan infections in children, a vulnerable population at high risk of infection. METHODOLOGY AND PRINCIPAL FINDINGS: In order to improve our understanding of the epidemiology of intestinal pathogenic protozoa, a cross-sectional study was conducted in a general pediatric population including both symptomatic and asymptomatic subjects. After obtaining informed consent from the parents or legal guardians, stool samples were collected in January 2013 from 249 children in 2 schools in Tripoli, Lebanon. Information obtained from a standard questionnaire included demographic characteristics, current symptoms, socioeconomic status, source of drinking water, and personal hygiene habits. After fecal examination by both microscopy and molecular tools, the overall prevalence of parasitic infections was recorded as 85%. Blastocystis spp. presented the highest infection rate (63%), followed by Dientamoeba fragilis (60.6%), Giardia duodenalis (28.5%) and Cryptosporidium spp. (10.4%). PCR was also performed to identify species and genotypes of Cryptosporidium, subtypes of Blastocystis, and assemblages of Giardia. Statistical analysis using a logistic regression model showed that contact with family members presenting gastrointestinal disorders was the primary risk factor for transmission of these protozoa. CONCLUSIONS: This is the first study performed in Lebanon reporting the prevalence and the clinical and molecular epidemiological data associated with intestinal protozoan infections among schoolchildren in Tripoli. A high prevalence of protozoan parasites was found, with Blastocystis spp. being the most predominant protozoans. Although only 50% of children reported digestive symptoms, asymptomatic infection was observed, and these children may act as unidentified carriers. This survey provides necessary information for designing prevention and control strategies to reduce the burden of these protozoan infections, especially in children. PMID- 26974338 TI - Emission-Tunable Multicolor Graphene Molecules with Controllable Synthesis, Excellent Optical Properties, and Specific Applications. AB - Series of graphene molecules with varied emission colors have been prepared by oxidative cyclodehydrogenation using anhydrous ferric chloride (FeCl3) as the catalyst under mild conditions. By controlling the oxidation time in the initial step only, molecules with different fluorescence colors are conveniently obtained. New colors can be recorded evidently because of the stepwise and controllable process, which highly related to the conjugation length. Blue emissive starting compounds in the solid state can be transformed into orange upon brief oxidation, whereas green emissive oligomers are varied to red with an emission wavelength redshift about 123 nm. Cyclic voltammetry measurements performed can give the corresponding data, which verify the results drawn from the UV and PL spectroscope. The gradual change of conjugation length with tunable emission is confirmed in the MALDI-TOF study as well. Further characterizations indicate that the graphene molecules possess satisfactory optical properties, which are highly emissive both in solution and in the solid state because of the alkyl group. In addition, the good thermal stability and the self-assembly of graphene molecules suggest that they are promising candidates for high-tech applications. Furthermore, the fabricated field-effect transistors possess the nice performance, whose mobilities are about 0.57 cm(2) V(-1) s(-1) with an on off ratio of 1 * 10(4) and 0.81 cm(2) V(-1) s(-1) with an on-off ratio of 1 * 10(3), respectively. PMID- 26974339 TI - Study of Class I and Class III Polyhydroxyalkanoate (PHA) Synthases with Substrates Containing a Modified Side Chain. AB - Polyhydroxyalkanoates (PHAs) are carbon and energy storage polymers produced by a variety of microbial organisms under nutrient-limited conditions. They have been considered as an environmentally friendly alternative to oil-based plastics due to their renewability, versatility, and biodegradability. PHA synthase (PhaC) plays a central role in PHA biosynthesis, in which its activity and substrate specificity are major factors in determining the productivity and properties of the produced polymers. However, the effects of modifying the substrate side chain are not well understood because of the difficulty to accessing the desired analogues. In this report, a series of 3-(R)-hydroxyacyl coenzyme A (HACoA) analogues were synthesized and tested with class I synthases from Chromobacterium sp. USM2 (PhaCCs and A479S-PhaCCs) and Caulobacter crescentus (PhaCCc) as well as class III synthase from Allochromatium vinosum (PhaECAv). It was found that, while different PHA synthases displayed distinct preference with regard to the length of the alkyl side chains, they could withstand moderate side chain modifications such as terminal unsaturated bonds and the azide group. Specifically, the specific activity of PhaCCs toward propynyl analogue (HHxyCoA) was only 5-fold less than that toward the classical substrate HBCoA. The catalytic efficiency (kcat/Km) of PhaECAv toward azide analogue (HABCoA) was determined to be 2.86 * 10(5) M(-1) s(-1), which was 6.2% of the value of HBCoA (4.62 * 10(6) M(-1) s(-1)) measured in the presence of bovine serum albumin (BSA). These side chain modifications may be employed to introduce new material functions to PHAs as well as to study PHA biogenesis via click-chemistry, in which the latter remains unknown and is important for metabolic engineering to produce PHAs economically. PMID- 26974340 TI - Allogeneic Haematopoietic Stem Cell Recipients Admitted to the Intensive Care Unit: Survival and Prognosis. PMID- 26974341 TI - Precise regulation of the guidance receptor DMA-1 by KPC-1/Furin instructs dendritic branching decisions. AB - Extracellular adhesion molecules and their neuronal receptors guide the growth and branching of axons and dendrites. Growth cones are attracted to intermediate targets, but they must switch their response upon arrival so that they can move away and complete the next stage of growth. Here, we show that KPC-1, a C. elegans Furin homolog, regulates the level of the branching receptor DMA-1 on dendrites by targeting it to late endosomes. In kpc-1 mutants, the level of DMA-1 is abnormally high on dendrites, resulting in trapping of dendrites at locations where a high level of the cognate ligand, the adhesion molecule SAX-7/L1, is present. The misregulation of DMA-1 also causes dendritic self-avoidance defects. Thus, precise regulation of guidance receptors creates flexibility of responses to guidance signals and is critical for neuronal morphogenesis. PMID- 26974342 TI - GSK3beta regulates AKT-induced central nervous system axon regeneration via an eIF2Bepsilon-dependent, mTORC1-independent pathway. AB - Axons fail to regenerate after central nervous system (CNS) injury. Modulation of the PTEN/mTORC1 pathway in retinal ganglion cells (RGCs) promotes axon regeneration after optic nerve injury. Here, we report that AKT activation, downstream of Pten deletion, promotes axon regeneration and RGC survival. We further demonstrate that GSK3beta plays an indispensable role in mediating AKT induced axon regeneration. Deletion or inactivation of GSK3beta promotes axon regeneration independently of the mTORC1 pathway, whereas constitutive activation of GSK3beta reduces AKT-induced axon regeneration. Importantly, we have identified eIF2Bepsilon as a novel downstream effector of GSK3beta in regulating axon regeneration. Inactivation of eIF2Bepsilon reduces both GSK3beta and AKT mediated effects on axon regeneration. Constitutive activation of eIF2Bepsilon is sufficient to promote axon regeneration. Our results reveal a key role of the AKT GSK3beta-eIF2Bepsilon signaling module in regulating axon regeneration in the adult mammalian CNS. PMID- 26974343 TI - Rhodopsin targeted transcriptional silencing by DNA-binding. AB - Transcription factors (TFs) operate by the combined activity of their DNA-binding domains (DBDs) and effector domains (EDs) enabling the coordination of gene expression on a genomic scale. Here we show that in vivo delivery of an engineered DNA-binding protein uncoupled from the repressor domain can produce efficient and gene-specific transcriptional silencing. To interfere with RHODOPSIN (RHO) gain-of-function mutations we engineered the ZF6-DNA-binding protein (ZF6-DB) that targets 20 base pairs (bp) of a RHOcis-regulatory element (CRE) and demonstrate Rho specific transcriptional silencing upon adeno associated viral (AAV) vector-mediated expression in photoreceptors. The data show that the 20 bp-long genomic DNA sequence is necessary for RHO expression and that photoreceptor delivery of the corresponding cognate synthetic trans-acting factor ZF6-DB without the intrinsic transcriptional repression properties of the canonical ED blocks Rho expression with negligible genome-wide transcript perturbations. The data support DNA-binding-mediated silencing as a novel mode to treat gain-of-function mutations. PMID- 26974344 TI - Localized JNK signaling regulates organ size during development. AB - A fundamental question of biology is what determines organ size. Despite demonstrations that factors within organs determine their sizes, intrinsic size control mechanisms remain elusive. Here we show that Drosophila wing size is regulated by JNK signaling during development. JNK is active in a stripe along the center of developing wings, and modulating JNK signaling within this stripe changes organ size. This JNK stripe influences proliferation in a non-canonical, Jun-independent manner by inhibiting the Hippo pathway. Localized JNK activity is established by Hedgehog signaling, where Ci elevates dTRAF1 expression. As the dTRAF1 homolog, TRAF4, is amplified in numerous cancers, these findings provide a new mechanism for how the Hedgehog pathway could contribute to tumorigenesis, and, more importantly, provides a new strategy for cancer therapies. Finally, modulation of JNK signaling centers in developing antennae and legs changes their sizes, suggesting a more generalizable role for JNK signaling in developmental organ size control. PMID- 26974345 TI - Mixed-mode oscillations and population bursting in the pre-Botzinger complex. AB - This study focuses on computational and theoretical investigations of neuronal activity arising in the pre-Botzinger complex (pre-BotC), a medullary region generating the inspiratory phase of breathing in mammals. A progressive increase of neuronal excitability in medullary slices containing the pre-BotC produces mixed-mode oscillations (MMOs) characterized by large amplitude population bursts alternating with a series of small amplitude bursts. Using two different computational models, we demonstrate that MMOs emerge within a heterogeneous excitatory neural network because of progressive neuronal recruitment and synchronization. The MMO pattern depends on the distributed neuronal excitability, the density and weights of network interconnections, and the cellular properties underlying endogenous bursting. Critically, the latter should provide a reduction of spiking frequency within neuronal bursts with increasing burst frequency and a dependence of the after-burst recovery period on burst amplitude. Our study highlights a novel mechanism by which heterogeneity naturally leads to complex dynamics in rhythmic neuronal populations. PMID- 26974346 TI - Serotonin modulates insect hemocyte phagocytosis via two different serotonin receptors. AB - Serotonin (5-HT) modulates both neural and immune responses in vertebrates, but its role in insect immunity remains uncertain. We report that hemocytes in the caterpillar, Pieris rapae are able to synthesize 5-HT following activation by lipopolysaccharide. The inhibition of a serotonin-generating enzyme with either pharmacological blockade or RNAi knock-down impaired hemocyte phagocytosis. Biochemical and functional experiments showed that naive hemocytes primarily express 5-HT1B and 5-HT2B receptors. The blockade of 5-HT1B significantly reduced phagocytic ability; however, the blockade of 5-HT2B increased hemocyte phagocytosis. The 5-HT1B-null Drosophila melanogaster mutants showed higher mortality than controls when infected with bacteria, due to their decreased phagocytotic ability. Flies expressing 5-HT1B or 5-HT2B RNAi in hemocytes also showed similar sensitivity to infection. Combined, these data demonstrate that 5 HT mediates hemocyte phagocytosis through 5-HT1B and 5-HT2B receptors and serotonergic signaling performs critical modulatory functions in immune systems of animals separated by 500 million years of evolution. PMID- 26974349 TI - Synthesis of Aryl Amine Derivatives from Benzyl Nitriles via Electrocyclization of in Situ Generated N-Silyl Ketene Imines. AB - The previously unexplored reactivity of N-silyl ketene imines in organic synthesis is reported. Benzyl nitriles containing an alkenyl or aryl group at the ortho position were smoothly converted into aryl amines in good yields under two sets of mild silylation conditions: (1) nonbasic conditions using TMSNTf2-iPr2NEt or (2) basic anionic conditions using lithium diisopropylamide-triisopropylsilyl chloride (LDA-TIPSCl). The reaction probably proceeds via in situ generation of an N-silyl ketene imine followed by 6pi-electrocyclization and aromatization. PMID- 26974348 TI - Hydrogenation of Aldehydes Catalyzed by an Available Ruthenium Complex. AB - A readily available ruthenium(II) catalyst was developed for the catalytic hydrogenation of aldehydes with a TON (turnover number) up to 340000. It can be performed without base and solvent, showing highly industrial potential. High chemoselectivity can be achieved in the presence of alkenyl and ketone groups. Further application of this protocol in glucose reduction showed good efficiency. Theoretical studies revealed that the rate-determining step is the hydrogenation step, not the carboxylate-assisted H2 activation step. PMID- 26974347 TI - Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit. AB - The nucleus of the solitary tract (NTS) is a key gateway for meal-related signals entering the brain from the periphery. However, the chemical mediators crucial to this process have not been fully elucidated. We reveal that a subset of NTS neurons containing cholecystokinin (CCK(NTS)) is responsive to nutritional state and that their activation reduces appetite and body weight in mice. Cell-specific anterograde tracing revealed that CCK(NTS) neurons provide a distinctive innervation of the paraventricular nucleus of the hypothalamus (PVH), with fibers and varicosities in close apposition to a subset of melanocortin-4 receptor (MC4R(PVH)) cells, which are also responsive to CCK. Optogenetic activation of CCK(NTS) axon terminals within the PVH reveal the satiating function of CCK(NTS) neurons to be mediated by a CCK(NTS)->PVH pathway that also encodes positive valence. These data identify the functional significance of CCK(NTS) neurons and reveal a sufficient and discrete NTS to hypothalamus circuit controlling appetite. PMID- 26974350 TI - Extracellular Calpain/Calpastatin Balance Is Involved in the Progression of Pulmonary Hypertension. AB - Excessive growth of pulmonary arterial (PA) smooth muscle cells (SMCs) is a major component of PA hypertension (PAH). The calcium-activated neutral cysteine proteases calpains 1 and 2, expressed by PASMCs, contribute to PH but are tightly controlled by a single specific inhibitor, calpastatin. Our objective was to investigate calpastatin during pulmonary hypertension (PH) progression and its potential role as an intracellular and/or extracellular effector. We assessed calpains and calpastatin in patients with idiopathic PAH and mice with hypoxic or spontaneous (SM22-5HTT(+) strain) PH. To assess intracellular and extracellular roles for calpastatin, we studied effects of the calpain inhibitor PD150606 on hypoxic PH in mice with calpastatin overexpression driven by the cytomegalovirus promoter (CMV-Cast) or C-reactive protein (CRP) promoter (CRP-Cast), inducing increased calpastatin production ubiquitously and in the liver, respectively. Chronically hypoxic and SM22-5HTT(+) mice exhibited increased lung calpastatin and calpain 1 and 2 protein levels and activity, both intracellularly and extracellularly. Prominent calpastatin and calpain immunostaining was found in PASMCs of remodeled vessels in mice and patients with PAH, who also exhibited increased plasma calpastatin levels. CMV-Cast and CRP-Cast mice showed similarly decreased PH severity compared with wild-type mice, with no additional effect of PD150606 treatment. In cultured PASMCs from wild-type and CMV-Cast mice, exogenous calpastatin decreased cell proliferation and migration with similar potency as PD150606 and suppressed fibronectin-induced potentiation. These results indicate that calpastatin limits PH severity via extracellular mechanisms. They suggest a new approach to the development of treatments for PH. PMID- 26974351 TI - Binding Mode and Induced Fit Predictions for Prospective Computational Drug Design. AB - Computer-aided drug design plays an important role in medicinal chemistry to obtain insights into molecular mechanisms and to prioritize design strategies. Although significant improvement has been made in structure based design, it still remains a key challenge to accurately model and predict induced fit mechanisms. Most of the current available techniques either do not provide sufficient protein conformational sampling or are too computationally demanding to fit an industrial setting. The current study presents a systematic and exhaustive investigation of predicting binding modes for a range of systems using PELE (Protein Energy Landscape Exploration), an efficient and fast protein-ligand sampling algorithm. The systems analyzed (cytochrome P, kinase, protease, and nuclear hormone receptor) exhibit different complexities of ligand induced fit mechanisms and protein dynamics. The results are compared with results from classical molecular dynamics simulations and (induced fit) docking. This study shows that ligand induced side chain rearrangements and smaller to medium backbone movements are captured well in PELE. Large secondary structure rearrangements, however, remain challenging for all employed techniques. Relevant binding modes (ligand heavy atom RMSD < 1.0 A) can be obtained by the PELE method within a few hours of simulation, positioning PELE as a tool applicable for rapid drug design cycles. PMID- 26974352 TI - Protein homeostasis-more than resisting a hot bath. AB - Maintenance of protein homeostasis is essential for survival of all organisms. In bacteria, the protein quality control system has a broad physiological impact beyond heat shock resistance, being involved in virulence, antibiotic resistance, as well as protection against environmental stresses. Its contribution to rejuvenation and growth arrest suggests interference with protein quality control to be a novel antimicrobial strategy. Remarkably, a protein quality control module originating from environmental strains has been found to be horizontally transferred to predominant clonal groups of bacteria providing exquisite thermotolerance to recently emerged global pathogens suggesting that novel features related to protein homeostasis contribute to the transition to new environments. PMID- 26974353 TI - Reproductive Life Planning and Preconception Care 2015: Attitudes of English Speaking Family Planning Patients. AB - BACKGROUND: Reproductive life planning has become an essential element in programs designed to promote preconceptional care and increase utilization of effective contraceptive methods. This study sought to determine if women have reproductive life plans and what they think women should do to prepare for pregnancy. MATERIALS AND METHODS: Indigent English-speaking women in a family planning clinic were asked individually about their reproductive life plans, preparations needed for pregnancy, and the relative health risks of pregnancy compared to oral contraceptives. RESULTS: Of the 250 women interviewed, only 53% were confident how many pregnancies they wanted in their lifetime; 46.3% were confident about when they desired their next pregnancy. Although virtually all agreed that women should plan and prepare for pregnancy, only 25.8% of women mentioned that any medical preparations were necessary before pregnancy. Women's choice of contraception did not match their pregnancy intentions. Over 60% of women thought that the pill was at least as hazardous to a woman's health as pregnancy. CONCLUSIONS: In this study, many English-speaking women had no distinct reproductive life plans. Most did not think that medical preparations are needed before pregnancy. New approaches may be useful to more productively identify women who need individualized counseling, preconception care, and/or more effective contraceptive methods. PMID- 26974354 TI - Antitumor polysaccharides from mushrooms: a review on the structural characteristics, antitumor mechanisms and immunomodulating activities. AB - Mushrooms are popular folk medicines that have attracted considerable attention because of their efficient antitumor activities. This review covers existing research achievements on the mechanisms of isolated mushroom polysaccharides, particularly (1->3)-beta-D-glucans. Our review also describes the function in modulating the immune system and potential tumor-inhibitory effects of polysaccharides. The antitumor mechanisms of mushroom polysaccharides are mediated by stimulated T cells or other immune cells. These polysaccharides are able to trigger various cellular responses, such as the expression of cytokines and nitric oxide. Most polysaccharides could bind other conjugate molecules, such as polypeptides and proteins, whose conjugation always possess strong antitumor activities. The purpose of this review is to summarize available information, and to reflect the present situation of polysaccharide research filed with a view for future direction. PMID- 26974355 TI - Synthesis of water soluble glycosides of pentacyclic dihydroxytriterpene carboxylic acids as inhibitors of alpha-glucosidase. AB - A series of compounds were synthesized by glycosylation of maslinic acid (MA) and corosolic acid (CA) with monosaccharides and disaccharides, and the structures of the derivatives were elucidated by standard spectroscopic methods including (1)H NMR, (13)C NMR and HRMS. The alpha-glucosidase inhibitory activities of all the novel compounds were evaluated in vitro. The solubility and inhibitory activity of alpha-glucosidase assays showed that the bis-disaccharide glycosides of triterpene acids possessed higher water solubility and alpha-glucosidase inhibitory activities than the bis-monosaccharide glycosides. Among these compounds, maslinic acid bis-lactoside (8e, IC50 = 684 uM) and corosolic acid bis lactoside (9e, IC50 = 428 uM) had the best water solubility, and 9e exhibited a better inhibitory activity than acarbose (IC50 = 478 uM). However, most of glycosylated derivatives possessed lower inhibitory activities than the parent compounds, although their water solubility was enhanced obviously. Moreover, the kinetic inhibition studies indicated that 9e was a non-competitive inhibitor, and structure-activity relationships of the derivatives are also discussed. PMID- 26974356 TI - Comparison between ensilage and fungal pretreatment for storage of giant reed and subsequent methane production. AB - Ensilage and fungal pretreatment of giant reed harvested from August through December were compared based on their effects on feedstock preservation, glucose yield, and subsequent methane production via anaerobic digestion (AD). Compared to fungal pretreatment, ensilage obtained lower total solids (<1.2%) and cellulose (<3.5%) losses, and comparable hemicellulose degradation, except for giant reed harvested in August. Ensilage increased glucose and methane yields by 7-15% and 4-14%, respectively, for giant reed harvested from August through December. Fungal pretreatment failed for giant reed harvested in August and October with reduced glucose yields, and was effective for that harvested in November and December, with about 20% increases in glucose yield. However, hydrocarbon losses during fungal pretreatment offset the increased glucose yield, resulting in decreased methane yields by AD. In summary, ensilage was found to be more suitable than fungal pretreatment for giant reed storage and its methane production via AD. PMID- 26974357 TI - Stillage reflux in food waste ethanol fermentation and its by-product accumulation. AB - Raw materials and pollution control are key issues for the ethanol fermentation industry. To address these concerns, food waste was selected as fermentation substrate, and stillage reflux was carried out in this study. Reflux was used seven times during fermentation. Corresponding ethanol and reducing sugar were detected. Accumulation of by-products, such as organic acid, sodium chloride, and glycerol, was investigated. Lactic acid was observed to accumulate up to 120g/L, and sodium chloride reached 0.14mol/L. Other by-products did not accumulate. The first five cycles of reflux increased ethanol concentration, which prolonged fermentation time. Further increases in reflux time negatively influenced ethanol fermentation. Single-factor analysis with lactic acid and sodium chloride demonstrated that both factors affected ethanol fermentation, but lactic acid induced more effects. PMID- 26974358 TI - Imidazolium-tagged glycan probes for non-covalent labeling of live cells. AB - Selective, bioorthogonal and fast labeling of glycoconjugates in living cells is a major challenge for synthetic and cellular biology. Here we report the use imidazolium tagged-mannosamine derivative (ITag-Man) for the non-covalent, rapid and site-specific labeling of sialic acid containing glycoproteins using commercial N-nitrilotriacetate fluorescent reagents in a range of cell lines. PMID- 26974359 TI - Childhood Psychosocial Factors and Coronary Artery Calcification in Adulthood: The Cardiovascular Risk in Young Finns Study. AB - IMPORTANCE: There is increasing evidence supporting the importance of psychosocial factors in the pathophysiology of atherosclerotic disease. They have been shown to be associated with the population attributable risk for myocardial infarction. OBJECTIVE: To determine if a score of favorable childhood psychosocial factors would be associated with decreased coronary artery calcification in adulthood. DESIGN, SETTING, AND PARTICIPANTS: The analyses were performed in 2015 using data gathered in 1980 and 2008 within the longitudinal Cardiovascular Risk in Young Finns Study. The data source consisted of 311 individuals who had psychosocial factors measured at ages 12 years to 18 years and coronary artery calcification measured 28 years later in adulthood. The summary measure of psychosocial factors in childhood comprised measures of socioeconomic factors, emotional factors, parental health behaviors, stressful events, self-regulation of the child, and social adjustment of the child. MAIN OUTCOMES AND MEASURES: Coronary artery calcification at ages 40 years to 46 years. RESULTS: Of the 311 participants, 48.2% were men. Of the participants, 55 (17.7%) had some calcium observed in their coronary arteries. A 1-SD increase in a favorable summary score of childhood psychological factors was associated with an adulthood coronary artery calcification probability of 0.85 (95% CI, 0.76 0.95) (P = .006). This inverse relationship remained significant after adjustment for age, sex, and conventional childhood risk factors (0.85; 95% CI, 0.74-0.97; P = .02) or for age, sex, adulthood conventional cardiovascular risk factors, socioeconomic status, social support, and depressive symptoms (0.83; 95% CI, 0.71 0.97; P = .02). CONCLUSIONS AND RELEVANCE: In this longitudinal study, we observed an independent association between childhood psychosocial well-being and reduced coronary artery calcification in adulthood. A positive childhood psychosocial environment may decrease cardiovascular risk in adulthood and may represent a potentially modifiable risk determinant. PMID- 26974360 TI - Organic Reference Materials for Hydrogen, Carbon, and Nitrogen Stable Isotope Ratio Measurements: Caffeines, n-Alkanes, Fatty Acid Methyl Esters, Glycines, L Valines, Polyethylenes, and Oils. AB - An international project developed, quality-tested, and determined isotope-delta values of 19 new organic reference materials (RMs) for hydrogen, carbon, and nitrogen stable isotope-ratio measurements, in addition to analyzing pre-existing RMs NBS 22 (oil), IAEA-CH-7 (polyethylene foil), and IAEA-600 (caffeine). These new RMs enable users to normalize measurements of samples to isotope-delta scales. The RMs span a range of delta(2)H(VSMOW-SLAP) values from -210.8 to +397.0 mUr or 0/00, for delta(13)C(VPDB-LSVEC) from -40.81 to +0.49 mUr and for delta(15)N(Air) from -5.21 to +61.53 mUr. Many of the new RMs are amenable to gas and liquid chromatography. The RMs include triads of isotopically contrasting caffeines, C16 n-alkanes, n-C20-fatty acid methyl esters (FAMEs), glycines, and l valines, together with polyethylene powder and string, one n-C17-FAME, a vacuum oil (NBS 22a) to replace NBS 22 oil, and a (2)H-enriched vacuum oil. A total of 11 laboratories from 7 countries used multiple analytical approaches and instrumentation for 2-point isotopic normalization against international primary measurement standards. The use of reference waters in silver tubes allowed direct normalization of delta(2)H values of organic materials against isotopic reference waters following the principle of identical treatment. Bayesian statistical analysis yielded the mean values reported here. New RMs are numbered from USGS61 through USGS78, in addition to NBS 22a. Because of exchangeable hydrogen, amino acid RMs currently are recommended only for carbon- and nitrogen-isotope measurements. Some amino acids contain (13)C and carbon-bound organic (2)H enrichments at different molecular sites to provide RMs for potential site specific isotopic analysis in future studies. PMID- 26974361 TI - Time to overcome fluconazole resistant Candida isolates: Solid lipid nanoparticles as a novel antifungal drug delivery system. AB - Antifungal therapy results in complications in management due to changes in the patterns of epidemiology and drug susceptibility of invasive fungal infections. In this study, we prepared fluconazole-loaded solid lipid nanoparticles (FLZ SLNs) and investigated the efficacy of the optimal formulation on fluconazole (FLZ)-resistant strains of several Candida species. FLZ-SLN was produced using probe ultrasonication techniques. The morphology of the obtained SLNs was characterized by field emission scanning electron microscopy. The minimum inhibitory concentrations for the new formulations against fluconazole-resistant strains of Candida were investigated using CLSI document M27-A3. The FLZ-SLNs presented a spherical shape with a mean diameter, zeta potential and entrapment efficiency of 84.8nm, -25mV and 89.6%, respectively. The drug release from FLZ SLNs exhibited burst release behaviour at the initial stage (the first 30min) followed by a sustained release over 24h FLZ-resistant yeast strains behaved as susceptible strains after treatment with FLZ-SLNs (<=8MUg/ml). The MIC50 drug concentrations were 2MUg/ml, 1MUg/ml and 2MUg/ml for FLZ-resistant strains of Candida albicans, Candida parapsilosis and Candida glabrata, respectively. In this study, we evaluated novel delivery systems for combating Candida strains that exhibit low susceptibility against the conventional formulation of FLZ as a first-line treatment. PMID- 26974362 TI - Exposure to particulate matter in India: A synthesis of findings and future directions. AB - Air pollution poses a critical threat to human health with ambient and household air pollution identified as key health risks in India. While there are many studies investigating concentration, composition, and health effects of air pollution, investigators are only beginning to focus on estimating or measuring personal exposure. Further, the relevance of exposures studies from the developed countries in developing countries is uncertain. This review summarizes existing research on exposure to particulate matter (PM) in India, identifies gaps and offers recommendations for future research. There are a limited number of studies focused on exposure to PM and/or associated health effects in India, but it is evident that levels of exposure are much higher than those reported in developed countries. Most studies have focused on coarse aerosols, with a few studies on fine aerosols. Additionally, most studies have focused on a handful of cities, and there are many unknowns in terms of ambient levels of PM as well as personal exposure. Given the high mortality burden associated with air pollution exposure in India, a deeper understanding of ambient pollutant levels as well as source strengths is crucial, both in urban and rural areas. Further, the attention needs to expand beyond the handful large cities that have been studied in detail. PMID- 26974363 TI - Lead in candy consumed and blood lead levels of children living in Mexico City. AB - BACKGROUND: Recent studies have shown that lead exposure continues to pose a health risk in Mexico. Children are a vulnerable population for lead effects and Mexican candy has been found to be a source of exposure in children. There are no previous studies that estimates lead concentrations in candy that children living in Mexico City consume and its association with their blood lead level. OBJECTIVES: To evaluate whether there is an association between reported recent consumption of candies identified to have lead, and blood lead levels among children in Mexico City. METHODS: A subsample of 171 children ages 2-6 years old, from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohort study was assessed between June 2006 and July 2007. The candy reported most frequently were analyzed for lead using ICP-MS. The total weekly intake of lead through the consumption of candy in the previous week was calculated. Capillary blood lead levels (BLL) were measured using LeadCare (anodic stripping voltammetry). RESULTS: Lead concentrations >=0.1ppm, the FDA permitted level (range: 0.13-0.7ppm) were found in 6 samples out of 138 samples from 44 different brands of candy. Median BLL in children was 4.5ug/dl. After adjusting for child's sex, age, BMI, maternal education & occupation, milk consumption, sucking the candy wrapper, use of lead-glazed pottery, child exposure behavior, living near a lead exposure site and use of folk remedies, an increase of 1ug of lead ingested through candy per week was associated with 3% change (95% CI: 0.1%, 5.2%) in BLL. CONCLUSIONS: Although lead concentrations in candy were mostly below the FDA permitted level, high lead concentrations were detected in 4% of the candy samples and 12% of brands analyzed. Although candy intake was modestly associated with children's BLL, lead should not be found in consumer products, especially in candy that children can consume due to the well documented long-lasting effect of lead exposure. PMID- 26974364 TI - Analysis of the presence of perfluoroalkyl substances in water, sediment and biota of the Jucar River (E Spain). Sources, partitioning and relationships with water physical characteristics. AB - The presence, sources and partitioning of 21 perfluoroalkyl substances (PFASs: C4 C14, C16, C18 carboxylate, C4, C6-C10 sulfonates and C8 sulfonamide) were assessed in water, sediment, and biota of the Jucar River basin (E Spain). Considering the three matrices, perfluoropentanoate (PFPeA) and perfluorooctane sulfonate (PFOS) were the most frequent compounds, being remarkable the high occurrence of short-chain PFASs (C<=8), which are intended to replace the long chain ones in several industrial and commercial applications. In general, all samples were contaminated with at least one PFAS, with the exception of three fish samples. Mean concentrations detected in sediments (0.22-11.5ng g(-1)) and biota (0.63-274ugkg(-1)) samples were higher than those measured in water (0.04 83.1ngL(-1)), which might suggest (bio) accumulation. The occurrence of PFAS is related to urban and industrial discharges (Cuenca city in the upper part of basin, and car's factory, and effluents of the sewage treatment plant (STP) of Alzira, in the lower part). Increasing pollution gradients were found. On the other hand, higher contamination levels were observed after regulation dams of the catchment pointing out their importance in the re-distribution of these contaminants. None of the hazard quotients (HQ) calculated indicate potential risk for the different tropic levels considered (algae, Daphnia sp. and fish). PFAS concentrations found in this study can be considered in acceptable levels if compared to existing Regulatory Legislation and, consequently, they do not pose an immediate human health risk. PMID- 26974365 TI - Juvenile penalty or leniency: Sentencing of juveniles in the criminal justice system. AB - The purpose of this study is to examine the impact of being juvenile on sentencing in the criminal justice system. More specifically, youth transferred to criminal court are compared to adults in terms of likelihood of incarceration, jail length, and prison length. In this study, 2 national data sets are merged. The juvenile sample includes 3,381 convicted offenders, and the adult sample is comprised of 6,529 convicted offenders. The final sample is 9,910 offenders across 36 U.S. counties. The key independent variable is juvenile status, and the dependent variables are incarceration, jail length, and prison length. Because of the multilevel nature of the data, hierarchical linear modeling is used across all models. Juveniles are punished less severely in the jail incarceration decision. However, when youth are actually sentenced to incarceration (either jail or prison), they are given longer confinement time than adults. (PsycINFO Database Record PMID- 26974366 TI - Criminal thought process as a dynamic risk factor: Variable- and person-oriented approaches to recidivism prediction. AB - The research question addressed in this study was whether an increase in criminal thought process predicted elevated risk for recidivism in a community sample of offenders. Using a 1-year change on the General Criminal Thinking (GCT) score of the Psychological Inventory of Criminal Thinking Styles (PICTS) as the independent variable, time until first arrest following a second administration of the GCT as the dependent variable, and age, criminal history, race, and ethnicity as control variables, the effect of an elevated GCT score on subsequent recidivism was tested in 35,147 male and 5,254 female federal probationers and supervised releases. Separate analyses were conducted on male and female participants. The results revealed that a rise in GCT was an incrementally valid predictor of time until first arrest in both men and women after controlling for age, criminal history, and race/ethnicity (variable-oriented analysis) and predicted the presence of a subsequent arrest during a 1-year follow-up in men regardless of initial GCT score and in women with a low initial GCT score (person oriented analysis). Although the effect sizes were, for the most part, small, they nonetheless demonstrated both clinical and statistical significance, thereby supporting the supposition that criminal thought process, as measured by the PICTS GCT score, is a dynamic risk factor. (PsycINFO Database Record PMID- 26974367 TI - Treatment of Thymoma-Associated Myasthenia Gravis With Stereotactic Body Radiotherapy: A Case Report. PMID- 26974368 TI - Caring for Coronary Artery Disease in China: Managing Modernization. PMID- 26974369 TI - Evaluation of toxicity on epithelial and tumor cells of biaryl dipeptide tyrosines. AB - We report a method to obtain biaryl dipeptide tyrosine via Suzuki-Miyaura and alkynyl dipeptide tyrosine by Sonogashira cross-coupling reactions. Analysis of the biological action of biaryl dipeptide tyrosine 4d compound showed its ability to impair the metabolism and proliferation of SK-Mel-28 human melanoma lineage cells, independently of mitochondrial membrane depolarization, apoptosis and necrosis. Moreover, 4d compound did not cause toxicity to human umbilical vein endothelial cells (HUVEC), suggesting its toxic specificity to cancer cells. PMID- 26974370 TI - Efficient synthesis and activity of beneficial intestinal flora of two lactulose derived oligosaccharides. AB - Lactulose is considered as a prebiotic because it promotes the intestinal proliferation of Lactobacillus acidophilus which is added to various milk products. Moreover, lactulose is used in pharmaceuticals as a gentle laxative and to treat hyperammonemia. This study was aimed at the total synthesis of two Lactulose-derived oligosaccharides: one is 3-O-beta-d-galactopyranosyl-d fructose, d-fructose and beta-d-galactose bounded together with beta-1,3 glycosidic bound, the other is 1-O-beta-d-galactopyranosyl-d-fructose, d-fructose and beta-d-galactose bounded together with beta-1,1-glycosidic bound, which were accomplished in seven steps from d-fructose and beta-d-galactose and every step of yield above 75%. This synthetic route provided a practical and effective synthetic strategy for galactooligosaccharides, starting from commercially available monosaccharides. Then we evaluated on their prebiotic properties in the search for potential agents of regulating and improving the intestinal flora of human. The result showed that the prebiotic properties of Lactulose-derived oligosaccharides was much better than Lactulose. Among them, 3-O-beta-d galactopyranosyl-d-fructose displayed the most potent activity of proliferation of L. acidophilus. PMID- 26974371 TI - Synthesis and biological evaluation of quinoline analogues of flavones as potential anticancer agents and tubulin polymerization inhibitors. AB - A new series of 2-aryl-trimethoxyquinoline analogues was designed and synthesized as tubulin inhibitors using methoxylated flavones as the lead compounds. The cytotoxic activity of the synthesized compounds was evaluated against four human cancer cell lines including MCF-7, MCF-7/MX, A-2780, and A-2780/RCIS. All the alcoholic derivatives (6a-6e) showed significant cytotoxic activity with IC50 in the range of 7.98-60 MUM. The flow cytometry analysis of the four human cancer cell lines treated with 6e and 5b showed that 6e induced cell cycle arrest at G2/M phase and apoptosis as well. The effect of quinolines on tubulin polymerization was also evaluated. Compound 6e that demonstrated the best antiproliferative activity in the series was identified as the most potent inhibitor of tubulin polymerization as well. Molecular docking studies of 6e into the colchicine-binding site of tubulin displayed possible mode of interaction between this compound and tubulin. PMID- 26974372 TI - Protective effects of kaempferol against reactive oxygen species-induced hemolysis and its antiproliferative activity on human cancer cells. AB - The protective effects of kaempferol against reactive oxygen species (ROS) induced hemolysis and its antiproliferative activity on human cancer cells were evaluated in this study. Kaempferol exhibited strong cellular antioxidant ability (CAA) with a CAA value of 59.80 +/- 0.379 MUM of quercetin (QE)/100 MUM (EC50 = 7.74 +/- 0.049 MUM). Pretreatment with kaempferol significantly attenuated the ROS-induced hemolysis of human erythrocyte (87.4% hemolysis suppressed at 100 MUg/mL) and reduced the accumulation of toxic lipid peroxidation product malondialdehyde (MDA). The anti-hemolytic activity of kaempferol was mainly through scavenging excessive ROS and preserving the intrinsic antioxidant enzymes (superoxide dismutase, SOD; catalase, CAT; and glutathione peroxidase, GPx) activities in normal levels. Additionally, kaempferol showed significant antiproliferative activity on a panel of human cancer cell lines including human breast carcinoma (MCF-7) cells, human stomach carcinoma (SGC-7901) cells, human cervical carcinoma (Hela) cells and human lung carcinoma (A549) cells. Kaemperol induced apoptosis of MCF-7 cells accompanied with nuclear condensation and mitochondria dysfunction. PMID- 26974374 TI - Structure of amyloid oligomers and their mechanisms of toxicities: Targeting amyloid oligomers using novel therapeutic approaches. AB - Protein misfolding is one of the leading causes of amyloidoses. Protein misfolding occurs from changes in environmental conditions and host of other factors, including errors in post-translational modifications, increase in the rate of degradation, error in trafficking, loss of binding partners and oxidative damage. Misfolding gives rise to the formation of partially unfolded or misfolded intermediates, which have exposed hydrophobic residues and interact with complementary intermediates to form oligomers and consequently protofibrils and fibrils. The amyloid fibrils accumulate as amyloid deposits in the brain and central nervous system in Alzheimer's disease (AD), Prion disease and Parkinson's disease (PD). Initial studies have shown that amyloid fibrils were the main culprit behind toxicity that cause neurodegenerative diseases. However, attention shifted to the cytotoxicity of amyloid fibril precursors, notably amyloid oligomers, which are the major cause of toxicity. The mechanism of toxicity triggered by amyloid oligomers remains elusive. In this review, we have focused on the current knowledge of the structures of different aggregated states, including amyloid fibril, protofibrils, annular aggregates and oligomers. Based on the studies on the mechanism of toxicities, we hypothesize two major possible mechanisms of toxicities instigated by oligomers of Abeta (amyloid beta), PrP (prion protein) (106-126), and alpha-Syn (alpha-synuclein) including direct formation of ion channels and neuron membrane disruption by the increase in membrane conductance or leakage in the presence of small globulomers to large prefibrillar assemblies. Finally, we have discussed various novel innovative approaches that target amyloid oligomers in Alzheimer's diseases, Prion disease and Parkinson's disease. PMID- 26974375 TI - Chroman-4-one and chromone based somatostatin beta-turn mimetics. AB - A scaffold approach has been used to develop somatostatin beta-turn mimetics based on chroman-4-one and chromone ring systems. Such derivatives could adopt conformations resembling type II or type II' beta-turns. Side chain equivalents of the crucial Trp8 and Lys9 in somatostatin were introduced in the 2- and 8 positions of the scaffolds using efficient reactions. Interestingly, this proof of-concept study shows that 4 and 9 have Ki-values in the low MUM range when evaluated for their affinity for the sst2 and sst4 receptors. PMID- 26974373 TI - Anticoagulant and antithrombotic activities of low-molecular-weight propylene glycol alginate sodium sulfate (PSS). AB - Propylene glycol alginate sodium sulfate (PSS), a sulfated polysaccharide derivative, has been used as a heparinoid drug to prevent and treat hyperlipidemia and ischemic cardio-cerebrovascular diseases in China for nearly 30 years. To extend the applications of PSS, a series of low-molecular-weight PSSs (named FPs) were prepared by oxidative-reductive depolymerization, and the antithrombotic activities were investigated thoroughly in vitro and in vivo. The bioactivity evaluation demonstrated a positive correlation between the molecular weight and the anticoagulant and antithrombotic activities of FPs. FPs could prolong the APTT and clotting time and reduce platelet aggregation significantly. FPs could also effectively inhibit factor IIa in the presence of AT-III and HC II. FPs decreased the wet weights and lengths of the thrombus and increased occlusion times in vivo. FP-6k, a PSS fragment with a molecular weight of 6 kDa, is an optimal antithrombotic candidate for further study and showed little chance for hemorrhagic action. PMID- 26974376 TI - Discovery of non-peptide small molecular CXCR4 antagonists as anti-HIV agents: Recent advances and future opportunities. AB - CXCR4 plays vital roles in HIV-1 life cycle for it's essential in mediating the interaction of host and virus and completing the entry process in the lifecycle of HIV-1 infection. Compared with some traditional targets, CXCR4 provides a novel and less mutated drug target in the battle against AIDS. Its antagonists have no cross resistance with other antagonists. Great achievements have been made recent years and a number of small molecular CXCR4 antagonists with diversity scaffolds have been discovered. In this review, recent advances in the discovery of CXCR4 antagonists with special attentions on their evolution and structure-activity relationships of representative CXCR4 antagonists are described. Moreover, some classical medicinal chemistry strategies and novel methodologies are also introduced. PMID- 26974377 TI - Indolyl-3-ethanone-alpha-thioethers: A promising new class of non-toxic antimalarial agents. AB - The success of chemotherapeutics in easing the burden of malaria is under continuous threat from ever-evolving parasite resistance, including resistance to artemisinin combination therapies. Therefore, the discovery of new classes of antimalarials which inhibit new biological targets is imperative to controlling malaria. Accordingly, we report here the discovery of indolyl-3-ethanone-alpha thioethers, a new class of antimalarial compounds with encouraging activity. Synthesis of a focused library of compounds revealed important insight into the SAR of this class of compounds, including critical information regarding the position and chemical nature of substituents on both the thiophenol and indole rings. This investigation ultimately led to the discovery of two hit compounds (16 and 27) which exhibited nano molar in vitro antimalarial activity coupled to no observable toxicity against a HeLa cell line. PMID- 26974378 TI - Synthesis and biological evaluation of novel tetrahydroisoquinoline-C-aryl glucosides as SGLT2 inhibitors for the treatment of type 2 diabetes. AB - A series of novel tetrahydroisoquinoline-C-aryl glucosides has been synthesized and evaluated for the inhibition of human SGLT2. Compared with dapagliflozin, compound 13h exhibited equivalent in vitro inhibitory activity against SGLT2, which might become a promising candidate for the treatment of type 2 diabetes. PMID- 26974379 TI - Synthesis and anticancer activity of novel fluorinated asiatic acid derivatives. AB - A series of novel fluorinated Asiatic Acid (AA) derivatives were successfully synthesized, tested for their antiproliferative activity against HeLa and HT-29 cell lines, and their structure activity relationships were evaluated. The great majority of fluorinated derivatives showed stronger antiproliferative activity than AA in a concentration dependent manner. The most active compounds have a pentameric A-ring containing an alpha,beta-unsaturated carbonyl group. The compounds with better cytotoxic activity were then evaluated against MCF-7, Jurkat, PC-3, A375, MIA PaCa-2 and BJ cell lines. Derivative 14 proved to be the most active compound among all tested derivatives and its mechanism of action was further investigated in HeLa cell line. The results showed that compound 14 induced cell cycle arrest in G0/G1 stage as a consequence of up-regulation of p21(cip1/waf1) and p27(kip1) and down-regulation of cyclin D3 and Cyclin E. Furthermore, compound 14 was found to induce caspase driven-apoptosis with activation of caspases-8 and caspase-3 and the cleavage of PARP. The cleavage of Bid into t-Bid, the up-regulation of Bax and the down-regulation of Bcl-2 were also observed after treatment of HeLa cells with compound 14. Taken together, these mechanistic studies revealed the involvement of extrinsic and intrinsic pathways in the apoptotic process induced by compound 14. Importantly, the antiproliferative activity of this compound on the non-tumor BJ human fibroblast cell line is weaker than in the tested cancer cell lines. The enhanced potency (between 45 and 90-fold more active than AA in a panel of cancer cell lines) and selectivity of this new AA derivative warrant further preclinical evaluation. PMID- 26974380 TI - Iminolactones as tools for inversion of the absolute configuration of alpha-amino acids and as inhibitors of cancer cell proliferation. AB - A library of iminolactones was prepared by esterification of several 2 hydroxyketones with a number of N-protected d- and l-alpha-amino acids. Some of the hydroxyketones were of terpenoid origin while others were obtained via synthesis. After N-deprotection of the intermediate esters, the free amines spontaneously underwent condensation with the ketone to form iminolactones. Esters of (1S,2S,5S)-2-hydroxypinan-3-one with both d- and l-alpha-amino acids were partially epimerized at the alpha-carbon atom to give a diastereomeric ester mixture. Only iminolactones of l-amino acids were formed after cyclization of (1S,2S,5S)-2-hydroxypinan-3-one, and correspondingly only d-amino acid iminolactones were formed after reaction with (1R,2R,5R)-2-hydroxypinan-3-one. The protocol thus enables inversion of the absolute configuration of amino acids. Some members of the prepared library of iminolactones displayed significant anti proliferative effects toward three cancer cell lines (EL4, MCF7, PC3) with insignificant effect on non-malign cell lines (McCoy, MCF10A, NIH3T3). Thus, iminolactones appear to be potential lead structures for preparation of drugs selectively affecting proliferation of malign cell lines. PMID- 26974381 TI - Toward overcoming cisplatin resistance via sterically hindered platinum(II) complexes. AB - A number of platinum(II) complexes with steric hindrance derived from (1R,2R) N(1)-benzylcyclohexane-1,2-diamine derivatives were designed and prepared. Biological assay indicated that most complexes showed antitumor activity against the tested cancer cell lines, especially those with chloride anions as leaving groups had compatible or superior activity to cisplatin and oxaliplatin. Complex 2a, as the most potent agent, is also sensitive to cisplatin resistant SGC7901/CDDP cancer cell line, which has been subsequently studied by cellular uptake, flow cytometry, gel electrophoresis and western blot assays. The steric hindrance resulting from a pending 2-fluorobenzyl moiety of the ligand might be the key factor for its ability to overcome cisplatin resistant cancer cells. PMID- 26974382 TI - Synthesis and biological evaluation of salicylic acid conjugated isoxazoline analogues on immune cell proliferation and angiogenesis. AB - Mitogenicity is the ability of the natural or synthetic compounds to induce cell division or proliferation. A series of salicylic acid derivatives containing isoxazoline moiety (8a-j) were synthesized and their immunopharmacological activities targeting lymphocyte proliferation and angiogenesis were evaluated. The compounds 8a-j mitogenicity were investigated on immunological cells that include human peripheral blood lymphocytes and murine splenocytes in-vitro. The results implicate that among the series of 8a-j, compound 8e showed a potent proliferative response on both human and murine lymphocytes. The proliferative index of the compound 8e was comparable to the reference mitogen Con A and mitogenecity is due to increased secretion IL-2. In -vivo CAM and rat corneal angiogenesis assays were performed to assess the compound's effect on endothelial cell migration and proliferation which inferred that 8e also induces the proliferation of endothelial cells. The study reports the synthetic immunostimulatory and pro-angiogenic activity of novel mitogen 8e which could be translated into new drug in future. PMID- 26974384 TI - Sulfatase inhibitors for recidivist breast cancer treatment: A chemical review. AB - Steroid sulfatase (STS) plays a momentous role in the conversion of sulfated steroids, which are biologically inactive, into biologically active un-sulfated steroid hormones, which support the development and growth of a number of hormone dependent cancers, including breast cancer. Therefore, inhibitors of STS are supposed to be potential drugs for the treatment of breast and other steroid dependent cancers. The present review concentrates on broad chemical classification of steroid sulfatase inhibitors. The inhibitors reviewed are classified into four main categories: Steroid sulfamate based inhibitors; Steroid non-sulfamate based inhibitors; Non-steroidal sulfamate based inhibitors; Non steroidal non-sulfamate based inhibitors. A succinct overview of current treatment of cancer, estradiol precursors, STS enzyme and its role in breast cancer is herein described. PMID- 26974383 TI - Design and synthesis of novel chalcones as potent selective monoamine oxidase-B inhibitors. AB - A novel series of substituted chalcones were designed and synthesized to be evaluated as selective human MAO-B inhibitors. A combination of either methylsulfonyl or trifluoromethyl substituents on the aromatic ketone moiety with a benzodioxol ring on the other end of the chalcone scaffold was investigated. The compounds were tested for their inhibitory activities on both human MAO-A and B. All compounds appeared to be selective MAO-B inhibitors with Ki values in the micromolar to submicromolar range. Molecular modeling studies have been performed to get insight into the binding mode of the synthesized compounds to human MAO-B active site. PMID- 26974385 TI - Synthesis, in vitro evaluation, and molecular modeling investigation of benzenesulfonimide peroxisome proliferator-activated receptors alpha antagonists. AB - Recent evidences suggest a moderate activation of Peroxisome Proliferator Activated Receptors (PPARs) could be favorable in metabolic diseases, reducing side effects given from full agonists. PPAR partial agonists and antagonists represent, to date, interesting tools to better elucidate biological processes modulated by these receptors. In this work are reported new benzenesulfonimide compounds able to block PPARalpha, synthesized and tested by transactivation assays and gene expression analysis. Some of these compounds showed a dose dependent antagonistic behavior on PPARalpha, submicromolar potency, different profiles of selectivity versus PPARgamma, and a repressive effect on CPT1A expression. Dockings and molecular dynamics on properly selected benzenesulfonimide derivatives furnished fresh insights into the molecular determinant most likely responsible for PPARalpha antagonism. PMID- 26974386 TI - Cinnamic acid amides from Tribulus terrestris displaying uncompetitive alpha glucosidase inhibition. AB - The alpha-glucosidase inhibitory potential of Tribulus terrestris extracts has been reported but as yet the active ingredients are unknown. This study attempted to isolate the responsible metabolites and elucidate their inhibition mechanism of alpha-glucosidase. By fractionating T. terristris extracts, three cinnamic acid amide derivatives (1-3) were ascertained to be active components against alpha-glucosidase. The lead structure, N-trans-coumaroyltyramine 1, showed significant inhibition of alpha-glucosidase (IC50 = 0.42 MUM). Moreover, all active compounds displayed uncompetitive inhibition mechanisms that have rarely been reported for alpha-glucosidase inhibitors. This kinetic behavior was fully demonstrated by showing a decrease of both Km and Vmax, and Kik/Kiv ratio ranging between 1.029 and 1.053. We progressed to study how chemical modifications to the lead structure 1 may impact inhibition. An alpha, beta-unsaturation carbonyl group and hydroxyl group in A-ring of cinnamic acid amide emerged to be critical functionalities for alpha-glucosidase inhibition. The molecular modeling study revealed that the inhibitory activities are tightly related to pi-pi interaction as well as hydrogen bond interaction between enzyme and inhibitors. PMID- 26974388 TI - Regression to the Mean: A Commonly Overlooked and Misunderstood Factor Leading to Unjustified Conclusions in Pediatric Obesity Research. AB - OBJECTIVE: In this paper we discuss what regression to the mean (RTM) is, the magnitude of RTM in realistic situations, interpretation of RTM, and recommendations for how to address RTM in study design. METHODS: Public health research faces many challenges in conducting gold standard randomized, controlled trials (RCT). Although there are many threats to validity in uncontrolled trials, RTM is often overlooked or not adequately considered. RTM is a statistical phenomenon that occurs with any pair of variables that have a correlation not equal to |1.0|. With RTM, subjects' average values on an outcome variable (e.g., BMI) change in a systematic direction over time despite there being no treatment effect. Without a proper control group, changes thought to be associated with an intervention may be due entirely to RTM. Investigators may draw erroneous conclusions based on results showing greater declines in a variable among participants with higher baseline of that variable compared to those with lower baseline of that variable, and label this evidence for differential treatment efficacy. CONCLUSIONS: Ignoring RTM can lead to unsubstantiated conclusions about the effects of treatments. These conclusions can lead to the waste of time, money, and other resources, which distract from finding appropriate interventions. When a true RCT design is not feasible, reasonable design alternatives involving nonrandomized control groups should be implemented. PMID- 26974387 TI - Calcium Uncaging with Visible Light. AB - We have designed a nitroaromatic photochemical protecting group that absorbs visible light in the violet-blue range. The chromophore is a dinitro derivative of bisstyrylthiophene (or BIST) that absorbs light very effectively (epsilon440 = 66,000 M(-1) cm(-1) and two-photon cross section of 350 GM at 775 nm). We developed a "caged calcium" molecule by conjugation of BIST to a Ca(2+) chelator that upon laser flash photolysis rapidly releases Ca(2+) in <0.2 ms. Using the patch-clamp method the optical probe, loaded with Ca(2+), was delivered into acutely isolated mouse cardiac myocytes, where either one- and two-photon uncaging of Ca(2+) induced highly local or cell-wide physiological Ca(2+) signaling events. PMID- 26974389 TI - Carbapenemase-producing Enterobacteriaceae: a 2-year surveillance in a hospital in Iasi, Romania. AB - AIM: Limited information is currently available about the prevalence of carbapenemase-producing Enterobacteriaceae (CPE) in Romania. MATERIALS & METHODS: Routine tests of 1,993 clinical isolates at a hospital in Iasi yielded 46 isolates that were resistant to carbapenems. All 46 isolates were phenotypically and genotypically analyzed using VITEK-2 and DNA microarray-based assays. RESULTS: Isolates were assigned to Klebsiella pneumoniae and Enterobacter cloacae. For 39 isolates, carbapenem resistance was confirmed and 37 harbored at least one carbapenem resistance gene. Two isolates were probably resistant due to AmpC beta-lactamases in combination with a porin loss. The overall concordance between detected phenotype and genotype was 95%. CONCLUSION: Our data show that carbapenemase-producing isolates with different underlying resistance mechanisms are still rare in Iasi, but the global rise of CPE warrants intensified surveillance. PMID- 26974390 TI - Obesity, Oral Contraceptive Use, and Cerebral Venous Thrombosis in Women. PMID- 26974392 TI - Transfer Printing of Semiconductor Nanowires with Lasing Emission for Controllable Nanophotonic Device Fabrication. AB - Accurate positioning and organization of indium phosphide (InP) nanowires (NWs) with lasing emission at room temperature is achieved using a nanoscale transfer printing (TP) technique. The NWs retained their lasing emission after their transfer to targeted locations on different receiving substrates (e.g., polymers, silica, and metal surfaces). The NWs were also organized into complex spatial patterns, including 1D and 2D arrays, with a controlled number of elements and dimensions. The developed TP technique enables the fabrication of bespoke nanophotonic systems using NW lasers and other NW devices as building blocks. PMID- 26974393 TI - The association between platelet-to-lymphocyte ratio and inflammatory markers with the severity of aortic stenosis. AB - AIM: Platelet-to-lymphocyte ratio (PLR) was proposed as a novel indirect marker of inflammation. We aimed to evaluate the relationship between PLR and aortic stenosis (AS). PATIENTS & METHODS: The study population included 453 patients of which 98 patients with severe AS, 206 patients with mild-to-moderate AS and 149 patients as control. RESULTS: PLR was significantly increased in parallel to the severity of AS (p < 0.001). There was significant positive correlation between PLR and maximum, and mean systolic transaortic gradient (all p < 0.001). Also, PLR was correlated with C-reactive protein and neutrophil-to-lymphocyte ratio (all p < 0.001) and PLR was independently associated with the presence of AS (p < 0.001). CONCLUSION: We found a significant relationship between PLR and AS. PMID- 26974395 TI - Surveys for Antibodies Against Mosquitoborne Encephalitis Viruses in California Birds, 1996-2013. AB - From 1996 through 2013, 54,546 individual birds comprising 152 species and 7 orders were banded, bled, and released at four study areas within California, from which 28,388 additional serum samples were collected at one or more recapture encounters. Of these, 142, 99, and 1929 birds from 41 species were positive for neutralizing antibodies against western equine encephalomyelitis virus (WEEV), St. Louis encephalitis virus (SLEV), or West Nile virus (WNV) at initial capture or recapture, respectively. Overall, 83% of the positive serum samples were collected from five species: House Finch, House Sparrow, Mourning Dove, California Quail, and Western Scrub-Jay. Temporal data supported concurrent arbovirus surveillance and documented the disappearance of birds positive for WEEV in 2008 and SLEV in 2003 and the appearance of birds positive for WNV after its invasion in 2003. Results of these serosurveys agreed well with the host selection patterns of the Culex vectors as described from bloodmeal sequencing data and indicated that transmission of WNV seemed most effective within urban areas where avian and mosquito host diversity was limited to relatively few competent species. PMID- 26974396 TI - Severe ocular phenotypes in Rbp4-deficient mice in the C57BL/6 genetic background. AB - Retinol-binding protein 4 (RBP4) is a specific carrier for retinol in the blood. In hepatocytes, newly synthesized RBP4 associates with retinol and transthyretin and is secreted into the blood. The ternary transthyretin-RBP4-retinol complex transports retinol in the circulation and delivers it to target tissues. Rbp4 deficient mice in a mixed genetic background (129xC57BL/6J) have decreased sensitivity to light in the b-wave amplitude on electroretinogram. Sensitivity progressively improves and approaches that of wild-type mice at 24 weeks of age. In the present study, we produced Rbp4-deficient mice in the C57BL/6 genetic background. These mice displayed more severe phenotypes. They had decreased a- and b-wave amplitudes on electroretinograms. In accordance with these abnormalities, we found structural changes in these mice, such as loss of the peripheral choroid and photoreceptor layer in the peripheral retinas. In the central retinas, the distance between the inner limiting membrane and the outer plexiform layer was much shorter with fewer ganglion cells and fewer synapses in the inner plexiform layer. Furthermore, ocular developmental defects of retinal depigmentation, optic disc abnormality, and persistent hyaloid artery were also observed. All these abnormalities had not recovered even at 40 weeks of age. Our Rbp4-deficient mice accumulated retinol in the liver but it was undetectable in the serum, indicating an inverse relation between serum and liver retinol levels. Our results suggest that RBP4 is critical for the mobilization of retinol from hepatic storage pools, and that such mobilization is necessary for ocular development and visual function. PMID- 26974398 TI - Scratching the surface: the processing of pain from deep tissues. AB - Although most pain research focuses on skin, muscles, joints and viscerae are major sources of pain. We discuss the mechanisms of deep pains arising from somatic and visceral structures and how this can lead to widespread manifestations and chronification. We include how both altered peripheral and central sensory neurotransmission lead to deep pain states and comment on key areas such as top-down modulation where little is known. It is vital that the clinical characterization of deep pain in patients is improved to allow for back translation to preclinical models so that the missing links can be ascertained. The contribution of deeper somatic and visceral tissues to various chronic pain syndromes is common but there is much we need to know. PMID- 26974399 TI - Unprecedented layered coordination polymers of dithiolene group 10 metals: magnetic and electrical properties. AB - One-pot reactions between Ni(ii), Pd(ii) or Pt(ii) salts and 3,6-dichloro-1,2 benzenedithiol (HSC6H2Cl2SH) in KOH medium under argon lead to a series of bis dithiolene coordination polymers. X-ray analysis shows the presence of a common square planar complex [M(SC6H2Cl2S)2](2-) linked to potassium cations forming either a two-dimensional coordination polymer network for {[K2(MU-H2O)2(MU thf)(thf)2][M(SC6H2Cl2S)2]}n [M = Ni () and Pd ()] or a one-dimensional coordination polymer for {[K2(MU-H2O)2(thf)6][Pt(SC6H2Cl2S)2]}n (). In the coordination environment of the potassium ions may slightly change leading to the two-dimensional coordination polymer {[K2(MU-H2O)(MU-thf)2][Pt(SC6H2Cl2S)2]}n () that crystallizes together with . The physical characterization of compounds show similar trends, they are diamagnetic and behave as semiconductors. PMID- 26974400 TI - Continuous cell sorting in a flow based on single cell resonance Raman spectra. AB - Single cell Raman spectroscopy measures a spectral fingerprint of the biochemistry of cells, and provides a powerful method for label-free detection of living cells without the involvement of a chemical labelling strategy. However, as the intrinsic Raman signals of cells are inherently weak, there is a significant challenge in discriminating and isolating cells in a flowing stream. Here we report an integrated Raman-microfluidic system for continuous sorting of a stream of cyanobacteria, Synechocystis sp. PCC6803. These carotenoid-containing microorganisms provide an elegant model system enabling us to determine the sorting accuracy using the subtly different resonance Raman spectra of microorganism cultured in a (12)C or (13)C carbon source. Central to the implementation of continuous flow sorting is the use of "pressure dividers" that eliminate fluctuations in flow in the detection region. This has enabled us to stabilise the flow profile sufficiently to allow automated operation with synchronisation of Raman acquisition, real-time classification and sorting at flow rates of ca. <100 MUm s(-1), without the need to "trap" the cells. We demonstrate the flexibility of this approach in sorting mixed cell populations with the ability to achieve 96.3% purity of the selected cells at a speed of 0.5 Hz. PMID- 26974401 TI - On the mechanism of electrochemical ammonia synthesis on the Ru catalyst. AB - We theoretically investigate the electrochemical N2 reduction reaction (NRR) mechanism to produce NH3 on the Ru catalyst. All possible N-N dissociation steps during the reduction processes were evaluated along with the conventional associative and dissociative pathways. Based on the calculated free energy diagrams, it is revealed that the kinetically facile intermediate dissociative pathways during the NRR require a thermodynamic limiting potential (-0.71 V) similar to the associative pathway (-0.68 V), although the initial dissociative pathway as in the Haber-Bosch process has a substantial kinetic barrier for the N N bond dissociation. The competitive hydrogen evolution is found to be a major hurdle for achieving a high efficiency for the electrochemical nitrogen reduction. In the low overpotential region, the hydrogen adsorption is thermodynamically more favorable than the protonation of N2, thereby reducing the number of active sites for the N2 activation. A comparison of free energies in the presence of different H-coverages on the Ru further demonstrates that the H coverage can significantly increase the energy barrier for the first protonation of N2, resulting in a change of the potential determining step and an increase in the overpotentials. PMID- 26974397 TI - Secretory leukocyte protease inhibitor gene deletion alters bleomycin-induced lung injury, but not development of pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis is a progressive, fatal disease with limited treatment options. Protease-mediated transforming growth factor-beta (TGF-beta) activation has been proposed as a pathogenic mechanism of lung fibrosis. Protease activity in the lung is tightly regulated by protease inhibitors, particularly secretory leukocyte protease inhibitor (SLPI). The bleomycin model of lung fibrosis was used to determine the effect of increased protease activity in the lungs of Slpi(-/-) mice following injury. Slpi(-/-), and wild-type, mice received oropharyngeal administration of bleomycin (30 IU) and the development of pulmonary fibrosis was assessed. Pro and active forms of matrix metalloproteinase (MMP)-2 and MMP-9 were measured. Lung fibrosis was determined by collagen subtype specific gene expression, hydroxyproline concentration, and histological assessment. Alveolar TGF-beta activation was measured using bronchoalveolar lavage cell pSmad2 levels and global TGF-beta activity was assessed by pSmad2 immunohistochemistry. The active-MMP-9 to pro-MMP-9 ratio was significantly increased in Slpi(-/-) animals compared with wild-type animals, demonstrating enhanced metalloproteinase activity. Wild-type animals showed an increase in TGF beta activation following bleomycin, with a progressive and sustained increase in collagen type I, alpha 1 (Col1alpha1), III, alpha 1(Col3alpha1), IV, alpha 1(Col4alpha1) mRNA expression, and a significant increase in total lung collagen 28 days post bleomycin. In contrast Slpi(-/-) mice showed no significant increase of alveolar TGF-beta activity following bleomycin, above their already elevated levels, although global TGF-beta activity did increase. Slpi(-/-) mice had impaired collagen gene expression but animals demonstrated minimal reduction in lung fibrosis compared with wild-type animals. These data suggest that enhanced proteolysis does not further enhance TGF-beta activation, and inhibits sustained Col1alpha1, Col3alpha1, and Col4alpha1 gene expression following lung injury. However, these changes do not prevent the development of lung fibrosis. Overall, these data suggest that the absence of Slpi does not markedly modify the development of lung fibrosis following bleomycin-induced lung injury. PMID- 26974402 TI - Synergizing nanocomposites of CdSe/TiO2 nanotubes for improved photoelectrochemical activity via thermal treatment. AB - In this work, we show the effect of the thermal treatment temperature on the photoelectrochemical (PEC) activity of CdSe/TiO2 nanocomposites. TiO2 nanotubes (NTs) were synthesized by anodization and the nanocomposites were obtained by depositing CdSe clusters via magnetron sputtering. A two-step thermal treatment was performed: heating the TiO2 NTs at different temperatures prior to CdSe deposition and further heating the CdSe/TiO2 nanocomposites. The nanocomposites were characterized by Rutherford backscattering spectroscopy (RBS), scanning electron microscopy (SEM), scanning transmission electron microscopy (STEM), high resolution transmission electron microscopy (HRTEM), energy dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), UV-Vis spectrophotometry, and electrochemical impedance spectroscopy (EIS). To compare the PEC performance of the CdSe/TiO2 nanocomposites and pristine TiO2 NTs, linear sweep voltammetry (LSV) curves were obtained under visible light and under 1 sun illumination. It was observed that CdSe incorporation into the TiO2 template enhances the visible light absorbance thereby improving the PEC performance of the nanocomposites. We have found that the optical, structural and PEC properties of the CdSe/TiO2 nanocomposites are dependent on the thermal treatment temperature of the TiO2 nanotubular substrate, prior to CdSe deposition. Moreover, a three-fold improvement in photocurrent was observed upon further thermal treatment of the obtained nanocomposite. PMID- 26974403 TI - Peak Stress in the Annulus Fibrosus Under Cyclic Biaxial Tensile Loading. AB - Numerous in vitro studies have examined the initiation and propagation of fatigue injury pathways in the annulus fibrosus (AF) using isolated motion segments; however, the cycle-varying changes to the AF under cyclic biaxial tensile loading conditions have yet to be examined. Therefore, the primary objective of this study was to characterize the cycle-varying changes in peak tensile stress in multilayer AF tissue samples within a range of physiologically relevant loading conditions at subacute magnitudes of tissue stretch up to 100 loading cycles. A secondary aim was to examine whether the stress-relaxation response would be different across loading axes (axial and circumferential) and whether this response would vary across regions of the intervertebral disk (IVD) (anterior and posterior-lateral). The results from the study demonstrate that several significant interactions emerged between independent factors that were examined in the study. Specifically, a three-way interaction between the radial location, magnitude of peak tissue stretch, and cycle rate (p = 0.0053) emerged. Significant two-way interactions between the magnitude of tissue stretch and cycle number (p < 0.0001) and the magnitude of tissue stretch and loading axis (p < 0.0001) were also observed. These findings are discussed in the context of known mechanisms for structural damage, which have been linked to fatigue loading in the IVD (e.g., cleft formation, radial tearing, increased neutral zone, disk bulging, and loss of intradiscal pressure). PMID- 26974406 TI - Bipiperidine conjugates as soluble sugar surrogates in DNA-intercalating antiproliferative polyketides. AB - DNA-intercalating polyketide glycosides are important leads for cancer therapeutics, yet their use is often limited by their low solubility and challenging synthetic protocols. To overcome these limitations, we employed 1,4' bipiperidine-1'-carbamate residues as sugar surrogates in daunorubicin and chartreusin, yielding water-soluble derivatives and prodrugs with dramatically improved antiproliferative activities. PMID- 26974408 TI - Engineered hybrid cardiac patches with multifunctional electronics for online monitoring and regulation of tissue function. AB - In cardiac tissue engineering approaches to treat myocardial infarction, cardiac cells are seeded within three-dimensional porous scaffolds to create functional cardiac patches. However, current cardiac patches do not allow for online monitoring and reporting of engineered-tissue performance, and do not interfere to deliver signals for patch activation or to enable its integration with the host. Here, we report an engineered cardiac patch that integrates cardiac cells with flexible, freestanding electronics and a 3D nanocomposite scaffold. The patch exhibited robust electronic properties, enabling the recording of cellular electrical activities and the on-demand provision of electrical stimulation for synchronizing cell contraction. We also show that electroactive polymers containing biological factors can be deposited on designated electrodes to release drugs in the patch microenvironment on demand. We expect that the integration of complex electronics within cardiac patches will eventually provide therapeutic control and regulation of cardiac function. PMID- 26974409 TI - Paramagnetic fluorinated nanoemulsions for sensitive cellular fluorine-19 magnetic resonance imaging. AB - Fluorine-19 magnetic resonance imaging ((19)F MRI) probes enable quantitative in vivo detection of cell therapies and inflammatory cells. Here, we describe the formulation of perfluorocarbon-based nanoemulsions with improved sensitivity for cellular MRI. Reduction of the (19)F spin-lattice relaxation time (T1) enables rapid imaging and an improved signal-to-noise ratio, thereby improving cell detection sensitivity. We synthesized metal-binding beta-diketones conjugated to linear perfluoropolyether (PFPE), formulated these fluorinated ligands as aqueous nanoemulsions, and then metallated them with various transition and lanthanide ions in the fluorous phase. Iron(III) tris-beta-diketonate ('FETRIS') nanoemulsions with PFPE have low cytotoxicity (<20%) and superior MRI properties. Moreover, the (19)F T1 can readily be reduced by an order of magnitude and tuned by stoichiometric modulation of the iron concentration. The resulting (19)F MRI detection sensitivity is enhanced by three- to fivefold over previously used tracers at 11.7 T, and is predicted to increase by at least eightfold at the clinical field strength of 3 T. PMID- 26974410 TI - Coordination polymer structure and revisited hydrogen evolution catalytic mechanism for amorphous molybdenum sulfide. AB - Molybdenum sulfides are very attractive noble-metal-free electrocatalysts for the hydrogen evolution reaction (HER) from water. The atomic structure and identity of the catalytically active sites have been well established for crystalline molybdenum disulfide (c-MoS2) but not for amorphous molybdenum sulfide (a-MoSx), which exhibits significantly higher HER activity compared to its crystalline counterpart. Here we show that HER-active a-MoSx, prepared either as nanoparticles or as films, is a molecular-based coordination polymer consisting of discrete [Mo3S13](2-) building blocks. Of the three terminal disulfide (S2(2 )) ligands within these clusters, two are shared to form the polymer chain. The third one remains free and generates molybdenum hydride moieties as the active site under H2 evolution conditions. Such a molecular structure therefore provides a basis for revisiting the mechanism of a-MoSx catalytic activity, as well as explaining some of its special properties such as reductive activation and corrosion. Our findings open up new avenues for the rational optimization of this HER electrocatalyst as an alternative to platinum. PMID- 26974412 TI - Out of touch? Visual load induces inattentional numbness. AB - It is now well known that the absence of attention can leave people unaware of both visual and auditory stimuli (e.g., Dalton & Fraenkel, 2012; Mack & Rock, 1998). However, the possibility of similar effects within the tactile domain has received much less research. Here, we introduce a new tactile inattention paradigm and use it to test whether tactile awareness depends on the level of perceptual load in a concurrent visual task. Participants performed a visual search task of either low or high perceptual load, as well as responding to the presence or absence of a brief vibration delivered simultaneously to either the left or the right hand (50% of trials). Detection sensitivity to the clearly noticeable tactile stimulus was reduced under high (vs. low) visual perceptual load. These findings provide the first robust demonstration of "inattentional numbness," as well as demonstrating that this phenomenon can be induced by concurrent visual perceptual load. (PsycINFO Database Record PMID- 26974413 TI - The Role of HIV-1 in Affecting the Proliferation Ability of HPCs Derived From BM. AB - HIV-1 causes chronic infection characterized by the depletion of CD4+ T lymphocytes and the development of AIDS. Current antiretroviral drugs inhibit viral spread, but they do not lead to a full immune recovery. Hematopoietic stem cells (HSCs) and multipotent hematopoietic progenitor cells (HPCs) give rise to all blood and immune cells, and in HIV infection, hematological abnormalities frequently occur in patients. Here, we used bone marrow samples from HIV-1 infected people to study the relationship between the proliferation ability of HSCs/HPCs and peripheral CD4+ T lymphocytes. Three indexes were used to reflect the proliferation ability of HSCs and HPCs: (1) colony-forming units of bone marrow mononuclear cells (BMMCs), (2) amplification of CD34+ cells purified from bone marrow mononuclear cells, (3) expression of HOXB4 and HOXA9 in CD34+ cells. We observed a direct correlation between peripheral number of CD4+ T lymphocytes and the HSCs/HPCs proliferation ability in our study. We also compared HIV infected patients with or without antiretroviral therapy (ART). Our results demonstrated that after antiretroviral therapy, CD4+ T-cell recovery and HPCs proliferation ability are correlated. Our findings have implications in understanding whether bone marrow-derived HPCs can supplement for the loss of CD4+ T lymphocytes during HIV-1 infection. PMID- 26974411 TI - Directed migration of cancer cells guided by the graded texture of the underlying matrix. AB - Living cells and the extracellular matrix (ECM) can exhibit complex interactions that define key developmental, physiological and pathological processes. Here, we report a new type of directed migration-which we term 'topotaxis'-guided by the gradient of the nanoscale topographic features in the cells' ECM environment. We show that the direction of topotaxis is reflective of the effective cell stiffness, and that it depends on the balance of the ECM-triggered signalling pathways PI(3)K-Akt and ROCK-MLCK. In melanoma cancer cells, this balance can be altered by different ECM inputs, pharmacological perturbations or genetic alterations, particularly a loss of PTEN in aggressive melanoma cells. We conclude that topotaxis is a product of the material properties of cells and the surrounding ECM, and propose that the invasive capacity of many cancers may depend broadly on topotactic responses, providing a potentially attractive mechanism for controlling invasive and metastatic behaviour. PMID- 26974414 TI - Return on Investment From Expenditures Incurred to Eliminate Mother-To-Child Transmission Among HIV-Infected Women in New York State: 1998-2013. AB - BACKGROUND: Eliminating mother-to-child transmission (MTCT) of HIV has been one of New York State's public health priorities, and the goal has been virtually accomplished by meeting criteria established by the Centers for Disease Control and Prevention. METHODS: We use a return on investment (ROI) approach, from the perspective of the state, to compare expenditures incurred to prevent MTCT of HIV in NYS during the period 1998-2013 to benefits realized, as expressed as HIV treatment costs saved from averting an estimated number of HIV infections among newborns. Extrapolating from the 11.5% incidence rate of HIV-infected newborns in 1997, we projected the number of cases of MTCT of HIV that were averted over the 16-year period. A published estimate of lifetime HIV treatment costs was used to estimate HIV treatment costs saved from the averted infections; expenditures for clinical protocols and other services directly associated with preventing MTCT of HIV were also estimated. The ROI was then calculated by dividing program benefits by the expenditures incurred to achieve these benefits. RESULTS: We estimate that 898 cases of MTCT of HIV were averted between 1998 and 2013, resulting in a savings of $321.03 million in HIV treatment costs. Expenditures to achieve these benefits totaled $81.07 million, yielding an ROI of $3.96. CONCLUSIONS: Aside from the human suffering from MTCT of HIV that is averted, expenditures for treatment protocols and interventions to prevent MTCT of HIV are relatively inexpensive and can result in almost 4 times their value in HIV treatment cost savings realized. PMID- 26974415 TI - Developing the Pediatric Gastrointestinal Endoscopy Unit: A Clinical Report by the Endoscopy and Procedures Committee. AB - There is significant variability in the design and management of pediatric endoscopy units. Although there is information on adult endoscopy units, little guidance is available to the pediatric endoscopy practitioner. The purpose of this clinical report, prepared by the NASPGHAN Endoscopy and Procedures Committee, is to review the important considerations for setting up an endoscopy unit for children. A systematic review of the literature was undertaken in the preparation of this report regarding the design, management, needed equipment, motility setup, billing and coding, and pediatric specific topics. PMID- 26974418 TI - A Prospective, Comparative Study of the Pain of Local Anesthesia Using 2% Lidocaine, 2% Lidocaine With Epinephrine, and 2% Lidocaine With Epinephrine Bupivicaine Mixture for Eyelid Surgery. AB - PURPOSE: A mixture of 2% lidocaine with epinephrine and bupivacaine was developed to achieve the fast-onset anesthetic effect of lidocaine and the long-lasting effect of bupivacaine. The authors compared pain scores between 2% lidocaine, 2% lidocaine with epinephrine, and 2% lidocaine with epinephrine-bupivicaine mixture during local anesthesia for eyelid surgeries. METHODS: This was a double-blind, randomized, prospective, comparative study. In total, 120 consecutive patients (43 males, 77 females, mean age = 47.2 +/- 21.2) who underwent bilateral eyelid surgery under subcutaneous anesthesia were asked to report pain scores for each eye during the first injection of anesthesia. Each patient was randomly assigned to receive 1 of the 3 anesthetic agents in 1 eyelid, and 1 of the remaining 2 agents in the other. RESULTS: The pH values of the 2% lidocaine, 2% lidocaine with epinephrine, and 2% lidocaine with epinephrine-bupivicaine mixture were 6.23 +/- 0.21, 4.21 +/- 0.37, and 3.87 +/- 0.19, respectively. The pain scores of each were 4.3 +/- 1.8, 5.1 +/- 1.8, and 5.7 +/- 1.9, respectively. The 2% lidocaine with epinephrine produced a statistically significantly higher pain score than 2% lidocaine (p = 0.044, generalized estimating equation method). The mixture also showed a significantly higher pain score than 2% lidocaine (p = 0.003, generalized estimating equation method). CONCLUSIONS: Epinephrine seemed to increase subjective pain scores. Compared with 2% lidocaine with epinephrine, 2% lidocaine with epinephrine-bupivicaine mixture was not significantly different in terms of subjective symptoms or pH. PMID- 26974417 TI - Cause and management of muscle wasting in chronic liver disease. AB - PURPOSE OF REVIEW: Sarcopenia or loss of skeletal muscle mass is the major component of malnutrition and occurs in the majority of patients with liver disease. Lower muscle contractile function also contributes to the adverse consequences of sarcopenia. There are no effective therapies to prevent or reverse sarcopenia in liver disease. This review will discuss the advances in diagnosis, pathogenesis, and treatment options for sarcopenia in liver disease. RECENT FINDINGS: Sarcopenia increases mortality and risk of development of other complications of cirrhosis, and worsens postliver transplant outcomes while quality of life is decreased. Unlike other complications of cirrhosis that reverse after liver transplantation, sarcopenia may not improve and actually worsens. Impaired skeletal muscle protein synthesis and increased proteolysis via autophagy contribute to sarcopenia. Hyperammonemia is the best-studied mediator of the liver-muscle axis. Molecular studies show increased expression of myostatin whereas metabolic studies show impaired mitochondrial function and tricarboxylic acid cycle intermediates because of cataplerosis of alpha ketoglutarate. Impaired skeletal muscle pyruvate and fatty acid oxidation during hyperammonemia suggest amino acids are diverted to acetyl CoA and potentially aggravate hyperammonemia. Nutritional supplementation is of limited or no benefit and suggests that cirrhosis is a state of anabolic resistance. Exercise may be beneficial but whether it overcomes anabolic resistance is not known. SUMMARY: The high clinical significance of sarcopenia is well established. Current approaches to nutritional supplementation have not been effective in reversing sarcopenia because of anabolic resistance. Myostatin antagonists, specific amino acid supplementation, mitochondrial protection, and combination endurance resistance exercise are potential future therapeutic options. PMID- 26974419 TI - Epidemiology and Prognosis of Primary Periocular Sweat Gland Carcinomas. AB - PURPOSE: To characterize the clinical presentation, management, and outcomes of patients with sweat gland carcinoma of the periocular region. To review the pathologic classification scheme, compare the clinical behavior between subtypes, and discuss treatment recommendations for periocular sweat gland carcinomas. METHODS: Retrospective study from 2 tertiary centers, which are part of the American Society of Ophthalmic Plastic and Reconstructive Surgery Oncology Database. RESULTS: Twenty-two patients, of whom 13 (59%) were female, were included in the study. The median age was 69 years. The median follow-up time was 23 months. Twenty (91%) patients had lesions that were slow growing and were present for several months to years before diagnosis. Presentation was varied, and pathology included mucinous carcinoma (7; 32%), microcystic adnexal carcinoma (4; 18%), endocrine mucin-producing sweat gland carcinoma (4; 18%), eccrine carcinoma (2; 9%), apocrine carcinoma (2; 9%), poorly differential adnexal carcinoma (2; 9%), and hidroadenocarcinoma (1; 5%). Microcystic adnexal carcinoma tended to present with the largest tumor dimension (range: 25-32 mm) and mucinous carcinoma the smallest (range: 5-13 mm). Treatments included Mohs micrographic excision in 10 patients (45.5%), wide local excision in 10 patients (45.5%), and orbital exenteration in 2 patients (9%). No lesions <=T2b (by AJCC 7th edition classification for eyelid carcinomas) had local recurrence or nodal metastasis. No patients had distant metastasis. CONCLUSIONS: Sweat gland carcinomas tend to grow slowly and be present for several months to years before diagnosis. Overall, microcystic adnexal carcinoma subtype showed more aggressive clinical behavior than mucinous subtypes. Eyelid carcinomas AJCC category T2b or less were associated with better outcomes. PMID- 26974416 TI - Environmental Enteric Dysfunction in Children. AB - Diarrheal diseases are a major cause of childhood death in resource-poor countries, killing approximately 760,000 children younger than 5 years each year. Although deaths due to diarrhea have declined dramatically, high rates of stunting and malnutrition have persisted. Environmental enteric dysfunction (EED) is a subclinical condition caused by constant fecal-oral contamination with resultant intestinal inflammation and villous blunting. These histological changes were first described in the 1960s, but the clinical effect of EED is only just being recognized in the context of failure of nutritional interventions and oral vaccines in resource-poor countries. We review the existing literature regarding the underlying causes of and potential interventions for EED in children, highlighting the epidemiology, clinical and histologic classification of the entity, and discussing novel biomarkers and possible therapies. Future research priorities are also discussed. PMID- 26974420 TI - Metastatic Colon Cancer to the Sphenoid Wing and Ethmoid Sinus Mimicking Orbital Cellulitis: A Rare Presentation. AB - Metastatic lesions to the orbit are most commonly seen with breast, lung, and prostate cancer, but are less commonly seen with colon cancer. Furthermore, the presence of metastatic colon cancer involving the sphenoid wing has only been reported once previously. The authors present a case of a 68-year-old woman with right upper and lower eyelid edema and erythema along with decreased vision, relative afferent pupillary defect, limitation of extraocular movements, and chemosis suggestive of orbital cellulitis. Imaging revealed an erosive lesion of the sphenoid wing along with unilateral ethmoid sinusitis. Biopsies taken from both lesions revealed metastatic adenocarcinoma, consistent with colonic primary. The extensive inflammatory component of her disease required life-long high-dose steroids to maintain quiescence and preserve vision. PMID- 26974421 TI - Idiopathic Orbital Inflammation Associated With Relapsing Polychondritis. AB - The authors describe a patient with recurrent idiopathic orbital inflammatory disease as an unusual presentation of relapsing polychondritis. There are very few reported cases in the literature of relapsing polychondritis associated with idiopathic orbital inflammation. Clinicians should be aware of the orbital and ophthalmic presentations of relapsing polychondritis. PMID- 26974422 TI - Neutralization of Osteopontin Ameliorates Acute Lung Injury Induced by Intestinal Ischemia-Reperfusion. AB - Intestinal ischemia-reperfusion (I/R) is associated with acute respiratory distress syndrome. Osteopontin (OPN), a glycoprotein secreted from immune reactive cells, plays a deleterious role in various inflammatory diseases. Considering OPN as a pro-inflammatory molecule, we hypothesize that the treatment with its neutralizing antibody (anti-OPN Ab) protects mice against intestinal I/R induced acute lung injury (ALI). Intestinal I/R was induced in mice by superior mesenteric artery occlusion with a vascular clip. After 45 min of occlusion, the clip was removed and anti-OPN Ab (25 MUg/mouse) or normal IgG isotype control (25 MUg/mouse) was immediately administrated intravenously. Blood, small intestine, and lung tissues were collected at 4 h after reperfusion for various analyses. After intestinal I/R, mRNA and protein levels of OPN were significantly induced in the small intestine, lungs, and blood relative to sham-operated animals. Compared with the IgG control group, treatment of anti-OPN Ab significantly reduced plasma levels of pro-inflammatory cytokine and chemokine (IL-6 and MIP-2) and organ injury markers (AST, ALT, and LDH). The histological architecture of the gut and lung tissues in anti-OPN Ab-treated intestinal I/R-induced mice showed significant improvement versus the IgG control mice. The lung inflammation measured by the levels of IL-6, IL-1beta, and MIP-2 was also significantly downregulated in the anti-OPN Ab-treated mice as compared with the IgG control mice. Besides, the lung MPO and neutrophil infiltration in anti-OPN Ab-treated mice showed significant reduction as compared with the IgG control animals. In conclusion, we have demonstrated beneficial outcomes of anti-OPN Ab treatment in protecting against ALI, implicating a novel therapeutic potential in intestinal I/R. PMID- 26974423 TI - Comparative Evaluation of Crystalloid Resuscitation Rate in a Human Model of Compensated Haemorrhagic Shock. AB - INTRODUCTION: The most effective rate of fluid resuscitation in haemorrhagic shock is unknown. METHODS: We performed a randomized crossover pilot study in a healthy volunteer model of compensated haemorrhagic shock. Following venesection of 15 mL/kg of blood, participants were randomized to 20 mL/kg of crystalloid over 10 min (FAST treatment) or 30 min (SLOW treatment). The primary end point was oxygen delivery (DO2). Secondary end points included pressure and flow-based haemodynamic variables, blood volume expansion, and clinical biochemistry. RESULTS: Nine normotensive healthy adult volunteers participated. No significant differences were observed in DO2 and biochemical variables between the SLOW and FAST groups. Blood volume was reduced by 16% following venesection, with a corresponding 5% reduction in cardiac index (CI) (P < 0.001). Immediately following resuscitation the increase in blood volume corresponded to 54% of the infused volume under FAST treatment and 69% of the infused volume under SLOW treatment (P = 0.03). This blood volume expansion attenuated with time to 24% and 25% of the infused volume 30 min postinfusion. During fluid resuscitation, blood pressure was higher under FAST treatment. However, CI paradoxically decreased in most participants during the resuscitation phase; a finding not observed under SLOW treatment. CONCLUSION: FAST or SLOW fluid resuscitation had no significant impact on DO2 between treatment groups. In both groups, changes in CI and blood pressure did not reflect the magnitude of intravascular blood volume deficit. Crystalloid resuscitation expanded intravascular blood volume by approximately 25%. PMID- 26974424 TI - Splenectomy Versus Sham Splenectomy in a Swine Model of Controlled Hemorrhagic Shock. AB - INTRODUCTION: Splenectomy is controversial in acute hemorrhagic shock models. OBJECTIVE: To compare splenectomized (SP) versus sham-splenectomized (SSP) swine during acute controlled hemorrhage. METHODS: Twenty-six male Landrace White swine (mean body weight +/- standard deviation, 33.8 +/- 2.9 kg) were used. Ethics approval was obtained. Landrace swine underwent splenectomy (n = 13) or sham splenectomy (n = 13), were bled to mean arterial blood pressure (MAP) of 40 mm Hg, which was held for 60 min, given 125 mL IV RescueFlow, held for a further 60 min, given whole blood, and held for a final 60 min. Tissue oxygen saturation, thromboelastography, oncotic pressure, urine volume and specific gravity, complete blood count, serum chemistry, body temperature, hematocrit, total solids, arterial and mixed venous blood gas, bispectral index, SAP, MAP, DAP, cardiac index, total blood volume (TBV) removed and returned, rate of hemorrhage and transfusion, spleen weight, heart rate (HR), arterial pH, lactate, PaO2, PaCO2, respiratory rate, cranial mesenteric and renal artery blood flow were recorded. Groups were compared using two-way ANOVA with post hoc Bonferroni (P < 0.05) for repeated measures or t test for non-repeated measures. RESULTS: Compared with the SSP swine, SP swine had higher HR post-splenectomy for the duration of the experiment (P < 0.03), and higher hematocrits at 15 and 60 min post splenectomy (P < 0.01, P < 0.001, respectively). SSP swine had greater TBV removed during hemorrhage (P < 0.01); however, when blood loss based on splenic weight was considered, TBV removed was similar between groups. CONCLUSION: Splenectomy likely accounts for the transient increase in hematocrit and the higher HR in SP swine prior to hemorrhage, and the differences in TBV removed between the two groups during hemorrhage. With a fixed end point model using a moderate rate of acute hemorrhage and an MAP of 40 mm Hg, splenectomy is not necessary and may confound results. PMID- 26974426 TI - 99MTc-Hexamethylpropyleneamine Oxime Imaging for Early Detection of Acute Lung Injury in Rats Exposed to Hyperoxia or Lipopolysaccharide Treatment. AB - Tc-Hexamethylpropyleneamine oxime (HMPAO) is a clinical single-photon emission computed tomography biomarker of tissue oxidoreductive state. Our objective was to investigate whether HMPAO lung uptake can serve as a preclinical marker of lung injury in two well-established rat models of human acute lung injury (ALI).Rats were exposed to >95% O2 (hyperoxia) or treated with intratracheal lipopolysaccharide (LPS), with first endpoints obtained 24 h later. HMPAO was administered intravenously before and after treatment with the glutathione depleting agent diethyl maleate (DEM), scintigraphy images were acquired, and HMPAO lung uptake was quantified from the images. We also measured breathing rates, heart rates, oxygen saturation, bronchoalveolar lavage (BAL) cell counts and protein, lung homogenate glutathione (GSH) content, and pulmonary vascular endothelial filtration coefficient (Kf).For hyperoxia rats, HMPAO lung uptake increased after 24 h (134%) and 48 h (172%) of exposure. For LPS-treated rats, HMPAO lung uptake increased (188%) 24 h after injury and fell with resolution of injury. DEM reduced HMPAO uptake in hyperoxia and LPS rats by a greater fraction than in normoxia rats. Both hyperoxia exposure (18%) and LPS treatment (26%) increased lung homogenate GSH content, which correlated strongly with HMPAO uptake. Neither of the treatments had an effect on Kf at 24 h. LPS-treated rats appeared healthy but exhibited mild tachypnea, BAL, and histological evidence of inflammation, and increased wet and dry lung weights. These results suggest the potential utility of HMPAO as a tool for detecting ALI at a phase likely to exhibit minimal clinical evidence of injury. PMID- 26974427 TI - Shed Pleural Blood from Traumatic Hemothorax Contains Elevated Levels of Pro Inflammatory Cytokines. AB - PURPOSE: The autotransfusion of unwashed (or unprocessed) shed hemothorax blood (USHB) in trauma patients is widely assumed to be beneficial; however, the inflammatory potential of shed pleural blood has not been thoroughly studied. Since previous studies have documented marked changes in coagulation function of shed pleural blood, we hypothesized that its level of inflammatory cytokines would be elevated. METHODS: A prospective observational study of trauma patients in whom cytokine levels from USHB were compared to venous samples from healthy volunteers was conducted. Differences between the cytokine content of patient derived samples were compared to those from healthy subjects. RESULTS: There was a statistically significant increase in pro-inflammatory cytokines (IL-6, IL-8, TNFalpha, GM-CSF), a pro-inflammatory Th-1 cytokine (IFNgamma), and anti inflammatory Th-2 cytokines (IL-4 and IL-10) in shed pleural blood over four hours when compared with samples from healthy controls (P <0.05). Cytokine levels in USHB are approximately 10- to 100-fold higher compared with healthy control venous samples. CONCLUSIONS: USHB, even collected within the accepted four-hour window, contains significantly elevated cytokine levels, suggesting the potential for deleterious effects from autotransfusion. Randomized trials are needed to determine the safety and efficacy of autotransfusion in trauma patients. PMID- 26974425 TI - Pancreatic Islet Responses to Metabolic Trauma. AB - Carbohydrate, lipid, and protein metabolism are largely controlled by the interplay of various hormones, which includes those secreted by the pancreatic islets of Langerhans. While typically representing only 1% to 2% of the total pancreatic mass, the islets have a remarkable ability to adapt to disparate situations demanding a change in hormone release, such as peripheral insulin resistance. There are many different routes to the onset of insulin resistance, including obesity, lipodystrophy, glucocorticoid excess, and the chronic usage of atypical antipsychotic drugs. All of these situations are coupled to an increase in pancreatic islet size, often with a corresponding increase in insulin production. These adaptive responses within the islets are ultimately intended to maintain glycemic control and to promote macronutrient homeostasis during times of stress. Herein, we review the consequences of specific metabolic trauma that lead to insulin resistance and the corresponding adaptive alterations within the pancreatic islets. PMID- 26974428 TI - Size and dimensionality dependent phonon conductivity in nanocomposites. AB - We have studied size and dimensionality dependent phonon conductivity of PbTe PbSe nanocomposites by considering three configurations: superlattice, embedded nanowire and embedded nanodot. Calculations have been performed in the framework of an effective medium theory. The required bulk thermal conductivities of PbTe and PbSe are evaluated by using Callaway's effective relaxation-time theory, and by accounting for relevant scattering mechanism including three-phonon Normal and Umklapp interactions involving acoustic as well as optical branches. The thermal interface resistance is computed using the diffuse mismatch theory. It is found that the size (thickness) and volume fraction of PbSe are the two main factors that control the effective thermal conductivity in these nanocomposites. In particular, for PbSe size d = 10 nm and volume fraction Vf = 0.1, our results predict significant reductions over the weighted average of room-temperature bulk results of 9%, 17% and 15% in the conductivity across the interfaces for the superlattice, embedded nanowire, and nanosphere structures, respectively. For a given Vf, an increase in d reduces the interface density and the effective conductivity varies approximately as [Formula: see text]. It is shown that nanocompositing in any of the three configurations can beat the alloy limit for lattice thermal conductivity. PMID- 26974429 TI - Sodium Selenite Acts as an Otoprotectant against Neomycin-Induced Hair Cell Damage in a Zebrafish Model. AB - Sodium selenite is a trace element essential for many physiological functions in the body. It is involved in various biological processes; it acts as a cofactor for antioxidant enzymes that protect against free radicals and is reported to limit metal-mediated oxidative DNA damage. In the present study, we investigated the effect of sodium selenite on neomycin ototoxicity in wild-type and transgenic zebrafish (Brn3C: EGFP). Five or six days post-fertilization, zebrafish larvae were co-exposed to 125 MUM neomycin and various concentrations (10 MUM, 100 MUM, 250 MUM, and 500 MUM) of sodium selenite for 1 h. Hair cells within neuromasts of the supraorbital (SO1 and SO2), otic (O1), and occipital (OC1) lateral lines were analyzed by fluorescence microscopy (n = 10 fish per treatment). Hair cell survival was estimated as the ratio of the hair cell numbers in each group compared to those of the control group that were not exposed to neomycin. Apoptosis and hair cell damage of neuromasts were evaluated using the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) assay and 2-[4-(dimethylamino) styryl]-N-ethylpyridinium iodide (DASPEI) assay, respectively. Ultrastructural changes were evaluated using scanning electron microscopy and transmission electron microscopy. Neuromast hair cells were preserved in zebrafish exposed to 125 MUM neomycin and 500 MUM sodium selenite for 1 h. Sodium selenite protected against neomycin-induced hair cell loss of neuromasts, reduced apoptosis, and prevented zebrafish ultrastructural changes. We propose that sodium selenite protects against neomycin-induced hair cell damage by inhibiting apoptosis, decreasing the disarray of stereocilia, and preventing ultrastructural changes in the neuromast hair cells of the zebrafish. PMID- 26974431 TI - A prognostic index for patients within the intermediate stage of hepatocellular carcinoma. AB - OBJECTIVE: The Barcelona Clinic Liver Cancer algorithm is the most widely used staging system for hepatocellular carcinoma, but the intermediate stage of this classification comprises a very heterogeneous group of patients with different survival probabilities. The aim of our study was to construct a simple prognostic index for identifying subgroups of patients with different prognoses within the intermediate stage. PATIENTS AND METHODS: Three-hundred and seven patients were retrospectively analyzed and randomly divided into a training sample (n=205), from which the model was developed, and a test sample (n=102), to independently assess the model's performance. RESULTS: Four variables were retained in the final multivariate model: hepatic failure, number of nodules, alpha-fetoprotein, and albumin, with hazard ratios equal to 2.22 (95% confidence interval: 1.52 3.24), 1.47 (1.00-2.18), 2.34 (1.56-3.52), and 1.75 (1.26-2.44), respectively. The score system was derived by summing up the linear weights assigned to the four covariates according to the observed regression coefficients. The score ranged between 4 and 13; to avoid sparse-data bias arising from small numbers within strata, only four categories (4-5, 6-7, 8-9, 10-13) were identified. The prognosis worsened significantly with increasing score and the C-index for discriminatory accuracy was equal to 0.66 (95% confidence interval: 0.60-0.72). The score was validated in the test sample (log-rank test P=0.02). Similar results were found when evaluating the score as a continuous variable. CONCLUSION: The simple prognostic index predicts survival in patients with intermediate-stage hepatocellular carcinoma. This score might help guide treatment selection and patient stratification in clinical studies. PMID- 26974430 TI - Effects of Group Drumming Interventions on Anxiety, Depression, Social Resilience and Inflammatory Immune Response among Mental Health Service Users. AB - Growing numbers of mental health organizations are developing community music making interventions for service users; however, to date there has been little research into their efficacy or mechanisms of effect. This study was an exploratory examination of whether 10 weeks of group drumming could improve depression, anxiety and social resilience among service users compared with a non music control group (with participants allocated to group by geographical location.) Significant improvements were found in the drumming group but not the control group: by week 6 there were decreases in depression (-2.14 SE 0.50 CI 3.16 to -1.11) and increases in social resilience (7.69 SE 2.00 CI 3.60 to 11.78), and by week 10 these had further improved (depression: -3.41 SE 0.62 CI 4.68 to -2.15; social resilience: 10.59 SE 1.78 CI 6.94 to 14.24) alongside significant improvements in anxiety (-2.21 SE 0.50 CI -3.24 to -1.19) and mental wellbeing (6.14 SE 0.92 CI 4.25 to 8.04). All significant changes were maintained at 3 months follow-up. Furthermore, it is now recognised that many mental health conditions are characterised by underlying inflammatory immune responses. Consequently, participants in the drumming group also provided saliva samples to test for cortisol and the cytokines interleukin (IL) 4, IL6, IL17, tumour necrosis factor alpha (TNFalpha), and monocyte chemoattractant protein (MCP) 1. Across the 10 weeks there was a shift away from a pro-inflammatory towards an anti-inflammatory immune profile. Consequently, this study demonstrates the psychological benefits of group drumming and also suggests underlying biological effects, supporting its therapeutic potential for mental health. TRIAL REGISTRATION: ClinicalTrials.gov NCT01906892. PMID- 26974434 TI - Small-Field Measurements of 3D Polymer Gel Dosimeters through Optical Computed Tomography. AB - With advances in therapeutic instruments and techniques, three-dimensional dose delivery has been widely used in radiotherapy. The verification of dose distribution in a small field becomes critical because of the obvious dose gradient within the field. The study investigates the dose distributions of various field sizes by using NIPAM polymer gel dosimeter. The dosimeter consists of 5% gelatin, 5% monomers, 3% cross linkers, and 5 mM THPC. After irradiation, a 24 to 96 hour delay was applied, and the gel dosimeters were read by a cone beam optical computed tomography (optical CT) scanner. The dose distributions measured by the NIPAM gel dosimeter were compared to the outputs of the treatment planning system using gamma evaluation. For the criteria of 3%/3 mm, the pass rates for 5 * 5, 3 * 3, 2 * 2, 1 * 1, and 0.5 * 0.5 cm2 were as high as 91.7%, 90.7%, 88.2%, 74.8%, and 37.3%, respectively. For the criteria of 5%/5 mm, the gamma pass rates of the 5 * 5, 3 * 3, and 2 * 2 cm2 fields were over 99%. The NIPAM gel dosimeter provides high chemical stability. With cone-beam optical CT readouts, the NIPAM polymer gel dosimeter has potential for clinical dose verification of small-field irradiation. PMID- 26974433 TI - Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations. AB - Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy. We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD. C21orf2 mutations have been recently found to cause isolated retinal degeneration and Jeune syndrome. We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds. The pathogenic effects of the splicing (splice-site and branch-point) mutations were confirmed on RNA level, which showed complex patterns of abnormal splicing. C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora. Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD. Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation. C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function. Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina. PMID- 26974432 TI - Association of Maternal Immunity with Rotavirus Vaccine Immunogenicity in Zambian Infants. AB - INTRODUCTION: Live attenuated oral vaccines against rotavirus (RV) have been shown to be less efficacious in children from developing countries. Reasons for this disparity are not fully understood. We assessed the role of maternal factors including breast milk RV-specific IgA, transplacentally acquired infant serum RV specific IgG and maternal HIV status in seroconversion among Zambian infants routinely immunized with RotarixTM (RV1). METHODS: 420 mother-child pairs were recruited at infant age 6-12 weeks in Lusaka. Clinical information and samples were collected at baseline and at one month following the second dose of RV1. Determination of breast milk RV-specific IgA and serum RV-specific IgA and IgG was done using standardized ELISA. Seroconversion was defined as a >= 4 fold rise in serum IgA titre from baseline to one-month post RV1 dose 2, while seropositivity of IgA was defined as serum titre >= 40 and antibody variables were modelled on log-base 2. Logistic regression was used to identify predictors of the odds of seroconversion. RESULTS: Baseline infant seropositivity was 25.5% (91/357). The seroconversion frequency was 60.2% (130/216). Infants who were IgA seropositive at baseline were less likely to seroconvert compared to their seronegative counterparts (P = 0.04). There was no evidence of an association between maternal HIV status and seroconversion (P = 0.25). Higher titres of breast milk rotavirus-specific IgA were associated with a lower frequency of seroconverson (Nonparametric test for trend Z = -2.84; P<0.01): a two-fold increase in breast milk RV-specific IgA titres was associated with a 22% lower odds of seroconversion (OR = 0.80; 95% CI = 0.68-0.94; P = 0.01). There was seasonal variation in baseline breast milk rotavirus-specific IgA titres, with significantly higher GMTs during the cold dry months (P = 0.01). CONCLUSION: Low immunogenicity of RV1 vaccine could be explained in part by exposure to high antibody titres in breast milk and early exposure to wild-type rotavirus infections. Potential interference of anti-RV specific IgA in breast milk and pre vaccination serum RV specific-IgA and IgG titres with RV1 seroconversion and effectiveness requires further research. PMID- 26974435 TI - Seeking Optimal Region-Of-Interest (ROI) Single-Value Summary Measures for fMRI Studies in Imaging Genetics. AB - A data-driven hypothesis-free genome-wide association (GWA) approach in imaging genetics studies allows screening the entire genome to discover novel genes that modulate brain structure, chemistry, and function. However, a whole brain voxel wise analysis approach in such genome-wide based imaging genetic studies can be computationally intense and also likely has low statistical power since a stringent multiple comparisons correction is needed for searching over the entire genome and brain. In imaging genetics with functional magnetic resonance imaging (fMRI) phenotypes, since many experimental paradigms activate focal regions that can be pre-specified based on a priori knowledge, reducing the voxel-wise search to single-value summary measures within a priori ROIs could prove efficient and promising. The goal of this investigation is to evaluate the sensitivity and reliability of different single-value ROI summary measures and provide guidance in future work. Four different fMRI databases were tested and comparisons across different groups (patients with schizophrenia, their siblings, vs. normal control subjects; across genotype groups) were conducted. Our results show that four of these measures, particularly those that represent values from the top most activated voxels within an ROI are more powerful at reliably detecting group differences and generating greater effect sizes than the others. PMID- 26974436 TI - Geranylated 4-Phenylcoumarins Exhibit Anticancer Effects against Human Prostate Cancer Cells through Caspase-Independent Mechanism. AB - Geranylated 4-phenylcoumarins, DMDP-1 & -2 isolated from Mesua elegans were investigated for anticancer potential against human prostate cancer cells. Treatment with DMDP-1 & -2 resulted in cell death in a time and dose dependent manner in an MTT assay on all cancer cell lines tested with the exception of lung adenocarcinoma cells. DMDP-1 showed highest cytotoxic efficacy in PC-3 cells while DMDP-2 was most potent in DU 145 cells. Flow cytometry indicated that both coumarins were successful to induce programmed cell death after 24 h treatment. Elucidation on the mode-of-action via protein arrays and western blotting demonstrated death induced without any significant expressions of caspases, Bcl-2 family proteins and cleaved PARP, thus suggesting the involvement of caspase independent pathways. In identifying autophagy, analysis of GFP-LC3 showed increased punctate in PC-3 cells pre-treated with CQ and treated with DMDP-1. In these cells decreased expression of autophagosome protein, p62 and cathepsin B further confirmed autophagy. In contrary, the DU 145 cells pre-treated with CQ and treated with DMDP-2 has reduced GFP-LC3 punctate although the number of cells with obvious GFP-LC3 puncta was significantly increased in the inhibitor-treated cells. The increase level of p62 suggested leakage of cathepsin B into the cytosol to trigger potential downstream death mediators. This correlated with increased expression of cathepsin B and reduced expression after treatment with its inhibitor, CA074. Also auto-degradation of calpain-2 upon treatment with DMDP 1 &-2 and its inhibitor alone, calpeptin compared with the combination treatment, further confirmed involvement of calpain-2 in PC-3 and DU 145 cells. Treatment with DMDP-1 & -2 also showed up-regulation of total and phosphorylated p53 levels in a time dependent manner. Hence, DMDP-1 & -2 showed ability to activate multiple death pathways involving autophagy, lysosomal and endoplasmic reticulum death proteins which could potentially be manipulated to develop anti-cancer therapy in apoptosis resistant cells. PMID- 26974437 TI - The Role of Porcine Monocyte Derived Dendritic Cells (MoDC) in the Inflammation Storm Caused by Streptococcus suis Serotype 2 Infection. AB - BACKGROUND: Streptococcus suis is an important swine pathogen and zoonotic agent. Infection with this highly pathogenic strain can cause streptococcal toxic shock like syndrome (STSLS), characterized by a Th-1 inflammatory cytokine storm, and a high mortality rate. Monocyte derived dendritic cells (MoDCs) are known to stimulate Th-1 cell differentiation, but the role of MoDCs in STSLS remains to be elucidated. METHODOLOGY AND FINDINGS: Porcine CD14-positive monocytes, purified from peripheral blood mononuclear cells (PBMCs), were used to generate MoDCs using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Highly pure MoDCs were generated, as proved by their morphology, phenotype analysis, phagocytic ability, and induction of T cells proliferation. The MoDCs were further stimulated by the virulent S. suis serotype 2 (SS2) SC19 strain which triggered a strong release of several pro-inflammatory cytokines, including IL-1beta, IL-8, TNF-alpha, IFN-gamma, and IL-12. Furthermore, the stimulated MoDCs induced CD4+ T cell differentiation towards Th-1 cells in vitro. CONCLUSIONS: The results of this study indicated that the porcine MoDCs stimulated by SS2 could release high levels of Th-1 inflammatory cytokines and induce CD4+ T cell differentiation towards Th-1 cells. Hence, it is likely that porcine MoDCs play an important role in the STSLS caused by SS2. PMID- 26974439 TI - Abiotic Protein Fragmentation by Manganese Oxide: Implications for a Mechanism to Supply Soil Biota with Oligopeptides. AB - The ability of plants and microorganisms to take up organic nitrogen in the form of free amino acids and oligopeptides has received increasing attention over the last two decades, yet the mechanisms for the formation of such compounds in soil environments remain poorly understood. We used Nuclear Magnetic Resonance (NMR) and Electron Paramagnetic Resonance (EPR) spectroscopies to distinguish the reaction of a model protein with a pedogenic oxide (Birnessite, MnO2) from its response to a phyllosilicate (Kaolinite). Our data demonstrate that birnessite fragments the model protein while kaolinite does not, resulting in soluble peptides that would be available to soil biota and confirming the existence of an abiotic pathway for the formation of organic nitrogen compounds for direct uptake by plants and microorganisms. The absence of reduced Mn(II) in the solution suggests that birnessite acts as a catalyst rather than an oxidant in this reaction. NMR and EPR spectroscopies are shown to be valuable tools to observe these reactions and capture the extent of protein transformation together with the extent of mineral response. PMID- 26974438 TI - Control of Methicillin-Resistant Staphylococcus aureus Pneumonia Utilizing TLR2 Agonist Pam3CSK4. AB - The spread of methicillin-resistant Staphylococcus aureus (MRSA) is a critical health issue that has drawn greater attention to the potential use of immunotherapy. Toll-like receptor 2 (TLR2), a pattern recognition receptor, is an essential component in host innate defense system against S. aureus infection. However, little is known about the innate immune response, specifically TLR2 activation, against MRSA infection. Here, we evaluate the protective effect and the mechanism of MRSA murine pneumonia after pretreatment with Pam3CSK4, a TLR2 agonist. We found that the MRSA-pneumonia mouse model, pretreated with Pam3CSK4, had reduced bacteria and mortality in comparison to control mice. As well, lower protein and mRNA levels of TNF-alpha, IL-1beta and IL-6 were observed in lungs and bronchus of the Pam3CSK4 pretreatment group. Conversely, expression of anti inflammatory cytokine IL-10, but not TGF-beta, increased in Pam3CSK4-pretreated mice. Our additional studies showed that CXCL-2 and CXCL1, which are necessary for neutrophil recruitment, were less evident in the Pam3CSK4-pretreated group compared to control group, whereas the expression of Fcgamma receptors (FcgammaI/III) and complement receptors (CR1/3) increased in murine lungs. Furthermore, we found that increased survival and improved bacterial clearance were not a result of higher levels of neutrophil infiltration, but rather a result of enhanced phagocytosis and bactericidal activity of neutrophils in vitro and in vivo as well as increased robust oxidative activity and release of lactoferrin. Our cumulative findings suggest that Pam3CSK4 could be a novel immunotherapeutic candidate against MRSA pneumonia. PMID- 26974442 TI - Correction: Decreased TUSC3 Promotes Pancreatic Cancer Proliferation, Invasion and Metastasis. PMID- 26974443 TI - Compressible Graphene-Coated Polymer Foams with Ultralow Density for Adjustable Electromagnetic Interference (EMI) Shielding. AB - The fabrication of low-density and compressible polymer/graphene composite (PGC) foams for adjustable electromagnetic interference (EMI) shielding remains a daunting challenge. Herein, ultralightweight and compressible PGC foams have been developed by simple solution dip-coating of graphene on commercial polyurethane (PU) sponges with highly porous network structure. The resultant PU/graphene (PUG) foams had a density as low as ~0.027-0.030 g/cm(3) and possessed good comprehensive EMI shielding performance together with an absorption-dominant mechanism, possibly due to both conductive dissipation and multiple reflections and scattering of EM waves by the inside 3D conductive graphene network. Moreover, by taking advantage of their remarkable compressibility, the shielding performance of the PUG foams could be simply adjusted through a simple mechanical compression, showing promise for adjustable EMI shielding. We believe that the strategy for fabricating PGC foams through a simple dip-coating method could potentially promote the large-scale production of lightweight foam materials for EMI shielding. PMID- 26974441 TI - Experimental Persistent Infection of BALB/c Mice with Small-Colony Variants of Burkholderia pseudomallei Leads to Concurrent Upregulation of PD-1 on T Cells and Skewed Th1 and Th17 Responses. AB - BACKGROUND: Burkholderia pseudomallei (B. pseudomallei), the causative agent of melioidosis, is a deadly pathogen endemic across parts of tropical South East Asia and Northern Australia. B. pseudomallei can remain latent within the intracellular compartment of the host cell over prolonged periods of time, and cause persistent disease leading to treatment difficulties. Understanding the immunological mechanisms behind persistent infection can result in improved treatment strategies in clinical melioidosis. METHODS: Ten-day LD50 was determined for the small-colony variant (SCV) and its parental wild-type (WT) via intranasal route in experimental BALB/c mice. Persistent B. pseudomallei infection was generated by administrating sub-lethal dose of the two strains based on previously determined LD50. After two months, peripheral blood mononuclear cells (PBMCs) and plasma were obtained to investigate host immune responses against persistent B. pseudomallei infection. Lungs, livers, and spleens were harvested and bacterial loads in these organs were determined. RESULTS: Based on the ten-day LD50, the SCV was ~20-fold less virulent than the WT. The SCV caused higher bacterial loads in spleens compared to its WT counterparts with persistent B. pseudomallei infection. We found that the CD4+ T cell frequencies were decreased, and the expressions of PD-1, but not CTLA-4 were significantly increased on the CD4+ and CD8+ T cells of these mice. Notably, persistent infection with the SCV led to significantly higher levels of PD-1 than the WT B. pseudomallei. Plasma IFN-gamma, IL-6, and IL-17A levels were elevated only in SCV-infected mice. In addition, skewed plasma Th1 and Th17 responses were observed in SCV-infected mice relative to WT-infected and uninfected mice. CONCLUSION: B. pseudomallei appears to upregulate the expression of PD-1 on T cells to evade host immune responses, which likely facilitates bacterial persistence in the host. SCVs cause distinct pathology and immune responses in the host as compared to WT B. pseudomallei. PMID- 26974440 TI - Effects of Hormone Therapy on Brain Volumes Changes of Postmenopausal Women Revealed by Optimally-Discriminative Voxel-Based Morphometry. AB - BACKGROUNDS: The Women's Health Initiative Memory Study Magnetic Resonance Imaging (WHIMS-MRI) provides an opportunity to evaluate how menopausal hormone therapy (HT) affects the structure of older women's brains. Our earlier work based on region of interest (ROI) analysis demonstrated potential structural changes underlying adverse effects of HT on cognition. However, the ROI-based analysis is limited in statistical power and precision, and cannot provide fine grained mapping of whole-brain changes. METHODS: We aimed to identify local structural differences between HT and placebo groups from WHIMS-MRI in a whole brain refined level, by using a novel method, named Optimally-Discriminative Voxel-Based Analysis (ODVBA). ODVBA is a recently proposed imaging pattern analysis approach for group comparisons utilizing a spatially adaptive analysis scheme to accurately locate areas of group differences, thereby providing superior sensitivity and specificity to detect the structural brain changes over conventional methods. RESULTS: Women assigned to HT treatments had significant Gray Matter (GM) losses compared to the placebo groups in the anterior cingulate and the adjacent medial frontal gyrus, and the orbitofrontal cortex, which persisted after multiple comparison corrections. There were no regions where HT was significantly associated with larger volumes compared to placebo, although a trend of marginal significance was found in the posterior cingulate cortical area. The CEE-Alone and CEE+MPA groups, although compared with different placebo controls, demonstrated similar effects according to the spatial patterns of structural changes. CONCLUSIONS: HT had adverse effects on GM volumes and risk for cognitive impairment and dementia in older women. These findings advanced our understanding of the neurobiological underpinnings of HT effects. PMID- 26974444 TI - A Lifetime of Critical Care: Changes. PMID- 26974445 TI - Give Me Your Tired, Your Poor, Your Huddled Masses Yearning to Breathe Free. PMID- 26974446 TI - Elderly Patients in the ICU: Worth It or Not? PMID- 26974447 TI - Measuring Impact: Citation Rates and the Quest to Identify Meaningful Clinical Research in Critical Care Medicine. PMID- 26974448 TI - Cytokine Imbalance Predicts Poor Outcomes in Staphylococcus aureus Bacteremia- But What Can We Do About It? PMID- 26974449 TI - Can a Lack of Extended-Spectrum beta-Lactamase-Producing Enterobacteriaceae Rectal Carriage Help Avoid Carbapenem Prescription? PMID- 26974450 TI - Biomarkers in Severe Sepsis and Septic Shock: Just Listen to the Heart? PMID- 26974451 TI - Analgesia, Sedation, and Intracranial Pressure: Questioning Our Approach in Pediatric Traumatic Brain Injury. PMID- 26974452 TI - Multiple Ways of Targeting the Adenosine/Adenosine Receptor Axis in Lung Inflammation and Injury. PMID- 26974453 TI - Is Matrix Metalloproteinase-8 Activity in the Mucosal Barrier a Requirement for Leakage of Cecal Material in Peritonitis? PMID- 26974454 TI - Appropriate Antibiotic Therapy and WBC in Sepsis: Factors to Consider. PMID- 26974455 TI - The authors reply. PMID- 26974456 TI - First-Line Vasoactive Drugs for Pediatric Septic Shock: Changing the Paradigm? PMID- 26974457 TI - The authors reply. PMID- 26974458 TI - Systematic Bias in Meta-Analyses of Time to Antimicrobial in Sepsis Studies. PMID- 26974459 TI - The authors reply. PMID- 26974460 TI - Time for a Randomized Controlled Trial to Investigate Optimal Time to Antibiotics for Patients With Sepsis. PMID- 26974461 TI - The authors reply. PMID- 26974462 TI - Targeted Temperature Management: A Potential Adjuvant Antiepileptic Therapy in Postanoxic Status Epilepticus. PMID- 26974463 TI - Reverse Physiology, i.e., Cellular Versus Integrative Versus Comparative Physiology? alpha-2 Agonists and Septic Shock. PMID- 26974464 TI - Soy Consumption with Risk of Coronary Heart Disease and Stroke: A Meta-Analysis of Observational Studies. AB - BACKGROUND: The association of soy product consumption with the relative risk of cardiovascular disease remains controversial. This meta-analysis aimed at investigating whether an association exists between soy consumption and the risk of stroke and coronary heart disease (CHD) in observational studies. METHODS: A systematic search of the PubMed and EMBASE databases was performed for case control and cohort studies that assessed soy consumption and the risk of stroke and CHD. Summary relative risks (SRRs) and 95% CIs were combined by using a random-effects model. RESULTS: Of a total of 1,266 abstracts, 5 prospective cohort and 6 case-control studies met our inclusion criteria, and comprised 4,954 stroke and 7,616 CHD events. Based on the high vs. low analyses, combining cohort studies showed no association between soy intake and risk of stroke (SRR 0.92; 95% CI 0.70-1.10; Pheterogeneity = 0.236; I2 = 29.4%) or CHD (SRR 0.97; 95% CI 0.74-1.27; Pheterogeneity = 0.020; I2 = 62.7%), although a significantly inverse association between soy intake and the risk of stroke (SRR 0.54; 95% CI 0.34 0.87; Pheterogeneity = 0.001; I2 = 79.3%) and CHD (SRR 0.66; 95% CI 0.56-0.77; Pheterogeneity = 0.421; I2 = 0) was observed in case-control studies. No association between soy isoflavone intake and the risk of stroke and CHD was identified. CONCLUSION: There was limited evidence to indicate that soy consumption was inversely associated with the risk of stroke and CHD, although further studies, with prospective designs that use validated questionnaires and control for important confounders, are warranted. PMID- 26974465 TI - Roots of Acetate-Vanadium Linkage Isomerism: A QTAIM Study. AB - The possibility of linkage isomerism in a number of vanadium(IV) and vanadium(V) complexes with acetate was surveyed using Density Functional Theory (DFT) and Bader's Quantum Theory of Atoms in Molecules (QTAIM). The results show that vanadium-acetate linkages may be classified as bidentate symmetrical, bidentate asymmetrical, or monodentate, the latter being observed in about 40% of the cases. These latter ones correspond to situations where the two oxygen atoms of the acetate moiety are not equivalent. They are associated with an energy penalty of about 263 kJ.mol(-1), as determined by the distribution of the scaled kinetic energy of the atomic basins forming the acetate ligand. In the presence of bidentate symmetrical vanadium-acetate linkages, the inner valence-shell charge concentrations on the vanadium atom deviate from the traditional VSEPR-derived arrangement, with an energy penalty of about 780 kJ.mol(-1). A compromise situation is partially accomplished in the case of bidentate asymmetrical linkages, which allow a Gillespiean-like arrangement of the inner valence-shell charge concentrations. In this case, one of these local charge concentrations lies close to a V-OAcO bond, which slightly disrupts the equivalence between the two oxygen atoms in the acetate ligand. PMID- 26974466 TI - Post-Surgical and Oncologic Outcomes of Supracricoid Partial Laryngectomy: A Single-Institution Report of Ninety Cases. AB - OBJECTIVE: The aim of this study was to report the post-surgical and oncologic outcomes of patients who underwent supracricoid partial laryngectomy (SCPL). METHODS: 90 patients who underwent SCPL between 1994 and 2014 were reviewed. 45 patients underwent cricohyoidopexy (CHP) and 45 patients cricohyoidoepiglottopexy (CHEP). Median nasogastric (NG) tube removal time, decannulation time, overall survival, disease-free survival and local control rates were calculated. The effect of the type of surgery on functional and oncologic outcomes were assessed. RESULTS: Median NG tube removal time was 16.5 days (IQR = 10) and 14 days (IQR = 9) in CHP and CHEP patients, respectively (p > 0.05). Median decannulation time was 30 days (IQR = 26) and 19 days (IQR = 15) in CHP and CHEP patients, respectively (p < 0.05). Resection of one arytenoid significantly increased NG tube removal time. Median follow-up time was 55 months. There were 15 oncologic failures and the median time interval for tumor recurrence was 9 months. Five year overall survival rate was 80.4%. The 3- and 5-year disease-free specific survival rates were 81.7 and 76.7%, respectively. CONCLUSIONS: Given the more extensive surgery applied for CHP, functional outcomes were better in patients with CHEP. Resection of an arytenoid had a negative outcome on swallowing. PMID- 26974467 TI - Diversely Substituted Quinolines via Rhodium-Catalyzed Alkyne Hydroacylation. AB - The Rh-catalyzed hydroacylative union of aldehydes and o-alkynyl anilines leads to 2-aminophenyl enones, and onward to substituted quinolines. The mild reaction conditions employed in this chemistry result in a process that displays broad functional group tolerance, allowing the preparation of diversely substituted quinolines in high yields. Extension to the use of o-alkynyl nitro arenes as substrates leads to 2-nitrochalcones, from which both quinolines and quinoline N oxides can be accessed. PMID- 26974468 TI - Comparison of Macular Integrity Assessment (MAIA TM), MP-3, and the Humphrey Field Analyzer in the Evaluation of the Relationship between the Structure and Function of the Macula. AB - PURPOSE: This study was conducted in order to compare relationships between the macular visual field (VF) mean sensitivity measured by MAIATM (Macular Integrity Assessment), MP-3, or Humphry field analyzer (HFA) and the ganglion cell and inner plexiform layer (GCA) thicknesses. METHODS: This cross-sectional study examined 73 glaucoma patients and 19 normal subjects. All subjects underwent measurements for GCA thickness by Cirrus HD-OCT and static threshold perimetry using MAIATM, MP-3, or HFA. VF and OCT in the retinal view were used to examine both the global relationship between the VF sensitivity and GCA thickness, and the superior hemiretina and inferior hemiretina. The relationship between the GCA thickness and macular sensitivity was examined by Spearman correlation analysis. RESULTS: For each instrument, statistically significant macular VF sensitivity (dB) and GCA thickness relationships were observed using the decibel scale (R = 0.547-0.687, all P < 0.001). The highest correlation for the global (R = 0.682) and the superior hemiretina (R = 0.594) GCA thickness-VF mean sensitivity was observed by the HFA. The highest correlation for the inferior hemiretina (R = 0.687) GCA thickness-VF mean sensitivity was observed by the MP-3. Among the three VF measurement instruments, however, no significant differences were found for the structure-function relationships. CONCLUSIONS: All three VF measurement instruments found similar structure-function relationships in the central VF. PMID- 26974469 TI - Hydrogen Peroxide Promoted Mizoroki-Heck Reactions of Phenyldiazenes with Acrylates, Acrylamides, and Styrenes. AB - Mizoroki-Heck reactions, which are well-known for aryldiazonium salts and which have recently been described for arylhydrazines, have now been extended to phenyldiazenes. In situ generation of phenyldiazenes from azocarboxylates allowed clean and selective reactions with styrenes, acrylates, and acrylamides using palladium(II) acetate in the presence of silver(I) acetate or hydrogen peroxide as oxidant. Hydrogen peroxide was thereby shown to be a cheap and broadly applicable alternative for the established palladium-silver(I) system. PMID- 26974470 TI - Impact of Knowledge-Based Iterative Model Reconstruction in Abdominal Dynamic CT With Low Tube Voltage and Low Contrast Dose. AB - OBJECTIVE: The purpose of this study was to compare iterative model reconstruction (IMR) and hybrid iterative reconstruction (HIR) of 80-kVp abdominal dynamic CT scans obtained with a low-dose contrast agent. SUBJECTS AND METHODS: A group of 27 consecutively registered patients underwent abdominal dynamic CT with an 80-kVp protocol and a low dose of contrast agent (300 mg I/kg). Another 27 patients who had previously undergone a 120-kVp protocol with filtered back projection (FBP) and a standard contrast dose (600 mg I/kg) acted as control subjects. Effective dose, image noise, CT number, and contrast-to noise ratio were compared between the 120-kVp and 80-kVp images with FBP, HIR, and IMR. Image contrast, image noise, image sharpness, noise texture, and overall image quality were evaluated for the four protocols. RESULTS: The effective dose of the 80-kVp protocol was lower than that with the 120-kVp protocol. The 80-kVp protocol with HIR and IMR decreased image noise by 45% and 70% compared with the 80-kVp protocol with FBP. The contrast-to-noise ratio of the 80-kVp protocol with IMR was higher than that of the 120-kVp protocol. Qualitatively, the 80-kVp protocol with IMR improved image noise more than the 120-kVp protocol did, but noise texture was worse. HIR and the 120-kVp protocol yielded similar subjective image quality. CONCLUSION: Use of the 80-kVp protocol with HIR allowed an approximately 50% reduction in contrast dose and an approximately 40% reduction in radiation dose compared with use of the 120-kVp protocol while preserving image quality. IMR reduced image noise more than HIR with this protocol but worsened noise texture. PMID- 26974471 TI - Three-Year Follow-Up of a Prenatally Ascertained Apparently Non-Mosaic sSMC(10): Delineation of a Non-Critical Region. AB - Small supernumerary marker chromosomes (sSMC) originating from chromosome 10 are rare and usually found in mosaic form. We present a de novo apparently non-mosaic sSMC(10) prenatally diagnosed in amniotic fluid and postnatally confirmed in peripheral blood. Characterization by array-CGH showed a pericentromeric duplication of 7.1 Mb of chromosome 10. The fetus did not show ultrasound abnormalities, and a normal female phenotype was observed during a 3-year postnatal follow-up. The absence of phenotypic abnormalities in the present case provides evidence of a non-critical pericentromeric region in 10p11.21q11.1 (hg19 35,355,570-42,448,569) associated with a duplication. PMID- 26974472 TI - Correction: Human cytomegalovirus IE1 alters the higher-order chromatin structure by targeting the acidic patch of the nucleosome. PMID- 26974473 TI - Studying the R-branch and the Q-branch emission spectral lines of diatomic molecules using improved analytical formula. AB - The difference converging method (DCM) used to predict the R-branch and the Q branch high-lying rotational lines for diatomic systems is improved in this study. The key analytical formulae of the DCM method are modified by adding a higher order spectral term Hupsilon, and adding a physical converging criterion to improve the accuracy of predictions. Applications of the improved DCM method to the R-branch of the TiF molecule and the Q-branch of the (193)IrN molecule show that the accuracy of the R-branch and the Q-branch rotational lines is about one order of magnitude better than the results obtained using the previous formulae, which demonstrate the necessity of the added small term Hupsilon and the physical converging criterion. The DCM results are also shown to be better than the extrapolated rotational lines using the least-squares method. PMID- 26974474 TI - Intramolecular interactions, isomerization and vibrational frequencies of two paracetamol analogues: A spectroscopic and a computational approach. AB - The aim of this investigation was to determine the molecular properties and provide an interpretation of the vibrational mode couplings of these two paracetamol analogues: 2-bromo-2-methyl-N-(4-nitrophenyl)-propanamide and 2-bromo 2-methyl-N-p-tolyl-propanamide. E/Z isomers, keto/enol unimolecular rearrangement and prediction of the transition state structures in each mechanism were also assessed using the Density Functional Theory (DFT). The DFT estimates a high energy gap between E and Z isomers (9-11 kcal.mol(-1)), with barrier heights ranging from 16 to 19 kcal.mol(-1). In contrast, the barrier energies on the keto/enol isomerization are almost 10 kcal.mol(-1) higher than those estimated for the E/Z rearrangement. The kinetic rate constant was also determined for each reaction mechanism. Natural bond orbital analysis and the quantum theory of atoms in molecules were used to interpret the intramolecular hydrogen bonds and to understand the most important interactions that govern the stabilization of each isomer. Furthermore, an analysis of the atomic charge distribution using different population methodologies was also performed. PMID- 26974475 TI - Local structures and the dissolving behavior of aqueous ammonia and its KCl and NH4Cl solutions: A Raman spectroscopy and X-ray scattering study. AB - The aqueous ammonia (5%-15%) and its KCl and NH4Cl solutions have been studied by Raman spectroscopy and X-ray scattering. The microscopic structures in these solutions were proposed. The addition of KCl reinforced the hydrogen bond between NH3 and H2O. On contrary, NH4Cl destroyed this interaction by forming hydrogen bond NH4(+)-NH3. This study gave an interpretation of the different dissolving behavior of KCl and NH4Cl in aqueous ammonia, which may have important implications in the separation of potassium and ammonium salt during the industrial production. PMID- 26974476 TI - Student Evaluation of Faculty Physicians: Gender Differences in Teaching Evaluations. AB - PURPOSE: To investigate whether there is a difference in medical student teaching evaluations for male and female clinical physician faculty. METHODS: The authors examined all teaching evaluations completed by clinical students at one North American medical school in the surgery, obstetrics and gynecology, pediatrics, and internal medicine clinical rotations from 2008 to 2012. The authors focused on how students rated physician faculty on their "overall quality of teaching" using a 5-point response scale (1 = Poor to 5 = Excellent). Linear mixed-effects models provided estimated mean differences in evaluation outcomes by faculty gender. RESULTS: There were 14,107 teaching evaluations of 965 physician faculty. Of these evaluations, 7688 (54%) were for male physician faculty and 6419 (46%) were for female physician faculty. Female physicians received significantly lower mean evaluation scores in all four rotations. The discrepancy was largest in the surgery rotation (males = 4.23, females = 4.01, p = 0.003). Pediatrics showed the next greatest difference (males = 4.44, females = 4.29, p = 0.009), followed by obstetrics and gynecology (males = 4.38, females = 4.26, p = 0.026), and internal medicine (males = 4.35, females = 4.27, p = 0.043). CONCLUSIONS: Female physicians received lower teaching evaluations in all four core clinical rotations. This comprehensive examination adds to the medical literature by illuminating subtle differences in evaluations based on physician gender, and provides further evidence of disparities for women in academic medicine. PMID- 26974477 TI - Hyperspectral imaging of plasmon resonances in metallic nanoparticles. AB - The spectroscopy of metal nanoparticles shows great potential for label-free sensing. In this article we present a hyper-spectral imaging system combined with a microfluidic system, which allows full spectroscopic characterization of many individual nanoparticles simultaneously (>50 particles). With such a system we were able overcome several limitations that are present in LSPR sensing with nanoparticle ensemble. We experimentally quantified (incorporating atomic force microscopy as well) the correlation between geometry, position of plasmon resonance (lambdaPeak) and sensitivity of the particles (Sb=1.63lambdaPeak 812.47[nm/RIU]). We were able to follow the adsorption of protein layers and determined their spatial inhomogeneity with the help of the hyperspectral imaging. PMID- 26974479 TI - Occurrence, distribution, and potential affecting factors of organophosphate flame retardants in sewage sludge of wastewater treatment plants in Henan Province, Central China. AB - Organophosphate esters (OPEs) are widely used as flame retardants. In this study, the occurrence and distribution of six OPEs were investigated in sewage sludge from 24 wastewater treatment plants (WWTPs) in 18 cities of Henan province, Central China. The results indicated that all target OPEs were detected in the sludge samples with the detection rate of 95.8%, except tris(dichloropropyl)phosphate (TDCP). The total concentration of the six OPEs ranged from 38.6 to 508 MUg kg(-1). Tris(2-chloroethyl)phosphate (TCEP), tris(2 butoxyethyl)phosphate (TBEP), and tris(2-chloroiso-propyl)phosphate (TCPP) were found to be predominant, with concentrations ranging from 2.50 to 203, 1.60 to 383, and 6.70-161 MUg kg(-1), respectively. The potential factors affecting OPE levels in sewage sludge, such as wastewater source, sludge characteristics, operational conditions, treatment techniques, and total organic carbon (TOC) of sludge in WWTPs were investigated. The results indicated that the total concentration of OPEs in sewage sludge has no significant relationship with the individual parameters (p > 0.05). However, significant correlations were found between triphenyl phosphate (TPhP) level and treatment capacity (R = 0.484, p < 0.05), processing volume (R = 0.495, p < 0.05), and serving population (R = 0.591, p < 0.05). Furthermore, the relationship between treatment techniques and the total concentration of OPEs in sewage sludge was also investigated in this study, and the results illustrated that the levels of OPEs in sludge were independent of the solid retention time (SRT). PMID- 26974478 TI - Staying local-antigen presentation in the liver. AB - The liver is known as organ with unique immune competence. Besides its unique microenvironment that is determined by gut-derived portal venous blood constituents and the presence of enzymes with immune regulatory properties, liver antigen presenting cell populations regulate antigen-specific immunity in a local fashion. In addition to bone marrow-derived dendritic cells and myeloid cells such as macrophages and monocytes, also truly liver-resident cell populations function as antigen presenting cells such as liver sinusoidal endothelial cells and hepatocytes. The functional outcome of antigen-presentation by these cell populations is diverse and ranges from generation of regulatory CD4 cells, to induction of memory CD8 T cells or deletional tolerance, which generates a complex network of antigen-presenting cells that determines hepatic immune regulation and local immune surveillance against viral infection. PMID- 26974480 TI - Incorporating rice residues into paddy soils affects methylmercury accumulation in rice. AB - Paddy fields are characterized by frequent organic input (e.g., fertilization and rice residue amendment), which may affect mercury biogeochemistry and bioaccumulation. To explore potential effects of rice residue amendment on methylmercury (MMHg) accumulation in rice, a mercury-contaminated paddy soil was amended with rice root (RR), rice straw (RS) or composted rice straw (CS), and planted with rice. Incorporating RS or CS increased grain MMHg concentration by 14% or 11%. The observed increases could be attributed to the elevated porewater MMHg levels and thus enhanced MMHg uptake by plants, as well as increased MMHg translocation to grain within plants. Our results indicated for the first time that rice residue amendment could significantly affect MMHg accumulation in rice grain, which should be considered in risk assessment of MMHg in contaminated areas. PMID- 26974481 TI - The levels of mercury, methylmercury and selenium and the selenium health benefit value in grey-eel catfish (Plotosus canius) and giant mudskipper (Periophthalmodon schlosseri) from the Strait of Malacca. AB - The present study examined the concentrations of mercury (Hg), methylmercury (MeHg), and selenium (Se) in the multiple tissues of the Plotosus canius and Periophthalmodon schlosseri collected from the Strait of Malacca. The mean value in mg kg(-1) of Hg (P. canius: 0.34 +/- 0.19; P. schlosseri: 0.32 +/- 0.18) and MeHg in muscle (P. canius: 0.14 +/- 0.11; P. schlosseri: 0.17 +/- 0.11) were below the Codex general standard for contaminants and toxins in food and feed (CODEX STAN 193-1995), the Malaysian Food Regulation 1985 and the Japan Food Sanitation Law. For P. canius, the liver contained the highest concentrations of Hg (0.48 +/- 0.07 mg kg(-1)) and MeHg (0.21 +/- 0.00 mg kg(-1)), whereas for P. schlosseri, the gill contained the highest concentrations of Hg (0.36 +/- 0.06 mg kg(-1)) and MeHg (0.21 +/- 0.05 mg kg(-1)). The highest concentration of (80)Se (mg kg(-1)) was observed in the liver of P. canius (20.34 +/- 5.68) and in the gastrointestinal tract (3.18 +/- 0.42) of P. schlosseri. The selenium:mercury (Se:Hg) molar ratios were above 1 and the positive selenium health benefit value (HBVSe) suggesting the possible protective effects of Se against Hg toxicity. The estimate weekly intakes (EWIs) in MUg kg(-1) body weight (bw) week(-1) of Hg (P. canius: 0.27; P. schlosseri: 0.15) and MeHg (P. canius: 0.11; P. schlosseri: 0.08) were found to be lower than the provisional tolerable weekly intake established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). Based on the calculated EWIs, P. canius, and P. schlosseri were found to be unlikely to cause mercury toxicity in human consumption. PMID- 26974482 TI - Role of reducing agent in extraction of arsenic and heavy metals from soils by use of EDTA. AB - Although many metal-contaminated sites contain both anionic arsenic and cationic heavy metals, the current remediation technologies are not effective for the simultaneous removal of both anionic and cationic elements from the contaminated sites due to their different characteristics. In this study, the role of reducing agent in simultaneous extraction of As, Cu, Pb, and Zn from contaminated soils was investigated using EDTA. The addition of reducing agents, which includes sodium oxalate (Na2C2O4), ascorbic acid (C6H8O6) and sodium dithionite (Na2S2O4), greatly enhanced the EDTA extraction of both As and heavy metals from the contaminated soils due to the increased mobility of the metals under the reduced conditions. The extent of the enhancement of the EDTA extraction was greatly affected by the reducing conditions. Strong reducing conditions (0.1 M of dithionite) were required for the extraction of metals strongly bound to the soil, while weak reducing conditions (0.01 M of dithionite or 0.1 M of oxalate/ascorbic acid) were sufficient for extraction of metals that were relatively weakly bound to the soil. An almost 90% extraction efficiency of total metals (As, Cu, Zn, and Pb) was obtained from the contaminated soils using the combination of dithionite and EDTA. Our results clearly showed that the combination of dithionite and EDTA can effectively extract As and heavy metals simultaneously from soils under a wide range of pH conditions. PMID- 26974483 TI - Isotope Inversion Experiment evaluating the suitability of calibration in surrogate matrix for quantification via LC-MS/MS-Exemplary application for a steroid multi-method. AB - For quotable quantitative analysis of endogenous analytes in complex biological samples by isotope dilution LC-MS/MS, the creation of appropriate calibrators is a challenge, since analyte-free authentic material is in general not available. Thus, surrogate matrices are often used to prepare calibrators and controls. However, currently employed validation protocols do not include specific experiments to verify the suitability of a surrogate matrix calibration for quantification of authentic matrix samples. The aim of the study was the development of a novel validation experiment to test whether surrogate matrix based calibrators enable correct quantification of authentic matrix samples. The key element of the novel validation experiment is the inversion of nonlabelled analytes and their stable isotope labelled (SIL) counterparts in respect to their functions, i.e. SIL compound is the analyte and nonlabelled substance is employed as internal standard. As a consequence, both surrogate and authentic matrix are analyte-free regarding SIL analytes, which allows a comparison of both matrices. We called this approach Isotope Inversion Experiment. As figure of merit we defined the accuracy of inverse quality controls in authentic matrix quantified by means of a surrogate matrix calibration curve. As a proof-of-concept application a LC-MS/MS assay addressing six corticosteroids (cortisol, cortisone, corticosterone, 11-deoxycortisol, 11-deoxycorticosterone, and 17-OH-progesterone) was chosen. The integration of the Isotope Inversion Experiment in the validation protocol for the steroid assay was successfully realized. The accuracy results of the inverse quality controls were all in all very satisfying. As a consequence the suitability of a surrogate matrix calibration for quantification of the targeted steroids in human serum as authentic matrix could be successfully demonstrated. The Isotope Inversion Experiment fills a gap in the validation process for LC-MS/MS assays quantifying endogenous analytes. We consider it a valuable and convenient tool to evaluate the correct quantification of authentic matrix samples based on a calibration curve in surrogate matrix. PMID- 26974484 TI - Effect of Korean Red Ginseng on Cognitive Function and Quantitative EEG in Patients with Alzheimer's Disease: A Preliminary Study. AB - BACKGROUND: Korean red ginseng (KRG) has a nootropic effect. This study assessed the efficacy of KRG on cognitive function and quantitative electroencephalography (EEG) in patients with Alzheimer's disease (AD). METHODS: Fourteen patients with AD (mean age, 74.93 years; 11 women and 3 men) were recruited and treated with KRG (4.5 g per day) for 12 weeks. Cognitive function was assessed by the Korean Mini-Mental State Examination (K-MMSE) and the Frontal Assessment Battery (FAB). EEG performed before and after treatment were analyzed with quantitative spectral analysis. RESULTS: The FAB score improved significantly after 12 weeks of treatment. In the relative power spectrum analysis performed according to responsiveness, alpha power increased significantly in the right temporal area of the responders. The increments of relative alpha power in the right temporal, parietal, and occipital areas were significantly higher in the responders than the nonresponders. CONCLUSIONS: This study indicates the efficacy of KRG on frontal lobe function in AD, related to increasing relative alpha power. PMID- 26974485 TI - A new automated and precise calibration method for gamma level gauges with rod detector arrangement. AB - Gamma-ray liquid level gauging is of particular importance in several industries. Industrial vessels, tanks, and reactors, which work at high temperatures and pressures, usually have thick metal walls up to 20cm. These factors make it impossible to know the exact level of liquid or fluid while the system is operating. For this reason, the calibration process of the gamma level gauges is difficult as it is impossible to gain access to the inside of the vessels, which is important during the calibration process. In this study, a new auto calibration method was proposed for the aforementioned situations. PMID- 26974486 TI - Effect of external magnetic field on valence-electron structures of Fe and Ni in Invar, Permalloy and the other Fe-Ni alloys by using Kbeta-to-Kalpha X-ray intensity ratios. AB - The effect of external magnetic field on the valence-electron structures of Fe and Ni in various Fe-Ni alloy compositions was investigated by using X-ray fluorescence spectroscopy. Firstly, Kbeta-to-Kalpha X-ray intensity ratios of Fe and Ni in Invar (Fe0.64Ni0.36), Permalloy (Fe0.20Ni0.80) and FexNi1-x (x=0, 0.40, 0.52, 0.55, 0.61, and 1) alloys were measured without any magnetic field and under 0.5 and 1T external magnetic fields, separately. Later, the valence electron structures of Fe and Ni in both pure form and alloys were obtained by comparison of measured X-ray intensity ratios with the results of multi configurations Dirac-Fock (MCDF) calculations. The results obtained for valence electron structures of Fe and Ni in various Fe-Ni alloys were evaluated in terms of magnetic field effect, delocalization and/or charge transfer phenomena. The results have shown that valence electron structure of Fe and Ni in Fe-Ni alloys are dependent on both external magnetic field and concentration of alloy elements. PMID- 26974487 TI - Grafting of [(64)Cu]-TPPF20 porphyrin complex on Functionalized nano-porous MCM 41 silica as a potential cancer imaging agent. AB - Mesoporous silica, MCM-41, functionalized with 3-aminopropyltriethoxysilane (APTES) was investigated as a potential drug delivery system, using [(64)Cu]-5, 10, 15, 20-tetrakis penta fluorophenyl porphyrin complex. [(64)Cu]-TPPF20 complex was grafted on functionalized MCM-41. The product was characterized by paper chromatography, FTIR spectroscopy, low angle X-ray diffraction, CHN and TGA/DTA analyses and atomic force microscopy. The biological evaluations of the grafted complex, [(64)Cu]-TPPF20@NH2-MCM-41, were done in Fibrosarcoma tumor-bearing Sprague-Dawley rats using scarification studies and Sopha DST-XL Dual-Head SPECT system. The actual loading amount of aminopropyl groups was found about 1.6mmol per gram of final silica. The specific activity of the final compound was found to be 3Ci/g. Amine functionalized MCM-41 was found to be a good platform for theranostic radiopharmaceuticals such as copper-64 complexes. Considering the accumulation of the tracer in tumor cells, fast wash-out from normal tissues, the short half-life copper-64 and less imposed radiation doses to patients, [(64)Cu] TPPF20@NH2-MCM-41 can potentially be a suitable candidate for tumor imaging applications and future PET studies. PMID- 26974488 TI - Principle component analysis for radiotracer signal separation. AB - Radiotracers can be used in several industrial applications by injecting the radiotracer into the industrial system and monitoring the radiation using radiation detectors for obtaining signals. These signals are analyzed to obtain indications about what is happening within the system or to determine the problems that may be present in the system. For multi-phase system analysis, more than one radiotracer is used and the result is a mixture of radiotracers signals. The problem is in such cases is how to separate these signals from each other. The paper presents a proposed method based on Principle Component Analysis (PCA) for separating mixed two radiotracer signals from each other. Two different radiotracers (Technetium-99m (Tc(99m)) and Barium-137m (Ba(137m))) were injected into a physical model for simulation of chemical reactor (PMSCR-MK2) for obtaining the radiotracer signals using radiation detectors and Data Acquisition System (DAS). The radiotracer signals are mixed and signal processing steps are performed include background correction and signal de-noising, then applying the signal separation algorithms. Three separation algorithms have been carried out; time domain based separation algorithm, Independent Component Analysis (ICA) based separation algorithm, and Principal Components Analysis (PCA) based separation algorithm. The results proved the superiority of the PCA based separation algorithm to the other based separation algorithm, and PCA based separation algorithm and the signal processing steps gives a considerable improvement of the separation process. PMID- 26974489 TI - Barriers and Facilitators to Scaling Up Outpatient Palliative Care. AB - BACKGROUND: The Institute of Medicine recommends people with serious advanced illness have access to skilled palliative care. However, the predominant delivery model of nonhospice palliative care is inpatient, consultative care focused on the end of life, with a small specialist palliative care workforce. OBJECTIVE: The study objective was to understand organizational factors that could influence the adoption and scale-up of outpatient palliative care in chronic advanced illness, using the example of heart failure. METHODS: This was a cross-sectional qualitative study. Participants were 17 health care providers and local, regional, and national health system leaders from the Veterans Health Administration (VHA) who were considering whether and how to adopt and sustain outpatient palliative care. Individual interviews using semistructured questions assessed domains of the Consolidated Framework for Implementation Science. RESULTS: Most providers and leaders perceived outpatient palliative care as high priority in the VHA given its patient-centeredness and potential to decrease health care use and costs associated with conditions like heart failure. They also supported a collaborative care team model of outpatient palliative care delivery where a palliative care specialist collaborates with medical nurses and social workers. They reported lack of performance measures/incentives for patient centered care processes and outcomes as a potential barrier to implementation. Features of outpatient palliative care viewed as important for successful adoption and scale-up included coordination and communication with other providers, ease of integration into existing programs, and evidence of improving quality of care while not substantially increasing overall health care costs. CONCLUSION: Incentives such as performance measures and collaboration with local VHA providers and leaders could improve adoption and scale-up of outpatient palliative care. PMID- 26974490 TI - Fatigue strength of Co-Cr-Mo alloy clasps prepared by selective laser melting. AB - We aimed to investigate the fatigue strength of Co-Cr-Mo clasps for removable partial dentures prepared by selective laser melting (SLM). The Co-Cr-Mo alloy specimens for tensile tests (dumbbell specimens) and fatigue tests (clasp specimens) were prepared by SLM with varying angles between the building and longitudinal directions (i.e., 0 degrees (TL0, FL0), 45 degrees (TL45, FL45), and 90 degrees (TL90, FL90)). The clasp specimens were subjected to cyclic deformations of 0.25mm and 0.50mm for 10(6) cycles. The SLM specimens showed no obvious mechanical anisotropy in tensile tests and exhibited significantly higher yield strength and ultimate tensile strength than the cast specimens under all conditions. In contrast, a high degree of anisotropy in fatigue performance associated with the build orientation was found. For specimens under the 0.50mm deflection, FL90 exhibited significantly longer fatigue life (205,418 cycles) than the cast specimens (112,770 cycles). In contrast, the fatigue lives of FL0 (28,484 cycles) and FL45 (43,465 cycles) were significantly shorter. The surface roughnesses of FL0 and FL45 were considerably higher than those of the cast specimens, whereas there were no significant differences between FL90 and the cast specimens. Electron backscatter diffraction (EBSD) analysis indicated the grains of FL0 showed preferential close to <001> orientation of the gamma phase along the normal direction to the fracture surface. In contrast, the FL45 and FL90 grains showed no significant preferential orientation. Fatigue strength may therefore be affected by a number of factors, including surface roughness and crystal orientation. The SLM process is a promising candidate for preparing tough removable partial denture frameworks, as long as the appropriate build direction is adopted. PMID- 26974491 TI - A direct thrombin inhibitor suppresses protein C activation and factor Va degradation in human plasma: Possible mechanisms of paradoxical enhancement of thrombin generation. AB - We have demonstrated that antithrombin (AT)-independent thrombin inhibitors paradoxically increase thrombin generation (TG) in human plasma in a thrombomodulin (TM)- and protein C (PC)-dependent manner. We determined the effects of AT-independent thrombin inhibitors on the negative-feedback system, activation of PC and production and degradation of factor Va (FVa), as possible mechanisms underlying the paradoxical enhancement of TG. TG in human plasma containing 10nM TM was assayed by means of the calibrated automated thrombography. As an index of PC activation, plasma concentration of activated PC PC inhibitor complex (aPC-PCI) was measured. The amounts of FVa heavy chain and its degradation product (FVa(307-506)) were examined by western blotting. AT independent thrombin inhibitors, melagatran and dabigatran (both at 25-600nM) and 3-30MUg/ml active site-blocked thrombin (IIai), increased peak levels of TG. Melagatran, dabigatran and IIai significantly decreased plasma concentration of aPC-PCI complex at 25nM or more, 75nM or more, and 10 and 30MUg/ml, respectively. Melagatran (300nM) significantly increased FVa and decreased FVa(307-506). In contrast, a direct factor Xa inhibitor edoxaban preferentially inhibited thrombin generation (>=25nM), and higher concentrations were required to inhibit PC activation (>=150nM) and FVa degradation (300nM). The present study suggests that the inhibitions of protein C activation and subsequent degradation of FVa and increase in FVa by antithrombin-independent thrombin inhibitors may contribute to the paradoxical TG enhancement, and edoxaban may inhibit PC activation and FVa degradation as a result of TG suppression. PMID- 26974492 TI - Long-Acting Reversible Contraception and Condom Use Among Female US High School Students: Implications for Sexually Transmitted Infection Prevention. AB - IMPORTANCE: Long-acting reversible contraception (LARC), specifically intrauterine devices and implants, offers an unprecedented opportunity to reduce unintended pregnancies among adolescents because it is highly effective even with typical use. However, adolescent LARC users may be less likely to use condoms for preventing sexually transmitted infections compared with users of moderately effective contraceptive methods (ie, oral, Depo-Provera injection, patch, and ring contraceptives). OBJECTIVE: To compare condom use between sexually active female LARC users and users of moderately effective contraceptive methods. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis using data from the 2013 national Youth Risk Behavior Survey, a nationally representative sample of US high school students in grades 9 through 12. Descriptive analyses were conducted among sexually active female students (n = 2288); logistic regression analyses were restricted to sexually active female users of LARC and moderately effective contraception (n = 619). The analyses were conducted in July and August 2015. MAIN OUTCOMES AND MEASURES: Contraceptive method at last sexual intercourse was assessed by 1 item-respondents could select birth control pills; condoms; an intrauterine device or implant; injection, patch, or ring; withdrawal or other method; or not sure. A separate item asked whether respondents used a condom at last sexual intercourse. We created an indicator variable to distinguish those reporting use of (1) LARC (intrauterine device or implant), (2) oral contraceptives, and (3) Depo-Provera, patch, or ring. RESULTS: Among the 2288 sexually active female participants (56.7% white; 33.6% in 12th grade), 1.8% used LARC; 5.7% used Depo-Provera, patch, or ring; 22.4% used oral contraceptives; 40.8% used condoms; 11.8% used withdrawal or other method; 15.7% used no contraceptive method; and 1.9% were not sure. In adjusted analyses, LARC users were about 60% less likely to use condoms compared with oral contraceptive users (adjusted prevalence ratio [aPR], 0.42; 95% CI, 0.21-0.84). No significant differences in condom use were observed between LARC users and Depo-Provera injection, patch, or ring users (aPR, 0.57; 95% CI, 0.26-1.25). The LARC users were more than twice as likely to have 2 or more recent sexual partners compared with oral contraceptive users (aPR, 2.61; 95% CI, 1.75-3.90) and Depo-Provera, patch, or ring users (aPR, 2.58; 95% CI, 1.17-5.67). CONCLUSIONS AND RELEVANCE: Observed differences in condom use may reflect motivations to use condoms for backup pregnancy prevention. Users of highly effective LARC methods may no longer perceive a need for condoms even if they have multiple sexual partners, which places them at risk for sexually transmitted infections. As uptake of LARC increases among adolescents, a clear need exists to incorporate messages about condom use specifically for sexually transmitted infection prevention. PMID- 26974494 TI - Molecular switching involving metastable states: molecular thermal hysteresis and sensing of environmental changes by chiral helicene oligomeric foldamers. AB - Molecular switching is a phenomenon in which the molecular structure reversibly changes in response to external stimulation. It is crucial in biology and is used in various biological sensing applications and responses. In contrast to the well studied molecular switching involving two or more thermodynamically stable states, switching involving metastable states exhibits notable non-equilibrium thermodynamic properties. Synthetic chiral helicene oligomeric foldamers that exhibit molecular thermal hysteresis in dilute solution are examples. Molecular switching can be used for sensing environmental changes, including temperature threshold, temperature decrease/increase, rate of temperature decrease, counting the numbers 1 and 2, and concentration increase. PMID- 26974493 TI - Multiplexed Detection of Epigenetic Markers Using Quantum Dot (QD)-Encoded Hydrogel Microparticles. AB - Epigenetic alterations in gene expression are influenced by experiences and environment, resulting in significant variation of epigenetic markers from individual to individual. Therefore, it is imperative to measure various epigenetic markers simultaneously from samples of individual subjects to accurately analyze the epigenetic markers in biological samples. Moreover, the individualized genome-wide analysis has become a critical technology for recent trends in clinical applications such as early diagnosis and personalized medicine screening of numerous diseases. The array-based detection of modified histones, conventionally used for multiplexed analysis of epigenetic changes, requires pooling of samples from many subjects to analyze population-wise differences in the expression of histone markers and does not permit individualized analysis. Here, we report multiplexed detection of genome-wide changes in various histone modifications at a single-residue resolution using quantum dot (QD)-encoded polyethylene glycol diacrylate (PEGDA) hydrogel microparticles. To demonstrate the potential of our methodology, we present the simultaneous detection of (1) acetylation of lysine 9 of histone 3 (Ac-H3K9), (2) dimethylation of H3K9 (2Me H3K9), and (3) trimethylation of H3K9 (3Me-H3K9) from three distinct regions in the brain [nucleus accumbens (NAc), dorsal striatum (DSt), and cerebellum (Cbl)] of cocaine-exposed mice. Our hydrogel-based epigenetic assay enabled relative quantification of the three histone variants from only 10 MUL of each brain lysate (protein content = ~ 1 MUg/MUL) per mouse. We verified that the exposure to cocaine induced a significant increase of acetylation while a notable decrease in methylation in NAc. PMID- 26974496 TI - Emerging Infections and Blood Safety in the 21st Century. PMID- 26974495 TI - Enhancing well-being at work: The role of emotion regulation skills as personal resources. AB - Dealing with negative emotions is a crucial work demand, particularly for employees in health care. Job resources (e.g., autonomy, social support, or reward) but also personal resources (such as emotion regulation strategies) might reduce job stress and support well-being. Following this, the present study focused on strengthening emotion regulation as 1 way of dealing with high job demands. The aim of this study was to evaluate the impact of a standardized emotion regulation training (Affect Regulation Training [ART]; Berking, 2010) to improve emotion regulation skills and well-being of employees in elderly health care. Therefore, 96 elderly care workers filled out an established questionnaire of emotion regulation skills as well as a measure of well-being at pretreatment, posttreatment and at 6-month follow-up. The findings show that the ART fosters emotion regulation skills. In particularly, acceptance, tolerance, and modification of negative emotions was enhanced in the training groups in comparison to a control-group. Modification, meaning the ability to actively change emotions, improved even more over the follow-up-period. Simultaneously, well-being of participants increased over all measurement time points in the ART group compared with the control-group. Additionally, the improvement in emotion regulation skills from pre to posttreatment was related to well-being at follow up. In summary, our results support the ART as an effective intervention for dealing with negative emotions and to enhance well-being among employees in elderly care. (PsycINFO Database Record PMID- 26974497 TI - Reducing the Burden of Hypertension: China's Long March Ahead. PMID- 26974498 TI - Serum IL-18 level, clinical symptoms and IL-18-607A/C polymorphism among chronic patients with schizophrenia in a Chinese Han population. AB - Literature suggests that alterations in the inflammatory and immune systems are involved in the pathogenesis of schizophrenia. Specifically, patients diagnosed with schizophrenia exhibit increased IL-18, a pleiotropic proinflammatory cytokine in type 1 T-helper (Th1) responses. The functional 607A/C promoter polymorphism of the IL-18 gene is also associated with the psychopathology of this disorder. However, no current study has explored its role in the clinical symptoms of schizophrenia as mediated through IL-18 levels. We recruited 772 inpatients with schizophrenia and 775 healthy controls in a Han Chinese population and genotyped the IL-18-607A/C polymorphism. Patient psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Serum IL-18 levels were measured in 80 patients and 93 healthy controls. Our results showed that there were no significant differences in the distribution of the allele and genotype frequencies between the patients and controls. Both increased IL-18 serum level and the IL-18-607A/C polymorphism were positively associated with the PANSS general psychopathology subscore and the PANSS total score. Moreover, interaction of increased IL-18 serum level and the IL-18-607A/C polymorphism influenced the clinical psychopathological symptoms, indicating that association of IL-18 level with the PANSS general psychopathology subscale or the total scores was present only among patients carrying the C allele. We demonstrate an association between the IL-18-607A/C variant and clinical psychopathological symptoms in schizophrenia. Findings suggest that the association between higher IL-18 levels and clinical symptoms in schizophrenia is dependent on the IL-18 607A/C polymorphism. PMID- 26974499 TI - Plasma insulin-like growth factor I levels are higher in depressive and anxiety disorders, but lower in antidepressant medication users. AB - It has been postulated that many peripheral and (neuro)biological systems are involved in psychiatric disorders such as depression. Some studies found associations of depression and antidepressant treatment with insulin-like growth factor 1 (IGF-I) - a pleiotropic hormone affecting neuronal growth, survival and plasticity - but evidence is mixed. We therefore studied whether depressive and anxiety disorders were associated with plasma IGF-I, and explored the role of antidepressant medication in this association in a large observational study. The sample consisted of 2714 participants enrolled in The Netherlands Study of Depression and Anxiety, classified as healthy controls (n=602), antidepressant users (76 remitted and 571 with current depressive and/or anxiety disorder(s), n=647), persons having remitted depressive and/or anxiety disorder(s) without antidepressant use (n=502), and persons having current depressive and/or anxiety disorder(s) without antidepressant use (n=963). Associations with IGF-I concentrations were studied and adjusted for socio-demographic, health, and lifestyle variables. Relative to healthy controls, antidepressant-free individuals with current disorders had significantly higher IGF-I levels (Cohen's d=0.08, p=0.006), whereas antidepressant-free individuals with remitted disorders had a trend towards higher IGF-I levels (d=0.06, p=0.09). Associations were evident for depressive and for anxiety disorders. In contrast, antidepressant users had significantly lower IGF-I levels compared to healthy controls (d=-0.08, p=0.028). Our findings suggests that antidepressant medication use modifies the association between depressive/anxiety disorders and plasma IGF-I. These results corroborate with findings of some previous small-scale case-control and intervention studies. The higher IGF-I levels related to depression and anxiety might point to a compensatory mechanism to counterbalance the impaired neurogenesis, although future studies are needed to support this hypothesis. PMID- 26974500 TI - Septal oxytocin administration impairs peer affiliation via V1a receptors in female meadow voles. AB - The peptide hormone oxytocin (OT) plays an important role in social behaviors, including social bond formation. In different contexts, however, OT is also associated with aggression, social selectivity, and reduced affiliation. Female meadow voles form social preferences for familiar same-sex peers under short, winter-like day lengths in the laboratory, and provide a means of studying affiliation outside the context of reproductive pair bonds. Multiple lines of evidence suggest that the actions of OT in the lateral septum (LS) may decrease affiliative behavior, including greater density of OT receptors in the LS of meadow voles that huddle less. We infused OT into the LS of female meadow voles immediately prior to cohabitation with a social partner to determine its effects on partner preference formation. OT prevented the formation of preferences for the partner female. Co-administration of OT with a specific OT receptor antagonist did not reverse the effect, but co-administration of OT with a specific vasopressin 1a receptor (V1aR) antagonist did, indicating that OT in the LS likely acted through V1aRs to decrease partner preference. Receptor autoradiography revealed dense V1aR binding in the LS of female meadow voles. These results suggest that the LS is a brain region that may be responsible for inhibitory effects of OT administration on affiliation, which will be important to consider in therapeutic administrations of OT. PMID- 26974502 TI - Sensitive NMR Approach for Determining the Binding Mode of Tightly Binding Ligand Molecules to Protein Targets. AB - Structure-guided drug design relies on detailed structural knowledge of protein ligand complexes, but crystallization of cocomplexes is not always possible. Here we present a sensitive nuclear magnetic resonance (NMR) approach to determine the binding mode of tightly binding lead compounds in complex with difficult target proteins. In contrast to established NMR methods, it does not depend on rapid exchange between bound and free ligand or on stable isotope labeling, relying instead on a tert-butyl group as a chemical label. tert-Butyl groups are found in numerous protein ligands and deliver an exceptionally narrow and tall (1)H NMR signal. We show that a tert-butyl group also produces outstandingly intense intra and intermolecular NOESY cross-peaks. These enable measurements of pseudocontact shifts generated by lanthanide tags attached to the protein, which in turn allows positioning of the ligand on the protein. Once the ligand has been located, assignments of intermolecular NOEs become possible even without prior resonance assignments of protein side chains. The approach is demonstrated with the dengue virus NS2B-NS3 protease in complex with a high-affinity ligand containing a tert butyl group. PMID- 26974501 TI - Sympathetic nervous system contributes to enhanced corticosterone levels following chronic stress. AB - Exposure to chronic stress often elevates basal circulating glucocorticoids during the circadian nadir and leads to exaggerated glucocorticoid production following exposure to subsequent stressors. While glucocorticoid production is primarily mediated by the hypothalamic-pituitary-adrenal (HPA) axis, there is evidence that the sympathetic nervous system can affect diurnal glucocorticoid production by direct actions at the adrenal gland. Experiments here were designed to examine the role of the HPA and sympathetic nervous system in enhancing corticosterone production following chronic stress. Rats were exposed to a four day stress paradigm or control conditions then exposed to acute restraint stress on the fifth day to examine corticosterone and ACTH responses. Repeated stressor exposure resulted in a small increase in corticosterone, but not ACTH, during the circadian nadir, and also resulted in exaggerated corticosterone production 5, 10, and 20min following restraint stress. While circulating ACTH levels increased after 5min of restraint, levels were not greater in chronic stress animals compared to controls until following 20min. Administration of astressin (a CRH antagonist) prior to restraint stress significantly reduced ACTH responses but did not prevent the sensitized corticosterone response in chronic stress animals. In contrast, administration of chlorisondamine (a ganglionic blocker) returned basal corticosterone levels in chronic stress animals to normal levels and reduced early corticosterone production following restraint (up to 10min) but did not block the exaggerated corticosterone response in chronic stress animals at 20min. These data indicate that increased sympathetic nervous system tone contributes to elevated basal and rapid glucocorticoid production following chronic stress, but HPA responses likely mediate peak corticosterone responses to stressors of longer duration. PMID- 26974503 TI - Seed-borne viral dsRNA elements in three cultivated Raphanus and Brassica plants suggest three cryptoviruses. AB - Since the 1970s, several dsRNA viruses, including Radish yellow edge virus, Raphanus sativus virus 1, Raphanus sativus virus 2, and Raphanus sativus virus 3, have been identified and reported as infecting radish. In the present study, in conjunction with a survey of seed-borne viruses in cultivated Brassica and Raphanus using the dsRNA diagnostic method, we discovered 3 novel cryptoviruses that infect Brassica and Raphanus: Raphanus sativus partitivirus 1, which infects radish (Raphanus sativus); Sinapis alba cryptic virus 1, which infects Sinapis alba; and Brassica rapa cryptic virus 1 (BrCV1), which infects Brassica rapa. The genomic organization of these cryptoviruses was analyzed and characterized. BrCV1 might represent the first plant partitivirus found in Gammapartitivirus. Additionally, the evolutionary relationships among all of the partitiviruses reported in Raphanus and Brassica were analyzed. PMID- 26974504 TI - Identification of virulence factors and antibiotic resistance markers using bacterial genomics. AB - In recent years, the number of multidrug-resistant bacteria has increased rapidly and several epidemics were signaled in different regions of the world. Faced with this situation that presents a major global public health concern, the development and the use of new and rapid technologies is more than urgent. The use of the next-generation sequencing platforms by microbiologists and infectious disease specialists has allowed great progress in the medical field. Here, we review the usefulness of whole-genome sequencing for the detection of virulence and antibiotic resistance associated genes. PMID- 26974505 TI - Longitudinally Extensive Spinal Cord Lesions Disclosing Occult Systemic Sarcoidosis. PMID- 26974506 TI - Selectivity on Etching: Creation of High-Energy Facets on Copper Nanocrystals for CO2 Electrochemical Reduction. AB - Creating high-energy facets on the surface of catalyst nanocrystals represents a promising method for enhancing their catalytic activity. Herein we show that crystal etching as the reverse process of crystal growth can directly endow nanocrystal surfaces with high-energy facets. The key is to avoid significant modification of the surface energies of the nanocrystal facets by capping effects from solvents, ions, and ligands. Using Cu nanocubes as the starting material, we have successfully demonstrated the creation of high-energy facets in metal nanocrystals by controlled chemical etching. The etched Cu nanocrystals with enriched high-energy {110} facets showed significantly enhanced activity toward CO2 reduction. We believe the etching-based strategy could be extended to the synthesis of nanocrystals of many other catalysts with more active high-energy facets. PMID- 26974507 TI - Preparation of Scaffold-Free Tissue-Engineered Constructs Derived from Human Synovial Mesenchymal Stem Cells Under Low Oxygen Tension Enhances Their Chondrogenic Differentiation Capacity. AB - Low oxygen tension (LOT) has been reported to promote chondrogenic differentiation and prevent cellular senescence of stem cells. Therefore, the introduction of LOT conditions into conventional tissue engineering processes could further improve the potential of the constructs generated for cartilage repair. The purpose of this study was to elucidate the feasibility of LOT preparation on the chondrogenic differentiation of a scaffold-free tissue engineered construct (TEC) derived from synovial mesenchymal stem cells (MSCs), construct whose feasibility for cartilage repair has been demonstrated in previous preclinical and clinical studies. Culture of MSCs under LOT conditions prevented cellular senescence and promoted the proliferative capacity of human synovial MSCs. In addition, TEC prepared from human synovial MSCs under LOT conditions (5% O2; LOT-TEC) showed superior in vitro chondrogenic differentiation capacity compared to that prepared under the usual 20% O2 (normal oxygen tension [NOT]; NOT-TEC), with elevated glycosaminoglycan production and elevated levels of chondrogenic marker gene expression. Notably, LOT-TEC differentiated into a hyaline-like cartilaginous tissue of approximately 1 cm in diameter without the detectable presence of fibrous tissue, while conventional NOT-TEC differentiated into a mixture of hyaline-like and fibrocartilaginous tissues. This is the first demonstration of in vitro development of a hyaline-like cartilaginous tissue of an implantable size to chondral lesion that was derived from human MSCs without the use of an exogenous scaffold. The manipulation of oxygen tension is a safe procedure with low cost and, thus, may be a clinically relevant option to improve the quality of TEC-mediated cartilage repair. PMID- 26974509 TI - ADMA: a specific biomarker for pathologic progress in diabetic microvascular complications? AB - BACKGROUND: This study highlights the role of glycated hemoglobin (HbA1c), asymmetric demethylargine (ADMA) and N-epsilon-(carboxymethyl)-lysine (CML) in different periods of progress in Type 2 diabetes, and identifies a pathomechanism based biomarker that is linked not only to the metabolic progresses but also to the underlying angiopathic progresses. METHODS: Peripheral blood samples from 100 healthy volunteers, 227 subjects with prediabetes, 173 subjects with Type 2 diabetes and 92 subjects with early diabetic microvascular complications were collected and analyzed for HbA1c, ADMA and CML. RESULTS: Compared to HbA1c and CML, ADMA is the strongest independent predictor and a significantly discriminative receiver operating characteristics profile, clearly distinguishing those with early diabetic microvascular complications. CONCLUSIONS: ADMA maybe serve as a pathomechanism-based biomarker, predicting the progression of microvascular complications. PMID- 26974508 TI - Far-Red Light-Activatable Prodrug of Paclitaxel for the Combined Effects of Photodynamic Therapy and Site-Specific Paclitaxel Chemotherapy. AB - Paclitaxel (PTX) is one of the most useful chemotherapeutic agents approved for several cancers, including ovarian, breast, pancreatic, and nonsmall cell lung cancer. However, it causes systemic side effects when administered parenterally. Photodynamic therapy (PDT) is a new strategy for treating local cancers using light and photosensitizer. Unfortunately, PDT is often followed by recurrence due to incomplete ablation of tumors. To overcome these problems, we prepared the far red light-activatable prodrug of PTX by conjugating photosensitizer via singlet oxygen-cleavable aminoacrylate linker. Tubulin polymerization enhancement and cytotoxicity of prodrugs were dramatically reduced. However, once illuminated with far-red light, the prodrug effectively killed SKOV-3 ovarian cancer cells through the combined effects of PDT and locally released PTX. Ours is the first PTX prodrug that can be activated by singlet oxygen using tissue penetrable and clinically useful far-red light, which kills the cancer cells through the combined effects of PDT and site-specific PTX chemotherapy. PMID- 26974510 TI - In Vivo Determination of Body Composition in Zebrafish (Danio rerio) by Quantitative Magnetic Resonance. AB - Zebrafish (Danio rerio) as a model research organism continues to expand its relevance and role in multiple research disciplines, with recent work directed toward models of metabolism, nutrition, and energetics. Multiple technologies exist to assess body composition in animal research models at various levels of detail (tissues/organs, body regions, and whole organism). The development and/or validation of body composition assessment tools can open new areas of research questions for a given organism. Using fish from a comparative nutrition study, quantitative magnetic resonance (QMR) assessment of whole body fat and fat-free mass (FFM) in live fish was performed. QMR measures from two cohorts (n = 26 and n = 27) were compared with chemical carcass analysis (CCA) of FM and FFM. QMR was significantly correlated with chemical carcass values (fat, p < 0.001; lean, p = 0.002), although QMR significantly overestimated fat mass (FM) (0.011 g; p < 0.0001) and underestimated FFM (-0.024 g; p < 0.0001) relative to CCA. In a separate cross-validation group of fish, prediction equations corrected carcass values for FM (p = 0.121) and FFM (p = 0.753). These results support the utilization of QMR-a nonlethal nondestructive method-for cross-sectional or longitudinal body composition assessment outcomes in zebrafish. PMID- 26974512 TI - Correction to Light-Assisted, Templated Self-Assembly Using a Photonic-Crystal Slab. PMID- 26974513 TI - Marketing Residential Treatment Programs for Eating Disorders: A Call for Transparency. AB - Residential behavioral treatment is a growing sector of the health care industry and is used by a large proportion of adolescent and adult patients with eating disorders. These programs and the organizations that own them have developed extensive marketing strategies that target clinicians and include promotional gifts, meals, travel reimbursement, and continuing education credit. Legislation and policy changes have limited these types of activities when conducted by the pharmaceutical industry, and awareness of conflicts of interest associated with clinician-targeted advertising of drugs and devices has increased. However, similar practices by the behavioral health care industry have evolved without oversight. The authors urge clinicians to consider how marketing strategies by treatment facilities may influence their referral behaviors and call for improved transparency regarding gifts and payments from treatment facilities. PMID- 26974514 TI - A facile, green and efficient surfactant-free method for synthesis of aluminum nanooxides with an extraordinary high surface area. AB - Nano boehmite with unprecedented high surface area and pore volume (802 m(2) g( 1), 2.35 cm(3) g(-1)) was prepared using a facile, green and efficient surfactant free synthesis method. The structure of the material is characterized by the presence of plates with varying thicknesses and morphologies. The calcined samples show curved and rolled plates with a nanotube-like appearance. PMID- 26974511 TI - An injectable nanoparticle generator enhances delivery of cancer therapeutics. AB - The efficacy of cancer drugs is often limited because only a small fraction of the administered dose accumulates in tumors. Here we report an injectable nanoparticle generator (iNPG) that overcomes multiple biological barriers to cancer drug delivery. The iNPG is a discoidal micrometer-sized particle that can be loaded with chemotherapeutics. We conjugate doxorubicin to poly(L-glutamic acid) by means of a pH-sensitive cleavable linker, and load the polymeric drug (pDox) into iNPG to assemble iNPG-pDox. Once released from iNPG, pDox spontaneously forms nanometer-sized particles in aqueous solution. Intravenously injected iNPG-pDox accumulates at tumors due to natural tropism and enhanced vascular dynamics and releases pDox nanoparticles that are internalized by tumor cells. Intracellularly, pDox nanoparticles are transported to the perinuclear region and cleaved into Dox, thereby avoiding excretion by drug efflux pumps. Compared to its individual components or current therapeutic formulations, iNPG pDox shows enhanced efficacy in MDA-MB-231 and 4T1 mouse models of metastatic breast cancer, including functional cures in 40-50% of treated mice. PMID- 26974515 TI - Identifying relevant positions in proteins by Critical Variable Selection. AB - Evolution in its course has found a variety of solutions to the same optimisation problem. The advent of high-throughput genomic sequencing has made available extensive data from which, in principle, one can infer the underlying structure on which biological functions rely. In this paper, we present a new method aimed at the extraction of sites encoding structural and functional properties from a set of protein primary sequences, namely a multiple sequence alignment. The method, called critical variable selection, is based on the idea that subsets of relevant sites correspond to subsequences that occur with a particularly broad frequency distribution in the dataset. By applying this algorithm to in silico sequences, to the response regulator receiver and to the voltage sensor domain of ion channels, we show that this procedure recovers not only the information encoded in single site statistics and pairwise correlations but also captures dependencies going beyond pairwise correlations. The method proposed here is complementary to statistical coupling analysis, in that the most relevant sites predicted by the two methods differ markedly. We find robust and consistent results for datasets as small as few hundred sequences that reveal a hidden hierarchy of sites that are consistent with the present knowledge on biologically relevant sites and evolutionary dynamics. This suggests that critical variable selection is capable of identifying a core of sites encoding functional and structural information in a multiple sequence alignment. PMID- 26974516 TI - Bifunctional alloys for the electroreduction of CO2 and CO. AB - We use density functional theory to study the reduction of CO2 and CO to hydrocarbons through a formyl pathway on (111) and (211) facets of L12 alloys with an A3B composition. We find that several alloys may reduce the thermodynamic overpotential for CO reduction by more than 0.2 V compared to a copper step, however, these alloys are most often rather unstable in aqueous environment or have low alloy formation energies and may be susceptible to segregation destroying the active sites. Strategies to improve alloy stability against corrosion or segregation would likely be needed in order to realize the full potential of these alloys. PMID- 26974517 TI - Complete voltage recovery in quantum dot solar cells due to suppression of electron capture. AB - Extensive investigations in recent years have shown that addition of quantum dots (QDs) to a single-junction solar cell decreases the open circuit voltage, VOC, with respect to the reference cell without QDs. Despite numerous efforts, the complete voltage recovery in QD cells has been demonstrated only at low temperatures. To minimize the VOC reduction, we propose and investigate a new approach that combines nanoscale engineering of the band structure and the potential profile. Our studies of GaAs solar cells with various InAs QD media demonstrate that the main cause of the VOC reduction is the fast capture of photoelectrons from the GaAs conduction band (CB) to the localized states in QDs. As the photoelectron capture into QDs is mainly realized via the wetting layers (WLs), we substantially reduced the WLs using two monolayer AlAs capping of QDs. In the structures with reduced WLs, the direct CB-to-QD capture is further suppressed due to charging of QDs via doping of the interdot space. The QD devices with suppressed photoelectron capture show the same VOC as the GaAs reference cell together with some improvements in the short circuit current. PMID- 26974518 TI - Challenges in assignment of orbital populations in a high spin manganese(III) complex. AB - Magnetic, structural and computational data of four complex salts with the same mononuclear high spin octahedral Mn(iii) complex cation are reported. The manifestation of Jahn-Teller-like distortions in the Mn(iii) cation is dependent on the nature of the charge-balancing anion, with small anions yielding a planar elongation and large anions freezing out a preferential axial elongation along one of the amine-Mn-imine directions within that same plane. Modulation of the lattice by changing the charge balancing anion results in mixing of the orbital symmetry due to vibrational perturbation. PMID- 26974519 TI - Small molecule activation by mixed methyl/methylidene rare earth metal complexes. AB - Diverse reactivity patterns of mixed tetramethyl/methylidene rare-earth complexes bearing bulky benzamidinate coligands L3Ln3(MU2-Me)3(MU3-Me)(MU3-CH2) [L = [PhC(NC6H3(i)Pr2-2,6)2](-); Ln = Y(), Lu()] with PhCN, alkynes, and CS2 have been established. Reaction of complexes with PhCN gave the MU3-CH2 addition complexes (NCN(dipp))3Lu3(MU2-Me)3(MU3-Me)[MU-eta(1):eta(1):eta(3)-CH2C(Ph)N] [Ln = Y(), Lu()]. Treatment of complexes with phenylacetylene afforded unexpected alkenyl dianion complexes L3Ln3(MU2-Me)3(MU3-Me)(MU-eta(1):eta(3)-PhC[double bond, length as m-dash]CMe) [Ln = Y(), Lu()] through the insertion of rare earth methylidene into a C-H bond in a reductive fashion. However, reaction of complexes and HC[triple bond, length as m-dash]CSiMe3 gave MU3-Me protonolysis complexes L3Ln3(MU2-Me)3(MU3-C[triple bond, length as m-dash]CSiMe3)(MU3-CH2) [Ln = Y (), Lu ()] in excellent yields. Treatment of complexes with CS2 led to the formation of the methyl activation complexes L3Ln3(MU2-Me)2(MU3-CH2)(MU3 eta(1):eta(2):eta(2)-S2C[double bond, length as m-dash]CH2) [Ln = Y(), Lu()]. All the new complexes were fully characterized. PMID- 26974520 TI - A Female Ligamentous Cervical Spine Finite Element Model Validated for Physiological Loads. AB - Mathematical cervical spine models allow for studying of impact loading that can cause whiplash associated disorders (WAD). However, existing models only cover the male anthropometry, despite the female population being at a higher risk of sustaining WAD in automotive rear-end impacts. The aim of this study is to develop and validate a ligamentous cervical spine intended for biomechanical research on the effect of automotive impacts. A female model has the potential to aid the design of better protection systems as well as improve understanding of injury mechanisms causing WAD. A finite element (FE) mesh was created from surface data of the cervical vertebrae of a 26-year old female (stature 167 cm, weight 59 kg). Soft tissues were generated from the skeletal geometry and anatomical literature descriptions. Ligaments were modeled with nonlinear elastic orthotropic membrane elements, intervertebral disks as composites of nonlinear elastic bulk elements, and orthotropic anulus fibrosus fiber layers, while cortical and trabecular bones were modeled as isotropic plastic-elastic. The model has geometrical features representative of the female cervical spine-the largest average difference compared with published anthropometric female data was the vertebral body depth being 3.4% shorter for the model. The majority the cervical segments compare well with respect to biomechanical data at physiological loads, with the best match for flexion-extension loads and less biofidelity for axial rotation. An average female FE ligamentous cervical spine model was developed and validated with respect to physiological loading. In flexion-extension simulations with the developed female model and an existing average male cervical spine model, a greater range of motion (ROM) was found in the female model. PMID- 26974522 TI - Epitaxially-crystallized oriented naphthalene bis(dicarboximide) morphology for significant performance improvement of electron-transporting thin-film transistors. AB - Large-area highly-ordered F-NDI films were obtained by epitaxial-crystallization on highly-oriented PE substrates through vacuum deposition. An electron mobility of 0.2 cm(2) V(-1) s(-1) was achieved based on such epitaxially-crystallized F NDI films, which is 4 times higher than that of its un-oriented thin film devices. PMID- 26974524 TI - Configurational space discretization and free energy calculation in complex molecular systems. AB - We sought to design a free energy calculation scheme with the hope of saving cost for generating dynamical information that is inherent in trajectories. We demonstrated that snapshots in a converged trajectory set are associated with implicit conformers that have invariant statistical weight distribution (ISWD). Since infinite number of sets of implicit conformers with ISWD may be created through independent converged trajectory sets, we hypothesized that explicit conformers with ISWD may be constructed for complex molecular systems through systematic increase of conformer fineness, and tested the hypothesis in lipid molecule palmitoyloleoylphosphatidylcholine (POPC). Furthermore, when explicit conformers with ISWD were utilized as basic states to define conformational entropy, change of which between two given macrostates was found to be equivalent to change of free energy except a mere difference of a negative temperature factor, and change of enthalpy essentially cancels corresponding change of average intra-conformer entropy. By implicitly taking advantage of entropy enthalpy compensation and forgoing all dynamical information, constructing explicit conformers with ISWD and counting thermally accessible number of which for interested end macrostates is likely to be an efficient and reliable alternative end point free energy calculation strategy. PMID- 26974525 TI - Degradation of oxytetracycline and its impacts on biogas-producing microbial community structure. AB - The effect of veterinary antibiotics in anaerobic digesters is a concern where methane production efficiency is highly dependent on microbial community structure. In this study, both anaerobic degradation of a common veterinary antibiotic, oxytetracycline (OTC), and its effects on an anaerobic digester microbial community were investigated. Qualitative and quantitative molecular tools were used to monitor changes in microbial community structure during a 60 day batch incubation period of cow manure with the addition of different concentrations of the antibiotic. Molecular data were interpreted by a further redundancy analysis as a multivariate statistics approach. At the end of the experiment, approximately 48, 33, and 17 % of the initially added 50, 100, and 200 mg l(-1) of OTC was still present in the serum bottles which reduced the biogas production via accumulation of some of the volatile fatty acids (VFAs). Biogas production was highly correlated with Methanobacteriales and Methanosarcinales gene copy numbers, and those parameters were negatively affected with oxytetracycline and VFA concentrations. PMID- 26974528 TI - Fixation of Displaced Medial Epicondyle Fractures in Adolescents. AB - BACKGROUND: Open reduction and internal fixation of displaced medial epicondyle fracture dislocations in adolescents is recommended for incarceration of the epicondyle in the joint and for athletes who need a stable elbow for their sport. A screw placed across the epicondyle into the medial column avoiding the olecranon fossa is a common fixation method. One author has recommended adding a metal washer to the screw fixation because of the perceived risk of epicondyle fragmentation or penetration when using a screw alone. The purpose of this study was to determine whether the use of a screw and washer for the fixation of pediatric medial epicondyle fractures results in less fragmentation of the epicondyle at the time of surgery and more complaints of hardware prominence leading to a second surgery to remove a deep implant. METHODS: A retrospective review was performed of patients treated surgically for displaced medial epicondyle fracture dislocations between 2008 and 2014. RESULTS: Sixteen patients with a total of 17 fracture dislocations were included in the study. The average follow-up was 11.5 months. Twelve fractures were treated with a screw and washer and 5 fractures were treated with a screw alone. All fractures healed. No fracture treated with a screw alone resulted in fragmentation or penetration of the epicondyle fragment. Seven of 12 patients treated with a screw and washer requested deep metal removal due to prominence and irritation at the medial epicondyle. No patient treated with a screw alone requested metal removal (58% vs. 0%; P=0.04). CONCLUSIONS: One author suggested that adding a washer to the screw for fixation of medial epicondyle fractures improved the ability to safely compress the fragment. However, the results of the present study report no case of fragmentation or penetration of the epicondyle when a washer was not used. In addition, the use of a screw and washer significantly increased the likelihood of a second surgery for removal of prominent hardware. LEVEL OF EVIDENCE: Level IV. PMID- 26974526 TI - The Effect of Dolutegravir on the Pharmacokinetics of Metformin in Healthy Subjects. AB - BACKGROUND: Dolutegravir is an integrase strand transfer inhibitor (INSTI) licensed for use in HIV-1 infection and is an inhibitor of organic cation transporter 2 (OCT2). This study assessed the effect of dolutegravir on the pharmacokinetics of metformin, an OCT2 substrate. DESIGN: This was an open-label, parallel-group, 3-period crossover study in healthy adult subjects. Subjects were enrolled into 1 of 2 treatment cohorts (15 subjects/cohort) receiving metformin 500 mg q12h for 5 days in period 1; metformin 500 mg q12h plus dolutegravir 50 mg q24h (cohort 1) or 50 mg q12h (cohort 2) for 7 days in period 2; and metformin 500 mg q12h for 10 days in period 3. There were no washout periods between treatments. Effects of dolutegravir on metformin transport and paracellular permeability were evaluated in vitro. RESULTS: Co-administration of dolutegravir 50 mg q24h increased metformin area under the curve(0-tau) by 79% and Cmax by 66%, whereas dolutegravir 50 mg q12h increased metformin area under the curve(0 tau) and Cmax by 145% and 111%, respectively. Metformin t(1/2) remained unchanged. Increased metformin exposure during dolutegravir co-administration returned to period 1 levels after dolutegravir discontinuation in period 3. Co administration of dolutegravir and metformin was well tolerated. In vitro, dolutegravir was not a clinically relevant inhibitor of OCT1, OCT3, multidrug and toxin extrusion protein 1, multidrug and toxin extrusion protein 2-K, or plasma membrane monoamine transporter, and it did not affect metformin paracellular permeability or uptake into an intestinal cell line. CONCLUSIONS: Dolutegravir significantly increased metformin plasma exposure, which can be partially explained by OCT2 inhibition. It is recommended that dose adjustments of metformin be considered to maintain optimal glycemic control when patients are starting/stopping dolutegravir while taking metformin. PMID- 26974527 TI - Does the Modified Gartland Classification Clarify Decision Making? AB - HYPOTHESIS: The modified Gartland classification system for pediatric supracondylar fractures is often utilized as a communication tool to aid in determining whether or not a fracture warrants operative intervention. This study sought to determine the interobserver and intraobserver reliability of the Gartland classification system, as well as to determine whether there was agreement that a fracture warranted operative intervention regardless of the classification system. METHODS: A total of 200 anteroposterior and lateral radiographs of pediatric supracondylar humerus fractures were retrospectively reviewed by 3 fellowship-trained pediatric orthopaedic surgeons and 2 orthopaedic residents and then classified as type I, IIa, IIb, or III. The surgeons then recorded whether they would treat the fracture nonoperatively or operatively. The kappa coefficients were calculated to determine interobserver and intraobserver reliability. RESULTS: Overall, the Wilkins-modified Gartland classification has low-moderate interobserver reliability (kappa=0.475) and high intraobserver reliability (kappa=0.777). A low interobserver reliability was found when differentiating between type IIa and IIb (kappa=0.240) among attendings. There was moderate-high interobserver reliability for the decision to operate (kappa=0.691) and high intraobserver reliability (kappa=0.760). Decreased interobserver reliability was present for decision to operate among residents. For fractures classified as type I, the decision to operate was made 3% of the time and 27% for type IIa. The decision was made to operate 99% of the time for type IIb and 100% for type III. SUMMARY: There is almost full agreement for the nonoperative treatment of Type I fractures and operative treatment for type III fractures. There is agreement that type IIb fractures should be treated operatively and that the majority of type IIa fractures should be treated nonoperatively. However, the interobserver reliability for differentiating between type IIa and IIb fractures is low. Our results validate the Gartland classfication system as a method to help direct treatment of pediatric supracondylar humerus fractures, although the modification of the system, IIa versus IIb, seems to have limited reliability and utility. Terminology based on decision to treat may lead to a more clinically useful classification system in the evaluation and treatment of pediatric supracondylar humerus fractures. LEVEL OF EVIDENCE: Level III-diagnostic studies. PMID- 26974529 TI - Clinical and MRI Outcomes After Surgical Treatment of Osteochondral Lesions of the Talus in Skeletally Immature Children. AB - BACKGROUND: The literature on the osteochondral lesion of the talus (OLT) in skeletally immature children is scarce and little is known about the clinical outcomes and the radiologic appearance of these lesions after surgical treatment. The aim of this study was to assess mid-term clinical and magnetic resonance imaging (MRI) outcomes after arthroscopic microfracture (AM) of OLT in skeletally immature children. METHODS: Thirteen patients with OLT treated by AM before skeletal maturity were included in the study. The Berndt and Harty outcome question, the Single Assessment Numeric Evaluation question, and the Martin questionnaire were used to obtain patients' subjective satisfaction with their operated ankle. Functional outcomes preoperatively and postoperatively were evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) score. MRI scans were performed postoperatively using a magnetic resonance observation of cartilage repair tissue (MOCART) scoring system for 11 ankles. RESULTS: The median age was 15 years (range, 13 to 16 y) and the median follow-up period was 5.6 years (range, 3.8 to 13.6 y). According to the Berndt and Harty outcome question, good clinical results were reported in 10 (76.9%) and fair in 3 (23.1%) patients. The postoperative AOFAS score was significantly improved when compared with the preoperative AOFAS score, with a mean increase of 35 points (P<0.001). The overall MOCART score was 65 (range, 10 to 75). MRI variables of the MOCART scoring system showed no association with clinical outcomes. CONCLUSIONS: AM seems to be an effective surgical method for the treatment of OLT in skeletally immature children. LEVEL OF EVIDENCE: Level IV-therapeutic studies, case series. PMID- 26974530 TI - Free energy model for solid high-pressure phases of carbon. AB - Analytic free energy models for three solid high-pressure phases--diamond, body centered cubic phase with eight atoms in the unit cell (BC8), and simple cubic (SC)--are developed using density functional theory. We explicitly include anharmonic effects by performing molecular dynamics simulations and investigate their density and temperature dependence in detail. Anharmonicity in the nuclear motion shifts the phase transitions significantly compared to the harmonic approximation. Furthermore, we apply a thermodynamically constrained correction that brings the equation of state in accordance with diamond anvil cell experiments. The performance of our thermodynamic functions is validated against Hugoniot experiments. PMID- 26974531 TI - The First Case of Total Laparoscopic Living Donor Right Hemihepatectomy in Mainland China and Literature Review. AB - BACKGROUND: Total laparoscopic living donor right hemihepatectomy (LDRH) has been successfully performed in several transplant centers. Here we report the first LDRH performed in mainland China and review current literature, focusing on perioperative donor evaluation and surgical procedure to secure donor safety. METHODS: A 47-year-old man volunteered for living donation to his wife who suffered from sclerosing cholangitis-related liver cirrhosis and hepatocellular carcinoma. Donor height is 165 cm and weight is 65 kg, whereas the body mass index is 23.9. The CT volume evaluation showed that the graft-to-body weight ratio was 1.42%, and the remnant liver volume was 36.3% for right graft without middle hepatic vein (MHV). The anatomy of hepatic vein, artery, portal vein, and bile duct was normal. Preoperative liver function tests were normal. RESULTS: Intraoperative biopsy result showed minimal steatosis. A transection was performed along the right side of the MHV. Two branches of MHV (V5 and V8) were <5 mm in diameter, and there was no need for reconstruction in the back table. Hilar dissection was meticulously performed. Right portal vein, hepatic artery, and bile duct were transected above the bifurcation. The right hepatic vein was transected by a laparoscopic linear stapler. The real graft volume was 660 mL, with a revised graft-to-body weight ratio of 1.14%. Warm ischemia time was about 4 minutes. The donor's postoperative course was uneventful. CONCLUSIONS: Total LDRH has been proven to be technically feasible in selected adult donors. Following increased experience, it might be a safe and minimally invasive option for adult donors. PMID- 26974532 TI - Shocking HIV out of hiding: where are we with clinical trials of latency reversing agents? AB - PURPOSE OF REVIEW: To provide an overview of the initial experiences with the use of latency-reversing agents (LRAs) in clinical trials in HIV and to discuss and contrast results arising from these studies. RECENT FINDINGS: Although the clinical administration of histone deacetylase inhibitors (HDACis) and disulfiram to HIV-infected individuals on antiretroviral therapy significantly increased cell-associated HIV RNA in CD4 T cells and in some cases plasma HIV RNA, this did not reduce the frequency of latently infected cells in blood. Potential reasons for this include insufficient potency in latency reversal, lack of virus or immune-mediated cytolysis of virus-expressing cells and/or a high frequency of immune escape mutations in the recently activated virus. Analyses of HIV-specific T-cell responses in vivo did not demonstrate that HDACis impair immune cell effector functions. SUMMARY: More effective latency-reversing interventions and additional strategies to eliminate virus-expressing cells are needed. Key challenges include testing combinations of LRAs and/or LRAs with immune modulation to optimize potency in the absence of adverse events. A better understanding of the mechanisms of action of LRAs as well as strategies to enhance potency and penetration in tissue are key challenges for future studies. PMID- 26974533 TI - Anterior Segment Biometry of the Accommodating Intraocular Lens and its Relationship With the Amplitude of Accommodation. AB - OBJECTIVES: To evaluate the anterior segment biometry of the Tetraflex accommodating intraocular lens (AIOL) and the contribution of forward movement to the amplitude of accommodation (AMP). METHODS: Patients who underwent phacoemulsification with implantation of Tetraflex AIOLs and control nonaccommodating intraocular lenses were imaged by custom-built, long scan depth spectral-domain optical coherence tomography at relaxed and maximal accommodative states. Anterior segment biometry was performed and correlated with the clinical manifestation including AMP. RESULTS: Patients in the Tetraflex group showed better distance-corrected near visual acuity (logMAR 0.43+/-0.10 vs. logMAR 0.51+/-0.10, P<0.05) and greater AMP (1.99+/-0.58 diopters [D] vs. 1.59+/-0.45 D, P<0.05) compared with the control group. The measurement of the postoperative anterior chamber depth (ACD) during accommodation showed a forward movement of the AIOLs in 16 eyes (69.6%). Compared with the control group, a greater proportion of cases in the Tetraflex group experienced forward movement (chi test, P<0.001). The AMP in the AIOL group negatively correlated with changes in postoperative ACD during accommodation (r=-0.47, P<0.05), whereas AMP in the control group negatively correlated with postoperative pupil diameter (r=-0.57, P<0.05). CONCLUSIONS: The Tetraflex AIOLs seemed to have a tendency for forward movement; however, the slight forward axial shifts of the Tetraflex AIOL during natural accommodation may not produce a clinically relevant change in optical power. PMID- 26974534 TI - Organoselenium Polymer Inhibits Biofilm Formation in Polypropylene Contact Lens Case Material. AB - OBJECTIVES: Contact lens-acquired bacterial infections are a serious problem. Of the reported cases, inadequate cleaning of the lens case was the most common cause of lens contamination. Organoselenium has been shown to inhibit bacterial attachment to different polymer materials. This study evaluates the ability of an organoselenium monomer, incorporated into the polymer of a polypropylene contact lens case coupon, to block the formation of biofilms in a lens case. METHODS: The bacteria tested were Pseudomonas aeruginosa, Staphylococcus aureus, Stenotrophomonas maltophilia, and Serratia marcescens. For this study, the bacteria were allowed to grow overnight, in trypticase soy broth media, in the presence of the selenium-containing polymer or the same polymer without organoselenium. The material was studied by both colony-forming unit determination and by confocal laser scanning microscopy. RESULTS: The results showed that the organoselenium polymer versus the control polymer resulted in the following effect on biofilm formation: (1) a reduction in P. aeruginosa of 7.3 logs (100%); (2) a reduction in S. aureus of 7.3 logs (100%); (3) a reduction in S. maltophilia of 7.5 logs (100%); and (4) a reduction in S. marcescens reduction of 3.3 logs (99.9%). To test the stability of the organoselenium polypropylene contact lens coupon, the coupon was soaked in PBS for eight weeks at room temperature. It was found that when these soaked coupons were tested against S. aureus, complete inhibition (8.1 logs) was obtained. Because organoselenium cannot leach from the polymer, this would imply that the organoselenium polypropylene contact lens case coupon would be inhibitory toward bacterial biofilm for the life of the case. CONCLUSION: The organoselenium polypropylene contact lens case coupon shows the ability to inhibit biofilm formation. The use of organoselenium copolymer should play an important role in protecting against contact lens case-acquired infection. PMID- 26974535 TI - Association Between Hay Fever and High Myopia in United States Adolescents and Adults. AB - OBJECTIVES: To investigate the relationship between hay fever and refractive error in a representative sample of adolescents and adults in the United States. METHODS: This cross-sectional study included 5,744 participants aged >=12 years from the 2005 to 2006 National Health and Nutrition Examination Survey who participated in the allergy questionnaire, completed objective refraction and keratometry in both eyes, and had immunoglobulin E (IgE) serology. The primary predictor variable, refractive error, was classified as emmetropia (-0.99 to +0.99 diopters [D]), low myopia (-1.00 to -2.99 D), moderate myopia (-3.00 to 5.99 D), high myopia (>=-6.00 D), or hyperopia (>=1.00 D). Covariates included age, gender, race, asthma, eczema, total serum IgE >=120 kU/L, corneal steepness, and corneal astigmatism. The primary outcome was hay fever. RESULTS: The study population's mean age was 41.7 years; 48.8% of subjects were men and 51.2% were women. The prevalence of hay fever was 12.1% overall. High myopes had 2.7 times higher odds of hay fever compared to emmetropes (OR 2.67, CI, 1.57-4.51, P=0.001), which was independent of demographics, atopic conditions, IgE serology, and keratometry measurements. CONCLUSIONS: The association between hay fever and high myopia identified in this large cross-sectional study remains speculative and was not mediated through corneal steepness or corneal astigmatism. Further prospective studies may help elucidate the directionality of the association between hay fever and high myopia. PMID- 26974536 TI - Time Trends in Fast Food Consumption and Its Association with Obesity among Children in China. AB - OBJECTIVE: Study the trends in Western fast food consumption (FFC) among Chinese school-age children and the association between FFC and obesity using nationwide survey data. DESIGN: Cross-sectional and longitudinal analyses were conducted to study the trends in FFC and the associations between FFC and weight status (overweight, obesity and body mass index (BMI) z-score). SETTING: Longitudinal data from families were collected in the 2004 and 2009 China Health and Nutrition Survey (covering nine provinces throughout China). SUBJECTS: The analysis included 2656 Chinese children aged 6 to 18 years (1542 and 1114 children in the 2004 and 2009 survey, respectively). RESULTS: FFC (reported having consumed Western fast food in the past three months) has increased between 2004 and 2009, from 18.5% to 23.9% in those aged 6-18, and increased more rapidly among those aged 13-17, from 17.9% to 26.3%. The increase was significant in almost all groups by age, sex, family income, and residence. Our cross-sectional and longitudinal analyses did not detect a significant association between FFC and obesity/overweight or BMI z-score (e.g., for BMI z-score, boys: beta = 0.02, 95% CI: -0.71, 0.75; girls: beta = -0.14, 95% CI: -1.03, 0.75). CONCLUSIONS: FFC has increased in Chinese school-age children, especially in older children, boys, and those from low- and medium-income families, rural areas, and East China, but decreased among those from high-income families during 2004-2009. The data did not show a significant association between FFC and obesity. PMID- 26974537 TI - Intranasal Administration of Recombinant Mycobacterium smegmatis Inducing IL-17A Autoantibody Attenuates Airway Inflammation in a Murine Model of Allergic Asthma. AB - Asthma is a chronic inflammatory disorder, previous studies have shown that IL 17A contributes to the development of asthma, and there is a positive correlation between the level of IL-17A and the severity of disease. Here, we constructed recombinant Mycobacterium smegmatis expressing fusion protein Ag85A-IL-17A (rMS Ag85a-IL-17a) and evaluated whether it could attenuate allergic airway inflammation, and further investigated the underlying mechanism. In this work, the murine model of asthma was established with ovalbumin, and mice were intranasally vaccinated with rMS-Ag85a-IL-17a. Autoantibody of IL-17A in sera was detected, and the airway inflammatory cells infiltration, the local cytokines and chemokines production and the histopathological changes of lung tissue were investigated. We found that the administration of rMS-Ag85a-IL-17a induced the autoantibody of IL-17A in sera. The vaccination of rMS-Ag85a-IL-17a remarkably reduced the infiltration of inflammatory cells and the secretion of mucus in lung tissue and significantly decreased the numbers of the total cells, eosinophils and neutrophils in BALF. Th1 cells count in spleen, Th1 cytokine levels in BALF and supernatant of splenocytes and mediastinal lymph nodes, and T-bet mRNA in lung tissue were significantly increased with rMS-Ag85a-IL-17a administration. Meanwhile, rMS-Ag85a-IL-17a vaccination markedly decreased Th2 cells count, Th2 cytokine and Th17 cytokine levels in BALF and supernatant of splenocytes and mediastinal lymph nodes, and chemokines mRNA expression in lung tissue. These data confirmed that recombinant Mycobacterium smegmatis in vivo could induce autoantibody of IL-17A, which attenuated asthmatic airway inflammation. PMID- 26974538 TI - The Role of Biliary Carcinoembryonic Antigen-Related Cellular Adhesion Molecule 6 (CEACAM6) as a Biomarker in Cholangiocarcinoma. AB - OBJECTIVE: The aim of the present study is to determine if CEACAM6 can be detected in the bile of patients with biliary cancer and can serve as a diagnostic biomarker for cholangiocarcinoma. SUMMARY BACKGROUND DATA: Distinguishing bile duct carcinoma from other diagnoses is often difficult using endoscopic or percutaneous techniques. The cell surface protein CEACAM6 is over expressed in many gastrointestinal cancers and may be selectively elevated in biliary adenocarcinoma. METHODS: Bile from patients with benign biliary disease and cholangiocarcinoma (hilar, intrahepatic and distal) was collected at the time of index operation. The concentration of CEACAM6 was quantified by sandwich enzyme-linked immunosorbent assay (ELISA) and correlated to pathologic diagnosis. Diagnostic capability of CEACAM6 was evaluated by Wilcoxon rank-sum, linear regression, multiple regression, and receiver operating characteristic (ROC) curve analysis. RESULTS: Bile from 83 patients was analyzed: 42 with benign disease and 41 with cholangiocarcinoma. Patients in the benign cohort were younger, predominantly female, and had lower median biliary CEACAM6 levels than patients in the malignant cohort (7.5 ng/ml vs. 40 ng/ml; p = <.001). ROC curve analysis determined CEACAM6 to be a positive predictor cholangiocarcinoma with a CEACAM6 level >14 ng/ml associated with 87.5% sensitivity, 69.1% specificity, and a likelihood ratio of 2.8 (AUC 0.74). Multiple regression analysis suggested elevated alkaline phosphatase and the presence of biliary endoprostheses may influence CEACAM6 levels. CONCLUSION: Biliary CEACAM6 can identify patients with extrahepatic cholangiocarcinoma with a high degree of sensitivity and should be investigated further as a potential screening tool. PMID- 26974539 TI - Pharmacokinetics and Bioequivalence of Two Formulations of Febuxostat 40-Mg and 80-Mg Tablets: A Randomized, Open-Label, 4-Way Crossover Study in Healthy Chinese Male Volunteers. AB - The present study aimed to investigate the pharmacokinetic properties of febuxostat in healthy Chinese male volunteers and evaluate whether the two formulations of febuxostat 40-mg and 80-mg tablets are bioequivalent. A randomized, open-label, 4-way crossover study was conducted in healthy Chinese male volunteers under fasting conditions. 24 eligible subjects were randomized in a 1:1:1:1 ratio to receive a single dose of test or reference formulation of febuxostat 40-mg or 80-mg tablet. The washout period between each administration was 1 week. Plasma febuxostat was quantified by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Tolerability was evaluated by monitoring adverse events, physical examinations, 12-lead ECG and laboratory tests. After single-dosing of 1 tablet of 40-mg febuxostat, the pharmacokinetic parameters of test and reference formulations were: Tmax 1.22+/-0.87 and 1.85+/ 1.03 h, Cmax 1689.16+/-461.31 and 1613.80+/-608.43 ng.mL-1, AUC0-t 5139.87+/ 1349.28 and 5517.91+/-2024.26 ng.mL-1.h, AUC0-infinity 5263.06+/-1339.16 and 5640.48+/-2040.22 ng.mL-1.h, t1/2 4.82+/-2.61 and 4.85+/-1.78 h, respectively. After single-dosing of 1 tablet of 80-mg febuxostat, the pharmacokinetic parameters of test and reference formulations were: Tmax 1.71+/-1.21 and 2.23+/ 1.55 h, Cmax 2744.47+/-1157.44 and 2998.17+/-1200.13 ng.mL-1, AUC0-t 9634.03+/ 2768.25 and 10467.95+/-3501.65 ng.mL-1.h, AUC0-infinity 9834.32+/-2730.51 and 10626.63+/-3504.08 ng.mL-1.h, t1/2 6.25+/-2.44 and 5.46+/-1.65 h, respectively. For single-dosing of 1 tablet of 40-mg febuxostat, 90% CIs for the test/reference ratio of AUC0-t, AUC0-infinity and Cmax were 89.79 to 102.55, 90.14 to 102.56 and 93.99 to 129.63, respectively. For single-dosing of 1 tablet of 80-mg febuxostat, 90% CIs for the test/reference ratio of AUC0-t, AUC0-infinity and Cmax were 86.67 to 100.00, 87.50 to 100.51 and 79.48 to 105.99, respectively. This single dose study revealed similar pharmacokinetic properties in healthy Chinese male volunteers as those found in Caucasic population. The test and reference febuxostat tablets formulations met the regulatory criteria for bioequivalence at 40-mg and 80-mg strengths in fasting healthy Chinese male volunteers. TRIAL REGISTRATION: Chictr.org ChiCTR-TTRCC-14004288. PMID- 26974540 TI - Genetic Relationships among Tall Coconut Palm (Cocos nucifera L.) Accessions of the International Coconut Genebank for Latin America and the Caribbean (ICG-LAC), Evaluated Using Microsatellite Markers (SSRs). AB - The diversity and genetic relationships among two accessions of tall coconut palms collected in Brazil and seven accessions introduced from different geographic regions of the world were analyzed using 25 microsatellite primers, 19 of which were polymorphic and detected between 4 and 10 alleles per locus, with an average of 6.57. The observed and expected heterozygosity ranged from 0.25 and 0.40 in the Rennell Islands Tall (RIT) accession to 0.54 and 0.62 in the Polynesian Tall (PYT) accession. The analysis of genetic structure resulted in the formation of five distinct groups. The first group was formed by the accessions Brazilian Tall-Praia do Forte (BRTPF), Brazilian Tall-Merepe (BRTMe) and West African Tall (WAT); the second group consisted of Malaysian Tall (MLT); the third group of RIT; the fourth group of Vanuatu Tall (VTT); and the fifth group of Rotuman Tall (RTMT), Tonga Tall (TONT) and PYT. The dendrogram based on the nearest-neighbor method detected the formation of two main groups and five subgroups, indicating that the genetic relationships of the accessions are based on their geographic regions of origin. The analyses revealed genetic relationships between the accessions collected in Brazil and the accession from Africa, and among palms from South East Asia and the South Pacific, confirming the common origin of these accessions. The information obtained in this study can guide decisions on germplasm conservation activities and the efficient selection of genetically divergent parents for use in coconut breeding programs in Brazil, which are attempting to select for disease resistance, mainly to lethal yellowing, among other characteristics. PMID- 26974542 TI - Novel Ion-Exchange Coagulants Remove More Low Molecular Weight Organics than Traditional Coagulants. AB - Low molecular weight (MW) charged organic matter is poorly removed by conventional coagulants but contributes to disinfection byproduct formation during chlorination of drinking waters. We hypothesized that CIEX, a new Al-based hybrid coagulant with ion-exchange functional groups, would be new mechanistic approach to remove low MW organic matter during coagulation and would perform better than polyaluminum chloride (PACl) or metal-salt based coagulants. We measured coagulation performance using dissolved organic carbon (DOC) in a high hardness surface water. CIEX achieved excellent turbidity removal and removed 20% to 46% more DOC than FeCl3, Al2(SO4)3, or PACl, depending on dose. The improved DOC removal was attributable to better removal of low MW organic matter (<2 kDa). We further studied removal mechanisms in a model water containing a low MW organic acid (salicylic acid (SA)). CIEX achieved high removal of organic acids (>90% of SA) independent of pH, whereas removal by metal salts was lower (<15%) and was strongly pH dependent. CIEX ion-exchange capability is facilitated by its covalently bound quaternary ammonium group, which conventional coagulants lack. Plus, unlike other cationic polymers that react with chloramines to form N nitrosodimethylamine (NDMA), CIEX has a low molar yield (9.3 * 10(-7) mol NDMA per mol CIEX-N). PMID- 26974541 TI - Oridonin Attenuates Synaptic Loss and Cognitive Deficits in an Abeta1-42-Induced Mouse Model of Alzheimer's Disease. AB - Synaptic loss induced by beta-amyloid (Abeta) plays a critical role in the pathophysiology of Alzheimer's disease (AD), but the mechanisms underlying this process remain unknown. In this study, we found that oridonin (Ori) rescued synaptic loss induced by Abeta1-42 in vivo and in vitro and attenuated the alterations in dendritic structure and spine density observed in the hippocampus of AD mice. In addition, Ori increased the expression of PSD-95 and synaptophysin and promoted mitochondrial activity in the synaptosomes of AD mice. Ori also activated the BDNF/TrkB/CREB signaling pathway in the hippocampus of AD mice. Furthermore, in the Morris water maze test, Ori reduced latency and searching distance and increased the number of platform crosses in AD mice. These data suggest that Ori might prevent synaptic loss and improve behavioral symptoms in Abeta1-42-induced AD mice. PMID- 26974543 TI - Pulmonary Neoplasms in Patients with Birt-Hogg-Dube Syndrome: Histopathological Features and Genetic and Somatic Events. AB - Birt-Hogg-Dube syndrome (BHD) is an inherited disorder caused by genetic mutations in the folliculin (FLCN) gene. Individuals with BHD have multiple pulmonary cysts and are at a high risk for developing renal cell carcinomas (RCCs). Currently, little information is available about whether pulmonary cysts are absolutely benign or if the lungs are at an increased risk for developing neoplasms. Herein, we describe 14 pulmonary neoplastic lesions in 7 patients with BHD. All patients were confirmed to have germline FLCN mutations. Neoplasm histologies included adenocarcinoma in situ (n = 2), minimally invasive adenocarcinoma (n = 1), papillary adenocarcinoma (n = 1), micropapillary adenocarcinoma (n = 1), atypical adenomatous hyperplasia (n = 8), and micronodular pneumocyte hyperplasia (MPH)-like lesion (n = 1). Five of the six adenocarcinoma/MPH-like lesions (83.3%) demonstrated a loss of heterozygosity (LOH) of FLCN. All of these lesions lacked mutant alleles and preserved wild-type alleles. Three invasive adenocarcinomas possessed additional somatic events: 2 had a somatic mutation in the epidermal growth factor receptor gene (EGFR) and another had a somatic mutation in KRAS. Immunohistochemical analysis revealed that most of the lesions were immunostained for phospho-mammalian target of rapamycin (p-mTOR) and phospho-S6. Collective data indicated that pulmonary neoplasms of peripheral adenocarcinomatous lineage in BHD patients frequently exhibit LOH of FLCN with mTOR pathway signaling. Additional driver gene mutations were detected only in invasive cases, suggesting that FLCN LOH may be an underlying abnormality that cooperates with major driver gene mutations in the progression of pulmonary adenocarcinomas in BHD patients. PMID- 26974544 TI - Detection of a Serum Siderophore by LC-MS/MS as a Potential Biomarker of Invasive Aspergillosis. AB - Invasive aspergillosis (IA) is a life-threatening systemic mycosis caused primarily by Aspergillus fumigatus. Early diagnosis of IA is based, in part, on an immunoassay for circulating fungal cell wall carbohydrate, galactomannan (GM). However, a wide range of sensitivity and specificity rates have been reported for the GM test across various patient populations. To obtain iron in vivo, A. fumigatus secretes the siderophore, N,N',N"-triacetylfusarinine C (TAFC) and we hypothesize that TAFC may represent a possible biomarker for early detection of IA. We developed an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for TAFC analysis from serum, and measured TAFC in serum samples collected from patients at risk for IA. The method showed lower and upper limits of quantitation (LOQ) of 5 ng/ml and 750 ng/ml, respectively, and complete TAFC recovery from spiked serum. As proof of concept, we evaluated 76 serum samples from 58 patients with suspected IA that were investigated for the presence of GM. Fourteen serum samples obtained from 11 patients diagnosed with probable or proven IA were also analyzed for the presence of TAFC. Control sera (n = 16) were analyzed to establish a TAFC cut-off value (>=6 ng/ml). Of the 36 GM-positive samples (>=0.5 GM index) from suspected IA patients, TAFC was considered positive in 25 (69%). TAFC was also found in 28 additional GM-negative samples. TAFC was detected in 4 of the 14 samples (28%) from patients with proven/probable aspergillosis. Log-transformed TAFC and GM values from patients with proven/probable IA, healthy individuals and SLE patients showed a significant correlation with a Pearson r value of 0.77. In summary, we have developed a method for the detection of TAFC in serum that revealed this fungal product in the sera of patients at risk for invasive aspergillosis. A prospective study is warranted to determine whether this method provides improved early detection of IA. PMID- 26974545 TI - The "Pure Marriage" between 3D Printing and Well-Ordered Nanoarrays by Using PEALD Assisted Hydrothermal Surface Engineering. AB - For the first time, homogeneous and well-ordered functional nanoarrays were grown densely on the complex structured three-dimensional (3D) printing frameworks through a general plasma enhanced atomic layer deposition (PEALD) assisted hydrothermal surface engineering process. The entire process was free from toxic additives or harmful residues and, therefore, can meet the critical requirements of high-purity products. As a practical example, 3D customized earplugs were precisely manufactured according to the model of ear canals at the 0.1 mm level. Meanwhile, well-ordered ZnO nanoarrays, formed on the surfaces of these 3D printed earplugs, could effectively prevent the growth of five main pathogens derived from the patients with otitis media and exhibited excellent wear resistance as well. On the basis of both animal experiments and volunteers' investigations, the 3D customized earplugs showed sound insulation capabilities superior to those of traditional earplugs. Further animal experiments demonstrated the potential of as-modified implant scaffolds in practical clinical applications. This work, exemplified with earplugs and implant scaffolds, oriented the development direction of 3D printing in biomedical devices, which precisely integrated customized architecture and tailored surface performance. PMID- 26974546 TI - Potential Influence of Advance Care Planning and Palliative Care Consultation on ICU Costs for Patients With Chronic and Serious Illness. AB - OBJECTIVES: To estimate the potential ICU-related cost savings if in-hospital advance care planning and ICU-based palliative care consultation became standard of care for patients with chronic and serious illness. DESIGN AND SETTING: Decision analysis using literature estimates and inpatient administrative data from Premier. PATIENTS: Patients with chronic, life-limiting illness admitted to a hospital within the Premier network. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Using Premier data (2008-2012), ICU resource utilization and costs were tracked over a 1-year time horizon for 2,097,563 patients with chronic life limiting illness. Using a Markov microsimulation model, we explored the potential cost savings from the hospital system perspective under a variety of scenarios by varying the interventions' efficacies and availabilities. Of 2,097,563 patients, 657,825 (31%) used the ICU during the 1-year time horizon; mean ICU spending per patient was 11.3k (SD, 17.6k). In the base-case analysis, if in-hospital advance care planning and ICU-based palliative care consultation were systematically provided, we estimated a mean reduction in ICU costs of 2.8k (SD, 14.5k) per patient and an ICU cost saving of 25%. Among the simulated patients who used the ICU, the receipt of both interventions could have resulted in ICU cost savings of 1.9 billion, representing a 6% reduction in total hospital costs for these patients. CONCLUSIONS: In-hospital advance care planning and palliative care consultation have the potential to result in significant cost savings. Studies are needed to confirm these findings, but our results provide guidance for hospitals and policymakers. PMID- 26974547 TI - An Exploratory Study of Long-Term Outcome Measures in Critical Illness Survivors: Construct Validity of Physical Activity, Frailty, and Health-Related Quality of Life Measures. AB - OBJECTIVE: Functional capacity is commonly impaired after critical illness. We sought to clarify the relationship between objective measures of physical activity, self-reported measures of health-related quality of life, and clinician reported global functioning capacity (frailty) in such patients, as well as the impact of prior chronic disease status on these functional outcomes. DESIGN: Prospective outcome study of critical illness survivors. SETTING: Community-based follow-up. PATIENTS: Participants of the Musculoskeletal Ultrasound Study in Critical Care: Longitudinal Evaluation Study (NCT01106300), invasively ventilated for more than 48 hours and on the ICU greater than 7 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Physical activity levels (health-related quality of life [36-item short-form health survey] and daily step counts [accelerometry]) were compared to norm-based or healthy control scores, respectively. Controls for frailty (Clinical Frailty Score) were non-morbid, age- and gender-matched to survivors. Ninety-one patients were recruited on ICU admission: 41 were contacted for post-discharge assessment, and data were collected from 30 (14 female; mean age, 55.3 yr [95% CI, 48.3-62.3]; mean post-discharge, 576 d [95% CI, 539-614]). Patients' mean daily step count (5,803; 95% CI, 4,792-6,813) was lower than that in controls (11,735; 95% CI, 10,928-12,542; p < 0.001), and lower in those with preexisting chronic disease than without (2,989 [95% CI, 776-5,201] vs 7,737 [95% CI, 4,907-10,567]; p = 0.013). Physical activity measures (accelerometry, health related quality of life, and frailty) demonstrated good construct validity across all three tools. Step variability (from SD) was highly correlated with daily steps (r = 0.67; p < 0.01) demonstrating a potential boundary constraint. CONCLUSIONS: Subjective and objective measures of physical activity are all informative in ICU survivors. They are all reduced 18 months post-discharge in ICU survivors, and worse in those with pre-admission chronic disease states. Investigating interventions to improve functional capacity in ICU survivors will require stratification based on the presence of premorbidity. PMID- 26974548 TI - High Intracranial Pressure Induced Injury in the Healthy Rat Brain. AB - OBJECTIVES: We recently showed that increased intracranial pressure to 50 mm Hg in the healthy rat brain results in microvascular shunt flow characterized by tissue hypoxia, edema, and increased blood-brain barrier permeability. We now determined whether increased intracranial pressure results in neuronal injury by Fluoro-Jade stain and whether changes in cerebral blood flow and cerebral metabolic rate for oxygen suggest nonnutritive microvascular shunt flow. DESIGN: Intracranial pressure was elevated by a reservoir of artificial cerebrospinal fluid connected to the cisterna magna. Arterial blood gases, cerebral arterial venous oxygen content difference, and cerebral blood flow by MRI were measured. Fluoro-Jade stain neurons were counted in histologic sections of the right and left dorsal and lateral cortices and hippocampus. SETTING: University laboratory. SUBJECTS: Male Sprague Dawley rats. INTERVENTIONS: Arterial pressure support if needed by IV dopamine infusion and base deficit corrected by sodium bicarbonate. MEASUREMENTS AND MAIN RESULTS: Fluoro-Jade stain neurons increased 2.5- and 5.5 fold at intracranial pressures of 30 and 50 mm Hg and cerebral perfusion pressures of 57 +/- 4 (mean +/- SEM) and 47 +/- 6 mm Hg, respectively (p < 0.001) (highest in the right and left cortices). Voxel frequency histograms of cerebral blood flow showed a pattern consistent with microvascular shunt flow by dispersion to higher cerebral blood flow at high intracranial pressure and decreased cerebral metabolic rate for oxygen. CONCLUSIONS: High intracranial pressure likely caused neuronal injury because of a transition from normal capillary flow to nonnutritive microvascular shunt flow resulting in tissue hypoxia and edema, and it is manifest by a reduction in the cerebral metabolic rate for oxygen. PMID- 26974549 TI - Hydrolytic Amino Acids Employed as a Novel Organic Nitrogen Source for the Preparation of PGPF-Containing Bio-Organic Fertilizer for Plant Growth Promotion and Characterization of Substance Transformation during BOF Production. AB - Opportunity costs seriously limit the large-scale production of bio-organic fertilizers (BOFs) both in China and internationally. This study addresses the utilization of amino acids resulting from the acidic hydrolysis of pig corpses as organic nitrogen sources to increase the density of TrichodermaharzianumT-E5 (a typical plant growth-promoting fungi, PGPF). This results in a novel, economical, highly efficient and environmentally friendly BOF product. Fluorescence excitation-emission matrix (EEM) spectroscopy combined with fluorescence regional integration (FRI) was employed to monitor compost maturity levels, while pot experiments were utilized to test the effects of this novel BOF on plant growth. An optimization experiment, based on response surface methodologies (RSMs), showed that a maximum T-E5 population (3.72 * 108 ITS copies g-1) was obtained from a mixture of 65.17% cattle manure compost (W/W), 19.33% maggot manure (W/W), 15.50% (V/W)hydrolytic amino acid solution and 4.69% (V/W) inoculum at 28.7 degrees C after a 14 day secondary solid fermentation. Spectroscopy analysis revealed that the compost transformation process involved the degradation of protein-like substances and the formation of fulvic-like and humic-like substances. FRI parameters (PI, n, PII, n, PIII, n and PV, n) were used to characterize the degree of compost maturity. The BOF resulted in significantly higher increased chlorophyll content, shoot length, and shoot and root dry weights of three vegetables (cucumber, tomato and pepper) by 9.9%~22.4%, 22.9%~58.5%, 31.0%~84.9%, and 24.2%~34.1%, respectively. In summary, this study presents an operational means of increasing PGPF T-E5 populations in BOF to promote plant growth with a concomitant reduction in production cost. In addition, a BOF compost maturity assessment using fluorescence EEM spectroscopy and FRI ensured its safe field application. PMID- 26974550 TI - Influence of Different Nanomaterials on Growth and Mycotoxin Production of Penicillium verrucosum. AB - Nanoparticles are ubiquitous in the environment. They originate from anthropogenic or natural sources or they are intentionally produced for different purposes. There exist manifold applications of nanoparticles in modern life leading unavoidably to a confrontation and interaction between nanomaterial and living organisms. Based on their wide distribution tending to increase steadily, the influence of particles based on silica and silver, exhibiting nominal sizes between 0.65 nm and 200 nm, on the physiology of the mycotoxigenic filamentous fungus Penicillium verrucosum was analyzed. The applied concentration and time point, the size and the chemical composition of the particles was shown to have a strong influence on growth and mycotoxin biosynthesis. On microscopic scale it could be shown that silver nanoparticles attach to the mycelial surface. Moreover, silver nanoparticles with 0.65 nm and 5 nm in size were shown to internalize within the cell, form agglomerates in the cytoplasm and associate to cell organelles. PMID- 26974551 TI - Evaluation of Parasiticide Treatment with Benznidazol in the Electrocardiographic, Clinical, and Serological Evolution of Chagas Disease. AB - INTRODUCTION: Chagas disease is one of the most important endemic parasitic diseases in Latin America. In its chronic phase, progression to cardiomyopathy has high morbidity and mortality. The persistence of a normal electrocardiogram (ECG) provides a similar prognosis to that of a non-diseased population. Benznidazole (BNZ) is the only drug with trypanocidal action available in Brazil. MATERIALS/METHODS/RESULTS: A group of 310 patients with chronic Chagas disease who had normal ECGs at the first medical visit performed before 2002 were included. There were 263 patients treated with BNZ and 47 untreated. The follow up period was 19.59 years. Univariate analyses showed that those treated were younger and predominantly male. As many as 79.08% of those treated and 46.81% of those untreated continued with normal electrocardiograms (p <0.0001). The occurrence of electrocardiographic abnormalities and relevant clinical events (heart failure, stroke, total mortality, and cardiovascular death) was less prevalent in treated patients (p <0.001, p: 0.022, p: 0.047 respectively). In multivariate analyses, the parasiticide treatment was an independent variable for persistence of a normal ECG pattern, which was an independent variable in the prevention of significant clinical events. The immunofluorescence titers decreased with the parasitological treatment. However, the small number of tests in untreated patients did not allow the correlation of the decrease of these titers with electrocardiographic alterations. CONCLUSION: These data suggest that treatment with benznidazole prevents the occurrence of electrocardiographic alterations. On the other hand, patients who develop ECG abnormalities present with more significant clinical events. PMID- 26974552 TI - Correction: Curcumin Significantly Enhances Dual PI3K/Akt and mTOR Inhibitor NVP BEZ235-Induced Apoptosis in Human Renal Carcinoma Caki Cells through Down Regulation of p53-Dependent Bcl-2 Expression and Inhibition of Mcl-1 Protein Stability. PMID- 26974553 TI - Metal Dilution Effects on the Reverse Spin Transition in Mixed Crystals of Type [Co(1-x)Zn(x)(C16-terpy)2](BF4)2 (x = 0.1-0.7). AB - Metal dilution effects on reverse spin transition (rST) in mixed crystals of type [Co(1-x)Zn(x)(C16-terpy)2](BF4)2 (x = 0.1-0.7) were investigated by comparison with behavior of [Co(1-x)Fe(x)(C16-terpy)2](BF4)2 (x = 0.1-0.4). In the mixed crystals, the Zn complexes increased rST temperatures linearly with increasing values of x, without changing the hysteresis width, while the Fe complexes decreased rST temperatures. Moreover, the strength of the metal dilution effects in the CoZn mixed crystals is weaker than what occurs in the CoFe mixed crystals. PMID- 26974554 TI - Enantioselective Construction of Functionalized Tetrahydrocarbazoles Enabled by Asymmetric Relay Catalysis of Gold Complex and Chiral Bronsted Acid. AB - An intramolecular hydroamination/Michael addition cascade is realized using a combination of gold(I) complex and chiral BINOL-phosphoric acid, affording fused tetrahydrocarbazole scaffolds in excellent yields and high enantioselectivities. PMID- 26974555 TI - Cobalt-Catalyzed Asymmetric Hydrogenation of 1,1-Diarylethenes. AB - Highly enantioselective cobalt-catalyzed hydrogenation of 1,1-diarylethenes was developed by using bench-stable chiral oxazoline iminopyridine-cobalt complexes as precatalysts. A unique o-chloride effect was observed to achieve high enantioselectivity. Easy removal as well as further transformations of the chloro group make this protocol a potentially useful alternative to synthesize various chiral 1,1-diarylethanes. This process can be successfully performed under 1 atm of hydrogen at room temperature on gram scale. PMID- 26974556 TI - Clinical Features in a Danish Population-Based Cohort of Probable Multiple System Atrophy Patients. AB - BACKGROUND: Multiple system atrophy (MSA) is a rare, sporadic and progressive neurodegenerative disorder. We aimed to describe the clinical features of Danish probable MSA patients, evaluate their initial response to dopaminergic therapy and examine mortality. METHODS: From the Danish National Patient Registry, we identified 782 patients diagnosed with conditions potentially compatible with probable MSA (International Classification of Diseases, version 10 (ICD-10) codes G23.2, G23.8 and G23.9) during 1994-2009. Through medical record review, we narrowed our sample to 115 patients who fulfilled the criteria for probable MSA. We recorded clinical features, examined differences by MSA subtype and used Kaplan-Meier survival analysis to examine mortality. RESULTS: The mean age at onset of patients with probable MSA was 60.2 years (range 36-75 years) and mean time to wheelchair dependency was 4.7 years (range 0-15 years). One-third of patients experienced a transient improvement in motor symptoms with use of levodopa. Median survival from disease onset was 6.9 years (range 1-16 years, 95% CI 6.3-7.5) with no apparent variation according to gender or subtype. CONCLUSIONS: Our nationwide approach corroborated that MSA is associated with diverse and grave symptoms, only limited response to levodopa, and poor prognosis. PMID- 26974557 TI - Global Health Education in Pulmonary and Critical Care Medicine Fellowships. AB - A growing number of pulmonary and critical care medicine fellowship programs in the United States offer global health training opportunities. Formal, integrated global health programs within pulmonary and critical care fellowships are relatively new but are built on principles and ideals of global health that focus on the mutually beneficial exchange of knowledge and social justice. Although core competencies consistent with these overarching themes in global health education have not been formalized for pulmonary and critical care trainees, relevant competency areas include clinical knowledge, international research training, cultural competency, and clinical and research capacity building. Existing global health education in U.S. pulmonary and critical care medicine training programs can generally be classified as one of three different models: integrated global health tracks, global health electives, and additional research years. Successful global health education programs foster partnerships and collaborations with international sites that emphasize bidirectional exchange. This bidirectional exchange includes ongoing, equitable commitments to mutual opportunities for training and professional development, including a focus on the particular knowledge and skill sets critical for addressing the unique priorities of individual countries. However, barriers related to the availability of mentorship, funding, and dedicated time exist to expanding global health education in pulmonary and critical care medicine. The implementation of global health training within pulmonary and critical care medicine programs requires continued optimization, but this training is essential to prepare the next generation of physicians to address the global aspects of respiratory disease and critical illness. PMID- 26974558 TI - Endovascular Therapeutic Occlusion of the Posterior Cerebral Artery: An Option for Ruptured Giant Aneurysm in a Child. AB - The incidence of intracranial aneurysms in the pediatric population is low, and surgical clipping remains a good long-term treatment option. However, posterior circulation aneurysms are even more complex to manage in children than in adults. We report a case of a giant aneurysm of the posterior cerebral artery in a 10 year-old boy presenting with subarachnoid hemorrhage. Endovascular treatment with platinum coils was performed with total occlusion of the aneurysm and the affected arterial segment without complications. The patient achieved good recovery, and a late control angiogram confirmed exclusion of the aneurysm. Occurrence of special features of cerebral aneurysm in children, in comparison to adults, is also described. Parent artery sacrifice is an effective therapeutic option, but long-term follow-up is necessary to avoid recurrence and rebleeding. PMID- 26974559 TI - Psychosomatic and physical responses to a multi-component stress management program among teaching professionals: A randomized study of cognitive behavioral intervention (CB) with complementary and alternative medicine (CAM) approach. AB - BACKGROUND: The present study aims to assess psychosomatic and physical responses to a multi-component stress management program with the use of CAM and CB approaches among teaching professionals in Hong Kong. METHOD: A random controlled trial (RCT) was used to compare between CB group (n = 26) and the CAM-CB group (n = 30). Interventions were administered for 1.5 h once a week for eight consecutive weeks. A self-administered questionnaire including perceived stress scale (PSS) and frequency of psychosomatic symptoms were measured at baseline (T1), immediate after the program (T2), and 4 weeks after the program (T3). Physical parameters were measured at T1 and T2. RESULTS: A reduction of 23% in PSS was observed in the CB group, while the CAM-CB group yielded 18% reductions in PSS from T1 to T3 [F(2,108) = 3.099; p = .049]. No significant interactions were observed in the frequency of psychosomatic symptoms and physical parameters. However, a significant downward time trend was observed (p < .001) and larger percentage changes in physical responses were shown in the CAM-CB group than CB group. CONCLUSION: Clinical evidence of both the CAM-CB and CB program has been demonstrated in the current study and both approaches are easy to be self implemented. The CAM technique might serve as an alternative choice for self administered stress management to replace the additional time needed for professional follow-up contacts. It might further improve some physical responses such as handgrip strength and resting heart rate, which are associated with better psychosomatic health and better occupational stress management. PMID- 26974560 TI - Power-Hop: A Pervasive Observation for Real Complex Networks. AB - Complex networks have been shown to exhibit universal properties, with one of the most consistent patterns being the scale-free degree distribution, but are there regularities obeyed by the r-hop neighborhood in real networks? We answer this question by identifying another power-law pattern that describes the relationship between the fractions of node pairs C(r) within r hops and the hop count r. This scale-free distribution is pervasive and describes a large variety of networks, ranging from social and urban to technological and biological networks. In particular, inspired by the definition of the fractal correlation dimension D2 on a point-set, we consider the hop-count r to be the underlying distance metric between two vertices of the network, and we examine the scaling of C(r) with r. We find that this relationship follows a power-law in real networks within the range 2 <= r <= d, where d is the effective diameter of the network, that is, the 90-th percentile distance. We term this relationship as power-hop and the corresponding power-law exponent as power-hop exponent h. We provide theoretical justification for this pattern under successful existing network models, while we analyze a large set of real and synthetic network datasets and we show the pervasiveness of the power-hop. PMID- 26974562 TI - The Highs and Lows of Hemoglobin A1c. PMID- 26974561 TI - Characterization of a Novel Anti-Human HB-EGF Monoclonal Antibody Applicable for Paraffin-Embedded Tissues and Diagnosis of HB-EGF-Related Cancers. AB - Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of growth factors that bind to and activate the EGF receptor (EGFR/ErbB1) and ErbB4. HB-EGF plays pivotal roles in pathophysiological processes, including cancer. Thus, monoclonal antibodies (mAbs) for HB-EGF detection could be an important tool in the therapeutic diagnosis of HB-EGF-related cancers and other diseases. However, few mAbs, especially those applicable for immunohistochemistry (IHC), have been established to date. In this study, we generated a clone of hybridoma derived mAb 2-108 by immunizing mice with recombinant human HB-EGF protein expressed by human cells. The mAb 2-108 specifically bound to human HB-EGF but not to mouse HB-EGF and was successful in immunoblotting, even under reducing conditions, immunoprecipitation, and immunofluorescence for unfixed as well as paraformaldehyde-fixed cells. Notably, this mAb was effective in IHC of paraffin embedded tumor specimens. Epitope mapping analysis showed that mAb 2-108 recognized the N-terminal prodomain in HB-EGF. These results indicate that this new anti-HB-EGF mAb 2-108 would be useful in the diagnosis of HB-EGF-related cancers and would be a strong tool in both basic and clinical research on HB-EGF. PMID- 26974563 TI - Opportunities and challenges in biological lignin valorization. AB - Lignin is a primary component of lignocellulosic biomass that is an underutilized feedstock in the growing biofuels industry. Despite the fact that lignin depolymerization has long been studied, the intrinsic heterogeneity of lignin typically leads to heterogeneous streams of aromatic compounds, which in turn present significant technical challenges when attempting to produce lignin derived chemicals where purity is often a concern. In Nature, microorganisms often encounter this same problem during biomass turnover wherein powerful oxidative enzymes produce heterogeneous slates of aromatics compounds. Some microbes have evolved metabolic pathways to convert these aromatic species via 'upper pathways' into central intermediates, which can then be funneled through 'lower pathways' into central carbon metabolism in a process we dubbed 'biological funneling'. This funneling approach offers a direct, biological solution to overcome heterogeneity problems in lignin valorization for the modern biorefinery. Coupled to targeted separations and downstream chemical catalysis, this concept offers the ability to produce a wide range of molecules from lignin. This perspective describes research opportunities and challenges ahead for this new field of research, which holds significant promise towards a biorefinery concept wherein polysaccharides and lignin are treated as equally valuable feedstocks. In particular, we discuss tailoring the lignin substrate for microbial utilization, host selection for biological funneling, ligninolytic enzyme-microbe synergy, metabolic engineering, expanding substrate specificity for biological funneling, and process integration, each of which presents key challenges. Ultimately, for biological solutions to lignin valorization to be viable, multiple questions in each of these areas will need to be addressed, making biological lignin valorization a multidisciplinary, co-design problem. PMID- 26974564 TI - Identification of complex septic odorants in Huangpu River source water by combining the data from gas chromatography-olfactometry and comprehensive two dimensional gas chromatography using retention indices. AB - Identification of the trace odorants causing the septic odors in source waters with complex matrixes has long been a big challenge. The Huangpu (HP) River, an important source water for Shanghai, has long been suffering from septic and musty odors, although major odorants have not been identified. In this study, combining the data from gas chromatography-olfactometry with mass spectrometry (GC-O/MS) and comprehensive two-dimensional gas chromatography with time-of flight mass spectrometry (GC*GC-TOFMS) using retention indices (RIs) was used for the identification of odorants in HP source water. Olfactometry peaks detected in water extracts by GC-O/MS were combined with the chromatography peaks detected by GC*GC-TOFMS based on the RIs determined using the retention times (RTs) of alkanes C7-C30. A total of thirteen olfactometry peaks were obtained though GC O/MS analysis, and potential odorants corresponding to each of the olfactometry peaks were screened based on the odor characteristics and match similarity using GC*GC-TOFMS. Finally, fourteen odorants (one odorant was detected in GC*GC-TOFMS without an olfactometry peak), including three septic odorants (bis(2 chloroisopropyl) ether, diethyl disulfide and dimethyl disulfide) and two musty ones (geosmin and 2-MIB), were confirmed by using authentic standards. The septic and musty odorants in six source water samples taken over a period of six months were quantified. Bis(2-chloroisopropyl) ether, with an odor activity value (OAV) of 1.84-3.2, was found to be a major septic odorant in HP source water, followed by diethyl disulfide (OAV 1.56-1.96) and dimethyl disulfide (OAV 0.37-2.42), while geosmin (OAV 4.37-11.44) was the major musty odorant, followed by 2-MIB (OAV 1.13-1.89). This is the first comprehensive study focusing on the identification of odorants in a complex source water. The integrated approach used in this study could be applied for the identification of odorants in other complex source waters suffering similar odor problems. PMID- 26974565 TI - Biochar affects soil organic matter cycling and microbial functions but does not alter microbial community structure in a paddy soil. AB - The application of biochar (BC) in conjunction with mineral fertilizers is one of the most promising management practices recommended to improve soil quality. However, the interactive mechanisms of BC and mineral fertilizer addition affecting microbial communities and functions associated with soil organic matter (SOM) cycling are poorly understood. We investigated the SOM in physical and chemical fractions, microbial community structure (using phospholipid fatty acid analysis, PLFA) and functions (by analyzing enzymes involved in C and N cycling and Biolog) in a 6-year field experiment with BC and NPK amendment. BC application increased total soil C and particulate organic C for 47.4-50.4% and 63.7-74.6%, respectively. The effects of BC on the microbial community and C cycling enzymes were dependent on fertilization. Addition of BC alone did not change the microbial community compared with the control, but altered the microbial community structure in conjunction with NPK fertilization. SOM fractions accounted for 55% of the variance in the PLFA-related microbial community structure. The particulate organic N explained the largest variation in the microbial community structure. Microbial metabolic activity strongly increased after BC addition, particularly the utilization of amino acids and amines due to an increase in the activity of proteolytic (l-leucine aminopeptidase) enzymes. These results indicate that microorganisms start to mine N from the SOM to compensate for high C:N ratios after BC application, which consequently accelerate cycling of stable N. Concluding, BC in combination with NPK fertilizer application strongly affected microbial community composition and functions, which consequently influenced SOM cycling. PMID- 26974566 TI - A review of atmospheric and land surface processes with emphasis on flood generation in the Southern Himalayan rivers. AB - Floods in the southern rim of the Indian Himalayas are a major cause of loss of life, property, crops, infrastructure, etc. They have long term socio-economic impacts on the habitat living along/across the Himalayas. In the recent decade extreme precipitation events have led to numerous flash floods in and around the Himalayan region. Sporadic case-based studies have tried to explain the mechanisms causing the floods. However, in some of the cases, the causative mechanisms have been elusive. Various types of flood events have been debated at different spatial and temporal scales. The present study provides an overview of mechanisms that lead to floods in and around the southern rim of the Indian Himalayas. Atmospheric processes, landuse interaction, and glacier-related outbreaks are considered in the overview. PMID- 26974567 TI - A study of ambient fine particles at Tianjin International Airport, China. AB - The total count number concentration of particles from 10 to 1000nm, particle size distribution, and PM2.5 (aerodynamic diameter<=2.5MUm) mass concentration were measured on a parking apron next to the runway at Tianjin International Airport in China. The data were collected 250, 270, 300, 350, and 400m from the runway. Wind direction and wind speed played important roles in determining the characteristics of the atmospheric particles. An inverted U-shaped relationship was observed between the measured particle number concentration and wind speed, with an average peak concentration of 2.2*10(5)particles/cm(3) at wind speeds of approximately 4-5m/s. The atmospheric particle number concentration was affected mainly by aircraft takeoffs and landings, and the PM2.5 mass concentration was affected mainly by the relative humidity (RH) of the atmosphere. Ultrafine particles (UFPs, diameter<100nm), with the highest number concentration at a particle size of approximately 16nm, dominated the measured particle size distributions. The calculated particle emission index values for aircraft takeoff and landing were nearly the same, with mean values of 7.5*10(15)particles/(kg fuel) and 7.6*10(15)particles/(kg fuel), respectively. The particle emission rate for one aircraft during takeoff is two orders of magnitude higher than for all gasoline-powered passenger vehicles in Tianjin combined. The particle number concentrations remained much higher than the background concentrations even beyond 400m from the runway. PMID- 26974568 TI - Initial geochemical characteristics of fluid fine tailings in an oil sands end pit lake. AB - Geochemical characteristics of fluid fine tailings (FFT) were examined in Base Mine Lake (BML), which is the first full-scale demonstration oil sands end pit lake (EPL) in northern Alberta, Canada. Approximately 186Mm(3) of FFT was deposited between 1994 and 2012, before BML was established on December 31, 2012. Bulk FFT samples (n=588) were collected in July and August 2013 at various depths at 15 sampling sites. Temperature, solid content, electrical conductivity (EC), pH, Eh and alkalinity were measured for all samples. Detailed geochemical analyses were performed on a subset of samples (n=284). Pore-water pH decreased with depth by approximately 0.5 within the upper 10m of the FFT. Major pore-water constituents included Na (880+/-96mgL(-1)) and Cl (560+/-95mgL(-1)); Ca (19+/ 4.1mgL(-1)), Mg (11+/-2.0mgL(-1)), K (16+/-2.3mgL(-1)) and NH3 (9.9+/-4.7mgL(-1)) were consistently observed. Iron and Mn concentrations were low within FFT pore water, whereas SO4 concentrations decreased sharply across the FFT-water interface. Geochemical modeling indicated that FeS(s) precipitation was favoured under SO4-reducing conditions. Pore water was also under-saturated with respect to gypsum [CaSO4.2H2O], and near saturation with respect to calcite [CaCO3], dolomite [CaMg(CO3)2] and siderite [FeCO3]. X-ray diffraction (XRD) suggested that carbonate-mineral dissolution largely depleted calcite and dolomite. X-ray absorption near edge structure (XANES) spectroscopy revealed the presence of FeS(s), pyrite [FeS2], and siderite. Carbonate-mineral dissolution and secondary mineral precipitation have likely contributed to FFT dewatering and settlement. However, the long-term importance of these processes within EPLs remains unknown. These results provide a reference for assessing the long-term geochemical evolution of oil sands EPLs, and offer insight into the chemistry of pore water released from FFT to the overlying water cover. PMID- 26974569 TI - The long-term effects of invasive signal crayfish (Pacifastacus leniusculus) on instream macroinvertebrate communities. AB - Non-native species represent a significant threat to indigenous biodiversity and ecosystem functioning worldwide. It is widely acknowledged that invasive crayfish species may be instrumental in modifying benthic invertebrate community structure, but there is limited knowledge regarding the temporal and spatial extent of these effects within lotic ecosystems. This study investigates the long term changes to benthic macroinvertebrate community composition following the invasion of signal crayfish, Pacifastacus leniusculus, into English rivers. Data from long-term monitoring sites on 7 rivers invaded by crayfish and 7 rivers where signal crayfish were absent throughout the record (control sites) were used to examine how invertebrate community composition and populations of individual taxa changed as a result of invasion. Following the detection of non-native crayfish, significant shifts in invertebrate community composition were observed at invaded sites compared to control sites. This pattern was strongest during autumn months but was also evident during spring surveys. The observed shifts in community composition following invasion were associated with reductions in the occurrence of ubiquitous Hirudinea species (Glossiphonia complanata and Erpobdella octoculata), Gastropoda (Radix spp.), Ephemeroptera (Caenis spp.), and Trichoptera (Hydropsyche spp.); although variations in specific taxa affected were evident between regions and seasons. Changes in community structure were persistent over time with no evidence of recovery, suggesting that crayfish invasions represent significant perturbations leading to permanent changes in benthic communities. The results provide fundamental knowledge regarding non native crayfish invasions of lotic ecosystems required for the development of future management strategies. PMID- 26974570 TI - Conversion to drip irrigated agriculture may offset historic anthropogenic and wildfire contributions to sediment production. AB - This study is an investigation into the roles of wildfire and changing agricultural practices in controlling the inter-decadal scale trends of suspended sediment production from semi-arid mountainous rivers. In the test case, a decreasing trend in suspended sediment concentrations was found in the lower Salinas River, California between 1967 and 2011. Event to decadal scale patterns in sediment production in the Salinas River have been found to be largely controlled by antecedent hydrologic conditions. Decreasing suspended sediment concentrations over the last 15years of the record departed from those expected from climatic/hydrologic forcing. Sediment production from the mountainous headwaters of the central California Coast Ranges is known to be dominated by the interaction of wildfire and large rainfall/runoff events, including the Arroyo Seco, an ~700km(2) subbasin of the Salinas River. However, the decreasing trend in Salinas River suspended sediment concentrations run contrary to increases in the watershed's effective burn area over time. The sediment source area of the Salinas River is an order of magnitude larger than that of the Arroyo Seco, and includes a more complicated mosaic of land cover and land use. The departure from hydrologic forcings on suspended sediment concentration patterns was found to coincide with a rapid conversion of irrigation practices from sprinkler and furrow to subsurface drip irrigation. Changes in agricultural operations appear to have decreased sediment supply to the Salinas River over the late 20th to early 21st centuries, obscuring the influence of wildfire on suspended sediment production. PMID- 26974571 TI - Vulnerability to climate change of cocoa in West Africa: Patterns, opportunities and limits to adaptation. AB - The West African cocoa belt, reaching from Sierra Leone to southern Cameroon, is the origin of about 70% of the world's cocoa (Theobroma cacao), which in turn is the basis of the livelihoods of about two million farmers. We analyze cocoa's vulnerability to climate change in the West African cocoa belt, based on climate projections for the 2050s of 19 Global Circulation Models under the Intergovernmental Panel on Climate Change intermediate emissions scenario RCP 6.0. We use a combination of a statistical model of climatic suitability (Maxent) and the analysis of individual, potentially limiting climate variables. We find that: 1) contrary to expectation, maximum dry season temperatures are projected to become as or more limiting for cocoa as dry season water availability; 2) to reduce the vulnerability of cocoa to excessive dry season temperatures, the systematic use of adaptation strategies like shade trees in cocoa farms will be necessary, in reversal of the current trend of shade reduction; 3) there is a strong differentiation of climate vulnerability within the cocoa belt, with the most vulnerable areas near the forest-savanna transition in Nigeria and eastern Cote d'Ivoire, and the least vulnerable areas in the southern parts of Cameroon, Ghana, Cote d'Ivoire and Liberia; 4) this spatial differentiation of climate vulnerability may lead to future shifts in cocoa production within the region, with the opportunity of partially compensating losses and gains, but also the risk of local production expansion leading to new deforestation. We conclude that adaptation strategies for cocoa in West Africa need to focus at several levels, from the consideration of tolerance to high temperatures in cocoa breeding programs, the promotion of shade trees in cocoa farms, to policies incentivizing the intensification of cocoa production on existing farms where future climate conditions permit and the establishment of new farms in already deforested areas. PMID- 26974572 TI - Snowmelt-driven changes in dissolved organic matter and bacterioplankton communities in the Heilongjiang watershed of China. AB - Bacterioplankton plays a significant role in the circulation of materials and ecosystem function in the biosphere. Dissolved organic matter (DOM) from dead plant material and surface soil leaches into water bodies when snow melts. In our study, water samples from nine sampling sites along the Heilongjiang watershed were collected in February and June 2014 during which period snowmelt occurred. The goal of this study was to characterize changes in DOM and bacterioplankton community composition (BCC) associated with snowmelt, the effects of DOM, environmental and geographical factors on the distribution of BCC and interactions of aquatic bacterioplankton populations with different sources of DOM in the Heilongjiang watershed. BCC was measured by denaturing gradient gel electrophoresis (DGGE). DOM was measured by excitation-emission matrix (EEM) fluorescence spectroscopy. Bacterioplankton exhibited a distinct seasonal change in community composition due to snowmelt at all sampling points except for EG. Redundancy analysis (RDA) indicated that BCC was more closely related to DOM (Components 1 and 4, dissolved organic carbon, biochemical oxygen demand and chlorophyll a) and environmental factors (water temperature and nitrate nitrogen) than geographical factors. Furthermore, DOM had a greater impact on BCC than environmental factors (29.80 vs. 15.90% of the variation). Overall, spring snowmelt played an important role in altering the quality and quantity of DOM and BCC in the Heilongjiang watershed. PMID- 26974573 TI - Heavy metal bioaccumulation and histopathological alterations in wild Arctic hares (Lepus arcticus) inhabiting a former lead-zinc mine in the Canadian high Arctic: A preliminary study. AB - A preliminary study was undertaken to determine post-mining baseline accumulation of selected trace metals, and histopathological alterations in free-living arctic hares (Lepus arcticus) inhabiting the vicinity of a former lead-zinc mine located on North Baffin Island in the Canadian High Arctic. Trace metal analysis included measurement of As, Cd, Fe, Pb and Zn in tissues, and histopathological assessment comprised of evaluation and scoring the severity of metal-induced hepatic and renal lesions. Metal contents in hepatic and renal tissues from hares from the mine area compared with the reference locations did not differ significantly suggesting that the animals are not uniformly exposed to background levels of metals in the environment. However, relatively higher accumulation pattern of Pb and Cd were noted in liver tissues of hare from the mine area compared to the background area, but did not induce increased lesions. Surface soils near the mine area contained relatively higher levels of trace metals (Zn>Mn>Pb>Cd>As) compared to reference soils, and with soil levels of Cd showing strong correlation with Cd accumulation in kidney tissues. Generally, both case and reference animals showed similar but varying severities of hepatic and renal lesions at the sublethal level, notably vascular congestion, occasional large hepatocyte nuclei, binucleate hepatocytes, yellow-brown pigmentation in the cytoplasm of hepatocytes and clustering of lymphocytes. Only hares with relatively higher accumulation of Pb from the mine area showed evidence of renal edema and hemorrhage of the capsular surface. This study constitutes the first assessment of metal induced histopathological alterations in arctic hares exposed to a historical mining area in the high arctic. PMID- 26974574 TI - Economic gains from targeted measures related to non-point pollution in agriculture based on detailed nitrate reduction maps. AB - From 1990 to 2003, Denmark reduced N-leaching from the root zone by 50%. However, more measures are required, and in recent years, the focus has been on how to differentiate measures in order to ensure that they are implemented where the effect on N-loss reductions per ha is the greatest. The purpose of the NiCA project has been to estimate the natural nitrate reduction in the groundwater more precisely than before using a plot size down to 1ha. This article builds on these findings and presents the possible economic gains for the farmer when using this information to reach a given N-loss level. Targeted measures are especially relevant where the subsurface N-reduction varies significantly within the same farm and national analyses have shown that a cost reduction of around 20-25% using targeted measures is likely. The analyses show an increasing potential with increasing variation in N-reduction in the catchment. In this analysis, the knowledge of spatial variation in N-reduction potential is used to place measures like catch crops or set-a-side at locations with the greatest effect on 10 case farms in the Norsminde Catchment, Denmark. The findings suggest that the gains are from 0 to 32?/ha and the average farm would gain approximately 14-21?/ha/year from the targeted measures approach. The analysis indicates that the economic gain is greater than the costs of providing the detailed maps of 5-10?/ha/year. When N-loss reduction requirements are increased, the economic gains are greater. When combined with new measures like mini-wetlands and early sowing the economic advantage is increased further. The paper also shows that not all farms can use the detailed information on N-reduction and there is not a clear link between spatial variation in N-reduction at the farm level and possible economic gains for all these 10 farms. PMID- 26974575 TI - Improving the identification of hydrologically sensitive areas using LiDAR DEMs for the delineation and mitigation of critical source areas of diffuse pollution. AB - Identifying critical source areas (CSAs) of diffuse pollution in agricultural catchments requires the accurate identification of hydrologically sensitive areas (HSAs) at highest propensity for generating surface runoff and transporting pollutants. A new GIS-based HSA Index is presented that improves the identification of HSAs at the sub-field scale by accounting for microtopographic controls. The Index is based on high resolution LiDAR data and a soil topographic index (STI) and also considers the hydrological disconnection of overland flow via topographic impediment from flow sinks. The HSA Index was applied to four intensive agricultural catchments (~7.5-12km(2)) with contrasting topography and soil types, and validated using rainfall-quickflow measurements during saturated winter storm events in 2009-2014. Total flow sink volume capacities ranged from 8298 to 59,584m(3) and caused 8.5-24.2% of overland-flow-generating-areas and 16.8-33.4% of catchment areas to become hydrologically disconnected from the open drainage channel network. HSA maps identified 'breakthrough points' and 'delivery points' along surface runoff pathways as vulnerable points where diffuse pollutants could be transported between fields or delivered to the open drainage network, respectively. Using these as proposed locations for targeting mitigation measures such as riparian buffer strips reduced potential costs compared to blanket implementation within an example agri-environment scheme by 66% and 91% over 1 and 5years respectively, which included LiDAR DEM acquisition costs. The HSA Index can be used as a hydrologically realistic transport component within a fully evolved sub-field scale CSA model, and can also be used to guide the implementation of 'treatment-train' mitigation strategies concurrent with sustainable agricultural intensification. PMID- 26974576 TI - Fermentation enhances Ginkgo biloba protective role on gamma-irradiation induced neuroinflammatory gene expression and stress hormones in rat brain. AB - Ionizing radiation has attracted a lot of attention due to its beneficial and possible harmful effects to the human population. The brain displays numerous biochemical and functional alterations after exposure to irradiation, which induces oxidative-stress through generation of reactive oxygen species (ROS). The present study evaluated the neuro-protective role of fermented Ginkgo biloba (FGb) leaf extract, compared to non-fermented G. biloba (Gb) leaf extract against gamma-irradiation (6Gy) in the rats' brain. The changes of the Gb phytochemical constituents after fermentation, using Aspergillus niger were evaluated by Gas Chromatography-Mass Spectrometry. The results showed a significant decrease in superoxide dismutase (SOD), glutathione peroxidase (GPx) activities and elevation of the calcium level in the brain cytosolic fraction of gamma-irradiated rats. Further, significant increases in the malondialdehyde (MDA), the stress hormones (catecholamines); epinephrine (EN), norepinephrine (NE) and dopamine (DA) levels and the interleukin-1-beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) gene expression relative ratio in parallel with a significant decrease in the glutathione (GSH) content and DNA fragmentation in the brain tissues of the gamma irradiated rats were observed. The pre-treatment with Gb extract significantly amended these biochemical parameters. Meanwhile, the pre-treatment with the FGb showed more improvement, compared to Gb, of these biochemical parameters in the brain of gamma-irradiated rats, which could be attributed to the enhancement of its antioxidant activity after fermentation. These findings suggested that fermentation enhances the protective effect of Gb in the brain on the neuroinflammation, release of the stress hormones, apoptosis and oxidative damage induced by gamma-irradiation. IN CONCLUSION: fermentation improved the bio activities of Gb leaf extract and thus enhanced the in-vivo antioxidant, anti apoptotic and anti-inflammatory activities, leading to amelioration of the stress hormones and Ca level. Accordingly, the fermentation enhances the protective role of Gb against gamma-irradiation induced physiological disturbance in the rat's brain. PMID- 26974577 TI - Synthesis, spectral characterization, DNA interaction, radical scavenging and cytotoxicity studies of ruthenium(II) hydrazone complexes. AB - Three new ruthenium(II) complexes with hydrazone ligands, furan-2-carboxylic acid (2,4-dihydroxy-benzylidene)-hydrazide (HL(1)), furan-2-carboxylic acid [4-(ethyl propyl-amino)-2-hydroxy-benzylidene]-hydrazide (HL(2)) and furan-2-carboxylic acid (3-ethoxy-2-hydroxy-benzylidene)-hydrazide (HL(3)) were synthesized and characterized by various spectro-analytical techniques. The hydrazone ligands act as a tridendate ligand with ONO as the donor sites and are preferably found in the enol form in all the complexes. The molecular structure of the ligands was determined by single crystal X-ray diffraction technique. The interaction of the ligands and the complexes with CT-DNA were evaluated by an absorption titration method which revealed that the compounds interact with CT-DNA through intercalation. Gel electrophoresis assay demonstrated the ability of the complexes to cleave the calf thymus DNA hydrolytically. Antioxidant studies showed that the ruthenium(II) complexes have a strong radical-scavenging properties. Further, the cytotoxic effect of the compounds examined on cancerous cell lines showed that the complexes exhibited substantial anticancer activity. PMID- 26974578 TI - Pharmacological investigations and Petra/Osiris/Molinspiration (POM) analyses of newly synthesized potentially bioactive organotin(IV) carboxylates. AB - A series of organotin(IV) carboxylate complexes: [Me2SnL2] (1), [n-Bu2SnL2] (2), [n-Oct2SnL2] (3), [Me3SnL] (4), [n-Bu3SnL] (5) and [Ph3SnL] (6), where L=3-(4 fluorophenyl)acrylic acid, have been successfully synthesized and characterized by FT-IR, NMR ((1)H, (13)C) and single crystal analysis. The ligand coordinates to tin atom via carboxylate group. Compound 4 was also analyzed by single crystal XRD analysis. Crystallographic data for trimethyltin(IV) complex showed that the tin has approximate trigonal bipyramidal geometry with the CH3 groups in the trigonal plane. The carboxylate groups bridge the adjacent tin atoms, resulting in polymeric chains. FT-IR and NMR data also support the 5-coordination geometry for the triorganotin(IV) derivatives. In the case of the diorganotin(IV) derivatives a six-coordinate geometry at the tin atom is proposed from spectroscopic data. The Me-Sn-Me bond angle in complexes 1 and 4 was determined from the (2)J[(119)Sn-(1)H] value as 138.4 degrees and 111 degrees that falls in the range of 5-coordinated trigonal bipyramidal and 6-coordinated octahedral geometries, respectively. The synthesized compounds were screened for their biological activities including antibacterial, antifungal and cytotoxicity. The compounds 4-6 exhibit excellent antibacterial, antifungal and cytotoxic activities. The cytotoxicity data reveals that the HL and 1-3 are almost non toxic and exhibited LD50 values in the range 73.45-675.1MUg/mL while 4-6 are found to be cytotoxic to mildly cytotoxic with LD50 values in the range 6.43 13.49MUg/mL. The compound interacts with DNA via intercalation of aromatic ring into the base pairs of DNA resulting in hypochromism and minor red shift. PMID- 26974579 TI - Wood degradation under UV irradiation: A lignin characterization. AB - The photodegradation of white spruce by artificial ageing was studied by several techniques: colourimetry, FTIR-ATR and FT-Raman spectroscopy. Samples were exposed at a xenon lamp for 2000h. Two distinct colour changes were found by colourimetric analysis, yellowing and silvering. These colour modifications indicate the formation of chromophoric structures which supports previous FTIR ATR experiments. The degradation of lignin to generate the first chromophoric group for yellowing and then the appearance of surface layer cellulose. New carbonyl compounds conjugated with double bond at 1615cm(-1) are probably the second chromophoric group. The crystallinity index was also calculated and showed an increase of cellulose crystallinity by prior degradation of amorphous cellulose. The FT-Raman analysis confirms the wood sensitivity to photodegradation but the most remarkable results is the increase of fluorescence as a function of time. In softwood lignin, the compound able to produce fluorescence is a free rotating 5-5' linkage of one biphenyl structure. At native state these linkages are not free rotating, this phenomenon means the release of 5-5' linkage of lignin structure by cleavage of both alpha carbon linkages (Norrish type I reaction). These data confirm also the photosensitivity of alpha and beta carbon in lignin and the resistance of 5-5' linkages. PMID- 26974580 TI - Fluorescence properties and sequestration of peripheral anionic site specific ligands in bile acid hosts: Effect on acetylcholinesterase inhibition activity. AB - The increase in fluorescence intensity of model acetyl cholinesterase (AChE) inhibitors like propidium iodide (PI) and ethidium bromide (EB) is due to sequestration of the probes in primary micellar aggregates of bile acid (BA) host medium with moderate binding affinity of ca. 10(2)-10(3)M(-1). Multiple regression analysis of solvent dependent fluorescence behavior of PI indicates the decrease in total nonradiative decay rate due to partial shielding of the probe from hydrogen bond donation ability of the aqueous medium in bile acid bound fraction. Both PI and EB affects AChE activity through mixed inhibition and consistent with one site binding model; however, PI (IC50=20+/-1MUM) shows greater inhibition in comparison with EB (IC50=40+/-3MUM) possibly due to stronger interaction with enzyme active site. The potency of AChE inhibition for both the compounds is drastically reduced in the presence of bile acid due to the formation of BA-inhibitor complex and subsequent reduction of active inhibitor fraction in the medium. Although the inhibition mechanism still remains the same, the course of catalytic reaction critically depends on equilibrium binding among several species present in the solution; particularly at low inhibitor concentration. All the kinetic parameters for enzyme inhibition reaction are nicely correlated with the association constant for BA-inhibitor complex formation. PMID- 26974581 TI - Interferon Stimulated Gene Expression in HIV/HCV Coinfected Patients Treated with Nitazoxanide/Peginterferon-Alfa-2a and Ribavirin. AB - A combination of nitazoxanide (NTZ), peginterferon (PegIFN), and ribavirin (RBV) may result in higher sustained virologic response (SVR) rates in hepatitis C virus (HCV) monoinfected patients. This study evaluated the effect of NTZ on interferon-stimulated gene (ISG) expression in vitro and in vivo among HIV/HCV genotype-1 (GT-1) treatment-naive patients. The ability of NTZ to enhance host response to interferon (IFN) signaling using the HCV cell culture system was initially evaluated. Second, ISG expression in 53 patients with treatment outcomes [21 SVR and 32 nonresponders (NR)] in the ACTG A5269 trial, a phase-II study (4-week lead in of NTZ 500 mg daily followed by 48 weeks of NTZ, PegIFN, and weight-based RBV), was assessed. The relative expression of 48 ISGs in peripheral blood mononuclear cells (PBMCs) was measured at baseline, week 4, and week 8 of treatment in a blinded manner. In vitro NTZ produced a direct and additive antiviral effect with IFN-alfa, with pretreatment of NTZ resulting in maximal HCV suppression. NTZ augmented IFN-mediated ISG induction in PBMCs from relapsers and SVRs (p < 0.05), but not NR. In ACTG A5269, baseline expression of most ISGs was similar between NR and SVR. NTZ minimally induced 17 genes in NR and 13 genes in SVR after 4 weeks of therapy. However, after initiation of PegIFN and RBV, ISG induction was predominantly observed in the SVR group and not NR group. NTZ treatment facilitates IFN-induced suppression of HCV replication. Inability to achieve SVR with IFN-based therapy in this clinical trial is associated with diminished ISG response to therapy that is refractory to NTZ. PMID- 26974583 TI - Paving Pathways on Proven Ground: The Future of Home-Based Palliative Care. PMID- 26974582 TI - The role of self-monitoring in the maintenance of weight loss success. AB - INTRODUCTION: Self-monitoring has been shown to be a crucial part of initial weight loss success in behavioral interventions. However, little is known about the impact of self-monitoring during the period following initial treatment. METHODS: The current study examined the role of self-monitoring on weight loss during an initial 6-month intervention period (Phase 1) and a 12-month extended care period (Phase 2) in a group of 167 obese women (M+/-SD: BMI=37.0+/ 5.1kg/m(2), age=59.9+/-6.2years) enrolled in a behavioral weight loss program. RESULTS: Cluster analysis identified three groups of participants with low, moderate, and high rates of weight loss success during Phase 1 and Phase 2. A one way ANOVA revealed no significant differences in self-monitoring frequency between groups during Phase 1 (p=.645), but significant differences between all three groups during Phase 2 (p=.001). High success participants completed the most self-monitoring records, followed by the moderate group. The low success group completed the least number of records. Furthermore, self-monitoring during Phase 2 significantly mediated the relationship between extended-care session attendance and percent weight change during that time (95% CI [-.004, -.001], p<.001). CONCLUSION: These results highlight the importance of continuing self monitoring after the initial phase of treatment to maintain lost weight. PMID- 26974584 TI - Experimental validation of a flat punch indentation methodology calibrated against unconfined compression tests for determination of soft tissue biomechanics. AB - Mechanical characterisation of soft biological tissues using standard compression or tensile testing presents a significant challenge due to specimen geometrical irregularities, difficulties in cutting intact and appropriately sized test samples, and issues with slippage or damage at the grips. Indentation can overcome these problems but requires fitting a model to the resulting load displacement data in order to calculate moduli. Despite the widespread use of this technique, few studies experimentally validate their chosen model or compensate for boundary effects. In this study, viscoelastic hydrogels of different concentrations and dimensions were used to calibrate an indentation technique performed at large specimen-strain deformation (20%) and analysed with a range of routinely used mathematical models. A rigid, flat-ended cylindrical indenter was applied to each specimen from which 'indentation moduli' and relaxation properties were calculated and compared against values obtained from unconfined compression. Only one indentation model showed good agreement (<10% difference) with all moduli values obtained from compression. A sample thickness to indenter diameter ratio >=1:1 and sample diameter to indenter diameter ratio >=4:1 was necessary to achieve the greatest accuracy. However, it is not always possible to use biological samples within these limits, therefore we developed a series of correction factors. The approach was validated using human diseased omentum and bovine articular cartilage resulting in mechanical properties closely matching compression values. We therefore present a widely useable indentation analysis method to allow more accurate calculation of material mechanics which is important in the study of soft tissue development, ageing, health and disease. PMID- 26974585 TI - A MUCT-based investigation of the influence of tissue modulus variation, anisotropy and inhomogeneity on ultrasound propagation in trabecular bone. AB - Ultrasound propagation is widely used in the diagnosis of osteoporosis by providing information on bone mechanical quality. When it loses calcium, the tissue properties will first decrease. However, limited research about the influence of tissue properties on ultrasound propagation have been done due to the cumbersome experiment. The goal of this study was to explore the relationships between tissue modulus (Es) and speed of sound (SOS) through numerical simulations, and to study the influence of Es on the acoustical behavior in characterizing the local structural anisotropy and inhomogeneity. In this work, three-dimensional finite element (FE) simulations were performed on a cubic high-resolution (15MUm) bovine trabecular bone sample (4*4*4mm(3), BV/TV=0.18) mapped from micro-computed tomography. Ultrasound excitations of 50kHz, 500kHz and 2MHz were applied in three orthogonal axes and the first arriving signal (FAS) was collected to quantify wave velocity. In this study, a strong power law relationship between Es and SOS was measured with estimated exponential index beta=2.08-3.44 for proximal-distal (PD), anterior-posterior (AP) and medial-lateral (ML), respectively (all R(2)>0.95). For various Es, a positive dispersion of sound speed with respect to sound frequency was observed and the velocity dispersion magnitude (VDM) was measured. Also, with Es=15GPa in three orientations, the SOS in PD axis is 2009+/-120m/s, faster than that of AP (1762+/-106m/s) and ML (1798+/-132m/s) (f=2MHz) directions. Besides, the standard deviation of SOS increases with the sound frequency and the Es in all directions except for that at 50kHz. For the mechanical properties, the apparent modulus with certain Es was highest in the longitudinal direction compared with the transverse directions. It indicates that the tissue modulus combining with anisotropy and inhomogeneity has great influence on ultrasound propagation. Simulation results agree well with theoretical and experimental results. PMID- 26974586 TI - Subpicomolar Iron Sensing Platform Based on Functional Lipid Monolayer Microarrays. AB - We report herein the fabrication of novel microarrays based on air-stable functional lipid monolayers over silicon using a combination of e-beam lithography and lift-off. We demonstrate these microarrays can be use as ultrasensitive platform for Kelvin probe force microscopy in sensing experiments. Specificity of the detection is given by the functional group grafted at the lipid headgroup. The arrays developed for the detection of ferric ions, Fe(3+), using a gamma-pyrone derivative chelator, demonstrate subpicomolar limit of detection with high specificity. In addition, the technique takes advantage of the structure of the array with the silicon areas playing the role of reference for the measurement, and we determine critical pattern dimensions below which the probe size/shape impacts the measured results. PMID- 26974587 TI - The Problem and Promise of Prognosis Research. PMID- 26974588 TI - Soil amendment affects Cd uptake by wheat - are we underestimating the risks from chloride inputs? AB - Many parts of the world are investigating the efficacy of recycling nutrient resources to agriculture from different industry and domestic sectors as part of a more circular economy. The complex nature of recycled products as soil amendments coupled to the large diversity of soil types and their inherent properties make it difficult to optimize the benefits and minimize the risks from potentially toxic elements often present in recycled materials. Here we investigated how wheat grain cadmium (Cd) concentration was affected by soil amendments, namely human urine and biogas digestate compared to traditional farm manures and mineral fertilizers. We show that Cl(-) inadvertently added to soils with e.g. urine or biogas digestate strongly increased crop Cd concentrations, largely by mobilizing inherent soil Cd. This resulted in wheat grain Cd levels that could result in exceeding recommended WHO limits for dietary intake. This was evident even in soils with low inherent Cd content and when Cd inputs were low. The future of a circular economy that helps to underpin global food security needs to ensure that the effects of applying complex materials to different types of agricultural land are fully understood and do not jeopardize food safety. PMID- 26974589 TI - A cross-lagged model of the reciprocal associations of loneliness and memory functioning. AB - The study was designed to evaluate the reciprocal associations of loneliness and memory functioning using a cross-lagged model. The study was based on the psychosocial questionnaire of the Health and Retirement Study, which is a U.S. nationally representative survey of individuals over the age of 50 and their spouses of any age. A total of 1,225 respondents had complete data on the loneliness measure in 2004 and at least in 1 of the subsequent waves (e.g., 2008, 2012) and were maintained for analysis. A cross-lagged model was estimated to examine the reciprocal associations of loneliness and memory functioning, controlling for age, gender, education, depressive symptoms, number of medical conditions, and the number of close social relationships. The model had adequate fit indices: chi2(860, N = 1,225) = 1,401.54, p < .001, Tucker-Lewis index = .957, comparative fit index = .963, and root mean square error of approximation = .023 (90% confidence interval [.021, .025]). The lagged effect of loneliness on memory functioning was nonsignificant, B(SE) = -.11(.08), p = .15, whereas the lagged effect of memory functioning on loneliness was significant, B(SE) = .06(.02), p = .01, indicating that lower levels of memory functioning precede higher levels of loneliness 4 years afterward. Further research is required to better understand the mechanisms responsible for the temporal association between reduced memory functioning and increased loneliness. (PsycINFO Database Record PMID- 26974590 TI - Time perspective and positivity effects in Alzheimer's disease. AB - This study tested whether time perspective, a central tenant of socioemotional selectivity theory (Carstensen, 2006), moderates positivity effects in emotional memory. To provide measures of time perspective, young (YA; M = 22.48 years), young-old (YO; M = 67.56 years), old-old adults (OO; M = 80.24 years), and participants with moderate severity Alzheimer's disease (PAD; M = 84.28 years) completed a line task and reported subjective age. As expected, YA, YO, and OO reported successively more constrained future time perspectives. PAD showed distortion in time perspective, envisioning a future comparable with the YO, although closer matched in chronological age to OO adults. To evince positivity effects, participants were oriented to pairs of emotional images and were then tested for memory (recall and recognition) of the images. Recall and recognition memory for the images indicated an age-related advantage for positive over negative material (positivity effects). Time perspective, however, did not moderate these age effects. In memory performance, PAD were more comparable with OO adults with whom they shared a similar chronological age, rather than YO adults, who had a corresponding time perspective. These results suggest that age correlates that are shared by PAD and OO, such as reduced processing resources, rather than time perspective, may drive the age associated positivity effects. (PsycINFO Database Record PMID- 26974591 TI - Going Slow May Not Be Best When Quitting Smoking. PMID- 26974592 TI - Multidrug-Resistant Organisms on Patients' Hands: A Missed Opportunity. PMID- 26974593 TI - Effect of valsartan on cardiac senescence and apoptosis in a rat model of cardiotoxicity. AB - The clinical application of doxorubicin is limited by its cardiotoxicity. The present study investigated the effect of valsartan on doxorubicin-induced cardiotoxicity in rats. Rats were divided into 6 groups: control, control + valsartan (10 mg/kg, for 14 days, orally), doxorubicin-treated (2.5 mg/kg, 3 times/week for 2 weeks, intraperitoneally), valsartan then doxorubicin, valsartan + doxorubicin, and doxorubicin then valsartan. ECG, isolated heart, lipid peroxidation (thiobaribituric acid reactive substances (TBARS)), total antioxidant capacity (TAC), and Bax, Bcl-2, and senescence marker protein 30 (SMP30) gene expression were measured in cardiac tissue. Blood samples were collected to measure lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB). Doxorubicin significantly increased LDH, CK-MB, TBARS, heart rate (HR), Bax gene expression, and -dP/dtmax and decreased TAC, Bcl-2 and SMP30 gene expression, left ventricular developed pressure (LVDP), and +dP/dtmax. Also, doxorubicin lengthened ST, QT, and QTc intervals. Concurrent or post- but not pre-treatment of doxorubicin-treated rats with valsartan reduced LDH, CK-MB, TBARS, HR, Bax gene expression, -dP/dtmax, and ST, QT, and QTc intervals and increased TAC, Bcl 2 and SMP30 gene expression, LVDP, and +dP/dtmax. Therefore, we conclude that concurrent or post- but not pre-treatment of doxorubicin-induced rats with valsartan attenuated doxorubicin-induced cardiotoxicity through inhibiting oxidative stress, apoptosis, and senescence. PMID- 26974594 TI - The impact of genetics on retail meat value in Australian lamb. AB - Lean (muscle), fat, and bone composition of 1554 lamb carcasses from Maternal, Merino and Terminal sired lambs was measured using computed tomography scanning. Lamb sires were diverse in their range of Australian Sheep Breeding Values for post weaning c-site eye muscle depth (PEMD) and fat depth (PFAT), and post weaning weight (PWWT). Lean value, representing predicted lean weight multiplied by retail value, was determined for lambs at the same carcass weight or the same age. At the same carcass weight, lean value was increased the most by reducing sire PFAT, followed by increasing PEMD and PWWT. However for lambs of the same age, increasing sire PWWT increased lean value the most. Terminal sired lambs, on average, had greater lean value irrespective of whether comparisons were made at the same age or weight. Lean value was greater in Merino compared to Maternal sired lambs at equal carcass weight, however the reverse was true when comparisons were made at the same age. PMID- 26974595 TI - The influence of diet on collagen content and quality attributes of infraspinatus muscle from Holstein-Friesian young bulls. AB - The aim of the study was to determine effects of feeding intensity on collagen content and eating quality of infraspinatus (INF) muscle. Twenty Polish Holstein Friesian bulls (11-month-old) were fed either intensively (I, n=10, with triticale meal addition to total mixed ration) or semi-intensively (SI, n=10, without triticale meal) before slaughter at 19months. The animals from I group showed higher body weight at the end of fattening, average daily gain and dressing percentage than SI group. The INF muscle from I treatment had higher fat content and the proportion of water-soluble collagen, whereas lower insoluble collagen content compared with SI treatment. There were no differences in shear force values, cooking loss and eating quality between the treatments. In conclusion, feeding Holstein-Friesian bulls with increased energy value fodder beneficially affected its slaughter value and collagen profile in infraspinatus muscle. PMID- 26974596 TI - Cu(I)-Catalyzed Asymmetric Multicomponent Cascade Inverse Electron-Demand Aza Diels-Alder/Nucleophilic Addition/Ring-Opening Reaction Involving 2-Methoxyfurans as Efficient Dienophiles. AB - An unprecedented multicomponent cascade asymmetric inverse-electron-demand Diels Alder/nucleophilic addition/ring-opening reaction involving 2-methoxyfurans as efficient dienophiles was successfully developed with Cu(I)/(t)Bu-Box complex as the catalyst. A diverse array of tetrahydropyridazines containing unexpectedly stable gamma-hydroxyl ester moiety was obtained in generally good yield with exclusive regioselectivity and excellent stereoselectivity. PMID- 26974597 TI - Reversible Cerebral Vasoconstriction Syndrome vs Posterior Reversible Encephalopathy Syndrome. PMID- 26974598 TI - The susceptibility of primary cultured rhesus macaque kidney epithelial cells to rhesus cytomegalovirus strains. AB - Kidney epithelial cells are common targets for human and rhesus cytomegalovirus (HCMV and RhCMV) in vivo, and represent an important reservoir for long-term CMV shedding in urine. To better understand the role of kidney epithelial cells in primate CMV natural history, primary cultures of rhesus macaque kidney epithelial cells (MKE) were established and tested for infectivity by five RhCMV strains, including two wild-type strains (UCD52 and UCD59) and three strains containing different coding contents in UL/b'. The latter strains included 180.92 [containing an intact RhUL128-RhUL130-R hUL131 (RhUL128L) locus but deleted for the UL/b' RhUL148-rh167-loci], 68-1 (RhUL128L-defective and fibroblast-tropic) and BRh68-1.2 (the RhUL128L-repaired version of 68-1). As demonstrated by RhCMV cytopathic effect, plaque formation, growth kinetics and early virus entry, we showed that MKE were differentially susceptible to RhCMV infection, related to UL/b' coding contents of the different strains. UCD52 and UCD59 replicated vigorously in MKE, 68-1 replicated poorly, and 180.92 grew with intermediate kinetics. Reconstitution of RhUL128L in 68-1 (BRh68-1.2) restored its replication efficiency in MKE as compared to UCD52 and UCD59, consistent with the essential role of UL128L for HCMV epithelial tropism. Further analysis revealed that the UL/b' UL148-rh167-loci deletion in 180.92 impaired RhUL132 (rh160) expression. Given that 180.92 retains an intact RhUL128L, but genetically or functionally lacks genes from RhUL132 (rh160) to rh167 in UL/b', its attenuated infection efficiency indicated that, along with RhUL128L, an additional protein(s) encoded within the UL/b' RhUL132 (rh160)-rh167 region (potentially, RhUL132 and/or RhUL148) is indispensable for efficient replication in MKE. PMID- 26974600 TI - Transition Metal-Free Amidoalkylation of Benzothiazoles and Amidoalkylarylation of Activated Alkenes with N,N-Dialkylamides. AB - A general and practical amidoalkylation reaction, using N,N-dialkylamides in the presence of potassium persulfate as the sole reagent, has been developed. 2 Amidoalkylated benzothiazole- and 3-amidoalkyl-substituted indolinone derivatives were obtained by using benzothiazoles and N-aryl-N-methyl-methacrylamides as substrates, respectively. The transformation proceeded smoothly through amidoalkyl radical intermediates that were trapped by benzothiazoles or activated alkenes. PMID- 26974599 TI - Investigation of the Binding Interaction of Fatty Acids with Human G Protein Coupled Receptor 40 Using a Site-Specific Fluorescence Probe by Flow Cytometry. AB - Human G protein-coupled receptor 40 (hGPR40), with medium- and long-chain free fatty acids (FFAs) as its natural ligands, plays an important role in the enhancement of glucose-dependent insulin secretion. To date, information about the direct binding of FFAs to hGPR40 is very limited, and how carbon-chain length affects the activities of FFAs on hGPR40 is not yet understood. In this study, a fluorescein-fasiglifam analogue (F-TAK-875A) conjugate was designed and synthesized as a site-specific fluorescence probe to study the interaction of FFAs with hGPR40. hGPR40 was expressed in human embryonic kidney 293 cells and labeled with F-TAK-875A. By using flow cytometry, competitive binding of FFA and F-TAK-875A to hGPR40-expressed cells was measured. Binding affinities of 18 saturated FFAs, with carbon-chain lengths ranging from C6 to C23, were analyzed. The results showed that the binding potencies of FFAs to hGPR40 were dependent on carbon length. There was a positive correlation between length and binding potency for seven FFAs (C9-C15), with myristic acid (C15) showing the highest potency, 0.2% relative to TAK-875. For FFAs with a length of fewer than C9 or more than C15, they had very weak or no binding. Molecular docking results showed that the binding pocket of TAK-875 in hGPR40 could enclose FFAs with lengths of C15 or fewer. However, for FFAs with lengths longer than C15, part of the alkyl chain extended out of the binding pocket. This study provided insights into the structural dependence of FFAs binding to and activation of hGPR40. PMID- 26974601 TI - Dihydrogen Complexation. AB - Dihydrogen complexation with retention of the H-H bond, once an exotic concept, has by now appeared in a very wide range of contexts. Three structural types are currently recognized: Kubas dihydrogen, stretched dihydrogen, and compressed dihydrides. These can be difficult to distinguish, hence the development of a number of novel spectroscopic methods for doing so, mainly based on NMR spectroscopy. Three important reactivity patterns are identified: proton loss, oxidative addition, and dissociation, each of which often contributes to larger reaction schemes, as in homogeneous hydroformylation. Main group examples are beginning to appear, although here it is mainly by computational studies that the relevant structures can be identified. Enzymes such as the hydrogenases and nitrogenases are also proposed to involve these structures. PMID- 26974602 TI - Successful perioperative management of factor XI deficiency with administration of fresh-frozen plasma in a subdural hematoma patient. PMID- 26974603 TI - Breakable mesoporous silica nanoparticles for targeted drug delivery. AB - "Pop goes the particle". Here we report on the preparation of redox responsive mesoporous organo-silica nanoparticles containing disulfide (S-S) bridges (ss NPs) that, even upon the exohedral grafting of targeting ligands, retained their ability to undergo structural degradation, and increase their local release activity when exposed to a reducing agent. This degradation could be observed also inside glioma C6 cancer cells. Moreover, when anticancer drug-loaded pristine and derivatized ss-NPs were fed to glioma C6 cells, the responsive hybrids were more effective in their cytotoxic action compared to non-breakable particles. The possibility of tailoring the surface functionalization of this hybrid, yet preserving its self-destructive behavior and enhanced drug delivery properties, paves the way for the development of effective biodegradable materials for in vivo targeted drug delivery. PMID- 26974605 TI - Time-resolved subtraction method for measuring optical properties of turbid media. AB - Near-infrared spectroscopy is a noninvasive optical method used primarily to monitor tissue oxygenation due to the absorption properties of hemoglobin. Accurate estimation of hemoglobin concentrations and other light absorbers requires techniques that can separate the effect of absorption from the much greater effect of light scattering. One of the most advanced methods is time resolved near-infrared spectroscopy (TR-NIRS), which measures the absorption and scattering coefficients of a turbid medium by modeling the recorded distribution time of flight of photons. A challenge with TR-NIRS is that it requires accurate characterization of the dispersion caused by the system. In this study, we present a method for circumventing this problem by applying statistical moment analysis to two time-of-flight distributions measured at separated source detector distances. Simulations based on analytical models and Monte Carlo code, and tissue-mimicking phantoms, were used to demonstrate its accuracy for source detector distances typically used in neuroimaging applications. The simplicity of the approach is well suited to real-time applications requiring accurate quantification of the optical properties of a turbid medium. PMID- 26974604 TI - Cyclopenta[b]benzofuran and Secodammarane Derivatives from the Stems of Aglaia stellatopilosa. AB - Four new 2,3-secodammarane triterpenoids, stellatonins A-D (3-6), together with a new 3,4-secodammarane triterpenoid, stellatonin E (7), and the known silvestrol (1), 5'''-episilvestrol (2), and beta-sitosterol, were isolated from a methanol extract of the stems of Aglaia stellatopilosa through bioassay-guided fractionation. The structures of the new compounds were elucidated using spectroscopic and chemical methods. The compounds were evaluated for their cytotoxic activity against three human cancer cell lines and for their antimicrobial activity using a microtiter plate assay against a panel of Gram positive and Gram-negative bacteria and fungi. PMID- 26974606 TI - Integrating 5 * 5 Dammann gratings to detect orbital angular momentum states of beams with the range of -24 to +24. AB - The 5*5 2D binary Dammann vortex grating can distribute energy among different diffraction orders equally and can realize measurement of orbital angular momentum (OAM) states from -12 to +12. Here we combine a 5*5 Dammann vortex grating and a spiral phase plate with the order +12 or -12, which makes the topological charge of beams in the array increase or decrease by 12; thus, the range of measuring OAM states can be extended to a range from -24 to +24. We upload the holograms of such gratings on a liquid crystal spatial light modulator to do the experiment. The experimental results fit well with the simulation results. This method is also effective for multiplexed OAM beams and can be used in optical communications in the future. PMID- 26974607 TI - Transmission line model for strained quantum well lasers including carrier transport and carrier heating effects. AB - This paper reports a new model for strained quantum well lasers, which are based on the quantum well transmission line modeling method where effects of both carrier transport and carrier heating have been included. We have applied this new model and studied the effect of carrier transport on the output waveform of a strained quantum well laser both in time and frequency domains. It has been found that the carrier transport increases the turn-on, turn-off delay times and damping of the quantum well laser transient response. Also, analysis in the frequency domain indicates that the carrier transport causes the output spectrum of the quantum well laser in steady state to exhibit a redshift which has a narrower bandwidth and lower magnitude. The simulation results of turning-on transients obtained by the proposed model are compared with those obtained by the rate equation laser model. The new model has also been used to study the effects of pump current spikes on the laser output waveforms properties, and it was found that the presence of current spikes causes (i) wavelength blueshift, (ii) larger bandwidth, and (iii) reduces the magnitude and decreases the side-lobe suppression ratio of the laser output spectrum. Analysis in both frequency and time domains confirms that the new proposed model can accurately predict the temporal and spectral behaviors of strained quantum well lasers. PMID- 26974608 TI - D-shaped fiber grating refractive index sensor induced by an ultrashort pulse laser. AB - The fabrication of fiber Bragg gratings was here demonstrated using ultrashort pulse laser point-by-point inscription. This is a very convenient means of creating fiber Bragg gratings with different grating periods and works by changing the translation speed of the fiber. The laser energy was first optimized in order to improve the spectral properties of the fiber gratings. Then, fiber Bragg gratings were formed into D-shaped fibers for use as refractive index sensors. A nonlinear relationship was observed between the Bragg wavelength and liquid refractive index, and a sensitivity of ~30 nm/RIU was observed at 1.450. This shows that D-shaped fiber Bragg gratings might be used to develop promising biochemical sensors. PMID- 26974609 TI - Unified matrix approach to the description of phase-space rotators. AB - In optics, the rotation of a phase-space can be realized via light propagation through both an inhomogeneous medium with a radial gradient of refractive index and two special kinds of mirror-symmetrical optical systems suggested by Lohmann. Although light propagation through Lohmann's systems is described in terms of matrix optics, light propagation through the gradient-index medium is traditionally described as a solution of the wave equation. The difference in these descriptions hinders the understanding of the phase-space rotators. Fortunately, there is a matrix description of light propagation through a gradient-index medium too. A general description of the phase-space rotators is presented, which can be used to treat light propagation through both Lohmann's systems and the gradient-index medium in a unified matrix manner. PMID- 26974610 TI - Miniature anastigmatic spectrometer design with a concave toroidal mirror. AB - An advanced optical design for a low-cost and astigmatism-corrected spectrometer with a high resolution is presented. The theory and method of astigmatism correction are determined with the use of a concave toroidal mirror. The performances of a modified spectrometer and a traditional spectrometer are compared, and the analysis is verified. Experimentally, the limiting resolution of our spectrometer is 0.1 nm full width at half-maximum, as measured for 579.1 nm. PMID- 26974611 TI - Design and performance analysis of an ultraprecision ion beam polishing tool. AB - First, we introduce requirements for the ion beam polishing tool used in the subnanometer precision process. Based on the ion beam figuring (IBF) principle, the definitive factor of the IBF capability is analyzed, and the deficiencies of the ion beam polishing tool are identified. The effect of focused ion optics on the ion beam removal function is based on theoretic calculation and computer simulation; and focused three-grid ion optics are developed and tested. Finally, a 150 mm flat optics element is figured and results show that the contour error decreases from 15.58 nm RMS to 0.796 nm RMS, demonstrating that the ion beam polishing tool is very efficient for optical IBF. PMID- 26974612 TI - Fluorescence characteristics of the fuel tracers triethylamine and trimethylamine for the investigation of fuel distribution in internal combustion engines. AB - Laser-induced fluorescence based on fuel tracers like amines is a suitable measurement technique for mixing studies in internal combustion (IC) engines. Triethylamine has often been used in gasoline IC engines; however, no detailed fluorescence characterization for excitation at 263 or 266 nm is available. Trimethylamine (TMA) exhibits high potential as a gaseous fuel tracer but little information about TMA fluorescence is currently available. A picosecond laser source combined with a streak camera equipped with a spectrograph was used to determine the spectral fluorescence emission and fluorescence decay time of both tracers. The tracers were investigated at various temperatures and pressures in a calibration cell with nitrogen as bath gas. The results provide an in-depth understanding of the fluorescence characteristics of both tracers and allow assessment of their application to the investigation of fuel distribution in IC engines. PMID- 26974614 TI - Self-triggered method for characterization of single-photon detectors. AB - Single-photon avalanche photodiodes (SPADs) are instruments capable of measuring light at the single-photon level. Some important features of these devices must be correctly characterized for reliable application. In this paper, I present a high-resolution self-triggered method for characterization of SPADs based on the analysis of the time intervals between consecutive detection events with the detector under continuous-wave illumination. The self-triggered method is employed for characterization of the detection dead time-a limiting feature for the maximum counting rate achievable under free-running or gated modes--and of the temporal gate width--an important parameter when the detector is operated under gated mode. The measurement results are presented and the method is experimentally validated. PMID- 26974613 TI - Reducing the influence of direct reflection on return signal detection in a 3D imaging lidar system by rotating the polarizing beam splitter. AB - The direction rule of the laser beam traveling through a deflected polarizing beam splitter (PBS) cube is derived. It reveals that, due to the influence of end face reflection of the PBS at the detector side, the emergent beam coming from the incident beam parallels the direction of the original case without rotation, with only a very small translation interval between them. The formula of the translation interval is also given. Meanwhile, the emergent beam from the return signal at the detector side deflects at an angle twice that of the PBS rotation angle. The correctness has been verified by an experiment. The intensity transmittance of the emergent beam when propagating in the PBS is changes very little if the rotation angle is less than 35 deg. In a 3D imaging lidar system, by rotating the PBS cube by an angle, the direction of the return signal optical axis is separated from that of the origin, which can decrease or eliminate the influence of direct reflection caused by the prism end face on target return signal detection. This has been checked by experiment. PMID- 26974615 TI - Morphological processing of ultraviolet emissions of electrical corona discharge for analysis and diagnostic use. AB - Electron cascades from electrical discharge produce secondary emissions from atmospheric plasma in the ultraviolet band. For a single point of discharge, these emissions exhibit a stereotypical discharge morphology, with latent information about the discharge location. Morphological processing can uncover the location and therefore have diagnostic utility. PMID- 26974617 TI - Field tests for round-trip imaging at a 1.4 km distance with change detection and ranging using a short-wave infrared super-continuum laser. AB - Field tests have been conducted of a broadband illuminator for active hyperspectral imaging (HSI) using a short-wave infrared supercontinuum laser (SWIR-SCL). We demonstrated irradiance comparable to the sun for two-way measurements at a 1.4 km distance between laser and target, and performed change detection and ranging. The experimental results suggest that the range resolution of our method is ~1.5 cm even at the 1.4 km distance. Hence, we demonstrated the possibility to perform HSI with active broadband illumination using the SWIR-SCL. To our knowledge, this experiment is the first-ever to test two-way propagation of the active HSI illumination over a long distance. The 64 W SWIR-SCL provides near sunlight-equivalent illumination over multiple square meters, and the laser could enable HSI 24 h a day, even under a cloud cover, as well as enhanced capabilities such as change detection and ranging. PMID- 26974616 TI - Active optics system of the VLT Survey Telescope. AB - This paper describes the active optics system of the VLT Survey Telescope, the 2.6-m survey telescope designed for visible wavelengths of the European Southern Observatory at Cerro Paranal, in the Atacama desert. The telescope is characterized by a wide field of view (1.42 deg diameter), leading to tighter active optics than in conventional telescopes, in particular for the alignment requirements. We discuss the effects of typical error sources on the image quality and present the specific solutions adopted for wavefront sensing and correction of the aberrations, which are based on the shaping of a monolithic primary mirror and the positioning of the secondary in five degrees of freedom. PMID- 26974618 TI - Spatio-temporal characterization of pulses obtained from a high-energy sub nanosecond laser system. AB - Spatio-temporal profiles of laser pulses, obtained from each stage of a high energy sub-nanosecond laser system, are investigated. The laser system is composed of a Q-switched Nd:YAG unstable oscillator, a chain of Nd:YAG amplifiers, a second-harmonic generator, and a high-energy pulse compressor based on stimulated Brillouin scattering (SBS). A curved energy front, i.e., the pulses emerging away from the beam center being gradually delayed from the center pulse, is shown to originate from the unstable oscillator. Our comparative study shows that injection seeding will enlarge the energy front curvature, via reduction of the effective gain. After the laser amplifiers, the energy front curvature is more than doubled due to the gain saturation effect. The latter also modifies the spatial pulse width distribution. While there is a negligible pulse duration spread across the oscillator beam, the amplified pulses are found to have gradually reduced pulse duration away from the beam center. More interestingly, after the SBS pulse compression, not only the pulse width but also the delay is compressed down. This is, to the best of our knowledge, the first study of the spatio-temporal profile of the SBS compressed pulse. To compare with the experiments, two numerical models are developed to simulate the evolution of spatio-temporal profiles within the Nd:YAG laser system and during the SBS pulse compression, respectively. The first model is demonstrated to reproduce the experimental results very well, while the second model predicts part of the features of the SBS compressed pulse. The limitation on the latter is discussed. PMID- 26974619 TI - Time of flight dependent linearity in diffuse imaging: how effective is it to evaluate the spatial resolution by measuring the edge response function? AB - We describe the behavior of linearity in diffuse imaging by evaluating the differences between time-resolved images produced by photons arriving at the detector at different times. Two approaches are considered: Monte Carlo simulations and experimental results. The images of two complete opaque bars embedded in a transparent or in a turbid medium with a slab geometry are analyzed; the optical properties of the turbid medium sample are close to those of breast tissue. A simple linearity test was designed involving a direct comparison between the intensity profile produced by two bars scanned at the same time and the intensity profile obtained by adding two profiles of each bar scanned one at a time. It is shown that the linearity improves substantially when short time of flight photons are used in the imaging process, but even then the nonlinear behavior prevails. As the edge response function (ERF) has been used widely for testing the spatial resolution in imaging systems, the main implication of a time dependent linearity is the weakness of the linearity assumption when evaluating the spatial resolution through the ERF in diffuse imaging systems, and the need to evaluate the spatial resolution by other methods. PMID- 26974620 TI - Design and optimization of a volume-phase holographic grating for simultaneous use with red, green, and blue light using unpolarized light. AB - Volume-phase holographic (VPH) gratings have been designed for use in many areas of science and technology, such as optical communication, optical imaging, and astronomy. In this paper, the design of a volume-phase holographic grating, simultaneously optimized to operate in the red, green, and blue wavelengths, is presented along with a study of its fabrication tolerances. The grating is optimized to produce 98% efficiency at lambda=532 nm and at least 75% efficiency in the region between 400 and 700 nm, when the incident light is unpolarized. The optimization is done for recording in dichromated gelatin with a thickness of 12 MUm, an average refractive index of 1.5, and a refractive index modulation of 0.022. PMID- 26974621 TI - Performance improvement of power-over-fiber system using noise-modulated laser diode. AB - In a power-over-fiber system, the key limiting factor for transmission light power is the stimulated Brillouin scattering effect, which leads to a decrease in transmission light power at the end of the optical fiber. Therefore, we propose and experimentally demonstrate a broadband laser generated by a noise-modulated distributed-feedback laser diode to suppress the stimulated Brillouin scattering effect in the optical fiber. Experimental results show that the linewidth of the noise-modulated distributed-feedback laser diode broadens from 2.43 to 379.89 MHz when the noise modulation amplitude is increased from 0 to 400 mV. Due to the broadening of the laser linewidth, the stimulated Brillouin scattering threshold raises 7.19 dB, and the peak power of the Brillouin Stokes light is reduced by 40.90 dB. At the same time, the output electrical power at the end of the optical fiber increases 13.55 dB. PMID- 26974622 TI - Shaping of cylindrical and 3D ellipsoidal beams for electron photoinjector laser drivers. AB - With the use of spatial light modulators it became possible to implement in experiments the method of controlling the space-time intensity distribution of femtosecond laser pulses stretched to picosecond duration. Cylindrical and quasi ellipsoidal intensity distributions were obtained and characterized by means of a 2D spectrograph and a cross-correlator. PMID- 26974623 TI - Scalability of components for kW-level average power few-cycle lasers. AB - In this paper, the average power scalability of components that can be used for intense few-cycle lasers based on nonlinear compression of modern femtosecond solid-state lasers is investigated. The key components of such a setup, namely, the gas-filled waveguides, laser windows, chirped mirrors for pulse compression and low dispersion mirrors for beam collimation, focusing, and beam steering are tested under high-average-power operation using a kilowatt cw laser. We demonstrate the long-term stable transmission of kW-level average power through a hollow capillary and a Kagome-type photonic crystal fiber. In addition, we show that sapphire substrates significantly improve the average power capability of metal-coated mirrors. Ultimately, ultrabroadband dielectric mirrors show negligible heating up to 1 kW of average power. In summary, a technology for scaling of few-cycle lasers up to 1 kW of average power and beyond is presented. PMID- 26974624 TI - 3D robust digital image correlation for vibration measurement. AB - Discrepancies of speckle images under dynamic measurement due to the different viewing angles will deteriorate the correspondence in 3D digital image correlation (3D-DIC) for vibration measurement. Facing this kind of bottleneck, this paper presents two types of robust 3D-DIC methods for vibration measurement, SSD-robust and SWD-robust, which use a sum of square difference (SSD) estimator plus a Geman-McClure regulating term and a Welch estimator plus a Geman-McClure regulating term, respectively. Because the regulating term with an adaptive rejecting bound can lessen the influence of the abnormal pixel data in the dynamical measuring process, the robustness of the algorithm is enhanced. The robustness and precision evaluation experiments using a dual-frequency laser interferometer are implemented. The experimental results indicate that the two presented robust estimators can suppress the effects of the abnormality in the speckle images and, meanwhile, keep higher precision in vibration measurement in contrast with the traditional SSD method; thus, the SWD-robust and SSD-robust methods are suitable for weak image noise and strong image noise, respectively. PMID- 26974625 TI - Finite-difference time-domain methods to analyze ytterbium-doped Q-switched fiber lasers. AB - Q-switched lasers are widely used in material processing, laser ranging, medicine, and nonlinear optics--in particular, Q-switched lasers in optical fibers are important since they cannot only generate high peak powers but can also concentrate high peak powers in small areas. In this paper, we present new finite-difference time-domain methods that analyze the dynamics of Q-switched fiber lasers, which are more flexible and robust than previous methods. We extend the method to analyze fiber ring lasers and compare the results with our experiments. PMID- 26974626 TI - Format-independent polarization-demultiplexing technique for dual-polarization intensity modulated signals. AB - We show through simulations how polarization demultiplexing of dual-polarization, intensity modulated signals of arbitrary format can be performed by only using the information in Stokes space. The technique would be applicable for short range communications within data centers. PMID- 26974627 TI - Phase-derivative-based estimation of a digital reference wave from a single off axis digital hologram. AB - This paper describes a method to obtain an estimated digital reference wave from a single off-axis digital hologram that matches the actual experimental reference wave as closely as possible. The proposed method is independent of a reference flat plate and speckles. The digital reference wave parameters are estimated directly from the recorded phase information. The parameters include both the off axis tilt angle and the curvature of the reference wave. Phase derivatives are used to extract the digital reference wave parameters without the need for a phase unwrapping process. Thus, problems associated with phase wrapping are avoided. Experimental results for the proposed method are provided. The simulated effect of the digital reference wave parameters on the reconstructed image phase distribution is shown. The pseudo phase gradient originating from incorrect estimation of the digital reference wave parameters and its effect on object reconstruction are discussed. PMID- 26974628 TI - Hysteresis compensation of photoluminescence in ZnS:Cu for noncontact shaft torque sensing. AB - This paper presents a preliminary investigation of loading rate-dependent hysteresis of photoluminescence (PL) by phosphorescence quenching of copper-doped zinc sulfide (ZnS:Cu) microparticles in response to dynamic torsional loading. Precision sinusoidal torque waveforms in the frequency range of 0.5-3 Hz are used to identify the loading rate-dependent (i.e., frequency-dependent) nonlinear hysteresis phenomenon. The potential of the application of PL is demonstrated by successfully measuring the sinusoidal torque applied to a rotational shaft by evaluating the loading rate-dependent PL intensity signature using a photomultiplier tube. In addition, the potential of noncontact shaft torque sensing is demonstrated successfully by the simple compensation derived from ad hoc heuristic characterization. PMID- 26974629 TI - Optimal design of multilayer diffractive optical elements with effective area method. AB - The effective area method is described to design high-efficiency multiplayer diffractive optical elements (MLDOEs) with finite feature sizes for wide wave band. This method is presented with consideration of the shield effect between two elements of MLDOEs, and the optimal surface relief heights of MLDOEs are calculated with the effective area method. Then the comparisons of diffraction efficiency and polychromatic integral diffraction efficiency for MLDOEs with different period widths are described and simulated with the effective area method and scalar diffraction theory (SDT). Finally, the design results of MLDOEs obtained by SDT and the effective area method are compared by a rigorous electromagnetic analysis method, specifically, the finite-difference time-domain method. These results show that the limits of SDT for MLDOEs, ascertain and quantify the greatest sources of the diffraction efficiency loss due to the shield effect. The design results of the effective area method can obtain higher polychromatic integral diffraction efficiency than that of the SDT when the period width of MLDOEs is taken into account. PMID- 26974630 TI - Restraint of range walk error in a Geiger-mode avalanche photodiode lidar to acquire high-precision depth and intensity information. AB - There exists a range walk error in a Geiger-mode avalanche photodiode (Gm-APD) lidar because of the fluctuation in the number of signal photoelectrons. To restrain this range walk error, we propose a new returning-wave signal processing technique based on the Poisson probability response model and the Gaussian functions fitting method. High-precision depth and intensity information of the target at the distance of 5 m is obtained by a Gm-APD lidar using a 6 ns wide pulsed laser. The experiment results show that the range and intensity precisions are 1.2 cm and 0.015 photoelectrons, respectively. PMID- 26974631 TI - Designs for a large-aperture telescope to map the CMB 10* faster. AB - Current large-aperture cosmic microwave background (CMB) telescopes have nearly maximized the number of detectors that can be illuminated while maintaining diffraction-limited image quality. The polarization-sensitive detector arrays being deployed in these telescopes in the next few years will have roughly 104 detectors. Increasing the mapping speed of future instruments by at least an order of magnitude is important to enable precise probes of the inflationary paradigm in the first fraction of a second after the big bang and provide strong constraints on cosmological parameters. The CMB community has begun planning a next generation "Stage IV" CMB project that will be comprised of multiple telescopes with between 105-106 detectors to pursue these goals. This paper introduces the new crossed Dragone telescope and receiver optics designs that increase the usable diffraction-limited field-of-view, and therefore the mapping speed, by an order of magnitude compared to the upcoming generation of large aperture instruments. Polarization systematics and engineering considerations are presented, including a preliminary receiver model to demonstrate that these designs will enable high efficiency illumination of >105 detectors in a next generation CMB telescope. PMID- 26974632 TI - Application of quantum weak measurement for glucose concentration detection. AB - A quantum weak measurement scheme based on a Mach-Zehnder interferometer is proposed to detect the concentration of glucose, bringing this mechanism into the field of biomedical sensing for the first time, to the best of our knowledge. With a Mach-Zehnder interferometer system, we can analyze tiny phase differences between the two paths by measuring spectrum shift. We measured the concentration of glucose with weak measurement to achieve a concentration resolution of 8.98*10 5 g/L corresponding to a volume refractive index of 1.39*10-8 RIU, which was more than five times higher than the resolution achieved by conventional interference, 4.99*10-4 g/L. In the detection of glucose concentration in the blood serum of mice, a resolution of 1.0136*10-7 g/L for weak measurement was obtained. PMID- 26974633 TI - High-contrast pattern reconstructions using a phase-seeded point CGH method. AB - A major challenge encountered in digital holography applications is the need to synthesize computer-generated holograms (CGHs) that are realizable as phase-only elements while also delivering high quality reconstruction. This trade-off is particularly acute in high-precision applications such as photolithography where contrast typically must exceed 0.6. A seeded-phase point method is proposed to address this challenge, whereby patterns composed of fine lines that intersect and form closed shapes are reconstructed with high contrast while maintaining a phase-only CGH. The method achieves superior contrast to that obtained by uniform or random seeded-phase methods while maintaining computational efficiency for large area exposures. It is also shown that binary phase modulation achieves similar contrast performance with benefits for the fabrication of simpler diffractive optical elements. PMID- 26974634 TI - Better three-dimensional inspection with structured illumination: speed. AB - Three-dimensional (3D) inspection in the factory requires precision and speed. While customers can select from a wide spectrum of high-precision sensors, the real challenge today is "speed." We discuss the speed of 3D sensors in a general context to provide an understanding of why high-resolution 3D sensors deliver significantly fewer 3D points per second than the available camera pixel rates suggest. The major cause of low speed is the large number E of required exposures due to the unavoidable depth scanning. Through the example of structured illumination microscopy (SIM), we demonstrate how E can be minimized without reducing precision. We further demonstrate a lateral scanning strategy that operates at a significantly higher speed for macroscopic measurements by avoiding explicit depth scanning. This paper is a follow up on an earlier paper about the precision limits of SIM and exploits the earlier results. PMID- 26974635 TI - Spoof surface plasmon polaritons based on ultrathin corrugated metallic grooves at terahertz frequency. AB - We investigate the dispersion properties of an ultrathin spoof plasmonic waveguide based on metal strip grooves using the finite element method. The confinement ability of the surface plasmon polariton (SPP) waves are influenced by the dispersion curves, which can be modulated by the structure parameters. The propagation characteristics of a subwavelength planar plasmonic waveguide ring resonator have also been studied. Furthermore, a gain medium is introduced to compensate for the propagation loss of the SPP wave in the device at terahertz frequency. It is demonstrated that the gain medium provides an enhancement for the control of on/off states of the signal with the presence of pumping, which paves a way for gain-assisted switching and lasing applications in the terahertz regime. PMID- 26974636 TI - Optimization of polarizer azimuth in improving signal-to-noise ratio in Kerr microscopy. AB - The magneto optical Kerr effect (MOKE) is a widely used technique in magnetic domain imaging for its high surface sensitivity and external magnetic compatibility. Optimization of Kerr microscopy will improve the detecting sensitivity and provide high-quality domain images. In this work, we provide a method to optimize the polarizer azimuth in improving the signal-to-noise ratio (S/N) in longitudinal Kerr microscopy with the generalized magneto optical ellipsometry. Detailed analysis of the MOKE signal and the noise components are provided to study the optimum polarizer and analyzer azimuth combinations. Results show that, for a fixed polarizer angle 1 degrees , the laser intensity noise and the shot noise, which vary with the input laser power, have a similar amplitude and decline with the analyzer azimuth increasing. When the analyzer is set at the extinction place, the Johnson noise plays a dominate role in the total noise. Then, the S/N values are calculated to find the optimum polarizer and analyzer azimuth. Results show that the optimum polarizer and analyzer azimuth combination for Permalloy is (18.35 degrees , 68.35 degrees ) under an incident angle of 45 degrees . After that, the S/N of 200 nm Permalloy at different analyzer angles with the polarizer azimuth set at 18.35 degrees is measured to verify the validity of the simulation results. At last, the S/N at different incident angles is calculated. Results show that the optimum incident angle of 200 nm Permalloy film to improve the S/N is 70.35 degrees under the polarizer and analyzer angles set at the optimal combinations (18.35 degrees , 68.35 degrees ). PMID- 26974637 TI - Formation and emission characteristics of CN molecules in laser induced low pressure He plasma and its applications to N analysis in coal and fossilization study. AB - Presented in this paper are the results of an experimental study on the laser induced plasma emission of a number of CN free samples (urea, sucrose) with 40 mJ pulse energy using He and N2 ambient gases. It is shown that the CN emission has its exclusive sources in the molecules produced as the result of chemical bonding either between the ablated C and N ions in the He plasma or between the ablated C and dissociated N from the N2 ambient gas. The emission intensities in both cases are found to have the highest values at the low gas pressure of 2 kPa. The emission in He gas is shown to exhibit the typical characteristics related to a shockwave generated excitation mechanism. The experiments using He ambient gas further demonstrate the feasible laser-induced breakdown spectroscopy application to quantitative and sensitive N analysis of coal and promising application for practical in situ carbon dating of fossils. PMID- 26974638 TI - On the modeling of hyperspectral remote-sensing reflectance of high-sediment-load waters in the visible to shortwave-infrared domain. AB - We evaluated three key components in modeling hyperspectral remote-sensing reflectance in the visible to shortwave-infrared (Vis-SWIR) domain of high sediment-load (HSL) waters, which are the relationship between remote-sensing reflectance (R(rs)) and inherent optical properties (IOPs), the absorption coefficient spectrum of pure water (a(w)) in the IR-SWIR region, and the spectral variation of sediment absorption coefficient (a(sed)). Results from this study indicate that it is necessary to use a more generalized R(rs)-IOP model to describe the spectral variation of R(rs) of HSL waters from Vis to SWIR; otherwise it may result in a spectrally distorted R(rs) spectrum if a constant model parameter is used. For hyperspectral a(w) in the IR-SWIR domain, the values reported in Kou et al. (1993) provided a much better match with the spectral variation of R(rs) in this spectral range compared to that of Segelstein (1981). For a(sed) spectrum, an empirical a(sed) spectral shape derived from sample measurements is found working much better than the traditional exponential-decay function of wavelength in modeling the spectral variation of R(rs) in the visible domain. These results would improve our understanding of the spectral signatures of R(rs) of HSL waters in the Vis-SWIR domain and subsequently improve the retrieval of IOPs from ocean color remote sensing, which could further help the estimation of sediment loading of such waters. Limitations in estimating chlorophyll concentration in such waters are also discussed. PMID- 26974639 TI - High-resolution Fourier hologram synthesis from photographic images through computing the light field. AB - We present a technique for synthesizing the Fourier hologram of a three dimensional scene from its light field. The light field captures the volumetric information of an object, and an important advantage is that it does not require coherent illumination, as in conventional holography. In this work, we show how to obtain a high-resolution digital hologram with the light field obtained from a series of photographic images captured along the optical axis. The method is verified both by simulations and experimentally captured light field. PMID- 26974640 TI - Atmospheric propagation and combining of high-power lasers. AB - In this paper, we analyze beam combining and atmospheric propagation of high power lasers for directed-energy (DE) applications. The large linewidths inherent in high-power fiber and slab lasers cause random phase and intensity fluctuations that occur on subnanosecond time scales. Coherently combining these high-power lasers would involve instruments capable of precise phase control and operation at rates greater than ~10 GHz. To the best of our knowledge, this technology does not currently exist. This presents a challenging problem when attempting to phase lock high-power lasers that is not encountered when phase locking low-power lasers, for example, at milliwatt power levels. Regardless, we demonstrate that even if instruments are developed that can precisely control the phase of high power lasers, coherent combining is problematic for DE applications. The dephasing effects of atmospheric turbulence typically encountered in DE applications will degrade the coherent properties of the beam before it reaches the target. Through simulations, we find that coherent beam combining in moderate turbulence and over multikilometer propagation distances has little advantage over incoherent combining. Additionally, in cases of strong turbulence and multikilometer propagation ranges, we find nearly indistinguishable intensity profiles and virtually no difference in the energy on the target between coherently and incoherently combined laser beams. Consequently, we find that coherent beam combining at the transmitter plane is ineffective under typical atmospheric conditions. PMID- 26974641 TI - Semianalytical approach to study the loss characteristics of a symmetrical multilayered plasmonic waveguide. AB - A metal waveguide of finite width and thickness surrounded by a dielectric provides increased propagation length of the surface plasmon polariton and is therefore called long-range surface plasmon polaritons (LR-SPP). In this work, a new structure is proposed by modifying the refractive index of the dielectric surrounding the metal waveguide, leading to further improvement of the propagation length. It is shown that, when the single dielectric surrounding is replaced by a multilayered surrounding where each layer has different thicknesses and refractive index, the propagation loss gets reduced, leading to increased propagation length of the LR-SPP. The propagation loss is calculated semianalytically from the FWHM of the Lorentzian peak obtained in the plot of excitation efficiency of such waveguide for different values of the propagation constant. Before doing this calculation, the 2D variation of refractive index is first converted into a 1D effective refractive index. All the steps of analysis are discussed in detail, and, wherever necessary, the calculated results are matched with similar results of other researchers. PMID- 26974642 TI - Photodiode-based cutting interruption sensor for near-infrared lasers. AB - We report on a photodiode-based sensor system to detect cutting interruptions during laser cutting with a fiber laser. An InGaAs diode records the thermal radiation from the process zone with a ring mirror and optical filter arrangement mounted between a collimation unit and a cutting head. The photodiode current is digitalized with a sample rate of 20 kHz and filtered with a Chebyshev Type I filter. From the measured signal during the piercing, a threshold value is calculated. When the diode signal exceeds this threshold during cutting, a cutting interruption is indicated. This method is applied to sensor signals from cutting mild steel, stainless steel, and aluminum, as well as different material thicknesses and also laser flame cutting, showing the possibility to detect cutting interruptions in a broad variety of applications. In a series of 83 incomplete cuts, every cutting interruption is successfully detected (alpha error of 0%), while no cutting interruption is reported in 266 complete cuts (beta error of 0%). With this remarkable high detection rate and low error rate, the possibility to work with different materials and thicknesses in combination with the easy mounting of the sensor unit also to existing cutting machines highlight the enormous potential for this sensor system in industrial applications. PMID- 26974643 TI - Plasmon-enhanced performance of an ultrathin silicon solar cell using metal semiconductor core-shell hemispherical nanoparticles and metallic back grating. AB - This paper presents a concept to significantly improve the photocurrent of ultrathin crystalline silicon solar cells using plasmonic hemispherical dielectric-metal (core-shell) nanoparticles and backside gratings. The design of three-dimensional spherical and hemispherical arrays of nanoparticles on top of the surface of 0.8 MUm crystalline silicon solar cells was simulated using finite difference time-domain (FDTD) method. We used the FDTD results to investigate the photocurrent by solving the Poisson and drift diffusion equations. The results indicate an enhancement of between 80% and 93% in the photocurrent for cells with hemispherical Ag and Ag-SiO2 core-shell nanoparticles, respectively, compared to a cell with spherical nanoparticles. In addition, for obtaining a higher photocurrent, triangular gratings were applied on the back side of the absorber and we obtained a photocurrent of 22 mA/cm2. The simulated results indicate that the proposed structures increase the spectral response of thin-film crystalline silicon solar cells over a solar spectrum in the range of 400 nm-1200 nm. Finally, we investigated photocurrent as a function of incidence light angle and concluded that this approach is applicable to various thicknesses and shapes of nanoparticles. PMID- 26974644 TI - Superluminal, luminal, and subluminal nondiffracting pulses applied to free-space optical systems: theoretical description. AB - In this paper, we show theoretically nondiffracting pulses with arbitrary peak velocities that are suitable for data signal transmission without distortion over long distances using different techniques of signal modulation. Our results provide closed-form analytical solutions to the wave equation describing superluminal, luminal, and subluminal ideal nondiffracting pulses with frequency spectra commonly used in the field of optical communications. PMID- 26974645 TI - Compact InGaAsP/InP 3 * 3 multimode-interference coupler-based electro-optic switch. AB - Optical switches are key components in data links for optical communication networks requiring low crosstalk and insertion loss, high switching speed, and power efficiency. A multimode-interference (MMI)-coupler-based switch with multiple inputs and outputs serving as a switching unit is desired toward forming a large-scale switch matrix. Here we demonstrate a compact 3*3 MMI coupler electro-optic switch based on the carrier injection effect on InGaAsP/InP substrates. This switch device is 2780 MUm long by 18 MUm wide. The switching states can be controlled by two index-modulation regions through applied bias voltages. Our simulation results show that the device exhibits low crosstalk of < 22 dB, high extinction ratio of ?23 dB, low electrical switching energy of ~2.0 pJ/bit, maximum operational frequency of ~1.0 GHz, and optical bandwidth of ~20 nm in the C band. We experimentally validated one of the switching states on a fabricated device with maximum current injections of ~25 mA under combined bias voltages of ~2.5 and ~3.0 V. Such monolithic integration schemes make them an ideal candidate for future on-chip photonic integrated circuits. PMID- 26974646 TI - Application of white light Fresnel diffractometry to film thickness measurement. AB - In this work we present the theoretical background and experimental procedure to measure the thickness of thin films by analyzing Fresnel diffraction patterns obtained from polychromatic illumination of phase-step samples. As examples of this technique, we measured the thicknesses of thin aluminum layers on glass substrates using three different broad-spectrum light sources. The results are in excellent agreement with independent interferometric measurements within less than 5% relative uncertainties. PMID- 26974647 TI - Optical modeling of sunlight by using partially coherent sources in organic solar cells. AB - We investigate the effects of coherent and partially coherent sources in optical modeling of organic solar cells. Two different organic solar cells are investigated: one without substrate and the other with a millimeter-sized glass substrate. The coherent light absorption is calculated with rigorous coupled-wave analysis. The result of this method is convolved with a distribution function to calculate the partially coherent light absorption. We propose a new formulation to accurately model sunlight as a set of partially coherent sources. In the structure with glass substrate, the accurate sunlight modeling results in the elimination of coherent effects in the thick substrate, but the coherency in other layers is not affected. Using partially coherent sources instead of coherent sources for simulations with sunlight results in a smoother absorption spectrum, but the change in the absorption efficiency is negligible. PMID- 26974648 TI - Image fusion via nonlocal sparse K-SVD dictionary learning. AB - Image fusion aims to merge two or more images captured via various sensors of the same scene to construct a more informative image by integrating their details. Generally, such integration is achieved through the manipulation of the representations of the images concerned. Sparse representation plays an important role in the effective description of images, offering a great potential in a variety of image processing tasks, including image fusion. Supported by sparse representation, in this paper, an approach for image fusion by the use of a novel dictionary learning scheme is proposed. The nonlocal self-similarity property of the images is exploited, not only at the stage of learning the underlying description dictionary but during the process of image fusion. In particular, the property of nonlocal self-similarity is combined with the traditional sparse dictionary. This results in an improved learned dictionary, hereafter referred to as the nonlocal sparse K-SVD dictionary (where K-SVD stands for the K times singular value decomposition that is commonly used in the literature), and abbreviated to NL_SK_SVD. The performance of the NL_SK_SVD dictionary is applied for image fusion using simultaneous orthogonal matching pursuit. The proposed approach is evaluated with different types of images, and compared with a number of alternative image fusion techniques. The resultant superior fused images using the present approach demonstrates the efficacy of the NL_SK_SVD dictionary in sparse image representation. PMID- 26974649 TI - Assessment of Workspace Attributes Under Simulated Index Finger Proximal Interphalangeal Arthrodesis. AB - This article presented an assessment of quantitative measures of workspace (WS) attributes under simulated proximal interphalangeal (PIP) joint arthrodesis of the index finger. Seven healthy subjects were tested with the PIP joint unconstrained (UC) and constrained to selected angles using a motion analysis system. A model of the constrained finger was developed in order to address the impact of the inclusion of prescribed joint arthrodesis angles on WS attributes. Model parameters were obtained from system identification experiments involving flexion-extension (FE) movements of the UC and constrained finger. The data of experimental FE movements of the constrained finger were used to generate the two dimensional (2D) WS boundaries and to validate the model. A weighted criterion was formulated to define an optimal constraint angle among several system parameters. Results indicated that a PIP joint immobilization angle of 40-50 deg of flexion maximized the 2D WS. The analysis of the aspect ratio of the 2D WS indicated that the WS was more evenly distributed as the imposed PIP joint constraint angle increased. With the imposed PIP joint constraint angles of 30 deg, 40 deg, 50 deg, and 60 deg of flexion, the normalized maximum distance of fingertip reach was reduced by approximately 3%, 4%, 7%, and 9%, respectively. PMID- 26974650 TI - Exotic s-wave superconductivity in alkali-doped fullerides. AB - Alkali-doped fullerides (A3C60 with A = K, Rb, Cs) show a surprising phase diagram, in which a high transition-temperature (Tc) s-wave superconducting state emerges next to a Mott insulating phase as a function of the lattice spacing. This is in contrast with the common belief that Mott physics and phonon-driven s wave superconductivity are incompatible, raising a fundamental question on the mechanism of the high-Tc superconductivity. This article reviews recent ab initio calculations, which have succeeded in reproducing comprehensively the experimental phase diagram with high accuracy and elucidated an unusual cooperation between the electron-phonon coupling and the electron-electron interactions leading to Mott localization to realize an unconventional s-wave superconductivity in the alkali-doped fullerides. A driving force behind the exotic physics is unusual intramolecular interactions, characterized by the coexistence of a strongly repulsive Coulomb interaction and a small effectively negative exchange interaction. This is realized by a subtle energy balance between the coupling with the Jahn-Teller phonons and Hund's coupling within the C60 molecule. The unusual form of the interaction leads to a formation of pairs of up- and down-spin electrons on the molecules, which enables the s-wave pairing. The emergent superconductivity crucially relies on the presence of the Jahn-Teller phonons, but surprisingly benefits from the strong correlations because the correlations suppress the kinetic energy of the electrons and help the formation of the electron pairs, in agreement with previous model calculations. This confirms that the alkali-doped fullerides are a new type of unconventional superconductors, where the unusual synergy between the phonons and Coulomb interactions drives the high-Tc superconductivity. PMID- 26974651 TI - Effect of Direct-Fed Microbial Dosage on the Fecal Concentrations of Enterohemorrhagic Escherichia coli in Feedlot Cattle. AB - Contamination of beef products by Shiga toxin-producing Escherichia coli is a concern for food safety with a particular subset, the enterohemorrhagic E. coli (EHEC), being the most relevant to human disease. To mitigate food safety risks, preharvest intervention strategies have been implemented with the aim to reduce EHEC in cattle. One class of interventions that has been widely used in feedlots is direct-fed microbials (DFMs), which can contain various dosing rates of probiotic bacteria. Here we compare the use of two different doses of a commercially available DFM on total EHEC load in a commercial feedlot setting. The DFMs used were the standard 10(9) Propionibacterium freudenreichii and 10(6) Lactobacillus acidophilus colony forming units (CFUs)/head/day dose of Bovamine((r)) (Nutrition Physiology Company, Guymon, OK) and the higher dose, Bovamine DefendTM (Nutrition Physiology Company), which is dosed at 10(9) P. freudenreichii and 10(9) Lactobacillus acidophilus CFUs/head/day. To analyze the total EHEC fecal concentration, 2200 head of cattle were assigned a DFM feed regimen lasting approximately 5 months. At harvest, 480 head of cattle were sampled using rectoanal mucosal swabs. A quantitative polymerase chain reaction assay targeting ecf1 was used to enumerate the total EHEC fecal concentration for 240 head fed the low-dose DFM and 240 head fed the high-dose DFM. No significant difference (p > 0.05) in the fecal concentration of total EHEC was observed between the two doses. This suggests that using an increased dosage provides no additional reduction in the total EHEC fecal concentration of feedlot cattle compared to the standard dosage. PMID- 26974652 TI - In Vitro Optimization of Enzymes Involved in Precorrin-2 Synthesis Using Response Surface Methodology. AB - In order to maximize the production of biologically-derived chemicals, kinetic analyses are first necessary for predicting the role of enzyme components and coordinating enzymes in the same reaction system. Precorrin-2 is a key precursor of cobalamin and siroheme synthesis. In this study, we sought to optimize the concentrations of several molecules involved in precorrin-2 synthesis in vitro: porphobilinogen synthase (PBGS), porphobilinogen deaminase (PBGD), uroporphyrinogen III synthase (UROS), and S-adenosyl-l-methionine-dependent urogen III methyltransferase (SUMT). Response surface methodology was applied to develop a kinetic model designed to maximize precorrin-2 productivity. The optimal molar ratios of PBGS, PBGD, UROS, and SUMT were found to be approximately 1:7:7:34, respectively. Maximum precorrin-2 production was achieved at 0.1966 +/- 0.0028 MUM/min, agreeing with the kinetic model's predicted value of 0.1950 MUM/min. The optimal concentrations of the cofactor S-adenosyl-L-methionine (SAM) and substrate 5-aminolevulinic acid (ALA) were also determined to be 200 MUM and 5 mM, respectively, in a tandem-enzyme assay. By optimizing the relative concentrations of these enzymes, we were able to minimize the effects of substrate inhibition and feedback inhibition by S-adenosylhomocysteine on SUMT and thereby increase the production of precorrin-2 by approximately five-fold. These results demonstrate the effectiveness of kinetic modeling via response surface methodology for maximizing the production of biologically-derived chemicals. PMID- 26974653 TI - Chlamydia trachomatis Pgp3 Antibody Persists and Correlates with Self-Reported Infection and Behavioural Risks in a Blinded Cohort Study. AB - Chlamydia trachomatis (Ct) serological studies in populations could help monitor changes in lifetime cumulative risk of infection. We developed a double-antigen sandwich ELISA based on the Ct-specific Pgp3 antigen, then tested blind stored sera from over 800 participants in a New Zealand birth cohort from Dunedin at ages 26, 32 and 38. The double-antigen sandwich ELISA was more sensitive than our previously characterised indirect Pgp3 ELISA. Pgp3 antibody was detected more often in women compared to men and correlated with increasing numbers of sexual partners, self-reported Ct, and younger age at sexual debut in both women and men. At age 26, 24.1% (99/411) of women were Pgp3 seropositive, as were 79.5% (35/44) of those reporting Ct infection; Pgp3 antibody persisted to age 38 in 96.5% (83/86). In men at age 26, the figures were 10.7% (47/442) and 25.0% (6/24), respectively, with high (83.9%) antibody persistence to age 38. At age 38, among those Pgp3 seropositive, 63.3% of women and 83.1% of men had not reported Ct infection. Thus, Ct-specific Pgp3 antibody was detected in most women reporting Ct infection and correlated with risk of infection in those who did not, with most infections remaining undetected. As this antibody persisted for at least twelve years in 96% of these women, serology could be used to evaluate Ct prevention programmes among women. PMID- 26974654 TI - Serotonin and Dopamine Gene Variation and Theory of Mind Decoding Accuracy in Major Depression: A Preliminary Investigation. AB - Theory of mind-the ability to decode and reason about others' mental states-is a universal human skill and forms the basis of social cognition. Theory of mind accuracy is impaired in clinical conditions evidencing social impairment, including major depressive disorder. The current study is a preliminary investigation of the association of polymorphisms of the serotonin transporter (SLC6A4), dopamine transporter (DAT1), dopamine receptor D4 (DRD4), and catechol O-methyl transferase (COMT) genes with theory of mind decoding in a sample of adults with major depression. Ninety-six young adults (38 depressed, 58 non depressed) completed the 'Reading the Mind in the Eyes task' and a non mentalistic control task. Genetic associations were only found for the depressed group. Specifically, superior accuracy in decoding mental states of a positive valence was seen in those homozygous for the long allele of the serotonin transporter gene, 9-allele carriers of DAT1, and long-allele carriers of DRD4. In contrast, superior accuracy in decoding mental states of a negative valence was seen in short-allele carriers of the serotonin transporter gene and 10/10 homozygotes of DAT1. Results are discussed in terms of their implications for integrating social cognitive and neurobiological models of etiology in major depression. PMID- 26974656 TI - Correction: Seasonality in Polyps of a Tropical Cubozoan: A latina nr mordens. PMID- 26974657 TI - Tobacco Smoking Kills Slowly, while Smoking on Oxygen Is a Burning Issue. PMID- 26974658 TI - Clay nanotube-biopolymer composite scaffolds for tissue engineering. AB - Porous biopolymer hydrogels doped at 3-6 wt% with 50 nm diameter/0.8 MUm long natural clay nanotubes were produced without any cross-linkers using the freeze drying method. The enhancement of mechanical strength (doubled pick load), higher water uptake and thermal properties in chitosan-gelatine-agarose hydrogels doped with halloysite was demonstrated. SEM and AFM imaging has shown the even distribution of nanotubes within the scaffolds. We used enhanced dark-field microscopy to visualise the distribution of halloysite nanotubes in the implantation area. In vitro cell adhesion and proliferation on the nanocomposites occur without changes in viability and cytoskeleton formation. In vivo biocompatibility and biodegradability evaluation in rats has confirmed that the scaffolds promote the formation of novel blood vessels around the implantation sites. The scaffolds show excellent resorption within six weeks after implantation in rats. Neo-vascularization observed in newly formed connective tissue placed near the scaffold allows for the complete restoration of blood flow. These phenomena indicate that the halloysite-doped scaffolds are biocompatible as demonstrated both in vitro and in vivo. The chitosan-gelatine agarose doped clay nanotube nanocomposite scaffolds fabricated in this work are promising candidates for tissue engineering applications. PMID- 26974659 TI - Neonatal Abstinence Syndrome: Presentation and Treatment Considerations. AB - The increase in opioid use among the general population is reflected in pregnant women and neonatal abstinence syndrome (NAS) statistics. This increase has produced an unprecedented focus on NAS from both the political-judicial sphere and the medical community. Under the banner of fetal protection, judges and prosecutors have implemented punitive approaches against women who use prescribed and nonprescribed opioids during pregnancy, including arrest, civil commitment, detention, prosecution, and loss of custody or termination of parental rights. Within the medical community, questions have been raised regarding protocols to detect prenatal drug exposure at delivery, NAS treatment protocols, the need for quality-improvement strategies to standardize care and reduce length of stay for mother and infant, and the benefits of engaging the mother in the care of her infant. It is not uncommon for the expression of strong discordant views on these issues both between and among these political-judicial and medical constituencies. Closely examining the issues often reveal a lack of understanding of substance use disorders, their treatment, and the occurrence and treatment of NAS. This study provides an in-depth examination of NAS, including variations in presentation and factors that impact the efficacy of treatment, and also identifying questions that remain unanswered. Finally, 4 key areas on which future research should focus to guide both medical care and public policy are discussed. PMID- 26974655 TI - Iminosugars Inhibit Dengue Virus Production via Inhibition of ER Alpha Glucosidases--Not Glycolipid Processing Enzymes. AB - It has long been thought that iminosugar antiviral activity is a function of inhibition of endoplasmic reticulum-resident alpha-glucosidases, and on this basis, many iminosugars have been investigated as therapeutic agents for treatment of infection by a diverse spectrum of viruses, including dengue virus (DENV). However, iminosugars are glycomimetics possessing a nitrogen atom in place of the endocyclic oxygen atom, and the ubiquity of glycans in host metabolism suggests that multiple pathways can be targeted via iminosugar treatment. Successful treatment of patients with glycolipid processing defects using iminosugars highlights the clinical exploitation of iminosugar inhibition of enzymes other than ER alpha-glucosidases. Evidence correlating antiviral activity with successful inhibition of ER glucosidases together with the exclusion of alternative mechanisms of action of iminosugars in the context of DENV infection is limited. Celgosivir, a bicyclic iminosugar evaluated in phase Ib clinical trials as a therapeutic for the treatment of DENV infection, was confirmed to be antiviral in a lethal mouse model of antibody-enhanced DENV infection. In this study we provide the first evidence of the antiviral activity of celgosivir in primary human macrophages in vitro, in which it inhibits DENV secretion with an EC50 of 5 MUM. We further demonstrate that monocyclic glucose mimicking iminosugars inhibit isolated glycoprotein and glycolipid processing enzymes and that this inhibition also occurs in primary cells treated with these drugs. By comparison to bicyclic glucose-mimicking iminosugars which inhibit glycoprotein processing but do not inhibit glycolipid processing and galactose mimicking iminosugars which do not inhibit glycoprotein processing but do inhibit glycolipid processing, we demonstrate that inhibition of endoplasmic reticulum resident alpha-glucosidases, not glycolipid processing, is responsible for iminosugar antiviral activity against DENV. Our data suggest that inhibition of ER alpha-glucosidases prevents release of virus and is the primary antiviral mechanism of action of iminosugars against DENV. PMID- 26974660 TI - How the kinetochore couples microtubule force and centromere stretch to move chromosomes. AB - The Ndc80 complex (Ndc80, Nuf2, Spc24 and Spc25) is a highly conserved kinetochore protein essential for end-on anchorage to spindle microtubule plus ends and for force generation coupled to plus-end polymerization and depolymerization. Spc24/Spc25 at one end of the Ndc80 complex binds the kinetochore. The N-terminal tail and CH domains of Ndc80 bind microtubules, and an internal domain binds microtubule-associated proteins (MAPs) such as the Dam1 complex. To determine how the microtubule- and MAP-binding domains of Ndc80 contribute to force production at the kinetochore in budding yeast, we have inserted a FRET tension sensor into the Ndc80 protein about halfway between its microtubule-binding and internal loop domains. The data support a mechanical model of force generation at metaphase where the position of the kinetochore relative to the microtubule plus end reflects the relative strengths of microtubule depolymerization, centromere stretch and microtubule-binding interactions with the Ndc80 and Dam1 complexes. PMID- 26974663 TI - Insights into the flexibility of ZrMxOy (M = Na, Mg, Al) nanofibrous membranes as promising infrared stealth materials. AB - A surprising brittle to flexible transition in ZrMxOy (M = Na, Mg, Al) nanofibrous membranes was found by varying the undersized dopant species and content. The fiber morphology, crystalline structure, and pore structure of the ZrMxOy nanofibrous membranes can be significantly modulated by varying the dopant valence from +1 to 3 and the dopant content from 1 to 20 mol%, respectively. Meanwhile, a classical Hall-Petch effect was revealed for the ZrMxOy nanofibrous membranes systems, which corresponded to a nanocrystalline size of 22.8 nm and an enhanced flexibility of 23 mN. Moreover, the substitutional solid solution and interstitial solid solution dissolution processes of Na, Mg, and Al into ZrO2 were analyzed using vacancy compensation and dopant interstitial compensation mechanisms, respectively. Most importantly, the flexible Al doped zirconia nanofibrous membranes exhibit a low infrared emissivity of 0.589 and 0.703 in the 3-5 MUm and 8-14 MUm wavebands, respectively, which suggests them to be a promising candidate for infrared stealth materials in the confrontation strategy field for personnel, aircraft, missiles, satellites, etc. PMID- 26974664 TI - Near-IR luminescent lanthanide complexes with 1,8-diaminoanthraquinone-based chromophoric ligands. AB - Three new chromophoric anthraquinone-based multidentate ligands have been synthesised in a step-wise manner from 1,8-dichloroanthraquinone. The ligands each comprise two dipicolyl amine units and react with trivalent lanthanide ions to form monometallic complexes of the form [Ln(L)](OTf)3 as indicated by MS studies and elemental analyses. Supporting DFT studies show that the monometallic species are highly favoured (>1000 kJ mol(-1)) over the formation of a 2 : 2 dimetallic congener. Both ligands and complexes absorb light efficiently (epsilon ~ 10(4) M(-1) cm(-1)) in the visible part of the spectrum, with lambdaabsca. 535 550 nm through an intramolecular charge transfer (ICT) transition localised on the substituted anthraquinone unit. In all cases the complexes show a fluorescence band at ca. 675 nm due to the ICT emitting state. The corresponding Nd(iii), Yb(iii) and Er(iii) complexes also reveal sensitised near-IR emission characteristic of each ion following excitation of the ICT visible absorption band at 535 nm. PMID- 26974661 TI - C/EBPalpha creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4. AB - Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) is typically inefficient and has been explained by elite-cell and stochastic models. We recently reported that B cells exposed to a pulse of C/EBPalpha (Balpha' cells) behave as elite cells, in that they can be rapidly and efficiently reprogrammed into iPSCs by the Yamanaka factors OSKM. Here we show that C/EBPalpha post-transcriptionally increases the abundance of several hundred proteins, including Lsd1, Hdac1, Brd4, Med1 and Cdk9, components of chromatin modifying complexes present at super-enhancers. Lsd1 was found to be required for B cell gene silencing and Brd4 for the activation of the pluripotency program. C/EBPalpha also promotes chromatin accessibility in pluripotent cells and upregulates Klf4 by binding to two haematopoietic enhancers. Balpha' cells share many properties with granulocyte/macrophage progenitors, naturally occurring elite cells that are obligate targets for leukaemic transformation, whose formation strictly requires C/EBPalpha. PMID- 26974662 TI - Godzilla-dependent transcytosis promotes Wingless signalling in Drosophila wing imaginal discs. AB - The apical and basolateral membranes of epithelia are insulated from each other, preventing the transfer of extracellular proteins from one side to the other. Thus, a signalling protein produced apically is not expected to reach basolateral receptors. Evidence suggests that Wingless, the main Drosophila Wnt, is secreted apically in the embryonic epidermis. However, in the wing imaginal disc epithelium, Wingless is mostly seen on the basolateral membrane where it spreads from secreting to receiving cells. Here we examine the apico-basal movement of Wingless in Wingless-producing cells of wing imaginal discs. We find that it is presented first on the apical surface before making its way to the basolateral surface, where it is released and allowed to interact with signalling receptors. We show that Wingless transcytosis involves dynamin-dependent endocytosis from the apical surface. Subsequent trafficking from early apical endosomes to the basolateral surface requires Godzilla, a member of the RNF family of membrane anchored E3 ubiquitin ligases. Without such transport, Wingless signalling is strongly reduced in this tissue. PMID- 26974665 TI - Involvement of Nitric Oxide on Bothropoides insularis Venom Biological Effects on Murine Macrophages In Vitro. AB - Viperidae venom has several local and systemic effects, such as pain, edema, inflammation, kidney failure and coagulopathy. Additionally, bothropic venom and its isolated components directly interfere on cellular metabolism, causing alterations such as cell death and proliferation. Inflammatory cells are particularly involved in pathological envenomation mechanisms due to their capacity of releasing many mediators, such as nitric oxide (NO). NO has many effects on cell viability and it is associated to the development of inflammation and tissue damage caused by Bothrops and Bothropoides venom. Bothropoides insularis is a snake found only in Queimada Grande Island, which has markedly toxic venom. Thus, the aim of this work was to evaluate the biological effects of Bothropoides insularis venom (BiV) on RAW 264.7 cells and assess NO involvement. The venom was submitted to colorimetric assays to identify the presence of some enzymatic components. We observed that BiV induced H2O2 production and showed proteolytic and phospholipasic activities. RAW 264.7 murine macrophages were incubated with different concentrations of BiV and then cell viability was assessed by MTT reduction assay after 2, 6, 12 and 24 hours of incubation. A time and concentration-dependent effect was observed, with a tendency to cell proliferation at lower BiV concentrations and cell death at higher concentrations. The cytotoxic effect was confirmed after lactate dehydrogenase (LDH) measurement in the supernatant from the experimental groups. Flow cytometry analyses revealed that necrosis is the main cell death pathway caused by BiV. Also, BiV induced NO release. The inhibition of both proliferative and cytotoxic effects with L-NAME were demonstrated, indicating that NO is important for these effects. Finally, BiV induced an increase in iNOS expression. Altogether, these results demonstrate that B. insularis venom have proliferative and cytotoxic effects on macrophages, with necrosis participation. We also suggest that BiV acts by inducing iNOS expression and causing NO release. PMID- 26974666 TI - Distinct Clinical Characteristics of Pediatric Guillain-Barre Syndrome: A Comparative Study between Children and Adults in Northeast China. AB - OBJECTIVE: Clinical characteristics of pediatric Guillain-Barre syndrome (GBS) have been extensively studied whereas scarcely been compared with those of adult GBS. Herein we compared the clinical features of GBS between pediatric and adult patients. METHODS: We retrospectively collected the clinical data of 750 patients with GBS (541 adults and 209 children), and compared the clinical characteristics between children and adults. RESULTS: Pain was a more frequent complaint in children (17.2% vs 9.6%, p < 0.01), who were also found with shorter interval from disease onset to nadir (6.3d vs 7.3d, p < 0.01) and higher incidence of bulbar dysfunction (22.0% vs 14.8%, p < 0.05). The disease severity in children was comparable with adults. In addition, a higher incidence of pediatric GBS was found in summer, especially in July and August (both p < 0.01). However, the incidence of antecedent infections of different seasons in adult and pediatric patients was comparable (p > 0.05). The clinical features of acute motor axonal neuropathy (AMAN) and acute inflammatory demyelinating polyneuropathy (AIDP) in children were overall comparable with adult ones (p > 0.05). Similar to adults, bulbar dysfunction (odds ratio [OR]: 4.621, 95% confidence interval [CI]: 1.240 17.218, p < 0.05) and lower nadir Medical Research Council (MRC) sum score (OR: 0.897, 95% CI: 0.855-0.941, p < 0.01) were also risk factors for mechanical ventilation in children. However, distinct from adult ones, autonomic dysfunction was significantly higher in mechanically ventilated childhood GBS (39.1% vs 8.8%, p < 0.01), which also served as a predictor for mechanical ventilation in pediatric GBS (OR: 70.415, 95% CI: 9.265-535.158, p < 0.01). As to the efficacy of intravenous immunoglobulin, insignificant difference was identified between children and adults. CONCLUSION: The clinical features of pediatric GBS differ from those of adults. Autonomic dysfunction is an independent risk factor for mechanical ventilation in pediatric patients. PMID- 26974667 TI - Toxoplasma gondii Infection in Seagull Chicks Is Related to the Consumption of Freshwater Food Resources. AB - Understanding the spread of Toxoplasma gondii (T. gondii) in wild birds, particularly in those with opportunistic feeding behavior, is of interest for elucidating the epidemiological involvement of these birds in the maintenance and dissemination of the parasite. Overall, from 2009 to 2011, we collected sera from 525 seagull chicks (Yellow-legged gull (Larus michahellis) and Audouin's gull (L. audouinii)) from 6 breeding colonies in Spain and tested them using the modified agglutination test (MAT) for the presence of antibodies against T. gondii. Chick age was estimated from bill length. Main food source of seagull chicks was evaluated using stable isotope analyses from growing scapular feathers. Overall T. gondii seroprevalence was 21.0% (IC95% 17.5-24.4). A generalized linear mixed effects model indicated that year (2009) and food source (freshwater) were risk factors associated to the individual risk of infection by T. gondii, while age (days) was close to significance. Freshwater food origin was related to the highest seroprevalence levels, followed by marine origin, supporting freshwater and sewages as important routes of dispersion of T. gondii. Year differences could indicate fluctuating rates of exposure of seagull chicks to T. gondii. Age ranged from 4 to 30 days and seropositivity tended to increase with age (P = 0.07), supporting that seropositivity is related to T. gondii infection rather than to maternal transfer of antibodies, which in gulls is known to sharply decrease with chick age. This study is the first to report T. gondii antibodies in Yellow-legged and Audouin's gulls, thereby extending the range of intermediate hosts for this parasite and underscoring the complexity of its epidemiology. PMID- 26974668 TI - Effect of Aminated Mesoporous Bioactive Glass Nanoparticles on the Differentiation of Dental Pulp Stem Cells. AB - Mesoporous bioactive nanoparticles (MBNs) have been developed as promising additives to various types of bone or dentin regenerative material. However, biofunctionality of MBNs as dentin regenerative additive to dental materials have rarely been studied. We investigated the uptake efficiency of MBNs-NH2 with their endocytosis pathway and the role of MBNs-NH2 in odontogenic differentiation to clarify inherent biofunctionality. MBNs were fabricated by sol-gel synthesis, and 3% APTES was used to aminate these nanoparticles (MBNs-NH2) to reverse their charge from negative to positive. To characterize the MBNs-NH2, TEM, XRD, FTIR, zeta(xi)-potential measurements, and Brunauer-Emmett-Teller analysis were performed. After primary cultured rat dental pulp stem cells (rDPSCs) were incubated with various concentrations of MBNs-NH2, stem cell viability (24 hours) with or without differentiated media, internalization of MBNs-NH2 in rDPSCs (~4 hours) via specific endocytosis pathway, intra or extracellular ion concentration and odontoblastic differentiation (~28 days) were investigated. Incubation with up to 50 MUg/mL of MBNs-NH2 had no effect on rDPSCs viability with differentiated media (p>0.05). The internalization of MBNs-NH2 in rDPSCs was determined about 92% after 4 hours of incubation. Uptake was significantly decreased with ATP depletion and after 1 hour of pre-treatment with the inhibitor of macropinocytosis (p<0.05). There was significant increase of intracellular Ca and Si ion concentration in MBNs-NH2 treated cells compared to no-treated counterpart (p<0.05). The expression of odontogenic-related genes (BSP, COL1A, DMP-1, DSPP, and OCN) and the capacity for biomineralization (based on alkaline phosphatase activity and alizarin red staining) were significantly upregulated with MBNs-NH2. These results indicate that MBNs-NH2 induce odontogenic differentiation of rDPSCs and may serve as a potential dentin regenerative additive to dental material for promoting odontoblast differentiation. PMID- 26974669 TI - Recombination-Mediated Telomere Maintenance in Saccharomyces cerevisiae Is Not Dependent on the Shu Complex. AB - In cells lacking telomerase, telomeres shorten progressively during each cell division due to incomplete end-replication. When the telomeres become very short, cells enter a state that blocks cell division, termed senescence. A subset of these cells can overcome senescence and maintain their telomeres using telomerase independent mechanisms. In Saccharomyces cerevisiae, these cells are called 'survivors' and are dependent on Rad52-dependent homologous recombination and Pol32-dependent break-induced replication. There are two main types of survivors: type I and type II. The type I survivors require Rad51 and maintain telomeres by amplification of subtelomeric elements, while the type II survivors are Rad51 independent, but require the MRX complex and Sgs1 to amplify the C1-3A/TG1-3 telomeric sequences. Rad52, Pol32, Rad51, and Sgs1 are also important to prevent accelerated senescence, indicating that recombination processes are important at telomeres even before the formation of survivors. The Shu complex, which consists of Shu1, Shu2, Psy3, and Csm2, promotes Rad51-dependent homologous recombination and has been suggested to be important for break-induced replication. It also promotes the formation of recombination intermediates that are processed by the Sgs1-Top3-Rmi1 complex, as mutations in the SHU genes can suppress various sgs1, top3, and rmi1 mutant phenotypes. Given the importance of recombination processes during senescence and survivor formation, and the involvement of the Shu complex in many of the same processes during DNA repair, we hypothesized that the Shu complex may also have functions at telomeres. Surprisingly, we find that this is not the case: the Shu complex does not affect the rate of senescence, does not influence survivor formation, and deletion of SHU1 does not suppress the rapid senescence and type II survivor formation defect of a telomerase-negative sgs1 mutant. Altogether, our data suggest that the Shu complex is not important for recombination processes at telomeres. PMID- 26974670 TI - Survival Outcomes According to Adjuvant Treatment and Prognostic Factors Including Host Immune Markers in Patients with Curatively Resected Ampulla of Vater Cancer. AB - BACKGROUND: Ampulla of Vater cancer (AoV Ca) is a rare tumor, and its adjuvant treatment has not been established. The purpose of this study was to find out prognostic factors including host immunity and role of adjuvant treatment in AoV Ca. METHODS AND FINDINGS: We reviewed 227 AoV Ca patients with curative resection. Clinical characteristics, adjuvant treatment, disease-free survival (DFS) and overall survival (OS) were analyzed. Among all patients, 63.9, 36.1 and 33.9% had T1/T2, T3/T4 stage and lymph node-positive disease (LN+), respectively. OS of all patients was 90.9 months (95% CI: 52.9-129.0). OS was different according to neutrophil-to-lymphocyte ratio (HR 1.651, 95% CI: 1.11-2.47), platelet-to-lymphocyte ratio (HR 1.488, 95% CI: 1.00-2.21) and systemic inflammatory index (HR 1.669, 95% CI: 1.13-2.47). In multivariate analysis, adverse prognostic factors for OS included vascular invasion (HR 2.571, 95% CI: 1.20-5.53) and elevated CA 19-9 (HR 1.794, 95% CI: 1.07-3.05). A total of 104 patients (46.3%) received adjuvant treatment (25 out of 111of T1/T2 & LN (-), 79 out of 116 of T3/T4 or LN (+)). In T3/T4 or LN (+) stage, adjuvant CCRT with maintenance chemotherapy provided the longest OS (5-year OS rate: 47.0 vs. 41.4%). CONCLUSIONS: Vascular invasion and elevated CA 19-9 were adverse prognostic factors in resected AoV Ca. In T3/T4 or LN (+) stage, adjuvant CCRT with maintenance chemotherapy provided the best survival outcome. Adjuvant treatment should be further defined in AoV Ca, especially with poor prognostic factors. PMID- 26974671 TI - Abnormal Hypermethylation at Imprinting Control Regions in Patients with S Adenosylhomocysteine Hydrolase (AHCY) Deficiency. AB - S-adenosylhomocysteine hydrolase (AHCY) deficiency is a rare autosomal recessive disorder in methionine metabolism caused by mutations in the AHCY gene. Main characteristics are psychomotor delay including delayed myelination and myopathy (hypotonia, absent tendon reflexes etc.) from birth, mostly associated with hypermethioninaemia, elevated serum creatine kinase levels and increased genome wide DNA methylation. The prime function of AHCY is to hydrolyse and efficiently remove S-adenosylhomocysteine, the by-product of transmethylation reactions and one of the most potent methyltransferase inhibitors. In this study, we set out to more specifically characterize DNA methylation changes in blood samples from patients with AHCY deficiency. Global DNA methylation was increased in two of three analysed patients. In addition, we analysed the DNA methylation levels at differentially methylated regions (DMRs) of six imprinted genes (MEST, SNRPN, LIT1, H19, GTL2 and PEG3) as well as Alu and LINE1 repetitive elements in seven patients. Three patients showed a hypermethylation in up to five imprinted gene DMRs. Abnormal methylation in Alu and LINE1 repetitive elements was not observed. We conclude that DNA hypermethylation seems to be a frequent but not a constant feature associated with AHCY deficiency that affects different genomic regions to different degrees. Thus AHCY deficiency may represent an ideal model disease for studying the molecular origins and biological consequences of DNA hypermethylation due to impaired cellular methylation status. PMID- 26974673 TI - Knowledge of Sub-Types Important to Understanding of the Prevalence of Myotonic Dystrophy. PMID- 26974672 TI - Next Generation Mapping of Enological Traits in an F2 Interspecific Grapevine Hybrid Family. AB - In winegrapes (Vitis spp.), fruit quality traits such as berry color, total soluble solids content (SS), malic acid content (MA), and yeast assimilable nitrogen (YAN) affect fermentation or wine quality, and are important traits in selecting new hybrid winegrape cultivars. Given the high genetic diversity and heterozygosity of Vitis species and their tendency to exhibit inbreeding depression, linkage map construction and quantitative trait locus (QTL) mapping has relied on F1 families with the use of simple sequence repeat (SSR) and other markers. This study presents the construction of a genetic map by single nucleotide polymorphisms identified through genotyping-by-sequencing (GBS) technology in an F2 mapping family of 424 progeny derived from a cross between the wild species V. riparia Michx. and the interspecific hybrid winegrape cultivar, 'Seyval'. The resulting map has 1449 markers spanning 2424 cM in genetic length across 19 linkage groups, covering 95% of the genome with an average distance between markers of 1.67 cM. Compared to an SSR map previously developed for this F2 family, these results represent an improved map covering a greater portion of the genome with higher marker density. The accuracy of the map was validated using the well-studied trait berry color. QTL affecting YAN, MA and SS related traits were detected. A joint MA and SS QTL spans a region with candidate genes involved in the malate metabolism pathway. We present an analytical pipeline for calling intercross GBS markers and a high-density linkage map for a large F2 family of the highly heterozygous Vitis genus. This study serves as a model for further genetic investigations of the molecular basis of additional unique characters of North American hybrid wine cultivars and to enhance the breeding process by marker-assisted selection. The GBS protocols for identifying intercross markers developed in this study can be adapted for other heterozygous species. PMID- 26974674 TI - Elaborative retrieval: Do semantic mediators improve memory? AB - The elaborative retrieval account of retrieval-based learning proposes that retrieval enhances retention because the retrieval process produces the generation of semantic mediators that link cues to target information. We tested 2 assumptions that form the basis of this account: that semantic mediators are more likely to be generated during retrieval than during restudy and that the generation of mediators facilitates later recall of targets. Although these assumptions are often discussed in the context of retrieval processes, we noted that there was little prior empirical evidence to support either assumption. We conducted a series of experiments to measure the generation of mediators during retrieval and restudy and to examine the effect of the generation of mediators on later target recall. Across 7 experiments, we found that the generation of mediators was not more likely during retrieval (and may be more likely during restudy), and that the activation of mediators was unrelated to subsequent free recall of targets and was negatively related to cued recall of targets. The results pose challenges for both assumptions of the elaborative retrieval account. (PsycINFO Database Record PMID- 26974675 TI - The Role of Bias by Emergency Department Providers in Care for American Indian Children. AB - BACKGROUND: American Indian children have high rates of emergency department (ED) use and face potential discrimination in health care settings. OBJECTIVE: Our goal was to assess both implicit and explicit racial bias and examine their relationship with clinical care. RESEARCH DESIGN: We performed a cross-sectional survey of care providers at 5 hospitals in the Upper Midwest. Questions included American Indian stereotypes (explicit attitudes), clinical vignettes, and the Implicit Association Test. Two Implicit Association Tests were created to assess implicit bias toward the child or the parent/caregiver. Differences were assessed using linear and logistic regression models with a random effect for study site. RESULTS: A total of 154 care providers completed the survey. Agreement with negative American Indian stereotypes was 22%-32%. Overall, 84% of providers had an implicit preference for non-Hispanic white adults or children. Older providers (50 y and above) had lower implicit bias than those middle aged (30-49 y) (P=0.01). American Indian children were seen as increasingly challenging (P=0.04) and parents/caregivers less compliant (P=0.002) as the proportion of American Indian children seen in the ED increased. Responses to the vignettes were not related to implicit or explicit bias. CONCLUSIONS: The majority of ED care providers had an implicit preference for non-Hispanic white children or adults compared with those who were American Indian. Provider agreement with negative American Indian stereotypes differed by practice and respondents' characteristics. These findings require additional study to determine how these implicit and explicit biases influence health care or outcomes disparities. PMID- 26974676 TI - Are Older Adults With Hip Fractures Disadvantaged in Level 1 Trauma Centers? AB - BACKGROUND: Large regional hospitals achieve good outcomes for patients with complex conditions. However, recent studies have suggested that some patient groups might not benefit from treatment in higher-level trauma centers. OBJECTIVE: To test the hypothesis that older adults with isolated hip fractures experience delayed surgical treatment and worse clinical outcomes when treated in higher-level trauma centers. RESEARCH DESIGN: Retrospective cohort study using a statewide longitudinal database that captured 98% of inpatients within California (2007-2011). SUBJECTS: All older adults (aged 65 y and above) admitted with an isolated hip fracture who did not require interhospital transfer. MEASURES: Days to operation, length of stay, inhospital mortality, 30-day risk of unplanned readmission, 30-day venous thromboembolism, decubitus ulcers, and pneumonia. RESULTS: There were 91,401 patients, 6.1% of whom were treated in a level 1 trauma center (L1TC), 17.7% in a level 2 trauma center (L2TC), and 70.2% in a nontrauma center (NTC). Within multivariable logistic and generalized linear regression models, patients treated in L1TCs underwent surgery later (predicted mean difference: 0.30 d; 95% CI, 0.08-0.53), had prolonged inpatient stays (0.99 d, 0.40-1.59), and had higher odds of both 30-day readmission (aOR=1.62; 95% CI, 1.35-1.93) and venous thromboembolism (aOR=1.32, 1.01-1.74) relative to NTCs. There were no differences in mortality, decubitus ulcers, or pneumonias. L2TCs were not different from NTCs across any of the measured outcomes. CONCLUSIONS: Older adults with hip fractures may be disadvantaged in L1TCs. Further research should aim to develop our understanding of this disparity to ensure that all patient groups benefit from the resources and expertise available within these hospitals. PMID- 26974677 TI - Income Inequities and Medicaid Expansion are Related to Racial and Ethnic Disparities in Delayed or Forgone Care Due to Cost. AB - BACKGROUND: Monitoring political and social determinants of delayed or forgone care due to cost is necessary to evaluate efforts to reduce racial and ethnic disparities in access to care. Our objective was to examine the extent to which state Medicaid expansion decisions and personal household income may be associated with individual-level racial and ethnic disparities in delayed or forgone care due to cost, at baseline, before the implementation of the Affordable Care Act. METHODS: We used 2012 Behavioral Risk Factor Surveillance System survey data to examine racial and ethnic differences in delayed or forgone care due to cost in states that do and do not plan Medicaid expansion. We examined personal household income as a social factor that could contribute to racial and ethnic disparities in delayed or forgone care. RESULTS: We found that personal income differences were strongly related to disparities in delayed or forgone care in places with and without plans to expand Medicaid. In addition, while delayed or forgone care disparities between non-Hispanic whites and non Hispanic blacks were lowest in places with plans to expand Medicaid access, disparities between non-Hispanic whites and Hispanics did not differ by state Medicaid expansion plans. CONCLUSIONS: As access to insurance improves for diverse groups, health systems must develop innovative strategies to overcome social determinants of health, including income inequities, as barriers to accessing care for Hispanic and non-Hispanic blacks. Additional efforts may be needed to ensure Hispanic groups achieve the benefits of investments in health care access. PMID- 26974679 TI - The Use of Enhanced Appointment Access Strategies by Medical Practices. AB - BACKGROUND: Strategies to enhance appointment access are being adopted by medical practices as part of patient-centered medical home (PCMH) implementation, but little is known about the use of these strategies nationally. OBJECTIVES: We examine practice use of open access scheduling and after-hours care. RESEARCH DESIGN: Data were analyzed from the Third National Study of Physician Organizations (NSPO3) to examine which enhanced appointment access strategies are more likely to be used by practices with more robust PCMH capabilities and with greater external incentives. Logistic regression estimated the effect of PCMH capabilities and external incentives on practice use of open access scheduling and after-hours care. SUBJECTS: Physician organizations with >20% primary care physicians (n=1106). MEASURES: PCMH capabilities included team-based care, health information technology capabilities, quality improvement orientation, and patient experience orientation. External incentives included public reporting, pay-for performance (P4P), and accountable care organization participation. RESULTS: A low percentage of practices (19.8%) used same-day open access scheduling, while after-hours care (56.1%) was more common. In adjusted analyses, system-owned practices and practices with greater use of team-based care, health information technology capabilities, and public reporting were more likely to use open access scheduling. Accountable care organization-affiliated practices and practices with greater use of public reporting and P4P were more likely to provide after-hours care. CONCLUSIONS: Open access scheduling may be most effectively implemented by practices with robust PCMH capabilities. External incentives appear to influence practice adoption of after-hours care. Expanding open access scheduling and after hours care will require distinct policies and supports. PMID- 26974678 TI - Health Care Use, Health Behaviors, and Medical Conditions Among Individuals in Same-Sex and Opposite-Sex Partnerships: A Cross-Sectional Observational Analysis of the Medical Expenditures Panel Survey (MEPS), 2003-2011. AB - BACKGROUND: Prior research documents disparities between sexual minority and nonsexual minority individuals regarding health behaviors and health services utilization. However, little is known regarding differences in the prevalence of medical conditions. OBJECTIVES: To examine associations between sexual minority status and medical conditions. RESEARCH DESIGN: We conducted multiple logistic regression analyses of the Medical Expenditure Panel Survey (2003-2011). We identified individuals who reported being partnered with an individual of the same sex, and constructed a matched cohort of individuals in opposite-sex partnerships. SUBJECTS: A total of 494 individuals in same-sex partnerships and 494 individuals in opposite-sex partnerships. MEASURES: Measures of health risk (eg, smoking status), health services utilization (eg, physician office visits), and presence of 15 medical conditions (eg, cancer, diabetes, arthritis, HIV, alcohol disorders). RESULTS: Same-sex partnered men had nearly 4 times the odds of reporting a mood disorder than did opposite-sex partnered men [adjusted odds ratio (aOR)=3.96; 95% confidence interval (CI), 1.85-8.48]. Compared with opposite-sex partnered women, same-sex partnered women had greater odds of heart disease (aOR=2.59; 95% CI, 1.19-5.62), diabetes (aOR=2.75; 95% CI, 1.10-6.90), obesity (aOR=1.92; 95% CI, 1.26-2.94), high cholesterol (aOR=1.89; 95% CI, 1.03 3.50), and asthma (aOR=1.90; 95% CI, 1.02-1.19). Even after adjusting for sociodemographics, health risk behaviors, and health conditions, individuals in same-sex partnerships had 67% increased odds of past-year emergency department utilization and 51% greater odds of >=3 physician visits in the last year compared with opposite-sex partnered individuals. CONCLUSIONS: A combination of individual-level, provider-level, and system-level approaches are needed to reduce disparities in medical conditions and health care utilization among sexual minority individuals. PMID- 26974680 TI - Hospital Readmission and Length of Stay Over Time in Patients Undergoing Major Cardiovascular and Orthopedic Surgery: A Tale of 2 States. AB - BACKGROUND: Readmission and length of stay (LOS) are increasingly accepted as quality measures for surgical care. Centers for Medicare & Medicaid Services will soon assess penalties for excessive readmissions after coronary artery bypass graft (CABG) surgery and hip and knee replacements. OBJECTIVE: To determine and compare population level changes in LOS and relationship with 30-day readmission over time for patients undergoing CABG and hip and knee replacements. Secondary objective was to determine relationship between LOS and discharge disposition as well as mortality. RESEARCH DESIGN: Observational cohort study of patients undergoing CABG and hip and knee replacements in New York and California. Temporal trends in LOS, discharge disposition, 30-day readmission, and mortality were examined. Generalized linear-mixed models, accounting for hospital clustering, were used to assess differences in outcomes. SUBJECTS: Patients undergoing CABG and hip and knee replacements in New York and California between 2005 and 2011. MEASURES: Trends in LOS, discharge disposition, 30-day readmission and mortality, and risk-adjusted odds of all-cause 30-day readmission. RESULTS: We identified 206,784, 336,271, and 416,391 patients who underwent CABG, hip, and knee replacements, respectively, in New York State and California between 2005 and 2011. The risks of readmission within 30 days decreased over time in both states. LOS decreased by 1 day after hip and knee surgery and remained unchanged after CABG. Adjusted analysis confirmed these trends. In secondary analyses patients in New York had higher overall odds of 30-day readmission compared with patients in California. CONCLUSIONS: We found no evidence of inverse relationship between LOS and readmission over time. In hip and knee replacement there is strong evidence that both LOS and readmission have been reduced simultaneously. PMID- 26974681 TI - Distribution of circulating cardiac biomarkers in healthy children: from birth through adulthood. AB - AIM: While circulating biomarkers are critical tools for cardiovascular adult care, their relevance in childhood is unknown. METHODS: We evaluated the behavior of plasma concentrations of clinically relevant cardiac biomarkers (NT-proBNP, hs cTnI, sST2, Galectin-3) in 106 healthy children. RESULTS: Subjects were divided into age subgroups: 24 newborns (0-30 days), 26 infants (1-12 months), 30 children (1-12 years) and 26 adolescents (13-18 years). Healthy adults were used as control. NT-proBNP (newborns: 504.3 [211.07-942.7] ng/L, median [25-75 percentiles]; infants: 200.64 [76.88-306.73]; children: 97.27 [49.24-271.80]; adolescents: 24.35 [13.14-58.83]; p < 0.001) and hs-cTnI (newborns: 9.3 [3.3 93.8] ng/L; infants: 13.8 [4.82-72.52]; children: 11.45 [4.0-48.10]; adolescents: 2.6[2.07-3.90]; p < 0.001) were highest in the first month of life, showing a decline in the next years. sST2 and Galectin-3 showed no differences. CONCLUSION: Changes in hs-cTnI and NT-proBNP suggest the design of age- and sex-based reference intervals that will have to be explored in a larger population. PMID- 26974682 TI - The Importance of Leisure Activities in the Relationship between Physical Health and Well-Being in a Life Span Sample. AB - BACKGROUND: Previous studies have examined the relationships between physical health and leisure activities and between leisure activities and well-being, but, to our knowledge, none has examined these relationships simultaneously. OBJECTIVE: This study investigated the relationships between leisure activities, health and well-being considering the role of age, and whether leisure activities mediate the relationship between physical health and well-being. METHODS: Utilizing a cross-sectional database of 259 adults (ages 18-81 years) who completed several questionnaires, linear regression models and mediation models were tested. RESULTS: Regression analyses indicated that physical health was related to leisure activities and leisure activities were related to well-being. When physical health was measured by subjective ratings, age had a stronger relationship with leisure activities. However, when physical health was indicated by health restrictions, physical health had a stronger relationship with leisure activities than did age. Leisure activities were a partial mediator of the relationship between physical health and well-being. CONCLUSION: The results demonstrated that the reduction in leisure activities with age has more to do with physical health limitations than with older age itself. In addition, regardless of age, the benefits of physical health for well-being are due in part to the level of leisure activity participation. These results highlight the importance of leisure activities for successful aging throughout the adult life span. Interventions designed to improve well-being through increasing leisure activity participation should take physical health into consideration, particularly for older adults. PMID- 26974684 TI - New outcomes of Lewis base addition to diboranes(4): electronic effects override strong steric disincentives. AB - Two surprising new outcomes of the reaction of Lewis bases with dihalodiboranes(4) are presented, including sp(2)-sp(3) diboranes in which the Lewis base unit is bound to a highly sterically congested boron atom, and a rearranged double base adduct. The results provide a fuller understanding of the reactivity of diboranes, a poorly-understood class of molecule of critical importance to synthetic organic chemistry. PMID- 26974686 TI - Sitting Phases of Polymerizable Amphiphiles for Controlled Functionalization of Layered Materials. AB - Precisely tailoring surface chemistry of layered materials is a growing need for fields ranging from electronics to biology. For many applications, the need for noncovalently adsorbed ligands to simultaneously control interactions with a nonpolar substrate and a polar solvent is a particular challenge. However, biology routinely addresses a similar challenge in the context of the lipid bilayer. While conventional standing phases of phospholipids (such as those found in a bilayer) would not provide spatially ordered interactions with the substrate, here we demonstrate formation of a sitting phase of polymerizable phospholipids, in which the two alkyl chains extend along the surface and the two ionizable functionalities (a phosphate and an amine) sit adjacent to the substrate and project into the solvent, respectively. Interfacial ordering and polymerization are assessed by high-resolution scanning probe measurements. Water contact angle titrations demonstrate interfacial pKa shifts for the lipid phosphate but not for the amine, supporting localization of the phosphate near the nonpolar graphite surface. PMID- 26974685 TI - Histopathological, oxidative damage, biochemical, and genotoxicity alterations in hepatic rats exposed to deltamethrin: modulatory effects of garlic (Allium sativum). AB - Deltamethrin is a pesticide widely used as a synthetic pyrethroid. The aim of this study was undertaken to investigate the effects of deltamethrin to induce oxidative stress and changes in biochemical parameters, hepatotoxicity and genotoxicity in female rats following a short-term (30 days) oral exposure and attenuation of these effects by Allium sativum extract. Indeed, Allium sativum is known to be a good antioxidant food resource which helps destroy free radical particles. Our results showed that deltamethrin treatment caused an increase in liver enzyme activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH); and hepatic lipid peroxidation (LPO) level. However, it induced a decrease in activities of hepatic catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) (p < 0.01). Allium sativum extract normalized significantly (p < 0.01) the mentioned parameters in deltamethrin-treated rats. For genotoxic evaluation, deltamethrin treatment showed a significant increase in frequencies of micronucleus in bone-marrow cells. Micronucleus formation is an indicator of chromosomal damage which has been increasingly used to detect the genotoxic potential of environmental pests. The present study showed that Allium sativum diminished the adverse effects induced by this synthetic pyrethroid insecticide. PMID- 26974688 TI - Correction to "Synthesis and Study of 7,12,17-Trioxa[11]helicene". PMID- 26974689 TI - Characteristics and Prevalence of Asthma/Chronic Obstructive Pulmonary Disease Overlap in the United States. AB - RATIONALE: The asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) occurs in patients with fixed airway obstruction that defines COPD and with symptoms more typical of asthma. ACOS prevalence and the comorbidities associated with this syndrome have been inadequately characterized. OBJECTIVES: Because this population is prone to more frequent exacerbations, we hypothesized that comorbidities associated with ACOS are higher than those with COPD, asthma, and control populations in the United States. METHODS: We examined the self-reported demographics, smoking status, comorbidities, and hospitalization or emergency department (ED) visitation experience among study respondents older than 35 years of age (n = 90,851) in the Behavioral Risk Factor Surveillance System survey and compared participants with ACOS to COPD, asthma, and control groups. We used logistic regression to compare ACOS and COPD populations to model the impact of comorbid conditions and hospitalization/ED visits after adjusting for demographic factors and smoking status to generate odds ratios and confidence intervals. MEASUREMENTS AND MAIN RESULTS: The U.S. prevalence of ACOS was 3.2%, COPD alone was 6.0%, and both increased with age. Respondents with ACOS were younger (64.0 +/- 11.7 yr) than respondents with COPD (67.1 +/- 11.8 yr) and older than respondents with asthma (59.0 +/- 13.1 yr; P < 0.0001). The prevalence of comorbidities was higher in the group with ACOS and COPD than in asthma or control groups. The ACOS group had a higher body mass index, lower income, and lower education than other groups. The ACOS group was more likely to have at least one comorbidity (90.2 vs. 84%, P < 0.0001), more hospitalization or ED visits (22.0 vs. 13.2%, P < 0.0001), less exercise (50.0 vs. 58.6%, P = 0.0024), and more disability (70.8 vs. 58.6%, P < 0.0001) than the COPD group. CONCLUSIONS: The patients with a dual diagnosis of asthma and COPD are younger and with more disparities than those diagnosed with COPD alone. ACOS has a higher burden of self-reported comorbidity, disability, and hospitalization or ED visitation than COPD alone. PMID- 26974687 TI - Progression of nicotine dependence, mood level, and mood variability in adolescent smokers. AB - Mood processes are theorized to play a role in the initiation and progression of smoking behavior. Available work using real-time assessments in samples of young smokers, including several reports from the Social and Emotional Contexts of Adolescent Smoking Patterns (SECASP) study, has indicated that smoking events acutely improve mood and that escalating smoking frequency may stabilize mood. However, prior analyses have not specifically evaluated within-person change in nicotine dependence, which is conceptually distinguishable from frequent smoking and may be associated with unique mood consequences. The current investigation addressed this question using data from 329 adolescent SECASP participants (9th or 10th grade at recruitment) who contributed mood reports via ecological momentary assessment in up to four 1-week bursts over the course of 24 months. Mixed-effects location scale analyses revealed that within-person increases in scores on the Nicotine Dependence Syndrome Scale were associated with elevations in negative mood level and increased variability of both positive and negative moods. These effects remained when within-person changes in smoking frequency were covaried and were not fully attributable to a subgroup of youth who rapidly escalated their smoking frequency over time. The findings indicate that adolescents tend to show increasing levels of positive mood states, decreasing levels of negative mood, and diminishing mood variability between ages 16 to 18, but progression of nicotine dependence may counteract some of these developmental gains. Emergence of withdrawal symptoms is a likely explanation for the adverse mood effects associated with dependence progression. (PsycINFO Database Record PMID- 26974690 TI - On My Honor. PMID- 26974692 TI - Hybrid Organic-Inorganic Coordination Complexes as Tunable Optical Response Materials. AB - Novel lead and bismuth dipyrido complexes have been synthesized and characterized by single-crystal X-ray diffraction, which shows their structures to be directed by highly oriented pi-stacking of planar fully conjugated organic ligands. Optical band gaps are influenced by the identity of both the organic and inorganic component. Density functional theory calculations show optical excitation leads to exciton separation between inorganic and organic components. Using UV-vis, photoluminescence, and X-ray photoemission spectroscopies, we have determined the materials' frontier energy levels and show their suitability for photovoltaic device fabrication by use of electron- and hole-transport materials such as TiO2 and spiro-OMeTAD respectively. Such organic/inorganic hybrid materials promise greater electronic tunability than the inflexible methylammonium lead iodide structure through variation of both the metal and organic components. PMID- 26974691 TI - Antituberculosis Activity of a Naturally Occurring Flavonoid, Isorhamnetin. AB - Isorhamnetin (1) is a naturally occurring flavonoid having anticancer and anti inflammatory properties. The present study demonstrated that 1 had antimycobacterial effects on Mycobacterium tuberculosis H37Rv, multi-drug- and extensively drug-resistant clinical isolates with minimum inhibitory concentrations of 158 and 316 MUM, respectively. Mycobacteria mainly affect the lungs, causing an intense local inflammatory response that is critical to the pathogenesis of tuberculosis. We investigated the effects of 1 on interferon (IFN)-gamma-stimulated human lung fibroblast MRC-5 cells. Isorhamnetin suppressed the release of tumor necrosis factor (TNF)-alpha and interleukin (IL)-12. A nontoxic dose of 1 reduced mRNA expression of TNF-alpha, IL-1beta, IL-6, IL-12, and matrix metalloproteinase-1 in IFN-gamma-stimulated cells. Isorhamnetin inhibited IFN-gamma-mediated stimulation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase and showed high-affinity binding to these kinases (binding constants: 4.46 * 10(6) M(-1) and 7.6 * 10(6) M(-1), respectively). The 4'-hydroxy group and the 3'-methoxy group of the B-ring and the 5-hydroxy group of the A-ring of 1 play key roles in these binding interactions. A mouse in vivo study of lipopolysaccharide-induced lung inflammation revealed that a nontoxic dose of 1 reduced the levels of IL-1beta, IL-6, IL-12, and INF-gamma in lung tissue. These data provide the first evidence that 1 could be developed as a potent antituberculosis drug. PMID- 26974693 TI - Reversible Cerebral Vasoconstriction Syndrome or Posterior Reversible Encephalopathy Syndrome-Reply. PMID- 26974694 TI - MicroRNA deep sequencing reveals chamber-specific miR-208 family expression patterns in the human heart. AB - BACKGROUND: Heart chamber-specific mRNA expression patterns have been extensively studied, and dynamic changes have been reported in many cardiovascular diseases. MicroRNAs (miRNAs) are also important regulators of normal cardiac development and functions that generally suppress gene expression at the posttranscriptional level. Recent focus has been placed on circulating miRNAs as potential biomarkers for cardiac disorders. However, miRNA expression levels in human normal hearts have not been thoroughly studied, and chamber-specific miRNA expression signatures in particular remain unclear. METHODS AND RESULTS: We performed miRNA deep sequencing on human paired left atria (LA) and ventricles (LV) under normal physiologic conditions. Among 438 miRNAs, miR-1 was the most abundant in both chambers, representing 21% of the miRNAs in LA and 26% in LV. A total of 25 miRNAs were differentially expressed between LA and LV; 14 were upregulated in LA, and 11 were highly expressed in LV. Notably, the miR-208 family in particular showed prominent chamber specificity; miR-208a-3p and miR-208a-5p were abundant in LA, whereas miR-208b-3p and miR-208b-5p were preferentially expressed in LV. Subsequent real-time polymerase chain reaction analysis validated the predominant expression of miR-208a in LA and miR-208b in LV. CONCLUSIONS: Human atrial and ventricular tissues display characteristic miRNA expression signatures under physiological conditions. Notably, miR-208a and miR-208b show significant chamber specificity as do their host genes, alpha-MHC and beta-MHC, which are mainly expressed in the atria and ventricles, respectively. These findings might also serve to enhance our understanding of cardiac miRNAs and various heart diseases. PMID- 26974695 TI - Usefulness of sheathless guide catheter for the percutaneous coronary intervention of left main disease by radial approach. PMID- 26974696 TI - Does chemo-radiation predispose to structural valve deterioration? PMID- 26974697 TI - Similarities between the renal artery and pulmonary vein denervation trials: Do we have to use sham procedures for atrial fibrillation catheter ablation trials? PMID- 26974698 TI - Role of functional polymorphisms of the IL-10 gene promoter in the risk of ischemic stroke in Chinese Uyghur population: One case-control study. PMID- 26974700 TI - Tricuspid L and L' waves. PMID- 26974699 TI - Lack of IkappaBNS accelerates atherosclerosis in LDL receptor-deficient mice via increased interleukin-6 production. PMID- 26974701 TI - Atherosclerosis--do we know enough already to prevent it? AB - In this review, we have briefly summarized the characteristics of lipids and lipoproteins and the atherosclerotic process. The development of atherosclerosis is a continuous process that involves numerous cellular and acellular processes that influence the behavior of each other. These include oxidative stress, lipoprotein modifications, macrophage polarization, macrophage lipid accumulation, generation of pro- and anti-inflammatory components, calcification, cellular growth and proliferation, and plaque rupture. The precise role(s) of many of these are unknown. Understanding the events at each particular stage might shed more light onto the process as a whole and could potentially reveal targets for intervention. Therapeutic modalities that work at one stage may have little to no influence on other stages of the disease. PMID- 26974702 TI - Structure and Reactivity of X-ray Amorphous Uranyl Peroxide, U2O7. AB - Recent accidents resulting in worker injury and radioactive contamination occurred due to pressurization of uranium yellowcake drums produced in the western U.S.A. The drums contained an X-ray amorphous reactive form of uranium oxide that may have contributed to the pressurization. Heating hydrated uranyl peroxides produced during in situ mining can produce an amorphous compound, as shown by X-ray powder diffraction of material from impacted drums. Subsequently, studtite, [(UO2)(O2)(H2O)2](H2O)2, was heated in the laboratory. Its thermal decomposition produced a hygroscopic anhydrous uranyl peroxide that reacts with water to release O2 gas and form metaschoepite, a uranyl-oxide hydrate. Quantum chemical calculations indicate that the most stable U2O7 conformer consists of two bent (UO2)(2+) uranyl ions bridged by a peroxide group bidentate and parallel to each uranyl ion, and a MU2-O atom, resulting in charge neutrality. A pair distribution function from neutron total scattering supports this structural model, as do (1)H- and (17)O-nuclear magnetic resonance spectra. The reactivity of U2O7 in water and with water in air is higher than that of other uranium oxides, and this can be both hazardous and potentially advantageous in the nuclear fuel cycle. PMID- 26974703 TI - In vivo and in vitro evaluation of hydroxyapatite nanoparticle morphology on the acute inflammatory response. AB - Biomedical implants have been widely used in bone repair applications. However, nanosized degradation products from these implants could elicit an inflammatory reaction, which may lead to implant failure. It is well known that the size, chemistry, and charge of these nanoparticles can modulate this response, but little is known regarding the role that the particle's morphology plays in inducing inflammation. The present study aims to investigate the effect of hydroxyapatite nanoparticle (HANPs) morphology on inflammation, in-vitro and in vivo. Four distinct HANP morphologies were fabricated and characterized: long rods, dots, sheets, and fibers. Primary human polymorphonuclear cells (PMNCs), mononuclear cells (MNCs), and human dermal fibroblasts (hDFs) were exposed to HANPs and alterations in cell viability, morphology, apoptotic activity, and reactive oxygen species (ROS) production were evaluated, in vitro. PMNCs and hDFs experienced a 2-fold decrease in viability following exposure to fibers, while MNC viability decreased 5-fold after treatment with the dots. Additionally, the fibers stimulated an elevated ROS response in both PMNCs and MNCs, and the largest apoptotic behavior for all cell types. Furthermore, exposure to fibers and dots resulted in greater capsule thickness when implanted subcutaneously in mice. Collectively, these results suggest that nanoparticle morphology can significantly impact the inflammatory response. PMID- 26974704 TI - Integrated self-assembling drug delivery system possessing dual responsive and active targeting for orthotopic ovarian cancer theranostics. AB - Ovarian cancers are the leading cause for mortality among gynecologic malignancies with five-year survival rate less than 30%. The purpose of this study is to develop a redox and pH-sensitive self-assembling hyaluronic acid nanoparticle with active targeting peptide for anticancer drug delivery. Anti cancer drug is grafted onto hyaluronic acid (HA) via cis-aconityl linkage and disulfide bond to possess pH sensitivity and redox property, respectively. This conjugate is amphiphilic and can self-assemble into nanoparticle (NP) in aqueous solution. The results show that the nanoconjugate is successfully developed and the grafting ratio of cystamine (cys) is 17.8% with drug loading amount about 6.2% calculated by (1)H NMR spectra. The particle size is approximately 229.0 nm using dynamic light scatting measurement, and the morphology of nanoparticles is observed as spherical shape by transmission electron microscope. The pH and redox sensitivities are evaluated by changing either pH value or concentration of dithiothreitol in the medium. It is proved that the drug carrier is capable of achieving sustained controlled release of anti-cancer drug to 95% within 150 h. The intracellular uptake is observed by fluorescent microscope and the images show that conjugating luteinizing hormone-releasing hormone (LHRH) peptide can enhance specific uptake of nanoparticles by OVCAR-3 cancer cells; thus, resulting in inhibitory cell growth to less than 20% in 72 h in vitro. Orthotopic ovarian tumor model is also established to evaluate the therapeutic and diagnostic efficacy using non-invasive in vivo imaging system. The representative results demonstrate that LHRH-conjugated NPs possess a preferable tumor imaging capability and an excellent antitumor ability to almost 30% of original size in 20 days. PMID- 26974705 TI - Updating the Toxic Substances Control Act to Protect Human Health. PMID- 26974706 TI - X-ray Computed Tomographic Investigation of the Porosity and Morphology of Plasma Electrolytic Oxidation Coatings. AB - Plasma electrolytic oxidation (PEO) is of increasing interest for the formation of ceramic coatings on metals for applications that require diverse coating properties, such as wear and corrosion resistance, low thermal conductivity, and biocompatibility. Porosity in the coatings can have an important impact on the coating performance. However, the quantification of the porosity in coatings can be difficult due to the wide range of pore sizes and the complexity of the coating morphology. In this work, a PEO coating formed on titanium is examined using high resolution X-ray computed tomography (X-ray CT). The observations are validated by comparisons of surface views and cross-sectional views of specific coating features obtained using X-ray CT and scanning electron microscopy. The X ray CT technique is shown to be capable of resolving pores with volumes of at least 6 MUm(3). Furthermore, the shapes of large pores are revealed and a correlation is demonstrated between the locations of the pores, nodules on the coating surface, and depressions in the titanium substrate. The locations and morphologies of the pores, which constitute 5.7% of the coating volume, indicate that they are generated by release of oxygen gas from the molten coating. PMID- 26974707 TI - Chemoradiation in rectal squamous cell carcinoma: Bi-institutional case series. AB - BACKGROUND AND PURPOSE: Primary rectal squamous cell carcinoma (SCC) is an uncommon disease. Early reports stated that surgery is the most effective treatment. However, recent publications suggest conservative strategy with chemoradiation provides satisfactory results. PATIENTS AND METHODS: We have retrospectively studied the medical charts of 23 patients treated for a rectal SCC in two teaching hospitals in France between 1992 and 2013. Twenty-one patients received an exclusive chemoradiotherapy (CRT) and two a pre-operative CRT followed by a planned surgery. Patients received pelvic irradiation with a dose ranging from 36-45 Gy followed by a boost of 15-23 Gy. Twenty-two patients received a concurrent chemotherapy. RESULTS: After CRT, the rate of clinical complete response was 83%. With a median follow-up of 85 months, 5-year overall survival rate was 86%. Five patients presented with a relapse. The 5-year disease free survival rate was 81%. The 5-year colostomy-free survival rate was 65%. Three patients (13%) presented with grade III-IV late rectal toxicity. CONCLUSIONS: Although retrospective, this is the largest cohort of patients treated with CRT for a rectal SCC. Exclusive CRT could result in high local control rate and prolonged survival in rectal SCC patients with a high rate of organ preservation. PMID- 26974709 TI - Polymorphisms in double strand break repair related genes influence radiosensitivity phenotype in lymphocytes from healthy individuals. AB - BACKGROUND: A range of individual radiosensitivity observed in humans can influence individual's susceptibility toward cancer risk and radiotherapy outcome. Therefore, it is important to measure the variation in radiosensitivity and to identify the genetic factors influencing it. METHODS: By adopting a pathway specific genotype-phenotype design, we established the variability in cellular radiosensitivity by performing gamma-H2AX foci assay in healthy individuals. Further, we genotyped ten selected SNPs in candidate genes XRCC3 (rs861539), XRCC4 (rs1805377), XRCC5 (rs3835), XRCC6 (rs2267437), ATM (rs3218698, rs1800057), LIG4 (rs1805388), NBN (rs1805794), RAD51 (rs1801320) and PRKDC (rs7003908), and analysed their influence on observed variation in radiosensitivity. RESULTS: The rs2267437 polymorphisms in XRCC6 was associated (P=0.0326) with increased DSB induction while rs1805388 in LIG4 (P=0.0240) was associated with increased radioresistance. Further, multiple risk alleles decreased the DSB repair capacity in an additive manner. Polymorphisms in candidate DSB repair genes can act individually or in combination to the efficacy of DSB repair process, resulting in variation of cellular radiosensitivity. CONCLUSIONS: Current study suggests that gamma-H2AX assay may fulfil the role of a rapid and sensitive biomarker that can be used for epidemiological studies to measure variations in radiosensitivity. DSB repair gene polymorphisms can impact the formation and repair of DSBs. IMPACT: gamma-H2AX foci analysis as well as DSBs repair gene polymorphisms can be used to assess cellular radiosensitivity, which will be useful in population risk assessment, disease prediction, individualization of radiotherapy and also in setting the radiation protection standards. PMID- 26974710 TI - Building a Decision Support System for Inpatient Admission Prediction With the Manchester Triage System and Administrative Check-in Variables. AB - The usage of decision support tools in emergency departments, based on predictive models, capable of estimating the probability of admission for patients in the emergency department may give nursing staff the possibility of allocating resources in advance. We present a methodology for developing and building one such system for a large specialized care hospital using a logistic regression and an artificial neural network model using nine routinely collected variables available right at the end of the triage process.A database of 255.668 triaged nonobstetric emergency department presentations from the Ramon y Cajal University Hospital of Madrid, from January 2011 to December 2012, was used to develop and test the models, with 66% of the data used for derivation and 34% for validation, with an ordered nonrandom partition. On the validation dataset areas under the receiver operating characteristic curve were 0.8568 (95% confidence interval, 0.8508-0.8583) for the logistic regression model and 0.8575 (95% confidence interval, 0.8540-0. 8610) for the artificial neural network model. chi Values for Hosmer-Lemeshow fixed "deciles of risk" were 65.32 for the logistic regression model and 17.28 for the artificial neural network model. A nomogram was generated upon the logistic regression model and an automated software decision support system with a Web interface was built based on the artificial neural network model. PMID- 26974711 TI - Elvitegravir/Cobicistat/Tenofovir/Emtricitabine Penetration in the Cerebrospinal Fluid of Three HIV-Positive Patients. PMID- 26974708 TI - Management of desmoid tumours: A nationwide survey of labelled reference centre networks in France. AB - PURPOSE: The optimal management of rare tumours (i.e. from accurate diagnosis to management in reference centres) is a public health challenge. In 2009, the French National Cancer Institute (INCa) identified and financially supported the two expert networks for pathological and clinical diagnosis and management of soft tissue tumours. METHODS: The activities of both networks were prospectively collected using a nationwide database (rreps.org). Data describing the diagnosis management of 863 successive cases of desmoids tumours (DT) were prospectively collected from 2010 to 2013 and analysed. RESULTS: The number of confirmed DT constantly improved from January 2010 to December 2013 (from 173 to 273 cases per year); the expected incidence ranged from 132 to 330 cases/year. The rate of cases diagnosed with core-needle biopsies and CTNNB1 mutational status analysis increased from 30.6 to 40.7% and from 87.8 to 94.1%, respectively. The mean delay for pathological diagnosis confirmation constantly decreased from 107 to 47 d. Among the 846 adult patients, 414 (48.9%) patients were treated by reference centres. The rate of patients managed by reference centres constantly increased with time from 36.9 to 49.5% since 2010. The median management time of the referral centres constantly decreased from 440 to 67 d. CONCLUSION: The two expert networks worked synergistically and improved diagnosis modalities of rare desmoid tumours at a national level. The impact of management by expert networks on the outcome will be prospectively analysed in the future. PMID- 26974712 TI - Band structures of 4f and 5f materials studied by angle-resolved photoelectron spectroscopy. AB - Recent remarkable progress in angle-resolved photoelectron spectroscopy (ARPES) has enabled the direct observation of the band structures of 4f and 5f materials. In particular, ARPES with various light sources such as lasers (hnu ~ 7 eV) or high-energy synchrotron radiations (hnu >/~ 400 eV) has shed light on the bulk band structures of strongly correlated materials with energy scales of a few millielectronvolts to several electronvolts. The purpose of this paper is to summarize the behaviors of 4f and 5f band structures of various rare-earth and actinide materials observed by modern ARPES techniques, and understand how they can be described using various theoretical frameworks. For 4f-electron materials, ARPES studies of CeMIn5(M = Rh, Ir, and Co) and YbRh2Si2 with various incident photon energies are summarized. We demonstrate that their 4f electronic structures are essentially described within the framework of the periodic Anderson model, and that the band-structure calculation based on the local density approximation cannot explain their low-energy electronic structures. Meanwhile, electronic structures of 5f materials exhibit wide varieties ranging from itinerant to localized states. For itinerant U5f compounds such as UFeGa5, their electronic structures can be well-described by the band-structure calculation assuming that all U5f electrons are itinerant. In contrast, the band structures of localized U5f compounds such as UPd3 and UO2 are essentially explained by the localized model that treats U5f electrons as localized core states. In regards to heavy fermion U-based compounds such as the hidden-order compound URu2Si2, their electronic structures exhibit complex behaviors. Their overall band structures are generally well-explained by the band-structure calculation, whereas the states in the vicinity of EF show some deviations due to electron correlation effects. Furthermore, the electronic structures of URu2Si2 in the paramagnetic and hidden-order phases are summarized based on various ARPES studies. The present status of the field as well as possible future directions are also discussed. PMID- 26974713 TI - The cutting of cocaine and heroin: A critical review. AB - The illicit drug cutting represents a complex problem that requires the sharing of knowledge from addiction studies, toxicology, criminology and criminalistics. Therefore, cutting is not well known by the forensic community. Thus, this review aims at deciphering the different aspects of cutting, by gathering information mainly from criminology and criminalistics. It tackles essentially specificities of cocaine and heroin cutting. The article presents the detected cutting agents (adulterants and diluents), their evolution in time and space and the analytical methodology implemented by forensic laboratories. Furthermore, it discusses when, in the history of the illicit drug, cutting may take place. Moreover, researches studying how much cutting occurs in the country of destination are analysed. Lastly, the reasons for cutting are addressed. According to the literature, adulterants are added during production of the illicit drug or at a relatively high level of its distribution chain (e.g. before the product arrives in the country of destination or just after its importation in the latter). Their addition seems hardly justified by the only desire to increase profits or to harm consumers' health. Instead, adulteration would be performed to enhance or to mimic the illicit drug effects or to facilitate administration of the drug. Nowadays, caffeine, diltiazem, hydroxyzine, levamisole, lidocaine and phenacetin are frequently detected in cocaine specimens, while paracetamol and caffeine are almost exclusively identified in heroin specimens. This may reveal differences in the respective structures of production and/or distribution of cocaine and heroin. As the relevant information about cutting is spread across different scientific fields, a close collaboration should be set up to collect essential and unified data to improve knowledge and provide information for monitoring, control and harm reduction purposes. More research, on several areas of investigation, should be carried out to gather relevant information. PMID- 26974714 TI - Immunohistochemical detection of CD14 and combined assessment with CD32B and CD68 for wound age estimation. AB - Estimation of wound age is a major topic of study for forensic pathologists, but few markers exist that can indicate a specific period 1-5 days postinfliction, and a method to estimate wound age with high accuracy has not yet been established. This study examined CD14 as such a marker in mouse skin wounds of different ages (0min and 1, 2, 3, 5, 7, and 9 days) and in human subjects (group 1, 0-1 day; group 2, 1-5 days; group 3, >7 days) using Western blot analysis and/or immunohistochemical staining. In addition, we evaluated a combination of immunohistochemical markers in human skin wounds using transmembrane proteins, CD14, CD32B, and CD68, expressed on inflammatory cells. The expression of CD14 was detected only during 1-5 days postinfliction and, thus, the evaluation of CD14-expressing cells could specify wound age during 1-5 days postinfliction in mouse skin wounds. The ratio of samples assessed to be CD14(+) was significantly high in human skin wounds in group 2. Combined assessment using the three markers increased the specificity of diagnosis and shortened the range of wound age, compared with the assessment using a single marker. Our results indicate that CD14 may be a useful marker of wound age, 1-5 days postinfliction, and that combined assessment with CD14, CD32B, and CD68 may be a good method for the accurate estimation of wound age. PMID- 26974715 TI - Dynamic Parameter Identification of Subject-Specific Body Segment Parameters Using Robotics Formalism: Case Study Head Complex. AB - Accurate knowledge of body segment inertia parameters (BSIP) improves the assessment of dynamic analysis based on biomechanical models, which is of paramount importance in fields such as sport activities or impact crash test. Early approaches for BSIP identification rely on the experiments conducted on cadavers or through imaging techniques conducted on living subjects. Recent approaches for BSIP identification rely on inverse dynamic modeling. However, most of the approaches are focused on the entire body, and verification of BSIP for dynamic analysis for distal segment or chain of segments, which has proven to be of significant importance in impact test studies, is rarely established. Previous studies have suggested that BSIP should be obtained by using subject specific identification techniques. To this end, our paper develops a novel approach for estimating subject-specific BSIP based on static and dynamics identification models (SIM, DIM). We test the validity of SIM and DIM by comparing the results using parameters obtained from a regression model proposed by De Leva (1996, "Adjustments to Zatsiorsky-Seluyanov's Segment Inertia Parameters," J. Biomech., 29(9), pp. 1223-1230). Both SIM and DIM are developed considering robotics formalism. First, the static model allows the mass and center of gravity (COG) to be estimated. Second, the results from the static model are included in the dynamics equation allowing us to estimate the moment of inertia (MOI). As a case study, we applied the approach to evaluate the dynamics modeling of the head complex. Findings provide some insight into the validity not only of the proposed method but also of the application proposed by De Leva (1996, "Adjustments to Zatsiorsky-Seluyanov's Segment Inertia Parameters," J. Biomech., 29(9), pp. 1223-1230) for dynamic modeling of body segments. PMID- 26974716 TI - Unsupervised Quality Assessment of Mass Spectrometry Proteomics Experiments by Multivariate Quality Control Metrics. AB - Despite many technological and computational advances, the results of a mass spectrometry proteomics experiment are still subject to a large variability. For the understanding and evaluation of how technical variability affects the results of an experiment, several computationally derived quality control metrics have been introduced. However, despite the availability of these metrics, a systematic approach to quality control is often still lacking because the metrics are not fully understood and are hard to interpret. Here, we present a toolkit of powerful techniques to analyze and interpret multivariate quality control metrics to assess the quality of mass spectrometry proteomics experiments. We show how unsupervised techniques applied to these quality control metrics can provide an initial discrimination between low-quality experiments and high-quality experiments prior to manual investigation. Furthermore, we provide a technique to obtain detailed information on the quality control metrics that are related to the decreased performance, which can be used as actionable information to improve the experimental setup. Our toolkit is released as open-source and can be downloaded from https://bitbucket.org/proteinspector/qc_analysis/ . PMID- 26974717 TI - Compositional Analysis of Aerosols Using Calibration-Free Laser-Induced Breakdown Spectroscopy. AB - We demonstrate that the elemental composition of aerosols can be measured using laser-induced breakdown spectroscopy (LIBS) without any preliminary calibration with standard samples. Therefore, a nanosecond Nd:YAG laser beam was focused into a flux of helium charged with alumina aerosols of a few micrometers diameter. The emission spectrum of the laser-generated breakdown plasma was recorded with an echelle spectrometer coupled to a gated detector. The spectral features including emission from both the helium carrier gas and the Al2O3 aerosols were analyzed on the base of a partial local thermodynamic equilibrium. Thus, Boltzmann equilibrium distributions of population number densities were assumed for all plasma species except of helium atoms and ions. By analyzing spectra recorded for different delays between the laser pulse and the detector gate, it is shown that accurate composition measurements are only possible for delays <=1 MUs, when the electron density is large enough to ensure collisional equilibrium for the aerosol vapor species. The results are consistent with previous studies of calibration-free LIBS measurements of solid alumina and glass and promote compositional analysis of aerosols via laser-induced breakdown in helium. PMID- 26974720 TI - The Integration of Care for Mental Health, Substance Abuse, and Other Behavioral Health Conditions Into Primary Care. PMID- 26974721 TI - The Integration of Care for Mental Health, Substance Abuse, and Other Behavioral Health Conditions Into Primary Care. PMID- 26974722 TI - Breast Cancer Recommendation Statement From the U.S. Preventive Services Task Force. PMID- 26974724 TI - Web Exclusives. The Consult Guys--Homans Sign: A Sign of What? PMID- 26974726 TI - Review: Mammography screening reduces breast cancer mortality in women at average risk. PMID- 26974727 TI - Evidence-Based Guideline: ACR made 10 strong treatment recommendations for RA, but high-quality evidence was sparse. PMID- 26974728 TI - TDF-FTC before and after sex reduced HIV infection but increased GI, renal events in men who have sex with men. PMID- 26974729 TI - In chronic nonspecific neck pain, adding Alexander Technique lessons or acupuncture to usual care improved pain. PMID- 26974730 TI - Review: In obstructive sleep apnea, CPAP and mandibular devices do not differ for reducing blood pressure. PMID- 26974731 TI - Review: PCSK9 inhibitors reduce mortality but increase neurocognitive events in hypercholesterolemia. PMID- 26974732 TI - Review: Peripheral thermometers do not have clinically acceptable accuracy for measuring core body temperature. PMID- 26974733 TI - Restarting antithrombotics after GI bleeding was linked to better outcomes in patients with AF. PMID- 26974734 TI - Review: In patients with chest pain, risk scores better predict high risk for ACS than individual risk factors. PMID- 26974735 TI - In adults without CVD, the MESA score, including coronary artery calcium, predicted 10-y risk for CHD events. PMID- 26974736 TI - Solution-Liquid-Solid Synthesis, Properties, and Applications of One-Dimensional Colloidal Semiconductor Nanorods and Nanowires. AB - The solution-liquid-solid (SLS) and related solution-based methods for the synthesis of semiconductor nanowires and nanorods are reviewed. Since its discovery in 1995, the SLS mechanism and its close variants have provided a nearly general strategy for the growth of pseudo-one-dimensional nanocrystals. The various metallic-catalyst nanoparticles employed are summarized, as are the syntheses of III-V, II-VI, IV-VI, group IV, ternary, and other nanorods and nanowires. The formation of axial heterojunctions, core/shell nanowires, and doping are also described. The related supercritical-fluid-liquid-solid (SFLS), electrically controlled SLS, flow-based SLS, and solution-solid-solid (SSS) methods are discussed, and the crystallographic characteristics of the wires and rods grown by these methods are summarized. The presentation of optical and electronic properties emphasizes electronic structures, absorption cross sections, polarization anisotropies, and charge-carrier dynamics, including photoluminescence intermittency (blinking) and photoluminescence modulation by charges and electric fields. Finally, developing applications for the pseudo-one dimensional nanostructures in field-effect transistors, lithium-ion batteries, photocathodes, photovoltaics, and photodetection are discussed. PMID- 26974737 TI - The Burden of Inbox Notifications in Commercial Electronic Health Records. PMID- 26974738 TI - Tele-Nephrology: A Feasible Way to Improve Access to Care for Patients with Kidney Disease Who Reside in Underserved Areas. AB - BACKGROUND: The Miami VA Healthcare System serves veterans in three South Florida counties: Miami-Dade, Broward, and Monroe, with an estimated veteran population of 175,000. To overcome geographical barriers and facilitate the access to nephrology clinics, we implemented provider-patient tele-nephrology using secured videoconferencing. METHODS: A retrospective and descriptive study design was used to evaluate the effect of the tele-nephrology clinic intervention. Multiple clinical indicators were included in the analysis: blood pressure (BP) control, stabilization of the renal function, and electrolyte/metabolic control. One hundred one patients who were evaluated in the clinic between 2013 and 2015 were included in the analysis, and the indicators were collected retrospectively. RESULTS: One hundred one patients were included in the analysis, with 95% of patients being male (n = 96) and 5% female (n = 5). The mean age was 65.5 years. Fifty patients had chronic kidney disease (CKD) stage III (49.5%), 14 patients had CKD stage IV (13%), and 8 patients had CKD stage II (7.9%). A one-way analysis of variance between subjects was conducted and showed that the effect of the tele-nephrology clinic intervention on reducing BP was statistically significant (systolic BP less than 140 p value <0.0001). Renal function stabilized but the creatinine changes over time were not statistically significant (p value: 0.50). Potassium showed a significant improvement in this sample (p value: 0.0076). Phosphorous and bicarbonate did not show a statistically significant improvement (p value 0.79 and 0.91, respectively). CONCLUSION: With the tele-nephrology clinic intervention, we were able to effectively improve BP and stabilize renal function in patients with kidney disease who reside in underserved areas. PMID- 26974740 TI - What has health care reform meant for the field of psychiatric rehabilitation? AB - The year 2010 saw passage of an historic piece of legislation in Public Law 111 148, entitled the Patient Protection and Affordable Care Act or ACA (2010). Since that time, the ACA has contributed to a number of improvements to the U.S. health care system including a large decrease in the number of uninsured individuals, substantially expanded access to health care services, and relief of the burden of uncompensated care provided by hospitals and other health care organizations (Jost, 2015). Various analyses of the law's impact on people with mental illnesses suggest that there have been both positive and negative outcomes from the first five years of ACA implementation. In this editorial, we reflect on these impacts as well as their current and future effects on the field of psychiatric rehabilitation. (PsycINFO Database Record PMID- 26974739 TI - Wellness for life: A pilot of an interprofessional intervention to address metabolic syndrome in adults with serious mental illnesses. AB - OBJECTIVE: This paper evaluates a pilot multidisciplinary intervention intended to increase health-promoting behaviors and reduce the negative effects of metabolic syndrome disorders among persons with serious mental illnesses. Exercise, nutritional counseling, health literacy education, and peer wellness coaching were provided by allied health professionals and students. METHOD: Participants with serious mental illnesses were recruited from partial hospitalization and supported housing programs. Initially, there were 77 participants, with 64 completing the study measures. A single-group, pre-post design was used. They participated in an 8-week program (3 hr each week). Individuals set their own personal health goals and received the interprofessional set of allied health interventions. Body weight, body mass index (BMI), blood pressure, and several measures of physical strength and flexibility were collected. Paired t tests evaluate the statistical significance of possible changes. RESULTS: Average blood pressure decreased. Waist circumference decreased. Participants improved on measures of strength and flexibility as measured by the functional reach test, the half sit-up test, and the sit-to-stand test. Participants reported increased readiness to exercise and make dietary changes. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Significant improvements in metabolic syndrome risk factors, physical strength, and flexibility were found. Next steps include a longer intervention likely to further reduce metabolic syndrome risk factors. Future studies should include a comparison intervention group and a follow-up to see if gains are maintained. The study highlights the potential utility of psychiatric rehabilitation providers collaborating with other allied health practitioners to promote overall health. (PsycINFO Database Record PMID- 26974741 TI - The role of self-determination in mental health recovery. AB - TOPIC: This contribution describes a personal recovery journey and highlights the importance of growth and renewal of self-determination as a critical part of recovery from mental health challenges. PURPOSE: Five factors that foster the development of self-determination are highlighted and include access to information about treatment and rehabilitation options and resources, support from trusted others, exposure to mentors or coaches who have the lived experience of mental health challenges, willingness to experiment with various interventions and recovery strategies, and opportunities to be engaged in personally meaningful activities such as work, parenting, or teaching. SOURCES USED: Personal life experiences are shared and resource information is provided as a guide for readers. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Attention to these factors that foster self-determination by service users, peers, clinicians, teachers, and loved ones may help cultivate self-determination and contribute to the process of recovery. PMID- 26974742 TI - Putting the face in context: Body expressions impact facial emotion processing in human infants. AB - Body expressions exert strong contextual effects on facial emotion perception in adults. Specifically, conflicting body cues hamper the recognition of emotion from faces, as evident on both the behavioral and neural level. We examined the developmental origins of the neural processes involved in emotion perception across body and face in 8-month-old infants by measuring event-related brain potentials (ERPs). We primed infants with body postures (fearful, happy) that were followed by either congruent or incongruent facial expressions. Our results revealed that body expressions impact facial emotion processing and that incongruent body cues impair the neural discrimination of emotional facial expressions. Priming effects were associated with attentional and recognition memory processes, as reflected in a modulation of the Nc and Pc evoked at anterior electrodes. These findings demonstrate that 8-month-old infants possess neural mechanisms that allow for the integration of emotion across body and face, providing evidence for the early developmental emergence of context-sensitive facial emotion perception. PMID- 26974744 TI - CE: Original Research: An Investigation into the Health-Promoting Lifestyle Practices of RNs. AB - PURPOSE: The purpose of this study was to gather baseline data on the health promoting lifestyle practices of RNs working in six major health care and educational institutions in a southeast Pennsylvania community. METHODS: A descriptive correlational study design was used. The 52-item Health-Promoting Lifestyle Profile II instrument was used to explore participants' self-reported health-promoting behaviors and measure the dimensions of health responsibility, physical activity, nutrition, interpersonal relations, spiritual growth, and stress management. RESULTS: Findings revealed that physical activity and stress management scores were low for the entire group of RNs. There were statistically significant differences between nurses 50 years of age and older and those 30 to 39 years of age for the subscales of health responsibility, nutrition, and stress management, suggesting that older nurses are more concerned about their health. There were also statistically significant differences between nurses 50 years of age and older and those 29 years of age and younger for the subscale of health responsibility. Sixty-seven percent of participants reported having too many competing priorities and had significantly lower subscale scores for spiritual growth, interpersonal relations, and stress management, as well as significantly lower total scores. CONCLUSION: This study's findings provided baseline data that will be useful in planning health-promoting lifestyle interventions for participants specific to their institutions, and may help guide future research and educational initiatives related to numerous issues common to the RN workforce. The failure of many nurses to take adequate care of themselves needs to be better understood and addressed, by both individual nurses and their employers. PMID- 26974745 TI - CE: Cardiotoxicity and Breast Cancer as Late Effects of Pediatric and Adolescent Hodgkin Lymphoma Treatment. AB - The American Cancer Society estimates that in 2014 nearly 16,000 U.S. children and adolescents developed cancer, and in roughly 1,200 of these cases the cancer was Hodgkin lymphoma (HL). The great majority of these patients will survive, joining the thousands who have been diagnosed and treated successfully in decades past. Nurses' familiarity with and attention to the late effects of the chemotherapy and radiation therapy used to treat HL, which include breast cancer as well as cardiotoxicity and its sequelae, are essential in helping these patients maintain their overall health. PMID- 26974743 TI - Longitudinal stability of the folding pattern of the anterior cingulate cortex during development. AB - Prenatal processes are likely critical for the differences in cognitive ability and disease risk that unfold in postnatal life. Prenatally established cortical folding patterns are increasingly studied as an adult proxy for earlier development events - under the as yet untested assumption that an individual's folding pattern is developmentally fixed. Here, we provide the first empirical test of this stability assumption using 263 longitudinally-acquired structural MRI brain scans from 75 typically developing individuals spanning ages 7 to 32 years. We focus on the anterior cingulate cortex (ACC) - an intensely studied cortical region that presents two qualitatively distinct and reliably classifiable sulcal patterns with links to postnatal behavior. We show - without exception-that individual ACC sulcal patterns are fixed from childhood to adulthood, at the same time that quantitative anatomical ACC metrics are undergoing profound developmental change. Our findings buttress use of folding typology as a postnatally-stable marker for linking variations in early brain development to later neurocognitive outcomes in ex utero life. PMID- 26974746 TI - Travelers' Diarrhea in Children at Risk: An Observational Study From a Spanish Database. AB - BACKGROUND: Gastrointestinal symptoms are a common cause of consultation about children traveling to or coming from developing countries. The aim of this study was to identify the risk factors associated with gastrointestinal syndrome in children who travel. METHODS: A prospective observational analytical and multicenter study was performed within +Redivi, a Spanish Tropical Medicine network on imported infections, from January 2009 to December 2013. All participants aged 16 years and younger were included in the analysis. Ethical approval was obtained from all the participating centers. RESULTS: A total of 606 children <=16 years of age were registered in the +Redivi database during the study period. Median age was 8.7 years (interquartile range, 4.4-12.4 years), 65.8% (399/606) were immigrants, 90% were >2 years old and 54% were male. Median travel duration, excluding immigrants, was 50 days (interquartile range, 30-150 days). Children with gastrointestinal symptoms represented 13.5% (82/606) of total consultations. A significant association was found in bivariate analysis between gastrointestinal disorder and age <2 years (P < 0.01) and travel duration (P = 0.046). Immigrants had less gastrointestinal disorders than tourists (P < 0.05). The most prevalent infection was protozoan in 23.4% (142/606), and Giardia intestinalis was the most common pathogen in 10.1% (61/606) of total children. Independent risk factors for gastrointestinal symptoms were tourist and traveler child visiting friends and relatives (P = 0.03), travel duration <90 days (P = 0.008) and bacterial cause (P < 0.001). CONCLUSIONS: Traveling children who developed a gastrointestinal syndrome represented 13.5% of the total pediatric consultations in +Redivi. Independent risk factors were tourist or traveler visiting friends and relatives, travel duration <90 days and bacterial infection. G. intestinalis was the most common infectious agent causing a gastrointestinal disorder in the traveler children. PMID- 26974747 TI - Burden of Rotavirus Disease in Norway: Using National Registries for Public Health Research. AB - BACKGROUND: Norway introduced routine rotavirus immunization for all children born on or after September 1, 2014. We estimated the healthcare burden of all cause gastroenteritis and rotavirus disease in children <5 years old to establish the prevaccine baseline and support the ongoing immunization program. METHODS: We examined national registry data on gastroenteritis-associated primary care consultations and hospitalizations for 2009-2013 and data on all deaths in children <5 years old reported during 2000-2013. We also established rotavirus hospital surveillance from February 2014 through January 2015. RESULTS: Before vaccine introduction, 114.5 cases per 1000 children <5 years old were treated in primary care and 11.8 children per 1000 were hospitalized with gastroenteritis annually. During hospital surveillance, rotavirus was detected in 65% (95% confidence interval: 60-70) of inpatient gastroenteritis cases. We estimated that 4.0 inpatient and 2.3 outpatient cases per 1000 children were seen in hospital with rotavirus disease annually, suggesting that 1 in 32 children was hospitalized by age 5. Additional 30.6 rotavirus cases per 1000 children consulted primary care annually or 1 in every 7 children by the age of 5 years. Rotavirus-associated mortality was estimated at 0.17 deaths per 100,000 children <5 years old, corresponding to 1 death every second year. CONCLUSIONS: Rotavirus remains the primary cause of severe gastroenteritis in children in Norway. The unique population-based registers, in combination with an established rotavirus surveillance platform, provide a well-suited setting to evaluate the impact of rotavirus vaccination. PMID- 26974748 TI - The Burden of Pediatric Invasive Meningococcal Disease in Spain (2008-2013). AB - BACKGROUND: Invasive meningococcal disease remains a rare infectious disease not only with high mortality but also with important morbidity. Until recently no universal vaccine existed against serogroup B, which explains most of the cases in settings like Europe. The objective of this study was to analyze the clinical course and sequelae of meningococcal disease in Spain. METHODS: Retrospective review of all children younger than 15 years admitted to any of the 36 hospitals in the MENDICOS Spanish network (www.mendicos.org) with confirmed or probable invasive meningococcal disease in children between January 2008 and December 2013. RESULTS: A total of 458 cases were identified across the country, most of them occurring in previously healthy children (91.5%; n = 419/458). Median (interquartile range) age was 1.7 (0.7 and 4.6) years, with 53.1% of the cases occurring in children younger than 2 years; 82.1% (n = 368) were laboratory confirmed cases; 95.2% (n = 256) of those serogrouped were serogroup B. The diagnosis was meningitis in 24.9% (n = 114) of the cases, sepsis in 37.1% (n = 170) and both in 38.0% (n = 174). Mean hospital length of stay was 11.6 (10.9) days; 79.2% (n = 354) of the patients required pediatric intensive care unit admission, with a mean pediatric intensive care unit stay of 3.9 (4.9) days; 3.5% (n = 16) died; 12.9% (n = 59) of the survivors were discharged with some kind of physical sequelae, mainly neurological (n = 23). CONCLUSIONS: Serogroup B invasive meningococcal infection explains substantial morbidity and mortality in Spain, occurring mainly in infants. The recent availability of a vaccine against serogroup B may change this scenario. Given that the vast majority of the cases occur in otherwise healthy children, inclusion of the meningococcal B vaccine in the national immunization program should be carefully considered. PMID- 26974750 TI - Bacteremia Caused by Raoultella ornithinolytica in Two Children. AB - We encountered 2 immunocompromised children complicated by Raoultella ornithinolytica bacteremia. One had received methylprednisolone pulse therapy for IgA nephropathy, and the other had leukopenia because of chemotherapy for leukemia. Both children had no specific symptoms, and R. ornithinolytica bacteremia was identified by routine blood culture. Both patients were successfully treated with antibiotic treatment. PMID- 26974751 TI - The Etiology, Clinical Presentation and Long-term Outcome of Spondylodiscitis in Children. AB - BACKGROUND: Spondylodiscitis (SD) is a rare disease in children and diagnosis can be delayed because of the scarcity in incidence and lack of awareness. The purpose of this study was to evaluate and report the microbiologic epidemiology and clinical features of pediatric SD in South Korea. METHODS: This was a retrospective study of children <19 years old admitted for the treatment of SD between 2000 and 2014. Electronic medical records were reviewed for clinical parameters and etiologic agents. RESULTS: During the 15-year period, 25 patients were diagnosed with SD. The median age was 13.8 years, and 60% were male. Back pain was the most common presenting symptom (n = 17; 68%), and only 52% (n = 13) of the patients had a history of fever (>=38.0 degrees C). In patients younger than 3 years, irritability (n = 5; 62.5%) was the most predominant symptom. Microorganisms were isolated in 22 cases, the most common being Staphylococcus aureus (40%) and Mycobacterium tuberculosis (32%). Of the 25 patients, 64% (n = 16) had blood cultures taken, 56% (n = 14) underwent percutaneous fluoroscopy guided biopsy, and 48% (n = 12) underwent open surgical biopsy. The positive rate for microbiologic diagnosis of each method was 18.8% (n = 3) for blood culture, 71.4% (n = 10) for percutaneous biopsy and 100% (n = 12) for surgical biopsy. Overall, 52% (n = 13) needed surgical treatment along with antibiotic therapy. Patients who needed surgery had a significant delay in diagnosis compared with those that did not (median, 60 vs. 31 days; P = 0.014). CONCLUSIONS: S. aureus and M. tuberculosis are the predominant causes of SD in children in South Korea. Obtaining tissue culture is important to confirm the bacterial etiology of the infection and appropriately guide antibiotic therapy in a community in which the endemic organisms require treatment pathways that are widely divergent. PMID- 26974752 TI - Effectiveness of Pneumococcal Conjugate Vaccines of Different Valences Against Invasive Pneumococcal Disease Among Children in Taiwan: A Nationwide Study. AB - BACKGROUND: For the scarcity of data, we investigated the vaccine effectiveness (VE) of the combined use of pneumococcal conjugate vaccines (PCVs) of different valences against invasive pneumococcal disease (IPD) in children. METHODS: We conducted a matched case-control study using the national IPD surveillance database and the national vaccination registry. Four age-matched, gender-matched and neighborhood-matched controls were identified for each incident IPD case ?5 years with disease onsets between October 2007 and December 2013. Conditional logistic regression was used to assess VE against all serotype and serotype 19A IPD. RESULTS: In 523 cases (median age: 28.5 months; range: 2.0-69.4 months) and 2086 controls (28.7; 2.2-70.1), a similar VE against all-serotype IPD was found between PCV13 (76%; 61-85%) and combined 7-valent PCV (PCV7)/10-valent PCV (PCV10) plus PCV13 (78%; 56-89%). The VE for PCV7/PCV10 was slightly lower (48%; 32-60%). Regarding serotype 19A, a significantly reduced risk was observed for both PCV13 (82%; 63-91%) and combined PCV7/PCV10 plus PCV13 (87%; 61-96%). PCV7/PCV10 had only a borderline protective association (31%; 4-51%). For children receiving PCV13 alone, VE against all-serotype IPD did not differ between starting the dosing at >=2 (78%; 56-89%) or <2 (74%; 51-87%) years of age. VE was 81% (69-88%) within 6 months of the last dose of PCV and 19% (95% CI: -21 to 45%) after 2 years. CONCLUSIONS: PCVs are effective against IPD during immunization with either the same or with a mixed series, but protection might be differential over time. PMID- 26974749 TI - Bacterial Density, Serotype Distribution and Antibiotic Resistance of Pneumococcal Strains from the Nasopharynx of Peruvian Children Before and After Pneumococcal Conjugate Vaccine 7. AB - BACKGROUND: Pneumococcal conjugate vaccines (PCV) have decreased nasopharyngeal carriage of vaccine types but little data exist from rural areas. We investigated bacterial density, serotype distribution and antibiotic resistance of pneumococcal strains within the nasopharynx of young children in the Peruvian Andes, 2 years after PCV7 was introduced. METHODS: Pneumococcal strains were isolated from a subset of 125 children from our Peruvian cohort, who entered the study in 2009 and had pneumococcus detected in the nasopharynx in both 2009 and during follow-up in 2011. Strains were Quellung serotyped and tested for susceptibility to antibiotics. Bacterial density was determined by quantitative polymerase chain reaction. RESULTS: The prevalence of PCV7 strains decreased from 48% in 2009 to 28.8% in 2011, whereas non-PCV7 types increased from 52% to 71.2% (P = 0.002). There was a 3.5-fold increase in carriage of serotype 6C in 2011 (P = 0.026). Vaccination with PCV7 did not affect pneumococcal density in children colonized by a PCV7 type but did increase density in those colonized with a non PCV7 type. Antibiotic resistance did not change after vaccine introduction; strains were nonsusceptible to tetracycline (97.2%), trimethoprim sulfamethoxazole (56.4%), penicillin (34%), erythromycin (22.4%), chloramphenicol (18.8%) and clindamycin (12.4%). CONCLUSIONS: Serotype replacement was observed post-PCV7 vaccination with a concomitant, not previously recognized, increased nasopharyngeal density. PMID- 26974753 TI - Utility of Emergency Department Use of Abdominal Pelvic Computed Tomography in the Management of Crohn's Disease. AB - GOAL: The primary aim of this study was to determine predictors of clinically significant computed tomography (CT) scans, paying particular attention to findings of previous CT scans. BACKGROUND: Use of CT to assess patients with Crohn's disease (CD) in the Emergency Department (ED) is both costly and exposes patients to high levels of ionizing radiation while not clearly improving outcomes. STUDY: Patients with CD who underwent CT scan in the Emergency Department from 2008 to 2011 at a tertiary referral center were assessed for clinically significant findings. A multivariable generalized estimating equation model with logit link and exchangeable working correlation structure was constructed to assess for independent predictors of CT scans with clinically significant findings. RESULTS: A total of 118 patients with CD underwent 194 CT scans. Ninety-two of 194 (47%) CT scans demonstrated clinically significant findings. Predictors of clinically significant CT scans included ileal disease involvement [odds ratios (OR) 3.47, P=0.01] and white blood cell count >12 (OR 2.1, P=0.03). Most notably, patients with a CT scan without clinically significant findings performed in the preceding month were significantly less likely to have a clinically significant CT scan (OR 0.23, P=0.005). CONCLUSIONS: Patients with CD who had a CT scan without significant findings the month prior are unlikely to have clinically significant CT findings. Ileal disease and an elevated white blood cell are predictive of clinically significant CT scans. PMID- 26974754 TI - Self-Expandable Stents for Benign Esophageal Disorders: When do the Benefits Outweigh the Risks? PMID- 26974755 TI - An Analysis of the Clinical, Endoscopic, and Pathologic Features of Intestinal Tuberculosis. AB - GOALS: The aim of this study was to retrospectively analyze the clinical, endoscopic, and pathologic features of intestinal tuberculosis (TB). BACKGROUND: The prevalence of intestinal TB has been increasing in China. STUDY: The clinical, imaging and laboratory examination, endoscopic, and pathologic data of 81 cases of intestinal TB patients were retrospectively analyzed. RESULTS: There were 48 male and 33 female cases whose age ranged from 17 to 76 years (mean, 32.4+/-1.6 y). Fifty-five cases were diagnosed by endoscopic biopsy, and 26 cases by postoperative pathologic examination. The common symptoms were chronic right lower abdominal and periumbilical pain (87.7%), weight loss (80.2%), anemia (64.2%), diarrhea (46.9%), fever (43.2%), diarrhea alternating with constipation (38.3%), and night sweats (30.9%). Purified protein derivative test (51.9%), TB antibody (34.6%), and TB protein chip (40.7%) had lower sensitivity. T-spot test sensitivity was 86.4%. Endoscopic types included ulcerative (52.7%), ulcero proliferative (27.3%), and proliferative (20.0%) with mucosal hyperemia and edema (87.2%), mucosal erosion (76.4%), patulous ileocecal valve (65.5%), polypoid hyperplasia (58.2%), annular ulcer (52.7%), nodular hyperplasia (45.5%), and luminal stenosis (29.1%). Histopathologic findings were chronic mucosal inflammation (87.3%), ulceration (74.5%), lymphocytic aggregation (69.1%), and granulomatous fusion (58.2%). The presence of caseating granulomas (74.5%) and necrosis (25.5%) was helpful, but not common. CONCLUSIONS: The clinical symptoms of intestinal TB are nonspecific. The most common anatomic locations for intestinal TB are the ileocecal valve and cecum. The T-spot test has high sensitivity, and it can be used to support the diagnosis of intestinal TB. The typical endoscopic features are circumscribed intestinal ulcers, and histopathologic findings of biopsy specimens can be also useful in making the diagnosis. PMID- 26974756 TI - Differential Diagnosis of Immunoglobulin G4-associated Cholangitis From Cholangiocarcinoma. AB - BACKGROUND AND AIM: Immunoglobulin G4-associated cholangitis (IAC) shares many similar symptoms with cholangiocarcinoma (CCA). However, the treatment and the prognosis are substantially different. This study aimed to identify the important markers for the differential diagnosis of these 2 diseases. METHODS: Thirty IAC patients and 275 CCA patients were reviewed retrospectively for their clinical symptoms, serological tests, and imaging characteristics. Posttreatment responses were also studied. RESULTS: IgG4 had 100% specificity for IAC at a cutoff of 6 times the upper normal limit. IAC patients had a significantly higher incidence of weight loss (P=0.025) and a higher level of weight loss (P=0.008) than CCA patients. The positive rates of biological markers CA199, CA242, and CEA in CCA and IAC were 81.5% versus 42.9%, 45.5% versus 4.5%, and 29.2% versus 7.1%, respectively. Levels of these tumor markers in CCA were significantly higher than in IAC (P<0.05). The thickened wall [17/18 (94.4%) vs. 3/10 (30%), P=0.001] and the occupying lesion on the bile duct [1/18 (5.6%) vs. 8/10 (80%), P<0.001] were found to be significantly different in IAC and CCA, respectively, by endoscopic ultrasonography. Autoimmune pancreatitis was the most frequently observed comorbidity of IAC (25/30). All IAC patients respond positively to steroid treatment. CONCLUSIONS: Increased tumor markers, 6-fold higher levels of serum IgG4, and other organs' involvement could be the reference factors for a differential diagnosis of IAC and CCA. Endoscopic ultrasonography might be an effective imaging tool for diagnosis, although clinical signs and symptoms of IAC and CCA are similar. Experimental steroid treatment can be useful in the diagnosis for certain difficult cases. PMID- 26974757 TI - Colonoscopy After Computed Tomography-diagnosed Acute Right-sided Diverticulitis May Be Unnecessary. PMID- 26974758 TI - Upper Versus Lower Gastrointestinal Delivery for Transplantation of Fecal Microbiota in Recurrent or Refractory Clostridium difficile Infection: A Collaborative Analysis of Individual Patient Data From 14 Studies. AB - GOALS: The aim of this study was to compare upper gastrointestinal (UGI) versus lower gastrointestinal (LGI) delivery routes of fecal microbiota transplantation (FMT) for refractory or recurrent/relapsing Clostridium difficile infection (CDI). BACKGROUND: FMT has been proven to be a safe and highly effective therapeutic option for CDI. Delivery, however, could be via the UGI or LGI routes, and it is unclear as to which route provides better clinical outcome. STUDY: A systematic search for studies that reported the use of FMT for CDI treatment was conducted. Individual patient data that included demographic (age and sex) and clinical (route of FMT delivery, CDI outcome after FMT, and follow up time) information were obtained. Kaplan-Meier cumulative hazard curves and Cox proportional hazard models were used to assess clinical failure after FMT by the route of delivery. RESULTS: Data from 305 patients treated with FMT (208 via LGI route and 97 via UGI route) for CDI were analyzed. At 30 and 90 days, the risk of clinical failure was 5.6% and 17.9% in the UGI group compared with 4.9% and 8.5% in the LGI delivery route group, respectively. A time-varying analysis suggested a 3-fold increase in hazard of clinical failure for UGI delivery (hazard ratio, 3.43; 95% confidence interval, 1.32-8.93) in the period after 30 days. CONCLUSIONS: FMT delivered via the LGI seems to be the most effective route for the prevention of recurrence/relapse of CDI. A randomized controlled trial is necessary to confirm whether FMT delivered via the LGI is indeed superior to that delivered via the UGI route. PMID- 26974759 TI - Cutaneous Pseudolymphoma in a Patient With Crohn's Disease Under Infliximab: First Report. PMID- 26974760 TI - Intestinal Failure: Adaptation, Rehabilitation, and Transplantation. AB - Intestinal failure (IF) is a state in which the nutritional demands are not met by the gastrointestinal absorptive surface. A majority of IF cases are associated with short-bowel syndrome, which is a result of malabsorption after significant intestinal resection for numerous reasons, some of which include Crohn's disease, vascular thrombosis, and radiation enteritis. IF can also be caused by obstruction, dysmotility, and congenital defects. Recognition and management of IF can be challenging, given the complex nature of this condition. This review discusses the management of IF with a focus on intestinal rehabilitation, parenteral nutrition, and transplantation. PMID- 26974761 TI - Intestinal, Systemic, and Oral Gluten-related Alterations in Patients With Nonceliac Gluten Sensitivity. AB - BACKGROUND: Nonceliac gluten sensitivity (NCGS) is an emergent condition, the framework of which is yet unclear, whereas the diagnosis is suggested only by gluten-dependent symptoms after excluding wheat allergy and celiac disease (CD). Our goal was to highlight intestinal, systemic, and oral alterations to clarify the NCGS pathogenesis and identify new diagnostic tools. STUDY: A total of 60 NCGS patients, 20 untreated CD, 20 treated CD, and 20 healthy volunteers were recruited. The differential diagnosis among gluten-related disorders was performed by serological, allergy, and histologic tools. NCGS patients were also subjected to antigliadin antibody (AGA) detection and HLA typing. All participants underwent an oral mucosa patch test for gluten (GOMPT), whereas an oral provocation test (OPT) for gluten was performed in 26 NCGS patients. RESULTS: About 6/60 (10%) NCGS patients showed IgG AGA-positive results, whereas 45/60 (75%) patients carried HLA-DQ2 and/or HLA-DQ8 genes. GOMPT showed positive results in 45/60 (75%) NCGS patients, 3/20 (15%) untreated CD patients, 5/20 (25%) treated CD patients, and in no healthy volunteers. No significant difference was found between the severity of symptoms reported by NCGS patients subjected to OPT with gluten-containing croissants and those who underwent OPT with gluten-free croissants. CONCLUSIONS: GOMPT seems to be a specific tool for NCGS diagnosis, although further investigations are needed to overcome limits due to the small population studied and to contextualize GOMPT false-positive results. PMID- 26974763 TI - Identification and Fibrosis Staging of Hepatitis C Patients Using the Electronic Medical Record System. AB - BACKGROUND AND AIMS: The aim of this study was to noninvasively assess the severity of chronic hepatitis C virus (HCV) in large patient populations. It would be helpful if fibrosis scores could be calculated solely on the basis of data contained in the patients' electronic medical records (EMR). We performed a pilot study to identify all HCV-infected patients in a large health care system, and predict their fibrosis stage on the basis of demographic and laboratory data using common data from their EMR. MATERIALS AND METHODS: HCV-infected patients were identified using the EMR. The liver biopsies of 191 HCV patients were graded using the Ishak and Metavir scoring systems. Demographic and laboratory data were extracted from the EMR and used to calculate the aminotransferase to platelet ratio index, Fib-4, Fibrosis Index, Forns, Goteborg University Cirrhosis Index, Lok Index, and Vira-HepC. RESULTS: In total, 869 HCV-infected patients were identified from a population of over 1 million. In the subgroup of patients with liver biopsies, all 7 algorithms were significantly correlated with the fibrosis stage. The degree of correlation was moderate, with correlation coefficients ranging from 0.22 to 0.60. For the detection of advanced fibrosis (Metavir 3 or 4), the areas under the receiver operating characteristic curve ranged from 0.71 to 0.84, with no significant differences between the individual scores. Sensitivities, specificities, and positive and negative predictive values were within the previously reported range. All scores tended to perform better for higher fibrosis stages. CONCLUSIONS: Our study demonstrates that HCV-infected patients can be identified and their fibrosis staged using commonly available EMR based algorithms. PMID- 26974762 TI - Mean Platelet Volume, Red Cell Distribution Width to Platelet Count Ratio, Globulin Platelet Index, and 16 Other Indirect Noninvasive Fibrosis Scores: How Much Do Routine Blood Tests Tell About Liver Fibrosis in Chronic Hepatitis C? AB - BACKGROUND AND AIM: Many indirect noninvasive scores to predict liver fibrosis are calculated from routine blood investigations. Only limited studies have compared their efficacy head to head. We aimed to compare these scores with liver biopsy fibrosis stages in patients with chronic hepatitis C. MATERIALS AND METHODS: From blood investigations of 1602 patients with chronic hepatitis C who underwent a liver biopsy before initiation of antiviral treatment, 19 simple noninvasive scores were calculated. The area under the receiver operating characteristic curves and diagnostic accuracy of each of these scores were calculated (with reference to the Scheuer staging) and compared. RESULTS: The mean age of the patients was 41.8+/-9.6 years (1365 men). The most common genotype was genotype 4 (65.6%). Significant fibrosis, advanced fibrosis, and cirrhosis were seen in 65.1%, 25.6, and 6.6% of patients, respectively. All the scores except the aspartate transaminase (AST) alanine transaminase ratio, Pohl score, mean platelet volume, fibro-alpha, and red cell distribution width to platelet count ratio index showed high predictive accuracy for the stages of fibrosis. King's score (cutoff, 17.5) showed the highest predictive accuracy for significant and advanced fibrosis. King's score, Goteborg university cirrhosis index, APRI (the AST/platelet count ratio index), and Fibrosis-4 (FIB-4) had the highest predictive accuracy for cirrhosis, with the APRI (cutoff, 2) and FIB-4 (cutoff, 3.25) showing the highest diagnostic accuracy.We derived the study score 8.5 - 0.2(albumin, g/dL) +0.01(AST, IU/L) -0.02(platelet count, 10(9)/L), which at a cutoff of >4.7 had a predictive accuracy of 0.868 (95% confidence interval, 0.833-0.904) for cirrhosis. CONCLUSIONS: King's score for significant and advanced fibrosis and the APRI or FIB-4 score for cirrhosis could be the best simple indirect noninvasive scores. PMID- 26974764 TI - Mycosis Fungoides-like Eruption and Infliximab. PMID- 26974765 TI - How Solid Is the Scientific Evidence on Probiotics? PMID- 26974766 TI - Comparison and relationship of thyroid hormones, IL-6, IL-10 and albumin as mortality predictors in case-mix critically ill patients. AB - OBJECTIVE: To compare the ability of thyroid hormones, IL-6, IL-10, and albumin to predict mortality, and to assess their relationship in case-mix acute critically ill patients. METHODS: APACHE II scores and serum thyroid hormones (FT3, FT4, and TSH), IL-6, IL-10, and albumin were obtained at EICU admission for 79 cases of mix acute critically ill patients without previous history of thyroid disease. Patients were followed for 28 days with patient's death as the primary outcome. All mean values were compared, correlations assessed with Pearson' test, and mortality prediction assessed by multivariate logistic regression and ROC. RESULTS: Non survivors were older, with higher APACHE II score (p=0.000), IL-6 (p<0.05), IL-10 (p=0.000) levels, and lower albumin (p=0.000) levels compared to survivors at 28 days. IL-6 and IL-10 had significant negative correlation with albumin (p=0.001) and FT3 (p ? 0.05) respectively, while low albumin had a direct correlation with FT3 (p<0.05). In the mortality prediction assessment, IL-10, albumin and APACHE II were independent morality predictors and showed to have a good (0.70-0.79) AUC-ROC (p<0.05). Despite that the entire cohort showed low FT3 serum levels (p=0.000), there was not statistical difference between survivors and non-survivors; neither showed any significance as mortality predictor. CONCLUSIONS: IL-6 and IL-10 are correlated with Low FT3 and hypoalbuminemia. Thyroid hormones assessed at EICU admission did not have any predictive value in our study. And finally, high levels of IL-6 and IL-10 in conjunction with albumin could improve our ability to evaluate disease's severity and predict mortality in the critically ill patients. When use in combination with APACHE II scores, our model showed improved mortality prediction. PMID- 26974768 TI - Dual-wavelength Nd:LGGG laser intracavity pumped simultaneous OPO and SRS processes in single KTP. AB - Simultaneous optical parametric oscillation (OPO) and stimulated Raman scattering (SRS) in a single KTiOPO4 (KTP) intracavity pumped by a dual-wavelength Nd:LGGG laser were demonstrated for the first time, to the best of our knowledge. A maximum output power for the signal beam was 448 mW, while for the Stokes radiations it was 40 mW, corresponding to an overall conversion efficiency of about 4.65%. The shortest pulse durations for OPO and SRS waves were directly measured to be 850 ps and 1.526 ns, respectively. The highest peak power of 30.6 kW and the pulse energy of 26 MUJ for the signal beam were also obtained. A set of coupled rate equations for the dual-wavelength pumped OPO and SRS was also established. The numerical solutions fit with the experimental results. PMID- 26974767 TI - Anions Govern Cell Volume: A Case Study of Relative Astrocytic and Neuronal Swelling in Spreading Depolarization. AB - Cell volume changes are ubiquitous in normal and pathological activity of the brain. Nevertheless, we know little about the dynamics of cell and tissue swelling, and the differential changes in the volumes of neurons and glia during pathological states such as spreading depolarizations (SD) under ischemic and non ischemic conditions, and epileptic seizures. By combining the Hodgkin-Huxley type spiking dynamics, dynamic ion concentrations, and simultaneous neuronal and astroglial volume changes into a comprehensive model, we elucidate why glial cells swell more than neurons in SD and the special case of anoxic depolarization (AD), and explore the relative contributions of the two cell types to tissue swelling. Our results demonstrate that anion channels, particularly Cl-, are intrinsically connected to cell swelling and blocking these currents prevents changes in cell volume. The model is based on a simple and physiologically realistic description. We introduce model extensions that are either derived purely from first physical principles of electroneutrality, osmosis, and conservation of particles, or by a phenomenological combination of these principles and known physiological facts. This work provides insights into numerous studies related to neuronal and glial volume changes in SD that otherwise seem contradictory, and is broadly applicable to swelling in other cell types and conditions. PMID- 26974769 TI - Relaxation of mask design for single-shot phase imaging with a coded aperture. AB - We present a method of relaxing the conditions of mask design in single-shot phase imaging with a coded aperture (SPICA), for extending the applications of SPICA. SPICA, based on compressive sensing, enables the acquisition of wide, high resolution optical complex fields in a single exposure without the need for reference light. In our previous work on SPICA, a coded aperture (CA) was implemented with only amplitude modulation, resulting in a low transmission factor and low light efficiency because of the need for an independent phase retrieval process in the reconstruction. We attempt to alleviate these limitations by adapting a reconstruction algorithm to directly associate the phase-retrieval process with a sparsity-based reconstruction. With this approach, it is possible to realize SPICA with an amplitude-modulation-based CA having a high transmission factor, a phase-modulation-based CA, and a complex-amplitude (amplitude and phase)-modulation-based CA. We verified the effectiveness of these relaxed CA designs numerically and experimentally. PMID- 26974770 TI - Polarization-dependent loss characterization method based on optical frequency beat. AB - Characterization of the polarization-dependent loss (PDL) of optical components is fundamental for the reliable operation of fiber-optic communication systems. Here we present a method for determining the PDL of optical devices based on optical frequency beating and spectral analysis. Depending on the beat note between components of two orthogonally polarized probe signals modulated at different frequencies, the PDL value and its axis can be determined from a single sweep of an optical spectrum analyzer. Our proposal represents an alternative high-speed option for PDL characterization. PMID- 26974771 TI - Dual-wavelength Nd:YAG laser operation at 1319 and 1338 nm by direct pumping at 885 nm. AB - This paper presents a continuous wave and a Q-switched Nd:YAG laser pumped by diode laser at 885 nm. The maximum output power of the CW laser is 8.28 W with an absorbed slope efficiency of 35.01%. The Q-switching is achieved using a V3+:YAG crystal as the saturable absorber. The maximum output power of the passively Q switched laser is 3.55 W with an absorbed pumping power of 28.65 W operated with a dual wavelength at 1319 and 1338 nm. The shortest pulse widths of the Q switched laser are 20.20 and 20.86 ns, with a maximum repetition rate of 64.10 kHz. PMID- 26974772 TI - Designing spectrum-splitting dichroic filters to optimize current-matched photovoltaics. AB - We have developed an approach for designing a dichroic coating to optimize performance of current-matched multijunction photovoltaic cells while diverting unused light. By matching the spectral responses of the photovoltaic cells and current matching them, substantial improvement to system efficiencies is shown to be possible. A design for use in a concentrating hybrid solar collector was produced by this approach, and is presented. Materials selection, design methodology, and tilt behavior on a curved substrate are discussed. PMID- 26974773 TI - Noise spectrum characterization of optoelectronic oscillators in the presence of laser frequency noise. AB - Frequency domain formulation for computing the noise spectrum of a single loop optoelectronic oscillator (OEO) under the effect of laser frequency noise (LFN) based on the conversion matrix approach is presented. The validity of this approach is verified by comparing its results regarding the phase noise of the OEO with the measurements and simulations of two references in the literature. By performing various simulations, it is observed that the LFN-induced phase noise is approximately independent of the length of the fiber delay line at offset frequencies less than the free spectral range, i.e., the inverse of the time delay of the fiber, and, at larger offset frequencies, the phase noise grows even with increasing the fiber length. Furthermore, it is observed that this phase noise is approximately independent of the distance between the oscillation frequency and the center frequency of the RF filter as well as the value of the small signal loop gain of the OEO. However, the LFN-induced amplitude noise is affected by the distance between the oscillation frequency and the center frequency of the RF filter. PMID- 26974774 TI - Autofocusing system for spatial light modulator-based maskless lithography. AB - To produce diffractive or holographic structures in a photolithographic process, an optical projection system enabling structure resolution in the submicrometer range is highly desirable. To ensure that the optical focus of such a system lies on the substrate surface during the whole lithographic fabrication process, an autofocus system able to focus on a depth of field of a few hundred nanometers is usually required. In this work, we developed an autofocus system for spatial light modulator (SLM)-based maskless photolithographic applications. The system is capable of high-precision focusing without affecting the photoresist performance. It is based on contrast measurement combined with focus-pattern illumination to ensure high contrast at the substrate surface. In addition, we evaluated various autofocus algorithms with respect to time efficiency and accuracy to determine suitable focus-pattern and focus-algorithm combinations. PMID- 26974775 TI - Single-mode deep-UV light source at 191.7 nm by seventh-harmonic generation of a high-power, Q-switched, injection-locked 1342 nm Nd:YVO4 laser. AB - A single-mode deep-UV laser at 191.7 nm is demonstrated by seventh-harmonic generation of a single-mode 1342 nm Nd:YVO4 laser. The fundamental laser is an injection-locked, Q-switched ring laser at 10 kHz pulse repetition frequency. By cascaded second-harmonic and sum-frequency generation, an average power of 230 mW at 191.7 nm is achieved. At 185 mW, the setup features a Gaussian beam with a beam quality factor of M2<1.5. A pulse duration of 9 ns with pulse energy fluctuations of sigma<3% is obtained. The long-term spectral width is approximately 240 MHz full width at half-maximum, measured with a homemade scanning confocal Fabry-Perot interferometer. This work opens possibilities in fiber Bragg grating production, allowing the inscription of long gratings. PMID- 26974776 TI - Investigation of plasmonic properties of graphene multilayer nano-ribbon waveguides. AB - In this paper, we investigate the plasmonic properties of a graphene-silica silicon (G-SiO2-Si) multilayer nano-ribbon waveguide in the mid-IR spectral range using the finite element method. Numerical results show that single-mode operation and modal cut-off properties of the G-SiO2-Si are highly sensitive to the width and chemical potential. In particular, we demonstrate that by properly tuning the geometric and material parameters of the spacer layer or by decreasing the operation frequency, the graphene-based waveguide exhibits a propagation length higher than that of its metal-based counterpart. We believe that this study will provide a valuable reference for designing ultra-compact and low-loss graphene-based novel integrated plasmonic devices. PMID- 26974777 TI - Vibration-immune high-sensitivity profilometer built with the technique of composite interferometry. AB - A prototype of a profilometer was built with the technique of composite interferometry for measurement of the distribution of both the amplitude and phase information of the surface of a material simultaneously. The composite interferometer was composed of a Michelson interferometer for measuring the surface profile of the sample and a Mach-Zehnder interferometer for measuring the phase deviation caused by the scanning component and environmental perturbations. A high-sensitivity surface profile can be obtained by use of the phase compensation mechanism through subtraction of the phases of the interferograms detected in the two interferometers. With the new design and improvement of robustness of the optical system, the measurement speed and accuracy were significantly improved. Furthermore, an additional optical delay component results in a higher sensitivity of the interference signal. This prototype of vibration-immune profilometer was examined to have a displacement sensitivity of 0.64 nm. PMID- 26974778 TI - Short pulse-width gain-switched Ho:YAG ceramic laser at ~2.09 MUm. AB - This paper presents a short pulse-width gain-switched Ho:YAG ceramic laser at 2089 nm resonantly pumped by a homemade Q-switched Tm:fiber laser at ~1908 nm. We generated stable pulses of 44-103 ns duration and 0.13-2 kW peak power at 20 kHz of pulse repetition frequency when the incident pump pulse energy increased from ~0.1 to 0.3 mJ. We also obtained an average output power of 1.76 W under an incident pump power of 6 W, corresponding to a slope efficiency of 41.8%. Finally, this paper discusses the prospects to further improve the results with even a shorter pulse-width and higher peak power. PMID- 26974779 TI - Characterization of periodic cavitation in optical tweezers. AB - Microscopic vapor explosions or cavitation bubbles can be generated repeatedly in optical tweezers with a microparticle that partially absorbs at the trapping laser wavelength. In this work we measure the size distribution and the production rate of cavitation bubbles for microparticles with a diameter of 3 MUm using high-speed video recording and a fast photodiode. We find that there is a lower bound for the maximum bubble radius R(max)~2 MUm which can be explained in terms of the microparticle size. More than 94% of the measured R(max) are in the range between 2 and 6 MUm, while the same percentage of the measured individual frequencies f(i) or production rates are between 10 and 200 Hz. The photodiode signal yields an upper bound for the lifetime of the bubbles, which is at most twice the value predicted by the Rayleigh equation. We also report empirical relations between R(max), f(i), and the bubble lifetimes. PMID- 26974780 TI - Laser-driven phosphor-converted white light source for solid-state illumination. AB - Energy efficiency and lighting quality considerations are driving research into laser-pumped white light sources. Laser diodes as pump sources for downconversion phosphors promise freedom from "droop" that adversely affects the efficiency of light-emitting diodes (LEDs). High-intensity laser diode-pumped light sources for applications such as search lights and automobile headlights have been demonstrated recently. Our paper describes the design and construction of a domestic/office-type solid-state luminaire driven by light from an integrated violet laser-diode module. A trichromatic phosphor made from a blend of separate europium-containing rare-earth phosphors was used as the downconversion medium. Mechanical and optical design of the reflector and the phosphor plate are described. Characteristics of both the pump light and the downconverted light are also described. Our studies also looked at the variation of chromaticity coordinates with variation in pump power and the effect of laser speckle on the lamp's light output. Finally, there is a brief discussion of energy conversion efficiency and longevity considerations, comparing pumping with LEDs versus pumping with laser diodes. PMID- 26974781 TI - Freeform three-dimensional embedded polymer waveguides enabled by external diffusion assisted two-photon lithography. AB - This paper introduces a unique method to fabricate free-form symmetrical three dimensional single-mode waveguides embedded in a newly developed photopolymer. The fabrication process requires only one layer of a single material by combining two-photon lithography and external monomer diffusion resulting in a high refractive index contrast of 0.013. The cured material exhibits high chemical and thermal stability. Transmission loss of 0.37 dB/cm at 850 nm is achieved. Due to the fact that waveguide arrays are produced with high density, this technique could pave the way for three-dimensional optical interconnects at the board level with high complexity and bandwidth density. PMID- 26974782 TI - Methods of phase reconstruction for time-averaging electronic speckle pattern interferometry. AB - Electronic speckle pattern interferometry is useful for the qualitative depiction of the deformation profile of harmonically vibrating objects. However, extending the process to achieve quantitative results requires unwrapping the phase in the interferogram, which contains significant noise due to the speckle. Two methods to achieve accurate phase information from time-averaged speckle pattern interferograms are presented. The first is based on a direct inverse of the regions within corresponding phase intervals, and the second is based on optimization of four independent parameters. The optimization method requires less time than more commonly used algorithms and shows higher precision of the resulting surface displacement. PMID- 26974783 TI - Carrier squeezing interferometry with pi/4 phase shift: phase extraction in the presence of multi-beam interference. AB - Multi-beam interference exists in testing high-reflectivity surfaces with a Fizeau interferometer. In this paper, the multi-beam interference intensity was estimated as the sum of the first six order harmonics using the Fourier series expansion. Then, by adopting carrier squeezing interferometry with a pi/4 phase shift, an algorithm was proposed to extract the phase from multi-beam interferograms. To ensure the separation of the lobes of phase-shift errors and the phase in the frequency domain, conditions of the necessary linear carrier in the proposed algorithm were derived. Simulation results indicated that the phase retrieving precision is better than PV 0.008lambda and RMS 0.001lambda, even when the reflection coefficient of the test surface is as high as 0.9 and the phase shift varies within pi/4+/-pi/20. Compared with the other algorithms, the proposed algorithm for multi-beam interference was validated by its good performance in the experiments, especially when the phase-shift error exists. PMID- 26974784 TI - Intensity-modulating graphene metamaterial for multiband terahertz absorption. AB - In this paper, we design a tunable strength multiband absorber consisting of a graphene metamaterial structure and a thick dielectric interlayer deposited on a metal ground plane. We investigate the tunable conductivity properties of the graphene metamaterial and demonstrate multiband absorbers with three absorption bands using a polyimide interlayer in the 0-2.25 THz range by numerical simulation. The results show that the mix absorptivity reached 99.8% at 1.99 THz, and the absorptive strength can be tuned with the modulation depth up to 84.2%. We present a theoretical interpretation based on a standing wave field, which shows that the field energy is localized inside the thicker spacer and then dissipated, effectively trapping the light in the metamaterial absorbers with negligible near-field interactions. The standing wave field theory developed here explains all the features of the multiband metamaterial absorbers and provides a profound understanding of the underlying physics. PMID- 26974785 TI - Alignment error analysis of the snapshot imaging polarimeter. AB - A snapshot imaging polarimeter (SIP) system is able to reconstruct two dimensional spatial polarization information through a single interferogram. In this system, the alignment errors of the half-wave plate (HWP) and the analyzer have a predominant impact on the accuracies of reconstructed complete Stokes parameters. A theoretical model for analyzing the alignment errors in the SIP system is presented in this paper. Based on this model, the accuracy of the reconstructed Stokes parameters has been evaluated by using different incident states of polarization. An optimum thickness of the Savart plate for alleviating the perturbation introduced by the alignment error of the HWP is found by using the condition number of the system measurement matrix as an objective function in a minimization procedure. The result shows that when the thickness of a Savart plate is 23 mm, corresponding to the condition number 2.06, the precision of the SIP system can reach to 0.21% at 1 degrees alignment tolerance of the HWP. PMID- 26974786 TI - All-fiber high-average power nanosecond-pulsed master-oscillator power amplifier at 2 MUm with mJ-level pulse energy. AB - We present a high-power nanosecond-pulsed Tm-doped fiber amplifier at 1.971 MUm based on a master-oscillator power amplifier (MOPA) configuration. When the repetition rate is 500 kHz and the pulse width is 63.3 ns, the average power reaches 238 W, the peak power reaches 7.06 kW, and the pulse energy is 0.477 mJ. When the pulse train's repetition rate is 300 kHz with a pulse width of 63.7 ns, the average power reaches 197 W, the peak power reaches 9.73 kW, and the pulse energy is 0.66 mJ. When the pulse train's repetition rate is 200 kHz with a pulse width of 58.2 ns, the average power reaches 150 W, the peak power reaches 12.1 kW, and the pulse energy is 0.749 mJ. The spectral linewidths of the pulse trains are 0.15, 0.14, and 0.10 nm for 500 kHz repetition rate, 300 kHz repetition rate, and 200 kHz repetition rate, respectively. To the best of our knowledge, this is the first demonstration of high-power nanosecond-pulsed MOPA at 2 MUm with the maximum average power reaching 238 W, the maximum peak power reaching 12.1 kW, and the maximum pulse energy reaching 0.749 mJ. PMID- 26974787 TI - Control of the Goos-Hanchen shifts of a probe light beam using phase tunability of the intracavity medium. AB - This paper presents the Goos-Hanchen (GH) shifts of a probe light beam in a fixed cavity configuration containing the three level V-type atomic medium. We found that in the presence of decay-induced interference, the lateral shifts of both the reflected and transmitted probe light beam can easily be controlled just by the relative phase of applied fields. We also discuss the intensity of the applied field on GH shifts of the reflected and transmitted probe light beam. PMID- 26974788 TI - Resonantly pumped actively mode-locked Ho:YAG ceramic laser at 2122.1 nm. AB - We discuss what we believe is the first continuous-wave mode-locked Ho:YAG ceramic laser. We produced a mode-locked pulse using an acousto-optic modulator. We used a 1.91 MUm Tm-fiber laser as the pump source. At the incident pump power of 11.4 W, we achieved the maximum output power of 1.84 W at 2122.1 nm in a continuous-wave mode-locked regime. We obtained a short-duration pulse of 241.5 ps at a repetition frequency of 82.15 MHz and achieved the beam quality factor M2 of 1.2. In addition, the maximum single pulse energy was 22.4 nJ. PMID- 26974789 TI - Waveform model of a laser altimeter for an elliptical Gaussian beam. AB - The current waveform model of a laser altimeter is based on the Gaussian laser beam of the fundamental mode, whose cross section is a circular spot, whereas some of the cross sections of Geoscience Laser Altimeter System lasers are closer to elliptical spots. Based on the expression of the elliptical Gaussian beam and the waveform theory of laser altimeters, the primary parameters of an echo waveform were derived. In order to examine the deduced expressions, a laser altimetry waveform simulator and waveform processing software were programmed and improved under the circumstance of an elliptical Gaussian beam. The result shows that all the biases between the theoretical and simulated waveforms were less than 0.5%, and the derived model of an elliptical spot is universal and can also be used for the conventional circular spot. The shape of the waveforms is influenced by the ellipticity of the laser spot, the target slope, and the "azimuth angle" between the major axis and the slope direction. This article provides the waveform theoretical basis of a laser altimeter under an elliptical Gaussian beam. PMID- 26974790 TI - Optimizing Yb concentration of fiber amplifiers in the presence of transverse modal instabilities and photodarkening. AB - The Yb concentration of double-clad optical fiber amplifiers is numerically optimized with respect to maximizing the transverse modal instability threshold in the presence of absorption arising from photodarkening. The pump cladding area is scaled with the Yb concentration to approximately maintain the pump absorption in operation. It is found that approximate analytical expressions can predict the optimized concentration levels found in numerical simulations with sufficient accuracy to be useful in fiber design. PMID- 26974791 TI - Modified Sagnac interferometer for contact-free length measurement of a direct absorption cell. AB - Accurate path length measurements in absorption cells are recurrent requirements in quantitative molecular absorption spectroscopy. A new twin path laser interferometer for length measurements in a simple direct path absorption geometry is presented, along with a full uncertainty budget. The path in an absorption cell is determined by measuring the optical path length change due to the diminution of the refractive index when the cell originally filled with nitrogen gas is evacuated. The performance of the instrument based on a stabilized HeNe laser is verified by comparison with the results of direct mechanical length measurements of a roughly 45 mm long, specially designed absorption cell. Due to a resolution of about 1/300 of a HeNe fringe, an expanded (coverage factor k=2) uncertainty of 16 MUm in the length measurement is achieved, providing an expanded relative uncertainty of 3.6.10-4 for the length of our test absorption cell. This value is about 8 times lower than what has been reported previously. The instrument will be useful for precision measurements of absorption cross sections of strong absorbers which require short light paths, such as ozone, halogen oxides, sulfur dioxide, and volatile organic compounds in the UV. PMID- 26974792 TI - Lidar reflectance from snow at 2.05 MUm wavelength as measured by the JPL Airborne Laser Absorption Spectrometer. AB - We report airborne measurements of lidar directional reflectance (backscatter) from land surfaces at a wavelength in the 2.05 MUm CO2 absorption band, with emphasis on snow-covered surfaces in various natural environments. Lidar backscatter measurements using this instrument provide insight into the capabilities of lidar for both airborne and future global-scale CO2 measurements from low Earth orbit pertinent to the NASA Active Sensing of CO2 Emissions over Nights, Days, and Seasons mission. Lidar measurement capability is particularly useful when the use of solar scattering spectroscopy is not feasible for high accuracy atmospheric CO2 measurements. Consequently, performance in high-latitude and winter season environments is an emphasis. Snow-covered surfaces are known to be dark in the CO2 band spectral regions. The quantitative backscatter data from these field measurements help to elucidate the range of backscatter values that can be expected in natural environments. PMID- 26974793 TI - New time-space-time optical packet switching node based on nonlinear polarization rotation of a semiconductor optical amplifier. AB - In this paper, we establish a simple model to analyze the semiconductor optical amplifier's (SOA) nonlinear polarization rotation (NPR) and acquire the variable curves of phase difference between TE and TM modes with bias current, pump power, probe power, and linewidth enhancement factor (LEF). The results indicate that the optical switch based on the SOA's NPR can be realized by changing the pump's optical power and the main operating parameters, such as bias current and hold beam power, and then the pump power can be determined. On this basis, a time space-time (T-S-T) optical packet switching node is proposed, in which the SOA's NPR switch is the basic element. Then, the T-S and S-T experimental systems are set up, and the experimental results demonstrate that the proposed switch scheme can implement the optical switching function in accordance with the routing requirement. The signal-to-noise ratio (SNR) exceeds 20 dB, and the extinction ratio (ER) is more than 10 dB after being delayed and switched in the node. PMID- 26974794 TI - Parameter optimization analysis to minimize the polarization error in a localized thermal tunable fiber ring resonator gyro. AB - The accuracy of the resonant frequency servo loop is a major concern for the high performance operation of a resonant fiber optic gyro. For instance, a bias error as large as tens or even hundreds of degrees/hour has been observed at the demodulated output of the resonant frequency servo loop. The traditional frequency servo mechanism is not an efficient tool to address this problem. In our previous work, we proposed a novel method to minimize the laser frequency noise to the level of the shot noise by refractive index modulation by a thermally tunable resonator. In this paper, we performed the parameter optimization for the resonator coil, multifunction integrated-optics chip, and couplers by the transition matrix using the Jones matrix methodology to minimize the polarization error. With the optimized parameter values, we achieved the bias value of the resonator fiber optic gyro to 1.924 degrees /h. PMID- 26974795 TI - Three-dimensional ray tracing in spherical and elliptical generalized Luneburg lenses for application in the human eye lens. AB - Ray tracing in spherical Luneburg lenses has always been represented in 2D. All propagation planes in a 3D spherical Luneburg lens generate the same ray tracing, due to its radial symmetry. A geometry without radial symmetry generates a different ray tracing. For this reason, a new ray tracing method in 3D through spherical and elliptical Luneburg lenses using 2D methods is proposed. The physics of the propagation is shown here, which allows us to make a ray tracing associated with a vortex beam. A 3D ray tracing in a composite modified Luneburg lens that represents the human eye lens is also presented. PMID- 26974796 TI - Asymmetric liquid-core cylindrical lens used to measure liquid diffusion coefficient. AB - We design and fabricate an asymmetric liquid-core cylindrical lens (ALCL), which is used to measure the binary liquid diffusion coefficient (D). Acting as both diffusion cell and key imaging element, ALCL is of the function to measure the refractive index (RI) of liquid filled in its core in the way of spatial resolution. Comparing the ALCL with a symmetric liquid-core cylindrical lens (SLCL), the spherical aberration is reduced from about 300 MUm (SLCL) to less than 5 MUm (ALCL) when the RI of filled liquid is near 1.333, while the measurement accuracy of the RI of the ALCL is superior to 0.0002, which is much better than that of the SLCL. Equipped with the ALCL, the D value of triethylene glycol diffusing in water is measured at 25 degrees C. The result is D=0.7515*10 5 cm2/s, a value very close to the literature value. The rational design of ALCL gives the optical method for measuring the D value good measurement precision and direct observation of the diffusive process as well as a simple experimental instrument. PMID- 26974797 TI - Visualizing detecting low-frequency underwater acoustic signals by means of optical diffraction. AB - A novel and simple technique based on the light diffraction effect for visualization of low-frequency underwater acoustic waves (LFUAWs) in real time has been developed in this paper. A cylindrical object has been put on the surface of the water. A low-frequency underwater longitudinal wave can be generated into a water surface transversal capillary wave around the cylinder by our technique. Modulating the phase of a laser beam reflected from a water surface by surface acoustic waves (SAWs) realizes the acousto-optic effect. Then, a steady and visible diffraction pattern is experimentally observed. A physical model of the SAW is established to verify the feasibility of our technique. An analytical expression of wavelength, wave amplitude, and excitation frequency has been derived to study the physical properties of LFUAWs, and it explains the experimental phenomenon very well. As a result, the technique is effective, easy, and practical for visualizing LFUAWs and has significance for applications. PMID- 26974798 TI - Sensitivity in frequency dependent angular rotation of optical vortices. AB - This paper presents robust strategies to enhance the rotation sensitivity (and resolution) of a coherent superposition of optical vortices emerging from a single spiral phase plate (SPP) device when light's optical frequency (or wavelength) going into the SPP device is varied. The paper discusses the generation and measurement of ultrasmall rotation. Factors that affect the ability to perform precision rotation measurements include the linewidth and stability of the input light source, the number of photon counts making position rotation measurements on the CCD detector, SPP reflectivity, the length of SPP device, and the angular modulation frequency of the intensity pattern due to a coherent superposition of optical vortices in a single SPP device. This paper also discusses parameters to obtain a high-sensitivity single shot measurement and multiple measurements. Furthermore, it presents what I believe is a new scaling showing the enhancement in sensitivity (and resolution) in the standard quantum limit and Heisenberg limit. With experimentally realizable parameters, there is an enhancement of rotation sensitivity by at least one order of magnitude compared to previous rotation measurements with optical vortices. Understanding robust strategies to enhance the rotation sensitivity in an SPP device is important to metrology in general and for building compact SPP sensors such as gyroscopes, molecular sensors, and thermal sensors. PMID- 26974800 TI - Modeling of carrier dynamics in InGaAs/GaAs self-assembled quantum dot lasers. AB - In this study, a theoretical model is used to simulate the lasing characteristics of InGaAs/GaAs self-assembled quantum dot lasers. The rate equation for InGaAs/GaAs is numerically solved using the fourth-order Runge-Kutta method. We consider the homogeneous and inhomogeneous broadening of the optical gain, both with and without considering the nonlinear gain. The results indicate that for a certain injected current, there is a specific homogeneous broadening (HB) with the best lasing performance when HB is near, comparable, or equal to inhomogeneous broadening for every laser-injected current. We show that if the linear optical gain is replaced by the total gain, the output power will reduce a little and the peaks will be more broadened and the maximum of the gain spectrum decreases. The time evolution of the photon number for different currents and different HBs is shown. The results indicate that by increasing the HB, the number of photons in the steady state and the delay in the starting oscillation will increase. In addition, we show that there is threshold coverage for quantum dots to begin lasing and an optimum quantum dot coverage in which the self assembled quantum dot lasers operate with the lowest possible threshold current and maximum output power. PMID- 26974799 TI - Automated interferometric synthetic aperture microscopy and computational adaptive optics for improved optical coherence tomography. AB - In this paper, we introduce an algorithm framework for the automation of interferometric synthetic aperture microscopy (ISAM). Under this framework, common processing steps such as dispersion correction, Fourier domain resampling, and computational adaptive optics aberration correction are carried out as metrics-assisted parameter search problems. We further present the results of this algorithm applied to phantom and biological tissue samples and compare with manually adjusted results. With the automated algorithm, near-optimal ISAM reconstruction can be achieved without manual adjustment. At the same time, the technical barrier for the nonexpert using ISAM imaging is also significantly lowered. PMID- 26974801 TI - Goniospectrometric space: identifiable presentation of spectral goniometric data for complex diffractive samples. AB - Optical security takes advantage of complex gonioapparent effects of diffractive samples having strong angular and spectral dependence of reflected light. However, resolving the full angular and spectral properties of these kinds of targets might be a tremendous task. Preferably, one would like to measure a more limited number of illumination-viewing directions, using a multiangle goniometer, and still reveal the complex and unique properties of the target. In this study, we use a method for converting the full angular reflection data into reduced goniospectrometric space and further on into an xDNA graph, which we find to show good potential as a fingerprint for gonioapparent surfaces when limited measurement geometries are available. For the evaluation of the xDNA graph, we use two goniometric devices with a 45 degrees incident angle illumination, a high-resolution bidirectional spectrometer, and a portable multiangle goniometer. This study tests the xDNA graph by evaluating the effects of geometry count and spectral resolution in goniometric measurements and further finds that the xDNA graph indeed works best with a reduced count of geometries and is not sensitive to lowered spectral resolution. PMID- 26974802 TI - Improved phase-measuring deflectometry for aspheric surfaces test. AB - An improved phase-measuring deflectometry (PMD) is presented for the aspheric surfaces test. We explore this method from the Ronchi test in a reverse way. With this concept, a camera aperture is placed near the center of curvature of the test mirror, and fringes are displayed on a liquid crystal display screen. The fringes reflected off the test mirror are observed by the camera. By analyzing the captured fringes, the deviations of the test mirror from its ideal shape are obtained and the aspheric surface under test is reconstructed. Compared with traditional PMD, this method needs only to determine reflected rays and doesn't need to know the corresponding incident rays by calibrations, moving screen, or approximation. Both a computer simulation and preliminary experiment have been carried out to demonstrate the validity of the improved PMD. This improved PMD provides a new tool to measure aspheric surfaces quantitatively in full field for optical manufacturing. PMID- 26974803 TI - Ho3+/Yb3+ codoped silicate glasses for 2 MUm emission performances. AB - This paper discuss a series of Ho3+/Yb3+ codoped silicate glasses prepared by the melting method. 2 MUm emissions of the samples are observed under the pump of 980 nm LD. The Judd-Ofelt parameters (Omega(lambda)) and radiative properties are calculated and analyzed; the spontaneous transition probability can reach 78.71 s-1. From the fluorescence spectra, the peak absorption and emission cross section of Ho3+ are 2.36*10-21 and 5.05*10-21 cm2, respectively. In addition, we analyze the energy transfer process of Yb3+: 2F(5/2) level to Ho3+: 5I6 level. Considering the luminance properties and good thermal property, we indicate that Ho3+/Yb3+ codoped silicate glass is a potential laser glass for the efficient 2 MUm laser. PMID- 26974804 TI - Dual band sensitivity enhancements of a VO(x) microbolometer array using a patterned gold black absorber. AB - Infrared-absorbing gold black has been selectively patterned onto the active surfaces of a vanadium-oxide-based infrared bolometer array. Patterning by metal lift-off relies on protection of the fragile gold black with an evaporated oxide, which preserves much of gold black's high absorptance. This patterned gold black also survives the dry-etch removal of the sacrificial polyimide used to fabricate the air-bridge bolometers. For our fabricated devices, infrared responsivity is improved 22% in the long-wave IR and 70% in the mid-wave IR by the gold black coating, with no significant change in detector noise, using a 300 degrees C blackbody and 80 Hz chopping rate. The increase in the time constant caused by the additional mass of gold black is ~15%. PMID- 26974806 TI - Single-negative metamaterial periodic multilayer doped by magnetized cold plasma. AB - This study theoretically investigates the properties of the defect mode in a 1D defective single-negative photonic crystal containing a magnetized cold plasma defect layer. The considered photonic crystal structure is made of epsilon negative and mu-negative metamaterials. We investigate the defect mode as a function of the thickness and the electron density of the defect layer and the magnetic field. The results show that the thickness, electron density, and variations of the magnetic field affect the frequency of the defect mode. In addition, the shift trend in the defect mode is shown to rely on the polarization due to the presence of polarization-dependent magnetized cold plasma. The results lead to some new information concerning the designing of new types of tunable narrowband filters at microwave frequency. PMID- 26974805 TI - Spectrophotometric determination of turbid optical parameters without using an integrating sphere. AB - Spectrophotometric quantification of turbidity by multiple optical parameters has wide-ranging applications in material analysis and life sciences. A robust system design needs to combine hardware for precise measurement of light signals with software to accurately model measurement configuration and rapidly solve a sequence of challenging inverse problems. We have developed and validated a design approach and performed system validation based on radiative transfer theory for determination of absorption coefficient, scattering coefficient, and anisotropy factor without using an integrating sphere. Accurate and rapid determination of parameters and spectra is achieved for microsphere suspension samples by combining photodiode-based measurement of four signals with the Monte Carlo simulation and perturbation-based inverse calculations. The three parameters of microsphere suspension samples have been determined from the measured signals as functions of wavelength from 400 to 800 nm and agree with calculated results based on the Mie theory. It has been shown that the inverse problems in the cases of microsphere suspension samples are well posed with convex cost functions to yield unique solutions, and it takes about 1 min to obtain the three parameters per wavelength. PMID- 26974807 TI - Slope-deviation measurement of Fresnel-shaped mold surfaces. AB - Molds are used to dictate their shape to other materials in embossing or filling processes. In optics fabrication especially, the exact surface slope of the polymer replica is of high relevance. The quality control of molds is challenging: non-invasive, optical metrologies struggle with shiny surfaces that minimize the scattering of light. In addition, the inspection of complex shaped molds with a stepped optical surface can be difficult. In response, the authors show a backward ray-tracing approach combined with fringe-reflection technique to determine the slopes of a Fresnel-shaped mold surface with topography features in the magnitude order of a quarter millimeter. The error is kept small by stitching together several measurements with different sample rotations. PMID- 26974808 TI - Orbital-angular-momentum-multiplexed free-space optical communication link using transmitter lenses. AB - In this paper, we explore the potential benefits and limitations of using transmitter lenses in an orbital-angular-momentum (OAM)-multiplexed free-space optical (FSO) communication link. Both simulation and experimental results indicate that within certain transmission distances, using lenses at the transmitter to focus OAM beams could reduce power loss in OAM-based FSO links and that this improvement might be more significant for higher-order OAM beams. Moreover, the use of transmitter lenses could enhance system tolerance to angular error between transmitter and receiver, but they might degrade tolerance to lateral displacement. PMID- 26974809 TI - Influence of laser coherence on reference-matched laser Doppler velocimetry. AB - The probe length is investigated under the influence of the coherence length of Gaussian and Lorentzian spectra for the case that the focal point and the point of highest interference are matched in a strongly focused laser Doppler velocimetry setup (LDV). Isosurfaces of a -3 dB drop of the intensity maximum are estimated and suggested as an alternative, comprehensible way to define probe volumes. In the end, the equations are applied for an exemplary lidar setup to show the reduction of requirements for the coherence length of the laser source in comparison to unmatched cases. PMID- 26974811 TI - Presentation advice: editorial. AB - Editor-in-Chief Ron Driggers shares advice for giving good presentations. PMID- 26974810 TI - Experimental verification of long-term evolution radio transmissions over dual polarization combined fiber and free-space optics optical infrastructures. AB - This paper describes the experimental verification of the utilization of long term evolution radio over fiber (RoF) and radio over free space optics (RoFSO) systems using dual-polarization signals for cloud radio access network applications determining the specific utilization limits. A number of free space optics configurations are proposed and investigated under different atmospheric turbulence regimes in order to recommend the best setup configuration. We show that the performance of the proposed link, based on the combination of RoF and RoFSO for 64 QAM at 2.6 GHz, is more affected by the turbulence based on the measured difference error vector magnitude value of 5.5%. It is further demonstrated the proposed systems can offer higher noise immunity under particular scenarios with the signal-to-noise ratio reliability limit of 5 dB in the radio frequency domain for RoF and 19.3 dB in the optical domain for a combination of RoF and RoFSO links. PMID- 26974812 TI - Liquid-Gated High Mobility and Quantum Oscillation of the Two-Dimensional Electron Gas at an Oxide Interface. AB - Electric field effect in electronic double layer transistor (EDLT) configuration with ionic liquids as the dielectric materials is a powerful means of exploring various properties in different materials. Here, we demonstrate the modulation of electrical transport properties and extremely high mobility of two-dimensional electron gas at LaAlO3/SrTiO3 (LAO/STO) interface through ionic liquid-assisted electric field effect. With a change of the gate voltages, the depletion of charge carrier and the resultant enhancement of electron mobility up to 19 380 cm(2)/(V s) are realized, leading to quantum oscillations of the conductivity at the LAO/STO interface. The present results suggest that high-mobility oxide interfaces, which exhibit quantum phenomena, could be obtained by ionic liquid assisted field effect. PMID- 26974813 TI - Methyl-esterified 3-hydroxybutyrate oligomers protect bacteria from hydroxyl radicals. AB - Bacteria rely mainly on enzymes, glutathione and other low-molecular weight thiols to overcome oxidative stress. However, hydroxyl radicals are the most cytotoxic reactive oxygen species, and no known enzymatic system exists for their detoxification. We now show that methyl-esterified dimers and trimers of 3 hydroxybutyrate (ME-3HB), produced by bacteria capable of polyhydroxybutyrate biosynthesis, have 3-fold greater hydroxyl radical-scavenging activity than glutathione and 11-fold higher activity than vitamin C or the monomer 3 hydroxybutyric acid. We found that ME-3HB oligomers protect hypersensitive yeast deletion mutants lacking oxidative stress-response genes from hydroxyl radical stress. Our results show that phaC and phaZ, encoding polymerase and depolymerase, respectively, are activated and polyhydroxybutyrate reserves are degraded for production of ME-3HB oligomers in bacteria infecting plant cells and exposed to hydroxyl radical stress. We found that ME-3HB oligomer production is widespread, especially in bacteria adapted to stressful environments. We discuss how ME-3HB oligomers could provide opportunities for numerous applications in human health. PMID- 26974815 TI - Optoepigenetics: An acetylation photoswitch. PMID- 26974816 TI - Gold(iii)-catalyzed synthesis of aroylbenzo[b]oxepin-3-ones from ortho-O propargyl-1-one substituted arylaldehydes. AB - An efficient gold-catalyzed intramolecular cyclization of ortho-O-propargyl-1-one substituted arylaldehydes has been achieved for the generation of substituted aroylbenzo[b]oxepin-3-one derivatives in moderate to good yields. This synthetic transformation proceeds via gold-catalysed oxidation of the internal alkyne moiety followed by an intramolecular condensation leading to seven-membered oxacycles. PMID- 26974814 TI - Light-controlled modulation of gene expression by chemical optoepigenetic probes. AB - Epigenetic gene regulation is a dynamic process orchestrated by chromatin modifying enzymes. Many of these master regulators exert their function through covalent modification of DNA and histone proteins. Aberrant epigenetic processes have been implicated in the pathophysiology of multiple human diseases. Small molecule inhibitors have been essential to advancing our understanding of the underlying molecular mechanisms of epigenetic processes. However, the resolution offered by small molecules is often insufficient to manipulate epigenetic processes with high spatiotemporal control. Here we present a generalizable approach, referred to as 'chemo-optical modulation of epigenetically regulated transcription' (COMET), enabling high-resolution, optical control of epigenetic mechanisms based on photochromic inhibitors of human histone deacetylases using visible light. COMET probes may be translated into new therapeutic strategies for diseases where conditional and selective epigenome modulation is required. PMID- 26974819 TI - Correction: Development of Salivary Cortisol Circadian Rhythm and Reference Intervals in Full-Term Infants. PMID- 26974817 TI - Influences of Plant Species, Season and Location on Leaf Endophytic Bacterial Communities of Non-Cultivated Plants. AB - Bacteria are known to be associated endophytically with plants. Research on endophytic bacteria has identified their importance in food safety, agricultural production and phytoremediation. However, the diversity of endophytic bacterial communities and the forces that shape their compositions in non-cultivated plants are largely uncharacterized. In this study, we explored the diversity, community structure, and dynamics of endophytic bacteria in different plant species in the Tallgrass Prairie Preserve of northern Oklahoma, USA. High throughput sequencing of amplified segments of bacterial rDNA from 81 samples collected at four sampling times from five plant species at four locations identified 335 distinct OTUs at 97% sequence similarity, representing 16 phyla. Proteobacteria was the dominant phylum in the communities, followed by the phyla Bacteriodetes and Actinobacteria. Bacteria from four classes of Proteobacteria were detected with Alphaproteobacteria as the dominant class. Analysis of molecular variance revealed that host plant species and collecting date had significant influences on the compositions of the leaf endophytic bacterial communities. The proportion of Alphaproteobacteria was much higher in the communities from Asclepias viridis than from other plant species and differed from month to month. The most dominant bacterial groups identified in LDA Effect Size analysis showed host-specific patterns, indicating mutual selection between host plants and endophytic bacteria and that leaf endophytic bacterial compositions were dynamic, varying with the host plant's growing season in three distinct patterns. In summary, next generation sequencing has revealed variations in the taxonomic compositions of leaf endophytic bacterial communities dependent primarily on the nature of the plant host species. PMID- 26974820 TI - Balance Recovery Prediction with Multiple Strategies for Standing Humans. AB - Human balance recovery from external disturbances is a complex process, and simulating it remains an open challenge. In particular, there still is a need for a comprehensive numerical tool capable of predicting the outcome of a balance perturbation, including in particular the three elementary recovery strategies: ankle, hip and stepping with variable step duration. In order to fill this gap we further developed a previously proposed multiple step balance recovery prediction tool to include the use of the hip strategy and variable step duration. Simulated recovery reactions are compared against observations from different experimental situations from the literature. Reasonable accuracy in terms of step positions and durations were obtained for these different situations using a single set of controller parameters. Moreover, variations in the use of the hip strategy and the step duration between situations were consistent with biomechanical observations. Such a model could be useful to better understand the balance recovery mechanisms, and could also be used to identify potentially hazardous situations. PMID- 26974821 TI - Effects of Subsetting by Parent Materials on Prediction of Soil Organic Matter Content in a Hilly Area Using Vis-NIR Spectroscopy. AB - Assessment and monitoring of soil organic matter (SOM) quality are important for understanding SOM dynamics and developing management practices that will enhance and maintain the productivity of agricultural soils. Visible and near-infrared (Vis-NIR) diffuse reflectance spectroscopy (350-2500 nm) has received increasing attention over the recent decades as a promising technique for SOM analysis. While heterogeneity of sample sets is one critical factor that complicates the prediction of soil properties from Vis-NIR spectra, a spectral library representing the local soil diversity needs to be constructed. The study area, covering a surface of 927 km2 and located in Yujiang County of Jiangsu Province, is characterized by a hilly area with different soil parent materials (e.g., red sandstone, shale, Quaternary red clay, and river alluvium). In total, 232 topsoil (0-20 cm) samples were collected for SOM analysis and scanned with a Vis-NIR spectrometer in the laboratory. Reflectance data were related to surface SOM content by means of a partial least square regression (PLSR) method and several data pre-processing techniques, such as first and second derivatives with a smoothing filter. The performance of the PLSR model was tested under different combinations of calibration/validation sets (global and local calibrations stratified according to parent materials). The results showed that the models based on the global calibrations can only make approximate predictions for SOM content (RMSE (root mean squared error) = 4.23-4.69 g kg-1; R2 (coefficient of determination) = 0.80-0.84; RPD (ratio of standard deviation to RMSE) = 2.19 2.44; RPIQ (ratio of performance to inter-quartile distance) = 2.88-3.08). Under the local calibrations, the individual PLSR models for each parent material improved SOM predictions (RMSE = 2.55-3.49 g kg-1; R2 = 0.87-0.93; RPD = 2.67 3.12; RPIQ = 3.15-4.02). Among the four different parent materials, the largest R2 and the smallest RMSE were observed for the shale soils, which had the lowest coefficient of variation (CV) values for clay (18.95%), free iron oxides (15.93%), and pH (1.04%). This demonstrates the importance of a practical subsetting strategy for the continued improvement of SOM prediction with Vis-NIR spectroscopy. PMID- 26974822 TI - Physicochemical aspects of epoxide driven nano-ZrO2 hydrogel formation: milder kinetics for better properties. AB - Robust and highly transparent quasi amorphous ZrO2-water-glycerol hydrogels were obtained in a mild one pot procedure, based on the 2,3-epoxy-1-propanol driven alkalinization. SAXS-based characterization of the sol-gel transition revealed that an homogeneously nucleated sol composed of 2 nm primary particles continuously grows up to a critical size of 5-6 nm, when gelation takes place. These particles reach a size of 8-10 nm, depending on the Zr(iv) concentration. Conductivity measurements offer an overall in situ assessment of the reaction rate. The gelled samples share a common trend: once the conductivity decays to 40% of the starting value, the primary particles nucleate and when this decay reaches 20%, the sol-gel transition takes place. The mild conditions employed herein prevent massive ripening and recrystallization leaving hydrogels with extremely low undesired visible light scattering. This suitable nanostructure was achieved in a wide range of total Zr(iv) concentrations or water to glycerol ratios. PMID- 26974823 TI - Antitumor and biological investigation of doubly cyclometalated ruthenium(II) organometallics derived from benzimidazolyl derivatives. AB - In this study, we report the synthesis, anticancer and biological properties of three doubly cyclometalated phenylbenzimidazole derived ruthenium(ii) organometallics () and their corresponding three organic ligands. The structures of were fully characterized by various analytical techniques, and the meso stereoisomer of the doubly cyclometalated ruthenacycle was unambiguously confirmed by single crystal X-ray diffraction. The anticancer effects of the newly synthesized compounds were tested against selected human cancer cell lines AGS (gastric carcinoma), SK-hep-1 (hepatocellular carcinoma), and HCT-15 (colorectal carcinoma). The growth inhibitory effects of ruthenacycles on cancer cells were found to be considerably more effective against the abovementioned cancer cells than the reference drug oxaliplatin. Compound exhibited a more specific effect on the AGS cells. Gene-fishing and ELISA array were performed to analyze the target genes and cytokine secretion by . As a result, a significant reduction was observed in RPS21 by . Moreover, increased the secretion of cytokines such as IFNgamma in macrophages and reduced the release of cytokines such as rantes and IGF-1. These results show that could be a very good anticancer drug through the regulation of the RPS21 gene and cytokines. PMID- 26974825 TI - Detection of Porcine Parvovirus 2 (Ungulate Tetraparvovirus 3) Specific Antibodies and Examination of the Serological Profile of an Infected Swine Herd. AB - Porcine parvovirus 2 (PPV2) is a member of a recently discovered group of swine parvoviruses occurring worldwide. It is frequently detected in lung samples suggesting some pathological role of the virus in diseases. To study this possibility an indirect ELISA was developed to detect PPV2 specific antibodies and to examine the serological profile of an infected swine herd where 185 serum samples collected from different age groups including sows were analyzed. According to the results maternal antibody levels decreased until 14 days of age and PPV2 specific antibodies started to rise between 28 to 43 days of age when respiratory signs were also observed in the examined swine herd. At 57 days of age the clinical signs disappeared and a rapid increase of PPV2 specific antibody levels could be measured simultaneously, peaking at 57 days of age. The viraemic status of different age groups was determined by qPCR using serum samples. At least a low level of viraemia was measured in every age group, but higher copy number of PPV2 was only detected at 57 days of age and the level decreased in older age groups. The changes in virus load and antibody levels together with the onset and decrease of clinical signs suggested that PPV2 had a role in the development of respiratory signs. PMID- 26974824 TI - Lack of Thromboxane Synthase Prevents Hypertension and Fetal Growth Restriction after High Salt Treatment during Pregnancy. AB - Preeclampsia (PE) is a potentially fatal pregnancy-related hypertensive disorder characterized by poor placenta development that can cause fetal growth restriction. PE-associated pathologies, including thrombosis, hypertension, and impaired placental development, may result from imbalances between thromboxane A2 (TXA2) and prostacyclin. Low-dose aspirin, which selectively inhibits TXA2 production, is used to prevent high-risk PE. However, the role of TXA2 in aspirin mediated protective effects in women with PE is not understood fully. In this study, we examined the role of prostanoids in PE using human samples and an induced PE mouse model. We demonstrated that the administration of salted drinking water (2.7% NaCl) to wild-type mice resulted in elevated placental TXA2 synthase (TXAS) and plasma TXA2, but not prostacyclin, levels, which was also found in our clinical PE placenta samples. The high salt-treated wild-type pregnant mice had shown unchanged maternal body weight, hypertension (MAP increase 15 mmHg), and decreased pup weight (~50%) and size (~24%), but these adverse effects were ameliorated in TXAS knockout (KO) mice. Moreover, increased expression of interleukin-1beta and downstream phosphorylated-p38-mitogen activated protein kinase were concordant with apoptosis induction in the placentas of salt water-treated wild-type mice. These alterations were not observed in TXAS KO mice. Together, our data suggest that TXA2 depletion has anti PE effects due to the prevention of hypertension and placental damage through downregulation of the interleukin-1beta pathway. PMID- 26974826 TI - Short-Term Effects of Traditional and Alternative Community Interventions to Address Food Insecurity. AB - BACKGROUND: Despite the effects of food insecurity on health are well documented, clear governmental policies to face food insecurity do not exist in western countries. In Canada, interventions to face food insecurity are developed at the community level and can be categorized into two basic strategies: those providing an immediate response to the need for food, defined "traditional" and those targeting the improvement of participants' social cohesion, capabilities and management of their own nutrition, defined "alternative". OBJECTIVE: The objective of this study was to evaluate the effects of food insecurity interventions on food security status and perceived health of participants. DESIGN: This was a longitudinal multilevel study implemented in Montreal, Quebec, Canada. Participants were recruited in a two-stage cluster sampling frame. Clustering units were community organizations working on food insecurity; units of analysis were participants in community food security interventions. A total of 450 participants were interviewed at the beginning and after 9 months of participation in traditional or alternative food security interventions. Food security and perceived health were investigated as dependent variables. Differences overtime were assessed through multilevel regression models. RESULTS: Participants in traditional interventions lowered their food insecurity at follow up. Decreases among participants in alternative interventions were not statistically significant. Participants in traditional interventions also improved physical (B coefficient 3.00, CI 95% 0.42-5.59) and mental health (B coefficient 6.25, CI 95% 4.15-8.35). CONCLUSIONS: Our results challenge the widely held view suggesting the ineffectiveness of traditional interventions in the short term. Although effects may be intervention-dependent, food banks decreased food insecurity and, in so doing, positively affected perceived health. Although study findings demonstrate that food banks offer short term reprise from the effects of food insecurity, the question as to whether food banks are the most appropriate solution to food insecurity still needs to be addressed. PMID- 26974827 TI - Level of job satisfaction amongst nurses in the North-West Province, South Africa: Post occupational specific dispensation. AB - BACKGROUND: Job satisfaction and burnout have been recurring problems amongst nurses in the Republic of South Africa (RSA). As a result, nurses are still leaving the rural public sector in search of lucrative work at the urban and private sectors and in developed countries. Accordingly, Occupational Specific Dispensation (OSD) was introduced as a strategy to ircumvent the problem. However, since the implementation of OSD in 2007, there have been no studies conducted regarding the level of job satisfaction amongst nurses after the implementation of OSD in the North-West Province, especially because each province has its own challenges that are unique to the area. OBJECTIVES: The study had two objectives: to describe the level of job satisfaction amongstprofessional and other category nurses (OCNs) at a public hospital in the North-West Provinceand describe the perceptions of nurses about OSD and their intention to continue working inthe hospital. METHOD: A quantitative descriptive cross-sectional design was used. Stratified random sampling was used to select a sample of 92 professional nurses (PNs), 90 enrolled nurses and enrolled nursing assistants (Nursing Act 2005), which made a total of 182 participants. For the purpose of the study, the enrolled nurses and enrolled nursing assistants were referred to as OCNs. Data were collected using the Minnesota Satisfaction Questionnaire-short form and OSD statements and analysed with Statistical Package for Social Science (SPSS, version 18). RESULTS: The majority of PNs (79.3%, n = 73) and OCNs (86.7%, n = 77) were dissatisfied with the working conditions and salary: PNs (80.4%, n = 74) and OCNs (87.8%, n = 79). The nurses mostly discredited the current state of the OSD implementation. Majority of the PNs (84%, n = 77) and OCNs (91%, n = 82) disagreed with the statement that 'level of job satisfaction has improved after the implementation of OSD'. CONCLUSIONS: The National Department of Health should consider a holistic approach to address all work-related conditions for nurses in order to curb the attrition rates. Policy makers and unions should urgently review OSD for all categories of nurses. PMID- 26974828 TI - Navigating conflicting laws in sexual and reproductive health service provision for teenagers. AB - BACKGROUND: The South African legal and policy framework for sexual and reproductive healthcare provision for teenagers is complex. OBJECTIVE: The article outlines the dilemmas emanating from the legal and policy framework, summarises issues with implementation of the legal and policy framework in practice, and summarises recent changes to the law. METHODS: In-depth analysis of the legal and policy framework. Training workshops with a purposive sample of nurses and other healthcare providers in the Western Cape. FINDINGS: Tensions between consent and confidentiality imposed by the Termination of Pregnancy Act, the Children's Act, the National Health Act and the Criminal Law (Sexual Offences and Related Matters) Amendment Act render conflicting obligations on healthcare providers. Healthcare providers' experiences with service provision in this context show that the conflicting roles they inhabit render their service provision to teenagers more challenging. CONCLUSION: Healthcare providers need to learn about their legal obligations surrounding adolescent sexual and reproductive health services. PMID- 26974829 TI - Assessment of activities performed by clinical nurse practitioners and implications for staffing and patient care at primary health care level in South Africa. AB - BACKGROUND: The shortage of nurses in public healthcare facilities in South Africa is well documented; finding creative solutions to this problem remains a priority. OBJECTIVE: This study sought to establish the amount of time that clinical nurse practitioners (CNPs) in one district of the Western Cape spend on clinical services and the implications for staffing and skills mix in order to deliver quality patient care. METHODS: A descriptive cross-sectional study was conducted across 15 purposively selected clinics providing primary health services in 5 sub-districts. The frequency of activities and time CNPs spent on each activity in fixed and mobile clinics were recorded. Time spent on activities and health facility staff profiles were correlated and predictors of the total time spent by CNPs with patients were identified. RESULTS: The time spent on clinical activities was associated with the number of CNPs in the facilities. CNPs in fixed clinics spent a median time of about 13 minutes with each patient whereas CNPs in mobile clinics spent 3 minutes. Fixed-clinic CNPs also spent more time on their non-core functions than their core functions, more time with patients, and saw fewer patients compared to mobile-clinic CNPs. CONCLUSIONS: The findings give insight into the time CNPs in rural fixed and mobile clinics spend with their patients, and how patient caseload may affect consultation times. Two promising strategies were identified - task shifting and adjustments in health workerd eployment - as ways to address staffing and skills mix, which skills mix creates the potential for using healthcare workers fully whilst enhancing the long-term health of these rural communities. PMID- 26974830 TI - Multilevel Corpectomy With Anterior Column Reconstruction and Plating for Subaxial Cervical Osteomyelitis. AB - STUDY DESIGN: A retrospective case series. OBJECTIVE: The aim of this study was to evaluate patients with cervical spine osteomyelitis who underwent multilevel (>=2) subaxial corpectomies and anterior column reconstruction and plating. SUMMARY OF BACKGROUND DATA: Neglected multilevel subaxial cervical osteomyelitis is a potentially dangerous disease. As it is rare, early radiographic and clinical outcomes after multilevel anterior corpectomy and reconstruction for subaxial cervical osteomyelitis are incompletely defined. METHODS: Adults who underwent multilevel corpectomy and anterior plating/reconstruction for subaxial cervical osteomyelitis at two institutions were reviewed. Analysis of patient demographics, operative details, and radiographic cervical alignment parameters [segmental kyphosis, cervical lordosis, C2-7 sagittal vertical axis (SVA)] was performed. RESULTS: Nineteen patients [15 males, four females; average age 48 years (20-81 yrs)] met inclusion criteria. The majority had pre-operative neurologic deficits or was immunosuppressed. All were treated with >=6 weeks of intravenous antibiotics following operation. All had anterior plating/reconstruction with titanium cages (expandable-6; mesh-6) or structural bone graft (fibular allogaft-6; tricortical iliac crest-1). The average number of corpectomies was 2.4 (2-4). The average numbers of levels fused anteriorly was 4.4 (4-6) and posteriorly was 6.3 (4-9). The majority of patients (74%) was treated with an anterior/posterior approach. Average follow-up was 16 +/- 9 months. There was significant improvement in all cervical alignment parameters (segmental kyphosis, C2-7 SVA, cervical lordosis). No intraoperative complications occurred and no patient deteriorated neurologically postoperatively. Postoperative complications included anterior cage/graft dislodgement (n = 2), recurrent neck hematomas requiring revision (n = 1), epidural hematoma (n = 1), and wound infection (n = 1). Sixty percent of patients had persistent neurologic dysfunction at final follow-up. None required reoperation for recurrent infection or pseudarthrosis. CONCLUSION: Although overall prognosis and neurologic recovery are guarded in medically fragile patients with multilevel subaxial cervical osteomyelitis, reconstruction with multilevel (>=2) corpectomy and anterior reconstruction/plating results in excellent restoration of cervical alignment and low rates of recurrent infection and pseudarthrosis. LEVEL OF EVIDENCE: 4. PMID- 26974831 TI - The Influence of Diabetes on Surgical Outcomes in Cervical Myelopathy. AB - STUDY DESIGN: A retrospective cohort. OBJECTIVE: The objective of the study was to determine what effect, if any, diabetes has on surgical outcomes in patients with cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: Diabetes is known to impair healing and has been shown to affect outcomes in lumbar surgery, but few studies have assessed outcomes in cervical surgery, and cervical myelopathy in particular. METHODS: The records of 113 patients operated on by one surgeon were reviewed. Inclusion criteria were a diagnosis of CSM with a Nurick score, surgical interventions, and minimum 2 years follow-up. Patients were divided into two groups according to diabetes status (33 diabetic patients vs. 80 controls) and diabetic patients were further categorized by degree of perioperative glucose control. Simple and multiple regression analyses were done to compare outcomes as recorded by the Nurick score, controlling for age, gender, duration of symptoms, alcohol use, cocaine use, surgical approach, prior surgery, and signal change on preoperative magnetic resonance imaging. RESULTS: There was no relationship between diabetes status and preoperative Nurick score. However, diabetes status was associated with impaired improvement in Nurick score. Average perioperative glucose in diabetic individuals was linearly associated with impaired improvement in Nurick score. CONCLUSION: We conclude that hyperglycemia may impair postoperative healing of the spinal cord in patients with CSM. LEVEL OF EVIDENCE: 3. PMID- 26974832 TI - Do Caucasians and East Asians have Different Outcomes Following Surgery for the Treatment of Degenerative Cervical Myelopathy?: Results From the Prospective Multicenter AOSpine International Study. AB - STUDY DESIGN: A prospective multicenter cohort study. OBJECTIVE: The aim of this study was to compare outcomes of surgery for the treatment for degenerative cervical myelopathy (DCM) between Caucasians and East Asians. SUMMARY OF BACKGROUND DATA: Numerous studies have indicated that race can influence both disease prevalence and clinical prognosis in a variety of medical conditions; however, none have evaluated the impact of race on surgical outcomes in patients with DCM. METHODS: Four hundred and seventy-nine patients with symptomatic DCM were enrolled in the prospective AOSpine CSM-International study at 16 global sites. Preoperatively, and at each follow-up, patients were evaluated using the modified Japanese Orthopedic Association scale (mJOA), the Nurick score, the Neck Disability Index (NDI), and the Short- Form 36 (SF-36) Health Survey. A mixed model analytic approach was used to evaluate differences in outcomes between races at 24 months postoperatively, while controlling for relevant baseline characteristics and surgical factors. RESULTS: Three hundred and twenty-four (67.64%) patients were Caucasian and 106 (22.13%) were East Asian. There was no difference in the incidence of ossification of the posterior longitudinal ligament (OPLL) between the two races; however a greater percentage of Caucasians in India (46.15%) and Turkey (41.38%) displayed evidence of OPLL than Caucasians in other regions (P < 0.001). The frequency of spondylosis was significantly higher in Caucasians (P < 0.001). Caucasians had a longer duration of symptoms (27.33 +/- 34.47 months) than East Asians (23.11 +/- 35.68 months) (P < 0.001), and a lower preoperative score on the SF-36 Physical Component Score (33.85 +/- 9.04) than East Asians (37.47 +/- 8.67) (P < 0.001). At 24 months after surgery, there were no differences in functional status or QOL between East Asians and Caucasians, after adjusting for baseline characteristics, surgical preferences, and disease causation. Rates of perioperative complications were not significantly different between the races (P = 0.261). CONCLUSION: Decompressive surgery for DCM results in comparable functional gains and is equally safe in Caucasians and East Asians. LEVEL OF EVIDENCE: 2. PMID- 26974833 TI - Resistin Promotes Intervertebral Disc Degeneration by Upregulation of ADAMTS-5 Through p38 MAPK Signaling Pathway. AB - STUDY DESIGN: Rat nucleus pulposus (NP) cells were activated with resistin with or without p38 mitogen-activated protein kinase (MAPK) pathway inhibition. The expression of a disintegrin and metalloprotease with thrombospondin motif-5 (ADAMTS-5), which plays an important role in intervertebral disc degeneration (IDD), was determined. OBJECTIVE: The aim of this study was to demonstrate whether resistin can influence the ADAMTS-5 expression and to further investigate the underlying mechanisms. SUMMARY OF BACKGROUND DATA: Obesity has been demonstrated to promote IDD, whereas the exact mechanism remains poorly understood. Resistin, as an important adipokine, is increased with obesity and has been shown to play pro-inflammatory and catabolic role in cartilage metabolism. However, the effect of resistin on the catabolic enzymes within NP cells remains unknown. METHODS: We exposed NP cells to resistin, and the transcriptional activity, gene expression, and protein levels of ADAMTS-5 were measured by luciferase reporter assay, qRT-polymerase chain reaction, immunofluorescence, and western blot, respectively. The activation of p38 MAPK pathways was detected using western blot analysis. RESULTS: Resistin had no effect on cell viability. Resistin increased ADAMTS-5 expression in rat NP cells time and dose dependently. The p38 MAPK signaling pathway was activated after exposure to resistin. Treatment with p38 inhibitor decreased the upregulation of ADAMTS-5 by resistin. CONCLUSION: The current study, for the first time, investigated the role of resistin in ADAMTS-5 regulation in IDD. These findings provide novel evidence supporting the causative role of obesity in IDD, which is important to develop novel preventative or therapeutic treatment in disc degenerative disorders. LEVEL OF EVIDENCE: N/A. PMID- 26974834 TI - Magnetically controlled Growing Rods for Early-onset Scoliosis: A Multicenter Study of 23 Cases With Minimum 2 years Follow-up. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To report 2-year clinical and radiographic results of patients treated with magnetically controlled growing rods (MCGR). SUMMARY OF BACKGROUND DATA: MCGR for early-onset scoliosis has been reported to provide adequate spinal growth and curve correction by eliminating surgical lengthening procedures. This study was designed to report the results of MCGR patients with 2-year follow-up. METHODS: A retrospective study of MCGR patients with the following inclusion criteria: (i) major curve size >=30 degrees , (ii) T1-T12 height <22 cm, (iii) <11-years old; all at the time of index surgery was performed. Of 54 patients enrolled, 23 had 2-year follow-up. Both primary and conversion patients were evaluated at baseline 6, 12, and 24 months. RESULTS: Mean preoperative age in the primary group was 6.6 +/- 2.6 years versus 8.3 +/- 2.2 years for the conversion group. A total of 41 adverse events occurred in 11 patients, of which 14 events were implant related. Major coronal curve magnitude improved from 61.3 degrees to 34.3 degrees from baseline to postoperation in primary cases and from 49.4 degrees to 43.8 degrees in conversion cases. Curve correction was maintained for 2 years in both groups. T1 S1 height improved from 252.7 to 288.9 mm in primary cases and was maintained for 2 years. However, conversion cases had some decline in T1- S1 height (270.3 at baseline to 294.4 mm post-MCGR and 290.2 mm at 2-year follow-up; mean loss of 4.2 mm (1.5%) from postoperation to 2 years, P > 0.05). CONCLUSION: This study showed satisfactory curve correction and growth is achieved among primary cases. T1-S1 height in conversion cases had a slight decline in 2 years. However, this decline was not statistically significant. LEVEL OF EVIDENCE: 3. PMID- 26974835 TI - Effects of Intraoperative Anesthetic Medications on Postoperative Urinary Retention After Single-Level Lumbar Fusion. AB - STUDY DESIGN: Retrospective cohort analysis. OBJECTIVE: The aim of the study was to identify medications that may potentially contribute to developing postoperative urinary retention (POUR) after lumbar spinal fusion procedures. SUMMARY OF BACKGROUND DATA: POUR is a concerning event that may occur after routine orthopedic surgery. The relation between intraoperative medications and POUR after lumbar spine surgery has not been well characterized. METHODS: A prospectively maintained database of patients who underwent a primary single level, minimally invasive transforaminal lumbar interbody fusion between 2009 and 2013 was reviewed. POUR was defined as a bladder scan of 300 mL or higher, the postoperative necessity of a straight catheterization, or a urology consult for urinary retention. The use and dose-response of intraoperative medications between patients with and without POUR were compared. Potential risk factors for developing POUR were analyzed using multivariate analysis. RESULTS: A total of 205 patients were included in the study, 17% of whom experienced POUR (n = 34). Administration of phenylephrine and neostigmine was associated with POUR (phenylephrine: 32.3% vs. 13.8%, P = 0.017; neostigmine: 19.5% vs. 6.5%, P = 0.042). Parametric analysis demonstrated an association of increasing dose of neostigmine with POUR (4.66 vs. 4.22 mg, P = 0.023). Similarly, a nonparametric analysis demonstrated an association of increasing doses of both neostigmine and phenylephrine with POUR (neostigmine: 4.25 vs. 3.16 mg, P = 0.02; phenylephrine: 105.88 vs. 40.64 mg, P = 0.008). CONCLUSION: Approximately 20% of patients may develop POUR after routine lumbar spine surgery. The use of certain intraoperative anesthetics such as phenylephrine and neostigmine is strongly associated with the development of POUR postoperatively. This finding suggests that there may be modifiable anesthetic risk factors to prevent the development of POUR in patients undergoing lumbar spine surgery. Future prospective, controlled studies specifically addressing these findings could lead to improved patient care and decreased healthcare costs. LEVEL OF EVIDENCE: 4. PMID- 26974836 TI - Sagittal Plane Correction Using the Lateral Transpsoas Approach: A Biomechanical Study on the Effect of Cage Angle and Surgical Technique on Segmental Lordosis. AB - STUDY DESIGN: Cadaveric biomechanical study. OBJECTIVE: To determine the degree of segmental correction that can be achieved through lateral transpsoas approach by varying cage angle and adding anterior longitudinal ligament (ALL) release and posterior element resection. SUMMARY OF BACKGROUND DATA: Lordotic cage insertion through the lateral transpsoas approach is being used increasingly for restoration of sagittal alignment. However, the degree of correction achieved by varying cage angle and ALL release and posterior element resection is not well defined. METHODS: Thirteen lumbar motion segments between L1 and L5 were dissected into single motion segments. Segmental angles and disk heights were measured under both 50 N and 500 N compressive loads under the following conditions: intact specimen, discectomy (collapsed disk simulation), insertion of parallel cage, 10 degrees cage, 30 degrees cage with ALL release, 30 degrees cage with ALL release and spinous process (SP) resection, 30 degrees cage with ALL release, SP resection, facetectomy, and compression with pedicle screws. RESULTS: Segmental lordosis was not increased by either parallel or 10 degrees cages as compared with intact disks, and contributed small amounts of lordosis when compared with the collapsed disk condition. Placement of 30 degrees cages with ALL release increased segmental lordosis by 10.5 degrees . Adding SP resection increased lordosis to 12.4 degrees . Facetectomy and compression with pedicle screws further increased lordosis to approximately 26 degrees . No interventions resulted in a decrease in either anterior or posterior disk height. CONCLUSION: Insertion of a parallel or 10 degrees cage has little effect on lordosis. A 30 degrees cage insertion with ALL release resulted in a modest increase in lordosis (10.5 degrees ). The addition of SP resection and facetectomy was needed to obtain a larger amount of correction (26 degrees ). None of the cages, including the 30 degrees lordotic cage, caused a decrease in posterior disk height suggesting hyperlordotic cages do not cause foraminal stenosis. LEVEL OF EVIDENCE: N/A. PMID- 26974837 TI - Quality of Life in Rural Communities: Residents Living Near to Tembeling, Pahang and Muar Rivers, Malaysia. AB - The main aim of this study is to identify the quality of life (QoL) among communities residing near the Tembeling, Pahang and Muar Rivers in Malaysia. This quantitative study used a constructed questionnaire as main tool to collect data on the QoL of river communities. A total of 240 villagers were selected as respondents. The results indicated that the dimensions of settlement, safety, involvement and social relationships, as well as education scored highest, while dimensions of physical environment, financial and job security yielded moderate scores. Dimensions of infrastructure facilities yielded a low mean score. Recommendations are provided, in the hope that our results may be useful for strategies that could enhance QoL of these river communities. PMID- 26974838 TI - Transient Pinning and Pulling: A Mechanism for Bending Microtubules. AB - Microtubules have a persistence length of the order of millimeters in vitro, but inside cells they bend over length scales of microns. It has been proposed that polymerization forces bend microtubules in the vicinity of the cell boundary or other obstacles, yet bends develop even when microtubules are polymerizing freely, unaffected by obstacles and cell boundaries. How these bends are formed remains unclear. By tracking the motions of microtubules marked by photobleaching, we found that in LLC-PK1 epithelial cells local bends develop primarily by plus-end directed transport of portions of the microtubule contour towards stationary locations (termed pinning points) along the length of the microtubule. The pinning points were transient in nature, and their eventual release allowed the bends to relax. The directionality of the transport as well as the overall incidence of local bends decreased when dynein was inhibited, while myosin inhibition had no observable effect. This suggests that dynein generates a tangential force that bends microtubules against stationary pinning points. Simulations of microtubule motion and polymerization accounting for filament mechanics and dynein forces predict the development of bends of size and shape similar to those observed in cells. Furthermore, simulations show that dynein-generated bends at a pinning point near the plus end can cause a persistent rotation of the tip consistent with the observation that bend formation near the tip can change the direction of microtubule growth. Collectively, these results suggest a simple physical mechanism for the bending of growing microtubules by dynein forces accumulating at pinning points. PMID- 26974840 TI - Food Value of Mealworm Grown on Acrocomia aculeata Pulp Flour. AB - Insects have played an important role as human food throughout history, especially in Africa, Asia and Latin America. A good example of edible insects is the mealworm, Tenebrio molitor Linnaeus, 1758 (Coleoptera, Tenebrionidae), which are eaten in Africa, Asia, the Americas and Australia. This species is easily bred in captivity, requiring simple management. The bocaiuva (Acrocomia aculeata (Jacq.) Lodd) is an abundant palm tree found in the Brazilian Cerrado, providing fruits with high nutritional value. The aim of this work was to determine the chemical composition of T. molitor grown in different artificial diets with bocaiuva pulp flour. The nutritional composition, fatty acid composition, antioxidant activity, trypsin activity and anti-nutritional factors of larvae were analyzed. The results showed that mealworms grown on artificial diet with bocaiuva are a good source of protein (44.83%) and lipid (40.45%), with significant levels of unsaturated fatty acids (65.99%), antioxidant activity (4.5 MUM Trolox/g of oil extracted from larvae) and absence of anti-nutritional factors. This study indicates a new source of biomass for growing mealworms and shows that it is possible to breed mealworms in artificial diet with bocaiuva flour without compromising the nutritional quality of the larvae. PMID- 26974839 TI - Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium. AB - Defences against the bacteria that usually infect the endometrium of postpartum cattle are impaired when there is metabolic energy stress, leading to endometritis and infertility. The endometrial response to bacteria depends on innate immunity, with recognition of pathogen-associated molecular patterns stimulating inflammation, characterised by secretion of interleukin (IL)-1beta, IL-6 and IL-8. How metabolic stress impacts tissue responses to pathogens is unclear, but integration of energy metabolism and innate immunity means that stressing one system might affect the other. Here we tested the hypothesis that homeostatic pathways integrate energy metabolism and innate immunity in bovine endometrial tissue. Glucose deprivation reduced the secretion of IL-1beta, IL-6 and IL-8 from ex vivo organ cultures of bovine endometrium challenged with the pathogen-associated molecular patterns lipopolysaccharide and bacterial lipopeptide. Endometrial inflammatory responses to lipopolysaccharide were also reduced by small molecules that activate or inhibit the intracellular sensor of energy, AMP-activated protein kinase (AMPK). However, inhibition of mammalian target of rapamycin, which is a more global metabolic sensor than AMPK, had little effect on inflammation. Similarly, endometrial inflammatory responses to lipopolysaccharide were not affected by insulin-like growth factor-1, which is an endocrine regulator of metabolism. Interestingly, the inflammatory responses to lipopolysaccharide increased endometrial glucose consumption and induced the Warburg effect, which could exacerbate deficits in glucose availability in the tissue. In conclusion, metabolic energy stress perturbed inflammatory responses to pathogen-associated molecular patterns in bovine endometrial tissue, and the most fundamental regulators of cellular energy, glucose availability and AMPK, had the greatest impact on innate immunity. PMID- 26974841 TI - Feasibility of cell-free circulating tumor DNA testing for lung cancer. AB - Tumor tissue genotyping is used routinely for lung cancer to identify specific targetable oncogenic alterations, including EGFR mutations and ALK rearrangements. However, tumor tissue from a single biopsy is often insufficient for molecular testing, may offer a limited evaluation because of tumor heterogeneity and can be difficult to obtain. Cell-free circulating tumor DNA has been widely investigated as a potential surrogate for tissue biopsy for noninvasive assessment of tumor-related genomic alterations. New techniques have improved EGFR mutations detection in ctDNA, thus supporting the use of this liquid biopsy for predicting response to EGFR tyrosine kinase inhibitors (TKIs) and monitoring the emergence of resistance. The serial evaluation of ctDNA during treatment is feasible and can be used to track tumor changes in real time and for a wide range of clinically useful applications. PMID- 26974843 TI - High Prevalence of Stroke in Rural Gadchiroli, India: A Community-Based Study. AB - BACKGROUND: In the near future, a majority of strokes are projected to occur in developing countries. However, population-level information on the prevalence of stroke from rural areas of developing countries, including India, is rare. We estimated the prevalence of stroke in a rural area of one of the most underdeveloped districts of India. METHODS: Trained surveyors conducted a house to-house survey using a validated screening questionnaire in a well-defined population of 45,053 living in 39 villages in a demographic surveillance site in Gadchiroli district. A trained physician and a neurologist evaluated screen positive patients and diagnosed stroke using the World Health Organization's criteria. RESULTS: In the screened population, 175 patients had stroke. The mean age of patients with stroke was 60.9 +/- 14.7 years and 32.5% were women. The crude prevalence rate of stroke was 388.43 (95% CI 335.04-450.33) and the age standardized prevalence rate of stroke was 535.58 (95% CI 492.41-583.01) per 100,000 population. The crude prevalence rate of stroke was significantly higher among men than among women (520 vs. 255/100,000 population, p < 0.05). CONCLUSION: In this prevalence study, conducted after a gap of 20 years in rural India, the prevalence of stroke was high and was more than twice the prevalence reported from the previous study. The prevalence was double among men compared to women. Stroke is emerging as a public health priority in rural India. PMID- 26974842 TI - Quantitative Susceptibility Mapping-Based Microscopy of Magnetic Resonance Venography (QSM-mMRV) for In Vivo Morphologically and Functionally Assessing Cerebromicrovasculature in Rat Stroke Model. AB - Abnormal cerebral oxygenation and vessel structure is a crucial feature of stroke. An imaging method with structural and functional information is necessary for diagnosis of stroke. This study applies QSM-mMRV (quantitative susceptibility mapping-based microscopic magnetic resonance venography) for noninvasively detecting small cerebral venous vessels in rat stroke model. First, susceptibility mapping is optimized and calculated from magnetic resonance (MR) phase images of a rat brain. Subsequently, QSM-mMRV is used to simultaneously provide information on microvascular architecture and venous oxygen saturation (SvO2), both of which can be used to evaluate the physiological and functional characteristics of microvascular changes for longitudinally monitoring and therapeutically evaluating a disease model. Morphologically, the quantification of vessel sizes using QSM-mMRV was 30% smaller than that of susceptibility weighted imaging (SWI), which eliminated the overestimation of conventional SWI. Functionally, QSM-mMRV estimated an average SvO2 ranging from 73% to 85% for healthy rats. Finally, we also applied QSM to monitor the revascularization of post-stroke vessels from 3 to 10 days after reperfusion. QSM estimations of SvO2 were comparable to those calculated using the pulse oximeter standard metric. We conclude that QSM-mMRV is useful for longitudinally monitoring blood oxygen and might become clinically useful for assessing cerebrovascular diseases. PMID- 26974844 TI - New developments in prostate cancer biomarkers. AB - PURPOSE OF REVIEW: The initial management of localized prostate cancer is increasingly complex with the identification of a growing number of prognostic subgroups. Molecular and genetic biomarkers have been proposed to help clinicians and patients navigate treatment decisions. RECENT FINDINGS: Three commercially available tests, the Genomic Prostate score, Cell Cycle Progression score, and Genomic Classifier appear to currently have the most supporting data for their use in localized prostate cancer. All three have been shown to identify men at higher risk for poor outcome following radical prostatectomy in retrospective studies whereas the first two have also shown promise in addressing which men might be appropriate for active surveillance. Only the Genomic Classifier has data supporting its use as a predictive marker in addition to a prognostic marker. SUMMARY: Over the past several years, the management of localized prostate cancer has seen the development of several novel biomarkers aimed at improving decision making. Although a lack of prospective validation makes it challenging to know how best to change management based on the results from any of the tests, the growing body of retrospective data suggests significant promise in this arena. PMID- 26974845 TI - Management of advanced nodal disease in patients treated with primary chemoradiotherapy. AB - PURPOSE OF REVIEW: The management of advanced nodal disease in patients treated with chemoradiotherapy has been a controversial topic for many years. New data have recently been reported, including the results of a multicentre randomized trial making this review timely. RECENT FINDINGS: The PET-NECK trial showed that PET-computer tomography (CT) surveillance is as effective as planned neck dissection in terms of overall survival, but results in much fewer neck dissections, less complications and is more cost effective. Cost-effectiveness data from a single centre study demonstrated that strategies that include PET-CT were more effective than CT-alone-guided strategies. SUMMARY: There is now level 1 evidence to support image-guided surveillance strategies as the standard of care for advanced nodal disease in patients treated with primary chemoradiotherapy. PMID- 26974847 TI - MYB-fusions and other potential actionable targets in adenoid cystic carcinoma. AB - PURPOSE OF REVIEW: Adenoid cystic carcinoma (ACC) is a rare cancer of the secretory glands, typically originating in the salivary glands of the head and neck. The impact of chemotherapy on survival is unclear and there are no standard of-care treatments for patients with recurrent or metastatic disease. This article reviews recently completed and ongoing clinical trials for patients with ACC and describes recently identified potentially targetable genomic alterations in this orphan disease. RECENT FINDINGS: In spite of an overall low mutational burden, genotyping of ACC samples has shed some light about the disease biology. In addition to the frequent translocations involving MYB or MYBL, recurrent alterations in genes involved in chromatin deregulation, FGF, PI3K, NOTCH1, and DNA damage repair pathways have been identified. Many of these genomic alterations are targetable and drug screening is ongoing in genotyped ACC patient derived murine xenografts. SUMMARY: Clinical studies with targeted agents in unselected ACC patients have not been promising thus far. The identification of potential driver oncogenes suggests that targeted therapy might be effective in molecularly-defined patient subgroups and merits investigation in future clinical studies. PMID- 26974846 TI - Vitamin D and cancer: does it really matter? AB - PURPOSE OF REVIEW: This article provides a background for an evidence-based decision regarding the prescription of vitamin D for cancer prevention and improvement of outcomes in oncology. RECENT FINDINGS: In 2014, Feldman and colleagues published a review suggesting a beneficial role for vitamin D in cancer development. In the same year, a Cochrane meta-analysis that included 18 randomized clinical trials comparing vitamin D administration versus no intervention in healthy population found no difference regarding cancer incidence between the groups. One year later, a phase III trial published in the New England Journal of Medicine did not show any protective effect of vitamin D against adenoma development. SUMMARY: Vitamin D is well known for its importance in calcium and phosphate homeostasis, being essential for bone mineralization. However, calcitriol, or 1,25-dyhydroxy-vitamin D3, is a multifunctional steroid hormone with many extra skeletal actions and may regulate signaling pathways related to cancer development and progression. In preclinical studies, it was shown that vitamin D can promote cell differentiation and inhibit proliferation, angiogenesis, and cell migration. Inconsistent results are found in epidemiological studies and early trials regarding clinical effects of vitamin D supplementation and cancer in terms of prevention and impact in cancer-related mortality. PMID- 26974848 TI - Cerebral Microbleeds and Lacunar Infarcts Are Associated with Walking Speed Independent of Cognitive Performance in Middle-Aged to Older Adults. AB - BACKGROUND: The positive relationship between cognitive and physical performance has been widely established. The influence of brain structure on both domains has been shown as well. OBJECTIVE: We studied whether the relationship between brain structure and physical performance is independent of cognitive performance. METHODS: This was a cross-sectional analysis of 297 middle-aged to older adults (mean age +/- SD 65.4 +/- 6.8 years). Memory function, executive function and physical performance measured by the Tandem Stance Test, Chair Stand Test, 4 meter walk and 25-meter walk were assessed. Magnetic resonance imaging was available in 237 participants and used to determine the (sub)cortical gray matter, white matter, hippocampal and basal ganglia volumes and the presence of cerebral small-vessel disease, i.e. white matter hyperintensities, cerebral microbleeds (CMBs) and lacunar infarcts (LIs). Regression analysis was used adjusting for age, gender, education and whole-brain volume. A Bonferroni correction was applied considering p values <0.017 as statistically significant. RESULTS: Poor memory function was associated with a slower 4-meter walking speed (p < 0.01). No association was found between brain structure and cognitive performance. The presence of CMBs and LIs was associated with a slower 25-meter walking speed (p < 0.001). This result did not change after additional adjustment for cognitive performance. CONCLUSIONS: In middle-aged to older adults, CMBs and LIs are associated with walking speed independent of cognitive performance. This emphasizes the clinical relevance of identifying each of the possible underlying mechanisms of physical performance, which is required for the development of timely and targeted therapies. PMID- 26974851 TI - ORA47 (octadecanoid-responsive AP2/ERF-domain transcription factor 47) regulates jasmonic acid and abscisic acid biosynthesis and signaling through binding to a novel cis-element. AB - ORA47 (octadecanoid-responsive AP2/ERF-domain transcription factor 47) of Arabidopsis thaliana is an AP2/ERF domain transcription factor that regulates jasmonate (JA) biosynthesis and is induced by methyl JA treatment. The regulatory mechanism of ORA47 remains unclear. ORA47 is shown to bind to the cis-element (NC/GT)CGNCCA, which is referred to as the O-box, in the promoter of ABI2. We proposed that ORA47 acts as a connection between ABA INSENSITIVE1 (ABI1) and ABI2 and mediates an ABI1-ORA47-ABI2 positive feedback loop. PORA47:ORA47-GFP transgenic plants were used in a chromatin immunoprecipitation (ChIP) assay to show that ORA47 participates in the biosynthesis and/or signaling pathways of nine phytohormones. Specifically, many abscisic acid (ABA) and JA biosynthesis and signaling genes were direct targets of ORA47 under stress conditions. The JA content of the P35S:ORA47-GR lines was highly induced under wounding and moderately induced under water stress relative to that of the wild-type plants. The wounding treatment moderately increased ABA accumulation in the transgenic lines, whereas the water stress treatment repressed the ABA content. ORA47 is proposed to play a role in the biosynthesis of JA and ABA and in regulating the biosynthesis and/or signaling of a suite of phytohormone genes when plants are subjected to wounding and water stress. PMID- 26974849 TI - Effects of egg-adaptation on receptor-binding and antigenic properties of recent influenza A (H3N2) vaccine viruses. AB - Influenza A virus (subtype H3N2) causes seasonal human influenza and is included as a component of influenza vaccines. The majority of vaccine viruses are isolated and propagated in eggs, which commonly results in amino acid substitutions in the haemagglutinin (HA) glycoprotein. These substitutions can affect virus receptor-binding and alter virus antigenicity, thereby, obfuscating the choice of egg-propagated viruses for development into candidate vaccine viruses. To evaluate the effects of egg-adaptive substitutions seen in H3N2 vaccine viruses on sialic acid receptor-binding, we carried out quantitative measurement of virus receptor-binding using surface biolayer interferometry with haemagglutination inhibition (HI) assays to correlate changes in receptor avidity with antigenic properties. Included in these studies was a panel of H3N2 viruses generated by reverse genetics containing substitutions seen in recent egg propagated vaccine viruses and corresponding cell culture-propagated wild-type viruses. These assays provide a quantitative approach to investigating the importance of individual amino acid substitutions in influenza receptor-binding. Results show that viruses with egg-adaptive HA substitutions R156Q, S219Y, and I226N, have increased binding avidity to alpha2,3-linked receptor-analogues and decreased binding avidity to alpha2,6-linked receptor-analogues. No measurable binding was detected for the viruses with amino acid substitution combination 156Q+219Y and receptor-binding increased in viruses where egg-adaptation mutations were introduced into cell culture-propagated virus. Substitutions at positions 156 and 190 appeared to be primarily responsible for low reactivity in HI assays with post-infection ferret antisera raised against 2012-2013 season H3N2 viruses. Egg-adaptive substitutions at position 186 caused substantial differences in binding avidity with an insignificant effect on antigenicity. PMID- 26974852 TI - The Economic and Health-related Impact of Crohn's Disease in the United States: Evidence from a Nationally Representative Survey. AB - BACKGROUND: Approximately 593,000 to 780,000 people in the United States (US) have been diagnosed with Crohn's disease (CD), and an additional 33,000 are diagnosed yearly. Our objective was to estimate CD's impact on medical costs, lost earnings, work and school absences, health status, and health-related quality of life (HRQOL) in the US and to compute current and forecasted national costs. METHODS: We used the nationally representative Medical Expenditure Panel Survey to match 539 respondents with CD to similar respondents without any inflammatory bowel disease (IBD). We estimated annual costs, work and school absences, and self-assessed health status. HRQOL was assessed by the SF-12 Physical Component Summary and Mental Component Summary (PCS and MCS) scores. CD prevalence rates, population counts, and costs were used to forecast total national costs. RESULTS: CD is associated with higher medical costs ($13,446 versus $6029) and lost earnings ($1249 versus $644) and is responsible for $3.48 billion in total national costs (expected to increase to $3.72 billion in 2025). Respondents with CD were more likely to miss work (38% versus 33%) or school (64% versus 33%), less likely to report being in excellent or very good physical health (24% versus 63%), and experienced lower HRQOL measured by the Physical Component Summary (43.4 versus 48.5) and Mental Component Summary (48.6 versus 50.0) than those without IBD. CONCLUSIONS: CD is responsible for increased medical care costs and lower earnings, health status, and HRQOL. These data can serve as benchmarks when examining future CD-related costs and HRQOL. PMID- 26974853 TI - Portuguese Validation of the Internet Gaming Disorder Scale-Short-Form. AB - In the latest (fifth) edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), Internet Gaming Disorder (IGD) was included as a tentative disorder worthy of future research. Since then, several psychometric instruments to assess IGD have emerged in the literature, including the nine-item Internet Gaming Disorder Scale-Short-Form (IGDS9-SF), the most brief tool available to date. Research on the effects of IGD in Portugal has been minimal and may be due to the lack of a psychometrically validated tool to assess this construct within this particular cultural background. Therefore, the aim of the present study was to develop and examine the psychometric properties of the Portuguese IGDS9-SF. A total of 509 adolescents were recruited to the present study. Construct validity of the IGDS9-SF was assessed in two ways. First, confirmatory factor analysis was performed to investigate the factorial structure of the IGDS9-SF in the sample, and the unidimensional structure of the IGDS9-SF fitted the data well. Second, nomological validation of the IGDS9-SF was carried out and the nomological network analyzed was replicated as expected, further supporting the construct validity of the IGDS9-SF. Criterion validity of the IGDS9-SF was also established using key criterion variables. Finally, the IGDS9-SF also showed satisfactory levels of reliability using several indicators of internal consistency. Based on the results found, the IGDS9-SF appears to be a valid and reliable instrument to assess IGD among Portuguese adolescents and further research on IGD in Portugal is warranted. PMID- 26974854 TI - Formulating an Ideal Protein Photoresist for Fabricating Dynamic Microstructures with High Aspect Ratios and Uniform Responsiveness. AB - The physical properties of aqueous-based stimuli-responsive photoresists are crucial in fabricating microstructures with high structural integrity and uniform responsiveness during two-photon lithography. Here, we quantitatively investigate how various components within bovine serum albumin (BSA) photoresists affect our ability to achieve BSA microstructures with consistent stimuli-responsive properties over areas exceeding 10(4) MUm(2). We unveil a relationship between BSA concentration and dynamic viscosity, establishing a threshold viscosity to achieve robust BSA microstructures. We also demonstrate the addition of an inert polymer to the photoresist as viscosity enhancer. A set of systematically optimized processing parameters is derived for the construction of dynamic BSA microstructures. The optimized BSA photoresists and processing parameters enable us to extend the two-dimensional (2D) microstructures to three-dimensional (3D) ones, culminating in arrays of micropillars with aspect ratio > 10. Our findings foster the development of liquid stimuli-responsive photoresists to build multifunctional complex 3D geometries for applications such as bioimplantable devices or adaptive photonic systems. PMID- 26974855 TI - Transcription Driven Phase Separation in Chromatin Brush. AB - We theoretically predict the local density of nucleosomes on DNA brushes in a solution of molecules, which are necessary for transcription and the assembly of nucleosomes. Our theory predicts that in a confined space, DNA brushes show phase separation, where a region of relatively large nucleosomal occupancy coexists with a region of smaller nucleosomal occupancy. This phase separation is driven by an instability arising from the fact that the rate of transcription increases as the nucleosomal occupancy decreases due to the excluded volume interactions between nucleosomes and RNA polymerase during thermal diffusion and, in turn, nucleosomes are (in some cases) desorbed from DNA when RNA polymerase collides with nucleosomes during transcription. The miscibility phase diagram shows critical points, which are sensitive to the rate constants involved in transcription, the changes of interactions of DNA chain segments by assembling nucleosomes, and pressures that are applied to the brushes. PMID- 26974856 TI - Neuroscience meets salivary bioscience: An integrative perspective. AB - Advances in salivary bioscience enable unique opportunities to explore individual differences in biological mechanisms related to learning and memory, psychiatric disorders, and more recently neurodegenerative diseases, neurotrauma/stroke, pain, and sleep. Sampling oral fluid is not only minimally invasive, but specimens can be collected easily and quickly in clinical and field settings. Salivary analytes allow neuroscientists to index endocrine, autonomic, immune, metabolic, and inflammatory processes within close proximity of discrete behavioral, biological, and social events, which is particularly important to advancing our understanding of human neuroscience. This review provides an update on the advances in salivary bioscience for specialty fields within neuroscience, presents novel salivary analytes of interest to neuroscience and the status of their development, and outlines a procedural framework to facilitate integration of these concepts and methods into neuroscience. (PsycINFO Database Record PMID- 26974859 TI - anti-Selective Asymmetric Henry Reaction Catalyzed by a Heterobimetallic Cu-Sm Aminophenol Sulfonamide Complex. AB - A novel heterobimetallic Cu/Sm/aminophenol sulfonamide complex has been developed by a convenient one-pot method for the anti-selective asymmetric Henry reaction. The corresponding anti-beta-nitro alcohols are obtained in up to 99% yield, >30:1 dr, and 98% ee. The results of control experiments and ESI-MS analysis of the complex indicate that the monomeric bimetallic Cu/Sm/1 complex would be the active species. PMID- 26974858 TI - Environmentally Benign CO2-Based Copolymers: Degradable Polycarbonates Derived from Dihydroxybutyric Acid and Their Platinum-Polymer Conjugates. AB - (S)-3,4-Dihydroxybutyric acid ((S)-3,4-DHBA), an endogenous straight chain fatty acid, is a normal human urinary metabolite and can be obtained as a valuable chiral biomass for synthesizing statin-class drugs. Hence, its epoxide derivatives should serve as promising monomers for producing biocompatible polymers via alternating copolymerization with carbon dioxide. In this report, we demonstrate the production of poly(tert-butyl 3,4-dihydroxybutanoate carbonate) from racemic-tert-butyl 3,4-epoxybutanoate (rac-(t)Bu 3,4-EB) and CO2 using bifunctional cobalt(III) salen catalysts. The copolymer exhibited greater than 99% carbonate linkages, 100% head-to-tail regioselectivity, and a glass transition temperature (Tg) of 37 degrees C. By way of comparison, the similarly derived polycarbonate from the sterically less congested monomer, methyl 3,4 epoxybutanoate, displayed 91.8% head-to-tail content and a lower Tg of 18 degrees C. The tert-butyl protecting group of the pendant carboxylate group was removed using trifluoroacetic acid to afford poly(3,4-dihydroxybutyric acid carbonate). Depolymerization of poly(tert-butyl 3,4-dihydroxybutanoate carbonate) in the presence of strong base results in a stepwise unzipping of the polymer chain to yield the corresponding cyclic carbonate. Furthermore, the full degradation of the acetyl-capped poly(potassium 3,4-dihydroxybutyrate carbonate) resulted in formation of the biomasses, beta-hydroxy-gamma-butyrolacetone and 3,4 dihydroxybutyrate, in water (pH = 8) at 37 degrees C. In addition, water-soluble platinum-polymer conjugates were synthesized with platinum loading of 21.3-29.5%, suggesting poly(3,4-dihydroxybutyric acid carbonate) and related derivatives may serve as platinum drug delivery carriers. PMID- 26974860 TI - Calculation of the Local Free Energy Landscape in the Restricted Region by the Modified Tomographic Method. AB - The free energy landscape is the most important information in the study of the reaction mechanisms of the molecules. However, it is difficult to calculate. In a large collective variable space, a molecule must take a long time to obtain the sufficient sampling during the simulation. To save the calculation quantity, decreasing the sampling region and constructing the local free energy landscape is required in practice. However, the restricted region in the collective variable space may have an irregular shape. Simply restricting one or more collective variables of the molecule cannot satisfy the requirement. In this paper, we propose a modified tomographic method to perform the simulation. First, it divides the restricted region by some hyperplanes and connects the centers of hyperplanes together by a curve. Second, it forces the molecule to sample on the curve and the hyperplanes in the simulation and calculates the free energy data on them. Finally, all the free energy data are combined together to form the local free energy landscape. Without consideration of the area outside the restricted region, this free energy calculation can be more efficient. By this method, one can further optimize the path quickly in the collective variable space. PMID- 26974857 TI - Elevation of 2-AG by monoacylglycerol lipase inhibition in the visceral insular cortex interferes with anticipatory nausea in a rat model. AB - Anticipatory nausea (AN) is a conditioned nausea reaction experienced by chemotherapy patients upon returning to the clinic. Currently, there are no specific treatments for this phenomenon, with the classic antiemetic treatments (e.g., ondansetron) providing no relief. The rat model of AN, contextually elicited conditioned gaping reactions in rats, provides a tool for assessing potential treatments for this difficult to treat disorder. Systemically administered drugs which elevate the endocannabinoids, anandamide (AEA) and 2 arachidonoyl glycerol (2-AG), by interfering with their respective degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) interfere with AN in the rat model. We have shown that MAGL inhibition within the visceral insular cortex (VIC) interferes with acute nausea in the gaping model (Sticht et al., 2015). Here we report that bilateral infusion of the MAGL inhibitor, MJN110 (but neither the FAAH inhibitor, PF3845, nor ondansetron) into the VIC suppressed contextually elicited conditioned gaping, and this effect was reversed by coadministration of the CB1 antagonist, AM251. These findings suggest that 2-AG within the VIC plays a critical role in the regulation of both acute nausea and AN. Because there are currently no specific therapeutics for chemotherapy patients that develop anticipatory nausea, MAGL inhibition by MJN110 may be a candidate treatment. (PsycINFO Database Record PMID- 26974861 TI - Pilot Screening to Determine Antimicrobial Synergies in a Multidrug-Resistant Bacterial Strain Library. AB - With the rise in multidrug-resistant (MDR) bacterial infections, there has been increasing interest in combinations of >=2 antimicrobial agents with synergistic effects. We established an MDR bacterial strain library to screen for in vitro antimicrobial synergy by using a broth microdilution checkerboard method and high throughput luciferase-based bacterial cell viability assay. In total, 39 MDR bacterial strains, including 23 carbapenem-resistant gram-negative bacteria, 9 vancomycin-intermediate Staphylococcus aureus, and 7 vancomycin-resistant Enterococcus faecalis, were used to screen for potential antimicrobial synergies. Synergies were more frequently identified with combinations of imipenem plus trimethoprim-sulfamethoxazole for carbapenem-resistant Acinetobacter baumannii in the library. To verify this finding, we tested 34 A. baumannii clinical isolates resistant to both imipenem and trimethoprim-sulfamethoxazole by the checkerboard method. The imipenem plus trimethoprim-sulfamethoxazole combination showed synergy in the treatment of 21 (62%) of the clinical isolates. The results indicate that pilot screening for antimicrobial synergy in the MDR bacterial strain library could be valuable in the selection of combination therapeutic regimens to treat MDR bacterial infections. Further studies are warranted to determine whether this screening system can be useful to screen for the combined effects of conventional antimicrobials and new-generation antimicrobials or nonantimicrobials. PMID- 26974863 TI - Inhibition of Gene Expression and Cancer Cell Migration by CD44v3/6-Targeted Polyion Complexes. AB - In recent years, siRNA technology has emerged as a promising strategy for gene silencing in cancer therapy. We have designed novel CD44-targeted polyion complexes (PICs) composed of poly(ethylene glycol)-block-polyethylenimine (PEG-b PEI) and laminin-derived peptides (mA5G27D or mA5G27F) for in vivo siRNA delivery and gene silencing in tumors. The full-length A5G27 peptide (RLVSYNGIIFFLK), from which mA5G27D and mA5G27F are derived, binds to CD44v3 and CD44v6 and inhibits tumor cell migration, invasion, and angiogenesis. Thus, when attached to the surface of PICs, A5G27-based peptides can serve both as targeting ligands to navigate siRNA molecules directly to CD44-overexpressing tumors, and as anti migratory agents to inhibit tumor progression. The mA5G27D- or mA5G27F-harboring PEG-b-PEI copolymers strongly condensed siRNA molecules into nanosized PICs presenting positive surface charges, low in vitro cytotoxicity, and high serum stability. mA5G27D- or mA5G27F-bearing PICs demonstrated high efficacy and selectivity in delivering siRAC1 into CD44-overexpressing cells, thereby silencing RAC1 mRNA and protein levels in such cells. These PICs presented substantial anti-migratory features in vitro and accumulated significantly in SK OV-3 tumor-bearing mice, following 3 sequential intraperitoneal (i.p.) injections. Treatment of mice with 8 or 9 sequential parenteral (intravenous, (i.v.) or i.p.) injections of mA5G27F-PEG-b-PEI/siRNA efficiently inhibited tumor growth in two different CD44-overexpressing tumor mouse models (A549 and SK-OV 3), regardless of the type of siRNA (siPLK1 or siLUC) used. The results thus reveal the potential utility of this system for targeted delivery of siRNA molecules into solid tumors to prolong the survival time of mice, while at the same time reducing potential toxicity. PMID- 26974862 TI - The Minimal Important Difference in Borg Dyspnea Score in Pulmonary Arterial Hypertension. AB - RATIONALE: Despite therapeutic advances, pulmonary arterial hypertension remains a disease without a cure. Focusing on symptoms, such as dyspnea, is an important part of assessing response to therapy. OBJECTIVES: To determine the minimal important differences for the Borg dyspnea score and the Borg fatigue score in adult patients undergoing initial therapy for pulmonary arterial hypertension. METHODS: We studied 129 patients enrolled between 2003 and 2013 in the Pulmonary Arterial Hypertension Program registry at Johns Hopkins University Hospital in Baltimore, Maryland. We analyzed baseline demographics, clinical characteristics, 6-minute-walk test distance, and Borg dyspnea and fatigue scores at baseline and at follow up 3 months after initiation of pulmonary arterial hypertension therapy. The minimal important differences for the Borg dyspnea and fatigue scores were determined using distributional and anchor-based methods, using 6 minute-walk test distance as the anchor. MEASUREMENTS AND MAIN RESULTS: Most subjects were in New York Heart Association functional class II or III and had moderate to severe pulmonary arterial hypertension. The baseline Borg dyspnea score was 3.4 +/- 1.9 units; the baseline Borg fatigue score was 2.8 +/- 2.2 units. After therapy, the average change in the dyspnea score was -0.16 +/- 1.9 units and the average change in the fatigue score was -0.21 +/- 2.4 units. Using distributional methods, the minimum important difference for Borg dyspnea score ranged from 0.7 to 1.24 units and for Borg fatigue score ranged from 0.73 to 1.39 units. Using anchor-based methods, the minimum important difference for the Borg dyspnea scales was 0.36; this could not be calculated for the Borg fatigue score. CONCLUSIONS: Using distributional and anchor-based methods, we estimate the minimum important difference for Borg dyspnea scale in pulmonary arterial hypertension is approximately 0.9 units. Using distributional methods only, we estimate the minimum important difference for the Borg fatigue scale is around 1 unit. Further studies are needed to determine the clinical utility of these scores in patients with pulmonary arterial hypertension. PMID- 26974864 TI - Life Expectancy. PMID- 26974865 TI - Aminoxidation of Arenethiols to N-Chloro-N-sulfonyl Sulfinamides. AB - A simple and efficient method to synthesize N-chloro-N-sulfonylsulfinamides by the direct aminoxidation of arenethiols under aqueous and mild conditions is disclosed, geminally installing the oxo and amino groups on the sulfur atom of arenethiols. The products have been primarily developed as sulfinylation reagents to convert Grignard reagents into sulfoxides, and as amination reagents to convert secondary amines into hydrazine derivatives. PMID- 26974866 TI - Group 13 Superacid Adducts of [PCl2N]3. AB - Irrespective of the order of the addition of reagents, the reactions of [PCl2N]3 with MX3 (MX3 = AlCl3, AlBr3, GaCl3) in the presence of water or gaseous HX give the air- and light-sensitive superacid adducts [PCl2N]3.HMX4. The reactions are quantitative when HX is used. These reactions illustrate a Lewis acid/Bronsted acid dichotomy in which Lewis acid chemistry can become Bronsted acid chemistry in the presence of adventitious water or HX. The crystal structures of all three [PCl2N]3.HMX4 adducts show that protonation weakens the two P-N bonds that flank the protonated nitrogen atom. Variable-temperature NMR studies indicate that exchange in solution occurs in [PCl2N]3.HMX4, even at lower temperatures than those for [PCl2N]3.MX3. The fragility of [PCl2N]3.HMX4 at or near room temperature and in the presence of light suggests that such adducts are not involved directly as intermediates in the high-temperature ring-opening polymerization (ROP) of [PCl2N]3 to give [PCl2N]n. Attempts to catalyze or initiate the ROP of [PCl2N]3 with the addition of [PCl2N]3.HMX4 at room temperature or at 70 degrees C were not successful. PMID- 26974867 TI - Risk of Cerebral Venous Thrombosis in Obese Women. AB - IMPORTANCE: Obesity is a risk factor for deep vein thrombosis of the leg and pulmonary embolism. To date, however, whether obesity is associated with adult cerebral venous thrombosis (CVT) has not been assessed. OBJECTIVE: To assess whether obesity is a risk factor for CVT. DESIGN, SETTING, AND PARTICIPANTS: A case-control study was performed in consecutive adult patients with CVT admitted from July 1, 2006 (Amsterdam), and October 1, 2009 (Berne), through December 31, 2014, to the Academic Medical Center in Amsterdam, the Netherlands, or Inselspital University Hospital in Berne, Switzerland. The control group was composed of individuals from the control population of the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis study, which was a large Dutch case-control study performed from March 1, 1999, to September 31, 2004, and in which risk factors for deep vein thrombosis and pulmonary embolism were assessed. Data analysis was performed from January 2 to July 12, 2015. MAIN OUTCOMES AND MEASURES: Obesity was determined by body mass index (BMI). A BMI of 30 or greater was considered to indicate obesity, and a BMI of 25 to 29.99 was considered to indicate overweight. A multiple imputation procedure was used for missing data. We adjusted for sex, age, history of cancer, ethnicity, smoking status, and oral contraceptive use. Individuals with normal weight (BMI <25) were the reference category. RESULTS: The study included 186 cases and 6134 controls. Cases were younger (median age, 40 vs 48 years), more often female (133 [71.5%] vs 3220 [52.5%]), more often used oral contraceptives (97 [72.9%] vs 758 [23.5%] of women), and more frequently had a history of cancer (17 [9.1%] vs 235 [3.8%]) compared with controls. Obesity (BMI >=30) was associated with an increased risk of CVT (adjusted odds ratio [OR], 2.63; 95% CI, 1.53-4.54). Stratification by sex revealed a strong association between CVT and obesity in women (adjusted OR, 3.50; 95% CI, 2.00-6.14) but not in men (adjusted OR, 1.16; 95% CI, 0.25-5.30). Further stratification revealed that, in women who used oral contraceptives, overweight and obesity were associated with an increased risk of CVT in a dose dependent manner (BMI 25.0-29.9: adjusted OR, 11.87; 95% CI, 5.94-23.74; BMI >=30: adjusted OR, 29.26; 95% CI, 13.47-63.60). No association was found in women who did not use oral contraceptives. CONCLUSIONS AND RELEVANCE: Obesity is a strong risk factor for CVT in women who use oral contraceptives. PMID- 26974868 TI - Dissect style response to pollination using metabolite profiling in self compatible and self-incompatible tomato species. AB - Tomato style is the pathway for pollen germination and pollen tubes growth from the stigma to the ovules where fertilization occurs. It is essential to supplying the nutrients for pollen tube growth and guidance for the pollen tubes. To our knowledge, style also regulates gametophytic self-incompatibility (SI) in tomato species. This study identified the metabolites and monitored the metabolic changes of self-incompatible and self-compatible tomato with self-pollinated or unpollinated styles by gas chromatography-mass spectrometry (GC-MS). A total of 9 classes of compounds were identified in SI and self-compatibility (SC) self pollinated and unpollinated styles which included amino acids, sugars, fatty acids/lipids, amines, organic acids, alcohols, nitriles, inorganic acids and other compounds. The contents of d-Mannose-6-phosphate, Cellobiose, Myristic acid, 2,4-Diaminobutyric acid, Inositol and Urea were significantly decreased and the rest did not significantly change in SI styles. But change of metabolites content significantly happened in SC styles. In addition, among the total 9 classes of compounds, the different metabolites accounted for a different proportion in amino acids, sugars, amines, organic acids and alcohols compared SC and SI. The result indicated that the physiological changes of styles existed differences in SC and SI after self pollination. PMID- 26974869 TI - Separation of human IgG fragments using copper, nickel, zinc, and cobalt chelated to CM-Asp-agarose by positive and negative chromatography. AB - This study evaluated the feasibility of using immobilized metal-ion affinity chromatography (IMAC) for separation of human Fab fragments using four different transition metal ions copper, nickel, zinc, and cobalt chelated to CM-Asp (carboxymethylaspartate) immobilized on the agarose gel. The Fab and Fc fragments (from human IgG digested with papain) interacted differently with the chelates studied, depending on the adsorption buffer system. The interaction between chelate and Fc fragment is predominantly based on the coordination bonds using adsorption buffer containing NaCl. Negative chromatography was performed on Cu(II)-CM-Asp-agarose obtaining 2.9mg of Fab per mL of adsorbent in nonretained fractions (Fc fragment-free without uncleaved IgG). The adsorption of Fab fragments is governed by electrostatic forces in the absence of NaCl in the adsorption buffer. High selectivity was achieved on Co(II)-CM-Asp-agarose and 5.7mg of Fab per mL of adsorbent was obtained in eluted fractions without Fc fragments, although having uncleaved IgG. The results showed that chromatography on transition metal ions chetated to CM-Asp-agarose is a promising approach to separation of Fab fragments from papain-digested human IgG solution. PMID- 26974870 TI - Linguistic Masking Release in School-Age Children and Adults. AB - PURPOSE: This study assessed if 6- to 8-year-old children benefit from a language mismatch between target and masker speech for sentence recognition in a 2-talker masker. METHOD: English sentence recognition was evaluated for English monolingual children (ages 6-8 years, n = 15) and adults (n = 15) in an English 2 talker and a Spanish 2-talker masker. A regression analysis with subject as a random variable was used to test the fixed effect of listener group and masker language and the interaction of these two effects. RESULTS: Thresholds were approximately 5 dB higher for children than for adults in both maskers. However, children and adults benefited to the same degree from a mismatch between the target and masker language with approximately 3 dB lower thresholds in the Spanish than the English masker. CONCLUSIONS: Results suggest that children are able to take advantage of linguistic differences between English and Spanish speech maskers to the same degree as adults. Yet, overall worse performance for children may indicate general cognitive immaturity compared with adults, perhaps causing children to be less efficient when combining glimpses of degraded speech information into a meaningful sentence. PMID- 26974871 TI - Interaction of epibrassinolide and selenium ameliorates the excess copper in Brassica juncea through altered proline metabolism and antioxidants. AB - 24-Epibrassinolide (EBL) and Selenium (Se) individually confer tolerance to various abiotic stresses, but their interactive effect in the regulation of copper (Cu) homeostasis in plants exposed to toxic levels of Cu is poorly investigated. This study provides an insight into the effects of EBL (foliar) and/or Se (through sand) on Brassica juncea plants exposed to toxic levels of Cu. The combined effect of EBL and Se on compartmentalization of Cu, oxidative stress markers, photosynthetic machinery and biochemical traits in B. juncea were analyzed. Application of EBL and Se through different mode modulated the compartmentalization of Cu in different parts of plants, enhanced the photosynthetic traits, and activities of various antioxidant enzymes and proline accumulation in B. juncea under excess copper levels. These enhanced levels of antioxidant enzymes, proline (osmolyte) accumulation triggered by combination of EBL and Se could have conferred tolerance to the B. juncea plants under toxic level of copper and also maintained Cu homeostasis in various parts of plants. This study indicates that combination of EBL and Se through different mode is an operative approach for Cu detoxification in plants and could be exploited for removal of excess copper from polluted soil. PMID- 26974872 TI - K8(K5F)U6Si8O40: An Intergrowth Uranyl Silicate. AB - Single crystals of K8(K5F)U6Si8O40 were grown from a mixed alkali halide flux. K8(K5F)U6Si8O40 is the first intergrowth uranyl silicate, being composed of alternating slabs related to two previously reported uranyl silicates: Cs2USiO6 and [Na9F2][(UO2)(UO2)2(Si2O7)2]. It exhibits intense luminescence, which is influenced by the [(UO2)2O] dimers present in the structure. PMID- 26974873 TI - PS-BEMP as a basic catalyst for the phospha-Michael addition to electron-poor alkenes. AB - PS-BEMP was used as a heterogeneous catalyst for the phospha-Michael addition of phosphorus nucleophiles to a variety of electron-poor alkenes. The addition reactions were generally performed with equimolar amounts of reagents under solvent free conditions. The protocol proved to be very efficient for the addition to aromatic, non-aromatic and cyclic ketones, giving good yields (78 85%) in all cases. The protocol was also extended with good results to alpha,beta unsaturated esters and nitriles. This demonstrates that PS-BEMP is a good catalyst for the phospha-Michael addition to electron-poor alkenes. PMID- 26974874 TI - Sequence-Independent Cloning and Post-Translational Modification of Repetitive Protein Polymers through Sortase and Sfp-Mediated Enzymatic Ligation. AB - Repetitive protein-based polymers are important for many applications in biotechnology and biomaterials development. Here we describe the sequential additive ligation of highly repetitive DNA sequences, their assembly into genes encoding protein-polymers with precisely tunable lengths and compositions, and their end-specific post-translational modification with organic dyes and fluorescent protein domains. Our new Golden Gate-based cloning approach relies on incorporation of only type IIS BsaI restriction enzyme recognition sites using PCR, which allowed us to install ybbR-peptide tags, Sortase c-tags, and cysteine residues onto either end of the repetitive gene polymers without leaving residual cloning scars. The assembled genes were expressed in Escherichia coli and purified using inverse transition cycling (ITC). Characterization by cloud point spectrophotometry, and denaturing polyacrylamide gel electrophoresis with fluorescence detection confirmed successful phosphopantetheinyl transferase (Sfp) mediated post-translational N-terminal labeling of the protein-polymers with a coenzyme A-647 dye (CoA-647) and simultaneous sortase-mediated C-terminal labeling with a GFP domain containing an N-terminal GG-motif in a one-pot reaction. In a further demonstration, we installed an N-terminal cysteine residue into an elastin-like polypeptide (ELP) that was subsequently conjugated to a single chain poly(ethylene glycol)-maleimide (PEG-maleimide) synthetic polymer, noticeably shifting the ELP cloud point. The ability to straightforwardly assemble repetitive DNA sequences encoding ELPs of precisely tunable length and to post-translationally modify them specifically at the N- and C- termini provides a versatile platform for the design and production of multifunctional smart protein-polymeric materials. PMID- 26974875 TI - Underlying mechanisms of cyclic peptide inhibitors interrupting the interaction of CK2alpha/CK2beta: comparative molecular dynamics simulation studies. AB - Protein-protein interactions (PPIs) are fundamental to all biological processes. Recently, the CK2beta-derived cyclic peptide Pc has been demonstrated to efficiently antagonize the CK2alpha/CK2beta interaction and strongly affect the phosphorylation of CK2beta-dependent CK2 substrate specificity. The binding affinity of Pc to CK2alpha is destroyed to different extents by two single-point mutations of Tyr188 to Ala (Y188A) and Phe190 to Ala (F190A), which exert negative effects on the inhibitory activity (IC50) of Pc against the CK2alpha/CK2beta interaction from 3.0 MUM to 54.0 MUM and ?100 MUM, respectively. However, the structural influences of Y188A and F190A mutations on the CK2alpha Pc complex remain unclear. In this study, comparative molecular dynamics (MD) simulations, principal component analysis (PCA), domain cross-correlation map (DCCM) analysis and energy calculations were performed on wild type (WT), Y188A mutant, and F190A mutant systems. The results revealed that ordered communications between hydrophobic and polar interactions were essential for CK2alpha-Pc binding in the WT system. In addition to the loss of the hydrogen bond between Gln36 of CK2alpha and Gly189 of Pc in the two mutants, the improper recognition mechanisms occurred through different pathways. These pathways included the weakened hydrophobic interactions in the Y188A mutant as well as decreased polar and hydrophobic interactions in the F190A mutant. The energy analysis results qualitatively elucidated the instability of the two mutants and energetic contributions of the key residues. This study not only revealed the structural mechanisms for the decreased binding affinity of Y188A and F190A mutant CK2alpha-Pc complexes, but also provided valuable clues for the rational design of CK2alpha/CK2beta subunit interaction inhibitors with high affinity and specificity. PMID- 26974876 TI - Association between elimination disorders and abusive maternal attitudes. AB - OBJECTIVE: Enuresis and encopresis, both conditions are very distressful to children and their family members and it is responsible for significant social and psychological consequences in children and adolescents. The present study aims to determine the rate of abusive maternal attitudes towards children and adolescents with elimination disorders (EDs) and to investigate the maternal psychological and socio-cultural factors associated with abusive parenting attitudes. METHOD: N = 180 children with ED were included in the study. Family Assessment Device (FAD), and Symptom Check List (SCL-90-R) were administered to mothers. RESULTS: Our results indicated that prevalence of abusive maternal attitudes in our sample was 73.8%. Children and adolescents with ED who live with low-educated parents (p = 0.008), low socio economic status (p = 0.014), and in cases with living in a large or divorced family (p = 0.014), disorganized or chaotic families can be considered a population at risk (p < 0.05), since it is more likely that they suffer more severe abusive maternal attitudes. CONCLUSION: Present study showed high rates of abusive parenting attitudes in cases of EDs in a sample of Turkish children and adolescents. Further research on the etiological and therapeutic importance of the family in the case of ED referred to a psychiatry clinic should be carried out. PMID- 26974877 TI - Mental health risk factors in sexual assault: What should Sexual Assault Referral Centre staff be aware of? AB - INTRODUCTION: In England, people who have been raped can attend a national network of Sexual Assault Referral Centres (SARCs) for physical examination, the collection of evidence and sign-posting onto other appropriate services. The impact of rape on mental health is not always assessed comprehensively in SARCs despite national policy guidance. AIM: To highlight the relationship between mental health and rape; thereby increasing SARCs staff and NHS commissioners awareness of the issue and the potential for longer-term risks to mental health. METHOD: A secondary analysis was carried out using the Adult Psychiatric Morbidity Survey (APMS) 2007 in England. Sexual abuse was categorised as 'rape', 'touched in a sexual way' or 'talked to in a sexual way' versus 'none'. Bivariate analysis describes the prevalence of various mental health indicators and service use measures by different 'levels' of sexual abuse. Multiple logistic regression was applied to determine independent risk factors for sexual abuse. RESULTS: There was a consistent increase in the prevalence of mental health problems and in the use of mental health services as the severity of sexual abuse increased. For individuals who had been raped, the prevalence of need was highest in those raped both before and after the age of 16 years. Multivariate logistic regression identified that sex and age were the only demographic risk factors remaining significant. After controlling for these, individuals who had been raped were over 2.5 times more likely to have a history of a neurotic disorder than individuals experiencing no sexual abuse. In addition, rape victims were also significantly more likely to be dependent on drugs and alcohol, admitted to a mental health ward and at risk of suicide. CONCLUSION: Rape is likely to have a considerable impact on the use of mental health services, self-harm and alcohol/drug dependency. Full mental health assessments should be undertaken in SARCs and commissioners should ensure accessible pathways into mental health services where appropriate. PMID- 26974878 TI - Dysphagia and Dysphonia Assessment Tools After Anterior Cervical Spine Surgery. AB - The Smith-Robinson approach to the anterior cervical spine is being increasingly used, but it is not without complication. Dysphagia and dysphonia are the most common complications of the procedure. Many classification systems have been developed to stage and grade postoperative dysphagia and dysphonia, but inconsistent usage and lack of consensus adoption has limited research progress. A discussion of the merits and limitations of the most common classification systems is outlined within this review. Broad adoption of comprehensive and simple classification metrics is needed, but, first, prospective reliability and validity must be established in the anterior cervical fusion population. PMID- 26974879 TI - Continuous versus Intermittent beta-Lactam Infusion in Severe Sepsis. A Meta analysis of Individual Patient Data from Randomized Trials. AB - RATIONALE: Optimization of beta-lactam antibiotic dosing for critically ill patients is an intervention that may improve outcomes in severe sepsis. OBJECTIVES: In this individual patient data meta-analysis of critically ill patients with severe sepsis, we aimed to compare clinical outcomes of those treated with continuous versus intermittent infusion of beta-lactam antibiotics. METHODS: We identified relevant randomized controlled trials comparing continuous versus intermittent infusion of beta-lactam antibiotics in critically ill patients with severe sepsis. We assessed the quality of the studies according to four criteria. We combined individual patient data from studies and assessed data integrity for common baseline demographics and study endpoints, including hospital mortality censored at 30 days and clinical cure. We then determined the pooled estimates of effect and investigated factors associated with hospital mortality in multivariable analysis. MEASUREMENTS AND MAIN RESULTS: We identified three randomized controlled trials in which researchers recruited a total of 632 patients with severe sepsis. The two groups were well balanced in terms of age, sex, and illness severity. The rates of hospital mortality and clinical cure for the continuous versus intermittent infusion groups were 19.6% versus 26.3% (relative risk, 0.74; 95% confidence interval, 0.56-1.00; P = 0.045) and 55.4% versus 46.3% (relative risk, 1.20; 95% confidence interval, 1.03-1.40; P = 0.021), respectively. In a multivariable model, intermittent beta-lactam administration, higher Acute Physiology and Chronic Health Evaluation II score, use of renal replacement therapy, and infection by nonfermenting gram-negative bacilli were significantly associated with hospital mortality. Continuous beta lactam administration was not independently associated with clinical cure. CONCLUSIONS: Compared with intermittent dosing, administration of beta-lactam antibiotics by continuous infusion in critically ill patients with severe sepsis is associated with decreased hospital mortality. PMID- 26974880 TI - Error in Text and Table. PMID- 26974881 TI - Proteomic Profiling of Serological Responses to Aspergillus fumigatus Antigens in Patients with Invasive Aspergillosis. AB - Aspergillus fumigatus is the species that most commonly causes the opportunistic infection invasive aspergillosis (IA) in patients being treated for hematological malignancies. Little is known about the A. fumigatus proteins that trigger the production of Aspergillus-specific IgG antibodies during the course of IA. To characterize the serological response to A. fumigatus protein antigens, mycelial proteins were separated by 2-D gel electrophoresis. The gels were immunoblotted with sera from patients with probable and proven IA and control patients without IA. We identified 49 different fungal proteins, which gave a positive IgG antibody signal. Most of these antigens play a role in primary metabolism and stress responses. Overall, our analysis identified 18 novel protein antigens from A. fumigatus. To determine whether these antigens can be used as diagnostic or prognostic markers or exhibit a protective activity, we employed supervised machine learning with decision trees. We identified two candidates for further analysis, the protein antigens CpcB and Shm2. Heterologously produced Shm2 induced a strongly proinflammatory response in human peripheral blood mononuclear cells after in vitro stimulation. In contrast, CpcB did not activate the immune response of PBMCs. These findings could serve as the basis for the development of an immunotherapy of IA. PMID- 26974882 TI - Improving Drug Design: An Update on Recent Applications of Efficiency Metrics, Strategies for Replacing Problematic Elements, and Compounds in Nontraditional Drug Space. AB - Drug discovery and development is a complex and lengthy enterprise that suffers from high rates of candidate attrition at all stages of the process. The physical, biological, and toxicological properties of a drug candidate are inextricably linked to its structure, and once a molecule has been synthesized, all subsequent studies along the development path are focused only on assessing and understanding its properties in greater detail. Unfortunately, a full prediction of the biological properties of a molecule from an analysis of its 2- or 3-dimensional structure is currently beyond our expertise. This backdrop mandates that considerable care be taken at the design stage if a molecule is to be successful in testing a mechanistic concept underlying a disease process and to progress into late stage clinical trials and, ultimately, marketing approval. While there are multiple potential causes of candidate attrition, an introspective analysis of drug design practices over the past decade has focused attention on the perception that contemporary molecules are unnecessarily obese, burdened by high molecular weight and excessive lipophilicity. This practice is believed to have its roots in the singular pursuit of enhancing potency during lead optimization rather than adopting a more holistic approach to drug design that gives broader consideration to how structural features affect developability properties. In an effort to provide the medicinal chemistry community with practical guideposts to enhancing compound quality in the drug design phase and which can readily be applied, a series of efficiency indices have been proposed that attempt to define aspects of compound quality in the context of a series of physicochemical parameters. Of these metrics, lipophilic ligand efficiency (LLE or LipE), which provides an index of the dependence of the potency of a molecule on its intrinsic lipophilicity, has been characterized as the most robust metric that has potential for broad-based application. In this review, after describing the background literature behind the derivation of efficiency metrics and approaches to assessing compound aesthetics, synopses of some recent practical application in lead optimization campaigns are presented. However, molecules that fall into space beyond that associated with traditional drug-like properties are an important part of the current and future landscape, exemplified by the summary of direct acting hepatitis C virus NS3 and NS5A inhibitors that have transformed clinical therapy for this chronic disease. While drug development in nontraditional drug-like space is more challenging and the rules for compound quality will be different with much still to be understood, careful and disciplined drug design practices will be an essential element of success. PMID- 26974884 TI - Impact of Sleep Telemedicine Protocol in Management of Sleep Apnea: A 5-Year VA Experience. AB - BACKGROUND: There is growing evidence that demonstrates an important role for telemedicine technologies in enhancing healthcare delivery. A comprehensive sleep telemedicine protocol was implemented at the Veterans Administration Medical Center (VAMC), Milwaukee, WI, in 2008 in an effort to improve access to sleep specialty care. The telemedicine protocol relied heavily on sleep specialist interventions based on chart review (electronic consult [e-consult]). This was done in response to long wait time for sleep clinic visits as well as delayed sleep study appointments. Since 2008 all consults are screened by sleep service to determine the next step in intervention. Based on chart review, the following steps are undertaken: (1) eligibility for portable versus in-lab sleep study is determined, and a sleep study order is placed accordingly, (2) positive airway pressure (PAP) therapy is prescribed for confirmed sleep apnea, and (3) need for in-person evaluation in the sleep clinic is determined, and the visit is scheduled. This study summarizes the 5-year trend in various aspects of access to sleep care after implementation of sleep telemedicine protocol at the Milwaukee VAMC. PATIENTS AND METHODS: This is a retrospective system efficiency study. The electronic medical record was interrogated 5 years after starting the sleep telemedicine protocol to study annual trends in the following outcomes: (1) interval between sleep consult and prescription of PAP equipment, (2) total sleep consults, and (3) sleep clinic wait time. RESULTS: Two part-time sleep physicians provided sleep-related care at the Milwaukee VAMC between 2008 and 2012. During this period, the interval between sleep consult and PAP prescription decreased from >=60 days to <=7 days. This occurred in spite of an increase in total sleep consults and sleep studies. There was also a significant increase in data downloads, indicating overall improved follow-up. There was no change in clinic wait time of >=60 days. CONCLUSIONS: Implementation of a sleep telemedicine protocol at the Milwaukee VAMC was associated with increased efficiency of sleep services. Timeliness of sleep management interventions for sleep apnea improved in spite of the increased volume of service. PMID- 26974886 TI - Correction Re: Tissue Engineering, Part A, 2016;22(1-2):17-30. PMID- 26974885 TI - Synthesis, characterization, and antitumor activity of three ternary dinuclear copper (II) complexes with a reduced Schiff base ligand and diimine coligands in vitro and in vivo. AB - Three ternary copper (II) complexes containing 1,10-phenanthroline (phen, 1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq, 2) and dipyrido[3,2-a:2',3'-c]phenazine (dppz, 3), with the formulation [Cu2(NCL)2(H4PASP)].4.5H2O (1-3) (where NCL=the diimine coligand, H4PASP=N,N'-(p-xylylene)di-2-aminosuccinic acid), were isolated and characterized. The binding of these complexes with calf thymus DNA was studied using UV-visible absorption titration, emission, and circular dichroism spectroscopy, among other methods. The changes in physicochemical properties that occurred upon binding of these complexes with DNA indicate that binding occurs primarily through intercalative interactions. Human tumor cell lines HeLa, PC3, and HepG2 were treated with the copper(II) complexes in vitro and cell survival rate was assessed by 3-(4,5-dimethyl thiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay and crystal violet survival assay. Flow cytometry was performed on treated cells labeled with AnnexinV/Propidium Iodide staining to determine rates of apoptosis. Western blot was performed to determine the expression levels of the apoptotic markers p53, Bax, and Bcl-2. The complexes reduced cell viability and induced apoptosis in cells of human tumor cell lines in a dose-dependent manner. In addition, using a nude mouse xenograft model, we found that the three ternary copper (II) complexes inhibited human tumor cell growth in vivo. In conclusion, these novel synthetic copper complexes have profound antitumor effects on human tumor cells and are promising therapeutic agents for human tumors. PMID- 26974883 TI - Coronary Catheterization and Percutaneous Coronary Intervention in China: 10-Year Results From the China PEACE-Retrospective CathPCI Study. AB - IMPORTANCE: The use of coronary catheterization and percutaneous coronary intervention (PCI) is increasing in China, but, to date, there are no nationally representative assessments of the quality of care and outcomes in patients undergoing these procedures. OBJECTIVE: To assess the quality of care and outcomes of patients undergoing coronary catheterization and PCI in China. DESIGN, SETTING, AND PARTICIPANTS: In a clinical observational study (China PEACE [Patient-Centered Evaluative Assessment of Cardiac Events]-Retrospective CathPCI Study), we used a 2-stage, random sampling strategy to create a nationally representative sample of 11 241 patients undergoing coronary catheterization and PCI at 55 urban Chinese hospitals in calendar years 2001, 2006, and 2011. Data analysis was performed from July 11, 2014, to November 20, 2015. MAIN OUTCOMES AND MEASURES: Patient characteristics, treatment patterns, quality of care, and outcomes associated with these procedures and changes over time. RESULTS: Of the 11 241 patients included in the study, the samples included, for 2001, 285 women (weighted percentage, 28.6%); for 2006, 826 women (weighted percentage, 32.2%), and for 2011, 2588 women (weighted percentage, 35.7%). Mean (SD) ages were 58 (8), 60 (11), and 61 (11) years, respectively. Between 2001 and 2011, estimated national rates of hospitalizations for coronary catheterization increased from 26 570 to 452 784 and for PCI, from 9678 to 208 954 (17-fold and 21-fold), respectively. More than half of stable patients undergoing coronary catheterization had nonobstructive coronary artery disease; this amount did not change significantly over time (2001: 60.3% [95% CI, 56.1%-64.5%]; 2011: 57.5% [95% CI, 55.8%-59.3%], P = .05 for trend). The proportion of PCI procedures performed via radial approach increased from 3.5% (95% CI, 1.7%-5.3%) in 2001 to 79.0% (95% CI, 77.7%-80.3%) in 2011 (P < . 001 for trend). The use of drug eluting stents (DESs) increased from 18.0% (95% CI, 14.2%-21.7%) in 2001 to 97.3% (95% CI, 96.9%-97.7%) in 2011 (P < .001 for trend) largely owing to increased use of domestic DESs. The median length of stay decreased from 14 days (interquartile range [IQR], 9-20) in 2001 to 10 days (IQR, 7-14) in 2011 (P < .001 for trend). In-hospital mortality did not change significantly, but both adjusted risk of any bleeding (odds ratio [OR], 0.53 [95% CI, 0.36-0.79], P < .001 for trend) and access bleeding (OR, 0.23 [95% CI, 0.12-0.43], P < .001) were decreased between 2001 and 2011. The medical records lacked documentation needed to calculate commonly used process metrics including door to balloon times for primary PCI and the prescription of evidence-based medications at discharge. CONCLUSIONS AND RELEVANCE: Although the use of catheterization and PCI in China has increased dramatically, we identified critical quality and documentation gaps that represent opportunities to improve care. Our findings can serve as a foundation to guide future quality improvement initiatives in China. PMID- 26974887 TI - Human influenza viruses and CD8(+) T cell responses. AB - Influenza A viruses (IAVs) cause significant morbidity and mortality worldwide, despite new strain-specific vaccines being available annually. As IAV-specific CD8(+) T cells promote viral control in the absence of neutralizing antibodies, and can mediate cross-reactive immunity toward distinct IAVs to drive rapid recovery from both mild and severe influenza disease, there is great interest in developing a universal T cell vaccine. However, despite detailed studies in mouse models of influenza virus infection, there is still a paucity of data on human epitope-specific CD8(+) T cell responses to IAVs. This review focuses on our current understanding of human CD8(+) T cell immunity against distinct IAVs and discusses the possibility of achieving a CD8(+) T cell mediated-vaccine that protects against multiple, distinct IAV strains across diverse human populations. We also review the importance of CD8(+) T cell immunity in individuals highly susceptible to severe influenza infection, including those hospitalised with influenza, the elderly and Indigenous populations. PMID- 26974888 TI - Diagnosis of Pediatric Acute Adenovirus Infections: Is a Positive PCR Sufficient? AB - BACKGROUND: Human adenovirus (HAdV), especially species C (HAdV-C), can be detected incidentally by polymerase chain reaction in nasopharyngeal (NP) samples, making it difficult to interpret clinical significance of a positive result. We classified patients into groups based on HAdV culture positivity from respiratory specimens and the presence of an identified co-pathogen. We hypothesized that HAdV-C would be over-represented and viral burden would be lower in patients most likely to have incidental detection (ie, with a negative viral culture and documented co-pathogen). METHODS: Immunocompetent children with HAdV + nasopharyngeal specimens were classified into 4 groups: group I (HAdV culture (+) and no co-infection), group II (culture (+) and co-infection), group III (culture (-) and no co-infection) and group IV (culture (-) and co infection). Viral burden (cycle threshold) and species were compared among groups. RESULTS: Of 483 nasopharyngeal specimens, HAdV was isolated in culture in 252 (52%); co-infection was found in 265 (55%) patients. Group I (most consistent with acute disease) had significantly lower cycle thresholds (median 23.9; interquarile range 22.2-28.1) compared with group IV (most consistent with incidental detection; median 37.3; interquarile range 35.3-38.9; P < 0.0001). HAdV-C accounted for 41% samples of group I and 83% of group IV (P < 0.0001). We identified a subset of 22 patients with bacterial or fungal co-pathogens, 18 of whom had no growth on viral culture (group IV) with a median cycle threshold of 37.4 (interquarile range 33.9-39.2). CONCLUSIONS: Species identification and viral burden may assist in interpretation of a positive HAdV result. Low viral burden with HAdV-C may be consistent with incidental detection. PMID- 26974889 TI - A Phase 2, Randomized, Active-controlled, Observer-blinded Study to Assess the Immunogenicity, Tolerability and Safety of Bivalent rLP2086, a Meningococcal Serogroup B Vaccine, Coadministered With Tetanus, Diphtheria and Acellular Pertussis Vaccine and Serogroup A, C, Y and W-135 Meningococcal Conjugate Vaccine in Healthy US Adolescents. AB - BACKGROUND: Bivalent rLP2086, targeting meningococcal serogroup B, will extend prevention of meningococcal disease beyond that provided by quadrivalent serogroup ACWY vaccines; coadministration with recommended vaccines may improve adherence to vaccine schedules. This phase 2, randomized, active-controlled, observer-blinded study assessed whether immune responses induced by coadministration of Menactra (meningococcal A, C, Y and W-135 polysaccharide conjugate vaccine [MCV4]) and Adacel (tetanus toxoid, reduced diphtheria toxoid, acellular pertussis vaccine [Tdap]) with bivalent rLP2086 (Trumenba [meningococcal serogroup B vaccine], approved in the United States) were noninferior to MCV4 + Tdap or bivalent rLP2086 alone. METHODS: Healthy adolescents aged 10 to <13 years received MCV4 + Tdap + bivalent rLP2086, MCV4 + Tdap or bivalent rLP2086. Bivalent rLP2086 response was assessed with serum bactericidal assays using human complement with 2 meningococcal serogroup B test strains expressing vaccine-heterologous factor H-binding protein variants; MCV4 with SBAs using rabbit complement; and Tdap with multiplexed Luminex assays. Safety was evaluated. RESULTS: Two thousand six hundred forty-eight subjects were randomized. Immune responses to MCV4 + Tdap + bivalent rLP2086 were noninferior to MCV4 + Tdap or bivalent rLP2086 alone. Seroprotective serum bactericidal assays using human complement titers were documented for 62.3%-68.0% and 87.5% 90% of MCV4 + Tdap + bivalent rLP2086 recipients after doses 2 and 3, respectively. A >=4-fold rise in serum bactericidal assays using human complement titers from baseline was achieved by 56.3%-64.3% and 84.0%-85.7% of subjects after doses 2 and 3, respectively. Bivalent rLP2086 alone induced similar responses. Concomitant administration did not substantially increase reactogenicity compared with bivalent rLP2086 alone. CONCLUSIONS: Bivalent rLP2086 given concomitantly with MCV4 + Tdap met all noninferiority immunogenicity criteria without a clinically meaningful increase in reactogenicity. MCV4 and bivalent rLP2086 coadministration would provide coverage against the 5 major disease-causing serogroups. PMID- 26974890 TI - Probable Levofloxacin-associated Secondary Intracranial Hypertension in a Child With Multidrug-resistant Tuberculosis. AB - Fluoroquinolones are a key component of multidrug-resistant tuberculosis treatment. We describe the first reported case of probable levofloxacin associated intracranial hypertension in a 6-year-old girl with pulmonary multidrug-resistant tuberculosis. The case highlights the potential risk of secondary intracranial hypertension in multidrug-resistant tuberculosis patients who require prolonged fluoroquinolone therapy and the need for ophthalmologic screening in children with suggestive signs and symptoms. PMID- 26974891 TI - Population-based Surveillance for Medically Attended Human Parainfluenza Viruses From the Influenza Incidence Surveillance Project, 2010-2014. AB - BACKGROUND: Parainfluenza viruses (PIV) have been shown to contribute substantially to pediatric hospitalizations in the United States. However, to date, there has been no systematic surveillance to estimate the burden among pediatric outpatients. METHODS: From August 2010 through July 2014, outpatient health care providers with enumerated patient populations in 13 states and jurisdictions participating in the Influenza Incidence Surveillance Project conducted surveillance of patients with influenza-like illness (ILI). Respiratory specimens were collected from the first 10 ILI patients each week with demographic and clinical data. Specimens were tested for multiple respiratory viruses, including PIV1-4, using reverse transcriptase-polymerase chain reaction assays. Cumulative incidence was calculated using provider patient population size as the denominator. RESULTS: PIVs 1-3 were detected in 8.0% of 7716 ILI related outpatient specimens: 30% were PIV1, 26% PIV2 and 44% PIV3. PIV circulation varied noticeably by year and type, with PIV3 predominating in 2010 2011 (incidence 110 per 100,000 children), PIV1 in 2011-2012 (89 per 100,000), dual predominance of PIV2 and PIV3 (88 and 131 per 100,000) in 2012-2013 and PIV3 (100 per 100,000) in 2013-2014. The highest incidence of PIV detections was among patients aged <5 years (259-1307 per 100,000). The median age at detection for PIV3 (3.4 years) was significantly lower than the median ages for PIV1 (4.5 years) and PIV2 (7.0 years; P < 0.05). CONCLUSIONS: PIVs 1-3 comprise a substantial amount of medically attended pediatric ILI, particularly among children aged <5 years. Distinct seasonal circulation patterns as well as significant differences in rates by age were observed between PIV types. PMID- 26974892 TI - Primary Cutaneous Aspergillosis in a Preterm Infant. AB - Primary cutaneous aspergillosis is rare in premature infants. It requires combined medical and surgical strategies. Liposomal amphotericin B is recommended as first-line therapy, but salvage regimens with others antifungal agents, such as voriconazole, have been reported. Voriconazole's pharmacodynamics is unknown in this population. We report a case of severe toxicity to voriconazole in a preterm patient with primary cutaneous aspergillosis. PMID- 26974893 TI - Potential of Food and Natural Products to Promote Endothelial and Vascular Health. AB - Endothelial dysfunction is now well established as a pivotal early event in the development of major cardiovascular diseases including hypertension, atherosclerosis, and diabetes. The alteration of the endothelial function is often triggered by an imbalance between the endothelial formation of vasoprotective factors including nitric oxide (NO) and endothelium-dependent hyperpolarization, and an increased level of oxidative stress involving several prooxidant enzymes such as NADPH oxidase and, often also, the appearance of cyclooxygenase-derived vasoconstrictors. Preclinical studies have indicated that polyphenol-rich food and food-derived products such as grape-derived products, black and red berries, green and black teas and cocoa, and omega-3 fatty acids can trigger activating pathways in endothelial cells promoting an increased formation of nitric oxide and endothelium-dependent hyperpolarization. Moreover, intake of such food-derived products has been associated with the prevention and/or the improvement of an established endothelial dysfunction in several experimental models of cardiovascular diseases and in humans with cardiovascular diseases. This review will discuss both experimental and clinical evidences indicating that different types of food and natural products are able to promote endothelial and vascular health, as well as the underlying mechanisms. PMID- 26974894 TI - Gender differences in the relationship between language and social competence in preschool children. AB - The present study examined gender differences in the relation between language and social competence in 268 children aged 18 to 35 months. Correlational and regression analyses demonstrated that the association between expressive language and social ability was significantly stronger in boys than in girls. PMID- 26974895 TI - A Practical Approach to the Evaluation of Gastrointestinal Tract Carcinomas for Lynch Syndrome. AB - Lynch syndrome accounts for roughly 1 of every 35 patients with colorectal carcinoma, making it the most common hereditary form of colorectal carcinoma. Identifying patients at risk for Lynch syndrome is essential, as these patients can develop additional Lynch syndrome-related tumors, and patients and their relatives benefit from genetic counseling. The hallmark of Lynch syndrome associated neoplasms is DNA mismatch repair protein deficiency. In most instances, the pathologist is the first to identify patients at risk for Lynch syndrome and is tasked with communicating these results to treating clinicians and genetics counselors. This review will attempt to provide the tools for pathologists to identify patients at risk for Lynch syndrome through evaluation of tumors of the gastrointestinal tract and provide up-to-date knowledge on evaluating mismatch repair protein deficiency in tumors of the gastrointestinal tract. PMID- 26974896 TI - Launching surface plasmon waves via vanishingly small periodic gratings. AB - The scattering of electromagnetic waves by periodic layered media plays a crucial role in many applications in optics and photonics, in particular in nanoplasmonics for topics as diverse as extraordinary optical transmission, photonic crystals, metamaterials, and surface plasmon resonance biosensing. With these applications in mind, we focus on surface plasmon resonances excited in the context of insulator-metal structures with a periodic, corrugated interface. The object of this contribution is to study the geometric limits required to generate these fundamentally important phenomena. For this we use the robust, rapid, and highly accurate field expansions method to investigate these delicate phenomena and demonstrate how very small perturbations (e.g., a 5 nm deviation on a 530 nm period grating) can generate strong (in this instance 20%) plasmonic absorption, and vanishingly small perturbations (e.g., a 1 nm deviation on a 530 nm period grating) can generate nontrivial (in this instance 1%) plasmonic absorption. PMID- 26974897 TI - Shannon information for joint estimation/detection tasks and complex imaging systems. AB - Shannon information is defined for imaging tasks where signal detection is combined with parameter estimation. The first task considered is when the parameters are associated with the signal and parameter estimates are only produced when the signal is present. The second task examined is when the parameters are associated with the object being imaged, and parameter estimates are produced whether the signal is present or not. In each case, the Shannon information expression has a simple additive form. PMID- 26974898 TI - Phase-shift effect of amplitude spread function on spectrum and image formation in coherent Raman scattering microspectroscopy. AB - Coherent Raman scattering microspectroscopy, which includes coherent anti-Stokes Raman scattering (CARS) and stimulated Raman scattering (SRS) microspectroscopy, permits label-free hyperspectral imaging. We report the theoretical study of the phase-shift effect of the impulse response function on the spectral and image forming properties of coherent Raman scattering microspectroscopy. We show that the spectrum and image are influenced by not only the NA of objective for excitation (NA(ex)) but also that for signal collection (NA(col)), in association with the phase-shift effect. We discuss that, under the condition NA(ex)?NA(col), both the spectrum and the image become deformed by the phase-shift effect, which can be applied to the direct measurement of the imaginary part of the nonlinear susceptibility in CARS spectroscopy. We point out that, even in SRS microscopy, the nonresonant background can contribute to the image formation and cause the artifact in the image. PMID- 26974899 TI - Change detection in underwater imagery. AB - In this work, we deal with the problem of change detection in an underwater scenario given an unblurred-blurred image pair of a planar scene taken at different times. The blur is primarily due to the dynamic nature of the water surface and its nature is space-invariant in the presence of cyclic water flows. Exploiting the sparsity of the induced blur as well as the occlusions, we propose a distort-difference pipeline that employs an alternating minimization framework to perform change detection in the presence of geometric distortions (skew) as well as photometric degradations (blur and global illumination variations). The method can effectively yield both sharp and blurred occluder maps. Using synthetic as well as real data, we demonstrate how the proposed technique advances the state of the art. PMID- 26974900 TI - Eye center localization and gaze gesture recognition for human-computer interaction. AB - This paper introduces an unsupervised modular approach for accurate and real-time eye center localization in images and videos, thus allowing a coarse-to-fine, global-to-regional scheme. The trajectories of eye centers in consecutive frames, i.e., gaze gestures, are further analyzed, recognized, and employed to boost the human-computer interaction (HCI) experience. This modular approach makes use of isophote and gradient features to estimate the eye center locations. A selective oriented gradient filter has been specifically designed to remove strong gradients from eyebrows, eye corners, and shadows, which sabotage most eye center localization methods. A real-world implementation utilizing these algorithms has been designed in the form of an interactive advertising billboard to demonstrate the effectiveness of our method for HCI. The eye center localization algorithm has been compared with 10 other algorithms on the BioID database and six other algorithms on the GI4E database. It outperforms all the other algorithms in comparison in terms of localization accuracy. Further tests on the extended Yale Face Database b and self-collected data have proved this algorithm to be robust against moderate head poses and poor illumination conditions. The interactive advertising billboard has manifested outstanding usability and effectiveness in our tests and shows great potential for benefiting a wide range of real-world HCI applications. PMID- 26974901 TI - Particle-filter-based phase estimation in digital holographic interferometry. AB - In this paper, we propose a particle-filter-based technique for the analysis of a reconstructed interference field. The particle filter and its variants are well proven as tracking filters in non-Gaussian and nonlinear situations. We propose to apply the particle filter for direct estimation of phase and its derivatives from digital holographic interferometric fringes via a signal-tracking approach on a Taylor series expanded state model and a polar-to-Cartesian-conversion-based measurement model. Computation of sample weights through non-Gaussian likelihood forms the major contribution of the proposed particle-filter-based approach compared to the existing unscented-Kalman-filter-based approach. It is observed that the proposed approach is highly robust to noise and outperforms the state-of the-art especially at very low signal-to-noise ratios (i.e., especially in the range of -5 to 20 dB). The proposed approach, to the best of our knowledge, is the only method available for phase estimation from severely noisy fringe patterns even when the underlying phase pattern is rapidly varying and has a larger dynamic range. Simulation results and experimental data demonstrate the fact that the proposed approach is a better choice for direct phase estimation. PMID- 26974902 TI - Gender recognition from facial images: two or three dimensions? AB - This paper seeks to compare encoded features from both two-dimensional (2D) and three-dimensional (3D) face images in order to achieve automatic gender recognition with high accuracy and robustness. The Fisher vector encoding method is employed to produce 2D, 3D, and fused features with escalated discriminative power. For 3D face analysis, a two-source photometric stereo (PS) method is introduced that enables 3D surface reconstructions with accurate details as well as desirable efficiency. Moreover, a 2D+3D imaging device, taking the two-source PS method as its core, has been developed that can simultaneously gather color images for 2D evaluations and PS images for 3D analysis. This system inherits the superior reconstruction accuracy from the standard (three or more light) PS method but simplifies the reconstruction algorithm as well as the hardware design by only requiring two light sources. It also offers great potential for facilitating human computer interaction by being accurate, cheap, efficient, and nonintrusive. Ten types of low-level 2D and 3D features have been experimented with and encoded for Fisher vector gender recognition. Evaluations of the Fisher vector encoding method have been performed on the FERET database, Color FERET database, LFW database, and FRGCv2 database, yielding 97.7%, 98.0%, 92.5%, and 96.7% accuracy, respectively. In addition, the comparison of 2D and 3D features has been drawn from a self-collected dataset, which is constructed with the aid of the 2D+3D imaging device in a series of data capture experiments. With a variety of experiments and evaluations, it can be proved that the Fisher vector encoding method outperforms most state-of-the-art gender recognition methods. It has also been observed that 3D features reconstructed by the two-source PS method are able to further boost the Fisher vector gender recognition performance, i.e., up to a 6% increase on the self-collected database. PMID- 26974903 TI - Propagation properties of a radially polarized partially coherent twisted beam in free space. AB - We introduce a radially polarized partially coherent twisted beam based on the unified theory of coherence and polarization. We also derive expressions of this beam propagating in free space and examine the influence of twist factor and coherence of the source plane on its propagation properties. It is found that both twist factor and coherence of the source plane affect its average intensity, polarization, and coherence. Those results also show that the beam is rotating with beam propagation, and the beam's rotation is independent of coherence of the source plane. PMID- 26974904 TI - Role of extrinsic noise in the sensitivity of the rod pathway: rapid dark adaptation of nocturnal vision in humans. AB - Rod-mediated 500 nm test spots were flashed in Maxwellian view at 5 deg eccentricity, both on steady 10.4 deg fields of intensities (I) from 0.00001 to 1.0 scotopic troland (sc td) and from 0.2 s to 1 s after extinguishing the field. On dim fields, thresholds of tiny (5') tests were proportional to ?I (Rose DeVries law), while thresholds after extinction fell within 0.6 s to the fully dark-adapted absolute threshold. Thresholds of large (1.3 deg) tests were proportional to I (Weber law) and extinction thresholds, to ?I. CONCLUSIONS: rod thresholds are elevated by photon-driven noise from dim fields that disappears at field extinction; large spot thresholds are additionally elevated by neural light adaptation proportional to ?I. At night, recovery from dimly lit fields is fast, not slow. PMID- 26974905 TI - Effective impedance modeling of metamaterial structures. AB - We present methods for retrieving the effective impedance of metamaterials from the Fresnel reflection coefficients at the interface between two semi-infinite media. The derivation involves the projection of rigorous modal expansions onto the dominant modes of the two semi-infinite media. It is shown that the effective impedance can also be written as a ratio of averaged field quantities. Thus, a number of effective impedance formulas, previously obtained by field averaging techniques, can also be derived from the scattering-based formalism by an appropriate choice of projection. Within the effective medium limit, it is observed that a simple semianalytic modeling technique based on the effective impedance can be used to reliably compute the reflection coefficients of metamaterials over a wide range of incidence angles. We use this technique to model planar metamaterial waveguides or surface modes. PMID- 26974906 TI - Reflection of diffuse light from dielectric one-dimensional rough surfaces. AB - We study the reflection of diffuse light from 1D randomly rough dielectric interfaces. Results for the reflectance under diffuse illumination are obtained by rigorous numerical simulations and then contrasted with those obtained for flat surfaces. We also explore the possibility of using perturbation theories and conclude that they are limited for this type of study. Numerical techniques based on Kirchhoff approximation and reduced Rayleigh equations yield better results. We find that, depending on the refractive index contrast and nature of the irregularities, the roughness can increase or decrease the diffuse reflectance of the surface. PMID- 26974907 TI - Light transport in refractive turbid media. AB - Light scattering in refractive media can be used for visualization of caustics and singularities of wavefronts of the incident radiation. Its modeling requires solving the radiative transfer equation. Numerical solution of the radiative transfer equation in turbid media with a spatially varying refractive index is presented and discussed in this paper. The approach is based on the self consistent approximation of the radiative transfer equation and results in a relatively inexpensive and robust numerical algorithm. Simulations are presented for several cases including a weakly scattering medium with varying refractive index and a refractive weakly scattering medium with embedded highly scattering objects. PMID- 26974908 TI - Near- and far-field scattering resonance frequency shift in dielectric and perfect electric conducting cylinders. AB - The ability to infer near-field scattering properties from far-field measurements is of paramount importance in nano-optics. Recently we derived an approximate formula for predicting the frequency shift between near- and far-field intensity peaks in the case of a dielectric sphere. In this work we demonstrate that almost an identical formula can be used to predict the resonance shift of a dielectric cylinder and a perfectly conducting cylinder. We find the redshift of the resonance peak of the perfect electric conducting cylinder to be approximately 2 orders of magnitude greater than for the dielectric cylinder. The errors in our approximate analytic formula for predicting the redshift are approximately only twice as great. Furthermore, we apply the redshift formula to a silicon cylinder and discuss its magneto-dielectric properties, which may be of interest in design of metamaterials. PMID- 26974909 TI - Retrieval of refractive index fields in two-dimensional gradient-index elements from external deflectometry data. AB - In a previous work, we presented a numerical method for retrieving inhomogeneous refractive index fields in rectangular gradient-index elements from boundary positions and internal boundary slopes associated with a set of interrogating probe beams that transit the medium. The present work extends this method to external boundary beam slopes without knowledge of the refractive index along the surface of the optical element, requiring minimal additional information (outside of beam position and slope data) such as a single known index point inside the medium. The inverse problem is cast as a linear algebraic system describing the deflection of probe beams inside the optical material, and an iterative inversion algorithm is used to generate an index field that produces the boundary value data. By incorporating Snell's law into the system equation through surface values derived from tentative reconstructions of the refractive index, we show in simulation that a series of inversion cycles applied to the system equation accurately recovers the index profile used to generate the test data. PMID- 26974910 TI - Collaborative multicue fusion using the cross-diffusion process for salient object detection. AB - Salient object detection is very useful in a large variety of image and vision related applications. A recent trend in salient object detection is to explore novel top-down visual cues and combine them with bottom-up saliency to improve the performance. However, a basic and important problem, i.e., how to effectively fuse multiple visual cues, has rarely been addressed in previous works. To this end, the paper presents a multicue fusion method using the cross-diffusion process (CDP) for salient object detection. The CDP algorithm is deployed to combine the affinity matrices constructed over individual visual cue channels, which is then embedded into a saliency propagation framework to accomplish salient object detection. Different from other multicue fusion strategies, our proposed approach allows for collaborative fusion, that is, the individual visual cues to be fused are able to interact and exchange information with each other during the fusion procedure, which can possibly correct the noise or corruption included in the individual visual cue channels, leading to more robust and effective fusion results. Intensive experiments on publicly available datasets demonstrate the effectiveness and superior performance of our proposed method. PMID- 26974911 TI - Investigation of the moire patterns of defected radial and circular gratings using the reciprocal vectors approach. AB - In this work, for the first time to the best of our knowledge, an investigation on the moire patterns of superimpositions of two radial or two circular gratings consisting of topological defects and their mutual superimpositions with each other, or with linear forked gratings or defected zone plates, is presented. For characterization of the resulting moire patterns, we use the reciprocal vectors approach. In this approach, by considering local spatial frequencies for the superimposed structures, their reciprocal vectors are determined from the transmission function of the structures. The local reciprocal vector of the resulting moire pattern at a given point is determined in terms of the local reciprocal vectors of the superimposed structures defined at the same point. In this approach, the topological singularities of the superimposed structures are described by the azimuthal component of the reciprocal vectors. This formulation is very simple, uniform, and comprehensive. In this work, we offer a detailed discussion on the different resulting moire patterns for the above-mentioned superimpositions and some potential applications of the proposed superimpositions are introduced. In addition, different resulting moire patterns are simulated. PMID- 26974912 TI - Two efficient approaches for modeling of Raman scattering in homogeneous turbid media. AB - The quantitative analysis of Raman spectroscopic signals in biological tissue is generally difficult. Typical samples contain a multitude of molecular species and, in addition, measurements are altered by attenuation of the Raman signal. Realistic numerical modeling of the Raman process can help to facilitate the quantitative analysis of the Raman spectra, but approaches so far are scarce and often time-consuming. In this work, we report on two different and very efficient approaches for modeling of Raman scattering in turbid media irradiated by laser light. Both approaches utilize the Monte Carlo method to simulate the Raman scattering process. We compare the efficiency of both approaches and discuss possible future extensions and experimental validation. PMID- 26974913 TI - Spatial properties of L- and M-cone driven incremental (On-) and decremental (Off ) electroretinograms: evidence for the involvement of multiple post-receptoral mechanisms. AB - An overview of electroretinogram response components to incremental and decremental steps in L- and M-cone excitation was obtained in human observers, while varying the spatial properties of the stimulus. Responses to L- and M-cone stimuli of opposite polarity resembled each other, particularly within the central 35 degrees of the retina. All amplitudes grew as stimulus size increased; however, earlier and later components of the On- and Off-responses showed differing degrees of dependency on stimulus size. Thus, they may reflect different proportions of responses originating in parvocellular (less stimulus size-dependent) and magnocellular (more stimulus size-dependent) streams. PMID- 26974916 TI - Dichoptic perception of brown. AB - Two experiments assessed mechanisms underlying brown induction by presenting a foveal target disk and concentric annular surround stimuli that varied in contrast relative to larger backgrounds. Stimuli were presented under monocular, binocular, and dichoptic viewing conditions. Observers adjusted the luminance of the target disk to a criterion brown level. We found evidence for at least two separate mechanisms for brown induction: one mechanism that is dependent on physically contiguous contrast and operates in monocular pathways and another mechanism that responds to high luminance contrast anywhere in the visual field and can operate after convergence of signals from the two eyes. PMID- 26974915 TI - Influence of surround proximity on induction of brown and darkness. AB - A bright white surround makes a yellow long-wavelength target look both browner and darker. We explored the parallel between these two types of induction by examining their dependence on the proximity of the bright surround to the target at two different time scales with 27 ms and 1 s stimulus durations. We assessed (a) brown induction by adjustment of target luminance to perceptual brown and yellow boundaries and (b) darkness induction by a successive matching procedure. We found that brown induction is a quick process that is robust even for 27 ms stimuli. For darkness induction, there was a strong, spatially localized surround proximity effect for the 27 ms stimuli and much weaker proximity effect for the 1 s stimuli. For brown induction, proximity effects were generally weaker but still showed relatively stronger localized proximity effects for 27 ms stimuli than for 1 s stimuli. For these stimuli, darkness induction predicts the relative pattern but not the magnitudes of brown induction. Both brown and darkness inductions show the operation of quick, spatially localized processes that are apparently superseded by other processes for extended stimulus presentations. PMID- 26974917 TI - Do normal pupil diameter differences in the population underlie the color selection of #thedress? AB - The fundamental question that arises from the color conundrum of #thedress is "What are the phenomena that underlie the individual differences in the reported colors when all other conditions like light and device for the display are identical?" A survey of 384 participants showed near-equal distribution into blue/black (b/b) and white/gold (w/g) groups. We looked at pupil size differences in a sample population of 53 individuals from these two groups and a group that switched from w/g to b/b. Our results showed that the w/g and switch groups had significantly lower pupil size than the b/b group (w/g2 mm) melanomas. In addition, this difference in TILs was only present in men and not in women. Our finding suggests that nodular melanomas are more frequently associated with absent TILs, providing an avenue for further investigation into differences in immunogenicity of the primary melanoma and whether they underlie the unique virulence of nodular melanoma. PMID- 26974965 TI - The mitogen-activated protein kinase pathway plays a critical role in regulating immunological properties of BRAF mutant cutaneous melanoma cells. AB - The advent of drugs targeting the mitogen-activated protein kinase (MAPK) pathway has markedly changed the treatment of advanced-stage melanoma harboring BRAF mutations. However, drug resistance, through mechanisms not well elucidated, often occurs. A better understanding of how melanoma-derived immunologically active molecules change in response to MAPK inhibition of BRAF mutated (BRAF) and BRAF wild type (BRAF) melanomas could help identify promising treatment combinations of small molecule inhibitors and immunotherapy. To this aim, we treated 13 BRAF and 13 BRAF mutated human melanoma cell lines with either a specific BRAF inhibitor or an MEK1/2 inhibitor and analyzed changes in the secretion of 42 selected cytokines, chemokines, and growth factors. We also measured changes in the expression levels of immunologically relevant melanoma cell surface markers. The BRAF melanomas showed minimal changes in response to the inhibitors, whereas the BRAF cell lines showed, on average, a significant decrease in IFNalpha2, interleukin-7, Fractalkine, GCSF, GRO, TGFalpha2, interleukin-8, and VEGF, as well as a reduction in pERK and pMEK protein levels, upon MAPK pathway blockade. BRAF inhibition in BRAF cell lines also resulted in significant changes in the expression of several surface markers including upregulation of beta2-microglobulin as well as a decrease in MIC A/B and TRAIL R2. These results indicate that MAPK pathway inhibition leads to changes in the immunological properties of mutant BRAF melanoma cells and lends support for future studies aimed at designing effective treatment strategies that combine BRAF and MEK inhibition with immunotherapy. PMID- 26974967 TI - Vemurafenib in leptomeningeal carcinomatosis from melanoma: a case report of near complete response and prolonged survival. AB - Targeted therapies such as the BRAF inhibitors vemurafenib and dabrafenib are highly effective in the treatment of systemic metastatic melanoma and have been shown to be effective in controlling solid brain metastases; however, limited data exist on their activity in leptomeningeal spread. Here, we present a case of a 60-year-old woman who developed leptomeningeal carcinomatosis from melanoma after resection and stereotactic radiotherapy of melanoma brain metastases, with poor performance status, who received vemurafenib as first-line treatment, resulting in significant clinical and imaging response as well as prolonged survival. PMID- 26974968 TI - A Comparative Analysis of Genetic Diversity and Structure in Jaguars (Panthera onca), Pumas (Puma concolor), and Ocelots (Leopardus pardalis) in Fragmented Landscapes of a Critical Mesoamerican Linkage Zone. AB - With increasing anthropogenic impact and landscape change, terrestrial carnivore populations are becoming more fragmented. Thus, it is crucial to genetically monitor wild carnivores and quantify changes in genetic diversity and gene flow in response to these threats. This study combined the use of scat detector dogs and molecular scatology to conduct the first genetic study on wild populations of multiple Neotropical felids coexisting across a fragmented landscape in Belize, Central America. We analyzed data from 14 polymorphic microsatellite loci in 1053 scat samples collected from wild jaguars (Panthera onca), pumas (Puma concolor), and ocelots (Leopardus pardalis). We assessed levels of genetic diversity, defined potential genetic clusters, and examined gene flow for the three target species on a countrywide scale using a combination of individual- and population based analyses. Wild felids in Belize showed moderate levels of genetic variation, with jaguars having the lowest diversity estimates (HE = 0.57 +/- 0.02; AR = 3.36 +/- 0.09), followed by pumas (HE = 0.57 +/- 0.08; AR = 4.20 +/- 0.16), and ocelots (HE = 0.63 +/- 0.03; AR = 4.16 +/- 0.08). We observed low to moderate levels of genetic differentiation for all three target species, with jaguars showing the lowest degree of genetic subdivision across the country, followed by ocelots and pumas. Although levels of genetic diversity and gene flow were still fairly high, we detected evidence of fine-scale genetic subdivision, indicating that levels of genetic connectivity for wild felids in Belize are likely to decrease if habitat loss and fragmentation continue at the current rate. Our study demonstrates the value of understanding fine-scale patterns of gene flow in multiple co-occurring felid species of conservation concern, which is vital for wildlife movement corridor planning and prioritizing future conservation and management efforts within human-impacted landscapes. PMID- 26974969 TI - Gender differences for uric acid as predictor of hard events in patients referred for coronary angiography. AB - AIM: To assess gender differences in uric acid (UA) as predictor for hard events (HE, mortality and nonfatal myocardial infarction) in a large cohort of patients referred for coronary angiography. Design & patients: 3020 inpatients (2177 males, age: 68 +/- 9 years, mean +/- SD) were retrospectively studied, collecting data from the Institute electronic databank which included demographic, clinical, instrumental and follow-up data. RESULTS: Although the Kaplan-Meier survival estimates showed a significantly worst outcome in female patients, high UA did not remained a significant predictor for HE after adjustment. Moreover, UA correlated with antioxidant capacity in both sexes. CONCLUSION: Hyperuricemia was not an independent risk for HE, and being correlated with antioxidant capacity, its elevation appears more likely compensatory than causative for HE. PMID- 26974970 TI - Amino-Terminal Fusion of Epidermal Growth Factor 4,5,6 Domains of Human Thrombomodulin on Streptokinase Confers Anti-Reocclusion Characteristics along with Plasmin-Mediated Clot Specificity. AB - Streptokinase (SK) is a potent clot dissolver but lacks fibrin clot specificity as it activates human plasminogen (HPG) into human plasmin (HPN) throughout the system leading to increased risk of bleeding. Another major drawback associated with all thrombolytics, including tissue plasminogen activator, is the generation of transient thrombin and release of clot-bound thrombin that promotes reformation of clots. In order to obtain anti-thrombotic as well as clot specificity properties in SK, cDNAs encoding the EGF 4,5,6 domains of human thrombomodulin were fused with that of streptokinase, either at its N- or C termini, and expressed these in Pichia pastoris followed by purification and structural-functional characterization, including plasminogen activation, thrombin inhibition, and Protein C activation characteristics. Interestingly, the N-terminal EGF fusion construct (EGF-SK) showed plasmin-mediated plasminogen activation, whereas the C-terminal (SK-EGF) fusion construct exhibited 'spontaneous' plasminogen activation which is quite similar to SK i.e. direct activation of systemic HPG in absence of free HPN. Since HPN is normally absent in free circulation due to rapid serpin-based inactivation (such as alpha-2 antiplasmin and alpha-2-Macroglobin), but selectively present in clots, a plasmin dependent mode of HPG activation is expected to lead to a desirable fibrin clot specific response by the thrombolytic. Both the N- and C-terminal fusion constructs showed strong thrombin inhibition and Protein C activation properties as well, and significantly prevented re-occlusion in a specially designed assay. The EGF-SK construct exhibited fibrin clot dissolution properties with much lowered levels of fibrinogenolysis, suggesting unmistakable promise in clot dissolver therapy with reduced hemorrhage and re-occlusion risks. PMID- 26974971 TI - Long Term Effect on Professionals' Knowledge, Practice and Attitudes towards User Involvement Four Years after Implementing an Organisational Development Plan: A Controlled Study. AB - BACKGROUND: Health service organisations are increasingly implementing user involvement initiatives according to requirements from governments, such as user representation in administrational boards, better information to users, and more involvement of the users during treatment. Professionals are vital in all initiatives to enhance user involvement, and initiatives to increase involvement should influence the professionals' practice and attitudes. The implementation of a development plan intending to enhance user involvement in a mental health hospital in Central Norway had no effect on the professionals after 16 months. The objective was therefore to investigate the long term effect on the professionals' knowledge, practice and attitudes towards user involvement after four years. METHODS: This was a non-randomized controlled study including professionals from three mental health hospitals in Central Norway. A development plan intended to enhance user participation was implemented in one of the hospitals, including establishing a patient education centre and a user office, purchasing of user expertise, appointing contact professionals for next of kin, and improving of the centre's information and the professional culture. The professionals at two other hospitals constituted the control group. All professionals were invited to answer the Consumer Participation Questionnaire (CPQ) and additional questions, at a four year interval. RESULTS: A total of 399 professionals participated (43% response rate). Comparing the changes in the intervention group with the changes in the control group, the results showed that the plan had improved some aspects of the professionals' knowledge about the user involvement taking place in the hospital. In addition, some parts of the professionals' practice of providing information to the service users was improved, and the development plan might have raised their awareness about insufficient involvement of next of kin. CONCLUSIONS: This is the first controlled study on the long term effect on professionals from implementing a development plan to enhance user participation in a mental health hospital. Since there was more effect after four years than after 16 months, this study indicates that it takes time before the effect of complex interventions to enhance patient participation in organisations can be detected among the professionals. More long term studies are thus warranted. PMID- 26974973 TI - Structural Characterization of the Loop at the Alpha-Subunit C-Terminus of the Mixed Lineage Leukemia Protein Activating Protease Taspase1. AB - Type 2 asparaginases, a subfamily of N-terminal nucleophile (Ntn) hydrolases, are activated by limited proteolysis. This activation yields a heterodimer and a loop region at the C-terminus of the alpha-subunit is released. Since this region is unresolved in all type 2 asparaginase crystal structures but is close to the active site residues, we explored this loop region in six members of the type 2 asparaginase family using homology modeling. As the loop model for the childhood cancer-relevant protease Taspase1 differed from the other members, Taspase1 activation as well as the conformation and dynamics of the 56 amino acids loop were investigated by CD and NMR spectroscopy. We propose a helix-turn-helix motif, which can be exploited as novel anticancer target to inhibit Taspase1 proteolytic activity. PMID- 26974972 TI - Enabling Metabolomics Based Biomarker Discovery Studies Using Molecular Phenotyping of Exosome-Like Vesicles. AB - Identification of sensitive and specific biomarkers with clinical and translational utility will require smart experimental strategies that would augment expanding the breadth and depth of molecular measurements within the constraints of currently available technologies. Exosomes represent an information rich matrix to discern novel disease mechanisms that are thought to contribute to pathologies such as dementia and cancer. Although proteomics and transcriptomic studies have been reported using Exosomes-Like Vesicles (ELVs) from different sources, exosomal metabolome characterization and its modulation in health and disease remains to be elucidated. Here we describe methodologies for UPLC-ESI-MS based small molecule profiling of ELVs from human plasma and cell culture media. In this study, we present evidence that indeed ELVs carry a rich metabolome that could not only augment the discovery of low abundance biomarkers but may also help explain the molecular basis of disease progression. This approach could be easily translated to other studies seeking to develop predictive biomarkers that can subsequently be used with simplified targeted approaches. PMID- 26974974 TI - Influence of Berry Heterogeneity on Phenolics and Antioxidant Activity of Grapes and Wines: A Primary Study of the New Winegrape Cultivar Meili (Vitis vinifera L.). AB - Wine grapes are usually harvested in vineyards when they ripen. However, not all of the berries in a vineyard ripen homogeneously because of different microclimates around the clusters and berries. In this study, the influence of berry heterogeneity on the phenolic content and antioxidant capacity of grapes and wines under a continental monsoon climate was evaluated for a new wine grape cultivar Meili (Vitis vinifera L.). The total phenolic, flavonoid, flavanol, and monomeric anthocyanin contents in the skin and wine significantly increased with grape density; however, there was no significant difference in the seeds between the two lower densities. The highest values of DPPH free radical-scavenging activity, cupric-reducing antioxidant capacity, and hydroxyl radical-scavenging activity in the skin, seed and wine were detected for the densest berries. The sum of individual phenolic compounds in skin, seed and wine increased with berry density, though no significant difference for skin was observed between the two higher density classes. Hence, the chemical components of Meili grapes and wines were positively associated with the berry density at harvest under the continental monsoon climate. PMID- 26974975 TI - Management of acute pediatric pain in the emergency department. AB - PURPOSE OF REVIEW: This article provides a summary of recommendations for the multimodal and multidisciplinary approach to acute pediatric pain management and highlights recent research on this topic. RECENT FINDINGS: Recent literature has focused on updating recommendations for the use of various analgesics in the pediatric population. While codeine is no longer recommended due to increasing evidence of adverse effects, the more liberal use of intranasal fentanyl is now encouraged because of the ease of administration and rapid delivery. The evidence base for the use of ultrasound-guided regional nerve blocks by qualified providers in the acute pediatric pain setting continues to grow. SUMMARY: The pediatric emergency medicine provider should be able to assess pain and develop individualized pain plans by utilizing a range of nonpharmacologic and pharmacologic strategies. Knowledge of the most recent literature and changes in recommendations for various pain medications is essential. PMID- 26974976 TI - Management of gastroschisis. AB - PURPOSE OF REVIEW: The diagnosis and treatment of gastroschisis spans the perinatal disciplines of maternal fetal medicine, neonatology, and pediatric surgery. Since gastroschisis is one of the commonest and costliest structural birth defects treated in neonatal ICUs, a comprehensive review of its epidemiology, prenatal diagnosis, postnatal treatment, and short and long-term outcomes is both timely and relevant. RECENT FINDINGS: The incidence of gastroschisis has increased dramatically over the past 20 years, leading to a renewed interest in causation. The widespread availability of maternal screening and ultrasound results in very high rates of prenatal diagnosis, which enables evaluation of the optimal timing and mode of delivery. The preferred method of surgical closure continues to be an issue of debate among pediatric surgeons, whereas postsurgical treatment seeks to expedite the initiation and progression of enteral feeding and minimize complications. A small subset of babies with complex gastroschisis leading to intestinal failure benefit from the knowledge and expertise of dedicated interdisciplinary teams, which seek to bring novel therapies and improved clinical outcomes. SUMMARY: The opportunities to increase the knowledge of causation, and identify best practices leading to improved outcomes, drive the ongoing need for collaborative clinical research in gastroschisis. PMID- 26974977 TI - Highest Vaccine Uptake after School-Based Delivery - A County-Level Evaluation of the Implementation Strategies for HPV Catch-Up Vaccination in Sweden. AB - BACKGROUND: The Swedish school-based vaccination programme offers HPV vaccine to girls born >=1999 in 5-6th grade. In 2012, all counties introduced free-of-charge catch-up vaccination campaigns targeting girls born 1993-1998. Varying vaccine uptake in the catch-up group by December 2012 suggested that some implementation strategies were more successful than others. In order to inform future vaccination campaigns, we assessed the impact of different implementation strategies on the county-level catch-up vaccine uptake. METHODS: We conducted an ecological study including all Swedish counties (n = 21), asking regional health offices about the information channels they used and where vaccination of the catch-up target group took place in their counties. The uptake of >=1 dose by 30 September 2014 was estimated using data from the voluntary national vaccination register. We investigated associations between counties' catch-up vaccine uptake, information channels and vaccination settings by calculating incidence rate ratios (IRR) and 95% confidence intervals (CI), using negative binomial regression models. RESULTS: County level catch-up vaccine uptake varied between 49-84%. All counties offered vaccination through primary health care settings. Apart from this eight (34%) also offered the vaccine in some of their schools, four (19%) in all their schools, and two (10%) in other health care centres. The information channels most frequently used were: information at the national on line health care consulting web-page (100%), letter/invitations (90%), and advertisement (81%). Counties offering vaccination to girls in all schools and counties offering vaccination in some of their schools, reached higher vaccine uptake compared to counties not offering vaccination in any of their schools (all schools adjusted IRR: 1.3, 95% CI: 1.1-1.5, some schools adjusted IRR: 1.2, 95% CI: 1.1-1.3). CONCLUSION: Counties offering HPV vaccination to catch-up groups in schools reached the highest vaccine uptake. No information channel explained differences in county-level vaccine uptake. Our findings suggest that catch-up vaccination outside the national vaccination program can reach a high uptake at the population level if it is implemented primarily with an organized delivery (e.g. in schools). PMID- 26974978 TI - Electronic Structure, Surface Doping, and Optical Response in Epitaxial WSe2 Thin Films. AB - High quality WSe2 films have been grown on bilayer graphene (BLG) with layer-by layer control of thickness using molecular beam epitaxy. The combination of angle resolved photoemission, scanning tunneling microscopy/spectroscopy, and optical absorption measurements reveal the atomic and electronic structures evolution and optical response of WSe2/BLG. We observe that a bilayer of WSe2 is a direct bandgap semiconductor, when integrated in a BLG-based heterostructure, thus shifting the direct-indirect band gap crossover to trilayer WSe2. In the monolayer limit, WSe2 shows a spin-splitting of 475 meV in the valence band at the K point, the largest value observed among all the MX2 (M = Mo, W; X = S, Se) materials. The exciton binding energy of monolayer-WSe2/BLG is found to be 0.21 eV, a value that is orders of magnitude larger than that of conventional three dimensional semiconductors, yet small as compared to other two-dimensional transition metal dichalcogennides (TMDCs) semiconductors. Finally, our finding regarding the overall modification of the electronic structure by an alkali metal surface electron doping opens a route to further control the electronic properties of TMDCs. PMID- 26974979 TI - Theory for spiralling ions for 2D FT-ICR and comparison with precessing magnetization vectors in 2D NMR. AB - Two-dimensional (2D) Fourier transform ion cyclotron resonance (FT-ICR) offers an approach to mass spectrometry (MS) that pursuits similar objectives as MS/MS experiments. While the latter must focus on one ion species at a time, 2D FT ICR can examine all possible correlations due to ion fragmentation in a single experiment: correlations between precursors, charged and neutral fragments. We revisited the original 2D FT-ICR experiment that has hitherto fallen short of stimulating significant analytical applications, probably because it is technically demanding. These shortcomings can now be overcome by improved FT-ICR instrumentation and computer hard- and software. We seek to achieve a better understanding of the intricacies of the behavior of ions during a basic two dimensional ICR sequence comprising three simple monochromatic pulses. Through simulations based on Lorentzian equations, we have mapped the ion trajectories for different pulse durations and phases. PMID- 26974980 TI - Prevalence of Common Types of Compression Neuropathies in Qena Governorate/Egypt: A Population-Based Survey. AB - BACKGROUND: No epidemiological studies on the prevalence of compressive neuropathy have been undertaken in Arab countries. The aim of the study was to estimate the prevalence of the most common types of compressive neuropathies in Qena governorate/Egypt. METHODS: The study was part of a community-based survey carried out to assess the prevalence of neuromuscular disorders among the Qena population. A random sampling of 10 districts, 5,039 inhabitants aged >=20. There were 3,050 urban residents (60.5%) and 1,989 (39.5%) from the rural community. Patients were diagnosed using a screening questionnaire for diagnosis of entrapment neuropathies. Positive cases were referred to the Qena University Hospital. They were given full clinical, electrophysiological and laboratory investigations. RESULTS: Compressive neuropathy was recorded in 165 cases giving a CPR = 3.3% of population at risk (>=20 years). Carpal tunnel syndrome (CTS) was diagnosed in 155 cases giving a CPR = 3.1% with a significantly higher prevalence among females than males (5.3 vs. 0.9%) and in rural compared with urban populations (4.6 vs. 2.1%). Ulnar neuropathy at the elbow was the second common type of entrapment with a CPR = 0.1% followed by radial nerve palsy, tarsal tunnel syndrome and common peroneal nerve palsy. CONCLUSION: The overall crude prevalence rate of CTS is comparable with that in other countries. PMID- 26974981 TI - When we need to remember that it is more than a job. PMID- 26974982 TI - To the Editor: The PARADIGM-HF trial. PMID- 26974983 TI - In Reply: The PARADIGM-HF trial. PMID- 26974984 TI - Can patients with infectious endocarditis be safely anticoagulated? PMID- 26974985 TI - It is not the critic's voice that should count. PMID- 26974986 TI - The emotional impact of a malpractice suit on physicians: Maintaining resilien. PMID- 26974987 TI - Fungal folliculitis masquerading as acute exanthematous pustulosis. PMID- 26974988 TI - Advances in the treatment of dyslipidemia. AB - Although current guidelines do not set specific targets for lowering levels of low-density lipoprotein cholesterol (LDL-C), several lines of evidence support the concept that "lower is better." Statin drugs in combination with new agents now make it possible to lower LDL-C to new lows. Determining the risk of cardiovascular disease in apparently healthy adults and how far to extend treatment for primary prevention has critical implications for public health. PMID- 26974989 TI - Interpreting SPRINT: How low should you go? AB - The Systolic Blood Pressure Intervention Trial (SPRINT) found evidence of cardiovascular benefit with intensive lowering of systolic blood pressure (goal < 120 mm Hg) compared with the currently recommended goal (< 140 mm Hg) in older patients with cardiovascular risk but without diabetes or stroke. This article reviews the trial design and protocol, summarizes the results, and briefly discusses the implications of these results. PMID- 26974990 TI - Blood pressure management in the wake of SPRINT. PMID- 26974991 TI - Managing patients at genetic risk of breast cancer. AB - Hereditary syndromes that increase the risk of breast cancer are not common, but it is critical to recognize and manage them appropriately. This paper reviews the management of patients with the most common hereditary breast cancer syndromes, ie, hereditary breast and ovarian cancer syndrome, hereditary diffuse gastric cancer, Cowden syndrome (PTEN hamartoma tumor syndrome), Peutz-Jeghers syndrome, and Li-Fraumeni syndrome. PMID- 26974993 TI - Celiac disease: Managing a multisystem disorder. AB - Celiac disease is a multisystem autoimmune disorder that can cause symptoms involving the gastrointestinal tract and other organ systems such as the skin and bones. This paper reviews the pathogenesis, diagnosis, and management of celiac disease and associated diseases. PMID- 26974992 TI - Prescribing opioids in primary care: Safely starting, monitoring, and stopping. AB - Chronic noncancer pain is common and often managed in the outpatient setting with chronic opioid therapy, even though the efficacy of this approach is uncertain and adverse effects are common. Some patients report meaningful benefit from opioids, but prescription drug abuse has reached epidemic proportions, and many suffer harm from opioid misuse, abuse, and diversion. Primary care providers and their care teams often struggle to balance these risks and benefits with little outside support. The authors review common challenges when starting, monitoring, and discontinuing opioids, and offer strategies for risk-reduction and patient communication. PMID- 26974994 TI - The microbiome in celiac disease: Beyond diet-genetic interactions. PMID- 26974995 TI - Rare Skin Adnexal and Melanocytic Tumors Arising in Ovarian Mature Cystic Teratomas: A Report of 3 Cases and Review of the Literature. AB - Mature teratoma of the ovary is the most common primary ovarian tumor accounting for 15% (10%-20%) of all ovarian neoplasms. Skin and skin adnexal structures are the most common elements identified in mature teratomas. Benign and malignant skin tumors can arise in ovarian teratomas, the most common being epithelial tumors. Melanocytic and adnexal tumors developing in a teratoma are rare and can be easily overlooked. We report 3 cases and review melanocytic and skin adnexal tumors encountered in ovarian teratomas. PMID- 26974997 TI - Non-Neoplastic Conditions of the Ovaries in Grossly Normal Adnexa: A Clinicopathologic Study of 403 Completely Embedded Cases. AB - Most non-neoplastic lesions of the ovaries have not been comprehensively examined in the contemporary literature. We evaluated completely embedded ovaries from 403 unselected, consecutive patients who had grossly normal adnexa. These included prophylactic specimens in high-risk women with BRCA mutations (38 women) and women with a personal history of breast cancer or a family history of breast and/or ovarian cancer (79 women). Transitional cell (Brenner) nests were found in 9.1%; 31% of these lesions were smaller than 1 mm, and 8 were solitary nests. Cortical granulomas were found in 20.5%, fatty metaplasia in 5.3%, mucinous metaplasia of surface epithelial inclusions in 5.5%, and smooth muscle stromal metaplasia in 2%. One or more types of stromal hyperplasia were found in 24.3%. Endometriosis was found in 22% of adnexa. There were no significant differences in the findings in high-risk women compared with non-high-risk except those attributable to age differences between the groups. These findings establish baseline frequencies for non-neoplastic ovarian lesions, and suggest that transitional cell nests are so common that they can be regarded as a normal finding. PMID- 26974996 TI - An Immunohistochemical Algorithm for Ovarian Carcinoma Typing. AB - There are 5 major histotypes of ovarian carcinomas. Diagnostic typing criteria have evolved over time, and past cohorts may be misclassified by current standards. Our objective was to reclassify the recently assembled Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type cohorts using immunohistochemical (IHC) biomarkers and to develop an IHC algorithm for ovarian carcinoma histotyping. A total of 1626 ovarian carcinoma samples from the Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type were subjected to a reclassification by comparing the original with the predicted histotype. Histotype prediction was derived from a nominal logistic regression modeling using a previously reclassified cohort (N=784) with the binary input of 8 IHC markers. Cases with discordant original or predicted histotypes were subjected to arbitration. After reclassification, 1762 cases from all cohorts were subjected to prediction models (chi Automatic Interaction Detection, recursive partitioning, and nominal logistic regression) with a variable IHC marker input. The histologic type was confirmed in 1521/1626 (93.5%) cases of the Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type cohorts. The highest misclassification occurred in the endometrioid type, where most of the changes involved reclassification from endometrioid to high-grade serous carcinoma, which was additionally supported by mutational data and outcome. Using the reclassified histotype as the endpoint, a 4-marker prediction model correctly classified 88%, a 6-marker 91%, and an 8-marker 93% of the 1762 cases. This study provides statistically validated, inexpensive IHC algorithms, which have versatile applications in research, clinical practice, and clinical trials. PMID- 26974998 TI - Involvement of Chromosome 8 in Mullerian Adenosarcoma. AB - Mullerian adenosarcoma (MA) is an uncommon biphasic neoplasm of the female genital tract, composed of malignant stroma and benign epithelium. Little is known about the molecular and cytogenetic aberrations in MA pathogenesis, including those with progression to sarcomatous overgrowth (SO). Herein, we report all cases of MA in which karyotyping was attempted at our institution. Twenty-one samples from 20 subjects consisted of 15 primary (7 without SO, 8 with SO) and 6 metastatic MA, were cytogenetically investigated in our institution. Karyotypes were successfully obtained in 14/21 (67%) cases and 9 (45%) had cytogenetic aberrations. Two (1 MA with SO and 1 metastatic MA) were markedly complex, displaying extreme aneuploidy with numerous rearrangements. Seven (2 MA without SO, 3 MA with SO, and 2 metastatic MA) demonstrated noncomplex clonal aberrations, of which 5 (71%) included an abnormality involving chromosome 8. Two tumors had rearrangements at 8q13 and another 3 tumors had extra copies of chromosome 8. In 5 cases, a normal karyotype (46,XX) was obtained (2 MA without SO, 2 MA with SO, and 1 metastatic MA). Further study is warranted to explore the genetic mechanism by which chromosome abnormalities, particularly those at 8q13, contribute to MA tumorigenesis. PMID- 26974999 TI - The Natural History of Vulvar Intraepithelial Neoplasia, Differentiated Type: Evidence for Progression and Diagnostic Challenges. AB - Squamous cell carcinoma of the vulva (SCCV) develops through either human papillomavirus (HPV)-dependent or HPV-independent pathways. Approximately 60% of SCCV arise independently of HPV, commonly in a background of an inflammatory dermatosis, particularly lichen sclerosus. The likely direct precursor to most of these lesions is vulvar intraepithelial neoplasia (VIN), differentiated type (dVIN), although the evidence is largely circumstantial. There are few reports of progression to carcinoma, and the natural history of this pathway is not well understood. Nevertheless, dVIN is widely regarded as a potentially aggressive lesion. We identified dVIN adjacent to SCCV in 97 of 212 women (45.8%). Twenty four of the 97 women (24.7%) had biopsies performed at least 6 mo before presentation with SCCV; slides for 47 biopsies from 21 women were available for review. dVIN was identified in 18 biopsies from 8 women (38.1%), which in 14 biopsies had been previously unrecognized. The subsequent cancer developed in the same region as the previous biopsy showing dVIN in 6 of the 8 women. The median interval between biopsy and invasive cancer was 43.5 mo (range, 8-102 mo). dVIN associated SCCV was strongly associated with both lichen sclerosus, and HPV negative status compared with usual type VIN (relative risk=38.35 (9.755-150.8) and 0.06485 (0.02764-0.1522), respectively). This study adds to the evidence linking dVIN with SCCV, and indicates that both clinical and histologic underrecognition contribute to the apparent rarity of dVIN as a solitary diagnosis. The morphologic spectrum of dVIN is likely to be wider than commonly appreciated; however, histologically defining the lower threshold is difficult and controversial. PMID- 26975000 TI - Aryl(silyl)amino group stabilized hydridosilanediols: synthesis and characterization and use for preparation of alumino(hydrido)siloxanes. AB - Aryl(silyl)amino group stabilized hydridosilanediols RSiH(OH)2 (R = N(SiMe2Ph) 2,6-iPr2C6H3 (), N(SiMe3)-2,6-iPr2C6H3 (), and N(SiMe2Ph)-2,4,6-Me3C6H2 ()) were prepared from the controlled hydrolysis of the related RSiHCl2 () each in the presence of aniline as the HCl acceptor. Reactions of with AlMe3, AliBu3, AlH(iBu)2, and AlH3.NMe3, respectively, yielded alumino(hydrido)siloxanes [2,6 iPr2C6H3N(SiMe2Ph)Si(H)OAlMe(THF)]2 (), [2,6-iPr2C6H3N(SiMe2Ph)Si(H)OAliBu(THF)]2 (), [2,6-iPr2C6H3N(SiMe2Ph)Si(H)O2]3[Al(THF)]2 (), and [2,6 iPr2C6H3N(SiMe2Ph)Si(H)OAlH(THF)]2 (). The reaction of with AlMe3 gave [2,6 iPr2C6H3N(SiMe3)Si(H)OAlMe(THF)]2 (), a compound similar to . Compounds are characterized by NMR ((1)H, (13)C, and (29)Si) and IR spectroscopy and CHN elemental analysis, of which and are further studied by X-ray crystallography. Compounds and feature cyclic structures all with the skeleton core of Si2O4Al2 while compound exhibits a bicyclic structure having a core of Si3O6Al2. Melting point measurements indicated that are thermally stable bearing the geminal SiH and SiOH groups. Compounds and are thermally stable as well with the O atom bridged SiH and AlR (R = Me, iBu, or H) groups. PMID- 26975001 TI - Reply to the Letter to the Editor: Polyethylene Liner Dissociation is a Complication of the DePuy Pinnacle Cup: A Report of 23 Cases. PMID- 26975002 TI - Associated Factors and Prognostic Implications of Stimulus-Induced Rhythmic, Periodic, or Ictal Discharges. AB - IMPORTANCE: The implications of stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs) sometimes found on prolonged electroencephalographic (EEG) recordings are uncertain. OBJECTIVE: To evaluate the incidence of SIRPIDs and their clinical implications in critically ill patients. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, international retrospective study was performed from October 1, 2012, through September 30, 2014, of consecutive adult patients hospitalized in intensive care units with alteration of consciousness who underwent EEG recordings at 3 separate centers. Demographic data, including admission diagnosis, age, sex, history of epilepsy, and EEG findings, were noted. Characteristics of SIRPIDs were documented. Data were evaluated for predictors of SIRPIDs and in-hospital mortality. Data analysis was performed from January 16, 2015, to June 15, 2015. MAIN OUTCOMES AND MEASURES: Incidence of SIRPIDs, association of SIRPIDs with mortality and other EEG characteristics, and EEG and clinical predictors of mortality. RESULTS: A total of 416 patients were studied. The median age of patients was 60 years (interquartile range, 46-71 years), and 252 (60.6%) were male. A total of 104 patients (25.0%) did not survive to hospital discharge. SIRPIDs were identified in 43 patients (10.3%). The proportion of patients with SIRPIDs was not significantly different across the 3 sites (P = .34). Anoxic brain injury (odds ratio [OR], 3.80; 95% CI, 1.73-8.33; P < .001), the use of antiepileptic medications (OR, 3.24; 95% CI, 1.31-8.00; P = .01), electrographic seizures (OR, 2.85; 95% CI, 1.13-7.19; P = .03), generalized periodic discharges with triphasic morphologic features (OR, 3.66; 95% CI, 1.67 8.02; P = .001), and sporadic sharp waves and periodic discharges (OR, 2.59; 95% CI, 1.13-5.92; P = .02) were independently associated with the presence of SIRPIDs. Older age (OR, 1.02; 95% CI, 1.01-1.04; P = .005), anoxic brain injury (OR, 3.49; 95% CI, 1.96-6.21; P <= .001), and absence of EEG reactivity (OR, 8.14; 95% CI, 4.20-15.79; P < .001) but not SIRPIDs (OR, 1.73; 95% CI, 0.79-3.78; P = .17) were independently associated with in-hospital mortality. CONCLUSIONS AND RELEVANCE: In critically ill patients undergoing EEG recordings, SIRPIDs occurred in 43 (10.3%) and were associated with other electrographic abnormalities previously reported to indicate poor prognosis. However, SIRPIDs were not independently associated with in-hospital mortality. PMID- 26975003 TI - Air-sea exchange of gaseous mercury in the East China Sea. AB - Two oceanographic cruises were carried out in the East China Sea (ECS) during the summer and fall of 2013. The main objectives of this study are to identify the spatial-temporal distributions of gaseous elemental mercury (GEM) in air and dissolved gaseous mercury (DGM) in surface seawater, and then to estimate the Hg(0) flux. The GEM concentration was lower in summer (1.61 +/- 0.32 ng m(-3)) than in fall (2.20 +/- 0.58 ng m(-3)). The back-trajectory analysis revealed that the air masses with high GEM levels during fall largely originated from the land, while the air masses with low GEM levels during summer primarily originated from ocean. The spatial distribution patterns of total Hg (THg), fluorescence, and turbidity were consistent with the pattern of DGM with high levels in the nearshore area and low levels in the open sea. Additionally, the levels of percentage of DGM to THg (%DGM) were higher in the open sea than in the nearshore area, which was consistent with the previous studies. The THg concentration in fall was higher (1.47 +/- 0.51 ng l(-1)) than those of other open oceans. The DGM concentration (60.1 +/- 17.6 pg l(-1)) and Hg(0) flux (4.6 +/- 3.6 ng m(-2) h( 1)) in summer were higher than those in fall (DGM: 49.6 +/- 12.5 pg l(-1) and Hg(0) flux: 3.6 +/- 2.8 ng m(-2) h(-1)). The emission flux of Hg(0) from the ECS was estimated to be 27.6 tons yr(-1), accounting for ~0.98% of the global Hg oceanic evasion though the ECS only accounts for ~0.21% of global ocean area, indicating that the ECS plays an important role in the oceanic Hg cycle. PMID- 26975004 TI - Joint effects of trihalomethanes and trichloroacetic acid on semen quality: A population-based cross-sectional study in China. AB - Exposure to trihalomethanes (THMs) and haloacetic acids (HAAs) has been individually associated with adverse male reproductive effects; however, their joint male reproductive toxicity is largely unknown. This study aimed to explore the joint effects of THMs and trichloroacetic acid (TCAA) on semen quality in a Chinese population. A total of 337 men presenting to the Reproductive Center of Tongjing Hospital, in Wuhan, China to seek semen analysis were included this study. Baseline blood THMs [chloroform (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and bromoform (TBM)] and urinary TCAA were analyzed and dichotomized at their median levels. The joint effects of THMs and TCAA on below-reference semen quality parameters were evaluated by calculating the relative excess risk due to interaction (RERI). After adjusting for potential confounders, we found a suggestive synergistic effect between Br-THMs (sum of BDCM, DBCM, and TBM) and TCAA for below-reference sperm count (RERI = 2.14, 95% CI: -0.37, 4.91) (P = 0.076); men with high Br-THMs and TCAA levels (above the median) had 3.31 times (95% CI: 1.21, 9.07) elevated risk of having below reference sperm count than men with low Br-THMs and TCAA levels (below the median). No apparent joint effects were observed between THMs and TCAA for other semen quality parameters. Our results suggest that co-exposure to Br-THMs and TCAA is associated with additive effects on decreased semen quality. However, further studies in a larger sample size and mechanistic studies are needed to confirm the findings. PMID- 26975005 TI - Mechanisms of cadmium accumulation (adsorption and absorption) by the freshwater bivalve Corbicula fluminea under hydrodynamic conditions. AB - Many heavy metals in sediments and water have potential adverse effects on aquatic organisms such as Corbicula fluminea (O.F. Muller, 1774), a bivalve species frequently used as a biomonitor for metal pollution. Studies over the past decades examining the heavy metal uptake by C. fluminea, very few has investigated the effect of hydrodynamic conditions on accumulation of heavy metal by C. fluminea. Therefore, in this study, to investigate the mechanism of intracellular and extracellular accumulation of metal, individuals of C. fluminea were exposed to cadmium (Cd)-treated water under three different hydrodynamic conditions. These included exposures in two set ups: three rates of rotation (500, 350, 200 r/min) in beakers for 10 days, and then exposure to Cd-treated sediment under two naturally turbulent water conditions (14 cm/s and 3.2 cm/s) in experimental flumes for 23 days. Hydrodynamic force increased the burrowing rate but decreased the activity of C. fluminea. After 10 days of exposure, the extracellular concentrations of Cd in the tissues of C. fluminea in the sand group were significantly higher than that in the gravel groups. The intracellular and extracellular concentrations of Cd in the tissues of C. fluminea dramatically increased in the Cd-treated sediment test. Moreover, the concentration of the extracellular Cd adsorbed on the tissues of C. fluminea in the 14 cm/s and 3.2 cm/s groups was significantly higher than that in the control group, whereas the effect of hydrodynamic force on absorption of Cd by C. fluminea was not obvious. These results suggest that hydrodynamic condition plays an important role in extracellular accumulation of Cd by C. fluminea. In future study, when using C. fluminea to assess Cd pollution in aquatic environment, extracellular Cd adsorbed on the tissue should be removed to avoid the influence of hydrodynamics. PMID- 26975006 TI - Secular growth trends among children in Beijing (1955-2010). AB - OBJECTIVES: To analyze the growth trends of children in Beijing from 1955 to 2010. METHODS: Data for the period 1955-1975 were derived from published records. Data for the period 1985-2010 were derived from the Chinese National Survey on Students' Constitution and Health (CNSSCH). Since 1985, the overall sampling and measurement methods have been consistent. The mean, the standard deviation, and the variance (ANOVA) of height, weight, and BMI by age and sex of students aged 7 17 were calculated and analyzed. RESULTS: Between 1955 and 2010, the average height and weight of children in Beijing has increased. The average increments per decade for boys and girls were 2.45cm and 2.03cm in height and 2.68kg and 1.68kg in weight, respectively. The largest height increase per decade occurred between 1975 and 1985: 4.51cm and 3.23cm for boys and girls, respectively. The largest height increase for the entire 55-year period under study occurred among boys at age 13 (17.85cm) and among girls at age 11 (15.90cm.) CONCLUSIONS: During the period 1955-2010, growth trends among children in Beijing were positive. The health and nutritional status of these children improved significantly. Since 2007, might be related to government intervention, childhood obesity has been curbed. PMID- 26975007 TI - Gradual Versus Abrupt Smoking Cessation: A Randomized, Controlled Noninferiority Trial. AB - BACKGROUND: Most smoking cessation guidelines advise quitting abruptly. However, many quit attempts involve gradual cessation. If gradual cessation is as successful, smokers can be advised to quit either way. OBJECTIVE: To examine the success of quitting smoking by gradual compared with abrupt quitting. DESIGN: Randomized, controlled noninferiority trial. (International Standardized Randomized Controlled Trial Number Register: ISRCTN22526020). SETTING: Primary care clinics in England. PARTICIPANTS: 697 adult smokers with tobacco addiction. INTERVENTION: Participants quit smoking abruptly or reduced smoking gradually by 75% in the 2 weeks before quitting. Both groups received behavioral support from nurses and used nicotine replacement before and after quit day. MEASUREMENTS: The primary outcome measure was prolonged validated abstinence from smoking 4 weeks after quit day. The secondary outcome was prolonged, validated, 6-month abstinence. RESULTS: At 4 weeks, 39.2% (95% CI, 34.0% to 44.4%) of the participants in the gradual-cessation group were abstinent compared with 49.0% (CI, 43.8% to 54.2%) in the abrupt-cessation group (relative risk, 0.80 [CI, 0.66 to 0.93]). At 6 months, 15.5% (CI, 12.0% to 19.7%) of the participants in the gradual-cessation group were abstinent compared with 22.0% (CI, 18.0% to 26.6%) in the abrupt-cessation group (relative risk, 0.71 [CI, 0.46 to 0.91]). Participants who preferred gradual cessation were significantly less likely to be abstinent at 4 weeks than those who preferred abrupt cessation (38.3% vs 52.2%; P = 0.007). LIMITATIONS: Blinding was impossible. Most participants were white. CONCLUSION: Quitting smoking abruptly is more likely to lead to lasting abstinence than cutting down first, even for smokers who initially prefer to quit by gradual reduction. PRIMARY FUNDING SOURCE: British Heart Foundation. PMID- 26975008 TI - 68Ga-PSMA-PET/CT in Patients With Biochemical Prostate Cancer Recurrence and Negative 18F-Choline-PET/CT. AB - PURPOSE: Investigating the value of Ga-PSMA-PET/CT in biochemically recurring prostate cancer patients with negative F-choline-PET/CT. PATIENTS AND METHODS: One hundred thirty-nine consecutive patients with biochemical recurrence after curative (surgery and/or radiotherapy) therapy were offered participation in this sequential clinical imaging approach. Patients first underwent an F-choline PET/CT. If negative, an additional Ga-PSMA-PET/CT was offered. One hundred twenty five of 139 eligible patients were included in the study; 32 patients underwent additional Ga-PSMA-PET/CT. Patients with equivocal findings (n = 5) on F-choline PET/CT and those who declined the additional Ga-PSMA-PET/CT (n = 9) were excluded. Images were analyzed visually for the presence of suspicious lesions. Findings on PET/CT were correlated with PSA level, PSA doubling time (dt), and PSA velocity (vel). RESULTS: The overall detection rates were 85.6% (107/125) for the sequential imaging approach and 74.4% (93/125) for F-choline-PET/CT alone. Ga PSMA-PET/CT detected sites of recurrence in 43.8% (14/32) of the choline-negative patients. Detection rates of the sequential imaging approach and F-choline-PET/CT alone increased with higher serum PSA levels and PSA vel. Subgroup analysis of Ga PSMA-PET/CT in F-choline negative patients revealed detection rates of 28.6%, 45.5%, and 71.4% for PSA levels of 0.2 or greater to less than 1 ng/mL, 1 to 2 ng/mL, and greater than 2 ng/mL, respectively. CONCLUSIONS: The sequential imaging approach designed to limit Ga-PSMA imaging to patients with negative choline scans resulted in high detection rates. Ga-PSMA-PET/CT identified sites of recurrent disease in 43.8% of the patients with negative F-choline PET/CT scans. PMID- 26975009 TI - Skin Uptake of 99mTc-HDP in a Case of Annular Elastolytic Giant Cell Granuloma. AB - Sometimes unexpected extraosseous uptakes appear in a bone scintigraphy as a consequence of a wide spectrum of nonosseous disorders. Recognition of these findings is important to enhance the diagnostic value of bone scintigraphy. We report a case of intense bone scintigraphy cutaneous uptake due to elastolytic actinic giant cell granuloma (EAGCG). We present the case of a patient with intense extraosseous uptakes of Tc-HDP that appeared in a bone scintigraphy that was performed for lumbar pain. PMID- 26975010 TI - Spectrum of the Breast Lesions With Increased 18F-FDG Uptake on PET/CT. AB - Interpretation of F-FDG PET/CT studies in breast is challenging owing to nonspecific FDG uptake in various benign and malignant conditions. Benign conditions include breast changes in pregnancy and lactation, gynecomastia, mastitis, fat necrosis, fibroadenoma, intraductal papilloma, and atypical ductal hyperplasia. Among malignancies, invasive ductal carcinoma and invasive lobular carcinoma are common histological types of breast carcinoma. Rarely, other unusual histological types of breast carcinomas (eg, intraductal papillary carcinoma, invasive micropapillary carcinoma, medullary carcinoma, mucinous carcinoma, and metaplastic carcinoma), lymphoma, and metastasis can be the causes. Knowledge of a wide spectrum of hypermetabolic breast lesions on FDG PET/CT is essential in accurate reading of FDG PET/CT. The purpose of this atlas article is to demonstrate features of various breast lesions encountered at our institution, both benign and malignant, which can result in hypermetabolism on FDG PET/CT imaging. PMID- 26975012 TI - Thrombus in a Patient With an Inverse Takotsubo Syndrome. PMID- 26975011 TI - Reduced 123I Ioflupane Binding in Bilateral Diabetic Chorea: Findings With 18F FDG PET, 99mTc ECD SPECT, and 123I MIBG Scintigraphy. AB - We report a 64-year-old man with diabetic chorea whom we investigated with dopamine transporter SPECT, F FDG PET, Tc ethylcysteinate dimer (ECD) SPECT, and I metaiodobenzylguanidine (MIBG) scintigraphy. Dopamine transporter SPECT revealed reduced I ioflupane binding in the bilateral striatum. F FDG PET showed metabolic dysfunction in the bilateral striatum, as shown in earlier studies. Tc ECD SPECT revealed reduced brain perfusion in the bilateral caudate nucleus and putamen. I MIBG scintigraphy revealed no cardiac sympathetic nerve dysfunction. Our case suggests a possible nigrostriatal presynaptic dopaminergic involvement in diabetic chorea. PMID- 26975013 TI - Silicone Granuloma in the Buttocks Incidentally Detected by 18F-FDG PET/CT 30 Years After Free Liquid Silicone Injections. AB - A 59-year-old transexual (male to female) patient presented with a squamous cell carcinoma of the larynx. She underwent an F-FDG PET/CT for initial staging. The examination showed high F-FDG uptake of the primary lesion and a homolateral lymphadenopathy. Incidental heterogeneous uptake of round hyperdense lesions in the gluteal muscles and subcutaneous fat was visualized. The medical history revealed secondly that the patient had had free liquid silicone injections 30 years before the examination. Although the injection of free silicone is not practised since the 1980s, this incidental finding should prompt to check the patient's medical history over several decades. PMID- 26975014 TI - Extramedullary Involvement of Mast Cell Leukemia Detected by 18F-FDG PET/CT. AB - Mast cell leukemia (MCL) is a very rare subtype of systemic mastocytosis, characterized by the leukemic expansion of immature mast cells. We present a case of MCL with extramedullary involvement of cervical lymph node and lung demonstrated by the initial F-FDG PET/CT scan. After a transient complete remission by induction chemotherapy and allogeneic hematopoietic stem cell transplantation, the follow-up PET/CT showed extensive extramedullary relapse involving multiple lymph nodes and small bowel. F-FDG PET/CT may be a useful tool to comprehensively stage and follow-up MCL. PMID- 26975016 TI - Quality and Safety in Health Care, Part XI: Introduction to Diagnostic Errors. AB - The process of reaching a diagnosis in health care has not been emphasized in safety programs carried out by health care organizations as much as many other aspects of care such as handoffs, medication errors, patient falls, wrong-side surgery, and decreasing hospital-acquired infections. However, diagnostic errors are a fairly frequent cause of harm that can contribute to serious injury or death. This article is the first in a series discussing the diagnostic process and how to define, measure, and prevent errors in diagnosis. PMID- 26975015 TI - FDG PET/CT in IgG4-Related Peripulmonary Arteritis. AB - IgG4-related peripulmonary arteritis is rare. A 60-year-old woman presented with fatigue for more than 2 years. Transthoracic echocardiography revealed a lesion measuring 2.1 * 1.5 cm in the pulmonary artery bifurcation. CT pulmonary angiography showed marked stenosis of the right and left pulmonary arteries. FDG PET/CT showed increased FDG uptake of the thickened walls in the bilateral pulmonary arteries with SUVmax of 5.8. The patient underwent partial resection of the pulmonary artery lesion. IgG4-related peripulmonary arteritis was confirmed by pathology. PMID- 26975017 TI - Dual Diagnostic Role of 123I-MIBG Scintigraphy in Inverted Takotsubo Cardiomyopathy: Reply. PMID- 26975018 TI - Quality and Safety in Health Care, Part XII: The Work System, Testing, and Clinical Reasoning. AB - Donabedian felt the 3 major components affecting quality were process, structure, and outcome. Later investigators often substitute the word "structure" for a broader concept called the "work system." One component of the latter is the people involved, and for diagnosis, this often is best done with a diagnostic team. The work system in diagnosis has many obstacles to achieve optimum performance. There are also important problems with how tests are ordered and interpreted and clinical reasoning and biases. PMID- 26975019 TI - Re: Incidental Detection of a Hodgkin Lymphoma on 18F-Choline PET/CT and Comparison With 18FDG PET/CT in a Patient With Prostate Cancer. PMID- 26975020 TI - Survival of patients with metastatic melanoma and brain metastases in the era of MAP-kinase inhibitors and immunologic checkpoint blockade antibodies: A systematic review. AB - BACKGROUND: The incidence of brain metastases (BM) in melanoma patients is common and associated with poor prognosis. MAP-kinase inhibitors and immunologic checkpoint blockade antibodies led to improved survival of metastatic melanoma patients; however, patients with BM are under-represented or excluded from the majority of clinical trials and the impact of new drugs on their survival is less clear. With the present systematic review, we aimed to analyze outcomes of patients with melanoma BM treated with the new drugs, both in the setting of phase I-II-III clinical trials and in the "real world". METHODS: An electronic search was performed to identify studies reporting survival outcomes of patients with melanoma BM treated with MAP-kinase inhibitors and/or immunologic checkpoint blockade antibodies, regardless of study design. RESULTS: Twenty-two studies were included for a total of 2153 patients. Median OS was 7.9 months in phase I-II-III trials and 7.7 months in "real world" studies. In clinical trials, median OS was 7.0 months for patients treated with immunotherapy and 7.9 months for patients treated with BRAF inhibitors. In "real world" studies, median OS was 4.3 months and 7.7 months for patients treated with immunotherapy and BRAF inhibitors, respectively. Evidence of clinical activity exists for both immunotherapy and MAP kinase inhibitors. CONCLUSIONS: MAP-kinase inhibitors and immunologic checkpoint blockade antibodies have clinical activity and may achieve improved OS in patients with metastatic melanoma and BM. These results support the inclusion of patients with BM in investigations of new agents and new treatment regimens for metastatic melanoma. PMID- 26975021 TI - Metabolic phenotype of bladder cancer. AB - Metabolism of bladder cancer represents a key issue for cancer research. Several metabolic altered pathways are involved in bladder tumorigenesis, representing therefore interesting targets for therapy. Tumor cells, including urothelial cancer cells, rely on a peculiar shift to aerobic glycolysis-dependent metabolism (the Warburg-effect) as the main energy source to sustain their uncontrolled growth and proliferation. Therefore, the high glycolytic flux depends on the overexpression of glycolysis-related genes (SRC-3, glucose transporter type 1 [GLUT1], GLUT3, lactic dehydrogenase A [LDHA], LDHB, hexokinase 1 [HK1], HK2, pyruvate kinase type M [PKM], and hypoxia-inducible factor 1-alpha [HIF-1alpha]), resulting in an overproduction of pyruvate, alanine and lactate. Concurrently, bladder cancer metabolism displays an increased expression of genes favoring the pentose phosphate pathway (glucose-6-phosphate dehydrogenase [G6PD]) and the fatty-acid synthesis (fatty acid synthase [FASN]), along with a decrease of AMP activated protein kinase (AMPK) and Krebs cycle activities. Moreover, the PTEN/PI3K/AKT/mTOR pathway, hyper-activated in bladder cancer, acts as central regulator of aerobic glycolysis, hence contributing to cancer metabolic switch and tumor cell proliferation. Besides glycolysis, glycogen metabolism pathway plays a robust role in bladder cancer development. In particular, the overexpression of GLUT-1, the loss of the tumor suppressor glycogen debranching enzyme amylo-alpha-1,6-glucosidase, 4-alpha-glucanotransferase (AGL), and the increased activity of the tumor promoter enzyme glycogen phosphorylase impair glycogen metabolism. An increase in glucose uptake, decrease in normal cellular glycogen storage, and overproduction of lactate are consequences of decreased oxidative phosphorylation and inability to reuse glucose into the pentose phosphate and de novo fatty acid synthesis pathways. Moreover, AGL loss determines augmented levels of the serine-to-glycine enzyme serine hydroxymethyltransferase-2 (SHMT2), resulting in an increased glycine and purine ring of nucleotides synthesis, thus supporting cells proliferation. A deep understanding of the metabolic phenotype of bladder cancer will provide novel opportunities for targeted therapeutic strategies. PMID- 26975022 TI - Association Between Starting Hemodialysis for End-Stage Renal Disease and Incident Cataract Surgery: A 12-Year Nationwide Cohort Study. AB - PURPOSE: To evaluate incident cataract surgery in subjects who started hemodialysis for end-stage renal disease. METHODS: A nationwide propensity score matched cohort study was performed by using a 12-year longitudinal national health insurance database of 1,025,340 subjects. The hemodialysis cohort was composed of patients who started hemodialysis between January 2003 and December 2007 (n = 291). The control cohort was composed of randomly selected patients (5 per patient in the hemodialysis cohort; n = 1467) who were matched to the hemodialysis cohort according to a propensity score based on year of hemodialysis initiation, age, sex, residential area, household income, and frequency of medical attention. Each selected patient was followed up until 2013. Cox proportional hazard regression analysis was used to calculate the overall hazard of hemodialysis initiation in regard to incident cataract surgery after adjusting for the above factors, hypertension, and diabetes mellitus. RESULTS: Starting hemodialysis was associated with increased incident cataract surgery (hazard ratio [HR] = 1.79; 95% confidence interval [CI], 1.34-2.41). Diabetes mellitus (HR = 1.68; 95% CI, 1.22-2.32) also increased the incidence of cataract surgery. With respect to age, the effect size of hemodialysis for incident cataract surgery was greater among younger adults (aged <60 years; HR = 5.32; 95% CI, 3.06 9.26) than among older adults (aged >=60 years; HR = 1.17; 95% CI, 0.79-1.72). CONCLUSIONS: Patients who began hemodialysis for end-stage renal disease were more likely to undergo cataract surgery than control subjects, and this risk was more pronounced in younger patients. PMID- 26975023 TI - Degeneration of Photoreceptor Cells in Arylsulfatase G-Deficient Mice. AB - PURPOSE: Retinal degeneration is a common feature of several lysosomal storage disorders, including the mucopolysaccharidoses, a group of metabolic disorders that is characterized by widespread accumulation of glycosaminoglycans due to lysosomal enzyme dysfunction. We used a new mouse model of mucopolysaccharidosis IIIE to study the effect of Arylsulfatase G (ARSG) deficiency on retina integrity. METHODS: The retina of Arsg knockout mice aged 1 to 24 months was studied by immunohistochemistry and Western blot analysis. Electron microscopic analyses were performed on retinas from 15- and 22-month-old animals. Photoreceptor and microglia cell numbers and retina thickness were determined to quantitatively characterize retinal degeneration in ARSG-deficient mice. RESULTS: Arsg knockout mice showed a progressive degeneration of photoreceptor cells starting between 1 and 6 months of age, resulting in the loss of more than 50% of photoreceptor cells in 24-month-old mice. Photoreceptor loss was accompanied by reactive astrogliosis, reactive microgliosis that was evident in the outer but not inner retina, and elevated expression levels of some lysosomal proteins. Electron microscopic analyses of retinas revealed no evidence for the presence of storage vacuoles. Of note, expression of ARSG protein in wild-type mice was detectable only in the RPE which, however, appeared morphologically unaffected in knockout mice at the electron microscopic level. CONCLUSIONS: To our knowledge, this is the first study demonstrating that ARSG deficiency results in progressive photoreceptor degeneration and dysregulation of various lysosomal proteins. PMID- 26975024 TI - Two-Dimensional Plane for Multi-Scale Quantification of Corneal Subbasal Nerve Tortuosity. AB - PURPOSE: To assess the performance of a novel system for automated tortuosity estimation and interpretation. METHODS: A supervised strategy (driven by observers' grading) was employed to automatically identify the combination of tortuosity measures (i.e., tortuosity representation) leading to the best agreement with the observers. We investigated 18 tortuosity measures including curvature and density of inflection points, computed at multiple spatial scales. To leverage tortuosity interpretation, we propose the tortuosity plane (TP) onto which each image is mapped. Experiments were carried out on 140 images of subbasal nerve plexus of the central cornea, covering four levels of tortuosity. Three experienced observers graded each image independently. RESULTS: The best tortuosity representation was the combination of mean curvature at spatial scales 2 and 5. These tortuosity measures were the axes of the proposed TP (interpretation). The system for tortuosity estimation revealed strong agreement with the observers on a global and per-level basis. The agreement with each observer (Spearman's correlation) was statistically significant (alphas = 0.05, P < 0.0001) and higher than that of at least one of the other observers in two out of three cases (rhoOUR = 0.7594 versus rhoObs3 = 0.7225; rhoOUR = 0.8880 versus rhoObs1 = 0.8017, rhoObs3 = 0.7315). Based on paired-sample t-tests, these improvements were significant (P < 0.001). CONCLUSIONS: Our automated system stratifies images by four tortuosity levels (discrete scale) matching or exceeding the accuracy of experienced observers. Of importance, the TP allows the assessment of tortuosity on a two-dimensional continuous scale, thus leading to a finer discrimination among images. PMID- 26975025 TI - Short Pulse of Clinical Concentration of Bevacizumab Modulates Human Retinal Pigment Epithelial Functionality. AB - PURPOSE: Cross-talk between Notch signaling and vascular endothelial growth factor (VEGF) is a major driver of angiogenesis. Here we investigated the temporal effect of bevacizumab (BEV) on Notch signaling and the functional features of cultured primary retinal pigment epithelial (PRPE) cells. METHODS: Human (cadaver) PRPE cells were treated with clinical concentrations of BEV (0.25 mg/mL). Notch signaling pathway receptors, ligands, and downstream target genes were analyzed with quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation along with phagocytosis and transmembrane potential was analyzed by fluorescent activated cell sorter (FACS) and immunofluorescence. RESULTS: Bevacizumab-treated PRPE cultures revealed a significant temporal downregulation of notch4 (P < 0.05) and Delta-like-4 (P < 0.005) gene (16% reduced) and protein (29.7% reduced) expression only at the 2-hour exposure, though secreted VEGF levels were significantly blocked (P < 0.005) at all the time points (2, 4, 6 hours). Further, a significant downregulation (P < 0.005) in cell cycle (reduced by 34.1%) and a concurrent (P < 0.005) upregulation of F actin staining (increased by 2.5-fold) could be detected. Bevacizumab-treated PRPE cells revealed an elevated transmembrane potential (by 63%) and significant decrease (P < 0.01) in phagocytosis (by 19.25%) in comparison to untreated controls. CONCLUSIONS: There is temporal interaction between BEV and the Notch signaling pathway, specifically with Notch4 and Delta-like-ligand-4 in PRPE cultures. This transient decrease in Notch signaling can impact the functionality of RPE cells. These findings can help to provide a better understanding of the effect of long-term usage of anti-VEGF agents in the treatment of retinal degenerative and vitreoretinopathy diseases. PMID- 26975026 TI - Anatomical Variation of Human Collector Channel Orifices. AB - PURPOSE: To examine the anatomical variation of normal human collector channel orifices and their relationship with Schlemm's canal. METHODS: Ten human anterior segments fixed by immersion or perfusion were dissected radially and further divided by fine dissection into corresponding inner and outer wall segments. The tissues were dehydrated, critical-point dried, sputter coated, and examined by scanning electron microscopy. Images were obtained at magnifications from *200 to *10,000. Selected radial collector channel regions were processed for plastic embedding. RESULTS: Two classes of collector channel orifices were identified. Simple oval orifices (54.7 +/- 4.6-MUm diameter) were lined with endothelial cells and most often occurred on a planar region of Schlemm's canal outer wall. Complex orifices (62.7 +/- 3.4-MUm diameter) were often found associated with septal columns and bridges, and typically covered with flap-like structures (10 40 MUm) that extended between the inner and outer wall and over the collector channel orifices. Both simple and complex orifices had complete or partial lip like rims. In orifices with partial rims, a trough-like groove was often visible on the outer wall surface opposite the lip. Transected septa and inner and outer wall adhesion sites were often found in association with complex collector channel orifices. CONCLUSIONS: Collector channel orifice structure varied from simple ovals to complex tethered flaps and bridges. Collector channel orifices with complex flaps connect the inner and outer walls of Schlemm's canal, and may serve to enhance and regulate aqueous outflow in these regions. PMID- 26975028 TI - Erratum. PMID- 26975027 TI - Relationships of Macular Pigment Optical Density With Plasma Lutein, Zeaxanthin, and Diet in an Elderly Population: The Montrachet Study. AB - PURPOSE: To investigate the association of macular pigment optical density (MPOD) with plasma lutein, zeaxanthin, and diet in an elderly population. METHODS: We conducted a population-based study, the Montrachet (Maculopathy Optic Nerve, nuTRition neurovAsCular, and HEarT disease) study, in subjects older than 75 years. The MPOD was measured by means of the two-wavelength autofluorescence technique. Plasma lutein and zeaxanthin were measured in fasting blood samples using HPLC. Food frequency consumption was assessed with self-reported food frequency questionnaires. RESULTS: Overall, 433 healthy participants (62.1% females) were included. Mean age was 82.0 +/- 3.6 years. Mean MPOD at 0.5 degrees eccentricity was 0.57 +/- 0.25 density units (DU) and was higher in women than in men (0.59 +/- 0.25 vs. 0.53 +/- 0.25, P = 0.017). The MPOD was lower in alcohol consumers than in non-alcohol consumers (0.55 +/- 0.25 vs. 0.61 +/- 0.25, P = 0.016). Median plasma lutein and zeaxanthin levels were 281.4 MUg/L and 20.0 MUg/L, respectively, and were higher in women (P = 0.010 and P = 0.003, respectively). The MPOD was positively correlated with plasma lutein and zeaxanthin (r = 0.10, P = 0.030 and r = 0.11, P = 0.027, respectively). A higher consumption of squash was associated with higher plasma lutein and zeaxanthin. Adjusting for confounders and diet revealed that MPOD was weakly associated with plasma lutein in nonsmokers (beta = 0.11, P = 0.021). CONCLUSIONS: This study suggests that plasma lutein is associated with MPOD after taking into account potential confounding factors in an elderly population. PMID- 26975030 TI - Ketorolac Administration Attenuates Retinal Ganglion Cell Death After Axonal Injury. AB - PURPOSE: To assess the neuroprotective effects of ketorolac administration, in solution or delivered from biodegradable microspheres, on the survival of axotomized retinal ganglion cells (RGCs). METHODS: Retinas were treated intravitreally with a single injection of tromethamine ketorolac solution and/or with ketorolac-loaded poly(D,L-lactide-co-glycolide) (PLGA) microspheres. Ketorolac treatments were administered either 1 week before optic nerve crush (pre-ONC) or right after the ONC (simultaneous). In all cases, animals were euthanized 7 days after the ONC. As control, nonloaded microspheres or vehicle (balanced salt solution, BSS) were administered in parallel groups. All retinas were dissected as flat mounts; RGCs were immunodetected with brain-specific homeobox/POU domain protein 3A (Brn3a), and their number was automatically quantified. RESULTS: The percentage of Brn3a+RGCs was 36% to 41% in all control groups (ONC with or without BSS or nonloaded microparticles). Ketorolac solution administered pre-ONC resulted in 63% survival of RGCs, while simultaneous administration promoted a 53% survival. Ketorolac-loaded microspheres were not as efficient as ketorolac solution (43% and 42% of RGC survival pre-ONC or simultaneous, respectively). The combination of ketorolac solution and ketorolac loaded microspheres did not have an additive effect (54% and 55% survival pre-ONC and simultaneous delivery, respectively). CONCLUSIONS: Treatment with the nonsteroidal anti-inflammatory drug ketorolac delays RGC death triggered by a traumatic axonal insult. Pretreatment seems to elicit a better output than simultaneous administration of ketorolac solution. This may be taken into account when performing procedures resulting in RGC axonal injury. PMID- 26975029 TI - DNA Damage Response in Proliferating Muller Glia in the Mammalian Retina. AB - PURPOSE: Muller glia, the principal glial cell type in the retina, have the potential to proliferate and regenerate neurons after retinal damage. However, unlike the situation in fish and birds, this capacity of Muller glia is extremely limited in mammals. To gain new insights into the mechanisms that hamper retinal regeneration in mammals, we examined the cell cycle progression and DNA damage response in Muller glia after retinal damage. METHODS: Expression of cell cycle related proteins and DNA damage response were analyzed in adult rat and mouse retinas after N-methyl-N-nitrosourea (MNU)- or N-methyl-D-aspartate (NMDA) induced retinal damage. Zebrafish and postnatal rat retinas were also investigated for comparison. Analysis was conducted by using immunofluorescence, Western blotting, and quantitative real-time polymerase chain reaction. RESULTS: In the rat retina, most Muller glia reentered the cell cycle after MNU-induced photoreceptor damage while no proliferative response was observed in the mouse model. Cell cycle reentry of rat Muller glia was accompanied by DNA damage response including the phosphorylation of the histone variant H2AX and upregulation of p53 and p21. The DNA damage response was also observed in rat Muller glia after NMDA-induced loss of inner retinal neurons, but not in zebrafish Muller glia or rat retinal progenitor cells. CONCLUSIONS: Our findings suggest that the DNA damage response induced by unscheduled cell cycle reentry may be one of the mechanisms that limit the proliferative and regenerative capacity of Muller glia in the mammalian retina. PMID- 26975031 TI - Prevalence of Age-Related Cataract and Cataract Surgery in a Chinese Adult Population: The Taizhou Eye Study. AB - PURPOSE: To study the prevalence of age-related cataract (ARC), cataract surgery, and visual outcomes in a Chinese adult population in Taizhou, China. METHODS: A population-based, cross-sectional study was conducted using a random cluster sampling method. We evaluated 10,234 eligible subjects 45 years or older (response rate 78.1%) in the Taizhou Eye Study. We conducted a detailed eye examination in all participants, including presenting visual acuity (PVA), best corrected visual acuity (BCVA), slit-lamp assessment of lens opacities using the Lens Opacities Classification System III (LOCS III), and fundus examination. RESULTS: The standardized prevalences of cortical, nuclear, and posterior subcapsular cataract (PSC) were 28.6%, 24.3%, and 4.4%, respectively, and combined nuclear and cortical cataract was the most common cataract type (40.0%). According to the US visual impairment (VI) criteria and World Health Organization VI criteria, 40.6% and 21.8% of PSC participants had binocular VI, respectively; these values were higher than the VI rates in cortical and nuclear cataract (all P < 0.001). Of 148 patients (3.5%) who had cataract surgeries, 41.2% had PVA <20/63, and 19.6% had PVA <20/200. The main causes of poor visual outcome after cataract surgery were ocular comorbidities (41.3%), uncorrected refractive error (30.0%), surgical complications (15.0%), and posterior capsular opacification (PCO; 13.7%). CONCLUSIONS: The high prevalence of cataract and high rate of VI from ARC in the adult Chinese population remains a severe public health problem. Cataract surgery remains insufficient in mainland China and poor visual outcomes were frequent. Surgical complications and PCO were important avoidable causes that attributed to poor visual outcomes after cataract surgeries. PMID- 26975032 TI - The Burden of Hypertension and Associated Risk for Cardiovascular Mortality in China. AB - IMPORTANCE: Hypertension is a leading cause of premature death in China, but limited evidence is available on the prevalence and management of hypertension and its effect on mortality from cardiovascular disease (CVD). OBJECTIVES: To examine the prevalence, diagnosis, treatment, and control of hypertension and to assess the CVD mortality attributable to hypertension in China. DESIGN, SETTING AND PARTICIPANTS: This prospective cohort study (China Kadoorie Biobank Study) recruited 500 223 adults, aged 35 to 74 years, from the general population in China. Blood pressure (BP) measurements were recorded as part of the baseline survey from June 25, 2004, to August 5, 2009, and 7028 deaths due to CVD were recorded before January 1, 2014 (mean duration of follow-up: 7.2 years). Data were analyzed from June 9, 2014, to July 17, 2015. EXPOSURES: Prevalence and diagnosis of hypertension (systolic BP >=140 mm Hg, diastolic BP >=90 mm Hg, or receiving treatment for hypertension) and treatment and control rates overall and in various population subgroups. MAIN OUTCOMES AND MEASURES: Cox regression analysis yielded age- and sex-specific rate ratios for deaths due to CVD comparing participants with and without uncontrolled hypertension, which were used to estimate the number of CVD deaths attributable to hypertension. RESULTS: The cohort included 205 167 men (41.0%) and 295 056 women (59.0%) with a mean (SD) age of 52 (10) years for both sexes. Overall, 32.5% of participants had hypertension; the prevalence increased with age (from 12.6% at 35-39 years of age to 58.4% at 70-74 years of age) and varied substantially by region (range, 22.7% 40.7%). Of those with hypertension, 30.5% had received a diagnosis from a physician; of those with a diagnosis of hypertension, 46.4% were being treated; and of those treated, 29.6% had their hypertension controlled (ie, systolic BP <140 mm Hg; diastolic BP <90 mm Hg), resulting in an overall control rate of 4.2%. Even among patients with hypertension and prior CVD, only 13.0% had their hypertension controlled. Uncontrolled hypertension was associated with relative risks for CVD mortality of 4.1 (95% CI, 3.7-4.6), 2.6 (95% CI, 2.4-2.9) and 1.9 (95% CI, 1.8-2.0) at ages 35 to 59, 60 to 69, and 70 to 79 years, respectively, and accounted for about one-third of deaths due to CVD (approximately 750 000) at 35 to 79 years of age in 2010. CONCLUSIONS AND RELEVANCE: About one-third of Chinese adults in this national cohort population had hypertension. The levels of diagnosis, treatment, and control were much lower than in Western populations, and were associated with significant excess mortality. PMID- 26975033 TI - A rare case of recurrent malignant triton tumor in a male with NF1: Case report and mini-review. AB - BACKGROUND: Malignant triton tumors (MTT) represent a rare subset of tumors with rhabdomyoblastic differentiation within the heterogeneous group of malignant peripheral nerve sheath tumors (MPNST). CASE PRESENTATION: Here, we report on a case of a 25 year-old male with a history of neurofibromatosis type I and MTT of the mediastinal wall who presented in our clinic with a pelvic tumor and multiple hypervascular mesenteric masses and underwent resection. Upon resection, histological findings revealed an MTT of the omentum and an atypical neurofibroma of the pelvis with focal transitions to a low-grade MPNST. The patient relapsed just one month later and died 3 months after the surgery. CONCLUSION: Clinically, MTTs are characterized as highly aggressive tumors that are fast-growing and prone to local recurrence and distant metastasis. To date, there is no treatment consensus available yet and many patients succumb to the disease shortly after diagnosis. This is because the pathogenesis of MTT remains unknown and patients with MTT are often diagnosed at a late stage of disease. Our case presents valuable teaching points in terms of providing a possible progression model based on the coexistence of a low-grade MPNST and MTT in the context of NF1 and an atypical neurofibroma in this patient. Close monitoring of patients with NF1 and atypical neurofibromas or MPNST might therefore help to diagnose MTT at an earlier stage. PMID- 26975034 TI - Absorption of impinging water droplet in porous stones. AB - This paper presents an experimental investigation and numerical analysis of the absorption of water droplets impacting porous stones. The absorption process of an impinging droplet is here fully characterized from spreading to evaporation in terms of absorbed mass during droplet depletion and moisture content distribution in a time-resolved manner for three different natural stones. High-speed imaging and neutron radiography are used to quantify moisture absorption in porous stones of varying moisture properties from deposition until depletion. During impact and spreading, the droplet exhibits a dynamic non-wetting behavior. At maximum spreading, the droplet undergoes pinning, resulting into the contact radius remaining constant until droplet depletion. Absorption undergoes two phases: initially, absorption is hindered due a contact resistance attributed to entrapped air; afterwards, a more perfect capillary contact occurs and absorption goes on until depletion, concurrently with evaporation and further redistribution. A finite-element numerical model for isothermal unsaturated moisture transport in porous media captures the phases of mass absorption in good agreement with the experimental data. Droplet spreading and absorption are highly determined by the impact velocity of the droplet, while moisture content redistribution after depletion is much less dependent on impact conditions. PMID- 26975035 TI - Clinicopathologic Spectrum of Gastrointestinal T-cell Lymphoma: Reappraisal Based on T-cell Receptor Immunophenotypes. AB - The differential diagnosis of primary gastrointestinal EBV T-cell lymphoma (GITCL) includes enteropathy-associated T-cell lymphoma (EATL), peripheral T-cell lymphoma, not otherwise specified, adult T-cell leukemia/lymphoma, and anaplastic large cell lymphoma. Type II EATL is considered to be a tumor of intraepithelial lymphocytes. However, the evaluation of intraepithelial lymphocytosis by biopsy specimens is challenging, which poses a diagnostic problem between the EATL and peripheral T-cell lymphoma, not otherwise specified. This situation requested us to establish a pragmatic diagnostic approach for the classification of GITCL. We identified 42 cases of GITCL and analyzed clinicopathologic features, especially addressing their T-cell receptor (TCR) phenotype. Nine (21%) of 42 GITCL cases were positive for TCRgamma protein expression. Among these TCRgamma cases, TCRbeta expression or not was detected in 5 and 4, respectively, but resulted in no further clinicopathologic differences. TCRbeta positivity without TCRgamma expression (betagamma) was seen in 9 GITCL patients (21%). Twenty-four patients (57%) were negative for TCRbeta and gamma expression (betagamma). Compared with TCRbetagamma or betagamma type, TCRgamma cases were characterized by exclusive involvement of intestinal sites (100% vs. 11%, P<0.001; 100% vs. 58%, P=0.032, respectively), but not of stomach (0% vs. 78%, P=0.002; 0% vs. 38%, P=0.039, respectively). Notably, TCRgamma positivity was an independent unfavorable prognostic factor among our GITCL patients (P<0.001). Considering our results, TCRgamma GITCL, that is, intestinal gammadelta T-cell lymphoma, appears to constitute a distinct disease entity. PMID- 26975037 TI - Renal Cell Carcinoma Occurring in Patients With Prior Neuroblastoma: A Heterogenous Group of Neoplasms. AB - Renal cell carcinoma (RCC) associated with neuroblastoma (NB) was included as a distinct entity in the 2004 World Health Organization classification of kidney tumors. A spectrum of RCC subtypes has been reported in NB survivors. We herein describe a series of 8 RCCs diagnosed in 7 patients with a history of NB. Microscopic evaluation, immunohistochemical staining for PAX8, cathepsin K, and succinate dehydrogenase subunit B (SDHB), and fluorescence in situ hybridization (FISH) for TFE3 and TFEB were performed. Four distinct morphologic subtypes were identified: 3 tumors were characterized by cells with abundant oncocytoid cytoplasm and irregular nuclei; 3 showed features of microphthalmia transcription factor family translocation RCC (MiTF-RCC); 1 had features of hybrid oncocytic chromophobe tumor; 1 had papillary RCC histology. All RCCs expressed PAX8 and retained SDHB expression. Cathepsin K was positive in 2 MiTF-RCCs, 1 was TFEB FISH positive, and the other was indeterminate. Cathepsin K was negative in a third MiTF-RCC with TFE3 rearrangement. TFE3 FISH was negative in 4 and insufficient in 1 of the other 5 RCCs. While a subset of RCCs associated with NB is characterized by cells with prominent oncocytoid cytoplasm, other RCC subtypes also occur in post-NB patients. Renal neoplasms occurring in patients with a history of NB do not represent a single entity but a heterogenous group of RCCs. SDHB mutations do not explain the subset of nontranslocation RCCs with oncocytoid features; therefore, further studies are needed to clarify whether they may represent a distinct entity with unique molecular abnormalities or may belong to other emerging RCC subtypes. PMID- 26975036 TI - TFE3-Fusion Variant Analysis Defines Specific Clinicopathologic Associations Among Xp11 Translocation Cancers. AB - Xp11 translocation cancers include Xp11 translocation renal cell carcinoma (RCC), Xp11 translocation perivascular epithelioid cell tumor (PEComa), and melanotic Xp11 translocation renal cancer. In Xp11 translocation cancers, oncogenic activation of TFE3 is driven by the fusion of TFE3 with a number of different gene partners; however, the impact of individual fusion variant on specific clinicopathologic features of Xp11 translocation cancers has not been well defined. In this study, we analyze 60 Xp11 translocation cancers by fluorescence in situ hybridization using custom bacterial artificial chromosome probes to establish their TFE3 fusion gene partner. In 5 cases RNA sequencing was also used to further characterize the fusion transcripts. The 60 Xp11 translocation cancers included 47 Xp11 translocation RCC, 8 Xp11 translocation PEComas, and 5 melanotic Xp11 translocation renal cancers. A fusion partner was identified in 53/60 (88%) cases, including 18 SFPQ (PSF), 16 PRCC, 12 ASPSCR1 (ASPL), 6 NONO, and 1 DVL2. We provide the first morphologic description of the NONO-TFE3 RCC, which frequently demonstrates subnuclear vacuoles leading to distinctive suprabasal nuclear palisading. Similar subnuclear vacuolization was also characteristic of SFPQ-TFE3 RCC, creating overlapping features with clear cell papillary RCC. We also describe the first RCC with a DVL2-TFE3 gene fusion, in addition to an extrarenal pigmented PEComa with a NONO-TFE3 gene fusion. Furthermore, among neoplasms with the SFPQ-TFE3, NONO-TFE3, DVL2-TFE3, and ASPL-TFE3 gene fusions, the RCCs are almost always PAX8 positive, cathepsin K negative by immunohistochemistry, whereas the mesenchymal counterparts (Xp11 translocation PEComas, melanotic Xp11 translocation renal cancers, and alveolar soft part sarcoma) are PAX8 negative, cathepsin K positive. These findings support the concept that despite an identical gene fusion, the RCCs are distinct from the corresponding mesenchymal neoplasms, perhaps due to the cellular context in which the translocation occurs. We corroborate prior data showing that the PRCC-TFE3 RCCs are the only known Xp11 translocation RCC molecular subtype that are consistently cathepsin K positive. In summary, our data expand further the clinicopathologic features of cancers with specific TFE3 gene fusions and should allow for more meaningful clinicopathologic associations to be drawn. PMID- 26975038 TI - Clinicopathologic Characterization of Aggressive Natural Killer Cell Leukemia Involving Different Tissue Sites. AB - Aggressive natural killer cell leukemia (ANKL) is a rare disease with an extremely aggressive clinical course. The etiology of ANKL is unclear with few genetic/epigenetic aberrations described to date. Moreover, misdiagnosis of ANKL is a frequent problem. Clinicopathologic characteristics of 35 retrospective cases of ANKL were investigated with the aim of improving diagnosis and to find the genetic/epigenetic aberrations associated with ANKL etiology. Because of the relatively low number of leukemic cells in the peripheral blood and bone marrow, diagnosis of ANKL can be missed; therefore, it is important to perform biopsy on solid tissues, if necessary. We describe the pathology of ANKL in the lymph nodes, bone marrow, spleen, liver, and skin, with focus on diagnosis and differentiated diagnosis. We observed young male predominance in our cohort, and the clinical course was more aggressive than reported previously. Low lactate dehydrogenase (<712 IU/L), chemotherapy or L-asparaginase administration were found to be associated with more favorable outcomes. SH2 domains of STAT5B and STAT3 also were screened for the presence of activating mutations. Moreover, CpG island methylation status of HACE1, a candidate tumor-suppressor gene, was determined in ANKL samples. We observed activating STAT5B mutations (1/5) and hypermethylation of HACE1 (3/4) in ANKL cases, suggesting that these aberrations may contribute to ANKL pathogenesis. PMID- 26975039 TI - Interlaboratory Variability in the Histologic Grading of Colorectal Adenocarcinomas in a Nationwide Cohort. AB - Differentiation grade of colorectal adenocarcinoma (CRC) is a prognostic factor and important for therapy selection. In patients with stage II colon cancer, poor differentiation is an indication for adjuvant chemotherapy. The variability in daily practice in the grading of CRC was assessed in a nationwide cohort. Using the Dutch Pathology Registry (PALGA), all synoptically reported CRC resections from 2010 to 2013 were identified. Proportions of poorly differentiated (PD) adenocarcinomas were determined and compared between 35 laboratories by univariable and multivariable logistic regression analyses. In total, 11,719 resections of 11,681 patients were included, of which 1427 (12.2%) were PD (range between 35 laboratories: 5.0% to 33.2%). After adjustment for case mix, 4 (11%) laboratories still reported a significantly lower (n=2) or higher (n=2) proportion of PD adenocarcinoma compared with the reference laboratory. Seven of 8 investigated laboratories showed considerable intralaboratory variation between pathologists as well. In a subgroup of 2812 patients (2813 tumors) who could have been eligible for adjuvant chemotherapy solely on the basis of the differentiation grade (stage II colon cancer patients without other high-risk factors [ie, T4, <10 lymph nodes evaluated, perforation, ileus, or angioinvasion]), 258 (9.2%) were PD (range between laboratories: 0% to 22.7%). In this subgroup, 4 laboratories still diagnosed significantly more PD adenocarcinomas after multivariable logistic regression analysis, increasing the number of colon cancer patients eligible for adjuvant therapy. In conclusion, this large nationwide cohort demonstrates considerable interlaboratory and intralaboratory variation in differentiation grading of CRC. Better standardization of grading criteria is needed for optimal determination of prognosis and treatment selection. PMID- 26975040 TI - Mixed and Ambiguous Endometrial Carcinomas: A Heterogenous Group of Tumors With Different Clinicopathologic and Molecular Genetic Features. AB - Besides endometrioid, serous, and clear cell carcinomas, there are endometrial carcinomas exhibiting mixed and ambiguous morphologic features. We have analyzed the immunophenotype (p53, p16, beta-catenin, ER, HNF-1B, MLH1, and Ki-67) and mutational status (PTEN, KRAS, PIK3CA, and POLE) of 7 mixed carcinomas and 13 ambiguous carcinomas, all of them classified initially as mixed carcinomas. Only 2 of the 7 (28%) mixed carcinomas showed different immunophenotypes in different components. All but 2 tumors (5/7, 71%) overexpressed p53 and p16 and were negative for ER. Both carcinomas (2/7, 28%) showed a prominent micropapillary component that resembled an ovarian low-grade serous carcinoma and merged with villoglandular endometrioid carcinoma. The ambiguous carcinomas exhibited glandular architecture, high nuclear grade, and overlapping features of endometrioid and serous carcinomas. All tumors overexpressed p53 and p16, and the majority of cases (12/13, 92%) were negative for ER. KRAS mutations were identified in 3 of 7 (42%) mixed carcinomas, including the 2 cases with a "low grade" serous-like component. PIK3CA mutations occurred in 2 (2/13, 15%) ambiguous carcinomas and PTEN mutations in 1 (1/7, 14%) mixed and 1 (1/13, 8%) ambiguous carcinoma. POLE exonuclease domain mutations were encountered in a case of mixed undifferentiated and well-differentiated (dedifferentiated) carcinoma. Two of the 7 (29%) mixed endometrial carcinomas and 5 of the 13 (38%) ambiguous carcinomas had extended beyond the pelvis (stages III and IV). Two of the 7 (29%) patients with mixed endometrial carcinoma and 6 of 12 (50%) patients with ambiguous endometrial carcinoma were alive with disease or had died of tumor. Our results show that, biologically, many so-called mixed carcinomas represent serous carcinomas with ambiguous morphology. Our series include 2 true mixed endometrial carcinomas with a "low-grade serous"-like component, microcystic, elongated, or fragmented features, KRAS mutations, and aggressive behavior. PMID- 26975041 TI - Diagnostic Challenges Caused by Endoscopic Biopsy of Colonic Polyps: A Systematic Evaluation of Epithelial Misplacement With Review of Problematic Polyps From the Bowel Cancer Screening Program, United Kingdom. AB - Endoscopic mucosal biopsy may misplace mucosal elements into the submucosa of colonic adenomas, mimicking invasive adenocarcinoma. Biopsy-related misplacement can be more challenging to recognize than typical misplaced epithelium (pseudoinvasion) in pedunculated polyps. We compared the features of 16 polyps with biopsy-related misplaced epithelium with those of 10 adenomas with pseudoinvasion and 10 adenomas with invasive adenocarcinoma and performed Ki67 and p53 immunostaining on all cases. Features of misplaced epithelium in polyps referred to the Bowel Cancer Screening Program Expert Board in the United Kingdom were also evaluated for the same morphologic features. Biopsy-related epithelial misplacement occurred in adenomas throughout the colon and often appeared infiltrative (69%), including epithelial cells singly dispersed within reactive fibroinflammatory stroma or granulation tissue (44%). Misplaced epithelium displayed only low-grade cytologic features and was associated with extruded mucin (75%), tattoo pigment (63%), and misplaced normal glands (38%); scant lamina propria and muscularis mucosae were often present (88% and 44%, respectively). Cases referred to the Bowel Cancer Screening Program Expert Board also contained infiltrative-appearing misplaced epithelium (91%) that was cytologically low grade (72%), contained nondysplastic glands (11%), and showed other signs of injury. In contrast, misplaced epithelium in pedunculated polyps always had a lobular contour with a rim of lamina propria, hemorrhage, and/or hemosiderin. Invasive carcinomas showed malignant cytology and desmoplasia; most (70%) lacked features of trauma. Ki67 and p53 staining was patchy and weak in the misplaced epithelium, whereas invasive carcinomas showed increased staining for one or both markers. Pathologists should be aware that endoscopically manipulated adenomas may contain misplaced epithelium that simulates malignancy. PMID- 26975042 TI - About BRAF Mutations and p16 Expression in Melanomas Associated With Blue Nevi or Mimicking Cellular Blue Nevi: Author's Reply. PMID- 26975043 TI - Transcriptomic changes underlie altered egg protein production and reduced fecundity in an estuarine model fish exposed to bifenthrin. AB - Pyrethroid pesticides are a class of insecticides found to have endocrine disrupting properties in vertebrates such as fishes and in human cell lines. Endocrine disrupting chemicals (EDCs) are environmental contaminants that mimic or alter the process of hormone signaling. In particular, EDCs that alter estrogen and androgen signaling pathways are of major concern for fishes because these EDCs may alter reproductive physiology, behavior, and ultimately sex ratio. Bifenthrin, a pyrethroid with escalating usage, is confirmed to disrupt estrogen signaling in several species of fish, including Menidia beryllina (inland silverside), an Atherinid recently established as a euryhaline model. Our main objective was to broadly assess the molecular and physiological responses of M. beryllina to the ng/L concentrations of bifenthrin typically found in the environment, with a focus on endocrine-related effects, and to discern links between different tiers of the biological hierarchy. As such, we evaluated the response of juvenile Menidia to bifenthrin using a Menidia-specific microarray, quantitative real-time polymerase chain reaction (qPCR) on specific endocrine related genes of interest, and a Menidia-specific ELISA to the egg-coat protein choriogenin, to evaluate a multitude of molecular-level responses that would inform mechanisms of toxicity and any underlying causes of change at higher biological levels of organization. The sublethal nominal concentrations tested (0.5, 5 and 50ng/L) were chosen to represent the range of concentrations observed in the environment and to provide coverage of a variety of potential responses. We then employed a 21-day reproductive assay to evaluate reproductive responses to bifenthrin (at 0.5ng/L) in a separate group of adult M. beryllina. The microarray analysis indicated that bifenthrin influences a diverse suite of molecular pathways, from baseline metabolic processes to carcinogenesis. A more targeted examination of gene expression via qPCR demonstrated that bifenthrin downregulates a number of estrogen-related transcripts, particularly at the lowest exposure level. Choriogenin protein also decreased with exposure to increasing concentrations of bifenthrin, and adult M. beryllina exposed to 0.5ng/L had significantly reduced reproductive output (fertilized eggs per female). This reduction in fecundity is consistent with observed changes in endocrine-related gene expression and choriogenin production. Taken together, our results demonstrate that environmental concentrations of bifenthrin have potential to interfere with metabolic processes, endocrine signaling, and to decrease reproductive output. PMID- 26975044 TI - Adult-onset refractory epilepsy with hypothalamic hamartoma and no gelastic seizures successfully treated by stereotactic thermocoagulation: A case report. PMID- 26975046 TI - Impact of Dissolved Oxygen during UV-Irradiation on the Chemical Composition and Function of CHO Cell Culture Media. AB - Ultraviolet (UV) irradiation is advantageous as a sterilization technique in the biopharmaceutical industry since it is capable of targeting non-enveloped viruses that are typically challenging to destroy, as well as smaller viruses that can be difficult to remove via conventional separation techniques. In this work, we investigated the influence of oxygen in the media during UV irradiation and characterized the effect on chemical composition using NMR and LC-MS, as well as the ability of the irradiated media to support cell culture. Chemically defined Chinese hamster ovary cell growth media was irradiated at high fluences in a continuous-flow UV reactor. UV-irradiation caused the depletion of pyridoxamine, pyridoxine, pyruvate, riboflavin, tryptophan, and tyrosine; and accumulation of acetate, formate, kynurenine, lumichrome, and sarcosine. Pyridoxamine was the only compound to undergo complete degradation within the fluences considered; complete depletion of pyridoxamine was observed at 200 mJ/cm2. Although in both oxygen- and nitrogen-saturated media, the cell culture performance was affected at fluences above 200 mJ/cm2, there was less of an impact on cell culture performance in the nitrogen-saturated media. Based on these results, minimization of oxygen in cell culture media prior to UV treatment is recommended to minimize the negative impact on sensitive media. PMID- 26975045 TI - PSGL-1 on Leukocytes is a Critical Component of the Host Immune Response against Invasive Pneumococcal Disease. AB - Bacterial uptake by phagocytic cells is a vital event in the clearance of invading pathogens such as Streptococcus pneumoniae. A major role of the P selectin glycoprotein ligand-1 (PSGL-1) on leukocytes against invasive pneumococcal disease is described in this study. Phagocytosis experiments using different serotypes demonstrated that PSGL-1 is involved in the recognition, uptake and killing of S. pneumoniae. Co-localization of several clinical isolates of S. pneumoniae with PSGL-1 was demonstrated, observing a rapid and active phagocytosis in the presence of PSGL-1. Furthermore, the pneumococcal capsular polysaccharide and the main autolysin of the bacterium--the amidase LytA--were identified as bacterial ligands for PSGL-1. Experimental models of pneumococcal disease including invasive pneumonia and systemic infection showed that bacterial levels were markedly increased in the blood of PSGL-1-/- mice. During pneumonia, PSGL-1 controls the severity of pneumococcal dissemination from the lung to the bloodstream. In systemic infection, a major role of PSGL-1 in host defense is to clear the bacteria in the systemic circulation controlling bacterial replication. These results confirmed the importance of this receptor in the recognition and clearance of S. pneumoniae during invasive pneumococcal disease. Histological and cellular analysis demonstrated that PSGL-1-/- mice have increased levels of T cells migrating to the lung than the corresponding wild-type mice. In contrast, during systemic infection, PSGL-1-/- mice had increased numbers of neutrophils and macrophages in blood, but were less effective controlling the infection process due to the lack of this functional receptor. Overall, this study demonstrates that PSGL-1 is a novel receptor for S. pneumoniae that contributes to protection against invasive pneumococcal disease. PMID- 26975049 TI - Correction: A Novel High Content Imaging-Based Screen Identifies the Anti Helminthic Niclosamide as an Inhibitor of Lysosome Anterograde Trafficking and Prostate Cancer Cell Invasion. PMID- 26975048 TI - Gestational Age at Birth and 'Body-Mind' Health at 5 Years of Age: A Population Based Cohort Study. AB - Numerous studies have identified the effects of prematurity on the neonate's physical health, however few studies have explored the effects of prematurity on both the physical and mental health of the child as they develop. Secondary analysis of data from the Millennium Cohort Study, a longitudinal study of infants (n = 18 818, born 2000-2002 in the United Kingdom) was performed. Effects of gestational age at birth on health outcomes at 5 years were measured using parental rating of their children's general health and severity of behavior problems. The association between parent's general health ratings and behavior problem ratings was low: 86% of those reporting serious behavior problems (5% of the sample, n = 764) rated their child as being in excellent, very good, or good health. Still, a gradient of increasing risk of poorer outcome with decreasing gestational age was observed for a composite health measure (poor/fair health and/or serious behavior problems), suggesting an association with prematurity for this composite assessment of health status. The greatest contribution to the childhood composite health measure at 5 years was for children born at 32-36 weeks gestation: population attributable fractions for having poor outcomes was 3.4% (Bonferroni-adjusted 95% confidence interval 1.1%-6.2%), compared to 1% (0.2 2.3) for birth at less than 32 weeks. Results suggest that preterm children, by school entry, are not only at high risk of physical health problems, but also of behavioral health problems. The recognition of, and response to comprehensive health and well-being outcomes related to prematurity are important in order to correctly plan and deliver adequate paediatric health services and policies. PMID- 26975047 TI - Exploring the Conserved Role of MANF in the Unfolded Protein Response in Drosophila melanogaster. AB - Disturbances in the homeostasis of endoplasmic reticulum (ER) referred to as ER stress is involved in a variety of human diseases. ER stress activates unfolded protein response (UPR), a cellular mechanism the purpose of which is to restore ER homeostasis. Previous studies show that Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) is an important novel component in the regulation of UPR. In vertebrates, MANF is upregulated by ER stress and protects cells against ER stress-induced cell death. Biochemical studies have revealed an interaction between mammalian MANF and GRP78, the major ER chaperone promoting protein folding. In this study we discovered that the upregulation of MANF expression in response to drug-induced ER stress is conserved between Drosophila and mammals. Additionally, by using a genetic in vivo approach we found genetic interactions between Drosophila Manf and genes encoding for Drosophila homologues of GRP78, PERK and XBP1, the key components of UPR. Our data suggest a role for Manf in the regulation of Drosophila UPR. PMID- 26975050 TI - Investigation of Proposed Ladderane Biosynthetic Genes from Anammox Bacteria by Heterologous Expression in E. coli. AB - Ladderanes are hydrocarbon chains with three or five linearly concatenated cyclobutane rings that are uniquely produced as membrane lipid components by anammox (anaerobic ammonia-oxidizing) bacteria. By virtue of their angle and torsional strain, ladderanes are unusually energetic compounds, and if produced biochemically by engineered microbes, could serve as renewable, high-energy density jet fuel components. The biochemistry and genetics underlying the ladderane biosynthetic pathway are unknown, however, previous studies have identified a pool of 34 candidate genes from the anammox bacterium, Kuenenia stuttgartiensis, some or all of which may be involved with ladderane fatty acid biosynthesis. The goal of the present study was to establish a systematic means of testing the candidate genes from K. stuttgartiensis for involvement in ladderane biosynthesis through heterologous expression in E. coli under anaerobic conditions. This study describes an efficient means of assembly of synthesized, codon-optimized candidate ladderane biosynthesis genes in synthetic operons that allows for changes to regulatory element sequences, as well as modular assembly of multiple operons for simultaneous heterologous expression in E. coli (or potentially other microbial hosts). We also describe in vivo functional tests of putative anammox homologs of the phytoene desaturase CrtI, which plays an important role in the hypothesized ladderane pathway, and a method for soluble purification of one of these enzymes. This study is, to our knowledge, the first experimental effort focusing on the role of specific anammox genes in the production of ladderanes, and lays the foundation for future efforts toward determination of the ladderane biosynthetic pathway. Our substantial, but far from comprehensive, efforts at elucidating the ladderane biosynthetic pathway were not successful. We invite the scientific community to take advantage of the considerable synthetic biology resources and experimental results developed in this study to elucidate the biosynthetic pathway that produces unique and intriguing ladderane lipids. PMID- 26975051 TI - Time Efficient 3D Radial UTE Sampling with Fully Automatic Delay Compensation on a Clinical 3T MR Scanner. AB - This work's aim was to minimize the acquisition time of a radial 3D ultra-short echo-time (UTE) sequence and to provide fully automated, gradient delay compensated, and therefore artifact free, reconstruction. The radial 3D UTE sequence (echo time 60 MUs) was implemented as single echo acquisition with center-out readouts and improved time efficient spoiling on a clinical 3T scanner without hardware modifications. To assess the sequence parameter dependent gradient delays each acquisition contained a quick calibration scan and utilized the phase of the readouts to detect the actual k-space center. This calibration scan does not require any user interaction. To evaluate the robustness of this automatic delay estimation phantom experiments were performed and 19 in vivo imaging data of the head, tibial cortical bone, feet and lung were acquired from 6 volunteers. As clinical application of this fast 3D UTE acquisition single breath-hold lung imaging is demonstrated. The proposed sequence allowed very short repetition times (TR~1ms), thus reducing total acquisition time. The proposed, fully automated k-phase based gradient delay calibration resulted in accurate delay estimations (difference to manually determined optimal delay -0.13 +/- 0.45 MUs) and allowed unsupervised reconstruction of high quality images for both phantom and in vivo data. The employed fast spoiling scheme efficiently suppressed artifacts caused by incorrectly refocused echoes. The sequence proved to be quite insensitive to motion, flow and susceptibility artifacts and provides oversampling protection against aliasing foldovers in all directions. Due to the short TR, acquisition times are attractive for a wide range of clinical applications. For short T2* mapping this sequence provides free choice of the second TE, usually within less scan time as a comparable dual echo UTE sequence. PMID- 26975052 TI - Investigating Pollen and Gene Flow of WYMV-Resistant Transgenic Wheat N12-1 Using a Dwarf Male-Sterile Line as the Pollen Receptor. AB - Pollen-mediated gene flow (PMGF) is the main mode of transgene flow in flowering plants. The study of pollen and gene flow of transgenic wheat can help to establish the corresponding strategy for preventing transgene escape and contamination between compatible genotypes in wheat. To investigate the pollen dispersal and gene flow frequency in various directions and distances around the pollen source and detect the association between frequency of transgene flow and pollen density from transgenic wheat, a concentric circle design was adopted to conduct a field experiment using transgenic wheat with resistance to wheat yellow mosaic virus (WYMV) as the pollen donor and dwarf male-sterile wheat as the pollen receptor. The results showed that the pollen and gene flow of transgenic wheat varied significantly among the different compass sectors. A higher pollen density and gene flow frequency was observed in the downwind SW and W sectors, with average frequencies of transgene flow of 26.37 and 23.69% respectively. The pollen and gene flow of transgenic wheat declined dramatically with increasing distance from its source. Most of the pollen grains concentrated within 5 m and only a few pollen grains were detected beyond 30 m. The percentage of transgene flow was the highest where adjacent to the pollen source, with an average of 48.24% for all eight compass directions at 0 m distance. Transgene flow was reduced to 50% and 95% between 1.61 to 3.15 m, and 10.71 to 20.93 m, respectively. Our results suggest that climate conditions, especially wind direction, may significantly affect pollen dispersal and gene flow of wheat. The isolation-by-distance model is one of the most effective methods for achieving stringent transgene confinement in wheat. The frequency of transgene flow is directly correlated with the relative density of GM pollen grains in air currents, and pollen competition may be a major factor influencing transgene flow. PMID- 26975053 TI - Role of Breastfeeding and Complementary Food on Hemoglobin and Ferritin Levels in a Cambodian Cross-Sectional Sample of Children Aged 3 to 24 Months. AB - BACKGROUND: Iron deficiency derives from a low intake of dietary iron, poor absorption of iron, and high requirements due to growth as well as blood loss. An estimated number of about 50% of all anemia may be attributed to iron deficiency among young children in Cambodia. METHODS: A cross-sectional survey was conducted in rural Cambodia in September 2012. Villages in pre-selected communes were randomly chosen using stunting as a primary indicator of nutritional status. In total, 928 randomly selected households with children aged 3-23 months were included. Hemoglobin, ferritin, soluble transferrin receptor (sTfR), and retinol binding protein (RBP) were assessed from capillary blood samples. In addition, length/height and weight of mothers and children were taken and data on dietary diversity was collected. A child feeding index (CFI) was created. Associations between biomarkers of iron and vitamin A status and nutritional status or food intake were explored. RESULTS: Anemia prevalence was highest among 6- to 12 months-olds (71%). Ferritin and sTfR inversely correlated and were significantly associated with hemoglobin concentrations. The consumption of animal source foods (ASF) significantly impacts on the interaction between ferritin, sTfR and hemoglobin. Concentrations of RBP were significantly higher in children who had received a vitamin A supplement. The CFI was associated with sTfR and hemoglobin. Lower length and weight were associated with lower ferritin levels and showed an indirect effect on hemoglobin through ferritin. CONCLUSION: Nutrition programs targeting children under 2 years of age need to focus on the preparation of complementary foods with high nutrient density to sustainably prevent micronutrient deficiency and generally improve nutritional status. Future assessments of the micronutrient status should include identification of hemoglobinopathies and parasitic infections to better understand all causes of anemia in Cambodian infants and young children. TRIAL REGISTRATION: German Clinical Trials Register DRKS00004379. PMID- 26975054 TI - Economic Burden of Hypoglycemia in Patients with Type 2 Diabetes Mellitus from Korea. AB - BACKGROUND: Hypoglycemia is a very serious complication in patients with type 2 diabetes mellitus (T2DM) and affects the economic burden of treatment. This study aims to create models of the cost of treating hypoglycemia in patients with T2DM based upon physician estimates of medical resource usage. METHODS: Using a literature review and personal advice from endocrinologists and emergency physicians, we developed several models for managing patients with hypoglycemia. The final model was approved by the consulting experts. We also developed 3 unique surveys to allow endocrinologists, emergency room (ER) physicians, and primary care physicians to evaluate the resource usage of patients with hypoglycemia. Medical costs were calculated by multiplying the estimated medical resource usage by the corresponding health insurance medical care costs reported in 2014. RESULTS: In total, 40 endocrinologists, 20 ER physicians, and 30 primary care physicians completed the survey. We identified 12 types of standard medical models for secondary or tertiary hospitals and 4 for primary care clinics based on the use of ER, general ward, or intensive care unit (ICU) and patients' status of consciousness and self-respiration. Estimated medical costs per person per hypoglycemic event ranged from $17.28 to $1,857.09 for secondary and tertiary hospitals. These costs were higher for patients who were unconscious and for those requiring ICU admission. CONCLUSION: Hypoglycemia has a substantial impact on the medical costs and its prevention will result in economic benefits for T2DM patients and society. PMID- 26975055 TI - Understory Plant Community Composition Is Associated with Fine-Scale Above- and Below-Ground Resource Heterogeneity in Mature Lodgepole Pine (Pinus contorta) Forests. AB - Understory plant communities play critical ecological roles in forest ecosystems. Both above- and below-ground ecosystem properties and processes influence these communities but relatively little is known about such effects at fine (i.e., one to several meters within-stand) scales, particularly for forests in which the canopy is dominated by a single species. An improved understanding of these effects is critical for understanding how understory biodiversity is regulated in such forests and for anticipating impacts of changing disturbance regimes. Our primary objective was to examine the patterns of fine-scale variation in understory plant communities and their relationships to above- and below-ground resource and environmental heterogeneity within mature lodgepole pine forests. We assessed composition and diversity of understory vegetation in relation to heterogeneity of both the above-ground (canopy tree density, canopy and tall shrub basal area and cover, downed wood biomass, litter cover) and below-ground (soil nutrient availability, decomposition, forest floor thickness, pH, and phospholipid fatty acids (PLFAs) and multiple carbon-source substrate-induced respiration (MSIR) of the forest floor microbial community) environment. There was notable variation in fine-scale plant community composition; cluster and indicator species analyses of the 24 most commonly occurring understory species distinguished four assemblages, one for which a pioneer forb species had the highest cover levels, and three others that were characterized by different bryophyte species having the highest cover. Constrained ordination (distance based redundancy analysis) showed that two above-ground (mean tree diameter, litter cover) and eight below-ground (forest floor pH, plant available boron, microbial community composition and function as indicated by MSIR and PLFAs) properties were associated with variation in understory plant community composition. These results provide novel insights into the important ecological associations between understory plant community composition and heterogeneity in ecosystem properties and processes within forests dominated by a single canopy species. PMID- 26975056 TI - Detailed Report on 2014/15 Influenza Virus Characteristics, and Estimates on Influenza Virus Vaccine Effectiveness from Austria's Sentinel Physician Surveillance Network. AB - BACKGROUND: Influenza vaccine effectiveness (VE) is influenced by the antigenic similarity between vaccine- and circulating strains. MATERIAL AND METHODS: This paper presents data obtained by the Austrian sentinel surveillance system on the evolution of influenza viruses during the season 2014/15 and its impact on influenza vaccine effectiveness in primary care in Austria as estimated by a test negative case control design. VE estimates were performed for each influenza virus type/subtype, stratified by underlying diseases and adjusted for age, sex and calendar week of infection. RESULTS: Detailed genetic and antigenic analyses showed that circulating A(H3N2) viruses were genetically distinct from the 2014/15 A(H3N2) vaccine component indicating a profound vaccine mismatch. The Influenza A(H1N1)pdm09 viruses were antigenically conserved and matched the respective vaccine component. Influenza B viruses were lineage-matched B/Yamagata viruses with a clade-level variation. Consistent with substantial vaccine mismatch for the A(H3N2) viruses a crude overall VE of only 47% was estimated, whereas the VE estimates for A(H1N1)pdm09 were 84% and for influenza B viruses 70%. Increased VE estimates were obtained after stratification by underlying diseases and adjustment for the covariates sex and age, whereby the adjustment for the calendar week of infection was the covariate exerting the highest influence on adjusted VE estimates. CONCLUSION: In summary, VE data obtained in this study underscore the importance to perform VE estimates in the context of detailed characterization of the contributing viruses and also demonstrate that the calendar week of influenza virus infection is the most important confounder of VE estimates. PMID- 26975057 TI - Validation of Hospital Performance Measures of Acute Stroke Care Quality. Riksstroke, the Swedish Stroke Register. AB - BACKGROUND: Registers are increasingly used to monitor stroke care performance. Fair benchmarking requires sufficient data quality. We have validated acute care data in Riksstroke, the Swedish Stroke Register. METHODS: Completeness was assessed by comparisons with diagnoses at hospital discharge recorded in the compulsory National Patient Register and content validity by comparisons with (a) key variables identified by European stroke experts, and (b) items recorded in other European stroke care performance registers. Five test cases recorded by 67 hospitals were used to estimate inter-hospital reliability. RESULTS: All 72 Swedish hospitals admitting acute stroke patients participated in Riksstroke. The register was estimated to cover at least 90% of acute stroke patients. It includes 18 of 22 quality indicators identified by international stroke experts and 14 of 15 indicators used by at least 2 stroke performance registers in other European countries. Inter-hospital reliability was high (>=85%) in 77 of 81 Riksstroke items. CONCLUSIONS: A nationwide stroke care register can be maintained with sufficient data quality to permit between-hospital performance benchmarking. Our experiences may serve as a model for other stroke registers while evaluating data quality. PMID- 26975058 TI - Stigma, health and incarceration: Turning the tide for children with a parent in prison. PMID- 26975059 TI - Virulence determinants, antimicrobial susceptibility, and molecular profiles of Erysipelothrix rhusiopathiae strains isolated from China. AB - The aim of this study was to understand the epidemiology, serotype, antibiotic sensitivity, and clonal structure of Erysipelothrix rhusiopathiae strains in China. Forty-eight strains were collected from seven provinces during the period from 2012 to 2013. Pulse-field electrophoresis identified 32 different patterns which were classified into clonal groups A-D. Most pulsed-field gel electrophoresis (PFGE) patterns were observed in clonal complex A and B, suggesting high diversity of genetic characterization in these two predominant clonal complexes. Antibiotic sensitivity test shows that all the stains were susceptible to ampicillin, erythromycin, and cefotaxime, and resistant to kanamycin, cefazolin, sulfadiazine, and amikacin. Erythromycin and ampicillin are recommended as first-line antibiotics for treatment of E. rhusiopathiae in China. The high variation in PFGE pattern among the main clonal groups shows that the E. rhusiopathiae in China may originate from different lineages and sources instead of from expansion of a single clonal lineage across different regions. PMID- 26975061 TI - [CROATIAN GUIDELINES FOR DIAGNOSIS AND MANAGEMENT OF BENIGN PAROXYSMAL POSITIONAL VERTIGO (BPPV)]. AB - BPPV is generally the most common cause of vertigo, caused by a pinch-off of tiny calcium carbonate crystals (called the otoconia or the otoliths) from the macula utriculi, most frequently due to the degenerative processes or a trauma, whereby the crystals, under the action of gravity in certain head positions coinciding with its direction, arrive to some of the semicircular canals, usually the posterior one, due to the existent anatomical circumstances and relationships, thus creating an inadequate stimulus of the cupular senses while floating through the endolymph and provoking symptoms of a strong and short-term dizziness. Two main clinical forms can be distinguished: canalolythiasis, with an accommodation of otolithic debris in the semicircular canal, and cupulolythiasis, with their location immediately next to the cupular sense. The diagnosis is established by a positive positioning test, Dix-Hallpike for the posterior and the supine roll for the lateral canal. Although one can expect a spontaneous recovery subsequent to few weeks or months, various methods of otolith repositioning to a less sensitive place lead to a prompt improvement while reducing or withdrawing the symptoms completely. These guidelines are intended for all who treat the BPPV in their work, with an intention to assist in the diagnosis and application of an appropriate therapeutic method. PMID- 26975060 TI - A novel norovirus GII.17 lineage contributed to adult gastroenteritis in Shanghai, China, during the winter of 2014-2015. AB - Norovirus (NoV) is now recognized as a leading cause of nonbacterial acute gastroenteritis; however, the NoV GII.17 genotype has rarely been reported as the predominant genotype in clinical diarrhea cases. During the winter of 2014-2015, the GII.17 genotype, together with the NoV GII.4 genotype, dominated in sporadic adult patients with gastroenteritis in Shanghai. Phylogenetic analysis based on full-length VP1 amino acid sequences showed that the GII.17 strains that emerged in Shanghai have close evolutionary relationships with strains recently collected in the Hong Kong area, Guangdong province of China, and Japan during the same period. This cluster in the phylogenetic tree may represent a novel NoV GII.17 lineage recently circulating in East Asia. Pairwise distances between clusters also revealed the evolution of the NoV GII.17 genotype in previous decades. Our study emphasizes the importance of combined surveillance of NoV-associated infections. PMID- 26975062 TI - [CLINICAL GUIDELINES FOR DIAGNOSING, TREATING AND MONITORING OF ADULT PATIENTS WITH GLIOMAS OF CENTRAL NERVOUS SYSTEM]. AB - Gliomas of the central nervous system are glial cell tumors that are divided in low and high grade group. Multidisciplinary approach to treatment consists of surgery, radiotherapy and chemotherapy. The type and order of treatment depend on the characteristics of the tumor and the patient. We present the clinical guidelines for diagnostic procedures, surgical treatment, oncological treatment and follow up of patients with this type of tumor in the Republic of Croatia. PMID- 26975063 TI - [CROATIAN POPULATION AND CLINICAL EPIDEMIOLOGICAL STUDIES OF CONGENITAL HEART DISEASE (1995-2011): THE USE OF ABC SCORE AND RACHS-1 CARDIOSURGICAL MODEL FOR THE ASSESSMENT OF QUALITY OF TREATMENT OF CONGENITAL HEART DISEASE]. AB - AIM: 1. To present an epidemiological (population and clinical) study of congenital heart defects (CHD) in Croatia in a 16-year period (1995-2011). 2. To analyze outcomes of surgical procedures for all patients in a five-year period (2002-2007) and to compare the results between Croatian and foreign centers. 3. To present the progress in surgical care of CHD in Croatia while acknowledging the requirement of achieving postsurgical mortality rate of below 5%. 4. To evaluate the projection of positive development of CHD management in Croatia in cooperation with major cardiac surgical centers in the neighboring countries. METHODS: Population study includes all children born from 1995 to 2000 and from 2002 to 2007 included in a database modeled by EUROCAT and BWIS. Outcome analysis was made using two models (ABC and RACHS-1) with early mortality rating and prolonged length of stay. Results: Based on two separate studies, mean value of CHD prevalence in Croatia is 7.6 per thousand. Outcome analysis according to the two mentioned evaluation models for the 2002-2007 period shows that children operated on in Croatia had a lower level of complexity compared to the complexity of those sent to foreign centers, but early mortality was below the assigned margin of 5% and there were also no differences in prolonged length of stay. As much as 63% of surgeries in the period were performed abroad, while the remaining 37% were performed in Croatia (351:202). In the following four-year period (2008 2011) there was a significant increase in the number of surgeries performed in Croatia when compared to those performed abroad (59:4% or 380:264). Independent EACTS analysis points to a positive trend of gradual increase in the number of surgeries and acceptance of higher complexity level of surgeries performed in Croatia, while maintaining the assigned margin (early mortality below 5%). Contribution: Proper selection of patients according to the complexity of cardiac surgical procedure is a prerequisite for both low mortality and fewer postsurgical complications. Professional advance relying on close cooperation with foreign centers is much faster and more acceptable than by "learning curves". CONCLUSION: Pediatric cardiac surgery in the developing countries must rely on the experiences of developed cardiac surgical centers in the neighboring countries due to complexity of congenital heart defects. Pediatric cardiology is inherently a public health problem, but the problem exacerbates with the appearance of a large number of adults with congenital heart defects (GUCH patients). PMID- 26975064 TI - [INCIDENCE AND SURGICAL IMPORTANCE OF PYRAMIDAL LOBE AND TUBERCLE OF THE THYROID GLAND: A PROSPECTIVE STUDY]. AB - The pyramidal lobe and tubercles are common anatomic variations of the thyroid gland, and their frequency is highly represented. While pyramidal lobe requires additional seriousness in identifying and its removal, especially in patients with hyperthyroidism and thyroid cancer, the presence of tubercles is desirable. Tubercle is covered by recurrent laryngeal nerve and directs the surgeon in his search and besides this, serves to facilitate detection of the upper parathyroid glands. In this prospective study we analysed 342 patients who underwent total thyroidectomy in the period from January 2009 to March 2015. We looked at the incidence and anatomic characteristics of pyramidal lobe and tubercles of the thyroid gland. The pyramidal lobe was present in 52.3% of the patients with more frequent central and left placement. Bilateral tubercles were present in 14.9%, while position right-sided phenomenon was represented in 39.5% and 18.5% in lower left (64.3% patients). Their prevalence by gender showed no significant difference (p = 0.59; p = 0.2). Associated presence of pyramidal lobe and tubercles on one or both sides is highly represented in our group of patients (34%), also with no differences by gender (p = 0.29). Length of the pyramidal lobe ranged from 1.3 to 4.7 cm (average 2.3 cm), and the size of tubercles in 36% of patients was over 1 cm. Recurrent laryngeal nerve was only in 1.8% placed laterally of tubercles, and the upper parathyroid gland in 95.4% was located above tubercle. Considering that only 16.5% of our patients did not have any of these anatomical variations, their presence during surgery is the rule, not the exception. PMID- 26975065 TI - [LAPAROSCOPIC PARTIAL PERICYSTECTOMY OF SPLENIC HYDATID CYST - A CASE REPORT]. AB - Echinococcal cyst of the spleen is usually a result of infection with the parasite Echinococcus granulosus. The spleen is the third most frequent localization of echinococcus after liver and lungs. Partial laparoscopic pericystectomy can be done without the loss of blood and scattering of scolexes with spleen preservation and conservation of its immune function. We present the patient with a large (1 8 x 16 x 12 cm) echinococcal cyst of the spleen that compressed the surrounding organs (stomach, transverse colon, pancreas and left kidney), and prevented normal passage causing vomiting after every meal. In this patient, PAIR procedure (puncture, aspiration, injection, reaspiration) and conservative treatment was attempted on several occasions without success. Finally, laparoscopic partial pericystectomy was performed, evacuating the contents of the cyst. The surgery lasted 120 minutes. Postoperatively the patient was without complications. Hospitalization lasted five days. Six months later, the patient is without problems. These echinococcus cysts of the spleen cannot be solved using PAIR technique and conservative treatment. Laparoscopic partial pericystectomy is a better solution than open surgery due to less trauma to the patient, especially in elderly people. PMID- 26975066 TI - [ULTRASOUND GUIDED PERCUTANEOUS SCLEROTHERAPY OF SIMPLE RENAL CYSTS: PRIMARY SUCCESS AND PROCEDURE SAFETY]. AB - OBJECTIVE: To evaluate primary (technical) success and procedure safety in ultrasound (US)-guided percutaneous sclerotherapy of simple renal cysts, using 96% ethanol. PATIENTS: 17 patients with symptomatic simple renal cysts referred by nephrologists or urologists. METHODS: US-guided percutaneous puncture of the cyst with an 18G (gauge) needle and a "pigtail" 5F (French) catheter, drainage and inspection of the cyst content, and injection of ethanol. RESULTS: Puncture was rejected in two referred patients because of Bosniak II cyst and renal hilum proximity. 15 patients underwent puncture and drainage of the cyst content. In 4 patients ethanol was not injected because: thick or bloody cyst, proximity of renal hilum and severe pain during injection of ethanol. 11 patients underwent sclerotherapy of the cyst. The average size of sclerosed cyst was 8 cm (range 6 12 cm). There were no significant complications. CONCLUSION: US-guided percutaneous sclerotherapy of simple renal cysts is easy to perform and safe procedure, with the previous good selection of cysts that are suitable for the sclerotherapy. PMID- 26975067 TI - [INFANTILE COLIC - NEWER APPROACH TO AN OLD PROBLEM]. AB - Infantile colic have been known for the long time and are one of the most common reasons for pediatrician's appointment in early infancy. However, their etiology and pathogenesis are yet to be determined. Diagnosis is based on thorough medical history and physical examination. Special attention should be given to red flags or warning signs which could indicate a presence of serious illness. If no other abnormality is present, except inconsolable crying, there is no need for further diagnostic procedures. There is an extensive range of proposed therapeutic measures; however scientific evidence for all of them is scarce. Therefore, the aim of this review article is to present currently available evidence for the management of infantile colic and to provide a possible therapeutic algorithm. PMID- 26975068 TI - [PHYSICAL PROPERTIES OF PLASTER BANDAGES]. AB - The physical properties of plaster bandages are a very important factor in achieving the basic functions of immobilization (maintaining bone fragments in the best possible position), which directly affects the speed and quality of fracture healing. This paper compares the differences between the physical properties of plaster bandages (mass, specific weight, drying rate, elasticity and strength) and records the differences in plaster modeling of fast bonding 10 cm wide plaster bandages, from three different manufacturers: Safix plus (Hartmann, Germany), Cellona (Lohman Rauscher, Austria) and Gipsan (Ivo Lola Ribar ltd., Croatia). Plaster tiles from ten layers of plaster, dimension 10 x 10 cm were made. The total number of tiles from each manufacturer was 48. The water temperature of 22 degrees C was used for the first 24 tiles and 34 'C was used for the remainder. The average specific weight of the original packaging was: Cellona (0.52 g/cm3), Gipsan (0.50 g/cm3), Safix plus (0.38 g/cm3). Three days after plaster tile modeling an average specific weight of the tiles was: Gipsan (1.15 g/cm3), Safix plus (1.00 g/cm3), Cellona (1.10 g/cm3). The average humidity of 50% for Safix plus and Cellona plaster tiles was recorded 18 hours after modeling, while for the Gipsan plaster tiles, this humidity value was seen after 48 hours. On the third day after plaster modeling the average humidity of the plaster tiles was 30% for Gipsan, 24% for Safix and 16% for Cellona. Cellona plaster tiles made with 34 degrees C water achieved the highest elasticity (11.75+/-3.18 MPa), and Gipsan plaster tiles made with 22 degrees C had the lowest (7.21+/-0.9 MPa). Cellona plaster tiles made with 34 degrees C water showed maximum material strength (4390+/-838 MPa), and Gipsan plaster tiles made with 22 degrees C water showed the lowest material strength (771+/-367 MPa). The rigidity and strength of Cellona and Gipsan plaster are higher in tiles made in warmer water, and for Safix plus are higher in tiles made in cooler water. All three types of plaster differentiate in physical properties. The differences in mass and specific weight before and after plaster modeling are minimal. There are greater differences in drying rate, elasticity and strength between the three different plaster materials. PMID- 26975069 TI - [FOUNDATION OF THE MUSEUM FOR THE HISTORY OF HEALTH IN 1944 AND ROLE OF ITS FIRST CURATOR STANKO SIELSKI]. AB - The Museum of the History of Health Care in Croatia, as the first such museum in the southeastern part of Europe, was established by the Croatian Medical Association in Zagreb in 1944. Beside Vladimir Cepulic (1891 - 1964) the head of the Croatian Medical Association, epidemiologist Stanko Sielski (1891 - 1958), was one of the most prominent personalities to be credited for realizing this project. He was born in Gracanica into a family of Polish origin. After his graduation in Vienna in 1919, he worked as an epidemiologist in Konjic, Prozor, Glamoc and other places in the area of Bosnia, mostly involved in typhoid fever and variola eradication. At the beginning of the Second World War he was in Banja Luka where he was given the duty of director of the Department of Endemic Syphilis Eradication. During 1942 and 1943 his correspondence took place with Vladimir Cepulic, which is today preserved in the Section of the History of Medicine of the Croatian Academy of Sciences and Arts in Zagreb. On the basis of this material it was possible to trace the circumstances of the foundation of the Museum of the History of Health Care, how items were collected for its first exhibition, and the role of Stanko Sielski in preserving the medical heritage and dissemination of knowledge of the history of medicine to a broader audience. PMID- 26975071 TI - [Doc. Prim. Ph. D.. Miroslav JELIC (10/16/1947 to 11/ 8/2015)]. PMID- 26975070 TI - [Course Category 1 "New challenges in the prevention of childhood diseases"]. PMID- 26975072 TI - [Synthetic cannabinoids and driving impairment]. PMID- 26975073 TI - [Poisoning due to carbon monoxide and cyanide gas generated in the occurrence of fire]. PMID- 26975074 TI - [Hydrogen sulfide]. PMID- 26975075 TI - [Butane]. PMID- 26975076 TI - [Helium gas]. PMID- 26975077 TI - [Effects of the new comprehensive system for designating illegal drug components on the abuse of designer drugs and future problems based on an online questionnaire]. AB - Recently, the abuse of designer drugs has become a social problem. Designer drugs are created by modifying part of the chemical structure of drugs that have already been categorized as illegal, thereby creating a different chemical compound in order to evade Pharmaceutical Affairs Law regulations. The new comprehensive system for designating illegal drug components has been in effect since March 2013, and many designer drugs can now be regulated. We conducted an online questionnaire survey of people with a history of designer drug use to elucidate the effects of the new system on the abuse of designer drugs and to identify potential future problems. Over half the subjects obtained designer drugs only before the new system was implemented. Awareness of the system was significantly lower among subjects who obtained designer drugs for the first time after its introduction than those who obtained the drugs only before its implementation. Due to the new system, all methods of acquiring designer drugs saw decreases in activity. However, the ratio of the acquisition of designer drugs via the Internet increased. Since over 50% of the subjects never obtained designer drugs after the new system was introduced, goals that aimed to make drug procurement more difficult were achieved. However, awareness of the new system among subjects who obtained designer drugs after the new system was introduced was significantly low. Therefore, fostering greater public awareness of the new system is necessary. The results of the questionnaire also suggested that acquiring designer drugs through the Internet has hardly been affected by the new system. We strongly hope that there will be a greater push to restrict the sale of designer drugs on the Internet in the near future. PMID- 26975078 TI - [Three cases of an extreme hyperkalemia associated with glyphosate potassium herbicide poisoning]. PMID- 26975079 TI - [A case of colchicine overdose progressing to death rapidly]. PMID- 26975080 TI - [The pre-hospital medical care for poisoning case]. PMID- 26975081 TI - [Amyl nitrite, sodium nitrite, sodium thiosulfate]. PMID- 26975082 TI - [Changes of toxicity assessment using LD50 values]. PMID- 26975083 TI - [Practical analysis of toxic substances useful for clinical toxicology: From sample preparation to screening. The novel serum lithium diagnostic reagent for TDM using probe of fluorine substituted tetra phenyl porphyrin ligand]. PMID- 26975084 TI - [First challenge for poster presentations abroad]. PMID- 26975085 TI - [Collection and sharing of case information on acute poisoning in Japan Poison Information Center]. PMID- 26975087 TI - [Construction of automatic elucidation platform for mechanism of traditional Chinese medicine]. AB - Aim at the two problems in the field of traditional Chinese medicine (TCM) mechanism elucidation, one is the lack of detailed biological processes information, next is the low efficient in constructing network models, we constructed an auxiliary elucidation system for the TCM mechanism and realize the automatic establishment of biological network model. This study used the Entity Grammar Systems (EGS) as the theoretical framework, integrated the data of formulae, herbs, chemical components, targets of component, biological reactions, signaling pathways and disease related proteins, established the formal models, wrote the reasoning engine, constructed the auxiliary elucidation system for the TCM mechanism elucidation. The platform provides an automatic modeling method for biological network model of TCM mechanism. It would be benefit to perform the in depth research on TCM theory of natures and combination and provides the scientific references for R&D of TCM. PMID- 26975088 TI - [Study on mechanism for anti-hyperlipidemia efficacy of rhubarb through assistant analysis systems for acting mechanisms of traditional Chinese medicine]. AB - Rhubarb is a traditional Chinese medicine (TCM), wildly used in treating the disease of hyperlipidemia. However, its components are complicated, so that it is still difficult to clear the specific roles of its various components in blood lipids regulation in. So we decide to systematically study the anti- hyperlipidemia mechanism of rhubarb. We integrated multiple databases, based on entity grammar systems model, constructed molecular interaction network between the chemical constituents of rhubarb and hyperlipidemia. The network includes 231 nodes and 638 edges. Thus we infer the interactions of active targets and disease targets to clarify the anti-hyperlipidemia mechanism. And find that rhubarb can promote excretion of cholesterol; inhibit clotting factors and improve blood circulation; inhibit the release of inflammatory cytokines and maintain fat metabolism balance; inhibit cholesterol and triglyceride synthesis; and other ways to achieve lipid-lowering effect. Thus this study provides reference for novel drug development and component compatibility, and also gives a new way for the systematically study of acting mechanism of traditional Chinese medicine. PMID- 26975090 TI - [Study on mechanism of Salvia miltiorrhiza treating cardiovascular disease through auxiliary mechanism elucidation system for Chinese medicine]. AB - Salvia miltiorrhiza is a traditional Chinese medicine (TCM) and is widely used as a clinically medication for its efficiency in treating cardiovascular disease. Due to TCM is a comprehensive system, the mechanism of S. miltiorrhiza treating cardiovascular disease through integrated multiple pathways are still unclear in some aspects. With the rapid progress of bioinformatics and systems biology, network pharmacology is considered as a promising approach toward reveal the underlying complex relationship between an herb and the disease. In order to discover the mechanism of S. miltiorrhiza treating cardiovascular disease systematically, we use the auxiliary mechanism elucidation system for Chinese medicine, built up a molecule interaction network on the active component targets of S. miltiorrhiza and the therapeutic targets of cardiovascular disease to offer an opportunity for deep understanding the mechanism of S. miltiorrhiza treating cardiovascular disease from the perspective of network pharmacology. The results showed that S. miltiorrhiza treating cardiovascular disease through ten pathways as follows: improve lipid metabolism, anti-inflammation, regulate blood pressure, negatively regulates blood coagulation factor and antithrombotic, regulate cell proliferation, anti-stress injury, promoting angiogenesis, inhibited apoptosis, adjust vascular systolic and diastolic, promoting wound repair. The results of this paper provide theoretical guidance for the development of new drugs to treat cardiovascular disease and the discovery of new drugs through component compatibility. PMID- 26975089 TI - [Elucidating hypoglycemic mechanism of Dendrobium nobile through auxiliary elucidation system for traditional Chinese medicine mechanism]. AB - To build the Dendrobium nobile -T2DM network, and elucidate the molecular mechanism of D. nobile to type 2 diabetes (T2DM). Collect the chemical composition of D. nobile and the targets on T2DM by retrieving database and documents, build the network of D. nobile to T2DM using the entity grammar systems inference rules. The molecular mechanism of D. nobile to T2DM includes: (1) regulating lipid metabolism by lowering triglyceride; (2) reducing insulin resistance; (3) protecting islet cells; (4) promoting the glucose-dependent insulin tropic peptide (GIP) secretion; (5) inhibiting calcium channel. Under the guidance of network pharmacology, through entity grammar systems inference rules we elucidate the molecular mechanism of D. nobile to T2DM, and provide the basis for the further development of health care products based on D. nobile. PMID- 26975091 TI - [Study on mechanism for anti-hypertension efficacy of Eucommiae Cortex through assistant analysis systems for acting mechanisms of traditional Chinese medicine]. AB - Elucidate the mechanism of Eucommiae Cortex in treatment of hypertension, to provide the basis for further research and development of Eucommiae Cortex. Our study using the entity grammar systems inference rules to analyse the interactions of chemical constituents of Eucommiae Cortex and disease target proteins at the molecular level, and got a biological network of Eucommiae Cortex anti-hypertension which inciude 602 nodes and 2 354 edges. We got 3 treatment of hypertension pathways of Eucommiae Cortex by analyzing biological network, that is, by inhibition of vascular remodeling to improve the deterioration of hypertension, reduce activity of polymorphism genetic genes related to essential hypertension, inhibition of carbonic anhydrase 1 to maintain the osmotic pressure, Eucommiae Cortex play the role of anti-hypertension. PMID- 26975092 TI - [Study on mechanism for anti-depression efficacy of Sini San through auxiliary mechanism elucidation system for Chinese medicine]. AB - As regulating the function of the liver and spleen of the famous traditional formula, Sini San is widely used in the treatment of various diseases caused by liver depression and Qi stagnation, and its efficacy is significant clinically. Recently it is discovered that Sini San is effective in the treatment of nervous system diseases such as depression. Furthermore, there is a lot of literature about the effect of Sini San on the molecular mechanism of antidepressant. However, the anti-depression mechanism of Sini San is not very clear, in our present study, based on the auxiliary mechanism elucidation system for Chinese medicine and network pharmacology system to construct the chemical ingredients of the target interactions and disease-related protein of the interaction network. Results show that there are 263 chemical ingredients and 19 corresponding targets of depression in Sini San network. Sini San can anti-depressant effect through G protein coupled receptor protein signaling pathway, cAMP system, neurological system process and neurotransmitter secretion, inflammatory response, neuroendocrine, metal ion transport and so on. These studies provided valuable clues for the mechanism and treatment of anti-depressant. PMID- 26975093 TI - [Application prospect and expectation of fungistatic agents of plants in preservation of Chinese herbal medicines]. AB - During the process of growth, harvesting, transportation, processing and storage, Chinese herbal medicines (CHMs) can be easily contaminated by fungi and their metabolites like mycotoxins, which not only express negative effects on the quality and safety of CHMs and their processed products, but also pose great threats to human health. Now, some chemical synthetic fungicides have been frequently used to control the growth of fungi and accumulation of mycotoxins in the preservation of CHMs. However, the concentration and type of chemical fungicides allowed for postharvest application are restricted due to the disadvantages of their high residual toxicity, long degradation period and pollution to the environment and so on. Therefore, it is critical to research and develop some highly effective, safe and non-toxic, natural, environment-friendly fungistatic agents from plants to prevent CHMs from being contaminated by fungi and mycotoxins. The paper reviews mycotoxins and their harmfulness, the effective compounds of fungistatic plants as well as the antifungal mechanism to provide scientific evidences for developing novel and effective fungistatic agents plants. Then, the application prospect of fungistatic agents from plants in the preservation of CHMs was discussed. PMID- 26975094 TI - [Progress in preparation of small monoclonal antibodies of knock out technique]. AB - With the application of monoclonal antibody technology more and more widely, its production technology is becoming more and more perfect. Small molecule monoclonal antibody technology is becoming a hot research topic for people. The application of traditional Chinese medicine small molecule monoclonal antibody technology has been more and more widely, the technology for effective Chinese medicine component knockout provide strong technical support. The preparation of monoclonal antibodies and small molecule knockout technology are reviewed in this paper. The preparation of several steps, such as: in the process of preparation of antigen, hapten carrier coupling, coupling ratio determination and identification of artificial antigen and establishment of animal immunization and hybridoma cell lines of monoclonal antibody, the large-scale preparation; small molecule monoclonal antibody on Immune in affinity chromatography column method is discussed in detail. The author believes that this technology will make the traditional Chinese medicine research on a higher level, and improve the level of internationalization of Chinese medicine research. PMID- 26975095 TI - [Research of chemotaxis response of Botrytis cinerea and Alternaria panax on total ginsenosides]. AB - In this paper, three kinds of chemotactic parameters (concentration, temperature and pH) were determined by plate assay and spore germination method to research the chemotactic response of Botrytis cinerea and Alternaria panax, and their spores on total ginsenosides. The results showed that Botrytis cinerea had strong chemotactic response at the mid-concentration of total ginsenosides (cultivation temperature was 20 degrees C and pH value was 6), and the data of chemotactic migration index (CMI) was 1.293 0, chemotactic growth rate (CGR) was 0.476 0, spore germination rate (SGR) was 53%, and dry weight of mycelial (DWM) was 0.452 6 g x L(-1); however, Alternaria panax had strong chemotactic response at the low concentration of total ginsenosides (cultivation temperature was 25 degrees C and pH value was 6), and the data of chemotactic migration index (CMI) was 1.235 4, chemotactic growth rate (CGR) was 0.537 0, spore germination rate (SGR) was 67%, and dry weight of mycelial (DWM) was 0.494 8 g x L(-1). The results indicated that the low and middle concentration (2, 20 mg x L(-1)) of total ginsenosides had significant promoting effect on chemotactic response of these two pathogens, and the spore germination, mycelial growth rate, dry weight of mycelial of them were also significantly improved by this chemotactic response, whereas it decreased as the increase of total ginsenosides concentration. PMID- 26975096 TI - [ITS sequences variation and phylogenetic analysis on 31 geographical populations of Notopterygium incisum]. AB - In this study, 31 Notopterygium incisum populations were analyzed using ITS sequences to investigate the genetic structure. The results showed that: the ITS region ranged in size from 634 to 635 bp and base composition was with high G + C content of 57.8%. Thirty-one polymorphic sites were detected from 402 sequences of 31 populations of N. incisum, and the proportion of polymorphic sites was 4.88%, in which parsimony informative sites were up to 12. And 31 haplotypes were identified based on these polymorphic sites. Molecular variance analysis (AMOVA) indicated that high genetic differentiation (57%) existed among population, and gene flow was low (N(m) = 0.38) among populations. Phylogenetic relationships of 31 haplotypes were analyzed using NJ method with N. forbesiias an out-group. Phylogenetic analysis showed that 31 haplotypes from different populations mixed together and did not form distinct geographically separated clades. PMID- 26975097 TI - [Effect of different nitrogen forms and ratio on growth and active ingredient content of Platycodon grandiflorum]. AB - To providing evidence about nitrogen adequate application of Platycodon grandiflorum, the pot culture experiment was conducted to study the effect of nitrogen on the growth, physiological metabolism and the quality of P. grandiflorum. The activity of NR, GS and SOD, POD and CAT were determined. And the nitrate and ammonium nitrogen content, photosynthetic characteristics, active components of P. grandiflorum were determined. The results showed that the nitrate nitrogen content and P. biomass reached its maximum value, when NH4(+) N/NO3(-) -N was 0: 100, the activity of NR. The activity of GS was the highest at the NH4(+) -N/NO3(-) -N ratio of 25:75 and ammonium nitrogen content was the highest at 75:25. The activity of SOD decreased and then increased with the increasing of NO3(-) -N. At the NH4(+) -N/NO3(-) -N ratio of 25: 75, the activity of CAT had its maximum value and the content of MDA had the minimum value. At the same time, the content of platycodon D was the highest at this treatment. The studies had shown that different nitrogen forms and ratio had a significant effect on the characteristics of photosynthetic physiology, nitrogen metabolism and resistance adjustment, growth and the quality of P. grandiflorum. The NH4(+) N/NO3(-) -N ratio of 25: 75 was a suitable ratio of nitrogen forms for the growth of P. Grandiflorum and accumulating the content of platycodon D. PMID- 26975098 TI - [Cloning and functional characterization of phytoene desaturase in Andrographis paniculata]. AB - A full-length cDNA of phytoene desaturase (PDS) gene from Andrographis paniculata was obtained through RACE-PCR. The cDNA sequence consists of 2 224 bp with an intact ORF of 1 752 bp (GeneBank: KP982892), encoding a ploypeptide of 584 amino acids. Homology analysis showed that the deduced protein has extensive sequence similarities to PDS from other plants, and contains a conserved NAD ( H) -binding domain of plant dehydrase cofactor binding-domain in N-terminal. Phylogenetic analysis demonstrated that ApPDS was more related to PDS of Sesamum indicum and Pogostemon cablin. The semi-quantitative RT-PCR analysis revealed that ApPDS expressed in whole aboveground tissues with the highest expression in leaves. Virus induced gene silencing (VIGS) was performed to characterize the functional of ApPDS in planta. Significant photobleaching was not observed in infiltrated leaves, while the PDS gene has been down-regulated significantly at the yellowish area. To the best of our knowledge, this represents the first report of PDS gene cloning and functional characterization from A. paniculata, which lays the foundation for further investigation of new genes, especially that correlative to andrographolide biosynthetic pathway. PMID- 26975099 TI - [Numerical taxonomy of corlor in Phellodendron Cortex]. AB - Through the investigation of Phellodendron Cortex on the market, and 28 batches of samples were collected. By using spectrophotometer the color values of outer surface, inner surface and cross - section of these samples were measured. These measured color data was translated into 3D structure diagram by using the Lab color space tool. The level difference value, the mean value and the threshold value were calculated based the measured color data of these different batches of samples. All 28 groups measured data was analyzed using the methods of Ward linkage and average Euclidean distance. At the same time, we invited Professor Jin Shiyuan, the "Chinese medicine master", to identify, quality-evaluate and grade these 28 batches of Phellodendron Cortex samples base on the traditional experience, then compared the traditional empirical results with the spectrophotometer measurement results. The result showed that, the Phellodendron Cortex could be divided into Phellodendri Amurensis Cortex and Phellodendri Chinensis Cortex by color numerical clustering, and classified according to quality. The classification result has a high degree of consistency with the traditional experience. PMID- 26975101 TI - [Development and characterization of TPGS modified proniosomes of docetaxel]. AB - A novel oral delivery system that TPGS modified docetaxel proniosomes, DTX-TPGS PN, was developed and the characterization after hydration was observed. Firstly, Doce-TPGS-PN was optimized by investing the factors, including the type of surfactant, methods of adding TPGS, content of TPGS and the molar ratio of span40/cholesterol, which may affecting the particle size, encapsulation efficiency and instantaneous release of drug in the formulation. Then, the morphology, particle size, Zeta potential, encapsulation efficiency and in vitro release of the formulation were evaluated. The result showed that hydrated nanoparticles of DTX-TPGS-PNs were (93 +/- 6.5) nm in size,(-83.95 +/- 3.69) mV in zeta potential, (97.31 +/- 0.60)% in encapsulation efficiency, exhibiting spherical morphology and biphasic release process that a low burst effect within the first 0.5 hour and a relative-sustained release for the next several hours in PBS. These results indicate the oral delivery system of DTX-TPGS-PN was successfully built with good properties. PMID- 26975100 TI - [Active ingredients and its pharmacokinetic behavior and anti-inflammatory effects of ginseng with different steamed times]. AB - HPLC analysis was performed to study the changes in chemical composition of ginseng extracts prepared from high quality ginseng with 0, 2, 4, 8 h of steamed times. An UFLC-MS/MS multiple-reaction monitoring (MRM) quantitative analysis was made to investigate the pharmacokinetic behavior differences of ginsenosides in mice ig administered of ginseng extracts with different steamed times in the negative ion mode, with Digoxin as the internal standard substance. The mice were injected with LPS to establish inflammation model after ig administration of ginseng for a week and the contents of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in mice plasma were detected by ELISA, in order to study on anti-inflammatory effects of ginseng with different steamed times. It was determined that levels of TNF-alpha and IL-1beta were significantly decreased in inflammation model group ig administered of ginseng extracts with 8h of steamed time. The results showed that the chemical components in ginseng changed after steaming and the components into the blood changed, correspondingly. Ginseng with steamed 8 h contributes to anti-inflammatory effects. These results provided an experimental basis for revealing the active substance basis and dose effect relationship of ginseng on anti-inflammatory effect. PMID- 26975102 TI - [Determination of aflatoxin B1, B2, G1, G2 in Ben Lamge granules by HPLC-FLD after multi-pretreatment clean-up]. AB - To establish a multi-pretreatment method for the determination of aflatoxin B1, B2, G1, G2 in Chinese patent medicines, aflatoxins were analyzed by high performance liquid chromatography-fluorescence detector with post-column derivatization, after the multi-pretreatment of samples. The results showed that after the samples extracted with MeOH-H2O, dehydrated by anhydrous magnesium sulphate and sodium chloride, and finally purified by neutral alumina, the impurity interference of different sources in Chinese patent medicines matrix can be effectively removed, and the main peak can be nicely separated from the impurity peak. The detection limits were 0.25, 0.25, 0.50, 0.25 MUg x L(-1) for AFB1, AFB2, AFG1, AFG2, respectively. The quantification limits were 1.00, 0.50, 1.00, 0.50 MUg x L(-1), respectively. Aflatoxin B1, G1 showed a good linear relationship at a range of 1.0-50 MUg x L(-1), aflatoxin B2, G2 at a range of 0.5 12.5 MUg x L(-1) (R2 > 0.99). The average recovery was 80.40% - 108.6%. The present method is simple, reproducible with the reasonable recoveries and can be applied for the determination of aflatoxins in Chinese patent medicines. PMID- 26975103 TI - [Monitor on influence of quality standard improvement upon Guizhi Fuling capsules efficacy]. AB - In 2012, the preparation process and quality standard for Guizhi Fuling capsule were improved. To compare the effects and differences of capsules before (2011) and after(2012-2014) the improvement, evaluation models for intrinsic dysmenorrhea, pelvic inflammation and hysteromyoma were applied in rats. Models were induced by oxytocin, liqiud bacteria mixture and estrogen loading, respectively. The capsules (12 batchs/year, 48 bathcs in all), sampled randomly in 2011-2014, the effects were assessed using the three models. In anti dysmenorrhea models, remarked reduction of writhing frequency, ET-1 and PGF2alpha content in uterus could be detected, as well as extension of writhing latency. In pelvic inflammation rats, depression of TNF-alpha and raise of IL-2 were induced by earh batch of capsules. In hysteromyoma model, uterine weight and smooth muscle proliferation, including E2 and P level in plasma, were lowered obviously by all batchs of capsules. Secondly, Guizhi Fuling capsules produced in 2012-2014 revealed better effectiveness than the ones manufactured in 2011. Moreover, pharmacodynamics indexes of the samples made in 2011 differed significantly between groups, which could not be observed in the ones ot 2012-2014. After tne preparation process and quality standard improvement, the effectiveness and homogeneity of Guizhi Fuling capsules were enhanced. PMID- 26975104 TI - [Optimization on alcohol precipitation techniques of Liuwei Dihuang decoction by response surface methodology]. AB - The theoretical basis of the alcohol precipitation process control was provided, the alcohol precipitation was optimized and the relationship equation was got. The monod glycoside, loganin and paeoniflorin were used as the evaluation indexes to determine the impact factors of alcohol precipitation techniques of Liuwei Dihuang decoction by the Plackett-Burman experimental design and the levels of non-significant factors were identified. Then, Box-Behnken response surface methodology was used to research and discuss the critical process parameters influence the effect of alcohol precipitation and draw interaction between key process parameters and the correlation equation with index components. Through the establishment and solving the quadratic regression model of composite score, the optimum preparation conditions of alcohol precipitation techniques of liuwei were as follows: stirring speed was 580 r x min(-1), standing time was 17 hours, alcohol concentration was 34%, the density of Liuwei Dihuang decoction was 1.13. The response surface methodology for optimized alcohol precipitation techniques of Liuwei Dihuang decoction is. reasonable and feasible. PMID- 26975105 TI - [Chemical constituents from Crepis crocea]. AB - Thirteen compounds were isolated from the ethyl acetate fraction of Crepis crocea by column chromatographies on silica gel, Sephadex LH-20 and semi-preparative HPLC. The structures were elucidated on the basis of spectral analysis as tectorone I (1), 8beta- (2-methyl- 2-hydroxy-3-oxobutanoyloxy) -glucozaluzanin C (2), tectoroside (3), luteolin-7-O-glucoside (4), cosmosiin (5), esculetin (6), 3,4-dihydroxybenzaldehyde (7), trans-4-hydroxycinnamic acid (8), Caffeic acid (9), methyl p-hydroxyphenyllactate (10), ethylp- hydroxyphenyllactate (11), cis 3,4-dihydroxy-beta-ionion (12). All the compounds, except for compounds 4 and 9, were isolated from this plant for the first time, and tectorone I (1) is a new natural product. PMID- 26975106 TI - [Chemical constituents from polarity part in roots of Angelica dahurica var. formosana cv. Chuanbaizhi]. AB - The chemical constituents from polarity part in the roots of Angelica dahurica var. formosana cv. Chuanbaizhi were studied in this paper. The compounds were separated and purified by repeated column chromatographic methods on silica gel and HPLC, and the chemical structures of compounds were determined by spectral data analyses. Fourteen compounds were obtained and identified as tert-O-beta-D glucopyranosyl-(R)-byakangelicin (1), (2"S) -3"-O-beta-D-glucopyranosyl oxypeucedanin hydrate (2), marmesinin (3), sec-O-beta-D-glucopyranosyl byakangelicin (4), isofraxidin-7-O-beta-D-glucopyranoside (5), benzyl-O-beta-D glucopyranoside (6), 8-O-beta-D-glycopyranosylxanthotoxol (7), prenyl-O-beta-D glucopyranoside (8), scopolin (9), (2' R) -5'-hydroxymarmesin-5'-O-beta-D glucopyranoside (10), (2'S,3'R) -3'-hydroxymarmesinin (11), skimmin (12), benzyl O-beta-D-apiofuranosyl-(1"--> 6')-beta-D-glucopyranoside (13), and decuroside IV (14). Among them, compounds 2, 5, 6, 8, and 10-13 were obtained from the roots of title plant for the first time. PMID- 26975107 TI - [Chemical constituents of Swertia kouitchensis Franch]. AB - This study is to investigate the chemical constituents of Swertia kouitchensis. The whole plants of air-dried Swertia kouitchensis was extracted with 90% EtOH. The water extract was suspended in H2O and extracted with petroleum ether, EtOAc and n-BuOH, successively. The compounds were isolated and purified by column chromatography from the EtOAc fraction, and their structures were identified based on spectral analyses (MS, 1H-NMR, 13C-NMR). Twenty-eight compounds were obtained, and characterized as erythrocentaurin (1), erythrocentaurin dimethylacetal (2), swertiamarin (3), vogeloside (4), 2'-O- actylswertiamarin (5), swertianoside D (6), gentiocrucines A-B (7-8), gentiocrucine (9), 1-hydroxy 3, 7, 8-trimethoxyxanthone (10), 1-hydroxy-3, 5, 6-trimethoxyxanthone (11), 3 epitaraxerol (12), erythrodiol 3-O-palmitate (13), (+) -syringaresinol (14), caffeic acid (15), trans-coniferyl aldehyde (16), trans-coniferyl alcohol (17), 3, 4-dihydroxybenzoic acid (18), 4-hydroxy-3-methoxybenzoic acid (19), 3, 4 dihydroxybenzoic aldehyde (20), 2, 3-dihydroxybenzoic acid (21), 4-hydroxybenzoic acid (22), 3-acetoxybenzoic acid (23), 3-hydroxybenzoic acid (24), 3 hydroxybenzoic alcohol (25), nicotinic acid (26), 2-furoic acid (27), and uracil (28). Compounds 1-4, 6-28 were obtained from S. kouitchensis for the first time. PMID- 26975108 TI - [Molecular docking analysis of xanthine oxidase inhibition by constituents of cichory]. AB - Human xanthine oxidase is considered to be a target for therapy of hyperuricemia. Cichorium intybus is a Chinese plant medicine which widely used in Xinjiang against various diseases. In order to screen the inhibitors of xanthine oxidase from C. intybus and to explore main pharmacological actions of cichory a compound collection of C. intybus was built via consulting related references about chemical research on cichory. The three-dimensional crystal structure of xanthine oxidase (PDB code: 1N5X) from Protein Data Bank was downloaded.. Autodock 4.2 was employed to screen the inhibitors of xanthine oxidase from cichory 70 compounds were found to possess quite low binding free energy comparing with TEI (febuxostat). C. intybus contains constituents possessing potential inhibitive activity against xanthine oxidase. It can explain the main pharmacological actions of cichory which can significantly lower the level of serum uric acid. PMID- 26975109 TI - [Analysis of HPLC and NIRS fingerprints of Chrysanthemum indicum of different processing methods]. AB - This paper studied the HPLC and NIRS fingerprints of Chrysanthemum with different processing methods, including directly drying, drying after steamed, and drying after fried. The method of discriminant analysis of TQ software was used to analysis the NIRS fingerprint of Chrysanthemum with three different processing methods, and the results were consistent with HPLC fingerprint similarity analysis. NIRS and HPLC fingerprints were of different characteristics, and the combination of the two methods can quickly and accurately identify Chrysanthemum with different processing methods. PMID- 26975110 TI - [Establishment of simultaneous quantitative model of five alkaloids from Corydalis Rhizoma by near-infrared spectrometry]. AB - This paper established a near-infrared spectroscopy quantitative model for simultaneous quantitative analysis of coptisine hydrochloride, dehydrocorydaline, tetrahydropalmatine, corydaline and glaucine in Corydalis Rhizoma. Firstly, the chemical values of the five components in Corydalis Rhizoma were determined by the reversed-phase high performance liquid chromatography (RP-HPLC) with UV detection. Then, the quantitative calibration model was established and optimized by fourier transformation near-infrared spectroscopy (NIRS) combined with partial least square (PLS) regression. The calibration model was evaluated by correlation coefficient (r), the root-mean-square error of calibration (RMSEC) and the root mean square of cross-validation (RMSECV) of the calibration model, as well as the correlation coefficient (r) and the root mean square of prediction (RMSEP) of prediction model. For the quantitative calibration model, the r, RMSEC and RMSECV of coptisine hydrochloride, dehydrocorydaline, tetrahydropalmatine, corydaline and glaucine were 0.941 0, 0.972 7, 0.964 3, 0.978 1, 0.979 9; 0.006 7, 0.003 5, 0.005 9, 0.002 8, 0.005 9; and 0.015, 0.011, 0.020, 0.010 and 0.022, respectively. For the prediction model, the r and RMSEP of the five components were 0.916 6, 0.942 9, 0.943 6, 0.916 7, 0.914 5; and 0.009, 0.006 6, 0.007 5, 0.006 9 and 0.011, respectively. The established near-infrared spectroscopy quantitative model is relatively stable, accurate and reliable for the simultaneous quantitative analysis of the five alkaloids, and is expected to be used for the rapid determination of the five components in crude drug of Corydalis Rhizoma. PMID- 26975111 TI - [Study on efficacy and accompanying toxic and side effects of volatile oil of Evodia Fructus based on stomach cold syndrome model]. AB - OBJECTIVE: To preliminarily study the effective dosage range and mechanism of the abirritation of volatile oil of Evodia Fructus on the stomach cold syndrome model in mice, and discuss the correlation between its accompanying toxicity and oxidative damage mechanism, in order to provide the experimental basis for explaining the efficacy-syndrome-toxicity correlation. METHOD: The stomach cold syndrome model in mice was induced by the classic hot plate test by orally administrating with different doses of volatile oil of Evodia Fructus, in order to observe its abirritation and companying toxic and side effects and detect serum ALT, AST, PGE2, NO, NOS, MDA, SOD, GSH, GSH-Px, BUN, CR and hepatic ALT, AST. The companying toxic symptoms in mice were recorded in toxic reaction integral table. RESULT: Volatile oil of Evodia Fructus had an obvious analgesic effect at 30 min after the oral administration and reached the peak effect at 60 min, with certain "dose-effect" and "time-effect" relations, rises in serum and hepatic ALT and AST levels, serum PGE2, MDA, NO and NOS and hepatic indexes, decreases in SOD, GSH and GSH-Px and no notable change in BUN, CR levels and kidney weight/body ratio. Conclusion: The abirritation mechanism of volatile oil of Evodia Fructus was related to the inhibition of pain transmitter release, peroxidative damage and NO damage, which is accompanied by certain hepatotoxicity, mainly mainly oxidative damage, with a concurrent "dose-time toxicity" relationship. PMID- 26975112 TI - [Effect of Yinghua Pinggan granule against influenza A/H1N1 virus in vivo]. AB - To study the effect of Yinghua Pinggan granule (YHPG) against influenza A/H1N1 virus in vivo and on the immunologic function of infected mice. The intranasal influenza virus infection was adopted in ICR mouse to establish the influenza virus pneumonia model. At the 3rd and 7th day after the infection, the lung index and pathologic changes in lung tissues of mice were detected. Realtime PCR and flow cytometry were employed to observe the virus load in lung tissues and the levels of CD4+, CD8+, and CD4+/CD8+ in peripheral blood. The result showed that at the 3rd and 7th day after the infection, YHPG (15, 30 g x kg(-1)) can significant decrease in the lung index and virus load in lung tissues of mice infected with influenza virus, alleviate the pathologic changes in lung tissues, significantly increase the levels of CD4+ and CD4+/CD8+ ratio and reduce the levels of CD8+ in whole blood. This indicated that YHPG can inhibit the influenza virus replication, alleviate pulmonary damage and adjust the weak immunologic function of infected mice, with a certain therapeutic effect on mice infected by H1N1 virus in vivo. PMID- 26975113 TI - [Investigation of metabolites of Triptergium wilfordii on liver toxicity by LC MS]. AB - In this paper, biomarkers of liver toxicity of Triptergium wilfordii based on metabolomics was screened, and mechanism of liver toxicity was explored to provide a reference for the clinical diagnosis for liver toxicity of Triptergium wilfordii. MS method was carried on the analysis to metabolic fingerprint spectrum between treatment group and control group. The potential biomarkers were compared and screened using the multivariate statistical methods. As well, metabolic pathway would be detailed description. Combined with PCA and OPLS-DA pattern recognition analysis, 20 metabolites were selected which showed large differences between model group and blank group (VIP > 1.0). Seven possible endogenous biomarkers were analyzed and identified. They were 6-phosphate glucosamine, lysophospholipid, tryptophan, guanidine acetic acid, 3-indole propionic acid, cortisone, and ubiquinone. The level changes of above metabolites indicated that the metabolism pathways of amino acid, glucose, phospholipid and hormone were disordered. It is speculated that liver damage of T. wilfordii may be associated with the abnormal energy metabolism in citric acid cycle, amino acid metabolism in urea cycle, and glucose metabolism. It will be helpful to further research liver toxicity ingredients of Triptergium wilfordii. PMID- 26975114 TI - [Determination of plasma concentration of quercetin, kaempferid and isorhamnetin in Hippophae rhamnoides extract by HPLC-MS/MS and pharmacokinetics in rats]. AB - To establish an HPLC-MS/MS method for the analysis of quercetin, kaempferid and isorhamnetin in rats plasma and study its pharmamacokinetics after an intragastrical administration of Hippophae rhamnoides extracts. Five healthy male Sprague-Dawley (SD) rats were given single doses of H. rhamnoides extracts (quercetin 26.35 mg x kg(-1), kaempferid 4.040 mg x kg(-1), isorhamnetin 31.37 mg x kg(-1)), and then their orbital sinus blood samples were collected at different time points. The drug plasma concentration of the three flavonoids was determined by HPLC-MS/MS method. After that, the main pharmacokinetics parameters were calculated by using Kinetica 5. 0. 11 software. The methodological test showed that the linear concentration ranges of quercetin, kaempferid and isorhamnetin were 7.500-600.0 MUg x L(-1) (R2 = 0.998 5), 1.000-80.00 MUg x L(-1) (R2 = 0.998 5 ) and 10.00-800.0 MUg x L(-1) (R2 = 0.998 0), respectively. The inner and inter days precisions were both less than 14.0%. The plasma samples showed a good stability and consistency with the requirement of biological sample analysis after the samples were frozen once and placed at - 20 degrees C for 15 d and room temperature for 6 h and the treated analytes were placed at -20 degrees C for 24 h. For quercetin, the pharmacokinetic parameter t(1/2beta), AUC(0-infinity), MRT(0.infinity), C.(max) and T(max) were (113.3 +/- 19.37) min, (12 542.14 +/- 3 504.05) MUg x h x L(-1), (119.6 +/- 13.29) h, (164.6 +/- 27.33) MUg x L(-1) and (5.199 +/- 0.840 3) h, respectively. For kaempferid, the pharmacokinetic parameters t(1/2beta), AUC(0-t), MRT(0-infinity), C(max) and T(max) were (79.85 +/- 17.15) min, (934.51 +/- 94.59) MUg x h x L(-1), (81.50 +/- 13.75) h, (80.15 +/- 14.24) MUg x L(-1) and (3.827 +/- 0.902 7) h, respectively. For isorhamnetin, the pharmacokinetic parameters t1,2,, AUC(0-t), MRT(0-infinity), C(max) and T(max) were (118.3 +/- 20.73) min, (26 067.77 +/- 4 124.60) MUg x h x L(-1), (129.0 +/- 16.30) h, (269.6 +/- 29.32) MUg x L(-1) and (6.513 +/- 1.450) h, respectively. The HPLC-MS/MS analysis method established in this study was proved to be sensitive and accurate and could be applied in the pharmacokinetic study of quercetin, kaempferid and isorhamnetin in rat plasma. PMID- 26975115 TI - [Medication rule for treatment of functional dyspepsia: an analysis of traditional Chinese medicine literature based on China National Knowledge Internet]. AB - By retrieving the clinical research literature of treatment functional dyspepsia by traditional Chinese medicine (TCM) from January 2004 to December 2014 based on China National Knowledge Internet (CNKI), we would establish a TCM decoction database for treating functional dyspepsia in this study. One hundred and sixty four literature were included, involving 159 prescriptions, 377 medicines, in a total of 1 990 herbs. These herbs can be divided into 18 categories according to the effectiveness; and qi-regulating herbs, blood circulation herbs, and antipyretic herbs ranked top three ones according to the frequency of usage of the herbs, whose medicine usage frequency accounted for 51.81%. Usage frequency of 16 herbs was over 30, and Atractylodes, Radix, Poriaranked top three according to the usage frequency. Medicinal properties were divided into 9 kinds according to the frequency statistics, and the top three were warm, flat, and cold. Taste frequency statistics were classifiedinto 9 kinds, and the top three were acrid, sweet, and bitter. In frequency statistics of the meridian tropism of herbs, it was classifiedinto 11 kinds, and the top three were spleen, stomach, lung. The analysis can provide a reference for treatment and study of TCM of functional dyspepsia. PMID- 26975116 TI - [Experience of LU Zhi-zheng to apply tenuifolia]. AB - Professor LU Zhi-zheng, one of the first traditional Chinese medicine masters, is good at using tenuifoliain clinical practice, which often brings unexpected surprises. Lu said, tenuifolia is a mild herbal medicine with the nature of upward dispersion and outward penetration but not dryness. Tenuifolia has the following functions: making people conscious, relieving sore throat, diverging incubated diseases, regulating functional activities of qi, sending up Yang, dispelling wind evil and eliminating dampness, and activating collaterals to relieve pain. When well used, it will not only enhance the effect of monarch drug, but also restrict the impetuosity nature in a prescription, achieving better efficacy. PMID- 26975117 TI - [Mutual information-based correlation analysis of herbs against insomnia]. AB - This paper aims to analyze Professor Guo Rongjuan's medication experience on insomnia therapy based on the Traditional Chinese Medicine (TCM) Inheritance Support Plat. First, TCM formulae prescribed by Professor Guo for insomnia therapy were collected from the TCM Inheritance Support Plat. Next, unsupervised data mining algorithms, including apriori, modified mutual-information, and entropy clustering of complex system were applied to obtain the frequencies for different herbs and identify the association rules among the herbs. Accordingly, we can gain new insights into Professor Guo's medication experience on insomnia therapy. Based on analysis of 3 084 formulae, we determined the frequencies for herbs in the formulae and identified the association rules among these herbs. At last, 41 core combinations and 7 new formulae were obtained. The identified medication experience conform with Professor Guo's views on the etiology and pathogenesis of insomnia: "pathogenic fire derived from stagnation of liver-QI (Gan Yu Hua Huo)" is the core pathogenesis of insomnia; "liver stagnation and spleen deficiency" and "chronic illness transferred to kidney" are the main features for insomnia. The TCM Inheritance Support Plat is of great practical value for mining clinical experience of famous TCM doctors. PMID- 26975118 TI - [Quality standard study on Tibetan medicine Gentianae Urnulae Herba]. AB - Gentianae Urnulae Herba, dried whole herb of Gentiana urnula,is a commonly used Tibetan medicine. However, only the character identification is used as quality control standard officially at present. As a part of project for the Chinese Pharmacopoeia (2015 edition), the quality standard of this species was established in this study. The tests of water content, total ash, acid-insoluble ash and ethanol-soluble extractives of the crude drugs were carried out following the methods recorded in appendix of Chinese Pharmacopeia (2010 edition, volume 1). The TLC identification method was established by using gentiournoside A as reference substance, and a mixture of ethyl acetate-methanol-water-formic acid(7:1. 5:1: 0. 2) as the developing solvent system on silica gel G TLC plate. The content of gentiournoside A was assayed by HPLC on an Agilent Zorbax SB-C18 (4.6 mm x 250 mm,5 MUm) column, using acetonitrile-water (0.1% phosphoric acid) (26:74) as the mobile phase at a flow rate of 1.0 mL x min(-1). The column temperature is at 30 degrees C and the detection wavelength is at 240 nm. As a result, gentiournoside A and the other constituents were separated and presented the same fluorescence light comparing with the reference substance on TLC detected under the UV light(366 nm). The methodology validation for the assay of gentiournoside A showed that it was in a good linear correlation in the range of 0.009 95-0.398 g x L(-1) with the regression equation of Y = 1 467.1X +41.407(r = 0.999 9), and the average recovery was 98. 3% (RSD 2.2%). The mass fractions of gentiournoside A, water content, ethanol-soluble extractives of 15 batches samples were varied in the ranges of 0.175% -1.83%, 8.60% - 9.93% and 29.2% - 35.2%, respectively. Total ash and acid-insoluble ash were 10.2% - 17.2% and 5.26% - 10.8% detected from 10 batches samples. The recommended standards of quantitative indexes are that the mass fractions of gentiournoside A and extractives are not less than 0.80% and 26.0%, respectively; the water, total ash and acid-insoluble ash are not more than 12.0%, 15.0% and 8.0%, respectively. PMID- 26975119 TI - [Studies on genetic diversity of three Tibetan herbs]. AB - The genetic diversity of three Tibetan herbs, i. e., Sang-Di, E-Dewa and Ye Xingba (Tibetan names), was studied based on the field collection, specimen identification and DNA sequence analysis. Swertia hispidicalyx, Gentiana lhassica and Scrophularia dentata, as the original plants of the three Tibetan herbs, were collected and identified. The regions of ITS, matK, rbcL, rpoC1, trnL(UAA), psbA trnH, atpB-rbcL, trnS (GCU)-trnG(UCC), rpl20-rps12, trnL(UAA)-trnF(GAA) and nadl 2nd intron were amplified and sequenced. The ITS regions of S. hispidicalyx and S. dentata were cloned and sequenced, and the sequences were classified into different genotypes. All the sequences were analyzed and compared with those of closely related species. Our studies may provide reference for the genetic diversity analysis and molecular identification of the three Tibetan herbs. PMID- 26975120 TI - [INDENA SPA company's patent portfolio of Ginkgo biloba preparation]. AB - INDENA SPA Company in Italy is a multi-national company that produces and sells plant extracts. Based on its own re- search advantages in the field of Ginkgo biloba preparation, the company protects its own products market effectively through building patent portfolio around the patents of its opponent. Based on the multi-angle analysis for patent portfolio of G. biloba preparation from the aspects of application time, legal status, technical development route, and patent portfolio layout, this article provides technical reference on research and development of G. biloba preparation, and the author suggest that Chinese applicants learn techniques and layout experiences of other patents fully to enhance the level of research and patent protection level. PMID- 26975121 TI - [Review on scientific connotation of leech processed under high temperature]. AB - Animal medicines mainly contain protein which was organic molecule with quaternary structure and had the property of thermal denaturation. When suffering from heat for a consistent time, the native conformation of protein would be destroyed. After denaturation the biological activity of protein will lose and some physicochemical and biochemical properties will be changed. Leech was a classical animal medicine in the views of traditional Chinese medicine (TCM) which had the functions of breaking stagnant and eliminating blood stasis. In the usage history, it was processed for a long time. No matter stir-frying leech with talc powder embodied in Chinese Pharmacopoeia or stir-baking with wine as a distinctive method in Beijing district, the process procedure was basically performed under high temperature. The purposes and intentions of process are mostly limited to technology conditions at specific historical period. In this article, based on existing processing procedure and its character of Leech, the changes of active components and pharmacological activities before and after processing under high temperature were summarized. The results demonstrate that the protein of leech would be denaturated; some active peptide such as hirudin were partly or totally destroyed; some toxic mineral elements, such as Pb, Hg, Cd, were decreased; at the same time, heating can promote some chemical components transforming into hypoxanthine which had the function of antihypertensive, antiasthmatic and antalgic. Consequently, after processed under high temperature, the purpose of decreasing toxicity and alleviating the strong property was achieved. Pharmacological changes of leech processed under high temperature were mainly manifested in the anticoagulant and antithrombotic activity, etc. Based on current processing research status about animal medicine leech, future research methods and directions on scientific connotation of leech processed under high temperature were put forward in this article. PMID- 26975122 TI - Time for the common good. PMID- 26975123 TI - The best use of time. PMID- 26975124 TI - 2015: MATERNITY'S BIG YEAR. PMID- 26975125 TI - The benefits of optimal cord clamping. AB - Optimal cord clamping is known and now widely recognised as having positive consequences for the neonate in the short- and medium-term. This review of some of the key literature published over the last five years on the effects of both ECC and OCC provides an insight into the evidence on this topic. The aim of this article is to summarise the key papers on the topic of the effect of timing of cord clamping, including some of those included in the Cochrane Review as well as the majority that have been published since, to provide an up-to-date overview. PMID- 26975126 TI - Clinical guidelines. AB - This article is part of the Advancing practice series which is aimed at exploring practice issues in more depth, considering topics that are frequently encountered and facilitating the development of new insights. Elaine Uppal focuses on the importance of all midwives developing guideline writing skills to ensure that local, national and international midwifery/maternity guidelines are up to date, relevant and reflect midwifery knowledge alongside 'gold' standard evidence. The article aims to consider the development, use and critical appraisal of clinical guidelines. It will define and explain guidelines; discuss their development and dissemination; and consider issues relating to their use in practice. Techniques to critique and develop guidelines using the AGREE tool will be outlined in the form of practice challenges to be undertaken by the individual or in a group. PMID- 26975127 TI - Emergency time: caring in Congo. AB - Midwifery practice in rural central Africa is full of joys (an abundance of twins, births by candlelight and resilience and stoicism that would leave even the very experienced birth practitioner speechless), but also a lot of challenges (every obstetric emergency in your wildest nightmares and worse) that are compounded by a lack of access to a skilled birth attendant. Women here have a strong culture of traditional practices and remedies, and hospital is often not the first port of call. Caring for women who cannot, themselves, consent to emergency life-saving caesarean sections, is a cultural aspect that we accept and respect as medical professionals working in the Democratic Republic of Congo (DRC). In a busy maternity ward in a low-resource setting, in a hospital supported by emergency humanitarian medical organisation Medecins sans Frontieres (MSF), just how are obstetric emergencies managed--and are the outcomes what you would expect? PMID- 26975128 TI - Learning to aid learning. AB - The National Health Service (NHS) is one of the largest employers in the world and, with 1.3 million staff, the biggest employer in Europe. With over three hundred different careers on offer (NHS 2015), the acquisition of skills and qualifications, through academic and clinical training, is an integral part of day-to-day life in the health service. As such, mentoring has become a significant feature in the preparation of healthcare professionals, to support students and ensure learning needs and experiences are appropriate to competency. This article examines the mentor's role, in relation to a teaching innovation designed to address students' identified learning needs to meet the requirements of the multi-professional learning and assessment in practice course NM6156. The effectiveness of the aids to learning will be assessed through an online quiz, and its usefulness will be analysed with reference to educational theories of learning and development. PMID- 26975129 TI - Midwifery: home and away. AB - The challenges faced by birthing women and maternity healthcare professionals in developing countries cannot not be over estimated. The experience of a midwife in a rural Tanzanian hospital described in this article gives a small insight into these challenges. With intermittent electricity, no running water, three beds, 20 births per day and lack of midwifery or obstetric education, morbidity and mortality rates are high, and teaching is difficult. Conversely, where monitoring is minimalistic and time limits are not applied, 'normal birth' is truly the norm and the trust in women to grow and birth their babies is consistent and commendable. Reflection upon midwifery in developing countries can help inform attitudes and practice in the UK. PMID- 26975130 TI - Domestic violence in pregnancy: midwives and routine questioning. AB - The Confidential enquiry into maternal and child health (CEMACH) (2004) set the standard for maternity care to protect women from domestic violence. Twelve women who were murdered by their partner and 43 further deaths from disclosure with no appropriate referrals prompted the routine enquiry for domestic violence to be initiated in 2000. The death rate from domestic violence had marginally decreased slightly in the latest report from The Centre for Maternal and Child Enquiries (CMACE) (2011) with 11 women murdered by their partner and 34 further deaths from disclosure with no referrals. The aim of this article is to review the current literature in order to explore evidence that questions the confidence of midwives when asking about domestic violence in pregnancy. The article aims to highlight the concerns that midwives face when confronted with a positive disclosure of domestic violence, and to provide a flow chart to aid in referral. PMID- 26975131 TI - Polish women's experiences of breastfeeding in Ireland. AB - Exclusive breastfeeding among Polish mothers at three-four months (38.6 per cent) is in keeping with the low rates of breastfeeding in Ireland overall (Begley et al 2008), and suggests that Polish women have begun to adopt the infant feeding practices of Irish women. Therefore, the aim of this study was to explore the factors that influence Polish women's decisions to initiate and continue breastfeeding in Ireland. A descriptive qualitative approach was utilised to explore participants' perspectives of breastfeeding. Results showed that professional and family support are key to a successful breastfeeding experience for these mothers. Recommendations include further individualised support in order to meet the needs of Polish women breastfeeding in Ireland. PMID- 26975132 TI - 4. Managing workload and prioritising care: top tips. AB - Preceptorship is the 15th series of 'Midwifery basics' targeted at practising midwives. The aim of these articles is to provide information to raise awareness of the impact of the work of midwives on women's experience, and encourage midwives to seek further information through a series of activities relating to the topic. In this fourth article of the series, Neesha Ridley and Kerry Taylor look into the barriers and challenges that present to all midwives, particularly in the prioritisation of care and management of workload. They provide top tips in order to help support newly qualified midwives manage their work well, thus providing safe, effective care to all women and newborns at all times. PMID- 26975133 TI - 'Oh no, no, no, we haven't got time to be doing that': challenges encountered introducing a breast-feeding support intervention on a postnatal ward. AB - Research unwrapped is a popular series to help readers make sense of published research by undertaking a detailed appraisal of an article in a careful and considered manner. In doing so we can advance our knowledge and understanding of a research topic and apply it to our practice. This process is designed to assess the usefulness of the evidence in terms of decision making and application to practice. The research being discussed here looks at the factors affecting the implementation of a breastfeeding support intervention, on a postnatal ward, which includes considerations of time, workload and clinical context. It has been evaluated using the Critical Appraisal Skills Programme (CASP) tool for evaluating qualitative research as a guide (CASP 2013). PMID- 26975134 TI - Whatever happened to the precautionary principle? AB - In this column, Sara Wickham takes a sideways look at issues relevant to midwives, students, women and families, inviting us to sit down with a cup of tea and ponder what we think we know. Here, she looks at one of the latest papers to join the trend of attempting to justify induction of labour in healthy women, raising questions about the language and stance used within the research and suggesting that women and midwives might gain from referring to the precautionary principle. PMID- 26975135 TI - DIRECT: creating a reflective model. PMID- 26975137 TI - The Activity of Cholinesterases in Diapausing and Flying Red Mason Bees Osmia bicornis (Megachilidae). AB - The red mason bee (Osmia bicornis) is a highly effective pollinator that is exposed to various xenobiotics. The organism's potential resistance to the toxic effects of xenobiotics can be determined based on cholinesterase activity. The activity of cholinesterases (ChEs) towards acetylcholine (ACh) and butyrylcholine (BCh) was determined in extracts of diapausing (between October and late March) and flying bees (May). In both males and females, enzyme activity was higher towards ACh than towards BCh. The ratio of ACh/BCh activity was determined in the range of 1.43 to 4.15 in diapausing females and 3.00 to 7.18 in diapausing males. No significant changes in ChE activity towards ACh were observed in females before December and in males before February. Enzyme activity towards ACh increased dynamically in the second half of March. Enzyme activity towards BCh remained stable in both sexes until mid-March, after which it increased significantly. Excluding mid-March, enzyme BCh activity was significantly higher in females than in males. The activity of carboxylesterase towards 4-p nitrophenyl butyrate was determined in females to assess the involvement of non specific esterases in the hydrolysis of choline esters. Carboxylesterase activity was low in comparison with cholinesterase activity, and it remained practically unchanged throughout diapause, suggesting that choline esters in female O. bicornis extracts were hydrolyzed mainly by acetylcholinesterases. PMID- 26975136 TI - Plasma-Glucocorticoids and ACTH Levels During Different Periods of Activity in the European Beaver (Castor fiber L.). AB - Glucocorticoids (GCs) and adrenocorticotropic hormone (ACTH) are major components of the classic endocrine stress response. Free-living vertebrates are characterized by circannual changes in the baseline and/or stress-induced secretion of GCs and ACTH. In mammalian species, GC and ACTH levels vary seasonally but there is no consensus to the season in which animals have elevated GC and ACTH levels. The aim of our study was to determine, for the first time, the type and amount of glucocorticoids produced in free-living beaver (Castor fiber L.)--the largest rodent in Eurasia, and to find out whether stress-induced plasma GC and ACTH levels show seasonal variations. Blood samples were obtained from animals under general anesthesia in April (pregnancy in females), July (offspring rearing) and November (preparing for the winter). The adrenals of beavers produce both cortisol and corticosterone, and plasma cortisol levels were higher than corticosterone. In the current experiment, plasma cortisol concentrations in beavers were affected by the season. The highest stress associated cortisol levels were noted in males in July during offspring rearing. Corticosterone and ACTH concentrations in beavers remained generally constant, regardless of the season and sex. In conclusion, seasonal changes were observed only in relation to stress-induced plasma cortisol levels in the beaver. PMID- 26975138 TI - Insulin-Like Growth Factor-I Increases Laminin, Integrin Subunits and Metalloprotease ADAM12 in Mouse Myoblasts. AB - The extracellular matrix (ECM) is considered a part of the myogenesis signaling mechanism. we hypothesized that insulin-like growth factor-I (IGF-I) modifies ECM during differentiation of mouse C2C12 cells. The myogenic effect of IGF-I (30 nmol/l) was manifested by increased myogenin and myosin heavy chain (MyHC) levels as well as fusion index (2.6 times over control) on the 3rd day of differentiation. IGF-I markedly augmented laminin, but not fibronectin. Cellular contents of integrin alpha3, alpha5 and beta1 during 3-day differentiation increased in the presence of IGF-I. Treatment with IGF-I increased the expression of the long form of metalloprotease ADAM12 (100 kDa) in myocytes. In conclusion: i) IGF-I caused an increase of laminin, integrin alpha3 and beta1 in C2C12 myogenic cells that can be secondary to stimulation of myogenesis; ii) IGF-I augmented integrin alpha5 and ADAM12 levels, suggesting a role of this growth factor in determination of the pool of reserve cells during myogenesis. PMID- 26975139 TI - Efficacy of Local Anesthetics in Detachment of Normal 3T3 Mouse Fibroblasts and Prostate Cancer AT-2 Cells from Substrata, in Maintenance of Viable Cells in a Non-Adherent State, and in Preservation of Cell Surface Markers Detected with FlowSight Image Cytometry. AB - The local anesthetics procaine, lidocaine and tetracaine permit the reversible detachment of viable cells and their passaging or preservation in a non-adherent state in the absence of proteolytic enzymes. The effects of these anesthetics, dissolved in various media, on cell viability, cell detachment from substrata and preservation of cells in a non-adherent state, were compared using the AT-2 line of rat prostate carcinoma cells of moderate malignancy and the 3T3 mouse fibroblast cell line. It was found that all three local anesthetics can induce cell rounding followed by detachment of over 95% of viable cells in both lines in Ca2+/Mg(2+)-free PBS. Tetracaine in 1 mM concentration was the most effective in induction of fast cell detachment. However, procaine and lidocaine in 16 mM concentrations were found to be optimal for preservation of cells in a non adherent state and for the maintenance of cell viability for at least 2 h. The tested anesthetics also cause cell rounding and detachment when present in various cell culture media but these processes occurred much more slowly and less efficiently than in Ca2+/Mg(2+)-free PBS. Normal 3T3 mouse fibroblasts after detachment and passaging undertake growth reaching the same saturation density in cultures after detachment with procaine or lidocaine as after passaging using trypsin solution. The results suggest that the application of local anesthetics can be a very simple and effective technique for cell passaging in tissue cultures. This technique might decrease side-effects and cell injury caused by trypsinization or cell scraping. The preservation of cells in suspension in a non adherent state may facilitate analysis of cell surface properties and fractionation of cell mixtures. Avoiding the use of trypsin allows for the preservation of cell surface proteins ICAM, CXCR4, and HCAM analyzed with FlowSight image flow cytometry. PMID- 26975140 TI - Taxonomic Position and Status of Arctic Gynaephora and Dicallomera Moths (Lepidoptera, Erebidae, Lymantriinae). AB - We use analysis of mitochondrial DNA barcodes in combination with published data on morphology to rearrange the taxonomy of two arctic species, Gynaephora groenlandica and G. rossii. We demonstrate that (1) the taxon lugens Kozhanchikov, 1948 originally described as a distinct species is a subspecies of Gynaephora rossii, and (2) the taxon kusnezovi Lukhtanov et Khruliova, 1989 originally described as a distinct species in the genus Dicallomera is a subspecies of Gynaephora groenlandica. We also provide the first evidence for the occurrence of G. groenlandica in the Palearctic region (Wrangel Island). PMID- 26975141 TI - Morphometric Parameters of Pyramidal Cells in CA1-CA4 Fields in the Hippocampus of Arctic Fox (Vulpes lagopus). AB - The aim of the study was a quantitative examination of neurons of hippocampal subfields (CA1-CA4) in mature male Arctic fox (Vulpes lagopus; syn. Alopex lagopus). The preparations were dyed using cresyl violet. Histological preparations were used to morphometricaly analyze the neurons of hippocampus. This analysis included the following parameters: average size of cells in MUm, periphery of cells in MUm, average cell area in MUm2, percentage of cells in area and size of the largest and smallest cells in MUm in CA1-CA4 fields. Morphometric observations show that the cells involved in hippocampal formation in polar fox in all layers CA1 -CA4 differ in size, shape, cell area and nucleus area. The size of the cell area in CA3 is the largest and fluctuates around 249.4 MUm2, whereas in CA2 the cell area is 184.1 MUm2. The cells of the CA2 field are densely arranged, pyramidal and contain a small amount of cytoplasm; their size fluctuates. Cells of CA2 and CA4 had the largest diameter of about 23.6 MUm, whereas cells of the CA3 field had the smallest diameter of about 8.3 MUm. PMID- 26975142 TI - Potential Alleviation of Chlorella vulgaris and Zingiber officinale on Lead Induced Testicular Toxicity: an Ultrastructural Study. AB - Natural, products were studied to combat reproductive alterations of lead. The current work aimed to disclose the efficacy of Chlorella vulgaris and Zingiber officinale to alleviate lead acetate induced toxicity. Sixty adult male Wistar rats were distributed into four groups. Group 1 was considered control, group 2 received 200 mg/l PbAc water, group 3 received 50 mg/kg/rat of C. vulgaris extract and 200 mg/l PbAc water, and group 4 received 100 mg/kg/rat of Z. officinale and 200 mg/l PbAc water for 90 days. Testis samples were subjected to ultrastructural examination. It was observed that PbAc caused degenerative alterations in the spermatogenic series in many tubules, with a loss of germ cells and vacuoles inside the cytoplasm and between the germ cells. Mitochondria exhibited ballooning, with lost cristae and widening of the interstitial tissue, while nuclear envelopes of primary spermatocytes were broken up, and axonemes of the mid-pieces of the sperms were distorted. With the treatment with C. vulgaris or Z. officinale, there were noticeable improvements in these modifications. It was concluded that both C. vulgaris and Z. officinale represent convincing medicinal components that may be used to ameliorate testicular toxicity in those exposed to lead in daily life with superior potentials revealed by C. vulgaris due to its chelating action. PMID- 26975143 TI - Influence of Selected Extenders for Liquid Storage at 4 degrees C of Breeding Chinchilla (Chinchilla lanigera) Semen on Sperm DNA Integrity. AB - The influence of two commercial and two laboratory oriented extenders on survival rate and DNA integrity of chinchilla (Chinchilla lanigera) sperm was determined during liquid storage. Semen was collected using an electroejaculator from 6 adult male chinchillas. Ejaculates (n = 16) were diluted with extenders to obtain a concentration of 40 x 10 (3) sperm/5 MUl. After dilution the semen samples were stored at 4"C. The percent motility, progressive motility, and morphology were assessed conventionally, whereas DNA integrity was evaluated by Single Cell Gel Electrophoresis (comet) assay at 0 (just after dilution), 24, 48 and 72 h. Conventional assessment of sperm quality showed that commercial extenders are characterized by the lowest sperm survival parameters out of the investigated extenders. In commercial extenders spermatozoa lost their capacity for progressive motility compared to laboratory extenders. After 24 h storage, from 21.67% to 30% of motile sperms were observed in commercial extender whereas total sperm motility was 63.33% (41.67% with progressive motility) in samples in which stallion semen extender was used. After 72 h storage, 10% of sperm were motile in stallion semen extender while no sperm movement was observed in tubes containing the commercial extender. Furthermore, a lower percentage of damaged spermatozoa in laboratory oriented extenders was demonstrated. It was also stated that along with the extended time of semen storage at 4 degrees C, commercial extenders lost their protective action. An analysis of DNA content in the heads of sperm cells and tail moment (TM) showed that the most useful extender for liquid preservation of chinchilla semen was the extender for stallions. PMID- 26975144 TI - New Stands of Species of the Paramecium aurelia Complex in Yakutia, Russia. AB - Paramecium is one of the most studied genera among ciliates. In particular, it is a model organism for investigation of the sibling species problem (also known as the cryptic species problem), spatial distribution, and its role in speciation. The global distribution of Paramecium species and of sibling species belonging to the P. aurelia species complex (Ciliophora, Protista) still need study, e.g. sampling in some territories has been quite limited, while Europe has been investigated for years with the majority of the P. aurelia species isolated from here. The large territory of Yakutia (republic Sakha in the Russian Federation), known for its climate extremes and continuous permafrost that extended over several glacial and interglacial cycles of the Pleistocene, has not been studied before. In the present study we collected paramecia in the central part of Yakutia. Newly established strains were identified to species according to morphology and, in case of the P. aurelia complex, by crossing with the test strains (the reference strains for the particular species). New stands of P. primaurelia, P. biaurelia and P. novaurelia were described from the territory of Yakutia. PMID- 26975145 TI - Taxonomic Position and Status of Polyommatus (Agrodiaetus) iphigenia (Lepidoptera, Lycaenidae) from the Peloponnese, Southern Greece. AB - In our study we use a 690 bp fragment of the COI gene to analyze a taxon from southern Greece, usually treated as Polyommatus (Agrodiaetus) iphigenia nonacriensis (Brown, 1977). The previous conclusions on taxonomy and nomenclature of P. (A.) iphigenia nonacriensis were not supported by molecular or cytological data, therefore the problem of identity of this taxon has remained unsolved. We found that with respect to COI haplotypes, P. (A.) iphigenia nonacriensis from Greece is similar to the studied populations of P. (A.) iphigenia (Herrich Schaffer, 1847) from Turkey and Armenia. Thus, we confirm that the only Greek Agrodiaetus butterfly with blue wing coloration in males actually belongs to the species P. (A.) iphigenia. PMID- 26975146 TI - Magnesium Effects on Nonsynaptic Epileptiform Activity in Leech Retzius Neurons. AB - The effects of Mg2+ on Ni(2+)-induced epileptiform bursting activity and input membrane resistance during this activity of leech Retzius neurons were examined using intracellular recordings. To induce epileptiform activity, 3 mmol/l NiCl2 was added into superfusing Ringer (Ri) saline. To test for dose-dependence of the effects of Mg2+ on the induced epileptiform activity, MgCl2 was added in concentrations from 1 mmol/l to 20 mmol/l Mg2+ to the Ni(2+)-containing Ri saline. Input membrane resistance (IMR) was measured in standard Ri, Ni2+ Ri and 20 mmol/l Mg2+Ni2+ Ri saline. Superfusion with Ni2+ Ri induced epileptiform bursting activity characterized by generation of paroxysmal depolarization shifts (PDSs). Parameters of epileptiform activity including PDS frequency, PDS duration, PDS amplitude and the number of spikes/PDS were measured. Magnesium suppressed Ni(2+)-induced epileptiform activity, significantly reducing values of all parameters observed in a concentration-dependent manner. The highest concentration applied of 20 mmol/l Mg2+ completely eliminated epileptiform activity. To test for the effect of Mg2+ on membrane conductance during bursting, IMR was measured. Magnesium significantly increased IMR during bursting suppression. PMID- 26975147 TI - Optimal staffing. New resource aims to help RNs implement evidence-based staffing plans. PMID- 26975148 TI - A matter of life or death. Offering competencies to address suicide prevention, management. PMID- 26975149 TI - Stay healthy. Get vaccinated against the flu. PMID- 26975150 TI - Nurses unite with pride (and stethoscopes). PMID- 26975151 TI - Take the pledge to engage in infection prevention. PMID- 26975153 TI - Lead exposure impacts children's sleep. PMID- 26975152 TI - A cultural experience. Committed to ensuring healthy outcomes for Native American, Indigenous youth. PMID- 26975154 TI - World AIDS Day: On the road to zero. PMID- 26975155 TI - Primary care-focused effort to reduce HIV infections. PMID- 26975156 TI - ANA partners to address a challenging public health problem. PMID- 26975158 TI - The Reason Why. PMID- 26975157 TI - Sharing her passion for nursing, education. PMID- 26975159 TI - Stopping HIV One Patient at a Time: The Continuum of Care Model. PMID- 26975160 TI - Taking a Sexual History and Creating Affirming Environments for Lesbian, Gay, Bisexual, and Transgender People. AB - MISSISSIPPI RANKS AMONG THE TOP STATES IN THE COUNTRY FOR RATES OF HIV AND STDs. Among those at highest risk are gay and bisexual men and transgender women; yet these groups often delay or avoid care because they fear being misunderstood or stigmatized. This article focuses on how providers in Mississippi can minimize these barriers by taking sexual histories that are inclusive and affirming of all sexual orientations and gender identities. The article also offers strategies for improving the environment of care within health care organizations in order to create welcoming and safe spaces for lesbian, gay, bisexual, and transgender people. PMID- 26975161 TI - Vital Signs: Estimated Percentages and Numbers of Adults with Indications for Preexposure Prophylaxis to Prevent HIV Acquisition--United States, 2015. AB - BACKGROUND: In 2014, approximately 40,000 persons in the United States received a diagnosis of human immunodeficiency virus (HIV) infection. Preexposure prophylaxis (PrEP) with daily oral antiretroviral medication is a new, highly effective intervention that could reduce the number of new HIV infections. METHODS: CDC analyzed nationally representative data to estimate the percentages and numbers of persons in the United States, by transmission risk group, with indications for PrEP consistent with the 2014 U.S. Public Health Service's PrEP clinical practice guideline. RESULTS: Approximately 24.7% of sexually active adult men who have sex with men (MSM) (492,000 [95% confidence interval {CI} = 212,000-772,000]), 18.5% of persons who inject drugs (115,000 [CI = 45,000 185,000]), and 0.4% of heterosexually active adults (624,000 [CI = 404,000 846,000]), had substantial risks for acquiring HIV consistent with PrEP indications. CONCLUSIONS: Based on current guidelines, many MSM, persons who inject drugs, and heterosexually active adults have indications for PrEP. A higher percentage of MSM and persons who inject drugs have indications for PrEP than heterosexually active adults, consistent with distribution of new HIV diagnoses across these populations. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Clinical organizations, health departments, and community-based organizations should raise awareness of PrEP among persons with substantial risk for acquiring HIV infection and their health care providers. These data can be used to inform scale-up and evaluation of PrEP coverage. Increasing delivery of PrEP and other highly effective HIV prevention services could lower the number of new HIV infections occurring in the United States each year. PMID- 26975162 TI - Sexually Transmitted Diseases: Summary of 2015 CDC Treatment Guidelines. PMID- 26975163 TI - State of the ART: Characteristics of HIV infected patients receiving care in Mississippi (MS), USA from the Medical Monitoring Project, 2009-2010. AB - BACKGROUND: Mississippi, the poorest state in the US, has a very high prevalence of HIV and among the highest HIV infection rates and AIDS-adjusted mortality rates in the country. African Americans, who suffer the worst health care disparities in the US, account for 76% of people with HIV in MS. The purpose of this study is to describe those in care for HIV and determine the factors associated with anti-retroviral treatment (ART) and viral suppression. METHODS: The CDC's Medical Monitoring Project collects surveillance data from 23 project areas in the US, including Mississippi, using annual probability sampling of persons in care for HIV. Data were collected from in-person interviews and medical record abstraction in 2009. The surveillance period was the 12 months prior to the interview date. RESULTS: 212 randomly selected participants represented a nationally representative weighted sample of 3190.4. Participants had a mean of 3.71 provider visits during the surveillance period. Geometric mean for CD4 count = 438.91 (95% CI 402.25-475.56). Overall 80.80% (95% CI 75.30%- 86.29%) were on ART, and 68.12% (95% CI 62.69%-73-56%) had undetectable viral load. Males (65.15%) were less likely to achieve undetectable viral load compared to females (78.30%) after controlling for individuals who were on ART (p = 0.01). Viral suppression was not associated with age, race or sexual risk factors. CONCLUSIONS: Although Mississippi has a high proportion of individuals out of HIV care, the majority in care is on ART and has suppressed viral loads. However, men are less likely to achieve virological suppression than females. PMID- 26975164 TI - MISSISSIPPI HeARTS AGAINST AIDS. PMID- 26975165 TI - Sharon McDonald, MD. PMID- 26975166 TI - Daily Pill Can Prevent HIV. Reaching people who could benefit from PrEP. PMID- 26975167 TI - [Angiotensin-receptor- and neprilysin-inhibition: a new option against heart failure]. AB - The molecular combination of sacubitril and valsartan (Entresto) is a new drug for reducing the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It is usually administered in conjunction with other heart failure therapies, instead of an ACE inhibitor or an angiotensin-receptor blocker (ARB). In studies, sacubitril/ valsartan was superior to enalapril in reducing the risks of death and hospitalization for heart failure. Possible side effects of sacubitril/valsartan are hypotension, angioedema, impaired renal function and elevation in serum potassium levels. The drug should not be used in times of pregnancy and breast feeding, in patients with servere hepatic impairment (Child Pugh C) and in combination with aliskiren in patients with diabetes. PMID- 26975168 TI - [Epidemiology, etiology and pathophysiology of heart failure]. PMID- 26975169 TI - [Diagnostic methods and differential diagnosis of heart failure]. PMID- 26975170 TI - [Evidence-based and guideline-based treatment of heart failure]. PMID- 26975171 TI - [The heart failure patient with acute dyspnea and weight gain]. PMID- 26975172 TI - [Risk reduction by pharmaceutical intervention. Medication management using the example of salbutamol]. PMID- 26975173 TI - [The patient is a measure of the treatment]. PMID- 26975174 TI - [Simvastatin and vitamin D3 for prevention]. PMID- 26975176 TI - [Many challenges - a common task]. PMID- 26975175 TI - [Can proton pump inhibitors prevent gastrointestinal bleeding?]. PMID- 26975178 TI - [Insulin resistance affects neuronal degeneration]. PMID- 26975177 TI - [Acetylsalicylic acid-renaissance with venous thrombosis? ]. PMID- 26975179 TI - [Treatment of cancer-related bone pain]. PMID- 26975180 TI - [Combined administration of lumacaftor and ivacaftor as a causal therapeutic approach]. PMID- 26975181 TI - [Beautiful Scars - is that possible?]. PMID- 26975182 TI - Metal-free intermolecular formal cycloadditions enable an orthogonal access to nitrogen heterocycles. AB - Nitrogen-containing heteroaromatic cores are ubiquitous building blocks in organic chemistry. Herein, we present a family of metal-free intermolecular formal cycloaddition reactions that enable highly selective and orthogonal access to isoquinolines and pyrimidines at will. Applications of the products are complemented by a density functional theory mechanistic analysis that pinpoints the crucial factors responsible for the selectivity observed, including stoichiometry and the nature of the heteroalkyne. PMID- 26975184 TI - Proteolytic degradation and deactivation of amphibian skin peptides obtained by electrical stimulation of their dorsal glands. AB - Amphibians are among the oldest creatures on our planet. Their only defensive weapon efficient against microorganisms and predators involves their skin secretion. The wide range of biological activities of the peptides in the skin secretion of amphibians makes these compounds rather interesting for generation of prospective pharmaceuticals. The first step in studying these molecules requires their structures to be established. Mass spectrometry is the most powerful tool for this purpose. The sampling and sample preparation stages preceding mass spectrometry experiments appear to be rather crucial. The results obtained here demonstrate that these preparation procedures might lead to partial or complete loss of the bioactive peptides in the secretion. Five minutes in water was enough to completely destroy all of the bioactive peptides in the skin secretion of the marsh frog (Rana ridibunda); even immediate addition of methanol to the water solution of the peptides did not prevent partial destruction. Concerted effort should be directed towards development of the most efficient procedure to keep the secreted peptides intact. Graphical Abstract ?. PMID- 26975183 TI - Abnormal movements in critical care patients with brain injury: a diagnostic approach. AB - Abnormal movements are frequently encountered in patients with brain injury hospitalized in intensive care units (ICUs), yet characterization of these movements and their underlying pathophysiology is difficult due to the comatose or uncooperative state of the patient. In addition, the available diagnostic approaches are largely derived from outpatients with neurodegenerative or developmental disorders frequently encountered in the outpatient setting, thereby limiting the applicability to inpatients with acute brain injuries. Thus, we reviewed the available literature regarding abnormal movements encountered in acutely ill patients with brain injuries. We classified the brain injury into the following categories: anoxic, vascular, infectious, inflammatory, traumatic, toxic-metabolic, tumor-related and seizures. Then, we identified the abnormal movements seen in each category as well as their epidemiologic, semiologic and clinicopathologic correlates. We propose a practical paradigm that can be applied at the bedside for diagnosing abnormal movements in the ICU. This model seeks to classify observed abnormal movements in light of various patient-specific factors. It begins with classifying the patient's level of consciousness. Then, it integrates the frequency and type of each movement with the availability of ancillary diagnostic tests and the specific etiology of brain injury. PMID- 26975186 TI - Management of Pediatric Acute Liver Failure in a Region With Insufficient Deceased Donor Support: A Single-Center Experience. AB - OBJECTIVES: Acute liver failure is a rapidly progressive and life-threatening disease in children, whose clinical features differ from those of adults. MATERIALS AND METHODS: This is a review of a single center's experience with pediatric acute liver failure in a region with insufficient deceased donor support. The study is a retrospective review and analysis of 22 pediatric patients with acute liver failure between January 2007 and May 2013. RESULTS: The cause of acute liver failure was indeterminate in 45.4% of cases. Listing for liver transplant was required in 72.7% of patients, whereas 27.3% developed spontaneous remission. In the patients placed on the liver transplant wait list, 75% underwent liver transplant and 25% died before undergoing liver transplant. The presence of ascites, high-grade encephalopathy, and laboratory findings including high lactate dehydrogenase and phosphorous levels and international normalized ratio were significant parameters in selecting patients needing liver transplants. All liver transplants were from living donors. One- and 3-year patient survival rates after liver transplant were 75% and 75%. No serious donor complications occurred. CONCLUSIONS: Living-donor liver transplant may be the only option to save the lives of pediatric patients with acute liver failure, especially in regions with insufficient deceased-donor support. Timely referral to a multidisciplinary transplant center, expedient evaluation of living donors, and appropriate timing of transplant are crucial for a successful outcome. PMID- 26975185 TI - Influenza-like illness in an urban community of Salvador, Brazil: incidence, seasonality and risk factors. AB - BACKGROUND: Our understanding of the epidemiology of influenza is limited in tropical regions, which in turn has hampered identifying optimal region-specific policy to diminish disease burden. Influenza-like illness (ILI) is a clinical diagnosis that can be used as a surrogate for influenza. This study aimed to define the incidence and seasonality of ILI and to assess its association with climatic variables and school calendar in an urban community in the tropical region of Salvador, Brazil. METHODS: Between 2009 and 2013, we conducted enhanced community-based surveillance for acute febrile illnesses (AFI) among patients >= 5 years of age in a slum community emergency unit in Salvador, Brazil. ILI was defined as a measured temperature of >= 37.8 degrees C or reported fever in a patient with cough or sore throat for <= 7 days, and negative test results for dengue and leptospirosis. Seasonality was analyzed with a harmonic regression model. Negative binomial regression models were used to correlate ILI incidence with rainfall, temperature, relative humidity and the number of days per month that schools were in session while controlling for seasonality. RESULTS: There were 2,651 (45.6% of 5,817 AFI patients) ILI cases with a mean annual incidence of 60 cases/1,000 population (95% CI 58-62). Risk of ILI was highest among 5-9 year olds with an annual incidence of 105 cases/1,000 population in 2009. ILI had a clear seasonal pattern with peaks between the 35-40th week of the year. ILI peaks were higher and earlier in 5-9 year olds compared with > 19 year olds. No association was seen between ILI and precipitation, relative humidity or temperature. There was a significant association between the incidence of ILI in children 5-9 years of age and number of scheduled school days per month. CONCLUSIONS: We identified a significant burden of ILI with distinct seasonality in the Brazilian tropics and highest rates among young school-age children. Seasonal peaks of ILI in children 5-9 years of age were positively associated with the number of school days, indicating that children may play a role in the timing of seasonal influenza transmission. PMID- 26975188 TI - Effect of ALDH1 on prognosis and chemoresistance by breast cancer subtype. AB - Aldehyde dehydrogenase 1 (ALDH1) has been identified as a breast cancer stem cell marker, but its value as a predictor of prognosis and chemoresistance is controversial. This study investigated the effect of ALDH1 on prognosis and chemoresponse by breast cancer subtype. We immunohistochemically analyzed 653 invasive breast cancer specimens and evaluated correlations among clinicopathological factors, survival status, response to neoadjuvant chemotherapy, and ALDH1 expression. Of 653 specimens, 139 (21.3 %) expressed ALDH1 in tumor cells. ALDH1 expression was correlated significantly with larger tumor size, node metastasis, higher nuclear grade, and with HER2(+) and progesterone/estrogen receptor (HR)(-) subtypes. ALDH1 expression was significantly observed in HER2 type and triple-negative breast cancer (TNBC). Patients with ALDH1(+) cancers had significantly shorter disease-free survival (P < 0001) and overall survival (P = 0.044). ALDH1 expression significantly affected prognosis of luminal types, but not TNBC and HER2-enriched types. For the 234 patients treated with neoadjuvant chemotherapy, pathological complete response (pCR) rate was significantly lower in ALDH1(+) cases (13.5 vs. 30.3 %, P = 0.003). pCR and ALDH1 expression were significantly correlated in TNBC patients (P = 0.003). ALDH1(+) breast cancers tended to be aggressive, with poor prognoses. Although ALDH1(+) TNBC showed higher chemoresistance, ALDH1 had significant impact on prognosis in the luminal type but not in TNBC. PMID- 26975189 TI - A phase I/II trial of the safety and clinical activity of a HER2-protein based immunotherapeutic for treating women with HER2-positive metastatic breast cancer. AB - The objectives of this phase I/II study (NCT00140738) were to evaluate the safety and clinical activity of a cancer immunotherapeutic agent (recombinant HER2 protein (dHER2) and the immunostimulant AS15) in patients with HER2 overexpressing metastatic breast cancer (MBC). Forty HER2-positive MBC patients received up to 18 doses (12q2w, 6q3w) of dHER2 immunotherapeutic, as first- or second-line therapy following response to trastuzumab-based treatment as maintenance. Toxicity was graded by the Common Terminology Criteria for Adverse Events (CTCAE) and clinical activity was evaluated by target lesion assessment according to the Response Evaluation Criteria in Solid Tumors (RECIST). Immunogenicity was assessed. The dHER2 immunotherapeutic was well tolerated: grade 1/2 adverse events (AEs) were most common. No cardiac events were observed and one patient experienced an asymptomatic decrease of left ventricular ejection fraction below the normal range (47 %). Both humoral and cellular immunogenicity to the dHER2 antigen was observed. No patient discontinued the immunizations because of AEs but 35/40 withdrew prematurely, 34 because of disease progression (24/34 before or at the tumor assessment after dose 6). One patient achieved a complete response lasting 11 months and one patient had a partial response lasting 3.5 months. Ten patients experienced stable disease >=26 weeks with 4/10 still in stable disease at the last tumor assessment after 47 weeks. Immunization of MBC patients with the dHER2 immunotherapeutic was associated with minimal toxicity and no cardiac events. Clinical activity was observed with two objective responses and prolonged stable disease for 10/40 patients. PMID- 26975191 TI - How are Sensory Features associated with seven anxiety disorders in boys with Autism Spectrum Disorder? AB - The association between Sensory Features (SF) and seven anxiety disorders was investigated using self-reports and parental reports about 140 young males with an Autism Spectrum Disorder (ASD). Although there were significant correlations between SF and self- and parent-ratings of some of the seven anxiety disorders, overall, SF was found to have an inconsistent association across the seven anxiety disorders and this was also found for the 8 symptoms of Generalised Anxiety Disorder. These data challenge the practice of assessing SF and anxiety via global measures and argue for individualized disorder-specific assessments to develop more effective diagnoses and treatments for the effects of SF. PMID- 26975187 TI - Task shifting of frontline community health workers for cardiovascular risk reduction: design and rationale of a cluster randomised controlled trial (DISHA study) in India. AB - BACKGROUND: Effective task-shifting interventions targeted at reducing the global cardiovascular disease (CVD) epidemic in low and middle-income countries (LMICs) are urgently needed. METHODS: DISHA is a cluster randomised controlled trial conducted across 10 sites (5 in phase 1 and 5 in phase 2) in India in 120 clusters. At each site, 12 clusters were randomly selected from a district. A cluster is defined as a small village with 250-300 households and well defined geographical boundaries. They were then randomly allocated to intervention and control clusters in a 1:1 allocation sequence. If any of the intervention and control clusters were <10 km apart, one was dropped and replaced with another randomly selected cluster from the same district. The study included a representative baseline cross-sectional survey, development of a structured intervention model, delivery of intervention for a minimum period of 18 months by trained frontline health workers (mainly Anganwadi workers and ASHA workers) and a post intervention survey in a representative sample. The study staff had no information on intervention allocation until the completion of the baseline survey. In order to ensure comparability of data across sites, the DISHA study follows a common protocol and manual of operation with standardized measurement techniques. DISCUSSION: Our study is the largest community based cluster randomised trial in low and middle-income country settings designed to test the effectiveness of 'task shifting' interventions involving frontline health workers for cardiovascular risk reduction. TRIAL REGISTRATION: CTRI/2013/10/004049 . Registered 7 October 2013. PMID- 26975190 TI - [Regulatory T-cells in systemic lupus erythematosus. IL-2 is decisive for loss of tolerance]. AB - Systemic lupus erythematosus (SLE) results from loss of immunological tolerance. Regulatory T-cells (Treg) are major gatekeepers of peripheral tolerance by suppression of autoreactive lymphocytes. Defects in Treg function are therefore possible pathogenetic mechanisms of SLE. Despite this fact published work about numbers and functions of Tregs in SLE are contradictory and the definitive role of Treg in SLE remains unclear. In this review we summarize the current literature about Treg subtypes and the phenotypic markers in human SLE. We also discuss data from mouse models and ex vivo experiments, which provide indications for possible mechanisms that contribute to loss of tolerance. We also discuss the role of interleukin 2 (IL-2), which is decisive for the function of Treg and has been used therapeutically in preliminary trials in human SLE. The identification of novel Treg markers and the development of novel therapeutic approaches, which restore the balance between Treg and autoreactive T-cells are future goals for research in SLE. PMID- 26975192 TI - Cyclosporine A induced histological changes of Cathepsin L and CD2AP expression in renal glomeruli and tubules. AB - BACKGROUND: Cyclosporine A (CsA) is used globally as an immunosuppressant for the treatment of immune-mediated nephrotic syndrome (NS). However, its long-term use causes nephrotoxicity characterized by tubulointerstitial injury and glomerulosclerosis. The present study aimed to investigate the associations between histomorphological findings and immunohistological expression of Cathepsin L (CatL) and CD2-associated protein (CD2AP) in patients with NS mediated with CsA. METHODS: A total of 18 patients with child-onset NS were divided into two groups after treatment with CsA for 2 years (group A; n = 10) and more than 4 years (group B; n = 8), respectively. Analyses of relationships between tubulointerstitial disorders and expression of CatL and CD2AP proteins were performed using immunohistochemistry of paired renal specimens. RESULTS: Glomeruli with arteriole hyalinization were significantly increased in both groups depending on dosage periods, although degrees of tubule and interstitial injury did not differ between groups. CD2AP expression was significantly greater in podocytes (P = 0.046) and was significantly less in proximal tubule cells (P = 0.014) in patients of group B compared with those of group A. Moreover, CD2AP expression was significantly increased in lateral tubule cells in both groups (group A, P = 0.02; group B, P = 0.001), and CatL expression in glomeruli and tubule cells did not change with the duration of CsA treatment in either patient group. CONCLUSIONS: CD2AP expression in renal tubules may histologically associate with tissue hypoxia and reflected recovery from CsA-mediated renal injury in patients, even with mild histological features of tubulointerstitial disorder. PMID- 26975193 TI - Responsiveness and Minimal Important Change of the Pain Self-Efficacy Questionnaire and Short Forms in Patients With Chronic Low Back Pain. AB - The Pain Self-Efficacy Questionnaire (PSEQ) is a valid and reliable patient reported instrument used to assess pain self-efficacy in patients with chronic low back pain (CLBP). Recently, the 2-item (PSEQ-2) and the 4-item (PSEQ-4) short versions were developed showing satisfactory measurement properties in mixed populations with chronic pain. The aim of this study was to examine responsiveness and minimal important change (MIC) of PSEQ, PSEQ-2, and PSEQ-4 in patients with CLBP. We used a sample of 104 patients undergoing multimodal physical therapy designed to partly change pain self-efficacy beliefs. Responsiveness was assessed by testing 16 a priori formulated hypotheses regarding effect sizes, areas under the curve, and correlations with changes in other instruments measuring other constructs. The MIC was calculated using an external anchor specific for pain self-efficacy and the receiver operator characteristic (ROC) method. The PSEQ and the PSEQ-4 met all hypotheses, whereas the PSEQ-2 met all but 1. The MICs were 5.5 for the PSEQ (9% of the scale range) and 1.5 for PSEQ-2 (13% scale range) and PSEQ-4 (6% scale range). MIC values were different for patients with low or high baseline values for all 3 instruments. The PSEQ and its short versions are adequately responsive instruments in patients with CLBP. PERSPECTIVE: This study suggests that the PSEQ and its short versions are responsive measures of pain self-efficacy in patients with CLBP, adding to previous literature on their validity and reliability. Considering their similar responsiveness, the 4-item PSEQ could replace the original 10-item version in busy clinical or research settings. PMID- 26975194 TI - Serotonin and the Brain's Rich Club-Association Between Molecular Genetic Variation on the TPH2 Gene and the Structural Connectome. AB - The rich club comprises a densely mutually connected set of hub regions in the brain, thought to serve as a processing and integration core. We assessed the impact of normal variation of the tryptophane hydroxylase 2 gene's promotor region (TPH2 rs4570625) on structural connectivity of the rich club pathways by means of a candidate gene association design. Tryptophane hydroxylase 2 (TPH2) is a rate-limiting enzyme in the biosynthesis of serotonin and is known to inhibit, in addition to its role as a trans-synaptic messenger, axonal and dendritic growth. The TPH2 T-variant has been associated with reduced mRNA expression and reduced serotonin levels, which may particularly influence the development of macroscale anatomical connectivity. Here, we show larger mean connectivity in the rich club in carriers of the T-variant, suggesting potential effects of upregulation of neural connectivity growth in this central core system. In addition, by edge-removal statistics, we show that the TPH2-associated higher levels of rich club connectivity are of importance for the functioning of the total structural network. The observed association is speculated to result from an effect of serotonin levels on brain development, potentially leading to stronger structural connectivity in heavily interconnected hubs. PMID- 26975197 TI - Hexaminolevulinate hydrochloride blue-light flexible cystoscopy in the detection and follow-up of nonmuscle-invasive bladder cancer: cost consequences during outpatient surveillance in Sweden. AB - AIM: This study explored the cost consequences of introducing hexaminolevulinate hydrochloride-guided blue-light flexible cystoscopy (HAL BLFC) as an adjunct to white-light flexible cystoscopy compared with white-light flexible cystoscopy alone, for the detection and management of nonmuscle invasive bladder cancer in Sweden. METHODS: The model evaluated 231 patients in the outpatient setting after successful initial transurethral resection of the bladder tumor. RESULTS: HAL BLFC introduction across all risk groups resulted in minimal budget impact (+1.6% total cost/5 years, or 189 Swedish Krona [SEK] per patient/year), and translated to cost savings in intermediate- and high-risk groups from year 2. CONCLUSION: HAL BLFC allowed more outpatient treatment with improved recurrence detection and reduced transurethral resection of the bladder tumors, cystectomies, bed days and operating room time, with minimal cost impact across all risk groups, demonstrating the economic benefits of introducing HAL. PMID- 26975196 TI - Sequencing and comparative analyses of the genomes of zoysiagrasses. AB - Zoysiais a warm-season turfgrass, which comprises 11 allotetraploid species (2n= 4x= 40), each possessing different morphological and physiological traits. To characterize the genetic systems of Zoysia plants and to analyse their structural and functional differences in individual species and accessions, we sequenced the genomes of Zoysia species using HiSeq and MiSeq platforms. As a reference sequence of Zoysia species, we generated a high-quality draft sequence of the genome of Z. japonica accession 'Nagirizaki' (334 Mb) in which 59,271 protein coding genes were predicted. In parallel, draft genome sequences of Z. matrella 'Wakaba' and Z. pacifica 'Zanpa' were also generated for comparative analyses. To investigate the genetic diversity among the Zoysia species, genome sequence reads of three additional accessions, Z. japonica'Kyoto', Z. japonica'Miyagi' and Z. matrella'Chiba Fair Green', were accumulated, and aligned against the reference genome of 'Nagirizaki' along with those from 'Wakaba' and 'Zanpa'. As a result, we detected 7,424,163 single-nucleotide polymorphisms and 852,488 short indels among these species. The information obtained in this study will be valuable for basic studies on zoysiagrass evolution and genetics as well as for the breeding of zoysiagrasses, and is made available in the 'Zoysia Genome Database' at http://zoysia.kazusa.or.jp. PMID- 26975195 TI - Bacterial glycobiology: rhamnose-containing cell wall polysaccharides in Gram positive bacteria. AB - The composition of the Gram-positive cell wall is typically described as containing peptidoglycan, proteins and essential secondary cell wall structures called teichoic acids, which comprise approximately half of the cell wall mass. The cell walls of many species within the genera Streptococcus, Enterococcus and Lactococcus contain large amounts of the sugar rhamnose, which is incorporated in cell wall-anchored polysaccharides (CWP) that possibly function as homologues of well-studied wall teichoic acids (WTA). The presence and chemical structure of many rhamnose-containing cell wall polysaccharides (RhaCWP) has sometimes been known for decades. In contrast to WTA, insight into the biosynthesis and functional role of RhaCWP has been lacking. Recent studies in human streptococcal and enterococcal pathogens have highlighted critical roles for these complex polysaccharides in bacterial cell wall architecture and pathogenesis. In this review, we provide an overview of the RhaCWP with regards to their biosynthesis, genetics and biological function in species most relevant to human health. We also briefly discuss how increased knowledge in this field can provide interesting leads for new therapeutic compounds and improve biotechnological applications. PMID- 26975199 TI - The struggle for inter-professional teamwork and collaboration in maternity care: Austrian health professionals' perspectives on the implementation of the Baby Friendly Hospital Initiative. AB - BACKGROUND: The health benefits of breastfeeding for mothers and babies are well documented in the scientific literature. Research suggests that support of breastfeeding during pre- and postnatal maternity care is an important determinant of breastfeeding initiation and duration. To support and promote breastfeeding on maternity units, the Baby-Friendly Hospital Initiative (BFHI) was launched in 1991. In Austria, however, less than one fifth of hospitals with a maternity unit are currently BFHI-certified. Implementation of BFHI and adjunct changes in work practices seem to represent a major challenge to maternity units. This article builds upon previous research that has identified a number of facilitators of and barriers to BFHI implementation in Austria. A major barrier has been the lack of intra- and inter-professional collaboration. Therefore, this article investigates the ways in which different healthcare professionals struggle to work together to successfully integrate the BFHI into practice. METHODS: In this study, a qualitative research approach was used. Thirty-six semi structured interviews with 11 midwives, 11 nurses, 13 physicians, and one quality manager, working across three maternity units, were interviewed on-site. Data analysis followed thematic analysis. RESULTS: Midwives, nurses, and physicians had diverse approaches to childbirth and breastfeeding (medicalization vs. naturalness) and worked along different jurisdictions that became manifest in strict spatial divisions of maternity units. In their engagement within the BFHI, midwives, nurses, and physicians pursued different strategies (safeguarding vs. circumvention strategies). These differences hindered inter-professional teamwork and collaboration and, therefore, the integration of BFHI into practice. CONCLUSIONS: Differing approaches to childbirth and breastfeeding, deep seated professional jurisdictions, as well as spatial constraints, challenge inter professional teamwork and collaboration on maternity units. Inter-professional teamwork and collaboration are widely espoused goals of contemporary healthcare improvement strategies. Yet, critical debate on how these goals can be integrated into practice is needed. To enable collaboration and facilitate the implementation of programs such as BFHI, the different perspectives of health professionals should be brought together and the potential for integrating different forms of knowledge and practices should be considered. PMID- 26975198 TI - Comprehensive transcriptome analysis identifies novel molecular subtypes and subtype-specific RNAs of triple-negative breast cancer. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is a highly heterogeneous group of cancers, and molecular subtyping is necessary to better identify molecular based therapies. While some classifiers have been established, no one has integrated the expression profiles of long noncoding RNAs (lncRNAs) into such subtyping criterions. Considering the emerging important role of lncRNAs in cellular processes, a novel classification integrating transcriptome profiles of both messenger RNA (mRNA) and lncRNA would help us better understand the heterogeneity of TNBC. METHODS: Using human transcriptome microarrays, we analyzed the transcriptome profiles of 165 TNBC samples. We used k-means clustering and empirical cumulative distribution function to determine optimal number of TNBC subtypes. Gene Ontology (GO) and pathway analyses were applied to determine the main function of the subtype-specific genes and pathways. We conducted co-expression network analyses to identify interactions between mRNAs and lncRNAs. RESULTS: All of the 165 TNBC tumors were classified into four distinct clusters, including an immunomodulatory subtype (IM), a luminal androgen receptor subtype (LAR), a mesenchymal-like subtype (MES) and a basal-like and immune suppressed (BLIS) subtype. The IM subtype had high expressions of immune cell signaling and cytokine signaling genes. The LAR subtype was characterized by androgen receptor signaling. The MES subtype was enriched with growth factor signaling pathways. The BLIS subtype was characterized by down-regulation of immune response genes, activation of cell cycle, and DNA repair. Patients in this subtype experienced worse recurrence-free survival than others (log rank test, P = 0.045). Subtype-specific lncRNAs were identified, and their possible biological functions were predicted using co-expression network analyses. CONCLUSIONS: We developed a novel TNBC classification system integrating the expression profiles of both mRNAs and lncRNAs and determined subtype-specific lncRNAs that are potential biomarkers and targets. If further validated in a larger population, our novel classification system could facilitate patient counseling and individualize treatment of TNBC. PMID- 26975200 TI - Evidence for Health II: Overcoming barriers to using evidence in policy and practice. AB - Even the highest quality evidence will have little impact unless it is incorporated into decision-making for health. It is therefore critical to overcome the many barriers to using evidence in decision-making, including (1) missing the window of opportunity, (2) knowledge gaps and uncertainty, (3) controversy, irrelevant and conflicting evidence, as well as (4) vested interests and conflicts of interest. While this is certainly not a comprehensive list, it covers a number of main themes discussed in the knowledge translation literature on this topic, and better understanding these barriers can help readers of the evidence to be more savvy knowledge users and help researchers overcome challenges to getting their evidence into practice. Thus, the first step in being able to use research evidence for improving population health is ensuring that the evidence is available at the right time and in the right format and language so that knowledge users can take the evidence into consideration alongside a multitude of other factors that also influence decision-making. The sheer volume of scientific publications makes it difficult to find the evidence that can actually help inform decisions for health. Policymakers, especially in low- and middle-income countries, require context-specific evidence to ensure local relevance. Knowledge synthesis and dissemination of policy-relevant local evidence is important, but it is still not enough. There are times when the interpretation of the evidence leads to various controversies and disagreements, which act as barriers to the uptake of evidence. Research evidence can also be influenced and misused for various aims and agendas. It is therefore important to ensure that any new evidence comes from reliable sources and is interpreted in light of the overall body of scientific literature. It is not enough to simply produce evidence, nor even to synthesize and package evidence into a more user friendly format. Particularly at the policy level, political savvy is also needed to ensure that vested interests do not undermine decisions that can impact the health of individuals and populations. PMID- 26975201 TI - Iota2-mediated amination/cyclization of ketones with 2-aminopyridines under high speed ball milling: solvent- and metal-free synthesis of 2,3-substituted imidazo[1,2-a]pyridines and zolimidine. AB - Under solvent-free high-speed ball milling, an I[Formula: see text]-promoted condensation/cyclization of easily available methyl ketones or 1,3-dicarbonyl compounds with 2-aminopyridines has been developed, which allows the quick assembly of 2,3-substituted imidazo[1,2-a]pyridines (IPs) with broad molecular diversity, including the antiulcer drug zolimidine. The advantages of high yields, good functional group compatibility, short reaction time (within 90 min), free use of heating, solvent and metal, employment of cheap starting materials, and simple work-up procedure make this protocol a very efficient alternative to traditional synthesis of IPs. PMID- 26975202 TI - Late Intragastric Balloon Induced Gastric Perforation. AB - Intragastric balloon (IGB) has been introduced in the 1980's for weight reduction. It can be classified into nonadjustable IGB, such as the BioEnterics Intragastric Balloon (BIB), or newer generation Spatz adjustable balloon system. Late IGB-induced gastric perforation is a rare major complication, presenting as acute abdominal pain weeks to months after its insertion. We herein present a 20 year-old patient, with gastric perforation occurring 10 months after Spatz IGB deployment. The patient underwent a successful endoscopic IGB retrieval and laparoscopic exploration with abdominal lavage. We also review the literature of late IGB-induced gastric perforation. PMID- 26975203 TI - Approach to Poor Weight Loss After Laparoscopic Sleeve Gastrectomy: Re-sleeve Vs. Gastric Bypass. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is increasing worldwide; however, long-term follow-up results included insufficient weight loss and weight regain. This study aims at assessing the outcomes of converting LSG to laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic re-sleeve gastrectomy (LRSG). METHODS: A total of 1300 patients underwent LSG from 2009 to 2012, of which 12 patients underwent LRYGB and 24 patients underwent LRSG in Al Amiri Hospital alone. Data included length of stay, percentage excessive weight loss (EWL%), and body mass index (BMI). RESULTS: Twenty-four patients underwent conversion from LSG to LRSG, and 12 patients underwent conversion from LSG to LRYGB due to insufficient weight loss and weight regain. Eighty-five percent were females. The mean weight and BMI prior to LSG for the LRYGB and LRSG patients were 136.5 kg and 52, and 134 kg and 50, respectively. The EWL% after the initial LSG was 37.9 and 43 %, for LRYGB and LRSG, respectively. There were no complications recorded. Results of conversion of LSG to LRYGB involved a mean EWL% 61.3 % after 1 year (p value 0.009). Results of LRSG involved a mean EWL% of 57 % over interval of 1 year (p value 0.05). Comparison of the EWL% of LRYGB and LRSG for failed primary LSG was not significant (p value 0.097). CONCLUSION: Following our algorithm, revising an LSG with an LRSG or LRYGB for poor weight loss is feasible with good outcomes. Larger and longer follow-up studies are needed to verify our results. PMID- 26975204 TI - The assessment of pore connectivity in hierarchical zeolites using positron annihilation lifetime spectroscopy: instrumental and morphological aspects. AB - Recent studies demonstrated the power of positron annihilation lifetime spectroscopy (PALS) to characterise the connectivity and corresponding effectiveness of hierarchical pore networks in zeolites. This was based on the fractional escape of ortho-positronium (Ps), formed within the micropore framework, to vacuum. To further develop this technique, here we assess the impact of the positron implantation energy and of the zeolite crystal size and the particle morphology. Conventional measurements using fast positrons and beam measurements applying moderated positrons both readily distinguish purely microporous ZSM-5 zeolites comprised of single crystals or crystal aggregates. Unlike beam measurements, however, conventional measurements fail to discriminate model hierarchical zeolites with open or constricted mesopore architectures. Several steps are taken to rationalise these observations. The dominant contribution of Ps diffusion to the PALS response is confirmed by capping the external surface of the zeolite crystals with tetraethylorthosilicate, which greatly enhances the sensitivity to the micropore network. A one-dimensional model is constructed to predict the out-diffusion of Ps from a zeolite crystal, which is validated experimentally by comparing coffin-shaped single crystals of varying size. Calculation of the trends expected on the application of fast or moderated positrons indicates that the distinctions in the initial distribution of Ps at the crystal level cannot explain the limited sensitivity of the former to the mesopore architecture. Instead, we propose that the greater penetration of fast positrons within the sample increases the probability of Ps re-entry from intercrystalline voids into mesopores connected with the external surface of zeolite crystals, thereby reducing their fractional escape. PMID- 26975205 TI - Effects of Geriatric Interdisciplinary Home Rehabilitation on Walking Ability and Length of Hospital Stay After Hip Fracture: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate if Geriatric Interdisciplinary Home Rehabilitation could improve walking ability for older people with hip fracture compared with conventional geriatric care and rehabilitation. A secondary aim was to investigate the postoperative length of hospital stay (LOS). DESIGN: Randomized controlled trial. SETTING: Geriatric ward, ordinary housing, and residential care facilities. PARTICIPANTS: People operated on for a hip fracture (n = 205), aged 70 or older, including those with cognitive impairment, and living in the north of Sweden. INTERVENTION: Home rehabilitation with the aim of early hospital discharge that was individually designed and carried out by an interdisciplinary team for a maximum of 10 weeks. Special priority was given to prevention of falls, independence in daily activities, and walking ability both indoors and outdoors. MEASUREMENTS: Walking ability and the use of walking device was assessed in an interview during the hospital stay. These assessments were repeated along with gait speed measurements at 3- and 12-month follow-up. The length of the hospital stay after the hip fracture was recorded. RESULTS: No significant differences were observed in walking ability, use of walking device, and gait speed at the 3- and 12-month follow-up between the groups. At 12 months, 56.3% of the intervention group and 57.7% of the control group had regained or improved their prefracture walking ability. The median postoperative LOS in the geriatric ward was 6 days shorter for the intervention group (P = .003). CONCLUSION: Participants receiving Geriatric Interdisciplinary Home Rehabilitation regained walking ability in the short- and long-term similar to those receiving conventional geriatric care and rehabilitation according to a multifactorial rehabilitation program. The intervention group had a significantly shorter postoperative LOS in the hospital. PMID- 26975206 TI - Development of an Applied Framework for Understanding Health Information Technology in Nursing Homes. AB - There is growing evidence that Health Information Technology (HIT) can play a role in improving quality of care and increasing efficiency in the nursing home setting. Most research in this area, however, has examined whether nursing homes have or use any of a list of available technologies. We sought to develop an empirical framework for understanding the intersection between specific uses of HIT and clinical care processes. Using the nominal group technique, we conducted a series of focus groups with different types of personnel who work in nursing homes (administrators, directors of nursing, physicians, mid-level practitioners, consultant pharmacists, and aides). The resulting framework identified key domain areas that can benefit from HIT: transfer of data, regulatory compliance, quality improvement, structured clinical documentation, medication use process, and communication. The framework can be used to guide both descriptive and normative research. PMID- 26975207 TI - The Relevance of Assessing Cognitive Performances in Patients With Cerebrovascular Diseases. PMID- 26975208 TI - Flexible heat-flow sensing sheets based on the longitudinal spin Seebeck effect using one-dimensional spin-current conducting films. AB - Heat-flow sensing is expected to be an important technological component of smart thermal management in the future. Conventionally, the thermoelectric (TE) conversion technique, which is based on the Seebeck effect, has been used to measure a heat flow by converting the flow into electric voltage. However, for ubiquitous heat-flow visualization, thin and flexible sensors with extremely low thermal resistance are highly desired. Recently, another type of TE effect, the longitudinal spin Seebeck effect (LSSE), has aroused great interest because the LSSE potentially offers favourable features for TE applications such as simple thin-film device structures. Here we demonstrate an LSSE-based flexible TE sheet that is especially suitable for a heat-flow sensing application. This TE sheet contained a Ni0.2Zn0.3Fe2.5O4 film which was formed on a flexible plastic sheet using a spray-coating method known as "ferrite plating". The experimental results suggest that the ferrite-plated film, which has a columnar crystal structure aligned perpendicular to the film plane, functions as a unique one-dimensional spin-current conductor suitable for bendable LSSE-based sensors. This newly developed thin TE sheet may be attached to differently shaped heat sources without obstructing an innate heat flux, paving the way to versatile heat-flow measurements and management. PMID- 26975209 TI - A strategy to optimize the thermoelectric performance in a spark plasma sintering process. AB - Spark plasma sintering (SPS) is currently widely applied to existing alloys as a means of further enhancing the alloys' figure of merit. However, the determination of the optimal sintering condition is challenging in the SPS process. This report demonstrates a systematic way to independently optimize the Seebeck coefficient S and the ratio of electrical to thermal conductivity (sigma/kappa) and thus achieve the maximum figure of merit zT = S(2)(sigma/kappa)T. Sb2-xInxTe3 (x = 0-0.2) were chosen as examples to validate the method. Although high sintering temperature and pressure are helpful in enhancing the compactness and electrical conductivity of pressed samples, the resultant deteriorated Seebeck coefficient and increasing thermal conductivity eventually offset the benefit. We found that the optimal sintering temperature coincides with temperatures at which the maximum Seebeck coefficient begins to degrade, whereas the optimal sintering pressure coincided with the pressure at which the sigma/kappa ratio reaches a maximum. Based on this principle, the optimized sintering conditions were determined, and the zT of Sb1.9In0.1Te3 is raised to 0.92 at 600 K, showing an approximately 84% enhancement. This work develops a facile strategy for selecting the optimal SPS sintering condition to further enhance the zT of bulk specimens. PMID- 26975210 TI - Hypothyroidism in patients treated with radiotherapy for head and neck carcinoma: standardised long-term follow-up study. AB - OBJECTIVE: Hypothyroidism is a common complication when radiotherapy is part of the treatment for head and neck tumours. This study aimed to show the incidence of hypothyroidism and possible risk factors in these patients. METHODS: Factors related to the population, tumour, treatment and occurrence of hypothyroidism were analysed in 241 patients diagnosed with head and neck carcinoma. RESULTS: Approximately 53 per cent of patients were diagnosed with radiation-induced hypothyroidism. Its occurrence was related to: tumour location, laryngeal surgery type, neck dissection type, post-operative complications, cervical radiotherapy and radiotherapy unit type (linear particle accelerator or telecobalt therapy technology). CONCLUSION: Control of thyroid function should be standardised for several years after treatment, particularly in patients with risk factors, such as those treated with telecobalt therapy, those with post-operative complications and for whom the thyroid parenchyma is included in the irradiated area (laryngeal or pharyngeal location and bilateral cervical radiation). PMID- 26975212 TI - The C-terminal region of the transcriptional regulator THAP11 forms a parallel coiled-coil domain involved in protein dimerization. AB - Thanatos associated protein 11 (THAP11) is a cell cycle and cell growth regulator differentially expressed in cancer cells. THAP11 belongs to a distinct family of transcription factors recognizing specific DNA sequences via an atypical zinc finger motif and regulating diverse cellular processes. Outside the extensively characterized DNA-binding domain, THAP proteins vary in size and predicted domains, for which structural data are still lacking. We report here the crystal structure of the C-terminal region of human THAP11 protein, providing the first 3D structure of a coiled-coil motif from a THAP family member. We further investigate the stability, dynamics and oligomeric properties of the determined structure combining molecular dynamics simulations and biophysical experiments. Our results show that the C-ter region of THAP11 forms a left-handed parallel homo-dimeric coiled-coil structure possessing several unusual features. PMID- 26975213 TI - Defects in Mitochondrial Iron-Sulfur Cluster Assembly Induce Cysteine S Polythiolation on Iron-Sulfur Apoproteins. AB - AIMS: Mitochondria play a central role in the maturation of proteins with iron sulfur (Fe/S) clusters. During their biogenesis, the apoforms of Fe/S proteins expose unprotected Fe/S cluster-coordinating cysteine side chains, rendering them vulnerable to oxidative modifications that interfere with subsequent Fe/S cluster insertion. Whether and how cells protect these delicate cysteine residues are unknown. RESULTS: In this study, we show that sulfhydryl groups of Fe/S cluster coordinating cysteine residues of mitochondrial Fe/S apoproteins acquire cyclic S polythiol modifications. These adducts are the result of persulfide addition, followed by a subsequent oxidation step. These modifications not only accumulate upon defects in the early stages of the mitochondrial Fe/S cluster assembly system but are also found in wild-type cells under normal growth conditions. They are, however, not found on Fe/S apoproteins in the cytosol. INNOVATION AND CONCLUSION: Our work describes a novel in vivo chemical modification of cysteine side chains in mitochondrial Fe/S apoproteins. These cyclic S-polythiolation adducts are resistant to oxidation, yet can be removed by reductive cleavage, suggesting that they serve as a reversible protection device for cysteine ligands sensitive to oxidative modification. Antioxid. Redox Signal. 25, 28-40. PMID- 26975214 TI - PPARgamma helix 12 exhibits an antagonist conformation. AB - Although the peroxisome proliferator-activated receptor gamma (PPARgamma) is one of the most studied nuclear receptors (NR), it is still unknown whether its activation helix (helix 12, H12) could exhibit an antagonist conformation as previously demonstrated for most of the NRs. The high H12 flexibility in the apo PPARgamma form and the lack of appropriate antagonist ligands complicate the structural and dynamics description by most of the experimental techniques. Based on intensive (~12 MUs) accelerated molecular dynamics (aMD) simulations together with metadynamics and conventional MD runs, we reveal that H12 could exist in an antagonist conformation. This H12 state and the well-known agonist configuration have virtually identical free energy. Notably, significant deviations in the H12 conformations are detected in a homodimer. In chain A the activation helix is stabilized only in a full agonist conformation whereas in chain B, due to agonist to antagonist state exchanges, H12 is oriented toward helix 4. In summary, the results provide an explanation of the observed asymmetry in most of the PPARgamma homodimer crystal structures. They also suggest selection guidance for protein moieties and structure candidates that would best serve as potential ligand binding sites to achieve a stable antagonist form of the receptor. PMID- 26975211 TI - Accurate Determination of Conformational Transitions in Oligomeric Membrane Proteins. AB - The structural dynamics governing collective motions in oligomeric membrane proteins play key roles in vital biomolecular processes at cellular membranes. In this study, we present a structural refinement approach that combines solid-state NMR experiments and molecular simulations to accurately describe concerted conformational transitions identifying the overall structural, dynamical, and topological states of oligomeric membrane proteins. The accuracy of the structural ensembles generated with this method is shown to reach the statistical error limit, and is further demonstrated by correctly reproducing orthogonal NMR data. We demonstrate the accuracy of this approach by characterising the pentameric state of phospholamban, a key player in the regulation of calcium uptake in the sarcoplasmic reticulum, and by probing its dynamical activation upon phosphorylation. Our results underline the importance of using an ensemble approach to characterise the conformational transitions that are often responsible for the biological function of oligomeric membrane protein states. PMID- 26975215 TI - Modulation of aquaporins 3 and 9 after exposure of ovine ovarian tissue to cryoprotectants followed by in vitro culture. AB - Our aim has been to evaluate the effect of cryoprotective agents (CPAs) on the exposure, vitrification (VIT), and in vitro culture (IVC) of ovarian tissue with regard to the expression and immunolocalization of aquaporins (AQPs) 3 and 9 in ovine preantral follicles. Tissues were treated as follows: Experiment I: (1) control (without exposure to CPAs), (2) e-EG (exposure to ethylene glycol), (3) er-EG (exposure to and removal of EG), (4) e-DMSO (exposure to dimethyl sulfoxide), (5) er-DMSO (exposure to and removal of DMSO), (6) e-EG+DMSO (exposure to EG+DMSO), (7) er-EG+DMSO (exposure to and removal of EG+DMSO); Experiment II: (1) control, (2) VIT, (3) IVC, (4) VIT-IVC. In Experiment I, following er-EG or er-DMSO, tissue showed the down-regulation (P < 0.05) of AQP3 mRNA. The mRNA transcript levels were reduced (P < 0.05) for AQP9 in tissue following er-EG+DMSO. Immunolocalization was positive for both proteins (AQP3 and AQP9) on ovine preantral follicles following all treatments, except in the e EG+DMSO group. In Experiment II, the mRNA levels of AQP3 and AQP9 following VIT treatment were similar (P > 0.05) to that of the control group. Nevertheless, VIT IVC treatment led to the down-regulation of mRNA of AQP3 and AQP9. Thus, AQP3 and AQP9 act in a mutually dependent way, maintaining the cell homeostasis that is essential for the ovary cryopreservation process. Furthermore, the changes in the expression profiles of mRNA and protein after culture are a strong indicator that in vitro conditions have to be strictly controlled to ensure follicle viability and functionality. PMID- 26975216 TI - Enhanced Performance of PbS-quantum-dot-sensitized Solar Cells via Optimizing Precursor Solution and Electrolytes. AB - This work reports a PbS-quantum-dot-sensitized solar cell (QDSC) with power conversion efficiency (PCE) of 4%. PbS quantum dots (QDs) were grown on mesoporous TiO2 film using a successive ion layer absorption and reaction (SILAR) method. The growth of QDs was found to be profoundly affected by the concentration of the precursor solution. At low concentrations, the rate-limiting factor of the crystal growth was the adsorption of the precursor ions, and the surface growth of the crystal became the limiting factor in the high concentration solution. The optimal concentration of precursor solution with respect to the quantity and size of synthesized QDs was 0.06 M. To further increase the performance of QDSCs, the 30% deionized water of polysulfide electrolyte was replaced with methanol to improve the wettability and permeability of electrolytes in the TiO2 film, which accelerated the redox couple diffusion in the electrolyte solution and improved charge transfer at the interfaces between photoanodes and electrolytes. The stability of PbS QDs in the electrolyte was also improved by methanol to reduce the charge recombination and prolong the electron lifetime. As a result, the PCE of QDSC was increased to 4.01%. PMID- 26975217 TI - Understanding why veterans are reluctant to access help for alcohol problems: Considerations for nurse education. AB - BACKGROUND: To effectively engage veterans with substance misuse services, nurses need to understand their unique needs and the potential barriers that prevent them from accessing care. Nurses need to have an understanding and awareness of the cultural sensitivities associated with having been a member of the armed forces. OBJECTIVES: The aim of this study was to investigate the perceived barriers to care amongst those planning, commissioning and delivering services for veterans with substance misuse problems, and to identify and explore subject areas which nurse educators should consider for inclusion in nursing and health education programmes. DESIGN: The findings reported in this paper come from one phase of a larger three phase research project and used an applied qualitative research approached based on methods developed for applied social policy research. SETTINGS: The study was undertaken in the north-east of England. PARTICIPANTS: The study consisted of a purposive sample of planners, commissioners of services, and service providers in the North East of England. METHODS: Data was collected using a semi-structured interview schedule. Framework analysis was used to analyse the data. RESULTS: Complexity of services and care, complexity of need and a lack of understanding of veterans were identified as factors that made accessing substance misuse care difficult. To help nurses better understand the unique needs of veterans three educational topics were identified for consideration in pre-registration nurse education: understanding military and veteran culture and the nature of modern warfare, the military 'veteran as institutionalised' hypothesis and stigma. CONCLUSIONS: Health and social services can struggle to truly understand the unique needs and experiences of the veteran community. We have identified three broad subject areas that should be considered as the theoretical basis for a veteran specific education programme within pre and post-registration nurse education. PMID- 26975218 TI - American Society of Hypertension position article: central blood pressure waveforms in health and disease. PMID- 26975220 TI - Understanding viruses: Philosophical investigations. AB - Viruses have been virtually absent from philosophy of biology. In this editorial introduction, we explain why we think viruses are philosophically important. We focus on six issues (the definition of viruses, the individuality and diachronic identity of a virus, the possibility to classify viruses into species, the question of whether viruses are living, the question of whether viruses are organisms, and finally the biological roles of viruses in ecology and evolution), and we show how they relate to classic questions of philosophy of biology and even general philosophy. PMID- 26975219 TI - Deep Learning in Label-free Cell Classification. AB - Label-free cell analysis is essential to personalized genomics, cancer diagnostics, and drug development as it avoids adverse effects of staining reagents on cellular viability and cell signaling. However, currently available label-free cell assays mostly rely only on a single feature and lack sufficient differentiation. Also, the sample size analyzed by these assays is limited due to their low throughput. Here, we integrate feature extraction and deep learning with high-throughput quantitative imaging enabled by photonic time stretch, achieving record high accuracy in label-free cell classification. Our system captures quantitative optical phase and intensity images and extracts multiple biophysical features of individual cells. These biophysical measurements form a hyperdimensional feature space in which supervised learning is performed for cell classification. We compare various learning algorithms including artificial neural network, support vector machine, logistic regression, and a novel deep learning pipeline, which adopts global optimization of receiver operating characteristics. As a validation of the enhanced sensitivity and specificity of our system, we show classification of white blood T-cells against colon cancer cells, as well as lipid accumulating algal strains for biofuel production. This system opens up a new path to data-driven phenotypic diagnosis and better understanding of the heterogeneous gene expressions in cells. PMID- 26975221 TI - Health determinants of nutritional status in community-dwelling older population: the VERISAUDE study. AB - OBJECTIVE: Malnutrition is a common and relevant syndrome in elderly people due to its influence on quality of life. The main aim of the present study was to identify health determinants of malnutrition or risk of malnutrition. DESIGN: Cross-sectional study collecting information on sociodemographic and health factors (co-morbidity, cognitive or affective problems, prescription medication use, frailty status, self-rated health) as determinants of nutritional status, assessed by the short form of the Mini Nutritional Assessment. SETTING: Forty three senior centres from Galicia (north-western Spain) participated to recruit participants. SUBJECTS: A representative community-dwelling sample of 749 elderly people aged >=65 years. RESULTS: Of the total participants, 14.3 % were malnourished/at risk of malnutrition. Presence of overweight or obesity, depressive symptoms, polypharmacy (use of five or more prescription medications), presence of pre-frailty or frailty status and poor self-rated health showed the strongest relationship to malnutrition/risk of malnutrition. This model predicted 86.0 % of the cases correctly. The best determinants for women were polypharmacy and poor self-rated health, reaching 82.8 % of cases of malnourishment/risk of malnutrition predicted correctly. In men, the main determinants were overweight or obesity, depressive symptomatology and polypharmacy, with 89.8 % of cases of malnourishmen/risk of malnutrition predicted correctly. CONCLUSIONS: Screening for nutritional status and its determinant factors should be included as part of comprehensive assessments to ensure an early screening of malnutrition and to propose possible intervention strategies that would be important for both elderly people and the health-care system. PMID- 26975222 TI - [New genetic mutation associated with Pierson syndrome]. PMID- 26975223 TI - From Azo-Linked Polymers to Microporous Heteroatom-Doped Carbons: Tailored Chemical and Textural Properties for Gas Separation. AB - Heteroatom-doped porous carbons with ultrahigh microporosity were prepared from a nitrogen-rich azo-linked polymer (ALP-6) as a precursor for gas separation applications. Direct carbonization and chemical activation of ALP-6 with ZnCl2 and KOH were successfully applied to obtain three different classes of porous carbons (ALPDCs). Synthetic processes were conducted at relatively mild temperatures (500-800 degrees C),which resulted in retention of appreciable levels of nitrogen content (4.7-14.3 wt %). Additionally, oxygen functionalities were found to be present in chemically activated samples. The resultant porous carbons feature a diverse range of textural properties with a predominant microporous nature in common. The highest CO2 uptake value of 5.2 mmol g(-1) at 1 bar and 298 K in ALPDCK600 was originated from well-developed porosity and basic heteroatoms (N and O) on the pore walls. The highest heteroatom doping level (12 wt % nitrogen and 20 wt % oxygen) coupled with the high level of microporosity (84%) for ALPDCK500 led to notable CO2/N2 (62) and CO2/CH4 (11) selectivity values and a high CO2 uptake capacity (1.5 mmol g(-1), at 0.15 bar) at 298 K. This study illustrates the effective use of a single-source precursor with robust nitrogen bonds in combination with diverse carbonization methods to tailor the chemical and textural properties of heteroatom-doped porous carbons for CO2 capture and separation applications. PMID- 26975224 TI - The Wearable Cardioverter Defibrillator in Nonischemic Cardiomyopathy: A US National Database Analysis. AB - BACKGROUND: The wearable cardioverter defibrillator (WCD) is often used in patients at risk of sudden cardiac death (SCD) who are not yet candidates for an implantable cardioverter defibrillator (ICD). Newly diagnosed cardiomyopathy may be reversible, and a WCD may protect patients during the initial period of risk. We evaluate the benefit and compliance of the WCD in patients with nonischemic cardiomyopathy (NICM). METHODS: We reviewed a national database of patients with NICM who used WCDs and who self-reported a history of excess alcohol use, although other causes of cardiomyopathy could not be excluded. The database contained demographic data, initial ejection fraction (EF), reason for WCD prescription, compliance and use data, any detected arrhythmias, therapies, and reason for discontinuing WCD. Statistical analyses were performed using SAS, version 9.3 (SAS Institute, Cary, NC). RESULTS: Of the 127 patients, 88% were men with a mean age of 52.6 +/- 11.0 years. The mean initial EF was 19.9% +/- 7.4%. Patients wore the WCD for a median of 51 days and a median daily use of 18.0 hours per day. The most common reasons for discontinuing the WCD were improvement in EF (33%) or ICD implantation (23.6%). Seven patients (5.5%) had 9 sustained ventricular arrhythmia events, which were successfully treated with 100% conversion. There were 11 deaths (8.6%) during 100 days of follow-up. No deaths resulted from WCD shock failure or undersensing. CONCLUSIONS: NICM may have a significant risk of ventricular arrhythmias and death in the first few months. The WCD delivered appropriate therapy in 5.5% of patients. This study suggests that a WCD may be effective temporary prophylaxis for prevention of SCD in patients with newly diagnosed NICM. PMID- 26975225 TI - Efficacy of Early Invasive Management After Fibrinolysis for ST-Segment Elevation Myocardial Infarction in Relation to Initial Troponin Status. AB - BACKGROUND: We examined whether the efficacy of an early invasive strategy after fibrinolysis in ST-segment elevation myocardial infarction (STEMI) differs in relation to the initial troponin status. METHODS: In the Trial of Routine Angioplasty and Stenting After Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction (TRANSFER-AMI), patients with STEMI presenting to a non percutaneous coronary intervention (PCI)-capable hospital who received fibrinolysis were randomized to either a pharmacoinvasive or standard strategy for subsequent angiography and PCI. In this post hoc subgroup analysis, we compared the efficacy of these strategies in relation to the initial troponin status at hospital presentation for the primary composite end point of mortality, reinfarction, recurrent ischemia, heart failure, and cardiogenic shock at 30 days. We assessed the heterogeneity of treatment effect with initial troponin status using the Breslow-Day test and tested for interaction after adjustment for baseline Global Registry of Acute Coronary Events (GRACE) risk score. RESULTS: Among 1059 patients, those with abnormal initial troponin levels (n = 514 [48.5%]) were older with worse Killip class, had a longer time from symptom onset to fibrinolysis, and had higher GRACE and Thrombolysis In Myocardial Infarction risk scores. Patients with abnormal troponin levels had higher rates of the primary end point (17.5% vs 10.8%; P = 0.002) and cumulative mortality or reinfarction at 1 year (14.0% vs 8.1%; P = 0.003). In stratified analyses, pharmacoinvasive management reduced the primary end point only among patients with normal initial troponin status. However, there was no significant treatment heterogeneity (all P >= 0.10) and no interaction between initial troponin status and treatment assignment after adjusting for GRACE risk score. CONCLUSIONS: Patients with STEMI and abnormal initial troponin levels had worse short-term and long-term outcomes. Accounting for overall baseline risk with the GRACE risk score, troponin status did not modulate the efficacy of pharmacoinvasive management. PMID- 26975226 TI - Management of Loeffler's Endocarditis With Bivalvular Involvement and a FIP1L1/PDGFRA-Negative Mutation. AB - Hypereosinophilic syndromes (HESs) are a group of disorders characterized by end organ damage caused by eosinophilic infiltration. We present a patient with idiopathic HES with severe tricuspid and mitral regurgitation secondary to Loeffler's endocarditis. In addition to prednisone, imatinib therapy initially helped control the eosinophil count. However, successful long-term remission was achieved with hydroxyurea therapy. PMID- 26975227 TI - Pharmacogenetics of ABCB5, ABCC5 and RLIP76 and doxorubicin pharmacokinetics in Asian breast cancer patients. AB - This study investigated the impact of ABCB5, ABCC5 and RLIP76 polymorphisms on doxorubicin pharmacokinetics in Asian breast cancer patients (N=62). Direct sequencing was performed to screen for previously identified ABCC5 polymorphisms as well as polymorphisms in the exons and exon-intron boundaries of ABCB5 and RLIP76 genes. Genotype-phenotype correlations were analyzed using Mann-Whitney U test. The homozygous variant allele at the ABCC5 g.+7161G>A (rs1533682) locus was significantly associated with higher doxorubicin clearance (g.+7161AA vs g.+7161GG, CL/BSA (Lh-1m-2): 30.34 (25.41-33.60) vs 22.46 (15.04-49.4), P=0.04). Homozygosity for the reference allele at the ABCC5 g.-1679T>A locus was associated with significantly higher doxorubicinol exposure (g.-1679TT vs g. 1679TA, AUC0-infinity/dose/BSA (hm-5): 15.48 (6.18-67.17) vs 8.88 (3.68-21.71), P=0.0001). No significant influence of the three newly identified ABCB5 polymorphisms (c.2T>C, c.343A>G and c.1573G>A) on doxorubicin pharmacokinetics was observed. No polymorphisms were identified in the RLIP76 gene. These findings suggest that ABCC5 polymorphisms may explain partially the interpatient variability in doxorubicin disposition. PMID- 26975228 TI - Integrated Drug Expression Analysis for leukemia: an integrated in silico and in vivo approach to drug discovery. AB - Screening for drug compounds that exhibit therapeutic properties in the treatment of various diseases remains a challenge even after considerable advancements in biomedical research. Here, we introduce an integrated platform that exploits gene expression compendia generated from drug-treated cell lines and primary tumor tissue to identify therapeutic candidates that can be used in the treatment of acute myeloid leukemia (AML). Our framework combines these data with patient survival information to identify potential candidates that presumably have a significant impact on AML patient survival. We use a drug regulatory score (DRS) to measure the similarity between drug-induced cell line and patient tumor gene expression profiles, and show that these computed scores are highly correlated with in vitro metrics of pharmacological activity. Furthermore, we conducted several in vivo validation experiments of our potential candidate drugs in AML mouse models to demonstrate the accuracy of our in silico predictions. PMID- 26975230 TI - The CYP2D6 VCF Translator. PMID- 26975231 TI - Endoscopic mucosal resection of large and giant lateral spreading lesions of the duodenum: success, adverse events, and long-term outcomes. AB - BACKGROUND AND AIMS: Large sporadic duodenal adenomas are uncommon but they harbor malignant potential, which requires consideration of definitive treatment. EMR is gaining acceptance as an effective and safe alternative to high-risk surgical procedures, but data on long-term outcomes are limited. Herein we describe the short- and long-term outcomes of these lesions in a tertiary referral center. METHODS: Prospectively collected data were analyzed to identify risk factors for adverse events and outcomes. Patient demographics, lesion characteristics, and procedural technical data were collected. RESULTS: From 2007 to 2015, 106 adenomas >=10 mm were resected (mean patient age, 69 years; 54% male; median size, 25 mm; interquartile range [IQR], 19-40). Complete endoscopic resection was achieved in 96%. Intraprocedural bleeding occurred in 43% of cases and was associated with lesion size (P < .001), number of resected specimens (P = .003), and longer procedures (P = .001). Delayed bleeding occurred in 15% (56% did not require active intervention) and was associated with lesion size (P = .03). Perforation occurred in 3 patients. The 30-day mortality was 0%. Median follow-up was 22 months (IQR, 7-45). Histologically proven adenoma recurrence was identified and treated in 12 of 83 patients (14.4%) on first surveillance endoscopy. For the 53 patients for whom follow-up >=12 months was available (median follow-up, 36 months; IQR, 24-51), 48 patients (90.6%) were free of adenoma and considered cured. CONCLUSIONS: In a tertiary referral center, endoscopic resection of duodenal adenomas is a safe and effective alternative to surgery. Lesion size is strongly associated with adverse events, particularly intraprocedural bleeding and delayed bleeding. Good long-term outcomes are demonstrated. PMID- 26975229 TI - KIR2DS2 as predictor of thrombocytopenia secondary to pegylated interferon-alpha therapy. AB - Our aim was to evaluate the killer cell immunoglobulin-like receptors (KIRs) as a marker for the development of thrombocytopenia secondary to Peg-interferon (IFN) therapy in a cohort of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients. Patients were naive to HCV treatment, receiving a first course of Peg-IFN/Ribavirin combination therapy. Total platelet count (cells ml 1) was determined at each visit, determining platelet decline from baseline to weeks 1, 2, 4, 8 and 12 after starting therapy. The end point of the study was development of thrombocytopenia, defined as a platelet count of <1 50 000 cells ml-1. Fifty-eight HIV/HCV co-infected patients were included in the study, of whom 20 (34.4%) developed thrombocytopenia. The absence of KIR2DS2 was associated with higher and faster rate of thrombocytopenia (54.2% vs 22.5%; P=0.012; 6.6 vs 10.3 weeks; P=0.008). The absence of KIR2DS2 was associated with a greater decline in platelet count and development of thrombocytopenia during Peg-IFN treatment in HIV/HCV co-infected patients. PMID- 26975232 TI - Successful endoscopic dilation for anastomotic stricture after pancreaticojejunostomy. PMID- 26975234 TI - Acute gastric dilatation in a bulimic patient. PMID- 26975235 TI - Single-session laparoscopic cholecystectomy and ERCP: a valid option for the management of choledocholithiasis. AB - BACKGROUND AND AIMS: The option for performing ERCP and laparoscopic cholecystectomy (LC) for the management of choledocholithiasis in the same operative session is often overlooked. We compared the success, safety, and cost of ERCP and LC when performed in either a single session or in separate sessions. METHODS: We conducted a retrospective cohort study at a U.S. tertiary care hospital. We identified patients undergoing ERCP and LC between April 2011 and August 2014 in either a single operative session (n = 33) or in 2 separate sessions within a 30-day period (n = 80). Technical success, total anesthesia duration, operative time, length of hospitalization, cost of care, and morbidity and mortality were evaluated. RESULTS: Bile duct clearance was achieved in all patients at ERCP in the same-session cohort. The separate versus single-session groups, respectively, did not differ in terms of total procedure times (mean +/- SD = 142 +/- 64 vs 142 +/- 58 min; t test, P =.98), anesthesia duration (251 +/- 64 vs 225 +/- 69 min; P =.06), or overall cost (49.3 +/- 24.5 vs 42.3 +/- 23.2 *1000 USD; P =.167), but hospitalization was longer in the separate-sessions group (6.2 +/- 3.3 vs 4.8 +/- 2.6 days; P =.03). The rates of adverse events were similarly low (7% vs 2%, P =.70). CONCLUSIONS: Performing single-session ERCP and LC is safe, effective, economically viable, and reduces hospital stay compared with performing ERCP and LC during separate sessions. PMID- 26975233 TI - Association between adenoma location and risk of recurrence. AB - BACKGROUND AND AIMS: The biological environment varies across the colorectum and may therefore affect neoplastic growth differently in the proximal and distal colon. The aim of the study was to evaluate the risk for recurrent adenomas and their anatomic location based on adenoma location at baseline colonoscopy. METHODS: Data were extracted from 3 adenoma prevention trials (n = 2430). Participants had at least 1 adenoma at baseline colonoscopy and underwent subsequent surveillance colonoscopy, at which time metachronous adenomas could be detected. We calculated the risk ratio (RR) and the 95% confidence interval (CI) for metachronous adenomas by location of the baseline lesion and considered the impact of advanced neoplasia and multiplicity. RESULTS: At baseline, 522 patients (21.5%) had adenomas only in the proximal colon, 1266 patients (52.1%) had adenomas only in the distal colorectum, and 642 (26.4%) had adenomas in both regions. Overall, 877 patients (36.5%) had metachronous adenomas during the follow-up period. Those with only proximal adenomas at baseline had a higher risk of metachronous adenomas compared with patients with only distal adenomas (RR, 1.17; 95% CI, 1.01-1.35). A greater proximal risk was found after restricting the analysis to patients with multiple proximal adenomas versus multiple distal adenomas (RR, 1.35; 95% CI, 1.10-1.67). The risk of recurrent adenomas on the same side was 48% higher for patients with only proximal adenomas at baseline compared with those with only distal adenomas at baseline (RR, 1.48; 95% CI, 1.22 1.80). CONCLUSIONS: Patients with proximal adenomas only have a modestly greater risk of adenoma recurrence than patients with adenomas limited to the distal colon, and have a greater likelihood of adenoma recurrence on the same side compared with patients with distal adenomas. This observation suggests that biological factors may differentially affect neoplasia growth across the colon. PMID- 26975236 TI - Over-the-wire technique to facilitate over-the-scope clip closure of fistulae. PMID- 26975237 TI - Stent migration into the abdominal cavity after EUS-guided hepaticogastrostomy. PMID- 26975239 TI - Metal catalyst-free substitution of allylic and propargylic phosphates with diarylmethyl anions. AB - Substitution of secondary allylic phosphates with the anions derived from Ar2CH2 with BuLi or LDA proceeded regioselectively and stereoselectively without a metal catalyst, affording inversion products in good yield. Similarly, propargylic phosphates gave propargylic products selectively. PMID- 26975238 TI - A new approach to the automatic identification of organism evolution using neural networks. AB - Automatic identification of organism evolution still remains a challenging task, which is especially exiting, when the evolution of human is considered. The main aim of this work is to present a new idea to allow organism evolution analysis using neural networks. Here we show that it is possible to identify evolution of any organisms in a fully automatic way using the designed EvolutionXXI program, which contains implemented neural network. The neural network has been taught using cytochrome b sequences of selected organisms. Then, analyses have been carried out for the various exemplary organisms in order to demonstrate capabilities of the EvolutionXXI program. It is shown that the presented idea allows supporting existing hypotheses, concerning evolutionary relationships between selected organisms, among others, Sirenia and elephants, hippopotami and whales, scorpions and spiders, dolphins and whales. Moreover, primate (including human), tree shrew and yeast evolution has been reconstructed. PMID- 26975240 TI - Analysing the integration of MR images acquired in a non-radiotherapy treatment position into the radiotherapy workflow using deformable and rigid registration. AB - AIM: Our aim was to analyse the feasibility of integrating an MRI acquired in a non-radiotherapy set-up into the prostate cancer radiotherapy workflow. MATERIAL AND METHODS: The MRIs of 15 prostate cancer patients, acquired with a flat table top (MRI-flat), and with a curved tabletop (MRI-curve) were analysed. MRIs were rigidly (RIR) and non-rigidly registered (DIR) with CT images. The prostate and rectum were contoured in each image set and translated to the CT, and IMRT plans were computed taking into account structural changes after RIR and DIR (P flatRIR, P-curveRIR and P-curveDIR). In addition the P-curveDIR was overlaid with RIR structures. Spatial overlap parameters and dose-volume histogram metrics were generated. RESULTS: No significant differences were observed among P-flatRIR and P-curveRIR or P-flatRIR and P-curveDIR. Median gamma-values: P-curveRIR, 95.3%; P curveDIR, 96%, translated-P-curveDIR, 95%. DVH metrics for translated-P-curveDIR were: Dmin, 64.5Gy; Dmean, 70.06Gy; V95%, 100%. No statistically significant differences were found in the dosimetric MRI-flatDIR values. CONCLUSIONS: The dosimetric reproduction of treatment position image following image registration of non-radiotherapy set-up images suggests that it is feasible to integrate these images into the radiotherapy workflow. PMID- 26975241 TI - Dual energy CT in radiotherapy: Current applications and future outlook. AB - Dual energy CT (DECT) scanners are nowadays available in many radiology departments. For radiotherapy purposes, new strategies using DECT imaging are investigated to optimize radiation treatment for multiple steps in the radiotherapy chain. This review describes how DECT based methods can be used for electron density estimation, effective atomic number decomposition and contrast material quantification. Clinical radiotherapy related applications for improved dose calculation accuracy of brachytherapy and proton therapy, metal artifact reduction techniques and normal tissue characterization are also summarized together with future perspectives on the use of DECT for radiotherapy purposes. PMID- 26975242 TI - Management of Chronic Spontaneous Urticaria Exacerbated by Antihistamines: When Treatment Can Act as a Causal Agent Itself. PMID- 26975243 TI - Immunosuppression and Secondary Infection in Sepsis: Part, Not All, of the Story. PMID- 26975244 TI - Olfactory perception and behavioral effects of sex pheromone gland components in Helicoverpa armigera and Helicoverpa assulta. AB - Two sympatric species Helicoverpa armigera and Helicoverpa assulta use (Z)-11 hexadecenal and (Z)-9-hexadecenal as sex pheromone components in reverse ratio. They also share several other pheromone gland components (PGCs). We present a comparative study on the olfactory coding mechanism and behavioral effects of these additional PGCs in pheromone communication of the two species using single sensillum recording, in situ hybridization, calcium imaging, and wind tunnel. We classify antennal sensilla types A, B and C into A, B1, B2, C1, C2 and C3 based on the response profiles, and identify the glomeruli responsible for antagonist detection in both species. The abundance of these sensilla types when compared with the number of OSNs expressing each of six pheromone receptors suggests that HarmOR13 and HassOR13 are expressed in OSNs housed within A type sensilla, HarmOR14b within B and C type sensilla, while HassOR6 and HassOR16 within some of C type sensilla. We find that for H. armigera, (Z)-11-hexadecenol and (Z)-11 hexadecenyl acetate act as behavioral antagonists. For H. assulta, instead, (Z) 11-hexadecenyl acetate acts as an agonist, while (Z)-9-hexadecenol, (Z)-11 hexadecenol and (Z)-9-hexadecenyl acetate are antagonists. The results provide an overall picture of intra- and interspecific olfactory and behavioral responses to all PGCs in two sister species. PMID- 26975245 TI - Hyaluronic Acid-Based Biocompatible Supramolecular Assembly for Sustained Release of Antiretroviral Drug. AB - Human immunodeficiency virus (HIV) infection and its associated diseases continue to increase despite the progress in our understanding of HIV biology and the availability of a number of antiretroviral drugs. Adherence is a significant factor in the success of HIV therapy and current HIV treatment regimens require a combination of antiviral drugs to be taken at least daily for the remainder of a patient's life. A drug delivery system that allows sustained drug delivery could reduce the medical burden and costs associated with medication nonadherence. Here, we describe a novel supramolecular assembly or matrix that contains an anionic polymer hyaluronic acid, cationic polymer poly-l-lysine, and anionic oligosaccharide sulfobutylether-beta-cyclodextrin. HIV reverse transcriptase inhibitors Zidovudine and Lamivudine were successfully encapsulated into the polymer assembly in a noncovalent manner. The physicochemical properties and antiviral activity of the polymer assemblies were studied. The results of this study suggest that the supramolecular assemblies loaded with HIV drugs exert potent antiviral activity and allow sustained drug release. A novel drug delivery formulation such as the one described here could facilitate our efforts to reduce the morbidity and mortality associated with HIV infections and could be utilized in the design of therapeutic approaches for other diseases. PMID- 26975247 TI - On the crystal structure of colloidally prepared CsPbBr3 quantum dots. AB - Colloidally synthesized quantum dots of CsPbBr3 are highly promising for light emitting applications. Previous reports based on benchtop diffraction conflict as to the crystal structure of CsPbBr3 quantum dots. We present X-ray diffraction and PDF analysis of X-ray total scattering data that indicate that the crystal structure is unequivocally orthorhombic (Pnma). PMID- 26975246 TI - Self-Assembly of Cyclodextrins and Their Complexes in Aqueous Solutions. AB - Cyclodextrins (CDs) are enabling pharmaceutical excipients that can be found in numerous pharmaceutical products worldwide. Because of their favorable toxicologic profiles, CDs are often used in toxicologic and phase I assessments of new drug candidates. However, at relatively high concentrations, CDs can spontaneously self-assemble to form visible microparticles in aqueous mediums and formation of such visible particles may cause product rejections. Formation of subvisible CD aggregates are also known to affect analytical results during product development. How and why these CD aggregates form is largely unknown, and factors contributing to their formation are still not elucidated. The physiochemical properties of CDs are very different from simple amphiphiles and lipophilic molecules that are known to self-assemble and form aggregates in aqueous solutions but very similar to those of linear oligosaccharides. In general, negligible amounts of aggregates are formed in pure CD solutions, but the aggregate formation is greatly enhanced on inclusion complex formation, and the extent of aggregation increases with increasing CD concentration. The diameter of the aggregates formed is frequently less than about 300 nm, but visible aggregates can also be formed under certain conditions. PMID- 26975249 TI - Neurogenesis reunited. AB - Experiments on fruit flies are shedding new light on the evolution and development of the nervous system in metamorphosing insects. PMID- 26975248 TI - Lineage mapping identifies molecular and architectural similarities between the larval and adult Drosophila central nervous system. AB - Neurogenesis in Drosophila occurs in two phases, embryonic and post-embryonic, in which the same set of neuroblasts give rise to the distinct larval and adult nervous systems, respectively. Here, we identified the embryonic neuroblast origin of the adult neuronal lineages in the ventral nervous system via lineage specific GAL4 lines and molecular markers. Our lineage mapping revealed that neurons born late in the embryonic phase show axonal morphology and transcription factor profiles that are similar to the neurons born post-embryonically from the same neuroblast. Moreover, we identified three thorax-specific neuroblasts not previously characterized and show that HOX genes confine them to the thoracic segments. Two of these, NB2-3 and NB3-4, generate leg motor neurons. The other neuroblast is novel and appears to have arisen recently during insect evolution. Our findings provide a comprehensive view of neurogenesis and show how proliferation of individual neuroblasts is dictated by temporal and spatial cues. PMID- 26975250 TI - Toxin-induced pore formation is hindered by intermolecular hydrogen bonding in sphingomyelin bilayers. AB - Sticholysin I and II (StnI and StnII) are pore-forming toxins that use sphingomyelin (SM) for membrane binding. We examined how hydrogen bonding among membrane SMs affected the StnI- and StnII-induced pore formation process, resulting in bilayer permeabilization. We compared toxin-induced permeabilization in bilayers containing either SM or dihydro-SM (lacking the trans Delta(4) double bond of the long-chain base), since their hydrogen-bonding properties are known to differ greatly. We observed that whereas both StnI and StnII formed pores in unilamellar vesicles containing palmitoyl-SM or oleoyl-SM, the toxins failed to similarly form pores in vesicles prepared from dihydro-PSM or dihydro-OSM. In supported bilayers containing OSM, StnII bound efficiently, as determined by surface plasmon resonance. However, StnII binding to supported bilayers prepared from dihydro-OSM was very low under similar experimental conditions. The association of the positively charged StnII (at pH7.0) with unilamellar vesicles prepared from OSM led to a concentration-dependent increase in vesicle charge, as determined from zeta-potential measurements. With dihydro-OSM vesicles, a similar response was not observed. Benzyl alcohol, which is a small hydrogen-bonding compound with affinity to lipid bilayer interfaces, strongly facilitated StnII induced pore formation in dihydro-OSM bilayers, suggesting that hydrogen bonding in the interfacial region originally prevented StnII from membrane binding and pore formation. We conclude that interfacial hydrogen bonding was able to affect the membrane association of StnI- and StnII, and hence their pore forming capacity. Our results suggest that other types of protein interactions in bilayers may also be affected by hydrogen-bonding origination from SMs. PMID- 26975251 TI - Alanine scan and (2)H NMR analysis of the membrane-active peptide BP100 point to a distinct carpet mechanism of action. AB - The short membrane-active peptide BP100 [KKLFKKILKYL-NH2] is known as an effective antimicrobial and cell penetrating agent. For a functional alanine scan each of the 11 amino acids was replaced with deuterated Ala-d3, one at a time. MIC assays showed that a substitution of Lys did not affect the antimicrobial activity, but it decreased when a hydrophobic residue was replaced. In most cases, a reduction in hydrophobicity led to a decrease in hemolysis, and some peptide analogues had an improved therapeutic index. Circular dichroism showed that BP100 folds as an amphiphilic alpha-helix in a bilayer. Its alignment was determined from (2)H NMR in oriented membranes of different composition. The azimuthal rotation angle was the same under all conditions, but the average helix tilt angle and the dynamical behavior of the peptide varied in a systematic manner. In POPC/POPG bilayers, with a negative spontaneous curvature, the peptide was found to lie flat on the bilayer surface, and with little wobble. In DMPC/DMPG, with a positive spontaneous curvature, BP100 at higher concentrations became tilted obliquely into the membrane, with the uncharged C-terminus inserted more deeply into the lipid bilayer, experiencing significant fluctuations in tilt angle. In DMPC/DMPG/lyso-MPC, with a pronounced positive spontaneous curvature, the helix tilted even further and became even more mobile. The 11-mer BP100 is obviously too short to form transmembrane pores. We conclude that BP100 operates via a carpet mechanism, whereby the C-terminus gets inserted into the hydrophobic core of the bilayer, which leads to membrane perturbation and induces transient permeability. PMID- 26975252 TI - Comparative analysis of local effects caused by Bothrops alternatus and Bothrops moojeni snake venoms: enzymatic contributions and inflammatory modulations. AB - Bothropic envenomation is characterised by severe local damage caused by the toxic action of venom components and aggravated by induced inflammation. In this comparative study, the local inflammatory effects caused by the venoms of Bothrops alternatus and Bothrops moojeni, two snakes of epidemiological importance in Brazil, were investigated. The toxic action of venom components induced by bothropic venom was also characterised. Herein, the oedema, hyperalgesia and myotoxicity induced by bothropic venom were monitored for various lengths of time after venom injection in experimental animals. The intensity of the local effects caused by B. moojeni venom is considerably more potent than B. alternatus venom. Our results also indicate that metalloproteases and phospholipases A2 have a central role in the local damage induced by bothropic venoms, but serine proteases also contribute to the effects of these venoms. Furthermore, we observed that specific anti-inflammatory drugs were able to considerably reduce the oedema, the pain and the muscle damage caused by both venoms. The inflammatory reaction induced by B. moojeni venom is mediated by eicosanoid action, histamine and nitric oxide, with significant participation of bradykinin on the hyperalgesic and myotoxic effects of this venom. These mediators also participate to inflammation caused by B. alternatus venom. However, the inefficient anti-inflammatory effects of some local modulation suggest that histamine, leukotrienes and nitric oxide have little role in the oedema or myotoxicity caused by B. alternatus venom. PMID- 26975254 TI - Genetics of bipolar disorders. AB - Advances towards the understanding of the etiological mechanisms involved in mood disorders provide interesting yet diverse hypotheses and promising models. In this context, molecular genetics has now been widely incorporated into genetic epidemiological research in psychiatry. Affective disorders and, in particular, bipolar affective disorder (BPAD) have been examined in many molecular genetic studies which have covered a large part of the genome, specific hypotheses such as mutations have also been studied. Most recent studies indicate that several chromosomal regions may be involved in the aetiology of BPAD. Other studies have reported the presence of anticipation in BPAD. This phenomenon describes the increase in clinical severity and decrease in age of onset observed in successive generations. This mode of transmission correlates with the presence of specific mutations (Trinucleotide Repeat Sequences) and may represent a genetic factor involved in the transmission of the disorder. In parallel to these new developments in molecular genetics, the classical genetic epidemiology, represented by twin, adoption and family studies, provided additional evidence in favour of the genetic hypothesis in mood disorders. Moreover, these methods have been improved through models to test the gene-environment interactions. While significant advances have been made in this major field of research, it appears that integrative models, taking into account the interactions between biological (genetic) factors and social (psychosocial environment) variables offer the most reliable way to approach the complex mechanisms involved in the etiology and outcome of mood disorders. PMID- 26975255 TI - Acute tryptophan depletion in bipolar disorders; literature review and directives for further research. AB - Serotonin (5-HT) has been implicated in the pathophysiology of bipolar disorders. Acute tryptophan depletion (ATD), which decreases serotonergic turnover, is an established paradigm to study serotonergic vulnerability in affective disorders. Literature on the application of ATD as a research tool in bipolar patients is limited to three studies, which revealed inconsistent results on mood modification. These inconsistencies may be attributed to differences in methodological procedures and / or characteristics of included patients. Patient selection, methodological aspects and procedures of these studies are critically considered and recommendations given. A research protocol to test the 5-HT vulnerability in bipolar disorder is proposed. PMID- 26975256 TI - Epidemiology and pathobiology of bipolar disorder, and their exploration within a complete catchment area population. AB - Epidemiological and pathobiological findings in bipolar disorder [BP] have often been limited by selection bias and lack of epidemiological representativeness. In a rural, circumscribed catchment area, 'all' patients with BP were identified and assessed. On preliminary analysis, morbid risk [MR] for BP over the area as a whole was 5.0 +/- 0.6/1000. The distribution of MR for BP over geographical subregions showed no significant deviation from a statistical model for random occurrences in space by place at birth, in contrast to schizophrenia [SZ], and varied only modestly among males by place at onset. These results imply different etiological factors acting in BP in comparison with SZ, particularly with regard to the role of early versus later life events. In preliminary analyses of psychotic and cognitive features, current severity of positive symptoms was predicted in BP only by increasing dominance of the left hand; negative symptoms by duration of illness and current anticholinergic exposure; poorer general and frontal cognitive function by older age at onset of illness, increasing duration of illness, and current anticholinergic exposure. The finding on handedness suggests disturbance of cerebral asymmetry associated with positive symptoms in BP, while both negative symptoms and cognitive impairment may involve progressive processes. Further analysis of this epidemiologically complete population, including systematic comparisons of BP with schizoaffective disorder and SZ, continues. PMID- 26975253 TI - Epigenetic and Transcriptional Alterations in Human Adipose Tissue of Polycystic Ovary Syndrome. AB - Genetic and epigenetic factors may predispose women to polycystic ovary syndrome (PCOS), a common heritable disorder of unclear etiology. Here we investigated differences in genome-wide gene expression and DNA methylation in adipose tissue from 64 women with PCOS and 30 controls. In total, 1720 unique genes were differentially expressed (Q < 0.05). Six out of twenty selected genes with largest expression difference (CYP1B1, GPT), genes linked to PCOS (RAB5B) or type 2 diabetes (PPARG, SVEP1), and methylation (DMAP1) were replicated in a separate case-control study. In total, 63,213 sites (P < 0.05) and 440 sites (Q < 0.15) were differently methylated. Thirty differentially expressed genes had corresponding changes in 33 different DNA methylation sites. Moreover, a total number of 1913 pairs of differentially expressed "gene-CpG" probes were significantly correlated after correction for multiple testing and corresponded with 349 unique genes. In conclusion, we identified a large number of genes and pathways that are affected in adipose tissue from women with PCOS. We also identified specific DNA methylation pathways that may affect mRNA expression. Together, these novel findings show that women with PCOS have multiple transcriptional and epigenetic changes in adipose tissue that are relevant for development of the disease. PMID- 26975257 TI - Towards a new model for cellular pathophysiology in affective disorder. AB - The mode of action of serotonin in depression is unclear. We tested the modulation of hippocampal long-term plasticity, a model for learning and memory, by 5-HT and found a selective impairment of long-term depression resulting in a positive modification of synaptic network properties. We hypothetize a role for long-term plasticity in emotional regulation and the pathophysiology of affective disorders. PMID- 26975258 TI - Dysregulation of ion fluxes in bipolar affective disorder. AB - Bipolar disorder has attracted numerous research from different neurobiological angles. This review will summarize selected findings focusing on the role of disturbed transmem-braneous ion fluxes. Several mood stabilizers exhibit a distinct profile including effects on sodium, calcium and potassium conductance. In summary, some decisive mechanisms of action as calcium antagonism and modulation of potassium currents may play a crucial role in the success of any given mood stabilizer in bipolar disorder. PMID- 26975259 TI - Immunological aspects of bipolar disorder. AB - INTRODUCTION: Significant changes in immune function have been found in mood disorders. Controlled studies in bipolar disorder concerning cell-mediated immunity and thyroid autoimmunity are reviewed, and presented together with preliminary findings from our own ongoing study. METHOD: Using Medline and other sources, 14 controlled studies as well as some other relevant studies were found. RESULTS: Bipolar disorder is associated with an acute phase response and activation of the cell-mediated immune system, and with an increased prevalence of antithyroid autoantibodies. CONCLUSION: Changes in immune function, in connection with neuroendocrine changes, may provide new hypotheses for the pathophysiology of mood disorders. PMID- 26975260 TI - Brain 5-HT function in bipolar affective disorder. AB - BACKGROUND: Previous studies suggest that brain serotonin neurotransmission may mediate the actions of lithium carbonate. Acute tryptophan depletion (ATD) reduces brain serotonin and allows the study of this neurotransmitter in patient groups. Serotonin modulates electroencephalographic (EEG) activity, which is abnormal in bipolar disorder, and EEG abnormalities persist in euthymic bipolar patients. The EEG may therefore be a sensitive marker of 5-HT function in bipolar disorder. AIMS: This study examined the effects of ATD on mood, suicidal ideation and EEG activity in bipolar patients who were symptomatically stable on lithium. METHODS: 19 subjects satisfying DSM-IV criteria for bipolar I disorder participated in a within-subject, double-blind, placebo-controlled random-order crossover study. Following acute tryptophan depletion (induced by a 100g amino acid drink following an overnight fast) symptoms were evaluated, quantitative power spectrum brain mapping and measurement of auditory evoked potentials were carried out. RESULTS: ATD produced a significant fall in the amplitude of N1P2 and P300 components of the auditory evoked potential, but no significant changes in the power spectrum. There was an 83% reduction in plasma tryptophan (p<0.05, paired t-test) after the depleting but not the control drink. No significant changes in mood or suicidally scores were recorded after ATD. CONCLUSIONS: ATD attenuates auditory evoked potentials in bipolar disorder but does not reverse lithium's effects on mood and suicidally in bipolar disorder. PMID- 26975261 TI - Neuropathological studies of bipolar disorder. AB - The few available neuropathological studies of bipolar disorder are reviewed and placed in the context of structural imaging findings. Candidate pathological processes include cy-toarchitectural abnormalities, particularly in the anterior cingulate cortex and affecting glia, and disruption of white matter connections. The possible neuropathological relationship of bipolar disorder with major depression and with schizophrenia is discussed. PMID- 26975262 TI - The epidemiology of bipolar affective disorder; a review of the literature and introduction to work in progress. AB - The past 20 years have seen much research into affective disorders, reflecting advances in both pharmacological and psychological treatments. However, there has been little basic epidemiological research into bipolar illness. This is particularly apparent regarding its basic occurrence and possible epigenetic causes. This presentation will attempt to bring together and integrate the available evidence regarding the basic epidemiology of bipolar disorder, define areas where further research is needed, and outline a large epidemiological study including bipolar affective disorder that has been supported by the Stanley Foundation. PMID- 26975263 TI - Are schizophrenics neuropsychologically impaired affected psychotics? Neuropsychological performance and personality traits in relatives. AB - Neuropsychological deficits are found in both schizophrenic patients and their relatives, and some studies have shown similar, but less severe, deficits in affective psychotic patients and their relatives. We set out to establish - whether schizophrenia spectrum personality traits are more common in the relatives of schizophrenic patients than relatives of affective psychotic patients; - what is the relationship between spectrum personality traits and neuropsychological deficits in these relatives. Relatives were interviewed using the International Personality Disorder Examination (IPDE), and also completed the National Adult Reading Test (NART), the Trail Making Test (TMT: Parts A and B) and Thurstone's Verbal Fluency Test (TVFT). Spectrum personality traits were equally common in the 129 relatives of schizophrenic and 106 relatives of affective psychotic patients. Relatives of psychotic patients who themselves had high paranoid traits had lower NART scores than those without such personality traits (p=0.007);similarly, those with high schizoid personality traits took longer to complete the TMT, part B than those without such traits (p=0.0l); and relatives with high schizotypal traits generated significantly fewer words on the verbal fluency test than those without such traits (p=0.04). PMID- 26975264 TI - Bipolar disorder: is psychiatry's Cinderella starting to get out a little more? AB - Bipolar Disorder is a neglected disease. In the last twenty years fewer than 2,000 articles have been published with mania or bipolar disorder in the title, compared to 11,000 for schizophrenia and 19,000 for depression (data from EMBASE). This relative neglect of bipolar disorder is true both for neurobiological investigations and for investigations of treatment. Interest is reviving, I believe, in no small part because of the consistent support by the Stanley Foundation. Genuine advances in understanding neurobiology and treatment may be now be possible. The presentations made at this meeting are testimony to that. PMID- 26975265 TI - Accuracy of register- and record-based bipolar I disorder diagnoses in Finland; a study of twins. AB - Registers have been widely used in schizophrenia studies. For bipolar disorder, the use has been more limited and no studies exist concerning accuracy of bipolar I diagnoses in registers. We have collected an unselected twin sample for a study of bipolar I disorder. We report here the diagnostic procedures and accuracy of bipolar I diagnoses in a nation-wide hospital discharge registry. We evaluated also the accuracy of the medical record-based best-estimate diagnoses, comparing these with the SCID interview diagnoses. From the National Hospital Discharge Register we identified all like-sex twins, born 1940-1957, (N=42), and all like- or opposite-sex twins, born 1961-1969, (N=15), who had at least once a diagnosis of bipolar I disorder. The best-estimate diagnoses based on medical records, and were made by two doctors blind to each other, and according to DSM-IV-criteria. Diag-noses were then confirmed by SCID interviews, with the mi-nimum follow-up time after the first admission being 6 years. The accuracy of bipolar diagnoses in the register was 92% and 87%, accordingly. When comparing the best-estimate diagnoses to SCID interview diagnoses, there was one false positive case in the first sample, 3.4% [95% CI 0.1% to 7.8%], and none in the second sample. Our study shows that a diagnosis of bipolar I disorder in the hospital discharge register, or if based only on medical records, is highly reliable and stable. These results strengthen the usefulness of regis-ters also in bipolar disorder. PMID- 26975266 TI - Stabilization in the treatment of mania, depression and mixed states. AB - While one major need for improved therapeutic approaches in bipolar disease is the development of long-term treatment strategies, a systematic approach during the acute phase of bipolar disorder is also required. In our own studies we have arbitrarily divided the initial treatment of subjects by the predominant polarity for which they are treated acutely: manic, depressed, or mixed/cycling.1 In this larger investigation of over 150 patients with bipolar disorder, we now demonstrated again that the time to initial stabilization is generally the shortest with a manic episode and the longest with a mixed/cycling episode with the depressed episode in the middle (although almost as long as the mixed/cycling episode). These findings indicate the difficulty of treating both the depressed phase and mixed/cycling episodes in bipolar disorder. It is also noteworthy that gender does not have a significant effect on time to stabilization. Such findings in the acute phase have profound implications in designing and carrying out long term therapeutic strategies for this disorder. PMID- 26975267 TI - Typical and atypical antipsychotics in bipolar disorder. AB - BACKGROUND: In clinical practice, typical antipsychotics are widely used in the treatment of bipolar disorder, albeit in treatment guidelines often considered as adjunctive agents only. Recently, focus has shifted towards the use of atypical antipsychotics. This paper reviews the advantages and disadvantages associated with the use of antipsychotics in bipolar disorder. METHODS: Randomised controlled trials (RCTs) were selected for review. A few review articles were also cited. RESULTS: Typical antipsychotics, at least some of them, are powerful antimanics, beneficial for severe agitation in particular. However, in the long term treatment, typical antipsychics may precipitate depression. Among the atypical antipsychotics, both risperidone and olanzapine are clearly antimanic alternatives, although olanzapine is the best studied. Clozapine seems to be useful when other treatments fail to work. CONCLUSIONS: Antipsychotics are beneficial for some clinical presentations of mania. To minimize side effets, atypical agents should be preferred before typical agents, unless parenteral administration is needed. Despite the lack of RCTs, antipsychotics also seem to be useful as adjunctive agents in the treatment of psychotic bipolar depression. For the long term treatment of bipolar disorder, typical antipsychotics should be used only under certain circumstances. The place of atypical antipsychotics in the long term treatment of bipolar disorder remains to be studied. PMID- 26975268 TI - Lithium and carbamazepine in bipolar disorder. AB - Lithium is considered first choice in the prevention of prospective episodes in patients with bipolar disorder. However, efficacy is not satisfactory in all patients and side effects sometimes prevent the use of lithium. It is argued that efficacy in clinical practice may be less impressive than anticipated from clinical trials, and alternative treatments are beinu advocated increasingly for that reason, such as the anticonvulsants, carbamazepine and valproate. PMID- 26975269 TI - The efficacy of valproate, lamotrigine and gabapentin in bipolar disorder; review of double-blind controlled studies. AB - AIMS: The efficacy of the anticonvulsants valproate, lamotrigine and gabapentin in bipolar disorder is reviewed. METHOD: Using Medline (r) and other sources of information, 12 double-blind controlled studies with either of these compounds were identified. RESULTS: None of the compounds has been proven effective in the prophylaxis of bipolar disorder. Valproate has been found an effective drug in acute mania, while in continuation treatment after acute mania it proved to be save, i.e. not causing switches into depression. Lamotrigine is the only anticonvulsant with proven efficacy in acute bipolar depression. So far gabapentin has not been found effective. CONCLUSION: For the prophylaxis of bipolar disorder, lithium is still the treatment of choice. Carbamazepine and valproate are good alternatives, especially for patients not responding to lithium or not tolerating it. Lamotrigine may be a good alternative in bipolar depression. PMID- 26975270 TI - Predicting medication non-adherence in severe affective disorders. AB - Objective This study explored the utility of the Health Belief Models (HBM) in explaining medication adherence in subjects with severe affective disorders. Method Well established measuring instruments, with confirmed reliability and validity, were used to assess each component of two HBMs and adherence with mood stabilising medication in 104 subjects with bipolar (n=82), unipolar (n=18) or schizo-affective (n=4) disorders. Results Highly adherent and partially adherent subjects differed significantly in the stability of the level and the overall serum level of drug acheived. Subject's beliefs about themselves and their illness and their control over the disorder were more important than side-effects in predicting medication adherence. There were marked differences in the primary reasons for non-adherence identified by patients and their clinicians. Conclusion Although the study has a number of methodological limitations, the results suggest that clinical assessment of components of HBMs may improve the detection of patients at risk of non-adherence with mood stabilising medication. PMID- 26975271 TI - Pediatric mania: a developmental subtype of bipolar disorder? AB - Despite ongoing controversy, the view that pediatric mania is rare or non existent has been increasingly challenged not only by case reports but also by systematic research. This research strongly suggests that pediatric mania may not be rare but that it may be difficult to diagnose. Since children with mania are likely to become adults with bipolar disorder, the recognition and characterization of childhood-onset mania may help identify a meaningful developmental subtype of bipolar disorder worthy of further investigation. The major difficulties that complicate the diagnosis of pediatric mania include: - its pattern of comorbidity may be unique by adult standards, especially its overlap with ADHD, aggression and conduct disorder; - its overlap with substance use disorders; - its association with trauma and adversity; - its response to treatment is atypical by adult standards. These issues will be reviewed in the presentation. PMID- 26975272 TI - Bipolar disorder in children and adolecents: a clinical reality? AB - The appearance, the differential diagnosis and the prevalence of bipolar disorder in children and adolescents is discussed. Among adolescents bipolar disorder appears to have a similar prevalence in the US and The Netherlands. However, among children it is frequently diagnosed in the US and hardly in The Netherlands. It is concluded that bipolar disorder tends to start earlier in the US than in the Netherlands. It is hypothesized that this may be related to a higher use of stimulants and antidepressants by US children diagnosed as ADHD or depression, respectively. PMID- 26975273 TI - The rationale, design, and progress of two novel maintenance treatment studies in pediatric bipolarity. AB - INTRODUCTION: There are no definitively established acute or maintenance treatments for juvenile bipolar disorder. METHOD: Two randomized, blind, maintenance clinical trials in children and adolescents with bipolar disorders are ongoing at the University Hospitals of Cleveland/Case Western Reserve University Stanley Clinical Research Center for bipolar disorder. The first is comparing the safety and effectiveness of lithium carbonate (Li+) to divalproex sodium (VPA) for up to 76 weeks in youths with stabilized bipolar illness (type 1 or 2). The second study is designed to compare the efficacy of VPA to placebo in the acute management of subsyndromal symptoms of bipolar disorder ('cyclotaxia') and the prevention of the full syndrome in children at risk. Both studies use the prospective life-chart method as an outcome measure. RESULTS: Sixty-six youths have received study medication as part of the trial that is comparing Li+ to VPA as a maintenance therapy. In addition, 32 youths have received blinded treatment as part of the 'cyclotaxia' prevention study. Combination Li+A/PA treatment appears generally well tolerated and seems to have robust anti-manic and antidepressant effects. DISCUSSION: Since the blind has not been broken on either of these clinical trials, conclusions about the maintenance effectiveness of either VPA or Li+ in youths with bipolar disorder type 1 or 2 cannot be made yet. Similarly, it is unclear whether VPA is superior to placebo in genetically high risk youths with cyclotaxia. The final results of these trials should provide valuable information about the treatment of juvenile bipolar disorders. PMID- 26975274 TI - Neural mechanisms of childhood-onset bipolar illness. AB - Substantial evidence exists for a cohort effect (earlier onset and increased prevalence) for both unipolar and bipolar affective disorder in every generation born since World War II. This effect could be related to inherited mechanisms (e.g., bi-Hneal pedigrees or genetic anticipation) or to environmental/experiential effects on gene expression (e.g., stressor effects on the induction of transcription and growth factors, enzymes, hormones and their receptors, and signal transduction molecules) as documented in preclinical models of neonatal maternal separation. This laboratory evidence is summarized and new clinical data on the impact of severe stressors on the unfolding course of bipolar illness are noted. The reported occurrence of childhood or adolescent physical or sexual abuse, compared to those who report their absence, is associated with: earlier bipolar illness onset; faster cycling (including ultradian) patterns; increased Axis I and II comorbidities; and increased time ill in a prospective year of follow-up. Selectively, physical abuse was associated with a reported pattern of increasingly severe mania and sexual abuse with increased numbers of serious suicide attempts. In a retrospective survey of parents of children with an approximate average age of 13 who were diagnosed with bipolar illness (compared to those with other diagnoses and those with no diagnosis), a cluster of symptoms related to irritability and dyscontrol differentiated the bipolar children earliest. These symptoms included: temper tantrums, irritability, inattention, hyperactivity, impulsivity, poor frustration tolerance, and increased aggression. Given the growing evidence that episodes of affective dysfunction can not only convey morbidity and mortality, but may also sensitize to further recurrence and thus change the course of illness, opportunities abound for early recognition and intervention in childhood onset bipolar illness. Such a successful endeavor would both allow a more normal psychobiological development and allow the possibility of preventing the unfolding of more full-blown bipolar illness altogether. PMID- 26975275 TI - Prevalence of psychopathology in children of bipolar parents. AB - The purpose of this study was to determine psychopathology in a large sample of adolescent children (N = 140) of parents (N = 86) with bipolar disorders, using multiple sources of information (child, parent, teacher). The main aims of the study were: 1) to compare parent, teacher and self reported problem behavior ratings of children of bipolar parents with those of children from the general population, and 2) to determine the prevalence of DSM-IV diagnoses in offspring of bipolar parents, and 3) to examine the possible association between gender of the bipolar parent and psychopathology among the offspring. PMID- 26975276 TI - Acute and continuation pharmacological treatment of children and adolescents with bipolar disorders; a summary of two previous studies. AB - We report the results of an acute-phase and continuation-phase study of the pharmacological treatment of children and adolescents with bipolar disorders. The acute phase study, with a duration of 6-8 weeks, aimed at developing effect sizes (ES) for lithium, divalproex sodium, and carbamazepine, in the acute phase treatment of Bipolar I or II children and adolescents during a mixed or manic episode. During the acute-phase of treatment, 42 outpatients with a mean age of 11.4 yr. (20 with Bipolar I Disorder and 22 with Bipolar II Disorder) were randomly assigned to 6-8 weeks of open treatment with either lithium, divalproex sodium, or carbamazepine. The primary efficacy measures were the weekly CGI Improvement scores and the Young Mania Rating Scale. Using a >= 50% change from baseline to exit in the Y-MRS scores to define response, the effect size for divalproex sodium was 1.63,1.06 for lithium, and 1.00 for carbamazepine. Using this same response measure with the intent-to-treat sample, the response rates were: sodium divalproex 53%; lithium 38%; and carbamazepine 38% (x 2=0.85, 2 d.f., p=0.60). Thirty-five subjects continued in open, treatment for another 16 18 weeks, for a total of 24 weeks of prospective treatment. Overall, of the thirty-five continuation phase subjects, thirty (85%) were categorized as responders at the end of the continuation phase of treatment. Of these thirty five subjects, 13 (37%) were only on a single mood stabilizer and no other psychotropic agents at the end of the continuation phase. Thirty-one percent of subjects in continuation were also treated with a stimulant medication in addition to mood stabilizers. PMID- 26975277 TI - beta-lactams resistance gene quantification in an antibiotic resistant Escherichia coli water suspension treated by advanced oxidation with UV/H2O2. AB - Water is one of the most important habitats and route for the spread of antibiotic resistance (AR) in the environment and disinfection processes can be a potential barrier to minimise this risk. In this study the effect of UV/H2O2 process on the potential of AR transfer was investigated through cultivation methods vs (polymerase chain reaction) PCR based methods. blaTEM was selected as target antibiotic resistance gene (ARG) and was quantified by qPCR in the survived colonies and the whole suspension (total DNA). The detection limit of residual antibiotic resistant Escherichia coli (E. coli) colonies (5CFUmL-1) was reached after 240min treatment, but blaTEM gene was still present in total DNA after 300min (2.8*106 copies mL-1), and no effect was observed in DNA extracted from cell cultures (3.8*108 copies mL-1 after 90min). Accordingly, the investigated disinfection process may select for unaffected ARGs, therefore contributing to the potential transfer of AR in the environment. PMID- 26975278 TI - The Modulatory Effect of Anthocyanins from Purple Sweet Potato on Human Intestinal Microbiota in Vitro. AB - In order to investigate the modulatory effect of purple sweet potato anthocyanins (PSPAs) on human intestinal microbiota, PSPAs were prepared by column chromatography and their influence on intestinal microbiota was analyzed by monitoring the bacterial populations and analyzing short-chain fatty acid (SCFA) concentrations at different time points. The numbers (log10 cell/mL) of Bifidobacterium and Lactobacillus/Enterococcus spp., Bacteroides-Prevotella, Clostridium histolyticum, and total bacteria after 24 h of culture in anaerobic fermentation broth containing PSPAs were 8.44 +/- 0.02, 8.30 +/- 0.01, 7.80 +/- 0.03, 7.60 +/- 0.03, and 9.00 +/- 0.02, respectively, compared with 8.21 +/- 0.03, 8.12 +/- 0.02, 7.95 +/- 0.02, 7.77 +/- 0.02, and 9.01 +/- 0.03, respectively, in the controls. The results showed that PSPAs induced the proliferation of Bifidobacterium and Lactobacillus/Enterococcus spp., inhibited the growth of Bacteroides-Prevotella and Clostridium histolyticum, and did not affect the total bacteria number. Total SCFA concentrations in the cultures with PSPAs were significantly higher than in the controls (P < 0.05). Moreover, during the fermentation, the PSPAs were partially fragmented to phenolic acids, which may exert a better effect on intestinal microecology, suggesting that PSPAs may have prebiotic-like activity by generating SCFAs and modulating the intestinal microbiota, contributing to improvements in human health. PMID- 26975279 TI - Endoscopic transluminal drainage of walled-off necrosis: Does size matter? PMID- 26975280 TI - Is the glass ceiling in gastroenterology gone? PMID- 26975281 TI - Measuring quality of endoscopic eradication therapy in Barrett's esophagus. PMID- 26975282 TI - Palliative treatment of malignant dysphagia: stent by and await further instructions. PMID- 26975283 TI - Endoscopic myotomy of Zenker's diverticulum: lessons from 3 decades of experience. PMID- 26975284 TI - Confocal laser endomicroscopy in inflammatory bowel disease: achieving new depths in mucosal healing. PMID- 26975285 TI - Response. PMID- 26975286 TI - Clip closure for the prevention of polypectomy bleeding: Could antiplatelet therapy be a confounding factor? PMID- 26975287 TI - Questions for confirming superiority of endoscopy for GI stromal tumors in the upper GI tract. PMID- 26975288 TI - Response. PMID- 26975289 TI - Self-expandable metal stents versus plastic stents for malignant biliary obstruction. PMID- 26975290 TI - Removal of buried gastroduodenal stents after drainage of pancreatic fluid collections: Silence of the LAMS (with video). PMID- 26975291 TI - In search of the optimal technique to overcome cold polypectomy cutting failure: pulling up may be better than resnaring (with video). PMID- 26975292 TI - Response. PMID- 26975293 TI - Life-threatening hyponatremia, hypokalemia, and metabolic alkalosis after intragastric balloon placement. PMID- 26975294 TI - Treatment of pancreaticoportal fistula by endosonography-guided rendezvous. PMID- 26975295 TI - Peroral cholangioscopy: use of a Roth Net retriever for difficult biliary stones. PMID- 26975296 TI - Iatrogenic duodenal perforation during underwater ampullectomy: endoscopic repair using polyglycolic acid sheets. PMID- 26975298 TI - Potency of different red light sources in photodynamic induction of cell death in a squamous cell carcinoma cell line. AB - LED illumination systems were found to be more efficacious than broad spectrum lamps in recent phase III trials on photodynamic treatment of actinic keratosis. However, a detailed comparison of the light doses emitted at the appropriate spectral range and its correlation to photodynamic effects is thus far not available for the most frequently used devices. Here, we compared the spectral emissions of three different PDT lamps with their potency of inducing cell death in ALA-loaded A431 cells, including a new system equipped with more advanced LEDs matching the photosensitizer absorption peak more precisely and emitting more homogeneous light over time. Cells were exposed to two different ALA concentrations, incubated for 1 or 3h and then illuminated by one of two different LED or a broad-spectrum system at four different light doses, whereupon viability was assessed. Maximal doses were selected in accordance to clinically applied light doses in recent phase III studies and the manufacturers' recommendations. The data gathered here clearly demonstrate that the two LED systems were significantly more effective in inducing cell death than the broad spectrum system. Most efficient was the newer LED system, in agreement with emission parameters that more accurately corresponded to the photosensitizer's absorption peak. PMID- 26975297 TI - Perceived benefits and negative consequences of alcohol consumption in women living with HIV: a qualitative study. AB - BACKGROUND: Women living with HIV have increased prevalence of medical and psychological comorbidities that could be adversely affected by alcohol consumption. Little is known about their unique motivations for drinking or perceptions of HIV-related consequences. In preparation for an alcohol intervention study, we sought to better understand reasons for drinking and perceived consequences of alcohol consumption among a sample of women living with HIV. METHODS: Four focus groups, with a total of 24 adult women (96% African American, 88% HIV-positive), were conducted in Jacksonville, FL, Washington, DC and Chicago, IL. Focus group discussions were tape-recorded and transcribed verbatim; a conventional content analysis approach was used to identify themes, that were then grouped according to a biopsychosocial model. RESULTS: Regarding reasons for drinking, women described themes that included biological (addiction, to manage pain), psychological (coping, to escape bad experiences, to feel in control), and social (peer pressure, family). Themes related to consequences from alcohol included biological (damage to body, poor adherence to medications), psychological (risky or regrettable behavior, memory loss), and social (jail, loss of respect, poor choices). When discussing how their drinking impacted their health, women focused on broader issues, rather than HIV-specific issues. CONCLUSION: Many women living with HIV are drinking alcohol in order to self manage pain or emotions, and their perceived consequences from drinking extend beyond HIV-specific medical issues. Most participants described themes related to psychological issues and situations that are common in women living with HIV. Interventions to address drinking should inquire more specifically about drinking to manage pain or emotion, and help women to recognize the potential adverse impact of alcohol on comorbid health issues, including their own HIV infection. PMID- 26975299 TI - A systematic review to examine the evidence regarding discussions by midwives, with women, around their options for where to give birth. AB - BACKGROUND: Discussion of place of birth is important for women and maternity services, yet the detail, content and delivery of these discussions are unclear. The Birthplace Study found that for low risk, multiparous women, there was no significant difference in neonatal safety outcomes between women giving birth in obstetric units, midwifery-led units, or home. For low risk, nulliparous women giving birth in a midwifery-led unit was as safe as in hospital, whilst birth at home was associated with a small, increased risk of adverse perinatal outcomes. Intervention rates were reduced in all settings outside hospital. NICE guidelines recommend all women are supported in their choice of birth setting. Midwives have the opportunity to provide information to women about where they choose to give birth. However, research suggests women are sometimes unaware of all the options available. This systematic review will establish what is known about midwives' perspectives of discussions with women about their options for where to give birth and whether any interventions have been implemented to support these discussions. METHODS: The systematic review was PROSPERO registered (registration number: CRD42015017334). The PRISMA statement was followed. Medline, Cochrane, CINAHL, PsycINFO, Popline and EMBASE databases were searched between 2000-March 2015 and grey literature was searched. All identified studies were screened for inclusion. Qualitative data was thematically analysed, whilst quantitative data was summarised. RESULTS: The themes identified relating to influences on midwives' place of birth discussions with women were organisational pressures and professional norms, inadequate knowledge and confidence of midwives, variation in what midwives told women and the influence of colleagues. None of the interventions identified provided sufficient evidence of effectiveness and were of poor quality. CONCLUSIONS: The review has suggested the need for a pragmatic, understandable place of birth dialogue containing standard content to ensure midwives provide low risk women with adequate information about their place of birth options and the need to improve midwives knowledge about place of birth. A more robust, systematic evaluation of any interventions designed is required to improve the quality of place of birth discussions. By engaging with co-produced research, more effective interventions can be designed, implemented and sustained. PMID- 26975301 TI - Factors Affecting Resilience in Families of Adults With Diabetes. AB - PURPOSE: The purpose of the study was to investigate the impact of family resilience on families of adults with type 1 or type 2 diabetes. METHODS: A convenience sample of 77 participants was recruited from several diabetes education/support group programs and 1 private medical practice to participate in this descriptive correlational study. Participants completed several instruments measuring family member satisfaction with components of family functioning, family resilience, life orientation (measure of optimism), and diabetes knowledge. RESULTS: Family members were predominantly female (71%) and white (97%), and they had a minimum of a college education (79%). A significant positive relationship was found between family functioning and family resilience (r = 0.59, P < .01). Regression analysis revealed that family functioning was the only predictor of family resilience, explaining 46% of the variance. Positive outlook and diabetes knowledge were not significant contributors to the model. A significant low correlation was found between family member's level of diabetes knowledge and measure of optimism. Additional findings demonstrated that the Family Resilience Assessment tool was a reliable measure, with a Cronbach alpha of 0.91. CONCLUSION: Family functioning was associated with family resilience. Future research should focus on replicating the study in a more heterogeneous population, with further investigation into the needs of family members of adults with diabetes. PMID- 26975302 TI - Predicting Handwriting Difficulties Through Spelling Processes. AB - This study examined whether spelling tasks contribute to the prediction of the handwriting status of children with poor and good handwriting skills in a cross sectional study with 276 Spanish children from Grades 1 and 3. The main hypothesis was that the spelling tasks would predict the handwriting status of the children, although this influence would decrease with age due to a gradual automatization of handwriting skills. The results confirmed this hypothesis. Another interesting result was that the pattern of pseudoword and irregular word spellings as predictors of handwriting status changed from Grade 1 to Grade 3. In Grade 1, the pseudoword spelling task made a significant contribution, whereas the irregular word spelling task did not. The opposite pattern was found in Grade 3. These results may be a consequence of progressive acquisition of orthographic representations. The orthographic role of the task of writing the alphabet in order from memory in the prediction model was also analyzed. The writing of the alphabet in order from memory task made a significant contribution to the prediction of handwriting status of the children beyond the orthographic influence of spelling tasks. The additional effect of this task on the prediction of handwriting status is presumably due to the fact that this measure is based on fluency. PMID- 26975303 TI - Family Caregivers' Pain Management in End-of-Life Care: A Systematic Review. AB - CONTEXT: Pain management was the most identified burden faced by family caregivers in end-of-life caregiving. OBJECTIVES: To synthesize current scientific evidence on family caregivers' experience of pain management in end-of life care. METHODS: A systematic review was conducted using CINAHL, Embase, PubMed, and Cochrane Library electronic databases. Data were extracted from each included paper and organized into tables to synthesize the findings. RESULTS: Fourteen research papers focusing on family caregivers' experience of pain management and strategies in end-of-life care were included. Nine were observational studies, 3 were case studies, and 2 were experimental studies. These studies mainly focused on exploring family caregivers' engagement in pain management and communication with the hospice care team about pain control; family caregivers' knowledge, skills, and self-efficacy in pain management; and family caregivers' concerns and experience of pain management. CONCLUSION: This review identified themes similar to previous reviews on family caregivers of patients with cancer or in palliative care: inadequate knowledge and assessment skills in pain management, misunderstanding of pain medications, and poor communication with the care team. Future research should design educational programs and material for family caregivers to improve their pain management knowledge and skills, communication, and engagement in care. The scientific knowledge on this topic is scarce, and level of evidence is low; it is therefore imperative to have more exploratory studies to expand the quality and quantity of evidence and increase our understanding of family caregivers' needs and barriers to pain management based on larger and more diverse patient and caregiver samples. PMID- 26975304 TI - Estimation of photoneutron yield in linear accelerator with different collimation systems by Geant4 and MCNPX simulation codes. AB - At present, the bremsstrahlung photon beams produced by linear accelerators are the most commonly employed method of radiotherapy for tumor treatments. A photoneutron source based on three different energies (6, 10 and 15 MeV) of a linac electron beam was designed by means of Geant4 and Monte Carlo N-Particle eXtended (MCNPX) simulation codes. To obtain maximum neutron yield, two arrangements for the photo neutron convertor were studied: (a) without a collimator, and (b) placement of the convertor after the collimator. The maximum photon intensities in tungsten were 0.73, 1.24 and 2.07 photon/e at 6, 10 and 15 MeV, respectively. There was no considerable increase in the photon fluence spectra from 6 to 15 MeV at the optimum thickness between 0.8 mm and 2 mm of tungsten. The optimum dimensions of the collimator were determined to be a length of 140 mm with an aperture of 5 mm * 70 mm for iron in a slit shape. According to the neutron yield, the best thickness obtained for the studied materials was 30 mm. The number of neutrons generated in BeO achieved the maximum value at 6 MeV, unlike that in Be, where the highest number of neutrons was observed at 15 MeV. Statistical uncertainty in all simulations was less than 0.3% and 0.05% for MCNPX and the standard electromagnetic (EM) physics packages of Geant4, respectively. Differences among spectra in various regions are due to various cross-section and stopping power data and different simulations of the physics processes. PMID- 26975305 TI - Neuromodulation: a focus on dorsal root ganglion stimulation. PMID- 26975307 TI - Pension funds: tobacco investment up in smoke. PMID- 26975306 TI - Clinical features for diagnosis and management of patients with PRDM12 congenital insensitivity to pain. AB - BACKGROUND: Congenital insensitivity to pain (CIP) is a rare extreme phenotype characterised by an inability to perceive pain present from birth due to lack of, or malfunction of, nociceptors. PRDM12 has recently been identified as a new gene that can cause CIP. The full phenotype and natural history have not yet been reported. METHODS: We have ascertained five adult patients and report their clinical features. RESULTS: Based on our findings, and those of previous patients, we describe the natural history of the PRDM12-CIP disorder, and derive diagnostic and management features to guide the clinical management of patients. CONCLUSIONS: PRDM12-CIP is a distinct and diagnosable disorder, and requires specific clinical management to minimise predictable complications. PMID- 26975308 TI - Editorial: Computer-Assisted Approaches as Decision Support Systems in the Overall Strategy of Combating Emerging Diseases: Some Comments Regarding Drug Design, Vaccinomics, and Genomic Surveillance of the Zika Virus. PMID- 26975310 TI - Provider attributes correlation analysis to their referral frequency and awards. AB - BACKGROUND: There has been a recent growth in health provider search portals, where patients specify filters-such as specialty or insurance-and providers are ranked by patient ratings or other attributes. Previous work has identified attributes associated with a provider's quality through user surveys. Other work supports that intuitive quality-indicating attributes are associated with a provider's quality. METHODS: We adopt a data-driven approach to study how quality indicators of providers are associated with a rich set of attributes including medical school, graduation year, procedures, fellowships, patient reviews, location, and technology usage. In this work, we only consider providers as individuals (e.g., general practitioners) and not organizations (e.g., hospitals). As quality indicators, we consider the referral frequency of a provider and a peer-nominated quality designation. We combined data from the Centers for Medicare and Medicaid Services (CMS) and several provider rating web sites to perform our analysis. RESULTS: Our data-driven analysis identified several attributes that correlate with and discriminate against referral volume and peer-nominated awards. In particular, our results consistently demonstrate that these attributes vary by locality and that the frequency of an attribute is more important than its value (e.g., the number of patient reviews or hospital affiliations are more important than the average review rating or the ranking of the hospital affiliations, respectively). We demonstrate that it is possible to build accurate classifiers for referral frequency and quality designation, with accuracies over 85 %. CONCLUSIONS: Our findings show that a one-size-fits-all approach to ranking providers is inadequate and that provider search portals should calibrate their ranking function based on location and specialty. Further, traditional filters of provider search portals should be reconsidered, and patients should be aware of existing pitfalls with these filters and educated on local factors that affect quality. These findings enable provider search portals to empower patients and to "load balance" patients between younger and older providers. PMID- 26975309 TI - A probabilistic generative model for quantification of DNA modifications enables analysis of demethylation pathways. AB - We present a generative model, Lux, to quantify DNA methylation modifications from any combination of bisulfite sequencing approaches, including reduced, oxidative, TET-assisted, chemical-modification assisted, and methylase-assisted bisulfite sequencing data. Lux models all cytosine modifications (C, 5mC, 5hmC, 5fC, and 5caC) simultaneously together with experimental parameters, including bisulfite conversion and oxidation efficiencies, as well as various chemical labeling and protection steps. We show that Lux improves the quantification and comparison of cytosine modification levels and that Lux can process any oxidized methylcytosine sequencing data sets to quantify all cytosine modifications. Analysis of targeted data from Tet2-knockdown embryonic stem cells and T cells during development demonstrates DNA modification quantification at unprecedented detail, quantifies active demethylation pathways and reveals 5hmC localization in putative regulatory regions. PMID- 26975312 TI - Effect of interferential current therapy on pain perception and disability level in subjects with chronic low back pain: a randomized controlled trial. AB - OBJECTIVE: To assess the short-term efficacy of transregional interferential current therapy on pain perception and disability level in chronic non-specific low back pain. DESIGN: A randomized, single-blinded (the assessor collecting the outcome data was blinded), controlled trial. SETTING: A private physiotherapy research clinic. SUBJECTS: A total of 64 individuals, 20 men and 44 women, mean (SD) age was 51 years (11.93), with low back pain of more than three months, with or without pain radiating to the lower extremities above the knee, were distributed into a control ( n = 20) or an experimental group ( n = 44). A 2:1 randomization ratio was used in favour of the latter. INTERVENTIONS: A transregional interferential current electrotherapy protocol was performed for participants in the experimental group, while the control group underwent a 'usual care' treatment (massage, mobilization and soft-tissue techniques). All subjects received up to 10 treatment sessions of 25 minutes over a two-week period, and completed the intervention and follow-up evaluations. OUTCOME MEASURES: Self-perceived pain was assessed with a Visual Analogue Scale. Secondary measure included the Oswestry Low Back Disability Index. Evaluations were collected at baseline and after the intervention protocol. RESULTS: Significant between-group differences were found for interferential current therapy on pain perception ( p = 0.032) and disability level ( p = 0.002). The observed differences in the between-group mean changes were of 11.34 mm (1.77/20.91) and 13.38 points (4.97/21.78), respectively. CONCLUSIONS: A two-week transregional interferential current treatment has shown significant short-term efficacy, when compared with a 'usual care' protocol, on self-perceived pain and functionality in subjects with chronic low back pain. PMID- 26975311 TI - Evidence for Health I: Producing evidence for improving health and reducing inequities. AB - In an ideal world, researchers and decision-makers would be involved from the outset in co-producing evidence, with local health needs assessments informing the research agenda and research evidence informing the actions taken to improve health. The first step in improving the health of individuals and populations is therefore gaining a better understanding of what the main health problems are, and of these, which are the most urgent priorities by using both quantitative data to develop a health portrait and qualitative data to better understand why the local population thinks that addressing certain health challenges should be prioritized in their context. Understanding the causes of these health problems often involves analytical research, such as case-control and cohort studies, or qualitative studies to better understand how more complex exposures lead to specific health problems (e.g. by interviewing local teenagers discovering that watching teachers smoke in the school yard, peer pressure, and media influence smoking initiation among youth). Such research helps to develop a logic model to better map out the proximal and distal causes of poor health and to determine potential pathways for intervening and impacting health outcomes. Rarely is there a single 'cure' or stand-alone intervention, but rather, a continuum of strategies are needed from diagnosis and treatment of patients already affected, to disease prevention, health promotion and addressing the upstream social determinants of health. Research for developing and testing more upstream interventions must often go beyond randomized controlled trials, which are expensive, less amenable to more complex interventions, and can be associated with certain ethical challenges. Indeed, a much neglected area of the research cycle is implementation and evaluation research, which often involves quasi experimental research study designs as well as qualitative research, to better understand how to derive the greatest benefit from existing interventions and ways of maximizing health improvements in specific local contexts. There is therefore a need to alter current incentive structures within the research enterprise to place greater emphasis on implementation and evaluation research conducted in collaboration with knowledge users who are in a position to use the findings in practice to improve health. PMID- 26975313 TI - Does the use of Nintendo Wii SportsTM improve arm function? Trial of WiiTM in Stroke: a randomized controlled trial and economics analysis. AB - OBJECTIVE: The Trial of WiiTM in Stroke investigated the efficacy of using the Nintendo Wii SportsTM (WiiTM) to improve affected arm function after stroke. DESIGN: Multicentre, pragmatic, parallel group, randomized controlled trial. SETTING: Home-based rehabilitation. SUBJECTS: A total of 240 participants aged 24 90 years with arm weakness following a stroke within the previous six months. INTERVENTION: Participants were randomly assigned to exercise daily for six weeks using the WiiTM or arm exercises at home. MAIN MEASURES: Primary outcome was change in the affected arm function at six weeks follow-up using the Action Research Arm Test. Secondary outcomes included occupational performance, quality of life, arm function at six months and a cost effectiveness analysis. RESULTS: The study was completed by 209 participants (87.1%). There was no significant difference in the primary outcome of affected arm function at six weeks follow-up (mean difference -1.7, 95% CI -3.9 to 0.5, p = 0.12) and no significant difference in secondary outcomes, including occupational performance, quality of life or arm function at six months, between the two groups. No serious adverse events related to the study treatment were reported. The cost effectiveness analysis showed that the WiiTM was more expensive than arm exercises L1106 (SD 1656) vs. L730 (SD 829) (probability 0.866). CONCLUSION: The trial showed that the WiiTM was not superior to arm exercises in home-based rehabilitation for stroke survivors with arm weakness. The WiiTM was well tolerated but more expensive than arm exercises. PMID- 26975314 TI - The effect of injury on whole-plant senescence: an experiment with two root sprouting Barbarea species. AB - BACKGROUND AND AIMS: Senescence is the process of losing fitness when growing old, and is shaped by the trade-off between maintenance and reproduction that makes reproduction more unsure and maintenance more costly with age. In repeatedly reproducing plants, reductions in growth and fertility are signs of senescence. Disturbance, however, provides an opportunity to reset the ageing clock and consequently potentially ameliorate senescence. METHODS: To test the effects of disturbance on traits closely related to fitness and thus to senescence, a long-term garden experiment was established with two short-lived perennial congeners,Barbarea vulgaris and Barbarea stricta, that differ in their ability to resprout after injury. In the experiment, five damage treatments were applied to plants in four different phenophases. KEY RESULTS: It was found that damage to the plant body significantly prolonged life span in B. vulgaris but decreased whole-life seed production in both species. High concentration of seed production in one growing season characterized short life spans. Both more severe damage and a more advanced phenological phase at the time of damage caused reproduction to be spread over more than one growing season and equalized per season seed production. In terms of seed quality, average weight of a single seed decreased and seed germination rate increased with age regardless of damage. CONCLUSIONS: Although disturbance is able to reset the ageing clock of plants, it is so harmful to plant fitness that resprouting serves, at best, only to alleviate slightly the signs of senescence. Thus, in terms of whole-life seed production, injured plants were not more successful than uninjured ones in the two studied species. Indeed, in these species, injury only slightly postponed or decelerated senescence and did not cause effective rejuvenation. PMID- 26975315 TI - Allometric exponents as a tool to study the influence of climate on the trade-off between primary and secondary growth in major north-eastern American tree species. AB - BACKGROUND AND AIMS: Trees invest in both primary (e.g. height) and secondary (e.g. diameter) growth. The trade-off between these investments varies between species and changes with the tree growing environment. To better establish this trade-off, readily available allometric exponents relating height to diameter at breast height (gamma(h,dbh)) and stem volume to diameter at breast height (alpha(v,dbh)) were simultaneously studied. METHODS: Allometric exponents alpha(v,dbh) and gamma(h,dbh) were obtained from 8893 individual tree stem analyses from two broadleaved species (Betula papyrifera, Populus tremuloides) and four conifers (Picea glauca, Picea mariana, Pinus banksiana, Abies balsamea) in the temperate and boreal forests of the province of Quebec, Canada. alpha(v,dbh) and gamma(h,dbh) were related to tree age, stand density index (SDI), and mean temperature (TGS) and total precipitation (PGS) of the growing season. KEY RESULTS: alpha(v,dbh) and gamma(h,dbh) were found to be invariant with PGS and positively related to SDI and TGS for all species except Pinus banksiana. The parameter values associated with SDI and TGS were of higher value for conifers than for broadleaved species. CONCLUSIONS: This suggests that conifers and broadleaved species have different growth patterns. This could be explained by their different mode of development, the conifer species having a stronger apical dominance than broadleaved species. Such results could be further considered in allocation studies to quantify future carbon stocks in managed forests. PMID- 26975316 TI - Leptin augments coronary vasoconstriction and smooth muscle proliferation via a Rho-kinase-dependent pathway. AB - Leptin has been implicated as a key upstream mediator of pathways associated with coronary vascular dysfunction and disease. The purpose of this investigation was to test the hypothesis that leptin modifies the coronary artery proteome and promotes increases in coronary smooth muscle contraction and proliferation via influences on Rho kinase signaling. Global proteomic assessment of coronary arteries from lean swine cultured with obese concentrations of leptin (30 ng/mL) for 3 days revealed significant alterations in the coronary artery proteome (68 proteins) and identified an association between leptin treatment and calcium signaling/contraction (four proteins) and cellular growth and proliferation (35 proteins). Isometric tension studies demonstrated that both acute (30 min) and chronic (3 days, serum-free media) exposure to obese concentrations of leptin potentiated depolarization-induced contraction of coronary arteries. Inhibition of Rho kinase significantly reduced leptin-mediated increases in coronary artery contractions. The effects of leptin on the functional expression of Rho kinase were time-dependent, as acute treatment increased Rho kinase activity while chronic (3 day) exposure was associated with increases in Rho kinase protein abundance. Proliferation assays following chronic leptin administration (8 day, serum-containing media) demonstrated that leptin augmented coronary vascular smooth muscle proliferation and increased Rho kinase activity. Inhibition of Rho kinase significantly reduced these effects of leptin. Taken together, these findings demonstrate that leptin promotes increases in coronary vasoconstriction and smooth muscle proliferation and indicate that these phenotypic effects are associated with alterations in the coronary artery proteome and dynamic effects on the Rho kinase pathway. PMID- 26975317 TI - Expression of Tyrosine Hydroxylase is Negatively Regulated Via Prion Protein. AB - Cellular prion protein (PrP(C)) is a glycoprotein of the plasma membrane that plays pleiotropic functions by interacting with multiple signaling complexes at the cell surface. Recently, a number of studies have reported the involvement of PrP(C) in dopamine metabolism and signaling, including its interactions with tyrosine hydroxylase (TH) and dopamine receptors. However, the outcomes reported by independent studies are still debatable. Therefore in this study, we investigated the effects of PrP(C) on the TH expression during the differentiation of N2a cells with dibutyryl-cAMP, a well-known cAMP analog that activates TH transcription. Upon differentiation, TH was induced with concomitant reduction of PrP(C) at protein level, but not at mRNA level. shRNA-mediated PrP(C) reduction increased the basal level of TH at both mRNA and protein levels without dibutyryl-cAMP treatment. This phenotype was reversed by re-expression of PrP(C). PrP(C) knockdown also potentiated the effect of dibutyryl-cAMP on TH expression. Our findings suggest that PrP(C) has suppressive effects on TH expression. As a consequence, altered PrP(C) functions may affect the regulation of dopamine metabolism and related neurological disorders. PMID- 26975318 TI - Frequency-Dependent Modulation of Dopamine Release by Nicotine and Dopamine D1 Receptor Ligands: An In Vitro Fast Cyclic Voltammetry Study in Rat Striatum. AB - Nicotine is a highly addictive drug and exerts this effect partially through the modulation of dopamine release and increasing extracellular dopamine in regions such as the brain reward systems. Nicotine acts in these regions on nicotinic acetylcholine receptors. The effect of nicotine on the frequency dependent modulation of dopamine release is well established and the purpose of this study was to investigate whether dopamine D1 receptor (D1R) ligands have an influence on this. Using fast cyclic voltammetry and rat corticostriatal slices, we show that D1R ligands are able to modulate the effect of nicotine on dopamine release. Nicotine (500 nM) induced a decrease in dopamine efflux at low frequency (single pulse or five pulses at 10 Hz) and an increase at high frequency (100 Hz) electrical field stimulation. The D1R agonist SKF-38393, whilst having no effect on dopamine release on its own or on the effect of nicotine upon multiple pulse evoked dopamine release, did significantly prevent and reverse the effect of nicotine on single pulse dopamine release. Interestingly similar results were obtained with the D1R antagonist SCH-23390. In this study we have demonstrated that the modulation of dopamine release by nicotine can be altered by D1R ligands, but only when evoked by single pulse stimulation, and are likely working via cholinergic interneuron driven dopamine release. PMID- 26975319 TI - Prior knowledge of spatiotemporal configuration facilitates crossmodal saccadic response : A TWIN analysis. AB - Saccadic reaction times from a focused-attention task with a visual target and an acoustic nontarget support the hypothesis that the amount of saccadic facilitation in the presence of a nontarget increases with the prior knowledge of alignment with the target across different blocks of trials. The time-window-of integration model can account for the size of the effect by having window size depend on the prior knowledge of alignment. Some efforts to identify the neural correlates of the effect are discussed. PMID- 26975320 TI - Lethal and sublethal effects of pesticides on Chrysoperla carnea larvae (Neuroptera: Chrysopidae) and the influence of rainfastness in their degradation pattern over time. AB - The predator Chrysoperla carnea is a model species for the study of non-target effects of pesticides under different scenarios: registration of plant protection products under the European Union and effects of the Bt toxin. Laboratory and persistence studies were carried out with six pesticides currently used in corn crops in Spain that were applied at their maximum field recommended concentrations. The assessed end-points were larval mortality, survivorship until adult stage, duration of the larval and pupal periods, fecundity, fertility and sex ratio of the emerged adults. Based on the total effect (lethal and sublethal) caused to L3 larvae in contact with fresh residues in the laboratory, pendimethalin was harmless (IOBC 1), lambda-cyhalothrin, abamectin, and hexythiazox were slightly harmful (IOBC 2), deltamethrin was moderately harmful (IOBC 3) and chlorpyrifos was harmful (IOBC 4). Afterwards, the residues of the two most toxic pesticides in the lab (deltamethrin and chlorpyrifos) were aged under greenhouse conditions (22 +/- 2 degrees C, 40 +/- 10 % R.H., 16.9 MUmol m( 2) s(-1) UV radiation) in the presence and absence of artificial rainfall (10 l m(-2) h(-1), applied 24 h after pesticide application). Deltamethrin was classified as short lived (IOBC A) in both cases. However, degradation of chlorpyrifos residues was accelerated in the presence of rainfall, leading to the classification as slightly persistent (IOBC B), while in absence of rainfall it behaved as persistent (IOBC D). Every pesticide can be recommended for inclusion in corn IPM programs where the predator is present except chlorpyrifos that exhibited high direct toxicity in the lab and prolonged residual action even in the presence of rainfall. PMID- 26975321 TI - Exploration of photocatalytic properties of microbially designed silver nanoparticles on Victoria blue B. AB - Victoria blue B (VBB) belongs to triphenylmethane group of dyes, which is widely used in textile industries. Hence development of novel treatment methods are of considerable applications in its removal. In the current study, silver nanoparticles (AgNPs) formed by Bacillus amyloliquefaciens was investigated for the degradation of VBB. Interestingly, the UV-Vis spectroscopy analysis of VBB AgNPs treated samples showed a decrease in absorption at 615 nm, which is characteristic of pure VBB. This time-dependent degradation process was further investigated by changing the initial dye concentration, AgNPs concentration and pH. Approximately 78 % of reduction was observed within 8 h of the study and hence the result of the study is with promising applications for the development of novel dye degradation technologies. Phytotoxicity analysis of degradation product using Vigna unguiculata revealed the non-toxic effect of degradation product when compared to VBB and this confirms the promising potential and applications of the study. PMID- 26975322 TI - Odontogenic myxoma of the maxilla: surgical management and case report. AB - BACKGROUND: Odontogenic myxoma is a benign odontogenic tumour of the jaw [1]. This tumour often presents as an asymptomatic expansile lesion without sensory nerve changes [2]. It is thought to arise from mesenchymal origin with cells of microscopic similarity to dental pulp and follicle [3]. Radiographically it presents most often as a multiloculated radiolucency [2]. It is a locally aggressive lesion which may require extensive treatment to prevent recurrence. METHOD: The authors present the case of a 13-year-old boy with an extensive lesion in the maxilla. CONCLUSION: We discuss various treatment approaches for management of this tumour. PMID- 26975323 TI - MiR-181a-5p promotes anoikis by suppressing autophagy during detachment induction in the mammary epithelial cell line MCF10A. PMID- 26975324 TI - People living with HIV and procreation: 30 years of progress from prohibition to freedom? AB - The emergence of human immunodeficiency virus (HIV) infection in the 1980s drastically changed the prospects of conceiving a child for the man or woman infected with the virus. Advances in treatment then made it possible to envisage pregnancy while decreasing the risk of transmission to the child when the mother was infected. For couples where one partner was HIV-positive and who desired a child, recourse to medical help, notably medically assisted procreation, was discouraged, and very few centres offered such assistance in the 1980s and 1990s. Improved knowledge of viral excretion in the genital tracts, together with more effective treatment, made it possible to envisage medically assisted procreation for these couples, allowing them to have a child while at the same time likely reducing the risk of transmitting HIV to their partner. Several programmes have demonstrated their effectiveness in this domain. Owing to continually increasing knowledge over the past decade, natural conception can now be proposed. Couples where one or both partners are HIV-positive may opt for medically assisted procreation or natural reproduction. Specialists in reproductive medicine and HIV specialists need to provide couples with objective information allowing them to achieve near-optimal conditions that minimize HIV transmission risk. Couples will then be able to choose freely the mode of procreation most appropriate for them. PMID- 26975325 TI - Psychosocial counselling of identifiable sperm donors. AB - STUDY QUESTION: What do identifiable sperm donors feel about psychosocial counselling? SUMMARY ANSWER: Identifiable sperm donors found it important that psychosocial counselling focused on emotional consequences and on rules and regulations and they expected to have access to psychosocial counselling at the time that donor-offspring actually sought contact. WHAT IS KNOWN ALREADY: Most studies on sperm donors are on anonymous donors and focus on recruitment, financial compensation, anonymity and motivations. There is limited knowledge on the value that identifiable sperm donors place on psychosocial counselling and what their needs are in this respect. STUDY DESIGN, SIZE AND DURATION: We performed a qualitative study from March until June 2014 with 25 identifiable sperm donors, who were or had been a donor at the Centre for Reproductive Medicine of the Academic Medical Centre in Amsterdam any time between 1989 and 2014. PARTICIPANTS/MATERIALS, SETTING AND METHODS: We held semi-structured in depth interviews with identifiable sperm donors with an average age of 44 years. The interviews were fully transcribed and analysed using the constant comparative method of grounded theory. MAIN RESULTS AND THE ROLE OF CHANGE: Twelve out of 15 donors (former donors ITALIC! n = 8, active donors ITALIC! n = 7) who had received a counselling session during their intake procedure found it important that they had been able to talk about issues such as the emotional consequences of donation, disclosure to their own children, family and friends, future contact with donor-offspring and rules and regulations. Of the 10 former donors who had received no counselling session, 8 had regretted the lack of intensive counselling. In the years following their donation, most donors simply wanted to know how many offspring had been born using their sperm and had no need for further counselling. Nevertheless, they frequently mentioned that they were concerned about the well-being of 'their' offspring. In addition, they would value the availability of psychosocial counselling in the event that donor offspring actually sought contact. LIMITATIONS, REASONS FOR CAUTION: A limitation of our study is its generalizability, since only a small number of identifiable donors at a single centre were studied. Variation in how donors are counselled upon intake may affect how donors value psychosocial counselling. WIDER IMPLICATIONS OF THE FINDINGS: This study reports on the issues that identifiable donors value being addressed during their intake procedure, as well as during counselling in the event that donor-offspring actually seek contact. These findings can be used to achieve a higher quality of care for identifiable sperm donors and may be the starting point for developing guidelines on psychosocial counselling for sperm donors. STUDY FUNDING/COMPETING INTERESTS: No funding was obtained for this study. The authors have no conflicts of interest to declare. PMID- 26975326 TI - HT-COMET: a novel automated approach for high throughput assessment of human sperm chromatin quality. AB - STUDY QUESTION: Can we make the comet assay (single-cell gel electrophoresis) for human sperm a more accurate and informative high throughput assay? SUMMARY ANSWER: We developed a standardized automated high throughput comet (HT-COMET) assay for human sperm that improves its accuracy and efficiency, and could be of prognostic value to patients in the fertility clinic. WHAT IS KNOWN ALREADY: The comet assay involves the collection of data on sperm DNA damage at the level of the single cell, allowing the use of samples from severe oligozoospermic patients. However, this makes comet scoring a low throughput procedure that renders large cohort analyses tedious. Furthermore, the comet assay comes with an inherent vulnerability to variability. Our objective is to develop an automated high throughput comet assay for human sperm that will increase both its accuracy and efficiency. STUDY DESIGN, SIZE, DURATION: The study comprised two distinct components: a HT-COMET technical optimization section based on control versus DNAse treatment analyses ( ITALIC! n = 3-5), and a cross-sectional study on 123 men presenting to a reproductive center with sperm concentrations categorized as severe oligozoospermia, oligozoospermia or normozoospermia. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sperm chromatin quality was measured using the comet assay: on classic 2-well slides for software comparison; on 96 well slides for HT-COMET optimization; after exposure to various concentrations of a damage-inducing agent, DNAse, using HT-COMET; on 123 subjects with different sperm concentrations using HT-COMET. Data from the 123 subjects were correlated to classic semen quality parameters and plotted as single-cell data in individual DNA damage profiles. MAIN RESULTS AND THE ROLE OF CHANCE: We have developed a standard automated HT-COMET procedure for human sperm. It includes automated scoring of comets by a fully integrated high content screening setup that compares well with the most commonly used semi-manual analysis software. Using this method, a cross-sectional study on 123 men showed no significant correlation between sperm concentration and sperm DNA damage, confirming the existence of hidden chromatin damage in men with apparently normal semen characteristics, and a significant correlation between percentage DNA in the tail and percentage of progressively motile spermatozoa. Finally, the use of DNA damage profiles helped to distinguish subjects between and within sperm concentration categories, and allowed a determination of the proportion of highly damaged cells. LIMITATIONS, REASONS FOR CAUTION: The main limitations of the HT-COMET are the high, yet indispensable, investment in an automated liquid handling system and heating block to ensure accuracy, and the availability of an automated plate reading microscope and analysis software. WIDER IMPLICATIONS OF THE FINDINGS: This standardized HT-COMET assay offers many advantages, including higher accuracy and evenness due to automation of sensitive steps, a 14.4-fold increase in sample analysis capacity, and an imaging and scoring time of 1 min/well. Overall, HT COMET offers a decrease in total experimental time of more than 90%. Hence, this assay constitutes a more efficient option to assess sperm chromatin quality, paves the way to using this assay to screen large cohorts, and holds prognostic value for infertile patients. STUDY FUNDING/COMPETING INTERESTS: Funded by the CIHR Institute of Human Development, Child and Youth Health (IHDCYH; RHF 100625). O.A. is a fellow supported by the Fonds de la Recherche du Quebec - Sante (FRQS) and the CIHR Training Program in Reproduction, Early Development, and the Impact on Health (REDIH). B.R. is a James McGill Professor. The authors declare no conflicts of interest. PMID- 26975327 TI - Demonstration of Herpes Simplex Virus, Cytomegalovirus, and Epstein-Barr Virus in Colorectal Cancer. AB - BACKGROUND: The present study sought to investigate molecular evidence for association between the presence of herpes simplex virus (HSV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV) in CRC and colorectal polyp by using the PCR method in Iran. METHODS: In this analytical case-control study, we selected 15 patients with CRC, 20 patients with colorectal polyp, and 35 patients without malignancy as controls. After DNA extraction, PCR was used to determine HSV, CMV, and EBV genome by specific primers. Statistical analysis was performed using chi2 tests. RESULTS: Our findings demonstrated that there is no direct molecular evidence to support the association between HSV, CMV, and EBV and human colorectal malignancies. CONCLUSION: The results from this study do not exclude a possible oncogenic role of these viruses in neoplastic development of colon cells. PMID- 26975328 TI - Suppression of Structural Phase Transition in VO2 by Epitaxial Strain in Vicinity of Metal-insulator Transition. AB - Mechanism of metal-insulator transition (MIT) in strained VO2 thin films is very complicated and incompletely understood despite three scenarios with potential explanations including electronic correlation (Mott mechanism), structural transformation (Peierls theory) and collaborative Mott-Peierls transition. Herein, we have decoupled coactions of structural and electronic phase transitions across the MIT by implementing epitaxial strain on 13-nm-thick (001) VO2 films in comparison to thicker films. The structural evolution during MIT characterized by temperature-dependent synchrotron radiation high-resolution X ray diffraction reciprocal space mapping and Raman spectroscopy suggested that the structural phase transition in the temperature range of vicinity of the MIT is suppressed by epitaxial strain. Furthermore, temperature-dependent Ultraviolet Photoelectron Spectroscopy (UPS) revealed the changes in electron occupancy near the Fermi energy EF of V 3d orbital, implying that the electronic transition triggers the MIT in the strained films. Thus the MIT in the bi-axially strained VO2 thin films should be only driven by electronic transition without assistance of structural phase transition. Density functional theoretical calculations further confirmed that the tetragonal phase across the MIT can be both in insulating and metallic states in the strained (001)-VO2/TiO2 thin films. This work offers a better understanding of the mechanism of MIT in the strained VO2 films. PMID- 26975329 TI - Surface wave excitations and backflow effect over dense polymer brushes. AB - Polymer brushes are being increasingly used to tailor surface physicochemistry for diverse applications such as wetting, adhesion of biological objects, implantable devices and much more. Here we perform Dissipative Particle Dynamics simulations to study the behaviour of dense polymer brushes under flow in a slit pore channel. We discover that the system displays flow inversion at the brush interface for several disconnected ranges of the imposed flow. We associate such phenomenon to collective polymer dynamics: a wave propagating on the brush surface. The relation between the wavelength, the amplitude and the propagation speed of the flow-generated wave is consistent with the solution of the Stokes equations when an imposed traveling wave is assumed as the boundary condition (the famous Taylor's swimmer). PMID- 26975330 TI - Controlled synthesis of Ni/CuOx/Ni nanowires by electrochemical deposition with self-compliance bipolar resistive switching. AB - We demonstrate synthesis of Ni/CuOx/Ni nanowires (NWs) by electrochemical deposition on anodized aluminum oxide (AAO) membranes. AAO with pore diameter of ~70 nm and pore length of ~50 MUm was used as the template for synthesis of NWs. After deposition of Au as the seed layer, NWs with a structure of Ni/CuOx/Ni were grown with a length of ~12 MUm. The lengths of 1(st) Ni, CuOx, and 2(nd) Ni were ~4.5 MUm, ~3 MUm, and ~4.5 MUm, respectively. The Ni/CuOx/Ni device exhibits bipolar resistive switching behavior with self-compliance characteristics. Due to the spatial restriction of the current path in NW the Ni/CuOx/Ni NW devices are thought to exhibit self-compliance behaviour. Ni/CuOx/Ni NWs showed bipolar resistive changes possibly due to conducting filaments that are induced by oxygen vacancies. The reliability of the devices was confirmed by data retention measurement. The NW-based resistive switching memory has applications in highly scalable memory devices and neuromorphic devices. PMID- 26975331 TI - The absence of an Atlantic imprint on the multidecadal variability of wintertime European temperature. AB - Northern Hemisphere climate responds sensitively to multidecadal variability in North Atlantic sea surface temperature (SST). It is therefore surprising that an imprint of such variability is conspicuously absent in wintertime western European temperature, despite that Europe's climate is strongly influenced by its neighbouring ocean, where multidecadal variability in basin-average SST persists in all seasons. Here we trace the cause of this missing imprint to a dynamic anomaly of the atmospheric circulation that masks its thermodynamic response to SST anomalies. Specifically, differences in the pathways Lagrangian particles take to Europe during anomalous SST winters suppress the expected fluctuations in air-sea heat exchange accumulated along those trajectories. Because decadal variability in North Atlantic-average SST may be driven partly by the Atlantic Meridional Overturning Circulation (AMOC), the atmosphere's dynamical adjustment to this mode of variability may have important implications for the European wintertime temperature response to a projected twenty-first century AMOC decline. PMID- 26975332 TI - Triggered self-assembly of magnetic nanoparticles. AB - Colloidal magnetic nanoparticles are candidates for application in biology, medicine and nanomanufacturing. Understanding how these particles interact collectively in fluids, especially how they assemble and aggregate under external magnetic fields, is critical for high quality, safe, and reliable deployment of these particles. Here, by applying magnetic forces that vary strongly over the same length scale as the colloidal stabilizing force and then varying this colloidal repulsion, we can trigger self-assembly of these nanoparticles into parallel line patterns on the surface of a disk drive medium. Localized within nanometers of the medium surface, this effect is strongly dependent on the ionic properties of the colloidal fluid but at a level too small to cause bulk colloidal aggregation. We use real-time optical diffraction to monitor the dynamics of self-assembly, detecting local colloidal changes with greatly enhanced sensitivity compared with conventional light scattering. Simulations predict the triggering but not the dynamics, especially at short measurement times. Beyond using spatially-varying magnetic forces to balance interactions and drive assembly in magnetic nanoparticles, future measurements leveraging the sensitivity of this approach could identify novel colloidal effects that impact real-world applications of these nanoparticles. PMID- 26975333 TI - Online Measurement of Exhaled NO Concentration and Its Production Sites by Fast Non-equilibrium Dilution Ion Mobility Spectrometry. AB - Exhaled nitric oxide (NO) is one of the most promising breath markers for respiratory diseases. Its profile for exhalation and the respiratory NO production sites can provide useful information for medical disease diagnosis and therapeutic procedures. However, the high-level moisture in exhaled gas always leads to the poor selectivity and sensitivity for ion spectrometric techniques. Herein, a method based on fast non-equilibrium dilution ion mobility spectrometry (NED-IMS) was firstly proposed to directly monitor the exhaled NO profile on line. The moisture interference was eliminated by turbulently diluting the original moisture to 21% of the original with the drift gas and dilution gas. Weak enhancement was observed for humid NO response and its limit of detection at 100% relative humidity was down to 0.58 ppb. The NO concentrations at multiple exhalation flow rates were measured, while its respiratory production sites were determined by using two-compartment model (2CM) and Hogman and Merilainen algorithm (HMA). Last but not the least, the NO production sites were analyzed hourly to tentatively investigate the daily physiological process of NO. The results demonstrated the capacity of NED-IMS in the real-time analysis of exhaled NO and its production sites for clinical diagnosis and assessment. PMID- 26975335 TI - Single and double nitroxide labeled bis(terpyridine)-copper(II): influence of orientation selectivity and multispin effects on PELDOR and RIDME. AB - A rigid, nitroxide substituted terpyridine ligand has been used to synthesize hetero- and homoleptic bis-terpyridine complexes of copper(II). The homoleptic complex represents a three-spin system, while the metal ion in the heteroleptic complex is in average bound to one nitroxide bearing ligand. Both complexes are used as model systems for EPR distance measurements using pulsed electron electron double resonance (PELDOR or DEER) and relaxation induced dipolar modulation enhancement (RIDME) sequences. The results of both methods are analyzed using detailed geometric data obtained from the crystal structure of the homoleptic complex as well as information concerning ligand scrambling and the electronic structure of the copper center. In addition, both methods are compared with respect to their sensitivity, the extent of orientation selectivity and the influence of multispin effects. PMID- 26975334 TI - Relative Frequency, Clinical Features, and Survival Outcomes of 395 Patients with Cutaneous Lymphoma in Korea: A Subgroup Analysis per 10-year Period. AB - Long-term changes in the relative frequency of cutaneous lymphoma (CL) have not been investigated in Asian populations. The aim of this study was to investigate the relative frequency, clinical characteristics, and survival outcomes of CL in Korean patients, and to evaluate the changes in relative frequency of CL over a 20-year period. The present retrospective cohort study included 395 patients, of whom 289 had primary CL and 106 secondary CL, seen at a tertiary referral hospital in Seoul, Korea. Primary CL included T-/NK-cell linage lymphoma (CTCL, 85.1%) and B-cell lineage lymphoma (CBCL, 14.9%). The relative frequency of CBCL increased over time, as shown by a decrease in the CTCL/CBCL ratio from 10.3 in 1994 to 2003 to 4.5 in 2004 to 2013. CTCL was more commonly associated with multiple and extensive skin lesions than CBCL. Extranodal NK/T-cell lymphoma and subcutaneous panniculitis-like T-cell lymphoma were commonly associated with extensive skin lesions. The 5-year overall survival rate for all patients with primary CL was 81%. PMID- 26975337 TI - Intensive Plasmonic Flash Light Sintering of Copper Nanoinks Using a Band-Pass Light Filter for Highly Electrically Conductive Electrodes in Printed Electronics. AB - In this work, an intensive plasmonic flash light sintering technique was developed by using a band-pass light filter matching the plasmonic wavelength of the copper nanoparticles. The sintering characteristics, such as resistivity and microstructure, of the copper nanoink films were studied as a function of the range of the wavelength employed in the flash white light sintering. The flash white light irradiation conditions (e.g., wavelength range, irradiation energy, pulse number, on-time, and off-time) were optimized to obtain a high conductivity of the copper nanoink films without causing damage to the polyimide substrate. The wavelength range corresponding to the plasmonic wavelength of the copper nanoparticles could efficiently sinter the copper nanoink and enhance its conductivity. Ultimately, the sintered copper nanoink films under optimal light sintering conditions showed the lowest resistivity (6.97 MUOmega.cm), which was only 4.1 times higher than that of bulk copper films (1.68 MUOmega.cm). PMID- 26975336 TI - Selenium Augments microRNA Directed Reprogramming of Fibroblasts to Cardiomyocytes via Nanog. AB - We have recently shown that a combination of microRNAs, miR combo, can directly reprogram cardiac fibroblasts into functional cardiomyocytes in vitro and in vivo. However, direct reprogramming strategies are inefficient and slow. Moving towards the eventual goal of clinical application it is necessary to develop new methodologies to overcome these limitations. Here, we report the identification of a specific media composition, reprogramming media (RM), which augmented the effect of miR combo by 5-15-fold depending upon the cardiac marker tested. RM alone was sufficient to strongly induce cardiac gene and protein expression in neonatal tail-tip as well as cardiac fibroblasts. Expression of pluripotency markers Nanog, Oct4, Sox2, and Klf4 was significantly enhanced by RM, with miR combo augmenting the effect further. Knockdown of Nanog by siRNA inhibited the effect of RM on cardiac gene expression. Removal of insulin-transferrin-selenium completely inhibited the effect of reprogramming media upon cardiac gene expression and the addition of selenium to standard culture media recapitulated the effects of RM. Moreover, selenium enhanced the reprogramming efficiency of miR combo. PMID- 26975338 TI - Transferase Activity of Lactobacillal and Bifidobacterial beta-Galactosidases with Various Sugars as Galactosyl Acceptors. AB - The beta-galactosidases from Lactobacillus reuteri L103 (Lreubetagal), Lactobacillus delbrueckii subsp. bulgaricus DSM 20081 (Lbulbetagal), and Bifidobacterium breve DSM 20281 (Bbrebetagal-I and Bbrebetagal-II) were investigated in detail with respect to their propensity to transfer galactosyl moieties onto lactose, its hydrolysis products D-glucose and D-galactose, and certain sugar acceptors such as N-acetyl-D-glucosamine (GlcNAc), N-acetyl-D galactosamine (GalNAc), and L-fucose (Fuc) under defined, initial velocity conditions. The rate constants or partitioning ratios (kNu/kwater) determined for these different acceptors (termed nucleophiles, Nu) were used as a measure for the ability of a certain substance to act as a galactosyl acceptor of these beta galactosidases. When using Lbulbetagal or Bbrebetagal-II, the galactosyl transfer to GlcNAc was 6 and 10 times higher than that to lactose, respectively. With lactose and GlcNAc used in equimolar substrate concentrations, Lbulbetagal and Bbrebetagal-II catalyzed the formation of N-acetyl-allolactosamine with the highest yields of 41 and 24%, respectively, as calculated from the initial GlcNAc concentration. PMID- 26975339 TI - A Preclinical Study Evaluating AAVrh10-Based Gene Therapy for Sanfilippo Syndrome. AB - Mucopolysaccharidosis type IIIA (MPS IIIA) is predominantly a disorder of the central nervous system, caused by a deficiency of sulfamidase (SGSH) with subsequent storage of heparan sulfate-derived oligosaccharides. No widely available therapy exists, and for this reason, a mouse model has been utilized to carry out a preclinical assessment of the benefit of intraparenchymal administration of a gene vector (AAVrh10-SGSH-IRES-SUMF1) into presymptomatic MPS IIIA mice. The outcome has been assessed with time, measuring primary and secondary storage material, neuroinflammation, and intracellular inclusions, all of which appear as the disease progresses. The vector resulted in predominantly ipsilateral distribution of SGSH, with substantially less detected in the contralateral hemisphere. Vector-derived SGSH enzyme improved heparan sulfate catabolism, reduced microglial activation, and, after a time delay, ameliorated GM3 ganglioside accumulation and halted ubiquitin-positive lesion formation in regions local to, or connected by projections to, the injection site. Improvements were not observed in regions of the brain distant from, or lacking connections with, the injection site. Intraparenchymal gene vector administration therefore has therapeutic potential provided that multiple brain regions are targeted with vector, in order to achieve widespread enzyme distribution and correction of disease pathology. PMID- 26975340 TI - Platform switching from ELISA to GyrolabTM: a novel generic reagent omits the need to change critical reagents. AB - During development of biotherapeutics, availability of specific assay reagents is usually limited. The possibility to switch from one ligand binding assay technology to another, while using the same reagents, would be desirable. Here, we report on an Alexa647((r))-labeled monoclonal antibody against digoxigenin (mAb-Alexa647((r))) that enables the detection of digoxigenylated analyte specific ELISA reagents by Gyrolab(TM). In an analysis of non-monoclonal antibody (mAb) and mAb drugs, this approach maintained the dynamic range, accuracy and precision of the standard GyrolabTM approach using analyte-specific Alexa647((r)) labeled Ab. In a rat PK study, results of our approach, standard GyrolabTM and ELISA were comparable, with difference values within the incurred sample reanalysis acceptance criteria. Therefore, mAb-Alexa647((r)) enables an easy switch between ELISA and GyrolabTM, providing an effective way to benefit from both platforms. PMID- 26975341 TI - Tuft cell-derived IL-25 activates and maintains ILC2. PMID- 26975343 TI - Friction and adhesion mediated by supramolecular host-guest complexes. AB - The adhesive and frictional response of an AFM tip connected to a substrate through supramolecular host-guest complexes is investigated by dynamic Monte Carlo simulations. Here, the variation of the pull-off force with the unloading rate recently observed in experiments is unraveled by evidencing simultaneous (progressive) breaking of the bonds at fast (slow) rates. The model reveals the origin of the observed plateaus in the retraction force as a function of the tip surface distance, showing that they result from the tip geometrical features. In lateral sliding, the model exhibits a wide range of dynamic behaviors ranging from smooth sliding to stick-slip at different velocities, with the average friction force determined by the characteristic formation/rupture rates of the complexes. In particular, it is shown that for some molecular complexes friction can become almost constant over a wide range of velocities. Also, we show the possibility of exploiting the ageing effect through slide-hold-slide experiments, in order to infer the characteristic formation rate. Finally, our model predicts a novel "anti-ageing" effect which is characterized by a decrease of the static friction force with the hold time. Such an effect is explained in terms of enhancement of adhesion during sliding, especially observed at high driving velocities. PMID- 26975342 TI - Cutting-edge single-cell genomics and modelling in immunology. PMID- 26975344 TI - Fast and efficient synthesis of Zorro-LNA type 3'-5'-5'-3' oligonucleotide conjugates via parallel in situ stepwise conjugation. AB - Zorro-LNA is a new class of therapeutic anti-gene oligonucleotides (ONs) capable of invading supercoiled DNA. The synthesis of single stranded Zorro-LNA is typically complex and laborious, requiring reverse phosphoramidites and a chemical linker connecting the two separate ON arms. Here, a simplified synthesis strategy based on 'click chemistry' is presented with a high potential for screening Zorro-LNA ONs directed against new anti-gene targets. Four different Zorro type 3'-5' 5'-3' constructs were synthesized via parallel in situ Cu(i) [3 + 2] catalysed cycloaddition. They were prepared from commercially obtained ONs functionalized on solid support (one ON with the azide and the other ON with the activated triple bond linker N-propynoylamino)-p-toluic acid (PATA)) and after cleavage from resin, they were conjugated in solution. Our report shows the benefit of combining different approaches when developing anti-gene ONs, (1) the ability for rapid and robust screening of potential targets and (2) refining the hits with more anti-gene optimized constructs. We present as well the first report showing double-strand invasion (DSI) efficiency of two combined Zorro LNAs. PMID- 26975346 TI - Effect of Different Doses of Oral Cholecalciferol on Serum 1,25(OH)2D in Vitamin D Deficient Schoolchildren. AB - Data regarding 1,25-dihydroxycholecalciferol in adolescents are limited. We aimed to determine serum levels of this active metabolite of vitamin D and the effects of different doses of vitamin D on its concentration in schoolchildren with high prevalence of vitamin D deficiency. In a previously published randomized double blind, placebo-controlled trial, 210 subjects, aged 14-20 years, were assigned to 3 regimens of vitamin D treatment: group A (n=70) received 50 000 U oral cholecalciferol monthly, group B (n=70), 50 000 U bimonthly, and group C (n=70), placebo. Serum 25(OH)D, calcium, parathyroid hormone, and bone markers were measured at baseline and after 2 and 5 months of treatment. In the present study, serum levels of 1,25(OH)2D were measured in 97 boys and 95 girls. At baseline, girls had significantly higher concentrations of 1,25(OH)2D than boys (36, IQR: 24, 63 vs. 30, IQR: 15, 57.5 pmol/l; p<0.01). There was no significant correlation between serum levels of 25(OH)D and 1,25(OH)2D in the total population (Spearman rho=- 0.111; p=0.126), boys (Spearman rho=0.008; p=0.941), and girls (Spearman rho=0.036; p=0.729). Also, 1,25(OH)2D values did not change over time in different study groups. Moreover, total and sex-stratified analysis did not show any significant difference between different groups at different times of the study period. In an adolescent population with high prevalence of hypovitaminosis D especially in girls, 1,25(OH)2D values were higher in girls than boys. There was no significant change in 1,25(OH)2D concentrations with different doses of vitamin D. PMID- 26975345 TI - Adaptive engineering of a hyperthermophilic archaeon on CO and discovering the underlying mechanism by multi-omics analysis. AB - The hyperthermophilic archaeon Thermococcus onnurineus NA1 can grow and produce H2 on carbon monoxide (CO) and its H2 production rates have been improved through metabolic engineering. In this study, we applied adaptive evolution to enhance H2 productivity. After over 150 serial transfers onto CO medium, cell density, CO consumption rate and H2 production rate increased. The underlying mechanism for those physiological changes could be explained by using multi-omics approaches including genomic, transcriptomic and epigenomic analyses. A putative transcriptional regulator was newly identified to regulate the expression levels of genes related to CO oxidation. Transcriptome analysis revealed significant changes in the transcript levels of genes belonging to the categories of transcription, translation and energy metabolism. Our study presents the first genome-scale methylation pattern of hyperthermophilic archaea. Adaptive evolution led to highly enhanced H2 productivity at high CO flow rates using synthesis gas produced from coal gasification. PMID- 26975347 TI - Vasodilator Effect of Glucagon: Receptorial Crosstalk Among Glucagon, GLP-1, and Receptor for Glucagon and GLP-1. AB - Glucagon is known for its insulin-antagonist effect in the blood glucose homeostasis, while it also reduces vascular resistance. The mechanism of the vasoactive effect of glucagon has not been studied before; thereby we aimed to investigate the mediators involved in the vasodilatation induced by glucagon. The vasoactive effect of glucagon, insulin, and glucagon-like peptide-1 was studied on isolated rat thoracic aortic rings using a wire myograph. To investigate the mechanism of the vasodilatation caused by glucagon, we determined the role of the receptor for glucagon and the receptor for GLP-1, and studied also the effect of various inhibitors of gasotransmitters, inhibitors of reactive oxygen species formation, NADPH oxidase, prostaglandin synthesis, protein kinases, potassium channels, and an inhibitor of the Na(+)/Ca(2+)-exchanger. Glucagon causes dose dependent relaxation in the rat thoracic aorta, which is as potent as that of insulin but greater than that of GLP-1 (7-36) amide. Vasodilatation by GLP-1 is partially mediated by the glucagon receptor. The vasodilatation due to glucagon evokes via the glucagon-receptor, but also via the receptor for GLP-1, and it is endothelium-independent. Contribution of gasotransmitters, prostaglandins, the NADPH oxidase enzyme, free radicals, potassium channels, and the Na(+)/Ca(2+) exchanger is also significant. Glucagon causes dose-dependent relaxation of rat thoracic aorta in vitro, via the receptor for glucagon and the receptor for GLP 1, while the vasodilatation evoked by GLP-1 also evolves partially via the receptor for glucagon, thereby, a possible crosstalk between the 2 hormones and receptors could occur. PMID- 26975348 TI - Study protocol: developing a decision system for inclusive housing: applying a systematic, mixed-method quasi-experimental design. AB - BACKGROUND: Identifying the housing preferences of people with complex disabilities is a much needed, but under-developed area of practice and scholarship. Despite the recognition that housing is a social determinant of health and quality of life, there is an absence of empirical methodologies that can practically and systematically involve consumers in this complex service delivery and housing design market. A rigorous process for making effective and consistent development decisions is needed to ensure resources are used effectively and the needs of consumers with complex disability are properly met. METHODS/DESIGN: This 3-year project aims to identify how the public and private housing market in Australia can better respond to the needs of people with complex disabilities whilst simultaneously achieving key corporate objectives. First, using the Customer Relationship Management framework, qualitative (Nominal Group Technique) and quantitative (Discrete Choice Experiment) methods will be used to quantify the housing preferences of consumers and their carers. A systematic mixed-method, quasi-experimental design will then be used to quantify the development priorities of other key stakeholders (e.g., architects, developers, Government housing services etc.) in relation to inclusive housing for people with complex disabilities. Stakeholders randomly assigned to Group 1 (experimental group) will participate in a series of focus groups employing Analytical Hierarchical Process (AHP) methodology. Stakeholders randomly assigned to Group 2 (control group) will participate in focus groups employing existing decision making processes to inclusive housing development (e.g., Risk, Opportunity, Cost, Benefit considerations). Using comparative stakeholder analysis, this research design will enable the AHP methodology (a proposed tool to guide inclusive housing development decisions) to be tested. DISCUSSION: It is anticipated that the findings of this study will enable stakeholders to incorporate consumer housing preferences into commercial decisions. Housing designers and developers will benefit from the creation of a parsimonious set of consumer-led housing preferences by which to make informed investments in future housing and contribute to future housing policy. The research design has not been applied in the Australian research context or elsewhere, and will provide a much needed blueprint for market investment to develop viable, consumer directed inclusive housing options for people with complex disability. PMID- 26975349 TI - Serum level and polymorphisms of retinol-binding protein-4 and risk for gestational diabetes mellitus: a meta-analysis. AB - BACKGROUND: Retinol-binding protein-4 (RBP4) has been reported to be potentially involved in the pathogenesis of gestational diabetes mellitus (GDM); however, the findings are inconsistent. Our aims were to review the studies that investigated the association of serum levels and polymorphisms of RBP4 with GDM risk, and to provide recommendations for future research. METHODS: The databases PubMed, EBSCO, ScienceDirect, and Web of Knowledge were searched up to October 2015 to find out studies evaluating the relationship between serum RBP4 level/ RBP4 polymorphisms and GDM risk. In the meta-analysis of serum RBP4 levels the key inclusion was that studies were designed as BMI-matched studies or had observed non-significant differences in BMI between cases and controls. RESULTS: Fourteen case-control studies (647 cases and 620 controls) reporting the association between serum RBP4 level and GDM risk, and three studies (1012 cases and 1605 controls) investigating the association between RBP4 polymorphisms and GDM risk were involved. Our results showed that high serum RBP4 levels represent a risk factor for GDM (pooled standardized mean difference =0.758, 95% confidence interval [0.387, 1.128]). The results of subgroup analyses based on "gestational age at blood sampling" or "diagnostic criteria" are consistent with the overall results. However, the postpartum subgroup and "before 24 weeks" subgroup both only include one article and indicate no association between serum RBP4 level and GDM risk. The meta-analysis on the association between rs3758539 polymorphism and GDM risk shows that RBP4 rs3758539 polymorphism is not associated with the development of GDM. CONCLUSIONS: The results of this meta-analysis support the hypothesis that RBP4 is a modest independent risk factor for GDM (i.e., nonobese patients with GDM might express RBP4 at abnormal levels). The serum RBP4 level is associated with the risk of GDM. However, the association in the first-trimester and postpartum period should be validated by further research. The association between RBP4 rs3758539 polymorphism and GDM risk was not confirmed. PMID- 26975351 TI - Extent and Predictors of Decision Regret about Health Care Decisions: A Systematic Review. AB - BACKGROUND: People often face difficult decisions about their health and may later regret the choice that they made. However, little is known about the extent of decision regret in health care or its predictors. We systematically reviewed evidence about the extent of decision regret and its risk factors among individuals making health decisions. METHODS: The data sources were Medline, Embase, and reverse citation searches in Google Scholar and Web of Science. Studies using the Decision Regret Scale (DRS) to measure decision regret among individuals making nonhypothetical health decisions were included. There were no restrictions on study design, setting, or language. We extracted characteristics of included studies, measures of central tendency for DRS scores (0 = no regret, 100 = high regret), and all risk factors from published analyses. Quality appraisal was conducted using the Mixed Methods Appraisal Tool. A narrative synthesis was performed owing to the heterogeneity of studies. RESULTS: The initial search yielded 372 unique titles, and 59 studies were included. The overall mean DRS score across studies was 16.5, and the median of the mean scores was 14.3 (standard deviation range = 2.2-34.5) (n = 44 studies). The risk factors most frequently reported to be associated with decision regret in multivariate analyses included higher decisional conflict, lower satisfaction with the decision, adverse physical health outcomes, and greater anxiety levels. CONCLUSIONS: The extent of decision regret as assessed with the DRS in nonhypothetical health decisions was often low but reached high levels for some decisions. Several risk factors related to the decision-making process significantly predicted decision regret. Additional research into the psychometrics of the DRS and the relevance of scores for clinicians and patients would increase the validity of decision regret as a patient-reported outcome. PMID- 26975352 TI - Renal leiomyosarcoma in a cat. AB - Renal leiomyosarcoma was diagnosed in a 10-year-old Domestic Shorthair cat with a 3-year history of clinically managed, chronic renal disease. Sudden death was preceded by a brief episode of mental dullness and confusion. At postmortem examination, the gross appearance of the left kidney was suggestive of hydronephrosis, and a nephrolith was present in the contralateral kidney. However, histology revealed an infiltrative, poorly differentiated, spindle cell sarcoma bordering the grossly cavitated area. Neoplastic cells were immunoreactive for vimentin and smooth muscle actin, which led to a diagnosis of renal leiomyosarcoma; neoplastic cells were not immunoreactive for desmin. Leiomyosarcoma arising in the kidney is a rare occurrence in humans and an even rarer occurrence in veterinary medicine with no prior cases being reported in cats in the English literature. The macroscopic appearance of the tumor at postmortem examination was misleadingly suggestive of hydronephrosis as a result of the large cavitation and may be similar to particularly unusual cases of renal leiomyosarcomas in humans that have a cystic or cavitated appearance. PMID- 26975350 TI - A literature review and case report of hand, foot and mouth disease in an immunocompetent adult. AB - BACKGROUND: To report an uncommon case of hand, foot and mouth disease, (HFMD) in an immunocompetent adult; a highly infectious disease, characterized by the appearance of vesicles on the mouth, hands and feet, associated with coxsackieviruses and enteroviruses; including a literature review. CASE REPORT: A 23 year Caucasian male with no medical or surgical history, no allergies, was not taking any medication and smoked ten cigarettes a day, suffering from discomfort in the oral cavity; itching, burning and pain when swallowing associated with small erythematous lesions located on the hard palate, and small ulcers in tonsillar pillars and right buccal mucosa. Mild fever of 37.8 degrees C and general malaise. The patient reported he had had contact with a child diagnosed with HFMD. From his background and symptoms, the patient was diagnosed with HFMD. Following symptomatic treatment, the symptoms remitted in 7 days. METHODS: A literature review in MEDLINE (PubMed). The inclusion criteria were for studies on humans over the last 5 years, using the keywords HFMD. RESULTS: We found 925 articles, which were subsequently reduced to 52 documents after applying the inclusion criteria. Maculopapular lesions were found on hands and feet. CONCLUSIONS: Dentists may have a key role diagnosing the disease. A surveillance system to predict future outbreaks, encourage early diagnosis, put appropriate public health measures in place and research vaccine development is vitally important in order to control the disease. PMID- 26975353 TI - Spatiotemporal variation of mammalian protein complex stoichiometries. AB - BACKGROUND: Recent large-scale studies revealed cell-type specific proteomes. However, protein complexes, the basic functional modules of a cell, have been so far mostly considered as static entities with well-defined structures. The co expression of their members has not been systematically charted at the protein level. RESULTS: We used measurements of protein abundance across 11 cell types and five temporal states to analyze the co-expression and the compositional variations of 182 well-characterized protein complexes. We show that although the abundance of protein complex members is generally co-regulated, a considerable fraction of all investigated protein complexes is subject to stoichiometric changes. Compositional variation is most frequently seen in complexes involved in chromatin regulation and cellular transport, and often involves paralog switching as a mechanism for the regulation of complex stoichiometry. We demonstrate that compositional signatures of variable protein complexes have discriminative power beyond individual cell states and can distinguish cancer cells from healthy ones. CONCLUSIONS: Our work demonstrates that many protein complexes contain variable members that cause distinct stoichometries and functionally fine-tune complexes spatiotemporally. Only a fraction of these compositional variations is mediated by changes in transcription and other mechanisms regulating protein abundance contribute to determine protein complex stoichiometries. Our work highlights the superior power of proteome profiles to study protein complexes and their variants across cell states. PMID- 26975354 TI - Gene expression analysis of bone metastasis and circulating tumor cells from metastatic castrate-resistant prostate cancer patients. AB - BACKGROUND: Characterization of genes linked to bone metastasis is critical for identification of novel prognostic or predictive biomarkers and potential therapeutic targets in metastatic castrate-resistant prostate cancer (mCRPC). Although bone marrow core biopsies (BMBx) can be obtained for gene profiling, the procedure itself is invasive and uncommon practice in mCRPC patients. Conversely, circulating tumor cells (CTCs), which are likely to stem from bone metastases, can be isolated from blood. The goals of this exploratory study were to establish a sensitive methodology to analyze gene expression in BMBx and CTCs, and to determine whether the presence or absence of detectable gene expression is concordant in matching samples from mCRPC patients. METHODS: The CellSearch((r)) platform was used to enrich and enumerate CTCs. Low numbers of PC3 prostate cancer (PCa) cells were spiked into normal blood to assess cell recovery rate. RNA extracted from recovered PC3 cells was amplified using an Eberwine-based procedure to obtain antisense mRNA (aRNA), and assess the linearity of the RNA amplification method. In this pilot study, RNAs extracted from CTCs and PCa cells microdissected from formalin-fixed paraffin-embedded BMBx, were amplified to obtain aRNA and assess the expression of eight genes functionally relevant to PCa bone metastasis using RT-PCR. RESULTS: RNAs were successfully extracted from as few as 1-5 PCa cells in blood samples. The relative expression levels of reference genes were maintained after RNA amplification. The integrity of the amplified RNA was also demonstrated by RT-PCR analysis using primer sets that target the 5'-end, middle, and 3'-end of reference mRNA. We found that in 21 out of 28 comparisons, the presence or absence of detectable gene expression in CTCs and PCa cells microdissected from single bone lesions of the same patients was concordant. CONCLUSIONS: This exploratory analysis suggests that aRNA amplification through in vitro transcription may be useful as a method to detect gene expression in small numbers of CTCs and tumor cells microdissected from bone metastatic lesions. In some cases, gene expression in CTCs and BMBxs was not concordant, raising questions about using CTC gene expression to make clinical decisions. PMID- 26975355 TI - Ino80 is essential for proximal-distal axis asymmetry in part by regulating Bmp4 expression. AB - BACKGROUND: Understanding how embryos specify asymmetric axes is a major focus of biology. While much has been done to discover signaling pathways and transcription factors important for axis specification, comparatively little is known about how epigenetic regulators are involved. Epigenetic regulators operate downstream of signaling pathways and transcription factors to promote nuclear processes, most prominently transcription. To discover novel functions for these complexes in axis establishment during early embryonic development, we characterized phenotypes of a mouse knockout (KO) allele of the chromatin remodeling Ino80 ATPase. RESULTS: Ino80 KO embryos implant, but fail to develop beyond the egg cylinder stage. Ino80 KO embryonic stem cells (ESCs) are viable and maintain alkaline phosphatase activity, which is suggestive of pluripotency, but they fail to fully differentiate as either embryoid bodies or teratomas. Gene expression analysis of Ino80 KO early embryos by in situ hybridization and embryoid bodies by RT-PCR shows elevated Bmp4 expression and reduced expression of distal visceral endoderm (DVE) markers Cer1, Hex, and Lefty1. In culture, Bmp4 maintains stem cell pluripotency and when overexpressed is a known negative regulator of DVE differentiation in the early embryo. Consistent with the early embryo, we observed upregulated Bmp4 expression and down-regulated Cer1, Hex, and Lefty1 expression when Ino80 KO ESCs are differentiated in a monolayer. Molecular studies in these same cells demonstrate that Ino80 bound to the Bmp4 promoter regulates its chromatin structure, which correlates with enhanced SP1 binding. These results in combination suggest that Ino80 directly regulates the chromatin structure of the Bmp4 promoter with consequences to gene expression. CONCLUSIONS: In contrast to Ino80 KO differentiated cells, our experiments show that undifferentiated Ino80 KO ESCs are viable, but fail to differentiate in culture and in the early embryo. Ino80 KO ESCs and the early embryo up-regulate Bmp4 expression and down-regulate the expression of DVE markers Cer1, Hex and Lefty1. Based on this data, we propose a model where the Ino80 chromatin remodeling complex represses Bmp4 expression in the early embryo, thus promoting DVE differentiation and successful proximal-distal axis establishment. These results are significant because they show that epigenetic regulators have specific roles in establishing embryonic axes. By further characterizing these complexes, we will deepen our understanding of how the mammalian embryo is patterned by epigenetic regulators. PMID- 26975356 TI - Vascular basement membranes as pathways for the passage of fluid into and out of the brain. AB - In the absence of conventional lymphatics, drainage of interstitial fluid and solutes from the brain parenchyma to cervical lymph nodes is along basement membranes in the walls of cerebral capillaries and tunica media of arteries. Perivascular pathways are also involved in the entry of CSF into the brain by the convective influx/glymphatic system. The objective of this study is to differentiate the cerebral vascular basement membrane pathways by which fluid passes out of the brain from the pathway by which CSF enters the brain. Experiment 1: 0.5 ul of soluble biotinylated or fluorescent Abeta, or 1 ul 15 nm gold nanoparticles was injected into the mouse hippocampus and their distributions determined at 5 min by transmission electron microscopy. Abeta was distributed within the extracellular spaces of the hippocampus and within basement membranes of capillaries and tunica media of arteries. Nanoparticles did not enter capillary basement membranes from the extracellular spaces. Experiment 2: 2 ul of 15 nm nanoparticles were injected into mouse CSF. Within 5 min, groups of nanoparticles were present in the pial-glial basement membrane on the outer aspect of cortical arteries between the investing layer of pia mater and the glia limitans. The results of this study and previous research suggest that cerebral vascular basement membranes form the pathways by which fluid passes into and out of the brain but that different basement membrane layers are involved. The significance of these findings for neuroimmunology, Alzheimer's disease, drug delivery to the brain and the concept of the Virchow-Robin space are discussed. PMID- 26975357 TI - A Tunable, Biodegradable, Thin-Film Polymer Device as a Long-Acting Implant Delivering Tenofovir Alafenamide Fumarate for HIV Pre-exposure Prophylaxis. AB - PURPOSE: The effectiveness of Tenofovir based HIV pre-exposure prophylaxis (PrEP) is proven, but hinges on correct and consistent use. User compliance and therapeutic effectiveness can be improved by long acting drug delivery systems. Here we describe a thin-film polymer device (TFPD) as a biodegradable subcutaneous implant for PrEP. METHODS: A thin-film polycaprolactone (PCL) membrane controls drug release from a reservoir. To achieve membrane controlled release, TAF requires a formulation excipient such as PEG300 to increase the dissolution rate and reservoir solubility. Short-term In vitro release studies are used to develop an empirical design model, which is applied to the production of in vitro prototype devices demonstrating up to 90-days of linear release and TAF chemical stability. RESULTS: The size and shape of the TFPD are tunable, achieving release rates ranging from 0.5 to 4.4 mg/day in devices no larger than a contraceptive implant. Based on published data for oral TAF, subcutaneous constant-rate release for HIV PrEP is estimated at <2.8 mg/day. Prototype devices demonstrated linear release at 1.2 mg/day for up to 90 days and at 2.2 mg/day for up to 60 days. CONCLUSIONS: We present a biodegradable TFPD for subcutaneous delivery of TAF for HIV PrEP. The size, shape and release rate of the device are tunable over a >8-fold range. PMID- 26975358 TI - Hybrid Electrospun Polycaprolactone Mats Consisting of Nanofibers and Microbeads for Extended Release of Dexamethasone. AB - PURPOSE: We designed electrospun polycaprolactone mats consisting of nanofibers and microbeads for extended delivery of dexamethasone. METHODS: Thin flexible dexamethasone loaded polycaprolactone mats were prepared by electrospinning. The solvents, polymer loading, voltage and tip-to-collector distance were varied to explore the effects on microstructure of the mats. The microstructure was determined by scanning electron microscope imaging; drug transport was measured and modeled, and X-ray diffraction was used to gauge the crystallinity. Drug transport and X-ray diffraction studies were also conducted with a spin cast film for comparison. RESULTS: Thin mats, about 10 MUm in thickness, were prepared by electrospinning. By controlling the voltage and tip-to-collector distance, we achieved a hybrid structure comprising of nanorods (nanofibers) and microbeads. The release profiles were fitted to the diffusion equation to obtain the diffusivities in the spheres and the rods. The diffusivity in the electrospun nanofibers was significantly lower compared to the casted films due to increased crystallinity, which was estimated from X-ray diffraction analysis. The electrospun hybrid mats sustained drug release for the desired duration of a month, in spite of the small thickness of about 10 MUm. By comparison, a ten-fold thicker cast film sustains release for about the same duration suggesting about 100-fold decrease in diffusivity in the electrospun mats due to increased crystallinity. CONCLUSIONS: Electrospun polycaprolactone mats are optimal for achieving long release durations due to increased crystallinity. Designing a hybrid structure by controlling the electrospinning parameters can be a useful approach to increase the release durations. PMID- 26975359 TI - How Natural Product Research has Contributed to Oral Care Product Development? A Critical View. AB - PURPOSES: Despite the high number of studies on the biological effects of natural products (NP) and molecules isolated therefrom, only a small part of them reach the clinical phase and become commercially available. In this perspective we make an analysis on how plant research has impacted oral health care over the last 15 years. METHODS: Sixteen major clinical trial registry databases across the globe were searched for completed randomized clinical trials of herbal/natural product interventions (RCTHI) in theperiod 2000-2015. RESULTS: There was a considerable increase in the number of RCTHI, which points out an interest of academia and industry in the development of novel NP-based therapeutics. There is a trendfor greater heterogeneity of targeted dental conditions, mostly oral mucositis, periodontitis and dental caries. Topical application rather than systemic use predominated in the dental scope as mouthwashes, toothpastes, oral patches and gels have been the most commonly tested pharmaceutical forms. Today, despite the high number of in vitro, in vivo and clinical studies testing NP and/or NP isolated molecules, only 11% (n = 9) of them are phase IV clinical trials assessing commercially available herbal products. This may be a result of poorly designed, superficial basic research that does not provide evidence to support the clinical testing of NP and derived molecules. CONCLUSION: As of now, plant research is promising although still accounts for a modest participation in the oral health care industry due to limited investment and incomplete or inconsistent information from preclinical and clinical testing. PMID- 26975360 TI - Development of an Improved Inhalable Powder Formulation of Pirfenidone by Spray Drying: In Vitro Characterization and Pharmacokinetic Profiling. AB - PURPOSE: Previously, a respirable powder (RP) formulation of pirfenidone (PFD) was developed for reducing phototoxic risk; however, PFD-RP demonstrated unacceptable in vitro inhalation performance. The present study aimed to develop a new RP system of PFD with favorable inhalation properties by spray-drying method. METHODS: Spray-dried PFD (SD/PFD) was prepared by spray-drying with L leucine, and the physicochemical properties and efficacy in an antigen-sensitized airway inflammation model were assessed. A pharmacokinetic study was also conducted after intratracheal and oral administration of PFD formulations. RESULTS: Regarding powder characterization, SD/PFD had dimpled surface with the mean diameter of 1.793 MUm. In next generation impactor analysis, SD/PFD demonstrated high in vitro inhalation performance without the need of carrier particles, and the fine particle fraction of SD/PFD was calculated to be 62.4%. Insufflated SD/PFD (0.3 mg-PFD/rat) attenuated antigen-evoked inflammatory events in the lung, including infiltration of inflammatory cells and myeloperoxidase activity. Systemic exposure level of PFD after insufflation of SD/PFD at the pharmacologically effective dose was 600-fold lower than that after oral administration of PFD at the phototoxic dose. CONCLUSION: SD/PFD would be suitable for inhalation, and the utilization of an RP system with SD/PFD would provide a safer medication compared with oral administration of PFD. PMID- 26975361 TI - Characteristics of the Human Upper Gastrointestinal Contents in the Fasted State Under Hypo- and A-chlorhydric Gastric Conditions Under Conditions of Typical Drug - Drug Interaction Studies. AB - OBJECTIVE: Evaluate the impact of reduced gastric acid secretion after administration of two acid-reducing agents on the physicochemical characteristics of contents of upper gastrointestinal lumen of fasted adults. MATERIALS AND METHODS: Eight healthy male adults, fasted from food for 12 h, participated in a three-phase crossover study. Phase 1: No drug treatment prior to aspirations. Phase 2: Oral administration of 40 mg pantoprazole at ~9 am the last 3 days prior to aspirations and at ~7 am on aspiration day. Phase 3: Oral administration of 20 mg famotidine at ~7 pm prior to aspirations and at ~7 am on aspiration day. Samples from the contents of upper gastrointestinal lumen were aspirated for 50 min, after administration of 240 ml table water at ~9 am. RESULTS: Reduction of gastric acid secretion was accompanied by reduced buffer capacity, chloride ion concentration, osmolality and surface tension in stomach and by increased pH (up to ~0.7 units) in upper small intestine during the first 50 min post-water administration. The mechanism of reduction of acid secretion seems to be important for the buffer capacity in stomach and for the surface tension in upper gastrointestinal lumen. CONCLUSIONS: Apart from gastric pH, reduced acid secretion affects physicochemical characteristics of contents of upper gastrointestinal lumen which may be important for the performance of certain drugs/products in the fasted state. PMID- 26975362 TI - Personality traits in patients with cluster headache: a comparison with migraine patients. AB - BACKGROUND: Cluster headache (CH) has been associated with certain personality traits and lifestyle features, but there are few studies assessing personality profiles in CH. We aimed to analyze personality traits in patients with CH, and to compare them with those found in migraine. METHODS: We included all consecutive patients with CH attending 5 outpatient offices between January and December 2013. Personality traits were evaluated using the Salamanca screening test, a validated inventory assessing 11 personality traits grouped in 3 clusters. We analyzed the test results in this population, and compared them with those of a migraine population previously assessed with the same test. RESULTS: Eighty patients with CH (75 men, 5 women; mean age, 43.2 +/- 9.9 years) were recruited. The reference population consisted of 164 migraine patients (30 men, 134 women; mean age 36.4 +/- 12.7 years). In CH patients, the most frequent personality traits were anancastic (52.5 %), anxious (47.5 %), histrionic (45 %), schizoid (42.5 %), impulsive (32.5 %) and paranoid (30 %). When compared to migraine patients, paranoid (p < 0.001; chi2 test), and schizoid traits (p = 0.007; chi2 test) were significantly more prevalent in CH patients. In logistic regression analysis the paranoid trait was significantly associated with CH (p = 0.001; OR: 3.27, 95 % CI [1.66-6.43]). CONCLUSION: According to the Salamanca screening test, personality traits included in cluster A (odd or eccentric disorders) are more prevalent in CH patients than in a population of migraineurs. Larger studies are needed to determine whether certain personality traits are related to CH. PMID- 26975363 TI - Phenotypic features of chronic migraine. AB - BACKGROUND: Chronic migraine is a disabling, under-recognized, and undertreated disorder that increases health burdens. The aim of this study was to evaluate phenotypic features and the relevance of accompanying symptoms of migraine attacks in chronic migraine. METHOD: This study was conducted as part of an ongoing Turkish Headache Database Study investigating the clinical characteristics and outcomes of headache syndromes in the Turkish population. The electronic database was examined retrospectively, and 835 patients with chronic migraine were included. RESULTS: Patient group consisted of 710 women and 125 men (85 and 15 %, respectively). Mean patient age was 36.8 +/- 13.5 years, median value of migraine onset was 60 months (18-120), median headache frequency was 25 days per month (16-30), median of attack duration was 12 h (4-24), and median of intensity was eight (7-9). Increasing headache days per month were inversely related with the presence of nausea, vomiting, phonophobia, and photophobia. Longer duration of headache (months) and higher visual analog scale (VAS) for headache intensity were associated with all accompanying symptoms. Phonophobia, nausea, photophobia, and vomiting were the most frequent accompanying symptoms (experienced by 80.2, 77.6, 71.2, and 40.9 % of patients, respectively). Osmophobia was also frequent in chronic migraine patients (53.4 %) and was closely associated with other accompanying symptoms. Vertigo and dizziness were observed less frequently, and they were not associated with accompanying symptoms. CONCLUSION: Phenotype of chronic migraine may be associated with the course of chronification. Duration of illness and attack intensity were closely related with the presence of accompanying symptoms, although headache frequency was found to be inversely related to the presence of accompanying symptoms. Osmophobia was also a frequent symptom and was closely related with other accompanied symptoms, unlike vertigo and dizziness. Inclusion of osmophobia into the diagnostic criteria might improve accurate diagnosis of chronic migraine. PMID- 26975364 TI - Distinct Histomorphology in Molecular Subgroups of Glioblastomas in Young Patients. AB - Glioblastomas (GBMs) are malignant brain tumors that can be divided into different molecular subtypes based on genetics, global gene expression, and methylation patterns. Among these subgroups, "IDH" GBMs carry mutations within IDH1 or IDH2 The "K27" and "G34" subgroups are characterized by distinct mutations within Histone 3 (H3). These subtypes can be identified by sequencing methods and are particularly found in younger patients. To determine whether the molecular subtypes correlate with distinct histological features among the diverse histologic patterns of GBM, we performed a blinded assessment of the histology of GBMs of 77 patients <=30 years old at the time of biopsy. The tumors were of the following molecular subtypes: IDH (n = 12), H3 K27M (n = 25), H3 G34R (n = 12), or no IDH/H3 mutations (n = 28). Of IDH-mutated cases, 75% had microcystic features or gemistocytic tumor cells. K27 GBMs had higher cell densities and pronounced nuclear pleomorphism, with 28% harboring tumor giant cells. All G34 GBMs had variable extents of a poorly differentiated/primitive neuroectodermal tumor-like morphology. GBMs without IDH/H3 mutations had foci of epitheliod-appearing cells. Thus, molecular GBM subgroups are associated with distinct histological patterns, suggesting that morphological features reflect the specific underlying molecular genetic abnormalities. PMID- 26975365 TI - Understanding existing exposure situations. AB - International Commission on Radiological Protection (ICRP) Publication 103 removed the distinction between practices and interventions, and introduced three types of exposure situation: existing, planned, and emergency. It also emphasised the optimisation principle in connection with individual dose restrictions for all controllable exposure situations. Existing exposure situations are those resulting from sources, natural or man-made, that already exist when a decision on control has to be taken. They have common features to be taken into account when implementing general recommendations, such as: the source may be difficult to control; all exposures cannot be anticipated; protective actions can only be implemented after characterisation of the exposure situation; time may be needed to reduce exposure below the reference level; levels of exposure are highly dependent on individual behaviour and present a wide spread of individual dose distribution; exposures at work may be adventitious and not considered as occupational exposure; there is generally no potential for accident; many stakeholders have to be involved; and many factors need to be considered. ICRP is currently developing a series of reports related to the practical implementation of Publication 103 to various existing exposure situations, including exposure from radon, exposure from cosmic radiation in aviation, exposure from processes using naturally occurring radioactive material, and exposure from contaminated sites due to past activities. PMID- 26975366 TI - New recruitment contract for health and care services regulator dismays lay experts. PMID- 26975367 TI - University students' beliefs about unit-based guidelines: A qualitative study. AB - UK government guidance for alcohol consumption is expressed in 'units' of alcohol. This study employed semi-structured interviews to explore university students' knowledge of, attitudes towards, and use of unit-based guidelines. Thematic analysis revealed that participants were not motivated to adhere to unit based guidelines and that they lacked the skills required to apply them to reduce their own drinking. Instead, interviewees used individual strategies to monitor their drinking. The results suggest that public health interventions should include provision of information, efforts to motivate young people to change their behaviour and strategies to develop skills for managing alcohol consumption. PMID- 26975368 TI - High Content, Multi-Parameter Analyses in Buccal Cells to Identify Alzheimer's Disease. AB - Alzheimer's disease (AD) is a degenerative brain disorder and is the most common form of dementia. Minimally invasive approaches are required that combine biomarkers to identify individuals who are at risk of developing mild cognitive impairment (MCI) and AD, to appropriately target clinical trials for therapeutic discovery as well as lifestyle strategies aimed at prevention. Buccal mucosa cells from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing cohort (n=60) were investigated for cytological markers that could be used to identify both MCI and AD individuals. Visual scoring of the buccal cytome demonstrated a significantly lower frequency of basal and karyorrhectic cells in the MCI group compared with controls. A high content, automated assay was developed using laser scanning cytometry to simultaneously measure cell types, nuclear DNA content and aneuploidy, neutral lipid content, putative Tau and amyloid-beta (Abeta) in buccal cells. DNA content, aneuploidy, neutral lipids and Tau were similar in all groups. However, there was significantly lower Tau protein in both basal and karyolytic buccal cell types compared with differentiated buccal cells. Abeta, as measured by frequency of cells containing Abeta signal, as well as area and integral of Abeta signal, was significantly higher in the AD group compared with the control group. Buccal cell Abeta was correlated with mini-mental state examination (MMSE) scores (r = -0.436, P=0.001) and several blood-based biomarkers. Combining newly identified biomarkers from buccal cells with those already established may offer a potential route for more specific biomarker panels which may substantially increase the likelihood of better predictive markers for earlier diagnosis of AD. PMID- 26975369 TI - 2015 ASMS Fall Workshop: Lipids and Lipidomics. PMID- 26975370 TI - Making Mass Spectrometry See the Light: The Promises and Challenges of Cryogenic Infrared Ion Spectroscopy as a Bioanalytical Technique. AB - The detailed chemical information contained in the vibrational spectrum of a cryogenically cooled analyte ion would, in principle, make infrared (IR) ion spectroscopy a gold standard technique for molecular identification in mass spectrometry. Despite this immense potential, there are considerable challenges in both instrumentation and methodology to overcome before the technique is analytically useful. Here, we discuss the promise of IR ion spectroscopy for small molecule analysis in the context of metabolite identification. Experimental strategies to address sensitivity constraints, poor overall duty cycle, and speed of the experiment are intimately tied to the development of a mass-selective cryogenic trap. Therefore, the most likely avenues for success, in the authors' opinion, are presented here, alongside alternative approaches and some thoughts on data interpretation. PMID- 26975371 TI - The Small C-terminal Domain Phosphatase 1 Inhibits Cancer Cell Migration and Invasion by Dephosphorylating Ser(P)68-Twist1 to Accelerate Twist1 Protein Degradation. AB - Twist1 is a basic helix-loop-helix transcription factor that strongly promotes epithelial-to-mesenchymal transition, migration, invasion, and metastasis of cancer cells. The MAPK-phosphorylated Twist1 on its serine 68 (Ser(P)(68)-Twist1) has a significantly enhanced stability and function to drive cancer cell invasion and metastasis. However, the phosphatase that dephosphorylates Ser(P)(68)-Twist1 and destabilizes Twist1 has not been identified and characterized. In this study, we screened a serine/threonine phosphatase cDNA expression library in HEK293T cells with ectopically coexpressed Twist1. We found that the small C-terminal domain phosphatase 1 (SCP1) specifically dephosphorylates Ser(P)(68)-Twist1 in both cell-free reactions and living cells. SCP1 uses its amino acid residues 43 63 to interact with the N terminus of Twist1. Increased SCP1 expression in cells decreased Ser(P)(68)-Twist1 and total Twist1 proteins, whereas knockdown of SCP1 increased Ser(P)(68)-Twist1 and total Twist1 proteins. Furthermore, the levels of SCP1 are negatively correlated with Twist1 protein levels in several cancer cell lines. SCP1-dephosphorylated Twist1 undergoes fast degradation via the ubiquitin proteasome pathway. Importantly, an increase in SCP1 expression in breast cancer cells with either endogenous or ectopically expressed Twist1 largely inhibits the Twist1-induced epithelial-to-mesenchymal transition phenotype and the migration and invasion capabilities of these cells. These results indicate that SCP1 is the phosphatase that counterregulates the MAPK-mediated phosphorylation of Ser(68) Twist1. Thus, an increase in SCP1 expression and activity may be a useful strategy for eliminating the detrimental roles of Twist1 in cancer cells. PMID- 26975372 TI - Positive Allosteric Modulation of the Glucagon-like Peptide-1 Receptor by Diverse Electrophiles. AB - Therapeutic intervention to activate the glucagon-like peptide-1 receptor (GLP 1R) enhances glucose-dependent insulin secretion and improves energy balance in patients with type 2 diabetes mellitus. Studies investigating mechanisms whereby peptide ligands activate GLP-1R have utilized mutagenesis, receptor chimeras, photo-affinity labeling, hydrogen-deuterium exchange, and crystallography of the ligand-binding ectodomain to establish receptor homology models. However, this has not enabled the design or discovery of drug-like non-peptide GLP-1R activators. Recently, studies investigating 4-(3-benzyloxyphenyl)-2-ethylsulfinyl 6-(trifluoromethyl)pyrimidine (BETP), a GLP-1R-positive allosteric modulator, determined that Cys-347 in the GLP-1R is required for positive allosteric modulator activity via covalent modification. To advance small molecule activation of the GLP-1R, we characterized the insulinotropic mechanism of BETP. In guanosine 5'-3-O-(thio)triphosphate binding and INS1 832-3 insulinoma cell cAMP assays, BETP enhanced GLP-1(9-36)-NH2-stimulated cAMP signaling. Using isolated pancreatic islets, BETP potentiated insulin secretion in a glucose dependent manner that requires both the peptide ligand and GLP-1R. In studies of the covalent mechanism, PAGE fluorography showed labeling of GLP-1R in immunoprecipitation experiments from GLP-1R-expressing cells incubated with [(3)H]BETP. Furthermore, we investigated whether other reported GLP-1R activators and compounds identified from screening campaigns modulate GLP-1R by covalent modification. Similar to BETP, several molecules were found to enhance GLP-1R signaling in a Cys-347-dependent manner. These chemotypes are electrophiles that react with GSH, and LC/MS determined the cysteine adducts formed upon conjugation. Together, our results suggest covalent modification may be used to stabilize the GLP-1R in an active conformation. Moreover, the findings provide pharmacological guidance for the discovery and characterization of small molecule GLP-1R ligands as possible therapeutics. PMID- 26975373 TI - Disulfide Cross-linking of a Multidrug and Toxic Compound Extrusion Transporter Impacts Multidrug Efflux. AB - Multidrug and toxic compound extrusion (MATE) transporters contribute to multidrug resistance by extruding different drugs across cell membranes. The MATE transporters alternate between their extracellular and intracellular facing conformations to propel drug export, but how these structural changes occur is unclear. Here we combine site-specific cross-linking and functional studies to probe the movement of transmembrane helices in NorM from Neiserria gonorrheae (NorM-NG), a MATE transporter with known extracellular facing structure. We generated an active, cysteine-less NorM-NG and conducted pairwise cysteine mutagenesis on this variant. We found that copper phenanthroline catalyzed disulfide bond formation within five cysteine pairs and increased the electrophoretic mobility of the corresponding mutants. Furthermore, copper phenanthroline abolished the activity of the five paired cysteine mutants, suggesting that these substituted amino acids come in spatial proximity during transport, and the proximity changes are functionally indispensable. Our data also implied that the substrate-binding transmembrane helices move up to 10 A in NorM-NG during transport and afforded distance restraints for modeling the intracellular facing transporter, thereby casting new light on the underlying mechanism. PMID- 26975374 TI - Ubiquitin-specific Peptidase 10 (USP10) Deubiquitinates and Stabilizes MutS Homolog 2 (MSH2) to Regulate Cellular Sensitivity to DNA Damage. AB - MSH2 is a key DNA mismatch repair protein, which plays an important role in genomic stability. In addition to its DNA repair function, MSH2 serves as a sensor for DNA base analogs-provoked DNA replication errors and binds to various DNA damage-induced adducts to trigger cell cycle arrest or apoptosis. Loss or depletion of MSH2 from cells renders resistance to certain DNA-damaging agents. Therefore, the level of MSH2 determines DNA damage response. Previous studies showed that the level of MSH2 protein is modulated by the ubiquitin-proteasome pathway, and histone deacetylase 6 (HDAC6) serves as an ubiquitin E3 ligase. However, the deubiquitinating enzymes, which regulate MSH2 remain unknown. Here we report that ubiquitin-specific peptidase 10 (USP10) interacts with and stabilizes MSH2. USP10 deubiquitinates MSH2 in vitro and in vivo Moreover, the protein level of MSH2 is positively correlated with the USP10 protein level in a panel of lung cancer cell lines. Knockdown of USP10 in lung cancer cells exhibits increased cell survival and decreased apoptosis upon the treatment of DNA methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and antimetabolite 6-thioguanine (6-TG). The above phenotypes can be rescued by ectopic expression of MSH2. In addition, knockdown of MSH2 decreases the cellular mismatch repair activity. Overall, our results suggest a novel USP10-MSH2 pathway regulating DNA damage response and DNA mismatch repair. PMID- 26975375 TI - Parkin Regulates the Activity of Pyruvate Kinase M2. AB - Parkin, a ubiquitin E3 ligase, is mutated in most cases of autosomal recessive early onset Parkinson disease. It was discovered that Parkin is also mutated in glioblastoma and other human malignancies and that it inhibits tumor cell growth. Here, we identified pyruvate kinase M2 (PKM2) as a unique substrate for parkin through biochemical purification. We found that parkin interacts with PKM2 both in vitro and in vivo, and this interaction dramatically increases during glucose starvation. Ubiquitylation of PKM2 by parkin does not affect its stability but decreases its enzymatic activity. Parkin regulates the glycolysis pathway and affects the cell metabolism. Our studies revealed the novel important roles of parkin in tumor cell metabolism and provided new insight for therapy of Parkinson disease. PMID- 26975376 TI - The F-box Protein Rcy1 Is Involved in the Degradation of Histone H3 Variant Cse4 and Genome Maintenance. AB - Cse4, a histone H3-like centromeric protein, plays critical functions in chromosome segregation. Cse4 level is tightly regulated, but the underlying mechanism remains poorly understood. We employed a toxicity-based screen to look for the degradation components involved in Cse4 regulation. Here, we show that the F-box containing protein Rcy1 is required for efficient Cse4 turnover as Cse4 degradation is compromised in yeast cells lacking RCY1 Excessive Cse4 accumulation in rcy1Delta cells leads to growth retardation. Furthermore, the deletion of RCY1 is tied to enhanced chromosome instability and temperature sensitive cell growth. Our results reveal the involvement of Rcy1 in chromosome regulation and another regulatory pathway controlling the Cse4 level and activity. PMID- 26975377 TI - Mechanism of Concerted RNA-DNA Primer Synthesis by the Human Primosome. AB - The human primosome, a 340-kilodalton complex of primase and DNA polymerase alpha (Polalpha), synthesizes chimeric RNA-DNA primers to be extended by replicative DNA polymerases delta and epsilon. The intricate mechanism of concerted primer synthesis by two catalytic centers was an enigma for over three decades. Here we report the crystal structures of two key complexes, the human primosome and the C terminal domain of the primase large subunit (p58C) with bound DNA/RNA duplex. These structures, along with analysis of primase/polymerase activities, provide a plausible mechanism for all transactions of the primosome including initiation, elongation, accurate counting of RNA primer length, primer transfer to Polalpha, and concerted autoregulation of alternate activation/inhibition of the catalytic centers. Our findings reveal a central role of p58C in the coordinated actions of two catalytic domains in the primosome and ultimately could impact the design of anticancer drugs. PMID- 26975378 TI - Anti-MRSA and anti-TB metabolites from marine-derived Verrucosispora sp. MS100047. AB - Microbes belonging to the genus Verrucosispora possess significant chemical diversity and biological properties. They have attracted the interests of many researchers and are becoming promising resources in the marine natural product research field. A bioassay-guided isolation from the crude extract of Verrucosispora sp. strain MS100047, isolated from sediments collected from the South China Sea, has led to the identification of a new salicylic derivative, glycerol 1-hydroxy-2,5-dimethyl benzoate (1), along with three known compounds, brevianamide F (2), abyssomicin B (3), and proximicin B (4). Compound 1 showed selective activity against methicillin-resistant Staphylococcus aureus (MRSA) with a minimum inhibitory concentration (MIC) value of 12.5 MUg/mL. Brevianamide F (2), which was isolated from actinomycete for the first time, showed a good anti-BCG activity with a MIC value of 12.5 MUg/mL that has not been reported previously in literatures. Proximicin B (4) showed significant anti-MRSA (MIC = 3.125 MUg/mL), anti-BCG (MIC = 6.25 MUg/mL), and anti-tuberculosis (TB) (MIC = 25 MUg/mL) activities. This is the first report on the anti-tubercular activities of proximicins. In addition, Verrucosispora sp. strain MS100047 was found to harbor 18 putative secondary metabolite gene clusters based on genomic sequence analysis. These include the biosynthetic loci encoding polyketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) consistent with abyssomicins and proximicins, respectively. The biosynthetic pathways of these isolated compounds have been proposed. These results indicate that MS100047 possesses a great potential as a source of active secondary metabolites. PMID- 26975380 TI - CORR Insights((r)): Does Brachial Plexus Blockade Result in Improved Pain Scores After Distal Radius Fracture Fixation? A Randomized Trial. PMID- 26975379 TI - Deconstructing the smoking-preeclampsia paradox through a counterfactual framework. AB - Although smoking during pregnancy may lead to many adverse outcomes, numerous studies have reported a paradoxical inverse association between maternal cigarette smoking during pregnancy and preeclampsia. Using a counterfactual framework we aimed to explore the structure of this paradox as being a consequence of selection bias. Using a case-control study nested in the Icelandic Birth Registry (1309 women), we show how this selection bias can be explored and corrected for. Cases were defined as any case of pregnancy induced hypertension or preeclampsia occurring after 20 weeks' gestation and controls as normotensive mothers who gave birth in the same year. First, we used directed acyclic graphs to illustrate the common bias structure. Second, we used classical logistic regression and mediation analytic methods for dichotomous outcomes to explore the structure of the bias. Lastly, we performed both deterministic and probabilistic sensitivity analysis to estimate the amount of bias due to an uncontrolled confounder and corrected for it. The biased effect of smoking was estimated to reduce the odds of preeclampsia by 28 % (OR 0.72, 95 %CI 0.52, 0.99) and after stratification by gestational age at delivery (<37 vs. >=37 gestation weeks) by 75 % (OR 0.25, 95 %CI 0.10, 0.68). In a mediation analysis, the natural indirect effect showed and OR > 1, revealing the structure of the paradox. The bias adjusted estimation of the smoking effect on preeclampsia showed an OR of 1.22 (95 %CI 0.41, 6.53). The smoking-preeclampsia paradox appears to be an example of (1) selection bias most likely caused by studying cases prevalent at birth rather than all incident cases from conception in a pregnancy cohort, (2) omitting important confounders associated with both smoking and preeclampsia (preventing the outcome to develop) and (3) controlling for a collider (gestation weeks at delivery). Future studies need to consider these aspects when studying and interpreting the association between smoking and pregnancy outcomes. PMID- 26975381 TI - Letter to the Editor: Polyethylene Liner Dissociation is a Complication of the DePuy Pinnacle Cup: A Report of 23 Cases. PMID- 26975382 TI - What Are the Conditional Survival and Functional Outcomes After Surgical Treatment of 115 Patients With Sacral Chordoma? AB - BACKGROUND: Conditional survival is a measure of prognosis for patients who have already survived for a specific period of time; however, data on conditional survival after sacrectomy in patients with sacral chordoma are lacking. In addition, because sacral tumors are rare and heterogeneous, classifying them in a way that allows physicians to predict functional outcomes after sacrectomy remains a challenge. QUESTIONS/PURPOSES: (1) What is the overall survival and disease-free survival in patients treated by sacrectomy for chordoma? (2) What is the conditional survival probability and how do prognostic factors change over time in patients undergoing surgical resection for sacral chordoma? (3) What is the local recurrence rate after surgery, how was it treated, and what factors impact on local recurrence? (4) What is the postoperative motor, sensory, bowel, and bladder function by level of resection as determined by using a newly designed scoring method? METHODS: Between 2003 and 2012, our center treated 122 patients surgically for sacral chordoma. Of those, two died and five were lost before a minimum followup of 1 year was achieved, leaving 115 patients available for analysis in this retrospective study at a mean of 4.9 years (range, 1.3-10.8 years). Basically, single posterior or combined approaches were chosen based on the most cephalad extent of the tumor and resection level was normally at half or one sacral vertebrae above the tumor. The 5-year conditional survival rate was calculated based on Kaplan-Meier survival analysis. The effect of prognostic factors on conditional survival was also explored. A newly designed score method was proposed and adopted in the current study to critically evaluate the functional outcome after resection of the sacrum. Inter- and intraobserver reliability was tested by a preliminary study using kappa statistics and Spearman rank correlation coefficients. Significant interobserver (p < 0.01) and intraobserver agreement (kappa > 0.75) were found in nine items between each observer. RESULTS: The estimated 5-year overall survival rate was 81% (95% confidence interval [CI], 72%-90%) at diagnosis. The 5-year disease-free survival rate was 52% (95% CI, 43%-63%). The 5-year conditional overall survival decreased with each additional year in the first 4 years (81% at diagnosis versus 60% at the fourth year, p < 0.0001) and increased slightly in the fifth year. Patients with adequate surgical margins displayed a higher 5-year survival than those with an inadequate margin (86% [95% CI, 76%-95%] versus 67% [95% CI, 48%-85%], p = 0.01) at diagnosis. Conditional survival estimates for patients who received operations elsewhere were lower than that of newly diagnosed patients treated by us at diagnosis (64% [95% CI, 46%-83%] versus 90% [95% CI, 82%-99%], p = 0.012), but with the numbers we had, we could not detect a difference in conditional survival between those treated elsewhere first compared with those initially treated by us at 5 years. The proposed score system for function evaluation was able to distinguish different levels of resection. The overall functional results for the preservation of bilateral S1, S2, and S3 were 40 +/- 8%, 60 +/- 12%, and 82 +/- 11%, respectively. Patients who had preservation of only one S3 nerve root had more severe incontinence (1.99 +/- 0.79 versus 2.60 +/- 0.63, p = 0.01) and more sensory loss (1.88 +/- 0.82 versus 2.31 +/- 0.59, p = 0.02) than those patients with preservation of bilateral S3 nerve roots. CONCLUSIONS: The 5-year conditional survival for sacral chordoma decreased with each additional year and began to improve after the fourth year. In addition, the effect of the surgical margin and influence of previous surgery on conditional survival were not linear over time. The level of nerve root resections corresponded with the overall function scores according to the proposed scoring method. This information and scoring system should be valuable in discussing outcomes of sacrectomy in patients with chordoma who are considering this operation and serve as the basis for further study. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26975383 TI - Higher Pavlik Harness Treatment Failure Is Seen in Graf Type IV Ortolani-positive Hips in Males. AB - BACKGROUND: Patients with developmental dysplasia of the hip (DDH) whose hips are dislocated but reducible (Ortolani positive) are more likely to experience Pavlik harness treatment failure than are patients with dysplastic and reduced but dislocatable (Barlow positive) hips. However, data regarding factors associated with failure are limited and conflicting. QUESTIONS/PURPOSES: We asked: (1) What is the frequency of Pavlik harness treatment failure among Ortolani-positive hips, Barlow-positive hips, and dysplastic hips? (2) What are the factors predictive of failure of Pavlik harness treatment for Ortolani-positive hips? METHODS: In this retrospective study we identified 150 patients who underwent the Pavlik harness method for treatment of DDH between August 2011 and July 2015. Six patients initially treated at an outside facility, four patients with associated conditions, and three who pursued treatment elsewhere were excluded. A total of 137 patients (215 hips) with a median age at the time of Pavlik placement of 30 days (range, 4-155 days) were included. Of the 215 hips, 78 (36.3%) were Ortolani positive, 60 (27.9%) were Barlow positive, and 77 (35.8%) were stable, with the diagnosis of dysplasia made on ultrasound. All patients were treated with the Pavlik harness method. The primary outcome was failure of the Pavlik harness to achieve and maintain concentric hip reduction assessed by examination and ultrasound. All patients were followed after completion of Pavlik treatment for a minimum of 2 months (mean, 3 months; range, 2-4 months). In addition, 90% (122 of 137) of the patients were followed for a minimum of 6 months. Patient-specific data including family history, breech versus cephalic presentation at birth, age, sex, laterality, and hip abduction were recorded. Ultrasound data at the time of diagnosis included Graf classification, alpha angle, and percentage of femoral head coverage. RESULTS: The Pavlik harness method failed in 27% (21 of 78) of hips that were Ortolani positive, 8% (six of 77) with dysplasia, and 5% (three of 60) that were Barlow positive. After controlling for potential confounding variables, such as range of hip abduction, male sex (adjusted odds ratio [OR], 6.9; 95% CI, 2.0-24.2; p = 0.002) and Graf Type IV ultrasound classification (dislocated hip with alpha angle less than 43 degrees and labrum displaced downward) (OR, 4.4; 95% CI, 1.3-15.4; p = 0.019) were identified as independent predictors of failure of Pavlik treatment among Ortolani-positive hips. CONCLUSIONS: Ultrasound imaging of the hip should be part of the initial assessment for Ortolani-positive hips, as the ultrasound classification was found to have prognostic implications. Parents of male infants with Graf Type IV hips should be counseled regarding the higher risk of Pavlik failure. Future well designed prospective controlled studies are necessary to establish whether alternative strategies to the Pavlik harness might improve the early outcomes of DDH in males with Graf Type IV hips. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26975384 TI - Survival in Mesenchymal Chondrosarcoma Varies Based on Age and Tumor Location: A Survival Analysis of the SEER Database. AB - BACKGROUND: Studies suggest that mesenchymal chondrosarcoma is associated with a poorer prognosis and a higher proportion of extraskeletal tumors than conventional chondrosarcoma. However, these investigations have been small heterogeneous cohorts, limiting analysis of prognostic factors. QUESTIONS/PURPOSES: (1) What is the 5- and 10-year survival rate of patients diagnosed with mesenchymal chondrosarcoma? (2) What is the effect of demographic and tumor characteristics on survival in patients with mesenchymal chondrosarcoma? METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify all patients diagnosed with mesenchymal chondrosarcoma from 1973 to 2011. SEER reports survival data on over 8.2 million patients with cancer and has attained 98% completeness in reporting. Using variables within the database, this study designated each patient's tumor as skeletal or extraskeletal and cranial, axial, or appendicular, respectively. Overall survival (OS) was determined for the entire series as well as each group. Median survival was calculated using Kaplan-Meier methods. Cox proportional hazards regression was used to determine whether demographic and tumor variables affected survival. Two hundred five patients with mesenchymal chondrosarcoma were identified, including 82 (40%) skeletal and 123 (60%) extraskeletal. RESULTS: OS for the entire series was 51% (95% confidence interval [CI], 43%-58%) and 43% (95% CI, 35%-51%) at 5 and 10 years, respectively. No difference in OS was detected between extraskeletal and skeletal tumors. Kaplan-Meier analyses showed OS was worse for tumors in axial locations compared with appendicular and cranial locations. Appendicular tumors demonstrated an OS of 50% (95% CI, 36%-63%) at 5 years and 39% (95% CI, 26%-52%) at 10 years. OS for axial tumors was 37% (95% CI, 25%-49%) and 31% (95% CI, 20%-43%), whereas it was 74% (95% CI, 59%-84%) and 67% (95% CI, 50%-79%) for cranial tumors at 5 and 10 years, respectively. When controlling for age, sex, tumor origin, and tumor location, the presence of metastasis (hazard ratio [HR], 12.38; 95% CI, 5.75-26.65; p < 0.001) and 1-cm size increase (HR, 1.16; 95% CI, 1.09-1.23; p < 0.001) were both independently associated with an increased risk of death. Tumor location showed different behaviors depending on patient age. In comparison to cranial tumors at age 20 years, the HR was 5.56 (95% CI, 1.47-21.05; p = 0.01) for axial tumors and 6.26 (95% CI, 1.54-25.42; p = 0.01) for appendicular tumors. At age 60 years, those ratios were 0.10 (95% CI, 0.02-0.55; p = 0.01) and 0.14 (95% CI, 0.04-0.58; p = 0.01), respectively. CONCLUSIONS: Our data suggest that extraskeletal tumors are more common than previously reported; however, this factor does not have clear prognostic value. Presence of metastatic disease and increased tumor size are the main predictors of poor survival outcome. Cranial tumors appear to have a different clinical behavior with our data suggesting better overall survival in young patients (compared with axial and appendicular locations) and a worse survival outcome in older patients. LEVEL OF EVIDENCE: Level IV, prognostic study. PMID- 26975385 TI - The Fate of Reconstructive Surgery Following Colectomy for Inflammatory Bowel Disease in Sweden: A Population-based Cohort Study. AB - BACKGROUND AND AIMS: Previous studies describing the cumulative failure rate after reconstructive surgery in patients with inflammatory bowel disease have been restricted to specific hospitals, and the generalizability of these results in a population-based setting is unknown. The aim of this study was to investigate the cumulative failure rate and risk factors for failure after reconstructive surgery in patients with inflammatory bowel disease. METHODS: The study cohort includes all patients with inflammatory bowel disease in Sweden who underwent colectomy in 2000 through 2013 who were later treated with reconstructive surgery with ileal pouch-anal anastomosis or ileorectal anastomosis. Each patient was followed from admission for reconstructive surgery until admission for failure (a diverting stoma or permanent stoma), date of death, migration or December 31, 2013. Cumulative failure distributions were obtained with the Kaplan-Meier method, and multivariable Cox regression models were used to calculate the risk of failure. RESULTS: Of the 1809 patients with inflammatory bowel disease treated with colectomy and reconstructive surgery, 83% had ulcerative colitis. During follow-up, 270 patients failed, and the cumulative failure rate was 4.1%, 13.2%, and 15.3% after 1, 3, and 5 years, respectively. The risk of failure was lower after treatment with ileal pouch-anal anastomosis than with ileorectal anastomosis [hazard ratio (95% confidence interval): 0.72 (0.56-0.93)]. Gender, hospital volume, and timing of reconstruction were not significantly associated with the risk of failure. CONCLUSIONS: The 5-year cumulative failure rate in a nationwide setting was 15.3%, and hospital volume was not associated with the risk of failure. PMID- 26975386 TI - Fluid overload and outcomes in neonates receiving continuous renal replacement therapy. AB - BACKGROUND: Continuous renal replacement therapy (CRRT) has emerged as the modality of choice for the management of high-risk neonates with acute kidney injury (AKI), inborn errors of metabolism and multi-organ dysfunction. The aim of this study was to evaluate fluid overload (FO) and investigate the factors associated with outcomes in neonates undergoing CRRT. METHODS: We retrospectively reviewed the medical records of 34 neonates with AKI who were admitted to the neonatal intensive care unit (NICU) of Samsung Medical Center, Seoul, Republic of Korea between January 2007 and December 2014 where they underwent at least 24 h of CRRT. RESULTS: The survival rates of patients with an FO of >=30 % at the time of CRRT initiation were lower than those of patients with an FO of <30 % at the same time-point. Univariate Cox regression analysis revealed that a higher percentage FO at CRRT initiation and decreased urine output at the end of CRRT were associated with mortality, and multivariate Cox regression analysis indicated that mortality was associated with decreased urine output at the end of CRRT. Univariate linear regression analysis revealed that the length of hospital stay was associated with higher levels of serum creatinine at CRRT initiation, longer stay in the NICU prior to initiation of CRRT, longer duration of CRRT and lower body weight at the time of NICU admission. CONCLUSIONS: Neonates with a higher percentage FO and higher levels of serum creatinine at CRRT initiation showed poor outcomes. Early initiation of CRRT before the development of severe FO or azotemia might improve the outcomes of neonates requiring CRRT. PMID- 26975387 TI - Urinary tract infection in infants caused by extended-spectrum beta-lactamase producing Escherichia coli: comparison between urban and rural hospitals. AB - BACKGROUND: Community-acquired urinary tract infection (UTI) caused by extended spectrum beta-lactamase (ESBL)-producing Escherichia coli is an emerging problem. Compared with urban infants, rural infants may encounter different distributions of community-acquired resistant strains and various barriers to efficient management. METHODS: A retrospective survey and comparison was conducted for infants with UTI caused by ESBL-producing E. coli admitted to an urban hospital (n = 111) and a rural hospital (n = 48) in southern Taiwan from 2009 to 2012. RESULTS: Compared with 2009 and 2010, the total number of cases at both hospitals significantly increased in 2011 and 2012 (p < 0.001). Compared with the rural patients, the urban patients were significantly younger, and they had fewer days of fever before and after admission, fewer presentations of poor activity and poor appetite, and a lower serum creatinine level. Most of the patients had no prior history of illness, and we could not identify any significant different risk factors for acquiring ESBL-producing E. coli, such as past antimicrobial use, hospitalization, UTI, and underlying renal diseases, between the urban and rural populations. CONCLUSIONS: The increase in community-acquired UTI in infants caused by ESBL-producing E. coli was similar between the urban and rural populations. Our preliminary data suggest that the rural-urban disparities were probably related to easy access to health care by the urban population. ESBL complicates disease management, and the increase in the prevalence of ESBL producers is a major health concern and requires further healthy carrier and environmental surveillance. PMID- 26975389 TI - The putative ABC transporter encoded by the orf19.4531 plays a role in the sensitivity of Candida albicans cells to azole antifungal drugs. AB - ATP-binding cassette (ABC) transporters constitute a large superfamily of integral membrane proteins in prokaryotic and eukaryotic cells. In the human fungal pathogen Candida albicans, there are 28 genes encoding ABC transporters and many of them have not been characterized so far. The orf19.4531 (also known as IPF7530) encodes a putative ABC transporter. In this study, we have demonstrated that disruption of orf19.4531 causes C. albicans cells to become tolerant to azoles, but not to polyene antifungals and terbinafine. Therefore, the protein encoded by orf19.4531 is involved in azole sensitivity and we name it as ROA1, the regulator of azole sensitivity 1 gene. Consistently, we show that the expression of ROA1 is responsive to treatment of either fluconazole or ketoconazole inC. albicans In addition, through a GFP tagging approach, Roa1 is localized in a small punctuate compartment adjacent to the vacuolar membrane. However, ROA1 is not essential for the in vitro filamentation of C. albicans cells. PMID- 26975388 TI - Development of a Candida glabrata dominant nutritional transformation marker utilizing the Aspergillus nidulans acetamidase gene (amdS). AB - The gene encoding Aspergillus nidulans acetamidase (amdS) was placed under control of Candida albicans ACT1 promoter and terminator sequences and then cloned into a plasmid containing C. glabrata ARS10,CEN8 or ARS10+CEN8 sequences. All plasmids transformed C. glabrata wild-type cells to acetamide+, with the ARS only containing plasmid transforming cells at the highest frequencies (>1.0 * 10(4) transformants MUg(-1)). Plasmids were rapidly lost under non-selective conditions with the frequency dependent on chromosomal element, thus recycling the acetamide- phenotype. The amdS plasmid was used to transform a set of clinical isolates resistant to a variety of antifungal drugs. All strains were successfully transformed to the acetamide+ phenotype at high frequency, confirming that this plasmid construct could be used as a simple dominant marker on virtually any strain. Gap repair experiments demonstrated that just as in Saccharomyces cerevisiae, gap repair functions efficiently inC. glabrata, suggesting that C. glabrata has numerous similarities toS. cerevisiae with regard to ease of molecular manipulation. The amdS system is inexpensive and efficient, and combined with existing C. glabrata plasmid elements, confers a high transformation frequency for C. glabrata with a phenotype that can be easily recycled. PMID- 26975390 TI - The transcription factor Ace2 and its paralog Swi5 regulate ethanol production during static fermentation through their targets Cts1 and Rps4a in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae is the most widely used fermentation organism for ethanol production. However, the gene expression regulatory networks behind the ethanol fermentation are still not fully understood. Using a static fermentation model, we examined the ethanol yields on biomass of deletion mutants for 77 yeast genes encoding nonessential transcription factors, and found that deletion mutants for ACE2 and SWI5 showed dramatically increased ethanol yields. Overexpression of ACE2 or SWI5 in wild type cells reduced their ethanol yields. Furthermore, among the 34 target genes regulated by Ace2 and Swi5, deletion of CTS1,RPS4a,SIC1,EGT2,DSE2, or SCP160 led to increased ethanol yields, with the former two showing higher effects. Overexpression of CTS1 or RPS4a in both ace2/ace2 and swi5/swi5 mutants reduced their ethanol yields. In contrast, deletion of MCR1 or HO significantly decreased ethanol yields, with the former one showing the highest effect. Therefore, Ace2 and Swi5 are two negative regulators of ethanol yield during static fermentation of yeast cells, and both CTS1 and RPS4a are major effectors mediating these two transcription factors in regulating ethanol production. PMID- 26975391 TI - Does TSH Trigger the Anti-thyroid Autoimmune Processes? Observation on a Large Cohort of Naive Patients with Thyroid Hemiagenesis. AB - Thyroid hemiagenesis (THA) is a rare abnormality characterized by the absence of one thyroid lobe. Elevated thyroid stimulating hormone (TSH) level and higher incidence of thyroid diseases were reported in THA. The aim of the study is to evaluate the thyroid autoimmunity incidence in patients with THA and influence of higher than average TSH level on thyroid volume (TV) and its change with age. The study included a group of naive patients with THA and a control group of subjects with bilobate thyroid. All patients underwent clinical examination, thyroid ultrasound, scintiscan and laboratory tests. In the studied and control group the presence of thyroid autoantibodies (TAb) was evaluated. The THA group consisted of 65 patients. In THA group 53.85 % of patients were positive for TAb. Patients with positive TAb were older (46.0 +/- 18.3 years) than those with negative (35.0 +/- 19.8 years); p = 0.02. The incidence of TAb was lower in controls (13.85 %, p < 0.0001). In the study group, positive correlation between the age and TV (r = 0.46, p = 0.0001), and negative correlations between the age and TSH level (r = 0.31, p = 0.01), and TSH concentration and TV (r = -0.35, p = 0.004) were found. In a subgroup of 30 patients with THA negative for TAb, even stronger correlations were observed. The median single lobe volume and median TSH level were higher in patients with THA when compared to controls (13.60 vs 8.20 ml, p < 0.0001; 3.23 vs 1.48 uU/ml, p < 0.0001, respectively). Patients with THA constitute an in vivo model of long-term thyroid TSH overstimulation. Further studies are needed to reveal, whether TSH overstimulation may be the trigger for thyroid autoimmunity. PMID- 26975393 TI - IgG4-related disease presenting with an epidural inflammatory pseudotumor: a case report. AB - BACKGROUND: Inflammatory pseudotumor is a rare clinical condition that can be related to immunoglobulin G4 disease. Only a few cases of spinal inflammatory pseudotumors have been reported in the literature and an association with immunoglobulin G4 disease was not conclusive in any of them. We describe what we believe to be the first biopsy-proven case of an epidural inflammatory pseudotumor related to immunoglobulin G4 disease. CASE PRESENTATION: A 57-year old Caucasian woman presented to our hospital with severe paraparesis, gait disturbance, and sensory loss secondary to a relapsing epidural mass. Examination of a biopsy specimen revealed a lymphoplasmacytic infiltration with fibrosis and an immunoglobulin G4-positive plasma cell ratio of over 50 %, which are compatible with a diagnosis of immunoglobulin G4-related inflammatory pseudotumor. Our patient was successfully treated with systemic and epidural administration of glucocorticoids. CONCLUSION: Immunoglobulin G4-related disease is an emerging clinical condition in which central nervous system involvement is still uncommon. We describe the case of a patient with an epidural mass with medullar compression, which was proved to be an immunoglobulin G4-related epidural inflammatory pseudotumor. Our findings suggest a new manifestation of immunoglobulin G4-related disease. This disorder should be considered in the differential diagnosis of spinal tumors as a potentially treatable condition with glucocorticoids. PMID- 26975392 TI - Relevance of miR-21 in regulation of tumor suppressor gene PTEN in human cervical cancer cells. AB - BACKGROUND: Expression of the microRNA miR-21 has been found to be altered in almost all types of cancers and it has been classified as an oncogenic microRNA or oncomir. Due to the critical functions of its target proteins in various signaling pathways, miR-21 is an attractive target for genetic and pharmacological modulation in various cancers. Cervical cancer is the second most common cause of death from cancer in women worldwide and persistent HPV infection is the main etiologic agent. This malignancy merits special attention for the development of new treatment strategies. In the present study we analyze the role of miR-21 in cervical cancer cells. METHODS: To identify the downstream cellular target genes of upstream miR-21, we silenced endogenous miR-21 expression in a cervical intraepithelial neoplasia-derived cell lines using siRNAs. The effect of miR-21 on gene expression was assessed in cervical cancer cells transfected with the siRNA expression plasmid pSIMIR21. We identified the tumor suppressor gene PTEN as a target of miR-21 and determined the mechanism of its regulation throughout reporter construct plasmids. Using this model, we analyzed the expression of miR-21 and PTEN as well as functional effects such as autophagy and apoptosis induction. RESULTS: In SiHa cells, there was an inverse correlation between miR-21 expression and PTEN mRNA level as well as PTEN protein expression in cervical cancer cells. Transfection with the pSIMIR21 plasmid increased luciferase reporter activity in construct plasmids containing the PTEN-3'-UTR microRNA response elements MRE21-1 and MRE21-2. The role of miR-21 in cell proliferation was also analyzed in SiHa and HeLa cells transfected with the pSIMIR21 plasmid, and tumor cells exhibited markedly reduced cell proliferation along with autophagy and apoptosis induction. CONCLUSIONS: We conclude that miR 21 post-transcriptionally down-regulates the expression of PTEN to promote cell proliferation and cervical cancer cell survival. Therefore, it may be a potential therapeutic target in gene therapy for cervical cancer. PMID- 26975394 TI - Phosphatase of regenerating liver 3 (PRL-3) is overexpressed in human prostate cancer tissue and promotes growth and migration. AB - BACKGROUND: PRL-3 is a phosphatase implicated in oncogenesis in multiple cancers. In some cancers, notably carcinomas, PRL-3 is also associated with inferior prognosis and increased metastatic potential. In this study we investigated the expression of PRL-3 mRNA in fresh-frozen samples from patients undergoing radical prostatectomy because of prostate cancer (PC) and the biological function of PRL 3 in prostate cancer cells. METHODS: Samples from 41 radical prostatectomy specimens (168 samples in total) divided into low (Gleason score <= 6), intermediate (Gleason score = 7) and high (Gleason score >= 8) risk were analyzed with gene expression profiling and compared to normal prostate tissue. PRL-3 was identified as a gene with differential expression between healthy and cancerous tissue in these analyses. We used the prostate cancer cell lines PC3 and DU145 and a small molecular inhibitor of PRL-3 to investigate whether PRL-3 had a functional role in cancer. Relative ATP-measurement and thymidine incorporation were used to assess the effect of PRL-3 on growth of the cancer cells. We performed an in vitro scratch assay to investigate the involvement of PRL-3 in migration. Immunohistochemistry was used to identify PRL-3 protein in prostate cancer primary tumor and corresponding lymph node metastases. RESULTS: Compared to normal prostate tissue, the prostate cancer tissue expressed a significantly higher level of PRL-3. We found PRL-3 to be present in both PC3 and DU145, and that inhibition of PRL-3 led to growth arrest and apoptosis in these two cell lines. Inhibition of PRL-3 led to reduced migration of the PC3 cells. Immunohistochemistry showed PRL-3 expression in both primary tumor and corresponding lymph node metastases. CONCLUSIONS: PRL-3 mRNA was expressed to a greater extent in prostate cancer tissue compared to normal prostate tissue. PRL 3 protein was expressed in both prostate cancer primary tumor and corresponding lymph node metastases. The results from our in vitro assays suggest that PRL-3 promotes growth and migration in prostate cancer. In conclusion, these results imply that PRL-3 has a role in the pathogenesis of prostate cancer. PMID- 26975395 TI - Phenotypic and genetic characterization of Piscirickettsia salmonis from Chilean and Canadian salmonids. AB - BACKGROUND: The study presents the phenotypic and genetic characterization of selected P. salmonis isolates from Atlantic salmon and rainbow trout suffering from SRS (salmonid rickettsial septicemia) in Chile and in Canada. The phenotypic characterization of the P. salmonis isolates were based on growth on different agar media (including a newly developed medium), different growth temperatures, antibiotics susceptibility and biochemical tests. RESULTS: This is the first study differentiating Chilean P. salmonis isolates into two separate genetic groups. Genotyping, based on 16S rRNA-ITS and concatenated housekeeping genes grouped the selected isolates into two clades, constituted by the Chilean strains, while the Canadian isolates form a branch in the phylogenetic tree. The latter consisted of two isolates that were different in both genetic and phenotypic characteristics. The phylogenies and the MLST do not reflect the origin of the isolates with respect to host species. The isolates included were heterogeneous in phenotypic tests. CONCLUSIONS: The genotyping methods developed in this study provided a tool for separation of P. salmonis isolates into distinct clades. The SRS outbreaks in Chile are caused by minimum two different genetic groups of P. salmonis. This heterogeneity should be considered in future development of vaccines against this bacterium in Chile. Two different strains of P. salmonis, in regards to genetic and phenotypic characteristics, can occur in the same contemporary outbreak of SRS. PMID- 26975397 TI - Fat infiltration of left ventricle - a rare cause of sudden cardiac death. AB - Cor adiposum is a rare disorder of the heart, where the normal heart tissue is replaced by fibro-fatty infiltrates. We report one such case of a middle-aged female who was declared dead shortly after a syncopal episode. At autopsy, the pericardium was intact and firmly adhered to the heart. Histopathology revealed fatty infiltrates extending into the left ventricle of the heart. A post-mortem diagnosis of Cor adiposum was made which is an uncommonly reported cause of sudden cardiac death. PMID- 26975396 TI - International survey and surgeon's preferences in diagnostic work-up towards treatment of anterior shoulder instability. AB - PURPOSE: Recurrent anterior shoulder instability after surgical treatment can be caused by bony defects. Several diagnostic tools have been designed to measure the extent of these bony lesions. Currently, there is no consensus which measurement tool to use and decide which type of surgery is most appropriate. We therefore performed an evaluation of agreement in surgeons' preference of diagnostic work-up and surgical treatment of anterior shoulder instability. METHODS: An international survey was conducted amongst orthopaedic shoulder surgeons. The survey contained questions about surgeons' experience, clinical and radiological examination and the subsequent treatment for anterior shoulder instability. Descriptive statistics were used to present the data, and percentages of responding surgeons were calculated. RESULTS: The questionnaire was completed by 197 delegates from 46 countries. 55 % of the respondents think evidence in current literature is sufficient on diagnostic work-up for anterior shoulder instability. Anamnestic, number of dislocations was most frequently asked (by 95 % of respondents), the most frequently used test is the apprehension test (91 %). For imaging, conventional X-ray in various directions was most performed, followed by MR arthrography and plane CT scan respectively. The responding surgeons perform surgery (labrum repair or Latarjet) in 51 % of the patients. A median of 25 % glenoid bone loss was given by the respondents, as cut off from when to perform a bony repair. CONCLUSION: Many different diagnostic examinations for assessing shoulder instability are used and a high variety is seen in the use of diagnostic tools. Also no consensus is seen in the use of different surgical options (arthroscopic and open procedures). This implies the need for more research on diagnostic imaging and the correlation with specific subsequent surgical treatment. LEVEL OF EVIDENCE: Survey, level of evidence IV. PMID- 26975398 TI - Comment on "Adjacent segment infection after surgical treatment of spondylodiscitis" by Siam AE et al. PMID- 26975399 TI - The effect of topical sodium diclofenac on macular thickness in diabetic eyes after phacoemulsification: a randomized controlled trial. AB - To evaluate the efficacy of prophylactic administration of the topical diclofenac 0.1 % on macular thickness in diabetic patients following phacoemulsification and intraocular lens implantation surgery. In a Randomized double-masked clinical trial, 108 eyes of 108 diabetic patients underwent phacoemulsification and intraocular lens implantation surgery were enrolled. Fifty four eyes received the conventional postoperative care with steroid drop, whereas the other group (54 eyes) was given a preoperative diclofenac drop four times daily in addition to steroid drop and continued 6 weeks after surgery. All patients were evaluated by optical coherence tomography (OCT) preoperatively and days 1, 30, and 90. The outcome measures including best-corrected visual acuity and OCT findings were compared in and between both groups. Mean CMT changed from 239 +/- 16 and 235 +/- 17 at baseline to 249 +/- 15 and 254 +/- 28 at 3 months in the case and control groups, respectively(p = 0.003). Mean total volume of macula changed from 7.61 +/ 0.22 and 7.56 +/- 0.3 at baseline to 7.64 +/- 0.22 and 7.65 +/- 0.31 at 3 months in the case and control groups, respectively (p = 0.820). In comparison to the quadrants thicknesses and mean of them between groups did not reach the significant level. This study showed that there is a beneficial effect of topical diclofenac for prevention of macular thickness increasing following phacoemulsification in diabetic patients. PMID- 26975400 TI - Evaluating the presence of Toxoplasma gondii in peripheral blood of patients with diverse forms of uveitis. AB - The purpose of this study was to evaluate the presence of Toxoplasmosis gondii in samples of peripheral blood from patients with varying etiologies of uveitis. Whole blood from patients with different forms of uveitis was tested for the presence of T. gondii using real-time PCR targeting the well-characterized 529 bp fragment. Extracted DNA was both frozen. Thirty-one patients were included in the current study and grouped as follows: acute toxoplasmosis (n = 10); toxoplasmic retinal scars (n = 9); non-infectious etiologies of uveitis (n = 6); and IgG negative for toxoplasmosis (n = 6). In total, only two patients were shown to have circulating T. gondii in peripheral blood; both of these patients were IgG positive for toxoplasmosis, were receiving immunosuppressive therapy for autoimmune uveitis, and had no clinical features of toxoplasmosis. T. gondii was identified in peripheral blood of some immunosuppressed patients. No other patients, including those with acute toxoplasmosis, had circulating parasites in peripheral blood. PMID- 26975401 TI - Intraocular lens implantation without the use of ophthalmic viscosurgical device. AB - The purpose of this study was to determine whether single-piece hydrophilic acrylic intraocular lens can be safely implanted without the use of ophthalmic viscosurgical devices. This retrospective study comprised 100 eyes having phacoemulsification and intraocular lens implantation without the use of ophthalmic viscosurgical device. 80 eyes with the use of a viscosurgical device are used as control group. In this intraocular lens implantation technique, the anterior chamber was maintained with an irrigation cannula and intraocular lens was implanted with a lens injector. Visual acuity, corneal clarity and edema, intraocular pressure, and corneal endothelial cell count were evaluated preoperatively and postoperatively at days 1, 7, and 30. Corneal endothelial cell count was repeated 2 weeks after surgery. Complications of this technique were also evaluated. No significant complications of this intraocular lens implantation technique, such as posterior capsule rupture, intraocular lens buttonholing, zonular dialysis, Descemet's tear/detachment, occurred. On the seventh postoperative day, 90 % of eyes achieved 20/20 or better vision. There was no difference in corneal endothelial cell loss between viscoelastic device used and not-used cases (p = 0.356). When implanting intraocular lens without the use of ophthalmic viscosurgical device, significant intraoperative complications did not occur. The possible advantages are shortened surgery time, avoidance of postoperative IOP spike from ocular viscosurgical device (OVD) remnant, and reduced cost. PMID- 26975403 TI - Cerebral Edema After Cardiac Arrest: Tell Tale Sign of Catastrophic Injury or a Treatable Complication? PMID- 26975402 TI - Mechanistic interrogation of combination bevacizumab/dual PI3K/mTOR inhibitor response in glioblastoma implementing novel MR and PET imaging biomarkers. AB - PURPOSE: Resistance to bevacizumab (BEV) in glioblastoma is believed to occur via activation of molecular networks including the mTOR/PI3K pathway. Using an MR/PET molecular imaging biomarker approach, we investigated the response to combining BEV with the mTOR/PI3K inhibitor BEZ235. METHODS: Tumours were established by orthotopically implanting U87MG-luc2 cells in mice. Animals were treated with BEZ235 and/or BEV, and imaged using diffusion-weighted-MRI, T2-weighted and T2* weighted before and after administration of superparamagnetic iron oxide contrast agent. Maps for changes in relaxation rates (DeltaR2, DeltaR2* and apparent diffusion coefficient) were calculated. Vessel size index and microvessel density index were derived. 3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) PET and O-(2 [(18)F]fluoroethyl)-L-tyrosine ([(18)F]FET) PET were further performed and tumour endothelium/proliferation markers assessed by immunohistochemistry. RESULTS: Treatment with BEV resulted in a pronounced decrease in tumour volume (T2 weighted MRI). No additive effect on tumour volume was observed with the BEV/BEZ235 combination compared with BEV monotherapy. The Ki67 proliferation index and [(18)F]FLT uptake studies were used to support the observations. Using DeltaR2* and DeltaR2 values, respectively, the BEV/BEZ235 combination significantly reduced tumour microvessel volume in comparison to BEV alone. Decreased microvessel density index was further observed in animals treated with the combination, supported by von Willebrand factor (vWF) immunohistochemistry. [(18)F]FET uptake was decreased following treatment with BEV alone, but was not further reduced following treatment with the combination. vWF immunohistochemistry analysis showed that the mean tumour vessel size was increased in all cohorts. CONCLUSION: Assessing MR imaging biomarker parameters together with [(18)F]FET and [(18)F]FLT PET provided information on mechanism of action of the drug combination and clues as to potential clinical responses. Following translation to clinical use, treatment with a BEV/BEZ235 combination could reduce peritumoral oedema obviating the requirement for steroids. The use of hypothesis-driven molecular imaging studies facilitates the preclinical evaluation of drug response. Studies of this kind may more accurately predict the clinical potential of the BEV/BEZ235 combination regimen as a novel therapeutic approach in oncology. PMID- 26975404 TI - TiO2-SO4(2-) Catalyzed Synthesis and Antimicrobial Activity / Molecular Docking Studies of beta-Indolylnitroalkanes. AB - Michael addition of indole derivatives with various substituted nitrostyrenes to yield beta- indolylnitroalkanes is accomplished effectively under solvent free conditions using TiO2-SO4(2-) as efficient catalyst at 60 o C. All the synthesized compounds were screened for their antibacterial activity through in silico and in vitro methods. The molecular docking studies against FabH enzyme, a potential drug target of bacterial fatty acid biosynthetic pathway indicated the scope of developing them a new class of antimicrobial agents. Among the title compounds, 5h exhibited the highest dock score and the highest antibacterial activity when compared with other compounds and the standard drug Ampicillin. In addition, the compounds 5d, 5e, 5g, 5h, 5i, 5j and 5l showed significant inhibitory activity at different dose concentrations under in vitro conditions against the specified bacterial strains thus qualifying for further clinical evaluation so that they can be used as effective anti-bacterial agents. PMID- 26975405 TI - Not Just Any Job Will Do: A Study on Employment Characteristics and Recidivism Risks After Release. AB - Ex-prisoners' recidivism risks are high. Several theories state that employment can reduce these risks but emphasize that the protective role of employment is conditional on job qualities (work intensity, job duration, etc.). Longitudinal research on the role of employment in ex-prisoners' recidivism patterns is scarce, and most existing work used a simplistic employment measure (i.e., employed vs. unemployed), leaving the topic of job quality underexplored. This study examines the association between employment characteristics and recidivism among Dutch ex-prisoners. Using longitudinal data of the Prison Project ( n = 714), we found that not just any job, but particularly stable employment and jobs with a higher occupational level could help reduce crime rates among these high risk offenders. Many ex-prisoners face a human capital deficit that complicates the guidance to high-quality jobs. It might, however, be possible to help place ex-prisoners in stable employment. PMID- 26975406 TI - Epigenetic factors MeCP2 and HDAC6 control alpha-tubulin acetylation in cardiac fibroblast proliferation and fibrosis. AB - AIM AND OBJECTIVE: Cardiac fibrosis is an important pathological feature of cardiac remodeling in heart diseases. Methyl-CpG-binding protein 2 (MeCP2) is a transcription inhibitor, and plays a key role in the fibrotic diseases. However, the precise role of MeCP2 in cardiac fibrosis remains unclear. alpha-tubulin plays an essential role in cell function, whereby the acetylation state of alpha Tubulin dictates the efficiency of cell proliferation and differentiation. This study was undertaken to investigate that MeCP2 dynamics affect the acetylation state of alpha-tubulin in the cardiac fibrosis. METHODS: Forty adult male Sprague Dawley (SD) rats were randomly divided into two groups, cardiac fibrosis was produced by common ISO. Cardiac fibroblasts (CFs) were harvested from SD neonate rats and cultured. The expression of HDAC6, MeCP2, alpha-SMA, collagen I was measured by western blotting and qRT-PCR. siRNA of HDAC6 and MeCP2 effect the proliferation of cardiac fibroblasts, and affect the acetylation state of alpha tubulin. RESULTS: We have found the acetylation state of alpha-tubulin in cardiac fibroblasts as well as cardiac tissue from a ISO-induced rat cardiac fibrosis model and observed a reduction in acetylated alpha-tubulin and an increase in the alpha-tubulin-specific deacetylase, histone deacetylase 6 (HDAC6). Furthermore, we have shown that treatment of cardiac fibroblasts with HDAC6 inhibitor Tubastatin A and HDAC6-siRNA can restore alpha-tubulin acetylation levels. In addition, treatment of cardiac fibroblasts with MeCP2-siRNA blocked cell proliferation. Knockdown of MeCP2 suppresses HDAC6 expression in activated cardiac fibroblasts but increases the acetylation of alpha-tubulin. CONCLUSIONS: We demonstrated that MeCP2 may negatively control the acetylation of alpha tubulin through HDAC6 in cardiac fibroblast proliferation and fibrosis. This study indicated that MeCP2 could be a potentially new therapeutic option for cardiac fibrosis. PMID- 26975407 TI - Evaluation of the role of remission status in a heterogeneous limited disease small-cell lung cancer patient cohort treated with definitive chemoradiotherapy. AB - BACKGROUND: The role of remission status in limited disease (LD) small-cell lung cancer (SCLC) patients treated with definitive chemoradiotherapy (CRT) remains to be finally clarified. METHODS: Individual data from 184 patients treated with definitive CRT concurrently or sequentially were retrospectively reviewed. Kaplan Meier analysis as well as univariate and multivariate Cox regression models were used to describe survival within patient subgroups defined by remission status. RESULTS: 71 (39%) patients were treated in the concurrent, 113 (61%) in the sequential CRT mode. Prophylactic cranial irradiation (PCI) was applied in 71 (39%) patients. 37 (20%) patients developed local, while 89 (48%) distant recurrence. 58 (32%) patients developed metachronous brain metastases. Complete, partial remission and non-response (defined as stable and progressive disease) were documented in 65 (35%), 77 (42%), and 37 (20%) patients, respectively. In complete responders median overall survival was 21.8 months (95CI: 18.6 - 25) versus 14.9 (95% CI: 11.7 - 18.2) (p = 0.041, log-rank test) and 11.5 months (95% CI: 8.9 - 15.0) (p < 0.001, log-rank test) in partial and non-responders, respectively. The same effect was documented for the time to progression and distant metastasis-free survival. In the multivariate analysis achievement of complete remission as a variable shows a trend for the prolonged time to progression (p = 0.1, HR 1.48) and distant metastasis-free survival (p = 0.06, HR 1.63) compared to partial responders and was highly significant compared to non responders. CONCLUSION: In this treated heterogeneous LD SCLC patient cohort complete remission was associated with longer time to progression, distant metastasis-free and overall survival compared to the non- and especially partial responders. PMID- 26975408 TI - Scientific literature on infectious diseases affecting livestock animals, longitudinal worldwide bibliometric analysis. AB - The objectives of this bibliometric analysis of the scientific literature were to describe the research subjects and the international collaborations in the field of research on infectious diseases in livestock animals including fishes and honeybees. It was based on articles published worldwide from 2006 through 2013. The source of data was the Web of Science, Core collection((r)) and only papers fully written in English were considered. Queries were built that combined 130 descriptors related to animal species and 1213 descriptors related to diseases and pathogens. To refine and assess the accuracy of the extracted database, supplementary filters were applied to discard non-specific terms and neighbouring topics, and numerous tests were carried out on samples. For pathogens, annotation was done using a thematic terminology established to link each disease with its corresponding pathogen, which was in turn classified according to its family. A total of 62,754 articles were published in this field during this 8-year period. The average annual growth rate of the number of papers was 5%. This represents the reference data to which we compared the average annual growth rate of articles produced in each of the sub-categories that we defined. Thirty-seven percent of the papers were dedicated to ruminant diseases. Poultry, pigs and fishes were covered by respectively 21, 13 and 14% of the total. Thirty-seven percent of papers concerned bacteria, 33% viruses, 19% parasites, 2% prions, the remaining being multi-pathogens. Research on virology, especially on pigs and poultry, is increasing faster than the average. There also is increasing interest in monogastric species, fish and bees. The average annual growth rate for Asia was 10%, which is high compared to 3% for Europe and 2% for the Americas, indicating that Asia is currently playing a leading role in this field. There is a well established network of international collaborations. For 75% of the papers, the co-authors were from the same country, for 10%, they were from different countries on the same continent, and for 15%, they were from different continents. The annual growth rate of papers representing international collaborations generally is increasing more quickly than the overall average. PMID- 26975409 TI - On Sequence Learning Models: Open-loop Control Not Strictly Guided by Hick's Law. AB - According to the Hick's law, reaction times increase linearly with the uncertainty of target stimuli. We tested the generality of this law by measuring reaction times in a human sequence learning protocol involving serial target locations which differed in transition probability and global entropy. Our results showed that sigmoid functions better describe the relationship between reaction times and uncertainty when compared to linear functions. Sequence predictability was estimated by distinct statistical predictors: conditional probability, conditional entropy, joint probability and joint entropy measures. Conditional predictors relate to closed-loop control models describing that performance is guided by on-line access to past sequence structure to predict next location. Differently, joint predictors relate to open-loop control models assuming global access of sequence structure, requiring no constant monitoring. We tested which of these predictors better describe performance on the sequence learning protocol. Results suggest that joint predictors are more accurate than conditional predictors to track performance. In conclusion, sequence learning is better described as an open-loop process which is not precisely predicted by Hick's law. PMID- 26975410 TI - Transcriptome analysis of the effect of Vibrio alginolyticus infection on the innate immunity-related TLR5-mediated induction of cytokines in Epinephelus lanceolatus. AB - Epinephelus lanceolatus, considered to be an aquaculture fish species of high economic value in East Asia, is one of the largest groupers in the Epinephelus genus. Vibrio alginolyticus is a bacterial species that causes high morbidity in marine fish; infection can cause exophthalmia, ulcers, septicemia, and corneal opaqueness in fish. Epinephelus lanceolatus larvae infected with Vibrio alginolyticus were subjected to transcriptome analysis to study the immune regulation pathway. Grouper larvae were injected with 2.6 * 10(4) CFU/fish in 20 MUl of V. alginolyticus and control larvae were injected with TSB; RNA samples were then collected at 4, 6, 8, 10, 12, 16, 24, and 48 h after infection. Extracted RNA was subjected to reverse transcription, and used to examine the immune gene response of E. lanceolatus by Real-time PCR. Samples taken at 6 h were subjected to next-generation sequencing, resulting in a total read value of 28,705,411 and total base number of 2,152,905,850. The unigene number was 100,848, and 5913 unigenes were filtered using FPKM>0.3, 2FC, p < 0.05. Gene Ontology (GO) analysis of the filtered genes revealed a total of 30 GO numbers in the cellular component, and 58 GO numbers for both biological processes and molecular functions. Of the GO group related to immune pathways, 27 unigenes related to biological processes involving the immune response, 31 related to the immune system, 9 related to the inflammatory response, and 43 related to the response to stress were identified. KEGG pathway analysis only detected 1 to 4 genes, and as such, we selected the GO analysis results for further analysis using GeneSpring. This demonstrated that V. alginolyticus probably stimulates TLR5 activity via the bacterial flagellum, through an MyD88-dependent pathway; the resulting production of IL-1beta and IL-8 through the NFkappaB pathway induces pro-inflammatory and/or chemotactic effects. Alternatively, serum amyloid A may stimulate neutrophils that induce the secretion of MMP9 from infected tissues, resulting in the cleavage and activation of IL-8. IL-8, in turn, would enhance neutrophil chemotaxis. Infection also induced expression of genes encoding C3, C6, C7, C8, and C9, which induce the complement system and form the membrane attack complex to lyse the bacteria membrane. The qPCR results indicated that TLR5 is significantly increased between 10 and 16 h, IL-1beta between 8 and 16 h, IL-8 between 8 and 12 h, and C6 between 4 and 16 h, as compared to levels in the control. One antimicrobial peptide, hepcidin, was also strongly expressed between 4 and 10 h in infected fish. The results indicate that V. alginolyticus infection probably induces an immune response via TLR5-mediated regulation of down-stream cytokine gene expression. A second possibility is that the complement system and hepcidin may be involved in the immune response. These results may be applied by examining the immune effects of feeding E. lanceolatus larvae on a recombinant protein mixture based on the up-regulated genes. PMID- 26975411 TI - Changes in microRNAs expression profile of olive flounder (Paralichthys olivaceus) in response to viral hemorrhagic septicemia virus (VHSV) infection. AB - To know the effect of viral hemorrhagic septicemia virus (VHSV) infection on the cellular microRNA expression profile in olive flounder (Paralichthys olivaceus), fish were infected with VHSV, and cellular microRNAs expression was analyzed at 0 (control), 6, 12, 24, 48 and 72 h post-infection (h.p.i.) by the high-throughput sequencing. A total of 372 mature miRNAs were identified, and, among them, 63 miRNAs were differentially expressed during VHSV infection. The differentially expressed microRNAs number was greatly increased from 24 h.p.i. compared to the number at 6 and 12 h.p.i., suggesting that the alteration of microRNAs expression by VHSV infection may be related to the progression of VHSV disease. The target prediction analysis, the GO enrichment analysis, and the KEGG pathway analysis of the predicted target genes showed that various biological pathways could be affected by VHSV infection through the down-regulation or up-regulation of host miRNAs. The present results provide a basic information on the microRNAs related to VHSV infection in olive flounder. Considering broad effects of microRNAs on various biological pathways, data in this study can be used to interpret the mechanism of VHSV pathogenesis, which, vice versa, can be used to develop control measures against VHSV. PMID- 26975412 TI - Identification and functional characterization of fish-egg lectin in zebrafish. AB - Fish-egg lectins (FELs) are identified in several species of fishes, but their activity and mode of action remain largely unknown in early life stages. Here we showed that zebrafish FEL (zFEL) was a maternal factor, which was capable of interacting with Gram-negative and Gram-positive bacteria and enhancing the phagocytosis of the bacteria by macrophages. Interestingly, microinjection of purified native zFEL into the embryos (resulting in the increase of zFEL in the embryos) markedly promoted the resistance of the embryos to the pathogenic Aeromonas hydrophila. Taken together, zFEL appears a maternal immune-relevant molecule capable of defending the developing embryos/larvae from pathogenic attacks. PMID- 26975413 TI - The inhibitory role of gamma-aminobutyric acid (GABA) on immunomodulation of Pacific oyster Crassostrea gigas. AB - gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter to suppress the immune-mediated pro-inflammatory reactions, and it has been used in the treatment of many inflammation-related diseases in vertebrates, while its immunomodulatory role in invertebrates has never been reported. In the present study, GABA was found to exist in the hemolymph of Pacific oyster Crassostrea gigas, and its concentration decreased slightly from 8.00 +/- 0.37 MUmol L(-1) at normal condition to 7.73 +/- 0.15 MUmol L(-1) at 6 h after LPS stimulation, and then increased to 9.34 +/- 0.15 MUmol L(-1), 8.86 +/- 0.68 MUmol L(-1) at 12 h and 48 h, respectively. After LPS stimulation, the mRNA expressions of pro-inflammatory cytokines (CgIL-17 and CgTNF) and immune effectors (CgSOD and CgBPI), and the protein expression of NOS increased significantly, and these increased trends were remarkably inhibited by GABA stimulation. At the same time, the phagocytosis rate and apoptosis rate of immunocytes also increased obviously after LPS stimulation, whereas the increase was repressed with the addition of GABA. The results collectively demonstrated that GABA was an indispensable inhibitory agent for both humoral and cellular immune response, which mainly functioned at the late phase of immune response to avoid the excess immune reactions and maintain the immune homeostasis. PMID- 26975415 TI - Mineralization Effect of Hyaluronan on Dental Pulp Cells via CD44. AB - INTRODUCTION: CD44 is a cell-surface glycoprotein involved in various cellular functions. Recent studies have suggested that CD44 is involved in early mineralization of odontoblasts. Hyaluronic acid (HA) is the principal ligand for receptor CD44. Whether and how HA regulated the mineralization process of dental pulp cells were investigated. METHODS: The effects of high-molecular-weight HA on differentiation and mineral deposition of dental pulp cells were tested by using alkaline phosphatase (ALP) activity assay and alizarin red S staining. Osteogenesis real-time polymerase chain reaction array, quantitative polymerase chain reaction, and Western blotting were performed to identify downstream molecules involved in the mineralization induction of HA. CD44 was knocked down and examined to confirm whether the mineralization effect of HA was mediated by receptor CD44. Immunohistochemistry was used to understand the localization patterns of CD44 and the identified downstream proteins in vivo. RESULTS: Pulse treatment of HA enhanced ALP activity and mineral deposition in dental pulp cells. Tissue-nonspecific ALP, bone morphogenetic protein 7 (BMP7), and type XV collagen (Col15A1) were upregulated via the HA-CD44 pathway in vitro. Immunohistochemistry of tooth sections showed that the staining pattern of BMP7 was very similar to that of CD44. CONCLUSIONS: Results of this study indicated that high-molecular-weight HA enhanced early mineralization of dental pulp cells mediated via CD44. The process involved important mineralization-associated molecules including tissue-nonspecific ALP, BMP7, and Col15A1. The findings may help develop new strategies in regenerative endodontics. PMID- 26975416 TI - Micro-Computed Tomography Assessment of Apical Accessory Canal Morphologies. AB - INTRODUCTION: The morphologic features of accessory canals (ACs) were investigated by using micro-computed tomography technique with a centerline fitting algorithm. METHODS: Ninety-three 3-mm-long apical root segments with unobstructed ACs were scanned by micro-computed tomography at 2.5-MUm scanning resolution. After automatic segmentation, a centerline of the reconstructed lateral canal was developed, and the diameter, length, shape, and undulation of ACs were analyzed along the centerline. RESULTS: Of 178 unobstructed ACs identified, the median diameter was 67.0 MUm, the average length was 786.6 MUm, the predominant shape was oval, and the undulation was tortuous rather than straight. CONCLUSIONS: The diameter, length, shape, and undulation may vary among ACs in particular from the pulpal space to the external root surface, which may complicate the debridement of the ACs. PMID- 26975417 TI - Balance training improves postural balance, gait, and functional strength in adolescents with intellectual disabilities: Single-blinded, randomized clinical trial. AB - BACKGROUND: Adolescents with intellectual disabilities often present with problems of balance and mobility. Balance training is an important component of physical activity interventions, with growing evidence that it can be beneficial for people with intellectual disabilities. OBJECTIVE: The aim of this study was to investigate the effect of balance training on postural balance, gait, and functional strength in adolescents with intellectual disabilities. METHODS: Thirty-two adolescents with intellectual disabilities aged 14-19 years were randomly assigned either to a balance training group (n = 15) or a control group (n = 16). Subjects in the balance training group underwent balance training for 40 min per day, two times a week, for 8 weeks. All subjects were assessed with posture sway and the one-leg stance test for postural balance; the timed up-and go test and 10-m walk test for gait; and sit to stand test for functional strength. RESULTS: Postural balance and functional strength showed significant improvements in the balance training group (p < 0.05) as compared to baseline; however, postural balance and muscle strength showed no significant improvements in the control group. Further, postural balance and functional strength significantly improved in the balance training group compared with those in the control group. CONCLUSIONS: Balance training for adolescents with intellectual disabilities might be beneficial for improving postural balance and functional strength. PMID- 26975414 TI - Human H7N9 virus induces a more pronounced pro-inflammatory cytokine but an attenuated interferon response in human bronchial epithelial cells when compared with an epidemiologically-linked chicken H7N9 virus. AB - BACKGROUND: Avian influenza virus H7N9 has jumped species barrier, causing sporadic human infections since 2013. We have previously isolated an H7N9 virus from a patient, and an H7N9 virus from a chicken in a live poultry market where the patient visited during the incubation period. These two viruses were genetically highly similar. This study sought to use a human bronchial epithelial cell line model to infer the virulence of these H7N9 viruses in humans. METHODS: Human bronchial epithelial cell line Calu-3 was infected with two H7N9 viruses (human H7N9-HU and chicken H7N9-CK), a human H5N1 virus and a human 2009 pandemic H1N1 virus. The infected cell lysate was collected at different time points post infection for the determination of the levels of pro-inflammatory cytokines (tumor necrosis factor alpha [TNF-alpha] and interleukin 6 [IL-6]), anti inflammatory cytokines (interleukin 10 [IL-10] and transforming growth factor beta [TGF-beta]), chemokines (interleukin 8 [IL-8] and monocyte chemoattractant protein 1 [MCP-1]), and interferons (interferon beta [IFN-beta] and interferon lambda 1 [IFNL1]). The viral load in the cell lysate was also measured. RESULTS: Comparison of the human and chicken H7N9 viruses showed that H7N9-HU induced significantly higher levels of TNF-alpha at 12 h post-infection, and significantly higher levels of IL-8 from 12 to 48 h post-infection than those of H7N9-CK. However, the level of IFNL1 was lower for H7N9-HU than that of H7N9-CK at 48 h post-infection (P < 0.001). H7N9-HU had significantly higher viral loads than H7N9-CK at 3 and 6 h post-infection. H5N1 induced significantly higher levels of TNF-alpha, IL-6, IL-8, IL-10 and MCP-1 than those of H7N9 viruses at 48 h post-infection. Conversely, H1N1 induced lower levels of TNF-alpha, IL-10, MCP 1, IFNL1 and IFN-beta when compared with H7N9 viruses at the same time point. CONCLUSIONS: H7N9-HU induced higher levels of pro-inflammatory IL-6 and IL-8 and exhibited a more rapid viral replication than H7N9-CK. However, the level of antiviral IFNL1 was lower for H7N9-HU than H7N9-CK. Our results suggest that the gained properties in modulating human innate immunity by H7N9-HU transformed it to be a more virulent virus in humans than H7N9-CK. PMID- 26975418 TI - A Phase II Efficacy and Safety, Open-Label, Multicenter Study of Imprime PGG Injection in Combination With Cetuximab in Patients With Stage IV KRAS-Mutant Colorectal Cancer. AB - BACKGROUND: Imprime PGG (beta(1,6)-[poly-(1,3)-D-glucopyranosyl]-poly-beta(1,3)-D glucopyranose) is an innate immune cell modulator that primes neutrophils and monocytes/macrophages to exert antitumor activity against complement opsonized tumor cells. In patients with KRAS-mutant colorectal cancer (CRC), cetuximab alone is ineffective; however, it can bind to tumor cells and induce opsonization for recognition by Imprime PGG-bound innate immune cells. The primary objective of this study was to determine the antitumor activity of Imprime PGG in combination with cetuximab in patients with KRAS-mutant metastatic CRC. PATIENTS AND METHODS: The study had a 2-stage Simon optimal design with 80% power to detect a target objective response rate (ORR) of >=10% at a 10% significance level. Patients received weekly Imprime PGG (4 mg/kg) and cetuximab (loading dose, 400 mg/m(2), then 250 mg/m(2)) intravenously. The primary end point was ORR; secondary end points included duration of response (DOR), time to progression (TTP), overall survival (OS), disease control rate, progression-free survival, and safety. Stage 1 of the study was to enroll 17 evaluable patients. RESULTS: One partial response (5.6%) was observed among 18 patients enrolled into stage 1. Median DOR was 4.2 months, TTP 2.7 months, and OS 6.6 months. Overall, observed toxicity was as expected from cetuximab alone. The most common (>=20%) adverse events related to Imprime PGG were fatigue (7 patients; 38.9%), infusion reaction (4 patients; 22.2%), and headache (4 patients; 22.2%). There was no Grade 4 toxicity nor treatment-related deaths. CONCLUSION: Imprime PGG in combination with cetuximab treatment in patients with KRAS-mutant CRC showed compelling, albeit modest, clinical activity. This study provides proof of principle that Imprime PGG, in combination with complement-activating antibodies, is associated with clinical activity. PMID- 26975420 TI - The Ecological Role of Sharks on Coral Reefs. AB - Sharks are considered the apex predator of coral reefs, but the consequences of their global depletion are uncertain. Here we explore the ecological roles of sharks on coral reefs and, conversely, the importance of reefs for sharks. We find that most reef-associated shark species do not act as apex predators but instead function as mesopredators along with a diverse group of reef fish. While sharks perform important direct and indirect ecological roles, the evidence to support hypothesised shark-driven trophic cascades that benefit corals is weak and equivocal. Coral reefs provide some functional benefits to sharks, but sharks do not appear to favour healthier reef environments. Restoring populations of sharks is important and can yet deliver ecological surprise. PMID- 26975419 TI - Resilience, tipping, and hydra effects in public health: emergent collective behavior in two agent-based models. AB - BACKGROUND: Collective health behavior often demonstrates counter-intuitive dynamics, sometimes resisting interventions designed to produce change, or even producing effects that are in the opposite direction than intended by the intervention, e.g. lowering infectivity resulting in increased infections. At other times collective health behavior exhibits sudden large-scale change in response to small interventions or change in the environment, a phenomenon often called "tipping." I hypothesize that these seemingly very different phenomena can all be explained by the same dynamic, a type of collective resilience. METHODS: I compared two simple agent-based models of interactions in networks: a public health behavior game, in which individuals decide whether or not to adopt protective behavior, and a microbial-level game, in which three different strains of bacteria attack each other. I examined the type of networks and other conditions that support a dynamic balance, and determined what changes of conditions will tip the balance. RESULTS: Both models show lasting dynamic equilibrium and resilience, resulting from negative feedback that supports oscillating coexistence of diversity under a range of conditions. In the public health game, health protection is followed by free-riding defectors, followed by a rise in infection, in long-lasting cycles. In the microbial game, each of three strains takes turns dominating. In both games, the dynamic balance is tipped by lowering the level of local clustering, changing the level of benefit, or lowering infectivity or attack rate. Lowering infectivity has the surprising effect of increasing the numbers of infected individuals. We see parallel results in the microbial game of three bacterial strains, where lowering one strain's attack rate (analogous to lowering infectivity) increases the numbers of the restrained attacker, a phenomenon captured by the phrase, "the enemy of my enemy is my friend." CONCLUSIONS: Collective behavior often shows a dynamic balance, resulting from negative feedback, supporting diversity and resisting change. Above certain threshold conditions, the dynamic balance is tipped towards uniformity of behavior. Under a certain range of conditions we see "hydra effects" in which interventions to lower attack rate or infectivity are self defeating. Simple models of collective behavior can explain these seemingly disparate dynamics. PMID- 26975421 TI - There is no human interactome. AB - Protein complexes are dynamic. A new analysis of two quantitative proteomic datasets reveals cell type-specific changes in the stoichiometry of complexes, which often involve paralog switching. PMID- 26975422 TI - Dipeptidyl peptidase-4 is highly expressed in bronchial epithelial cells of untreated asthma and it increases cell proliferation along with fibronectin production in airway constitutive cells. AB - BACKGROUND: Type 2 helper T-cell cytokines including IL-13 play a central role in the pathogenesis of bronchial asthma (BA). During the course of our research, our attention was drawn to dipeptidyl peptidase-4 (DPP4) as one of the molecules that were induced from bronchial epithelial cells (BECs) by IL-13 stimulation. DPP4 could become a new biomarker or therapeutic target. The aim of this study was to investigate the expression of DPP4 in the asthmatic airway, and its role in the pathophysiology of asthma. METHODS: BECs were isolated from patients with inhaled corticosteroid-treated asthma (stBA) and inhaled corticosteroid-naive asthma (snBA) using bronchoscopy. DPP4 mRNA expression in freshly isolated BECs and primary cultured BECs with or without IL-13 stimulation was investigated by microarray analysis and quantitative real-time PCR (qPCR). The distribution of DPP4 protein was determined by immunostaining of transbronchial lung biopsy specimens from asthma patients. The effect of recombinant human (rh) DPP4 on the proliferation of lung fibroblasts (HFL-1) and bronchial smooth muscle cells (BSMCs) was examined, as well as its effect on the production of fibronectin (FN). RESULTS: DPP4 mRNA was strongly expressed in freshly isolated BECs in snBA, and its expression was significantly enhanced by IL-13 stimulation. DPP4 mRNA expression in BECs of snBA significantly correlated with exhaled nitric oxide. Biopsied tissues of the asthmatic airway revealed strong expression of DPP4 protein in BECs from snBA subjects. rhDPP4 stimulated the proliferation of HFL-1 and BSMCs, and it also enhanced production of FN from these airway cells. CONCLUSION: DPP4 may be involved in the pathologic features of asthmatic airway inflammation and cell proliferation and FN production. PMID- 26975423 TI - Implementation of parental feeding practices: does parenting style matter? AB - OBJECTIVES: To combat childhood obesity, researchers have focused on parental feeding practices that promote child health. The current study investigated how parenting style relates to twelve parental feeding practices. DESIGN: Data on parenting style and parental feeding practices were obtained for a correlational study from users of Amazon's Mechanical Turk, an online survey system. SETTING: USA. SUBJECTS: Mothers of children aged 7-11 years (n 193). RESULTS: Parenting style related differentially to eleven out of the twelve measured practices. Authoritative mothers displayed more feeding practices that promote child health and fewer practices that impede child health. Authoritarian and permissive mothers displayed more unhealthy practices than authoritative mothers, but differed from each other on the practices they employed. CONCLUSIONS: Parenting style may relate to more aspects of feeding than previously realized. The inclusion of numerous healthy feeding practices along with unhealthy practices in the current study provides suggestions for the application of healthy feeding behaviours. Instruction on feeding behaviours and parenting style should be a focus of future educational programmes. PMID- 26975424 TI - Long-term outcomes of radical vaginal trachelectomy and laparoscopic pelvic lymphadenectomy after neoadjuvant chemotherapy for the IB1 cervical cancer: A series of 60 cases. AB - OBJECTS: The present study sought to analyze the long-time clinical outcomes of the stage IB1 cervical cancer patients who had received the radical vaginal trachelectomy (RVT) and laparoscopic lymphadenectomy after neoadjuvant chemotherapy (NACT). METHOD: This is a prospective study of 60 patients potentially selected for RVT for a clinical and radiologic cervical cancer (stages IB 1) less than 2 cm. These patients were treated with surgery combined with preoperative NACT in the Department of Obstetrics and Gynecology, PLA General Hospital. We collected the patients' general clinical information, surgical characteristics and obstetric data, and then assessed their long-term oncological outcomes. RESULTS: The average operative time of the enrolled cases was 204 min and the average blood loss was 443 mL. The average postoperative hospitalization time was 10.6 days. The postoperative pathologic results indicated that the average parametrical width was 1.99 cm; the average length of removed of cervical was 2.6 cm; the average number of excised pelvic lymph node was 20. The median of the follow-up was 43 months (range between 13month and 12 years). Only one case of recurrence was found. Thus far, totally 42 women had tried to conceive, and 36 of them had live births. The live birth pregnancy rate was 86% (36/42). CONCLUSION: The radical vaginal trachelectomy in combination with the laparoscopic lymphadenectomy surgical is a safe and effective therapeutic strategy for the for IB 1 cervical cancer. PMID- 26975425 TI - The genesis and correction of unprofessional behavior in surgeons: The role of society, education and genetics. AB - BACKGROUND: Most surgeons are ethical. Increasingly, however, a variety of unprofessional behaviors are surfacing. Awareness of these behaviors and their causation is required to plan their eradication. OBJECTIVES: To (i) identify the prevalent causes of unprofessional behaviors amongst surgeons; and (ii) suggest corrective interventions. METHODS: Literature was searched and models constructed to interpret interrelationships between causes. FINDINGS: Unprofessional behaviors extend beyond those frequently discussed, necessitating the term 'dysprofessionalism'. Causal influences arise from (i) an overpowering society; (ii) limited education and (iii) the underdeveloped state of human nature at birth. Societies corrupt by role-modeling avarice and encouraging industry despite consequent pollution. Society brooks no interference. Surgeons are loath to oppose, resulting in an unprofessional silence. Surgical education based on best evidence is an indoctrination, with little opportunity to deploy alternatives. Evidence based guidelines increasingly risk errors, as publication fraud increases. Effective interaction with government/legislation is not taught. Human nature and our brain remain arrested in a stage of strongly stabilized evolutionary selection. Humans are born with larval brains requiring intense educational interventions. Genetic modification holds promise as it can circumvent birth in undeveloped states, and facilitate trans-generational transfer of knowledge. CRISPR/Cas-9 techniques make this possible, necessitating ethical discussion-an urgent issue. Reforming society would otherwise be an impossible task as behaviors cannot be taught in classrooms. CONCLUSION: Instances of dysprofessionalism are unlikely to diminish using current approaches. Discussion of the ethics of genetically modifying embryos is urgently needed, as this could provide a possible shortcut to positive changes in human behavior, but risks unwanted changes and misuse. PMID- 26975426 TI - A systematic review comparing single-incision versus multi-incision laparoscopic surgery for inguinal hernia repair with mesh. AB - OBJECTIVE: The objective of this article is to evaluate whether the surgical outcomes differ between single incision laparoscopic surgery (SILS) versus multi incision laparoscopic surgery (MILS) for the repair of inguinal hernia. METHODS: A systematic review of the literature on published studies reporting the surgical outcomes following SILS versus MILS for inguinal hernia repair was undertaken using the principles of meta-analysis. RESULTS: Fifteen comparative studies on 1651 patients evaluating the surgical outcomes in patients undergoing SILS versus MILS for inguinal hernia repair were systematically analysed. The post-operative recovery time was significantly quicker [odds ratio, -0.35 (CI, -0.57 - 0.14), p = 0.001] following SILS compared to MILS procedure. However, the statistical equivalence was seen in outcomes of length of hospital stay, operative time both for unilateral and bilateral hernias, post-operative pain score, one-week pain score, hernia recurrence [odds ratio, 1.24 (CI, 0.47-3.23), p = 0.66], conversion [odds ratio, 1.07 (CI, 0.37-3.12), p = 0.90], and post-operative complications [odds ratio, 0.95 (CI, 0.66-1.36, p = 0.78] between two approaches. The sub-group analysis of four included randomized, controlled trials showed similarities between outcomes following SILS and MILS except slightly higher postoperative pain score in MILS group. CONCLUSIONS: Both SILS and MILS approaches of inguinal hernia repair are feasible, safe and can be offered to patients depending upon the availability of expertise and resources. PMID- 26975427 TI - Robotic partial nephrectomy - Evaluation of the impact of case mix on the procedural learning curve. AB - INTRODUCTION: Although Robotic partial nephrectomy (RPN) is an emerging technique for the management of small renal masses, this approach is technically demanding. To date, there is limited data on the nature and progression of the learning curve in RPN. AIMS: To analyse the impact of case mix on the RPN LC and to model the learning curve. METHODS: The records of the first 100 RPN performed, were analysed at our institution that were carried out by a single surgeon (B.C) (June 2010-December 2013). Cases were split based on their Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) score into the following groups: 6-7, 8 9 and >10. Using a split group (20 patients in each group) and incremental analysis, the mean, the curve of best fit and R(2) values were calculated for each group. RESULTS: Of 100 patients (F:28, M:72), the mean age was 56.4 +/- 11.9 years. The number of patients in each PADUA score groups: 6-7, 8-9 and >10 were 61, 32 and 7 respectively. An increase in incidence of more complex cases throughout the cohort was evident within the 8-9 group (2010: 1 case, 2013: 16 cases). The learning process did not significantly affect the proxies used to assess surgical proficiency in this study (operative time and warm ischaemia time). CONCLUSIONS: Case difficulty is an important parameter that should be considered when evaluating procedural learning curves. There is not one well fitting model that can be used to model the learning curve. With increasing experience, clinicians tend to operate on more difficult cases. PMID- 26975428 TI - Using methylene blue as a marker to find and remove tiny metallic foreign bodies embedded in the soft tissues of children: A randomised controlled trial. AB - BACKGROUND: Embedment of metallic foreign bodies in the soft tissues is commonly encountered in the emergency room. Most foreign bodies are easily removed, but removal is difficult if the foreign body is very small or deeply embedded. OBJECTIVE: To determine the usefulness of methylene blue staining in the surgical removal of tiny metallic foreign bodies embedded in the soft tissue. METHODS: This prospective study involved 41 children treated between May 2007 and May 2012. The patients were randomly divided into a methylene blue group and a control group. In the control group, foreign bodies were located using a C-arm and removed via direct incision. In the methylene blue group, foreign bodies were located using a C-arm, marked with an injection of methylene blue and then removed surgically. The clinical outcomes, complications, operation time, surgical success rate, incision length, frequency of C-arm use, and length and depth of the foreign body were compared between the two groups. RESULTS: The surgical success rate was significantly higher in the methylene blue group. The average operation time was significantly shorter in the methylene blue group. The C-arm was used significantly less frequently in the methylene blue group than in the control group. The incision length was significantly shorter in the methylene blue group than in the control group. CONCLUSIONS: Methylene blue staining facilitated the location and removal of tiny metallic foreign bodies from the soft tissue, and significantly reduced operation time, incision length and radiation exposure compared to the conventional method. PMID- 26975429 TI - Complication of bariatric surgery: Legal complaints in France. PMID- 26975430 TI - The future of partial nephrectomy. AB - Innovation in recent times has accelerated due to factors such as the globalization of communication; but there are also more barriers/safeguards in place than ever before as we strive to streamline this process. From the first planned partial nephrectomy completed in 1887, it took over a century to become recommended practice for small renal tumours. At present, identified areas for improvement/innovation are 1) to preserve renal parenchyma, 2) to optimise pre operative eGFR and 3) to reduce global warm ischaemia time. All 3 of these, are statistically significant predictors of post-operative renal function. Urologists, have a proud history of embracing innovation & have experimented with different clamping techniques of the renal vasculature, image guidance in robotics, renal hypothermia, lasers and new robots under development. The DaVinci model may soon no longer have a monopoly on this market, as it loses its stranglehold with novel technology emerging including added features, such as haptic feedback with reduced costs. As ever, our predictions of the future may well fall wide of the mark, but in order to progress, one must open the mind to the possibilities that already exist, as evolution of existing technology often appears to be a revolution in hindsight. PMID- 26975432 TI - Skin conductance and schizophrenic symptomatology. AB - Skin conductance is a psychophysiological parameter that reflects fundamental processes such as attention and arousal. The present study explored whether deviations in skin conductance activity are associated with severity of schizophrenic symptoms. For this purpose, Skin Conductance Responses (SCRs) to discrete stimuli (80 dB noises) and Skin Conductance Levels (SCLs) of 37 schizophrenic patients and 31 healthy volunteers were recorded. In accordance with previous studies, schizophrenic patients were found to be hyporesponsive compared to healthy controls. More specifically, almost half of the patients (46%) did not react with any SCR to the first 3 stimuli, whereas only 10% of the control group exhibited such a non-responding. Accordingly, the mean amplitude of the first 3 SCRs - as measured in u Siemens - was found to be significantly lower in patients compared to controls. As well, mean SCL was found to be (marginally) elevated in the patient group. This was especially the case for patients who did exhibit SCRs. In the patient group, a negative correlation was found between amplitude of SCRs and symptom severity. This association was mainly carried by a significant correlation between positive symptoms and reduced SCRs. The clinical relevance of these findings is discussed in detail. PMID- 26975431 TI - Selenoproteins of African trypanosomes are dispensable for parasite survival in a mammalian host. AB - The trace element selenium is found in polypeptides as selenocysteine, the 21(st) amino acid that is co-translationally inserted into proteins at a UGA codon. In proteins, selenocysteine usually plays a role as an efficient redox catalyst. Trypanosomatids previously examined harbor a full set of genes encoding the machinery needed for selenocysteine biosynthesis and incorporation into three selenoproteins: SelK, SelT and, the parasite-specific, Seltryp. We investigated the selenoproteome of kinetoplastid species in recently sequenced genomes and assessed the in vivo relevance of selenoproteins for African trypanosomes. Database mining revealed that SelK, SelT and Seltryp genes are present in most kinetoplastids, including the free-living species Bodo saltans, and Seltryp was lost in the subgenus Viannia from the New World Leishmania. Homology and sinteny with bacterial sulfur dioxygenases and sulfur transferases suggest a putative role for Seltryp in sulfur metabolism. A Trypanosoma brucei selenocysteine synthase (SepSecS) null-mutant, in which selenoprotein synthesis is abolished, displayed similar sensitivity to oxidative stress induced by a short-term exposure to high concentrations of methylglyoxal or H2O2 to that of the parental wild-type cell line. Importantly, the infectivity of the SepSecS knockout cell line was not impaired when tested in a mouse infection model and compensatory effects via up-regulation of proteins involved in thiol-redox metabolism were not observed. Collectively, our data show that selenoproteins are not required for survival of African trypanosomes in a mammalian host and exclude a role for selenoproteins in parasite antioxidant defense and/or virulence. On this basis, selenoproteins can be disregarded as drug target candidates. PMID- 26975434 TI - Chronicity, genes en behavior. AB - Since 1863 psychiatry is dominated by the nosological conceptual paradigm that was further stimulated by the introduction of the DSM-III. This has resulted in an ignorance of the European psychiatric diagnostic tradition and a loss of the necessary critical observations and descriptions of psychopathology. This unfortunate process may be observed in the diagnosis of psychiatric disorders in mentally retarded patients where entities such as atypical psychoses, unstable mood disorder and motivational deficit syndrome are not recognized in general. The enormous increase of neuroscienti-fic knowledge, particularly the impact of genetic and intracellular mechanisms in the pathophysiology of psychiatric disorders, warrants the use of a more dimensional and functional psychiatric paradigm. It concerns the effect of gene transcription on the expression of neurotransmitters and receptors that may account for an increased vulnerability or a relapsing course. A so called anticipatory treatment approach is therefore advocated. PMID- 26975433 TI - Efficacy of risperidone, olanzapine and clozapine in the treatment of therapy resistant schizophrenia. AB - Therapy-resistance for positive symptoms is one of the most important problems that occurs with the medical treatment of schizophrenia. In the past years, clozapine has proven its effectiveness in this area and has been included in the treatment protocols and guidelines. Because of the risk of agranulocytosis with this compound and the intensive laboratory controls to be done, several studies have been performed with the new antipsychotics risperidone and olanzapine as alternative treatments. A review of the literature suggests that both drugs are as effective as the classic antipsychotics for therapy-resistant patients. A switch to risperidone or olanzapine possibly would be a alternative for those patients who have favourable effects on a low dose of clozapine. Furthermore the new antipsychotics have less side effects and ameliorating effects on negative and cognitive symptoms, so contributing to overall improvement in chronic schizophrenic disorders. However, in case of persistent positive symptopathology, clozapine remains the golden standard. The new antipsychotics should be included in treatment protocols before clozapine. PMID- 26975435 TI - Special issue of the third biennial meeting of the North American Society for Comparative Endocrinology (Sociedad Norteamericana de Endocrinologia Comparada; Societe Nord-Americaine d'Endocrinologie Comparee). PMID- 26975436 TI - PPh3O as an Activating Reagent for One-Pot Stereoselective Syntheses of Di- and Polybrominated Esters from Simple Aldehydes. AB - An efficient one-pot method for the syntheses of di- and polybrominated esters from readily available aldehydes is reported. The direct use of the in situ generated byproduct PPh3O in the following reactions greatly improves the efficiency of the cascade. Also, the substrate scope of the reaction is proved to be broad. PMID- 26975437 TI - Sinorhizobium meliloti Functionally Replaces 3-Oxoacyl-Acyl Carrier Protein Reductase (FabG) by Overexpressing NodG During Fatty Acid Synthesis. AB - In Sinorhizobium meliloti, the nodG gene is located in the nodFEG operon of the symbiotic plasmid. Although strong sequence similarity (53% amino acid identities) between S. meliloti NodG and Escherichia coli FabG was reported in 1992, it has not been determined whether S. meliloti NodG plays a role in fatty acid synthesis. We report that expression of S. meliloti NodG restores the growth of the E. coli fabG temperature-sensitive mutant CL104 under nonpermissive conditions. Using in vitro assays, we demonstrated that NodG is able to catalyze the reduction of the 3-oxoacyl-ACP intermediates in E. coli fatty acid synthetic reaction. Moreover, although deletion of the S. meliloti nodG gene does not cause any growth defects, upon overexpression of nodG from a plasmid, the S. meliloti fabG gene encoding the canonical 3-oxoacyl-ACP reductase (OAR) can be disrupted without any effects on growth or fatty acid composition. This indicates that S. meliloti nodG encodes an OAR and can play a role in fatty acid synthesis when expressed at sufficiently high levels. Thus, a bacterium can simultaneously possess two or more OARs that can play a role in fatty acid synthesis. Our data also showed that, although SmnodG increases alfalfa nodulation efficiency, it is not essential for alfalfa nodulation. PMID- 26975438 TI - Validation of a Three-Dimensional Method for Counting and Sizing Podocytes in Whole Glomeruli. AB - Podocyte depletion is sufficient for the development of numerous glomerular diseases and can be absolute (loss of podocytes) or relative (reduced number of podocytes per volume of glomerulus). Commonly used methods to quantify podocyte depletion introduce bias, whereas gold standard stereologic methodologies are time consuming and impractical. We developed a novel approach for assessing podocyte depletion in whole glomeruli that combines immunofluorescence, optical clearing, confocal microscopy, and three-dimensional analysis. We validated this method in a transgenic mouse model of selective podocyte depletion, in which we determined dose-dependent alterations in several quantitative indices of podocyte depletion. This new approach provides a quantitative tool for the comprehensive and time-efficient analysis of podocyte depletion in whole glomeruli. PMID- 26975440 TI - N-acetylcysteine decreases binge eating in a rodent model. AB - Binge-eating behavior involves rapid consumption of highly palatable foods leading to increased weight gain. Feeding in binge disorders resembles other compulsive behaviors, many of which are responsive to N-acetylcysteine (NAC), which is a cysteine prodrug often used to promote non-vesicular glutamate release by a cystine-glutamate antiporter. To examine the potential for NAC to alter a form of compulsive eating, we examined the impact of NAC on binge eating in a rodent model. Specifically, we monitored consumption of standard chow and a high fat, high carbohydrate western diet (WD) in a rodent limited-access binge paradigm. Before each session, rats received either a systemic or intraventricular injection of NAC. Both systemic and central administration of NAC resulted in significant reductions of binge eating the WD without decreasing standard chow consumption. The reduction in WD was not attributable to general malaise as NAC did not produce condition taste aversion. These results are consistent with the clinical evidence of NAC to reduce or reverse compulsive behaviors, such as, drug addiction, skin picking and hair pulling. PMID- 26975439 TI - MicroRNA-489 Induction by Hypoxia-Inducible Factor-1 Protects against Ischemic Kidney Injury. AB - MicroRNAs have been implicated in ischemic AKI. However, the specific microRNA species that regulates ischemic kidney injury remains unidentified. Our previous microarray analysis revealed microRNA-489 induction in kidneys of mice subjected to renal ischemia-reperfusion. In this study, we verified the induction of microRNA-489 during ischemic AKI in mice and further examined the underlying mechanisms. Hypoxia-inducible factor-1alpha deficiency associated with diminished microRNA-489 induction in cultured rat proximal tubular cells subjected to hypoxia and kidney tissues of mice after renal ischemia-reperfusion injury. Moreover, genomic analysis revealed that microRNA-489 is intronic in the calcitonin receptor gene, and chromatin immunoprecipitation assays showed increased binding of hypoxia-inducible factor-1 to a specific site in the calcitonin receptor gene promoter after hypoxia. Inhibition of microRNA-489 increased apoptosis in renal tubular cells after ATP depletion injury in vitro, whereas microRNA-489 mimics mediated protection. In mice, inhibition of microRNA 489 enhanced tubular cell death and ischemic AKI without significantly affecting tubular cell proliferation. Deep sequencing identified 417 mRNAs that were recruited to the RNA-induced silencing complex by microRNA-489. Of the identified mRNAs, 127 contain microRNA-489 targeting sites, and of those, 18 are involved in the cellular stress response, including the poly(ADP-ribose) polymerase 1 gene implicated in ischemic kidney injury. Sequence analysis and in vitro studies validated poly(ADP-ribose) polymerase 1 as a microRNA-489 target. Together, these results suggest that microRNA-489 is induced via hypoxia-inducible factor-1 during ischemic AKI to protect kidneys by targeting relevant genes. PMID- 26975441 TI - Reprogramming of hepatic fat accumulation and 'browning' of adipose tissue by the short-chain fatty acid acetate. AB - BACKGROUND/OBJECTIVES: Short-chain fatty acids, produced by microbiome fermentation of carbohydrates, have been linked to a reduction in appetite, body weight and adiposity. However, determining the contribution of central and peripheral mechanisms to these effects has not been possible. SUBJECTS/METHODS: C57BL/6 mice fed with either normal or high-fat diet were treated with nanoparticle-delivered acetate, and the effects on metabolism were investigated. RESULTS: In the liver, acetate decreased lipid accumulation and improved hepatic function, as well as increasing mitochondrial efficiency. In white adipose tissue, it inhibited lipolysis and induced 'browning', increasing thermogenic capacity that led to a reduction in body adiposity. CONCLUSIONS: This study provides novel insights into the peripheral mechanism of action of acetate, independent of central action, including 'browning' and enhancement of hepatic mitochondrial function. PMID- 26975442 TI - Protein intake in early childhood and body composition at the age of 6 years: The Generation R Study. AB - BACKGROUND: Previous studies suggest that high protein intake in infancy leads to a higher body mass index (BMI) in later childhood. We examined the associations of total, animal and vegetable protein intake in early childhood with detailed measures of body composition at the age of 6 years. METHODS: This study was performed in 2911 children participating in a population-based cohort study. Protein intake at the age of 1 year was assessed with a validated food-frequency questionnaire and was adjusted for total energy intake. At the children's age of 6 years, we measured their anthropometrics and body fat (with dual-energy X-ray absorptiometry). We calculated age- and sex-specific s.d. scores for BMI, fat mass index (FMI) and fat-free mass index (FFMI). RESULTS: After adjustment for confounders, a 10 g per day higher total protein intake at 1 year of age was associated with a 0.05 s.d. (95% confidence interval (CI) 0.00, 0.09) higher BMI at age 6. This association was fully driven by a higher FMI (0.06 s.d. (95%CI 0.01, 0.11)) and not FFMI (-0.01 s.d. (95%CI -0.06, 0.05)). The associations of protein intake with FMI at 6 years remained significant after adjustment for BMI at the age of 1 year. Additional analyses showed that the associations of protein intake with FMI were stronger in girls than in boys (P for interaction=0.03), stronger among children who had catch-up growth in the first year of life (P for interaction<0.01) and stronger for intake of animal protein (both dairy and non dairy protein) than protein from vegetable sources. CONCLUSIONS: Our results suggest that high protein intake in early childhood is associated with higher body fat mass, but not fat-free mass. Future studies are needed to investigate whether these changes persist into adulthood and to examine the optimal range of protein intake for infants and young children. PMID- 26975444 TI - Cost of diabetic eye, renal and foot complications: a methodological review. AB - INTRODUCTION: Diabetic retinopathy (DR), diabetic kidney disease (DKD) and diabetic foot ulcer (DFU) represent a public health and economic concern that may be assessed with cost-of-illness (COI) studies. OBJECTIVES: (1) To review COI studies published between 2000 and 2015, about DR, DKD and DFU; (2) to analyse methods used. METHODS: Disease definition, epidemiological approach, perspective, type of costs, activity data sources, cost valuation, sensitivity analysis, cost discounting and presentation of costs may be described in COI studies. Each reviewed study was assessed with a methodological grid including these nine items. RESULTS: The five following items have been detailed in the reviewed studies: epidemiological approach (59 % of studies described it), perspective (75 %), type of costs (98 %), activity data sources (91 %) and cost valuation (59 %). The disease definition and the presentation of results were detailed in fewer studies (respectively 50 and 46 %). In contrast, sensitivity analysis was only performed in 14 % of studies and cost discounting in 7 %. Considering the studies showing an average cost per patient and per year with a societal perspective, DR cost estimates were US $2297 (range 5-67,486), DKD cost ranged from US $1095 to US $16,384, and DFU cost was US $10,604 (range 1444-85,718). DISCUSSION: This review reinforces the need to adequately describe the method to facilitate literature comparisons and projections. It also recalls that COI studies represent complementary tools to cost-effectiveness studies to help decision makers in the allocation of economic resources for the management of DR, DKD and DFU. PMID- 26975443 TI - Central administration of vaspin inhibits glucose production and augments hepatic insulin signaling in high-fat-diet-fed rat. AB - OBJECTIVE: To investigate the effects of vaspin signaling conveyed by the brain on liver glucose fluxes in rats. METHODS: To determine the effects and underlying mechanisms of central vaspin signaling, normal-chow-diet- and high-fat-diet (HFD) fed rats with or without hepatic branch vagotomy (HBV) received acute infusion of vaspin to the third cerebral ventricle or MK801, a dorsal vagal complex (DVC) N methyl-D-aspartate (NMDA) receptor inhibitor, to the DVC during the pancreatic euglycemic clamp. RESULTS: Central administration of vaspin in HFD-fed rats significantly increased glucose infusion required to maintain euglycemia owing to an inhibition of glucose production during the clamps. These changes were accompanied by decreased hepatic phosphoenolpyruatecarboxykinase and G6Pase expression levels and increased hepatic insulin receptor, insulin receptor substrate-1, Akt kinase and the forkhead box-containing protein of the O subfamily-1 phosphorylation, suggesting improving hepatic insulin sensitivity in these animals. Conversely, selective HBV or DVC MK-801 infusion in HFD-fed rats blocked the effect of central vaspin on glucose production and hepatic insulin sensitivity. CONCLUSIONS: Our findings suggest that brain vaspin inhibited hepatic glucose production and improved insulin sensitivity via DVC to the hepatic branch of the vagus nerve in insulin resistance rats induced by HFD. PMID- 26975445 TI - Prevalence and pattern of humoral immunodeficiency in chronic refractory sinusitis. AB - The purpose of this study is to readdress the issue of primary humoral immunodeficiency frequency and pattern in medically resistant chronic rhinosinusitis (CRS) based on the new guidelines for CRS diagnosis and management. Two hundred and fifty-seven consecutive patients with refractory CRS were included in this study. The results of their IgA, IgM, IgG, and IgG subclasses were analyzed and compared with 75 age- and gender-matched control groups. The average age of CRS patients was 34 years (SD +/- 13). In the refractory CRS group, there was no significant difference between patients with or without humoral immunodeficiency based on age, gender and status of allergy, polyps and revision. Low level of one of the major immunoglobulin isotypes was found in 15 patients (6 %). Six patients had low IgG, two had low IgA, and seven had low IgM. IgG subclasses were low in 37 patients (14 %), and IgG4 was the most common deficient subclass. Multiple immunoglobulins deficiencies were found in eight patients. Compared with the control group, CRS patients had a significant higher prevalence of major immunoglobulins as well as total major immunoglobulins and IgG subclasses deficiency. Because of high prevalence of subtle humoral immunodeficiency in medically resistant CRS and inability to find unique clinical and demographic characteristic of these patients, we recommend routine screening of major immunoglobulins and IgG subclasses on the group of CRS patients who failed medical treatment. PMID- 26975446 TI - The influence of frequency-dependent hearing loss to unaided APHAB scores. AB - Hearing loss can be measured by pure-tone and speech audiometry. The subjective hearing impairment can be assessed using questionnaires. The APHAB determines this for four typical hearing situations. It has not been researched previously whether a particular frequency-specific hearing loss leads to a particular unaided APHAB score in one of the subscales or not. Clarification could be helpful using the unaided APHAB as an instrument for primary diagnostics of hearing loss independently of whether hearing aids were subsequently fitted or not. A total of 4546 records from a database were analysed; the average age of the subjects was 69.3 years. Using a multivariant mixed linear model, a possible correlation was examined between a frequency-specific hearing loss (0.5-8.0 kHz) and particular unaided APHAB scores for its subscales. Furthermore, it was determined whether the subject's gender has a corresponding impact. There was no evidence of gender-specific dependence of the unaided APHAB scores. For the EC scale frequencies above 0.5 kHz, for the RV scale all frequencies and for the AV scale the frequencies at 1.0 and 2.0 kHz showed a significant correlation between hearing loss and the APHAB score. For each decibel of hearing loss there was an average rise in the APHAB score for the EC and RV scale of approximately 0.2 percentage points and an average decrease in the AV scale of 0.1 percentage points for each frequency. For the BN scale there was no evidence of this kind of correlation. The very varied possibility between individuals compensating for hearing loss in situations with background noises could be that there is no correlation between frequency-specific hearing loss and an associated unaided APHAB score. The described frequency-specific influence of hearing loss to the EC and RV score could be explained by fewer compensating possibilities for the patients in these specific hearing situations than for the BN scale described. Using the unaided APHAB form in primary diagnostics of hearing impairment is helpful for understanding individual problems. PMID- 26975447 TI - A novel framework of classical and quantum prisoner's dilemma games on coupled networks. AB - Evolutionary games on multilayer networks are attracting growing interest. While among previous studies, the role of quantum games in such a infrastructure is still virgin and may become a fascinating issue across a myriad of research realms. To mimick two kinds of different interactive environments and mechanisms, in this paper a new framework of classical and quantum prisoner's dilemma games on two-layer coupled networks is considered. Within the proposed model, the impact of coupling factor of networks and entanglement degree in quantum games on the evolutionary process has been studied. Simulation results show that the entanglement has no impact on the evolution of the classical prisoner's dilemma, while the rise of the coupling factor obviously impedes cooperation in this game, and the evolution of quantum prisoner's dilemma is greatly impacted by the combined effect of entanglement and coupling. PMID- 26975448 TI - Evaluation of cyclosporine-sparing effects of polyunsaturated fatty acids in the treatment of canine atopic dermatitis. AB - A randomised, double-blinded, placebo-controlled multicentre trial was conducted in 36 dogs with atopic dermatitis to evaluate the cyclosporine-sparing effect of polyunsaturated fatty acids. Dogs were stable on their individual cyclosporine dosage and received either a mainly omega-3 fatty acid product with a minor omega 6 fatty acid fraction or placebo, orally for 12 weeks. Dogs were examined every 4 weeks and the Canine Atopic Dermatitis Extent and Severity Index (CADESI-03) was determined by a clinician. Pruritus, quality of life, global condition and coat quality were scored by the owner. If the dog's CADESI-03 and/or pruritus score improved by at least 25% compared with the previous visit, the cyclosporine dosage was decreased by approximately 25%. If the scores deteriorated by at least 25%, the cyclosporine dosage was increased by the same percentage. The median daily cyclosporine dosage/kg bodyweight decreased in the active group from 4.1 mg to 2.6 mg and in the placebo group from 3.5 mg to 3.3 mg over the study period. The difference between the two groups was significant (P = 0.009). The improvement in median pruritus score from inclusion to completion was significantly greater in the active group than in the placebo group (P = 0.04). There was no significant difference in CADESI-03 changes between groups (P = 0.38). The results of this study indicate a cyclosporine-sparing effect of a mainly omega-3 fatty acid supplement in dogs with atopic dermatitis. PMID- 26975449 TI - Lack of association between arterial oxygen tensions in horses during exploratory coeliotomy and post-operative incisional complications: A retrospective study. AB - The aim of this retrospective study was to determine if there was an association between the lowest arterial blood oxygen tensions (PaO2) measured during anaesthesia and post-operative incisional complications in horses. Clinical records of 278 horses undergoing ventral midline coeliotomy from 1 January 2010 to 31 December 2013 were examined. The frequency of incisional complications was 32.0% (n = 89). In a multivariable model, intra-operative arterial blood oxygen tensions (PaO2) were not significantly associated with development of an incisional complication (P = 0.351). Using hypertonic (7.2%) saline (P = 0.028, OR 3.167, 95% CI 1.132-8.861), increasing total plasma protein concentration (TP) (P = 0.002, OR 1.061 per g/L, 95% CI 1.021-1.102), an intestinal resection (P <0.001, OR 4.056, 95% CI 2.231-9.323), increasing body mass (P = 0.004, OR 1.004 per kg, 95% CI 1.001-1.006) and the use of penicillin alone compared with penicillin and gentamicin pre-operatively (P = 0.009, OR 4.145, 95% CI 1.568 10.958) increased the risk of incisional complications. The study was unable to demonstrate a link between low intra-operative PaO2 and increased risk of post operative incisional complications. PMID- 26975450 TI - Cue informativeness constrains visual tracking during an interceptive timing task. AB - Interceptive actions, such as catching, are a fundamental component of many activities and require knowledge of advanced kinematic information and ball flight characteristics to achieve successful performance. Rather than combining these sources of information, recent exploration of interceptive actions has presented them individually. Thus, it still is unclear how the information available from advanced cues influences eye movement behaviour. By integrating advanced visual information with novel ball projection technology, this study examined how the availability of advanced information, using four different cueing conditions: no image (ball flight only with no advanced information), non informative (ball flight coupled with ball release information), directional (ball flight coupled with directional information), and kinematic (ball flight coupled with video of a throwing action), influenced visual tracking during a one handed catching task. The findings illustrated no differences in catching performance across conditions; however, tracking of the ball was initiated earlier, for a longer duration, and over a greater proportion of the ball's trajectory in the directional and kinematic conditions. Significant differences between a directional cue and kinematic cue were not evident, suggesting a simple cue that provided information on the time of release and direction of ball flight was sufficient for successfully anticipating ball release and constraining eye movements. These findings highlight the relationship between advanced information and gaze behaviour during ball flight, and the performance of dynamic interceptive actions. We discuss the implications and potential limitations (e.g. variability between throwing image and ball projection) of the findings in the context of recent research on catching. PMID- 26975451 TI - The Relationship Between Clinicians' Confidence and Accuracy, and the Influence of Child Characteristics, in the Screening of Autism Spectrum Disorder. AB - The study examined the confidence accuracy relationship, and the influence of child characteristics on clinician confidence, when predicting a diagnosis of Autism Spectrum Disorder during screening of 125 referred children aged under 3.5 years. The diagnostic process included observation, interview, language and developmental testing. Clinical judgement accuracy was compared against final diagnosis for high and low confidence levels (with confidence assessed on a 0-100 % scale). We identified a significant CA relationship with predictive accuracy highest at confidence levels of 90-100 %. Parent report of unusual behaviors was the only significant independent predictor of confidence. Clinicians' confidence may be important when evaluating decisions to refer, or not to refer, children for further diagnostic assessment. PMID- 26975452 TI - Incremental value of global longitudinal strain in prediction of all-cause mortality in predialysis and dialysis chronic kidney disease patients. AB - BACKGROUND: The aim of this prospective study was to investigate the prediction of all-cause mortality from global longitudinal strain (GLS) in two groups of chronic kidney disease patients (CKD): predialysis and dialysis. METHODS: In 89 patients undergoing echocardiography, 37.2 % predialysis (16/43) and 58.6 % dialysis patients (27/46) died during the mean follow-up 70.2 +/- 35 months. In addition to conventional echocardiographic measurements, GLS was assessed by velocity vector imaging from three standard apical views. RESULTS: Cox proportional hazards regression enter model showed the following variables to predict survival: the only significant predictor of survival in predialysis patients, among the set of conventional echocardiographic parameters was GLS (HR, 0.58; 95 % CI, 0.39-0.87; p = 0.01). In the group of dialysis patients GLS with E/Em ratio remained as significant predictors of survival (HR, 0.72; 95 % CI, 0.56-0.92; p = 0.01, and HR, 1.02; 95 % CI, 1.004-1.04; p = 0.01, respectively). GLS >= - 13.2 % had 58.3 % sensitivity and 91.7 % specificity for prediction of mortality in predialysis patients, and GLS >= - 12.02 % had 73.3 % sensitivity and 78.9 % specificity for prediction of mortality in dialysis patients. In dialysis group E/Em ratio ? 17.02 had 71.4 % sensitivity and 84.2 % specificity for prediction of mortality. CONCLUSIONS: Our study demonstrates the incremental value of GLS in prediction of all-cause mortality during a long follow-up period in CKD patients. GLS together with E/Em ratio may be used for the assessment of left ventricular systolic and diastolic function and risk stratification of CKD patients in different stages of renal failure. PMID- 26975453 TI - Xanthelasma palpebrarum associated with increased cardio-ankle vascular index in asymptomatic subjects. AB - BACKGROUND: Xanthelasma palpebrarum (XP) is associated with increased risk of ischemic heart disease and myocardial infarction independent of other well-known cardiovascular risk factors. Cardio-ankle vascular index (CAVI) is a novel index of arterial stiffness and important marker of subclinical atherosclerosis. The purpose of this study was to investigate the association between XP and CAVI in asymptomatic subjects. METHODS: Consecutive 50 subjects with XP and age-gender matched 50 control subjects were enrolled. Patients with known atherosclerotic vascular disease were excluded. Arterial stiffness was assessed by CAVI and defined as abnormal if CAVI is >= 8. RESULTS: Subjects with XP had higher mean CAVI than control subjects (8.05 +/- 1.72 vs. 6.76 +/- 1.18, p < 0.001). Frequency of abnormal CAVI was higher in subjects with XP (n = 27) compared to those without XP (n = 9, 54 vs. 18 %, p < 0.001). There was a significant correlation between XP and CAVI (r = 0.42, p < 0.001). Conditional logistic regression analysis showed that XP (odds ratio OR 8.80, 95 % confidence interval CI 2.63-29.49, p < 0.001) and age (OR 1.17, 95 % CI 1.08-1.26, p < 0.001) were independent predictors for abnormal CAVI. CONCLUSION: The study suggests that XP is associated with increased arterial stiffness in asymptomatic subjects. PMID- 26975454 TI - Crizotinib-induced toxicity in an experimental rat model. AB - AIM: The aim of the present study was to evaluate the effect of crizotinib on visceral organs in an experimental rat model. METHODS: Eighteen Wistar albino rats were divided into three groups: experimental toxicity was induced with crizotinib (10 mg/kg) administered for 28 days (Group 1), 42 days (Group 2) orally by gavage. Control group received only distilled water. Rats in Group 1 and Group 2 were sacrificed after the collection of blood and tissue samples on the 28th and 42nd days, respectively. RESULTS: Subjects in Group 1 and Group 2 had abnormal histology mainly in lung and liver. There were intraalveolar hemorrhage in lungs; mild portal inflammation, perivenular focal and confluent necrosis in liver; inflammatory reaction in renal pelvis and periureteral areas, and focal pancreatitis in pancreas. CONCLUSION: This study is the first to evaluate the histopathological features of toxicity of crizotinib in a rat model. PMID- 26975456 TI - A rare case of atlantoaxial dislocation combined with multilesion spinal fusion and basilar invagination. PMID- 26975455 TI - Insights into Adaptations to a Near-Obligate Nematode Endoparasitic Lifestyle from the Finished Genome of Drechmeria coniospora. AB - Nematophagous fungi employ three distinct predatory strategies: nematode trapping, parasitism of females and eggs, and endoparasitism. While endoparasites play key roles in controlling nematode populations in nature, their application for integrated pest management is hindered by the limited understanding of their biology. We present a comparative analysis of a high quality finished genome assembly of Drechmeria coniospora, a model endoparasitic nematophagous fungus, integrated with a transcriptomic study. Adaptation of D. coniospora to its almost completely obligate endoparasitic lifestyle led to the simplification of many orthologous gene families involved in the saprophytic trophic mode, while maintaining orthologs of most known fungal pathogen-host interaction proteins, stress response circuits and putative effectors of the small secreted protein type. The need to adhere to and penetrate the host cuticle led to a selective radiation of surface proteins and hydrolytic enzymes. Although the endoparasite has a simplified secondary metabolome, it produces a novel peptaibiotic family that shows antibacterial, antifungal and nematicidal activities. Our analyses emphasize the basic malleability of the D. coniospora genome: loss of genes advantageous for the saprophytic lifestyle; modulation of elements that its cohort species utilize for entomopathogenesis; and expansion of protein families necessary for the nematode endoparasitic lifestyle. PMID- 26975457 TI - Surgical management of Gorham disease involving the upper cervical spine with occipito-cervical-thoracic fusion: a case report. AB - BACKGROUND CONTEXT: Gorham disease is a rare osteolytic condition, with only 17 reported cases primarily affecting the cervical spine. PURPOSE: We report the case of a 31-year-old woman with severe kyphotic instability and myelopathy of the upper cervical spine secondary to massive osteolysis of the posterior elements. The surgical management, clinical outcome, and review of the relevant literature are discussed. STUDY DESIGN: This is a case report and a literature review. PATIENT SAMPLE: This is a report of one patient with Gorham disease of the cervical spine. METHODS: We report the case of a 31-year-old woman with Gorham disease affecting the upper cervical spine. Combined posterior and anterior stabilization and fusion was performed from the occiput to the thoracic spine. RESULTS: Six-year follow-up with annual computed tomography imaging showed solid fusion from the occiput to T2. No spread or local recurrence has developed to date. CONCLUSIONS: Correction of severe instability with myelopathy due to Gorham disease of the upper cervical spine was achieved through posterior and anterior occipito-cervical-thoracic fusion. PMID- 26975458 TI - Thirty-day readmissions following adult spinal deformity surgery: an analysis of the National Surgical Quality Improvement Program (NSQIP) database. AB - BACKGROUND: Adult spine deformity surgery (ASDS) is a significantly invasive procedure with a relatively high complication rate. The thirty-day hospital readmission rate following surgery is an important quality measure monitored by multiple quality reporting agencies. PURPOSE: This study seeks to determine the risk factors for 30- day readmission rate in patients undergoing ASDS and identify the risk factors associated with readmission. STUDY DESIGN: This is a retrospective multicenter study. METHODS: The National Surgical Quality Improvement Program database, which is a large multi-institutional database, was searched for patients that underwent ASDS from 2011 to 2013. The patients were identified by searching seven Current Procedural Terminology codes most commonly used for spinal deformity surgery. Twenty-seven preoperative variables, including patient demographics and comorbidities, intraoperative parameters, and postoperative complications were analyzed to identify risk factors for readmission. RESULTS: A total of 747 adult patients who underwent ASDS were identified. Of the 747 patients, 7.5% (56/747) were readmitted within 30 days. The most common causes of readmission were infection (n=11), hematoma or seroma formation (n=5), and postoperative pain (n=3). Univariate analysis revealed male gender (p=.038, odds ratio [OR]=1.83) and pulmonary embolism before discharge (p=.048, OR=8.44) to be associated with readmission. In multivariate analysis, obesity (p=.047, OR=1.80), peripheral vascular disease (p=.045, OR=17.52), pulmonary embolism before discharge (p=.012, OR=10.35), and total or partial dependent preoperative functional health status (p=.041, OR=2.45), were found to be independent risk factors for readmission. Age, smoking, and resident involvement during surgical procedure were among the many factors not associated with increased risk of readmission. CONCLUSIONS: The 30-day readmission rate for ASDS is increasingly becoming a significant health-care quality indicator. Patients with the aforementioned significant risk factors should be closely followed up, which can potentially avoid subsequent readmission. PMID- 26975459 TI - Cytokine profile in degenerated painful intervertebral disc: variability with respect to duration of symptoms and type of disease. AB - BACKGROUND CONTEXT: Neuroinflammation is supposed to play a crucial role in the generation of chronic pain. Numerous trials have documented the contribution of proinflammatory cytokines in the pathophysiology of pain associated with peripheral and central nociception. Local and systemic expressions of proinflammatory cytokines have been implicated as mediators of pain. Among these cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) are especially notable because of their hyperalgesic impacts after nerve damage. PURPOSE: The aim of the present study was to evaluate and compare the tissue levels of IL-1beta, IL-6, interleukin-10 (IL-10), and TNF alpha in subligamentous and free fragment types of degenerated intervertebral disc in acute and chronic periods. STUDY DESIGN: This was a cross-sectional study. PATIENT SAMPLE: A cross-sectional study was implemented on a total of 49 patients (24 women, 25 men) with an average age of 38.2+/-4.9 treated surgically by means of microdiscectomy. OUTCOME MEASURES: Of these cases, 19 had complaints for less than 6 months, whereas 30 patients had been suffering from low back pain and leg pain for more than 6 months. Thirty-eight patients have been diagnosed with subligamentous type and 11 patients had free fragment type of disc degeneration. METHODS: The levels of IL-1beta, IL-6, IL-10, and TNF-alpha were assessed in tissue samples prepared from nucleus pulposus tissue obtained during microdiscectomy. Results were compared in patients with acute and chronic duration of complaints, as well as subligamentous and free fragment types of intervertebral disc degeneration. RESULTS: The levels of IL-1beta (p<.001), IL-6 (p<.001), IL-10 (p<.001), and TNF-alpha (p<.001) were significantly higher in patients with acute duration of complaints. Similarly, free fragment type of intervertebral disc degeneration displayed remarkably higher levels of IL-1beta (p=.009), IL-6 (p<.001), IL-10 (p=.024), and TNF-alpha (p=.017) compared with the subligamentous type. CONCLUSIONS: Inflammatory cytokines seem to have a more apparent role in intervertebral disc degeneration especially in acute period and in free fragment type. Further trials should be performed for elucidation of pathophysiology at the molecular level and the development of more effective diagnostic and therapeutic measures. PMID- 26975460 TI - Back pain due to spinal metastatic leiomyosarcoma. PMID- 26975461 TI - The Effects of Kangaroo Care in the Neonatal Intensive Care Unit on the Physiological Functions of Preterm Infants, Maternal-Infant Attachment, and Maternal Stress. AB - This study was conducted to identify the effects of kangaroo care on the physiological functions of preterm infants, maternal-infant attachment, and maternal stress. DESIGN AND METHODS: For this study, a quasi-experiment design was used with a nonequivalent control group, and a pre- and post-test. Data were collected from preterm infants with corrected gestational ages of >=33weeks who were hospitalized between May and October 2011. Twenty infants were assigned to the experimental group and 20 to the control group. As an intervention, kangaroo care was provided in 30-min sessions conducted thrice a week for a total of 10 times. The collected data were analyzed by using the t test, repeated-measures ANOVA, and the ANCOVA test. RESULTS: After kangaroo care, the respiration rate significantly differed between the two groups (F=5.701, p=.020). The experimental group had higher maternal-infant attachment scores (F=25.881, p<.001) and lower maternal stress scores (F=47.320, p<.001) than the control group after the test. In other words, kangaroo care showed significantly positive effects on stabilizing infant physiological functions such as respiration rate, increasing maternal-infant attachment, and reducing maternal stress. CONCLUSION: This study suggests that kangaroo care can be used to promote emotional bonding and support between mothers and their babies, and to stabilize the physiological functions of premature babies. PRACTICE IMPLICATIONS: Kangaroo care may be one of the most effective nursing interventions in the neonatal intensive care unit for the care of preterm infants and their mothers. PMID- 26975463 TI - Identifying modifiable factors associated with postoperative ileus. PMID- 26975466 TI - Enhancing the Personalization of Psychotherapy With Dynamic Assessment and Modeling. AB - Clinicians have long recognized the importance of tailoring psychotherapy interventions to the needs and characteristics of the individual patient. However, traditional approaches to clinical assessment, service delivery, and intervention research have not been conducive to such personalization. Contrary to traditional nomothetic approaches, idiographic assessment and modeling of intraindividual dynamic processes holds tremendous promise for tailoring the implementation of psychotherapy to the individual patient. In this article, we (a) present an argument for assessing person-specific dynamics, (b) provide a detailed description of a method that harnesses person-specific dynamic assessment and modeling for use in routine psychotherapy, PMID- 26975462 TI - A low-cost, multiplexed MUECoG system for high-density recordings in freely moving rodents. AB - OBJECTIVE: Micro-electrocorticography (MUECoG) offers a minimally invasive neural interface with high spatial resolution over large areas of cortex. However, electrode arrays with many contacts that are individually wired to external recording systems are cumbersome and make recordings in freely behaving rodents challenging. We report a novel high-density 60-electrode system for MUECoG recording in freely moving rats. APPROACH: Multiplexed headstages overcome the problem of wiring complexity by combining signals from many electrodes to a smaller number of connections. We have developed a low-cost, multiplexed recording system with 60 contacts at 406 MUm spacing. We characterized the quality of the electrode signals using multiple metrics that tracked spatial variation, evoked-response detectability, and decoding value. Performance of the system was validated both in anesthetized animals and freely moving awake animals. MAIN RESULTS: We recorded MUECoG signals over the primary auditory cortex, measuring responses to acoustic stimuli across all channels. Single-trial responses had high signal-to-noise ratios (SNR) (up to 25 dB under anesthesia), and were used to rapidly measure network topography within ~10 s by constructing all single-channel receptive fields in parallel. We characterized evoked potential amplitudes and spatial correlations across the array in the anesthetized and awake animals. Recording quality in awake animals was stable for at least 30 days. Finally, we used these responses to accurately decode auditory stimuli on single trials. SIGNIFICANCE: This study introduces (1) a MUECoG recording system based on practical hardware design and (2) a rigorous analytical method for characterizing the signal characteristics of MUECoG electrode arrays. This methodology can be applied to evaluate the fidelity and lifetime of any MUECoG electrode array. Our MUECoG-based recording system is accessible and will be useful for studies of perception and decision-making in rodents, particularly over the entire time course of behavioral training and learning. PMID- 26975467 TI - Factorial Structure and Validity of the Quantified Behavior Test Plus (Qb+(c)). AB - This study investigates the factorial structure and validity of the Quantified Behavior Test Plus (Qb+(c)), a computerized test to objectively evaluate the three attention deficit/hyperactivity disorder core symptoms, hyperactivity, inattention, and impulsivity, independently. Confirmatory and exploratory factor analyses were conducted with an outpatient sample of 773 subjects >=12 years old. In a second sample of 297 patients >=16 years, a multitrait-multimethod analysis was performed to examine concurrent and discriminant validity. The discriminative power of the Qb+ was investigated using a general linear model and logistic regression analysis. The three factorial structure (Hyperactivity, Inattention, Impulsivity) was verified in the confirmatory factor analysis. Fit indices demonstrated a good model fit and factor loadings were almost all moderate to high. In the multitrait-multimethod analysis, the criterion for convergent validity was fulfilled. The discriminant validity of the Qb+ was partially supported. Significant but small gender and age effects were found. In the logistic regression analysis, omission errors and reaction time variability, belonging to the Inattention factor, were able to discriminate between subjects with and without attention deficit/hyperactivity disorder. The internal structure of the Qb+ was verified. Its validity was partially supported. Results regarding discriminative power were mixed. PMID- 26975468 TI - Erratum. AB - [This corrects the article DOI: 10.1177/1756287214565637.]. PMID- 26975469 TI - Interaction of human chymase with ginkgolides, terpene trilactones of Ginkgo biloba investigated by molecular docking simulations. AB - The search for natural chymase inhibitors has a good potential to provide a novel therapeutic approach against the cardiovascular diseases and other heart ailments. We selected from literature 20 promising Ginkgo biloba compounds, and tested them for their potential ability to bind chymase enzyme using docking and a deep analysis of surface pocket features. Docking results indicated that the compounds may interact with the active site of human chymase, with favorable distinct interactions with important residues Lys40, His57, Lys192, Phe191, Val146, Ser218, Gly216, and Ser195. In particular, proanthocyanidin is the one with the best-predicted binding energy, with seven hydrogen bonds. Interestingly, all active G. biloba compounds have formed the hydrogen bond interactions with the positively charged Lys192 residue at the active site, involved in the mechanism of pH enhancement for the cleavage of angiotensin I site. Ginkgolic acid and proanthocyanidin have better predicted binding energy towards chymase than other serine proteases, i.e kallikrein, tryptase and elastase, suggesting specificity for chymase inhibition. Our study suggests these G. biloba compounds are a promising starting point for developing chymase inhibitors for the potential development of future drugs. PMID- 26975470 TI - Myomir dysregulation and reactive oxygen species in aged human satellite cells. AB - Satellite cells that reside on the myofibre surface are crucial for the muscle homeostasis and regeneration. Aging goes along with a less effective regeneration of skeletal muscle tissue mainly due to the decreased myogenic capability of satellite cells. This phenomenon impedes proper maintenance and contributes to the age-associated decline in muscle mass, known as sarcopenia. The myogenic potential impairment does not depend on a reduced myogenic cell number, but mainly on their difficulty to complete a differentiation program. The unbalanced production of reactive oxygen species in elderly people could be responsible for skeletal muscle impairments. microRNAs are conserved post-transcriptional regulators implicated in numerous biological processes including adult myogenesis. Here, we measure the ROS level and analyze myomiR (miR-1, miR-133b and miR-206) expression in human myogenic precursors obtained from Vastus lateralis of elderly and young subjects to provide the molecular signature responsible for the differentiation impairment of elderly activated satellite cells. PMID- 26975471 TI - Deciphering the role of Atg5 in nucleotide dependent interaction of Rab33B with the dimeric complex, Atg5-Atg16L1. AB - Autophagy is a lysosomal degradation pathway that degrades cytosolic constituents, including whole organelles and intracellular pathogens. Previous studies on various autophagy related genes revealed the importance of the Atg12 Atg5-Atg16 complex in autophagy. Atg16L1 is an effector of Golgi-resident Rab33B and the molecular mechanism of the interaction of Rab33B with either Atg16L1 or in complex with Atg5 is still elusive. In the current study, using the pull down and calorimetric approaches, we have dissected the molecular insights into the interaction of Rab33B with different regions of mouse Atg16L1 as well as with the dimeric complex, Atg5-mAtg16L1. Our in vitro observation suggests that Atg5 is pre-requisite for the augmented nucleotide dependent interaction of Rab33B with the dimeric complex, Atg5-Atg16L1. Moreover, the results reported here suggest that Arg-24 of Atg16L1 is crucial for its interaction with Atg5 which will have further implication in the binding of the dimeric complex to Rab33B. PMID- 26975472 TI - Membrane insertion of alphaA-crystallin is oligomer-size dependent. AB - Vertebrate lens is one of the tissues with the highest soluble protein concentration. The predominant soluble proteins in lens fiber cells are crystallins, and among them, alpha-crystallins belong to the small heat shock protein family with chaperone-like activity. Although alpha-crystallins are highly soluble in waters, alpha-crystallins have been detected in the membrane bound fraction of lens, which will increase in the aged or cataractous lens. In this research, we found alphaA-crystallin exhibited a complex thermal transition with remarkable changes in secondary and quaternary structures. Treatment of alphaA-crystallin at high temperatures induced larger oliogomers with higher hydrophobic exposure. Both heat-treated and untreated alphaA-crystallin could insert into lipid monolayer directly as revealed by monolayer surface pressure experiments. Heat-treatment facilitated the membrane insertion of alphaA crystallin and increased the membrane-bound fraction in the cells. The membrane binding ability of alphaA-crystallin could be altered by cataract-causing mutations R116C, R116H and Y118D. Our results suggested that the irreversible changes in oligomer size induced by various stresses might promote the membrane association of alphaA-crystallin and therefore might play a role in aged cataract. Alternations in the membrane binding ability of alpha-crystallins might be important to the understanding of both aged and congenital cataracts. PMID- 26975473 TI - Meat and milk intake in the rice-based Korean diet: impact on cancer and metabolic syndrome. AB - Over a few decades, Korean diet has changed from traditional diet, mainly composed of rice and vegetables, to Westernised diet rich, in meat and milk, along with the economic development and globalisation. Increasing prevalence of diet-related chronic diseases such as cancer and metabolic syndrome (MetS) is becoming a heavy burden to society and requires further attention. In this review, the association of meat and milk consumption with cancer and MetS among Koreans was discussed. Previous meta-analyses showed that meat intake was positively associated with increased risk of cancers, especially colon, as well as obesity and type 2 diabetes mellitus, and that the intake of milk and dairy products was negatively associated with colorectal cancer, obesity, and type 2 diabetes mellitus, based on studies conducted mostly in Western countries. In Korea and other Asian countries, the association of meat and milk intake with cancers were inconclusive and varied by types of cancers. Conversely, milk intake was negatively associated with MetS risk as reported in Western countries. The difference in results between Korea and Western countries might come from the differences in dietary patterns and study designs. Most Koreans still maintain traditional dietary pattern, although rapid change towards Westernised diet is underway among the younger age group. Randomised clinical trials or prospective cohort studies with consideration of combined effects of various dietary factors in Korea and other Asian countries are needed to elucidate the impact of meat and milk or related dietary patterns in their diet. PMID- 26975475 TI - Intraparenchymal hemorrhage from dural metastasis of breast cancer mimicking meningioma. AB - Intraparenchymal hemorrhage from dural metastasis of breast cancer is rare. A 54 year-old woman without a significant medical history showed altered consciousness and left hemiparesis. Radiological examination revealed an extra-axial mass in the right middle fossa with intraparenchymal hemorrhage and another mass invading the skull in the right parietal region. The pre-operative diagnosis was a sphenoid ridge meningioma presenting with intraparenchymal hemorrhage and another meningioma in the convexity. The tumors and hematoma were removed. Pathological findings of the tumors were compatible with adenocarcinoma. Systemic examination revealed breast cancer with metastasis to the spine. Although the radiological findings were similar to those of meningioma, a differential diagnosis of metastatic brain tumor with intraparenchymal hemorrhage should be taken into consideration. PMID- 26975474 TI - Mitochondrial Thioredoxin System as a Modulator of Cyclophilin D Redox State. AB - The mitochondrial thioredoxin system (NADPH, thioredoxin reductase, thioredoxin) is a major redox regulator. Here we have investigated the redox correlation between this system and the mitochondrial enzyme cyclophilin D. The peptidyl prolyl cis-trans isomerase activity of cyclophilin D was stimulated by the thioredoxin system, while it was decreased by cyclosporin A and the thioredoxin reductase inhibitor auranofin. The redox state of cyclophilin D, thioredoxin 1 and 2 and peroxiredoxin 3 was measured in isolated rat heart mitochondria and in tumor cell lines (CEM-R and HeLa) by redox Western blot analysis upon inhibition of thioredoxin reductase with auranofin, arsenic trioxide, 1-chloro-2,4 dinitrobenzene or after treatment with hydrogen peroxide. A concomitant oxidation of thioredoxin, peroxiredoxin and cyclophilin D was observed, suggesting a redox communication between the thioredoxin system and cyclophilin. This correlation was further confirmed by i) co-immunoprecipitation assay of cyclophilin D with thioredoxin 2 and peroxiredoxin 3, ii) molecular modeling and iii) depleting thioredoxin reductase by siRNA. We conclude that the mitochondrial thioredoxin system controls the redox state of cyclophilin D which, in turn, may act as a regulator of several processes including ROS production and pro-apoptotic factors release. PMID- 26975476 TI - Prior thromboprophylaxis and outcome in patients experiencing acute venous thromboembolism after an acute medical illness. AB - BACKGROUND: Even despite the use of thromboprophylaxis, some patients with an acute medical illness develop symptomatic venous thromboembolism (VTE). It is unclear whether the outcome in these patients is different in those in whom prophylaxis was not prescribed. PATIENTS AND METHODS: We used the RIETE (Registro Informatizado Enfermedad TromboEmbolica) database to compare the 3-month outcome (death, fatal pulmonary embolism, VTE recurrences, major bleeding) of patients with acute VTE after immobilization for an acute medical disease, according to the use of prophylaxis. RESULTS: Thromboprophylaxis was prescribed in 1313 (37%) of the 3527 patients included in August 2014. Acute infection was the most frequent cause of immobilization. Patients who received prophylaxis were more frequently immobilized in hospital than at home (70% vs. 22%), and fewer patients were immobilized for cancer (13% vs. 22%). During the first 3months of treatment, the rates of all-cause death (23 vs. 21%), fatal PE (2.6 vs. 3.1%), VTE recurrences (2.4% vs. 2.8%), and major bleeding (4.2% for both) did not differ between the two groups. Thromboprophylaxis was not associated with each outcome in multivariate analysis. CONCLUSIONS: The outcome in patients with VTE provoked by medical immobilization was not influenced by the use of thromboprophylaxis during the period of immobility. PMID- 26975477 TI - Immuno-enhancement of Taishan Pinus massoniana pollen polysaccharides on recombinant Bordetella avium ompA expressed in Pichia pastoris. AB - Bordetellosis, caused by Bordetella avium, continues to be an economic problem in the poultry industry of China. Vaccines with good protective ability are lacking. Thus, developing a novel vaccine against the B. avium infection is crucial. Here, we constructed a recombinant Pichia pastoris transformant capable of expressing the outer membrane protein A (ompA) of B. avium to prepare the recombinant ompA subunit vaccine and then evaluated its immune effects. To further investigate the immunomodulation effects of Taishan Pinus massoniana pollen polysaccharides (TPPPS) on this subunit vaccine, three concentrations (20, 40, and 60 mg/mL) of TPPPS were used as the adjuvants of the ompA subunit vaccine respectively. The conventional Freund's incomplete adjuvant served as the control of TPPPS. Chickens in different groups were separately vaccinated with these vaccines thrice. During the monitoring period, serum antibody titers, concentrations of serum IL-4, percentages of CD4(+) and CD8(+) T-lymphocytes in the peripheral blood, lymphocyte transformation rate, and protection rate were detected. Results showed that the pure ompA vaccine induced the production of anti-ompA antibody, the secretion of IL-4, the increase of CD4(+) T-lymphocytes counts and lymphocyte transformation rate in the peripheral blood. Moreover, the pure ompA vaccine provided a protection rate of 71.67% after the B. avium challenge. Notably, TPPPS adjuvant vaccines induced higher levels of immune responses than the pure ompA vaccine, and 60 mg/mL TPPPS adjuvant vaccine showed optimal immune effects and had a 91.67% protection rate. Our findings indicated that this recombinant B. avium ompA subunit vaccine combined with TPPPS had high immunostimulatory potential. Results provided a new perspective for B. avium subunit vaccine research. PMID- 26975479 TI - Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials. PMID- 26975478 TI - Exposure of preimplantation embryos to low-dose bisphenol A impairs testes development and suppresses histone acetylation of StAR promoter to reduce production of testosterone in mice. AB - Previous studies have shown that bisphenol A (BPA) is a potential endocrine disruptor and testicular toxicant. The present study focused on exploring the impact of exposure to low dose of BPA on male reproductive development during the early embryo stage and the underlying mechanisms. BPA (20 MUg/kg/day) was orally administered to female mice on days 1-5 of gestation. The male offspring were euthanized at PND10, 20, 24, 35 or PND50. We found that the mice exposed to BPA before implantation (BPA-mice) displayed retardation of testicular development with reduction of testosterone level. The diameter and epithelium height of seminiferous tubules were reduced in BPA-mice at PND35. The numbers of spermatogenic cells at different stages were significantly reduced in BPA-mice at PND50. BPA-mice showed a persistent reduction in serum and testicular testosterone levels starting from PND24, whereas GnRH mRNA was significantly increased at PND35 and PND50. The expressions of testicular StAR and P450scc in BPA-mice also decreased relative to those of the controls at PND35 and PND50. Further analysis found that the levels of histone H3 and H3K14 acetylation (Ac-H3 and H3K14ac) in the promoter of StAR were decreased relative to those of control mice, whereas the level of Ac-H3 in the promoter of P450scc was not significantly different between the groups. These results provide evidence that exposure to BPA in preimplantation embryo retards the development of testes by reducing histone acetylation of the StAR promoter to disrupt the testicular testosterone synthesis. PMID- 26975480 TI - Fabrication of Ti substrate grain dependent C/TiO2 composites through carbothermal treatment of anodic TiO2. AB - Composite materials of titania and graphitic carbon, and their optimized synthesis are highly interesting for application in sustainable energy conversion and storage. We report on planar C/TiO2 composite films that are prepared on a polycrystalline titanium substrate by carbothermal treatment of compact anodic TiO2 with acetylene. This thin film material allows for the study of functional properties of C/TiO2 as a function of chemical composition and structure. The chemical and structural properties of the composite on top of individual Ti substrate grains are examined by scanning photoelectron microscopy and micro Raman spectroscopy. Through comparison of these data with electron backscatter diffraction, it is found that the amount of generated carbon and the grade of anodic film crystallinity correlate with the crystallographic orientation of the Ti substrate grains. On top of Ti grains with ~(0001) orientations the anodic TiO2 exhibits the highest grade of crystallinity, and the composite contains the highest fraction of graphitic carbon compared to Ti grains with other orientations. This indirect effect of the Ti substrate grain orientation yields new insights into the activity of TiO2 towards the decomposition of carbon precursors. PMID- 26975481 TI - Compound eye and ocellar structure for walking and flying modes of locomotion in the Australian ant, Camponotus consobrinus. AB - Ants are unusual among insects in that individuals of the same species within a single colony have different modes of locomotion and tasks. We know from walking ants that vision plays a significant role in guiding this behaviour, but we know surprisingly little about the potential contribution of visual sensory structures for a flying mode of locomotion. Here we investigate the structure of the compound eye and ocelli in pedestrian workers, alate females and alate males of an Australian ant, Camponotus consobrinus, and discuss the trade-offs involved in optical sensitivity and spatial resolution. Male ants have more but smaller ommatidia and the smallest interommatidial angles, which is most likely an adaptation to visually track individual flying females. Both walking and flying forms of ants have a similar proportion of specialized receptors sensitive to polarized skylight, but the absolute number of these receptors varies, being greatest in males. Ocelli are present only in the flying forms. Each ocellus consists of a bipartite retina with a horizon-facing dorsal retina, which contains retinula cells with long rhabdoms, and a sky-facing ventral retina with shorter rhabdoms. We discuss the implications of these and their potential for sensing the pattern of polarized skylight. PMID- 26975482 TI - Characterization by microarray and meiotic segregation study of a der(10)t(10;18) in a patient with infertility and normal phenotype. PMID- 26975483 TI - Performance of the Prostate Health Index in predicting prostate biopsy outcomes among men with a negative digital rectal examination and transrectal ultrasonography. AB - The [-2]proPSA (p2PSA) and its derivatives, the p2PSA-to-free PSA ratio (%p2PSA), and the Prostate Health Index (PHI) have greatly improved discrimination between men with and without prostate cancer (PCa) in prostate biopsies. However, little is known about their performance in cases where a digital rectal examination (DRE) and transrectal ultrasonography (TRUS) are negative. A prospective cohort of 261 consecutive patients in China with negative DRE and TRUS were recruited and underwent prostate biopsies. A serum sample had collected before the biopsy was used to measure various PSA derivatives, including total prostate-specific antigen (tPSA), free PSA, and p2PSA. For each patient, the free-to-total PSA ratio (%fPSA), PSA density (PSAD), p2PSA-to-free PSA ratio (%p2PSA), and PHI were calculated. Discriminative performance was assessed using the area under the receiver operating characteristic curve (AUC) and the biopsy rate at 91% sensitivity. The AUC scores within the entire cohort with respect to age, tPSA, %fPSA, PSAD, p2PSA, %p2PSA, and PHI were 0.598, 0.751, 0.646, 0.789, 0.814, 0.808, and 0.853, respectively. PHI was the best predictor of prostate biopsy results, especially in patients with a tPSA of 10.1-20 ng ml-1 . Compared with other markers, at a sensitivity of 91%, PHI was the most useful for determining which men did not need to undergo biopsy, thereby avoiding unnecessary procedures. The use of PHI could improve the accuracy of PCa detection by predicting prostate biopsy outcomes among men with a negative DRE and TRUS in China. PMID- 26975484 TI - Human semen quality and the secondary sex ratio. AB - The aim of this study was to evaluate the association between semen quality and the secondary sex ratio (SSR), defined as the ratio of male to female live births. Our study cohort comprised 227 male partners who were enrolled prior to conception in Michigan and Texas between 2005 and 2009, and prospectively followed through delivery of a singleton birth. The male partners provided a baseline and a follow-up semen sample a month apart. Semen analysis was conducted to assess 27 parameters including five general characteristics, six sperm head measures, 14 morphology measures, and two sperm chromatin stability assay measures. Modified Poisson regression models with a robust error variance were used to estimate the relative risk (RR) and 95% confidence interval (95% CI) of a male birth for each semen parameter, after adjusting for potential confounders. Of the 27 semen parameters, only the percentage of bicephalic sperm was significantly associated with the SSR (2 nd vs 1 st quartile, RR, 0.65, 95% CI, 0.45-0.95, P = 0.03; 4 th vs 1 st quartile, RR, 0.61, 95% CI, 0.38-1.00, P < 0.05 before rounding to two decimal places), suggestive of a higher percentage of bicephalic sperm being associated with an excess of female births. Given the exploratory design of the present study, this preconception cohort study suggests no clear signal that human semen quality is associated with offspring sex determination. PMID- 26975485 TI - Inverse correlation between reactive oxygen species in unwashed semen and sperm motion parameters as measured by a computer-assisted semen analyzer. AB - This study investigated the correlation between sperm motion parameters obtained by a computer-assisted semen analyzer and levels of reactive oxygen species in unwashed semen. In total, 847 patients, except for azoospermic patients were investigated. At the time of each patient's first consultation, semen parameters were measured using SMASTM or CellSoft 3000TM, and production of reactive oxygen species was measured using a computer-driven LKB Wallac Luminometer 1251 Analyzer. The patients were divided into two groups: reactive oxygen species - positive and negative. The semen parameters within each group were measured using one of the two computer-assisted semen analyzer systems and then compared. Correlations between reactive oxygen species levels and sperm motion parameters in semen from the reactive oxygen species - positive group were also investigated. Reactive oxygen species were detected in semen samples of 282 cases (33.3%). Sperm concentration (P < 0.01; P < 0.01), motility (P < 0.01; P < 0.05), and progressive motility (P < 0.01; P < 0.01) were markedly lower in the reactive oxygen species - positive group than in the reactive oxygen species - negative group. Among the sperm motion parameters in the reactive oxygen species - positive group, sperm concentration (P < 0.01; P < 0.01), motility (P < 0.05; P < 0.01), mALH (P < 0.05; P < 0.01), and progressive motility (P < 0.05; P < 0.01) also showed inverse correlations with the logarithmic transformed reactive oxygen species levels. Therefore, this study demonstrated that excessive reactive oxygen species in semen damage sperm concentration, motility, and other sperm motion parameters. PMID- 26975486 TI - Use of a disposable circumcision suture device versus conventional circumcision: a systematic review and meta-analysis. AB - This systematic review assessed the safety and efficacy of the disposable circumcision suture device (DCSD) and conventional circumcision (CC) in the treatment of redundant prepuce and phimosis. Two independent reviewers conducted a literature search for randomized controlled trials (RCTs) using the DCSD and CC for the treatment of redundant prepuce or phimosis in China and abroad. Nine RCTs (1898 cases) were included. Compared with the CC group, the DCSD group had a shorter operative time (standardized mean difference [SMD] = -21.44; 95% confidence intervals [95% CIs] [-25.08, -17.79]; P < 0.00001), shorter wound healing time (SMD = -3.66; 95% CI [-5.46, -1.85]; P < 0.0001), less intraoperative blood loss (SMD = -9.64; 95% CI [-11.37, -7.90]; P < 0.00001), better cosmetic penile appearance (odds ratio [OR] =8.77; 95% CI [5.90, 13.02]; P < 0.00001), lower intraoperative pain score, lower 24-h postoperative pain score, lower incidence of infection, less incision edema, and fewer adverse events. There were no differences between the CC and DCSD groups in the incidences of dehiscence, or hematoma. The results of this meta-analysis indicate that the DCSD appears to be safer and more effective than CC. However, additional high-quality RCTs with larger study populations are needed. PMID- 26975487 TI - Serum testosterone level predicts the effective time of androgen deprivation therapy in metastatic prostate cancer patients. AB - Androgen deprivation therapy (ADT) is the standard of care for patients with metastatic prostate cancer. However, whether serum testosterone levels, using a cut-off point of 50 ng dl-1 , are related to the effective time of ADT in newly diagnosed prostate cancer patients remains controversial. Moreover, recent studies have shown that some patients may benefit from the addition of upfront docetaxel chemotherapy. To date, no studies have been able to distinguish patients who will benefit from the combination of ADT and docetaxel chemotherapy. This study included 206 patients who were diagnosed with metastatic prostate cancer and showed progression to castrate-resistance prostate cancer (CRPC). Serum testosterone levels were measured prospectively after ADT for 1, 3, and 6 months. The endpoint was the time to CRPC. In univariate and multivariate analyses, testosterone levels <50 ng dl-1 were not associated with the effective time of ADT. Receiver operating characteristic and univariate analysis showed that testosterone levels of <=25 ng dl-1 after the first month of ADT offered the best overall sensitivity and specificity for prediction of a longer time to CRPC (adjusted hazard ratio [HR], 1.46; 95% confidence interval [95% CI], 1.08-1.96; P = 0.013). Our results show that serum testosterone level of 25 ng dl-1 plays a prognostic role in prostate cancer patients receiving ADT. A testosterone value of 25 ng dl-1 after the first month of ADT can distinguish patients who benefit from ADT effectiveness for only a short time. These patients may need to receive ADT and concurrent docetaxel chemotherapy. PMID- 26975488 TI - Vasectomy reversal: a clinical update. AB - Vasectomy is a safe and effective method of contraception used by 42-60 million men worldwide. Approximately 3%-6% of men opt for a vasectomy reversal due to the death of a child or divorce and remarriage, change in financial situation, desire for more children within the same marriage, or to alleviate the dreaded postvasectomy pain syndrome. Unlike vasectomy, vasectomy reversal is a much more technically challenging procedure that is performed only by a minority of urologists and places a larger financial strain on the patient since it is usually not covered by insurance. Interest in this procedure has increased since the operating microscope became available in the 1970s, which consequently led to improved patency and pregnancy rates following the procedure. In this clinical update, we discuss patient evaluation, variables that may influence reversal success rates, factors to consider in choosing to perform vasovasostomy versus vasoepididymostomy, and the usefulness of vasectomy reversal to alleviate postvasectomy pain syndrome. We also review the use of robotics for vasectomy reversal and other novel techniques and instrumentation that have emerged in recent years to aid in the success of this surgery. PMID- 26975489 TI - Relationship between circumcision and human papillomavirus infection: a systematic review and meta-analysis. AB - Male circumcision (MC) is reported to reduce human papillomavirus (HPV) prevalence in men. However, the efficacy remains imprecise. The aim of this study was to conduct a systematic review and meta-analysis to assess the relationship between MC and genital HPV infection and genital warts. PUBMED, EMBASE, and Web of Science were searched from inception to March 22, 2015. We identified 30 papers, including a total of 12149 circumcised and 12252 uncircumcised men who were evaluated for the association of circumcision with genital HPV or genital warts. Compared with men who were not circumcised, circumcised men may have had significantly reduced odds of genital HPV prevalence (odds ratio [OR]: 0.68; 95% confidence interval [95% CI]: 0.56-0.82). There was no significant association between MC and genital HPV acquisition of new infections (OR: 0.99; 95% CI: 0.62 1.60), genital HPV clearance (OR: 1.38; 95% CI: 0.96-1.97), and prevalence of genital warts (OR: 1.17; 95% CI: 0.63-2.17). This meta-analysis suggests that circumcision reduces the prevalence of genital HPV infections. However, no clear evidence was found that circumcision was associated with decreased HPV acquisition, increased HPV clearance, or decreased the prevalence of genital warts. More studies are required to evaluate adequately the effect of MC on the acquisition and clearance of HPV infections and prevalence of genital warts. PMID- 26975490 TI - Clinically available RNA profiling tests of prostate tumors: utility and comparison. AB - In the postscreening era, physicians are in need of methods to discriminate aggressive from nonaggressive prostate cancer (PCa) to reduce overdiagnosis and overtreatment. However, studies have shown that prognoses (e.g., progression and mortality) differ even among individuals with similar clinical and pathological characteristics. Existing risk classifiers (TMN grading system, Gleason score, etc.) are not accurately enough to represent the biological features of PCa. Using new genomic technologies, novel biomarkers and classifiers have been developed and shown to add value to clinical or pathological risk factors for predicting aggressive disease. Among them, RNA testing (gene expression analysis) is useful because it can not only reflect genetic variations but also reflect epigenetic regulations. Commercially available RNA profiling tests (Oncotype Dx, Prolaris, and Decipher) have demonstrated strong abilities to discriminate PCa with poor prognosis from less aggressive diseases. For instance, these RNA profiling tests can predict disease progression in active surveillance patients or early recurrence after radical treatments. These tests may offer more dependable methods for PCa prognosis prediction to make more accurate and personal medical decisions. PMID- 26975491 TI - Paternal aging and increased risk of congenital disease, psychiatric disorders, and cancer. AB - As couples are increasingly delaying parenthood, the effect of the aging men and women on reproductive outcomes has been an area of increased interest. Advanced paternal age has been shown to independently affect the entire spectrum of male fertility as assessed by reductions in sperm quality and fertilization (both assisted and unassisted). Moreover, epidemiological data suggest that paternal age can lead to higher rates of adverse birth outcomes and congenital anomalies. Mounting evidence also suggests increased risk of specific pediatric and adult disease states ranging from cancer to behavioral traits. While disease states associated with advancing paternal age have been well described, consensus recommendations for neonatal screening have not been as widely implemented as have been with advanced maternal age. PMID- 26975493 TI - Superficial angiomyxoma of penis: a case report of a 6-year follow-up. PMID- 26975492 TI - Seminal biomarkers for the evaluation of male infertility. AB - For men struggling to conceive with their partners, diagnostic tools are limited and often consist of only a standard semen analysis. This baseline test serves as a crude estimation of male fertility, leaving patients and clinicians in need of additional diagnostic biomarkers. Seminal fluid contains the highest concentration of molecules from the male reproductive glands, therefore, this review focuses on current and novel seminal biomarkers in certain male infertility scenarios, including natural fertility, differentiating azoospermia etiologies, and predicting assisted reproductive technique success. Currently available tests include antisperm antibody assays, DNA fragmentation index, sperm fluorescence in situ hybridization, and other historical sperm functional tests. The poor diagnostic ability of current assays has led to continued efforts to find more predictive biomarkers. Emerging research in the fields of genomics, epigenetics, proteomics, transcriptomics, and metabolomics holds promise for the development of novel male infertility biomarkers. Seminal protein-based assays of TEX101, ECM1, and ACRV1 are already available or under final development for clinical use. Additional panels of DNA, RNA, proteins, or metabolites are being explored as we attempt to understand the pathophysiologic processes of male infertility. Future ventures will need to continue data integration and validation for the development of clinically useful infertility biomarkers to aid in male infertility diagnosis, treatment, and counseling. PMID- 26975495 TI - Quantitative measurement of blood flow in paediatric brain tumours-a comparative study of dynamic susceptibility contrast and multi time-point arterial spin labelled MRI. AB - OBJECTIVE: Arterial spin-labelling (ASL) MRI uses intrinsic blood water to quantify the cerebral blood flow (CBF), removing the need for the injection of a gadolinium-based contrast agent used for conventional perfusion imaging such as dynamic susceptibility contrast (DSC). Owing to the non-invasive nature of the technique, ASL is an attractive option for use in paediatric patients. This work compared DSC and multi-timepoint ASL measures of CBF in paediatric brain tumours. METHODS: Patients (n = 23; 20 low-grade tumours and 3 high-grade tumours) had DSC and multi-timepoint ASL with and without vascular crushers (VC). VC removes the contribution from larger vessel blood flow. Mean perfusion metrics were extracted from control and T1-enhanced tumour regions of interest (ROIs): arterial arrival time (AAT) and CBF from the ASL images with and without VC, relative cerebral blood flow (rCBF), relative cerebral blood volume, delay time (DT) and mean transit time (MTT) from the DSC images. RESULTS: Significant correlations existed for: AAT and DT (r = 0.77, p = 0.0002) and CBF and rCBF (r = 0.56, p = 0.02) in control ROIs for ASL-noVC. No significant correlations existed between DSC and ASL measures in the tumour region. Significant differences between control and tumour ROI were found for MTT (p < 0.001) and rCBF (p < 0.005) measures. CONCLUSION: Significant correlations between ASL-noVC and DSC measures in the normal brain suggest that DSC is most sensitive to macrovascular blood flow. The absence of significant correlations within the tumour ROI suggests that ASL is sensitive to different physiological mechanisms compared with DSC measures. ADVANCES IN KNOWLEDGE: ASL provides information which is comparable with that of DSC in healthy tissues, but appears to reflect a different physiology in tumour tissues. PMID- 26975496 TI - Characterization of in vitro radiosensitization in mammalian cells using biomathematical modelling: implications for hypofractionated radiotherapy with a combined modality approach. AB - OBJECTIVE: It is unclear whether radiosensitization is beneficial when radiotherapy is administered at a high dose per fraction. The aim of this study was to assess the impact of radiation dose on the effectiveness of a broad range of radiosensitizers. METHODS: We analyzed 653 pairs of clonogenic survival curves in 285 published articles, in which modifications of radiosensitivity were studied using the colony-forming assay. The modifications of radiosensitivity were arbitrarily classified into 20 classes. The survival curves were fitted to two biomathematical models: the linear-quadratic model and the repair-misrepair (RMR) model. RESULTS: We found that radiosensitization was predominantly characterized by an increase of the alpha value (alpha-sensitization) without an increase of the beta value (beta-sensitization). A subset analysis revealed that all 20 classes showed significant alpha-sensitization. In contrast, only oxygen/hypoxic sensitizers (oxygen) and poly(adenosine diphosphate-ribose) polymerase inhibition (PARPi) exhibited beta-sensitization. An analysis using the RMR model revealed two major sources of radiosensitization: an increased residual DNA lesion through repair inhibition and a shift from linear repairs to quadratic misrepairs, leading to enhanced lethal chromosomal aberrations. CONCLUSION: Oxygen and PARPi were found to show beta-sensitization, which was favourable for eliciting a comparable degree of sensitization in the higher dose range. Reduced fidelity of the repair was suggested to be a possible mechanism of beta sensitization. Further study targeting beta-sensitization is needed to develop a novel combined modality therapy with high-dose-per-fraction radiotherapy. ADVANCES IN KNOWLEDGE: Radiosensitization can be classified into two groups, alpha- and beta-sensitizations. These two phenomena may stem from distinct underlying mechanisms. PMID- 26975494 TI - DNA alterations in the tumor genome and their associations with clinical outcome in prostate cancer. AB - Although most prostate cancer (PCa) cases are not life-threatening, approximately 293 000 men worldwide die annually due to PCa. These lethal cases are thought to be caused by coordinated genomic alterations that accumulate over time. Recent genome-wide analyses of DNA from subjects with PCa have revealed most, if not all, genetic changes in both germline and PCa tumor genomes. In this article, I first review the major, somatically acquired genomic characteristics of various subtypes of PCa. I then recap key findings on the relationships between genomic alterations and clinical parameters, such as biochemical recurrence or clinical relapse, metastasis and cancer-specific mortality. Finally, I outline the need for, and challenges with, validation of recent findings in prospective studies for clinical utility. It is clearer now than ever before that the landscape of somatically acquired aberrations in PCa is highlighted by DNA copy number alterations (CNAs) and TMPRSS2-ERG fusion derived from complex rearrangements, numerous single nucleotide variations or mutations, tremendous heterogeneity, and continuously punctuated evolution. Genome-wide CNAs, PTEN loss, MYC gain in primary tumors, and TP53 loss/mutation and AR amplification/mutation in advanced metastatic PCa have consistently been associated with worse cancer prognosis. With this recently gained knowledge, it is now an opportune time to develop DNA based tests that provide more accurate patient stratification for prediction of clinical outcome, which will ultimately lead to more personalized cancer care than is possible at present. PMID- 26975497 TI - Methods for the analysis of ordinal response data in medical image quality assessment. AB - The assessment of image quality in medical imaging often requires observers to rate images for some metric or detectability task. These subjective results are used in optimization, radiation dose reduction or system comparison studies and may be compared to objective measures from a computer vision algorithm performing the same task. One popular scoring approach is to use a Likert scale, then assign consecutive numbers to the categories. The mean of these response values is then taken and used for comparison with the objective or second subjective response. Agreement is often assessed using correlation coefficients. We highlight a number of weaknesses in this common approach, including inappropriate analyses of ordinal data and the inability to properly account for correlations caused by repeated images or observers. We suggest alternative data collection and analysis techniques such as amendments to the scale and multilevel proportional odds models. We detail the suitability of each approach depending upon the data structure and demonstrate each method using a medical imaging example. Whilst others have raised some of these issues, we evaluated the entire study from data collection to analysis, suggested sources for software and further reading, and provided a checklist plus flowchart for use with any ordinal data. We hope that raised awareness of the limitations of the current approaches will encourage greater method consideration and the utilization of a more appropriate analysis. More accurate comparisons between measures in medical imaging will lead to a more robust contribution to the imaging literature and ultimately improved patient care. PMID- 26975498 TI - Effect of Postextubation High-Flow Nasal Cannula vs Conventional Oxygen Therapy on Reintubation in Low-Risk Patients: A Randomized Clinical Trial. AB - IMPORTANCE: Studies of mechanically ventilated critically ill patients that combine populations that are at high and low risk for reintubation suggest that conditioned high-flow nasal cannula oxygen therapy after extubation improves oxygenation compared with conventional oxygen therapy. However, conclusive data about reintubation are lacking. OBJECTIVE: To determine whether high-flow nasal cannula oxygen therapy is superior to conventional oxygen therapy for preventing reintubation in mechanically ventilated patients at low risk for reintubation. DESIGN, SETTING, AND PARTICIPANTS: Multicenter randomized clinical trial conducted between September 2012 and October 2014 in 7 intensive care units (ICUs) in Spain. Participants were 527 adult critical patients at low risk for reintubation who fulfilled criteria for planned extubation. Low risk for reintubation was defined as younger than 65 years; Acute Physiology and Chronic Health Evaluation II score less than 12 on day of extubation; body mass index less than 30; adequate secretions management; simple weaning; 0 or 1 comorbidity; and absence of heart failure, moderate-to-severe chronic obstructive pulmonary disease, airway patency problems, and prolonged mechanical ventilation. INTERVENTIONS: Patients were randomized to undergo either high-flow or conventional oxygen therapy for 24 hours after extubation. MAIN OUTCOMES AND MEASURES: The primary outcome was reintubation within 72 hours, compared with the Cochran-Mantel-Haenszel chi2 test. Secondary outcomes included postextubation respiratory failure, respiratory infection, sepsis and multiorgan failure, ICU and hospital length of stay and mortality, adverse events, and time to reintubation. RESULTS: Of 527 patients (mean age, 51 years [range, 18-64]; 62% men), 264 received high-flow therapy and 263 conventional oxygen therapy. Reintubation within 72 hours was less common in the high-flow group (13 patients [4.9%] vs 32 [12.2%] in the conventional group; absolute difference, 7.2% [95% CI, 2.5% to 12.2%]; P = .004). Postextubation respiratory failure was less common in the high-flow group (22/264 patients [8.3%] vs 38/263 [14.4%] in the conventional group; absolute difference, 6.1% [95% CI, 0.7% to 11.6%]; P = .03). Time to reintubation was not significantly different between groups (19 hours [interquartile range, 12-28] in the high-flow group vs 15 hours [interquartile range, 9-31] in the conventional group; absolute difference, -4 [95% CI, -54 to 46]; P = .66]. No adverse effects were reported. CONCLUSIONS AND RELEVANCE: Among extubated patients at low risk for reintubation, the use of high-flow nasal cannula oxygen compared with conventional oxygen therapy reduced the risk of reintubation within 72 hours. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01191489. PMID- 26975499 TI - Predictive information speeds up visual awareness in an individuation task by modulating threshold setting, not processing efficiency. AB - Theories on visual awareness claim that predicted stimuli reach awareness faster than unpredicted ones. In the current study, we disentangle whether prior information about the upcoming stimulus affects visual awareness of stimulus location (i.e., individuation) by modulating processing efficiency or threshold setting. Analogous research on stimulus identification revealed that prior information modulates threshold setting. However, as identification and individuation are two functionally and neurally distinct processes, the mechanisms underlying identification cannot simply be extrapolated directly to individuation. The goal of this study was therefore to investigate how individuation is influenced by prior information about the upcoming stimulus. To do so, a drift diffusion model was fitted to estimate the processing efficiency and threshold setting for predicted versus unpredicted stimuli in a cued individuation paradigm. Participants were asked to locate a picture, following a cue that was congruent, incongruent or neutral with respect to the picture's identity. Pictures were individuated faster in the congruent and neutral condition compared to the incongruent condition. In the diffusion model analysis, the processing efficiency was not significantly different across conditions. However, the threshold setting was significantly higher following an incongruent cue compared to both congruent and neutral cues. Our results indicate that predictive information about the upcoming stimulus influences visual awareness by shifting the threshold for individuation rather than by enhancing processing efficiency. PMID- 26975500 TI - Perceptual-binding in a rotating Necker cube: The effect of context motion and position. AB - Previous studies have shown that spatial context influences the perceptual interpretation of ambiguous figures such as the Necker cube; however, the properties that mediate the influences of an unambiguous spatial context have yet to be investigated. Here we consider the effect of the motion and position of an unambiguous rotating skeleton cube on the perceived motion direction of an ambiguous rotating Necker cube. We aimed to determine whether the motion of the two figures could be perceptually bound, and if it could, to determine the properties of the binding. We employed a novel procedure analogous to reverse correlation to establish the correlation between the rotation directions of the context and the perceived rotation directions of the target, across 32s trial presentations. Our results showed that changes in the rotation direction of the context triggered above-chance changes in the perceived rotation direction of the target. However, the relative speeds of rotation of the context and target had little effect on the correlations. Position on the other hand had a significant effect: correlations were higher when the context was below compared to when above the target. Our results reveal that change-synchrony not common fate is the factor mediating perceptual motion binding between the context and Necker cube. We also suggest that prior knowledge of friction forces could underlie the position dependency of the context and Necker-cube correlation. PMID- 26975501 TI - Rejecting probability summation for radial frequency patterns, not so Quick! AB - Radial frequency (RF) patterns are used to assess how the visual system processes shape. They are thought to be detected globally. This is supported by studies that have found summation for RF patterns to be greater than what is possible if the parts were being independently detected and performance only then improved with an increasing number of cycles by probability summation between them. However, the model of probability summation employed in these previous studies was based on High Threshold Theory (HTT), rather than Signal Detection Theory (SDT). We conducted rating scale experiments to investigate the receiver operating characteristics. We find these are of the curved form predicted by SDT, rather than the straight lines predicted by HTT. This means that to test probability summation we must use a model based on SDT. We conducted a set of summation experiments finding that thresholds decrease as the number of modulated cycles increases at approximately the same rate as previously found. As this could be consistent with either additive or probability summation, we performed maximum-likelihood fitting of a set of summation models (Matlab code provided in our Supplementary material) and assessed the fits using cross validation. We find we are not able to distinguish whether the responses to the parts of an RF pattern are combined by additive or probability summation, because the predictions are too similar. We present similar results for summation between separate RF patterns, suggesting that the summation process there may be the same as that within a single RF. PMID- 26975502 TI - [Cervical spine injury in equestrian sports]. AB - The cervical spine is considered fragile and vulnerable to injuries in equestrian sport. This retrospective study investigates the injury pattern and severity. Patients of the medical university in Hannover from the years 2006-2011, who had an equestrian accident, were identified. Patients who had been injured in the course of their work were excluded. Results counted with a p-value < 0.05 were considered significant. In 13.1% of patients, there were 71 cervical spine injuries (92.4% female; 7.6% male). The mean age was 27.1 +/- 13.2 years. Of these, 86.4% associated the injury to the riding accident. In 56 cases, it concerned falls from the horse. In 13.6% of the cases, the injury was caused while handling the horse. Sprains were most common (70.4%). Fractures of the neck vertebrae were found in 22.5% of the cases. The mean ISS was 7.0 +/- 5.8 pts. Polytrauma was identified in 6.1% of patients (ISS >= 16 Pkt). The most common accompanying injury presented was an injury to the head (29.2%; p = 0.003). Of the 30 hospitalized patients, 13.3% were admitted to intensive medical care for 2.3 +/- 15.4 d. The mortality was 0%. Injuries of the cervical spine are not to be underestimated in their frequency and severity. It is shown that, especially with injuries of the head and thoracic and lumbar spine area, patients are at increased risk of concurrent cervical lesions. The prevention of neck injuries is currently done in the form of riding helmets, airbag jackets, riding behavior and education. Further study of the prevention of neck injuries is required. PMID- 26975504 TI - Progress in Research of KV1.1 and KV1.3 Channels as Therapeutic Targets. AB - Voltage-gated potassium channels (KV) mainly response in action potential repolarization in excitable cells and also participate in regulating resting potentials in non-excitable cells, involved in diverse physiological processes. This review focuses on potential drug developments targeting the KV1.1 and KV1.3 channels. KV1.1 mainly existing in the nervous system plays key roles in controlling neuronal excitability; while the distribution of KV1.3 in different types of cells contributes to a variety of cellular processes. This article seeks to review the distributions of two channels, their roles in diseases, phenotypes of knockout mice, human channelopathies and selective modulators. PMID- 26975503 TI - MiR-29c regulates the expression of miR-34c and miR-449a by targeting DNA methyltransferase 3a and 3b in nasopharyngeal carcinoma. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is prevalent in South East Asia and Southern China particularly, despite the reported 5-year survival ratio is relative higher than other deadly cancers such as liver, renal, pancreas cancer, the lethality is characterized by high metastatic potential in the early stage and high recurrence rate after radiation treatment. MicroRNA-29c was found to be down-regulated in the serum as well as in the tissue of nasopharyngeal carcinoma tissue. METHODS: In this study, we found accidentally that the transfection of pre-miR-29c or miR-29c mimics significantly increases the expression level of miR 34c and miR-449a but doesn't affect that of miR-222 using real-time quantitative PCR in nasopharyngeal carcinoma cell lines. To explore the molecular mechanism of the regulatory role, the cells are treated with 5-Aza-2-deoxycytidine (5-Aza-CdR) treatment and the level of miR-34c and miR-449a but not miR-222 accumulated by the treatment. DNA methyltransferase 3a, 3b were down-regulated by the 5-Aza-CdR treatment with western blot and real-time quantitative PCR. RESULTS: We found that pre-miR-29c or miR-29c mimics significantly increases the expression level of miR-34c and miR-449a. We further found DNA methyltransferase 3a and 3b are the target gene of miR-29c. Restoration of miR-29c in NPC cells down-regulated DNA methyltransferase 3a, 3b, but not DNA methyltransferase T1. CONCLUSIONS: The regulation of miR-29c/DNMTs/miR-34c?449a is an important molecular axis of NPC development and targeting DNMTs or restoring of miR-29c might be a promising therapy strategy for the prevention of NPC. PMID- 26975505 TI - Kv1.5 Inhibitors for Treatment of Atrial Fibrillation: A Tradeoff between Selectivity and Non-selectivity. AB - Atrial fibrillation (AF) is one of the common arrhythmias that threatens human health and brings a huge burden to society. Current treatments of AF possess limited efficacy and considerable risks, so a lot of efforts have been made to develop new AF therapies. Kv1.5 potassium channel is considered as an efficacious and safe therapeutic target of AF for its selective existence in atrium. This review will give a brief profile of Kv1.5 potassium channel and describe the progress of Kv1.5 inhibitors in this decade from nonselective drugs to selective agents. The final section will discuss the advantages and disadvantages between selectivity and non-selectivity. PMID- 26975507 TI - Computer-Aided Drug Discovery and Design Targeting Ion Channels. AB - Ion channels are widely expressed in living cells and play critical roles in various cellular biological functions. Dysfunctional ion channels can cause a variety of diseases, making ion channels attractive targets for drug discovery. Computational approaches, such as molecular docking and molecular dynamic simulations, provide economic and efficient tools for finding modulators of ion channels and for elucidating the action mechanisms of small molecules. In this review, we focus primarily on four types of ion channels (voltage-gated, ligand gated, acid-sensing, and virus matrix 2 ion channels). The current advancements in computer-aided drug discovery and design targeting ion channels are summarized. First, ligand-based studies for drug design are briefly outlined. Then, we focus on the structurebased studies targeting pore domains, endogenous binding sites and allosteric sites of ion channels. Moreover, we also review the contribution of computational methods to the field of ligand binding and unbinding pathways of ion channels. Finally, we propose future developments for the field. PMID- 26975506 TI - Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors. AB - Positron emission tomography (PET) neuroimaging of ion channel linked receptors is a developing area of preclinical and clinical research. The present review focuses on recent advances with radiochemistry, preclinical and clinical PET imaging studies of three receptors that are actively pursued in neuropsychiatric drug discovery: namely the gamma-aminobutyric acid-benzodiazapine (GABA) receptor, nicotinic acetylcholine receptor (nAChR), and N-methyl-D-aspartate (NMDA) receptor. Recent efforts to develop new PET radioligands for these targets with improved brain uptake, selectivity, stability and pharmacokinetics are highlighted. PMID- 26975508 TI - Implications of Dynamic Occupancy, Binding Kinetics, and Channel Gating Kinetics for hERG Blocker Safety Assessment and Mitigation. AB - Blockade of the hERG potassium channel prolongs the ventricular action potential (AP) and QT interval, and triggers early after depolarizations (EADs) and torsade de pointes (TdP) arrhythmia. Opinions differ as to the causal relationship between hERG blockade and TdP, the relative weighting of other contributing factors, definitive metrics of preclinical proarrhythmicity, and the true safety margin in humans. Here, we have used in silico techniques to characterize the effects of channel gating and binding kinetics on hERG occupancy, and of blockade on the human ventricular AP. Gating effects differ for compounds that are sterically compatible with closed channels (becoming trapped in deactivated channels) versus those that are incompatible with the closed/closing state, and expelled during deactivation. Occupancies of trappable blockers build to equilibrium levels, whereas those of non-trappable blockers build and decay during each AP cycle. Occupancies of ~83% (non-trappable) versus ~63% (trappable) of open/inactive channels caused EADs in our AP simulations. Overall, we conclude that hERG occupancy at therapeutic exposure levels may be tolerated for nontrappable, but not trappable blockers capable of building to the proarrhythmic occupancy level. Furthermore, the widely used Redfern safety index may be biased toward trappable blockers, overestimating the exposure-IC50 separation in nontrappable cases. PMID- 26975511 TI - Comparison of the clinical effectiveness of 3D and 2D imaging systems for laparoscopic radical cystectomy with pelvic lymph node dissection. AB - OBJECTIVE: To compare the clinical effectiveness of three-dimensional (3D) and two-dimensional (2D) laparoscopic imaging systems for radical cystectomy (RC) with pelvic lymph node dissection. METHODS: This was a retrospective analysis of data collected from all patients who underwent RC with pelvic lymph node dissection between January 2013 and May 2014, performed by a single surgeon in our clinic. Demographic characteristics and operative data from the procedure were collected and compared. RESULTS: Data were available from 42 patients (mean age 63 +/- 6.7 years) of whom 18 were operated on using a 3D imaging laparoscope (Group 3D) and 24 were operated on using a conventional 2D laparoscope (Group 2D). There were no statistically significant differences in patient characteristics between the two groups (P > 0.05). There was no difference between groups in the mean (+/-SD) number of lymph nodes retrieved from each patient (13.2 +/- 4.6 and 12.5 +/- 4.3, for the 3D and 2D groups respectively), or in blood loss. PLND duration and total operative time were statistically significantly lower in Group 3D than in group 2D. There were no statistically significant between-group differences in postoperative hospital stay or total cost of the procedures. Serious postoperative complications occurred in one patient (5.6%) in group 3D, and four patients (16.7%) in group 2D (P = 0.075). CONCLUSIONS: With the assistance of 3D stereoscopic imaging, surgeons may be able to reduce both the duration of lymph node dissection and overall operative time during laparoscopic RC with pelvic lymph node dissection, without increasing postoperative hospital stay or total cost. PMID- 26975512 TI - Multiple vertebral fractures in young man as first manifestation of systemic mastocytosis. AB - Systemic mastocytosis (SM) is a clonal disease of mast cell progenitors from the bone marrow. The clinical picture varies from asymptomatic forms (indolent) to a highly aggressive form with a very short (mast cell leukemia) survival. Between 28-34% of patients with SM are related to bone condition at the time of diagnosis and 16% have symptomatic fractures. The presentation of SM as clinical vertebral fractures in young men is rare. Here, we describe a case of established osteoporosis as the only manifestation of SM. PMID- 26975513 TI - The Research Network for Inflammation and Rheumatic Diseases (RIER). PMID- 26975510 TI - Bloom and bust: intestinal microbiota dynamics in response to hospital exposures and Clostridium difficile colonization or infection. AB - BACKGROUND: Clostridium difficile infection (CDI) is the leading infectious cause of nosocomial diarrhea. Hospitalized patients are at increased risk of developing CDI because they are exposed to C. difficile spores through contact with the hospital environment and often receive antibiotics and other medications that can disrupt the integrity of the indigenous intestinal microbiota and impair colonization resistance. Using whole metagenome shotgun sequencing, we examined the diversity and composition of the fecal microbiota in a prospective cohort study of 98 hospitalized patients. RESULTS: Four patients had asymptomatic C. difficile colonization, and four patients developed CDI. We observed dramatic shifts in the structure of the gut microbiota during hospitalization. In contrast to CDI cases, asymptomatic patients exhibited elevated relative abundance of potentially protective bacterial taxa in their gut at the onset of C. difficile colonization. Use of laxatives was associated with significant reductions in the relative abundance of Clostridium and Eubacterium; species within these genera have previously been shown to enhance resistance to CDI via the production of secondary bile acids. Cephalosporin and fluoroquinolone exposure decreased the frequency of Clostridiales Family XI Incertae Sedis, a bacterial family that has been previously associated with decreased CDI risk. CONCLUSIONS: This study underscores the detrimental impact of antibiotics as well as other medications, particularly laxatives, on the intestinal microbiota and suggests that co colonization with key bacterial taxa may prevent C. difficile overgrowth or the transition from asymptomatic C. difficile colonization to CDI. PMID- 26975514 TI - Biphenyl end-capped bithiazole co-oligomers for high performance organic thin film field effect transistors. AB - Two new regiospecific biphenyl end-capped bithiazole co-oligomers, BP2Tz(in) and BP2Tz(out), have been synthesized for application in thin film field effect transistors (TFTs). BP2Tz(in) with a 2,2'-bithiazole central unit exhibits a field effect hole mobility as high as 3.5 cm(2) V(-1) s(-1). Green light emission is demonstrated for highly balanced ambipoar TFTs based on both BP2Tz(in) and BP2Tz(out). PMID- 26975515 TI - Interface Engineering to Create a Strong Spin Filter Contact to Silicon. AB - Integrating epitaxial and ferromagnetic Europium Oxide (EuO) directly on silicon is a perfect route to enrich silicon nanotechnology with spin filter functionality. To date, the inherent chemical reactivity between EuO and Si has prevented a heteroepitaxial integration without significant contaminations of the interface with Eu silicides and Si oxides. We present a solution to this long standing problem by applying two complementary passivation techniques for the reactive EuO/Si interface: (i) an in situ hydrogen-Si (001) passivation and (ii) the application of oxygen-protective Eu monolayers-without using any additional buffer layers. By careful chemical depth profiling of the oxide-semiconductor interface via hard x-ray photoemission spectroscopy, we show how to systematically minimize both Eu silicide and Si oxide formation to the sub monolayer regime-and how to ultimately interface-engineer chemically clean, heteroepitaxial and ferromagnetic EuO/Si (001) in order to create a strong spin filter contact to silicon. PMID- 26975509 TI - HCN Channels Modulators: The Need for Selectivity. AB - Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, the molecular correlate of the hyperpolarization-activated current (If/Ih), are membrane proteins which play an important role in several physiological processes and various pathological conditions. In the Sino Atrial Node (SAN) HCN4 is the target of ivabradine, a bradycardic agent that is, at the moment, the only drug which specifically blocks If. Nevertheless, several other pharmacological agents have been shown to modulate HCN channels, a property that may contribute to their therapeutic activity and/or to their side effects. HCN channels are considered potential targets for developing drugs to treat several important pathologies, but a major issue in this field is the discovery of isoform-selective compounds, owing to the wide distribution of these proteins into the central and peripheral nervous systems, heart and other peripheral tissues. This survey is focused on the compounds that have been shown, or have been designed, to interact with HCN channels and on their binding sites, with the aim to summarize current knowledge and possibly to unveil useful information to design new potent and selective modulators. PMID- 26975517 TI - Characteristics of U.S. Substance Abuse Treatment Facilities Offering HIV Services: Results From a National Survey. AB - OBJECTIVE: Substance use disorders are common among persons with HIV/AIDS. This study examined the prevalence and correlates of the provision of four HIV services in a national sample of substance abuse treatment facilities. METHODS: Data were from the 2011 National Survey of Substance Abuse Treatment Services. RESULTS: Prevalence estimates indicated that 28% of facilities offered HIV testing, 26% early intervention, 58% HIV/AIDS education, and 8% special programs for HIV/AIDS. Facilities offering inpatient substance abuse care were more than six times as likely to offer HIV testing but not more likely to offer any other type of HIV service. Facilities offering methadone treatment were 2.5 times more likely to offer HIV services. CONCLUSIONS: Given the high rates of substance use among persons with HIV, the prevalence of facilities offering HIV services was low in most domains, with different barriers identified in multivariable models. Integrating comprehensive HIV prevention, testing, and support services into programs that address substance abuse is needed. PMID- 26975516 TI - Diagnosis of PTSD by Army Behavioral Health Clinicians: Are Diagnoses Recorded in Electronic Health Records? AB - OBJECTIVE: The study sought to identify the extent to which posttraumatic stress disorder (PTSD) diagnoses are recorded in the electronic health record (EHR) in Army behavioral health clinics and to assess clinicians' reasons for not recording them and treatment factors associated with recording or not recording the diagnosis. METHODS: A total of 543 Army mental health providers completed the anonymous, Web-based survey. Clinicians reported clinical data for 399 service member patients, of whom 110 (28%) had a reported PTSD diagnosis. Data were weighted to account for sampling design and nonresponses. RESULTS: Of those given a diagnosis of PTSD by their clinician, 59% were reported to have the diagnosis recorded in the EHR, and 41% did not. The most common reason for not recording was reducing stigma or protecting the service member's career prospects. Psychiatrists were more likely than psychologists or social workers to record the diagnosis. CONCLUSIONS: Findings indicate that for many patients presenting with PTSD in Army behavioral health clinics at the time of the survey (2010), clinicians did not record a PTSD diagnosis in the EHR, often in an effort to reduce stigma. This pattern may exist for other diagnoses. Recent Army policy has provided guidance to clinicians on diagnostic recording practice. An important implication concerns the reliance on coded diagnoses in PTSD surveillance efforts by the U.S. Department of Defense (DoD). The problem of underestimated prevalence rates may be further compounded by overly narrow DoD surveillance definitions of PTSD. PMID- 26975518 TI - Receipt of Depression Treatment From General Medical Providers and Specialty Mental Health Providers. AB - OBJECTIVE: This study compared sociodemographic characteristics and health conditions of adults with a major depressive episode who received treatment from general medical providers or specialty mental health providers. METHODS: The sample included 17,700 respondents ages 18-64 from the 2008-2012 National Survey on Drug Use and Health who met the DSM-IV criteria for a major depressive episode in the past 12 months and of whom 8,900 (61.5%) received treatment for depression. RESULTS: Approximately 21% of adults with a major depressive episode received depression care from general providers only, 19% from specialists only, and 19% from both. Compared with adults receiving care from general providers only, adults who received care from both types of provider were younger, had higher education, were more likely to have suicidal ideation and functional impairment, and were more likely to reside in a county with more psychiatrists providing patient care. These adults, compared with those who received care from a specialty mental health provider only, were more likely to be female, have higher education, have a greater number of general medical comorbidities, and have functional impairment, but they were less likely to be non-Hispanic black or Hispanic. CONCLUSIONS: Adults with major depressive episodes who received depression care from both general and specialty providers differed from those who received care from either provider type. Continued efforts to understand differences in depression care in specialty mental health and general medical settings may help improve the provision of mental health services as health care reform continues. PMID- 26975519 TI - Public Stigma in China Associated With Schizophrenia, Depression, Attenuated Psychosis Syndrome, and Psychosis-Like Experiences. AB - OBJECTIVE: Attenuated psychosis syndrome (APS) has recently been included in the appendix of DSM-5 as a condition for further study. This study compared public stigma associated with four mental health conditions among study participants in Hong Kong. METHODS: The cross-sectional study involved 204 participants (154 members of the general public general public and 50 health care professionals) recruited through a public awareness campaign and the e-mail network of the University of Hong Kong. Participants read four vignettes describing persons with schizophrenia, depression, APS, or psychosis-like experiences. For each vignette, they used a scale to rate their level of stigma in seven domains: social distance, traditional prejudice, exclusionary sentiments, negative affect, perceptions of dangerousness, treatment carryover, and disclosure carryover. Analyses compared ratings within and across vignettes. RESULTS: Schizophrenia received the highest public stigma ratings, followed by APS, depression, and psychosis-like experiences. Total stigma scores were higher for the general public than for health care professionals. Public stigma associated with APS was similar to that associated with depression. Ratings of treatment carryover indicated that participants believed that being known to have received treatment for APS or depression would have lasting consequences. CONCLUSIONS: Stigma should be considered in the development of mental health services and research in China, particularly in regard to people with schizophrenia and those at risk of psychosis. PMID- 26975520 TI - Perception of Need and Receipt of Mental Health Treatment: A Three-Group Comparison of Young Adults With Psychological Distress. AB - OBJECTIVE: This study examined mental health service use among three groups of young adults with assessed psychological distress: no perceived need for treatment, reported unmet need, and received treatment. METHODS: Data came from participants ages 18 to 25 in the National Survey on Drug Use and Health (2008 2013) who met criteria for psychological distress (N=19,775). Demographic, access , and need-related predictors of perceived need and treatment group were examined by using multinomial logistic regression. RESULTS: Half the sample did not perceive a need for treatment (51.0%), and only one-third had received treatment (33.7%). White youths were more likely than those from other racial-ethnic groups to perceive a need and to receive treatment. Men were less likely than women to perceive need but equally likely to receive treatment. Higher education and having insurance also predicted treatment receipt. CONCLUSIONS: Efforts to increase service utilization among young adults should increase awareness of mental health problems and facilitate access, particularly for racial-ethnic minority groups. PMID- 26975521 TI - Barriers to Engaging Service Members in Mental Health Care Within the U.S. Military Health System. AB - OBJECTIVE: Over the past decade, there has been growing recognition of the mental health consequences associated with deployment and service by military service personnel. This study examined potential barriers to mental health care faced by members of the military in accessing needed services. METHODS: This qualitative study of stakeholders was conducted across six large military installations, encompassing 18 Army primary care clinics, within the context of a large randomized controlled trial. Stakeholders included patients recruited for the study (N=38), health care providers working within site clinics (N=31), and the care managers employed to implement the intervention protocol (N=7). RESULTS: Issues raised across stakeholder groups fell into two main categories: structural factors associated with the Army medical system and institutional attitudes and cultural issues across the U.S. military. Structural issues included concerns about the existing capacity of the system, for example, the number of providers available to address the population's needs and the constraints on clinic hours and scheduling practices. The institutional attitude and cultural issues fell into two main areas: attitudes and perceptions by the leadership and the concern that those attitudes could have negative career repercussions for those who access care. CONCLUSIONS: Although there have been significant efforts to improve access to mental health care, stakeholders within the military health system still perceive significant barriers to care. Efforts to ensure adequate and timely access to high-quality mental health care for service members will need to appropriately respond to capacity constraints and organizational and institutional culture. PMID- 26975522 TI - Expedited Medicaid Enrollment, Mental Health Service Use, and Criminal Recidivism Among Released Prisoners With Severe Mental Illness. AB - OBJECTIVE: This study investigated whether Washington State's 2006 policy of expediting Medicaid enrollment for offenders with severe mental illness released from state prisons increased Medicaid access and use of community mental health services while decreasing criminal recidivism. METHODS: A quasi-experimental design with linked administrative data was used to select all prisoners with a severe mental illness (schizophrenia or bipolar disorder) released during the policy's first two years (January 1, 2006, through December 31, 2007), and those referred for expedited Medicaid (N=895) were separated from a propensity-weighted control group of those not referred (N=2,191). Measures included binary indicators of Medicaid enrollment, other public insurance enrollment, postrelease use of inpatient and outpatient health services, and any postrelease criminal justice contacts. All data were collapsed to person-level observations during the 12 months after the index release, and outcomes were estimated via propensity weighted logit models. RESULTS: Referral for expedited Medicaid on release from prison greatly increased Medicaid enrollment (p<.01) and use of community mental health and general medical services (p<.01) for persons with severe mental illness. No evidence was found that expediting Medicaid reduced criminal recidivism. CONCLUSIONS: Expediting Medicaid was associated with increased Medicaid enrollment and both mental health and general medical service use, but study findings strongly suggest that rather than relying on indirect spillover effects from Medicaid to reduce criminal recidivism, advocates and policy makers would better address the needs of offenders with severe mental illness through direct interventions targeted at underlying causes of recidivism. PMID- 26975523 TI - Enrollment and Service Use Patterns Among Persons With Severe Mental Illness Receiving Expedited Medicaid on Release From State Prisons, County Jails, and Psychiatric Hospitals. AB - OBJECTIVE: This study examined postrelease patterns of Medicaid coverage and use of services among persons with severe mental illness who were referred for expedited Medicaid enrollment before their release from state prisons, county jails, and psychiatric hospitals in Washington State during 2006, the first year of a new policy authorizing this practice. METHODS: A retrospective cohort design was used with linked administrative data to identify persons with severe mental illness (schizophrenia, bipolar disorder, or major depression) who were referred for expedited Medicaid enrollment from state prisons (N=252), county jails (N=489), and psychiatric hospitals (N=507). For each cohort, logistic regression was used to compare those who were approved for expedited Medicaid with those who were not approved; for the 30-, 60-, and 90-day periods after release, Medicaid enrollment status and use of outpatient mental health services were also compared. RESULTS: Approval rates were higher for persons released from psychiatric hospitals (91%) and state prisons (83%) than for those released from jails (66%) (p<.001). Across settings, approval was more likely for those with a diagnosis of schizophrenia and for women (p<.001), as well as for whites and older offenders (p<.01). At the 90-day follow-up, those who were approved were more likely than those who were denied to be enrolled in Medicaid (p<.001) and to have used outpatient mental health services (p<.001). CONCLUSIONS: Expediting Medicaid benefits for persons with severe mental illness was associated with increased enrollment and outpatient mental health service use in the 90 days after release from state prisons, county jails, and psychiatric hospitals in Washington State. PMID- 26975524 TI - A Prescription for "Deprescribing" in Psychiatry. AB - The term "deprescribing," initially coined in geriatric medicine, describes a process of pharmacologic regimen optimization through reduction or cessation of medications for which benefits no longer outweigh risks. Burgeoning rates of polypharmacy, growing appreciation of long-term adverse effects, and a focus on patient-centered practice present specific indications for deprescribing in psychiatry. A strong therapeutic alliance, appropriate timing, and consideration of the meaning of medication for the patient must accompany the following established elements: review of all medications, identification of medications that could be ceased or reduced, collaborative planning of the deprescribing regimen, and provision of review and support to the patient and caregivers. The authors discuss how deprescribing might be adapted for and implemented in psychiatry, identify potential barriers, and make recommendations for future directions. PMID- 26975525 TI - Is the Evidence Strong Enough to Warrant Long-Term Antipsychotic Use in Compulsory Outpatient Treatment? AB - Debate surrounding assisted outpatient treatment has mostly focused on issues of due process, cost-effectiveness, and efficacy as measured by readmission and incarceration rates. Less attention has been paid to whether long-term use of antipsychotic treatment is supported by sufficient evidence to warrant its compulsory use in assisted outpatient treatment programs. The authors examine the rationale and evidence for long-term use of antipsychotics, noting the pervasive belief within the psychiatric community that psychotic illness, especially schizophrenia, requires lifelong medication. They argue that although antipsychotics are clearly indicated for patients in the acute phase of psychotic illness, the evidence for long-term use is less convincing and may not justify compulsory long-term use. PMID- 26975526 TI - Implementing Cognitive Remediation Programs in France: The "Secret Sauce". AB - Cognitive remediation (CR) is a psychosocial therapy that seeks to restore patients' cognitive abilities by providing strategies to improve functioning in cognitive domains and helping them transfer acquired capabilities to everyday life. Since 2008, CR programs have been introduced in several regional health ministry areas in France. This column describes that implementation initiative, which includes creation of a network of the most active CR programs to conduct multicenter trials; establishment of a university degree in CR, awarded after completion of a one-year clinical training program; and implementation activities of regional health agencies. The authors describe three core elements of a "secret sauce"-a common language, timing, and leadership-that has helped ensure the success of the implementation efforts and that may be useful in other countries. PMID- 26975527 TI - What Exactly Does Femtosecond Technology Add to Phacoemulsification Based on Objective Studies To Date? PMID- 26975528 TI - Reply. PMID- 26975529 TI - Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer. AB - Mounting evidence suggests that long noncoding RNAs (lncRNAs) can function as microRNA sponges and compete for microRNA binding to protein-coding transcripts. However, the prevalence, functional significance and targets of lncRNA-mediated sponge regulation of cancer are mostly unknown. Here we identify a lncRNA mediated sponge regulatory network that affects the expression of many protein coding prostate cancer driver genes, by integrating analysis of sequence features and gene expression profiles of both lncRNAs and protein-coding genes in tumours. We confirm the tumour-suppressive function of two lncRNAs (TUG1 and CTB-89H12.4) and their regulation of PTEN expression in prostate cancer. Surprisingly, one of the two lncRNAs, TUG1, was previously known for its function in polycomb repressive complex 2 (PRC2)-mediated transcriptional regulation, suggesting its sub-cellular localization-dependent function. Our findings not only suggest an important role of lncRNA-mediated sponge regulation in cancer, but also underscore the critical influence of cytoplasmic localization on the efficacy of a sponge lncRNA. PMID- 26975530 TI - Distinct metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein(a). AB - OBJECTIVES: Lipoprotein(a) [Lp(a)] is mainly similar in composition to LDL, but differs in having apolipoprotein (apo) (a) covalently linked to apoB-100. Our purpose was to examine the individual metabolism of apo(a) and apoB-100 within plasma Lp(a). MATERIALS AND METHODS: The kinetics of apo(a) and apoB-100 in plasma Lp(a) were assessed in four men with dyslipidemia [Lp(a) concentration: 8.9-124.7nmol/L]. All subjects received a primed constant infusion of [5,5,5 (2)H3] L-leucine while in the constantly fed state. Lp(a) was immunoprecipitated directly from whole plasma; apo(a) and apoB-100 were separated by gel electrophoresis; and isotopic enrichment was determined by gas chromatography/mass spectrometry. RESULTS: Multicompartmental modeling analysis indicated that the median fractional catabolic rates of apo(a) and apoB-100 within Lp(a) were significantly different at 0.104 and 0.263 pools/day, respectively (P=0.04). The median Lp(a) apo(a) production rate at 0.248nmol/kg.day(-1) was significantly lower than that of Lp(a) apoB-100 at 0.514nmol/kg.day(-1) (P=0.03). CONCLUSION: Our data indicate that apo(a) has a plasma residence time (11days) that is more than twice as long as that of apoB 100 (4days) within Lp(a), supporting the concept that apo(a) and apoB-100 within plasma Lp(a) are not catabolized from the bloodstream as a unit in humans in the fed state. PMID- 26975531 TI - The role of nerve inflammation and exogenous iron load in experimental peripheral diabetic neuropathy (PDN). AB - BACKGROUND: Iron is an essential but potentially toxic metal in mammals. Here we investigated a pathogenic role of exogenous iron in peripheral diabetic neuropathy (PDN) in an animal model for type 1 diabetes. METHODS: Diabetes was induced by a single injection of streptozotocin (STZ) in 4-month-old Sprague Dawley rats. STZ-diabetic rats and non-diabetic rats were fed with high, standard, or low iron diet. After three months of feeding, animals were tested. RESULTS: STZ-rats on standard iron diet showed overt diabetes, slowed motor nerve conduction, marked degeneration of distal intraepidermal nerve fibers, mild intraneural infiltration with macrophages and T-cells in the sciatic nerve, and increased iron levels in serum and dorsal root ganglion (DRG) neurons. While motor fibers were afflicted in all STZ-groups, only a low iron-diet led also to reduced sensory conduction velocities in the sciatic nerve. In addition, only STZ rats on a low iron diet showed damaged mitochondria in numerous DRG neurons, a more profound intraepidermal nerve fiber degeneration indicating small fiber neuropathy, and even more inflammatory cells in sciatic nerves than seen in any other experimental group. CONCLUSIONS: These results indicate that dietary iron deficiency rather than iron overload, and mild inflammation may both promote neuropathy in STZ-induced experimental PDN. PMID- 26975532 TI - Nutrients, foods, dietary patterns and telomere length: Update of epidemiological studies and randomized trials. AB - Identifying simple strategies to prevent or delay age-associated pathologies is a major public health concern. Attrition of telomeres, chromatin structures that help maintain genome stability, leads to cell death or senescence. Thus telomere length is a reliable hallmark of biological aging and the risk of developing age related chronic diseases through common oxidation and inflammation mechanisms. Variability in telomere shortening that is independent of chronological age suggests that it is a modifiable factor, which may be explained in part by lifestyle variables such as smoking, adiposity, physical exercise, and diet. Here we summarize data from published studies focused on nutrition (nutrients, foods, and dietary patterns) and telomere length. Research on the topic is incipient and most data comes from epidemiologic studies, often cross-sectional in design. Consistent with well-known evidence of benefit or harm for chronic age-related diseases, dietary antioxidants and consumption of antioxidant-rich, plant-derived foods help maintain telomere length. In contrast, total and saturated fat intake and consumption of refined flour cereals, meat and meat products, and sugar sweetened beverages relate to shorter telomeres. Data on alcohol and dairy products is controversial. There is evidence that adherence to the Mediterranean diet is associated with longer telomeres. Randomized clinical trials are limited to seafood-derived long-chain n-3 polyunsaturated fatty acids, with promising results. To fill the many gaps in our knowledge of the aging process and confirm nutrition as a useful tool to counteract biological aging more research is warranted, particularly observational studies using repeated measurements of telomere length and randomized trials of foods and dietary patterns with sequential telomere analyses. PMID- 26975533 TI - Altered metabolic homeostasis is associated with appetite regulation during and following 48-h of severe energy deprivation in adults. AB - BACKGROUND: Military personnel frequently endure intermittent periods of severe energy deficit which can compromise health and performance. Physiologic factors contributing to underconsumption, and the subsequent drive to overeat, are not fully characterized. This study aimed to identify associations between appetite, metabolic homeostasis and endocrine responses during and following severe, short term energy deprivation. METHODS: Twenty-three young adults (17M/6F, 21+/-3years, BMI 25+/-3kg/m(2)) participated in a randomized, controlled, crossover trial. During separate 48-h periods, participants increased habitual energy expenditure by 1647+/-345kcal/d (mean+/-SD) through prescribed exercise at 40-65% VO2peak, and consumed provided isovolumetric diets designed to maintain energy balance at the elevated energy expenditure (EB; 36+/-93kcal/d energy deficit) or to produce a severe energy deficit (ED; 3681+/-716kcal/d energy deficit). Appetite, markers of metabolic homeostasis and endocrine mediators of appetite and substrate availability were periodically measured. Ad libitum energy intake was measured over 36h following both experimental periods. RESULTS: Appetite increased during ED and was greater than during EB despite maintenance of diet volume (P=0.004). Ad libitum energy intake was 907kcal/36h [95% CI: 321, 1493kcal/36h, P=0.004] higher following ED compared to following EB. Serum beta-hydroxybutyrate, free fatty acids, branched-chain amino acids, dehydroepiandrosterone-sulfate (DHEA-S) and cortisol concentrations were higher (P<0.001 for all), whereas whole-body protein balance was more negative (P<0.001), and serum glucose, insulin, and leptin concentrations were lower (P<0.001 for all) during ED relative to during EB. Cortisol concentrations, but not any other hormone or metabolic substrate, were inversely associated with satiety during EB (R(2)=0.23, P=0.04). In contrast, serum glucose and DHEA-S concentrations were inversely associated with satiety during ED (R(2)=0.68, P<0.001). No associations between physiologic variables measured during EB and ad libitum energy intake following EB were observed. However, serum leptin and net protein balance measured during ED were inversely associated with ad libitum energy intake following ED (R(2)=0.48, P=0.01). CONCLUSION: These findings suggest that changes in metabolic homeostasis during energy deprivation modulate appetite independent of reductions in diet volume. Following energy deprivation, physiologic signals of adipose and lean tissue loss may drive restoration of energy balance. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov #NCT01603550. PMID- 26975534 TI - There is no 'universal fit': Reflections on the use of l-triiodothyronine in the treatment of hypothyroidism. PMID- 26975535 TI - Serum uric acid: A strong and independent predictor of metabolic syndrome after adjusting for body composition. AB - BACKGROUND: Some observational studies have suggested that serum uric acid (SUA) levels are one of the determinants of the metabolic syndrome (MetS). However, previous studies reported combined results for men and women after adjusting for sex and few studies take body composition into consideration. Therefore, we performed this sex-specific longitudinal study to investigate how baseline SUA levels influence incident MetS, including body composition as an adjusting factor in a large number of subjects. METHODS: A total of 14,442 participants (8715 men and 5727 women) participating in a medical health check-up program without diagnosed MetS at baseline were enrolled. Separate analyses were performed for men and women including body composition as a confounding factor. Cox proportional hazards models were used to quantify independent associations between SUA levels and incident MetS. RESULTS: During 63,940person-years of follow-up, there were 4215 (2974 men, 1241 women) incident cases of MetS between 2006 and 2012. After adjustments for age, systolic BP, diastolic BP, BMI, eGFR, smoking status, TG, LDL-C, HDL-C, fasting glucose, and proportion of fat-free mass (100-fat mass, %), the hazard ratios (HR) [95% confidence interval (CI)] for incident MetS comparing the second, the third, and the fourth quartiles to the first quartile of SUA levels were 0.862 (0.770-0.965), 1.102 (0.991-1.225), and 1.246 (1.121-1.385) in men (p for trend<0.001), and 1.045 (0.862-1.266), 1.251 (1.050-1.490), and 1.321 (1.109-1.574) in women (p for trend<0.001), respectively. As a continuous variable, in fully-adjusted models, the HRs (95% CI) for incident MetS associated with each increase of 1mg/dl of SUA levels were 1.094 (1.060-1.130) in men (p<0.001) and 1.148 (1.072-1.228) in women (p<0.001), respectively. CONCLUSION: We demonstrated that SUA levels are strong and independent predictors of MetS. This relationship remained significant after full adjustments for multiple associated confounders including body composition in both men and women. PMID- 26975536 TI - Atorvastatin prevents advanced glycation end products (AGEs)-induced cardiac fibrosis via activating peroxisome proliferator-activated receptor gamma (PPAR gamma). AB - BACKGROUND: Previous studies have shown that the activation of advanced glycation end products (AGEs) contributed to the cardiac fibrosis in diabetic patients. Although it had been reported that statins have beneficial effects on cardiac fibrosis in hypertension and myocardial ischemia models, their effects on AGEs models have not been studied. We aimed to investigate the effects of atorvastatin (Ator) on the AGEs-induced cardiac fibrosis both in vitro and vivo. METHODS: Male Sprague-Dawley rats were randomly divided into four groups: Control, AGEs, Ator or AGEs+Ator. The cardiac function was evaluated with the echocardiography at the second and the third month. Fibrosis area, alpha-SMA and RAGE expression in cardiac tissue were measured. For in vitro study, rat cardiac fibroblasts were treated with PD98059 (ERK inhibitor), Ator or Ator+GW9662 (PPAR-gamma antagonist), and then were stimulated with AGEs. Fibroblasts proliferation, ERK1/2, phosphorylated ERK1/2, alpha-SMA, and RAGE expression were studied. RESULTS: Compared with the control group, in vivo treatment with Ator significantly retarded the AGEs-induced diastolic function and attenuated cardiac fibrosis, alpha-SMA, and RAGE over expression induced by AGEs. Consistently, Ator prominently downregulated RAGE and alpha-SMA, while inhibited phosphorylation of ERK1/2 and fibroblast proliferation induced by AGEs in vitro. The GW9662 neutralized these effects of Ator on cardiac fibroblasts stimulated by AGEs. CONCLUSION: In this study, we demonstrated that AGEs-induced fibroblast proliferation and differentiation were dependent on AGEs-RAGE-ERK1/2 pathway and that atorvastatin could block this pathway via activating PPAR-gamma. PMID- 26975537 TI - The potential regulatory roles of NAD(+) and its metabolism in autophagy. AB - (Macro)autophagy mediates the bulk degradation of defective organelles, long lived proteins and protein aggregates in lysosomes and plays a critical role in cellular and tissue homeostasis. Defective autophagy processes have been found to contribute to a variety of metabolic diseases. However, the regulatory mechanisms of autophagy are not fully understood. Increasing data indicate that nicotinamide adenine nucleotide (NAD(+)) homeostasis correlates intimately with autophagy. NAD(+) is a ubiquitous coenzyme that functions primarily as an electron carrier of oxidoreductase in multiple redox reactions. Both NAD(+) homeostasis and its metabolism are thought to play critical roles in regulating autophagy. In this review, we discuss how the regulation of NAD(+) and its metabolism can influence autophagy. We focus on the regulation of NAD(+)/NADH homeostasis and the effects of NAD(+) consumption by poly(ADP-ribose) (PAR) polymerase-1 (PARP-1), NAD(+) dependent deacetylation by sirtuins and NAD(+) metabolites on autophagy processes and the underlying mechanisms. Future studies should provide more direct evidence for the regulation of autophagy processes by NAD(+). A better understanding of the critical roles of NAD(+) and its metabolites on autophagy will shed light on the complexity of autophagy regulation, which is essential for the discovery of new therapeutic tools for autophagy-related diseases. PMID- 26975538 TI - Methylglyoxal mediates streptozotocin-induced diabetic neuropathic pain via activation of the peripheral TRPA1 and Nav1.8 channels. AB - OBJECTIVE: Methylglyoxal is known to be associated with the development of nephropathy, retinopathy, and other complications in diabetes. The present study tested the hypothesis that endogenously increased levels of methylglyoxal in diabetes are causally associated with the induction of neuropathic pain. MATERIALS AND METHODS: Streptozotocin- and methylglyoxal-induced pain models were established in rats, and the anti-nociceptive effects of the methylglyoxal scavenging agents, selective transient receptor potential channel ankyrin 1 (TRPA1) antagonist, and Nav1.8 antagonist were tested. RESULTS: Systemic injection of streptozotocin in rats induced a prolonged increase in plasma methylglyoxal by approximately 60%, which was correlated with the progressive development of mechanical allodynia and thermal hyperalgesia. Local subcutaneous injection of methylglyoxal into the hindpaw produced dose-dependent and biphasic flinching nociceptive responses, which resembled formaldehyde (formalin)-induced nociception. The local methylglyoxal nociception was significantly blocked by co injection into the hindpaw of the selective transient receptor potential channel ankyrin 1 (TRPA1) antagonist, A967079, and the Nav1.8 antagonist, A803467. Co incubation with the methylglyoxal scavengers, aminoguanidine, d-arginine, and metformin, reduced the level of free methylglyoxal by more than 90%, and injection of their incubation solutions into the hindpaw produced negligible (3 17%) nociception. Like the clinically effective anti-diabetic neuropathic pain drug gabapentin, systemic injection of aminoguanidine, d-arginine, and metformin at doses that effectively inhibit paw-injected methylglyoxal-induced nociception significantly blocked streptozotocin-induced mechanical allodynia. CONCLUSION: Endogenously increased methylglyoxal may mediate diabetic neuropathic pain via activation of both TRPA1 and Nav1.8 expressed on primary afferent sensory neurons, and injection of methylglyoxal into the hindpaw may serve as a simple and robust model for testing the anti-diabetic pain drugs. PMID- 26975539 TI - Plasma osteoprotegerin levels are inversely associated with nonalcoholic fatty liver disease in patients with type 2 diabetes: A case-control study in China. AB - OBJECTIVE: Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor (TNF) receptor superfamily, is a decoy receptor for the receptor activator of nucleus factor-kappaB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). OPG has an effect on systemic insulin sensitivity and glucose homeostasis. The objective of this study was to evaluate the relationship between plasma osteoprotegerin (OPG) levels and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes. MATERIALS/METHODS: A case-control study was performed with 746 patients with type 2 diabetes. Of the study population, 367 patients had B-mode ultrasound-proven NAFLD and 379 were controls. The plasma OPG levels were measured using ELISA methods. NAFLD was diagnosed by hepatic ultrasound after the exclusion of alcohol abuse and other liver diseases. RESULTS: The OPG levels were significantly decreased in patients with NAFLD (2.3+/-1.1MUg/L vs. 2.8+/-1.3MUg/L, p=3.75*10(5)) compared to controls. Pearson correlation analysis showed that the OPG levels were associated with age and systolic blood pressure (both p<0.05). The participants in the lowest OPG quartile had a significantly increased risk for NAFLD (OR=3.49, 95% CI 1.86-6.94) after adjusting for potential cofounders. CONCLUSIONS: The plasma OPG level is negatively associated with NAFLD independent of potential cofounders. PMID- 26975540 TI - Loss of circadian rhythm of circulating insulin concentration induced by high-fat diet intake is associated with disrupted rhythmic expression of circadian clock genes in the liver. AB - OBJECTIVE: Peripheral clock genes show a circadian rhythm is correlated with the timing of feeding in peripheral tissues. It was reported that these clock genes are strongly regulated by insulin action and that a high-fat diet (HFD) intake in C57BL/6J mice for 21days induced insulin secretion during the dark phase and reduced the circadian rhythm of clock genes. In this study, we examined the circadian expression patterns of these clock genes in insulin-resistant animal models with excess secretion of insulin during the day. MATERIALS/METHODS: We examined whether insulin resistance induced by a HFD intake for 80days altered blood parameters (glucose and insulin concentrations) and expression of mRNA and proteins encoded by clock and functional genes in the liver using male ICR mice. RESULTS: Serum insulin concentrations were continuously higher during the day in mice fed a HFD than control mice. Expression of lipogenesis-related genes (Fas and Accbeta) and the transcription factor Chrebp peaked at zeitgeber time (ZT)24 in the liver of control mice. A HFD intake reduced the expression of these genes at ZT24 and disrupted the circadian rhythm. Expression of Bmal1 and Clock, transcription factors that compose the core feedback loop, showed circadian variation and were synchronously associated with Fas gene expression in control mice, but not in those fed a HFD. CONCLUSIONS: These results indicate that the disruption of the circadian rhythm of insulin secretion by HFD intake is closely associated with the disappearance of circadian expression of lipogenic and clock genes in the liver of mice. PMID- 26975541 TI - Effect of sprint training on resting serum irisin concentration - Sprint training once daily vs. twice every other day. AB - OBJECTIVE: Exercise twice every other day has been shown to lead to increasing peroxisome proliferator receptor gamma coactivator-1alpha (PGC-1alpha) expression (up-stream factor of irisin) via lowered muscle glycogen level during second of exercise compared with exercise once daily. This study determined the influence of 4weeks of sprint training (training once daily vs. twice every other day) on the serum irisin concentration. MATERIALS AND METHODS: Twenty healthy males (20.9+/-1.3years) were assigned randomly to either the SINGLE or REPEATED group (n=10 per group). The subjects in the SINGLE group participated in a sprint training session once daily (5days per week), whereas those in the REPEATED group performed two consecutive training sessions on the same day with a 1-h rest between sessions (2-3days per week). Both groups completed 20 training sessions over 4weeks. Each training session consisted of three consecutive 30-s maximal pedaling exercises with a 10-min rest between sets. Blood samples were collected before and after training period (48h after completing the last training session). RESULTS: The serum irisin concentration decreased significantly after training in each group (SINGLE, 338.5+/-77.8 to 207.6+/-64.6ng/mL; REPEATED, 329.5+/-83.9 to 234.2+/-72.8ng/mL, p<0.05). The plasma interleukin-6 (IL-6) concentration tended to be lower after training in both groups (main effect for period, p=0.054). However, there was no significant difference in the serum irisin or plasma IL-6 concentration between groups after training. The serum high molecular-weight adiponectin concentration did not change significantly after training in either group. CONCLUSION: Sprint training for 4weeks significantly decreased the resting serum irisin concentration, despite different training programs (training once daily vs. twice every other day). PMID- 26975542 TI - Energy replacement diminishes the effect of exercise on postprandial lipemia in boys. AB - PURPOSE: Acute bouts of exercise reduce postprandial triacylglycerol concentrations ([TAG]) in healthy boys and girls; however, it is not known whether this effect is mediated by the energy deficit. This study examined whether the exercise-induced reduction in postprandial [TAG] persists after immediate dietary replacement of the exercise energy expenditure (EE). METHODS: Eighteen healthy 11- to 13-year-old boys (mean (SD): body mass 41.3 (8.4)kg; peak oxygen uptake (VO2) 55 (5)mL.kg(-1).min(-1)) completed three, 2-day conditions in a within-measures, crossover design separated by 14days. On day 1, participants rested (CON), exercised at 60% peak VO2 inducing a net EE of 32kJ.kg(-1) body mass (EX-DEF) or completed the same exercise with the net EE replaced immediately (EX-REP). On day 2, capillary blood samples were taken in the fasted state and at pre-determined intervals throughout the 6.5h postprandial period. A standardised breakfast and lunch meal were consumed immediately and 4h, respectively, after the fasting sample. RESULTS: Based on ratios of the geometric means (95% confidence intervals (CI) for ratios), EX-DEF fasting [TAG] was 19% and 15% lower than CON (-32 to -4%, ES=1.15, P=0.02) and EX-REP (-29 to 0%, ES=0.91, P=0.05) respectively; CON and EX-REP were similar (-4%; P=0.59). The EX-DEF total area under the [TAG] versus time curve was 15% and 16% lower than CON (-27 to 0%, ES=0.55, P=0.05) and EX-REP (-29 to -2%, ES=0.62, P=0.03) respectively; CON and EX-REP were not different (2%; -13 to 20%, P=0.80). CONCLUSION: Immediate replacement of the exercise-induced energy deficit negates the reduction in postprandial [TAG] in boys; this highlights the importance of maintaining a negative energy balance immediately post-exercise to maximise the metabolic health benefits of exercise. PMID- 26975543 TI - The evolution of diabetic ketoacidosis: An update of its etiology, pathogenesis and management. AB - The prognosis of diabetic ketoacidosis has undergone incredibly remarkable evolution since the discovery of insulin nearly a century ago. The incidence and economic burden of diabetic ketoacidosis have continued to rise but its mortality has decreased to less than 1% in good centers. Improved outcome is attributable to a better understanding of the pathophysiology of the disease and widespread application of treatment guidelines. In this review, we present the changes that have occurred over the years, highlighting the evidence behind the recommendations that have improved outcome. We begin with a discussion of the precipitants and pathogenesis of DKA as a prelude to understanding the rationale for the recommendations. A brief review of ketosis-prone type 2 diabetes, an update relating to the diagnosis of DKA and a future perspective are also provided. PMID- 26975546 TI - Impaired adipogenic capacity in induced pluripotent stem cells from lipodystrophic patients with BSCL2 mutations. AB - OBJECTIVE: Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by marked scarcity of adipose tissue, extreme insulin resistance, hypertriglyceridemia, hepatic steatosis and early-onset diabetes. Mutation of the BSCL2/SEIPIN gene causes the most severe form of CGL. The aim of this study was to generate induced pluripotent stem (iPS) cells from patients with CGL harboring BSCL2/SEIPIN mutations. METHODS: Skin biopsies were obtained from two Japanese patients with CGL harboring different nonsense mutations (E189X and R275X) in BSCL2/SEIPIN. The fibroblasts thus obtained were infected with retroviruses encoding OCT4, SOX2, c-MYC, and KLF4. The generated iPS cells were evaluated for pluripotency by examining the expression of pluripotency markers (alkaline phosphatase, SSEA-4, TRA-1-60, and NANOG) and their ability to differentiate to three germ layers in vitro by forming embryoid bodies, and to form teratomas in vivo. Adipogenic capacity of differentiated BSCL2-iPS cells was determined by oil red O and adipose differentiation-related protein (ADRP) staining. Rescue experiments were also performed using stable expression of wild type BSCL2. A coimmunoprecipitation assay was conducted to investigate the interaction of SEIPIN with ADRP. RESULTS: iPS cells were generated from fibroblasts of the two patients with CGL. Each of the patient-derived iPS (BSCL2 iPS) clones showed all of the hallmarks of pluripotency and could differentiate into derivatives of all three germ layers in vitro by forming embryoid bodies, and form teratomas after injection into mouse testes. BSCL2-iPS cells maintained the mutations in BSCL2 and lacked intact BSCL2. Upon adipogenic differentiation, BSCL2-iPS cells exhibited marked reduction of lipid droplet formation concomitant with diffuse cytoplasmic distribution of ADRP, compared with iPS cells from healthy individuals. Forced expression of BSCL2 not only rescued the lipid accumulation defects, but also restored cytoplasmic punctate localization of ADRP in BSCL2-iPS cells. Coimmunoprecipitation indicated SEIPIN interacted with ADRP. CONCLUSION: BSCL2-iPS cells that recapitulate the lipodystrophic phenotypes in vitro could provide valuable models with which to study the physiology of lipid accumulation and the pathology of human lipodystrophy. We found that BSCL2 defines the localization of ADRP, which has a role in lipid accumulation and adipogenic differentiation. PMID- 26975545 TI - DMC (2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone) improves glucose tolerance as a potent AMPK activator. AB - OBJECTIVE: We investigated the effect and regulatory mechanism of 2',4'-dihydroxy 6'-methoxy-3',5'-dimethylchalcone (DMC) isolated from Cleistocalyx operculatus on metabolic parameters in myotubes, adipocytes and an obese mouse model. MATERIALS AND METHODS: Myotubes and adipocytes were incubated with or without DMC. Glucose uptake, fatty acid oxidation, AMPK activation and adipocytes differentiation were investigated. To examine in vivo effect of DMC, 30mg/kg/day DMC was administered by oral gavage for 2weeks in high fat fed C57BL/6 male mice and intra-peritoneal glucose tolerance test was performed. In order to examine whether DMC directly activates AMPK, we performed cell free AMPK assay and surface plasmon resonance spectroscopy analysis. RESULT: DMC increases glucose uptake and fatty acid oxidation (FAO) in myotubes. Also, DMC inhibits adipocyte differentiation in 3T3 L1 cells. Interestingly, DMC stimulates phosphorylation of AMP-dependent protein kinase (AMPK) alpha subunit (T172) by directly binding to AMPK, which results in the activation of AMPK. Furthermore, DMC binds AMPK with a higher affinity than AMP. When AMPK was knocked down, the stimulatory effect of DMC on FAO and its inhibitory effect on adipogenesis were abolished. These results suggest that the effects of DMC were primarily mediated by AMPK activation. In addition, treating mice fed a high fat diet with DMC improved glucose tolerance and significantly increased FAO of the muscles. CONCLUSION: DMC, as a novel AMPK activator, shows anti-diabetic effects in cell culture systems, such as myotubes and adipocytes, and in a diet-induced obese mouse model. PMID- 26975544 TI - Visualizing estrogen receptor-alpha-expressing neurons using a new ERalpha ZsGreen reporter mouse line. AB - BACKGROUND: A variety of biological functions of estrogens, including regulation of energy metabolism, are mediated by neurons expressing estrogen receptor-alpha (ERalpha) in the brain. However, complex intracellular processes in these ERalpha expressing neurons are difficult to unravel, due to the lack of strategy to visualize ERalpha-expressing neurons, especially in unfixed brain tissues. RESULTS AND CONCLUSIONS: Here we generated a novel ERalpha-ZsGreen reporter mouse line in which expression of a green fluorescent reporter protein, ZsGreen, is driven by a 241kb ERalpha gene promoter. We validated that ZsGreen is highly colocalized with endogenous ERalpha in the brain. Native ZsGreen signals were visualized in unfixed brain tissue, and were used to assist single cell collection and electrophysiological recordings. Finally, we demonstrated that this ERalpha-ZsGreen mouse allele can be used in combination with other genetic reporter alleles to allow experiments in highly selective neural populations. PMID- 26975548 TI - Anti-TNFalpha treatment for recalcitrant ulcerative necrobiosis lipoidica diabeticorum: A case report and review of the literature. AB - INTRODUCTION: Necrobiosis lipoidica diabeticorum (NLD) is a rare degenerative connective tissue disorder associated with diabetes mellitus, which usually presents with red papules or plaques with raised edges and occasional ulceration. Ulcerating NLD is notoriously difficult to treat. We present a young patient with ulcerative NLD who was successfully treated with the anti-TNFalpha agent infliximab. Case presentation is followed by a review of therapeutic TNFalpha blockade in NLD. CASE PRESENTATION: A 17-year old woman with type 1 diabetes since the age of 8, presented with a long-standing and extensively ulcerated and infected NLD lesion on her left shin. After achieving better glycemic control and treating her for infection of the wound, several NLD treatments failed to help, including corticosteroids and hyperbaric oxygen. She was treated successfully with 4 monthly sessions of 5mg/kg body weight intravenous infliximab, achieving complete resolution of ulceration. DISCUSSION: A multitude of available treatments have been suggested for NLD over the past decades, based on two axes, one through wound healing and the other through immunosuppression. Anti-TNFalpha agents are relatively new drugs that brought a revolution in chronic inflammatory diseases and have been on the rise as novel potential treatments for NLD. Three out of the five available anti-TNFalpha agents have been safely tested so far, both topically and systematically, with mostly favorable results. CONCLUSION: Intravenous infliximab was successful in the treatment of recalcitrant ulcerating NLD in our patient. Taken together with an increasing number of similar reports revealing a pathogenetic role of TNFalpha in NLD, we suggest that anti-TNFalpha agents are promising drugs in the management of this condition. PMID- 26975547 TI - Altered somatotroph feedback regulation improves metabolic efficiency and limits adipose deposition in male mice. AB - Several transgenic mouse models with disruption in the growth hormone (GH) axis support the role of GH in augmenting metabolic homeostasis. Specifically, interest has focused on GH's lipolytic properties and ability to affect adipose deposition. Furthermore, both GH and insulin growth factor 1 (IGF-1) may also play a direct or indirect role in adipose development. The somatotroph insulin like growth factor-1 receptor knockout (SIGFRKO) mouse with only a modest increase in serum GH and IGF-1 demonstrates less adipose tissue than controls. In order to characterize the metabolic phenotype of SIGFRKO mice, histologic analysis of fat depots confirmed a smaller average diameter of adipocytes in the SIGFRKO mice compared to controls. These changes were accompanied by an increase in lipolytic gene expression in fat depots. Indirect calorimetry performed on 6 8week old male mice and again at 25weeks of age demonstrated that SIGFRKO mice, at both ages, had a higher VO2 and increased energy expenditure when compared with controls. The calculated respiratory exchange ratio (RER) was lower in the younger SIGFRKO mice compared to controls. No differences in food consumption or in either ambulatory or total activity were seen between SIGFRKO and control mice in either age group. These studies highlight the role of GH in adipose deposition and its influence on the expression of lipolytic genes resulting in an altered metabolic state, thus providing a mechanism for the decrease in weight gain seen in the SIGFRKO mouse model. PMID- 26975549 TI - Hierarchical ZnO Nanosheet-Nanorod Architectures for Fabrication of Poly(3 hexylthiophene)/ZnO Hybrid NO2 Sensor. AB - A facile one-step solution method has been developed here to fabricate hierarchical ZnO nanosheet-nanorod architectures for compositing with poly(3 hexylthiophene) (P3HT) for fabricating a hybrid NO2 sensor. The hierarchical ZnO nanosheet-nanorod architectures were controllably synthesized by aging the solutions containing 0.05 mol.L(-1) Zn(2+) and 0.33 mol.L(-1) OH(-) at 60 degrees C through a metastable phase-directed mechanism. The concentration of OH( ) played a huge role on the morphology evolution. When the [OH(-)] concentration was decreased from 0.5 to 0.3 mol.L(-1), the morphology of the ZnO nanostructures changed gradually from monodispersed nanorods (NR) to nanorod assemblies (NRA), and then to nanosheet-nanorod architectures (NS-NR) and nanosheet assemblies (NSA), depending on the formation of various metastable, intermediate phases. The formation of NS-NR included the initial formation of ZnO nanosheets/gamma-Zn(OH)2 mixed intermediates, followed by the dissolution of Zn(OH)2, which served as soluble zinc source. Soluble Zn(OH)2 facilitated the dislocation-driven secondary growth of ZnO nanorod arrays on the primary defect-rich nanosheet substrates. Hybrid sensors based on composite films composed of P3HT and the as-prepared ZnO nanostructures were fabricated for the detection of NO2 at room temperature. The P3HT/ZnO NS-NR bilayer film exhibited not only the highest sensitivity but also good reproducibility and selectivity to NO2 at room temperature. The enhanced sensing performance was attributed to the formation of the P3HT/ZnO heterojunction in addition to the enhanced adsorption of NO2 by NS-NR ZnO rich in oxygen-vacancy defects. PMID- 26975550 TI - The first day is always the hardest: Functional connectivity during cue exposure and the ability to resist smoking in the initial hours of a quit attempt. AB - Quitting smoking is the single best change in behavior that smokers can make to improve their health and extend their lives. Although most smokers express a strong desire to stop using cigarettes, the vast majority of quit attempts end in relapse. Relapse is particularly likely when smokers encounter cigarette cues. A striking number of relapses occur very quickly, with many occurring within as little as 24h. Characterizing what distinguishes successful quit attempts from unsuccessful ones, particularly just after cessation is initiated, is a research priority. We addressed this significant issue by examining the association between functional connectivity during cigarette cue exposure and smoking behavior during the first 24h of a quit attempt. Functional MRI was used to measure brain activity during cue exposure in nicotine-deprived daily smokers during the first day of a quit attempt. Participants were then given the opportunity to smoke. Using data collected in two parent studies, we identified a subset of participants who chose to smoke and a matched subset who declined (n=38). Smokers who were able to resist smoking displayed significant functional connectivity between the left anterior insula and the dorsolateral prefrontal cortex, whereas there was no such connectivity for those who chose to smoke. Notably, there were no differences in mean levels of activation in brain regions of interest, underscoring the importance of assessing interregional connectivity when investigating the links between cue-related neural responses and overt behavior. To our knowledge, this is the first study to link patterns of functional connectivity and actual cigarette use during the pivotal first hours of attempt to change smoking behavior. PMID- 26975552 TI - Visual high-level regions respond to high-level stimulus content in the absence of low-level confounds. AB - High-level regions of the ventral stream exhibit strong category selectivity to stimuli such as faces, houses, or objects. However, recent studies suggest that at least part of this selectivity stems from low-level differences inherent to images of the different categories. For example, visual outdoor and indoor scenes as well as houses differ in spatial frequency, rectilinearity and obliqueness when compared to face or object images. Correspondingly, scene responsive para hippocampal place area (PPA) showed strong preference to low-level properties of visual scenes also in the absence of high-level scene content. This raises the question whether all high-level responses in PPA, the fusiform face area (FFA), or the object-responsive lateral occipital compex (LOC) may actually be explained by systematic differences in low-level features. In the present study we contrasted two classes of simple stimuli consisting of ten rectangles each. While both were matched in visual low-level features only one class of rectangle arrangements gave rise to a percept compatible with a high-level 3D layout such as a scene or an object. We found that areas PPA, transverse occipital sulcus (TOS, also referred to as occipital place area, OPA), as well as FFA and LOC showed robust responses to the visual scene class compared to the low-level matched control. Our results suggest that visual category responsive regions are not purely driven by low-level visual features but also by the high-level perceptual stimulus interpretation. PMID- 26975554 TI - Parietal cortex mediates perceptual Gestalt grouping independent of stimulus size. AB - The integration of local moving elements into a unified gestalt percept has previously been linked to the posterior parietal cortex. There are two possible interpretations for the lack of involvement of other occipital regions. The first is that parietal cortex is indeed uniquely functionally specialized to perform grouping. Another possibility is that other visual regions can perform grouping as well, but that the large spatial separation of the local elements used previously exceeded their neurons' receptive field (RF) sizes, preventing their involvement. In this study we distinguished between these two alternatives. We measured whole-brain activity using fMRI in response to a bistable motion illusion that induced mutually exclusive percepts of either an illusory global Gestalt or of local elements. The stimulus was presented in two sizes, a large version known to activate IPS only, and a version sufficiently small to fit into the RFs of mid-level dorsal regions such as V5/MT. We found that none of the separately localized motion regions apart from parietal cortex showed a preference for global Gestalt perception, even for the smaller version of the stimulus. This outcome suggests that grouping-by-motion is mediated by a specialized size-invariant mechanism with parietal cortex as its anatomical substrate. PMID- 26975551 TI - Oscillatory phase modulates the timing of neuronal activations and resulting behavior. AB - Human behavioral response timing is highly variable from trial to trial. While it is generally understood that behavioral variability must be due to trial-by-trial variations in brain function, it is still largely unknown which physiological mechanisms govern the timing of neural activity as it travels through networks of neuronal populations, and how variations in the timing of neural activity relate to variations in the timing of behavior. In our study, we submitted recordings from the cortical surface to novel analytic techniques to chart the trajectory of neuronal population activity across the human cortex in single trials, and found joint modulation of the timing of this activity and of consequent behavior by neuronal oscillations in the alpha band (8-12Hz). Specifically, we established that the onset of population activity tends to occur during the trough of oscillatory activity, and that deviations from this preferred relationship are related to changes in the timing of population activity and the speed of the resulting behavioral response. These results indicate that neuronal activity incurs variable delays as it propagates across neuronal populations, and that the duration of each delay is a function of the instantaneous phase of oscillatory activity. We conclude that the results presented in this paper are supportive of a general model for variability in the effective speed of information transmission in the human brain and for variability in the timing of human behavior. PMID- 26975553 TI - Amide proton signals as pH indicator for in vivo MRS and MRI of the brain Responses to hypercapnia and hypothermia. AB - Using proton MRS and MRI of mouse brain at 9.4T, this work provides the first in vivo evidence of pH-dependent concurrent changes of three amide signals and related metabolic responses to hypercapnia and hypothermia. During hypercapnia, amide proton MRS signals of glutamine at 6.8-6.9ppm and 7.6ppm as well as of unspecific compounds at 8.1-8.3ppm increase by at least 50% both at 37 degrees C and 22 degrees C. These changes reflect a reduced proton exchange with water. They are strongly correlated with intracellular pH which ranges from 6.75+/-0.10 to 7.13+/-0.06 as determined from a shift in creatine phosphokinase equilibrium. In MRI, saturation transfer from aliphatic as well as aromatic and/or amide protons alters slightly during hypercapnia and significantly during hypothermia. The asymmetry in magnetization transfer ratios decreased slightly during hypercapnia and hypothermia. Regardless of pH or temperature, saturation transfer from aliphatic protons between -2 and -4ppm frequency offset to water protons is significantly greater than that from aromatic/amide protons at corresponding offsets between +2 and +4ppm. Irradiation of aliphatic compounds at -3.5ppm frequency offset from water predominantly saturates lipids and water associated with myelin. Taken together, the results indicate that, for the B1 power used in this study, dipolar coupling between aliphatic and water protons rather than proton exchange is the dominant factor in Z-spectra and magnetization transfer ratio asymmetry of the brain in vivo. PMID- 26975555 TI - Causal relationship between effective connectivity within the default mode network and mind-wandering regulation and facilitation. AB - Transcranial direct current stimulation (tDCS) can modulate mind wandering, which is a shift in the contents of thought away from an ongoing task and/or from events in the external environment to self-generated thoughts and feelings. Although modulation of the mind-wandering propensity is thought to be associated with neural alterations of the lateral prefrontal cortex (LPFC) and regions in the default mode network (DMN), the precise neural mechanisms remain unknown. Using functional magnetic resonance imaging (fMRI), we investigated the causal relationships among tDCS (one electrode placed over the right IPL, which is a core region of the DMN, and another placed over the left LPFC), stimulation induced directed connection alterations within the DMN, and modulation of the mind-wandering propensity. At the behavioral level, anodal tDCS on the right IPL (with cathodal tDCS on the left LPFC) reduced mind wandering compared to the reversed stimulation. At the neural level, the anodal tDCS on the right IPL decreased the afferent connections of the posterior cingulate cortex (PCC) from the right IPL and the medial prefrontal cortex (mPFC). Furthermore, mediation analysis revealed that the changes in the connections from the right IPL and mPFC correlated with the facilitation and inhibition of mind wandering, respectively. These effects are the result of the heterogeneous function of effective connectivity: the connection from the right IPL to the PCC inhibits mind wandering, whereas the connection from the mPFC to the PCC facilitates mind wandering. The present study is the first to demonstrate the neural mechanisms underlying tDCS modulation of mind-wandering propensity. PMID- 26975557 TI - Contextually sensitive power changes across multiple frequency bands underpin cognitive control. AB - Flexible control of cognition bestows a remarkable adaptability to a broad range of contexts. While cognitive control is known to rely on frontoparietal neural architecture to achieve this flexibility, the neural mechanisms that allow such adaptability to context are poorly understood. In the current study, we quantified contextual demands on the cognitive control system via a priori estimation of information across three tasks varying in difficulty (oddball, go/nogo, and switch tasks) and compared neural responses across these different contexts. We report evidence of the involvement of multiple frequency bands during preparation and implementation of cognitive control. Specifically, a common frontoparietal delta and a central alpha process corresponded to rule implementation and motor response respectively. Interestingly, we found evidence of a frontal theta signature that was sensitive to increasing amounts of information and a posterior parietal alpha process only seen during anticipatory rule updating. Importantly, these neural signatures of context processing match proposed frontal hierarchies of control and together provide novel evidence of a complex interplay of multiple frequency bands underpinning flexible, contextually sensitive cognition. PMID- 26975556 TI - Bi-directional changes in fractional anisotropy after experiment TBI: Disorganization and reorganization? AB - The current dogma to explain the extent of injury-related changes following rodent controlled cortical impact (CCI) injury is a focal injury with limited axonal pathology. However, there is in fact good, published histologic evidence to suggest that axonal injury is far more widespread in this model than generally thought. One possibility that might help to explain this is the often-used region of-interest data analysis approach taken by experimental traumatic brain injury (TBI) diffusion tensor imaging (DTI) or histologic studies that might miss more widespread damage, when compared to the whole brain, statistically robust method of tract-based analysis used more routinely in clinical research. To determine the extent of DTI changes in this model, we acquired in vivo DTI data before and at 1 and 4weeks after CCI injury in 17 adult male rats and analyzed parametric maps of fractional anisotropy (FA), axial, radial, and mean diffusivity (AD, RD, MD), tensor mode (MO), and fiber tract density (FTD) using tract-based spatial statistics. Contusion volume was used as a surrogate marker of injury severity and as a covariate for investigating severity dependence of the data. Mean fiber tract length was also computed from seeds in the cortical spinal tract regions. In parallel experiments (n=3-5/group), we investigated corpus callosum neurofilaments and demyelination using immunohistochemistry (IHC) at 3days and 6weeks, callosal tract patency using dual-label retrograde tract tracing at 5weeks, and the contribution of gliosis to DTI parameter maps using GFAP IHC at 4weeks post-injury. The data show widespread ipsilateral regions of significantly reduced FA at 1week post-injury, driven by temporally changing values of AD, RD, and MD that persist to 4weeks. Demyelination, retrograde label tract loss, and reductions in MO (tract degeneration) and FTD were shown to underpin these data. Significant FA increases occurred in subcortical and corticospinal tract regions that were spatially distinct from regions of FA decrease, grossly affected gliotic areas, and MO changes. However, there was good spatial correspondence between regions of increased FA and areas of increased FTD and mean fiber length. We discuss these widespread changes in DTI parameters in terms of axonal degeneration and potential reorganization, with reference to a resting state fMRI companion paper (Harris et al., 2016, Exp. Neurol. 227:124-138) that demonstrated altered functional connectivity data acquired from the same rats used in this study. PMID- 26975558 TI - The average baboon brain: MRI templates and tissue probability maps from 89 individuals. AB - The baboon (Papio) brain is a remarkable model for investigating the brain. The current work aimed at creating a population-average baboon (Papio anubis) brain template and its left/right hemisphere symmetric version from a large sample of T1-weighted magnetic resonance images collected from 89 individuals. Averaging the prior probability maps output during the segmentation of each individual also produced the first baboon brain tissue probability maps for gray matter, white matter and cerebrospinal fluid. The templates and the tissue probability maps were created using state-of-the-art, freely available software tools and are being made freely and publicly available: http://www.nitrc.org/projects/haiko89/ or http://lpc.univ-amu.fr/spip.php?article589. It is hoped that these images will aid neuroimaging research of the baboon by, for example, providing a modern, high quality normalization target and accompanying standardized coordinate system as well as probabilistic priors that can be used during tissue segmentation. PMID- 26975559 TI - Measuring Personal Exposure to Organophosphate Flame Retardants Using Silicone Wristbands and Hand Wipes. AB - Organophosphate flame retardants (PFRs) are widely used as replacements for polybrominated diphenyl ethers in consumer products. With high detection in indoor environments and increasing toxicological evidence suggesting a potential for adverse health effects, there is a growing need for reliable exposure metrics to examine individual exposures to PFRs. Silicone wristbands have been used as passive air samplers for quantifying exposure in the general population and occupational exposure to polycyclic aromatic hydrocarbons. Here we investigated the utility of silicone wristbands in measuring exposure and internal dose of PFRs through measurement of urinary metabolite concentrations. Wristbands were also compared to hand wipes as metrics of exposure. Participants wore wristbands for 5 consecutive days and collected first morning void urine samples on 3 alternating days. Urine samples were pooled across 3 days and analyzed for metabolites of the following PFRs: tris(1,3-dichloroisopropyl) phosphate (TDCIPP), tris(1-chloro-2-isopropyl) phosphate (TCIPP), triphenyl phosphate (TPHP), and monosubstituted isopropylated triaryl phosphate (mono-ITP). All four PFRs and their urinary metabolites were ubiquitously detected. Correlations between TDCIPP and TCIPP and their corresponding urinary metabolites were highly significant on the wristbands (rs = 0.5-0.65, p < 0.001), which suggest that wristbands can serve as strong predictors of cumulative, 5-day exposure and may be an improved metric compared to hand wipes. PMID- 26975560 TI - School environment, sedentary behavior and physical activity in preschool children. AB - OBJECTIVE: To analyze physical activity and sedentary behavior in preschool children during their stay at school and the associated factors. METHODS: 370 preschoolers, aged 4 to 6 years, stratified according to gender, age and school region in the city of Londrina, PR, participated in the study. A questionnaire was applied to principals of preschools to analyze the school infrastructure and environment. Physical activity and sedentary behavior were estimated using accelerometers for five consecutive days during the children's stay at school. The odds ratio (OR) was estimated through binary logistic regression. RESULTS: At school, regardless of age, preschoolers spend relatively more time in sedentary behaviors (89.6%-90.9%), followed by light (4.6%-7.6%), moderate (1.3%-3.0%) and vigorous (0.5%-2.3%) physical activity. The indoor recreation room (OR=0.20; 95%CI 0.05 to 0.83) and the playground (OR=0.08; 95%CI 0.00 to 0.80) protect four year-old schoolchildren from highly sedentary behavior. An inverse association was found between the indoor recreation room and physical activity (OR=0.20; 95%CI 0.00 to 0.93) in five-year-old children. The indoor recreation room (OR=1.54; 95%CI 1.35 to 1.77), the playground (OR=2.82; 95%CI 1.14 to 6.96) and the recess (OR=1.54; 95%CI 1.35 to 1.77) are factors that increase the chance of six-year-old schoolchildren to be active. CONCLUSIONS: The school infrastructure and environment should be seen as strategies to promote physical activity and reduce sedentary behavior in preschool children. PMID- 26975561 TI - Assessing the nutritional information for children younger than two years old available on popular websites. AB - OBJECTIVE: To analyze whether the information found on popular Internet sites are in accordance with the steps recommended by the Food Guide for Children Younger than Two Years of the Ministry of Health (2010). METHODS: Descriptive/comparative study, carried out between August and October 2014, which carried out a search for popular sites (for lay people) in Portuguese, containing information on nutrition of children younger than two years. The Google search engine was used. These findings were compared with the Food Guide for Children Younger than Two Years of the Ministry of Health (2010). It was verified whether the information shown on the websites was in accordance with the Guide. RESULTS: A total of 50 sites were analyzed, including blogs, food company websites and websites specialized in child nutrition. Only 10% of those pages correctly showed every step of the Food Guide. The recommendations were: exclusive breastfeeding up to six months of life (80%); complementary feeding from six months of life (36%); baby food consistency according to the guide (48%); encouraging the consumption of fruits and vegetables daily (60%). Regarding the complementary feeding safety and hygiene, 26% contained correct information. Only 36% correctly warned about which foods should be avoided in the first years of life. CONCLUSIONS: The information found on the sites is largely in disagreement with the Ministry of Health recommendations, which can lead to misconceptions in the nutritional care of the children younger than two years. PMID- 26975563 TI - Electrical Nerve Stimulation Enhances Perilesional Branching after Nerve Grafting but Fails to Increase Regeneration Speed in a Murine Model. AB - Background Electrical stimulation immediately following nerve lesion helps regenerating axons cross the subsequently grafted nerve repair site. However, the results and the mechanisms remain open to debate. Some findings show that stimulation after crush injury increases axonal crossing of the repair site without affecting regeneration speed. Others show that stimulation after transection and fibrin glue repair doubles regeneration distance. Methods Using a sciatic-nerve-transection-graft in vivo model, we investigated the morphological behavior of regenerating axons around the repair site after unilateral nerve stimulation (20 Hz, 1 hour). With mice expressing axonal fluorescent proteins (thy1-YFP), we were able to calculate the following at 5 and 7 days: percentage of regenerating axons and arborizing axons, branches per axon, and regeneration distance and speed. Results Brief stimulation significantly increases the percentage of regenerating axons (5 days: 35.5 vs. 27.3% nonstimulated, p < 0.05; 7 days: 43.3 vs. 33.9% nonstimulated, p < 0.05), mainly by increasing arborizing axons (5 days: 49.3 [4.4] vs. 33.9 [4.1]% [p < 0.001]; 7 days: 42.2 [5.6] vs. 33.2 [3.1]% [p < 0.001]). Neither branches per arborizing axon nor regeneration speed were affected. Conclusion Our morphological data analysis revealed that electrical stimulation in this model increases axonal crossing of the repair site and promotes homogeneous perilesional branching, but does not affect regeneration speed. PMID- 26975562 TI - [Socioeconomic status indicators, physical activity, and overweight/obesity in Brazilian children]. AB - OBJECTIVE: To analyze the associations between socioeconomic status (SES) indicators and physical activity and overweight/obesity in children. METHODS: 485 children wore accelerometers for 7 days. Variables included time in sedentary behavior and moderate-to-vigorous physical activity (MVPA), and steps/day. Children were further categorized as meeting or not meeting guidelines of >=60min/day MVPA and >=12,000 steps/day. Body mass index (BMI) and body fat percentage (BF%) were measured using bioelec-trical impedance. Overweight/obesity was defined as BMI>+1 SD and BF%>=85th percentile. Parents answered questionnaires that questioned total annual household income, parental education level, parental employment status and automobile ownership. RESULTS: Children averaged 59.5min/day in MVPA (44.1% met MVPA guidelines), and 9639 steps/day (18.4% met steps/day guidelines). 45.4% and 33% were overweight/obese classified by BMI and BF% respectively. Higher relative total annual household income level (Odds Ratio 0.31; 95% confidence interval=0.15-0.65), and relatively higher maternal (OR=0.38; 95%CI=0.20-0.72) and paternal (OR=0.36; 95%CI=0.17-0.75) education levels were associ-ated with lower odds of children meeting MVPA guidelines. Household automobile ownership was associated with lower odds of children meeting MVPA (OR=0.48; 95%CI=0.31-0.75) and steps/day guidelines (OR=0.44; 95%CI=0.26-0.74). CONCLUSIONS: SES indicators were not associated with overweight/obesity, but higher SES was associated with lower odds of children meeting MVPA guidelines. PMID- 26975564 TI - Barcelona Lymphedema Algorithm for Surgical Treatment in Breast Cancer-Related Lymphedema. AB - Background Breast cancer-related lymphedema is a prevalent condition that has a major impact on quality of life. Surgical treatment has become an alternative to help affected patients with good results. However, there is no consensus on surgical procedure and protocol. Methods We analyzed our data in two periods: from June 2007 to December 2011 and from January 2012 to June 2014. Data included the analysis of the limb circumferences and the subjective symptoms felt by patients. Results Of the 200 patients treated in the study, 81 had lymphaticovenous anastomosis, 7 had autologous lymph node transfer, 16 had total breast anatomy restoration, 52 had vibroliposuction, and 44 had combined reconstructive procedures. In the first period, the circumference of the superior limb showed a decrease of 0.9 to 6.1 cm (average 2.75 cm). In the second period, the circumference of the superior limb showed a decrease of 2.9 to 6.1 cm (average 3.85 cm). Clinical results and data from the questionnaires confirmed the improvement and subjective benefits. Conclusion We have obtained considerable improvements in results of limb circumferences and subjective symptoms after incorporating several modifications into our surgical strategy for lymphedema treatment. A detailed preoperative assessment should be performed to determine whether reconstructive surgery or palliative surgery is indicated. PMID- 26975565 TI - Competitive effects of oxygen vacancy formation and interfacial oxidation on an ultra-thin HfO2-based resistive switching memory: beyond filament and charge hopping models. AB - We studied the quantum transport mechanism of an ultra-thin HfO2-based resistive random access memory (ReRAM) cell with TiN electrodes and proposed the design of a sub-10 nm scale device. It is believed that formation and rupture of the conduction path in the local filament causes the switching between high and low resistive states. However, the validity of this simple filament model is not obvious in the sub-10 nm scale device because the redox processes occur mainly in a few nm range at the interface. Furthermore, the intrinsic transport mechanism of the device, in particular, quantum coherence, depends on device materials and length-scale. The relationship between the redox states and the transport mechanism like ballistic or hopping is still under debate when the device length scale is less than 10 nm. In the present study, we performed first-principles calculations of the non-equilibrium Green's function including electron-phonon interactions. We examined several characteristic structures of the HfO(x) wire (nano-scale conduction path) and the interfaces between the resistive switching layer and electrodes. We found that the metal buffer layer induced a change in the oxygen-reduction site from the interface of HfO(x)/TiN to the buffer layer. Even when the inserted buffer layer is a few atomic layers, this effect plays an important role in the enhancement of the performance of ON/OFF resistive switching and in the reduction of the inelastic electric current by electron phonon scattering. The latter suppresses the hopping mechanism, which makes the ballistic conduction the dominant mechanism. We evaluated the activation energy in the high temperature limit by using the first-principles results of inelastic current. Our theoretical model explains the observed crossover of the temperature dependence of ReRAM cells and gives a new insight into the principle of operation on a sub-10 nm scale ReRAM device. PMID- 26975567 TI - Structural insights into the methyl donor recognition model of a novel membrane binding protein UbiG. AB - UbiG is a SAM-dependent O-methyltransferase, catalyzing two O-methyl transfer steps for ubiquinone biosynthesis in Escherichia coli. UbiG possesses a unique sequence insertion between beta4 and alpha10, which is used for membrane lipid interaction. Interestingly, this sequence insertion also covers the methyl donor binding pocket. Thus, the relationship between membrane binding and entrance of the methyl donor of UbiG during the O-methyl transfer process is a question that deserves further exploration. In this study, we reveal that the membrane-binding region of UbiG gates the entrance of methyl donor. When bound with liposome, UbiG displays an enhanced binding ability toward the methyl donor product S adenosylhomocysteine. We further employ protein engineering strategies to design UbiG mutants by truncating the membrane interacting region or making it more flexible. The ITC results show that the binding affinity of these mutants to SAH increases significantly compared with that of the wild-type UbiG. Moreover, we determine the structure of UbiG?(165-187) in complex with SAH. Collectively, our results provide a new angle to cognize the relationship between membrane binding and entrance of the methyl donor of UbiG, which is of benefit for better understanding the O-methyl transfer process for ubiquinone biosynthesis. PMID- 26975566 TI - Newcastle disease virus infection in chicken embryonic fibroblasts but not duck embryonic fibroblasts is associated with elevated host innate immune response. AB - BACKGROUND: Chickens and ducks are major hosts of Newcastle disease virus (NDV) with distinct responses to infection. However, whereas ducks are generally asymptomatic or exhibit only mild symptoms following NDV infection and are thus regarded as potential long-term reservoirs of the virus, chickens exhibit severe clinical lesions, transient infections and even death due to NDV infection. These differences may in part result from the host innate immune response to NDV infection. METHODS: To better understand the host innate immune response to NDV infection in avian species, by using the quantitative real-time polymerase chain reaction method we examined the messenger RNA expression levels of immune-related genes in chicken embryonic fibroblasts (CEFs) and duck embryonic fibroblasts (DEFs) when infected with NDV of different pathogenicities. RESULTS: Gene expression profiles showed that the expression of IL-1beta, TNF-alpha-like factor (LITAF) and interferon (IFN)-beta was upregulated in both CEFs and DEFs infected with SS-10 and NH-10 viruses or treated with polyinosinic:polycytidylic acid [poly(I:C)], as well as that expression levels were greater in CEFs than in DEFs. The expression of TLR3, TLR7, IL-6, IFN-alpha, IFN-gamma, MHC-I and MHC-II, except for IL-8, were also greater in CEFs than in DEFs in response to infection to both viruses or treatment with poly(I:C). However, unlike moderate virulent NH 10, highly virulent SS-10 induced greater pattern recognition receptors and cytokines, except for IFNs, in CEFs and DEFs. CONCLUSION: Results show distinct expression patterns of cytokines, Toll-like receptors and IFNs associated with inflammatory immune responses to NDV between species and by virulence. PMID- 26975568 TI - Association between weight control failure and suicidal ideation in overweight and obese adults: a cross-sectional study. AB - BACKGROUND: Korea has the highest suicide rate in the OECD and is one of the few OECD countries whose suicide rates have not decreased in recent years. To address these issues, we investigated the effects of weight control failure on suicidal ideation in the overweight and obese populations. METHODS: We performed a cross sectional study using data from the Korea National Health and Nutrition Examination Survey (2008-2012) consisting of 6621 individuals 40 years of age or older. Logistic regression analysis was used to identify the relationship between weight control failure and suicidal ideation in the overweight and obese populations. RESULTS: A total of 6621 participants were analyzed in this study (overweight group: 2439; obese group: 4182). Among them, weight control failure (weight gain with weight loss efforts) was experienced in 962 obese (males 16.3%, females 29.6%) and 412 overweight individuals (males 9.1%, females 23.4%). Weight control failure was significantly associated with suicidal ideation in obese females (OR = 1.70, 95% CI 1.21-2.39), but this association was not significant in obese males or in either sex of the overweight group. CONCLUSIONS: Findings from this study suggest that weight control failure is associated with an increased risk of suicidal ideation among obese women. Furthermore, intervention programs that aim to address the prevalence of suicide, especially for obese women, are needed. PMID- 26975569 TI - Neglected tropical diseases in the genomics era: re-evaluating the impact of new drugs and mass drug administration. AB - Simon Croft answers Genome Biology's questions on ways to approach neglected tropical diseases in the genomics era, including re-evaluating the impact of new drugs and mass drug administration. PMID- 26975572 TI - Staged extubation to manage the airway after operations on the head and neck. AB - Management of the airway after operations on the head and neck is potentially problematic. We describe leaving a guidewire in the trachea after successful extubation in two patients, to make reintubation easier if the airway was later compromised. PMID- 26975570 TI - The diagnostic accuracy of the hand-held Raman spectrometer for the identification of anti-malarial drugs. AB - BACKGROUND: There is a need for accurate and field-applicable instruments for the evaluation of the quality of anti-malarial drugs. The aim of this study was to determine the diagnostic accuracy of the NanoRam((r)), a handheld Raman spectrometer (RS), to identify anti-malarial drugs. METHODS: In total, 289 anti malarial drugs collected in a randomized field survey in Gabon were evaluated. The samples were compared with authentic products as supplied by the official manufacturer. To determine the sensitivity and specificity of the handheld NanoRam((r)) spectrometer in the identification of anti-malarial drugs, a two gate reversed-flow design was applied. The standards for reporting of diagnostic accuracy studies (STARD) were followed. The index test was the handheld RS. The reference test standards were thin layer chromatography and high performance liquid chromatography with ultraviolet photo diode array detection. RESULTS: The sensitivity [95% confidence interval (95% CI)] and specificity of the RS to correctly identify an anti-malarial drug were 100% (95% CI 94.9-100%) and 96% (95% CI 92.3-99.0%), respectively. The RS could not differentiate between different batches of the same product or different manufacturers of the same product. Intra-observer agreement for 289 samples was 100%. The average time to conduct the RS was 15 s per sample compared to 45 min per sample for TLC. CONCLUSION: The handheld RS holds promise as an easy-to-use, quick and field applicable instrument for the evaluation of quality of anti-malarial drugs, potentially empowering pharmacists, drug inspectors and medical regulatory authorities. Trial registration NTR4341 (Dutch Trial Registry). PMID- 26975573 TI - Anatomical study of the submandibular gland duct after removal of a distal stone without sialodochoplasty: a sialographic evaluation of a clinical phase II trial. AB - Transoral removal of a distal salivary stone is common. We have used postoperative sialography to evaluate the results and changes in the salivary ducts after removal of a salivary distal stone without sialodochoplasty. Of 20 patients who had had transoral operations for submandibular stones, 19 recovered normally with no recurrence. One developed partial stenosis and one a spontaneous neo-opening as a result of severe adhesions and inflammation between the salivary stone and the duct. None of the patients had any symptoms of recurrence during the 12-month follow-up. Sialodochoplasty may not be necessary in patients who have had a distal salivary stone removed. Removal without sialodochoplasty resulted in full anatomical recovery of the salivary ducts. PMID- 26975571 TI - Isoliquiritigenin Attenuates Adipose Tissue Inflammation in vitro and Adipose Tissue Fibrosis through Inhibition of Innate Immune Responses in Mice. AB - Isoliquiritigenin (ILG) is a flavonoid derived from Glycyrrhiza uralensis and potently suppresses NLRP3 inflammasome activation resulting in the improvement of diet-induced adipose tissue inflammation. However, whether ILG affects other pathways besides the inflammasome in adipose tissue inflammation is unknown. We here show that ILG suppresses adipose tissue inflammation by affecting the paracrine loop containing saturated fatty acids and TNF-alpha by using a co culture composed of adipocytes and macrophages. ILG suppressed inflammatory changes induced by the co-culture through inhibition of NF-kappaB activation. This effect was independent of either inhibition of inflammasome activation or activation of peroxisome proliferator-activated receptor-gamma. Moreover, ILG suppressed TNF-alpha-induced activation of adipocytes, coincident with inhibition of IkappaBalpha phosphorylation. Additionally, TNF-alpha-mediated inhibition of Akt phosphorylation under insulin signaling was alleviated by ILG in adipocytes. ILG suppressed palmitic acid-induced activation of macrophages, with decreasing the level of phosphorylated Jnk expression. Intriguingly, ILG improved high fat diet-induced fibrosis in adipose tissue in vivo. Finally, ILG inhibited TLR4- or Mincle-stimulated expression of fibrosis-related genes in stromal vascular fraction from obese adipose tissue and macrophages in vitro. Thus, ILG can suppress adipose tissue inflammation by both inflammasome-dependent and independent manners and attenuate adipose tissue fibrosis by targeting innate immune sensors. PMID- 26975574 TI - Telephone review after minor oral surgery. AB - An audit of outpatient clinic attendances at Cardiff Dental Hospital (between September 2009 and March 2010) showed that 30% of patients failed to attend review appointments after minor operations. To reduce rates of non-attendance we set up a system of telephone review in March 2010. Patients were given a telephone appointment two weeks after their minor operation (mainly removal of lower third molars), instead of an appointment at the outpatient clinic. A trained nurse contacted each patient to complete a structured questionnaire that included questions about numbness, pain, and swelling. During the first year of the project, 1020 patients were booked for telephone review and of these 90% were discharged. 674 (66%) were discharged after telephone review, and 245 (24%) were not contactable. A total of 101 patients (10%) were brought in for clinic review because they reported complications. Estimated staff costs per patient for telephone review and clinic review were L3.05 and L23.55 respectively. Telephone review resulted in a significant reduction in the number of patients who failed to attend the clinic (OR=0.88, 95% CI 0.81 to 0.96) and facilitated audit of complications. The use of telephone review in conjunction with clinical follow-up for those with postoperative problems allows for cost-effective care with reduced rates of non-attendance. PMID- 26975575 TI - Epidemiological study of alendronate-related osteonecrosis of the jaw in the southeast of Scotland. AB - We aimed to establish the incidence of alendronate-related osteonecrosis of the jaw (ONJ) in the southeast of Scotland, and to assess the effect of corticosteroids on it. We studied a prospective case series of patients between June 2004 and March 2012 separated into steroid and non-steroid groups. There were 34 cases of alendronate-related ONJ and 78732 drug patient years (DPY) of alendronate, making the overall occurrence 43.1 cases/100000 DPY. There were 12 patients in the steroid group (mean (range) age 68.2 (48-87) years) making 42.5 cases/100000 DPY, and 22 in the non-steroid group (mean (range) age 76.2 (63-91) years) making 119.6 cases/100000 DPY. The mean (range) age at presentation of alendronate-related ONJ was significantly lower in the steroid group (68.2 (48 87) compared with 76.2 (63-91) years, p=0.019) as was the duration of exposure to alendronate before it developed (28.9 (6-120) compared with 61.3 (13-168) months, p=0.03). The overall incidence seems to be higher in the southeast of Scotland than elsewhere. Concurrent use of corticosteroids is not associated with an increased incidence of alendronate-related ONJ, but it seems to reduce the duration of exposure before it develops. Age is likely to be a confounding factor. PMID- 26975576 TI - Bleeding after tooth extraction in patients taking aspirin and clopidogrel (Plavix(r)) compared with healthy controls. AB - The risk of perioperative bleeding is high in patients who take aspirin and clopidogrel after a percutaneous coronary intervention, and whether to stop the drugs is a matter of concern for dentists. The aim of this study was to answer the specific question: should aspirin and clopidogrel bisulphate (Plavix(r)) be discontinued during a conventional forceps extraction? We studied 64 patients during the first year after percutaneous insertion of coronary stents who were taking aspirin (ASA) 80mg and clopidogrel (Plavix((r))) 75mg, and 50 healthy patients who were to have a conventional forceps extraction at this polyclinic in 2013-2014 and acted as controls. Clinical details (underlying diseases; number of roots; type of tooth; type of haemostasis; and bleeding immediately, 30minutes, and 48hours after intervention) were compared. We evaluated 114 patients with the mean (range) age of 56 (43-76) years, and there were no significant differences in demographic data, underlying diseases, type of tooth, number of roots, and dose of anaesthetic between the groups. There were also no significant differences in the number of bleeds immediately and 30minutes after intervention (P=0.310 and 0.205). The time that the last dose of aspirin had been taken correlated with 30-minute haemostasis (20 compared with 12hours, p=0.037). During the 48hours after the intervention, there were no uncontrolled bleeds or emergency referrals. We conclude that using aspirin and Plavix(r) simultaneously has no considerable effect on the risk of bleeding in patients having conventional forceps extraction of a single tooth. PMID- 26975577 TI - Prophylactic use of pentoxifylline and tocopherol in patients who require dental extractions after radiotherapy for cancer of the head and neck. AB - Osteoradionecrosis (ORN) is a complication seen intermittently in patients who have had radiotherapy to the head and neck, and results of treatment with pentoxifylline and tocopherol (PVe) have been encouraging. As a consequence, some argue that this should be used prophylactically to lower the risk of ORN after dental extractions in this group. We retrospectively analysed data on 390 dental extractions in 82 patients who had had radiotherapy for cancer of the head and neck. Each had been given PVe prophylactically. Only one patient (1.2%) developed ORN (rate/tooth 0.26%). Patients had taken PVe for a mean (SD) of 11 (23) weeks preoperatively and 13.6 (18) weeks postoperatively. The incidence we found was lower than that normally associated with dental extractions in irradiated patients (7%). PMID- 26975579 TI - Ratiometric fluorophore for quantification of iodide under physiological conditions: applications in urine analysis and live cell imaging. AB - Dipod 1 bearing two pyrenyl tethered benzimidazolium moieties gives a fluorescence spectrum in aqueous medium which reveals a structured emission band between 330-400 nm and a broad emission band centered at 475 nm, respectively due to monomer and excimer emission of the pyrene moieties. The presence of an excimer emission band points to the formation of a pseudocyclic structure. Dipod 1 undergoes highly selective fluorescence quenching of the excimer emission band in the presence of iodide ions, whereas the fluorescence intensity of the monomer emission band remains stable. The ratio of fluorescence intensity I395 nm/I475 nmvs. log [I(-)] undergoes a linear change over a broad iodide concentration range of 10(-9) to 10(-5) M with KSV 3.7 * 10(5) M(-1). Dipod 1 can be used to determine iodide ions in urine samples, tap water and sea water conditions with 1 nM iodide as the lowest detection limit. On using paper strips coated with dipod 1, ~1.7 pg cm(-2) iodide ions could be detected. Dipod 1 shows a fluorescence quenching response to 100 nM iodide ions in C6 glioma cells using confocal microscopy. The life time of the dipod 1 shows a linear decrease with log [I(-)] and points to coordination based recognition of iodide ion. PMID- 26975578 TI - Do low-carbon-emission diets lead to higher nutritional quality and positive health outcomes? A systematic review of the literature. AB - OBJECTIVE: To evaluate what is known about the relative health impacts, in terms of nutrient intake and health outcomes, of diets with reduced greenhouse gas emissions (GHGE). DESIGN: We systematically reviewed the results of published studies that link GHGE of dietary patterns to nutritional content or associated consequences for health. SETTING: We included studies published in English in peer-reviewed journals that included data on actual and modelled diets and enabled a matched comparison of GHGE with nutrient composition and/or health outcomes. SUBJECTS: Studies included used data from subjects from the general population, who had taken part in dietary surveys or prospective cohort studies. RESULTS: We identified sixteen eligible studies, with data on 100 dietary patterns. We present the results as dietary links between GHGE reduction and impact on nutrients to limit (n 151), micronutrient content (n 158) and health outcomes (n 25). The results were highly heterogeneous. Across all measures of 'healthiness', 64 % (n 214) of dietary links show that reduced GHGE from diets were associated with worse health indicators. However, some trends emerged. In particular, reduced saturated fat and salt are often associated with reduced GHGE in diets that are low in animal products (57/84). Yet these diets are also often high in sugar (38/55) and low in essential micronutrients (129/158). CONCLUSIONS: Dietary scenarios that have lower GHGE compared with average consumption patterns may not result in improvements in nutritional quality or health outcomes. Dietary recommendations for reduced GHGE must also address sugar consumption and micronutrient intake. PMID- 26975580 TI - Overexpression of angiotensin II type 1 receptor in breast cancer cells induces epithelial-mesenchymal transition and promotes tumor growth and angiogenesis. AB - The angiotensin II type I receptor (AGTR1) has been implicated in diverse aspects of human disease, from the regulation of blood pressure and cardiovascular homeostasis to cancer progression. We sought to investigate the role of AGTR1 in cell proliferation, epithelial-mesenchymal transition (EMT), migration, invasion, angiogenesis and tumor growth in the breast cancer cell line MCF7. Stable overexpression of AGTR1 was associated with accelerated cell proliferation, concomitant with increased expression of survival factors including poly(ADP ribose) polymerase (PARP) and X-linked inhibitor of apoptosis (XIAP), as well as extracellular signal-regulated kinase (ERK) activation. AGTR1-overexpressing MCF7 cells were more aggressive than their parent line, with significantly increased activity in migration and invasion assays. These observations were associated with changes in EMT markers, including reduced E-cadherin expression and increased p-Smad3, Smad4 and Snail levels. Treatment with the AGTR1 antagonist losartan attenuated these effects. AGTR1 overexpression also accelerated tumor growth and increased Ki-67 expression in a xenograft model. This was associated with increased tumor angiogenesis, as evidenced by a significant increase in microvessels in the intratumoral and peritumoral areas, and enhanced tumor invasion, with the latter response associated with increased EMT marker expression and matrix metallopeptidase 9 (MMP-9) upregulation. In vivo administration of losartan significantly reduced both tumor growth and angiogenesis. Our findings suggest that AGTR1 plays a significant role in tumor aggressiveness, and its inhibition may have therapeutic implications. PMID- 26975581 TI - The C-terminal domain controls the mobility of Crumbs 3 isoforms. AB - The physiological function of epithelia depends on an asymmetric distribution of their membrane domains. Polarity proteins play a crucial role for distribution processes, however, little is known about their mobility in epithelial cells. In this study, we analyzed the intracellular and plasma-membrane-associated mobility of fluorescence-labeled Crb3A and Crb3B. Both variants belong to the Crumbs protein family, which control size and identity of apical membranes in epithelial cells. Fluorescence recovery after photo-bleaching measurements revealed different mobilities for the two Crb3 variants. They also differentially affected mobility and localization of the Pals1/Mpp5 protein, which binds to Crb3A but not to Crb3B. In addition, tracking of intracellular vesicles indicated that Crb3A containing vesicles are slightly more immobile than Crb3B ones. Taken together, our data revealed different intracellular mobility patterns for Crb3A and Crb3B. PMID- 26975582 TI - Interaction with epsin 1 regulates the constitutive clathrin-dependent internalization of ErbB3. AB - BACKGROUND: In contrast to other members of the EGF receptor family, ErbB3 is constitutively internalized in a clathrin-dependent manner. Previous studies have shown that ErbB3 does not interact with the coated pit localized adaptor complex 2 (AP-2), and that ErbB3 lacks two AP-2 interacting internalization signals identified in the EGF receptor. Several other clathrin-associated sorting proteins which may recruit cargo into coated pits have, however, been identified, and the study was performed to identify adaptors needed for constitutive internalization of ErbB3. METHODS: A high-throughput siRNA screen was used to identify adaptor proteins needed for internalization of ErbB3. Upon knock-down of candidate proteins internalization of ErbB3 was identified using an antibody based internalization assay combined with automatic fluorescence microscopy. RESULTS: Among 29 candidates only knock-down of epsin 1 turned out to inhibit ErbB3. Epsin 1 has ubiquitin interacting motifs (UIMs) and we show that ErbB3 interacts with an epsin 1 deletion mutant containing these UIMs. In support of an ErbB3-epsin 1 UIM dependent interaction, we show that ErbB3 is constitutively ubiquitinated, but that both ubiquitination and the ErbB3-epsin 1 interaction increase upon ligand binding. CONCLUSION: Altogether the results are consistent with a model whereby both constitutive and ligand-induced internalization of ErbB3 are regulated through interaction with epsin 1. GENERAL SIGNIFICANCE: Internalization is an important regulator of growth factor receptor mediated signaling and the current study identify mechanisms regulating plasma membrane turnover of ErbB3. PMID- 26975583 TI - Rapamycin requires AMPK activity and p27 expression for promoting autophagy dependent Tsc2-null cell survival. AB - Tuberous sclerosis complex (TSC) disease results from inactivation of the TSC1 or TSC2 gene, and is characterized by benign tumors in several organs. Because TSC tumorigenesis correlates with hyperactivation of mTORC1, current therapies focus on mTORC1 inhibition with rapamycin or its analogs. Rapamycin-induced tumor shrinkage has been reported, but tumor recurrence occurs on withdrawal from rapamycin. Autophagy has been associated with development of TSC tumors and with tumor cell survival during rapamycin treatment. mTORC1 and AMPK directly inhibit and activate autophagy, respectively. AMPK is hyperactivated in TSC cells and tumors, and drives cytoplasmic sequestration of the cell-cycle inhibitor p27KIP (p27). Whether AMPK and p27 are involved in rapamycin-induced autophagy and survival of TSC cells remain unexplored. Here, we show that inhibition of AMPK by compound C or by shRNA-mediated depletion of LKB1 reduces activation of autophagy by rapamycin in Tsc2-null cells. Similarly, shRNA-mediated depletion of p27 inhibited rapamycin-induced autophagy. In support of p27 lying downstream of AMPK on the activation of autophagy in Tsc2-null cells, a p27 mutant that preferentially localizes in the cytosol recovered the effect of rapamycin on autophagy in both p27- and LKB1-depleted cells, but a nuclear p27 mutant was inactive. Finally, we show that p27-dependent activation of autophagy is involved in Tsc2-null cell survival under rapamycin treatment. These results indicate that an AMPK/p27 axis is promoting a survival mechanism that could explain in part the relapse of TSC tumors treated with rapamycin, exposing new avenues for designing more efficient treatments for TSC patients. PMID- 26975584 TI - Focal cortical dysplasia, microcephaly and epilepsy in a boy with 1q21.1-q21.3 duplication. AB - The recent advance of new molecular technologies like array - Comparative Genomic Hybridization has fostered the detection of genomic imbalances in subjects with intellectual disability, epilepsy, and/or congenital anomalies. Though some of the rearrangements are relatively frequent, their consequences on phenotypes can be strongly variable. We report on a boy harbouring a de novo 8.3 Mb duplication of chromosome 1q21.1-q21.3 whose complex unusual phenotype deserves attention, due to the presence of focal cortical dysplasia, microcephaly, and epilepsy. Loss of-function (LOF) effects of genes associated with human disease involved in the rearrangement have been only partially established, and have not been previously associated with brain malformations in several deletion syndromes. Less is known, instead, about the consequences of their duplication on neuronal migration and brain development process. Further advance in neuroimaging and genetic research will help in defining their actual role in neurodevelopment and cerebral cortex malformations. PMID- 26975585 TI - Genetic predisposition and hematopoietic malignancies in children: Primary immunodeficiency. AB - It is assumed that patients with some forms of primary immunodeficiency (PID) have a markedly increased risk of cancer as compared to the healthy population. This increased incidence is seen in children as well as adult patients. The type of malignancy depends on the underlying genetic defect, but hematopoietic cancers are most frequent in almost any subtype of PID. In some patients, a malignancy can even be the first or only symptom of an underlying genetic defect. The possibility of an underlying PID is important for the pediatric oncologist as this might influence the treatment. Also, patients with a known PID should be screened for the occurrence of cancer. It is therefore important to raise awareness on this subject among clinicians involved in the treatment of children with cancer as well as in the treatment of children with PID. PMID- 26975586 TI - Oxytocin (OT) and arginine-vasopressin (AVP) act on OT receptors and not AVP V1a receptors to enhance social recognition in adult Syrian hamsters (Mesocricetus auratus). AB - Social recognition is a fundamental requirement for all forms of social relationships. A majority of studies investigating the neural mechanisms underlying social recognition in rodents have investigated relatively neutral social stimuli such as juveniles or ovariectomized females over short time intervals (e.g., 2h). The present study developed a new testing model to study social recognition among adult males using a potent social stimulus. Flank gland odors are used extensively in social communication in Syrian hamsters and convey important information such as dominance status. We found that the recognition of flank gland odors after a 3min exposure lasted for at least 24h, substantially longer than the recognition of other social cues in rats and mice. Intracerebroventricular injections of OT and AVP prolonged the recognition of flank gland odor for up to 48h. Selective OTR but not V1aR agonists, mimicked these enhancing effects of OT and AVP. Similarly, selective OTR but not V1aR antagonists blocked recognition of the odors after 20min. In contrast, the recognition of non-social stimuli was not blocked by either the OTR or the V1aR antagonists. Our findings suggest both OT and AVP enhance social recognition via acting on OTRs and not V1aRs and that the recognition enhancing effects of OT and AVP are limited to social stimuli. PMID- 26975587 TI - Towards understanding of heat effects in metallic glasses on the basis of macroscopic shear elasticity. AB - It is shown that all heat effects taking place upon annealing of a metallic glass within the glassy and supercooled liquid states, i.e. heat release below the glass transition temperature and heat absorption above it, as well as crystallization-induced heat release, are related to the macroscopic shear elasticity. The underlying physical reason can be understood as relaxation in the system of interstitialcy-type "defects" (elastic dipoles) frozen-in from the melt upon glass production. PMID- 26975588 TI - Glucose variability, HbA1c and microvascular complications. AB - Microvascular complications in diabetes are associated with poor long-term diabetes control as measured by HbA1c levels. Glucose fluctuations are related to oxidative stress, endothelial dysfunction, and inflammation, factors traditionally associated with the pathogenesis of vascular damage. Glucose variability has been associated with macrovascular disease in some studies but any association with microvascular disease remains controversial. This overview summarizes recent findings in the field of glucose variability and its possible relationship with retinopathy, nephropathy and neuropathy. It is concluded that randomized prospective follow-up trials could possibly help estimate whether short-term glucose variability should be considered as an independent risk factor for microvascular complications in diabetes. PMID- 26975589 TI - Biotin and Thiamine Responsive Basal Ganglia Disease--A vital differential diagnosis in infants with severe encephalopathy. AB - We report two siblings of Swedish origin with infantile Biotin and Thiamine Responsive Basal Ganglia Disease (BTRBG). CASE REPORT: Initial symptoms were in both cases lethargia, with reduced contact and poor feeding from the age of 5 weeks. Magnetic resonance imaging showed altered signal in the basal ganglia, along with grey and white matter abnormalities. The diagnosis BTRBG was not recognized in the first sibling who died at the age of 8 weeks. The second sibling was started on biotin and thiamine immediately upon development of symptoms, leading to clinical improvement and partial reversion of the magnetic resonance imaging findings. Genetic analysis of the SLC19A3 gene identified two mutations, c.74dupT and c.1403delA, carried in compound heterozygous form in both boys, each inherited from one parent. COMMENTS: The first mutation has previously been described in children with BTRBG, and the second mutation is novel. Although the clinical picture in BTRGB is very severe it is also rather unspecific and the diagnosis may be missed. CONCLUSION: This report highlights the importance of considering biotin and thiamine treatment also in a European infant born to non consanguineous parents, who presents with symptoms of acute/subacute encephalopathy. PMID- 26975591 TI - Not a Stone Unturned. PMID- 26975590 TI - Early versus Late Parenteral Nutrition in Critically Ill Children. AB - BACKGROUND: Recent trials have questioned the benefit of early parenteral nutrition in adults. The effect of early parenteral nutrition on clinical outcomes in critically ill children is unclear. METHODS: We conducted a multicenter, randomized, controlled trial involving 1440 critically ill children to investigate whether withholding parenteral nutrition for 1 week (i.e., providing late parenteral nutrition) in the pediatric intensive care unit (ICU) is clinically superior to providing early parenteral nutrition. Fluid loading was similar in the two groups. The two primary end points were new infection acquired during the ICU stay and the adjusted duration of ICU dependency, as assessed by the number of days in the ICU and as time to discharge alive from ICU. For the 723 patients receiving early parenteral nutrition, parenteral nutrition was initiated within 24 hours after ICU admission, whereas for the 717 patients receiving late parenteral nutrition, parenteral nutrition was not provided until the morning of the 8th day in the ICU. In both groups, enteral nutrition was attempted early and intravenous micronutrients were provided. RESULTS: Although mortality was similar in the two groups, the percentage of patients with a new infection was 10.7% in the group receiving late parenteral nutrition, as compared with 18.5% in the group receiving early parenteral nutrition (adjusted odds ratio, 0.48; 95% confidence interval [CI], 0.35 to 0.66). The mean (+/-SE) duration of ICU stay was 6.5+/-0.4 days in the group receiving late parenteral nutrition, as compared with 9.2+/-0.8 days in the group receiving early parenteral nutrition; there was also a higher likelihood of an earlier live discharge from the ICU at any time in the late-parenteral-nutrition group (adjusted hazard ratio, 1.23; 95% CI, 1.11 to 1.37). Late parenteral nutrition was associated with a shorter duration of mechanical ventilatory support than was early parenteral nutrition (P=0.001), as well as a smaller proportion of patients receiving renal-replacement therapy (P=0.04) and a shorter duration of hospital stay (P=0.001). Late parenteral nutrition was also associated with lower plasma levels of gamma-glutamyltransferase and alkaline phosphatase than was early parenteral nutrition (P=0.001 and P=0.04, respectively), as well as higher levels of bilirubin (P=0.004) and C-reactive protein (P=0.006). CONCLUSIONS: In critically ill children, withholding parenteral nutrition for 1 week in the ICU was clinically superior to providing early parenteral nutrition. (Funded by the Flemish Agency for Innovation through Science and Technology and others; ClinicalTrials.gov number, NCT01536275.). PMID- 26975592 TI - The Business of Bundling: Joining Forces on Joint Replacement. AB - A mandated bundled-payment program for joint replacement is in place in several regions across the country, and practitioners such as pharmacists are still sorting out their roles in this federal initiative. To get involved, pharmacists need to establish connections with area hospitals and physician groups to promote and document their ability to manage medications, reduce and eliminate medication related problems and rehospitalizations, and work with patients to maximize adherence and improve communication for those undergoing hip and knee replacement. PMID- 26975593 TI - Antidepressant-Induced Hyponatremia in Older Adults. AB - OBJECTIVE: To describe the prevalence of hyponatremia in older adults related to antidepressive agents and identify potential alternative options in older adults with a low-baseline serum sodium concentration and/or when a patient has experienced hyponatremia as a result of taking an antidepressant. DATA SOURCES: A PubMed search was conducted on November 10, 2015. Search terms included: antidepressive agents, antidepressive agents second-generation, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, hyponatremia, milnacipran, mirtazapine, paroxetine, reboxetine, syndrome of inappropriate antidiuretic hormone, sertraline, trazodone, venlafaxine, and vilazodone. Filters included English language. A search of product labeling was also conducted. STUDY SELECTION: Out of 363 results, 124 publications were identified and reviewed along with 11 additional references. Publications were chosen based on relevance to the review: case reports of patients 60 years of age or older or clinical investigations of the association between hyponatremia and antidepressants in older adults. DATA EXTRACTION: Hyponatremia was counted as an adverse effect if an antidepressant was the likely cause of hyponatremia, and hyponatremia was resolved after withdrawal. DATA SYNTHESIS: Antidepressant induced hyponatremia in older adults is fairly common. Selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, and mirtazapine were implicated in the majority of the case reports and clinical studies evaluating older adults. Bupropion, trazodone, and tricyclic antidepressants were implicated less often in the same literature. CONCLUSION: Given its unique mechanism of action, bupropion may be the most appropriate antidepressant for older adults at risk for antidepressant-induced hyponatremia. PMID- 26975594 TI - Antidepressant Use and Incident Urinary Incontinence: A Literature Review. AB - OBJECTIVE: To review available data examining antidepressant use and incident urinary incontinence (UI). DATA SOURCES: PubMed was used to conduct the literature search for this review. In the primary search, the term "antidepressive agents" was searched as a medical subject heading, a pharmacological action, and a keyword phrase. This choice was made so that any relevant articles would include complete results for antidepressive agents. "Antidepressive agents" was combined with the key phrase "drug-induced urinary incontinence" to complete this primary search. STUDY SELECTION: Relevant articles published in English and examining human subjects were included. DATA EXTRACTION: The study authors determined appropriateness of articles for inclusion, focusing on those examining antidepressant-associated UI. DATA SYNTHESIS: This literature review identified three cohort studies and 11 case reports examining various associations between antidepressant use and incident UI. CONCLUSION: All 11 case reports and 1 cohort study reviewed suggest an association between antidepressant use and incident UI. It remains unclear which drugs are most problematic and which patients are at greatest risk, and more data are needed to confirm an association, especially in older adults. Comprehensive medication reviews should be employed by pharmacists to identify potential medication-related causes of UI. PMID- 26975595 TI - Assessed Value of Consultant Pharmacist Services in a Home Health Care Agency. AB - OBJECTIVE: To report results of a survey administered to clinicians in a home health care agency regarding reasons for them to initiate consultation with a pharmacist working onsite at the agency and the perceived value of the interaction. DESIGN: The survey listed 16 reasons why an agency clinician commonly makes referrals and 9 questions assessing the perceived value of these services provided by the onsite consultant pharmacist. Responses were reported on a five-point Likert scale where 1 = Almost always/strongly agree and 5 = Almost never/strongly disagree. SETTING: Home health care agency in Spokane, Washington, with onsite and in-home consultant pharmacy services for 20 years via a partnership with Washington State University. PARTICIPANTS: All clinicians employed by the home health care agency. RESULTS: Twenty-eight of 101 part-time and full-time clinicians responded to the survey. Eighty-nine percent of respondents strongly agreed that it is valuable to have a consultant pharmacist onsite and pharmacy personnel serve as a helpful source of information. The most common reasons for referral were pain management, drug side effects, and drug interactions. CONCLUSION: Clinicians indicated consultant pharmacist services are beneficial and they used the consultant pharmacist primarily for pain management, drug side effects, and drug interactions, but made referrals for a wide range of reasons. This indicates that an onsite consultant pharmacist is valuable to home care providers. Further research regarding the benefit of an onsite consultant pharmacist in the home care setting is warranted. PMID- 26975597 TI - The Third Policy Arena: Standard-Setting Organizations. PMID- 26975596 TI - Prevalence of Anticholinergic Medication Use in the Program of All-Inclusive Care for the Elderly. AB - OBJECTIVES: Evaluate the prevalence of anticholinergic medication use in the Program of All-Inclusive Care for the Elderly (PACE). DESIGN: Cross-sectional, retrospective chart review. SETTING: The Basics at Jan Werner PACE, Amarillo, Texas. PARTICIPANTS: PACE participants (n = 128) and long-term care residents (n = 105) 65 years of age and older. MAIN OUTCOME MEASURE: The primary outcome was percentage of prescribed medications with anticholinergic properties and risk factors associated with prescribing: study site, gender, race, age, and creatinine clearance. RESULTS: Anticholinergic medication prescribing was significantly lower in the PACE program (2.3% of total medications vs. 3.9%; P < 0.05) as well as total medication use (12.1 medications per subject vs. 20.8; P < 0.05 in the long-term care environment). Only the long-term care study site had a significant association with anticholinergic prescribing (odds ratio = 5.04, confidence interval 2.71-9.38). PACE participants also had lower Anticholinergic Risk Scale scores (score of 0, 60.2% PACE vs. 16.2%), reduced fall rates (23.8 per month PACE vs. 66.9), and similar hospitalization rates (5.4 per month PACE vs. 5.7). CONCLUSION: PACE participants were prescribed fewer medications and had lower anticholinergic burden, which potentially lowers their risk of adverse effects. These data support the PACE interdisciplinary model by demonstrating the benefit of team care in appropriate use of medications. It provides a potential blueprint to organizations aimed at reducing potentially inappropriate medication prescribing in older adults. PMID- 26975598 TI - Visual straight-ahead preference in saccadic eye movements. AB - Ocular saccades bringing the gaze toward the straight-ahead direction (centripetal) exhibit higher dynamics than those steering the gaze away (centrifugal). This is generally explained by oculomotor determinants: centripetal saccades are more efficient because they pull the eyes back toward their primary orbital position. However, visual determinants might also be invoked: elements located straight-ahead trigger saccades more efficiently because they receive a privileged visual processing. Here, we addressed this issue by using both pro- and anti-saccade tasks in order to dissociate the centripetal/centrifugal directions of the saccades, from the straight ahead/eccentric locations of the visual elements triggering those saccades. Twenty participants underwent alternating blocks of pro- and anti-saccades during which eye movements were recorded binocularly at 1 kHz. The results confirm that centripetal saccades are always executed faster than centrifugal ones, irrespective of whether the visual elements have straight-ahead or eccentric locations. However, by contrast, saccades triggered by elements located straight ahead are consistently initiated more rapidly than those evoked by eccentric elements, irrespective of their centripetal or centrifugal direction. Importantly, this double dissociation reveals that the higher dynamics of centripetal pro-saccades stem from both oculomotor and visual determinants, which act respectively on the execution and initiation of ocular saccades. PMID- 26975599 TI - Toward automated e-cigarette surveillance: Spotting e-cigarette proponents on Twitter. AB - BACKGROUND: Electronic cigarettes (e-cigarettes or e-cigs) are a popular emerging tobacco product. Because e-cigs do not generate toxic tobacco combustion products that result from smoking regular cigarettes, they are sometimes perceived and promoted as a less harmful alternative to smoking and also as means to quit smoking. However, the safety of e-cigs and their efficacy in supporting smoking cessation is yet to be determined. Importantly, the federal drug administration (FDA) currently does not regulate e-cigs and as such their manufacturing, marketing, and sale is not subject to the rules that apply to traditional cigarettes. A number of manufacturers, advocates, and e-cig users are actively promoting e-cigs on Twitter. OBJECTIVE: We develop a high accuracy supervised predictive model to automatically identify e-cig "proponents" on Twitter and analyze the quantitative variation of their tweeting behavior along popular themes when compared with other Twitter users (or tweeters). METHODS: Using a dataset of 1000 independently annotated Twitter profiles by two different annotators, we employed a variety of textual features from latest tweet content and tweeter profile biography to build predictive models to automatically identify proponent tweeters. We used a set of manually curated key phrases to analyze e-cig proponent tweets from a corpus of over one million e-cig tweets along well known e-cig themes and compared the results with those generated by regular tweeters. RESULTS: Our model identifies e-cig proponents with 97% precision, 86% recall, 91% F-score, and 96% overall accuracy, with tight 95% confidence intervals. We find that as opposed to regular tweeters that form over 90% of the dataset, e-cig proponents are a much smaller subset but tweet two to five times more than regular tweeters. Proponents also disproportionately (one to two orders of magnitude more) highlight e-cig flavors, their smoke-free and potential harm reduction aspects, and their claimed use in smoking cessation. CONCLUSIONS: Given FDA is currently in the process of proposing meaningful regulation, we believe our work demonstrates the strong potential of informatics approaches, specifically machine learning, for automated e-cig surveillance on Twitter. PMID- 26975600 TI - Analysis of microarray leukemia data using an efficient MapReduce-based K-nearest neighbor classifier. AB - Microarray-based gene expression profiling has emerged as an efficient technique for classification, prognosis, diagnosis, and treatment of cancer. Frequent changes in the behavior of this disease generates an enormous volume of data. Microarray data satisfies both the veracity and velocity properties of big data, as it keeps changing with time. Therefore, the analysis of microarray datasets in a small amount of time is essential. They often contain a large amount of expression, but only a fraction of it comprises genes that are significantly expressed. The precise identification of genes of interest that are responsible for causing cancer are imperative in microarray data analysis. Most existing schemes employ a two-phase process such as feature selection/extraction followed by classification. In this paper, various statistical methods (tests) based on MapReduce are proposed for selecting relevant features. After feature selection, a MapReduce-based K-nearest neighbor (mrKNN) classifier is also employed to classify microarray data. These algorithms are successfully implemented in a Hadoop framework. A comparative analysis is done on these MapReduce-based models using microarray datasets of various dimensions. From the obtained results, it is observed that these models consume much less execution time than conventional models in processing big data. PMID- 26975601 TI - High Failure Rate of Modular Exchange With a Specific Design of a Constrained Liner in High-Risk Patients Undergoing Revision Total Hip Arthroplasty. AB - BACKGROUND: Addressing recurrent instability in patients with poor bone stock and inadequate abductor tensioning remains a challenge in revision total hip arthroplasty. One treatment method is implantation of a constrained liner. The purpose of this study was to determine clinical outcomes, redislocation rate, and revisions of a focally constrained liner in a high-risk patient cohort. METHODS: Fifty-eight hips between 2008 and 2011 underwent implantation of a focally constrained liner. Nineteen were placed concurrent with acetabular component revision and 39 were placed into a well-fixed acetabular shell. Mean age was 69 years and mean number of previous ipsilateral hip surgeries was 4.2. At mean follow-up of 3.5 years, we analyzed clinical outcomes, redislocation, and revisions. RESULTS: Mean Harris Hip Scores was 74. Fourteen hips (24%) were revised and 3 hips (5%) required reoperation at final follow-up. Eleven hips (19%) redislocated at a mean time to dislocation of 12.2 months; 31% (11 of 36 patients) that underwent modular exchange specifically for instability redislocated. Risk factors for redislocation included number of previous surgeries (P = .013), implantation of a 28 mm femoral head (hazards ratio 12.8), revision indication of instability (P = .04), and modular exchange with constrained liner implantation without acetabular shell revision (P = .01). CONCLUSION: Implantation of a focally constrained liner in revision total hip arthroplasty for recurrent instability has a high failure rate, especially with a modular exchange. Although concurrent acetabular revision had a lower redislocation rate, the decision to revise a well-fixed cup should be weighed with potential complications associated with cup revision. PMID- 26975602 TI - Major Complications and Transfusion Rates After Hemiarthroplasty and Total Hip Arthroplasty for Femoral Neck Fractures. AB - BACKGROUND: Postoperative complications and perioperative transfusions are common after hemiarthroplasty or total hip arthroplasty (THA) and can lead to increased morbidity and mortality. METHODS: The National Surgical Quality Improvement Program Database was queried to compare 30-day major complications and perioperative transfusions after femoral neck fractures. RESULTS: A total of 4058 patients were included in the study: 3192 were treated with hemiarthroplasty and 866 with THA. Multivariable logistic regression analysis revealed that having a THA was not an independent risk factor for major complications (odds ratio = 0.8, P = .18) but was an independent risk factor for requiring transfusions (odds ratio = 1.68, P < .001). CONCLUSION: The risk of major complications is influenced by patient factors rather than the choice of procedure. However, THA was a risk factor for transfusions after controlling for all other variables. PMID- 26975603 TI - Characterization of long-range functional connectivity in epileptic networks by neuronal spike-triggered local field potentials. AB - OBJECTIVE: Quantifying the relationship between microelectrode-recorded multi unit activity (MUA) and local field potentials (LFPs) in distinct brain regions can provide detailed information on the extent of functional connectivity in spatially widespread networks. These methods are common in studies of cognition using non-human animal models, but are rare in humans. Here we applied a neuronal spike-triggered impulse response to electrophysiological recordings from the human epileptic brain for the first time, and we evaluate functional connectivity in relation to brain areas supporting the generation of seizures. APPROACH: Broadband interictal electrophysiological data were recorded from microwires adapted to clinical depth electrodes that were implanted bilaterally using stereotactic techniques in six presurgical patients with medically refractory epilepsy. MUA and LFPs were isolated in each microwire, and we calculated the impulse response between the MUA on one microwire and the LFPs on a second microwire for all possible MUA/LFP pairs. Results were compared to clinical seizure localization, including sites of seizure onset and interictal epileptiform discharges. MAIN RESULTS: We detected significant interictal long range functional connections in each subject, in some cases across hemispheres. Results were consistent between two independent datasets, and the timing and location of significant impulse responses reflected anatomical connectivity. However, within individual subjects, the spatial distribution of impulse responses was unique. In two subjects with clear seizure localization and successful surgery, the epileptogenic zone was associated with significant impulse responses. SIGNIFICANCE: The results suggest that the spike-triggered impulse response can provide valuable information about the neuronal networks that contribute to seizures using only interictal data. This technique will enable testing of specific hypotheses regarding functional connectivity in epilepsy and the relationship between functional properties and imaging findings. Beyond epilepsy, we expect that the impulse response could be more broadly applied as a measure of long-range functional connectivity in studies of cognition. PMID- 26975604 TI - Endovascular Repair for Ruptured Abdominal Aortic Aneurysms has Improved Outcomes Compared to Open Surgical Repair. AB - INTRODUCTION: Ruptured abdominal aortic aneurysm (rAAA) remains a critical diagnosis, and research is needed to address outcomes following surgical repair. The purpose of this study was to compare nationwide outcomes for patients who received either endovascular repair (EVAR) or open surgical repair (OSAR) for rAAA. METHODS: The Medicare Provider Analysis and Review file from 2005 to 2009 was used to identify patients diagnosed with rAAA and treated with either EVAR or OSAR. Those patients with both procedures were excluded. Primary outcomes included mortality, postoperative complications, and readmission rates. Secondary outcomes included hospital resource utilization and length of stay (LOS). RESULTS: A total of 8480 patients with rAAA who underwent EVAR (n = 1939) or OSAR (n = 6541) were identified. On multivariate regression, the likelihood of dying in the hospital after OSAR compared to EVAR was significantly greater (odds ratio [OR] = 1.95; 95% confidence interval [CI] = 1.74-2.18). There was significantly greater frequency of postoperative complications after OSAR compared to EVAR (OR = 2.1, 95%CI = 1.86-2.37, P < .0001). Freedom from readmission after OSAR was significantly greater than that after EVAR. Total hospital cost for all services after EVAR was greater than that after OSAR (US$100 875 vs US$89 035; P < .0001), but intensive care unit (ICU) cost for EVAR was significantly less than that for OSAR (US$5516 vs US$8600; P < .0001). Total hospital and ICU LOS were shorter in EVAR compared to OSAR (P < .0001 for both). DISCUSSION: EVAR for rAAA has shown mortality benefits over OSAR as well as reduced ICU and total LOS. This data suggest EVAR is associated with a greater survival benefit, fewer postoperative complications, and may help improve hospital resource utilization. PMID- 26975605 TI - Hostile Neck in Abdominal Aortic Aneurysms: Does it Still Exist? PMID- 26975606 TI - Management of Iatrogenic Pseudoaneurysms in Patients Undergoing Coronary Artery Bypass Grafting. AB - OBJECTIVE: A plethora of papers have been written regarding postcatheterization femoral pseudoaneurysms. However, literature is lacking on pseudoaneurysmal management in patients undergoing coronary artery bypass grafting (CABG). Thus, we examined if pseudoaneurysms with subsequent CABG can be managed with the same strategies as those not exposed to the intense anticoagulation accompanying CABGs. METHODS: During a 14-year study period, we retrospectively examined femoral iatrogenic pseudoaneurysms (IPSAs) diagnosed postheart catheterization in patients having a subsequent CABG. Patient information was obtained from electronic medical records and included pseudoaneurysm characteristics, treatment, and resolution. Outcomes of interest included the occurrence of IPSA treatment failures and complications. RESULTS: In the 66 patients (mean age, 66 +/- 11 years, 46% male) meeting inclusion criteria, mean dose of heparin received during the CABG procedure was 34 000 +/- 23 000 units. The IPSA size distribution was the following: 17% of IPSAs measured <1 cm, 55% between 1 and 3 cm, and 21% measured >3 cm. Pseudoaneurysms were managed with compression, duplex-guided thrombin injection, and surgical repair (1%, 27%, and 26% of cases, respectively). Thrombin injection and surgical repair were 100% effective at treating pseudoaneurysms, with 1 patient experiencing a surgical site infection postsurgical repair. Observation-only management was employed in 30 (45%) patients. Nine of 30 patients with no intervention beyond observation had duplex documented resolution/thrombosis during follow-up. One patient initially managed by observation required readmission and surgical repair of an enlarging pseudoaneurysm (6 cm growth) following CABG. CONCLUSION: Management of pseudoaneurysms in patients prior to CABG should be similar to those patients not undergoing intense anticoagulation. In appropriate cases, small aneurysms can be safely observed, while thrombin injections are effective and safe as well. Thus, routine open surgical repair is not routinely required in patients with femoral pseudoaneurysms at time of CABG. PMID- 26975607 TI - Ehlers-Danlos Syndrome Type IV: A Case Report. AB - Ehlers-Danlos syndrome (EDS) encompasses a group of rare genetic connective tissue disorders. The vascular type (type IV) poses the most serious risk to patients. Diagnosis is usually difficult, especially if patients lack a family history. Life-threatening vascular emergency such as dissection or rupture can be the first presenting symptom. Management of the disease can pose a clinical challenge due to the emergency of presentation, tissue friability, and lack of clear management recommendations. We report a unique case of a 40-year-old man who presented with a ruptured celiac artery and a strong family history of EDS. This case highlights the difficulties and complications associated with treating this uncommon and serious disease. PMID- 26975609 TI - Application of empirical model to predict background metal concentration in mixed carbonate-alumosilicate sediment (Adriatic Sea, Croatia). AB - A 96m long sediment core (S10-33) from the Mali Ston Channel (Adriatic Sea) showed large natural variation in carbonate share (between 1% and 95%) and concentration of elements. These variations indicate rather significant changes in fine-grained sediment that was deposited in this area during Younger Pleistocene and Holocene. Unaffected by anthropogenic influence, sediment in the core was used to determine background concentration of trace elements in sediment with various carbonate content. Here we propose a method of the normalization of trace elements to carbonate share, in order to assess natural/background concentration of metals in sediments consisting of carbonates and alumosilicates in various proportions. Six characteristic metals (Co, Cr, Cu, Ni, Pb, and Zn) that were normalized to carbonate share showed very good correlation, with much higher background concentrations in alumosilicate than in carbonate end member. Simple formulas were proposed to easily determine background concentration of these elements, in coastal and shelf depositional environments with mixed carbonate-alumosilicate sediments. PMID- 26975608 TI - The domain-specific and domain-general relationships of visuospatial working memory to reasoning ability. AB - The degree to which visuospatial working memory (VSWM) is separable from working memory in general is an open question. On one hand, the construct is often researched as a unitary, domain-specific system. On the other, there is evidence that VWSM shares a common processing component with verbal memory. One might interpret this shared component as domain-general attention. We used confirmatory factor analysis to demonstrate that VSWM shares a domain-general component with verbal memory tasks and has a domain-specific component that is independent of verbal memory. Furthermore, the domain-general component was found to correlate with reasoning ability in both the visuospatial and verbal domains. The domain specific component only correlated with reasoning ability when the tests had a strong visuospatial component. We argue that theories of VSWM need to place greater emphasis on its multiply determined nature. PMID- 26975610 TI - Metal bioaccumulation and physiological condition of the Pacific oyster (Crassostrea gigas) reared in two shellfish basins and a marina in Normandy (northwest France). AB - A 5-month experiment combining a geochemical survey of metals with a bioaccumulation study in batches of Crassostrea gigas was conducted in two shellfish farming areas and a marina in Normandy (France). Various endpoints at different levels of biological organization were studied. ROCCH data showed differences in biota contamination between the two shellfish areas but the present study revealed only slight differences in metallic contamination and biomarkers. By contrast, significantly different values were recorded in the marina in comparison with the two other sites. Indeed, higher levels of Cd, Cu and Zn were measured in the oysters from the marina, and these oysters also showed a poorer physiological condition (e.g., condition index, histopathological alterations and neutral lipid content). For coastal monitoring, the multi biomarker approach coupled with an assessment of metallic contamination in biota appeared to be suitable for discriminating spatial differences in environmental quality after only a few months of exposure. PMID- 26975612 TI - Long-term fluctuations in Cystoseira populations along the west Istrian Coast (Croatia) related to eutrophication patterns in the northern Adriatic Sea. AB - An exploration of historical data suggested that eutrophication patterns might drive long-term fluctuations in Cystoseira populations along the west Istrian Coast (northern Adriatic Sea, Croatia). The regimes of northern Italian rivers, which flow approximately 100km west of the study area, mainly modulate the eutrophication levels of the northern Adriatic Sea. A regression of Cystoseira populations from the 1970s through the 1990s corresponded to increased levels of eutrophication in the study area. During the late 1990s, the density of sea urchins, which are efficacious macroalgal predators, decreased, likely due to an intense formation of pelagic mucilage aggregates that resulted in mass mortality episodes of macrozoobenthic species. During the 2000-2013 period, an oligotrophication of the northern Adriatic formed the basis for the recovery of Cystoseira taxa, whose abundances from 2009 to 2013 were similar to those characterising the most flourishing Mediterranean Cystoseira assemblages. PMID- 26975611 TI - Seasonal distribution of metals in vertical and horizontal profiles of sheltered and exposed beaches on Polish coast. AB - The distribution of alkali and heavy metals in coastal sediments of three Polish beaches was assessed. In all locations there are sandy beaches of different characteristics according to the anthropogenic impact and degree of sheltering. Core sediments collected in Czolpino and Ustka were characterized by the highest concentration of Cd, Ag, Ba, and Al, Cu, Cr, Bi, Na, respectively. Among the alkaline metals core sediments were the most abundant with Ca, Bi, Mg and Na, presenting almost stable decreasing order in all beaches. The majority of dredge material collected can be classified as light or trace contaminated by Cr, Cu, Zn, Cd and Hg. An abundance of mineralogical components in core sediments in Ustka increases in Summer and Autumn, while in Puck is stable throughout the year. The content of studied metals in core sediments collected in three Polish beaches changes both in the vertical and horizontal profiles of the beach. PMID- 26975613 TI - Combined nutrient and macroalgae loads lead to response in seagrass indicator properties. AB - Excess nutrients are potential factors that drive phase shifts from seagrasses to macroalgae. We carried out a manipulative field experiment to study the effects of macroalgae Ulva pertusa loading and nutrient addition to the water column on the nitrogen (N) and carbon (C) contents (i.e., fast indicators) as well as on the morphology and structure (i.e., slow indicators) of Zostera marina. Our results showed rapid impact of increased macroalgae and nutrient load on Z. marina C/N ratios. Also, macroalgae addition resulted in a trend of decreasing belowground biomass of seagrasses, and nutrient load significantly decreased above to belowground biomass ratio. Although some morphological/structural variables showed relatively fast responses, the effects of short-term disturbance by macroalgae and nutrients were less often significant than on physiological variables. Monitoring of seagrass physiological indicators may allow for early detection of eutrophication, which may initiate timely management interventions to avert seagrass loss. PMID- 26975614 TI - Nightmare frequency in adults with attention-deficit hyperactivity disorder. AB - Nightmare frequency in adult ADHD patients has not yet been studied systematically. In a sample of 65 patients, it could be shown that nightmare frequency was elevated in ADHD patients compared to a sample representative for Germany. Frequent nightmares (once a week or more often) were reported by 4.62 % of the patients and 1.77 % of the controls. This increase was neither explained by the increased dream recall in general nor by the presence of a comorbid mental disorder. Questions about nightmares should be included in the diagnostic procedures for ADHD patients, and it should be tested whether well-established nightmare treatment strategies like imagery rehearsal treatment might be beneficial to those patients with nightmares. PMID- 26975615 TI - A unified model for two modes of bursting in GnRH neurons. AB - Gonadotropin-releasing hormone (GnRH) neurons exhibit at least two intrinsic modes of action potential burst firing, referred to as parabolic and irregular bursting. Parabolic bursting is characterized by a slow wave in membrane potential that can underlie periodic clusters of action potentials with increased interspike interval at the beginning and at the end of each cluster. Irregular bursting is characterized by clusters of action potentials that are separated by varying durations of interburst intervals and a relatively stable baseline potential. Based on recent studies of isolated ionic currents, a stochastic Hodgkin-Huxley (HH)-like model for the GnRH neuron is developed to reproduce each mode of burst firing with an appropriate set of conductances. Model outcomes for bursting are in agreement with the experimental recordings in terms of interburst interval, interspike interval, active phase duration, and other quantitative properties specific to each mode of bursting. The model also shows similar outcomes in membrane potential to those seen experimentally when tetrodotoxin (TTX) is used to block action potentials during bursting, and when estradiol transitions cells exhibiting slow oscillations to irregular bursting mode in vitro. Based on the parameter values used to reproduce each mode of bursting, the model suggests that GnRH neurons can switch between the two through changes in the maximum conductance of certain ionic currents, notably the slow inward Ca(2+) current I s, and the Ca(2+) -activated K(+) current I KCa. Bifurcation analysis of the model shows that both modes of bursting are similar from a dynamical systems perspective despite differences in burst characteristics. PMID- 26975617 TI - Comment on "Safety and tolerability of Kinesio(r) Taping in patients with arm lymphedema: medical device clinical study". PMID- 26975616 TI - WINGLESS (WNT) signaling is a progesterone target for rat uterine stromal cell proliferation. AB - Preparation of mammalian uterus for embryo implantation requires a precise sequence of cell proliferation. In rodent uterus, estradiol stimulates proliferation of epithelial cells. Progesterone operates as a molecular switch and redirects proliferation to the stroma by down-regulating glycogen synthase kinase-3beta (GSK-3beta) and stimulating beta-catenin accumulation in the periluminal stromal cells. In this study, the WNT signal involved in the progesterone-dependent proliferative switch was investigated. Transcripts of four candidate Wnt genes were measured in the uteri from ovariectomized (OVX) rats, progesterone-pretreated (3 days of progesterone, 2mg/daily) rats, and progesterone-pretreated rats given a single dose (0.2ug) of estradiol. The spatial distribution of the WNT proteins was determined in the uteri after the same treatments. Wnt5a increased in response to progesterone and the protein emerged in the periluminal stromal cells of progesterone-pretreated rat uteri. To investigate whether WNT5A was required for proliferation, uterine stromal cell lines were stimulated with progesterone (1uM) and fibroblast growth factor (FGF, 50ng/mL). Proliferating stromal cells expressed a two-fold increase in WNT5A protein at 12h post stimulation. Stimulated stromal cells were cultured with actinomycin D (25ug/mL) to inhibit new RNA synthesis. Relative Wnt5a expression increased at 4 and 6 h of culture, suggesting that progesterone plus FGF preferentially increased Wnt5a mRNA stability. Knockdown of Wnt5a in uterine stromal cell lines inhibited stromal cell proliferation and decreased Wnt5a mRNA. The results indicate that progesterone initiates and synchronizes uterine stromal cell proliferation by increasing WNT5A expression and signaling. PMID- 26975618 TI - Pelvic floor electrophysiology in spinal cord injury. AB - OBJECTIVE: The study aimed to investigate sacral peripheral nerve function and continuity of pudendal nerve in patients with chronic spinal cord injury (SCI) using pelvic floor electrophysiological tests. METHODS: Twelve patients with low cervical or thoracic SCI were prospectively included. Quantitative external anal sphincter (EAS) muscle electromyography (EMG), pudendal nerve terminal motor latency (PNTML) testing, bulbocavernosus reflex (BCR) testing and pudendal short latency somatosensory-evoked potential (SEP) measurement were performed. RESULTS: In EAS muscle EMG, two patients had abnormal increased spontaneous activity and seven prolonged motor unit potential duration. PNTML was normal in 10 patients. BCR was present with normal latency in 11 patients and with prolonged latency in one. The second component of BCR could be recorded in four patients. SEPs showed absent cortical responses in 11 patients and normal latency in one. CONCLUSIONS: Pudendal nerve and sacral lower motor neuron involvement are significantly associated with chronic SCI, most prominently in EAS muscle EMG. The frequent finding of normal PNTML latencies supports earlier concerns on the utility of this test; however, BCR and pudendal SEPs may have clinical relevance. SIGNIFICANCE: As intact peripheral nerves including pudendal nerve are essential for efficient supportive therapies, pelvic floor electrophysiological testing prior to these interventions is highly recommended. PMID- 26975619 TI - A brief update on potential molecular mechanisms underlying antimicrobial and wound-healing potency of snake venom molecules. AB - Infectious diseases remain a significant cause of morbidity and mortality worldwide. A wide range of diverse, novel classes of natural antibiotics have been isolated from different snake species in the recent past. Snake venoms contain diverse groups of proteins with potent antibacterial activity against a wide range of human pathogens. Some snake venom molecules are pharmacologically attractive, as they possess promising broad-spectrum antibacterial activities. Furthermore, snake venom proteins (SVPs)/peptides also bind to integrins with high affinity, thereby inhibiting cell adhesion and accelerating wound healing in animal models. Thus, SVPs are a potential alternative to chemical antibiotics. The mode of action for many antibacterial peptides involves pore formation and disruption of the plasma membrane. This activity often includes modulation of nuclear factor kappa B (NF-kappaB) activation during skin wound healing. The NF kappaB pathway negatively regulates the transforming growth factor (TGF) beta1/Smad pathway by inducing the expression of Smad7 and eventually reducing in vivo collagen production at the wound sites. In this context, SVPs that regulate the NF-kappaB signaling pathway may serve as potential targets for drug development. PMID- 26975620 TI - Gene expression profiling gut microbiota in different races of humans. AB - The gut microbiome is shaped and modified by the polymorphisms of microorganisms in the intestinal tract. Its composition shows strong individual specificity and may play a crucial role in the human digestive system and metabolism. Several factors can affect the composition of the gut microbiome, such as eating habits, living environment, and antibiotic usage. Thus, various races are characterized by different gut microbiome characteristics. In this present study, we studied the gut microbiomes of three different races, including individuals of Asian, European and American races. The gut microbiome and the expression levels of gut microbiome genes were analyzed in these individuals. Advanced feature selection methods (minimum redundancy maximum relevance and incremental feature selection) and four machine-learning algorithms (random forest, nearest neighbor algorithm, sequential minimal optimization, Dagging) were employed to capture key differentially expressed genes. As a result, sequential minimal optimization was found to yield the best performance using the 454 genes, which could effectively distinguish the gut microbiomes of different races. Our analyses of extracted genes support the widely accepted hypotheses that eating habits, living environments and metabolic levels in different races can influence the characteristics of the gut microbiome. PMID- 26975622 TI - Erratum to: The Case for Oxygen in Global Surgical Care. PMID- 26975621 TI - Depressive vulnerability, stressful life events and episode onset of major depression: a longitudinal model. AB - BACKGROUND: The nature of the relationship between depressive vulnerability (DV) and acute adversity in the etiology of major depression (MD) remains poorly understood. METHOD: Stressful life events (SLEs) and MD onsets in the last year were assessed at four waves in cohort 1 (females) and at two waves in cohort 2 (males and females) from the Virginia Adult Twin Study. Structural equation modeling was conducted in Mplus. RESULTS: In cohort 1, DV was strongly indexed by depressive episodes over the four waves (paths from +0.72 to 0.79) and predicted by SLEs in the month of their occurrence (+0.31 to 0.36). Wave-specific DV was associated both with stable DV (+0.29 to 0.33) and by forward transmission of DV from the preceding wave (+0.33 to 0.36). SLEs were predicted by stable DV (+0.29) and from SLEs in the preceding month (+0.06). As the cohort aged, MD onsets were better indexed by DV and more poorly predicted by SLEs. Parameter estimates were similar in males and females from cohort 2. In individuals with prior depressive episodes, the association between MD onset and SLEs was weakened while the prediction of SLEs from DV was substantially strengthened. We found no evidence for 'reverse causation' from MD episodes to SLEs. CONCLUSION: The interrelationship between DV and acute adversity in the etiology of MD is complex and temporally dynamic. DV impacts on MD risk both directly and indirectly through selection into high stress environments. Over time, depressive episodes become more autonomous. Both DV and SLEs transmit forward over time and therefore form clear targets for intervention. PMID- 26975623 TI - A practical proposal for solving the world's cigarette butt problem: Recycling in fired clay bricks. AB - The disposal and littering of cigarette butts (CBs) is a serious environmental problem. Trillions of cigarettes are produced every year worldwide, resulting in millions of tonnes of toxic waste being dumped into the environment in the form of cigarette butts. As CBs have poor biodegradability, it can take many years for them to break down. This paper reviews and presents some of the results of a study on the recycling of CBs into fired clay bricks. Bricks with 2.5%, 5%, 7.5%, and 10% CB content by weight were manufactured and tested, and then compared against control clay bricks with 0% CB content. The results showed that the dry density decreased by up to 30% and the compressive strength decreased by 88% in bricks with 10% CBs. The calculated compressive strength of bricks with 1% CBs was determined to be 19.53Mpa. To investigate the effect of mixing time, bricks with 7.5% CB content were manufactured with different mixing times of 5, 10, and 15min. To test the effect of heating time on the properties of CB bricks, the heating rate used during manufacturing was changed to 0.7, 2, 5, and 10 degrees Cmin(-1). Bricks with 0% and 5% CB content were fired with these heating rates. Leachate tests were carried out for bricks with 0%, 2.5%, 5%, and 10% CB content. The emissions released during firing were tested for bricks with 0% and 5% CB content using heating rates of 0.7, 2, 5, and 10 degrees Cmin(-1). The gases tested were carbon monoxide (CO), carbon dioxide (CO2), chlorine (Cl2), nitrogen oxide (NO), and hydrogen cyanide (HCN). Finally, estimations were made for the energy that could be saved by firing bricks incorporating CBs. Calculations showed that up to 58% of the firing energy could potentially be saved. Bricks were shown to be a viable solution for the disposal of CBs. They can reduce contamination caused by cigarette butts and provide a masonry construction material that can be either loadbearing or non-loadbearing, depending on the quantity of CBs incorporated. This paper proposes the use of bricks with 1% CB content throughout the brick-manufacturing industry. If bricks contained as little as 1% CB content, they would still provide a solution for the issue of CB recycling while maintaining properties very similar to those of a non-CB brick. Our calculations show that, theoretically, only 2.5% of the world's annual brick production is necessary to completely offset the worldwide, annual cigarette production. PMID- 26975624 TI - A Rasch Analysis of Assessments of Morning and Evening Fatigue in Oncology Patients Using the Lee Fatigue Scale. AB - CONTEXT: To accurately investigate diurnal variations in fatigue, a measure needs to be psychometrically sound and demonstrate stable item function in relationship to time of day. Rasch analysis is a modern psychometric approach that can be used to evaluate these characteristics. OBJECTIVES: To evaluate, using Rasch analysis, the psychometric properties of the Lee Fatigue Scale (LFS) in a sample of oncology patients. METHODS: The sample comprised 587 patients (mean age 57.3 +/- 11.9 years, 80% women) undergoing chemotherapy for breast, gastrointestinal, gynecological, or lung cancer. Patients completed the 13-item LFS within 30 minutes of awakening (i.e., morning fatigue) and before going to bed (i.e., evening fatigue). Rasch analysis was used to assess validity and reliability. RESULTS: In initial analyses of differential item function, eight of the 13 items functioned differently depending on whether the LFS was completed in the morning or in the evening. Subsequent analyses were conducted separately for the morning and evening fatigue assessments. Nine of the morning fatigue items and 10 of the evening fatigue items demonstrated acceptable goodness-of-fit to the Rasch model. Principal components analyses indicated that both morning and evening assessments demonstrated unidimensionality. Person-separation indices indicated that both morning and evening fatigue scales were able to distinguish four distinct strata of fatigue severity. CONCLUSION: Excluding four items from the morning fatigue scale and three items from the evening fatigue scale improved the psychometric properties of the LFS for assessing diurnal variations in fatigue severity in oncology patients. PMID- 26975625 TI - Effects of a Short-Term Dance Movement Therapy Program on Symptoms and Stress in Patients With Breast Cancer Undergoing Radiotherapy: A Randomized, Controlled, Single-Blind Trial. AB - CONTEXT: Integrated interventions with combined elements of body movement and psychotherapy on treatment-related symptoms in cancer patients are relatively scarce. OBJECTIVES: The aim of the present study is to investigate the effectiveness of dance movement therapy (DMT) on improving treatment-related symptoms in a randomized controlled trial. METHODS: A total of 139 Chinese patients with breast cancer awaiting adjuvant radiotherapy were randomized to DMT or control group. The intervention included six 1.5-hour DMT sessions provided twice a week over the course of radiotherapy. Self-report measures on perceived stress, anxiety, depression, fatigue, pain, sleep disturbance, and quality of life were completed before and after the three-week program. RESULTS: DMT showed significant effects on buffering the deterioration in perceived stress, pain severity, and pain interference (Cohen d = 0.34-0.36, P < 0.05). No significant intervention effects were found on anxiety, depression, fatigue, sleep disturbance, and quality of life (Cohen d = 0.01-0.20, P > 0.05). CONCLUSION: The short-term DMT program can counter the anticipated worsening of stress and pain in women with breast cancer during radiotherapy. PMID- 26975626 TI - Respiratory Factors Contributing to Exercise Intolerance in Breast Cancer Survivors: A Case-Control Study. AB - CONTEXT: Breast cancer survivors often experience activity-related dyspnea and exercise intolerance, but the underlying mechanisms remain unknown. OBJECTIVES: We evaluated physiological contributors to reduced peak oxygen uptake (VO2), with particular attention to the role of respiratory impairment. METHODS: We compared symptom assessments, respiratory and peripheral muscle strength, pulmonary function, and ventilatory responses to symptom-limited incremental treadmill exercise in 29 women who had survived breast cancer and 29 age-matched healthy controls. RESULTS: Peak VO2 was reduced more than 20%, on average, in the cancer group compared with controls (P < 0.001). Slopes of dyspnea intensity ratings over ventilation or VO2 were >50% greater in the cancer group compared to controls (P < 0.05). Women with breast cancer had lower lung diffusing capacity for carbon monoxide (DLCO), respiratory and limb muscle strength, and ventilatory thresholds during exercise compared with controls (all P < 0.05). During exercise, indices of ventilatory efficiency were similar to controls, but inspiratory capacity (IC) was lower and breathing pattern was more rapid and shallow in the cancer group (P < 0.05). The lower peak VO2 in the cancer group was associated with greater dyspnea intensity, and lower DLCO, IC and ventilatory threshold (all P < 0.05). CONCLUSION: Breast cancer survivors had greater peripheral and respiratory muscle weakness, greater reduction of IC, impaired lung diffusion, and evidence of deconditioning compared with controls. Exercise intolerance was multifactorial and correlated well with the combination of these factors as well as with exertional dyspnea. Individualized physiological testing in breast cancer survivors can identify important contributors to exercise intolerance which can be targeted for treatment. PMID- 26975627 TI - MY APPROACH to elevated cholesterol in women. PMID- 26975628 TI - Genodermatosis Affecting the Skin and Mucosa of the Head and Neck: Clinicopathologic, Genetic, and Molecular Aspect--PTEN-Hamartoma Tumor Syndrome/Cowden Syndrome. AB - PTEN hamartoma tumor syndrome refers to a spectrum of disorders caused by mutations in the phosphatase and tensin homolog (PTEN) gene. Cowden syndrome, the principal PTEN-related disorder is characterized by multiple neoplasms and hamartomas, mucosal papillomatosis, and skin lesions, trichilemmomas. Trichilemmomas and mucocutaneous papillomatous papules are one of the first signs of the disease. Early recognition of these skin lesions may help on diagnosing an underlying malignancy and early cancer screening. PMID- 26975629 TI - Xeroderma Pigmentosum. AB - Xeroderma pigmentosum (XP) is a rare disorder of defective UV-radiation induced damage repair that is characterized by photosensitivity with easy skin burning following minimal sun exposure, early freckling and development of lentiginous pigmentation along with other features of poikiloderma and a propensity for developing skin cancer at an early age. In this short review, the clinical, pathological, genetic and molecular aspects of XP are reviewed in the current literature. XP encompasses a spectrum of disease that overlaps with other diseases of DNA repair systems. In addition to cutaneous complications, patients are susceptible to eye conditions, neurodegenerative processes, central nervous system tumors and other tumors as a result of UV radiation exposure and its byproducts. Patients with XP frequently experience a shorter life span due to skin cancer and neurodegenerative sequelae, but aggressive preventative measures to minimize UV radiation exposure and damage can improve the course of disease and prolong life. The disease has served as a model for photoaging and UV radiation-induced cancer and has led to a better understanding of cell processes that prevent development of these disease features in normal individuals. PMID- 26975630 TI - NLRC5 regulates cell proliferation, migration and invasion in hepatocellular carcinoma by targeting the Wnt/beta-catenin signaling pathway. AB - NLRC5, the largest member of nucleotide-binding and oligomerization domain (NOD) like receptor (NLR) family, has been reported to regulate immune responses and is associated with chronic inflammatory diseases. However, the biological function of NLRC5 in hepatocellular carcinoma (HCC) has not yet been well demonstrated. In this study, the role of NLRC5 in hepatocellular carcinoma cell proliferation, migration and invasion capacities was evaluated by using MTT, flow cytometry, wound healing, transwell assay, and tumor formation assay in nude mice. Western blot analysis and qPCR assay were performed to assess NLRC5 interacting with the activation of Wnt/beta-catenin signaling pathway. Here, we demonstrate that NLRC5 was highly expressed in HCC. Knockdown of NLRC5 significantly inhibited cell proliferation, migration, invasion and the tumor formation in nude mice, and arrested the cell cycle at G0/G1 phase. Furthermore, overexpression of NLRC5 promoted the proliferation, migration and invasion of HCC cells in vitro. Interestingly, we found that up-regulation of NLRC5 not only positively correlates with the increase of beta-catenin but also coordinates the activation of downstream Wnt/beta-catenin signaling pathway. Thus, our findings suggest that NLRC5 may play an important role in progression of HCC and provide a potential therapeutic value in this tumor. PMID- 26975631 TI - SIRT1 promotes epithelial-mesenchymal transition and metastasis in colorectal cancer by regulating Fra-1 expression. AB - Understanding molecular mechanisms of colorectal cancer (CRC) metastasis is urgently required for targeted therapy and prognosis of metastatic CRC. In this study, we explored potential effects of silent mating type information regulation 2 homolog 1 (SIRT1) on CRC metastasis. Our data showed that ectopic expression of SIRT1 markedly increased the migration and invasion of CRC cells. In contrast, silencing SIRT1 repressed this behavior in aggressive CRC cells. Tumor xenograft experiments revealed that knockdown of SIRT1 impaired CRC metastasis in vivo. Silencing SIRT1 in CRC cells induced mesenchymal-epithelial transition (MET), which is the reverse process of epithelial-mesenchymal transition (EMT) and characterized by a gain of epithelial and loss of mesenchymal markers. We provided a mechanistic insight toward regulation of Fra-1 by SIRT1 and demonstrated a direct link between the SIRT1-Fra-1 axis and EMT. Moreover, SIRT1 expression correlated positively with Fra-1 expression, metastasis and overall survival in patients with CRC. Taken together, our data provide a novel mechanistic role of SIRT1 in CRC metastasis, suggesting that SIRT1 may serve as a potential therapeutic target for metastatic CRC. PMID- 26975632 TI - Gankyrin activates mTORC1 signaling by accelerating TSC2 degradation in colorectal cancer. AB - Gankyrin is overexpressed in some malignancies. However its roles in colorectal carcinogenesis and underlying mechanisms remain largely unexplored. Here we report that gankyrin promotes the initiation and development of colorectal carcinogenesis by activating mTORC1 signaling through TSC/Rheb dependent mechanism. We further show that Gankyrin overexpression accelerated TSC2 degradation, while knockdown in a panel of colorectal cancer (CRC) cell lines, cell line derived xenografts and CRC patient derived xenograft (PDX) tumors delayed TSC2 degradation, restored the TSC2 protein level, and inhibited mTORC1 signaling and CRC growth. Our findings reveal a unique mechanism by which gankyrin promotes colorectal carcinogenesis and show that gankyrin is a potential therapeutic target to improve the clinical management of CRC. PMID- 26975633 TI - APR-246 (PRIMA-1(MET)) strongly synergizes with AZD2281 (olaparib) induced PARP inhibition to induce apoptosis in non-small cell lung cancer cell lines. AB - APR-246 (PRIMA-1(Met)) is able to bind mutant p53 and restore its normal conformation and function. The compound has also been shown to increase intracellular ROS levels. Importantly, the poly-[ADP-ribose] polymerase-1 (PARP 1) enzyme plays an important role in the repair of ROS-induced DNA damage. We hypothesize that by blocking this repair with the PARP-inhibitor AZD2281 (olaparib), DNA damage would accumulate in the cell leading to massive apoptosis. We observed that APR-246 synergistically enhanced the cytotoxic response of olaparib in TP53 mutant non-small cell lung cancer cell lines, resulting in a strong apoptotic response. In the presence of wild type p53 a G2/M cell cycle block was predominantly observed. NOXA expression levels were significantly increased in a TP53 mutant background, and remained unchanged in the wild type cell line. The combined treatment of APR-246 and olaparib induced cell death that was associated with increased ROS production, accumulation of DNA damage and translocation of p53 to the mitochondria. Out data suggest a promising targeted combination strategy in which the response to olaparib is synergistically enhanced by the addition of APR-246, especially in a TP53 mutant background. PMID- 26975634 TI - Understanding the synergistic effect of WO3-BiVO4 heterostructures by impedance spectroscopy. AB - WO3-BiVO4 n-n heterostructures have demonstrated remarkable performance in photoelectrochemical water splitting due to the synergistic effect between the individual components. Although the enhanced functional capabilities of this system have been widely reported, in-depth mechanistic studies explaining the carrier dynamics of this heterostructure are limited. The main goal is to provide rational design strategies for further optimization as well as to extend these strategies to different candidate systems for solar fuel production. In the present study, we perform systematic optoelectronic and photoelectrochemical characterization to understand the carrier dynamics of the system and develop a simple physical model to highlight the importance of the selective contacts to minimize bulk recombination in this heterostructure. Our results collectively indicate that while BiVO4 is responsible for the enhanced optical properties, WO3 controls the transport properties of the heterostructured WO3-BiVO4 system, leading to reduced bulk recombination. PMID- 26975636 TI - [Perioperative Oral Management of Lung Cancer Patients; Medical, Dental, and Regional Dental Clinic Collaboration]. AB - PURPOSE: To prevent oral problems in lung cancer patients, dental intervention should be performed in conjunction with cancer treatment in cancer base hospitals. This paper reports on the perioperative oral care management of lung cancer patients. PATIENTS AND METHODS: From January 2013 to August 2015, perioperative oral management was performed in 123 patients undergoing pulmonary lobectomy. We ensure cooperation between the departments of medicine and dentistry. First, the dentist plans oral management based on the patient's individual oral status. Then, the actual oral management is performed by an in hospital dentist and at the regional dental clinic. RESULTS: The patients comprised 70 males and 53 females with an average age of 69.4 years;118 had primary lung cancer and 5 had metastatic lung cancer. Abnormal findings were detected in approximately 50% of the patients, of whom 6 received oral treatment before starting their cancer treatment. Two patients(1.3%)had postoperative complications. In all cases, the oral care support team provided both tooth and oral mucosal care. CONCLUSION: About half of the referred patients required oral treatment. There were no serious adverse events due to the oral care intervention. Further investigation is necessary to establish appropriate treatment policy guidelines for dental disease requiring oral maintenance. PMID- 26975637 TI - [Contribution of Perioperative Oral Health Care and Management for Patients who Underwent General Thoracic Surgery]. AB - Due to the recent advances in radiological diagnostic technology, the role of video-assisted thoracoscopic surgery in thoracic disease has expanded, surgical indication extended to the elderly patients. Cancer patients receiving surgery, radiation therapy and/or chemotherapy may encounter complications in conjunction with the oral cavity such as aspiration pneumonia, surgical site infection and various type of infection. Recently, it is recognized that oral health care management is effective to prevent the postoperative infectious complications, especially pneumonia. Therefore, oral management should be scheduled before start of therapy to prevent these complications as supportive therapy of the cancer treatment. In this background, perioperative oral function management is highlighted in the remuneration for dental treatment revision of 2012,and the importance of oral care has been recognized in generally. In this manuscript, we introduce the several opinions and evidence based on the recent previous reports about the perioperative oral health care and management on thoracic surgery. PMID- 26975638 TI - [Cross-sectoral Approach of a Perioperative Management Center for General Thoracic Surgery]. AB - Perioperative assessment and care, such as enhanced recovery after surgery (ERAS), is very important for improving the clinical outcomes of patients who have undergone surgery. However, professional assessments and care cannot be achieved through the actions of only 1 surgical department. We established a perioperative management center(PERIO) comprised of surgeons, dedicated nurses, anesthesiologists, dentists, physiotherapists, pharmacists, and nutritionists to perform intensive cross-sectoral perioperative management. In this manuscript, we investigated the impact of PERIO on the clinical outcomes of 127 elderly patients who underwent thoracic surgery for the resection of non-small cell lung cancer (NSCLC). We categorized these 127 patients into 3 groups:1 those treated before the introduction of PERIO (between January 2006 to August 2008), 2 those treated during the early phase after PERIO introduction (September 2008 to December 2011), and 3 those treated during the late phase after PERIO introduction( January 2012 to December 2014). Radical operations were performed significantly more frequently after PERIO introduction than before PERIO introduction, while the postoperative complication rates were similar among the 3 groups. The duration of postoperative hospitalization was reduced after the introduction of PERIO, and the hospital surplus increased after the introduction of PERIO. In conclusion, PERIO may play an important role in improving the clinical outcomes of thoracic surgery, especially for elderly patients with NSCLC. PMID- 26975635 TI - A novel pyrazole derivative protects from ovariectomy-induced osteoporosis through the inhibition of NADPH oxidase. AB - Osteoclast cells (OCs) are differentiated from bone marrow-derived macrophages (BMMs) by activation of receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL). Activation of NADPH oxidase (Nox) isozymes is involved in RANKL dependent OC differentiation, implicating Nox isozymes as therapeutic targets for treatment of osteoporosis. Here, we show that a novel pyrazole derivative, Ewha 18278 has high inhibitory potency on Nox isozymes. Blocking the activity of Nox with Ewha-18278 inhibited the responses of BMMs to RANKL, including reactive oxygen species (ROS) generation, activation of mitogen-activated protein (MAP) kinases and NF-kappaB, and OC differentiation. To evaluate the anti-osteoporotic function of Ewha-18278, the derivative was applied to estrogen-deficient ovariectomized (OVX) ddY mice. Oral administration of Ewha-18278 (10 mg/kg/daily, 4 weeks) into the mice recovered bone mineral density, trabecular bone volume, trabecular bone length, number and thickness, compared to control OVX ddY mice. Moreover, treatment of OVX ddY mice with Ewha-18278 increased bone strength by increasing cortical bone thickness. We provide that Ewha-18278 displayed Nox inhibition and blocked the RANKL-dependent cell signaling cascade leading to reduced differentiation of OCs. Our results implicate Ewha-18278 as a novel therapeutic agent for the treatment of osteoporosis. PMID- 26975639 TI - [Current Status of Preoperative Professional Oral Care by Dentists for Elderly Patients Undergoing Lung Resection and Occurrence of Postoperative Pneumonia]. AB - Pneumonia in elderly people is mainly caused by silent aspiration due to an age related impairment of cough and swallowing reflexes. Because most of the patients with lung cancer are elderly people, we hypothesized that the age-related impairment of these protective reflexes might exist or occur in patients undergoing lung surgery, and cause postoperative pneumonia. We revealed that many elderly patients showed depressed swallowing reflex even before surgery and transient attenuation of cough reflex after surgery, and that postoperative pneumonia occurred only in the patients whose cough and/or swallowing reflex was abnormal postoperatively. Then, we prospectively showed that 30 elderly patients who received perioperative intensive oral care, including professional assessment of oral status, dental cleaning, and patient education for self-oral care by dentists, followed by intensive oral care by intensive care unit nurses, and encouragement of self-oral care by floor nurses, did not develop pneumonia after lung resection. In this study, we retrospectively reviewed the execution status of professional oral care by dentists and the occurrence of postoperative pneumonia in 159 consecutive patients aged 65 or older undergoing lung resection from 2013 to 2014. Thoracic surgeons in our institute asked dentists to provide professional oral care before lung resection only in 30.3% of the subjects in 2013, and 45.8% in 2014. Postoperative pneumonia occurred in 3 out of 76 subjects(3.9%)in 2013, and 1 out of 83(1.2%) in 2014. In 2013, 1 patient who did not receive preoperative professional oral care developed aspiration pneumonia postoperatively followed by acute exacerbation of idiopathic pulmonary fibrosis and in-hospital death. We need to make an effective system to provide preoperative professional oral care by dentists especially for elderly patients and high-risk patients before lung resection. PMID- 26975640 TI - [Current Status and Effectiveness of Perioperative Oral Health Care Management for Lung Cancer and Esophageal Cancer Patients]. AB - The effectiveness of perioperative oral health care management to decrease the risk of postoperative pneumonia have been reported lately. Since 2014, we introduced perioperative oral health care management for lung cancer and esophageal cancer patients. We report current status and effectiveness of perioperative oral health care management for lung cancer and esophageal cancer patients. Every 100 cases of lung cancer and esophageal cancer patients treated by surgery were classified 2 group with or without perioperative oral health care management and compared about postoperative complications retrospectively. In the lung cancer patients, the group with oral health care management could prevent postoperative pneumonia significantly and had shorter length of hospital stay than the group without oral health care management. In the esophageal cancer patients, there was little occurrence of postoperative pneumonia without significant difference between both group with or without oral health care management. A large number of esophageal cancer patients received neo-adjuvant chemotherapy and some patients developed oral mucositis and received oral care treatment before surgery. Treatment for oral mucositis probably improved oral environment and affected prevention of postoperative pneumonia. Perioperative oral health care management can prevent postoperative pneumonia of lung cancer and esophageal cancer patients by improvement of oral hygiene. PMID- 26975641 TI - [Perioperative Oral Management for Esophageal Cancer Patients]. AB - Aspiration pneumonia, known as one of the most common postoperative complication after esophagectomy for esophageal cancer, can be critical profoundly affecting upon postoperative course of patients. Since oral bacteria can be one of causes for development of postoperative pneumonia, perioperative oral management has very important role in reducing morbidity and improving function of dysphagia. We started perioperative oral management as a team approach for patients undergoing esophageal surgery since 1997. In the present study, we are going to introduce details of these our efforts including reoperative evaluation of oral status, education and tutorship for patients, and oral treatment to reduce postoperative complications after esophagectomy of esophageal cancer. PMID- 26975642 TI - [Perioperative Pulmonary Rehabilitation for Lung Cancer Surgeries in Patients with Poor Pulmonary Function]. AB - To properly perform preoperative pulmonary rehabilitation is important for lung cancer surgeries in patients with poor pulmonary function such as severe chronic obstructive pulmonary disease( COPD) to prevent postoperative complications. Those programs include exercise training, pursed-lip breathing technique, activities of dairy living training and facilitating physical activities, all which are almost same as those for patients with stable COPD. Pedometer is a useful tool to lead patient's physical activities. Postoperative therapeutic programs are also important, which includes early mobilization, nutritional support, and so on. PMID- 26975643 TI - [Can Pulmonary Rehabilitation during Preoperative Chemoradiotherapy for Non-small Cell Lung Cancer Improve the Respiratory Function?]. AB - OBJECTIVE: Chemoradiotherapy for non-small cell lung cancer (NSCLC) can impair pulmonary function, particularly when it is followed by surgery. This study aimed to document the changes in respiratory function as a result of a perioperative intensive pulmonary rehabilitation program in patients with NSCLC who underwent induction chemoradiotherapy. METHODS: A total of 82 consecutive patients underwent pulmonary resection after undergoing induction chemoradiotherapy. A pulmonary rehabilitation program was started at the same time as the induction chemoradiotherapy. Standard respiratory function tests were performed before and after induction chemoradiotherapy. Treatment-related mortality and the incidence of postoperative respiratory complications were investigated. The Wilcoxon signed rank test was used to analyze the differences in spirometric changes. RESULTS: All patients underwent a pulmonary rehabilitation program for an average of 10 weeks. Significant increases were observed in forced vital capacity (FVC) [+6.4%, p=.0096] and forced expiratory volume in 1 second( FEV(1))[ +10.4%, p<.0001]. Diffusing capacity of the lung for carbon monoxide decreased(-14.0%, p<.0001). Patients with respiratory impairment (FVC <80% predicted or FEV(1)/FVCp<70%) showed significant improvements in FVC( +13.9%, p=.0025) and FEV(1)( +22.5%, p<.0001). Significant increases were observed in FVC( +7.0%, p=.0042) and FEV(1)( +10.8%, p<.0001) in patients with a smoking history. There was no mortality, and postoperative respiratory morbidity was 6.1%. PMID- 26975644 TI - [Perioperative Rehabilitation for Patients with Esophageal Cancer]. AB - Transthoracic esophagectomy for patients with esophageal cancer is one of the most invasive of all gastrointestinal surgery. Postoperative management and surgical techniques are improved. However, many patients are more elderly or suffering from comorbid diseases or in malnutrition status. In order to prevent for postoperative complications after esophagectomy, especially for respiratory complication and swallowing dysfunction, adequate rehabilitation approaches are necessary depending on the various conditions. PMID- 26975645 TI - [Current Status of Perioperative Rehabilitation in Patients who Undergo Esophagectomy for Cancer]. AB - The esophagectomy for esophageal cancer is major surgery and has the highest rate of postoperative pulmonary complications. Respiratory physiotherapy in patients undergoing esophagectomy has been applied to improve oxygenation and airway secretion clearance. Recently, the utility and effectiveness of enhanced recovery after surgery for gastroenterological surgery have been reported in Japan, and patients should be encouraged to participate in early mobilization. Perioperative rehabilitation which includes early mobilization reduces postoperative complications and improves fast-track recovery after esophagectomy. These interventions play important role in postoperative care. PMID- 26975646 TI - [Current Status and Future Aspects of Heart Transplantation in Japan]. AB - By renewal of Japanese Organ Transplantation Act on 17th July in 2010, organs can be donated after brain death with consent from their family, if he or she did not deny organ donation and brain dead organ donation increased from 10 to 50 cases in a year. Despite of an increase of heart transplantation (HTx), a waiting period for HTx has become longer because more candidates for HTx have been registered to Japan Organ Transplant Network. By renewal of the act, organ donation from brain dead children can be performed since then and pediatric left ventricular assist device, EXCOR was finally accepted to use in August 1st, 2015. However, only 3 children under 6 years of age have donated since then and oversea HTx increased again. PMID- 26975649 TI - Food industry body admits that voluntary agreements lack punch. PMID- 26975648 TI - Novel insights in the dysfunction of human blood-brain barrier after glycation. AB - The blood-brain barrier (BBB) provides a dynamic and complex interface consisting of endothelial cells, pericytes and astrocytes, which are embedded in a collagen and fibronectin-rich basement membrane. This complex structure restricts the diffusion of small hydrophilic solutes and macromolecules as well as the transmigration of leukocytes into the brain. It has been shown that carbonyl stress followed by the formation of advanced glycation endproducts (AGE=glycation) interfere with the BBB integrity and function. Here, we present data that carbonyl stress induced by methylglyoxal leads to glycation of endothelial cells and the basement membrane, which interferes with the barrier function and with the expression of RAGE, occludin and ZO-1. Furthermore, methylglyoxal induced carbonyl stress promotes the expression of the pro inflammatory interleukins IL-6 and IL-8. In summary, this study provides new insights into the relationship between AGE formation by carbonyl stress and brain microvascular endothelial barrier dysfunction. PMID- 26975650 TI - Agreement between an online dietary assessment tool (myfood24) and an interviewer administered 24-h dietary recall in British adolescents aged 11-18 years. AB - myfood24 Is an online 24-h dietary assessment tool developed for use among British adolescents and adults. Limited information is available regarding the validity of using new technology in assessing nutritional intake among adolescents. Thus, a relative validation of myfood24 against a face-to-face interviewer-administered 24-h multiple-pass recall (MPR) was conducted among seventy-five British adolescents aged 11-18 years. Participants were asked to complete myfood24 and an interviewer-administered MPR on the same day for 2 non consecutive days at school. Total energy intake (EI) and nutrients recorded by the two methods were compared using intraclass correlation coefficients (ICC), Bland-Altman plots (using between and within-individual information) and weighted kappa to assess the agreement. Energy, macronutrients and other reported nutrients from myfood24 demonstrated strong agreement with the interview MPR data, and ICC ranged from 0.46 for Na to 0.88 for EI. There was no significant bias between the two methods for EI, macronutrients and most reported nutrients. The mean difference between myfood24 and the interviewer-administered MPR for EI was -230 kJ (-55 kcal) (95 % CI -490, 30 kJ (-117, 7 kcal); P=0.4) with limits of agreement ranging between 39 % (3336 kJ (-797 kcal)) lower and 34 % (2874 kJ (687 kcal)) higher than the interviewer-administered MPR. There was good agreement in terms of classifying adolescents into tertiles of EI (kappa w =0.64). The agreement between day 1 and day 2 was as good for myfood24 as for the interviewer administered MPR, reflecting the reliability of myfood24. myfood24 Has the potential to collect dietary data of comparable quality with that of an interviewer-administered MPR. PMID- 26975651 TI - Quasi two-dimensional astigmatic solitons in soft chiral metastructures. AB - We investigate a non-homogeneous layered structure encompassing dual spatial dispersion: continuous diffraction in one transverse dimension and discrete diffraction in the orthogonal one. Such dual diffraction can be balanced out by one and the same nonlinear response, giving rise to light self-confinement into astigmatic spatial solitons: self-focusing can compensate for the spreading of a bell-shaped beam, leading to quasi-2D solitary wavepackets which result from 1D transverse self-localization combined with a discrete soliton. We demonstrate such intensity-dependent beam trapping in chiral soft matter, exhibiting one dimensional discrete diffraction along the helical axis and one-dimensional continuous diffraction in the orthogonal plane. In nematic liquid crystals with suitable birefringence and chiral arrangement, the reorientational nonlinearity is shown to support bell-shaped solitary waves with simple astigmatism dependent on the medium birefringence as well as on the dual diffraction of the input wavepacket. The observations are in agreement with a nonlinear nonlocal model for the all-optical response. PMID- 26975647 TI - Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients With Agitated Delirium: A Randomized Clinical Trial. AB - IMPORTANCE: Effective therapy has not been established for patients with agitated delirium receiving mechanical ventilation. OBJECTIVE: To determine the effectiveness of dexmedetomidine when added to standard care in patients with agitated delirium receiving mechanical ventilation. DESIGN, SETTING, AND PARTICIPANTS: The Dexmedetomidine to Lessen ICU Agitation (DahLIA) study was a double-blind, placebo-controlled, parallel-group randomized clinical trial involving 74 adult patients in whom extubation was considered inappropriate because of the severity of agitation and delirium. The study was conducted at 15 intensive care units in Australia and New Zealand from May 2011 until December 2013. Patients with advanced dementia or traumatic brain injury were excluded. INTERVENTIONS: Bedside nursing staff administered dexmedetomidine (or placebo) initially at a rate of 0.5 ug/kg/h and then titrated to rates between 0 and 1.5 ug/kg/h to achieve physician-prescribed sedation goals. The study drug or placebo was continued until no longer required or up to 7 days. All other care was at the discretion of the treating physician. MAIN OUTCOMES AND MEASURES: Ventilator-free hours in the 7 days following randomization. There were 21 reported secondary outcomes that were defined a priori. RESULTS: Of the 74 randomized patients (median age, 57 years; 18 [24%] women), 2 withdrew consent later and 1 was found to have been randomized incorrectly, leaving 39 patients in the dexmedetomidine group and 32 patients in the placebo group for analysis. Dexmedetomidine increased ventilator-free hours at 7 days compared with placebo (median, 144.8 hours vs 127.5 hours, respectively; median difference between groups, 17.0 hours [95% CI, 4.0 to 33.2 hours]; P = .01). Among the 21 a priori secondary outcomes, none were significantly worse with dexmedetomidine, and several showed statistically significant benefit, including reduced time to extubation (median, 21.9 hours vs 44.3 hours with placebo; median difference between groups, 19.5 hours [95% CI, 5.3 to 31.1 hours]; P < .001) and accelerated resolution of delirium (median, 23.3 hours vs 40.0 hours; median difference between groups, 16.0 hours [95% CI, 3.0 to 28.0 hours]; P = .01). Using hierarchical Cox modeling to adjust for imbalanced baseline characteristics, allocation to dexmedetomidine was significantly associated with earlier extubation (hazard ratio, 0.47 [95% CI, 0.27-0.82]; P = .007). CONCLUSIONS AND RELEVANCE: Among patients with agitated delirium receiving mechanical ventilation in the intensive care unit, the addition of dexmedetomidine to standard care compared with standard care alone (placebo) resulted in more ventilator-free hours at 7 days. The findings support the use of dexmedetomidine in patients such as these. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01151865. PMID- 26975653 TI - [Schizophrenia: pars pro toto for psychiatry? : A historical essay on the status of schizophrenia in psychiatric discourse]. AB - In the history of psychiatry, "schizophrenia" has often been portrayed as the discipline's pars pro toto, which prototypically represents mental illness as such and which draws together the fundamental questions concerning psychiatric epistemology and practice. Taking a conceptual history approach, this essay examines how "schizophrenia" is represented in psychiatric discourse and what aspects of its representation account for the pars pro toto status. Three such aspects are identified: a pragmatic, an existential and a justificatory aspect. Following up these aspects in present day psychiatric discourse, it is concluded that "schizophrenia" is losing its special status as the representations of psychiatry and of mental illness have changed and become more diverse. Tentative conclusions regarding current debates about the abolition of "schizophrenia" are drawn. PMID- 26975652 TI - [Dermatological diseases and their importance for psychiatry]. AB - The relationship between skin and psychiatric disorders is not an uncommon occurrence in the clinical practice; however, there are only a few systematic studies and in addition knowledge about the neurobiological and immunological mechanisms is lacking. Impairments and disorders of the skin are often an (early) sign of a psychiatric disorder. In the sense of true psychosomatics, psychiatrists should also be aware of this relationship as far as possible. This review article focuses on the most important dermatological diagnoses in relation to the respective psychiatric comorbidities and presents the most important aspects of epidemiology, symptomatology, pathophysiology and treatment options. PMID- 26975655 TI - Structural insights into DNA sequence recognition by Type ISP restriction modification enzymes. AB - Engineering restriction enzymes with new sequence specificity has been an unaccomplished challenge, presumably because of the complexity of target recognition. Here we report detailed analyses of target recognition by Type ISP restriction-modification enzymes. We determined the structure of the Type ISP enzyme LlaGI bound to its target and compared it with the previously reported structure of a close homologue that binds to a distinct target, LlaBIII. The comparison revealed that, although the two enzymes use almost a similar set of structural elements for target recognition, the residues that read the bases vary. Change in specificity resulted not only from appropriate substitution of amino acids that contacted the bases but also from new contacts made by positionally distinct residues directly or through a water bridge. Sequence analyses of 552 Type ISP enzymes showed that the structural elements involved in target recognition of LlaGI and LlaBIII were structurally well-conserved but sequentially less-conserved. In addition, the residue positions within these structural elements were under strong evolutionary constraint, highlighting the functional importance of these regions. The comparative study helped decipher a partial consensus code for target recognition by Type ISP enzymes. PMID- 26975654 TI - Global analyses of endonucleolytic cleavage in mammals reveal expanded repertoires of cleavage-inducing small RNAs and their targets. AB - In mammals, small RNAs are important players in post-transcriptional gene regulation. While their roles in mRNA destabilization and translational repression are well appreciated, their involvement in endonucleolytic cleavage of target RNAs is poorly understood. Very few microRNAs are known to guide RNA cleavage. Endogenous small interfering RNAs are expected to induce target cleavage, but their target genes remain largely unknown. We report a systematic study of small RNA-mediated endonucleolytic cleavage in mouse through integrative analysis of small RNA and degradome sequencing data without imposing any bias toward known small RNAs. Hundreds of small cleavage-inducing RNAs and their cognate target genes were identified, significantly expanding the repertoire of known small RNA-guided cleavage events. Strikingly, both small RNAs and their target sites demonstrated significant overlap with retrotransposons, providing evidence for the long-standing speculation that retrotransposable elements in mRNAs are leveraged as signals for gene targeting. Furthermore, our analysis showed that the RNA cleavage pathway is also present in human cells but affecting a different repertoire of retrotransposons. These results show that small RNA guided cleavage is more widespread than previously appreciated. Their impact on retrotransposons in non-coding regions shed light on important aspects of mammalian gene regulation. PMID- 26975656 TI - Rational design of novel N-alkyl-N capped biostable RNA nanostructures for efficient long-term inhibition of gene expression. AB - Computational techniques have been used to design a novel class of RNA architecture with expected improved resistance to nuclease degradation, while showing interference RNA activity. The in silico designed structure consists of a 24-29 bp duplex RNA region linked on both ends by N-alkyl-N dimeric nucleotides (BCn dimers; n = number of carbon atoms of the alkyl chain). A series of N-alkyl N capped dumbbell-shaped structures were efficiently synthesized by double ligation of BCn-loop hairpins. The resulting BCn-loop dumbbells displayed experimentally higher biostability than their 3'-N-alkyl-N linear version, and were active against a range of mRNA targets. We studied first the effect of the alkyl chain and stem lengths on RNAi activity in a screen involving two series of dumbbell analogues targeting Renilla and Firefly luciferase genes. The best dumbbell design (containing BC6 loops and 29 bp) was successfully used to silence GRB7 expression in HER2+ breast cancer cells for longer periods of time than natural siRNAs and known biostable dumbbells. This BC6-loop dumbbell-shaped structure displayed greater anti-proliferative activity than natural siRNAs. PMID- 26975657 TI - CLASS2: accurate and efficient splice variant annotation from RNA-seq reads. AB - Next generation sequencing of cellular RNA is making it possible to characterize genes and alternative splicing in unprecedented detail. However, designing bioinformatics tools to accurately capture splicing variation has proven difficult. Current programs can find major isoforms of a gene but miss lower abundance variants, or are sensitive but imprecise. CLASS2 is a novel open source tool for accurate genome-guided transcriptome assembly from RNA-seq reads based on the model of splice graph. An extension of our program CLASS, CLASS2 jointly optimizes read patterns and the number of supporting reads to score and prioritize transcripts, implemented in a novel, scalable and efficient dynamic programming algorithm. When compared against reference programs, CLASS2 had the best overall accuracy and could detect up to twice as many splicing events with precision similar to the best reference program. Notably, it was the only tool to produce consistently reliable transcript models for a wide range of applications and sequencing strategies, including ribosomal RNA-depleted samples. Lightweight and multi-threaded, CLASS2 requires <3GB RAM and can analyze a 350 million read set within hours, and can be widely applied to transcriptomics studies ranging from clinical RNA sequencing, to alternative splicing analyses, and to the annotation of new genomes. PMID- 26975658 TI - A novel transition pathway of ligand-induced topological conversion from hybrid forms to parallel forms of human telomeric G-quadruplexes. AB - The folding topology of DNA G-quadruplexes (G4s) depends not only on their nucleotide sequences but also on environmental factors and/or ligand binding. Here, a G4 ligand, 3,6-bis(1-methyl-4-vinylpyridium iodide)-9-(1-(1-methyl piperidinium iodide)-3,6,9-trioxaundecane) carbazole (BMVC-8C3O), can induce topological conversion of non-parallel to parallel forms in human telomeric DNA G4s. Nuclear magnetic resonance (NMR) spectroscopy with hydrogen-deuterium exchange (HDX) reveals the presence of persistent imino proton signals corresponding to the central G-quartet during topological conversion of Tel23 and Tel25 G4s from hybrid to parallel forms, implying that the transition pathway mainly involves local rearrangements. In contrast, rapid HDX was observed during the transition of 22-CTA G4 from an anti-parallel form to a parallel form, resulting in complete disappearance of all the imino proton signals, suggesting the involvement of substantial unfolding events associated with the topological transition. Site-specific imino proton NMR assignments of Tel23 G4 enable determination of the interconversion rates of individual guanine bases and detection of the presence of intermediate states. Since the rate of ligand binding is much higher than the rate of ligand-induced topological conversion, a three-state kinetic model was evoked to establish the associated energy diagram for the topological conversion of Tel23 G4 induced by BMVC-8C3O. PMID- 26975659 TI - NetDecoder: a network biology platform that decodes context-specific biological networks and gene activities. AB - The sequential chain of interactions altering the binary state of a biomolecule represents the 'information flow' within a cellular network that determines phenotypic properties. Given the lack of computational tools to dissect context dependent networks and gene activities, we developed NetDecoder, a network biology platform that models context-dependent information flows using pairwise phenotypic comparative analyses of protein-protein interactions. Using breast cancer, dyslipidemia and Alzheimer's disease as case studies, we demonstrate NetDecoder dissects subnetworks to identify key players significantly impacting cell behaviour specific to a given disease context. We further show genes residing in disease-specific subnetworks are enriched in disease-related signalling pathways and information flow profiles, which drive the resulting disease phenotypes. We also devise a novel scoring scheme to quantify key genes network routers, which influence many genes, key targets, which are influenced by many genes, and high impact genes, which experience a significant change in regulation. We show the robustness of our results against parameter changes. Our network biology platform includes freely available source code (http://www.NetDecoder.org) for researchers to explore genome-wide context dependent information flow profiles and key genes, given a set of genes of particular interest and transcriptome data. More importantly, NetDecoder will enable researchers to uncover context-dependent drug targets. PMID- 26975661 TI - Utility of factor analysis in optimization of resident assessment and faculty evaluation. AB - BACKGROUND: Increasing focus on more granular assessment in medical education has led to more lengthy instruments, with concern that the increased complexity undermines the utility of these tools. This study evaluated the relative contribution of individual questions in an assessment of resident performance and a faculty performance evaluation by residents. METHODS: The authors performed factor analysis on the individual items in the resident assessment instrument (3,009 assessments of 71 residents) and faculty evaluations (7,328 evaluations of 61 faculty) collected from 2006 to 2012. RESULTS: Factor analysis of the resident assessment tool revealed that 1 component was responsible for 96.6% of the variance. This component encompassed each question from the assessment form, and could also be termed "overall resident competency." Factor analysis of the attending evaluation form revealed 2 unique components, representing "clinical care" and "interpersonal skills," which accounted for 89.9% of variance. CONCLUSIONS: Three components accounted for 90% to 97% of the observed variance in our analysis. Factor analysis represents a useful strategy for analyzing the utility of data obtained from individual items in the assessment and evaluation instruments. PMID- 26975660 TI - Dynamic changes of alkaline phosphatase are strongly associated with PSA-decline and predict best clinical benefit earlier than PSA-changes under therapy with abiraterone acetate in bone metastatic castration resistant prostate cancer. AB - BACKGROUND: Significant progress in treatment of metastatic castration resistant prostate cancer (mCRPC) has been made. Biomarkers to tailor therapy are scarce. To facilitate decision-making we evaluated dynamic changes of alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and prostate specific antigen (PSA) under therapy with Abiraterone. METHODS: Men with bone mCRPC (bmCRPC) on Abiraterone 12/2009-01/2014 were analyzed. Dynamic ALP-, LDH- and PSA-changes were analyzed as predictors of best clinical benefit and overall survival (OS) with logistic-regression, Cox-regression and Kaplan-Meier-analysis. RESULTS: Thirty-nine pre- and 45 post-chemotherapy patients with a median follow up of 14.0 months were analyzed. ALP-Bouncing can be observed very early during therapy with Abiraterone. ALP-Bouncing is defined as rapidly rising ALP-levels independent of baseline ALP during the first 2-4 weeks of Abiraterone-therapy with subsequent equally marked decline to pretreatment levels or better within 8 weeks of therapy, preceding potentially delayed PSA-decline. In univariate analysis failure of PSA-reduction >= 50% and failure of ALP-Bouncing were the strongest predictors of progressive disease (p = 0.003 and 0.021). Rising ALP at 12 weeks, no PSA-reduction >= 50% and no ALP-Bouncing were strongest predictors of poor OS, (all p < 0.001). Kaplan-Meier-analysis showed worse OS for rising ALP at 12 weeks, no PSA-reduction >= 50% and no ALP-Bouncing (p < 0.001). In subgroup analysis of oligosymptomatic patients all parameters remained significant predictors of poor OS, with no PSA-reduction >= 50% and rising ALP at 12 weeks being the strongest (p < 0.001). In multivariate analysis PSA-reduction >= 50% remained an independent predictor of OS for the whole cohort and for the oligosymptomatic subgroup (both p = 0.014). No patient with ALP-Bouncing had PD for best clinical benefit. Patients with rising ALP at 12 weeks had no further benefit of Abiraterone. CONCLUSIONS: Dynamic changes of ALP, LDH and PSA during Abiraterone-therapy are associated with best clinical benefit and OS in bmCRPC. ALP-Bouncing occurring earlier than PSA-changes as well as prior to equivocal imaging results and rising ALP at 12 weeks under Abiraterone may help to decide whether to discontinue Abiraterone. An external validation of these findings on a prospective cohort is planned. PMID- 26975662 TI - Mortality after inpatient open ventral hernia repair: developing a risk stratification tool based on 55,760 operations. AB - BACKGROUND: The medical complexity of hernia patients imparts higher risk for complications, and mortality is a distinct reality. No study has stratified patients based on preoperative risk for open ventral hernia repair (VHR) specifically. We utilized the American College of Surgeons National Surgical Quality Improvement Program to create a mortality risk stratification model following VHR. METHODS: Patients undergoing open VHR were identified from American College of Surgeons National Surgical Quality Improvement Program databases. Baseline variables correlated with mortality risk were entered into stepwise regression and bootstrap analysis. beta-Coefficients were used to weigh each factor, yielding the risk assessment tool. RESULTS: A total of 55,760 patients were included with a mortality of 1.34%. Predictors of mortality included the following: functional status (odds ratio [OR] = 2.87), liver disease (OR = 3.61), malnutrition (OR = 1.43), age greater than 65 years (OR = 2.39), American Society of Anesthesiologists 4 or higher (OR = 2.90), systemic inflammation (OR = 1.99), and contamination (OR = 2.15). Patients were risk stratified into low risk (mortality .33%), moderate risk (mortality 1.86%), high risk (mortality 8.76%), and extreme risk groups (mortality 34.2%). Unplanned reoperations and medical complications increased across risk groups. The model demonstrated high discriminatory ability with a C-statistic value of .86. CONCLUSIONS: This study provides an accurate model to predict mortality risk specific to open VHR. The strongest predictors were American Society of Anesthesiologists, liver disease, functional status, and older age. This tool may inform clinical decision making to reduce complications. PMID- 26975666 TI - Withdrawn: Controversies Related to Diabetes and Risk of Bladder Cancer. AB - Withdrawn by the publisher. PMID- 26975663 TI - Type 1 diabetes vaccine candidates promote human Foxp3(+)Treg induction in humanized mice. AB - Immune tolerance is executed partly by Foxp3(+)regulatory T (Treg) cells, which suppress autoreactive T cells. In autoimmune type 1 diabetes (T1D) impaired tolerance promotes destruction of insulin-producing beta-cells. The development of autoantigen-specific vaccination strategies for Foxp3(+)Treg-induction and prevention of islet autoimmunity in patients is still in its infancy. Here, using human haematopoietic stem cell-engrafted NSG-HLA-DQ8 transgenic mice, we provide direct evidence for human autoantigen-specific Foxp3(+)Treg-induction in vivo. We identify HLA-DQ8-restricted insulin-specific CD4(+)T cells and demonstrate efficient human insulin-specific Foxp3(+)Treg-induction upon subimmunogenic vaccination with strong agonistic insulin mimetopes in vivo. Induced human Tregs are stable, show increased expression of Treg signature genes such as Foxp3, CTLA4, IL-2Ralpha and TIGIT and can efficiently suppress effector T cells. Such Foxp3(+)Treg-induction does not trigger any effector T cells. These T1D vaccine candidates could therefore represent an expedient improvement in the challenge to induce human Foxp3(+)Tregs and to develop novel precision medicines for prevention of islet autoimmunity in children at risk of T1D. PMID- 26975667 TI - A Review of Molecular Predictors of Response to Neoadjuvant Chemotherapy in Muscle-invasive Bladder Cancer. AB - Locally advanced, muscle-invasive urothelial carcinoma of the bladder (MIBC) may be definitively treated with either radiotherapy or radical cystectomy (RC) with urinary diversion. Neoadjuvant chemotherapy (NAC) is typically administered prior to treatment with either modality. Receiving NAC prior to RC might confer a survival advantage compared to undergoing RC alone. However, its usefulness has been questioned due to concerns about over treatment and toxicity. Having the ability to predict whether individual patients would benefit from or be harmed by NAC would be an important tool in precision medicine. Unfortunately, to date no prognostic or predictive molecular markers have been validated for this purpose. In this manuscript, we review the current state of molecular markers in MIBC treatment and outline how recent advances in whole-genome sequencing may soon improve the selection of precisely targeted therapeutics for the benefit of individual patients. PMID- 26975664 TI - Integration of Orthogonal Signaling by the Notch and Dpp Pathways in Drosophila. AB - The transcription factor Suppressor of Hairless and its coactivator, the Notch intracellular domain, are polyglutamine (pQ)-rich factors that target enhancer elements and interact with other locally bound pQ-rich factors. To understand the functional repertoire of such enhancers, we identify conserved regulatory belts with binding sites for the pQ-rich effectors of both Notch and BMP/Dpp signaling, and the pQ-deficient tissue selectors Apterous (Ap), Scalloped (Sd), and Vestigial (Vg). We find that the densest such binding site cluster in the genome is located in the BMP-inducible nab locus, a homolog of the vertebrate transcriptional cofactors NAB1/NAB2 We report three major findings. First, we find that this nab regulatory belt is a novel enhancer driving dorsal wing margin expression in regions of peak phosphorylated Mad in wing imaginal discs. Second, we show that Ap is developmentally required to license the nab dorsal wing margin enhancer (DWME) to read out Notch and Dpp signaling in the dorsal compartment. Third, we find that the nab DWME is embedded in a complex of intronic enhancers, including a wing quadrant enhancer, a proximal wing disc enhancer, and a larval brain enhancer. This enhancer complex coordinates global nab expression via both tissue-specific activation and interenhancer silencing. We suggest that DWME integration of BMP signaling maintains nab expression in proliferating margin descendants that have divided away from Notch-Delta boundary signaling. As such, uniform expression of genes like nab and vestigial in proliferating compartments would typically require both boundary and nonboundary lineage-specific enhancers. PMID- 26975665 TI - Wnt/Wingless Pathway Activation Is Promoted by a Critical Threshold of Axin Maintained by the Tumor Suppressor APC and the ADP-Ribose Polymerase Tankyrase. AB - Wnt/beta-catenin signal transduction directs metazoan development and is deregulated in numerous human congenital disorders and cancers. In the absence of Wnt stimulation, a multiprotein "destruction complex," assembled by the scaffold protein Axin, targets the key transcriptional activator beta-catenin for proteolysis. Axin is maintained at very low levels that limit destruction complex activity, a property that is currently being exploited in the development of novel therapeutics for Wnt-driven cancers. Here, we use an in vivo approach in Drosophila to determine how tightly basal Axin levels must be controlled for Wnt/Wingless pathway activation, and how Axin stability is regulated. We find that for nearly all Wingless-driven developmental processes, a three- to fourfold increase in Axin is insufficient to inhibit signaling, setting a lower-limit for the threshold level of Axin in the majority of in vivo contexts. Further, we find that both the tumor suppressor adenomatous polyposis coli (APC) and the ADP ribose polymerase Tankyrase (Tnks) have evolutionarily conserved roles in maintaining basal Axin levels below this in vivo threshold, and we define separable domains in Axin that are important for APC- or Tnks-dependent destabilization. Together, these findings reveal that both APC and Tnks maintain basal Axin levels below a critical in vivo threshold to promote robust pathway activation following Wnt stimulation. PMID- 26975668 TI - Bladder Cancer Chemopreventive Agents: Current Knowledge and Concepts. AB - Bladder cancer is the most prevalent malignancy of the urinary tract and is associated with significant morbidity and mortality. Preventative efforts to reduce the medical and financial burdens of bladder cancer are highly desirable. However, the utilization of natural and pharmaceutical products for the prevention and treatment of bladder cancer remains largely controversial. Herein, we review the current body of evidence surrounding a number of natural dietary substances and their roles in chemoprevention of bladder cancer. Possible chemopreventative properties of several pharmaceutical agents are also reviewed. Overall, the current body of evidence is insufficient to establish a clear link between these proposed chemopreventive agents and risk of bladder cancer. PMID- 26975670 TI - The neuroanatomy of autism spectrum disorder: An overview of structural neuroimaging findings and their translatability to the clinical setting. AB - Autism spectrum disorder is a complex neurodevelopmental disorder, which is accompanied by differences in brain anatomy, functioning and brain connectivity. Due to its neurodevelopmental character, and the large phenotypic heterogeneity among individuals on the autism spectrum, the neurobiology of autism spectrum disorder is inherently difficult to describe. Nevertheless, significant progress has been made in characterizing the neuroanatomical underpinnings of autism spectrum disorder across the human life span, and in identifying the molecular pathways that may be affected in autism spectrum disorder. Moreover, novel methodological frameworks for analyzing neuroimaging data are emerging that make it possible to characterize the neuroanatomy of autism spectrum disorder on the case level, and to stratify individuals based on their individual phenotypic make up. While these approaches are increasingly more often employed in the research setting, their applicability in the clinical setting remains a vision for the future. The aim of the current review is to (1) provide a general overview of recent structural neuroimaging findings examining the neuroanatomy of autism spectrum disorder across the human life span, and in males and females with the condition, (2) highlight potential neuroimaging (bio)markers that may in the future be used for the stratification of autism spectrum disorder individuals into biologically homogeneous subgroups and (3) inform treatment and intervention strategies. PMID- 26975671 TI - Highly selective Markovnikov hydroboration of alkyl-substituted terminal alkenes with a phosphine-copper(i) catalyst. AB - A new method has been developed for the Markovnikov hydroboration of alkyl substituted terminal alkenes. Notably, the use of a bulky bisphosphine-copper(i) catalyst system resulted in high regioselectivity to afford secondary alkylboronates from the corresponding terminal alkenes (branch/linear = 92 : 8-97 : 3). This method also exhibited good functional group compatibility. PMID- 26975669 TI - Attitudes of the autism community to early autism research. AB - Investigation into the earliest signs of autism in infants has become a significant sub-field of autism research. This work invokes specific ethical concerns such as use of 'at-risk' language, communicating study findings to parents and the future perspective of enrolled infants when they reach adulthood. This study aimed to ground this research field in an understanding of the perspectives of members of the autism community. Following focus groups to identify topics, an online survey was distributed to autistic adults, parents of children with autism and practitioners in health and education settings across 11 European countries. Survey respondents (n = 2317) were positively disposed towards early autism research, and there was significant overlap in their priorities for the field and preferred language to describe infant research participants. However, there were also differences including overall less favourable endorsement of early autism research by autistic adults relative to other groups and a dislike of the phrase 'at-risk' to describe infant participants, in all groups except healthcare practitioners. The findings overall indicate that the autism community in Europe is supportive of early autism research. Researchers should endeavour to maintain this by continuing to take community perspectives into account. PMID- 26975672 TI - [Not Available]. PMID- 26975673 TI - [Technology in the nurse-patient relationship in diabetology, a true metronome?]. AB - Technology is evolving to keep pace with patients' and caregivers' needs and advances in research. In diabetology, this progress concerns administration systems, the devices for monitoring blood sugar levels, accessories and technical support, and provides hope for tomorrow. In this context, it is essential that the patient remains at the centre of the nurse-patient relationship and that technology remains simply a source of reference points and comfort. PMID- 26975674 TI - [Nursing care in prison]. AB - In France, nurses practising in the prison environment work in a health care unit, for somatic care, or in a regional medical-psychological unit for large facilities and psychological care. These units belong to the regional hospitals. Located at the heart of the prison, they cater for prisoner-patients. On the frontline, the nurse has specific autonomy and responsibility in this unique context. PMID- 26975676 TI - [Not Available]. PMID- 26975675 TI - [Use of heparin and its derivatives in nursing care]. AB - Heparin is an injectable anti-coagulant indicated in the treatment of venous thromboembolic diseases. In the case of major kidney failure, unfractionated heparins (UFHs) can be administered while low molecular weight heparins (LMWHs) are contraindicated at a curative dose. Platelet count must be monitored in patients treated with UFHs and when an LMWH is prescribed in a surgical context. PMID- 26975677 TI - [Carers and the policy for autonomy]. AB - Long-time invisible, the role of informal carers in providing assistance to elderly patients losing their autonomy is gaining recognition. A policy in favour of carers coordinated with that aimed at the people being cared for is necessary, but it is struggling to establish itself in France. Some progress can however be seen with the French bill on adapting society to the ageing of the population. PMID- 26975678 TI - [What role for the family carers of elderly people losing their autonomy?]. AB - The qualitative analysis of the role of family carers shows that supporting a family member losing their autonomy not only involves providing physical assistance and care but also, increasingly, adopting a role of coordinator. These activities can be a source of stress or they can be rewarding, depending on the shared history of the carer-patient relationship. PMID- 26975679 TI - [A platform for support and respite for family carers]. AB - Carers of elderly people with neurodegenerative diseases sometimes see their quality of life suffer. They have to remain constantly alert, usually both day and night. Respite platforms offer these carers solutions giving them the opportunity to recharge their batteries. PMID- 26975680 TI - [Supporting family carers in psychiatry]. AB - The families of patients with psychiatric disorders are often ill-informed of the consequences of the condition of their loved one. The therapeutic alliance between the family and caregiving team enables the patient to derive the maximum possible benefit from remaining longer at home. PMID- 26975681 TI - [Impact of occupational therapy on the experience of carers]. AB - A study was carried out in 2014 and 2015 analysing the effects of occupational therapy on the carers of patients with Alzheimer's disease or related conditions. The level of "burden" felt by carers was measured before and after this therapy. The results show a real improvement in the quality of their daily life. PMID- 26975682 TI - [Identifying and treating frailty in carers within a geriatric hospital]. AB - In order to enable frailty in carers to be identified early, support projects have been set up within a day hospital for geriatric patients with neurodegenerative diseases. "Help for carers" training groups have been offered for several years in order to provide carers with support and information. This approach favours the global care of the patient and the family. PMID- 26975683 TI - [A centre for carers, a place of information and sharing]. AB - Carers are often a vulnerable population, in need of support. The role of the Maison des Aidants is to guide them, to give them the opportunity to talk and to help them find ways to improve their situation. The Maison des Aidants also aims to train professional carers in providing support to family carers. Establishing good cooperation between family carers and professional caregivers can help to improve the patient's quality of life. PMID- 26975684 TI - [The French carers' association, daily support]. AB - Structuring the help for carers ensures they can be offered adapted support. A policy plan involving all the organisations who provide this type of assistance has resulted in the creation of get-togethers called "Les Cafes des Aidants" ("Carers' Cafes"), where people caring for a family member with any type of disability can talk and share their experience. PMID- 26975685 TI - [Alzheimer's disease, supporting carers]. AB - The association France Alzheimer provides carers with resources. It runs training programmes and organises "Memory Cafes". These initiatives give carers the opportunity to talk about their daily struggles, close to home, and to obtain advice on how to better manage their situation. PMID- 26975686 TI - [Carers and the multi-disciplinary hospital-at-home team]. AB - The home hospitalisation of patients provides the nursing team with a global perspective of their environment. Allowing the patient to remain at home is often only possible thanks to the presence and commitment of the carers. They need support adapted to their specific needs in order to be able to continue to perform their role. The coordination of the hospital-at-home teams is essential in this context. PMID- 26975687 TI - [Not Available]. PMID- 26975688 TI - [Not Available]. PMID- 26975690 TI - A comprehensive molecular phylogeny of spoon worms (Echiura, Annelida): Implications for morphological evolution, the origin of dwarf males, and habitat shifts. AB - Echiurans (spoon worms) are derived annelids that have secondarily lost segmentation. Recently, two molecular phylogenetic studies were performed to resolve the interfamily relationship of echiurans. However, the tree topologies were incongruent and taxon sampling was limited in both the studies. Thus, the phylogenetic relationships within echiurans remain contentious. In this study, I reevaluated the molecular phylogeny of echiurans, using three nuclear (18S, 28S, and H3) and two mitochondrial (16S and COI) genes of 49 echiuran species belonging to 17-19 genera and five families. Results showed that echiurans form the following two major clades: a sexually monomorphic group (Echiuridae, Urechidae, and Thalassematidae) and a sexually dimorphic group (Bonelliidae and Ikedidae). The sister group relationships between Urechidae and Echiuridae, as well as between Ikedidae and Bonelliidae, were supported. The analysis also supported the following relationships among genera within Thalassematidae: {Arhynchite [(Thalassema, Lissomyema) (Ochetostoma, Listriolobus, Ikedosoma, Anelassorhynchus)]}. Furthermore, I evaluated the evolutionary patterns of important taxonomic characteristics (body-wall longitudinal musculature, proboscis shape, gonostmal lip shape, and body color) and habitat shifts (water depth and substrate type), using ancestral state reconstruction analyses. The analyses showed that sexually dimorphic echiurans originated in the shallow waters and secondarily invaded the deep sea, although deep-to-shallow habitat reversal was also detected. In contrary to the previous hypothesis, sexual dimorphism with dwarf males in echiurans may have been a preadaptation to the deep-sea environment. The analyses also showed that habitat shifts from soft sediments to hard substrates occurred in Thalassematidae and Bonelliidae, respectively. A new classification of echiurans, in which Echiura comprises two superfamilies, namely Echiuroidea (with Echiuridae, Urechidae, and Thalassematidae) and Bonellioidea (with Bonelliidae and Ikedidae), is proposed. PMID- 26975689 TI - Metalloprotein Crystallography: More than a Structure. AB - Metal ions and metallocofactors play important roles in a broad range of biochemical reactions. Accordingly, it has been estimated that as much as 25-50% of the proteome uses transition metal ions to carry out a variety of essential functions. The metal ions incorporated within metalloproteins fulfill functional roles based on chemical properties, the diversity of which arises as transition metals can adopt different redox states and geometries, dictated by the identity of the metal and the protein environment. The coupling of a metal ion with an organic framework in metallocofactors, such as heme and cobalamin, further expands the chemical functionality of metals in biology. The three-dimensional visualization of metal ions and complex metallocofactors within a protein scaffold is often a starting point for enzymology, highlighting the importance of structural characterization of metalloproteins. Metalloprotein crystallography, however, presents a number of implicit challenges including correctly incorporating the relevant metal or metallocofactor, maintaining the proper environment for the protein to be purified and crystallized (including providing anaerobic, cold, or aphotic environments), and being mindful of the possibility of X-ray induced damage to the proteins or incorporated metal ions. Nevertheless, the incorporated metals or metallocofactors also present unique advantages in metalloprotein crystallography. The significant resonance that metals undergo with X-ray photons at wavelengths used for protein crystallography and the rich electronic properties of metals, which provide intense and spectroscopically unique signatures, allow a metalloprotein crystallographer to use anomalous dispersion to determine phases for structure solution and to use simultaneous or parallel spectroscopic techniques on single crystals. These properties, coupled with the improved brightness of beamlines, the ability to tune the wavelength of the X-ray beam, the availability of advanced detectors, and the incorporation of spectroscopic equipment at a number of synchrotron beamlines, have yielded exciting developments in metalloprotein structure determination. Here we will present results on the advantageous uses of metals in metalloprotein crystallography, including using metallocofactors to obtain phasing information, using K-edge X-ray absorption spectroscopy to identify metals coordinated in metalloprotein crystals, and using UV-vis spectroscopy on crystals to probe the enzymatic activity of the crystallized protein. PMID- 26975691 TI - Diverse sampling of East African haemosporidians reveals chiropteran origin of malaria parasites in primates and rodents. AB - Phylogenies of parasites provide hypotheses on the history of their movements between hosts, leading to important insights regarding the processes of host switching that underlie modern-day epidemics. Haemosporidian (malaria) parasites lack a well resolved phylogeny, which has impeded the study of evolutionary processes associated with host-switching in this group. Here we present a novel phylogenetic hypothesis that suggests bats served as the ancestral hosts of malaria parasites in primates and rodents. Expanding upon current taxon sampling of Afrotropical bat and bird parasites, we find strong support for all major nodes in the haemosporidian tree using both Bayesian and maximum likelihood approaches. Our analyses support a single transition of haemosporidian parasites from saurian to chiropteran hosts, and do not support a monophyletic relationship between Plasmodium parasites of birds and mammals. We find, for the first time, that Hepatocystis and Plasmodium parasites of mammals represent reciprocally monophyletic evolutionary lineages. These results highlight the importance of broad taxonomic sampling when analyzing phylogenetic relationships, and have important implications for our understanding of key host switching events in the history of malaria parasite evolution. PMID- 26975692 TI - Phylogeny and biogeography of the most diverse clade of South American gymnophthalmid lizards (Squamata, Gymnophthalmidae, Cercosaurinae). AB - Nearly 50% of the diversity of the speciose Neotropical lizard clade Gymnophthalmidae is nested within the subclade Cercosaurinae. The taxonomy of Cercosaurinae lizards has been historically confusing because many diagnostic characters of those clades traditionally ranked as genera do not represent true diagnostic apomorphies. Even though molecular phylogenies of several 'genera' have been presented in the last few years, some of them remain poorly sampled (e.g., Anadia, Echinosaura, Potamites, Riama). In this paper we present a more comprehensive phylogeny of Cercosaurinae lizards with emphasis on Andean taxa from Ecuador and Peru, as well as a time-calibrated phylogeny with reconstruction of ancestral areas. Our analysis includes 52% of all recognized species of Cercosaurinae (67 species) and 1914 characters including three mitochondrial and one nuclear gene. We find that Anadia, Echinosaura, Euspondylus, Potamites, Proctoporus, and Riama are not monophyletic: the Tepuian Anadia mcdiarmidi is not sister to Andean species of Anadia; Echinosaura sulcarostrum is not included in the same clade formed by other species of Echinosaura and their more recent common ancestor; Teuchocercus is nested within Echinosaura; species of Euspondylus included in this study are nested within Proctoporus; Riama laudahnae is included in Proctoporus; and Potamites is paraphyletic and split in two separate clades, one of which we name Gelanesaurus, also a new genus-group name. Within Potamites, P. ecpleopus is paraphyletic, and P. strangulatus strangulatus and P. strangulatus trachodus are recognized as two distinct species. We also identify three unnamed clades (i.e., not nested within any of the recognized 'genera') from Andean populations in Ecuador and Peru. The estimated age of the clade Cercosaurinae (~60Ma) corresponds to the early stages of the northern Andes. Even though the distribution of the most recent common ancestor of Cercosaurinae remains equivocal, our analysis shows that these lizards colonized and radiated along the northern Andes before reaching the central Andes in Peru. Finally, we present phylogenetic definitions for some of the recovered clades to promote a clear and precise classification of Cercosaurinae lizards. PMID- 26975693 TI - Resilience as moderator of the relationship between left-behind experience and mental health of Chinese adolescents. AB - BACKGROUND: In China, since the rural labor, leaving their children in the hometown to other caregivers is a trend that has been increasing, and the impact of parental absence on the well-being of left-behind children is increasingly drawing attention in the Chinese society. However, there is a lack of study on the potential impacts of being left behind on later psychosocial outcomes in adolescence and associated protective factors. AIM: This study was conducted on a large sample of Chinese college students to test the moderating effect of resilience between left-behind experience and mental health problems. METHODS: The Connor-Davidson Resilience Scale and Symptom Checklist as well as a self reported questionnaire about left-behind experience designed by the authors were adopted for a survey with 2,968 Chinese college students as respondents. RESULTS: Totally, 1,063 students (35.8%) had 1 year or more left-behind experience. Compared to those who had no left-behind experience, the students who had left behind experience were rated lower on resilience score and higher on mental health problem score. Mental health problems had a negative correlation with resilience. Regression analysis showed that resilience moderated left-behind experience and mental health problems. CONCLUSION: Individuals with left-behind experience are more vulnerable to mental health problems. Promoting resilience may be helpful for prevention of mental health problems in college students with left-behind experience. PMID- 26975694 TI - Six-session caregiver psychoeducation on bipolar disorder: Does it bring benefits to caregivers? AB - AIM: To evaluate the impact of psychoeducational intervention on the levels of burden, of self-esteem and quality of life in caregivers of patients diagnosed with Bipolar Disorders. METHOD: In this randomized clinical trial, changes in degree of burden, levels of self-esteem and quality of life were evaluated. Caregivers could participate in the group of psychoeducation (six sessions) or usual treatment (without psychoeducation following a manual). RESULTS: There were no significant differences regarding levels of objective burden between groups. Both groups presented improvement in subjective burden scores throughout the interventions. Objective burden scores showed significant reduction in the usual treatment group (p = .003) and a trend toward decrease in the psychoeducational intervention (p = .081). There are no differences regarding improvement in perceived self-esteem and quality of life when comparing means between the groups with and without intervention. CONCLUSION: A six-session caregiver psychoeducational intervention on bipolar disorder did not bring benefits to caregiver's health. A longer longitudinal follow-up study would be crucial to see whether there were differences in degree of burden, perceived self-esteem and quality of life over time in caregivers. PMID- 26975696 TI - On the absolute photoionization cross section and dissociative photoionization of cyclopropenylidene. AB - We report the determination of the absolute photoionization cross section of cyclopropenylidene, c-C3H2, and the heat of formation of the C3H radical and ion derived by the dissociative ionization of the carbene. Vacuum ultraviolet (VUV) synchrotron radiation as provided by the Swiss Light Source and imaging photoelectron photoion coincidence (iPEPICO) were employed. Cyclopropenylidene was generated by pyrolysis of a quadricyclane precursor in a 1 : 1 ratio with benzene, which enabled us to derive the carbene's near threshold absolute photoionization cross section from the photoionization yield of the two pyrolysis products and the known cross section of benzene. The cross section at 9.5 eV, for example, was determined to be 4.5 +/- 1.4 Mb. Upon dissociative ionization the carbene decomposes by hydrogen atom loss to the linear isomer of C3H(+). The appearance energy for this process was determined to be AE(0K)(c-C3H2; l-C3H(+)) = 13.67 +/- 0.10 eV. The heat of formation of neutral and cationic C3H was derived from this value via a thermochemical cycle as Delta(f)H(0K)(C3H) = 725 +/ 25 kJ mol(-1) and Delta(f)H(0K)(C3H(+)) = 1604 +/- 19 kJ mol(-1), using a previously reported ionization energy of C3H. PMID- 26975695 TI - A practice-based research network on the survival of ceramic inlay/onlay restorations. AB - OBJECTIVE: To evaluate prospectively the longevity of ceramic inlay/onlay restorations placed in a web-based practice-based research network and to investigate risk factors associated with restoration failures. MATERIALS AND METHODS: Data were collected by a practice-based research network called Ceramic Success Analysis (CSA). 5791 inlay/onlay ceramic restorations were placed in 5523 patients by 167 dentists between 1994 and 2014 in their dental practices. For each restoration specific information related to the tooth, procedures and materials used were recorded. Annual failure rates (AFRs) were calculated and variables associated with failure were assessed by a multivariate Cox-regression analysis with shared frailty. RESULTS: The mean observation time was 3 years (maximum 15 years) of clinical service, and AFRs at 3 and 10 years follow up were calculated as 1.0% and 1.6%. Restorations with cervical outline in dentin showed a 78% higher risk for failure compared to restorations with margins in enamel. The presence of a liner or base of glass-ionomer cement resulted in a risk for failure twice as large as that of restorations without liner or base material. Restorations performed with simplified adhesive systems (2-step etch-and-rinse and 1-step self-etch) presented a risk of failure 142% higher than restorations performed with adhesives with bonding resin as a separate step (3-step etch-and rinse and 2-step self-etch). 220 failures were recorded and the most predominant reason for failure was fracture of the restoration or tooth (44.5%). CONCLUSIONS: Ceramic inlay/onlay restorations made from several glass ceramic materials and applied by a large number of dentists showed a good survival. Deep cervical cavity outline, presence of a glass ionomer lining cement, and use of simplified adhesive systems were risk factors for survival. PMID- 26975697 TI - Voltage Controlled Magnetic Skyrmion Motion for Racetrack Memory. AB - Magnetic skyrmion, vortex-like swirling topologically stable spin configurations, is appealing as information carrier for future nanoelectronics, owing to the stability, small size and extremely low driving current density. One of the most promising applications of skyrmion is to build racetrack memory (RM). Compared to domain wall-based RM (DW-RM), skyrmion-based RM (Sky-RM) possesses quite a few benefits in terms of energy, density and speed etc. Until now, the fundamental behaviors, including nucleation/annihilation, motion and detection of skyrmion have been intensively investigated. However, one indispensable function, i.e., pinning/depinning of skyrmion still remains an open question and has to be addressed before applying skyrmion for RM. Furthermore, Current research mainly focuses on physical investigations, whereas the electrical design and evaluation are still lacking. In this work, we aim to promote the development of Sky-RM from fundamental physics to realistic electronics. First, we investigate the pinning/depinning characteristics of skyrmion in a nanotrack with the voltage controlled magnetic anisotropy (VCMA) effect. Then, we propose a compact model and design framework of Sky-RM for electrical evaluation. This work completes the elementary memory functionality of Sky-RM and fills the technical gap between the physicists and electronic engineers, making a significant step forward for the development of Sky-RM. PMID- 26975698 TI - Inhalation injury after exposure to indoor fire and smoke: The Brazilian disaster experience. AB - OBJECTIVE: To describe the pre-hospital, emergency department, and intensive care unit (ICU) care and prognosis of patients with inhalation injury after exposure to indoor fire and smoke. MATERIALS AND METHODS: This is a prospective observational cohort study that includes patients admitted to seven ICUs after a fire disaster. The following data were collected: demographic characteristics; use of fiberoptic bronchoscopy; degree of inhalation injury; percentage of burned body surface area; mechanical ventilation parameters; and subsequent events during ICU stay. Patients were followed to determine the ICU and hospital mortality rates. RESULTS: Within 24h of the incident, 68 patients were admitted to seven ICUs. The patients were young and had no comorbidities. Most patients (n=35; 51.5%) only had an inhalation injury. The mean ventilator-free days for patients with an inhalation injury degree of 0 or I was 12.5+/-8.1 days. For patients with an inhalation injury degree of II or III, the mean ventilator-free days was 9.4+/-5.8 days (p=0.12). In terms of the length of ICU stay for patients with degrees 0 or I, and patients with degrees II or III, the median was 7.0 days (5.0-8.0 days) and 12.0 days (8.0-23.0 days) (p<0.001), respectively. In addition, patients with a larger percentage of burned surface areas also had a longer ICU stay; however, no association with ventilator-free days was found. The patients with <10% of burned body surface area showed a mean of 9.2+/-5.4 ventilator-free days. The mean ventilator-free days for patients who had >10% burned body surface area was 11.9+/-9.5 (p=0.26). The length of ICU stay for the <10% and >10% burned body surface area patients was 7.0 days (5.0-10.0 days) and 23.0 days (11.5-25.5 days) (p<0.001), respectively. CONCLUSIONS: We conclude that burn patients with inhalation injuries have different courses of disease, which are mainly determined by the percentage of burned body surface area. PMID- 26975699 TI - Analysis of the predictive efficiency of S100P on adverse prognosis and the pathogenesis of S100P-mediated invasion and metastasis of colon adenocarcinoma. AB - Elevated expression of S100P has been detected in several tumor types. To analyze the potential use of S100P for the prediction of colorectal cancer (CRC) metastasis and prognosis, S100P expression was detected in 125 patients with colon adenocarcinoma by immunohistochemistry, followed by correlation and survival analysis. High S100P expression was correlated with metastasis, as demonstrated by clinically relevant data, and predicted poor survival more effectively than preoperative serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels in colon adenocarcinoma. Stable S100P knockdown CRC cell lines were established to elucidate the relationship between S100P expression and tumor progression in vitro and in vivo. S100P knockdown resulted in reductions in the invasiveness and metastasis of CRC cells. Xenograft growth in nude mice also demonstrated that down-regulated S100P dramatically inhibited peritoneal metastasis of CRC cells. S100P promoted the invasion and metastasis of CRC by activating RAGE/ERK signaling and promoting the epithelial mesenchymal transition (EMT). RAGE was found to be crucial for S100P-mediated EMT in colon cancer. Knockdown of RAGE in S100P-overexpressing colon cancer cells dramatically suppressed EMT process. Our results indicate that overexpression of S100P is related with an invasive and metastatic phenotype of CRC which is EMT involved and RAGE dependent. PMID- 26975700 TI - Time course and predictive factors for lung volume reduction following stereotactic ablative radiotherapy (SABR) of lung tumors. AB - BACKGROUND: Stereotactic ablative volume reduction (SAVR) is a potential alternative to lung-volume reduction surgery in patients with severe emphysema and excessive surgical risk. Having previously observed a dose-volume response for localized lobar volume reduction after stereotactic ablative radiotherapy (SABR) for lung tumors, we investigated the time course and factors associated with volume reduction. METHODS: We retrospectively identified 70 eligible patients receiving lung tumor SABR during 2007-2013. We correlated lobar volume reduction (relative to total, bilateral lung volume [TLV]) with volume receiving high biologically effective doses (VXXBED3) and other pre-treatment factors in all patients, and measured the time course of volume changes on 3-month interval CT scans in patients with large V60BED3 (n = 21, V60BED3 >=4.1 % TLV). RESULTS: Median CT follow-up was 15 months. Median volume reduction of treated lobes was 4.5 % of TLV (range 0.01-13.0 %), or ~9 % of ipsilateral lung volume (ILV); median expansion of non-target adjacent lobes was 2.2 % TLV (-4.6-9.9 %; ~4 % ILV). Treated lobe volume reduction was significantly greater with larger VXXBED3 (XX = 20-100 Gy, R (2) = 0.52-0.55, p < 0.0001) and smaller with lower pre treatment FEV1% (R (2) = 0.11, p = 0.005) in a multivariable linear model. Maximum volume reduction was reached by ~12 months and persisted. CONCLUSIONS: We identified a multivariable model for lobar volume reduction after SABR incorporating dose-volume and pre-treatment FEV1% and characterized its time course. PMID- 26975701 TI - Physiological and proteomic responses to salt stress in chloroplasts of diploid and tetraploid black locust (Robinia pseudoacacia L.). AB - Salinity is an important abiotic stressor that negatively affects plant growth. In this study, we investigated the physiological and molecular mechanisms underlying moderate and high salt tolerance in diploid (2*) and tetraploid (4*) Robinia pseudoacacia L. Our results showed greater H2O2 accumulation and higher levels of important antioxidative enzymes and non-enzymatic antioxidants in 4* plants compared with 2* plants under salt stress. In addition, 4* leaves maintained a relatively intact structure compared to 2* leaves under a corresponding condition. NaCl treatment didn't significantly affect the photosynthetic rate, stomatal conductance or leaf intercellular CO2 concentrations in 4* leaves. Moreover, proteins from control and salt treated 2* and 4* leaf chloroplast samples were extracted and separated by two-dimensional gel electrophoresis. A total of 61 spots in 2* (24) and 4* (27) leaves exhibited reproducible and significant changes under salt stress. In addition, 10 proteins overlapped between 2* and 4* plants under salt stress. These identified proteins were grouped into the following 7 functional categories: photosynthetic Calvin Benson Cycle (26), photosynthetic electron transfer (7), regulation/defense (5), chaperone (3), energy and metabolism (12), redox homeostasis (1) and unknown function (8). This study provides important information of use in the improvement of salt tolerance in plants. PMID- 26975702 TI - Comparison of UK's Minor Ailments Scheme and US's retail clinic model: a narrative review. AB - There is a raising demand for unscheduled care in the United Kingdom. Minor Ailments Schemes (MAS) were introduced to reduce the burden of minor ailments on higher cost settings such as general practices and emergency departments. The number of visits for minor ailments at GPs often declined following the implementation of MAS. Retail clinics in America employ nurse practitioners (NPs) and physician assistants (PAs) who can diagnose and treat minor illness, and minor injuries. Similar to the retail clinics, MAS can merge with walk-in centres. PAs and NPs can take over some primary care workload from pharmacists to prevent the pharmacists from being overwhelmed with all their current duties. MAS can also initiate the development of telehealth service to accommodate the home bound patients. MAS must continue to change and evolve to meet the current and future demands of health care. PMID- 26975703 TI - Midkine Deteriorates Cardiac Remodeling via Epidermal Growth Factor Receptor Signaling in Chronic Kidney Disease. AB - In chronic kidney disease, activation of the epidermal growth factor receptor (EGFR) leads to cardiac hypertrophy, which affects morbidity and mortality. In patients with renal insufficiency and heart failure, the expression of midkine, a heparin-binding growth factor, is increased. Therefore, we investigated the association between midkine and EGFR in the induction of cardiac hypertrophy and dysfunction in chronic kidney disease. We performed subtotal nephrectomies in midkine-knockout mice and wild-type mice. We found that subtotal nephrectomy induced cardiac hypertrophy and phosphorylation of extracellular signal-regulated kinase 1/2 and AKT were attenuated in midkine-knockout mice compared with wild type mice. An antiphosphotyrosine receptor antibody array was used to demonstrate that EGFR phosphorylation in the heart was also lower in midkine-knockout mice than in wild-type mice. Midkine induced EGFR, extracellular signal-regulated kinase 1/2, and AKT phosphorylation and led to hypertrophy in neonatal rat cardiomyocytes. Pretreatment with EGFR inhibitors or EGFR silencing suppressed midkine-stimulated phosphorylation of extracellular signal-regulated kinase 1/2 and AKT, induction of fetal cardiac gene expression, and hypertrophy in cardiomyocytes. To confirm the association between midkine and EGFR in vivo, mice subjected to subtotal nephrectomy were treated with the EGFR inhibitor gefitinib. Gefitinib treatment attenuated subtotal nephrectomy-induced cardiac hypertrophy. These results indicate that midkine might be a key mediator of cardiorenal interactions through EGFR activation, which plays a crucial role in cardiac hypertrophy in chronic kidney disease. PMID- 26975705 TI - Combination of Flow-Mediated Vasodilation and Nitroglycerine-Induced Vasodilation Is More Effective for Prediction of Cardiovascular Events. AB - Measurement of nitroglycerine-induced vasodilation has been performed to differentiate endothelium-dependent vasodilation from endothelium-independent vasodilation as a control test for flow-mediated vasodilation (FMD). Recently, nitroglycerine-induced vasodilation per se has been reported to be a useful marker of the grade of atherosclerosis. The present study aimed to evaluate the prognostic value of FMD combined with nitroglycerine-induced vasodilation for future cardiovascular events. We measured FMD and nitroglycerine-induced vasodilation in 402 subjects, including patients with cardiovascular diseases. During a median follow-up period of 32.3 months, 38 first major cardiovascular events (death from cardiovascular causes, acute myocardial infarction, stroke, and coronary revascularization) occurred. Receiver-operator characteristic curve analysis revealed that FMD alone and nitroglycerine-induced vasodilation alone can predict cardiovascular events with areas under the curve of 0.671 (cutoff 3.3%) and 0.692 (cutoff 11.6%), respectively. FMD combined with nitroglycerine induced vasodilation predicts cardiovascular events with an area under the curve of 0.701. After adjustment for age, sex, and cardiovascular risk factors, above cutoff FMD (>=3.3%) and below cutoff nitroglycerine-induced vasodilation (<11.6%; hazard ratio, 5.55; 95% confidence interval, 1.61-25.46;P=0.006) and below cutoff FMD (<3.3%) and below cutoff nitroglycerine-induced vasodilation (<11.6%; hazard ratio, 7.20; 95% confidence interval, 2.37-31.36;P<0.001) remained strong independent indicator of cardiovascular events. These findings suggest that the combination of FMD and nitroglycerine-induced vasodilation measurements can more accurately predict cardiovascular events compared with FMD alone. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: UMIN000001167. PMID- 26975704 TI - Age- and Hypertension-Associated Protein Aggregates in Mouse Heart Have Similar Proteomic Profiles. AB - Neurodegenerative diseases are largely defined by protein aggregates in affected tissues. Aggregates contain some shared components as well as proteins thought to be specific for each disease. Aggregation has not previously been reported in the normal, aging heart or the hypertensive heart. Detergent-insoluble protein aggregates were isolated from mouse heart and characterized on 2-dimensional gels. Their levels increased markedly and significantly with aging and after sustained angiotensin II-induced hypertension. Of the aggregate components identified by high-resolution proteomics, half changed in abundance with age (392/787) or with sustained hypertension (459/824), whereas 30% (273/901) changed concordantly in both, each P<0.05. One fifth of these proteins were previously associated with age-progressive neurodegenerative or cardiovascular diseases, or both (eg, ApoE, ApoJ, ApoAIV, clusterin, complement C3, and others involved in stress-response and protein-homeostasis pathways). Because fibrosis is a characteristic of both aged and hypertensive hearts, we posited that aging of fibroblasts may contribute to the aggregates observed in cardiac tissue. Indeed, as cardiac myofibroblasts "senesced" (approached their replicative limit) in vitro, they accrued aggregates with many of the same constituent proteins observed in vivo during natural aging or sustained hypertension. In summary, we have shown for the first time that compact (detergent-insoluble) protein aggregates accumulate during natural aging, chronic hypertension, and in vitro myofibroblast senescence, sharing many common proteins. Thus, aggregates that arise from disparate causes (aging, hypertension, and replicative senescence) may have common underlying mechanisms of accrual. PMID- 26975706 TI - Report of the National Heart, Lung, and Blood Institute Working Group on Sex Differences Research in Cardiovascular Disease: Scientific Questions and Challenges. PMID- 26975708 TI - An Expert Opinion From the European Society of Hypertension-European Union Geriatric Medicine Society Working Group on the Management of Hypertension in Very Old, Frail Subjects. PMID- 26975707 TI - Chronic Angiotensin-(1-7) Improves Insulin Sensitivity in High-Fat Fed Mice Independent of Blood Pressure. AB - Angiotensin-(1-7) improves glycemic control in animal models of cardiometabolic syndrome. The tissue-specific sites of action and blood pressure dependence of these metabolic effects, however, remain unclear. We hypothesized that Ang-(1-7) improves insulin sensitivity by enhancing peripheral glucose delivery. Adult male C57BL/6J mice were placed on standard chow or 60% high-fat diet for 11 weeks. Ang (1-7) (400 ng/kg per minute) or saline was infused subcutaneously during the last 3 weeks of diet, and hyperinsulinemic-euglycemic clamps were performed at the end of treatment. High-fat fed mice exhibited modest hypertension (systolic blood pressure: 137 +/- 3 high fat versus 123 +/- 5 mm Hg chow;P=0.001), which was not altered by Ang-(1-7) (141 +/- 4 mm Hg;P=0.574). Ang-(1-7) did not alter body weight or fasting glucose and insulin in chow or high-fat fed mice. Ang-(1-7) increased the steady-state glucose infusion rate needed to maintain euglycemia in high-fat fed mice (31 +/- 5 Ang-(1-7) versus 16 +/- 1 mg/kg per minute vehicle;P=0.017) reflecting increased whole-body insulin sensitivity, with no effect in chow-fed mice. The improved insulin sensitivity in high-fat fed mice was because of an enhanced rate of glucose disappearance (34 +/- 5 Ang-(1-7) versus 20 +/- 2 mg/kg per minute vehicle;P=0.049). Ang-(1-7) enhanced glucose uptake specifically into skeletal muscle by increasing translocation of glucose transporter 4 to the sarcolemma. Our data suggest that Ang-(1-7) has direct insulin-sensitizing effects on skeletal muscle, independent of changes in blood pressure. These findings provide new insight into mechanisms by which Ang-(1-7) improves insulin action, and provide further support for targeting this peptide in cardiometabolic disease. PMID- 26975709 TI - Contribution of Orexin to the Neurogenic Hypertension in BPH/2J Mice. AB - BPH/2J mice are a genetic model of hypertension associated with an overactive sympathetic nervous system. Orexin is a neuropeptide which influences sympathetic activity and blood pressure. Orexin precursor mRNA expression is greater in hypothalamic tissue of BPH/2J compared with normotensive BPN/3J mice. To determine whether enhanced orexinergic signaling contributes to the hypertension, BPH/2J and BPN/3J mice were preimplanted with radiotelemetry probes to compare blood pressure 1 hour before and 5 hours after administration of almorexant, an orexin receptor antagonist. Mid frequency mean arterial pressure power and the depressor response to ganglion blockade were also used as indicators of sympathetic nervous system activity. Administration of almorexant at 100 (IP) and 300 mg/kg (oral) in BPH/2J mice during the dark-active period (2 hours after lights off) markedly reduced blood pressure (-16.1 +/- 1.6 and -11.0 +/- 1.1 mm Hg, respectively;P<0.001 compared with vehicle). However, when almorexant (100 mg/kg, IP) was administered during the light-inactive period (5 hours before lights off) no reduction from baseline was observed (P=0.64). The same dose of almorexant in BPN/3J mice had no effect on blood pressure during the dark (P=0.79) or light periods (P=0.24). Almorexant attenuated the depressor response to ganglion blockade (P=0.018) and reduced the mid frequency mean arterial pressure power in BPH/2J mice (P<0.001), but not BPN/3J mice (P=0.70). Immunohistochemical labeling revealed that BPH/2J mice have 29% more orexin neurons than BPN/3J mice which are preferentially located in the lateral hypothalamus. The results suggest that enhanced orexinergic signaling contributes to sympathetic overactivity and hypertension during the dark period in BPH/2J mice. PMID- 26975710 TI - Association of Circulating Renin and Aldosterone With Osteocalcin and Bone Mineral Density in African Ancestry Families. AB - Hypertension is associated with accelerated bone loss, and the renin-angiotensin aldosterone system is a key regulator of blood pressure. Although components of this system are expressed in human bone cells, studies in humans are sparse. Thus, we studied the association of circulating renin and aldosterone with osteocalcin and bone mineral density. We recruited 373 African ancestry family members without regard to health status from 6 probands (mean family size: 62 and relative pairs: 1687). Participants underwent a clinical examination, dual-energy x-ray absorptiometry, and quantitative computed tomographic scans. Renin activity, aldosterone concentration, and osteocalcin were measured in fasting blood samples. Aldosterone/renin ratio was calculated as aldosterone concentration/renin activity. All models were analyzed using pedigree-based variance components methods. Full models included adjustment for age, sex, body composition, comorbidities, lifestyle factors, blood pressure, and antihypertensive medication. Higher renin activity was significantly associated with lower total osteocalcin and with higher trabecular bone mineral density (both P<0.01). There were also significant genetic correlations between renin activity and whole-body bone mineral density. There were no associations with aldosterone concentration in any model and results for aldosterone/renin ratio were similar to those for renin activity. This is the first study to report a significant association between renin activity and a marker of bone turnover and bone mineral density in generally healthy individuals. Also, there is evidence for significant genetic pleiotropy and, thus, there may be a shared biological mechanism underlying both the renin-angiotensin-aldosterone system and bone metabolism that is independent of hypertension. PMID- 26975711 TI - SmgGDS as a Crucial Mediator of the Inhibitory Effects of Statins on Cardiac Hypertrophy and Fibrosis: Novel Mechanism of the Pleiotropic Effects of Statins. AB - The detailed molecular mechanisms of the pleiotropic effects of statins remain to be fully elucidated. Here, we hypothesized that cardioprotective effects of statins are mediated by small GTP-binding protein GDP dissociation stimulator (SmgGDS). SmgGDS(+/-) and wild-type (WT) mice were treated with continuous infusion of angiotensin II (Ang II) for 2 weeks with and without oral treatment with atorvastatin or pravastatin. At 2 weeks, the extents of Ang II-induced cardiac hypertrophy and fibrosis were comparable between the 2 genotypes. However, statins significantly attenuated cardiomyocyte hypertrophy and fibrosis in WT mice, but not in SmgGDS(+/-) mice. In SmgGDS(+/-) cardiac fibroblasts (CFs), Rac1 expression, extracellular signal-regulated kinases 1/2 activity, Rho kinase activity, and inflammatory cytokines secretion in response to Ang II were significantly increased when compared with WT CFs. Atorvastatin significantly reduced Rac1 expression and oxidative stress in WT CFs, but not in SmgGDS(+/-) CFs. Furthermore, Bio-plex analysis revealed significant upregulations of inflammatory cytokines/chemokines and growth factors in SmgGDS(+/-) CFs when compared with WT CFs. Importantly, conditioned medium from SmgGDS(+/-) CFs increased B-type natriuretic peptide expression in rat cardiomyocytes to a greater extent than that from WT CFs. Furthermore, atorvastatin significantly increased SmgGDS secretion from mouse CFs. Finally, treatment with recombinant SmgGDS significantly reduced Rac1 expression in SmgGDS(+/-) CFs. These results indicate that both intracellular and extracellular SmgGDS play crucial roles in the inhibitory effects of statins on cardiac hypertrophy and fibrosis, partly through inhibition of Rac1, Rho kinase, and extracellular signal-regulated kinase 1/2 pathways, demonstrating the novel mechanism of the pleiotropic effects of statins. PMID- 26975713 TI - Disposable single-use receptacles in a tertiary hospital: A large survey of staff after a hospital-wide implementation. AB - In March 2014, our 1,100-bed tertiary hospital fully converted from a traditional system of reusable receptacles to a single-use disposable pulp receptacle system. Almost 12 months later, in February 2015, we undertook a large survey questionnaire to investigate user acceptance, perceptions, and any areas for improvement. The disposable pulp receptacle system was seen to be more convenient, more hygienic, and less of a risk in spreading infectious diseases. Occasional human error in its use was featured in the rare negative feedback. PMID- 26975712 TI - Adrenal Venous Sampling in Patients With Positive Screening but Negative Confirmatory Testing for Primary Aldosteronism. AB - Adrenal venous sampling is considered to be the most reliable diagnostic procedure to lateralize aldosterone excess in primary aldosteronism (PA). However, normative criteria have not been established partially because of a lack of data in non-PA hypertensive patients. The aim of the study was to investigate aldosterone concentration and its gradient in the adrenal vein of non-PA hypertensive patients. We retrospectively studied the results of cosyntropin stimulated adrenal venous sampling in 40 hypertensive patients who showed positive screening testing but negative results in 2 confirmatory tests/captopril challenge test and saline infusion test. Plasma aldosterone concentration, aldosterone/cortisol ratio, its higher/lower ratio (lateralization index) in the adrenal vein with cosyntropin stimulation were measured. Median plasma aldosterone concentration in the adrenal vein was 25 819 pg/mL (range, 5154-69 920) in the higher side and 12 953 (range, 1866-36 190) pg/mL in the lower side (P<0.001). There was a significant gradient in aldosterone/cortisol ratio between the higher and the lower sides (27.2 [5.4-66.0] versus 17.3 [4.0-59.0] pg/mL per MUg/dL;P<0.001) with lateralization index ranging from 1.01 to 3.87. The aldosterone lateralization gradient was between 1 to 2 in 32 patients and 2 to 4 in 8 patients. None of the patients showed lateralization index >=4. The present study demonstrated that plasma aldosterone concentration in the adrenal veins showed significant variation and lateralization gradient even in non-PA hypertensive patients. Adrenal venous sampling aldosterone lateralization gradients between 2 and 4 should be interpreted with caution in patients with PA because these gradients can be found even in patients with negative confirmatory testing for PA. PMID- 26975714 TI - Impact of monitoring surgical prophylactic antibiotics and a computerized decision support system on antimicrobial use and antimicrobial resistance. AB - BACKGROUND: Monitoring of performance indicators and implementation of a computerized decision support system (CDSS) have been suggested as effective measures to improve quality of care. We conducted this study to evaluate the effect of monitoring of surgical prophylactic antibiotics (SPAs) and the CDSS on the antimicrobial use and resistance rate of major nosocomial pathogens. METHODS: An interrupted time series with segmented regression analysis in 3 periods (preintervention, SPAs monitoring, and CDSS) was conducted in a tertiary care hospital. Immediate change and change in trends of antimicrobial use density, resistance rate of nosocomial pathogens, and cost of antibiotics in each intervention period were compared with those of the preintervention period. RESULTS: Compared with the preintervention period, the change in the slope of the total use of antibiotics was -8.71 defined daily dose (DDD) per 1,000 patient days per month (95% confidence interval [CI], -11.43 to -5.98; P < .01) in the SPAs monitoring period and -1.95 DDD per 1,000 patient days per month (95% CI, 2.93 to -0.96; P < .01) in the CDSS period. Use of third-generation cephalosporins and aminoglycosides showed change comparable with that of total antibiotics use, but use of vancomycin and carbapenem was unchanged in the CDSS period. Trends of the proportions of extended-spectrum beta-lactamase-producing Escherichia coli, meropenem-resistant Pseudomonas aeruginosa, and methicillin resistant Staphylococcus aureus have been reversed or decreased in slope in the CDSS period. Length of hospital stay also showed a negative change in slope in the CDSS period. CONCLUSIONS: Monitoring of SPAs and implementation of the CDSS can be effective measures for antimicrobial stewardship. PMID- 26975715 TI - Risk factors for cesarean surgical site infections at a Thai-Myanmar border hospital. AB - BACKGROUND: Cesarean surgical site infections (SSIs) are a major challenge in Thai-Myanmar border hospital settings. This study aimed to examine risk factors for SSIs after cesarean section. METHODS: This was a prospective cohort study conducted in a Thai-Myanmar border hospital between January 2007 and December 2012. Data were collected from the medical record database by trained infection control nurses. Stepwise multivariable logistic regression was used for risk factor analysis and expressed as a risk ratio (RR). RESULTS: The cesarean SSI rate was 5.9% (293 SSIs in 4,988 cases). Of these, 17.1% were incisional SSIs (10.9% superficial and 6.2% deep incisional SSIs), and 82.9% were organ or space SSIs. Risk factors for cesarean organ-space SSIs included a wound class >=3 (RR, 4.82; 95% confidence interval [CI], 3.41-6.83), ethnic minority (RR, 2.51; 95% CI, 1.61-3.92), hemoglobin <11 g/dL (RR, 2.19; 95% CI, 1.57-3.04), pelvic examination before delivery on >=5 occasions (RR, 4.16; 95% CI, 2.89-5.99), preterm (RR, 1.98; 95% CI, 1.33-2.95), being a local referral (RR, 3.37; 95% CI, 2.29-4.97), and foul-smelling amniotic fluid (RR, 21.08; 95% CI, 10.23-43.41). CONCLUSIONS: Most cesarean SSIs in this study seem to have a high severity. Their risk factors reflected delayed appropriate perinatal maternal care that resulted in late cesarean delivery. Early prenatal care may help reduce cesarean SSIs among this population. PMID- 26975716 TI - International Nosocomial Infection Control Consortium (INICC) resources: INICC multidimensional approach and INICC surveillance online system. AB - BACKGROUND: The International Nosocomial Infection Control Consortium (INICC) is an international, nonprofit, multicentric health care-associated infection (HAI) cohort surveillance network with a methodology based on the U.S. Centers for Disease Control and Prevention's National Healthcare Safety Network (CDC-NHSN). The INICC was founded in 1998 to promote evidence-based infection control in limited-resource countries through the analysis of surveillance data collected by their affiliated hospitals. The INICC is comprised of >3,000-affiliated infection control professionals from 1,000 hospitals in 67 countries and is the only source of aggregate standardized international data on HAI epidemiology. Having published reports on device-associated (DA) HAI (HAI) and surgical site infections (SSIs) from 43 countries and several reports per individual country, the INICC showed DA HAI and SSI rates in limited-resources countries are 3-5 times higher than in high-income countries. METHODS: The INICC developed the INICC Multidimensional Approach (IMA) for HAI prevention with 6 components, bundles with 7-13 elements, and the INICC Surveillance Online System (ISOS) with 15 modules. RESOURCES: In this article the IMA, the ISOS for outcome surveillance of HAIs and process surveillance of bundles to prevent HAIs, and the use of surveillance data feedback are described. COMMENTS: Remarkable features of the IMA and ISOS are INICC's applying of the latest published CDC-NHSN HAI definitions, including their updates and revisions in 2008, 2013, 2015 and 2016; INICC's informatics system to check accuracy of fulfillment of CDC-NHSN HAI criteria; and INICC's system to check compliance with each bundle element. PMID- 26975717 TI - C-ON bond homolysis in alkoxyamines. Part 12: the effect of the para-substituent in the 1-phenylethyl fragment. AB - The application of alkoxyamines as initiators/controllers in nitroxide mediated polymerization and as agents for theranostics requires the development of switchable (from stable one to labile one) alkoxyamines. One way to achieve this is to tune the polarity of various groups carried by either the alkyl fragment or the nitroxyl fragment. Thus, the effect of protonation/deprotonation of the para functionalized aryl moiety carried by the alkyl fragment in diethyl(2,2-dimethyl 1-((1,1-dimethylethyl)(1-para-subsitutedphenylethoxy)amino)propyl)phosphonate is investigated. An increase in kd is observed with increasing localized electrical effect, i.e., in the presence of electron withdrawing groups at the para position of the phenyl ring. A striking effect of the intimate ion pair on kd is also observed. PMID- 26975718 TI - Implementation challenges and opportunities for HIV Treatment as Prevention (TasP) among young men in Vancouver, Canada: a qualitative study. AB - BACKGROUND: Despite evidence supporting the preventative potential of HIV Treatment as Prevention (TasP), scientific experts and community stakeholders have suggested that the success of TasP at the population level will require overcoming a set of complex and population-specific implementation challenges. For example, the factors that might influence decisions to initiate 'early' treatment have yet to be thoroughly understood; neither have questions about the factors that enhance or impede their ability to achieve long-term adherence to ARVs or the social norms regarding various treatment regimens been examined in detail. This knowledge gap may hamper opportunities to effectively develop public health practices that are informed by the various challenges and opportunities related to TasP implementation and scale up. METHODS: Drawing on 50 in-depth, individual interviews with young men ages 18-24 in Vancouver, Canada, this study examines young men's perspectives regarding factors that might affect their engagement with TasP. RESULTS: While findings from the current study indicate young men generally have a high receptiveness to TasP, our findings also identify key social and structural forces that will warrant ongoing consideration for TasP implementation. For example, participants described how an enhanced awareness regarding treatment (including awareness of the universal availability of treatment in Vancouver) would be a necessary, but not sufficient, condition to decide to endorse TasP. Their decisions about engaging in HIV care in the context of TasP (e.g., HIV testing, treatment initiation, long-term adherence) also appear to be contingent on their ability to negotiate or 'balance' the risks and benefits to themselves and others. The findings also offer insight into the complex and sometimes controversial narratives that continue to emerge regarding risk compensation practices in the context of TasP. CONCLUSION: Based on the results of this study, we identify several areas that hold promise for informing the effective scale up of TasP, including new information regarding implementation adaptation strategies. PMID- 26975719 TI - Vertical position of Chinese power words influences power judgments: Evidence from spatial compatibility task and event-related Potentials. AB - The present study used event-related potentials (ERPs) to explore the influence of vertical position on power judgments. Participants were asked to identify whether a Chinese word represented a powerful or powerless group (e.g., "king" or "servant"), which was presented in the top or bottom of the screen. The behavioral analysis showed that judging the power of powerful words were significantly faster when they were presented at the top position, compared with when they were presented at the bottom position. The ERP analysis showed enhanced N1 amplitude for congruent trials (i.e., the powerful words in the top and the powerless words in the bottom of the screen) and larger P300 and LPC amplitude for incongruent trials (i.e., the powerful words in the bottom and the powerless words in the top of the screen). The present findings provide further electrophysiological evidence that thinking about power can automatically activate the underlying spatial up-down (verticality) image schema and that the influence of vertical position on the power judgments not only occurs at the early perceptual stage of power word processing, but also at the higher cognitive stage (i.e., allocation of attention resources, conflict solving and response selection). This study revealed the neural underpinnings of metaphor congruent effect which have great significance to our understanding of the abstract concept power. PMID- 26975720 TI - Contacting authors to retrieve individual patient data: study protocol for a randomized controlled trial. AB - BACKGROUND: Individual patient data (IPD) meta-analysis is considered the "gold standard" for exploring the effectiveness of interventions in different subgroups of patients. However, obtaining IPD is time-consuming and contact with the researchers responsible for the original trials is usually required. To date, there are no studies evaluating different strategies to optimize the process for retrieval of IPD from such researchers. Our aim is to examine the impact of providing incentives to the researchers responsible for the trials eligible for a meta-analysis to submit their IPD. METHODS/DESIGN: We updated our previously published systematic reviews for type 1 diabetes mellitus comparing long- and intermediate-acting insulin regimens (from January 2013 to June 2015) and for Alzheimer's dementia comparing cognitive enhancers (from January 2015 to May 2015). Eligible were randomized controlled trials (RCTs) fulfilling the eligibility criteria of the systematic reviews. We will randomly allocate authors of the reports of these RCTs into an intervention or control group. Those allocated to the intervention group will be contacted by email, mail, and phone, and will be asked to provide the IPD from their RCT and will be given a financial incentive. Those allocated to the control group will be contacted by email, mail, and phone, but will not receive a financial incentive. Our primary outcome will be the proportion of authors who provide the IPD. The secondary outcomes will be the time to return the dataset (defined as the period between the information request and the authors' response with the dataset), and completeness of data. We will compare the response rates in the two groups using the odds ratio and the corresponding 95 % confidence interval. We will also use binary logistic regression and cox regression analyses to examine whether different RCT characteristics, such as study size and sponsor information, influence the probability of providing IPD and the time needed to share the data. DISCUSSION: This study will determine whether a financial incentive affects response rates when seeking IPD from the original researchers. We will disseminate our findings in an open access scientific journal and present results at national and international conferences. TRIAL REGISTRATION: This trial is registered in Clinical Trials.gov, ID number NCT02569411 . Date of registration 5 October 2015. PMID- 26975722 TI - Large-scale identification of membrane proteins based on analysis of trypsin protected transmembrane segments. AB - : Integral membrane proteins are generally under-represented in routine proteomic analyses, mostly because of their relatively low abundance, hydrophobicity and lack of trypsin-cleavage sites. To increase the coverage of membrane proteomes, various strategies have been developed, targeting mostly the extra-membrane segments of membrane proteins. We focused our attention to the rather overlooked hydrophobic transmembrane segments. Such peptides can be isolated after carbonate stripping and protease "shaving" of membranes isolated by simple centrifugation procedure. The treated membranes with embedded hydrophobic peptides can then be solubilized in organic solvents, re-digested with CNBr, delipidated and subjected to LC-MS/MS analysis. We modified the original "hppK" method, and applied it for the analysis of human lymphoma cells. We identified 1224 proteins of which two thirds were IMPs with 1-16 transmembrane segments. This method allowed us to identify 13 "missing proteins" - proteins with no previous evidence on protein level. BIOLOGICAL SIGNIFICANCE: Integral membrane proteins execute numerous essential functions and represent substantial part of eukaryotic proteomes. Our knowledge of their function and expression is, however, limited. Novel approaches extending our knowledge of membrane proteome are therefore highly desired. As we demonstrate here, a non-conventional method which targets rather overlooked hydrophobic transmembrane segments of integral membrane proteins has wide potential to provide the missing information on the membrane proteome. We show that it can deliver identification and potentially also quantification of hundreds of integral membrane proteins including the so called "missing proteins". PMID- 26975721 TI - Immunogenicity of a chimeric Plasmodium falciparum merozoite surface protein vaccine in Aotus monkeys. AB - BACKGROUND: The production of properly folded, recombinant sub-unit Plasmodium falciparum malaria vaccine candidates in sufficient quantities is often a challenge. Success in vaccine immunogenicity studies in small animal models does not always predict immunogenicity in non-human primates and/or human subjects. The aim of this study was to assess the immunogenicity of a chimeric blood-stage malaria vaccine in Aotus monkeys. This vaccine candidate includes the neutralizing B cell epitopes of P. falciparum merozoite surface protein 1 (rPfMSP119) genetically linked to a highly immunogenic, well-conserved P. falciparum merozoite surface protein 8 (rPfMSP8 (DeltaAsn/Asp)) partner. METHODS: Aotus nancymaae monkeys were immunized with purified rPfMSP1/8 or rPfMSP8 (DeltaAsn/Asp) formulated with Montanide ISA 720 as adjuvant, or with adjuvant alone. Antibody responses to MSP119 and MSP8 domains were measured by ELISA following primary, secondary and tertiary immunizations. The functionality of vaccine-induced antibodies was assessed in a standard P. falciparum blood-stage in vitro growth inhibition assay. Non-parametric tests with corrections for multiple comparisons when appropriate were used to determine the significance of differences in antigen-specific IgG titres and in parasite growth inhibition. RESULTS: The chimeric rPfMSP1/8 vaccine was shown to be well tolerated and highly immunogenic with boost-able antibody responses elicited to both PfMSP8 and PfMSP119 domains. Elicited antibodies were highly cross-reactive between FVO and 3D7 alleles of PfMSP119 and potently inhibited the in vitro growth of P. falciparum blood-stage parasites. CONCLUSIONS: Similar to previous results with inbred and outbred mice and with rabbits, the PfMSP1/8 vaccine was shown to be highly effective in eliciting P. falciparum growth inhibitory antibodies upon immunization of non-human primates. The data support the further assessment of PfMSP1/8 as a component of a multivalent vaccine for use in human subjects. As important, the data indicate that rPfMSP8 (DeltaAsn/Asp) can be used as a malaria specific carrier protein to: (1) drive production of antibody responses to neutralizing B cell epitopes of heterologous vaccine candidates and (2) facilitate production of properly folded, recombinant P. falciparum subunit vaccines in high yield. PMID- 26975723 TI - Photovoltaic Properties of Two-Dimensional (CH3NH3)2Pb(SCN)2I2 Perovskite: A Combined Experimental and Density Functional Theory Study. AB - We explore the photovoltaic-relevant properties of the 2D MA2Pb(SCN)2I2 (where MA = CH3NH3(+)) perovskite using a combination of materials synthesis, characterization and density functional theory calculation, and determine electronic properties of MA2Pb(SCN)2I2 that are significantly different from those previously reported in literature. The layered perovskite with mixed-anions exhibits an indirect bandgap of ~2.04 eV, with a slightly larger direct bandgap of ~2.11 eV. The carriers (both electrons and holes) are also found to be confined within the 2D layers. Our results suggest that the 2D MA2Pb(SCN)2I2 perovskite may not be among the most promising absorbers for efficient single junction solar cell applications; however, use as an absorber for the top cell of a tandem solar cell may still be a possibility if films are grown with the 2D layers aligned perpendicular to the substrates. PMID- 26975724 TI - Two Ancient Gene Families Are Critical for Maintenance of the Mammalian Skin Barrier in Postnatal Life. AB - The skin barrier is critical for mammalian survival in the terrestrial environment, affording protection against fluid loss, microbes, toxins, and UV exposure. Many genes indispensable for barrier formation in the embryo have been identified, but loss of these genes in adult mice does not induce barrier regression. We describe a complex regulatory network centered on two ancient gene families, the grainyhead-like (Grhl) transcription factors and the protein cross linking enzymes (tissue transglutaminases [Tgms]), which are essential for skin permeability barrier maintenance in adult mice. Embryonic deletion of Grhl3 induces loss of Tgm1 expression, which disrupts the cornified envelope, thus preventing permeability barrier formation leading to neonatal death. However, gene deletion of Grhl3 in adult mice does not disrupt the preformed barrier, with cornified envelope integrity maintained by Grhl1 and Tgm5, which are up-regulated in response to postnatal loss of Grhl3. Concomitant deletion of both Grhl factors in adult mice induced loss of Tgm1 and Tgm5 expression, perturbation of the cornified envelope, and complete permeability barrier regression that was incompatible with life. These findings define the molecular safeguards for barrier function that accompany the transition from intrauterine to terrestrial life. PMID- 26975725 TI - Identification of Alpha-Adrenergic Agonists as Potential Therapeutic Agents for Dermatomyositis through Drug-Repurposing Using Public Expression Datasets. PMID- 26975726 TI - Familial associations of monoclonal gammopathy of unknown significance with autoimmune diseases. PMID- 26975727 TI - JAK2(V617F) allele burden ?50% is associated with response to ruxolitinib in persons with MPN-associated myelofibrosis and splenomegaly requiring therapy. PMID- 26975729 TI - Rationalization of the selectivity between 1,3- and 1,2-migration: a DFT study on gold(i)-catalyzed propargylic ester rearrangement. AB - Gold catalyzed rearrangement of propargylic esters can undergo 1,3-acyloxy migration to form allenes, or undergo 1,2-acyloxy migration to access gold carbenoids. The variation in migration leads to different reactivities and diverse cascade transformations. The effect of terminal substituents is very important for the rearrangement. However, it remains ambiguous how terminal substituents govern the selectivity of the rearrangement. This study presents a theoretical model based on the resonance structure of gold activated propargylic ester complexes to rationalize the rearrangement selectivity. Substrates with a major resonance contributor A prefer 5-exo-dig cyclization (1,2-migration), while those with a major resonance contributor B prefer 6-endo-dig cyclization (1,3 migration). This concise model would be helpful in understanding and tuning the selectivity of the metal catalyzed rearrangement of propargylic esters. PMID- 26975728 TI - Bacterial regulon modeling and prediction based on systematic cis regulatory motif analyses. AB - Regulons are the basic units of the response system in a bacterial cell, and each consists of a set of transcriptionally co-regulated operons. Regulon elucidation is the basis for studying the bacterial global transcriptional regulation network. In this study, we designed a novel co-regulation score between a pair of operons based on accurate operon identification and cis regulatory motif analyses, which can capture their co-regulation relationship much better than other scores. Taking full advantage of this discovery, we developed a new computational framework and built a novel graph model for regulon prediction. This model integrates the motif comparison and clustering and makes the regulon prediction problem substantially more solvable and accurate. To evaluate our prediction, a regulon coverage score was designed based on the documented regulons and their overlap with our prediction; and a modified Fisher Exact test was implemented to measure how well our predictions match the co-expressed modules derived from E. coli microarray gene-expression datasets collected under 466 conditions. The results indicate that our program consistently performed better than others in terms of the prediction accuracy. This suggests that our algorithms substantially improve the state-of-the-art, leading to a computational capability to reliably predict regulons for any bacteria. PMID- 26975730 TI - Management of uveal tract melanoma: A comprehensive review. AB - Uveal tract melanoma is the most common primary intraocular malignancy in adults, accounting for about 5-10% of all the melanomas. Since there are no lymphatic vessels in the eye, uveal melanoma can only spread hematogenously leading to liver metastasis. A wide variety of treatment modalities are available for its management, leading to dilemma in selecting the appropriate therapy. This article reviews the diagnostic and therapeutic modalities available and thus, can help to individualize the treatment plan for each patient. PMID- 26975731 TI - Parenteral Nutrition in Critically Ill Children. PMID- 26975732 TI - Minicircle DNA Provides Enhanced and Prolonged Transgene Expression Following Airway Gene Transfer. AB - Gene therapy for cystic fibrosis using non-viral, plasmid-based formulations has been the subject of intensive research for over two decades but a clinically viable product has yet to materialise in large part due to inefficient transgene expression. Minicircle DNA give enhanced and more persistent transgene expression compared to plasmid DNA in a number of organ systems but has not been assessed in the lung. In this study we compared minicircle DNA with plasmid DNA in transfections of airway epithelial cells. In vitro, luciferase gene expression from minicircles was 5-10-fold higher than with plasmid DNA. In eGFP transfections in vitro both the mean fluorescence intensity and percentage of cells transfected was 2-4-fold higher with minicircle DNA. Administration of equimolar amounts of DNA to mouse lungs resulted in a reduced inflammatory response and more persistent transgene expression, with luciferase activity persisting for 2 weeks from minicircle DNA compared to plasmid formulations. Transfection of equal mass amounts of DNA in mouse lungs resulted in a 6-fold increase in transgene expression in addition to more persistent transgene expression. Our findings have clear implications for gene therapy of airway disorders where plasmid DNA transfections have so far proven inefficient in clinical trials. PMID- 26975734 TI - The factor in EDHF: Cytochrome P450 derived lipid mediators and vascular signaling. AB - Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to generate epoxyeicosatrienoic acids (EETs). The latter are biologically active and reported to act as an endothelium-derived hyperpolarizing factor (EDHF) as well as to affect angiogenic and inflammatory signaling pathways. In addition to arachidonic acid, the CYP epoxygenases also metabolize the Omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid and docosahexaenoic acid, to generate bioactive lipid epoxide mediators. The latter can be more potent than the EETs but their actions are under investigated. The Omega3-epoxides, like the EETs, are metabolized by the soluble epoxide hydrolase to corresponding diols and epoxide hydrolase inhibition increases epoxide levels and demonstrates anti-hypertensive as well as anti-inflammatory effects. It seems that the overall consequences of CYP epoxygenase activation largely depend on enzyme substrate preference and the endogenous Omega-3/Omega-6 PUFA ratio. This review outlines the evidence for a physiological role for EETs in the regulation of vascular homeostasis. PMID- 26975733 TI - The C-terminus of DSX(F5) protein acts as a novel regulatory domain in Bombyx mori. AB - The doublesex gene regulates the somatic sexual development of Bombyx mori by alternatively splicing into sex-specific splice forms. In our previous study, the splice form Bmdsx (F7) , which encodes the BmDSX(F5) protein, was found to be expressed in a female-specific manner and to contain a novel C-terminus. In this study, we aimed to investigate the role of this C-terminus. Two transgenic lines, L1 and L2, were constructed to ectopically express Bmdsx (F7) in males. Phenotype and W chromosome-specific polymerase chain reaction (PCR) analysis showed that developmental abnormalities and sex reversal did not occur. Moreover, the sex ratio was also normal. Quantitative PCR revealed that the expression levels of SP1 and Vg were upregulated in the fat body of transgenic males. Additionally, the expression level of PBP was downregulated in the antenna of transgenic males. The results suggested that the C-terminus of BmDSX(F5) functioned as a regulatory domain during regulation of downstream target gene expression and that BmDSX(F5) participated in the sexual development of somatic cells together with other DSX proteins in B. mori. PMID- 26975735 TI - Organ doses can be estimated from the computed tomography (CT) dose index for cone-beam CT on radiotherapy equipment. AB - Cone beam computed tomography (CBCT) systems are fitted to radiotherapy linear accelerators and used for patient positioning prior to treatment by image guided radiotherapy (IGRT). Radiotherapists' and radiographers' knowledge of doses to organs from CBCT imaging is limited. The weighted CT dose index for a reference beam of width 20 mm (CTDIw,ref) is displayed on Varian CBCT imaging equipment known as an On-Board Imager (OBI) linked to the Truebeam linear accelerator. This has the potential to provide an indication of organ doses. This knowledge would be helpful for guidance of radiotherapy clinicians preparing treatments. Monte Carlo simulations of imaging protocols for head, thorax and pelvic scans have been performed using EGSnrc/BEAMnrc, EGSnrc/DOSXYZnrc, and ICRP reference computational male and female phantoms to derive the mean absorbed doses to organs and tissues, which have been compared with values for the CTDIw,ref displayed on the CBCT scanner console. Substantial variations in dose were observed between male and female phantoms. Nevertheless, the CTDIw,ref gave doses within +/-21% for the stomach and liver in thorax scans and 2 * CTDIw,ref can be used as a measure of doses to breast, lung and oesophagus. The CTDIw,ref could provide indications of doses to the brain for head scans, and the colon for pelvic scans. It is proposed that knowledge of the link between CTDIw for CBCT should be promoted and included in the training of radiotherapy staff. PMID- 26975736 TI - Coupled plasma filtration adsorption improves hemodynamics in septic shock. AB - PURPOSE: Septic shock involves a dysregulation of the immune response to an infection. This may lead to hemodynamic dysfunction and multiple-organ failure. The main aim of this study was to evaluate the effect of coupled plasma filtration adsorption (CPFA) on the hemodynamic profile in patients with septic shock. MATERIALS AND METHODS: We retrospectively analyzed data from 21 adult patients admitted to the intensive care unit with a diagnosis of septic shock, comparing data between pre-CPFA and post-CPFA treatment. They received a maximum of 5 cycles of treatment. RESULTS: Coupled plasma filtration adsorption treatment was associated with a significant increase of mean arterial pressure (P < .001), reduction of the vasoactive/inotropic requirement (P = .007), and renal improvement. In patients with leukocytosis or leucopenia, the leukocyte count was restored to a reference range of values. CONCLUSION: Treatment with CPFA improves hemodynamic parameters in septic shock patients, ameliorating organ failure. PMID- 26975737 TI - The organizational structure of an intensive care unit influences treatment of hypotension among critically ill patients: A retrospective cohort study. AB - PURPOSE: Prior studies report that weekend admission to an intensive care unit is associated with increased mortality, potentially attributed to the organizational structure of the unit. This study aims to determine whether treatment of hypotension, a risk factor for mortality, differs according to level of staffing. METHODS: Using the Multiparameter Intelligent Monitoring in Intensive Care database, we conducted a retrospective study of patients admitted to an intensive care unit at Beth Israel Deaconess Medical Center who experienced one or more episodes of hypotension. Episodes were categorized according to the staffing level, defined as high during weekday daytime (7 am-7 pm) and low during weekends or nighttime (7 pm-7 am). RESULTS: Patients with a hypotensive event on a weekend were less likely to be treated compared with those that occurred during the weekday daytime (P = .02). No association between weekday daytime vs weekday nighttime staffing levels and treatment of hypotension was found (risk ratio, 1.02; 95% confidence interval, 0.98-1.07). CONCLUSION: Patients with a hypotensive event on a weekend were less likely to be treated than patients with an event during high-staffing periods. No association between weekday nighttime staffing and hypotension treatment was observed. We conclude that treatment of a hypotensive episode relies on more than solely staffing levels. PMID- 26975738 TI - Evaluating the Impact of Total Intravenous Anesthesia on the Clinical Outcomes and Perioperative NLR and PLR Profiles of Patients Undergoing Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy. AB - PURPOSE: The aim of this study was to assess the impact of total intravenous anesthesia (TIVA) on the perioperative inflammatory profile and clinical outcomes of patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). METHODS: A retrospective review of patients undergoing CRS-HIPEC was performed. Patients receiving a combination of preoperative tramadol extended release (ER), celecoxib, and pregabalin, along with combined intraoperative infusions of propofol, dexmedetomidine, lidocaine, and ketamine were classified as receiving a TIVA regimen (TIVA group). The second group consisted of patients receiving volatile-opioid-based anesthesia (VO group). The neutrophil:leukocyte (NLR) and platelet: leukocyte (PLR) ratios were calculated to evaluate the perioperative inflammatory status of both groups. Length of stay (LOS) and complications of both groups were also evaluated. RESULTS: A total of 213 patients were included in the study-139 in the VO group and 74 in the TIVA group. No statistically significant differences were observed between the groups with regard to their postoperative inflammatory profiles, LOS, or complications by organ system; however, the incidence of renal complications was higher in the TIVA group (8.1 vs. 2.2 %) and approached statistical significance (p = 0.068). CONCLUSIONS: In this retrospective study of patients undergoing CRS-HIPEC, the combined use of preoperative celecoxib, tramadol ER and pregabalin followed by intraoperative TIVA with infusions of propofol, dexmedetomidine, ketamine, and lidocaine was not associated with a reduction in LOS or complications by organ system. Postoperative NLR and PLR profiles were also not significantly impacted. PMID- 26975739 TI - Sentinel Lymph Node Biopsy Versus Axillary Dissection in Node-Negative Early Stage Breast Cancer: 15-Year Follow-Up Update of a Randomized Clinical Trial. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) allows for staging of the axillary node status in early-stage breast cancer (BC) patients and avoiding complete axillary lymph node dissection (ALND) when the sentinel lymph node (SLN) is proven to be free of disease. In a previous randomized trial we compared SLNB followed by ALND (ALND arm) with SLNB followed by ALND only if the SLN presented metastasis (SLNB arm). At a mid-term of ~ 6 years median follow-up, the two strategies appeared to ensure similar survival and locoregional control. We have revised these previous findings and update the results following a 15-year observation period. METHODS: Patients were randomly assigned to either the ALND or SLNB arm. The main endpoints were event-free survival (EFS), overall survival (OS), and axillary disease recurrence. EFS and OS were assessed using Kaplan Meier analysis and the log-rank test. RESULTS: The ALND and SLNB arms included 115 and 110 patients, respectively. At 14.3 years median follow-up, 39 primary BC related recurrences occurred, 22 (19 %) of which occurred in the ALND arm and 17 (16 %) occurred in the SLNB arm (p = 0.519). No axillary relapse developed in the SLNB arm, while two were observed in the ALND arm. OS (82.0 vs. 78.8 %) and EFS (72.8 vs. 72.9 %) were not statistically different between the ALND and SLNB arms (p = 0.502 and 0.953, respectively). CONCLUSIONS: SLNB is a safe and efficacious component of the surgical treatment of early-stage BC patients. In the long-term, SLNB is equivalent to ALND in terms of locoregional nodal disease control and survival in this subset of patients. PMID- 26975741 TI - Trust your struggle. PMID- 26975740 TI - MSH2 rs2303425 Polymorphism is Associated with Early-Onset Breast Cancer in Taiwan. AB - BACKGROUND: Accumulated evidence indicates that the incidence of early-onset breast cancer has rapidly increased in Taiwan and other Asian compared to Western countries. The mismatch repair (MMR) pathway might be one of the crucial mechanisms of predisposition to early breast cancer. In this study, we explored whether MMR gene polymorphisms contribute to the risk of breast cancer in young women. METHODS: This was a 2-stage case-control study including 737 cases and 719 controls. After eight single nucleotide polymorphisms (SNPs) were genotyped in MMR pathway genes in the stage I study, a promising SNP, MSH2 rs2303425, was selected for validation in the stage II study. A luciferase reporter assay was used to evaluate the transcriptional activity of MSH2. RESULTS: Logistic regression analysis showed that individuals with the MSH2 rs2303425 C/C genotype had a significantly increased risk of breast cancer compared to those with the T/T genotype (adjusted odds ratio 2.0; 95 % confidence interval 1.1-3.8), particularly in early-onset breast cancer patients with the luminal A subtype. The luciferase assay in three cell lines indicated that the MSH2 rs2303425 T/C substitution decreased MSH2 expression, which is consistent with the finding of an association study. CONCLUSIONS: A common variant SNP in MSH2 may contribute to the susceptibility to early-onset breast cancer functionally, particularly for the luminal A subtype. PMID- 26975742 TI - Tablet versus paper marking in assessment: feedback matters. AB - BACKGROUND: The Objective Structured Clinical Examination (OSCE) is a cornerstone in healthcare assessment. As a potential tool for providing learner-centred feedback on a large scale, the use of tablet devices has been proposed for the recording of OSCE marks, moving away from the traditional, paper-based checklist. METHODS: Examiner-recorded comments were collated from successive first year formative and summative OSCE examinations, with paper-based checklists used in 2012 and iPad-based checklists used in 2013. A total of 558 and 498 examiner candidate interactions took place in the January OSCE examinations, and 1402 and 1344 for the May OSCE examination for 2012 and 2013 respectively. Examiner comments were analyzed for quantity and quality. A tool was developed and validated to assess the quality of the comments left by examiners for use as feedback (Kappa = 0.625). RESULTS: A direct comparison of paper-based checklists and iPad-recorded examinations showed an increase in the quantity of comments left from 41 to 51 % (+ 10 %). Furthermore, there was an increase in the number of comments left for students deemed 'borderline': + 22 %. In terms of the quality of the comments for feedback, there was a significant improvement (p < 0.001) between comments left in written-recorded and iPad-recorded examinations. CONCLUSIONS: iPad-marked examinations resulted in a greater quantity and quality of examiner comment for use as feedback, particularly for students performing less well, enabling tutors to direct further learning for these students. PMID- 26975743 TI - Exploring the effects of medical trainee naming: a randomized experiment. AB - PURPOSE: There is no rigorous exploration of how the different titles used by medical trainees in medical school affect patients' perceptions of trainees. This study has two aims: (1) to understand the effects of medical trainee title on subjects' perceptions, and (2) to understand the effects of informing subjects about the medical education system on comfort with trainees. METHODS: A survey was distributed utilizing Amazon's Mechanical Turk (n = 432). To explore aim 1 and 2, the survey included one randomized experimental treatment asking participants to imagine they were partaking in a hypothetical clinical encounter with a medical trainee using one of three titles. To explore aim 2, the survey instrument included an educational section and assessed changes in subjects' comfort with trainees. RESULTS: There was no association between trainee title and subjects' perceptions of trainee responsibility, education level, or comfort with being examined. However, 41.4 % (n = 179) of subjects were not aware of the medical trainees' training level, and education resulted in significant increases in comfort with being interviewed and examined by a trainee (p < 0.001). CONCLUSIONS: While trainee naming was not directly associated with subjects' perceptions, educating patients about the medical education system may increase comfort level when they are with medical trainees. PMID- 26975744 TI - Developing an appreciation of patient safety: analysis of interprofessional student experiences with health mentors. AB - INTRODUCTION: A critical task for health profession educators is to foster student appreciation of patient quality and safety issues. Although instructional methods vary, few focus on the direct communication of the patient experience to students. This qualitative study explores the experiences and learning of health profession students participating in a Safety Module in the Health Mentor Programme. METHODS: Small interprofessional groups of students were paired with a health mentor, an individual experiencing chronic health challenges. Students followed a 90-minute, semi-structured interview format exploring issues regarding quality care and safety. Following the interviews, students participated in a facilitated asynchronous online discussion and completed a reflective practice paper. An inductive thematic analysis of both of these text-based datasets revealed emerging themes. RESULTS: Themes identified in the data included: Patient partnerships as critical to optimal care; consideration of a variety of safety issues; importance of advocacy in promoting safety; improvement of future practice enabled through patient perspectives on clinical error; and embracing of interprofessional communication and collaboration. CONCLUSIONS: The findings suggest that engagement with the health mentor narratives facilitated students' appreciation of quality and safety issues related to patient care. PMID- 26975745 TI - Candidate gene variants of the immune system and sudden infant death syndrome. AB - BACKGROUND: Sudden infant death syndrome (SIDS) causes early infant death with an incidence between 0.5 and 2.5 cases among 1000 live births. Besides central sleep apnea and thermal dysregulation, infections have been repeatedly suggested to be implicated in SIDS etiology. METHODS: To test the risk contribution of common genetic variants related to infection, we genotyped 40 single-nucleotide polymorphisms (SNPs) from 15 candidate genes for association with SIDS in a total of 579 cases and 1124 controls from Germany and the UK in a two-stage case control design. RESULTS: The discovery-stage series (267 SIDS cases and 303 controls) revealed nominally significant associations for variants in interleukin 6 (IL6) (rs1880243), interleukin 10 (IL10) (rs1800871, rs1800872), and mannose binding lectin 2 (MBL2) (rs930506), and for several other variants in subgroups. Meta-analyses were then performed in adding genotype information from a genome wide association study of another 312 European SIDS cases and 821 controls. Overall associations were observed for two independent variants in MBL2: rs930506 in a co-dominant model (odds ratio (OR) = 0.82, p = 0.04) and rs1838065 in a dominant model (OR = 1.27, p = 0.03). CONCLUSION: Our study did not replicate published associations of IL10 variants with SIDS. However, the evidence for two independent MBL2 variants in the combined analysis of two large series seems consistent with the hypothesis that infection may play a role in SIDS pathogenesis. PMID- 26975746 TI - Porous nano-hydroxyapatite/collagen scaffold containing drug-loaded ADM-PLGA microspheres for bone cancer treatment. AB - To develop adriamycin (ADM)-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles in a porous nano-hydroxyapatite/collagen scaffold (ADM-PLGA-NHAC). To provide novel strategies for future treatment of osteosarcoma, the properties of the scaffold, including its in vitro extended-release properties, the inhibition effects of ADM-PLGA-NHAC on the osteosarcoma MG63 cells, and its bone repair capacity, were investigated in vivo and in vitro. The PLGA copolymer was utilized as a drug carrier to deliver ADM-PLGA nanoparticles (ADM-PLGA-NP). Porous nano-hydroxyapatite and collagen were used to materials to produce the porous nano-hydroxyapatite/collagen scaffold (NHAC), into which the ADM-PLGA-NP was loaded. The performance of the drug-carrying scaffold was assessed using multiple techniques, including scanning electron microscopy and in vitro extended release. The antineoplastic activities of scaffold extracts on the human osteosarcoma MG63 cell line were evaluated in vitro using the cell counting kit-8 (CCK8) method and live-dead cell staining. The bone repair ability of the scaffold was assessed based on the establishment of a femoral condyle defect model in rabbits. ADM-PLGA-NHAC and NHAC were implanted into the rat muscle bag for immune response experiments. A tumor-bearing nude mice model was created, and the TUNEL and HE staining results were observed under optical microscopy to evaluate the antineoplastic activity and toxic side effects of the scaffold. The composite scaffold demonstrated extraordinary extended-release properties, and its extracts also exhibited significant inhibition of the growth of osteosarcoma MG63 cells. In the bone repair experiment, no significant difference was observed between ADM-PLGA-NHAC and NHAC by itself. In the immune response experiments, ADM PLGA-NHAC exhibited remarkable biocompatibility. The in vivo antitumor experiment revealed that the implantation of ADM-PLGA-NHAC in the tumor resulted in a improved antineoplastic effect and fewer adverse side effects than direct intraperitoneal injection of ADM. The ADM-PLGA-NHAC developed in this study exhibited excellent extended-release drug properties, bone repairing and antineoplastic efficacy, which make it a promising osteoconductivity material with the capability to inhibit osteosarcoma. PMID- 26975747 TI - Resistance to protein adsorption and adhesion of fibroblasts on nanocrystalline diamond films: the role of topography and boron doping. AB - Boron-doped nanocrystalline diamond (BNCD) films exhibit outstanding electrochemical properties that make them very attractive for the fabrication of electrodes for novel neural interfaces and prosthetics. In these devices, the physicochemical properties of the electrode materials are critical to ensure an efficient long-term performance. The aim of this study was to investigate the relative contribution of topography and doping to the biological performance of BNCD films. For this purpose, undoped and boron-doped NCD films were deposited on low roughness (LR) and high roughness (HR) substrates, which were studied in vitro by means of protein adsorption and fibroblast growth assays. Our results show that BNCD films significantly reduce the adsorption of serum proteins, mostly on the LR substrates. As compared to fibroblasts cultured on LR BNCD films, cells grown on the HR BNCD films showed significantly reduced adhesion and lower growth rates. The mean length of fibronectin fibrils deposited by the cells was significantly increased in the BNCD coated substrates, mainly in the LR surfaces. Overall, the largest influence on protein adsorption, cell adhesion, proliferation, and fibronectin deposition was due to the underlying sub-micron topography, with little or no influence of boron doping. In perspective, BNCD films displaying surface roughness in the submicron range may be used as a strategy to reduce the fibroblast growth on the surface of neural electrodes. PMID- 26975748 TI - In vitro study on an antibacterial Ti-5Cu alloy for medical application. AB - Health of human beings is subjected to severe threats from the spread of harmful bacteria and the implant-associated infection remains a serious problem in clinic. In this study, a copper-bearing antibacterial titanium alloy, Ti-5Cu, has been developed for dental and orthopedic implant applications. The microstructure, mechanical property, electrochemical corrosion behavior, in vitro antibacterial performance, cytocompatibility and hemocompatibility of the alloy are systematically investigated. The results reveal that the Ti-5Cu alloy which consists of alpha-phase matrix and intermetallic compound Ti2Cu not only possesses strong antibacterial activity against both E. coli and S. aureus, but also exhibits better mechanical properties than the commercial pure titanium. It is confirmed that the release of trace amount of Cu ions from the alloy plays an important role in killing bacteria. In spite of the ion release, Ti-5Cu alloy still reveals excellent corrosion resistance. Moreover, good cytocompatibility and superior hemocompatibility make Ti-5Cu alloy to be a potential solution that could prevent the peri-implant infection in dental and orthopaedic applications. PMID- 26975749 TI - Opioid Use in Fibromyalgia: A Cautionary Tale. AB - Multiple pharmacotherapies are available for the treatment of fibromyalgia (FM), including opioid analgesics. We postulate that the mechanism of action of traditional opioids predicts their lack of efficacy in FM. Literature searches of the MEDLINE and Cochrane Library databases were conducted using the search term opioid AND fibromyalgia to identify relevant articles, with no date limitations set. Citation lists in returned articles and personal archives of references were also examined for additional relevant items, and articles were selected based on the expert opinions of the authors. We found no evidence from clinical trials that opioids are effective for the treatment of FM. Observational studies have found that patients with FM receiving opioids have poorer outcomes than patients receiving nonopioids, and FM guidelines recommend against the use of opioid analgesics. Despite this, and despite the availability of alternative Food and Drug Administration-approved pharmacotherapies and the efficacy of nonpharmacologic therapies, opioids are commonly used in the treatment of FM. Factors associated with opioid use include female sex; geographic variation; psychological factors; a history of opioid use, misuse, or abuse; and patient or physician preference. The long-term use of opioid analgesics is of particular concern in the United States given the ongoing public health emergency relating to excess prescription opioid consumption. The continued use of opioids to treat FM despite a proven lack of efficacy, lack of support from treatment guidelines, and the availability of approved pharmacotherapy options provides a cautionary tale for their use in other chronic pain conditions. PMID- 26975750 TI - Clinical evaluation of chitotriosidase enzyme activity in Gaucher and Niemann Pick A/B diseases: A retrospective study from India. AB - Plasma chitotriosidase originates from activated macrophages and is reported to be elevated in many Lysosomal Storage Disorders. Measurement of this enzyme activity has been an available tool for monitoring therapy of Gaucher disease. The degree of elevation of chitotriosidase is useful for differential diagnosis of Gaucher disease and Niemann Pick A/B. However the potential utility of this chitotriosidase assay depends on the frequency of deficient chitotriosidase activity in a particular population. We therefore aim to study the clinical utility of this assay Gaucher and Niemann Pick A/B diseases in the backdrop of chitotriosidase deficiency in our population. The study comprises 173 patients with clinical suspicion of either Gaucher disease (n=108) or Niemann Pick A/B (n=65) and 92 healthy controls. The plasma samples of controls, Gaucher disease, and Niemann Pick A/B showed chitotriosidase deficiency of 12%, 25% and 27% respectively. The degree of elevation of chitotriosidase in Gaucher disease and Niemann Pick A/B patients is 40-326 (11,325.7+/-6395.4nmol/h/ml) and 7-22 folds (1192.5+/-463.0nmol/h/ml) respectively. In view of these findings of distinguishable fold elevation of chitotriosidase in Gaucher disease or Niemann Pick A/B, it can be a potential surrogate differential diagnostic marker for these groups of diseases, except in the patients in whom this enzyme is deficient. PMID- 26975751 TI - Utility of surrogate markers for the prediction of relapses in inflammatory bowel diseases. AB - Patients with diagnosed inflammatory bowel disease (IBD) will commonly experience a clinical relapse in spite of a prolonged therapy-induced period of clinical remission. The current methods of assessing subclinical levels of low-grade inflammation which predispose patients to relapse are not optimal when considering both cost and patient comfort. Over the past few decades, much investigation has discovered that proteins such as calprotectin that are released from inflammatory cells are capable of indicating disease activity. Along with C reactive protein and erythrocyte sedimentation rate, calprotectin has now become part of the current methodology for assessing IBD activity. More recently, research has identified that other fecal and serum biomarkers such as lactoferrin, S100A12, GM-CSF autoantibodies, alpha1-antitrypsin, eosinophil derived proteins, and cytokine concentrations have variable degrees of utility in monitoring gastrointestinal tract inflammation. In order to provide direction toward novel methods of predicting relapse in IBD, we provide an up-to-date review of these biomarkers and their potential utility in the prediction of clinical relapse, given their observed activities during various stages of clinical remission. PMID- 26975753 TI - Enhanced xylitol production: Expression of xylitol dehydrogenase from Gluconobacter oxydans and mixed culture of resting cell. AB - Xylitol has numerous applications in food and pharmaceutical industry, and it can be biosynthesized by microorganisms. In the present study, xdh gene, encoding xylitol dehydrogenase (XDH), was cloned from the genome of Gluconobacter oxydans CGMCC 1.49 and overexpressed in Escherichia coli BL21. Sequence analysis revealed that XDH has a TGXXGXXG NAD(H)-binding motif and a YXXXK active site motif, and belongs to the short-chain dehydrogenase/reductase family. And then, the enzymatic properties and kinetic parameter of purified recombinant XDH were investigated. Subsequently, transformations of xylitol from d-xylulose and d arabitol, respectively, were studied through mixed culture of resting cells of G. oxydans wild-type strain and recombinant strain BL21-xdh. We obtained 28.80 g/L xylitol by mixed culture from 30 g/L d-xylulose in 28 h. The production was increased by more than three times as compared with that of wild-type strain. Furthermore, 25.10 g/L xylitol was produced by the mixed culture from 30 g/L d arabitol in 30 h with a yield of 0.837 g/g, and the max volumetric productivity of 0.990 g/L h was obtained at 22 h. These contrast to the fact that wild-type strain G. oxydans only produced 8.10 g/L xylitol in 30 h with a yield of 0.270 g/g. To our knowledge, these values are the highest among the reported yields and productivity efficiencies of xylitol from d-arabitol with engineering strains. PMID- 26975754 TI - Overexpressing enzymes of the Ehrlich pathway and deleting genes of the competing pathway in Saccharomyces cerevisiae for increasing 2-phenylethanol production from glucose. AB - 2-Phenylethanol (2-PE) is a higher aromatic alcohol that is used in the cosmetics and food industries. The budding yeast Saccharomyces cerevisiae is considered to be a suitable host for the industrial production of higher alcohols, including 2 PE. To produce 2-PE from glucose in S. cerevisiae, we searched for suitable 2 keto acid decarboxylase (KDC) and alcohol dehydrogenase (ADH) enzymes of the Ehrlich pathway for overexpression in strain YPH499, and found that overexpression of the ARO10 and/or ADH1 genes increased 2-PE production from glucose. Further, we screened ten BY4741 single-deletion mutants of genes involved in the competing pathways for 2-PE production, and found that strains aro8Delta and aat2Delta displayed increased 2-PE production. Based on these results, we engineered a BY4741 strain that overexpressed ARO10 and contained an aro8Delta deletion, and demonstrated that the strain produced 96 mg/L 2-PE from glucose as the sole carbon source. As this engineered S. cerevisiae strain showed a significant increase in 2-PE production from glucose without the addition of an intermediate carbon substrate, it is a promising candidate for the large-scale production of 2-PE. PMID- 26975752 TI - Growth inhibition and apoptosis in cancer cells induced by polyphenolic compounds of Acacia hydaspica: Involvement of multiple signal transduction pathways. AB - Acacia hydaspica R. Parker is known for its medicinal uses in multiple ailments. In this study, we performed bioassay-guided fractionation of cytotoxic compounds from A. hydaspica and investigated their effects on growth and signaling activity in prostate and breast cancer cell lines. Four active polyphenolic compounds were identified as 7-O-galloyl catechin (GC), catechin (C), methyl gallate (MG), and catechin-3-O-gallate (CG). The four compounds inhibited prostate cancer PC-3 cell growth in a dose-dependent manner, whereas CG and MG inhibited breast cancer MDA MB-231 cell growth. All tested compounds inhibited cell survival and colony growth in both cell lines, and there was evidence of chromatin condensation, cell shrinkage and apoptotic bodies. Further, acridine orange, ethidium bromide, propidium iodide and DAPI staining demonstrated that cell death occurred partly via apoptosis in both PC-3 and MDA-MB-231 cells. In PC-3 cells treatment repressed the expression of anti-apoptotic molecules Bcl-2, Bcl-xL and survivin, coupled with down-regulation of signaling pathways AKT, NFkappaB, ERK1/2 and JAK/STAT. In MDA-MB-231 cells, treatment induced reduction of CK2alpha, Bcl-xL, survivin and xIAP protein expression along with suppression of NFkappaB, JAK/STAT and PI3K pathways. Our findings suggest that certain polyphenolic compounds derived from A. hydaspica may be promising chemopreventive/therapeutic candidates against cancer. PMID- 26975757 TI - USING CLAIMS DATA FOR EVIDENCE GENERATION IN MANAGED ENTRY AGREEMENTS. AB - OBJECTIVES: This study assesses the use of routinely collected claims data for managed entry agreements (MEA) in the illustrative context of German statutory health insurance (SHI) funds. METHODS: Based on a nonsystematic literature review, the data needs of different MEA were identified. A value-based typology to classify MEA on the basis of these data needs was developed. The typology is oriented toward health outcomes and utilization and costs, key components of a new technology's value. For each MEA type, the suitability of claims data in establishing evidence of the novel technology's value in routine care was systematically assessed. Assessment criteria were data availability, completeness, timeliness, confidentiality, reliability, and validity. RESULTS: Claims data are better suited to MEA addressing uncertainty regarding the utilization and costs of a novel technology in routine care. In schemes where safety aspects or clinical effectiveness are assessed, the role of claims data is limited because clinical information is not included in sufficient detail. CONCLUSIONS: The suitability of claims data depends on the source of uncertainty and, in consequence, the outcome measures chosen in the agreements. In all schemes, the validity of claims data should be judged with caution as data are collected for billing purposes. This framework may support manufacturers and payers in selecting the most suitable contract type and agreeing on contract conditions. More research is necessary to validate these results and to address remaining medical, economic, legal, and ethical questions of using claims data for MEA. PMID- 26975755 TI - Denitrification by Pseudomonas stutzeri coupled with CO2 reduction by Sporomusa ovata with hydrogen as an electron donor assisted by solid-phase humin. AB - A co-culture system comprising an acetogenic bacterium, Sporomusa ovata DSMZ2662, and a denitrifying bacterium, Pseudomonas stutzeri JCM20778, enabled denitrification using H2 as the sole external electron donor and CO2 as the sole external carbon source. Acetate produced by S. ovata supported the heterotrophic denitrification of P. stutzeri. A nitrogen balance study showed the reduction of nitrate to nitrogen gas without the accumulation of nitrite and nitrous oxide in the co-culture system. S. ovata did not show nitrate reduction to ammonium in the co-culture system. Significant proportions of the consumed H2 were utilized for denitrification: 79.9 +/- 4.6% in the co-culture system containing solid-phase humin and 62.9+/-11.1% in the humin-free co-culture system. The higher utilization efficiency of hydrogen in the humin-containing system was attributed to the higher denitrification activity of P. stutzeri under the acetate deficient conditions. The nitrogen removal rate of the humin-containing co-culture system reached 0.19 kg NO3(-)-N.m(-3).d(-1). Stable denitrification activity for 61 days of successive sub-culturing suggested the robustness of this co-culture system. This study provides a novel strategy for the in situ enhancement of microbial denitrification. PMID- 26975758 TI - Separation of Perifix(r) FX epidural catheter components in a laboring patient. PMID- 26975756 TI - Genome-wide gene expression analysis of mouse embryonic stem cells exposed to p dichlorobenzene. AB - Because of the limitations of whole animal testing approaches for toxicological assessment, new cell-based assay systems have been widely studied. In this study, we focused on two biological products for toxicological assessment: mouse embryonic stem cells (mESCs) and long noncoding RNAs (lncRNAs). mESCs possess the abilities of self-renewal and differentiation into multiple cell types. LlncRNAs are an important class of pervasive non-protein-coding transcripts involved in the molecular mechanisms associated with responses to chemicals. We exposed mESCs to p-dichlorobenzene (p-DCB) for 1 or 28 days (daily dose), extracted total RNA, and performed deep sequencing analyses. The genome-wide gene expression analysis indicated that mechanisms modulating proteins occurred following acute and chronic exposures, and mechanisms modulating genomic DNA occurred following chronic exposure. Moreover, our results indicate that three novel lncRNAs (Snora41, Gm19947, and Scarna3a) in mESCs respond to p-DCB exposure. We propose that these lncRNAs have the potential to be surrogate indicators of p-DCB responses in mESCs. PMID- 26975759 TI - Recognition of obstructive sleep apnea in pregnancy survey. PMID- 26975760 TI - Disruption of a wire-reinforced epidural catheter upon removal: importance of having a set protocol. PMID- 26975761 TI - Treatment of Small Hepatocellular Carcinoma (<=2 cm) in the Caudate Lobe with Sequential Transcatheter Arterial Chemoembolization and Radiofrequency Ablation. AB - PURPOSE: To evaluate technical feasibility and treatment results of sequential transcatheter arterial chemoembolization (TACE) and cone-beam computed tomography guided percutaneous radiofrequency ablation (CBCT-RFA) for small hepatocellular carcinoma (HCC) in the caudate lobe. MATERIALS AND METHODS: Institutional review board approved this retrospective study. Radiologic database was searched for the patients referred to perform TACE and CBCT-RFA for small caudate HCCs (<=2 cm) between February 2009 and February 2014. A total of 14 patients (12 men and 2 women, mean age; 61.3 years) were included. Percutaneous ultrasonography-guided RFA (pUS-RFA) and surgery were infeasible due to poor conspicuity, inconspicuity or no safe electrode pathway, and poor hepatic reserve. Procedural success (completion of both TACE and CBCT-RFA), technique efficacy (absence of tumor enhancement at 1 month after treatment), and complication were evaluated. Treatment results including local tumor progression (LTP), intrahepatic distant recurrence (IDR), overall survival (OS), and progression-free survival (PFS) were analyzed. RESULTS: Procedural success and technique efficacy rates were 78.6 % (11/14) and 90.9 % (10/11), respectively. Average follow-up period was 45.3 months (range, 13.4-64.6 months). The 1-, 3-, and 5-year LTP probabilities were 0, 12.5, and 12.5 %, respectively. IDR occurred in seven patients (63.6 %, 7/11). The 1-, 3-, and 5-year PFS probabilities were 81.8, 51.9, and 26 %, respectively. The 1-, 3-, and 5-year OS probabilities were 100, 80.8, and 80.8 %, respectively. CONCLUSION: Combination of TACE and CBCT-RFA seems feasible for small HCC in the caudate lobe not amenable to pUS-RFA and effective in local tumor control. PMID- 26975762 TI - Artificial Intelligence and Semantics through the Prism of Structural, Post Structural and Transcendental Approaches. AB - There is a problem associated with contemporary studies of philosophy of mind, which focuses on the identification and convergence of human and machine intelligence. This is the problem of machine emulation of sense. In the present study, analysis of this problem is carried out based on concepts from structural and post-structural approaches that have been almost entirely overlooked by contemporary philosophy of mind. If we refer to the basic definitions of "sign" and "meaning" found in structuralism and post-structuralism, we see a fundamental difference between the capabilities of a machine and the human brain engaged in the processing of a sign. This research will exemplify and provide additional evidence to support distinctions between syntactic and semantic aspects of intelligence, an issue widely discussed by adepts of contemporary philosophy of mind. The research will demonstrate that some aspect of a number of ideas proposed in relation to semantics and semiosis in structuralism and post structuralism are similar to those we find in contemporary analytical studies related to the theory and philosophy of artificial intelligence. The concluding part of the paper offers an interpretation of the problem of formalization of sense, connected to its metaphysical (transcendental) properties. PMID- 26975763 TI - Seasonal Assessment of Biomass and Fatty Acid Productivity by Tetraselmis sp. in the Ocean Using Semi-Permeable Membrane Photobioreactors. AB - A green microalga, Tetraselmis sp., was cultivated in the coastal seawater of Young-Heung Island using semi-permeable membrane photobioreactors (SPM-PBRs) in different seasons. The microalgae in the SPM-PBRs were able to grow on nutrients diffused into the PBRs from the surrounding seawater through SPMs. The biomass productivity varied depending on the ion permeabilities of the SPMs and environmental conditions, whereas the quality and quantity of fatty acids were constant. The temperature of seawater had a greater influence than solar radiation did on productivity of Tetraselmis sp. in SPM-PBRs. SPM-PBRs could provide technologies for concurrent algal biomass and fatty acids production, and eutrophication reduction in the ocean. PMID- 26975764 TI - Characterization of Glycerol Dehydrogenase from Thermoanaerobacterium thermosaccharolyticum DSM 571 and GGG Motif Identification. AB - Glycerol dehydrogenases (GlyDHs) are essential for glycerol metabolism in vivo, catalyzing its reversible reduction to 1,3-dihydroxypropranone (DHA). The gldA gene encoding a putative GlyDH was cloned from Thermoanaerobacterium thermosaccharolyticum DSM 571 (TtGlyDH) and expressed in Escherichia coli. The presence of Mn(2+) enhanced its enzymatic activity by 79.5%. Three highly conserved residues (Asp(171), His(254), and His(271)) in TtGlyDH were associated with metal ion binding. Based on an investigation of glycerol oxidation and DHA reduction, TtGlyDH showed maximum activity towards glycerol at 60 degrees C and pH 8.0 and towards DHA at 60 degrees C and pH 6.0. DHA reduction was the dominant reaction, with a lower Km(DHA) of 1.08 +/- 0.13 mM and Vmax of 0.0053 +/- 0.0001 mM/s, compared with glycerol oxidation, with a Km(glycerol) of 30.29 +/- 3.42 mM and Vmax of 0.042 +/- 0.002 mM/s. TtGlyDH had an apparent activation energy of 312.94 kJ/mol. The recombinant TtGlyDH was thermostable, maintaining 65% of its activity after a 2-h incubation at 60 degrees C. Molecular modeling and site directed mutagenesis analyses demonstrated that TtGlyDH had an atypical dinucleotide binding motif (GGG motif) and a basic residue Arg(43), both related to dinucleotide binding. PMID- 26975765 TI - Cloning, Expression, and Characterization of a Cold-Active and Organic Solvent Tolerant Lipase from Aeromicrobium sp. SCSIO 25071. AB - The gene encoding lipase (Lip98) from Aeromicrobium sp. SCSIO 25071 was cloned and functionally expressed in Escherichia coli. Lip98 amino acid sequence shares the highest (49%) identity to Rhodococcus jostii RHA1 lipase and contains a novel motif (GHSEG), which is different from other clusters in the lipase superfamily. The recombinant lipase was purified to homogeneity with Ni-NTA affinity chromatography. Lip98 showed an apparent molecular mass of 30 kDa on SDS gel. The optimal temperature and pH value for enzymatic activity were recorded at 30 degrees C and 7.5, respectively. Lip98 exhibited high activity at low temperatures with 35% maximum activity at 0 degrees C and good stability at temperatures below 35 degrees C. Its calculated activation energy was 4.12 kcal/mol at the low temperature range of 15-30 degrees C. Its activity was slightly affected by some metal ions such as K(+), Ca(2+), and Na(+). The activity of Lip98 was increased by various organic solvents such as DMSO, ethanol, acetone, and hexane with the concentration of 30% (v/v) and retained more than 30% residual activity in neat organic solvent. The unique characteristics of Lip98 imply that it is a promising candidate for industrial application as a nonaqueous biocatalyst and food additive. PMID- 26975766 TI - RV-23, a Melittin-Related Peptide with Cell-Selective Antibacterial Activity and High Hemocompatibility. AB - RV-23 is a melittin-related antibacterial peptide (MRP) with lower cytotoxicity than either melittin or AR-23, another MRP. The aim of this study was to explore the mechanism of RV- 23's antibacterial selectivity and its hemocompatibility. The results showed that all the peptides exhibited lytic activity against Staphylococcus aureus and Escherichia coli, with RV-23 showing the highest potency. Moreover, RV-23 had lower cytotoxicity than melittin or AR-23 at their minimal inhibitory concentration. In addition, CD experiments showed that melittin, RV-23, and AR-23 all had a typical alpha-helical structure, and RV-23 had the lowest alpha-helix content. The structural information showed that RV-23 has the lowest hydrophobicity and highest hydrophobic moment. Because hydrophobicity and alpha-helix content are believed to correlate with hemolysis, the results indicate that the selective lytic activity against bacteria of RV-23 may be due to its low hydrophobicity and alpha-helicity, which lead to low cytotoxicity without affecting antibacterial activity. Furthermore, RV-23 did not affect the structure and function of blood components such as red blood cells, platelets, albumin, and the blood coagulation system. In conclusion, RV-23 is a cell-selective antibacterial peptide with high hemocompatibility due to its unique structure. PMID- 26975767 TI - Lactic Acid Bacteria Improves Peyer's Patch Cell-Mediated Immunoglobulin A and Tight-Junction Expression in a Destructed Gut Microbial Environment. AB - To evaluate the effects of lactic acid bacteria (LAB) on Peyer's patch cells, mice were treated with a high dose of kanamycin to disturb the gut microbial environment. The overarching goal was to explore the potential of LAB for use as a dietary probiotic that buffers the negative consequences of antibiotic treatment. In vitro, LAB stimulated the production of immunoglobulin A (IgA) from isolated Peyer's patch cells. Inflammation-related genes (TNF-alpha, IL-1beta, and IL-8) were up-regulated in Caco-2 cells stimulated with lipopolysaccharide (LPS), while tight-junction-related genes (ZO-1 and occludin) were down regulated; the effects of LPS on inflammatory gene and tight-junction gene expression were reversed by treatment with LAB. Mice treated with a high dose of kanamycin showed increased serum IgE levels and decreases in serum IgA and fecal IgA levels; the number of Peyer's patch cells decreased with kanamycin treatment. However, subsequent LAB treatment was effective in reducing the serum IgE level and recovering the serum IgA and fecal IgA levels, as well as the number of Peyer's patch cells. In addition, ZO-1 and occludin mRNA levels were up-regulated in the ileum tissues of mice receiving LAB treatment. Lactic acid bacteria can enhance the intestinal immune system by improving the integrity of the intestinal barrier and increasing the production of IgA in Peyer's patches. Lactic acid bacteria should be considered a potential probiotic candidate for improving intestinal immunity, particularly in mitigating the negative consequences of antibiotic use. PMID- 26975768 TI - Longan (Dimocarpus longan Lour.) Fruit Extract Stimulates Osteoblast Differentiation via Erk1/2-Dependent RUNX2 Activation. AB - Longan (Dimocarpus longan Lour.) has been used as a traditional oriental medicine and possesses a number of physiological activities. In this study, we used cell based herbal extract screening to identify longan fruit extract (LFE) as an activator of osteoblast differentiation. LFE up-regulated alkaline phosphatase (ALP) activity, induced mineralization, and activated Runx2 gene expression in MC3T3-E1 cells. Furthermore, treatment of MC3T3-E1 cells with LFE promoted the phosphorylation of extracellular signal-regulated kinase1/2 (Erk1/2); however, abrogation of Erk1/2 activation with PD98059 resulted in down-regulation of the phospho- SMAD1/5/8 and Runx2 levels, which in turn reduced the ALP activity. Our findings suggest that LFE exerts its osteogenic activity through activation of the ERK signaling pathway and may have potential as an herbal therapeutic or a preventive agent for the treatment of osteoporosis. PMID- 26975769 TI - Achieving High Yield of Lactic Acid for Antimicrobial Characterization in Cephalosporin-Resistant Lactobacillus by the Co-Expression of the Phosphofructokinase and Glucokinase. AB - Lactobacilli are universally recognized as probiotics that are widely used in the adjuvant treatment of inflammatory diseases, such as vaginitis and enteritis. With the overuse of antibiotics in recent years, the lactobacilli in the human body are killed, which could disrupt the microecological balance in the human body and affect health adversely. In this work, cephalosporin-resistant Lactobacillus casei RL20 was obtained successfully from the feces of healthy volunteers, which possessed a stable genetic set. However, the shortage of lactic acid (72.0 g/l at 48 h) by fermentation did not meet the requirement for its use in medicine. To increase the production of lactic acid, the functional genes pfk and glk were introduced into the wild strain. A yield of 144.2 g/l lactic acid was obtained in the transgenic L. casei RL20-2 after fermentation for 48 h in 1 L of basic fermentation medium with an initial glucose concentration of 100 g/l and increasing antibacterial activity. These data suggested that L. casei RL20-2 that exhibited a high yield of lactic acid may be a potential probiotic to inhibit the spread of bacterial infectious diseases and may be used for vaginitis therapy. PMID- 26975770 TI - Foliar Application of Extract from an Azalomycin-Producing Streptomyces malaysiensis Strain MJM1968 Suppresses Yam Anthracnose Caused by Colletotrichum gloeosporioides. AB - Yam anthracnose caused by Colletotrichum gloeosporioides (C.g) is the most devastating disease of yam (Dioscorea sp.). In the present study, we evaluated the culture filtrate extract (CFE) of azalomycin-producing Streptomyces malaysiensis strain MJM1968 for the control of yam anthracnose. MJM1968 showed strong antagonistic activity against C.g in vitro. Furthermore, the MJM1968 CFE was tested for inhibition of spore germination in C.g, where it completely inhibited spore germination at a concentration of 50 MUg/ml. To assess the in planta efficacy of the CFE and spores of MJM1968 against C.g, a detached leaf bioassay was conducted, which showed both the treatments suppressed anthracnose development on detached yam leaves. Furthermore, a greenhouse study was conducted to evaluate the CFE from MJM1968 as a fungicide for the control of yam anthracnose. The CFE non-treated plants showed a disease severity of >92% after 90 days of artificial inoculation with C.g, whereas the disease severity of CFE treated and benomyl-treated yam plants was reduced to 26% and 15%, respectively, after 90 days. Analysis of the yam tubers from the CFE-treated and non-treated groups showed that tubers from the CFE-treated plants were larger than that of non-treated plants, which produced abnormal smaller tubers typical of anthracnose. This study demonstrated the utility of the CFE from S. malaysiensis strain MJM1968 as a biofungicide for the control of yam anthracnose. PMID- 26975771 TI - In Vitro and in Vivo Wound Healing Properties of Plasma and Serum from Crocodylus siamensis Blood. AB - The plasma and serum of Crocodylus siamensis have previously been reported to exhibit potent antimicrobial, antioxidant, and anti-inflammatory activities. During wound healing, these biological properties play a crucial role for supporting the formation of new tissue around the injured skin in the recovery process. Thus, this study aimed to evaluate the wound healing properties of C. siamensis plasma and serum. The collected data demonstrate that crocodile plasma and serum were able to activate in vitro proliferation and migration of HaCaT, a human keratinocyte cell line, which represents an essential phase in the wound healing process. With respect to investigating cell migration, a scratch wound experiment was performed which revealed the ability of plasma and serum to decrease the gap of wounds in a dose-dependent manner. Consistent with the in vitro results, remarkably enhanced wound repair was also observed in a mouse excisional skin wound model after treatment with plasma or serum. The effects of C. siamensis plasma and serum on wound healing were further elucidated by treating wound infections by Staphylococcus aureus ATCC 25923 on mice skin coupled with a histological method. The results indicate that crocodile plasma and serum promote the prevention of wound infection and boost the re epithelialization necessary for the formation of new skin. Therefore, this work represents the first study to demonstrate the efficiency of C. siamensis plasma and serum with respect to their wound healing properties and strongly supports the utilization of C. siamensis plasma and serum as therapeutic products for injured skin treatment. PMID- 26975772 TI - Constructing Proteome Reference Map of the Porcine Jejunal Cell Line (IPEC-J2) by Label-Free Mass Spectrometry. AB - In this study, the global proteome of the IPEC-J2 cell line was evaluated using ultra-high performance liquid chromatography coupled to a quadrupole Q ExactiveTM Orbitrap mass spectrometer. Proteins were isolated from highly confluent IPEC-J2 cells in biological replicates and analyzed by label-free mass spectrometry prior to matching against a porcine genomic dataset. The results identified 1,517 proteins, accounting for 7.35% of all genes in the porcine genome. The highly abundant proteins detected, such as actin, annexin A2, and AHNAK nucleoprotein, are involved in structural integrity, signaling mechanisms, and cellular homeostasis. The high abundance of heat shock proteins indicated their significance in cellular defenses, barrier function, and gut homeostasis. Pathway analysis and annotation using the Kyoto Encyclopedia of Genes and Genomes database resulted in a putative protein network map of the regulation of immunological responses and structural integrity in the cell line. The comprehensive proteome analysis of IPEC-J2 cells provides fundamental insights into overall protein expression and pathway dynamics that might be useful in cell adhesion studies and immunological applications. PMID- 26975773 TI - A Newly Identified Glutaminase-Free L-Asparaginase (L-ASPG86) from the Marine Bacterium Mesoflavibacter zeaxanthinifaciens. AB - L-Asparaginase (E.C. 3.5.1.1) is an enzyme involved in asparagine hydrolysis and has the potential to effect leukemic cells and various other cancer cells. We identified the Lasparaginase gene (L-ASPG86) in the genus Mesoflavibacter, which consists of a 1,035 bp open reading frame encoding 344 amino acids. Following phylogenetic analysis, the deduced amino acid sequence of L-ASPG86 (L-ASPG86) was grouped as a type I asparaginase with respective homologs in Escherichia coli and Yersinia pseudotuberculosis. The L-ASPG86 gene was cloned into the pET-16b vector to express the respective protein in E. coli BL21 (DE3) cells. Recombinant L asparaginase (r-L-ASPG86) showed optimum conditions at 37-40oC, pH 9. Moreover, r L-ASPG86 did not exhibit glutaminase activity. In the metal ions test, its enzymatic activity was highly improved upon addition of 5 mM manganese (3.97 fold) and magnesium (3.35-fold) compared with the untreated control. The specific activity of r-LASPG86 was 687.1 units/mg under optimum conditions (37 degrees C, pH 9, and 5 mM MnSO4). PMID- 26975774 TI - Toxicological evaluation of representative silver nanoparticles in macrophages and epithelial cells. AB - Silver nanoparticles (Ag-NPs) are highly relevant for human and environmental exposure due to their widespread use in consumer and medical products and various applications. Thus, there is a need for evaluating potential toxicity of these NPs. The objective of this study was to investigate the toxic effects of the OECD (Organization for Economic Co-operation and Development) representative Ag-NPs, NM300K, in mouse macrophage J774A.1 and human colonic epithelial HT29 cells, using multiple endpoint assays. Exposure of test cells to different concentrations (1-250 MUg/mL; total silver content) of NM300K for 24h showed a dose-dependent decrease in cell viability. At high doses, NM300K altered cell shape and induced the formation of vacuolar structures, as examined by confocal and electron microscopy. Moreover, NM300K induced inflammation as evidenced by the elevated levels of pro-inflammatory cytokines. Finally, high doses of NM300K led to increased production of reactive oxygen species and induction of oxidative stress, leading to oxidative DNA damage and apoptosis in test cells. At equivalent silver concentrations, NM300K were less cytotoxic than AgNO3. However, the similar patterns in the effects of NM300K and AgNO3 throughout the assessed toxicological endpoints suggest that Ag(+) released from these NPs by dissolution could be a primary contributor to toxicity. This study is among the first to characterize the potential toxicity of OECD representative AgNPs in vitro, and provides additional insight into the biological mechanisms associated with Ag-NP toxicity. PMID- 26975775 TI - Protective Effect of Myo-Inositol Hexaphosphate (Phytate) on Abdominal Aortic Calcification in Patients With Chronic Kidney Disease. AB - OBJECTIVE: The aim of this study was to evaluate the relationship between physiological levels of myo-inositol hexaphosphate (phytate) and cardiovascular (CV) calcification in patients with chronic kidney disease (CKD). DESIGN AND METHODS: This was a prospective cross-sectional study conducted from December 2012 to June 2013. SUBJECTS: Sixty-nine consecutive patients with CKD who were not undergoing renal replacement therapy. INTERVENTION: All subjects were given lateral lumbar X-rays to quantify abdominal aortic calcification (AAC). Clinical laboratory analyses and phytate food frequency questionnaires were also performed. MAIN OUTCOME MEASURE: Phytate urinary excretion, estimated phytate consumption (based on food frequency questionnaire) and AAC score. Patients were divided into two groups based on median abdominal aortic calcification (AAC) score: no/mild AAC (AAC <= 6, n = 35) and moderate/severe AAC (AAC > 6, n = 34). RESULTS: Patients with no/mild AAC were younger, had lower pulse pressure, greater dietary intake of phytate, greater urinary phytate and the prevalence of prior CV disease was significantly lower compared to patients with moderate/severe AAC. Among the top 10 phytate-rich foods, lentil consumption was significantly greater in patients with no/mild AAC than in those with moderate/severe AAC. Multivariate logistic regression analysis indicated that age, prior CV disease, urinary phytate (or lentil consumption) were independently associated to AAC. CONCLUSION: Our results suggest that adequate consumption of phytate can prevent AAC in patients with CKD. Further prospective studies must be performed to elucidate the benefits of a phytate-rich diet and the associated risk of phosphorus bioavailability in these patients. PMID- 26975776 TI - Diet and Major Renal Outcomes: A Prospective Cohort Study. The NIH-AARP Diet and Health Study. AB - BACKGROUND: Chronic kidney disease (CKD) is prevalent and associated with significant morbidity and mortality. Dietary modification may be an approach to reducing CKD. DESIGN: In this prospective cohort study, we evaluated the association between diet quality, sodium and potassium intakes, and major renal outcomes. A total of 544,635 community-dwelling adults, aged 51 to 70 years, living in 6 states and 2 urban areas in the United States, from the National Institutes of Health-American Association of Retired Persons Diet and Health Study. Using a food frequency questionnaire completed at baseline, we assessed diet quality using the Alternate Healthy Eating Index (AHEI), Healthy Eating Index (HEI), Mediterranean Diet Score (MDS), Recommended Food Score, and Dietary Approaches to Stop Hypertension (DASH) scores. This was also used to estimate daily sodium and potassium intakes. MAIN OUTCOME MEASURES: Multivariable adjusted competing risks regression calculated sub-hazard ratios (sHRs) for a composite of death due to a renal cause and dialysis, with death due to a nonrenal cause as the competing event. RESULTS: During a mean of 14.3-year follow-up, a total of 4,848 participants died from a renal cause or initiated dialysis. Four diet quality scores (AHEI, HEI, MDS, and DASH) were significantly associated with the composite renal outcome; the Recommended Food Score was not. Compared to the lowest score quintile, the highest quintiles of AHEI (sHR 0.71; 95% confidence interval [CI] 0.65-0.79), HEI (sHR 0.82; 95% CI 0.74-0.91), MDS (sHR 0.84; 95% CI 0.74-0.95), and DASH (sHR 0.85; 95% CI 0.77-0.94) were associated with a reduced hazard of the composite. The highest sodium quintile (sHR 1.17; 95% CI 1.02-1.33 for sodium intake > 3.6 g/day) was associated with an increased hazard, whereas the highest potassium quintile (sHR 0.83 [0.73-0.95]) with a reduced hazard. CONCLUSIONS: Our findings support an association between healthy dietary patterns and reduced risk of major renal outcomes and provide observational evidence to inform dietary guideline recommendations for CKD prevention. PMID- 26975777 TI - Nutrient Non-equivalence: Does Restricting High-Potassium Plant Foods Help to Prevent Hyperkalemia in Hemodialysis Patients? AB - Hemodialysis patients are often advised to limit their intake of high-potassium foods to help manage hyperkalemia. However, the benefits of this practice are entirely theoretical and not supported by rigorous randomized controlled trials. The hypothesis that potassium restriction is useful is based on the assumption that different sources of dietary potassium are therapeutically equivalent. In fact, animal and plant sources of potassium may differ in their potential to contribute to hyperkalemia. In this commentary, we summarize the historical research basis for limiting high-potassium foods. Ultimately, we conclude that this approach is not evidence-based and may actually present harm to patients. However, given the uncertainty arising from the paucity of conclusive data, we agree that until the appropriate intervention studies are conducted, practitioners should continue to advise restriction of high-potassium foods. PMID- 26975779 TI - Efficacy and safety of Vinflunine for advanced or metastatic urothelial carcinoma in routine practice based on the French multi-centre CURVE study. AB - BACKGROUND: To retrospectively assess the efficacy and safety of Vinflunine (VFL) under routine conditions and identify overall survival (OS) prognostic factors. METHODS: Twenty centres participated in the retrospective study (minimum 4 patients undergoing VFL treatment for advanced/metastatic UC after platinum-based regimen progression. Primary endpoint was OS. Secondary endpoints: progression free survival (PFS), radiological response rate (RR) RECIST criteria and toxicity (CTC NCI v3). RESULTS: These centres enrolled 134 patients. Prior chemotherapy (CT) lines (>= 1 palliative): 1 and >= 2 in 69% and 26% of patients, respectively. Performance status (PS): 0, 1, 2 in 25%, 46% and 23% of patients. Median OS = 8.2 months [6.5-9.4], PFS = 4.2 months and RR 22%, median number of 5 cycles. In risk groups based on 0-3 presence of adverse prognostic factors (PS >= 1, haemoglobin <= 10 g/dl and liver metastasis), median OS: 13.2, 9.9, 3.6, and 2.4 months (P < .0001), respectively; 3.3 months (1.9-5.6) in PS >= 2 subgroup. CONCLUSION: This study reflects routine UC management and confirmed VFL patient efficacy. The drug is safe with gastro-intestinal and haematological prophylaxis. Analysis of prognostic factors for OS is consistent with pivotal trials. PMID- 26975780 TI - Intraoral Vacuum of Breast-Feeding Newborns Within the First 24 Hr: Cesarean Section Versus Vaginal Delivery. AB - OBJECTIVES: To explore whether newborns born via Cesarean section have a weaker intraoral vacuum compared with those born vaginally and to determine whether a weaker intraoral vacuum is related to a delayed onset of lactation. METHODS: For this prospective cohort study, 71 mother-infant dyads were enrolled and divided into birthing groups, vaginal or Cesarean. The newborn intraoral vacuum was measured via a tube placed alongside the nipple and connected to a pressure sensor during a breast-feeding session within the first 24 hr after birth. Onset of lactation was confirmed by maternal perception of breast fullness. The intraoral vacuum and its relationship with the onset of lactation were analyzed. RESULTS: After adjustment for confounding factors, the peak intraoral vacuum was 19.50 kPa in the vaginal group, which was significantly stronger than the -13.78 kPa in the Cesarean group (p = .005). Additionally, the baseline intraoral vacuum in the vaginal group (-2.35 kPa) was significantly stronger than that in the Cesarean group (-1.18 kPa; p = .022). Strength of the newborn intraoral vacuum was associated with the time of onset of maternal lactation. CONCLUSION: Cesarean section may weaken newborns' intraoral vacuum within the first 24 hr after birth. Stronger intraoral vacuum was related to earlier onset of lactation. Early intervention aimed at the weaker intraoral vacuum should be provided to promote the onset of lactation. PMID- 26975781 TI - Transformation of microcystins to 2-methyl-3-methoxy-4-phenylbutyric acid by room temperature ozone oxidation for rapid quantification of total microcystins. AB - Microcystins (MCs) are cyanobacterial hepatotoxins capable of accumulation into animal tissues. To determine the total microcystins in water, a novel analytical method, including ozonolysis, methylation of 2-methyl-3-methoxy-4-phenylbutyric acid (MMPB) with methylchloroformate (MCF) and gas chromatography mass spectrometry (GC-MS) detection was developed. The results show that MCs can be oxidized by ozone to produce MMPB at ambient temperature, proving ozonation is an effective, rapid and green method for the transformation of MCs to MMPB without secondary pollution. The oxidation conditions as well as the esterification process were optimized and, subsequently applied to analysis of environmental samples. The method shows wide linear range and high sensitivity with a detection limit of 0.34 MUg L(-1). The established method was successfully applied to the analysis of microcystins in water samples. PMID- 26975778 TI - An extended set of yeast-based functional assays accurately identifies human disease mutations. AB - We can now routinely identify coding variants within individual human genomes. A pressing challenge is to determine which variants disrupt the function of disease associated genes. Both experimental and computational methods exist to predict pathogenicity of human genetic variation. However, a systematic performance comparison between them has been lacking. Therefore, we developed and exploited a panel of 26 yeast-based functional complementation assays to measure the impact of 179 variants (101 disease- and 78 non-disease-associated variants) from 22 human disease genes. Using the resulting reference standard, we show that experimental functional assays in a 1-billion-year diverged model organism can identify pathogenic alleles with significantly higher precision and specificity than current computational methods. PMID- 26975782 TI - Patterning highly ordered arrays of complex nanofeatures through EUV directed polarity switching of non chemically amplified photoresist. AB - Given the importance of complex nanofeatures in the filed of micro /nanoelectronics particularly in the area of high-density magnetic recording, photonic crystals, information storage, micro-lens arrays, tissue engineering and catalysis, the present work demonstrates the development of new methodology for patterning complex nanofeatures using a recently developed non-chemically amplified photoresist (n-CARs) poly(4 (methacryloyloxy)phenyl)dimethylsulfoniumtriflate) (polyMAPDST) with the help of extreme ultraviolet lithography (EUVL) as patterning tool. The photosensitivity of polyMAPDST is mainly due to the presence of radiation sensitive trifluoromethanesulfonate unit (triflate group) which undergoes photodegradation upon exposure with EUV photons, and thus brings in polarity change in the polymer structure. Integration of such radiation sensitive unit into polymer network avoids the need of chemical amplification which is otherwise needed for polarity switching in the case of chemically amplified photoresists (CARs). Indeed, we successfully patterned highly ordered wide-raging dense nanofeatures that include nanodots, nanowaves, nanoboats, star-elbow etc. All these developed nanopatterns have been well characterized by FESEM and AFM techniques. Finally, the potential of polyMAPDST has been established by successful transfer of patterns into silicon substrate through adaptation of compatible etch recipes. PMID- 26975783 TI - Meta-analyses of four polymorphisms of lipoprotein lipase associated with the risk of Alzheimer's disease. AB - AIMS: We evaluated the contributions of four polymorphisms of the lipoprotein lipase (LPL) gene to the risk of Alzheimer's disease (AD). METHODS: Through a comprehensive literature search for genetic variants of LPL involved in AD association studies, we found four polymorphisms for the current meta-analyses. These polymorphisms were Asn291Ser(rs268), PvuII(rs285), HindIII(rs320) and Ser447Ter(rs328). RESULTS: In total, eight studies with 5064 cases and 5016 controls were retrieved for the meta-analyses of the four genetic variants. The analyses showed that Asn291Ser(rs268) (OR=2.34, 95% CI=1.05-5.25, P=0.04), HindIII(rs320) (OR=1.44, 95% CI=1.17-1.78, P=0.0006), and Ser447Ter(rs328) (OR=0.80, 95% CI=0.66-0.98, P=0.03) were significantly associated with a risk of AD. No association was found between the PvuII(rs285) polymorphism and the risk of AD. CONCLUSIONS: Our results showed that Asn291Ser(rs268), HindIII(rs320) and Ser447Ter(rs328) polymorphisms of LPL were associated with a risk of AD. Asn291Ser(rs268) and HindIII(rs320) were predisposing factors of AD, whereas Ser447Ter(rs328) showed a protective effect for AD. PMID- 26975784 TI - Nesfatin-1 increases intracellular calcium concentration by protein kinase C activation in cultured rat dorsal root ganglion neurons. AB - Nesfatin-1 is a recently identified anorexigenic hypothalamic polypeptide derived from the posttranslational processing of nucleobindin 2 (NUCB2). Several studies have indicated that this neuropeptide may be participated in somatosensory and visceral transmission including pain signals in addition to energy metabolism. The aim of this study was to explore the possible role of nesfatin-1 in the transmission of peripheral neural signals by investigating the effects of nesfatin-1 on intracellular free calcium levels ([Ca(2+)]i) in cultured neonatal rat dorsal root ganglion (DRG) neurons. The effects of nesfatin-1 on [Ca(2+)]i in DRG neurons were investigated by using an in vitro calcium imaging system. DRG neurons were grown in primary culture following enzymatic and mechanical dissociation of ganglia from 1-or 2-day-old neonatal Wistar rats. Using the fura 2-based calcium imaging technique, the effects of nesfatin-1 on [Ca(2+)]i and role of the protein kinase C (PKC)-mediated pathway in nesfatin-1 effect were assessed. Nesfatin-1 elevated [Ca(2+)]i in cultured DRG neurons. The response was prevented by pretreating the cells with pertussis toxin. The protein kinase C inhibitor chelerythrine chloride suppressed nesfatin-1-induced rise in [Ca(2+)]i. The result shows that nesfatin-1 interacts with a G protein-coupled receptor, leading to an increase of [Ca(2+)]i, which is linked to protein kinase C activation in cultured rat DRG neurons. PMID- 26975786 TI - Immediate breast reconstruction with a myocutaneous latissimus dorsi flap and implant following skin-sparing salvage mastectomy after irradiation as part of breast-conserving therapy. AB - BACKGROUND: Local relapse after breast-conserving therapy including whole breast irradiation is typically treated by salvage mastectomy. Immediate reconstruction by pedicled transfer of a latissimus dorsi flap in combination with implantation of a definitive prosthesis or temporary tissue expander following skin sparing salvage mastectomy has been shown to be feasible. However, it has never been shown to be justifiable. AIM: The aim of the study was to compare the outcome of this procedure to the widely accepted secondary breast reconstruction by combined latissimus dorsi flap and implant after mastectomy and adjuvant radiotherapy. METHODOLOGY: The surgical outcome of 93 immediate latissimus dorsi and implant reconstructions after skin-sparing salvage mastectomy performed from 2007 to 2011 after radiotherapy was compared to that of 83 secondary reconstructions with the latissimus dorsi and an implant. The follow-up duration was 3.5 years in both groups. Complications were categorized as minor (conservative treatment sufficed) or major (flap loss, mammary skin loss, implant loss, seroma or haematoma indicating repeat surgery). RESULTS: The salvage group scored significantly less on half of the patient-related and procedure-related risk factors. Nevertheless, we observed 27% of short-term major surgical complications and an ultimate success rate of 94% in the salvage group compared to those observed in our series of secondary reconstruction in post-radiation women (27% and 93%, respectively). CONCLUSION: Skin-sparing salvage mastectomy combined with immediate reconstruction by transfer of a latissimus dorsi flap with an implant is a justifiable reconstructive option for women with a recurrence after irradiation as part of breast-conserving therapy. PMID- 26975787 TI - Intensive care unit-acquired weakness in the burn population. AB - Intensive care unit-acquired weakness is an evolving problem in the burn population. As patients are surviving injuries that previously would have been fatal, the focus of treatment is shifting from survival to long-term outcome. The rehabilitation of burn patients can be challenging; however, a certain subgroup of patients have worse outcomes than others. These patients may suffer from intensive care unit-acquired weakness, and their treatment, physiotherapy and expectations need to be adjusted accordingly. This study investigates the condition of intensive care unit-acquired weakness in our burn centre. We conducted a retrospective analysis of all the admissions to our burn centre between 2008 and 2012 and identified 22 patients who suffered from intensive care unit-acquired weakness. These patients were significantly younger with significantly larger burns than those without intensive care unit-acquired weakness. The known risk factors for intensive care unit-acquired weakness are commonplace in the burn population. The recovery of these patients is significantly affected by their weakness. PMID- 26975785 TI - Incidence, Risk Factors, and Attributable Mortality of Secondary Infections in the Intensive Care Unit After Admission for Sepsis. AB - IMPORTANCE: Sepsis is considered to induce immune suppression, leading to increased susceptibility to secondary infections with associated late mortality. OBJECTIVE: To determine the clinical and host genomic characteristics, incidence, and attributable mortality of intensive care unit (ICU)-acquired infections in patients admitted to the ICU with or without sepsis. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study comprising consecutive admissions of more than 48 hours in 2 ICUs in the Netherlands from January 2011 to July 2013 stratified according to admission diagnosis (sepsis or noninfectious). MAIN OUTCOMES AND MEASURES: The primary outcome was ICU-acquired infection (onset >48 hours). Attributable mortality risk (fraction of mortality that can be prevented by elimination of the risk factor, acquired infection) was determined using time to-event models accounting for competing risk. In a subset of sepsis admissions (n = 461), blood gene expression (whole-genome transcriptome in leukocytes) was analyzed at baseline and at onset of ICU-acquired infectious (n = 19) and noninfectious (n = 9) events. RESULTS: The primary cohort included 1719 sepsis admissions (1504 patients; median age, 62 years; interquartile range [IQR], 51-71 years]; 924 men [61.4%]). A comparative cohort included 1921 admissions (1825 patients, median age, 62 years; IQR, 49-71 years; 1128 men [61.8%] in whom infection was not present in the first 48 hours. Intensive care unit-acquired infections occurred in 13.5% of sepsis ICU admissions (n = 232) and 15.1% of nonsepsis ICU admissions (n = 291). Patients with sepsis who developed an ICU acquired infection had higher disease severity scores on admission than patients with sepsis who did not develop an ICU-acquired infection (Acute Physiology and Chronic Health Evaluation IV [APACHE IV] median score, 90 [IQR, 72-107] vs 79 [IQR, 62-98]; P < .001) and throughout their ICU stay but did not have differences in baseline gene expression. The population attributable mortality fraction of ICU-acquired infections in patients with sepsis was 10.9% (95% CI, 0.9%-20.6%) by day 60; the estimated difference between mortality in all patients with a sepsis admission diagnosis and mortality in those without ICU-acquired infection was 2.0% (95% CI, 0.2%-3.8%; P = .03) by day 60. Among nonsepsis ICU admissions, ICU-acquired infections had a population attributable mortality fraction of 21.1% (95% CI, 0.6%-41.7%) by day 60. Compared with baseline, blood gene expression at the onset of ICU-acquired infections showed reduced expression of genes involved in gluconeogenesis and glycolysis. CONCLUSIONS AND RELEVANCE: Intensive care unit-acquired infections occurred more commonly in patients with sepsis with higher disease severity, but such infections contributed only modestly to overall mortality. The genomic response of patients with sepsis was consistent with immune suppression at the onset of secondary infection. PMID- 26975789 TI - Ionised concentrations in calcium and magnesium buffers: Standards and precise measurement are mandatory. AB - In Ca(2+) and Mg(2+) buffer solutions the ionised concentrations ([X(2+)]) are either calculated or measured. Calculated values vary by up to a factor of seven due to the following four problems: 1) There is no agreement amongst the tabulated constants in the literature. These constants have usually to be corrected for ionic strength and temperature. 2) The ionic strength correction entails the calculation of the single ion activity coefficient, which involves non-thermodynamic assumptions; the data for temperature correction is not always available. 3) Measured pH is in terms of activity i.e. pHa. pHa measurements are complicated by the change in the liquid junction potentials at the reference electrode making an accurate conversion from H(+) activity to H(+) concentration uncertain. 4) Ligands such as EGTA bind water and are not 100% pure. Ligand purity has to be measured, even when the [X(2+)] are calculated. The calculated [X(2+)] in buffers are so inconsistent that calculation is not an option. Until standards are available, the [X(2+)] in the buffers must be measured. The Ligand Optimisation Method is an accurate and independently verified method of doing this (McGuigan & Stumpff, Anal. Biochem. 436, 29, 2013). Lack of standards means it is not possible to compare the published [Ca(2+)] in the nmolar range, and the apparent constant (K(/)) values for Ca(2+) and Mg(2+) binding to intracellular ligands amongst different laboratories. Standardisation of Ca(2+)/Mg(2+) buffers is now essential. The parameters to achieve this are proposed. PMID- 26975788 TI - Influence of different stool types on muscle activity and lumbar posture among dentists during a simulated dental screening task. AB - Whereas in the past dental stools typically facilitated a 90 degrees hip angle, a number of currently available alternative designs allow for a more extended hip posture. The present study investigated the influence of different stool types on muscle activity and lumbar posture. Twenty five participants completed a simulated dental procedure on a standard stool, a saddle and the Ghopec. The latter stool comprises a seat pan consisting of a horizontal rear part for the pelvis and an inclinable sloping down front part for the upper legs, with a vertically and horizontally adjustable back rest. Lumbar posture was most close to neutral on the Ghopec, whereas sitting on a standard/saddle stool resulted in more flexed/extended postures respectively. Sitting with a 90 degrees angle (standard stool) resulted in higher activation of back muscles while sitting with a 125 degrees angle (saddle and Ghopec) activated abdominal muscles more, although less in the presence of a backrest (Ghopec). To maintain neutral posture during dental screening, the Ghopec is considered the most suitable design for the tasks undertaken. PMID- 26975790 TI - Evidences of the static magnetic field influence on cellular systems. AB - Efforts to elucidate the doubtful character of the static magnetic field (SMF) influence on living cells have been made, although the topic still faces controversies because confusing reports in the scientific literature. This study intended to collect the most relevant issues separated by different topics (relating the SMF to its action on cellular systems) and analyze how the many field intensities, cell types and exposure time would affect the cell or intracellular structures. The analysis was based in the search in online databases aiming to give a general view of how the data can show conformity. It is proposed that scientists have been searching for linearity in what is actually a well characterized nonlinear system and two outputs are considered: the high sensitivity of parameters in which specific cell responses are generated and also the complexity and particularity of each cellular system. It is possible to trigger effects from a SMF, however in a stochastic way and depending on the cell system. PMID- 26975791 TI - Ketamine--the real perspective. PMID- 26975792 TI - Haemochromatosis. AB - Haemochromatosis is now known to be an iron-storage disease with genetic heterogeneity but with a final common metabolic pathway resulting in inappropriately low production of the hormone hepcidin. This leads to increase in intestinal absorption and deposition of excessive amounts of iron in parenchymal cells which in turn results in eventual tissue damage and organ failure. A clinical enigma has been the variable clinical expression with some patients presenting with hepatic cirrhosis at a young age and others almost asymptomatic for life. Research is unravelling this puzzle by identifying environmental factors-especially alcohol consumption-and associated modifying genes that modulate phenotypic expression. A high index of suspicion is required for early diagnosis but this can lead to presymptomatic therapy and a normal life expectancy. Venesection (phlebotomy) therapy remains the mainstay of therapy, but alternative therapies are the subject of current research. PMID- 26975793 TI - Biomechanical effect of the configuration of screw hole style on locking plate fixation in proximal humerus fracture with a simulated gap: A finite element analysis. AB - BACKGROUND: Locking plate fixation for proximal humeral fractures is a commonly used device. Recently, plate breakages were continuously reported that the implants all have a mixture of holes allowing placement of both locking and non locking screws (so-called combi plates). In commercialized proximal humeral plates, there still are two screw hole styles included "locking and dynamic holes separated" and "locking hole only" configurations. It is important to understand the biomechanical effect of different screw hole style on the stress distribution in bone plate. METHODS: Finite element method was employed to conduct a computational investigation. Three proximal humeral plate models with different screw hole configurations were reconstructed depended upon an identical commercialized implant. A three-dimensional model of a humerus was created using process of thresholding based on the grayscale values of the CT scanning of an intact humerus. A "virtual" subcapital osteotomy was performed. Simulations were performed under an increasing axial load. The von Mises stresses around the screw holes of the plate shaft, the construct stiffness and the directional displacement within the fracture gap were calculated for comparison. RESULTS: The mean value of the peak von Mises stresses around the screw holes in the plate shaft was the highest for combi hole design while it was smallest for the locking and dynamic holes separated design. The stiffness of the plate-bone construct was 15% higher in the locking screw only design (132.6N/mm) compared with the combi design (115.0N/mm), and it was 4% higher than the combi design for the locking and dynamic holes separated design (119.5N/mm). The displacement within the fracture gap was greatest in the combi hole design, whereas it was smallest for the locking hole only design. CONCLUSIONS: The computed results provide a possible explanation for the breakages of combi plates revealed in clinical reports. The locking and dynamic holes separated design may be a better configuration to reduce the risk of plate fracture. PMID- 26975794 TI - Radiographical definition of the proximal tibiofibular joint - A cross-sectional study of 2984 knees and literature review. AB - BACKGROUND: Proximal tibiofibular joint (PTFJ) injuries are not uncommon but relatively understudied. This study evaluates the effectiveness of 2 radiographic methods in assessing the integrity of the PTFJ. STUDY DESIGN: This is a cross sectional study of 2984 consecutive patients with knee X-rays done in a single institution over a 4-month period. A total of 5968 knee X-rays were assessed using 2 methods-[1] The direction in which the fibula points to in relation to the lateral femoral epicondyle on anteroposterior view and Blumensaat line on lateral view. [2] The degree of tibiofibular overlap as percentage of widest portion of the fibula head. Sensitivity and specificity of these methods in diagnosing a disrupted PTFJ are calculated. Variables including quality of X rays, weight-bearing status of AP views and degree of knee flexion on lateral views are also recorded. Univariate analysis was carried out to investigate the association between variables using chi-square test for nominal data and student t-test for continuous data. RESULTS: The fibular points towards the lateral femoral epicondyle on AP view in 94.4% of the patients and points towards the posterior half of the Blumensaat line on lateral view in 98.1% of the patients. Using this method, weight-bearing X-rays are significantly associated with the direction the fibula is pointing (p<0.01) on the AP view and the degree of knee flexion is associated with the direction the fibula is pointing (p<0.01) on the lateral view. The AP tibiofibular overlap ranges from >0% to <75% in 94.1% of the patients and the lateral tibiofibular overlap ranges from >0% to <75% in 84.5% of the patients. This method is associated with whether true orthogonal X-rays of the knees are taken (p=0.048). CONCLUSION: The direction in which the fibula is pointing and the percentage of tibiofibular overlap are highly specific radiographic methods useful in defining the PTFJ. The first method requires a weight-bearing view on AP assessment and >20 degrees of flexion on lateral assessment. True orthogonal AP and lateral views are required for the second method to be used. PMID- 26975795 TI - Factors associated with removal of a radial head prosthesis placed for acute trauma. AB - PURPOSE: This study tests the hypothesis that there are no factors associated with removal or revision of a radial head prosthesis. A secondary analysis addressed the time to removal or revision. METHODS: We reviewed the database of two large hospitals from 2000 to 2014 and identified 278 patients that had radial head replacement after an acute fracture or fracture dislocation of the elbow: 19 had removal and 3 had revision of the radial head implant within the study period. Explanatory variables including demographics, the type of injury, prosthesis type, surgeon, medical centre, and associated injuries were evaluated. Survival analysis using Kaplan-Meier curves evaluated time to removal/revision. RESULTS: After adjustment for potential confounders using Cox regression multivariable analysis, hospital was the only factor independently associated with removal or revision (Hazard ratio=2.4, Confidence interval: 1.03-5.8, P value=0.043). The highest proportion of removal/revision was during the first year after implantation and decreased by half each year over the second to fourth years. The most common reason for removal of the prosthesis was to facilitate removal of heterotopic ossification (the majority with proximal radioulnar synostosis) rather than technical error or problems with the prostheses. CONCLUSION: These findings suggest that the decision to remove a radial head prosthesis may depend more on surgeon or hospital preferences than on objective problems with the prosthesis. Until clarified by additional study, removal of a prosthesis should not be considered an objective outcome in research. In addition, patients offered removal of a radial head prosthesis, might get the opinion of more than one surgeon at more than one hospital before deciding whether or not to proceed. LEVEL OF EVIDENCE: Level III Prognostic. PMID- 26975796 TI - The timing of the evening meal: how is this associated with weight status in UK children? AB - There is some evidence from studies in adults and limited evidence from studies in children that eating later in the day may increase the risk of overweight and obesity. In this cross-sectional study, we investigated associations between evening meal timing in children and their weight status and energy intake. Dietary data obtained from the UK's National Diet and Nutrition Survey Rolling Programme (2008-2012) for 768 children aged 4-10 years and 852 children aged 11 18 years were analysed. We tested for an association between evening meal timing (consuming the evening meal before or after 20.00 hours) and risk of overweight and/or obesity, adjusting for relevant confounding variables. We also explored whether evening meal timing was associated with overall nutrient intake. We found no association between evening meal timing and risk of obesity or risk of overweight and obesity combined in either the 4-10 years age group (obesity: OR 1.43; 95 % CI 0.49, 4.13; obesity and overweight combined: OR 1.33; 95 % CI 0.53, 3.33) or the 11-18 years age group (obesity: OR 0.50; 95 % CI 0.24, 1.02; obesity and overweight combined: OR 0.83; 95 % CI 0.50, 1.38), split by sex or as combined. No significant associations were found between evening meal timing and energy intake, and no clear patterns in variation of nutrient intakes with evening meal times were identified. In conclusion, we found no evidence that, for children aged 4-18 years in the UK, eating the evening meal after 20.00 hours was associated with excess weight or increased energy intake. PMID- 26975797 TI - Redox condensation of o-halonitrobenzene with 1,2,3,4-tetrahydroisoquinoline: involvement of an unexpected auto-catalyzed redox cascade. AB - A practical synthesis of fused benzimidazoles 5 has been developed by simply heating o-halonitrobenzenes 1 with tetrahydroisoquinolines 2. In this transformation, 2 played multiple roles as a building block, base and a double hydride donor in a cascade of uncatalyzed aromatic substitution, reduction of the nitro group, oxidation of the alpha-methylene group and condensation. PMID- 26975799 TI - The Perovskite Fever and Beyond. PMID- 26975800 TI - Abstracts of the Fifth Asian and Oceanian Parkinson's Disease and Movement Disorders Congress. PMID- 26975798 TI - Mesangiogenic Progenitor Cells Derived from One Novel CD64(bright)CD31(bright)CD14(neg) Population in Human Adult Bone Marrow. AB - Mesenchymal stromal cells (MSCs) have been the object of extensive research for decades, due to their intrinsic clinical value. Nonetheless, the unambiguous identification of a unique in vivo MSC progenitor is still lacking, and the hypothesis that these multipotent cells could possibly arise from different in vivo precursors has been gaining consensus in the last years. We identified a novel multipotent cell population in human adult bone marrow that we first named Mesodermal Progenitor Cells (MPCs) for the ability to differentiate toward the mesenchymal lineage, while still retaining angiogenic potential. Despite extensive characterization, MPCs positioning within the differentiation pathway and whether they can be ascribed as possible distinctive progenitor of the MSC lineage is still unclear. In this study, we describe the ex vivo isolation of one novel bone marrow subpopulation (Pop#8) with the ability to generate MPCs. Multicolor flow cytometry in combination with either fluorescence-activated cell sorting or magnetic-activated cell sorting were applied to characterize Pop#8 as CD64(bright)CD31(bright)CD14(neg). We defined Pop#8 properties in culture, including the potential of Pop#8-derived MPCs to differentiate into MSCs. Gene expression data were suggestive of Pop#8 in vivo involvement in hematopoietic stem cell niche constitution/maintenance. Pop#8 resulted over three logs more frequent than other putative MSC progenitors, corroborating the idea that most of the controversies regarding culture-expanded MSCs could be the consequence of different culture conditions that select or promote particular subpopulations of precursors. PMID- 26975801 TI - Synthesis of 2-fluoro-2-pyrrolines via tandem reaction of alpha-trifluoromethyl alpha,beta-unsaturated carbonyl compounds with N-tosylated 2-aminomalonates. AB - A simple base-mediated tandem SN2'/SNV reaction of the readily available alpha trifluoromethyl-alpha,beta-unsaturated carbonyl compounds with N-tosylated 2 aminomalonates was developed, which provide an efficient access to functionalized tetrasubstituted 2-fluoro-2-pyrrolines in good to excellent yields. In contrast, simple 1,2-nucleophilic adducts were produced when alpha-trifluoromethyl styrenes were used. PMID- 26975803 TI - Comment on: concomitant removal of gastric band and sleeve gastrectomy: analysis of outcomes and complications from the ACS-NSQIP database. PMID- 26975802 TI - Dioxins reformation and destruction in secondary copper smelting fly ash under ball milling. AB - Secondary copper recovery is attracting increasing interest because of the growth of copper containing waste including e-waste. The pyrometallurgical treatment in smelters is widely utilized, but it is known to produce waste fluxes containing a number of toxic pollutants due to the large amount of copper involved, which catalyses the formation of polychlorinated dibenzo-p-dioxins and dibenzofurans ("dioxins"). Dioxins are generated in secondary copper smelters on fly ash as their major source, resulting in highly contaminated residues. In order to assess the toxicity of this waste, an analysis of dioxin-like compounds was carried out. High levels were detected (79,090 ng TEQ kg(-1)) in the ash, above the Basel Convention low POPs content (15,000 ng TEQ kg(-1)) highlighting the hazardousness of this waste. Experimental tests of high energy ball milling with calcium oxide and silica were executed to assess its effectiveness to detoxify such fly ash. Mechanochemical treatment obtained 76% dioxins reduction in 4 h, but longer milling time induced a partial de novo formation of dioxins catalysed by copper. Nevertheless, after 12 h treatment the dioxin content was substantially decreased (85% reduction) and the copper, thanks to the phenomena of incorporation and amorphization that occur during milling, was almost inactivated. PMID- 26975805 TI - Unorthodox Interactions at Work. AB - This Perspective elaborates on the currently unfolding interest in integrating unorthodox non-covalent interactions into functional systems. Initial emphasis is on anion-pi interactions at work, particularly in catalysis. Recent highlights are described in comparison to a coinciding renaissance of the more conventional, charge-inverted cation-pi catalysis. Progress with these complementary aromatic systems is then compared to recent efforts to integrate halogen and chalcogen bonds, the unorthodox counterparts of hydrogen bonds, into functional systems. General focus is on catalysis, pertinent examples on self-assembly, transport, sensing, and templation are covered as well. PMID- 26975804 TI - Comment on: Perioperative noninvasive ventilation in obese patients: a qualitative review and meta-analysis. PMID- 26975806 TI - Chemistry supports the identification of gender-specific reproductive tissue in Tyrannosaurus rex. AB - Medullary bone (MB), an estrogen-dependent reproductive tissue present in extant gravid birds, is texturally, histologically and compositionally distinct from other bone types. Phylogenetic proximity led to the proposal that MB would be present in non-avian dinosaurs, and recent studies have used microscopic, morphological, and regional homologies to identify this reproductive tissue in both theropod and ornithischian dinosaurs. Here, we capitalize on the unique chemical and histological fingerprint of MB in birds to characterize, at the molecular level, MB in the non-avian theropod Tyrannosaurus rex (MOR 1125), and show that the retention of original molecular components in fossils allows deeper physiological and evolutionary questions to be addressed. PMID- 26975808 TI - Reply by the Authors of the Original Article. PMID- 26975807 TI - Is Clipping the Sympathetic Chain Effective for Palmar Skin Temperature? PMID- 26975809 TI - German Registry for Acute Aortic Dissection Type A: Structure, Results, and Future Perspectives. AB - The German Registry for Acute Aortic Dissection Type A (GERAADA) as an international registry for acute aortic dissection type A (AADA) offers a unique opportunity to answer questions regarding acute dissections that cannot be answered by single institution's database alone. GERAADA was started in 2006 by the German Society for Thoracic and Cardiovascular Surgery (GSTCVS) and has collected more than 3,300 AADA patients' data from 56 centers in Germany, Austria, and Switzerland up to now. In the second generated validated dataset comprising the years from 2006 to 2010, 2,137 patients were surgically treated for AADA with an overall 30-day mortality of 16.9%, and a new postoperative neurologic dysfunction of 9.5%. Risk factors for neurologic dysfunction were malperfusion syndromes, dissections of the supra-aortic vessels, and longer operating time. Neuroprotective drugs had no influence on stroke rates. Hypothermic circulatory arrest and antegrade selective cerebral perfusion (ACP) led to similar results if arrest times were less than 30 minutes while ACP for longer arrest periods is advisable. Septuagenarians had an early mortality rate (15.8%) similar to the whole cohort's, but the mortality rate in octogenarians (34.9%) was much higher. GERAADA with its validated 2,137 patient files (2006 2010) is the largest database on AADA worldwide and continues to collect data. Structured follow-up of more than 5 years will be available in the future. PMID- 26975811 TI - Treatment of pulmonary hypertension. AB - The most common forms of pulmonary hypertension are pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, and pulmonary hypertension due to left-sided heart and lung disease. The treatment of pulmonary arterial hypertension has advanced substantially over the past 20 years. Five different classes of drugs are now available-ie, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin analogues, and prostacyclin receptor agonists. Long-term studies have provided evidence that various combinations of these compounds improve the progression-free survival of patients with pulmonary arterial hypertension. For patients with chronic thromboembolic pulmonary hypertension, surgical pulmonary endarterectomy is the treatment of choice. For patients who are inoperable and have chronic thromboembolic pulmonary hypertension, riociguat, a stimulator of soluble guanylate cyclase, has proven efficacious. Additionally, interventional approaches could become a treatment option for these patients. For patients with pulmonary hypertension due to left-sided heart disease or lung disease, the use of pulmonary vasodilator treatment has not been proven to be safe and effective. PMID- 26975810 TI - A global view of pulmonary hypertension. AB - Pulmonary hypertension is a substantial global health issue. All age groups are affected with rapidly growing importance in elderly people, particularly in countries with ageing populations. Present estimates suggest a pulmonary hypertension prevalence of about 1% of the global population, which increases up to 10% in individuals aged more than 65 years. In almost all parts of the world, left-sided heart and lung diseases have become the most frequent causes of pulmonary hypertension. About 80% of affected patients live in developing countries, where pulmonary hypertension is frequently associated with congenital heart disease and various infectious disorders, including schistosomiasis, HIV, and rheumatic heart disease. These forms of pulmonary hypertension occur predominantly in those younger than 65 years. Independently of the underlying disease, the development of pulmonary hypertension is associated with clinical deterioration and a substantially increased mortality risk. Global research efforts are needed to establish preventive strategies and treatments for the various types of pulmonary hypertension. PMID- 26975812 TI - Expression of TGFbeta-family signalling components in ageing cartilage: age related loss of TGFbeta and BMP receptors. AB - OBJECTIVE: Ageing is the main risk factor for osteoarthritis (OA). We investigated if expression of transforming growth factor beta (TGFbeta)-family components, a family which is crucial for the maintenance of healthy articular cartilage, is altered during ageing in cartilage. Moreover, we investigated the functional significance of selected age-related changes. DESIGN: Age-related changes in expression of TGFbeta-family members were analysed by quantitative PCR in healthy articular cartilage obtained from 42 cows (age: 3/4-10 years). To obtain functional insight of selected changes, cartilage explants were stimulated with TGFbeta1 or bone morphogenetic protein (BMP) 9, and TGFbeta1 and BMP response genes were measured. RESULTS: Age-related cartilage thinning and loss of collagen type 2a1 expression (~256-fold) was observed, validating our data set for studying ageing in cartilage. Expression of the TGFbeta-family type I receptors; bAlk2, bAlk3, bAlk4 and bAlk5 dropped significantly with advancing age, whereas bAlk1 expression did not. Of the type II receptors, expression of bBmpr2 decreased significantly. Type III receptor expression was unaffected by ageing. Expression of the ligands bTgfb1 and bGdf5 also decreased with age. In explants, an age-related decrease in TGFbeta1-response was observed for the pSmad3-dependent gene bSerpine1 (P = 0.016). In contrast, ageing did not affect BMP9 signalling, an Alk1 ligand, as measured by expression of the pSmad1/5 dependent gene bId1. CONCLUSIONS: Ageing negatively affects both the TGFbeta-ALK5 and BMP-BMPR signalling routes, and aged chondrocytes display a lowered pSmad3 dependent response to TGFbeta1. Because pSmad3 signalling is essential for cartilage homeostasis, we propose that this change contributes to OA development. PMID- 26975813 TI - [Effect and safety of intensive phototherapy in treatment of neonatal hyperbilirubinemia]. AB - OBJECTIVE: To study the effect and safety of intensive phototherapy in the treatment of neonatal hyperbilirubinemia. METHODS: A total of 144 neonates with neonatal hyperbilirubinemia were randomly and prospectively divided into intensive phototherapy group and conventional phototherapy group, with 72 neonates in each group. The therapeutic effect and incidence of complications were compared between the two groups. RESULTS: Within 12 hours after phototherapy, the total serum bilirubin level in the intensive phototherapy group was significantly lower than in the conventional phototherapy group (P<0.05), and the intensive phototherapy group had a significantly greater reduction in serum bilirubin level than the conventional phototherapy group (P<0.05). The intensives phototherapy group had a significantly shorter time of phototherapy than the conventional phototherapy group (P<0.05). The incidence rates of fever, diarrhea, rash, and hypocalcemia and reductions in blood calcium and hemoglobin levels after phototherapy showed no significant differences between the two groups. CONCLUSIONS: During the initial stage of phototherapy, intensive phototherapy can quickly and effectively reduce the serum level of bilirubin in neonates with neonatal hyperbilirubinemia. It can also shorten the total phototherapy time, and does not increase the incidence of adverse events. Therefore, it is superior to conventional phototherapy. PMID- 26975814 TI - [Value of hour-specific transcutaneous bilirubin nomogram for prediction of hyperbilirubinemia in healthy neonates]. AB - OBJECTIVE: To plot a hour-specific transcutaneous bilirubin (TCB) nomogram for healthy neonates, and to evaluate its value for prediction of the risk of neonatal hyperbilirubinemia. METHODS: A total of 5,250 healthy full-term or near term neonates (gestational age>=35 weeks, birth weight>=2 000 g) were enrolled as subjects. Their TCB values were continuously recorded for 168 hours after birth. The TCB values in the high-risk zones of three time periods, 24-48, 49-72, and 73 96 hours after birth, were used as predictors. The hour-specific TCB nomogram combined with the receiver operating characteristic (ROC) curve was used to evaluate the predictive value of hour-specific TCB nomogram for hyperbilirubinemia. RESULTS: According to the hour-specific TCB nomogram, the TCB value dramatically increased during 16-72 hours after birth, and the increase slowed down gradually during 72-144 hours. Finally, the curve reached a plateau after 144 hours. Particularly, the P95 of TCB had been stabilized at 96 hours. The P40, P75, and P95 peak values of TCB were 173, 217, and 248 umol/L, respectively. For the prediction of hyperbilirubinemia, the areas under the ROC curve of TCB at 24-48, 49-72, and 73-96 hours after birth were 0.77, 0.85, and 0.87, respectively. The high-risk zones at 24-48, 49-72, and 73-96 hours after birth predicted the incidence rates of neonatal hyperbilirubinemia as 35.03%, 43.35%, and 79.95%, respectively, with positive likelihood ratios of 3.35, 4.75, and 22.70, respectively. CONCLUSIONS: The hour-specific TCB nomogram and the division of TCB risk zones can give a satisfactory prediction of the incidence of neonatal hyperbilirubinemia. The neonate with a bilirubin level in the high-risk zone within 73-96 hours after birth is likely to have hyperbilirubinemia after 73 96 hours. PMID- 26975815 TI - [Effect of caffeine citrate on early pulmonary function in preterm infants with apnea]. AB - OBJECTIVE: To investigate the effect of caffeine citrate treatment on early pulmonary function in preterm infants with apnea. METHODS: Forty preterm infants with apnea were randomly divided into aminophylline treatment group (20 infants) and caffeine citrate treatment group (20 infants). When the preterm infants experienced apnea after birth, they were given aminophylline or caffeine citrate in addition to assisted ventilation with continuous positive airway pressure (NCPAP). After drug discontinuation, pulmonary function was measured and compared between the two groups. RESULTS: After treatment, compared with the aminophylline treatment group, the caffeine citrate treatment group had significantly higher tidal volume, minute ventilation volume, ratio of time to peak tidal expiratory flow to total expiratory time, ratio of volume to peak tidal expiratory flow to total expiratory volume, peak expiratory flow, and breathing flow at 75%, 50%, and 25% of tidal volume (P<0.05). The caffeine citrate treatment group had a significantly shorter time of oxygen use and NCPAP support than the aminophylline treatment group (P<0.01). Compared with the aminophylline treatment group, the caffeine citrate treatment group had a significantly lower frequency of apnea attacks (P<0.01). CONCLUSIONS: In the treatment of apnea in preterm infants, caffeine citrate can improve early pulmonary function and reduce the incidence of apnea. PMID- 26975816 TI - [Changes in 25-hydroxyvitamin D3 level and its significance in children with Kawasaki disease]. AB - OBJECTIVE: To investigate the changes in the serum level of 25-hydroxyvitamin D3 [25-(OH)D3] and its significance in children with Kawasaki disease (KD). METHODS: The clinical data of 242 KD children were collected. According to the presence or absence of coronary artery lesion (CAL), these children were classified into CAL group (63 children) and non-CAL (NCAL) group (179 children). According to the efficacy of intravenous immunoglobulin (IVIG), these children were classified into IVIG-sensitive group (219 children) and no-IVIG-response group (23 children). A total of 40 healthy children (control group) and 40 children with acute upper respiratory tract infection (AURI group) were enrolled as controls. Enzyme-linked immunosorbent assay was applied to measure the serum level of 25 (OH)D3. RESULTS: Before IVIG treatment, the AURI, NCAL, and CAL groups had significantly lower serum levels of 25-(OH)D3 than the control group (P<0.05); the CAL group had a significantly lower serum level of 25-(OH)D3 than the AURI and NCAL groups (P<0.05); the AURI, IVIG-sensitive, and no-IVIG-response groups had significantly lower serum levels of 25-(OH)D3 than the control group (P<0.05); the no-IVIG-response group had a significantly lower serum level of 25 (OH)D3 than the AURI and IVIG-sensitive groups (P<0.05). After IVIG treatment, the CAL group had a significantly lower serum level of 25-(OH)D3 than the NCAL and control groups (P<0.05); the no-IVIG-response group had a significantly lower serum level of 25-(OH)D3 than the IVIG-sensitive and control groups (P<0.05). CONCLUSIONS: KD children may experience a reduction in the serum level of 25 (OH)D3. With a greater reduction in the serum level of 25-(OH)D3, the possibility of CAL and KD with no response to treatment increases. PMID- 26975817 TI - [Vitamin D level in children with bloodstream infection]. AB - OBJECTIVE: To investigate the difference in serum 25(OH)D level between children with bloodstream infection and healthy children. METHODS: A case-control study was conducted among 60 children with bloodstream infection who were hospitalized between January 2010 and December 2013 and had positive results of two blood cultures. Meanwhile, 60 aged-matched healthy children who underwent physical examination during the same period of time were enrolled as the healthy control group. Chemiluminescence was applied to measure the serum 25(OH)D level, and the constituent ratios of children with different serum 25(OH)D levels were compared between the two groups. RESULTS: The bloodstream infection group had a significantly lower serum 25(OH)D level than the healthy control group (P<0.01). Compared with the healthy control group, the bloodstream group had significantly lower constituent ratios of children with normal Vitamin D level (8% vs 35%) or vitamin D insufficiency (22% vs 43%) (P<0.05). Compared with the healthy control group, the bloodstream group had significantly higher constituent ratios of children with vitamin D deficiency (42% vs 13%) or severely vitamin D deficiency (28% vs 8%) (P<0.01). CONCLUSIONS: Vitamin D insufficiency prevails among children, and children with bloodstream infection have a significantly lower serum 25(OH)D level than healthy children. PMID- 26975818 TI - [Effect of continuous hemofiltration on inflammatory mediators and hemodynamics in children with severe hand, foot and mouth disease]. AB - OBJECTIVE: To investigate the effect of continuous veno-venous hemofiltration (CVVH) on inflammatory mediators in children with severe hand, foot and mouth disease (HFMD), and to investigate its clinical efficacy. METHODS: A total of 36 children with stage IV HFMD were enrolled and randomly divided into conventional treatment group and CVVH group (n=18 each). The children in the CVVH group were given CVVH for 48 hours in addition to the conventional treatment. The levels of interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and lactic acid in peripheral venous blood, heart rate, blood pressure, and left ventricular ejection fraction were measured before treatment and after 24 and 48 hours of treatment. RESULTS: After 24 hours of treatment, the conventional treatment group had a significantly reduced serum IL-2 level (P<0.01), and the CVVH treatment group had significantly reduced serum levels of IL-2, IL-6, IL-10, and TNF-alpha (P<0.05). After 48 hours of treatment, both groups had significantly reduced serum levels of IL-2, IL-6, IL-10, and TNF alpha (P<0.01), and the CVVH group had significantly lower levels of these inflammatory factors than the conventional treatment group (P<0.01). After 48 hours of treatment, heart rate, systolic pressure, and blood lactic acid level were significantly reduced, and left ventricular ejection fraction was significantly increased in both groups, and the CVVH group had significantly greater changes in these indices except systolic pressure than the conventional treatment group (P<0.01). CONCLUSIONS: CVVH can effectively eliminate inflammatory factors, reduce heart rate and venous blood lactic acid, and improve heart function in children with severe HFMD. PMID- 26975820 TI - [Changes in lymphocyte subsets in infants with common lower respiratory tract infectious diseases]. AB - OBJECTIVE: To investigate the changes and clinical significance of lymphocyte subsets in infants with bronchitis, bronchopneumonia, and bronchiolitis. METHODS: A total of 111 children with bronchitis, 418 children with bronchopneumonia, and 83 children with bronchiolitis were enrolled as disease groups, and 235 healthy children were enrolled as control group. Flow cytometry was applied to measure lymphocyte subsets. RESULTS: The bronchitis group had significantly lower numbers of T cells and CD3+CD8+ T cells than the control group (P<0.05). The bronchopneumonia group had significantly lower numbers of T cells and CD3+CD8+ T cells, a significantly higher number of T helper (Th) cells, and a significantly higher CD4/CD8 ratio than the control group, as well as a significantly higher number of Th cells than the bronchitis group. Compared with the children with mild bronchopneumonia, those with severe bronchopneumonia showed a reduction in T cells and an increase in B cells (P<0.05). The bronchiolitis group had a significantly higher number of Th cells, a significantly higher CD4/CD8 ratio, and a significantly lower number of CD3+CD8+ T cells than the control group (P<0.01). The disease groups showed a significantly higher number of B cells and a significantly lower number of natural killer cells than the control group (P<0.05). CONCLUSIONS: A low, disturbed cellular immune function and a high humoral immune function are involved in the development and progression of lower respiratory tract infectious diseases. The changes in immune function are related to the type and severity of diseases. PMID- 26975819 TI - [Risk factors for hearing impairment induced by cytomegalovirus infection]. AB - OBJECTIVE: To investigate the risk factors for hearing impairment induced by cytomegalovirus (CMV) infection in children. METHODS: One hundred and fifty-eight children diagnosed with CMV infection were enrolled as subjects. Based on the results of the brainstem auditory evoked potential (BAEP) test, patients were classified into normal hearing group (n=117; BAEP<=35) and abnormal hearing group (n=41; BAEP>35). A retrospective analysis was performed on the general information, routine blood indices, liver function, copy number of CMV-DNA in urine and breast milk. The receiver operating characteristic (ROC) curve was used to predict the copy number of CMV-DNA resulting in abnormal BAEP. The Spearman rank correlation analysis was used to test the correlations of the copy number of CMV-DNA in urine with the degree of hearing impairment and platelet count. RESULTS: The incidence rates of platelet abnormality and abnormal liver function and the copy number of CMV-DNA in urine were significantly higher in the abnormal hearing group than in the normal hearing group (P<0.01). According to the ROC curve, the copy number of CMV-DNA in urine had a sensitivity of 46.3% and a specificity of 93.2% in predicting hearing impairment when it reached 1.415*10(6) per mL. The results of correlation analysis showed that the degree of hearing impairment was positively correlated with the copy number of CMV-DNA (r=0.382, P<0.01); the platelet count was negatively correlated with the copy number of CMV DNA in urine (r=-0.233, P=0.003). CONCLUSIONS: An increased copy number of CMV DNA in urine might be a risk factor for hearing impairment induced by CMV infection. Children are likely to have hearing impairment when the copy number of CMV-DNA reaches 1.415*10(6) per mL. The monitoring of hearing should be strengthened in CMV-infected children with a decreased platelet count. PMID- 26975821 TI - [Relationship of cystatin C, fibrinogen, and 24-hour urinary protein with renal pathological grade in children with Henoch-Schonlein purpura nephritis]. AB - OBJECTIVE: To study the relationship of cystatin C (CysC), fibrinogen (Fbg), and 24-hour urinary protein with renal pathological grade in children with Henoch Schonlein purpura nephritis (HSPN), and to explore their values. METHODS: The clinical data of 48 children diagnosed with HSPN by renal biopsy from January 2011 to January 2015 were reviewed. According to renal pathological grading, in the 48 children with HSPN, 12 had stage IIa or lower, 12 stage IIb, 17 stage IIIa, and 7 stage IIIb or higher. The latex-enhanced immunoturbidimetric assay, turbidimetric measurement, and end-point method were used to determine the levels of serum CysC, Fbg, and 24-hour urinary protein, respectively. Pearson and Spearman correlation analyses were used to test the correlations between the indices and between the indices and renal pathological grade. RESULTS: There were significant differences in the levels of serum CysC, Fbg, and 24-hour urinary protein between patients with different pathological grades (P<0.05). The level of each index increased with increasing pathological grade (P<0.05). In the 48 children with HSPN, the level of 24-hour urine protein was positively correlated with the levels of serum CysC (r=0.51, P<0.05) and Fbg (r=0.63, P<0.05). The level of Fbg was positively correlated with that of serum CysC (r=0.55, P<0.05). The levels of CysC, Fbg, and 24-hour urinary protein were all positively correlated with renal pathological grade (r=0.66, 0.64 and 0.68; respectively, P<0.05). CONCLUSIONS: The levels of CysC, Fbg, and 24-hour urine protein can reflect the severity of renal injury, providing satisfactory prediction of the severity of renal injury in children with HSPN. PMID- 26975822 TI - [Significance of Th17/Treg imbalance in children with primary immune thrombocytopenia]. AB - OBJECTIVE: To investigate the significance of Th17/Treg imbalance in the development and treatment of primary immune thrombocytopenia (ITP) in children. METHODS: Thirty-two children diagnosed with ITP between May and August, 2015 and 22 healthy children were enrolled. Flow cytometry was used to determine the Th17/Treg ratio in peripheral blood of healthy children and children with ITP before and after treatment with immunoglobulin. RESULTS: Compared with the patients with ITP before treatment, the healthy children and the patients treated with immunoglobulin had a significantly lower percentage of Th17 cells in CD4+ T cells, a significantly lower Th17/Treg ratio, and a significantly higher percentage of Treg cells in CD4+ T cells in peripheral blood (P<0.05). In the 32 ITP children treated with immunoglobulin, 20 had complete response, 4 had response, and 8 had no response. The patients with complete response had a significantly lower percentage of Th17 cells in CD4+ T cells and a significantly lower Th17/Treg ratio in peripheral blood than the patients without response (P<0.05). CONCLUSIONS: The Th17/Treg imbalance can be found in children with ITP. Immunoglobulin can improve the cellular immune function by regulation of the Th17/Treg ratio. The Th17/Treg ratio may serve as an indicator for assessing the therapeutic effects of ITP. PMID- 26975823 TI - [Association between IL1R1 gene polymorphisms and childhood asthma]. AB - OBJECTIVE: To investigate the association of two single-nucleotide polymorphisms (SNPs) in IL1R1 gene (rs1558641 and rs949963) with the susceptibility to asthma in children from Central China. METHODS: A case-control study was performed in the asthma group and the control group, consisting of 208 children with asthma and 223 normal children from Central China, respectively. The genotypes of two SNPs in IL1R1 gene, rs1558641 and rs949963, were identified using polymerase chain reaction-restriction fragment length polymorphism. The serum level of IL1R1 was determined by enzyme-linked immunosorbent assay. RESULTS: There were no significant differences in genotype and allele frequencies of rs1558641 between the asthma and control groups. In terms of rs949963, the frequencies of GG genotype and alleles were significantly higher in the asthma group than in the control group (P<0.05). The asthma group had a significantly higher serum level of IL1R1 than the control group (P=0.011). Moreover, the serum level of IL1R1 was significantly higher in patients with GG genotype than in those with AA or AG genotype for rs949963 (P=0.028). CONCLUSIONS: IL1R1 SNP rs949963 is associated with the susceptibility to asthma in children from Central China and may increase the serum expression of IL1R1. PMID- 26975824 TI - [Efficacy of different doses of recombinant human growth hormone in the treatment of short stature in children born small for gestational age]. AB - OBJECTIVE: To investigate the efficacy and safety of different doses of recombinant human growth hormone (rhGH) in the treatment of short stature in children born small for gestational age (SGA). METHODS: A total of 37 children with short stature born SGA were enrolled, and based on the dose of rhGH treatment, they were divided into low-dose rhGH group (0.1-0.15 IU/kg daily) and high-dose rhGH group (0.16-0.2 IU/kg daily). The changes in height standard deviation score (DeltaHtSDS), height velocity (HV), serum levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP 3), and fasting blood glucose at 3, 6, 9, 12, and 24 months after treatment were compared between the two groups. RESULTS: DeltaHtSDS and HV both increased after the treatment with high- and low-dose rhGH, but DeltaHtSDS and HV in the high dose rhGH group were significantly higher than in the low-dose rhGH group 9, 12 and 24 months after treatment (P<0.05). Both high- and low-dose rhGH treatment increased serum levels of IGF-1 and IGFBP-3. Serum levels of IGF-1 and IGFBP-3 were positively correlated with HtSDS in both groups. One child each in the high- and low-dose rhGH groups experienced transient slight increase in fasting blood glucose (6.1 mmol/L). There were no cases of abnormal thyroid function. CONCLUSIONS: rhGH has good efficacy in the treatment of short stature in children born SGA, with few adverse events, and high-dose rhGH has some advantages over low-dose rhGH. PMID- 26975825 TI - [Brain injury after induction chemotherapy in children with acute lymphoblastic leukemia]. AB - OBJECTIVE: To investigate the changes in brain injury after the induction chemotherapy in children with acute lymphoblastic leukemia (ALL) by cranial MRI. METHODS: The clinical data and cranial MRI results of 62 children with ALL who were hospitalized from March 2014 to June 2015 were analyzed retrospectively. RESULTS: Before chemotherapy, MRI showed bone marrow infiltration of the skull in 33 patients (53%); the children with WBC<20*10(9)/Lhad a significantly lower incidence rate of bone marrow infiltration of the skull than those with WBC>=20*10(9)/L (16 patients/42% vs 17 patients/71%; P<0.05), and the high-risk group had a significantly higher incidence rate of bone marrow infiltration of the skull than the non-high-risk group (71% vs 44%; P<0.05). Before chemotherapy, there were 4 cases (7%) of brain atrophy, and 2 cases (3%) of abnormal signals in the sensory conduction bundle. MRI reexamination in 28 patients after 3 months of chemotherapy showed 3 new cases (11%) of brain atrophy and 1 aggravated case of brain atrophy. CONCLUSIONS: The children with ALL have bone marrow infiltration of the skull, brain atrophy, and abnormal signals in the sensory conduction bundle before chemotherapy, especially bone marrow infiltration of the skull, and some changes in brain injury disappear after treatment. PMID- 26975826 TI - [Recurrent bleeding tendency in a school-aged boy]. AB - The study reports a boy with alpha1-antitrypsin Pittsburgh mutation. The boy was admitted into the hospital because of recurrent joint hematoma. The laboratory examinations revealed that prothrombin time and activated partial thromboplastin time were prolonged and cannot be corrected by 1:1 fresh plasma. The inhibitor of factor VIII, anticardiolipin antibody and lupus anticoagulant were all negative. Platelet aggregation test indicated the existence of the inhibitor of thrombin. Alpha1-antitrypsin Pittsburgh mutation was confirmed by genomic sequencing. The clinical manifestations, diagnosis and treatment of this disorder are discussed in this paper. PMID- 26975827 TI - [Effects of PINK1 gene on cell apoptosis and cell autophagy in neonatal mice with hypoxic-ischemic brain damage]. AB - OBJECTIVE: To study the effect of PINK1 (phosphatase and tensin homolog deleted on chromosome ten induced putative kinase 1) gene on cell apoptosis and cell autophagy in neonatal mice with hypoxic-ischemic brain damage (HIBD). METHODS: Seventy-two wild-type C57BL/6 mice and 72 PINK1 gene knockout neonatal C57BL/6 mice were randomly divided into four groups: sham-operated wild-type (SWT), HIBD model wild-type (MWT), sham-operated knockout (SKO) and HIBD model knockout (MKO). HIBD model was prepared by low oxygen exposure for 2.5 hours after right carotid artery ligation. After 24 hours of hypoxia-ischemia treatment, TTC (2,3,5 triphenyl four azole nitrogen chloride) staining was used to measure brain infarct volume. The immunohistochemical staining was used to measure the expression of cell apoptosis protein cleaved-caspase-3 (CC3) in brain tissues. The TUNEL method was used to measure cell apoptosis. The immunofluorescence staining and Western blot were used to measure the expression of cell autophagy protein LC3. RESULTS: Compared with the MWT group, the infarct volume of brain tissues was markedly reduced in the MKO group (P<0.05), the number of apoptotic cells and the cell apoptosis index were markedly decreased in the MKO group (P<0.05), the expression of apoptosis protein CC3 was significantly reduced in the MKO group (P<0.05), the expression of cell autophagy protein LC3 was significantly decreased in the MKO group, and the autophagy indicator LC3II/LC3I was also markedly reduced in the MKO group (P<0.05). CONCLUSIONS: PINK1 gene knockout can protect neonatal mice from HIBD. PMID- 26975828 TI - [Expression profiles of miRNA-182 and Clock mRNA in the pineal gland of neonatal rats with hypoxic-ischemic brain damage]. AB - OBJECTIVE: To study the changes of miRNA expression in the pineal gland of neonatal rats with hypoxic-ischemic brain damage (HIBD) and the possible roles of miRNA in the pathogenesis of circadian rhythm disturbance after HIBD. METHODS: Seven-day-old Sprague-Dawley (SD) rats were randomly divided into 2 groups: HIBD and sham-operated. HIBD was induced according to the Rice-Vannucci method. The pineal glands were obtained 24 hours after the HIBD event. The expression profiles of miRNAs were determined using GeneChip technigue and quantitative real time PCR (RT-PCR). Then the miRNA which was highly expressed was selected. The expression levels of the chosen miRNA were detected in different tissues (lungs, intestines, stomach, kidneys, cerebral cortex, pineal gland). RT-PCR analysis was performed to measure the expression profiles of the chosen miRNA and the targeted gene Clock mRNA in the pineal gland at 0, 24, 48 and 72 hours after HIBD. RESULTS: miRNA-182 that met the criteria was selected by GeneChip and RT-PCR. miRNA-182 was highly expressed in the pineal gland. Compared with the sham operated group, the expression of miRNA-182 was significantly up-regulated in the pineal gland at 24 and 48 hours after HIBD (P<0.05). Compared with the sham operated group, Clock mRNA expression in the HIBD group increased at 0 hour after HIBD, decreased at 48 hours after HIBD and increased at 72 hours after HIBD (P<0.05). CONCLUSIONS: miRNA-182 may be involved in the pathogenesis of circadian rhythm disturbance after HIBD. PMID- 26975829 TI - [Expression profiles of brain-derived neurotrophic factor in the spinal dorsal horn of young rats with visceral hypersensitivity]. AB - OBJECTIVE: To explore the relationship between the expression of brain-derived neurotrophic factor (BDNF) in the spinal dorsal horn and the increase in visceral hypersensitivity in young rats by establishing a young rat model of visceral hypersensitivity by neonatal maternal separation (NMS). METHODS: Thirty-two newborn Sprague-Dawley rats were randomly and equally divided into four groups by a 2*2 factorial design: control, NMS, colorectal distension (CRD), and NMS+CRD. The newborn rats in the NMS and NMS+CRD groups were subjected to 3-hour daily maternal separation from days 2 to 14 after birth to establish a model of visceral hypersensitivity, while the rats in the control and CRD groups received no treatment after birth. At 6 weeks after birth, the CRD and CRD+NMS groups received CRD stimulation. The streptavidin-biotin complex immunohistochemical method was used to determine the expression of BDNF in the spinal dorsal horn. The immunohistochemical score (IHS) was calculated based on the percentage of BDNF-positive cells and color intensity. The percentage of BDNF-positive cells in the spinal dorsal horn and IHS were analyzed by factorial analysis of variance. RESULTS: The expression of BDNF was detected bilaterally in the spinal dorsal horn at different levels in the four groups. The percentage of BDNF-positive cells and IHS were significantly higher in the NMS and NMS+CRD groups than in the control group (P<0.05). The results of factorial analysis of variance indicated that NMS significantly increased the percentage of BDNF-positive cells in the spinal dorsal horn and IHS; a single CRD stimulation had no effects on the IHS of BDNF-positive cells in the spinal dorsal horn; there was no interaction between NMS and a single CRD stimulation. CONCLUSIONS: The over-expression of BDNF in the spinal dorsal horn may be involved in high visceral hypersensitivity in young rats induce by NMS. PMID- 26975830 TI - [Research advances in candidate genes for autism spectrum disorder]. AB - Autism spectrum disorder (ASD) is a kind of neurodevelopmental multigenic disorder. More than one hundred of candidate genes for ASD have been reported. The candidate gene research for ASD involves in chromosome loci and screening of candidate genes and epigenetic abnormalities for candidate genes. The reported genes encode neural adhesion molecules, ion channels, scaffold proteins, protein kinases, receptor protein and carrier protein, signaling modulate molecules and circadian relevant proteins. The research of mutation screening and expression regulation of candidate genes can help to elucidate genetic mechanisms for ASD, and may provide new approaches for the diagnosis and treatment of this disorder. This article reviews the research advance in candidate genes for ASD. PMID- 26975832 TI - When cancer cannot be cured: A qualitative study on relationship changes in couples facing advanced melanoma. AB - OBJECTIVE: The aim of this qualitative study was to gain a deeper understanding about couples' relationship changes over time (the first six months) after one partner is diagnosed with an incurable advanced melanoma (stage III or IV). METHOD: In semistructured interviews, eight patients and their partners were asked separately about potential changes in their relationship since diagnosis. The same questions were asked again six months later, but focusing on relationship changes over the preceding six months. Some 32 audiotaped interviews were analyzed applying qualitative content analysis. RESULTS: At baseline (t1), relationship changes were mostly reported in terms of caring, closeness/distance regulation, and communication patterns. While changes in caregiving and distance/closeness regulation remained main issues at six months follow-up (t2), greater appreciation of the relationship and limitations in terms of planning spare time also emerged as major issues. Unexpectedly, 50% of patients and partners reported actively hiding their negative emotions and sorrows from their counterparts to spare them worry. Furthermore, qualitative content analysis revealed relationship changes even in those patients and partners who primarily reported no changes over the course of the disease. SIGNIFICANCE OF RESULTS: Our findings revealed a differentiated and complex picture about relationship changes over time, which also might aid in the development of support programs for couples dealing with advanced cancer, focusing on the aspects of caring, closeness/distance regulation, and communication patterns. PMID- 26975831 TI - Perinuclear Arp2/3-driven actin polymerization enables nuclear deformation to facilitate cell migration through complex environments. AB - Cell migration has two opposite faces: although necessary for physiological processes such as immune responses, it can also have detrimental effects by enabling metastatic cells to invade new organs. In vivo, migration occurs in complex environments and often requires a high cellular deformability, a property limited by the cell nucleus. Here we show that dendritic cells, the sentinels of the immune system, possess a mechanism to pass through micrometric constrictions. This mechanism is based on a rapid Arp2/3-dependent actin nucleation around the nucleus that disrupts the nuclear lamina, the main structure limiting nuclear deformability. The cells' requirement for Arp2/3 to pass through constrictions can be relieved when nuclear stiffness is decreased by suppressing lamin A/C expression. We propose a new role for Arp2/3 in three-dimensional cell migration, allowing fast-moving cells such as leukocytes to rapidly and efficiently migrate through narrow gaps, a process probably important for their function. PMID- 26975834 TI - Dealloying-driven nanoporous palladium with superior electrochemical actuation performance. AB - Metal-hydrogen (in particular, Pd-H) interactions have been receiving considerable attention over the past 150 years within the scope of hydrogen storage, catalytic hydrogenation, hydrogen embrittlement and hydrogen-induced interfacial failure. Here, for the first time, we show that the coupling of hydrogen adsorption and absorption could trigger giant reversible strain in bulk nanoporous Pd (np-Pd) in a weakly adsorbed NaF electrolyte. The bulk np-Pd with a hierarchically porous structure and a ligament/channel size of ~10 nm was fabricated using a dealloying strategy with compositional/structural design of the precursor. The np-Pd actuator exhibits a giant reversible strain of up to 3.28% (stroke of 137.8 MUm), which is a 252% enhancement in comparison to the state-of-the-art value of 1.3% in np-AuPt. The strain rate (~10(-5) s(-1)) of np Pd is two orders of magnitude higher than that of current metallic actuators. Moreover, the volume-/mass-specific strain energy density (10.71 MJ m(-3)/3811 J kg(-1)) of np-Pd reaches the highest level compared with that of previously reported actuator materials. The outstanding actuation performance of np-Pd could be attributed to the coupling of hydrogen adsorption/absorption and its unique hierarchically nanoporous structure. Our findings provide valuable information for the design of novel high-performance metallic actuators. PMID- 26975835 TI - Improving household-level nutrition-specific and nutrition-sensitive conditions key to reducing child undernutrition in India. PMID- 26975833 TI - REGene: a literature-based knowledgebase of animal regeneration that bridge tissue regeneration and cancer. AB - Regeneration is a common phenomenon across multiple animal phyla. Regeneration related genes (REGs) are critical for fundamental cellular processes such as proliferation and differentiation. Identification of REGs and elucidating their functions may help to further develop effective treatment strategies in regenerative medicine. So far, REGs have been largely identified by small-scale experimental studies and a comprehensive characterization of the diverse biological processes regulated by REGs is lacking. Therefore, there is an ever growing need to integrate REGs at the genomics, epigenetics, and transcriptome level to provide a reference list of REGs for regeneration and regenerative medicine research. Towards achieving this, we developed the first literature based database called REGene (REgeneration Gene database). In the current release, REGene contains 948 human (929 protein-coding and 19 non-coding genes) and 8445 homologous genes curated from gene ontology and extensive literature examination. Additionally, the REGene database provides detailed annotations for each REG, including: gene expression, methylation sites, upstream transcription factors, and protein-protein interactions. An analysis of the collected REGs reveals strong links to a variety of cancers in terms of genetic mutation, protein domains, and cellular pathways. We have prepared a web interface to share these regeneration genes, supported by refined browsing and searching functions at http://REGene.bioinfo-minzhao.org/. PMID- 26975836 TI - The Volunteering-in-Place (VIP) Program: Providing meaningful volunteer activity to residents in assisted living with mild cognitive impairment. AB - The Volunteering-in-Place (VIP) Program was developed to provide individualized meaningful volunteer activities matched to interests and capabilities for older adults with MCI in assisted living. The purposes of this single-site pre test/post-test pilot study were to (1) establish feasibility of the VIP Program based on treatment fidelity (design, treatment, delivery, enactment); and (2) evaluate preliminary efficacy via improvement in psychological health (depressive symptoms, usefulness, purpose, resilience, and life satisfaction) and decreased sedentary activity (survey and Fitbit) at 3 and 6 months. Ten residents participated. The majority was white, female and educated, and on average 88 years old. The VIP Program was feasible and most participants continued to volunteer at 6 months. There were non-significant improvements in depressive symptoms, usefulness, purpose, resilience and recreational physical activity. The results of this study provide support for the feasibility of the VIP Program. Further study is necessary to examine efficacy. PMID- 26975838 TI - Factors Associated With Accidental Injuries in Children With ADHD-Combined Type: More Than a Motor Problem? AB - OBJECTIVE: We explored the relationship between accidental injuries, motor impairment, and co-occurring autism spectrum disorder (ASD) symptoms in children with ADHD-combined type (ADHD-CT). METHOD: Participants were 32 male children diagnosed with ADHD-CT and 23 typically developing male children (7-12 years, full scale IQ [FSIQ] > 80). Parents completed a customized questionnaire on the occurrence of accidental injuries (e.g., bruises, cuts) their child experienced in the past 12 months. Motor proficiency was assessed using the Movement ABC-2 (MABC-2). Parents rated motor, ADHD-CT, ASD, and anxiety symptoms. RESULTS: Children with ADHD-CT had significantly increased parent-reported accidental injuries compared with typically developing children. Among children with ADHD CT, Spearman's rho rank correlations revealed no association between increased accidental injuries and MABC-2 score, but significant associations with increased hyperactivity/impulsivity, ASD, and anxiety symptoms. CONCLUSION: Although these findings require validation, they suggest a need for further research investigating the contribution of co-occurring ASD and anxiety symptoms to accidental injuries in children with ADHD-CT. PMID- 26975837 TI - Involving the consumers: An exploration of users' and caregivers' needs and expectations on a fall prevention brochure: A qualitative study. AB - This study aims to explore and compare nursing home residents', family members', and nursing staff's needs and expectations regarding a fall prevention brochure. Focus groups were carried out with 25 residents, 12 family members and 14 nursing staff separately, from three randomly selected nursing homes. Qualitative content analysis was used to analyze the data using a concept-driven coding frame. Results showed that residents want to be informed about dealing with extrinsic fall risks and coping strategies after a fall event. In addition, family members wanted to have detailed information on intrinsic fall risks as well as specific fall prevention strategies, such as body exercises. Of special importance for nursing staff was that not all falls are preventable even when preventive measures were taken. As the need and expectations of users differ substantially, one brochure could not comprise all postulated criteria and different brochures are necessary for residents and for family members. PMID- 26975839 TI - Active push deployment technique improves stent/vessel-wall interaction in endovascular treatment of acute stroke with stent retrievers. AB - BACKGROUND: The optimal interaction between stent struts and thrombus is crucial for successful revascularization in endovascular stroke therapy with stent retrievers. Deploying the stent retriever by actively pushing it into the thrombus increases the radial force with which the stent struts expand into the thrombus. OBJECTIVE: To examine the active push deployment (APD) technique in an in vitro model and present our clinical experience with this technique. METHODS: In an in vitro experiment we investigated the configuration of a Solitaire and a Trevo ProVue device (both 4*20 mm), depending on whether the devices were deployed using the APD technique or simple unsheathing. We retrospectively assessed the effectiveness and safety of this technique by analyzing 130 patients with large vessel occlusions (carotid T or M1 segment of the middle cerebral artery), who received endovascular treatment with a Trevo device (4*20 mm) that was deployed using the APD technique. RESULTS: In vitro experiment: the APD technique improved apposition of the devices to the vessel wall. There was widening of 30% (Trevo) and 19% (Solitaire) at the cost of a shortening of 5% and 4%, respectively, when the devices were deployed in a carotid T model. Clinical study: the revascularization rate (Thrombolysis in Cerebral Infarction >=2b) with the Trevo device was 90%. There were no retriever-associated dissections or perforations in 278 retrieval maneuvers. CONCLUSIONS: The APD technique improves apposition of the tested devices to the vessel wall. The widening effect comes at the cost of minimal shortening of the devices. Our clinical experience shows that using the APD technique to deploy the Trevo device is effective and safe. PMID- 26975840 TI - Concomitant coiling reduces metalloproteinase levels in flow diverter-treated aneurysms but anti-inflammatory treatment has no effect. AB - BACKGROUND AND PURPOSE: Flow diverters (FD) can cause rare but devastating delayed aneurysm ruptures in which matrix metalloproteinases (MMPs) have been potentially implicated. Concomitant coiling or anti-inflammatory medications have been proposed to prevent the risk of delayed ruptures. The aim of this study was to evaluate concomitant coiling and ciclosporin in regulating the expression of MMPs in FD-treated aneurysms. MATERIALS AND METHODS: Elastase-induced aneurysms were created in 20 rabbits. Aneurysms were treated with (1) FD alone; (2) FD with concomitant coiling; (3) FD+ ciclosporin; or (4) left untreated as controls. At sacrifice, MMP levels were analyzed by zymography. Kruskal-Wallis one-way non parametric ANOVA was performed for each enzyme. If significant results were observed for the Kruskal-Wallis test, pairwise group comparisons were performed using Dunn's test with Bonferroni multiple-testing correction. RESULTS: Significant differences were observed among groups for pro-MMP9 (p=0.0337). Pairwise comparison demonstrated higher levels of pro-MMP9 with concomitant coiling compared with untreated aneurysms (p=0.012), with higher though not significantly different levels of pro-MMP9 in FD with concomitant coiling versus FD alone. While not statistically significant, trends were noted regarding differences in active-MMP9 across groups, with a lower level of active-MMP9 with concomitant coiling compared with the other FD groups. No significant differences were observed for pro- or active-MMP2 across groups, or for FD + ciclosporin compared with FD alone. CONCLUSIONS: FD implantation increases the level of pro MMP9 expression in aneurysms. Provocative trends regarding modulation of active MMP9 expression with concomitant coiling suggest the need for larger confirmatory preclinical studies. Anti-inflammatory treatment with ciclosporin appears to have a minimal biological effect. TRIAL REGISTRATION NUMBER: R01NS076491. PMID- 26975841 TI - Degraded and osteogenic properties of coated magnesium alloy AZ31; an experimental study. AB - BACKGROUND: Degraded and osteogenic property of coated magnesium alloy was evaluated for the fracture fixation in rabbits. METHODS: Magnesium alloy AZ31 with a different coating thickness by microarc oxidation was used, and the bilateral radial fracture model was created by the bite bone clamp. Thirty-six New Zealand white rabbits in weight of 2.5~3.0 kg were randomly divided into A, B, and C groups at four time points and other 3 rabbits as the control group without magnesium alloy. Coated magnesium alloy AZ31 was implanted on the fracture and fixed with silk thread. Indexes such as general observation, histology, X-ray, hematology, and mechanical properties were observed and detected at 2nd, 4th, 8th, and 12th week after implantation. RESULTS: Fracture in each rabbit was healed at 12th week after implantation. Among the three groups, the best results of general observation, histology, and X-ray appeared in A group without coating. However, A group showed the worst results from the perspective of mechanical properties about tensile strength and flexural strength, which failed to reach that of the natural bone at the 12th week. Comprehensive results displayed that C group with 20-MUm coating was better than others in mechanical properties, while there is no difference between B and C groups in hematology. CONCLUSIONS: Degradation rate is inversely proportional to the coating thickness. And magnesium alloy with a 20-MUm coating is more suitable for the fracture fixation. PMID- 26975842 TI - Acetylpyrene-labelled 7-methylguanine nucleotides: unusual fluorescence properties and application to decapping scavenger activity monitoring. AB - 7-Methylguanosine (m(7)G) nucleotides labelled with acetylpyrene (AcPy) were synthesized as fluorescent mRNA 5' end (cap) analogues. The unique fluorescent properties of m(7)G-AcPy conjugates, different from G-AcPy, can be applied to studying various mRNA cap-related processes including the evaluation of putative inhibitors of DcpS enzyme-a therapeutic target in neuromuscular diseases. PMID- 26975843 TI - Alternate carbohydrate and nontraditional inducer leads to increased productivity of a collagen binding domain fusion protein via fed-batch fermentation. AB - The production of collagen binding domain fusion proteins is of significant importance because of their potential as therapeutic biomaterials. It was previously reported that the expression of collagen-binding domain fusion proteins in Escherichia coli was higher when expressed using lactose as an inducer and chemically defined growth media on a shake flask scale. In an effort to further investigate factors that affect expression levels on a fed-batch scale, alternative induction techniques were tested in conjunction with fed-batch fermentation. In this paper, we discuss ten fed-batch fermentation experiments utilizing either glucose or glycerol feed and using lactose or isopropyl-beta-d thiogalactopyranoside (IPTG) as an induction source. It was found that glycerol fed fermentations induced with lactose allowed for greater expression of target protein, though lesser cell densities were achieved. PMID- 26975844 TI - Genome wide transcription start sites analysis of Xanthomonas campestris pv. campestris B100 with insights into the gum gene cluster directing the biosynthesis of the exopolysaccharide xanthan. AB - Xanthomonas campestris pv. campestris (Xcc) is the major producer of the exopolysaccharide xanthan, the commercially most important natural polysaccharide of microbial origin. The current work provides deeper insights into the yet uncharacterized transcriptomic features of the xanthan producing strain Xcc-B100. Towards this goal, RNA sequencing of a library based on the selective enrichment of the 5' ends of native transcripts was performed. This approach resulted in the genome wide identification of 3067 transcription start sites (TSSs) that were further classified based on their genomic positions. Among them, 1545 mapped upstream of an actively transcribed CDS and 1363 were classified as novel TSSs representing antisense, internal, and TSSs belonging to previously unidentified genomic features. Analyzing the transcriptional strength of primary and antisense TSSs revealed that in some instances antisense transcription seemed to be initiated at a higher level than its sense counterpart. Mapping the exact positions of TSSs aided in the identification of promoter consensus motifs, ribosomal binding sites, and enhanced the genome annotation of 159 in silico predicted translational start (TLS) sites. The global view on length distribution of the 5' untranslated regions (5'-UTRs) deduced from the data pointed to the occurrence of leaderless transcripts and transcripts with unusually long 5'-UTRs, in addition to identifying seven putative riboswitch elements for Xcc-B100. Concerning the biosynthesis of xanthan, we focused on the transcriptional organization of the gum gene cluster. Under the conditions tested, we present evidence for a complex transcription pattern of the gum genes with multiple TSSs and an obvious considerable role of antisense transcription. The gene gumB, encoding an outer membrane xanthan exporter, is presented here as an example for genes that possessed a strong antisense TSS. PMID- 26975846 TI - Bilateral gluteal advancement flap for treatment of recurrent sacrococcygeal pilonidal disease: A prospective cohort study. AB - BACKGROUND: There is controversy about the best surgical approach for recurrent pilonidal disease (PND) up till now. This study aims to evaluate the efficacy of bilateral gluteal fascio-myo-cutaneous advancement flap (BGFMCF) in treatment of recurrent PND. PATIENT AND METHODS: Forty patients (35 males, 5 females) with recurrent PND were admitted and treated with BGFMCF. Variables assessed were incidence of recurrence, postoperative complications, patients' satisfaction and quality of life. RESULTS: Patients had a mean age of 25 +/- 6.8 years and a mean body mass index of 28.4 +/- 2.7. Mean operative time was 87 +/- 13 min and mean length of hospital stay was 3 +/- 0.7 days. Mean period of follow-up was 15.8 +/- 4.9 months. Recurrence was detected in 2 (5%) patients and minor complications occurred in 6 (15%) patients. Thirty eight (95%) patients were satisfied by the procedure at the end of follow-up period. CONCLUSION: BGFMCF is an effective procedure for treatment of recurrent sacrococcygeal PND with low recurrence rate and acceptable morbidity. PMID- 26975845 TI - Cross-sectional relations of race and poverty status to cardiovascular risk factors in the Healthy Aging in Neighborhoods of Diversity across the Lifespan (HANDLS) study. AB - BACKGROUND: Examine interactive relations of race and poverty status with cardiovascular disease (CVD) risk factors in a socioeconomically diverse sample of urban-dwelling African American (AA) and White adults. METHODS: Participants were 2,270 AAs and Whites (57% AA; 57% female; ages 30-64 years) who completed the first wave of the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. CVD risk factors assessed included body mass index (BMI), waist circumference (WC), total cholesterol (TC), high- and low-density lipoprotein cholesterol (HDL-C, LDL-C), triglycerides (TG), glycated hemoglobin (HbA1c), high-sensitivity C-reactive protein (CRP), and systolic, diastolic, and pulse pressure (SBP, DBP, PP). Interactive and independent relations of race, poverty status, and sex were examined for each outcome via ordinary least squares regression adjusted for age, education, literacy, substance use, depressive symptoms, perceived health care barriers, medical co-morbidities, and medications. RESULTS: Significant interactions of race and poverty status (p's < .05) indicated that AAs living in poverty had lower BMI and WC and higher HDL-C than non-poverty AAs, whereas Whites living in poverty had higher BMI and WC and lower HDL-C than non-poverty Whites. Main effects of race revealed that AAs had higher levels of HbA1c, SBP, and PP, and Whites had higher levels of TC, LDL-C and TG (p's < .05). CONCLUSION: Poverty status moderated race differences for BMI, WC, and HDL-C, conveying increased risk among Whites living in poverty, but reduced risk in their AA counterparts. Race differences for six additional risk factors withstood extensive statistical adjustments including SES indicators. PMID- 26975847 TI - Jim Kadonaga: Exploring transcription and chromatin. PMID- 26975848 TI - Lysosomes relax in the cellular suburbs. AB - Lysosomes support cellular homeostasis by degrading macromolecules and recycling nutrients. In this issue, Johnson et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201507112) reveal a heterogeneity in lysosomal pH and degradative ability that correlates with lysosome subcellular localization, raising questions about the functional implications and mechanisms underlying these observations. PMID- 26975849 TI - The position of lysosomes within the cell determines their luminal pH. AB - We examined the luminal pH of individual lysosomes using quantitative ratiometric fluorescence microscopy and report an unappreciated heterogeneity: peripheral lysosomes are less acidic than juxtanuclear ones despite their comparable buffering capacity. An increased passive (leak) permeability to protons, together with reduced vacuolar H(+)-adenosine triphosphatase (V-ATPase) activity, accounts for the reduced acidifying ability of peripheral lysosomes. The altered composition of peripheral lysosomes is due, at least in part, to more limited access to material exported by the biosynthetic pathway. The balance between Rab7 and Arl8b determines the subcellular localization of lysosomes; more peripheral lysosomes have reduced Rab7 density. This in turn results in decreased recruitment of Rab-interacting lysosomal protein (RILP), an effector that regulates the recruitment and stability of the V1G1 component of the lysosomal V ATPase. Deliberate margination of lysosomes is associated with reduced acidification and impaired proteolytic activity. The heterogeneity in lysosomal pH may be an indication of a broader functional versatility. PMID- 26975850 TI - Loss of miR-203 regulates cell shape and matrix adhesion through ROBO1/Rac/FAK in response to stiffness. AB - Breast tumor progression is accompanied by changes in the surrounding extracellular matrix (ECM) that increase stiffness of the microenvironment. Mammary epithelial cells engage regulatory pathways that permit dynamic responses to mechanical cues from the ECM. Here, we identify a SLIT2/ROBO1 signaling circuit as a key regulatory mechanism by which cells sense and respond to ECM stiffness to preserve tensional homeostasis. We observed that Robo1 ablation in the developing mammary gland compromised actin stress fiber assembly and inhibited cell contractility to perturb tissue morphogenesis, whereas SLIT2 treatment stimulated Rac and increased focal adhesion kinase activity to enhance cell tension by maintaining cell shape and matrix adhesion. Further investigation revealed that a stiff ECM increased Robo1 levels by down-regulating miR-203. Consistently, patients whose tumor expressed a low miR-203/high Robo1 expression pattern exhibited a better overall survival prognosis. These studies show that cells subjected to stiffened environments up-regulate Robo1 as a protective mechanism that maintains cell shape and facilitates ECM adherence. PMID- 26975852 TI - Correction: Negative regulation of phosphatidylinositol 3-phosphate levels in early-to-late endosome conversion. PMID- 26975853 TI - Erratum to: Reference point detection for camera-based fingerprint image based on wavelet transformation. PMID- 26975851 TI - Collagen-derived matricryptins promote inhibitory nerve terminal formation in the developing neocortex. AB - Inhibitory synapses comprise only ~20% of the total synapses in the mammalian brain but play essential roles in controlling neuronal activity. In fact, perturbing inhibitory synapses is associated with complex brain disorders, such as schizophrenia and epilepsy. Although many types of inhibitory synapses exist, these disorders have been strongly linked to defects in inhibitory synapses formed by Parvalbumin-expressing interneurons. Here, we discovered a novel role for an unconventional collagen-collagen XIX-in the formation of Parvalbumin(+) inhibitory synapses. Loss of this collagen results not only in decreased inhibitory synapse number, but also in the acquisition of schizophrenia-related behaviors. Mechanistically, these studies reveal that a proteolytically released fragment of this collagen, termed a matricryptin, promotes the assembly of inhibitory nerve terminals through integrin receptors. Collectively, these studies not only identify roles for collagen-derived matricryptins in cortical circuit formation, but they also reveal a novel paracrine mechanism that regulates the assembly of these synapses. PMID- 26975854 TI - Epigenetic regulators: Polycomb-miRNA circuits in cancer. AB - Polycomb group (PcG) proteins belong to a family of epigenetic modifiers and play a key role in dynamic control of their target genes. Several reports have found that aberrations in PcG-microRNA (miRNA) interplay in various cancer types often associated with poor clinical prognosis. This review discusses important PcG miRNA molecular networks which act as critical interfaces between chromatin remodeling, and transcriptional and post-transcriptional regulation of their target genes in cancer. Moreover, here are discussed several compounds influencing the activity of PcG proteins entered in clinical arena for the treatment of solid tumors, multiple myeloma and B lymphomas, thus highlighting the therapeutic potential of targeting this protein family. PMID- 26975855 TI - Answer to the Letter to the Editor of V. Bartanusz concerning "Surgery and survival outcomes of 30 patients with neurological deficit due to clear cell renal cell carcinoma spinal metastases" by Shuai Han, et al. (Eur Spine J, 2015; DOI 10.1007/s00586-015-3912-3). PMID- 26975856 TI - Validity and reliability of photographic measures to evaluate waistline asymmetry in idiopathic scoliosis. AB - OBJECTIVE: Evaluate the relationship between radiological, clinical and perceived waistline asymmetry (WLA) in a sample of idiopathic scoliosis (IS) patients. METHODS: 77 patients were included (mean age 20.3 years; 85 % women). We obtained a full X-ray of the spine and back clinical photography for all patients. On photographs, waist height angle (WHA), right/left waist angles (WA) and right/left waistline distance ratio were measured. SRS22, Trunk Appearance Perception Scale (TAPS) and Spinal Appearance Questinnaire (SAQ) questionnaires were also completed. The intra and inter-observer reliability of each photographic measure was assessed. A correlation analysis between all variables was done using Pearson Correlations Coefficient. RESULTS: All measures reported have excellent intra- and inter-observer (ICC >=0.8) reliability. A significant correlation was found between WHA and Cobb angle, mainly with Main Thoracic (MT) (r = -0.56). Right and left waist angles, and especially the difference between them (RLWAD), is related to the thoracolumbar/lumbar (TLL) curve. We have found a significant correlation between RLWAD and TLL curve magnitude (r = -0.54) and with the inclination of the lower end vertebra (LEV) (r = 0.74). Only WHA has a significant, but poor correlation (r ? 0.3) with trunk perception scales (TAPS and SAQ). No other significant correlations were found between WLA measures and patient related outcome scores. CONCLUSION: WLA measures proposed in this article are reliable tools to assess WLA. We have found a significant correlation between clinical WLA and skeletal deformity (Cobb angle). WHA is related with MT curve while the RLWAD depends on the TLL curve magnitude and its LEV. We have also found a significant relation between WHA and the patient's perception of the deformity. It seems that WLA is a cosmetic concern to take into account in clinical evaluation of IS patients. PMID- 26975857 TI - Descemet stripping automated endothelial keratoplasty using corneas from elderly donors. AB - PURPOSE: To evaluate the outcomes of Descemet stripping automated endothelial keratoplasty (DSAEK) using corneas from elderly donors. METHODS: A total of 90 eyes that underwent DSAEK at Juntendo University Hospital between January 2008 and December 2012 were divided into two groups. Group 1 was eyes that received corneas from elderly donors aged 80 years or older (29 eyes), and group 2 was eyes that received corneas from donors aged 79 years or younger (61 eyes). Patient characteristics and visual acuity, endothelial cell density, and postoperative complications at 2 years after surgery were examined retrospectively. RESULTS: The mean age of the donors was 86.3 +/- 28.9 years (range, 80-98 years) in group 1 and 62.1 +/- 23.2 years (range, 26-79 years) in group 2. At 2 years after surgery, median logMAR visual acuity was 0.48 +/- 0.38 in group 1 and 0.42 +/- 0.47 in group 2, while the median loss of endothelial cell density was 38.9 +/- 22.5 % and 39.7 +/- 23.8 %, respectively. There was no significant difference between the two groups for all the parameters. CONCLUSIONS: The rate of endothelial cell loss at 2 years after surgery was similar regardless of donor age (>=80 years vs <=79 years). It seems reasonable to use corneas from donors aged 80 years or older for DSAEK provided the selection criteria are fulfilled. PMID- 26975858 TI - Should I Perform Genetic Testing? A Qualitative Look into the Decision Making Considerations of Religious Israeli Undergraduate Students. AB - The aim of this study is to draw a picture of the concerns that guide the decision making of Israeli religious undergraduate students and the complex considerations they take into account while facing the need to have genetic testing or to attend a genetic counseling session. We examined how the religious affiliation of the students influences their perceptions toward genetics and how these are expressed. Qualitative data were collected from 51 semi-structured interviews with students, in which recurring themes were identified using 'thematic analysis.' The codes from the thematic analysis were obtained according to 'grounded theory'. Our results show that religious undergraduate students' decision making in these issues is influenced by factors that fall under three main categories: knowledge and perceptions, values, and norms. In order to include all the components of influence, we created the Triple C model: "Culture influences Choices towards genetic Counseling" which aims to generalize the complex decision making considerations that we detected. Our model places religion, as part of culture, as its central point of influence that impacts all three of the main categories we detected. It also traces the bidirectional influences that each of these main categories have on one another. Using this model may help identify the sociocultural differences between different types of patients, helping genetic counselors to better assist them in addressing their genetic status by tailoring the counseling more specifically to the patient's cultural uniqueness. PMID- 26975860 TI - Non-Exposed Endoscopic Wall-Inversion Surgery for Gastrointestinal Stromal Tumor of the Stomach: First Case Report in Korea. AB - Laparoscopic wedge resection of the stomach is a widely accepted treatment for primary resectable gastrointestinal stromal tumors (GISTs). However, it is difficult to determine the appropriate incision line from outside of the stomach, and many attempts have been made to avoid unnecessary resection of unaffected gastric tissues. Recently a technique called non-exposed endoscopic wall inversion surgery (NEWS) was introduced to avoid exposure of GIST to the peritoneum. Here, we describe the first published case of NEWS for GIST of the stomach practiced in Korea. PMID- 26975859 TI - PET Imaging Study of S1PR1 Expression in a Rat Model of Multiple Sclerosis. AB - PURPOSE: Upregulation of sphingosine-1-phosphate receptor 1 (S1PR1) expression in multiple sclerosis (MS) lesions is associated with neuroinflammatory response. This study investigated the correlation between neuroinflammation and S1PR1 expression in the spinal cord of an experimental autoimmune encephalomyelitis (EAE) rat model of MS, using the S1PR1 positron emission tomography (PET) radiotracer [(11)C]TZ3321. PROCEDURES: MicroPET imaging studies of [(11)C]TZ3321 were performed to measure uptake of [(11)C]TZ3321 in the spinal cord of EAE rats. Immunohistochemical staining was performed to confirm the overexpression of S1PR1 and other inflammatory biomarkers. RESULTS: MicroPET imaging demonstrated a 20-30 % increase in [(11)C]TZ3321 uptake in the lumbar spinal cord of EAE rats versus sham controls at 35-60 min post injection. The increased uptake of [(11)C]TZ3321 was correlated with the overexpression of S1PR1 in the lumbar spinal cord of EAE rats that was confirmed by immunohistochemical staining. Upregulated S1PR1 expression was associated with glial cell activation and immune cell infiltration. CONCLUSIONS: MicroPET imaging modality with a specific radioligand [(11)C]TZ3321 is able to assess the expression of S1PR1 in EAE rat lumbar spinal cord. This may provide a new approach to the assessment of neuroinflammatory response in MS and other inflammatory diseases. PMID- 26975861 TI - Endosonographic Features of Gastric Schwannoma: A Single Center Experience. AB - BACKGROUND/AIMS: Gastric schwannomas are rare benign mesenchymal tumors that are difficult to differentiate from other mesenchymal tumors with malignant potential, such as gastrointestinal stromal tumors. This study aimed to evaluate the characteristic findings of gastric schwannomas via endoscopic ultrasonography (EUS). METHODS: We retrospectively reviewed the EUS findings of 27 gastric schwannoma cases that underwent surgical excision at Pusan National University Hospital during 2007 to 2014. RESULTS: Gastric schwannomas were mainly located in the middle third of the stomach with a mean tumor size of 32 mm. All lesions exhibited hypoechoic echogenicity, and 24 lesions (88.9%) exhibited heterogeneous echogenicity. Seventeen lesions (63.0%) exhibited decreased echogenicity compared to the normal proper muscle layer. Distinct borders were observed in 24 lesions (88.9%), lobulated margins were observed in six lesions (22.2%), and marginal haloes were observed in 24 lesions (88.9%). Hyperechogenic spots were observed in 21 lesions (77.8%), calcifications were observed in one lesion (3.7%), and cystic changes were observed in two lesions (7.4%). CONCLUSIONS: During EUS, gastric schwannomas appear as heterogeneously hypoechoic lesions with decreased echogenicity compared to the normal proper muscle layer. These features may be helpful for differentiating gastric schwannomas from other mesenchymal tumors. PMID- 26975862 TI - Double-Scope Peroral Endoscopic Myotomy (POEM) for Esophageal Achalasia: The First Trial of a New Double-Scope POEM. AB - With the accumulation of clinical trials demonstrating its efficacy and safety, peroral endoscopic myotomy (POEM) has emerged as a less invasive treatment option for esophageal achalasia compared with laparoscopic Heller myotomy. However, the difficulty in determining the exact extent of myotomy, a critical factor associated with the success and safety of the procedure, remains a limitation. Although the various endoscopic landmarks and ancillary techniques have been applied, none of these has been proven sufficient. As a solution for this limitation, the double-scope POEM technique with a second endoscope to assure the exact length of the submucosal tunnel has been applied since 2014. Before double scope POEM was introduced, the second endoscope was applied only to confirm the accuracy of the procedure. In the present study, we performed double-scope POEM in the treatment of esophageal achalasia through a novel procedure of simultaneous application of the second endoscope to assist in the conventional POEM procedure. PMID- 26975863 TI - Risk Factors for Developing Skeletal-Related Events in Breast Cancer Patients With Bone Metastases Undergoing Treatment With Bone-Modifying Agents. AB - BACKGROUND: Bone-modifying agents (BMAs) reduce the incidence of skeletal-related events (SREs) and are thus recommended for breast cancer patients with bone metastases. However, the risk factors for SREs during BMA treatment are not well understood. This study evaluated the number and timing of SREs from case studies to identify these factors. METHODS: The medical records of 534 women with breast cancer who developed bone metastases between 1999 and 2011 were reviewed. SREs were defined as a pathologic fracture, spinal cord compression, or the need for bone irradiation or surgery. Multiple variables were assessed and were analyzed by using the Cox proportional hazard analyses and the Andersen and Gill method. RESULTS: Multivariate analyses for both the time to the first SRE and the primary and subsequent SRE frequency demonstrated that significant baseline risk factors included luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at the time of the initial BMA dose. Additionally, for the time to the first SRE and for the primary and subsequent SRE frequency, the presence of extraskeletal metastases and BMA administration initiation >=6 months after the detection of bone metastases were also significant risk factors, respectively. CONCLUSION: In breast cancer patients with bone metastases, more vigilant observation should be considered for patients with the identified risk factors. To reduce the risk for SRE, BMAs should be administered within 6 months of bone metastases diagnosis and before palliative radiation therapy. IMPLICATIONS FOR PRACTICE: Retrospectively, risk factors were identified for skeletal-related events (SREs) in breast cancer patients with bone metastasis who were treated with bone-modifying agents (BMAs). For the time to the first SRE and for the SRE frequency, presence of extraskeletal metastases and BMA initiation >=6 months after the detection of bone metastases were risk factors, respectively. Luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at initial BMA dose were risk factors for both first SRE and SRE frequency. More vigilant observation should be considered for patients with these risk factors. PMID- 26975865 TI - The Log Odds of Positive Lymph Nodes Stratifies and Predicts Survival of High Risk Individuals Among Stage III Rectal Cancer Patients. AB - INTRODUCTION: The log odds of positive lymph nodes (LODDS) is an empiric transform formula that incorporates positive and negative lymph node data into a single ratio for prognostic utility. We sought to determine the value of the log odds ratio as a prognostic indicator compared with established lymph node indices in advanced-stage rectal cancer patients who have undergone curative resection. METHODS: Retrospective analysis of rectal cancer operations from 1995 to 2013 identified all stage III cancer patients who underwent curative resection. Patients were stratified into three groups according to calculated lymph node ratios (LNRs) and log odds ratios (LODDS). The relationship between LNR, LODDS, and 5-year overall survival (OS) were assessed. RESULTS: OS for all patients was 81.4%. Both LNR and LODDS stratifications identified differences in 5-year OS. LODDS stratification was significantly associated with OS (p = .04). Additional significant clinicopathologic demographic variables included sex (p = .02), venous invasion (p = .02), tumor location (p < .001), and receipt of adjuvant chemotherapy (p = .047). LODDS separated survival among patients in the low LNR group (LNR1). CONCLUSION: This study confirms that the measure of lymph node involvement transformed by the log odds ratio is a suitable predictor of 5-year overall survival in stage III rectal cancer. LODDS may be applied to stratify high-risk patients in the management of adjuvant therapy. IMPLICATIONS FOR PRACTICE: Traditionally, clinicians have relied solely on the total number of positive lymph nodes affected when determining patient prognosis in rectal cancer. However, the current staging strategy does not account for "high-risk," biologically aggressive tumors that fall into the same risk categories as less clinically aggressive tumors. The log odds of positive lymph nodes is a logistic transform formula that uses pathologic lymph node data to stratify survival differences among patients within a single stage of disease. This formula allows clinicians to identify whether patients with clinically aggressive tumors fall into higher-risk groups, providing additional insight into how to better counsel patients and manage postoperative therapies. PMID- 26975864 TI - Where to Turn for Second-Line Cytoreduction After Hydroxyurea in Polycythemia Vera? AB - The goals of therapy in patients with polycythemia vera (PV) are to improve disease-related symptoms, prevent the incidence or recurrence of thrombosis, and possibly delay or prevent the transformation into myelofibrosis or acute myeloid leukemia (AML). Cytoreductive therapies have been used in older patients and those with a history of thrombosis to achieve these goals. Hydroxyurea (HU) remains the first-line cytoreductive choice; however, up to one in four patients treated with HU over time will develop resistance or intolerance to HU. More importantly, patients who fail HU have a 5.6-fold increase in mortality and a 6.8 fold increase risk of transformation to myelofibrosis or AML; therefore, alternative therapies are needed for these patients. Interferon-alpha has been used in PV and has shown significant activity in achieving hematologic responses and decreasing JAK2 V617F mutation allele burden. JAK inhibition has also been investigated and recently garnered regulatory approval for this indication. In this review, we will discuss the current treatment options that are available for patients after HU and the novel therapies that are currently under investigation. IMPLICATIONS FOR PRACTICE: The outcomes of PV patients who fail or who are intolerant of hydroxyurea are poor. Although pegylated interferon can be considered in younger patients, currently, ruxolitinib is the only U.S. Food and Drug Administration-approved agent in this setting, representing a viable option, leading to hematocrit control and a reduction in spleen size and constitutional symptoms. Although a small number of patients will achieve a molecular response with continuous treatment, the implications of such response on the clinical outcomes are still unknown. Patients whose disease is not adequately controlled with ruxolitinib, or who lose their response, can be treated with low-dose busulfan or pipobroman; however, they should be encouraged to participate in trials with novel therapies. PMID- 26975866 TI - WITHDRAWN:A Practical Approach for Management of QT Prolongation Induced by Anticancer Drugs. AB - Ahead of Print article withdrawn by publisher. PMID- 26975869 TI - Round window chamber and fustis: endoscopic anatomy and surgical implications. AB - The round window region is of critical importance in the anatomy of the middle ear. The aim of this paper is to describe its anatomy from an endoscopic point of view, emphasizing structures that have important surgical implications, in particular the fustis and the subcochlear canaliculus. The fustis, a smooth bony structure that forms the floor of the round window region, is a constant and important structure. It seems to indicate the round window membrane and the correct position of scala tympani. A structure connecting the round window region to the petrous apex, named the subcochlear canaliculus, is also described. A retrospective review of video recordings of endoscopic dissection and surgical procedures, carried out between June 2014 and February 2015, was conducted across two Tertiary university referral centers. A total of 42 dissections were analyzed in the study. We observed the fustis in all the cases and we identify two different anatomical conformations. The subcochlear canaliculus was found in 81.0 %, with a pneumatization direct to the petrous apex in 47.7 %. Conformation and limits of the round window niche may influence the surgical view of the round window membrane. Endoscopic approaches allow a very detailed view, which enables a comprehensive exploration of the round window region. Accurate knowledge of the anatomical relationships of this region has important advantages during middle ear surgery. PMID- 26975868 TI - Hyperammonemic Encephalopathy Associated With Fibrolamellar Hepatocellular Carcinoma: Case Report, Literature Review, and Proposed Treatment Algorithm. AB - We report a case of a 31-year-old man with metastatic fibrolamellar hepatocellular carcinoma (FLHCC) treated with gemcitabine and oxaliplatin complicated by hyperammonemic encephalopathy biochemically consistent with acquired ornithine transcarbamylase deficiency. Awareness of FLHCC-associated hyperammonemic encephalopathy and a pathophysiology-based management approach can optimize patient outcome and prevent serious complications. A discussion of the management, literature review, and proposed treatment algorithm of this rare metabolic complication are presented. IMPLICATIONS FOR PRACTICE: Pathophysiology guided management of cancer-associated hyperammonemic encephalopathy can improve patient outcome and prevent life-threatening complications. Community and academic oncologists should be aware of this serious metabolic complication of cancer and be familiar with its management. PMID- 26975867 TI - Financial Burden of Cancer Clinical Trial Participation and the Impact of a Cancer Care Equity Program. AB - INTRODUCTION: Cancer clinical trial (CT) participation rates are low and financial barriers likely play a role. We implemented a cancer care equity program (CCEP) to address financial burden associated with trial participation. We sought to examine the impact of the CCEP on CT enrollment and to assess barriers to participation. METHODS: We used an interrupted time series design to determine trends in CT enrollment before and after CCEP implementation. Linear regression models compared trial enrollment before and after the CCEP. We also compared patient characteristics before and after the CCEP and between CCEP and non-CCEP participants. We surveyed CCEP and non-CCEP participants to compare pre enrollment financial barriers. RESULTS: After accounting for increased trial availability and the trends in accrual for prior years, we found that enrollment increased after CCEP implementation (18.97 participants per month greater than expected; p < .001). A greater proportion of CCEP participants were younger, female, in phase I trials, lived farther away, had lower incomes, and had metastatic disease. Of 87 participants who completed the financial barriers survey, 49 CCEP and 38 matched, non-CCEP participants responded (63% response rate). CCEP participants were more likely to report concerns regarding finances (56% vs. 11%), medical costs (47% vs. 14%), travel (69% vs. 11%), lodging (60% vs. 9%), and insurance coverage (43% vs. 14%) related to trial participation (all p < .01). CONCLUSION: CT participation increased following implementation of the CCEP and the program enrolled patients experiencing greater financial burden. These findings highlight the need to address the financial burden associated with CT participation. IMPLICATIONS FOR PRACTICE: Financial barriers likely discourage patients from participating in clinical trials. Implementation of a cancer care equity program (CCEP) seeking to reduce financial barriers by assisting with travel and lodging costs was associated with increased trial accrual. The CCEP provided assistance to patients particularly in need, including those living farther away, those with lower incomes, and those reporting financial barriers related to trial participation. These findings suggest that financial concerns represent a major barrier to patient participation in clinical trials and underscore the importance of efforts to address these concerns. PMID- 26975870 TI - Design and Characterization of Metformin-Loaded Solid Lipid Nanoparticles for Colon Cancer. AB - Colorectal cancer is a global concern, and its treatment is fraught with non selective effects including adverse side effects requiring hospital visits and palliative care. A relatively safe drug formulated in a bioavailability enhancing and targeting delivery platform will be of significance. Metformin-loaded solid lipid nanoparticles (SLN) were designed, optimized, and characterized for particle size, zeta potential, drug entrapment, structure, crystallinity, thermal behavior, morphology, and drug release. Optimized SLN were 195.01 +/- 6.03 nm in size, -17.08 +/- 0.95 mV with regard to surface charge, fibrous in shape, largely amorphous, and release of metformin was controlled. The optimized size, charge, and shape suggest the solid lipid nanoparticles will migrate and accumulate in the colon tumor preventing its proliferation and subsequently leading to tumor shrinkage and cell death. PMID- 26975871 TI - Diffuse chorioretinal atrophy after a single standard low- dose intravitreal melphalan injection in a child with retinoblastoma: a case report. AB - BACKGROUND: Controlling retinoblastoma with seeding is challenging despite advances in treatment modalities. Intravitreal melphalan is an alternative to external beam radiation or enucleation for recurrent or refractory vitreous seeds. Significant ocular side effects following intravitreal melphalan injections are uncommon. Complications have been reported in eyes receiving higher concentrations of melphalan and repetitive injections. We report a case in which diffuse chorioretinal atrophy was developed at the injection site after a single, standard low-dose intravitreal melphalan injection. CASE PRESENTATION: A 12-month-old female child without a family history of retinoblastoma presented with unilateral group C retinoblastoma in her right eye. A solitary tumour with retinal breaks on the tumour surface, and vitreous seeds overlying the tumour were observed at the 8 o'clock position of the retina. After two cycles of intra arterial chemotherapy with melphalan, the main tumour displayed significant regression, but the vitreous seeds overlying the main tumour were still active. Because of the persistence of vitreous seeds and the inadequate response to intra arterial melphalan treatment, intravitreal melphalan (8 MUg in 0.05 mL) was injected using a 32-gauge needle 2.5 mm from the 5 o'clock position of the limbus, the meridian opposite to the vitreous seeds. After 1 month, the retina around the injection site demonstrated diffuse retinal pigment epithelium alterations with dense hard exudates. Although the main retinal mass, and vitreous seeds resolved, the hard exudates persisted for more than 2 years after the single low-dose melphalan injection. CONCLUSIONS: Intravitreal melphalan injections should be cautiously used for eyes with refractory seeds, particularly when multiple injections are required to control retinoblastoma seeds. Dose- related retinal toxicity could occur in pre-treated eyes even when a relatively low standard dose is used. Such patients should be followed up closely to monitor the treatment response and to assess potential delayed toxicity. PMID- 26975874 TI - Survey of patient exposure from general radiography and mammography in Japan in 2014. AB - With the objective of reducing patient exposure to radiation, we conducted a questionnaire survey regarding radiographic conditions in 2014. Here we report estimates of dose exposure in general radiography and mammography through an investigation and comparison of present patient exposure conditions. Questionnaires were sent to 3000 facilities nationwide in Japan. Surveys asked questions on a total of 16 items related to general radiography, including the chest, abdomen, and breast. Output data from x-ray tubes measured in the Chubu area of Japan were used as the mean in these estimates. The index of patient exposure was adopted as the entrance skin dose (ESD) for general radiography and as the mean glandular dose (MGD) for mammography. The response rate for this survey was 21.9%. Our results showed that doses received through the use of flat panel detector (FPD) devices were lower than those received through computed radiography devices, except for the ankle joint (e.g. in chest examination, the dose from FPD and CR was 0.24 mGy, 0.31 mGy on the average, respectively). These results suggest that more widespread use of FPD devices could lead to decreases in the ESD and MGD, thereby reducing patient exposure. PMID- 26975872 TI - Combining the Antipsychotic Drug Haloperidol and Environmental Enrichment after Traumatic Brain Injury Is a Double-Edged Sword. AB - Environmental enrichment (EE) confers significant benefits after experimental traumatic brain injury (TBI). In contrast, the antipsychotic drug (APD) haloperidol (HAL) exerts deleterious effects on neurobehavioral and cognitive recovery. Neurorehabilitation and management of agitation, however, are integral components of the treatment strategy for patients with TBI. Hence, the goal of this study was to determine how the two therapeutic approaches interact and influence motor and cognitive recovery. Anesthetized adult male rats received a controlled cortical impact (2.8 mm tissue deformation at 4 m/sec) or sham injury and then were provided HAL (0.5 mg/kg; intraperitoneally [IP]) or vehicle (VEH; 1 mL/kg; IP) commencing 24 h after surgery and once daily for 19 days while housed in EE or standard (STD) conditions. Beam balance/walk and Morris water maze performance were assessed on post-injury days 1-5 and 14-19, respectively, followed immediately by quantification of cortical lesion volumes. The data revealed both expected and unexpected findings. It was not surprising that the TBI groups receiving EE performed significantly better than those in STD housing and that the TBI + STD + HAL group performed worse than the TBI + STD + VEH group (p < 0.05). What was surprising was that the therapeutic effects of EE were greatly reduced by concomitant administration of HAL. No differences in cortical lesion volumes were observed among the groups (p > 0.05). The potential clinical implications of these findings suggest that administering HAL to patients undergoing neurorehabilitation may be a double-edged sword because agitation must be controlled before rehabilitation can be safely initiated and executed, but its use may compromise therapeutic efficacy. PMID- 26975875 TI - Combination of red cell distribution width and American Society of Anesthesiologists score for hip fracture mortality prediction. AB - The prognostic value of red cell distribution width (RDW) and a combination of RDW and the American Society of Anesthesiologists (ASA) score for long-term hip fracture mortality remains unknown. Our data showed that both RDW and ASA were independent risk predictors. A combination of these two parameters may provide a more powerful strategy for the prediction of hip fracture mortality. INTRODUCTION: Red cell distribution width (RDW) has recently been suggested as an independent predictor of prognosis in a variety of disorders. The American Society of Anesthesiologists (ASA) system has been widely used to stratify patients for outcome evaluations. However, the prognostic value of RDW and a combination of RDW and the ASA score for long-term hip fracture mortality has yet to be studied. METHODS: This prospective cohort study included 1402 subjects from 2000 to 2011 with a follow-up study over a 2 year period. Cox proportional hazards models with a bootstrap validation were used to evaluate associations of RDW, ASA, and a combination of both with long-term mortality. The global fit and the area under the receiver operating characteristic (ROC) curve (AUC) for model discrimination were further analyzed. RESULTS: Both RDW and ASA exhibited as independent risk predictors of 2-year mortality. The population with elevation of either RDW or ASA increased the risk of mortality (bootstrap validated hazard ratio (HR) 1.971 95 % confidence interval (CI) [1.336-3.005] p < 0.01) while those with an increase in both assessments (bootstrap validated HR 2.667 95 % CI [1.526-4.515] p < 0.01) were at the highest risk for mortality. The addition of the combination of ASA and RDW improved the discrimination power of risk prediction models (AUC increased from 0.700 to 0.723, p < 0.05). CONCLUSION: Both RDW and ASA exhibited as independent risk predictors of 2-year hip fracture mortality. The combination of these two readily available parameters may provide a more powerful and effective strategy for the assessment of all-cause mortality in hip fracture patients. PMID- 26975873 TI - Redox Imbalance Underlies the Fitness Defect Associated with Inactivation of the Pta-AckA Pathway in Staphylococcus aureus. AB - The phosphotransacetylase-acetate kinase (Pta-AckA) pathway is thought to be a vital ATP generating pathway for Staphylococcus aureus. Disruption of the Pta AckA pathway during overflow metabolism causes significant reduction in growth rate and viability, albeit not due to intracellular ATP depletion. Here, we demonstrate that toxicity associated with inactivation of the Pta-AckA pathway resulted from an altered intracellular redox environment. Growth of the pta and ackA mutants under anaerobic conditions partially restored cell viability. NMR metabolomics analyses and (13)C6-glucose metabolism tracing experiments revealed the activity of multiple pathways that promote redox (NADH/NAD(+)) turnover to be enhanced in the pta and ackA mutants during anaerobic growth. Restoration of redox homeostasis in the pta mutant by overexpressing l- lactate dehydrogenase partially restored its viability under aerobic conditions. Together, our findings suggest that during overflow metabolism, the Pta-AckA pathway plays a critical role in preventing cell viability defects by promoting intracellular redox homeostasis. PMID- 26975876 TI - Contrasting responses to a climate regime change by sympatric, ice-dependent predators. AB - BACKGROUND: Models that predict changes in the abundance and distribution of fauna under future climate change scenarios often assume that ecological niche and habitat availability are the major determinants of species' responses to climate change. However, individual species may have very different capacities to adapt to environmental change, as determined by intrinsic factors such as their dispersal ability, genetic diversity, generation time and rate of evolution. These intrinsic factors are usually excluded from forecasts of species' abundance and distribution changes. We aimed to determine the importance of these factors by comparing the impact of the most recent climate regime change, the late Pleistocene glacial-interglacial transition, on two sympatric, ice-dependent meso predators, the emperor penguin (Aptenodytes forsteri) and Weddell seal (Leptonychotes weddellii). METHODS: We reconstructed the population trend of emperor penguins and Weddell seals in East Antarctica over the past 75,000 years using mitochondrial DNA sequences and an extended Bayesian skyline plot method. We also assessed patterns of contemporary population structure and genetic diversity. RESULTS: Despite their overlapping distributions and shared dependence on sea ice, our genetic data revealed very different responses to climate warming between these species. The emperor penguin population grew rapidly following the glacial-interglacial transition, but the size of the Weddell seal population did not change. The expansion of emperor penguin numbers during the warm Holocene may have been facilitated by their higher dispersal ability and gene flow among colonies, and fine-scale differences in preferred foraging locations. CONCLUSIONS: The vastly different climate change responses of two sympatric ice dependent predators suggests that differing adaptive capacities and/or fine-scale niche differences can play a major role in species' climate change responses, and that adaptive capacity should be considered alongside niche and distribution in future species forecasts. PMID- 26975877 TI - Association between Testicular Cancer and Epididymoorchitis: A Population-Based Case-Control Study. AB - Even though epididymoorchitis and testicular cancer (TC) may have similar pathophysiological pathways, no prior study has attempted to determine the association between these two diseases. This case-control study investigated the relationship between TC and prior epididymoorchitis by using a large population based database. We used the Taiwan Longitudinal Health Insurance Database 2005 to select 372 patients who had received a diagnosis of TC and 3,720 age-matched controls without TC. We found that of the total sample of 4,092 patients, 53 (1.3%) had received a diagnosis of epididymoorchitis prior to the index date. Patients with TC had a higher prevalence of prior epididymoorchitis than that of patients without TC (11.0% vs. 0.3%, p < 0.001). Conditional logistic regression showed that prior epididymoorchitis was significantly associated with TC (crude OR = 38.24, 95% CI = 19.91-73.46). The association remained statistically significant even after adjustment for the other variables (OR = 47.17, 95% CI = 23.83-93.40). This study showed that patients with TC have higher odds of prior epididymoorchitis than do those without TC even after adjustment for potential confounders. PMID- 26975878 TI - Serum and Urinary Orosomucoid in Young Patients With Type 1 Diabetes: A Link Between Inflammation, Microvascular Complications, and Subclinical Atherosclerosis. AB - Orosomucoid is an acute-phase serum protein that is upregulated in urine samples of patients with diabetic nephropathy. We assessed serum and urinary orosomucoid levels in children and adolescents with type 1 diabetes and their relation to microvascular complications and carotid intima-media thickness (CIMT). Sixty patients with type 1 diabetes were divided into 2 groups according to the presence of microvascular complications and compared with 60 healthy controls. High-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c (HbA1c), urinary albumin-creatinine ratio (UACR), serum and urinary orosomucoid, and CIMT were assessed. Both serum and urinary orosomucoid levels were significantly increased in patients with and without microvascular complications compared with controls, and the highest levels were in patients with complications (P < .001). Serum and urinary orosomucoid were higher in patients with microalbuminuria than normoalbuminuric group (P < .001). The cutoff value of urinary orosomucoid at 2825 ng/mL could differentiate patients with and without microvascular complications. Serum and urinary orosomucoid were positively correlated. Multiple regression analysis showed that HbA1c, UACR, hs-CRP, and CIMT were independently related to orosomucoid. We suggest that orosomucoid is a significant independent factor for diabetic microvascular complications and can be considered as an early marker of renal injury. High orosomucoid levels in type 1 diabetes reflect endothelial dysfunction and subclinical atherosclerosis. PMID- 26975879 TI - [Aneurysmal subarachnoid haemorrhage: Results after introducing endovascular therapy in a medium-low volume centre]. AB - OBJECTIVE: To evaluate the impact of introducing endovascular therapy for patients with aneurysmal subarachnoid haemorrhage (aSAH) in a medium-low volume centre. MATERIAL AND METHODS: A retrospective observational study was conducted by comparing the clinical outcome of patients with aSAH before and after introducing endovascular therapy in our centre. The main variables analysed were: type of treatment, hospital and late mortality, intra-procedural morbidity, rate of re-bleeding and vasospasm, and clinical outcome according to the Glasgow Outcome Score (GOS). RESULTS: Seventy-one patients were treated in two periods: 2010-2011 (32 patients; 19 clipped, 6 coiled, 7 untreated), and 2012-2013 (39 patients, 3 clipped, 34 coiled, 2 untreated). No significant differences were found in age, sex, clinical grade at admission, type and location of aneurysm, Fisher score, or in hospital mortality (28.1% vs 25.6%, P=.35), GOS (except for GOS 5: 43.37% vs 53.8%, P=.045), rate of hydrocephalus and rate of vasospasm. The second cohort obtained better results for aggregated GOS 1+2+3 (36.3% vs 43.75%, P=.034) and for GOS 4+5 (61.5% vs 56.25%, P=.078). The percentage of patients left untreated was significantly lower in the second period (5.1% vs 21.8%, P<.01), as well as the rate of re-bleeding (0% vs 9.4%, P<.01). Patients were treated earlier (2.51 vs 3.95 days), and hospital and total stay were lower (15.2 and 24.6 vs 10.3 and 18 days) in the second period, these differences not reaching statistical significance. CONCLUSIONS: Endovascular therapy allowed treating more patients with aSAH, and with a lower re-bleeding rate. This led to a modest reduction in morbidity and mortality. PMID- 26975881 TI - Phonon-assisted nonlinear optical processes in ultrashort-pulse pumped optical parametric amplifiers. AB - Optically active phonon modes in ferroelectrics such as potassium titanyl phosphate (KTP) and potassium titanyl arsenate (KTA) in the ~7-20 THz range play an important role in applications of these materials in Raman lasing and terahertz wave generation. Previous studies with picosecond pulse excitation demonstrated that the interaction of pump pulses with phonons can lead to efficient stimulated Raman scattering (SRS) accompanying optical parametric oscillation or amplification processes (OPO/OPA), and to efficient polariton phonon scattering. In this work, we investigate the behavior of infrared OPAs employing KTP or KTA crystals when pumped with ~800-nm ultrashort pulses of duration comparable to the oscillation period of the optical phonons. We demonstrate that under conditions of coherent impulsive Raman excitation of the phonons, when the effective chi((2)) nonlinearity cannot be considered instantaneous, the parametrically amplified waves (most notably, signal) undergo significant spectral modulations leading to an overall redshift of the OPA output. The pump intensity dependence of the redshifted OPA output, the temporal evolution of the parametric gain, as well as the pump spectral modulations suggest the presence of coupling between the nonlinear optical polarizations P(NL) of the impulsively excited phonons and those of parametrically amplified waves. PMID- 26975880 TI - Donor cell leukemia arising from clonal hematopoiesis after bone marrow transplantation. PMID- 26975882 TI - Esophageal Intramural Pseudodiverticulosis With Tract Formation, Without Evidence of Candidiasis, in a Patient With HIV Infection. PMID- 26975885 TI - Calibrating Sickle Cell Disease. AB - Sickle cell disease is fundamentally a kinetic disorder, in which cells containing the mutated hemoglobin (hemoglobin S; HbS) will cause occlusion if they sickle in the microvasculature, but have minimal (or no) consequences if they sickle in the venous return. Physiologically, sickling always occurs when some ligands are present; nonetheless, the kinetics in the presence of ligands are virtually unstudied. Sickling arises from nucleation-controlled polymer formation, triggered when the HbS loses ligands (e.g., oxygen). Thus, understanding how nucleation responds to the presence of oxygen is the key to understanding how sickling proceeds in a physiological context. We have measured the rate of nucleus formation in HbS partially liganded with NO or CO, which we find have equivalent effects in reducing the nucleation rates. We find that hemoglobin must be in the T (tense) quaternary structure for nucleation, but the presence of ligands inhibits nucleus formation even when the correct quaternary structure is present. From these results, we can predict the fraction of cells that will sickle at any given partial ligand saturations. The ability to make such predictions may prove especially useful in designing future therapies, particularly those where the oxygen affinity is perturbed. PMID- 26975886 TI - DARPin-Based Crystallization Chaperones Exploit Molecular Geometry as a Screening Dimension in Protein Crystallography. AB - DARPin libraries, based on a Designed Ankyrin Repeat Protein consensus framework, are a rich source of binding partners for a wide variety of proteins. Their modular structure, stability, ease of in vitro selection and high production yields make DARPins an ideal starting point for further engineering. The X-ray structures of around 30 different DARPin complexes demonstrate their ability to facilitate crystallization of their target proteins by restricting flexibility and preventing undesired interactions of the target molecule. However, their small size (18 kDa), very hydrophilic surface and repetitive structure can limit the DARPins' ability to provide essential crystal contacts and their usefulness as a search model for addressing the crystallographic phase problem in molecular replacement. To optimize DARPins for their application as crystallization chaperones, rigid domain-domain fusions of the DARPins to larger proteins, proven to yield high-resolution crystal structures, were generated. These fusions were designed in such a way that they affect only one of the terminal capping repeats of the DARPin and do not interfere with residues involved in target binding, allowing to exchange at will the binding specificities of the DARPin in the fusion construct. As a proof of principle, we designed rigid fusions of a stabilized version of Escherichia coli TEM-1 beta-lactamase to the C-terminal capping repeat of various DARPins in six different relative domain orientations. Five crystal structures representing four different fusion constructs, alone or in complex with the cognate target, show the predicted relative domain orientations and prove the validity of the concept. PMID- 26975884 TI - Crystal structure of Anoxybacillus alpha-amylase provides insights into maltose binding of a new glycosyl hydrolase subclass. AB - A new subfamily of glycosyl hydrolase family GH13 was recently proposed for alpha amylases from Anoxybacillus species (ASKA and ADTA), Geobacillus thermoleovorans (GTA, Pizzo, and GtamyII), Bacillus aquimaris (BaqA), and 95 other putative protein homologues. To understand this new GH13 subfamily, we report crystal structures of truncated ASKA (TASKA). ASKA is a thermostable enzyme capable of producing high levels of maltose. Unlike GTA, biochemical analysis showed that Ca(2+) ion supplementation enhances the catalytic activities of ASKA and TASKA. The crystal structures reveal the presence of four Ca(2+) ion binding sites, with three of these binding sites are highly conserved among Anoxybacillus alpha amylases. This work provides structural insights into this new GH13 subfamily both in the apo form and in complex with maltose. Furthermore, structural comparison of TASKA and GTA provides an overview of the conformational changes accompanying maltose binding at each subsite. PMID- 26975883 TI - Hybrid Microscopy: Enabling Inexpensive High-Performance Imaging through Combined Physical and Optical Magnifications. AB - To date, much effort has been expended on making high-performance microscopes through better instrumentation. Recently, it was discovered that physical magnification of specimens was possible, through a technique called expansion microscopy (ExM), raising the question of whether physical magnification, coupled to inexpensive optics, could together match the performance of high-end optical equipment, at a tiny fraction of the price. Here we show that such "hybrid microscopy" methods--combining physical and optical magnifications--can indeed achieve high performance at low cost. By physically magnifying objects, then imaging them on cheap miniature fluorescence microscopes ("mini-microscopes"), it is possible to image at a resolution comparable to that previously attainable only with benchtop microscopes that present costs orders of magnitude higher. We believe that this unprecedented hybrid technology that combines expansion microscopy, based on physical magnification, and mini-microscopy, relying on conventional optics--a process we refer to as Expansion Mini-Microscopy (ExMM)- is a highly promising alternative method for performing cost-effective, high resolution imaging of biological samples. With further advancement of the technology, we believe that ExMM will find widespread applications for high resolution imaging particularly in research and healthcare scenarios in undeveloped countries or remote places. PMID- 26975887 TI - [Clinical practice guidelines for systemic lupus erythematosus: Recommendations for general clinical management]. AB - Systemic lupus erythematosus (SLE) is a complex rheumatic multisystemic disease of autoimmune origin with significant potential morbidity and mortality. It is one of the most common autoimmune diseases with an estimated prevalence of 20-150 cases per 100,000 inhabitants. The clinical spectrum of SLE is wide and variable both in clinical manifestations and severity. This prompted the Spanish Ministry of Health, Social Services and Equality to promote and fund the development of a clinical practice guideline (CPG) for the clinical care of SLE patients within the Programme of CPG in the National Health System which coordinates GuiaSalud. This CPG is is intended as the reference tool in the Spanish National Health System in order to support the comprehensive clinical management of people with SLE by all health professionals involved, regardless of specialty and level of care, helping to standardize and improve the quality of clinical decisions in our context in order to improve the health outcomes of the people affected. The purpose of this document is to present and discuss the rationale of the recommendations on the general management of SLE, specifically, clinical follow up, general therapeutic approach, healthy lifestyles, photoprotection, and training programmes for patients. These recommendations are based on the best available scientific evidence, on discussion and the consensus of expert groups. PMID- 26975888 TI - Aging with a traumatic brain injury: Could behavioral morbidities and endocrine symptoms be influenced by microglial priming? AB - A myriad of factors influence the developmental and aging process and impact health and life span. Mounting evidence indicates that brain injury, even moderate injury, can lead to lifetime of physical and mental health symptoms. Therefore, the purpose of this mini-review is to discuss how recovery from traumatic brain injury (TBI) depends on age-at-injury and how aging with a TBI affects long-term recovery. TBI initiates pathophysiological processes that dismantle circuits in the brain. In response, reparative and restorative processes reorganize circuits to overcome the injury-induced damage. The extent of circuit dismantling and subsequent reorganization depends as much on the initial injury parameters as other contributing factors, such as genetics and age. Age-at-injury influences the way the brain is able to repair itself, as a result of developmental status, extent of cellular senescence, and injury-induced inflammation. Moreover, endocrine dysfunction can occur with TBI. Depending on the age of the individual at the time of injury, endocrine dysfunction may disrupt growth, puberty, influence social behaviors, and possibly alter the inflammatory response. In turn, activation of microglia, the brain's immune cells, after injury may continue to fuel endocrine dysfunction. With age, the immune system develops and microglia become primed to subsequent challenges. Sustained inflammation and microglial activation can continue for weeks to months post-injury. This prolonged inflammation can influence developmental processes, behavioral performance and age-related decline. Overall, brain injury may influence the aging process and expedite glial and neuronal alterations that impact mental health. PMID- 26975889 TI - Microglia, physiology and behavior: A brief commentary. PMID- 26975891 TI - Systematic review: Is Metoclopramide more effective than Sumatriptan in relieving pain from migraine in adults in the Emergency Department (ED) setting? AB - Migraine headache is a common disorder; patients attending Emergency Departments (ED) for migraine symptoms internationally account for 1-3% of total ED annual attendances. A systematic review was undertaken of reports comparing the effectiveness of metoclopramide intravenously (IV) with that of sumatriptan subcutaneously (SC), in an ED setting, for the immediate relief of migraine and their measurable effects in relieving pain intensity. Findings of two identified comparable reports confirm the individual efficacy of the study drugs in pain relief. However, whilst one report concludes that there is no statistical or significant clinical advantage for one drug over the other, the other report suggests that metoclopramide has a distinct advantage. One study is well structured methodologically, but the other has significant risk of bias. The analysis of the chosen studies demonstrates the need for rigorous study design and robust reporting requirements to obviate this risk. Further studies are required to explore comparable effect. Implications for clinical practice from the report outcomes indicate the individual effectiveness of both study drugs in providing pain relief for migraine in the Emergency setting, but not the comparable efficacy of one drug over the other. PMID- 26975892 TI - Sensitivity of left ventricular mechanics to myofiber architecture: A finite element study. AB - The goal of this study was to investigate the sensitivity of computational models of the heart to their incorporated myofiber architecture during diastole. This architecture plays a critical role in the mechanical and electrical function of the heart and changes after myocardial tissue remodeling, which is associated with some of the most common heart diseases. In this study, a left ventricular finite element model of the porcine heart was created using magnetic resonance imaging, which represents the in vivo geometry. Various myofiber architectures were assigned to the finite element mesh, in the form of fiber and sheet angles. A structural-based material law was used to model the behavior of passive myocardium and its parameters were estimated using measured in vivo strains and cavity volume from magnetic resonance imaging. The final results showed noticeable sensitivity of the stress distribution to both the fiber and sheet angle distributions. This implies that a structural-based material law that takes into account the effect of both fiber and sheet angle distributions should be used. The results also show that although the simulation results improve using available data from histological studies of myocardial structure, the need for individualized myofiber architecture data is crucial. PMID- 26975893 TI - Cloning of the promoter of NDE1, a gene implicated in psychiatric and neurodevelopmental disorders through copy number variation. AB - Copy number variation at 16p13.11 has been associated with a range of neurodevelopmental and psychiatric conditions, with duplication of this region being more common in individuals with schizophrenia. A prominent candidate gene within this locus is NDE1 (Nuclear Distribution Element 1) given its known importance for neurodevelopment, previous associations with mental illness and its well characterized interaction with the Disrupted in Schizophrenia 1 (DISC1) protein. In order to accurately model the effect of NDE1 duplication, it is important to first gain an understanding of how the gene is expressed. The complex promoter system of NDE1, which produces three distinct transcripts, each encoding for the same full-length NDE1 protein (also known as NudE), was therefore cloned and tested in human cell lines. The promoter for the longest of these three NDE1 transcripts was found to be responsible for the majority of expression in these systems, with its extended 5' untranslated region (UTR) having a limiting effect on its expression. These results thus highlight and clone the promoter elements required to generate systems in which the NDE1 protein is exogenously expressed under its native promoter, providing a biologically relevant model of 16p13.11 duplication in major mental illness. PMID- 26975890 TI - Effect of Noninvasive Ventilation on Tracheal Reintubation Among Patients With Hypoxemic Respiratory Failure Following Abdominal Surgery: A Randomized Clinical Trial. AB - IMPORTANCE: It has not been established whether noninvasive ventilation (NIV) reduces the need for invasive mechanical ventilation in patients who develop hypoxemic acute respiratory failure after abdominal surgery. OBJECTIVE: To evaluate whether noninvasive ventilation improves outcomes among patients developing hypoxemic acute respiratory failure after abdominal surgery. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, parallel-group clinical trial conducted between May 2013 and September 2014 in 20 French intensive care units among 293 patients who had undergone abdominal surgery and developed hypoxemic respiratory failure (partial oxygen pressure <60 mm Hg or oxygen saturation [SpO2] <=90% when breathing room air or <80 mm Hg when breathing 15 L/min of oxygen, plus either [1] a respiratory rate above 30/min or [2] clinical signs suggestive of intense respiratory muscle work and/or labored breathing) if it occurred within 7 days after surgical procedure. INTERVENTIONS: Patients were randomly assigned to receive standard oxygen therapy (up to 15 L/min to maintain SpO2 of 94% or higher) (n = 145) or NIV delivered via facial mask (inspiratory pressure support level, 5-15 cm H2O; positive end-expiratory pressure, 5-10 cm H2O; fraction of inspired oxygen titrated to maintain SpO2 >=94%) (n = 148). MAIN OUTCOMES AND MEASURES: The primary outcome was tracheal reintubation for any cause within 7 days of randomization. Secondary outcomes were gas exchange, invasive ventilation-free days at day 30, health care-associated infections, and 90-day mortality. RESULTS: Among the 293 patients (mean age, 63.4 [SD, 13.8] years; n=224 men) included in the intention-to-treat analysis, reintubation occurred in 49 of 148 (33.1%) in the NIV group and in 66 of 145 (45.5%) in the standard oxygen therapy group within+ 7 days after randomization (absolute difference, -12.4%; 95% CI, -23.5% to -1.3%; P = .03). Noninvasive ventilation was associated with significantly more invasive ventilation-free days compared with standard oxygen therapy (25.4 vs 23.2 days; absolute difference, -2.2 days; 95% CI, -0.1 to 4.6 days; P = .04), while fewer patients developed health care associated infections (43/137 [31.4%] vs 63/128 [49.2%]; absolute difference, 17.8%; 95% CI, -30.2% to -5.4%; P = .003). At 90 days, 22 of 148 patients (14.9%) in the NIV group and 31 of 144 (21.5%) in the standard oxygen therapy group had died (absolute difference, -6.5%; 95% CI, -16.0% to 3.0%; P = .15). There were no significant differences in gas exchange. CONCLUSIONS AND RELEVANCE: Among patients with hypoxemic respiratory failure following abdominal surgery, use of NIV compared with standard oxygen therapy reduced the risk of tracheal reintubation within 7 days. These findings support use of NIV in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01971892. PMID- 26975894 TI - Calbindin-D-28K like immunoreactivity in superficial dorsal horn neurons and effects of sciatic chronic constriction injury. AB - The neuropathic pain that results from peripheral nerve injury is associated with alterations in the properties of neurons in the superficial spinal laminae. Chronic constriction injury (CCI) of the rat sciatic nerve increases excitatory synaptic drive to excitatory neurons in the substantia gelatinosa while limiting that to inhibitory neurons. Since the calcium-binding protein calbindin D-28K has been associated with excitatory neurons, we examined whether CCI altered the properties of neurons expressing calbindin-like immunoreactivity (Cal+). These account for 30% of the neurons in lamina I and II. Calbindin did not co-localize with any particular electrophysiological phenotype of neuron; in substantia gelatinosa, it was found in some tonic, delay, irregular, phasic and transient firing neurons and in some cells that displayed central, radial or vertical morphology. When neuronal phenotype was defined more precisely in terms of both morphology and electrophysiological properties, no strong correlation with calbindin expression was found. The frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSC) in calbindin negative (Cal-) neurons was greater than that in Cal+ neurons. CCI did not alter the proportion of Cal+ neurons in the dorsal horn. Although CCI promoted a fourfold increase in sEPSC frequency in Cal+ neurons, sEPSC amplitude was reduced by 22% and charge transfer per second was unchanged. Since synaptic drive to Cal+ neurons is weak and there is no firm correlation between neuronal phenotype and calbindin expression, it is doubtful whether these neurons play a major role in the generation of central sensitization. PMID- 26975895 TI - Chronic stress-induced memory deficits are reversed by regular exercise via AMPK mediated BDNF induction. AB - Chronic stress has a detrimental effect on neurological insults, psychiatric deficits, and cognitive impairment. In the current study, chronic stress was shown to impair learning and memory functions, in addition to reducing in hippocampal Adenosine monophosphate-activated protein kinase (AMPK) activity. Similar reductions were also observed for brain-derived neurotrophic factor (BDNF), synaptophysin, and post-synaptic density-95 (PSD-95) levels, all of which was counter-regulated by a regime of regular and prolonged exercise. A 21-day restraint stress regimen (6 h/day) produced learning and memory deficits, including reduced alternation in the Y-maze and decreased memory retention in the water maze test. These effects were reversed post-administration by a 3-week regime of treadmill running (19 m/min, 1 h/day, 6 days/week). In hippocampal primary culture, phosphorylated-AMPK (phospho-AMPK) and BDNF levels were enhanced in a dose-dependent manner by 5-amimoimidazole-4-carboxamide riboside (AICAR) treatment, and AICAR-treated increase was blocked by Compound C. A 7-day period of AICAR intraperitoneal injections enhanced alternation in the Y-maze test and reduced escape latency in water maze test, along with enhanced phospho-AMPK and BDNF levels in the hippocampus. The intraperitoneal injection of Compound C every 4 days during exercise intervention diminished exercise-induced enhancement of memory improvement during the water maze test in chronically stressed mice. Also, chronic stress reduced hippocampal neurogenesis (lower Ki-67- and doublecortin positive cells) and mRNA levels of BDNF, synaptophysin, and PSD-95. Our results suggest that regular and prolonged exercise can alleviate chronic stress-induced hippocampal-dependent memory deficits. Hippocampal AMPK-engaged BDNF induction is at least in part required for exercise-induced protection against chronic stress. PMID- 26975896 TI - Multi-Dimensional Voice Program (MDVP) vs Praat for Assessing Euphonic Subjects: A Preliminary Study on the Gender-discriminating Power of Acoustic Analysis Software. AB - OBJECTIVES: The aim of this study was to compare the discriminatory power of the Multi-Dimensional Voice Program (MDVP) and Praat in distinguishing the gender of euphonic adults. STUDY DESIGN: This is a cross-sectional study. METHODS: The recordings of 100 euphonic volunteers (50 males and 50 females) producing a sustained vowel /a/ were analyzed with MDVP and Praat software. RESULTS: Both computer programs identified significant differences between male and female volunteers in absolute jitter (MDVP P < 0.00001 and Praat P < 0.00001) and in shimmer in decibel (dB) (MDVP P = 0.006 and Praat P = 0.001). Using the scale proposed by Hosmer and Lemeshow, we found no gender discrimination for shimmer in dB with either the MDVP (area under the receiver operating characteristics curve [AUC] = 0.658) or Praat (AUC = 0.682). In our series, on the other hand, MDVP absolute jitter achieved an acceptable discrimination between males and females (AUC = 0.752), and Praat absolute jitter achieved an outstanding discrimination (AUC = 0.901). The discriminatory power of Praat absolute jitter was significantly higher than that of the MDVP (P = 0.003). Absolute jitter sensitivity and specificity were also higher for Praat (83% and 80%) than for the MDVP (74% and 49%). CONCLUSIONS: Differences attributable to a subject's gender and to the software used to measure acoustic parameters should be carefully considered in both research and clinical settings. Further studies are needed to test the discriminatory power of different voice analysis programs when differentiating between normal and dysphonic voices. PMID- 26975898 TI - Correction to To see bruxism: a functional MRI study. PMID- 26975897 TI - Do acting out verbs with dolls and comparison learning between scenes boost toddlers' verb comprehension? AB - To better understand how toddlers integrate multiple learning strategies to acquire verbs, we compared sensorimotor recruitment and comparison learning because both strategies are thought to boost children's access to scene-level information. For sensorimotor recruitment, we tested having toddlers use dolls as agents and compared this strategy with having toddlers observe another person enact verbs with dolls. For comparison learning, we compared providing pairs of: (a) training scenes in which animate objects with similar body-shapes maintained agent/patient roles with (b) scenes in which objects with dissimilar body-shapes switched agent/patient roles. Only comparison learning boosted verb comprehension. PMID- 26975899 TI - Identification of EFHD1 as a novel Ca(2+) sensor for mitoflash activation. AB - Mitochondrial flashes (mitoflashes) represent stochastic and discrete mitochondrial events that each comprises a burst of superoxide production accompanied by transient depolarization and matrix alkalinization in a respiratory mitochondrion. While mitochondrial Ca(2+) is shown to be an important regulator of mitoflash activity, little is known about its specific mechanism of action. Here we sought to determine possible molecular players that mediate the Ca(2+) regulation of mitoflashes by screening mitochondrial proteins containing the Ca(2+)-binding motifs. In silico analysis and targeted siRNA screening identified four mitoflash activators (MICU1, EFHD1, SLC25A23, SLC25A25) and one mitoflash inhibitor (LETM1) in terms of their ability to modulate mitoflash response to hyperosmotic stress. In particular, overexpression or down-regulation of EFHD1 enhanced or depressed mitoflash activation, respectively, under various conditions of mitochondrial Ca(2+) elevations. Yet, it did not alter mitochondrial Ca(2+) handling, mitochondrial respiration, or ROS-induced mitoflash production. Further, disruption of the two EF-hand motifs of EFHD1 abolished its potentiating effect on the mitoflash responses. These results indicate that EFHD1 functions as a novel mitochondrial Ca(2+) sensor underlying Ca(2+)-dependent activation of mitoflashes. PMID- 26975900 TI - Pattern of and reason for postoperative residual disease in patients with advanced ovarian cancer following upfront radical debulking surgery. AB - OBJECTIVE: Describing the pattern of and reasons for post-operative tumor residuals in patients with advanced epithelial ovarian cancer (AOC) operated in a specialized gynecologic cancer center following a strategy of maximum upfront debulking followed by systemic chemotherapy. METHODS: All consecutive AOC patients treated between 2005 and 2015 due to stages FIGO IIIB/IV were included in this single-center analysis. RESULTS: 739 patients were included in this analysis. In 81 (11.0%) patients, chemotherapy had already started before referral. Of the remaining 658 patients, upfront debulking was indicated in 578 patients (87.8%), while 80 patients (12.8%) were classified ineligible for upfront debulking; mostly due to comorbidities. A complete tumor resection was achieved in 66.1% of the 578 patients with upfront surgery, 25.4% had residuals 1 10mm and 8.5% had residuals exceeding 10mm, and 12.5% of patients had multifocal residual disease. Most common localization was small bowel mesentery and serosa (79.8%), porta hepatis/hepatoduodenal ligament (10.1%), liver parenchyma (4.3%), pancreas (8.0%), gastric serosa (3.2%), and tumor surrounding/infiltrating the truncus coeliacus (2.7%); 14.9% of the patients had non-resectable supra diaphragmatic lesions. Size of residual tumor was significantly associated with progression-free and overall survival. CONCLUSIONS: Upfront debulking for AOC followed by systemic chemotherapy was our main treatment strategy in almost 90% of all patients. The majority experienced a benefit by this approach; while 11.7% of patients probably did not. Understanding sites and reason for residual disease may help to develop adequate surgical training programs but also to identify patients that would better benefit from alternative treatment strategies. PMID- 26975901 TI - The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type. AB - OBJECTIVE: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive tumor, with long term survival at ~30% in early stage disease. SCCOHT is caused by germline and somatic SMARCA4 mutations, but the effect of the mutation type on patients remains unknown. Furthermore, the rarity of SCCOHT has resulted in varied treatment, with no standardized protocols. We analyzed 293 cases to determine the effect of treatment modalities and SMARCA4 mutations on patient diagnosis and outcome. METHODS: In 293 SCCOHT patients we collected information on age and stage at diagnosis, treatment modality (surgery, chemotherapy, radiotherapy, and/or high-dose chemotherapy with autologous stem cell rescue (HDC-aSCR)), SMARCA4 mutation origin (germline/somatic), and overall survival. Cox analysis and log-rank tests were performed on 257 cases with available survival data. RESULTS: The strongest prognostic factors were stage at diagnosis (p=2.72e-15) and treatment modality (p=3.87e-13). For FIGO stages II IV, 5-year survival was 71% for patients who received HDC-aSCR, compared to 25% in patients who received conventional chemotherapy alone following surgery (p=0.002). Patients aged >=40 had a worse outcome than younger patients (p=0.04). Twenty-six of 60 tested patients carried a germline SMARCA4 mutation, including all patients diagnosed <15years; carriers presented at a younger age than non carriers (p=0.02). CONCLUSIONS: Stage at diagnosis is the most significant prognostic factor in SCCOHT and consolidation with HDC-aSCR may provide the best opportunity for long-term survival. The large fraction of SMARCA4 germline mutations carriers warrants genetic counseling for all patients. PMID- 26975903 TI - Cocoa and cocoa fibre differentially modulate IgA and IgM production at mucosal sites. AB - Previous studies have shown that a 10 % cocoa (C10) diet, containing polyphenols and fibre among others, modifies intestinal and systemic Ig production. The present study aimed at evaluating the impact of C10 on IgA and IgM production in the intestinal and extra-intestinal mucosal compartments, establishing the involvement of cocoa fibre (CF) in such effects. Mechanisms by which C10 intake may affect IgA synthesis in the salivary glands were also studied. To this effect, rats were fed either a standard diet, a diet containing C10, CF or inulin. Intestinal (the gut wash (GW), Peyer's patches (PP) and mesenteric lymph nodes (MLN)) and extra-intestinal (salivary glands) mucosal tissues and blood samples were collected for IgA and IgM quantification. The gene expressions of IgA production- and homing-related molecules were studied in the salivary glands. The C10 diet decreased intestinal IgA and IgM production. Although the CF diet decreased the GW IgA concentration, it increased PP, MLN and serum IgA concentrations. Both the C10 and the CF diets produced a down-regulatory effect on IgA secretion in the extra-intestinal tissues. The C10 diet interacted with the mechanisms involved in IgA synthesis, whereas the CF showed particular effects on the homing and transcytosis of IgA across the salivary glands. Overall, CF was able to up-regulate IgA production in the intestinal-inductor compartments, whereas it down-regulated its production at the mucosal-effector ones. Further studies must be directed to ascertain the mechanisms involved in the effect of particular cocoa components on gut-associated lymphoid tissue. PMID- 26975902 TI - Determinants of minimal elevation in high-sensitivity cardiac troponin T in the general population. AB - OBJECTIVES: To study the relationship between cardiovascular risk factors and detectable cardiac troponin-T using a highly sensitive assay (hs-cTnT) among persons without a history of cardiovascular disease. DESIGN AND METHODS: We examined the cross-sectional associations between cardiovascular risk factors and hs-cTnT in 9593 participants (mean age 65.6 (SD, 5.6), 41% female, 22% black) free of cardiovascular disease in a community-based cohort, through the Atherosclerosis Risk in Communities (ARIC) Study. We used multivariable logistic regression to characterize the association between cardiovascular risk factors and detectable (>=3.0 to 13.9ng/L) and elevated (>=14.0ng/L) hs-cTnT. RESULTS: hs cTnT was detectable in 59% and elevated in 7% of the study population. Among persons with ideal cardiovascular health, hs-cTnT was detectable in 44%. In models adjusting for significant determinants of hs-cTnT concentration, detectable hs-cTnT was more frequent among males, blacks and persons with diabetes and hypertension and less frequent among statin users, current smokers and drinkers. Other risk factors associated with detectable hs-cTnT were older age, lower kidney function and higher body mass index. These risk factors were associated with elevated hs-cTnT in a similar pattern. CONCLUSION: In a community based sample without cardiovascular disease hs-cTnT is detectable in most adults, even among those with ideal cardiovascular health. Although most traditional cardiovascular risk factors were significant determinants of detectable and elevated hs-cTnT, the associations were particularly robust for sex, age, race, hypertension and diabetes. PMID- 26975904 TI - Monocyte cell membrane-derived nanoghosts for targeted cancer therapy. AB - Core-shell type 'nanoghosts' were synthesized with a drug-loaded biodegradable PLGA core and a monocyte cell membrane-derived shell. The nanoghosts were monodisperse with an average size <200 nm, and showed good serum stability for 120 h. Doxorubicin-loaded nanoghosts showed greater cellular uptake and cytotoxicity compared to non-coated nanoparticle controls in metastatic MCF-7 breast cancer cell lines. PMID- 26975905 TI - Prospective cohort study of persistent hypertension following pre-eclampsia at Medani Hospital, Sudan. AB - OBJECTIVE: To evaluate the incidence of, and factors associated with, persistent hypertension in patients with pre-eclampsia. METHODS: A prospective cohort study enrolled patients presenting with pre-eclampsia at Wad Medani Maternity Hospital, Sudan, between March 1 and October 31, 2014. Obstetric, clinical, and biochemical variables were recorded at presentation and at 6weeks after delivery. RESULTS: Of 188 patients enrolled in the study, 6-week follow-up data were available for 165. Among these patients, 136 (82.4%) and 29 (17.6) had mild and severe pre eclampsia, respectively. At 6-week follow-up, 58 (35.2%) patients were experiencing persistent hypertension. Patients with persistent hypertension demonstrated significantly lower platelet counts at baseline (P=0.001) and neonatal weight at delivery (P<0.001) than patients who were normotensive at 6weeks. Severe pre-eclampsia was more common among patients who experienced persistent hypertension than those who were normotensive 6weeks after delivery (P<0.001). In a logistic-regression analysis, none of the investigated factors was associated with persistent hypertension; however, patients experiencing severe pre-eclampsia were 7.3-times more likely to experience persistent hypertension than patients with mild pre-eclampsia (95% confidence interval 1.6 32.2; P=0.008). CONCLUSION: Persistent hypertension 6weeks after delivery was common among patients who experienced pre-eclampsia in Sudan (particularly severe pre-eclampsia) regardless of patients' age and parity. PMID- 26975906 TI - The association between midwifery experience and perinatal mortality-Authors' reply. PMID- 26975909 TI - Addressing overuse starts with physicians: Choosing Wisely Canada. PMID- 26975907 TI - The 1% versus the 99%: Reducing unnecessary health care costs. PMID- 26975910 TI - Pandemics, Ebola, and the family doctor. PMID- 26975912 TI - Recommendations on routine screening pelvic examination: Canadian Task Force on Preventive Health Care adoption of the American College of Physicians guideline. AB - OBJECTIVE: To review the 2014 American College of Physicians (ACP) guideline on the use of pelvic examinations to screen for cancer (other than cervical), pelvic inflammatory disease, or other benign gynecologic conditions to determine whether the ACP guideline on routine pelvic examinations was consistent with Canadian Task Force on Preventive Health Care (CTFPHC) standards and could be adapted or adopted. METHODS: The SNAP-IT (Smooth National Adaptation and Presentation of Guidelines to Improve Thrombosis Treatment) method was used to determine whether the ACP guideline was consistent with CTFPHC standards and could be adapted or adopted. RECOMMENDATIONS: The CTFPHC recommends not performing a screening pelvic examination to screen for noncervical cancer, pelvic inflammatory disease, or other gynecological conditions in asymptomatic women. This is a strong recommendation with moderate-quality evidence. CONCLUSION: The CTFPHC adopts the recommendation on screening pelvic examination as published by the ACP in 2014. PMID- 26975913 TI - Digoxin toxicity: Case for retiring its use in elderly patients? PMID- 26975915 TI - Choosing Wisely Canada recommendations: Interview with Dr Anthony Train. PMID- 26975914 TI - To cut or not to cut? Approach to ankyloglossia. PMID- 26975916 TI - Anti-CCP: a truly helpful rheumatoid arthritis test? PMID- 26975918 TI - The heart of being alive. PMID- 26975919 TI - Sharing a cup of tea. PMID- 26975917 TI - Potential effects of rational prescribing on national health care spending: More than half a billion dollars in annual savings. AB - OBJECTIVE: To estimate the cost savings that could result from implementation of a rational prescribing model for drug classes that are equivalent in terms of efficacy, toxicity, and convenience. DESIGN: The top 10 drug classes based on annual spending were gathered from the Canadian Institute for Health Information. They were reviewed for potential inclusion in the study based on the ability to compare intraclass medications. When equivalence in efficacy, toxicity, and convenience was determined from a literature review, annual prescribing data were gathered from the National Prescription Drug Utilization Information Systems Database. The potential cost savings were then calculated by comparing current market shares with potential future market shares. SETTING: Canada. MAIN OUTCOME MEASURES: Estimated differences in spending produced by a rational prescribing model. RESULTS: Statins, proton pump inhibitors, angiotensin-converting enzyme inhibitors, and selective serotonin reuptake inhibitors were determined to have class equivalence for efficacy, toxicity, and convenience. Total current annual spending on these classes is $856 million through public drug programs, and an estimated $1.97 billion nationally. Through rational prescribing, annual savings could reach $222 million for public drug programs, and $521 million nationally. CONCLUSION: Most of the potential savings are derived from deprescribing the newest patent-protected medications in each class. Avoiding prescribing the newest intraclass drug, particularly in the absence of research to support its superiority in relevant clinical outcomes, could lead to considerable savings in health care expenditures and might push the pharmaceutical industry to innovate rather than imitate. PMID- 26975920 TI - Impact of family medicine research: Bibliometrics and beyond. PMID- 26975921 TI - Welcoming Syrian refugees. PMID- 26975924 TI - Making the case for primary care. PMID- 26975927 TI - Facile Diversity-Oriented Synthesis of Polycyclic Pyridines and Their Cytotoxicity Effects in Human Cancer Cell Lines. AB - A three-component cascade method has been developed for the direct synthesis of polysubstituted pyridines. This strategy provides a very convenient route to pyridines using a variety of beta-bromo-alpha,beta-unsaturated aldehydes, 1,3 diketones, and ammonium acetate without any additional catalyst or metal salt under mild conditions. A variety of beta-ketoesters and 4-hydroxycoumarin were also used instead of 1,3-diketones for the diverse synthesis of polycyclic pyridines. One of the synthesized pyridines has been unambiguously established by a single crystal XRD study. All of the synthesized pyridine derivatives were evaluated for their antiproliferative properties in vitro against the human cancer cell lines HeLa, Me180, and ZR751. Compounds 4{4,1} and 4{2,4} showed significant cytotoxicity in the human breast cancer cell line ZR751 and cervical cancer cell line Me180, respectively, and a few other compounds were found to have moderate activities. PMID- 26975929 TI - Early Radiosurgery Improves Hearing Preservation in Vestibular Schwannoma Patients With Normal Hearing at the Time of Diagnosis. AB - PURPOSE: Vestibular schwannomas (VS) are increasingly diagnosed in patients with normal hearing because of advances in magnetic resonance imaging. We sought to evaluate whether stereotactic radiosurgery (SRS) performed earlier after diagnosis improved long-term hearing preservation in this population. METHODS AND MATERIALS: We queried our quality assessment registry and found the records of 1134 acoustic neuroma patients who underwent SRS during a 15-year period (1997 2011). We identified 88 patients who had VS but normal hearing with no subjective hearing loss at the time of diagnosis. All patients were Gardner-Robertson (GR) class I at the time of SRS. Fifty-seven patients underwent early (<=2 years from diagnosis) SRS and 31 patients underwent late (>2 years after diagnosis) SRS. At a median follow-up time of 75 months, we evaluated patient outcomes. RESULTS: Tumor control rates (decreased or stable in size) were similar in the early (95%) and late (90%) treatment groups (P=.73). Patients in the early treatment group retained serviceable (GR class I/II) hearing and normal (GR class I) hearing longer than did patients in the late treatment group (serviceable hearing, P=.006; normal hearing, P<.0001, respectively). At 5 years after SRS, an estimated 88% of the early treatment group retained serviceable hearing and 77% retained normal hearing, compared with 55% with serviceable hearing and 33% with normal hearing in the late treatment group. CONCLUSIONS: SRS within 2 years after diagnosis of VS in normal hearing patients resulted in improved retention of all hearing measures compared with later SRS. PMID- 26975930 TI - Wee1 Kinase Inhibitor AZD1775 Radiosensitizes Hepatocellular Carcinoma Regardless of TP53 Mutational Status Through Induction of Replication Stress. AB - PURPOSE: Wee1 kinase inhibitors are effective radiosensitizers in cells lacking a G1 checkpoint. In this study we examined the potential effect of Wee1 kinase inhibition on inducing replication stress in hepatocellular carcinoma (HCC). METHODS AND MATERIALS: Five independent datasets from the Oncomine database comparing gene expression in HCC compared to normal tissue were combined and specific markers associated with Wee1 sensitivity were analyzed. We then performed a series of in vitro experiments to study the effect of Wee1 inhibition on irradiated HCC cell lines with varying p53 mutational status. Clonogenic survival assays and flow cytometry using anti-gammaH2AX and phospho-histone H3 antibodies with propidium iodide were performed to study the effect of AZD1775 on survival, cell cycle, and DNA repair. Additionally, nucleoside enriched medium was used to examine the effect of altering nucleotide pools on Wee1 targeted radiation sensitization. RESULTS: Our analysis of the Oncomine database found high levels of CDK1 and other cell cycle regulators indicative of Wee1 sensitivity in HCC. In our in vitro experiments, treatment with AZD1775 radiosensitized and chemosensitized Hep3B, Huh7, and HepG2 cell lines and was associated with delayed resolution of gammaH2AX foci and the induction of pan nuclear gammaH2AX staining. Wee1 inhibition attenuated radiation-induced G2 arrest in the Hep3B (TP53 null) and Huh7 (TP53 mutant) cell lines but not in the TP53 wild-type cell line HepG2. Supplementation with nucleosides reversed the radiation-sensitizing effect of AZD1775 and reduced the amount of cells with pan nuclear gammaH2AX staining after radiation. CONCLUSIONS: Radiation sensitization with Wee1 inhibition occurs in cells regardless of their p53 mutational status. In this study we show for the first time that replication stress via the overconsumption of nucleotides plays an important role in AZD1775-induced radiation sensitization. PMID- 26975931 TI - Development of a method for detection and quantification of B. brongniartii and B. bassiana in soil. AB - A culture independent method based on qPCR was developed for the detection and quantification of two fungal inoculants in soil. The aim was to adapt a genotyping approach based on SSR (Simple Sequence Repeat) marker to a discriminating tracing of two different species of bioinoculants in soil, after their in-field release. Two entomopathogenic fungi, Beauveria bassiana and B. brongniartii, were traced and quantified in soil samples obtained from field trials. These two fungal species were used as biological agents in Poland to control Melolontha melolontha (European cockchafer), whose larvae live in soil menacing horticultural crops. Specificity of SSR markers was verified using controls consisting of: i) soil samples containing fungal spores of B. bassiana and B. brongniartii in known dilutions; ii) the DNA of the fungal microorganisms; iii) soil samples singly inoculated with each fungus species. An initial evaluation of the protocol was performed with analyses of soil DNA and mycelial DNA. Further, the simultaneous detection and quantification of B. bassiana and B. brongniartii in soil was achieved in field samples after application of the bio inoculants. The protocol can be considered as a relatively low cost solution for the detection, identification and traceability of fungal bio-inoculants in soil. PMID- 26975932 TI - Evaluating the implementation fidelity of New Medicines Service for asthma patients in community pharmacies in Belgium. AB - BACKGROUND: In October 2013, a New Medicines Service (NMS) was introduced in community pharmacies in Belgium to support asthma patients who are novice users of inhaler devices with corticosteroids. The protocol-based intervention used the Asthma Control Test (ACT) and the Medication Adherence Report Scale (MARS) to assess asthma control and medication adherence. The NMS is the first initiative that puts advanced pharmaceutical care into practice in Belgium. The present study evaluated the degree to which the NMS program is delivered as intended, drawing on the concept of implementation fidelity (IF). METHODS: The main dimensions of IF and potential moderating and facilitating factors for the implementation of NMS in community pharmacies were evaluated using telephone interviews with pharmacists (n = 497), semi-structured interviews with patients eligible for NMS (n = 30), focus groups among general practitioners (n = 72) and lung specialists (n = 5), and a work system analysis in community pharmacies (n = 19). RESULTS: The uptake of NMS in Belgian community pharmacies remains low. In addition to practical barriers, pharmacists found it difficult to identify new asthmatic patients when they were not informed about the diagnosis. A lack of commitment from physicians, patients and pharmacists was noted in the early start up phase of the program. Many pharmacists did not see how NMS differed from existing pharmaceutical care. Physicians considered this service as part of their own tasks and discouraged ACT for asthma follow-up in the community pharmacy. CONCLUSIONS: The introduction of the NMS program was not sufficiently embedded in the Belgian health care organization, causing low uptake and resistance to its implementation by pharmacists, patients, and other health care professionals. To increase the uptake of this type of service and its possible extension to other patient groups, more collaboration among the different health care professionals during design and implementation is necessary, as well as systematic data collection to monitor the quality of the service, better training of pharmacists, and more information for patients and physicians. PMID- 26975933 TI - Analysis of the sex ratio of reported gonorrhoea incidence in Shenzhen, China. AB - OBJECTIVE: To assess the clinical process of gonorrhoea diagnosis and report in China, and to determine the difference of sex ratio between reported incidence based on reporting data and true diagnosis rate based on reference tests of gonorrhoea. SETTING: A total of 26 dermatology and sexually transmitted disease (STD) departments, 34 obstetrics-gynaecology clinics and 28 urology outpatient clinics selected from 34 hospitals of Shenzhen regarded as our study sites. PARTICIPANTS: A total of 2754 participants were recruited in this study, and 2534 participants completed the questionnaire survey and provided genital tract secretion specimens. There were 1106 male and 1428 female participants. Eligible participants were patients who presented for outpatient STD care at the selected clinics for the first time in October 2012 were at least 18 years old, and were able to give informed consent. OUTCOME MEASURES: Untested rate, true-positive rate, false-negative rate and unreported rate of gonorrhoea, as well as reported gonorrhoea incidence sex ratio and true diagnosis sex ratio were calculated and used to describe the results. RESULTS: 2534 participants were enrolled in the study. The untested rate of gonorrhoea among females was significantly higher than that among males (female 88.1%, male 68.3%, p=0.001). The male-to-female sex ratios of untested rate, true-positive rate, false-negative rate and unreported rate were 1:1.3, 1.2:1, 1:1.6 and 1:1.4, respectively. The reported gonorrhoea incidence sex ratio of new diagnosed gonorrhoea was 19.8:1 (male vs female: 87/1106 vs 5/1420), while the true diagnosis sex ratio was 2.5:1 (male vs female: 161/1106 vs 84/1420). These data indicate that the sex ratio of reported gonorrhoea incidence has been overestimated by a factor of 7.9 (19.8/2.5). CONCLUSIONS: We found the current reported gonorrhoea incidence and sex ratios to be inaccurate due to underestimations of gonorrhoea incidence, especially among women. PMID- 26975935 TI - Waist-to-height ratio as an indicator of 'early health risk': simpler and more predictive than using a 'matrix' based on BMI and waist circumference. AB - OBJECTIVES: There is now good evidence that central obesity carries more health risks compared with total obesity assessed by body mass index (BMI). It has therefore been suggested that waist circumference (WC), a proxy for central obesity, should be included with BMI in a 'matrix' to categorise health risk. We wanted to compare how the adult UK population is classified using such a 'matrix' with that using another proxy for central obesity, waist-to-height ratio (WHtR), using a boundary value of 0.5. Further, we wished to compare cardiometabolic risk factors in adults with 'healthy' BMI divided according to whether they have WHtR below or above 0.5. SETTING, PARTICIPANTS AND OUTCOME MEASURES: Recent data from 4 years (2008-2012) of the UK National Diet and Nutrition Survey (NDNS) (n=1453 adults) were used to cross-classify respondents on anthropometric indices. Regression was used to examine differences in levels of risk factors (triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), high density lipoprotein (HDL), TC: HDL, glycated haemoglobin (HbA1c), fasting glucose, systolic (SBP) and diastolic blood pressure (DBP)) according to WHtR below and above 0.5, with adjustment for confounders (age, sex and BMI). RESULTS: 35% of the group who were judged to be at 'no increased risk' using the 'matrix' had WHtR >= 0.5. The 'matrix' did not assign 'increased risk' to those with a 'healthy' BMI and 'high' waist circumference. However, our analysis showed that the group with 'healthy' BMI, and WHtR >= 0.5, had some significantly higher cardiometabolic risk factors compared to the group with 'healthy' BMI but WHtR below 0.5. CONCLUSIONS: Use of a simple boundary value for WHtR (0.5) identifies more people at 'early health risk' than does a more complex 'matrix' using traditional boundary values for BMI and WC. WHtR may be a simpler and more predictive indicator of the 'early heath risks' associated with central obesity. PMID- 26975934 TI - Depressive symptomatology, weight status and obesogenic risk among Australian adolescents: a prospective cohort study. AB - OBJECTIVES: Adolescence is a period of increased risk for mental health problems and development of associated lifestyle risk behaviours. This study examined cross-sectional and longitudinal associations between obesogenic risk factors, weight status, and depressive symptomatology in a cohort of Australian adolescents. DESIGN: Prospective cohort study. SETTING: The study used repeated measures data from the Australian Capital Territory (ACT) It's Your Move project, an Australian community-based obesity prevention intervention. Intervention effect was non-significant therefore intervention and comparison groups were combined in this study. PARTICIPANTS: Total sample was 634 secondary school students (female n=338, male n=296) with mean age 13 years (SD=0.6) at baseline (2012) and 15 years (SD=0.6) at follow-up (2014) recruited from 6 government secondary schools in the ACT. PRIMARY AND SECONDARY OUTCOMES MEASURES: Primary outcome was depressive symptomatology measured by Short Mood and Feelings Questionnaire. Secondary outcomes were weight status, physical activity, screen time and diet related measures. RESULTS: Increased physical activity was associated to lower depressive symptomatology among males (OR=0.35, p<0.05). Sweet drink (OR=1.15, p<0.05) and takeaway consumption (OR=1.84, p<0.05) were associated with higher levels of depressive symptomatology among females at follow-up. Males who were classified as overweight or obese at baseline, and remained so over the study period, were at increased risk of depressive symptomatology at follow-up (b=1.63, 95% CI 0.33 to 2.92). Inactivity among males over the 2-year study period was predictive of higher depressive symptomatology scores at follow-up (b=2.55, 95% CI 0.78 to 4.32). For females, those who increased their consumption of takeaway foods during the study period were at increased risk for developing depressive symptomatology (b=1.82, 95% CI -0.05 to 3.71). CONCLUSIONS: There are multiple, probably complex, relationships between diet, physical activity and outcomes of obesity and mental health as well as between the outcomes themselves. Healthier diets and increased physical activity should be foundations for healthier body weight and mental health. TRIAL REGISTRATION NUMBER: ACTRN12615000842561; Results. PMID- 26975937 TI - Effects of different metabolic states and surgical models on glucose metabolism and secretion of ileal L-cell peptides: protocol for a cross-sectional study. AB - INTRODUCTION: Obesity and type 2 diabetes mellitus are increasing worldwide, reaching pandemic proportions. The understanding of the role of functional restriction and gut hormones can be a beneficial tool in treating obesity and diabetes. However, the exact hormonal profiles in different metabolic states and surgical models are not known. METHODS AND ANALYSIS: The HIPER-1 Study is a single-centre cross-sectional study in which 240 patients (in different metabolic states and surgical models) will receive an oral mixed-meal tolerance test (OMTT). At baseline and after 30, 60 and 120 min, peptide YY and glucagon-like peptide 1 levels and glucose and insulin sensitivity will be measured. The primary end point of the study will be the area under the glucagon-like peptide 1 and peptide YY curves after the OMTT. Secondary study end points will include examination of the difference in plasma levels of the distal ileal hormones in subjects with various health statuses and in patients who have been treated with different surgical techniques. ETHICS AND DISSEMINATION: An independent ethics committee, the Institutional Review Board of Istanbul Sisli Kolan International Hospital, Turkey, has approved the study protocol. Dissemination will occur via publication, national and international conference presentations, and exchanges with regional, provincial and national stakeholders. TRIAL REGISTRATION NUMBER: NCT02532829; Pre-results. PMID- 26975936 TI - Do health literacy and patient empowerment affect self-care behaviour? A survey study among Turkish patients with diabetes. AB - OBJECTIVE: This study aimed to assess the impact of health literacy and patient empowerment on diabetes self-care behaviour in patients in metropolitan Turkish diabetes centres. The conceptual background is provided by the psychological health empowerment model, which holds that health literacy without patient empowerment comes down to wasting health resources, while empowerment without health literacy can lead to dangerous or suboptimal health behaviour. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional study was conducted with 167 patients over the age of 18 from one of two diabetes clinics in a major Turkish City. Self administered questionnaires were distributed to eligible outpatients who had an appointment in one of the clinics. Health literacy was measured by a newly translated Turkish version of the Short Test of Functional Health Literacy in Adults (S-TOFHLA) and the Chew self-report scale. Patient empowerment was measured by a 12-item scale based on Spreitzer's conceptualisation of psychological empowerment in the workplace. Self-care behaviour was measured by the Self-care behaviours were measured by the Summary of Diabetes Self-Care Activities Measure (SDSCA). Level of diabetes knowledge was measured by Diabetes Knowledge Test. RESULTS: Two subscales of empowerment, impact and self determination, predicted self-reported frequency of self-care behaviours. Neither health literacy nor diabetes knowledge had an effect on self-care behaviours. CONCLUSIONS: Health literacy might be more effective in clinical decisions while empowerment might exert a stronger influence on habitual health behaviours. PMID- 26975938 TI - Artificial trans fat in popular foods in 2012 and in 2014: a market basket investigation in six European countries. AB - OBJECTIVE: To minimise the intake of industrially produced trans fat (I-TF) and thereby decrease the risk of coronary heart disease (CHD), nearly all European countries rely on food producers to voluntarily reduce the I-TF content in food. The objective of this study was to monitor the change in presence of I-TF in biscuits/cakes/wafers in six countries in South-eastern Europe from 2012 to 2014, including two members of the European Union (Slovenia and Croatia). DESIGN: Three large supermarkets were visited in each of the six capitals in 2012. Pre-packaged biscuits/cakes/wafers were bought if the products contained more than 15 g of total fat per 100 g of product and if partially hydrogenated oil or a similar term was disclosed at the beginning of the ingredients list. These same supermarkets were revisited in 2014 and the same collection procedure was followed. All foods were subsequently analysed for total fat and trans fat in the same laboratory. RESULTS: The number of packages bought in the six countries taken together was 266 in 2012 and 643 in 2014. Some were identical, and therefore only 226 were analysed in 2012 and 434 in 2014. Packages with less than 2% of fat from I-TF went up from 69 to 235, while products with more than 2% (illegal in Denmark) doubled from an average of 33 to an average of 68 products for the six countries, with considerable variation across countries. The per cent of I-TF in total fat decreased slightly, from a mean (SD) of 22 (13) in 2012 to 18 (9) in 2014. CONCLUSIONS: The findings suggest that voluntary reduction of I TF in foods with high amounts is an ineffective strategy in several European countries. Alternative strategies both within and outside the European Union are necessary to protect all subgroups of the populations against an increased risk of CHD. PMID- 26975940 TI - [National survey: Avulsion of included wisdom teeth in mandibular orthognathic surgery]. AB - INTRODUCTION: There is no recommendation concerning wisdom teeth (WT) extraction in mandibular orthognathic surgery. We carried out an investigation among the members of the French Society of Stomatology and Oro-maxillofacial Surgery (SFSCMFCO), in order to evaluate the practices and habits of maxillofacial surgeons in this field. MATERIALS AND METHODS: We emailed the 424 members of the SFSCMFCO with a questionnaire. RESULTS: We obtained 143 feedbacks that could be exploited. In total, 72.5% of practitioners prefer WT to be extracted before performing a bilateral sagittal spilt osteotomy (BSSO). In this case, a period of 6 months between the two surgeries was considered as desirable by more than 70% of the surgeons. In total, 74.6% of the surgeons thought that the presence of WT could make a BSSO more complicated. However, 73.9% of the surgeons would not postpone the BBSO in a patient ready for surgery but with remaining impacted WT. DISCUSSION: A majority of surgeons think that the presence of impacted WT may complicate a BSSO and increases the risk of bad split. Most of the authors recommend extracting the impacted WT 6 months before BSSO at least. However, these potential complications are easy to overcome and don't compromise the final result. Therefore, we think that impacted WT should not delay a BSSO if the orthodontic preparation makes the patient ready for surgery. PMID- 26975939 TI - Genomic identification of WRKY transcription factors in carrot (Daucus carota) and analysis of evolution and homologous groups for plants. AB - WRKY transcription factors belong to one of the largest transcription factor families. These factors possess functions in plant growth and development, signal transduction, and stress response. Here, we identified 95 DcWRKY genes in carrot based on the carrot genomic and transcriptomic data, and divided them into three groups. Phylogenetic analysis of WRKY proteins from carrot and Arabidopsis divided these proteins into seven subgroups. To elucidate the evolution and distribution of WRKY transcription factors in different species, we constructed a schematic of the phylogenetic tree and compared the WRKY family factors among 22 species, which including plants, slime mold and protozoan. An in-depth study was performed to clarify the homologous factor groups of nine divergent taxa in lower and higher plants. Based on the orthologous factors between carrot and Arabidopsis, 38 DcWRKY proteins were calculated to interact with other proteins in the carrot genome. Yeast two-hybrid assay showed that DcWRKY20 can interact with DcMAPK1 and DcMAPK4. The expression patterns of the selected DcWRKY genes based on transcriptome data and qRT-PCR suggested that those selected DcWRKY genes are involved in root development, biotic and abiotic stress response. This comprehensive analysis provides a basis for investigating the evolution and function of WRKY genes. PMID- 26975942 TI - Defining Advanced Heart Failure: A Systematic Review of Criteria Used in Clinical Trials. AB - BACKGROUND: Enrollment criteria used in advanced heart failure (HF) clinical trials might identify a common set of widely accepted quantitative characteristics as the basis of a consensus definition for advanced HF, which is currently lacking. METHODS: We reviewed all clinical trials investigating interventions in patients with advanced HF as of July 31, 2015. Eligible publications (N = 134) reported original data from clinical trials explicitly defining advanced HF in adults. RESULTS: New York Heart Association (NYHA) class was the most common criterion (119 trials, 88.8%; classes ranged from II to IV), followed by left ventricular ejection fraction (LVEF) (84 trials, 62.7%; cutoff range, 20% to 45%; mode 35%). Other criteria included inotrope-dependent status (12.7%), peak oxygen consumption (10.4%), >=1 previous HF admissions (10.4%), cardiac index (10.4%), pulmonary capillary wedge pressure (9.0%), left ventricular end-diastolic diameter (6.0%), and transplant listing status (5.2%). Cutoff points for quantitative criteria varied considerably. Previous HF admission was more frequently required in recent trials (P = .007 for temporal trend), whereas use of hemodynamic criteria decreased over time (P = .050 for temporal trend). Average LVEF among participants increased over time. CONCLUSIONS: There is considerable variation in the definition of advanced HF for clinical trial purposes. Beyond NYHA and LVEF, a wide array of criteria has been used, with little consistency both in criteria selection and quantitative cutoff points. PMID- 26975943 TI - Mayo Clinic/Renal Pathology Society Consensus Classification of Glomerulonephritides: A Giant Leap in Right Direction. PMID- 26975941 TI - The Obesity and Heart Failure Epidemics Among African Americans: Insights From the Jackson Heart Study. AB - BACKGROUND: Higher rates of obesity and heart failure have been observed in African Americans, but associations with mortality are not well-described. We examined intermediate and long-term clinical implications of obesity in African Americans and associations between obesity and all-cause mortality, heart failure, and heart failure hospitalization. METHODS AND RESULTS: We conducted a retrospective analysis of a community sample of 5292 African Americans participating in the Jackson Heart Study between September 2000 and January 2013. The main outcomes were associations between body mass index (BMI) and all-cause mortality at 9 years and heart failure hospitalization at 7 years using Cox proportional hazards models and interval development of heart failure (median 8 years' follow-up) using a modified Poisson model. At baseline, 1406 (27%) participants were obese and 1416 (27%) were morbidly obese. With increasing BMI, the cumulative incidence of mortality decreased (P= .007), whereas heart failure increased (P < .001). Heart failure hospitalization was more common among morbidly obese participants (9.0%; 95% confidence interval [CI] 7.6-11.7) than among normal-weight patients (6.3%; 95% CI 4.7-8.4). After risk adjustment, BMI was not associated with mortality. Each 1-point increase in BMI was associated with a 5% increase in the risk of heart failure (hazard ratio 1.05; 95% CI 1.03 1.06; P < .001) and the risk of heart failure hospitalization for BMI greater than 32 kg/m(2) (hazard ratio 1.05; 95% CI 1.03-1.07; P < .001). CONCLUSIONS: Obesity and morbid obesity were common in a community sample of African Americans, and both were associated with increased heart failure and heart failure hospitalization. PMID- 26975945 TI - Vitiligo in Children: A Distinct Subset. AB - OBJECTIVE: To determine clinical profile of vitiligo in children. STUDY DESIGN: A descriptive study. PLACE AND DURATION OF STUDY: Combined Military Hospital, Abbottabad, from January 2010 to June 2013. METHODOLOGY: All new patients below the age of 15 years, clinically diagnosed to have vitiligo, were included in the study. A detailed history was obtained, thorough physical examination was performed, and findings were recorded on a specially designed proforma for each patient separately. Computer programme SPSS-14 was used to manage and analyze the data. RESULTS: Out of 157 children, 68 (43.3%) were males and 89 (56.7%) were females. Mean age at onset was 6.55 +/-3.43 years. The disease started before 10 years of age in 123 (78.3%) children. Average duration of the disease was 1.48 +/ 1.87 years. Average duration of the disease was 1.73 +/-2.09 years in male children and 1.29 +/-1.67 years in female children. Generalized vitiligo was the commonest type (n = 83, 52.9%). The disease started most commonly from head and neck (n = 75, 47.8%). A family history of vitiligo was found in forty-nine (31.2%) children, Koebner phenomenon in 39 (24.8%) children and associated autoimmune or endocrine diseases in 8 (5.1%) patients. CONCLUSION: Majority of the children developed the disease before 10 years of age. Generalized vitiligo was the commonest type. Childhood vitiligo was more common in female children. PMID- 26975944 TI - Early Laparoscopic Sleeve Gastrectomy Outcomes in Terms of Weight Loss. AB - OBJECTIVE: To investigate the outcomes of laparoscopic sleeve gastrectomy (LSG) in terms of weight loss. STUDY DESIGN: Descriptive cohort study. PLACE AND DURATION OF STUDY: Department of Surgery, Shifa International Hospital, Islamabad, from January 2009 to January 2015. METHODOLOGY: A total of 100 consecutive patients were included in the study through retrospective chart review. A5-port technique was utilized with the gastric sleeve being created using endostapler. Postoperatively, patients gradually progressed from clear liquid diet and oral rehydration salts to nutritional supplements over three days. By two weeks postoperatively, patients had progressed to a solid diet. SPSS was used for data entry and analysis. Body mass index (BMI) and weight in kg were determined. RESULTS: From 100 patients, 17 were lost to follow-up less than a week into the postoperative period. Of the remaining, average age of the patients was 34.7 +/-11.3 years at the time of surgery. The majority of patients were females (72%). Mean preoperative and postoperative BMI was 45.3 +/-10.4 kg/m2 and 35.0 +/-10 kg/m2, respectively. Of the 83 patients, 62 were followed-up for longer than 1 month (average 419 days). For patients in this category, mean reduction in BMI was 10.3 +/-6.5 kg/m2 with average weight loss of 34.3 +/-18.2 kg. There were no mortalities associated with LSG. CONCLUSION: Laparoscopic sleeve gastrectomy is a safe and effective intervention in young Pakistani females with encouraging outcomes at a mean follow-up of over one year. PMID- 26975946 TI - Perception of Diabetic Patients Regarding Basal Bolus Insulin Injections and Outcome of its Use. AB - OBJECTIVE: To assess the perceptions regarding basal bolus insulin injections and the changes in blood glucose levels and glycosylated hemoglobin (HbA1c) before and after 3 months of such treatment in diabetic patients. STUDY DESIGN: Quasi experimental study. PLACE AND DURATION OF STUDY: Department of Endocrinology, Liaquat National Hospital, Karachi, from December 2014 to March 2015. METHODOLOGY: A total of 222 diabetic patients started on basal bolus insulin injection were enrolled and asked to answer 17 questions. Those with complications of diabetes were excluded. Fasting blood glucose (FBS), random blood glucose (RBS) and HbA1c levels were checked initially, and after 3 months of getting basal bolus insulin. Paired t-test and chi-square test were used for determining p-value with significance at p < 0.05. RESULTS: Majority (n=217, 97.7%) of the patients were previously taking other insulins. Before starting this treatment, the mean FBS was 260.5 +/-52.2 mg/dl, RBS was 385.5 +/-47.61 mg/dl and HbA1c was 12.76 +/-1.92%. After 3 months of treatment, FBS improved to 117.9 +/-14.2 mg/dl, RBS was 156.7 +/-17.09 mg/dl and HbA1c was 7.72 +/-4.41% (p < 0.001). Two hundred and sixteen (97.3%) patients believed that basal bolus insulin was started as their diabetes worsened; 157 (70.70%) thought that their blood glucose control would improve with the use of this form of insulin. One hundred and ninety four (87.4%) had fear of needle injections. Perceptions regarding hypoglycemia with this form of insulin were observed in 157 (70.7%). One hundred and twenty seven (84.1%) of the females and 51 (71.8%) of the males thought that the basal bolus insulin regimen was too expensive (p=0.032). CONCLUSION: There were many misconceptions in patients who were started on basal bolus insulin. Marked improvement in blood glucose levels and HbA1c were observed after the use of this regimen. PMID- 26975947 TI - Comparison of Micro-Leakage around Temporary Restorative Materials Placed in Complex Endodontic Access Cavities: An In-Vitro Study. AB - OBJECTIVE: To compare mean micro-leakage around 3 types of temporary restorative materials in-vitro, when placed adjacent to permanent restorations (amalgam) in complex endodontic access cavities. STUDY DESIGN: Randomized controlled trial. PLACE AND DURATION OF STUDY: Dental Clinics, Dental Laboratory and Research Laboratory at The Aga Khan University Hospital, Karachi, from January to June 2014. METHODOLOGY: After random allocation of 60 teeth into 3 experimental groups, each group had conventional class II cavities prepared and amalgam placed. After 14 days, endodontic access cavities were made in these teeth, followed by placement of Cavit, IRM and CLIP(depth of 4 mm each). After thermo cycling and immersion in 0.5% methylene blue dye, the teeth were sectioned mesio distally and observed under stereoscopic microscope (magnification x4) along 2 interfaces 'a' and 'b' (tooth-temporary restoration and temporary restoration primary restoration), respectively. Depth of dye penetration was measured in millimeters. RESULTS: IRM was leakiest at interface 'a', cavit had highest dye penetration at interface 'b', while CLIP exhibited least micro-leakage at 'a' and 'b'. The mean dye penetration for Cavit was 0.80 +/- 0.23 mm at 'a', and 2.24 +/- 0.48 mm at 'b'. For IRM, it was 1.82 +/- 0.09 mm at 'a', and 0.44 +/- 0.13 mm at 'b'. For CLIP, the mean dye penetration was 0.43 +/- 0.05 mm at 'a', and 0.32 +/- 0.12 mm at 'b'. The difference in dye penetration observed between the 3 groups at both interfaces was statistically significant. CONCLUSION: In a complex access cavity made adjacent to a pre-existing amalgam restoration, CLIP exhibits the least micro-leakage, followed by IRM and Cavit. PMID- 26975948 TI - Interleukin-10 as a Marker of Disease Progression in Dengue Hemorrhagic Fever. AB - OBJECTIVE: To evaluate the plasma interleukin-10 (IL-10) levels in patients suffering from dengue hemorrhagic fever between 4 to 7 days of onset of disease and 24 hours after the first sample, to find out the association of plasma IL-10 levels with the outcome. STUDY DESIGN: Analytical study. PLACE AND DURATION OF STUDY: All major hospitals of Lahore, Pakistan, from August to November 2012. METHODOLOGY: Participants included 50 registered patients of dengue hemorrhagic fever (DHF) aged between 15 - 50 years. Plasma IL-10 concentrations were measured on above stated day. Outcome was described as recovery and shock. Platelet count and hematocrit percentages were also recorded. Statistical analyses were done using SPSS version 19. Ap-value <=0.05 was considered significant. RESULTS: Plasma IL-10 levels were found to be raised in DHF patients and were associated with fatal outcome (p=0.004). In recovered DHF patients, plasma IL-10 levels decreased after 24 hours (mean 26.54 +/- 16.03 pg/ml) as compared to admission time (mean 74.39 +/- 61.69 pg/ml) but in case of DHF patients suffering from shock, plasma IL-10 was found to be higher after 24 hours (mean 87.69 +/- 7.77 pg/ml) as compared to levels at admission time (mean 42.56 +/- 28.09 pg/ml). ROC curve analysis revealed a change (30 units pg/ml) of plasma IL-10 concentration, within 24 hours of admission, raised from the base line to be 105 times more critical for shock in DHF patients (100% sensitivity and 71.4% specificity, p < 0.001). CONCLUSION: Elevated plasma IL-10 is a potential predictor of disease severity and fatal outcome in DHF patients. PMID- 26975949 TI - The Trends of CRP Levels at Different Waist-to-Hip Ratios Among Normotensive Overweight and Obese Patients: A Pilot Study. AB - OBJECTIVE: To determine the correlation between CRP (C-reactive protein) and Waist to Hip Ratio (WHR) among over weight and obese patients with normal blood pressure. STUDY DESIGN: An analytical study. PLACE AND DURATION OF STUDY: Medical indoor and outpatient clinics of Mayo Hospital, Lahore, from March to August 2013. METHODOLOGY: Willing patients with Body Mass Index (BMI) of > 23 kg/m2, normal blood pressures, and age between 18 - 65 years were inducted in the study. Patients with signs of fluid retention, collagen vascular disease, CAD, on corticosteroids, immunomodulators or lipid lowering medications, hypertensives and febrile patients were excluded. Patients were considered to be at low risk for cardiovascular events if WHR among males and females was < 0.95 and < 0.80, respectively. Similarly, males and females with WHR > 1 and > 0.85, respectively were taken as high risk. Levels in-between these ranges were taken as moderate risk. Data was analyzed on SPSS 15. Descriptive statistics were determined. The p value was calculated by ANOVA and independent sample t-test among males and females respectively, to compare WHR in relation to different CRP levels and < 0.05 was taken as significant. RESULTS: There were 34 male and 74 female patients. The gender-wise mean WHR did not show statistically significant difference categorized CRP levels (p=0.072 in male, and 0.052 in females). There was an increasing trend in CRP levels as WHR increased among females, but this was statistically insignificant (p=0.05). CONCLUSION: Although the impact of central obesity on cardiac health is well known, however, WHR alone is an unreliable indicator of systemic inflammation and raised CRP level. PMID- 26975950 TI - Role of Skill Laboratory Training in Medical Education - Students’ Perspective. AB - OBJECTIVE: To evaluate the perceptions of medical students regarding their training utilizing facilities provided in the skill laboratory of a public sector medical college. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Army Medical College, Rawalpindi, from October to December 2014. METHODOLOGY: Students of final year MBBS who had underwent skill laboratory training were recruited through convenience purposive sampling. Students not exposed to skill laboratory training were excluded. Data collection tool was a questionnaire having 23 questions with responses on Likert Scale as strongly disagree, disagree, agree and strongly agree coded as 1, 2, 3 and 4, respectively. Data was analysed on SPSS version 22. RESULTS: There were 78 (57%) male and 59 (43%) female students out of 137, with mean age of 22.59 ±0.74 years. The response rate was 68.5%. Cronbach's Alpha test was 0.84 showing high reliability. The mean of sum of all the 23 items was 63.85 ±8.71, whereas item means was 2.78 ±0.38, reflecting a high inclination of students towards skill laboratory training. Frequency of students responding in favour of skill laboratory training was significantly high (p < 0.05). CONCLUSION: Medical students perceived skill laboratory training as a favoured learning strategy as compared to practising on real patients for acquisition of various aspects of clinical skills, knowledge and attitude. PMID- 26975951 TI - Clinical Spectrum of Disorders of Sexual Differentiation. AB - OBJECTIVE: To describe the mode of presentation and causes of the disorders of sexual differentiation in patients presenting in the Endocrine Clinic. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: The Endocrine and Diabetes Unit of Jinnah Postgraduate Medical Centre (JPMC), Karachi, from July 2012 to July 2014. METHODOLOGY: Patients with phenotypic, psychosocial gender confusion or absence of gender appropriate secondary sexual maturation were enrolled in the study. Patients having chronic systemic disease, as cause of delayed puberty, were excluded from the study. SPSS 13 was used to evaluate the data. RESULTS: A total of 48 patients registered in the study with mean age of 19.9 +/-8 years. Female gender was assigned to 28 (58.3%) of which 8 (28.57%) had genital ambiguity. Male gender was assigned to 20 (41.66%) patients at the time of birth and 7 (35%) of them had ambiguous genitalia. Karyotyping could be done in 36 (75%) patients of which 17 (47.2%) were females and 19 (52.7%) were males. Karyotypic gender of the 19 (48.57%) male patients was 46 XX, 46 XY and 47 XXY; in 4 (21.05%), 5 (26.3%) and 10 (52.6%) patients, respectively with 9 Klinfelter syndrome. Karyotypic gender of 17 (47.42%) female patients were 46 XX, 46 XY and 45 X0; in 5 (29.4%), 3 (17.64%) and 9 (52.9%) patients, respectively. CONCLUSION: Disorder of sexual development constitutes a small but difficult area of endocrinology with disastrous consequences, especially if assigned wrong sex at birth. Mode of presentation of these cases was diverse ranging from delayed puberty, to gender confusion, to pregnancy in a male. Eventually in an adult patient assignment or reassignment of gender identity was primarily the patient's prerogative. PMID- 26975952 TI - Functional Outcome of Anorectal Malformations and Associated Anomalies in Era of Krickenbeck Classification. AB - OBJECTIVE: To describe the management and functional outcome of anorectal malformations and associated anomalies according to Krickenbeck classification. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: The Aga Khan University Hospital, Karachi, from January 2002 to December 2012. METHODOLOGY: Anorectal anomalies were classified according to Krickenbeck classification. Data was collected and proforma used regarding the primary disease associated anomalies, its management and functional outcome, according to Krickenbeck classification. Cases included were: all those children with imperforate anus managed during the study period. Qualitative variables like gender and functional outcome were reported as frequencies and percentages. Quantitative variables like age were reported as medians with interquartile ranges. RESULTS: There were 84 children in study group. Most common associated anomaly was cardiac (38%), followed by urological anomaly (33%). All children were treated by Posterior Sagittal Anorectoplasty (PSARP). Fistula was present in 64 out of 84 (76%) cases. The most common fistula was rectourethral (33%), followed by recto vestibular (31%). According to Krickenbeck classification, continence was achieved in 62% children; however 27% children were constipated, followed by 12% children having fecal soiling. CONCLUSION: Functional outcome of anorectal malformation depends upon severity of disease. A thorough evaluation of all infants with ARM should be done with particular focus on cardiovascular (38%) and genitourinary abnormalities (33%). PMID- 26975953 TI - Forgotten Ureteral Stents: An Avoidable Morbidity. AB - OBJECTIVE: To assess the clinical presentation of forgotten ureteral stents and highlight the etiological factors resulting in the retention of these stents. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Department of Urology, Armed Forces Institute of Urology, Rawalpindi, from January 2010 to June 2011. METHODOLOGY: Thirty-eight patients, with forgotten ureteral stents, retained for more than 6 months duration, were enrolled. A detailed evaluation was performed, along with the questions regarding the patients' opinion about the ureteral stents. They were specially asked whether they knew about the stents or were they formally informed regarding the stents. Subsequently, the patients were managed according to their clinical condition. RESULTS: The male to female ratio was 2.1:1 aged 23 - 69 years, mean being 40.24 ±12.59 years. The time of presentation after the ureteral stenting was 7 - 180 months (mean = 28.89 ±33.435 years). Seven patients (18.4%) reported with chronic kidney disease, including ESRD in two cases. Recurrent UTI was seen in 28 cases (73.6%), calculus formed over the stents in 20 cases (52.6%), and stent fragmented in 5 patients (13.1%). Majority of patients, (n = 23, 60.5%), were not even aware of the placement of these stents while 8 (21.0%) knew but were reluctant about its removal. In 3 cases (7.8%), the relatives knew about the stent but never informed the patients. The stent had been removed in 2 cases (5.2%), but the other broken fragment was missed. One case (2.6%) each had a misconception about the permanent placement of the stents like cardiac stents and regarding degradation of the stents in situ. CONCLUSION: Forgotten ureteral stents produce clinical features ranging from recurrent UTI to ESRD. This preventable urological complication is primarily due to the unawareness or ignorance of the patients and their relatives regarding the stent. PMID- 26975954 TI - The Effect of Two Weeks Preoperative Finasteride Therapy in Reducing Prostate Vascularity. AB - OBJECTIVE: To determine the effect of two weeks preoperative finasteride therapy in reducing prostate vascularity in terms of mean microvessel density (MVD) and expression of VEGF in prostate urothelium among patients of BPH by comparing with controls. STUDY DESIGN: Randomized controlled trial. PLACE AND DURATION OF STUDY: Shifa International Hospital, Islamabad, from January 2013 to January 2014. METHODOLOGY: A total of 80 patients of Benign Prostatic Hyperplasia (BPH) planned for Trans-Urethral Resection of Prostate (TURP) having prostate size of more than 40 grams on trans-abdominal ultrasonography was randomized into two groups, each group having 40 patients. The finasteride group (Group A) was prescribed oral 5 mg of finasteride daily for 2 weeks before surgery. The control group (Group B) did not receive any agent. After 2 weeks, TURP was performed and prostate samples were sent for histopathological determination of MVD and expression of VEGF. RESULTS: The mean age of patients was 66.21 +/-10.08 years, ranging from 48 to 86 years. The mean prostate gland size was comparable in both groups (55 +/-10.7 vs. 58.1 +/-10.8 grams, p=0.21). Mean MVD in finasteride group (20.25 +/-10.3) was significantly lower as compared to control group (48.9 +/-22.6, p < 0.001). Similarly expression of VEGF was also significantly lower in finasteride group (30%) as compared to control group (65%) [p= 0.0017]. Mean MVD had a significant weak correlation with the size of prostate gland on Pearson correlation test (2 tailed) with r = 0.222. CONCLUSION: Finasteride reduces microvessel density and hence prostate vascularity with only 2-week therapy and the mean MVD is clearly correlated with size of prostate. PMID- 26975955 TI - Scar Pain, Cosmesis and Patient Satisfaction in Laparoscopic and Open Cholecystectomy. AB - OBJECTIVE: To compare patient-satisfaction, scar-pain and cosmesis between laparoscopic and open-cholecystectomy. STUDY DESIGN: Cross-sectional survey. PLACE AND DURATION OF STUDY: Khyber Teaching Hospital, Peshawar, from August 2012 to May 2014. METHODOLOGY: A total of 400 patients, who had undergone open or laparoscopic cholecystectomy in all units of the Surgical Department, were included. Data was collected on questionnaires given and read to the patients along with counselling and information regarding scar-pain using visual analog score, and satisfaction and cosmesis on a 0 - 10 scale, by a medical professional in the patients' native language. This was done postoperatively on patients' follow-up visits at 1 and 4 weeks. RESULTS: Mean scar pain score at 1 and 4 weeks postoperatively was higher for open-cholecystectomy; 4.96 +/-1 and 0.96 +/-1, compared to 2.24 +/-0.6 and 0, respectively for laparoscopic-cholecystectomy (p < 0.001 and < 0.001). Cosmesis was higher for laparoscopic-group; 8.6 +/-1.2 vs. 6.2 +/-1.46 for open-cholecystectomy (p < 0.001). Patient-satisfaction was higher for laparoscopic-cholecystectomy; 9.28 +/-1.5 vs. 8.32 +/-2.3 for open cholecystectomy (p < 0.001). Mean-cosmesis score was higher for laparoscopic cholecystectomy for those younger than 40, females and unmarried. Mean patient satisfaction score was higher for those older than 40 years who had undergone open-cholecystectomy, women who had undergone laparoscopic-cholecystectomy and for unmarried patients who had laparoscopic-cholecystectomy. CONCLUSION: Overall patient-satisfaction and cosmesis scoring was higher for laparoscopic cholecystectomy especially among females, unmarried and younger than 40 years. Patients of 40 years and older had greater satisfaction scoring for open cholecystectomy. Therefore, laparoscopic-cholecystectomy should be favoured in females and unmarried patients and those younger than 40 years. PMID- 26975956 TI - Current Practice: The Bilobed Flap from the Classic Indication to Cover a Small Defect on Face to Covering a Large Defect on the Chest. AB - A variety of flaps are available to cover skin defects after surgery or trauma in the head and neck area. The bilobed flap is a double transposition flap commonly used in reconstruction of small-to-medium skin defects of the face where skin is less mobile. However, larger defects can also be effectively treated with a bilobed flap in certain cases. The classic indication to cover a small defect on the nose and covering a large skin-defect after tumour resection in the jugular notch. After sufficient mobilization, the defects could easily be closed with no wound complications and with very good aesthetic and functional outcome. The bilobed flap, as a local flap, is possible in suitable locations even for larger skin defects. In addition to the simplicity of the procedure, good aesthetic results can be expected. PMID- 26975957 TI - Development of Systemic Lupus Erythematosus Following Interferon-α Therapy for Hepatitis C Infection. AB - Interferon-alpha (IFN-alpha) therapy has been associated with de novo development of systemic lupus erythematosus (SLE). We report a 48-year woman with chronic hepatitis C, who developed low grade fever, joint aches and pains, painful mouth ulcers, shortness of breath, dry cough and pleuritic chest pain after 2 months of completion of treatment with pegylated interferon-alpha. These clinical manifestations and the relevant immunologic investigations were in favour of SLE. She responded well to corticosteroids and hydroxychloroquine treatment. PMID- 26975958 TI - Diabetic Ketoacidosis with Ebstein's Anomaly in an Adult. AB - Ebstein's anomaly is a rare form of congenital malformation of the heart, characterized by apical displacement of the septal and posterior tricuspid valve leaflets, leading to atrialisation of the right ventricle with a variable degree of malformation and displacement of the anterior leaflet. It may not be detected until late in adolescence or adulthood. The clinical manifestations of Ebstein's anomaly vary greatly. We are reporting a case of 35-year male who presented with generalized fatigue, palpitation and effort intolerance. Laboratory investigations confirmed the diagnosis of diabetes ketosis. Transthoracic echocardiography showed severe Ebstein's anomaly with severe tricuspid regurgitation, no residual atrial septal defect, but with severe right ventricular dysfunction. Though only few studies showed the high prevalence of abnormal glucose metabolism in young adult patients with complex congenital heart disease, but Epstein's anomaly with diabetes ketosis was nowhere mentioned. PMID- 26975959 TI - Primary Hepatic Carcinoid Tumor with Poor Outcome. AB - Primary Hepatic Carcinoid Tumor (PHCT) represents an extremely rare clinical entity with only a few cases reported to date. These tumors are rarely associated with metastasis and surgical resection is usually curative. Herein, we report two cases of PHCT associated with poor outcomes due to late diagnosis. Both cases presented late with non-specific symptoms. One patient presented after a 2-week history of symptoms and the second case had a longstanding two years symptomatic interval during which he remained undiagnosed and not properly worked up. Both these cases were diagnosed with hepatic carcinoid tumor, which originates from neuroendocrine cells. Case 1 opted for palliative care and expired in one month’s time. Surgical resection was advised to the second case, but he left against medical advice. PMID- 26975960 TI - Effect of Iron Deficiency on the Phenotype of β-Thalassaemia Trait. AB - The objective of this study was to determine the effect of iron deficiency on Hb A2 level in beta-thalassaemia trait and to determine the frequency of individuals with beta-thalassaemia trait who could be missed due to concomitant iron deficiency. A total of 120 patients were studied, out of which 23 were iron deficient (serum ferritin < 20 ng/ml). Mean Hb-A2 in the iron deficient individuals was 4.1 +/- 0.47% as compared to 5.1 +/- 0.58% in the remaining 97 individuals without iron deficiency (p < 0.001). In the 120 individuals with beta thalassaemia trait, mean Hb-A2 was 5.8% with range 3 - 6.8% and confidence interval was 95%. In 2 individuals with beta-thalassaemia trait, Iron deficiency was observed and showed Hb-A2 less than 3.5%. These could have been missed while screening by Hb-A2 estimation alone. Co-existence of Iron deficiency and beta thalassaemia trait may mask the diagnosis of beta thalassaemia trait and such individuals can be missed during screening by Hb-A2 estimation alone. PMID- 26975961 TI - Effectiveness of Case-Based Learning During Small Groups Sessions at Army Medical College. AB - A pragmatic and sequential mixed method study was conducted at Army Medical College, from October to December 2014 to determine medical students' perceptions regarding effectiveness of small groups during the CBL(case-based learning) sessions. Tutorial Group Effectiveness Instrument (TGEI) was used after written and informed consent. Free text comments about CBL were invited from the respondents and common ones, and were tabulated. The mean scores were calculated and compared among different subgroups of respondents using appropriate independent sample t-test. Content analysis of qualitative segment was done. Ap value of less than 0.05 was taken as statistically significant. The analysis of qualitative and quantitative variables was integrated in the final interpretation phase to draw conclusion. The average age of the participants was 19.33 +/-0.657 years. The difference in scores was statistically insignificant for cognitive (p = 0.537), motivational (p = 0.868), and demotivational (p = 0.125) effectiveness between males and females. Insignificant difference was also observed for qualification of the overall group productivity among male and female students (p = 0.162), and exposed and non-exposed groups (p = 0.272). The perceptions of overwhelming number of participants were in favour of small group discussion as a component of CBL. PMID- 26975962 TI - Newborn Observation Track and Trigger (NOTT) Chart. AB - Use of early warning system scores and track-and-trigger charts is widespread in adult and paediatric hospitalized patients; but its use in neonatal group is not well recognized. The authors aimed to develop and implement neonatal observation track-and-trigger chart for use in babies on postnatal wards and to assess its efficacy in identifying neonates in need of urgent medical assessment and intervention. Core group developed Newborn Observation Track and Trigger (NOTT) chart for "At-Risk" and "At-High-Risk" Infants. A decision tree was devised based on 'low', 'medium' and 'high' scores. Sensitivity and specificity of NOTT chart's 'medium' and 'high' score was 96% and 90%, respectively. Positive and negative predictive value was 43% and 100%, respectively. NOTT chart is a valuable tool for assessment of neonates on postnatal wards. A prospective study, using large number of participants, would be beneficial to further corroborate this useful tool. PMID- 26975963 TI - Dengue Infection. What Criteria Do we Use? PMID- 26975964 TI - Occupational Health of Self-Employed Skilled Labourers and Daily-Wage Workers in Pakistan. PMID- 26975965 TI - Peeling the Persistent Pupillary Membrane. PMID- 26975967 TI - High glucose concentration-induced expression of pentraxin-3 in a rat model of continuous peritoneal dialysis. AB - BACKGROUND: Continuous exposure to peritoneal dialysis fluids (PDFs) is associated with pathological responses such as persistent micro-inflammation, which leads to ultrafiltration failure. Pentraxin-3 (PTX3), a multifunctional soluble pattern recognition receptor, is produced at sites of inflammation by a wide range of cell types. This study investigates the in vivo expression of PTX3 in the peritoneal membrane of a rat continuous peritoneal dialysis (PD) model, as well as the effect of high glucose on the in vitro expression of PTX3. METHODS: The expression of PTX3 was analyzed using RT-PCR, real-time PCR, immunohistochemistry and western blotting in a PD rat model receiving saline or conventional PDF containing 3.86% glucose for 8 weeks. The effects of high glucose on the expression of PTX3 were examined in cultured rat peritoneal mesothelial cells (RPMCs), mouse macrophage-like cells, and mouse fibroblasts. RESULTS: In a rat model of PD, eight-week instillation of the conventional PDF produced increased submesothelial thickening, followed by substantially enhanced PTX3 protein levels in the submesothelial layer of peritoneal membrane. PTX3 was detected in peritoneal mesothelial cells, macrophages and fibroblasts in the thickened submesothelial area. Glucose was found to induce PTX3 protein expression in RPMCs as well as macrophage-like cells and fibroblasts. CONCLUSION: Continuous exposure to conventional PDF induces PTX3 expression in the peritoneal membrane of rats. High glucose may be involved in the mechanism of PDF-induced local micro-inflammation in the peritoneum. PMID- 26975968 TI - Antibodies to Phosphatidylserine/Prothrombin Complex in Antiphospholipid Syndrome: Analytical and Clinical Perspectives. AB - Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis and/or pregnancy-related morbidity accompanied by persistently positive antiphospholipid antibodies (aPL). Current laboratory criteria for APS classification recommend testing for lupus anticoagulant as well as IgG and IgM anticardiolipin, and beta-2 glycoprotein I (anti-beta2GPI) antibodies. However, there appears to be a subset of patients with classical APS manifestations who test negative for the recommended criteria aPL tests. While acknowledging that such patients may have clinical features that are not of an autoimmune etiology, experts also speculate that these "seronegative" patients may test negative for relevant autoantibodies as a result of a lack of harmonization and/or standardization. Alternatively, they may have aPL that target other antigens involved in the pathogenesis of APS. In the latter, autoantibodies that recognize a phosphatidylserine/prothrombin (PS/PT) complex have been reported to be associated with APS and may have diagnostic relevance. This review highlights analytical and clinical attributes associated with PS/PT antibodies, taking into consideration the performance characteristics of criteria aPL tests in APS with specific recommendations for harmonization and standardization efforts. PMID- 26975966 TI - Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist. AB - The inherent disadvantages of using granulocyte colony-stimulating factor (G-CSF) for hematopoietic stem cell (HSC) mobilization have driven efforts to identify alternate strategies based on single doses of small molecules. Here, we show targeting alpha9beta1/alpha4beta1 integrins with a single dose of a small molecule antagonist (BOP (N-(benzenesulfonyl)-L-prolyl-L-O-(1 pyrrolidinylcarbonyl)tyrosine)) rapidly mobilizes long-term multi-lineage reconstituting HSC. Synergistic engraftment augmentation is observed when BOP is co-administered with AMD3100. Impressively, HSC in equal volumes of peripheral blood (PB) mobilized with this combination effectively out-competes PB mobilized with G-CSF. The enhanced mobilization observed using BOP and AMD3100 is recapitulated in a humanized NODSCIDIL2Rgamma(-/-) model, demonstrated by a significant increase in PB CD34(+) cells. Using a related fluorescent analogue of BOP (R-BC154), we show that this class of antagonists preferentially bind human and mouse HSC and progenitors via endogenously primed/activated alpha9beta1/alpha4beta1 within the endosteal niche. These results support using dual alpha9beta1/alpha4beta1 inhibitors as effective, rapid and transient mobilization agents with promising clinical applications. PMID- 26975969 TI - Copeptin in Heart Failure. AB - Heart failure (HF) is one of the most common causes of hospitalization and mortality in the modern Western world and an increasing proportion of the population will be affected by HF in the future. Although HF management has improved quality of life and prognosis, mortality remains very high despite therapeutic options. Medical management consists of a neurohormonal blockade of an overly activated neurohormonal axis. No single marker has been able to predict or monitor HF with respect to disease progression, hospitalization, or mortality. New methods for diagnosis, monitoring therapy, and prognosis are warranted. Copeptin, a precursor of pre-provasopressin, is a new biomarker in HF with promising potential. Copeptin has been found to be elevated in both acute and chronic HF and is associated with prognosis. Copeptin, in combination with other biomarkers, could be a useful marker in the monitoring of disease severity and as a predictor of prognosis and survival in HF. PMID- 26975970 TI - Immunosensors in Clinical Laboratory Diagnostics. AB - The application of simple, cost-effective, rapid, and accurate diagnostic technologies for detection and identification of cardiac and cancer biomarkers has been a central point in the clinical area. Biosensors have been recognized as efficient alternatives for the diagnostics of various diseases due to their specificity and potential for application on real samples. The role of nanotechnology in the construction of immunological biosensors, that is, immunosensors, has contributed to the improvement of sensitivity, since they are based in the affinity between antibody and antigen. Other analytes than biomarkers such as hormones, pathogenic bacteria, and virus have also been detected by immunosensors for clinical point-of-care applications. In this chapter, we first introduced the various types of immunosensors and discussed their applications in clinical diagnostics over the recent 6 years, mainly as point-of-care technologies for the determination of cardiac and cancer biomarkers, hormones, pathogenic bacteria, and virus. The future perspectives of these devices in the field of clinical diagnostics are also evaluated. PMID- 26975971 TI - Cancer Stem Cell Biomarker Discovery Using Antibody Array Technology. AB - Cancer is a complex disease involving hundreds of pathways and numerous levels of disease progression. In addition, there is a growing body of evidence that the origins and growth rates of specific types of cancer may involve "cancer stem cells," which are defined as "cells within a tumor that possess the capacity to self-renew and to cause the development of heterogeneous lineages of cancer cells that comprise the tumor.(1)" Many types of cancer are now thought to harbor cancer stem cells. These cells themselves are thought to be unique in comparison to other cells types present within the tumor and to exhibit characteristics that allow for the promotion of tumorigenesis and in some cases metastasis. In addition, it is speculated that each type of cancer stem cell exhibits a unique set of molecular and biochemical markers. These markers, alone or in combination, may act as a signature for defining not only the type of cancer but also the progressive state. These biomarkers may also double as signaling entities which act autonomously or upon neighboring cancer stem cells or other cells within the local microenvironment to promote tumorigenesis. This review describes the heterogeneic properties of cancer stem cells and outlines the identification and application of biomarkers and signaling molecules defining these cells as they relate to different forms of cancer. Other examples of biomarkers and signaling molecules expressed by neighboring cells in the local tumor microenvironment are also discussed. In addition, biochemical signatures for cancer stem cell autocrine/paracrine signaling, local site recruitment, tumorigenic potential, and conversion to a stem-like phenotype are described. PMID- 26975972 TI - Biochemistry of Statins. AB - Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Elevated blood lipids may be a major risk factor for CVD. Due to consistent and robust association of higher low-density lipoprotein (LDL) cholesterol levels with CVD across experimental and epidemiologic studies, therapeutic strategies to decrease risk have focused on LDL-cholesterol reduction as the primary goal. Current medication options for lipid-lowering therapy include statins, bile acid sequestrants, a cholesterol-absorption inhibitor, fibrates, nicotinic acid, and omega-3 fatty acids, which all have various mechanisms of action and pharmacokinetic properties. The most widely prescribed lipid-lowering agents are the HMG-CoA reductase inhibitors, or statins. Since their introduction in the 1980s, statins have emerged as the one of the best selling medication classes to date, with numerous trials demonstrating powerful efficacy in preventing cardiovascular outcomes (Kapur and Musunuru, 2008 [1]). The statins are commonly used in the treatment of hypercholesterolemia and mixed hyperlipidemia. This chapter focuses on the biochemistry of statins including their structures, pharmacokinetics, and mechanism of actions as well as the potential adverse reactions linked to their clinical uses. PMID- 26975973 TI - The Importance of Magnesium in the Human Body: A Systematic Literature Review. AB - Magnesium, the second and fourth most abundant cation in the intracellular compartment and whole body, respectively, is of great physiologic importance. Magnesium exists as bound and free ionized forms depending on temperature, pH, ionic strength, and competing ions. Free magnesium participates in many biochemical processes and is most commonly measured by ion-selective electrode. This analytical approach is problematic because complete selectivity is not possible due to competition with other ions, i.e., calcium, and pH interference. Unfortunately, many studies have focused on measurement of total magnesium rather than its free bioactive form making it difficult to correlate to disease states. This systematic literature review presents current analytical challenges in obtaining accurate and reproducible test results for magnesium. PMID- 26975974 TI - Inborn Errors of Metabolism. AB - Inborn errors of metabolism are single gene disorders resulting from the defects in the biochemical pathways of the body. Although these disorders are individually rare, collectively they account for a significant portion of childhood disability and deaths. Most of the disorders are inherited as autosomal recessive whereas autosomal dominant and X-linked disorders are also present. The clinical signs and symptoms arise from the accumulation of the toxic substrate, deficiency of the product, or both. Depending on the residual activity of the deficient enzyme, the initiation of the clinical picture may vary starting from the newborn period up until adulthood. Hundreds of disorders have been described until now and there has been a considerable clinical overlap between certain inborn errors. Resulting from this fact, the definite diagnosis of inborn errors depends on enzyme assays or genetic tests. Especially during the recent years, significant achievements have been gained for the biochemical and genetic diagnosis of inborn errors. Techniques such as tandem mass spectrometry and gas chromatography for biochemical diagnosis and microarrays and next-generation sequencing for the genetic diagnosis have enabled rapid and accurate diagnosis. The achievements for the diagnosis also enabled newborn screening and prenatal diagnosis. Parallel to the development the diagnostic methods; significant progress has also been obtained for the treatment. Treatment approaches such as special diets, enzyme replacement therapy, substrate inhibition, and organ transplantation have been widely used. It is obvious that by the help of the preclinical and clinical research carried out for inborn errors, better diagnostic methods and better treatment approaches will high likely be available. PMID- 26975975 TI - Preface. PMID- 26975976 TI - Computational analysis of the MCoTI-II plant defence knottin reveals a novel intermediate conformation that facilitates trypsin binding. AB - MCoTI-I and II are plant defence proteins, potent trypsin inhibitors from the bitter gourd Momordica cochinchinensis. They are members of the Knottin Family, which display exceptional stability due to unique topology comprising three interlocked disulfide bridges. Knottins show promise as scaffolds for new drug development. A crystal structure of trypsin-bound MCoTI-II suggested that loop 1, which engages the trypsin active site, would show decreased dynamics in the bound state, an inference at odds with an NMR analysis of MCoTI-I, which revealed increased dynamics of loop 1 in the presence of trypsin. To investigate this question, we performed unrestrained MD simulations of trypsin-bound and free MCoTI-II. This analysis found that loop 1 of MCoTI-II is not more dynamic in the trypsin-bound state than in the free state. However, it revealed an intermediate conformation, transitional between the free and bound MCoTI-II states. The data suggest that MCoTI-II binding involves a process in which initial interaction with trypsin induces transitions between the free and intermediate conformations, and fluctuations between these states account for the increase in dynamics of loop 1 observed for trypsin-bound MCoTI-I. The MD analysis thus revealed new aspects of the inhibitors' dynamics that may be of utility in drug design. PMID- 26975977 TI - Effective PEGylation of gold nanorods. AB - Standard procedures to coat gold nanorods (AuNR) with poly(ethylene glycol) (PEG) based ligands are not reliable and high PEG-grafting densities are not achieved. In this work, the ligand exchange of AuNR with PEGMUA, a tailored PEG-ligand bearing a C10 alkylene spacer, is studied. PEGMUA provides AuNR with very high stability against oxidative etching with cyanide. This etching reaction is utilized to study the ligand exchange in detail. Ligand exchange is faster, less ligand consuming and more reproducible with assisting chloroform extraction. Compared to PEG ligands commonly used, PEGMUA provides much higher colloidal and chemical stability. Further analyses based on NMR-, IR- and UV/Vis-spectroscopy reveal that significantly higher PEG-grafting densities, up to ~3 nm(-2), are obtained with PEGMUA. This demonstrates how the molecular structure of the PEG ligand can be used to dramatically improve the ligand exchange and to synthesize PEGylated AuNR with high chemical and colloidal stability and high PEG grafting densities. Such AuNR are especially interesting for applications in nanomedicine. PMID- 26975978 TI - Cardiac platypnea-orthodeoxia syndrome: A "mysterious" cause of hypoxemia. PMID- 26975979 TI - Application of EQ-5D-5L questionnaire in patients suffering from urinary incontinence. AB - BACKGROUND: Urinary incontinence is associated with reduced quality of life and given the high prevalence of people with this condition, it could be useful to know the impact of having urinary incontinence on physical, psychological and social aspects. The Spanish value set of EQ-5D was used to assign single scores to the EQ-5D-5L health states. EQ-5D-5L is a health-related quality of life questionnaire, which allows assessing health status. The aim of this study was to provide normative values of EQ-5D-5L in a population sample with urinary incontinence. STUDY DESIGN: Cross-sectional study. METHODS: A total of 965 people with urinary incontinence (297 men and 668 women) were included in this study. EQ 5D-5L index, VAS and health status are showed in the current study considering gender, age group, region, marital status, smoking status, net monthly incomes of household and educational level. RESULTS: Higher prevalence was observed in women (69.22%) compared with men (30.78%). Mean (SD) EQ-5D-5L utility index and VAS score were 0.58 (0.40) and 53.91 (22.16), respectively, for overall population. The 16.1% (155 people) reported perfect health status (11111). The utility equivalent to set values 55555 was not reported by anyone. CONCLUSION: This study provides normative values of EQ-5D-5L in a Spanish population sample with urinary incontinence. PMID- 26975980 TI - Astrocyte response to St. Louis encephalitis virus. AB - St. Louis encephalitis virus (SLEV), a flavivirus transmitted to humans by Culex mosquitoes, causes clinical symptoms ranging from acute febrile disorder to encephalitis. To reach the central nervous system (CNS) from circulating blood, the pathogen must cross the blood-brain barrier formed by endothelial cells and astrocytes. Because astrocytes play an essential role in CNS homeostasis, in this study these cells were infected with SLEV and investigated for astrogliosis, major histocompatibility complex (MHC)-I-dependent immune response, and apoptosis by caspase-3 activation. Cultures of Vero cells were used as a positive control for the viral infection. Cytopathic effects were observed in both types of cell cultures, and the cytotoxicity levels of the two were compared. Astrocytes infected with a dilution of 1E-01 (7.7E+08 PFU/mL) had a reduced mortality rate of more than 50% compared to the Vero cells. In addition, the astrocytes responded to the flavivirus infection with increased MHC-I expression and astrogliosis, characterized by intense glial fibrillary acidic protein expression and an increase in the number and length of cytoplasmic processes. When the astrocytes were exposed to higher viral concentrations, a proportional increase in caspase-3 expression was observed, as well as nuclear membrane destruction. SLEV immunostaining revealed a perinuclear location of the virus during the replication process. Together, these results suggest that mechanisms other than SLEV infection in astrocytes must be associated with the development of the neuroinvasive form of the disease. PMID- 26975981 TI - Objectively Measured Physical Activity and Changes in Life-Space Mobility Among Older People. AB - BACKGROUND: Our aim was to study the relationship between objectively measured physical activity and subsequent changes in life-space mobility over 2 years among older people. Life-space mobility refers to the area a person moves through in daily life, taking into account frequency, and need of assistance. Life-space mobility and physical activity correlate, but whether different intensities of objectively assessed physical activity predicts decline in life-space mobility is not known. METHODS: Prospective cohort study of the "Life-space Mobility in Old Age" (LISPE) project accelerometer substudy. Participants were community-dwelling older people aged 75-90 (n = 164). Life-space mobility was measured with the Life Space Assessment at baseline face-to-face home interview and telephone follow-up interviews 1 and 2 years after baseline. Physical activity (step count and time spent in moderate activity, low activity, and sedentary behavior) was measured by a tri-axial accelerometer (Hookie "AM20 Activity Meter") for 7 days at baseline. Generalized estimating equations (GEE models) were used to compare changes in life-space mobility between participants categorized according to the baseline physical activity measures. RESULTS: Median age of the participants was 79.5 (IQR 6.7) and 64% were women. Over the 2 years, life-space mobility declined significantly among those with lower step counts and less time spent in moderate activity measured at baseline. Time spent in low activity and sedentary behavior did not predict changes in life-space mobility. CONCLUSIONS: In old age, more time spent walking outdoors and accumulation of moderate-intensity physical activity may help to maintain higher life-space mobility, a correlate of good quality of life. PMID- 26975985 TI - Letter Regarding Article, "Efficacy of Flow-Diverting Devices for Cerebral Aneurysms: A Systematic Review and Meta-analysis". PMID- 26975984 TI - Five-Level Posterior Total En Bloc Spondylectomy of Severe Myelomeningocele Kyphosis. AB - BACKGROUND: In this case report we discuss a case of thoracolumbar kyphectomy associated with myelomeningocoele. To our knowledge, no such total spondylectomy and fascinating alignment, with no skin defect on the outcome, has been reported in the literature. CASE DESCRIPTION: A 15-year-old paraplegic girl, suffering from severe kyphosis, was not able to sit in a wheelchair. Her lumbar myelomeningocele was repaired perinatally. Surgery reduced the 137-degree angle deformity to a 30-degree kyphosis. At 12-month follow-up, the fusion consolidated as shown on the computed tomography scans and the instruments were good position with a 5-degree correction loss. CONCLUSIONS: In most cases of kyphosis, anterior wedging occurs in the vertebral body where the apex of the deformity is located. In our patient kyphosis had a round curve with no definite apex that could be marked out. These deformities demand special attention regarding the surgical techniques and postoperative course. PMID- 26975982 TI - Metabolites Associated With Circulating Interleukin-6 in Older Adults. AB - Background: Circulating levels of the pro-inflammatory cytokine interleukin-6 (IL 6) levels are elevated in older adults, but mechanisms are unclear. In the current study, we used an untargeted metabolomic approach to develop an improved understanding about mechanisms related to circulating IL-6 in older adults. Methods: Serum IL-6 values were log-transformed to normalize its distribution. Multivariable-adjusted linear regression was used to examine the association between 324 serum metabolites with log IL-6. Backward elimination linear regression was used to develop a metabolite predictor set representative of log IL-6. Results: Thirty-six metabolites were significantly associated (p < 0.05 and q < 0.30) with log IL-6 in 73 older adults (average age, 78 years). Metabolites related to tryptophan metabolism (kynurenine, 3-indoxyl sulfate, indoleacetate, indolepropionate, C-glycosyltryptophan), infectious burden (C-glycosyltryptophan, N6-carbamoylthreonyladenosine, 1-methylurate, N-formylmethionine, N1 methyladenosine, 3-indoxyl sulfate, bilirubin (E,E), indoleacetate, gamma-CEHC, N acetylneuraminate), aryl hydrocarbon receptor activation and cytochrome P450 (CYP) 1A expression (kynurenine, 3-indoxyl sulfate, indoleacetate, N6 carbamoylthreonyladenosine, bilirubin, 1-methylurate) were positively associated, whereas metabolites related to CYP-mediated omega-oxidation (adipate, 8 hydroxyoctanoate, azelate, sebacate, undecanedioate, gamma-CEHC), and peroxisome proliferator activated receptor-alpha (PPAR-alpha) activation (13 + 9-HODE, bilirubin, 5-oxoproline, cholesterol, glycerate, uridine) were negatively associated with log IL-6. The use of backward elimination regression identified tyrosine, cysteine, uridine, bilirubin, N-formylmethionine, indoleacetate, and 3 indoxyl sulfate to collectively explain 51% of the variance inherent in log IL-6. Conclusions: These data suggest roles for tryptophan metabolism, infectious burden, activation of host defense, and detoxification through CYP1A-mediated pathways in mechanisms related to elevated inflammation, whereas CYP-mediated omega-oxidation and PPAR-alpha activation may be related to decreased inflammation in older adults. PMID- 26975987 TI - Prevention: from molecular mechanisms to novel risk factors and patient management. PMID- 26975986 TI - Predictors of Surgical Outcome in Acute Spinal Cord Injury Patients with Cervical Ossification of the Posterior Longitudinal Ligament. AB - OBJECTIVE: A retrospective study was conducted to clarify the predictors of the operation results for ossification of the posterior longitudinal ligament (OPLL) patients with acute spinal cord injury (SCI). Detailed analyses of surgical outcomes of OPLL patients with SCI have been rare because most surveys have aimed to investigate OPLL or SCI, but not both. PATIENTS AND METHODS: A total of 36 patients who underwent operation for OPLL between January 2011 and December 2011 were included in this analysis. We investigated the patients' characteristics and surgical approaches and compared the radiographic characteristics of OPLL patients with SCI. RESULTS: The mean modified Japanese Orthopaedic Association (mJOA) score improved dramatically after operation (P = 0.006). The mean preoperative mJOA score was greater in patients with Nurick 3 than in patients with Nurick 4 and 5 (P = 0.041). The preoperative mJOA score was dramatically lower in patients caused by traffic accident and in patients with segmental OPLL lesion (P < 0.05). The postoperative mJOA score was dramatically lower in patients with continuous OPLL lesion than in the segmental OPLL lesion (P = 0.028). Changing in mJOA score was significantly different between the patients with high-intensity zone (HIZ) and without HIZ on magnetic resonance imaging. CONCLUSIONS: HIZ on magnetic resonance imaging was significantly related to the surgical outcomes, which should be highlighted in the preoperative communication with patients. Patients with lower Nirick grade and segmental OPLL would show better symptom before the operation. In addition, SCI caused by slipping or falling showed better symptoms before the operation. Patients with segmental OPLL should show better resolution of symptoms after the operation. PMID- 26975983 TI - Age-Related Change in Mobility: Perspectives From Life Course Epidemiology and Geroscience. AB - Mobility is the most studied and most relevant physical ability affecting quality of life with strong prognostic value for disability and survival. Natural selection has built the "engine" of mobility with great robustness, redundancy, and functional reserve. Efficient patterns of mobility can be acquired during development even by children affected by severe impairments. Analogously, age associated impairments in mobility-related physiological systems are compensated and overt limitations of mobility only occur when the severity can no longer be compensated. Mobility loss in older persons usually results from multiple impairments in the central nervous system, muscles, joints, and energetic and sensory physiological systems. Early preclinical changes in these physiological systems that precede mobility loss have been poorly studied. Peak performance, rate of decline, compensatory behaviors, or subclinical deterioration of physiological resources may cumulatively influence both timing of mobility loss and chances of recovery, but their role as risk factors has not been adequately characterized. Understanding the natural history of these early changes and intervening on them would likely be the most effective strategy to reduce the burden of disability in the population. For example, young women with low bone peak mass could be counseled to start strength resistance exercise to reduce their high risk of developing osteoporosis and fracture later in life. Expanding this approach to other physiological domains requires collecting and interpreting data from life course epidemiological studies, establishing normative measures of mobility, physical function, and physical activity, and connecting them with life course trajectories of the mobility-relevant physiological domains. PMID- 26975988 TI - CardioPulse: Anticoagulants reduce risk of death in atrialfibrillation patients by 38%. PMID- 26975989 TI - Pancreatic cancer cell-derived IGFBP-3 contributes to muscle wasting. AB - BACKGROUND: Progressive loss of skeletal muscle, termed muscle wasting, is a hallmark of cancer cachexia and contributes to weakness, reduced quality of life, as well as poor response to therapy. Previous studies have indicated that systemic host inflammatory response regarding tumor development results in muscle wasting. However, how tumor directly regulates muscle wasting via tumor-derived secreted proteins is still largely unknown. METHODS: In this study, we performed bioinformatics analysis in two datasets of pancreatic ductal adenocarcinoma, which causes cancer cachexia and muscle wasting with the highest prevalence, and uncovered that IGFBP3, which encodes IGF-binding protein-3 (IGFBP-3), is dramatically up-regulated in pancreatic tumor samples. We also verified the wasting effect of IGFBP-3 on C2C12 muscle cells with biochemical and genetic assays. RESULTS: IGFBP-3 potently leads to impaired myogenesis and enhanced muscle protein degradation, the major features of muscle wasting, via IGF signaling inhibition. Moreover, conditioned medium from Capan-1 pancreatic cancer cells, which contains abundant IGFBP-3, significantly induces muscle cell wasting. This wasting effect is potently alleviated by IGFBP3 knockdown in Capan 1 cells or IGFBP-3 antibody neutralization. Strikingly, compared to muscle cells, IGF signaling and proliferation rate of Capan-1 cells were rarely affected by IGFBP-3 treatment. CONCLUSIONS: Our results demonstrated that pancreatic cancer cells induce muscle wasting via IGFBP-3 production. PMID- 26975990 TI - Bacterial Dose-Dependent Role of G Protein-Coupled Receptor Kinase 5 in Escherichia coli-Induced Pneumonia. AB - G protein-coupled receptor kinase 5 (GRK5) is a serine/threonine kinase previously shown to mediate polymicrobial sepsis-induced inflammation. The goal of the present study was to examine the role of GRK5 in monomicrobial pulmonary infection by using an intratracheal Escherichia coli infection model of pneumonia. We used sublethal and lethal doses of E. coli to examine the mechanistic differences between low-grade and high-grade inflammation induced by E. coli infection. With a sublethal dose of E. coli, GRK5 knockout (KO) mice exhibited higher plasma CXCL1/KC levels and enhanced lung neutrophil recruitment early after infection, and lower bacterial loads, than wild-type (WT) mice. The inflammatory response was also diminished, and resolution of inflammation advanced, in the lungs of GRK5 KO mice. In contrast to the reduced bacterial loads in GRK5 KO mice following a sublethal dose, at a lethal dose of E. coli, the bacterial burdens remained high in GRK5 KO mice relative to those in WT mice. This occurred in spite of enhanced plasma CXCL1 levels as well as neutrophil recruitment in the KO mice. But the recruited neutrophils (following high-dose infection) exhibited decreased CD11b expression and reduced reactive oxygen species production, suggesting decreased neutrophil activation or increased neutrophil exhaustion in the GRK5 KO mice. In agreement with the increased bacterial burden, KO mice showed poorer survival than WT mice following E. coli infection at a lethal dose. Overall, our data suggest that GRK5 negatively regulates CXCL1/KC levels during bacterial pneumonia but that the role of GRK5 in the clinical outcome in this model is dependent on the bacterial dose. PMID- 26975991 TI - The Cryptosporidium parvum C-Type Lectin CpClec Mediates Infection of Intestinal Epithelial Cells via Interactions with Sulfated Proteoglycans. AB - The apicomplexan parasite Cryptosporidium causes significant diarrheal disease worldwide. Effective anticryptosporidial agents are lacking, in part because the molecular mechanisms underlying Cryptosporidium-host cell interactions are poorly understood. Previously, we identified and characterized a novel Cryptosporidium parvum C-type lectin domain-containing mucin-like glycoprotein, CpClec. In this study, we evaluated the mechanisms underlying interactions of CpClec with intestinal epithelial cells by using an Fc-tagged recombinant protein. CpClec-Fc displayed Ca(2+)-dependent, saturable binding to HCT-8 and Caco-2 cells and competitively inhibited C. parvum attachment to and infection of HCT-8 cells. Binding of CpClec-Fc was specifically inhibited by sulfated glycosaminoglycans, particularly heparin and heparan sulfate. Binding was reduced after the removal of heparan sulfate and following the inhibition of glycosaminoglycan synthesis or sulfation in HCT-8 cells. Like CpClec-Fc binding, C. parvum attachment to and infection of HCT-8 cells were inhibited by glycosaminoglycans and were reduced after heparan sulfate removal or inhibition of glycosaminoglycan synthesis or sulfation. Lastly, CpClec-Fc binding and C. parvum sporozoite attachment were significantly decreased in CHO cell mutants defective in glycosaminoglycan synthesis. Together, these results indicate that CpClec is a novel C-type lectin that mediates C. parvum attachment and infection via Ca(2+)-dependent binding to sulfated proteoglycans on intestinal epithelial cells. PMID- 26975992 TI - Persisting Rickettsia typhi Causes Fatal Central Nervous System Inflammation. AB - Rickettsioses are emerging febrile diseases caused by obligate intracellular bacteria belonging to the family Rickettsiaceae. Rickettsia typhi belongs to the typhus group (TG) of this family and is the causative agent of endemic typhus, a disease that can be fatal. In the present study, we analyzed the course of R. typhi infection in C57BL/6 RAG1(-/-) mice. Although these mice lack adaptive immunity, they developed only mild and temporary symptoms of disease and survived R. typhi infection for a long period of time. To our surprise, 3 to 4 months after infection, C57BL/6 RAG1(-/-) mice suddenly developed lethal neurological disorders. Analysis of these mice at the time of death revealed high bacterial loads, predominantly in the brain. This was accompanied by a massive expansion of microglia and by neuronal cell death. Furthermore, high numbers of infiltrating CD11b(+) macrophages were detectable in the brain. In contrast to the microglia, these cells harbored R. typhi and showed an inflammatory phenotype, as indicated by inducible nitric oxide synthase (iNOS) expression, which was not observed in the periphery. Having shown that R. typhi persists in immunocompromised mice, we finally asked whether the bacteria are also able to persist in resistant C57BL/6 and BALB/c wild-type mice. Indeed, R. typhi could be recultivated from lung, spleen, and brain tissues from both strains even up to 1 year after infection. This is the first report demonstrating persistence and reappearance of R. typhi, mainly restricted to the central nervous system in immunocompromised mice. PMID- 26975993 TI - Binding of CFA/I Pili of Enterotoxigenic Escherichia coli to Asialo-GM1 Is Mediated by the Minor Pilin CfaE. AB - CFA/I pili are representatives of a large family of related pili that mediate the adherence of enterotoxigenic Escherichia coli to intestinal epithelial cells. They are assembled via the alternate chaperone-usher pathway and consist of two subunits, CfaB, which makes up the pilus shaft and a single pilus tip-associated subunit, CfaE. The current model of pilus-mediated adherence proposes that CFA/I has two distinct binding activities; the CfaE subunit is responsible for binding to receptors of unknown structure on erythrocyte and intestinal epithelial cell surfaces, while CfaB binds to various glycosphingolipids, including asialo-GM1. In this report, we present two independent lines of evidence that, contrary to the existing model, CfaB does not bind to asialo-GM1 independently of CfaE. Neither purified CfaB subunits nor CfaB assembled into pili bind to asialo-GM1. Instead, we demonstrate that binding activity toward asialo-GM1 resides in CfaE and this is essential for pilus binding to Caco-2 intestinal epithelial cells. We conclude that the binding activities of CFA/I pili for asialo-GM1, erythrocytes, and intestinal cells are inseparable, require the same amino acid residues in CfaE, and therefore depend on the same or very similar binding mechanisms. PMID- 26975994 TI - Trypanosoma cruzi Differentiates and Multiplies within Chimeric Parasitophorous Vacuoles in Macrophages Coinfected with Leishmania amazonensis. AB - The trypanosomatids Leishmania amazonensis and Trypanosoma cruzi are excellent models for the study of the cell biology of intracellular protozoan infections. After their uptake by mammalian cells, the parasitic protozoan flagellates L. amazonensis and T. cruzi lodge within acidified parasitophorous vacuoles (PVs). However, whereas L. amazonensis develops in spacious, phagolysosome-like PVs that may enclose numerous parasites, T. cruzi is transiently hosted within smaller vacuoles from which it soon escapes to the host cell cytosol. To investigate if parasite-specific vacuoles are required for the survival and differentiation of T. cruzi, we constructed chimeric vacuoles by infection of L. amazonensis amastigote-infected macrophages with T. cruzi epimastigotes (EPIs) or metacyclic trypomastigotes (MTs). These chimeric vacuoles, easily observed by microscopy, allowed the entry and fate of T. cruzi in L. amazonensis PVs to be dynamically recorded by multidimensional imaging of coinfected cells. We found that although T. cruzi EPIs remained motile and conserved their morphology in chimeric vacuoles, T. cruzi MTs differentiated into amastigote-like forms capable of multiplying. These results demonstrate that the large adaptive vacuoles of L. amazonensis are permissive to T. cruzi survival and differentiation and that noninfective EPIs are spared from destruction within the chimeric PVs. We conclude that T. cruzi differentiation can take place in Leishmania-containing vacuoles, suggesting this occurs prior to their escape into the host cell cytosol. PMID- 26975995 TI - Multiscale Model of Mycobacterium tuberculosis Infection Maps Metabolite and Gene Perturbations to Granuloma Sterilization Predictions. AB - Granulomas are a hallmark of tuberculosis. Inside granulomas, the pathogen Mycobacterium tuberculosis may enter a metabolically inactive state that is less susceptible to antibiotics. Understanding M. tuberculosis metabolism within granulomas could contribute to reducing the lengthy treatment required for tuberculosis and provide additional targets for new drugs. Two key adaptations of M. tuberculosis are a nonreplicating phenotype and accumulation of lipid inclusions in response to hypoxic conditions. To explore how these adaptations influence granuloma-scale outcomes in vivo, we present a multiscale in silico model of granuloma formation in tuberculosis. The model comprises host immunity, M. tuberculosis metabolism, M. tuberculosis growth adaptation to hypoxia, and nutrient diffusion. We calibrated our model to in vivo data from nonhuman primates and rabbits and apply the model to predict M. tuberculosis population dynamics and heterogeneity within granulomas. We found that bacterial populations are highly dynamic throughout infection in response to changing oxygen levels and host immunity pressures. Our results indicate that a nonreplicating phenotype, but not lipid inclusion formation, is important for long-term M. tuberculosis survival in granulomas. We used virtual M. tuberculosis knockouts to predict the impact of both metabolic enzyme inhibitors and metabolic pathways exploited to overcome inhibition. Results indicate that knockouts whose growth rates are below ~66% of the wild-type growth rate in a culture medium featuring lipid as the only carbon source are unable to sustain infections in granulomas. By mapping metabolite- and gene-scale perturbations to granuloma-scale outcomes and predicting mechanisms of sterilization, our method provides a powerful tool for hypothesis testing and guiding experimental searches for novel antituberculosis interventions. PMID- 26975997 TI - Screening for Non-Pore-Binding Modulators of EAG K+ Channels. AB - Members of the ether-a-go-go (EAG) family of voltage-gated K(+) channels are involved in several pathophysiological diseases, and there has been a great interest in screening for drugs that modulate the activity of these channels. Many drugs have been shown to bind in the pore of these channels, blocking ion flux and causing disease pathology. In this report, we present two independent screening campaigns in which we wanted to identify small molecules that bind to either the intracellular cytoplasmic amino terminal Per-Arnt-Sim (PAS) domain from the human EAG-related gene (ERG) channel or the amino or carboxy terminal globular domains from the mouse EAG1 channel, affecting their interaction. We report that in both cases, compounds were identified that showed weak, nonspecific binding. We suggest alternative routes should be pursued in future efforts to identify specific, high-affinity binders to these cytoplasmic domains. PMID- 26975996 TI - EGR1 controls divergent cellular responses of distinctive nucleus pulposus cell types. AB - BACKGROUND: Immediate early genes (IEGs) encode transcription factors which serve as first line response modules to altered conditions and mediate appropriate cell responses. The immediate early response gene EGR1 is involved in physiological adaptation of numerous different cell types. We have previously shown a role for EGR1 in controlling processes supporting chondrogenic differentiation. We recently established a unique set of phenotypically distinct cell lines from the human nucleus pulposus (NP). Extensive characterization showed that these NP cellular subtypes represented progenitor-like cell types and more functionally mature cells. METHODS: To further understanding of cellular heterogeneity in the NP, we analyzed the response of these cell subtypes to anabolic and catabolic factors. Here, we test the hypothesis that physiological responses of distinct NP cell types are mediated by EGR1 and reflect specification of cell function using an RNA interference-based experimental approach. RESULTS: We show that distinct NP cell types rapidly induce EGR1 exposure to either growth factors or inflammatory cytokines. In addition, we show that mRNA profiles induced in response to anabolic or catabolic conditions are cell type specific: the more mature NP cell type produced a strong and more specialized transcriptional response to IL-1beta than the NP progenitor cells and aspects of this response were controlled by EGR1. CONCLUSIONS: Our current findings provide important substantiation of differential functionality among NP cellular subtypes. Additionally, the data shows that early transcriptional programming initiated by EGR1 is essentially restrained by the cells' epigenome as it was determined during development and differentiation. These studies begin to define functional distinctions among cells of the NP and will ultimately contribute to defining functional phenotypes within the adult intervertebral disc. PMID- 26975998 TI - Superficial zone cellularity is deficient in mice lacking lubricin: a stereoscopic analysis. AB - BACKGROUND: Lubricin, a mucinous glycoprotein secreted by synoviocytes and chondrocytes plays an important role in reducing the coefficient of friction in mammalian joints. Elevated cartilage surface friction is thought to cause chondrocyte loss; however, its quantification and methodological approaches have not been reported. We adapted a stereological method and incorporated vital cell staining to assess cellular loss in superficial and upper intermediate zones in lubricin deficient mouse cartilage. METHODS: The femoral condyle cartilage of the intact knees from lubricin wild type (Prg4 (+/+)), heterozygote (Prg4 (+/-)), and knockout (Prg4 (-/-)) mice was imaged using fluorescein diacetate (FDA), propidium iodide (PI), and Hoechst staining, and confocal microscopy. Three dimensional reconstructions of confocal images to a depth of 14 MUm were analyzed using Matlab to determine the volume fraction occupied by chondrocytes in cartilage of both medial and lateral femoral condyles. Living chondrocyte volume fraction was defined as FDA stained chondrocyte volume/total volume of superficial + upper intermediate zone. Living and dead (total) chondrocyte volume fraction was defined as FDA + PI stained chondrocyte volume/total volume of superficial + upper intermediate zone. MicroCT provided an orthogonal measure of cartilage thickness. Immunohistology for activated caspase-3 and TUNEL staining were performed to evaluate the presence of apoptotic chondrocytes in Prg4 mutant mice. RESULTS: Living chondrocyte volume fraction of the medial femoral condyle was significantly lower in Prg4 (-/-) mice compared to Prg4 (+/+) (p = 0.002) and Prg4 (+/-) (p = 0.002) littermates. There was no significant difference in medial condyle chondrocyte volume fraction between Prg4 (+/+) and Prg4 (+/-) mice (p = 0.82). No significant differences were observed for the chondrocyte volume fraction for the lateral condyle (p > 0.26). Cartilage thickness increased in the medial condyle for Prg4 (-/-) mice compared to Prg4 (+/+) (p = 0.02) and Prg4 (+/ ) (p = 0.03) littermates, and the lateral condyle for Prg4 (-/-) mice compared to Prg4 (+/+) (p < 0.0001) and Prg4 (+/-) (p < 0.0001) littermates, indicating that a multi-dimensional increase in cartilage volume did not artifactually lower the chondrocyte volume fraction in the medial condyle. Significantly higher number of caspase-3 positive cells were observed in the superficial and upper intermediate zone cartilage of the medial femoral condyle of Prg4 (-/-) mice compared to Prg4 (+/+) (p = 0.01) and Prg4 (+/-) (p = 0.04) littermates, and the lateral femoral condyle of Prg4 (-/-) mice compared to Prg4 (+/+) (p = 0.02) and Prg4 (+/-) (p = 0.02) littermates. There were no significant differences in TUNEL staining among different Prg4 genotypes in both condyles (p > 0.05 for all comparisons). CONCLUSIONS: Increased Caspase-3 activation is observed in Prg4 deficient mice compared to Prg4 sufficient littermates. Absence of Prg4 induces loss of chondrocytes in the superficial and upper intermediate zone of mouse cartilage that is quantifiable by a novel image processing technique. PMID- 26975999 TI - Cost-Effectiveness Analysis of Iodine-123 Meta-Iodobenzylguanidine Imaging for Screening Heart Failure Patients Eligible for an Implantable Cardioverter Defibrillator in the USA. AB - BACKGROUND: Many guideline-eligible heart failure (HF) patients do not receive a survival benefit from implantable cardioverter defibrillators (ICDs). Improved risk stratification may help to reduce costs and improve the cost effectiveness of ICDs. OBJECTIVE: To estimate the potential outcomes, costs, and cost effectiveness of using iodine-123 meta-iodobenzylguanidine (I-mIBG) to screen HF patients eligible for an ICD. METHODS: A decision-analytic model was developed to compare screening with I-mIBG imaging and no screening over 2-year and 10-year time horizons from a US payer perspective. Data on I-mIBG imaging and risk stratification were obtained from the ADMIRE-HF/HFX (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) trial. Data on ICD effectiveness for prevention of sudden cardiac death (SCD) were obtained from a meta-analysis. Costs of ICDs and costs of generator and lead procedures were obtained from the Agency for Healthcare Research and Quality National Inpatient Sample. Age specific mortality was modeled using US life tables and data from the ACT (Advancements in ICD Therapy) Registry on risks of SCD and non-SCD mortality. Sensitivity analyses were conducted. RESULTS: In the analysis, screening with I mIBG imaging was associated with a reduction in ICD utilization of 21 %, resulting in a number needed to screen to prevent 1 ICD implantation of 5. Screening reduced the costs per patient by US$5500 and US$13,431 (in 2013 dollars) over 2 and 10 years, respectively, in comparison with no screening and resulted in losses of 0.001 and 0.040 life-years, respectively, over 2 and 10 years. Screening was decrementally cost effective, with savings of US$5,248,404 and US$513,036 per quality-adjusted life-year lost over 2 and 10 years, respectively. In subgroup analyses, cost savings were greater for patients with an ejection fraction (EF) of 25-35 % than for those with an EF <25 %. CONCLUSIONS: According to the model, screening of guideline-eligible patients selected for ICDs with I-mIBG imaging may be cost effective and may help reduce costs associated with implantation of ICDs, with a minimal impact on survival. PMID- 26976001 TI - Intraforaminal ozone therapy and particular side effects: preliminary results and early warning. PMID- 26976000 TI - Rab proteins in the brain and corpus allatum of Bombyx mori. AB - In eukaryotic cells, Rab guanosine triphosphate-ases serve as key regulators of membrane-trafficking events, such as exocytosis and endocytosis. Rab3, Rab6, and Rab27 control the regulatory secretory pathway of neuropeptides and neurotransmitters. The cDNAs of Rab3, Rab6, and Rab27 from B. mori were inserted into a plasmid, transformed into Escherichia coli, and then subsequently purified. We then produced antibodies against Rab3, Rab6, and Rab27 of Bombyx mori in rabbits and rats for use in western immunoblotting and immunohistochemistry. Western immunoblotting of brain tissue revealed a single band at approximately 26 kDa. Immunohistochemistry results revealed that Rab3, Rab6, and Rab27 expression was restricted to neurons in the pars intercerebralis and dorsolateral protocerebrum of the brain. Rab3 and Rab6 co-localized with bombyxin, an insect neuropeptide. However, there was no Rab that co-localized with prothoracicotropic hormone. The corpus allatum secretes neuropeptides synthesized in the brain into the hemolymph. Results showed that Rab3 and Rab6 co localized with bombyxin in the corpus allatum. These findings suggest that Rab3 and Rab6 are involved in neurosecretion in B. mori. This study is the first to report a possible relationship between Rab and neurosecretion in the insect corpus allatum. PMID- 26976002 TI - Weight-Related Eating Among Less-Acculturated Latina College Students. AB - Less-acculturated Latinos have been found to have unique patterns of weight related eating attitudes and behaviors. This study examined body mass index (BMI), body image, and various facets of emotional distress as contributors to weight-related eating among less-acculturated female Latina college students. It was hypothesized that unique combinations of BMI, body image, depression, anxiety, and stress would predict routine restraint, compensatory restraint, susceptibility to external cues, and emotional eating in less-acculturated Latina college students. Participants were 141 college students from a rural region in southeastern California who completed questionnaires. Preoccupation with being overweight, a body-image variable, significantly predicted routine and compensatory restraint whereas stress was an important correlate of reasons for eating other than hunger. Implications of the findings include the potential to inform models of weight-related eating among less-acculturated Latina college students. Limitations include homogeneity of sample pertinent to Latino descent. Future directions are discussed. PMID- 26976003 TI - Depression and Chronic Health Conditions Among Latinos: The Role of Social Networks. AB - The purpose of this study was to examine the "buffering hypothesis" of social network characteristics in the association between chronic conditions and depression among Latinos. Cross-sectional self-report data from the San Diego Prevention Research Center's community survey of Latinos were used (n = 393). Separate multiple logistic regression models tested the role of chronic conditions and social network characteristics in the likelihood of moderate-to severe depressive symptoms. Having a greater proportion of the network comprised of friends increased the likelihood of depression among those with high cholesterol. Having a greater proportion of women in the social network was directly related to the increased likelihood of depression, regardless of the presence of chronic health conditions. Findings suggest that network characteristics may play a role in the link between chronic conditions and depression among Latinos. Future research should explore strategies targeting the social networks of Latinos to improve health outcomes. PMID- 26976004 TI - Health and Socio-Cultural Experiences of Refugee Women: An Integrative Review. AB - Approximately half of the global refugee population are women, yet they remain largely understudied from the perspective of gender. The aim of this review was to investigate the impact of refugee women's resettlement and socio-cultural experiences on their health. This review also explored factors promoting resilience in refugee women. Eight databases were searched for peer-reviewed manuscripts published from 2005 to 2014. Grey literature was also reviewed. Data were extracted for population, data collection methods, data analysis, and findings. The Resource-Based Model was used as an overarching framework for data synthesis. Following the screening of titles and abstracts, 20 studies met the study inclusion criteria. Cultural factors, social and material factors, personal factors, and resilience factors were identified as main themes influencing the health of refugee women. Promotion of factors that enables resettlement is important in promoting the health and wellbeing of refugee women. PMID- 26976006 TI - Diabetes Among United States-Bound Adult Refugees, 2009-2014. AB - We reported diabetes prevalence among all US-bound adult refugees and assessed factors associated with disease. We analyzed overseas medical evaluations of US bound refugees from 2009 through 2014 by using CDC's Electronic Disease Notification System. We identified refugees with diabetes by searching for diabetes-related keywords and medications in examination forms with text-parsing techniques. Age-adjusted prevalence rates were reported and factors associated with diabetes were assessed by using logistic regression. Of 248,850 refugees aged >=18 years examined over 5 years, 5767 (2.3 %) had diabetes. Iraqis had the highest crude (5.1 %) and age-adjusted (8.9 %) prevalence of disease. Higher age group and body mass index were associated with diabetes in all regions. Diabetes prevalence varied by refugee nationality. Although the absolute rates were lower than rates in the United States, the prevalence is still concerning given the younger age of the population and their need for health services upon resettlement. PMID- 26976005 TI - Seeking Asylum: Challenges Faced by the LGB Community. AB - A retrospective chart review was completed of patients self-identified as lesbian, gay, or bisexual seen through a program for survivors of torture between June 9, 2009 and December 31, 2014 (n = 50). Almost all (98 %) experienced persecution due to their sexual orientation and 84 % were survivors of torture. The circumstances under which the disclosure of sexual orientation took place in the country of origin were often traumatic. In several, efforts were made to change their sexual orientation often through forced marriage. Those in same sex relationships had relationships often marred by tragedy. Women were more likely to be forced to move from place to place, experience rape/sexual assault and threats whereas men were more likely to be persecuted by people on the street. All presented with symptoms of depression and anxiety. Providers need to be attuned to the potential traumatic histories of those fleeing persecution due to sexual orientation, and the medical, social, psychological, and legal implications. PMID- 26976007 TI - The Feasibility of Recruiting and Retaining Perinatal Latinas in a Biomedical Study Exploring Neuroendocrine Function and Postpartum Depression. AB - This study evaluates the feasibility of enrolling and retaining perinatal immigrant and U.S.-born Latinas in a laboratory-based study that includes the collection of biomarkers implicated in the development of postpartum depression. This prospective study followed Latinas from third trimester of pregnancy to 12 weeks postpartum. Women were enrolled during pregnancy and interviewed at 4, 8 and 12 weeks postpartum. Demographic information, depression status and breastfeeding practices were ascertained using validated Spanish- and English measures. Blood samples were collected at the 8-week postpartum laboratory visit during infant feeding and pain testing. Feasibility was demonstrated with 85 % retention of the original 34 prenatal women enrolled in the study. The majority (88 %) of women enrolled attended the 8-week laboratory visit regardless of depression status. This is the first study to demonstrate feasibility of enrolling and retaining depressed and nondepressed perinatal immigrant and U.S. born Latinas in biomedical research. PMID- 26976008 TI - Changes and characteristics of dissolved organic matter in a constructed wetland system using fluorescence spectroscopy. AB - Domestic wastewater was treated by five constructed wetland beds in series. Dissolved organic matter (DOM) collected from influent and effluent samples from the constructed wetland was investigated using fluorescence spectroscopy combined with fluorescence regional integration (FRI), parallel factor (PARAFAC) analysis, and two-dimensional correlation spectroscopy (2D-COS). This study evaluates the capability of these methods in detecting the spectral characteristics of fluorescent DOM fractions and their changes in constructed wetlands. Fluorescence excitation-emission matrix (EEM) combined with FRI analysis showed that protein like materials displayed a higher removal ratio compared to humic-like substances. The PARAFAC analysis of wastewater DOM indicated that six fluorescent components, i.e., two protein-like substances (C1 and C6), three humic-like substances (C2, C3 and C5), and one non-humic component (C4), could be identified. Tryptophan-like C1 was the dominant component in the influent DOM. The removal ratios of six fluorescent components (C1-C6) were 56.21, 32.05, 49.19, 39.90, 29.60, and 45.87 %, respectively, after the constructed wetland treatment. Furthermore, 2D-COS demonstrated that the sequencing of spectral changes for fluorescent DOM followed the order 298 nm -> 403 nm -> 283 nm (310 360 nm) in the constructed wetland, suggesting that the peak at 298 nm is associated with preferential tryptophan fluorescence removal. Variation of the fluorescence index (FI) and the ratio of fluorescence components indicated that the constructed wetland treatment resulted in the decrease of fluorescent organic pollutant with increasing the humification and chemical stability of the DOM. PMID- 26976009 TI - Tetrabromobisphenol A (TBBPA)-stimulated reactive oxygen species (ROS) production in cell-free model using the 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) assay-limitations of method. AB - Tetrabromobisphenol A (TBBPA) is a widely used brominated flame retardant, applied in a variety of commercial and household products, mainly electronic ones. Since the production of reactive oxygen species (ROS) is considered one of the principal cytotoxicity mechanisms, numerous studies undertake that aspect of TBBPA's mechanism of action. The present study verifies if the fluorogenic substrate 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) should be used to detect ROS production induced by TBBPA. To determine the ability of TBBPA alone to stimulate the conversion of H2DCFDA to its fluorescent product 2',7' dichlorofluorescein (DCF), we used a cell-free model. In the experiments we check different cultured media also in combination with free radical scavenger N-acetyl l-cysteine (NAC). Additionally, experiments with stable free radical 2,2-diphenyl 1-picrylhydrazyl (DPPH.) have been made. The presented data showed that TBBPA in all tested concentrations interacts with H2DCFDA in phosphate-buffered saline (PBS) buffer while in micromolar concentrations in the DMEM/F12 medium with and without serum. The addition of NAC inhibited the interaction of TBBPA with H2DCFDA. Experiments with DPPH. showed that, in the presence of NAC, TBBPA acts like a free radical. TBBPA has similar properties to free radical and is susceptible to free radical scavenging properties of NAC. Our results indicated that H2DCFDA assay cannot be used to evaluate cellular ROS production in TBBPA studies. The study connected with TBBPA-stimulated ROS production in cell culture models using the H2DCFDA assay should be revised using a different method. However, due to the free radical-like nature of TBBPA, it can be very difficult. Therefore, further investigation of the nature of TBBPA as a compound with similar properties to free radical is required. PMID- 26976010 TI - Physical properties of particulate matter from animal houses-empirical studies to improve emission modelling. AB - Maintaining and preserving the environment from pollutants are of utmost importance. Particulate matter (PM) is considered one of the main air pollutants. In addition to the harmful effects of PM in the environment, it has also a negative indoor impact on human and animal health. The specific forms of damage of particulate emission from livestock buildings depend on its physical properties. The physical properties of particulates from livestock facilities are largely unknown. Most studies assume the livestock particles to be spherical with a constant density which can result in biased estimations, leading to inaccurate results and errors in the calculation of particle mass concentration in livestock buildings. The physical properties of PM, including difference in density as a function of particle size and shape, can have a significant impact on the predictions of particles' behaviour. The aim of this research was to characterize the physical properties of PM from different animal houses and consequently determine PM mass concentration. The mean densities of collected PM from laying hens, dairy cows and pig barns were 1450, 1520 and 2030 kg m(-3), respectively, whilst the mass factors were 2.17 * 10(-3), 2.18 * 10(-3) and 5.36 * 10(-3) MUm, respectively. The highest mass concentration was observed in pig barns generally followed by laying hen barns, and the lowest concentration was in dairy cow buildings. Results are presented in such a way that they can be used in subsequent research for simulation purposes and to form the basis for a data set of PM physical properties. PMID- 26976011 TI - Manganese accumulation in hair and teeth as a biomarker of manganese exposure and neurotoxicity in rats. AB - Manganese (Mn) is an essential trace element to humans. However, excessive Mn causes cognitive impairment resulting from injury to the central nervous system within the hippocampus. No ideal biomarker is currently available for evaluating Mn exposure and associated neurotoxicity in the body. Hence, this study used Mn levels in the serum (MnS), teeth (MnT), and hair (MnH) as biomarkers for evaluating the association between Mn exposure and cognitive impairment in Mn treated rats. A total of 32 male Sprague-Dawley rats were randomly divided into four groups, received 0, 5, 10, and 20 mg/(kg day) of MnCl2.4H2O for 5 days a week for 18 weeks, respectively. Lifetime Mn cumulative dose (LMCD) was used to evaluate external Mn exposure. Hippocampus, serum, teeth, and hair specimens were collected from the rats for Mn determination by graphite furnace atomic absorption spectrometry. Learning and memory functions were assessed using the Morris water maze test. Results showed that chronic Mn exposure increased the hippocampus (MnHip), MnS, MnT, and MnH levels, as well as impaired learning and memory function in rats. MnHip, MnT, and MnH levels were positively correlated with LMCD (r = 0.759, r = 0.925, and r = 0.908, respectively; p < 0.05), escape latency (r = 0.862, r = 0.716, and r = 0.814, respectively; p < 0.05), and the number of platform crossings (r = -0.734, r = -0.514, and r = -0.566, respectively; p < 0.05). No association was observed between MnS levels and the number of platform crossings (r = -0.286, p > 0.05). Thus, MnT and MnH detected long-term low-dose Mn exposure. These parameters can be reliable biomarkers for Mn exposure and associated neurotoxicity in Mn-treated rats. PMID- 26976012 TI - Phagocytic cell responses to silica-coated dithiocarbamate-functionalized iron oxide nanoparticles and mercury co-exposures in Anguilla anguilla L. AB - Immune system responses in fish are considered as suitable and sensitive biomarkers for monitoring aquatic pollution. However, a clear knowledge gap persists in the literture on the immunotoxic potential of engineered nanoparticles toward aquatic organisms such as fish. Employing major enzymatic- (glutathione reductase, GR; glutathione peroxidase, GPX; glutathione sulfo transferase, GST; catalase, CAT) and thiol- (non-protein thiols, NP-SH; total glutathione, TGSH)-based defense biomarkers, this study assessed the response of phagocytes isolated from peritoneum (P-phagocytes), gill (G-phagocytes), head kidney (HK-phagocytes), and spleen (S-phagocytes) of European eel (Anguilla anguilla L.) to silica-coated magnetite particles (Fe3O4@SiO2/SiDTC, hereafter called IONP; size range: 82 +/- 21 to 100 +/- 30 nm; 2.5 mg L(-1)) alone and IONP and mercury (Hg; 50 MUg L(-1)) concomitant exposures. Responses of previous biomarkers were studied in P-phagocytes, G-phagocytes, HK-phagocytes, and S phagocytes collected during 0, 2, 4, 8, 16, 24, 48, and 72 h of exposures. Contingent to hour of exposure to IONP, Hg, and IONP + Hg GST, GPX, CAT, NP-SH, and TGSH exhibited their differential responses in all the phagocytic cells considered. In particular, under IONP exposure, the potential occurrence of the GSH-independent antioxidant defense was indicated by the observed herein inhibition in the enzymatic- and thiol-based defense in A. anguilla phagocytes. In contrast, the response of P-, G-, HK-, and S-phagocytes to the increasing Hg exposure period reflected an increased detoxification activity. Notably, the occurrence of an antagonism between IONP and Hg was depicted during late hours (72 h) under IONP + Hg concomitant exposure, where elevations in the defense biomarkers were depicted. Overall, the P-, G-, HK-, and S-phagocytic cells exhibited a differential induction in the studied enzymes and thiols to counteract impacts of IONP, Hg, and IONP + Hg concomitant exposures. Future studies on the fish immunotoxicity responses to IONP exposure in multi-pollution conditions can be benefited with the major outcomes of the present study. PMID- 26976013 TI - Microwave-irradiation-assisted hybrid chemical approach for titanium dioxide nanoparticle synthesis: microbial and cytotoxicological evaluation. AB - Titanium dioxide nanoparticles (TNPs) are widely used in the pharmaceutical and cosmetics industries. It is used for protection against UV exposure due to its light-scattering properties and high refractive index. Though TNPs are increasingly used, the synthesis of TNPs is tedious and time consuming; therefore, in the present study, microwave-assisted hybrid chemical approach was used for TNP synthesis. In the present study, we demonstrated that TNPs can be synthesized only in 2.5 h; however, the commonly used chemical approach using muffle furnace takes 5 h. The activity of TNP depends on the synthetic protocol; therefore, the present study also determined the effect of microwave-assisted hybrid chemical approach synthetic protocol on microbial and cytotoxicity. The results showed that TNP has the best antibacterial activity in decreasing order from Escherichia coli, Bacillus subtilis, and Staphylococcus aureus. The IC50 values of TNP for HCT116 and A549 were found to be 6.43 and 6.04 ppm, respectively. Cell death was also confirmed from trypan blue exclusion assay and membrane integrity loss was observed. Therefore, the study determines that the microwave-assisted hybrid chemical approach is time-saving; hence, this technique can be upgraded from lab scale to industrial scale via pilot plant scale. Moreover, it is necessary to find the mechanism of action at the molecular level to establish the reason for greater bacterial and cytotoxicological toxicity. Graphical abstract A graphical representation of TNP synthesis. PMID- 26976014 TI - Cytotoxicity and alterations at transcriptional level caused by metals on fish erythrocytes in vitro. AB - The in vitro use of fish erythrocytes to test the toxicity of aquatic pollutants could be a valuable alternative to fish bioassays but has received little attention. In this study, erythrocytes from marine gilthead sea bream (Sparus aurata L.) and European sea bass (Dicentrarchus labrax L.) specimens were exposed for 24 h to Cd, Hg, Pb and As and the resulting cytotoxicity was evaluated. Exposure to metals produced a dose-dependent reduction in the viability, and mercury showed the highest toxicity followed by MeHg, Cd, As and Pb. Moreover, fish erythrocytes incubated with each one of the metals exhibited alteration in gene expression profile of metallothionein, superoxide dismutase, catalase, peroxiredoxin, glutathione reductase, heat shock proteins 70 and 90, Bcl2 associated X protein and calpain1 indicating cellular protection, stress and apoptosis death as well as oxidative stress. This study points to the benefits for evaluating the toxicological mechanisms of marine pollution using fish erythrocytes in vitro. PMID- 26976015 TI - Effects of biochar amendment on relieving cadmium stress and reducing cadmium accumulation in pepper. AB - Biochar is widely used in agricultural soils or heavy metal-polluted soils to improve the quality of the soils, which would affect the growth of the plant. However, the information of biochars' effect on the plant growth was still lacking, especially for the physiological response of the plant. Pot experiments were used to examine the effect of willow-derived biochars at two temperatures (450 and 600 degrees C) on cadmium (Cd) accumulation in pepper and to reveal the response of physiological parameters to exogenous Cd stress (1 and 5 mg/kg). The results showed that the accumulation of Cd in pepper roots was higher than that in pepper shoots. For low level of Cd treatments, high additional rates of the biochars could obviously reduce the accumulation of Cd in the pepper roots. Moreover, there was a negative correlation between the C content of the biochar amended soils and the Cd content of the pepper root, suggesting that the application of biochar to the soil decreased the Cd accumulation in the root. A positive relationship between the H/C ratios of biochar-amended soils and their corresponding Cd concentrations in pepper root indicated that low thermal temperature-derived biochar could play an important role in immobilizing Cd in the soil. Furthermore, on the condition of low Cd level of treatments, the malondialdehyde content decreased in biochar-amended soils, especially at high biochar application rate. The chlorophyll content increased with increasing the rates of the biochar application. The physiological parameters indirectly proved that the application of biochar did not always alleviate the toxic effects of Cd on pepper leaves at high Cd concentration. PMID- 26976016 TI - Efficacy and safety of topical ganciclovir in the management of cytomegalovirus (CMV)-related anterior uveitis. AB - BACKGROUND: The aim of this study was to evaluate the efficacy and safety of topical ganciclovir 0.15 % gel in the management of patients with cytomegalovirus (CMV) anterior uveitis. RESULTS: This was a retrospective cohort study of the disease course of 31 patients (33 eyes) with aqueous polymerase chain reaction (PCR) positive for CMV. Data from a total of 160 episodes of anterior uveitis flare for 20 years, dating from December 1992 to December 2012, was collected. All patients were treated with concomitant topical anti-inflammatory medication. The disease course of each eye was analysed before and after the use of topical ganciclovir 0.15 %. The mean age at initial presentation of anterior uveitis was 57.5 +/- 12.6 years. Twenty-eight (90.3 %) patients were Chinese. Patients on topical ganciclovir gel had a statistically significant fewer episodes of uveitis flare per person year (median -0.88 episodes/person years, p = 0.029). The time to-quiescence was not significantly affected by topical ganciclovir use (median 1.25 days, p = 0.610). In the survival analysis using the Cox regression model, the use of topical ganciclovir was associated with a lower risk of recurrence, but this was not statistically significant (hazard ratio = 0.857, 95 % CI 0.543 1.36, p = 0.511). The overall median time-to-recurrence was 290 days (95 % CI 113 to 274 days) and 164 days (125 to 404 days) (p = 0.492), with and without topical ganciclovir, respectively. CONCLUSIONS: Topical ganciclovir may be beneficial in reducing the frequency of recurrence in patients with CMV anterior uveitis, but it was not statistically associated with prolonging the time-to-recurrence. The time-to-quiescence was also not significantly affected by topical ganciclovir. Prospective studies with a larger number of patients would be required to verify our findings. PMID- 26976017 TI - Bloodstream infections in patients with chronic lymphocytic leukemia: a longitudinal single-center study. AB - Infectious complications in chronic lymphocytic leukemia (CLL) represent a major cause of morbidity and mortality. The aim of the study was to investigate temporal trends in bloodstream infections (BSIs) among patients with CLL. Individuals with blood cultures were linked to Swedish Cancer Registry and divided into three time periods (1988-1993, 1994-1999, and 2000-2006) according to year of CLL diagnosis. CLL patients (n = 275) with 1092 blood culture episodes were identified and linked to the nationwide Cause of Death Registry and Swedish Patient Registry (to retrieve information on splenectomies). The most common causes of BSI among CLL patients were Escherichia coli (11/43, 15/78, and 9/33), Streptococcus pneumoniae (7/43, 13/78, and 6/33), Pseudomonas aeruginosa (2/43, 8/78, and 3/33), Staphylococcus aureus (1/43, 6/78, and 6/33), and Viridans streptococci (5/43, 6/78, and 2/33). Coagulase-negative staphylococci was the most frequent microorganism found in blood cultures (22/70, 23/106, and 5/41, respectively) but is a frequent contaminant. Based on the largest study to date on BSI in CLL patients, we found a stable proportion of Gram-positive to Gram negative bacteria and no temporal change of distribution was observed for BSIs 1988-2006. PMID- 26976018 TI - Fitting the pieces of the puzzle together: a case report of the Dunnigan-type of familial partial lipodystrophy in the adolescent girl. AB - BACKGROUND: Familial partial lipodystrophy of the Dunnigan type (FPLD 2) is a rare autosomal dominant disorder caused by the mutations of the lamin A/C gene leading to the defective adipogenesis, premature death of adipocytes and lipotoxicity. FPLD 2 is characterized by a progressive loss of subcutaneous adipose tissue in the limbs and trunk, and accumulation of body fat in the face and neck with accompanying severe metabolic derangements including insulin resistance, glucose intolerance, diabetes, dyslipidemia, steatohepatitis. Clinical presentation of FPLD 2 can often lead to misdiagnosis with metabolic syndrome, type 2 diabetes or Cushing syndrome. CASE PRESENTATION: We report a case of a 14-year-old girl admitted to the Department of Paediatrics due to chronic hypertransaminasemia. On physical examination the girl appeared to have athletic posture. She demonstrated the absence of subcutaneous adipose tissue in the extremities, sparing the face, neck and gluteal area, pseudo-hypertrophy of calves, prominent peripheral veins of limbs, massive acanthosis nigricans around the neck, in axillary and inguinal regions and natural skin folds, hepatosplenomegaly. Laboratory results revealed hypertransaminasemia, elevated gamma-glutamyltranspeptydase, and dyslipidemia, hyperinsulinaemia with insulin resistance, impaired glucose tolerance, and hyperuricemia. Diffuse steatoheptitis in the liver biopsy was stated. Clinical suspicion of FPLD 2 was confirmed genetically. The pathogenic mutation, R482W (p.Arg482Trp), responsible for the FPLD 2 phenotype was identified in one allele of the LMNA gene. CONCLUSIONS: Presented case highlights the importance of the holistic approach to a patient and the need of accomplished collaboration between paediatricians and geneticists. FPLD 2 should be considered in the differential diagnosis of diabetes, dyslipidemia, steatohepatitis, acanthosis nigricans and polycystic ovary syndrome. PMID- 26976019 TI - Comparison of Anthropometric Data Between Asian and Caucasian Patients With Obstructive Sleep Apnea: A Meta-Analysis. AB - OBJECTIVES: Obesity is considered to be one of the most important risk factors for obstructive sleep apnea (OSA) but less is known about the role of ethnicity in OSA. The purpose of this study was to investigate the interethnic difference of obesity-related phenotypes in OSA and to reveal the role of ethnicity in OSA. METHODS: We searched MEDLINE, LILACS, Scopus, and the Cochrane Library using the key words "sleep apnea," "body mass index," "neck circumference," "waist circumference," "waist to hip ratio," etc. Inclusion criteria were adults over 18 years of age, and studies that included polysomnography, obesity-related parameters, and a clear demarcation of ethnicity in the patient population. Included studies were reviewed by 2 independent reviewers. The following information was collected for controls and OSA: number, age, gender, country, ethnicity (Asian or Caucasian), study design, apnea-hypopnea index/respiratory disturbance index, body mass index (BMI), neck circumference (NC), waist circumference (WC), and/or waist to hip ratio (WHR). RESULTS: A total of 8,312 publications were retrieved with a subsequent 19 manuscripts that met the selection criteria. A total of 2,966 patients were included for analysis. The main findings were as follows: There was no difference in BMI, WC, and WHR between patients with OSA and controls after accounting for publication bias; Patients with OSA have greater NC than controls (standard mean difference, 0.89; 95% confidence interval, 0.63 to 1.14); and There was no difference in NC between Asian and Caucasians patients (P=0.178). CONCLUSION: OSA might not be related with BMI, WC, and WHR. Only NC demonstrated a strong association with OSA, and this finding was not different between Asians and Caucasians. PMID- 26976020 TI - Granulomatosis With Polyangiitis in Otolaryngologist Practice: A Review of Current Knowledge. AB - Granulomatosis with polyangiitis (GPA) is an idiopathic vasculitis of medium and small arteries, characterized by necrotizing granulomatous inflammation. GPA typically affects upper and lower respiratory tract with coexisting glomerulonephritis. This disease is generally characterized by antineutrophil cytoplasm antibodies (ANCA), nevertheless, there are rare cases with negative ANCA. GPA affects people at any age, with predominance of the sixth and seventh decade of life. In 80%-95% of the patients the first symptoms of GPA are otorhinolaryngological manifestations of head and neck including nose/sinuses, ears, eyes, larynx/trachea, oral cavity, and salivary glands. Diagnosis of GPA is based on Criteria of the American College of Rheumatology. In clinical practice diagnosis, the presence of distinctive ANCA antibodies and biopsy of affected organ are crucial. GPA must be differentiated from neoplastic, infectious or inflammatory ulcerative lesions of the head and neck. The standard treatment procedure is divided into two essential phases, induction and maintenance. The induction phase is based on combination of systemic corticosteroid and immunosuppressant therapy, whereas the maintenance phase comprises corticosteroids and azathioprine/methotrexate supplementation. Surgical treatment ought to be considered for patients who are not responding to pharmacotherapy. PMID- 26976021 TI - The Effect of Dexpanthenol on Ototoxicity Induced by Cisplatin. AB - OBJECTIVES: This study was aimed to investigate the protective effects of dexpanthenol (Dxp) on against cisplatin-induced ototoxicity. METHODS: To examine this effect, distortion product otoacoustic emissions (DPOAEs) measurements and serum levels of oxidative and antioxidant status (including malondialdehyde, superoxide dismutase, catalase, glutathione, glutathione peroxidase, total oxidant status, total antioxidant status, and oxidative stress index) were evaluated. Thirty-two adult female Wistar albino rats were randomly divided into 4 equal groups; control (K), cisplatin (C), cisplatin plus Dxp (CD), and Dxp (D). In all groups DPOAEs measurements, between 996 and 10,078 Hz as DPOAEs and input/output functions, were performed on days 0, 1th, 5th, and 12th. Prior to death, the last DPOAEs measurements and blood samples were taken. RESULTS: In the C group, statistically significant differences were detected at all frequencies between 0 and 5 days and 0 and 12 days measurements (P<0.05). Serum level of oxidant and antioxidant status were detected statistically significantly changed in this group versus K group (P<0.05). Contrary to the C group, in the CD group hearing ability was seen largely preserved at many frequencies and serum levels of all biochemical parameters were shifted toward normal values, similar to the K group. No significant differences were detected in the either D or K group's measurements. CONCLUSION: According to these results, Dxp may prevent cisplatin induced ototoxicity. PMID- 26976022 TI - Surgical and Audiologic Comparison Between Sophono and Bone-Anchored Hearing Aids Implantation. AB - OBJECTIVES: Bone-anchored hearing aids (BAHA) occasionally cause soft tissue problems due to abutment. Because Sophono does not have abutment penetrating skin, it is thought that Sophono has no soft tissue problem relating to abutment. On the other hand, transcutaneous device's output is reported to be 10 to 15 dB lower than percutaneous device. Therefore, in this study, Sophono and BAHA were compared to each other from surgical and audiological points of view. METHODS: We retrospectively reviewed the medical records of 9 Sophono patients and 10 BAHA patients. In BAHA cases, single vertical incision without skin thinning technique was done. We compared Sophono to BAHA by operation time, wound healing time, postoperative complications, postoperative hearing gain after switch on, and postoperative air-bone gap. RESULTS: The mean operation time was 60 minutes for Sophono and 25 minutes for BAHA. The wound healing time was 14 days for Sophono and 28 days for BAHA. No major intraoperative complication was observed. Skin problem was not observed in the 2 devices for the follow-up period. Postoperative hearing gain of bilateral aural atresia patients was 39.4 dB for BAHA (n=4) and 25.5 dB for Sophono (n=5). However, the difference was not statistically significant. In all patients included in this study, the difference of air-bone gap between two groups was 16.6 dB at 0.5 kHz and 18.2 dB at 4 kHz. BAHA was statistically significantly better than Sophono. CONCLUSION: Considering the audiologic outcome, BAHA users were thought to have more audiologic benefit than Sophono users. However, Sophono had advantages over BAHA with abutment in cosmetic outcome. Sophono needed no daily skin maintenance and soft tissue complication due to abutment would not happen in Sophono. Therefore, a full explanation about each device is necessary before deciding implantation. PMID- 26976023 TI - Normal Mastoid Air Cell System Geometry: Has Surface Area Been Overestimated? AB - OBJECTIVES: The aim of this study was to emphasize the necessity of a standard in segmentation threshold and algorithm for measuring volume and surface area of mastoid air cell system (MACS). METHODS: First, we obtained axial computed tomography scans of 54 normal temporal bones from 27 subjects. Then, we manipulated Hounsfield units (HU) image data in DICOM (digital imaging and communications in medicine) files directly using our program. The volume and surface area of MACS were computed and compared at segmentation thresholds (HU) from -700 to 0 at intervals of 50 using 2 algorithms; square pixel based (SP) algorithm and marching square (MS) algorithm. RESULTS: No significant difference was found between the volumes computed by SP and MS algorithms at each segmentation threshold. The surface area computed by SP algorithm, however, was significantly larger than that by MS algorithm. We could minimize this significant difference through a modification of the SP algorithm. As the lower HU threshold value was set, the smaller volume was measured. The surface area showed a plateau at a threshold of approximately -200 HU. The segmentation threshold had greater influence on the measured volume of MACS than the algorithm did. CONCLUSION: A standard method for measuring volume and surface area of MACS is thought to be necessary. We suggest that the MS algorithm and -200 HU of the threshold could be a standard in the measurement of volume and surface area of MACS. PMID- 26976024 TI - Endoscopic Adenoidectomy in Children With Otitis Media With Effusion and Mild Hearing Loss. AB - OBJECTIVES: Surgical management of children with chronic otitis media with effusion (OME) includes tympanostomy tube insertion or adenoidectomy, alone or with myringotomy and tube insertion. The aim of this study was to compare the effectiveness of transoral microdebrider endoscopic-assisted adenoidectomy (TOMEA) and traditional adenoidectomy in the management of children with mild hearing loss due to OME and chronic adenoiditis. METHODS: This prospective, double-blind and controlled study involved 120 consecutive patients aged 4-12 years, who were randomised 1:1 to undergo TOMEA or traditional adenoidectomy under general anesthesia. All the patients underwent a complete otolaryngological examination, including nasopharyngeal fibre endoscopy (NFE), pneumatic otoscopy, otomicroscopy, tympanometry and supraliminar tonal audiometry, upon enrolment, and three and nine months postoperatively. RESULTS: There were no statistically significant differences in age or gender distribution between the TOMEA group (mean age, 4.9+/-1.1 years; 53.3% males) and the traditional adenoidectomy group (mean age, 5.3+/-0.9 years; 56.7% males). Both procedures led to a significant improvement in choanal patency (P<0.01) and all of the otological and audiological parameters (P<0.01) 3 and 9 months postoperatively, although postoperative NFE showed that the mean percentage of residual choanal obstruction was significantly less in the TOMEA group (P=0.02). There was no significant between-group difference in the percentage of children with tympanic membrane changes, but the postoperative prevalence of children with a type B tympanogram was significantly lower in the TOMEA group after 3 (15.0% vs. 31.7%, P=0.05) and 9 months (18.3% vs. 38.3%, P=0.02), as was the percentage of children with mild conductive hearing loss (3.3% vs. 23.3%, P<0.01; and 8.3% vs. 28.3%, P<0.01). CONCLUSION: Although both TOMEA and traditional adenoidectomy are effective in treating children with mild hearing loss due to adenoidal hypertrophy and OME, the former achieves the greater reduction in residual adenoidal hypertrophy and better audiological outcomes. PMID- 26976025 TI - Clinical Implications of Septal Deviation in Lateralized Olfaction. AB - OBJECTIVES: Results of butanol threshold tests (BTTs) have shown that birhinal olfaction tends to converge toward monorhinal olfaction of the dominant nostril. However, birhinal olfaction may also be worse than dominant-side monorhinal olfaction. The goal of our study was to investigate the effect of deviated nasal septum on birhinal olfaction in patients with lateralized olfaction and to examine the effect of septoplasty in these patients. METHODS: A retrospective study with planned data collection was conducted in 518 patients who underwent BTTs. Lateralized olfaction was defined as monorhinal BTT scores that differed by >2 between sides. Underestimated birhinal olfaction was defined as a birhinal BTT score >2 lower than the dominant nostril monorhinal BTT score. Patients with lateralized olfaction were divided into 2 groups: group 1, underestimated birhinal olfaction; and group 2, without underestimated birhinal olfaction. RESULTS: Among 518 patients, 112 with lateralized olfaction were enrolled in this study. Group 1 included 23 patients (20.5%) and group 2 included 89 patients (79.5%). The severity of septal deviation (ratio of the distance of narrower side to wider side) did not differ between the 2 groups. Septal deviation to the dominant nostril was more common in group 1 than group 2 (73.9% vs. 37.6%; P=0.002). Five patients with septal deviation to the dominant nostril with underestimated birhinal olfaction underwent septoplasty. Improved lateralized olfaction occurred in all 5 patients postoperatively (P=0.041). CONCLUSION: Septal deviation of the dominant nostril in patients with lateralized olfaction is associated with underestimated birhinal olfaction. Septoplasty may improve olfaction by increasing airflow in the dominant olfactory side. PMID- 26976026 TI - The Healing Effects of Autologous Mucosal Grafts in Experimentally Injured Rabbit Maxillary Sinuses. AB - OBJECTIVES: Healing processes of the nose and paranasal sinuses are quite complex, and poorly understood. In this study, we aimed to compare the effect of mucosal autologous grafts on the degenerated rabbit maxillary sinus mucosa with spontaneous wound healing. It is hypothesized that mucosal grafts will enhance ciliogenesis and improve the morphology of regenerated cilia. METHODS: Ten female New Zealand rabbits were included in the study. They underwent external maxillary sinus surgery through a transcutaneous approach. A total of 20 maxillary sinuses were randomly divided into 2 groups: 'spontaneous healing group' and 'autologous graft group.' The animals were sacrificed at the 14th day after the surgery. Scanning electron microscope (SEM), and light microscope were used for the evaluation. RESULTS: Cellular composition of the graft group is better than the spontaneous healing group. The graft group had larger areas covered with ciliary epithelium than the spontaneous healing group, and the mean length of the cilias were also longer. Additionally, there were wider cilia with abnormal morphology areas in the spontaneous healing group. CONCLUSION: In our opinion, covering of the denuded areas with a graft improves re-epithelization, and may prevent the early complications after sinus surgeries. PMID- 26976028 TI - Histological Effect of Basic Fibroblast Growth Factor on Chronic Vocal Fold Scarring in a Rat Model. AB - OBJECTIVES: Vocal fold scarring is one of the most challenging laryngeal disorders to treat and there are currently no consistently effective treatments available. Our previous studies have shown the therapeutic potential of basic fibroblast growth factor (bFGF) for vocal fold scarring. However, the histological effects of bFGF on scarred vocal fold have not been elucidated. The aim of this study was to examine the histological effects of bFGF on chronic vocal fold scarring. METHODS: Sprague-Dawley rats were divided into phosphate buffered saline (sham) and bFGF groups. Unilateral vocal fold stripping was performed and the drug was injected into the scarred vocal fold for each group 2 months postoperatively. Injections were performed weekly for 4 weeks. Two months after the last injection, larynges were harvested and histologically analyzed. RESULTS: A significant increase of hyaluronic acid was observed in the vocal fold of the bFGF group compared with that of the sham group. However, there was no remarkable change in collagen expression nor in vocal fold contraction. CONCLUSION: Significant increase of hyaluronic acid by local bFGF injection was thought to contribute to the therapeutic effects on chronic vocal fold scarring. PMID- 26976027 TI - Improvement of Pulmonary Functions Following Septoplasty: How Are Lower Airways Affected? AB - OBJECTIVES: Nasal septal deviation is a frequent cause of increased nasal airway resistance. A narrow nasal airway would result in a decreased airflow into the lungs. The aim of the present study was to evaluate the alterations of the pulmonary functions following septoplasty using spirometry and 6 minutes walking test (6mWT). And reveal the correlation of symptom score improvement with nasal obstruction symptom score (NOSE) and sino-nasal outcome test (SNOT22) questionnaires following surgery. METHODS: Thirty patients with obvious nasal septal deviations were enrolled in the study. All patients had a detailed otorhinolaryngologic examination, filled NOSE/SNOT22 questionnaires, performed spirometry and 6mWT preoperatively. One month after surgery, NOSE/SNOT22 questionnaires filled by subjects and spirometry with 6mWT were performed again, and the results were compared. RESULTS: The mean total walking distance was 702.3+/-68.2 m preoperatively, and it improved to 753.2+/-72.6 m postoperatively (P<0.001). Total tour count increased from 11 (range, 10.8 to 12.0) to 12 (range, 11 to 13.3), and the difference was found statistically significant (P<0.001). When the preoperative and postoperative mean 6mWT results were compared, diastolic blood pressure increased from 70 to 80 mmHg (P=0.031), heart rate increased from 83.5+/-13.2 to 90.1+/-12.5 bpm (P=0.017), dyspnea rate decreased from 1 to 0 (P=0.002), and fatigue scores reduced from 2 to 1 (P=0.003). Evaluation on spirometry findings revealed that FIF50% (maximum inspiratory flow at 50% of forced vital capacity [FVC]) scores and peak expiratory flow (PEF) values improved significantly after surgery. Septoplasty improves the nasal breathing pattern. While reducing FEF50% (maximum expiratory flow at 50% of FVC)/FIF50%, it increases PEF and FIF50% values. In addition, as shown by 6mWT, exercise capacity improves following surgery. Postoperative NOSE and SNOT22 scores reduced markedly compared to preoperative values (P<0.001). CONCLUSION: These findings suggest that nasal septal surgery has a positive effect on pulmonary functions, and this can be an important clue for the relationship of lung disorders and nasal obstruction. PMID- 26976029 TI - Prognostic Impact of Ultrasonography Features and (18)F-Fluorodeoxyglucose Uptake in Patients With Papillary Thyroid Microcarcinoma. AB - OBJECTIVES: To evaluate the prognostic impact of ultrasonography (US) features and (18)F-fluorodeoxyglucose ((18)F-FDG) uptake in patients with papillary thyroid microcarcinoma (PTMC). METHODS: This study included 74 patients with a single PTMC diagnosed pathologically. Patients underwent total thyroidectomy, or near-total thyroidectomy and staging thyroid US and positron emission tomography (PET) were performed prior to surgery. US features of thyroid nodules were reviewed retrospectively and the maximum standard uptake value (SUV) of nodules was semiquantitatively analyzed on (18)F-FDG PET/computed tomography (CT). Patients were followed-up for recurrence, which was defined as PTC on cytology results, elevated serum thyroglobulin (Tg) or anti-Tg antibody levels, or uptake on whole-body scintigraphy. We used univariate and multivariate analyses to evaluate whether poor prognostic outcomes were associated with US features or SUV values derived from PET/CT of nodules. In addition, subjects were divided into 2 groups for subgroup analyses: one with nodules equal to or larger than 5 mm and one with nodules smaller than 5 mm. RESULTS: Among the 74 patients, there was no recurrence. Thus we evaluated the correlation between SUV value and US features with poor prognostic factors of PTMC which included extrathyroid extension, central and lateral lymph node (LN) metastasis. However no clinicopathologic factors were associated with extrathyroid extension, central LN metastasis, or lateral LN metastasis. CONCLUSION: In patients with PTMC, US features and SUV values on FDG-PET were not related to extrathyroid extension or LN metastasis. However, future studies with a larger sample size and longer follow-up should be performed to verify the results of this study. PMID- 26976030 TI - Voice Outcome in Patients Treated With Endoscopic Laryngopharyngeal Surgery for Superficial Hypopharyngeal Cancer. AB - OBJECTIVES: Endoscopic laryngopharyngeal surgery (ELPS) is a minimally invasive transoral surgery that was developed to treat superficial larygo-pharyngeal cancer, in which a mucosal lesion is resected transorally while preserving deeper structures by subepithelial injection. The purpose of this retrospective study is to evaluate voice outcome in patients who underwent ELPS for superficial hypopharyngeal cancer. As important structures in producing voice, such as intrinsic laryngeal muscles, their fascia, and recurrent laryngeal nerve, are located in the medial side of the piriform sinus and the postcricoid region of the hypopharynx, we focused on patients with cancer lesions involving these regions. METHODS: From April 2010 to March 2011, 25 consecutive patients with superficial laryngopharyngeal cancer were treated with ELPS at Kyoto University Hospital. Among the 25 patients, 11 patients with cancer lesions on the medial side of the piriform sinus or the postcricoid area were studied. Preoperative and postoperative voice functions including maximum phonation time (MPT), mean flow rate (MFR), jitter, shimmer, soft phonation index (SPI), and noise-to-harmonic ratio (NHR), were compared retrospectively. RESULTS: Five of 11 cancer lesions had submucosal invasion and no lesion had invaded the muscular layer pathologically. T stage was classified as Tis in 5 cases, T1 in 4 cases, and T2 in 2 cases. All lesions involved the medial side of the piriform sinus and 2 also involved the postcricoid area. Vocal fold movement was normal in all cases after the surgery. Average preoperative and postoperative values for MPT, MFR, jitter, shimmer, SPI, and NHR, were 22.7 seconds and 23.4 seconds, 165 mL/sec and 150 mL/sec, 1.53% and 1.77%, 3.82% and 5.17%, 35.5 and 36.6, and 0.13% and 0.14%, respectively. There was no statistical difference between preoperative and postoperative data for all values examined. CONCLUSION: ELPS is useful in preserving voice function in the treatment of superficial hypopharyngeal cancer. Preserving the deeper structures including intrinsic muscles and their fascia may be important for preserving voice function as long as the lesions are superficial. PMID- 26976031 TI - Metastatic Lymph Node Ratio of Central Neck Compartment Has Predictive Values for Locoregional Recurrence in Papillary Thyroid Microcarcinoma. AB - OBJECTIVES: This study aimed to evaluate the significance of metastatic lymph node ratio (the ratio between the metastatic lymph node and the harvested lymph nodes; MLNR) in the central neck for the prediction of locoregional recurrence in patients with papillary thyroid microcarcinoma. METHODS: After reviewing medical records of papillary thyroid microcarcinoma patients who received total thyroidectomy with central neck node dissection, 573 consecutive adult patients were enrolled in this study, with a follow-up period of more than 36 months. Regarding the risk of recurrence, multivariate analyses were performed with the following variables; sex, age, multiplicity of the primary tumor, presence of pathological extrathyroidal extension, the level of postoperative stimulated serum thyroglobulin, the number of harvested lymph nodes, the number of lymph node metastasis and MLNR. RESULTS: The MLNR showed a predictive significance for the locoregional recurrence (P<0.05). Most recurrences were occurred in the lateral neck (n=12, 80%) with a median interval of 20 months. The lowest cutoff value of the MLNR for a meaningful separation of disease recurrence was 0.44 (hazard ratio, 8.86; 95% confidence interval, 1.49 to 52.58; P=0.001). CONCLUSION: When the MLNR is higher than 0.44, there is an increased risk of locoregional recurrence mostly in the lateral neck. Therefore, MLNR of the central neck in a permanent or frozen biopsy may be helpful in decision making in the extent of thyroidectomy and/or the need for contralateral central neck lymph nodes dissection. PMID- 26976033 TI - Buccinator Myomucosal Flap for Treatment of Osteoradionecrosis of the Mandible. AB - The use of a myomucosal flap from the buccinator muscle is a valuable reconstruction method for intraoral defects. In this paper, we report the clinical advantages of using a buccinator myomucosal flap for the treatment of partial mandibular defects caused by osteoradionecrosis. We implemented a buccinator myomucosal flap for the reconstruction of a partial mandibular defect in a 55-year-old man with tonsil cancer and partial mandibular defects caused by osteoradionecrosis. The total operating time was 90 minutes. Twelve months after the reconstruction, the patient remains free of disease. A buccinator myomucosal flap can be used for the reconstruction of partial mandibular defects caused by osteoradionecrosis. It is a reliable method for reconstructing small mandibular defects. PMID- 26976032 TI - Metastases of Melanoma to Head and Neck Mucosa: A Report of Short Series. AB - OBJECTIVES: Metastasis of melanoma to the head and neck mucosa is a very unusual condition. The aim of this study was to report four cases of patients with metastatic melanoma in the head and neck mucosa treated at a single institution. METHODS: Clinical data were obtained from the medical records. All cases were histologically reviewed to confirm the diagnosis, and immunohistochemical reactions were performed in the cases submitted to biopsy. RESULTS: All patients were males and the mean age was 40.5 years old. The sites of the metastatic tumors were gingival mucosa, floor of the mouth, oropharynx, and larynx. Two tumors appeared as submucosal nodules with normal color; one lesion was a blackish nodular lesion, and one was shown to be an ulcerated lesion. The size of tumors ranged from 2.0 to 4.0 cm. All patients had developed systemic disease at time of diagnosis of metastatic tumor in the head and neck mucosa. Survival rates ranged from 2 to 19 months after the diagnosis of the metastatic mucosal melanoma in the head and neck region. CONCLUSION: Although rare, patients with melanoma must be closely and regularly followed up, with careful routine examination of head and neck, because metastatic tumors in this region seem to be part of a lethal widespread metastatic disease. PMID- 26976034 TI - Effect of High-Flow Nasal Oxygen on Pulmonary Complications and Outcomes After Adult Cardiothoracic Surgery: A Qualitative Review. PMID- 26976035 TI - Predicting Optimal Insertion Depth of a Left-sided Double-Lumen Endobronchial Tube. AB - OBJECTIVE: Appropriate placement of the double-lumen endobronchial tube (DLT) is essential for one-lung ventilation. Several formulae based on body height (BH) have been used for estimating the optimal insertion depth of a left-sided DLT. In this study, the authors examined the following 5 formulae for accuracy of prediction: 0.11*BH+10.53 (cm) from Brodsky et al(1); 0.15*BH+3.96 (cm) from Bahk and Oh(2); 0.148*BH+3.8 (cm) from Chow et al;(3) 0.1*BH+12.5 (cm) from Takita et al(4); and 0.1977*BH - 4.2423 (cm) (authors' formula). DESIGN: Single-center, retrospective, observational study. SETTING: University hospital. PARTICIPANTS: Anesthetic records of patients older than 20 years who received one-lung ventilation using a left-sided DLT were included. INTERVENTIONS: The patients' sex, age, body weight, BH, and the final correct insertion depth of the left sided DLT after fiberscope verification were recorded. Linear regression and correlation were used to analyze the data. MEASUREMENTS AND MAIN RESULTS: One hundred seventy anesthetic records were analyzed. The insertion depth was distributed normally in 4 groups with different BH intervals. The correlations between the correct insertion depth and all the lengths calculated using each formula were significant (p<0.001), with a similar high coefficient of determination (r = 0.809). The regression line derived from the authors' formula 0.1977*BH - 4.2423 (cm)-showed the most accuracy in predicting the correct insertion depth. CONCLUSIONS: The height-based formula of 170 - 29.5 - 5 - 1 (the insertion depth is 29.5 cm for patients who are 170 cm tall, and the insertion length is increased or decreased by 1 cm for every 5 cm increase or decrease in BH) modified by the equation of 0.1977*BH - 4.2423 is a useful tool to predict the optimal insertion depth in initially blind left-sided DLT insertion. PMID- 26976037 TI - Zero x-ray cardiac resynchronization therapy device implantation guided by a nonfluoroscopic mapping system: A pilot study. AB - BACKGROUND: Fluoroscopic guidance is the standard tool used in device implantation. This means that both the patient and the operator are exposed to radiation, which may sometimes be high. The possibility of single-lead permanent pacemaker implantation without fluoroscopy has already been demonstrated. OBJECTIVE: The aim of our study was to investigate the feasibility and reliability of biventricular device implantation guided only by an electroanatomic navigation system. METHODS: Sixty-one patients with heart failure underwent implantation of a cardiac resynchronization therapy (CRT) device with or without defibrillator (CRT-D; CRT-P). The procedure was performed with or without fluoroscopy guidance (Rx+; Rx0). In the latter case, the EnSite Velocity system was used; this system is able to reconstruct the anatomy and activation of the cardiac chambers by simultaneously collecting a "cloud" of anatomical points from multiple electrodes. RESULTS: Lead positioning was achieved in 24 of 26 patients undergoing CRT implantation without fluoroscopy (92% success). No complications were observed during the procedure and no catheter dislodgment occurred the day after the implantation or during 1-month follow-up. Procedure time progressively decreased from 136 minutes in the first case to 59 minutes in the last one, suggesting that operators gradually gained confidence while using the new technique. CONCLUSION: Our study demonstrates the feasibility, efficacy, and safety of lead positioning guided only by the nonfluoroscopic EnSite Velocity mapping system without the use of fluoroscopy in CRT-P or CRT-D implantation. The benefits in terms of significantly reduced fluoroscopy exposure are associated with technical and clinical advantages. PMID- 26976036 TI - Small RNA and PARE sequencing in flower bud reveal the involvement of sRNAs in endodormancy release of Japanese pear (Pyrus pyrifolia 'Kosui'). AB - BACKGROUND: In woody perennial plants, including deciduous fruit trees, such as pear, endodormancy is a strategy for surviving the cold winter. A better understanding of the mechanism underlying the endodormancy phase transition is necessary for developing countermeasures against the effects of global warming. In this study, we analyzed the sRNAome of Japanese pear flower buds in endodormant and ecodormant stages over two seasons by implementing of RNA-seq and degradome-sequencing. RESULTS: We identified 137 conserved or less conserved miRNAs and 50 pear-specific miRNAs. However, none of the conserved microRNAs or pear-specific miRNAs was differentially expressed between endodormancy and ecodormancy stages. On the contrast, 1540 of 218,050 loci that produced sRNAs were differentially expressed between endodormancy and ecodormancy, suggesting their potential roles on the phase transition from endodormancy to ecodomancy. We also characterized a multifunctional miRNA precursor MIR168, which produces two functional miR168 transcripts, namely miR168.1 and miR168.2; cleavage events were predominantly mediated by the non-conserved variant miR168.2 rather than the conserved variant miR168.1. Finally, we showed that a TAS3 trans-acting siRNA triggered phased siRNA within the ORF of one of its target genes, AUXIN RESPONSE FACTOR 4, via the analysis of phased siRNA loci, indicating that siRNAs are able to trigger phased siRNAs in pear. CONCLUSION: We analyzed the sRNAome of pear flower bud during dormant phase transition. Our work described the sRNA profiles of pear winter buds during dormant phase transition, showing that dormancy release is a highly coordinated physiological process involving the regulation of sRNAs. PMID- 26976038 TI - Percolation as a mechanism to explain atrial fractionated electrograms and reentry in a fibrosis model based on imaging data. AB - BACKGROUND: Complex fractionated atrial electrograms (CFAEs) have long been associated with proarrhythmic alterations in atrial structure or electrophysiology. Structural alterations disrupt and slow smoothly propagating wavefronts, leading to wavebreaks and electrogram (EGM) fractionation, but the exact nature and characteristics for arrhythmia remain unknown. Clinically, in atrial fibrillation (AF) patients, increases in frequency, whether by pacing or fibrillation, increase EGM fractionation and duration, and reentry can occur in relation with the conduction disturbance. Recently, percolation has been proposed as an arrhythmogenic mechanism, but its role in AF has not been investigated. OBJECTIVE: We sought to determine if percolation can explain reentry formation and EGM behavior observed in AF patients. METHODS: Computer models of fibrotic tissue with different densities were generated based on late gadolinium-enhanced magnetic resonance images, using pixel intensity as a fibrosis probability to avoid an arbitrary binary threshold. Clinical pacing protocols were followed to induce AF, and EGMs were computed. RESULTS: Reentry could be elicited, with a biphasic behavior dependent on fibrotic density. CFAEs were recorded above fibrotic regions, and consistent with clinical data, EGM duration and fractionation increased with more rapid pacing. CONCLUSION: These findings confirm percolation as a potential mechanism to explain AF in humans and give new insights into dynamics underlying conduction distortions and fractionated signals in excitable media, which correlate well with the experimental findings in fibrotic regions. The greater understanding of the different patterns of conduction changes and related EGMs could lead to more individualized and effective approaches to AF ablation therapy. PMID- 26976039 TI - Isoform switching of steroid receptor co-activator-1 attenuates glucocorticoid induced anxiogenic amygdala CRH expression. AB - Maladaptive glucocorticoid effects contribute to stress-related psychopathology. The glucocorticoid receptor (GR) that mediates many of these effects uses multiple signaling pathways. We have tested the hypothesis that manipulation of downstream factors ('coregulators') can abrogate potentially maladaptive GR mediated effects on fear-motivated behavior that are linked to corticotropin releasing hormone (CRH). For this purpose the expression ratio of two splice variants of steroid receptor coactivator-1 (SRC-1) was altered via antisense mediated 'exon-skipping' in the central amygdala of the mouse brain. We observed that a change in splicing towards the repressive isoform SRC-1a strongly reduced glucocorticoid-induced responsiveness of Crh mRNA expression and increased methylation of the Crh promoter. The transcriptional GR target gene Fkbp5 remained responsive to glucocorticoids, indicating gene specificity of the effect. The shift of the SRC-1 splice variants altered glucocorticoid-dependent exploratory behavior and attenuated consolidation of contextual fear memory. In conclusion, our findings demonstrate that manipulation of GR signaling pathways related to the Crh gene can selectively diminish potentially maladaptive effects of glucocorticoids. PMID- 26976040 TI - Connecting the dots, genome-wide association studies in substance use. PMID- 26976041 TI - Persistent inhibitory circuit defects and disrupted social behaviour following in utero exogenous cannabinoid exposure. AB - Placental transfer of Delta9-tetrahydrocannabinol (THC) during pregnancy has the potential to interfere with endogenous cannabinoid (CB) regulation of fetal nervous system development in utero. Here we examined the effect of maternal CB intake on mouse hippocampal interneurons largely focusing on cholecystokinin expressing interneurons (CCK-INTs), a prominent CB subtype-1 receptor (CB1R) expressing neuronal population throughout development. Maternal treatment with THC or the synthetic CB1R agonist WIN55,212-2 (WIN) produced a significant loss of CCK-INTs in the offspring. Further, residual CCK-INTs in animals prenatally treated with WIN displayed decreased dendritic complexity. Consistent with these anatomical deficits, pups born to CB-treated dams exhibited compromised CCK-INT mediated feedforward and feedback inhibition. Moreover, pups exposed to WIN in utero lacked constitutive CB1R-mediated suppression of inhibition from residual CCK-INTs and displayed altered social behavior. Our findings add to a growing list of potential cell/circuit underpinnings that may underlie cognitive impairments in offspring of mothers that abuse marijuana during pregnancy. PMID- 26976042 TI - DISC1 causes associative memory and neurodevelopmental defects in fruit flies. AB - Originally found in a Scottish family with diverse mental disorders, the DISC1 protein has been characterized as an intracellular scaffold protein that associates with diverse binding partners in neural development. To explore its functions in a genetically tractable system, we expressed the human DISC1 in fruit flies (Drosophila melanogaster). As in mammalian neurons, DISC1 is localized to diverse subcellular domains of developing fly neurons including the nuclei, axons and dendrites. Overexpression of DISC1 impairs associative memory. Experiments with deletion/mutation constructs have revealed the importance of amino-terminal domain (46-290) for memory suppression whereas carboxyl domain (598-854) and the amino-terminal residues (1-45) including the nuclear localization signal (NLS1) are dispensable. DISC1 overexpression also causes suppression of axonal and dendritic branching of mushroom body neurons, which mediate a variety of cognitive functions in the fly brain. Analyses with deletion/mutation constructs reveal that protein domains 598-854 and 349-402 are both required for the suppression of axonal branching, while amino-terminal domains including NLS1 are dispensable. In contrast, NLS1 was required for the suppression of dendritic branching, suggesting a mechanism involving gene expression. Moreover, domain 403-596 is also required for the suppression of dendritic branching. We also show that overexpression of DISC1 suppresses glutamatergic synaptogenesis in developing neuromuscular junctions. Deletion/mutation experiments have revealed the importance of protein domains 403 596 and 349-402 for synaptic suppression, while amino-terminal domains including NLS1 are dispensable. Finally, we show that DISC1 functionally interacts with the fly homolog of Dysbindin (DTNBP1) via direct protein-protein interaction in developing synapses. PMID- 26976046 TI - Infrared camera based thermometry for quality assurance of superficial hyperthermia applicators. AB - The purpose of this work was to provide a feasible and easy to apply phantom based quality assurance (QA) procedure for superficial hyperthermia (SHT) applicators by means of infrared (IR) thermography. The VarioCAM hr head (InfraTec, Dresden, Germany) was used to investigate the SA-812, the SA-510 and the SA-308 applicators (all: Pyrexar Medical, Salt Lake City, UT, USA). Probe referencing and thermal equilibrium procedures were applied to determine the emissivity of the muscle-equivalent agar phantom. Firstly, the disturbing potential of thermal conduction on the temperature distribution inside the phantom was analyzed through measurements after various heating times (5-50 min). Next, the influence of the temperature of the water bolus between the SA-812 applicator and the phantom's surface was evaluated by varying its temperature. The results are presented in terms of characteristic values (extremal temperatures, percentiles and effective field sizes (EFS)) and temperature-area histograms (TAH). Lastly, spiral antenna applicators were compared by the introduced characteristics. The emissivity of the used phantom was found to be epsilon = 0.91 +/- 0.03, the results of both methods coincided. The influence of thermal conduction with regard to heating time was smaller than expected; the EFS of the SA-812 applicator had a size of (68.6 +/- 6.7) cm(2), averaged group variances were +/-3.0 cm(2). The TAHs show that the influence of the water bolus is mostly limited to depths of <3 cm, yet it can greatly enhance or reduce heat generation in this regime: at a depth of 1 cm, measured maximal temperature rises were 14.5 degrees C for T Bolus = 30 degrees C and 8.6 degrees C for T Bolus = 21 degrees C, respectively. The EFS was increased, too. The three spiral antenna applicators generated similar heat distributions. Generally, the procedure proved to yield informative insights into applicator characteristics, thus making the application of an IR camera a very useful tool in SHT technical QA. PMID- 26976045 TI - Continuous time Bayesian networks identify Prdm1 as a negative regulator of TH17 cell differentiation in humans. AB - T helper 17 (TH17) cells represent a pivotal adaptive cell subset involved in multiple immune disorders in mammalian species. Deciphering the molecular interactions regulating TH17 cell differentiation is particularly critical for novel drug target discovery designed to control maladaptive inflammatory conditions. Using continuous time Bayesian networks over a time-course gene expression dataset, we inferred the global regulatory network controlling TH17 differentiation. From the network, we identified the Prdm1 gene encoding the B lymphocyte-induced maturation protein 1 as a crucial negative regulator of human TH17 cell differentiation. The results have been validated by perturbing Prdm1 expression on freshly isolated CD4(+) naive T cells: reduction of Prdm1 expression leads to augmentation of IL-17 release. These data unravel a possible novel target to control TH17 polarization in inflammatory disorders. Furthermore, this study represents the first in vitro validation of continuous time Bayesian networks as gene network reconstruction method and as hypothesis generation tool for wet-lab biological experiments. PMID- 26976047 TI - Triggering Receptor Expressed on Myeloid Cells 2 Deficiency Alters Acute Macrophage Distribution and Improves Recovery after Traumatic Brain Injury. AB - Traumatic brain injury (TBI) affects 1.7 million persons annually in the United States (Centers for Disease Control and Prevention). There is increasing evidence that persons exposed to TBI have increased risk of the development of multiple neurodegenerative conditions, including Alzheimer disease (AD). TBI triggers a strong neuroinflammatory response characterized by astrogliosis, activation of microglia, and infiltration of peripheral monocytes. Recent evidence suggests that alterations in innate immunity promote neurodegeneration. This includes genetic studies demonstrating that mutations in triggering receptor expressed on myeloid cells 2 (TREM2) is associated with a higher risk for not only AD but also multiple neurodegenerative diseases. To examine whether TREM2 deficiency affects pathological outcomes of TBI, Trem2 knockout (Trem2-/-) and C57BL/6J (B6) mice were given a lateral fluid percussion injury (FPI) and sacrificed at 3 and 120 days post-injury (DPI) to look at both acute and chronic consequences of TREM2 deficiency. Notably, at 3 DPI, B6 mice exposed to TBI exhibited increased expression of TREM2 in the brain. Further, Trem2-/- mice exposed to TBI exhibited enhanced macrophage activation near the lesion, but significantly less macrophage activation away from the lesion when compared with B6 mice exposed to TBI. In addition, at 120 DPI, Trem2-/- mice exposed to TBI demonstrated reduced hippocampal atrophy and rescue of TBI-induced behavioral changes when compared with B6 mice exposed to TBI. Taken together, this study suggests that TREM2 deficiency influences both acute and chronic responses to TBI, leading to an altered macrophage response at early time points, and improved pathological and functional outcomes at later time points. PMID- 26976044 TI - Universally Conserved Relationships between Nuclear Shape and Cytoplasmic Mechanical Properties in Human Stem Cells. AB - The ability of cells to proliferate, differentiate, transduce extracellular signals and assemble tissues involves structural connections between nucleus and cytoskeleton. Yet, how the mechanics of these connections vary inside stem cells is not fully understood. To address those questions, we combined two-dimensional particle-tracking microrheology and morphological measures using variable reduction techniques to measure whether cytoplasmic mechanics allow for discrimination between different human adherent stem cell types and across different culture conditions. Here we show that nuclear shape is a quantifiable discriminant of mechanical properties in the perinuclear cytoskeleton (pnCSK) of various stem cell types. Also, we find the pnCSK is a region with different mechanical properties than elsewhere in the cytoskeleton, with heterogeneously distributed locations exhibiting subdiffusive features, and which obeys physical relations conserved among various stem cell types. Finally, we offer a prospective basis to discriminate between stem cell types by coupling perinuclear mechanical properties to nuclear shape. PMID- 26976043 TI - Genome-wide significant risk factors for Alzheimer's disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment. AB - Few data are available concerning the role of risk markers for Alzheimer's disease (AD) in progression to AD dementia among subjects with mild cognitive impairment (MCI). We therefore investigated the role of well-known AD-associated single-nucleotide polymorphism (SNP) in the progression from MCI to AD dementia. Four independent MCI data sets were included in the analysis: (a) the German study on Aging, Cognition and Dementia in primary care patients (n=853); (b) the German Dementia Competence Network (n=812); (c) the Fundacio ACE from Barcelona, Spain (n=1245); and (d) the MCI data set of the Amsterdam Dementia Cohort (n=306). The effects of single markers and combined polygenic scores were measured using Cox proportional hazards models and meta-analyses. The clusterin (CLU) locus was an independent genetic risk factor for MCI to AD progression (CLU rs9331888: hazard ratio (HR)=1.187 (1.054-1.32); P=0.0035). A polygenic score (PGS1) comprising nine established genome-wide AD risk loci predicted a small effect on the risk of MCI to AD progression in APOE-E4 (apolipoprotein E-E4) carriers (HR=1.746 (1.029-2.965); P=0.038). The novel AD loci reported by the International Genomics of Alzheimer's Project were not implicated in MCI to AD dementia progression. SNP-based polygenic risk scores comprising currently available AD genetic markers did not predict MCI to AD progression. We conclude that SNPs in CLU are potential markers for MCI to AD progression. PMID- 26976048 TI - Clinical Practice Pattern of Immediate Intravesical Chemotherapy following Transurethral Resection of a Bladder Tumor in Korea: National Health Insurance Database Study. AB - We evaluated the frequency and practice pattern of immediate postoperative intravesical chemotherapy (PIC) after transurethral resection of a bladder tumor (TURBT) in suspected non-muscle-invasive bladder cancer (NMIBC). Information from the Health Insurance Review and Assessment Service database from January 1, 2008 to December 31, 2013 was used. Patients with bladder cancer who received TURBT were considered as the cases (37,941 patients and 59,568 cases). The time of PIC after TURBT, types of PIC regimens, and the potential effect of PIC on the delay for additional treatment were analyzed. The study cohort included 23,726 subjects and 30,473 cases with a mean age of 66.8 +/- 12.0 years, including 19,362 (81.6%) male patients. The rate of immediate PIC was 11.0% of cases (3,359 cases). There was significant difference in the frequency rate of additional treatment among patients with immediate PIC and patients without immediate PIC within 1 year from the first TURBT (15.2% vs 16.6%, p = 0.035). However, no difference was revealed for whole observational period (33.7% vs 34.5%, p = 0.373). The frequency rate of immediate PIC after TURBT for suspected NMIBC was low in real clinical practice. More efforts are needed to improve the usage rate of PIC after TURBT for suspected NMIBC. PMID- 26976049 TI - Local Light-Induced Modification of the Inside of Microfluidic Glass Chips. AB - The ability to locally functionalize the surface of glass allows for myriad biomedical and chemical applications. This would be the case if the surface functionalization can be induced using light with wavelengths for which standard glass is almost transparent. To this aim, we present the first example of a photochemical modification of hydrogen-terminated glass (H-glass) with terminal alkenes. Both flat glass surfaces and the inside of glass microchannels were modified with a well-defined, covalently attached organic monolayer using a range of wavelengths, including sub-band-gap 302 nm ultraviolet light. A detailed characterization thereof was conducted by measurements of the static water contact angle, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and scanning Auger microscopy (SAM). Germanium attenuated total reflection Fourier transform infrared (GATR-FTIR) indicates that the mechanism of the surface modification proceeds via an anti-Markovnikov substitution. Reacting H-glass with 10-trifluoro-acetamide-1-decene (TFAAD) followed by basic hydrolysis affords the corresponding primary amine-terminated monolayer, enabling additional functionalization of the substrate. Furthermore, we show the successful formation of a photopatterned amine layer by the specific attachment of fluorescent nanoparticles in very discrete regions. Finally, a microchannel was photochemically patterned with a functional linker allowing for surface-directed liquid flow. These results demonstrate that H-glass can be modified with a functional tailor-made organic monolayer, has highly tunable wetting properties, and displays significant potential for further applications. PMID- 26976050 TI - Interplay between insecticide-treated bed-nets and mosquito demography: implications for malaria control. AB - Although malaria prevalence has witnessed a significant reduction within the past decade, malaria still constitutes a major health and economic problem, especially to low-income countries. Insecticide-treated nets (ITNs) remain one of the primary measures for preventing the malignant disease. Unfortunately, the success of ITN campaigns is hampered by improper use and natural decay in ITN-efficacy over time. Many models aimed at studying malaria transmission and control fail to account for this decay, as well as mosquito demography and feeding preferences exhibited by mosquitoes towards humans. Omitting these factors can misrepresent disease risk, while understanding their effects on malaria dynamics can inform control policy. We present a model for malaria dynamics that incorporates these factors, and a systematic analysis, including stability and sensitivity analyses of the model under different conditions. The model with constant ITN-efficacy exhibits a backward bifurcation emphasizing the need for sustained control measures until the basic reproduction number, R0, drops below a critical value at which control is feasible. The infectious and partially immune human populations and R0 are highly sensitive to the probability that a mosquito feeds successfully on a human, ITN coverage and the maximum biting rate of mosquitoes, irrespective of whether ITN-efficacy is constant or declines over time. This implies that ITNs play an important role in disease control. When ITN-efficacy wanes over time, we identify disease risks and corresponding ITN coverage, as well as feeding preference levels for which the disease can be controlled or eradicated. Our study leads to important insights that could assist in the design and implementation of better malaria control strategies. We conclude that ITNs that can retain their effectiveness for longer periods will be more appropriate in the fight against malaria and that making more ITNs available to highly endemic regions is necessary for malaria containment. PMID- 26976051 TI - Evolution of worker policing. AB - Workers in insect societies are sometimes observed to kill male eggs of other workers, a phenomenon known as worker policing. We perform a mathematical analysis of the evolutionary dynamics of policing. We investigate the selective forces behind policing for both dominant and recessive mutations for different numbers of matings of the queen. The traditional, relatedness-based argument suggests that policing evolves if the queen mates with more than two males, but does not evolve if the queen mates with a single male. We derive precise conditions for the invasion and stability of policing alleles. We find that the relatedness-based argument is not robust with respect to small changes in colony efficiency caused by policing. We also calculate evolutionarily singular strategies and determine when they are evolutionarily stable. We use a population genetics approach that applies to dominant or recessive mutations of any effect size. PMID- 26976053 TI - The lag-time approach improved drug-outcome association estimates in presence of protopathic bias. AB - OBJECTIVES: Protopathic bias is a systematic error which occurs when measured exposure status may be affected by the latent onset of the target outcome. In this article, we aimed to discuss the benefits and drawbacks of the lag-time approach to address this type of bias. STUDY DESIGN AND SETTING: The lag-time approach consists in excluding from exposure assessment the period immediately preceding the outcome detection date. With the help of simple causal diagrams, we illustrate the rationale and limitations of such strategy. The lag-time approach was illustrated in a case-crossover study, based on the health care utilization databases of the Italian Lombardy Region, on the real-world effectiveness of some respiratory drugs (exposure) in preventing asthma exacerbations (outcome). RESULTS: A total of 7,300 of patients who were admitted to an emergency department (ED) for asthma during 2010-2012 (cases) were included. Use (vs. nonuse) of short-acting beta-agonists (SABAs, an asthma reliever medication) during the 90 days before the ED admission date was associated with an increased risk of the outcome [odds ratio (OR): 1.95; 95% confidence interval (CI): 1.72, 2.22]. This paradoxical finding may be explained by protopathic bias, as SABA use prior the ED admission may be affected by preceding respiratory distress. Indeed, when a 120-day period preceding the ED admission was ignored from drug exposure assessment (lag time), SABAs were found to be associated with a reduced risk of the outcome (OR: 0.81; 95% CI: 0.84, 0.92), as expected. CONCLUSIONS: The lag time approach can be a useful strategy to circumvent protopathic bias in observational studies. PMID- 26976054 TI - Complementary approaches to searching MEDLINE may be sufficient for updating systematic reviews. AB - OBJECTIVES: To maximize the proportion of relevant studies identified for inclusion in systematic reviews (recall), complex time-consuming Boolean searches across multiple databases are common. Although MEDLINE provides excellent coverage of health science evidence, it has proved challenging to achieve high levels of recall through Boolean searches alone. STUDY DESIGN AND SETTING: Recall of one Boolean search method, the clinical query (CQ), combined with a ranking method, support vector machine (SVM), or PubMed-related articles, was tested against a gold standard of studies added to 6 updated Cochrane reviews and 10 Agency for Healthcare Research and Quality (AHRQ) evidence reviews. For the AHRQ sample, precision and temporal stability were examined for each method. RESULTS: Recall of new studies was 0.69 for the CQ, 0.66 for related articles, 0.50 for SVM, 0.91 for the combination of CQ and related articles, and 0.89 for the combination of CQ and SVM. Precision was 0.11 for CQ and related articles combined, and 0.11 for CQ and SVM combined. Related articles showed least stability over time. CONCLUSIONS: The complementary combination of a Boolean search strategy and a ranking strategy appears to provide a robust method for identifying relevant studies in MEDLINE. PMID- 26976055 TI - [Renal medulla]. AB - The ability to produce hyperosmotic urine allows mammals, including humans, to excrete their soluble mineral and organic waste products in the urine with a limited amount of water. The urinary concentrating capacity depends primarily on a special "loop-shaped" architecture of the nephrons and vessels, observed only in mammals. It also depends on the influence of antidiuretic hormone on the permeability to water of the collecting ducts on their entire length, and on the permeability to urea limited to the terminal portion of these ducts in the inner medulla. The ability to concentrate urine also requires (1) an "engine" able to produce an active (energy demanding) transport that generates a transepithelial concentration difference leading to increase the solute concentration in the surrounding interstitium; and (2) the expression of several membrane transporters or channels localized very specifically to limited portions of some nephron segments, collecting ducts and arterial vasa recta. These transporters and channels greatly accelerate the transport of water and some solutes across the cell membranes. Even if some nephron segments and parts of the collecting system are present in both the renal cortex and medulla (namely, the proximal tubule, the thick ascending limb and the collecting duct), their functions in the two renal zones may not be strictly similar, owing to their different peritubular environment, to the composition of the fluid running in their lumen, and to some differences in their epithelium. This paper describes some characteristics and specific functions of these structures in the renal medulla, as opposed to their corresponding structures in the cortex. These specific functions operating in the medulla may lead to various adverse consequences in some pathological situations. PMID- 26976056 TI - Maremar, prevalence of chronic kidney disease, how to avoid over-diagnosis and under-diagnosis. AB - Chronic kidney disease is considered as a major public health problem. Recent studies mention a prevalence rate between 8%-12%. Several editorials, comments, short reviews described the weaknesses (lack of confirmation of proteinuria, and of chronicity of decreased estimated glomerular filtration rate) of a substantial number of studies and the irrational of using a single arbitrary set point, i.e. diagnosis of chronic kidney disease whenever the estimated glomerular filtration rate is less than 60mL/min/1.73m(2). Maremar (Maladies renales chroniques au Maroc) is a prevalence study of chronic kidney disease, hypertension, diabetes and obesity in a randomized, representative, high response rate (85%), sample of the adult population of Morocco, strictly applying the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Compared to the vast majority of the available studies, Maremar has a low prevalence of chronic kidney disease (2.9% adjusted to the actual adult population of Morocco). The population pyramid, and particularly the confirmation of proteinuria and "chronicity" of the decreased estimated glomerular filtration rate are the main reasons for this low prevalence of chronic kidney disease. The choice of arbitrary single threshold of estimated glomerular filtration rate for classifying stage 3-5 chronic kidney disease inevitably leads to "over-diagnosis" (false positives) of the disease in the elderly, particularly those without proteinuria, hematuria or hypertension, and to "under-diagnosed" (false negatives) in younger individuals with an estimated glomerular filtration rate above 60mL/min/1.73m(2) and below the 3rd percentile of their age/gender category. There is an urgent need for quality studies using in a correct way the recent KDIGO guidelines when investigating the prevalence of chronic kidney disease, in order to avoid a 50 to 100% overestimation of a disease state with potential dramatic consequences. The combination of the general population screening encompassing four different major health problems in the same screening procedure, using the correct methodologies and procedures, combined with a prevention/follow-up program results in a clinically/scientifically relevant program. PMID- 26976052 TI - Hemodynamic (fNIRS) and EEG (N200) correlates of emotional inter-species interactions modulated by visual and auditory stimulation. AB - The brain activity, considered in its hemodynamic (optical imaging: functional Near-Infrared Spectroscopy, fNIRS) and electrophysiological components (event related potentials, ERPs, N200) was monitored when subjects observed (visual stimulation, V) or observed and heard (visual + auditory stimulation, VU) situations which represented inter-species (human-animal) interactions, with an emotional positive (cooperative) or negative (uncooperative) content. In addition, the cortical lateralization effect (more left or right dorsolateral prefrontal cortex, DLPFC) was explored. Both ERP and fNIRS showed significant effects due to emotional interactions which were discussed at light of cross modal integration effects. The significance of inter-species effect for the emotional behavior was considered. In addition, hemodynamic and EEG consonant results and their value as integrated measures were discussed at light of valence effect. PMID- 26976059 TI - Full-field velocity imaging of red blood cells in capillaries with spatiotemporal demodulation autocorrelation. AB - We propose a full-field optical method for the label-free and quantitative mapping of the velocities of red blood cells (RBCs) in capillaries. It integrates spatiotemporal demodulation and an autocorrelation algorithm, and measures RBC velocity according to the ratio of RBC length to lag time. Conventionally, RBC length is assumed to be a constant and lag time is taken as a variable, while our method treats both of them as variables. We use temporal demodulation and the Butterworth spatial filter to separate RBC signal from background signal, based on which we obtain the RBC length by image segmentation and lag time by autocorrelation analysis. The RBC velocity calculated now is more accurate. The validity of our method is verified by an in vivo experiment on a mouse ear. Owing to its higher image signal-to-noise ratio, our method can be used for mapping RBC velocity in the turbid tissue case. PMID- 26976058 TI - [Renal elastography]. AB - Renal elastography has become available with the development of noninvasive quantitative techniques (including shear-wave elastography), following the rapidly growing field of diagnosis and quantification of liver fibrosis, which has a demonstrated major clinical impact. Ultrasound or even magnetic resonance techniques are leaving the pure research area to reach the routine clinical use. With the increased incidence of chronic kidney disease and its specific morbidity and mortality, the noninvasive diagnosis of renal fibrosis can be of critical value. However, it is difficult to simply extend the application from one organ to the other due to a large number of anatomical and technical issues. Indeed, the kidney exhibits various features that make stiffness assessment more complex, such as the presence of various tissue types (cortex, medulla), high spatial orientation (anisotropy), local blood flow, fatty sinus with variable volume and echotexture, perirenal space with variable fatty content, and the variable depth of the organ. Furthermore, the stiffness changes of the renal parenchyma are not exclusively related to fibrosis, as renal perfusion or hydronephrosis will impact the local elasticity. Renal elastography might be able to diagnose acute or chronic obstruction, or to renal tumor or pseudotumor characterization. Today, renal elastography appears as a promising application that still requires optimization and validation, which is the contrary for liver stiffness assessment. PMID- 26976057 TI - [The French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort study: To better understand chronic kidney disease]. AB - BACKGROUND: Preserving kidney function and improving the transition from chronic kidney disease to end stage is a research and healthcare challenge. The national Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort was established to identify the determinants, biomarkers and practice patterns associated with chronic kidney disease outcomes. METHODS: The study will include more than 3000 adult patients with moderate to advanced chronic kidney disease from a representative sample of 40 nephrology clinics with respect to regions and legal status, public or private. Patients are recruited during a routine visit and followed for 5 years, before and after starting renal replacement therapy. Patient-level clinical, biological, and lifestyle data are collected annually, as well as provider-level data on clinical practices, coordinated with the International Chronic Kidney Disease Outcomes and Practice Pattern Study. Blood and urine samples are stored in a biobank. Major studied outcomes include survival, patient-reported outcomes, disease progression and hospitalizations. RESULTS: More than 13,000 eligible patients with chronic kidney disease were identified, 60% with stage 3 and 40% with stage 4. Their median age is 72 years [interquartile range, 62-80 years], 60% are men and 38% have diabetes. By the end of December 2015, 2885 patients were included. CONCLUSION: The CKD-REIN cohort will serve to improve our understanding of chronic kidney disease and provide evidence to improve patient survival and quality of life as well as health care system performances. PMID- 26976060 TI - Speciation and transformation of heavy metals during vermicomposting of animal manure. AB - This work was conducted to evaluate the effects of vermicomposting on the speciation and mobility of heavy metals (Zn, Pb, Cr, and Cu) in cattle dung (CD) and pig manure (PM) using tessier sequential extraction method. Results showed that the pH, total organic carbon and C/N ratio were reduced, while the electric conductivity and humic acid increased after 90days vermicomposting. Moreover, the addition of earthworm could accelerate organic stabilization in vermicomposting. The total heavy metals in final vermicompost from CD and PM were higher than the initial values and the control without worms. Sequential extraction indicated that vermicomposting decreased the migration and availability of heavy metals, and the earthworm could reduce the mobile fraction, while increase the stable fraction of heavy metals. Furthermore, these results indicated that vermicomposting played a positive role in stabilizing heavy metals in the treatment of animal manure. PMID- 26976061 TI - Purification and characterisation of processive-type endoglucanase and beta glucosidase from Aspergillus ochraceus MTCC 1810 through saccharification of delignified coir pith to glucose. AB - The study describes purification and characterisation of processive-type endoglucanase and beta-glucosidase from Aspergillus ochraceus MTCC 1810 through bioconversion of delignified coir pith to fermentable glucose. The purified processive endoglucanase (AS-HT-Celuz A) and beta-glucosidase (AS-HT-Celuz B) were found to have molecular mass of ~78-kDa and 43-kDa respectively with optimum endoglucanase (35.63U/ml), total cellulase (28.15FPU/ml) and beta-glucosidase (15.19U/ml) activities at 40 degrees C/pH 6. The unique feature of AS-HT-Celuz A is the multiple substrate specificity and processivity towards both amorphous and crystalline cellulose. Zymogram indicated both endo and exoglucanase activities residing in different binding sites of a single protein exhibiting sequential synergy with its own beta-glucosidase. Accordingly, the identified enzymes could be implemented as synergistic cellulases for complete cellulose saccharification which still considered an unresolved issue in bio-refineries. PMID- 26976062 TI - Mild hydrothermal conditioning prior to torrefaction and slow pyrolysis of low value biomass. AB - The aim of this research was to establish whether hydrothermal conditioning and subsequent thermochemical processing via batch torrefaction or slow pyrolysis may improve the fuel quality of grass residues. A comparison in terms of fuel quality was made of the direct thermochemical processing of the feedstock versus hydrothermal conditioning as a pretreatment prior to thermochemical processing. Hydrothermal conditioning reduced ash content, and particularly nitrogen, potassium and chlorine contents in the biomass. The removal of volatile organic matter associated with thermochemical processes can increase the HHV to levels of volatile bituminous coal. However, slow pyrolysis only increased the HHV of biomass provided a low ash content (<6%) feedstock was used. In conclusion, hydrothermal conditioning can have a highly positive influence on the efficiency of thermochemical processes for upgrading low-value (high-ash) biomass to a higher quality fuel. PMID- 26976063 TI - Ayahuasca: Pharmacology, neuroscience and therapeutic potential. AB - Ayahuasca is the Quechua name for a tea obtained from the vine Banisteriopsis caapi, and used for ritual purposes by the indigenous populations of the Amazon. The use of a variation of the tea that combines B. caapi with the leaves of the shrub Psychotria viridis has experienced unprecedented expansion worldwide for its psychotropic properties. This preparation contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT) from P. viridis, plus beta carboline alkaloids with monoamine-oxidase-inhibiting properties from B. caapi. Acute administration induces a transient modified state of consciousness characterized by introspection, visions, enhanced emotions and recollection of personal memories. A growing body of evidence suggests that ayahuasca may be useful to treat substance use disorders, anxiety and depression. Here we review the pharmacology and neuroscience of ayahuasca, and the potential psychological mechanisms underlying its therapeutic potential. We discuss recent findings indicating that ayahuasca intake increases certain mindfulness facets related to acceptance and to the ability to take a detached view of one's own thoughts and emotions. Based on the available evidence, we conclude that ayahuasca shows promise as a therapeutic tool by enhancing self-acceptance and allowing safe exposure to emotional events. We postulate that ayahuasca could be of use in the treatment of impulse-related, personality and substance use disorders and also in the handling of trauma. More research is needed to assess the full potential of ayahuasca in the treatment of these disorders. PMID- 26976064 TI - Deep Brain Stimulation Target Selection for Parkinson's Disease. AB - During the "DBS Canada Day" symposium held in Toronto July 4-5, 2014, the scientific committee invited experts to discuss three main questions on target selection for deep brain stimulation (DBS) of patients with Parkinson's disease (PD). First, is the subthalamic nucleus (STN) or the globus pallidus internus (GPi) the ideal target? In summary, both targets are equally effective in improving the motor symptoms of PD. STN allows a greater medications reduction, while GPi exerts a direct antidyskinetic effect. Second, are there further potential targets? Ventral intermediate nucleus DBS has significant long-term benefit for tremor control but insufficiently addresses other motor features of PD. DBS in the posterior subthalamic area also reduces tremor. The pedunculopontine nucleus remains an investigational target. Third, should DBS for PD be performed unilaterally, bilaterally or staged? Unilateral STN DBS can be proposed to asymmetric patients. There is no evidence that a staged bilateral approach reduces the incidence of DBS-related adverse events. PMID- 26976065 TI - Laparoscopic Pyeloplasty: Always Dismembered? AB - OBJECTIVE: To compare three laparoscopic surgical techniques for the treatment of ureteropelvic junction obstruction (UPJO), assessing their difficulty, operating time, effectiveness, and complications. MATERIALS AND METHODS: The clinical histories of 54 patients with UPJO who underwent a laparoscopic procedure between June 2003 and September 2013 were reviewed. Anderson-Hynes (A-H) pyeloplasty was performed on 34 patients, nondismembered pyeloplasty on 11 cases (8 Y-V Foley plasty and 3 Fenger plasty), and cephalad vascular displacement or Hellstrom technique (HT) on 9 patients. The patients were selected for the different techniques depending on the findings during the procedures, according to renal pelvic size and the presence of crossing vessels. We compared the techniques according to intraoperative and postoperative outcomes. Complications were interpreted following the Clavien-Dindo classification. The success rate was defined as the absence of clinical symptoms and normal diuretic renography. Analysis of variance and chi-square tests were used for the statistical analysis. RESULTS: Mean follow-up was 55.58 months. The success rate achieved was 88.5% for A-H pyeloplasty, 90.9% for nondismembered pyeloplasty, and 100% for HT (p > 0.05). HT was the least time-consuming: 124 +/- 30 vs 202 +/- 44 minutes of A-H pyeloplasty and 147 +/- 27 minutes of nondismembered plasty (p < 0.005). Mean hospital stay was 6.7 +/- 1.4 days for A-H pyeloplasty, 6.6 +/- 2 days for nondismembered pyeloplasty, and 3.42 +/- 1.5 days for HT (p < 0.05). The postoperative complication rate was 21.1% for A-H pyeloplasty, 18.8% for nondismembered pyeloplasty, and 12.5% for HT (p > 0.05). None of the cases required open surgery, and urinary fistula was the most frequent complication. CONCLUSION: Intraoperative observation of ureteropelvic junction allows selecting cases to undergo nondismembered pyeloplasty techniques, achieving similar results to A-H pyeloplasty, reducing operating time, complication rate, and hospital stay. PMID- 26976066 TI - Automatic assessment of cardiac load due to acute pulmonary embolism: Saddle vs. central and peripheral emboli distribution. AB - BACKGROUND: Changes in cardiac chambers' volumes in relations to different distributions of pulmonary embolism (PE) have not been investigated. OBJECTIVES: To compare cardiac chambers' volumes of patients with saddle, central or peripheral PE. METHODS: Consecutive patients with PE on computed tomography pulmonary angiography (CTPA), 1/2007-12/2010, divided according to emboli distribution. Software automatically provided the volumes of each cardiac compartment. We measured the ability of each chamber's volume and ratios between the right and left ventricles (RV/LV) and right and left atria (RA/LA) to discriminate between emboli locations. RESULTS: Among the 636 patients, 325 (51%) had peripheral, 278 (44%) central and 33 (5%) had saddle emboli. The RV/LV and RA/LA volume ratios discriminated well between saddle and central PE (AUC >=0.74) and saddle and peripheral PE (AUC >=0.83), but not between central and peripheral PE (AUC <=0.6). CONCLUSION: Automatic volumetric analysis of diagnostic CTPAs provides rapid tool which can discriminate between cardiac responses in saddle, central or peripheral PE. PMID- 26976067 TI - Resveratrol inhibits Trypanosoma cruzi arginine kinase and exerts a trypanocidal activity. AB - Arginine kinase catalyzes the reversible transphosphorylation between ADP and phosphoarginine which plays a critical role in the maintenance of cellular energy homeostasis. Arginine kinase from the protozoan parasite Trypanosoma cruzi, the etiologic agent of Chagas disease, meets the requirements to be considered as a potential therapeutic target for rational drug design including being absent in its mammalian hosts. In this study a group of polyphenolic compounds was evaluated as potential inhibitors of arginine kinase using molecular docking techniques. Among the analyzed compounds with the lowest free binding energy to the arginine kinase active site (<-6.96kcal/mol), resveratrol was chosen for subsequent assays. Resveratrol inhibits 50% of recombinant arginine kinase activity at 325MUM. The trypanocidal effect of resveratrol was evaluated on the T. cruzi trypomastigotes bursting from infected CHO K1 cells, with IC50=77MUM. Additionally epimastigotes overexpressing arginine kinase were 5 times more resistant to resveratrol compared to controls. Taking into account that: (1) resveratrol is considered as completely nontoxic; (2) is easily accessible due to its low market price; and (3) has as a well-defined target enzyme which is absent in the mammalian host, it is a promising compound as a trypanocidal drug for Chagas disease. PMID- 26976068 TI - Physico-chemical, functional and structural properties of RS3/RS4 from kidney bean (Phaseolus vulgaris) cultivars. AB - Starch isolated from four kidney bean cultivars (Yellow bean, Red bean, Black bean and White bean) were physically and chemically modified in order to prepare resistant starch (RS3/RS4). Following the Heat-moisture treatment (HMT) and Citric acid modification (CT) of the native starch, the amylose content got decreased whereas bulk and tapped density (g/ml) increased. Both HMT and CT reduced the swelling power and the solubility of native starch. Pasting temperature increased and peak, breakdown, final, and set-back viscosity decreased after both the modifications. Fourier Transform Infrared Spectroscopy (FTIR) analysis displayed peaks at 1020cm(-1) in HMT and 1724cm(-1) in CT starches. Differential Scanning Calorimetry (DSC) analysis revealed that samples were more stable after modification. X-ray diffraction (XRD) analysis revealed reordering of chain segments to more crystalline structure. These results suggested modifications resulted in starch with improved properties and could be a possible method for the RS preparation with better thermal stability. PMID- 26976069 TI - Quantification and evaluation of thymoquinone loaded mucoadhesive nanoemulsion for treatment of cerebral ischemia. AB - Stroke is an important cause of deaths worldwide, resulting in an irreversible deterioration of the central nervous system. Finally, production of more free radicals. Therefore, Thymoquinone is having antioxidant property and reported to have a potential role in the amelioration of cerebral ischemia but due to low solubility and poor absorption; they exhibit low serum and tissue levels. Present work aims to prepare nanoemulsions in order enhance the bioavailability of drug and hence evaluate the drug targeting in brain via non-invasive nasal route administration. Thymoquinone Mucoadhesive Nanoemulsion (TMNE) was prepared by ionic gelation method; characterized for particles size, entrapment efficiency, zeta potential, and ex vivo permeation study. Optimized TMNE ended up with a mean globule size 94.8+/-6.61nm; zeta potential -13.5+/-1.01mV; drug content 99.86+/ 0.35% and viscosity 110+/-12cp. Ultra Performance Liquid Chromatography Photodiode Array (UPLC-PDA) based bioanalytical method was developed and validated for pharmacokinetics, biodistribution, brain-targeting efficiency (628.5786+/-44.79%) and brain drug-targeting potential (89.97+/-2.94%) studies via post intranasal administration which revealed enhanced bioavailability of TQ in brain as compared to intravenous administration. Improved neurobehavioural activity (locomotor and grip strength) was observed in middle cerebral artery occlusion induced cerebral ischemic rats after i.n. administration of TMNE. PMID- 26976070 TI - Immobilization of a novel cold active esterase onto Fe3O4~cellulose nano composite enhances catalytic properties. AB - A novel esterase, EstH was cloned, purified and characterized from the marine bacterium Zunongwangia sp. The purified EstH showed optimum activity at 30 degrees C and pH 8.5 with ~50% of original activity at 0 degrees C. EstH was stable in high salt conditions (0-4.5M NaCl). To improve the characteristics and explore the possibilities for application, a new immobilization matrix, Fe3O4~cellulose nano-composite, was prepared and was characterized by Fourier Transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscope (SEM). Interestingly the optimal temperature of immobilized EstH elevated to 35 degrees C. Compared to its free form, immobilized EstH showed better temperature stability (48.5% compared to 22.40% at 50 degrees C after 30min), prolonged half life (32h compared to 18h), higher storage stability (~71% activity compared to ~40% after 50days of storage), improved pH tolerance (~73% activity at pH 4 and 10), and, more importantly, reusability (~50% activity after 8 repetitive cycles of usage). Enzyme kinetics showed an increase in the Vmax (from 35.76 to 51.14MUM/min) and Kcat (from 365s(-1) to 520s(-1)) after immobilization. The superior catalytic properties of immobilized EstH suggest its great potential in biotechnology and industrial processes. PMID- 26976071 TI - Design, synthesis, and evaluation of chitosan conjugated GGRGDSK peptides as a cancer cell-targeting molecular transporter. AB - Targeting cancer cells using integrin receptor is one of the promising targeting strategies in drug delivery. In this study, we conjugated an integrin-binding ligand (GGRGDSK) peptide to chitosan oligosaccharide (COS) using sulfo-SMCC as a bifunctional linker to afford COS-SMCC-GGRGDSK. The conjugated polymer was characterized by FT-IR, (1)H NMR, (13)C NMR, and SEM. COS-SMCC-GGRGDSK did not show cytotoxicity up to a concentration of 1mg/mL in the human leukemia cell line (CCRF-CEM). The conjugate was evaluated for its ability to enhance the cellular uptake of a cell-impermeable cargo (e.g., F'-G(pY)EEI phosphopeptide) in CCRF CEM, and human ovarian carcinoma (SK-OV-3) cancer cell lines. Additionally, RGD modified and unmodified COS polymers were used to prepare nanoparticles by ionic gelation and showed particle size ranging from 187 to 338nm, and zeta potential of 12.2-18.3mV using dynamic light scattering. The efficiency of COS-NPs and COS SMCC-RGDSK NPs was assayed for translocation of two synthetic cytotoxic agents ((2-(2-aminoethylamino)-4-(4-chlorophenyl)-6-(1H-indol-3-yl) nicotinonitrile (ACIN), and 2-(2-aminoethylamino)-6-(1H-indol-3-yl)-4-(4-methoxyphenyl) nicotinonitrile (AMIN)) into CCRF-CEM and human prostate (DU-145) cancer cell lines. The results showed a dramatic reduction in the cell viability on their treatment with RGD targeted COS NPs in comparison to paclitaxel (PTX), free drug, and drug-loaded COS NPs. PMID- 26976072 TI - Contraceptive service delivery in Kenya: A qualitative study to identify barriers and preferences among female sex workers and health care providers. AB - OBJECTIVE: Female sex workers (FSWs) need access to contraceptive services, yet programs often focus on HIV prevention and less on the broader sexual and reproductive health needs of FSWs. We aimed to identify barriers to accessing contraceptive services among FSWs and preferences for contraceptive service delivery options among FSWs and health care providers (HCPs) in order to inform a service delivery intervention to enhance access to and use of contraceptives for FSWs in Kenya. STUDY DESIGN: Twenty focus group discussions were conducted with FSWs and HCPs in central Kenya. RESULTS: Three barriers were identified that limited the ability of FSWs to access contraceptive services: (1) an unsupportive clinic infrastructure, which consisted of obstructive factors such as long wait times, fees, inconvenient operating hours and perceived compulsory HIV testing; (2) discriminatory provider-client interactions, where participants believed negative and differential treatment from female and male staff members impacted FSWs' willingness to seek medical services; and (3) negative partner influences, including both nonpaying and paying partners. Drop-in centers followed by peer educators and health care facilities were identified as preferred service delivery options. CONCLUSIONS: FSWs may not be able to regularly access contraceptive services until interpersonal (male partners) and structural (facilities and providers) barriers are addressed. Alternative delivery options, such as drop-in centers coupled with peer educators, may be an approach worth evaluating. IMPLICATIONS STATEMENT: An unsupportive clinic infrastructure, discriminatory provider-client interactions and negative partner influences are barriers to FSWs accessing the contraception services they need. Alternative service delivery options, such integrating contraceptive service delivery at drop in centers designed for FSWs and information delivery through peer educators, might provide improved access and better service quality to FSWs seeking contraception. PMID- 26976073 TI - Susceptibility and possible resistance mechanisms in the palm species Phoenix dactylifera, Chamaerops humilis and Washingtonia filifera against Rhynchophorus ferrugineus (Olivier, 1790) (Coleoptera: Curculionidae). AB - Rhynchophorus ferrugineus, known as the Red Palm Weevil (RPW), is reported as a pest of up to 40 palm species. However, the susceptibility degree and the defense mechanisms of these species against this weevil are still poorly known. In Europe, the RPW is a major pest of Phoenix canariensis while other palm species, including the congeneric Phoenix dactylifera, seem to be less suitable hosts for this insect. The aim of our study was to compare the defensive response of P. dactylifera, Chamaerops humilis and Washingtonia filifera against R. ferrugineus and try to define the mechanisms of resistance that characterize these species. Bioassays were carried out to evaluate the mortality induced on RPW larvae by extracts from the leaf rachis of the studied palm species. Tests at semi-field scale were also conducted, based either on forced palm infestation, with larvae of RPW, or on natural infestation, with adult females. Rachis extracts from C. humilis and W. filifera caused 100% larval mortality after 2 days of exposure, while extracts of P. dactylifera did not impair larval survival. Independently of the effect of the leaf extracts, the weevils were unable to naturally infest the three palm species, although larval survival was high after forced infestation of the plants. We concluded that the observed lack of infestation of P. dactylifera by RPW is due to factors other than antibiosis. In W. filifera and C. humilis, although the presence of antixenosis mechanisms cannot be excluded, resistance to R. ferrugineus seems to rely on the presence of antibiosis compounds. PMID- 26976074 TI - In vitro cardiomyocyte-driven biogenerator based on aligned piezoelectric nanofibers. AB - Capturing the body's mechanical energy from the heart, lungs, and diaphragm can probably meet the requirements for in vivo applications of implantable biomedical devices. In this work, we present a novel contractile cardiomyocyte (CM)-driven biogenerator based on piezoelectric nanofibers (NFs) uniaxially aligned on a PDMS thin film. Flexible nanostructures interact with the CMs, as a physical cue to guide the CMs to align in a specific way, and create mechanical interfaces of contractile CMs and piezoelectric NFs. As such, the cellular construct features specific alignment and synchronous contraction, which realizes the maximal resultant force to drive the NFs to bend periodically. Studies on contraction mapping show that neonatal rat CMs self-assemble into a functional bio-bot film with well-defined axes of force generation. Consequently, the biogenerator produces an average voltage of 200 mV and current of 45 nA at the cell concentration of 1.0 million per ml, offering a biocompatible and scalable platform for biological energy conversion. PMID- 26976077 TI - Ambient-Temperature Trap/Release of Arsenic by Dielectric Barrier Discharge and Its Application to Ultratrace Arsenic Determination in Surface Water Followed by Atomic Fluorescence Spectrometry. AB - A novel dielectric barrier discharge reactor (DBDR) was utilized to trap/release arsenic coupled to hydride generation atomic fluorescence spectrometry (HG-AFS). On the DBD principle, the precise and accurate control of trap/release procedures was fulfilled at ambient temperature, and an analytical method was established for ultratrace arsenic in real samples. Moreover, the effects of voltage, oxygen, hydrogen, and water vapor on trapping and releasing arsenic by DBDR were investigated. For trapping, arsenic could be completely trapped in DBDR at 40 mL/min of O2 input mixed with 600 mL/min Ar carrier gas and 9.2 kV discharge potential; prior to release, the Ar carrier gas input should be changed from the upstream gas liquid separator (GLS) to the downstream GLS and kept for 180 s to eliminate possible water vapor interference; for arsenic release, O2 was replaced by 200 mL/min H2 and discharge potential was adjusted to 9.5 kV. Under optimized conditions, arsenic could be detected as low as 1.0 ng/L with an 8-fold enrichment factor; the linearity of calibration reached R(2) > 0.995 in the 0.05 MUg/L-5 MUg/L range. The mean spiked recoveries for tap, river, lake, and seawater samples were 98% to 103%; and the measured values of the CRMs including GSB-Z50004-200431, GBW08605, and GBW(E)080390 were in good agreement with the certified values. These findings proved the feasibility of DBDR as an arsenic preconcentration tool for atomic spectrometric instrumentation and arsenic recycling in industrial waste gas discharge. PMID- 26976076 TI - Enhanced Bone Repair by Guided Osteoblast Recruitment Using Topographically Defined Implant. AB - The rapid recruitment of osteoblasts in bone defects is an essential prerequisite for efficient bone repair. Conventionally, osteoblast recruitment to bone defects and subsequent bone repair has been achieved using growth factors. Here, we present a methodology that can guide the recruitment of osteoblasts to bone defects with topographically defined implants (TIs) for efficient in vivo bone repair. We compared circular TIs that had microgrooves in parallel or radial arrangements with nonpatterned implants for osteoblast migration and in vivo bone formation. In vitro, the microgrooves in the TIs enhanced both the migration and proliferation of osteoblasts. Especially, the microgrooves with radial arrangement demonstrated a much higher efficiency of osteoblast recruitment to the implants than did the other types of implants, which may be due to the efficient guidance of cell migration toward the cell-free area of the implants. The expression of the intracellular signaling molecules responsible for the cell migration was also upregulated in osteoblasts on the microgrooved TIs. In vivo, the TI with radially defined topography demonstrated much greater bone repair in mouse calvarial defect models than in the other types of implants. Taken together, these results indicate that implants with physical guidance can enhance tissue repair by rapid cell recruitment. PMID- 26976080 TI - [Morphea or juvenile localised scleroderma: Case report]. AB - INTRODUCTION: Morphea or juvenile localised scleroderma (JLS) is an autoimmune, inflammatory, chronic, slowly progressive connective tissue disease of unknown cause that preferably affects skin and underlying tissues. OBJECTIVE: To report a case of Juvenil Localised scleroderma in an 8-year old girl, contributing to an early diagnosis and treatment. CLINICAL CASE: The case is presented of an 8 year old girl who presented with indurated hypopigmented plaques, of linear distribution in the right upper extremity of two years onset, together with papery texture hyperpigmented indurated plaques with whitish areas of thinned skin in right lower extremity, and leg and ankle swelling. The clinical features and diagnostic tests, including histology were compatible with linear and pansclerotic JLS. She started with immunosuppressive therapy, physiotherapy, and occupational therapy. CONCLUSIONS: We report a case of linear and pansclerotic ELJ type, in which there was a 2 year delay in diagnosis, however the response to treatment was positive as expected. PMID- 26976079 TI - [Dandy-Walker variant: Case report]. AB - INTRODUCTION: Dandy Walker variant is defined by a variable hypoplasia of the cerebellar vermix with or without posterior fossa increase and without tentorium elevation. OBJECTIVE: describe the case of a rare disease and emphasise the need to clarify the aetiology of prenatal malformations, as well as its multidisciplinary management. CASE REPORT: A male patient, 8 years of age, with a history of Infantile Cerebral Palsy and epilepsy, who was admitted with a history of tonic-clonic seizures. He was admitted due to psycho-motor developmental delay. During his hospitalisation, he had multiple seizure episodes, controlled with anticonvulsants. A computerized tomography was performed, in which communication was observed between the cisterna magna and fourth ventricle (the latter increased in size). In addition, the cerebellar vermix showed a partial hypoplasia. All these findings were compatible with a variant of the Dandy Walker syndrome. CONCLUSION: Dandy Walker variant may be asymptomatic and the images found may not indicate them as the cause of developmental disorders, due to its association with multiple syndromes and chromosomal abnormalities. Clinical presentation and prognosis depends on the related disorders, and a multidisciplinary approach is important, because the treatment depends on the symptoms presented. PMID- 26976081 TI - [Cloverleaf skull and bilateral facial clefts: Additional care]. PMID- 26976082 TI - A Perceptual Pathway to Bias: Interracial Exposure Reduces Abrupt Shifts in Real Time Race Perception That Predict Mixed-Race Bias. AB - In two national samples, we examined the influence of interracial exposure in one's local environment on the dynamic process underlying race perception and its evaluative consequences. Using a mouse-tracking paradigm, we found in Study 1 that White individuals with low interracial exposure exhibited a unique effect of abrupt, unstable White-Black category shifting during real-time perception of mixed-race faces, consistent with predictions from a neural-dynamic model of social categorization and computational simulations. In Study 2, this shifting effect was replicated and shown to predict a trust bias against mixed-race individuals and to mediate the effect of low interracial exposure on that trust bias. Taken together, the findings demonstrate that interracial exposure shapes the dynamics through which racial categories activate and resolve during real time perceptions, and these initial perceptual dynamics, in turn, may help drive evaluative biases against mixed-race individuals. Thus, lower-level perceptual aspects of encounters with racial ambiguity may serve as a foundation for mixed race prejudice. PMID- 26976078 TI - Pharyngeal pumping in Caenorhabditis elegans depends on tonic and phasic signaling from the nervous system. AB - Rhythmic movements are ubiquitous in animal locomotion, feeding, and circulatory systems. In some systems, the muscle itself generates rhythmic contractions. In others, rhythms are generated by the nervous system or by interactions between the nervous system and muscles. In the nematode Caenorhabditis elegans, feeding occurs via rhythmic contractions (pumping) of the pharynx, a neuromuscular feeding organ. Here, we use pharmacology, optogenetics, genetics, and electrophysiology to investigate the roles of the nervous system and muscle in generating pharyngeal pumping. Hyperpolarization of the nervous system using a histamine-gated chloride channel abolishes pumping, and optogenetic stimulation of pharyngeal muscle in these animals causes abnormal contractions, demonstrating that normal pumping requires nervous system function. In mutants that pump slowly due to defective nervous system function, tonic muscle stimulation causes rapid pumping, suggesting tonic neurotransmitter release may regulate pumping. However, tonic cholinergic motor neuron stimulation, but not tonic muscle stimulation, triggers pumps that electrophysiologically resemble typical rapid pumps. This suggests that pharyngeal cholinergic motor neurons are normally rhythmically, and not tonically active. These results demonstrate that the pharynx generates a myogenic rhythm in the presence of tonically released acetylcholine, and suggest that the pharyngeal nervous system entrains contraction rate and timing through phasic neurotransmitter release. PMID- 26976083 TI - Infections and Elections: Did an Ebola Outbreak Influence the 2014 U.S. Federal Elections (and if so, How)? AB - In the studies reported here, we conducted longitudinal analyses of preelection polling data to test whether an Ebola outbreak predicted voting intentions preceding the 2014 U.S. federal elections. Analyses were conducted on nationwide polls pertaining to 435 House of Representatives elections and on state-specific polls pertaining to 34 Senate elections. Analyses compared voting intentions before and after the initial Ebola outbreak and assessed correlations between Internet search activity for the term "Ebola" and voting intentions. Results revealed that (a) the psychological salience of Ebola was associated with increased intention to vote for Republican candidates and (b) this effect occurred primarily in states characterized by norms favoring Republican Party candidates (the effect did not occur in states with norms favoring Democratic Party candidates). Ancillary analyses addressed several interpretational issues. Overall, these results suggest that disease outbreaks may influence voter behavior in two psychologically distinct ways: increased inclination to vote for politically conservative candidates and increased inclination to conform to popular opinion. PMID- 26976085 TI - Efficacy of Curcuma for Treatment of Osteoarthritis. AB - The objective of this review is to identify, summarize, and evaluate clinical trials to determine the efficacy of curcuma in the treatment of osteoarthritis. A literature search for interventional studies assessing efficacy of curcuma was performed, resulting in 8 clinical trials. Studies have investigated the effect of curcuma on pain, stiffness, and functionality in patients with knee osteoarthritis. Curcuma-containing products consistently demonstrated statistically significant improvement in osteoarthritis-related endpoints compared with placebo, with one exception. When compared with active control, curcuma-containing products were similar to nonsteroidal anti-inflammatory drugs, and potentially to glucosamine. While statistical significant differences in outcomes were reported in a majority of studies, the small magnitude of effect and presence of major study limitations hinder application of these results. Further rigorous studies are needed prior to recommending curcuma as an effective alternative therapy for knee osteoarthritis. PMID- 26976084 TI - Deletion of endogenous Tau proteins is not detrimental in Drosophila. AB - Human Tau (hTau) is a highly soluble and natively unfolded protein that binds to microtubules within neurons. Its dysfunction and aggregation into insoluble paired helical filaments is involved in the pathogenesis of Alzheimer's disease (AD), constituting, together with accumulated beta-amyloid (Abeta) peptides, a hallmark of the disease. Deciphering both the loss-of-function and toxic gain-of function of hTau proteins is crucial to further understand the mechanisms leading to neurodegeneration in AD. As the fruit fly Drosophila melanogaster expresses Tau proteins (dTau) that are homologous to hTau, we aimed to better comprehend dTau functions by generating a specific tau knock-out (KO) fly line using homologous recombination. We observed that the specific removal of endogenous dTau proteins did not lead to overt, macroscopic phenotypes in flies. Indeed, survival, climbing ability and neuronal function were unchanged in tau KO flies. In addition, we did not find any overt positive or negative effect of dTau removal on human Abeta-induced toxicity. Altogether, our results indicate that the absence of dTau proteins has no major functional impact on flies, and suggests that our tau KO strain is a relevant model to further investigate the role of dTau proteins in vivo, thereby giving additional insights into hTau functions. PMID- 26976086 TI - Gastroprotective Effect of Combination of Hot Water Extracts of Licorice (Glycyrrhiza glabra), Pulasari Stem Bark (Alyxia reinwardtii), and Sembung Leaf (Blumea balsamifera) Against Aspirin-Induced Gastric Ulcer Model Rats. AB - Licorice (Glycyrrhiza glabra), Pulasari stem bark (Alyxia reinwardtii) and Sembung leaf (Blumea balsamifera) are traditionally used to treat gastrointestinal disorders. The aim of the study was to investigate gastroprotective effect of hot water extracts combination of those herbal against aspirin-induced gastric ulcer model in rats. The combination consisted of fixed doses of Licorice 273 mg/kg BW and Sembung leaf 457.5 mg/kg BW, and also consisted of Pulasari stem in various doses i.e. 100 mg/kg BW (first group), 200 mg/kg BW (second and sixth group) and 300 mg/kg BW (third group). The fourth grup rats received sucralfate 360 mg/kg BW. Ten minute after seven consecutive days of drug administration, the rats were induced with aspirin 450 mg/kg BW except sixth group rats. The fifth group rats only received aspirin without any protective agents. The number and area of gastric ulcers were evaluated macroscopically. Whereas, histopatological observation was used for evaluation of mucosal damage score, and the number of eosinophils and mast cells. In the study, herbal extracts combination markedly exhibited protective effects indicated by less number and smaller area of gastric ulcers in comparison to those of aspirin group (P < 0.05). The score of mucosal damages were also decreased in herbal extracts combination groups. The number of eosinophils and mast cells of herbal combination groups were observed to be smaller than those of aspirin group (P < 0.05). In conclusion, herbal combination of Licorice (Glycyrrhiza glabra), Pulasari stem bark (Alyxia reinwardtii) and Sembung leaf (Blumea balsamifera) is potential to develop as a gastroprotective agent. PMID- 26976087 TI - Nutrition and Lifestyle Intervention on Mood and Neurological Disorders. AB - This group study explored how an intervention of diet and lifestyle, including a vegan diet, fruit and vegetable juicing, nutritional supplements, regular exercise, and destressing techniques, would affect 27 subjects with anxiety, depression, poor memory, dementia, Alzheimer's disease, Parkinson's disease, history of stroke, or multiple sclerosis. Several subjects had overlapping conditions. Videotaped testimonials were obtained describing subjective results. Testimonials stated multiple benefits across all conditions addressed by the study, with subjects often reporting substantial benefits. These results demonstrate that an intervention of diet, juicing, supplements, exercise, and lifestyle may provide considerable benefits for all conditions addressed. PMID- 26976088 TI - Differential Arc expression in the hippocampus and striatum during the transition from attentive to automatic navigation on a plus maze. AB - The strategies utilized to effectively perform a given task change with practice and experience. During a spatial navigation task, with relatively little training, performance is typically attentive enabling an individual to locate the position of a goal by relying on spatial landmarks. These (place) strategies require an intact hippocampus. With task repetition, performance becomes automatic; the same goal is reached using a fixed response or sequence of actions. These (response) strategies require an intact striatum. The current work aims to understand the activation patterns across these neural structures during this experience-dependent strategy transition. This was accomplished by region specific measurement of activity-dependent immediate early gene expression among rats trained to different degrees on a dual-solution task (i.e., a task that can be solved using either place or response navigation). As expected, rats increased their reliance on response navigation with extended task experience. In addition, dorsal hippocampal expression of the immediate early gene Arc was considerably reduced in rats that used a response strategy late in training (as compared with hippocampal expression in rats that used a place strategy early in training). In line with these data, vicarious trial and error, a behavior linked to hippocampal function, also decreased with task repetition. Although Arc mRNA expression in dorsal medial or lateral striatum alone did not correlate with training stage, the ratio of expression in the medial striatum to that in the lateral striatum was relatively high among rats that used a place strategy early in training as compared with the ratio among over-trained response rats. Altogether, these results identify specific changes in the activation of dissociated neural systems that may underlie the experience-dependent emergence of response-based automatic navigation. PMID- 26976090 TI - The effect of sleep deprivation on the encoding of contextual and non-contextual aspects of emotional memory. AB - Sleep loss affects emotional memory, but the specific effects on its contextual and non-contextual aspects are unknown. In this study we investigated the possible differential influence of one night of sleep deprivation on the encoding and subsequent recall of these two aspects of emotional information. Forty-eight healthy subjects, divided in a sleep deprivation (SD) and a well-rested group (WR), completed two testing sessions: the encoding session took place after one night of sleep for the WR and after one night of sleep deprivation for the SD group; the recall session after two nights of recovery sleep for both groups. During the encoding session, 6 clips of films of different valence (2 positive, 2 neutral and 2 negative) were presented to the participants. During the recall session, the non-contextual emotional memory was assessed by a recognition task, while the contextual emotional memory was evaluated by a temporal order task. The SD group showed a worst non-contextual recognition of positive and neutral events compared to WR subjects, while recognition of negative items was similar in the two groups. Instead, the encoding of the temporal order resulted deteriorated in the SD participants, independent of the emotional valence of the items. These results indicate that sleep deprivation severely impairs the encoding of both contextual and non-contextual aspects of memory, resulting in significantly worse retention two days later. However, the preserved recognition of negative non contextual events in sleep deprived subjects suggests that the encoding of negative stimuli is more "resistant" to the disruptive effects of sleep deprivation. PMID- 26976089 TI - Pedunculopontine tegmental nucleus lesions impair probabilistic reversal learning by reducing sensitivity to positive reward feedback. AB - Recent findings indicate that pedunculopontine tegmental nucleus (PPTg) neurons encode reward-related information that is context-dependent. This information is critical for behavioral flexibility when reward outcomes change signaling a shift in response patterns should occur. The present experiment investigated whether NMDA lesions of the PPTg affects the acquisition and/or reversal learning of a spatial discrimination using probabilistic reinforcement. Male Long-Evans rats received a bilateral infusion of NMDA (30nmoles/side) or saline into the PPTg. Subsequently, rats were tested in a spatial discrimination test using a probabilistic learning procedure. One spatial location was rewarded with an 80% probability and the other spatial location rewarded with a 20% probability. After reaching acquisition criterion of 10 consecutive correct trials, the spatial location - reward contingencies were reversed in the following test session. Bilateral and unilateral PPTg-lesioned rats acquired the spatial discrimination test comparable to that as sham controls. In contrast, bilateral PPTg lesions, but not unilateral PPTg lesions, impaired reversal learning. The reversal learning deficit occurred because of increased regressions to the previously 'correct' spatial location after initially selecting the new, 'correct' choice. PPTg lesions also reduced the frequency of win-stay behavior early in the reversal learning session, but did not modify the frequency of lose-shift behavior during reversal learning. The present results suggest that the PPTg contributes to behavioral flexibility under conditions in which outcomes are uncertain, e.g. probabilistic reinforcement, by facilitating sensitivity to positive reward outcomes that allows the reliable execution of a new choice pattern. PMID- 26976091 TI - SSRI enhances sensitivity to background outcomes and modulates response rates: A randomized double blind study of instrumental action and depression. AB - Serotonin reuptake inhibitors (SSRIs) have immediate effects on synaptic levels of serotonin but their therapeutic effects are often delayed. This delay has been suggested to reflect time required for new learning and therefore that SSRIs might be having effects on the learning process. We examined the effects of elevating serotonin levels, through short-term SSRI administration (escitalopram), on learning about perceptions of instrumental control. A randomised double blind procedure was used to allocate healthy people, categorised as mildly depressed (high BDI?10: n=76) or not depressed (low BDI?5: n=78) to either a drug (escitalopram, 10mg/7days) or placebo control group. Following treatment, participants were trained with a simple task that involved learning the effectiveness of an instrumental action (key press) and the background context at eliciting an outcome (auditory cue) where there was no programmed contingency. The effects of the drug were (i) to moderate response rates and (ii) to enhance sensitivity to the background or context rate of occurrence of the outcome. These findings suggest that serotonin modulates learning about the long-term rate of outcomes, which supports perception of instrumental control, and that this may provide a clue to the mechanism for supporting the development of the therapeutic effects of the drug. PMID- 26976092 TI - GPR40 receptor activation leads to CREB phosphorylation and improves cognitive performance in an Alzheimer's disease mouse model. AB - Alzheimer's disease (AD) is a very complex neurodegenerative disorder as neuronal loss is a prominent and initial feature of AD. This loss correlates with cognitive deficits more closely than amyloid load. GPR40 receptor belongs to the class of G-protein coupled receptors, is expressed in wide parts of the brain including the hippocampus which is involved in spatial learning and memory. Till now, there are few studies investigating the functional role of GPR40 in brain. In this study, we evaluated the functional role of GPR40 receptor in the A-beta AD mice model. Administration of Abeta1-42 (410pmol) intracerebroventricularly (i.c.v.) once at the beginning of experiment significantly impaired cognitive performance (in step-through passive test), the ability of spatial learning and memory in (Morris water maze test), working memory, attention, anxiety in (Novel object recognition test), and spatial working and reference-memory in (Hole board discrimination test) compared with the control group. The results revealed that GPR40 receptor treatment groups significantly ameliorated model mice cognitive performance. All GPR40 receptor agonist GW9508, treatment groups enhanced the learning and memory ability in Step-through passive test, Morris water maze test, Hole board discrimination test, Novel object recognition test. Furthermore, we have observed that activation of GPR40 receptor provoked the phosphorylation of the cAMP response element binding protein (CREB) and significant increase in neurotropic factors including brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrohin-4 (NT-4) in mouse hippocampal neurons and contribute to neurogenesis. These results suggest that GPR40 is a suitable therapeutic candidate for neurogenesis and neuroprotection in the treatment and prevention of AD. PMID- 26976093 TI - Strategy breakdown following muscarinic blockade in rats. AB - The present study examined the effects of systemically administered atropine sulfate, a muscarinic cholinergic antagonist, on a series of probe tests in the retention of a highly-structured serial pattern in a serial multiple choice (SMC) task. Rats were trained on a 24-element pattern composed of eight 3-element chunks ending with a violation element: 123-234-345-456-567-678-781-818 where the digits represent the clockwise position of levers in an octagonal chamber, dashes indicate 3-s pauses termed "phrasing cues," and other intertrial intervals were 1s. In daily acquisition trials rats were given either 50mg/kg of atropine sulfate or an equivalent amount of saline (Chenoweth & Fountain, 2015). Following acquisition, rats were given a series of drug challenges, and the present study reports a series of Phrasing Cue Removal Probes that tested rats' abilities to make correct responses in the absence of phrasing cues. Rats tested under atropine demonstrated more difficulty in recalling encoded responses in these probe trials than did rats tested under saline. The results indicate that intact central muscarinic cholinergic systems were needed for rats to display efficient adaptive response strategies under conditions where some features of the previously-learned pattern change. PMID- 26976094 TI - Basal dendritic length is reduced in the rat hippocampus following bilateral vestibular deafferentation. AB - Some previous studies in humans have shown that bilateral loss of vestibular function is associated with a significant bilateral atrophy of the hippocampus, which correlated with the patients' spatial memory deficits. By contrast, studies in rats have failed to detect any changes in hippocampal volume following bilateral vestibular loss. Therefore, in this study we investigated whether bilateral vestibular deafferentation (BVD) might result in more subtle morphological changes in the rat hippocampus, involving alterations in dendritic intersections, using Golgi staining and Sholl analysis. We found that at 1month following BVD, there was a significant decrease in basal (P?0.0001) but not apical dendritic intersections in the CA1 region of the hippocampus compared to sham-operated animals and anaesthetic controls. However, dendritic branching was not significantly affected. These results suggest that the rat hippocampus does undergo subtle morphological changes following bilateral vestibular loss, and that they may be in the form of alterations in dendritic structure. PMID- 26976095 TI - Brain death criteria formulated for transplantation purposes: fact or myth? AB - Medical progress has moved the boundaries of life that were set many centuries ago. The development of medical techniques has allowed us to witness cases that were unknown prior to the introduction of reanimation procedures and mechanical ventilation. Towards the end of the 1950s, the term "irreversible coma" was coined, and has evolved into what is currently known as the "brain death" concept. This latter concept, proposed in 1968, is very often referred to as the new definition of death, even in medical circles. What, up until this time, used to be the classic definition of death, namely cessation of circulation and respiration, should now be recognized as the classic criteria for death. Indeed, the new criteria for recognizing death has not resulted in changing the current criteria, but in complementing them. The first part of this paper presents brief descriptions of death in the humanities over the centuries and the impact of progress in medicine on changes in how death is defined today. The second part brings to light the complexity of creating the foundations of the neurological criteria for death. The integration of concepts from two complementary medical fields - neurology and transplantology - is described. Although for some period of time they have been linked together, they may grow independently in the future. The jargon phrase "brain death" is nowadays recognized as synonym of death, but in fact should be considered tantamount to declaring pronouncing a person's death. PMID- 26976096 TI - Dimensional models and neurobiology of personality disorders. AB - Since the introduction of a separate axis in DSM-III (1980), the validity of the categorical nature of the classification of personality disorders has been seriously questioned. Subsequently, a number of multidimensional alternatives have been proposed based on statistical procedures or theoretical considerations. At the same time, the study of the neurobiological underpinnings of personality and personality disorders has created a better understanding of etiological and pathogenetic processes responsible for these chronic disorders. The findings of these studies corroborate some of the major findings of statistical studies regarding the nature of the frequent comorbidity of axis II disorders. In the discussion, a mixed, two-tier diagnostic model is proposed to serve both scientific and clinical aims without the disadvantages of an exclusive choice for either categorical or dimensional approaches to the classification of personality pathology. PMID- 26976097 TI - Neurobiology or agression and impulsivity. AB - Because of the graded nature of adaptational processes, a dimensional diagnostic approach is more adequate than the categorical classification. The broad concept of the serotonin-aggression relationship, irrespective of the diagnostic category, is increasingly questionable and seems to be present in young, white male adults with antisocial personality disorders only. In this group, dopaminergic and neurosteroid-linked mechanisms are important as well. PMID- 26976098 TI - Neurobiology of adaptation disorders. AB - A fundamental issue in the neurobiology of adaptation disorders is how the hormones of the hypothalamic-pituitary-adrenal (HPA) axis protect the brain from such disorders, and how in a different context these very same stress hormones may enhance vulnerability. This contribution focuses on the corticosteroids which exert through two distinct nuclear receptor types control over gene networks underlying stress system activity in brain. The mineralocorticoid receptor mediates the pro-active mode of corticosteroid action involved in maintenance of basal stress system activity. The glucocorticoid receptor mediates the reactive feedback mode aimed to facilitate recovery from stress-induced disturbance. The balance between these pro-active and reactive modes of control is thought to be of critical importance for homeostasis, and thus for control of hormone responsive genes which enhance vulnerability to stress-related affective and neurodegenerative disorders. PMID- 26976099 TI - Therapeutic drug monitoring. AB - The cytochrome P450 iso-enzyme system plays a key role in the biotransformation of many drugs, including psychotropics. Its activity is determined by both genetic and environmental factors. The most important iso-enzymes for psychiatry in general are P450 IID6, 3A4 and 1A2. Knowledge about the involvement of these enzymes and biotransformation processes is mandatory because of the individual variability in their metabolic capacity. Regular measurement of plasmaconcentrations of (psycho)pharmacological compounds is therefore essential. In addition, the potential value of pheno- and/or genotyping has to be investigated. PMID- 26976100 TI - Integratie van opleiding en onderzoek in de opleiding tot psychiater. AB - In the training program for residents in psychiatry, scientific education and participation in research projects are relatively underdeveloped. This may result in a gap between recently acquired scientific knowledge and its implementation in clinical practice. Since the start of the residency training in psychiatry in 1989 in the Vincent van Gogh Institute for Psychiatry, several research lines have been developed especially concerning dimensional diagnostic procedures, evaluation of treatment effects, stress and psychopathology, pharmacokinetics of psychotropic compounds and disordered impulse and aggression regulation. It is concluded that active participation in research projects by both psychiatrists and residents in psychiatry is increasingly mandatory due to social-economic en scientific developments. Despite several countervailing factors, the Vincent van Gogh Institute for Psychiatry has succeeded in the creation of a scientific orientation in the residency program resulting in a number of publications. PMID- 26976101 TI - Cognitive aging and early neurophychological diagnostics. AB - With aging, most cognitive functions decline, especially processes concerning memorizing, attention, concentration, organizing, planning and problem solving. Neuropsychology can make an important contribution in early and differential diagnostics. The borderline between normal and pathological cognitive aging is especially important in this respect. The neuropsychologist gains insight in medical, biological, psychological and social factors of the aging person. Has the profile of complaints and deficits a normal background or is a pathological process taking place? It is important to people who are unnecessarily worried about possible dementia. Neuropsychological assessment also provides information about a patient's disturbed and undisturbed cognitive functions, their personality and their way of coping with problems in every day's life. This is of major importance, because it provides information and possibilities for biological or psychological interventions. Because of the complexity of problems that may occur, it is necessary that the neuropsychologist is experienced and works in a multidisciplinary team in which neurological and psychiatric expertise is present. PMID- 26976102 TI - Diagnosis and dimensional pharmacotherapy of challenging behaviour in mental retardation. AB - Classical psychiatric taxonomy appears to be increasingly inadequate in the diagnostic process of mentally retarded subjects. The reasons for this are the atypical presentation of classical psychiatric disorders, special diagnostic entities like cycloid psychosis and unstable mood disorder and the existence of so-called behavioural phenotypes related to syndromes with a known genetic etiology. In addition, disturbed behaviour may be the result of somatic or neurologic comorbidity and induced to adverse drug events. PMID- 26976103 TI - Atypical psychoses. AB - The European psychiatric literature is rich in descriptions and studies of atypical psychotic disorders. Most of these are finally deemed to be varieties of the affective or schizophrenic disorders, which in turn are regarded to be typical. The acute polymorphic psychotic disorder according to the ICD-10, and the periodic catatonia of Gjessing, although hardly recognized and acknowledged, are good candidates to be considered as separate psychotic disease entities. PMID- 26976104 TI - A comparison of the 'Hamilton Rating Scale for Depression' and the 'Montgomery Asberg Depression rating Scale'. AB - Although the Hamilton Rating Scale for Depression (HRSD) is the most frequently used rating scale for quantifying depressive states, it has been criticized for its reliability and its usability in clinical practice. This criticism is less applying to the Montgomery-Asberg Depression Rating Scale (MADRS). Goal of the present study is to investigate the reliability and validity, and clinical relationship between the HRSD and the MADRS. For 60 out-patients with diagnosed depression (DSM IV296.2x, 296.3x, 300.40 and 311.00), the HRSD and MADRS were scored at baseline and 6 weeks later by an independent rater according to a structured interview. Also the Clinical Global Impression (CGI) was assessed by a psychiatrist. Satisfying agreement was found between the totalscores (r= .75, p>.000 en r=.92, p>.000 respectively, at baseline and 6 weeks later). Furthermore agreement was found between the items of both scales, and these agree with the clinical impression. The reliability of the MADRS is more stable than the reliability of the HRSD (alpha = .6367 and alpha =.8900 vs alpha = .2193 and alpha = .8362 at baseline and at endpoint respectively). Considering the ease of scoring both scales in one interview and the widely international use of the HRSD, scoring both the HRSD and the MADRS to measure the severity of a depression seems to be an acceptabel covenant. PMID- 26976105 TI - Five years of European Journal of Psychotraumatology. PMID- 26976107 TI - Editorial Comment. PMID- 26976108 TI - Author Reply. PMID- 26976106 TI - A cationic tetrapyrrole inhibits toxic activities of the cellular prion protein. AB - Prion diseases are rare neurodegenerative conditions associated with the conformational conversion of the cellular prion protein (PrP(C)) into PrP(Sc), a self-replicating isoform (prion) that accumulates in the central nervous system of affected individuals. The structure of PrP(Sc) is poorly defined, and likely to be heterogeneous, as suggested by the existence of different prion strains. The latter represents a relevant problem for therapy in prion diseases, as some potent anti-prion compounds have shown strain-specificity. Designing therapeutics that target PrP(C) may provide an opportunity to overcome these problems. PrP(C) ligands may theoretically inhibit the replication of multiple prion strains, by acting on the common substrate of any prion replication reaction. Here, we characterized the properties of a cationic tetrapyrrole [Fe(III)-TMPyP], which was previously shown to bind PrP(C), and inhibit the replication of a mouse prion strain. We report that the compound is active against multiple prion strains in vitro and in cells. Interestingly, we also find that Fe(III)-TMPyP inhibits several PrP(C)-related toxic activities, including the channel-forming ability of a PrP mutant, and the PrP(C)-dependent synaptotoxicity of amyloid-beta (Abeta) oligomers, which are associated with Alzheimer's Disease. These results demonstrate that molecules binding to PrP(C) may produce a dual effect of blocking prion replication and inhibiting PrP(C)-mediated toxicity. PMID- 26976109 TI - Editorial Comment. PMID- 26976110 TI - Author Reply. PMID- 26976111 TI - Editorial Comment. PMID- 26976112 TI - Author Reply. PMID- 26976113 TI - Editorial Comment. PMID- 26976115 TI - Silicene/germanene on MgX2 (X = Cl, Br, and I) for Li-ion battery applications. AB - Silicene is a promising electrode material for Li-ion batteries due to its high Li capacity and low Li diffusion barrier. Germanene is expected to show a similar performance due to its analogous structural and electronic properties. However, the performance of both the materials will be determined by the substrate, since freestanding configurations are unstable. We propose Si/MgX2 and Ge/MgX2 (X = Cl, Br, and I) as suitable hybrid structures, based on first-principles calculations. We find that Li will not cluster and that the Li capacity is very high (443 and 279 mA h g(-1) for silicene and germanene on MgCl2, respectively). Sandwich structures can be used to further enhance the performance. Low diffusion barriers of less than 0.3 eV are predicted for all the hybrid structures. PMID- 26976114 TI - Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628. AB - The antineoplastic, prodifferentiative effects of bromodomain and extra-terminal (BET) bromodomain (BRD) inhibitors were initially discovered in NUT midline carcinoma (NMC), an aggressive subtype of squamous cancer driven by the BRD4-NUT fusion oncoprotein. BRD4-NUT blocks differentiation and maintains tumor growth through a potent chromatin-modifying mechanism. OTX015/MK-8628, a novel oral BET inhibitor, targets BRD2/3/4/T with preclinical activity in NMC and several other tumor types and is currently in clinical development. Antitumor activity was evaluated in four patients with advanced-stage NMC with confirmed BRD4-NUT fusions who were treated with 80 mg OTX015/MK-8628 once daily in a compassionate use context. Two patients responded rapidly with tumor regression and symptomatic relief, and a third had meaningful disease stabilization with a minor metabolic response. The main side effects were mild to moderate gastrointestinal toxicity and fatigue, and reversible grade 3 thrombocytopenia. This is the first proof-of concept evidence of clinical activity of a BRD inhibitor in targeting BRD4-NUT. SIGNIFICANCE: We present the first clinical proof-of-concept that targeting BRD4 NUT with a BET inhibitor results in impressive and rapid antitumor activity in NMC. It offers strong potential for future clinical application in this rare patient population as either a single agent or in combination with other agents. Cancer Discov; 6(5); 492-500. (c)2016 AACR.This article is highlighted in the In This Issue feature, p. 461. PMID- 26976117 TI - Clinical efficacy of fresh frozen plasma compared with coagulation factor concentrates for treating coagulopathy in patients with massive bleeding. PMID- 26976118 TI - Risk factors for worsened quality of life in patients on mechanical ventilation. A prospective multicenter study. AB - OBJECTIVE: To identify risk factors for worsened quality of life (QoL) and activities of daily living (ADL) at 3 and 12 months after discharge from the Intensive Care Unit (ICU) in patients on mechanical ventilation (MV). DESIGN: A prospective, multicentric observational study was made. SETTING: Three ICUs in Argentina. PATIENTS: The study included a total of 84 out of 129 mainly clinical patients admitted between 2011-2012 and requiring over 24hours of MV. INTERVENTIONS: No interventions were carried out. VARIABLES: Quality of life was assessed with the EQ-5D (version for Argentina), and ADL with the Barthel index. RESULTS: The EQ-5D and Barthel scores were assessed upon admission to the ICU (baseline) and after three months and one year of follow-up. Comorbidities, delirium, ICU acquired weakness (ICUAW), and medication received were daily assessed during ICU stay. The baseline QoL of the global sample showed a median index of [0.831 (IQR25-75% 0.527-0.931)], versus [0.513 (IQR0.245-0.838)] after three months and [0.850 (IQR0.573-1.00)] after one year. Significant differences were observed compared with QoL in the Argentinean general population [mean 0.880 (CI 0.872-0.888), p<0.001; p<0.001; p0.002]. Individual analysis showed that 67% of the patients had worsened their QoL at three months, while 33% had recovered their QoL. In the multivariate analysis, the variables found to be independent predictors of worsened QoL were a hospital stay >=21 days [OR 12.57 (2.75 57.47)], age >=50 years [OR 5.61 (1.27-24.83)], previous poor QoL [OR 0.11 (0.02 0.54)] and persistent ICUAW [OR 8.32 (1.22-56.74)]. Similar results were found for the worsening of ADL. CONCLUSIONS: Quality of life is altered after critical illness, and its recovery is gradual over time. Age, length of hospital stay, previous QoL and persistent ICUAW seem to be risk factors for worsened QoL. PMID- 26976119 TI - Emerging concepts: mast cell involvement in allergic diseases. AB - In a process known as overt degranulation, mast cells can release all at once a diverse array of products that are preformed and present within cytoplasmic granules. This occurs typically within seconds of stimulation by environmental factors and allergens. These potent, preformed mediators (ie, histamine, heparin, serotonin, and serine proteases) are responsible for the acute symptoms experienced in allergic conditions such as allergic conjunctivitis, allergic rhinitis, allergy-induced asthma, urticaria, and anaphylaxis. Yet, there is reason to believe that the actions of mast cells are important when they are not degranulating. Mast cells release preformed mediators and inflammatory cytokines for periods after degranulation and even without degranulating at all. Mast cells are consistently seen at sites of chronic inflammation, including nonallergic inflammation, where they have the ability to temper inflammatory processes and shape tissue morphology. Mast cells can trigger actions and chemotaxis in other important immune cells (eg, eosinophils and the newly discovered type 2 innate lymphocytes) that then make their own contributions to inflammation and disease. In this review, we will discuss the many known and theorized contributions of mast cells to allergic diseases, focusing on several prototypical allergic respiratory and skin conditions: asthma, chronic rhinosinusitis, aspirin exacerbated respiratory disease, allergic conjunctivitis, atopic dermatitis, and some of the more common medication hypersensitivity reactions. We discuss traditionally accepted roles that mast cells play in the pathogenesis of each of these conditions, but we also delve into new areas of discovery and research that challenge traditionally accepted paradigms. PMID- 26976121 TI - Still Eating Despite Decreased Olfactory Pleasure-The Influence of Odor Liking and Wanting on Food Intake. AB - Typically, the subjective pleasantness of an odor decreases after it has been repeatedly smelled. This study investigates how the pleasantness ("liking") and the wish to be further exposed to the same odor ("wanting") are affected by variety on a longer time scale, and how they relate to actual food intake. Twenty five participants rated a coconut odor presented 120 times for its liking and wanting before being offered coconut sweets. The amount eaten was assessed. Individual patterns of change were described by fitting 3 different models to the ratings. To study effects of variety on odor evaluation, the ratings were compared with a previous study where coconut was 1 of 3 odors presented in an alternating way. Initially, both liking and wanting the odors were high, but decreased over repetitions in 75% of the subjects. About 40% of all subjects showed an exponential change of ratings, 40% a step-like change, and 20% a linear change. Food intake was not related to the pattern of change in the ratings. Moreover, decreased olfactory pleasure did not seem to affect eating behavior. However, participants who rated the coconut odor higher at the beginning ate twice as many sweets as the others. Odor variety did not affect the experienced pleasure of smelling (liking), but did affect the motivation to experience the same smell again (wanting). This has not been reported for food or touch stimulation and may be specific for the perception of odors. PMID- 26976120 TI - Hepatic oleate regulates liver stress response partially through PGC-1alpha during high-carbohydrate feeding. AB - BACKGROUND & AIMS: High-carbohydrate diets contribute to the development of liver stress and fatty liver disease. While saturated fatty acids are known to induce liver stress, the role of monounsaturated fatty acids (MUFA), synthesized by the stearoyl-CoA desaturase (SCD) family of enzymes, in regulation of liver function during lipogenic dietary conditions remains largely unknown. The major products of SCD-catalyzed reactions are oleate (18:1n-9) and palmitoleate (16:1n-7). METHODS: We generated mouse models with restricted exogenous MUFA supply and reduced endogenous MUFA synthesis, in which SCD1 global knockout (GKO) or liver specific knockout (LKO) mice were fed a lipogenic high-sucrose very low-fat (HSVLF) or high-carbohydrate (HC) diet. In a gain-of-function context, we introduced liver-specific expression of either human SCD5, which synthesizes 18:1n-9, or mouse Scd3, which synthesizes 16:1n-7, into SCD1 GKO mice and fed the HSVLF diet. RESULTS: Lipogenic high-carbohydrate diets induced hepatic endoplasmic reticulum (ER) stress and inflammation in SCD1 GKO and LKO mice. Dietary supplementation with 18:1n-9, but not 18:0, prevented the HSVLF diet induced hepatic ER stress and inflammation in SCD1 LKO mice, while hepatic SCD5, but not Scd3, expression reduced the ER stress and inflammation in GKO mice. Additional experiments revealed liver-specific deletion of the transcriptional coactivator PGC-1alpha reduced hepatic inflammatory and ER stress response gene expression in SCD1 LKO mice. CONCLUSIONS: Our results demonstrate an indispensable role of hepatic oleate in protection against lipogenic diet-induced hepatic injury, and PGC-1alpha potentiates the ER stress response under conditions of restricted dietary oleate coupled to reduced capacity of endogenous hepatic oleate synthesis. LAY SUMMARY: Susceptibility to metabolic dysfunction is influenced by genetic and environmental factors. In this study we show that modulation of two genes regulates the liver response, including ER stress and inflammation, to a high-carbohydrate low-fat diet. We reveal that hepatic availability of oleate, a monounsaturated fatty acid, is important for maintenance of liver health. PMID- 26976123 TI - Adherence of French cardiologists to guidelines for non-cardiac surgery. AB - INTRODUCTION: In order to evaluate whether cardiologists follow guidelines, we studied patients who were seen for a preoperative cardiologic consultation prior to surgery. METHODS: This retrospective study took place in two surgical units (Vascular and Orthopaedic) in two different university hospitals in 2013. The patient eligibility criteria were: planned elective surgery, cardiologic consultation prior to anaesthesiology consultation and lack of any unstable cardiac condition. The primary endpoint was determination of appropriate use of preoperative cardiac stress exams (CSE). RESULTS: The study included 238 patients who were seen by 131 different cardiologists. Of 238 patients, 60 had a CSE before surgery, but only 7/60 (12%) were deemed to be necessary. Seven out 15 (47%) patients with an indication for a CSE actually underwent said exam. Sixty six percent of patients (156/238) had a resting trans-thoracic echocardiography before surgery, while only 27/156 (17%) were considered of appropriate use. Among patients with known coronary arterial disease, 59/73 (81%) received a statin, 60/73 (82%) received an antiplatelet agent, and 38/73 (52%) received a beta blocker. Among patients with planned arterial surgery, 86/137 (63%) received a statin and 100/137 (73%) patients received an antiplatelet agent. Of the 159 consultation reports that were examined, only 5 (3%) mentioned the Lee score and 117 (74%) were concluded with "no contraindication" or a similar phrase. DISCUSSION: In this study, we found that guidelines were generally not used when cardiologists evaluated patients for non-cardiac surgery. This is evidenced by the number of inappropriate exams performed, the lack of true perioperative risk stratification, and incomplete optimization of long-term treatment regimens. PMID- 26976124 TI - Epidemiological research on radiation-induced cancer in atomic bomb survivors. AB - The late effects of exposure to atomic bomb radiation on cancer occurrence have been evaluated by epidemiological studies on three cohorts: a cohort of atomic bomb survivors (Life Span Study; LSS), survivors exposed IN UTERO : , and children of atomic bomb survivors (F1). The risk of leukemia among the survivors increased remarkably in the early period after the bombings, especially among children. Increased risks of solid cancers have been evident since around 10 years after the bombings and are still present today. The LSS has clarified the dose-response relationships of radiation exposure and risk of various cancers, taking into account important risk modifiers such as sex, age at exposure, and attained age. Confounding by conventional risk factors including lifestyle differences is not considered substantial because people were non-selectively exposed to the atomic bomb radiation. Uncertainty in risk estimates at low-dose levels is thought to be derived from various sources, including different estimates of risk at background levels, uncertainty in dose estimates, residual confounding and interaction, strong risk factors, and exposure to residual radiation and/or medical radiation. The risk of cancer in subjects exposed IN UTERO : is similar to that in LSS subjects who were exposed in childhood. Regarding hereditary effects of radiation exposure, no increased risk of cancers associated with parental exposure to radiation have been observed in the F1 cohort to date. In addition to biological and pathogenetic interpretations of the present results, epidemiological investigations using advanced technology should be used to further analyze these cohorts. PMID- 26976122 TI - Separate functions for responses to oral temperature in thermo-gustatory and trigeminal neurons. AB - Oral temperature is a component and modifier of taste perception. Both trigeminal (V) and taste-sensitive cells, including those in the nucleus of the solitary tract (NTS), can respond to oral temperature. However, functional associations in thermal sensitivity between V and gustatory neurons are poorly understood. To study this we recorded electrophysiological responses to oral stimulation with cool (9, 15, 25, 32, and 34 degrees C) and warm (40 and 45 degrees C) temperatures from medullary V (n = 45) and taste-sensitive NTS (n = 27) neurons in anesthetized mice. Results showed temperatures below 34 degrees C activated the majority of V neurons but only a minority of NTS units. V neurons displayed larger responses to cooling and responded to temperatures that poorly stimulated NTS cells. Multivariate analyses revealed different temperatures induced larger differences in responses across V compared with NTS neurons, indicating V pathways possess greater capacity to signal temperature. Conversely, responses to temperature in NTS units associated with gustatory tuning. Further analyses identified two types of cooling-sensitive V neurons oriented toward innocuous or noxious cooling. Multivariate analyses indicated the combined response of these cells afforded distinction among a broad range of cool temperatures, suggesting multiple types of V neurons work together to represent oral cooling. PMID- 26976126 TI - Arterial blood gases predict long-term prognosis in stage I non-small cell lung cancer patients. AB - BACKGROUND: Preoperative hypercapnia and hypoxemia are reportedly risk factors for postoperative complications. This study aimed to establish the long-term survival risk associated with abnormal preoperative arterial blood gases (ABGs) in patients with non-small cell lung cancer (NSCLC). METHODS: This study involved 414 patients with stage I NSCLC who underwent lobectomy/bilobectomy with mediastinal lymph node dissection. The patients were divided into groups with normal (n = 269) and abnormal (n = 145) ABGs. RESULTS: The patients in the normal ABG group (median age 67 years) were significantly younger than those in the abnormal ABG group (median age 70 years). There were no significant differences between the groups in gender, performance status, pathological stage, histology, postoperative complications, or preoperative comorbidity, except for chronic obstructive pulmonary disease/pulmonary fibrosis. The 3-, 5- and 10-year survival rates in the normal and abnormal ABG groups were 87, 77 and 56, and 78, 63 and 42%, respectively (p = 0.006). According to multivariate analysis, age, gender, performance status, non-adenocarcinoma, differentiation of resected tumor, pathological stage, any prior tumor and abnormal ABGs (risk ratio, 1.61) were independent prognostic factors. CONCLUSIONS: Abnormal ABGs predict long-term survival risk in patients with NSCLC, which is important for planning therapeutic strategies. PMID- 26976125 TI - Comparison of implant quality between intraoperatively built custom-linked seeds and loose seeds in permanent prostate brachytherapy using sector analysis. AB - We compared the implant quality of intraoperatively built custom-linked (IBCL) seeds with loose seeds in permanent prostate brachytherapy. Between June 2012 and January 2015, 64 consecutive prostate cancer patients underwent brachytherapy with IBCL seeds (n = 32) or loose seeds (n = 32). All the patients were treated with 144 Gy of brachytherapy alone. Brachytherapy was performed using a dynamic dose calculation technique. Computed tomography/magnetic resonance imaging fusion based dosimetry was performed 1 month after brachytherapy. Post-implant dose volume histogram (DVH) parameters, prostate sector dosimetry, operation time, seed migration, and toxicities were compared between the IBCL seed group and the loose seed group. A sector analysis tool was used to divide the prostate into six sectors (anterior and posterior sectors at the base, mid-gland, and apex). V100 (95.3% vs 89.7%; P = 0.014) and D90 (169.7 Gy vs 152.6 Gy; P = 0.013) in the anterior base sector were significantly higher in the IBCL seed group than in the loose seed group. The seed migration rate was significantly lower in the IBCL seed group than in the loose seed group (6% vs 66%; P < 0.001). Operation time per seed was significantly longer in the IBCL seed group than in the loose seed group (1.31 min vs 1.13 min; P = 0.003). Other post-implant DVH parameters and toxicities did not differ significantly between the two groups. Our study showed more dose coverage post-operatively in the anterior base prostate sector and less seed migration in IBCL seed implantation compared with loose seed implantation. PMID- 26976127 TI - Bedside myocardial perfusion assessment with contrast echocardiography. AB - This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901. PMID- 26976129 TI - Successful weight loss maintenance includes long-term increased meal responses of GLP-1 and PYY3-36. AB - OBJECTIVE: The hormones glucagon-like peptide 1 (GLP-1), peptide YY3-36 (PYY3 36), ghrelin, glucose-dependent insulinotropic polypeptide (GIP) and glucagon have all been implicated in the pathogenesis of obesity. However, it is unknown whether they exhibit adaptive changes with respect to postprandial secretion to a sustained weight loss. DESIGN: The study was designed as a longitudinal prospective intervention study with data obtained at baseline, after 8 weeks of weight loss and 1 year after weight loss. METHODS: Twenty healthy obese individuals obtained a 13% weight loss by adhering to an 8-week very low-calorie diet (800kcal/day). After weight loss, participants entered a 52-week weight maintenance protocol. Plasma levels of GLP-1, PYY3-36, ghrelin, GIP and glucagon during a 600-kcal meal were measured before weight loss, after weight loss and after 1 year of weight maintenance. Area under the curve (AUC) was calculated as total AUC (tAUC) and incremental AUC (iAUC). RESULTS: Weight loss was successfully maintained for 52 weeks. iAUC for GLP-1 increased by 44% after weight loss (P<0.04) and increased to 72% at week 52 (P=0.0001). iAUC for PYY3-36 increased by 74% after weight loss (P<0.0001) and by 36% at week 52 (P=0.02). tAUC for ghrelin increased by 23% after weight loss (P<0.0001), but at week 52, the increase was reduced to 16% compared with before weight loss (P=0.005). iAUC for GIP increased by 36% after weight loss (P=0.001), but returned to before weight loss levels at week 52. Glucagon levels were unaffected by weight loss. CONCLUSIONS: Meal responses of GLP-1 and PYY3-36 remained increased 1 year after weight maintenance, whereas ghrelin and GIP reverted toward before-weight loss values. Thus, an increase in appetite inhibitory mechanisms and a partly decrease in appetite-stimulating mechanisms appear to contribute to successful long-term weight loss maintenance. PMID- 26976128 TI - Real-world daptomycin use across wide geographical regions: results from a pooled analysis of CORE and EU-CORE. AB - BACKGROUND: Pooled data from two large registries, Cubicin((r)) Outcomes Registry and Experience (CORE; USA) and European Cubicin((r)) Outcomes Registry and Experience (EU-CORE; Europe, Latin America, and Asia), were analyzed to determine the characteristics and clinical outcomes of daptomycin therapy in patients with Gram-positive infections across wide geographical regions. METHODS: Patients receiving at least one dose of daptomycin between 2004 and 2012 for the treatment of Gram-positive infections were included. Clinical success was defined as an outcome of 'cured' or 'improved'. Post-treatment follow-up data were collected for a subset of patients (CORE: osteomyelitis and orthopedic foreign body device infection; EU-CORE: endocarditis, intracardiac/intravascular device infection, osteomyelitis, and orthopedic device infection). Safety was assessed for up to 30 days after daptomycin treatment. RESULTS: In 11,557 patients (CORE, 5482; EU CORE, 6075) treated with daptomycin (median age, 62 [range, 1-103] years), the most frequent underlying conditions were cardiovascular disease (54.7 %) and diabetes mellitus (28.0 %). The most commonly treated primary infections were complicated skin and soft tissue infection (cSSTI; 31.2 %) and bacteremia (21.8 %). The overall clinical success rate was 77.2 % (uncomplicated SSTI, 88.3 %; cSSTI, 81.0 %; osteomyelitis, 77.7 %; foreign body/prosthetic infection (FBPI), 75.9 %; endocarditis, 75.4 %; and bacteremia, 69.5 %). The clinical success rate was 79.1 % in patients with Staphylococcus aureus infections (MRSA, 78.1 %). An increasing trend of high-dose daptomycin (>6 mg/kg/day) prescribing pattern was observed over time. Clinical success rates were higher with high-dose daptomycin treatment for endocarditis and FBPI. Adverse events (AEs) and serious AEs possibly related to daptomycin therapy were reported in 628 (5.4 %) and 133 (1.2 %) patients, respectively. CONCLUSIONS: The real-world data showed that daptomycin was effective and safe in the treatment of various Gram-positive infections, including those caused by resistant pathogens, across wide geographical regions. PMID- 26976130 TI - Conventional versus rapid-deployment aortic valve replacement: a single-centre comparison between the Edwards Magna valve and its rapid-deployment successor. AB - OBJECTIVES: Sutureless and rapid-deployment valves were recently introduced into clinical practice. The Edwards INTUITY valve system is a combination of the Edwards Magna pericardial valve and a subvalvular stent-frame to enable rapid deployment. We performed a parallel cohort study for comparison of the two valve types. METHODS: All patients receiving either an Edwards Magna Ease valve or an Edwards INTUITY valve system due to aortic stenosis from May 2010 until July 2014 were included. Patients undergoing bypass surgery, an additional valve procedure, atrial ablation surgery or replacement of the ascending aorta were excluded. Preoperative characteristics, operative specifications, survival, valve-related adverse events and transvalvulvar gradients were compared. RESULTS: One hundred sixteen patients underwent rapid-deployment aortic valve replacement [mean age 75 years (SD: 8); 62% female] and 132 patients underwent conventional aortic valve replacement [70 years (SD: 9); 31% female; P < 0.001]. Conventional valve patients were taller and heavier. The mean EuroSCORE II was 3.1% (SD: 2.7) and 4.4% (SD: 6.0) for rapid-deployment and conventional valve patients, respectively (P = 0.085). The mean implanted valve size was higher in the conventional group [23.2 mm (SD: 2.0) vs 22.5 mm (SD: 2.2); P = 0.007], but postoperative transvalvular mean gradients were comparable [15 mmHg (SD: 6) vs 14 mmHg (SD: 5); P = 0.457]. A subgroup analysis of the most common valve sizes (21 and 23 mm; implanted in 63% of patients) revealed significantly reduced mean postoperative transvalvular gradients in the rapid-deployment group [14 mmHg (SD: 4) vs 16 mmHg (SD: 5); P = 0.025]. A significantly higher percentage received minimally invasive procedures in the rapid-deployment group (59 vs 39%; P < 0.001). The 1- and 3-year survival rate was 96 and 90% in the rapid-deployment group and 95 and 89% in the conventional group (P = 0.521), respectively. Valve-related pacemaker implantations were more common in the rapid-deployment group (9 vs 2%; P = 0.014) and postoperative stroke was more common in the conventional group (1.6 vs 0% per patient year; P = 0.044). CONCLUSIONS: We conclude that this rapid-deployment valve probably facilitates minimally invasive surgery. Furthermore, a subgroup analysis showed reduced transvalvular gradients in smaller valve sizes compared with the conventionally implanted valve of the same type. The favourable haemodynamic profile and the potentially different spectrum of valve-related adverse events should be addressed in further clinical trials. PMID- 26976131 TI - Bio-Root and Implant-Based Restoration as a Tooth Replacement Alternative. AB - We previously reported that dental stem cell-mediated bioengineered tooth root (bio-root) regeneration could restore tooth loss in a miniature pig model. As a potential new method for tooth restoration, it is essential to compare this method with the widely used commercial dental implant-based method of tooth restoration. Tooth loss models were created by extracting mandibular incisors from miniature pigs. Allogeneic periodontal ligament stem cells (PDLSCs) and dental pulp stem cells (DPSCs) were isolated and cultured. A PDLSC sheet was prepared by adding 20.0 ug/mL vitamin C to the culture medium; in addition, a hydroxyapatite tricalcium phosphate (HA/TCP)/DPSC graft was fabricated and cultured in a 3-dimensional culture system. A total of 46 bio-root implantations and 9 dental implants were inserted, and crown restorations were performed 6 mo after implantation. Histological, radiological, biomechanical, and elemental analyses were used to evaluate and compare tissue-engineered bio-roots and dental implants to the natural tooth roots. After 6 mo, both computed tomography scans and histological examinations showed that root-like structures and dentin-like tissues had formed. Three months after crown restoration, clinical assessments revealed that tooth function was equivalent in the regenerated bio-root and the dental implant. Biomechanical testing showed that the bio-roots were similar to natural tooth roots in compressive strength, modulus of elasticity, and torsional force; however, these properties were significantly higher in the dental implants. Elemental analysis revealed a higher similarity in elemental composition between bio-roots and natural tooth roots than between bio-roots and dental implants. However, the dental implant success rate was 100% (9 of 9) and the bio-root success rate was only 22% (10 of 46). Taken together, we showed that an allogeneic HA/TCP/DPSC/PDLSC sheet could successfully build a bio-root with structure and function similar to the natural tooth root; however, tissue engineering procedures must be optimized further to improve the success rate. PMID- 26976132 TI - Short-duration increases in intraluminal pressure improve vasoconstrictor responses in aged skeletal muscle feed arteries. AB - PURPOSE: We tested the hypothesis that exposure to a short-duration (1 h) increase in intraluminal pressure, to mimic pressure associated with a bout of exercise, would attenuate age-induced impairments of vascular smooth muscle (VSM) constrictor responses in soleus muscle feed arteries (SFA) via the Rho pathway. METHODS: SFA from young (4 months) and old (24 months) Fischer 344 rats were cannulated and pressurized to 90 or 130 cmH2O for 1 h. Following the 1-h treatment, pressure in P130 arteries was lowered to 90 cmH2O for examination of vasoconstrictor responses to norepinephrine (NE), angiotensin II (Ang II), and phenylephrine (PE). To assess the role of the Rho pathway, vasoconstrictor responses were assessed in the absence or presence of a RhoA-kinase inhibitor (Y27632) or RhoA-kinase activator (LPA). RESULTS: Vasoconstrictor responses to NE, Ang II, and PE were impaired in old P90 SFA. Pretreatment of old SFA with increased pressure improved vasoconstrictor responses to NE, PE and Ang II. The beneficial effect of the pressure pretreatment in old SFA was eliminated in the presence of Y27632. In the presence of LPA, vasoconstrictor responses to Ang II were improved in old SFA such that responses were not different than young P90 SFA. CONCLUSION: These results indicate that a short-duration exposure to increased intraluminal pressure, to mimic pressure associated with a bout of exercise, attenuates or reverses the age-related decrement in VSM constrictor responses in SFA and that the beneficial response is mediated through Rho kinase. PMID- 26976133 TI - Validation of the Functional Assessment of Chronic Illness Therapy-Spiritual Well being (FACIT-Sp12) on French Old People. AB - The study aimed to develop a French version of the Functional Assessment of Chronic Illness Therapy-Spiritual Well-being short version (FACIT-Sp12), in order to provide a self-reported measure for French people in the field of gerontology. The study involving 63 nursing home residents was conducted to evaluate the construct validity, reliability, and convergence validity of the FACIT-Sp12. A confirmatory factor analysis corroborated a three-factor model (Meaning, Peace and Faith) with modifications for two items, also valid among people with cognitive impairment. Subscales showed good internal consistency and are correlated with quality of life and depression. In conclusion, the validated French version is an suitable instrument to study the maintenance and promotion of quality of life in the elderly. PMID- 26976134 TI - Seasonal changes in the fatty acid profile of the tick Ixodes ricinus (Acari, Ixodidae). AB - Fatty acids (FAs) from nymphs, females and males of Ixodes ricinus were analysed by gas chromatography/mass spectrometry. Ticks were collected from May to October 2013. The most abundant FAs were 18:1, 18:0, 16:0 and 18:2 which are also dominant FAs of insects. Adults contained higher concentrations of FAs in general than nymphs because they contain more fat body and probably a thicker layer of epicuticular lipids. Larger quantities of FAs > 20 carbon atoms in the carboxylic chain were present in females, which generally show higher content of lipids essential for oogenesis, whereas there were similar amounts of 14-18 in both sexes. In September and October, ticks contained large concentrations of the majority of FAs except for 18:1, the most abundant one in ticks collected from May through August. Thus, most FAs, especially those with more than 20 C atoms, tend to increase at lower temperatures. PMID- 26976136 TI - False Memories in Alzheimer's Disease: Intact Semantic Priming But Impaired Production of Critical Lures. AB - Objectives: This study explores the activation of the critical lure (CL) and its production in Deese-Roediger-McDermott (DRM) tasks in Alzheimer's disease and aging. In a previous lexical decision task including DRM lists, we showed that the activation of the CL occurs normally in Alzheimer's patients. Here, we reproduce this study and add a production (DRM) task in order to compare both processes in the same groups of participants. Method: Eighteen older adults and 20 Alzheimer's patients performed a conventional DRM task, followed by a lexical decision task with DRM lists intermixed with neutral words and nonwords. Results: Analyses indicated that Alzheimer's patients produced significantly fewer CLs than older participants in the DRM task, but that they showed, like older adults, shorter lexical decision latencies for CLs than for other types of words. Discussion: This study provides evidence that the low production of CLs regularly documented in Alzheimer's patients in the DRM paradigm is not necessarily explained by their nonactivation. The results are discussed in the light of the hypothesis of a rapid disappearance of the episodic mnemonic trace of the CLs in Alzheimer's patients. PMID- 26976135 TI - Inhibitory Selection Mechanisms in Clinically Healthy Older and Younger Adults. AB - Objective: Declines in working memory are a ubiquitous finding within the cognitive-aging literature. A unitary inhibitory selection mechanism that serves to guide attention toward task-relevant information and resolve interference from task-irrelevant information has been proposed to underlie such deficits. However, inhibition can occur at multiple time points in the memory-processing stream. Here, we tested whether the time point at which inhibition occurs in the memory processing stream affects age-related memory decline. Method: Clinically healthy younger (n = 23) and older (n = 22) adults performed two similar item-recognition working memory tasks. In one task, participants received an instruction cue telling them which words to attend to followed by a memory set, promoting perceptual inhibition at the time of encoding. In the other task, participants received the instruction cue after they received the memory set, fostering inhibition of items already in memory. Results: We found that older and younger adults differed in their ability to inhibit items both during encoding and when items had to be inhibited in memory but that these age differences were exaggerated when irrelevant information had to be inhibited from memory. These results provide insights into the mechanisms that support cognitive changes to memory processes in healthy aging. PMID- 26976137 TI - A novel dengue virus serotype 1 vaccine candidate based on Japanese encephalitis virus vaccine strain SA14-14-2 as the backbone. AB - To develop a potential dengue vaccine candidate, a full-length cDNA clone of a novel chimeric virus was constructed using recombinant DNA technology, with Japanese encephalitis virus (JEV) vaccine strain SA14-14-2 as the backbone, with its premembrane (prM) and envelope (E) genes substituted by their counterparts from dengue virus type 1 (DENV1). The chimeric virus (JEV/DENV1) was successfully recovered from primary hamster kidney (PHK) cells by transfection with the in vitro transcription products of JEV/DENV1 cDNA and was identified by complete genome sequencing and immunofluorescent staining. No neuroinvasiveness of this chimeric virus was observed in mice inoculated by the subcutaneous route (s.c.) or by the intraperitoneal route (i.p.), while some neurovirulence was displayed in mice that were inoculated directly by the intracerebral route (i.c.). The chimeric virus was able to stimulate high-titer production of antibodies against DENV1 and provided protection against lethal challenge with neuroadapted dengue virus in mice. These results suggest that the chimeric virus is a promising dengue vaccine candidate. PMID- 26976138 TI - Identification of the subgenomic promoter of the coat protein gene of cucumber fruit mottle mosaic virus and development of a heterologous expression vector. AB - Heterologous gene expression using plant virus vectors enables research on host virus interactions and the production of useful proteins, but the host range of plant viruses limits the practical applications of such vectors. Here, we aimed to develop a viral vector based on cucumber fruit mottle mosaic virus (CFMMV), a member of the genus Tobamovirus, whose members infect cucurbits. The subgenomic promoter (SGP) in the coat protein (CP) gene, which was used to drive heterologous expression, was mapped by analyzing deletion mutants from a CaMV 35S promoter-driven infectious CFMMV clone. The region from nucleotides (nt) -55 to +160 relative to the start codon of the open reading frame (ORF) of CP was found to be a fully active promoter, and the region from nt -55 to +100 was identified as the active core promoter. Based on these SGPs, we constructed a cloning site in the CFMMV vector and successfully expressed enhanced green fluorescent protein (EGFP) in Nicotiana benthamiana and watermelon (Citrullus lanatus). Co inoculation with the P19 suppressor increased EGFP expression and viral replication by blocking degradation of the viral genome. Our CFMMV vector will be useful as an expression vector in cucurbits. PMID- 26976139 TI - Phylogenetic analysis reveals that Japanese encephalitis virus genotype III is still prevalent in swine herds in Sichuan province in China. AB - The genome of JEV strain SC201301, which was isolated from an aborted fetal piglet in 2013 in Sichuan province in China, was completely sequenced and phylogenetically analyzed. Sequence alignments showed that the SC201301 strain shared 97-100% sequence identity with other genotype III strains but showed less similarity to genotype I representative JEVs. Phylogenetic analysis indicated that the SC201301 strain belonged to genotype III and was most closely related to representative strains such as SA14-14-2, HW and SH0601. Our findings suggest that JEV genotype III is still prevalent in swine herds in Sichuan province in China, and thus, there is an urgent need to monitor the infection status of JEV among swine herds in China. PMID- 26976140 TI - A novel method of transcriptome interpretation reveals a quantitative suppressive effect on tomato immune signaling by two domains in a single pathogen effector protein. AB - BACKGROUND: Effector proteins are translocated into host cells by plant-pathogens to undermine pattern-triggered immunity (PTI), the plant response to microbe associated molecular patterns that interferes with the infection process. Individual effectors are found in variable repertoires where some constituents target the same pathways. The effector protein AvrPto from Pseudomonas syringae has a core domain (CD) and C-terminal domain (CTD) that each promotes bacterial growth and virulence in tomato. The individual contributions of each domain and whether they act redundantly is unknown. RESULTS: We use RNA-Seq to elucidate the contribution of the CD and CTD to the suppression of PTI in tomato leaves 6 h after inoculation. Unexpectedly, each domain alters transcript levels of essentially the same genes but to a different degree. This difference, when quantified, reveals that although targeting the same host genes, the two domains act synergistically. AvrPto has a relatively greater effect on genes whose expression is suppressed during PTI, and the effect on these genes appears to be diminished by saturation. CONCLUSIONS: RNA-Seq profiles can be used to observe relative contributions of effector subdomains to PTI suppression. Our analysis shows the CD and CTD multiplicatively affect the same gene transcript levels with a greater relative impact on genes whose expression is suppressed during PTI. The higher degree of up-regulation versus down-regulation during PTI is plausibly an evolutionary adaptation against effectors that target immune signaling. PMID- 26976141 TI - Efficiently prepared ephedrine alkaloids-free Ephedra Herb extract: a putative marker and antiproliferative effects. AB - Ephedrine alkaloids (EAs) have been considered the main pharmacologically active substances in Ephedra Herb (, Mao; EH) since they were first identified by Prof. N. Nagai, and are known to induce palpitation, hypertension, insomnia, and dysuria as side effects. Therefore, the administration of drugs containing EH to patients with cardiovascular-related diseases is severely contraindicated. While our previous studies suggest that some of the effects of EH may not be due to EAs, considering their side effects would be expedient to develop a new EAs-free EH extract (EFE). Here, we established a preparation method for EFE and revealed its chemical composition, including the content of herbacetin, a flavonoid aglycon present in EH and a potential putative marker for EFE quality control. In addition, we showed the antiproliferative effects of EFE against the H1975 non small cell lung cancer (NSCLC) cell line. EFE was prepared from EH extract using the ion exchange resin SK-1B. LC/Orbitrap MS analysis revealed the removal of EAs, 6-methoxykynurenic acid, and 6-hydroxykynurenic acid from the original extract. Quantitative analysis of herbacetin using LC/MS in acid-hydrolyzed EFE showed that its content was 0.104 %. Although several alkaloidal constituents were removed from EH extract, the antiproliferative effect of EFE against H1975 cells was comparable to that of EH extract. These results indicate that EFE retained the anticancer effect of EH and demonstrated its potential for future development as a new herbal medicine with reduced side effects. PMID- 26976142 TI - Fast myocardial perfusion imaging with 99mTc in challenging patients using conventional SPECT cameras. AB - BACKGROUND: We attempted to validate the performance of a fast myocardial perfusion imaging (MPI) protocol in diagnostically challenging patients. METHODS: 78 patients with BetaMUIota > 24.9, LVH or three vessels disease underwent two sequential gated-MPI studies. The first at 15 (Early Imaging, EI) and the second at 45 (Late Imaging, LI) minutes post 99mTc-injection, at both stress and rest. Counts over heart (H), liver (Liv) and subdiaphragmatic space (Sub) and image quality, and myocardial perfusion and function parameters were compared between the two protocols. Coronary angiography was performed within 2 months from MPI, and ROC analysis was used to compare the diagnostic accuracy for the detection of >=50% diameter luminal stenosis. RESULTS: Quality was optimal-good in 93% of EI and 98% of LI studies (P = .12), H/Liv and stress H/Sub ratios were similar, but rest H/Sub ratio was lower in EI (P = .009). SSS [10 (0 to 46) vs 9 (0 to 36), P = .006] and SDS [3 (0 to 35) vs 2 (0 to 34), P = .02] were higher in EI protocol. LVEF, motion and thickening scores did not differ between the two protocols. A highly significant (P < .001) linear relationship with clinically negligible mean differences in Bland-Altman analysis was observed for all perfusion and function related data. Sensitivity (EI 81%, LI 80%) and specificity (65% for both) did not differ (P = .23) between the two protocols. CONCLUSION: The fast protocol is technically feasible and diagnostically accurate compared to the established protocol in diagnostically challenging patients. PMID- 26976143 TI - Editorial in response to: PET/CT evaluation of 18F-FDG uptake in pericoronary adipose tissue in patients with stable coronary artery disease: Independent predictor of atherosclerotic lesion formation? : Is there prognostic value in evaluation of 18F-FDG uptake in the pericoronary adipose tissue? PMID- 26976144 TI - Does the etiology of cardiac amyloidosis determine the myocardial uptake of [18F] NaF PET/CT? AB - Cardiac amyloidosis (CA) leads to variable degrees of myocardial infiltration with a final echocardiographic phenotype of "hypertrophy." Although many non invasive imaging techniques (MRI, CT, scintigraphy, PET) are useful, the definitive diagnosis is still based on myocardial histology. We explored the possible role of [18F]-NaF PET/CT in the diagnosis of this disease in two cases with wild-type (ATTRwt) or mutant (ATTRm) Ile68Leu transthyretin (TTR)-related CA. PMID- 26976145 TI - Microtubule dynamics decoded by the epigenetic state of centromeric chromatin. AB - Cell division with accurate chromosome segregation is fundamental to cell survival of all organisms. The precise molecular mechanisms that ensure accurate chromosome segregation are still being discovered using a variety of experimental systems and approaches. Microtubule attachment to the kinetochore is a prerequisite for mitotic progression, failure of which activates the spindle assembly checkpoint (SAC). The dynamic tension generated by interaction of the centromere, kinetochore and microtubules is a key regulator of the SAC. Here, in the context of current literature we discuss our recent observation in fission yeast that epigenetic alterations in centromeric and pericentromeric chromatin can compensate for altered dynamics of kinetochore-microtubule attachment to permit escape from mitotic arrest. A role for the spatial configuration of the centromere to influence the finely tuned regulators of mitotic progression opens up new avenues for research. PMID- 26976146 TI - Induced-anxiety differentially disrupts working memory in generalized anxiety disorder. AB - BACKGROUND: Anxiety is characterized by a bias towards threatening information, anxious apprehension, and disrupted concentration. Previous research in healthy subjects suggests that working memory (WM) is disrupted by induced anxiety, but that increased task-demand reduces anxiety and WM is preserved. However, it is unknown if patients with generalized anxiety disorder (GAD) can similarly normalize their performance on difficult WM tasks while reducing their anxiety. Increased threat-related bias and impoverished top-down control in trait anxiety suggests that patients may not reap the same cognitive and emotional benefits from demanding tasks that those low in anxiety. Here we examine this possibility using a WM task of varying difficulty. METHODS: GAD patients (N = 30) and healthy controls (N = 30) performed an n-back task (no-load, 1-back, 2-back, and 3-back) while at risk for shock (threat) or safe from shock (safe). Anxiety was measured via startle reflex and self-report. RESULTS: As predicted, healthy controls' performance was impaired under threat during low-load tasks and facilitated during high-load tasks. In contrast, GAD patients' performance was impaired under threat regardless of WM load. Anxiety was reduced as cognitive load increased in both groups. CONCLUSIONS: The divergence of emotion regulation (reduction) and performance (persistent impairment) in the patient but not the control group, suggests that different top-down mechanisms may be operating to reduce anxiety. Continued WM disruption in patients indicates that attentional resources are allocated to emotion regulation instead of goal-directed behavior. Implications for our understanding of cognitive disruption in patients, and related therapeutic interventions are discussed. PMID- 26976147 TI - Dissection and integration of the autophagy signaling network initiated by bluetongue virus infection: crucial candidates ERK1/2, Akt and AMPK. AB - Bluetongue virus (BTV), a complex double-stranded segmented RNA virus, has been found to initiate cellular autophagy for its own benefit. Here, with a view to understanding the underlying mechanisms, we first systematically dissected the exact signaling network in BTV-induced autophagy. We found that the activity of mTOR, a crucial pivot, was inhibited by BTV1 infection, subsequently leading to downstream p70S6K suppression and autophagy initiation. We then explored the upstream regulators of mTOR and analyzed their activities via a series of assays. We found BTV1-induced autophagy to be independent of the ERK1/2 signaling pathway. However, the BTV1-induced inhibition of PI3K/Akt was found to be partially responsible for mTOR inactivation and subsequent autophagy initiation. Furthermore, we found unexpectedly that AMPK seemed to play a more important role in BTV1-induced autophagy. Elevated [Ca(2+)]cyto-mediated activation of CaMKKbeta exactly managed the activation of AMPK, which then positively regulated autophagy through suppressing mTOR. We must emphasize that TSC2 is a fatal mediator between upstream Akt or AMPK and downstream mTOR through its phosphorylation. Taken together, our data suggested that the BTV1-induced inhibition of the Akt-TSC2 mTOR pathway and the upregulation of the AMPK-TSC2-mTOR pathway both contributed to autophagy initiation and further favored virus replication. PMID- 26976148 TI - Inclusion of Adolescents in Clinical Trials for Sexually Transmitted Infections: A Review of Existing Registered Studies. AB - PURPOSE: Despite their heightened risk of sexually transmitted infections, minor adolescents (<18 years old) are often excluded from clinical trials. The results of trials of adults should not be assumed to generalize to minors. METHODS: Two public clinical trial registries were first searched using microbicide or PrEP with STD, STI, HIV, or HSV and with gel, ring, or film, and then searched using prevention/sexually transmitted diseases with gel. Studies were classified based on the information provided in the registry. RESULTS: The searches yielded 111 unique studies. Only 9.0% (n = 10) included minors. They were under-represented in Phase 0-II studies and over-represented in studies of individuals infected with human immunodeficiency virus. CONCLUSIONS: Minor adolescents should be included during all stages of development and before they have acquired an infection. Future studies should examine the challenges of including minor adolescents in trials and how to overcome these barriers. PMID- 26976149 TI - Feelings of Safety at School, Socioemotional Functioning, and Classroom Engagement. AB - PURPOSE: Classroom engagement is a key indicator of student motivation, learning potential, and the eventual probability of persisting to high-school completion. This study investigated whether feeling unsafe at school interferes with classroom engagement and simultaneously considered whether this association is mediated by poorer student well-being in the form of experiencing symptoms of depression and demonstrating aggressive behavior problems. METHODS: Data were from the Quebec Longitudinal Study of Child Development, an ongoing study that began in 1998 with a population-based cohort of 2,120 Quebec 5-month-old infants. Structural equation modeling was used to test the central hypothesis that concurrent youth self-reported feelings of a lack of safety at school are associated with poorer teacher-reported student classroom engagement (at age 13 years) and the mediating role of emotional and behavioral problems. The model controlled for concurrent measures of victimization, the school safety climate, and earlier measures of students' academic adjustment. RESULTS: The findings support the central hypothesis that youth who feel safer at school are also more engaged in the classroom (p <= .05). Students who felt safer demonstrated less depressive symptoms, but this only partly explained the association between feeling safe and being engaged. CONCLUSIONS: Increasing student feelings of safety at school (e.g., by reducing victimization, improving the overall school and neighborhood safety climate) is likely to represent an effective strategy for promoting classroom engagement. Such interventions could also contribute to future academic achievement and high-school completion and decrease symptoms of mental health problems among youth. PMID- 26976150 TI - Induction chemotherapy in head and neck squamous cell carcinoma of the paranasal sinus and nasal cavity: a role in organ preservation. AB - BACKGROUND/AIMS: The role of induction chemotherapy (IC) for eyeball preservation has not been established in head and neck squamous cell carcinoma (HNSCC) of the paranasal sinus and nasal cavity (PNSNC). Periorbital involvement frequently leads to eyeball exenteration with a margin of safety. We evaluated the treatment outcomes, including survival and eyeball preservation, of patients who received IC for HNSCC of the PNSNC. METHODS: We reviewed 21 patients diagnosed with HNSCC of the PNSNC who were treated with IC. We analyzed response, eyeball preservation rate, and overall survival. RESULTS: Tumors were located in the paranasal sinus (n = 14) or nasal cavity (n = 7). Most patients had stage T4a (n = 10) or T4b (n = 7) disease. More than half of the patients received a chemotherapy regimen of docetaxel, fluorouracil, and cisplatin (n = 11). Thirteen patients (61.9%) achieved a partial response after IC and 15 patients (71.4%) achieved T down staging. Among 17 patients with stage T4 disease, which confers a high risk of orbital exenteration, 14 (82.4%) achieved preservation of the involved eye. The 3 year overall survival (OS) rate of patients who achieved a partial response to IC was 84.6%. The 3-year OS rate of patients with stable disease or disease progression after IC was 25.0% (p = 0.038). CONCLUSIONS: IC could be considered for down-staging patients with advanced T-stage disease. It could also be a reasonable option for eyeball preservation in locally advanced HNSCC of the PNSNC. PMID- 26976151 TI - An analysis of age-related loss of skeletal muscle mass and its significance on osteoarthritis in a Korean population. AB - BACKGROUND/AIMS: This study was conducted in order to analyze the effects of sarcopenia on age-related osteoarthritis (OA) of the knee in a Korean population. METHODS: All the Korean subjects who visited the Yeungnam University Medical Center Health Promotion Center between 2008 and 2012 in order to undergo a routine medical examination were enrolled. A total of 5,723 young, healthy people (2,959 males, 2,764 females) enrolled as normal subjects and 23,473 subjects (13,006 males and 10,467 females) were included for evaluation of the effects of sarcopenia on OA. There were 266 subjects who followed-up bioelectrical impedance analysis at a 4-year interval. Of 327 subjects enrolled in this study, knees with anteroposterior X-rays were assessed according to the Kellgren-Lawrence (K/L) grade. RESULTS: Skeletal muscle mass index (SMI) and basal metabolic rate (BMR) showed a steady decrease with the advance of age (p < 0.01), but SMI showed strong positive correlation with BMR (r = 0.72, beta = 30.96, p < 0.01). During the 4-year interval, BMR showed a significant decrease with aging (p < 0.01), consistently with the decrease of SMI. Knees with normal SMI were prone to be designated as K/L grade 0 or 1; however, subjects with sarcopenia showed a trend toward the higher K/L grade, classified as knee radiological osteoarthritis (ROA) (p < 0.01). CONCLUSIONS: The results of this study may indicate that sarcopenia as age-related loss of skeletal muscle mass is interactively correlated with the presence and severity of age-related OA. PMID- 26976196 TI - Automated 3D ultrasound elastography of the breast: a phantom validation study. AB - In breast cancer screening, the automated breast volume scanner (ABVS) was introduced as an alternative for mammography since the latter technique is less suitable for women with dense breasts. Although clinical studies show promising results, clinicians report two disadvantages: long acquisition times (>90 s) introducing breathing artefacts, and high recall rates due to detection of many small lesions of uncertain malignant potential. Technical improvements for faster image acquisition and better discrimination between benign and malignant lesions are thus required. Therefore, the aim of this study was to investigate if 3D ultrasound elastography using plane-wave imaging is feasible. Strain images of a breast elastography phantom were acquired by an ABVS-mimicking device that allowed axial and elevational movement of the attached transducer. Pre- and post deformation volumes were acquired with different constant speeds (between 1.25 and 40.0 mm s(-1)) and by three protocols: Go-Go (pre- and post-volumes with identical start and end positions), Go-Return (similar to Go-Go with opposite scanning directions) and Control (pre- and post-volumes acquired per position, this protocol can be seen as reference). Afterwards, 2D and 3D cross-correlation and strain algorithms were applied to the acquired volumes and the results were compared. The Go-Go protocol was shown to be superior with better strain image quality (CNRe and SNRe) than Go-Return and to be similar as Control. This can be attributed to applying opposite mechanical forces to the phantom during the Go Return protocol, leading to out-of-plane motion. This motion was partly compensated by using 3D cross-correlation. However, the quality was still inferior to Go-Go. Since these results were obtained in a phantom study with controlled deformations, the effect of possible uncontrolled in vivo tissue motion artefacts has to be addressed in future studies. In conclusion, it seems feasible to implement 3D ultrasound quasi-static elastography on an ABVS-like system and to reduce scan times within one breath-hold (~10 s) by plane-wave acquisitions. PMID- 26976197 TI - Molecular Diagnosis for Nodal Metastasis in Endoscopically Managed Cervical Cancer: The Accuracy of the APTIMA Test to Detect High-risk Human Papillomavirus Messenger RNA in Sentinel Lymph Nodes. AB - STUDY OBJECTIVE: To evaluate the feasibility and accuracy of a commercially available test to detect E6/E7 mRNA of 14 subtypes of high-risk HPVs (APTIMA; Hologic, Bedford, MA) in the sentinel lymph nodes of CC patients laparoscopically operated. DESIGN: Prospective pilot study. SETTING: The study was conducted in the Department of Advanced Operative and Oncologic Gynecology, Asklepios Hospital, Hamburg, Germany. PATIENTS: 54 women with HPV-positive CC submitted to laparoscopic sentinel node biopsy alone or sentinel node biopsy followed by systematic pelvic and/or para-aortic endoscopic lymphadenectomy. INTERVENTIONS: All removed sentinel lymph nodes (SLNs) underwent sample collection by cytobrush for the APTIMA assay before frozen section. MEASUREMENTS: Results obtained with the HPV mRNA test were compared with the definitive histopathological analysis of the SLNs and additional lymph nodes removed. RESULTS: A total of 125 SLNs (119 pelvic and 6 paraaortic) were excised with a mean number of 2.3 SLNs per patient. Final histopathologic analysis confirmed nodal metastases in 10 SLNs from 10 different patients (18%). All the histologically confirmed metastatic lymph nodes were also HPV E6/E7 mRNA positive, resulting in a sensitivity of 100%. Four histologically free sentinel nodes were positive for HPV E6/E7 mRNA, resulting in a specificity of 96.4%. CONCLUSION: The HPV E6/E7 mRNA assay in the SLNs of patients with CC is feasible and highly accurate. The detection of HPV mRNA in 4 women with negative SLNs might denote a shift from microscopic identification of metastasis to the molecular level. The prognostic value of this findings awaits further verification. PMID- 26976198 TI - Assessment of Long-Term Bowel Symptoms After Segmental Resection of Deeply Infiltrating Endometriosis: A Matched Cohort Study. AB - STUDY OBJECTIVE: To assess long-term bowel symptoms in women who underwent segmental bowel resection for deep-infiltrating endometriosis (DIE) compared with women who underwent resection of severe endometriosis without bowel resection. DESIGN: Cohort study with matched controls (Canadian Task Force classification II 2). SETTING: Cleveland Clinic. PATIENTS: 71 patients (36 cases and 35 controls). INTERVENTIONS: Patients who were at least 4 years out from undergoing segmental bowel resection due to DIE were matched with patients who had undergone resection of stage III/IV endometriosis without bowel resection. The patients completed validated questionnaires, and data were analyzed using the Wilcoxon rank-sum, chi(2), and Fisher exact tests. MEASUREMENTS AND MAIN RESULTS: The Bristol Stool Form Scale, Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYM), and St Mark's Vaizey Fecal Incontinence Grading System were used to elicit information. The median duration of follow-up was 10.1 years (range, 4-18 years). The mean patient age and body mass index were comparable in the cases and the controls. A larger proportion of cases than controls reported new bowel symptoms (58% [21 of 36] vs 14% [5 of 35]; p = .001), as well as abdominal pain, incomplete bowel movements, and false alarms on the PAC-SYM questionnaire; however, total PAC-SYM and Vaizey Fecal Incontinence Grading System scores were similar in the 2 groups (median, 8 [interquartile range, 8-10] vs 8 [8-10]; p = .86). Similarly, the proportion of patients with normal stool consistency (Bristol Stool Form Scale score 2-6) was similar in the 2 groups (80.6% [29 of 36] vs 94.3% [33 of 35]; p = .59). CONCLUSION: Segmental bowel resection for DIE may be associated with a higher incidence of new bowel symptoms (possibly due to abdominal pain, incomplete bowel movements, and/or false alarms), but not with worse constipation or fecal incontinence, compared with surgery without bowel resection. PMID- 26976199 TI - Frequency and amplitude modulation of ultra-compact terahertz quantum cascade lasers using an integrated avalanche diode oscillator. AB - Mode-locked comb sources operating at optical frequencies underpin applications ranging from spectroscopy and ultrafast physics, through to absolute frequency measurements and atomic clocks. Extending their operation into the terahertz frequency range would greatly benefit from the availability of compact semiconductor-based sources. However, the development of any compact mode-locked THz laser, which itself is inherently a frequency comb, has yet to be achieved without the use of an external stimulus. High-power, electrically pumped quantum cascade lasers (QCLs) have recently emerged as a promising solution, owing to their octave spanning bandwidths, the ability to achieve group-velocity dispersion compensation and the possibility of obtaining active mode-locking. Here, we propose an unprecedented compact architecture to induce both frequency and amplitude self-modulation in a THz QCL. By engineering a microwave avalanche oscillator into the laser cavity, which provides a 10 GHz self-modulation of the bias current and output power, we demonstrate multimode laser emission centered around 3 THz, with distinct multiple sidebands. The resulting microwave amplitude and frequency self-modulation of THz QCLs opens up intriguing perspectives, for engineering integrated self-mode-locked THz lasers, with impact in fields such as nano- and ultrafast photonics and optical metrology. PMID- 26976202 TI - Extent of resection in medulloblastoma: time to reconsider? PMID- 26976200 TI - NOD-like receptor signaling and inflammasome-related pathways are highlighted in psoriatic epidermis. AB - Psoriatic skin differs distinctly from normal skin by its thickened epidermis. Most gene expression comparisons utilize full-thickness biopsies, with substantial amount of dermis. We assayed the transcriptomes of normal, lesional, and non-lesional psoriatic epidermis, sampled as split-thickness skin grafts, with 5'-end RNA sequencing. We found that psoriatic epidermis contains more mRNA per total RNA than controls, and took this into account in the bioinformatic analysis. The approach highlighted innate immunity-related pathways in psoriasis, including NOD-like receptor (NLR) signaling and inflammasome activation. We demonstrated that the NLR signaling genes NOD2, PYCARD, CARD6, and IFI16 are upregulated in psoriatic epidermis, and strengthened these findings by protein expression. Interestingly, PYCARD, the key component of the inflammasome, showed an altered expression pattern in the lesional epidermis. The profiling of non lesional skin highlighted PSORS4 and mitochondrially encoded transcripts, suggesting that their gene expression is altered already before the development of lesions. Our data suggest that all components needed for the active inflammasome are present in the keratinocytes of psoriatic skin. The characterization of inflammasome pathways provides further opportunities for therapy. Complementing previous transcriptome studies, our approach gives deeper insight into the gene regulation in psoriatic epidermis. PMID- 26976203 TI - Base catalysed intermolecular cyclisation of N-protected o-amino benzaldehyde/acetophenone with phosphorus/sulphur based allenes: facile synthesis of substituted quinolines. AB - Reaction of N-Bz protected o-aminobenzaldehyde or acetophenone with allenylphosphonates in the presence of a simple base leads to quaternary carbon substituted phosphono-quinolines which undergo thermal rearrangement to O phosphorylated quinolines. The present one-pot reaction involves intermolecular cyclisation, dehydration, and benzoyl group rearrangement followed by a novel phosphoryl group migration. The migration was less facile/not observed in the reactions using allenylphosphine oxides and sulphur based allenes wherein only substituted quinolines were obtained in good yields. X-ray structures have been determined for the key products. PMID- 26976204 TI - Serum Vitamin D is Not Helpful for Predicting Prostate Cancer Aggressiveness Compared with the Prostate Health Index. AB - PURPOSE: We evaluated the usefulness of serum 25-hydroxyvitamin D as a marker of aggressive prostate cancer and for active surveillance compared to PHI (Prostate Health Index). MATERIALS AND METHODS: Of 480 prospectively biopsied men 222 had prostate cancer and 258 had no evidence of malignancy. In all men prostate specific antigen was less than 20 ng/ml. We measured 25-hydroxyvitamin D, prostate specific antigen, free prostate specific antigen and -2proPSA using a commercially available immunoassay system. PHI was calculated according to the equation, -2proPSA/free prostate specific antigen * ?PSA. We determined 25 hydroxyvitamin D using a 2-step competitive binding immunoenzymatic vitamin D assay. RESULTS: The 25-hydroxyvitamin D concentrations were not associated with Gleason grade according to the 2014 ISUP (International Society of Urological Pathology) consensus conference Gleason grading system. PHI values were higher with increasing Gleason grade. Median 25-hydroxyvitamin D did not differ between men with prostate cancer vs no evidence of malignancy (50.6 vs 48.2 nmol/l, p = 0.192) or in ISUP Gleason subgroups despite seasonal variations of 25 hydroxyvitamin D. However, PHI values significantly differed between the subgroup with no evidence of malignancy and all Gleason subgroups (p <0.0001). The ROCs of all men revealed an advantage of PHI over 25-hydroxyvitamin D (AUC 0.78 vs 0.535, p <0.0001). PHI could also significantly better separate patients with no evidence of malignancy from those with nonaggressive disease (ISUP Gleason grade 1) from those with aggressive prostate cancer (ISUP Gleason grades 2-5). CONCLUSIONS: It remains highly improbable that 25-hydroxyvitamin D could be used as decision or selection marker for aggressive prostate cancer or for active surveillance compared to accepted markers, as recently suggested. PMID- 26976205 TI - Vancouver Symptom Score for Dysfunctional Elimination Syndrome: Reliability and Validity of the Dutch Version. AB - PURPOSE: We sought to establish the reliability and validity of the Dutch version of the Vancouver Symptom Score for Dysfunctional Elimination Syndrome for children with dysfunctional voiding and their parents. MATERIALS AND METHODS: For this cross-sectional multicenter study the Vancouver Symptom Score for Dysfunctional Elimination Syndrome was translated and cross-culturally adapted to Dutch following a standardized process. Patients 16 years or younger with dysfunctional voiding and their parents were recruited at pediatric, pediatric urology and pelvic floor physical therapy outpatient clinics. The reference group consisted of children 6 to 16 years old without dysfunctional voiding and their parents. All groups completed questionnaires. The evaluated measurement properties included discriminative ability, internal consistency, test-retest reliability, interrater agreement, criterion validity using the Pediatric Incontinence Questionnaire and construct validity. A cutoff value for diagnosis of dysfunctional voiding was determined. RESULTS: A total of 50 patients and 60 references and their parents were included in the study. The Vancouver Symptom Score for Dysfunctional Elimination Syndrome showed good discriminative ability. A moderate internal consistency was found (Cronbach alpha 0.37-0.55). Test-retest reliability was moderate to good, and interrater agreement demonstrated good correlation between children and parents (ICC 0.85, 95% CI 0.79-0.89). A weak correlation with the Pediatric Incontinence Questionnaire was found in patients and construct validity was confirmed. Cutoff scores for dysfunctional voiding were 11 and 9 for patients and parents, respectively. CONCLUSIONS: The Dutch Vancouver Symptom Score for Dysfunctional Elimination Syndrome displayed moderate to good reliability and validity properties for the patient and parent versions. Use of this instrument in clinical practice will support the assessment of dysfunctional voiding and facilitate international reporting of research results. PMID- 26976206 TI - Prospective Quality of Life in Men Choosing Active Surveillance Compared to Those Biopsied but not Diagnosed with Prostate Cancer. AB - PURPOSE: Active surveillance is an important alternative to definitive therapy for men with low risk prostate cancer. However, the impact of active surveillance on health related quality of life compared to that in men without cancer remains unknown. In this study we evaluated health related quality of life outcomes in men on active surveillance compared to men followed after negative prostate needle biopsy. MATERIALS AND METHODS: A prospective study was conducted on men who were enrolled into the Center for Prostate Disease Research Multicenter National Database and underwent prostate needle biopsy for suspicion of prostate cancer between 2007 and 2014. Health related quality of life was assessed at biopsy (baseline) and annually for up to 3 years using SF-36 and EPIC questionnaires. Health related quality of life scores were modeled using generalized estimating equations, adjusting for baseline health related quality of life, and demographic and clinical characteristics. RESULTS: Of the 1,204 men who met the initial eligibility criteria 420 had a negative prostate needle biopsy (noncancer comparison group). Among the 411 men diagnosed with low risk prostate cancer 89 were on active surveillance. Longitudinal analysis revealed that for most health related quality of life subscales there were no significant differences between the groups in adjusted health related quality of life score trends over time. CONCLUSIONS: In this study most health related quality of life outcomes in patients with low risk prostate cancer on active surveillance did not differ significantly from those of men without prostate cancer. A comparison group of men with a similar risk of prostate cancer detection is critical to clarify the psychological and physical impact of active surveillance. PMID- 26976201 TI - Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis. AB - BACKGROUND: Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup specific manner. METHODS: We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1.5 cm(2) tumour remaining), or sub-total resection (>=1.5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs >=3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival. FINDINGS: We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1.45, 95% CI 1.07-1.96, p=0.16) but no overall survival benefit (HR 1.23, 0.87-1.72, p=0.24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1.05, 0.71-1.53, p=0.8158 for progression free survival and HR 1.14, 0.75-1.72, p=0.55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1.03, 0.67-1.58, p=0.89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1.97, 1.22-3.17, p=0.0056), especially for those with metastatic disease (HR 2.22, 1.00-4.93, p=0.050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1.67, 0.93-2.99, p=0.084). INTERPRETATION: The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection. FUNDING: Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research. PMID- 26976208 TI - Mesenchymal stem cells secretomes' affect multiple myeloma translation initiation. AB - Bone marrow mesenchymal stem cells' (BM-MSCs) role in multiple myeloma (MM) pathogenesis is recognized. Recently, we have published that co-culture of MM cell lines with BM-MSCs results in mutual modulation of phenotype and proteome (via translation initiation (TI) factors eIF4E/eIF4GI) and that there are differences between normal donor BM-MSCs (ND-MSCs) and MM BM-MSCs (MM-MSCs) in this crosstalk. Here, we aimed to assess the involvement of soluble BM-MSCs' (ND, MM) components, more easily targeted, in manipulation of MM cell lines phenotype and TI with specific focus on microvesicles (MVs) capable of transferring critical biological material. We applied ND and MM-MSCs 72h secretomes to MM cell lines (U266 and ARP-1) for 12-72h and then assayed the cells' (viability, cell count, cell death, proliferation, cell cycle, autophagy) and TI (factors: eIF4E, teIF4GI; regulators: mTOR, MNK1/2, 4EBP; targets: cyclin D1, NFkappaB, SMAD5, cMyc, HIF1alpha). Furthermore, we dissected the secretome into >100kDa and <100kDa fractions and repeated the experiments. Finally, MVs were isolated from the ND and MM-MSCs secretomes and applied to MM cell lines. Phenotype and TI were assessed. Secretomes of BM-MSCs (ND, MM) significantly stimulated MM cell lines' TI, autophagy and proliferation. The dissected secretome yielded different effects on MM cell lines phenotype and TI according to fraction (>100kDa- repressed; <100kDa- stimulated) but with no association to source (ND, MM). Finally, in analyses of MVs extracted from BM-MSCs (ND, MM) we witnessed differences in accordance with source: ND-MSCs MVs inhibited proliferation, autophagy and TI whereas MM-MSCs MVs stimulated them. These observations highlight the very complex communication between MM and BM-MSCs and underscore its significance to major processes in the malignant cells. Studies into the influential MVs cargo are underway and expected to uncover targetable signals in the regulation of the TI/proliferation/autophagy cascade. PMID- 26976207 TI - Association between chronic stress-induced structural abnormalities in Ranvier nodes and reduced oligodendrocyte activity in major depression. AB - Repeated stressful events are associated with the onset of major depressive disorder (MDD). We previously showed oligodendrocyte (OL)-specific activation of the serum/glucocorticoid-regulated kinase (SGK)1 cascade, increased expression of axon-myelin adhesion molecules, and elaboration of the oligodendrocytic arbor in the corpus callosum of chronically stressed mice. In the current study, we demonstrate that the nodes and paranodes of Ranvier in the corpus callosum were narrower in these mice. Chronic stress also led to diffuse redistribution of Caspr and Kv 1.1 and decreased the activity in white matter, suggesting a link between morphological changes in OLs and inhibition of axonal activity. OL primary cultures subjected to chronic stress resulted in SGK1 activation and translocation to the nucleus, where it inhibited the transcription of metabotropic glutamate receptors (mGluRs). Furthermore, the cAMP level and membrane potential of OLs were reduced by chronic stress exposure. We showed by diffusion tensor imaging that the corpus callosum of patients with MDD exhibited reduced fractional anisotropy, reflecting compromised white matter integrity possibly caused by axonal damage. Our findings suggest that chronic stress disrupts the organization of the nodes of Ranvier by suppressing mGluR activation in OLs, and that specific white matter abnormalities are closely associated with MDD onset. PMID- 26976209 TI - Role of AMPK in regulation of LC3 lipidation as a marker of autophagy in skeletal muscle. AB - During induction of the autophagosomal degradation process, LC3-I is lipidated to LC3-II and associates to the cargo isolation membrane allowing for autophagosome formation. Lipidation of LC3 results in an increased LC3-II/LC3-I ratio, and this ratio is an often used marker for autophagy in various tissues, including skeletal muscle. From cell studies AMPK has been proposed to be necessary and sufficient for LC3 lipidation. The aim of the present study was to investigate the role of AMPK in regulation of LC3 lipidation as a marker of autophagy in skeletal muscle. We observed an increase in the LC3-II/LC3-I ratio in skeletal muscle of AMPKalpha2 kinase-dead (KD) (p<0.001) and wild type (WT) (p<0.05) mice after 12h of fasting, which was greater (p<0.05) in AMPKalpha2 KD mice than in WT. The fasting-induced increase in the LC3-II/LC3-I ratio in both genotypes coincided with an initial decrease (p<0.01) in plasma insulin concentration, a subsequent decrease in muscle mTORC1 signaling and increased (p<0.05) levels of the autophagy-promoting proteins, FoxO3a and ULK1. Furthermore, a higher (p<0.01) LC3-II/LC3-I ratio was observed in old compared to young mice. We were not able to detect any change in LC3 lipidation with either in vivo treadmill exercise or in situ contractions. Collectively, these findings suggest that AMPKalpha2 is not necessary for induction of LC3 lipidation with fasting and aging. Furthermore, LC3 lipidation is increased in muscle lacking functional AMPKalpha2 during fasting and aging. Moreover, LC3 lipidation seems not to be a universal response to muscle contraction in mice. PMID- 26976210 TI - Additional oxidized and alkyl chain breakdown metabolites of the plasticizer DINCH in urine after oral dosage to human volunteers. AB - Hexamoll(r) DINCH(r) (diisononyl-cyclohexane-1,2-dicarboxylate) is a new high molecular weight plasticizer and a non-aromatic phthalate substitute. In this follow-up study, we further investigated the extensive oxidative metabolism of Hexamoll(r) DINCH(r) after oral dosage of 50 mg to three male volunteers (0.552 0.606 mg/kg body weight). Urine samples were consecutively collected over 48 h post-dose. Chemical analysis was carried out by HPLC-MS/MS with labeled internal standards. New metabolites were tentatively identified and quantified via fragmentation analogies and new standard substances. In addition to the five urinary DINCH metabolites previously reported by us, we identified two groups of extensively oxidized metabolites characterized (a) by multiple side chain oxidation and breakdown and (b) by hydroxylation at the cyclohexane ring. The five newly identified carboxylated breakdown metabolites represented in sum 5.12 +/- 0.49 % of the applied dose. MCHxCH (cyclohexane-1,2-dicarboxylic acid mono carboxyhexyl ester) was identified as a major metabolite (2.71 +/- 0.34 %) and thus represents the second most important specific metabolite of DINCH after OH MINCH (10.7 +/- 2.1 %). Less than 1 % was excreted as ring-hydroxylated metabolites (four metabolites identified). Based upon a new reference standard, we can also update oxo-MINCH to 2.6 % of the applied dose. This follow-up study increases the total amount of the recovered dose from 39.2 to 45.7 % and describes a new major metabolite (MCHxCH) of DINCH that can be used as an additional valuable and specific biomarker to assess DINCH(r) exposure in future human biomonitoring studies. PMID- 26976212 TI - Functional restoration programs in patients with chronic low back pain and body composition: No change in muscle mass assessed through Dual X-ray absorptiometry in 94 patients, a monocenter longitudinal study. PMID- 26976211 TI - Multicomponent assembly of novel antiproliferative steroidal dihydropyridinyl spirooxindoles. AB - Multicomponent assembly of steroidal dihydropyridinyl spirooxindoles from pregnenolone, isatins, malononitrile, and ammonium acetate is described, which involves the formation of two C-C bonds, two C-N bonds, and an all-carbon quaternary stereogenic center in a single operation. MTT assays showed that some of these compounds had moderate to excellent cytotoxicity against the tested cancer cell lines and were more potent than 5-FU. Particularly, compound 5o represented excellent inhibitory effect toward EC-109 (IC50=0.3 MUM), being about 33-fold more potent than 5-FU. PMID- 26976213 TI - Fragment-based discovery of inhibitor scaffolds targeting the metallo-beta lactamases NDM-1 and VIM-2. AB - Metallo-beta-lactamases (MBLs) render bacteria resistant to beta-lactam antibiotics and are interesting drug targets to prevent the hydrolysis of beta lactam antibiotics. So far, there are no MBL inhibitors in clinical use and particularly the design of broad spectrum inhibitors targeting several MBLs has been difficult. In this study, we report four fragments inhibiting the clinically relevant New Delhi metallo-beta-lactamase 1 (NDM-1) and Verona integron-encoded metallo-beta-lactamase 2 (VIM-2). The fragments were identified from a library using an orthogonal screening strategy combining a surface plasmon resonance (SPR) based assay and an enzyme inhibition assay. The identified fragments showed dissociation constants (KD) ranging from 181 to 2100 MUM. The binding mode of the fragments was explored using QM-polarized ligand docking. All four fragments represent interesting scaffolds for the design of broad-spectrum MBL inhibitors. PMID- 26976214 TI - Approaching the active conformation of 1,3-diaminopyrimidine based covalent inhibitors of Bruton's tyrosine kinase for treatment of Rheumatoid arthritis. AB - By applying conformational restrictions, we were able to discover highly potent 1,3-diaminopyrimidine based covalent inhibitors of BTK, such as 8a (IC50=3.76 nM), and providing useful information of its active conformation. We are developing these novel small molecule covalent inhibitors of BTK toward oral agents for Rheumatoid arthritis. PMID- 26976216 TI - Sesquiterpenes and a monoterpenoid with acetylcholinesterase (AchE) inhibitory activity from Valeriana officinalis var. latiofolia in vitro and in vivo. AB - Acetylcholinesterase Inhibitor (AchEI) is the most extensive in all anti-dementia drugs. The extracts and isolated compounds from the Valeriana genus have shown anti-dementia bioactivity. Four new sesquiterpenoids (1-4) and a new monoterpenoid (5) were isolated from the root of Valeriana officinalis var. latiofolia. The acetylcholinesterase (AchE) inhibitory activity of isolates was evaluated by modified Ellman method in vitro. Learning and memory ability of compound 4 on mice was evaluated by the Morris water maze. The contents of acetylcholine (Ach), acetylcholine transferase (ChAT) and AchE in mice brains were determined by colorimetry. The results showed IC50 of compound 4 was 0.161 MUM in vitro. Compared with the normal group, the learning and memory ability of mice and the contents of Ach and ChAT decreased in model group mice (P<0.01), while the AchE increased (P<0.01). Compared with the model group, Ach and ChAT in the positive control group, the high-dose group and the medium-dose group increased (P<0.01), while the AchE decreased (P<0.01). Compound 4 can improve the learning and memory abilities of APPswe/PSDeltaE9 double-transgenic mice, and the mechanism may be related to the regulation of the relative enzyme in the cholinergic system. PMID- 26976215 TI - Development of thieno- and benzopyrimidinone inhibitors of the Hedgehog signaling pathway reveals PDE4-dependent and PDE4-independent mechanisms of action. AB - From a high content in vivo screen for modulators of developmental patterning in embryonic zebrafish, we previously identified eggmanone (EGM1, 3) as a Hedgehog (Hh) signaling inhibitor functioning downstream of Smoothened. Phenotypic optimization studies for in vitro probe development utilizing a Gli transcription linked stable luciferase reporter cell line identified EGM1 analogs with improved potency and aqueous solubility. Mechanistic profiling of optimized analogs indicated two distinct scaffold clusters: PDE4 inhibitors able to inhibit downstream of Sufu, and PDE4-independent Hh inhibitors functioning between Smo and Sufu. Each class represents valuable in vitro probes for elucidating the complex mechanisms of Hh regulation. PMID- 26976217 TI - Pumpkin seed extract: Cell growth inhibition of hyperplastic and cancer cells, independent of steroid hormone receptors. AB - Pumpkin seeds have been known in folk medicine as remedy for kidney, bladder and prostate disorders since centuries. Nevertheless, pumpkin research provides insufficient data to back up traditional beliefs of ethnomedical practice. The bioactivity of a hydro-ethanolic extract of pumpkin seeds from the Styrian pumpkin, Cucurbita pepo L. subsp. pepo var. styriaca, was investigated. As pumpkin seed extracts are standardized to cucurbitin, this compound was also tested. Transactivational activity was evaluated for human androgen receptor, estrogen receptor and progesterone receptor with in vitro yeast assays. Cell viability tests with prostate cancer cells, breast cancer cells, colorectal adenocarcinoma cells and a hyperplastic cell line from benign prostate hyperplasia tissue were performed. As model for non-hyperplastic cells, effects on cell viability were tested with a human dermal fibroblast cell line (HDF-5). No transactivational activity was found for human androgen receptor, estrogen receptor and progesterone receptor, for both, extract and cucurbitin. A cell growth inhibition of ~40-50% was observed for all cell lines, with the exception of HDF-5, which showed with ~20% much lower cell growth inhibition. Given the receptor status of some cell lines, a steroid-hormone receptor independent growth inhibiting effect can be assumed. The cell growth inhibition for fast growing cells together with the cell growth inhibition of prostate-, breast- and colon cancer cells corroborates the ethnomedical use of pumpkin seeds for a treatment of benign prostate hyperplasia. Moreover, due to the lack of androgenic activity, pumpkin seed applications can be regarded as safe for the prostate. PMID- 26976218 TI - Evaluation of mandibular contour in patients with significant facial asymmetry. AB - Most previous studies on facial asymmetry have not specifically differentiated mandible deviation from structural asymmetry of the mandible. The purpose of this study was to assess the symmetry of the mandible by examining its contour in a cohort of patients with significant facial asymmetry. Eleven cases of facial asymmetry with chin deviation >=10mm were enrolled. A voxel-paired median plane (optimal symmetry plane, OSP) and two landmark-based median planes were generated. The OSP was created by computing the best pairing of the bony voxels on the two sides. One side of the mandibular contour was mirrored onto the other side using the test plane. The contour differences were measured by distance and by area ratio. They were examined both in frontal and frontal downward inclined view. The contour symmetry of the mandible was that revealed by the plane that presented the best symmetry. The results showed that the OSP worked best in bisecting the contour into two symmetrical halves. Contour analysis showed relatively small discrepancies between the two sides. In conclusion, the mandibles retained an acceptable contour symmetry despite the presence of significant mandibular deviations. It is suggested that proper mandibular alignment be the primary objective in the correction of facial asymmetry. PMID- 26976219 TI - Utility of a Novel Reflective Marker Visualized by Flash Photography for Assessment of Personnel Contamination During Removal of Personal Protective Equipment. AB - In an experimental study, the frequency of contamination of healthcare personnel during removal of contaminated personal protective equipment (PPE) was similar for bacteriophage MS2 and a novel reflective marker visualized using flash photography. The reflective marker could be a useful tool to visualize and document personnel contamination during PPE removal. Infect Control Hosp Epidemiol 2016;37:711-713. PMID- 26976220 TI - Resident research: why some do and others don't. AB - INTRODUCTION: Although research is widely considered to be a relevant and essential skill to resident development, the actual participation rate of residents in research remains low, and the factors associated with participation are unclear. METHODS: We examined the participation rate of junior residents in research, and their attitudes and perceived barriers toward research, via an anonymised survey carried out from October to November 2013. The residents were from an established Accreditation Council for Graduate Medical Education accredited internal medicine residency training programme in Singapore. RESULTS: The overall response rate was 64.1% (82/128 residents). The most frequently cited barrier was lack of time. Only a third of the residents surveyed were actively participating in research. Those with postgraduate qualifications were more likely to be involved in research (odds ratio 4.71, p = 0.015). Among the 82 residents, 40.2% reported an interest in research as part of their career; these were mainly graduates from overseas universities or postgraduates. A belief that research is an intrinsically valuable activity distinguished residents who chose research as a career path from those who were undecided (p = 0.004). The belief that research is a means to better clinical practice also divided those who chose research from those who rejected it (p = 0.02). CONCLUSION: Our findings suggest that specific beliefs determine the level of research activity and career interest among residents. Novel strategies may be incorporated in training programmes to improve the interest and participation of residents in research, and to facilitate the development of academic clinicians. PMID- 26976221 TI - Eosinophilic oesophagitis in children: an uncommon occurrence in a predominantly Chinese population in Singapore. AB - INTRODUCTION: We aimed to determine the prevalence and clinical manifestations of eosinophilic oesophagitis (EoE) in children who presented to a tertiary care hospital in Singapore. METHODS: We conducted a retrospective review of all oesophageal biopsies taken during oesophagogastroduodenoscopy (OGD) from March 2010 to December 2011. The patients' demographics and clinical characteristics were collected. Biopsies were reviewed by a single pathologist who was blinded to the original reports, using the current consensus criteria for the histological diagnosis of EoE. RESULTS: Of the 88 children who had biopsies during OGD, 4 (4.5%) children (three boys, one girl; three Chinese, one Caucasian) were diagnosed with EoE. Their median age was 9.5 (range 4.0-12.0) years. The main clinical presentations were abdominal pain (in the three older children) and vomiting (in the youngest child). Three children had a history of atopy. Three children were diagnosed with EoE in the original histology reports, while one was diagnosed after the second review following histology demonstrating > 15 eosinophil granulocytes per high power field and microabscess formation. Endoscopy findings revealed oesophagitis in two children, one of whom was already on acid suppression therapy. Although three children were started on acid suppression therapy, they continued to be symptomatic. One child was also treated with swallowed fluticasone and two with food allergen avoidance, resulting in symptom improvement. CONCLUSION: Although EoE is uncommon in Singapore, greater awareness is needed among family physicians and general paediatricians. Paediatric gastroenterologists should alert pathologists when sending biopsy specimens that are suspicious for EoE. PMID- 26976222 TI - Radiological analysis of the medial epicondyle in the adolescent throwing athlete. AB - INTRODUCTION: Injuries to the medial structures of the elbow due to overhead throwing games are well documented. However, variations of medial epicondyles are not well described, especially in athletes with fused medial epicondyles. In this study, we evaluated variations in the medial epicondyle of baseball players who were aged 15-17 years and had fused epicondyles. METHODS: In this cross-sectional observational study, 155 skeletally mature baseball players with unilateral medial elbow pain and 310 elbow radiographs were reviewed by two independent reviewers. The medial epicondyles were categorised into three groups: normal, elongated or separated. RESULTS: Among the 155 patients, 65 (41.9%) had normal epicondyles, 41 (26.5%) had elongated epicondyles and 49 (31.6%) had separated epicondyles. The medial epicondyle was larger on the dominant arm for 125 (80.6%) patients; the mean surface area on the dominant arm was 222.50 +/- 45.77 mm2, while that of the non-dominant arm was 189.14 +/- 39.56 mm2 (p < 0.01). Among the three categories of medial epicondyles, separated epicondyles had the largest surface area, followed by elongated and normal epicondyles. CONCLUSION: Medial epicondyles in adolescent throwing athletes can be categorised into three different groups according to their shape (normal, elongated and separated). We observed a correlation between the shape and the surface area of the medial epicondyle in adolescent throwing athletes, with separated medial epicondyles having the largest surface area. Further studies and follow-up are needed to determine the prognostic value and clinical significance of these morphological variations. PMID- 26976223 TI - Gap Between Official Guidelines and Clinical Practice for the Treatment of Rheumatoid Arthritis in Sao Paulo, Brazil. AB - PURPOSE: Biological agents used for the treatment of rheumatoid arthritis (RA) are associated with serious adverse events. Guidelines provide standards for the prescribing and monitoring of these drugs. In Sao Paulo, health litigation for access to medicines has fueled the demand for biological therapy. The extent to which biological agents are being appropriately prescribed and patients are being appropriately monitored is uncertain. Our goal was to determine whether RA clinical guidelines are being translated into clinical practice for patients receiving treatment as a result of lawsuits against the government. METHODS: We identified patients through records of the State Secretary of Health of Sao Paulo from 2003 to 2011. We consulted guidelines from 5 countries and chose those recommendations endorsed by all of the guidelines reviewed as standards. Pharmacy records provided data regarding biologic use. The guidelines recommended the use of biological agents only when patients had been receiving treatment with at least 1 disease-modifying antirheumatic drug (DMARD) and recommended annual monitoring of laboratory blood tests. FINDINGS: Of the 238 patients identified in the database, 216 patients were interviewed, and 124 (57.4%) patients were still using biological agents at the time of the survey. Of the patients interviewed, 167 patients (77.3%) started biological treatment when using >=2 DMARDs before, 22 patients (10.2%) were using 1 DMARD before, and 27 patients (12.5%) had never taken a DMARD. Of the 124 patients still taking biological drugs, 117 patients (94.3%) had visited a doctor at least once per year, but 28 patients (22.6%) did not undergo the recommended laboratory blood testing. Only 43 of the 124 patients (34.7%) still taking biological agents met the guideline criteria for both the use of previous agents and the appropriate monitoring. IMPLICATIONS: An important gap between clinical practice and the national guidelines exists among treatments prescribed for plaintiffs obtaining medicines for RA in Sao Paulo. The results suggest the need for intervention by health authorities. PMID- 26976224 TI - Definitive Management of Failure After Pyeloplasty. AB - INTRODUCTION: Failure after pyeloplasty is difficult to manage. We report our experience managing pyeloplasty failures. METHODS: We retrospectively reviewed the case log of a single surgeon, from August 1996 to August 2014, to identify all patients undergoing a surgical procedure after failed pyeloplasty. We excluded patients without follow-up exceeding 1 year from initial postpyeloplasty procedure. Failure was defined as a need for additional definitive intervention. RESULTS: Of 247 laparoscopic pyeloplasties, 68 endopyelotomies and 305 simple laparoscopic nephrectomies reviewed, 41 were performed after previous pyeloplasty and had sufficient follow-up. Laparoscopic nephrectomy was performed in nine patients. All three secondary laparoscopic pyeloplasties were successful. Of 29 secondary endopyelotomies, 10 (34%) were successful. Of the 19 failures after secondary endopyelotomy, 12 patients had tertiary pyeloplasty (5 laparoscopic and 7 open surgical), 5 (26%) underwent tertiary endopyelotomy, and 2 (11%) required nephrectomy. Our overall endopyelotomy success rate was 38% (13/34) vs 100% (11/11) for secondary or tertiary pyeloplasty (4 patients lost to follow-up). Median time to failure was 5 months for endopyelotomy. Median follow-up for patients free from intervention was 40.2 months. CONCLUSIONS: Secondary pyeloplasty (including both laparoscopic and open surgical approach) is more than twice as successful as endopyelotomy after failed pyeloplasty. Secondary pyeloplasty is an excellent alternative to endopyelotomy in select patients with failure after initial pyeloplasty. PMID- 26976226 TI - Force reduction induced by unidirectional transversal muscle loading is independent of local pressure. AB - Transversal unidirectional compression applied to muscles via external loading affects muscle contraction dynamics in the longitudinal direction. A recent study reported decreasing longitudinal muscle forces with increasing transversal load applied with a constant contact area (i.e., leading to a simultaneous increase in local pressure). To shed light on these results, we examine whether the decrease in longitudinal force depends on the load, the local pressure, or both. To this end, we perform isometric experiments on rat M. gastrocnemius medialis without and with transversal loading (i) changing the local pressure from 1.1-3.2Ncm(-2) (n=9) at a constant transversal load (1.62N) and (ii) increasing the transversal load (1.15-3.45N) at a constant local pressure of 2.3Ncm(-2) (n=7). While we did not note changes in the decrease in longitudinal muscle force in the first experiment, the second experiment resulted in an almost-linear reduction of longitudinal force between 7.5+/-0.6% and 14.1+/-1.7%. We conclude that the observed longitudinal force reduction is not induced by local effects such as malfunction of single muscle compartments, but that similar internal stress conditions and myofilament configurations occur when the local pressure changes given a constant load. The decreased longitudinal force may be explained by increased internal pressure and a deformed myofilament lattice that is likely associated with the decomposition of cross-bridge forces on the one hand and the inhibition of cross-bridges on the other hand. PMID- 26976225 TI - A study of the osmotic characteristics, water permeability, and cryoprotectant permeability of human vaginal immune cells. AB - Cryopreservation of specimens taken from the genital tract of women is important for studying mucosal immunity during HIV prevention trials. However, it is unclear whether the current, empirically developed cryopreservation procedures for peripheral blood cells are also ideal for genital specimens. The optimal cryopreservation protocol depends on the cryobiological features of the cells. Thus, we obtained tissue specimens from vaginal repair surgeries, isolated and flow cytometry-purified immune cells, and determined fundamental cryobiological characteristics of vaginal CD3(+) T cells and CD14(+) macrophages using a microfluidic device. The osmotically inactive volumes of the two cell types (Vb) were determined relative to the initial cell volume (V0) by exposing the cells to hypotonic and hypertonic saline solutions, evaluating the equilibrium volume, and applying the Boyle van't Hoff relationship. The cell membrane permeability to water (Lp) and to four different cryoprotective agent (CPA) solutions (Ps) at room temperature were also measured. Results indicated Vb values of 0.516 V0 and 0.457 V0 for mucosal T cells and macrophages, respectively. Lp values at room temperature were 0.196 and 0.295 MUm/min/atm for T cells and macrophages, respectively. Both cell types had high Ps values for the three CPAs, dimethyl sulfoxide (DMSO), propylene glycol (PG) and ethylene glycol (EG) (minimum of 0.418 * 10(-3) cm/min), but transport of the fourth CPA, glycerol, occurred 50 150 times more slowly. Thus, DMSO, PG, and EG are better options than glycerol in avoiding severe cell volume excursion and osmotic injury during CPA addition and removal for cryopreservation of human vaginal immune cells. PMID- 26976227 TI - Determination of a new uniform thorax density representative of the living population from 3D external body shape modeling. AB - Body segment parameters (BSP) for each body's segment are needed for biomechanical analysis. To provide population-specific BSP, precise estimation of body's segments volume and density are needed. Widely used uniform densities, provided by cadavers' studies, did not consider the air present in the lungs when determining the thorax density. The purpose of this study was to propose a new uniform thorax density representative of the living population from 3D external body shape modeling. Bi-planar X-ray radiographies were acquired on 58 participants allowing 3D reconstructions of the spine, rib cage and human body shape. Three methods of computing the thorax mass were compared for 48 subjects: (1) the Dempster Uniform Density Method, currently in use for BSPs calculation, using Dempster density data, (2) the Personalized Method using full-description of the thorax based on 3D reconstruction of the rib cage and spine and (3) the Improved Uniform Density Method using a uniform thorax density resulting from the Personalized Method. For 10 participants, comparison was made between the body mass obtained from a force-plate and the body mass computed with each of the three methods. The Dempster Uniform Density Method presented a mean error of 4.8% in the total body mass compared to the force-plate vs 0.2% for the Personalized Method and 0.4% for the Improved Uniform Density Method. The adjusted thorax density found from the 3D reconstruction was 0.74g/cm(3) for men and 0.73g/cm(3) for women instead of the one provided by Dempster (0.92g/cm(3)), leading to a better estimate of the thorax mass and body mass. PMID- 26976228 TI - A comparison of acromion marker cluster calibration methods for estimating scapular kinematics during upper extremity ergometry. AB - Accurate measurement of joint kinematics is required to understand the musculoskeletal effects of a therapeutic intervention such as upper extremity (UE) ergometry. Traditional surface-based motion capture is effective for quantifying humerothoracic motion, but scapular kinematics are challenging to obtain. Methods for estimating scapular kinematics include the widely-reported acromion marker cluster (AMC) which utilizes a static calibration between the scapula and the AMC to estimate the orientation of the scapula during motion. Previous literature demonstrates that including additional calibration positions throughout the motion improves AMC accuracy for single plane motions; however this approach has not been assessed for the non-planar shoulder complex motion occurring during UE ergometry. The purpose of this study was to evaluate the accuracy of single, dual, and multiple AMC calibration methods during UE ergometry. The orientations of the UE segments of 13 healthy subjects were recorded with motion capture. Scapular landmarks were palpated at eight evenly spaced static positions around the 360 degrees cycle. The single AMC method utilized one static calibration position to estimate scapular kinematics for the entire cycle, while the dual and multiple AMC methods used two and four static calibration positions, respectively. Scapulothoracic angles estimated by the three AMC methods were compared with scapulothoracic angles determined by palpation. The multiple AMC method produced the smallest RMS errors and was not significantly different from palpation about any axis. We recommend the multiple AMC method as a practical and accurate way to estimate scapular kinematics during UE ergometry. PMID- 26976229 TI - Temporomandibular joint involvement as a positive clinical prognostic factor in necrotising external otitis. AB - OBJECTIVE: Necrotising otitis externa is associated with high morbidity and mortality rates. This study investigated whether temporomandibular joint involvement had any prognostic effect on the course of necrotising otitis externa in patients who had undergone hyperbaric oxygen therapy after failed medical and sometimes surgical therapy. METHODS: A retrospective case series was conducted of patients in whom antibiotic treatment and surgery had failed, who had been hospitalised for further treatment and hyperbaric oxygen therapy. RESULTS: Twenty three patients with necrotising otitis externa were identified. The temporomandibular joint was involved in four patients (17 per cent); these patients showed a constant gradual improvement in C-reactive protein and were eventually discharged free of disease, except one patient who was lost to follow up. Four patients (16 per cent) without temporomandibular joint involvement died within 90 days of discharge, while all patients with temporomandibular joint involvement were alive. Three patients (13 per cent) without temporomandibular joint involvement needed recurrent hospitalisation including further hyperbaric oxygen therapy; no patients with temporomandibular joint involvement required such treatment. CONCLUSION: Patients with temporomandibular joint involvement had lower rates of recurrent disease and no mortality. Therefore, we suggest considering temporomandibular joint involvement as a positive prognostic factor in necrotising otitis externa management. PMID- 26976230 TI - Developmental regulation of chicken surfactant protein A and its localization in lung. AB - Surfactant Protein A (SP-A) is a collagenous C-type lectin (collectin) that plays an important role in the early stage of the host immune response. In chicken, SP A (cSP-A) is expressed as a 26 kDa glycosylated protein in the lung. Using immunohistochemistry, cSP-A protein was detected mainly in the lung lining fluid covering the parabronchial epithelia. Specific cSP-A producing epithelial cells, resembling mammalian type II cells, were identified in the parabronchi. Gene expression of cSP-A markedly increased from embryonic day 14 onwards until the time of hatch, comparable to the SP-A homologue chicken lung lectin, while mannan binding lectin and collectins CL-L1 and CL-K1 only showed slightly changed expression during development. cSP-A protein could be detected as early as ED 18 in lung tissue using Western blotting, and expression increased steadily until day 28 post-hatch. Our observations are a first step towards understanding the role of this protein in vivo. PMID- 26976233 TI - Diminished Quality of Life and Increased Brain Functional Connectivity in Patients with Hypothyroidism After Total Thyroidectomy. AB - BACKGROUND: Acute hypothyroidism induced by thyroid hormone withdrawal (THW) in patients with thyroid cancer after total thyroidectomy can affect mood and quality of life (QoL). While loss or dysregulation of thyroid hormone (TH) has these well-known behavioral consequences, the effects of TH alterations on brain function are not well understood. Resting state functional connectivity (FC) measured by functional magnetic resonance imaging (fMRI) allows non-invasive evaluation of human brain function. This study therefore examined whether THW affects resting state FC and whether changes in FC correlate with the mood or QoL of the patients with THW status. METHODS: Twenty-one patients who had undergone total thyroidectomy for thyroid cancer were recruited. Resting state fMRI scanning of the brain, thyroid function tests, and administration of the 12-Item Short Form Health Survey (SF-12) and the Patient Health Questionnaire-9 (PHQ-9) were performed before and after two weeks of THW. Regional homogeneity (ReHo), one of the measures of resting state FC, was calculated, and each voxel was compared between before and after THW in 19 patients. The ReHo values were extracted from the regions of interest showing within-group differences in ReHo values after THW, and correlations of ReHo values with thyrotropin (TSH) levels, total score of the PHQ-9, and composite scores of the SF-12 were statistically evaluated. RESULTS: Higher ReHo was observed after THW in the brain cortical regions across primary motor and sensory, visual, and association cortices. Among the regions, the ReHo values in the bilateral pre- and postcentral gyri, bilateral middle occipito-temporal cortices, the left precuneus, and the left lingual gyrus showed positive correlations with serum TSH levels after THW. Higher ReHo values in the bilateral pre- and postcentral gyri, the left middle temporo-occipital cortices, and the left ligual gyrus correlated with the lower mental component summary score from the SF-12, while higher ReHo values in the bilateral pre- and postcentral gyri correlated with higher total scores in the PHQ-9. CONCLUSIONS: Local brain FC is increased in the acute hypothyroid state. Higher FC correlates with a poorer mental QoL and increased depression in the hypothyroid state. PMID- 26976235 TI - Tribute to Donald Metcalf. AB - A collection of tributes and remembrances from esteemed colleagues, mentees, and friends on the life and work of "the father of hematopoietic cytokines". PMID- 26976231 TI - Characterization and regulation of expression of an antifungal peptide from hemolymph of an insect, Manduca sexta. AB - Insects secrete antimicrobial peptides as part of the innate immune response. Most antimicrobial peptides from insects have antibacterial but not antifungal activity. We have characterized an antifungal peptide, diapausin-1 from hemolymph of a lepidopteran insect, Manduca sexta (tobacco hornworm). Diapausin-1 was isolated by size exclusion chromatography from hemolymph plasma of larvae that were previously injected with a yeast, Saccharomyces cerevisiae. Fractions containing activity against S. cerevisiae were analyzed by SDS-PAGE and MALDI-TOF MS/MS and found to contain a 45-residue peptide that was encoded by sequences identified in M. sexta transcriptome and genome databases. A cDNA for diapausin-1 was cloned from cDNA prepared from fat body RNA. Diapausin-1 is a member of the diapausin family of peptides, which includes members known to have antifungal activity. The M. sexta genome contains 14 genes with high similarity to diapausin 1, each with 6 conserved Cys residues. Diapausin-1 was produced as a recombinant protein in Escherichia coli. Purified recombinant diapausin-1 was active against S. cerevisiae, with IC50 of 12 MUM, but had no detectable activity against bacteria. Spores of some plant fungal pathogens treated with diapausin-1 had curled germination tubes or reduced and branched hyphal growth. Diapausin-1 mRNA level in fat body strongly increased after larvae were injected with yeast or with Micrococcus luteus. In addition, diapausin-1 mRNA levels increased in midgut and fat body at the wandering larval stage prior to pupation, suggesting developmental regulation of the gene. Our results indicate that synthesis of diapausin-1 is part of an antifungal innate immune response to infection in M. sexta. PMID- 26976236 TI - A Novel Method for Tracer Concentration Plutonium(V) Solution Preparation. AB - Preparation of relatively pure low concentration Pu(V) solutions for environmental studies is nontrivial due to the complex redox chemistry of Pu. Ozone gas generated by an inexpensive unit designed for household-use was used to oxidize a 2 * 10(-8) M Pu(IV) solution to predominantly Pu(VI) with some Pu(V) present. Over several days, the Pu(VI) in the solution reduced to Pu(V) without further reducing to Pu(IV). The reduction from Pu(VI) to Pu(V) could be accelerated by raising the pH of the solution, which led to an immediate conversion without substantial conversion to Pu(IV). The aqueous Pu was found to be stable as predominately Pu(V) for greater than one month from pH 3-7; however, at circumneutral pH, a sizable fraction of Pu was lost from solution by either precipitation or sorption to the vial walls. This method provides a fast means of preparing Pu(V) solutions for tracer concentration studies without numerous extraction or cleanup steps. PMID- 26976234 TI - Targeted disruption of sp7 and myostatin with CRISPR-Cas9 results in severe bone defects and more muscular cells in common carp. AB - The common carp (Cyprinus carpio) as one of the most important aquaculture fishes produces over 3 million metric tones annually, approximately 10% the annual production of the all farmed freshwater fish worldwide. However, the tetraploidy genome and long generation-time of the common carp have made its breeding and genetic studies extremely difficult. Here, TALEN and CRISPR-Cas9, two versatile genome-editing tools, are employed to target common carp bone-related genes sp7, runx2, bmp2a, spp1, opg, and muscle suppressor gene mstn. TALEN were shown to induce mutations in the target coding sites of sp7, runx2, spp1 and mstn. With CRISPR-Cas9, the two common carp sp7 genes, sp7a and sp7b, were mutated individually, all resulting in severe bone defects; while mstnba mutated fish have grown significantly more muscle cells. We also employed CRISPR-Cas9 to generate double mutant fish of sp7a;mstnba with high efficiencies in a single step. These results demonstrate that both TALEN and CRISPR-Cas9 are highly efficient tools for modifying the common carp genome, and open avenues for facilitating common carp genetic studies and breeding. PMID- 26976237 TI - Cardiac output determination using a widely available direct continuous oxygen consumption measuring device: a practical way to get back to the gold standard. AB - BACKGROUND: Accurate assessment of cardiac output (CO) is essential for the hemodynamic assessment of valvular heart disease. Estimation of oxygen consumption (VO2) and thermodilution (TD) are employed in many cardiac catheterization laboratories (CCL) given the historically cumbersome nature of direct continuous VO2 measurement, the "gold standard" for this technique. A portable facemask device simplifies the direct continuous measurement of VO2, allowing for relatively rapid and continuous assessment of CO. METHODS AND MATERIALS: Thirty consecutive patients undergoing right heart catheterization had simultaneous determination of CO by both direct continuous and assumed VO2 and TD. Assessments were only made when a plateau of VO2 had occurred. All measurements of direct continuous and assumed VO2, as well as, TD CO were obtained in triplicate. RESULTS: Direct continuous VO2 CO and assumed VO2 CO correlated poorly (R=0.57; ICC=0.59). Direct continuous VO2 CO and TD CO also correlated poorly (R=0.51; ICC=0.60). Repeated direct continuous VO2 CO measurements were extremely correlated and reproducible [(R=0.93; ICC=0.96) suggesting that this was the most reliable measurement of CO. CONCLUSIONS: CO calculated from direct continuous VO2 measurement varies substantially from both assumed VO2 and TD based CO, which are widely used in most CCL. These differences may significantly impact the CO measurements. Furthermore, continuous, rather than average, measurement of VO2 appears to give highly reproducible results. PMID- 26976239 TI - Hydatid cyst of the liver. PMID- 26976238 TI - The Mexican consensus on irritable bowel syndrome. AB - BACKGROUND: Since the publication in 2009 of the Guidelines on the Diagnosis and Treatment of Irritable Bowel Syndrome of the Asociacion Mexicana de Gastroenterologia (2009 Guidelines), there have been significant advances in our knowledge of the epidemiology, pathophysiology, diagnosis, and treatment of this disease. AIMS: To present a consensus review of the most current knowledge of IBS, updating the 2009 Guidelines by incorporating new internationally published scientific evidence, with a special interest in Mexican studies. METHODS: The PubMed literature from January 2009 to March 2015 was reviewed and complemented through a manual search. Articles in English and Spanish were included and preference was given to consensuses, guidelines, systematic reviews, and meta analyses. Statements referring to the different aspects of the disease were formulated and voted upon by 24 gastroenterologists employing the Delphi method. Once a consensus on each statement was reached, the quality of evidence and strength of recommendation were determined through the GRADE system. RESULTS: Forty-eight statements were formulated, updating the information on IBS and adding the complementary data that did not appear in the 2009 Guidelines regarding the importance of exercise and diet, diagnostic strategies, and current therapy alternatives that were analyzed with more stringent scientific vigor or that emerged within the last 5 years. CONCLUSIONS: We present herein a consensus review of the most relevant advances in the study of IBS, updating and complementing the 2009 Guidelines. Several studies conducted in Mexico were included. PMID- 26976240 TI - The isotype ZnO/SiC heterojunction prepared by molecular beam epitaxy--A chemical inert interface with significant band discontinuities. AB - ZnO/SiC heterojunctions show great potential for various optoelectronic applications (e.g., ultraviolet light emitting diodes, photodetectors, and solar cells). However, the lack of a detailed understanding of the ZnO/SiC interface prevents an efficient and rapid optimization of these devices. Here, intrinsic (but inherently n-type) ZnO were deposited via molecular beam epitaxy on n-type 6H-SiC single crystalline substrates. The chemical and electronic structure of the ZnO/SiC interfaces were characterized by ultraviolet/x-ray photoelectron spectroscopy and x-ray excited Auger electron spectroscopy. In contrast to the ZnO/SiC interface prepared by radio frequency magnetron sputtering, no willemite like zinc silicate interface species is present at the MBE-ZnO/SiC interface. Furthermore, the valence band offset at the abrupt ZnO/SiC interface is experimentally determined to be (1.2 +/- 0.3) eV, suggesting a conduction band offset of approximately 0.8 eV, thus explaining the reported excellent rectifying characteristics of isotype ZnO/SiC heterojunctions. These insights lead to a better comprehension of the ZnO/SiC interface and show that the choice of deposition route might offer a powerful means to tailor the chemical and electronic structures of the ZnO/SiC interface, which can eventually be utilized to optimize related devices. PMID- 26976241 TI - Long-term Survival, Organ Function, and Malignancy after Hematopoietic Stem Cell Transplantation for Fanconi Anemia. AB - We report on long-term survival in 157 patients with Fanconi anemia (FA) who survived 2 years or longer after their first transplantation with a median follow up of 9 years. Marrow failure (80%) was the most common indication for transplantation. There were 20 deaths beyond 2 years after transplantation, with 12 of the deaths occurring beyond 5 years after transplantation. Donor chimerism was available for 149 patients: 112 (76%) reported > 95% chimerism, 27 (18%) reported 90% to 95% chimerism, and 8 (5%) reported 20% to 89% donor chimerism. Two patients have < 20% donor chimerism. The 10- and 15-year probabilities of survival were 90% and 79%, respectively. Results of multivariate analysis showed higher mortality risks for transplantations before 2003 (hazard ratio [HR], 7.87; P = .001), chronic graft-versus-host disease (GVHD) (HR, 3.80; P = .004) and squamous cell carcinoma after transplantation (HR, 38.17; P < .0001). The predominant cause of late mortality was squamous cell carcinoma, with an incidence of 8% and 14% at 10 and 15 years after transplantation, respectively, and was more likely to occur in those with chronic GVHD. Other causes of late mortality included chronic GVHD, infection, graft failure, other cancers, and hemorrhage. Although most patients are disease free and functional long term, our data support aggressive surveillance for long periods to identify those at risk for late mortality. PMID- 26976242 TI - Pretransplantation Supportive and Palliative Care Consultation for High-Risk Hematopoietic Cell Transplantation Patients. AB - Early palliative care (EPC) for patients with metastatic solid tumors is now standard of care, but the effect of EPC in hematopoietic cell transplantation (HCT) is less well understood. We studied the acceptability of pre-HCT EPC as measured by trial participation, changes in patient-reported outcomes, and follow up with palliative care providers. English-speaking adults (age >17 years) with an HCT comorbidity index of >= 3, relapse risk > 25%, or planned HLA-mismatched allogeneic or myeloablative HCT received EPC before HCT admission with monthly or more frequent visits. Twenty-two (69%) of 32 subjects provided consent; 2 were later excluded (HCT cancelled, consent retracted) for a 63% participation rate. Comfort with EPC was high (82% very comfortable). Subjects reported stable or improved mood and sense of hope, without apparent negative effects with a median of 3 visits. Follow-up surveys were returned by 75% of participants at 60 days and by 65% at 90 days. Four (20%) were admitted to the intensive care unit before day 100 and 3 (15%) received life-support measures. Five (25%) died with median follow-up of 14 months. EPC is feasible, acceptable, and has the potential to improve the HCT experience, whether or not the patient survives. EPC for HCT patients should be tested in a randomized trial. PMID- 26976243 TI - Hepatic Oncostatin M Receptor beta Regulates Obesity-Induced Steatosis and Insulin Resistance. AB - The liver is an essential insulin-responsive organ that is critical for maintaining glucose homeostasis and lipid metabolism. Oncostatin M receptor beta chain (OSMRbeta) is implicated in adipose tissue- and immune cell-mediated metabolic regulation. However, the role of hepatocyte-derived OSMRbeta in metabolic disorders remains unclear. Here, we report on the central role of OSMRbeta in the protection against obesity and deregulation of glucose and lipids. We observed significantly varied expression levels of OSMRbeta in hepatic tissues in both human samples and mouse models of nonalcoholic fatty liver disease. Mice lacking either whole-body or hepatic OSMRbeta displayed exacerbated diet-induced insulin resistance, hepatic steatosis, and inflammation, both in diet-induced and genetically (ob/ob) obese mice. These adverse effects were markedly attenuated by hepatocyte-specific overexpression of OSMRbeta. Mechanistically, we showed that OSMRbeta phosphorylates and activates the Janus kinase 2 (JAK2)/STAT3 signaling pathway in the liver. More importantly, the liver restricted overexpression of STAT3 rescued glucose tolerance and ameliorated hepatic steatosis and inflammation in OSMRbeta knockout mice, whereas OSMRbeta overexpression failed to protect against hepatic steatosis, insulin resistance, and hepatic inflammation in STAT3-deficient mice. Thus, activation of STAT3 is both sufficient and required to produce OSMRbeta-mediated beneficial effects. In conclusion, hepatic OSMRbeta expression alleviates obesity-induced hepatic insulin resistance and steatosis through the activation of JAK2/STAT3 signaling cascades. PMID- 26976245 TI - Prostate cancer: 'Stem-like' prostate basal cells. PMID- 26976244 TI - Erection rehabilitation following prostatectomy--current strategies and future directions. AB - Despite continued advances in urological surgery, erectile dysfunction (ED) remains a serious adverse effect of radical prostatectomy. In this setting, ED is predominantly caused by injury to the neurovascular bundles, which lie alongside the prostate and are responsible for initiating and maintaining the erectile response. Most men will experience some degree of ED after radical prostatectomy, although erectile function outcomes have already remarkably improved since the development of nerve-sparing surgical techniques. To further improve outcomes, erection rehabilitation strategies are being investigated, which emphasize early treatment regimens with the aim of preventing adverse remodelling after surgery and preserving erectile function. Strategies include pharmacological therapy, mechanical therapy and psychosocial support. In addition, novel therapeutic approaches involving new targets for small-molecule treatments and regenerative medicine therapies are being developed to aid in restoring erectile function. Although ED treatments can be effective following radical prostatectomy, no specific erection rehabilitation regimen has currently been shown to be superior to other investigated rehabilitation regimens. Nevertheless, the different strategies rightfully remain an area of intensive research, as preservation of erectile function is a critical part of providing comprehensive care for men with prostate cancer to ensure their overall well-being, in contrast to just treating a patient's tumour. PMID- 26976246 TI - Development: Adult Leydig cell maintenance. PMID- 26976248 TI - Strategies for identification of disease genes. AB - Many genetic disorders are caused by mutations in single genes (monogenic diseases), and the inheritance pattern of these diseases follows simple rules. If a mutation in both copies of the gene on both chromosome homologues is necessary to cause the disease, the inheritance pattern is recessive, and a patient is the offspring of two clinically unaffected carriers. However, if a mutation in a single homologue is sufficient, the inheritance pattern is dominant and the disease is transmitted from generation to generation. Monogenic diseases are responsible for only a small fraction of all patients with genetic diseases. Many common diseases, including cancer, heart disease, diabetes and several psychiatric diseases, are the results of a complex interaction between genetic and environmental factors. However, these diseases can have important genetic components and can therefore still be considered genetic diseases. The identification of genes involved in complex genetic diseases can be very important for the understanding and treatment of these diseases. Over the last 15 years, much progress has been made in the identification of genes responsible for monogenic diseases, but the identification of genes involved in complex diseases has been more difficult, and at this moment little is known about the genes involved in most common diseases. PMID- 26976247 TI - Spectral entropy monitoring for adults and children undergoing general anaesthesia. AB - BACKGROUND: Anaesthetic drugs during general anaesthesia are titrated according to sympathetic or somatic responses to surgical stimuli. It is now possible to measure depth of anaesthesia using electroencephalography (EEG). Entropy, an EEG based monitor can be used to assess the depth of anaesthesia using a strip of electrodes applied to the forehead, and this can guide intraoperative anaesthetic drug administration. OBJECTIVES: The primary objective of this review was to assess the effectiveness of entropy monitoring in facilitating faster recovery from general anaesthesia. We also wanted to assess mortality at 24 hours, 30 days, and one year following general anaesthesia with entropy monitoring.The secondary objectives were to assess the effectiveness of the entropy monitor in: preventing postoperative recall of intraoperative events (awareness) following general anaesthesia; reducing the amount of anaesthetic drugs used; reducing cost of the anaesthetic as well as in reducing time to readiness to leave the postanaesthesia care unit (PACU). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE via Ovid SP (1990 to September 2014) and EMBASE via Ovid SP (1990 to September 2014). We reran the search in CENTRAL, MEDLINE via Ovid SP and EMBASE via Ovid SP in January 2016. We added one potential new study of interest to the list of 'Studies awaiting Classification' and we will incorporate this study into the formal review findings during the review update. SELECTION CRITERIA: We included randomized controlled trials (RCTs) conducted in adults and children (aged greater than two years of age), where in one arm entropy monitoring was used for titrating anaesthesia, and in the other standard practice (increase in heart rate, mean arterial pressure, lacrimation, movement in response to noxious surgical stimuli) was used for titrating anaesthetic drug administration. We also included trials with an additional third arm, wherein another EEG monitor, the Bispectral index (BIS) monitor was used to assess anaesthetic depth. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently extracted details of trial methodology and outcome data from trials considered eligible for inclusion. All analyses were made on an intention-to-treat basis. We used a random-effect model where there was heterogeneity. For assessments of the overall quality of evidence for each outcome that included pooled data from RCTs, we downgraded evidence from 'high quality' by one level for serious (or by two for very serious) study limitations (risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect or potential publication bias). MAIN RESULTS: We included 11 RCTs (962 participants). Eight RCTs (762 participants) were carried out on adults (18 to 80 years of age), two (128 participants) involved children (two to 16 years) and one RCT (72 participants) included patients aged 60 to 75 years. Of the 11 included studies, we judged three to be at low risk of bias, and the remaining eight RCTs at unclear or high risk of bias.Six RCTs (383 participants) estimated the primary outcome, time to awakening after stopping general anaesthesia, which was reduced in the entropy as compared to the standard practice group (mean difference (MD) 5.42 minutes, 95% confidence interval (CI) -8.77 to -2.08; moderate quality of evidence). We noted heterogeneity for this outcome; on performing subgroup analysis this was found to be due to studies that included participants undergoing major, long duration surgeries (off-pump coronary artery bypass grafting, major urological surgery). The MD for time to awakening with four studies on ambulatory procedures was -3.20 minutes (95% CI -3.94 to -2.45). No trial reported the second primary outcome, mortality at 24 hours, 30 days, and one year with the use of entropy monitoring.Eight trials (797 participants) compared the secondary outcome, postoperative recall of intraoperative events (awareness) in the entropy and standard practice groups. Awareness was reported by only one patient in the standard practice group, making meaningful estimation of benefit of entropy monitoring difficult; moderate quality of evidence.All 11 RCTs compared the amount of anaesthetic agent used between the entropy and standard practice groups. Six RCTs compared the amount of propofol, four compared the amount of sevoflurane and one the amount of isoflurane used between the groups. Analysis of three studies (166 participants) revealed that the MD of propofol consumption between the entropy group and control group was -11.56 mcg/kg/min (95% CI -24.05 to 0.92); low quality of evidence. Analysis of another two studies (156 participants) showed that the MD in sevoflurane consumption in the entropy group compared to the control group was -3.42 mL (95% CI -6.49 to 0.35); moderate quality of evidence.No trial reported on the secondary outcome of the cost of general anaesthesia.Three trials (170 participants) estimated MD in time to readiness to leave the PACU of the entropy group as compared to the control group (MD -5.94 minutes, 95% CI -16.08 to 4.20; low quality of evidence). Heterogeneity was noted, which was due to the difference in anaesthetic technique (propofol-based general anaesthesia) in one study. The remaining two studies had used volatile-based general anaesthesia. The MD in time to readiness to leave the PACU was -4.17 minutes (95% CI -6.84 to -1.51) with these two studies. AUTHORS' CONCLUSIONS: The evidence as regards time to awakening, recall of intraoperative awareness and reduction in inhalational anaesthetic agent use was of moderate quality. The quality of evidence of as regards reduction in intravenous anaesthetic agent (propofol) use, as well as time to readiness to leave the PACU was found to be of low quality. As the data are limited, further studies consisting of more participants will be required for ascertaining benefits of entropy monitoring.Further studies are needed to assess the effect of entropy monitoring on focal issues such as short-term and long-term mortality, as well as cost of general anaesthesia. PMID- 26976249 TI - Behavioural genetics: An introduction. AB - Behavioural genetics is the study of the hereditary influence on behaviour, and can therefore be regarded as the intersection between behavioural sciences and genetics. As with most other fields of research it is difficult to exactly pinpoint when behavioural genetics started. In fact, one might say that the notion behavioural traits can be inherited may have appeared in human thought as early at 8000 BC, when the domestication of the dog began. The scientific era of behavioural genetics is generally considered to start with Charles Darwin. In his famous book On the Origin of Species by Means of natural Selection, or the Preservation of favoured Races in the Struggle for Life, published in 1859 (and sold out the first day), he devoted an entire chapter on instinctive behavioural patterns. Some years later, in his book The Descent of Man and Selection in Relation to Sex, he clearly stated that the difference between the mind of a human being and the mind of an animal 'is certainly one of degree and not of kind'. Moreover he gave considerable thought that mental powers (and insanity) are heritable aspects. PMID- 26976250 TI - Methodology of genetic research in psychiatry. AB - Most forms of behaviour whether normal or abnormal, show a tendency to run in families. However, these can range from symptoms of dementia and movement disorder caused by the comparatively rare autosomal dominant Huntington's disease to common everyday aspects of behaviour such as religious persuasion or career choice. Normal behaviours and most common disorders do not show simple mendelian inheritance but instead have more complex patterns of transmission involving either major genes with incomplete penetrance, multiple genes of small effect, or a combination of the two. In addition, common complex phenotypes usually involve the combination of genetic and environmental factors. Therefore once family studies have shown that a disorder or trait is familial the next stage is to perform twin studies and, if possible adoption studies to investigate whether this results from shared genes, shared environment or a combination of the two. PMID- 26976251 TI - Genotype-environment interactions and schizophrenia. AB - Nature and nurture are not separate. Instead it is important to investigate the interplay between genes and environment and how they influence on another. To an important degree, genetic effects on behavior come about because they either influence the extent to which the individual is likely to be exposed to individual differences in environmental risk or they affect how susceptible the individual is to environmental adversities. The current inability to explain or predict which genetically predisposed individuals will finally become schizophrenic has forced us to confront our ignorance of the precise mechanism and mode of the transmission of this disorder. Zubin's proposal to view the schizophrenic as a vulnerable individual who develops a temporary episode only under certain provocations can help place the controversy in proper perspective. Vulnerability (predisposition, diathesis) to schizophrenia can be defined as the individual's characteristic treshold beyond which stressful events produce decompensation manifest in the clinically diagnosable symptom picture. PMID- 26976252 TI - Searching for genes in Schizophrenia. AB - Decades of research into the etiology of schizophrenia on a phenotypic level, i.e. studies of neuroanatomy, neuropathology, neurophysiology and other areas such as immunology have yielded only fragmentary results. A contribution of genetic factors, has been consistently shown, however, beginning with E. Kraepelin's pioneering studies at the turn of the century. Evidence has accumulated from family-, twin-, and adoption studies. Identical twins have a 48% risk of developing schizophrenia if one of them is affected. In contrast, a 17 % risk is reported for nonidentical twins. These rates are similar to other complex genetic disorders such as diabetes, hypertension and asthma. Advances in the genetic analysis of complex traits as well as progress in the Human Genome Project should provide a basis for uncovering the molecular causes of schizophrenic disorders and for investigating the neuropathology of this individually and socially devastating neuropsychiatrie disorder. There is no doubt, that discovery of the genetic variation associated with the illness would help in identifying specific targets for development of more effective, targeted treatments. PMID- 26976253 TI - The case for an Xq21.3/Yp homologous locus in the evolution of language and the origins of psychosis. AB - The distribution of schizophrenia within populations bears upon the genetic nature of the disorder. From the World Health Organization Ten-Country Study of incidence Jablensky et al concluded that: Schizophrenic illnesses are ubiquitous, appear with similar incidence in different cultures and have clinical features that are more remarkable by their similarity across cultures than by their difference. The WHO study included populations in Japan, India and Europe that have been separated for tens of thousands of years. Moreover illnesses with essentially the same characteristics are commonplace in the Australian aboriginal population that separated from other human populations 50,000 years ago. PMID- 26976254 TI - Serotonergic gene variation: implications for personality traits and psychopathology. AB - Serotonin 5-hydroxytryptamine (5-HT) is an important regulator of morphogenetic activities during early central nervous system development, including cell proliferation, migration, and differentiation as well as synapto-genesis. Serotonergic raphe neurons diffusely project to a variety of brain regions (e.g. cortex, amygdala, hippocampus) and play known roles in integrating emotion, cognition, motor function as well as in food intake, sleep, pain, and sexual activity. The diversity of physiologic functions is due to the fact that 5-HT acts as a master control neurotransmitter within a highly complex system of neural communication mediated by multiple pre- and postsynaptic 5-HT receptors, thus orchestrating the activity and interaction of several other neurotransmitter systems. Since proteins involved in the regulation of central serotonergic activity (e.g. enzymes, receptors, transporter) play pivotal role in brain 5-HT homeostasis, polymorphisms in the regulatory regions of their genes resulting in variation of expression and function are likely to influence complex traits, such as temperament/personality and psychopathology. PMID- 26976255 TI - Genes for Alzheimer Dementia. AB - Alzheimer disease (AD), the most common form of dementia in the elderly, is rapidly becoming a major health problem in developed countries where the number of elderly people continuously grows due to improved medical care. Consequently, the number of AD patients is increasing and thus far no effective therapies are available. Clinically the disease can be diagnosed with 90% reliability on the basis of neurological examination, neuropsychological testing and brain imaging techniques. A definite diagnosis, however, requires the post-mortem detection of senile plaques (SPs) and neurofibrillary tangles (NFTs) in the brain. The SPs are extracellular deposits mainly composed of amyloid P (Ap) surrounded by dystrophic neurites. NFT are intraneural inclusions of paired helical filaments composed of hyperphosphorylated tau. Although age is the major risk factor for AD, population survey and family studies have provided substantial evidence that genetic factors are major contributors to the expression of AD. PMID- 26976256 TI - The genetics of anxiety disorders. AB - The common denominator of anxiety disorders is that they share inappropriate levels of emotions and cognitions that affect rather than enable adaptive behaviours. The variety of symptoms include 'spontaneous' panic attacks with mental and physical symptoms, stimulus bound anxiety associated with avoidance behaviour, and almost constant 'generalized' anxious feelings. According to the DSM-IV criteria the anxiety disorders are classified as shown in Table I. PMID- 26976257 TI - Molecular genetic findings in mood disorders. AB - Traditional methods used to asses genetic effects, such as twins, adoption and family studies, have demonstrated the role genetic vulnerability factors in the etiology of major psychiatric diseases such as affective disorders and schizophrenia. It remains however impossible, using these methods, to specify the genetic variables involved and the exact mode of transmission of these diseases. New genetic approaches in psychiatry include the use of DNA markers in sophisticated strategies to examine families and populations. Genetic linkage (in families) and allelic association (in unrelated subjects) are the most frequent techniques applied searching for genes in psychiatric diseases. Advances in these methods have permitted their application to complex diseases in which the mode of genetic transmission is unknown. Affective disorders and, in particular, bipolar affective disorder (BPAD) have been examined in many molecular genetic studies which have covered a large part of the genome, specific hypotheses such as mutations have also, been studied. Most recent studies indicate that several chromosomal regions may be involved in the aetiology of affective disorders. Large multi-centre and multi-disciplinary projects are currently underway in Europe and in the US and hopefully will improve our understanding of the genetic factors involved in affective disorders. In parallel to these new developments in molecular genetics, the classical genetic epidemiology, represented by twin, adoption and family studies, have been improved, providing validated models to test the gene-environment interactions. PMID- 26976258 TI - Molecular players in the development and maintenance of mesencephalic dopamine systems. AB - Several psychiatric diseases are considered to be neuro-developmental disorders. Amongst these are schizophrenia and autism, in which genetic and environmental components have been indicated. In these disorders intrinsic molecular mechanisms of brain development may be deranged due to genetic predispositions, or modified by external influences. Brain development is a delicate process of well-tuned cellular proliferation and differentiation of multipotent neural progenitor cells driven by spatiotemporal cues. One of the fundamental mechanisms is the interaction between external signals, e.g. growth factors, and internal regulators, e.g. transcription factors. An important transmitter system involved in behavioural and affective functions relevant for psychiatric disorders is the mesencephalic dopamine (DA) system. The mesencephalic DA system is organized in two anatomically and functionally different systems. DA neurons in the ventral tegmental area project to the mesolimbic system and are mostly related to control of behaviour. It has been implicated in drug addiction and affective disorders like dipolar disorder and schizophrenia. The dopamine system of the substantia nigra (nigro-striatal pathway) is implicated in movement control. Degeneration of this system, as in Parkinson's disease, or altered function in tardive dyskinesia have highlighted its importance in human disease. Recent findings in molecular neurobiology have provided the first clues to molecular mechanisms involved in developing and mature DA neurons. These may have clinical implications in novel therapeutic strategies. PMID- 26976259 TI - Coping with genetic burden. AB - An increasing number of neurodegenerative diseases have been defined at the molecular level in recent years, making it possible to determine precisely the genotype before the onset of symptoms. Pre-symptomatic testing programs are available for Huntington disease (HD), hereditary cerebral haemorrhage with amyloid-Dutch type, inherited cerebral ataxia, myotonic dystrophy, and Alzheimer disease. Although treatment options such as gene therapy have no widespread application until now, and much has to be developed, the use of predictive DNA diagnostics has become a clinical application for a number of hereditary diseases. For psychiatric disorders such as schizophrenia or bipolar disorders, there are indications for localisation of the genetic factors, but clinical use of genetics is still far from reality. Yet, the increasing knowledge about genetics will have far-reaching influence in most fields of modern medicine and in health care provisions. PMID- 26976260 TI - The developing role of pharmacogenetics in psychiatry. AB - A great interindividual variability exists in biological response to drugs. This variability is partly attributable to pharmacodynamic factors (drug - receptor interactions) and partly to pharmacokinetic factors. Drugs can be eliminated from the body by renal clearance, metabolism or both. Although every tissue has some ability to metabolise xenobiotics like drugs, the liver is the principal organ of biotransformation. Major metabolising enzymes are the cytochrome-P450 mono oxygenases, epoxide hydrolase, glucuronosyl-transferase, acetyl-transferase, sulfo-transferase and xanthine oxidase. Some of these enzymes display in a subset of subjects a 'normal' activity and in another subset of subjects a reduced or a greatly increased activity. This altered activity may be genetically determined and is then called genetic polymorphism. Clinically relevant metabolic differences traditionally have been defined by their genotypie expression such as 'poor' and 'extensive' metaboliser. The recent developments of powerful methods for DNA (or genomic) analysis portends a revolutionary expansion of our understanding of physiology as well as pathology. Pharmacogenetics is the study of genetic variation underlying differential response to drugs. Genotyping may become a useful tool in optimising drug treatment. Another part of the genetic research is directed towards the discovery of genetic alterations leading to diseases. Once identified, these genetic alterations can become targets for drug treatment (e.g. gene therapy). Pharmaco-genomics applies the large-scale systematic approaches of genomics to speed the discovery of drug response markers, whether they act at the level of the drug target, drug metabolism or disease pathway. Table I gives some examples of genetic alterations that are identified together with their effects. Some of these examples will be briefly discussed here. PMID- 26976261 TI - Neuropsychiatrie of biologische psychiatrie; een toekomstvisie in historisch perspectief. AB - Neuropsychiatry or Biological Psychiatry There is an urgent need to reconsider the position of psychiatry within the neurosciences because of the exploding knowledge about the relationship between brain and behaviour and the delay in implementation of new findings due to the separation of neurology and psychiatry. Biological psychiatry and psychopharmacology originate from the discovery by chance of psycho-active compounds in the early fifties and have contributed to the scientification of psychiatry. The impact of biological psychiatry for the pathophysiology of psychiatric disorders, however, is limited as a result of its biased orientation on neurotransmitters and receptors. The neuropsychiatric paradigm integrates knowledge from several domains, such as functional neuroanatomy, genetics and endocrinology and opens new vistas for the involvement of neuronal circuits in the initiation and maintenance of behavioural disturbances. In addition, novel and more specific treatment modalities may emerge. PMID- 26976263 TI - Erythema Multiforme in Children and Mycoplasma pneumoniae Aetiology. AB - Erythema multiforme (EM) in children is understudied and confused with Stevens Johnson syndrome (SJS) despite their being separate diseases with unique aetiologies and clinical presentations. The goal of this study was to determine the prevalence of Mycoplasma pneumoniae in paediatric patients with EM minor, EM major (EMM), and SJS. This retrospective cohort at The Hospital for Sick Children accrued all cases of EM minor, EMM, and SJS from 1999 to 2013. Sixty-five cases were identified: 20 of EM minor, 23 of EMM, and 22 of SJS. Aetiologies were attributed in 58% of cases: 79% infection and 21% drug aetiology. Sixty-one percent of patients with EMM were M pneumoniae positive, compared with 14% of those with SJS and 22% of those with EM minor (P < .01). M pneumoniae patients were older at presentation (P = .03) and more frequently had sore throat (P < .01) and atypical targets with central blistering (P < .01). These findings suggest that M pneumoniae should be suspected and treated until laboratory confirmation becomes available in patients presenting with atypical target lesions with central blistering. PMID- 26976264 TI - A photopolymerized composite hydrogel and surgical implanting tool for a nucleus pulposus replacement. AB - Nucleus pulposus replacements have been subjected to highly controversial discussions over the last 40 years. Their use has not yet resulted in a positive outcome to treat herniated disc or degenerated disc disease. The main reason is that not a single implant or tissue replacement was able to withstand the loads within an intervertebral disc. Here, we report on the development of a photo polymerizable poly(ethylene glycol)dimethacrylate nano-fibrillated cellulose composite hydrogel which was tuned according to native tissue properties. Using a customized minimally-invasive medical device to inject and photopolymerize the hydrogel insitu, samples were implanted through an incision of 1 mm into an intervertebral disc of a bovine organ model to evaluate their long-term performance. When implanted into the bovine disc model, the composite hydrogel implant was able to significantly re-establish disc height after surgery (p < 0.0025). The height was maintained after 0.5 million loading cycles (p < 0.025). The mechanical resistance of the novel composite hydrogel material combined with the minimally invasive implantation procedure into a bovine disc resulted in a promising functional orthopedic implant for the replacement of the nucleus pulposus. PMID- 26976265 TI - Knowledge and experiences of Chagas disease in Bolivian women living in Spain: a qualitative study. AB - BACKGROUND: In Europe, Spain has the highest number of people with Chagas disease (CD). Bolivian migrants account for 81% of the reported cases. One of the priorities in controlling the disease is prevention of mother-to-child transmission. Despite under-diagnosis in Spain being estimated at 90%, there are currently few studies that explore the social and cultural dimensions of this disease. OBJECTIVE: The aim of this study was to explore the knowledge and experiences of Bolivian women with CD, in order to generate a useful understanding for the design and implementation of public health initiatives. DESIGN: Qualitative study based on semi-structured interviews, triangular groups, and field notes. PARTICIPANTS: Fourteen Bolivian women with CD living in Madrid. RESULTS: The participants were aware that the disease was transmitted through the vector, that it could be asymptomatic, and that it could also be associated with sudden death by heart failure. They opined that the treatment as such could not cure the disease but only slow it down. There was a sense of indifference along with a lack of understanding of the risk of contracting the disease. Participants who presented with symptoms, or those with relatives suffering from the disease, were concerned about fatalities, cardiac problems, and possible vertical transmission. There was also a fear of being rejected by others. The disease was described as something that affected a large number of people but only showed up in a few cases and that too after many years. There was a widespread assumption that it was better not to know because doing so, allows the disease to take hold. CONCLUSIONS: Disease risk perception was very low in Bolivian women living in Madrid. This factor, together with the fear of being screened, may be contributing to the current rate of under-diagnosis. PMID- 26976266 TI - Dimensionality effects on the luminescence properties of hBN. AB - Cathodoluminescence (CL) experiments at low temperature have been undertaken on various bulk and exfoliated hexagonal boron nitride (hBN) samples. Different bulk crystals grown from different synthesis methods have been studied. All of them present the same so-called S series in the 5.6-6 eV range, proving its intrinsic character. Luminescence spectra of flakes containing 100 down to 6 layers have been recorded. Strong modifications in the same UV range are observed and discussed within the general framework of 2D exciton properties in lamellar crystals. PMID- 26976262 TI - A Stress-Activated Transposon in Arabidopsis Induces Transgenerational Abscisic Acid Insensitivity. AB - Transposable elements (TEs), or transposons, play an important role in adaptation. TE insertion can affect host gene function and provides a mechanism for rapid increases in genetic diversity, particularly because many TEs respond to environmental stress. In the current study, we show that the transposition of a heat-activated retrotransposon, ONSEN, generated a mutation in an abscisic acid (ABA) responsive gene, resulting in an ABA-insensitive phenotype in Arabidopsis, suggesting stress tolerance. Our results provide direct evidence that a transposon activated by environmental stress could alter the genome in a potentially positive manner. Furthermore, the ABA-insensitive phenotype was inherited when the transcription was disrupted by an ONSEN insertion, whereas ABA sensitivity was recovered when the effects of ONSEN were masked by IBM2. These results suggest that epigenetic mechanisms in host plants typically buffered the effect of a new insertion, but could selectively "turn on" TEs when stressed. PMID- 26976268 TI - Haemodialysis session: The perfect storm for vascular calcification. PMID- 26976269 TI - Autosomal recessive polycystic kidney disease diagnosed in a 39 year-old women with kidney failure and cramps. PMID- 26976271 TI - Cyclic peptides identified by phage display are competitive inhibitors of the tRNA-dependent amidotransferase of Helicobacter pylori. AB - In Helicobacter pylori, the heterotrimeric tRNA-dependent amidotransferase (GatCAB) is essential for protein biosynthesis because it catalyzes the conversion of misacylated Glu-tRNA(Gln) and Asp-tRNA(Asn) into Gln-tRNA(Gln) and Asn-tRNA(Asn), respectively. In this study, we used a phage library to identify peptide inhibitors of GatCAB. A library displaying loop-constrained heptapeptides was used to screen for phages binding to the purified GatCAB. To optimize the probability of obtaining competitive inhibitors of GatCAB with respect to its substrate Glu-tRNA(Gln), we used that purified substrate in the biopanning process of the phage-display technique to elute phages bound to GatCAB at the third round of the biopanning process. Among the eluted phages, we identified several that encode cyclic peptides rich in Trp and Pro that inhibit H. pylori GatCAB in vitro. Peptides P10 and P9 were shown to be competitive inhibitors of GatCAB with respect to its substrate Glu-tRNA(Gln), with Ki values of 126 and 392MUM, respectively. The docking models revealed that the Trp residues of these peptides form pi-pi stacking interactions with Tyr81 of the synthetase active site, as does the 3'-terminal A76 of tRNA, supporting their competitive behavior with respect to Glu-tRNA(Gln) in the transamidation reaction. These peptides can be used as scaffolds in the search for novel antibiotics against the pathogenic bacteria that require GatCAB for Gln-tRNA(Gln) and/or Asn-tRNA(Asn) formation. PMID- 26976270 TI - C-terminal amidation of PACAP-38 and PACAP-27 is dispensable for biological activity at the PAC1 receptor. AB - PACAP-27 and PACAP-38 are the exclusive physiological ligands for the mammalian PAC1 receptor. The role of C-terminal amidation of these ligands at that receptor was examined in neuroendocrine cells expressing the PAC1 receptor endogenously and in non-neuroendocrine cells in which the human and rat PAC1 receptors were expressed from stable single-copy genes driven by the CMV promoter, providing stoichiometrically appropriate levels of this Gs-coupled GPCR in order to examine the potency and intrinsic activity of PACAP ligands and their des-amidated congeners. We found that replacement of the C-terminal glycine residues of PACAP 27 and -38 with a free acid; or extension of either peptide with the two to three amino acids normally found at these positions in PACAP processing intermediates in vivo following endoproteolytic cleavage and after exoproteolytic trimming and glycine-directed amidated, were equivalent in potency to the fully processed peptides in a variety of cell-based assays. These included real-time monitoring of cyclic AMP generation in both NS-1 neuroendocrine cells and non-neuroendocrine HEK293 cells; PKA-dependent gene activation in HEK293 cells; and neuritogenesis and cell growth arrest in NS-1 cells. The specific implications for the role of amidation in arming of secretin-related neuropeptides for biological function, and the general implications for neuropeptide-based delivery in the context of gene therapy, are discussed. PMID- 26976272 TI - Cross-protective efficacy of Leishmania infantum LiHyD protein against tegumentary leishmaniasis caused by Leishmania major and Leishmania braziliensis species. AB - Vaccination can be considered the most cost-effective strategy to control neglected diseases, but nowadays there is not an effective vaccine available against leishmaniasis. In the present study, a vaccine based on the combination of the Leishmania-specific hypothetical protein (LiHyD) with saponin was tested in BALB/c mice against infection caused by Leishmania major and Leishmania braziliensis species. This antigen was firstly identified in Leishmania infantum and showed to be protective against infection of BALB/c mice using this parasite species. The immunogenicity of rLiHyD/saponin vaccine was evaluated, and the results showed that immunized mice produced high levels of IFN-gamma, IL-12 and GM-CSF after in vitro stimulation with rLiHyD, as well as by using L. major or L. braziliensis protein extracts. After challenge, vaccinated animals showed significant reductions in the infected footpad swellings, as well as in the parasite burden in the infection site, liver, spleen, and infected paws draining lymph nodes, when compared to those that were inoculated with the vaccine diluent (saline) or immunized with saponin. The immunization of rLiHyD without adjuvant was not protective against both challenges. The partial protection obtained by the rLiHyD/saponin vaccine was associated with a parasite-specific IL-12 dependent IFN-gamma secretion, which was produced mainly by CD4(+) T cells. In these animals, a decrease in the parasite-mediated IL-4 and IL-10 responses, associated with the presence of high levels of LiHyD- and parasite-specific IgG2a isotype antibodies, were also observed. The present study showed that a hypothetical protein that was firstly identified in L. infantum, when combined to a Th1 adjuvant, was able to confer a cross-protection against highly infective stationary-phase promastigotes of two Leishmania species causing tegumentary leishmaniasis. PMID- 26976273 TI - Trusting Social Media as a Source of Health Information: Online Surveys Comparing the United States, Korea, and Hong Kong. AB - BACKGROUND: The Internet has increasingly become a popular source of health information by connecting individuals with health content, experts, and support. More and more, individuals turn to social media and Internet sites to share health information and experiences. Although online health information seeking occurs worldwide, limited empirical studies exist examining cross-cultural differences in perceptions about user-generated, experience-based information compared to expertise-based information sources. OBJECTIVE: To investigate if cultural variations exist in patterns of online health information seeking, specifically in perceptions of online health information sources. It was hypothesized that Koreans and Hongkongers, compared to Americans, would be more likely to trust and use experience-based knowledge shared in social Internet sites, such as social media and online support groups. Conversely, Americans, compared to Koreans and Hongkongers, would value expertise-based knowledge prepared and approved by doctors or professional health providers more. METHODS: Survey questionnaires were developed in English first and then translated into Korean and Chinese. The back-translation method ensured the standardization of questions. Surveys were administered using a standardized recruitment strategy and data collection methods. RESULTS: A total of 826 participants living in metropolitan areas from the United States (n=301), Korea (n=179), and Hong Kong (n=337) participated in the study. We found significant cultural differences in information processing preferences for online health information. A planned contrast test revealed that Koreans and Hongkongers showed more trust in experience-based health information sources (blogs: t451.50=11.21, P<.001; online support group: t455.71=9.30, P<.001; social networking sites [SNS]: t466.75=11.36, P<.001) and also reported using blogs (t515.31=6.67, P<.001) and SNS (t529.22=4.51, P<.001) more frequently than Americans. Americans showed a stronger preference for using expertise-based information sources (eg, WebMD and CDC) compared to Koreans and Hongkongers (t360.02=3.01, P=.003). Trust in expertise-based information sources was universal, demonstrating no cultural differences (Brown-Forsythe F2,654=1.82, P=.16). Culture also contributed significantly to differences in searching information on behalf of family members (t480.38=5.99, P<.001) as well as to the goals of information searching. CONCLUSIONS: This research found significant cultural differences in information processing preferences for online health information. Further discussion is included regarding effective communication strategies in providing quality health information. PMID- 26976274 TI - What's in the tank? Nematodes and other major components of the meiofauna of bromeliad phytotelms in lowland Panama. AB - BACKGROUND: Nematodes are a very diverse and extremely abundant group of animals, but their occurrence in the tropics is surprisingly little understood. We investigated the meiofauna of epiphytic tank bromeliads in the lowlands of Panama with particular emphasis on nematodes. RESULTS: We encountered 89 morphospecies of nematodes in 54 bromeliad tanks, which were sampled in the wet and the dry season. Rotifers were by far the most abundant group in both the dry and the wet season (with up to 960 individual ml(-1)), followed by nematodes, annelids and harpacticoid copepods. Individual plants hosted up to 25 nematode species. These nematodes represented a diversity of feeding guilds, suction-feeders and deposit feeders being most abundant. The relative abundances of feeding-types of nematodes differed considerably in the wet and dry season. Both species richness and abundance were strongly correlated with the size of the phytotelms and the season, while species diversity assessed with the Shannon-index was affected by neither of the two. CONCLUSION: This is the first study with a particular focus on the diversity of nematodes in tank bromeliads. We document a meiofauna of considerable abundance and diversity, which suggests important functional roles in ecological processes such as decomposition, which in turn warrants further study. PMID- 26976276 TI - Erratum to: Stop spoon dosing: milliliter instructions reduce inclination to spoon dosing. PMID- 26976275 TI - Lumbar spine osteomyelitis and epidural abscess formation secondary to acupuncture. AB - A 39-year-old male with no previous medical history presented with abdominal and low back pain. Based on clinical and radiological findings he was diagnosed with L1/L2 osteomyelitis and epidural abscess. Further history taking revealed recent use of acupuncture for treatment of mechanical back pain. The patient was treated conservatively with an extended course of antibiotics, monitored with repeat MRI scans and had a full recovery with no neurological deficit. This is the first reported case of epidural abscess formation and osteomyelitis after acupuncture in the UK. As acupuncture becomes more commonly used in western countries, it is important to be aware of this rare but serious complication. PMID- 26976277 TI - Crystalloid fluid therapy. AB - This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901. PMID- 26976278 TI - Elevated serum alpha-fetoprotein in poorly differentiated adenocarcinoma with neuroendocrine differentiation of the ascending colon: a case report. AB - BACKGROUND: Colorectal cancer (CRC) is the most common form of cancer and the third leading cause of death in Taiwan. Serum alpha-fetoprotein (AFP) has been extensively used as a biomarker for hepatocellular carcinoma (HCC) and yolk sac tumors. CASE PRESENTATION: This case report presents a 90-year-old woman with right abdominal pain and poor appetite for 1 week. The computed tomography (CT) showed wall thickening in the proximal ascending colon with ruptured appendicitis. Preoperative serum AFP was high. There was no definite liver metastasis or other abnormal findings in the hepatobiliary systems. After initial empirical antibiotic treatment, we performed laparoscopic right hemicolectomy. The pathological assessment was poorly differentiated adenocarcinoma with neuroendocrine differentiation in the ascending colon. The tumor cells did not produce AFP. Amazingly, the follow-up serum AFP level 1 month after the surgery declined to normal range. The patient had an uneventful course after the surgery and was free of recurrence or metastasis within 5 months of follow-up. CONCLUSIONS: AFP may be a useful tumor marker in poorly differentiated colorectal cancer with neuroendocrine component patients and a prediction of early treatment response. PMID- 26976279 TI - Manipulating proteostasis to repair the F508del-CFTR defect in cystic fibrosis. AB - Cystic fibrosis (CF) is a lethal monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that entails the (diagnostic) increase in sweat electrolyte concentrations, progressive lung disease with chronic inflammation and recurrent bacterial infections, pancreatic insufficiency, and male infertility. Therapies aimed at restoring the CFTR defect have emerged. Thus, a small molecule which facilitates chloride channel opening, the potentiator Ivacaftor, has been approved for the treatment of CF patients bearing a particular class of rare CFTR mutations. However, small molecules that directly target the most common misfolded CFTR mutant, F508del, and improve its intracellular trafficking in vitro, have been less effective than expected when tested in CF patients, even in combination with Ivacaftor. Thus, new strategies are required to circumvent the F508del-CFTR defect. Airway and intestinal epithelial cells from CF patients bearing the F508del-CFTR mutation exhibit an impressive derangement of cellular proteostasis, with oxidative stress, overactivation of the tissue transglutaminase (TG2), and disabled autophagy. Proteostasis regulators such as cysteamine can rescue and stabilize a functional F508del-CFTR protein through suppressing TG2 activation and restoring autophagy in vivo in F508del-CFTR homozygous mice, in vitro in CF patient-derived cell lines, ex vivo in freshly collected primary patient's nasal cells, as well as in a pilot clinical trial involving homozygous F508del-CFTR patients. Here, we discuss how the therapeutic normalization of defective proteostasis can be harnessed for the treatment of CF patients with the F508del-CFTR mutation. PMID- 26976280 TI - The Impact of WIC on Birth Outcomes: New Evidence from South Carolina. AB - Objectives To investigate the impact of the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) on a variety of infant health outcomes using recent South Carolina Vital Statistics data (2004-2012). Methods To account for non-random WIC participation, the study relies on a maternal fixed effects estimation, due to the availability of unique maternally linked data. Results The results indicate that WIC participation is associated with an increase in birth weight and length of gestation, decrease in the probability of low birth weight, prematurity, and Neonatal Intensive Care Unit admission. Additionally, addressing gestational bias and accounting for the length of gestation, WIC participation is associated with a decrease in the probability of delivering a low weight infant and a small for gestational age infant among black mothers. Conclusions for Practice Accounting for non-random program participation, the study documents a large improvement in birth outcomes among infants of WIC participating mothers. Even in the context of somewhat restrictive gestation-adjusted specification, the positive impact of WIC remains within the subsample of black mothers. PMID- 26976281 TI - Contactable Non-responders Show Different Characteristics Compared to Lost to Follow-Up Participants: Insights from an Australian Longitudinal Birth Cohort Study. AB - Objective This research aims to identify predictors of attrition in a longitudinal birth cohort study in Australia and assess differences in baseline characteristics and responses in subsequent follow-up phases between contactable non-responders and uncontactable non-responders deemed "lost to follow-up (LTF)". Methods 3368 women recruited from three public hospitals in Southeast Queensland and Northern New South Wales during antenatal visits in 2006-2011 completed a baseline questionnaire to elicit information on multiple domains of exposures. A follow-up questionnaire was posted to each participant at 1 year after birth to obtain mother's and child's health and development information. Multivariate logistic regression was used to model the association between exposures and respondents' status at 1 year. The effect of an inverse-probability-weighting method to adjust for non-response was studied. Results Overall attrition at 1 year was 35.4 %; major types of attrition were "contactable non-response" (27.6 %) and "LTF" (6.7 %). These two attrition types showed different responses at the 3-year follow-up and involved different predictors. Besides shared predictors (first language not English, higher risk of psychological distress, had smoked during pregnancy, higher levels of family conflict), distinguishable predictors of contactable non-responders were younger age, having moved home in the past year and having children under 16 in the household. Attrition rates increased substantially from 20 % in 2006 to 54 % in 2011. Conclusions This observed trend of increased attrition rates raises concern about the use of traditional techniques, such as "paper-based" questionnaires, in longitudinal cohort studies. The supplementary use of electronic communications, such as online survey tools and smart-device applications, could provide a better alternative. PMID- 26976282 TI - Investigating Preterm Care at the Facility Level: Stakeholder Qualitative Study in Central and Southern Malawi. AB - Objectives Malawi is estimated to have one of the highest preterm birth rates in the world. However, care of preterm infants at facility level in Malawi has not been explored. We aimed to explore the views of health stakeholders about the care of preterm infants in health facilities and the existence of any policy protocol documents guiding the delivery of care to these infants. Methods We conducted 16 in-depth interviews with health stakeholders (11 service providers and 5 policy makers) using an interview guide and asked for any existing policy protocol documents guiding care for preterm infants in the health facilities in Malawi. The collected documents were reviewed and all the interviews were digitally recorded, transcribed and translated. All data were analysed using content analysis approach. Results We identified four policy protocol documents and out of these, one had detailed information explaining the care of preterm infants. Policy makers reported that policy protocol documents to guide care for preterm infants were available in the health facilities but majority (63.6 %) of the service providers lacked knowledge about the existence of these documents. Health stakeholders reported several challenges in caring for preterm infants including lack of trained staff in preterm infant care, antibiotics, space, supervision and poor referral system. Conclusions Our study highlights that improving health care service provider knowledge of preterm infant care is an integral part in preterm child birth. Our findings suggests that policy makers and health decision makers should retain those trained in preterm new born care in the health facility's preterm unit. PMID- 26976283 TI - Measuring Implicit Sexual Response Biases to Nude Male and Female Pictures in Androphilic and Gynephilic Men. AB - Snowden, Wichter, and Gray (2008) demonstrated that an Implicit Association Test and a Priming Task both predicted the sexual orientation of gynephilic and androphilic men in terms of their attraction biases towards pictures of nude males and females. For both measures, relative bias scores were obtained, with no information on the separate response biases to each target gender. The present study sought to extend this research by assessing both relative and individual implicit biases using the Implicit Relational Assessment Procedure (IRAP). An explicit measure screened for men with androphilic (n = 16) or gynephilic (n = 16) orientations on the dimensions of "sexual attraction," "sexual behavior," "sexual fantasies," "hetero/gay lifestyle," and "self identification." The IRAP involved responding "True" or "False" to pictures of nude males and females as either attractive or unattractive. Participants were required to respond in a manner consistent with their reported sexual orientation for half of the IRAP's test blocks and inconsistent for the other half. Response latencies were recorded and analyzed. The IRAP revealed a non-orthogonal pattern of biases across the two groups and had an excellent ability to predict sexual orientation with areas under the curves of 1.0 for the relative bias score and .94 and .95 for the bias scores for the male and female pictures, respectively. Correlations between the IRAP and explicit measures of sexual orientation were consistently high. The findings support the IRAP as a potentially valuable tool in the study of sexual preferences. PMID- 26976284 TI - Evaluation of secondary alveolar bone grafting outcomes performed after canine eruption in complete unilateral cleft lip and palate. AB - OBJECTIVES: Evaluate the results of secondary alveolar bone grafting (SABG) in patients with complete unilateral cleft lip and palate (UCLP), operated after permanent canine eruption (CE). MATERIALS AND METHODS: Seventy-four periapical radiographs from patients with complete UCLP (mean age 14 years) submitted to SABG were retrospectively analyzed for the amount of bone in the cleft site through the Bergland and Chelsea scales. RESULTS: Of the cases, 47.3 % was classified as Bergland type I and Chelsea type A, 35.2 % as type II/C, 6.7 % as type III/D, and 10.8 % as type IV/failure. When the canine was moved into the grafted area, the success rate (type I/A) was 56.8 %; for cases in which the space was maintained for an implant or prosthetic finishing, the index was 45.8 %; however, this difference was not statistically significant. CONCLUSION: Even in advanced ages, after permanent canine eruption, SABG can be considered a highly successful procedure. CLINICAL RELEVANCE: This research shows good results of secondary alveolar bone grafting performed in patients with unilateral complete cleft lip and palate, even when it was performed after eruption of the permanent canine in the cleft area. PMID- 26976285 TI - Comparative experimental investigation on the efficacy of mono- and multiprobiotic strains in non-alcoholic fatty liver disease prevention. AB - BACKGROUND: To investigate the efficacy of different probiotic strains, their combinations and forms (alive or lyophilized) in nonalcoholic fatty liver disease (NAFLD) prevention. METHODS: In this study, 70 rats have been used divided into 7 groups of 10 animals in each: I - intact rats, II-VII - rats with monosodium glutamate (MSG)-induced NAFLD. Rats with NAFLD were untreated (group II, MSG obesity group) and treated with probiotics (groups III-VII). In order to develop NAFLD, newborn rats of groups II-VII were injected with a solution of monosodium glutamate (MSG) (4 mg/g) subcutaneously (s.c.) at 2nd,4th, 6th, 8th,10th postnatal day. The groups III-V received lyophilized monoprobiotics B. animalis VKL, B. animalis VKB, L.casei IMVB-7280, respectively. The group VI received 2.5 ml/kg of an aqueous solution of a mixture of the three probiotic strains (2:1:1 Lactobacillus casei IMVB-7280, Bifidobacterium animalis VKL, Bifidobacterium animalis VKB) at a dose of 50 mg/kg (5 * 10(9) CFU/kg) (g) (intragastrically). The group VII was treated with multiprobiotic "Symbiter" containing biomass of 14 alive probiotic strains (Lactobacillus + Lactococcus (6 * 10(10) CFU/g), Bifidobacterium (1 * 10(10)/g), Propionibacterium (3 * 10(10)/g), Acetobacter (1 * 10(6)/g)) at a dose of 140 mg/kg (1.4 * 10(10) CFU/kg). The treatment with probiotics was started at the age of 1 month. There were 3 courses of treatment, each included 2-week administration and 2-week break. All parameters were measured in 4-month aged rats. RESULTS: Introduction of MSG during the neonatal period leads to the NAFLD development in the 4-months old rats. For steatosis degree there was no significant difference between MSG-obesity group and lyophilized monocomponent probiotics groups (III-V). The highest manifestation of steatosis was observed for B. animalis VKL group (2.0 +/- 0.25) as compared to B. animalis VKB (1.70 +/- 0.21) and L. casei IMVB-7280 (1.80 +/- 0.20). The steatosis score changes between all monoprobiotics groups (III-V) were insignificant. Administration from birth of both alive (VII) and lyophilized (VI) probiotic mixture lead to a significant decrease by 69.5 % (p < 0.001) and 43.5 % (p < 0.025) of steatosis score respectively as compared to the MSG-obesity group (2.3 +/- 0.21 %). For both alive and lyophilized probiotic mixtures, reduction of lobular inflammation was observed. These histological data were confirmed by the significant decrease of total lipids and triglycerides content in the liver approximately by 22-25 % in groups treated with probiotic mixtures (VI, VII) compared to the MSG-obesity group. CONCLUSION: We established failure of NAFLD prevention with lyophilized monoprobiotic strains and the efficacy of probiotic mixture with the preference of alive probiotic strains. PMID- 26976286 TI - CD36 regulates lipopolysaccharide-induced signaling pathways and mediates the internalization of Escherichia coli in cooperation with TLR4 in goat mammary gland epithelial cells. AB - The scavenger receptor CD36 is involved in pathogen recognition, phagocytosis, and pathogen-induced signaling. This study investigated the relationship between CD36 and TLR4 in modifying lipopolysaccharide (LPS)-induced signaling pathways and mediating Escherichia coli (E. coli) endocytosis in primary goat mammary epithelial cells (pGMECs). The manipulation of CD36 expression significantly influenced TLR4 and nuclear factor kappa B (NF-kappaB) mRNA expression in pGMECs stimulated with LPS for 12 h. NF-kappaB and activator protein-1 (AP-1) activity was regulated by the manipulation of CD36 expression in LPS-induced pGMECs. However, CD36-mediated AP-1 activation occurred primarily through c-Jun N terminal kinase (c-JNK). Adaptor proteins and proinflammatory cytokines were also involved in these signaling pathways and acted by regulating CD36 expression in LPS-stimulated cells. Moreover, CD36 cooperated with TLR4 in TLR4-mediated phagocytosis following E. coli simulation, but this complex was not induced by LPS treatment. Our study is the first to illuminate CD36 as a scavenger receptor in ruminants. Additionally, this study indicates that CD36 plays a vital role in the LPS-induced activation of downstream signaling cascades and mediates E. coli phagocytosis via TLR4 in pGMECs, which offers a novel treatment strategy for mastitis. PMID- 26976288 TI - Generalized Pustular Psoriasis Associated with Shock. PMID- 26976289 TI - When the Illness Goes Off Script-An Exercise in Clinical Reasoning. PMID- 26976287 TI - Individual Versus Team-Based Financial Incentives to Increase Physical Activity: A Randomized, Controlled Trial. AB - BACKGROUND: More than half of adults in the United States do not attain the minimum recommended level of physical activity to achieve health benefits. The optimal design of financial incentives to promote physical activity is unknown. OBJECTIVE: To compare the effectiveness of individual versus team-based financial incentives to increase physical activity. DESIGN: Randomized, controlled trial comparing three interventions to control. PARTICIPANTS: Three hundred and four adult employees from an organization in Philadelphia formed 76 four-member teams. INTERVENTIONS: All participants received daily feedback on performance towards achieving a daily 7000 step goal during the intervention (weeks 1- 13) and follow up (weeks 14- 26) periods. The control arm received no other intervention. In the three financial incentive arms, drawings were held in which one team was selected as the winner every other day during the 13-week intervention. A participant on a winning team was eligible as follows: $50 if he or she met the goal (individual incentive), $50 only if all four team members met the goal (team incentive), or $20 if he or she met the goal individually and $10 more for each of three teammates that also met the goal (combined incentive). MAIN MEASURES: Mean proportion of participant-days achieving the 7000 step goal during the intervention. KEY RESULTS: Compared to the control group during the intervention period, the mean proportion achieving the 7000 step goal was significantly greater for the combined incentive (0.35 vs. 0.18, difference: 0.17, 95 % confidence interval [CI]: 0.07-0.28, p <0.001) but not for the individual incentive (0.25 vs 0.18, difference: 0.08, 95 % CI: -0.02-0.18, p = 0.13) or the team incentive (0.17 vs 0.18, difference: -0.003, 95 % CI: -0.11-0.10, p = 0.96). The combined incentive arm participants also achieved the goal at significantly greater rates than the team incentive (0.35 vs. 0.17, difference: 0.18, 95 % CI: 0.08-0.28, p < 0.001), but not the individual incentive (0.35 vs. 0.25, difference: 0.10, 95 % CI: -0.001-0.19, p = 0.05). Only the combined incentive had greater mean daily steps than control (difference: 1446, 95 % CI: 448-2444, p <= 0.005). There were no significant differences between arms during the follow up period (weeks 14- 26). CONCLUSIONS: Financial incentives rewarded for a combination of individual and team performance were most effective for increasing physical activity. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02001194. PMID- 26976290 TI - Implementation Science Workshop: Engaging Patients in Team-Based Practice Redesign - Critical Reflections on Program Design. PMID- 26976291 TI - Mitral Valve Perforation in Libman-Sacks Endocarditis: A Heart-Wrenching Case of Lupus. AB - Libman-Sacks (LS) endocarditis is one of the most common cardiac manifestations of systemic lupus erythematosus. Rarely, however, it can lead to serious complications, including severe valvular regurgitation or superimposed bacterial endocarditis. We describe the initial diagnostic challenges, clinical course, imaging studies and histopathological findings of a patient who presented with life-threatening lupus complicated by hemoptysis and respiratory failure secondary to a rare complication of LS endocarditis, acute mitral valve perforation. We review the current literature on valve perforation in the setting of LS endocarditis. In conclusion, although the disease is often asymptomatic and hemodynamically insignificant, it can result in serious and potentially fatal complications secondary to valve perforation, which may demand emergency surgical management. PMID- 26976292 TI - Incremental Cost-Effectiveness of 13-valent Pneumococcal Conjugate Vaccine for Adults Age 50 Years and Older in the United States. AB - BACKGROUND: Recently released results from a randomized controlled trial have shown that 13-valent pneumococcal conjugate vaccine (PCV13) is efficacious against vaccine-type nonbacteremic pneumonia in adults. OBJECTIVE: We examined the incremental cost-effectiveness of adding PCV13 to the Advisory Committee on Immunization Practices (ACIP) adult immunization schedule. METHODS: We used a probabilistic model following cohorts of 50-, 60-, or 65-year-olds. We used separate vaccination coverage and disease incidence data for healthy and high risk adults. Incremental cost-effectiveness ratios were determined for each potential vaccination strategy. RESULTS: In the base case scenario, our model indicated that adding PCV13 at age 65 or replacing 23-valent pneumococcal polysaccharide vaccine (PPSV23) at age 65 with PCV13 provided more value for money than adding PCV13 at ages 50 or 60. After projections of six additional years of herd protection from the childhood immunization program were incorporated, we found adding PCV13 dominated replacing PPSV23. For a cohort of 65-year-olds in 2013, the cost of adding PCV13 at age 65 to the schedule was $62,065 per quality-adjusted life year (QALY) gained, which rose to $272,621 after 6 years of projected herd protection. CONCLUSION: The addition of one dose of PCV13 for adults appears to have a cost-effectiveness ratio comparable to other vaccination interventions in the short run, though anticipated herd protection from the childhood immunization program may dramatically increase the cost per QALY after only a few years. PMID- 26976294 TI - Anticholinergic Medication Use and Risk of Dementia Among Elderly Nursing Home Residents with Depression. AB - OBJECTIVE: To examine the risk of dementia with anticholinergic use among elderly nursing home residents with depression. DESIGN: Population-based nested case control study. SETTING: Population-based study involving 2007-2010 Minimum Data Set-linked Medicare data from all 50 states. PARTICIPANTS: Medicare beneficiaries aged 65 years and older, diagnosed with depression, and no history of dementia as of 2007 (baseline period). Cases were identified as patients with incident dementia following the baseline period. For each case, four age- and sex-matched control subjects were selected using incidence density sampling. MEASUREMENTS: Anticholinergic exposure was defined using Anticholinergic Drug Scale. Prescription of clinically significant anticholinergic medications (levels 2 and 3) 30 days preceding the event date formed the primary exposure. The primary outcome was dementia diagnosis, between January 1, 2008, and December 31, 2010. A conditional logistic regression model stratified on matched case-control sets was performed to assess dementia risk, after controlling for other risk factors. RESULTS: The study sample included 28,388 cases diagnosed with dementia and 113,352 matched control subjects. After adjusting for other risk factors, clinically significant anticholinergic use was associated with significant risk of dementia (OR: 1.26; 95% CI: 1.22-1.29) compared with non-use. The findings remained consistent across levels of anticholinergic potency (level 2, OR: 1.37, 95% CI: 1.31-1.44; level 3, OR: 1.15, 95% CI: 1.10-1.19). CONCLUSION: Use of clinically significant anticholinergic medications was associated with a 26% increase in risk of dementia among elderly nursing home residents with depression. With increasing safety concerns, there is a significant need to optimize anticholinergic use, especially for those who are at risk for dementia. PMID- 26976293 TI - Defining a Good Death (Successful Dying): Literature Review and a Call for Research and Public Dialogue. AB - There is little agreement about what constitutes good death or successful dying. The authors conducted a literature search for published, English-language, peer reviewed reports of qualitative and quantitative studies that provided a definition of a good death. Stakeholders in these articles included patients, prebereaved and bereaved family members, and healthcare providers (HCPs). Definitions found were categorized into core themes and subthemes, and the frequency of each theme was determined by stakeholder (patients, family, HCPs) perspectives. Thirty-six studies met eligibility criteria, with 50% of patient perspective articles including individuals over age 60 years. We identified 11 core themes of good death: preferences for a specific dying process, pain-free status, religiosity/spirituality, emotional well-being, life completion, treatment preferences, dignity, family, quality of life, relationship with HCP, and other. The top three themes across all stakeholder groups were preferences for dying process (94% of reports), pain-free status (81%), and emotional well being (64%). However, some discrepancies among the respondent groups were noted in the core themes: Family perspectives included life completion (80%), quality of life (70%), dignity (70%), and presence of family (70%) more frequently than did patient perspectives regarding those items (35%-55% each). In contrast, religiosity/spirituality was reported somewhat more often in patient perspectives (65%) than in family perspectives (50%). Taking into account the limitations of the literature, further research is needed on the impact of divergent perspectives on end-of-life care. Dialogues among the stakeholders for each individual must occur to ensure a good death from the most critical viewpoint-the patient's. PMID- 26976295 TI - A Single-Center Comparison of 22 Competing Definitions of Delayed Graft Function After Kidney Transplantation. AB - BACKGROUND: This study compared 22 different definitions of delayed graft function (DGF) following kidney transplantation. MATERIAL AND METHODS: Our study included 497 kidney transplantations from deceased donors at our center between 2005 and 2011. Graft survival analysis including log-rank tests and Cox proportional hazards model was performed. Sensitivity and specificity were calculated in relation to graft failure. RESULTS: Mean follow-up time was 5.1 years. All dialysis-based definitions were associated with graft failure and characterized by high specificity (88-97%), but low sensitivity (25-29%). Hazard ratios ranged from 2.87 to 13.73, with increased risk when dialysis was required earlier and more frequently. The urine output-based definition performed similarly, with an association with graft failure and high specificity (96%), but low sensitivity (21%). Serum creatinine-based definitions were more heterogeneous. Higher sensitivity (4-67%) was found in some of these definitions, but was often associated with lower specificity (47-96%), losing the association with graft failure. Definitions combining different criteria varied in sensitivity (17-62%) and specificity (60-96%). However, some were able to achieve higher sensitivity without compromising too much on specificity, while keeping the association with graft failure. CONCLUSIONS: Our results indicate a potential advantage of combined definitions, because they are able to detect a larger group of recipients with increased risk of graft failure. PMID- 26976298 TI - Universities examine nurse role in helping patients to self-manage their conditions. AB - Three UK universities are analysing the effects of nurse support for patients trying to self-manage their conditions. PMID- 26976296 TI - Morin attenuates hepatic insulin resistance in high-fat-diet-induced obese mice. AB - Morin is a natural bioflavonoid that exhibits antioxidant and anti-inflammatory properties. The present study was designed to evaluate the effect of morin on insulin resistance, oxidative stress, and inflammation in a high-fat-diet (HFD) induced obese mice. Obesity was induced in ICR mice by feeding a HFD (60 % kcal from fat) for 12 weeks. After the first 6 weeks, obese mice were treated with morin (50 or 100 mg/kg/day) once daily for further 6 weeks. Blood glucose, lipid profile, insulin, leptin, adiponectin, and markers of oxidative stress and inflammation were then measured. Liver was excised, subjected to histopathology, glycogen determination, and gene and protein expression analysis. Morin administration reduced blood glucose, serum insulin, leptin, malondialdehyde, interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1) levels and increased serum adiponectin levels. Moreover, there was a reduction in serum lipid and liver triglyceride levels. Liver histology indicated that morin limited accumulation of lipid droplets. Interestingly, morin reduced expression of hepatic sterol regulatory element binding protein 1c (SREBP1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) and up-regulated hepatic carnitine palmitoyltransferase 1a (CPT1a) expression. Morin also stimulated glycogen storage and suppressed phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) protein expression. Furthermore, hepatic superoxide dismutase (SOD) and catalase (CAT) expression were increased after morin treatment. These findings indicate that morin has a positive effect in the HFD-induced obesity condition by suppressing lipogenesis, gluconeogenesis, inflammation, and oxidative stress activities. PMID- 26976300 TI - News digest April 01 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26976299 TI - School nurses to take greater responsibility for young carers. AB - School nurses should be 'champions' for young carers and support them in times of crisis, according to new government guidance. PMID- 26976301 TI - NMC urges ministers to support bill on reforming healthcare regulation. AB - Seven healthcare regulators, including the Nursing and Midwifery Council, have called for cross-party support for a bill published this week that would create a single legal framework for healthcare regulation. PMID- 26976297 TI - Impact of CT perfusion imaging on the assessment of peripheral chronic pulmonary thromboembolism: clinical experience in 62 patients. AB - PURPOSE: To evaluate the impact of CT perfusion imaging on the detection of peripheral chronic pulmonary embolisms (CPE). MATERIALS AND METHODS: 62 patients underwent a dual-energy chest CT angiographic examination with (a) reconstruction of diagnostic and perfusion images; (b) enabling depiction of vascular features of peripheral CPE on diagnostic images and perfusion defects (20 segments/patient; total: 1240 segments examined). The interpretation of diagnostic images was of two types: (a) standard (i.e., based on cross-sectional images alone) or (b) detailed (i.e., based on cross-sectional images and MIPs). RESULTS: The segment-based analysis showed (a) 1179 segments analyzable on both imaging modalities and 61 segments rated as nonanalyzable on perfusion images; (b) the percentage of diseased segments was increased by 7.2 % when perfusion imaging was compared to the detailed reading of diagnostic images, and by 26.6 % when compared to the standard reading of images. At a patient level, the extent of peripheral CPE was higher on perfusion imaging, with a greater impact when compared to the standard reading of diagnostic images (number of patients with a greater number of diseased segments: n = 45; 72.6 % of the study population). CONCLUSION: Perfusion imaging allows recognition of a greater extent of peripheral CPE compared to diagnostic imaging. KEY POINTS: * Dual-energy computed tomography generates standard diagnostic imaging and lung perfusion analysis. * Depiction of CPE on central arteries relies on standard diagnostic imaging. * Detection of peripheral CPE is improved by perfusion imaging. PMID- 26976302 TI - News digest March 31 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26976303 TI - A&E targets that measure patient outcomes to be trialled in Wales. AB - Emergency care performance targets that reflect treatment outcomes rather than simple waiting times are to be trialled in Wales. PMID- 26976304 TI - Nurses to help homeless patients after discharge from hospital. AB - The first phase of a L10 million project to help homeless people when they leave hospital is to be launched later this spring. PMID- 26976305 TI - News digest March 28 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26976306 TI - News digest March 27 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26976308 TI - Dosimetric response of variable-size cavities in photon-irradiated media and the behaviour of the Spencer-Attix cavity integral with increasing Delta. AB - Cavity theory is fundamental to understanding and predicting dosimeter response. Conventional cavity theories have been shown to be consistent with one another by deriving the electron (+positron) and photon fluence spectra with the FLURZnrc user-code (EGSnrc Monte-Carlo system) in large volumes under quasi-CPE for photon beams of 1 MeV and 10 MeV in three materials (water, aluminium and copper) and then using these fluence spectra to evaluate and then inter-compare the Bragg Gray, Spencer-Attix and 'large photon' 'cavity integrals'. The behaviour of the 'Spencer-Attix dose' (aka restricted cema), D S-A(?), in a 1-MeV photon field in water has been investigated for a wide range of values of the cavity-size parameter ?: D S-A(?) decreases far below the Monte-Carlo dose (D MC) for ? greater than ~ 30 keV due to secondary electrons with starting energies below ? not being 'counted'. We show that for a quasi-scatter-free geometry (D S-A(?)/D MC) is closely equal to the proportion of energy transferred to Compton electrons with initial (kinetic) energies above ?, derived from the Klein-Nishina (K-N) differential cross section. (D S-A(?)/D MC) can be used to estimate the maximum size of a detector behaving as a Bragg-Gray cavity in a photon-irradiated medium as a function of photon-beam quality (under quasi CPE) e.g. a typical air-filled ion chamber is 'Bragg-Gray' at (monoenergetic) beam energies ?260 keV. Finally, by varying the density of a silicon cavity (of 2.26 mm diameter and 2.0 mm thickness) in water, the response of different cavity 'sizes' was simulated; the Monte-Carlo-derived ratio D w/D Si for 6 MV and 15 MV photons varied from very close to the Spencer-Attix value at 'gas' densities, agreed well with Burlin cavity theory as rho increased, and approached large photon behaviour for rho ~ 10 g cm(-3). The estimate of ? for the Si cavity was improved by incorporating a Monte-Carlo-derived correction for electron 'detours'. Excellent agreement was obtained between the Burlin 'd' factor for the Si cavity and D S-A(?)/D MC at different (detour-corrected) ?, thereby suggesting a further application for the D S-A(?)/D MC ratio. PMID- 26976309 TI - [Not Available]. PMID- 26976310 TI - [Not Available]. PMID- 26976307 TI - The influence of 5-HTTLPR and Val66Met polymorphisms on cortical thickness and volume in limbic and paralimbic regions in depression: a preliminary study. AB - BACKGROUND: Structural brain abnormalities have been investigated in multi genetic and complex disorders such as major depressive disorder (MDD). Among the various candidate genes implicated in MDD, the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and 5-HT transporter gene linked polymorphism (5 HTTLPR) have garnered the most attention due to their putative roles in neural plasticity and antidepressant response. However, relatively few studies have assessed the influence of these polymorphysims on cortical thickness or brain volume in para-limbic and limbic regions in MDD, which was the aim of this study. METHODS: Forty-three adults with MDD and 15 healthy controls (HC) underwent structural magnetic resonance imaging (MRI). Cortical thickness was assessed in frontal, cingulate and temporal regions. Volumetric measures were carried out in the thalamus, caudate, putamen, pallidum, hippocampus and amygdala. Participants were genotyped to determine their 5-HTTLPR (tri-allelic) and Val66Met polymorphisms. RESULTS: In the combined sample (MDD + HC), smaller right pallidum volumes were found in LA/S (LA/S & LA/LG) heterozygotes compared to S/S (S/S, LG/S & LG/LG) homozygotes, though the effect was modest. In the MDD group, larger left thalamus and putamen volumes were observed in LA/LA homozygotes. No Val66Met or 5-HTTLPR genotype effects existed on cortical thickness and no main effects of the Val66Met polymorphism were observed. CONCLUSION: Our preliminary results suggest that the 5-HTTLPR polymorphism is associated with morphometric changes in regions known to play an important role in emotional and reward processing in depression. A larger sample size is required to replicate these findings and to potentially reveal subtle morphometric changes. PMID- 26976311 TI - [Residential care for elderly dependent people]. AB - Today, nursing homes increasingly offer different care solutions to elderly people with Alzheimer's or related forms of dementia. This policy of support forms part of an approach to prevent the risk factors of the loss of autonomy of elderly people. Different types of care within the same nursing home demonstrate their real importance. PMID- 26976312 TI - [Review of the personalised project for elderly people in Bearn and Soule]. AB - A review was carried out of the implementation of personalised projects, defined in the recommendations of the French national agency for the assessment and the quality of social and medical-social services and institutions (ANSEM), in nursing homes and long-term care units in Bearn and Soule. While highlighting the diversity of the practices and analysing the difficulty of their implementation, the question is raised whether the recommendations can be considered as a systemised and feasible reference. The relevance of the standardisation of the practices of the personalised project in institutions is thereby questioned. PMID- 26976313 TI - [Training for nurse coordinators in nursing homes]. AB - For the last three years, the Poitou-Charentes regional health agency has organised and funded training for nurse coordinators in nursing homes. The training programme, created in partnership with the Poitiers healthcare manager training institute, enables professionals with multiple responsibilities and missions, who deserve greater recognition, to acquire the necessary skills. PMID- 26976314 TI - [Training and representation of dementia of workers in nursing homes]. AB - Training could be a lever for improving the quality of care of residents with dementia in nursing homes by changing social representations. Beyond a simple assessment of acquired knowledge, a change of social representations could be indicative of a true appropriation of the content of the training. A study was carried out to assess the impact of training on nursing home caregivers' representations of dementia and Alzheimer's disease. PMID- 26976315 TI - [What happened after meprobamate's withdrawal? Survey in two nursing homes]. AB - We have conducted in two nursing homes a survey to study the impact of meprobamate's withdrawal, at the beginning of 2012, in terms of extent of prescribing to others psychotropic drugs and occurrence of adverse events. After meprobamate's withdrawal, 65 % of residents did not receive alternative medication and within three months after meprobamate stopping, adverse events (drowsiness, falls and hospitalization) decreased while agitation did not increase. PMID- 26976316 TI - [Interests of an olfactory stimulation activity in a nursing home]. AB - The comparison between the memories productions of residents in a nursing home through two reminiscence activities, one including olfaction and not the other one, can highlight an increasing occurrence of recent memories in the case of olfactory activity. A longer talk time is also observed and a better self-esteem can be assessed. This suggests the possibility of a specific relational and psychotherapeutic work. PMID- 26976317 TI - [A photographic competition on hand hygiene in a nursing home]. AB - Hand hygiene is often considered as the attribute of caregivers. However, it is the patient who is increasingly targeted by improved communication around hygiene in care notably in the framework of the "Clean Hands Mission". In this sense, the French regional centres for the fight against nosocomial infections in Burgundy has proved itself innovative on two levels by organising a photo competition in nursing homes. The aim was to show residents how to prevent care-related infections through the simple act of handwashing. PMID- 26976318 TI - [Hospital auxiliary staff, between polyvalence and invisibility]. AB - Often underestimated, hospital auxiliary staff carry out on a daily basis a professional activity that may be difficult to define and/or recognize. What does their work consist in and what are the boundaries of the scope of their activity? Faced with a growing rate of absenteeism among these members of staff in a nursing home for elderly people attached to a hospital, an issue emerges: does the content of their professional activity have an impact on the causes and evolution of this phenomenon? PMID- 26976319 TI - [A Swiss medical-social institution and the Snoezelen concept]. AB - In collaboration with six student nurses from the Geneva Haute Ecole de Sante, the Les Franchises medical-social institution in Geneva has launched an innovative project: the integration of the Snoezelen concept into its care programme, which will benefit residents with moderate or advanced dementia. PMID- 26976320 TI - [Not Available]. PMID- 26976321 TI - [Not Available]. PMID- 26976323 TI - Regulation of twin of eyeless during Drosophila development. AB - The Pax-6 protein is vital for eye development in all seeing animals, from sea urchins to humans. Either of the Pax6 genes in Drosophila (twin of eyeless and eyeless) can induce a gene cascade leading to formation of entire eyes when expressed ectopically. The twin of eyeless (toy) gene in Drosophila is expressed in the anterior region of the early fly embryo. At later stages it is expressed in the brain, ventral nerve cord and (eventually) the visual primordium that gives rise to the eye-antennal imaginal discs of the larvae. These discs subsequently form the major part of the adult head, including compound eyes. We have searched for genes that are required for normal toy expression in the early embryo to elucidate initiating events of eye organogenesis. Candidate genes identified by mutation analyses were subjected to further knock-out and miss expression tests to investigate their interactions with toy. Our results indicate that the head-specific gap gene empty spiracles can act as a repressor of Toy, while ocelliless (oc) and spalt major (salm) appear to act as positive regulators of toy gene expression. PMID- 26976322 TI - Galunisertib inhibits glioma vasculogenic mimicry formation induced by astrocytes. AB - Gliomas are among the most lethal primary brain tumors found in humans. In high grade gliomas, vasculogenic mimicry is often detected and has been correlated with prognosis, thus suggesting its potential as a therapeutic target. Vasculogenic mimicry mainly forms vascular-like channels independent of endothelial cells; however, little is known about the relationship between astrocytes and vasculogenic mimicry. In our study, we demonstrated that the presence of astrocytes promoted vasculogenic mimicry. With suspension microarray technology and in vitro tube formation assays, we identified that astrocytes relied on TGF-beta1 to enhance vasculogenic mimicry. We also found that vasculogenic mimicry was inhibited by galunisertib, a promising TGF-beta1 inhibitor currently being studied in an ongoing trial in glioma patients. The inhibition was partially attributed to a decrease in autophagy after galunisertib treatment. Moreover, we observed a decrease in VE-cadherin and smooth muscle actin-alpha expression, as well as down-regulation of Akt and Flk phosphorylation in galunisertib-treated glioma cells. By comparing tumor weight and volume in a xenograft model, we acquired promising results to support our theory. This study expands our understanding of the role of astrocytes in gliomas and demonstrates that galunisertib inhibits glioma vasculogenic mimicry induced by astrocytes. PMID- 26976325 TI - The adrenergic alpha2 antagonist atipamezole alters the behavioural effects of pramipexole and increases pramipexole concentration in blood plasma. AB - Pramipexole is a dopaminergic agonist used in Parkinson's disease treatment. It is thought to exert its therapeutic and side effects through actions on dopamine D3 receptors. In a recent study, we found that at doses occupying D3 but not D2 receptors pramipexole reduced locomotion and operant responding for primary and conditioned reinforcement. These effects, however, were not blocked by a D3 receptor antagonist and were present in D3 knockout mice, suggesting non-D3 receptor mechanisms. Among the next highest affinity binding sites of pramipexole are adrenergic alpha2 receptors. Here we explored alpha2 receptor involvement in the behavioural effects of pramipexole. We found that the alpha2 antagonist atipamezole, which was itself behaviourally silent, counteracted pramipexole's reduction of locomotion, but not operant responding for water or a conditioned reinforcer. The resulting behavioural profile was similar to that of a higher dose of pramipexole, leading to the hypothesize that atipamezole mediates its behavioural effects by increasing pramipexole effective dose. In support of this hypothesis, we found that atipamezole increased pramipexole concentration in blood plasma. This is not likely due to an effect on drug metabolism since pramipexole is not known to undergo metabolic transformation. Future work should examine two alternative hypotheses; that pramipexole plasma concentration is elevated as the result of 1) competition with atipamezole for renal excretion, or 2) atipamezole blockade of peripheral alpha2 binding sites, thereby preventing pramipexole distribution to alpha2-rich tissues. The suggestion of adrenergic effects of pramipexole is important in light of recent interest in adrenergic pathophysiology in Parkinson's disease. PMID- 26976324 TI - A generic screening platform for inhibitors of virus induced cell fusion using cellular electrical impedance. AB - Fusion of the viral envelope with host cell membranes is an essential step in the life cycle of all enveloped viruses. Despite such a clear target for antiviral drug development, few anti-fusion drugs have progressed to market. One significant hurdle is the absence of a generic, high-throughput, reproducible fusion assay. Here we report that real time, label-free measurement of cellular electrical impedance can quantify cell-cell fusion mediated by either individually expressed recombinant viral fusion proteins, or native virus infection. We validated this approach for all three classes of viral fusion and demonstrated utility in quantifying fusion inhibition using antibodies and small molecule inhibitors specific for dengue virus and respiratory syncytial virus. PMID- 26976326 TI - Endothelin receptor antagonist macitentan or deletion of mouse mast cell protease 4 delays lesion development in atherosclerotic mice. AB - AIMS: To determine the impact of mixed endothelin receptor antagonist and mouse mast cell protease-4 (mMCP-4) in the development of atherosclerosis in the mouse model. MATERIALS AND METHODS: Apolipoprotein E (ApoE) KO mice were crossed with mMCP-4 KO mice to generate ApoE/mMCP-4 double KO mice. Atherosclerosis was induced with a normal- or high-fat diet for 12, 27 or 52weeks. Macitentan (30mg/kg/day), a dual ETA/ETB receptor antagonist, was given orally for 6weeks (27week protocol). At sacrifice, aortas and brachiocephalic arteries (BCAs) were collected. En face Sudan IV staining was performed on aortas and BCA sections were subjected to Masson's trichrome stain and alpha-smooth muscle actin labeling. KEY FINDINGS: Under normal diet, both macitentan treatment and the absence of mMCP-4 reduced the development of aortic atherosclerotic lesions in 27 week old ApoE KO mice, but mMCP-4 deletion failed to maintain this effect on 52 week old mice. Under high-fat diet (WD), macitentan, but not the absence of mMCP 4, reduced aortic lesion development in ApoE KO mice. On BCA lesions of 27-week old WD mice, macitentan treatment had a small impact while mMCP-4 deletion showed improved features of plaque stability. SIGNIFICANCE: These results suggest that the inhibition of mMCP-4 reduces lesion spreading in the earlier phases of atherosclerosis development and can help stabilise the more advanced plaque. Macitentan treatment was more effective to prevent lesion spreading but did not improve plaque features to the same extent. PMID- 26976327 TI - The Whiteboard Revolution: Illuminating Science Communication in the Digital Age. AB - Journal-based science communication is not accessible or comprehensible to a general public curious about science and eager for the next wave of scientific innovation. We propose an alternative medium for scientists to communicate their work to the general public in an engaging and digestible way through the use of whiteboard videos. We describe the process of producing science whiteboard videos and the benefits and challenges therein. PMID- 26976329 TI - Caspase 6 has a protective role in SOD1(G93A) transgenic mice. AB - In amyotrophic lateral sclerosis (ALS), it has been suggested that the process of neurodegeneration starts at the neuromuscular junction and is propagated back along axons towards motor neurons. Caspase-dependent pathways are well established as a cause of motor neuron death, and recent work in other disease models indicated a role for caspase 6 in axonal degeneration. Therefore we hypothesised that caspase 6 may be involved in motor neuron death in ALS. To investigate the role of caspase 6 in ALS we profiled protein levels of caspase-6 throughout disease progression in the ALS mouse model SOD1(G93A); this did not reveal differences in caspase 6 levels during disease. To investigate the role of caspase 6 further we generated a colony with SOD1(G93A) transgenic mice lacking caspase 6. Analysis of the transgenic SOD1(G93A); Casp6(-/-) revealed an exacerbated phenotype with motor dysfunction occurring earlier and a significantly shortened lifespan when compared to transgenic SOD1(G93A); Casp6(+/+) mice. Immunofluorescence analysis of the neuromuscular junction revealed no obvious difference between caspase 6(+/+) and caspase 6(-/-) in non transgenic mice, while the SOD1(G93A) transgenic mice showed severe degeneration compared to non-transgenic mice in both genotypes. Our data indicate that caspase 6 does not exacerbate ALS pathogenesis, but may have a protective role. PMID- 26976328 TI - Developing informative microsatellite markers for non-model species using reference mapping against a model species' genome. AB - Microsatellites have a wide range of applications from behavioral biology, evolution, to agriculture-based breeding programs. The recent progress in the next-generation sequencing technologies and the rapidly increasing number of published genomes may greatly enhance the current applications of microsatellites by turning them from anonymous to informative markers. Here we developed an approach to anchor microsatellite markers of any target species in a genome of a related model species, through which the genomic locations of the markers, along with any functional genes potentially linked to them, can be revealed. We mapped the shotgun sequence reads of a non-model rodent species Apodemus semotus against the genome of a model species, Mus musculus, and presented 24 polymorphic microsatellite markers with detailed background information for A. semotus in this study. The developed markers can be used in other rodent species, especially those that are closely related to A. semotus or M. musculus. Compared to the traditional approaches based on DNA cloning, our approach is likely to yield more loci for the same cost. This study is a timely demonstration of how a research team can efficiently generate informative (neutral or function-associated) microsatellite markers for their study species and unique biological questions. PMID- 26976330 TI - Vascular pentraxin 3 controls arterial thrombosis by targeting collagen and fibrinogen induced platelets aggregation. AB - AIM: The long pentraxin PTX3 plays a non-redundant role during acute myocardial infarction, atherosclerosis and in the orchestration of tissue repair and remodeling during vascular injury, clotting and fibrin deposition. The aim of this work is to investigate the molecular mechanisms underlying the protective role of PTX3 during arterial thrombosis. METHODS AND RESULTS: PTX3 KO mice transplanted with bone marrow from WT or PTX3 KO mice presented a significant reduction in carotid artery blood flow following FeCl3 induced arterial thrombosis (-80.36+/-11.5% and -95.53+/-4.46%), while in WT mice transplanted with bone marrow from either WT or PTX3 KO mice, the reduction was less dramatic (-45.55+/-1.37% and -53.39+/-9.8%), thus pointing to a protective effect independent of a hematopoietic cell's derived PTX3. By using P-selectin/PTX3 double KO mice, we further excluded a role for P-selectin, a target of PTX3 released by neutrophils, in vascular protection played by PTX3. In agreement with a minor role for hematopoietic cell-derived PTX3, platelet activation (assessed by flow cytometric expression of markers of platelet activation) was similar in PTX3 KO and WT mice as were haemostatic properties. Histological analysis indicated that PTX3 localizes within the thrombus and the vessel wall, and specific experiments with the N-terminal and the C-terminal PTX3 domain showed the ability of PTX3 to selectively dampen either fibrinogen or collagen induced platelet adhesion and aggregation. CONCLUSION: PTX3 interacts with fibrinogen and collagen and, by dampening their pro-thrombotic effects, plays a protective role during arterial thrombosis. PMID- 26976333 TI - Proteomic analysis of mature barley grains from C-hordein antisense lines. AB - Hordeins are the major storage proteins in barley grains and are responsible for their low nutritional quality. Previously, antisense C-hordein barley lines were generated and were shown to contain a more balanced amino acid composition and an altered storage protein profile. In the present study, a proteomic approach that combined two-dimensional gel electrophoresis (2-DE) and mass spectrometry was used to (1) identify the changes in the protein profile of non-storage proteins (salt soluble fraction) in antisense C-hordein barley lines (L1, L2 and L3) and (2) map the differentially expressed proteins compared to the non-transgenic control line (Hordeum vulgare cv. Golden Promise). Moreover, the changes in the proteins were correlated with the more balanced amino acid composition of these lines, with special attention to the lysine content. The results showed that suppression of C-hordein expression does not exclusively affect hordein synthesis and accumulation. The more balanced amino acid composition observed in the transgenic lines L1, L2 and L3 was an indirect result of the profound alterations in the patterns of the non-storage proteins. The observed changes included up regulated expression of the proteins involved in stress and detoxification (L1), defence (L2 and L3), and storage globulins (L1, L2 and L3). To a lesser extent, the proteins involved in grain metabolism were also changed. Thus, the increased essential amino acids content results from changes in distinct protein sources among the three antisense C-hordein lines analyzed, although the up-regulated expression of lysine-rich proteins was consistently observed in all lines. PMID- 26976331 TI - Homeostasis of the astrocytic glutamate transporter GLT-1 is altered in mouse models of Lafora disease. AB - Lafora disease (LD, OMIM 254780) is a fatal rare disorder characterized by epilepsy and neurodegeneration. Although in recent years a lot of information has been gained on the molecular basis of the neurodegeneration that accompanies LD, the molecular basis of epilepsy is poorly understood. Here, we present evidence indicating that the homeostasis of glutamate transporter GLT-1 (EAAT2) is compromised in mouse models of LD. Our results indicate that primary astrocytes from LD mice have reduced capacity of glutamate transport, probably because they present a reduction in the levels of the glutamate transporter at the plasma membrane. On the other hand, the overexpression in cellular models of laforin and malin, the two proteins related to LD, results in an accumulation of GLT-1 (EAAT2) at the plasma membrane and in a severe reduction of the ubiquitination of the transporter. All these results suggest that the laforin/malin complex slows down the endocytic recycling of the GLT-1 (EAAT2) transporter. Since, defects in the function of this transporter lead to excitotoxicity and epilepsy, we suggest that the epilepsy that accompanies LD could be due, at least in part, to deficiencies in the function of the GLT-1 (EAAT2) transporter. PMID- 26976332 TI - The impact of cardiac ischemia/reperfusion on the mitochondria-cytoskeleton interactions. AB - Cardiac ischemia-reperfusion (IR) injury compromises mitochondrial oxidative phosphorylation (OxPhos) and compartmentalized intracellular energy transfer via the phosphocreatine/creatine kinase (CK) network. The restriction of ATP/ADP diffusion at the level of the mitochondrial outer membrane (MOM) is an essential element of compartmentalized energy transfer. In adult cardiomyocytes, the MOM permeability to ADP is regulated by the interaction of voltage-dependent anion channel with cytoskeletal proteins, particularly with beta tubulin II. The IR injury alters the expression and the intracellular arrangement of cytoskeletal proteins. The objective of the present study was to investigate the impact of IR on the intracellular arrangement of beta tubulin II and its effect on the regulation of mitochondrial respiration. Perfused rat hearts were subjected to total ischemia (for 20min (I20) and 45min (I45)) or to ischemia followed by 30min of reperfusion (I20R and I45R groups). High resolution respirometry and fluorescent confocal microscopy were used to study respiration, beta tubulin II and mitochondrial arrangements in cardiac fibers. The results of these experiments evidence a heterogeneous response of mitochondria to IR-induced damage. Moreover, the intracellular rearrangement of beta tubulin II, which in the control group colocalized with mitochondria, was associated with increased apparent affinity of OxPhos for ADP, decreased regulation of respiration by creatine without altering mitochondrial CK activity and the ratio between octameric to dimeric isoenzymes. The results of this study allow us to highlight changes of mitochondrial interactions with cytoskeleton as one of the possible mechanisms underlying cardiac IR injury. PMID- 26976334 TI - Synthesis of rebaudioside A from stevioside and their interaction model with hTAS2R4 bitter taste receptor. AB - Steviol glycosides (SG's) from Stevia rebaudiana (Bertoni) have been used as a natural low-calorie sweeteners. Its aftertaste bitterness restricts its use for human consumption and limits its application in food and pharmaceutical products. In present study, we have performed computational analysis in order to investigate the interaction of two major constituents of SG's against homology model of the hTAS2R4 receptor. Molecular simulation study was performed using stevioside and rebaudioside A revealed that, sugar moiety at the C-3'' position in rebaudioside A causes restriction of its entry into the receptor site thereby unable to trigger the bitter reception signaling cascade. Encouraged by the current finding, we have also developed a greener route using beta-1,3-glucanase from Irpex lacteus for the synthesis of de-bittered rebaudioside A from stevioside. The rebaudioside A obtained was of high quality with percent conversion of 62.5%. The results here reported could be used for the synthesis of rebaudioside A which have large application in food and pharmaceutical industry. PMID- 26976336 TI - Filaggrin exists in human nose. PMID- 26976335 TI - Myorelaxant action of fluorine-containing pinacidil analog, flocalin, in bladder smooth muscle is mediated by inhibition of L-type calcium channels rather than activation of KATP channels. AB - Flocalin (FLO) is a new ATP-sensitive K(+) (KATP) channel opener (KCO) derived from pinacidil (PIN) by adding fluorine group to the drug's structure. FLO acts as a potent cardioprotector against ischemia-reperfusion damage in isolated heart and whole animal models primarily via activating cardiac-specific Kir6.2/SUR2A KATP channels. Given that FLO also confers relaxation on several types of smooth muscles and can partially inhibit L-type Ca(2+) channels, in this study, we asked what is the mechanism of FLO action in bladder detrusor smooth muscle (DSM). The actions of FLO and PIN on contractility of rat and guinea pig DSM strips and membrane currents of isolated DSM cells were compared by tensiometry and patch clamp. Kir6 and SUR subunit expression in rat DSM was assayed by reverse transcription PCR (RT-PCR). In contrast to PIN (10 MUM), FLO (10 MUM) did not produce glibenclamide-sensitive DSM strips' relaxation and inhibition of spontaneous and electrically evoked contractions. However, FLO, but not PIN, inhibited contractions evoked by high K(+) depolarization. FLO (40 MUM) did not change the level of isolated DSM cell's background K(+) current, but suppressed by 20 % L-type Ca(2+) current. Determining various Kir6 and SUR messenger RNA (mRNA) expressions in rat DSM by RT-PCR indicated that dominant KATP channel in rat DSM is of vascular type involving association of Kir6.1 and SUR2B subunits. Myorelaxant effects of FLO in bladder DSM are explained by partial blockade of L type Ca(2+) channel-mediated Ca(2+) influx rather than by hyperpolarization associated with increased K(+) permeability. Thus, insertion of fluorine group in PIN's structure made the drug more discriminative between Kir6.2/SUR2A cardiac- and Kir6.1/SUR2B vascular-type KATP channels and rendered it partial L-type Ca(2+) channel-blocking potency. PMID- 26976337 TI - Maculopapular type drug eruption caused by pregabalin: A case and literature review. PMID- 26976338 TI - Paediatric mucoepidermoid carcinoma. PMID- 26976339 TI - Pharmacogenomics for personalized pain medicine. AB - Pharmacogenomics aims to unravel the way that human genetic variation affects drug efficacy and toxicity. Genome-wide association studies and candidate gene findings suggest that genetic approaches may help choose the most appropriate drug and dosage while preventing adverse drug reactions (ADRs). Pain is an unpleasant feeling that usually results from tissue damage. The management of different types of pain (acute, chronic, inflammatory, neuropathic, or cancer) is challenging. Currently, drug intervention is the first-line therapy for resolving pain. However, differences in drug efficacy between individuals are common with pain medications. Moreover, some patients experience ADRs after being treated with specific pain drugs. This review discusses the use of drugs for pain management in the context of the recent pharmacogenomic studies on ADRs and drug efficacy. PMID- 26976340 TI - Epidemiological investigations on the potential transmissibility of a rare disease: the case of atypical scrapie in Great Britain. AB - Multiple cases of atypical scrapie in the same holding and co-existence with classical scrapie have been reported in Great Britain. A two-stage simulation tool was developed by combining a sampling algorithm and a hierarchical Bayesian model to simulate the number of positive cases of atypical scrapie from: (i) random sampling and (ii) using the actual sampled population in Great Britain, being the output probability of detection of flocks with one and more cases. Cluster analysis was conducted to assess the level of geographical over- and under-sampling over the years. The probability of detecting at least two cases of atypical scrapie in the same holding is much lower in simulated random data than in simulated actual data for all scenarios. Sampling bias in the selection of sheep for testing led to multiple sampling from fewer but larger holdings, Scotland, and areas of Wales were under-sampled and the South-West and East of England oversampled. The pattern of atypical scrapie cases observed is unlikely to be explained by a multi-case event epidemiologically linked. The co-existence of classical and atypical scrapie is a rare event with 19 holdings detected in GB and does not suggest an epidemiological link between the two types of disease. PMID- 26976341 TI - Cryoballoon ablation for persistent atrial fibrillation - Large single-center experience. AB - BACKGROUND: Different catheter ablation (CA) strategies have been established in the treatment of persistent atrial fibrillation (persAF). Pulmonary vein isolation (PVI) only might be an option for the initial ablation procedure. There is a paucity of outcome data on second-generation cryoballoon (CBG2) PVI in persAF. METHODS: Patients with symptomatic drug-refractory persAF who underwent initial CA of AF were prospectively enrolled and PVI was performed with CBG2. The primary composite endpoint was freedom from AF, atrial tachycardia, or related symptoms after a 3-month blanking period. The secondary endpoint referred to periprocedural complications. RESULTS: One hundred seventy-three consecutive patients (64+/-10 years, 29% female) with symptomatic drug-refractory persAF were identified. Acute PVI was achieved in 100% of pulmonary veins with the CB technique. The left atrial procedure time was 112+/-30min. Major complications occurred in 1.7% (3 of 173 patients) including two phrenic nerve palsies (1%), which resolved until discharge, and one pericardial effusion (0.6%). Follow-up >=12 months was completed for 157 of 173 patients (91%). Median follow-up was 14 months. At 12 months, the primary composite endpoint was achieved in 129 of 157 patients (82%). However, 22 of 129 patients at risk (17%) were still on antiarrhythmic drugs. A relapse during the blanking period was identified as the only independent predictor for AF recurrence. CONCLUSION: PVI using the second generation cryoballoon is a reasonable treatment option for patients with symptomatic drug-refractory persAF with a favorable rate of freedom from AF and a low complication rate. PMID- 26976342 TI - A significant association between BDNF promoter methylation and the risk of drug addiction. AB - As a member of the neurotrophic factor family, brain derived neurotrophic factor (BDNF) plays an important role in the survival and differentiation of neurons. The aim of our work was to evaluate the role of BDNF promoter methylation in drug addiction. A total of 60 drug abusers (30 heroin and 30 methylamphetamine addicts) and 52 healthy age- and gender-matched controls were recruited for the current case control study. Bisulfite pyrosequencing technology was used to determine the methylation levels of five CpGs (CpG1-5) on the BDNF promoter. Among the five CpGs, CpG5 methylation was significantly lower in drug abusers than controls. Moreover, significant associations were found between CpG5 methylation and addictive phenotypes including tension-anxiety, anger-hostility, fatigue-inertia, and depression-dejection. In addition, luciferase assay showed that the DNA fragment of BDNF promoter played a key role in the regulation of gene expression. Our results suggest that BDNF promoter methylation is associated with drug addiction, although further studies are needed to understand the mechanisms by which BDNF promoter methylation contributes to the pathophysiology of drug addiction. PMID- 26976343 TI - STAT3-dependent TXNDC17 expression mediates Taxol resistance through inducing autophagy in human colorectal cancer cells. AB - Taxol (paclitaxel) is one of the taxane class of anticancer drugs as a first-line chemotherapeutic agent against many cancers including colorectal cancer, breast cancer, non-small cell lung cancer, ovarian cancer and so on. It is verified to induce cytotoxicity in a concentration and time-dependent manner. Numerous novel formulations of Taxol have been remanufactured for better therapeutic effect. Though Taxol works as a common anticancer drug for a long time in clinical practice, drug resistance is a major limitation of its long-term administration. In-depth research on drug resistance is still in progress and researchers have made some achievements, however, the mechanism or key molecule related to Taxol resistance in colorectal cancer still remains to be explored. In the present study, we observed that the high expression of TXNDC17 (thioredoxin domain containing 17) was associated with Taxol resistance in colorectal cancer cells. And TXNDC17 mediated Taxol resistance was related with increased basal autophagy level. Taxol exposure induced high levels of phospho-STAT3 (Tyr 705) and TXNDC17; and increase of basal autophagy in colorectal cancer cells. TXNDC17 overexpression cells obtained Taxol resistance and a high level of autophagy, and it is not surprising that stable downregulation of TXNDC17 accordingly reversed these phenomena. Interestingly, STAT3 could similarly work as TXNDC17 in spite of slighter effect compared to TXNDC17. And it has been proved that phospho-STAT3 (Tyr 705) possesses transcriptional regulation activity through forming dimmers. Many research revealed that transcription factor STAT3 affected more than 1000 gene products, and TXNDC17 is predicted to be a target gene of STAT3 at UCSC database. For the first time, we found STAT3 could bind promoter region of TXNDC17 (-623 bp to -58 bp relative to the transcription start site (TSS)) for regulating its expression. These results suggest the possibility that TXNDC17 could play an important role in Taxol resistance via enhancing autophagy in human colorectal cancer cells. TXNDC17 may become a potential target of colorectal cancer therapeutics. PMID- 26976344 TI - Visual afference mediates head and trunk stability in vestibular hypofunction. AB - Humans must maintain head and trunk stability while walking. The purpose of this study was to compare the kinematics of healthy controls and patients with vestibular hypofunction (VH) when walking and making head rotations of different frequencies in both light and dark conditions. We recruited eight individuals with VH and nine healthy control subjects to perform four tasks at their preferred gait speed, being normal walk, walking and making yaw head rotations at 1.5Hz and 2Hz, and walking in the dark and making yaw head rotations at 1.5Hz. Linear kinematics as well as head, trunk, and pelvis angular velocities were captured using the Vicon motion analysis system (Vicon Motion Systems, Oxford, UK). We found no difference in walking velocities for any of the four walking conditions across groups. The lateral displacement of the center of mass was increased in VH patients. In the dark, patients had more head instability in pitch (larger amplitudes and velocities) even though they were walking and making active yaw head rotations. Patients also had a smaller relative phase angle (mean 3.50+/-standard deviation 2.13 degrees ) than controls (mean 10.31+/-standard deviation 2.70 degrees ) (p<0.01). Our data suggest that patients with VH have difficulty walking with a straight trajectory when turning their head. Additionally, patients with VH have an abnormal excursion of spontaneous pitch head rotation while walking and making active yaw head turns, which is dependent on vision. Rehabilitation for these patients should consider applying unique head rotation frequencies when training gait with head turns as well as alternating their exposure to light. PMID- 26976345 TI - Itchy Papules and Nodules: A Quiz. PMID- 26976346 TI - Endovascular techniques for the management of wide-neck intracranial bifurcation aneurysms: A critical review of the literature. AB - Endovascular treatment is the first line treatment for intracranial aneurysms, but wide-neck aneurysms are often difficult to treat due to the difficulty in stabilizing the coils inside the aneurysm. It is singularly true for wide-neck bifurcation aneurysms (WNBA) as bifurcation branches often arise from the aneurysm neck. To overcome these difficulties, several approaches are available to treat both ruptured and unruptured aneurysms (balloon-assisted coiling and intra-aneurysmal flow disruption), while some techniques are essentially restricted to unruptured aneurysms due to the need of concomitant use of antiplatelet medications (stent-assisted coiling and flow diversion). Several ways of performing balloon-assisted coiling have been proposed for WNBA. Two stent-assisted techniques are available for WNBA (Y-stenting and the waffle-cone technique), but these techniques have yet to be evaluated in large, prospective series. Off-label use of flow diverters in WNBA has been proposed but efficacy has still to be established, and the technique presents unique potential safety issues (the potential modifications of bifurcation branches covered by the flow diverter) that has to be assessed. Intrasaccular flow disruption devices are promising tools for the endovascular treatment of WNBA. The WEB device has been extensively evaluated with prospective, multicenter studies showing high safety and good efficacy. PMID- 26976347 TI - Three-dimensional Printing and 3D Slicer: Powerful Tools in Understanding and Treating Structural Lung Disease. AB - Recent advances in the three-dimensional (3D) printing industry have enabled clinicians to explore the use of 3D printing in preprocedural planning, biomedical tissue modeling, and direct implantable device manufacturing. Despite the increased adoption of rapid prototyping and additive manufacturing techniques in the health-care field, many physicians lack the technical skill set to use this exciting and useful technology. Additionally, the growth in the 3D printing sector brings an ever-increasing number of 3D printers and printable materials. Therefore, it is important for clinicians to keep abreast of this rapidly developing field in order to benefit. In this Ahead of the Curve, we review the history of 3D printing from its inception to the most recent biomedical applications. Additionally, we will address some of the major barriers to wider adoption of the technology in the medical field. Finally, we will provide an initial guide to 3D modeling and printing by demonstrating how to design a personalized airway prosthesis via 3D Slicer. We hope this information will reduce the barriers to use and increase clinician participation in the 3D printing health-care sector. PMID- 26976348 TI - Identification and optimization of hydrazone-gallate derivatives as specific inhibitors of DNA methyltransferase 3A. AB - DNA methylation is the most studied epigenetic event. Since the methylation profile of the genome is widely modified in cancer cells, DNA methyltransferases are the target of new anticancer therapies. Nucleosidic inhibitors suffer from toxicity and chemical stability, while non-nucleosidic inhibitors lack potency. Here, we found a novel DNMT inhibitor scaffold by enzymatic screening and structure-activity relationship studies. The optimization studies led to an inhibitor containing three fragments: a gallate frame, a hydrazone linker and a benzothiazole moiety. Interestingly, the compound inhibits DNMT3A with micromolar potency (EC50 = 1.6 MUM) and does not inhibit DNMT1; this DNMT3A selectivity is supported by a docking study. Finally, the compound reactivates a reporter gene in leukemia KG-1 cells. PMID- 26976349 TI - Effect of polyethylene glycol on pore structure and separation efficiency of silica-based monolithic capillary columns. AB - Monolithic silica materials (first unclad monolith rods, then monolithic capillary columns) were prepared using various amounts of polyethylene glycols (PEGs) with different molecular weight (MW). The monolith rods were used to examine the mesoporosity by argon physisorption technique, and the macroporosity by mercury intrusion porosimetry. Subsequently, silica-based monolithic capillary columns with an inner diameter of 100 MUm were produced using the same preparation conditions as used for the rods. The results obtained with the monolith rods showed the following important findings: (1) it is feasible to fabricate monolithic silica rods possessing macropore size of 0.5-1.4 MUm by tuning the amount of PEGs (independently of the MW), whereas the macropore volume and the mesoporosity remain similar. (2) the smallest macropore size (0.5 MUm) rod prepared with PEG having a MW=20,000g/mol provided a narrower macropore size distribution than with PEG with MW=10,000g/mol. The monolithic capillary columns produced with the different PEG type showed similar retention factors for hexylbenzene (k=2.3-2.4) and similar t0-based column permeability (Kv0=2.3 2.4*10(-14)m(2)) in 20:80% (v/v) water:methanol, as expected from the results obtained with the monolith rods. The column prepared with PEG of MW=20,000g/mol gave a plate height of H=4.0 MUm for hexylbenzene at an optimal linear velocity of u0=2.6mm/s in 20:80% (v/v) water containing 0.1% formic acid:acetonitrile. To the best of our knowledge, this is the lowest plate height ever recorded for a monolithic column. Comparing the kinetic performance at 30MPa shows that the best monolithic silica column obtained in the present study performs better than the second-generation monolithic silica columns developed up till now in the practically most relevant range of plate numbers (N<=40,000). In this range, the performance is now similar to that of 2.7 MUm core-shell particle columns. PMID- 26976350 TI - Identification and quantification of seven fused aromatic rings C26H14 peri condensed benzenoid polycyclic aromatic hydrocarbons in a complex mixture of polycyclic aromatic hydrocarbons from coal tar. AB - A methodology for the characterization of groups of polycyclic aromatic hydrocarbons (PAHs) using a combination of normal phase liquid chromatography with ultraviolet-visible spectroscopy (NPLC/UV-vis) and gas chromatography with mass spectrometry (GC/MS) was used for the identification and quantification of seven fused aromatic rings C26H14 peri-condensed benzenoid polycyclic aromatic hydrocarbons, PAHs, in standard reference material (SRM) 1597a, complex mixture of PAHs from coal tar. The NPLC/UV-vis isolated the fractions based on the number of aromatic carbons and the GC/MS allowed the identification and quantification of five of the nine C26H14 PAH isomers; naphtho[1,2,3,4-ghi]perylene, dibenzo[b,ghi]perylene, dibenzo[b,pqr]perylene, naphtho[8,1,2-bcd]perylene, and dibenzo[cd,lm]perylene using a retention time comparison with authentic reference standards. For the other four benzenoid isomers with no available reference standards the following two approaches were used. First, the annellation theory was used to achieve the potential identification of benzo[qr]naphtho[3,2,1,8 defg]chrysene, and second, the elution distribution in the GC fractions was used to support the potential identification of benzo[qr]naphtho[3,2,1,8-defg]chrysene and to reach the tentative identifications of dibenzo[a,ghi]perylene, naphtho[7,8,1,2,3-pqrst]pentaphene, and anthra[2,1,9,8-opqra]naphthacene. It is the first time that naphtho[1,2,3,4-ghi]perylene, dibenzo[b,ghi]perylene, dibenzo[b,pqr]perylene, naphtho[8,1,2-bcd]perylene, and dibenzo[cd,lm]perylene are quantified, and the first time that benzo[qr]naphtho[3,2,1,8-defg]chrysene is potentially identified, in any sample, in any context. PMID- 26976351 TI - Outcomes of synchronous pulmonary nodules detected on computed tomography in head and neck cancer patients: 12-year retrospective review of a consecutive cohort. AB - OBJECTIVE: To investigate the long-term outcomes of pulmonary nodules detected on chest computed tomography in a consecutive cohort of patients with newly diagnosed or recurrent head and neck squamous cell cancer staged between 2001 and 2003. RESULTS: The study included 222 patients, 148 patients with newly diagnosed head and neck cancer (group 1) and 74 patients with recurrent cancer (group 2). Abnormalities were identified in 101 patients (45.4 per cent); these were predominantly benign in group 1 (61.7 per cent) as compared to predominantly malignant in group 2 (64.3 per cent) (Fisher's exact test; p = 0.0009). Only four patients (7.4 per cent) with an initially benign-looking pulmonary nodule went on to develop malignancy over time, conferring a negative predictive value of 93 per cent for the whole cohort. CONCLUSION: Chest computed tomography abnormalities in patients with recurrent head and neck cancer are statistically more likely to be malignant. Very few patients with an initially benign-appearing nodule develop chest malignancy over time. PMID- 26976352 TI - On the neurocognitive origins of human tool use : A critical review of neuroimaging data. AB - Since more than a century, neuropsychological models have assumed that the left inferior parietal cortex is central to tool use by storing manipulation knowledge (the manipulation-based approach). Interestingly, recent neuropsychological evidence indicates that the left inferior parietal cortex might rather support the ability to reason about physical object properties (the reasoning-based approach). Historically, these two approaches have been developed from data obtained in left brain-damaged patients. This review is the first one to (1) give an overview of the two aforementioned approaches and (2) reanalyze functional neuroimaging data of the past decade to examine their predictions. Globally, we demonstrate that the left inferior parietal cortex is involved in the understanding of tool-use actions, providing support for the reasoning-based approach. We also discuss the functional involvement of the different regions of the tool-use brain network (left supramarginal gyrus, left intraparietal sulcus, left posterior temporal cortex). Our findings open promising avenues for future research on the neurocognitive basis of human tool use. PMID- 26976353 TI - 5HT3 receptors: Target for new antidepressant drugs. AB - 5HT3 receptors (5HT3Rs) have long been identified as a potential target for antidepressants. Several studies have reported that antagonism of 5HT3Rs produces antidepressant-like effects. However, the exact role of 5HT3Rs and the mode of antidepressant action of 5HT3R antagonists still remain a mystery. Here, we provide a comprehensive overview of 5HT3Rs: (a) regional and subcellular distribution of 5HT3Rs in discrete brain regions, (b) preclinical and clinical evidence supporting the antidepressant effect of 5HT3R antagonists, and (c) neurochemical, biological and neurocellular signaling pathways associated with the antidepressant action of 5HT3R antagonists. 5HT3Rs located on the serotonergic and other neurotransmitter interneuronal projections control their release and affect mood and emotional behavior; however, new evidence suggests that apart from modulating the neurotransmitter functions, 5HT3R antagonists have protective effects in the pathogenic events including hypothalamic-pituitary adrenal-axis hyperactivity, brain oxidative stress and impaired neuronal plasticity, pointing to hereby unknown and novel mechanisms of their antidepressant action. Nonetheless, further investigations are warranted to establish the exact role of 5HT3Rs in depression and antidepressant action of 5HT3R antagonists. PMID- 26976354 TI - Association of smoking with myocardial injury and clinical outcome in patients undergoing mechanical reperfusion for ST-elevation myocardial infarction. AB - AIMS: There is evidence suggesting a positive effect of cigarette smoking on myocardial tissue reperfusion and clinical outcomes in patients with myocardial infarction ('smoker's paradox'). We aimed to evaluate the relationship of smoking with cardiac magnetic resonance (CMR)-determined myocardial salvage and damage as well as clinical outcomes in patients undergoing primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: This multicentre study included 727 consecutive STEMI patients reperfused within 12 h after symptom onset. CMR imaging parameters [area at risk (AAR), infarct size (IS), myocardial salvage index (MSI), and microvascular obstruction (MVO) and intramyocardial haemorrhage (IMH)] were compared according to admission smoking status. Major adverse cardiac event (MACE) rates at 12 months after infarction were compared between groups. Three hundred and thirty nine (46.6%) patients were current smokers. There was no difference in the extent of AAR [35 (24-47) vs. 37 (27-49) % of left ventricular volume (LV), P = 0.10], IS [16 (8-25) vs. 17 (10-26) %LV, P = 0.21], MSI [53 (29-70) vs. 52 (34-71), P = 0.47], MVO [0 (0-1.7) vs. 0 (0-1.6) %LV, P = 0.91], or in the frequency of IMH (42 vs. 39%, P = 0.58) between smokers and non-smokers. Smokers had lower MACE (3.8 vs. 8.2%, P = 0.01) rates. However, adjustment for differences in baseline risk factors attenuated the association of smoking with MACE markedly (hazard ratio = 0.71, 95% confidence interval 0.36-1.38, P = 0.31). CONCLUSION: Smoking is not associated with PPCI efficacy (myocardial salvage) or irreversible myocardial damage in patients with STEMI. The lower MACE rate of smokers was entirely explained by differences in baseline risk characteristics, thus challenging the existence of a smoker's paradox. PMID- 26976356 TI - Normal reference values for echocardiography: a call for comparison between ethnicities. PMID- 26976355 TI - 3D Ultrasound: seeing is understanding-from imaging to pathophysiology to developing therapies in secondary MR. PMID- 26976357 TI - Left atrial remodelling assessed by 2D and 3D echocardiography identifies paroxysmal atrial fibrillation. AB - AIMS: Paroxysmal atrial fibrillation (PAF) is common, often silent, and can be difficult to detect. Echocardiographic parameters assessing left atrial (LA) remodelling correlated with atrial fibrosis in permanent AF, but less is known about earlier stages such as PAF. We aimed to evaluate whether 2D and 3D echocardiographic (2DE and 3DE) assessment of LA anatomy and function is able to identify patients with PAF. METHODS AND RESULTS: This case-control study included 102 patients without overt heart disease, 44 patients with PAF. Anatomical remodelling was assessed using indexed maximal, minimal, and pre-atrial contraction volumes. Reservoir, conduit, and pump functions were assessed by volume and strain methods. All parameters were assessed by 2DE and 3DE and were compared between the two groups. Receiver-operating characteristic curves were constructed for each parameter for PAF prediction. PAF patients had bigger LA volumes than non-PAF group. Using 3DE, all atrial functions were impaired in the PAF group, regardless of the parameters used (all P < 0.05), whereas using 2DE, conduit function did not reach significant difference. Areas under the curve (AUCs) for 3D parameters were higher than those for equivalent 2DE parameters. PAF was best predicted by LA minimal indexed volume assessed by 2DE or 3DE (AUC 0.82 and 0.86, respectively) and 3D-LA ejection fraction and area strain (AUC = 0.82 and 0.81, respectively). CONCLUSION: Anatomical and functional LA remodelling assessed by 2DE and 3DE is independently and strongly associated with PAF, suggesting that these parameters can help identify PAF. PMID- 26976360 TI - De novo proliferative glomerulonephritis with monoclonal IgG deposits of the IgG1kappa subtype in a kidney allograft. AB - Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) has recently been described in cases with glomerular disease. Only 16 cases of recurrent or de novo PGNMID have been reported in the transplanted kidney. Here we report a case of de novo PGNMID in a renal allograft diagnosed in the early stage by protocol biopsy. A 41-year-old male with end-stage kidney disease caused by focal glomerular sclerosis received a living-related kidney transplant. The post-transplantation course was stable, except for an early episode of acute T cell-mediated rejection. Mesangial C1q deposition was found on the 3-year protocol biopsy. On the 4-year protocol biopsy, mild mesangioproliferative changes and deposition of IgG, C1q, C3, IgG1, and kappa light chain were evident, confirming the diagnosis of PGNMID of the IgG1kappa subtype. Furthermore, mild proteinuria was detected at that time. Because a subsequent haematological examination revealed high copy number Epstein-Barr virus (EBV) DNA and free kappa light chain in blood, the post-transplant lymphoproliferative disorder (PTLD) was suspected. Mycophenolate mofetil (MMF) was discontinued and rituximab was administered for the treatment of PTLD; subsequently, the improvement in proteinuria and serum creatinine was found 2 months after rituximab administration. PMID- 26976359 TI - Acute stimulation of mesenchymal stem cells with cigarette smoke extract affects their migration, differentiation, and paracrine potential. AB - Mesenchymal stem cells (MSCs) are known to play a key role in tissue regeneration, while smoking cigarettes is described to impair it. This work focuses on the effect cigarette smoke extract (CSE) has on the migration, differentiation, and paracrine potential of human adipose derived MSCs (AdMSCs). To mimic native conditions in vitro, AdMSCs were cultured in either monolayer or three-dimensional pellet cultures. While constant exposure to high concentrations of CSE had lethal effects on AdMSCs, lower concentrations of CSE impaired cell migration when compared to control conditions. The secretion of key interleukins was downregulated when CSE was exposed to the cells at low concentrations. Moreover, in this work AdMSCs were exposed to CSE while simultaneously being induced to differentiate into adipocytes, osteoblasts, and chondrocytes to determine the effect of CSE on the cells potential to differentiate. While adipogenic differentiation showed no significant variation, AdMSCs exposed to osteogenic and chondrogenic supplements showed both early and late genetic level variation when acutely exposed to low concentrations of CSE. Our results indicate that even a small amount of cigarette smoke can have detrimental effects on the regenerative potential of MSCs. PMID- 26976361 TI - Broad-Specificity Chemiluminescence Enzyme Immunoassay for (Fluoro)quinolones: Hapten Design and Molecular Modeling Study of Antibody Recognition. AB - On the basis of the structural features of (fluoro)quinolones (FQs), pazufloxacin was first used as a generic immunizing hapten to raise a broad-specificity antibody. The obtained polyclonal antibody exhibited broad cross-reactivity ranging from 5.19% to 478.77% with 21 FQs. Furthermore, the antibody was able to recognize these FQs below their maximum residue limits (MRLs) in an indirect competitive chemiluminescence enzyme immunoassay (ic-CLEIA), with the limit of detection (LOD) ranging from 0.10 to 33.83 ng/mL. For simply pretreated milk samples with spiked FQs, the ic-CLEIA exhibited an excellent recovery with a range of 84.6-106.9% and an acceptable coefficient of variation below 15%, suggesting its suitability and reliability for the use of a promising tool to detect FQs. Meanwhile, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models, with statistically significant correlation coefficients (q(2)CoMFA = 0.559, r(2)CoMFA = 0.999; q(2)CoMSIA = 0.559, r(2)CoMSIA = 0.994), were established to investigate the antibody recognition mechanism. These two models revealed that in the antibody, the active cavity binding FQs' 7-position substituents worked together with another cavity (binding FQs' 1-position groups) to crucially endow the high cross-reactivity. This investigation will be significant for better exploring the recognition mechanism and for designing new haptens. PMID- 26976363 TI - Ultra-high dynamic range electro-optic sampling for detecting millimeter and sub millimeter radiation. AB - Time-domain spectroscopy using coherent millimeter and sub-millimeter radiation (also known as terahertz radiation) is rapidly expanding its application, owing greatly to the remarkable advances in generating and detecting such radiation. However, many current techniques for coherent terahertz detection have limited dynamic range, thus making it difficult to perform some basic experiments that need to directly compare strong and weak terahertz signals. Here, we propose and demonstrate a novel technique based on cross-polarized spectral-domain interferometry to achieve ultra-high dynamic range electro-optic sampling measurement of coherent millimeter and sub-millimeter radiation. In our scheme, we exploit the birefringence in a single-mode polarization maintaining fiber in order to measure the phase change induced by the electric field of terahertz radiation in the detection crystal. With our new technique, we have achieved a dynamic range of 7 * 10(6), which is 4 orders of magnitude higher than conventional electro-optic sampling techniques, while maintaining comparable signal-to-noise ratio. The present technique is foreseen to have great impact on experiments such as linear terahertz spectroscopy of optically thick materials (such as aqueous samples) and nonlinear terahertz spectroscopy, where the higher dynamic range is crucial for proper interpretation of experimentally obtained results. PMID- 26976362 TI - Low-Dose Valacyclovir for Cytomegalovirus Infection Prophylaxis After a Heart Transplant. AB - OBJECTIVES: Cytomegalovirus infection is a major cause of morbidity and mortality in solid-organ transplant. Low doses of valacyclovir have been administered as cytomegalovirus prophylaxis in our institution for years. To the best of our knowledge, there is no published study of a low-dose regimen for cytomegalovirus prophylaxis in heart transplant patients. Therefore, our aim was to determine the results of low doses of valacyclovir in heart transplant. MATERIALS AND METHODS: Between September 2006 and December 2014, sixty-eight patients underwent orthotopic heart transplants. All of the patients received triple immunosuppressive therapy after surgery. During the next 6 months, sulfamethoxazole/trimethoprim was administered for Pneumocystis jiroveci pneumonia, and toxoplasmosis. Additionally all patients received valacyclovir hydrochloride (1000 mg/d, oral) for cytomegalovirus prophylaxis and nystatin oral rinse for prophylaxis of fungal infections. RESULTS: There was only 1 cytomegalovirus infection at follow-up. The patient had cytomegalovirus pneumonia at 17-month follow-up. In response to treatment with 1-week intravenous ganciclovir, the patient was discharged with a further 6-month oral valacyclovir therapy (1000 mg/d). CONCLUSIONS: In this study, we hypothesized that daily use of low-dose valacyclovir (1000 mg/d) is not only sufficient for cytomegalovirus prophylaxis but also beneficial in terms of cost. PMID- 26976364 TI - Evidence of the chemical reaction of (18)O-labelled nitrite with CO2 in aqueous buffer of neutral pH and the formation of (18)OCO by isotope ratio mass spectrometry. AB - Inorganic nitrite (NO2(-), ON-O(-) <--> (-)O-NO) is the autoxidation product of nitric oxide (NO). Nitrite can also be formed from inorganic nitrate (ONO2(-)), the major oxidation product of NO in erythrocytes, by the catalytic action of bacterial nitrate reductase in gut and oral microflora. Nitrite can be reduced to NO by certain cellular proteins and enzymes, as well as in the gastric juice under acidic conditions. Hemoglobin, xanthine oxidoreductase and carbonic anhydrase (CA) have been reported to convert nitrite to NO. Renal CA isoforms are involved in the reabsorption of nitrite and may, therefore, play an important role in NO homeostasis. Yet, the mechanisms underlying the action of CA on nitrite are incompletely understood. The nitrate/nitrite system is regarded as a reservoir of NO. We have recently shown that nitrite reacts chemically with carbon dioxide (CO2), the regular substrate of CA. The present communication reports a stable isotope ratio mass spectrometry (IRMS) study on the reaction of NO2(-) and CO2 performed in 50 mM HEPES buffer of pH 7.4 at 37 degrees C. By using (18)O-labelled nitrite ((18)ON-O(-)/(-18)O-NO) and CO2 we observed formation of (18)O-labelled CO2. This finding is an unequivocal evidence of the chemical reaction of (18)ON-O(-)/(-18)O-NO with CO2. The reaction is rapid and involves nucleophilic attack of the negatively charged nitrite via one of its oxygen atoms on the partially positively charged CO2 molecule to form the putative intermediate (18)ON-O-CO2(-)/(-)O2C-(18)O-NO. The by far largest fraction of this intermediate decomposes back to (18)ON-O(-)/(-18)O-NO and CO2. A very small fraction of the intermediate, however, rearranges and finally decomposes to form (18)OCO and nitrite. This reaction is slower in the presence of an isolated erythrocytic CA isoform II. In summary, NO2(-), CO2 and CA are ubiquitous. The chemical reaction of NO2(-) with CO2 and its modulation by CA isoforms may play important roles in the transport of nitrite in red blood cells, the kidney and other cells and organs. PMID- 26976368 TI - Antidepressieve onderhoudsbehandeling na elektroconvulsieve therapie Een overzicht van de recente literatuur en een enquete onder de Nederlandse ECT centra. AB - The different forms of antidepressive continuation therapy, used in the Netherlands, to prevent relapse after electroconvulsive therapy, were examined by sending a questionaire to all ECT centers. Common practice is in agreement with the results of current research. However, recent studies suggest that pharmacological continuation therapy is less usefull to prevent relapse when pharmacotherapeutic resistance has been proven in the past. In these cases ECT continuation therapy might bring a solution. On the effect of ECT-continuation therapy are few valid research results available. PMID- 26976367 TI - Recent antipsychotics in the treatment of psychoses. AB - Antipsychotic drugs are effective in psychoses, whatever the etiology of the disorder. The positive symptoms tend to respond more readily. The need for developing new drugs arises from the refractoriness of the negative symptoms, the 10-25% of the patients that are treatment-resistant and the problems of short-, and long-term extrapyramidal side-effects. Thus far, six drugs, differing from the classical antipsychotics, have been licensedfor use: olanzepine, risperidone and quetiapine; the longest registration exists for sulpiride and clozapine while the most recent one is for amisulpride. This review starts with a brief introduction to symptomatology, and takes differences with the classical drugs in pharmacology, pharmacokinetics, clinical aspects and side-effects into consideration. Clozapine, risperidone and sulpiride may be considered for clinical use in refractory patients; these three, olanzapine and amisulpride when extrapyramidal side-effects cause a clinical problem. Amisulpride and sulpiride have a dual therapeutic acion: On negative symptoms at low dose, on positive symptomen at high doses. PMID- 26976369 TI - Positron emissie tomografie (PET) bij stemmingsstoornissen: een overzicht. AB - Positron emission tomography is one of the most important techniques of functional imaging in psychiatry. This paper gives a synopsis of the findings in mood disorders: determination of brain glucose metabolism, cerebral blood flow and receptor studies. Investigation in a resting state as well as after activation are discussed. Although findings are somewhat discrepant hypometabolism, and/or hypoperfusion, most often in frontal and limbic areas are frequently described. Further research is needed, and standardization of the methodology would be most wellcome. PMID- 26976366 TI - Perioperative fluid volume optimization following proximal femoral fracture. AB - BACKGROUND: Proximal femoral fracture (PFF) is a common orthopaedic emergency that affects mainly elderly people at high risk of complications. Advanced methods for managing fluid therapy during treatment for PFF are available, but their role in reducing risk is unclear. OBJECTIVES: To compare the safety and effectiveness of the following methods of perioperative fluid optimization in adult participants undergoing surgical repair of hip fracture: advanced invasive haemodynamic monitoring, such as transoesophageal Doppler and pulse contour analysis; a protocol using standard measures, such as blood pressure, urine output and central venous pressure; and usual care.Comparisons of fluid types (e.g. crystalloid vs colloid) and other methods of optimizing oxygen delivery, such as blood product therapies and pharmacological treatment with inotropes and vasoactive drugs, are considered in other reviews. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 9); MEDLINE (October 2012 to September 2015); and EMBASE (October 2012 to September 2015) without language restrictions. We ran forward and backward citation searches on identified trials. We searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform for unpublished trials. This is an updated version of a review published originally in 2004 and updated first in 2013 and again in 2015. Original searches were performed in October 2003 and October 2012. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in adult participants undergoing surgical treatment for PFF that compared any two of advanced haemodynamic monitoring, protocols using standard measures or usual care, irrespective of blinding, language or publication status. DATA COLLECTION AND ANALYSIS: Two review authors assessed the impact of fluid optimization interventions on outcomes of mortality, length of hospital stay, time to medical fitness, whether participants were able to return to pre-fracture accommodation at six months, participant mobility at six months and adverse events in-hospital. We pooled data using risk ratio (RR) or mean difference (MD) for dichotomous or continuous data, respectively, on the basis of random-effects models. MAIN RESULTS: We included in this updated review five RCTs with a total of 403 participants, and we added two new trials identified during the 2015 search. One of the included studies was found to have a high risk of bias; no trial featured all pre-specified outcomes. We found two trials for which data are awaited for classification and one ongoing trial.Three studies compared advanced haemodynamic monitoring with a protocol using standard measures; three compared advanced haemodynamic monitoring with usual care; and one compared a protocol using standard measures with usual care. Meta-analyses for the two advanced haemodynamic monitoring comparisons are consistent with both increased and decreased risk of mortality (RR Mantel-Haenszel (M-H) random effects 0.41, 95% confidence interval (CI) 0.14 to 1.20; 280 participants; RR M-H random-effects 0.45, 95% CI 0.07 to 2.95; 213 participants, respectively). The study comparing a protocol with usual care found no difference between groups for this outcome.Three studies comparing advanced haemodynamic monitoring with usual care reported data for length of stay and time to medical fitness. There was no statistically significant difference between groups for these outcomes in the two studies that we were able to combine (MD IV fixed 0.63, 95% CI -1.70 to 2.96); MD IV fixed 0.01, 95% CI -1.74 to 1.71, respectively) and no statistically significant difference in the third study. One study reported reduced time to medical fitness when comparing advanced haemodynamic monitoring with a protocol, and when comparing protocol monitoring with usual care.The number of participants with one or more complications showed no statistically significant differences in each of the two advanced haemodynamic monitoring comparisons (RR M-H random effects 0.83, 95% CI 0.59 to 1.17; 280 participants; RR M-H random-effects 0.72, 95% CI 0.40 to 1.31; 173 participants, respectively), nor any differences in the protocol and usual care comparison.Only one study reported the number of participants able to return to normal accommodation after discharge with no statistically significant difference between groups.There were few studies with a small number of participants, and by using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation Working Group) approach, we judged the quality of the outcome evidence as low. We had included one study with a high risk of bias, but upon applying GRADE, we downgraded the quality of this outcome evidence to very low. AUTHORS' CONCLUSIONS: Five studies including a total of 403 participants provided no evidence that fluid optimization strategies improve outcomes for participants undergoing surgery for PFF. Further research powered to test some of these outcomes is ongoing. PMID- 26976365 TI - Chemotherapy for metastatic castrate-sensitive prostate cancer. AB - BACKGROUND: The role of docetaxel chemotherapy in combination with androgen deprivation therapy for metastatic castrate-sensitive prostate cancer is emerging. METHODS: We reviewed the results from the pivotal randomized phase III trials in this area: GETUG15, CHAARTED and STAMPEDE. RESULTS: All three studies demonstrated a benefit in progression-free survival with the use of docetaxel. However, two of the studies demonstrated a clinically meaningful overall survival benefit (CHAARTED and STAMPEDE), whereas the GETUG15 study did not demonstrate a major benefit. CONCLUSIONS: Docetaxel is an important option to consider for men who are fit for chemotherapy with newly diagnosed metastatic prostate cancer commencing androgen deprivation therapy. PMID- 26976370 TI - Cardiovasculaire adaptiviteit aan de verrichting van aandachts-taken bij kinderen met contact- en communicatieproblemen. AB - A psychofysiological study of the cardiac adaptivity to attention-demanding reaction time tasks demonstrated that children with a lesser variant of the pervasive developmental disorder (DSM-IV: PDDNOS) exhibit less cardiac responsiveness to attention tasks than healthy children do. We studied changes in heart rate variability (HRV), which were measured in a frequency band ranging from 0.07 to 0.14Hz. During the performance of an attention task, healthy children exhibited task load-related decreases in HRV. These decreases were found to be significantly smaller and not task load-related in a group of children with a PDDNOS who were judged to be not hyperactive. The decreases in HRV during task performance were almost absent in children with a PDDNOS who were moreover judged to be hyperactive. The magnitude of HRV decreases appeared to be significantly related to one of our task performance measures and to behaviour problems reported by the parents. Our results suggest a diminished vagal adaptivity to attention-demanding task situations in children with a PDDNOS, which is related to their resistance to unexpected changes in their daily routines. PMID- 26976371 TI - Acoustic startle responses of rats with cerebral developmental abnormalities: implications for schizophrenia. AB - Mounting evidence suggests involvement of prenatal factors in the pathogenesis of schizophrenia. The objective of the present study was to provide evidence for the hypothesis on schizophrenia that abnormal fetal brain development leads to impaired sensorimotor gating of acoustic startle stimuli. To this purpose, pregnant rats were treated with methylazoxymethanol acetate on one of four subsequent days of gestation, from E9 to E12. These procedures inhibit early stages of cortical proliferation in the foetuses, resulting in adult brain abnormalities that were mainly found in the entorhinal region. At the adult age, habituation andprepulse inhibition (PPI) of startle responses to acoustic stimuli were investigated. Our results show impaired habituation and PPI in rats treated at embryonic days 10 and 11. It is concluded that sensorimotor gating deficits can result from a developmental abnormality involving the entorhinal region, supporting the hypothesis that similar deficits, often observed in schizophrenic subjects, may be the result of entorhinal cortex dysfunction. PMID- 26976372 TI - Multi-functional magnesium alloys containing interstitial oxygen atoms. AB - A new class of magnesium alloys has been developed by dissolving large amounts of oxygen atoms into a magnesium lattice (Mg-O alloys). The oxygen atoms are supplied by decomposing titanium dioxide nanoparticles in a magnesium melt at 720 degrees C; the titanium is then completely separated out from the magnesium melt after solidification. The dissolved oxygen atoms are located at the octahedral sites of magnesium, which expand the magnesium lattice. These alloys possess ionic and metallic bonding characteristics, providing outstanding mechanical and functional properties. A Mg-O-Al casting alloy made in this fashion shows superior mechanical performance, chemical resistance to corrosion, and thermal conductivity. Furthermore, a similar Mg-O-Zn wrought alloy shows high elongation to failure (>50%) at room temperature, because the alloy plastically deforms with only multiple slips in the sub-micrometer grains (<300 nm) surrounding the larger grains (~15 MUm). The metal/non-metal interstitial alloys are expected to open a new paradigm in commercial alloy design. PMID- 26976373 TI - The Effectiveness of Multimodal Care for Soft Tissue Injuries of the Lower Extremity: A Systematic Review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. AB - OBJECTIVE: The purpose of this systematic review was to evaluate the effectiveness of multimodal care for the management of soft tissue injuries of the lower extremity. METHODS: We systematically searched MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane Central Register of Controlled Trials from 1990 to 2015. Random pairs of independent reviewers screened studies for relevance and critically appraised eligible studies using the Scottish Intercollegiate Guidelines Network criteria. We included studies with a low risk of bias in our best evidence synthesis. RESULTS: We screened 6794 articles. Six studies had a low risk of bias and addressed the following: plantar heel pain (n = 2), adductor-related groin pain (n = 1), and patellofemoral pain (n = 3). The evidence suggests that multimodal care for the management of persistent plantar heel pain may include mobilization and stretching exercise. An intensive, clinic based, group exercise program (strengthening, stretching, balance, agility) is more effective than multimodal care for the management of adductor-related groin pain in male athletes. There is inconclusive evidence to support the use of multimodal care for the management of persistent patellofemoral pain. Our search did not identify any low risk of bias studies examining multimodal care for the management of other soft tissue injuries of the lower extremity. CONCLUSION: A multimodal program of care for the management of persistent plantar heel pain may include mobilization and stretching exercise. Multimodal care for adductor related groin pain is not recommended based on the current evidence. There is inconclusive evidence to support the use of multimodal care for the management of persistent patellofemoral pain. PMID- 26976374 TI - The Effectiveness of Exercise on Recovery and Clinical Outcomes in Patients With Soft Tissue Injuries of the Hip, Thigh, or Knee: A Systematic Review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. AB - OBJECTIVE: The purpose of this systematic review was to determine the effectiveness of exercise for the management of soft tissue injuries of the hip, thigh, and knee. METHODS: We conducted a systematic review and searched MEDLINE, EMBASE, PsycINFO, the Cochrane Central Register of Controlled Trials, and CINAHL Plus with Full Text from January 1, 1990, to April 8, 2015, for randomized controlled trials (RCTs), cohort studies, and case-control studies evaluating the effect of exercise on pain intensity, self-rated recovery, functional recovery, health-related quality of life, psychological outcomes, and adverse events. Random pairs of independent reviewers screened titles and abstracts and assessed risk of bias using the Scottish Intercollegiate Guidelines Network criteria. Best evidence synthesis methodology was used. RESULTS: We screened 9494 citations. Eight RCTs were critically appraised, and 3 had low risk of bias and were included in our synthesis. One RCT found statistically significant improvements in pain and function favoring clinic-based progressive combined exercises over a "wait and see" approach for patellofemoral pain syndrome. A second RCT suggests that supervised closed kinetic chain exercises may lead to greater symptom improvement than open chain exercises for patellofemoral pain syndrome. One RCT suggests that clinic-based group exercises may be more effective than multimodal physiotherapy in male athletes with persistent groin pain. CONCLUSION: We found limited high-quality evidence to support the use of exercise for the management of soft tissue injuries of the lower extremity. The evidence suggests that clinic based exercise programs may benefit patients with patellofemoral pain syndrome and persistent groin pain. Further high-quality research is needed. PMID- 26976375 TI - The Effectiveness of Multimodal Care for the Management of Soft Tissue Injuries of the Shoulder: A Systematic Review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. AB - OBJECTIVE: The purpose of this systematic review was to evaluate the effectiveness of multimodal care for the management of soft tissue injuries of the shoulder. METHODS: We conducted a systematic review and searched MEDLINE, EMBASE, CINAHL, PsycINFO, and the Cochrane Central Register of Controlled Trials from 1990 to 2015. Two independent reviewers critically appraised studies using the Scottish Intercollegiate Guidelines Network criteria. We used best evidence synthesis to synthesize evidence from studies with low risk of bias. RESULTS: We screened 5885 articles, and 19 were eligible for critical appraisal. Ten randomized controlled trials had low risk of bias. For persistent subacromial impingement syndrome, multimodal care leads to similar outcomes as sham therapy, radial extracorporeal shock-wave therapy, or surgery. For subacromial impingement syndrome, multimodal care may be associated with small and nonclinically important improvement in pain and function compared with corticosteroid injections. For rotator cuff tendinitis, dietary-based multimodal care may be more effective than conventional multimodal care (exercise, soft tissue and manual therapy, and placebo tablets). For nonspecific shoulder pain, multimodal care may be more effective than wait list or usual care by a general practitioner, but it leads to similar outcomes as exercise or corticosteroid injections. CONCLUSIONS: The current evidence suggests that combining multiple interventions into 1 program of care does not lead to superior outcomes for patients with subacromial impingement syndrome or nonspecific shoulder pain. One randomized controlled trial suggested that dietary-based multimodal care (dietary advice, acupuncture, and enzyme tablets) may provide better outcomes over conventional multimodal care. However, these results need to be replicated. PMID- 26976377 TI - Same day HIV diagnosis and antiretroviral therapy initiation affects retention in Option B+ prevention of mother-to-child transmission services at antenatal care in Zomba District, Malawi. AB - INTRODUCTION: Data from the Option B+ prevention of mother-to-child transmission (PMTCT) program in Malawi show considerable variation between health facilities in retention on antiretroviral therapy (ART). In a programmatic setting, we studied whether the "model of care," based on the degree of integration of antenatal care (ANC), HIV testing and counselling (HTC) and ART service provision influenced uptake of and retention on ART. METHODS: We conducted a retrospective cohort study of pregnant women seeking ANC at rural primary health facilities in Zomba District, Malawi. Data were extracted from standardized national ANC registers, ART registers and ART master cards. The "model of care" of Option B+ service delivery was determined at each health facility, based on the degree of integration of ANC, HTC and ART. Full integration (Model 1) of HTC and ART initiation at ANC was compared with integration of HTC only into ANC services (Model 2) with subsequent referral to an existing ART clinic for treatment initiation. RESULTS AND DISCUSSION: A total of 10,528 women were newly registered at ANC between October 2011 and March 2012 in 23 rural health facilities (12 were Model 1 and 11 Model 2). HIV status was ascertained in 8,572 (81%) women. Among 914/8,572 (9%) HIV-positive women enrolling at ANC, 101/914 (11%) were already on ART; of those not on treatment, 456/813 (56%) were started on ART. There was significantly higher ART uptake in Model 1 compared with Model 2 sites (63% vs. 51%; p=0.001), but significantly lower ART retention in Model 1 compared with Model 2 sites (79% vs. 87%; p=0.02). Multivariable analysis showed that initiation of ART on the same day as HIV diagnosis, but not model of care, was independently associated with reduced retention in the first six months (adjusted odds ratio 2.27; 95% CI: 1.34-3.85; p=0.002). CONCLUSIONS: HIV diagnosis and treatment on the same day was associated with reduced retention on ART, independent of the level of PMTCT service integration at ANC. PMID- 26976378 TI - [Effectiveness of human papillomavirus genotyping for detection of high-grade anal intraepithelial neoplasia compared to anal cytology]. AB - INTRODUCTION: The incidence of high-grade anal intraepithelial neoplasia (HGAIN) with an aetiological based on high-risk types of human papillomavirus- is increasing in some high-risk groups. Screening for HGAIN includes routine anal cytology and, more recently, HPV genotyping. The main objective of this study was to determine the sensitivity and specificity of anal cytology and HPV genotyping for the detection of HGAIN. MATERIALS AND METHODS: This is a study to determine the correlation of cytological and microbiological findings with anal biopsy findings in a cohort of patients at high risk of developing AIN referred to the department of sexually transmitted infections of the Hospital Costa del Sol, Spain, between January 2008 and December 2014. RESULTS: Of the 151 patients subjected to screening, a total of 92 patients, all of them with the result of three screening test (anal cytology, genotyping and biopsy) were included in the study. Just under two-thirds (62%) of them were HIV-positive. The sensitivity and specificity of anal cytology to detect HGAIN were 52.8 and 85.7%, respectively (k: 0.328), and 78 and 62.8% to detect two or more HPV oncogenic genotypes (k: 0.417). The detection of oncogenic HPV genotypes allowed the identification of 23 new cases of HGAIN that had been underdiagnosed with anal cytology, with 14 cases containing at least three high-risk genotypes. CONCLUSION: Anal cytology did not show enough sensitivity in HGAIN screening. HPV genotyping has shown to be a useful tool to detect HGAIN cases, although it could lead to an over-diagnosis as a solitary screening procedure. PMID- 26976379 TI - Community-acquired febrile urinary tract infection caused by extended-spectrum beta-lactamase-producing bacteria in hospitalised infants. AB - INTRODUCTION: Extended-spectrum beta-lactamase (ESBL) producing bacteria are infrequent pathogens of urinary tract infections in children. The objective of our study was to investigate the presence, clinically associated characteristics and risk factors for acquisition of urinary tract infection/acute pyelonephritis (UTI/APN) in hospitalised children <2years old caused by community-acquired ESBL. METHODS: A case-control study in a second level community hospital in Spain, in which 537 episodes of UTI/APN were investigated in a retrospective study between November 2005 and August 2014. Cases were patients with ESBL strains. For each case, four ESBL-negative controls were selected. A questionnaire with the variables of interest was completed for every patient, and the groups were compared. RESULTS: ESBL-positive strains were found in 19 (3,5%) cultures. Of these 16 (84%) were Escherichia coli. Vesicoureteral reflux (VUR) of any grade was more frequent in the ESBL group (60 vs. 29%), although without statistical significance. Relapses were more frequent in the ESBL group (42% vs. 18%) (P=.029; OR=3.2; 95%CI: 1.09-9.5). The prevalence of UTI/APN due to ESBL-positive strains increased slightly from 2.7% in the period 2005-2009 to 4.4% in the period 2010-2014. CONCLUSIONS: ESBL UTI/APN were associated with more frequent relapses. VUR of any grade was twice more frequent in the ESBL group. Piperacillin/tazobactam, fosfomycin and meropenem showed an excellent activity. Aminoglycosides may be a therapeutic option, and in our patients gentamicin was the antibiotic most used. PMID- 26976380 TI - HIV-1 p24 and CD4+ T cell count during boosted protease-inhibitor monotherapy in HIV-infected patients. AB - BACKGROUND: Plasma HIV p24 is considered a significant predictor of CD4+ T cell decline and progression to AIDS in HIV-infected patients. We evaluated the p24 levels in patients on triple therapy and after switching to ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv), as well as the relationships with virological and immunological evolution. MATERIALS AND METHODS: Plasma samples from patients participating in two studies of simplification to mtPI/rtv were analysed for presence of p24, using a boosted enzyme-linked immunosorbent assay specific for mature p24. Only patients with available samples at baseline (on triple therapy) and during a follow-up of at least 12 months after switching to mtPI/rtv were included. RESULTS: A total of 233 samples from 51 patients were analysed. After switching to mtPI/rtv and a median follow-up of 24 months, 14 patients maintained continuous undetectable viraemia, and 37 patients experienced a total of 49 transient viraemic episodes. Unexpectedly, the evolutionary p24 patterns were uniform for most patients, both before and after switching to mtPI/rtv, independently of the virological behaviour, fitting into one of three categories: persistent undetectable p24 levels, positive p24, matching only with the viraemic episodes, and persistent detectable p24 levels. The last group showed lower CD4+ T cell counts and percentages, as well as lower CD4+/CD8+ T cell ratios after 12 and 24 months of follow up. CONCLUSION: Treatment simplification to mtPI/rtv does not influence the behaviour of p24 in plasma. Patients with continuous positive p24, despite undetectable viraemia, showed worse immunological evolution. PMID- 26976382 TI - [Rickettsiosis after tick bite: A subtle clinic picture on many occasions, we must be vigilant]. AB - Rickettsia diseases are a group of tick-borne transmitted diseases, classified into 2 large groups: spotted fevers and typhus fevers. In addition, a new condition has been described recently, known as tick-borne lymphadenopathy. A retrospective series is presented of paediatric cases of rickettsia diseases diagnosed in 2013 and 2014. A total of 8 patients were included, of which 2 of them were diagnosed as Mediterranean spotted fever, and 6 as tick-borne lymphadenopathy. Rickettsia slovaca, Rickettsia sibirica mongolitimonae, and Rickettsia massiliae were identified in 3 of them. Aetiology, clinical features and treatment carried out in each of them are described. The interest of these cases is that, although most have a benign course, the high diagnostic suspicion and early treatment seem to be beneficial for its outcome. PMID- 26976381 TI - Prevention and treatment of opportunistic infections and other coinfections in HIV-infected patients: May 2015. AB - Despite the huge advance that antiretroviral therapy represents for the prognosis of infection by the human immunodeficiency virus (HIV), opportunistic infections (OIs) continue to be a cause of morbidity and mortality in HIV-infected patients. OIs often arise because of severe immunosuppression resulting from poor adherence to antiretroviral therapy, failure of antiretroviral therapy, or unawareness of HIV infection by patients whose first clinical manifestation of AIDS is an OI. The present article updates our previous guidelines on the prevention and treatment of various OIs in HIV-infected patients, namely, infections by parasites, fungi, viruses, mycobacteria, and bacteria, as well as imported infections. The article also addresses immune reconstitution inflammatory syndrome. PMID- 26976383 TI - Comment on Amchova et al., 2015 review of food color safety. PMID- 26976384 TI - Migrating Susceptibility Vessel Sign in Posterior Circulation Stroke. PMID- 26976385 TI - Chronic Acetaminophen Use Associated with Anion-Gap Metabolic Acidosis. PMID- 26976386 TI - Hospital Readmissions Following Physician Call System Change: A Comparison of Concentrated and Distributed Schedules. AB - BACKGROUND: Physician call schedules are a critical element for medical practice and hospital efficiency. We compared readmission rates prior to and after a change in physician call system at Sunnybrook Health Sciences Centre. METHODS: We studied patients discharged over a decade (2004 through 2013) and identified whether or not each patient was readmitted within the subsequent 28 days. We excluded patients discharged for a surgical, obstetrical, or psychiatric diagnosis. We used time-to-event analysis and time-series analysis to compare rates of readmission prior to and after the physician call system change (January 1, 2009). RESULTS: A total of 89,697 patients were discharged, of whom 10,001 (11%) were subsequently readmitted and 4280 died. The risk of readmission was increased by about 26% following physician call system change (9.7% vs 12.2%, P <.001). Time-series analysis confirmed a 26% increase in the readmission rate after call system change (95% confidence interval, 22%-31%; P <.001). The increase in readmission rate after call system change persisted across patients with diverse ages, estimated readmission risks, and medical diagnoses. The net effect was equal to 7240 additional patient days in the hospital following call system change. A modest increase was observed at a nearby acute care hospital that did not change physician call system, and no increase in risk of death was observed with increased hospital readmissions. CONCLUSION: We suggest that changes in physician call systems sometimes increase subsequent hospital readmission rates. Further reductions in readmissions may instead require additional resources or ingenuity. PMID- 26976387 TI - Automated Behavioral Text Messaging and Face-to-Face Intervention for Parents of Overweight or Obese Preschool Children: Results From a Pilot Study. AB - BACKGROUND: Children are 5 times more likely to be overweight at the age of 12 years if they are overweight during the preschool period. OBJECTIVE: The purpose of this study was to establish the feasibility, acceptability, and preliminary effects of a cognitive behavioral intervention (TEXT2COPE) synergized with tailored mobile technology (mHealth) on the healthy lifestyle behaviors of parents of overweight and obese preschoolers delivered in a primary care setting. METHODS: Fifteen preschooler-parent dyads recruited through primary care clinics completed a manualized 7-week cognitive behavioral skills building intervention. Beck's Cognitive Theory guided the TEXT2COPE intervention content and Fogg's Behavior Model guided the implementation. The intervention employed a combination of face-to-face clinic visits and ecological momentary interventions using text messaging (short message service, SMS). To enhance the intervention's relevance to the family's needs, parents dictated the wording of the text messages and also were able to adapt the frequency and timing of delivery throughout program implementation. RESULTS: Self-reported findings indicate that the program is feasible and acceptable in this population. The intervention showed preliminary effects with significant improvements on parental knowledge about nutrition (P=.001) and physical activity (P=.012) for their children, parental beliefs (P=.001) toward healthy lifestyles, and parental behaviors (P=.040) toward engaging in healthy lifestyle choices for their children. Effect sizes were medium to large for all variables. The timing, frequency, and wording of the text messages were tailored to the individual families, with 69% of parents (9/13) increasing the frequency of the tailored SMS from being sent once weekly to as many as 5 times a week. CONCLUSIONS: Utilizing a cognitive behavioral skills intervention with SMS has great potential for supporting clinical care of overweight and obese preschool children and their families. Further exploration of the potential effects on health and behavioral outcomes is warranted. PMID- 26976389 TI - Stable or improved health status in the population 65 years and older in Stockholm, Sweden - an 8-year follow-up of self-reported health items. AB - BACKGROUND: Previous studies have reached different conclusions about whether health is improving in the ageing population. More studies with narrow age groups analyzed separately for men and women will contribute to the literature. AIM: To describe trends in self-reported indicators of health and health-related quality of life between 2002 and 2010, focusing on differences between gender and age groups. A population-based survey of individuals 65+ in the Stockholm County was used. RESULTS: Prevalence of health problems increased with age both among men and women. Men generally reported having no health problems to a larger extent than women, but the proportions reporting severe problems were similar. The larger picture is one of stability in health-related quality of life, even if several items developed for the better, especially among women. While the proportions reporting no health/functional problems increased for many items, the proportions reporting severe problems remained unchanged among men and improved only for two items among women. CONCLUSIONS OVERALL, IMPROVEMENTS WERE SEEN IN MANY OF THE HEALTH-RELATED QUALITY OF LIFE ITEMS AS WELL AS FOR SELF-RATED HEALTH AMONG WOMEN THE PROPORTIONS REPORTING LONG-TERM ILLNESS OR PERSISTENT HEALTH PROBLEMS INCREASED, BUT FEWER SEEM TO BE LIMITED IN THEIR DAILY ACTIVITIES BY THESE PROBLEMS THE STABLE PROPORTIONS OF POOR SELF-RATED HEALTH INDICATES THAT WHILE HEALTH AND FUNCTIONING SEEM TO BE IMPROVING FOR THE MAJORITY OF THE OLDER POPULATION, SOME GROUPS MAY BE LAGGING BEHIND FUTURE STUDIES SHOULD PAY ATTENTION TO CHANGES BOTH IN THE UPPER AND LOWER ENDS OF THE HEALTH SPECTRUM. PMID- 26976388 TI - Cost effectiveness of adherence to IDSA/ATS guidelines in elderly patients hospitalized for Community-Aquired Pneumonia. AB - BACKGROUND: Adherence to guidelines for the treatment of hospitalized elderly patients with community-acquired pneumonia (CAP) has been associated with improved clinical outcomes. This study evaluated the cost-effectiveness of adherence to guidelines for the treatment of CAP in an elderly hospitalized patient cohort. METHODS: Data from an international, multicenter observational study for patients age 65 years or older hospitalized with CAP from 2001 to 2007 were used to estimate transition probabilities for a multi-state Markov model traversing multiple health states during hospitalization for CAP. Empiric antibiotic therapy was classified as adherent, over-treated, and under-treated according to 2007 Infectious Disease Society of America/American Thoracic Society IDSA/ATS guidelines. Utilities were estimated from an expert panel of active clinicians. Costs were estimated from a tertiary referral hospital and adjusted for inflation to 2013 US dollars. Costs, utilities, and transition probabilities were all modeled using probability distributions to handle their inherit uncertainty. Cost-effectiveness analysis was based on the first 14 days of hospitalization. Patients admitted to the intensive care unit (ICU) were analyzed separately from those admitted to the ward. Sensitivity analyses with regards to time frame (out to 30 days hospitalization), cost estimates, and willingness to pay values were performed. RESULTS: The model parameters were estimated using data from 1635 patients (1438 admitted to the ward and 197 admitted to the ICU). For the ward model, adherence to antibiotic guidelines was the dominant strategy and associated with lower costs (-$1379 and -$799) and improved quality of life compared to over- and under-treatment. In the ICU model, however, adherence to guidelines was associated with greater costs (+$13,854 and + $3461 vs. over- and under-treatment, respectively) and lower quality of life. Acceptance rates across the willingness to pay ranges evaluated were 42-48 % for guideline adherence on the ward and 61-64 % for over-treatment on the ICU. Results were robust over sensitivity analyses concerning cost and utility estimates. CONCLUSIONS: While adherence to antibiotic guidelines was the most cost-effective strategy for elderly patients hospitalized with CAP and admitted to the ward, in the ICU over treatment of patients relative to the guidelines was the most cost-effective strategy. PMID- 26976390 TI - Conceptualisation of ageing in relation to factors of importance for extending working life - a review. AB - AIM: The aim of this study was to explore and understand the complexity of ageing in relation to factors of importance for extending working life. METHOD: Discourse analysis of documents was used in an integrative review including 128 articles. RESULT: Four different conceptualisation of ageing are shown to affect older workers' ability to extend their working life: (a) biological ageing people's health in relation to their physical and mental work environment, their pace of work and recuperation needs; (b) chronological ageing statutory retirement age and policies and economic incentives devised for older workers by society, unions and organisations/enterprises; (c) social ageing inclusion in different social groups, the attitude of managers, organisations and family members, the leisure activities and surrounding environment; and (d) mental/cognitive ageing self-crediting, motivating and meaningful activities, competence and skills in working life. CONCLUSIONS SOCIETIES TODAY FOCUS MOSTLY ON CHRONOLOGICAL AGEING AND ARE LOOKING TO INCREASE THE RETIREMENT AGE WITH REGARD TO STATUTORY PENSION SYSTEMS, EG BEYOND 65 YEARS OF AGE THE INTER RELATIONSHIPS BETWEEN CHRONOLOGICAL, MENTAL, BIOLOGICAL AND SOCIAL AGEING AND THE NINE AREAS IDENTIFIED AS BEING IMPORTANT TO OLDER WORKERS IN THESE RESPECTS NEED TO BE CONSIDERED WHEN AIMING TO PROVIDE A SUSTAINABLE WORKING LIFE FOR THE INCREASING NUMBERS OF OLDER WORKERS IN MODERN SOCIETY THE THEORETICAL MODEL DEVELOPED IS A CONTRIBUTION TO THE CRITICAL DEBATE THAT CAN BE APPLIED BY SOCIETIES, EMPLOYERS AND MANAGERS IN ORDER TO PROVIDE OLDER WORKERS WITH AN INCLUSIVE AND SUSTAINABLE EXTENDED WORKING LIFE. PMID- 26976391 TI - Erratum to: The 5As team intervention: bridging the knowledge gap in obesity management among primary care practitioners. PMID- 26976392 TI - Detrimental cross-talk between sepsis and acute kidney injury: new pathogenic mechanisms, early biomarkers and targeted therapies. AB - This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901. PMID- 26976393 TI - Evidence for Health III: Making evidence-informed decisions that integrate values and context. AB - Making evidence-informed decisions with the aim of improving the health of individuals or populations can be facilitated by using a systematic approach. While a number of algorithms already exist, and while there is no single 'right' way of summarizing or ordering the various elements that should be involved in making such health-related decisions, an algorithm is presented here that lays out many of the key issues that should be considered, and which adds a special emphasis on balancing the values of individual patients and entire populations, as well as the importance of incorporating contextual considerations. Indeed many different types of evidence and value judgements are needed during the decision making process to answer a wide range of questions, including (1) What is the priority health problem? (2) What causes this health problem? (3) What are the different strategies or interventions that can be used to address this health problem? (4) Which of these options, as compared to the status quo, has an added benefit that outweighs the harms? (5) Which options would be acceptable to the individuals or populations involved? (6) What are the costs and opportunity costs? (7) Would these options be feasible and sustainable in this specific context? (8) What are the ethical, legal and social implications of choosing one option over another? (9) What do different stakeholders stand to gain or lose from each option? and (10) Taking into account the multiple perspectives and considerations involved, which option is most likely to improve health while minimizing harms? This third and final article in the 'Evidence for Health' series will go through each of the steps in the algorithm in greater detail to promote more evidence-informed decisions that aim to improve health and reduce inequities. PMID- 26976394 TI - Addressing Intimate Partner Violence: Reducing Barriers and Improving Residents' Attitudes, Knowledge, and Practices. AB - OBJECTIVE: This study aims to assess residents' attitudes, knowledge, practices, and barriers in addressing intimate partner violence and create a curriculum targeting self-identified deficits. METHODS: The authors developed and distributed a survey to residents across multiple specialties at a large academic institution. A workshop was developed using obstetrics/gynecology residents' data, with post-intervention data collected to assess for changes. RESULTS: One hundred forty-seven residents (41 %) completed the survey. Though all identified assessing intimate partner violence as physicians' responsibility, only 40 % reported consistent screening with new female patients, 36 % with pregnant patients, and 18 % with post-partum patients. Half reported inadequate training and felt unprepared to counsel patients regarding intimate partner violence. Post intervention data suggest gains in knowledge and perceived preparedness. CONCLUSIONS: Although residents appreciate the significance of intimate partner violence assessment, in this particular institution few consistently perform or feel comfortable screening. Development of comprehensive intimate partner violence curricula is therefore critical. PMID- 26976396 TI - Developing a Mental Health Curriculum to Build Capacity and Improve Access to Mental Health Care in Rural Guatemala. PMID- 26976395 TI - Proposed Training Areas for Global Mental Health Researchers. PMID- 26976397 TI - Contract Negotiation for Academic Psychiatrists. PMID- 26976398 TI - Entrustable Professional Activities: Enhancing Meaningful Use of Evaluations and Milestones in a Psychiatry Residency Program. PMID- 26976399 TI - Attitudes Towards Substance Use Disorders and Association with Motivational Interviewing Education: A Survey of Psychiatry Chief Residents. PMID- 26976400 TI - Using Meaningful Outcomes to Differentiate Change from Innovation in Medical Education. PMID- 26976402 TI - Inadequate Sleep and Exercise Associated with Burnout and Depression Among Medical Students. AB - OBJECTIVE: The authors studied whether low levels of exercise or inadequate sleep correlated with higher levels of burnout and depression in medical students. METHODS: Medical students of all years at the University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, were invited to participate in an anonymous online survey in Fall 2012 and Winter 2013. Validated measures were used to assess exercise, sleep, burnout, and depression. RESULTS: Response rates were 28.7 % at the beginning of the school year and 22.6 % at the middle of the school year. Burnout rates overall were 22.4 % at the beginning of the year and 19.2 % in the middle of the year. Eight percent of students screened positive for depression at the beginning of the year and 9.3 % in the middle of the year. Decreased exercise frequency was significantly correlated with lower professional efficacy. Pathological sleepiness was significantly associated with a higher prevalence of burnout. Inadequate sleep correlated with significantly lower professional efficacy and higher exhaustion scores. Burnout was associated with a positive depression screen. Positive depression screening, pathological sleepiness, and sleeping less than 7 h a night were independent predictors of burnout. CONCLUSIONS: Sleep habits, exercise, and a positive depression screen were associated with burnout risk within the medical student population. PMID- 26976401 TI - Evaluation of Branched-Narrative Virtual Patients for Interprofessional Education of Psychiatry Residents. AB - OBJECTIVE: This pilot study evaluated the utility of branched-narrative virtual patients in an interprofessional education series for psychiatry residents. METHODS: Third-year psychiatry residents attended four interprofessional education advanced psychopharmacology sessions that involved completion of a branched-narrative virtual patient and a debriefing session with a psychiatric pharmacist. Pre- and post-assessments analyzed resident learning and were administered around each virtual patient. Simulation 4 served as a comprehensive review. The primary outcome was differences in pre- and post-assessment scores. Secondary outcomes included resident satisfaction with the virtual patient format and psychiatric pharmacist involvement. RESULTS: Post-test scores for simulations 1, 2, and 3 demonstrated significant improvement (p < 0.05) from pre-test scores. Scores for simulation 4 did not retain significance. Resident satisfaction with the branched-narrative virtual patient format and psychiatric pharmacist involvement was high throughout the series (100 %; n = 18). CONCLUSIONS: Although there are important methodological limitations to this study including a small sample size and absence of a comparator group, this pilot study supports the use of branched-narrative virtual patients in an interprofessional education series for advanced learners. PMID- 26976403 TI - The Role of the Psychiatry Resident in Integrative Behavioral Care. PMID- 26976404 TI - What Is the Role of Academic Departments of Psychiatry in Advancing Global Mental Health? PMID- 26976405 TI - Forging Steel from Fire: Emerging as a Forensic Psychiatrist. PMID- 26976406 TI - Nosema spp. infections cause no energetic stress in tolerant honeybees. AB - Host-pathogen coevolution leads to reciprocal adaptations, allowing pathogens to increase host exploitation or hosts to minimise costs of infection. As pathogen resistance is often associated with considerable costs, tolerance may be an evolutionary alternative. Here, we examined the effect of two closely related and highly host dependent intracellular gut pathogens, Nosema apis and Nosema ceranae, on the energetic state in Nosema tolerant and sensitive honeybees facing the infection. We quantified the three major haemolymph carbohydrates fructose, glucose, and trehalose using high-performance liquid chromatography (HPLC) as a measure for host energetic state. Trehalose levels in the haemolymph were negatively associated with N. apis infection intensity and with N. ceranae infection regardless of the infection intensity in sensitive honeybees. Nevertheless, there was no such association in Nosema spp. infected tolerant honeybees. These findings suggest that energy availability in tolerant honeybees was not compromised by the infection. This result obtained at the individual level may also have implications at the colony level where workers in spite of a Nosema infection can still perform as well as healthy bees, maintaining colony efficiency and productivity. PMID- 26976407 TI - Evaluation of conventional therapeutic methods versus maggot therapy in the evolution of healing of tegumental injuries in Wistar rats with and without diabetes mellitus. AB - Larval therapy consists on the application of sterilized carrion flies larvae, reared in laboratory, on acute, chronic, and/or infected wounds in order to promote healing. Conventional methods for treating injuries include mechanical debridement or silver-based dressings; however, they are not always effective for wound healing. Larval therapy is a feasible and safe treatment for therapeutic application and, in many cases, the only and the most recommended alternative for difficult healing injuries. Thus, this study aimed to evaluate the competence of Cochliomyia macellaria F. (Diptera: Calliphoridae) as a suitable species for therapeutic application and evaluate time and effectiveness of the types of treatments most commonly used to treat integumental injuries. C. macellaria eggs were obtained from colonies established in laboratory and sterilized prior to application. Twenty-five larvae were applied for each centimeter squared of lesion. Lesions were induced in 24 Wistar rats; type 1 diabetes mellitus was induced in 12 of them. Animals were divided in four groups with three individuals each, being denominated: larval therapy, larval therapy associated with foam dressing with silver release, mechanical debridement with foam dressing silver and control group, without treatment. All treatments were applied once and held for 24 h. Medical application of larvae was found to be safe, as only dead tissue was removed, and efficient to accelerate healing process when compared to other treatments. PMID- 26976408 TI - Reply to M. Minden. PMID- 26976409 TI - Reply to M.C. Chamberlain and T.J. Kruser. PMID- 26976410 TI - Reply to O.O. Eren et al and S. Mikhail. PMID- 26976411 TI - "Does the Punishment Fit the Crime?". PMID- 26976412 TI - Is It Time to Redefine Prognostic and Predictive in Oncology? PMID- 26976413 TI - What Lessons Are Imparted From SWOG S9005 for Recurrent Meningioma? PMID- 26976414 TI - Systemic Therapy in Unresectable Meningioma Before Radiotherapy. PMID- 26976415 TI - Is It Time for Maintenance Chemotherapy for Advanced Gastric Adenocarcinoma? PMID- 26976416 TI - Panel Testing Is Not a Panacea. PMID- 26976417 TI - Can an Acidic Beverage Reduce Interactions Between Proton Pump Inhibitors and Erlotinib? PMID- 26976418 TI - Short Androgen Suppression and Radiation Dose Escalation for Intermediate- and High-Risk Localized Prostate Cancer: Results of EORTC Trial 22991. AB - PURPOSE: Up to 30% of patients who undergo radiation for intermediate- or high risk localized prostate cancer relapse biochemically within 5 years. We assessed if biochemical disease-free survival (DFS) is improved by adding 6 months of androgen suppression (AS; two injections of every-3-months depot of luteinizing hormone-releasing hormone agonist) to primary radiotherapy (RT) for intermediate- or high-risk localized prostate cancer. PATIENTS AND METHODS: A total of 819 patients staged: (1) cT1b-c, with prostate-specific antigen (PSA) >= 10 ng/mL or Gleason >= 7, or (2) cT2a (International Union Against Cancer TNM 1997), with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread, with PSA <= 50 ng/mL, were centrally randomized 1:1 to either RT or RT plus AS started on day 1 of RT. Centers opted for one dose (70, 74, or 78 Gy). Biochemical DFS, the primary end point, was defined from entry until PSA relapse (Phoenix criteria) and clinical relapse by imaging or death of any cause. The trial had 80% power to detect hazard ratio (HR), 0.714 by intent-to-treat analysis stratified by dose of RT at the two-sided alpha = 5%. RESULTS: The median patient age was 70 years. Among patients, 74.8% were intermediate risk and 24.8% were high risk. In the RT arm, 407 of 409 patients received RT; in the RT plus AS arm, 403 patients received RT plus AS and three patients received RT only. At 7.2 years median follow-up, RT plus AS significantly improved biochemical DFS (HR, 0.52; 95% CI, 0.41 to 0.66; P < .001, with 319 events), as well as clinical progression-free survival (205 events, HR, 0.63; 95% CI, 0.48 to 0.84; P = .001). In exploratory analysis, no statistically significant interaction between treatment effect and dose of RT could be evidenced (heterogeneity P = .79 and P = .66, for biochemical DFS and progression-free survival, respectively). Overall survival data are not mature yet. CONCLUSION: Six months of concomitant and adjuvant AS improves biochemical and clinical DFS of intermediate- and high-risk cT1b-c to cT2a (with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread) prostatic carcinoma, treated by radiation. PMID- 26976419 TI - Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. AB - PURPOSE: Testing for germline mutations in BRCA1/2 is standard for select patients with breast cancer to guide clinical management. Next-generation sequencing (NGS) allows testing for mutations in additional breast cancer predisposition genes. The frequency of germline mutations detected by using NGS has been reported in patients with breast cancer who were referred for BRCA1/2 testing or with triple-negative breast cancer. We assessed the frequency and predictors of mutations in 25 cancer predisposition genes, including BRCA1/2, in a sequential series of patients with breast cancer at an academic institution to examine the utility of genetic testing in this population. METHODS: Patients with stages I to III breast cancer who were seen at a single cancer center between 2010 and 2012, and who agreed to participate in research DNA banking, were included (N = 488). Personal and family cancer histories were collected and germline DNA was sequenced with NGS to identify mutations. RESULTS: Deleterious mutations were identified in 10.7% of women, including 6.1% in BRCA1/2 (5.1% in non-Ashkenazi Jewish patients) and 4.6% in other breast/ovarian cancer predisposition genes including CHEK2 (n = 10), ATM (n = 4), BRIP1 (n = 4), and one each in PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2. Whereas young age (P < .01), Ashkenazi Jewish ancestry (P < .01), triple-negative breast cancer (P = .01), and family history of breast/ovarian cancer (P = .01) predicted for BRCA1/2 mutations, no factors predicted for mutations in other breast cancer predisposition genes. CONCLUSION: Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group. Additional cohorts will be helpful to define individuals at higher risk of carrying mutations in genes other than BRCA1/2. PMID- 26976420 TI - International Myeloma Working Group Recommendations for the Diagnosis and Management of Myeloma-Related Renal Impairment. AB - PURPOSE: The aim of the International Myeloma Working Group was to develop practical recommendations for the diagnosis and management of multiple myeloma related renal impairment (RI). METHODS: Recommendations were based on published data through December 2015, and were developed using the system developed by the Grading of Recommendation, Assessment, Development, and Evaluation Working Group. RECOMMENDATIONS: All patients with myeloma at diagnosis and at disease assessment should have serum creatinine, estimated glomerular filtration rate, and electrolytes measurements as well as free light chain, if available, and urine electrophoresis of a sample from a 24-hour urine collection (grade A). The Chronic Kidney Disease Epidemiology Collaboration, preferably, or the Modification of Diet in Renal Disease formula should be used for the evaluation of estimated glomerular filtration rate in patients with stabilized serum creatinine (grade A). International Myeloma Working Group criteria for renal reversibility should be used (grade B). For the management of RI in patients with multiple myeloma, high fluid intake is indicated along with antimyeloma therapy (grade B). The use of high-cutoff hemodialysis membranes in combination with antimyeloma therapy can be considered (grade B). Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI (grade A). High-dose dexamethasone should be administered at least for the first month of therapy (grade B). Thalidomide is effective in patients with myeloma with RI, and no dose modifications are needed (grade B). Lenalidomide is effective and safe, mainly in patients with mild to moderate RI (grade B); for patients with severe RI or on dialysis, lenalidomide should be given with close monitoring for hematologic toxicity (grade B) with dose reduction as needed. High-dose therapy with autologous stem cell transplantation (with melphalan 100 mg/m(2) to 140 mg/m(2)) is feasible in patients with RI (grade C). Carfilzomib can be safely administered to patients with creatinine clearance > 15 mL/min, whereas ixazomib in combination with lenalidomide and dexamethasone can be safely administered to patients with creatinine clearance > 30 mL/min (grade A). PMID- 26976421 TI - Weighing the Addition of Androgen Suppression Therapy to Radiotherapy Dose Escalation for Intermediate-Risk Prostate Cancer. PMID- 26976422 TI - Contemporary Locoregional Recurrence Rates in Young Patients With Early-Stage Breast Cancer. AB - PURPOSE: The aim of this study was to evaluate contemporary rates of local recurrence (LR) and regional recurrence (RR) in young patients with breast cancer in relation to tumor biology as expressed by biomarker subtypes. PATIENTS AND METHODS: Women < 35 years of age who underwent surgery for primary unilateral invasive breast cancer between 2003 and 2008 were selected from the Netherlands Cancer Registry. Patients were categorized according to biomarker subtypes on the basis of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. The 5-year risks of developing LR and regional lymph node recurrence were estimated by using Kaplan-Meier statistics. RESULTS: A total of 1,000 patients were identified, of whom 59% had a known subtype: 39% HR positive/HER2-negative; 17% HR-positive/HER2-positive; 10% HR-negative/HER2 positive; and 34% HR-negative/HER2-negative (triple negative). Overall 5-year LR and RR rates were 3.5% and 3.7%, respectively. A decreasing trend for both rates was observed over time and was accompanied by a significant decrease in the risk of distant metastases (DM). LR occurred in 4.2%, RR in 6.1%, and DM in 17.8% of patients in 2003, and in 3.2%, 4.4%, and 10.0%, respectively, in 2008. LR and RR rates varied with biomarker subtype. These differences were borderline significant when analyzed for the entire study period (P = .056 and P = .014, respectively) and leveled off after the introduction of trastuzumab after 2005 (P = .24 and P = .42, respectively). Patients with lymph node metastases at the time of diagnosis had an increased risk of RR. The type of surgery performed-breast conserving or mastectomy-did not influence rates of LR and RR. CONCLUSION: Overall, the rates of LR and RR in young patients with early-stage breast cancer were relatively low and varied by biomarker subtype. PMID- 26976424 TI - Phase II Trial of Temsirolimus for Relapsed/Refractory Primary CNS Lymphoma. AB - PURPOSE: In this phase II study (NCT00942747), temsirolimus was tested in patients with relapsed or refractory primary CNS lymphoma (PCNSL). PATIENTS AND METHODS: Immunocompetent adults with histologically confirmed PCNSL after experiencing high-dose methotrexate-based chemotherapy failure who were not eligible for or had experienced high-dose chemotherapy with autologous stem-cell transplant failure were included. The first cohort (n = 6) received 25 mg temsirolimus intravenously once per week. All consecutive patients received 75 mg intravenously once per week. RESULTS: Thirty-seven eligible patients (median age, 70 years) were included whose median time since their last treatment was 3.9 months (range, 0.1 to 14.6 months). Complete response was seen in five patients (13.5%), complete response unconfirmed in three (8%), and partial response in 12 (32.4%) for an overall response rate of 54%. Median progression-free survival was 2.1 months (95% CI, 1.1 to 3.0 months). The most frequent Common Toxicity Criteria >= 3 degrees adverse event was hyperglycemia in 11 (29.7%) patients, thrombocytopenia in eight (21.6%), infection in seven (19%), anemia in four (10.8%), and rash in three (8.1%). Fourteen blood/CSF pairs were collected in nine patients (10 pairs in five patients in the 25-mg cohort and four pairs in four patients in the 75-mg cohort). The mean maximum blood concentration was 292 ng/mL for temsirolimus and 37.2 ng/mL for its metabolite sirolimus in the 25-mg cohort and 484 ng/mL and 91.1 ng/mL, respectively, in the 75-mg cohort. Temsirolimus CSF concentration was 2 ng/mL in one patient in the 75-mg cohort; in all others, no drug was found in their CSF. CONCLUSION: Single-agent temsirolimus at a weekly dose of 75 mg was found to be active in relapsed/refractory patients with PCNSL; however, responses were usually short lived. PMID- 26976423 TI - Bevacizumab Plus Irinotecan Versus Temozolomide in Newly Diagnosed O6 Methylguanine-DNA Methyltransferase Nonmethylated Glioblastoma: The Randomized GLARIUS Trial. AB - PURPOSE: In patients with newly diagnosed glioblastoma that harbors a nonmethylated O(6)-methylguanine-DNA methyltransferase promotor, standard temozolomide (TMZ) has, at best, limited efficacy. The GLARIUS trial thus explored bevacizumab plus irinotecan (BEV+IRI) as an alternative to TMZ. PATIENTS AND METHODS: In this phase II, unblinded trial 182 patients in 22 centers were randomly assigned 2:1 to BEV (10 mg/kg every 2 weeks) during radiotherapy (RT) followed by maintenance BEV (10 mg/kg every 2 weeks) plus IRI(125 mg/m(2) every 2 weeks) or to daily TMZ (75 mg/m(2)) during RT followed by six courses of TMZ (150 200 mg/m(2)/d for 5 days every 4 weeks). The primary end point was the progression-free survival rate after 6 months (PFS-6). RESULTS: In the modified intention-to-treat (ITT) population, PFS-6 was increased from 42.6% with TMZ (95% CI, 29.4% to 55.8%) to 79.3% with BEV+IRI (95% CI, 71.9% to 86.7%; P <.001). PFS was prolonged from a median of 5.99 months (95% CI, 2.7 to 7.3 months) to 9.7 months (95% CI, 8.7 to 10.8 months; P < .001). At progression, crossover BEV therapy was given to 81.8% of all patients who received any sort of second-line therapy in the TMZ arm. Overall survival (OS) was not different in the two arms: the median OS was 16.6 months (95% CI, 15.4 to 18.4 months) with BEV+IRI and was 17.5 months (95% CI, 15.1 to 20.5 months) with TMZ. The time course of quality of life (QOL) in six selected domains of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ) -C30 and QLQ-BN20 (which included cognitive functioning), of the Karnofsky performance score, and of the Mini Mental State Examination score was not different between the treatment arms. CONCLUSION: BEV+IRI resulted in a superior PFS-6 rate and median PFS compared with TMZ. However, BEV+IRI did not improve OS, potentially because of the high crossover rate. BEV+IRI did not alter QOL compared with TMZ. PMID- 26976425 TI - Efficacy and Biomarker Study of Bevacizumab for Hearing Loss Resulting From Neurofibromatosis Type 2-Associated Vestibular Schwannomas. AB - PURPOSE: Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by bilateral vestibular schwannomas (VSs) resulting in deafness and brainstem compression. This study evaluated efficacy and biomarkers of bevacizumab activity for NF2-associated progressive and symptomatic VSs. PATIENTS AND METHODS: Bevacizumab 7.5 mg/kg was administered every 3 weeks for 46 weeks, followed by 24 weeks of surveillance after treatment with the drug. The primary end point was hearing response defined by word recognition score (WRS). Secondary end points included toxicity, tolerability, imaging response using volumetric magnetic resonance imaging analysis, durability of response, and imaging and blood biomarkers. RESULTS: Fourteen patients (estimated to yield > 90% power to detect an alternative response rate of 50% at alpha level of 0.05) with NF2, with a median age of 30 years (range, 14 to 79 years) and progressive hearing loss in the target ear (median baseline WRS, 60%; range 13% to 82%), were enrolled. The primary end point, confirmed hearing response (improvement maintained >= 3 months), occurred in five (36%) of 14 patients (95% CI, 13% to 65%; P < .001). Eight (57%) of 14 patients had transient hearing improvement above the 95% CI for WRS. No patients experienced hearing decline. Radiographic response was seen in six (43%) of 14 target VSs. Three grade 3 adverse events, hypertension (n = 2) and immune-mediated thrombocytopenic purpura (n = 1), were possibly related to bevacizumab. Bevacizumab treatment was associated with decreased free vascular endothelial growth factor (not bound to bevacizumab) and increased placental growth factor in plasma. Hearing responses were inversely associated with baseline plasma hepatocyte growth factor (P = .019). Imaging responses were associated with high baseline tumor vessel permeability and elevated blood levels of vascular endothelial growth factor D and stromal cell-derived factor 1alpha (P = .037 and .025, respectively). CONCLUSION: Bevacizumab treatment resulted in durable hearing response in 36% of patients with NF2 and confirmed progressive VS associated hearing loss. Imaging and plasma biomarkers showed promising associations with response that should be validated in larger studies. PMID- 26976428 TI - Nanostructured Bi2Te3 Prepared by a Straightforward Arc-Melting Method. AB - Thermoelectric materials constitute an alternative source of sustainable energy, harvested from waste heat. Bi2Te3 is the most utilized thermoelectric alloy. We show that it can be readily prepared in nanostructured form by arc-melting synthesis, yielding mechanically robust pellets of highly oriented polycrystals. This material has been characterized by neutron powder diffraction (NPD), scanning electron microscopy (SEM), and electronic and thermal transport measurements. A microscopic analysis from NPD data demonstrates a near-perfect stoichiometry of Bi2Te3 and a fair amount of anharmonicity of the chemical bonds. The as-grown material presents a metallic behavior, showing a record-low resistivity at 320 K of 2 MUOmega m, which is advantageous for its performance as a thermoelectric material. SEM analysis shows a stacking of nanosized sheets, each of them presumably single-crystalline, with large surfaces perpendicular to the c crystallographic axis. This nanostructuration notably affects the thermoelectric properties, involving many surface boundaries that are responsible for large phonon scattering factors, yielding a thermal conductivity as low as 1.2 W m(-1) K(-1) around room temperature. PMID- 26976427 TI - Clinical course and outcomes of diagnosing Inflammatory Bowel Disease in children 10 years and under: retrospective cohort study from two tertiary centres in the United Kingdom and in Italy. AB - BACKGROUND: Most children with Inflammatory Bowel Disease (IBD) are diagnosed between 11 and 16 years of age, commonly presenting with features of typical IBD. Children with onset of gut inflammation under 5 years of age often have a different underlying pathophysiology, one that is genetically and phenotypically distinct from other children with IBD. We therefore set out to assess whether children diagnosed after the age of 5 years, but before the age of 11, have a different clinical presentation and outcome when compared to those presenting later. METHODS: Retrospective cohort study conducted at two European Paediatric Gastroenterology Units. Two cohorts of children with IBD (total number = 160) were compared: 80 children diagnosed between 5 and 10 years (Group A), versus 80 children diagnosed between 11 and 16 (Group B). Statistical analysis included multiple logistic regression. RESULTS: Group A presented with a greater disease activity (p = 0.05 for Crohn's disease (CD), p = 0.03 for Ulcerative Colitis (UC); Odds Ratio 1.09, 95 % Confidence Interval: 1.02-1.1), and disease extent (L2 location more frequent amongst Group A children with CD (p = 0.05)). No significant differences were observed between age groups in terms of gastro intestinal and extra-intestinal signs and symptoms at disease presentation, nor was there a difference in the number of hospitalisations due to relapsing IBD during follow-up. However, children in Group A were treated earlier with immunosuppressants and had more frequent endoscopic assessments. CONCLUSION: While clinicians feel children between 5 and 10 years of age have a more severe disease course than adolescents, our analysis also suggests a greater disease burden in this age group. Nevertheless, randomized trials to document longer-term clinical outcomes are urgently needed, in order to address the question whether a younger age at disease onset should prompt per se a more "aggressive" treatment. We speculate that non-clinical factors (e.g. genetics, epigenetics) may have more potential to predict longer term outcome than simple clinical measures such as age at diagnosis. PMID- 26976426 TI - Phase II Randomized Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole Compared With Anastrozole Alone in Patients With Estrogen Receptor-Positive Breast Cancer. AB - PURPOSE: Preclinical data support a key role for the PI3K pathway in estrogen receptor-positive breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. This preoperative window study assessed whether adding the PI3K inhibitor pictilisib (GDC-0941) can increase the antitumor effects of anastrozole in primary breast cancer and aimed to identify the most appropriate patient population for combination therapy. PATIENTS AND METHODS: In this randomized, open-label phase II trial, postmenopausal women with newly diagnosed operable estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers were recruited. Participants were randomly allocated (2:1, favoring the combination) to 2 weeks of preoperative treatment with anastrozole 1 mg once per day (n = 26) or the combination of anastrozole 1 mg with pictilisib 260 mg once per day (n = 49). The primary end point was inhibition of tumor cell proliferation as measured by change in Ki-67 protein expression between tumor samples taken before and at the end of treatment. RESULTS: There was significantly greater geometric mean Ki-67 suppression of 83.8% (one-sided 95% CI, >= 79.0%) for the combination and 66.0% (95% CI, <= 75.4%) for anastrozole (geometric mean ratio [combination:anastrozole], 0.48; 95% CI, <= 0.72; P = .004). PIK3CA mutations were not predictive of response to pictilisib, but there was significant interaction between response to treatment and molecular subtype (P = .03); for patients with luminal B tumors, the combination:anastrozole geometric mean ratio of Ki-67 suppression was 0.37 (95% CI, <= 0.67; P = .008), whereas no significant Ki-67 response was observed for pictilisib in luminal A tumors (1.01; P = .98). Multivariable analysis confirmed Ki-67 response to the combination treatment of patients with luminal B tumors irrespective of progesterone receptor status or baseline Ki-67 expression. CONCLUSION: Adding pictilisib to anastrozole significantly increases suppression of tumor cell proliferation in luminal B primary breast cancer. PMID- 26976429 TI - Large Area Nano-transfer Printing of Sub-50-nm Metal Nanostructures Using Low cost Semi-flexible Hybrid Templates. AB - In this work, we present a method for printing metal micro- and nanopatterns down to sub-50-nm feature sizes using replicated, defect-tolerant stamps made out of OrmoStamp(r); material. The relevant parameters for a successful transfer over large areas were investigated and yields above 99 % have been achieved. Comparing our results to conventional nano-transfer printing using PDMS stamps, we find that the more rigid hybrid polymer used here prevents unintended transfer from interspaces between structures of large distance due to roof collapse and deformation of nano-sized structures due to lateral collapse. Yet, our stamps are flexible enough to ensure intimate contact with the underlying substrate over large areas even in the presence of defect particles. Additionally, the presented patterning technique is resist-, solvent-, and chemical-free and is therefore ideally suited for applications in organic nanoelectronics where standard nanostructuring methods can harm or destroy the organic material. PMID- 26976430 TI - Expression, purification and characterization of a vascular endothelial growth factor fusion protein. AB - OBJECTIVES: To prepare recombinant tPep-(vascular endothelial growth factor) VEGF B and assess its biological activity. RESULTS: This new VEGF fusion protein was constructed using a targeting peptide and prepared using E.coli. The tPep-VEGF-B was refolded from inclusion bodies and purified using affinity chromatography. Its bioactivity was determined in vitro using proliferation assay and wounding healing assay, and in vivo in zebrafish. By using the optimized downstream process, recombinant tPep-VEGF-B can be obtained with a purity of >90 % and a yield of 80 mg protein/l culture medium. The refolded protein is highly effective in promoting cell migration in vitro and in enhancing angiogenesis in vivo. CONCLUSION: We have constructed a new VEGF fusion protein with potential therapeutic application in treating metabolic diseases. PMID- 26976431 TI - Impact of transduction towards the proliferation and migration as well as the transduction efficiency of human umbilical cord-derived late endothelial progenitor cells with nine recombinant adeno-associated virus serotypes. AB - OBJECTIVES: To evaluate the transduction efficiency of human umbilical cord derived, late endothelial progenitor cells late (HUCB-late EPCs) with nine recombinant adeno-associated virus (rAAV) serotypes and the ability of proliferation and migration of the cells after transduction. RESULTS: rAAV2 and rAAV6 showed a greater ability than other serotypes to transduce late EPCs (P < 0.05). After transduction, cell proliferation ability weakened (P < 0.05), but the ability of migration to stromal cell-derived factor (SDF-1) unchanged. CONCLUSION: There is an advantage of choosing the optimal rAAV serotype as a gene vector to alter the biologic characteristics of late EPCs. PMID- 26976433 TI - An Evaluation of Two Dating Violence Prevention Programs on a College Campus. AB - Dating violence is a serious and prevalent public health problem that is associated with numerous negative physical and psychological health outcomes, and yet there has been limited evaluation of prevention programs on college campuses. A recent innovation in campus prevention focuses on mobilizing bystanders to take action. To date, bystander programs have mainly been compared with no treatment control groups raising questions about what value is added to dating violence prevention by focusing on bystanders. This study compared a single 90-min bystander education program for dating violence prevention with a traditional awareness education program, as well as with a no education control group. Using a quasi-experimental pre-test/post-test design with follow-up at 2 months, a sample of predominately freshmen college students was randomized to either the bystander ( n = 369) or traditional awareness ( n = 376) dating violence education program. A non-randomized control group of freshmen students who did not receive any education were also surveyed ( n = 224). Students completed measures of attitudes, including rape myth acceptance, bystander efficacy, and intent to help as well as behavioral measures related to bystander action and victimization. Results showed that the bystander education program was more effective at changing attitudes, beliefs, efficacy, intentions, and self-reported behaviors compared with the traditional awareness education program. Both programs were significantly more effective than no education. The findings of this study have important implications for future dating violence prevention educational programming, emphasizing the value of bystander education programs for primary dating violence prevention among college students. PMID- 26976432 TI - Acetylcarnitine Is a Candidate Diagnostic and Prognostic Biomarker of Hepatocellular Carcinoma. AB - The identification of serum biomarkers to improve the diagnosis and prognosis of hepatocellular carcinoma has been elusive to date. In this study, we took a mass spectroscopic approach to characterize metabolic features of the liver in hepatocellular carcinoma patients to discover more sensitive and specific biomarkers for diagnosis and progression. Global metabolic profiling of 50 pairs of matched liver tissue samples from hepatocellular carcinoma patients was performed. A series of 62 metabolites were found to be altered significantly in liver tumors; however, levels of acetylcarnitine correlated most strongly with tumor grade and could discriminate between hepatocellular carcinoma tumors and matched normal tissues. Post hoc analysis to evaluate serum diagnosis and progression potential further confirmed the diagnostic capability of serum acetylcarnitine. Finally, an external validation in an independent batch of 58 serum samples (18 hepatocellular carcinoma patients, 20 liver cirrhosis patients, and 20 healthy individuals) verified that serum acetylcarnitine was a meaningful biomarker reflecting hepatocellular carcinoma diagnosis and progression. These findings present a strong new candidate biomarker for hepatocellular carcinoma with potentially significant diagnostic and prognostic capabilities. Cancer Res; 76(10); 2912-20. (c)2016 AACR. PMID- 26976435 TI - The Faces on Our Educational Materials: Real Stories behind the Messages. AB - This article considers how cancer education research programs affect the lives of research participants in terms of their cancer screening and diagnosis experiences. Using examples from research with Latina immigrant women in rural Georgia and Quechua women in rural Andean Peru, the author explains how cervical cancer education research can produce meaningful and empowering change in women's lives. PMID- 26976434 TI - Breast Cancer Patients' Preferences for Adjuvant Radiotherapy Post Lumpectomy: Whole Breast Irradiation vs. Partial Breast Irradiation-Single Institutional Study. AB - This study was conducted to elucidate patients with early breast cancer preference for standard whole breast irradiation (WBI) or partial breast irradiation (PBI) following lumpectomy, as well as identify important factors for patients when making their treatment decisions. Based on relevant literature and ASTRO consensus statement guidelines, an educational tool and questionnaire were developed. Consenting, eligible women reviewed the educational tool and completed the trade-off questionnaire. Descriptive statistics were calculated, as well as chi-squares and a logistic regression model. Of the 90 patients who completed the study, 62 % preferred WBI, 30 % preferred PBI, 4 % required more information, and 3 % had no preferences. Of the patients who chose WBI, 58 % preferred hypofractionated RT, whereas 25 % preferred the conventional RT regimen. The majority of patients rated recurrence rate [WBI = 55/55 (100 %), PBI = 26/26 (100 %)] and survival [WBI = 54/55 (98 %), PBI = 26/26 (100 %)] as important factors contributing to their choice of treatment preference. Financial factors [WBI = 21/55 (38 %), PBI = 14/26 (53 %)] and convenience [WBI = 36/54 (67 %), PBI = 18/26 (69 %)] were rated as important less frequently. Significantly, more patients who preferred WBI also rated standard method of treatment as important when compared to patients who preferred PBI [WBI = 52/54 (96 %), PBI = 16/26 (61 %), chi 2 = 16.63, p = 0.001]. The majority of patients with early breast cancer who were surveyed for this study preferred WBI as an adjuvant treatment post lumpectomy, yet there was a sizeable minority who preferred PBI. This was associated with the importance patients place on standard treatment. These results will help medical professionals treat patients according to patient values. PMID- 26976436 TI - Development and Evaluation of a Hematology-Oriented Clinical Research Training Program in Latin America. AB - The objectives of the study were to describe the development of a patient oriented clinical research training program in a low- or middle-income country (LMIC) setting, to describe perceived benefits of the program and barriers to application, and to make recommendations for future training programs. The program was developed by the American Society of Hematology in collaboration with Latin American stakeholders and clinical researchers. Session types were didactic, small group, and one-on-one faculty/participant dyad formats. Outcomes were assessed by quantitative surveys of trainees and qualitative feedback from both trainees and faculty members. The program is an annual 2-day course specifically for Latin American hematologists. Through course evaluations, all trainees described that the didactic sessions were relevant. All session types were useful for gaining knowledge and skills, particularly one-on-one meetings. The potential for networking was highly valued. Barriers to trainee applications were the concerns that skill level, proposed research program, and knowledge of English were not sufficiently strong to warrant acceptance into the course, and financial costs of attendance. We have described the development and initial evaluation of a clinical research training program in a LMIC setting. We learned several valuable lessons that are applicable to other research training programs. PMID- 26976438 TI - Gene Regulatory Evolution During Speciation in a Songbird. AB - Over the last decade, tremendous progress has been made toward a comparative understanding of gene regulatory evolution. However, we know little about how gene regulation evolves in birds, and how divergent genomes interact in their hybrids. Because of the unique features of birds - female heterogamety, a highly conserved karyotype, and the slow evolution of reproductive incompatibilities - an understanding of regulatory evolution in birds is critical to a comprehensive understanding of regulatory evolution and its implications for speciation. Using a novel complement of analyses of replicated RNA-seq libraries, we demonstrate abundant divergence in brain gene expression between zebra finch (Taeniopygia guttata) subspecies. By comparing parental populations and their F1 hybrids, we also show that gene misexpression is relatively rare among brain-expressed transcripts in male birds. If this pattern is consistent across tissues and sexes, it may partially explain the slow buildup of postzygotic reproductive isolation observed in birds relative to other taxa. Although we expected that the action of genetic drift on the island-dwelling zebra finch subspecies would be manifested in a higher rate of trans regulatory divergence, we found that most divergence was in cis regulation, following a pattern commonly observed in other taxa. Thus, our study highlights both unique and shared features of avian regulatory evolution. PMID- 26976437 TI - A Forward Genetic Screen for Molecules Involved in Pheromone-Induced Dauer Formation in Caenorhabditis elegans. AB - Animals must constantly assess their surroundings and integrate sensory cues to make appropriate behavioral and developmental decisions. Pheromones produced by conspecific individuals provide critical information regarding environmental conditions. Ascaroside pheromone concentration and composition are instructive in the decision of Caenorhabditis elegans to either develop into a reproductive adult or enter into the stress-resistant alternate dauer developmental stage. Pheromones are sensed by a small set of sensory neurons, and integrated with additional environmental cues, to regulate neuroendocrine signaling and dauer formation. To identify molecules required for pheromone-induced dauer formation, we performed an unbiased forward genetic screen and identified phd (pheromone response-defective dauer) mutants. Here, we describe new roles in dauer formation for previously identified neuronal molecules such as the WD40 domain protein QUI 1 and MACO-1 Macoilin, report new roles for nociceptive neurons in modulating pheromone-induced dauer formation, and identify tau tubulin kinases as new genes involved in dauer formation. Thus, phd mutants define loci required for the detection, transmission, or integration of pheromone signals in the regulation of dauer formation. PMID- 26976439 TI - Patterns of Transcriptional Response to 1,25-Dihydroxyvitamin D3 and Bacterial Lipopolysaccharide in Primary Human Monocytes. AB - The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), plays an important immunomodulatory role, regulating transcription of genes in the innate and adaptive immune system. The present study examines patterns of transcriptome wide response to 1,25D, and the bacterial lipopolysaccharide (LPS) in primary human monocytes, to elucidate pathways underlying the effects of 1,25D on the immune system. Monocytes obtained from healthy individuals of African-American and European-American ancestry were treated with 1,25D, LPS, or both, simultaneously. The addition of 1,25D during stimulation with LPS induced significant upregulation of genes in the antimicrobial and autophagy pathways, and downregulation of proinflammatory response genes compared to LPS treatment alone. A joint Bayesian analysis enabled clustering of genes into patterns of shared transcriptional response across treatments. The biological pathways enriched within these expression patterns highlighted several mechanisms through which 1,25D could exert its immunomodulatory role. Pathways such as mTOR signaling, EIF2 signaling, IL-8 signaling, and Tec Kinase signaling were enriched among genes with opposite transcriptional responses to 1,25D and LPS, respectively, highlighting the important roles of these pathways in mediating the immunomodulatory activity of 1,25D. Furthermore, a subset of genes with evidence of interethnic differences in transcriptional response was also identified, suggesting that in addition to the well-established interethnic variation in circulating levels of vitamin D, the intensity of transcriptional response to 1,25D and LPS also varies between ethnic groups. We propose that dysregulation of the pathways identified in this study could contribute to immune-mediated disease risk. PMID- 26976440 TI - Preparing for Winter: The Transcriptomic Response Associated with Different Day Lengths in Drosophila montana. AB - At northern latitudes, the most robust cue for assessing the onset of winter is the shortening of day lengths. Many species use day length as a cue to increase their cold tolerance and/or enter into diapause, but little is known about changes in gene expression that occur under different day lengths. We investigate the gene expression changes associated with differences in light/dark cycles in Drosophila montana, a northerly distributed species with a strong adult photoperiodic reproductive diapause. To examine gene expression changes induced by light both prior to and during diapause, we used both nondiapausing and diapausing flies. We found that the majority of genes that are differentially expressed between different day lengths in nondiapausing and diapausing flies differ. However, the biological processes involved were broadly similar. These included neuron development and metabolism, which are largely consistent with an increase in cold tolerance previously observed to occur in these flies. We also found that many genes associated with reproduction change in expression level between different day lengths, suggesting that D. montana use changes in day length to cue changes in reproduction both before and after entering into diapause. Finally, we also identified several interesting candidate genes for light-induced changes including Lsp2, para, and Ih. PMID- 26976441 TI - The HIST1 Locus Escapes Reprogramming in Cloned Bovine Embryos. AB - Epigenetic reprogramming is necessary in somatic cell nuclear transfer (SCNT) embryos in order to erase the differentiation-associated epigenetic marks of donor cells. However, such epigenetic memories often persist throughout the course of clonal development, thus decreasing cloning efficiency. Here, we explored reprogramming-refractory regions in bovine SCNT blastocyst transcriptomes. We observed that histone genes residing in the 1.5 Mb spanning the cow HIST1 cluster were coordinately downregulated in SCNT blastocysts. In contrast, both the nonhistone genes of this cluster, and histone genes elsewhere remained unaffected. This indicated that the downregulation was specific to HIST1 histone genes. We found that, after trichostatin A treatment, HIST1 histone genes were derepressed, and DNA methylation at their promoters was decreased to the level of in vitro fertilization embryos. Therefore, our results indicate that the reduced expression of HIST1 histone genes is a consequence of poor epigenetic reprogramming in SCNT blastocysts. PMID- 26976442 TI - Multiple Targets on the Gln3 Transcription Activator Are Cumulatively Required for Control of Its Cytoplasmic Sequestration. AB - A remarkable characteristic of nutritional homeostatic mechanisms is the breadth of metabolite concentrations to which they respond, and the resolution of those responses; adequate but rarely excessive. Two general ways of achieving such exquisite control are known: stoichiometric mechanisms where increasing metabolite concentrations elicit proportionally increasing responses, and the actions of multiple independent metabolic signals that cumulatively generate appropriately measured responses. Intracellular localization of the nitrogen responsive transcription activator, Gln3, responds to four distinct nitrogen environments: nitrogen limitation or short-term starvation, i.e., nitrogen catabolite repression (NCR), long-term starvation, glutamine starvation, and rapamycin inhibition of mTorC1. We have previously identified unique sites in Gln3 required for rapamycin-responsiveness, and Gln3-mTor1 interaction. Alteration of the latter results in loss of about 50% of cytoplasmic Gln3 sequestration. However, except for the Ure2-binding domain, no evidence exists for a Gln3 site responsible for the remaining cytoplasmic Gln3-Myc(13) sequestration in nitrogen excess. Here, we identify a serine/threonine-rich (Gln3477-493) region required for effective cytoplasmic Gln3-Myc(13) sequestration in excess nitrogen. Substitutions of alanine but not aspartate for serines in this peptide partially abolish cytoplasmic Gln3 sequestration. Importantly, these alterations have no effect on the responses of Gln3-Myc(13) to rapamycin, methionine sulfoximine, or limiting nitrogen. However, cytoplasmic Gln3-Myc(13) sequestration is additively, and almost completely, abolished when mutations in the Gln3-Tor1 interaction site are combined with those in Gln3477 493 cytoplasmic sequestration site. These findings clearly demonstrate that multiple individual regulatory pathways cumulatively control cytoplasmic Gln3 sequestration. PMID- 26976443 TI - Genomic Selection in Multi-environment Crop Trials. AB - Genomic selection in crop breeding introduces modeling challenges not found in animal studies. These include the need to accommodate replicate plants for each line, consider spatial variation in field trials, address line by environment interactions, and capture nonadditive effects. Here, we propose a flexible single stage genomic selection approach that resolves these issues. Our linear mixed model incorporates spatial variation through environment-specific terms, and also randomization-based design terms. It considers marker, and marker by environment interactions using ridge regression best linear unbiased prediction to extend genomic selection to multiple environments. Since the approach uses the raw data from line replicates, the line genetic variation is partitioned into marker and nonmarker residual genetic variation (i.e., additive and nonadditive effects). This results in a more precise estimate of marker genetic effects. Using barley height data from trials, in 2 different years, of up to 477 cultivars, we demonstrate that our new genomic selection model improves predictions compared to current models. Analyzing single trials revealed improvements in predictive ability of up to 5.7%. For the multiple environment trial (MET) model, combining both year trials improved predictive ability up to 11.4% compared to a single environment analysis. Benefits were significant even when fewer markers were used. Compared to a single-year standard model run with 3490 markers, our partitioned MET model achieved the same predictive ability using between 500 and 1000 markers depending on the trial. Our approach can be used to increase accuracy and confidence in the selection of the best lines for breeding and/or, to reduce costs by using fewer markers. PMID- 26976445 TI - The "spastic" coronary plaque: dynamic deformation of an atheromatous plaque demonstrated by optical coherence tomography. PMID- 26976444 TI - The Arabidopsis Auxin Receptor F-Box Proteins AFB4 and AFB5 Are Required for Response to the Synthetic Auxin Picloram. AB - The plant hormone auxin is perceived by a family of F-box proteins called the TIR1/AFBs. Phylogenetic studies reveal that these proteins fall into four clades in flowering plants called TIR1, AFB2, AFB4, and AFB6. Genetic studies indicate that members of the TIR1 and AFB2 groups act as positive regulators of auxin signaling by promoting the degradation of the Aux/IAA transcriptional repressors. In this report, we demonstrate that both AFB4 and AFB5 also function as auxin receptors based on in vitro assays. We also provide genetic evidence that AFB4 and AFB5 are targets of the picloram family of auxinic herbicides in addition to indole-3-acetic acid. In contrast to previous studies we find that null afb4 alleles do not exhibit obvious defects in seedling morphology or auxin hypersensitivity. We conclude that AFB4 and AFB5 act in a similar fashion to other members of the family but exhibit a distinct auxin specificity. PMID- 26976446 TI - EMD in periodontal regenerative surgery modulates cytokine profiles: A randomised controlled clinical trial. AB - The enamel matrix derivative (EMD) contains hundreds of peptides in different levels of proteolytic processing that may provide a range of biological effects of importance in wound healing. The aim of the present study was to compare the effect of EMD and its fractions on the cytokine profiles from human gingival fibroblasts in vitro and in gingival crevicular fluid (GCF) in a randomized controlled split-mouth clinical study (n = 12). Levels of cytokines in cell culture medium and in GCF were measured by Luminex over a 2-week period. In the clinical study, levels of pro-inflammatory cytokines and chemokines were increased, whereas the levels of transforming growth factor-alpha (TGF-alpha) and platelet-derived growth factor-BB (PDGF-BB) were reduced. The in vitro study showed that EMD and its high and low molecular weight fractions reduced the secretion of pro-inflammatory cytokines and chemokines compared to untreated cells. EMD had an effect on levels of cytokines related to fibroplasia, angiogenesis, inflammation and chemotaxis both in vitro and in vivo, however, the anti-inflammatory effect induced by EMD observed in the in vitro study could not be confirmed clinically. PMID- 26976448 TI - Modes of surface premelting in colloidal crystals composed of attractive particles. AB - Crystal surfaces typically melt into a thin liquid layer at temperatures slightly below the melting point of the crystal. Such surface premelting is prevalent in all classes of solids and is important in a variety of metallurgical, geological and meteorological phenomena. Premelting has been studied using X-ray diffraction and differential scanning calorimetry, but the lack of single-particle resolution makes it hard to elucidate the underlying mechanisms. Colloids are good model systems for studying phase transitions because the thermal motions of individual micrometre-sized particles can be tracked directly using optical microscopy. Here we use colloidal spheres with tunable attractions to form equilibrium crystal vapour interfaces, and study their surface premelting behaviour at the single particle level. We find that monolayer colloidal crystals exhibit incomplete premelting at their perimeter, with a constant liquid-layer thickness. In contrast, two- and three-layer crystals exhibit conventional complete melting, with the thickness of the surface liquid diverging as the melting point is approached. The microstructures of the surface liquids differ in certain aspects from what would be predicted by conventional premelting theories. Incomplete premelting in the monolayer crystals is triggered by a bulk isostructural solid solid transition and truncated by a mechanical instability that separately induces homogeneous melting within the bulk. This finding is in contrast to the conventional assumption that two-dimensional crystals melt heterogeneously from their free surfaces (that is, at the solid-vapour interface). The unexpected bulk melting that we observe for the monolayer crystals is accompanied by the formation of grain boundaries, which supports a previously proposed grain boundary-mediated two-dimensional melting theory. The observed interplay between surface premelting, bulk melting and solid-solid transitions challenges existing theories of surface premelting and two-dimensional melting. PMID- 26976447 TI - Nuclear DNA sequences from the Middle Pleistocene Sima de los Huesos hominins. AB - A unique assemblage of 28 hominin individuals, found in Sima de los Huesos in the Sierra de Atapuerca in Spain, has recently been dated to approximately 430,000 years ago. An interesting question is how these Middle Pleistocene hominins were related to those who lived in the Late Pleistocene epoch, in particular to Neanderthals in western Eurasia and to Denisovans, a sister group of Neanderthals so far known only from southern Siberia. While the Sima de los Huesos hominins share some derived morphological features with Neanderthals, the mitochondrial genome retrieved from one individual from Sima de los Huesos is more closely related to the mitochondrial DNA of Denisovans than to that of Neanderthals. However, since the mitochondrial DNA does not reveal the full picture of relationships among populations, we have investigated DNA preservation in several individuals found at Sima de los Huesos. Here we recover nuclear DNA sequences from two specimens, which show that the Sima de los Huesos hominins were related to Neanderthals rather than to Denisovans, indicating that the population divergence between Neanderthals and Denisovans predates 430,000 years ago. A mitochondrial DNA recovered from one of the specimens shares the previously described relationship to Denisovan mitochondrial DNAs, suggesting, among other possibilities, that the mitochondrial DNA gene pool of Neanderthals turned over later in their history. PMID- 26976449 TI - Mycocerosic acid synthase exemplifies the architecture of reducing polyketide synthases. AB - Polyketide synthases (PKSs) are biosynthetic factories that produce natural products with important biological and pharmacological activities. Their exceptional product diversity is encoded in a modular architecture. Modular PKSs (modPKSs) catalyse reactions colinear to the order of modules in an assembly line, whereas iterative PKSs (iPKSs) use a single module iteratively as exemplified by fungal iPKSs (fiPKSs). However, in some cases non-colinear iterative action is also observed for modPKSs modules and is controlled by the assembly line environment. PKSs feature a structural and functional separation into a condensing and a modifying region as observed for fatty acid synthases. Despite the outstanding relevance of PKSs, the detailed organization of PKSs with complete fully reducing modifying regions remains elusive. Here we report a hybrid crystal structure of Mycobacterium smegmatis mycocerosic acid synthase based on structures of its condensing and modifying regions. Mycocerosic acid synthase is a fully reducing iPKS, closely related to modPKSs, and the prototype of mycobacterial mycocerosic acid synthase-like PKSs. It is involved in the biosynthesis of C20-C28 branched-chain fatty acids, which are important virulence factors of mycobacteria. Our structural data reveal a dimeric linker-based organization of the modifying region and visualize dynamics and conformational coupling in PKSs. On the basis of comparative small-angle X-ray scattering, the observed modifying region architecture may be common also in modPKSs. The linker based organization provides a rationale for the characteristic variability of PKS modules as a main contributor to product diversity. The comprehensive architectural model enables functional dissection and re-engineering of PKSs. PMID- 26976452 TI - Emergency nurse calls for an end to the use of A&E as a 'place of safety' under the Mental Health Act. AB - A leading emergency nurse is concerned about potential changes to the Mental Health Act that might result in more patients being brought to overstretched emergency departments. PMID- 26976450 TI - Bioavailability of Polycyclic Aromatic Hydrocarbons and their Potential Application in Eco-risk Assessment and Source Apportionment in Urban River Sediment. AB - Traditional risk assessment and source apportionment of sediments based on bulk polycyclic aromatic hydrocarbons (PAHs) can introduce biases due to unknown aging effects in various sediments. We used a mild solvent (hydroxypropyl-beta cyclodextrin) to extract the bioavailable fraction of PAHs (a-PAHs) from sediment samples collected in Pearl River, southern China. We investigated the potential application of this technique for ecological risk assessments and source apportionment. We found that the distribution of PAHs was associated with human activities and that the a-PAHs accounted for a wide range (4.7%-21.2%) of total PAHs (t-PAHs), and high risk sites were associated with lower t-PAHs but higher a PAHs. The correlation between a-PAHs and the sediment toxicity assessed using tubificid worms (r = -0.654, P = 0.021) was greater than that from t-PAH-based risk assessment (r = -0.230, P = 0.472). Moreover, the insignificant correlation between a-PAH content and mPEC-Q of low molecular weight PAHs implied the potential bias of t-PAH-based risk assessment. The source apportionment from mild extracted fractions was consistent across different indicators and was in accordance with typical pollution sources. Our results suggested that mild extraction-based approaches reduce the potential error from aging effects because the mild extracted PAHs provide a more direct indicator of bioavailability and fresher fractions in sediments. PMID- 26976453 TI - Older patients receiving substandard care from the NHS are suffering in silence, says health service ombudsman. AB - Older people may be 'suffering in silence' over unacceptable care in the NHS, according to the parliamentary and health service ombudsman. PMID- 26976451 TI - MicroRNA-454 regulates stromal cell derived factor-1 in the control of the growth of pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant carcinoma with an extremely high lethality. We recently reported that hypoxia-inducible factor 1 (HIF-1) targets quiescin sulfhydryl oxidase 1 to facilitate PDAC cell growth and invasion. Here, we analyzed the control of another HIF-1 target, stromal cell derived factor-1 (SDF-1), in PDAC cells. We detected significantly more CD68+ macrophages in the PDAC, compared to normal human pancreas (NT). Since macrophages are recruited to the tissue through their expression of CXCR4 in response to SDF-1, we thus examined the SDF-1 levels in the PDAC specimens. Surprisingly, the SDF-1 protein but not mRNA significantly increased in PDAC, compared to NT. Moreover, a SDF-1-targeting microRNA, miR-454, was found to decrease in PDAC. Promoter luciferase assay confirmed that bindings of miR-454 to 3'-UTR of SDF-1 mRNAs inhibited SDF-1 protein translation. Co-culture of bone marrow derived macrophages and miR-454-modified PDAC cells in a transwell migration experiment showed that macrophages migrated less towards miR-454 overexpressing PDAC cells, and migrated more towards miR-454-depleted cells. Implanted miR-454-depleted PDAC cells grew significantly faster than control, while implanted miR-454-overexpressing PDAC cells grew significantly slower than control. Together, our data suggest that miR-454 may regulate SDF-1 in the control of the growth of PDAC. PMID- 26976454 TI - News digest April 08 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26976455 TI - New nurses should be encouraged to explore community sector's rich career opportunities, says nurse lecturer. AB - Newly qualified nurses should be encouraged to head straight into community nursing to boost the sector's ageing workforce, a nurse lecturer said. PMID- 26976456 TI - News digest April 07 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26976459 TI - More support needed for older nurses vulnerable to burnout. AB - Older nurses should be given better support from employers to reduce the risk of burnout and clinical errors occurring, the RCN has warned. PMID- 26976458 TI - NHS nurses' pay: what will you earn this year? AB - New pay rates for the UK's 678,000-strong nursing workforce have been introduced this week. PMID- 26976457 TI - News digest April 04 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26976460 TI - News digest April 03 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26976461 TI - Forensic Science - a science, an art - does it matter? PMID- 26976462 TI - Evaluation of infrared spectra analyses using a likelihood ratio approach: A practical example of spray paint examination. AB - Depending on the forensic disciplines and on the analytical techniques used, Bayesian methods of evaluation have been applied both as a two-step approach (first comparison, then evaluation) and as a continuous approach (comparison and evaluation in one step). However in order to use the continuous approach, the measurements have to be reliably summarized as a numerical value linked to the property of interest, which occurrence can be determined (e.g., refractive index measurement of glass samples). For paint traces analyzed by Fourier transform infrared spectroscopy (FTIR) however, the statistical comparison of the spectra is generally done by a similarity measure (e.g., Pearson correlation, Euclidean distance). Although useful, these measures cannot be directly associated to frequencies of occurrence of the chemical composition (binders, extenders, pigments). The continuous approach as described above is not possible, and a two step evaluation, 1) comparison of the spectra and 2) evaluation of the results, is therefore the common practice reported in most of the laboratories. Derived from a practical question that arose during casework, a way of integrating the similarity measure between spectra into a continuous likelihood ratio formula was explored. This article proposes the use of a likelihood ratio approach with the similarity measure of infrared spectra of spray paints based on distributions of sub-populations given by the color and composition of spray paint cans. Taking into account not only the rarity of paint composition, but also the "quality" of the analytical match provides a more balanced evaluation given source or activity level propositions. We will demonstrate also that a joint statistical-expertal methodology allows for a more transparent evaluation of the results and makes a better use of current knowledge. PMID- 26976463 TI - A survey of adulterants used to cut cocaine in samples seized in the Espirito Santo State by GC-MS allied to chemometric tools. AB - Cocaine is a stimulant drug of the central nervous system (CNS) extracted from the leaves of Erytroxylum coca. It is defined as a tropane alkaloid containing 1R (exo,exo)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylic acid methyl esther. However, despite its defined composition, a wide variety of chemical additives are present in cocaine found in the illicit market, such as benzocaine, lidocaine, caffeine, procaine and phenacetin. In this work, 512 cocaine samples seized by the Civil Police of Espirito Santo state (PC-ES, Brazil) were analyzed by gas chromatography mass spectrometry (GC-MS) allied to principal component analysis (PCA) in order to classify the samples as a function of seizure year (2008, 2009, 2010, 2011 and 2012) and location (metropolitan, north, south and central). The cocaine content (wt.%) and its adulterants were also estimated. Analyzing the samples seized between 2008 and 2011, three sample sets are clearly grouped according to the degree of adulteration with caffeine and lidocaine: 100-50 wt.% of cocaine; 50-20 wt.% of cocaine; and 20-80 wt.% of lidocaine and 60-80 wt.% of caffeine, simultaneously. The last group is formed by samples seized between 2008 and 2009, which proves the higher degree of adulteration during this period. In 2012, higher cocaine content was observed for the 191 analyzed samples than in samples from previous years. The PCA data also suggests that the metropolitan region samples had a higher degree of adulteration than the state countryside samples. PMID- 26976464 TI - Isolation and unnatural death of elderly people in the aging Japanese society. AB - PURPOSE: Japanese society has reached an unprecedented level of aging, with elderly people accounting for 25.1% of the population in October 2013. These changes have created concerns regarding deaths among the elderly. In this study, we compared recent forensic autopsy cases with cases from about 20 years ago, with the goal of understanding the context of death among the elderly within Japanese society today. METHODS: We investigated the forensic autopsy records of 297 people aged 65 years or above. In order to examine the effect of residential circumstances, we classified these cases into two groups: people who lived alone (group A) and those who lived with their family (group B). Forty-five of these autopsy cases were conducted about 20 years ago (1989 to 1993) and 252 cases were recent (2009 to 2013). The cases were limited to people who had been found dead or in a critical situation at home. We investigated the first finder, the period of time elapsed between death and discovery, and the cause of death. RESULTS: The incidence of the first finder being a family member was more than 20% greater in group B compared with group A. The proportions of cases for which it took more than three days for someone to find the body or an abnormal situation were about 14% and 7% in groups A and B, respectively, 20 years ago, and about 48% and 19% among the recent cases. These proportions were significantly higher among the recent cases. Among recent cases, a post-mortem elapsed time of more than 3 days occurred more often in group A than group B (p=0.0002). None of the older cases had an unknown cause of death in either group. However, among the recent cases from both groups, 20-30% of cases resulted in unknown causes of death. The incidences of unknown causes of death were significantly higher among the recent cases in both groups (p=0.015) and in group B alone (p=0.037). The incidences of murder cases were significantly lower in group B among the recent cases (p=0.0022). DISCUSSION: Elderly people who live alone are not easily found or aided when in critical situations, and they may only be discovered after death. Prolongation of the postmortem interval (PMI) results in the deterioration of the corpse making determination of cause of death problematic. The results of this study suggest that there are three factors that isolate elderly people and increase the difficulty in determining their cause of death: reduced communication with family members, reduced communication with neighbors or the community, and the increasing prevalence of the nuclear family. In group B, the prolonged discovery time and the increased incidence of unknown causes of death suggest reduced communication with family members, even though the incidence of being found by a family member was higher than in group A. The murder rate was significantly lower in group B, which may suggest that cases of domestic murder were overlooked. Support for a safe life and peaceful ending for the elderly requires a system based on three factors: remote monitoring to ensure safety, the establishment of elderly groups providing mutual support, and increased visits from welfare workers. Understanding the circumstances of the elderly who die alone is beneficial to countries facing an aging society with weakened family or community structures, and who hope for better support for the elderly. PMID- 26976465 TI - Sex determination using the mesio-distal dimension of permanent maxillary incisors and canines in a modern Chilean population. AB - The pelvis and skull have been shown to be the most accurate skeletal elements for the determination of sex. Incomplete or fragmentary bones are frequently found at forensic sites however teeth are often recovered in forensic cases due to their postmortem longevity. The goal of the present research was to investigate sexual dimorphism between the mesio-distal dimension of the permanent maxillary incisors and canines for the determination of sex in a contemporary Chilean population. Three hundred and three dental models (126 males and 177 females) from individuals ranging in age from 13 years to 37 years old were used from the School of Dentistry, University of Chile. The statistical analyses showed that only the central incisors and canines were sexually dimorphic. Discriminant function score equations were generated for use in sex determination. The average accuracy of sex classification ranged from 59.7% to 65.0% for the univariate analysis and 60.1% to 66.7% for the multivariate analysis. Comparisons to other populations were made. Overall, the accuracies ranged from 54.4% to 63.3% with males most often identified correctly and females most often misidentified. The determination of sex from the mesio-distal width of incisors and canines in Chilean populations does not adhere to the Mohan and Daubert criteria and therefore would not be presented as evidence in court. PMID- 26976466 TI - DNA transfer through nonintimate social contact. AB - The UK and Ireland Association of Forensic Science Providers' (AFSP) Body Fluid Forum (BFF) set out to assist in the interpretation of sexual offence cases where semen is absent on vaginal swabs but female DNA is present on penile swabs or male underwear, and the issue to be addressed is whether or not sexual intercourse occurred. This study aims to investigate the frequency and amount of female DNA transferred to the penis and underwear of males following staged nonintimate social contact with females and to compare the findings with the amount of female DNA transferred to the penis and subsequently to the underwear of a male who had engaged in unprotected sexual intercourse with a female. In this study, no matching female DNA was detected on the inside front of the 44 items of male underwear used in this research following staged contact of a nonintimate nature and subsequent secondary transfer to the penis. After sexual intercourse, full profiles matching the female participant were found on the inside front of the males underwear with maximum peak heights in the range between 1898 and 3157 rfu. It was possible to demonstrate that DNA can occasionally transfer to the waistband and outside front of underwear worn by a male following staged nonintimate social contact. Data obtained in this study suggest that a matching female DNA profile below a peak height of 1000 rfu on the waistband of a male's underwear might be explained by nonintimate social contact with secondary transfer of female DNA from the male's hands. PMID- 26976467 TI - Development of a control region-based mtDNA SNaPshotTM selection tool, integrated into a mini amplicon sequencing method. AB - Mitochondrial DNA (mtDNA) analysis is regularly applied to forensic DNA samples with limited amounts of nuclear DNA (nDNA), such as hair shafts and bones. Generally, this mtDNA analysis involves examination of the hypervariable control region by Sanger sequencing of amplified products. When samples are severely degraded, small-sized amplicons can be applied and an earlier described mini mtDNA method by Eichmann et al. [1] that accommodates ten mini amplicons in two multiplexes is found to be a very robust approach. However, in cases with large numbers of samples, like when searching for hairs with an mtDNA profile deviant from that of the victim, the method is time (and cost) consuming. Previously, Chemale et al. [2] described a SNaPshotTM-based screening tool for a Brazilian population that uses standard-size amplicons for HVS-I and HVS-II. Here, we describe a similar tool adapted to the full control region and compatible with mini-mtDNA amplicons. Eighteen single nucleotide polymorphisms (SNPs) were selected based on their relative frequencies in a European population. They showed a high discriminatory power in a Dutch population (97.2%). The 18 SNPs are assessed in two SNaPshotTM multiplexes that pair to the two mini-mtDNA amplification multiplexes. Degenerate bases are included to limit allele dropout due to SNPs at primer binding site positions. Three SNPs provide haplogroup information. Reliability testing showed no differences with Sanger sequencing results. Since mini-mtSNaPshot screening uses only a small portion of the same PCR products used for Sanger sequencing, no additional DNA extract is consumed, which is forensically advantageous. PMID- 26976468 TI - Validation of probabilistic genotyping software for use in forensic DNA casework: Definitions and illustrations. AB - A number of new computer programs have recently been developed to facilitate the interpretation and statistical weighting of complex DNA profiles in forensic casework. Acceptance of such software in the user community, and subsequent acceptance by the court, relies heavily upon their validation. To date, few guidelines exist that describe the appropriate and sufficient validation of such software used in forensic DNA casework. In this paper, we discuss general principles of software validation and how they could be applied to the interpretation software now being introduced into the forensic community. Importantly, we clarify the relationship between a statistical model and its implementation via software. We use the LRmix program to provide specific examples of how these principles can be implemented. PMID- 26976469 TI - Fraud, individuals, and networks: A biopsychosocial model of scientific frauds. AB - The problem of fraud, especially scientific fraud, is global and its identification risk is still in its infancy. Based on an in-depth analysis of several financial and scientific fraud trials, the authors propose a new and integrative model of scientific fraud. This model identifies two major levels for committing fraud: (i) at the personal skills level (micro-level) and (ii) at the network skills level (macro-level). Interacting continuously with each other, they form a dynamic, efficient, and integrative system: an integrative model of fraud. The micro-level refers to three factors: (i) personality organization, (ii) social competence, and (iii) the so-called triangle of fraud. The macro level refers essentially to social network organization and social engineering. Then, the key to understanding and mostly controlling fraud is to consider both the individual and the environment in which they operate. Based on our model, several steps at the micro- and macro-levels can be proposed. PMID- 26976470 TI - Implementing context information management in forensic casework: Minimizing contextual bias in firearms examination. AB - Managing context information in forensic casework aims to minimize task irrelevant information while maximizing the task-relevant information that reaches the examiner. A design and implementation of context information management (CIM) is described for forensic firearms examination. Guided by a taxonomy of different sources of context information, a flow-chart was constructed that specifies the process of casework examination and context information management. Due to the risk of bias, another examiner may need to be involved when context information management is unsuccessful. Application of context information management does not make a subjective examination objective, but can limit the risks of bias with a minimal investment of time and resources. PMID- 26976471 TI - Bloodstain pattern classification: Accuracy, effect of contextual information and the role of analyst characteristics. AB - It is becoming increasingly apparent that contextual information can exert a considerable influence on decisions about forensic evidence. Here, we explored accuracy and contextual influence in bloodstain pattern classification, and how these variables might relate to analyst characteristics. Thirty-nine bloodstain pattern analysts with varying degrees of experience each completed measures of compliance, decision-making style, and need for closure. Analysts then examined a bloodstain pattern without any additional contextual information, and allocated votes to listed pattern types according to favoured and less favoured classifications. Next, if they believed it would assist with their classification, analysts could request items of contextual information - from commonly encountered sources of information in bloodstain pattern analysis - and update their vote allocation. We calculated a shift score for each item of contextual information based on vote reallocation. Almost all forms of contextual information influenced decision-making, with medical findings leading to the highest shift scores. Although there was a small positive association between shift scores and the degree to which analysts displayed an intuitive decision making style, shift scores did not vary meaningfully as a function of experience or the other characteristics measured. Almost all of the erroneous classifications were made by novice analysts. PMID- 26976472 TI - Preventing miscarriages of justice: A review of forensic firearm identification. AB - The role of a firearm examiner is wide ranging, involving tasks that require scientific understanding in aspects of chemistry, physics and biology. This article aims to provide a critical review of the key scientific principles and practices specifically involved with forensic firearm identification and to discuss how misidentifications have resulted in cases of injustice. Implementation of quality assured examination practice, demonstration of individual examiner competence and more objective methods of reporting are being adopted by firearm examiners and laboratories to address some of the criticisms relating to subjectivity and standardisation inherent within the discipline. The impact of these changes is outlined and further recommendations are made for both examiners and legal professionals to minimise the potential for future injustices involving firearms evidence. Latest research in the field is cited, continuing to support the theory and use of firearm identification as admissible evidence in court. PMID- 26976473 TI - Techniques that acquire donor profiling information from fingermarks - A review. AB - Fingermarks are among the most important types of evidence that can be encountered at the scene of a crime since the unique ridge pattern of a fingerprint can be used for individualization. But fingermarks contain more than the characteristic pattern of ridges and furrows, they are composed of a wide variety of different components that originate from endogenous and exogenous sources. The chemical composition can be used to obtain additional information from the donor of the fingermark, which in turn can be used to create a donor profile. Donor profiling can serve at least two purposes i) to enhance the evidential value of fingermarks and ii) to provide valuable tactical information during the crime scene investigation. Retrieving this additional information is not limited to fingermarks that have been used for individualization, but can also be applied on partial and/or distorted fingermarks. In this review we have summarized the types of information that can be obtained from fingermarks. Additionally, an overview is given of the techniques that are available addressing their unique characteristics and limitations. We expect that in the nearby future, donor profiling from contact traces, including fingermarks will be possible. PMID- 26976474 TI - Correlation Between IGFs-Related Proteins Expression and Incidence of Colorectal Cancer in Diabetic Patients and Related Mechanisms. AB - BACKGROUND: Diabetes mellitus a common metabolic disorder with hyperglycemia, is caused by the interaction of genetic and environmental factors. Approximately 12~20% of diabetic patients have risk of colorectal cancer. Recent studies revealed that the insulin-like growth factor system (IGFs) plays an important role in tumor occurrence. This study thus investigated the relationship between IGFs-related proteins in diabetic patients and the incidence of colorectal carcinoma. MATERIAL/METHODS: A retrospective study was performed in a total of 206 individuals, including 85 diagnosed with diabetes. The incidence of colorectal cancer was tracked, along with the detection of IGFs expression in serum. During the surgical resection, tumor tissues and adjacent tissues were collected and quantified for IGFs expression level. RESULTS: We found no significant difference in age or sex between the diabetic and control groups. Diabetic patients, however, had elevated body weight and higher incidence of colorectal cancer compared to non-diabetic controls (p<0.05). The diabetic group also had higher IGF-I and IGF-IR mRNA levels in serum, while IGFBP-6 expression was down-regulated. In comparison to adjacent healthy tissues, tumor tissue had higher levels of IGF-I and IGF-IR but lower levels of IGFBP-6 (p<0.05). CONCLUSIONS: Our study showed higher incidence of colorectal cancer in diabetics compared to non-diabetics. The occurrence of colorectal cancer in diabetic patients may be associated with elevated IGFs-related protein expression level. PMID- 26976475 TI - Molecular identification of Borrelia genus in questing hard ticks from Portugal: Phylogenetic characterization of two novel Relapsing Fever-like Borrelia sp. AB - In the last decades, several studies have reported pathogenic species of Borrelia related to those that cause Tick-borne Relapsing Fever (RF), but unexpectedly suggesting their transmission by hard ticks, known vectors of Borrelia burgdorferi sensu lato (B. burgdorferi s.l.) species, rather than by soft ticks. This study was designed to update the presence of B. burgdorferi s.l. species in ticks from several districts of mainland Portugal, where Ixodes ricinus had been previously described. Ticks (a total of 2915 specimens) were collected in seven districts throughout the country, and analyzed using molecular methods. Three nested-PCR protocols, targeting the flagellin gene (flaB), the intergenic spacer region (IGS) located between 5S and 23S rRNA, and the glpQ gene, and a conventional PCR targeting the 16S rRNA, were used for Borrelia DNA detection. Borrelia DNA was detected in 3% of the ticks from Braga, Vila Real, Lisboa, Setubal, Evora and Faro districts. The obtained amplicons were sequenced and analyzed by BLASTn, and 15/63 (24%) matched with homologous sequences from Borrelia lusitaniae and 15/63 (24%) with B. garinii, being these the most prevalent species. DNA from B. burgdorferi sensu stricto (s.s.), B. valaisiana and B. afzelii were detected in 7/63 (11%), 6/63 (10%), and 2/63 (3%) of the specimens, respectively. Unexpectedly, DNA sequence (flaB) analysis from eight (13%) samples, two from Rhipicephalus sanguineus and six from Haemaphysalis punctata tick species, revealed high homology with RF-like Borrelia. Phylogenetic analyses obtained from three genetic markers (16S rRNA, flaB, and glpQ) confirmed their congruent inclusion in a strongly supported RF cluster, where they segregated in two subgroups which differ from the other Relapsing Fever species. Therefore, the results confirm the circulation of multiple species of B. burgdorferi s.l. over a wide geographic range, covering most of the Portuguese mainland territory. Surprisingly, the obtained data also revealed two putative Relapsing Fever-like Borrelia species in different species of hard ticks, possibly disclosing the circulation of novel RF-like Borrelia species with different associated tick vectors. PMID- 26976476 TI - Remembering Austin L. Hughes. PMID- 26976477 TI - Genetic diversity and molecular characterization of Babesia motasi-like in small ruminants and ixodid ticks from China. AB - Ovine babesioses, an important tick-borne disease of sheep and goats in China, is caused by the reproduction of intraerythrocytic protozoa of the Babesia genus. Babesia motasi-like is a Babesia parasite that infects small ruminant in China, and two sub-groups of B. motasi-like can be subdivided based on differences in the rhoptry-associated-protein-1 gene. This study aimed to characterize the distribution, epidemiology and genetics of B. motasi-like in animals and ticks. A molecular investigation was carried out from 2009 to 2015 in 16 provinces in China. In total, 1081 blood samples were collected from sheep and goats originating from 27 different regions, and 778 ixodid tick samples were collected from 8 regions; the samples were tested for the presence of B. motasi-like using a specific nested PCR assay based on the rap-1b gene. The results indicated that 139 (12.9%), 91 (8.4%), 48 (4.4%) and 6 (0.7%) of the blood samples were positive for general B. motasi-like, Babesia sp. BQ1 (Lintan and Ningxian), Babesia sp. Tianzhu and Babesia sp. Hebei sub-groups, mixed infections, respectively. Among the collected 778 ixodid ticks (including Haemaphysalis longicornis, Haemaphysalis qinghaiensis, Dermacentor silvarum, Ixodes persulcatus, Rhipicephalus sanguineus and Rhipicephalus (Boophilus) microplus), the most frequently infected with Babesia were D. silvarum and I. persulcatus (35.7%), followed by H. longicornis (26.8%), H. qinghaiensis (24.8%) and R. sanguineus (9.3%). The PCR results were confirmed by DNA sequencing. The positive rates of B. motasi-like infection in ticks were found to be higher in China, compared with previous studies in other countries. B. motasi-like infections have not previously been reported in D. silvarum, I. persulcatus or R. sanguineus. The findings obtained in this study could be used for planning effective control strategies against babesiosis in China. PMID- 26976478 TI - Patient-specific Monte Carlo dose calculations for (103)Pd breast brachytherapy. AB - This work retrospectively investigates patient-specific Monte Carlo (MC) dose calculations for (103)Pd permanent implant breast brachytherapy, exploring various necessary assumptions for deriving virtual patient models: post-implant CT image metallic artifact reduction (MAR), tissue assignment schemes (TAS), and elemental tissue compositions. Three MAR methods (thresholding, 3D median filter, virtual sinogram) are applied to CT images; resulting images are compared to each other and to uncorrected images. Virtual patient models are then derived by application of different TAS ranging from TG-186 basic recommendations (mixed adipose and gland tissue at uniform literature-derived density) to detailed schemes (segmented adipose and gland with CT-derived densities). For detailed schemes, alternate mass density segmentation thresholds between adipose and gland are considered. Several literature-derived elemental compositions for adipose, gland and skin are compared. MC models derived from uncorrected CT images can yield large errors in dose calculations especially when used with detailed TAS. Differences in MAR method result in large differences in local doses when variations in CT number cause differences in tissue assignment. Between different MAR models (same TAS), PTV [Formula: see text] and skin [Formula: see text] each vary by up to 6%. Basic TAS (mixed adipose/gland tissue) generally yield higher dose metrics than detailed segmented schemes: PTV [Formula: see text] and skin [Formula: see text] are higher by up to 13% and 9% respectively. Employing alternate adipose, gland and skin elemental compositions can cause variations in PTV [Formula: see text] of up to 11% and skin [Formula: see text] of up to 30%. Overall, AAPM TG-43 overestimates dose to the PTV ([Formula: see text] on average 10% and up to 27%) and underestimates dose to the skin ([Formula: see text] on average 29% and up to 48%) compared to the various MC models derived using the post-MAR CT images studied herein. The considerable differences between TG-43 and MC models underline the importance of patient-specific MC dose calculations for permanent implant breast brachytherapy. Further, the sensitivity of these MC dose calculations due to necessary assumptions illustrates the importance of developing a consensus modelling approach. PMID- 26976480 TI - The use of second allogeneic hematopoietic stem cell transplantation for hematologic malignancies relapsed after the first: Does it worth to do? AB - Allogeneic (allo) hematopoietic stem cell transplantation (HSCT) is the only curative option for many malignant and benign hematological disorders. It seems hopeless for patients who relapse after this strategy. In the era of developing breakthrough therapies, we can hope for better, but for patients relapsed after the first allo HSCT probably the best therapy option for long term survival is still another allo HSCT. Interval between first allo HSCT and relapse of primary disease and achievement of complete response after the relapse are the most prominent factors for long time survival for patient after second all HSCT. PMID- 26976479 TI - Crystal Field Splitting is Limiting the Stability and Strength of Ultra incompressible Orthorhombic Transition Metal Tetraborides. AB - The lattice stability and mechanical strengths of the supposedly superhard transition metal tetraborides (TmB4, Tm = Cr, Mn and Fe) evoked recently much attention from the scientific community due to the potential applications of these materials, as well as because of general scientific interests. In the present study, we show that the surprising stabilization of these compounds from a high symmetry to a low symmetry structure is accomplished by an in-plane rotation of the boron network, which maximizes the in-plane hybridization by crystal field splitting between d orbitals of Tm and p orbitals of B. Studies of mechanical and electronic properties of TmB4 suggest that these tetraborides cannot be intrinsically superhard. The mechanical instability is facilitated by a unique in-plane or out-of-plane weakening of the three-dimensional covalent bond network of boron along different shear deformation paths. These results shed a novel view on the origin of the stability and strength of orthorhombic TmB4, highlighting the importance of combinational analysis of a variety of parameters related to plastic deformation of the crystalline materials when attempting to design new ultra-incompressible, and potentially strong and hard solids. PMID- 26976481 TI - Computer modeling of airway deposition distribution of Foster((r)) NEXThaler((r)) and Seretide((r)) Diskus((r)) dry powder combination drugs. AB - Asthma is a serious global health problem with rising prevalence and treatment costs. Due to the growing number of different types of inhalation devices and aerosol drugs, physicians often face difficulties in choosing the right medication for their patients. The main objectives of this study are (i) to elucidate the possibility and the advantages of the application of numerical modeling techniques in aerosol drug and device selection, and (ii) to demonstrate the possibility of the optimization of inhalation modes in asthma therapy with a numerical lung model by simulating patient-specific drug deposition distributions. In this study we measured inhalation parameter values of 25 healthy adult volunteers when using Foster((r)) NEXThaler((r)) and Seretide((r)) Diskus((r)). Relationships between emitted doses and patient-specific inhalation flow rates were established. Furthermore, individualized emitted particle size distributions were determined applying size distributions at measured flow rates. Based on the measured breathing parameter values, we calculated patient-specific drug deposition distributions for the active components (steroid and bronchodilator) of both drugs by the help of a validated aerosol lung deposition model adapted to therapeutic aerosols. Deposited dose fractions and deposition densities have been computed in the entire respiratory tract, in distinct anatomical regions of the airways and at the level of airway generations. We found that Foster((r)) NEXThaler((r)) deposits more efficiently in the lungs (average deposited steroid dose: 42.32+/-5.76% of the nominal emitted dose) than Seretide((r)) Diskus((r)) (average deposited steroid dose: 24.33+/-2.83% of the nominal emitted dose), but the variance of the deposition values of different individuals in the lung is significant. In addition, there are differences in the required minimal flow rates, therefore at certain patients Seretide((r)) Diskus((r)) or pMDIs could be a better choice. Our results show that validated computer deposition models could be useful tools in providing valuable deposition data and assisting health professionals in the personalized drug selection and delivery optimization. Patient-specific modeling could open a new horizon in the treatment of asthma towards a more effective personalized medicine in the future. PMID- 26976482 TI - Efficient search and responsiveness trade-offs in a Markov chain model of evolution in dynamic environments. AB - Motivated by the desire to study evolutionary responsiveness in fluctuating environments, and by the current interest in analyses of evolution that merge notions of fitness maximization with dynamical systems concepts such as Lyapunov functions, this paper models natural evolution with a simple stochastic dynamical system that can be represented as a Markov chain. The process maximizes fitness globally via search and has links to information and entropy. These links suggest that a possible rationale for evolution with the exponential fitness functions observed in nature is that of optimally-efficient search in a dynamic environment, which represents the quickest trade-off of prior information about the genotype search space for search effort savings after an environment perturbation. A Lyapunov function is also provided that relates the stochastic dynamical system model with search information, and the model shows that evolution is not gradient-based but dwells longer on more fit outcomes. The model further indicates that tuning the amount of selection trades off environment responsiveness with the time to reach fit outcomes, and that excessive selection causes a loss of responsiveness, a result that is validated by the literature and impacts efforts in directed evolution. PMID- 26976483 TI - A mathematical model verifying potent oncolytic efficacy of M1 virus. AB - Motivated by the latest findings in a recent medical experiment [19] which identify a naturally occurring alphavirus (M1) as a novel selective killer targeting zinc-finger antiviral protein (ZAP)-deficient cancer cells, we propose a mathematical model to illustrate the growth of normal cells, tumor cells and the M1 virus with limited nutrient. In order to better understand biological mechanisms, we discuss two cases of the model: without competition and with competition. In the first part, the explicit threshold conditions for the persistence of normal cells (or tumor cells) is obtained accompanying with the biological explanations. The second part indicates that when competing with tumor cells, the normal cells will extinct if M1 virus is ignored; Whereas, when M1 virus is considered, the growth trend of normal cells is similar to the one without competition. And by using uniformly strong repeller theorem, the minimum effective dosage of medication is explicitly found which is not reported in [19]. Furthermore, numerical simulations and corresponding biological interpretations are given to support our results. PMID- 26976484 TI - Surveillance for adverse events following immunization (AEFI) for 7 years using a computerised vaccination system. AB - OBJECTIVES: The surveillance of vaccine safety is an essential requirement in vaccination programmes. Computerized immunization registries such as the Vaccination Information System (SIV) of Valencian Community (Spain) offer the opportunity to estimate the incidence of adverse events according to individual information. The aim of the study was to analyze adverse events following immunization reported through SIV from 2005 to 2011 by age, sex, type of vaccine and dose, and adverse event, and highlight the advantages of this type of reporting. STUDY DESIGN: A retrospective cohort study of subjects vaccinated in the Valencian Community using population health databases was carried out. METHODS: Analysis of vaccinations and reported AEFI via SIV in Valencian Community was carried out. RESULTS: More than 13 million vaccines doses were administered during 2005 through 2011, the reporting rate of adverse events was 12.4/100,000 doses administered with the highest value in 2009 (27.4), with differences by age and sex. DTaP vaccine had the highest reporting in children (96.6/100,000) while influenza A(H1N1)pdm09 in adults (87.7/100,000). An increased reporting of adverse events was seen with DTaP in children 5-6 years of age, detected in real time, drove to swap this vaccine to a low dose Tdap which was followed by a decrease in administration site events. CONCLUSIONS: SIV demonstrates advantages for passive surveillance. Reporting rates by individual characteristics are calculated accurately and it also allows detecting shifts in reporting rate on real time for specific vaccines. The study shows that vaccines included in the routine vaccination schedule for children and adult vaccination programs are safe. PMID- 26976485 TI - Subjective health of adolescents from families in receipt of social assistance. AB - OBJECTIVE: To compare the subjective health of adolescents from families in receipt and not in receipt of social assistance. STUDY DESIGN: Nationwide cross sectional study of 1812 pupils aged 13-18 years in Poland in 2010-2011. METHODS: The analysis focused on two dimensions of the Child Health and Illness Profile - Adolescent Edition questionnaire: discomfort and satisfaction with health. Age, sex and seven socio-economic factors were considered as determinants. RESULTS: Overall, 10.8% of the respondents reported that their families were in receipt of social welfare benefits. Among the families of low socio-economic status and living in poor regions, the percentage in receipt of social welfare benefits increased to 22.1%; however, this figure was lower (4.4%) if both parents had a higher level of education. After adjustment for six sociodemographic variables, the standardized regression coefficient of the social welfare benefits variable amounted to 0.072 (P = 0.004) in the discomfort model and -0.044 (P = 0.079) in the satisfaction model. A significant three-level interaction was found (P = 0.007) between residential location, neighbourhood affluence and being in receipt of social welfare benefits as predicators of discomfort score (general linear model). CONCLUSIONS: Being in receipt of social welfare benefits has a stronger impact on experiencing discomfort than diminishing satisfaction with one's health. It also has a stronger effect on physical problems than on emotional problems. The item 'on social assistance' is recommended as it helps to identify families particularly exposed to the health consequences of poverty. PMID- 26976486 TI - Effective risk communication and contact tracing for Ebola virus disease prevention and control - Experiences from Port Harcourt, Nigeria. PMID- 26976487 TI - Blood pressure profiles, and awareness and treatment of hypertension in Europe - results from the EHES Pilot Project. PMID- 26976488 TI - Glycaemic control and associated factors among patients with diabetes at public health clinics in Johor, Malaysia. AB - OBJECTIVES: To determine the prevalence of glycaemic control and factors associated with poor glycaemic control [glycosylated haemoglobin (HbA1c) >=6.5%] among patients with type 2 diabetes treated in public health clinics in Johor, Malaysia. STUDY DESIGN: Cross-sectional study. METHODS: A review of all patients aged over 18 years and with a diagnosis of type 2 diabetes for >1 year. The National Diabetic Registry was used as the database for attendees at public health clinics in Johor Bahru between January and December 2013. A required sample of 660 was calculated, and a random sampling method was applied to acquire patient information across the 13 public health clinics in Johor Bahru. All relevant information (e.g. HbA1c, type of treatment and other parameters for glycaemic control) were abstracted from the registry. RESULTS: Sixty-eight percent of 706 patients had HbA1c >6.5%, and mean HbA1c was 7.8%. Younger patients (72.3%) had poorer glycaemic control than older patients (63.0%), and most patients with poor glycaemic control were obese (79.2%). Approximately 31.7% of patients did not achieve the target blood pressure <130/80 mmHg, and 58.5% did not achieve the target lipid profile. Multiple logistic regression analysis revealed that age (<60 years), sex (male), duration of diabetes (>5 years), body mass index (obese), type of treatment (diet therapy vs combination therapy) and abnormal lipid profile were significantly associated with increased odds of HbA1C >6.5%. CONCLUSIONS: More than half (68%) of the patients with diabetes had HbA1c >6.5%. This highlights the importance of providing organized care to manage patients with diabetes in the primary care setting, such as weight reduction programmes, proper prescribing treatment, and age- and gender-specific groups to ensure good glycaemic control. PMID- 26976489 TI - Tracking search engine queries for suicide in the United Kingdom, 2004-2013. AB - OBJECTIVES: First, to determine if a cyclical trend is observed for search activity of suicide and three common suicide risk factors in the United Kingdom: depression, unemployment, and marital strain. Second, to test the validity of suicide search data as a potential marker of suicide risk by evaluating whether web searches for suicide associate with suicide rates among those of different ages and genders in the United Kingdom. STUDY DESIGN: Cross-sectional. METHODS: Search engine data was obtained from Google Trends, a publicly available repository of information of trends and patterns of user searches on Google. The following phrases were entered into Google Trends to analyse relative search volume for suicide, depression, job loss, and divorce, respectively: 'suicide'; 'depression + depressed + hopeless'; 'unemployed + lost job'; 'divorce'. Spearman's rank correlation coefficient was employed to test bivariate associations between suicide search activity and official suicide rates from the Office of National Statistics (ONS). RESULTS: Cyclical trends were observed in search activity for suicide and depression-related search activity, with peaks in autumn and winter months, and a trough in summer months. A positive, non significant association was found between suicide-related search activity and suicide rates in the general working-age population (15-64 years) (rho = 0.164; P = 0.652). This association is stronger in younger age groups, particularly for those 25-34 years of age (rho = 0.848; P = 0.002). CONCLUSIONS: We give credence to a link between search activity for suicide and suicide rates in the United Kingdom from 2004 to 2013 for high risk sub-populations (i.e. male youth and young professionals). There remains a need for further research on how Google Trends can be used in other areas of disease surveillance and for work to provide greater geographical precision, as well as research on ways of mitigating the risk of internet use leading to suicide ideation in youth. PMID- 26976491 TI - Perceptions of safety and exposure to violence in public places among working age adults with disabilities or long-term health conditions in the UK: cross sectional study. AB - OBJECTIVES: To examine perceptions of safety and exposure to violence in public places among working age adults with and without disabilities in the UK and to assess the extent to which any between-group differences may be moderated by gender and socio-economic situation. STUDY DESIGN: Cross-sectional study. METHODS: Secondary analysis of data collected in Wave 3 (2011-13) of Understanding Society. Data were extracted on a subsample of 5069 respondents aged 16 to 64 years (28% of whom had a disability/long-term health condition) who were administered a questionnaire module addressing experiences of harassment. Between-group comparisons were made on four self-reported indicators of safety. RESULTS: Respondents with disabilities/long-term health conditions were significantly more likely to have been attacked (adjusted OR 2.30, 95%CI 1.17 4.50, P < 0.05), insulted (adjusted OR 1.48, 95%CI 1.16-1.90, P < 0.01) and to feel unsafe in public places (adjusted OR 1.32, 95%CI 1.16-1.56, P < 0.01) over the previous 12 months. There were no statistically significant differences between groups with regard to self-reported avoidance of public places. These associations were moderated by both gender and poverty status, with the increased risk of exposure to violence among people with disabilities being greater for both women and people living in poverty. CONCLUSIONS: The data add further support to the growing evidence base suggesting that people with a disability/long-term health condition are at significantly increased risk of exposure to interpersonal violence, particularly if they are living in poverty or are women. As such, there is a clear need to develop interventions that are targeted to the particular circumstances and needs of these high risk groups. PMID- 26976490 TI - Parental awareness and attitude towards environmental tobacco smoke exposure in children with respiratory illnesses. PMID- 26976492 TI - Genetic engineering of Bacillus megaterium for high-yield production of the major teleost progestogens 17alpha,20beta-di- and 17alpha,20beta,21alpha-trihydroxy-4 pregnen-3-one. AB - 17alpha,20beta-Dihydroxy-4-pregnen-3-one (17alpha,20betaDiOH-P) and 17alpha,20beta,21alpha-trihydroxy-4-pregnen-3-one (20betaOH-RSS) are the critical hormones required for oocyte maturation in fish. We utilized B. megaterium's endogenous 20beta-hydroxysteroid dehydrogenase (20betaHSD) for the efficient production of both progestogens after genetically modifying the microorganism to reduce side-product formation. First, the gene encoding the autologous cytochrome P450 CYP106A1 was deleted, resulting in a strain devoid of any steroid hydroxylation activity. Cultivation of this strain in the presence of 17alpha hydroxyprogesterone (17alphaOH-P) led to the formation of 17alpha,20alpha dihydroxy-4-pregnen-3-one (17alpha,20alphaDiOH-P) as a major and 17alpha,20betaDiOH-P as a minor product. Four enzymes were identified as 20alphaHSDs and their genes deleted to yield a strain with no 20alphaHSD activity. The 3-oxoacyl-(acyl-carrier-protein) reductase FabG was found to exhibit 20betaHSD-activity and overexpressed to create a biocatalyst yielding 0.22g/L 17alpha,20betaDiOH-P and 0.34g/L 20betaOH-RSS after 8h using shake-flask cultivation, thus obtaining products that are at least a thousand times more expensive than their substrates. PMID- 26976494 TI - Congenital Chylothorax: Antenatal Intervention, Survival, and Outcome. PMID- 26976493 TI - Mineralocorticoid receptor stimulation induces urinary storage dysfunction via upregulation of epithelial sodium channel expression in the rat urinary bladder epithelium. AB - We aimed to evaluate mineralocorticoid receptor (MR) expression in rat bladder and the physiological role of the MR-epithelial sodium channel (ENaC) pathway in controlling bladder function in 10-12-week-old, male Sprague-Dawley rats. First, we examined the mRNA expression of MR and localization of MR and ENaC-alpha proteins in the urinary bladder. MR mRNA expression was observed in untreated-rat urinary bladders, and MR and ENaC-alpha proteins were localized in the epithelium. Next, rats were treated with vehicle (controls) or fludrocortisone (an MR agonist) for 3 days, and ENaC-alpha protein expression levels and bladder function were evaluated on day 4. ENaC-alpha protein expression was significantly higher in fludrocortisone-treated rats than in controls. In addition, cystometry was performed during intravesical infusion of saline and amiloride (an ENaC inhibitor). While intercontraction intervals (ICIs) during saline infusion were significantly shorter in the fludrocortisone group than in the controls, infusion of amiloride normalized the ICIs in the fludrocortisone group. However, no intra- or inter-group differences in maximum intravesical pressure were observed. Taken together, MR protein is localized in the rat urinary bladder epithelium, and may regulate ENaC expression and bladder afferent input. The MR-ENaC pathway may be a therapeutic target for ameliorating storage symptoms. PMID- 26976495 TI - Caffeine Administration to Prevent Apnea in Very Premature Infants. AB - BACKGROUND: Apnea intervals frequently occur in premature infants. Periods of apnea occur more often with decreases in gestational age. Periods of apnea can cause damage to the infant's developing brain and other organs. This study was designed to investigate the preventive effects of caffeine on apnea incidence in higher-risk neonates. METHODS: In this single-center randomized control trial study, premature infants with a birth weight of <=1200 g were eligible for enrollment. Twenty-six infants were randomly assigned to receive 20 mg/kg caffeine, as the loading dose, which was followed by 5 mg/kg daily as the maintenance dose until the 10th day of life; these infants were compared with 26 infants in the control group. Primary outcomes were incidence of apnea, bradycardia, and cyanosis. RESULTS: Fifty-two infants were enrolled (26 in the caffeine group and 26 in the control group). The preventive effect of caffeine on apnea was significant in these infants. The relative risk for incidence of apnea in preterm neonates with a birth weight of <1200 g was 0.250 (95% confidence interval, 0.097-0.647). Only four infants (15.4%) in the caffeine group developed apnea, compared with 16 (61.5%) in the control group (p = 0.001). CONCLUSION: It seems that preventative effects of caffeine on apnea become apparent by using the drug in very premature infants. PMID- 26976496 TI - Regional functional synchronizations in dementia with Lewy bodies and Alzheimer's disease. AB - BACKGROUND: Dementia with Lewy bodies (DLB) is a common cause of dementia in the elderly population after Alzheimer's disease (AD), and at early stages differential diagnosis between DLB and AD might be difficult due to their symptomatic overlap, e.g. cognitive and memory impairments. We aimed to investigate functional brain differences between both diseases in patients recently diagnosed. METHODS: We investigated regional functional synchronizations using regional homogeneity (ReHo) in patients clinically diagnosed with DLB (n = 19) and AD (n = 18), and for comparisons we also included healthy controls (HC, n = 16). Patient groups were matched by age, education, and by the level of cognitive impairment (MMSE p-value = 0.36). Additionally, correlations between ReHo values and clinical scores were investigated. RESULTS: The DLB group showed lower ReHo in sensory-motor cortices and higher ReHo in left middle temporal gyrus when compared with HCs (p-value < 0.001 uncorrected). The AD group demonstrated lower ReHo in the cerebellum and higher ReHo in the left/right lingual gyri, precuneus cortex, and other occipital and parietal regions (p-value < 0.001 uncorrected). CONCLUSIONS: Our results agree with previous ReHo investigations in Parkinson's disease (PD), suggesting that functional alterations in motor-related regions might be a characteristic of the Lewy body disease spectrum. However, our results in AD contradict previously reported findings for this disease and ReHo, which we speculate are a reflection of compensatory brain responses at early disease stages. ReHo differences between patient groups were at regions related to the default mode and sensory-motor resting state networks which might reflect the aetiological divergences in the underlying disease processes between AD and DLB. PMID- 26976497 TI - Michelin Baby Associated With Facial Abnormalities. PMID- 26976499 TI - Roll compaction/dry granulation: Suitability of different binders. AB - As dry granulation as a continuous process becomes steadily more important, the interest of different materials and their processing is growing. Binders are of high importance as they have to compensate granule hardening, reduce the fines, and ensure adequate tablet tensile strengths. A simple formulation was used for roll compaction/dry granulation with subsequent tableting to produce granules and tablets, containing paracetamol (70% w/w), a filler and a binder (10%). With this formulation other influences were negligible and the influence of the binder was almost isolated. Eight different binders were compared with special attention to raw material properties. Six of them were cellulose based and two of them were based on povidone. Granule size distributions were typically bimodal. With the same method of preparation, large differences between the formulations occurred. The median particle size of granules differed from 200 MUm, up to barely 700 MUm. The larger the resulted particles, the higher was the tensile strength after tableting. Tablets with fine grades of HPC and copovidone achieved highest tensile strength exceeding 2.5 MPa at a compaction pressure of 350 MPa. Formulations with other binders were inferior, but mostly adequate. MCC performed insufficient and led to capping. PMID- 26976500 TI - Stereolithographic (SLA) 3D printing of oral modified-release dosage forms. AB - The aim of this work was to evaluate the suitability of stereolithography (SLA) to fabricate drug-loaded tablets with modified-release characteristics. The SLA printer creates solid objects by using a laser beam to photopolymerise monomers. In this work polyethylene glycol diacrylate (PEGDA) was used as a monomer and diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide was used as a photo-initiator. 4 aminosalicylic acid (4-ASA) and paracetamol (acetaminophen) were selected as model drugs. Tablets were successfully printed and formulations with different properties were fabricated by adding polyethylene glycol 300 (PEG 300) to the printing solution. The loading of paracetamol and 4-ASA in the printed tablets was 5.69% and 5.40% respectively. In a realistic dynamic dissolution simulation of the gastrointestinal tract, drug release from the tablets was dependent on the composition of the formulations, but independent of dissolution pH. In conclusion SLA 3DP technology allows the manufacture of drug loaded tablets with specific extended-release profiles. In the future this technology could become a manufacturing technology for the elaboration of oral dosage forms, for industrial production or even for personalised dose. PMID- 26976498 TI - The impact of aerobic exercise training on cardiopulmonary functioning in individuals with schizophrenia. PMID- 26976501 TI - Percutaneous absorption of benzophenone-3 loaded lipid nanoparticles and polymeric nanocapsules: A comparative study. AB - For the last years, the increase of the number of skin cancer cases led to a growing awareness of the need of skin protection against ultraviolet (UV) radiations. Chemical UV filters are widely used into sunscreen formulations as benzophenone-3 (BP-3), a usually used broad spectrum chemical UV filter that has been shown to exercise undesirable effects after topical application. Innovative sunscreen formulations are thus necessary to provide more safety to users. Lipid carriers seem to be a good alternative to formulate chemical UV filters reducing their skin penetration while maintaining good photo-protective abilities. The aim of this work was to compare percutaneous absorption and cutaneous bioavailability of BP-3 loaded into solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), nanostructured polymeric lipid carriers (NPLC) and nanocapsules (NC). Particle size, zeta potential and in vitro sun protection factor (SPF) of nanoparticle suspensions were also investigated. Results showed that polymeric lipid carriers, comprising NPLC and NC, significantly reduced BP-3 skin permeation while exhibiting the highest SPF. This study confirms the interesting potential of NPLC and NC to formulate chemical UV filters. PMID- 26976502 TI - Immune response elicited by an intranasally delivered HBsAg low-dose adsorbed to poly-epsilon-caprolactone based nanoparticles. AB - Among new strategies to increase hepatitis B virus (HBV) vaccination, especially in developing countries, the development of self-administered vaccines is considered one of the most valuable. Nasal vaccination using polymeric nanoparticles (NPs) constitutes a valid approach to this issue. In detail, poly epsilon-caprolactone (PCL)/chitosan NPs present advantages as a mucosal vaccine delivery system: the high resistance of PCL against degradation in biological fluids and the mucoadhesive and immunostimulatory properties of chitosan. In vitro studies revealed these NPs were retained in a mucus-secreting pulmonary epithelial cell line and were capable of entering into differentiated epithelial cells. The intranasal (IN) administration of 3 different doses of HBsAg (1.5 MUg, 5 MUg and 10 MUg) adsorbed on a fixed amount of PCL/chitosan NPs (1614 MUg) generated identical titers of serum anti-HBsAg IgG and anti-HBsAg sIgA in mice nasal secretions. Besides other factors, the NP surface characteristics, particularly, zeta potential differences among the administered formulations are believed to be implicated in the outcome of the immune response generated. PMID- 26976503 TI - Acoustic spectroscopy: A powerful analytical method for the pharmaceutical field? AB - Acoustics is one of the emerging technologies developed to minimize processing, maximize quality and ensure the safety of pharmaceutical, food and chemical products. The operating principle of acoustic spectroscopy is the measurement of the ultrasound pulse intensity and phase after its propagation through a sample. The main goal of this technique is to characterise concentrated colloidal dispersions without dilution, in such a way as to be able to analyse non transparent and even highly structured systems. This review presents the state of the art of ultrasound-based techniques in pharmaceutical pre-formulation and formulation steps, showing their potential, applicability and limits. It reports in a simplified version the theory behind acoustic spectroscopy, describes the most common equipment on the market, and finally overviews different studies performed on systems and materials used in the pharmaceutical or related fields. PMID- 26976504 TI - Patient centric formulations for paediatrics and geriatrics: Similarities and differences. AB - Paediatrics and geriatrics both represent highly heterogenous populations and require special consideration when developing appropriate dosage forms. This paper discusses similarities, differences and considerations with respect to the development of appropriate medicine formulations for paediatrics and geriatrics. Arguably the most significant compliance challenge in older people is polypharmacy, whereas for children the largest barrier is taste. Pharmaceutical technology has progressed rapidly and technologies including FDCs, multi particulates and orodispersible dosage forms provide unprecedented opportunities to develop novel and appropriate formulations for both old and new drugs. However, it is important for the formulation scientists to work closely with patients, carers and clinicians to develop such formulations for both the paediatric and geriatric population. PMID- 26976507 TI - [History of immunotherapy. Paradigm change?] PMID- 26976506 TI - Exploration of 2-benzylbenzimidazole scaffold as novel inhibitor of NF-kappaB. AB - For finding the novel inhibitor of nuclear factor kappaB activity, a series of benzimidazole derivatives were rationally designed, synthesized and systematically studied for their in vitro activities against LPS induced NF kappaB inhibition in RAW 264.7 cells using the SEAP assay based on the flexible chalcone JSH ((E)-1-(2-hydroxy-6-(isopentyloxy)phenyl)-3-(4-hydroxy phenyl)prop-2 en-1-one) which was previously reported. Although most of the benzimidazole derivatives showed strong inhibitory activity in low micromolar potency, 2-(4 methoxybenzyl)-1H-benzo[d]imidazole (3m; IC50=1.7 MUM) and 2-(2-methoxybenzyl)-1H benzo[d]imidazole (3n; IC50=2.4 MUM) showed the best inhibition. The structure activity relationship revealed that 2-benzylbenzimidazole scaffold with hydrogen bonding acceptor on phenyl ring appears as a pharmacophore. PMID- 26976505 TI - The effects of acute alcohol intoxication on the cognitive mechanisms underlying false facial recognition. AB - RATIONALE: False face recognition rates are sometimes higher when faces are learned while under the influence of alcohol. Alcohol myopia theory (AMT) proposes that acute alcohol intoxication during face learning causes people to attend to only the most salient features of a face, impairing the encoding of less salient facial features. Yet, there is currently no direct evidence to support this claim. OBJECTIVES: Our objective was to test whether acute alcohol intoxication impairs face learning by causing subjects to attend to a salient (i.e., distinctive) facial feature over other facial features, as per AMT. METHODS: We employed a balanced placebo design (N = 100). Subjects in the alcohol group were dosed to achieve a blood alcohol concentration (BAC) of 0.06 %, whereas the no alcohol group consumed tonic water. Alcohol expectancy was controlled. Subjects studied faces with or without a distinctive feature (e.g., scar, piercing). An old-new recognition test followed. Some of the test faces were "old" (i.e., previously studied), and some were "new" (i.e., not previously studied). We varied whether the new test faces had a previously studied distinctive feature versus other familiar characteristics. RESULTS: Intoxicated and sober recognition accuracy was comparable, but subjects in the alcohol group made more positive identifications overall compared to the no alcohol group. CONCLUSIONS: The results are not in keeping with AMT. Rather, a more general cognitive mechanism appears to underlie false face recognition in intoxicated subjects. Specifically, acute alcohol intoxication during face learning results in more liberal choosing, perhaps because of an increased reliance on familiarity. PMID- 26976508 TI - Dermoscopic and Reflectance Confocal Microscopy Findings in Extra-genital HPV16 associated Pigmented Squamous Cell Carcinoma in situ. PMID- 26976509 TI - DNA binding activity of Ku during chemotherapeutic agent-induced early apoptosis. AB - Ku protein is a heterodimer composed of two subunits, and is capable of both sequence-independent and sequence-specific DNA binding. The former mode of DNA binding plays a crucial role in DNA repair. The biological role of Ku protein during apoptosis remains unclear. Here, we show characterization of Ku protein during apoptosis. In order to study the DNA binding properties of Ku, we used two methods for the electrophoresis mobility shift assay (EMSA). One method, RI-EMSA, which is commonly used, employed radiolabeled DNA probes. The other method, WB EMSA, employed unlabeled DNA followed by western blot and detection with anti-Ku antiserum. In this study, Ku-DNA probe binding activity was found to dramatically decrease upon etoposide treatment, when examined by the RI-EMSA method. In addition, pre-treatment with apoptotic cell extracts inhibited Ku-DNA probe binding activity in the non-treated cell extract. The inhibitory effect of the apoptotic cell extract was reduced by DNase I treatment. WB-EMSA showed that the Ku in the apoptotic cell extract bound to fragmented endogenous DNA. Interestingly, Ku in the apoptotic cell extract purified by the Resource Q column bound 15-bp DNA in both RI-EMSA and WB-EMSA, whereas Ku in unpurified apoptotic cell extracts did not bind additional DNA. These results suggest that Ku binds cleaved chromosomal DNA and/or nucleosomes in apoptotic cells. In conclusion, Ku is intact and retains DNA binding activity in early apoptotic cells. PMID- 26976510 TI - International Research Interdisciplinary School (IRIS) initiative: sponsorship of journals in training of participants in peer-review. PMID- 26976511 TI - Surface electrocardiogram detects signs of right ventricular pressure overload among acute-decompensated heart failure with preserved ejection fraction patients. AB - BACKGROUND: Pulmonary hypertension (PH) is a common finding among patients with heart failure and preserved ejection fraction (HFpEF) and contributes to develop right ventricular systolic dysfunction (RVSD). AIMS: We evaluated the diagnostic accuracy of Flowers and Horan electrocardiographic criteria to detect significant right ventricular pressure overload. METHODS: 123 patients were prospectively included. We used the Flowers and Horan (FH) ECG criteria to define RV enlargement (score >10). Echocardiographic measurements were performed blinded to the electrocardiographic results. RESULTS: Severe PH was found in 51.5%. Seventeen patients (16.5%) had a FH score >10 points. This was associated to RVSD (RR 2.66; 1.51-4.67 CI 95%, p=0.002), with 90.5% specificity and 34.4% sensitivity and to severe PH (RR 1.70; 1.16-2.50 CI 95%, p=0.028) with 91.9% specificity and 27.5% sensitivity. CONCLUSIONS: The ECG is a useful tool to classify HFpEF patients with echocardiographic signs of right ventricular pressure overload, in the absence of RBBB. PMID- 26976512 TI - Tracking preference as unusual trigger of pacemaker-mediated tachycardia in a resynchronization device. AB - A 59-year-old woman with a history of congestive heart failure, who previously received a biventricular cardioverter-defibrillator was admitted with dyspnea and peripheral edema. She was noted on telemetry to have multiple self-terminated episodes of rapid ventricular pacing, consistent with pacemaker-mediated tachycardia. All episodes started after three consecutive ventricular extrasystoles. "Tracking preference" algorithm, designed to maintain atrial tracked biventricular pacing in CRT devices, resulted turned on. It affected minimum PVARP and resulted the trigger for pacemaker mediated tachycardia. PMID- 26976513 TI - Primary brain calcification in patients undergoing treatment with the biphosphanate alendronate. AB - Brain calcification might be associated with various metabolic, infectious or vascular conditions. Clinically, brain calcification can include symptoms such as migraine, parkinsonism, psychosis or dementia. The term Primary Brain Calcification was recently used for those patients without an obvious cause (formerly idiopathic) while Primary Familial Brain Calcifications was left for the cases with autosomal dominant inheritance. Recent studies found mutations in four genes (SLC20A2, PDGFRB, PDGFB and XPR1). However, these gene represent only 60% of all familial cases suggesting other genes remain to be elucidated. Studies evaluating treatments for such a devastating disease are scattered, usually appearing as single case reports. In the present study, we describe a case series of 7 patients treated with Alendronate, a widely prescribed biphosphanate. We observed good tolerance and evidence of improvements and stability by some patients. No side effects were reported and no specific symptoms related to medication. Younger patients and one individual continuing a prescription (prior to study commencement) appeared to respond more positively with some referred improvements in symptoms. Biphosphanates may represent an excellent prospect for the treatment of brain calcifications due to their being well tolerated and easily available. Conversely, prospective and controlled studies should promptly address weaknesses found in the present analysis. PMID- 26976514 TI - Aetiology and pathology of otitis media with effusion in adult life. AB - OBJECTIVES: To gather and analyse information concerning the aetiology and pathology of otitis media with effusion in adults. METHOD: A review of the English language literature from 1970 to the present was conducted. RESULTS: The available evidence suggests that otitis media with effusion in adult life is best viewed as a syndrome with a number of causes, including: infiltration of the eustachian tube by nasopharyngeal carcinoma and other local malignancies; changes in the middle ear and eustachian tube induced by radiotherapy; and systemic disease. CONCLUSION: There is now a body of evidence specifically related to the aetiology and pathology of otitis media with effusion in adult life. However, further research is required to fill in the gaps in our knowledge and understanding of this condition. PMID- 26976516 TI - Bilateral tadpole pupils. PMID- 26976517 TI - Status epilepticus of inflammatory etiology: A cohort study. PMID- 26976518 TI - Higher neutrophil counts before thrombolysis for cerebral ischemia predict worse outcomes. PMID- 26976520 TI - Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy. PMID- 26976521 TI - Pearls & Oy-sters: Tacrolimus neurotoxicity presenting as an isolated brainstem lesion. PMID- 26976522 TI - Education Research: Neurology resident education: Trending skills, confidence, and professional preparation. AB - OBJECTIVE: To survey US-trained graduating neurology residents who are American Academy of Neurology members, in an effort to trend perceived quality and completeness of graduate neurology education. METHODS: An electronic survey was sent to all American Academy of Neurology members graduating from US neurology residency programs in the Spring of 2014. RESULTS: Of 805 eligible respondents, 24% completed the survey. Ninety-three percent of adult neurology residents and 56% of child neurology residents reported plans to pursue fellowship training after residency. Respondents reported a desire for additional training in neurocritical care, neuro-oncology, neuromuscular diseases, botulinum toxin injection, and nerve blocks. There remains a clear deficit in business training of neurology residents, although there was notable improvement in knowledge of coding and office management compared to previous surveys. DISCUSSION: Although there are still areas of perceived weakness in neurology training, graduating neurology residents feel generally well prepared for their chosen careers. However, most still pursue fellowship training for reasons that are little understood. In addition to certain subspecialties and procedures, practice management remains deficient in neurology training and is a point of future insecurity for most residents. Future curriculum changes should consider resident reported gaps in knowledge, with careful consideration of improving business training. PMID- 26976524 TI - Whole spine MRI should be recommended for pyogenic spondylodiscitis; response to Abbara et al. PMID- 26976523 TI - Teaching Video NeuroImages: Finger clonus: When the pupil surpassed his master. PMID- 26976525 TI - Teicoplanin - An old new treatment for enterococcal prosthetic joint infections. PMID- 26976526 TI - Cancer genomics: opportunities for medicinal chemistry? PMID- 26976527 TI - Controlled Growth of Rubrene Nanowires by Eutectic Melt Crystallization. AB - Organic semiconductors including rubrene, Alq3, copper phthalocyanine and pentacene are crystallized by the eutectic melt crystallization. Those organic semiconductors form good eutectic systems with the various volatile crystallizable additives such as benzoic acid, salicylic acid, naphthalene and 1,3,5-trichlorobenzene. Due to the formation of the eutectic system, organic semiconductors having originally high melting point (Tm > 300 degrees C) are melted and crystallized at low temperature (Te = 40.8-133 degrees C). The volatile crystallizable additives are easily removed by sublimation. For a model system using rubrene, single crystalline rubrene nanowires are prepared by the eutectic melt crystallization and the eutectic-melt-assisted nanoimpinting (EMAN) technique. It is demonstrated that crystal structure and the growth direction of rubrene can be controlled by using different volatile crystallizable additives. The field effect mobility of rubrene nanowires prepared using several different crystallizable additives are measured and compared. PMID- 26976529 TI - Interventions for improving outcomes in patients with multimorbidity in primary care and community settings. AB - BACKGROUND: Many people with chronic disease have more than one chronic condition, which is referred to as multimorbidity. The term comorbidity is also used but this is now taken to mean that there is a defined index condition with other linked conditions, for example diabetes and cardiovascular disease. It is also used when there are combinations of defined conditions that commonly co exist, for example diabetes and depression. While this is not a new phenomenon, there is greater recognition of its impact and the importance of improving outcomes for individuals affected. Research in the area to date has focused mainly on descriptive epidemiology and impact assessment. There has been limited exploration of the effectiveness of interventions to improve outcomes for people with multimorbidity. OBJECTIVES: To determine the effectiveness of health-service or patient-oriented interventions designed to improve outcomes in people with multimorbidity in primary care and community settings. Multimorbidity was defined as two or more chronic conditions in the same individual. SEARCH METHODS: We searched MEDLINE, EMBASE, CINAHL and seven other databases to 28 September 2015. We also searched grey literature and consulted experts in the field for completed or ongoing studies. SELECTION CRITERIA: Two review authors independently screened and selected studies for inclusion. We considered randomised controlled trials (RCTs), non-randomised clinical trials (NRCTs), controlled before-after studies (CBAs), and interrupted time series analyses (ITS) evaluating interventions to improve outcomes for people with multimorbidity in primary care and community settings. Multimorbidity was defined as two or more chronic conditions in the same individual. This includes studies where participants can have combinations of any condition or have combinations of pre-specified common conditions (comorbidity), for example, hypertension and cardiovascular disease. The comparison was usual care as delivered in that setting. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the included studies, evaluated study quality, and judged the certainty of the evidence using the GRADE approach. We conducted a meta-analysis of the results where possible and carried out a narrative synthesis for the remainder of the results. We present the results in a 'Summary of findings' table and tabular format to show effect sizes across all outcome types. MAIN RESULTS: We identified 18 RCTs examining a range of complex interventions for people with multimorbidity. Nine studies focused on defined comorbid conditions with an emphasis on depression, diabetes and cardiovascular disease. The remaining studies focused on multimorbidity, generally in older people. In 12 studies, the predominant intervention element was a change to the organisation of care delivery, usually through case management or enhanced multidisciplinary team work. In six studies, the interventions were predominantly patient-oriented, for example, educational or self-management support-type interventions delivered directly to participants. Overall our confidence in the results regarding the effectiveness of interventions ranged from low to high certainty. There was little or no difference in clinical outcomes (based on moderate certainty evidence). Mental health outcomes improved (based on high certainty evidence) and there were modest reductions in mean depression scores for the comorbidity studies that targeted participants with depression (standardized mean difference (SMD) -2.23, 95% confidence interval (CI) -2.52 to -1.95). There was probably a small improvement in patient-reported outcomes (moderate certainty evidence) although two studies that specifically targeted functional difficulties in participants had positive effects on functional outcomes with one of these studies also reporting a reduction in mortality at four year follow-up (Int 6%, Con 13%, absolute difference 7%). The intervention may make little or no difference to health service use (low certainty evidence), may slightly improve medication adherence (low certainty evidence), probably slightly improves patient-related health behaviours (moderate certainty evidence), and probably improves provider behaviour in terms of prescribing behaviour and quality of care (moderate certainty evidence). Cost data were limited. AUTHORS' CONCLUSIONS: This review identifies the emerging evidence to support policy for the management of people with multimorbidity and common comorbidities in primary care and community settings. There are remaining uncertainties about the effectiveness of interventions for people with multimorbidity in general due to the relatively small number of RCTs conducted in this area to date, with mixed findings overall. It is possible that the findings may change with the inclusion of large ongoing well-organised trials in future updates. The results suggest an improvement in health outcomes if interventions can be targeted at risk factors such as depression, or specific functional difficulties in people with multimorbidity. PMID- 26976528 TI - Pitfalls and Challenges of Lung Transplant in a Patient With Kartagener Syndrome and Scoliosis. AB - We present a 22-year-old woman with Kartagener syndrome and scoliosis who died 112 days after single lung transplant. The classic thoracic involvement of situs inversus totalis and the asymmetric arrangement of the thoracic vascular structures might be a pitfall for surgeon. Anatomic obstacles have forced the surgeon to perform a single transplant. The period of primary graft dysfunction in a single transplanted lung patient was a challenge; supporting the patient with a high flow and long period of extracorporeal membrane oxygenation might lead to a vanishing bronchus. Immotile cilia, a feature of Kartagener syndrome, were another challenge and patient needed several daily aspiration bronchoscopies. Vanishing bronchus is a gradual process with high mortality rates; commonly, stenosis is at the non anastomotic bronchial tree because of insufficient nourishment of the bronchial cartilages. Several repeat bronchoscopic balloon dilatations accompanied with medical treatment were unsuccessful. PMID- 26976530 TI - The effect from maximal bench press strength training on work economy during wheelchair propulsion in men with spinal cord injury. AB - OBJECTIVE: To assess the effect from maximal bench press strength training (MST) on wheelchair propulsion work economy (WE). STUDY DESIGN: Pretest-posttest case control group design. SETTING: St Olavs Hospital, Trondheim, Norway. METHODS: Seventeen male individuals with spinal cord injury (SCI) paraplegia were allocated to either MST bench press (n=11) or the control group (CG) (n=7). The MST group trained bench press three times per week, for 6 weeks, starting at 85 95% of their pretest bench press one-repetition maximum (1RM). For calculation of WE during wheelchair propulsion, oxygen uptake (VO2) measurements were collected during wheelchair ergometry (WCE) at submaximal workload of 50 W. Similarly, peak oxygen uptake (VO2peak) and peak power output (W) were measured during WCE. RESULTS: Individuals in the MST regimen significantly improved WE compared with the CG by 17.3 % (mean between-group differences: 95% confidence interval) of 2.63 ml kg-1 min-1: (-4.34, -0.91) (P=0.007). Between pretest and posttest, the increase in bench press 1RM was by 17% higher in the MST group compared with the CG. At peak testing, the MST group generated significantly higher peak power compared with the CG. All other physiological variables were comparable within and between groups. CONCLUSIONS: A 6-week MST bench press regimen significantly improved WE during wheelchair propulsion at 50 W workload. These preliminary data support a possible beneficial role for MST to reduce the energy cost of wheelchair propulsion for SCI individuals. PMID- 26976533 TI - Niet bij medicatie alleen: het voorschrijven van farmaca bij de terugvalpreventie bij alcoholafhankelijkheid. PMID- 26976534 TI - De klinische praktijk van de medicamenteuze behandeling van alcoholverslaving. PMID- 26976531 TI - Investigating the status of using lower extremity orthoses recommended to patients with spinal cord injury. AB - STUDY DESIGN: Retrospective descriptive study. OBJECTIVES: The present study aimed to investigate the rate of using orthosis among spinal cord injury (SCI) patients for whom orthosis was recommended for standing and walking, the relationship between the clinical and demographic characteristics of SCI and the use of orthosis and the reasons for not using orthosis. SETTING: Ankara Physical Medicine and Rehabilitation Training and Research Hospital, Turkey. METHODS: The study included 62 SCI patients for whom orthosis was recommended for standing and ambulation. The patients were classified into two groups as individuals using and not using the recommended orthosis every day in order to evaluate the effect of age, gender, residence, duration of disease/recommended duration of orthosis, recommended orthosis, lesion level-degree, lower extremity tonus-range of motion and ambulation level on the frequency of orthosis use. RESULTS: The orthosis most commonly recommended was hip-knee-ankle-foot orthosis with waist or pelvic belt (45.2%). Of the patients, 25.8% have never used the orthosis. The most common reason for not using the recommended orthosis was the failure to facilitate the daily life activities of the patient (30%), the difficulties in putting them on and taking them off (20%), the belief that it is unnecessary (15%) and the pressure (15%). In addition, the assessed clinical and demographic features were detected as not important risk factors for not using orthosis. CONCLUSION: At least one out of four patients with SCI do not use the recommended lower extremity orthosis. Selecting eligible patients, patient training and follow-up are important for increased frequency of orthosis usage. PMID- 26976532 TI - Vitamin D deficiency in Swiss elite wheelchair athletes. AB - STUDY DESIGN: This is a retrospective analysis of total serum 25-hydroxyvitamin D (25[OH]D) in Swiss elite wheelchair athletes. OBJECTIVES: The aim was to investigate the occurrence of vitamin D deficiency in Swiss elite wheelchair athletes over the whole year and to detect differences between winter and summer months, and between indoor and outdoor athletes. SETTING: This study was conducted in Switzerland. METHODS: A total of 164 blood samples from 72 Swiss elite wheelchair athletes (mean+/-s.d.: age 32+/-13 years) were analyzed for total serum 25[OH]D. All participants were members of the national team in their discipline. The following disciplines have been included: rugby, athletics, cycling, tennis, ski alpine, curling and basketball. According to general guidelines, insufficient vitamin D status was defined between 50 and 75 nmol l-1, deficiency below 50 nmol l-1 and severe deficiency below 27.5 nmol l-1. RESULTS: In all, 73.2% of all samples showed an insufficiency/deficiency in vitamin D status. Total serum 25[OH]D was significantly higher during summer compared with winter months (69.5+/-21.4 nmol l-1 vs 51.5+/-21.9 nmol l-1; P<0.001). Indoor sports showed a higher amount of vitamin D insufficiency/deficiency (80.9%) than outdoor sports (70.1%), with a significantly higher 25[OH]D concentration in outdoor sports (P=0.042). CONCLUSION: A high percentage of vitamin D deficiency was found among Swiss elite wheelchair athletes. Conclusively, we recommend supplementation with vitamin D-especially during winter-to prevent a deficiency and an impairment of performance. PMID- 26976535 TI - Effectieve interventie bij de behandeling van patienten met alcoholproblemen. PMID- 26976536 TI - Commentaar. AB - Het mag als een verworvenheid beschouwd worden dat er sinds kort stoffen op de markt zijn die de kans op terugval van alcoholisten verkleinen. Natuurlijk hebben deze stoffen, zoals acamprosaat en naltrexon indicaties en contra-indicaties, en die zijn in de voorgaande artikelen beschreven. Het is daarmee echter nog niet gemakkelijk geworden een richtlijn voor de dagelijkse praktijk te formuleren. Dat blijkt wel uit deze artikelen. Immers, acamprosaat is effectief gebleken, maar nu ook weer niet zo effectief dat het niet voorschrijven ervan per definitie een gemiste kans moet worden beschouwd. De Jong en Schippers wijzen er terecht op dat als stoffen te enthousiast worden voorgeschreven, zoals dat met disulfiram is gebeurd, het grote aantal mislukkingen ertoe kan leiden dat men zich weer teleurgesteld van zo'n stof afwendt. En het risico op dit soort therapeutisch enthousiasme is juist bij de behandeling van verslavingen levensgroot. Er zijn weinig ziektebeelden die bij een behandelaar zoveel machteloosheid kunnen oproepen en dus zoveel neiging naar strohalmen te grijpen. PMID- 26976537 TI - Cardiopsychiatry. AB - Affective disorders cluster in patients with cardiac diseases, in particular in coronary artery disease (CAD) which has become one of the most prevalent chronic disorders in the western world. Affective dysregulation has been recognized as a major riskfactor for cardiac death in patients with CAD. Therefore treatment of affective dysregulation is important from both the psychiatric and cardiac perspective. An evidence based treatment algorithm for affective disorders is as yet not available. In this paper a possible etiological model for the relationship between affective and cardiac dysregulation is proposed, based on the stress-diathesis model. PMID- 26976538 TI - Somatization disorders in non psychiatric settings: A multidimensional diagnostic approach. AB - Given the diagnostic ambiguity of physically unexplained complaints we wanted to study whether the clinically and symptomatically characterized groups, all of them defined according to DSM-III-R criteria, could be reclassified using selected empirical and theoretical variables of operationally defined parameters. Patients with conversion (N = 75), somatization or undifferentiated somatoform disorders (N = 74) and major depression (N = 70) according to DSM-III-R underwent multidimensional work-up including psychopathological, personality-psychological, illness, behavioral and coping assessment. The clinically characterized groups should be statistically reclassified by discriminant analytic techniques. The existing diagnostic categories according to DSM-III-R could be widely confirmed by the statistical reconstitution of the clinical groups. Conversion, somatization and depressive disorder presented as distinct clinical categories. A classification relying widely on symptoms still seems to be too superficial and does not represent the complexity of these patients. Thus, the modern classification systems with their purely phenomenological criteria should be added with further dimensions. PMID- 26976539 TI - Management of psychiatric adverse events with immunotherapy with interferon-alfa. AB - Immunotherapy with interferon-alfa has become standard therapy in selected patients with viral hepatitis and chronic myelogenous leukemia. In addition, it is used in a variety of other diseases, both as standard therapy and in clinical trials. Its use is expected to expand in the following decade. Interferon can cause (severe) neuropsychiatric side effects. These side effects are discussed. Adequate management of these side effects is important, as is close collaboration between the oncologist and the psychiatrist. The cornerstone of management is patient education: this prevents interruption of therapy by patients who were not warned for neuropsychiatric side effects. Furthermore, patients should report in case of rapidly arising mood disorders. Interferon-alfa induced mood disorder is reported to be treatable. Three case descriptions illustrate this, but also illustrate some limits to successful treatment. PMID- 26976540 TI - Cytokines in de obsessief compulsieve stoornis en in anorexia nervosa: een overzicht. AB - The alterations in the inflammatory response system (IRS) appear to be quite different between OCD and anorexia nervosa and are also different from the changes observed in major depression. In anorexia nervosa, there is some evidence for increased production of monocytic cytokines, i.e. tumor necrosis factor-alpha (TNFalpha) and interleukin-6 (IL-6), and decreased production of Th-1 like cytokines, i.e. IL-2 and IFNgamma. In the same patients there are also signs of immunosuppression, e.g. lowered numbers of CD4 and CD8 T cells and increased production of transforming growth factor-beta (TGFbeta). The increased production of monocytic cytokines may be the consequence of the hyponutritional status of those patients. The diminished production of the Th-1 like cytokines may be the consequence of at least four different factors: 1) the deficiency in nutritional factors; 2) neuroendocrine disorders, such as increased Cortisol production; 3) the increased TGFbeta production; and 4) lower serum dipeptidyl peptidase activity. In OCD no consistent or specific alterations in the IRS are observed. There is no evidence that IRS activation may play a role in the pathophysiology of OCD and anorexia nervosa. PMID- 26976541 TI - Chronic unexplained fatigue. AB - Fatigue is a common symptom in the community and the commonest associations are with stress or mood disturbance. One in a hundred people complain of unexplained and prolonged fatigue, with half that number meeting the strictest criteria for the chronic fatigue syndrome (CFS). Discrete fatigue syndromes have been described, particularly after Epstein Barr virus infection. The majority of patients with CFS have a syndrome similar to the ICD-10 definition of neurasthenia. Mood and somatoform disorders are common comorbid or differential diagnoses. The prognosis is poor, particularly in patients attending hospitals and those with comorbid psychiatric disorders. The aetiology of both CFS and chronic unexplained fatigue are essentially unknown, perhaps reflecting the heterogenenous natures of both the symptom and syndrome. There is reasonable evidence to suggest that particular infections may trigger both prolonged fatigue and CFS. Maintaining factors are different from triggering factors and include mood and sleep disorders, illness beliefs and behaviours, and possibly inactivity. Treatments aimed at reversing these maintaining factors show promise. PMID- 26976542 TI - Whiplash associated disorders: is there a place for psychiatrists and psychologists? AB - Between 25 and 30% of the victims of a whiplash injury have complaints after one year. This condition is referred to as late whiplash syndrome. This syndrome is characterized by pain of the neck, headache, forgetfulness, poor concentration, mental fatigue, and affective symptoms. The causes of the persistent symptoms are unknown. In all, the evidence that late-whiplash syndrome is a neurological disorder is flimsy. Current opinion holds that the acute basis is the painful injury of the neck. In the months following the accident, pain is the substrate on which psychological and social factors may act. Emotional symptoms such as lability of affect and disturbed mood, or posttraumatic stress disorders are common after whiplash. Although there is definitely a place for psychiatrists and psychologists in the treatment of late whiplash syndrome, these professionals are not involved in late whiplash disorder as much as they should be. Brief psychological treatment has proven to significantly reduce the severity and duration of symptoms. Optimal management must cover the treatment of pain, depression, anxiety, and fatigue; adequate psycho-education, stressing the good long-term outcome; and education of patients and relatives on possible cognitive symptoms. PMID- 26976543 TI - Epilepsy and psychiatric disorders. AB - The relationship between epilepsy and behavior disorders will be briefly outlined, and an initial distinction between periictal and interictal disorders made. This paper will concentrate on the periictal disorders. These include the ictally driven psychoses, such as complex partial seizure status and absence status. There will then be a discussion of the postictal psychoses. It will be noted how these form a constant clinical picture, which sometimes goes unrecognized. The phenomenology may be typically paranoid or schizophrenia-like, andpatients often present in a setting of clear consciousness. The fascinating phenomenon of the lucid interval will be noted. Following this there will be some discussions on the management of these disorders. The rest of the paper will discuss the phenomenon of forced normalization, first discovered by Landolt. This often remains unrecognised, but is of interest to both neurology and psychiatry. Essentially this is about patients who, following suppression of seizures, develop an acute psychotic state or some other kind of behavior disorder. With the return of the seizures the behavior disorder resolves. Various theories in relationship to this condition will be noted, and the fascinating paradox that in psychiatry we give a seizure to resolve a psychosis, whereas in epileptology suppression of seizures can lead to a psychosis will be presented. PMID- 26976544 TI - Med Psych Units: Proceedings and abstracts of the Triptych Workshop 9 december 1999 Maastricht. AB - Med Psych Units (MPU) are neither clear-cut medical nor psychiatric units. This makes it difficult to acquire funding for these often expensive units. Despite this, there are many reasons why MPU's should be a necessary part of any larger scale inpatient service of a general and teaching hospital. It is therefore even more remarkable that such units hardly exist in Europe and that only about twenty exist in the USA. Five main reasons why such units should be opened are: The increasing average age of the population of the Western World, with high co morbidity and polypharmacy in the elderly and elderly elderly. An increase in the number of chronic physical diseases resulting in co-morbid psychiatric disorders. This increase in chronicity is the consequence of increasingly successful treatment of acute and potentially lethal diseases; for example, acute myocardial infarction and the subsequent development of chronic heart disease. The decreasing duration of hospital admission. On average the duration of stay in a general hospital in The Netherlands is now nine days. The number of day treatments has doubled in the last decade. This situation means that it is not possible to observe the behavior of patients on a general medical ward or to carry out a psychiatric consultation. Inadequate medical evaluation of psychiatric patients. According to a recent survey by the Dutch Ministry of Health, the care given for physical disease to psychiatric patients in mental hospitals in The Netherlands needs much to be desired for. The psychiatric co morbidity of somatic diseases is accompanied by a high consumption of medical facilities and high economic losses, unless adequately recognized and treated. PMID- 26976546 TI - Vocal-fold vibration of patients with Reinke's edema observed using high-speed digital imaging. AB - OBJECTIVE: We aimed to assess the vocal-fold vibration of patients with moderate to-severe Reinke's edema using high-speed digital imaging (HSDI) and videostroboscopy and to confirm HSDI usefulness in examining the vocal folds with Reinke's edema. METHODS: We examined the vocal folds of seven patients (six severe and one moderate; six females and one male; aged 55-74 years; mean 64.7 years) with Reinke's edema using HSDI and videostroboscopy. The following characteristics were analyzed: glottic closure, mucosal-wave propagation, left right asymmetry, phase shift, frequency difference, periodicity, and contact of the true vocal fold with the false vocal fold. RESULTS: HSDI revealed complete glottic closure, anterior-posterior phase shift, and obvious contact of at least one side of the edematous true vocal fold with the ipsilateral false vocal fold in all patients. Mucosal-wave propagation increased in six patients and decreased in one. Left-right asymmetry was observed in six patients. Left-right phase shifts and left-right frequency differences were observed in four and two patients, respectively. The vibration was periodic in four patients, quasi periodic in three, and aperiodic in none. Anterior-posterior frequency differences were not observed for any patient. The vocal-fold vibration always synchronized with strobolights in two patients, while the vibration occasionally and never synchronized in two and three patients, respectively. In one patient whose vibration occasionally synchronized, videostroboscopy could not reveal the slight left-right frequency difference of the vibration. CONCLUSION: It was often difficult to observe vocal-fold vibration correctly in patients with severe Reinke's edema using videostroboscopy. However, HSDI was useful for examining these patients. Our results suggest that HSDI can be very useful for examining the vocal folds of patients with severe Reinke's edema. PMID- 26976545 TI - Merging Electronic Health Record Data and Genomics for Cardiovascular Research: A Science Advisory From the American Heart Association. AB - The process of scientific discovery is rapidly evolving. The funding climate has influenced a favorable shift in scientific discovery toward the use of existing resources such as the electronic health record. The electronic health record enables long-term outlooks on human health and disease, in conjunction with multidimensional phenotypes that include laboratory data, images, vital signs, and other clinical information. Initial work has confirmed the utility of the electronic health record for understanding mechanisms and patterns of variability in disease susceptibility, disease evolution, and drug responses. The addition of biobanks and genomic data to the information contained in the electronic health record has been demonstrated. The purpose of this statement is to discuss the current challenges in and the potential for merging electronic health record data and genomics for cardiovascular research. PMID- 26976547 TI - Outcomes review of modern hearing preservation technique in cochlear implant. AB - INTRODUCTION: Preservation of residual hearing in cochlear implantation is a main concern for patients and otologists. New electrode arrays as well as development of minimally invasive technique have allowed the expansion of indication criteria for cochlear implantation. The loss of residual low-frequency hearing is thought to be the result of many factors. Opinions differ in regards with the electrodes array characteristics, the surgical implantation technique and the pharmacological therapy used. OBJECTIVE: The aim of this research is to analyze the available information pertaining to hearing preservation with cochlear implantation. RESULTS: Both cochleostomy and round window approaches are adequate, but should rely on the anatomic position of the round window membrane. No electrode design had a higher rate of hearing preservation, either a standard or shorter length was used, or a straight or contoured array. The speed of insertion has a significant impact on hearing preservation and vestibular function. A slow insertion should be used for all cochlear implant insertion, hearing preservation or not. However, the optimal speed of insertion is still unclear. Moreover, the use of steroids regardless of the route or the timing, along with intraoperative topical steroids, had a positive impact on hearing preservation. CONCLUSION: Classic atraumatic insertion maneuvers, very slow and delicate insertion and the use of intraoperative corticosteroids improve hearing outcomes. Whichever the surgeon's preferences, all surgical modifications are aimed at the same goal: protection of the delicate intracochlear structures with preservation of residual low-frequency hearing to improve speech perception abilities. PMID- 26976548 TI - Cardiomyocytes in Young Infants With Congenital Heart Disease: a Three-Month Window of Proliferation. AB - Perinatal reduction in cardiomyocyte cell cycle activity is well established in animal models and humans. However, cardiomyocyte cell cycle activity in infants with congenital heart disease (CHD) is unknown, and may provide important information to improve treatment. Human right atrial specimens were obtained from infants during routine surgery to repair ventricular septal defects. The specimens were divided into three groups: group A (age 1-3 months); group B (age, 4-6 months); and group C (age 7-12 months). A dramatic fall in the number of Ki67 positive CHD cardiac myocytes occurred after three months. When cultured in vitro, young CHD myocytes (<= 3 months) showed more abundant Ki67-positive cardiomyocytes and greater incorporation of EdU, indicating enhanced proliferation. YAP1 and NICD-important transcript factors in cardiomyocyte development and proliferation-decreased with age and beta-catenin increased with age. Compared with those of older infants, cardiomyocytes of young CHD infants (<= 3 months) have a higher proliferating capacity in vivo and in vitro. From the perspective of cardiac muscle regeneration, CHD treatment at a younger age (<= 3 months) may be more optimal. PMID- 26976549 TI - Update on pulmonary disease due to non-tuberculous mycobacteria. AB - Non-tuberculous mycobacteria (NTM) are emerging worldwide as significant causes of chronic pulmonary infection, posing a number of challenges for both clinicians and researchers. While a number of studies worldwide have described an increasing prevalence of NTM pulmonary disease over time, population-based data are relatively sparse and subject to ascertainment bias. Furthermore, the disease is geographically heterogeneous. While some species are commonly implicated worldwide (Mycobacterium avium complex, Mycobacterium abscessus), others (e.g., Mycobacterium malmoense, Mycobacterium xenopi) are regionally important. Thoracic computed tomography, microbiological testing with identification to the species level, and local epidemiology must all be taken into account to accurately diagnose NTM pulmonary disease. A diagnosis of NTM pulmonary disease does not necessarily imply that treatment is required; a patient-centered approach is essential. When treatment is required, multidrug therapy based on appropriate susceptibility testing for the species in question should be used. New diagnostic and therapeutic modalities are needed to optimize the management of these complicated infections. PMID- 26976551 TI - Tolosa-Hunt syndrome with spontaneous remission and recurrence. PMID- 26976550 TI - A comparison of B cell subsets in primary immune deficiencies that progress with antibody deficiency and age-matched healthy children. AB - BACKGROUND: The objective of this study was to examine the B lymphocyte subsets in primary immunodeficiency that progress with antibody deficiency. METHODS: The patients' naive, memory, class-switched memory and non-switched memory B cells were compared with those of healthy individuals of matching ages using flow cytometry. RESULTS: A total of 67 patients with antibody deficiency and 28 healthy children of matching ages were included in the study. The median age of the patients was six years (min-max: 1-24) and 40 (59.7%) were male. The median age of the healthy controls was again six years (min-max: 1-17) and 12 (42.8%) were male. Patients with common variable immunodeficiency had higher relative counts of naive cells when compared with the control group; however, they were found to have lower relative counts of memory, relative and absolute counts of non-switched and relative counts of switched B lymphocytes (p=0.001, 0.023, 0.003 0.003, 0.001, respectively). In patients with selective IgA deficiency, similar to patients with common variable immunodeficiency, the relative counts of naive cells were found to be higher, while the relative counts of memory and relative and absolute counts of non-switched B lymphocytes were found to be lower when compared with the control group (p=0.011, 0.032, 0.006-0.009, respectively). Although patients with selective IgM deficiency had higher relative counts of naive B cells when compared with the control group, they had lower relative and absolute counts of non-switched B lymphocytes (p=0.008-0.016). CONCLUSIONS: The B lymphocyte subsets of patients with selective IgA deficiency are largely similar to those of patients with common variable immunodeficiency. Both illness groups exhibit low levels of memory B cells. PMID- 26976552 TI - The Evolving Approach to Brain Dysfunction in Critically Ill Patients. PMID- 26976553 TI - Crown vs. composite for post-retained restorations: A randomized clinical trial. AB - OBJECTIVES: This randomized clinical trial compared the survival of composite resin restorations and metal-ceramic crowns on endodontically treated teeth that received a glass fiber post using 2 different cementation methods. METHODS: Forty seven patients (age 42.5 +/- 11.5) with fifty-seven endodontically treated teeth with extensive coronal damage but always with one intact surface were randomly allocated according to the type of coronal restoration: metal-ceramic crown or composite resin. In case of crown restoration, a core buildup was performed with microhybrid composite resin. The dentin bonding agent and composite resin used were the same for both direct and indirect restorations. Descriptive analysis was performed using FDI clinical criteria and survival of restorations/teeth analyzed using Kaplan-Meier statistics and log-rank tests. RESULTS: 57 restorations (30 composite resin and 27 crowns) were made in 47 patients. The recall rate was 100% and follow up time ranged between 1 and 5 years. One tooth was extracted 11 months post-restoration due to root fracture (composite group). Eight composite restorations and one crown had reparable failures, all due to secondary caries or restoration fracture. The overall annual failure rate (AFR) was 0.92% after 50 months for success of the restorations, with 1.83% for the composite group and 0.26% for the metal-ceramic crown group. The log-rank test showed no difference for survival according to the type of restoration (p=0.344). However, for success rates, metal-ceramic crowns demonstrated better performance (p=0.022). CONCLUSIONS: Indirect restorations provided higher acceptable clinical performance and lower need for re-intervention, but both types of restorations presented good survival rates. (NCT01461239). CLINICAL SIGNIFICANCE: When endodontically treated teeth with at least one intact surface must be restored, composite resin restorations and metal-ceramic crows are acceptable alternatives to achieve good survival and success rates. PMID- 26976554 TI - The influence of intrinsic water permeation on different dentin bonded interfaces formation. AB - OBJECTIVES: To determine the effects of intrinsic wetness on the formation of dentin bonding interfaces of four resin cement systems bonded to dentin under different pulpal pressures. METHODS: Thirty-six freshly extracted third molars were selected and processed for dentin MUTBS. The teeth were randomly assigned into 12 experimental groups, according to the adhesive luting system [Adper Single Bond Plus (3M ESPE) combined with two luting agents RelyX ARC (3M ESPE) and heated Filtek Z250 Universal Restorative (3M ESPE), Clearfil CD Bond (Kuraray) combined with Clearfil Esthetic Cement (Kuraray), and RelyX Unicem 2 Automix (3M ESPE)] and pulpal pressure (0, 5, and 20 cm of simulated pulpal pressure). Leucite-reinforced glass-ceramic slabs (IPS Empress CAD, Ivoclar Vivadent) of 3mm thickness were bonded to dentin. The samples were stored in distilled water for 24h and then sectioned in X/Y directions across the adhesive interface to obtain specimens with a cross section of 0.8 +/- 0.2mm(2). All sticks were fractured by tension at a crosshead speed of 1.0mm/min and the data were submitted to Kruskal-Wallis and Mann-Whitney Tests (alpha=0.05). Ultrastructural analysis of the interfaces was performed using Confocal Laser Scanning Microscopy (CLSM) and Scanning Electron Microscopy (SEM). RESULTS: The statistical analyses showed that pulpal pressure decreased MUTBS for all groups. Significantly higher MUTBS values were obtained in heated Z250 group restored without any pulpal pressure. CLSM showed that the uptake of water through the dentin tubuli and their anastomosis of lateral branches during the adhesive luting procedures prevented adequate formation of the dentin bonding interfaces. SEM showed that the luting film created is material- dependent and all adhesive failure occurred at the resin-dentin interface. CONCLUSION: The constant intrinsic wetness replenishment prevents adequate formation of the hybrid layer. CLINICAL SIGNIFICANCE: Intrinsic moisture during adhesive luting procedures significantly affects the interaction between luting materials and dentin subtract and decreases the quality and bonding strength of the resin-dentin bond. PMID- 26976555 TI - Conversion and temperature rise of remineralizing composites reinforced with inert fillers. AB - OBJECTIVES: Remineralizing experimental composites based on amorphous calcium phosphate (ACP) were investigated. The impact of curing time (20 and 40s), curing depth (1, 2, 3 and 4mm) and addition of inert fillers (barium glass and silica) on the conversion and temperature rise during curing were examined. METHODS: Five ACP-composites and two control composites were prepared based on the light curable EBPADMA-TEGDMA-HEMA resin. For temperature measurements, a commercial composite was used as an additional control. Conversion was assessed using FT Raman spectroscopy by comparing the relative change of the band at 1640 cm(-1) before and after polymerization. The temperature rise during curing was recorded in real-time using a T-type thermocouple. RESULTS: At 1mm depth, the ACP composites attained significantly higher conversion (77.8-87.3%) than the control composites based on the same resin (60.5-66.3%). The addition of inert fillers resulted in approximately 5% lower conversion at clinically relevant depths (up to 2mm) for the curing time of 40s. Conversion decline through depths depended on the added inert fillers. Conversion values higher than 80% of the maximum conversion were observed for all of the ACP-composites at depths up to 3mm, when cured for 40s. Significantly higher total temperature rise for the ACP-composites (11.5-13.1 degrees C) was measured compared to the control composites (8.6-10.8 degrees C) and the commercial control (8.7 degrees C). CONCLUSIONS: The admixture of inert fillers represents a promising strategy for further development of ACP-composites, as it reduced the temperature rise while negligibly impairing the conversion. CLINICAL SIGNIFICANCE: High conversions of ACP-composites are favorable in terms of mechanical properties and biocompatibility. However, high conversions were accompanied with high temperature rise, which might present a pulpal hazard. PMID- 26976556 TI - Managing acute hypercapnic respiratory failure in adults: where do we need to get to? PMID- 26976558 TI - Timing of delivery and pregnancy outcomes in women with gestational diabetes. AB - BACKGROUND: Women with gestational diabetes mellitus (GDM) commonly undergo induction of labor (IOL) at term, but the risks and benefits of IOL are incompletely understood. OBJECTIVE: We examined the relationship among gestational age, IOL, and the rate of cesarean delivery (CD) in women with GDM. STUDY DESIGN: We identified 863 women with GDM who underwent either IOL or spontaneous labor >=37 0/7 weeks. Demographic, cervical favorability, and outcome data were abstracted from the medical record. We compared the CD rate in women undergoing IOL at each week of gestation with expectant management to a later gestational age. RESULTS: When compared to women who were expectantly managed, IOL at 37 weeks (adjusted odds ratio [aOR], 1.53; 95% confidence interval [CI], 0.76-3.06; P = .23), 38 weeks (aOR, 2.07; 95% CI, 0.89-4.80; P = .09), and 39 weeks (aOR, 0.79; 95% CI, 0.44-1.42; P = .43)) was associated with similar risk for CD as expectant management after adjustment for nulliparity, body mass index, baseline simplified Bishop score, and maternal age. CD rates were higher in nulliparous women, but did not differ significantly in those undergoing IOL or expectant management. In multiparous women, IOL was significantly associated with an increased risk for CD at 38 weeks (aOR, 7.47; 95% CI, 1.6-34.8; P = .01) and rates of CD (17.39% vs 2.2%, P = .001) were significantly higher in multiparous women with an unfavorable Bishop score induced <39 weeks. Neonatal morbidity was similar across gestational ages after adjustment for maternal body mass index and maternal glycemic control. CONCLUSION: IOL results in similar risk for CD as expectant management between 37-40 weeks of gestation. Rates of CD differed based on cervical exam and parity. These findings suggest that gestational age alone does not significantly impact maternal and neonatal outcomes, but that decisions regarding delivery in women with GDM should take into account cervical exam and parity. PMID- 26976559 TI - "Will my work affect my pregnancy?" Resources for anticipating and answering patients' questions. AB - BACKGROUND: Authoritative information on occupational reproductive hazards is scarce and complex because exposure levels vary, multiple exposures may be present, and the reproductive toxicity of many agents remains unknown. For these reasons, women's health providers may find it challenging to effectively address workplace reproductive health issues with their patients who are pregnant, breast feeding, or considering pregnancy. Reproductive epidemiologists at the Centers for Disease Control and Prevention National Institute for Occupational Safety and Health answered >200 public requests for occupational reproductive health information during 2009 through 2013. The most frequent occupations represented were health care (41%) and laboratory work (18%). The most common requests for exposure information concerned solvents (14%), anesthetic gases (10%), formaldehyde (7%), infectious agents in laboratories (7%) or health care settings (7%), and physical agents (14%), including ionizing radiation (6%). Information for developing workplace policies or guidelines was sought by 12% of the requestors. Occupational exposure effects on breast-feeding were an increasing concern among working women. Based on information developed in response to these requestors, information is provided for discussing workplace exposures with patients, assessing potential workplace reproductive hazards, and helping patients determine the best options for safe work in pregnancy. Appendices provide resources to address specific occupational exposures, employee groups, personal protective equipment, breast-feeding, and workplace regulations regarding work and pregnancy. These tools can help identify those most at risk of occupational reproductive hazards and improve workers' reproductive health. The information can also be used to inform research priorities and assist the development of workplace reproductive health policies. PMID- 26976560 TI - High-seas fish wars generate marine reserves. AB - The effective management of marine fisheries is an ongoing challenge at the intersection of biology, economics, and policy. One way in which fish stocks-and their habitats-can be protected is through the establishment of marine reserves, areas that are closed to fishing. Although the potential economic benefits of such reserves have been shown for single-owner fisheries, their implementation quickly becomes complicated when more than one noncooperating harvester is involved in fishery management, which is the case on the high seas. How do multiple self-interested actors distribute their fishing effort to maximize their individual economic gains in the presence of others? Here, we use a game theoretic model to compare the effort distributions of multiple noncooperating harvesters with the effort distributions in the benchmark sole owner and open access cases. In addition to comparing aggregate rent, stock size, and fishing effort, we focus on the occurrence, size, and location of marine reserves. We show that marine reserves are a component of many noncooperative Cournot-Nash equilibria. Furthermore, as the number of harvesters increases, (i) both total unfished area and the size of binding reserves (those that actually constrain behavior) may increase, although the latter eventually asymptotically decreases; (ii) total rents and stock size both decline; and (iii) aggregate effort used (i.e., employment) can either increase or decrease, perhaps nonmonotonically. PMID- 26976561 TI - Carbon isotopes characterize rapid changes in atmospheric carbon dioxide during the last deglaciation. AB - An understanding of the mechanisms that control CO2 change during glacial interglacial cycles remains elusive. Here we help to constrain changing sources with a high-precision, high-resolution deglacial record of the stable isotopic composition of carbon in CO2(delta(13)C-CO2) in air extracted from ice samples from Taylor Glacier, Antarctica. During the initial rise in atmospheric CO2 from 17.6 to 15.5 ka, these data demarcate a decrease in delta(13)C-CO2, likely due to a weakened oceanic biological pump. From 15.5 to 11.5 ka, the continued atmospheric CO2 rise of 40 ppm is associated with small changes in delta(13)C CO2, consistent with a nearly equal contribution from a further weakening of the biological pump and rising ocean temperature. These two trends, related to marine sources, are punctuated at 16.3 and 12.9 ka with abrupt, century-scale perturbations in delta(13)C-CO2 that suggest rapid oxidation of organic land carbon or enhanced air-sea gas exchange in the Southern Ocean. Additional century scale increases in atmospheric CO2 coincident with increases in atmospheric CH4 and Northern Hemisphere temperature at the onset of the Bolling (14.6-14.3 ka) and Holocene (11.6-11.4 ka) intervals are associated with small changes in delta(13)C-CO2, suggesting a combination of sources that included rising surface ocean temperature. PMID- 26976562 TI - New tyrannosaur from the mid-Cretaceous of Uzbekistan clarifies evolution of giant body sizes and advanced senses in tyrant dinosaurs. AB - Tyrannosaurids--the familiar group of carnivorous dinosaurs including Tyrannosaurus and Albertosaurus--were the apex predators in continental ecosystems in Asia and North America during the latest Cretaceous (ca. 80-66 million years ago). Their colossal sizes and keen senses are considered key to their evolutionary and ecological success, but little is known about how these features developed as tyrannosaurids evolved from smaller basal tyrannosauroids that first appeared in the fossil record in the Middle Jurassic (ca. 170 million years ago). This is largely because of a frustrating 20+ million-year gap in the mid-Cretaceous fossil record, when tyrannosauroids transitioned from small-bodied hunters to gigantic apex predators but from which no diagnostic specimens are known. We describe the first distinct tyrannosauroid species from this gap, based on a highly derived braincase and a variety of other skeletal elements from the Turonian (ca. 90-92 million years ago) of Uzbekistan. This taxon is phylogenetically intermediate between the oldest basal tyrannosauroids and the latest Cretaceous forms. It had yet to develop the giant size and extensive cranial pneumaticity of T. rex and kin but does possess the highly derived brain and inner ear characteristic of the latest Cretaceous species. Tyrannosauroids apparently developed huge size rapidly during the latest Cretaceous, and their success in the top predator role may have been enabled by their brain and keen senses that first evolved at smaller body size. PMID- 26976563 TI - Correction for Petroff and Libchaber, Hydrodynamics and collective behavior of the tethered bacterium Thiovulum majus. PMID- 26976565 TI - Artificial eye for scotopic vision with bioinspired all-optical photosensitivity enhancer. AB - The ability to acquire images under low-light conditions is critical for many applications. However, to date, strategies toward improving low-light imaging primarily focus on developing electronic image sensors. Inspired by natural scotopic visual systems, we adopt an all-optical method to significantly improve the overall photosensitivity of imaging systems. Such optical approach is independent of, and can effectively circumvent the physical and material limitations of, the electronics imagers used. We demonstrate an artificial eye inspired by superposition compound eyes and the retinal structure of elephantnose fish. The bioinspired photosensitivity enhancer (BPE) that we have developed enhances the image intensity without consuming power, which is achieved by three dimensional, omnidirectionally aligned microphotocollectors with parabolic reflective sidewalls. Our work opens up a previously unidentified direction toward achieving high photosensitivity in imaging systems. PMID- 26976564 TI - Mitochondrial calcium uniporter regulator 1 (MCUR1) regulates the calcium threshold for the mitochondrial permeability transition. AB - During the mitochondrial permeability transition, a large channel in the inner mitochondrial membrane opens, leading to the loss of multiple mitochondrial solutes and cell death. Key triggers include excessive reactive oxygen species and mitochondrial calcium overload, factors implicated in neuronal and cardiac pathophysiology. Examining the differential behavior of mitochondrial Ca(2+) overload in Drosophila versus human cells allowed us to identify a gene, MCUR1, which, when expressed in Drosophila cells, conferred permeability transition sensitive to electrophoretic Ca(2+) uptake. Conversely, inhibiting MCUR1 in mammalian cells increased the Ca(2+) threshold for inducing permeability transition. The effect was specific to the permeability transition induced by Ca(2+), and such resistance to overload translated into improved cell survival. Thus, MCUR1 expression regulates the Ca(2+) threshold required for permeability transition. PMID- 26976566 TI - Impacts of classifying New York City students as overweight. AB - US schools increasingly report body mass index (BMI) to students and their parents in annual fitness "report cards." We obtained 3,592,026 BMI reports for New York City public school students for 2007-2012. We focus on female students whose BMI puts them close to their age-specific cutoff for categorization as overweight. Overweight students are notified that their BMI "falls outside a healthy weight" and they should review their BMI with a health care provider. Using a regression discontinuity design, we compare those classified as overweight but near to the overweight cutoff to those whose BMI narrowly earned them a "healthy" BMI grouping. We find that overweight categorization generates small impacts on girls' subsequent BMI and weight. Whereas presumably an intent of BMI report cards was to slow BMI growth among heavier students, BMIs and weights did not decline relative to healthy peers when assessed the following academic year. Our results speak to the discrete categorization as overweight for girls with BMIs near the overweight cutoff, not to the overall effect of BMI reporting in New York City. PMID- 26976567 TI - Discovery of fairy circles in Australia supports self-organization theory. AB - Vegetation gap patterns in arid grasslands, such as the "fairy circles" of Namibia, are one of nature's greatest mysteries and subject to a lively debate on their origin. They are characterized by small-scale hexagonal ordering of circular bare-soil gaps that persists uniformly in the landscape scale to form a homogeneous distribution. Pattern-formation theory predicts that such highly ordered gap patterns should be found also in other water-limited systems across the globe, even if the mechanisms of their formation are different. Here we report that so far unknown fairy circles with the same spatial structure exist 10,000 km away from Namibia in the remote outback of Australia. Combining fieldwork, remote sensing, spatial pattern analysis, and process-based mathematical modeling, we demonstrate that these patterns emerge by self organization, with no correlation with termite activity; the driving mechanism is a positive biomass-water feedback associated with water runoff and biomass dependent infiltration rates. The remarkable match between the patterns of Australian and Namibian fairy circles and model results indicate that both patterns emerge from a nonuniform stationary instability, supporting a central universality principle of pattern-formation theory. Applied to the context of dryland vegetation, this principle predicts that different systems that go through the same instability type will show similar vegetation patterns even if the feedback mechanisms and resulting soil-water distributions are different, as we indeed found by comparing the Australian and the Namibian fairy-circle ecosystems. These results suggest that biomass-water feedbacks and resultant vegetation gap patterns are likely more common in remote drylands than is currently known. PMID- 26976568 TI - Recombinant thiopeptides containing noncanonical amino acids. AB - Thiopeptides are a subclass of ribosomally synthesized and posttranslationally modified peptides (RiPPs) with complex molecular architectures and an array of biological activities, including potent antimicrobial activity. Here we report the generation of thiopeptides containing noncanonical amino acids (ncAAs) by introducing orthogonal amber suppressor aminoacyl-tRNA synthetase/tRNA pairs into a thiocillin producer strain of Bacillus cereus .We demonstrate that thiopeptide variants containing ncAAs with bioorthogonal chemical reactivity can be further postbiosynthetically modified with biophysical probes, including fluorophores and photo-cross-linkers. This work allows the site-specific incorporation of ncAAs into thiopeptides to increase their structural diversity and probe their biological activity; similar approaches can likely be applied to other classes of RiPPs. PMID- 26976570 TI - Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function. AB - Clinically available drugs active against Epstein-Barr virus (EBV) and other human herpesviruses are limited to those targeting viral DNA replication. To identify compounds directed against other steps in the viral life cycle, we searched for drugs active against the EBV SM protein, which is essential for infectious virus production. SM has a highly gene-specific mode of action and preferentially enhances expression of several late lytic cycle EBV genes. Here we demonstrate that spironolactone, a mineralocorticoid receptor antagonist approved for clinical use, inhibits SM function and infectious EBV production. Expression of EBV viral capsid antigen is highly SM dependent, and spironolactone inhibits viral capsid antigen synthesis and capsid formation, blocking EBV virion production at a step subsequent to viral DNA replication. In addition, spironolactone inhibits expression of other SM-dependent genes necessary for infectious virion formation. We further demonstrate that molecules structurally related to spironolactone with similar antimineralocorticoid blocking activity do not inhibit EBV production. These findings pave the way for development of antiherpesvirus drugs with new mechanisms of action directed against SM and homologous essential proteins in other herpesviruses. PMID- 26976569 TI - Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress. AB - Depression is a severe and chronic psychiatric disease, affecting 350 million subjects worldwide. Although multiple antidepressants have been used in the treatment of depressive symptoms, their beneficial effects are limited. The soluble epoxide hydrolase (sEH) plays a key role in the inflammation that is involved in depression. Thus, we examined here the role of sEH in depression. In both inflammation and social defeat stress models of depression, a potent sEH inhibitor, TPPU, displayed rapid antidepressant effects. Expression of sEH protein in the brain from chronically stressed (susceptible) mice was higher than of control mice. Furthermore, expression of sEH protein in postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder, and schizophrenia, was higher than controls. This finding suggests that increased sEH levels might be involved in the pathogenesis of certain psychiatric diseases. In support of this hypothesis, pretreatment with TPPU prevented the onset of depression-like behaviors after inflammation or repeated social defeat stress. Moreover, sEH KO mice did not show depression-like behavior after repeated social defeat stress, suggesting stress resilience. The sEH KO mice showed increased brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor TrkB in the prefrontal cortex, hippocampus, but not nucleus accumbens, suggesting that increased BDNF-TrkB signaling in the prefrontal cortex and hippocampus confer stress resilience. All of these findings suggest that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression. PMID- 26976572 TI - Conservation triage or injurious neglect in endangered species recovery. AB - Listing endangered and threatened species under the US Endangered Species Act is presumed to offer a defense against extinction and a solution to achieve recovery of imperiled populations, but only if effective conservation action ensues after listing occurs. The amount of government funding available for species protection and recovery is one of the best predictors of successful recovery; however, government spending is both insufficient and highly disproportionate among groups of species, and there is significant discrepancy between proposed and actualized budgets across species. In light of an increasing list of imperiled species requiring evaluation and protection, an explicit approach to allocating recovery funds is urgently needed. Here I provide a formal decision-theoretic approach focusing on return on investment as an objective and a transparent mechanism to achieve the desired recovery goals. I found that less than 25% of the $1.21 billion/year needed for implementing recovery plans for 1,125 species is actually allocated to recovery. Spending in excess of the recommended recovery budget does not necessarily translate into better conservation outcomes. Rather, elimination of only the budget surplus for "costly yet futile" recovery plans can provide sufficient funding to erase funding deficits for more than 180 species. Triage by budget compression provides better funding for a larger sample of species, and a larger sample of adequately funded recovery plans should produce better outcomes even if by chance. Sharpening our focus on deliberate decision making offers the potential to achieve desired outcomes in avoiding extinction for Endangered Species Act-listed species. PMID- 26976571 TI - Aurone synthase is a catechol oxidase with hydroxylase activity and provides insights into the mechanism of plant polyphenol oxidases. AB - Tyrosinases and catechol oxidases belong to the family of polyphenol oxidases (PPOs). Tyrosinases catalyze theo-hydroxylation and oxidation of phenolic compounds, whereas catechol oxidases were so far defined to lack the hydroxylation activity and catalyze solely the oxidation of o-diphenolic compounds. Aurone synthase from Coreopsis grandiflora (AUS1) is a specialized plant PPO involved in the anabolic pathway of aurones. We present, to our knowledge, the first crystal structures of a latent plant PPO, its mature active and inactive form, caused by a sulfation of a copper binding histidine. Analysis of the latent proenzyme's interface between the shielding C-terminal domain and the main core provides insights into its activation mechanisms. As AUS1 did not accept common tyrosinase substrates (tyrosine and tyramine), the enzyme is classified as a catechol oxidase. However, AUS1 showed hydroxylase activity toward its natural substrate (isoliquiritigenin), revealing that the hydroxylase activity is not correlated with the acceptance of common tyrosinase substrates. Therefore, we propose that the hydroxylase reaction is a general functionality of PPOs. Molecular dynamics simulations of docked substrate-enzyme complexes were performed, and a key residue was identified that influences the plant PPO's acceptance or rejection of tyramine. Based on the evidenced hydroxylase activity and the interactions of specific residues with the substrates during the molecular dynamics simulations, a novel catalytic reaction mechanism for plant PPOs is proposed. The presented results strongly suggest that the physiological role of plant catechol oxidases were previously underestimated, as they might hydroxylate their--so far unknown--natural substrates in vivo. PMID- 26976573 TI - Reevaluation of whether a soma-to-germ-line transformation extends lifespan in Caenorhabditis elegans. AB - The germ lineage is considered to be immortal. In the quest to extend lifespan, a possible strategy is to drive germ-line traits in somatic cells, to try to confer some of the germ lineage's immortality on the somatic body. Notably, a study in Caenorhabditis elegans suggested that expression of germ-line genes in the somatic cells of long-lived daf-2 mutants confers some of daf-2's long lifespan. Specifically, mRNAs encoding components of C. elegans germ granules (P granules) were up-regulated in daf-2 mutant worms, and knockdown of individual P-granule and other germ-line genes in daf-2 young adults modestly reduced their lifespan. We investigated the contribution of a germ-line program to daf-2's long lifespan and also tested whether other mutants known to express germ-line genes in their somatic cells are long-lived. Our key findings are as follows. (i) We could not detect P-granule proteins in the somatic cells of daf-2 mutants by immunostaining or by expression of a P-granule transgene. (ii) Whole-genome transcript profiling of animals lacking a germ line revealed that germ-line transcripts are not up regulated in the soma of daf-2 worms compared with the soma of control worms. (iii) Simultaneous removal of multiple P-granule proteins or the entire germ-line program from daf-2 worms did not reduce their lifespan. (iv) Several mutants that robustly express a broad spectrum of germ-line genes in their somatic cells are not long-lived. Together, our findings argue against the hypothesis that acquisition of a germ-cell program in somatic cells increases lifespan and contributes to daf-2's long lifespan. PMID- 26976574 TI - Galapagos hydroclimate of the Common Era from paired microalgal and mangrove biomarker 2H/1H values. AB - Tropical maritime precipitation affects global atmospheric circulation, influencing storm tracks and the size and location of subtropical deserts. Paleoclimate evidence suggests centuries-long changes in rainfall in the tropical Pacific over the past 2,000 y, but these remain poorly characterized across most of the ocean where long, continuous proxy records capable of resolving decadal-to centennial climate changes are still virtually nonexistent despite substantial efforts to develop them. Here we apply a new climate proxy based on paired hydrogen isotope ratios from microalgal and mangrove-derived sedimentary lipids in the Galapagos to reconstruct maritime precipitation changes during the Common Era. We show that increased rainfall during the Little Ice Age (LIA) (~1400-1850 CE) was likely caused by a southward migration of the Intertropical Convergence Zone (ITCZ), and that this shift occurred later than previously recognized, coeval with dynamically linked precipitation changes in South America and the western tropical Pacific. Before the LIA, we show that drier conditions at the onset of the Medieval Warm Period (~800-1300 CE) and wetter conditions ca. 2 ka were caused by changes in the El Nino/Southern Oscillation (ENSO). Collectively, the large natural variations in tropical rainfall we detect, each linked to a multicentury perturbation of either ENSO-like variability or the ITCZ, imply a high sensitivity of tropical Pacific rainfall to climate forcings. PMID- 26976575 TI - Identification and characterization of influenza variants resistant to a viral endonuclease inhibitor. AB - The influenza endonuclease is an essential subdomain of the viral RNA polymerase. It processes host pre-mRNAs to serve as primers for viral mRNA and is an attractive target for antiinfluenza drug discovery. Compound L-742,001 is a prototypical endonuclease inhibitor, and we found that repeated passaging of influenza virus in the presence of this drug did not lead to the development of resistant mutant strains. Reduced sensitivity to L-742,001 could only be induced by creating point mutations via a random mutagenesis strategy. These mutations mapped to the endonuclease active site where they can directly impact inhibitor binding. Engineered viruses containing the mutations showed resistance to L 742,001 both in vitro and in vivo, with only a modest reduction in fitness. Introduction of the mutations into a second virus also increased its resistance to the inhibitor. Using the isolated wild-type and mutant endonuclease domains, we used kinetics, inhibitor binding and crystallography to characterize how the two most significant mutations elicit resistance to L-742,001. These studies lay the foundation for the development of a new class of influenza therapeutics with reduced potential for the development of clinical endonuclease inhibitor resistant influenza strains. PMID- 26976576 TI - Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives. AB - The Escherichia coli AcrAB-TolC efflux pump is the archetype of the resistance nodulation cell division (RND) exporters from Gram-negative bacteria. Overexpression of RND-type efflux pumps is a major factor in multidrug resistance (MDR), which makes these pumps important antibacterial drug discovery targets. We have recently developed novel pyranopyridine-based inhibitors of AcrB, which are orders of magnitude more powerful than the previously known inhibitors. However, further development of such inhibitors has been hindered by the lack of structural information for rational drug design. Although only the soluble, periplasmic part of AcrB binds and exports the ligands, the presence of the membrane-embedded domain in AcrB and its polyspecific binding behavior have made cocrystallization with drugs challenging. To overcome this obstacle, we have engineered and produced a soluble version of AcrB [AcrB periplasmic domain (AcrBper)], which is highly congruent in structure with the periplasmic part of the full-length protein, and is capable of binding substrates and potent inhibitors. Here, we describe the molecular basis for pyranopyridine-based inhibition of AcrB using a combination of cellular, X-ray crystallographic, and molecular dynamics (MD) simulations studies. The pyranopyridines bind within a phenylalanine-rich cage that branches from the deep binding pocket of AcrB, where they form extensive hydrophobic interactions. Moreover, the increasing potency of improved inhibitors correlates with the formation of a delicate protein- and water-mediated hydrogen bond network. These detailed insights provide a molecular platform for the development of novel combinational therapies using efflux pump inhibitors for combating multidrug resistant Gram-negative pathogens. PMID- 26976577 TI - Optogenetic skeletal muscle-powered adaptive biological machines. AB - Complex biological systems sense, process, and respond to their surroundings in real time. The ability of such systems to adapt their behavioral response to suit a range of dynamic environmental signals motivates the use of biological materials for other engineering applications. As a step toward forward engineering biological machines (bio-bots) capable of nonnatural functional behaviors, we created a modular light-controlled skeletal muscle-powered bioactuator that can generate up to 300 uN (0.56 kPa) of active tension force in response to a noninvasive optical stimulus. When coupled to a 3D printed flexible bio-bot skeleton, these actuators drive directional locomotion (310 um/s or 1.3 body lengths/min) and 2D rotational steering (2 degrees /s) in a precisely targeted and controllable manner. The muscle actuators dynamically adapt to their surroundings by adjusting performance in response to "exercise" training stimuli. This demonstration sets the stage for developing multicellular bio-integrated machines and systems for a range of applications. PMID- 26976578 TI - Autocratic strategies for iterated games with arbitrary action spaces. AB - The recent discovery of zero-determinant strategies for the iterated prisoner's dilemma sparked a surge of interest in the surprising fact that a player can exert unilateral control over iterated interactions. These remarkable strategies, however, are known to exist only in games in which players choose between two alternative actions such as "cooperate" and "defect." Here we introduce a broader class of autocratic strategies by extending zero-determinant strategies to iterated games with more general action spaces. We use the continuous donation game as an example, which represents an instance of the prisoner's dilemma that intuitively extends to a continuous range of cooperation levels. Surprisingly, despite the fact that the opponent has infinitely many donation levels from which to choose, a player can devise an autocratic strategy to enforce a linear relationship between his or her payoff and that of the opponent even when restricting his or her actions to merely two discrete levels of cooperation. In particular, a player can use such a strategy to extort an unfair share of the payoffs from the opponent. Therefore, although the action space of the continuous donation game dwarfs that of the classic prisoner's dilemma, players can still devise relatively simple autocratic and, in particular, extortionate strategies. PMID- 26976579 TI - Four-dimensional maps of the human somatosensory system. AB - A fine-grained description of the spatiotemporal dynamics of human brain activity is a major goal of neuroscientific research. Limitations in spatial and temporal resolution of available noninvasive recording and imaging techniques have hindered so far the acquisition of precise, comprehensive four-dimensional maps of human neural activity. The present study combines anatomical and functional data from intracerebral recordings of nearly 100 patients, to generate highly resolved four-dimensional maps of human cortical processing of nonpainful somatosensory stimuli. These maps indicate that the human somatosensory system devoted to the hand encompasses a widespread network covering more than 10% of the cortical surface of both hemispheres. This network includes phasic components, centered on primary somatosensory cortex and neighboring motor, premotor, and inferior parietal regions, and tonic components, centered on opercular and insular areas, and involving human parietal rostroventral area and ventral medial-superior-temporal area. The technique described opens new avenues for investigating the neural basis of all levels of cortical processing in humans. PMID- 26976580 TI - Identification of tissue-specific cell death using methylation patterns of circulating DNA. AB - Minimally invasive detection of cell death could prove an invaluable resource in many physiologic and pathologic situations. Cell-free circulating DNA (cfDNA) released from dying cells is emerging as a diagnostic tool for monitoring cancer dynamics and graft failure. However, existing methods rely on differences in DNA sequences in source tissues, so that cell death cannot be identified in tissues with a normal genome. We developed a method of detecting tissue-specific cell death in humans based on tissue-specific methylation patterns in cfDNA. We interrogated tissue-specific methylome databases to identify cell type-specific DNA methylation signatures and developed a method to detect these signatures in mixed DNA samples. We isolated cfDNA from plasma or serum of donors, treated the cfDNA with bisulfite, PCR-amplified the cfDNA, and sequenced it to quantify cfDNA carrying the methylation markers of the cell type of interest. Pancreatic beta cell DNA was identified in the circulation of patients with recently diagnosed type-1 diabetes and islet-graft recipients; oligodendrocyte DNA was identified in patients with relapsing multiple sclerosis; neuronal/glial DNA was identified in patients after traumatic brain injury or cardiac arrest; and exocrine pancreas DNA was identified in patients with pancreatic cancer or pancreatitis. This proof of-concept study demonstrates that the tissue origins of cfDNA and thus the rate of death of specific cell types can be determined in humans. The approach can be adapted to identify cfDNA derived from any cell type in the body, offering a minimally invasive window for diagnosing and monitoring a broad spectrum of human pathologies as well as providing a better understanding of normal tissue dynamics. PMID- 26976581 TI - Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid independent pain modulatory systems within the CNS. AB - The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3'-iodobenzoyl-6beta naltrexamide) mediate a potent analgesia without many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of alpha2 adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid induced seizure activity, aversion to the kappa drug U50, 488H, or alpha2 mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa1, and alpha2 actions from analgesia. PMID- 26976582 TI - Inhibition of SCF ubiquitin ligases by engineered ubiquitin variants that target the Cul1 binding site on the Skp1-F-box interface. AB - Skp1-Cul1-F-box (SCF) E3 ligases play key roles in multiple cellular processes through ubiquitination and subsequent degradation of substrate proteins. Although Skp1 and Cul1 are invariant components of all SCF complexes, the 69 different human F-box proteins are variable substrate binding modules that determine specificity. SCF E3 ligases are activated in many cancers and inhibitors could have therapeutic potential. Here, we used phage display to develop specific ubiquitin-based inhibitors against two F-box proteins, Fbw7 and Fbw11. Unexpectedly, the ubiquitin variants bind at the interface of Skp1 and F-box proteins and inhibit ligase activity by preventing Cul1 binding to the same surface. Using structure-based design and phage display, we modified the initial inhibitors to generate broad-spectrum inhibitors that targeted many SCF ligases, or conversely, a highly specific inhibitor that discriminated between even the close homologs Fbw11 and Fbw1. We propose that most F-box proteins can be targeted by this approach for basic research and for potential cancer therapies. PMID- 26976585 TI - Ultrahigh-pressure polyamorphism in GeO2 glass with coordination number >6. AB - Knowledge of pressure-induced structural changes in glasses is important in various scientific fields as well as in engineering and industry. However, polyamorphism in glasses under high pressure remains poorly understood because of experimental challenges. Here we report new experimental findings of ultrahigh pressure polyamorphism in GeO2 glass, investigated using a newly developed double stage large-volume cell. The Ge-O coordination number (CN) is found to remain constant at ~6 between 22.6 and 37.9 GPa. At higher pressures, CN begins to increase rapidly and reaches 7.4 at 91.7 GPa. This transformation begins when the oxygen-packing fraction in GeO2 glass is close to the maximal dense-packing state (the Kepler conjecture = ~0.74), which provides new insights into structural changes in network-forming glasses and liquids with CN higher than 6 at ultrahigh pressure conditions. PMID- 26976584 TI - LSD1 modulates stress-evoked transcription of immediate early genes and emotional behavior. AB - Behavioral changes in response to stressful stimuli can be controlled via adaptive epigenetic changes in neuronal gene expression. Here we indicate a role for the transcriptional corepressor Lysine-Specific Demethylase 1 (LSD1) and its dominant-negative splicing isoform neuroLSD1, in the modulation of emotional behavior. In mouse hippocampus, we show that LSD1 and neuroLSD1 can interact with transcription factor serum response factor (SRF) and set the chromatin state of SRF-targeted genes early growth response 1 (egr1) and c-fos Deletion or reduction of neuro LSD1 in mutant mice translates into decreased levels of activating histone marks at egr1 and c-fos promoters, dampening their psychosocial stress induced transcription and resulting in low anxiety-like behavior. Administration of suberoylanilide hydroxamine to neuroLSD1(KO)mice reactivates egr1 and c-fos transcription and restores the behavioral phenotype. These findings indicate that LSD1 is a molecular transducer of stressful stimuli as well as a stress-response modifier. Indeed, LSD1 expression itself is increased acutely at both the transcriptional and splicing levels by psychosocial stress, suggesting that LSD1 is involved in the adaptive response to stress. PMID- 26976583 TI - Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. AB - Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein-protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes, reduce fatty acid synthesis and stimulate fatty acid oxidation in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease. PMID- 26976586 TI - Bonobos (Pan paniscus) show an attentional bias toward conspecifics' emotions. AB - In social animals, the fast detection of group members' emotional expressions promotes swift and adequate responses, which is crucial for the maintenance of social bonds and ultimately for group survival. The dot-probe task is a well established paradigm in psychology, measuring emotional attention through reaction times. Humans tend to be biased toward emotional images, especially when the emotion is of a threatening nature. Bonobos have rich, social emotional lives and are known for their soft and friendly character. In the present study, we investigated (i) whether bonobos, similar to humans, have an attentional bias toward emotional scenes compared with conspecifics showing a neutral expression, and (ii) which emotional behaviors attract their attention the most. As predicted, results consistently showed that bonobos' attention was biased toward the location of the emotional versus neutral scene. Interestingly, their attention was grabbed most by images showing conspecifics such as sexual behavior, yawning, or grooming, and not as much-as is often observed in humans-by signs of distress or aggression. The results suggest that protective and affiliative behaviors are pivotal in bonobo society and therefore attract immediate attention in this species. PMID- 26976587 TI - Low rates of nitrogen fixation in eastern tropical South Pacific surface waters. AB - An extensive region of the Eastern Tropical South Pacific (ETSP) Ocean has surface waters that are nitrate-poor yet phosphate-rich. It has been proposed that this distribution of surface nutrients provides a geochemical niche favorable for N2fixation, the primary source of nitrogen to the ocean. Here, we present results from two cruises to the ETSP where rates of N2fixation and its contribution to export production were determined with a suite of geochemical and biological measurements. N2fixation was only detectable using nitrogen isotopic mass balances at two of six stations, and rates ranged from 0 to 23 umol N m( 2)d(-1)based on sediment trap fluxes. Whereas the fractional importance of N2fixation did not change, the N2-fixation rates at these two stations were several-fold higher when scaled to other productivity metrics. Regardless of the choice of productivity metric these N2-fixation rates are low compared with other oligotrophic locations, and the nitrogen isotope budgets indicate that N2fixation supports no more than 20% of export production regionally. Although euphotic zone integrated short-term N2-fixation rates were higher, up to 100 umol N m(-2)d(-1), and detected N2fixation at all six stations, studies of nitrogenase gene abundance and expression from the same cruises align with the geochemical data and together indicate that N2fixation is a minor source of new nitrogen to surface waters of the ETSP. This finding is consistent with the hypothesis that, despite a relative abundance of phosphate, iron may limit N2fixation in the ETSP. PMID- 26976588 TI - Diverse high-torque bacterial flagellar motors assemble wider stator rings using a conserved protein scaffold. AB - Although it is known that diverse bacterial flagellar motors produce different torques, the mechanism underlying torque variation is unknown. To understand this difference better, we combined genetic analyses with electron cryo-tomography subtomogram averaging to determine in situ structures of flagellar motors that produce different torques, from Campylobacter and Vibrio species. For the first time, to our knowledge, our results unambiguously locate the torque-generating stator complexes and show that diverse high-torque motors use variants of an ancestrally related family of structures to scaffold incorporation of additional stator complexes at wider radii from the axial driveshaft than in the model enteric motor. We identify the protein components of these additional scaffold structures and elucidate their sequential assembly, demonstrating that they are required for stator-complex incorporation. These proteins are widespread, suggesting that different bacteria have tailored torques to specific environments by scaffolding alternative stator placement and number. Our results quantitatively account for different motor torques, complete the assignment of the locations of the major flagellar components, and provide crucial constraints for understanding mechanisms of torque generation and the evolution of multiprotein complexes. PMID- 26976589 TI - New inducible genetic method reveals critical roles of GABA in the control of feeding and metabolism. AB - Currently available inducible Cre/loxP systems, despite their considerable utility in gene manipulation, have pitfalls in certain scenarios, such as unsatisfactory recombination rates and deleterious effects on physiology and behavior. To overcome these limitations, we designed a new, inducible gene targeting system by introducing an in-frame nonsense mutation into the coding sequence of Cre recombinase (nsCre). Mutant mRNAs transcribed from nsCre transgene can be efficiently translated into full-length, functional Cre recombinase in the presence of nonsense suppressors such as aminoglycosides. In a proof-of-concept model, GABA signaling from hypothalamic neurons expressing agouti-related peptide (AgRP) was genetically inactivated within 4 d after treatment with a synthetic aminoglycoside. Disruption of GABA synthesis in AgRP neurons in young adult mice led to a dramatic loss of body weight due to reduced food intake and elevated energy expenditure; they also manifested glucose intolerance. In contrast, older mice with genetic inactivation of GABA signaling by AgRP neurons had only transient reduction of feeding and body weight; their energy expenditure and glucose tolerance were unaffected. These results indicate that GABAergic signaling from AgRP neurons plays a key role in the control of feeding and metabolism through an age-dependent mechanism. This new genetic technique will augment current tools used to elucidate mechanisms underlying many physiological and neurological processes. PMID- 26976590 TI - Open complex scrunching before nucleotide addition accounts for the unusual transcription start site of E. coli ribosomal RNA promoters. AB - Most Escherichia coli promoters initiate transcription with a purine 7 or 8 nt downstream from the -10 hexamer, but some promoters, including the ribosomal RNA promoter rrnB P1, start 9 nt from the -10 element. We identified promoter and RNA polymerase determinants of this noncanonical rrnB P1 start site using biochemical and genetic approaches including mutational analysis of the promoter, Fe(2+) cleavage assays to monitor template strand positions near the active-site, and Bpa cross-linking to map the path of open complex DNA at amino acid and nucleotide resolution. We find that mutations in several promoter regions affect transcription start site (TSS) selection. In particular, we show that the absence of strong interactions between the discriminator region and sigma region 1.2 and between the extended -10 element and sigma region 3.0, identified previously as a determinant of proper regulation of rRNA promoters, is also required for the unusual TSS. We find that the DNA in the single-stranded transcription bubble of the rrnB P1 promoter complex expands and is "scrunched" into the active site channel of RNA polymerase, similar to the situation in initial transcribing complexes. However, in the rrnB P1 open complex, scrunching occurs before RNA synthesis begins. We find that the scrunched open complex exhibits reduced abortive product synthesis, suggesting that scrunching and unusual TSS selection contribute to the extraordinary transcriptional activity of rRNA promoters by increasing promoter escape, helping to offset the reduction in promoter activity that would result from the weak interactions with sigma. PMID- 26976592 TI - Correction for Hernandez et al., Solar energy development impacts on land cover change and protected areas. PMID- 26976591 TI - Functional polymorphisms of macrophage migration inhibitory factor as predictors of morbidity and mortality of pneumococcal meningitis. AB - Pneumococcal meningitis is the most frequent and critical type of bacterial meningitis. Because cytokines play an important role in the pathogenesis of bacterial meningitis, we examined whether functional polymorphisms of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) were associated with morbidity and mortality of pneumococcal meningitis. Two functional MIF promoter polymorphisms, a microsatellite (-794 CATT5-8; rs5844572) and a single-nucleotide polymorphism (-173 G/C; rs755622) were genotyped in a prospective, nationwide cohort of 405 patients with pneumococcal meningitis and in 329 controls matched for age, gender, and ethnicity. Carriages of the CATT7 and -173 C high-expression MIF alleles were associated with unfavorable outcome (P= 0.005 and 0.003) and death (P= 0.03 and 0.01). In a multivariate logistic regression model, shock [odds ratio (OR) 26.0, P= 0.02] and carriage of the CATT7 allele (OR 5.12,P= 0.04) were the main predictors of mortality. MIF levels in the cerebrospinal fluid were associated with systemic complications and death (P= 0.0002). Streptococcus pneumoniae strongly up-regulated MIF production in whole blood and transcription activity of high-expression MIF promoter Luciferase reporter constructs in THP-1 monocytes. Consistent with these findings, treatment with anti-MIF immunoglogulin G (IgG) antibodies reduced bacterial loads and improved survival in a mouse model of pneumococcal pneumonia and sepsis. The present study provides strong evidence that carriage of high-expression MIF alleles is a genetic marker of morbidity and mortality of pneumococcal meningitis and also suggests a potential role for MIF as a target of immune-modulating adjunctive therapy. PMID- 26976593 TI - Protein networks identify novel symbiogenetic genes resulting from plastid endosymbiosis. AB - The integration of foreign genetic information is central to the evolution of eukaryotes, as has been demonstrated for the origin of the Calvin cycle and of the heme and carotenoid biosynthesis pathways in algae and plants. For photosynthetic lineages, this coordination involved three genomes of divergent phylogenetic origins (the nucleus, plastid, and mitochondrion). Major hurdles overcome by the ancestor of these lineages were harnessing the oxygen-evolving organelle, optimizing the use of light, and stabilizing the partnership between the plastid endosymbiont and host through retargeting of proteins to the nascent organelle. Here we used protein similarity networks that can disentangle reticulate gene histories to explore how these significant challenges were met. We discovered a previously hidden component of algal and plant nuclear genomes that originated from the plastid endosymbiont: symbiogenetic genes (S genes). These composite proteins, exclusive to photosynthetic eukaryotes, encode a cyanobacterium-derived domain fused to one of cyanobacterial or another prokaryotic origin and have emerged multiple, independent times during evolution. Transcriptome data demonstrate the existence and expression of S genes across a wide swath of algae and plants, and functional data indicate their involvement in tolerance to oxidative stress, phototropism, and adaptation to nitrogen limitation. Our research demonstrates the "recycling" of genetic information by photosynthetic eukaryotes to generate novel composite genes, many of which function in plastid maintenance. PMID- 26976595 TI - Carnosic acid biosynthesis elucidated by a synthetic biology platform. AB - Synthetic biology approaches achieving the reconstruction of specific plant natural product biosynthetic pathways in dedicated microbial "chassis" have provided access to important industrial compounds (e.g., artemisinin, resveratrol, vanillin). However, the potential of such production systems to facilitate elucidation of plant biosynthetic pathways has been underexplored. Here we report on the application of a modular terpene production platform in the characterization of the biosynthetic pathway leading to the potent antioxidant carnosic acid and related diterpenes in Salvia pomifera and Rosmarinus officinalis.Four cytochrome P450 enzymes are identified (CYP76AH24, CYP71BE52, CYP76AK6, and CYP76AK8), the combined activities of which account for all of the oxidation events leading to the biosynthesis of the major diterpenes produced in these plants. This approach develops yeast as an efficient tool to harness the biotechnological potential of the numerous sequencing datasets that are increasingly becoming available through transcriptomic or genomic studies. PMID- 26976596 TI - A RhoA and Rnd3 cycle regulates actin reassembly during membrane blebbing. AB - The actin cytoskeleton usually lies beneath the plasma membrane. When the membrane-associated actin cytoskeleton is transiently disrupted or the intracellular pressure is increased, the plasma membrane detaches from the cortex and protrudes. Such protruded membrane regions are called blebs. However, the molecular mechanisms underlying membrane blebbing are poorly understood. This study revealed that epidermal growth factor receptor kinase substrate 8 (Eps8) and ezrin are important regulators of rapid actin reassembly for the initiation and retraction of protruded blebs. Live-cell imaging of membrane blebbing revealed that local reassembly of actin filaments occurred at Eps8- and activated ezrin-positive foci of membrane blebs. Furthermore, we found that a RhoA-ROCK Rnd3 feedback loop determined the local reassembly sites of the actin cortex during membrane blebbing. PMID- 26976594 TI - Force-producing ADP state of myosin bound to actin. AB - Molecular motors produce force when they interact with their cellular tracks. For myosin motors, the primary force-generating state has MgADP tightly bound, whereas myosin is strongly bound to actin. We have generated an 8-A cryoEM reconstruction of this state for myosin V and used molecular dynamics flexed fitting for model building. We compare this state to the subsequent state on actin (Rigor). The ADP-bound structure reveals that the actin-binding cleft is closed, even though MgADP is tightly bound. This state is accomplished by a previously unseen conformation of the beta-sheet underlying the nucleotide pocket. The transition from the force-generating ADP state to Rigor requires a 9.5 degrees rotation of the myosin lever arm, coupled to a beta-sheet rearrangement. Thus, the structure reveals the detailed rearrangements underlying myosin force generation as well as the basis of strain-dependent ADP release that is essential for processive myosins, such as myosin V. PMID- 26976597 TI - Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo. AB - Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstrated that the effects are prevented or reduced by bone marrow-derived multipotent mesenchymal stromal cells. We verified the in vivo relevance of these findings in mice experimentally infected with influenza A/H5N1. We found that, in vitro, the alveolar epithelium's protein permeability and fluid clearance were dysregulated by soluble immune mediators released upon infection with avian (A/Hong Kong/483/97, H5N1) but not seasonal (A/Hong Kong/54/98, H1N1) influenza virus. The reduced alveolar fluid transport associated with down-regulation of sodium and chloride transporters was prevented or reduced by coculture with mesenchymal stromal cells. In vivo, treatment of aged H5N1-infected mice with mesenchymal stromal cells increased their likelihood of survival. We conclude that mesenchymal stromal cells significantly reduce the impairment of alveolar fluid clearance induced by A/H5N1 infection in vitro and prevent or reduce A/H5N1-associated acute lung injury in vivo. This potential adjunctive therapy for severe influenza-induced lung disease warrants rapid clinical investigation. PMID- 26976598 TI - Small genome of the fungus Escovopsis weberi, a specialized disease agent of ant agriculture. AB - Many microorganisms with specialized lifestyles have reduced genomes. This is best understood in beneficial bacterial symbioses, where partner fidelity facilitates loss of genes necessary for living independently. Specialized microbial pathogens may also exhibit gene loss relative to generalists. Here, we demonstrate that Escovopsis weberi, a fungal parasite of the crops of fungus growing ants, has a reduced genome in terms of both size and gene content relative to closely related but less specialized fungi. Although primary metabolism genes have been retained, the E. weberi genome is depleted in carbohydrate active enzymes, which is consistent with reliance on a host with these functions. E. weberi has also lost genes considered necessary for sexual reproduction. Contrasting these losses, the genome encodes unique secondary metabolite biosynthesis clusters, some of which include genes that exhibit up regulated expression during host attack. Thus, the specialized nature of the interaction between Escovopsis and ant agriculture is reflected in the parasite's genome. PMID- 26976599 TI - Stability of the human polymerase delta holoenzyme and its implications in lagging strand DNA synthesis. AB - In eukaryotes, DNA polymerase delta (pol delta) is responsible for replicating the lagging strand template and anchors to the proliferating cell nuclear antigen (PCNA) sliding clamp to form a holoenzyme. The stability of this complex is integral to every aspect of lagging strand replication. Most of our understanding comes from Saccharomyces cerevisae where the extreme stability of the pol delta holoenzyme ensures that every nucleobase within an Okazaki fragment is faithfully duplicated before dissociation but also necessitates an active displacement mechanism for polymerase recycling and exchange. However, the stability of the human pol delta holoenzyme is unknown. We designed unique kinetic assays to analyze the processivity and stability of the pol delta holoenzyme. Surprisingly, the results indicate that human pol delta maintains a loose association with PCNA while replicating DNA. Such behavior has profound implications on Okazaki fragment synthesis in humans as it limits the processivity of pol delta on undamaged DNA and promotes the rapid dissociation of pol delta from PCNA on stalling at a DNA lesion. PMID- 26976600 TI - Biphasic regulation of InsP3 receptor gating by dual Ca2+ release channel BH3 like domains mediates Bcl-xL control of cell viability. AB - Antiapoptotic Bcl-2 family members interact with inositol trisphosphate receptor (InsP3R) Ca(2+)release channels in the endoplasmic reticulum to modulate Ca(2+)signals that affect cell viability. However, the molecular details and consequences of their interactions are unclear. Here, we found that Bcl-xL activates single InsP3R channels with a biphasic concentration dependence. The Bcl-xLBcl-2 homology 3 (BH3) domain-binding pocket mediates both high-affinity channel activation and low-affinity inhibition. Bcl-xL activates channel gating by binding to two BH3 domain-like helices in the channel carboxyl terminus, whereas inhibition requires binding to one of them and to a previously identified Bcl-2 interaction site in the channel-coupling domain. Disruption of these interactions diminishes cell viability and sensitizes cells to apoptotic stimuli. Our results identify BH3-like domains in an ion channel and they provide a unifying model of the effects of antiapoptotic Bcl-2 proteins on the InsP3R that play critical roles in Ca(2+) signaling and cell viability. PMID- 26976601 TI - BRCA2 regulates DMC1-mediated recombination through the BRC repeats. AB - In somatic cells, BRCA2 is needed for RAD51-mediated homologous recombination. The meiosis-specific DNA strand exchange protein, DMC1, promotes the formation of DNA strand invasion products (joint molecules) between homologous molecules in a fashion similar to RAD51. BRCA2 interacts directly with both human RAD51 and DMC1; in the case of RAD51, this interaction results in stimulation of RAD51 promoted DNA strand exchange. However, for DMC1, little is known regarding the basis and functional consequences of its interaction with BRCA2. Here we report that human DMC1 interacts directly with each of the BRC repeats of BRCA2, albeit most tightly with repeats 1-3 and 6-8. However, BRC1-3 bind with higher affinity to RAD51 than to DMC1, whereas BRC6-8 bind with higher affinity to DMC1, providing potential spatial organization to nascent filament formation. With the exception of BRC4, each BRC repeat stimulates joint molecule formation by DMC1. The basis for this stimulation is an enhancement of DMC1-ssDNA complex formation by the stimulatory BRC repeats. Lastly, we demonstrate that full-length BRCA2 protein stimulates DMC1-mediated DNA strand exchange between RPA-ssDNA complexes and duplex DNA, thus identifying BRCA2 as a mediator of DMC1 recombination function. Collectively, our results suggest unique and specialized functions for the BRC motifs of BRCA2 in promoting homologous recombination in meiotic and mitotic cells. PMID- 26976602 TI - Phasic, suprathreshold excitation and sustained inhibition underlie neuronal selectivity for short-duration sounds. AB - Sound duration is important in acoustic communication, including speech recognition in humans. Although duration-selective auditory neurons have been found, the underlying mechanisms are unclear. To investigate these mechanisms we combined in vivo whole-cell patch recordings from midbrain neurons, extraction of excitatory and inhibitory conductances, and focal pharmacological manipulations. We show that selectivity for short-duration stimuli results from integration of short-latency, sustained inhibition with delayed, phasic excitation; active membrane properties appeared to amplify responses to effective stimuli. Blocking GABAA receptors attenuated stimulus-related inhibition, revealed suprathreshold excitation at all stimulus durations, and decreased short-pass selectivity without changing resting potentials. Blocking AMPA and NMDA receptors to attenuate excitation confirmed that inhibition tracks stimulus duration and revealed no evidence of postinhibitory rebound depolarization inherent to coincidence models of duration selectivity. These results strongly support an anticoincidence mechanism of short-pass selectivity, wherein inhibition and suprathreshold excitation show greatest temporal overlap for long duration stimuli. PMID- 26976605 TI - Re-evaluation of the roles of DROSHA, Export in 5, and DICER in microRNA biogenesis. AB - Biogenesis of canonical microRNAs (miRNAs) involves multiple steps: nuclear processing of primary miRNA (pri-miRNA) by DROSHA, nuclear export of precursor miRNA (pre-miRNA) by Export in 5 (XPO5), and cytoplasmic processing of pre-miRNA by DICER. To gain a deeper understanding of the contribution of each of these maturation steps, we deleted DROSHA, XPO5, and DICER in the same human cell line, and analyzed their effects on miRNA biogenesis. Canonical miRNA production was completely abolished in DROSHA-deleted cells, whereas we detected a few DROSHA independent miRNAs including three previously unidentified noncanonical miRNAs (miR-7706, miR-3615, and miR-1254). In contrast to DROSHA knockout, many canonical miRNAs were still detected without DICER albeit at markedly reduced levels. In the absence of DICER, pre-miRNAs are loaded directly onto AGO and trimmed at the 3' end, yielding miRNAs from the 5' strand (5p miRNAs). Interestingly, in XPO5 knockout cells, most miRNAs are affected only modestly, suggesting that XPO5 is necessary but not critical for miRNA maturation. Our study demonstrates an essential role of DROSHA and an important contribution of DICER in the canonical miRNA pathway, and reveals that the function of XPO5 can be complemented by alternative mechanisms. Thus, this study allows us to understand differential contributions of key biogenesis factors, and provides with valuable resources for miRNA research. PMID- 26976603 TI - Recognition of the disordered p53 transactivation domain by the transcriptional adapter zinc finger domains of CREB-binding protein. AB - An important component of the activity of p53 as a tumor suppressor is its interaction with the transcriptional coactivators cyclic-AMP response element binding protein (CREB)-binding protein (CBP) and p300, which activate transcription of p53-regulated stress response genes and stabilize p53 against ubiquitin-mediated degradation. The highest affinity interactions are between the intrinsically disordered N-terminal transactivation domain (TAD) of p53 and the TAZ1 and TAZ2 domains of CBP/p300. The NMR spectra of simple binary complexes of the TAZ1 and TAZ2 domains with the p53TAD suffer from exchange broadening, but innovations in construct design and isotopic labeling have enabled us to obtain high-resolution structures using fusion proteins, uniformly labeled in the case of the TAZ2-p53TAD fusion and segmentally labeled through transintein splicing for the TAZ1-p53TAD fusion. The p53TAD is bipartite, with two interaction motifs, termed AD1 and AD2, which fold to form short amphipathic helices upon binding to TAZ1 and TAZ2 whereas intervening regions of the p53TAD remain flexible. Both the AD1 and AD2 motifs bind to hydrophobic surfaces of the TAZ domains, with AD2 making more extensive hydrophobic contacts consistent with its greater contribution to the binding affinity. Binding of AD1 and AD2 is synergistic, and structural studies performed with isolated motifs can be misleading. The present structures of the full-length p53TAD complexes demonstrate the versatility of the interactions available to an intrinsically disordered domain containing bipartite interaction motifs and provide valuable insights into the structural basis of the affinity changes that occur upon stress-related posttranslational modification. PMID- 26976606 TI - Moving beyond metagenomics to find the next pandemic virus. PMID- 26976604 TI - Inositol hexakisphosphate (IP6) generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function. AB - The family of cullin-RING E3 Ligases (CRLs) and the constitutive photomorphogenesis 9 (COP9) signalosome (CSN) form dynamic complexes that mediate ubiquitylation of 20% of the proteome, yet regulation of their assembly/disassembly remains poorly understood. Inositol polyphosphates are highly conserved signaling molecules implicated in diverse cellular processes. We now report that inositol hexakisphosphate (IP6) is a major physiologic determinant of the CRL-CSN interface, which includes a hitherto unidentified electrostatic interaction between the N-terminal acidic tail of CSN subunit 2 (CSN2) and a conserved basic canyon on cullins. IP6, with an EC50 of 20 nM, acts as an intermolecular "glue," increasing cullin-CSN2 binding affinity by 30-fold, thereby promoting assembly of the inactive CRL-CSN complexes. The IP6 synthase, Ins(1,3,4,5,6)P5 2-kinase (IPPK/IP5K) binds to cullins. Depleting IP5K increases the percentage of neddylated, active Cul1 and Cul4A, and decreases levels of the Cul1/4A substrates p27 and p21. Besides dysregulating CRL-mediated cell proliferation and UV-induced apoptosis, IP5K depletion potentiates by 28-fold the cytotoxic effect of the neddylation inhibitor MLN4924. Thus, IP5K and IP6 are evolutionarily conserved components of the CRL-CSN system and are potential targets for cancer therapy in conjunction with MLN4924. PMID- 26976608 TI - Guidelines for writing a commentary. PMID- 26976609 TI - The Evolving Methodology of Scoping Reviews. PMID- 26976607 TI - SARS-like WIV1-CoV poised for human emergence. AB - Outbreaks from zoonotic sources represent a threat to both human disease as well as the global economy. Despite a wealth of metagenomics studies, methods to leverage these datasets to identify future threats are underdeveloped. In this study, we describe an approach that combines existing metagenomics data with reverse genetics to engineer reagents to evaluate emergence and pathogenic potential of circulating zoonotic viruses. Focusing on the severe acute respiratory syndrome (SARS)-like viruses, the results indicate that the WIV1 coronavirus (CoV) cluster has the ability to directly infect and may undergo limited transmission in human populations. However, in vivo attenuation suggests additional adaptation is required for epidemic disease. Importantly, available SARS monoclonal antibodies offered success in limiting viral infection absent from available vaccine approaches. Together, the data highlight the utility of a platform to identify and prioritize prepandemic strains harbored in animal reservoirs and document the threat posed by WIV1-CoV for emergence in human populations. PMID- 26976611 TI - Causal or not: applying the Bradford Hill aspects of evidence to the association between Zika virus and microcephaly. PMID- 26976610 TI - Barriers and facilitators related to implementation of regulated midwifery in Manitoba: a case study. AB - BACKGROUND: In 2000, midwifery was regulated in the Canadian Province of Manitoba. Since the establishment of the midwifery program, little formal research has analyzed the utilization of regulated midwifery services. In Manitoba, the demand for midwifery services has exceeded the number of midwives in practice. The specific objective of this study was to explore factors influencing the implementation and utilization of regulated midwifery services in Manitoba. METHODS: The case study design incorporated qualitative exploratory descriptive methods, using data derived from two sources: interviews and public documents. Twenty-four key informants were purposefully selected to participate in semi-structured in-depth interviews. All documents analyzed were in the public domain. Content analysis was employed to analyze the documents and transcripts of the interviews. RESULTS: The results of the study were informed by the Behavioral Model of Health Services Use. Three main topic areas were explored: facilitators, barriers, and future strategies and recommendations. The most common themes arising under facilitators were funding of midwifery services and strategies to integrate the profession. Power and conflict, and lack of a productive education program emerged as the most prominent themes under barriers. Finally, future strategies for sustaining the midwifery profession focused on ensuring avenues for registration and education, improving management strategies and accountability frameworks within the employment model, enhancing the work environment, and evaluating both the practice and employment models. Results of the document analysis supported the themes arising from the interviews. CONCLUSION: These findings on factors that influenced the implementation and integration of midwifery in Manitoba may provide useful information to key stakeholders in Manitoba, as well as other provinces as they work toward successful implementation of regulated midwifery practice. Funding for new positions and programs was consistently noted as a successful strategy. While barriers such as structures of power within Regional Health Authorities and inter and intra-professional conflict were identified, the lack of a productive midwifery education program emerged as the most prominent barrier. This new knowledge highlights issues that impact the ongoing growth and capacity of the midwifery profession and suggests directions for ensuring its sustainability. PMID- 26976613 TI - CSF sTREM2: marking the tipping point between preclinical AD and dementia? PMID- 26976614 TI - One-step surgery for acute ischemia of the jejunal loop after pancreatoduodenectomy: report of a case. AB - BACKGROUND: Pancreatoduodenectomy (PD) is an extensive surgery, and its complications are grave. Acute ischemia of the jejunal loop due to thrombosis of the superior mesenteric vein (SMV) and its branches is one of the most dangerous complications that, although rare, if left untreated leads to abdominal sepsis and death of a patient. CASE PRESENTATION: A 77-year-old man underwent PD for pancreatic cancer. On postoperative day 2, the patient developed a severe anemia with hypotension. The computed tomography showed acute ischemia of the jejunal loop due to thrombosis. The emergent surgery was performed. The removal of the ischemic intestine and re-anastomoses of the biliary and pancreatic ducts could be performed all at once because necrosis and inflammation were still very mild in early stage. CONCLUSION: If suspicion for thrombosis of the SMV and its branches is raised, re-laparotomy should be considered. Early re-operation can lead to removal of the ischemic intestine and re-anastomoses in one-step surgery. PMID- 26976612 TI - OX40 ligand newly expressed on bronchiolar progenitors mediates influenza infection and further exacerbates pneumonia. AB - Influenza virus epidemics potentially cause pneumonia, which is responsible for much of the mortality due to the excessive immune responses. The role of costimulatory OX40-OX40 ligand (OX40L) interactions has been explored in the non infectious pathology of influenza pneumonia. Here, we describe a critical contribution of OX40L to infectious pathology, with OX40L deficiency, but not OX40 deficiency, resulting in decreased susceptibility to influenza viral infection. Upon infection, bronchiolar progenitors increase in number for repairing the influenza-damaged epithelia. The OX40L expression is induced on the progenitors for the antiviral immunity during the infectious process. However, these defense-like host responses lead to more extensive infection owing to the induced OX40L with alpha-2,6 sialic acid modification, which augments the interaction with the viral hemagglutinin. In fact, the specific antibody against the sialylated site of OX40L exhibited therapeutic potency in mitigating the OX40L-mediated susceptibility to influenza. Our data illustrate that the influenza-induced expression of OX40L on bronchiolar progenitors has pathogenic value to develop a novel therapeutic approach against influenza. PMID- 26976615 TI - Late-onset diaphragmatic hernia after percutaneous radiofrequency ablation of hepatocellular carcinoma: a case study. AB - Percutaneous radiofrequency ablation (RFA) is widely used as an effective treatment of liver tumors. Several reported complications associated with RFA are due to thermal damage of neighboring organs. The present report presents a case of diaphragmatic hernia associated with RFA and hepatocellular carcinoma (HCC). A 72-year-old woman with S5 and S8 HCCs was treated repeatedly with RFA and transcatheter arterial chemoembolization for 3 years. After the third course of RFA to target the recurring S5 HCC, acute abdominal pain and dyspnea suddenly occurred. Contrast-enhanced computed tomography revealed intrusion of the transverse colon through the right diaphragmatic hernia. In addition, the colon was dilated and showed changes suggestive of ischemic conditions. An emergency surgery was performed to close the hernia by using non-absorbable sutures to preserve the colon. The patient was discharged without any complications 13 days after the surgery. The first-line treatment of this disease involves surgical intervention. Diaphragmatic hernia is a rare complication of RFA. The present case suggests that patients who undergo several rounds of RFA require surveillance for diaphragmatic hernias. PMID- 26976616 TI - A case of splenic metastasis of ovarian cancer treated with complete laparoscopic splenectomy and transvaginal specimen extraction. AB - A 61-year-old woman was diagnosed with right inguinal lymph node and splenic metastasis of ovarian serous cystadenocarcinoma. We performed right inguinal lymph node dissection and total laparoscopic splenectomy in the supine position followed by transvaginal specimen extraction (TVSE). First, using three ports, we extracted the right inguinal lymph node. We repaired the posterior wall of the inguinal canal using a mesh plug. We added two ports and displaced the spleen from the retroperitoneum and lifted it using a snake retractor, disconnecting the hilum using an automatic suturing device. Next, the posterior wall of the vagina was intraperitoneally incised. And an Alexis(r) laparoscopic system was inserted into the vagina. The cap maintained aeroperitoneum, a collection bag was inserted in the abdominal cavity via the vagina, and the spleen was collected. When the spleen was removed from the body, partial fragmentation of the organ was required in the bag. Organ fragmentation was performed only within the bag, and we made sure not to tear the bag. The vaginal wound was laparoscopically sutured. The patient had no operative complications and was able to actively ambulate at the first day after surgery due to a slight postoperative pain. Total laparoscopic splenectomy with TVSE in the supine position may be a safe and feasible method for selected female patients. This technique enables minimally invasive surgery for female patients with splenic disease. PMID- 26976618 TI - Professional carers' experiences of caring for individuals with intellectual disability and dementia. AB - The number of people with intellectual disability living into old age and developing dementia continues to increase. Dementia presents a wide range of challenges for staff due to progressive deterioration. This article presents the findings from a narrative literature review of professional caregivers' experiences of caring for individuals with intellectual disability and dementia. Seven electronic databases were searched using Boolean operators and truncation to identify relevant literature. Search results were combined and narrowed to articles relevant to staff working with individuals with intellectual disability and dementia, and 14 articles met the criteria for review. Themes outlined in the review include staff knowledge of dementia, staff training in dementia, caregiving, challenging behaviour, pain management, mealtime support and coping strategies. Overall carers must review and adjust their care delivery and support to people with intellectual disability and dementia, not only in terms of identifying and responding to their health needs but also through collaborative team working within and across services. PMID- 26976617 TI - Overview on acute-on-chronic liver failure. AB - Liver failure (LF) is defined as severe dysfunction in hepatic synthesis, detoxification, and metabolism induced by various etiologies. Clinical presentation of LF typically includes severe jaundice, coagulation disorder, hepatic encephalopathy, and ascites. LF can be classified into acute LF, acute-on chronic LF (ACLF), and chronic LF. ACLF has been demonstrated as a distinct syndrome with unique clinical presentation and outcomes. The severity, curability, and reversibility of ACLF have attracted considerable attention. Remarkable developments in ACLF-related conception, diagnostic criteria, pathogenesis, and therapy have been achieved. However, this disease, especially its diagnostic criteria, remains controversial. In this paper, we systemically reviewed the current understanding of ACLF from its definition, etiology, pathophysiology, pathology, and clinical presentation to management by thoroughly comparing important findings between east and west countries, as well as those from other regions. We also discussed the controversies, challenges, and needs for future studies to promote the standardization and optimization of the diagnosis and treatment for ACLF. PMID- 26976619 TI - Conservation of anatomically restricted glycosaminoglycan structures in divergent nematode species. AB - Heparan sulfates (HS) are glycosaminoglycans of the extracellular matrices and characterized by complex modification patterns owing to sulfations, epimerization, and acetylation. Distinct HS modification patterns have been shown to modulate protein-protein interactions during development in general and of the nervous system in particular. This has led to the heparan sulfate code hypothesis, which posits that specifically modified HS epitopes are distributed in a tissue and cell-specific fashion to orchestrate neural circuit formation. Whether an HS code exists in vivo, how specific or how evolutionarily conserved the anatomical distribution of an HS code may be has remained unknown. Here we conduct a systematic comparison of HS modification patterns in the nematode Caenorhabditis elegans using transgenic expression of 33 different HS-specific single chain variable fragment antibodies. We find that some HS modification patterns are widely distributed in the nervous system. In contrast, other HS modification patterns appear highly cell-specific in both non-neuronal and neuronal cells. Some patterns can be as restricted in their localization as to single neurites or synaptic connections between two neurons. This restricted anatomical localization of specific HS patterns can be evolutionarily conserved over a span of 80-100 million years in the divergent nematode species Caenorhabditis briggsae suggesting structural and, possibly functional conservation of glycosaminoglycan structures similar to proteins. These findings suggest a HS code with subcellularly localized, unique glycan identities in the nervous system. PMID- 26976621 TI - miR-199-sponge transgenic mice develop physiological cardiac hypertrophy. AB - AIMS: Overexpression of either member of the miR-199 family, miR-199a-5p, or miR 199b-5p (hereinafter referred to as miR-199a or miR-199b) promotes pathological cardiac hypertrophy, but little is known about the role of endogenous miR-199 in cardiac development and disease. Our study aimed to determine the physiological function of the endogenous miR-199 family in cardiac homeostasis maintenance. METHODS AND RESULTS: We generated a sponge transgenic mouse model with a specific disruption of miR-199 in the heart. To our surprise, we found that knockdown of endogenous miR-199 caused physiological cardiac hypertrophy characterized by an increased heart weight and cardiomyocyte size, but with normal cardiac morphology and function. Furthermore, we also identified PGC1alpha as the target gene of the miR-199 family, and PGC1alpha was also increased in sponge transgenic mice. CONCLUSION: Inhibition of endogenous miR-199 led to physiological cardiac hypertrophy probably due to the up-regulation of PGC1alpha, uncovering a surprising role for endogenous miR-199 in the maintenance of cardiac homeostasis. PMID- 26976620 TI - Hsp70 protects from stroke in atrial fibrillation patients by preventing thrombosis without increased bleeding risk. AB - AIMS: Atrial fibrillation (AF) is a major risk factor for cardio-embolic stroke. Anticoagulant drugs are effective in preventing AF-related stroke. However, the high frequency of anticoagulant-associated major bleeding is a major concern. This study sought to identify new targets to develop safer antithrombotic therapies. METHODS AND RESULTS: Here, microarray analysis in peripheral blood cells in eight patients with AF and stroke and eight AF subjects without stroke brought to light a stroke-related gene expression pattern. HSPA1B, which encodes for heat-shock protein 70 kDa (Hsp70), was the most differentially expressed gene. This gene was down-regulated in stroke subjects, a finding confirmed further in an independent AF cohort of 200 individuals. Hsp70 knock-out mice subjected to different thrombotic challenges developed thrombosis significantly earlier than their wild-type (WT) counterparts. Remarkably, the tail bleeding time was unchanged. Accordingly, both TRC051384 and tubastatin A, i.e. two Hsp70 inducers via different pathways, delayed thrombus formation in WT mice, the tail bleeding time still being unaltered. Most interestingly, Hsp70 inducers did not increase the bleeding risk even when aspirin was concomitantly administered. Hsp70 induction was associated with an increased vascular thrombomodulin expression and higher circulating levels of activated protein C upon thrombotic stimulus. CONCLUSIONS: Hsp70 induction is a novel approach to delay thrombus formation with minimal bleeding risk, and is especially promising for treating AF patients and in other situations where there is also a major bleeding hazard. PMID- 26976622 TI - Differentiation of Diffuse Large B-cell Lymphoma From Follicular Lymphoma Using Texture Analysis on Conventional MR Images at 3.0 Tesla. AB - RATIONAL AND OBJECTIVES: Diffuse large B-cell lymphoma (DLBCL) represents the most common type of aggressive non-Hodgkin lymphoma (NHL); follicular lymphoma (FL) is the most frequent indolent NHL. The aim of this study was to investigate whether texture-based analysis of conventional magnetic resonance imaging (MRI) allows discrimination of DLBCL from FL, and further, to correlate the MRI texture features with diffusion-weighted imaging apparent diffusion coefficient (ADC) value and tumor tissue cellularity. MATERIALS AND METHODS: Forty-one patients with histologically proven NHL (30 DLBCL and 11 FL) underwent conventional MRI and diffusion-weighted imaging examination before treatment. Based on regions of interest, texture analysis was performed on T1-weighted images pre- and postcontrast enhancement and on T2-weighted images with and without fat suppression, and features derived from the run-length matrix- and co-occurrence matrix-based methods were analyzed. Receiver operating characteristic curves were performed for the three most discriminative texture features for the differentiation of the two most common types of lymphoma. The analyzed MRI texture features were correlated with the ADC value and the tumor tissue cellularity. RESULTS: We found that on T1-weighted images postcontrast enhancement, run-length matrix-based texture analysis for lesion classification differentiated DLBCL from FL, with specificity and sensitivity of 76.6% and 76.5%, respectively. There was no correlation between the texture features and the ADC value or tumor tissue cellularity. CONCLUSIONS: DLBCL and FL can be differentiated by means of texture analysis on T1-weighted MRI postcontrast enhancement. These results could serve as a basis for the use of the texture features on conventional MRI as adjunct to clinical examination to distinguish DLBCL from FL. PMID- 26976623 TI - Descriptors of Malignant Non-mass Enhancement of Breast MRI: Their Correlation to the Presence of Invasion. AB - RATIONALE AND OBJECTIVES: This study aims to investigate the clinical significance of malignant non-mass enhancement (NME) descriptors in breast magnetic resonance images by assessing their correlation to the presence of invasion or lymph node metastasis. MATERIALS AND METHODS: Three radiologists independently reviewed magnetic resonance images with malignant NMEs between January 2008 and December 2009. Distribution was assessed first, and then each of four internal enhancement patterns-clumped, clustered ring, branching, and hypointense area-was evaluated dichotomously (yes or no). Because clustered rings and hypointense areas were thought to be major structural elements of heterogeneous NMEs, they were also evaluated by integrating them into one collective descriptor we called the "heterogeneous structures." Chi-square test, Fisher exact test, or Student t test was used to analyze differences of variables by each reviewer. Positive predictive values (PPVs) of descriptors in predicting presence of invasion or lymph node metastasis were calculated. P < 0.05 was considered significant. RESULTS: We included 131 malignant NMEs (76 in situ and 55 invasive) in 129 patients (two bilateral). All three observers' results showed clustered rings (PPVs 54.5%, 54.5%, 50.0%) (P = 0.0005, 0.038, 0.029) and hypointense areas (PPVs 63.6%, 61.5%, 73.9%) (P = 0.004, 0.024, 0.0006) to be significantly associated with invasion. When clustered rings and hypointense areas were integrated into heterogeneous structures, they were significantly associated with invasion (PPVs 54.3%, 53.3%, 51.8%) (P = 0.0003, 0.016, 0.003). CONCLUSIONS: The NME descriptors clustered rings, hypoechoic areas, and heterogeneous structures, assessed collectively, were associated with invasive breast cancer. PMID- 26976624 TI - Magnetic Resonance Imaging of Osteochondritis Dissecans: Validation Study for the ICRS Classification System. AB - RATIONALE AND OBJECTIVES: In this retrospective case series, we utilize arthroscopy as the gold standard to determine if magnetic resonance imaging (MRI) of the knee can predict osteochondritis dissecans (OCD) lesion stability, the most important information to guide patient treatment decisions. It is hypothesized that the classification system of the International Cartilage Repair Society (ICRS) will allow for improved assessment of lesion grade and stability in OCD. MATERIALS AND METHODS: Routine MRI studies of 46 consecutive patients with arthroscopically proven OCD lesions (mean age: 23.7 years; 26 male, 16 female) were assessed by three radiologists who were blinded to arthroscopic results. Arthroscopic images were evaluated by two orthopedic surgeons in consensus. The OCD criteria of the ICRS were applied to arthroscopy and imaging interpretations. Inter-rater correlation statistics and accuracy of magnetic resonance (MR) grading with respect to arthroscopy were determined. RESULTS: Only 56% of the available MR reports assigned a label of stable or unstable to the lesion description. Of these, 58% of the lesions were deemed unstable and 42% were stable. Accuracy was 53% when reports addressed stability. Utilizing the ICRS classification system, for all three readers combined, the respective sensitivity, specificity, and accuracy of MR imaging to determine lesion stability were 70%, 81%, and 76%. When compared to the original MRI report, the overall accuracy increased from 53% to 76% when readers were given the specific criteria of the OCD ICRS classification. However, inter-reader variability remained high, with Krippendorf's alpha ranging from 0.48 to 0.57. CONCLUSIONS: In this paper, we utilize arthroscopy as the gold standard to determine if MRI can predict OCD lesion stability, the most important information to guide patient treatment decisions. To our surprise, the analysis of the existing radiology reports that addressed stability revealed an overall accuracy in defining OCD lesion stability of about 53%. The classification system of the ICRS, created by an international multidisciplinary, multi-expert consortium, did markedly improve the accuracy, but consistency among different readers was lacking. This retrospective study on OCD reporting and classification highlights the inadequacy of existing classification schemes, and emphasizes the critical need for improved diagnostic MRI protocols in musculoskeletal radiology in order to propel it toward evidence-based medicine. PMID- 26976626 TI - Is there an optimal basis to maximise optical information transfer? AB - We establish the concept of the density of the optical degrees of freedom that may be applied to any photonics based system. As a key example of this versatile approach we explore information transfer using optical communication. We demonstrate both experimentally, theoretically and numerically that the use of a basis set with fields containing optical vortices does not increase the telecommunication capacity of an optical system. PMID- 26976625 TI - Introduction and overview of the special issue "Brain imaging and aging": The new era of neuroimaging in aging research. AB - It is well known that the brain is one of the organs particularly affected by aging in terms of function, relative to the gastrointestinal tract and liver, which exhibit less functional decline. There is also a wide range of age-related neurological disorders such as stroke, Alzheimer's disease, and Parkinson's disease. Therefore, it is very important to understand the relationship between functional age-related change and neurological dysfunction. Neuroimaging techniques including magnetic resonance imaging and positron emission tomography have been significantly improved over recent years. Many physicians and researchers have investigated various mechanisms of age-related cerebral change and associated neurological disorders using neuroimaging techniques. In this special issue of Ageing Research Reviews, we focus on cerebral- and neuro imaging, which are a range of tools used to visualize structure, functions, and pathogenic molecules in the nervous system. In addition, we summarize several review articles about the history, present values, and future perspectives of neuroimaging modalities. PMID- 26976628 TI - Correction: In situ induction of dendritic cell-based T cell tolerance in humanized mice and nonhuman primates. PMID- 26976627 TI - Self-assembled hydrophobin for producing water-soluble and membrane permeable fluorescent dye. AB - Low water solubility and poor membrane permeability are major disadvantages that compromise applications of most fluorescent dyes. To resolve these problems, herein, using Boron-dipyrromethene (BODIPY) as a model fluorescent dye, for the first time, we provide a new strategy for the rapid and efficient production of a water-soluble and membrane-permeable dye by mixing with an amphiphilic protein named hydrophobin. Data shows BODIPY could be effectively solubilized and dispersed in 200 MUg/mL hydrophobin by simple mixing and sonication. Subsequent experiments indicated that hydrophobin self-assembled into a protein film on the surface of BODIPY forming stable hydrophobin-BODIPY complexes with a size range of 10-30 nm. Furthermore, we demonstrated hydrophobin-functionalized BODIPY are toxicity free to cells. The hydrophobin-BODIPY complex could pass through both the cell plasma membrane and nuclear membrane efficiently. Our work opens a novel route to modify and functionalize fluorescent dyes and may be developed as a general strategy for broadening their applications. PMID- 26976629 TI - Human studies at JEM: Immunology and beyond. PMID- 26976631 TI - 3D-MR-Neurography of axillary nerve injury: case report of a professional rugby player. PMID- 26976632 TI - Nesting-driven multipolar order in CeB6 from photoemission tomography. AB - Some heavy fermion materials show so-called hidden-order phases which are invisible to many characterization techniques and whose microscopic origin remained controversial for decades. Among such hidden-order compounds, CeB6 is of model character due to its simple electronic configuration and crystal structure. Apart from more conventional antiferromagnetism, it shows an elusive phase at low temperatures, which is commonly associated with multipolar order. Here we show that this phase roots in a Fermi surface instability. This conclusion is based on a full 3D tomographic sampling of the electronic structure by angle-resolved photoemission and comparison with inelastic neutron scattering data. The hidden order is mediated by itinerant electrons. Our measurements will serve as a paradigm for the investigation of hidden-order phases in f-electron systems, but also generally for situations where the itinerant electrons drive orbital or spin order. PMID- 26976630 TI - IL-12 drives functional plasticity of human group 2 innate lymphoid cells. AB - Group 2 innate lymphoid cells (ILC2) include IL-5- and IL-13-producing CRTh2(+)CD127(+)cells that are implicated in early protective immunity at mucosal surfaces. Whereas functional plasticity has been demonstrated for both human and mouse ILC3 subsets that can reversibly give rise to IFN-gamma-producing ILC1, plasticity of human or mouse ILC2 has not been shown. Here, we analyze the phenotypic and functional heterogeneity of human peripheral blood ILC2. Although subsets of human CRTh2(+)ILC2 differentially express CD117 (c-kit receptor), some ILC2 surface phenotypes are unstable and can be modulated in vitro. Surprisingly, human IL-13(+)ILC2 can acquire the capacity to produce IFN-gamma, thereby generating plastic ILC2. ILC2 cultures demonstrated that IFN-gamma(+)ILC2 clones could be derived and were stably associated with increased T-BET expression. The inductive mechanism for ILC2 plasticity was mapped to the IL-12-IL-12R signaling pathway and was confirmed through analysis of patients with Mendelian susceptibility to mycobacterial disease due to IL-12Rbeta1 deficiencies that failed to generate plastic ILC2. We also detected IL-13(+)IFN-gamma(+)ILC2 ex vivo in intestinal samples from Crohn's disease patients. These results demonstrate cytokine production plasticity for human ILC2 and further suggest that environmental cues can dictate ILC phenotype and function for these tissue resident innate effector cells. PMID- 26976636 TI - Both the Exact Target Site Sequence and a Long Poly(A) Tail Are Required for Precise Insertion of the 18S Ribosomal DNA-Specific Non-Long Terminal Repeat Retrotransposon R7Ag. AB - Ribosomal elements (R elements) are site-specific non-long terminal repeat (LTR) retrotransposons that target ribosomal DNA (rDNA). To elucidate how R elements specifically access their target sites, we isolated and characterized the 18S rDNA-specific R element R7Ag from Anopheles gambiae Using an in vivo and ex vivo recombinant baculovirus retrotransposition system, we found that the exact host 18S rDNA sequence at the target site is essential for the precise insertion of R7Ag. In addition, a long poly(A) tail is necessary for the accurate initiation of R7Ag reverse transcription, a novel mechanism found in non-LTR elements. We further compared the subcellular localizations of proteins in R7Ag as well as R1Bm, another R element that targets 28S rDNA. Although the open reading frame 1 proteins (ORF1ps) of both R7Ag and R1Bm localized predominantly in the cytoplasm, ORF2 proteins (ORF2ps) colocalized in the nucleus with the nucleolar marker fibrillarin. The ORF1ps and ORF2ps of both R elements colocalized largely in the nuclear periphery and to a lesser extent within the nucleus. These results suggest that R7Ag and R1Bm proteins may access nucleolar rDNA targets in an ORF2p dependent manner. PMID- 26976635 TI - Differential Involvement of the Npl4 Zinc Finger Domains of SHARPIN and HOIL-1L in Linear Ubiquitin Chain Assembly Complex-Mediated Cell Death Protection. AB - The linear ubiquitin chain assembly complex (LUBAC) participates in NF-kappaB activation and cell death protection. Loss of any of the three LUBAC subunits (catalytic HOIP, accessory HOIL-1L, or accessory SHARPIN subunit) leads to distinct phenotypes in mice and human. cpdm mice (chronic proliferative dermatitis in mice [cpdm]) that lack SHARPIN exhibit chronic inflammatory phenotypes, whereas HOIL-1L knockout mice exhibit no overt phenotypes, despite sharing highly homologous ubiquitin-like (UBL) and Npl4 zinc finger (NZF) domains. Here, we intercrossed mice lacking HOIL-1L and SHARPIN and found that reduction of HOIL-1L in cpdm mice exacerbated inflammatory phenotypes without affecting characteristic features of cpdm disease, whereas reduction of SHARPIN in HOIL-1L knockout mice provoked no overt phenotypes. Hence, loss of SHARPIN and reduction of LUBAC triggers cpdm phenotypes. We found that the NZF domain of SHARPIN, but not that of HOIL-1L, is critical for effective protection from programmed cell death by enhancing the recruitment of LUBAC to the activated TNFR complex. The binding activity to K63-linked ubiquitin chains that the NZF domain of SHARPIN, but not that of HOIL-1L, possesses appears to be involved in the recruitment. Thus, selective recognition of ubiquitin chains by NZFs in LUBAC underlies the regulation of LUBAC function. PMID- 26976637 TI - p38beta Mitogen-Activated Protein Kinase Modulates Its Own Basal Activity by Autophosphorylation of the Activating Residue Thr180 and the Inhibitory Residues Thr241 and Ser261. AB - Many enzymes are self-regulated and can either inhibit or enhance their own catalytic activity. Enzymes that do both are extremely rare. Many protein kinases autoactivate by autophosphorylating specific sites at their activation loop and are inactivated by phosphatases. Although mitogen-activated protein kinases (MAPKs) are usually activated by dual phosphorylation catalyzed by MAPK kinases (MAPKKs), the MAPK p38beta is exceptional and is capable of self-activation by cis autophosphorylation of its activation loop residue T180. We discovered that p38beta also autophosphorylates in trans two previously unknown sites residing within a MAPK-specific structural element known as the MAPK insert: T241 and S261. Whereas phosphorylation of T180 evokes catalytic activity, phosphorylation of S261 reduces the activity of T180-phosphorylated p38beta, and phosphorylation of T241 reduces its autophosphorylation in trans Both phosphorylations do not affect the activity of dually phosphorylated p38beta. T241 of p38beta is found phosphorylated in vivo in bone and muscle tissues. In myogenic cell lines, phosphorylation of p38beta residue T241 is correlated with differentiation to myotubes. T241 and S261 are also autophosphorylated in intrinsically active variants of p38alpha, but in this protein, they probably play a different role. We conclude that p38beta is an unusual enzyme that automodulates its basal, MAPKK independent activity by several autophosphorylation events, which enhance and suppress its catalytic activity. PMID- 26976638 TI - Chordin-Like 1 Suppresses Bone Morphogenetic Protein 4-Induced Breast Cancer Cell Migration and Invasion. AB - ShcA is an important mediator of ErbB2- and transforming growth factor beta (TGF beta)-induced breast cancer cell migration, invasion, and metastasis. We show that in the context of reduced ShcA levels, the bone morphogenetic protein (BMP) antagonist chordin-like 1 (Chrdl1) is upregulated in numerous breast cancer cells following TGF-beta stimulation. BMPs have emerged as important modulators of breast cancer aggressiveness, and we have investigated the ability of Chrdl1 to block BMP-induced increases in breast cancer cell migration and invasion. Breast cancer-derived conditioned medium containing elevated concentrations of endogenous Chrdl1, as well as medium containing recombinant Chrdl1, suppresses BMP4-induced signaling in multiple breast cancer cell lines. Live-cell migration assays reveal that BMP4 induces breast cancer migration, which is effectively blocked by Chrdl1. We demonstrate that BMP4 also stimulated breast cancer cell invasion and matrix degradation, in part, through enhanced metalloproteinase 2 (MMP2) and MMP9 activity that is antagonized by Chrdl1. Finally, high Chrdl1 expression was associated with better clinical outcomes in patients with breast cancer. Together, our data reveal that Chrdl1 acts as a negative regulator of malignant breast cancer phenotypes through inhibition of BMP signaling. PMID- 26976639 TI - Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity. AB - RNA polymerase I-mediated rRNA production is a key determinant of cell growth. Despite extensive studies, the signaling pathways that control RNA polymerase I mediated rRNA production are not well understood. Here we provide original evidence showing that RNA polymerase I transcriptional activity is tightly controlled by integrin signaling. Furthermore, we show that a signaling axis consisting of focal adhesion kinase (FAK), Src, phosphatidylinositol 3-kinase (PI3K), Akt, and mTOR mediates the effect of integrin signaling on rRNA transcription. Additionally, we show that in kindlin-2 knockout mouse embryonic fibroblasts, overactivation of Ras, Akt, and Src can successfully rescue the defective RNA polymerase I activity induced by the loss of kindlin-2. Finally, through experiments with inhibitors of FAK, Src, and PI3K and rescue experiments in MEFs, we found that the FAK/Src/PI3K/Akt signaling pathway to control rRNA transcription is linear. Collectively, these studies reveal, for the first time, a pivotal role of integrin signaling in regulation of RNA polymerase I transcriptional activity and shed light on the downstream signaling axis that participates in regulation of this key aspect of cell growth. PMID- 26976640 TI - Effects of Combined Tristetraprolin/Tumor Necrosis Factor Receptor Deficiency on the Splenic Transcriptome. AB - Tristetraprolin (TTP) acts by binding to AU-rich elements in certain mRNAs, such as tumor necrosis factor (TNF) mRNA, and increasing their decay rates. TTP knockout mice exhibit a profound inflammatory syndrome that is largely due to increased TNF levels. Although TTP's effects on gene expression have been well studied in cultured cells, little is known about its functions in intact tissues. We performed deep RNA sequencing on spleens from TTP knockout mice that were also deficient in both TNF receptors ("triple knockout" mice) to remove the secondary effects of excess TNF activity. To help identify posttranscriptionally regulated transcripts, we also compared changes in mature mRNA levels to levels of transiently expressed pre-mRNA. In the triple knockout spleens, levels of 3,014 transcripts were significantly affected by 1.5-fold or more, but only a small fraction exhibited differential mRNA/pre-mRNA changes suggestive of increased mRNA stability. Transferrin receptor mRNA, which contains two highly conserved potential TTP binding sites, was significantly upregulated relative to its pre mRNA. This was reflected in increased transferrin receptor expression and increased splenic iron/hemosiderin deposition. Our results suggest that TTP deficiency has profound effects on the splenic transcriptome, even in the absence of secondary increases in TNF activity. PMID- 26976641 TI - Myocardin-Related Transcription Factor A Activation by Competition with WH2 Domain Proteins for Actin Binding. AB - The myocardin-related transcription factors (MRTFs) are coactivators of serum response factor (SRF)-mediated gene expression. Activation of MRTF-A occurs in response to alterations in actin dynamics and critically requires the dissociation of repressive G-actin-MRTF-A complexes. However, the mechanism leading to the release of MRTF-A remains unclear. Here we show that WH2 domains compete directly with MRTF-A for actin binding. Actin nucleation-promoting factors, such as N-WASP and WAVE2, as well as isolated WH2 domains, including those of Spire2 and Cobl, activate MRTF-A independently of changes in actin dynamics. Simultaneous inhibition of Arp2-Arp3 or mutation of the CA region only partially reduces MRTF-A activation by N-WASP and WAVE2. Recombinant WH2 domains and the RPEL domain of MRTF-A bind mutually exclusively to cellular and purified G-actin in vitro The competition by different WH2 domains correlates with MRTF SRF activation. Following serum stimulation, nonpolymerizable actin dissociates from MRTF-A, and de novo formation of the G-actin-RPEL complex is impaired by a transferable factor. Our work demonstrates that WH2 domains activate MRTF-A and contribute to target gene regulation by a competitive mechanism, independently of their role in actin filament formation. PMID- 26976642 TI - Base Excision Repair, a Pathway Regulated by Posttranslational Modifications. AB - Base excision repair (BER) is an essential DNA repair pathway involved in the maintenance of genome stability and thus in the prevention of human diseases, such as premature aging, neurodegenerative diseases, and cancer. Protein posttranslational modifications (PTMs), including acetylation, methylation, phosphorylation, SUMOylation, and ubiquitylation, have emerged as important contributors in controlling cellular BER protein levels, enzymatic activities, protein-protein interactions, and protein cellular localization. These PTMs therefore play key roles in regulating the BER pathway and are consequently crucial for coordinating an efficient cellular DNA damage response. In this review, we summarize the presently available data on characterized PTMs of key BER proteins, the functional consequences of these modifications at the protein level, and also the impact on BER in vitro and in vivo. PMID- 26976643 TI - Coordinated Regulation of TIP60 and Poly(ADP-Ribose) Polymerase 1 in Damaged Chromatin Dynamics. AB - The dynamic exchange of histones alleviates the nucleosome barrier and simultaneously facilitates various aspects of cellular DNA metabolism, such as DNA repair and transcription. In response to DNA damage, the acetylation of Lys5 in the histone variant H2AX, catalyzed by TIP60, plays a key role in promoting histone exchange; however, the detailed molecular mechanism still is unclear. Here, we show that the TIP60 complex includes poly(ADP-ribose) polymerase 1 (PARP 1). PARP-1 is required for the rapid exchange of H2AX on chromatin at DNA damage sites. It is known that PARP-1 binds dynamically to damaged chromatin and is crucial for the subsequent recruitment of other repair factors, and its auto poly(ADP-ribosyl)ation is required for the dynamics. We also show that the acetylation of histone H2AX at Lys5 by TIP60, but not the phosphorylation of H2AX, is required for the ADP-ribosylation activity of PARP-1 and its dynamic binding to damaged chromatin. Our results indicate the reciprocal regulation of K5 acetylation of H2AX and PARP-1, which could modulate the chromatin structure to facilitate DNA metabolism at damage sites. This could explain the rather undefined roles of PARP-1 in various DNA damage responses. PMID- 26976645 TI - RNA Activation of the Vascular Endothelial Growth Factor Gene (VEGF) Promoter by Double-Stranded RNA and Hypoxia: Role of Noncoding VEGF Promoter Transcripts. AB - RNA activation (RNAa) is a gene regulation process in which promoter-targeted short double-stranded RNAs (dsRNAs) or microRNAs (miRs) induce target gene expression at the transcriptional level. Here, we investigate the presence of cryptic promoter transcripts within the VEGF promoter. Single-strand sense and antisense noncoding vascular endothelial growth factor (NcVEGF) promoter transcripts are identified, and their respective expression is studied in cells transfected with a VEGF promoter targeted dsRNA, namely, dsVEGF706, in hypoxic cells and in human malignant lung tissues. Interestingly, in dsVEGF706 transfected, as well as in hypoxic cells, NcVEGF expression levels increase coordinately with coding VEGF expression. Ago2 interaction with both sense and antisense NcVEGFs is increased in hypoxic cells, whereas in dsVEGF706-transfected cells, Ago2 and the antisense strand of the dsRNA interact specifically with the sense NcVEGF transcript. Furthermore, both dsVEGF706 and ectopic NcVEGF transcripts are able to activate the VEGF promoter endogenously present or in a reporter construct. Finally, using small interfering RNA targeting Ago2, we show that RNAa plays a role in the maintenance of increased VEGF and NcVEGF expression after hypoxia. Given the central role of VEGF in major human diseases, including cancer, this novel molecular mechanism is poised to reveal promising possibilities for therapeutic interventions. PMID- 26976644 TI - The Endothelial Prolyl-4-Hydroxylase Domain 2/Hypoxia-Inducible Factor 2 Axis Regulates Pulmonary Artery Pressure in Mice. AB - Hypoxia-inducible factors 1 and 2 (HIF-1 and -2) control oxygen supply to tissues by regulating erythropoiesis, angiogenesis and vascular homeostasis. HIFs are regulated in response to oxygen availability by prolyl-4-hydroxylase domain (PHD) proteins, with PHD2 being the main oxygen sensor that controls HIF activity under normoxia. In this study, we used a genetic approach to investigate the endothelial PHD2/HIF axis in the regulation of vascular function. We found that inactivation of Phd2 in endothelial cells specifically resulted in severe pulmonary hypertension (~118% increase in right ventricular systolic pressure) but not polycythemia and was associated with abnormal muscularization of peripheral pulmonary arteries and right ventricular hypertrophy. Concurrent inactivation of either Hif1a or Hif2a in endothelial cell-specific Phd2 mutants demonstrated that the development of pulmonary hypertension was dependent on HIF 2alpha but not HIF-1alpha. Furthermore, endothelial HIF-2alpha was required for the development of increased pulmonary artery pressures in a model of pulmonary hypertension induced by chronic hypoxia. We propose that these HIF-2-dependent effects are partially due to increased expression of vasoconstrictor molecule endothelin 1 and a concomitant decrease in vasodilatory apelin receptor signaling. Taken together, our data identify endothelial HIF-2 as a key transcription factor in the pathogenesis of pulmonary hypertension. PMID- 26976646 TI - A Pilot Study of the Pharmacokinetics of the Modified-Release Once-Daily Tacrolimus Formulation Administered to Living-Donor Liver Transplant Recipients. AB - OBJECTIVES: Sustained-release once-daily tacrolimus pharmacokinetics have not yet been characterized in de novo living-donor liver transplant recipients. Here, a 12-week, phase IV, single center, open-label, prospective pilot study was conducted to investigate the pharmacokinetics of this formulation in these patients. MATERIALS AND METHODS: Patients received continuous intravenous infusion of tacrolimus on days 0 to 5 after transplant, which was followed by oral once-daily sustained-release tacrolimus. Two 24-hour pharmacokinetics profiles were generated for 10 patients on days 6 and 14. Secondary endpoints were minimum (trough level) and maximum whole blood concentrations, time to maximum concentration, and incidences of acute rejection, patient and graft survival, and adverse events. RESULTS: Mean doses (+/- standard deviation) of sustained-release tacrolimus on days 6 and 14 were 0.14 +/- 0.03 and 0.17 +/- 0.04 mg/kg. Levels were within the recommended range throughout the study. When the actual dose was examined, area under the curve from 0 to 24 hours on day 14 was 1.8-fold higher than that on day 6 (423.9 vs 235.7 ng * h/mL). When tacrolimus was normalized to 0.1 mg/kg, area under the curve from 0 to 24 hours on day 14 was 1.5-fold higher than on day 6 (279.3 vs 183.4 ng * h/mL). When we used the actual dose, we found the correlation coefficient between area under the curve from 0 to 24 hours and trough level to be higher on day 6 (r = 0.87) than on day 14 (r = 0.691). No acute rejections, graft losses, patient deaths, or drug related adverse events were reported. CONCLUSIONS: Initial intravenous followed by sustained-release tacrolimus was safe and efficacious in living-donor liver transplant recipients. The mean area under the curve from 0 to 24 hours on day 14 was higher than previously reported; this difference may reflect cautious dosing regimens. PMID- 26976648 TI - BTS/ICS guideline for the ventilatory management of acute hypercapnic respiratory failure in adults. PMID- 26976649 TI - Theory and realization of a 2D high resolution and high sensitivity SPECT system with an angle-encoding attenuator pattern. AB - The camera of the conventional SPECT system requires a collimator to allow incoming photons from a specific range of incident angle to reach the detector. It is the major factor that determines the spatial resolution of the camera. Moreover, it also greatly reduces the number of detected photons and hence increases statistical fluctuations in the acquired image data. The goal of this paper is to propose a theory and design for a novel high resolution and high sensitivity SPECT system without conventional collimators. The key is to resolve the incident photons from all directional angles and detected by every detector bin. Special 'attenuators' were designed to 'encode' the incoming photons from different directions similar to coded aperture to form projection data for image reconstruction. Each encoded angular pattern of detected photons was recorded as one measurement. Different angular patterns were achieved by changing the configurations of the attenuators so that angular pattern of different measurements or measurement matrix (MM) is invertible, which guarantee a unique reconstructed image. In simulation, the attenuators were fitted on a virtual full ring gamma camera, as an alternative to the collimators in conventional SPECT systems. To evaluate the performance of the new SPECT system, analytical simulated projection data in 2D scenario were generated from the XCAT phantom. Noisy simulation using 100 noise realizations suggests that the new attenuator design provides much improved image quality in terms of contrast-noise trade-offs (~30% improvement). The results suggest that the new design of using attenuators to replace collimator is feasible and could potentially improve sensitivity without sacrificing resolution in today's SPECT systems. PMID- 26976647 TI - Neurocognitive factors in sensory restoration of early deafness: a connectome model. AB - Progress in biomedical technology (cochlear, vestibular, and retinal implants) has led to remarkable success in neurosensory restoration, particularly in the auditory system. However, outcomes vary considerably, even after accounting for comorbidity-for example, after cochlear implantation, some deaf children develop spoken language skills approaching those of their hearing peers, whereas other children fail to do so. Here, we review evidence that auditory deprivation has widespread effects on brain development, affecting the capacity to process information beyond the auditory system. After sensory loss and deafness, the brain's effective connectivity is altered within the auditory system, between sensory systems, and between the auditory system and centres serving higher order neurocognitive functions. As a result, congenital sensory loss could be thought of as a connectome disease, with interindividual variability in the brain's adaptation to sensory loss underpinning much of the observed variation in outcome of cochlear implantation. Different executive functions, sequential processing, and concept formation are at particular risk in deaf children. A battery of clinical tests can allow early identification of neurocognitive risk factors. Intervention strategies that address these impairments with a personalised approach, taking interindividual variations into account, will further improve outcomes. PMID- 26976651 TI - Structure activity relationship studies on cytotoxicity and the effects on steroid receptors of AB-functionalized cholestanes. AB - Structure-activity relationship analysis and profiling of a library of AB functionalized cholestane derivatives closely related to brassinosteroids (BRs) were performed to examine their antiproliferative activities and activities on steroid hormone receptors. Some of the compounds were found to have strong cytotoxic activity in several human normal and cancer cell lines. The presence of a 3-hydroxy or 3-oxo group and 2,3-vicinal diol or 3,4-vicinal diol moiety were found to be necessary for optimum biological activity, as well as a six-membered B ring. According to the profiling of all steroid receptors in both agonist and antagonist mode, the majority of the cholestanes were weakly active or inactive compared to the natural ligands. Estrogenic activity was detected for two compounds, two compounds possessed antagonistic properties on estrogen receptors and seven compounds showed agonistic activity. Two active cholestane derivatives were shown to strongly influence cell viability, proliferation, cell cycle distribution, apoptosis and molecular pathways responsible for these processes in hormone-sensitive/insensitive (MCF7/MDA-MB-468) breast cancer cell lines. PMID- 26976650 TI - Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy. AB - RATIONALE: Cardiac myocyte-specific deletion of either glycogen synthase kinase (GSK)-3alpha and GSK-3beta leads to cardiac protection after myocardial infarction, suggesting that deletion of both isoforms may provide synergistic protection. This is an important consideration because of the fact that all GSK-3 targeted drugs, including the drugs already in clinical trial target both isoforms of GSK-3, and none are isoform specific. OBJECTIVE: To identify the consequences of combined deletion of cardiac myocyte GSK-3alpha and GSK-3beta in heart function. METHODS AND RESULTS: We generated tamoxifen-inducible cardiac myocyte-specific mice lacking both GSK-3 isoforms (double knockout). We unexpectedly found that cardiac myocyte GSK-3 is essential for cardiac homeostasis and overall survival. Serial echocardiographic analysis reveals that within 2 weeks of tamoxifen treatment, double-knockout hearts leads to excessive dilatative remodeling and ventricular dysfunction. Further experimentation with isolated adult cardiac myocytes and fibroblasts from double-knockout implicated cardiac myocytes intrinsic factors responsible for observed phenotype. Mechanistically, loss of GSK-3 in adult cardiac myocytes resulted in induction of mitotic catastrophe, a previously unreported event in cardiac myocytes. Double knockout cardiac myocytes showed cell cycle progression resulting in increased DNA content and multinucleation. However, increased cell cycle activity was rivaled by marked activation of DNA damage, cell cycle checkpoint activation, and mitotic catastrophe-induced apoptotic cell death. Importantly, mitotic catastrophe was also confirmed in isolated adult cardiac myocytes. CONCLUSIONS: Together, our findings suggest that cardiac myocyte GSK-3 is required to maintain normal cardiac homeostasis, and its loss is incompatible with life because of cell cycle dysregulation that ultimately results in a severe fatal dilated cardiomyopathy. PMID- 26976652 TI - Role of cytochrome b5 in the modulation of the enzymatic activities of cytochrome P450 17alpha-hydroxylase/17,20-lyase (P450 17A1). AB - Cytochrome b5 (cyt b5) is a small hemoprotein that plays a significant role in the modulation of activities of an important steroidogenic enzyme, cytochrome P450 17alpha-hydroxylase/17,20-lyase (P450 17A1, CYP17A1). Located in the zona fasciculata and zona reticularis of the adrenal cortex and in the gonads, P450 17A1 catalyzes two different reactions in the steroidogenic pathway; the 17alpha hydroxylation and 17,20-lyase, in the endoplasmic reticulum of these respective tissues. The activities of P450 17A1 are regulated by cyt b5 that enhances the 17,20-lyase reaction by promoting the coupling of P450 17A1 and cytochrome P450 reductase (CPR), allosterically. Cyt b5 can also act as an electron donor to enhance the 16-ene-synthase activity of human P450 17A1. In this review, we discuss the many roles of cyt b5 and focus on the modulation of CYP17A1 activities by cyt b5 and the mechanisms involved. PMID- 26976655 TI - Pragmatic message to junior doctors. AB - Although several studies described the experience of doctors in their first postgraduate years, few shed the light on the ethical issues encountered by them. These doctors face a broad range of 'everyday' ethical challenges, from breach of confidentiality to truth-telling or improper informed consent. The daily ethical issues faced by junior doctors are not as dramatic as the major issues learned at medical school. Junior doctors have to make the best ethical decisions within the time limits available. Undergraduate medical ethics curricula should give priority to the real-life issues that doctors will face in their first years of practice. PMID- 26976654 TI - Effect of dehydroepiandrosterone (DHEA) on Akt and protein kinase C zeta (PKCzeta) phosphorylation in different tissues of C57BL6, insulin receptor substrate (IRS)1(-/-), and IRS2(-/-) male mice fed a high-fat diet. AB - We have previously reported that dehydroepiandrosterone (DHEA) suppresses the activity and mRNA expression of the hepatic gluconeogenic enzyme glucose-6 phosphatase (G6Pase), and hepatic glucose production in db/db mice. Tyrosine phosphorylation levels of Insulin receptor substrate (IRS)1 and IRS2 reportedly differ between the liver and muscle tissue and the effect of DHEA on insulin signaling has not been elucidated. Therefore, we examined DHEA's effect on the liver and muscle tissue of IRS1(-/-) and IRS2(-/-) mice. Eight-week-old male C57BL6, IRS1(-/-), and IRS2(-/-) mice were fed a high-fat diet (HFD), or an HFD containing 0.2% DHEA for 4 weeks. In a separate experiment, 8-week-old male C57BL6 mice were fed an HFD or an HFD containing 0.2% androstenedione for 4 weeks. In an insulin tolerance test, DHEA administration decreased the initial plasma glucose levels in the C57BL6, IRS1(-/-), and IRS2(-/-) mice but did not decrease the ratios to the basal blood glucose level. Although DHEA administration increased Akt phosphorylation in the liver of the C57BL6, IRS1(-/ ), and IRS2(-/-) mice, androstenedione administration did not increase Akt phosphorylation in the liver of C57BL6 mice. DHEA administration did not increase Akt and PKCzeta phosphorylation in the muscle tissue of C57BL6, IRS1(-/-), or IRS2(-/-) mice. However, androstenedione administration increased Akt and PKCzeta phosphorylation in the muscle tissue of C57BL6 mice. These findings suggest that the effect of DHEA on insulin action in the liver is self-mediated by DHEA or DHEA sulfate (DHEA-S) in the presence of IRS1, IRS2, or both. PMID- 26976653 TI - Sterols and oxysterols in plasma from Smith-Lemli-Opitz syndrome patients. AB - Smith-Lemli-Opitz syndrome (SLOS) is a severe autosomal recessive disorder resulting from defects in the cholesterol synthesising enzyme 7 dehydrocholesterol reductase (Delta7-sterol reductase, DHCR7, EC 1.3.1.21) leading to a build-up of the cholesterol precursor 7-dehydrocholesterol (7-DHC) in tissues and blood plasma. Although the underling enzyme deficiency associated with SLOS is clear there are likely to be multiple mechanisms responsible for SLOS pathology. In an effort to learn more of the aetiology of SLOS we have analysed plasma from SLOS patients to search for metabolites derived from 7-DHC which may be responsible for some of the pathology. We have identified a novel hydroxy-8-dehydrocholesterol, which is either 24- or 25-hydroxy-8 dehydrocholesterol and also the known metabolites 26-hydroxy-8 dehydrocholesterol, 4-hydroxy-7-dehydrocholesterol, 3beta,5alpha-dihydroxycholest 7-en-6-one and 7alpha,8alpha-epoxycholesterol. None of these metabolites are detected in control plasma at quantifiable levels (0.5ng/mL). PMID- 26976657 TI - Electrostatic potentials and average electron densities of bioisosteres in methylsquarate and acetic acid. AB - BACKGROUND: The bioisosterism in -CO2H and -C4HO3 is exploited using the quantum theory of atoms in molecules and molecular electrostatic potentials (ESP). RESULTS & DISCUSSION: Bioisosteres in methylsquarate and acetic acid, in the neutral/anionic forms, have average electron densities that differ by less than 2% (i.e., ~0.01 atomic units) while irrespective of the capping group. The topography of the ESP reveals similarities in the case of the neutral species but not in the anionic forms. CONCLUSION: The nonclassical bioisosteres in methylsquarate and acetic acid have average electron densities that are similar and relatively insensitive to the ionization state (neutral or anionic) or its studied capping group (H, CH3, Cl or phenyl). The ESP reveals similarities in the topography of neutral molecules. PMID- 26976656 TI - Unlocking the genetic diversity of Creole wheats. AB - Climate change and slow yield gains pose a major threat to global wheat production. Underutilized genetic resources including landraces and wild relatives are key elements for developing high-yielding and climate-resilient wheat varieties. Landraces introduced into Mexico from Europe, also known as Creole wheats, are adapted to a wide range of climatic regimes and represent a unique genetic resource. Eight thousand four hundred and sixteen wheat landraces representing all dimensions of Mexico were characterized through genotyping-by sequencing technology. Results revealed sub-groups adapted to specific environments of Mexico. Broadly, accessions from north and south of Mexico showed considerable genetic differentiation. However, a large percentage of landrace accessions were genetically very close, although belonged to different regions most likely due to the recent (nearly five centuries before) introduction of wheat in Mexico. Some of the groups adapted to extreme environments and accumulated high number of rare alleles. Core reference sets were assembled simultaneously using multiple variables, capturing 89% of the rare alleles present in the complete set. Genetic information about Mexican wheat landraces and core reference set can be effectively utilized in next generation wheat varietal improvement. PMID- 26976659 TI - Effects of yoga in patients with paroxysmal atrial fibrillation - a randomized controlled study. AB - BACKGROUND: Patients with atrial fibrillation often have an impaired quality of life (QoL). Practising yoga may decrease stress and have positive effects on mental and physical health. The aim of this study was to investigate whether yoga can improve QoL and decrease blood pressure and heart rate in patients with paroxysmal atrial fibrillation (PAF). METHODS: In this pilot study, 80 patients diagnosed with PAF were randomized to standard treatment (control group, n=40) or standard treatment in combination with yoga (yoga group, n=40) during a 12-week period. QoL, blood pressure and heart rate were evaluated at baseline and at the end of the study (12 (+2) weeks). EuroQoL-5D (EQ-5D) Visual Analogue Scale (VAS) and the two dimensions in Short-Form Health Survey (SF-36) were used to evaluate QoL. RESULTS: At baseline there was a significant difference in QoL between the groups in EQ-5D VAS- scale ( p=0.02) and SF-36 mental health score ( p<0.001) in which the control group had higher scores. At the end of the study, the yoga group averaged higher SF-36 mental health scores. There was a significant difference between the two groups ( p=0.016), but no differences in EQ-5D VAS- scale and physiological health score was seen between the two groups. At the end of the study, the yoga group had significantly lower heart rate ( p=0.024) and systolic ( p=0.033) and diastolic blood pressure ( p<0.001) compared to the control group. CONCLUSIONS: Yoga with light movements and deep breathing may lead to improved QoL, lower blood pressure and lower heart rate in patients with PAF compared to a control group. Yoga could be a complementary treatment method to standard therapy. PMID- 26976661 TI - Plerixafor for Hematopoietic Stem Cell Mobilization in Children With Neuroblastoma. PMID- 26976660 TI - Top 10 lessons from the Glasgow major incidents. PMID- 26976658 TI - The Structure of a Thermophilic Kinase Shapes Fitness upon Random Circular Permutation. AB - Proteins can be engineered for synthetic biology through circular permutation, a sequence rearrangement in which native protein termini become linked and new termini are created elsewhere through backbone fission. However, it remains challenging to anticipate a protein's functional tolerance to circular permutation. Here, we describe new transposons for creating libraries of randomly circularly permuted proteins that minimize peptide additions at their termini, and we use transposase mutagenesis to study the tolerance of a thermophilic adenylate kinase (AK) to circular permutation. We find that libraries expressing permuted AKs with either short or long peptides amended to their N-terminus yield distinct sets of active variants and present evidence that this trend arises because permuted protein expression varies across libraries. Mapping all sites that tolerate backbone cleavage onto AK structure reveals that the largest contiguous regions of sequence that lack cleavage sites are proximal to the phosphotransfer site. A comparison of our results with a range of structure derived parameters further showed that retention of function correlates to the strongest extent with the distance to the phosphotransfer site, amino acid variability in an AK family sequence alignment, and residue-level deviations in superimposed AK structures. Our work illustrates how permuted protein libraries can be created with minimal peptide additions using transposase mutagenesis, and it reveals a challenge of maintaining consistent expression across permuted variants in a library that minimizes peptide additions. Furthermore, these findings provide a basis for interpreting responses of thermophilic phosphotransferases to circular permutation by calibrating how different structure-derived parameters relate to retention of function in a cellular selection. PMID- 26976664 TI - Changes in spinal alignment. AB - Spinal misalignments are a common reason for consultation at primary care centers and specialized departments. Misalignment has diverse causes and is influenced by multiple factors: in adolescence, the most frequent misalignment is scoliosis, which is idiopathic in 80% of cases and normally asymptomatic. In adults, the most common cause is degenerative. It is important to know the natural history and to detect factors that might predict progression. The correct diagnosis of spinal deformities requires specific imaging studies. The degree of deformity determines the type of treatment. The aim is to prevent progression of the deformity and to recover the flexibility and balance of the body. PMID- 26976662 TI - Impact of 4-epi-oxytetracycline on the gut microbiota and blood metabolomics of Wistar rats. AB - The impact of 4-epi-oxytetracycline (4-EOTC), one of the main oxytetracycline (OTC) metabolites, on the gut microbiota and physiological metabolism of Wistar rats was analyzed to explore the dynamic alterations apparent after repeated oral exposure (0.5, 5.0 or 50.0 mg/kg bw) for 15 days as shown by 16S rRNA pyrosequencing and UPLC-Q-TOF/MS analysis. Both principal component analysis and cluster analysis showed consistently altered patterns with distinct differences in the treated groups versus the control groups. 4-EOTC treatment at 5.0 or 50.0 mg/kg increased the relative abundance of the Actinobacteria, specifically Bifidobacteriaceae, and improved the synthesis of lysophosphatidylcholine (LysoPC), as shown by the lipid biomarkers LysoPC(16:0), LysoPC(18:3), LysoPC(20:3), and LysoPC(20:4). The metabolomic analysis of urine samples also identified four other decreased metabolites: diacylglycerol, sphingomyelin, triacylglycerol, and phosphatidylglycerol. Notably, the significant changes observed in these biomarkers demonstrated the ongoing disorder induced by 4-EOTC. Blood and urine analysis revealed that residual 4-EOTC accumulated in the rats, even two weeks after oral 4-EOTC administration, ceased. Thus, through thorough analysis, it can be concluded that the alteration of the gut microbiota and disorders in blood metabolomics are correlated with 4-EOTC treatment. PMID- 26976663 TI - Circumferential flow of particles in the suprachoroidal space is impeded by the posterior ciliary arteries. AB - Microneedle injection into the suprachoroidal space (SCS) enables targeted drug delivery for treatment of posterior segment diseases. This study sought to identify and characterize anatomical barriers to circumferential spread of particles in the SCS of rabbit and human cadaver eyes. These barriers could make targeting specific regions within the SCS challenging. A hollow microneedle (33 gauge, 750 MUm long) was used to inject fluorescent particles into albino New Zealand White rabbit eyes ex vivo at six different positions around the limbus and a limited number of conditions in vivo. SCS injections were also performed in human cadaver eyes 8 mm and 2 mm from the optic nerve (ON). Eyes were dissected and particle distribution was quantified. In rabbit eyes, injections made in the superior or inferior hemispheres (even when injected temporally immediately adjacent to the long posterior ciliary artery (LPCA)) did not significantly cross into the other hemisphere, apparently due to a barrier formed by the LPCA. The vortex veins had a minor effect on particle deposition, limited to only around the vortex vein root. In human eyes, the short posterior ciliary arteries (SPCAs) prevented circumferential spread towards the macula and ON. In conclusion, the rabbit LPCA and the human SPCA were anatomical barriers to particle spread within the SCS. Therefore, design of drug delivery protocols targeting the SCS need to account for barriers formed by anatomical structures in order for injected drug to reach target tissues. PMID- 26976665 TI - Current status of synthetic hemozoin adjuvant: A preliminary safety evaluation. AB - Although adjuvants are a "must-have" component of successful vaccines, there are very few adjuvants licensed for use in humans, there is therefore an urgent need to develop new and safer adjuvants. Synthetic hemozoin (sHZ), a chemical analog of hemozoin which is produced by the malaria parasite, exhibits a potent adjuvant effect which enhances antigen-specific immune responses to vaccines. The potency of sHZ adjuvanticity is not limited to malaria specific vaccines, it has also been demonstrated to be effective in influenza and dog allergy models. While the synthesis of uniformly sized sHZ with consistent characteristics has proven difficult, we have recently successfully optimized the manufacture of sHZ product with an optimal adjuvant effect. Here, we summarize recent developments on the adjuvant properties of optimized sHZ adjuvant, including its good laboratory practice (GLP) non-clinical safety profile in animals. These studies ensure the safety of optimized sHZ product to be readily used as vaccine adjuvant beforehand in veterinary medicine. PMID- 26976666 TI - Some reflections on the past, present, and future of Physical and Rehabilitation Medicine (on the occasion of the 30th SOFMER congress). PMID- 26976668 TI - Influence of Educational Attainment on Cognition-Based Intervention Programs for Persons with Mild Alzheimer's Disease. AB - OBJECTIVES: This research retrospectively analyzed the effect of education on cognitive interventions carried out in patients with mild Alzheimer's disease (AD). METHODS: The total sample consisted of 75 patients with mild AD receiving treatment with cholinesterase inhibitors. The participants were divided into two groups: cognitive intervention (IG; n=45) and waiting list (WLG; n=30). Patients in the IG received either the Big Brain Academy (n=15) or the Integrated Psychostimulation Program (n=30) during 12 weeks. The influence of education on intervention effect was analyzed comparing mean change scores of the two study groups in the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), stratified by educational level. The potential effect of age, sex, cognitive status, and type of intervention was examined using post hoc stratification analyses. RESULTS: Higher education was associated with faster cognitive decline in the WLG (effect size=0.51; p<.01). However, cognitive evolution was not influenced by education in the IG (effect size=0.12; p=.42). CONCLUSIONS: Our results suggest that cognitive intervention might delay accelerated cognitive decline in higher educated individuals with mild AD. PMID- 26976669 TI - Fluoxetine protects against IL-1beta-induced neuronal apoptosis via downregulation of p53. AB - Fluoxetine, a selective serotonin reuptake inhibitor, exerts neuroprotective effects in a variety of neurological diseases including stroke, but the underlying mechanism remains obscure. In the present study, we addressed the molecular events in fluoxetine against ischemia/reperfusion-induced acute neuronal injury and inflammation-induced neuronal apoptosis. We showed that treatment of fluoxetine (40 mg/kg, i.p.) with twice injections at 1 h and 12 h after transient middle cerebral artery occlusion (tMCAO) respectively alleviated neurological deficits and neuronal apoptosis in a mouse ischemic stroke model, accompanied by inhibiting interleukin-1beta (IL-1beta), Bax and p53 expression and upregulating anti-apoptotic protein Bcl-2 level. We next mimicked neuroinflammation in ischemic stroke with IL-1beta in primary cultured cortical neurons and found that pretreatment with fluoxetine (1 MUM) prevented IL-1beta induced neuronal apoptosis and upregulation of p53 expression. Furthermore, we demonstrated that p53 overexpression in N2a cell line abolished the anti apoptotic effect of fluoxetine, indicating that p53 downregulation is required for the protective role of fluoxetine in IL-1beta-induced neuronal apoptosis. Fluoxetine downregulating p53 expression could be mimicked by SB203580, a specific inhibitor of p38, but blocked by anisomycin, a p38 activator. Collectively, our findings have revealed that fluoxetine protects against IL 1beta-induced neuronal apoptosis via p38-p53 dependent pathway, which give us an insight into the potential of fluoxetine in terms of opening up novel therapeutic avenues for neurological diseases including stroke. PMID- 26976670 TI - Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer's disease. AB - Cannabinoid CB2 receptors (CB2Rs) are emerging as important therapeutic targets in brain disorders that typically involve neurometabolic alterations. We here addressed the possible role of CB2Rs in the regulation of glucose uptake in the mouse brain. To that aim, we have undertaken 1) measurement of (3)H-deoxyglucose uptake in cultured cortical astrocytes and neurons and in acute hippocampal slices; 2) real-time visualization of fluorescently labeled deoxyglucose uptake in superfused hippocampal slices; and 3) in vivo PET imaging of cerebral (18)F fluorodeoxyglucose uptake. We now show that both selective (JWH133 and GP1a) as well as non-selective (WIN55212-2) CB2R agonists, but not the CB1R-selective agonist, ACEA, stimulate glucose uptake, in a manner that is sensitive to the CB2R-selective antagonist, AM630. Glucose uptake is stimulated in astrocytes and neurons in culture, in acute hippocampal slices, in different brain areas of young adult male C57Bl/6j and CD-1 mice, as well as in middle-aged C57Bl/6j mice. Among the endocannabinoid metabolizing enzymes, the selective inhibition of COX 2, rather than that of FAAH, MAGL or alpha,betaDH6/12, also stimulates the uptake of glucose in hippocampal slices of middle-aged mice, an effect that was again prevented by AM630. However, we found the levels of the endocannabinoid, anandamide reduced in the hippocampus of TgAPP-2576 mice (a model of beta amyloidosis), and likely as a consequence, COX-2 inhibition failed to stimulate glucose uptake in these mice. Together, these results reveal a novel general glucoregulatory role for CB2Rs in the brain, raising therapeutic interest in CB2R agonists as nootropic agents. PMID- 26976671 TI - Chinese herbal medicine for menopausal symptoms. AB - BACKGROUND: Chinese herbal medicine (CHM) usage is expected to increase as women suffering from menopausal symptoms are seeking alternative therapy due to concerns from the adverse effects (AEs) associated with hormone therapy (HT). Scientific evidence for their effectiveness and safety is needed. OBJECTIVES: To evaluate the effectiveness and safety of CHM in the treatment of menopausal symptoms. SEARCH METHODS: We searched the Gynaecology and Fertility Group's Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 3), MEDLINE, Embase, CINAHL, AMED, and PsycINFO (from inception to March 2015). Others included Current Control Trials, Citation Indexes, conference abstracts in the ISI Web of Knowledge, LILACS database, PubMed, OpenSIGLE database, and China National Knowledge Infrastructure database (CNKI, 1999 to 2015). Other resources included reference lists of articles as well as direct contact with authors. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the effectiveness of CHM with placebo, HT, pharmaceutical drugs, acupuncture, or another CHM formula in women over 18 years of age, and suffering from menopausal symptoms. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed 864 studies for eligibility. Data extractions were performed by them with disagreements resolved through group discussion and clarification of data or direct contact with the study authors. Data analyses were performed in accordance with Cochrane Collaboration guidelines. MAIN RESULTS: We included 22 RCTs (2902 women). Participants were from different ethnic backgrounds with the majority of Chinese origin.When CHM was compared with placebo (eight RCTs), there was little or no evidence of a difference between the groups for the following pooled outcomes: hot flushes per day (MD 0.00, 95% CI -0.88 to 0.89; 2 trials, 199 women; moderate quality evidence); hot flushes per day assessed by an overall hot flush score in which a difference of one point equates to one mild hot flush per day (MD -0.81 points, 95% CI -2.08 to 0.45; 3 RCTs, 263 women; low quality evidence); and overall vasomotor symptoms per month measured by the Menopause-Specific Quality of Life questionnaire (MENQOL, scale 0 to 6) (MD -0.42 points; 95% CI -1.52 to 0.68; 3 RCTs, 256 women; low quality evidence).In addition, results from individual studies suggested there was no evidence of a difference between the groups for daily hot flushes assessed by severity (MD -0.70 points, 95% CI -1.00, -0.40; 1 RCT, 108 women; moderate quality evidence); or overall monthly hot flushes scores (MD -2.80 points, 95% CI -8.93 to 3.33; 1 RCT, 84 women; very low quality evidence); or overall daily night sweats scores (MD 0.07 points, 95% CI -0.19 to 0.33, 1 RCT, 64 women; low quality evidence); or overall monthly night sweats scores (MD 1.30 points, 95% CI -1.76 to 4.36, 1 RCT, 84 women; very low quality evidence). However one study using the Kupperman Index reported that overall monthly vasomotor symptom scores were lower in the CHM group (MD -4.79 points, 95% CI -5.52 to -4.06; 1 RCT, 69 women; low quality evidence).When CHM was compared with hormone therapy (HT) (10 RCTs), only two RCTs reported monthly vasomotor symptoms using MENQOL. It was uncertain whether CHM reduces vasomotor symptoms (MD 0.47 points, 95% CI -0.50 to 1.44; 2 RCTs, 127 women; very low quality evidence).Adverse effects were not fully reported in the included studies. Adverse events reported by women taking CHM included mild diarrhoea, breast tenderness, gastric discomfort and an unpleasant taste. Effects were inconclusive because of imprecise estimates of effects: CHM versus placebo (RR 1.51; 95% CI 0.69 to 3.33; 7 trials, 705 women; I2 = 40%); CHM versus HT (RR 0.96; 95% CI 0.66 to 1.39; 2 RCTs, 864 women; I2 = 0%); and CHM versus specific conventional medications (such as Fluoxetine and Estazolam) (RR 0.20; 95% CI 0.03 to 1.17; 2 RCTs, 139 women; I2 = 61%). AUTHORS' CONCLUSIONS: We found insufficient evidence that Chinese herbal medicines were any more or less effective than placebo or HT for the relief of vasomotor symptoms. Effects on safety were inconclusive. The quality of the evidence ranged from very low to moderate; there is a need for well-designed randomised controlled studies. PMID- 26976673 TI - Response to Letter to the Editor: Effect of stretching with and without muscle strengthening exercises for the foot and hip in patients with plantar fasciitis: A randomized controlled single-blind clinical trial. PMID- 26976672 TI - Assessment of red blood cell deformability in type 2 diabetes mellitus and diabetic retinopathy by dual optical tweezers stretching technique. AB - A pilot cross sectional study was conducted to investigate the role of red blood cells (RBC) deformability in type 2 diabetes mellitus (T2DM) without and with diabetic retinopathy (DR) using a dual optical tweezers stretching technique. A dual optical tweezers was made by splitting and recombining a single Nd:YAG laser beam. RBCs were trapped directly (i.e., without microbead handles) in the dual optical tweezers where they were observed to adopt a "side-on" orientation. RBC initial and final lengths after stretching were measured by digital video microscopy, and a Deformability index (DI) calculated. Blood from 8 healthy controls, 5 T2DM and 7 DR patients with respective mean age of 52.4 yrs, 51.6 yrs and 52 yrs was analysed. Initial average length of RBCs for control group was 8.45 +/- 0.25 MUm, 8.68 +/- 0.49 MUm for DM RBCs and 8.82 +/- 0.32 MUm for DR RBCs (p < 0.001). The DI for control group was 0.0698 +/- 0.0224, and that for DM RBCs was 0.0645 +/- 0.03 and 0.0635 +/- 0.028 (p < 0.001) for DR group. DI was inversely related to basal length of RBCs (p = .02). DI of RBC from DM and DR patients was significantly lower in comparison with normal healthy controls. A dual optical tweezers method can hence be reliably used to assess RBC deformability. PMID- 26976675 TI - Mechanical chest compression devices at in-hospital cardiac arrest: A systematic review and meta-analysis. AB - AIM: To summarise the evidence in relation to the routine use of mechanical chest compression devices during resuscitation from in-hospital cardiac arrest. METHODS: We conducted a systematic review of studies which compared the effect of the use of a mechanical chest compression device with manual chest compressions in adults that sustained an in-hospital cardiac arrest. Critical outcomes were survival with good neurological outcome, survival at hospital discharge or 30 days, and short-term survival (ROSC/1-h survival). Important outcomes included physiological outcomes. We synthesised results in a random-effects meta-analysis or narrative synthesis, as appropriate. Evidence quality in relation to each outcome was assessed using the GRADE system. DATA SOURCES: Studies were identified using electronic databases searches (Cochrane Central, MEDLINE, EMBASE, CINAHL), forward and backward citation searching, and review of reference lists of manufacturer documentation. RESULTS: Eight papers, containing nine studies [689 participants], were included. Three studies were randomised controlled trials. Meta-analyses showed an association between use of mechanical chest compression device and improved hospital or 30-day survival (odds ratio 2.34, 95% CI 1.42-3.85) and short-term survival (odds ratio 2.14, 95% CI 1.11 4.13). There was also evidence of improvements in physiological outcomes. Overall evidence quality in relation to all outcomes was very low. CONCLUSIONS: Mechanical chest compression devices may improve patient outcome, when used at in hospital cardiac arrest. However, the quality of current evidence is very low. There is a need for randomised trials to evaluate the effect of mechanical chest compression devices on survival for in-hospital cardiac arrest. PMID- 26976674 TI - Resistance of Feather-Associated Bacteria to Intermediate Levels of Ionizing Radiation near Chernobyl. AB - Ionizing radiation has been shown to produce negative effects on organisms, although little is known about its ecological and evolutionary effects. As a study model, we isolated bacteria associated with feathers from barn swallows Hirundo rustica from three study areas around Chernobyl differing in background ionizing radiation levels and one control study site in Denmark. Each bacterial community was exposed to four different gamma radiation doses ranging from 0.46 to 3.96 kGy to test whether chronic exposure to radiation had selected for resistant bacterial strains. Experimental radiation duration had an increasingly overall negative effect on the survival of all bacterial communities. After exposure to gamma radiation, bacteria isolated from the site with intermediate background radiation levels survived better and produced more colonies than the bacterial communities from other study sites with higher or lower background radiation levels. Long-term effects of radiation in natural populations might be an important selective pressure on traits of bacteria that facilitate survival in certain environments. Our findings indicate the importance of further studies to understand the proximate mechanisms acting to buffer the negative effects of ionizing radiation in natural populations. PMID- 26976678 TI - Editorial. PMID- 26976679 TI - Relapse to drug and alcohol use: a matter of sensitization. AB - Repeated exposure of rats to cocaine, amphetamine, opiates, nicotine and alcohol causes a very long-lasting (months) increase in the behavioral effects of these addictive drugs and drug-associated environmental stimuli (sensitization). This hypersensitivity is associated with persistent changes in the reactivity of neurons of the motivational (mesocorticolim-bic) system in the brain. Using an animal model for relapse, recent studies in our laboratory show that relapse to drug-seeking behavior (following extinction of intravenous cocaine or heroin self administration) depends on the occurrence of sensitization. Accordingly, sensitization and conditioning seem to be more important for the persistence of drug and alcohol addiction then the occurrence of withdrawal phenomena. Biochemical research on the molecular and cellular basis of behavioral sensitization and behavioral studies on readjustment of stimulus responsiveness in rats, is of great importance for the development of an adequate pharmacotherapy of addiction. PMID- 26976680 TI - Benzodiazepines in perspective (II): The GABAA-Benzodiazepine Receptor Ligands. AB - A huge number of natural and synthetic compounds modulate the function of the gamma-aminobutyric acid type A receptor (GABAA-R) by interacting with several allosteric binding sites which may differ in the various GABAA-R subtypes. The benzodiazepine receptor (BDZ-R) is the most intensively studied allosteric site. It is the first allosteric modulatory site on a neurotransmitter receptor that has been found to mediate two opposite functions: facilitation and depression of GABAA-R function. The effects of BDZ-R ligands on behavior range from agonistic (anxiolytic, anticonvulsant, myore-laxant/ataxic and hypno-sedative effects) to inverse-agonistic (anxiety and panic, hypervigilance and convulsions). Of particular interest for the future are BDZ-R partial agonists, as they lack several of the undesired properties of classic full agonists. Furthermore the GABAA-R system shows a high plasticity. This polymorphism raises the possibility that ligands selective for distinct subtypes of BDZ-R may emerge as useful drugs. In both cases the possibility exists of achieving very subtle manipulations of GABAA-R function by using allosteric modulators. PMID- 26976676 TI - Themes and variations: An exploratory international investigation into resuscitation decision-making. AB - BACKGROUND: Do Not Attempt Cardiopulmonary Resuscitation (DNACPR) decisions are made in hospitals throughout the globe. International variation in clinicians' perception of DNACPR decision-making and implementation and the factors influencing such variation has not previously been explored. METHODS: A questionnaire asking how DNACPR decisions are made, communicated and perceived in their country was composed: it consisted of seven closed-answer and four open answer questions. It was distributed to 143 medical professionals with prior published material relating to DNACPR decisions. Under-represented geographical areas were identified and an additional 34 physicians were contacted through medical colleagues and students at the university hospital from which this study was based. The respondents had 4 weeks to answer the questionnaire. RESULTS: 78 responses (44%) were received from 43 countries. All continents were represented. 88% of respondents reported a method for implementing DNACPR decisions, 90% of which discussed resuscitation wishes with the patient at least half of the time. 94% of respondents thought that national guidance for DNACPR order implementation should exist; 53% of countries surveyed reported existence of such guidance. Cultural attitudes towards death, medical education and culture, health economics and the societal role of family were commonly identified as factors influencing perception of DNACPR decisions. CONCLUSIONS: The majority of countries surveyed make some form of DNACPR decision but differing cultures and economic status contribute towards a heterogeneity of approaches to resuscitation decision making. Adequacy of relevant medical education and national policy are two areas that were regularly identified as impacting upon the processes of DNACPR decision making and implementation. PMID- 26976681 TI - Serum prolactin levels and sexual dysfunctions in antipsychotic medication, such as risperidone: a review. AB - Classical antipsychotic drugs increase the level of serum prolactin. The atypical antipsychotic clozapine barely increases prolactin levels. An open naturalistic study in the University Hospital of Groningen suggests that treatment with risperidone in comparison to classical antipsychotics seems to increase the risk of erectile and ejaculatory disorders in male patients and to menstrual disturbances in female patients. In the literature reviewed, risperidone is associated with higher prolactin levels in comparison to classical antipsychotics. It is still unclear which mechanism is responsible for the increase of serum prolactin levels and sexual dysfunctions in patients using risperidone. Dopaminergic and serotonergic receptor blockade seems to play an important role. Other mechanisms are discussed. PMID- 26976682 TI - Perseveration in schizophrenic patients: a neuropsychological approach for research. AB - Perseveration is a core symptom of schizophrenia, the cause, however, is unknown. It has been shown that for people with frontal lobe lesions, perseveration can be explained with a set-maintenance problem. Perseveration in Parkinson's disease can be explained with problems shifting from one set to another without cues (set shifting). These disorders can be distinguished using a two-choice task and the Wisconsin Card Sorting Test, that is analysed in phases. Analogs of these tests can be used in animal research. By adding an animal part to the human research, more insight can be gained into the role of specific brain areas in set maintenance and set-shifting. PMID- 26976677 TI - Therapeutic and prophylactic activity of itraconazole against human rhinovirus infection in a murine model. AB - Human rhinovirus (HRV) is the most common viral infectious agent in humans and is the predominant cause of the common cold. There is a need for appropriate vaccines or therapeutic agents to treat HRV infection. In this study, we investigated whether itraconazole (ICZ) can protect cells from HRV-induced cytotoxicity. Replication of HRV1B was reduced by ICZ treatment in the lungs of HRV1B- as compared to vehicle-treated mice. The numbers of immune cells, including granulocytes and monocytes, were reduced in bronchoalveolar lavage fluid (BALF) by ICZ administration after HRV1B infection, corresponding to decreased pro-inflammatory cytokine and chemokine levels in BALF. A histological analysis of lung tissue showed that ICZ suppressed inflammation caused by HRV1B infection. Interestingly, pretreatment of mice with ICZ in the form of a nasal spray had potent prophylactic antiviral activity. Cholesterol accumulation in the plasma membrane was observed upon HRV infection; ICZ blocked cholesterol trafficking to the plasma membrane, as well as resulted in its accumulation in subcellular compartments near the nucleus. These findings suggest that ICZ is a potential antiviral agent for the treatment of HRV infection, which can be adopted preventatively as well as therapeutically. PMID- 26976683 TI - Set-maintenance and set-shifting problems in schizophrenic subtypes: relationship to dysfunctions of the fronto-striatal loops. AB - Research with patients suffering from Parkinson's disease and frontal lobe lesions has shown that disturbances in the fronto-striatal loops in the brain can cause perseveration. Perseveration is a core symptom of schizophrenia, yet the cause is not known. For schizophrenic patients disorders of many parts of the fronto-striatal loops are found, for example disturbances of the prefrontal cortex and the striatum. Perseveration in schizophrenia can be explained with set maintenance problems, related to dysfunction of the prefrontal cortex, or with set-shifting problems that are related to disorders in the striatum. These set maintenance and set-shifting problems can be distinguished with neuropsychological tests. Regarding the bloodflow patterns for the different subtypes of schizophrenia three problems are expected as explanations for perseveration: set-maintenance problems concerning abstract information, set maintenance problems shifting between stimuli and enhanced set-shifting with cues. PMID- 26976684 TI - [Differences between autonomous communities in austerity and healthcare privatization in times of crisis]. PMID- 26976685 TI - Nitrate fertilisation does not enhance CO2 responses in two tropical seagrass species. AB - Seagrasses are often considered "winners" of ocean acidification (OA); however, seagrass productivity responses to OA could be limited by nitrogen availability, since nitrogen-derived metabolites are required for carbon assimilation. We tested nitrogen uptake and assimilation, photosynthesis, growth, and carbon allocation responses of the tropical seagrasses Halodule uninervis and Thalassia hemprichii to OA scenarios (428, 734 and 1213 MUatm pCO2) under two nutrients levels (0.3 and 1.9 MUM NO3(-)). Net primary production (measured as oxygen production) and growth in H. uninervis increased with pCO2 enrichment, but were not affected by nitrate enrichment. However, nitrate enrichment reduced whole plant respiration in H. uninervis. Net primary production and growth did not show significant changes with pCO2 or nitrate by the end of the experiment (24 d) in T. hemprichii. However, nitrate incorporation in T. hemprichii was higher with nitrate enrichment. There was no evidence that nitrogen demand increased with pCO2 enrichment in either species. Contrary to our initial hypothesis, nutrient increases to levels approximating present day flood plumes only had small effects on metabolism. This study highlights that the paradigm of increased productivity of seagrasses under ocean acidification may not be valid for all species under all environmental conditions. PMID- 26976686 TI - 3-O-Laurylglyceryl ascorbate activates the intracellular antioxidant system through the contribution of PPAR-gamma and Nrf2. AB - BACKGROUND: Ascorbic acid (AsA) has multifunctional effects on physiology and aging including the prevention and improvement of skin pigmentation and wrinkles. AsA has scavenging effects against various types of reactive oxygen species (ROS), which are initiators of aging and premature aging of the skin. However, AsA not only has a quite unstable characteristic, but also has low skin penetration. In addition, existing water-soluble AsA derivatives are not effective to improve its penetration of the skin. OBJECTIVE: To investigate the antioxidant effect of a newly synthesized amphipathic derivative of AsA, 3-O laurylglyceryl ascorbate (VC-3LG), in which a laurylglyceryl group was introduced into AsA. METHODS: Intracellular ROS levels in keratinocytes were evaluated using the 2',7'-Dichlorofluorescein diacetate (DCFHDA) assay. Real-time PCR was used to investigate the mechanism of the antioxidant effect of VC-3LG. RESULTS: Although VC-3LG had less ability to scavenge ROS compared to AsA, it elicited a superior reduction of intracellular ROS levels, with or without extracellular stimuli such as exposure to H2O2 or UVB. The results show that VC-3LG up-regulates the expression of mRNAs encoding peroxisome proliferator activated receptor-gamma (PPAR-gamma) and nuclear factor E2-related factor 2 (Nrf2), which in turn up regulate the levels of mRNAs encoding gamma-glutamyl cysteine synthase (gamma GCS), heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase-1 (NQO1). Furthermore, the Nrf2 mRNA level is down-regulated in siPPAR-gamma treated cells, and the effects of VC-3LG on PPAR-gamma and Nrf2 mRNA levels are reduced by PPAR gamma knockdown. CONCLUSION: Taken together, we conclude that VC-3LG has an antioxidant effect and scavenges ROS directly as well as stimulating intracellular antioxidants such as GSH through the PPAR-gamma and Nrf2 signaling pathway. PMID- 26976687 TI - CX3CR1 deficiency attenuates imiquimod-induced psoriasis-like skin inflammation with decreased M1 macrophages. AB - BACKGROUND: CX3C chemokine receptor 1 (CX3CR1), a receptor for CX3CL1, mediates migration of inflammatory cells. Psoriasis is a common skin disorder that causes skin inflammation. The role of CX3CL1 and CX3CR1 in psoriasis remains unclear. OBJECTIVE: To elucidate the role of CX3CL1 and CX3CR1 in psoriasis, we assessed imiquimod-induced psoriasis-like dermatitis in CX3CR1-deficient mice. METHODS: We evaluated skin inflammation by assessing erythema, scaling, and ear thickness in CX3CR1(-/-) mice and wild-type (WT) mice. Furthermore, we measured cytokine production by quantitative reverse transcription-PCR. We investigated infiltrating cells in skin by immunohistochemistry and flow cytometry. After confirming phenotypical differences in macrophages between WT and CX3CR1(-/-) mice, we analyzed expression levels of IL-1beta, IL-6, and TNF-alpha in peritoneal macrophages with or without stimulation of CX3CL1. We finally transferred peritoneal macrophages into the ear before IMQ application. RESULTS: Skin inflammation assessed by erythema, scaling, and epidermal thickness was significantly reduced in CX3CR1(-/-) mice compared with wild-type (WT) mice, accompanied by decreases in cytokine production for IL-12, IL-23, IL-17A, IL-22, IL-1beta, IL-6, TNF-alpha, and IL-36. On day 6, increase in ear thickness from the baseline of CX3CR1(-/-) mice was one third of that of WT mice. Skin macrophages of CX3CR1(-/-) mice contained increased levels of CCR2 and decreased levels of MCP-1 compared with those from WT mice. Spontaneous expression levels of IL-1beta, IL-6, and TNF-alpha in peritoneal macrophages of naive CX3CR1(-/-) mice were significantly lower than those of WT mice. Furthermore, stimulation of WT macrophages with CX3CL1 decreased expression of these cytokines, suggesting that altered macrophage populations, but not loss of interaction between CX3CL1 and CX3CR1 signaling, caused differences in cytokine expression and skin inflammation. Moreover, transfer of macrophages from WT mice normalized IMQ induced psoriasis-like inflammation in CX3CR1(-/-) mice, suggesting that macrophages contributed to the decreased inflammation resulted from CX3CR1 deficiency. CONCLUSION: These data show that interactions between CX3CL1 and CX3CR1 play important roles for infiltration of M1 macrophages in a non inflammatory setting. Decreased M1 macrophages in naive CX3CR1(-/-) mice may be related to decreased cytokine expression and attenuated psoriasis-like inflammation. PMID- 26976688 TI - Effects of superimposed tissue weight on regional compliance of injured lungs. AB - Computed tomography (CT), together with image analysis technologies, enable the construction of regional volume (VREG) and local transpulmonary pressure (PTP,REG) maps of the lung. Purpose of this study is to assess the distribution of VREG vs PTP,REG along the gravitational axis in healthy (HL) and experimental acute lung injury conditions (eALI) at various positive end-expiratory pressures (PEEPs) and inflation volumes. Mechanically ventilated pigs underwent inspiratory hold maneuvers at increasing volumes simultaneously with lung CT scans. eALI was induced via the iv administration of oleic acid. We computed voxel-level VREG vs PTP,REG curves into eleven isogravitational planes by applying polynomial regressions. Via F-test, we determined that VREG vs PTP,REG curves derived from different anatomical planes (p-values<1.4E-3), exposed to different PEEPs (p values<1.5E-5) or subtending different lung status (p-values<3E-3) were statistically different (except for two cases of adjacent planes). Lung parenchyma exhibits different elastic behaviors based on its position and the density of superimposed tissue which can increase during lung injury. PMID- 26976689 TI - Effects of nasal CPAP on exhaled SIRT1 and tumor necrosis factor-alpha in patients with obstructive sleep apnea. AB - Exhaled breath condensate (EBC) has been used to examine airway inflammation and oxidative stress. This study aimed to evaluate if there were abnormal Sirtuin 1 (SIRT1) protein and tumor necrosis factor (TNF)-alpha levels in EBC and to determine if these levels could be improved after nasal continuous positive airway pressure (CPAP) treatment. Thirty-five patients with moderately severe to severe obstructive sleep apnea syndrome (OSAS) who wanted nasal CPAP treatment and 20 healthy controls were prospectively enrolled. The EBC SIRT1 protein levels and EBC TNF-alpha protein levels were assessed by ELISA. All patients underwent sleep studies that were repeated 3 months after nasal CPAP treatment in patients with OSAS. Results showed that in OSAS before nasal CPAP treatment, the EBC SIRT1 protein levels were lower than that in normal subjects, whereas the EBC TNF-alpha protein levels were higher. After nasal CPAP treatment, the EBC SIRT1 levels increased and EBC TNF-alpha levels decreased. In conclusion, successful treatment of OSAS by nasal CPAP can normalize the levels of EBC SIRT1 and EBC TNF-alpha. PMID- 26976690 TI - Novel therapeutic investigational strategies to treat severe and disseminated HSV infections suggested by a deeper understanding of in vitro virus entry processes. AB - The global burden of herpes simplex virus (HSV) legitimates the critical need to develop new prevention strategies, such as drugs and vaccines that are able to fight either primary HSV infections or reactivations. Moreover, the ever-growing number of patients receiving transplants increases the number of severe HSV infections that are unresponsive to current therapies. Finally, the high global incidence of genital HSV-2 infection increases the risk of perinatal transmission to newborns, in which disseminated infection or central nervous system (CNS) involvement is frequent, with associated high morbidity and mortality rates. There are several key features shared by novel anti-HSV drugs, from currently available optimized drugs to small molecules able to interfere with various virus replication steps. However, several virological aspects of the disease and associated clinical needs highlight why an ideal anti-HSV drug has yet to be developed. PMID- 26976691 TI - Applying lessons learned from cytomegalovirus infection in transplant patients to vaccine design. AB - Studies in transplant recipients over the past decade aiming to characterize the immune response to cytomegalovirus (CMV) replication have provided insights that can be used to guide CMV vaccine development. These studies have characterized multiple aspects of the immune response to virus infection in humans, and have identified immunologic variables that correlate with the ability to control virus replication. These findings can be used to guide vaccine development by informing decisions regarding antigen selection and the type of immune response that must be elicited by these antigens to promote protective immunity. In addition, these studies have provided information that could aid in the identification of immunologic endpoints in vaccine clinical trials, thus facilitating their design and implementation. PMID- 26976692 TI - Cancer stem cells, cancer-initiating cells and methods for their detection. AB - The cancer stem cell (CSC) hypothesis considers CSCs as the main culprits of tumor initiation, propagation, metastasis and therapy failure. CSCs represent a minority subpopulation of cells within a tumor. Their detection, characterization and monitoring are crucial steps toward a better understanding of the biological roles of these special cells in the development and propagation of tumors which, in turn, improves clinical reasoning and treatment options. Nowadays, in vitro and in vivo assays are available that address the self-renewal and differentiation potential of CSCs, and advanced in vivo molecular imaging technology facilitates the detection and provides an unprecedented in vivo observation platform to study the behavior of CSCs in their natural environment. Here, we provide a brief overview of CSCs and describe modern cellular models and labeling techniques to study and trace CSCs. PMID- 26976694 TI - Is the boundary layer of an ionic liquid equally lubricating at higher temperature? AB - Atomic force microscopy has been used to study the effect of temperature on normal forces and friction for the room temperature ionic liquid (IL) ethylammonium nitrate (EAN), confined between mica and a silica colloid probe at 25 degrees C, 50 degrees C, and 80 degrees C. Force curves revealed a strong fluid dynamic influence at room temperature, which was greatly reduced at elevated temperatures due to the reduced liquid viscosity. A fluid dynamic analysis reveals that bulk viscosity is manifested at large separation but that EAN displays a nonzero slip, indicating a region of different viscosity near the surface. At high temperatures, the reduction in fluid dynamic force reveals step like force curves, similar to those found at room temperature using much lower scan rates. The ionic liquid boundary layer remains adsorbed to the solid surface even at high temperature, which provides a mechanism for lubrication when fluid dynamic lubrication is strongly reduced. The friction data reveals a decrease in absolute friction force with increasing temperature, which is associated with increased thermal motion and reduced viscosity of the near surface layers but, consistent with the normal force data, boundary layer lubrication was unaffected. The implications for ILs as lubricants are discussed in terms of the behaviour of this well characterised system. PMID- 26976693 TI - Time-frequency decomposition of click evoked otoacoustic emissions in children. AB - Determining the time-frequency distributions of click-evoked otoacoustic emissions (CEOAEs) are scientifically and clinically relevant because of their relationship with cochlear mechanisms. This study investigated the time-frequency properties of CEOAEs in 5-10 year old children. In the first part, we examined the feasibility of the S transform to characterize the time-frequency features of CEOAEs. A synthetic signal with known gammatones was analyzed using the S transform, as well as a wavelet transform with the basis function used traditionally for CEOAE analysis. The S and wavelet transforms provided similar representations of the gammatones of the synthetic signal in the mid and high frequencies. However, the S transform yielded a slightly more precise time frequency representation at low frequencies (500 and 707 Hz). In the second part, we applied the S transform to compare the time-frequency distribution of CEOAEs between adults and children. Several confounding variables, such as spontaneous emissions and potential efferent effects from the use of higher click rates, were considered for obtaining reliable CEOAE recordings. The results revealed that the emission level, level versus frequency plot, latency, and latency versus frequency plot in 5-10 year old children are adult-like. The time-frequency characteristics of CEOAEs in 5-10 year old children are consistent with the maturation of various aspects of cochlear mechanics, including the basal to apical transition. In sum, the description of the time-frequency features in children and the use of the S transform to decompose CEOAEs, are novel aspects of this study. The S transform can be used as an alternative approach to characterize the time-frequency distribution of CEOAEs. PMID- 26976695 TI - Bullous Pemphigoid with Immunoglobulin G anti-LAD-1 Antibodies without Evident Erythema and Eosinophil Infiltration. PMID- 26976696 TI - Coronectomy of the mandibular third molar: Respect for the inferior alveolar nerve. AB - The aim of this study was to evaluate the outcomes of coronectomy as an alternative surgical procedure to complete removal of the impacted mandibular third molar in patients with a suspected close relationship between the tooth root(s) and the mandibular canal. A total of 151 patients underwent coronectomy and were followed up with clinical examinations and panoramic radiographs for a minimum of 6 months after surgery. None of the patients exhibited inferior alveolar nerve injury. Eruption of the retained root(s) was more frequent in younger patients (18-35 years). Thirty-six patients (23.8%) exhibited insufficient growth of new bone in the alveolar defect, and 11.3% required a second surgical procedure to remove the root remnant(s). Our results indicate that coronectomy can be a reliable alternative to complete removal of the impacted mandibular third molar in patients exhibiting an increased risk of damage to the inferior alveolar nerve on panoramic radiographs. PMID- 26976697 TI - The effects of surgical expansion of the maxillary arch and its consequences for the incisor axis. AB - PURPOSE: Reduced transverse maxillary dental arch width may be treated either by surgically supported rapid maxillary expansion (SRME) with conservative orthodontic appliances or by means of Le Fort I osteotomy (LFIO). Both are means of transverse maxillary expansion. METHODS: Both surgical methods (SRME and LFIO) were evaluated with regard to the presurgical and postsurgical form of the maxillary dental arch and its consequences for the incisor axis by means of 32 dental casts and cephalometric analysis. RESULTS: In both groups, anterior and posterior dental arch width showed significant changes after surgery, but changes in anterior dental arch width were less significant after LFIO (p = 0.004) than after SRME (p < 0.000; t-test). Cephalometric analysis (OK1/N1) did not show any significant differences between the two surgical methods (p = 0.1266; t-test). Anterior arch length was not reduced after LFIO but significantly reduced after SRME. Thus, the ideal elliptical shape of the dental arch was lost in the SRME group, which may impede esthetic outcome of the maxillary dental arch. CONCLUSION: Le Fort I osteotomy achieving direct transverse expansion should be favored over surgically supported rapid maxillary expansion if transverse expansion does not exceed 7 mm. PMID- 26976698 TI - Diagnosing oral squamous cell carcinoma: How much imaging do we really need? A review of the current literature. AB - Complementary imaging techniques that round out the clinical examination are fundamentally important in the work-up of patients with oral squamous cell carcinoma (OSCC). Above all, exact determination of primary tumour extent, metastatic spread, and treatment response highly depend on accurate imaging methods. Despite a multitude of recently published reviews, there is still an ongoing debate regarding the best imaging method. In order to update the current literature with the latest evidence, a systematic literature search via Pubmed was performed. In total, 56 studies were enrolled, 4170 patients were analysed, and twenty different imaging methods were evaluated referring to their sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV). In summary, CT (computed tomography) and MRI (magnetic resonance imaging) currently remain the gold standard for evaluating extension of the primary tumour site. No additional evidence could be obtained for functional imaging methods displaying metastatic spread in the cervical lymph nodes, but was found for distant metastases. Furthermore, functional imaging seems to be beneficial in evaluating treatment response. There is further evidence in the accuracy of the different imaging methods found in this update that could possibly be implemented into the revision of the current guidelines and obtain a clear and coherent approach in the clinical set-up. PMID- 26976700 TI - DNA conformational behavior and compaction in biomimetic systems: Toward better understanding of DNA packaging in cell. AB - In a living cell, long genomic DNA is strongly compacted and exists in the environment characterized by a dense macromolecular crowding, high concentrations of mono- and divalent cations, and confinement of ca. 10MUm size surrounded by a phospholipid membrane. Experimental modelling of such complex biological system is challenging but important to understand spatiotemporal dynamics and functions of the DNA in cell. The accumulated knowledge about DNA condensation/compaction in conditions resembling those in the real cell can be eventually used to design and construct partly functional "artificial cells" having potential applications in drug delivery systems, gene therapy, and production of synthetic cells. In this review, I would like to overview the past progress in our understanding of the DNA conformational behavior and, in particular, DNA condensation/compaction phenomenon and its relation to the DNA biological activity. This understanding was gained by designing relevant experimental models mimicking DNA behavior in the environment of living cell. Starting with a brief summary of classic experimental systems to study DNA condensation/compaction, in later parts, I highlight recent experimental methodologies to address the effects of macromolecular crowding and nanoscale and microscale confinements on DNA conformation dynamics. All the studies are discussed in the light of their relevance to DNA behavior in living cells, and future prospects of the field are outlined. PMID- 26976699 TI - High-Flow Nasal Oxygen or Noninvasive Ventilation for Postextubation Hypoxemia: Flow vs Pressure? PMID- 26976701 TI - High Variation of Intravitreal Injection Rates and Medicare Anti-Vascular Endothelial Growth Factor Payments per Injection in the United States. AB - PURPOSE: To estimate geographic variation of intravitreal injection rates and Medicare anti-vascular endothelial growth factor (VEGF) drug costs per injection in aging Americans. DESIGN: Observational cohort study using 2013 Medicare claims database. PARTICIPANTS: United States fee-for-service (FFS) Part B Medicare beneficiaries and their providers. METHODS: Medicare Provider Utilization and Payment Data furnished by the Centers for Medicare and Medicaid Services was used to identify all intravitreal injection claims and anti-VEGF drug claims among FFS Medicare beneficiaries in all 50 states and the District of Columbia in 2013. The rate of FFS Medicare beneficiaries receiving intravitreal injections and the mean Medicare-allowed drug payment per anti-VEGF injection was calculated nationally and for each state. Geographic variations were evaluated by using extremal quotient, coefficient of variation, and systematic component of variance (SCV). MAIN OUTCOME MEASURES: Rate of FFS Medicare Part B beneficiaries receiving intravitreal injections (Current Procedural Terminology [CPT] code, 67028), nationally and by state; mean Medicare-allowed drug payment per anti-VEGF injection (CPT code, 67028; and treatment-specific J-codes, J0178, J2778, J9035, J3490, and J3590) nationally and by state. RESULTS: In 2013, the rate of FFS Medicare beneficiaries receiving intravitreal injections varied widely by 7-fold across states (range by state, 4 per 1000 [Wyoming]-28 per 1000 [Utah]), averaging 19 per 1000 beneficiaries. The mean SCV was 8.5, confirming high nonrandom geographic variation. There were more than 2.1 million anti-VEGF drug claims, totaling more than $2.3 billion in Medicare payments for anti-VEGF agents in 2013. The mean national Medicare drug payment per anti-VEGF injection varied widely by 6.2-fold across states (range by state, $242 [South Carolina]-$1509 [Maine]), averaging $1078 per injection. Nationally, 94% of injections were office based and 6% were facility based. CONCLUSIONS: High variation was observed in intravitreal injection rates and in Medicare drug payments per anti-VEGF injection across the United States in 2013. Identifying factors that contribute to high variation may help the ophthalmology community to optimize further the delivery and use of anti-VEGF agents. PMID- 26976702 TI - Photoreceptor Progenitor mRNA Analysis Reveals Exon Skipping Resulting from the ABCA4 c.5461-10T->C Mutation in Stargardt Disease. AB - PURPOSE: To elucidate the functional effect of the ABCA4 variant c.5461-10T->C, one of the most frequent variants associated with Stargardt disease (STGD1). DESIGN: Case series. PARTICIPANTS: Seventeen persons with STGD1 carrying ABCA4 variants and 1 control participant. METHODS: Haplotype analysis of 4 homozygotes and 11 heterozygotes for c.5461-10T->C and sequence analysis of the ABCA4 gene for a homozygous proband. Fibroblasts were reprogrammed from 3 persons with STGD1 into induced pluripotent stem cells, which were differentiated into photoreceptor progenitor cells (PPCs). The effect of the c.5461-10T->C variant on RNA splicing by reverse-transcription polymerase chain reaction was analyzed using PPC mRNA. In vitro assays were performed with minigene constructs containing ABCA4 exon 39. We analyzed the natural history and ophthalmologic characteristics of 4 persons homozygous for c.5461-10T->C. MAIN OUTCOME MEASURES: Haplotype and rare variant data for ABCA4, RNA splice defects, age at diagnosis, visual acuity, fundus appearance, visual field, electroretinography (ERG) results, fluorescein angiography results, and fundus autofluorescence findings. RESULTS: The frequent ABCA4 variant c.5461-10T->C has a subtle effect on splicing based on prediction programs. A founder haplotype containing c.5461-10T->C was found to span approximately 96 kb of ABCA4 and did not contain other rare sequence variants. Patient-derived PPCs showed skipping of exon 39 or exons 39 and 40 in the mRNA. HEK293T cell transduction with minigenes carrying exon 39 showed that the splice defects were the result of the c.5461-10T->C variant. All 4 subjects carrying the c.5461-10T->C variant in a homozygous state showed a young age of STGD1 onset, with low visual acuity at presentation and abnormal cone ERG results. All 4 demonstrated severe cone-rod dystrophy before 20 years of age and were legally blind by 25 years of age. CONCLUSIONS: The ABCA4 variant c.5461-10T->C is located on a founder haplotype lacking other disease-causing rare sequence variants. In vitro studies revealed that it leads to mRNA exon skipping and ABCA4 protein truncation. Given the severe phenotype in persons homozygous for this variant, we conclude that this variant results in the absence of ABCA4 activity. PMID- 26976703 TI - Diversity of spotted fever group Rickettsia infection in hard ticks from Suifenhe, Chinese-Russian border. AB - In order to investigate the diversity of spotted fever group (SFG) Rickettsia infection in hard ticks, ticks were harvested from the forest areas in Suifenhe city, along the Chinese-Russian border and conventional PCR was carried out using universal SFG Rickettsia primers targeting gltA and ompA genes to screen for their infection with SFG Rickettsia organisms. Results showed that of the 215 ticks belonging to Ixodes persulcatus, Haemaphysalis concinna and Haemaphysalis japonica Warburton, 1908 species, 138 (64.2%) were positive for SFG Rickettsia. Three species of SFG Rickettsia were detected, Rickettsia raoultii, Rickettsia heilongjiangensis and Candidatus Rickettsia tarasevichiae. No co-infection with different species of SFG Rickettsia was found in any individual tick among the three tick species. We detected more than one SFG Rickettsia species in ticks from each of the three tick species with an overlapping distribution and potentially similar transmission cycles of SFG Rickettsia in the areas surveyed. Consequently, different pathogenic rickettsial species may be involved in human cases of rickettsiosis after a bite of the three above-mentioned tick species in that area Rickettsia. PMID- 26976704 TI - First report of Rickettsia raoultii in field collected Dermacentor reticulatus ticks from Austria. AB - In a set of pooled field collected Dermacentor reticulatus ticks, Rickettsia raoultii, the causative agent of Tick-borne lymphadenopathy/Dermacentor-borne necrosis erythema and lymphadenopathy, was found for the first time in Austria. The coordinates of the positive locations for tick and pathogen abundance are given and shown in a map. PMID- 26976705 TI - G6PD protects from oxidative damage and improves healthspan in mice. AB - Reactive oxygen species (ROS) are constantly generated by cells and ROS-derived damage contributes to ageing. Protection against oxidative damage largely relies on the reductive power of NAPDH, whose levels are mostly determined by the enzyme glucose-6-phosphate dehydrogenase (G6PD). Here, we report a transgenic mouse model with moderate overexpression of human G6PD under its endogenous promoter. Importantly, G6PD-Tg mice have higher levels of NADPH, lower levels of ROS derived damage, and better protection from ageing-associated functional decline, including extended median lifespan in females. The G6PD transgene has no effect on tumour development, even after combining with various tumour-prone genetic alterations. We conclude that a modest increase in G6PD activity is beneficial for healthspan through increased NADPH levels and protection from the deleterious effects of ROS. PMID- 26976706 TI - Reconstruction of diaminopimelic acid biosynthesis allows characterisation of Mycobacterium tuberculosis N-succinyl-L,L-diaminopimelic acid desuccinylase. AB - With the increased incidence of tuberculosis (TB) caused by Mycobacterium tuberculosis there is an urgent need for new and better anti-tubercular drugs. N succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is a key enzyme in the succinylase pathway for the biosynthesis of meso-diaminopimelic acid (meso-DAP) and L-lysine. DapE is a zinc containing metallohydrolase which hydrolyses N succinyl L,L diaminopimelic acid (L,L-NSDAP) to L,L-diaminopimelic acid (L,L-DAP) and succinate. M. tuberculosis DapE (MtDapE) was cloned, over-expressed and purified as an N-terminal hexahistidine ((His)6) tagged fusion containing one zinc ion per DapE monomer. We redesigned the DAP synthetic pathway to generate L,L-NSDAP and other L,L-NSDAP derivatives and have characterised MtDapE with these substrates. In contrast to its other Gram negative homologues, the MtDapE was insensitive to inhibition by L-captopril which we show is consistent with novel mycobacterial alterations in the binding site of this drug. PMID- 26976707 TI - Kinetic analysis of bypass of O(6)- methylguanine by the catalytic core of yeast DNA polymerase eta. AB - Alkylating agents can form O(6)-methylguansine (O(6)-MeG). To study the intrinsic kinetic behaviors of bypassing O(6)-MeG, we used the catalytic core of yeast DNA polymerase eta (Pol etacore, residues 1-513), instead of the full-length Pol eta, to study their elementary steps, eliminating the effects of the C-terminal C2H2 motif on dNTP incorporation. The misincorporation frequencies were 10(-4) for G and 0.055-0.446 for O(6)-MeG. O(6)-MeG does not affect the extension efficiency. Pol etacore showed no fast burst phase for any incorporation opposite G or O(6) MeG. Primer extension was greatly blocked by O(6)-MeG and about 67% dTTP, 31% dCTP and 2% dATP were incorporated opposite O(6)-MeG. This study provides further understanding of the mutation mechanism of alkylated lesion for yeast DNA polymerase eta. PMID- 26976708 TI - Xanthohumol improves dysfunctional glucose and lipid metabolism in diet-induced obese C57BL/6J mice. AB - Xanthohumol (XN) is a prenylated flavonoid found in hops (Humulus lupulus) and beer. The dose-dependent effects of XN on glucose and lipid metabolism in a preclinical model of metabolic syndrome were the focus of our study. Forty-eight male C57BL/6J mice, 9 weeks of age, were randomly divided into three XN dose groups of 16 animals. The mice were fed a high-fat diet (60% kcal as fat) supplemented with XN at dose levels of 0, 30, or 60 mg/kg body weight/day, for 12 weeks. Dietary XN caused a dose-dependent decrease in body weight gain. Plasma levels of glucose, total triglycerides, total cholesterol, and MCP-1 were significantly decreased in mice on the 60 mg/kg/day treatment regimen. Treatment with XN at 60 mg/kg/day resulted in reduced plasma LDL-cholesterol (LDL-C), IL-6, insulin and leptin levels by 80%, 78%, 42%, and 41%, respectively, compared to the vehicle control group. Proprotein Convertase Subtilisin Kexin 9 (PCSK-9) levels were 44% lower in the 60 mg/kg dose group compared to the vehicle control group (p <= 0.05) which may account for the LDL-C lowering activity of XN. Our results show that oral administration of XN improves markers of systemic inflammation and metabolic syndrome in diet-induced obese C57BL/6J mice. PMID- 26976711 TI - Interventional Endoscopy--Opportunities and Limitations. PMID- 26976710 TI - Effect of incretin therapies compared to pioglitazone and gliclazide in non alcoholic fatty liver disease in diabetic patients not controlled on metformin alone: An observational, pilot study. AB - AIM: To compare the effect of different hypoglycemic drugs on laboratory and ultrasonographic markers of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes not controlled on metformin alone. METHODS: Prospective study of diabetic patients treated with metformin in combination with gliclazide, pioglitazone, sitagliptin, exenatide, or liraglutide. NAFLD was assessed by abdominal ultrasound and NAFLD fibrosis score was calculated at baseline and 6 months. RESULTS: Fifty-eight patients completed 6 months of follow-up: 15 received gliclazide, 13 pioglitazone, 15 sitagliptin, 7 exenatide, and 8 liraglutide. NAFLD affected 57.8% of patients at baseline, and its ultrasonographic course varied depending on changes in weight (P=.009) and waist circumference (P=.012). The proportions of patients who experienced ultrasonographic improvement in the different treatment groups were: 33.3% with gliclazide, 37.5% with pioglitazone, 45.5% with sitagliptin, 80% with exenatide, and 33% with liraglutide (P=.28). CONCLUSIONS: Qualitative ultrasonographic NAFLD improvement in diabetic patients treated with metformin in combination with other hypoglycemic drugs is associated to change over time in weight and waist circumference. Long-term clinical trials are needed to assess whether incretin therapies result in better liver outcomes than other hypoglycemic therapies. PMID- 26976709 TI - Enhanced troponin I binding explains the functional changes produced by the hypertrophic cardiomyopathy mutation A8V of cardiac troponin C. AB - Higher affinity for TnI explains how troponin C (TnC) carrying a causative hypertrophic cardiomyopathy mutation, TnC(A8V), sensitizes muscle cells to Ca(2+). Muscle fibers reconstituted with TnC(A8V) require ~2.3-fold less [Ca(2+)] to achieve 50% maximum-tension compared to fibers reconstituted with wild-type TnC (TnC(WT)). Binding measurements rule out a significant change in N-terminus Ca(2+)-affinity of isolated TnC(A8V), and TnC(A8V) binds the switch-peptide of troponin-I (TnI(sp)) ~1.6-fold more strongly than TnC(WT); thus we model the TnC TnI(sp) interaction as competing with the TnI-actin interaction. Tension data are well-fit by a model constrained to conditions in which the affinity of TnC(A8V) for TnI(sp) is 1.5-1.7-fold higher than that of TnC(WT) at all [Ca(2+)]. Mean ATPase rates of reconstituted cardiac myofibrils is greater for TnC(A8V) than TnC(WT) at all [Ca(2+)], with statistically significant differences in the means at higher [Ca(2+)]. To probe TnC-TnI interaction in low Ca(2+), displacement of bis-ANS from TnI was monitored as a function of TnC. Whereas Ca(2+)-TnC(WT) displaces significantly more bis-ANS than Mg(2+)-TnC(WT), Ca(2+)-TnC(A8V) displaces probe equivalently to Mg(2+)-TnC(A8V) and Ca(2+)-TnC(WT), consistent with stronger Ca(2+)-independent TnC(A8V)-TnI(sp). A Matlab program for computing theoretical activation is reported. Our work suggests that contractility is constantly above normal in hearts made hypertrophic by TnC(A8V). PMID- 26976712 TI - The Endoscopic Treatment of Iatrogenic Gastrointestinal Perforation. AB - BACKGROUND: Iatrogenic gastrointestinal perforation is a life-threatening complication that arises very rarely in routine endoscopic procedures, with an incidence of 0.03-0.8%. It is more likely in highly complex and invasive therapeutic interventions. In certain situations, endoscopic closure of the perforation and treatment with antibiotics can obviate the need for emergency surgical repair. METHODS: This review is based on pertinent articles retrieved by a selective literature search in PubMed and on a relevant position paper. RESULTS: Existing clinical studies of treatment for iatrogenic gastrointestinal perforation are mainly retrospective and uncontrolled. No randomized and controlled trials have been performed to date. If the perforation is discovered soon after it arises, endoscopic treatment can be considered. Gastrointestinal perforations that are less than 30 mm in size can be closed with a clip. In the esophagus, expanding metal stents can be used as well. Clip application is successful in 80-100% of cases of gastrointestinal perforation, and the perforation remains permanently closed in 60-100% of cases. Reports on the endoscopic treatment of esophageal perforation show mixed results, with closure rates of roughly 90% and clinical success rates of roughly 80%. If endoscopic treatment is not possible, timely laparoscopic or open surgical repair is needed. CONCLUSION: The endoscopic treatment of iatrogenic perforations is safe and reliable. Success depends on early detection, adequate endoscopic closure with properly mastered technique, and the early initiation of concomitant antibiotic treatment, which must be continued for a full course. Most patients who are treated in this way do not need emergency surgery. PMID- 26976714 TI - Important: Asking Patients About Lead Symptoms. PMID- 26976715 TI - Additional New Therapeutic Options. PMID- 26976713 TI - The Periprocedural Management of Anticoagulation and Platelet Aggregation Inhibitors in Endoscopic Interventions. AB - BACKGROUND: In Germany, more than half a million persons, most of them elderly, are under long-term treatment with anticoagulants. The approval of new oral anticoagulants and platelet aggregation inhibitors, as well as new data on periprocedural bridging with heparins, have introduced marked complexity to the management of treatment with anticoagulants and platelet aggregation inhibitors for endoscopic interventions in visceral surgery. METHODS: This review is based on pertinent publications retrieved by a selective literature search in PubMed, as well as on the relevant guidelines. RESULTS: Robust data are available on the management of vitamin K antagonists (VKA) and platelet aggregation inhibitors for endoscopic procedures; on the other hand, the data on the periprocedural management of non-VKA oral anticoagulants (NOAC) are still inadequate. Endoscopic procedures that carry a low risk of bleeding can be performed under treatment with anticoagulants or platelet aggregation inhibitors. Before any procedure with a high risk of bleeding (>= 1.5%) oral anticoagulants of any type and P2Y12 inhibitors should generally be discontinued. Patients in whom VKA are temporarily discontinued for this reason need bridging treatment with heparin only if they are at high risk of thromboembolic events (>= 10% per year). For patients who are anticoagulated with NOAC, timely discontinuation of the drug depending on renal function is of key importance, and bridging is usually unnecessary. CONCLUSION: Adequate scientific evidence supports the current recommendations and treatment algorithms for the periprocedural management of oral anticoagulants and platelet aggregation inhibitors in endoscopic procedures. Larger-scale studies are still needed to provide a sound basis for the corresponding recommendations about NOAC. PMID- 26976716 TI - In Reply. PMID- 26976717 TI - Adipose-derived stem cell differentiation as a basic tool for vascularized adipose tissue engineering. AB - The development of in vitro adipose tissue constructs is highly desired to cope with the increased demand for substitutes to replace damaged soft tissue after high graded burns, deformities or tumor removal. To achieve clinically relevant dimensions, vascularization of soft tissue constructs becomes inevitable but still poses a challenge. Adipose-derived stem cells (ASCs) represent a promising cell source for the setup of vascularized fatty tissue constructs as they can be differentiated into adipocytes and endothelial cells in vitro and are thereby available in sufficiently high cell numbers. This review summarizes the currently known characteristics of ASCs and achievements in adipogenic and endothelial differentiation in vitro. Further, the interdependency of adipogenesis and angiogenesis based on the crosstalk of endothelial cells, stem cells and adipocytes is addressed at the molecular level. Finally, achievements and limitations of current co-culture conditions for the construction of vascularized adipose tissue are evaluated. PMID- 26976718 TI - Solubilizing and Stabilizing Proteins in Anhydrous Ionic Liquids through Formation of Protein-Polymer Surfactant Nanoconstructs. AB - Nonaqueous biocatalysis is rapidly becoming a desirable tool for chemical and fuel synthesis in both the laboratory and industry. Similarly, ionic liquids are increasingly popular anhydrous reaction media for a number of industrial processes. Consequently, the use of enzymes in ionic liquids as efficient, environment-friendly, commercial biocatalysts is highly attractive. However, issues surrounding the poor solubility and low stability of enzymes in truly anhydrous media remain a significant challenge. Here, we demonstrate for the first time that engineering the surface of a protein to yield protein-polymer surfactant nanoconstructs allows for dissolution of dry protein into dry ionic liquids. Using myoglobin as a model protein, we show that this method can deliver protein molecules with near native structure into both hydrophilic and hydrophobic anhydrous ionic liquids. Remarkably, using temperature-dependent synchrotron radiation circular dichroism spectroscopy to measure half denaturation temperatures, our results show that protein stability increases by 55 degrees C in the ionic liquid as compared to aqueous solution, pushing the solution thermal denaturation beyond the boiling point of water. Therefore, the work presented herein could provide a platform for the realization of biocatalysis at high temperatures or in anhydrous solvent systems. PMID- 26976720 TI - Bipolaris oryzae, a novel fungal opportunist causing keratitis. AB - We report a case of mycotic keratitis caused by Bipolaris oryzae with predisposing trauma from a foreign body. The fungus was identified by sequencing the internal transcribed spacer region, translation elongation factor 1alpha (TEF1) gene, and partial glyceraldehyde-3-phosphate dehydrogenase (GPDH) gene, and the species identity was confirmed on the basis of its characteristic conidial phenotype. The patient was treated with surgical intervention and antifungal agents, including intravenous fluconazole (FLC), oral itraconazole, topical 0.15% amphotericin B eye drops, and 0.5% FLC eye drops. To our knowledge, this is the first report of mycotic keratitis caused by B. oryzae worldwide. PMID- 26976719 TI - Incidence and Risk Factors Involved in the Development of Nephropathy in Patients with Type 1 Diabetes Mellitus: Follow Up Since Onset. AB - OBJECTIVES: Estimation of the incidence of nephropathy as well as potential risk factors involved in its onset in a cohort of patients with type 1 diabetes who were followed from diagnosis. METHODS: We studied 716 patients, who were followed for a mean (standard deviation [SD]) of 10.1 (SD: 5.3) years. We analyzed the influence of demographic characteristics and levels of glycated hemoglobin (A1C), lipids and blood pressure during the course of the disease by univariate and multivariate survival methods. RESULTS: The cumulative incidence of nephropathy was 2.6%, 6.3% and 11.9% at 5, 10 and 15 years of evolution, respectively. The factors associated with increased risk for nephropathy were systolic blood pressure and A1C levels. An increment of 10 mm Hg in systolic blood pressure increases the risk by 36%, and an increment of 1% in A1C levels raises the risk by 13% at 5 years since onset and 68% at 10 years, and it doubles the risk at 15 years. Women have higher risk than men (hazard ratio 1.79; p=0.024). CONCLUSIONS: Our study suggests that female gender and high levels of A1C and systolic blood pressure throughout the course of the disease are the main factors associated with an increased risk for development of nephropathy in patients with type 1 diabetes mellitus. PMID- 26976721 TI - A Dual-Colour Architecture for Pump-Probe Spectroscopy of Ultrafast Magnetization Dynamics in the Sub-10-femtosecond Range. AB - Current time-resolution-limited dynamic measurements clearly show the need for improved techniques to access processes on the sub-10-femtosecond timescale. To access this regime, we have designed and constructed a state-of-the-art time resolved magneto-optic Kerr effect apparatus, based on a new dual-color scheme, for the measurement of ultrafast demagnetization and precessional dynamics in magnetic materials. This system can operate well below the current temporal ranges reported in the literature, which typically lie in the region of around 50 fs and above. We have used a dual-colour scheme, based on ultra broadband hollow core fibre and chirped mirror pulse compression techniques, to obtain unprecedented sub-8-fs pump and probe pulse durations at the sample plane. To demonstrate the capabilities of this system for ultrafast demagnetization and precessional dynamics studies, we have performed measurements in a ferrimagnetic GdFeCo thin film. Our study has shown that the magnetization shows a sudden drop within the first picosecond after the pump pulse, a fast recovery (remagnetization) within a few picoseconds, followed by a clear oscillation or precession during a slower magnetization recovery. Moreover, we have experimentally confirmed for the first time that a sub-10-fs pulse is able to efficiently excite a magnetic system such as GdFeCo. PMID- 26976723 TI - Multivariate evoked response detection based on the spectral F-test. AB - BACKGROUND: Objective response detection techniques, such as magnitude square coherence, component synchrony measure, and the spectral F-test, have been used to automate the detection of evoked responses. The performance of these detectors depends on both the signal-to-noise ratio (SNR) and the length of the electroencephalogram (EEG) signal. NEW METHOD: Recently, multivariate detectors were developed to increase the detection rate even in the case of a low signal-to noise ratio or of short data records originated from EEG signals. In this context, an extension to the multivariate case of the spectral F-test detector is proposed. RESULTS: The performance of this technique is assessed using Monte Carlo. As an example, EEG data from 12 subjects during photic stimulation is used to demonstrate the usefulness of the proposed detector. COMPARISON WITH EXISTING METHOD(S): The multivariate method showed detection rates consistently higher than those ones when only one signal was used. CONCLUSIONS: It is shown that the response detection in EEG signals with the multivariate technique was statistically significant if two or more EEG derivations were used. PMID- 26976722 TI - Novel intrathecal and subcutaneous catheter delivery systems in the mouse. AB - BACKGROUND: Catheter systems that permit targeted delivery of genes, molecules, ligands, and other agents represent an investigative tool critical to the development of clinically relevant animal models that facilitate the study of neurological health and disease. The development of new sustained catheter delivery systems to spinal and peripheral sites will reduce the need for repeated injections, while ensuring constant levels of drug in plasma and tissues. NEW METHOD: Here, we introduce two novel catheter delivery systems in the mouse: the O'Buckley intrathecal catheter system for sustained delivery to the spinal region and a subcutaneous bifurcated catheter system for sustained drug delivery to both hindpaws. RESULTS: The O'Buckley intrathecal catheter system consistently distributed Evans Blue throughout the spinal cord, with the greatest concentration at the thoracic region, and with an 85% surgery success rate. The subcutaneous catheter system consistently distributed Evans Blue to the hindlimbs, with a 100% surgery success rate. COMPARISON TO EXISTING METHOD: The O'Buckley intrathecal catheter system accomplishes sustained drug delivery to the spinal region, with a 2-fold increase in surgery success rate, as compared to the traditional method. Our subcutaneous bifurcated catheter system accomplishes sustained drug delivery to both hindpaws, eliminating the need for repeated intraplantar injections. CONCLUSIONS: We have developed catheter systems that improve upon traditional methods in order to achieve sustained localized drug delivery to spinal tissues and to hindpaw tissues surrounding peripheral sciatic nerve terminals. These methods have a broad reach, and can be used to enhance behavioral, physiologic and mechanistic studies in mice. PMID- 26976724 TI - The supination assessment task: An automated method for quantifying forelimb rotational function in rats. AB - BACKGROUND: Neurological injuries or disease can impair the function of motor circuitry controlling forearm supination, and recovery is often limited. Preclinical animal models are essential tools for developing therapeutic interventions to improve motor function after neurological damage. Here we describe the supination assessment task, an automated measure of quantifying forelimb supination in the rat. NEW METHOD: Animals were trained to reach out of a slot in a cage, grasp a spherical manipulandum, and supinate the forelimb. The angle of the manipulandum was measured using a rotary encoder. If the animal exceeded the predetermined turn angle, a reward pellet was delivered. This automated task provides a large, high-resolution dataset of turn angle over time. Multiple parameters can be measured including success rate, peak turn angle, turn velocity, area under the curve, and number of rotations per trial. The task provides a high degree of flexibility to the user, with both software and hardware parameters capable of being adjusted. RESULTS: We demonstrate the supination assessment task can effectively measure significant deficits in multiple parameters of rotational motor function for multiple weeks in two models of ischemic stroke. COMPARISON WITH EXISTING METHODS: Preexisting motor assays designed to measure forelimb supination in the rat require high-speed video analysis techniques. This operant task provides a high-resolution, quantitative end-point dataset of turn angle, which obviates the necessity of video analysis. CONCLUSIONS: The supination assessment task represents a novel, efficient method of evaluating forelimb rotation and may help decrease the cost and time of running experiments. PMID- 26976725 TI - Enhancer of zeste homolog 2 (EZH2) expression in bladder cancer. AB - BACKGROUND: Studies evaluating enhancer of zeste homolog 2 (EZH2) expression and oncologic outcomes in bladder cancer have been discrepant. EZH2 expression in noninvasive bladder cancer is not well studied. We thus set out to address the discrepancy in previous reports, and to study expression of EZH2 in noninvasive bladder cancer and its associations, in a large cystectomy cohort. MATERIALS AND METHODS: EZH2 expression was evaluated in tissue microarray material (invasive and noninvasive cancer). Associations between EZH2 expression and oncologic outcomes, tumor stage, and disease type were determined. Receiver operating characteristic analysis was performed for EZH2 expression in the diagnosis of invasive carcinoma and flat carcinoma in situ (CIS) compared to benign urothelium. RESULTS: EZH2 expression was most common in CIS, followed by invasive carcinoma, noninvasive papillary urothelial carcinoma, and benign urothelium, in decreasing order (P<0.05 all comparisons, linear model). The receiver operating characteristic analysis demonstrated an area under the curve of 0.92 for CIS and 0.83 for invasive carcinoma, both compared to benign urothelium. At a cutoff of>=4, this corresponded to sensitivities of 89% and 73%, and specificities of 82% and 82%, for CIS and invasive carcinoma, respectively. The EZH2 expression was not associated with oncologic outcomes, including recurrence-free survival and death from bladder cancer. The EZH2 expression status (positive or negative) of noninvasive and invasive carcinomas taken from the same bladder correlated (P = 0.05, Fisher exact). CONCLUSION: That EZH2 status of noninvasive and invasive cancer correlated in individual patients suggests that EZH2 may be a marker of lineage. EZH2 may offer diagnostic utility, particularly in flat urothelial CIS vs. benign urothelium. The present study supports that EZH2 expression in bladder cancer is not predictive of oncologic outcome. PMID- 26976727 TI - Liver-specific expression of carboxylesterase 1g/esterase-x reduces hepatic steatosis, counteracts dyslipidemia and improves insulin signaling. AB - Ces1g/Es-x deficiency in mice results in weight gain, insulin resistance, fatty liver and hyperlipidemia through upregulation of de novo lipogenesis and oversecretion of triacylglycerol (TG)-rich lipoproteins. Here, we show that restoration of Ces1g/Es-x expression only in the liver significantly reduced hepatic TG concentration accompanied by decreased size of lipid droplets, reduced secretion of very low-density lipoproteins and improved insulin-mediated signal transduction in the liver. Collectively, these results demonstrate that hepatic Ces1g/Es-x plays a critical role in limiting hepatic steatosis, very low-density lipoprotein assembly and in augmenting insulin sensitivity. PMID- 26976728 TI - Incorporation of Bacterial Blight Resistance Genes Into Lowland Rice Cultivar Through Marker-Assisted Backcross Breeding. AB - Bacterial blight (BB) of rice caused by Xanthomonas oryzae pv. oryzae is a major disease of rice in many rice growing countries. Pyramided lines carrying two BB resistance gene combinations (Xa21+xa13 and Xa21+xa5) were developed in a lowland cultivar Jalmagna background through backcross breeding by integrating molecular markers. In each backcross generation, markers closely linked to the disease resistance genes were used to select plants possessing the target genes. Background selection was continued in those plants carrying resistant genes until BC(3) generation. Plants having the maximum contribution from the recurrent parent genome were selected in each generation and hybridized with the recipient parent. The BB-pyramided line having the maximum recipient parent genome recovery of 95% was selected among BC3F1 plants and selfed to isolate homozygous BC(3)F(2) plants with different combinations of BB resistance genes. Twenty pyramided lines with two resistance gene combinations exhibited high levels of tolerance against the BB pathogen. In order to confirm the resistance, the pyramided lines were inoculated with different X. oryzae pv. oryzae strains of Odisha for bioassay. The genotypes with combination of two BB resistance genes conferred high levels of resistance to the predominant X. oryzae pv. oryzae isolates prevalent in the region. The pyramided lines showed similarity with the recipient parent with respect to major agro-morphologic traits. PMID- 26976726 TI - Recent findings and future directions for interpolar mitotic kinesin inhibitors in cancer therapy. AB - The kinesin class of microtubule-associated motor proteins present attractive anticancer targets owing to their roles in key functions in dividing cells. Two interpolar mitotic kinesins Eg5 and HSET have opposing motor functions in mitotic spindle assembly with respect to microtubule movement, but both offer opportunities to develop cancer selective therapeutic agents. Here, we summarize the progress to date in developing inhibitors of Eg5 and HSET, with an emphasis on structural biology insights into the binding modes of allosteric inhibitors, compound selectivity and mechanisms of action of different chemical scaffolds. We discuss translation of preclinical studies to clinical experience with Eg5 inhibitors, recent findings on potential resistance mechanisms and explore the implications for future anticancer drug development against these targets. PMID- 26976730 TI - Mechanism of Action of the Benzimidazole Fungicide on Fusarium graminearum: Interfering with Polymerization of Monomeric Tubulin But Not Polymerized Microtubule. AB - Tubulins are the proposed target of clinically relevant anticancer drugs, anthelmintic, and fungicide. beta2-tubulin of the plant pathogen Fusarium graminearum was considered as the target of benzimidazole compounds by homology modeling in our previous work. In this study, alpha1-, alpha2-, and beta2-tubulin of F. graminearum were produced in Escherichia coli. Three benzimidazole compounds (carbendazim, benomyl, and thiabendazole) interacted with the recombinant beta2-tubulin and reduced the maximum fluorescence intensity of 2 MUM beta2-tubulin 47, 50, and 25%, respectively, at saturation of compound-tubulin complexes. Furthermore, carbendazim significantly inhibited the polymerization of alpha1-/beta2-tubulins and alpha2-/beta2-tubulins 90.9 +/- 0.4 and 93.5 +/- 0.05%, respectively, in vitro. A similar result appeared with benomyl on the polymerization of alpha1-/beta2-tubulins and alpha2-/beta2-tubulins at 89.9 +/- 0.1% and 92.6 +/- 1.2% inhibition ratios, respectively. In addition, thiabendazole inhibited 81.6 +/- 1% polymerization of alpha1-/beta2-tubulins, whereas it had less effect on alpha2-/beta2-tubulin polymerization, with 20.1 +/- 1.9% inhibition ratio. However, the three compounds cannot destabilize the polymerized microtubule. To illuminate the issue, mapping the carbendazim binding sites and beta/alpha subunit interface on beta/alpha-tubulin complexes by homology modeling showed that the two domains were closed to each other. Understanding the nature of the interaction between benzimidazole compounds and F. graminearum tubulin is fundamental for the development of tubulin-specific anti-F. graminearum compounds. PMID- 26976731 TI - Effect of antireflux surgery for Barrett's esophagus: long-term results. AB - INTRODUCTION: Barrett's esophagus is a metaplastic change in the lower esophagus that results from long-standing gastro-esophageal reflux disease, associated with a risk of development of esophageal adenocarcinoma. This review examines the role of antireflux surgery in the management of Barrett's esophagus. EVIDENCE ACQUISITION: A systematic review of the EMBASE and MEDLINE databases (1974-2016) was undertaken to identify studies with long-term follow-up examining the role of antireflux surgery in Barrett's esophagus. Outcomes examined were: number of subjects, follow-up, rates of progression, regression and adenocarcinoma. Symptomatic outcomes, surgical morbidity and rates of surgical failure were included when available. EVIDENCE SYNTHESIS: A total of 2403 articles were identified of which 9 met the inclusion criteria for this study using the PRISMA methodology. Citation tracking identified 3 further studies for inclusion. There were 962 patients included in this study, 731 who were found to have completed endoscopic follow up with a total of 3736 years of follow up. Annual incidence of esophageal adenocarcinoma was found to be 0.18%. Thirty-five percent of patients (260 patients) had regression. Progression was seen in 8% (57 patients) postoperatively. There was no mortality. CONCLUSIONS: There is insufficient evidence to recommend surgery over medical therapy to reduce cancer risk in Barrett's esophagus. Regression of features associated with cancer risk was more common after surgery than medical therapy. Surgery has been shown to improve patients' gastroesophageal reflux disease-specific quality of life. Long-term, antireflux surgery represents a cost effective method to manage Barrett's Esophagus with continued endoscopic surveillance. PMID- 26976729 TI - The U.S. Culture Collection Network Lays the Foundation for Progress in Preservation of Valuable Microbial Resources. AB - The U.S. Culture Collection Network was formed in 2012 by a group of culture collection scientists and stakeholders in order to continue the progress established previously through efforts of an ad hoc group. The network is supported by a Research Coordination Network grant from the U.S. National Science Foundation (NSF) and has the goals of promoting interaction among collections, encouraging the adoption of best practices, and protecting endangered or orphaned collections. After prior meetings to discuss best practices, shared data, and synergy with genome programs, the network held a meeting at the U.S. Department of Agriculture (USDA)-Agricultural Research Service (ARS) National Center for Genetic Resources Preservation (NCGRP) in Fort Collins, Colorado in October 2015 specifically to discuss collections that are vulnerable because of changes in funding programs, or are at risk of loss because of retirement or lack of funding. The meeting allowed collection curators who had already backed up their resources at the USDA NCGRP to visit the site, and brought collection owners, managers, and stakeholders together. Eight formal collections have established off-site backups with the USDA-ARS, ensuring that key material will be preserved for future research. All of the collections with backup at the NCGRP are public distributing collections including U.S. NSF-supported genetic stock centers, USDA ARS collections, and university-supported collections. Facing the retirement of several pioneering researchers, the community discussed the value of preserving personal research collections and agreed that a mechanism to preserve these valuable collections was essential to any future national culture collection system. Additional input from curators of plant and animal collections emphasized that collections of every kind face similar challenges in developing long-range plans for sustainability. PMID- 26976732 TI - Time-to-administration in postoperative chemotherapy for colorectal cancer: does minimally-invasive surgery help? AB - The optimal delay in the start of chemotherapy following rectal cancer surgery has not yet been identified. However, postponed adjuvant therapy has been proven to be connected with a significant survival detriment. We aimed to investigate whether the time to initiation of adjuvant treatment can be influenced by the application of minimally invasive surgery rather than traditional open surgery. By comprehensively evaluating the available inherent literature, several factors appear to be associated with delayed postoperative chemotherapy. Some of them are strictly related to surgical short-term outcomes. Laparoscopy results in shortened length of hospital stay, reduced surgical morbidity and lower rate of wound infection compared to conventional surgery. Probably due to such advantages, the application of minimally-invasive surgery to treat rectal malignancies seems to impact favorably the possibility to start adjuvant chemotherapy within an adequate timeframe following surgical resection, with potential improvement in patient survival. PMID- 26976733 TI - The learning curve to achieve satisfactory completion rates in upper GI endoscopy: an analysis of a national training database. AB - OBJECTIVE: The aim of this study was to determine the number of OGDs (oesophago gastro-duodenoscopies) trainees need to perform to acquire competency in terms of successful unassisted completion to the second part of the duodenum 95% of the time. DESIGN: OGD data were retrieved from the trainee e-portfolio developed by the Joint Advisory Group on GI Endoscopy (JAG) in the UK. All trainees were included unless they were known to have a baseline experience of >20 procedures or had submitted data for <20 procedures. The primary outcome measure was OGD completion, defined as passage of the endoscope to the second part of the duodenum without physical assistance. The number of OGDs required to achieve a 95% completion rate was calculated by the moving average method and learning curve cumulative summation (LC-Cusum) analysis. To determine which factors were independently associated with OGD completion, a mixed effects logistic regression model was constructed with OGD completion as the outcome variable. RESULTS: Data were analysed for 1255 trainees over 288 centres, representing 243 555 OGDs. By moving average method, trainees attained a 95% completion rate at 187 procedures. By LC-Cusum analysis, after 200 procedures, >90% trainees had attained a 95% completion rate. Total number of OGDs performed, trainee age and experience in lower GI endoscopy were factors independently associated with OGD completion. CONCLUSIONS: There are limited published data on the OGD learning curve. This is the largest study to date analysing the learning curve for competency acquisition. The JAG competency requirement for 200 procedures appears appropriate. PMID- 26976735 TI - Competitive intramolecular C-C vs. C-O bond coupling reactions toward C6 ring fused 2-pyridone synthesis. AB - An interesting competitive C-C vs. C-O bond coupling reaction on N,3,5 trisubstituted pyridones is reported. These coupling reactions provided selective access to C- or O-ring-fused pyridones, both at the challenging C6-pyridone position. 1,6-C-Annulated pyridones were generally achieved in good yields with excellent chemoselectivity under Pd(0) conditions. On the other hand, full C6 regioselective Csp(2) aryloxylation was achieved under oxidative coupling promoted by silver salts to access 5,6-O-annulated pyridones. Based on various experiments and observations, mechanistic evidence of these competitive reactions was provided and it was proposed that C-O bond formation proceeded through radical cyclization. These processes were performed under mild reaction conditions and offer an efficient and attractive methodology to selectively access a large scope of C-arylated and O-arylated pyridones of biological interest. PMID- 26976734 TI - FODMAPs alter symptoms and the metabolome of patients with IBS: a randomised controlled trial. AB - OBJECTIVE: To gain mechanistic insights, we compared effects of low fermentable oligosaccharides, disaccharides and monosaccharides and polyols (FODMAP) and high FODMAP diets on symptoms, the metabolome and the microbiome of patients with IBS. DESIGN: We performed a controlled, single blind study of patients with IBS (Rome III criteria) randomised to a low (n=20) or high (n=20) FODMAP diet for 3 weeks. Symptoms were assessed using the IBS symptom severity scoring (IBS-SSS). The metabolome was evaluated using the lactulose breath test (LBT) and metabolic profiling in urine using mass spectrometry. Stool microbiota composition was analysed by 16S rRNA gene profiling. RESULTS: Thirty-seven patients (19 low FODMAP; 18 high FODMAP) completed the 3-week diet. The IBS-SSS was reduced in the low FODMAP diet group (p<0.001) but not the high FODMAP group. LBTs showed a minor decrease in H2 production in the low FODMAP compared with the high FODMAP group. Metabolic profiling of urine showed groups of patients with IBS differed significantly after the diet (p<0.01), with three metabolites (histamine, p hydroxybenzoic acid, azelaic acid) being primarily responsible for discrimination between the two groups. Histamine, a measure of immune activation, was reduced eightfold in the low FODMAP group (p<0.05). Low FODMAP diet increased Actinobacteria richness and diversity, and high FODMAP diet decreased the relative abundance of bacteria involved in gas consumption. CONCLUSIONS: IBS symptoms are linked to FODMAP content and associated with alterations in the metabolome. In subsets of patients, FODMAPs modulate histamine levels and the microbiota, both of which could alter symptoms. TRIAL REGISTRATION NUMBER: NCT01829932. PMID- 26976736 TI - Light scattering microscopy measurements of single nuclei compared with GPU accelerated FDTD simulations. AB - Single cell nuclei were investigated using two-dimensional angularly and spectrally resolved scattering microscopy. We show that even for a qualitative comparison of experimental and theoretical data, the standard Mie model of a homogeneous sphere proves to be insufficient. Hence, an accelerated finite difference time-domain method using a graphics processor unit and domain decomposition was implemented to analyze the experimental scattering patterns. The measured cell nuclei were modeled as single spheres with randomly distributed spherical inclusions of different size and refractive index representing the nucleoli and clumps of chromatin. Taking into account the nuclear heterogeneity of a large number of inclusions yields a qualitative agreement between experimental and theoretical spectra and illustrates the impact of the nuclear micro- and nanostructure on the scattering patterns. PMID- 26976737 TI - Glycosphingolipid analysis in a naturally occurring ovine model of acute neuronopathic Gaucher disease. AB - Gaucher disease arises from mutations in the beta-glucocerebrosidase gene which encodes an enzyme required for the lysosomal catabolism of glucosylceramide. We have identified a naturally occurring mutation in the beta-glucocerebrosidase gene in sheep that leads to Gaucher disease with acute neurological symptoms. Here we have examined the clinical phenotype at birth and subsequently quantified lipids in Gaucher lamb brain, in order to characterise the disorder. Enzyme activity assessments showed that a reduction in beta-glucocerebrosidase activity to 1-5% of wild-type occurs consistently across newborn Gaucher lamb brain regions. We analyzed glucosylceramide, glucosylsphingosine, bis(monoacylglycero)phosphate and ganglioside profiles in brain, liver, and spleen, and observed 30- to 130-fold higher glucosylceramide, and 500- to 2000 fold higher glucosylsphingosine concentrations in Gaucher diseased lambs compared to wild-type. Significant increases of bis(monoacylglycero)phosphate and gangliosides [GM1, GM2, GM3] concentrations were also detected in the brain. As these glycosphingolipids are involved in many cellular events, an imbalance or disruption of the cell membrane lipid homeostasis would be expected to impair normal neuronal function. To our knowledge, this is the first detailed analysis of glycosphingolipids in various brain regions in a large animal model of neuronal disease, which permits the mechanistic investigation of lipid deregulation and their contribution to neurodegenerative process. PMID- 26976738 TI - Continuous bilateral infusion of vigabatrin into the subthalamic nucleus: Effects on seizure threshold and GABA metabolism in two rat models. AB - The subthalamic nucleus (STN) plays a crucial role as a regulator of basal ganglia outflow but also influences the activity of cortical and limbic structures, so that it is widely used as a therapeutic target in different brain diseases, including epilepsy. In addition to electrical stimulation of the STN, targeted delivery of anti-seizure drugs to the STN may constitute an alternative treatment approach in patients with pharmacoresistant epilepsy. In the present experimental study, we investigated the anti-seizure and adverse effects of chronic infusion of vigabatrin into the STN of rats. Vigabatrin is a clinically approved anti-seizure drug, which acts by increasing brain GABA levels by irreversibly inhibiting GABA-aminotransferase (GABA-T). Based on functional and neurochemical effects of acute STN microinjection, doses for continuous infusion were calculated and administered, using an innovative drug infusion technology. Bilateral infusion of only 10MUg/day vigabatrin over 3weeks into the STN resulted in an almost complete inhibition of GABA-T and 4-fold increase in GABA in the target region, which was associated with a significant increase in seizure threshold, determined once weekly by i.v. infusion of pentylenetetrazole (PTZ). Lower doses or unilateral infusion were less effective, both on PTZ seizures and on kindled seizures. Bilateral infusion into substantia nigra pars reticulata was less effective and more toxic than STN infusion. In part of the rats, tolerance to the anti-seizure effect developed. The data demonstrate that chronic administration of very low, nontoxic doses of vigabatrin into STN is an effective means of increasing local GABA concentrations and seizure threshold. PMID- 26976739 TI - High salt drives Th17 responses in experimental autoimmune encephalomyelitis without impacting myeloid dendritic cells. AB - Recently, we have shown that high dietary salt intake aggravates T helper cell (Th) 17 responses and neuroinflammation. Here, we employed in vitro assays for myeloid dendritic cell (mDC) maturation, DC cytokine production, T cell activation and ex vivo analyses in murine experimental autoimmune encephalomyelitis (EAE) to investigate whether the salt effect on Th17 cells is further mediated through DCs in vivo. In cell culture, an excess of 40mM sodium chloride did neither affect the generation, maturation nor the function of DCs, but, in different assays, significantly increased Th17 differentiation. During the initiation phase of MOG35-55 EAE, we did not observe altered DC frequencies or co-stimulatory capacities in lymphoid organs, while IL-17A production and Th17 cells in the spleen were significantly increased. Complementary ex vivo analyses of the spinal cord during the effector phase of EAE showed increased frequencies of Th17 cells, but did not reveal differences in phenotypes of CNS invading DCs. Finally, adaption of transgenic mice harboring a MOG specific T cell receptor to a high-salt diet led to aggravated clinical disease only after active immunization. Wild-type mice adapted to a high-salt diet in the effector phase of EAE, bypassing the priming phase of T cells, only displayed mildly aggravated disease. In summary, our data argue for a direct effect of NaCl on Th17 cells in neuroinflammation rather than an effect primarily exerted via DCs. These data may further fuel our understanding on the dietary impact on different immune cell subsets in autoimmune diseases, such as multiple sclerosis. PMID- 26976741 TI - Population sex-ratio affecting behavior and physiology of overwintering bank voles (Myodes glareolus). AB - Many boreal rodents are territorial during the breeding season but during winter become social and aggregate for more energy efficient thermoregulation. Communal winter nesting and social interactions are considered to play an important role for the winter survival of these species, yet the topic is relatively little explored. Females are suggested to be the initiators of winter aggregations and sometimes reported to survive better than males. This could be due to the higher social tolerance observed in overwintering females than males. Hormonal status could also affect winter behavior and survival. For instance, chronic stress can have a negative effect on survival, whereas high gonadal hormone levels, such as testosterone, often induce aggressive behavior. To test if the winter survival of females in a boreal rodent is better than that of males, and to assess the role of females in the winter aggregations, we generated bank vole (Myodes glareolus) populations of three different sex ratios (male-biased, female-biased and even density) under semi-natural conditions. We monitored survival, spatial behavior and hormonal status (stress and testosterone) during two winter months. We observed no significant differences in survival between the sexes or among populations with differing sex-ratios. The degree of movement area overlap was used as an indicator of social tolerance and potential communal nesting. Individuals in male biased populations showed a tendency to be solitary, whereas in female biased populations there was an indication of winter aggregation. Females living in male-biased populations had higher stress levels than the females from the other populations. The female-biased sex-ratio induced winter breeding and elevated testosterone levels in males. Thus, our results suggest that the sex-ratio of the overwintering population can lead to divergent overwintering strategies in bank voles. PMID- 26976740 TI - Correlations between behavior, memory, sleep-wake and melatonin in Williams Beuren syndrome. AB - Williams-Beuren syndrome (WBS), a neurodevelopmental disorder caused by a microdeletion on chromosomic region 7q11.23, presents with peculiar behavioral and neurocognitive phenotypes that are marked by apparently preserved social and communicative abilities, which contrasts with low overall cognitive and particularly visuospatial performance. In addition, parents often report complaints of sleep disorders and behavioral problems of unknown cause. Sleep is a biological phenomenon that is modulated by the plasma concentration of melatonin and with influence on behavioral aspects and memory. Thus, this study sought to investigate the behavior, memory and the presence of sleep disorders in WBS and to correlate these factors with each other and with the plasma melatonin content. We used the Child Behavior Checklist for ages 6-18 (CBCL), the digit subtest of the Wechsler scale for auditory memory, the visual sequential memory subtest of the Illinois Test of Psycholinguistic Abilities (ITPA) and the Sleep Disturbance Scale for Children (SDSC). Determination of urinary aMT6s, an indirect measure of plasma melatonin content, was held for 72h by ELISA, and the analysis of the circadian rhythm of this content was performed by the Cosinor method. The results of the CBCL showed that 87% of the WBS group presented with a clinical score on the overall competence and total behavioral problems. Furthermore, the behavioral problems that were most frequently reported by parents were anxiety and problems of thought. All individuals with WBS presented with impairments in auditory memory and 47% with impairments in visual sequential memory; 65% of the WBS group presented with an indicative of at least one sleep disorder, where respiratory, initiation and maintenance of sleep (DIMS) and hyperhidrosis were the most frequent disorders. The night time aMT6s levels were lower in individuals with WBS when compared with controls; 53% of the WBS group did not present with circadian rhythm variations in aMT6s levels. In addition, there was a negative correlation between the scores of auditory memory and the total score of sleep disorders and between the DIMS and nocturnal aMT6s content. In conclusion, in the present study, individuals with WBS showed a high frequency of behavioral and memory problems, sleep disturbances and no rhythm variation in aMT6s levels. The low melatonin content may be related with sleep disorders in this population, which, in turn, can have an adverse effect on specific cognitive skills such as memory. PMID- 26976743 TI - 'Breakfast: how important is it really?' A response. PMID- 26976742 TI - Single-molecule analysis of DNA replication reveals novel features in the divergent eukaryotes Leishmania and Trypanosoma brucei versus mammalian cells. AB - Leishmania and Trypanosoma are unicellular parasites that possess markedly original biological features as compared to other eukaryotes. The Leishmania genome displays a constitutive 'mosaic aneuploidy', whereas in Trypanosoma brucei, the megabase-sized chromosomes are diploid. We accurately analysed DNA replication parameters in three Leishmania species and Trypanosoma brucei as well as mouse embryonic fibroblasts (MEF). Active replication origins were visualized at the single molecule level using DNA molecular combing. More than one active origin was found on most DNA fibres, showing that the chromosomes are replicated from multiple origins. Inter-origin distances (IODs) were measured and found very large in trypanosomatids: the mean IOD was 160 kb in T. brucei and 226 kb in L. mexicana. Moreover, the progression of replication forks was faster than in any other eukaryote analyzed so far (mean velocity 1.9 kb/min in T. brucei and 2.4 2.6 kb/min in Leishmania). The estimated total number of active DNA replication origins in trypanosomatids is ~170. Finally, 14.4% of unidirectional replication forks were observed in T. brucei, in contrast to 1.5-1.7% in Leishmania and 4% in MEF cells. The biological significance of these original features is discussed. PMID- 26976744 TI - A reassessment of the presumed Torrener Barenhohle's Paleolithic human tooth. PMID- 26976745 TI - Diabetes knowledge and self-efficacy among rural women in Gujarat, India. AB - INTRODUCTION: Type II diabetes has risen dramatically among rural women in India, specifically in the states of Gujarat, Karnataka, Tamil Nadu and Uttar Pradesh. Recent studies suggest that rural Indian women's low level of self-efficacy, or confidence in their ability to carry out tasks, such as managing diabetes, is a key reason for this increase. Therefore, this study utilizes the Health Belief Model to analyze whether increased awareness of diabetes leads to a positive increase in levels of self-efficacy among diabetic women in two rural villages of Gujarat. METHODS: A cross-sectional study of 126 known cases of women with diabetes was carried out in the villages of Rajpur and Valam in the Mehsana District in the state of Gujarat, India, to assess the relationship between diabetes knowledge and self-efficacy. The instrument was adapted from the Michigan Diabetes Research and Training Center's Diabetes Empowerment Scale-Short Form and Knowledge, Attitudes and Practices Assessment of the Indian Institute of Public Health Gandhinagar. RESULTS: Participants' mean knowledge score was 10.77+/-2.86 out of a possible 24 points, for a mean percentage of 45%. The median self-efficacy score for the women was 7 with an interquartile range of 3. The age-adjusted multiple regression analysis demonstrated a significant positive correlation between knowledge and self-efficacy (p<0.001). CONCLUSIONS: The observations of this study suggest a positive correlation between diabetes knowledge and self-efficacy. Future diabetes educational interventions in India should place a greater emphasis on increasing knowledge among rural women. Specifically, these interventions should emphasize the major gaps in knowledge regarding causes of diabetes, complications and treatment procedures. Educational interventions that are catered more towards rural women will be critical for improving their self-efficacy. PMID- 26976746 TI - Alteration of Polyketide Stereochemistry from anti to syn by a Ketoreductase Domain Exchange in a Type I Modular Polyketide Synthase Subunit. AB - Polyketide natural products have broad applications in medicine. Exploiting the modular nature of polyketide synthases to alter stereospecificity is an attractive strategy for obtaining natural product analogues with altered pharmaceutical properties. We demonstrate that by retaining a dimerization element present in LipPks1+TE, we are able to use a ketoreductase domain exchange to alter alpha-methyl group stereochemistry with unprecedented retention of activity and simultaneously achieve a novel alteration of polyketide product stereochemistry from anti to syn. The substrate promiscuity of LipPks1+TE further provided a unique opportunity to investigate the substrate dependence of ketoreductase activity in a polyketide synthase module context. PMID- 26976747 TI - Adamantane derivatives of sulfonamides: sublimation, solubility, solvation and transfer processes in biologically relevant solvents. AB - Eight adamantane derivatives of sulfonamides were synthesized and characterized. Temperature dependencies of saturation vapor pressure were obtained using the transpiration method and thermodynamic functions of the sublimation processes were calculated. Solubility values of the selected compounds in buffer (pH 7.4), 1-octanol and 1-hexane were determined at different temperatures using the isothermal saturation method. Thermophysical characteristics of fusion processes (melting points and fusion enthalpies) of the substances were studied using the DSC method. Transfer processes from buffer to 1-octanol, from buffer to 1-hexane and 1-hexane to 1-octanol were analyzed. The impact of the molecules' structural modification on sublimation, solubility and solvation/hydration processes in the solvents was studied. Correlation equations connecting the thermodynamic functions with physicochemical descriptors were obtained. PMID- 26976748 TI - [Consensus document of the Spanish Society of Arteriosclerosis on indications of inhibitors of PCSK9]. PMID- 26976750 TI - Alterations of proteins in MDCK cells during acute potassium deficiency. AB - Chronic K(+) deficiency can cause hypokalemic nephropathy associated with metabolic alkalosis, polyuria, tubular dilatation, and tubulointerstitial injury. However, effects of acute K(+) deficiency on the kidney remained unclear. This study aimed to explore such effects by evaluating changes in levels of proteins in renal tubular cells during acute K(+) deficiency. MDCK cells were cultivated in normal K(+) (NK) (K(+)=5.3 mM), low K(+) (LK) (K(+)=2.5 mM), or K(+) depleted (KD) (K(+)=0 mM) medium for 24 h and then harvested. Cellular proteins were resolved by two-dimensional gel electrophoresis (2-DE) and visualized by SYPRO Ruby staining (5 gels per group). Spot matching and quantitative intensity analysis revealed a total 48 protein spots that had significantly differential levels among the three groups. Among these, 46 and 30 protein spots had differential levels in KD group compared to NK and LK groups, respectively. Comparison between LK and NK groups revealed only 10 protein spots that were differentially expressed. All of these differentially expressed proteins were successfully identified by Q-TOF MS and/or MS/MS analyses. The altered levels of heat shock protein 90 (HSP90), ezrin, lamin A/C, tubulin, chaperonin-containing TCP1 (CCT1), and calpain 1 were confirmed by Western blot analysis. Global protein network analysis showed three main functional networks, including 1) cell growth and proliferation, 2) cell morphology, cellular assembly and organization, and 3) protein folding in which the altered proteins were involved. Further investigations on these networks may lead to better understanding of pathogenic mechanisms of low K(+)-induced renal injury. PMID- 26976751 TI - Recombinant broad-range phospholipase C from Listeria monocytogenes exhibits optimal activity at acidic pH. AB - The broad-range phospholipase C (PLC) from Listeria monocytogenes has been expressed using an intein expression system and characterized. This zinc metalloenzyme, similar to the homologous enzyme from Bacillus cereus, targets a wide range of lipid substrates. With monomeric substrates, the length of the hydrophobic acyl chain has significant impact on enzyme efficiency by affecting substrate affinity (Km). Based on a homology model of the enzyme to the B. cereus protein, several active site residue mutations were generated. While this PLC shares many of the mechanistic characteristics of the B. cereus PLC, a major difference is that the L. monocytogenes enzyme displays an acidic pH optimum regardless of substrate status (monomer, micelle, or vesicle). This unusual behavior might be advantageous for its role in the pathogenicity of L. monocytogenes. PMID- 26976749 TI - Oxidative stress generated during monensin treatment contributes to altered Toxoplasma gondii mitochondrial function. AB - The ionophore monensin displays potent activities against several coccidian parasites of veterinary and medical importance including the opportunistic pathogen of humans, Toxoplasma gondii. While monensin is used widely in animals, toxicity impedes its use in humans. Nonetheless, given its potency, understanding its mode of action would reveal vulnerable aspects of the parasite that can be exploited for drug development. We previously established that monensin induces Toxoplasma to undergo cell cycle arrest and an autophagy-like cell death. Interestingly, these effects are dependent on the mitochondrion-localized TgMSH-1 protein, suggesting that monensin disrupts mitochondrial function. We demonstrate that monensin treatment results in decreased mitochondrial membrane potential and altered morphology. These effects are mitigated by the antioxidant compound N acetyl-cysteine suggesting that monensin causes an oxidative stress, which was indeed the case based on direct detection of reactive oxygen species. Moreover, over-expression of the antioxidant proteins glutaredoxin and peroxiredoxin 2 protect Toxoplasma from the deleterious effects of monensin. Thus, our studies show that the effects of monensin on Toxoplasma are due to a disruption of mitochondrial function caused by the induction of an oxidative stress and implicate parasite redox biology as a viable target for the development of drugs against Toxoplasma and related pathogenic parasites. PMID- 26976755 TI - Editorial. PMID- 26976753 TI - Development of a double-antibody sandwich ELISA for rapid detection of Bacillus Cereus in food. AB - Bacillus cereus is increasingly recognized as one of the major causes of food poisoning in the industrialized world. In this paper, we describe a sensitive double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) that was developed for rapid detection of B. cereus in food to minimize the risk of contamination. The polyclonal antibody (pAb) and monoclonal antibodies (mAbs) specific to B. cereus were generated from rabbit antiserum and mouse ascites, respectively, using the octanoic acid/saturated ammonium sulfate precipitation method and protein A-sepharose columns. IgG-isotype mAbs were specially developed to undergo a novel peripheral multiple sites immunization for rapid gain of hybridomas and a subtractive screen was used to eliminate cross reactivity with closely related species such as Bacillus thuringiensis, B. subtilis, B. licheniformis and B. perfringens. The linear detection range of the method was approximately 1 * 10(4)-2.8 * 10(6) cells/mL with a detection limit (LOD) of 0.9 * 10(3) cells/mL. The assay was able to detect B. cereus when the samples were prepared in meat with various pathogens. The newly developed analytical method provides a rapid method to sensitively detect B. cereus in food specimens. PMID- 26976756 TI - Different modes of action of alprazolam in the treatment of panic attacks. AB - Alprazolam (a benzodiazepine in the group of the triazolo-benzodiazepines) is a potent drug for the treatment of panic disorder. This is possible due to four different interactions with neurotransmitter systems. First, it facilitates, as all diazepines, the inhibitory acitivity of gamma-amino-butyricacid (GABA). The chemical structure differs from the benzodiazepines by incorporation of the triazoloring. Due to this triazoloring, the drug has three additional modes of action. These modes of action inhibit the locus coeruleus which plays a role in the origin of panic disorder. A first specific action is a stimulation of the serotonergic system. Triazolobenzodiazepines are also alpha2-adrenoreceptor agonists. Both mechanisms are responsible for inhibition of the locus coeruleus. Triazolo-benzodiazepines inhibit the platelet-activating-factor (PAF). PAF stimulates the corticotropin-releasing-hormone (CRH). This hormone stimulates the locus coeruleus. CRH in patients with panic attacks is elevated. This could be a result of hyperactive metabolism of the right parahippocampal area, which is observed in patients with panic attacks. Triazolo-benzodiazepines decrease the activity of the locus coeruleus because of a low CRH-level due to inhibited PAF. PMID- 26976754 TI - The importance of interacting climate modes on Australia's contribution to global carbon cycle extremes. AB - The global carbon cycle is highly sensitive to climate-driven fluctuations of precipitation, especially in the Southern Hemisphere. This was clearly manifested by a 20% increase of the global terrestrial C sink in 2011 during the strongest sustained La Nina since 1917. However, inconsistencies exist between El Nino/La Nina (ENSO) cycles and precipitation in the historical record; for example, significant ENSO-precipitation correlations were present in only 31% of the last 100 years, and often absent in wet years. To resolve these inconsistencies, we used an advanced temporal scaling method for identifying interactions amongst three key climate modes (El Nino, the Indian Ocean dipole, and the southern annular mode). When these climate modes synchronised (1999-2012), drought and extreme precipitation were observed across Australia. The interaction amongst these climate modes, more than the effect of any single mode, was associated with large fluctuations in precipitation and productivity. The long-term exposure of vegetation to this arid environment has favoured a resilient flora capable of large fluctuations in photosynthetic productivity and explains why Australia was a major contributor not only to the 2011 global C sink anomaly but also to global reductions in photosynthetic C uptake during the previous decade of drought. PMID- 26976752 TI - Cladribine, gemcitabine, busulfan, and SAHA combination as a potential pretransplant conditioning regimen for lymphomas: A preclinical study. AB - Hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with refractory lymphomas. Nucleoside analogs (NAs) and DNA alkylating agents are efficacious in treating hematologic malignancies. To design an efficacious and more economical pretransplant regimen for lymphoma patients, we analyzed the cytotoxicity of cladribine (Clad), gemcitabine (Gem), busulfan (Bu), and suberoylanilide hydroxamic acid (SAHA) in lymphoma cell lines. J45.01 and U937 lymphoma cell lines were exposed to drugs, alone or in combination, for 48 hours and analyzed with the MTT and annexin V assays, Western blotting, and flow cytometry. On the basis of the IC5-10 values of the drugs, the Clad+Gem+Bu combination inhibited the proliferation of both cell lines to ~55%-60%. Addition of SAHA to this combination decreased proliferation further to ~30%. Exposure to the Clad+Gem+Bu+SAHA combination activated the DNA damage response and ATM-CHK2 pathway; modified histones; decreased mitochondrial membrane potential, which caused leakage of apoptosis-inducing factors; and activated apoptosis. Pretreatment of cells with the pan-caspase inhibitor Z-VAD-FMK blocked the phosphorylation of histone 2AX and cleavage of PARP-1 and caspases. The Clad+Gem+Bu+SAHA combination provides synergistic cytotoxicity in lymphoma cell lines. Our results may be a basis for using this combination as a pretransplant conditioning regimen in a clinical trial for lymphoma patients undergoing hematopoietic stem cell transplantation, replacing the more expensive nucleoside analog clofarabine. PMID- 26976757 TI - Neurologic and psychiatric symptoms following chronic phenytoin intoxication. AB - Reported (ir)reversibility of neurological and psychiatric symptoms induced by Phenytoin intoxication is being discussed by means of a case report concerning a 40-year old man who sets fire to his house during a psychosis. Observation after admission to a general psychiatric hospital, following a short period of detention, leads to diagnosing neurological and psychiatric symptoms due to chronic Phenytoin intoxication. Discontinuation of Phenytoin supply induces partial remission of the symptoms. Literature on the subject is being revised. PMID- 26976758 TI - Neuroimmunological aspects of the alterations in zinc homeostasis in the pathophysiology and treatment of depression. AB - Zinc is a trace element which plays a fundamental role in a wide range of biochemical processes in living organisms. Zinc is an essential component of various proteins and is an important factor for physiological function of the mammalian nervous and immune systems. In the central nervous system (CNS), zinc is found at high concentrations in hippocampal neurons. These neurons possess mechanisms for zinc uptake and storage in synaptic terminals and for the stimulation of zinc release along with neurotransmitters. In the central nervous system, zinc modulates predominantly the excitatory (glutamatergic) and inhibitory (GABAergic) amino acid neurotransmission pathways. In the immune system, zinc is necessary for the physiological activity of the thymus and T-cell dependent responses. Zinc deficiency impairs the activities of the neuroendocrine and immune systems in mammalian organisms. This paper reviews the alterations in the blood and brain zinc concentrations in relation to the neuroimmune pathophysiology and treatment of depression. Major depression is related to lowered serum zinc concentrations, which may be caused by the acute phase and the inflammatory response in that illness. Repeated administration of antidepressants selectively increases and redistributes brain zinc in the hippocampus. Since zinc is an inhibitor of the glutama-te/NMDA receptor, these data are in accordance with the glutamate hypothesis of antidepressant action. PMID- 26976760 TI - Impact of litigation on the psychotherapy of posttraumatic stress disorder. PMID- 26976759 TI - Brain alterations in depression. AB - This article describes a number of studies by our research group to find brain structures that may be involved in the symptoms of idiopathic depression, depression in Alzheimer's disease and depression in Parkinson's disease. Until recently, idiopathic depression has generally been related to deficiencies of aminergic systems. In Alzheimer patients we found a strong decrease in the number of neurons in the locus coeruleus and brain noradrenaline concentrations, but in depressed Alzheimer patients we did not find an extra de crease. This is in agreement with the finding that there is no cell loss in the locus coeruleus in idiopathic depression. We did find, however, that the number of corticotropin releasing hormone-, vasopressin- and oxytocin expressing neurons, the number of corticotropin-releasing hormone neurons co-expressing vasopressin and the amount of corticotropin-releasing hormone -mRNA in idiopathic depression were strongly increased in the paraventricular nucleus of the hypothalamus. This result supports the hypothesis on the pathogenetic involvement of the hypothalamo pituitary-adrenal axis in depression and is of clinical relevance, since it may provide a theoretical rationale for antidepressive therapy with CRH antagonists. PMID- 26976761 TI - IL-9 signaling as key driver of chronic inflammation in mucosal immunity. AB - Recent studies have highlighted a crucial regulatory role of the cytokine IL-9 in driving immune responses in chronic inflammatory and autoimmune diseases at mucosal surfaces. IL-9 activates various types of immune and non-immune cells carrying the membrane bound IL-9R. IL-9 signaling plays a pivotal role in controlling the differentiation and activation of these cells by inducing the Jak/STAT pathway. In particular, IL-9 induces activation of T helper cells and affects the function of various tissue resident cells such as mast cells and epithelial cells in the mucosa. Importantly, recent findings suggest that blockade of IL-9 signaling is effective in treating experimental models of autoimmune and chronic inflammatory diseases such as inflammatory bowel diseases, allergic disorders such as food allergy and asthma. Thus, blockade of IL-9 and IL 9R signaling emerges as potentially novel approach for therapy of inflammatory diseases in the mucosal immune system. PMID- 26976762 TI - Regulation of TBK1 activity by Optineurin contributes to cell cycle-dependent expression of the interferon pathway. AB - The innate immune system has evolved to detect and neutralize viral invasions. Triggering of this defense mechanism relies on the production and secretion of soluble factors that stimulate intracellular antiviral defense mechanisms. The Tank Binding Kinase 1 (TBK1) is a serine/threonine kinase in the innate immune signaling pathways including the antiviral response and the host defense against cytosolic infection by bacteries. Given the critical roles of TBK1, important regulatory mechanisms are required to regulate its activity. Among these, Optineurin (Optn) was shown to negatively regulate the interferon response, in addition to its important role in membrane trafficking, protein secretion, autophagy and cell division. As Optn does not carry any enzymatic activity, its functions depend on its precise subcellular localization and its interaction with other proteins, especially with components of the innate immune pathway. This review highlights advances in our understanding of Optn mechanisms of action with focus on the relationships between Optn and TBK1 and their implication in host defense against pathogens. Specifically, how the antiviral immune system is controlled during the cell cycle by the Optn/TBK1 axis and the physiological consequences of this regulatory mechanism are described. This review may serve to a better understanding of the relationships between the different functions of Optn, including those related to immune responses and its associated pathologies such as primary open-angle glaucoma, amyotrophic lateral sclerosis and Paget's disease of bone. PMID- 26976764 TI - Proteomic analysis allows for identifying targets of Yinchenwuling Powder in hyperlipidemic rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Yinchenwuling Powder (YCL) is a traditional Chinese medicine formula originated from Synopsis of Golden Chamber, which is effective in positively modulating lipid levels in clinics. In this study, we utilized proteomic technology to identify the therapeutic targets of YCL on hyperlipidemic rats. METHODS: We established hyperlipidemic model rats and administrated them with different doses of YCL extracts (0.35g/ml, 0.75g/ml and 1.5g/ml). Serum lipid levels were quantified and proteomic analysis was performed on plasma samples at the end of the study. Total plasma proteins were separated by two-dimensional electrophoresis (2-DE), and protein spots with 1.5-fold difference were excised and then analyzed by MALDI-TOF MS. Proteomic results were verified by Western blotting. RESULTS: The results showed that the serum levels of TC, TG, and LDL-C were significantly decreased, while the HDL-C levels were significantly increased in different doses of YCL treatment groups. After being analyzed by 2-DE and MALDI-TOF MS, 12 proteins were identified. Eight proteins (T kininogen, C3, C4, C4BPA, Iglambda-2 chain C, Mbl2, Hpx and FGL1) were up regulated in hyperlipidemic model rats, while four proteins (ApoE, ALB, TTR and VDBP) were up-regulated in the control and the YCL-treated rats. Two plasma proteins, ApoE and FGL1, involved in lipid metabolism, were confirmed by western blotting, and the results were consistent with the data from the proteomics results. CONCLUSIONS: In this experiment, we identified 12 differentially expressed plasma proteins associated with therapeutic effects of YCL. The functions of those proteins are related with lipid metabolism, blood coagulation, anti-inflammation and substance transport. This study provided a clue for the mechanism that underlies the therapeutic effect of YCL on lipid metabolism. PMID- 26976763 TI - Anti-inflammatory and anti-allergic effects and underlying mechanisms of Huang Lian-Jie-Du extract: Implication for atopic dermatitis treatment. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Huang-Lian-Jie-Du Decoction (HLJDD), a well-known Chinese herbal formula recorded in the Tang dynasty, is composed of Coptidis rhizoma (Huang-Lian), Scutellariae radix (Huang-Qin), Phellodendri Chinensis cortex (Huang-Bai) and Gardenia fructus (Zhi-Zi). It has clinical efficacy of purging fire for removing toxin and is commonly used for the treatment of disease including Alzheimer's disease, stroke and gastrointestinal disorders. HLJDD is also frequently applied for the treatment of various skin diseases, such as atopic dermatitis (AD) and various types of eczema. The aim of this study is to investigate the anti-inflammatory and anti-allergic actions of Huang-Lian-Jie-Du ethanolic extract (HLJDE) and to elucidate underlying molecular mechanisms of action using relevant in vitro experimental models. MATERIALS AND METHODS: The anti-inflammatory effects of HLJDE were investigated through evaluating the change of nitric oxide (NO) and the production of several cytokines and chemokines in lipopolysaccharide (LPS)-stimulated RAW264.7 cell line. Expression of mitogen-activated protein kinases (MAPKs), NF-kappaB p65 phosphorylation, inhibitor-kappaBalpha (IkappaBalpha) degradation were further investigated to elucidate its anti-inflammatory molecular mechanisms. Meanwhile, the anti allergic activities of HLJDE was also evaluated using antigen-induced RBL-2H3 cell line. beta-hexosaminidase and histamine release and selected cytokines and chemokines were measured to evaluate the anti-allergic activities of HLJDE. In addition, intracellular Ca(2+)level, MAPKs and Lyn phosphorylation were further investigated to reveal its anti-allergic molecular mechanisms. RESULTS: HLJDE could significantly suppress the secretion of NO, IL-1beta, IL-4, MCP-1 and GM CSF in RAW264.7 cells in a dose-dependent manner. In addition, HLJDE also markedly reduced the phosphorylation of MAPKs, and inhibited the transcriptional activity of NF-kappaB and IkappaBalpha degradation. Furthermore, HLJDE exerted marked anti-allergic activity through inhibiting the release of beta hexosaminidase and histamine. The release of cytokines and chemokines (IL-4, TNF alpha, MCP-1) from activated RBL-2H3 cells were also attenuated by pretreatment with HLJDE. The inhibitory effects on intracellular Ca(2+)level, and reduced phosphorylation of MAPKs and Lyn are believed to be the anti-allergic mechanisms. CONCLUSIONS: HLJDE exerted significant anti-inflammatory and anti-allergic effects through suppressing the production of allergic and inflammatory mediators via the NF-kappaB and MAPKs inactivation and IkappaBalpha degradation in the LPS stimulated RAW24.7 cells, inactivation of MAPKs and Lyn pathway in antigen induced RBL-2H3 cells. The present study provides in vitro experimental evidence to support the use of HLJDE for the clinical treatment of AD. PMID- 26976765 TI - A systematic study of the dissolution and relative bioavailability of four ginsenosides in the form of ultrafine granular powder, common powder and traditional pieces of Panax quinquefolius L, in vitro and in beagles. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Panax quinquefolius L (PQ), also known as American ginseng, has been used as a medicinal herb for thousands of years in the Far East, which was wildly used actively in healing the cardiovascular, endocrine and immune systems, in supporting chemoprevention of cancer. MATERIALS AND METHODS: An integrated, rapid, sensitive and reliable UHPLC-ESI-QQQ MS/MS method was validated and successfully applied in a pharmacokinetics study in which four representative ginsenosides were measured in beagle plasma following oral administration of Panax quinquefolius L (PQ) in the form of ultrafine granular powder, standard powder and an extract. RESULTS: Two paired ions ([M+Na](+) in the positive MS process, and two characteristic ions [Q3](+) in the positive MS/MS process) of the target compounds were optimized and selected for improved qualitative and quantitative analysis of ginsenosides in beagle plasma. The relative bioavailability of the target ginsenosides in these three formulations was measured by the pharmacokinetic parameters, including Cmax, Tmax, AUC0 infinity and so on. The ultrafine granular powder had the highest bioavailability, as well as the greatest extent of and fastest dissolution in vitro. CONCLUSION: Our results show that improved formulations of PQ could facilitate the dissolution and promote absorption of the important compounds it contains. PMID- 26976766 TI - Geniposide attenuates inflammatory response by suppressing P2Y14 receptor and downstream ERK1/2 signaling pathway in oxygen and glucose deprivation-induced brain microvascular endothelial cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Fructus gardenia is widely used for treatment of stroke and infectious diseases in Chinese medicine. Geniposide is the key bioactive compound related to the pharmacodynamic actions of gardenia on ischemic stroke. The molecular mechanism by which geniposide improves the ischemic brain injury was observed in the study. AIM OF THE STUDY: Recent studies showed that geniposide had protective activities against the inflammatory response in ischemic stroke. However, the molecular mechanism of geniposide anti-inflammatory role has not yet been fully elucidated. In this study, we investigated the effect of geniposide on the expression of P2Y14 receptor and downstream signaling pathway in brain microvascular endothelial cells (BMECs). MATERIALS AND METHODS: An in vitro model of cerebral ischemia in BMECs was established by oxygen-glucose deprivation (OGD). To further confirm the specific effect of geniposide on P2Y14 receptor and downstream signaling pathways, we set up a UDP-glucose (an agonist of the P2Y14 receptor) stimulated model. After administration of geniposide, the expression of P2Y14 receptor, phosphorylation of RAF-1, mitogen activated protein kinase kinase1/2 (MEK1/2), extracellular signal-regulated kinase 1/2 (ERK1/2), level of interleukin-8 (IL-8), interleukin-1beta (IL-1beta), monocyte chemotactic protein 1 (MCP-1) in BMECs were determined. RESULTS: The mRNA and protein expression of P2Y14 in the rat BMECs were up-regulated in OGD-induced injury. After administration of Geniposide, the expression of P2Y14 receptor was significantly down-regulated, the phosphorylation of RAF-1, MEK1/2, ERK1/2 were suppressed. Similar data were obtained in UDP-glc stimulated model. We also observed that geniposide markedly declined the production of IL-8, IL-1beta and MCP-1 in OGD-induced BMECs. CONCLUSION: Geniposide exerted anti-inflammatory effects by interfering with the expression of P2Y14 receptor, which subsequently inhibits the downstream ERK1/2 signaling pathways and the release of the pro inflammatory cytokines IL-8, MCP-1, IL-1beta. Therefore, this study provides the evidence for gardenia's clinical application in cerebral ischemia. PMID- 26976767 TI - In vitro and in vivo mechanism of immunomodulatory and antiviral activity of Edible Bird's Nest (EBN) against influenza A virus (IAV) infection. AB - ETHNOPHARMACOLOGICAL RELEVANCE: For centuries, Edible Bird Nest (EBN) has been used in treatment of variety of respiratory diseases such as flu and cough as a Chinese natural medicine. AIM OF THE STUDY: This natural remedy showed the potential to inhibit influenza A virus (IAV). However, little is known about the mechanism of this process and also the evaluation of this product in an animal model. Hence, the current study was designed to elucidate the antiviral and immunomodulatory effects of EBN against IAV strain A/Puerto Rico/8/1934 (H1N1). MATERIALS AND METHODS: First, influenza infected MDCK cells treated with EBNs from two locations of Malaysia (Teluk Intan and Gua Madai) that prepared with different enzymatic preparations were analyzed by RT-qPCR and ELISA for detection of viral and cytokines genes. The sialic acid composition of these EBNs was evaluated by H-NMR. Subsequently, after toxicity evaluation of EBN from Teluk Intan, antiviral and immunomodulatory effects of this natural product was evaluated in BALB/c mice by analysis of the viral NA gene and cytokine expressions in the first week of the infection. RESULTS: EBN showed high neuraminidase inhibitory properties in both in vitro and in vivo, which was as effective as Oseltamivir phosphate. In addition, EBN decreased NS1 copy number (p<0.05) of the virus along with high immunomodulatory effects against IAV. Some of the immune changes during treatment of IAV with EBN included significant increase in IFNgamma, TNFalpha, NFkappaB, IL2, some proinflammatory cytokines like IL1beta, IL6, and cytokines with regulatory properties like IL10, IL27, IL12, CCL2 and IL4 depends on the stage of the infection. EBNs from two locations contained different composition of sialic acid and thymol derivatives, which gave them different antiviral properties. EBN from Gua Madai that contained more acetylated sialic acid (Neu2,4,7,8,9 Ac6) showed higher antiviral activity. CONCLUSION: The findings of this study support the antiviral activity of EBN against influenza virus and validate the traditional usage of this natural remedy by elucidation of toxicity and the molecular mechanism of action. PMID- 26976768 TI - The protective effect of total phenolics from Oenanthe Javanica on acute liver failure induced by D-galactosamine. AB - ETHNOPHARMACOLOGY RELEVANCE: Water dropwort [Oenanthe javanica (O. javanica)] is an aquatic perennial herb cultivated in East Asian countries. It has been popularly used in traditional Chinese medicine which is beneficial for the treatment of many diseases, including jaundice and various types of chronic and acute hepatitis. In the present study, we investigated the hepatoprotective effect of total phenolics from O. javanica (TPOJ) against D-galactosamine (D GalN) induced liver injury in mice. MATERIAL AND METHODS: The hepatoprotective activity of TPOJ (125, 250 and 500mg/kg) was investigated on D-GalN (800mg/kg) induced liver damages in mice. Blood and liver were collected for biochemical and microscopic analysis. RT-PCR was used to determine the changes in hepatic nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression. Protein levels of iNOS, COX-2, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were determined by western blotting. RESULTS: In the animal studies, TPOJ could improve the survival of acute liver failure model significantly and prevente the D-GalN-induced elevation of the serum enzymatic markers and nonenzymatic markers levels significantly. Meanwhile, TPOJ-treatment decreased the malondialdehyde (MDA) level and elevated the content of glutathione (GSH) in the liver as compared to those in the D-GalN group. Hepatic activities and protein expressions of antioxidative enzymes, including SOD, GPx, and CAT were enhanced dose dependently with TPOJ. At the same time, application of TPOJ effectively suppressed the D-GalN-induced proinflammatory mRNA and protein expression of iNOS and COX-2. Subsequently, the serum levels of proinflammatory mediators, nitric oxide (NO) and prostaglandin E2 (PGE2) were reduced. Additionally, histological analyses also showed that TPOJ reduced the extent of liver lesions induced by D-GalN. CONCLUSION: Our investigation demonstrated the hepatoprotective activity of TPOJ and revealed that TPOJ attributed its significance in the traditional use for treating liver diseases. PMID- 26976769 TI - Lactate clearance and mortality in septic patients with hepatic dysfunction. AB - BACKGROUND: Serum lactate clearance (LC) during initial resuscitation is a potentially useful prognostic marker in patients with severe sepsis or septic shock. However, it is unclear whether LC is also associated with the outcome in septic patients with hepatic dysfunction that may impair lactate elimination, which may contribute to elevated serum lactate levels or decreased LC. METHODS: The relationships between LC measured within 6 and 24h after initial resuscitation and hospital mortality were evaluated with multiple logistic regression analysis. RESULTS: Of 770 patients with severe sepsis or septic shock, 208 (27%) with hepatic dysfunction were included in the analysis. The median LC within 6h in survivors (31.4%) was significantly higher than that of non survivors (9.3%) (P=.010). In addition, the median LC within 24h was also significantly different between groups (51% vs. 12%, P<.001). Low LCs, defined as less than 10% of clearance, at 6 and 24h were associated with in-hospital mortality. After adjusting for potential confounding factors, low LCs at 6 and 24h remained associated with hospital mortality (adjusted OR 4.940, 95% CI 1.762 13.854 at 6h; adjusted OR 5.997, 95% CI 2.149-16.737 at 24h). However, LC at 24h (area under the curve of 0.704) had higher discriminatory power to predict hospital mortality than LC at 6h (area under the curve of 0.608) (P=.033). CONCLUSIONS: LC may be useful for predicting outcomes in septic patients with hepatic dysfunction. PMID- 26976770 TI - Rapid Ventricular Response or Tachycardia? The Three Faces of Atrial Fibrillation. PMID- 26976771 TI - Nonsuicidal self-injury and suicide attempts among ED patients older than 50 years: comparison of risk factors and ED visit outcomes. AB - BACKGROUND: Although the number of older adults who engage in nonsuicidal self injury (NSSI) is not insignificant, research on older adults' NSSI is scant. The current study examined the prevalence and characteristics of NSSI compared to suicide attempt (SA) in adults older than 50 years who were seen at Emergency Departments (EDs) and their ED visit outcomes. METHODS: Data came from the 2012 Nationwide Emergency Department Sample. We used binary logistic regression analysis to examine demographic and clinical characteristics of NSSI versus SA among 67,069 visits with a diagnosis of either SA or NSSI, and multinomial logistic regression analysis to examine associations between NSSI versus SA and ED outcomes. RESULTS: Of self-inflicted intentional injuries, 76.89% were SA and 23.11% were NSSI. Visits for NSSI were associated with lower levels of psychiatric disorders and alcohol use disorders than SA and were more likely than SA visits to occur among older age groups (65-74 and 75+), females, and those with multiple injuries and drug use disorders. NSSI visits were also associated with greater risks of hospital admission (relative risk ratio [RRR]=1.45, 95% CI=1.36-1.54) and death (RRR=18.64, 95% CI=14.19-24.49), as opposed to treat-and release, but lower risks of facility transfer/discharge with home health care (RRR=0.77, 95% CI=0.72-0.83). CONCLUSIONS: The findings of higher hospitalization and death rates among those with NSSI than SA show how lethal intentional self destructive behaviors in late life can be even if they are not classified as suicide attempts. The need for mental health and substance abuse treatment is discussed. PMID- 26976772 TI - Deadly right flank pain: inferior vena cava spontaneous rupture. PMID- 26976773 TI - Atrial standstill and thromboembolic complications. PMID- 26976774 TI - Protective effect of pterostilbene on testicular ischemia/reperfusion injury in rats. AB - PURPOSE: To evaluate protective effect of pterostilbene against testicular ischemia/reperfusion (I/R) injury, which results in increased formation of oxidative stress, leading to testicular apoptosis and impaired spermatogenesis. METHODS: Thirty two pubertal male Sprague-Dawley rats weighing 180-220g were selected and randomly divided into the following four groups: group A (normal control group), group B (sham-operated group), group C (induced I/R injury group), group D (induced I/R injury group receiving pterostilbene treatment). Johnsen's scores and mean seminiferous tubule diameters were evaluated for histopathologic assessment; germinal cell apoptosis was evaluated by the transferase dUTP nick end labeling (TUNEL) assay and immunohistochemistry for caspases. Malondialdehyde (MDA) levels were assessed as an indicator of oxidative stress and total antioxidant capacity (TAC) was measured. RESULTS: Germ cell apoptosis and MDA level significantly increased whereas TAC significantly decreased in group C; moreover, abnormal morphology and impaired spermatogenesis were observed in group C. In contrast, treatment with pterostilbene inhibited lipid peroxidation and apoptosis induced by ROS and restored the antioxidant capacity in group D. CONCLUSIONS: These results show that treatment with pterostilbene may be a promising therapy for testicular I/R injury. PMID- 26976775 TI - Strain induced esophageal growth in a novel rodent model. AB - PURPOSE: Longitudinal esophageal strain has been shown to increase esophageal length but the contribution of tissue hyperplasia to this growth is unknown. We used a novel model of esophageal stretch to determine the cellular response to the strain stimulus. METHODS: Male Sprague-Dawley rats underwent transection of the distal esophagus. The distal stump was ligated and stretched over a silicone tube. The proximal esophageal stump was anastomosed to the stomach to restore continuity. After two, four, or seven days, the silicone tube was removed and the esophageal segment was measured and compared to its initial length. Sham animals had only a thin piece of silicone tubing placed. Standardized histologic sections were evaluated for wall thickness. Immunofluorescence with DAPI, Ki-67, and Myogenin antibodies was used to assess nuclear density, proliferation indices, and myoblast differentiation indices. RESULTS: Experimental animals demonstrated a significant increase in esophageal length compared to sham controls at four and seven days with no difference at two days. There was significant lengthening between four and seven days among the experimental animals. There was no change in wall thickness between experimental and sham animals at any time point. Nuclear density was increased at all time points, although this only reached significance at day four. Proliferation indices were significantly increased relative to sham controls at all time points. Esophageal strain induced significantly increased myoblast differentiation. CONCLUSION: In this novel rat model of esophageal strain, lengthening is associated with stable esophageal wall thickness, increased nuclear density, increased cellular proliferation, and increased myogenin expression. These data suggest that true tissue hyperplasia may contribute to the increased length seen after esophageal strain. PMID- 26976776 TI - Evaluating the effect of time process measures on appendectomy clinical outcomes. AB - BACKGROUND: With varied reports on the impact of time to appendectomy on clinical outcomes, we examined the effects of pre-operative delays in pediatric acute appendicitis. METHODS: Children with acute appendicitis (January 2013-June 2014) were identified from a prospective database. Univariate analyses compared time metrics, patient characteristics, and disease severity with postoperative complications (POC) and organ space surgical site infection (OSSI), and multivariate logistic regression determined predictors of POC and OSSI. RESULTS: 1211 patients underwent appendectomy. Median age was 10.4years (IQR 7.8-13years). 537 patients (45%) had complex appendicitis. Overall, POC was 11% (n=133), and OSSI was 9% (n=105). Neither time from presentation to appendectomy nor diagnosis to appendectomy increased POCs. On univariate analyses, operative time (OT) was longer in patients with POC (57min (IQR 49-75) vs. 46min (IQR 36-57), p<0.001 and OSSI (60min (IQR 51-80) vs. 46min (IQR 37-57), p<0.001. However, after adjusting for confounding factors, disease severity remained the most significant predictor of POC (OR 6.5, 95% CI 2.79-15.23) and OSSI (OR 76.6, 95% CI 7.87-745.65). CONCLUSION: Pre-operative delays were not associated with increased POC or OSSI. The strongest predictor of POC or OSSI was disease severity, for which operative time may represent a surrogate. PMID- 26976777 TI - Letter to the Editor regarding Multimodal anesthesia with the addition of methadone is superior to epidural analgesia: A retrospective comparison of intraoperative anesthetic techniques and pain management for 124 pediatric patients undergoing the Nuss procedure. PMID- 26976778 TI - The pediatric surgeon's readiness to respond: commitment to advance preparation and effective coordinated response. PMID- 26976779 TI - An In vitro Model for Bacterial Growth on Human Stratum Corneum. AB - The diversity and dynamics of the skin microbiome in health and disease have been studied recently, but adequate model systems to study skin microbiotas in vitro are largely lacking. We developed an in vitro system that mimics human stratum corneum, using human callus as substrate and nutrient source for bacterial growth. The growth of several commensal and pathogenic bacterial strains was measured for up to one week by counting colony-forming units or by quantitative PCR with strain-specific primers. Human skin pathogens were found to survive amidst a minimal microbiome consisting of 2 major skin commensals: Staphylococcus epidermidis and Propionibacterium acnes. In addition, complete microbiomes, taken from the backs of healthy volunteers, were inoculated and maintained using this system. This model may enable the modulation of skin microbiomes in vitro and allow testing of pathogens, biological agents and antibiotics in a medium throughput format. PMID- 26976780 TI - Voriconazole minimum inhibitory concentrations are predictive of treatment outcome in experimental murine infections by Candida glabrata. AB - In this study, 27 clinical isolates of Candida glabrata with voriconazole (VRC) minimum inhibitory concentrations (MICs) ranging from <=0.03 MUg/mL to 8 MUg/mL were tested to determine whether in vitro data are predictive of in vivo efficacy. The efficacy of VRC administered at 40 mg/kg was assayed in a neutropenic murine model of disseminated infection by C. glabrata. The reduction in fungal tissue burden in the kidneys was used as a marker of treatment efficacy. VRC reduced the fungal tissue burden in mice infected with strains that had MICs below the epidemiological cut-off value (ECV) of 0.25 MUg/mL. Variable efficacy of VRC was obtained when the MIC equalled the ECV, and VRC was ineffective when the MIC exceeded the ECV. These results suggest that the use of in vitro data could be useful to predict the outcome for infections by this fungus. PMID- 26976781 TI - Fermented Goat's Milk Consumption Improves Duodenal Expression of Iron Homeostasis Genes during Anemia Recovery. AB - Despite the crucial roles of duodenal cytochrome b (Dcytb), divalent metal transporter 1 (DMT1), ferritin light chain (Ftl1), ferroportin 1 (FPN1), transferrin receptor 1 (TfR1), and hepcidin antimicrobial peptide (Hamp) in Fe metabolism, no studies have investigated the modulations of these genes during Fe repletion with fermented milks. Analysis included Fe status markers and gene and protein expression in enterocytes of control and anemic animals fed fermented milks. Fermented goat's milk up-regulated enterocyte Dcytb, DMT1, FPN1, and Ftl1 and down-regulated TfR1 and Hamp gene expression in control and anemic animals. Anemia decreased Dcytb, DMT1, and Ftl1 in animals fed fermented cow's milk and up regulated TfR1 and Hamp expression. Fe overload down-regulated Dcytb and TfR1 in animals fed fermented cow's milk and up-regulated DMT1 and FPN1 gene expression. Fermented goat's milk increased expression of duodenal Dcytb, DMT1, and FPN1 and decreased Hamp and TfR1, improving Fe metabolism during anemia recovery. PMID- 26976783 TI - Volumetric laser endomicroscopy in the detection of neoplastic lesions of the esophagus. PMID- 26976782 TI - Effect of desert dust exposure on allergic symptoms: A natural experiment in Japan. AB - BACKGROUND: Desert dust originating from arid and semiarid areas is transported to widespread regions, including Japan. Desert dust particles exert adjuvant effects in animals. OBJECTIVE: To examine whether desert dust enhances allergic symptoms in real-life settings and to explore its effect modifiers. METHODS: We conducted an observational study of 3,327 pregnant women during spring and fall in October 2011 to May 2013 in 3 regions in Japan as an adjunct study of the Japan Environment & Children's Study. We acquired participants' daily symptom scores by sending a questionnaire to their mobile phones on high desert-dust days (>0.07/km) and on some randomly selected other days (control days) for each participant. RESULTS: Pregnant women had an increased risk of allergic symptoms on high desert-dust days (adjusted odds ratio [OR], 1.10; 95% CI, 1.04-1.18). The increased OR was mostly driven by those who showed positive IgE to Japanese cedar pollen when pollen simultaneously dispersed (adjusted OR, 1.25; 95% CI, 1.13 1.38), whereas no clear risk increase was observed in the absence of pollen or for participants with negative IgE to Japanese cedar pollen. The risk elevation was observed from low levels of desert dust in a dose-dependent manner even on control days. CONCLUSION: Ambient desert dust level was associated with an increased risk of allergic symptoms in pollen-sensitized pregnant women when pollen was present in the air. The risk increase was dose dependent and was observed from low levels of desert dust. These results support a hypothesis that ambient desert dust particles exert adjuvant effects in human in real-life settings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: UMIN000010826. PMID- 26976784 TI - Spectral and morphological classification of different chronic and acute Taiwanese gallstones via FTIR, SEM and ESEM-EDX microanalyses. AB - BACKGROUND: Gallstone disease is one of the leading upper gastrointestinal surgical problems in different countries. AIMS: To analyze the chronic gallstones and acute gallbladder sludge retrieved from 36 Taiwanese patients. METHODS: FTIR microspectroscopy was used to classify the types of gallstones, and an ESEM-EDX microanalysis was first applied to determine the microstructural features and elemental compositions of the various gallstones. Bacteria presented on the surface of gallstones were also detected by SEM. RESULTS: Four types of gallstones were obtained from these 36 Taiwanese patients: calcium bilirubinate (CaBR) stones (30.6%), cholesterol stones (19.4%), mixed stones including 6 subtypes (47.2%), and acute gallbladder sludge (2.8%) made of CaBR and protein/insoluble biomaterials. Bacteria imprints and bacterial discharges or bacterial biofilms were also found on the surface of gallstones and acute sludge under a SEM observation. ESEM-EDX results revealed that calcium was found to be the main constituent of all of the types of stones except cholesterol stones, and aluminum was also presented in most of the stones and sludge samples. Chloride was only detected in the acute gallbladder sludge. CONCLUSION: FTIR spectra, morphological features, and elemental compositions of the acute gallbladder sludge were different from those of the chronic gallstones. PMID- 26976785 TI - Shear Wave Elastography and Cervical Lymph Nodes: Predicting Malignancy. AB - This prospective study evaluates the accuracy of virtual touch imaging quantification (VTIQ), a non-invasive shear wave elastography method for measuring cervical lymph nodes (LN) stiffness in differentiating benign from malignant LN. The study evaluated 270 LN in 236 patients with both conventional B mode ultrasound and VTIQ shear wave elastography before fine-needle aspiration biopsy (FNAB). LN stiffness was measured as shear wave velocity (SWV) in m/s. Surgical resection was advised for FNAB results that were not clearly benign. Surgical pathology confirmed 54 malignant LN. The receiver operating curve (ROC) identified a single cut-off value of 2.93 m/s as the maximum SWV for predicting a malignant cervical LN. The sensitivity and specificity were 92.59% and 75.46%, respectively. Positive predictive value (PPV) was 48.54% and negative predictive value (NPV) was 97.60%. LN stiffness measured by VTIQ-generated shear wave elastography is an independent predictor of malignancy. PMID- 26976786 TI - Structure of the H-NS-DNA nucleoprotein complex. AB - Nucleoid associated proteins (NAPs) play a key role in the compaction and expression of the prokaryotic genome. Here we report the organisation of a major NAP, the protein H-NS on a double stranded DNA fragment. For this purpose we have carried out a small angle neutron scattering study in conjunction with contrast variation to obtain the contributions to the scattering (structure factors) from DNA and H-NS. The H-NS structure factor agrees with a heterogeneous, two-state binding model with sections of the DNA duplex surrounded by protein and other sections having protein bound to the major groove. In the presence of magnesium chloride, we observed a structural rearrangement through a decrease in cross sectional diameter of the nucleoprotein complex and an increase in fraction of major groove bound H-NS. The two observed binding modes and their modulation by magnesium ions provide a structural basis for H-NS-mediated genome organisation and expression regulation. PMID- 26976787 TI - Postnatal depression and reproductive success in modern, low-fertility contexts. AB - BACKGROUND AND OBJECTIVES: Postnatal depression (PND) presents a puzzling phenomenon to evolutionary anthropologists as it is highly prevalent and yet detrimental to child development and maternal health. Adaptive explanations have been proposed, but have not been tested with data that directly link PND to female fertility. METHODOLOGY: A survey was designed to gather complete reproductive histories and retrospective measures of PND to measure the effects of PND on fitness. Respondents were born between 1930 and 1967, with the majority based in the UK during their childrearing years. The hypothesis that PND is detrimental to fitness is assessed using Mann-Whitney U tests on completed fertility. Binary logistic regression modelling is used to test the hypothesis that PND reduces the likelihood of parity progression. RESULTS: Women experiencing PND at their first or second birth have lower completed fertility, with PND at the first birth leading to lowered fertility. Logistic regression analyses show that this is the result of reductions in the likelihood of parity progression to a third birth when PND is experienced at the first birth or when repeat bouts occur. CONCLUSIONS AND IMPLICATIONS: Our results call into question adaptationist arguments, contribute to the growing understanding of the importance of emotional wellbeing to fertility decision making, and given the economic consequences of markedly below replacement fertility, highlight a potential new source of financial incentive to invest in screening and preventative measures to ensure good maternal mental health. PMID- 26976789 TI - Fractional Flow Reserve-Guided Revascularization in Patients With Aortic Stenosis. AB - Fractional flow reserve (FFR) has never been investigated in patients with aortic stenosis (AS). From 2002 to 2010, we identified 106 patients with AS and coronary artery disease with at least one intermediate lesion treated according to FFR guidance. We matched 212 contemporary control patients with AS in which revascularization was decided on angiography only. More patients in the FFR guided group underwent percutaneous coronary intervention (24% vs 13%; p = 0.019), whereas there was a trend toward less coronary artery bypass grafting (CABG) performed. After FFR, the number of diseased vessels was downgraded within the FFR-guided group (from 1.85 +/- 0.97 to 1.48 +/- 1; p <0.01) and compared with the angio-guided group (1.48 +/- 1 vs 1.8 +/- 0.97; p <0.01). Less aortic valve replacement was reported in the FFR-guided group (46% vs 57%; p = 0.056). In patients who underwent CABG, less venous conduits (0.5 +/- 0.69 vs 0.73 +/- 0.76; p = 0.05) and anastomoses (0.61 +/- 0.85 vs 0.94 +/- 1; p = 0.032) were necessary in the FFR-guided group. Up to 5 years, we found no difference in major adverse cardiac events (38% vs 39%; p = 0.98), overall death (32% vs 31%; p = 0.68), nonfatal myocardial infarction (2% vs 2%; p = 0.79), and revascularization (8% vs 7%; p = 0.76) between the 2 groups. In conclusion, FFR guidance impacts the management of selected patients with moderate or severe AS and coronary artery disease by resulting into deferral of aortic valve replacement, more patients treated with percutaneous coronary intervention, and in patients treated with CABG, into less venous grafts and anastomoses without increasing adverse event rates up to 5 years. PMID- 26976788 TI - Prognostic Usefulness of Acute Kidney Injury After Transcatheter Aortic Valve Replacement. AB - Acute kidney injury (AKI) after transcatheter aortic valve replacement (TAVR) has been associated with increased postoperative morbidity and mortality. Long-term outcomes after TAVR with the Edwards SAPIEN valve in patients who develop AKI postoperatively are currently not well described. We retrospectively reviewed 384 consecutive patients undergoing TAVR at 2 institutions from August 2006 to April 2012. AKI was defined and staged according to Valve Academic Research Consortium 2 criteria. The incidence, multivariate predictors, and association of AKI with 3 year mortality were evaluated. Stage 1 AKI occurred in 24.0% of patients (92 of 384), stage 2 in 5.5% (21 of 384), and stage 3 in 8.1% (31 of 384). The overall operative mortality rate was 7.6%, with a mortality of 3.0% in patients with no kidney injury, 7.6% in stage 1, 23.8% in stage 2, and 32.3% in stage 3. The incidence of new postoperative dialysis was 3.1%. Survival at 3 years for no AKI/stage 1/stage 2/stage 3 was 59.2 +/- 3.3%, 43.4 +/- 5.2%, 27.8 +/- 10.0%, and 25.4 +/- 7.9%, respectively. Logistic regression modeling for the combination of stage 2 or 3 AKI after surgery demonstrated that the last preoperative creatinine (for each 1 mg/dl increase, odds ratio = 3.23, 95% CI 1.83 to 5.69; p <0.001) and dye load (for each 10 ml increase, odds ratio = 1.04, 95% CI 1.01 to 1.08; p = 0.006) were significant predictors for AKI. In conclusion, AKI after TAVR is associated with increased postoperative and 3-year mortality. Significant multivariate predictors are potentially modifiable before the procedure. PMID- 26976790 TI - Racial Differences in the Prognostic Value of Cardiorespiratory Fitness (Results from the Henry Ford Exercise Testing Project). AB - The aim of this analysis was to determine whether racial differences exist in the prognostic value of cardiorespiratory fitness (CRF) in black and white patients undergoing stress testing. We included 53,876 patients (mean age 53 +/- 13, 49% women) from the Henry Ford Exercise Testing project free of established coronary disease or heart failure who completed a maximal exercise test from 1991 to 2009. Patients were followed for a mean duration of 11.5 years for all-cause mortality, ascertained by linkage with the Death Master File. Follow-up over mean 6.2 years was also available for incident myocardial infarction. Multivariate Cox proportional hazards regression models were used adjusting for demographic variables, risk factors, medications, and reason for stress test referral, including formal interaction testing by race (black vs white). Black patients (n = 16,725) were younger (54 +/- 13 vs 52 +/- 13, p <0.001) but had higher prevalence of hypertension (73% vs 57%, p <0.001) and obesity (28% vs 21%, p <0.001). On average, black patients achieved a lower CRF compared with whites (8.4 vs 9.5 metabolic equivalents, p <0.0001). A graded increase in mortality risk was noted with decreasing CRF for both black and white patients. In multivariate Cox regression, CRF was a predictor of both myocardial infarction and mortality, with no significant interaction between race, fitness, and outcomes (all interaction terms p >0.10). CRF is a strong predictor of all-cause mortality in both white and black patients, with no significant interaction observed between race, fitness, and outcomes. PMID- 26976792 TI - Usefulness of Diastolic Strain Measurements in Predicting Elevated Left Ventricular Filling Pressure and Risk of Rejection or Coronary Artery Vasculopathy in Pediatric Heart Transplant Recipients. AB - In pediatric heart transplant recipients, elevated pulmonary capillary wedge pressure (PCWP) is associated with rejection and coronary artery vasculopathy. This study aimed to evaluate which echocardiographic parameters track changes in PCWP and predict adverse outcomes (rejection or coronary artery vasculopathy). This prospective single-center study enrolled 49 patients (median 11.4 years old, interquartile range 7.4 to 16.5) at time of cardiac catheterization and echocardiography. Median follow-up was 2.4 years (range 1.2 to 3.1 years), with serial testing per clinical protocol. Ratio of early mitral inflow to annular velocity (E/E'), left atrial (LA) distensibility, peak LA systolic strain, E/left ventricular (LV) diastolic strain, and E/LV diastolic strain rate were measured from echocardiograms. Increase in PCWP >=3 mm Hg was associated with changes in LA distensibility, E/E', and E/LV diastolic strain, with highest area under the receiver operating characteristic curve for E/LV diastolic strain (0.76). In 9 patients who subsequently developed rejection or coronary artery vasculopathy, E/LV diastolic strain rate at baseline differed from patients without events (median 57.0 vs 43.6, p = 0.02). On serial studies, only change in LV ejection fraction differed in patients with events (median -10% vs -1%, p = 0.01); decrease in LV ejection fraction of -19% had a specificity of 100% and sensitivity of 44%. In conclusion, LV diastolic strain and strain rate measurements can track changes in PCWP and identify patients at risk for subsequent rejection or coronary artery vasculopathy. Further studies are necessary to confirm these data in a larger cohort. PMID- 26976791 TI - Usefulness of High-Sensitivity Cardiac Troponin T for the Identification of Outlier Patients With Diffuse Coronary Atherosclerosis and Low-Risk Factors. AB - Novel high-sensitivity assay can detect very low levels of circulating cardiac troponin (hs-cTnT) in apparently healthy subjects. Within normal range, higher levels are associated with coronary artery disease (CAD) and cardiac abnormalities commonly associated to traditional risk factors (RFs) for CAD. Therefore, we investigated the relation between circulating hs-cTnT and CAD in patients with a spectrum of RF burden aiming to assess the added value of hs-cTnT to identify "outlier" patients with CAD despite a low RF burden. Hs-cTnT was measured in 525 stable patients without previous diagnosis of ischemic heart disease with 0 to 1 RF, excluded diabetes, (low-RF group, n = 263) or >=2 RFs (multiple-RF group, n = 262) and without CAD (segment involvement score = 0) or diffuse CAD (segment involvement score >5) at coronary computed tomography angiography. Outlier patients with diffuse CAD despite low-RF burden had similar extent, severity, and plaque composition than patients with multiple RFs. Overall, hs-cTnT was measurable in 81% of patients with median value of 6.0 ng/L. In both groups, hs-cTnT concentration was higher in patients with CAD than in patients with normal coronary arteries (p <0.0001). Hs-cTnT was more accurate to detect patients with CAD in the low-RF group than in the multiple-RF group (p = 0.04). In multivariate analysis, higher level of hs-cTnT (>6 ng/L) was independently associated with CAD in low-RF group only. Despite very low circulating concentrations, hs-cTnT may identify with a good accuracy the outlier patients with diffuse CAD despite low-RF burden. PMID- 26976793 TI - Risk of Cardiovascular Hospitalizations from Exposure to Coarse Particulate Matter (PM10) Below the European Union Safety Threshold. AB - The association between exposure to air pollution and acute cardiovascular (CV) events is well documented; however, limited data are available evaluating the public health safety of various "doses" of particular matter (PM) below currently accepted safety thresholds. We explored the cross-sectional association between PM with aerodynamic diameter <10 MUm (PM10) and daily CV hospitalizations in Brescia, Italy, using Poisson regression models adjusted for age, gender, and meteorologic indices. Average daily exposure to PM10 obtained from arithmetic means of air pollution data were captured by 4 selected monitoring stations. PM10 data were expressed as daily means (lag 0-day) or 3-day moving averages (lag 3 day) and categorized according to the European Union daily limit value of 50 MUg/m(3). From September 2004 to September 2007, data from 6,000 acute CV admissions to a tertiary referral center were collected. An increase of 1 MUg/m(3) PM10 at lag 0-day was independently associated with higher rates of acute hospitalizations for composite CV-related events (relative risk [RR] 1.004, 95% confidence interval [CI] 1.002 to 1.006), acute heart failure (RR 1.004, 95% CI 1.001 to 1.008), acute coronary syndromes (RR 1.002, 95% CI 0.999 to 1.005), malignant ventricular arrhythmias (RR 1.004, 95% CI 0.999 to 1.010), and atrial fibrillation (RR 1.008, 95% CI 1.003 to 1.012). Similar results were obtained using PM10 lag 3-day data. The excess PM10 CV hospitalization risk (by lag 0-day and lag 3-day) did not vary significantly above and below the 50 MUg/m(3) safety threshold or by age and gender. In conclusion, increased levels of PM10, even below the current limits set by the European Union, were associated with excess risk for admissions for acute CV events. PMID- 26976794 TI - Suppression of Spry1 inhibits triple-negative breast cancer malignancy by decreasing EGF/EGFR mediated mesenchymal phenotype. AB - Sprouty (Spry) proteins have been implicated in cancer progression, but their role in triple-negative breast cancer (TNBC), a subtype of lethal and aggressive breast cancer, is unknown. Here, we reported that Spry1 is significantly expressed in TNBC specimen and MDA-MB-231 cells. To understand Spry1 regulation of signaling events controlling breast cancer phenotype, we used lentiviral delivery of human Spry1 shRNAs to suppress Spry1 expression in MDA-MB-231, an established TNBC cell line. Spry1 knockdown MDA-MB-231 cells displayed an epithelial phenotype with increased membrane E-cadherin expression. Knockdown of Spry1 impaired MDA-MB-231 cell migration, Matrigel invasion, and anchorage dependent and -independent growth. Tumor xenografts originating from Spry1 knockdown MDA-MB-231 cells grew slower, had increased E-cadherin expression, and yielded fewer lung metastases compared to control. Furthermore, suppressing Spry1 in MDA-MB-231 cells impaired the induction of Snail and Slug expression by EGF, and this effect was associated with increased EGFR degradation and decreased EGFR/Grb2/Shp2/Gab1 signaling complex formation. The same phenotype was also observed in the TNBC cell line MDA-MB-157. Together, our results show that unlike in some tumors, where Spry may mediate tumor suppression, Spry1 plays a selective role in at least a subset of TNBC to promote the malignant phenotype via enhancing EGF-mediated mesenchymal phenotype. PMID- 26976795 TI - Reduced in vivo toxicity of doxorubicin by encapsulation in cholesterol containing self-assembled nanoparticles. AB - We previously reported the development of an amphiphilic brush-like block copolymer composed of polynorbornene-cholesterol/polyethylene glycol (P(NBCh9-b NBPEG)) that self-assembles in aqueous media to form long circulating nanostructures capable of encapsulating doxorubicin (DOX-NPs). Biodistribution studies showed that this formulation preferentially accumulates in tumor tissue with markedly reduced accumulation in the heart and other major organs. The aim of the current study was to evaluate the in vivo efficacy and toxicity of DOX containing self-assembled polymer nanoparticles in a mouse xenograft tumor model and compare its effects with the hydrochloride non-encapsulated form (free DOX). DOX-NPs significantly reduced the growth of tumors without inducing any apparent toxicity. Conversely, mice treated with free DOX exhibited significant weight loss, early toxic cardiomyopathy, acute toxic hepatopathy, reduced hematopoiesis and fatal toxicity. The improved safety profile of the polymeric DOX-NPs can be explained by the low circulating concentration of non-nanoparticle-associated drug as well as the reduced accumulation of DOX in non-target organs. These findings support the use of P(NBCh9-b-NBPEG) nanoparticles as delivery platforms for hydrophobic anticancer drugs intended to reduce the toxicity of conventional treatments. PMID- 26976796 TI - Therapeutic potential of the dual peroxisome proliferator activated receptor (PPAR)alpha/gamma agonist aleglitazar in attenuating TNF-alpha-mediated inflammation and insulin resistance in human adipocytes. AB - Adipose tissue inflammation is a mechanistic link between obesity and its related sequelae, including insulin resistance and type 2 diabetes. Dual ligands of peroxisome proliferator activated receptor (PPAR)alpha and gamma, combining in a single molecule the metabolic and inflammatory-regulatory properties of alpha and gamma agonists, have been proposed as a promising therapeutic strategy to antagonize adipose tissue inflammation. Here we investigated the effects of the dual PPARalpha/gamma agonist aleglitazar on human adipocytes challenged with inflammatory stimuli. Human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were treated with aleglitazar or - for comparison - the selective agonists for PPARalpha or gamma fenofibrate or rosiglitazone, respectively, for 24h before stimulation with TNF-alpha. Aleglitazar, at concentrations as low as 10nmol/L, providing the half-maximal transcriptional activation of both PPARalpha and PPARgamma, reduced the stimulated expression of several pro-inflammatory mediators including interleukin (IL)-6, the chemokine CXC-L10, and monocyte chemoattractant protein (MCP)-1. Correspondingly, media from adipocytes treated with aleglitazar reduced monocyte migration, consistent with suppression of MCP-1 secretion. Under the same conditions, aleglitazar also reversed the TNF-alpha mediated suppression of insulin-stimulated ser473 Akt phosphorylation and decreased the TNF-alpha-induced ser312 IRS1 phosphorylation, two major switches in insulin-mediated metabolic activities, restoring glucose uptake in insulin resistant adipocytes. Such effects were similar to those obtainable with a combination of single PPARalpha and gamma agonists. In conclusion, aleglitazar reduces inflammatory activation and dysfunction in insulin signaling in activated adipocytes, properties that may benefit diabetic and obese patients. The effect of aleglitazar was consistent with dual PPARalpha and gamma agonism, but with no evidence of synergism. PMID- 26976797 TI - Cannabidiol and epilepsy: Rationale and therapeutic potential. AB - Despite the introduction of new antiepileptic drugs (AEDs), the quality of life and therapeutic response for patients with epilepsy remains still poor. Unfortunately, besides several advantages, these new AEDs have not satisfactorily reduced the number of refractory patients. Therefore, the need for different other therapeutic options to manage epilepsy is still a current issue. To this purpose, emphasis has been given to phytocannabinoids, which have been medicinally used since ancient time in the treatment of neurological disorders including epilepsy. In particular, the nonpsychoactive compound cannabidiol (CBD) has shown anticonvulsant properties, both in preclinical and clinical studies, with a yet not completely clarified mechanism of action. However, it should be made clear that most phytocannabinoids do not act on the endocannabinoid system as in the case of CBD. In in vivo preclinical studies, CBD has shown significant anticonvulsant effects mainly in acute animal models of seizures, whereas restricted data exist in chronic models of epilepsy as well as in animal models of epileptogenesis. Likewise, clinical evidence seems to indicate that CBD is able to manage epilepsy both in adults and children affected by refractory seizures, with a favourable side effect profile. However, to date, clinical trials are both qualitatively and numerically limited, thus yet inconsistent. Therefore, further preclinical and clinical studies are undoubtedly needed to better evaluate the potential therapeutic profile of CBD in epilepsy, although the actually available data is promising. PMID- 26976798 TI - Prevalence of food insecurity among military households with children 5 years of age and younger. AB - OBJECTIVE: Food insecurity increases risk of health conditions that may decrease military readiness. The aim of the present study was to define the prevalence of food insecurity among households with young children utilizing military installation childcare facilities and to describe household characteristics associated with food insecurity among this population. DESIGN: Cross-sectional survey including demographic questions and the US Department of Agriculture Food Security Survey Module six-item short form given to households (n 248) enrolled in Joint Base San Antonio Child Development Centers (JBSA-CDC) during the spring of 2015. SUBJECTS: Department of Defense families with at least one child less than 6 years old enrolled in a JBSA-CDC. Settings Joint Base San Antonio, TX, USA. RESULTS: Nearly one in seven families reported food insecurity. Households were more likely to be food-insecure if the head of household's highest level of education was high school or equivalent (P=0.003) and if the head of household was unmarried/unpartnered (P=0.001). Among food-insecure households headed by military service members, all were junior enlisted or non-commissioned officers (E1-E9). Food-insecure households were less likely to live off-post in owned or rented homes compared with those who were food-secure (P=0.016). Other characteristics associated with food insecurity included at least one family member enrolled in the Exceptional Family Member Program (P=0.020) and more children in the household (P=0.029). Few families reported enrolment in government supplemental food programmes. CONCLUSIONS: Food insecurity is prevalent in military families. Targeted interventions and policies can be developed using the demographic risk factors identified in the present study. PMID- 26976799 TI - Efficacy of Direct-Acting Antiviral Combination for Patients With Hepatitis C Virus Genotype 1 Infection and Severe Renal Impairment or End-Stage Renal Disease. AB - BACKGROUND & AIMS: Although hepatitis C virus (HCV) infection is common in patients with end-stage renal disease, highly efficacious, well-tolerated, direct acting antiviral regimens have not been extensively studied in this population. We investigated the safety and efficacy of ombitasvir co-formulated with paritaprevir and ritonavir, administered with dasabuvir (with or without ribavirin) in a prospective study of patients with stage 4 or 5 chronic kidney disease (CKD). METHODS: We performed a single-arm, multicenter study of treatment naive adults with HCV genotype 1 infection, without cirrhosis and with CKD stage 4 (estimated glomerular filtration rate, 15-30 mL/min/1.73 m(2)) or stage 5 (estimated glomerular filtration rate, <15 mL/min/1.73 m(2) or requiring hemodialysis). Twenty patients were given ombitasvir co-formulated with paritaprevir and ritonavir, administered with dasabuvir for 12 weeks. Patients with HCV genotype 1a infections also received ribavirin (n = 13), whereas those with genotype 1b infection did not (n = 7). The primary end point was sustained virologic response (serum HCV RNA <25 IU/mL) 12 weeks after treatment ended (SVR12). We collected data on on-treatment adverse events (AEs), serious AEs, and laboratory abnormalities. RESULTS: All 20 patients completed 12 weeks of treatment. Eighteen of the 20 patients achieved SVR12 (90%; 95% confidence interval: 69.9-97.2). One patient death after the end of the treatment (unrelated to the treatment) and 1 relapse accounted for the 2 non-SVRs. Adverse events were primarily mild or moderate, and no patient discontinued treatment due to an AE. Four patients experienced serious AEs; all were considered unrelated to treatment. Ribavirin therapy was interrupted in 9 patients due to anemia; 4 received erythropoietin. No blood transfusions were performed. CONCLUSIONS: In a clinical trial, the combination of ombitasvir, paritaprevir, and ritonavir, administered with dasabuvir, led to an SVR12 in 90% of patients with HCV genotype 1 infection and stage 4 or 5 CKD. The regimen is well tolerated, though RBV use may require a reduction or interruption to manage anemia. ClinicalTrials.gov ID NCT02207088. PMID- 26976800 TI - Estimation of Energy Expenditure for Wheelchair Users Using a Physical Activity Monitoring System. AB - OBJECTIVE: To develop and evaluate energy expenditure (EE) estimation models for a physical activity monitoring system (PAMS) in manual wheelchair users with spinal cord injury (SCI). DESIGN: Cross-sectional study. SETTING: University based laboratory environment, a semistructured environment at the National Veterans Wheelchair Games, and the participants' home environments. PARTICIPANTS: Volunteer sample of manual wheelchair users with SCI (N=45). INTERVENTION: Participants were asked to perform 10 physical activities (PAs) of various intensities from a list. The PAMS consists of a gyroscope-based wheel rotation monitor (G-WRM) and an accelerometer device worn on the upper arm or on the wrist. Criterion EE using a portable metabolic cart and raw sensor data from PAMS were collected during each of these activities. MAIN OUTCOME MEASURES: Estimated EE using custom models for manual wheelchair users based on either the G-WRM and arm accelerometer (PAMS-Arm) or the G-WRM and wrist accelerometer (PAMS-Wrist). RESULTS: EE estimation performance for the PAMS-Arm (average error +/- SD: 9.82%+/-37.03%) and PAMS-Wrist (-5.65%+/-32.61%) on the validation dataset indicated that both PAMS-Arm and PAMS-Wrist were able to estimate EE for a range of PAs with <10% error. Moderate to high intraclass correlation coefficients (ICCs) indicated that the EE estimated by PAMS-Arm (ICC3,1=.82, P<.05) and PAMS Wrist (ICC3,1=.89, P<.05) are consistent with the criterion EE. CONCLUSIONS: Availability of PA monitors can assist wheelchair users to track PA levels, leading toward a healthier lifestyle. The new models we developed can estimate PA levels in manual wheelchair users with SCI in laboratory and community settings. PMID- 26976801 TI - Disability in Adolescents and Adults Diagnosed With Hypermobility-Related Disorders: A Meta-Analysis. AB - OBJECTIVE: To (1) establish the association of the most common reported symptoms on disability; and (2) study the effectiveness of treatment on disability in patients with Ehlers-Danlos syndrome-hypermobility type (EDS-HT)/hypermobility syndrome (HMS). DATA SOURCES: An electronic search (Medical Subject Headings and free-text terms) was conducted in bibliographic databases CENTRAL/MEDLINE. STUDY SELECTION: Comparative, cross-sectional, longitudinal cohort studies and (randomized) controlled trials including patients with HMS/EDS-HT aged >=17 years were considered for inclusion. A class of symptoms was included when 5 publications were available. In regards to treatment (physical, cognitive interventions), only (randomized) controlled trials were considered. Surgical and medicinal interventions were excluded. DATA EXTRACTION: Bias was assessed according to the methodological scoring tools of the Cochrane collaboration. Z score transformations were applied to classify the extent of disability in comparison with healthy controls and to ensure comparability between studies. DATA SYNTHESIS: Initially, the electronic search yielded 714 publications, and 21 articles remained for analysis after selection. The following symptoms were included for meta-analysis: pain (n=12), fatigue (n=6), and psychological distress (n=7). Pain (r=.64, P=.021), fatigue (r=.91, P=.011), and psychological distress (r=.86, P=.018) had a significant impact on disability. Regarding treatment, a significant pain reduction was achieved by a variety of physical and cognitive approaches. Treatment effectiveness on disability was not established. CONCLUSIONS: Disability can affect patients with HMS/EDS-HT significantly and is highly correlated with both physical and psychological factors. Although evidence is available that physical and psychological treatment modalities can induce significant pain reduction, the evidence regarding disability reduction is lacking. PMID- 26976802 TI - Investigation into 9(S)-HPODE-derived allene oxide to cyclopentenone cyclization mechanism via diradical oxyallyl intermediates. AB - The cyclopentane core is ubiquitous among a large number of biologically relevant natural products. Cyclopentenones have been shown to be versatile intermediates for the stereoselective preparation of highly substituted cyclopentane derivatives. Allene oxides are oxygenated fatty acids which are involved in the pathways of cyclopentenone biosynthesis in plants and marine invertebrates; however, their cyclization behavior is not well understood. Recent work by Brash and co-workers (J. Biol. Chem., 2013, 288, 20797) revealed an unusual cyclization property of the 9(S)-HPODE-derived allene oxides: the previously unreported 10Z isomer cyclizes to a cis-dialkylcyclopentenone in hexane/isopropyl alcohol (100 : 3, v/v), but the known 10E-isomer does not yield cis-cyclopentenone under the same conditions. The mechanism for cyclization has been investigated for unsubstituted and methyl substituted vinyl allene oxide using a variety of methods including CASSCF, omegaB97xD, and CCSD(T) and basis sets up to cc-pVTZ. The lowest energy pathway proceeds via homolytic cleavage of the epoxide ring, formation of an oxyallyl diradical, which closes readily to a cyclopropanone intermediate. The cyclopropanone opens to the requisite oxyallyl which closes to the experimentally observed product, cis-cyclopentenone. The calculations show that the open shell, diradical pathway is lower in energy than the closed shell reactions of allene oxide to cyclopropanone, and cyclopropanone to cyclopentenone. PMID- 26976803 TI - Role of the private sector in vaccination service delivery in India: evidence from private-sector vaccine sales data, 2009-12. AB - BACKGROUND: India's Universal Immunization Programme (UIP) provides basic vaccines free-of-cost in the public sector, yet national vaccination coverage is poor. The Government of India has urged an expanded role for the private sector to help achieve universal immunization coverage. We conducted a state-by-state analysis of the role of the private sector in vaccinating Indian children against each of the six primary childhood diseases covered under India's UIP. METHODS: We analyzed IMS Health data on Indian private-sector vaccine sales, 2011 Indian Census data and national household surveys (DHS/NFHS 2005-06 and UNICEF CES 2009) to estimate the percentage of vaccinated children among the 2009-12 birth cohort who received a given vaccine in the private sector in 16 Indian states. We also analyzed the estimated private-sector vaccine shares as function of state specific socio-economic status. RESULTS: Overall in 16 states, the private sector contributed 4.7% towards tuberculosis (Bacillus Calmette-Guerin (BCG)), 3.5% towards measles, 2.3% towards diphtheria-pertussis-tetanus (DPT3) and 7.6% towards polio (OPV3) overall (both public and private sectors) vaccination coverage. Certain low income states (Uttar Pradesh, Rajasthan, Madhya Pradesh, Orissa, Assam and Bihar) have low private as well as public sector vaccination coverage. The private sector's role has been limited primarily to the high income states as opposed to these low income states where the majority of Indian children live. Urban areas with good access to the private sector and the ability to pay increases the Indian population's willingness to access private-sector vaccination services. CONCLUSION: In India, the public sector offers vaccination services to the majority of the population but the private sector should not be neglected as it could potentially improve overall vaccination coverage. The government could train and incentivize a wider range of private-sector health professionals to help deliver the vaccines, especially in the low income states with the largest birth cohorts. We recommend future studies to identify strengths and limitations of the public and private health sectors in each Indian state. PMID- 26976805 TI - A Case Report and Review of Early Symptomatic Congenital Syphilis Clinical Variations. PMID- 26976804 TI - Acquisition of negative complement regulators by the saprophyte Leptospira biflexa expressing LigA or LigB confers enhanced survival in human serum. AB - Leptospiral immunoglobulin-like (Lig) proteins are surface exposed molecules present in pathogenic but not in saprophytic Leptospira species. We have previously shown that Lig proteins interact with the soluble complement regulators Factor H (FH), FH like-1 (FHL-1), FH related-1 (FHR-1) and C4b Binding Protein (C4BP). In this study, we used the saprophyte L. biflexa serovar Patoc as a surrogate host to address the specific role of LigA and LigB proteins in leptospiral complement evasion. L. biflexa expressing LigA or LigB was able to acquire FH and C4BP. Bound complement regulators retained their cofactor activities of FI in the proteolytic cleavage of C3b and C4b. Moreover, heterologous expression of ligA and ligB genes in the saprophyte L. biflexa enhanced bacterial survival in human serum. Complement deposition on lig transformed L. biflexa was assessed by flow cytometry analysis. With regard to MAC deposition, L. biflexa expressing LigA or LigB presented an intermediate profile: MAC deposition levels were greater than those found in the pathogenic L. interrogans, but lower than those observed for L. biflexa wildtype. In conclusion, Lig proteins contribute to in vitro control of complement activation on the leptospiral surface, promoting an increased bacterial survival in human serum. PMID- 26976807 TI - Pediatric Emergency Physician Knowledge and Utilization of Prescription Drug Monitoring Program. PMID- 26976806 TI - A 16-Year-Old Girl With Altered Mental Status, Abducens Nerve Palsy, and Ataxia. PMID- 26976808 TI - Reflectance Confocal Microscopy for Diagnosis of Mammary Paget's Disease. PMID- 26976810 TI - The Whirl Sign and Small Intestinal Volvulus. PMID- 26976809 TI - Toxic Epidermal Necrolysis in Recessive Dystrophic Epidermolysis Bullosa following Bone Marrow Transplantation. AB - A 3-year-old child with recessive dystrophic epidermolysis bullosa treated with bone marrow transplantation subsequently developed body-wide epidermal detachment distinct from his epidermolysis bullosa. Toxic epidermal necrolysis was diagnosed by examination and skin biopsy. Although graft-vs-host disease was considered, he had no features of this diagnosis by laboratory studies or skin biopsy, and he improved without addition of further immune suppressants. Throughout the episode, the patient was maintained on cyclosporine A, a component of his transplant regimen, and also a reported therapy for toxic epidermal necrolysis. He had full recovery. Re-epithelialization occurred in a unique folliculocentric pattern, which we postulate was related to the patient's mesenchymal stem cell infusion, received as an adjunct to his marrow transplantation. PMID- 26976811 TI - Detrimental Effects of "Stretch" Goals in Specialty Substance Use Disorder Treatment Organizations. AB - BACKGROUND: "Stretch" goals, a rarely examined concept that represents seemingly impossible, highly ambitious organizational goals ostensibly established to fill performance gaps and motivate employees, are examined within a sample of substance use disorder (SUD) treatment centers in the United States in terms of their prevalence and effects on organizational behavior. Stretch goals are defined as "seemingly impossible" goals intended to motivate employees to achieve high performance. In light of the high level of environmental change and unpredictability faced by SUD treatment centers in recent decades, we theorize that stretch goals would be both common and often detrimental (in terms of capacity utilization rate and efficiency) in these settings. METHODS: In a temporally lagged analysis of data from leaders of a representative U. S. national sample of 219 SUD treatment centers characterized by entrepreneurial management structures, we examined the prevalence of stretch goals and their impact on key outcome variables of capacity utilization rate and efficiency. RESULTS: Widespread adoption of stretch goals was found, with 43% of our sample falling within the stretch category. Stretch goals had a negative main effect on capacity utilization rate as compared to less ambitious challenging goals. Stretch and prior performance interacted to further predict capacity utilization rate, whereas stretch and slack resource availability interacted to predict center efficiency. DISCUSSION: Although stretch goals are frequently used in the SUD treatment industry, we find them mostly detrimental to performance. Stretch goals may enhance the efficiency of treatment centers with prior limited resource availability, but they are negatively associated with capacity utilization, especially in centers with a record of already strong performance. Despite the high prevalence of such goals and positive values centered on aspirational behavior, these results strongly suggest caution in such goal setting in SUD treatment centers. PMID- 26976812 TI - Stem cells and injectable hydrogels: Synergistic therapeutics in myocardial repair. AB - One of the major problems in the treatment of cardiovascular diseases is the inability of myocardium to self-regenerate. Current therapies are unable to restore the heart's function after myocardial infarction. Myocardial tissue engineering is potentially a key approach to regenerate damaged heart muscle. Myocardial patches are applied surgically, whereas injectable hydrogels provide effective minimally invasive approaches to recover functional myocardium. These hydrogels are easily administered and can be either cell free or loaded with bioactive agents and/or cardiac stem cells, which may apply paracrine effects. The aim of this review is to investigate the advantages and disadvantages of injectable stem cell-laden hydrogels and highlight their potential applications for myocardium repair. PMID- 26976814 TI - Farming system context drives the value of deep wheat roots in semi-arid environments. AB - The capture of subsoil water by wheat roots can make a valuable contribution to grain yield on deep soils. More extensive root systems can capture more water, but leave the soil in a drier state, potentially limiting water availability to subsequent crops. To evaluate the importance of these legacy effects, a long-term simulation analysis at eight sites in the semi-arid environment of Australia compared the yield of standard wheat cultivars with cultivars that were (i) modified to have root systems which extract more water at depth and/or (ii) sown earlier to increase the duration of the vegetative period and hence rooting depth. We compared simulations with and without annual resetting of soil water to investigate the legacy effects of drier subsoils related to modified root systems. Simulated mean yield benefits from modified root systems declined from 0.1-0.6 t ha(-1) when annually reset, to 0-0.2 t ha(-1) in the continuous simulation due to a legacy of drier soils (mean 0-32mm) at subsequent crop sowing. For continuous simulations, predicted yield benefits of >0.2 t ha(-1) from more extensive root systems were rare (3-10% of years) at sites with shallow soils (<1.0 m), but occurred in 14-44% of years at sites with deeper soils (1.6 2.5 m). Earlier sowing had a larger impact than modified root systems on water uptake (14-31 vs 2-17mm) and mean yield increase (up to 0.7 vs 0-0.2 t ha(-1)) and the benefits occurred on deep and shallow soils and in more years (9-79 vs 3 44%). Increasing the proportion of crops in the sequence which dry the subsoil extensively has implications for the farming system productivity, and the crop sequence must be managed tactically to optimize overall system benefits. PMID- 26976813 TI - Massive cortical reorganization in sighted Braille readers. AB - The brain is capable of large-scale reorganization in blindness or after massive injury. Such reorganization crosses the division into separate sensory cortices (visual, somatosensory...). As its result, the visual cortex of the blind becomes active during tactile Braille reading. Although the possibility of such reorganization in the normal, adult brain has been raised, definitive evidence has been lacking. Here, we demonstrate such extensive reorganization in normal, sighted adults who learned Braille while their brain activity was investigated with fMRI and transcranial magnetic stimulation (TMS). Subjects showed enhanced activity for tactile reading in the visual cortex, including the visual word form area (VWFA) that was modulated by their Braille reading speed and strengthened resting-state connectivity between visual and somatosensory cortices. Moreover, TMS disruption of VWFA activity decreased their tactile reading accuracy. Our results indicate that large-scale reorganization is a viable mechanism recruited when learning complex skills. PMID- 26976815 TI - Root hair formation in rice (Oryza sativa L.) differs between root types and is altered in artificial growth conditions. AB - Root hairs are important sites for nutrient uptake, especially in P limiting conditions. Here we provide first insights into root hair development for the diverse root types of rice grown under different conditions, and show the first in situ images of rice root hairs in intact soil. Roots of plants grown in upland fields produced short root hairs that showed little responsiveness to P deficiency, and had a higher root hair density in the high P condition. These results were reproducible in rhizoboxes under greenhouse conditions. Synchrotron based in situ analysis of root hairs in intact soil further confirmed this pattern of root hair formation. In contrast, plants grown in nutrient solution produced more and longer root hairs in low P conditions, but these were unequally distributed among the different root types. While nutrient solution-grown main roots had longer hairs compared to upland field-grown main roots, second order lateral roots did not form any root hairs in nutrient solution-grown plants. Furthermore, root hair formation for plants grown in flooded lowland fields revealed few similarities with those grown in nutrient solution, thus defining nutrient solution as a possible measure of maximal, but not natural root hair development. By combining root hair length and density as a measure for root hair impact on the whole soil-grown root system we show that lateral roots provided the majority of root hair surface. PMID- 26976816 TI - Spreading the news: subcellular and organellar reactive oxygen species production and signalling. AB - As plants are sessile organisms that have to attune their physiology and morphology continuously to varying environmental challenges in order to survive and reproduce, they have evolved complex and integrated environment-cell, cell cell, and cell-organelle signalling circuits that regulate and trigger the required adjustments (such as alteration of gene expression). Although reactive oxygen species (ROS) are essential components of this network, their pathways are not yet completely unravelled. In addition to the intrinsic chemical properties that define the array of interaction partners, mobility, and stability, ROS signalling specificity is obtained via the spatiotemporal control of production and scavenging at different organellar and subcellular locations (e.g. chloroplasts, mitochondria, peroxisomes, and apoplast). Furthermore, these cellular compartments may crosstalk to relay and further fine-tune the ROS message. Hence, plant cells might locally and systemically react upon environmental or developmental challenges by generating spatiotemporally controlled dosages of certain ROS types, each with specific chemical properties and interaction targets, that are influenced by interorganellar communication and by the subcellular location and distribution of the involved organelles, to trigger the suitable acclimation responses in association with other well established cellular signalling components (e.g. reactive nitrogen species, phytohormones, and calcium ions). Further characterization of this comprehensive ROS signalling matrix may result in the identification of new targets and key regulators of ROS signalling, which might be excellent candidates for engineering or breeding stress-tolerant plants. PMID- 26976817 TI - Awns reduce grain number to increase grain size and harvestable yield in irrigated and rainfed spring wheat. AB - Genotypic variation in ear morphology is linked to differences in photosynthetic potential to influence grain yield in winter cereals. Awns contribute to photosynthesis, particularly under water-limited conditions when canopy assimilation is restricted. We assessed performance of up to 45 backcross derived, awned-awnletted NILs representing four diverse genetic backgrounds in 25 irrigated or rainfed, and droughted environments in Australia and Mexico. Mean environment grain yields were wide-ranging (1.38-7.93 t ha(-1)) with vegetative and maturity biomass, plant height, anthesis date, spike number, and harvest index all similar (P >0.05) for awned and awnletted NILs. Overall, grain yields of awned-awnletted sister-NILs were equivalent, irrespective of yield potential and genetic background. Awnletted wheats produced significantly more grains per unit area (+4%) and per spike (+5%) reflecting more fertile spikelets and grains in tertiary florets. Increases in grain number were compensated for by significant reductions in grain size (-5%) and increased frequency (+0.8%) of small, shrivelled grains ('screenings') to reduce seed-lot quality of awnletted NILs. Post-anthesis canopies of awnletted NILs were marginally warmer over all environments (+0.27 degrees C) but were not different and were sometimes cooler than awned NILs at cooler air temperatures. Awns develop early and represented up to 40% of total spikelet biomass prior to ear emergence. We hypothesize that the allocation of assimilate to large and rapidly developing awns decreases spikelet number and floret fertility to reduce grain number, particularly in distal florets. Individual grain size is increased to reduce screenings and to increase test weight and milling quality, particularly in droughted environments. Despite the average reduction in grain size, awnless lines could be identified that combined higher grain yield with larger grain size, increased grain protein concentration, and reduced screenings. PMID- 26976819 TI - Antibiotics or Appendectomy for Acute Non-Perforated Appendicitis--How to Interpret the Evidence? PMID- 26976821 TI - Identification of an epitope within the Bovine herpesvirus 1 glycoprotein E cytoplasmic tail and use of a monoclonal antibody directed against the epitope for the differentiation between vaccinated and infected animals. AB - We constructed a recombinant bovine herpesvirus type 1 triple mutant virus (BoHV 1 tmv) that lacks UL49.5 residues 30-32 and 80-96, gE cytoplasmic tail (gE CT) residues 452-575 and the entire 435 bp long Us9 ORF. To develop a gE CT-specific blocking ELISA test that is necessary to distinguish the BoHV-1 tmv vaccinated calves from the wild-type (wt) virus-infected calves, a mouse monoclonal antibody (mAb) 2H8F3 was generated by using the Escherichia coli expressed gE CT residues 452-575. Further, by performing a PEPSCAN analysis of 12 mer overlapping peptides spanning the entire gE CT, the epitope sequence recognized by the mAb2H8F3 was mapped within the gE CT residues 499SDDDGPASN507. A blocking ELISA test was then developed for detecting antibodies in wild-type BoHV-1 infected calves against the gE CT epitope specified by 499SDDDGPASN507. The assay is based on the use of HRP conjugated mAb2H8F3 and the E. coli expressed gE CT protein as an indicator antibody and a coating antigen, respectively. In this assay, serum from entire gE deleted and BoHV-1 tmv-infected calves scored negative, whereas serum from calves infected with BoHV-1 wt scored positive. Therefore, the gE CT-ELISA, based on the mAb2H8F3 and E. coli expressed gE CT protein, is suitable for differentiating the wt virus-infected and BoHV-1 tmv-vaccinated cattle. PMID- 26976822 TI - Inter-categorical intersectionality and leisure-based physical activity in Canada. AB - Leisure-based physical activity is socially stratified in Canada. To date, inequalities in physical activity by race or ethnicity, gender, class or sexual orientation, in Canada and elsewhere, have largely been investigated as distinct, additive phenomena. Informed by intersectionality theory, this paper examines whether racial identity, gender, class and sexuality 'intersect' with one another to predict physical activity in data from Cycles 2.1 and 3.1 of the Canadian Community Health Survey (n= 149 574). In particular, we apply the intersectional principle of multiplicativity which suggests that people's experiences of their gender identities are raced, classed and sexualized; their racial experiences are gendered, classed and sexualized, and so forth. We find that the positive effect of income on being physically active is strong among visible minority men, of moderate strength among White men and women and weak to non-existent among visible minority women. We also find that a lesbian, gay or bisexual orientation corresponds with a higher likelihood of being physically active among women (especially among less educated women) but not among men. These multiplicative findings undermine additive approaches to investigating social inequalities in leisure-based physical activity and pave the way for future intersectional analyses of axes of inequality and their diverse, intersecting effects. PMID- 26976818 TI - Most photorespiratory genes are preferentially expressed in the bundle sheath cells of the C4 grass Sorghum bicolor. AB - One of the hallmarks of C4 plants is the division of labor between two different photosynthetic cell types, the mesophyll and the bundle sheath cells. C4 plants are of polyphyletic origin and, during the evolution of C4 photosynthesis, the expression of thousands of genes was altered and many genes acquired a cell type specific or preferential expression pattern. Several lines of evidence, including computational modeling and physiological and phylogenetic analyses, indicate that alterations in the expression of a key photorespiration-related gene, encoding the glycine decarboxylase P subunit, was an early and important step during C4 evolution. Restricting the expression of this gene to the bundle sheath led to the establishment of a photorespiratory CO2 pump. We were interested in whether the expression of genes related to photorespiration remains bundle sheath specific in a fully optimized C4 species. Therefore we analyzed the expression of photorespiratory and C4 cycle genes using RNA in situ hybridization and transcriptome analysis of isolated mesophyll and bundle sheath cells in the C4 grass Sorghum bicolor It turns out that the C4 metabolism of Sorghum is based solely on the NADP-dependent malic enzyme pathway. The majority of photorespiratory gene expression, with some important exceptions, is restricted to the bundle sheath. PMID- 26976823 TI - IL-10-producing lung interstitial macrophages prevent neutrophilic asthma. AB - Inflammatory responses contribute to host defense against harmful organisms and allergens, whereas a failure of immune tolerance can cause chronic inflammation including asthma. The lung has several innate myeloid cell subsets. Among these subsets, there are two types of macrophages: alveolar macrophages (AMs) and interstitial macrophages (IMs). However, compared with AMs, the role of IMs in lung homeostasis remains poorly understood. In this study, we characterized AMs and IMs in healthy and inflammatory conditions. Pulmonary IMs constitutively produce the anti-inflammatory cytokine IL-10 through activation of the TLR4/MyD88 pathway in a microbiota-independent manner. In addition to IMs, Foxp3+ Treg cells show persistent IL-10 expression in the lung, with IL-10-producing IMs more prevalent than Foxp3+ Treg cells. IMs, but not Foxp3+ Treg cells, increased IL-10 production in house dust mite (HDM)-challenged mice, a model of human asthma. HDM challenged Il10 -/- mice exhibited severe lung pathology characterized by neutrophilia compared with that of wild-type mice. In addition, transplantation of wild-type IMs reduced neutrophilic inflammation, goblet cell mucus production and decreased expression of lung IL-13 and Th17-related neutrophil-activating cytokines such as IL-17, GM-CSF, and TNF-alpha. Together these results demonstrate that IL-10-producing IMs negatively regulate Th2- and Th17-mediated inflammatory responses, helping prevent neutrophilic asthma. PMID- 26976825 TI - Immunoreceptors on neutrophils. AB - Neutrophils play a critical role in the host defense against infection, and they are able to perform a variety of effector mechanisms for this purpose. However, there are also a number of pathological conditions, including autoimmunity and cancer, in which the activities of neutrophils can be harmful to the host. Thus the activities of neutrophils need to be tightly controlled. As in the case of other immune cells, many of the neutrophil effector functions are regulated by a series of immunoreceptors on the plasma membrane. Here, we review what is currently known about the functions of the various individual immunoreceptors and their signaling in neutrophils. While these immunoreceptors allow for the recognition of a diverse range of extracellular ligands, such as cell surface structures (like proteins, glycans and lipids) and extracellular matrix components, they commonly signal via conserved ITAM or ITIM motifs and their associated downstream pathways that depend on the phosphorylation of tyrosine residues in proteins and/or inositol lipids. This allows for a balanced homeostatic regulation of neutrophil effector functions. Given the number of available immunoreceptors and their fundamental importance for neutrophil behavior, it is perhaps not surprising that pathogens have evolved means to evade immune responses through some of these pathways. Inversely, some of these receptors evolved to specifically recognize these pathogens. Finally, some interactions mediated by immunoreceptors in neutrophils have been identified as promising targets for therapeutic intervention. PMID- 26976824 TI - Neutrophils: Critical components in experimental animal models of cancer. AB - Neutrophils have a crucial role in tumor development and metastatic progression. The contribution of neutrophils in tumor development is multifaceted and contradictory. On the one hand, neutrophils prompt tumor inception, promote tumor development by mediating the initial angiogenic switch and facilitate colonization of circulating tumor cells, and on the other hand, have cytotoxic and anti-metastatic capabilities. Our understanding of the role of neutrophils in tumor development has greatly depended on different experimental animal models of cancer. In this review we cover important findings that have been made about neutrophils in experimental animal models of cancer, point to their advantages and limitations, and discuss novel techniques that can be used to expand our knowledge of how neutrophils influence tumor progression. PMID- 26976827 TI - Stabilization of a prokaryotic LAT transporter by random mutagenesis. AB - The knowledge of three-dimensional structures at atomic resolution of membrane transport proteins has improved considerably our understanding of their physiological roles and pathological implications. However, most structural biology techniques require an optimal candidate within a protein family for structural determination with (a) reasonable production in heterologous hosts and (b) good stability in detergent micelles. SteT, the Bacillus subtilis L-serine/L threonine exchanger is the best-known prokaryotic paradigm of the mammalian L amino acid transporter (LAT) family. Unfortunately, SteT's lousy stability after extracting from the membrane prevents its structural characterization. Here, we have used an approach based on random mutagenesis to engineer stability in SteT. Using a split GFP complementation assay as reporter of protein expression and membrane insertion, we created a library of 70 SteT mutants each containing random replacements of one or two residues situated in the transmembrane domains. Analysis of expression and monodispersity in detergent of this library permitted the identification of evolved versions of SteT with a significant increase in both expression yield and stability in detergent with respect to wild type. In addition, these experiments revealed a correlation between the yield of expression and the stability in detergent micelles. Finally, and based on protein delipidation and relipidation assays together with transport experiments, possible mechanisms of SteT stabilization are discussed. Besides optimizing a member of the LAT family for structural determination, our work proposes a new approach that can be used to optimize any membrane protein of interest. PMID- 26976826 TI - Role of memory T cell subsets for adoptive immunotherapy. AB - Adoptive transfer of primary (unmodified) or genetically engineered antigen specific T cells has demonstrated astonishing clinical results in the treatment of infections and some malignancies. Besides the definition of optimal targets and antigen receptors, the differentiation status of transferred T cells is emerging as a crucial parameter for generating cell products with optimal efficacy and safety profiles. Long-living memory T cells subdivide into phenotypically as well as functionally different subsets (e.g. central memory, effector memory, tissue-resident memory T cells). This diversification process is crucial for effective immune protection, with probably distinct dependencies on the presence of individual subsets dependent on the disease to which the immune response is directed as well as its organ location. Adoptive T cell therapy intends to therapeutically transfer defined T cell immunity into patients. Efficacy of this approach often requires long-term maintenance of transferred cells, which depends on the presence and persistence of memory T cells. However, engraftment and survival of highly differentiated memory T cell subsets upon adoptive transfer is still difficult to achieve. Therefore, the recent observation that a distinct subset of weakly differentiated memory T cells shows all characteristics of adult tissue stem cells and can reconstitute all types of effector and memory T cell subsets, became highly relevant. We here review our current understanding of memory subset formation and T cell subset purification, and its implications for adoptive immunotherapy. PMID- 26976830 TI - Laparoscopic Confocal Laser Microscopy Without Fluorescent Injection: A Pilot Ex Vivo Study in Colon Cancer. AB - Introduction Histological analysis of surgical specimen is the gold standard for cancer classification. In particular, frozen histological diagnosis of vague peritoneal spots or uncertain excision of tumors plays a crucial role for proceeding with or without change of the operation procedure. Confocal laser microscopy (CLM) enables in vivo and real-time high-resolution tissue analysis. To evaluate a novel technique of CLM without any fluorescent dye, this pilot ex vivo study demonstrates a CLM camera device for minimal invasive surgical approach. Methods In 5 cases, a laparoscopic CLM camera was used for examining colon and rectum specimen. Images of nonmalignant and malignant intestinal mucosa were characterized in terms of specific signal-patterns. No fluorescent dye was used. Correlations to findings in conventional histology were systematically recorded and described. Results Using this CLM camera device, it is possible to analyze colon specimen mucosa. Nonmalignant and malignant intestinal mucosa show specific signal patterns. Nonmalignant mucosa is defined by honeycomb structure. There is deregulated structure in colon and rectum carcinoma mucosa. The inside lumen is irregular. The radial border appears swollen with reduced contrast. Discussion This pilot study shows that the assessment of colon mucosa with a prototype of CLM camera for minimally invasive surgical approach without any fluorescent dye is feasible. It is possible to differentiate between benign and malignant mucosa in colon specimen by easy to evaluate and reproducible parameters. These first steps of this pioneering achievement to establish CLM in minimal invasive surgical procedures show a great potential for a more reliable intraoperative evaluation of suspect foci. PMID- 26976829 TI - Anchoring Chest Drains With an Elegant Sailor's Tying Technique. PMID- 26976828 TI - Transient contractions of urinary bladder smooth muscle are drivers of afferent nerve activity during filling. AB - Activation of afferent nerves during urinary bladder (UB) filling conveys the sensation of UB fullness to the central nervous system (CNS). Although this sensory outflow is presumed to reflect graded increases in pressure associated with filling, UBs also exhibit nonvoiding, transient contractions (TCs) that cause small, rapid increases in intravesical pressure. Here, using an ex vivo mouse bladder preparation, we explored the relative contributions of filling pressure and TC-induced pressure transients to sensory nerve stimulation. Continuous UB filling caused an increase in afferent nerve activity composed of a graded increase in baseline activity and activity associated with increases in intravesical pressure produced by TCs. For each ~4-mmHg pressure increase, filling pressure increased baseline afferent activity by ~60 action potentials per second. In contrast, a similar pressure elevation induced by a TC evoked an ~10-fold greater increase in afferent activity. Filling pressure did not affect TC frequency but did increase the TC rate of rise, reflecting a change in the length-tension relationship of detrusor smooth muscle. The frequency of afferent bursts depended on the TC rate of rise and peaked before maximum pressure. Inhibition of small- and large-conductance Ca(2+)-activated K(+) (SK and BK) channels increased TC amplitude and afferent nerve activity. After inhibiting detrusor muscle contractility, simulating the waveform of a TC by gently compressing the bladder evoked similar increases in afferent activity. Notably, afferent activity elicited by simulated TCs was augmented by SK channel inhibition. Our results show that afferent nerve activity evoked by TCs represents the majority of afferent outflow conveyed to the CNS during UB filling and suggest that the maximum TC rate of rise corresponds to an optimal length tension relationship for efficient UB contraction. Furthermore, our findings implicate SK channels in controlling the gain of sensory outflow independent of UB contractility. PMID- 26976831 TI - SIMulation of Medication Error induced by Clinical Trial drug labeling: the SIMME CT study. AB - OBJECTIVE: To assess the impact of investigational drug labels on the risk of medication error in drug dispensing. DESIGN: A simulation-based learning program focusing on investigational drug dispensing was conducted. SETTING: The study was undertaken in an Investigational Drugs Dispensing Unit of a University Hospital of Lyon, France. PARTICIPANTS: Sixty-three pharmacy workers (pharmacists, residents, technicians or students) were enrolled. INTERVENTION: Ten risk factors were selected concerning label information or the risk of confusion with another clinical trial. Each risk factor was scored independently out of 5: the higher the score, the greater the risk of error. From 400 labels analyzed, two groups were selected for the dispensing simulation: 27 labels with high risk (score >=3) and 27 with low risk (score <=2). Each question in the learning program was displayed as a simulated clinical trial prescription. MAIN OUTCOME MEASURE: Medication error was defined as at least one erroneous answer (i.e. error in drug dispensing). For each question, response times were collected. RESULTS: High-risk investigational drug labels correlated with medication error and slower response time. Error rates were significantly 5.5-fold higher for high-risk series. Error frequency was not significantly affected by occupational category or experience in clinical trials. CONCLUSIONS: SIMME-CT is the first simulation-based learning tool to focus on investigational drug labels as a risk factor for medication error. SIMME-CT was also used as a training tool for staff involved in clinical research, to develop medication error risk awareness and to validate competence in continuing medical education. PMID- 26976832 TI - Dorsal pancreatic agenesis: description of CT signs. PMID- 26976833 TI - Not all gastric masses are gastric cancer. AB - Lung cancer metastasising to the gastrointestinal tract normally does not occur. However, as clinicians, we must be aware that lung adenocarcinoma, as in all cancers, can and will metastasise to any part of the body. We describe a case of a patient with a presumed primary gastric adenocarcinoma who presented with shortness of breath due to pleural effusion. Pathology from the pleural effusion was positive for primary lung adenocarcinoma. Further investigation revealed that the patient's gastric mass was misdiagnosed as gastric adenocarcinoma. We correctly diagnosed the mass as metastatic lung adenocarcinoma. This was very significant because the patient was transitioning to palliative care with possible tube feeding. After the correct diagnosis, her management drastically changed and her health improved. Clinical, pathological and medical management of lung cancer metastasis to the stomach are discussed. PMID- 26976834 TI - Conjunctival pedicle flap in management of open globe injury with corneal tissue loss. AB - Accidental injury with scissors led to an open globe injury with iris prolapse and corneal tissue loss in the right eye of a 15-year-old girl. Attempts to suture the laceration normally, led to persistent aqueous leak, and tight suturing was leading to unacceptable distortion of the corneal contour. In the absence of donor tissue or tissue glue, a bulbar conjunctival pedicle flap was used to augment sutures placed without undue tension, and watertight closure of the globe was achieved. Postoperatively, the flap retracted, and excellent tectonic, cosmetic and refractive outcomes were achieved. A conjunctival pedicle flap can be a useful adjunct in the armamentarium of the corneal surgeon while dealing with open globe injuries with corneal tissue loss. PMID- 26976836 TI - 'A problematic plum pit in the piping': a case of traumatic oesophageal perforation. AB - A 75-year-old man presented to accident and emergency having swallowed a plum pit. He initially experienced sharp neck pain, which was mild at presentation. He was otherwise haemodynamically stable and was able to subsequently eat a sandwich without consequence. He was referred to the ear, nose and throat senior house office (SHO), who reviewed the soft tissue radiograph, which appeared normal. The patient displayed no concerning clinical signs and was well; however, his pain persisted. Examination revealed a localised area of surgical emphysema on the left side of the neck. Retrospective review of the soft tissue radiograph showed a small region of subcutaneous free air. An urgent CT scan confirmed a pneumomediastinum indicative of an oesophageal perforation. The patient was admitted for observation, and was managed conservatively without surgical intervention. He was weaned onto sterile fluid and progressed to a solid diet. He was discharged from hospital with no long-term sequelae. PMID- 26976835 TI - Spontaneous fistulisation and drainage of a pyogenic liver abscess into the stomach in an adult patient with sickle cell disease. AB - Spontaneous endoluminal drainage of a pyogenic liver abscess is a rare phenomenon. Similarly, there are only a few cases in the English literature describing hepatic abscesses as an unusual complication of sickle cell anaemia. Having these two phenomena occurring in the same patient is truly a rarity. We describe a case of a 45-year-old man with homozygous sickle cell anaemia who presented to our institution with a pyogenic liver abscess. He had spontaneous drainage of the abscess after spontaneous fistulisation, with the stomach obviating the need for percutaneous drainage. PMID- 26976837 TI - Sympathetic ophthalmia following a conjunctival flap procedure for corneal perforation. AB - A 25-year-old man developed diminution of vision and redness in both eyes 5 weeks after a conjunctival flap procedure in the right eye. On examination, there was panuveitis and exudative retinal detachment in both eyes. The right eye had an inferotemporal conjunctival flap with iris incarceration. Fundus fluorescein angiography revealed typical pinpoint leaks and optical coherence tomography demonstrated multiple neurosensory detachments in the left eye. The patient received frequent topical steroids and cycloplegics. Intravenous dexamethasone pulse was given followed by high-dose oral prednisone, after which the patient recovered vision. The conjunctival flap in corneal perforation may predispose to sympathetic ophthalmia. PMID- 26976838 TI - Diastolic mitral regurgitation in a patient with coronary artery disease and anaemia. PMID- 26976839 TI - Foveal haemorrhage from makeshift 'Lightsaber': funduscopy and optical coherence tomography findings. PMID- 26976840 TI - Posterior C1-C2 calcium pyrophosphate dihydrate crystal deposition disease. AB - Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease rarely occurs in the posterior aspect of the craniocervical junction (CCJ). To the best of our knowledge, there have been only 2 previously reported cases of patients with posterior CPPD lesions in this region that have led to cervical myelopathy. We report the case of a 70-year-old man presenting with neck pain and cervical myelopathy with multilevel stenosis from C1-C6. The stenosis was worst at C1-C2, secondary to compression by a CPPD lesion posterior to the spinal cord. The patient underwent a C2-C6 laminectomy and fusion with resection of the CPPD lesion. In this report, we discuss the patient and present a novel theory to explain the preponderance of CPPD lesions in the CCJ occurring anteriorly and not posteriorly to the spinal cord. PMID- 26976841 TI - Evidence for marine origin and microbial-viral habitability of sub-zero hypersaline aqueous inclusions within permafrost near Barrow, Alaska. AB - Cryopegs are sub-surface hypersaline brines at sub-zero temperatures within permafrost; their global extent and distribution are unknown. The permafrost barrier to surface and groundwater advection maintains these brines as semi isolated systems over geological time. A cryopeg 7 m below ground near Barrow, Alaska, was sampled for geochemical and microbiological analysis. Sub-surface brines (in situtemperature of -6 degrees C, salinity of 115 ppt), and an associated sediment-infused ice wedge (melt salinity of 0.04 ppt) were sampled using sterile technique. Major ionic concentrations in the brine corresponded more closely to other (Siberian) cryopegs than to Standard seawater or the ice wedge. Ionic ratios and stable isotope analysis of water conformed to a marine or brackish origin with subsequent Rayleigh fractionation. The brine contained ~1000* more bacteria than surrounding ice, relatively high viral numbers suggestive of infection and reproduction, and an unusually high ratio of particulate to dissolved extracellular polysaccharide substances. A viral metagenome indicated a high frequency of temperate viruses and limited viral diversity compared to surface environments, with closest similarity to low water activity environments. Interpretations of the results underscore the isolation of these underexplored microbial ecosystems from past and present oceans. PMID- 26976842 TI - Aquaculture changes the profile of antibiotic resistance and mobile genetic element associated genes in Baltic Sea sediments. AB - Antibiotics are commonly used in aquaculture and they can change the environmental resistome by increasing antibiotic resistance genes (ARGs). Sediment samples were collected from two fish farms located in the Northern Baltic Sea, Finland, and from a site outside the farms (control). The sediment resistome was assessed by using a highly parallel qPCR array containing 295 primer sets to detect ARGs, mobile genetic elements and the 16S rRNA gene. The fish farm resistomes were enriched in transposon and integron associated genes and in ARGs encoding resistance to antibiotics which had been used to treat fish at the farms. Aminoglycoside resistance genes were also enriched in the farm sediments despite the farms not having used aminoglycosides. In contrast, the total relative abundance values of ARGs were higher in the control sediment resistome and they were mainly genes encoding efflux pumps followed by beta lactam resistance genes, which are found intrinsically in many bacteria. This suggests that there is a natural Baltic sediment resistome. The resistome associated with fish farms can be from native ARGs enriched by antibiotic use at the farms and/or from ARGs and mobile elements that have been introduced by fish farming. PMID- 26976843 TI - Isolation of 'Candidatus Nitrosocosmicus franklandus', a novel ureolytic soil archaeal ammonia oxidiser with tolerance to high ammonia concentration. AB - Studies of the distribution of ammonia oxidising archaea (AOA) and bacteria (AOB) suggest distinct ecological niches characterised by ammonia concentration and pH, arising through differences in substrate affinity and ammonia tolerance. AOA form five distinct phylogenetic clades, one of which, the 'Nitrososphaera sister cluster', has no cultivated isolate. A representative of this cluster, named 'Candidatus Nitrosocosmicus franklandus', was isolated from a pH 7.5 arable soil and we propose a new cluster name:'Nitrosocosmicus' While phylogenetic analysis of amoA genes indicates its association with the Nitrososphaera sister cluster, analysis of 16S rRNA genes provided no support for a relative branching that is consistent with a 'sister cluster', indicating placement within a lineage of the order Nitrososphaerales 'Ca.N. franklandus' is capable of ureolytic growth and its tolerances to nitrite and ammonia are higher than in other AOA and similar to those of typical soil AOB. Similarity of other growth characteristics of 'Ca.N. franklandus' with those of typical soil AOB isolates reduces support for niche differentiation between soil AOA and AOB and suggests that AOA have a wider physiological diversity than previously suspected. In particular, the high ammonia tolerance of 'Ca.N. franklandus' suggests potential contributions to nitrification in fertilised soils. PMID- 26976844 TI - Enterococcus growth on eelgrass (Zostera marina); implications for water quality. AB - Enterococci are fecal indicator bacteria used to monitor fecal pollution of recreational waters. When enterococci levels exceed health standards, fecal pollution is assumed as the cause. Enterococci growing on plants limit their usefulness as fecal indicator bacteria. Here we examined enterococcal growth on eelgrass in Mission Bay, CA where enterococci levels have exceeded water quality thresholds. A total of 69 eelgrass samples were collected from six sites, shaken to remove enterococci attached to plant surfaces and the eluant filtered onto culture media. Isolates were then identified to species using biochemical methods, and DNA typing by pulsed-field gel electrophoresis was done to assess clonality of strains. Enterococci concentrations among eelgrass ranged from 8 to 14 000 CFU g(-1) dry weight. The most predominant enterococcal species found were Enterococcus casseliflavus and E. hirae followed by E. faecalis. Cluster analysis indicated a high level of clonality among isolates across all species, with clonal isolates consistently associated with individual eelgrass samples. Finding high densities of E. casseliflavus, E. hirae and E. faecalis on eelgrass that included clonal strains indicates the capability of enterococcal growth on eelgrass. Amplification of enterococci on eelgrass presents challenges for regulatory agencies that interpret elevated levels of these bacteria as an indication of fecal pollution. PMID- 26976845 TI - Validating the HeartQoL questionnaire in patients with atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is associated with impaired health-related quality-of-life (HRQL). When assessing HRQL, disease-specific and generic instruments are used, which may hinder outcome comparisons across studies. A newly developed core ischaemic heart disease-specific HRQL questionnaire, the HeartQoL, offers a single measurement instrument which may allow outcome comparisons across cardiac diseases. The aim of the study was to evaluate the psychometric properties of HeartQoL in an AF population treated with ablation by assessing its factor structure, construct validity, internal consistency, and test-retest reliability. DESIGN AND METHODS: Data were collected in two phases: (a) a cross-sectional study including 462 patients with AF/atrial flutter who completed the HeartQoL and the Short-Form 36 (SF-36), allowing for the evaluation of internal consistency, factor structure and construct validity; and (b) a longitudinal study including 55 patients completing HeartQoL twice to evaluate test-retest reliability. RESULTS: The two-factor structure of HeartQoL was largely confirmed in patients with AF. Internal consistency was high (Cronbach's alpha (alpha) >= 0.90) and test-retest reliability good (intra-class correlation >= 0.90). The construct validity was supported, as subscales of HeartQoL correlated strongly with similar (r >= 0.78) and weakly (r <= 0.47) with dissimilar subscales of SF-36. The HeartQoL demonstrated ability to distinguish between different clinical subgroups of patients, indicating sensitivity. CONCLUSION: The HeartQoL showed overall satisfactory psychometric properties, demonstrating it to be a valid instrument in the evaluation of HRQL in patients with AF treated with ablation. This suggests that HeartQoL may be a valuable instrument for making HRQL comparisons across the spectrum of cardiac diseases. PMID- 26976846 TI - Cardiovascular risk prediction: Can Systematic Coronary Risk Evaluation (SCORE) be improved by adding simple risk markers? Results from the Copenhagen City Heart Study. AB - AIM: European society of cardiology (ESC) guidelines recommend that cardiovascular disease (CVD) risk stratification in asymptomatic individuals is based on the Systematic Coronary Risk Evaluation (SCORE) algorithm, which estimates individual 10-year risk of death from CVD. We assessed the potential improvement in CVD risk stratification of 19 easily available risk markers by adding them to the SCORE algorithm. METHODS AND RESULTS: We followed 8476 individuals without prior CVD or diabetes from the Copenhagen City Heart study. The 19 risk markers were: major and minor electrocardiographic (ECG) abnormalities, heart rate, family history (of ischaemic heart disease), body mass index (BMI), waist-hip ratio, walking duration and pace, leisure time physical activity, forced expiratory volume (FEV)1%pred, household income, education, vital exhaustion, high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), high-sensitive C-reactive protein (hsCRP) and fibrinogen. With the exception of family history, BMI, triglycerides and minor ECG changes, all risk markers remained significantly associated with CVD mortality after adjustment for SCORE variables. However, the addition of the remaining 15 risk markers resulted in only small changes in discrimination calculated by area under the curve (AUC) and integrated discrimination improvement (IDI) and no improvement in net reclassification improvement (NRI). HsCRP improved AUC by 0.006 (p = 0.015) and IDI by 0.012 (p = 0.002); FEV1%pred improved AUC by 0.006 (p = 0.032) and IDI by 0.006 (p = 0.029). In the intermediate risk group FEV1%pred, education, vital exhaustion and ApoA1 all improved NRI but FEV1%pred was the only risk marker to significantly improve both IDI, AUC and NRI. CONCLUSION: The SCORE algorithm predicted CVD mortality in a Danish cohort well. Despite strong association with CVD mortality, the individual addition of 19 easily available risk makers to the SCORE model resulted in small risk stratification improvements. PMID- 26976848 TI - Interventions to improve medication adherence in coronary disease patients: A systematic review and meta-analysis of randomised controlled trials. AB - BACKGROUND: Adherence to multiple cardiovascular (CV) medications is a cornerstone of coronary heart disease (CHD) management and prevention, but it is sub-optimal worldwide. This review aimed to examine whether interventions improve adherence to multiple CV medications in a CHD population. DESIGN: This study was based on a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. METHODS: Randomised controlled trials were identified by searching multiple databases and reference lists. Studies were selected if they evaluated interventions aiming to improve adherence to multiple CV medications targeting a CHD population and if they provided an appropriate measure of adherence. Interventions were classified as complex or simple interventions. Odds ratios (ORs) were calculated and pooled for a meta-analysis. Risk of bias, heterogeneity and publication bias were also assessed. RESULTS: Sixteen studies (10,706 patients) were included. The mean age was 62 years (standard deviation (SD) 3.6) and 72% were male. In a pooled analysis, the interventions significantly improved medication adherence (OR 1.52; 95% confidence interval (CI) 1.25-1.86; p < 0.001) and there were no significant differences based on intervention type (complex vs simple), components categories and adherence method. There was moderate heterogeneity (I(2) ( )= 61%) across the studies. After adjusting for publication bias, the effect size was attenuated but remained significant (OR 1.35; 95% CI 1.09-1.68). CONCLUSION: Interventions to improve adherence to multiple CV medication in a CHD population significantly improved the odds of being adherent. Simple one-component interventions might be a promising way to improve medication adherence in a CHD population, as they would be easier to replicate in different settings and on a large scale. PMID- 26976847 TI - Treatment with oral anticoagulant drugs restrained from patients with atrial fibrillation: An assessment in a geographically well-defined catchment area. AB - BACKGROUND: Atrial fibrillation (AF) affects about 3.2% of the adult population in the western world and incurs an annual stroke risk of 4.5%. The use of oral anticoagulant (OAC) drugs significantly reduces this risk. OAC drugs seem to be under-utilized, but little is known about why their use is restrained in routine clinical management. The aim of this study was to assess this issue and, from these data, to estimate the proportion of patients with AF in a general population who were eligible for treatment with OAC drugs. DESIGN: Retrospective study of medical records. METHODS: The study included all identified patients with AF in a well-defined catchment area of 65,532 people, among whom 1616 (3.2%) had documented AF. Of the patients with AF, 588 (36%) were originally reported not to be receiving OAC drugs. The patient-responsible physicians (n = 24) were requested to complete a standardized questionnaire to assess the reason for restraining the use of OAC drugs for each individual patient. RESULTS: Of the 588 patients originally reported not to be receiving OAC drugs, eight were shown to be using OAC drugs and seven were lost to follow up. Thus the reason for restraining OAC drugs was finally assessed in 573 patients. The primary reasons were: lack of indication, 26%; declined general condition, 14%; a history of bleeding, 12%; assumed poor compliance, 11%; repeated falls, 6%; and reason unknown, 9%. CONCLUSIONS: This is, to our knowledge, the first study to assess the reasons for restraining the use of OAC drugs in a geographically well-defined population including all hospital-based and non-hospital-based healthcare. Applying CHA2DS2-VASc and new strategies for OAC drugs to our study data indicated that between 72 and 88% of all patients with AF are eligible for treatment with OAC drugs. PMID- 26976850 TI - Cardiomyopathy responsive to gluten withdrawal in a patient with coeliac disease. AB - A 57-year-old man with iron deficiency anaemia developed general malaise, exertional dyspnoea and features of cardiac failure out of proportion to his anaemia (haemoglobin 120 g/L). Investigations showed a severely dilated left ventricle with an ejection fraction of 15%, due to dilated cardiomyopathy. He was treated with high-dose diuretics, ACE inhibitors and beta-blocker therapy. Subsequent investigation into his iron deficiency anaemia revealed a new diagnosis of coeliac disease. After starting a gluten-free diet, his cardiac function improved markedly, with ejection fraction reaching 70%, allowing his cardiac medications to be withdrawn. This case suggests a link between coeliac disease and cardiomyopathy. PMID- 26976849 TI - SLC52A3, A Brown-Vialetto-van Laere syndrome candidate gene is essential for mouse development, but dispensable for motor neuron differentiation. AB - Riboflavin, also known as vitamin B2, is essential for cellular reduction oxidation reactions, but is not readily synthesized by mammalian cells. It has been proposed that riboflavin absorption occurs through solute carrier family 52 members (SLC52) A1, A2 and A3. These transporters are also candidate genes for the childhood onset-neural degenerative syndrome Brown-Vialetto-Van Laere (BVVL). Although riboflavin is an essential nutrient, why mutations in its transporters result in a neural cell-specific disorder remains unclear. Here, we provide evidence that Slc52a3 is the mouse ortholog of SLC52A3 and show that Slc52a3 deficiency results in early embryonic lethality. Loss of mutant embryos was associated with both defects in placental formation and increased rates of apoptosis in embryonic cells. In contrast, Slc52a3 -/- embryonic stem cell lines could be readily established and differentiated into motor neurons, suggesting that this transporter is dispensable for neural differentiation and short-term maintenance. Consistent with this finding, examination of Slc52a3 gene products in adult tissues revealed expression in the testis and intestine but little or none in the brain and spinal cord. Our results suggest that BVVL patients with SCL52A3 mutations may be good candidates for riboflavin replacement therapy and suggests that either the mutations these individuals carry are hypomorphic, or that in these cases alternative transporters act during human embryogenesis to allow full-term development. PMID- 26976851 TI - De novo biosynthesis of resveratrol by site-specific integration of heterologous genes in Escherichia coli. AB - Resveratrol is a well-known triphenolic natural product present in red wine. For its contribution to human health, the demand for resveratrol as a food and nutrition supplement has increased significantly. In recent years, the rapid development of synthetic biology has promoted extensive work to increase the production of resveratrol in microbes. However, supplementation of expensive phenylpropanoic precursors was required in current engineered strains. Here, we first utilized the site-specific integration strategy to produce resveratrol in Escherichia coli The genes tal, 4cl and sts were site-specific integrated into the loci of genes tyrR and trpED in the chromosome of E. coli BW25113 (DE3). The final strain was capable of producing 4.612 mg L(-1) of resveratrol from glucose. PMID- 26976852 TI - LMOh7858_0369, a gene encoding a putative leucine-rich repeat-containing protein, is required for virulence of Listeria monocytogenes. AB - Listeria monocytogenes possesses the highest number of leucine-rich repeat (LRR) containing proteins among all Gram-positive bacteria; these LRR-containing molecules are known as the 'internalin' family. To understand the functions of largely uncharacterized LRR-containing molecules, we constructed seven deletion mutants in the L. monocytogenes H7858 strain targeting genes in this family and tested their virulence. Among the seven mutants, the DeltaLMOh7858_0369 strain and the DeltaLMOh7858_2546 strain showed significantly impaired invasiveness of HepG2 cells. We further tested the virulence of these two strains in the intravascular sepsis model using BALB/c mice. Interestingly, the DeltaLMOh7858_0369 strain showed significant reduction in organ colonization, bacteremia and invasion of the brain compared with the parental wild-type strain. Host immune responses to listerial intravascular infection were measured at 24 and 72 h post-infection. Transcript levels of several proinflammatory cytokines and chemokines were significantly lower when induced by the DeltalmOh7858_0369 strain than when induced by the wild type. These results suggest that the putative LRR-containing protein encoded by LMOh7858_0369 might be a novel virulence factor of the L. monocytogenes H7858 strain. PMID- 26976853 TI - Identification and sequence analysis of pWcMBF8-1, a bacteriocin-encoding plasmid from the lactic acid bacterium Weissella confusa. AB - Members of the Gram-positive lactic acid bacteria (LAB) are well-known for their beneficial properties as starter cultures and probiotics. Many LAB species produce ribosomally synthesized proteinaceous antibiotics (bacteriocins). Weissella confusa MBF8-1 is a strain isolated from a fermented soybean product that not only produces useful exopolysaccharides but also exhibits bacteriocin activity, which we call weissellicin MBF. Here, we show that bacteriocin production by W. confusa MBF8-1 is specified by a large plasmid, pWcMBF8-1. Plasmid pWcMBF8-1 (GenBank accession number KR350502), which was identified from the W. confusa MBF8-1 draft genome sequence, is 17 643 bp in length with a G + C content of 34.8% and contains 25 open reading frames (ORFs). Six ORFs constitute the weissellicin MBF locus, encoding three putative double-glycine-motif peptides (Bac1, Bac2, Bac3), an ABC transporter complex (BacTE) and a putative immunity protein (BacI). Two ORFs encode plasmid partitioning and mobilization proteins, suggesting that pWcMBF8-1 is transferable to other hosts. To the best of our knowledge, plasmid pWcMBF8-1 not only represents the first large Weissella plasmid to be sequenced but also the first to be associated with bacteriocin production in W. confusa. PMID- 26976854 TI - Protective role of host aquaporin 6 against Hazara virus, a model for Crimean Congo hemorrhagic fever virus infection. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) is an arthropod-borne pathogen that causes infectious disease with severe hemorrhagic manifestations in vascular system in humans. The proper function of the cells in the vascular system is critically regulated by aquaporins (AQP), water channels that facilitate fluxes of water and small solutes across membranes. With Hazara virus as a model for CCHFV, we investigated the effects of viruses on AQP6 and the impact of AQP6 on virus infectivity in host cells, using transiently expressed GFP-AQP6 cells, immunofluorescent assay for virus detection, epifluorescent imaging of living cells and confocal microscopy. In GFP-AQP6 expressing cells, Hazara virus reduced both the cellular and perinuclear AQP6 distribution and changed the cell area. Infection of human cell with CCHFV strain IbAR 10200 downregulated AQP6 expression at mRNA level. Interestingly, the overexpression of AQP6 in host cells decreased the infectivity of Hazara virus, speaking for a protective role of AQP6. We suggest the possibility for AQP6 being a novel player in the virus-host interactions, which may lead to less severe outcomes of an infection. PMID- 26976856 TI - Tonsillectomy and Incidence of Oropharyngeal Cancers. AB - BACKGROUND: Rising incidence of oropharyngeal cancers in numerous countries since the 1970s has been attributed to increased oral human papillomavirus (HPV) exposure. However, the contribution of coincidental declines in the surgical removal of the tonsils (tonsillectomy) is unknown. We quantified the association of tonsillectomy with risk of tonsillar, other oropharyngeal, and other head and neck cancers and the contribution of declines in tonsillectomies to cancer incidence trends. METHODS: We conducted a nation-wide cohort study in Sweden (1970-2009). Tonsillectomies (N = 225,718) were identified through national patient registers, which were linked with the cancer register. Cancer incidence in the tonsillectomy cohort was compared with Sweden's general population through standardized incidence ratios (SIR). RESULTS: Tonsillectomies were associated with reduced risk of tonsil cancers [SIRs 1+ years post-tonsillectomy = 0.31; 95% confidence interval (CI), 0.08-0.79 and 5+ years post-tonsillectomy = 0.17; 95% CI, 0.02-0.62], but unrelated to other oropharyngeal or other head and neck cancers (SIRs 1+ years post-tonsillectomy = 1.61; 95% CI, 0.77-2.95 and 0.92; 95% CI, 0.64-1.27, respectively). The cumulative incidence of tonsillectomy declined significantly (40%-50%) during 1970-2009. However, tonsil cancer incidence significantly increased during 1970-2009 both without and with corrections for declines in tonsillectomies (relative risks per 5-year periods = 1.23, P < 0.001 and 1.20, P < 0.001, respectively). CONCLUSIONS: The reduced tonsil cancer risk with tonsillectomy reflects the removal of most of the relevant tissue. The absence of associations with other head and neck cancers indicates that tonsillectomy may not impact carcinogenesis at other sites. IMPACT: The significant increases in oropharyngeal cancer incidence since the 1970s in Sweden appear independent of declines in tonsillectomies, reinforcing increased oral HPV exposure as the likely cause. Cancer Epidemiol Biomarkers Prev; 25(6); 944-50. (c)2016 AACR. PMID- 26976857 TI - Overdiagnosis in Mammographic Screening because of Competing Risk of Death. AB - BACKGROUND: Different definitions and estimates of overdiagnosis in mammographic screening reflect a substantial need to investigate and understand the complexity of the issue. This modeling study aims to estimate the number of overdiagnosed women, defined as those diagnosed with breast cancer who die from any cause within the lead-time period. METHODS: We used numbers from incidence and death statistics available online and published estimates of lead-time. Postulated cohorts of screened and not screened women ages 50 to 51 were followed for a period corresponding to 10 biennial screening exams during 20 years, and a further 10 years, to ages 78 to 79. The increase in breast cancer incidence because of screening was estimated based on lead-time. The proportion of women diagnosed with breast cancer who died within the lead-time period was assessed based on the differences in the cumulative number of breast cancer diagnosed in a nonscreened and screened cohort. RESULTS: The proportion of inevitable overdiagnosed women in a screened versus nonscreened cohort was 1.9% for England and Wales and 1.8% for Norway. Sensitivity analyses using various assumptions increased the estimates up to a maximum of 4%. CONCLUSION: The proportion of women with breast cancer diagnosed after participation in a screening program who died within the estimated lead-time period was less than 4%. This inevitable proportion of overdiagnosis should be emphasized in the definition and communication of the issue. IMPACT: The issue of overdiagnosis is complex and estimates should be interpreted with substantial care. Cancer Epidemiol Biomarkers Prev; 25(5); 759-65. (c)2016 AACR. PMID- 26976855 TI - Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors. AB - BACKGROUND: Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene-environment interactions related to hormone-related risk factors could differ between obese and non-obese women. METHODS: We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case-control studies (6,247 cases; 10,379 controls). Histotype specific analyses were also completed. RESULTS: SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 * 10(-6)) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 * 10(-5)). The most notable obesity-gene hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 * 10(-6)). CONCLUSIONS: We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2 Future work is needed to develop powerful statistical methods able to detect these complex interactions. IMPACT: Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780-90. (c)2016 AACR. PMID- 26976858 TI - Adverse Events Lead to Drug Discontinuation More Commonly among Patients Who Receive Nafcillin than among Those Who Receive Oxacillin. AB - Nafcillin and oxacillin are used interchangeably in clinical practice, yet few studies have evaluated the safety of these two agents. Our objective was to compare the differential tolerabilities of nafcillin and oxacillin among hospitalized patients. We conducted a retrospective cohort study of all patients who received 12 g/day of nafcillin or oxacillin for at least 24 h. Two hundred twenty-four patients were included. Baseline characteristics and comorbidities were similar among patients receiving nafcillin (n = 160) and those receiving oxacillin (n = 64). Hypokalemia, defined as a potassium level of <=3.3 mmol/liter or <=2.9 mmol/liter or as a >=0.5-mmol/liter decrease from the baseline level, occurred more frequently among patients who received nafcillin (51%, 20%, and 56%, respectively) than among those who received oxacillin (17%, 3%, and 34%, respectively; P < 0.0001, P = 0.0008, and P = 0.005, respectively). By multivariate logistic regression analysis, receipt of nafcillin was an independent predictor of severe hypokalemia (odds ratio [OR] = 6.74; 95% confidence interval [CI], 1.46 to 31.2; P = 0.02). Rates of hepatotoxicity did not differ between groups; however, acute kidney injury occurred more commonly with nafcillin than with oxacillin (18% versus 6%; P = 0.03). Overall, 18% of patients who received nafcillin discontinued therapy prematurely due to adverse events, compared to 2% of patients who received oxacillin (P = 0.0004). Nafcillin treatment is associated with higher rates of adverse events and treatment discontinuation than oxacillin among hospitalized adult patients. These findings have important implications for patients in both inpatient and outpatient settings, particularly patients who require long-term therapy and cannot be monitored routinely. Future randomized controlled studies evaluating the efficacy, costs, and tolerability of nafcillin versus oxacillin are warranted. PMID- 26976859 TI - VIM-47, a New Variant of the Autochthonous Metallo-beta-Lactamase VIM-13 from the Balearic Islands in Spain. PMID- 26976860 TI - Rapid Whole-Cell Assay of Antitubercular Drugs Using Second-Generation Fluoromycobacteriophages. PMID- 26976861 TI - A Polymorphism in leuS Confers Reduced Susceptibility to GSK2251052 in a Clinical Isolate of Staphylococcus aureus. AB - GSK2251052 is a broad-spectrum antibacterial inhibitor of leucyl tRNA-synthetase (LeuRS) that has been evaluated in phase II clinical trials. Here, we report the identification of a clinical isolate of Staphylococcus aureus that exhibits reduced susceptibility to GSK2251052 without prior exposure to the compound and demonstrate that this phenotype is attributable to a single amino acid polymorphism (P329) within the editing domain of LeuRS. PMID- 26976862 TI - Evaluation of the In Vitro Activity of Ceftazidime-Avibactam and Ceftolozane Tazobactam against Meropenem-Resistant Pseudomonas aeruginosa Isolates. AB - We compared ceftazidime-avibactam, ceftolozane-tazobactam, ceftazidime, cefepime, and piperacillin-tazobactam MICs for 38 meropenem-resistant Pseudomonas aeruginosa isolates. No isolates harbored carbapenemases; 74% were oprD mutants. Ceftazidime-avibactam and ceftolozane-tazobactam were active against 92% of the isolates, including 80% that were resistant to all three beta-lactams. Forty three percent of ceftazidime-avibactam-susceptible isolates and 6% of ceftolozane tazobactam-susceptible isolates exhibited MICs at the respective breakpoints. Ceftolozane-tazobactam and ceftazidime-avibactam are therapeutic options for meropenem-resistant P. aeruginosa infections that should be used judiciously to preserve activity. PMID- 26976863 TI - In Vitro Screening of the Open-Source Medicines for Malaria Venture Malaria Box Reveals Novel Compounds with Profound Activities against Theileria annulata Schizonts. AB - Intracellular schizonts of the apicomplexans Theileria annulata and Theileria parva immortalize bovine leukocytes and thereby cause fatal diseases. The hydroxynaphthoquinone buparvaquone is currently the only option for the treatment of theileriosis, and resistance development has been reported. It is therefore tempting to investigate the repurposing of compounds effective against related apicomplexan parasites, such as Plasmodium Here, we present the results of a screen of 400 compounds included in the open-access Medicines for Malaria Venture (MMV) malaria box on TaC12 cells, a macrophage-derived cell line immortalized by T. annulata schizonts. Using a combination of the classical alamarBlue vitality assay and a recently developed quantitative reverse transcriptase real-time PCR method based on the Theileria TaSP gene, we have identified 5 compounds, characterized their effects on the ultrastructure of TaC12 cells, and investigated whether they easily induce resistance formation. Two compounds, the quinolinols MMV666022 and MMV666054, have 50% inhibitory concentrations (IC50s) of 0.5 and 0.2 MUM on TaC12 cells and 5.3 and 5.2 MUM on BoMac cells, respectively. Thus, with therapeutic indexes of 11 and 18, they represent promising leads for further development of antitheilerial chemotherapeutics. PMID- 26976864 TI - Characterization of an IncA/C Multidrug Resistance Plasmid in Vibrio alginolyticus. AB - Cephalosporin-resistant Vibrio alginolyticus was first isolated from food products, with beta-lactamases encoded by blaPER-1, blaVEB-1, and blaCMY-2 being the major mechanisms mediating their cephalosporin resistance. The complete sequence of a multidrug resistance plasmid, pVAS3-1, harboring the blaCMY-2 and qnrVC4 genes was decoded in this study. Its backbone exhibited genetic homology to known IncA/C plasmids recoverable from members of the family Enterobacteriaceae, suggesting its possible origin in Enterobacteriaceae. PMID- 26976865 TI - First Detection of the mcr-1 Colistin Resistance Gene in Escherichia coli in Italy. PMID- 26976866 TI - Acquisition of Extended-Spectrum beta-Lactamases by Escherichia coli and Klebsiella pneumoniae in Gut Microbiota of Pilgrims during the Hajj Pilgrimage of 2013. AB - We reported the acquisition of extended-spectrum-beta-lactamase (ESBL)-producing bacteria in rectal samples of 129 pilgrims during the 2013 Hajj (pilgrimage to Makkah). When returning from the Hajj, there was a significant increase in the number of pilgrims carrying E. coli resistant to ceftriaxone (P = 0.008). The CTX M gene was detected in rectal samples, with the detection rate increasing from 10.08% to 32.56% of samples after the Hajj (P < 0.001). PMID- 26976867 TI - Inactivation of Lytic Transglycosylases Increases Susceptibility to Aminoglycosides and Macrolides by Altering the Outer Membrane Permeability of Stenotrophomonas maltophilia. AB - Stenotrophomonas maltophilia harbors six lytic transglycosylases (LTs): mltA, mltB1, mltB2, mltD1, mltD2, and slt LT deletion increased susceptibility of S. maltophilia to aminoglycosides (AGs) and macrolides, and the underlying mechanisms were investigated. The expression of AG-modifying enzymes and efflux pumps was evaluated by quantitative reverse transcription-PCR (qRT-PCR). Susceptibility to 1-N-phenylnaphthylamine, vancomycin, SDS, and bile salts was measured to assess outer membrane permeability. In conclusion, increased outer membrane permeability contributes to LT deletion-mediated increase in aminoglycoside and macrolide susceptibility. PMID- 26976868 TI - MIC of Delamanid (OPC-67683) against Mycobacterium tuberculosis Clinical Isolates and a Proposed Critical Concentration. AB - The increasing global burden of multidrug-resistant tuberculosis (MDR-TB) requires reliable drug susceptibility testing that accurately characterizes susceptibility and resistance of pathogenic bacteria to effectively treat patients with this deadly disease. Delamanid is an anti-TB agent first approved in the European Union in 2014 for the treatment of pulmonary MDR-TB in adults. Using the agar proportion method, delamanid MIC was determined for 460 isolates: 316 from patients enrolled in a phase 2 global clinical trial, 76 from two phase 2 early bactericidal activity trials conducted in South Africa, and 68 isolates obtained outside clinical trials (45 from Japanese patients and 23 from South African patients). With the exception of two isolates, MICs ranged from 0.001 to 0.05 MUg/ml, resulting in an MIC50 of 0.004 MUg/ml and an MIC90 of 0.012 MUg/ml. Various degrees of resistance to other anti-TB drugs did not affect the distribution of MICs, nor did origin of isolates from regions/countries other than South Africa. A critical concentration/breakpoint of 0.2 MUg/ml can be used to define susceptible and resistant isolates based on the distribution of MICs and available pharmacokinetic data. Thus, clinical isolates from delamanid-naive patients with tuberculosis have a very low MIC for delamanid and baseline resistance is rare, demonstrating the potential potency of delamanid and supporting its use in an optimized background treatment regimen for MDR-TB. PMID- 26976869 TI - Characterization of 22 Antituberculosis Drugs for Inhibitory Interaction Potential on Organic Anionic Transporter Polypeptide (OATP)-Mediated Uptake. AB - We investigated the inhibitory interaction potential of 22 currently marketed antituberculosis (TB) drugs on organic anion-transporting polypeptide 1B1 (OATP1B1)-, OATP2B1-, and OATP1B3-mediated uptake using in vitro Xenopus oocytes and HEK cells. Rifabutin, ethambutol, amoxicillin, linezolid, p-amino salicylic acid, and rifapentine exhibited mild to moderate inhibitory effects on OATP mediated uptake of estrone-3 sulfate, estradiol 17beta-d-glucuronide, and rosuvastatin. The 50% inhibitory concentration (IC50) values of rifabutin, amoxicillin, ethambutol, p-amino salicylic acid, and linezolid were 35.4, 36.2, 57.6, 72.6, and 65.9 MUM, respectively, for uptake mediated by organic anionic transporter polypeptide 1B1 (OATP1B1) and 28.8, 28.9, 53.9, 31.5, and 61.0 MUM, respectively, for uptake mediated by organic anionic transporter polypeptide 1B3 (OATP1B3). Streptomycin and linezolid showed greater inhibition of organic anionic transporter polypeptide 2B1 (OATP2B1)-mediated uptake, with IC50 values of 33.2 and 35.6 MUM, respectively, along with mild inhibition of other drugs. Furthermore, rifabutin, amoxicillin, and rifapentine significantly inhibited OATP1B1-mediated rosuvastatin uptake, with IC50 values of 12.3, 13.0, and 11.0 MUM, respectively, which showed a similar profile to estrone-3 sulfate uptake. The calculated R values ([I]u inlet,max/Ki, where [I]u inlet,max represents the maximum estimated inhibitor concentration inlet to the liver and Ki is the inhibition constant) as the drug-drug interaction (DDI) indexes of PAS, ethambutol, and amoxicillin were 26.1, 6.5, and 4.3 for OATP1B1 and 52.0, 8.0, and 4.6 for OATP1B3, and those for streptomycin, amikacin, and linezolid were 5.0, 4.2, and 4.4 for OATP2B1, respectively, suggesting a higher possibility of in vivo DDIs. This study is the first comprehensive report to show the novel inhibitory potential of 22 marketed anti-TB drugs on OATP-mediated uptake, providing evidence for future in vivo clinical DDI studies. PMID- 26976870 TI - Effect of Surotomycin, a Novel Cyclic Lipopeptide Antibiotic, on Intestinal Colonization with Vancomycin-Resistant Enterococci and Klebsiella pneumoniae in Mice. AB - Surotomycin (formerly called CB-183,315) is a novel, orally administered cyclic lipopeptide antibacterial in development for the treatment of Clostridium difficile infection (CDI) that has potent activity against vancomycin-resistant enterococci (VRE) but limited activity against Gram-negative bacilli, including Bacteroides spp. We used a mouse model to investigate the impact of surotomycin exposure on the microbiome, and to test the consequences of the disruption on colonization by vancomycin-resistant enterococci (VRE) and extended-spectrum beta lactamase-producing Klebsiella pneumoniae (ESBL-KP), in comparison with the effects of oral vancomycin and metronidazole. Mice (8 per group) received saline, vancomycin, metronidazole, or surotomycin through an orogastric tube daily for 5 days and were challenged with 10(5) CFU of VRE or ESBL-KP administered through an orogastric tube on day 2 of treatment. The concentrations of the pathogens in stool were determined during and after treatment by plating on selective media. A second experiment was conducted to determine if the antibiotics would inhibit established VRE colonization. In comparison to controls, oral vancomycin promoted VRE and ESBL-KP overgrowth in stool (8 log10 to 10 log10 CFU/g; P < 0.001), whereas metronidazole did not (<4 log10 CFU/g; P > 0.5). Surotomycin promoted ESBL-KP overgrowth (>8 log10 CFU/g; P, <0.001 for comparison with saline controls) but not VRE overgrowth. Surotomycin suppressed preexisting VRE colonization, whereas metronidazole and vancomycin did not. These results suggest that treatment of CDI with surotomycin could reduce levels of VRE acquisition and overgrowth from those with agents such as vancomycin and metronidazole. However, surotomycin and vancomycin may promote colonization by antibiotic-resistant Gram negative bacilli. PMID- 26976871 TI - Urinary Concentrations and Antibacterial Activity of BAL30072, a Novel Siderophore Monosulfactam, against Uropathogens after Intravenous Administration in Healthy Subjects. AB - This annex study to a phase 1 study aimed to correlate urinary concentrations and bactericidal titers (UBTs) of BAL30072, a novel siderophore monosulfactam, in healthy subjects in order to evaluate which dosage of BAL30072 should be investigated in a clinical study on complicated urinary tract infection (UTI). Three cohorts of a total of 19 healthy male subjects were included in the add-on study and received the following BAL30072 dosages. The 1st cohort received 1 g once a day (q.d.) intravenously (i.v.) (1 h) on day 1 and 1 g thrice daily (t.i.d.) on day 2, the 2nd cohort received 2 g q.d. i.v. (1 h) on day 1 and 2 g t.i.d. on day 2, and the 3rd cohort received 1 g q.d. i.v. (4-h infusion) on day 8. Urine was collected up to 24 h after drug administration. UBTs were determined for seven Escherichia coli isolates (three wild type [WT], CTX-M-15, TEM-3, TEM 5, NDM-1), two Klebsiella pneumoniae isolates (WT, KPC), one Proteus mirabilis isolate (WT), and two Pseudomonas aeruginosa isolates (WT, VIM-1 plus AmpC). Urine drug concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The median urinary excretions of BAL30072 ranged between 38% and 46% (3 cohorts). The median UBTs after i.v. administration of 1 or 2 g q.d. and after 1 or 2 g t.i.d. showed positive UBTs for 24 h after the lowest dosage (1 g q.d.) for 5 of 7 of the Enterobacteriaceae strains and after the higher dosage of 2 g administered i.v. t.i.d. for all strains tested. After i.v. infusion of 1 g over 4 h, positive UBTs were demonstrated for three E. coli strains for up to 12 h, for the K. pneumoniae (KPC) strain for up to 8 h, and for the P. aeruginosa (VIM-1 plus AmpC) strain for up to only 4 h. The minimal bactericidal concentrations (MBCs) of the E. coli (NDM-1) strain and the K. pneumoniae (WT) strain correlated well between broth and urine but did not correlate well for the two P. aeruginosa strains. BAL30072 exhibits positive UBTs for 24 h even after a dosage of 1 g administered i.v. q.d. for 5 of 7 Enterobacteriaceae strains and after 2 g administered i.v. t.i.d. for all strains except one P. aeruginosa strain (50% of the time). In general, the UBTs correlated well with the MICs of the Enterobacteriaceae but were lower for P. aeruginosa The clinical efficacy with a dosage regimen of BAL30072 of 2 g administered i.v. t.i.d. should be evaluated in the treatment of complicated UTI. PMID- 26976873 TI - In Vitro Activity of Delafloxacin against Clinical Neisseria gonorrhoeae Isolates and Selection of Gonococcal Delafloxacin Resistance. AB - We evaluated the in vitro activity of delafloxacin against a panel of 117 Neisseria gonorrhoeae strains, including 110 clinical isolates collected from 2012 to 2015 and seven reference strains, compared with the activities of seven antimicrobials currently or previously recommended for treatment of gonorrhea. We examined the potential for delafloxacin to select for resistant mutants in ciprofloxacin-susceptible and ciprofloxacin-resistant N. gonorrhoeae We characterized mutations in the gyrA, gyrB, parC, and parE genes and the multidrug resistant efflux pumps (MtrC-MtrD-MtrE and NorM) by PCR and sequencing and by whole-genome sequencing. The MIC50, MIC90, and MIC ranges of delafloxacin were 0.06 MUg/ml, 0.125 MUg/ml, and <=0.001 to 0.25 MUg/ml, respectively. The frequency of spontaneous mutation ranged from 10(-7) to <10(-9) The multistep delafloxacin resistance selection of 30 daily passages resulted in stable resistant mutants. There was no obvious cross-resistance to nonfluoroquinolone comparator antimicrobials. A mutant with reduced susceptibility to ciprofloxacin (MIC, 0.25 MUg/ml) obtained from the ciprofloxacin-susceptible parental strain had a novel Ser91Tyr alteration in the gyrA gene. We also identified new mutations in the gyrA and/or parC and parE genes and the multidrug-resistant efflux pumps (MtrC-MtrD-MtrE and NorM) of two mutant strains with elevated delafloxacin MICs of 1 MUg/ml. Although delafloxacin exhibited potent in vitro activity against N. gonorrhoeae isolates and reference strains with diverse antimicrobial resistance profiles and demonstrated a low tendency to select for spontaneous mutants, it is important to establish the correlation between these excellent in vitro data and treatment outcomes through appropriate randomized controlled clinical trials. PMID- 26976872 TI - Propensity Score Analysis of the Role of Initial Antifungal Therapy in the Outcome of Candida glabrata Bloodstream Infections. AB - Candida glabrata isolates have reduced in vitro susceptibility to azoles, which raises concerns about the clinical effectiveness of fluconazole for treating bloodstream infection (BSI) by this Candida species. We aimed to evaluate whether the choice of initial antifungal treatment (fluconazole versus echinocandins or liposomal amphotericin B [L-AmB]-based regimens) has an impact on the outcome of C. glabrata BSI. We analyzed data from a prospective, multicenter, population based surveillance program on candidemia conducted in 5 metropolitan areas of Spain (May 2010 to April 2011). Adult patients with an episode of C. glabrata BSI were included. The main outcomes were 14-day mortality and treatment failure (14 day mortality and/or persistent C. glabrata BSI for >=48 h despite antifungal initiation). The impact of using fluconazole as initial antifungal treatment on the patients' prognosis was assessed by logistic regression analysis with the addition of a propensity score approach. A total of 94 patients with C. glabrata BSI were identified. Of these, 34 had received fluconazole and 35 had received an echinocandin/L-AmB-based regimen. Patients in the echinocandin/L-AmB group had poorer baseline clinical status than did those in the fluconazole group. Patients in the fluconazole group were more frequently (55.9% versus 28.6%) and much earlier (median time, 3 versus 7 days) switched to another antifungal regimen. Overall, 14-day mortality was 13% (9/69) and treatment failure 34.8% (24/69), with no significant differences between the groups. On multivariate analysis, after adjusting for baseline characteristics by propensity score, fluconazole use was not associated with an unfavorable evolution (adjusted odds ratio [OR] for 14 day mortality, 1.16, with 95% confidence interval [CI] of 0.22 to 6.17; adjusted OR for treatment failure, 0.83, with 95% CI of 0.27 to 2.61). In conclusion, initial fluconazole treatment was not associated with a poorer outcome than that obtained with echinocandins/L-AmB regimens in patients with C. glabrata BSI. (This study has been registered at ClinicalTrials.gov under registration no. NCT01236261.). PMID- 26976874 TI - In Vitro Interactions between Target of Rapamycin Kinase Inhibitor and Antifungal Agents against Aspergillus Species. AB - In vitro interactions of INK128, a target of rapamycin (TOR) kinase inhibitor, and antifungals, including itraconazole, voriconazole, posaconazole, amphotericin B, and caspofungin, against Aspergillus spp. were assessed with the broth microdilution checkerboard technique. Our results suggested synergistic effects between INK128 and all azoles tested, against multiple Aspergillus fumigatus and Aspergillus flavus isolates. However, no synergistic effects were observed when INK128 was combined with amphotericin B or caspofungin. No antagonism was observed for any combination. PMID- 26976876 TI - Emergence of the Plasmid-Mediated mcr-1 Gene in Colistin-Resistant Enterobacter aerogenes and Enterobacter cloacae. PMID- 26976875 TI - In Vitro Activity of Quaternary Ammonium Surfactants against Streptococcal, Chlamydial, and Gonococcal Infective Agents. AB - Quaternary ammonium compounds (QAC) are widely used, cheap, and chemically stable disinfectants and topical antiseptics with wide-spectrum antimicrobial activities. Within this group of compounds, we recently showed that there are significant differences between the pharmacodynamics of n-alkyl quaternary ammonium surfactants (QAS) with a short (C12) alkyl chain when in vitro toxicities toward bacterial and mammalian epithelial cells are compared. These differences result in an attractive therapeutic window that justifies studying short-chain QAS as prophylactics for sexually transmitted infections (STI) and perinatal vertically transmitted urogenital infections (UGI). We have evaluated the antimicrobial activities of short-chain (C12) n-alkyl QAS against several STI and UGI pathogens as well as against commensal Lactobacillus species. Inhibition of infection of HeLa cells by Neisseria gonorrhoeae and Chlamydia trachomatis was studied at concentrations that were not toxic to the HeLa cells. We show that the pathogenic bacteria are much more susceptible to QAS toxic effects than the commensal vaginal flora and that QAS significantly attenuate the infectivity of N. gonorrhoeae and C. trachomatis without affecting the viability of epithelial cells of the vaginal mucosa. N-Dodecylpyridinium bromide (C12PB) was found to be the most effective QAS. Our results strongly suggest that short-chain (C12) n alkyl pyridinium bromides and structurally similar compounds are promising microbicide candidates for topical application in the prophylaxis of STI and perinatal vertical transmission of UGI. PMID- 26976877 TI - Outcomes According to Cardiac Catheterization Referral and Clopidogrel Use Among Medicare Patients With Non-ST-Segment Elevation Myocardial Infarction Discharged Without In-hospital Revascularization. AB - BACKGROUND: While use of P2Y12 receptor inhibitor is recommended by guidelines, few studies have examined its effectiveness among older non-ST-segment elevation myocardial infarction patients who did not undergo coronary revascularization. METHODS AND RESULTS: We included unrevascularized non-ST-segment elevation myocardial infarction patients >=65 years discharged home from 463 ACTION Registry-GWTG hospitals from 2007 to 2010. Rates of discharge clopidogrel use were described for patients with no angiography, angiography without obstructive coronary artery disease (CAD; >=50% stenosis in >=1 vessel), and angiography with obstructive CAD. Two-year outcomes were ascertained from linked Medicare data and included composite major adverse cardiac events (defined as all-cause death, myocardial infarction readmission, or revascularization), and individual components. Outcomes associated with clopidogrel use were adjusted using inverse probability-weighted propensity modeling. Of 14 154 unrevascularized patients, 54.7% (n=7745) did not undergo angiography, 10.6% (n=1494) had angiography without CAD, and 34.7% (n=4915) had angiography with CAD. Discharge clopidogrel was prescribed for 42.2% of all unrevascularized patients: 37.8% without angiography, 34.1% without obstructive CAD at angiography, and 51.6% with obstructive CAD at angiography. Discharge clopidogrel use was not associated with major adverse cardiac events in any group: without angiography (adjusted hazard ratio [95% CI]: 0.99 [0.93-1.06]), angiography without CAD (1.04 [0.74-1.47]), and angiography with CAD (1.12 [1.00-1.25], Pinteraction=0.20). CONCLUSIONS: We found no association between discharge clopidogrel use and long-term risk of major adverse cardiac events among older, unrevascularized non-ST-segment elevation myocardial infarction patients. Clopidogrel use in this population requires further prospective evaluation. PMID- 26976878 TI - Progression of Electrocardiographic Abnormalities in Type 1 Diabetes During 16 Years of Follow-up: The Epidemiology of Diabetes Interventions and Complications (EDIC) Study. AB - BACKGROUND: The electrocardiogram (ECG) is an objective tool for cardiovascular disease (CVD) risk assessment. METHODS AND RESULTS: We evaluated distribution of ECG abnormalities and risk factors for developing new abnormalities in 1314 patients with type 1 diabetes (T1D) from the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Annual ECGs were centrally read. ECG abnormalities were classified as major and minor according to the Minnesota ECG Classification. At EDIC year 1 (baseline), 356 (27.1%) of the participants had at least 1 ECG abnormality (major or minor) whereas 26 (2%) had at least one major abnormality. During 16 years of follow-up, 1016 (77.3%) participants developed at least 1 new ECG abnormality (major or minor), whereas 172 (13.1%) developed at least 1 new major abnormality. Independent risk factors for developing new major ECG abnormalities were: age, current smoking, increased systolic blood pressure, and higher glycosylated hemoglobin (hazard ratio [HR] [95% CI]: 1.04 [1.02-1.06] per 1-year increase, 1.75 [1.22-2.53], 1.03 [1.01 1.05] per 1 mm Hg increase, and 1.16 [1.04-1.29] per 10% increase, respectively). Independent risk factors for developing any new ECG abnormalities (major or minor) were age and systolic blood pressure (HR [95% CI]: 1.02 [1.01-1.03] per 1 year increase and 1.01 [1.00-1.02] per 1 mm Hg increase, respectively). CONCLUSIONS: New ECG abnormalities commonly occur in the course of T1D, consistent with the recognized increasing risk for CVD as patients age. Advanced age, increased systolic blood pressure, smoking, and higher HbA1c are independent risk factor for developing major ECG abnormalities, which underscores the importance of tight glucose control in T1D in addition to management of common CVD risk factors. PMID- 26976879 TI - Altered Cardiomyocyte Function and Trypanosoma cruzi Persistence in Chagas Disease. AB - Chagas disease, caused by the triatominae Trypanosoma cruzi, is one of the leading causes of heart malfunctioning in Latin America. The cardiac phenotype is observed in 20-30% of infected people 10-40 years after their primary infection. The cardiac complications during Chagas disease range from cardiac arrhythmias to heart failure, with important involvement of the right ventricle. Interestingly, no studies have evaluated the electrical properties of right ventricle myocytes during Chagas disease and correlated them to parasite persistence. Taking advantage of a murine model of Chagas disease, we studied the histological and electrical properties of right ventricle in acute (30 days postinfection [dpi]) and chronic phases (90 dpi) of infected mice with the Colombian strain of T. cruzi and their correlation to parasite persistence. We observed an increase in collagen deposition and inflammatory infiltrate at both 30 and 90 dpi. Furthermore, using reverse transcriptase polymerase chain reaction, we detected parasites at 90 dpi in right and left ventricles. In addition, we observed action potential prolongation and reduced transient outward K(+) current and L-type Ca(2+) current at 30 and 90 dpi. Taking together, our results demonstrate that T. cruzi infection leads to important modifications in electrical properties associated with inflammatory infiltrate and parasite persistence in mice right ventricle, suggesting a causal role between inflammation, parasite persistence, and altered cardiomyocyte function in Chagas disease. Thus, arrhythmias observed in Chagas disease may be partially related to altered electrical function in right ventricle. PMID- 26976880 TI - Disseminated Histoplasmosis with Skin Lesions and Osteomyelitis in a Patient from the Philippines. AB - Histoplasmosis, caused by the dimorphic fungus Histoplasma capsulatum, is a disease of protean manifestations and of global distribution. Although increasingly reported in Asia, there are few reports from the Philippines. Here, we describe a case of microbiologically diagnosed histoplasmosis, probably acquired from the Philippines, in a returning traveler who presented with a right foot wound and papular rash. The final diagnosis was disseminated histoplasmosis with cutaneous and bone involvement, both unusual manifestations of the disease. PMID- 26976882 TI - Spatial-Temporal Co-Circulation of Dengue Virus 1, 2, 3, and 4 Associated with Coinfection Cases in a Hyperendemic Area of Brazil: A 4-Week Survey. AB - Dengue is currently regarded as a major public health problem worldwide. In a hyperendemic region during an outbreak, we detected the co-circulation of all Dengue virus (DENV) serotypes including two different genotypes of DENV-3 and DENV-4, and concurrent infections with up to three serotypes were identified in symptomatic patients. A total of 49 acute phase plasma samples from patients clinically suspected of dengue were collected during the 4 weeks of May 2013. DENV-1-4 was detected by reverse transcriptase semi-nested polymerase chain reaction in 33 samples (67.3%), of which 26 DNA fragments were sequenced. Twenty samples (76.9%) were identified with a single DENV serotype and six (23.1%) with more than one serotype. DENV-3 was the predominant serotype of the outbreak. On the basis of phylogenetic analyses, DENV-1 isolates belong to genotype V, DENV-2 to American-Asian genotype, DENV-3 to genotypes I and III, and DENV-4 to genotypes I and II. PMID- 26976881 TI - Bacteriology of Naja atra Snakebite Wound and Its Implications for Antibiotic Therapy. AB - A total of 112 cases of Naja atra envenomation were examined at two referring hospitals: Taichung Veterans General Hospital in central Taiwan and Taipei Veterans General Hospital (VGH-TP) in northern Taiwan. Overall, 77% (86/112) of cases developed clinically suspected wound infections and 54% (61/112) required surgery secondary to tissue necrosis, finger or toe gangrene, and/or necrotizing fasciitis. Morganella morganii was the most abundant gram-negative bacterial strain isolated from bite wounds, followed by Proteus spp., Aeromonas hydrophila, Pseudomonas aeruginosa, and Providencia spp. in descending order; Enterococcus spp. were the most common gram-positive bacteria and Bacteroides spp. were the only anaerobic bacteria. A few episodes of bacteremia were caused by Bacteroides and Shewanella spp. There were no significant variations in the distribution of bacterial species between these two hospitals except for a higher incidence of M. morganii, Enterococcus spp., and polymicrobial infection observed at VGH-TP, which may have been related to variations in the fecal flora of prey and oral flora of individual snakes in different geographic areas in Taiwan. According to the susceptibility test involving various pathogens, first-line drug options for the management of N. atra snakebite wound infections may include monotherapy with ureidopenicillin or combination therapy with aminopenicillin and a third generation cephalosporin or fluoroquinolone. A prospective evaluation of empiric antibiotic therapy for the management of N. atra snakebite should be considered. PMID- 26976883 TI - Perceived Quality of Care of Community Health Worker and Facility-Based Health Worker Management of Pneumonia in Children Under 5 Years in Western Kenya: A Cross-Sectional Multidimensional Study. AB - Integrated community case management (iCCM) programs that train lay community health workers (CHWs) in the diagnosis and treatment of diarrhea, malaria, and pneumonia have been increasingly adopted throughout sub-Saharan Africa to provide services in areas where accessibility to formal public sector health services is low. One important aspect of successful iCCM programs is the acceptability and utilization of services provided by CHWs. To understand community perceptions of the quality of care in an iCCM intervention in western Kenya, we used the Primary Care Assessment Survey to compare caregiver attitudes about the diagnosis and treatment of childhood pneumonia as provided by CHWs and facility-based health workers (FBHWs). Overall, caregivers rated CHWs more highly than FBHWs across a set of 10 domains that capture multiple dimensions of the care process. Caregivers perceived CHWs to provide higher quality care in terms of accessibility and patient relationship and equal quality care on clinical aspects. These results argue for the continued implementation and scale-up of iCCM programs as an acceptable intervention for increasing access to treatment of childhood pneumonia. PMID- 26976884 TI - Differences in Liver Impairment Between Adults and Children with Dengue Infection. AB - Dengue infection (DI) is a major vector-borne disease in southeast Asia and an important cause of morbidity. The complications such as hepatic impairment are common, and because the physiology of the liver differs between children and adults, the DI-associated liver impairments might be expected to differ as well. This study aims to compare the differences in liver impairment between adults and children with DI. We retrospectively studied 158 adults and 79 children with serologically confirmed DI admitted to the Bangkok Hospital for Tropical Diseases from 2008 to 2012. In total, 93% of adults and 87% of children exhibited abnormal liver enzyme levels during hospitalization. Overall, 76 (42.4%) adults and 16 (20.3%) children had dengue hemorrhagic fever (DHF). Compared with children, adults with dengue fever (DF) presented a significantly higher incidence of liver function impairment (alanine transaminase [ALT] > 2 * upper limit of normal [ULN]) (47.1% versus 25.5%), hepatitis (ALT > 4 * ULN) (29.4% versus 12.8%), and severe hepatitis (aspartate transaminase [AST]/ALT > 10 * ULN) (16.5% versus 4.3%). Children with DHF showed a significantly higher incidence of liver function impairment due to AST derangement than did adults (100% versus 73%). There were no differences in the total bilirubin, albumin, or total protein levels between adults and children. Liver enzymes normalized significantly more slowly in adults, and AST recovery was faster than ALT. In conclusion, liver function impairment was more common among adults than children with DF. As the severity progressed to DHF, liver injury became more common in children. PMID- 26976885 TI - Persistent Symptoms of Dengue: Estimates of the Incremental Disease and Economic Burden in Mexico. AB - Dengue is mostly considered an acute illness with three phases: febrile, critical with possible hemorrhagic manifestations, and recovery. But some patients present persistent symptoms, including fatigue and depression, as acknowledged by the World Health Organization. If persistent symptoms affect a non-negligible share of patients, the burden of dengue will be underestimated. On the basis of a systematic literature review and econometric modeling, we found a significant relationship between the share of patients reporting persisting symptoms and time. We updated estimates of the economic burden of dengue in Mexico, addressing uncertainty in productivity loss and incremental expenses using Monte Carlo simulations. Persistent symptoms represent annually about US$22.6 (95% certainty level [CL]: US$13-US$29) million in incremental costs and 28.2 (95% CL: 21.6 36.2) additional disability-adjusted life years per million population, or 13% and 43% increases over previous estimates, respectively. Although our estimates have uncertainty from limited data, they show a substantial, unmeasured burden. Similar patterns likely extend to other dengue-endemic countries. PMID- 26976886 TI - Chronic Chagas Disease Diagnosis: A Comparative Performance of Commercial Enzyme Immunoassay Tests. AB - There is a significant heterogeneity in reported performance of serological assays for Chagas disease diagnosis. The conventional serology testing in laboratory diagnosis and in blood banks is unsatisfactory because of a high number of inconclusive and misclassified results. We aimed to assess the quality of four commercially available enzyme-linked immunosorbent assay tests for their ability to detect Trypanosoma cruzi antibodies in 685 sera samples. Cross reactivity was assessed by using 748 sera from patients with unrelated diseases. Initially, we found that the reactivity index against T. cruzi antigen was statistically higher in sera from Chagas disease patients compared with those from non-chagasic patients, supporting the notion that all evaluated tests have a good discriminatory ability toward the diagnosis of T. cruzi infection in patients in the chronic phase of the disease. Although all tests were similarly sensitive for diagnosing T. cruzi infection, there were significant variations in terms of specificity and cross-reactivity among them. Indeed, we obtained divergent results when testing sera from patient with unrelated diseases, particularly leishmaniasis, with the levels of cross-reactivity being higher in tests using whole T. cruzi extracts compared with those using recombinant proteins. Our data suggest that all four tests may be used for the laboratory diagnosis and routine blood screening diagnose for Chagas disease. We also emphasize that, despite their general good performance, caution is needed when analyzing the results when these tests are performed in areas where other diseases, particularly leishmaniasis, are endemic. PMID- 26976887 TI - Evaluation of Commercially Available Chikungunya Virus Immunoglobulin M Detection Assays. AB - Commercial chikungunya virus (CHIKV)-specific IgM detection kits were evaluated at the Centers for Disease Control and Prevention (CDC), the Public Health Agency of Canada National Microbiology Laboratory, and the Caribbean Public Health Agency (CARPHA). The Euroimmun Anti-CHIKV IgM ELISA kit had >= 95% concordance with all three reference laboratory results. The limit of detection for low CHIK IgM+ samples, as measured by serial dilution of seven sera up to 1:12,800 ranged from 1:800 to 1:3,200. The Euroimmun IIFT kit evaluated at CDC and CARPHA performed well, but required more retesting of equivocal results. The InBios CHIKjj Detect MAC-ELISA had 100% and 98% concordance with CDC and CARPHA results, respectively, and had equal sensitivity to the CDC MAC-ELISA to 1:12,800 dilution in serially diluted samples. The Abcam Anti-CHIKV IgM ELISA had high performance at CARPHA, but at CDC, performance was inconsistent between lots. After replacement of the biotinylated IgM antibody controls with serum containing CHIKV specific IgM and additional quality assurance/control measures, the Abcam kit was rereleased and reevaluated at CDC. The reformatted Abcam kit had 97% concordance with CDC results and limit of detection of 1:800 to 1:3,200. Two rapid tests and three other CHIKV MAC-ELISAs evaluated at CDC had low sensitivity, as the CDC CHIKV IgM in-house positive controls were below the level of detection. In conclusion, laboratories have options for CHIKV serological diagnosis using validated commercial kits. PMID- 26976888 TI - Epidemiology of Domestically Acquired Amebiasis in Japan, 2000-2013. AB - Notifications of amebiasis have been increasing in Japan. Using national surveillance data during 2000-2013, reported cases of amebiasis were analyzed. A case of amebiasis was defined as laboratory-confirmed Entamoeba histolytica infection, regardless of presence of symptoms. We described temporal trends and analyzed correlates of asymptomatic versus symptomatic cases based on odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. Of 9,946 cases reported during 2000-2013, 7,403 were domestic cases. During this period, the proportion of domestic cases increased from 63% to 85%. Among male cases, majority were middle aged, and from 2008, the number of cases attributed to heterosexual contact surpassed that of homosexual contact. During 2010-2013, increase in notifications was associated with asymptomatic cases, colonoscopy diagnosis, and males with unknown or heterosexual route of infection. Among males, colonoscopy (OR = 31.5; 95% CI = 14.0-71.0) and cases with unknown route of infection, relative to homosexual contact (OR = 2.2; 95% CI = 1.3-3.9), were associated with asymptomatic infections in multivariate analysis. Although the recent rise may have been due to enhanced detection by colonoscopy or reporting, the large number of asymptomatic cases, with reportedly unknown or heterosexual route of infection, has led to a better understanding of amebiasis in Japan and highlights the potential public health concern. PMID- 26976889 TI - Vitamin D Status in Botswana Children Under 2 Years Old With and Without Active Tuberculosis. AB - Additional strategies are needed to prevent and treat tuberculosis (TB). Although vitamin D may have antimycobacterial effects, it is unknown whether low vitamin D status confers a risk for active TB in African children. This case-control study assessed serum 25-hydroxyvitamin D (25(OH)D) concentration in children with and without active TB in Gaborone, Botswana. A total of 80 children under 2 years old with and without active TB, seen at hospitals and clinics in the greater Gaborone area between September 2010 and November 2012, were enrolled. Of these, 39 cases did not differ from the 41 controls in median 25(OH)D levels (P = 0.84). The 25(OH)D was < 20 ng/mL in 8/39 (21%) cases and 7/41 (17%) controls (P = 0.69, chi(2)). Univariate analyses of subject clinical characteristics (other than 25(OH)D levels) showed that any degree of weight loss was associated with a diagnosis of TB (P = 0.047). Other clinical characteristics, including age (P = 0.08) or weight below third percentile (P = 0.58), showed no association with TB. There was no significant difference in vitamin D status between children under 2 years old with and without active TB. Lower vitamin D status did not appear to be a risk factor for TB in this small Gaborone cohort. PMID- 26976890 TI - Local Production of a Liquid Direct Agglutination Test as a Sustainable Measure for Control of Visceral Leishmaniasis in Sudan. AB - A prerequisite for the control of visceral leishmaniasis (VL) is the accessibility to reference diagnostics. The high price of the freeze-dried direct agglutination test (FD-DAT) and the short shelf-life time of the rK39 strip test (rK39) have limited the application of these tests in Sudan. An original liquid DAT (LQ-DAT) with high reproducibility compared with the FD-DAT and rK39 has been routinely produced in our laboratory since 1999. In this study, a 3.4-year-old batch (of more than 90 test batches produced to date) was chosen to validate the diagnostic performance of this test against microscopy, FD-DAT, and rK39 in 96 VL and 42 non-VL serum samples. Relatively higher sensitivity (95/96, 99.0%) was recorded for the LQ-DAT than for the FD-DAT (92/96, 95.8%) and rK39 (76/96, 79.2%), probably because of the use of the endemic autochthonous Leishmania donovani isolate as the antigen. Experience with the LQ-DAT, its low cost of production, ease of providing this test, and diagnostic reliability compared with the FD-DAT suggest that widescale implementation of the LQ-DAT can contribute to sustainable VL control in Sudan. PMID- 26976891 TI - Chikungunya and Dengue Virus Infections Among United States Community Service Volunteers Returning from the Dominican Republic, 2014. AB - Chikungunya spread throughout the Dominican Republic (DR) after the first identified laboratory-confirmed cases were reported in April 2014. In June 2014, a U.S.-based service organization operating in the DR reported chikungunya-like illnesses among several staff. We assessed the incidence of chikungunya virus (CHIKV) and dengue virus (DENV) infection and illnesses and evaluated adherence to mosquito avoidance measures among volunteers/staff deployed in the DR who returned to the United States during July-August 2014. Investigation participants completed a questionnaire that collected information on demographics, medical history, self-reported illnesses, and mosquito exposures and avoidance behaviors and provided serum for CHIKV and DENV diagnostic testing by reverse transcription polymerase chain reaction and IgM enzyme-linked immunosorbent assay. Of 102 participants, 42 (41%) had evidence of recent CHIKV infection and two (2%) had evidence of recent DENV infection. Of the 41 participants with evidence of recent CHIKV infection only, 39 (95%) reported fever, 37 (90%) reported rash, and 37 (90%) reported joint pain during their assignment. All attended the organization's health trainings, and 89 (87%) sought a pretravel health consultation. Most (~95%) used insect repellent; however, only 30% applied it multiple times daily and < 5% stayed in housing with window/door screens. In sum, CHIKV infections were common among these volunteers during the 2014 chikungunya epidemic in the DR. Despite high levels of preparation, reported adherence to mosquito avoidance measures were inconsistent. Clinicians should discuss chikungunya with travelers visiting areas with ongoing CHIKV outbreaks and should consider chikungunya when diagnosing febrile illnesses in travelers returning from affected areas. PMID- 26976892 TI - Fasciola hepatica Infection in an Indigenous Community of the Peruvian Jungle. AB - Fasciola hepatica is a zoonotic infection with a worldwide distribution. Autochthonous cases have not been reported in the Amazon region of Peru. Operculated eggs resembling F. hepatica were identified in the stools of five out of 215 subjects in a remote indigenous community of the Peruvian jungle. Polymerase chain reaction targeting Fasciola hepatica cytochrome oxidase subunit 1 (COI) gene and sequencing of the products confirmed Fasciola infection. PMID- 26976893 TI - Association Between Schistosoma haematobium Exposure and Human Immunodeficiency Virus Infection Among Females in Mozambique. AB - Recent evidence suggests an association between human immunodeficiency virus (HIV) and female genital schistosomiasis (FGS) in sub-Saharan Africa, especially in Mozambique, South Africa, Tanzania, and Zimbabwe. Women with FGS have increased numbers of HIV target cells and cell receptors in genital and blood compartments, potentially increasing the risk of HIV transmission per sexual exposure, and the association may explain the high female:male ratio of HIV prevalence unique to sub-Saharan Africa. We investigate this association in Mozambique by linking two georeferenced, high-quality secondary data sources on HIV prevalence and Schistosoma haematobium: the AIDS Indicator Survey, and the Global Neglected Tropical Diseases (GNTD) open-source database, respectively. We construct a schistosomiasis exposure covariate indicating women reporting "unimproved" daily drinking water sources and living no more than 2-5 km from high-endemic global positioning system (GPS) coordinates in the GNTD. In logistic regression analyses predicting HIV-positive status, we show that exposure increases the odds of HIV-positive status by three times, controlling for demographic and sexual risk factors. PMID- 26976895 TI - Prevalence of avian respiratory viruses in broiler flocks in Egypt. AB - In this study, respiratory viral pathogens were screened using real-time RT-PCR in 86 broiler chicken flocks suffering from respiratory diseases problems in 4 Egyptian governorates between January 2012 and February 2014. The mortality rates in the investigated flocks ranged from 1 to 47%. Results showed that mixed infection represented 66.3% of the examined flocks. Mixed infectious bronchitis (IBV) and avian influenza (AI)-H9N2 viruses were the most common infection (41.7%). Lack of AI-H9N2 vaccination and high rates of mixed infections in which AI-H9N2 is involved indicate an early AI-H9N2 infection with a potential immunosuppressive effect that predisposes for other viral infections. High pathogenic AI-H5N1 and virulent Newcastle disease virus (vNDV) infections were also detected (26.7% and 8.1%, respectively). Interestingly, co-infection of AI H9N2 with either AIV-H5N1 or vNDV rarely resulted in high mortality. Partial cell mediated immunity against similar internal AI genes, as well as virus interference between AI and vNDV, could be an explanation for this. Highly prevalent IBV and AI-H9N2 were isolated and were molecularly characterized based on S1 gene hypervariable region 3 ( HVR3: ) and hemagglutinin gene (HA) sequences, respectively. IBV strains were related to the variant group of IBV with multiple mutations in HVR3. Though AI-H9N2 viruses showed low rate of evolution in comparison to recent strains, few amino acid substitutions indicative of antibody selection pressure were observed in the HA gene. In conclusion, mixed viral infections, especially with IBV and AI-H9N2 viruses, are the predominant etiology of respiratory disease problems in broiler chickens in Egypt. Further investigations of the role of AI, IBV, and ND viruses' co infections and interference in terms of altering the severity of clinical signs and lesions and/or generating novel reassortants within each virus are needed. PMID- 26976896 TI - Lower expression of sialic acid receptors in the cecum of silky fowl (Gallus gallus domesticus Brisson) compared to white leghorn. AB - Avian influenza virus has received increasing attention in recent years because of the potential for recombination with the human virus. Distributions of sialic acid receptors on target cells are determinants of the susceptibilities of different species to influenza virus infection. In this study, the distribution of sialic acid receptors in the respiratory and gastrointestinal tracts of Silky Fowl and White Leghorn chickens were compared. The results showed that sialic acid-alpha-2,3-galactose receptors and sialic acid-alpha6-galactose receptors were both observed in Silky Fowl and White Leghorn, but fewer positive cells were detected in Silky Fowl with significant difference in the cecum. The lower abundance of sialic acid receptors likely results from the lower abundance of CD3 and F4/80 immune cells in the cecum of Silky Fowl. PMID- 26976897 TI - Energy and nutrient utilization of broiler chickens fed corn-soybean meal and corn-based diets supplemented with xylanase. AB - A study was conducted to evaluate the effects of increased levels of a beta xylanase on energy and nutrient utilization of broiler chickens fed corn-soy diets. A total of 480 slow feathering Cobb * Cobb 500 male broilers were randomly distributed to 10 treatments having 8 replicates of 6 birds each. Birds were fed a common starter diet to d 14 post hatch (3,050 kcal/kg AMEn, 21.7% CP, 1.05% Ca, and 0.53% nPP). The experimental diets were provided afterwards until 25 d. Two experimental diets, a conventional corn/soy-based basal diet (CS) and the basal diet in which 40% of the diet was displaced by corn (CN), were fed as-is or supplemented with 50, 100, 150, or 200 fungal beta-xylanase units (FXU)/kg. Dietary treatments were distributed factorially as a 2 * 5 arrangement. Samples of feed, excreta, and ileal digesta were analyzed for determination of ileal digestible energy (IDE), metabolizable energy, and total tract retention of protein and lipid. No interactions between diet and xylanase were observed. The CS diets had higher (P < 0.05) energy utilization and nutrient digestibility when compared to the CN diets. AMEn and IDE were improved (P < 0.05) by 192 and 145 kcal/kg, respectively, when diets were supplemented with 100 FXU/kg xylanase. The xylanase added to the CN diet led to quadratic increases (P < 0.05) in IDE (Y = - 0.014x(2) + 2.570x + 3,155; r(2) = 0.60) and in AMEn (Y = - 0.016x(2) + 3.982x + 3,155; r(2) = 0.68). Crude protein digestibility and AMEn were linearly increased (P < 0.05) when xylanase was added to the CN diet. In conclusion, energy utilization and digestibility of crude protein and dry matter increased with xylanase supplementation in corn/soy-based diets. When xylanase was tested in the CS diet, 92 and 124 FXU/kg maximized the energy release effect; however, the maximum energy response in the CN diet or corn was not achieved until 200 FXU/kg. PMID- 26976898 TI - Estimating local, organic, and other price premiums of shell eggs in Hawaii. AB - Hedonic modeling and retail scanner data were utilized to investigate the influence of local, organic, nutrition benefits, and other attributes of shell eggs on retail price premium in Hawaii. Within a revealed preference framework, the analysis of local and organic attributes, simultaneously, under a single unified setting is important, as such work is highly deficient in the published literature. This paper finds high to moderate price premiums in four key attributes of shell eggs - organic (64%), local (40%), nutrition benefits claimed (33%), and brown shell (18.4%). Large and extra-large sized eggs also experience price premiums over medium sized eggs. With each larger packing size, the estimated coefficients were negative, indicating a price discount, relative to the baseline packing size. However, there is no evidence to support the overwhelming influence of "local" over "organic", as hypothesized in other research work. Overall, the findings in this paper suggest industry producers and retailers should highlight and market effusively the primary attributes of their shell eggs, including "local", to remain competitive in the marketplace. Effective communication channels are crucial to delivering the product information, capturing the attention of consumers, and securing retail sales. PMID- 26976899 TI - Effect of level of fiber of the rearing phase diets on egg production, digestive tract traits, and body measurements of brown egg-laying hens fed diets differing in energy concentration. AB - This research studied the effects of additional fiber in the rearing phase diets on egg production, gastrointestinal tract (GIT) traits, and body measurements of brown egg-laying hens fed diets varying in energy concentration from 17 to 46 wk of age. The experiment was completely randomized with 10 treatments arranged as a 5 * 2 factorial with 5 rearing phase diets and 2 laying phase diets. During the rearing phase, treatments consisted of a control diet based on cereals and soybean meal and 4 additional diets with a combination of 2 fiber sources (cereal straw and sugar beet pulp, SBP) at 2 levels (2 and 4%). During the laying phase, diets differed in energy content (2,650 vs. 2,750 kcal AMEn/kg) but had the same amino acid content per unit of energy. The rearing diet did not affect any production trait except egg production that was lower in birds fed SBP than in birds fed straw (91.6 and 94.1%, respectively; P < 0.05). Laying hens fed the high energy diet had lower feed intake (P < 0.001), better feed conversion (P < 0.01), and greater BW gain (P < 0.05) than hens fed the low energy diet but egg production and egg weight were not affected. At 46 wk of age, none of the GIT traits was affected by previous dietary treatment. At this age, hen BW was positively related with body length (r = 0.500; P < 0.01), tarsus length (r = 0.758; P < 0.001), and body mass index (r = 0.762; P < 0.001) but no effects of type of diet on these traits were detected. In summary, the inclusion of up to 4% of a fiber source in the rearing diets did not affect GIT development of the hens but SBP reduced egg production. An increase in the energy content of the laying phase diet reduced ADFI and improved feed efficiency but did not affect any of the other traits studied. PMID- 26976900 TI - Influence of chick hatch time and access to feed on broiler muscle development. AB - The effect of hatch time and the timing of access to feed on growth rate and breast muscle development was assessed in Ross 308 broiler chickens. Chicks were removed from the incubator upon hatching, and classified as early (EH), midterm (MH), or late (LH) hatchers, based on the duration of their incubation. Feed and water were available either immediately at hatch, or 24 h after the conclusion of the hatch period. Hatchling body weight was uniform regardless of hatch time. Subsequently, bodyweight was increased in EH compared to LH birds following immediate access to feed, until 7 d in female, and 14 d in male birds. Relative breast weight was increased until 28 d in birds with immediate access to feed, and also EH and MH birds regardless of access to feed. Pectoralis major muscle morphology and expression of the myogenic regulatory factors myogenic determination factor 1 (MYOD1) and myogenin, and the proteoglycans syndecan-4, glypican-1, and decorin were measured. Myogenin and glypican-1 stimulate satellite cell (SC) differentiation. Glypican-1 expression was unaffected by treatment. A late increase in myogenin expression was observed in MH birds with delayed access to feed, and all LH birds. Syndecan-4 and MYOD1, expressed in proliferating SC, and decorin, which stimulates satellite cell proliferation and differentiation, were variably upregulated in the first wk posthatch in the same birds. These data suggest SC were activated and proliferating, but had reduced differentiation in later hatching and feed deprived birds. Conversely, EH birds with immediate access to feed had maximal myofiber width at 7 d, while fiber width was increased in birds with immediate access to feed compared to those with delayed access to feed through 40 d of age. These results demonstrate that delaying chick access to feed for 24 h upon removal from the incubator will impair muscle growth. Additionally, hatch time influences muscle development, with accelerated muscle growth in EH and MH, compared to LH birds, irrespective of access to feed. PMID- 26976902 TI - Energy and phosphorus values of sunflower meal and rice bran for broiler chickens using the regression method. AB - The energy and phosphorus values of sunflower meal (SFM) and rice bran (RB) were determined in 2 experiments with Ross 708 broiler chickens from 15 to 22 d of age. In Exp.1, the diets consisted of a corn-soybean meal reference diet (RD) and 4 test diets (TD). The TD consisted of SFM and RB that partly replaced the energy sources in the RD at 100 or 200 g/kg and 75 or 150 g/kg, respectively, such that the equal ratios were maintained for all energy containing ingredients across all experimental diets. In Exp.2, a cornstarch-soybean meal diet was the RD and TD consisting of SFM and RB that partly replaced cornstarch in the RD at 100 or 200 g/kg and 60 or 120 g/kg, respectively. Addition of SFM and RB to the RD in Exp.1 linearly decreased (P < 0.01) the digestibility coefficients of DM, energy, ileal digestible energy (IDE), metabolizability coefficients of DM, nitrogen (N), energy, N correct energy, metabolize energy (ME), and nitrogen-corrected ME. Except for RB, the increased levels of the test ingredients in RD did affect the metabolizability coefficients of N. The IDE values (kcal/kg DM) were 1,953 for SFM and 2,498 for RB; ME values (kcal/kg DM) were 1,893 for SFM and 2,683 for RB; and MEn values (kcal/kg DM) were 1,614 for SFM and 2,476 for RB. In Exp.2, there was a linear relationship between phosphorus (P) intake and ileal P output for diets with increased levels of SFM and RB. In addition, there was a linear relationship between P intake and P digestibility and retention for diets with increased levels of SFM. There were a quadratic effect (P < 0.01) and a tendency of quadratic effect (P = 0.07) for P digestible and total tract P retained, respectively, in the RB diets. The P digestibility and total tract P retention from regression analyses for SFM were 46% and 38%, respectively. PMID- 26976901 TI - Influence of commercial laying hen housing systems on the incidence and identification of Salmonella and Campylobacter. AB - The housing of laying hens is important for social, industrial, and regulatory aspects. Many studies have compared hen housing systems on the research farm, but few have fully examined commercial housing systems and management strategies. The current study compared hens housed in commercial cage-free aviary, conventional cage, and enriched colony cage systems. Environmental and eggshell pool samples were collected from selected cages/segments of the housing systems throughout the production cycle and monitored for Salmonella and Campylobacter prevalence. At 77 wk of age, 120 hens per housing system were examined for Salmonella and Campylobacter colonization in the: adrenal glands, spleen, ceca, follicles, and upper reproductive tract. All isolates detected from environmental swabs, eggshell pools, and tissues were identified for serotype. Two predominant Salmonella were detected in all samples:S.Braenderup andS.Kentucky.Campylobacter coli and C. jejuni were the only Campylobacter detected in the flocks. Across all housing systems, approximately 7% of hens were colonized with Salmonella, whereas >90% were colonized with Campylobacter Salmonella Braenderup was the isolate most frequently detected in environmental swabs (P<0.0001) and housing system impacted Salmonella spp. shedding (P<0.0001).Campylobacter jejuni was the isolate most frequently found in environmental swabs (P<0.01), while housing system impacted the prevalence of C. coli and jejuniin ceca (P<0.0001). The results of this study provide a greater understanding of the impact of hen housing systems on hen health and product safety. Additionally, producers and academia can utilize the findings to make informed decisions on hen housing and management strategies to enhance hen health and food safety. PMID- 26976903 TI - Detection and molecular characterization of chicken astrovirus associated with chicks that have an unusual condition known as "white chicks" in Brazil. AB - Chicken astrovirus (CAstV) is one of many viruses related to enteric diseases in poultry that are associated with Runting-Stunting Syndrome (RSS), which affects young chickens. CAstV was also recently associated with an unusual condition in chicks called "white chicks." Some hatcheries in certain states of Brazil have reported several incubation problems, mortality, and the presence of chicks with white plumages over the past several months. These chicks were termed locally as "white chicks." The present work investigated 30 chicks with this unusual condition using a multidisciplinary approach. Postmortem examination of each chick showed enlarged livers and intestines that were full of liquid and gas (30/30). The pancreas, kidneys, and spleen were pale (30/30). The other organs did not show any macroscopic alterations. CAstV, chicken parvovirus (ChPV), avian nephritis virus (ANV), avian rotavirus (ARtV), avian reovirus (AReoV), infectious bronchitis virus (IBV), and fowl adenovirus group I (FAdV-1) were tested in the intestines, pancreas, proventriculus, gizzard, liver, spleen, bursa, kidneys, thymus, lung, heart, brain, and yolk sac in each chick. All organs and yolk sacs were positive for CAstV in different titres and negative for the other tested viruses. The partial molecular characterization of the ORF 1b gene of CAstV using 28 sequences revealed a high similarity of the nucleotides and amino acids with sequences of CAstV from North America, Europe, and Asia, and our CAstV sequences clustered into a unique group that was separate from the other sequences. These results demonstrated that CAstV was associated with the white chick condition in Brazil. The virus was distributed in most organs, including the brain and yolk sac. These results suggest that the virus could be transmitted vertically. The molecular characterization also revealed that the CAstV associated with white chick condition was molecularly related to other CAstV sequences found worldwide. PMID- 26976904 TI - History of the Athens Canadian Random Bred and the Athens Random Bred control populations. AB - The University of Georgia maintains two meat-type chicken control strains: the Athens Random Bred (ARB) and the Athens Canadian Random Bred (ACRB). The Athens Random Bred was developed from colored plumage commercial meat chicken strains in 1956. The ACRB is a replicate population of the Ottawa Meat Control strain which was developed in 1955 from white plumage commercial meat-type chickens. These genetic lines have been extremely valuable research resources and have been used extensively to provide comparative context to modern meat-type strains. The ACRB may be the oldest pedigreed control commercial meat-type chicken still in existence today. This paper reviews the history of the breed backgrounds for both control populations and reviews research utilizing the ACRB. PMID- 26976905 TI - Effects of early life dextran sulfate sodium administration on pathology and immune response in broilers and layers. AB - Intestinal pathology early in life may affect immune development and therefore immune responses later in life. Dextran sulfate sodium (DSS) induces colitis in rodents and is a widely used model for inflammatory bowel diseases. The present study investigated DSS as a model for early life intestinal pathology and its consequences on intestinal pathology, ileal cytokine, and immunoglobulin mRNA expression levels as well as the antibody response towards an immunological challenge later in life in chickens. Broiler and layer chicks received 2.5% DSS in drinking water during d 11 through d 18 post hatch or plain drinking water as a control. As an immunological challenge all birds received a combination of Escherichia coli lipopolysaccharide (LPS) and human serum albumin (HuSA) intramuscularly (i.m.) at d 35, and antibody titers against LPS, HuSA, and keyhole limpet hemocyanin (KLH) were determined to investigate effects of intestinal inflammation early in life on humoral immunity later in life. DSS treated birds showed a decrease in BW from which broilers quickly recovered, but which persisted for several weeks in layers. Histological examination of intestinal samples showed symptoms similar to those in rodents, including shortening and loss of villi and crypts as well as damage of the epithelial cell layer of different parts of the intestine. Effects of DSS on intestinal morphology were less severe in broilers that also showed a lower mortality in response to DSS than layers. No effect of DSS on ileal cytokine expression levels could be observed, but ileal immunoglobulin expression levels were decreased in DSS treated broilers that also showed lower antibody titers against LPS in response to the challenge. In conclusion, DSS may serve as a model for intestinal pathology early in life, although more research on the appropriate dose is necessary and is likely to differ between breeds. Results from the present study could indicate that broilers are less susceptible to DSS compared with layers or have a better capacity to recover from intestinal pathology. PMID- 26976907 TI - Isolation and pathogenic analysis of virulent Marek's disease virus field strain in China. AB - Marek's disease (MD) has become increasingly common in China, resulting in considerable economic loss. The etiological agent is unclear. In this study, we isolated a field MD virus (MDV) strain, designated SX1301, from CVI988/Rispens vaccinated chickens with tumors. Co-infection of avian leukosis virus, reticuloendotheliosis virus, and chicken infectious anemia virus was excluded by polymerase chain reaction, enzyme-linked immunosorbant assay, DNA blotting hybridization, and indirect immunofluorescence assay. As with most strains isolated in China, SX1301 had the same amino acid mutation of meq protein at positions 77(E), 80(Y), and 115(A) Animal experimental results showed development of lethal MD in 57% and MD tumor in 23% of the specific pathogen-free chickens inoculated with SX1301, with tumors mainly distributed in spleen, liver, and kidney. CVI988/Rispens protected 83% of chickens upon challenge with SX1301, with a mortality rate and tumor incidence of 10% and 7%, respectively. These results implicated SX1301 as a virulent MDV strain, with commercial MDV vaccine CVI988/Rispens unable to confer adequate protection against SX1301. There have been no reports of very virulent (vv) plus MDV in China, but frequently occurring virulent MDV may account for the repeated outbreaks of MD. Vaccines with greater efficacy are needed to protect against MDV. PMID- 26976906 TI - Long-term effects of early life microbiota disturbance on adaptive immunity in laying hens. AB - Due to an interplay between intestinal microbiota and immune system, disruption of intestinal microbiota composition during immune development may have consequences for immune responses later in life. The present study investigated the effects of antibiotic treatment in the first weeks of life on the specific antibody response later in life in chickens. Layer chicks received an antibiotic cocktail consisting of vancomycin, neomycin, metronidazole, and amphotericin-B by oral gavage every 12 h, and ampicillin and colistin in drinking water for the first week of life. After the first week of life, chicks received ampicillin and colistin in drinking water for two more weeks. Control birds received no antibiotic cocktail and plain drinking water. Fecal microbiota composition was determined during antibiotic treatment (d 8 and 22), two weeks after cessation of antibiotic treatment (d 36), and at the end of the experimental period at d 175 using a 16S ribosomal RNA gene targeted microarray, the Chicken Intestinal Tract Chip (ChickChip). During antibiotic treatment fecal microbiota composition differed strongly between treatment groups. Fecal microbiota of antibiotic treated birds consisted mainly of Proteobacteria, and in particular E.coli, whereas fecal microbiota of control birds consisted mainly of Firmicutes, such as lactobacilli and clostridia. Two weeks after cessation of antibiotic treatment fecal microbiota composition of antibiotic treated birds had recovered and was similar to that of control birds. On d 105, 12 weeks after cessation of antibiotic treatment, chicks of both treatment groups received an intra-tracheal lipopolysaccharide (LPS)/human serum albumin (HuSA) challenge. Antibody titers against LPS and HuSA were measured 10 days after administration of the challenge. While T cell independent antibody titers (LPS) were not affected by antibiotic treatment, antibiotic treated birds showed lower T cell dependent antibody titers (HuSA) compared with control birds. In conclusion, intestinal microbial dysbiosis early in life may still have effects on the specific antibody response months after cessation of antibiotic treatment and despite an apparent recovery in microbiota composition. PMID- 26976908 TI - The impact of graded levels of daylength on turkey productivity to eighteen weeks of age. AB - The impact of graded levels of day-length on the productivity of hens and toms was studied in two trials. Daylength treatments (trts) were 14 (14L), 17 (17L), 20 (20L), and 23 (23L) h and were started at 10 d of age. Turkeys (720 hens and 480 toms) were randomly allocated to 8 rooms (2 rooms per lighting trt) with six pens (3 hen--30 per pen and 3 tom--20 per pen) per room in each trial. Body weight (BW) was assessed at 0, 10, 21, 42, 63, 84, and 126 d of age; feed consumption (FC) was measured for the time periods between body weight determinations and feed efficiency (G:F; g of gain/g of feed) was calculated from BW and FC values. Birds were checked daily for mortality and culls, and affected birds were sent for necropsy. Data were analyzed according to a completely randomized block design with trial as the block and rooms nested within lighting trts. Regression analysis was used to study the relationship between dependent variables and daylength. Significance was declared at P<= 0.05 and trends at P<= 0.10. At both 21 and 42 d, body weight increased linearly with increasing daylength. At 84 d weights of toms decreased in a quadratic fashion and hen weights were unaffected. At 126 d, both tom and hen weights decreased linearly as daylength increased, with the magnitude of response gender dependent. Feed consumption corresponded with body weight changes, increasing for d 10 to 21, and 21 to 42 and decreasing for d 63 to 84, 84 to 105, and 105 to 126 with increasing daylength. Feed efficiency (G:F) was not affected by daylength for 10 to 84, 10 to 105 and 10 to 126 d periods. The incidence of mortality and culling was not affected by daylength for the 10 to 84 d period, but increased in a quadratic manner with increasing daylength for the 10 to 105 and 10 to 126 d periods. To conclude, daylength affects the growth and feed intake of turkeys in an age and gender-specific manner, and mortality and culling increase with longer daylength. PMID- 26976909 TI - Influence of hatch time and access to feed on intramuscular adipose tissue deposition in broilers. AB - The effect of hatch time and subsequent access to feed on intramuscular adipose tissue deposition was studied in the pectoralis major muscle of male Ross 308 broiler chickens. Based on their hatch time chicks were classified as early (EH), midterm (MH), or late (LH) hatchers, with an average incubation duration of 497.7 h for EH, 508.8 h for MH, and 514.5 h for LH birds. Chicks were provided access to feed either immediately at hatch, or 24 h after the conclusion of the hatch window. Expression of the adipogenic regulatory genes peroxisome proliferator activated receptor gamma (PPARgamma), and stearoyl-CoA desaturase (SCD), were measured at the time of hatch, and zero, one, 4, 7, 28, and 40 d. Intramuscular adipocyte cell width and visualization of adipose tissue deposition was observed at 28 and 40 d. Expression of PPARgamma was increased in the pectoralis major of LH birds at the time of hatch, zero, and one d. The expression of PPARgamma at one and 7 d, and SCD at 7 d were increased in all birds that received delayed access to feed. At 28 d, adipocyte cell width was increased in LH birds with delayed access to feed, compared to EH and MH birds with delayed access to feed and LH birds with immediate access to feed. At 40 d, adipocyte cell width was increased in all birds that received delayed access to feed. Also at 40 d, there was a trend (P = 0.078) for more extensive intramuscular adipose tissue deposition in LH than EH birds, and in birds with delayed access to feed (P = 0.075). These data indicate delayed access to feed increases intramuscular adipose tissue deposition in the pectoralis major muscle, and suggest that hatch time influences this regulation. PMID- 26976910 TI - Effect of anticoccidial monensin with oregano essential oil on broilers experimentally challenged with mixed Eimeria spp. AB - Essential oil of oregano ( OEO: ) has proven to be a potential candidate for controlling chicken coccidiosis. The aim of the current study is to determine whether OEO and an approved anticoccidial, monensin sodium ( MON: ), as in-feed supplements could create a synergism when combined at low dosages. Day-old broiler chickens were separated into six equal groups with six replicate pens of 36 birds. One of the groups was given a basal diet and served as the control ( CNT: ). The remaining groups received the basal diet supplemented with 100 mg/kg MON, 50 mg/kg MON, 24 mg/kg OEO, 12 mg/kg OEO, or 50 mg/kg MON + 12 mg/kg OEO. All of the chickens were challenged with field-type mixed Eimeria species at 12 d of age. Following the infection (i.e., d 13 to 42), the greatest growth gains and lowest feed conversion ratio values were recorded for the group of birds fed 100 mg/kg MON (P < 0.05), whereas results for the CNT treatment were inferior. Dietary OEO supplementations could not support growth to a level comparable with the MON (100 mg/kg). The MON programs were more efficacious in reducing fecal oocyst numbers compared to CNT and OEO treatments (P < 0.05). Serum malondialdehyde and nitric oxide concentrations were decreased (P < 0.01), whereas superoxide dismutase (P < 0.05) and total antioxidant status (P < 0.01) were increased in response to dietary medication with MON and OEO. All MON and OEO treatments conferred intestinal health benefits to chickens by improving their morphological development and enzymatic activities. The results suggest that OEO supported the intestinal absorptive capacity and antioxidant defense system during Eimeria infection; however, it displayed little direct activity on the reproductive capacity of Eimeria This might be the reason for inferior compensatory growth potential of OEO compared to that MON following the challenge. Combination MON with OEO was not considered to show promise for controlling chicken coccidiosis because of the lack of a synergistic or additive effect. PMID- 26976911 TI - Detection of virulence-associated genes in pathogenic and commensal avian Escherichia coli isolates. AB - Poultry colibacillosis due to Avian Pathogenic Escherichia coli (APEC) is responsible for several extra-intestinal pathological conditions, leading to serious economic damage in poultry production. The most commonly associated pathologies are airsacculitis, colisepticemia, and cellulitis in broiler chickens, and salpingitis and peritonitis in broiler breeders. In this work a total of 66 strains isolated from dead broiler breeders affected with colibacillosis and 61 strains from healthy broilers were studied. Strains from broiler breeders were typified with serogroups O2, O18, and O78, which are mainly associated with disease. The serogroup O78 was the most prevalent (58%). All the strains were checked for the presence of 11 virulence genes: 1) arginine succinyltransferase A (astA); ii) E.coli hemeutilization protein A (chuA); iii) colicin V A/B (cvaA/B); iv) fimbriae mannose-binding type 1 (fimC); v) ferric yersiniabactin uptake A (fyuA); vi) iron-repressible high-molecular-weight proteins 2 (irp2); vii) increased serum survival (iss); viii) iron-uptake systems of E.coli D (iucD); ix) pielonefritis associated to pili C (papC); x) temperature sensitive haemaglutinin (tsh), and xi) vacuolating autotransporter toxin (vat), by Multiplex-PCR. The results showed that all genes are present in both commensal and pathogenic E. coli strains. The iron uptake-related genes and the serum survival gene were more prevalent among APEC. The adhesin genes, except tsh, and the toxin genes, except astA, were also more prevalent among APEC isolates. Except for astA and tsh, APEC strains harbored the majority of the virulence associated genes studied and fimC was the most prevalent gene, detected in 96.97 and 88.52% of APEC and AFEC strains, respectively. Possession of more than one iron transport system seems to play an important role on APEC survival. PMID- 26976912 TI - Belgian citizens' and broiler producers' perceptions of broiler chicken welfare in Belgium versus Brazil. AB - New EU regulations require more stringent country-of-origin labeling, while imports of broiler meat from non-EU countries are increasing. In light of these trends, we have studied citizens' and producers' perceptions of broiler meat originating from Belgium versus Brazil and their perception of broiler production in Belgium versus Brazil. A particular focus was the association between country of origin and perceived level of animal welfare. We also investigated the perception of scaling-up and outdoor access in terms of perceived level of animal welfare. Cross-sectional survey data was collected among Flemish citizens (n = 541) and broiler producers (n = 114). In accordance with literature on general farm animal welfare, both stakeholder types claimed to allocate great importance to broiler welfare and generally agreed with the Welfare Quality model of broiler welfare. Citizens disagreed with the producers that 1) consumers are not willing to pay more for higher welfare products, 2) that broilers suffer little, 3) that broiler welfare in current Belgian production units is generally non-problematic, 4) that scaling-up production units would not have a positive impact on profitability nor a profoundly negative impact on broiler welfare, and 5) that the impact of providing broilers with outdoor access is negative for consumers, farmers, and broilers. Country of origin had a strong influence on the perception of both broiler production and broiler meat. Belgian citizens, and producers (much more than citizens) considered nearly all aspects related to broiler production and broiler meat to be significantly superior for chicken produced in Belgium compared to Brazil. Further research should focus on how these perceptions influence purchase intentions and production decisions. Future avenues for research are to quantify market opportunities for country-of-origin labeling and to investigate to which extent stakeholders' perceptions correspond with reality. PMID- 26976913 TI - Knowing the Prevalence of Familial Hypercholesterolemia Matters. PMID- 26976914 TI - Prevalence of Familial Hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). AB - BACKGROUND: The prevalence of familial hypercholesterolemia (FH) is commonly reported as 1 in 500. European reports suggest a higher prevalence; the US FH prevalence is unknown. METHODS AND RESULTS: The 1999 to 2012 National Health and Nutrition Examination Survey (NHANES) participants >=20 years of age (n=36 949) were analyzed to estimate the prevalence of FH with available Dutch Lipid Clinic criteria, including low-density lipoprotein cholesterol and personal and family history of premature atherosclerotic cardiovascular disease. Prevalence and confidence intervals of probable/definite FH were calculated for the overall population and by age, sex, obesity status (body mass index >=30 kg/m(2)), and race/ethnicity. Results were extrapolated to the 210 million US adults >=20 years of age. The estimated overall US prevalence of probable/definite FH was 0.40% (95% confidence interval, 0.32-0.48) or 1 in 250 (95% confidence interval, 1 in 311 to 209), suggesting that 834 500 US adults have FH. Prevalence varied by age, being least common in 20 to 29 year olds (0.06%, 1 in 1557) and most common in 60 to 69 year olds (0.85%, 1 in 118). FH prevalence was similar in men and women (0.40%, 1 in 250) but varied by race/ethnicity (whites: 0.40%, 1 in 249; blacks: 0.47%, 1 in 211; Mexican Americans: 0.24%, 1 in 414; other races: 0.29%, 1 in 343). More obese participants qualified as probable/definite FH (0.58%, 1 in 172) than nonobese (0.31%, 1 in 325). CONCLUSIONS: FH, defined with Dutch Lipid Clinic criteria available in NHANES, affects 1 in 250 US adults. Variations in prevalence by age and obesity status suggest that clinical criteria may not be sufficient to estimate FH prevalence. PMID- 26976915 TI - Shared Risk Factors in Cardiovascular Disease and Cancer. AB - Cardiovascular disease (CVD) and cancer are the 2 leading causes of death worldwide. Although commonly thought of as 2 separate disease entities, CVD and cancer possess various similarities and possible interactions, including a number of similar risk factors (eg, obesity, diabetes mellitus), suggesting a shared biology for which there is emerging evidence. Although chronic inflammation is an indispensable feature of the pathogenesis and progression of both CVD and cancer, additional mechanisms can be found at their intersection. Therapeutic advances, despite improving longevity, have increased the overlap between these diseases, with millions of cancer survivors now at risk of developing CVD. Cardiac risk factors have a major impact on subsequent treatment-related cardiotoxicity. In this review, we explore the risk factors common to both CVD and cancer, highlighting the major epidemiological studies and potential biological mechanisms that account for them. PMID- 26976917 TI - Perioperative Management to Reduce Cardiovascular Events. PMID- 26976919 TI - Giant J Waves and ST-Segment Elevation Associated With Acute Gastric Distension. PMID- 26976916 TI - Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition. AB - Heart failure affects ~5.7 million people in the United States alone. Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension. PMID- 26976920 TI - Letter by Barison et al Regarding Article, "Treatment of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: An International Task Force Consensus Statement". PMID- 26976922 TI - Letter by Olschewski et al Regarding Article, "Upregulation of K2P3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation". PMID- 26976921 TI - Response to Letter Regarding Article, "Treatment of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia: An International Task Force Consensus Statement". PMID- 26976924 TI - Correction. PMID- 26976923 TI - Response to Letter Regarding Article, "Upregulation of K2P3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation". PMID- 26976926 TI - Endothelial dysfunction in DOCA-salt-hypertensive mice: role of neuronal nitric oxide synthase-derived hydrogen peroxide. AB - Endothelial dysfunction is a common problem associated with hypertension and is considered a precursor to the development of micro- and macro-vascular complications. The present study investigated the involvement of nNOS (neuronal nitric oxide synthase) and H2O2 (hydrogen peroxide) in the impaired endothelium dependent vasodilation of the mesenteric arteries of DOCA (deoxycorticosterone acetate)-salt-hypertensive mice. Myograph studies were used to investigate the endothelium-dependent vasodilator effect of ACh (acetylcholine). The expression and phosphorylation of nNOS and eNOS (endothelial nitric oxide synthase) were studied by Western blot analysis. Immunofluorescence was used to examine the localization of nNOS and eNOS in the endothelial layer of the mesenteric artery. The vasodilator effect of ACh is strongly impaired in mesenteric arteries of DOCA salt-hypertensive mice. Non-selective inhibition of NOS sharply reduced the effect of ACh in both DOCA-salt-hypertensive and sham mice. Selective inhibition of nNOS and catalase led to a higher reduction in the effect of ACh in sham than in DOCA-salt-hypertensive mice. Production of H2O2 induced by ACh was significantly reduced in vessels from DOCA-salt-hypertensive mice, and it was blunted after nNOS inhibition. The expression of both eNOS and nNOS was considerably lower in DOCA-salt-hypertensive mice, whereas phosphorylation of their inhibitory sites was increased. The presence of nNOS was confirmed in the endothelial layer of mesenteric arteries from both sham and DOCA-salt hypertensive mice. These results demonstrate that endothelial dysfunction in the mesenteric arteries of DOCA-salt-hypertensive mice is associated with reduced expression and functioning of nNOS and impaired production of nNOS-derived H2O2 Such findings offer a new perspective for the understanding of endothelial dysfunction in hypertension. PMID- 26976928 TI - Organelles and spatial organization of the cell: organelle homeostasis and turnover. PMID- 26976925 TI - Human DC-SIGN binds specific human milk glycans. AB - Human milk glycans (HMGs) are prebiotics, pathogen receptor decoys and regulators of host physiology and immune responses. Mechanistically, human lectins (glycan binding proteins, hGBP) expressed by dendritic cells (DCs) are of major interest, as these cells directly contact HMGs. To explore such interactions, we screened many C-type lectins and sialic acid-binding immunoglobulin-like lectins (Siglecs) expressed by DCs for glycan binding on microarrays presenting over 200 HMGs. Unexpectedly, DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) showed robust binding to many HMGs, whereas other C-type lectins failed to bind, and Siglec-5 and Siglec-9 showed weak binding to a few glycans. By contrast, most hGBP bound to multiple glycans on other microarrays lacking HMGs. An alpha-linked fucose residue was characteristic of HMGs bound by DC-SIGN. Binding of DC-SIGN to the simple HMGs 2'-fucosyl-lactose (2'-FL) and 3-fucosyl lactose (3-FL) was confirmed by flow cytometry to beads conjugated with 2'-FL or 3-FL, as well as the ability of the free glycans to inhibit DC-SIGN binding. 2' FL had an IC50 of ~1 mM for DC-SIGN, which is within the physiological concentration of 2'-FL in human milk. These results demonstrate that DC-SIGN among the many hGBP expressed by DCs binds to alpha-fucosylated HMGs, and suggest that such interactions may be important in influencing immune responses in the developing infant. PMID- 26976929 TI - New technologies of molecular engineering and screening for cell signaling studies. PMID- 26976927 TI - British Neurotoxin Network recommendations for managing cervical dystonia in patients with a poor response to botulinum toxin. AB - Botulinum toxin (BoNT) injections are an effective treatment for cervical dystonia. Approximately 20% of patients eventually stop BoNT treatment, mostly because of treatment failure. These recommendations review the different therapeutic interventions for optimising the treatment in secondary poor responder patients. Immunoresistance has become less common over the years, but the diagnosis has to be addressed with a frontalis test or an Extensor Digitorum Brevis test. In case of immunoresistance to BoNT-A, we discuss the place the different therapeutic options (BoNT-A holidays, BoNT-B injections, alternative BoNT-A injections, deep brain stimulation). When poor responders are not immunoresistant, they benefit from reviewing (1) injections technique with electromyography or ultrasound guidance, (2) muscles selection and (3) dose of BoNT. In addition, in both scenarios, a holistic approach including drug treatment, retraining and psychological support is valuable in the management of these complex and severe cervical dystonia. PMID- 26976930 TI - Collective migration in tissues. PMID- 26976931 TI - Cell biology and the "real world". PMID- 26976932 TI - An exciting time to study the nucleus. PMID- 26976933 TI - Regulation and integrated functions of the actin cytoskeleton. PMID- 26976934 TI - Old knowledge and new technologies allow rapid development of model organisms. AB - Until recently the set of "model" species used commonly for cell biology was limited to a small number of well-understood organisms, and developing a new model was prohibitively expensive or time-consuming. With the current rapid advances in technology, in particular low-cost high-throughput sequencing, it is now possible to develop molecular resources fairly rapidly. Wider sampling of biological diversity can only accelerate progress in addressing cellular mechanisms and shed light on how they are adapted to varied physiological contexts. Here we illustrate how historical knowledge and new technologies can reveal the potential of nonconventional organisms, and we suggest guidelines for selecting new experimental models. We also present examples of nonstandard marine metazoan model species that have made important contributions to our understanding of biological processes. PMID- 26976940 TI - Repeated Habitat Disturbances by Fire Decrease Local Effective Population Size. AB - Effective population size is a fundamental parameter in population genetics, and factors that alter effective population size will shape the genetic characteristics of populations. Habitat disturbance may have a large effect on genetic characteristics of populations by influencing immigration and gene flow, particularly in fragmented habitats. We used the Florida Sand Skink (Plestiodon reynoldsi) to investigate the effect of fire-based habitat disturbances on the effective population size in the highly threatened, severely fragmented, and fire dependent Florida scrub habitat. We screened 7 microsatellite loci in 604 individuals collected from 12 locations at Archbold Biological Station. Archbold Biological Station has an active fire management plan and detailed records of fires dating to 1967. Our objective was to determine how the timing, number, and intervals between fires affect effective population size, focusing on multiple fires in the same location. Effective population size was higher in areas that had not been burned for more than 10 years and decreased with number of fires and shorter time between fires. A similar pattern was observed in abundance: increasing abundance with time-since-fire and decreasing abundance with number of fires. The ratio of effective population size to census size was higher at sites with more recent fires and tended to decrease with time-since-last-fire. These results suggest that habitat disturbances, such as fire, may have a large effect in the genetic characteristics of local populations and that Florida Sand Skinks are well adapted to the natural fire dynamics required to maintain Florida scrub. PMID- 26976948 TI - Rare case of epididymal dirofilariasis. PMID- 26976945 TI - Photolabeling a Nicotinic Acetylcholine Receptor (nAChR) with an (alpha4)3(beta2)2 nAChR-Selective Positive Allosteric Modulator. AB - Positive allosteric modulators (PAMs) of nicotinic acetylcholine (ACh) receptors (nAChRs) have potential clinical applications in the treatment of nicotine dependence and many neuropsychiatric conditions associated with decreased brain cholinergic activity, and 3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)-1H pyrrazol-4-yl)isoxazole (CMPI) has been identified as a PAM selective for neuronal nAChRs containing thealpha4 subunit. In this report, we compare CMPI interactions with low-sensitivity (alpha4)3(beta2)2 and high-sensitivity (alpha4)2(beta2)3 nAChRs, and with muscle-type nAChRs. In addition, we use the intrinsic reactivity of [(3)H]CMPI upon photolysis at 312 nm to identify its binding sites inTorpedonAChRs. Recording fromXenopusoocytes, we found that CMPI potentiated maximally the responses of (alpha4)3(beta2)2nAChR to 10MUM ACh (EC10) by 400% and with anEC50of ~1uM. CMPI produced a left shift of the ACh concentration-response curve without altering ACh efficacy. In contrast, CMPI inhibited (~35% at 10uM) ACh responses of (alpha4)2(beta2)3nAChRs and fully inhibited human muscle andTorpedonAChRs with IC50values of ~0.5uM. Upon irradiation at 312 nm, [(3)H]CMPI photoincorporated into eachTorpedo[(alpha1)2beta1gammadelta] nAChR subunit. Sequencing of peptide fragments isolated from [(3)H]CMPI-photolabeled nAChR subunits established photolabeling of amino acids contributing to the ACh binding sites (alphaTyr(190),alphaTyr(198),gammaTrp(55),gammaTyr(111),gammaTyr(117),deltaTrp(57 ) that was fully inhibitable by agonist and lower-efficiency, state-dependent [(3)H]CMPI photolabeling within the ion channel. Our results establish that CMPI is a potent potentiator of nAChRs containing analpha4:alpha4 subunit interface, and that its intrinsic photoreactivy makes it of potential use to identify its binding sites in the (alpha4)3(beta2)2nAChR. PMID- 26976949 TI - Imaging in central pontine myelonolysis: animals in the brain. PMID- 26976946 TI - Trends in mortality from occupational hazards among men in England and Wales during 1979-2010. AB - OBJECTIVES: To monitor the impact of health and safety provisions and inform future preventive strategies, we investigated trends in mortality from established occupational hazards in England and Wales. METHODS: We analysed data from death certificates on underlying cause of death and last full-time occupation for 3 688 916 deaths among men aged 20-74 years in England and Wales during 1979-2010 (excluding 1981 when records were incomplete). Proportional mortality ratios (PMRs), standardised for age and social class, were calculated for occupations at risk of specified hazards. Observed and expected numbers of deaths for each hazard were summed across occupations, and the differences summarised as average annual excesses. RESULTS: Excess mortality declined substantially for most hazards. For example, the annual excess of deaths from chronic bronchitis and emphysema fell from 170.7 during 1979-1990 to 36.0 in 2001 2010, and that for deaths from injury and poisoning from 237.0 to 87.5. In many cases, the improvements were associated with falling PMRs (suggesting safer working practices), but they also reflected reductions in the numbers of men employed in more hazardous jobs, and declining mortality from some diseases across the whole population. Notable exceptions to the general improvement were diseases caused by asbestos, especially in some construction trades and sinonasal cancer in woodworkers. CONCLUSIONS: The highest priority for future prevention of work-related fatalities is the minority of occupational disorders for which excess mortality remains static or is increasing, in particular asbestos-related disease among certain occupations in the construction industry and sinonasal cancer in woodworkers. PMID- 26976950 TI - Right upper lobe pulmonary edema. PMID- 26976947 TI - Antipsychotic prescription amongst hospitalized patients with dementia. AB - BACKGROUND: Antipsychotic drugs are used to treat behavioural and psychological symptoms of dementia, despite significant safety concerns regarding increased risk of stroke and mortality. The numbers of patients with dementia and related behavioural symptoms being treated in acute hospitals is increasing. AIM: (i) to determine pre-admission and in-hospital prevalence of antipsychotic use in a national sample of patients with dementia and acute illness; (ii) identify reasons for antipsychotic use; (iii) assess features of the ward environment which impact on patients with dementia; (iv) determine availability of dementia specific policies, training, appraisal and mentorship programs which influence service delivery. DESIGN AND METHODS: Four-part standardized audit in 35 public acute hospitals comprising (i) retrospective healthcare record review (n = 660); (ii) prospective assessment of ward environment (n = 77); (iii) ward organization interview with clinical managers (n = 77); (iv) hospital organisation interview with senior managers (n = 35). RESULTS: Antipsychotic drugs were prescribed to 29% of patients with dementia before hospitalization and to 41% during hospitalization; one quarter received new or additional prescriptions. Assessments for delirium (45%), dementia symptoms (39%), mood (26%), mental state (64%) and distress-provoking factors (3%) were suboptimal. Drug indications were documented in 78%. Non-pharmacological interventions were not documented. Most wards lacked environmental cues to promote orientation. Dementia-specific care pathways existed in 2 of 35 hospitals. Staff support and training programmes were suboptimal. 12% of patients were discharged with new antipsychotic prescriptions. CONCLUSION: Antipsychotic medications are commonly prescribed for hospitalized patients with dementia in Ireland. Ward environments and dementia-related governance structures are suboptimal. PMID- 26976951 TI - Metastatic pancreatic neuroendocrine tumour. PMID- 26976952 TI - Infected aortic aneurysmal rupture masquerading as pneumonia. PMID- 26976953 TI - Digital ischaemia during cooling is independently related to nailfold capillaroscopic pattern in patients with Raynaud's phenomenon. AB - OBJECTIVE: The aim of the study was to assess the association between plethysmographically measured vasospasms during stepwise cooling and recovery, as an index for digital ischaemia, and nailfold capillaroscopic pattern (NCP) severity in patients with primary or secondary RP, including SSc. METHODS: In 381 consecutive patients with suspected RP without a history of digital ulcers, NCP (assessed by widefield videocapillaroscopy), fingertip photoelectric plethysmography during cooling and recovery and clinical characteristics were analysed. NCPs were graded as follows: normal, non-specific, early and active. The mean ischaemic time was defined as the mean time of perfusion loss during cooling and recovery of five fingers. RESULTS: In the patients with loss of perfusion during cooling and recovery, the NCP was normal in 152, non-specific in 96, early in 61 and active in 39 patients. The mean ischaemic time was positively associated with the severity of NCP, with P < 0.05 for each two- or three-grade increase and independent of underlying SSc. The difference was most pronounced during recovery. CONCLUSION: We demonstrate that the degree of vasospasm and ischaemia provoked by stepwise cooling and recovery are positively associated with NCP in patients with RP of different aetiologies and without a history of digital ulcers. PMID- 26976954 TI - STAT3 Impairs STAT5 Activation in the Development of IL-9-Secreting T Cells. AB - Th cell subsets develop in response to multiple activating signals, including the cytokine environment. IL-9-secreting T cells develop in response to the combination of IL-4 and TGF-beta, although they clearly require other cytokine signals, leading to the activation of transcription factors including STAT5. In Th17 cells, there is a molecular antagonism of STAT5 with STAT3 signaling, although whether this paradigm exists in other Th subsets is not clear. In this paper, we demonstrate that STAT3 attenuates the ability of STAT5 to promote the development of IL-9-secreting T cells. We demonstrate that production of IL-9 is increased in the absence of STAT3 and cytokines that result in a sustained activation of STAT3, including IL-6, have the greatest potency in repressing IL-9 production in a STAT3-dependent manner. Increased IL-9 production in the absence of STAT3 correlates with increased endogenous IL-2 production and STAT5 activation, and blocking IL-2 responses eliminates the difference in IL-9 production between wild-type and STAT3-deficient T cells. Moreover, transduction of developing Th9 cells with a constitutively active STAT5 eliminates the ability of IL-6 to reduce IL-9 production. Thus, STAT3 functions as a negative regulator of IL-9 production through attenuation of STAT5 activation and function. PMID- 26976955 TI - ACKR4 on Stromal Cells Scavenges CCL19 To Enable CCR7-Dependent Trafficking of APCs from Inflamed Skin to Lymph Nodes. AB - Dermal dendritic cells and epidermal Langerhans cells are APCs that migrate from skin to draining lymph nodes (LN) to drive peripheral tolerance and adaptive immunity. Their migration requires the chemokine receptor CCR7, which directs egress from the skin via dermal lymphatic vessels and extravasation into the LN parenchyma from lymph in the subcapsular sinus. CCR7 is activated by two chemokines: CCL19 and CCL21. CCL21 alone is sufficient for the migration of APCs from skin to LN. CCL19 and CCL21 also bind atypical chemokine receptor (ACKR) 4. ACKR4-mediated CCL21 scavenging by lymphatic endothelial cells lining the subcapsular sinus ceiling stabilizes interfollicular CCL21 gradients that direct lymph-borne CCR7(+)APCs into the parenchyma of mouse LN. In this study, we show that ACKR4 also aids APC egress from mouse skin under steady-state and inflammatory conditions. ACKR4 plays a particularly prominent role during cutaneous inflammation when it facilitates Langerhans cell egress from skin and enables the accumulation of dermal dendritic cells in skin-draining LN. Stromal cells in mouse skin, predominantly keratinocytes and a subset of dermal lymphatic endothelial cells, express ACKR4 and are capable of ACKR4-dependent chemokine scavenging in situ. ACKR4-mediated scavenging of dermal-derived CCL19, rather than CCL21, is critical during inflammation, because the aberrant trafficking of skin-derived APCs inAckr4-deficient mice is completely rescued by genetic deletion ofCcl19 Thus, ACKR4 on stromal cells aids the egress of APCs from mouse skin, and, during inflammation, facilitates CCR7-dependent cell trafficking by scavenging CCL19. PMID- 26976956 TI - Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis. AB - Fibroblast-like synoviocytes (FLS) play a major role in invasive joint destruction in rheumatoid arthritis (RA). This prodestructive phenotype has been shown to involve autocrine TGF-beta that triggers formation of matrix-degrading invadosomes through molecular mechanisms that are not fully elucidated. The platelet-derived growth factor (PDGF) receptor (PDGFR) family of receptor tyrosine kinases (RTK) has been shown to cooperate with TGF-beta in various pathological conditions. We therefore sought to determine whether RTK activity played a role in invadosome biogenesis. We demonstrated that, among the common RTKs, PDGFR-alphabeta was specifically phosphorylated in FLS from RA patients. Phosphorylation of PDGFR-alphabeta was also elevated in RA synovial tissues. Interference with PDGFR activation or PDGF neutralization inhibited invadosome formation in RA synoviocytes, indicating the presence of an autocrine PDGFR activation loop that involved endogenous PDGF. Among the PDGF-A-D isoforms, only PDGF-B was found both significantly elevated in FLS lines from RA patients, and related to high-invadosome forming cells. Addition of TGF-beta upregulated invadosome formation, PDGF-B mRNA expression, and phosphorylation of PDGFR. All of these functions were efficiently suppressed by TGF-beta neutralization or interference with the Smad/TbetaR1or PI3K/Akt pathway. Among the class 1 PI3K family proteins known to be expressed in RA synoviocytes, PI3Kalpha was selectively involved in PDGF-B expression, whereas both PI3Kalpha and PI3Kdelta participated in invadosome formation. Our findings demonstrate that PDGFR is a critical RTK required for the prodestructive phenotype of RA synovial cells. They also provide evidence for an association between autocrine TGF-beta and PDGFR mediated invadosome formation in RA synoviocytes that involves the production of PDGF-B induced by TGF-beta. PMID- 26976958 TI - Closing a gap in tuberculosis care. PMID- 26976959 TI - "Irresponsible" not to adopt national hepatitis plan. PMID- 26976957 TI - Galphai2 and Galphai3 Differentially Regulate Arrest from Flow and Chemotaxis in Mouse Neutrophils. AB - Leukocyte recruitment to inflammation sites progresses in a multistep cascade. Chemokines regulate multiple steps of the cascade, including arrest, transmigration, and chemotaxis. The most important chemokine receptor in mouse neutrophils is CXCR2, which couples through Galphai2- and Galphai3-containing heterotrimeric G proteins. Neutrophils arrest in response to CXCR2 stimulation. This is defective in Galphai2-deficient neutrophils. In this study, we show that Galphai3-deficient neutrophils showed reduced transmigration but normal arrest in mice. We also tested Galphai2- or Galphai3-deficient neutrophils in a CXCL1 gradient generated by a microfluidic device. Galphai3-, but not Galphai2-, deficient neutrophils showed significantly reduced migration and directionality. This was confirmed in a model of sterile inflammation in vivo. Galphai2-, but not Galphai3-, deficient neutrophils showed decreased Ca(2+) flux in response to CXCR2 stimulation. Conversely, Galphai3-, but not Galphai2-, deficient neutrophils exhibited reduced AKT phosphorylation upon CXCR2 stimulation. We conclude that Galphai2 controls arrest and Galphai3 controls transmigration and chemotaxis in response to chemokine stimulation of neutrophils. PMID- 26976960 TI - Effect of surgical safety checklists on pediatric surgical complications in Ontario. AB - BACKGROUND: In health care, most preventable adverse events occur in the operating room. Surgical safety checklists have become a standard of care for safe operating room practice, but there is conflicting evidence for the effectiveness of checklists to improve perioperative outcomes in some populations. Our objective was to determine whether surgical safety checklists are associated with a reduction in the proportion of children who had perioperative complications. METHODS: We conducted a retrospective cohort study using administrative health care databases housed at the Institute for Clinical Evaluative Sciences to compare the risk of perioperative complications in children undergoing common types of surgery before and after the mandated implementation of surgical safety checklists in 116 acute care hospitals in Ontario. The primary outcome was a composite outcome of 30-day all-cause mortality and perioperative complications. RESULTS: We identified 14 458 and 14 314 surgical procedures in pre- and postchecklist groups, respectively. The proportion of children who had perioperative complications was 4.08% (95% confidence interval [CI] 3.76%-4.40%) before the implementation of the checklist and 4.12% (95% CI 3.80%-4.45%) after implementation. After we adjusted for confounding factors, we found no significant difference in the odds of perioperative complications after the introduction of surgical safety checklists (adjusted odds ratio 1.01, 95% CI 0.90-1.14, p = 0.9). INTERPRETATION: The implementation of surgical safety checklists for pediatric surgery in Ontario was not associated with a reduction in the proportion of children who had perioperative complications. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT02419053. PMID- 26976962 TI - Church going. PMID- 26976961 TI - Buckle fractures of the distal radius in children. PMID- 26976963 TI - Added sugars on nutrition labels: a way to support population health in Canada. PMID- 26976964 TI - US seeking more transparency from pharma. PMID- 26976966 TI - Antibiotic stewardship and pharma's social conscience. PMID- 26976967 TI - Podcast: Women's health pioneer Dr. May Cohen. PMID- 26976965 TI - Prescribing exercise interventions for patients with chronic conditions. PMID- 26976968 TI - Facility attacks in Syria contravene Geneva Convention. PMID- 26976969 TI - Anticancer Properties of Capsaicin Against Human Cancer. AB - There is persuasive epidemiological and experimental evidence that dietary phytochemicals have anticancer activity. Capsaicin is a bioactive phytochemical abundant in red and chili peppers. While the preponderance of the data strongly indicates significant anticancer benefits of capsaicin, more information to highlight molecular mechanisms of its action is required to improve our knowledge to be able to propose a potential therapeutic strategy for use of capsaicin against cancer. Capsaicin has been shown to alter the expression of several genes involved in cancer cell survival, growth arrest, angiogenesis and metastasis. Recently, many research groups, including ours, found that capsaicin targets multiple signaling pathways, oncogenes and tumor-suppressor genes in various types of cancer models. In this review article, we highlight multiple molecular targets responsible for the anticancer mechanism of capsaicin. In addition, we deal with the benefits of combinational use of capsaicin with other dietary or chemotherapeutic compounds, focusing on synergistic anticancer activities. PMID- 26976970 TI - Heterochromatin Protein 1 Binding Protein 3 Expression as a Candidate Marker of Intrinsic 5-Fluorouracil Resistance. AB - BACKGROUND: Despite receiving post-operative 5-fluorouracil (5-FU)-based chemotherapy, approximately 50% of patients with stage IIIC colon cancer experience recurrence. Currently, no molecular signature can predict response to 5-FU. MATERIALS AND METHODS: Mouse models of colon cancer have been developed and characterized. Individual tumors in these mice can be longitudinally monitored and assessed to identify differences between those that are responsive and those that are resistant to therapy. Gene expression was analyzed in serial biopsies that were collected before and after treatment with 5-FU. Colon tumors had heterogeneous responses to treatment with 5-FU. Microarray analysis of pre treatment biopsies revealed that Hp1bp3, a gene encoding heterochromatin protein 1 binding protein 3, was differentially expressed between sensitive and resistant tumors. CONCLUSION: Using mouse models of human colorectal cancer, Hp1bp3 was identified as a candidate marker of intrinsic 5-FU resistance and may represent a potential biomarker for patient stratification or a target of clinical importance. PMID- 26976971 TI - Genome-wide DNA Copy-number Analysis in ACTS-CC Trial of Adjuvant Chemotherapy for Stage III Colonic Cancer. AB - BACKGROUND: The adjuvant chemotherapy trial of TS-1 for colon cancer phase III trial was designed to validate the non-inferiority of the oral fluoropyrimidine S 1 to uracil and tegafur/leucovorin as adjuvant chemotherapy for stage III colonic cancer. As a prospective biomarker study of this trial, DNA copy number was studied using formalin-fixed, paraffin-embedded specimens. MATERIALS AND METHODS: FFPE blocks were obtained from 795 patients of the 1,535 patients enrolled in the study. The quality of extracted DNA was assessed using arbitrarily primed polymerase chain reaction and microfluidic analysis. Genomic copy-number alterations in cancer were analyzed by high-density single-nucleotide polymorphism arrays. Copy-number changes in Japanese patients with colonic cancer were compared with those in Western countries using data from a previously reported meta-analysis. We then compared genome-wide segment copy number and clinicopathological features of colorectal cancer. RESULTS: Genome-wide copy number was analyzed in 161 samples and DNA copy-number alteration profiles showed frequent DNA copy-number gains at chromosome 7, 8q and 13, and losses at 4, 5q, 8p, 17p and 18q. The weighted kappa statistic from comparing copy-number alteration status with data from Western countries was 0.828 (95% confidence interval=0.786 -0.871). DNA copy-number alterations of 8,684 segments were compared with clinicopathological features in 161 patients. Location of the tumor correlated with genomic segments of chromosome 4, 5, 7, 8, 13, 14, 18 and 20. Differentiation of the tumor correlated with segments in chromosome 4, 6, 8, 11, 13, 14,15, 16, 17 and 20. CONCLUSION: Somatic copy-number alteration profiles of stage III colonic cancer in the Japanese ACTS-CC trial closely agreed with the results of previous Western studies. Location and differentiation of the tumor correlated with DNA copy-number alterations. Our findings will facilitate understanding the characteristics of colonic cancer. Further investigation may contribute to the exploration of valid biomarkers. PMID- 26976972 TI - Demonstration of Calreticulin Expression in Hamster Pancreatic Adenocarcinoma with the Use of Fluorescent Gold Quantum Dots. AB - BACKGROUND: There is dire need for discovery of novel pancreatic cancer biomarkers and of agents with the potential for simultaneous diagnostic and therapeutic capacity. This study demonstrates calreticulin expression on hamster pancreatic adenocarcinoma via bio-conjugated gold quantum dots (AuQDs). MATERIALS AND METHODS: Hamster pancreatic adenocarcinoma cells were cultured, fixed and incubated with fluorescent AuQDs, bio-conjugated to anti-calreticulin antibodies. Anti-calreticulin and AuQDs were produced in-house. AuQDs were manufactured to emit in the near-infrared. Cells were further characterized under confocal fluorescence. RESULTS: AuQDs were confirmed to emit in the near-infrared. AuQD bio-conjugation to calreticulin was confirmed via dot-blotting. Upon laser excitation and post-incubation with bio-conjugated AuQDs, pancreatic cancer cell lines emitted fluorescence in near-infrared. CONCLUSION: Hamster pancreatic cancer cells express calreticulin, which may be labelled with AuQDs. This study demonstrates the application of nanoparticle-based theranostics in pancreatic cancer. Such biomarker-targeting nanosystems are anticipated to play a significant role in the management of pancreatic cancer. PMID- 26976973 TI - Decreased Expression of Tumor-suppressor Gene LKB1 Correlates with Poor Prognosis in Human Gastric Cancer. AB - BACKGROUND/AIM: The present report describes the correlation of liver kinase B1 (LKB1) expression with tumorigenesis and prognosis in gastric cancer. MATERIALS AND METHODS: LKB1 mRNA and protein expression was detected in gastric-cancer cell lines and patient specimens. Patients were followed-up and clinico-pathological parameters and overall survival (OS) were evaluated. RESULTS: The expression of LKB1 mRNA and protein was lower in gastric-cancer cell lines and tumor tissues compared to normal gastric cells (p<0.05) and tissues (p<0.001). Decreased expression of LKB1 mRNA and protein in patients with gastric cancer was significantly inversely related to TNM stage, T-stage (depth of invasion), lymph node metastasis and vascular invasion (p<0.05). Patients showing high LKB1 mRNA and high LKB1 protein expression had a significantly longer OS and better 5-year survival rate than those with low mRNA expression (61.3 months vs. 56.1 months and 75% vs. 58.7%, p<0.05, respectively) and low protein expression (64.8 months vs. 55.7 months and 72.9% vs. 64.5%, p<0.05, respectively). Multivariate Cox regression analysis indicated that both LKB1 mRNA and protein expression in gastric cancer were independent prognostic factors for OS. CONCLUSION: Patients with gastric cancer with decreased expression of LKB1 have a poor prognosis with a lower survival rate. PMID- 26976975 TI - NDRG2 and NDRG4 Expression Is Altered in Glioblastoma and Influences Survival in Patients with MGMT-methylated Tumors. AB - AIM: The N-myc down-regulated gene (NDRG) family is a group of genes that have predominantly tumor-suppressive effects. The goal of this study was to investigate the expression of NDRG2 and NDRG4 in surgical specimens of human glioblastoma and in normal brain tissue, and to search for correlations with overall (OS) and progression-free survival (PFS). MATERIALS AND METHODS: Samples from 44 patients (31 males, 13 females; mean age+/-SD=57.4+/-15.7 years) with primary (n=40) or recurrent glioblastoma (n=4) were analyzed by quantitative real time polymerase chain reaction and immunohistochemistry, with dimensionless semiquantitative immunoreactivity score (IRS), ranging from 0-30] for expression of NDRG2 and NDRG4. Five non-tumorous autopsy brain specimens were used as controls. RESULTS: On the protein level, expression of NDRG2 was significantly down-regulated in glioblastoma (IRS=3.5+/-3.0 vs. 8.8+/-3.3; p=0.001), while expression of NDRG4 was significantly up-regulated (IRS=5.4+/-3.7 vs. 0.75+/-0.4 vs, p<0.001). There was no statistically significant difference in PFS between a group of 15 patients with glioblastoma with MGMT methylation and enhanced expression of NDRG4 mRNA who were treated with adjuvant radiochemotherapy (temozolomide and 60 Gy) and a group of patients with low expression of NDRG4 mRNA [10 (range=5.5-14.2) months vs. 21 (range=10.7-31.3) months] (p=0.13). CONCLUSION: Expression of both NDRG2 and NDRG4 genes is significantly altered in glioblastomas. PFS among the patients with glioblastoma with MGMT methylation treated with radiochemotherapy differed significantly in high-expression groups compared to patients without MGMT methlation and without radiochemotherapy (p<0.05). PMID- 26976974 TI - Design, Synthesis and Biological Activities of Novel Gemini 20S-Hydroxyvitamin D3 Analogs. AB - Vitamin D3 (D3) can be metabolized by cytochrome P450scc (CYP11A1) into 20S hydroxyvitamin D3 (20D3) as a major metabolite. This bioactive metabolite has shown strong antiproliferative, antifibrotic, pro-differentiation and anti inflammatory effects while being non-toxic (non-calcemic) at high concentrations. Since D3 analogs with two symmetric side chains (Gemini analogs) result in potent activation of the vitamin D receptor (VDR), we hypothesized that the chain length and composition of these types of analogs also containing a 20-hydroxyl group would affect their biological activities. In this study, we designed and synthesized a series of Gemini 20D3 analogs. Biological tests showed that some of these analogs are partial VDR activators and can significantly stimulate the expression of mRNA for VDR and VDR-regulated genes including CYP24A1 and transient receptor potential cation channel V6 (TRPV6). These analogs inhibited the proliferation of melanoma cells with potency comparable to that of 1alpha,25 dihydroxyvitamin D3. Moreover, these analogs reduced the level of interferon gamma and up-regulated the expression of leukocyte associated immunoglobulin-like receptor 1 in splenocytes, indicating that they have potent anti-inflammatory activities. There are no clear correlations between the Gemini chain length and their VDR activation or biological activities, consistent with the high flexibility of the ligand-binding pocket of the VDR. PMID- 26976976 TI - Adaptive Immune Response to and Survival Effect of Temozolomide- and Valproic Acid-induced Autophagy in Glioblastoma. AB - BACKGROUND/AIM: The combination of radiotherapy, temozolomide and valproic acid (VPA) has shown some promise in retrospective analyses of patients with glioblastoma, although their mechanisms of action remain unknown. MATERIALS AND METHODS: We investigated the in vitro and in vivo effects of pretreating glioma cells with temozolomide and VPA as an immunization strategy to boost an adaptive immune response in a syngeneic mouse model. RESULTS: Temozolomide and VPA induced autophagy in GL261 glioma cells, and caused tumor antigen-specific T-cells to become activated effector T-cells. Mice with a pre-existing glioma showed no improvement in clinical outcome when immunized with temozolomide- and VPA-treated glioma cells. CONCLUSION: Although temozolomide and VPA treatment of glioma cells can boost the adaptive immune response, in the context of a vaccine therapy, additional factors are necessary to eradicate the tumor and improve survival. PMID- 26976977 TI - Novel Hyaluronan Formulation Enhances the Efficacy of Boron Neutron Capture Therapy for Murine Mesothelioma. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) is a refractory cancer of the pleura caused by asbestos exposure. MPM is difficult to treat because it easily disseminates. Boron neutron capture therapy (BNCT) is a radiotherapy in which cancer cells that selectively take up (10)Boron-containing compounds are destroyed, and normal cells are uninjured. Hyaluronan (HA) is a ligand of cluster of differentiation 44 (CD44), that is expressed on MPM cells. MATERIALS AND METHODS: In order to enhance BNCT for MPM tumors, we developed a novel HA containing (10)B (sodium borocaptate: BSH) formulation (HA-BND-S). We examined the efficacy of HA-BND-S using MPM cells and a mouse MPM model. RESULTS: HA-BND-S preferentially bound MPM cells dose-dependently, and increased the cytotoxicity of BNCT compared to BSH in vitro. HA-BND-S administration significantly increased the survival of MPM tumor-bearing mice compared to BSH at the same (10)B dosage in BNCT. CONCLUSION: Modifying BSH with HA is a promising strategy for enhancing the efficacy of BNCT for therapy of MPM. PMID- 26976978 TI - Inhibition of Survivin Is Associated with Zoledronic Acid-induced Apoptosis of Prostate Cancer Cells. AB - BACKGROUND/AIM: Evidence suggests that zoledronic acid (ZA) exerts direct antitumor effects on cancer cells but the underlying mechanisms of these actions are unknown. This study investigated the possible involvement of survivin in the antiproliferative effects of ZA in prostate cancer. MATERIALS AND METHODS: 3-(4,5 dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT) dye reduction assay was used to assess cell viability and acridine orange/ethidium bromide double staining to analyze cell death. Human Apoptosis Array evaluated the expression of apoptosis-related proteins. Survivin protein was measured by western blot technique and miR-203 levels were quantified by quantitative real-time polymerase chain reaction. RESULTS: ZA induced inhibition of cell proliferation and apoptosis activation, with down-regulation of survivin protein. A negative regulation at gene expression level may be hypothesized because we observed a significant decrease of survivin mRNA level and an increase of miR-203 expression after ZA exposure. CONCLUSION: This study provides evidence that ZA may directly inhibit cancer cell proliferation, identifying survivin as one of its downstream targets. PMID- 26976979 TI - Expression Pattern of CDX2, Estrogen and Progesterone Receptors in Primary Gastroenteropancreatic Neuroendocrine Tumors and Metastases. AB - BACKGROUND: A significant number of patients with gastroenteropancreatic neuroendocrine tumors (GEP NETs) present with metastatic disease and with unknown primary in about 15% of cases. MATERIALS AND METHODS: We analyzed 163 primaries of GEP NET and 115 metastases for expression of caudal type homebox 2 (CDX2), estrogen receptor (ER), progesterone receptor (PR), somatostatin receptor 2a (SSTR2a) and Ki67. RESULTS: PR was most often positive in pancreatic NET and only rarely in non-pancreatic NET (p<0.001). ER was more frequently expressed in non pancreatic NET (p<0.001) and was more often positive in females than males (p=0.019). CDX2 was positive in all primaries of the duodenum, ileum and appendix, but was also detected in 24% of metastases with pancreatic primary. SSTR2a and Ki67 did not differ significantly between primaries and metastases. CONCLUSION: Our data substantiate the value of PR, ER and CDX2 in GEP NET, and steroid hormone receptors, being differentially expressed in male and female patients. Differences between primaries and metastases were small but potentially relevant. PMID- 26976980 TI - Ginsenoside 20(S)-Protopanaxadiol Suppresses Viability of Human Glioblastoma Cells via Down-regulation of Cell Adhesion Proteins and Cell-cycle Arrest. AB - BACKGROUND: Pharmacologically active components of ginseng, particularly protopanaxadiol (PPD)-type ginsenosides, have potent anticancer effects, although their effects on highly malignant glioblastoma multiforme (GBM) have not been systemically evaluated. Identification of effective anticancer ginsenosides and further delineation of their mechanisms of action may provide valuable information that aids in the development of alternative or adjuvant therapy for malignant cancer. MATERIALS AND METHODS: We examined the viability of human GBM U251-MG and U87-MG cells treated with structurally related PPD-type ginsenosides, including F2, Rh2, compound K (C-K), and PPD. RESULTS: Incubation with PPD, C-K, and Rh2 significantly reduced the viability of U251-MG and U87-MG cells in a dose and time-dependent manner. The cytotoxic effect of PPD was accompanied by reduced expression of cell adhesion proteins, including N-cadherin and integrin beta1, which led to reduced phosphorylation of focal adhesion kinase. Furthermore, incubation with PPD reduced the expression of cyclin D1 and subsequently induced cell-cycle arrest at the G1 phase. CONCLUSION: These results collectively indicate that PPD might provide a new strategy for treating malignant GBM, which is quite resistant to conventional anticancer treatment. PMID- 26976981 TI - Split-Course Accelerated Hypofractionated Radiotherapy (SCAHRT): A Safe and Effective Option for Head and Neck Cancer in the Elderly or Infirm. AB - BACKGROUND: Achieving locoregional control in high-risk patients with head and neck cancer who are poor candidates for standard continuous-course (chemo) radiotherapy due to advanced age, comorbidities, or very advanced disease is challenging. At our Institution, we have significant experience with a regimen of split-course, accelerated, hypofractionated radiotherapy (SCAHRT) for these patients. PATIENTS AND METHODS: The SCAHRT regimen consisted of 60-72 Gy in 20-24 fractions separated by several weeks mid-course to allow for toxicity recovery and disease reassessment. It was used for patients with advanced age, significant co-morbidities, anticipated intolerance to definitive (chemo)radiation, and those with oligometastatic disease. Disease-free and overall survival rates were calculated using Kaplan-Meier analysis. RESULTS: Fifty-eight out of 65 patients (89%) completed both courses of treatment. Patients without metastatic or recurrent disease were evaluated for treatment response and survival (n=39). Among this group, total tumor response was 91%, and median locoregional failure free survival and overall survival were 25.7 and 8.9 months, respectively. CONCLUSION: In high-risk patients unable to tolerate continuous-course definitive (chemo)radiation, SCAHRT is a safe, well-tolerated and effective method of achieving durable locoregional disease control. In properly selected patients, this regimen is preferable to purely palliative approaches. PMID- 26976982 TI - The WHO Grade I Collagen-forming Meningioma Produces Angiogenic Substances. A New Meningioma Entity. AB - BACKGROUND: Meningiomas arise from arachnoid cap cells, the so-called meningiothelial cells. They account for 20-36% of all primary intracranial tumours, and arise with an annual incidence of 1.8-13 per 100,000 individuals/year. According to their histopathological features meningiomas are classified either as grade I (meningiothelial, fibrous/fibroblastic, transitional/mixed, psammomatous, angiomatous, microcystic, secretory and the lympholasmacyterich sub-type), grade II (atypical and clear-cell sub-type) or grade III (malignant or anaplastic phenotype). CASE REPORT: A 62-year-old female patient presented to the hospital because of progressive obliviousness and concentration difficulties. In the magnetic resonance imaging (MRI) of the brain, an occipital convexity-meningioma was found in the left hemisphere, which was subsequently resected. Within the tumour tissue there were multiple spheroid precipitates, i.e. secretion products that turned out to consist of collagen. Part of the tumour cells displayed positive reactions for vasogenic substances, namely for vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). Correspondingly, the diagnosis "WHO Grade I collagen-forming meningioma" seems to be most appropriate. CONCLUSION: The "WHO Grade I collagen forming meningioma" reported herein produces collagen and angiogenic substances. To the best of our knowledge, no such entity has been reported on in previous literature. We propose this collagen-producing meningioma as a novel WHO grade I meningioma sub-type. PMID- 26976983 TI - Expression of gamma-Synuclein in Bladder Carcinoma: A Possible Marker for Prognosis. AB - AIM: To investigate if gamma-synuclein (SNCG) could be used as a bladder cancer (BC) marker to predict prognosis of BC. PATIENTS AND METHODS: Medical records of 140 patients with BC (January, 2006 to December, 2009) were retrospectively reviewed. SNCG expression level was examined by immunohistological staining. The patients' survival rate was calculated by the Kaplan-Meier method. Cox proportional regression model was used to identify independent predictors for BC. RESULTS: Overexpression of SNCG was detected in BC tissues and the expression level of SNCG strongly positively correlated with BC recurrence. However, no correlation was found between SNCG level and tumor stage or survival rate. CONCLUSION: SNCG is a good marker to predict recurrence of BC, but not a reliable marker for staging or prediction of survival rate. PMID- 26976984 TI - A Biomarker Panel Increases the Diagnostic Performance for Epithelial Ovarian Cancer Type I and II in Young Women. AB - BACKGROUND/AIM: To assess preoperative blood levels of a biomarker panel in relation to the new classification system of epithelial ovarian cancer (EOC) type I and II. PATIENTS AND METHODS: Preoperative plasma levels of B7-family protein homolog 4 (B7-H4), intact and cleaved soluble urokinase plasminogen activator receptor (suPAR), human epididymis protein 4 (HE4) and cancer antigen 125 (CA125) were analyzed in 350 patients with adnexal lesions. RESULTS: The levels of suPAR(II-III), HE4, CA125 were all higher in EOC II than in EOC I, borderline and benign ovarian tumors. B7-H4 was increased in EOC II compared with benign ovarian tumors. The combination of suPAR(II-III), HE4, CA125 and age in premenopausal women discriminates EOC and borderline tumors from benign tumors to higher accuracy compared to the Risk of Ovarian Malignancy Algorithm (p=0.007). CONCLUSION: The biomarker panel suPAR(II-III), HE4, CA125 and age in premenopausal women improved discrimination of malignant and benign ovarian tumors. The plasma levels of B7-H4 were increased in patients with EOC II compared to those with benign ovarian tumors. PMID- 26976985 TI - First-line Bevacizumab-containing Therapy for HER2-negative Metastatic Breast Cancer: Final Results from a Prospective German Study. AB - AIM: The German ML21165 study evaluated bevacizumab-containing therapy for metastatic breast cancer (mBC) in routine oncology practice. PATIENTS AND METHODS: Patients received bevacizumab with chemotherapy until disease progression, unacceptable toxicity or consent withdrawal. Pre-specified end points were safety and efficacy [response rate, progression-free survival (PFS) and overall survival (OS)]. RESULTS: Between May 2007 and September 2009, 865 patients received first-line bevacizumab plus paclitaxel for mBC, of whom 16% were aged >=70 years and 9% had ECOG performance status of 2 or more. At data cut off (median of 15.9 months' follow-up), the median PFS was 9.6 months [95% confidence interval (CI)=9.0-10.4 months] and the median OS was 21.6 months (95% CI=19.4-23.5 months). The most common non-haematological adverse drug reactions of grade 3 or more were pain (9%), hypertension (5%), sensory neuropathy (3%) and proteinuria (3%). Prolonged bevacizumab was well-tolerated. CONCLUSION: The efficacy and safety of first-line bevacizumab-paclitaxel in routine oncology practice is consistent with results from randomized trials. PMID- 26976986 TI - Treatment of Oncological Post-surgical Wound Dehiscence with Autologous Skin Micrografts. AB - BACKGROUND/AIM: The closure of postoperative wounds is essential in order to prevent surgical site infections or wound dehiscence, mainly in oncological patients. We aimed to demonstrate the efficacy of autologous micrografts in the management of wound dehiscence in an oncology patient undergoing decompressive spinal laminectomy. CASE REPORT: A 57-year-old man with IgG multiple myeloma and medullary plasmocytoma C7-T3, was to undergo decompressive spinal laminectomy and vertebral fixation leading to a wound dehiscence with exposed instrumentation. Autologous micrografts were obtained by Rigenera protocol and directly applied to the dehisced wound. After 60 days of negative pressure wound therapy, we observed reduction of the diameter and depth of wound dehiscence, with a coverage of instrumentation, without complete re-epithelialization, that instead was reached by application of autologous micrografts after 70 days. CONCLUSION: The Rigenera protocol may be the solution for complex wounds in oncological and immune compromised patients where other treatments are contraindicated. PMID- 26976987 TI - Extent of Salvage Neck Dissection in Advanced Oro- and Hypopharyngeal Cancer. AB - BACKGROUND/AIM: Primary radiochemotherapy (RCT) is becoming increasingly important in patients with oro- and hypopharyngeal cancer. However, debate exists on the extent of salvage neck dissection (ND) in those patients. The purpose of the present study was to evaluate the regional control after salvage ND. PATIENTS AND METHODS: Clinical, histological and radiological data, results of 51 patients with oro- or hypopharyngeal cancer and N2 neck who underwent selective ND in case of radiological evidence of residual neck disease, were retrospectively analyzed. RESULTS: Altogether 52 metastases were detected in 20 (39.2%) patients by histological examination. They were localized in level II (n=23), III (n=13), IV (n=11) and V (n=5). Regional recurrence occurred in 4 patients (7.8%) in previous dissected neck levels in the follow-up. CONCLUSION: Selective ND of suspicious neck levels for residual disease after RCT of oro- and hypopharyngeal cancer seems to be a sufficient treatment. PMID- 26976988 TI - Phase I Study of Docetaxel, Cisplatin, and 5-Fluorouracil Chemoradiotherapy for Local or Metastatic Esophageal Cancer. AB - BACKGROUND/AIM: Chemoradiotherapy outcomes for unresectable esophageal cancer remain poor. We designed a phase I study of docetaxel, cisplatin (CDDP), and 5 fluorouracil (5-FU) chemoradiotherapy. PATIENTS AND METHODS: Patients with T4 or M1 esophageal squamous cell carcinoma were enrolled. They received 2 chemotherapy cycles every 4 weeks with these initial doses (Phase I): docetaxel and CDDP (50 mg/m(2), days 1 and 29) with continuous 5-FU infusion (600 mg/m(2)/day, days 1-5 and 29-33). Concurrent radiotherapy (60 Gy) was initiated on day 1. Docetaxel and CDDP plus 5-FU doses were increased to 60 mg/m(2) plus 800 mg/m(2)/day. RESULTS: Out of the 15 patients enrolled, 13 completed the treatment. The MTDs were as follows: docetaxel (60 mg/m(2)), CDDP (60 mg/m(2)), and 5-FU (800 mg/m(2)/day). The overall response rate was 73%, with 27% achieving complete responses. CONCLUSION: In this phase I trial, docetaxel (60 mg/m(2)), CDDP (60 mg/m(2)), and 5-FU (600 mg/m(2)/day) were considered as the tolerable and active doses. These are the recommended doses for a future phase II trial. PMID- 26976989 TI - Prognostic Significance of the Preoperative Ratio of C-Reactive Protein to Albumin in Patients with Colorectal Cancer. AB - BACKGROUND: Inflammation has been reported to play an important role in cancer progression, and several inflammatory markers, such as the neutrophil to lymphocyte ratio (NLR) and modified Glasgow prognostic score (mGPS), have been reported to be prognostic markers. The aim of this retrospective study was to evaluate the prognostic significance of the ratio of C-reactive protein to albumin (CRP/ALB ratio) in patients with colorectal cancer who undergo potentially curative surgery. PATIENTS AND METHODS: A total of 705 patients who underwent potentially curative surgery for colorectal cancer were enrolled. The CRP/ALB ratio was calculated form the preoperative samples by dividing the serum C-reactive protein level by the serum albumin level. We evaluated the correlation between the CRP/ALB ratio and survival. Furthermore, we compared the accuracy of the CRP/ALB ratio as a predictor for survival with the mGPS. RESULTS: We set 0.0271 as the cut-off value for the CRP/ALB ratio according to a receiver operating characteristic curve analysis. Based on the cut-off value of 0.0271, 347 patients were classified into the low CRP/ALB ratio group and 358 patients were classified into the high CRP/ALB ratio group. The group with high CRP/ALB ratio had significantly worse relapse-free survival (p=0.0003) and cancer specific survival (p=0.0026) rates than those of the low CRP/ALB ratio group. According to a multivariate analysis, the CRP/ALB ratio was identified as an independent prognostic factor for relapse-free survival (p=0.025) and cancer specific survival (p=0.045). Moreover, even in a sub-analysis limited to patients with an mGPS of 0, the high CRP/ALB ratio group had significantly worse relapse free survival (p=0.0015) and cancer-specific survival (p=0.0131) rates than the low CRP/ALB ratio group. CONCLUSION: The preoperative CRP/ALB ratio is a useful prognostic marker in patients with colorectal cancer who undergo potentially curative surgery. Moreover, the CRP/ALB ratio may be superior to the mGPS for predicting survival. PMID- 26976990 TI - Neuroendocrine Neoplasms of the Ovary: A Retrospective Study of the North Eastern German Society of Gynecologic Oncology (NOGGO). AB - BACKGROUND/AIM: Neuroendocrine neoplasms (NEN) of the female genital tract account for 2% of gynecological cancers. The aim of this study was to share our experience of 11 primary neuroendocrine neoplasms of the ovary. PATIENTS AND METHODS: All patients who presented and/or were treated at our Institution with histologically-confirmed NEN of the ovary were included. Clinical data including tumor stage, diagnostic and therapeutic management and survival were assessed. Pathological specimens were critically reviewed. RESULTS: We identified 11 patients with NEN of the ovary consisting of nine neuroendocrine cancers and two carcinoids. Median age was 55.9 years. NEN were mostly poorly differentiated (72.4%). Primary surgery was performed in all patients. Adjuvant chemotherapy was administered in five patients consisting of platinum-based regimens. Median overall survival was 20 months. CONCLUSION: We propose a diagnostic algorithm for NEN of the ovary and discuss possible treatments according to FIGO stages. Patients should be included in multicenter studies whenever possible. PMID- 26976991 TI - Postmyomectomic Uterine Rupture Despite Cesarean Section. AB - Uterine fibroids (leiomyomas) are benign smooth muscle tumors of the uterus. Fibroids can develop anywhere within the muscular wall. Leiomyomas may be associated with infertility. Laparoscopic myomectomy is often used to remove symptomatic intramural or subserosal fibroids. Advantages of the procedure include short recovery time and minimal perioperative morbidity. At the same time, the multilayer suture technique is more complicated during laparoscopy. A rare but serious complication of laparoscopic myomectomies is uterine rupture. A brief review of the literature and a clinical example of a 33-year-old woman with history of infertility, laparoscopic myomectomies and uterine rupture followed by peripartum hemorrhage is presented. The treatment of leiomyomas is a challenge not only because of possible recurrence but also due to long-term consequences following successful myomectomy. Management of patients with uterine scars should include careful planning of the route of delivery, as the risk of rupture may be increased. PMID- 26976993 TI - Results of Further Diagnostic Procedures Among Patients with Cytological Characteristics of Minor Changes on Pap Smears. AB - BACKGROUND: Atypical squamous cells of undetermined significance (ASCUS) and low grade squamous intraepithelial lesion (LSIL) are the two most common results of positive Pap smears. AIM: The aim of this study was to compare the management of patients with ASCUS and LSIL. PATIENTS AND METHODS: All procedures were performed between 2003 and 2014 in an outpatient clinic affiliated to a tertiary referral center, and included Pap smears, colposcopy, histology and invasive treatment. RESULTS: There were 131 patients in the ASCUS group and 84 in the LSIL group. Further negative cytological results were obtained more frequently among the ASCUS group than the LSIL group [relative risk (RR)=1.18, 95% confidence interval (CI)=1.33-2.40; p<0.001]. Histological results revealed higher occurrence of cervical intraepithelial neoplasia grade III or invasive squamous cancer in the LSIL group than the ASCUS group [RR=6.8 (95% CI=0.95-144.63), p=0.033]. Patients from the LSIL group more frequently required invasive treatment [RR=2.53, 95% CI=1.40-4.67, p=0.001]. CONCLUSION: Diagnosis of ASCUS is associated with more frequent cases of total remission in follow-up Pap smears and requires for less invasive management. PMID- 26976992 TI - Role of IGF-I in Primary Ovarian Cancer - A Study of the OVCAD European Consortium. AB - BACKGROUND/AIM: IGF-I (insulin growth factor 1) is crucially involved in cellular proliferation. Moreover, deregulation of IGF-I has been shown to be relevant in the carcinogenesis of various tumor entities. However, the impact of IGF-I in epithelial ovarian cancer (EOC) is unclear. In the present study, we investigated the predictive and prognostic role of circulatory IGF-I in primary EOC patients. PATIENTS AND METHODS: In the FP6 European Project "OVCAD", 275 consecutive primary EOC patients were enrolled. Patients were eligible if radical cytoreductive surgery and platinum-based chemotherapy were performed. Plasma IGF I was detected using ELISA. RESULTS: Increased plasma IGF-I levels were more frequently found in well-differentiated epithelial ovarian carcinoma (p=0.0047). A weak correlation was observed between IGF-I levels and CA-125 in patients with serous EOC (p=0.04). No association between IGF-I expression and other clinico pathological parameters was observed. CONCLUSION: IGF-I is overexpressed in patients with well-differentiated EOC. Further studies are warranted to elucidate the role of IGF-I in this sub-group of patients. PMID- 26976994 TI - Effect of Denosumab Administration on Lumbar Vertebral Strength of Patients with Vertebral Bony Metastases: Preliminary Study. AB - The purpose of this study was to examine the usefulness of administration of denosumab (antibody against tumor necrosis factor superfamily member 11) as a preventative therapy for skeletal-related events (SREs), such as fracture or paralysis, by computed-tomography (CT)-based on the finite element method (FEM). Patients who had undergone treatment for vertebral metastases with denosumab administration from December 2013 to August 2015 at our Institution were reviewed. We investigated patient data at the time before denosumab administration and at 1, 3 and 6 months using CT. A total of six patients were eligible; four males and two females, with ages ranging from 35 to 73 years, with a mean age of 56 years. Repeated measures analysis of variance showed a significant increase (p=0.0055, F=10.67). To our knowledge, this is the first article to substantiate the effects of the SRE-preventative drug denosumab. PMID- 26976995 TI - Clinical Outcomes of Patients with Extensive Peritoneal Carcinomatosis Following Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy. AB - AIM: The aims of this study were to explore clinical outcomes and assess the learning curve for cytoreductive surgery and perioperative intraperitoneal chemotherapy (PIC) for patients with a high peritoneal cancer index (PCI). PATIENTS AND METHODS: This was a retrospective study of patients with a PCI of 20 or more following CRS and PIC. Outcomes in five successive groups based on the operation date were analyzed. RESULTS: Three hundred and five patients were included in the study. The median overall survival (OS) was 89.3 months (95% confidence interval=58.9-107.6 months). OS at 1, 3 and 5 years of our study cohort was 89.4%, 70.4% and 57.5%, respectively. In terms of the learning curve, the mean duration of operation and hospital mortality decreased (p<0.001 and p=0.006 respectively). A trend for decreasing intensive care unit stay (p=0.497), high dependency unit stay (p=0.042) and total hospital stay (p=0.202) were also recorded. CONCLUSION: A high PCI alone should not be a contraindication for cytoreductive surgery and PIC in specialized centres. PMID- 26976996 TI - Prognostic Value of Carcinoembryonic Antigen (CEA), AFP, CA19-9 and CA125 for Patients with Colorectal Cancer with Peritoneal Carcinomatosis Treated by Cytoreductive Surgery and Intraperitoneal Chemotherapy. AB - BACKGROUND: This study aimed to clarify the prognostic significance of tumour markers on long-term survival in colorectal peritoneal carcinomatosis (CRPC) following cytoreductive surgery and intraperitoneal chemotherapy. PATIENTS AND METHODS: Preoperative serum tumour markers of 164 patients with CRPC were analyzed. Peritoneal cancer index (PCI) was measured and relationship to survival calculated. RESULTS: Carcinoembryonic antigen (CEA) >6.5 mg/l and cancer antigen 125 (CA125) >16 U/ml remained independent predictors of survival after adjusting for PCI [adjusted hazard ratio (aHR)=2.46, 95% confidence interval (CI)=1.3-4.5, p<0.01 and aHR=2.23, 95% CI=1.21-4.09, p<0.01, respectively]. Patients with high CEA and low CA125 or vice versa had an approximately triple risk of death (HR=3.34, 95% CI=1.21 9.25, p=0.02 and HR=2.76, 95% CI=1.01 7.77, p=0.04, respectively). High CEA with high CA125 produced an additive effect, reflecting a six-fold increase in death (HR=6.57, 95% CI=2.62 13.69, p<0.001, median survival: not reached vs. 22 months). CONCLUSION: Serum CEA and CA125 in patients with CRPC treated with cytoreductive surgery and intraperitoneal chemotherapy convey a negative prognostic effect independently of PCI. PMID- 26976997 TI - Prognostic Value of Anti-Mullerian Hormone and Inhibin B in Patients with Premenopausal Hormone Receptor-positive Breast Cancer. AB - AIM: We investigated whether the ovarian reserve determined on the basis of anti Mullerian hormone (AMH) and inhibin B predicted disease-free survival (DFS) in premenopausal patients with hormone receptor-positive breast cancer treated with neoadjuvant chemotherapy. PATIENTS AND METHODS: Our analysis included 32 premenopausal women with clinical stage III hormone receptor-positive invasive ductal breast cancer treated by neoadjuvant chemotherapy. Blood samples were obtained after neoadjuvant chemotherapy completion. The median follow-up period was 57.7 months. RESULTS: The median patient age was 41.5 years. The group with functional ovarian reserve was classified by higher AMH and higher inhibin B levels using cut-off values of 1,000 pg/ml and 30 pg/ml, respectively. The group with functional ovarian reserve had significantly worse DFS (p=0.043) than the group with ovarian failure. CONCLUSION: The functional ovarian reserve defined by higher serum AMH and inhibin B after neoadjuvant chemotherapy predicted poor DFS in premenopausal women with clinical stage III hormone receptor-positive breast cancer. PMID- 26976998 TI - Bortezomib, Thalidomide and Lenalidomide: Have They Really Changed the Outcome of Multiple Myeloma? AB - Treatment of multiple myeloma (MM) has significantly improved, although the disease remains incurable. Prospective clinical trials evaluating the impact on outcome of new drugs such as proteasome inhibitors or immunomodulating agents are limited since they are not able to reflect the clinical routine and available retrospective data are not detailed enough to directly evaluate the value of new drugs. To address these information gaps, we performed a retrospective real-life analysis. We retrospectively assessed 949 patients treated for multiple myeloma or plasma cell leukemia at three Italian cancer centers in the years 1979-2014. Clinical features at the time of diagnosis were consistent with what was observed in clinical routine. A total of 39% of patients underwent high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). The median overall survival (OS) of the whole group was 5.4 years and ranged from 3.4 years for patients who did not receive at least one of the new drugs compared to 5.9 years in the other patients (p<0.001). The improvement in OS due to administration of new drugs was also observed among different prognostic sub-groups such as age, Durie and Salmon stage, international staging system and renal impairment. Availability of new drugs significantly improved survival of patients who underwent ASCT and also those who did not. In conclusion, we provided evidence that the advent of the new drugs drastically improved the outcome of patients with MM, also in cases with poor risk at the time of diagnosis. ASCT is still of major importance in the treatment of this disease. Nevertheless, MM remains incurable and new therapeutic approaches are warranted. PMID- 26976999 TI - Computed Tomographic Features of Malignant Peritoneal Mesothelioma. AB - AIM: The objective of this study was to determine the computed tomographic (CT) features of malignant peritoneal mesothelioma (MPM). PATIENTS AND METHODS: We analyzed CT features of MPM cases and compared them to those of other malignant conditions (non-MPM). RESULTS: Multiple nodular lesions occurred more frequently in the MPM group compared to non-MPM cases (p=0.013). Thickening of the mesentery was detected more frequently in MPM cases than in non-MPM cases (56% vs. 18%, p=0.029). Pleural plaques were detected in 13 cases (45%) in the MPM group but were not detected in the non-MPM group. The MPM-CT index score, determined in each case as the sum of the findings which are potentially characteristic of MPM, was significantly higher in MPM than in non-MPM cases (p=0.001). CONCLUSION: MPM presented characteristic CT findings, and the MPM-CT index may be useful for differential diagnosis of MPM. PMID- 26977000 TI - A Survival Score for Patients Receiving Stereotactic Radiosurgery Alone for Brain Metastases from Breast Cancer. AB - AIM: To generate a survival score for patients with breast cancer treated with stereotactic radiosurgery (SRS) alone for brain metastases. PATIENTS AND METHODS: Seven factors were evaluated in 34 patients, namely age, performance score, number of brain metastases, maximum diameter of all brain metastases, location of brain metastases, extracerebral metastases and time between breast cancer diagnosis and SRS. The score was created from factors having a significant impact on survival. Points of 0 (worse survival) or 1 (better survival) were assigned. Factor scores were added to total prognostic scores for each patient. RESULTS: A significant impact on survival was found for performance score (p<0.001), maximum diameter of cerebral lesions (p=0.002), and extracerebral metastases (p=0.026). Three groups were designated by score: 0-1, 2 and 3 points. One-year survival rates were 48%, 71% and 100%, respectively (p<0.001). CONCLUSION: This score contributes to appropriate selection of personalized treatment in patients with breast cancer with few cerebral metastases. PMID- 26977001 TI - The Prognostic Role of KRAS Mutation in Patients with Advanced NSCLC Treated with Second- or Third-line Chemotherapy. AB - BACKGROUND/AIM: The prognostic and predictive value of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in non-small cell lung cancer (NSCLC) is not well established. The present study aimed at the elucidation of the role of KRAS mutation in prediction of outcome of patients with advanced NSCLC receiving second- or third-line chemotherapy. PATIENTS AND METHODS: The outcome of 127 patients with advanced NSCLC who recieved pemetrexed or docetaxel at second- or third-line therapy was retrospectively analyzed. RESULTS: Progression-free survival was not significantly different between patients with KRAS mutation and those with wild-type KRAS. The results were the same even when taking into account the specific KRAS mutation. Overall survival was significantly longer for patients with wild-type KRAS vs. those with KRAS mutation (16.1 vs. 7.2 months, p=0,008). We observed shorter overall survival for those with G12C KRAS mutation vs. other KRAS mutations (median 10.3 vs. 6.4 months, p=0.011). CONCLUSION: The presence of KRAS mutation (especially KRAS G12C mutation) correlated with adverse prognosis in patients treated with second- or third-line pemetrexed or docetaxel. PMID- 26977003 TI - Impact of the Radiation Dose on Survival after Radiochemotherapy for Small-cell Lung Cancer. AB - AIM: Radiochemotherapy for small-cell lung cancer may not be sufficiently tolerated by all patients. To contribute to better personalization of the radiochemotherapy programs, this study compared two radiotherapy doses and 10 characteristics for survival. PATIENTS AND METHODS: In 71 patients receiving radiochemotherapy for small-cell lung cancer, the radiation dose given as equivalent dose in 2 Gy fractions (EQD2: <56 vs. >=56 Gy) plus 10 characteristics, namely gender, age, Karnofsky performance score, T-category, N category, tumor stage, pack years, smoking during radiotherapy, respiratory insufficiency and hemoglobin prior to radiotherapy, were evaluated for survival. RESULTS: On multivariate analysis, EQD2 >=56 Gy (p=0.003), female gender (p=0.029), Karnofsky performance score >70 (p<0.001), very limited disease (p=0.043) and pre-radiotherapy hemoglobin >=12 g/dl (p=0.044) were significantly associated with better survival. CONCLUSION: This study identified several independent predictors of survival after radiochemotherapy of small-cell lung cancer. A radiation dose of >=56 Gy resulted in better survival than lower doses. PMID- 26977004 TI - Biomarkers in Colorectal Cancer. AB - Colorectal cancer is the third most common cancer worldwide, with 1.36 million people diagnosed in 2012. The prognosis of colorectal cancer is better with an earlier diagnosis. The outcome of colorectal cancer may also be improved by targeting pathways involved in colorectal cancer formation, such as anti epidermal growth factor receptor (EGFR) therapy. An understanding of colorectal carcinogenesis is essential for the design of molecular targeting. Recent advances in the molecular subtypes of colorectal cancer, methylation of DNA in colorectal cancer, and micro-RNA biogenesis, and their involvement in colorectal cancer have resulted in the identification of many new colorectal biomarkers. Such biomarkers may be used for earlier diagnosis of, selection of 'personalised' therapy for, and prognosis of colorectal cancer. Many of these biomarkers appear promising in small-scale studies. However, validation of their effectiveness with large-scale clinical trials is needed before routine clinical application. To this end, the recently established consensus molecular subtypes of colorectal cancer would enable like-for-like comparisons of the treatment outcomes of clinical trials. PMID- 26977002 TI - Locked Nucleic Acid In Situ Hybridization Analysis of MicroRNA-21 Predicts Clinical Outcome in Patients After Resection for Pancreatic Cancer Treated with Adjuvant Gemcitabine Monotherapy. AB - BACKGROUND: The overexpression of microRNA-21 (miR-21) in pancreatic cancer has been implicated in drug resistance to gemcitabine. Thus far, miR-21 has gained wide attention as a potential biomarker to predict the clinical response in patients with pancreatic cancer receiving gemcitabine. The aim of this study was to evaluate the predictive value of miR-21 expression, determined by locked nucleic acid in situ hybridization (LNA-ISH), in patients with pancreatic cancer who underwent adjuvant gemcitabine after curative surgery. MATERIALS AND METHODS: Tumor miR-21 expression was analyzed via LNA-ISH and correlated with the clinical outcomes of the patients treated with adjuvant gemcitabine. RESULTS: The overexpression of miR-21 in pancreatic cancer, determined by LNA-ISH, was significantly and independently associated with a shorter disease-free survival in patients who received adjuvant gemcitabine after curative resection. CONCLUSION: The LNA-ISH analysis of miR-21 may serve as a significant predictor for gemcitabine resistance in patients with pancreatic cancer undergoing adjuvant gemcitabine after curative resection. PMID- 26977005 TI - Phosphoinositide-3-Kinase Enhancers, PIKEs: Their Biological Functions and Roles in Cancer. AB - Phosphoinositide 3-kinase enhancer (PIKE) belongs to a family of GTP-binding proteins, including three isoforms, PIKE-S, PIKE-L and PIKE-A. PIKE-S and PIKE-L interact with PI3K to enhance the activity of PI3K, but PIKE-A directly binds to AKT and up-regulates its activity. PIKEs also interacts with a variety of signaling molecules in addition to PI3K and AKT, to trigger multiple physiological functions. Overexpression or mutation of PIKE has been observed in a variety of tumors, especially PIKE-A, which acts as a proto-oncogene, promoting cancer cell growth, transformation and invasion through AKT signaling. Knockdown of PIKE-A or blocking of PIKE-A/AKT interactions enhances apoptosis, inhibits cancer cell proliferation, migration and invasion. Moreover, PIKE plays an important role in tumorigenesis through other signaling pathways, such as focal adhesion kinase, signal transducer and activator of transcription 5A, and nuclear factor kappa-light-chain-enhancer of activated B cells. The current review explores the functional role of PIKE and its potential in cancer therapy. PMID- 26977006 TI - Update on Biomarkers in Development of Anti-angiogenic Drugs in Gastric Cancer. AB - The treatment of advanced gastric cancer remains challenging as the outcomes achieved with surgery alone or adjuvant or neoadjuvant chemotherapy and radiotherapy are poor. New treatment strategies are emerging and being tested in advanced gastric cancer. Vascular endothelial growth factor (VEGF) inhibitors have been confirmed as important therapeutic agents in randomised clinical trials in multiple solid tumour settings. Until now, results of phase II and phase III clinical trials of anti-angiogenic agents on gastric cancer have been relatively modest, with moderate improvement in overall survival. The effects of these drugs are limited due to development of resistance to them and the increased risk of tumour invasion and metastasis. If we are to optimise or develop combination regimens for advanced gastric cancer with VEGF inhibitors that build on their efficacy, it is critical to identify and validate biomarkers in order to enable selection of those patients who are prone to benefit and monitor their response to the drugs. Validated biomarkers can help to further personalise VEGF inhibitors and dosage determination for advanced or metastatic gastric cancer, particularly as these drugs can be toxic and expensive. Although no biomarker is validated for routine use for this purpose, several candidates are currently under investigation. In this review, we aim to give an overview of the recent developments in biomarkers for anti-angiogenic therapy in gastric cancer tumour angiogenesis. PMID- 26977007 TI - Tumour-Endothelial Cell Communications: Important and Indispensable Mediators of Tumour Angiogenesis. AB - Angiogenesis is an essential aspect of tumour growth and metastasis. Solid tumours cannot grow beyond 2-3 mm in diameter without inducing the formation of new blood vessels to support the energetic requirements of tumour cells. Angiogenesis is stimulated by cancer cells through a wide variety of cell-to-cell communication means. Cancer cells can induce endothelial changes by directly targeting cells via soluble factors, adhesion receptors, gap junctions and vesicles. They also can stimulate endothelial signaling pathways in an indirect way, e.g. by activating stromal cells, by secreting proteases into the extracellular space or even by changing the pH, temperature and availability of oxygen and nutrients. Anti-angiogenic drugs appear to be an effective cancer treatment in animal models but have been shown to have a limited effect in the long term. Resistance to anti-angiogenic therapies has been attributed to the ability of cancer cells to induce angiogenesis in a different way. We propose that cancer cells also change the way they communicate with endothelial cells in order to escape therapies that inhibit angiogenesis and that a better knowledge of this phenomenon will help us design more efficient drugs. PMID- 26977008 TI - Targeting of Receptor Activator of Nuclear Kappa B (RANK) in PC-3 Cells Increases Cell Proliferation and Matrix Adhesion In Vitro. AB - BACKGROUND: In Western societies, prostate cancer is the most frequently diagnosed cancer amongst men. Efforts to improve diagnosis and treatment remain a major focus and have been proven beneficial in the approach to localised disease. However, currently, metastatic disease management still remains palliative. Receptor activator of nuclear kappa B (RANK) has been extensively studied in bone biology and immunology, whilst several links have been made between RANK-positive breast cancer cells and disease progression. Its role in prostate cancer biology remains poorly understood, therefore the aim of this study was to explore the functional role of endogenously produced RANK in metastatic PC-3 prostate cancer cells in isolation and in response to hepatocyte growth factor (HGF). MATERIALS AND METHODS: RANK expression was targeted using hammerhead ribozyme technology in PC-3 prostate cancer cells, and verified by polymerase chain reaction and western blot. A variety of in vitro functional assays were conducted, including cell proliferation and matrix adhesion in the presence of HGF. RESULTS: Suppression of RANK expression was successfully targeted with anti-RANK hammerhead ribozyme transgenes, as verified by PCR and western blot. Reduced RANK expression resulted in significantly increased PC-3 cell proliferation (p<0.01) and cell-matrix adhesion (p<0.05) compared to control cells. CONCLUSION: Previous work into RANK and prostate cancer has focused on its interaction with the bone environment, particularly with regard to its receptor RANK ligand. This study has shown that endogenous RANK expression changes might also influence prostate cancer cell behaviour. Further work is now required to elucidate the signaling pathways involved in these processes. PMID- 26977009 TI - The Association Between WAVE1 and -3 and the ARP2/3 Complex in PC 3 Cells. AB - BACKGROUND: Actin polymerisation is stimulated by the actin-related protein (ARP) 2/3 complex and drives cell migration. This complex is activated by Wiskott Aldrich syndrome protein family (WASP) verprolin homologous protein (WAVE) proteins. WAVE1 and -3 have been implicated in the aggressiveness of metastatic prostate cancer cells. MATERIALS AND METHODS: Cell growth, motility and invasion were analyzed in WAVE1- and WAVE3-knockdown PC-3 cells along with the ARP2/3 inhibitor, CK-0944636. Confocal microscopy was adopted to examine protein co localisation. Immunoprecipitation approaches were used to determine protein tyrosine phosphorylation. RESULTS: Cell growth suppression was observed with WAVE3 knockdown and ARP2/3 inhibition. Reduced cell invasion effects observed with WAVE1 knockdown appeared to be rescued by ARP2/3 inhibition. WAVE1 and WAVE3 and ARP2 co-localisation was lost in PC-3 WAVE-knockdown cells, while increased ARP2 tyrosine phosphorylation was observed with WAVE3 knockdown. CONCLUSION: These results implicate a contributory role of WAVE1 and -3 to the metastatic phenotype of PC-3 cells through their interaction with the ARP2/3 complex. PMID- 26977010 TI - MDM2 and PSMA Play Inhibitory Roles in Metastatic Breast Cancer Cells Through Regulation of Matrix Metalloproteinases. AB - BACKGROUND/AIM: Mouse double minute 2 (MDM2) and prostate-specific membrane antigen (PSMA) are currently under investigation as individual therapeutic targets due to their overexpression in many cancer types, as well as their pro tumorigenic effect on cells. Recently, knockdown of PSMA was linked to a decrease in MDM2 and matrix metalloproteinase 2 (MMP2) and an increase in MMP3 and MMP13 expression. We aimed to assess the link between PSMA, MDM2 and the MMPs in metastatic breast cancer cell lines. MATERIALS AND METHODS: Real-time quantitative polymerase chain reaction (PCR) and western blotting were used to assess siRNA-mediated knockdown of MDM2 and PSMA in MDA-MB-231 and ZR-75.1 breast cancer cells. Assays to assess the growth, adhesion, migration and invasion of the cells following siRNA treatment were undertaken. MMP and tissue inhibitor of matrix metalloproteinases (TIMP) levels were assessed via quantitative PCR. RESULTS: Knockdown of MDM2 resulted in a decrease in PSMA expression levels and vice versa; although this trend was not replicated at the protein level. Knockdown of each of the molecules resulted in a decrease in growth, adhesion, migration and invasive ability of breast cancer cells. Both knockdowns led to a decrease in MMP2 and an increase in MMP3, -10 and -13 gene expression. CONCLUSION: MDM2 and PSMA may co-regulate the expression of certain MMPs and, thus, the functionality of cells in metastatic breast cancer. PMID- 26977011 TI - IL24 and its Receptors Regulate Growth and Migration of Pancreatic Cancer Cells and Are Potential Biomarkers for IL24 Molecular Therapy. AB - BACKGROUND: Pancreatic cancer is hard to diagnose and treat due to its asymptomatic development and early metastasis. Supplementary therapy including molecular targeted therapy is needed to improve the outcome of pancreatic cancer. The significance of interleukin 24 (IL24) and its receptors in pancreatic cancer were investigated in this study. MATERIALS AND METHODS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was carried out in 200 patient samples of pancreatic cancer. Transcript and protein expression were investigated in pancreatic cancer cells. Impact of IL24 recombinant protein on cell functions was examined. RESULTS: High IL20R1 transcript expression was related to early T stage, and advanced N, and M stage. They collectively correlated with the survival of the patients. Treatment with IL24 inhibited cell growth, but its impact on migration varied depending on protein concentration. CONCLUSION: IL20R1 correlated with prognosis of patients with pancreatic cancer, and mediates pancreatic cancer cell growth and migration. It may be a potential biomarker for IL24 molecular-targeted therapy. PMID- 26977012 TI - A Novel NHERF1 Mutation in Human Breast Cancer Inactivates Inhibition by NHERF1 Protein in EGFR Signaling. AB - BACKGROUND: Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) has been reported to interact with many cancer-related proteins. We recently identified a novel NHERF1 mutation (E43G) in breast tumours. MATERIALS AND METHODS: The candidates of NHERF1 mutation were identified in breast cancer tissues by polymerase chain reaction and DNA sequencing. Wild-type NHERF1 and E43G mutation were expressed in NHERF1-knockdown cells (MCF7DeltaNHERF1) and low-NHERF1-expressing cells (SKMES 1). The effects of mutated NHERF1 on cell functions were examined using in vitro methods. Glutathione S-transferase pull-down assays and western blotting were performed to study the effects of NHERF1 mutation on its interaction with cancer related proteins. RESULTS: Compared to wild-type NHERF1, expression of the mutated NHERF1 failed to suppress malignant traits in cancer cells, attenuated interaction of NHERF1 protein with epidermal growth factor receptor (EGFR), and inactivated its inhibition of EGF-induced Akt and extracellular regulated protein kinases (ERK) activation. CONCLUSION: The results show the causal role of NHERF1 in the regulation of the EGFR pathway and the progression of breast cancer. PMID- 26977013 TI - Biochemical Features of Recombinant Human Cyclophilin J. AB - AIM: To characterize the biochemical features of the newest member of cyclophilin family of peptidyl-prolyl cis/trans-isomerases (PPIases), cyclophilin J (CYPJ). MATERIALS AND METHODS: PPIase assays were performed on purified hCYPJ and its mutated variants. The substrate specificity, half-maximal inhibitory concentration (IC50) of cyclosporin A (CsA) inhibition and circular dichroism (CD) spectrum of CYPJ were measured. Mercury pathway profiling luciferase assays were also performed. RESULTS: The catalytic number/Michaelis constant (kcat/KM) value of CYPJ was 9.5*10(4) s(-1)M(-1). CYPJ additionally catalyzed norleucine proline, isoleucine-proline and glutamine-proline peptides compared to CYPA and Escherichia coli PPIases. CYPJ was inhibited by CsA in a dose-dependent manner with IC50 of 12.1+/-0.9 MUM. The CD spectrum of CYPJ was similar to CYPA. CYPJ significantly up-regulated the transcription of E-box, E2F, retinoblastoma (Rb), p53, activator protein 1 (AP1), NF-kappaB and phospho-cAMP response element (CRE) cis-response element in 293T cells. CONCLUSION: CYPJ structurally resembles CYPA. It is sensitive to inhibition by CsA and plays a role in regulating cell growth, proliferation, and apoptosis. PMID- 26977014 TI - Effect of YangZheng XiaoJi Extract, DME-25, on Endothelial Cells and their Response to Avastin. AB - BACKGROUND: Angiogenesis is a cellular process that has been identified as a key target for therapy in solid cancer. However, over the course of anti-angiogenic therapies, cancer cells acquire resistance to these therapies after an initial period of success. DME-25 is an extract from Yang Zheng Xiao Ji, a traditional Chinese medicine that has been reported to benefit patients with cancer by alleviating chemotherapy-associated symptoms and possibly inhibiting key cancer cell traits. This study aimed to explore if DME-25 on its own and in combination with avastin affected endothelial cell behaviour in vitro in the presence of hypoxic lung cancer-conditioned medium (CM). MATERIALS AND METHODS: Two lung cancer cell lines, A549 and SK-MES-1, were exposed to hypoxic conditions (O2 <=1%) for 4 h, after which CM, and RNA were collected. Transcript expression of several influential angiogenic markers in lung cancer cells were assessed following hypoxic/normoxic conditions. Lung cancer CM was added in combination with avastin and DME-25, before or after vascular endothelial growth factor (VEGF) depletion, to endothelial cells (HECV) and cell migration and microtubule formation were assessed in vitro. RESULTS: HECV cell migration was reduced in the presence of avastin, although less efficiently in the presence of lung cancer CM. A combination of DME-25 and avastin with lung cancer CM significantly reduced HECV cell migration irrespective of culture under hypoxia or normoxia. Depletion of VEGF from the CM reduced the inhibitory capacity of avastin, however, it appeared to have little impact on the anti-angiogenic effects of DME-25. CONCLUSION: DME-25 inhibits tubule formation irrespectively of the factors secreted by normoxic or hypoxic lung cancer cell CM depleted of VEGF. PMID- 26977015 TI - New Roles of Osteocytes in Proliferation, Migration and Invasion of Breast and Prostate Cancer Cells. AB - BACKGROUND: Most cases of prostate and breast cancer metastasis occur to the bone, and are responsible for the majority of cancer-related deaths. Osteocytes constitute over 90% of adult bone cells. They orchestrate bone remodelling through determining osteoclast activity and affecting osteoblasts. The osteocyte lacuno-canalicular network is also intimately associated with the blood vessel network in the bone matrix. However, the roles of osteocytes in cancer cell invasion and metastasis remain unknown. MATERIALS AND METHODS: In this study, we investigated the effects of early osteocytes on the behaviour of breast and prostate cancer cells. The proliferation of cultured cells was assessed using the AlamarBlue assay. The electric cell-substrate impedance sensing (ECIS) system was used to measure spreading, attachment and migratory behaviour of cancer cells in response to conditioned medium (CM) from mouse osteocytes. Other cell assays, including in vitro wound healing and transwell migration/invasion assays, were also applied to evaluate the effect of osteocytes on cancer cells. RESULTS: We found that CM from osteocytes from both monolayer and three-dimensional (3D) cultures, stimulated proliferation of DU145 and PC3 prostate cancer cells but not LNCaP cells compared to control medium. Osteocyte CM also stimulated proliferation of MDA-MB-231 and MCF-7 breast cancer cells. However, osteocyte CM promoted the migration and adhesion of PC3 and DU145 in prostate cancer cells but had the reverse effect on PZHPV7, a normal prostate epithelial cell line. In the breast cancer cells studied, osteocyte CM inhibited post-wound migration of MCF-7 and ZR-75.1 cells but not MDA-MB-231 cells. Moreover, osteocyte CM stimulated transwell chemotactic migration of MDA-MB-231 cells but not of MCF-7 and ZR-75.1 cells. CONCLUSION: Osteocytes play diverse roles in the proliferative and migratory potential of breast and prostate cancer cells that may be associated with cancer-specific bone metastasis and requires further investigation. PMID- 26977016 TI - Discovery of a Regulatory Motif for Human Satellite DNA Transcription in Response to BATF2 Overexpression. AB - BACKGROUND: One of the basic leucine zipper transcription factors, BATF2, has been found to suppress cancer growth and migration. However, little is known about the genes downstream of BATF2. MATERIALS AND METHODS: HeLa cells were stably transfected with BATF2, then chromatin immunoprecipitation-sequencing was employed to identify the DNA motifs responsive to BATF2. RESULTS: Comprehensive bioinformatics analyses indicated that the most significant motif discovered as TTCCATT[CT]GATTCCATTC[AG]AT was primarily distributed among the chromosome centromere regions and mostly within human type II satellite DNA. Such motifs were able to prime the transcription of type II satellite DNA in a directional and asymmetrical manner. Consistently, satellite II transcription was up regulated in BATF2-overexpressing cells. CONCLUSION: The present study provides insight into understanding the role of BATF2 in tumours and the importance of satellite DNA in the maintenance of genomic stability. PMID- 26977017 TI - Knockdown of EPHA1 by CRISPR/CAS9 Promotes Adhesion and Motility of HRT18 Colorectal Carcinoma Cells. AB - BACKGROUND: Erythropoietin-producing hepatocellular A1 (EPHA1) is the first member of the EPH superfamily. Its abnormal expression has been reported in various cancer types. However, the contribution of EPHA1 to the regulation of colorectal cancer cell behaviour remains unknown. MATERIALS AND METHODS: In this study, we investigated the expression profile of EPHA1 in human colorectal cancer and its effect on the adhesion and motility of colorectal cancer cells. We used human colorectal cancer specimens and the colorectal adenocarcinoma cell line HRT18 for this purpose. RESULTS: Our cohort screening data showed that in patients with colorectal cancer, low expression of EPHA1 gene is correlated with a remarkably reduced survival. After EPHA1 is knocked-down in colorectal cancer cells using a clustered regularly interspaced short palindromic repeats associated nuclease 9 (CRISPR-CAS9) genomic editing system, we observed an increase in the spreading and adhesion of HRT18 cells. Moreover, protein array data indicated that the extracellular-regulated kinase (ERK) and c-Jun NH2 terminal kinase (JNK) signaling pathways were activated as a consequence. Inhibition of ERK and JNK proteins with specific inhibitors led to suppression of migration of the colorectal cancer cells. CONCLUSION: EPHA1 suppresses spreading and adhesion of HRT18 colorectal cancer cells through deactivation of ERK and JNK signaling pathways. PMID- 26977018 TI - Microwave Ablation: The Differences Between Biliary Cirrhosis and Normal Porcine Liver Using a Cooled-tip Electrode. AB - AIM: To elucidate the difference in both in vivo and ex vivo microwave ablation in a biliary cirrhotic porcine liver model using a cooled-tip electrode. MATERIALS AND METHODS: Microwave ablation with cooled-tip electrode was conducted under laparotomy. Morphological and pathological characteristics of the ablated areas were compared. RESULTS: In the cirrhotic liver group, the in vivo ablated area was smaller than that ex vivo in terms of short and long axes, and volume. With the same ablation settings, both in vivo and ex vivo ablated areas in normal pig liver were larger than their counterparts in cirrhotic liver in terms of the short and long axes, and volume. CONCLUSION: Both in vivo and ex vivo ablated areas in biliary cirrhotic pig liver were smaller than their counterparts in normal liver, suggesting that for the same amount of power, it requires a significantly longer duration to achieve the same ablated volume in cirrhotic liver compared to normal liver. PMID- 26977020 TI - The Impact of TIMM17A on Aggressiveness of Human Breast Cancer Cells. AB - BACKGROUND: The mitochondrial protein translocase of inner mitochondrial membrane 17 homolog A (TIMM17A) has been identified as a biomarker of breast cancer. The present study aimed to investigate the biological role of TIMM17A in human breast cancer cells. MATERIALS AND METHODS: Anti-TIMM17A transgenes were stably transfected into MDA MB-231 and MCF-7 breast cancer cell lines. The impact of TIMM17A knock-down on cell migration and invasion were evaluated using the respective cell models. RESULTS: Reducing the expression of TIMM17A in breast cancer cells resulted in reduction of cell migration using electric cell substrate impedance sensing. It was also found that reduction of TIMM17A expression resulted in reduction of cell invasion compared to vector control. CONCLUSION: TIMM17A has a profound impact on the cellular function of breast cancer cells. A decrease of TIMM17A expression is associated with the reduction of the aggressiveness of breast cancer cells. TIMM17A, therefore, has potential in prognosis and treatment of breast cancer. PMID- 26977019 TI - Prostate Apoptosis Response-4 (PAR4) Suppresses Growth and Invasion of Breast Cancer Cells and Is Positively Associated with Patient Survival. AB - BACKGROUND: Prostate apoptosis response-4 (PAR4) plays an important role in apoptosis and survival of cancer cells. The current study aimed to further elucidate its role in breast cancer. MATERIALS AND METHODS: PAR4 expression in human breast cancer tissue was examined using quantitative polymerase chain reaction (qPCR) and immunohistochemical staining (IHC). Plasmids containing full length human PAR4 coding sequence were used to overexpress PAR4 in breast cancer cells and the effect on cellular functions was examined using both in vitro functional assays and an in vivo murine model. RESULTS: Patients with low PAR4 transcript levels had poorer overall survival. PAR4 expression may be associated with differential expression of oestrogen receptors alpha and beta in the tumours. Overexpression of PAR4 in MDA-MB-231 cells resulted in reduced cell growth and invasion, and also reduced in vivo tumour growth. CONCLUSION: Decreased PAR4 expression in breast cancer is associated with shorter survival. PAR4 suppresses growth and invasiveness of breast cancer cells. PMID- 26977021 TI - Relationship Between HSP70 and ERBB2 Expression in Breast Cancer Cell Lines Regarding Drug Resistance. AB - BACKGROUND: Heat shock protein 70 (HSP70) is known to be downstream of human epidermal growth factor receptor-2 (ERBB2), but little is known regarding the relationship between HSP70 and drug resistance mediated by ERBB2 in breast cancer. MATERIALS AND METHODS: After infecting breast cancer cells with lentivirus-mediated Lenti-ShHSP70 and Lenti-ShERBB2, we examined the expression of HSP70 and ERBB2 by real-time polymerase chain reaction and western blotting. RESULTS: Compared to the control groups, mRNA expression of HSP70 was decreased in lentivirus-infected, and western blotting indicated a concordant reduction of HSP70 protein. On the other hand, ERBB2 was significantly down-regulated by HSP70 silencing in SK-BR-3 cells at both the mRNA and protein levels. Expression of HSP70 in transfected cells was also reduced by Lenti-ShERBB2. CCK8 viability assay indicated that inhibition of HSP70 increased the sensitivity of SK-BR-3 cells to fluorouracil treatment. CONCLUSION: HSP70 affects ERBB2 and ERBB2 mediated drug-resistance in breast cancer cells. PMID- 26977022 TI - ADAM29 Expression in Human Breast Cancer and its Effects on Breast Cancer Cells In Vitro. AB - BACKGROUND: A Disintegrin and Metalloprotease Domain 29 (ADAM29) is involved in many important physiological processes. Recent studies have demonstrated that ADAM29 is a susceptibility locus showing traits as a risk factor for breast cancer under genome-wide significance, however, the clinical relevance and cellular function of ADAM29 in breast cancer have not been reported. MATERIALS AND METHODS: In this study, we assessed the expression levels of ADAM29 in a cohort of human breast cancer specimens. We also used MDA-MB-231 cells with differing ADAM29 expression and assessed the influence of ADAM29 and its mutations on the MDA-MB-231 cell line. RESULTS: Increased transcript expression of ADAM29 was observed in breast cancer tissues compared to normal ones. The expression of ADAM29 and its mutations in different domains significantly influenced proliferation, migration and invasion of breast cancer cells in vitro. CONCLUSION: ADAM29 may represent a prognostic factor in human breast cancer, as well as a novel molecular candidate to be used as a therapeutic target. PMID- 26977023 TI - Possible Effect of Muscle-relaxant Anaesthetics on Invasion, Adhesion and Migration of Breast Cancer Cells. AB - BACKGROUND: Aggressive surgical removal of the primary tumour is the preferred treatment, but with tumour progression, some tumours cannot be completely removed surgically. Anaesthetics are administered to facilitate surgery. However, anaesthetics act as a potential factor in tumour recurrence or metastasis. MATERIALS AND METHODS: Normal breast cells and cancer breast cells were treated with different doses of muscle-relaxant anaesthetics. The effects on breast cancer cell invasion, adhesion and migration of these anaesthetics were then investigated using in vitro models. RESULTS: With increasing dose of rocuronium bromide and suxamethonium chloride CRS, the number of MCF-10A and MCF-7 cells, but not that of MDA-MB-231 cells, decreased. There was almost no difference in the number of cells when the three cell lines were treated with different doses of vecuronium bromide. The study also demonstrated that rocuronium bromide promoted the invasion, adhesion and growth of MDA-231 cells, while suxamethonium chloride CRS had no effect. Interestingly, vecuronium bromide did not affect the motility and invasion of breast cancer cells significantly. CONCLUSION: An understanding of the effect of anaesthetics and their impact on tumour metastasis is important, thus using an appropriate aesthetic strategy could improve long term survival in some patients. PMID- 26977024 TI - The Clinical Implications of RSK1-3 in Human Breast Cancer. AB - BACKGROUND/AIM: The ribosomal S6 protein kinase (RSK) family is an important effector of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) that could influence tumour metastasis by phosphorylating proteins in both the nuclear and cytoplasmic compartments. Aberrant expression of RSK is evident in certain malignancies but the role played by RSK in breast cancer is still not clear. This study aimed to examine the expression of RSK in human breast cancer specimens and its role to breast cancer metastasis. MATERIALS AND METHODS: The expression of RSK1 to -3 were separately examined in human breast cancer tissues (normal, n=33; cancer, n=112) using quantitative real-time polymerase chain reaction (Q-PCR) and immunohistochemistry. Migration and adhesion of breast cancer cells treated with the RSK inhibitor SL0101 were investigated by electric cell impedance sensing (ECIS). The effect on growth and invasion of RSK1-3 was then investigated using in vitro models. RESULTS: The clinical data and immunohistochemistry revealed that expression of RSK1 and RSK3 were less in tumour tissues than normal. mRNA expression of RSK2 was negatively correlated with grade, TNM staging, and survival rate. SL0101 inhibited adhesion of the MCF-7 and MDA-231 breast cancer cell lines. SL0101 suppressed MDA-231 invasion and the alternate RSK inhibitor BRD7389 inhibited the invasion of MCF-7 and MDA-231 cells. CONCLUSION: RSK1 and 3 but not RSK2 are down-regulated in breast tumour and are associated with disease progression. RSK may be a key component in the progression and metastasis of breast cancer. PMID- 26977025 TI - Expression of PIN1 in Gastrointestinal Stromal Tumours and its Clinical Significance. AB - BACKGROUND: The malignancy of gastrointestinal stromal tumours (GIST) varies greatly. Due to the uncertainty of specific molecular pathogenesis and complexity of biological behaviour of GIST, the aggressiveness and prognosis of GIST cannot be precisely predicted. MATERIALS AND METHODS: We retrieved 40 paraffin-embedded specimens of surgically resected GIST between January 2013 and May 2015 at the Pathology Department of Yuhuangding Hospital Affiliated to Qingdao University and detected the expression of NIMA-interacting peptidylprolyl isomerase (PIN1) and Ki67, by immunohistochemical methods. RESULTS: The positivity rate of PIN1 and Ki67 in GIST was 80% and 32.5%, respectively. The expression of PIN1 was associated with risk of malignancy, tumour location, tumour size, and mitotic counts. The expression of Ki67 was also associated with risk of malignancy, tumour location, tumour size, and mitotic counts. The expression of Ki67 was positively related to the expression of PIN1. CONCLUSION: PIN1 and Ki67 may be potential factors predicting the malignancy of GIST. PIN1 may be an attractive prognostic indicator and therapeutic target for GIST. PMID- 26977026 TI - Expression of Semaphorin 3C in Breast Cancer and its Impact on Adhesion and Invasion of Breast Cancer Cells. AB - BACKGROUND: The aim of the current study was to examine the role of semaphorin 3C (SEMA3C) in breast cancer. MATERIALS AND METHODS: SEMA3C transcripts expressed by breast tissues were determined using real-time polymerase chain reaction (PCR). Knock-down of SEMA3C was performed in MDA-MB-231 and MCF-7 breast cancer cell lines using anti-SEMA3C hammerhead ribozyme transgenes. The effect of SEMA3C knockdown on cancer cells was determined using in vitro cellular function assays. RESULTS: Higher SEMA3C transcript levels were significantly associated with poor differentiation of cancer cells, and transcript levels were significantly reduced in oestrogen receptor-positive tumours. Knock-down of SEMA3C expression resulted in a decrease in cell proliferation, adhesion and invasion of breast cancer cells. CONCLUSION: Higher SEMA3C expression is correlated with tumour differentiation. Inhibition of SEMA3C reduces adhesion and invasion of breast cancer cells. This suggests that SEMA3C may play a significant role in morphological changes of cancer cells, leading to enhanced growth and dissemination. PMID- 26977027 TI - Metastasis to Bone in Human Cancer Is Associated with Loss of Occludin Expression. AB - BACKGROUND: Occludin is an integral membrane protein localised at tight junctions (TJ). There is no consensus regarding its paramount role in TJ. In previous work we showed that occludin is aberrantly expressed in both human breast tissues and cancer cell lines. This study demonstrates a link to bone metastasis in human cancer. MATERIALS AND METHODS: Primary breast tumours (n=124) and matched normal tissues (n=30) were processed for quantitative polymerase chain reaction (QPCR) analysis. A hammerhead ribozyme was constructed to create occludin knockdown cell lines, MDA-MB-231(DeltaOcc) and PC-3(DeltaOcc). The effect of human bone matrix extract (BME) was investigated using cell growth and electric cell impedance sensing (ECIS) technology to measure changes in attachment/migration. Trans epithelial resistance (TER) was measured for assessing changes in TJ function. Cells used were MDA-MB-231, PC-3, CORL-23, SKMES-1 and A-549 human cancer cell lines. RESULTS: Tumours from patients with bone metastasis had significantly lower occludin expression compared to those remaining alive/well (60.7+/-21 vs. 331+/-98, respectively, p=0.008). This was striking in ductal carcinomas, where patients alive/well had significantly higher occludin expression compared to those with bone metastasis (391+/-12.5 vs. 67.9+/-28, respectively, p=0.0014). ECIS demonstrated that MDA-MB-231(DeltaOcc) showed reduced attachment to 5% BME compared to controls (84% vs. 100%) that prevented closure of wounded cell layers. Moreover, these cells had reduced growth on BME. In addition, BME changed the TER of a number of human cell lines and was able to effect changes in the growth of MDA-MB-241 and PC-3 cells, with greater effect on knockdown cells. CONCLUSION: This is the first study to demonstrate that occludin expression has a clear relationship with bone metastasis in human cancer. The discrepancy between this and the in vitro data indicating a reduction in migration/growth rate of occludin knockdown indicates that loss of occludin leads to complex changes in human cancer cell phenotype. PMID- 26977028 TI - Reduced RanBPM Expression Is Associated with Distant Metastasis in Gastric Cancer and Chemoresistance. AB - AIM: Ran binding protein M (RanBPM) is a ubiquitous, nucleocytoplasmic protein that serves as a scaffolding molecule. This study aimed to investigate the role of RanBPM in gastric cancer. MATERIALS AND METHODS: RanBPM expression in human gastric cancer tissue samples was analyzed using real-time polymerase chain reaction. The effect of RanBPM on cellular functions was examined in RanBPM knockdown gastric cells and with in vitro cell functional assays. RESULTS: Gastric tumors with distant metastases expressed lower levels of RanBPM transcripts compared to tumours without detectable metastases (p=0.036). RanBPM knockdown in gastric cancer cells reduced adhesion and promoted survival of gastric cancer cells after exposure to methotrexate and fluorouracil. CONCLUSION: RanBPM levels were reduced in gastric tumors with distant metastases. This suggests that loss of RanBPM expression may play an important role in gastric cancer tumor development and metastasis. Reduced RanBPM expression is also associated with chemoresistance of gastric cancer cells. PMID- 26977029 TI - The Effects of Different Methods of Anaesthesia for Laparoscopic Radical Gastrectomy with Monitoring of Entropy. AB - AIM: To investigate the effects of methods of total intravenous anaesthesia (TIVA) and combined intravenous and inhaled anaesthesia (CIIA) for laparoscopic radical gastrectomy under the same anaesthetic depth monitored by entropy indices. PATIENTS AND METHODS: One hundred patients undergoing laparoscopic radical gastrectomy were randomly distributed into group I (anaesthetized by TIVA) and group II (anaesthetized by CIIA), each group including 50 patients. TIVA was performed with propofol and remifentanil by means of target controlled infusion (TCI) for the patients in group I. CIIA was performed for patients in group II by inhalation of sevoflurane and continuous infusion of remifentanil after anaesthesia induction, with state entropy (SE) maintained in the range of 45-60 and difference regarding response entropy (RE) and SE less than 10.3. The concentrations of epinephrine, norepinephrine and dopamine in plasma from radial artery blood samples were measured and the durations of surgical operation, breathing recovery, extubation, awakening, and postoperative orientation recovery recorded; and 48 h postoperative adverse reactions at the following times: the time at which the patient becomes calm for 5 min after entering the operating theatre (T0); upon completion of pneumoperitoneum (PPT) (T1); 15 min after PPT (T2); intraoperative detection (T3), immediately after extubation (T4); and 15 min after extubation (T5). RESULTS: Comparing the measurements of epinephrine, norepinephrine and dopamine in plasma of the above two groups at the same time, the difference between the measurements at T0 and T2, and T5 were not statistically significant (p>0.05), whereas those at T1, T3, and T4 were statistically significant (p<0.05). Specifically, the measurements for group I were significantly higher than those for group II; the differences regarding the duration of breathing recovery, extubation, and awakening in both groups were not statistically significant (p>0.05). The postoperative orientation recovery duration for group II was significantly less than that that for group I (p<0.05); none of the patients in either group had intraoperative awareness, and the incidence of adverse reactions, such as nausea, vomit, and agitation in both groups was not statistically significantly different (p>0.05). CONCLUSION: At the same anaesthetic depth, the CIIA method outperforms the TIVA method in suppressing the stress response and obtaining smooth awakening after laparoscopic radical gastrectomy for patients with gastric cancer; therefore, the CIIA method has a better anaesthetic effect. PMID- 26977030 TI - Hypocalcaemia After Total Knee Arthroplasty and its Clinical Significance. AB - BACKGROUND: Transient hypocalcaemia is a frequent complication after total knee arthroplasty (TKA). In this study, we investigated the factors associated with the development of hypocalcaemia after TKA in order to explore its clinical significance and treatment. PATIENTS AND METHODS: A retrospective analysis of the change of serum calcium levels for 40 patients after TKA was performed. We investigated the patients prospectively for age, gender, and amount of bleeding at operation. At 24 hours following the operation, serum calcium of the patients was evaluated and a t-test was performed to analyze the categorical variables. Pearson's correlation analysis was used to determine the risk of hypocalcaemia in univariate analysis. RESULTS: After TKA, the serum calcium level was significantly lower than that before the operation (p<0.01); the incidence of postoperative hypocalcaemia was 77.5%, the decline was positively correlated with intraoperative blood loss (Pearson's r=0.405, p=0.01). CONCLUSION: Hypocalcaemia occurs frequently after TKA, however, clinical symptoms associated with hypocalcaemia are rare. The calcium ion is an important electrolyte, neurotransmitter and blood coagulation factor. It is suggested that we should routinely monitor calcium ion levels during the perioperative period and deal with hypocalcaemia in a timely fashion. PMID- 26977031 TI - Effective Treatment for Malignant Pleural Effusion and Ascites with Combined Therapy of Bevacizumab and Cisplatin. AB - OBJECTIVE: To record the efficacy and toxicity of combining bevacizumab with cisplatin in treating malignant pleural effusion and ascites through intrapleural and intraperitoneal infusion. PATIENTS AND METHODS: Forty-three patients were admitted to the Oncology Department of Yantai Yuhuangding Hospital with confirmed malignant effusion since January, 2011. Twenty of them received intrapleural and intraperitoneal perfusion of 200 mg bevacizumab plus 60 mg cisplatin every three weeks, and 23 patients received 60 mg cisplatin alone after draining effusion as much as possible. Reduction of effusion was determined by type-B ultrasonography. RESULTS: The complete remission rate and effective rate of bevacizumab group was superior to that of the cisplatin group. The quality of life recovery rate of bevacizumab group was superior to that of the cisplatin group. The anhelation and abdominal distention of bevacizumab group was significantly improved. There was no significant difference in level III/IV toxicities and adverse effects between two groups. CONCLUSION: Bevacizumab significantly improved the objective response rate and quality of life of patients with malignant pleural effusion and ascites, while not causing notable adverse events. PMID- 26977032 TI - Partial Resection of the Pancreatic Head and Duodenum for Management of Carcinoma of the Ampulla of Vater: A Case Report. AB - A 57-year-old woman presented with spontaneous pain in the upper right quadrant of the abdominal region of one year's duration. Contrast-enhanced computed tomography (CT), magnetic resonance imaging, and magnetic resonance cholangiopancreaticography revealed the presence of a tumour in the periampullary region, gallstones, cholecystitis, and biliary obstruction, as well as atrophy of the pancreas and dense adhesions involving the pancreas, portal vein, and superior mesenteric vein. Duodenoscopy revealed a papillary neoplasm, measuring 2.5*3 cm, in the descending duodenum. Pathological analysis of the duodenoscopic biopsy suggested carcinoma of the ampulla of Vater. Partial resection of the pancreatic head and duodenum, together with lymph node dissection and digestive tract reconstruction, was performed. Postoperatively, the patient recovered well. CT at 14 months postoperatively showed no recurrence or metastasis. This surgical procedure avoids the potential risk of pancreaticoduodenectomy and retains the function of the pancreas as much as possible, while achieving radical tumour resection. PMID- 26977033 TI - Endoscopic Resection of Giant Ethmoid Osteomas with the Assistance of an Image guidance System. AB - AIM: To investigate the minimally invasive ablation of giant osteoma of the ethmoid sinuses endonasally with the assistance of an image-guidance system. PATIENTS AND METHODS: A retrospective analysis was carried out on 12 patients with osteomas of ethmoid sinuses treated by endoscopic surgery with the help of a navigation system from April 2005 to October 2013. RESULTS: Osteomas in all 12 patients were giant and connected extensively with the anterior skull base, lamina papyracea, or orbital apex, and were removed successfully with the help of an endoscope and image navigation system under general anaesthesia. In two cases (one through superciliary arch incision and the other one through labiogingival incision), the procedure was combined with an external procedure to remove osteomas. All patients were followed-up for 8 to 64 months. No recurrences were found. All symptoms gradually vanished or reduced dramatically after surgery. One case of frontal mucocele was observed and was successfully removed 5 years after removal of the osteoma. Anosmia occurred in both patients who underwent crista galli resection, and no recovery was noted 9 and 26 months later. Cerebrospinal fluid rhinorrhea was found in one case during surgery and was repaired with mucosa of inferior nasal concha immediately, and primary healing was successful. CONCLUSION: Endoscopic ablation of giant osteomas of the ethmoid sinuses with the guidance of a navigation system is an accurate, secure, minimally invasive procedure. A careful study of the preoperative computed tomographic scan is necessary for the success of the operation. If the lesion extensively affects the frontal sinus and maxillary sinus, a combination of superciliary arch incision and labiogingval groove incision is a simple, easy and elegant option. PMID- 26977034 TI - False-negative Frozen Section of Sentinel Lymph Node Biopsy in a Chinese Population with Breast Cancer. AB - AIM: This study aimed to investigate the accuracy of frozen section (FS) in diagnosis of sentinel lymph node metastasis and to analyze the predictive factors for false-negativity. PATIENTS AND METHODS: Patients with breast cancer and clinically negative axillary were recruited for sentinel lymph node biopsy (SLNB). All nodes were examined by intraoperative FS and underwent further paraffin sectioning. RESULTS: A total of 1,272 patients underwent SLNB over an 8 year period, and 53 patients had false-negative FS. Univariate and multivariate analysis revealed that younger age, stellate mammographic pattern, and ER positive status were statistically different when compared to the 53 members of the cohort who were truly negative on SLNB (control group). Eight patients were lost to clinical follow-up; the recurrence-free survival rate of the remaining 49 patients with false-negative SLNB did not differ from that of the 49-patient cohort (control group) (p=0.072), while these patients did experience poorer overall survival (p=0.035). CONCLUSION: Younger age, stellate mammographic pattern and ER-positive status were independent predictors for false-negative FS on biopsy. PMID- 26977035 TI - Biologic Effects of Light: An Enlighting Prospective. PMID- 26977036 TI - Biological Effects of Sunlight, Ultraviolet Radiation, Visible Light, Infrared Radiation and Vitamin D for Health. AB - Humans evolved in sunlight and had depended on sunlight for its life giving properties that was appreciated by our early ancestors. However, for more than 40 years the lay press and various medical and dermatology associations have denounced sun exposure because of its association with increased risk for skin cancer. The goal of this review is to put into perspective the many health benefits that have been associated with exposure to sunlight, ultraviolet A (UVA) ultraviolet B (UVB), visible and infrared radiation. PMID- 26977037 TI - Roles of Solar UVB and Vitamin D in Reducing Cancer Risk and Increasing Survival. AB - The present article reviews existing scientific evidence in support of the ultraviolet-B (UVB)-vitamin D-cancer hypothesis, now being in its 35th year. Literature evidence comes from geographical ecological and observational studies, two successful clinical trials, and an understanding of how vitamin D reduces risk of and increases survival from cancer. Each approach has its strengths and limitations, and considering findings from all of these approaches yields the best conclusions. There exist over 15 types of cancer for which UVB exposure and/or 25-hydroxyvitamin D [25(OH)D] concentrations have been found associated with reduced risk. The optimal 25(OH)D concentration for preventing and surviving cancer appears to be above 75-100 nmol/l. There exists mounting evidence that individuals with higher 25(OH)D concentration at the time of cancer diagnosis have better cancer-specific and overall survival rates, suggesting that cancer affected people should raise their 25(OH)D concentrations. PMID- 26977038 TI - Photocarcinogenesis and Skin Cancer Prevention Strategies. AB - In this review the basic principles of UV-induced carcinogenesis are summarized and the state of the art diagnosis and therapeutic strategies are discussed. The prevalent keratinocyte-derived neoplasms of the skin are basal cell and squamous cell carcinomas. Cutaneous melanoma is less frequent but associated with high mortality. Common risk factors for all three tumor entities include sun exposure and DNA-repair deficiencies. Photocarcinogenesis follows a multistep model of cancer development in which ultraviolet-induced DNA damage leads to mutations resulting in activation of oncogenes or silencing of tumor-suppressor genes. This ends in a cellular mutator phenotype even more prone to mutation acquisition. DNA repair, especially the nucleotide excision repair (NER) pathway, counteracts mutation formation and skin cancer development. This is vividly demonstrated by the NER-defective disorder xeroderma pigmentosum. Primary skin cancer preventative strategies, therefore, include reduction of DNA photodamage by protection from the sun. Secondary preventative strategies include skin cancer screening. This implies standard examination techniques with the naked eye, an epiluminescence microscope, or digital epiluminescence microscopy. More advanced techniques include confocal laser scan microscopy. PMID- 26977039 TI - Vitamin D and Mortality. AB - In this narrative review, we aim to summarize and discuss the current evidence linking vitamin D and mortality. Low 25-hydroxyvitamin D [25(OH)D] concentrations are associated with an increased risk of mortality. This has been shown in different cohort studies including general populations, as well as various patient cohorts. Some single-study results and meta-analyses indicate that the shape of the relationship between 25(OH)D and mortality follows a U- or a reverse J-shaped curve. Interassay and laboratory differences are, however, a limitation of most previous surveys, and standardization of 25(OH)D measurements is needed for future investigations. Apart from observational data, it has been documented in meta-analyses of randomized controlled trials that vitamin D3 supplementation is associated with a moderate, yet statistically significant, reduction in mortality. This latter finding must be interpreted in light of some limitations such as incomplete follow-up data, but such a reduction of mortality with vitamin D3 supplementation as the finding of meta-analyses of randomized controlled trials strongly argues for the benefits and, importantly, also the safety of vitamin D. PMID- 26977040 TI - Light - Instead of UV Protection: New Requirements for Skin Cancer Prevention. AB - The requirements on sunscreens have essentially changed, since some years ago it was demonstrated that approximately 50% of free radicals, that are formed in the skin by solar radiation, originate from the visible and infrared regions of the solar spectrum. In addition, a critical radical concentration threshold could be found. If this concentration, the free radical threshold value (FRTV), is exceeded, sunburn, immunosuppression and skin cancer may develop. Application of sunscreens and lotions protects against sunburn in the UV region of the solar spectrum and therefore is frequently used to extend people's stay in the sun. However, this behaviour can enhance the concentration of free radicals formed in the visible and infrared regions of the solar spectrum, so that the critical radical threshold is exceeded and the skin may be damaged. PMID- 26977041 TI - Extracorporeal Photopheresis for Non-skin GvHD. AB - Graft versus host disease (GvHD) is one of the most feared adverse events of allogeneic hematopoietic stem cell transplantation. In severe grades of GvHD patients die from infections due to impairment of their immune defense or therapy refractory involvement of intestines, liver and lung. Extracorporeal photopheresis is an effective treatment for acute and chronic graft versus host disease without severe impairment of the recipient's immune system. It is generally better known for its effect on skin GvHD but all other manifestations of GvHD can respond as well. Herein we report a brief review of its history and give an overview of the current knowledge of extracorporeal photopheresis in non skin GvHD. PMID- 26977042 TI - Vitamin D Status in Chronic Kidney Disease - UVB Irradiation Is Superior to Oral Supplementation. AB - BACKGROUND: In chronic kidney disease (CKD) a deficiency of 1,25-dihydroxyvitamin D is common. The aim of this review was to compare vitamin D status after oral supplementation of vitamin D3 to that of serial suberythemal irradiation in end stage kidney disease (ESKD) patients. PATIENTS AND METHODS: Ninety-five patients, with a mean age of 62 (range=35-82) years, were treated with a mean dose of 35,000 (20,000-60,000) IU vitamin D3 per week for a period of 18 months. Fourteen patients, with a mean age of 51 (range=41-57) years, were whole-body UVB irradiated for over 6 months. From 3 hemodialysis patients skin biopsies were performed. RESULTS: With oral supplementation 25(OH)D3 increased by 60%. With UV irradiation 25(OH)D3 increased by 400%. Gene expression analysis demonstrated an improvement in the vitamin D receptor (VDR) by 0.65 fold, in 1-alpha-hydroxylase (CYP27B1) by 1.0 fold, and in 25-hydroxylase (CYP2R) by 1.2 fold. CONCLUSION: Serial suberythemal UVB irradiation of patients with CKD on dialysis is capable to improve serum 25(OH)D3 and 1,25(OH)2D3 by enhancing the skin's ability to activate vitamin D. PMID- 26977044 TI - Layer Thickness of SPF 30 Sunscreen and Formation of Pre-vitamin D. AB - BACKGROUND: Most studies have demonstrated that sunscreens with lower sun protection factor (SPF) do not prevent the production of vitamin D because much lower amount of sunscreen (SPF<30) is applied than recommended (2 mg/cm(2)) indicating that a significant amount of UV radiation can penetrate the skin. Since less sunscreen is applied, higher SPF sunscreens may be used to achieve the desired protection. However, there is little information regarding the application of high-SPF sunscreen and vitamin D formation. The aim of this study was to measure the influence of the amount of two SPF 30 sunscreens on pre vitamin D formation in a cuvette with 7-dehydrocholesterol. RESULTS: Sunscreen with physical (reflecting) or chemical (absorbing) UV filters exhibits different levels of protection in vitro even if the SPF is the same. The level of photoprotection is differentially reduced when less sunscreen than the recommended application thickness is applied. CONCLUSION: The usual application of 0.8-1 mg/cm(2) is below the recommended value of 2 mg/cm(2), and pre-vitamin D may be formed when lower amounts of SPF <=30 sunscreen are applied, showing that a significant amount of UV radiation may enter the skin. PMID- 26977043 TI - UV Irradiation and Pleiotropic Effects of Vitamin D in Chronic Kidney Disease - Benefits on Cardiovascular Comorbidities and Quality of Life. AB - BACKGROUND: Vitamin D3 can be metabolized in the skin to 25(OH)D and 1,25(OH)2D because the skin expresses vitamin D-25-hydroxylase, 25(OH)D-1-alpha-hydroxylase, and the vitamin D receptor. The aim of this review was to discuss the pleiotropic effects after serial suberythemal UVB irradiation with a sun-simulating UV spectrum in end-stage kidney disease patients. PATIENTS AND METHODS: Fourteen hemodialysis patients, with a mean age of 51 (range 41-57) years, were whole-body UV irradiated over 6 months. RESULTS: Patients demonstrated an increase in their hematocrit and required less erythropoietin. An increase in maximal oxygen uptake and workload capacity was associated with decreased lactic acid production. The patients demonstrated a decreased heart rate and systolic and diastolic blood pressure with an increase in the R-R-interval and the beat-to-beat-differences. CONCLUSION: Cardiovascular disease is the most important comorbidity. Exposure to simulated sunlight that contains both UVB and UVA reduce cardiovascular risk factors and improve quality of life. PMID- 26977045 TI - Optimization of Chemical Syntheses of Vitamin D C3-Epimers. AB - Due to the widespread impact of vitamin D on human health, the development of appropriate assays to detect deficiency of all vitamin D metabolites of pharmacological interest is being continuously improved. Although over 50 naturally-occurring metabolites of vitamin D are known to date, only very few are routinely detected in commercially available assays. This is particularly true regarding C3-epimers of vitamin D3 and D2, which not only may interfere in analytical measurements with other metabolites of interest, but also have controversial and not yet fully understood physiological functions. In this study we optimized a synthetic method to obtain various vitamin D3 and D2 C3-epimers in order to make them available in gram quantities for further evaluation and for their use in assay development or drug discovery. Particularly, the inversion of the C3-OH group at the A-ring of vitamin D2, which, in turn, serves as a suitable starting material for most of chemical syntheses of vitamin D metabolites, can be converted to the corresponding C3-epimer under so-called "Mitsunobu conditions". Thus, the C3-OH group is converted into the corresponding ester by treatment with an aromatic acid, subsequent addition of an azodicarboxlate and triphenylphoshine, leading to the corresponding ester, concomitant to the inversion of the stereogenic center at C3. Reduction or saponification of the resulting ester finally leads to the corresponding C3-epimer, that may serve as starting material for a wide variety of vitamin D3 and D2 C3-epimers. PMID- 26977046 TI - Solar Simulators for Healthy Vitamin D Synthesis. AB - BACKGROUND/AIM: The angular distribution of solar radiance and its spectral characteristics is required for the determination of vitamin D3 production in humans. MATERIALS AND METHODS: The vitamin D3 weighted exposure can be calculated by integrating the incident solar spectral radiance over all relevant parts of the human body. A novel instrument allowing simultaneous measurements of spectral radiance from more than 100 directions has been developed. A large solar simulator for controlled experiments is described. RESULTS: In summer it is relatively easy to obtain sufficient vitamin D because sun exposure times are short. In winter solstice vitamin D3 cannot be obtained with realistic clothing even if the exposure were extended to all daylight hours. CONCLUSION: Improved and controlled experiments to determine vitamin D3 production are required to assess the positive effects of solar UV radiation and to assess its natural variability. PMID- 26977047 TI - Human Pigmentation, Cutaneous Vitamin D Synthesis and Evolution: Variants of Genes (SNPs) Involved in Skin Pigmentation Are Associated with 25(OH)D Serum Concentration. AB - Vitamin D deficiency is common and associated with higher risk for and unfavourable outcome of many diseases. Limited data exist on genetic determinants of serum 25(OH)D concentration. In a cohort of the LURIC study (n=2974, median 25(OH)D concentration 15.5 ng/ml), we tested the hypothesis that variants (SNPs, n=244) of several genes (n=15) involved in different aspects of skin pigmentation, including melanosomal biogenesis (ATP7A, DTNBP1, BLOC1S5, PLDN, PMEL), melanosomal transport within melanocytes (RAB27A, MYO5A, MLPH); or various melanocyte signaling pathways (MC1R, MITF, PAX3, SOX10, DKK1, RACK1, CNR1) are predictive of serum 25(OH)D levels. Eleven SNPs located in 6 genes were associated (p<0.05) with low or high serum 25(OH)D levels, 3 out of these 11 SNPs reached the aimed significance level after correction for multiple comparisons (FDR). In the linear regression model adjusted for sex, body mass index (BMI), year of birth and month of blood sample rs7565264 (MLPH), rs10932949 (PAX3), and rs9328451 (BLOC1S5) showed a significant association with 25(OH)D. The combined impact on variation of 25(OH)D serum levels (coefficient of determination (R(2))) for the 11 SNPs was 1.6% and for the 3 SNPs after FDR 0.3%. In Cox Regression we identified rs2292881 (MLPH) as having a significant association (advantage) with overall survival. Kaplan-Meier analysis did not show any significant impact of individual SNPs on overall survival. In conclusion, these results shed new light on the role of sunlight, skin pigmentation and vitamin D for human evolution. PMID- 26977049 TI - Errata. PMID- 26977048 TI - Prospective Investigation of 25(OH)D3 Serum Concentration Following UVB Narrow Band Phototherapy in Patients with Psoriasis and Atopic Dermatitis. AB - Vitamin D deficiency represents a major health issue. It is a worldwide endemic and is associated with a broad variety of severe diseases. The skin is a key tissue for the human body's vitamin D endocrine system. It represents a target tissue for biologically active vitamin D metabolites. Approximately 90% of the human body's requirements of vitamin D have to be synthesised in the skin by the action of UVB-radiation. However, individual factors that influence a person's cutaneous synthesis of vitamin D are still not well understood. In our present prospective study we investigated the effect of UVB narrow band (UVBnb, 311 nm) and PUVA phototherapy on 25(OH)D3 serum concentration, in patients with psoriasis, atopic dermatitis and a few cases with other dermatoses (n=41). We found that two weeks of UVBnb treatment resulted in an increase of 25(OH)D3 serum concentration from 11.4 to 20.5 ng/ml (p<0.001), while in contrast PUVA-treatment did not significantly alter vitamin D status. These findings question the hypothesis of a relevant vitamin D metabolizing effect of UVA. Psoriasis patients showed a trend for a stronger increase in 25(OH)D3 serum levels following UVBnb compared to patients with atopic dermatitis. Patients with relatively low baseline serum 25(OH)D3 concentrations had a stronger increase in 25(OH)D3 concentrations compared to patients with relatively high 25(OH)D serum concentrations. In general patients with skin types (Fitzpatrick) I and II (median=14.3 ng/ml) had a higher baseline of 25(OH)D3 serum concentration compared to patients with skin types III (median=11.2 ng/ml) or IV-V (median=12.3 ng/ml), although these differences were not statistically significant (p=0.106). Baseline 25(OH)D3 serum concentrations were correlated with presence of genetic variants (SNPs of VDR, CYP2R1, VDBP/GC) that influence vitamin D status, and with other individual factors such as body mass index, age and gender. We also investigated the effect of phototherapy on blood pressure and a variety of laboratory parameters such as CRP, HbA1c, LDL, HDL, triglycerides and cholesterol. In conclusion, our pilot study shows that UVBnb phototherapy efficiently increases 25(OH)D3 serum concentration and reports interesting preliminary findings that have to be re-evaluated in larger follow-up studies. PMID- 26977050 TI - Combined Inhibition of Complement and CD14 Attenuates Bacteria-Induced Inflammation in Human Whole Blood More Efficiently Than Antagonizing the Toll like Receptor 4-MD2 Complex. AB - BACKGROUND: Single inhibition of the Toll-like receptor 4 (TLR4)-MD2 complex failed in treatment of sepsis. CD14 is a coreceptor for several TLRs, including TLR4 and TLR2. The aim of this study was to investigate the effect of single TLR4 MD2 inhibition by using eritoran, compared with the effect of CD14 inhibition alone and combined with the C3 complement inhibitor compstatin (Cp40), on the bacteria-induced inflammatory response in human whole blood. METHODS: Cytokines were measured by multiplex technology, and leukocyte activation markers CD11b and CD35 were measured by flow cytometry. RESULTS: Lipopolysaccharide (LPS)-induced inflammatory markers were efficiently abolished by both anti-CD14 and eritoran. Anti-CD14 was significantly more effective than eritoran in inhibiting LPS binding to HEK-293E cells transfected with CD14 and Escherichia coli-induced upregulation of monocyte activation markers (P < .01). Combining Cp40 with anti CD14 was significantly more effective than combining Cp40 with eritoran in reducing E. coli-induced interleukin 6 (P < .05) and monocyte activation markers induced by both E. coli (P < .001) and Staphylococcus aureus (P < .01). Combining CP40 with anti-CD14 was more efficient than eritoran alone for 18 of 20 bacteria induced inflammatory responses (mean P < .0001). CONCLUSIONS: Whole bacteria induced inflammation was inhibited more efficiently by anti-CD14 than by eritoran, particularly when combined with complement inhibition. Combined CD14 and complement inhibition may prove a promising treatment strategy for bacterial sepsis. PMID- 26977051 TI - Physical Sequestration of Bacillus anthracis in the Pulmonary Capillaries in Terminal Infection. AB - The lung is the terminal target of Bacillus anthracis before death, whatever the route of infection (cutaneous, inhalational, or digestive). During a cutaneous infection in absence of toxins, we observed encapsulated bacteria colonizing the alveolar capillary network, bacteria and hemorrhages in alveolar and bronchiolar spaces, and hypoxic foci in the lung (endothelial cells) and brain (neurons and neuropil). Circulating encapsulated bacteria were as chains of approximately 13 um in length. Bacteria of such size were immediately trapped within the lung capillary network, but bacteria of shorter length were not. Controlling lung targeted pathology would be beneficial for anthrax treatment. PMID- 26977052 TI - Attract them anyway: benefits of large, showy flowers in a highly autogamous, carnivorous plant species. AB - Reproductive biology of carnivorous plants has largely been studied on species that rely on insects as pollinators and prey, creating potential conflicts. Autogamous pollination, although present in some carnivorous species, has received less attention. In angiosperms, autogamous self-fertilization is expected to lead to a reduction in flower size, thereby reducing resource allocation to structures that attract pollinators. A notable exception is the carnivorous pyrophyteDrosophyllum lusitanicum(Drosophyllaceae), which has been described as an autogamous selfing species but produces large, yellow flowers. Using a flower removal and a pollination experiment, we assessed, respectively, whether large flowers in this species may serve as an attracting device to prey insects or whether previously reported high selfing rates for this species in peripheral populations may be lower in more central, less isolated populations. We found no differences between flower-removed plants and intact, flowering plants in numbers of prey insects trapped. We also found no indication of reduced potential for autogamous reproduction, in terms of either seed set or seed size. However, our results showed significant increases in seed set of bagged, hand pollinated flowers and unbagged flowers exposed to insect visitation compared with bagged, non-manipulated flowers that could only self-pollinate autonomously. Considering that the key life-history strategy of this pyrophytic species is to maintain a viable seed bank, any increase in seed set through insect pollinator activity would increase plant fitness. This in turn would explain the maintenance of large, conspicuous flowers in a highly autogamous, carnivorous plant. PMID- 26977053 TI - A prospective study on the efficacy of two-dose influenza vaccinations in cancer patients receiving chemotherapy. AB - OBJECTIVE: Cancer patients receiving chemotherapy are at risk of acquiring influenza infections. Two-dose vaccination is a proposed strategy for increasing vaccination efficacy; however, this has yet to be confirmed in this population. The purpose of this study was to clarify the efficacy and safety of this strategy. METHODS: We conducted a multicentre prospective study on a two-dose vaccination regimen in cancer patients receiving chemotherapy. Second vaccinations were performed in patients who did not respond to all three viral strains after the first vaccination. Serum haemagglutination inhibition titres were measured to determine the patients' immunological response, 2 weeks prior to the first vaccination, 3-5 weeks after each vaccination, and at the end of the influenza season. RESULTS: We enrolled 109 patients, including 70 with solid tumours, 36 with haematological malignancies, and 3 with both cancer types. Among the total patients, the proportion of patients with protective titres against the three viral strains increased significantly from 3 to 27% (P < 0.01) following vaccination. Among the 79 patients who received a second vaccination, the proportion of those with protective titres against the individual strains increased by 10% (H1N1), 8% (H3N2), and 3% (B) compared with after the first vaccination. Serious adverse events were not observed. CONCLUSIONS: We recommend influenza vaccinations for cancer patients, including those receiving chemotherapy. Also, the additional benefit of the second vaccination may be limited. PMID- 26977054 TI - Characteristics and overall survival of EGFR mutation-positive non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors: a retrospective analysis for 1660 Japanese patients. AB - BACKGROUND: The Japan Guidelines of Lung Cancer Therapy recommend epidermal growth factor receptor-tyrosine kinase inhibitors as a first-line therapy for advanced/recurrent non-small cell lung cancer patients with epidermal growth factor receptor mutation. Although survival periods in recent reports of epidermal growth factor receptor-tyrosine kinase inhibitor treatment have been getting longer, the reasons why are unclear. We investigated the survival, prognostic factors and real-world treatment of non-small cell lung cancer patients with epidermal growth factor receptor mutation in clinical practice. METHODS: Non-small cell lung cancer patients (n = 1660) who started first-line treatment from January 2008 to December 2012 were enrolled. Patients were diagnosed with epidermal growth factor receptor mutation-positive advanced/recurrent non-small cell lung cancer by histology or cytology samples. The primary objective was to estimate overall survival. The secondary objectives were to determine prognostic factors, real-world treatment patterns and efficacy of gefitinib treatment. We calculated the treatment exposure rate for each treatment category using the following formula: exposure rate = person-years for the treatment category/total person-years * 100. RESULTS: The median overall survival was 30.8 months. Sex, age, histology, epidermal growth factor receptor mutation type, clinical stage and performance status affected overall survival. The exposure rates for all epidermal growth factor receptor-tyrosine kinase inhibitors, gefitinib and platinum-doublet chemotherapy were 62.1, 46.4 and 8.5% respectively. Overall 56.1% of patients were administered gefitinib as first-line therapy, and 39.0% were treated with >=2 epidermal growth factor receptor tyrosine kinase inhibitor regimens. The median progression-free survival in the first-line gefitinib group was 11.4 months. Factors affecting prognosis were sex, histology, clinical stage and performance status. CONCLUSION: Epidermal growth factor receptor-tyrosine kinase inhibitors, especially gefitinib, are major components of the treatment regimens for epidermal growth factor receptor mutation-positive non-small cell lung cancer. Switching and re-challenging with epidermal growth factor receptor-tyrosine kinase inhibitors were also practiced in Japan. PMID- 26977055 TI - A preoperative low cancer antigen 125 level (<=25.8 mg/dl) is a useful criterion to determine the optimal timing of interval debulking surgery following neoadjuvant chemotherapy in epithelial ovarian cancer. AB - OBJECTIVE: The purpose of this study is to investigate the clinical characteristics to determine the optimal timing of interval debulking surgery following neoadjuvant chemotherapy in patients with advanced epithelial ovarian cancer. METHODS: We reviewed the charts of women with advanced epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer who underwent interval debulking surgery following neoadjuvant chemotherapy at our cancer center from April 2006 to April 2014. RESULTS: There were 139 patients, including 91 with ovarian cancer [International Federation of Gynecology and Obstetrics (FIGO) Stage IIIc in 56 and IV in 35], two with fallopian tube cancers (FIGO Stage IV, both) and 46 with primary peritoneal cancer (FIGO Stage IIIc in 27 and IV in 19). After 3-6 cycles (median, 4 cycles) of platinum-based chemotherapy, interval debulking surgery was performed. Sixty-seven patients (48.2%) achieved complete resection of all macroscopic disease, while 72 did not. More patients with cancer antigen 125 levels <=25.8 mg/dl at pre-interval debulking surgery achieved complete resection than those with higher cancer antigen 125 levels (84.7 vs. 21.3%; P< 0.0001). Patients with no ascites at pre-interval debulking surgery also achieved a higher complete resection rate (63.5 vs. 34.1%; P< 0.0001). Moreover, most patients (86.7%) with cancer antigen 125 levels <=25.8 mg/dl and no ascites at pre-interval debulking surgery achieved complete resection. CONCLUSIONS: A low cancer antigen 125 level of <=25.8 mg/dl and the absence of ascites at pre-interval debulking surgery are major predictive factors for complete resection during interval debulking surgery and present useful criteria to determine the optimal timing of interval debulking surgery. PMID- 26977057 TI - Correction to 'Land plants and DNA barcodes: short-term and long-term goals'. PMID- 26977056 TI - Following the flux of long-chain bases through the sphingolipid pathway in vivo using mass spectrometry. AB - Sphingolipids are essential components of the plasma membrane. Their synthesis is tightly controlled by regulatory proteins, which impinge on the rate-limiting step of the pathway, the condensation of serine and palmitoyl-CoA to long-chain base (LCB). The subsequent conversion of LCB to ceramide by ceramide synthase (CerS) is also tightly regulated, because both the accumulation of LCB as well as an excess of ceramide is toxic. Here we describe an in vivo assay to monitor the flux of LCB through the sphingolipid pathway in yeast. Cells are provided with nonnatural odd-chain sphingosine analogs, C17-dihydrosphingosine or C17 phytosphingosine (PHS), and their incorporation into ceramide and more complex sphingolipids is monitored by mass spectrometry. Incorporation of C17-PHS is time and concentration dependent, is inhibited by fumonisin B1, an inhibitor of CerS, and greatly reduced in double mutant cells lacking components of the CerS, Lac1 and Lag1. The resulting C17-ceramides are further metabolized to more complex sphingolipids, inositol phosphorylceramide and mannosylinositol phosphorylceramide), indicating that the tracer can be used to decipher the regulation of later steps of the pathway. In support of this notion, we show that mutants lacking the Orm proteins, regulators of the rate-limiting step of the pathway, display increased steady-state levels of these intermediates without affecting their rate of synthesis. PMID- 26977059 TI - The uncertain role of diversity dependence in species diversification and the need to incorporate time-varying carrying capacities. AB - There is no agreement among palaeobiologists or biologists as to whether, or to what extent, there are limits on diversification and species numbers. Here, we posit that part of the disagreement stems from: (i) the lack of explicit criteria for defining the relevant species pools, which may be defined phylogenetically, ecologically or geographically; (ii) assumptions that must be made when extrapolating from population-level logistic growth to macro-evolutionary diversification; and (iii) too much emphasis being placed on fixed carrying capacities, rather than taking into account the opportunities for increased species richness on evolutionary timescales, for example, owing to increased biologically available energy, increased habitat complexity and the ability of many clades to better extract resources from the environment, or to broaden their resource base. Thus, we argue that a more effective way of assessing the evidence for and against the ideas of bound versus unbound diversification is through appropriate definition of the relevant species pools, and through explicit modelling of diversity-dependent diversification with time-varying carrying capacities. Here, we show that time-varying carrying capacities, either increases or decreases, can be accommodated through changing intrinsic diversification rates (diversity-independent effects), or changing the effects of crowding (diversity-dependent effects). PMID- 26977058 TI - The challenges to inferring the regulators of biodiversity in deep time. AB - Attempts to infer the ecological drivers of macroevolution in deep time have long drawn inspiration from work on extant systems, but long-term evolutionary and geological changes complicate the simple extrapolation of such theory. Recent efforts to incorporate a more informed ecology into macroevolution have moved beyond the descriptive, seeking to isolate generating mechanisms and produce testable hypotheses of how groups of organisms usurp each other or coexist over vast timespans. This theme issue aims to exemplify this progress, providing a series of case studies of how novel modelling approaches are helping infer the regulators of biodiversity in deep time. In this Introduction, we explore the challenges of these new approaches. First, we discuss how our choices of taxonomic units have implications for the conclusions drawn. Second, we emphasize the need to embrace the interdependence of biotic and abiotic changes, because no living organism ignores its environment. Third, in the light of parts 1 and 2, we discuss the set of dynamic signatures that we might expect to observe in the fossil record. Finally, we ask whether these dynamics represent the most ecologically informative foci for research efforts aimed at inferring the regulators of biodiversity in deep time. The papers in this theme issue contribute in each of these areas. PMID- 26977060 TI - How many dinosaur species were there? Fossil bias and true richness estimated using a Poisson sampling model. AB - The fossil record is a rich source of information about biological diversity in the past. However, the fossil record is not only incomplete but has also inherent biases due to geological, physical, chemical and biological factors. Our knowledge of past life is also biased because of differences in academic and amateur interests and sampling efforts. As a result, not all individuals or species that lived in the past are equally likely to be discovered at any point in time or space. To reconstruct temporal dynamics of diversity using the fossil record, biased sampling must be explicitly taken into account. Here, we introduce an approach that uses the variation in the number of times each species is observed in the fossil record to estimate both sampling bias and true richness. We term our technique TRiPS (True Richness estimated using a Poisson Sampling model) and explore its robustness to violation of its assumptions via simulations. We then venture to estimate sampling bias and absolute species richness of dinosaurs in the geological stages of the Mesozoic. Using TRiPS, we estimate that 1936 (1543-2468) species of dinosaurs roamed the Earth during the Mesozoic. We also present improved estimates of species richness trajectories of the three major dinosaur clades: the sauropodomorphs, ornithischians and theropods, casting doubt on the Jurassic-Cretaceous extinction event and demonstrating that all dinosaur groups are subject to considerable sampling bias throughout the Mesozoic. PMID- 26977061 TI - Phylogenetic fields through time: temporal dynamics of geographical co-occurrence and phylogenetic structure within species ranges. AB - Species co-occur with different sets of other species across their geographical distribution, which can be either closely or distantly related. Such co occurrence patterns and their phylogenetic structure within individual species ranges represent what we call the species phylogenetic fields (PFs). These PFs allow investigation of the role of historical processes--speciation, extinction and dispersal--in shaping species co-occurrence patterns, in both extinct and extant species. Here, we investigate PFs of large mammalian species during the last 3 Myr, and how these correlate with trends in diversification rates. Using the fossil record, we evaluate species' distributional and co-occurrence patterns along with their phylogenetic structure. We apply a novel Bayesian framework on fossil occurrences to estimate diversification rates through time. Our findings highlight the effect of evolutionary processes and past climatic changes on species' distributions and co-occurrences. From the Late Pliocene to the Recent, mammal species seem to have responded in an individualistic manner to climate changes and diversification dynamics, co-occurring with different sets of species from different lineages across their geographical ranges. These findings stress the difficulty of forecasting potential effects of future climate changes on biodiversity. PMID- 26977062 TI - Quantifying the effects of the break up of Pangaea on global terrestrial diversification with neutral theory. AB - The historic richness of most taxonomic groups increases substantially over geological time. Explanations for this fall broadly into two categories: bias in the fossil record and elevated net rates of diversification in recent periods. For example, the break up of Pangaea and isolation between continents might have increased net diversification rates. In this study, we investigate the effect on terrestrial diversification rates of the increased isolation between land masses brought about by continental drift. We use ecological neutral theory as a means to study geologically complex scenarios tractably. Our models show the effects of simulated geological events that affect all species equally, without the added complexity of further ecological processes. We find that continental drift leads to an increase in diversity only where isolation between continents leads to additional speciation through vicariance, and where higher taxa with very low global diversity are considered. We conclude that continental drift by itself is not sufficient to account for the increase in terrestrial species richness observed in the fossil record. PMID- 26977063 TI - Ecogeochemistry potential in deep time biodiversity illustrated using a modern deep-water case study. AB - The fossil record provides the only direct evidence of temporal trends in biodiversity over evolutionary timescales. Studies of biodiversity using the fossil record are, however, largely limited to discussions of taxonomic and/or morphological diversity. Behavioural and physiological traits that are likely to be under strong selection are largely obscured from the body fossil record. Similar problems exist in modern ecosystems where animals are difficult to access. In this review, we illustrate some of the common conceptual and methodological ground shared between those studying behavioural ecology in deep time and in inaccessible modern ecosystems. We discuss emerging ecogeochemical methods used to explore population connectivity and genetic drift, life-history traits and field metabolic rate and discuss some of the additional problems associated with applying these methods in deep time. PMID- 26977064 TI - The impact of Cenozoic cooling on assemblage diversity in planktonic foraminifera. AB - The Cenozoic planktonic foraminifera (PF) (calcareous zooplankton) have arguably the most detailed fossil record of any group. The quality of this record allows models of environmental controls on macroecology, developed for Recent assemblages, to be tested on intervals with profoundly different climatic conditions. These analyses shed light on the role of long-term global cooling in establishing the modern latitudinal diversity gradient (LDG)--one of the most powerful generalizations in biogeography and macroecology. Here, we test the transferability of environment-diversity models developed for modern PF assemblages to the Eocene epoch (approx. 56-34 Ma), a time of pronounced global warmth. Environmental variables from global climate models are combined with Recent environment-diversity models to predict Eocene richness gradients, which are then compared with observed patterns. The results indicate the modern LDG- lower richness towards the poles--developed through the Eocene. Three possible causes are suggested for the mismatch between statistical model predictions and data in the Early Eocene: the environmental estimates are inaccurate, the statistical model misses a relevant variable, or the intercorrelations among facets of diversity--e.g. richness, evenness, functional diversity--have changed over geological time. By the Late Eocene, environment-diversity relationships were much more similar to those found today. PMID- 26977065 TI - Fossil biogeography: a new model to infer dispersal, extinction and sampling from palaeontological data. AB - Methods in historical biogeography have revolutionized our ability to infer the evolution of ancestral geographical ranges from phylogenies of extant taxa, the rates of dispersals, and biotic connectivity among areas. However, extant taxa are likely to provide limited and potentially biased information about past biogeographic processes, due to extinction, asymmetrical dispersals and variable connectivity among areas. Fossil data hold considerable information about past distribution of lineages, but suffer from largely incomplete sampling. Here we present a new dispersal-extinction-sampling (DES) model, which estimates biogeographic parameters using fossil occurrences instead of phylogenetic trees. The model estimates dispersal and extinction rates while explicitly accounting for the incompleteness of the fossil record. Rates can vary between areas and through time, thus providing the opportunity to assess complex scenarios of biogeographic evolution. We implement the DES model in a Bayesian framework and demonstrate through simulations that it can accurately infer all the relevant parameters. We demonstrate the use of our model by analysing the Cenozoic fossil record of land plants and inferring dispersal and extinction rates across Eurasia and North America. Our results show that biogeographic range evolution is not a time-homogeneous process, as assumed in most phylogenetic analyses, but varies through time and between areas. In our empirical assessment, this is shown by the striking predominance of plant dispersals from Eurasia into North America during the Eocene climatic cooling, followed by a shift in the opposite direction, and finally, a balance in biotic interchange since the middle Miocene. We conclude by discussing the potential of fossil-based analyses to test biogeographic hypotheses and improve phylogenetic methods in historical biogeography. PMID- 26977066 TI - Understanding how biodiversity unfolds through time under neutral theory. AB - Theoretical predictions for biodiversity patterns are typically derived under the assumption that ecological systems have reached a dynamic equilibrium. Yet, there is increasing evidence that various aspects of ecological systems, including (but not limited to) species richness, are not at equilibrium. Here, we use simulations to analyse how biodiversity patterns unfold through time. In particular, we focus on the relative time required for various biodiversity patterns (macroecological or phylogenetic) to reach equilibrium. We simulate spatially explicit metacommunities according to the Neutral Theory of Biodiversity (NTB) under three modes of speciation, which differ in how evenly a parent species is split between its two daughter species. We find that species richness stabilizes first, followed by species area relationships (SAR) and finally species abundance distributions (SAD). The difference in timing of equilibrium between these different macroecological patterns is the largest when the split of individuals between sibling species at speciation is the most uneven. Phylogenetic patterns of biodiversity take even longer to stabilize (tens to hundreds of times longer than species richness) so that equilibrium predictions from neutral theory for these patterns are unlikely to be relevant. Our results suggest that it may be unwise to assume that biodiversity patterns are at equilibrium and provide a first step in studying how these patterns unfold through time. PMID- 26977067 TI - Towards a morphological metric of assemblage dynamics in the fossil record: a test case using planktonic foraminifera. AB - With a glance, even the novice naturalist can tell you something about the ecology of a given ecosystem. This is because the morphology of individuals reflects their evolutionary history and ecology, and imparts a distinct 'look' to communities--making it possible to immediately discern between deserts and forests, or coral reefs and abyssal plains. Once quantified, morphology can provide a common metric for characterizing communities across space and time and, if measured rapidly, serve as a powerful tool for quantifying biotic dynamics. Here, we present and test a new high-throughput approach for analysing community shape in the fossil record using semi-three-dimensional (3D) morphometrics from vertically stacked images (light microscopic or photogrammetric). We assess the potential informativeness of community morphology in a first analysis of the relationship between 3D morphology, ecology and phylogeny in 16 extant species of planktonic foraminifera--an abundant group in the marine fossil record--and in a preliminary comparison of four assemblages from the North Atlantic. In the species examined, phylogenetic relatedness was most closely correlated with ecology, with all three ecological traits examined (depth habitat, symbiont ecology and biogeography) showing significant phylogenetic signal. By contrast, morphological trees (based on 3D shape similarity) were relatively distantly related to both ecology and phylogeny. Although improvements are needed to realize the full utility of community morphometrics, our approach already provides robust volumetric measurements of assemblage size, a key ecological characteristic. PMID- 26977069 TI - The Role of Topical Vitamin E in Scar Management: A Systematic Review. AB - BACKGROUND: The practice of prescribing vitamin E after surgery for scar prevention and treatment is widespread and increasingly popular among both the public and clinicians. However, very little evidence exists for this "ritual." OBJECTIVES: This review was undertaken to critically analyze the current literature about the effect of vitamin E on treating scars. METHODS: The Cochrane, Medline, and PubMed databases were searched based on the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). The studies and levels of recommendation were graded according to the American Society of Plastic Surgeons (ASPS) criteria. Only prospective studies were included. RESULTS: Only six studies met the inclusion criteria. Of these six included studies, three reported a significant improvement in the cosmetic appearance of scars when using vitamin E: one study used topical vitamin E in white children as monotherapy, and two studies used vitamin E in an adult population as combination therapy. The other three selected studies showed no significant improvement in scar appearance when using topical vitamin E as monotherapy. Two of the six included studies reported adverse events of vitamin E application: contact dermatitis and increased incidence of itching and rash. CONCLUSIONS: We conclude that there is not yet sufficient evidence that monotherapy with topical vitamin E has a significant beneficial effect on scar appearance to justify its widespread use. Further prospective studies with vitamin E monotherapy and/or combination therapy are warranted to draw better conclusions regarding the value of vitamin E in the management of scar healing. LEVEL OF EVIDENCE: 2 Therapeutic. PMID- 26977068 TI - A promising future for integrative biodiversity research: an increased role of scale-dependency and functional biology. AB - Studies into the complex interaction between an organism and changes to its biotic and abiotic environment are fundamental to understanding what regulates biodiversity. These investigations occur at many phylogenetic, temporal and spatial scales and within a variety of biological and geological disciplines but often in relative isolation. This issue focuses on what can be achieved when ecological mechanisms are integrated into analyses of deep-time biodiversity patterns through the union of fossil and extant data and methods. We expand upon this perspective to argue that, given its direct relevance to the current biodiversity crisis, greater integration is needed across biodiversity research. We focus on the need to understand scaling effects, how lower-level ecological and evolutionary processes scale up and vice versa, and the importance of incorporating functional biology. Placing function at the core of biodiversity research is fundamental, as it establishes how an organism interacts with its abiotic and biotic environment and it is functional diversity that ultimately determines important ecosystem processes. To achieve full integration, concerted and ongoing efforts are needed to build a united and interactive community of biodiversity researchers, with education and interdisciplinary training at its heart. PMID- 26977070 TI - A Four-Layer Wound Closure Technique with Barbed Sutures for Stable Reset of the Inframammary Fold in Breast Augmentation. PMID- 26977071 TI - Commentary on: Lessons Learned After 15 Years of Circumferential Bodylift Surgery. PMID- 26977072 TI - Decrease in Seroma Rate After Adopting Progressive Tension Sutures Without Drains: A Single Surgery Center Experience of 451 Abdominoplasties Over 7 Years. AB - BACKGROUND: Abdominoplasty is a common aesthetic procedure in the United States. Pollock and Pollock described their progressive tension technique in 2000 and published a series of 597 patients in 2012 of their experience. The reported seroma rate in the literature ranges from 2% to 26% with drains and 0.1% to 4% with progressive tension sutures (PTS) without drains. OBJECTIVES: Given these data, we decided to use PTS and forego drains in abdominoplasty. Here we present our experience with the transition. METHODS: This is a retrospective chart review of 451 abdominoplasties performed at our outpatient surgery center over a 7-year period (2009-2015). We gathered data on patient demographics, concomitant liposuction, and complications and length of follow up. RESULTS: Five main differences were examined in PTS vs traditional abdominoplasty using drains groups. These included rate of seroma, wound complication, scar revision, hematoma, and follow up. We found a decreased rate of seroma in the PTS group, 2% vs 9%. Wound complications were similar. Scar revision was slightly higher in the PTS group at 17% vs 10% in traditional abdominoplasty, this association had a P value of .048. The rates of hematoma were similar (0% vs 1%). The mean follow up was 6 months in PTS and 9 months in traditional abdominoplasty. Addition of liposuction did not increase the rate of seroma. CONCLUSIONS: PTS without drains significantly decreased the seroma rate in our practice. Our experience adds to the mounting evidence that surgeons should consider using the PTS technique and abandon the use of drains in abdominoplasty. A well powered, multicenter, randomized controlled study is needed in order to definitively lay this question to rest. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 26977073 TI - SIMULATING LOCAL DENSE AREAS USING PMMA TO ASSESS AUTOMATIC EXPOSURE CONTROL IN DIGITAL MAMMOGRAPHY. AB - Current digital mammography (DM) X-ray systems are equipped with advanced automatic exposure control (AEC) systems, which determine the exposure factors depending on breast composition. In the supplement of the European guidelines for quality assurance in breast cancer screening and diagnosis, a phantom-based test is included to evaluate the AEC response to local dense areas in terms of signal to-noise ratio (SNR). This study evaluates the proposed test in terms of SNR and dose for four DM systems. The glandular fraction represented by the local dense area was assessed by analytic calculations. It was found that the proposed test simulates adipose to fully glandular breast compositions in attenuation. The doses associated with the phantoms were found to match well with the patient dose distribution. In conclusion, after some small adaptations, the test is valuable for the assessment of the AEC performance in terms of both SNR and dose. PMID- 26977074 TI - EVALUATION OF DOSE REDUCTION POTENTIALS OF A NOVEL SCATTER CORRECTION SOFTWARE FOR BEDSIDE CHEST X-RAY IMAGING. AB - Bedside chest X-rays (CXR) for catheter position control may add up to a considerable radiation dose for patients in the intensive care unit (ICU). In this study, image quality and dose reduction potentials of a novel X-ray scatter correction software (SkyFlow, Philips Healthcare, Hamburg, Germany) were evaluated. CXRs of a 'LUNGMAN' (Kyoto Kagaku Co., LTD, Kyoto, Japan) thoracic phantom with a portacath system, a central venous line and a dialysis catheter were performed in an experimental set-up with multiple tube voltage and tube current settings without and with an antiscatter grid. Images with diagnostic exposure index (EI) 250-500 were evaluated for the difference in applied mAs with and without antiscatter grid. Three radiologists subjectively assessed the diagnostic image quality of grid and non-grid images. Compared with a non-grid image, usage of an antiscatter grid implied twice as high mAs in order to reach diagnostic EI. SkyFlow significantly improved the image quality of images acquired without grid. CXR with grid provided better image contrast than grid less imaging with scatter correction. PMID- 26977075 TI - ORGAN DOSES AND EFFECTIVE DOSE FOR FIVE PET RADIOPHARMACEUTICALS. AB - Diagnostic investigations with positron-emitting radiopharmaceuticals are dominated by (18)F-fluorodeoxyglucose ((18)F-FDG), but other radiopharmaceuticals are also commercially available or under development. Five of them, which are all clinically important, are (18)F-fluoride, (18)F-fluoroethyltyrosine ((18)F-FET), (18)F-deoxyfluorothymidine ((18)F-FLT), (18)F-fluorocholine ((18)F-choline) and (11)C-raclopride. To estimate the potential risk of stochastic effects (mainly lethal cancer) to a population, organ doses and effective dose values were updated for all five radiopharmaceuticals. Dose calculations were performed using the computer program IDAC2.0, which bases its calculations on the ICRP/ICRU adult reference voxel phantoms and the tissue weighting factors from ICRP publication 103. The biokinetic models were taken from ICRP publication 128. For organ doses, there are substantial changes. The only significant change in effective dose compared with previous estimations was a 46 % reduction for (18)F-fluoride. The estimated effective dose in mSv MBq(-1) was 1.5E-02 for (18)F-FET, 1.5E-02 for (18)F-FLT, 2.0E-02 for (18)F-choline, 9.0E-03 for (18)F-fluoride and 4.4E-03 for (11)C-raclopride. PMID- 26977076 TI - Establishment and evaluation of a transgenic mouse model of arthritis induced by overexpressing human tumor necrosis factor alpha. AB - Tumor necrosis factor alpha (TNFalpha) plays a key role in the pathogenesis of rheumatoid arthritis (RA). Blockade of TNFalpha by monoclonal antibody has been widely used for the therapy of RA since the 1990s; however, its mechanism of efficacy, and potential safety concerns of the treatment are still not fully understood. This study sought to establish a transgenic arthritic mouse model by overexpressing human TNFalpha (hTNFalpha) and to apply this model as a means to evaluate therapeutic consequences of TNFalpha inhibitors. The transgenic mouse line (TgTC) with FVB background was generated by incorporating 3' modifiedhTNFalphagene sequences. A progressively erosive polyarthritis developed in the TgTC mice, with many characteristics observed in human rheumatoid arthritis, including polyarticular swelling, impairment of movement, synovial hyperplasia, and cartilage and bone erosion. Gene expression analysis demonstrated that hTNFalpha is not only expressed in hyperplastic synovial membrane, but also in tissues without lesions, including brain, lung and kidney. Treatment of the TgTC mice with anti-hTNFalpha monoclonal antibodies (mAb) significantly decreased the level of hTNFalpha in the diseased joint and effectively prevented development of arthritis in a dose-dependent response fashion. Our results indicated that the TgTC mice represent a genetic model which can be used to comprehensively investigate the pathogenesis and therapeutics of TNFalpha-related diseases. PMID- 26977078 TI - Doctors cite lack of time as greatest barrier to research. PMID- 26977077 TI - Dlc1 interaction with non-muscle myosin heavy chain II-A (Myh9) and Rac1 activation. AB - The Deleted in liver cancer 1 (Dlc1) gene codes for a Rho GTPase-activating protein that also acts as a tumour suppressor gene. Several studies have consistently found that overexpression leads to excessive cell elongation, cytoskeleton changes and subsequent cell death. However, none of these studies have been able to satisfactorily explain the Dlc1-induced cell morphological phenotypes and the function of the different Dlc1 isoforms. Therefore, we have studied the interacting proteins associated with the three major Dlc1 transcriptional isoforms using a mass spectrometric approach in Dlc1 overexpressing cells. We have found and validated novel interacting partners in constitutive Dlc1-expressing cells. Our study has shown that Dlc1 interacts with non-muscle myosin heavy chain II-A (Myh9), plectin and spectrin proteins in different multiprotein complexes. Overexpression of Dlc1 led to increased phosphorylation of Myh9 protein and activation of Rac1 GTPase. These data support a role for Dlc1 in induced cell elongation morphology and provide some molecular targets for further analysis of this phenotype. PMID- 26977079 TI - Home-Based Early Intervention and the Influence of Family Resources on Cognitive Development. AB - OBJECTIVE: To investigate whether early developmental intervention (EDI) can positively affect the trajectories of cognitive development among children from low-resource families. METHODS: Longitudinal analyses were conducted of data from 293 children in the Brain Research to Ameliorate Impaired Neurodevelopment Home based Intervention Trial, a randomized controlled trial of a home-based EDI program, to examine trajectories of Bayley Scales of Infant Development-Second Edition Mental Development Index (MDI) scores from 12 to 36 months of age among young children from high- and low-resource families in 3 low- to middle-resource countries. RESULTS: A 3-way interaction among family resources, intervention group, and age was statistically significant after controlling for maternal, child, and birth characteristics (Wald chi(2)(1) = 9.41, P = .002). Among children of families with high resources, both the intervention and control groups had significant increases in MDI scores over time (P < .001 and P = .002, respectively), and 36-month MDI scores for these 2 groups did not differ significantly (P = .602). However, in families with low resources, the EDI group displayed greater improvement, resulting in significantly higher 36-month MDI scores than the control group (P < .001). In addition, the 36-month MDI scores for children in families with low resources receiving EDI did not differ significantly from children from high-resource families in either the EDI (P = .509) or control (P = .882) groups. CONCLUSIONS: A home-based EDI during the first 3 years of life can substantially decrease the developmental gap between children from families with lower versus higher resources, even among children in low- to middle-resource countries. PMID- 26977080 TI - Global Sustainable Development Starts With Investment in the Early Brain Development of Children. PMID- 26977082 TI - Hospitals and GPs are offered incentives to reduce antibiotic prescribing. PMID- 26977083 TI - Rates of prophylactic mastectomy triple in decade, study shows. PMID- 26977081 TI - Varicella Vaccine Effectiveness in Preventing Community Transmission in the 2 Dose Era. AB - OBJECTIVES: We examined overall and incremental effectiveness of 2-dose varicella vaccination in preventing community transmission of varicella among children aged 4 to 18 years in 2 active surveillance sites. One-dose varicella vaccine effectiveness (VE) was examined in those aged 1 to 18 years. METHODS: From May 2009 through June 2011, varicella cases identified during active surveillance in Antelope Valley, CA and Philadelphia, PA were enrolled into a matched case control study. Matched controls within 2 years of the patient's age were selected from immunization registries. A standardized questionnaire was administered to participants' parents, and varicella vaccination history was obtained from health care provider, immunization registry, or parent records. We used conditional logistic regression to estimate varicella VE against clinically diagnosed and laboratory-confirmed varicella. RESULTS: A total of 125 clinically diagnosed varicella cases and 408 matched controls were enrolled. Twenty-nine cases were laboratory confirmed. One-dose VE (1-dose versus unvaccinated) was 75.6% (95% confidence interval [CI], 38.7%-90.3%) in preventing any clinically diagnosed varicella and 78.1% (95% CI, 12.7%-94.5%) against moderate or severe, clinically diagnosed disease (>=50 lesions). Among subjects aged >=4 years, 2-dose VE (2 dose versus unvaccinated) was 93.6% (95% CI, 75.6%-98.3%) against any varicella and 97.9% (95% CI, 83.0%-99.7%) against moderate or severe varicella. Incremental effectiveness (2-dose versus 1-dose) was 87.5% against clinically diagnosed varicella and 97.3% against laboratory-confirmed varicella. CONCLUSIONS: Two-dose varicella vaccination offered better protection against varicella from community transmission among school-aged children compared with 1-dose vaccination. PMID- 26977084 TI - Rice HOX12 Regulates Panicle Exsertion by Directly Modulating the Expression of ELONGATED UPPERMOST INTERNODE1. AB - Bioactive gibberellins (GAs) are key endogenous regulators of plant growth. Previous work identified ELONGATED UPPERMOST INTERNODE1 (EUI1) as a GA deactivating enzyme that plays an important role in panicle exsertion from the flag leaf sheath in rice (Oryza sativa). However, the mechanism that regulates EUI1 activity during development is still largely unexplored. In this study, we identified the dominant panicle enclosure mutant regulator of eui1 (ree1-D), whose phenotype is caused by the activation of the homeodomain-leucine zipper transcription factor HOX12. Diminished HOX12 expression by RNA interference enhanced panicle exsertion, mimicking the eui1 phenotype. HOX12 knockdown plants contain higher levels of the major biologically active GAs (such as GA1 and GA4) than the wild type. The expression of EUI1 is elevated in the ree1-D mutant but reduced in HOX12 knockdown plants. Interestingly, both HOX12 and EUI1 are predominantly expressed in panicles, where GA4 is highly accumulated. Yeast one hybrid, electrophoretic mobility shift assay, and chromatin immunoprecipitation analyses showed that HOX12 physically interacts with the EUI1 promoter both in vitro and in vivo. Furthermore, plants overexpressing HOX12 in the eui1 mutant background retained the elongated uppermost internode phenotype. These results indicate that HOX12 acts directly through EUI1 to regulate panicle exsertion in rice. PMID- 26977086 TI - Regression discontinuity designs in healthcare research. PMID- 26977087 TI - A pathway to chlamydia control: updated ECDC guidance. PMID- 26977085 TI - Functionally Similar WRKY Proteins Regulate Vacuolar Acidification in Petunia and Hair Development in Arabidopsis. AB - The WD40 proteins ANTHOCYANIN11 (AN11) from petunia (Petunia hybrida) and TRANSPARENT TESTA GLABRA1 (TTG1) from Arabidopsis thaliana and associated basic helix-loop-helix (bHLH) and MYB transcription factors activate a variety of differentiation processes. In petunia petals, AN11 and the bHLH protein AN1 activate, together with the MYB protein AN2, anthocyanin biosynthesis and, together with the MYB protein PH4, distinct genes, such as PH1 and PH5, that acidify the vacuole. To understand how AN1 and AN11 activate anthocyanin biosynthetic and PH genes independently, we isolated PH3. We found that PH3 is a target gene of the AN11-AN1-PH4 complex and encodes a WRKY protein that can bind to AN11 and is required, in a feed-forward loop, together with AN11-AN1-PH4 for transcription of PH5. PH3 is highly similar to TTG2, which regulates hair development, tannin accumulation, and mucilage production in Arabidopsis. Like PH3, TTG2 can bind to petunia AN11 and the Arabidopsis homolog TTG1, complement ph3 in petunia, and reactivate the PH3 target gene PH5. Our findings show that the specificity of WD40-bHLH-MYB complexes is in part determined by interacting proteins, such as PH3 and TTG2, and reveal an unanticipated similarity in the regulatory circuitry that controls petunia vacuolar acidification and Arabidopsis hair development. PMID- 26977089 TI - Medical management of renal stones. AB - The prevalence of kidney stones is increasing in industrialized nations, resulting in a corresponding rise in economic burden. Nephrolithiasis is now recognized as both a chronic and systemic condition, which further underscores the impact of the disease. Diet and environment play an important role in stone disease, presumably by modulating urine composition. Dietary modification as a preventive treatment to decrease lithogenic risk factors and prevent stone recurrence has gained interest because of its potential to be safer and more economical than drug treatment. However, not all abnormalities are likely to be amenable to dietary therapy, and in some cases drugs are necessary to reduce the risk of stone formation. Unfortunately, no new drugs have been developed for stone prevention since the 1980s when potassium citrate was introduced, perhaps because the long observation period needed to demonstrate efficacy discourages investigators from embarking on clinical trials. Nonetheless, effective established treatment regimens are currently available for stone prevention. PMID- 26977091 TI - Identifying skull fractures in young children. PMID- 26977088 TI - Relationships of Leaf Net Photosynthesis, Stomatal Conductance, and Mesophyll Conductance to Primary Metabolism: A Multispecies Meta-Analysis Approach. AB - Plant metabolism drives plant development and plant-environment responses, and data readouts from this cellular level could provide insights in the underlying molecular processes. Existing studies have already related key in vivo leaf gas exchange parameters with structural traits and nutrient components across multiple species. However, insights in the relationships of leaf gas-exchange with leaf primary metabolism are still limited. We investigated these relationships through a multispecies meta-analysis approach based on data sets from 17 published studies describing net photosynthesis (A) and stomatal (gs) and mesophyll (gm) conductances, alongside the 53 data profiles from primary metabolism of 14 species grown in different experiments. Modeling results highlighted the conserved patterns between the different species. Consideration of species-specific effects increased the explanatory power of the models for some metabolites, including Glc-6-P, Fru-6-P, malate, fumarate, Xyl, and ribose. Significant relationships of A with sugars and phosphorylated intermediates were observed. While gs was related to sugars, organic acids, myo-inositol, and shikimate, gm showed a more complex pattern in comparison to the two other traits. Some metabolites, such as malate and Man, appeared in the models for both conductances, suggesting a metabolic coregulation between gs and gm The resulting statistical models provide the first hints for coregulation patterns involving primary metabolism plus leaf water and carbon balances that are conserved across plant species, as well as species-specific trends that can be used to determine new biotechnological targets for crop improvement. PMID- 26977092 TI - Health benefits of hosting major international events. PMID- 26977093 TI - NOACs: drug-drug interactions. PMID- 26977094 TI - Behind the scenes of JAC: the Editorial Office. AB - This brief article takes a look at the work of the JAC Editorial Office and how it contributes to the delivery of JAC to its readers. The article considers how the Editorial Office interacts with authors, referees and Editorial Board members to facilitate the submission, review and final publication of articles. PMID- 26977097 TI - Hearing Parents' Appraisals of Parenting a Deaf or Hard-of-Hearing Child: Application of a Positive Psychology Framework. AB - Hearing parents of deaf and hard-of-hearing children face unique challenges and stressors, the understanding of which has been the focus of numerous studies; yet, relatively little is known about their positive experiences. Using a qualitative purposive sampling design, interviews were conducted with 11 hearing parents (8 mothers, 3 fathers) exploring parents' positive appraisals of their experiences in raising a child who is deaf or hard of hearing (D/HH). Interviews were transcribed and a thematic analysis was conducted, which allowed the researchers to identify themes and patterns in the parents' appraisals. Nine key themes emerged, which characterized parents' positive perceptions of raising a child who is D/HH: knowing the child, appreciating everyday positives, increasing involvement with the child, relishing the highs, taking less for granted, letting go, learning, advocating, and experiencing personal growth A positive psychology framework was employed to foster understanding of the interview findings and their implications. When asked about the positive aspects of raising a D/HH child, hearing parents were readily able to identify ways in which their parenting experience had been enhanced and their lives improved as a result of their unique situations. The implications of these findings are discussed. PMID- 26977099 TI - Examining Small Intestinal Transit Time as a Function of Age: Is There Evidence to Support Age-Dependent Differences among Children? AB - The small intestine represents the region where the majority of drug and nutrient absorption transpires. Among adults, small intestinal transit kinetics is well delineated; however, the applicability of these values toward children remains unclear. This article serves to examine the relationship between age and mean small intestinal transit time (SITT) based on the available literature. In addition, the influence of alterations in intestinal transit time was explored among children using a model-based approach. Primary literature sources depicting SITT from children to adults were ascertained via the PubMed database. Data were limited to subjects without pathologies that could influence intestinal motility. Random-effect meta-regression models with between-study variability were employed to assess the influence of age on SITT. Three separate models with age as a linear or higher-order (i.e., second- and third-order polynomial) regressor were implemented to assess for the potential of both linear and curvilinear relationships. Examination of the influence of altered intestinal transit kinetics on the absorption of a sustained release theophylline preparation was explored among children between 8 and 14 years using physiologically based pharmacokinetic (PBPK) modeling. Age was not found to be a significant modulator of small intestinal transit within either the linear or higher-order polynomial meta-regression models. PBPK simulations indicated a lack of influence of variations in SITT on the absorption of theophylline from the examined sustained release formulation in older children. Based on the current literature, there is no evidence to suggest that mean SITT differs between children and adults. PMID- 26977098 TI - Endotoxin-Mediated Downregulation of Hepatic Drug Transporters in HIV-1 Transgenic Rats. AB - Altered expression of drug transporters and metabolic enzymes is known to occur in infection-induced inflammation. We hypothesize that in human immunodeficiency virus (HIV)-infected individuals, further alteration could occur as a result of augmented inflammation. The HIV-1 transgenic (Tg) rat is used to simulate HIV pathologies associated with the presence of HIV viral proteins. Therefore, the objective of this study was to examine the effect of endotoxin administration on the gene expression of drug transporters in the liver of HIV-Tg rats. Male and female HIV-Tg and wild-type (WT) littermates were injected with 5 mg/kg endotoxin or saline (n= 7-9/group). Eighteen hours later, rats were euthanized and tissues were collected. Quantitative real-time polymerase chain reaction and Western blot analysis were used to measure hepatic gene and protein expression, respectively, and enzyme-linked immunosorbent assay was used to measure serum cytokine levels. Although an augmented inflammatory response was seen in HIV-Tg rats, similar endotoxin- mediated downregulation of Abcb1a, Abcc2, Abcg2, Abcb11, Slco1a1, Slco1a2, Slco1b2, Slc10a1, Slc22a1, Cyp3a2, and Cyp3a9 gene expression was seen in the HIV-Tg and WT groups. A significantly greater endotoxin- mediated downregulation of Ent1/Slc29a1 was seen in female HIV-Tg rats. Basal expression of inflammatory mediators was not altered in the HIV-Tg rat; likewise, the basal expression of most transporters was not significantly different between HIV-Tg and WT rats. Our findings suggest that hepatobiliary clearances of endogenous and exogenous substrates are altered in the HIV-Tg rat after endotoxin exposure. This is of particular importance because HIV-infected individuals frequently present with bacterial or viral infections, which are a potential source for drug-disease interactions. PMID- 26977101 TI - Precision medicine: opportunities, possibilities, and challenges for patients and providers. AB - Precision medicine approaches disease treatment and prevention by taking patients' individual variability in genes, environment, and lifestyle into account. Although the ideas underlying precision medicine are not new, opportunities for its more widespread use in practice have been enhanced by the development of large-scale databases, new methods for categorizing and representing patients, and computational tools for analyzing large datasets. New research methods may create uncertainty for both healthcare professionals and patients. In such situations, frameworks that address ethical, legal, and social challenges can be instrumental for facilitating trust between patients and providers, but must protect patients while not stifling progress or overburdening healthcare professionals. In this perspective, we outline several ethical, legal, and social issues related to the Precision Medicine Initiative's proposed changes to current institutions, values, and frameworks. This piece is not an exhaustive overview, but is intended to highlight areas meriting further study and action, so that precision medicine's goal of facilitating systematic learning and research at the point of care does not overshadow healthcare's goal of providing care to patients. PMID- 26977100 TI - A rational approach to legacy data validation when transitioning between electronic health record systems. AB - OBJECTIVE: The objective of this project was to use statistical techniques to determine the completeness and accuracy of data migrated during electronic health record conversion. METHODS: Data validation during migration consists of mapped record testing and validation of a sample of the data for completeness and accuracy. We statistically determined a randomized sample size for each data type based on the desired confidence level and error limits. RESULTS: The only error identified in the post go-live period was a failure to migrate some clinical notes, which was unrelated to the validation process. No errors in the migrated data were found during the 12- month post-implementation period. CONCLUSIONS: Compared to the typical industry approach, we have demonstrated that a statistical approach to sampling size for data validation can ensure consistent confidence levels while maximizing efficiency of the validation process during a major electronic health record conversion. PMID- 26977102 TI - Automatic detection of social rhythms in bipolar disorder. AB - OBJECTIVE: To evaluate the feasibility of automatically assessing the Social Rhythm Metric (SRM), a clinically-validated marker of stability and rhythmicity for individuals with bipolar disorder (BD), using passively-sensed data from smartphones. METHODS: Seven patients with BD used smartphones for 4 weeks passively collecting sensor data including accelerometer, microphone, location, and communication information to infer behavioral and contextual patterns. Participants also completed SRM entries using a smartphone app. RESULTS: We found that automated sensing can be used to infer the SRM score. Using location, distance traveled, conversation frequency, and non-stationary duration as inputs, our generalized model achieves root-mean-square-error of 1.40, a reasonable performance given the range of SRM score (0-7). Personalized models further improve performance with mean root-mean-square-error of 0.92 across users. Classifiers using sensor streams can predict stable (SRM score >=3.5) and unstable (SRM score <3.5) states with high accuracy (precision: 0.85 and recall: 0.86). CONCLUSIONS: Automatic smartphone sensing is a feasible approach for inferring rhythmicity, a key marker of wellbeing for individuals with BD. PMID- 26977103 TI - A patient-centered system in a provider-centered world: challenges of incorporating post-discharge wound data into practice. AB - OBJECTIVE: The proposed Meaningful Use Stage 3 recommendations require healthcare providers to accept patient-generated health data (PGHD) by 2017. Yet, we know little about the tensions that arise in supporting the needs of both patients and providers in this context. We sought to examine these tensions when designing a novel, patient-centered technology - mobile Post-Operative Wound Evaluator (mPOWEr) - that uses PGHD for post-discharge surgical wound monitoring. MATERIALS AND METHODS: As part of the iterative design process of mPOWEr, we conducted semistructured interviews and think-aloud sessions using mockups with surgical patients and providers. We asked participants how mPOWEr could enhance the current post-discharge process for surgical patients, then used grounded theory to develop themes related to conflicts and agreements between patients and providers. RESULTS: We identified four areas of agreement: providing contextual metadata, accessible and actionable data presentation, building on existing sociotechnical systems, and process transparency. We identified six areas of conflict, with patients preferring: more flexibility in data input, frequent data transfer, text-based communication, patient input in provider response prioritization, timely and reliable provider responses, and definitive diagnoses. DISCUSSION: We present design implications and potential solutions to the identified conflicts for each theme, illustrated using our work on mPOWEr. Our experience highlights the importance of bringing a variety of stakeholders, including patients, into the design process for PGHD applications. CONCLUSION: We have identified critical barriers to integrating PGHD into clinical care and describe design implications to help address these barriers. Our work informs future efforts to ensure the smooth integration of essential PGHD into clinical practice. PMID- 26977105 TI - To Measure or not to Measure? That is the NPS Question. PMID- 26977104 TI - Simultaneous Measurement of 3-Chlorotyrosine and 3,5-Dichlorotyrosine in Whole Blood, Serum and Plasma by Isotope Dilution HPLC-MS-MS. AB - Chlorine is a public health concern and potential threat due to its high reactivity, ease and scale of production, widespread industrial use, bulk transportation, massive stockpiles and history as a chemical weapon. This work describes a new, sensitive and rapid stable isotope dilution method for the retrospective detection and quantitation of two chlorine adducts. The biomarkers 3-chlorotyrosine (Cl-Tyr) and 3,5-dichlorotyrosine (Cl2-Tyr) were isolated from the pronase digest of chlorine exposed whole blood, serum or plasma by solid phase extraction (SPE), separated by reversed-phase HPLC and detected by tandem mass spectrometry (MS-MS). The calibration range is 2.50-1,000 ng/mL (R2 >= 0.998) with a lowest reportable limit (LRL) of 2.50 ng/mL for both analytes, an accuracy of >=93% and an LOD of 0.443 ng/mL for Cl-Tyr and 0.396 ng/mL for Cl2 Tyr. Inter- and intra-day precision of quality control samples had coefficients of variation of <=10% and <=7.0%, respectively. Blood and serum samples from 200 healthy individuals and 175 individuals with chronic inflammatory disease were analyzed using this method to assess background levels of chlorinated tyrosine adducts. Results from patients with no known inflammatory disease history (healthy) showed baseline levels of 30% from baseline) in the intervention group was greater than that in the control group (73.1% vs.42.3%, X (2)=5.04, p=0.025). CONCLUSION: Compared to treatment of AD with low-dose antipsychotic medications alone, the combination of low-dose antipsychotic medication with adjunctive treatment with high frequency rTMS can significantly improve both cognitive functioning and the behavioral and psychological symptoms that often accompany AD. PMID- 26977126 TI - Effectiveness of Traditional Chinese Medicine (TCM) treatments on the cognitive functioning of elderly persons with mild cognitive impairment associated with white matter lesions. AB - BACKGROUND: Cerebral white matter lesion (WML) is a pathological change of the white matter which is considered an early sign of brain impairment in elderly individuals, so it is reasonable to administer early dementia prevention programs to individuals with WML.Traditional Chinese Medicine (TCM) has developed several approaches to prevent or delay the onset of dementia that have, as yet, not been formally tested. AIM: Evaluate the effects of a 6-month TCM intervention for elderly persons with mild cognitive impairment and WML. METHODS: Eighty individuals 65 years of age or older with radiological evidence of WML and mild cognitive impairment based on the Montreal Cognitive Assessment (MoCA) were classified into the four main TCM constitutional types (qi deficiency, yang deficiency, phlegm dampness, or blood stasis) and randomly assigned to a treatment group or a treatment-as-usual control group. The treatment group participated in training focused on diet, lifestyle, exercises, and emotional regulation adjustment; they also received six monthly courses of moxibustion (heating acupoints by burning the moxa of dried mugwort), each of which involved 10 daily 15-minute sessions focused on three targeted acupoints (one of which was specific to the constitutional type). Changes in the MoCA and in the score of each of the four constitutional types were the main outcomes assessed. RESULTS: Two participants dropped out of each group over the 6 months, leaving 38 in each group. Based on repeated measures analysis of variance, the total MoCA score, four of the six MoCA subscales scores (visual space and executive function, naming, attention and calculation, and delayed memory), and all four of the TCM constitution type scores showed significantly greater improvement over the 6 months in the treatment group than in the control group. CONCLUSION: This study shows that TCM interventions can improve both the cognitive functioning and the severity of symptoms considered in the TCM assessment of constitutional types among elderly individuals with mild cognitive impairment and WML. Long-term follow-up studies that use blinded evaluation of the outcome are needed to determine whether or not constitution-specific TCM treatments can prevent the onset of dementia. PMID- 26977128 TI - Heredity in comorbid bipolar disorder and obsessive-compulsive disorder patients. AB - Partly due to the overlap of symptom groupings in DSM, psychiatric comorbidity is extremely common. One of the most common and difficult to manage comorbid conditions is the co-occurrence of bipolar disorder (BD) and obsessive compulsive disorder (OCD). However, the key nosological question about this condition - whether they are two distinct disorders or a subtype of one of the disorders - remains unresolved. In order to help address this unanswered question, we updated our recent systematic review, searching the electronic databases MEDLINE, Embase, and PsycINFO to specifically investigate the heredity in BD-OCD patients. We identified a total of 8 relevant papers, the majority of which found that, compared to non-BD-OCD patients, BD-OCD patients were more likely to have a family history for mood disorders and less likely to have a family history for OCD. These results support the view that the majority of cases of comorbid BD-OCD are, in fact, BD cases. If confirmed in larger, more focused studies, this conclusion would have important nosological and clinical implications. PMID- 26977127 TI - Assessment of a six-week computer-based remediation program for social cognition in chronic schizophrenia. AB - BACKGROUND: Programs to remediate cognitive deficits have shown promising results in schizophrenia, but remediation of social cognition deficits is less well understood. Social cognitive deficits may cause more disability than the widely recognized neurocognitive deficits, suggesting that this is an area worthy of further investigation. AIM: Implement and evaluate a brief computerized cognitive remediation program designed to improve memory, attention, and facial affect recognition (FAR) in outpatients with chronic schizophrenia. METHODS: Baseline assessments of FAR and of clinical, cognitive, and psychosocial functioning were completed on 20 males with schizophrenia enrolled in an outpatient rehabilitation program at the Shanghai Mental Health Center (the intervention group) and on 20 males with schizophrenia recruited from among regular outpatients at the Center (the control group). Both groups received treatment as usual, but the intervention group also completed an average of 12.7 sessions of a computer-based remediation program for neurocognitive, social, and FAR functioning over a 6-week period. The baseline measures were repeated in both groups at the end of the 6 week trial. RESULTS: There were no statistically significant differences in the changes in clinical symptoms (assessed by the Positive and Negative Syndrome Scale, PANSS) or cognitive measures (assessed using the Hong Kong List Learning Test and the Letter-Number Sequencing Task) between the intervention and control groups over the 6-week trial, but there were modest improvements on the PANSS for the intervention group between baseline and after the intervention. There was a significantly greater improvement in the social functioning measure (the Personal and Social Performance scale, PSP) in the intervention group than in the control group. The pre-post change in the total facial recognition score in the intervention group was statistically significant (paired t-test=-2.60, p=0.018), and there was a statistical trend of a greater improvement in facial recognition in the intervention group than in the control group (F (1,37) =2.93; p=0.092). CONCLUSION: Integration of FAR training with a short, computer-administrated cognitive remediation program may improve recognition of facial emotions by individuals with schizophrenia, and, thus, improve their social functioning. But more work on developing the FAR training modules and on testing them in larger, more diverse samples will be needed before this can be recommended as a standard part of cognitive remediation programs. PMID- 26977129 TI - Infanticide by a mother with untreated schizophrenia. AB - This case report describes a 30-year-old mother of four with a 6-year history of obvious paranoia and psychosis from a poor rural farming community in India. Her symptoms and social functioning deteriorated over time, but the family did not seek medical care until she killed her 3-month-old daughter while under the influence of command hallucinations. Subsequent treatment with antipsychotic medication resulted in control of her psychotic symptoms and greatly improved psychosocial functioning. This case is an example of one of the many negative consequences of a community's failure to recognize and treat mental illnesses. The patient had severe symptoms that were obvious to all for 6 years prior to the infanticide, but the family's lack of basic knowledge about mental illness, the lack of locally available mental health care, and the relatively high cost of care prevented family members from obtaining the treatment that almost certainly would have prevented the tragic death of her infant. Changing these three factors in poor rural communities of low- and middle-income countries is the challenge we must work together to address. Infanticide secondary to untreated mental illness is a glaring reminder of how urgent this task is. PMID- 26977130 TI - Sudden cardiac death after modified electroconvulsive therapy. AB - Sudden deaths associated with the use of electroconvulsive therapy are rare. In this case report a 58-year-old male with a 20-year history of bipolar disorder and no history or signs of cardiac illness died from cardiac arrest within one hour of receiving an initial session of modified electroconvulsive therapy (MECT) to treat a recurrent episode of non-psychotic mania. The patient regained consciousness and was medically stable immediately after the MECT session (which did not produce a convulsion) but deteriorated rapidly after transfer to the recovery room. It was not possible to conduct an autopsy, but the authors surmise that the most probable cause was that the use of haloperidol 17 hours prior to MECT exacerbated the cardiac effects of nonconvulsive MECT. The case highlights the need for a thorough cardiac work-up on patients being considered for MECT (possibly including assessment of cardiac enzymes in older individuals) and careful consideration of the concurrent use of antipsychotic medications and MECT. PMID- 26977131 TI - The effect of simple imputation on inferences about population means when data are missing in biomedical research due to detection limits. AB - The sample geometric mean has been widely used in biomedical and psychosocial research to estimate and compare population geometric means. However, due to the detection limit of measurement instruments, the actual value of the measurement is not always observable. A common practice to deal with this problem is to replace missing values by small positive constants and make inferences based on the imputed data. However, no work has been carried out to study the effect of this naive imputation method on inference. In this report, we show that this simple imputation method may dramatically change the reported outcomes of a study and, thus, make the results uninterpretable, even if the detection limit is very small. PMID- 26977132 TI - Persistent mental symptoms and rabies. PMID- 26977133 TI - Parents' Perception of Stepped Care and Standard Care Trauma-Focused Cognitive Behavioral Therapy for Young Children. AB - Delivery systems other than in-office therapist-led treatments are needed to address treatment barriers such as accessibility, efficiency, costs, and parents wanting an active role in helping their child. To address these barriers, stepped care trauma focused-cognitive behavioral therapy (SC-TF-CBT) was developed as a parent-led, therapist-assisted therapy that occurs primarily at-home so that fewer in-office sessions are required. The current study examines caregivers' perceptions of parent-led (SC-TF-CBT) and therapist-led (TF-CBT) treatment. Participants consisted of 52 parents/care-givers (25-68 years) of young trauma exposed children (3-7 years) who were randomly assigned to SC-TF-CBT (n = 34) or to TF-CBT (n = 18). Data were collected at mid-and post-treatment via interviews inquiring about what participants liked, disliked, found most helpful, and found least helpful about the treatment. Results indicated that parents/caregivers favored relaxation skills, affect modulation and expression skills, the trauma narrative, and parenting skills across both conditions. The majority of parents/caregivers in SC-TF-CBT favored the at-home parent-child meetings and the workbook that guides the parent-led treatment, and there were suggestions for improving the workbook. Reported disliked and least helpful aspects of treatments were minimal across conditions, but themes that emerged that will need further exploration included the content and structure, and implementation difficulties for both conditions. Collectively, these results highlight the positive impact that a parent-led, therapist-assisted treatment could have in terms of providing caregivers with more tools to help their child after trauma and reduce barriers to treatment. PMID- 26977134 TI - Do grammatical-gender distinctions learned in the second language influence native-language lexical processing? AB - How does learning a second language influence native language processing? In the present study, we examined whether knowledge of Spanish - a language that marks grammatical gender on inanimate nouns - influences lexical processing in English a language that does not mark grammatical gender. We tested three groups of adult English native speakers: monolinguals, emergent bilinguals with high exposure to Spanish, and emergent bilinguals with low exposure to Spanish. Participants engaged in an associative learning task in English where they learned to associate names of inanimate objects with proper names. For half of the pairs, the grammatical gender of the noun's Spanish translation matched the gender of the proper name (e.g., corn-Patrick). For half of the pairs, the grammatical gender of the noun's Spanish translation mismatched the gender of the proper noun (e.g., beach-William). High-Spanish-exposure bilinguals (but not monolinguals or low-Spanish-exposure bilinguals) were less accurate at retrieving proper names for gender-incongruent than for gender-congruent pairs. This indicates that second-language morphosyntactic information is activated during native-language processing, even when the second language is acquired later in life. PMID- 26977135 TI - Nursing intervention versus usual care to improve delirium among home-dwelling older adults receiving homecare after hospitalization: feasibility and acceptability of a Randomized Controlled Trail. AB - BACKGROUND: Delirium is an acute cognitive impairment among older hospitalized patients. It can persist until discharge and for months after that. Despite proof that evidence-based nursing interventions are effective in preventing delirium in acute hospitals, interventions among home-dwelling older patients is lacking. The aim was to assess feasibility and acceptability of a nursing intervention designed to detect and reduce delirium in older adults after discharge from hospital. METHODS: Randomized clinical pilot trial with a before/after design was used. One hundred and three older adults were recruited in a home healthcare service in French-speaking Switzerland and randomized into an experimental group (EG, n = 51) and a control group (CG, n = 52). The CG received usual homecare. The EG received usual homecare plus five additional nursing interventions at 48 and 72 h and at 7, 14 and 21 days after discharge. These interventions were tailored for detecting and reducing delirium and were conducted by a geriatric clinical nurse (GCN). All patients were monitored at the start of the study (M1) and throughout the month for symptoms of delirium (M2). This was documented in patients' records after usual homecare using the Confusion Assessment Method (CAM). At one month (M2), symptoms of delirium were measured using the CAM, cognitive status was measured using the Mini-Mental State Examination (MMSE), and functional status was measured using Katz and Lawton Index of activities of daily living (ADL/IADL). At the end of the study, participants in the EG and homecare nurses were interviewed about the acceptability of the nursing interventions and the study itself. RESULTS: Feasibility and acceptability indicators reported excellent results. Recruitment, retention, randomization, and other procedures were efficient, although some potentially issues were identified. Participants and nurses considered organizational procedures, data collection, intervention content, the dose-effect of the interventions, and methodology all to be feasible. Duration, patient adherence and fidelity were judged acceptable. Nurses, participants and informal caregivers were satisfied with the relevance and safety of the interventions. CONCLUSIONS: Nursing interventions to detect/improve delirium at home are feasible and acceptable. These results confirm that developing a large-scale randomized controlled trial would be appropriate. TRIAL REGESTRATION: ISRCTN registry no: 16103589 - 19 February 2016. PMID- 26977136 TI - External validation of prognostic rules for early post-pulmonary embolism mortality: assessment of a claims-based and three clinical-based approaches. AB - BACKGROUND: Studies show the In-hospital Mortality for Pulmonary embolism using Claims daTa (IMPACT) rule can accurately identify pulmonary embolism (PE) patients at low-risk of early mortality in a retrospective setting using only claims for the index admission. We sought to externally validate IMPACT, Pulmonary Embolism Severity Index (PESI), simplified PESI (sPESI) and Hestia for predicting early mortality. METHODS: We identified consecutive adults admitted for objectively-confirmed PE between 10/21/2010 and 5/12/2015. Patients undergoing thrombolysis/embolectomy within 48 h were excluded. All-cause in hospital and 30 day mortality (using available Social Security Death Index data through January 2014) were assessed and prognostic accuracies of IMPACT, PESI, sPESI and Hestia were determined. RESULTS: Twenty-one (2.6 %) of the 807 PE patients died before discharge. All rules classified 26.1-38.3 % of patients as low-risk for early mortality. Fatality among low-risk patients was 0 % (sPESI and Hestia), 0.4 % (IMPACT) and 0.6 % (PESI). IMPACT's sensitivity was 95.2 % (95 % confidence interval [CI] = 74.1-99.8 %), and the sensitivities of clinical rules ranged from 91 (PESI)-100 % (sPESI and Hestia). Specificities of all rules ranged between 26.8 and 39.1 %. Of 573 consecutive patients in the 30 day mortality analysis, 33 (5.8 %) died. All rules classified 27.9-38.0 % of patients as low risk, and fatality occurred in 0 (Hestia)-1.4 % (PESI) of low-risk patients. IMPACT's sensitivity was 97.0 % (95%CI = 82.5-99.8 %), while sensitivities for clinical rules ranged from 91 (PESI)-100 % (Hestia). Specificities of rules ranged between 29.6 and 39.8 %. CONCLUSION: In this analysis, IMPACT identified low-risk PE patients with similar accuracy as clinical rules. While not intended for prospective clinical decision-making, IMPACT appears useful for identification of low-risk PE patient in retrospective claims-based studies. PMID- 26977138 TI - Combined RT-qPCR of mRNA and microRNA Targets within One Fluidigm Integrated Fluidic Circuit. AB - The ability to profile expression levels of a large number of mRNAs and microRNAs (miRNAs) within the same sample, using a single assay method, would facilitate investigations of miRNA effects on mRNA abundance and streamline biomarker screening across multiple RNA classes. A protocol is described for reverse transcription of long RNA and miRNA targets, followed by preassay amplification of the pooled cDNAs and quantitative PCR (qPCR) detection for a mixed panel of candidate RNA biomarkers. The method provides flexibility for designing custom target panels, is robust over a range of input RNA amounts, and demonstrated a high assay success rate. PMID- 26977137 TI - Developing a Brief Suicide Prevention Intervention and Mobile Phone Application: a Qualitative Report. AB - Suicide is the second leading cause of death among youth and has become a serious public health problem. There has been limited research on strategies to decrease the likelihood of reattempt in adolescents. As phase one of a treatment development study, clinicians, parents and adolescents participated in qualitative interviews in order to gain new perspectives on developing a targeted intervention and a safety plan phone application for suicide prevention. Participants indicated that transition of care, specific treatment targets and safety planning were important parts of treatment. In addition, all participants endorsed the use of a smartphone application for these purposes. PMID- 26977140 TI - Synthesis, Crystal Structure, Spectroscopic Properties, and Interaction with Ct DNA of Zn(II) with 2-Aminoethanethiol Hydrochloride Ligand. AB - The zinc(II) complex (C2H6NS)2Zn.ZnCl2 was synthesized with 2-aminoethanethiol hydrochloride and zinc sulfate heptahydrate as the raw materials in aqueous solution. The composition and structure of the complex were characterized by elemental analysis, infrared spectra, single crystal X-ray diffraction, and thermogravimetry. The crystal structure of the zinc(II) complex belongs to monoclinic system, space group P 21/n, with cell parameters of a = 0.84294(4), b = 0.83920(4), c = 1.65787(8) nm, Z = 2, and D = 2.041 g/cm(3). In this paper, the interaction of complex with Ct-DNA was investigated by UV-visible and viscosimetric techniques. Upon addition of the complex, important changes were observed in the characteristic UV-Vis bands (hyperchromism) of calf thymus DNA and some changes in specific viscosity. The experimental results showed that the complex is bound to DNA intercalative (intercalation binding). PMID- 26977139 TI - Salt-Dependent Aggregation and Assembly of E coli-Expressed Ferritin. AB - Ferritin, with the primary function of iron storage, is a nearly ubiquitous protein found in most living organisms. Our recent investigations suggest that ferritin can assemble nanoparticles. So we use ferritin as a novel type of delivery vehicle for recombinant epitope vaccines. And, we found that ferritin form nonnative aggregates depended sensitively on NaCl concentrations. Here, we report that ferritin is an ion-sensitive protein and has the attribute of salt dependent aggregation. Our results indicate that recombinant ferritin can be released as a soluble form from Escherichia coli at low NaCl concentrations (<=50 mmol/L). Moreover, this result affords us to confirm a proper self-assembling solution for soluble ferritin or other ferritin-based fusion proteins to assemble nanoparticles. PMID- 26977141 TI - Effects of Osseointegration by Bone Morphogenetic Protein-2 on Titanium Implants In Vitro and In Vivo. AB - This study designed a biomimetic implant for reducing healing time and achieving early osseointegration to create an active surface. Bone morphogenetic protein-2 (BMP-2) is a strong regulator protein in osteogenic pathways. Due to hardly maintaining BMP-2 biological function and specificity, BMP-2 efficient delivery on implant surfaces is the main challenge for the clinic application. In this study, a novel method for synthesizing functionalized silane film for superior modification with BMP-2 on titanium surfaces is proposed. Three groups were compared with and without BMP-2 on modified titanium surfaces in vitro and in vivo: mechanical grinding; electrochemical modification through potentiostatic anodization (ECH); and sandblasting, alkali heating, and etching (SMART). Cell tests indicated that the ECH and SMART groups with BMP-2 markedly promoted D1 cell activity and differentiation compared with the groups without BMP-2. Moreover, the SMART group with a BMP-2 surface markedly promoted early alkaline phosphatase expression in the D1 cells compared with the other surface groups. Compared with these groups in vivo, SMART silaning with BMP-2 showed superior bone quality and created contact areas between implant and surrounding bones. The SMART group with BMP-2 could promote cell mineralization in vitro and osseointegration in vivo, indicating potential clinical use. PMID- 26977142 TI - Prevalence of chronic diseases among older patients in German general practices. AB - AIMS: To evaluate the prevalence of chronic diseases (CDs) among older patients in German general practices (GPs). METHODS: A total of 840,319 patients older than 65 years (359,289 male and 481,030 female) who consulted a GP between January and December 2014 were selected. Ten different CDs were considered: hypertension, lipid metabolism, diabetes, coronary heart disease, cancer, chronic obstructive pulmonary disease, heart failure, stroke, chronic kidney disease and osteoporosis. The prevalence, defined as the proportion of patients diagnosed with these disorders, was estimated. RESULTS: All CDs were very common in older subjects. Hypertension was the most common CD, affecting 65.7% of men and 66.1% of women. Stroke was the least frequent CD, with 6.6% of men and 5.1% of women displaying this condition. More than one out of two subjects had between one and three CDs (men: 57.7% and women: 59.3%). Approximately 25% of subjects had four or more CDs (men: 26.6% and women: 23.6%). CONCLUSIONS: Our study showed that the prevalence of CDs is high in the German elderly population. Hypertension was the most frequent chronic condition and around 25% of patients displayed at least four CDs. PMID- 26977143 TI - Involvement of Inflammatory Cytokines in Antiarrhythmic Effects of Clofibrate in Ouabain-Induced Arrhythmia in Isolated Rat Atria. AB - Considering the cardioprotective and anti-inflammatory properties of clofibrate, the aim of the present experiment was to investigate the involvement of local and systemic inflammatory cytokines in possible antiarrhythmic effects of clofibrate in ouabain-induced arrhythmia in rats. Rats were orally treated with clofibrate (300 mg/kg), and ouabain (0.56 mg/kg) was administered to animals intraperitoneally. After induction of anesthesia, the atria were isolated and the onset of arrhythmia and asystole was recorded. The levels of inflammatory cytokines in atria were also measured. Clofibrate significantly postponed the onset of arrhythmia and asystole when compared to control group (P <= 0.05 and P <= 0.01, resp.). While ouabain significantly increased the atrial beating rate in control group (P <= 0.05), same treatment did not show similar effect in clofibrate-treated group (P > 0.05). Injection of ouabain significantly increased the atrial and systemic levels of all studied inflammatory cytokines (P <= 0.05). Pretreatment with clofibrate could attenuate the ouabain-induced elevation of IL 6 and TNF-alpha in atria (P <= 0.01 and P <= 0.05, resp.), as well as ouabain induced increase in IL-6 in plasma (P <= 0.05). Based on our findings, clofibrate may possess antiarrhythmic properties through mitigating the local and systemic inflammatory factors including IL-6 and TNF-alpha. PMID- 26977144 TI - Robotic Partial Nephrectomy with the Da Vinci Xi. AB - Purpose. The surgical expertise to perform robotic partial nephrectomy is heavily dependent on technology. The Da Vinci Xi (XI) is the latest robotic surgical platform with significant advancements compared to its predecessor. We describe our operative technique and experience with the XI system for robotic partial nephrectomy (RPN). Materials and Methods. Patients with clinical T1 renal masses were offered RPN with the XI. We used laser targeting, autopositioning, and a novel "in-line" port placement to perform RPN. Results. 15 patients underwent RPN with the XI. There were no intraoperative complications and no operative conversions. Mean console time was 101.3 minutes (range 44-176 minutes). Mean ischemia time was 17.5 minutes and estimated blood loss was 120 mLs. 12 of 15 patients had renal cell carcinoma. Two patients had oncocytoma and one had benign cystic disease. All patients had negative surgical margins and pathologic T1 disease. Two postoperative complications were encountered, including one patient who developed a pseudoaneurysm and one readmitted for presumed urinary tract infection. Conclusions. RPN with the XI system can be safely performed. Combining our surgical technique with the technological advancements on the XI offers patients acceptable pathologic and perioperative outcomes. PMID- 26977145 TI - Papillary Thyroid Carcinoma Arising in Children and Adolescent Hashimoto's Thyroiditis: Ultrasonographic and Pathologic Findings. AB - Objectives. We compared the ultrasonography and pathology features of papillary thyroid carcinoma (PTC) in pediatric and adolescents with Hashimoto's thyroiditis (HT) with those of non-HT patients. Materials and Methods. Eleven patients who were surgically confirmed to have pediatric or adolescent PTC from 2006 to 2014 were included in this study. We retrospectively analyzed the preoperative ultrasonography and pathology features of PTC arising in HT and non-HT patients. Results. On ultrasonography, thyroid gland was lobulated and enlarged, with many scattered microcalcifications in four of five HT patients. Four of six non-HT patients had suspicious masses with calcifications. The diffuse sclerosing variant of PTC (DSVPTC) was found in three of five HT patients, but none in non HT patients. Macroscopic or microscopic extrathyroidal extension was evident in all of the HT patients and four of the non-HT patients. Neck lymph node metastases were in all HT patients and five of non-HT patients. Conclusions. Three of five PTCs in pediatric and adolescent HT patients were DSVPTC, whereas all PTCs of the non-HT patients were classic type. On ultrasonography, thyroid gland was diffusely enlarged with scattered microcalcifications in four of five HT patients. All five HT cases had aggressive disease, including extrathyroidal extension and cervical lymph node metastases. PMID- 26977146 TI - The Impacts of SLC22A1 rs594709 and SLC47A1 rs2289669 Polymorphisms on Metformin Therapeutic Efficacy in Chinese Type 2 Diabetes Patients. AB - Background. We aimed to investigate the distributive characteristics of SLC22A1 rs594709 and SLC47A1 rs2289669 polymorphisms and their influence on metformin efficacy in Chinese T2DM patients. Methods. The distributions of SLC22A1 rs594709 and SLC47A1 rs2289669 polymorphisms were determined in 267 T2DM patients and 182 healthy subjects. Subsequently, 53 newly diagnosed patients who received metformin monotherapy were recruited to evaluate metformin efficacy. Results. No significant difference was found between T2DM patients and healthy subjects in SLC22A1 rs594709 and SLC47A1 rs2289669 allele frequencies and genotype frequencies. After metformin treatment, SLC22A1 rs594709 GG genotype patients showed a higher increase in FINS (p = 0.015) and decrease in HOMA-IS (p = 0.001) and QUICKI (p = 0.002) than A allele carriers. SLC47A1 rs2289669 GG genotype patients had a higher decrease in TChol (p = 0.030) and LDL-C (p = 0.049) than A allele carriers. Among SLC22A1 rs594709 AA genotype, patients with SLC47A1 rs2289669 AA genotype showed a higher decrease in FBG (p = 0.015), PINS (p = 0.041), and HOMA-IR (p = 0.014) than G allele carriers. However, among SLC22A1 rs594709 G allele carriers, SLC47A1 rs2289669 AA genotype patients showed a higher decrease in TChol (p = 0.013) than G allele carriers. Conclusion. Our data suggest that SLC22A1 rs594709 and SLC47A1 rs2289669 polymorphisms may influence metformin efficacy together in Chinese T2DM patients. PMID- 26977147 TI - Long-Term Quality of Life and Pregnancy Outcomes of Differentiated Thyroid Cancer Survivors Treated by Total Thyroidectomy and I(131) during Adolescence and Young Adulthood. AB - Introduction. Differentiated thyroid cancer (DTC) is rare and confers good prognosis. Long-term health related quality of life (HRQoL) and pregnancy outcomes are not well known in subjects treated during adolescence and young adulthood. Methods. Cross-sectional analysis of HRQoL and global self-esteem, using SF-36 and ISP-25 surveys, and of pregnancy outcomes in female survivors of DTC treated by total thyroidectomy and I(131) before age of 25 years. Results. Forty-five of 61 patients (74%) responded to the survey. Cumulative I(131) activity was <=3.85 GBq in 18 subjects and >3.85 GBq in 27 subjects. Mean time from diagnosis was 7.6 +/- 5.2 years for the group <= 3.85 GBq versus 16.9 +/- 11.6 years for the group > 3.85 GBq (P < 0.05). No significant alteration in long term HRQoL and global self-esteem was observed. Thirty pregnancies after I(131) were noted in patients from the group > 3.85 GBq and 10 in patients from the group <= 3.85 GBq. Frequency of miscarriages was of 17% (group > 3.85 GBq) and 10% (group <= 3.85 GBq) with 9 and 24 live births, respectively. No congenital malformations or first year mortality was noted. Conclusion. Long-term HRQoL, global self-esteem, and pregnancy outcomes are not affected in young female survivors of DTC. PMID- 26977148 TI - Recombinant Human Thyroid Stimulating Hormone versus Thyroid Hormone Withdrawal for Radioactive Iodine Treatment of Differentiated Thyroid Cancer with Nodal Metastatic Disease. AB - Introduction. Recombinant human thyroid stimulating hormone (rhTSH) is approved for preparation of thyroid remnant ablation with radioactive iodine (RAI) in low risk patients with well differentiated thyroid cancer (DTC). We studied the safety and efficacy of rhTSH preparation for RAI treatment of thyroid cancer patients with nodal metastatic disease. Methods. A retrospective analysis was performed on 108 patients with histopathologically confirmed nodal metastatic DTC, treated with initial RAI between January 1, 2000, and December 31, 2007. Within this selected group, 31 and 42 patients were prepared for initial and all subsequent RAI treatments by either thyroid hormone withdrawal (THW) or rhTSH protocols and were followed up for at least 3 years. Results. The response to initial treatment, classified as excellent, acceptable, or incomplete, was not different between the rhTSH group (57%, 21%, and 21%, resp.) and the THW group (39%, 13%, and 48%, resp.; P = 0.052). There was no significant difference in the final clinical outcome between the groups. The rhTSH group received significantly fewer additional doses of RAI than the THW group (P = 0.03). Conclusion. In patients with nodal-positive DTC, preparation for RAI with rhTSH is a safe and efficacious alternative to THW protocol. PMID- 26977149 TI - Materials and Bioactive Factors in Dental Restoration and Periodontal Therapy. PMID- 26977150 TI - Surface Roughness, Microhardness, and Microleakage of a Silorane-Based Composite Resin after Immediate or Delayed Finishing/Polishing. AB - Objective. This study evaluated the effect of immediate or delayed finishing/polishing using different systems on the surface roughness, hardness, and microleakage of a silorane-based composite. Material and Methods. Specimens were made with silorane-based composite (Filtek P90, 3M ESPE) and assigned to the treatments: control (light-cured); aluminum oxide discs (Sof-Lex, 3M ESPE); diamond-impregnated silicone tips (Astropol, Ivoclar Vivadent); aluminum oxide impregnated silicone tips (Enhance, Dentsply). Half of the specimens were finished/polished immediately and the rest after 7 days. Surface roughness (Ra, MUm; n = 20) and Vickers microhardness (50 g; 45 s; n = 10) were measured. Cavities were prepared in bovine incisors and filled with Filtek P90. The fillings received immediate or delayed finishing/polishing (n = 10) and were subjected to dye penetration test (0.5% basic fuchsin, 24 h). Data were analyzed by ANOVA and Scheffe, Kruskal-Wallis, and Mann-Whitney tests (p < 0.05). Results. The finishing/polishing system significantly influenced roughness and microhardness (p < 0.0001). For enamel, microleakage was not affected by the finishing/polishing system (p = 0.309). For dentin, Sof-Lex discs and Astropol points promoted greater microleakage than Enhance points (p = 0.033). Conclusion. Considering roughness, microhardness, and microleakage together, immediate finishing/polishing of a silorane-based composite using aluminum oxide discs may be recommended. PMID- 26977151 TI - Liquid Chromatography with Electrospray Ionization and Tandem Mass Spectrometry Applied in the Quantitative Analysis of Chitin-Derived Glucosamine for a Rapid Estimation of Fungal Biomass in Soil. AB - This method employs liquid chromatography-tandem mass spectrometry to rapidly quantify chitin-derived glucosamine for estimating fungal biomass. Analyte retention was achieved using hydrophilic interaction liquid chromatography, with a zwitter-ionic stationary phase (ZIC-HILIC), and isocratic elution using 60% 5 mM ammonium formate buffer (pH 3.0) and 40% ACN. Inclusion of muramic acid and its chromatographic separation from glucosamine enabled calculation of the bacterial contribution to the latter. Galactosamine, an isobaric isomer to glucosamine, found in significant amounts in soil samples, was also investigated. The two isomers form the same precursor and product ions and could not be chromatographically separated using this rapid method. Instead, glucosamine and galactosamine were distinguished mathematically, using the linear relationships describing the differences in product ion intensities for the two analytes. The m/z transitions of 180 -> 72 and 180 -> 84 were applied for the detection of glucosamine and galactosamine and that of 252 -> 126 for muramic acid. Limits of detection were in the nanomolar range for all included analytes. The total analysis time was 6 min, providing a high sample throughput method. PMID- 26977152 TI - Synthesis and Characterization of Chitosan Nanoaggregates from Gladius of Uroteuthis duvauceli. AB - We report the synthesis, characterization, and biological properties of chitosan nanoaggregates from gladius of squid, Uroteuthis duvauceli. beta-Chitin extracted from gladius was deacetylated to chitosan and further reduced to nanosize using ionic gelation process. The morphology and occurrence of chitosan nanoaggregates (CSNA) were observed using transmission electron microscopy (TEM). The degree of deacetylation (DD%) calculated from Fourier transform infrared (FTIR) spectrum showed high value (~94 +/- 1.25%) for chitosan. The CSNA depicts low molecular weight, stable positive zeta potential, and less ash and moisture content with high water and fat binding capacity. The antimicrobial activity was tested against pathogenic microorganisms, which depicted significant rate of inhibition against Staphylococcus aureus and Escherichia coli due to high cellular uptake. The antioxidant analysis for CSNA demonstrated high reducing power and scavenging activity towards superoxide radicals compared with the commercially available chitosan. Furthermore, nanoaggregates exhibited low cytotoxic behavior in biological in vitro tests performed using cervical cancer cell line. These results indicate that chitosan nanoaggregates synthesized from waste gladius will be highly efficient and safe candidate for biological applications as food packing film, drug carrier, and tissue engineering. PMID- 26977154 TI - Factor-Reduced Human Induced Pluripotent Stem Cells Efficiently Differentiate into Neurons Independent of the Number of Reprogramming Factors. AB - Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by overexpression of the transcription factors OCT4, SOX2, KLF4, and c-Myc holds great promise for the development of personalized cell replacement therapies. In an attempt to minimize the risk of chromosomal disruption and to simplify reprogramming, several studies demonstrated that a reduced set of reprogramming factors is sufficient to generate iPSC. We recently showed that a reduction of reprogramming factors in murine cells not only reduces reprogramming efficiency but also may worsen subsequent differentiation. To prove whether this is also true for human cells, we compared the efficiency of neuronal differentiation of iPSC generated from fetal human neural stem cells with either one (OCT4; hiPSC1F NSC) or two (OCT4, KLF4; hiPSC2F-NSC) reprogramming factors with iPSC produced from human fibroblasts using three (hiPSC3F-FIB) or four reprogramming factors (hiPSC4F-FIB). After four weeks of coculture with PA6 stromal cells, neuronal differentiation of hiPSC1F-NSC and hiPSC2F-NSC was as efficient as iPSC3F-FIB or iPSC4F-FIB. We conclude that a reduction of reprogramming factors in human cells does reduce reprogramming efficiency but does not alter subsequent differentiation into neural lineages. This is of importance for the development of future application of iPSC in cell replacement therapies. PMID- 26977153 TI - Sensorineural Tinnitus: Its Pathology and Probable Therapies. AB - Tinnitus is not a single disease but a group of different diseases with different pathologies and therefore different treatments. Regarding tinnitus as a single disease is hampering progress in understanding of the pathophysiology of tinnitus and perhaps, more importantly, it is a serious obstacle in development of effective treatments for tinnitus. Subjective tinnitus is a phantom sound that takes many different forms and has similarities with chronic neuropathic pain. The pathology may be in the cochlea, in the auditory nerve, or, most commonly, in the brain. Like chronic neuropathic pain tinnitus is not life threatening but influences many normal functions such as sleep and the ability to concentrate on work. Some forms of chronic tinnitus have two components, a (phantom) sound and a component that may best be described as suffering or distress. The pathology of these two components may be different and the treatment that is most effective may be different for these two components. The most common form of treatment of tinnitus is pharmacological agents and behavioral treatment combined with sound therapy. Less common treatments are hypnosis and acupuncture. Various forms of neuromodulation are becoming in use in an attempt to reverse maladaptive plastic changes in the brain. PMID- 26977155 TI - Manufacturing of Human Umbilical Cord Mesenchymal Stromal Cells on Microcarriers in a Dynamic System for Clinical Use. AB - The great properties of human mesenchymal stromal cells (hMSCs) make these cells an important tool in regenerative medicine. Because of the limitations of hMSCs derived from the bone marrow during isolation and expansion, hMSCs derived from the umbilical cord stroma are a great alternative to overcome these issues. For a large expansion of these cells, we performed a process transfer from static culture to a dynamic system. For this reason, a microcarrier selection out of five microcarrier types was made to achieve a suitable growth surface for the cells. The growth characteristics and metabolite consumption and production were used to compare the cells growth in 12-well plate and spinner flask. The goal to determine relevant process parameters to transfer the expansion process into a stirred tank bioreactor was achieved. PMID- 26977156 TI - Temporal Analyses of the Response of Intervertebral Disc Cells and Mesenchymal Stem Cells to Nutrient Deprivation. AB - Much emphasis has been placed recently on the repair of degenerate discs using implanted cells, such as disc cells or bone marrow derived mesenchymal stem cells (MSCs). This study examines the temporal response of bovine and human nucleus pulposus (NP) cells and MSCs cultured in monolayer following exposure to altered levels of glucose (0, 3.15, and 4.5 g/L) and foetal bovine serum (0, 10, and 20%) using an automated time-lapse imaging system. NP cells were also exposed to the cell death inducers, hydrogen peroxide and staurosporine, in comparison to serum starvation. We have demonstrated that human NP cells show an initial "shock" response to reduced nutrition (glucose). However, as time progresses, NP cells supplemented with serum recover with minimal evidence of cell death. Human NP cells show no evidence of proliferation in response to nutrient supplementation, whereas MSCs showed greater response to increased nutrition. When specifically inducing NP cell death with hydrogen peroxide and staurosporine, as expected, the cell number declined. These results support the concept that implanted NP cells or MSCs may be capable of survival in the nutrient-poor environment of the degenerate human disc, which has important clinical implications for the development of IVD cell therapies. PMID- 26977159 TI - Epigallocatechin-3-gallate Protects against Hydrogen Peroxide-Induced Inhibition of Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells. AB - Oxidative stress induces bone loss and osteoporosis, and epigallocatechin-3 gallate (EGCG) may be used to combat these diseases due to its antioxidative property. Herein, oxidative stress in human bone marrow-derived mesenchymal stem cells (BM-MSCs) was induced by H2O2, resulting in an adverse effect on their osteogenic differentiation. However, this H2O2-induced adverse effect was nullified when the cells were treated with EGCG. In addition, treatment of BM MSCs with EGCG alone also resulted in the enhancement of osteogenic differentiation of BM-MSCs. After EGCG treatment, expressions of beta-catenin and cyclin D1 were upregulated, suggesting that the Wnt pathway was involved in the effects of EGCG on the osteogenic differentiation of BM-MSCs. This was also confirmed by the fact that the Wnt pathway inhibitor, Dickkopf-1 (DKK-1), can nullify the EGCG-induced enhancement effect on BM-MSC's osteogenic differentiation. Hence, our results suggested that EGCG can reduce the effects of oxidative stress on Wnt pathway in osteogenic cells, which supported a potentially promising therapy of bone disorders induced by oxidative stress. Considering its positive effects on BM-MSCs, EGCG may also be beneficial for stem cell-based bone repair. PMID- 26977161 TI - Orthopedic Manifestations of Mobius Syndrome: Case Series and Survey Study. AB - Background. Mobius Syndrome is a rare disease defined by bilateral congenital 7th nerve palsy. We focus on reporting the prevalence of orthopedic disease in this population. Methods. Twenty-three individuals with Mobius Syndrome underwent orthopedic physical examination, and additional 96 patients filled out a survey for self-reported orthopedic diagnoses. Results. Clubfoot was present in 60% of individuals in the physical exam series and 42% of those in the survey. Scoliosis was present in 26% and 28%, respectively. Poland's Syndrome was present in 17% and 30%. In addition to these findings, 27% of patients reported having difficulty with anesthesia, including difficulty in intubation and airway problems. Conclusion. An increased prevalence of scoliosis, clubfoot, transverse limb deficiencies, and Poland's Syndrome is identified in the setting of Mobius Syndrome. In the setting of several deformities often requiring surgical correction, a high incidence of anesthetic difficulty is noted and should be discussed with patients and other providers during surgical planning. PMID- 26977160 TI - Ear Infection and Its Associated Risk Factors in First Nations and Rural School Aged Canadian Children. AB - Background. Ear infections in children are a major health problem and may be associated with hearing impairment and delayed language development. Objective. To determine the prevalence and the associated risk factors of ear infections in children 6-17 years old residing on two reserves and rural areas in the province of Saskatchewan. Methodology. Data were provided from two rural cross-sectional children studies. Outcome variable of interest was presence/absence of an ear infection. Logistic regression analysis was conducted to examine the relationship between ear infection and the other covariates. Results. The prevalence of ear infection was 57.8% for rural Caucasian children and 43.6% for First Nations children living on-reserve. First Nations children had a lower risk of ear infection. Ear infection prevalence was positively associated with younger age; first born in the family; self-reported physician-diagnosed tonsillitis; self reported physician-diagnosed asthma; and any respiratory related allergy. Protective effect of breastfeeding longer than three months was observed on the prevalence of ear infection. Conclusions. While ear infection is a prevalent condition of childhood, First Nations children were less likely to have a history of ear infections when compared to their rural Caucasian counterparts. PMID- 26977162 TI - Risk Factors for Portal Vein Thrombosis in Patients With Cirrhosis Awaiting Liver Transplantation in Shiraz, Iran. AB - BACKGROUND: Portal vein thrombosis is a fairly common and potentially life threatening complication in patients with liver cirrhosis. The risk factors for portal vein thrombosis in these patients are still not fully understood. OBJECTIVES: This study aimed to investigate the associations between various risk factors in cirrhotic patients and the development of portal vein thrombosis. PATIENTS AND METHODS: In this case-control study performed at the Shiraz organ transplantation center, Iran, we studied 219 patients (> 18 years old) with liver cirrhosis, who were awaiting liver transplants in our unit, from November 2010 to May 2011. The patients were evaluated by history, physical examination, and laboratory tests, including factor V Leiden, prothrombin gene mutation, Janus Kinase 2 (JAK2) mutation, and serum levels of protein C, protein S, antithrombin III, homocysteine, factor VIII, and anticardiolipin antibodies. RESULTS: There was no statistically significant difference in the assessed hypercoagulable states between patients with or without portal vein thrombosis. A history of previous variceal bleeding with subsequent endoscopic treatment in patients with portal vein thrombosis was significantly higher than in those without it (P = 0.013, OR: 2.526, 95% CI: 1.200 - 5.317). CONCLUSIONS: In our population of cirrhotic patients, treatment of variceal bleeding predisposed the patients to portal vein thrombosis, but hypercoagulable disorders by themselves were not associated with portal vein thrombosis. PMID- 26977158 TI - Development of Synthetic and Natural Materials for Tissue Engineering Applications Using Adipose Stem Cells. AB - Adipose stem cells have prominent implications in tissue regeneration due to their abundance and relative ease of harvest from adipose tissue and their abilities to differentiate into mature cells of various tissue lineages and secrete various growth cytokines. Development of tissue engineering techniques in combination with various carrier scaffolds and adipose stem cells offers great potential in overcoming the existing limitations constraining classical approaches used in plastic and reconstructive surgery. However, as most tissue engineering techniques are new and highly experimental, there are still many practical challenges that must be overcome before laboratory research can lead to large-scale clinical applications. Tissue engineering is currently a growing field of medical research; in this review, we will discuss the progress in research on biomaterials and scaffolds for tissue engineering applications using adipose stem cells. PMID- 26977164 TI - Autologous Peripheral Blood Stem Cell Transplantation Improves Portal Hemodynamics in Patients with Hepatitis B Virus-related Decompensated Cirrhosis. AB - BACKGROUND: Chronic hepatitis B virus (HBV) infection may eventually lead to decompensated liver cirrhosis, which is a terminal illness. OBJECTIVES: The aim of this study was to investigate the therapeutic efficacy of autologous peripheral blood stem cell (APBSC) transplantation to improve portal vein hemodynamics in patients with HBV-related decompensated cirrhosis. PATIENTS AND METHODS: This prospective study included 68 hospitalized patients who were diagnosed with HBV-related decompensated cirrhosis. These patients were divided into two groups: the transplantation group included 33 patients, while the control group included 35. Both groups received conventional medical treatment simultaneously, and APBSC transplantation was performed on the patients in the transplantation group. We evaluated the effects of APBSC transplantation on postoperative liver function using the following indices: total bilirubin, serum prothrombin and albumin, spleen size, and portal vein hemodynamics. Postoperatively, all of the patients were followed up at 24, 36, and 48 weeks. RESULTS: The transplantation group had no serious reactions. Compared with the control group, albumin and prothrombin activity in the transplantation group was significantly improved at 24, 36, and 48 weeks after the procedure, and spleen length and portal vein diameter were substantially reduced at 48 weeks. The velocity of peak portal vein blood flow and mean maximum portal vein blood flow were greatly increased in the APBSC transplantation group at 36 and 48 weeks, respectively; however, there was also decreased portal vein diameter, which reduced portal vein pressure in patients with HBV-related decompensated cirrhosis. CONCLUSIONS: APBSC transplantation greatly benefits HBV-linked decompensated cirrhosis patients and should be recommended in clinical practice. PMID- 26977163 TI - Distribution of Hepatitis C Virus Genotypes in Bahrain. AB - BACKGROUND: Approximately 170 million people are infected with Hepatitis C virus (HCV) worldwide, making it one of the world's major infectious diseases. There are no published population based studies about the prevalence of HCV genotypes in Bahrain. OBJECTIVES: Therefore, the aim of the present study was to investigate the prevalence and distribution of HCV genotypes and subtypes among a large sample of patients with chronic HCV infection in Bahrain. PATIENTS AND METHODS: Serum samples were collected from 202 HCV positive patients; of them 128 had a viral load (> 500 IU/mL) suitable for the type-specific genotyping assay. Gender-wise and age-wise differences in the distribution of HCV genotypes were determined by Chi Square and Fisher's Exact tests. RESULTS: The predominant genotype among Bahraini patients was type 1 (36.71%), followed by genotypes 3 and 4 (15.6% each) and the lowest frequency was found for genotype 2 (3.9%). Among genotype 1, subtype 1b had the highest frequency (21.09%), followed by subtype 1a (14.06%). Among genotype 3, subtype 3a had the highest frequency (11.72%), while among genotype 4, most of subtypes were undetermined. The frequency of all different HCV genotypes was higher in male patients compared to female patients. Genotype 1 was most common in the age group of 51 - 60 years (38.3%), genotype 2 in 21 - 30 years (60%) and genotype 3 in 51 - 60 years (30%), while genotype 4 was most frequent among the age group > 61 (40%). CONCLUSIONS: The most common HCV genotype in Bahrain was subtype 1b followed by 1a and 3a. Further studies involving sources of transmission in Bahrain are required to enhance control measures for HCV infection. PMID- 26977157 TI - Glioma Stem Cells and Their Microenvironments: Providers of Challenging Therapeutic Targets. AB - Malignant gliomas are aggressive brain tumors with limited therapeutic options, possibly because of highly tumorigenic subpopulations of glioma stem cells. These cells require specific microenvironments to maintain their "stemness," described as perivascular and hypoxic niches. Each of those niches induces particular signatures in glioma stem cells (e.g., activation of Notch signaling, secretion of VEGF, bFGF, SDF1 for the vascular niche, activation of HIF2alpha, and metabolic reprogramming for hypoxic niche). Recently, accumulated knowledge on tumor-associated macrophages, possibly delineating a third niche, has underlined the role of immune cells in glioma progression, via specific chemoattractant factors and cytokines, such as macrophage-colony stimulation factor (M-CSF). The local or myeloid origin of this new component of glioma stem cells niche is yet to be determined. Such niches are being increasingly recognized as key regulators involved in multiple stages of disease progression, therapy resistance, immune escaping, and distant metastasis, thereby substantially impacting the future development of frontline interventions in clinical oncology. This review focuses on the microenvironment impact on the glioma stem cell biology, emphasizing GSCs cross talk with hypoxic, perivascular, and immune niches and their potential use as targeted therapy. PMID- 26977165 TI - Interferon Lambda 4 Polymorphism Predicts Sustained Viral Response in Hepatitis C Virus Patients Irrespective of Hepatitis C Virus Genotypes, Ethnicity or Treatment Regimen: Results From a Meta-Analysis. AB - CONTEXT: There is growing evidence that interferon lambda 4 (IFNL4) polymorphism is related to sustained virological response (SVR) in hepatitis C virus (HCV) infection. We analyzed the relationship between IFNL4 (rs368234815) polymorphism and SVR in dual- and triple- therapy in HCV genotype 1, 2, 3 and 4 infected Asian, Caucasian and African patients. EVIDENCE ACQUISITION: We performed a systematic search of PubMed, Medline, Embase, EBSCO and Web of Science databases up to July 2015. Data of qualified studies were analyzed using the meta-analysis method in Stata 12.0 software. RESULTS: Ten studies involving 4765 patients were included in the analysis. Of overall studies, SVR was more frequent in TT/TT genotype compared to TT /DeltaG+DeltaG /DeltaG (OR = 4.439, 95% CI: 3.410 - 5.778). Genotype stratification analyses revealed rs368234815 TT/ TT was associated with higher SVR in G1, G2/3 and G4 HCV patients (ORG1 = 4.661, 95% CI: 3.937 - 5.518; ORG2/3 = 1.896, 95% CI: 1.265 - 2.841; ORG4 = 6.074; 95% CI: 3.129 - 11.788). Ethnicity stratification analyses of G1 patients showed that SVR was more frequent with TT/ TT genotype in Asians (OR= 8.245, 95% CI: 5.475 - 12.416), Caucasians (OR = 4.166, 95% CI: 3.441 - 5.042) and Africans (SVR: 37.5% vs 17.0%, P = 0.017). Moreover, similar results presented in therapy stratification analyses both in patients with dual-therapy (OR = 3.857; 95% CI: 3.288 - 4.524) or triple-therapy (OR = 8.119; 95% CI: 4.942 - 13.340). CONCLUSIONS: Favorable IFNL4 rs368234815 genotype is a strong predictor of SVR in HCV patients, irrespective of HCV genotypes, ethnicity or treatment regimen. Thus, detection for IFNL4 rs368234815 polymorphism may be beneficial to guide the clinician in the individualization of therapy and design. PMID- 26977166 TI - Abnormal Expression of Golgi Protein 73 in Clinical Values and Their Role in HBV Related Hepatocellular Carcinoma Diagnosis and Prognosis. AB - BACKGROUND: The up-regulation of hepatic Golgi protein 73 (GP73) is associated with the progression of hepatocellular carcinoma (HCC). However, the exact mechanism and clinical values of its diagnosis and prognosis still need to be clarified. OBJECTIVES: To investigate the clinical values of abnormal liver or circulating GP73 expression and their effect on HCC diagnosis and prognosis. MATERIALS AND METHODS: The expression of GP73 was investigated in 88 cancerous and self-control non-cancerous tissues using tissue microarrays with immunohisto- chemistry and was confirmed by Western blotting. Circulating GP73 levels were detected in the sera of 281 patients with liver diseases using enzyme-linked immunosorbent assay. RESULTS: The levels of circulating GP73 expression in the HCC group were higher than those in any group of benign liver diseases or controls. No significant difference was found between GP73 expression and patients' sex or age, tumor size, or AFP level except for those with hepatitis B virus (HBV) infection or distal metastasis (P < 0.05). The area under the receiver operating characteristic curve, sensitivity, and specificity for HCC diagnosis were 0.881, 78.34%, and 77.59% for GP73 levels over 70 MUg/L or 0.754, 71.97%, and 84.48% for alpha-fetoprotein levels over 50 MUg/L, respectively. The total incidence of GP73 plus alpha-fetoprotein was up to 87.26% for HCC. A positive GP73 result with brown particles was mainly located in the cytosol, with a few in the nucleus and none in the cell membrane, with abnormal expression in HCC tissues (480.7 +/- 148.7) that was significantly higher (t = 10.730, P < 0.001) than those in their non-cancerous tissues (208.0 +/- 66.1). The high GP73 expression in HCC was related to lymph node metastasis (chi(2) = 6.940, P = 0.008), gross classification (chi(2) = 6.311, P = 0.012), HBV (chi(2) = 4.803, P = 0.028), tumor node metastasis staging (chi(2) = 4.887, P = 0.027), and five year survival (chi(2) = 5.206, P = 0.023). CONCLUSIONS: Abnormality of hepatic or circulating GP73 expression should be regarded as an emerging biomarker for HCC diagnosis and prognosis. PMID- 26977167 TI - Selective Toxicity of Persian Gulf Sea Cucumber (Holothuria parva) and Sponge (Haliclona oculata) Methanolic Extracts on Liver Mitochondria Isolated from an Animal Model of Hepatocellular Carcinoma. AB - BACKGROUND: Natural products isolated from marine environments are well known for their pharmacodynamic potential in diverse disease treatments, such as for cancer or inflammatory conditions. Sea cucumbers are marine animals of the phylum Echinoderm and the class Holothuroidea, with leathery skin and gelatinous bodies. Sponges are important components of Persian Gulf animal communities, and the marine sponges of the genus Haliclona have been known to display broad-spectrum biological activity. Many studies have shown that sea cucumbers and sponges contain antioxidants and anti-cancer compounds. OBJECTIVES: This study was designed to determine the selective toxicity of Persian Gulf sea cucumber (Holothuria parva) and sponge (Haliclona oculata) methanolic extracts on liver mitochondria isolated from an animal model of hepatocellular carcinoma, as part of a national project that hopes to identify novel potential anticancer candidates among Iranian Persian Gulf flora and fauna. MATERIALS AND METHODS: To induce hepatocarcinogenesis, rats were given diethylnitrosamine (DEN) injections (200 mg/kg i.p. by a single dose), and then the cancer was promoted with 2 acetylaminofluorene (2-AAF) (0.02 w/w) for two weeks. Histopathological evaluations were performed, and levels of liver injury markers and a specific liver cancer marker (alpha-fetoprotein), were determined for confirmation of hepatocellular carcinoma induction. Finally, mitochondria were isolated from cancerous and non-cancerous hepatocytes. RESULTS: Our results showed that H. parva methanolic extracts (250, 500, and 1000 ug/mL) and H. oculata methanolic extracts (200, 400, and 800 ug/mL) increased reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP), mitochondrial swelling, and cytochrome c release in the mitochondria obtained from cancerous hepatocytes, but not in mitochondria obtained from non-cancerous liver hepatocytes. These extracts also induced caspase-3 activation, which is known as a final mediator of apoptosis, in the hepatocytes obtained only from cancerous, not non-cancerous, rat livers. CONCLUSIONS: Our results suggest that H. parva and H. oculata may be promising therapeutic candidates for the treatment of HCC, following further confirmatory in vivo experiments and clinical trials. PMID- 26977168 TI - Association Between LYPLAL1 rs12137855 Polymorphism With Ultrasound-Defined Non Alcoholic Fatty Liver Disease in a Chinese Han Population. AB - BACKGROUND: Recent genome-wide association studies (GWAS) identified that gene Lysophospholipase-like 1 (LYPLAL1) rs12137855 associated with non-alcoholic fatty liver disease (NAFLD). No research has been performed regarding the association between LYPLAL1 and NAFLD in China. OBJECTIVES: The aim of the present study was to investigate the association between the gene LYPLAL1 rs12137855 and NAFLD, and the effect on serum lipid profiles in a Chinese Han population. PATIENTS AND METHODS: LYPLAL1 rs12137855 gene was genotyped in 184 patients with NAFLD and 114 healthy controls using sequencing and polymerase chain reaction analysis (PCR). We tested serum lipid profiles using biochemical methods. RESULTS: No significant differences in genotype and allele frequencies of LYPLAL1 rs12137855 was found between the NAFLD group and the controls group (P > 0.05). Subjects with the variant LYPLAL1 rs12137855 CC genotype had a higher mean weight, body mass index (BMI) and low density lipoprotein (LDL). CONCLUSIONS: Our results showed for the first time that LYPLAL1 gene is not associated with a risk of NAFLD development in the Chinese Han population. The variant carriers of overall subjects significantly increased weight, BMI and LDL. PMID- 26977169 TI - Cholangiocarcinoma Secondary to Primary Sclerosing Cholangitis in Explanted Livers: A Single-Center Study in the South of Iran. AB - BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic disease, characterized by chronic inflammation and fibrosis of bile duct epithelial cells. This is a significant contributory factor to the development of malignancy, most commonly cholangiocarcinoma (CCA), which is the second most common malignant liver tumor. OBJECTIVES: For the first time in Iran, we intend to describe our experience with cases of PSC, with and without CCA, in explanted livers, and compare our results with those found in other areas of the world. PATIENTS AND METHODS: The study population comprised 181 individuals with a diagnosis of PSC who had undergone liver transplantation in the main liver transplant center of Iran, the largest center of hepatobiliary surgery in the south of that country, over a 3-year period between 2012 and 2014. All explanted livers, with and without CCA, were evaluated. RESULTS: Of the 181 patients, 16 were found to have CCA, two of whom had been diagnosed after pathologic study of the explanted livers. Therefore it appeared that 8.8% of the patients with PSC in our center had developed CCA before liver transplantation. CONCLUSIONS: A comparison of our results with those obtained from other centers in both Western and Asian countries (which reported CCA in 3.6% - 36.5% of patients with PSC), shows that the incidence of CCA in the patients we studied is intermediate. PMID- 26977170 TI - A Single Center Study Comparing the Stainable Iron Depositions in 1000 Explanted Cirrhotic Livers of Different Causes. AB - BACKGROUND: There have been very few studies evaluating the close association between excess iron and cirrhosis; however, cirrhosis could be regarded as an iron-loading disorder. OBJECTIVES: In this study, the goal was to show the levels of the iron content in the liver tissue in certain types of cirrhosis. PATIENTS AND METHODS: In this 7 year study (2008 - 2014), in 1000 explanted livers, the amount of iron was scored and compared according to the cause of the cirrhosis. The amount of iron in the liver was determined via the histochemical staining of the liver tissue, using Prussian-blue staining. Additionally, in each patient, the serum iron was determined and compared according to the cause of cirrhosis. RESULTS: The highest content of iron has been found in cirrhosis caused by chronic hepatitis (i.e. hepatitis B, C, and autoimmune hepatitis), as well as in alcoholic cirrhosis. The least amount of stainable iron has been shown in biliary cirrhosis. CONCLUSIONS: The presence of high stainable iron in patients with cirrhosis, secondary to chronic viral hepatitis, autoimmune hepatitis, and alcoholic hepatitis, should not be considered indicative of the presence of hereditary hemochromatosis; however, in those patients with biliary cirrhosis, a high iron content is rare, and can be a sign of the presence of the high iron Fe (HFE) gene mutation, or another type of hereditary hemochromatosis. PMID- 26977171 TI - Hepatitis A Virus Infection, Vaccination and Iranian Healthcare Workers. AB - CONTEXT: Hepatitis A virus (HAV) infection is an important public health problem. It is estimated that about 1.4 million cases of HAV infection occur every year worldwide. Non-immune healthcare workers (HCWs) can be at higher risk of HAV infection in comparison to general population and an appropriate preventive method should be considered for them. EVIDENCE ACQUISITION: For finding related articles, a comprehensive search was performed in Scopus, PubMed and Google Scholar and all appropriate combinations of following keywords were considered; "healthcare provider", "healthcare personnel", "healthcare worker", "nurse" "medical students", "Iran", "Hepatitis A" and "vaccination". Also we did a search in Persian language in Google scholar and scientific information database (SID) to find related Persian literature. RESULTS: A gradual shift in age of HAV infection has been seen from childhood toward adulthood. Data about HAV seropositivity among Iranian HCWs are very limited. However based on the recent studies, it seems that HAV seropositivity has been reduced among HCWs in comparison with the past. All recent studies have suggested HAV vaccination for HCWs. CONCLUSIONS: Available limited studies show that Iranian healthcare personnel need HAV vaccination. However, for selecting an appropriate preventive method for this high risk group, more original studies are still needed. PMID- 26977172 TI - Acupuncture for Pain Management in Cancer: A Systematic Review and Meta-Analysis. AB - Objective. To evaluate the effectiveness and safety of acupuncture for cancer related pain. Methods. A systematic review of literatures published from database inception to February 2015 was conducted in eight databases. RCTs involving acupuncture for treatment of cancer-related pain were identified. Two researchers independently performed article selection, data extraction, and quality assessment of data. Results. 1,639 participants in twenty RCTs were analyzed. All selected RCTs were associated with high risk of bias. Meta-analysis indicated that acupuncture alone did not have superior pain-relieving effects as compared with conventional drug therapy. However, as compared with the drug therapy alone, acupuncture plus drug therapy resulted in increased pain remission rate, shorter onset time of pain relief, longer pain-free duration, and better quality of life without serious adverse effects. However, GRADE analysis revealed that the quality of all outcomes about acupuncture plus drug therapy was very low. Conclusions. Acupuncture plus drug therapy is more effective than conventional drug therapy alone for cancer-related pain. However, multicenter high-quality RCTs with larger sample sizes are needed to provide stronger evidence for the effectiveness of acupuncture in cancer-related pain due to the low data quality of the studies included in the current meta-analysis. PMID- 26977173 TI - Analgesic and Antipyretic Activities of Methanol Extract and Its Fraction from the Root of Schoenoplectus grossus. AB - The study aims to evaluate analgesic and antipyretic activities of the methanol extract and its different fractions from root of Schoenoplectus grossus using acetic acid induced writhing and radiant heat tail flick method of pain models in mice and yeast induced pyrexia in rats at the doses of 400 and 200 mg/kg. In acetic acid writhing test, the methanol extract, petroleum ether, and carbon tetrachloride fractions produced significant (P < 0.001 and P < 0.05) inhibition of writhing responses in dose dependent manner. The methanol extract at 400 and 200 mg/kg being more protective with 54% and 45.45% of inhibition compared to diclofenac sodium of 56% followed by petroleum ether fractions of 49.69% and 39.39% at the same doses. The extracts did not produce any significant antinociceptive activity in tail flick test except standard morphine. When studied on yeast induced pyrexia, methanol and petroleum ether fractions significantly lowered the rectal temperature time dependently in a manner similar to standard drug paracetamol and distinctly more significant (P < 0.001) after second hour. These findings suggest that the root extracts of S. grossus possess significant peripherally acting analgesic potential and antipyretic property. The phytochemical screening showed the presence of flavonoids, alkaloids, and tannins. PMID- 26977174 TI - Selective Inhibition of Bakuchicin Isolated from Psoralea corylifolia on CYP1A in Human Liver Microsomes. AB - Bakuchicin is a furanocoumarin isolated from Psoralea corylifolia and shows several biological activities. Although there have been studies on the biological effects of bakuchicin, its modulation potency of CYP activities has not been previously investigated. Here, we investigated the inhibitory effects of bakuchicin on the activities of CYP isoforms by using a cocktail of probe substrates in pooled human liver microsomes (HLMs) and human recombinant cDNA expressed CYP. Bakuchicin strongly inhibited CYP1A-mediated phenacetin O deethylation with an IC50 value of 0.43 MUM in HLMs. It was confirmed by human recombinant cDNA-expressed CYP1A1 and CYP1A2 with a K i value of 0.11 MUM and 0.32 MUM, respectively. A Lineweaver-Burk plot indicated that the inhibition mechanism of bakuchicin was competitive inhibition. Overall, this is the first study to investigate the potential CYP1A1 and CYP1A2 inhibition associated with bakuchicin and to report its competitive inhibitory effects on HLMs. PMID- 26977176 TI - Scope and limitations of the dual-gold-catalysed hydrophenoxylation of alkynes. AB - Due to the synthetic advantages presented by the dual-gold-catalysed hydrophenoxylation of alkynes, a thorough study of this reaction was carried out in order to fully define the scope and limitations of the methodology. The protocol tolerates a wide range of functional groups, such as nitriles, ketones, esters, aldehydes, ketals, naphthyls, allyls or polyphenols, in a milder and more efficient manner than the previously reported methodologies. We have also identified that while we are able to use highly steric hindered phenols, small changes on the steric bulk of the alkynes have a dramatic effect on the reactivity. More importantly, we have observed that the use of substrates that facilitate the formation of diaurated species such as gem-diaurated or sigma,pi digold-acetylide species, hinder the catalytic activity. Moreover, we have identified that the use of directing groups in unsymmetrical alkynes can help to achieve high regioselectivity in the hydrophenoxylation. PMID- 26977177 TI - Thermal and oxidative stability of Atlantic salmon oil (Salmo salar L.) and complexation with beta-cyclodextrin. AB - The thermal and oxidative stability of Atlantic salmon oil (Salmo salar L.) as well as its beta-cyclodextrin (beta-CD) complexation ability has been verified for the first time. The main omega-3 fatty acids, EPA and DHA, were significantly degraded, even at 50 degrees C. Their relative concentrations decrease from 6.1% for EPA and 4.1% for DHA to 1.7% and 1.5% after degradation at 150 degrees C, respectively. On the other hand, the relative concentrations of monounsaturated and saturated fatty acids remained constant or slightly increased by a few percent after degradation (e.g., from 10.7% to 12.9% for palmitic acid). Co crystallization of ASO with beta-CD at a host-guest ratio of 1:1 and 3:1 from an ethanol-water mixture and kneading methods has been used for the preparation of beta-CD/ASO complexes. The analysis of the complexes by thermogravimetry, differential scanning calorimetry (DSC), and Karl Fischer titration (KFT) as well as the decrease of the "strongly-retained" water content confirm the formation of the inclusion compound. Furthermore, the DSC parameters correlate well with the KFT kinetic data for beta-CD/ASO complexes. PMID- 26977178 TI - Synthesis and nucleophilic aromatic substitution of 3-fluoro-5-nitro-1 (pentafluorosulfanyl)benzene. AB - 3-Fluoro-5-nitro-1-(pentafluorosulfanyl)benzene was prepared by three different ways: as a byproduct of direct fluorination of 1,2-bis(3-nitrophenyl)disulfane, by direct fluorination of 4-nitro-1-(pentafluorosulfanyl)benzene, and by fluorodenitration of 3,5-dinitro-1-(pentafluorosulfanyl)benzene. The title compound was subjected to a nucleophilic aromatic substitution of the fluorine atom with oxygen, sulfur and nitrogen nucleophiles affording novel (pentafluorosulfanyl)benzenes with 3,5-disubstitution pattern. Vicarious nucleophilic substitution of the title compound with carbon, oxygen, and nitrogen nucleophiles provided 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzenes substituted in position four. PMID- 26977179 TI - Asymmetric alpha-amination of beta-keto esters using a guanidine-bisurea bifunctional organocatalyst. AB - An asymmetric alpha-amination of beta-keto esters with azodicarboxylate in the presence of a guanidine-bisurea bifunctional organocatalyst was investigated. The alpha-amination products were obtained in up to 99% yield with up to 94% ee. PMID- 26977182 TI - Regioselective palladium-catalyzed ring-opening reactions of C1-substituted oxabicyclo[2,2,1]hepta-2,5-diene-2,3-dicarboxylates. AB - Palladium-catalyzed ring-opening reactions of C1 substituted 7-oxanorbornadiene derivatives with aryl iodides were investigated. The optimal conditions for this reaction were found to be PdCl2(PPh3)2, ZnCl2, Et3N and Zn in THF. Both steric and electronic factors played a role in the outcome of the reaction as increasing the steric bulk on the bridgehead carbon decreased the yield. These reactions were found to be highly regioselective, giving only one of the two possible regioisomers in all cases. A diverse collection of novel, highly substituted biphenyl derivatives were obtained. PMID- 26977181 TI - My maize and blue brick road to physical organic chemistry in materials. AB - Similar to Dorothy's journey along the yellow brick road in The Wizard of Oz, this perspective carves out the path I took from my early childhood fascinations with science through my independent career at the University of Michigan (maize and blue). The influential research projects and mentors are highlighted, including some fortuitous experimental results that drew me into the field of supramolecular chemistry, specifically, and organic materials, broadly. My research group's efforts toward designing new sensors based on small molecule gelators are described. In particular, I highlight how our design strategy has evolved as we learn more about molecular gelators. This perspective concludes with some predictions about where molecular gels, as well as my personal and professional life, are headed. PMID- 26977183 TI - Amino-functionalized (meth)acryl polymers by use of a solvent-polarity sensitive protecting group (Br-t-BOC). AB - We describe the synthesis of bromo-tert-butyloxycarbonyl (Br-t-BOC)-amino protected monomers 2-((1-bromo-2-methylpropan-2-yl)oxycarbonylamino)ethyl (meth)acrylate 3a,b. For this purpose, 2-isocyanatoethyl (meth)acrylate 1a,b was reacted with 1-bromo-2-methylpropan-2-ol (2a). The free radical polymerization of (Br-t-BOC)-aminoethyl (meth)acrylates 3a,b yielded poly((Br-t-BOC)-aminoethyl (meth)acrylate) 6a,b bearing protected amino side groups. The subsequent solvolysis of the Br-t-BOC function led to the new polymers poly(2-aminoethyl (meth)acrylate) 8a,b with protonated free amino groups. The monomers and the resulting polymers were thoroughly characterized by (1)H NMR, IR, GPC and DSC methods. The kinetics of the deprotection step was followed by (1)H NMR spectroscopy. The solvent polarity and neighboring group effects on the kinetics of deprotection are discussed. PMID- 26977180 TI - Interactions of cyclodextrins and their derivatives with toxic organophosphorus compounds. AB - The aim of this review is to provide an update on the current use of cyclodextrins against organophosphorus compound intoxications. Organophosphorus pesticides and nerve agents play a determinant role in the inhibition of cholinesterases. The cyclic structure of cyclodextrins and their toroidal shape are perfectly suitable to design new chemical scavengers able to trap and hydrolyze the organophosphorus compounds before they reach their biological target. PMID- 26977184 TI - A quadruple cascade protocol for the one-pot synthesis of fully-substituted hexahydroisoindolinones from simple substrates. AB - A new and efficient synthetic method to obtain fully-substituted hexahydroisoindolinones was developed by using bifunctional tertiary amine thioureas as powerful catalysts. As far as we know, there is no efficient synthetic method developed toward fully-substituted hexahydroisoindolinones. The products were obtained in good yield and diastereoselectivity. The one-pot cascade quadruple protocol features readily available starting materials, simple manipulation, mild conditions and good atom economy. PMID- 26977185 TI - Tandem processes promoted by a hydrogen shift in 6-arylfulvenes bearing acetalic units at ortho position: a combined experimental and computational study. AB - 6-Phenylfulvenes bearing (1,3-dioxolan or dioxan)-2-yl substituents at ortho position convert into mixtures of 4- and 9-(hydroxy)alkoxy-substituted benz[f]indenes as result of cascade processes initiated by a thermally activated hydrogen shift. Structurally related fulvenes with non-cyclic acetalic units afforded mixtures of 4- and 9-alkoxybenz[f]indenes under similar thermal conditions. Mechanistic paths promoted by an initial [1,4]-, [1,5]-, [1,7]- or [1,9]-H shift are conceivable for explaining these conversions. Deuterium labelling experiments exclude the [1,4]-hydride shift as the first step. A computational study scrutinized the reaction channels of these tandem conversions starting by [1,5]-, [1,7]- and [1,9]-H shifts, revealing that this first step is the rate-determining one and that the [1,9]-H shift is the one with the lowest energy barrier. PMID- 26977186 TI - Highly stable and reusable immobilized formate dehydrogenases: Promising biocatalysts for in situ regeneration of NADH. AB - This study aimed to prepare robust immobilized formate dehydrogenase (FDH) preparations which can be used as effective biocatalysts along with functional oxidoreductases, in which in situ regeneration of NADH is required. For this purpose, Candida methylica FDH was covalently immobilized onto Immobead 150 support (FDHI150), Immobead 150 support modified with ethylenediamine and then activated with glutaraldehyde (FDHIGLU), and Immobead 150 support functionalized with aldehyde groups (FDHIALD). The highest immobilization yield and activity yield were obtained as 90% and 132%, respectively when Immobead 150 functionalized with aldehyde groups was used as support. The half-life times (t 1/2) of free FDH, FDHI150, FDHIGLU and FDHIALD were calculated as 10.6, 28.9, 22.4 and 38.5 h, respectively at 35 degrees C. FDHI150, FDHIGLU and FDHIALD retained 69, 38 and 51% of their initial activities, respectively after 10 reuses. The results show that the FDHI150, FDHIGLU and FDHIALD offer feasible potentials for in situ regeneration of NADH. PMID- 26977187 TI - Enabling technologies and green processes in cyclodextrin chemistry. AB - The design of efficient synthetic green strategies for the selective modification of cyclodextrins (CDs) is still a challenging task. Outstanding results have been achieved in recent years by means of so-called enabling technologies, such as microwaves, ultrasound and ball mills, that have become irreplaceable tools in the synthesis of CD derivatives. Several examples of sonochemical selective modification of native alpha-, beta- and gamma-CDs have been reported including heterogeneous phase Pd- and Cu-catalysed hydrogenations and couplings. Microwave irradiation has emerged as the technique of choice for the production of highly substituted CD derivatives, CD grafted materials and polymers. Mechanochemical methods have successfully furnished greener, solvent-free syntheses and efficient complexation, while flow microreactors may well improve the repeatability and optimization of critical synthetic protocols. PMID- 26977188 TI - Organocatalytic asymmetric Henry reaction of 1H-pyrrole-2,3-diones with bifunctional amine-thiourea catalysts bearing multiple hydrogen-bond donors. AB - For the first time, a catalytic asymmetric Henry reaction of 1H-pyrrole-2,3 diones was achieved with a chiral bifunctional amine-thiourea as a catalyst possessing multiple hydrogen-bond donors. With this developed method, a range of 3-hydroxy-3-nitromethyl-1H-pyrrol-2(3H)-ones bearing quaternary stereocenters were obtained in acceptable yield (up to 75%) and enantioselectivity (up to 73% ee). PMID- 26977189 TI - Cascade alkylarylation of substituted N-allylbenzamides for the construction of dihydroisoquinolin-1(2H)-ones and isoquinoline-1,3(2H,4H)-diones. AB - An oxidative reaction for the synthesis of 4-alkyl-substituted dihydroisoquinolin 1(2H)-ones with N-allylbenzamide derivatives as starting materials has been developed. The radical alkylarylation reaction proceeds through a sequence of alkylation and intramolecular cyclization. The substituent on the C-C double bond was found to play a key role for the progress of the reaction to give the expected products with good chemical yields. Additionally, N methacryloylbenzamides were also suitable substrates for the current reaction and provided the alkyl-substituted isoquinoline-1,3(2H,4H)-diones in good yield. PMID- 26977190 TI - Application of 7-azaisatins in enantioselective Morita-Baylis-Hillman reaction. AB - 7-Azaisatin and 7-azaoxindole skeletons are valuable building blocks in diverse biologically active substances. Here 7-azaisatins turned out to be more efficient electrophiles than the analogous isatins in the enantioselective Morita-Baylis Hillman (MBH) reactions with maleimides using a bifunctional tertiary amine, beta isocupreidine (beta-ICD), as the catalyst. This route allows a convenient approach to access multifunctional 3-hydroxy-7-aza-2-oxindoles with high enantiopurity (up to 94% ee). Other types of activated alkenes, such as acrylates and acrolein, could also be efficiently utilized. PMID- 26977192 TI - Mycothiol synthesis by an anomerization reaction through endocyclic cleavage. AB - Mycothiol is found in Gram-positive bacteria, where it helps in maintaining a reducing intracellular environment and it plays an important role in protecting the cell from toxic chemicals. The inhibition of the mycothiol biosynthesis is considered as a treatment for tuberculosis. Mycothiol contains an alpha aminoglycoside, which is difficult to prepare stereoselectively by a conventional glycosylation reaction. In this study, mycothiol was synthesized by an anomerization reaction from an easily prepared beta-aminoglycoside through endocyclic cleavage. PMID- 26977193 TI - Study on the synthesis of the cyclopenta[f]indole core of raputindole A. AB - The raputindoles from the rutaceous tree Raputia simulans share a cyclopenta[f]indole partial structure the synthesis of which is subject of this investigation. An efficient route to a series of 1,5-di(indol-6-yl)pentenones was developed via Mo/Au-catalyzed Meyer-Schuster rearrangement of tertiary propargylic alcohol precursors. However, none of the enones underwent the desired Nazarov cyclization to a cyclopenta[f]indole. More suitable were 6 hydroxyallylated indolines which gave good yields of cyclopenta[f]indolines after treatment with SnCl4, as soon as sterically demanding beta-cyclocitral adducts were reacted. Most successful were Pt(II) and Au(I)-catalyzed cyclizations of N TIPS-protected indolin-6-yl-substituted propargylacetates which provided the hydrogenated tricyclic cyclopenta[f]indole core system in high yield. PMID- 26977195 TI - Optimized methods for preparation of 6(I)-(omega-sulfanyl-alkylene-sulfanyl)-beta cyclodextrin derivatives. AB - A general high-yielding method for the preparation of monosubstituted beta cyclodextrin derivatives which have attached a thiol group in position 6 is described. The thiol group is attached through linkers of different lengths and repeating units (ethylene glycol or methylene). The target compounds were characterized by IR, MS and NMR spectra. A simple method for their complete conversion to the corresponding disulfides as well as a method for the reduction of the disulfides back to the thiols is presented. Both, thiols and disulfides are derivatives usable for well-defined covalent attachment of cyclodextrin to gold or polydopamine-coated solid surfaces. PMID- 26977191 TI - Natural products from microbes associated with insects. AB - Here we review discoveries of secondary metabolites from microbes associated with insects. We mainly focus on natural products, where the ecological role has been at least partially elucidated, and/or the pharmaceutical properties evaluated, and on compounds with unique structural features. We demonstrate that the exploration of specific microbial-host interactions, in combination with multidisciplinary dereplication processes, has emerged as a successful strategy to identify novel chemical entities and to shed light on the ecology and evolution of defensive associations. PMID- 26977194 TI - Enantioselective [3 + 2] annulation of alpha-substituted allenoates with beta,gamma-unsaturated N-sulfonylimines catalyzed by a bifunctional dipeptide phosphine. AB - The first enantioselective [3 + 2] annulation of alpha-substituted allenoates with beta,gamma-unsaturated N-sulfonylimines is described. In the presence of a dipeptide phosphine catalyst, a wide range of highly functionalized cyclopentenes bearing an all-carbon quaternary center were obtained in moderate to good yields and with good to excellent enantioselectivities. PMID- 26977196 TI - Diastereoselective synthesis of new O-alkylated and C-branched inositols and their corresponding fluoro analogues. AB - Efficient routes were developed for the diastereoselective synthesis of new O alkylated and C-branched inositols and their corresponding fluoro analogues. The key steps of the synthesis were the easy accessibility of different types of arms in term of configuration (myo and scyllo), the linking method and length, which could modulate the biological properties. These inositol derivatives, bearing an arm terminated either with a hydroxy group or a fluorine atom, could be interesting candidates for diastereoisomeric intermediates and biological evaluations, especially for PET imaging experiments. PMID- 26977198 TI - Is 10 000 hours enough for urology residency? PMID- 26977199 TI - Guideline development - A vital part of the CUA's mission. PMID- 26977197 TI - Art, auto-mechanics, and supramolecular chemistry. A merging of hobbies and career. AB - While the strict definition of supramolecular chemistry is "chemistry beyond the molecule", meaning having a focus on non-covalent interactions, the field is primarily associated with the creation of synthetic receptors and self-assembly. For synthetic ease, the receptors and assemblies routinely possess a high degree of symmetry, which lends them an aspect of aesthetic beauty. Pictures of electron orbitals similarly can be seen as akin to works of art. This similarity was an early draw for me to the fields of supramolecular chemistry and molecular orbital theory, because I grew up in a household filled with art. In addition to art, my childhood was filled with repairing and constructing mechanical entities, such as internal combustion motors, where many components work together to achieve a function. Analogously, the field of supramolecular chemistry creates systems of high complexity that achieve functions or perform tasks. Therefore, in retrospect a career in supramolecular chemistry appears to be simply an extension of childhood hobbies involving art and auto-mechanics. PMID- 26977200 TI - The effect of wide resection during radical prostatectomy on surgical margins. AB - INTRODUCTION: The impact of nerve-sparing on positive surgical margins during radical prostatectomy (RP) remains unclear. The objective of this study was to determine the incidence of positive surgical margins with a wide resection compared to a nerve-sparing technique. METHODS: A consecutive, single-surgeon patient cohort treated between August 2010 and November 2014 was reviewed. A standardized surgical approach of lobe-specific nerve-spare or wide resection was performed. Lobe-specific margin status and tumour stage were obtained from pathology reports. Univariable and multivariable associations between nerve management technique and lobe-specific positive surgical margin were determined. RESULTS: Of 388 prostate lobes, wide resection was performed in 105 (27%) and nerve-sparing in 283 (73%). In 273 lobes without extra-prostatic extension (EPE), 0 of 52 (0%) had a positive margin when wide resection was performed compared to 20 of 221 (9%) if nerve-sparing was performed (p=0.02). In 115 lobes with EPE, 11 of 53 (21%) had a positive margin if wide resection was performed compared to 28 of 62 (45%) if nerve-sparing was performed (p=0.006). In multivariable analysis, the risk of a positive margin was decreased among patients who received wide resection as compared to nerve-spare (RR 0.43, 95% CI 0.26-0.71; p=0.001). CONCLUSIONS: Surgical techniques to reduce positive surgical margins have become increasingly important as more patients with high-risk cancer are selecting surgery. The risk of a positive margin was greatly reduced using a standardized wide resection technique compared to nerve-sparing. PMID- 26977201 TI - Multicystic dysplastic kidney (MCDK) in the neonate: The role of the urologist. PMID- 26977203 TI - Perioperative chemotherapy for muscle-invasive bladder cancer: Closing the gap between evidence and practice. PMID- 26977202 TI - The initiation of a multidisciplinary bladder cancer clinic and the uptake of neoadjuvant chemotherapy: A time-series analysis. AB - INTRODUCTION: While level 1 evidence supports the use of neoadjuvant chemotherapy (NAC) for patients with muscle-invasive bladder cancer (MIBC), its uptake has been underwhelming, even in academic centres. Our aim was to determine if the initiation of a multidisciplinary bladder cancer clinic (MDBCC) in 2008 at our institution, where patients are assessed simultaneously by bladder cancer-focused urologists and radiation oncologists with easy access to a medical oncologist, was associated with an increased use of NAC. METHODS: Patients with MIBC initiating treatment between July 2000 and June 2013 were identified and classified by academic year (July 1 to June 30). Time-series analyses using interventional autoregressive integrated moving average (ARIMA) models with ramp intervention functions were then conducted. A sensitivity analysis was performed on clinical N0 patients. RESULTS: The cohort included 278 patients: 168 from 2000 2007 and 110 from 2008-2012 (academic years). Forty-two (15.1%) patients received NAC and 74 (26.6%) received adjuvant chemotherapy (AC). Overall the proportion of patients receiving NAC increased from 7.7% before the MDBCC to 47.6% in 2012 (Interventional ARIMA p=0.036). The results were similar when restricting to cN0 patients (p<0.001). NAC use gradually increased over time regardless of MDBCC attendance, although the proportion of patients receiving NAC appears to have risen more sharply among MDBCC attendees. CONCLUSIONS: At our institution, the initiation of the MDBCC was temporally associated with increased use of NAC. In addition to multidisciplinary collaboration, having a critical mass of NAC physician advocates and support from institutional leaders are essential to the uptake of NAC. PMID- 26977204 TI - Low compliance with guidelines for re-staging in high-grade T1 bladder cancer and the potential impact on patient outcomes in the province of Alberta. AB - INTRODUCTION: Despite high-level evidence of benefit, early repeat resection (ERR) among high-grade T1 bladder cancer (HGT1-BC) patients remains low in several non-Canadian jurisdictions and rates in Canada are largely unreported. We evaluated rates of ERR and trends over time in Alberta. We also examined factors associated with uptake of ERR. METHODS: We conducted a retrospective review of data from all patients diagnosed with HGT1-BC from 2007 through 2011. Patients were identified from the Alberta Cancer Registry. Patients with a non-urothelial carcinoma of the bladder and those with invasion into the prostate or metastatic disease were excluded. We collected demographic and clinicopathologic information from patients' electronic medical records. RESULTS: A total of 600 patients diagnosed with HGT1-BC were included. Overall, 167 patients (27.8%) received an ERR; however, the rate increased in a non-linear fashion from 27.4% in 2007 to 37.8% in 2011. Factors associated with ERR included age <80 years (p=0.021) and centre at which the initial transurethral resection of bladder tumour (TURBT) was performed (p=0.013). Median overall survival (OS) was not reached, but five-year OS was 72.7% (95% CI 68.9, 76.5) for those who received an ERR and 55.3% (95% CI 52.5, 58.1) for those who did not. CONCLUSIONS: Use of ERR in patients with HGT1 BC is improving over time. Regional variation in practice suggests the need for implementation strategies (i.e., provincial clinical care pathways) to standardize practice and set indicators for future measurement and reporting. Targeted interventions would require further investigation around the reasons for variation in practice. PMID- 26977205 TI - Qualitative Twitter analysis of participants, tweet strategies, and tweet content at a major urologic conference. AB - INTRODUCTION: The microblogging social media platform Twitter is increasingly being adopted in the urologic field. We aimed to analyze participants, tweet strategies, and tweet content of the Twitter discussion at a urologic conference. METHODS: A comprehensive analysis of the Twitter activity at the European Association of Urology Congress 2013 (#eau2013) was performed, including characteristics of user profiles, engagement and popularity measurements, characteristics and timing of tweets, and content analysis. RESULTS: Of 218 Twitter contributors, doctors (45%) were the most frequent, ahead of associations (15%), companies (10%), and journals (3%). However, journals had the highest tweet/participant rate (22 tweets/participant), profile activity (median: 1177, total tweets, 1805 followers, 979 following), and profile popularity (follower/following ratio: 2.1; retweet rank percentile: 96%). Links in a profile were associated with higher engagement (p<0.0001) and popularity (p<0.0001). Of 1572 tweets, 57% were original tweets, 71% contained mentions, 20% contained links, and 25% included pictures. The majority of tweets (88%) were during conference hours, with an average of 24.7 tweets/hour and a peak activity of 71 tweets/hour. Overall, 59% of tweets were informative, led by the topics uro oncology (21%), urologic research (21%), and urotechnology (12%). Limitations include the analysis of a single conference analysis, assessment of global profile and not domain-specific activity, and the rapid evolution in Twitter using habits. CONCLUSION: Results of this single conference qualitative analysis are promising for an enrichment of the scientific discussions at urologic conferences through the use of Twitter. PMID- 26977206 TI - Effect of radical prostatectomy surgeon volume on complication rates from a large population-based cohort. AB - INTRODUCTION: Surgical volume can affect several outcomes following radical prostatectomy (RP). We examined if surgical volume was associated with novel categories of treatment-related complications following RP. METHODS: We examined a population-based cohort of men treated with RP in Ontario, Canada between 2002 and 2009. We used Cox proportional hazard modeling to examine the effect of physician, hospital and patient demographic factors on rates of treatment-related hospital admissions, urologic procedures, and open surgeries. RESULTS: Over the study interval, 15 870 men were treated with RP. A total of 196 surgeons performed a median of 15 cases per year (range: 1-131). Patients treated by surgeons in the highest quartile of annual case volume (>39/year) had a lower risk of hospital admission (hazard ratio [HR]=0.54, 95% CI 0.47-0.61) and urologic procedures (HR=0.69, 95% CI 0.64-0.75), but not open surgeries (HR=0.83, 95% CI 0.47-1.45) than patients treated by surgeons in the lowest quartile (<15/year). Treatment at an academic hospital was associated with a decreased risk of hospitalization (HR=0.75, 95% CI 0.67-0.83), but not of urologic procedures (HR=0.94, 95% CI 0.88-1.01) or open surgeries (HR=0.87, 95% CI 0.54 1.39). There was no significant trend in any of the outcomes by population density. CONCLUSIONS: The annual case volume of the treating surgeon significantly affects a patient's risk of requiring hospitalization or urologic procedures (excluding open surgeries) to manage treatment-related complications. PMID- 26977207 TI - Do urologists follow the golden rule? A global urolithiasis management study by the Clinical Research Office of the Endourological Society. AB - INTRODUCTION: The primary objective of this study was to compare surgical management options for various urolithiasis scenarios that urologists would choose for themselves vs. the options they would recommend for their patients. The secondary objective was to identify the common recommended treatments for upper urinary tract stones of various sizes and locations. METHODS: Two surveys were sent by the Clinical Research Office of the Endourological Society (CROES) to members of the Endourological Society. Standard demographic information was collected. The first survey asked the urologists to recommend treatment for urolithiasis in 10 different scenarios assuming that they were the patient with stone disease. The second survey, sent eight months later, asked urologists to recommend treatment for the same 10 scenarios for a theoretical patient. Only urologists who responded to the first and the second survey were included. Recommended treatment options were compared between the surveys. Agreement between the two scenarios was measured with Cohen's kappa. Surveys were conducted on the Internet using SurveyMonkeyTM. All statistical analyses were performed using R statistical program version 2.12.2. RESULTS: The two surveys had response rates of 78% (160/205) and 84% (172/205), respectively with urologists from 38 countries. Median experience of respondents was seven years (range: 2-30). The majority of respondents, 117 (75%), were affiliated with academic hospitals. Recommended treatments for stone disease in different scenarios were not entirely consistent when the urologists considered themselves as the patients compared to the choice they might recommend for their patients. Cohen's kappa ranged from 0.292-0.534 for the different scenarios. Overall, shock wave lithotripsy (SWL) and ureteroscopy (URS) were the most commonly chosen treatment options, with medical expulsive therapy (MET) and laparoscopy being the least recommended by urologists for themselves, as well as for their patients. CONCLUSIONS: Although urologists were not entirely consistent in their recommendations for stone treatment, they generally followed the "golden rule" and treated their patients as they would want to be treated. The most commonly recommended treatments for upper urinary tract stones were SWL and URS. PMID- 26977208 TI - Medical management of benign prostatic hyperplasia: Results from a population based study. AB - INTRODUCTION: In men with bothersome lower urinary tract symptoms (LUTS), medical treatment usually represents the first line. We examined the patterns of medical management of benign prostatic hyperplasia (BPH) in the Montreal metropolitan area, within the context of a case control study focusing on incident prostate cancer. METHODS: Cases were 1933 men with incident prostate cancer. Population controls included 1994 age-matched men. In-person interviews collected sociodemographic characteristics and medical history, including BPH diagnosis, its duration, and type of medical treatment received. Baseline characteristics were compared by the chi-square likelihood test for categorical variables and by the students t-test for continuously coded variables. RESULTS: Overall, 1120 participants had history of BPH; of those 53.7% received medical treatment for BPH. Individuals with medically treated BPH, compared to individuals with medically untreated BPH, were older at index date [mean: 66.9 vs. 64.9 years, p<0.001)] and at diagnosis of BPH [mean: 62.3 vs. 60.3 years, p<0.001]. They also had a longer duration of BPH-history [mean: 4.7 vs. 4.0 years, p=0.02]. Regarding medical treatment, mono-therapy was more often used than combination therapy [87.6% vs. 12.4%, p<0.001]. Alpha-blockers (69.9%) were most commonly used as monotherapy, followed by 5alpha-reductase inhibitors (5ARIs) (26.6%). Alpha blockers plus 5ARIs were the most common combination therapy (97.3%). CONCLUSIONS: Despite evidence from randomized, controlled trials for better efficacy with use of combination therapy, monotherapy consisting of alpha blockers or 5ARI, in that order, is most frequently used. Additionally, 5ARI use was more common than previously reported (27% vs. 15%). PMID- 26977210 TI - Standard surgical approach of testis-sparing surgery for testicular tumour with benign or malignant tendency. PMID- 26977211 TI - Discussion of standard surgical approach of testis-sparing surgery for testicular tumour with benign tendency. PMID- 26977212 TI - [Not Available]. PMID- 26977209 TI - A primer on tumour immunology and prostate cancer immunotherapy. PMID- 26977214 TI - Departing Thoughts from IJTMB's Practice & Education Section Editor: Critical Inquiry, Dichotomy vs. Continuum, and Improving TMB Discourse. PMID- 26977215 TI - Comparing the Effects of Rest and Massage on Return to Homeostasis Following Submaximal Aerobic Exercise: a Case Study. AB - INTRODUCTION: Postexercise massage can be used to help promote recovery from exercise on the cellular level, as well as systemically by increasing parasympathetic activity. No studies to date have been done to assess the effects of massage on postexercise metabolic changes, including excess postexercise oxygen consumption (EPOC). The purpose of this study was to compare the effects of massage recovery and resting recovery on a subject's heart rate variability and selected metabolic effects following a submaximal treadmill exercise session. METHODS: One healthy 24-year-old female subject performed 30 minutes of submaximal treadmill exercise prior to resting or massage recovery sessions. Metabolic data were collected throughout the exercise sessions and at three 10 minute intervals postexercise. Heart rate variability was evaluated for 10 minutes after each of two 30-minute recovery sessions, either resting or massage. RESULTS: Heart rate returned to below resting levels (73 bpm) with 30 and 60 minutes of massage recovery (72 bpm and 63 bpm, respectively) compared to 30 and 60 minutes of resting recovery (77 bpm and 74 bpm, respectively). Heart rate variability data showed a more immediate shift to the parasympathetic state following 30 minutes of massage (1.152 LF/HF ratio) versus the 30-minute resting recovery (6.91 LF/HF ratio). It took 60 minutes of resting recovery to reach similar heart rate variability levels (1.216 LF/HF) found after 30 minutes of massage. Ventilations after 30 minutes of massage recovery averaged 7.1 bpm compared to 17.9 bpm after 30 minutes of resting recovery. CONCLUSIONS: No differences in EPOC were observed through either the resting or massage recovery based on the metabolic data collected. Massage was used to help the subject shift into parasympathetic activity more quickly than rest alone following a submaximal exercise session. PMID- 26977216 TI - Massage Therapy Treatment and Outcomes for a Patient with Parkinson's Disease: a Case Report. AB - INTRODUCTION: Parkinson's disease (PD) is a complex neurological disorder. The disease is progressive and, in time, results in severe disability. Many patients turn to massage in an attempt to alleviate symptoms of pain and rigidity, though the effects of massage with respect to PD are not well studied. This case adds one more instance in which massage therapy has provided temporary respite from resting tremor, one unrelenting symptom of PD. OBJECTIVE: To determine if massage therapy can produce favorable outcomes with respect to the severity of rigidity and tremor in a patient with PD. CASE PRESENTATION: A 63-year-old female patient with idiopathic, long-standing, Hoehn-Yahr Stage 4 PD was treated with massage therapy five times over the course of six weeks. A SPES/SCOPA Motor Impairments rating scale was used to measure rigidity and tremor pre- and post-treatment, to gauge treatment effectiveness. The massage treatments consisted of deep longitudinal stroking, muscle squeezing techniques, passive range of motion movements, and general relaxation techniques to encourage a soothing environment while promoting a decrease in muscular tone and hyperactivity. Massage therapy administration was by a student near the end of her two-year diploma. RESULTS: The results obtained indicated that massage therapy treatment had a positive effect on reducing resting and postural tremor in a patient with long-standing PD. The treatment was also effective in temporarily reducing rigidity during treatment, but did not produce a lasting effect. CONCLUSION: Further study is required; however, the results of this case were consistent with the limited research available on the subject of massage therapy and Parkinson's disease, in that positive change with respect to tremor-and to a lesser degree, rigidity-were achieved with focused, intentional treatment. PMID- 26977217 TI - Bowenwork for Migraine Relief: a Case Report. AB - INTRODUCTION: Migraine is a complex neurological disorder characterized by episodic, neurogenic, cerebrovascular inflammation and hypersensitization of brain tissues and the central nervous system, causing severe pain and debility. Research literature points mostly to pharmaceutical prophylactic and symptomatic treatments, nonpharmaceutical, complementary and alternative medicine (CAM) approaches, acupuncture, massage and bodywork studies, and none has been published on Bowenwork for migraine intervention. This prospective case report describes one migraineur's response to Bowenwork (a soft-tissue bodywork technique) with cessation of migraine, neck pain, and analgesic consumption, and improved well-being and activity function. METHODS: The client received 14 Bowenwork sessions over a four-month period using the self-reporting Measure Yourself Medical Outcome Profile version 2 (MYMOP2) to evaluate clinically meaningful changes. Baseline MYMOP2 data were recorded prior to the first and subsequent Bowenwork sessions to track changes in migraine and neck pain occurrences, other symptoms, medication use, functional ability and sense of well being. Specific Bowenwork procedures were applied in each session to address various symptoms. The client did not receive other migraine treatment during this study. PARTICIPANT: A 66-year-old Caucasian female with a history of debilitating migraine since childhood, and severe neck pain and jaw injuries resulting from two motor vehicle accidents (MVAs) sustained as an adult. She had previously sought medical, pharmaceutical and CAM treatments for migraine, neck pain, and right-sided thoracic outlet syndrome (TOS) symptoms, with no satisfactory relief. RESULTS: The client progressively reported decreased migraine and neck pain until acquiring a respiratory infection with prolonged coughing spells causing symptoms to recur (session 11). Prior to session 12, she experienced an allergic reaction to ingesting an unknown food allergen, requiring three days of prednisone and Benadryl treatment, exacerbating neck pain, but not migraine. At session 14, her MYMOP2 data showed no migraine, neck pain or medication use, improved activity function, and sense of well-being. Symptoms in her right arm and thumb persisted to a lesser extent. CONCLUSION: Bowenwork progressively offered migraine and neck pain relief for one chronic migraineur, with multiple somatic symptoms. Extenuating factors (jaw tension, TOS, respiratory infection, and allergic reaction) added complexity in monitoring progress and selecting appropriate Bowenwork procedures. Further research on Bowenwork's efficacy for migraine treatment on larger populations is needed. PMID- 26977218 TI - CORRECTING FOR MEASUREMENT ERROR IN LATENT VARIABLES USED AS PREDICTORS. AB - This paper represents a methodological-substantive synergy. A new model, the Mixed Effects Structural Equations (MESE) model which combines structural equations modeling and item response theory is introduced to attend to measurement error bias when using several latent variables as predictors in generalized linear models. The paper investigates racial and gender disparities in STEM retention in higher education. Using the MESE model with 1997 National Longitudinal Survey of Youth data, I find prior mathematics proficiency and personality have been previously underestimated in the STEM retention literature. Pre-college mathematics proficiency and personality explain large portions of the racial and gender gaps. The findings have implications for those who design interventions aimed at increasing the rates of STEM persistence among women and under-represented minorities. PMID- 26977219 TI - Amputation Following Hand Escharotomy in Patients with Burn Injury. AB - OBJECTIVE: Hand burns are commonly seen in patients with burn injury. In the past, focus was on lifesaving measures, but with advances in burn care during the last century, the paradigm shifted to digital salvage and eventually to functional digital salvage. Good outcomes are heavily dependent on the care that is rendered during the initial management of the burn. METHODS: A retrospective medical record review was conducted through the Central Illinois Regional Burn Center Patient Registry. Patients with burn injury treated with upper extremity and hand escharotomy between January 1, 2000, and December 31, 2005, were included in the study. RESULTS: We identified a total of 34 patients with 57 burned hands. Six hands required delayed amputation of digits despite recognition of neurovascular compromise and escharotomy, yielding a 10% amputation rate. No correlation could be drawn with regard to total body surface area, age, or sex. CONCLUSION: Important principles in the acute phase include early splinting, recognition of the need for escharotomy and complete escharotomy when necessary, early excision and grafting, and involvement of occupational therapy for splinting and to guide both active and passive exercises. Although uncommon, some extremity burns may require subsequent amputation despite prompt attention and optimal treatment. In our case series, the need for amputation after successful escharotomies of salvageable digits was associated with full-thickness and electrical burns. PMID- 26977220 TI - Complex partial seizure with severe depression and conduct disorder in a 15 year old female adolescent: a case report. AB - Complex partial seizure complicated by psychiatric comorbidities like depression and conduct disorder presents management challenges for both the physician and parents. The etiology of such psychiatric comorbidities may be related to the seizure or to several other unrelated risk factors. The psychiatric comorbidities and the seizure affects the child's activities of daily living and are often a source of worry to parents and school authorities A high index of suspicion and a multidisciplinary approach are essential in the management of the affected adolescents. PMID- 26977221 TI - Isolated anti-Ro/SSA thrombocytopenia: a rare feature of neonatal lupus. AB - We report a rare case of isolated thrombocytopenia related to anti-Ro/SSA antibodies. The mother was followed for unlabeled familial thrombocytopenia. The mother had positive anti-Ro/SSA antibodies. She was asymptomatic without skin lesions or other criteria neither of systemic lupus erythematosus nor other connective tissue disease. Pregnancy was uneventful. The postnatal examination was normal. On the first day of life, blood cells count showed thrombocytopenia at 40 x 10(9)/L. Within the second day of life, platelet level dropped to 20 x 10(9)/L. The management of thrombocytopenia included platelet transfusion and human immunoglobulin infusion. On the fifth day of life, there has been a drop in platelet count to 10 x 10(9)/L requiring renewed platelet transfusion and human immunoglobulin infusion. On the 10(th) of life platelets rate was stable around 60 x 10(9)/L. The infant had no evidence of cardiac, dermatologic or hepatobilary involvement initially or throughout follow up. PMID- 26977222 TI - [Nephrotoxicity secondary to hyperbilirubinemia: report of a case]. PMID- 26977223 TI - [Gestational gigantomastia at the Institute of Cancer Dakar: about 2 cases]. PMID- 26977224 TI - Sexuality in Nigerian older adults. AB - INTRODUCTION: Oftentimes the older adults are assumed to be asexual as few studies explore into the sexuality of this age group worldwide and even in Nigeria. It is an important aspect of quality of life which is often neglected by people in this age group, attending physicians and the society as a whole. The study was aimed at determining the perception of older adults about sexuality, identify the factors that could militate against sexuality and fill any void in information in this regard. METHODS: Descriptive study conducted in one hundred older adults. A semi-structured questionnaire was administered to consenting participants between 1(st) of September 2013 and 31(st) of March 2014. RESULTS: Mean age of respondents was 66.42 +/- 5.77 years. Seventy-eight percent of the male respondents considered engaging in sexual activity as safe compared to 45.8% of the female respondents. More of the women (33.3%) regarded sexuality in the older adults as a taboo when compared to the men (5.4%). However, the men were more favourably disposed to discussing sexual problems than the women with their spouses (42% vs 20%) and Physicians (23.2% vs 0.0%). Major factors responsible for sexual inactivity were participants' medical ailments (65%), partners' failing health (15%) as well as anxiety about sexual performance (25%) in the men and dyspareunia (25%) in women. CONCLUSION: There is an urgent need to correct the misconception about sexuality in this age group especially among the women and for the physicians to explore the sexual history of every patient. PMID- 26977226 TI - Unusual presentation of rare primary lymphoma of bone. PMID- 26977213 TI - Recommendations for the improvement of bladder cancer quality of care in Canada: A consensus document reviewed and endorsed by Bladder Cancer Canada (BCC), Canadian Urologic Oncology Group (CUOG), and Canadian Urological Association (CUA), December 2015. PMID- 26977225 TI - [Bilateral dislocation erecta: report of a case]. PMID- 26977227 TI - [Survey of counterfeit oral antiinfectives medecine sold in Lubumbashi]. PMID- 26977228 TI - [Spontaneous pneumothorax as an evolutionary manifestation of rheumatoid arthritis: report of clinical observation and review of the literature]. PMID- 26977229 TI - [Recurrence of malignant achromic melanoma of the nail: report of a case]. PMID- 26977230 TI - [Orbital cellulitis complicating acute pansinusitis: report of a case]. PMID- 26977232 TI - [Acute pyelonephritis in pregnant women: place of medical treatment and indications for drainage of the upper urinary tract (Are there predictive clinical, biological and radiological factors to make the drainage acceptable?)]. PMID- 26977231 TI - Pleomorphous leiomyosarcoma of the mesocolon: a case report. AB - Leiomyosarcoma is a rare tumor of the smooth muscle, but relatively frequent in the stomach and the small intestine. The mesocolic site is rare. Globally, leiomyosarcoma represents less than 0, 1% of the malignant tumors found in the colon and the anus. Because of the similarities with other digestive tumors, namely mesenchymatous or benign tumors of the smooth muscle, the diagnosis of a pleomorphic sarcoma remains difficult even at the histological stage. Surgery is the mainstay of the therapy. We report a case of leiomyosarcoma of the mesocolon and discuss about its main characteristics in the view of the current literature about this pathological condition. PMID- 26977233 TI - Childhood cancers in a referral hospital in south-south Nigeria: a review of the spectrum and outcome of treatment. AB - INTRODUCTION: Childhood malignancies are now recognized as a growing global challenge, especially in resource poor settings. Although they constitute a smaller percentage of childhood illnesses in developing countries, compared with infectious diseases, the burden of cancer is still a tremendous problem on patients, families, the healthcare system, and the society. Data on the burden of childhood cancers across different regions is important, as there may be variations in incidences in different locations even within the same country. It will assist government agencies in better healthcare planning. METHODS: An eight year retrospective analysis of all cancers diagnosed in children below the age of 18 years at the study centre between January 2007 and December 2014 was carried out. Case folders of all children diagnosed with malignancies within the study period were retrieved and analyzed with respect to age, gender, morphological or histological type of cancer, treatment modality, and outcome. RESULTS: Eighty four (84) children were diagnosed with various malignancies during the study period. Fourty-eight 48 (57.1%) were male and 36 (42.9%) were female giving a male to female ratio of 1.3:1. There were 27 cases (32.1%) of cancers recorded in children aged below 5 years and 35 cases (41.7%) were diagnosed in children between 5 to 10 years. Lymphomas were the most prevalent malignancies encountered accounting for 32 cases (38.1%). Burkitt's lymphoma constituted 22 (68.8%) of all lymphoma cases. The distribution of the four foremost malignancies recorded were as follows: Burkitt's lymphoma (22 cases; 26.2%), Nephroblastoma (12 cases; 14.3%), Rhabdomyosarcoma (6 cases; 7.1%) and 5 cases (6.0%) each Hodgkin's and non-hodgkin's lymphoma. Other malignancies included 4 cases (4.8%) each of acute leukaemia, neuroblastoma and retinoblastoma. There were three cases (3.6%) each of hepatoblastoma, and osteosarcoma among others. The cancer cure rate was very low 2.4%, losses to follow-up was 38.1% and 21.4% of patients died in the course of therapy either from advanced disease, complications of chemotherapy or late presentation. CONCLUSION: The distribution of the childhood malignancies in our environment shows similarity with reports from the same region and variation from other regions. The general outcome is very poor with a high percentage of discharge against medical advice and loss to follow up. PMID- 26977234 TI - [Study of bacterial flora contaminating mobile phones before and after disinfection: comparison between nursing professionals of the Military Hospital Mohammed V in Rabat and controls]. PMID- 26977235 TI - [Intralenticular bubbles after surgery for retinal detachment]. PMID- 26977236 TI - Electroencephalography as a tool for evidence-based diagnosis and improved outcomes in children with epilepsy in a resource-poor setting. AB - INTRODUCTION: Electroencephalography (EEG) remains the most important investigative modality in the diagnostic evaluation of individuals with epilepsy. Children living with epilepsy in the developing world are faced with challenges of lack of access to appropriate diagnostic evaluation and a high risk of misdiagnosis and inappropriate therapy. We appraised EEG studies in a cohort of Nigerian children with epilepsy seen in a tertiary center in order to evaluate access to and the impact of EEG in the diagnostic evaluation of the cases. METHODS: Inter-ictal EEG was requested in all cases of pediatric epilepsy seen at the pediatric neurology clinic of the University College Hospital, Ibadan, Nigeria over a period of 18 months. Clinical diagnosis without EEG evaluation was compared with the final diagnosis post- EEG evaluation. RESULTS: A total of 329 EEGs were recorded in 329 children, aged 3 months to 16 years, median 61.0 months. Clinical evaluation pre-EEG classified 69.3% of the epilepsies as generalized. The a posteriori EEG evaluations showed a considerably higher proportion of localization-related epilepsies (33.6%). The final evaluation post EEG showed a 21% reduction in the proportion of cases labeled as generalized epilepsy and a 55% increase in cases of localization-related epilepsy(p<0.001). CONCLUSION: Here we show that there is a high risk of misdiagnosis and therefore the use of inappropriate therapies in children with epilepsy in the absence of EEG evaluation. The implications of our findings in the resource-poor country scenario are key for reducing the burden of care and cost of epilepsy treatment on both the caregivers and the already overloaded tertiary care services. PMID- 26977237 TI - [Determinants of contraceptive use in Mumbunda health zone in Lubumbashi, Democratic Republic of Congo]. PMID- 26977238 TI - [Twin pregnancy on a pseudo-horned uterus: report of a case]. PMID- 26977239 TI - Puerperal uterine inversion managed by the uterine balloon tamponade. AB - The uterine inversion is a rare and severe puerperal complication. Uncontrolled cord traction and uterine expression are the common causes described. We report a case of uterine inversion stage III caused by poor management of the third stage of labor. It was about a 20 years old primigravida referred in our unit for postpartum hemorrhage due to uterine atony. After manual reduction of the uterus, the use of intra uterine balloon tamponade helped to stop the hemorrhage. The uterine inversion is a rare complication that may cause maternal death. The diagnosis is clinical and its management must be immediate to avoid maternal complications. PMID- 26977240 TI - Schizophrenia and Leigh syndrome, a simple comorbidity or the same etiopathogeny: about a case. AB - Leigh syndrome is a mitochondrial encephalomyopathy that occurs due to "cytochrome c oxidase deficiency". Few psychiatric disorders have been defined that are associated with Leigh syndrome. The objective of this work is to study relations between mitochondrial dysfunction and psychiatric disorders. It was a 20 year old male patient, who received Modopar, for severe extra pyramidal symptoms caused by Leigh syndrome. He developed, four months ago, acute psychotic symptoms such as audio-visual hallucinations, persecution and mystic delirium. The cerebral MRI has shown signal abnormalities in central grey nucleus. The EEG recording and blood test were normal. The hypothesis of drug induced psychiatric disorders (Modopar) was possible. The evolution under atypical antipsychotic was only partial. In this case, the cerebrospinal fluid and lactate levels mean that mitochondria were not an overall explanation for these psychiatric disorders but may at least play a partial role. Psychiatric disorders may just be acomorbidity. PMID- 26977241 TI - [Post infectious urethral stenosis and megacalycosis: a train that hides another]. PMID- 26977242 TI - [The role of the anesthesiologist in the care of the pregnant woman with Von Willebrand Disease]. PMID- 26977243 TI - Oral lesions in Tuberculosis. PMID- 26977244 TI - [Intra-articular osteoid osteoma of the knee simulating knee arthritis]. PMID- 26977246 TI - [Pleural fibrous solitary tumor]. PMID- 26977245 TI - The epidemiology and treatment of femur fractures at a northern Tanzanian referral centre. AB - INTRODUCTION: Femoral fractures are the most common presenting injury at the orthopaedic department in a large Tanzanian hospital. To date, there has been no current examination of the epidemiology of femoral fractures and the disease burden has not been quantified. METHODS: A retrospective descriptive study of patient records in the orthopaedic department at Kilimanjaro Christian Medical Centre (KCMC) was performed. Patient demographics, aetiology of fractures, diagnosis and treatment were all recorded. RESULTS: A total of 540 consecutive patient admission records were reviewed over a 9 month period. Of these 540 cases, 213 (39%) were diagnosed with a femoral fracture. The 21-30 age group were the most commonly affected by femur fractures (20% n = 42). Within this group, motor traffic accidents (MTA) were the cause of 71% of injuries (n = 30). For males, MTA's caused 59% of all femur fractures (n = 80), while falls were the most common cause of femur fractures in females (70%; n = 49). 80% of the fractures in the 51-100 age group were caused by falls (n = 52). In both the male and female groups the most common fracture seen was mid shaft femoral fracture (males 33% (n = 48), females 25% (n = 18)). The most common treatment was skeletal traction used in 40% (n = 85) of patients. CONCLUSION: Femur fracture most commonly presented in males under age 30. Femur fracture was most commonly cause by MTAs in males and by falls in females. The most common diagnosis was mid shaft of femur fracture. Skeletal traction was the most frequent treatment. PMID- 26977247 TI - [Orbital cellulitis: prospective study about 75 cases]. PMID- 26977248 TI - [Prolactin adenoma induced by antipsychotic medications]. PMID- 26977252 TI - Shedding New Lights with the Breakthrough Ideas to Understand Current Trends in Modern Toxicology. PMID- 26977251 TI - Enhancing Foster Parent Training with Parent-Child Interaction Therapy: Evidence from a Randomized Field Experiment. AB - OBJECTIVE: Research indicates that foster parents often do not receive sufficient training and support to help them meet the demands of caring for foster children with emotional and behavioral disturbances. Parent-Child Interaction Therapy (PCIT) is a clinically efficacious intervention for child externalizing problems, and it also has been shown to mitigate parenting stress and enhance parenting attitudes and behaviors. However, PCIT is seldom available to foster families, and it rarely has been tested under intervention conditions that are generalizable to community-based child welfare service contexts. To address this gap, PCIT was adapted and implemented in a field experiment using 2 novel approaches-group-based training and telephone consultation-both of which have the potential to be integrated into usual care. METHOD: This study analyzes 129 foster-parent-child dyads who were randomly assigned to 1 of 3 conditions: (a) waitlist control, (b) brief PCIT, and (c) extended PCIT. Self-report and observational data were gathered at multiple time points up to 14 weeks post baseline. RESULTS: Findings from mixed-model, repeated measures analyses indicated that the brief and extended PCIT interventions were associated with a significant decrease in self-reported parenting stress. Results from mixed effects generalized linear models showed that the interventions also led to significant improvements in observed indicators of positive and negative parenting. The brief course of PCIT was as efficacious as the extended PCIT intervention. CONCLUSIONS: The findings suggest that usual training and support services can be improved upon by introducing foster parents to experiential, interactive PCIT training. PMID- 26977250 TI - Role of Viral miRNAs and Epigenetic Modifications in Epstein-Barr Virus Associated Gastric Carcinogenesis. AB - MicroRNAs are short (21-23 nucleotides), noncoding RNAs that typically silence posttranscriptional gene expression through interaction with target messenger RNAs. Currently, miRNAs have been identified in almost all studied multicellular eukaryotes in the plant and animal kingdoms. Additionally, recent studies reported that miRNAs can also be encoded by certain single-cell eukaryotes and by viruses. The vast majority of viral miRNAs are encoded by the herpesviruses family. These DNA viruses including Epstein-Barr virus encode their own miRNAs and/or manipulate the expression of cellular miRNAs to facilitate respective infection cycles. Modulation of the control pathways of miRNAs expression is often involved in the promotion of tumorigenesis through a specific cascade of transduction signals. Notably, latent infection with Epstein-Barr virus is considered liable of causing several types of malignancies, including the majority of gastric carcinoma cases detected worldwide. In this review, we describe the role of the Epstein-Barr virus in gastric carcinogenesis, summarizing the functions of the Epstein-Barr virus-encoded viral proteins and related epigenetic alterations as well as the roles of Epstein-Barr virus-encoded and virally modulated cellular miRNAs. PMID- 26977253 TI - Advancing Risk Assessment through the Application of Systems Toxicology. AB - Risk assessment is the process of quantifying the probability of a harmful effect to individuals or populations from human activities. Mechanistic approaches to risk assessment have been generally referred to as systems toxicology. Systems toxicology makes use of advanced analytical and computational tools to integrate classical toxicology and quantitative analysis of large networks of molecular and functional changes occurring across multiple levels of biological organization. Three presentations including two case studies involving both in vitro and in vivo approaches described the current state of systems toxicology and the potential for its future application in chemical risk assessment. PMID- 26977254 TI - Advances in the Development and Validation of Test Methods in the United States. AB - The National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) provides validation support for US Federal agencies and the US Tox21 interagency consortium, an interagency collaboration that is using high throughput screening (HTS) and other advanced approaches to better understand and predict chemical hazards to humans and the environment. The use of HTS data from assays relevant to the estrogen receptor signaling data pathway is used as an example of how HTS data can be combined with computational modeling to meet the needs of US agencies. As brief summary of US efforts in the areas of biologics testing, acute toxicity, and skin sensitization will also be provided. PMID- 26977255 TI - Addressing Early Life Sensitivity Using Physiologically Based Pharmacokinetic Modeling and In Vitro to In Vivo Extrapolation. AB - Physiologically based pharmacokinetic (PBPK) modeling can provide an effective way to utilize in vitro and in silico based information in modern risk assessment for children and other potentially sensitive populations. In this review, we describe the process of in vitro to in vivo extrapolation (IVIVE) to develop PBPK models for a chemical in different ages in order to predict the target tissue exposure at the age of concern in humans. We present our on-going studies on pyrethroids as a proof of concept to guide the readers through the IVIVE steps using the metabolism data collected either from age-specific liver donors or expressed enzymes in conjunction with enzyme ontogeny information to provide age appropriate metabolism parameters in the PBPK model in the rat and human, respectively. The approach we present here is readily applicable to not just to other pyrethroids, but also to other environmental chemicals and drugs. Establishment of an in vitro and in silico-based evaluation strategy in conjunction with relevant exposure information in humans is of great importance in risk assessment for potentially vulnerable populations like early ages where the necessary information for decision making is limited. PMID- 26977256 TI - Toxicity and Carcinogenicity of Dichlorodiphenyltrichloroethane (DDT). AB - Dichlorodiphenyltrichloroethane (DDT) is still used in certain areas of tropics and subtropics to control malaria and other insect-transmitted diseases. DDT and its metabolites have been extensively studied for their toxicity and carcinogenicity in animals and humans and shown to have an endocrine disrupting potential affecting reproductive system although the effects may vary among animal species in correlation with exposure levels. Epidemiologic studies revealed either positive or negative associations between exposure to DDT and tumor development, but there has been no clear evidence that DDT causes cancer in humans. In experimental animals, tumor induction by DDT has been shown in the liver, lung, and adrenals. The mechanisms of hepatic tumor development by DDT have been studied in rats and mice. DDT is known as a non-genotoxic hepatocarcinogen and has been shown to induce microsomal enzymes through activation of constitutive androstane receptor (CAR) and to inhibit gap junctional intercellular communication (GJIC) in the rodent liver. The results from our previously conducted 4-week and 2-year feeding studies of p,p'-DDT in F344 rats indicate that DDT may induce hepatocellular eosinophilic foci as a result of oxidative DNA damage and leads them to hepatic neoplasia in combination with its mitogenic activity and inhibitory effect on GJIC. Oxidative stress could be a key factor in hepatocarcinogenesis by DDT. PMID- 26977249 TI - Cross Talk of Proteostasis and Mitostasis in Cellular Homeodynamics, Ageing, and Disease. AB - Mitochondria are highly dynamic organelles that provide essential metabolic functions and represent the major bioenergetic hub of eukaryotic cell. Therefore, maintenance of mitochondria activity is necessary for the proper cellular function and survival. To this end, several mechanisms that act at different levels and time points have been developed to ensure mitochondria quality control. An interconnected highly integrated system of mitochondrial and cytosolic chaperones and proteases along with the fission/fusion machinery represents the surveillance scaffold of mitostasis. Moreover, nonreversible mitochondrial damage targets the organelle to a specific autophagic removal, namely, mitophagy. Beyond the organelle dynamics, the constant interaction with the ubiquitin-proteasome-system (UPS) has become an emerging aspect of healthy mitochondria. Dysfunction of mitochondria and UPS increases with age and correlates with many age-related diseases including cancer and neurodegeneration. In this review, we discuss the functional cross talk of proteostasis and mitostasis in cellular homeodynamics and the impairment of mitochondrial quality control during ageing, cancer, and neurodegeneration. PMID- 26977259 TI - Associations of Low Environmental Exposure to Multiple Metals with Renal Tubular Impairment in Korean Adults. AB - Recently several studies reported that the renal toxicity of lead (Pb) and cadmium (Cd) may exist in even a low level exposure. In terms of the deterioration of tubular function, it affects the loss of divalent metals and leads to other complications, so renal tubular effect of heavy metals should be well managed. Considering the exposure to heavy metals in reality, it is hard to find the case that human is exposed to only one heavy metal. We designed a cross sectional study using Korean Research Project on the Integrated Exposure Assessment (KRIEFS) data to investigate the renal effects of multiple metal exposure in general population. We used blood Pb and urinary Cd as exposure measures, and urinary N-acetyl-beta-D-glucosaminidase (NAG) and beta2 microglobulin (beta2-MG) as renal tubular impairment outcome. We conducted linear regression to identify the association between each heavy metal and urinary NAG and beta2-MG. And then, we conducted linear regression including the interaction term. Of 1953 adults in KRIEFS (2010~2011), the geometric mean of blood Pb and urinary Cd concentration was 2.21 MUg/dL (geometric SD = 1.49 MUg/dL) and 1.08 MUg/g cr (geometric SD = 1.98 MUg/g cr), respectively. In urinary Cd, the strength of the association was also high after adjusting (urinary NAG: beta = 0.44, p < 0.001; urinary beta2-MG: beta = 0.13, p = 0.002). Finally, we identified the positive interactions for the two renal biomarkers. The interaction effect of the two heavy metals of beta2-MG was greater than that of NAG. It is very important in public health perspective if the low level exposure to multiple heavy metals has an interaction effect on kidney. More epidemiological studies for the interaction and toxicological studies on the mechanism are needed. PMID- 26977258 TI - Pyruvate Kinase M2: A Novel Biomarker for the Early Detection of Acute Kidney Injury. AB - The identification of biomarkers for the early detection of acute kidney injury (AKI) is clinically important. Acute kidney injury (AKI) in critically ill patients is closely associated with increased morbidity and mortality. Conventional biomarkers, such as serum creatinine (SCr) and blood urea nitrogen (BUN), are frequently used to diagnose AKI. However, these biomarkers increase only after significant structural damage has occurred. Recent efforts have focused on identification and validation of new noninvasive biomarkers for the early detection of AKI, prior to extensive structural damage. Furthermore, AKI biomarkers can provide valuable insight into the molecular mechanisms of this complex and heterogeneous disease. Our previous study suggested that pyruvate kinase M2 (PKM2), which is excreted in the urine, is a sensitive biomarker for nephrotoxicity. To appropriately and optimally utilize PKM2 as a biomarker for AKI requires its complete characterization. This review highlights the major studies that have addressed the diagnostic and prognostic predictive power of biomarkers for AKI and assesses the potential usage of PKM2 as an early biomarker for AKI. We summarize the current state of knowledge regarding the role of biomarkers and the molecular and cellular mechanisms of AKI. This review will elucidate the biological basis of specific biomarkers that will contribute to improving the early detection and diagnosis of AKI. PMID- 26977257 TI - Autophagy in Ischemic Livers: A Critical Role of Sirtuin 1/Mitofusin 2 Axis in Autophagy Induction. AB - No-flow ischemia occurs during cardiac arrest, hemorrhagic shock, liver resection and transplantation. Recovery of blood flow and normal physiological pH, however, irreversibly injures the liver and other tissues. Although the liver has the powerful machinery for mitochondrial quality control, a process called mitophagy, mitochondrial dysfunction and subsequent cell death occur after reperfusion. Growing evidence indicates that reperfusion impairs mitophagy, leading to mitochondrial dysfunction, defective oxidative phosphorylation, accumulation of toxic metabolites, energy loss and ultimately cell death. The importance of acetylation/deacetylation cycle in the mitochondria and mitophagy has recently gained attention. Emerging data suggest that sirtuins, enzymes deacetylating a variety of target proteins in cellular metabolism, survival and longevity, may also act as an autophagy modulator. This review highlights recent advances of our understanding of a mechanistic correlation between sirtuin 1, mitophagy and ischemic liver injury. PMID- 26977260 TI - Cadmium Exposure and Potential Health Risk from Foods in Contaminated Area, Thailand. AB - Man-made cadmium (Cd) emissions can be transported between environmental matrices and the food chain. Food is the primary source of Cd exposure among general population as a consequence of the bio-concentration of Cd from soil. Chronic Cd exposure has been reported to be associated with chronic kidney disease, osteoporosis, diabetes, cardiovascular disease and cancer. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) established the safe level of Cd intake as provisional tolerable monthly intake (PTMI) of 25 MUg/kg bw in 2010. The major food groups that contribute to the most Cd exposure are rice and grains, shellfish and sea food, meat including edible offal, and vegetables. A number of studies reported the high Cd contaminated levels in foods from polluted areas in Thailand. The results are of high concern since the contaminations occur in foods that are major Cd contributors. Thus, in this review, the current situations of Cd contaminated foods in polluted areas of Thailand are summarized. In addition, the Cd intakes from selected scenarios are estimated to assess the potential health risk to consumers and the suggestions are also included. PMID- 26977261 TI - Different Regulation of p53 Expression by Cadmium Exposure in Kidney, Liver, Intestine, Vasculature, and Brain Astrocytes. AB - Chronic exposure to cadmium (Cd) is known to adversely affect renal function. Our previous studies indicated that Cd induces p53-dependent apoptosis by inhibiting gene expression of the ubiquitin-conjugating enzyme (Ube) 2d family in both human and rat proximal tubular cells. In this study, the effects of Cd on protein expression of p53 and apoptotic signals in the kidney and liver of mice exposed to Cd for 12 months were examined, as well as the effects of Cd on p53 protein levels and gene expression of the Ube2d family in various cell lines. Results showed that in the kidney of mice exposed to 300 ppm Cd for 12 months, there was overaccumulation of p53 proteins in addition to the induction of apoptosis, which was triggered specifically in the proximal tubules. Interestingly, the site of apoptosis was the same as that of p53 accumulation in the proximal tubules. In the liver of mice chronically exposed to Cd, gene expression of the Ube2d family tended to be slightly decreased, together with slight apoptosis without the accumulation of p53 protein. In rat small intestine epithelial (IEC-6) cells, Cd decreased not only the p53 protein level but also gene expression of Ube2d1, Ube2d2 and Ube2d4. In human brain microvascular endothelial cells (HBMECs), Cd did not suppress gene expression of the Ube2d family, but increased the p53 protein level. In human brain astrocytes (HBASTs), Cd only increased gene expression of UBE2D3. These results suggest that Cd-induced apoptosis through p53 protein is associated with renal toxicity but not hepatic toxicity, and the modification of p53 protein by Cd may vary depending on cell type. PMID- 26977262 TI - A Rapid and Sensitive Detection of Aflatoxin-producing Fungus Using an Optimized Polymerase Chain Reaction (PCR). AB - Aflatoxin B1 (AFB1) is produced by Aspergillus flavus growing in feedstuffs. Early detection of maize contamination by aflatoxigenic fungi is advantageous since aflatoxins exert adverse health effects. In this study, we report the development of an optimized conventional PCR for AFB1 detection and a rapid, sensitive and simple screening Real-time PCR (qPCR) with SYBR Green and two pairs of primers targeting the aflR genes which involved aflatoxin biosynthesis. AFB1 contaminated maize samples were divided into three groups by the toxin concentration. Genomic DNA was extracted from those samples. The target genes for A. flavus were tested by conventional PCR and the PCR products were analyzed by electrophoresis. A conventional PCR was carried out as nested PCR to verify the gene amplicon sizes. PCR-RFLP patterns, obtained with Hinc II and Pvu II enzyme analysis showed the differences to distinguish aflatoxin-producing fungi. However, they are not quantitative and need a separation of the products on gel and their visualization under UV light. On the other hand, qPCR facilitates the monitoring of the reaction as it progresses. It does not require post-PCR handling, which reduces the risk of cross-contamination and handling errors. It results in a much faster throughout. We found that the optimal primer annealing temperature was 65 degrees C. The optimized template and primer concentration were 1.5 MUL (50 ng/MUL) and 3 MUL (10 MUM/MUL) respectively. SYBR Green qPCR of four genes demonstrated amplification curves and melting peaks for tub1, afIM, afIR, and afID genes are at 88.0 degrees C, 87.5 degrees C, 83.5 degrees C, and 89.5 degrees C respectively. Consequently, it was found that the four primers had elevated annealing temperatures, nevertheless it is desirable since it enhances the DNA binding specificity of the dye. New qPCR protocol could be employed for the determination of aflatoxin content in feedstuff samples. PMID- 26977263 TI - Editorial. PMID- 26977264 TI - The European Academy laparoscopic "Suturing Training and Testing'' (SUTT) significantly improves surgeons' performance. AB - The efficiency of suturing training and testing (SUTT) model by laparoscopy was evaluated, measuring the suturingskill acquisition of trainee gynecologists at the beginning and at the end of a teaching course. During a workshop organized by the European Academy of Gynecological Surgery (EAGS), 25 participants with three different experience levels in laparoscopy (minor, intermediate and major) performed the 4 exercises of the SUTT model (Ex 1: both hands stitching and continuous suturing, Ex 2: right hand stitching and intracorporeal knotting, Ex 3: left hand stitching and intracorporeal knotting, Ex 4: dominant hand stitching, tissue approximation and intracorporeal knotting). The time needed to perform the exercises is recorded for each trainee and group and statistical analysis used to note the differences. Overall, all trainees achieved significant improvement in suturing time (p < 0.005) as measured before and after completion of the training. Similar significantly improved suturing time differences (p < 0.005) were noted among the groups of trainees with different laparoscopic experience. In conclusion a short well-guided training course, using the SUTT model, improves significantly surgeon's laparoscopic suturing ability, independently of the level of experience in laparoscopic surgery. KEY WORDS: Endoscopy, laparoscopic suturing, psychomotor skills, surgery, teaching, training suturing model. PMID- 26977265 TI - Art meets science: The Cosmopolitan Chicken Research Project. AB - The Cosmopolitan Chicken Project is an artistic undertaking of renowned artist Koen Vanmechelen. In this project, the artist interbreeds domestic chickens from different countries aiming at the creation of a true Cosmopolitan Chicken as a symbol for global diversity. The unifying theme is the chicken and the egg, symbols that link scientific, political, philosophical and ethical issues. The Cosmopolitan Chicken Research Project is the scientific component of this artwork. Based on state of the art genomic techniques, the project studies the effect of the crossing of chickens on the genetic diversity. Also, this research is potentially applicable to the human population. The setup of the CC(r)P is quite different from traditional breeding experiments: starting from the crossbreed of two purebred chickens (Mechelse Koekoek x Poule de Bresse), every generation is crossed with a few animals from another breed. For 26 of these purebred and crossbred populations, genetic diversity was measured (1) under the assumption that populations were sufficiently large to maintain all informative SNP within a generation and (2) under the circumstances of the CCP breeding experiment. Under the first assumption, a steady increase in genetic diversity was witnessed over the consecutive generations, thus indeed indicating the creation of a "Cosmopolitan Chicken Genome". However, under the conditions of the CCP, which reflects the reality within the human population, diversity is seen to fluctuate within given boundaries instead of steadily increasing. A reflection on this might be that this is because, in humans, an evolutionary optimum in genetic diversity is reached. Key words. PMID- 26977266 TI - Semen analysis workshops: 17 years' experience. AB - The study reports on the results recorded during a series of semenology workshops presented from 1997 to 2014. The results were obtained from training workshops that were conducted in 6 continents in 38 cities including 1124 individuals. All workshops consisted of 2 sessions namely a pre-and post-training session. Results recorded from the pre-training sessions were used as a baseline value of current knowledge. In most cases pooled fresh or cryopreserved semen samples were provided by the organizing institution. The mixed effect linear regression model showed a significant decrease in the mean scores from the pre-training scores, p < .001. Training of technicians as well as regular proficiency testing will ensure continuous communication with the referring laboratory. PMID- 26977267 TI - The socio-economical impact of intravenous (IV) versus subcutaneous (SC) administration of trastuzumab: future prospectives. AB - Trastuzumab was the first targeted therapy for HER2 positive breast cancer. It has become the standard of care for HER2 positive metastatic breast cancer since 2000 and in the adjuvant setting since 2006. Adjuvant it is given for a year and in patients with metastatic disease until progression. The standard mode of administration is intravenous. Recently a subcutaneous form has become available. A phase III study showed that there is no difference between the intravenous and subcutaneous form in terms of safety and efficacy. The patient's preference however significantly favoured the subcutaneous form. It is estimated that the use of the SC form could contribute to a cost saving between 758 and 2576 euro per annual course. For Belgium alone this could mean an estimated saving of 1.4 to 4.6 million euros per year. The potential benefit of the SC administration for healthcare facilities could be further increased when applied in a LEAN working day-care chemotherapy unit. After reviewing the existing literature we suggest to further validate the potential financial impact of SC trastuzumab compared to the traditional IV form and to introduce a scientific proposal incorporating the benefits of this formulation in a LEAN working healthcare unit. PMID- 26977268 TI - Reimbursement for bone loss prevention is different between women with breast cancer and men with prostate cancer: time for a revision. AB - The hormone dependent breast and prostate cancers have in general a very good survival, due to the anti-hormonal treatment. A disadvantage of this treatment is the increased risk of osteoporosis and fractures. It is surprisingly to note that denosumab has the same impact on fracture reduction incidence for both sexes, but with different reimbursement criteria. Furthermore there is only reimbursement in case of osteoporosis and not for cancer patients who are at an increased risk of developing osteoporosis. The clinician detects the accelerated bone loss during follow-up, but has to wait until there is osteoporosis. The impact of osteoporosis on the quality of life is severe and underestimated. Management of cancer should not only focus on survival, therefore it is time to reconsider the reimbursement criteria, discuss the willingness of society to pay for bone health and make choices regarding the advice we give to our patients. PMID- 26977269 TI - Why Fertility Education is needed in schools. AB - Fertility education needs to be at the top of the agenda if we want to make a major impact in preventing infertility. We have been successful in reducing teenage pregnancies through Sex and Relationship education (SRE) and education on contraception. Sex and relationship education is for now and fertility education is for the future. Conception and contraception are two sides of the same coin. We need to empower our young people with education on fertility so that they can stand a better chance of falling pregnant when they choose to. Education empowers. PMID- 26977271 TI - Hemoglobin Analysis in the First Year of Life. AB - BACKGROUND AND OBJECTIVES: In newborns and infants during their first year of life, there is a dynamic change in the fraction of hemoglobin (Hb). To apply Hb analysis as a phenotypic diagnosis of thalassemia in newborns and infants, we need normal values of each Hb fraction for reference. METHODS: Seventeen cord bloods from normal deliveries were collected for analysis. One hundred and thirty seven infants from the pediatric outpatient clinic were recruited and were categorized by their ages into a series of short periods (month+/-2 weeks). Both alpha and beta thalassemia carriers detected were excluded. Samples with an Hb level less than 10.0 g/dL were also excluded. The proportion of Hb A (alpha2beta2), A2 (alpha2delta2), and F (alpha2gamma2) was obtained from high performance liquid chromatography and analyzed according to its categorized periods. RESULTS: There were 90 (58.4%) specimens left for evaluation. The percentage of Hb A, A2, and F gradually changed with increasing age. The percentage of Hb A was 21.14+/-7.04% (mean+/-SD) in cord blood and increased substantially to 83.38+/-1.31% at the sixth month. The level was sustained thereafter. The incremental pattern of Hb A2 was similar to Hb A. The value was 0.32+/-0.19% at the beginning and reached a plateau with 2.78+/-0.25% at the sixth month. The percentage of Hb F started at 78.39+/-7.59% in cord blood and decreased rapidly in the first 6 months. CONCLUSIONS: The data possibly can be applied as quick guidance for interpretation of Hb analysis in newborns and infants during their first year of life. PMID- 26977270 TI - BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia. AB - The B-cell receptor (BCR) signaling inhibitors ibrutinib and idelalisib are revolutionizing the treatment of chronic lymphocytic leukemia (CLL) and other B cell malignancies. These oral agents, both alone and in combination with other drugs, have shown remarkable clinical activity in relapsed or refractory CLL across all risk groups, and have been approved by the Food and Drug Administration for this indication. Preliminary data suggest that an even greater benefit can be expected in treatment-naive CLL patients. Both ibrutinib and idelalisib are well tolerated by most patients, including older, frailer individuals. Toxicities are usually mild and self-resolving. Clinicians must, however, be aware of a number of peculiar adverse events, the effects of which can be severe enough to limit the clinical use of these agents. In this review, we survey the salient aspects of the pharmacology and clinical experience with the use of BCR signaling inhibitors for the treatment of patients with CLL. We next focus on both the most common and the most clinically significant toxicities associated with these drugs. PMID- 26977273 TI - Patients Referred for Bleeding Symptoms of Unknown Cause: Does Evaluation of Thrombin Generation Contribute to Diagnosis? AB - INTRODUCTION: Patients with mild to moderate bleeding symptoms referred for coagulation investigation sometimes never receive a definitive diagnosis. Bleed assessment tools have been developed and validated to assess the severity of symptoms. Global coagulation assays, e.g., the thrombin generation test (thrombogram) have a potential to identify hemostatic defects that are not detected in specific assays. MATERIAL AND METHODS: One hundred and eighty-five patients referred to our centre because of bleeding symptoms were evaluated using the bleeding assessment tool (BAT) described by Tosetto and colleagues in 2006. Blood samples were investigated for thrombin generation (TG) capacity (Technoclone), in platelet poor (PPP) plasma, and specific clotting factors, i.e., von Willebrand factor, factor VIII and IX, as well as INR, APTT, platelet count, and platelet adhesion. RESULTS: Of the 185 patients, five women were diagnosed with mild von Willebrand disease and one male with mild hemophilia A. The remaining 179 subjects (76% females and 24% males with average ages of 33 and 28 years, respectively) were evaluated further. In the total cohort and among women, peak TG, and lag time correlated with bleeding score (p=0.01 and p=0.04, respectively with correlation coefficients). No such correlations were found among males. DISCUSSION AND CONCLUSION: Although our study showed some correlation between TG and bleeding score, results are generally consistent with a previous report which failed to demonstrate the value of TG measurement in a similar setting. In conclusion, the complexity of the mechanisms underlying clinical bleeding complicates the ability to use TG tests as reliable predictors of bleeding. Mild congenital bleeding disorders, especially VWD, should be specifically screened for in patients with mild/moderate symptoms. PMID- 26977272 TI - Impact of Mannose-Binding Protein Gene Polymorphisms in Omani Sickle Cell Disease Patients. AB - OBJECTIVES: Our aim was to study mannose-binding protein (MBP) polymorphisms in exonic and promoter region and correlate it with associated infections and vasoocculsive (VOC) episodes in sickle cell disease (SCD) patients since MBP plays an important role in innate immunity by activating the complement system. METHODS: We studied the genetic polymorphisms in the Exon 1 (alleles A/O) and promoter region (alleles Y/X; H/L, P/Q) of the MBL2 gene, in SCD patients as an increased incidence of infections is seen in these patients. A PCR-based, targeted genomic DNA sequencing of MBL2 was used to study 68 SCD Omani patients and 44 controls (healthy voluntary blood donors). RESULTS: In SCD patients, the frequency of the genotype related to the high production of MBL was 0.35 (YA/YA) and for intermediate/low production was 0.65 (YA/XA, XA/XA, YA/YO, XA/YO, YO/YO). The observed frequencies of MBL2 gene promoter polymorphism (-221, Y/X) were 44.4% and 20.5% for the heterozygous genotype Y/X and 3.2% and 2.2% for the homozygous (X/X) respectively between SCD patients and controls. MBL2 Exon1 gene mutations were 29.4% and 50% for the heterozygous genotype A/O and 5.9% and 6.8% respectively for the homozygous (O/O) genotype between SCD patients and controls. The distribution of variant MBL2 gene polymorphisms did not show any correlation in SCD patients with or without VOC attacks (p=0.16; OR -0.486; CI=0.177 -1.33), however, it was correlated with infections (p=0.0162; OR -3.55; CI 1.25-10.04). CONCLUSIONS: Although the frequency of the genotypes and haplotypes of MBL2 in SCD patients did not differ from controls, overall in the SCD patient cohort the increased representation of variant alleles was significantly correlated with infections (p<0.05). However, these variant MBL2 polymorphisms did not seem to play a significant role in the VOC episodes in this SCD cohort. PMID- 26977274 TI - Prevalence of Sickle Cell Trait in the Southern Suburb of Beirut, Lebanon. AB - OBJECTIVE: The objective of this study was to assess the prevalence, gender differences, and time trends of Sickle Cell Trait in the Southern Suburb of Beirut, Lebanon, as well as to highlight the importance of screening for Sickle Cell Trait carriers in this population. Another objective was to describe a new screening technique for Sickle Cell Trait carriers. METHODS: This was a retrospective cohort study carried out at a private laboratory in the Southern Suburb of Beirut, Lebanon between 2002 and 2014. The sickling test was carried out for each patient using two methods: the classical "sodium metabisulfite sickling test", and the new "sickling test method" used in the private lab. As a confirmatory test, hemoglobin electrophoresis was run on a random sample of 223 cases which were found to be positive using the two sickling tests. RESULTS: A total of 899 cases were found to be positive for the sickle cell trait out of 184,105 subjects screened during the 12-year period, prevalence = 0.49% (95% CI: 0.46 - 0.52). Among the total sample, females were found to have higher prevalence, where no time trend over the studied period was noted. The haemoglobin electrophoresis method confirmed the results of this new sickling test technique among the random sample of the 223 cases. CONCLUSION: We found that the prevalence of sickle cell trait is lower as compared to other Arab countries, higher in females, with no significant time trend. The sickle cell test was found to be an accurate, simple and cheap test that could be easily added as a requirement for the pre-marital testing to screen for Sickle Cell Trait carriers. PMID- 26977275 TI - Cutaneous Lesions Anticipating Accelerated Phase of Multidrug Resistant Chronic Myeloid Leukemia Responsive to Ponatinib. PMID- 26977276 TI - Anemia in the Elderly: not Always what it Seems. AB - Anemia in the elderly is a common but challenging clinical scenario. Here we describe the case of an older woman who presented with anemia and elevated inflammation markers. After a complete diagnostic work-up, a definite etiology of the anemia could not be found so eventually a bone marrow biopsy was performed and she was diagnosed with myelodysplastic syndrome. She responded well to erythropoietin treatment but her inflammation markers remained elevated thus a positron emission tomography was performed. It turned out that the patient suffered from giant cell artheritis and her anemia completely resolved after steroid treatment. Our case outlines that it is necessary to pay particular attention to anemia of inflammation, which could be due to several and often masked conditions. Myelodysplatic syndromes should be considered when other causes have been ruled out, but their diagnosis can be difficult and requires expertise in the field. PMID- 26977277 TI - Candida Associated Bloodstream Infections in Pediatric Hematology Patients: A Single Center Experience. AB - BACKGROUND AND OBJECTIVES: Candida-associated bloodstream infections are frequent and potentially life-threatening conditions in hematology patients. The aim of this study is to evaluate the characteristics, risk factors, and outcome of Candida-associated bloodstream infections in children with hematological diseases. METHODS: The medical records of the patients with hematological diseases and hematopoietic stem cell transplantation (HSCT) recipients who were diagnosed as Candida-associated bloodstream infection between February 2010 and February 2014 were reviewed retrospectively. RESULTS: Thirty episodes of candidemia involving 26 patients (38% female, and 62% male) with a median age of 7-year (range; 1 to 17) were noted. The incidence of candidemia in our study was 5.2 per 1000 hospital admissions. Infections with non-albicans Candida spp. occurred more frequently (63%) and C. krusei was the predominant microorganism among non-albicans Candida spp. (37%). Candida albicans was isolated from 11 of the 30 episodes (37%). Twenty-six of the episodes (88%) patients had a central venous catheter (CVC) prior to candidemia, and they were removed in 16 (62%). Thirty-day mortality rate was 20%. Isolated Candida spp, underlying disease and its status, presence of mucositis, neutropenia, using of broad spectrum antibiotics, corticosteroids or total parenteral nutrition were not identified as predictors of outcome. Multivariate analysis revealed that CVCs kept in place was the only significant factor associated with mortality (OR, 0.07; 95% CI, 0.006 0.716). CONCLUSIONS: Candida-associated bloodstream infections were common in children with hematological diseases and HSCT recipients, particularly in patients with CVCs. In addition to appropriate antifungal therapy, CVC removal improves the outcome of candidemia in children with hematological disease. PMID- 26977278 TI - Anorectal Complications During Neutropenic Period in Patients with Hematologic Diseases. AB - BACKGROUND: Neutropenic patients are susceptible to any anorectal disease, and symptomatic anorectal disease afflicts 2-32% of oncology patients. Perianal infections are the most feared complication, considering the lack of natural defense against infectious microorganisms. When septic complications develop, the anorectal disease is potentially fatal, especially in neutropenic patients in whom mortality rates range between 11-57%. Although anorectal diseases are a frequent complication with potentially fatal outcomes among patients with hematologic diseases, sufficient data are not available in the literature. In this study, we aimed to investigate the anorectal complications developing during the neutropenic period in patients with hematologic diseases. METHODS: A total of 79 patients whose neutropenic period (absolute neutrophil count <500/mcL) continued for 7 days, or longer were included in the study. RESULTS: A total of 34 patients out of 79 (43%) were detected to develop anorectal complications, of them 6 (7.6%) developed an anorectal infection. The patients were characterized according to the hematological disease and its status (active or not), the type of treatment and the presence of a history of an anorectal pathology before the onset of the hematologic disease. Nineteen (24.1%) patients had the history of anorectal disturbances before diagnosis of the hematologic disease, and recurrence of an anorectal pathology was found in 14 out of 19 patients(73.7%). In addition, the overall mortality rate was higher among the patients who developed anorectal complications compared to another group (41.2% vs. 22.2%, p=0.059). CONCLUSION: Anorectal pathology is a common complication with high recurrence rate in neutropenic patients. Perianal infections are important as they can cause life-threatening outcomes although they are relatively rare among all anorectal complications. Therefore perianal signs and symptoms should be meticulously evaluated concerning early diagnosis and treatment. PMID- 26977279 TI - The GLP-1 agonist, liraglutide, as a pharmacotherapy for obesity. AB - There is a global obesity epidemic that will continue to be a financial burden on healthcare systems around the world. Tackling obesity through diet and exercise should always be the first intervention, but this has not proved to be effective for a large number of patients. Pharmacotherapeutic options have been limited and many previously available drugs have been withdrawn due to safety concerns. Currently, only bariatric surgery has the capability to induce both substantial and durable weight loss. This article briefly reviews the history of pharmacotherapy for obesity before focusing on the clinical trial evidence for the use of the GLP-1 agonist liraglutide as a weight loss agent and comparing its efficacy with other emerging drug therapies for obesity. PMID- 26977280 TI - New perspectives on management of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive parenchymal lung disease characterized by a median survival of 3-5 years following diagnosis. The diagnosis is based on clinical, radiological and histopathological evaluation. Therefore, a multidisciplinary team is needed to reach the correct diagnosis. For a long time, supportive care and lung transplantation in selected cases, have been considered the only possible treatments for IPF. In the last decade many studies have investigated IPF pathogenesis, leading to an improved knowledge of the mechanisms underlying the disease and to the approval of two new drugs for IPF treatment (pirfenidone and nintedanib). The therapeutic approach of IPF cannot be limited to the administration of antifibrotic drugs, but it is necessary for improving the quality of life of patients and for facilitating, as far as possible, the performance of normal daily activities and relationships. IPF patients are also afflicted by disease-related complications such as gastroesophageal reflux, pulmonary hypertension, acute exacerbations and an increased risk of developing lung cancer. The clinician who treats IPF patients, should also treat these possible complications to slow disease progression, thus maintaining the possibility of a pulmonary transplantation. PMID- 26977281 TI - Opioid-induced constipation: advances and clinical guidance. AB - Currently opioids are the most frequently used medications for chronic noncancer pain. Opioid-induced constipation is the most common adverse effect associated with prolonged use of opioids, having a major impact on quality of life. There is an increasing need to treat opioid-induced constipation. With the recent approval of medications for the treatment of opioid-induced constipation, there are several therapeutic approaches. This review addresses the clinical presentation and diagnosis of opioid-induced constipation, barriers to its diagnosis, effects of opioids in the gastrointestinal tract, differential tolerance to opiates in different gastrointestinal organs, medications approved and in development for the treatment of opioid-induced constipation, and a proposed clinical management algorithm for treating opioid-induced constipation in patients with noncancer pain. PMID- 26977282 TI - Gout: optimizing treatment to achieve a disease cure. AB - Gout is one of the most common inflammatory arthritides. The disease is due to the deposition of monosodium urate crystals. These deposits are reversible with proper treatment, suggesting that gout is a curable disease. The main aim in gout is to lower serum uric acid levels to a pre-established target; there are different urate-lowering drugs (xanthine oxidase inhibitors, uricosurics and uricases) through which this can be achieved. Proper treatment of gout also involves correct management of acute flares and their prevention. To ensure treatment adherence it is necessary to explain to the patient what the objectives are. PMID- 26977283 TI - Vertical osteoconductivity of sputtered hydroxyapatite-coated mini titanium implants after dura mater elevation: Rabbit calvarial model. AB - This study evaluated the quantity and quality of newly formed vertical bone induced by sputtered hydroxyapatite-coated titanium implants compared with sandblasted acid-etched implants after dura mater elevation. Hydroxyapatite coated and non-coated implants (n = 20/group) were used and divided equally into two groups. All implants were randomly placed into rabbit calvarial bone (four implants for each animal) emerging from the inferior cortical layer, displacing the dura mater 3 mm below the original bone. Animals were sacrificed at 4 (n = 5) and 8 (n = 5) weeks post-surgery. Vertical bone height and area were analyzed histologically and radiographically below the original bone. Vertical bone formation was observed in both groups. At 4 and 8 weeks, vertical bone height reached a significantly higher level in the hydroxyapatite compared with the non coated group (p < 0.05). Vertical bone area was significantly larger in the hydroxyapatite compared with the non-coated group at 4 and 8 weeks (p < 0.05). This study indicates that vertical bone formation can be induced by dura mater elevation and sputtered hydroxyapatite coating can enhance vertical bone formation. PMID- 26977286 TI - Composite microsphere-functionalized scaffold for the controlled release of small molecules in tissue engineering. AB - Current tissue engineering strategies focus on restoring damaged tissue architectures using biologically active scaffolds. The ideal scaffold would mimic the extracellular matrix of any tissue of interest, promoting cell proliferation and de novo extracellular matrix deposition. A plethora of techniques have been evaluated to engineer scaffolds for the controlled and targeted release of bioactive molecules to provide a functional structure for tissue growth and remodeling, as well as enhance recruitment and proliferation of autologous cells within the implant. Recently, novel approaches using small molecules, instead of growth factors, have been exploited to regulate tissue regeneration. The use of small synthetic molecules could be very advantageous because of their stability, tunability, and low cost. Herein, we propose a chitosan-gelatin scaffold functionalized with composite microspheres consisting of mesoporous silicon microparticles and poly(dl-lactic-co-glycolic acid) for the controlled release of sphingosine-1-phospate, a small molecule of interest. We characterized the platform with scanning electron microscopy, Fourier transform infrared spectroscopy, and confocal microscopy. Finally, the biocompatibility of this multiscale system was analyzed by culturing human mesenchymal stem cells onto the scaffold. The presented strategy establishes the basis of a versatile scaffold for the controlled release of small molecules and for culturing mesenchymal stem cells for regenerative medicine applications. PMID- 26977285 TI - Biomimetic collagenous scaffold to tune inflammation by targeting macrophages. AB - The inflammatory response following implantation of a biomaterial is one of the major regulatory aspects of the overall regenerative process. The progress of inflammation determines whether functional tissue is restored or if nonfunctional fibrotic tissue is formed. This delicate balance is directed by the activity of different cells. Among these, macrophages and their different phenotypes, the inflammatory M1 to anti-inflammatory M2, are considered key players in the process. Recent approaches exploit macrophage's regenerative potential in tissue engineering. Here, we propose a collagen scaffold functionalized with chondroitin sulfate (CSCL), a glycosaminoglycan known to be able to tune inflammation. We studied CSCL effects on bone-marrow-derived macrophages in physiological, and lipopolysaccharides-inflamed, conditions in vitro. Our data demonstrate that CSCL is able to modulate macrophage phenotype by inhibiting the LPS/CD44/NF-kB cascade. As a consequence, an upregulation of anti-inflammatory markers (TGF beta, Arg, MRC1, and IL-10) was found concomitantly with a decrease in the expression of pro-inflammatory markers (iNOS, TNF-alpha, IL-1beta, IL-12beta). We then implanted CSCL subcutaneously in a rat model to test whether the same molecular mechanism could be maintained in an in vivo environment. In vivo data confirmed the in vitro studies. A significant reduction in the number of infiltrating cells around and within the implants was observed at 72 h, with a significant downregulation of pro-inflammatory genes expression. The present work provides indications regarding the immunomodulatory potential of molecules used for the development of biomimetic materials and suggests their use to direct macrophage immune modulation for tissue repair. PMID- 26977287 TI - Porcine acellular lung matrix for wound healing and abdominal wall reconstruction: A pilot study. AB - Surgical wound healing applications require bioprosthetics that promote cellular infiltration and vessel formation, metrics associated with increased mechanical strength and resistance to infection. Porcine acellular lung matrix is a novel tissue scaffold known to promote cell adherence while minimizing inflammatory reactions. In this study, we evaluate the capacity of porcine acellular lung matrix to sustain cellularization and neovascularization in a rat model of subcutaneous implantation and chronic hernia repair. We hypothesize that, compared to human acellular dermal matrix, porcine acellular lung matrix would promote greater cell infiltration and vessel formation. Following pneumonectomy, porcine lungs were processed and characterized histologically and by scanning electron microscopy to demonstrate efficacy of the decellularization. Using a rat model of subcutaneou implantation, porcine acellular lung matrices (n = 8) and human acellular dermal matrices (n = 8) were incubated in vivo for 6 weeks. To evaluate performance under mechanically stressed conditions, porcine acellular lung matrices (n = 7) and human acellular dermal matrices (n = 7) were implanted in a rat model of chronic ventral incisional hernia repair for 6 weeks. After 6 weeks, tissues were evaluated using hematoxylin and eosin and Masson's trichrome staining to quantify cell infiltration and vessel formation. Porcine acellular lung matrices were shown to be successfully decellularized. Following subcutaneous implantation, macroscopic vessel formation was evident. Porcine acellular lung matrices demonstrated sufficient incorporation and showed no evidence of mechanical failure after ventral hernia repair. Porcine acellular lung matrices demonstrated significantly greater cellular density and vessel formation when compared to human acellular dermal matrix. Vessel sizes were similar across all groups. Cell infiltration and vessel formation are well characterized metrics of incorporation associated with improved surgical outcomes. Porcine acellular lung matrices are a novel class of acellular tissue scaffold. The increased cell and vessel density may promote long-term improved incorporation and mechanical properties. These findings may be due to the native lung scaffold architecture guiding cell migration and vessel formation. Porcine acellular lung matrices represent a new alternative for surgical wound healing applications where increased cell density and vessel formation are sought. PMID- 26977284 TI - Impact of mechanical stretch on the cell behaviors of bone and surrounding tissues. AB - Mechanical loading is recognized to play an important role in regulating the behaviors of cells in bone and surrounding tissues in vivo. Many in vitro studies have been conducted to determine the effects of mechanical loading on individual cell types of the tissues. In this review, we focus specifically on the use of the Flexercell system as a tool for studying cellular responses to mechanical stretch. We assess the literature describing the impact of mechanical stretch on different cell types from bone, muscle, tendon, ligament, and cartilage, describing individual cell phenotype responses. In addition, we review evidence regarding the mechanotransduction pathways that are activated to potentiate these phenotype responses in different cell populations. PMID- 26977288 TI - Design of barrier coatings on kink-resistant peripheral nerve conduits. AB - Here, we report on the design of braided peripheral nerve conduits with barrier coatings. Braiding of extruded polymer fibers generates nerve conduits with excellent mechanical properties, high flexibility, and significant kink resistance. However, braiding also results in variable levels of porosity in the conduit wall, which can lead to the infiltration of fibrous tissue into the interior of the conduit. This problem can be controlled by the application of secondary barrier coatings. Using a critical size defect in a rat sciatic nerve model, the importance of controlling the porosity of the nerve conduit walls was explored. Braided conduits without barrier coatings allowed cellular infiltration that limited nerve recovery. Several types of secondary barrier coatings were tested in animal studies, including (1) electrospinning a layer of polymer fibers onto the surface of the conduit and (2) coating the conduit with a cross-linked hyaluronic acid-based hydrogel. Sixteen weeks after implantation, hyaluronic acid coated conduits had higher axonal density, displayed higher muscle weight, and better electrophysiological signal recovery than uncoated conduits or conduits having an electrospun layer of polymer fibers. This study indicates that braiding is a promising method of fabrication to improve the mechanical properties of peripheral nerve conduits and demonstrates the need to control the porosity of the conduit wall to optimize functional nerve recovery. PMID- 26977289 TI - A semi-analytical decomposition analysis of surface plasmon generation and the optimal nanoledge plasmonic device. AB - Surface plasmon resonance (SPR) of nanostructured thin metal films (so-called nanoplasmonics) has attracted intense attention due to its versatility for optical sensing and chip-based device integration. Understanding the underlying physics and developing applications of nanoplasmonic devices with desirable optical properties, e.g. intensity of light scattering and high refractive index (RI) sensitivity at the perforated metal film, is crucial for practical uses in physics, biomedical detection, and environmental monitoring. This work presents a semi-analytical model that enables decomposition and quantitative analysis of surface plasmon generation at a new complex nanoledge aperture structure under plane-wave illumination, thus providing insight on how to optimize plasmonic devices for optimal plasmonic generation efficiencies and RI sensitivity. A factor analysis of parameters (geometric, dielectric-RI, and incident wavelength) relevant to surface plasmon generation is quantitatively investigated to predict the surface plasmon polariton (SPP) generation efficiency. In concert with the analytical treatment, a finite-difference time-domain (FDTD) simulation is used to model the optical transmission spectra and RI sensitivity as a function of the nanoledge device's geometric parameters, and it shows good agreement with the analytical model. Further validation of the analytical approach is provided by fabricating subwavelength nanoledge devices and testing their optical transmission and RI sensitivity. PMID- 26977291 TI - An 81 Year Old with Back Pain. AB - You see an 81-year-old man in the emergency department. He has been troubled by abdominal and back pain that has been worsening over the last two days. He has smoked 20 cigarettes a day for the last 60 years. On examination his heart rate is 110 beats per minute and his blood pressure is 130/80 mmhg. He is tender over the central abdomen and you feel a pulsatile mass above the umbilicus. You request a CT scan of the abdomen. PMID- 26977290 TI - A Review of Recent Advances in Perioperative Patient Safety. AB - Major complications in surgery affect up to 16% of surgical procedures. Over the past 50 years, many patient safety initiatives have attempted to reduce such complications. Since the formation of the National Patient Safety Agency in 2001, there have been major advances in patient safety. Most recently, the production and implementation of the Surgical Safety Checklist by the World Health Organisation (WHO), a checklist ensuring that certain 'never events' (wrong-site surgery, wrong operation etc.) do not occur, irrespective of healthcare allowance. In this review, a summary of recent advances in patient safety are considered - including improvements in communication, understanding of human factors that cause mistakes, and strategies developed to minimise these. Additionally, the synthesis of best medical practice and harm minimisation is examined, with particular emphasis on communication and appreciation of human factors in the operating theatre. This is based on the resource management systems developed in other high risk industries (e.g. nuclear), and has also been adopted for other high risk medical areas. The WHO global movement to reduce surgical mortality has been highly successful, especially in the healthcare systems of developing nations where mortality reductions of up to 50% have been observed, and reductions in patient complications of 4%. Incident reporting has long been a key component of patient safety and continues to be so; allowing reflection and improved guideline formation. All patients are placed at risk in the surgical environment. It is crucial that this risk is minimised, whilst optimising the patient's outcome. In this review, recent advances in perioperative patient safety are examined and placed in context. PMID- 26977292 TI - 68-Year-Old Man with PR Bleed. AB - A 68-year-old man is referred to the colorectal clinic by his GP. He has lost 10 kg in weight over the last two months. He also noticed that his bowel motions have been loose and sometimes contain blood. You review the full blood count and faecal occult blood test the GP requested. What should you do next? PMID- 26977293 TI - Prevalence and associated factors of clinical manifestations of vitamin a deficiency among preschool children in asgede-tsimbla rural district, north Ethiopia, a community based cross sectional study. AB - BACKGROUND: Vitamin A Deficiency is a common form of micronutrient deficiency, globally affecting 33.3 % of preschool-age children. An estimated of 44.4 % of preschool children in Africa were at risk for vitamin A deficiency. In Ethiopia, vitamin A deficiency leads to 80,000 deaths a year and affects 61 % of preschool children. The aim of this study was to investigate the prevalence and associated factors with the night blindness, Bitot's spot and vitamin A intake among preschool children in rural area, Asgede-Tsimbla district, North Ethiopia. METHODS: Community based cross sectional study was conducted from January 27 to March 7, 2014. A total 1230 preschool children were selected by systematic random sampling from 8 randomly selected kebelles (smallest administrative unit). Structured and pretested questionnaires adapted from relevant studies and WHO/FAO was for data collection. In addition, sex, age, and height were taken and filled to Emergency Nutrition Assessment (ENA) for Standardized Monitoring and Assessment of Relief and Transition (SMART) 2007 software to convert the nutritional data into Z-scores of the indices. The data was then transported to SPSS version 20. Bivariate and Multivariable binary logistic regressions were carried out to investigate the effect of each independent variable on the dependent variable. Statistical significance was set at p-value < 0.05. RESULT: The odds of Bitot's spots (1.46 %) and night blindness (1.22 %) were higher than the WHO Cut-off levels used to define a public health problem. The odds of night blindness was 4 times higher among children belonging to family size greater or equal to four [Adjusted Odds Ratio (AOR) = 4.18, 95 % CI = 1.15,15.3] and 6 times higher among children of illiterate mothers [AOR = 5.96 , 95 % CI = 1.33,26.69]. The odds of Bitot's spots was 5.35 times higher among children belonging to family size greater or more four [AOR =5.35; 95 % CI = 1.49, 19.2], 4.75 times higher among children of illiterate mothers [AOR = 4.75, 95 % CI =1.32, 17.18] and 6 times higher in males than females [AOR = 5.8, 95 % CI = 1.65, 20.46]. CONCLUSIONS: The study revealed that night blindness and Bitot's spots are major nutritional problems in the study area. The independent predictors of night blindness were mother illiteracy status and large family size and also for Bitot's spots were mother illiteracy status, male sex of child and large family size. Therefore, the need to increase educational level of mother, use of family planning of women and emphasis on male children and children from large family size by involving the Education sector, Health sector, (Federal Ministry of Health) FMOH and (Tigray Regional Health Bureau) TRHB is crucial. PMID- 26977294 TI - Molecular modeling of antibodies for the treatment of TNFalpha-related immunological diseases. AB - Therapeutic monoclonal antibodies (mAbs) have high efficacy in treating TNF alpha related immunological diseases. Other than neutralizing TNF alpha, these IgG1 antibodies exert Fc receptor-mediated effector functions such as the complement dependent cytotoxicity (CDC) and antibody-dependent cell cytotoxicity (ADCC). The crystallizable fragment (Fc) of these IgG1 contains a single glycosylation site at Asn 297/300 that is essential for the CDC and ADCC. Glycosylated antibodies lacking core fucosylation showed an improved ADCC. However, no structural data are available concerning the ligand-binding interaction of these mAbs used in TNF alpha-related diseases and the role of the fucosylation. We therefore used comparative modeling for generating complete 3D mAb models that include the antigen-binding fragment (Fab) portions of infliximab, complexed with TNF alpha (4G3Y.pdb), the Fc region of the human IGHG1 fucosylated (3SGJ) and afucosylated (3SGK) complexed with the Fc receptor subtype Fcgamma RIIIA, and the Fc region of a murine immunoglobulin (1IGT). After few thousand steps of energy minimization on the resulting 3D mAb models, minimized final models were used to quantify interactions occurring between Fcgamma RIIIA and the fucosylated/afucosylated Fc fragments. While fucosylation does not affect Fab-TNF alpha interactions, we found that in the absence of fucosylation the Fc-mAb domain and Fcgamma RIIIA are closer and new strong interactions are established between G129 of the receptor and S301 of the Chimera 2 Fc mAb; new polar interactions are also established between the Chimera 2 Fc residues Y299, N300, and S301 and the Fcgamma RIIIA residues K128, G129, R130, and R155. These data help to explain the reduced ADCC observed in the fucosylated mAbs suggesting the specific AA residues involved in binding interactions. PMID- 26977295 TI - Anti-inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus-inducible cytokines. AB - Respiratory virus infections precipitate asthma and chronic obstructive pulmonary disease (COPD) exacerbations, with most exacerbations due to rhinovirus infection. Both asthma and COPD exacerbations are not well controlled by steroid therapies, and there is a much research interest in finding improved therapies or combinations of therapies for controlling exacerbations. CHF6001 is a new, inhaled highly potent and selective phosphodiesterase type 4 (PDE4) inhibitor. Using in vitro human bronchial epithelial cells (BEAS-2B), we investigated the potential anti-inflammatory effects of CHF6001 on rhinovirus (RV1B)-induced cytokines. Cytokine mRNA was measured by real-time PCR, while protein release was measured by ELISA. CHF6001 was used in a 7-point dose-response curve (1000-0.001 nmol/L) as a 1.5-h pretreatment prior to infection in comparison with roflumilast. Both roflumilast and CHF6001 reduced RV1B-induced IL-8, IL-29, IP 10, and RANTES mRNA and protein in a concentration-dependent manner. Generally, CHF6001 was 13- to 16-fold more potent (subnanomolar EC 50 values) than roflumilast at reducing IL-8, IL-29, IP-10, and RANTES mRNA and protein release, but had similar efficacies. In combination with the steroid fluticasone propionate (1 nmol/L), CHF6001 had additive effects, significantly reducing RV induced cytokines when compared with steroid or CHF6001 alone. Combined low-dose steroid and low-dose CHF6001 had a similar efficacy as high-dose steroid or CHF6001 alone, indicating the combination had steroid and PDE4 inhibitor sparing effects. Overall results indicate that PDE4 inhibitors have anti-inflammatory activity against virus-induced inflammatory mediators and that CHF6001 is more potent than roflumilast. PMID- 26977296 TI - Taurolidine and congeners activate hTRPA1 but not hTRPV1 channels and stimulate CGRP release from mouse tracheal sensory nerves. AB - Taurolidine has long been in clinical use as an antimicrobial irrigation that does not impede wound healing. It can even be administered intravenously (30 g/day) to treat sepsis or to exert newly recognized antineoplastic actions. Only one irritant effect is reported, that is, to temporarily induce burning pain of unknown origin when applied to body cavities or peripheral veins. The structure of the molecule suggested the chemoreceptor channel TRPA1 as a potential target, which was verified measuring stimulated CGRP release from sensory nerves of the isolated mouse trachea and calcium influx in hTRPA1-transfected HEK293 cells. With both methods, the concentration-response relationship of taurolidine exceeded the threshold value below 500 MUmol/L and 100 MUmol/L, respectively, and reached saturation at 1 mmol/L. The clinical 2% taurolidine solution did not evoke greater or longer lasting responses. The reversible tracheal response was abolished in TRPA1(-/-) but retained in TRPV1(-/-) mice. Consistently, hTRPV1-HEK showed no calcium influx as a response, likewise native HEK293 cells and hTRPA1 HEK deprived of extracellular calcium did not respond to taurolidine 1 mmol/L. The metabolite taurultam and its oxathiazine derivative, expected to cause less burning pain, showed weak tracheal irritancy only at 10 mmol/L, acting also through hTRPA1 but not hTRPV1. In conclusion, taurolidine, its metabolite, and a novel derivative showed no unspecific cellular effects but selectively, concentration-dependently and reversibly activated the irritant receptor TRPA1 in CGRP-expressing, thus nociceptive, neurons. The clinical solution of 2% taurolidine (~70 mmol/L) can, thus, rightly be expected to cause transient burning pain and neurogenic inflammation. PMID- 26977297 TI - Lack of cross-resistance to FF-10501, an inhibitor of inosine-5'-monophosphate dehydrogenase, in azacitidine-resistant cell lines selected from SKM-1 and MOLM 13 leukemia cell lines. AB - Resistance to azacitidine is a major issue in the treatments of myelodysplastic syndrome and acute myeloid leukemia, and previous studies suggest that changes in drug metabolism are involved in the resistance. Therefore, drugs with mechanisms resistant or alternative to such metabolic changes have been desired for the treatment of resistant disease. We generated azacitidine-resistant cells derived from SKM-1 and MOLM-13 leukemia cell lines in vitro, analyzed the mechanisms, and examined the impact on the efficacy of other antimetabolic drugs. It appeared that the cell growth-inhibitory effect of azacitidine, expression levels of uridine-cytidine kinase 2, and the concentrations of azacitidine triphosphate were remarkably decreased in the resistant cells compared with those in parent cells. These results were consistent with previous observations that azacitidine resistance is derived from metabolic changes. Cross-resistance of greater than 10 fold (shift in IC50 value) was observed in azacitidine-resistant cells for decitabine and for cytarabine, but not for gemcitabine or the inosine-5' monophosphate dehydrogenase (IMPDH) inhibitors FF-10501 and mycophenolate mofetil (cross-resistance to 5-fluorouracil was cell line dependent). The IMPDH inhibitors maintained their cell growth-inhibitory activities in the azacitidine resistant cell lines, in which the levels of adenine phosphoribosyltransferase (which converts FF-10501 to its active form, FF-10501 ribosylmonophosphate [FF 10501RMP]), FF-10501RMP, and the target enzyme, IMPDH, were equivalent to those in the parent cell lines. These results suggest that an IMPDH inhibitor such as FF-10501 could be an alternative therapeutic treatment for leukemia patients with acquired resistance to azacitidine. PMID- 26977298 TI - Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target. AB - The benefits of novel oral anticoagulants are hampered by bleeding. Since coagulation factor IX (fIX) lies upstream of fX in the coagulation cascade, and intermediate levels have been associated with reduced incidence of thrombotic events, we evaluated the viability of fIXa as an antithrombotic target. We applied translational pharmacokinetics/pharmacodynamics (PK/PD) principles to predict the therapeutic window (TW) associated with a selective small molecule inhibitor (SMi) of fIXa, compound 1 (CPD1, rat fIXa inhibition constant (Ki, 21 nmol/L) relative to clinically relevant exposures of apixaban (rat fXa Ki 4.3 nmol/L). Concentrations encompassing the minimal clinical plasma concentration (C min) of the 5 mg twice daily (BID) dose of apixaban were tested in rat arteriovenous shunt (AVS/thrombosis) and cuticle bleeding time (CBT) models. An I max and a linear model were used to fit clot weight (CW) and CBT. The following differences in biology were observed: (1) antithrombotic activity and bleeding increased in parallel for apixaban, but to a lesser extent for CPD1 and (2) antithrombotic activity occurred at high (>99%) enzyme occupancy (EO) for fXa or moderate (>65% EO) for fIXa. translational PK/PD analysis indicated that noninferiority was observed for concentrations of CPD1 that provided between 86% and 96% EO and that superior TW existed between 86% and 90% EO. These findings were confirmed in a study comparing short interfering (si)RNA-mediated knockdown (KD) modulation of fIX and fX mRNA. In summary, using principles of translational biology to relate preclinical markers of efficacy and safety to clinical doses of apixaban, we found that modulation of fIXa can be superior to apixaban. PMID- 26977299 TI - ADME studies of [5-(3)H]-2'-O-methyluridine nucleoside in mice: a building block in siRNA therapeutics. AB - The chemical modification 2'-O-methyl of nucleosides is often used to increase siRNA stability towards nuclease activities. However, the metabolic fate of modified nucleosides remains unclear. Therefore, the aim of this study was to determine the mass balance, pharmacokinetic, and absorption, distribution, metabolism, and excretion (ADME)-properties of tritium-labeled 2'-O methyluridine, following a single intravenous dose to male CD-1 mice. The single intravenous administration of [5-(3)H]-2'-O-methyluridine was well tolerated in mice. Radioactivity was rapidly and widely distributed throughout the body and remained detectable in all tissues investigated throughout the observation period of 48 h. After an initial rapid decline, blood concentrations of total radiolabeled components declined at a much slower rate. [(3)H]-2'-O-Methyluridine represented a minor component of the radioactivity in plasma (5.89% of [(3)H]-AUC 0-48 h). Three [(3)H]-2'-O-methyluridine metabolites namely uridine (M1), cytidine (M2), and uracil (M3) were the major circulating components representing 32.8%, 8.11%, and 23.6% of radioactivity area under the curve, respectively. The highest concentrations of total radiolabeled components and exposures were observed in kidney, spleen, pineal body, and lymph nodes. The mass balance, which is the sum of external recovery of radioactivity in excreta and remaining radioactivity in carcass and cage wash, was complete. Renal excretion accounted for about 52.7% of the dose with direct renal excretion of the parent in combination with metabolism to the endogenous compounds cytidine, uracil, cytosine, and cytidine. PMID- 26977300 TI - Slow drug delivery decreased total body clearance and altered bioavailability of immediate- and controlled-release oxycodone formulations. AB - Oxycodone is a commonly used analgesic with a large body of pharmacokinetic data from various immediate-release or controlled-release formulations, under different administration routes, and in diverse populations. Longer terminal half lives from extravascular administration as compared to IV administration have been attributed to flip-flop pharmacokinetics with the rate constant of absorption slower than elimination. However, PK parameters from the extravascular studies showed faster absorption than elimination. Sustained release formulations guided by the flip-flop concept produced mixed outcomes in formulation development and clinical studies. This research aims to develop a mechanistic knowledge of oxycodone ADME, and provide a consistent interpretation of diverging results and insight to guide further extended release development and optimize the clinical use of oxycodone. PK data of oxycodone in human studies were collected from literature and digitized. The PK data were analyzed using a new PK model with Weibull function to describe time-varying drug releases/ oral absorption, and elimination dependent upon drug input to the portal vein. The new and traditional PK models were coded in NONMEM. Sensitivity analyses were conducted to address the relationship between rates of drug release/absorption and PK profiles plus terminal half-lives. Traditional PK model could not be applied consistently to describe drug absorption and elimination of oxycodone. Errors were forced on absorption, elimination, or both parameters when IV and PO profiles were fitted separately. The new mechanistic PK model with Weibull function on absorption and slower total body clearance caused by slower absorption adequately describes the complex interplay between oxycodone absorption and elimination in vivo. Terminal phase of oxycodone PK profile was shown to reflect slower total body drug clearance due to slower drug release/absorption from oral formulations. Mechanistic PK models with Weibull absorption functions, and release rate-dependent saturable total body clearance well described the diverging oxycodone absorption and elimination kinetics in the literature. It showed no actual drug absorption during the terminal phase, but slower drug clearance caused by slower release/absorption producing the appearance of flip-flop and offered new insight for the development of modified release formulations and clinical use of oxycodone. PMID- 26977302 TI - The red-vine-leaf extract AS195 increases nitric oxide synthase-dependent nitric oxide generation and decreases oxidative stress in endothelial and red blood cells. AB - The red-vine-leaf extract AS195 improves cutaneous oxygen supply and the microcirculation in patients suffering from chronic venous insufficiency. Regulation of blood flow was associated to nitric oxide synthase (NOS)-dependent NO (nitric oxide) production, and endothelial and red blood cells (RBC) have been shown to possess respective NOS isoforms. It was hypothesized that AS195 positively affects NOS activation in human umbilical vein endothelial cells (HUVECs) and RBC. Because patients with microvascular disorders show increased oxidative stress which limits NO bioavailability, it was further hypothesized that AS195 increases NO bioavailability by decreasing the content of reactive oxygen species (ROS) and increasing antioxidant capacity. Cultured HUVECs and RBCs from healthy volunteers were incubated with AS195 (100 MUmol/L), tert butylhydroperoxide (TBHP, 1 mmol/L) to induce oxidative stress and with both AS195 and TBHP. Endothelial and red blood cell-nitric oxide synthase (RBC-NOS) activation significantly increased after AS195 incubation. Nitrite concentration, a marker for NO production, increased in HUVEC but decreased in RBC after AS195 application possibly due to nitrite scavenging potential of flavonoids. S nitrosylation of RBC cytoskeletal spectrins and RBC deformability were increased after AS195 incubation. TBHP-induced ROS were decreased by AS195, and antioxidative capacity was significantly increased in AS195-treated cells. TBHP also reduced RBC deformability, but reduction was attenuated by parallel incubation with AS195. Adhesion of HUVEC was also reduced after AS195 treatment. Red-vine-leaf extract AS195 increases NOS activation and decreases oxidative stress. Both mechanisms increase NO bioavailability, improve cell function, and may thus account for enhanced microcirculation in both health and disease. PMID- 26977304 TI - Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin induced neuropathic cold hypersensitivity. AB - Oxaliplatin is a first-line treatment for colorectal cancer. However, shortly following treatment, cold-evoked hypersensitivity appears in the extremities and over time, the pain is such that oxaliplatin dosing may need to be markedly reduced or even terminated. There is currently a lack of efficacious treatments for oxaliplatin-induced peripheral neuropathy, which is due in part to the difficulty in translating findings obtained from preclinical rodent models of chemotherapy-induced peripheral neuropathy. Nonhuman primates (NHP) are phylogenetically closer to humans than rodents and may show drug responses that parallel those of humans. A significant decrease in tail withdrawal latency to 10 degrees C water ("cold hypersensitivity") was observed beginning 3 days after intravenous infusion of oxaliplatin (5 mg/kg) in Macaca fascicularis. A single treatment of duloxetine (30 mg/kg, p.o.) ameliorated oxaliplatin-induced cold hypersensitivity, whereas pregabalin (30 mg/kg, p.o.) and tramadol (30 mg/kg, p.o.) did not. By contrast, in rats, no significant cold hypersensitivity, or increased responsiveness to acetone applied to the hind paws, was observed 3 days after the first injection of oxaliplatin (5 mg/kg, i.p., once per day, two injections). Therefore, rats were tested after six treatments of oxaliplatin, 17 days after the first treatment. All analgesics (30 mg/kg, p.o.) significantly ameliorated cold hypersensitivity in rats. The activity of analgesics in the oxaliplatin-treated macaques parallel clinical findings. The current results indicate that the NHP could serve as a bridge species to improve translatability of preclinical findings into clinically useful treatments for oxaliplatin-induced peripheral neuropathy. PMID- 26977303 TI - Daikenchuto (TU-100) shapes gut microbiota architecture and increases the production of ginsenoside metabolite compound K. AB - Many pharmaceutical agents not only require microbial metabolism for increased bioavailability and bioactivity, but also have direct effects on gut microbial assemblage and function. We examined the possibility that these actions are not mutually exclusive and may be mutually reinforcing in ways that enhance long-term of these agents. Daikenchuto, TU-100, is a traditional Japanese medicine containing ginseng. Conversion of the ginsenoside Rb1 (Rb1) to bioactive compound K (CK) requires bacterial metabolism. Diet-incorporated TU-100 was administered to mice over a period of several weeks. T-RFLP and 454 pyrosequencing were performed to analyze the time-dependent effects on fecal microbial membership. Fecal microbial capacity to metabolize Rb1 to CK was measured by adding TU-100 or ginseng to stool samples to assess the generation of bioactive metabolites. Levels of metabolized TU-100 components in plasma and in stool samples were measured by LC-MS/MS. Cecal and stool short-chain fatty acids were measured by GC MS. Dietary administration of TU-100 for 28 days altered the gut microbiota, increasing several bacteria genera including members of Clostridia and Lactococcus lactis. Progressive capacity of microbiota to convert Rb1 to CK was observed over the 28 days administration of dietary TU-100. Concomitantly with these changes, increases in all SCFA were observed in cecal contents and in acetate and butyrate content of the stool. Chronic consumption of dietary TU-100 promotes changes in gut microbiota enhancing metabolic capacity of TU-100 and increased bioavailability. We believe these findings have broad implications in optimizing the efficacy of natural compounds that depend on microbial bioconversion in general. PMID- 26977305 TI - Determining starting basal rates of insulin infusion for insulin pump users: a comparison between methods. AB - OBJECTIVE: We aimed to assess the accuracy and safety of presently available methods of estimating starting basal insulin rates for patients with type 1 and 2 diabetes, and to compare them against an empirically derived standard basal rate and a newly developed regression formula. RESEARCH DESIGN AND METHODS: Data on 61 patients with type 1 diabetes on continuous subcutaneous insulin infusion (CSII) therapy and 34 patients with type 2 diabetes on CSII were reviewed. Patient data were first analyzed for correlations between initial patient parameters and final basal rates. Starting basal rates were then retrospectively calculated for these patients according to the weight-based method (WB-M), the total daily dose (TDD) of insulin method (TDD-M), a flat empiric value, and a new formula developed by regression analysis of clinical data. These 4 methods were subsequently compared in their accuracy and potential risk of hypoglycemia. RESULTS: For type 1 diabetes, patient weight and TDD of long-acting insulin correlated with final basal rates. Both the regression formula and the TDD-M appeared safer than the WB M and empirical estimates. For type 2 diabetes, only patient TDD of long-acting insulin correlated with final basal rates. The regression formula was significantly more accurate for patients with type 2 diabetes overall, but the TDD-M estimate was marginally safer. CONCLUSIONS: The pre-existing TDD-M was found to be the safest presently recommended estimate of initial basal rates for pump initiation in both type 1 and 2 diabetes. The best-fit regression was found to have potential use for type 2 CSII initiation. PMID- 26977306 TI - Type 1 diabetes prevalence increasing globally and regionally: the role of natural selection and life expectancy at birth. AB - OBJECTIVE: Prevalence of type 1 diabetes (T1D) disease is increasing worldwide. We aim to test correlation of T1D prevalence to the reduced natural selection measured by Biological State Index (Ibs). RESEARCH DESIGN AND METHODS: Country specific estimates of T1D prevalence, life expectancy, obesity prevalence rate, urbanization rates, per capita sugars consumption and per capita gross domestic product (GDP) were obtained. Ibs and country-specific longevity (e50) increase for each country were self-calculated. These data were then matched to T1D prevalence by country for our ecological study among 118 countries. Countries were also grouped to study the associations in different regions. SPSS V.22 was used for correlation analysis. RESULTS: Worldwide, both Ibs and life expectancy at birth (Ibs proxy) were significantly correlated to T1D prevalence in Pearson r (r=0.713, p<0.001 and r=0.722, p<0.001, respectively) and Spearman's r (r=0.724, p<0.001 and r=0.689, p<0.001, respectively). T1D prevalence was not correlated to longevity increase measured as life expectancy at 50 years old. T1D prevalence was significantly associated with I bs (r=0.307, p<0.001) and newborn life expectancy (r=0.349, p<0.001) independent of per capita total sugar consumption, per capita GDP, urbanization and obesity prevalence in partial correlation. Globally, both life expectancy at birth and Ibs exponentially correlated to T1D prevalence. Pearson correlations generally existed in different country categorizations by geographic region, culture background and economic status. CONCLUSIONS: Reduced natural selection may have contributed to the increasing T1D prevalence worldwide. T1D epidemiology study in total population may be the practical solution to identify the causes of increasing T1D prevalence. PMID- 26977307 TI - Menu labelling and food choice in obese adults: a feasibility study. AB - BACKGROUND: To date research examining the benefits of menu labelling in the UK is sparse. The aim of the present study was to examine the impact of menu labelling in a UK obese population. METHODS: Using a repeated measures design, 61 patients at a tier 3 weight management service completed four questionnaires to assess their food choice (control) and behaviour change when presented with 3 menu labelling formats (calorie content; nutrient content; and energy expenditure). RESULTS: All three forms of labelling increased participants weight control concerns compared to the control condition. There was a significant difference in content of food ordered in the three menu labelling formats compared to the control condition. The calorie condition had the largest percentage decrease in calories selected followed by energy expenditure and nutrient content. However, no difference was observed between the three conditions in the desire for menu labelling in restaurants to be introduced in the UK. CONCLUSIONS: The findings suggest that menu labelling should be enforced in the UK as it is both beneficial to promoting healthy eating and in demand. This study is the first to examine menu labelling in a UK obese population using energy expenditure equivalents to provide nutritional information. PMID- 26977308 TI - Multimodality imaging in heart valve disease. AB - In patients with heart valve disease, echocardiography is the mainstay for diagnosis, assessment and serial surveillance. However, other modalities, notably cardiac MRI and CT, are used if echocardiographic imaging is suboptimal but can also give complementary information to improve assessment of the valve lesion and cardiac compensation to aid the timing of surgery and determine risk. This statement discusses the way these imaging techniques are currently integrated to improve care beyond what is possible with echocardiography alone. PMID- 26977301 TI - Role of endoplasmic reticulum stress in drug-induced toxicity. AB - Drug-induced toxicity is a key issue for public health because some side effects can be severe and life-threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug-induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug-induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models. PMID- 26977310 TI - Physical exercise and quantitative lower limb collateral function. AB - OBJECTIVE: This study tested the hypothesis that global physical activity and physical performance parameters are directly related to invasively obtained left superficial femoral artery (SFA) collateral flow index (CFI). BACKGROUND: So far, the association between different measures of physical exercise activity and quantitative lower limb collateral function has not been investigated. METHODS: The primary study end point was pressure-derived CFI as obtained during a 3 min left SFA balloon occlusion. CFI is the ratio of simultaneously recorded mean SFA distal occlusive pressure divided by mean aortic pressure, both subtracted by central venous pressure. As independent variables, the items of the Global Physical Activity Questionnaire (GPAQ) and physical exercise performance (maximal workload in watts) as achieved during a bicycle or treadmill exercise test were determined. The secondary study end point was transcutaneous left calf partial oxygen pressure (PO2 in mm Hg) divided by transcutaneous PO2 at a non-ischaemic reference site as obtained simultaneously to CFI measurement. RESULTS: Of the 110 study patients undergoing diagnostic coronary angiography, 79 belonged to the group without and 31 with engagement in regular intensive leisure time physical activity according to GPAQ. Left SFA CFI tended to be lower in the group without than with intensive leisure time physical activity: 0.514 +/-0.141 vs 0.560 +/ 0.184 (p =0.0566). Transcutaneous PO2 index was associated with simultaneous left SFA CFI: CFI =018 +0.57 PO2 index; p<0.0001. Maximal physical workload was directly associated with left SFA CFI: CFI =0.40 +0.0009 maximal workload; p =0.0044. CONCLUSIONS: Quantitative left SFA collateral function is directly reflected by maximal physical workload as achieved during an exercise test. TRIAL REGISTRATION NUMBER: NCTO02063347. PMID- 26977309 TI - Trial protocol for a randomised controlled trial of red cell washing for the attenuation of transfusion-associated organ injury in cardiac surgery: the REDWASH trial. AB - INTRODUCTION: It has been suggested that removal of proinflammatory substances that accumulate in stored donor red cells by mechanical cell washing may attenuate inflammation and organ injury in transfused cardiac surgery patients. This trial will test the hypotheses that the severity of the postoperative inflammatory response will be less and postoperative recovery faster if patients undergoing cardiac surgery receive washed red cells compared with standard care (unwashed red cells). METHODS AND ANALYSIS: Adult (>=16 years) cardiac surgery patients identified at being at increased risk for receiving large volume red cell transfusions at 1 of 3 UK cardiac centres will be randomly allocated in a 1:1 ratio to either red cell washing or standard care. The primary outcome is serum interleukin-8 measured at 5 postsurgery time points up to 96 h. Secondary outcomes will include measures of inflammation, organ injury and volumes of blood transfused and cost-effectiveness. Allocation concealment, internet-based randomisation stratified by operation type and recruiting centre, and blinding of outcome assessors will reduce the risk of bias. The trial will test the superiority of red cell washing versus standard care. A sample size of 170 patients was chosen in order to detect a small-to-moderate target difference, with 80% power and 5% significance (2-tailed). ETHICS AND DISSEMINATION: The trial protocol was approved by a UK ethics committee (reference 12/EM/0475). The trial findings will be disseminated in scientific journals and meetings. TRIAL REGISTRATION NUMBER: ISRCTN 27076315. PMID- 26977311 TI - Homozygosity for the V377I mutation in mevalonate kinase causes distinct clinical phenotypes in two sibs with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS). AB - OBJECTIVE: Mevalonate kinase (MVK) deficiency is a rare autosomal recessive auto inflammatory disorder characterised by recurring episodes of fever associated with multiple non-specific inflammatory symptoms and caused by mutations in the MVK gene. The phenotypic spectrum is wide and depends mostly on the nature of the mutations. Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is a relatively mild presentation and predominantly associated with a c.1129G>A (p.V377I) mutation in the MVK gene. We report cases of two sisters homozygous for this mutation but exhibiting distinct (symptomatic vs asymptomatic) phenotypes. METHODS: Patient history was obtained; physical and clinical examination and laboratory tests were performed; lipopolysaccharide (LPS) response of peripheral blood mononuclear cells was quantified. RESULTS: Low MVK enzymatic activity is not necessarily associated with inflammatory symptoms. Increased inflammatory cytokine secretion in response to LPS is associated with symptomatic MVK deficiency. CONCLUSIONS: Individuals who are homozygous for the common p.V377I mutation in the MVK gene may not display the characteristic inflammatory episodes diagnostic of MKD and thus may be lost for correct and timely diagnosis. PMID- 26977312 TI - Pilot Study on Visual Function and Fundus Autofluorescence Assessment in Diabetic Patients. AB - Purpose. Evaluate optimized fundus autofluorescence (FAF) imaging in early stages of diabetic retinopathy (DR) and relate findings with conventional colour fundus imaging and visual function in diabetic patients and control subjects. Materials and Methods. FAF and colour images were obtained using the CR-2 Plus digital nonmydriatic retinal camera in seven diabetic patients and thirteen control subjects. Visual-Functioning Questionnaire-25 (VFQ-25) and Diabetes Self Management Questionnaire (DSMQ) were used to assess the quality of life and diabetes self-care. Contrast sensitivity function (CSF) was evaluated with the Vistech 6500 chart. Results. FAF and optimized-FAF imaging showed more retinal alterations related to DR than colour imaging. In diabetic patients, compatible signs with microaneurysms, capillary dilations, and haemorrhages were less numerous in colour imaging than optimized-FAF and FAF imaging in areas analysed. Control subjects at risk of developing DM showed more retinal pigment epithelium defects than those without risk in all retinal areas. Significant differences were not found in VFQ-25 and CSF between diabetic patients and control subjects. Conclusions. FAF and optimized-FAF imaging showed significant alterations related to DR not observed in colour imaging. FAF and optimized-FAF images could be a useful complementary tool for detecting early alterations associated with the development and progression of DR. PMID- 26977313 TI - Intravitreal Melphalan for Vitreous Seeds: Initial Experience in China. AB - Purpose. To evaluate the efficacy of intravitreal melphalan for vitreous seeds from retinoblastoma in Chinese patients. Methods. This is a retrospective review of 17 consecutive Chinese patients (19 eyes) with viable vitreous seeds from retinoblastoma. The patients received multiple intravitreal injections of 20 ug melphalan. Results. The International Classification of Retinoblastoma groups were B in 1 eye, C in 5 eyes, D in 11 eyes, and E in 2 eyes. On average, 6 injections (range: 1-15) were given to each eye at the interval of 2-4 weeks. Successful control of vitreous seeds was achieved in 16 of 19 eyes (84.21%). Globe retention was achieved in 73.68% (14/19) eyes. The patients were followed up for 27 months on average (median: 26; range: 17-42 months). There is a significant difference in response to intravitreal melphalan for cloud, spheres, and dust seeds with a median number of injections of 9, 6, and 3, respectively (P = 0.003). Complications related to intravitreal melphalan included vitreous hemorrhage, cataract, salt-and-pepper retinopathy, and pupil posterior synechia. There was no case of epibulbar extension or systemic metastasis within the period of follow-up. Conclusion. Intravitreal melphalan achieved a high local control rate for vitreous seeds without extraocular extension and with acceptable toxicity in Chinese retinoblastoma patients. PMID- 26977314 TI - Neuromodulation Therapy with Vagus Nerve Stimulation for Intractable Epilepsy: A 2-Year Efficacy Analysis Study in Patients under 12 Years of Age. AB - To study the efficacy of vagus nerve stimulation (VNS) therapy as an adjunctive treatment for intractable epilepsy in patients under 12 years of age, we analyzed 2-year postimplant data of 35 consecutive patients. Of the 35 patients, 18 (51.4%) at 6 months, 18 (51.4%) at 12 months, and 21 (60.1%) at 24 months showed >=50% reduction in seizure frequency (responders). Although incremental seizure freedom was noted, no patient remained seizure-free throughout the 3 study periods. Partial response (>=50% seizure reduction in 2 or less study periods) was seen in 8 (22.9%) patients. Twelve patients (34.3%) were nonresponders. Out of 29 patients with primary generalized epilepsy, 20 (68.9%) and, out of 6 patients with focal epilepsy, 3 (50%) had >=50% seizure control in at least one study period. No major complications or side effects requiring discontinuation of VNS therapy were encountered. We conclude that (1) patients with intractable primary generalized epilepsy respond better to VNS therapy, (2) cumulative effect of neuromodulation with improving responder rate to seizure freedom with continuation of VNS therapy is noted, and (3) VNS therapy is safe and is well tolerated in children receiving implant under 12 years of age. PMID- 26977315 TI - Effect of Preemptive Flurbiprofen Axetil and Tramadol on Transurethral Resection of the Prostate under Spinal Anesthesia. AB - Objective. To investigate the efficacy of preoperative intravenous flurbiprofen axetil and tramadol on spinal anesthesia for transurethral resection of the prostate (TURP). Methodology. In this prospective clinical study, we enrolled 60 patients undergoing TURP under spinal anesthesia with small-dose bupivacaine and sufentanil. Patients were randomly divided in two: group flurbiprofen axetil and tramadol (Group FT) intravenously received 1 mg/kg flurbiprofen axetil and 1 mg/kg tramadol 20 min prior to the surgical procedures and group control (Group C) was given normal saline. The characteristics of spinal anesthesia, blood pressure, heart rate, analgesic requirement, visual analogue scale (VAS), and overall satisfaction degree were collected. Results. Time to the first analgesic requirement was significantly longer in Group FT. Patients who needed postoperative analgesics were fewer in Group FT. VAS scores were lower in Group FT at postoperative time points of 1, 2, 6, and 12 h. The patients in Group FT were more satisfied than in Group C. Conclusions. Preoperative flurbiprofen axetil and tramadol can reduce and delay postoperative pain and then decrease analgesic consumption for TURP under spinal anesthesia without an increase of side effects. PMID- 26977317 TI - An Analysis of Canadian Institute for Health Research Funding for Research on Autism Spectrum Disorder. AB - We examined patterns of Canadian Institute for Health Research (CIHR) funding on autism spectrum disorder (ASD) research. From 1999 to 2013, CIHR funded 190 ASD grants worth $48 million. Biomedical research received 43% of grants (46% of dollars), clinical research 27% (41%), health services 10% (7%), and population health research 8% (3%). The greatest number of grants was given in 2009, but 2003 saw the greatest amount. Funding is clustered in a handful of provinces and institutions, favouring biomedical research and disfavouring behavioural interventions, adaptation, and institutional response. Preference for biomedical research may be due to the detriment of clinical research. PMID- 26977316 TI - The Protective Effect of Naringin against Bleomycin-Induced Pulmonary Fibrosis in Wistar Rats. AB - The aim of the current study was to investigate the protective effect of naringin on bleomycin-induced pulmonary fibrosis in rats. Twenty-four Wistar rats randomly divided into four groups (control, bleomycin alone, bleomycin + naringin 40, and bleomycin + naringin 80) were used. Rats were administered a single dose of bleomycin (5 mg/kg; via the tracheal cannula) alone or followed by either naringin 40 mg/kg (orally) or naringin 80 mg/kg (orally) or water (1 mL, orally) for 14 days. Rats and lung tissue were weighed to determine the lung index. TNF alpha and IL-1beta levels, hydroxyproline content, and malondialdehyde (MDA) levels were assayed. Glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities were determined. Tissue sections were stained with hematoxylin eosin, Masson's trichrome, and 0.1% toluidine blue. TNF-alpha, IL-1beta, and MDA levels and hydroxyproline content significantly increased (p < 0.01) and GPx and SOD activities significantly decreased in bleomycin group (p < 0.01). Naringin at a dose of 80 mg/kg body weight significantly decreased TNF-alpha and IL-1beta activity, hydroxyproline content, and MDA level (p < 0.01) and increased GPx and SOD activities (p < 0.05). Histological evidence supported the results. These results show that naringin has the potential of reducing the toxic effects of bleomycin and may provide supportive therapy for conventional treatment methods for idiopathic pulmonary fibrosis. PMID- 26977318 TI - Impacts of Quebec Primary Healthcare Reforms on Patients' Experience of Care, Unmet Needs, and Use of Services. AB - Introduction. Healthcare reforms launched in the early 2000s in Quebec, Canada, involved the implementation of new forms of primary healthcare (PHC) organizations: Family Medicine Groups (FMGs) and Network Clinics (NCs). The objective of this paper is to assess how the organizational changes associated with these reforms have impact on patients' experience of care, use of services, and unmet needs. Methods. We conducted population and organization surveys in 2005 and 2010 in two regions of the province of Quebec. The design was a before and-after natural experiment. Changes over time between new models and other practices were assessed using difference-in-differences statistical procedures. Results. Accessibility decreased between 2003 and 2010, but less so in the treatment than in the comparison group. Continuity of care generally improved, but the increase was less for patients in the treatment group. Responsiveness also increased during the period and more so in the treatment group. There was no other significant difference between the two groups. Conclusion. PHC reform in Quebec has brought about major organizational changes that have translated into slight improvements in accessibility of care and responsiveness. However, the reform does not seem to have had an impact on continuity, comprehensiveness, perceived care outcomes, use of services, and unmet needs. PMID- 26977320 TI - Production and Characterization of Highly Thermostable beta-Glucosidase during the Biodegradation of Methyl Cellulose by Fusarium oxysporum. AB - Production of beta-glucosidase from Fusarium oxysporum was investigated during degradation of some cellulosic substrates (Avicel, alpha-cellulose, carboxymethyl cellulose (CMC), and methylcellulose). Optimized production of beta-glucosidase using the cellulosic substrate that supported highest yield of enzyme was examined over 192 h fermentation period and varied pH of 3.0-11.0. The beta glucosidase produced was characterized for its suitability for industrial application. Methyl cellulose supported the highest yield of beta-glucosidase (177.5 U/mg) at pH 6.0 and 30 degrees C at 96 h of fermentation with liberation of 2.121 MUmol/mL glucose. The crude enzyme had optimum activity at pH 5.0 and 70 degrees C. The enzyme was stable over broad pH range of 4.0-7.0 with relative residual activity above 60% after 180 min of incubation. beta-glucosidase demonstrated high thermostability with 83% of its original activity retained at 70 degrees C after 180 min of incubation. The activity of beta-glucosidase was enhanced by Mn(2+) and Fe(2+) with relative activities of 167.67% and 205.56%, respectively, at 5 mM and 360% and 315%, respectively, at 10 mM. The properties shown by beta-glucosidase suggest suitability of the enzyme for industrial applications in the improvement of hydrolysis of cellulosic compounds into fermentable sugars that can be used in energy generation and biofuel production. PMID- 26977319 TI - Schizophrenia and Suicide Attempts: Findings from a Representative Community Based Canadian Sample. AB - This study examined factors associated with suicide attempts among those with schizophrenia (n = 101) versus those without (n = 21,643) in a representative sample of noninstitutionalized Canadians. The lifetime prevalence of suicide attempts among persons with schizophrenia was 39.2% versus 2.8% of nonafflicted individuals. After adjusting for sociodemographics, childhood adversities, substance abuse/dependence, depression/anxiety, and chronic pain, those with schizophrenia had 6 times the odds (OR = 6.47) of attempting suicide. Among persons with schizophrenia, suicide attempts were associated with female gender (OR = 4.59), substance abuse/dependence (OR = 6.31), depression (OR = 4.93), and childhood physical abuse (OR = 5.75). Community-dwelling persons with schizophrenia appear to be at high risk for suicide attempts. PMID- 26977321 TI - Fortifying the Treatment of Prostate Cancer with Physical Activity. AB - Over the past decade, significant data have shown that obese men experience a survival detriment after treatment for prostate cancer. While methods to combat obesity are of utmost importance for the prostate cancer patient, newer data reveal the overall metabolic improvements that accompany increased activity levels and intense exercise beyond weight loss. Along these lines, a plethora of data have shown improvement in prostate cancer-specific outcomes after treatment accompanied with these activity levels. This review discusses the metabolic mechanisms in which increased activity levels and exercise can help improve both outcomes for men treated for prostate cancer while lowering the side effects of treatment. PMID- 26977322 TI - A Comparative Analysis of the Endocannabinoid System in the Retina of Mice, Tree Shrews, and Monkeys. AB - The endocannabinoid (eCB) system is widely expressed in various parts of the central nervous system, including the retina. The localization of the key eCB receptors, particularly CB1R and CB2R, has been recently reported in rodent and primate retinas with striking interspecies differences. Little is known about the distribution of the enzymes involved in the synthesis and degradation of these eCBs. We therefore examined the expression and localization of the main components of the eCB system in the retina of mice, tree shrews, and monkeys. We found that CB1R and FAAH distributions are well-preserved among these species. However, expression of NAPE-PLD is circumscribed to the photoreceptor layer only in monkeys. In contrast, CB2R expression is variable across these species; in mice, CB2R is found in retinal neurons but not in glial cells; in tree shrews, CB2R is expressed in Muller cell processes of the outer retina and in retinal neurons of the inner retina; in monkeys, CB2R is restricted to Muller cells. Finally, the expression patterns of MAGL and DAGLalpha are differently expressed across species. Overall, these results provide evidence that the eCB system is differently expressed in the retina of these mammals and suggest a distinctive role of eCBs in visual processing. PMID- 26977324 TI - A Retained Bullet in Pericardial Sac: Penetrating Gunshot Injury of the Heart. AB - Penetrating cardiac trauma is rarely seen but when present there is a short time lag to keep the patients alive. Cardiac gunshot injuries are exceptional and it occurs mostly during interpersonal disagreements casualties or a mistakenly fired gun nowadays. Here we present a case of cardiac gunshot injury from the war of Kobani, Syria. The patient was mistakenly diagnosed to have a sole bullet in the left shoulder while he had a penetrating cardiac trauma with a bullet in the heart and pericardial effusion possibly giving rise to pericardial tamponade. Luckily the cardiac gunshot injury was noticed one day later and the patient was referred to a tertiary hospital. Intrapericardial bullet was conservatively followed up. The patient was discharged one week later after resection of the bullet in the shoulder. PMID- 26977325 TI - Prosthodontic Management of Xerostomic Patient: A Technical Modification. AB - Xerostomia is often a contributing factor in both minor and serious health problems. It can affect nutrition and dental as well as psychological health. Common problems faced by such patients are glossitis, mucositis, angular cheilitis, dysgeusia, and difficulty in chewing and swallowing. One of the major problems associated with xerostomic patients is the poor tolerance and retention of removable dental prostheses because of thin dry atrophic mucosa and lack of a saliva film. This paper describes a new technique of incorporating a salivary reservoir in the maxillary complete denture. The salivary reservoir fabricated by this technique provided good lubrication of the oral tissues and was easily cleansed by the wearer and was fabricated from routine denture materials. PMID- 26977326 TI - Pegvisomant-Induced Cholestatic Hepatitis in an Acromegalic Patient with UGT1A1 (*) 28 Mutation. AB - Pegvisomant (PEGv) is a growth hormone receptor antagonist approved for the treatment of acromegaly; one of its documented adverse effects is reversible elevation of hepatic enzymes. We report a 39-year-old male acromegalic patient with a pituitary macroadenoma who underwent transsphenoidal surgery. The patient's condition improved but GH and IGF-I levels did not normalize; as a consequence, we first administered dopamine agonists and then somatostatin receptor ligands (SRLs) with poor response. PEGv 15 mg every other day was added to lanreotide 120 mg monthly. The patient developed a severe hepatitis five months after starting the combination therapy. Elevated ferritin, iron, and transferrin saturation suggested probable hepatitis due to haemochromatosis. We performed a liver biopsy which showed an acute cholestatic hepatitis consistent with toxic etiology. A heterozygous genotype UGT1A1 (*) 28 polymorphism associated with Gilbert's syndrome was also found in this Argentine patient. The predominant clinical presentation resembled an acute cholestatic hepatitis associated with severe hemosiderosis, a different and new pattern of PEGv hepatotoxicity. PMID- 26977327 TI - A Bilateral Traumatic Hip Obturator Dislocation. AB - A case of a bilateral simultaneous traumatic obturator dislocation of both hip joints in an 18-year-old young man following a traffic accident is presented. We reduced the dislocated femoral heads immediately under general anesthesia followed by passive and active exercises and early full-weight bearing mobilization. After 5 years, the result was excellent. PMID- 26977329 TI - Use of Scrambler Therapy in Acute Paediatric Pain: A Case Report and Review of the Literature. AB - We report our clinical experience on the effect of Scrambler Therapy (ST) for a child with acute mixed pain refractory to pharmacological treatment. ST, recently proposed as an alternative treatment for chronic neuropathic pain in adults, is a noninvasive approach to relieve pain, by changing pain perception at brain level. It is safe and has no side effects. Further research is needed to assess its efficacy for acute pain and for paediatric population. PMID- 26977328 TI - Surgical Treatment of Posttraumatic Radioulnar Synostosis. AB - Radioulnar synostosis is a rare complication of forearm fractures. The formation of a bony bridge induces functional disability due to limitation of the pronosupination. Although the etiology of posttraumatic synostosis is unknown, it seems that the incidence is higher in patients who have suffered a concomitant neurological or burn trauma, and extensive soft tissue injury, mainly due to high energy impact. Surgical treatment, such as reinsertion of distal biceps tendon into the radius, seems to be another possible factor. The aim of the surgical treatment is to remove the bony bridge and restore complete range of movement (ROM), thus preventing recurrence. Literature does not indicate a preferred type of surgical procedure for the aforementioned complication; however, it has been shown that surgical interposition of inert material reduces the formation rate of recurrent bony bridge. We describe a surgical technique in two cases in which the radius and ulna were wrapped with allogenic, cadaver fascia lata graft to prevent bony bridge formation. The data from 2 years of follow-up are reported, indicating full restoration of ROM and no recurrence of synostosis. PMID- 26977330 TI - Aortic Pseudoaneurysm Secondary to Mediastinitis due to Esophageal Perforation. AB - Esophageal perforation is a condition associated with high morbidity and mortality rates; it requires early diagnosis and treatment. The most common complication of esophageal rupture is mediastinitis. There are several case reports in the literature of mediastinitis secondary to esophageal perforation and development of aortic pseudoaneurysm as a complication. We report the case of a patient with an 8-day history of esophageal perforation due to foreign body (fishbone) with mediastinitis and aortic pseudoaneurysm. The diagnosis was made using Computed Tomography (CT) with intravenous and oral water-soluble contrast material. An esophagogastroduodenoscopy did not detect the perforation. PMID- 26977323 TI - Comorbidity Factors and Brain Mechanisms Linking Chronic Stress and Systemic Illness. AB - Neuropsychiatric symptoms and mental illness are commonly present in patients with chronic systemic diseases. Mood disorders, such as depression, are present in up to 50% of these patients, resulting in impaired physical recovery and more intricate treatment regimen. Stress associated with both physical and emotional aspects of systemic illness is thought to elicit detrimental effects to initiate comorbid mental disorders. However, clinical reports also indicate that the relationship between systemic and psychiatric illnesses is bidirectional, further increasing the complexity of the underlying pathophysiological processes. In this review, we discuss the recent evidence linking chronic stress and systemic illness, such as activation of the immune response system and release of common proinflammatory mediators. Altogether, discovery of new targets is needed for development of better treatments for stress-related psychiatric illnesses as well as improvement of mental health aspects of different systemic diseases. PMID- 26977331 TI - Video Assisted Thoracoscopic Surgical Enucleation of a Giant Esophageal Leiomyoma Presenting with Persistent Cough. AB - Esophageal leiomyoma is a relatively rare tumor of esophagus but it is the most common benign neoplasm of the esophagus. Small esophageal leiomyoma can be observed but larger ones and those producing symptoms should be excised. As observed for other esophageal tumors, dysphagia is its main symptom. Traditionally, open thoracotomy and enucleation are its main treatment but in the last few years video assisted thoracoscopic surgical (VATS) enucleation is gaining recognition with proven advantages of minimally invasive surgery. Herein we present our experience with patient presenting with cough rather than dysphagia as a main symptom, who was diagnosed to be having giant esophageal leiomyoma. VATS guided enucleation was accomplished successfully. Size of lesion was 16 * 4 * 3 cm. Postoperative recovery was uneventful and patient is not having any signs of recurrence, after three years during follow-up period. PMID- 26977333 TI - Medical Students' Perceptions of Dementia after Participation in Poetry Workshop with People with Dementia. AB - Purpose. Researchers assessed whether medical students' participation in a poetry workshop with people with Alzheimer's disease and related dementias (ADRD) affected their attitudes towards persons with ADRD. Objective. To add to the growing body of research summarizing the impact of nonclinical interventions on medical students' perspectives about people with ADRD. Design. Researchers used dementia attitudes scale (DAS) and interpretive phenomenological analysis (IPA) to analyze participants' attitudes. Setting. Osteopathic medical school and dementia care unit in the state of New Jersey. Participants. Eleven out of fourteen medical students completed the study. Measurements. Emerging themes were classified from the postintervention semistructured interviews and descriptive statistics were used to compare the preintervention to postintervention DAS. Results. Researchers found statistically significant differences between preintervention and postintervention DAS scores. Study participants scored a preintervention DAS mean, 107.09 (SD = 11.85), that changed positively and significantly to the postintervention DAS mean, 121.82 (SD = 10.38). DAS subdomains, "comfort" (P = 0.002) and "knowledge" (P = 0.01), and eleven of the twenty DAS items underwent a positive and statistically significant shift from preintervention to postintervention. IPA of the interviews yielded five primary and five secondary themes, supporting the measured statistical outcomes. Conclusion. Medical students' participation in a poetry workshop, with people with ADRD, positively impacts their attitudes. PMID- 26977332 TI - Hematospermia and Cloacogenic Transitional Cell Carcinoma: A Twist on Significance and Meaning. AB - A 52-year-old gentleman presented with recurrent hematospermia. Further history revealed recent onset of constipation and difficulty voiding. Rectal examination revealed a firm, polypoid mass and colonoscopy showed suspicious, ulcerated lesions of the rectal mucosa with narrowing of the rectal vault. Pathology demonstrated transitional cell carcinoma of the rectum. While transitional cell carcinoma is a common genitourinary cancer, its presence in the anus and rectum is exceedingly rare. Furthermore, hematospermia is generally not associated with malignancy. This case is a remarkable example of two pathologic processes presenting in rare form and underscores the value of a thorough investigation of hematospermia when associated with other clinical symptoms. PMID- 26977334 TI - Blindfolded Balance Training in Patients with Parkinson's Disease: A Sensory Motor Strategy to Improve the Gait. AB - Aim. Recent evidence suggested that the use of treadmill training may improve gait parameters. Visual deprivation could engage alternative sensory strategies to control dynamic equilibrium and stabilize gait based on vestibulospinal reflexes (VSR). We aimed to investigate the efficacy of a blindfolded balance training (BBT) in the improvement of stride phase percentage reliable gait parameters in patients with Parkinson's Disease (PD) compared to patients treated with standard physical therapy (PT). Methods. Thirty PD patients were randomized in two groups of 15 patients, one group treated with BBT during two weeks and another group treated with standard PT during eight weeks. We evaluated gait parameters before and after BBT and PT interventions, in terms of double stance, swing, and stance phase percentage. Results. BBT induced an improvement of double stance phase as revealed (decreased percentage of double stance phase during the gait cycle) in comparison to PT. The other gait parameters swing and stance phase did not differ between the two groups. Discussion. These results support the introduction of complementary rehabilitative strategies based on sensory-motor stimulation in the traditional PD patient's rehabilitation. Further studies are needed to investigate the neurophysiological circuits and mechanism underlying clinical and motor modifications. PMID- 26977335 TI - Determining Proportion of Exfoliative Vaginal Cell during Various Stages of Estrus Cycle Using Vaginal Cytology Techniques in Aceh Cattle. AB - The aim of this study was to investigate the period of estrus cycle in aceh cattle, Indonesia, based on vaginal cytology techniques. Four healthy females of aceh cattle with average weight of 250-300 kg, age of 5-7 years, and body condition score of 3-4 were used. All cattle were subjected to ultrasonography analysis for the occurrence of corpus luteum before being synchronized using intramuscular injections of PGF2 alpha 25 mg. A vaginal swab was collected from aceh cattle, stained with Giemsa 10%, and observed microscopically. Period of estrus cycle was predicted from day 1 to day 24 after estrus synchronization was confirmed using ultrasonography analysis at the same day. The result showed that parabasal, intermediary, and superficial epithelium were found in the vaginal swabs collected from proestrus, metestrus, and diestrus aceh cattle. Proportions of these cells in the particular period of estrus cycle were 36.22, 32.62, and 31.16 (proestrus); 21.33, 32.58, and 46.09 (estrus); 40.75, 37.58, and 21.67 (metestrus); and 41.07, 37.38, and 21.67 (diestrus), respectively. In conclusion, dominant proportion of superficial cell that occurred in estrus period might be used as the base for determining optimal time for insemination. PMID- 26977336 TI - Investigation of middle ear anatomy and function with combined video otoscopy phase sensitive OCT. AB - We report the development of a novel otoscopy probe for assessing middle ear anatomy and function. Video imaging and phase-sensitive optical coherence tomography are combined within the same optical path. A sound stimuli channel is incorporated as well to study middle ear function. Thus, besides visualizing the morphology of the middle ear, the vibration amplitude and frequency of the eardrum and ossicles are retrieved as well. Preliminary testing on cadaveric human temporal bone models has demonstrated the capability of this instrument for retrieving middle ear anatomy with micron scale resolution, as well as the vibration of the tympanic membrane and ossicles with sub-nm resolution. PMID- 26977337 TI - Miniature in vivo MEMS-based line-scanned dual-axis confocal microscope for point of-care pathology. AB - There is a need for miniature optical-sectioning microscopes to enable in vivo interrogation of tissues as a real-time and noninvasive alternative to gold standard histopathology. Such devices could have a transformative impact for the early detection of cancer as well as for guiding tumor-resection procedures. Miniature confocal microscopes have been developed by various researchers and corporations to enable optical sectioning of highly scattering tissues, all of which have necessitated various trade-offs in size, speed, depth selectivity, field of view, resolution, image contrast, and sensitivity. In this study, a miniature line-scanned (LS) dual-axis confocal (DAC) microscope, with a 12-mm diameter distal tip, has been developed for clinical point-of-care pathology. The dual-axis architecture has demonstrated an advantage over the conventional single axis confocal configuration for reducing background noise from out-of-focus and multiply scattered light. The use of line scanning enables fast frame rates (16 frames/sec is demonstrated here, but faster rates are possible), which mitigates motion artifacts of a hand-held device during clinical use. We have developed a method to actively align the illumination and collection beams in a DAC microscope through the use of a pair of rotatable alignment mirrors. Incorporation of a custom objective lens, with a small form factor for in vivo clinical use, enables our device to achieve an optical-sectioning thickness and lateral resolution of 2.0 and 1.1 microns respectively. Validation measurements with reflective targets, as well as in vivo and ex vivo images of tissues, demonstrate the clinical potential of this high-speed optical-sectioning microscopy device. PMID- 26977338 TI - Effect of a thin superficial layer on the estimate of hemodynamic changes in a two-layer medium by time domain NIRS. AB - In order to study hemodynamic changes involved in muscular metabolism by means of time domain fNIRS, we need to discriminate in the measured signal contributions coming from different depths. Muscles are, in fact, typically located under other tissues, e.g. skin and fat. In this paper, we study the possibility to exploit a previously proposed method for analyzing time-resolved fNIRS measurements in a two-layer structure with a thin superficial layer. This method is based on the calculation of the time-dependent mean partial pathlengths. We validated it by simulating venous and arterial arm cuff occlusions and then applied it on in vivo measurements. PMID- 26977339 TI - Toward in vivo biopsy of melanoma based on photoacoustic and ultrasound dual imaging with an integrated detector. AB - Melanoma is the most dangerous type of skin cancer with high lethal rate. Tumor thickness and tumor-associated vasculature are two key parameters for staging melanoma. Previous techniques for diagnosing melanoma have insurmountable restrictions, such as invasive, low specificity, or inaccurate depth measurement. Here we develop an integrated photoacoustic (PA) and ultrasound (US) imaging system dedicated to overcome these limitations. An integrated detector with sound light coaxial/confocal design and flexible coupling mode is employed for the combined PA/US imaging strategy. PA imaging results enable a clear characterization of tumor angiogenesis with high resolution and high contrast. Furthermore, accurate thickness measurements of melanoma in different stages can be resolved with the simultaneously obtained PA/US image. Phantom experiments and in vivo animal experimental results demonstrate the integrated PA/US system could provide potential for noninvasive biopsy of melanoma. PMID- 26977340 TI - Total retinal blood flow measurement by three beam Doppler optical coherence tomography. AB - We present measurements of total retinal blood flow in healthy volunteers using a three beam Doppler optical coherence tomography (D-OCT) technique. This technology has the advantage of a precise determination of the flow vector without the use of any a-priori information on the vessel geometry. Circular D OCT scans around the optic disc were recorded and venous as well as arterial total blood flow was determined and compared for each subject. The reproducibility of the method was assessed in 6 subjects by repeated measurements. Only small deviations of around 6% between the measurements were found which indicates the high precision of the proposed method. PMID- 26977341 TI - Visualization of podocyte substructure with structured illumination microscopy (SIM): a new approach to nephrotic disease. AB - A detailed microscopic analysis of renal podocyte substructure is essential to understand and diagnose nephrotic kidney disease. Currently only time consuming electron microscopy (EM) can resolve this substructure. We used structured illumination microscopy (SIM) to examine frozen sections of renal biopsies stained with an immunofluorescence marker for podocin, a protein localized to the perimeter of the podocyte foot processes and compared them with EM in both normal and nephrotic disease biopsies. SIM images of normal glomeruli revealed curvilinear patterns of podocin densely covering capillary walls similar to podocyte foot processes seen by EM. Podocin staining of all nephrotic disease biopsies were significantly different than normal, corresponding to and better visualizing effaced foot processes seen by EM. The findings support the first potential use of SIM in the diagnosis of nephrotic disease. PMID- 26977342 TI - High frame rate photoacoustic imaging at 7000 frames per second using clinical ultrasound system. AB - Photoacoustic tomography, a hybrid imaging modality combining optical and ultrasound imaging, is gaining attention in the field of medical imaging. Typically, a Q-switched Nd:YAG laser is used to excite the tissue and generate photoacoustic signals. But, such photoacoustic imaging systems are difficult to translate into clinical applications owing to their high cost, bulky size often requiring an optical table to house such lasers. Moreover, the low pulse repetition rate of few tens of hertz prevents them from being used in high frame rate photoacoustic imaging. In this work, we have demonstrated up to 7000 Hz photoacoustic imaging (B-mode) and measured the flow rate of a fast moving object. We used a ~140 nanosecond pulsed laser diode as an excitation source and a clinical ultrasound imaging system to capture and display the photoacoustic images. The excitation laser is ~803 nm in wavelength with ~1.4 mJ energy per pulse. So far, the reported 2-dimensional photoacoustic B-scan imaging is only a few tens of frames per second using a clinical ultrasound system. Therefore, this is the first report on 2-dimensional photoacoustic B-scan imaging with 7000 frames per second. We have demonstrated phantom imaging to view and measure the flow rate of ink solution inside a tube. This fast photoacoustic imaging can be useful for various clinical applications including cardiac related problems, where the blood flow rate is quite high, or other dynamic studies. PMID- 26977344 TI - U-shaped, double-tapered, fiber-optic sensor for effective biofilm growth monitoring. AB - To monitor biofilm growth on polydimethylsiloxane in a photobioreactor effectively, the biofilm cells and liquids were separated and measured using a sensor with two U-shaped, double-tapered, fiber-optic probes (Sen. and Ref. probes). The probes' Au-coated hemispherical tips enabled double-pass evanescent field absorption. The Sen. probe sensed the cells and liquids inside the biofilm. The polyimide-silica hybrid-film-coated Ref. probe separated the liquids from the biofilm cells and analyzed the liquid concentration. The biofilm structure and active biomass were also examined to confirm the effectiveness of the measurement using a simulation model. The sensor was found to effectively respond to the biofilm growth in the adsorption through exponential phases at thicknesses of 0 536 MUm. PMID- 26977343 TI - Deep in vivo two-photon microscopy with a low cost custom built mode-locked 1060 nm fiber laser. AB - Here we demonstrate that a mode-locked ytterbium fiber laser for two-photon fluorescence microscopy can be built for $13,000. The laser emits at a wavelength of 1060 nm with a usable average power of 1 W at a repetition rate of 40 MHz and a compressed pulse width of 81 fs at the sample. The laser is used to obtain deep in vivo two-color images of layer-V pyramidal neurons expressing YFP and vasculature labelled with Texas Red at depths up to 900 um. The sub-1 um features of dendritic spines can be resolved at a 200 um depth. PMID- 26977345 TI - Wide field-of-view fluorescence image deconvolution with aberration-estimation from Fourier ptychography. AB - This paper presents a method to simultaneously acquire an aberration-corrected, wide field-of-view fluorescence image and a high-resolution coherent bright-field image using a computational microscopy method. First, the procedure applies Fourier ptychographic microscopy (FPM) to retrieve the amplitude and phase of a sample, at a resolution that significantly exceeds the cutoff spatial frequency of the microscope objective lens. At the same time, redundancy within the set of acquired FPM bright-field images offers a means to estimate microscope aberrations. Second, the procedure acquires an aberrated fluorescence image, and computationally improves its resolution through deconvolution with the estimated aberration map. An experimental demonstration successfully improves the bright field resolution of fixed, stained and fluorescently tagged HeLa cells by a factor of 4.9, and reduces the error caused by aberrations in a fluorescence image by up to 31%, over a field of view of 6.2 mm by 9.3 mm. For optimal deconvolution, we show the fluorescence image needs to have a signal-to-noise ratio of at least ~18. PMID- 26977346 TI - In vivo deconvolution acoustic-resolution photoacoustic microscopy in three dimensions. AB - Acoustic-resolution photoacoustic microscopy (ARPAM) provides a spatial resolution on the order of tens of micrometers, and is becoming an essential tool for imaging fine structures, such as the subcutaneous microvasculature. High lateral resolution of ARPAM is achieved using high numerical aperture (NA) of acoustic transducer; however, the depth of focus and working distance will be deteriorated correspondingly, thus sacrificing the imaging range and accessible depth. The axial resolution of ARPAM is limited by the transducer's bandwidth. In this work, we develop deconvolution ARPAM (D-ARPAM) in three dimensions that can improve the lateral resolution by 1.8 and 3.7 times and the axial resolution by 1.7 and 2.7 times, depending on the adopted criteria, using a 20-MHz focused transducer without physically increasing its NA and bandwidth. The resolution enhancement in three dimensions by D-ARPAM is also demonstrated by in vivo imaging of the microvasculature of a chick embryo. The proposed D-ARPAM has potential for biomedical imaging that simultaneously requires high spatial resolution, extended imaging range, and long accessible depth. PMID- 26977347 TI - Low-dose, phase-contrast mammography with high signal-to-noise ratio. AB - Differential phase-contrast X-ray imaging using a Talbot-Lau interferometer has recently shown promising results for applications in medical imaging. However, reducing the applied radiation dose remains a major challenge. In this study, we consider the realization of a Talbot-Lau interferometer in a high Talbot order to increase the signal-to-noise ratio for low-dose applications. The quantitative performance of pi and pi/2 systems at high Talbot orders is analyzed through simulations, and the design energy and X-ray spectrum are optimized for mammography. It is found that operation even at very high Talbot orders is feasible and beneficial for image quality. As long as the X-ray spectrum is matched to the visibility spectrum, the SNR continuously increases with the Talbot order for pi-systems. We find that the optimal X-ray spectra and design energies are almost independent of the Talbot order and that the overall imaging performance is robust against small variations in these parameters. Discontinuous spectra, such as that from molybdenum, are less robust because the characteristic lines may coincide with minima in the visibility spectra; however, they may offer slightly better performance. We verify this hypothesis by realizing a prototype system with a mean fringe visibility of above 40% at the seventh Talbot order. With this prototype, a proof-of-principle measurement of a freshly dissected breast at reasonable compression to 4 cm is conducted with a mean glandular dose of only 3 mGy but with a high SNR. PMID- 26977348 TI - Spectral imaging using forward-viewing spectrally encoded endoscopy. AB - Spectrally encoded endoscopy (SEE) enables miniature, small-diameter endoscopic probes for minimally invasive imaging; however, using the broadband spectrum to encode space makes color and spectral imaging nontrivial and challenging. By careful registration and analysis of image data acquired by a prototype of a forward-viewing dual channel spectrally encoded rigid probe, we demonstrate spectral and color imaging within a narrow cylindrical lumen. Spectral imaging of calibration cylindrical test targets and an ex-vivo blood vessel demonstrates high-resolution spatial-spectral imaging with short (10 MUs/line) exposure times. PMID- 26977349 TI - Fast interferometric second harmonic generation microscopy. AB - We report the implementation of fast Interferometric Second Harmonic Generation (I-SHG) microscopy to study the polarity of non-centrosymmetric structures in biological tissues. Using a sample quartz plate, we calibrate the spatially varying phase shift introduced by the laser scanning system. Compensating this phase shift allows us to retrieve the correct phase distribution in periodically poled lithium niobate, used as a model sample. Finally, we used fast interferometric second harmonic generation microscopy to acquire phase images in tendon. Our results show that the method exposed here, using a laser scanning system, allows to recover the polarity of collagen fibrils, similarly to standard I-SHG (using a sample scanning system), but with an imaging time about 40 times shorter. PMID- 26977351 TI - Continuing the success of Biomedical Optics Express: editorial. AB - The new Editor-in-Chief and new Deputy Editor share their introductory message. PMID- 26977350 TI - Automated segmentation and characterization of esophageal wall in vivo by tethered capsule optical coherence tomography endomicroscopy. AB - Optical coherence tomography (OCT) is an optical diagnostic modality that can acquire cross-sectional images of the microscopic structure of the esophagus, including Barrett's esophagus (BE) and associated dysplasia. We developed a swallowable tethered capsule OCT endomicroscopy (TCE) device that acquires high resolution images of entire gastrointestinal (GI) tract luminal organs. This device has a potential to become a screening method that identifies patients with an abnormal esophagus that should be further referred for upper endoscopy. Currently, the characterization of the OCT-TCE esophageal wall data set is performed manually, which is time-consuming and inefficient. Additionally, since the capsule optics optimally focus light approximately 500 um outside the capsule wall and the best quality images are obtained when the tissue is in full contact with the capsule, it is crucial to provide feedback for the operator about tissue contact during the imaging procedure. In this study, we developed a fully automated algorithm for the segmentation of in vivo OCT-TCE data sets and characterization of the esophageal wall. The algorithm provides a two-dimensional representation of both the contact map from the data collected in human clinical studies as well as a tissue map depicting areas of BE with or without dysplasia. Results suggest that these techniques can potentially improve the current TCE data acquisition procedure and provide an efficient characterization of the diseased esophageal wall. PMID- 26977352 TI - Frapid: achieving full automation of FRAP for chemical probe validation. AB - Fluorescence Recovery After Photobleaching (FRAP) is an established method for validating chemical probes against the chromatin reading bromodomains, but so far requires constant human supervision. Here, we present Frapid, an automated open source code implementation of FRAP that fully handles cell identification through fuzzy logic analysis, drug dispensing with a custom-built fluid handler, image acquisition & analysis, and reporting. We successfully tested Frapid on 3 bromodomains as well as on spindlin1 (SPIN1), a methyl lysine binder, for the first time. PMID- 26977353 TI - Light controlled drug delivery containers based on spiropyran doped liquid crystal micro spheres. AB - We have developed a novel, light activated drug delivery containers, based on spiropyran doped liquid crystal micro spheres. Upon exposure to UV/violet light, the spiropyran molecules entrapped inside the nematic liquid crystal micro spheres, interconvert from the hydrophobic, oil soluble form, to the hydrophilic, water soluble merocyanine one, which stimulates the translocation of the merocyanine molecules across the nematic liquid crystal-water barrier and results their homogeneous distribution throughout in an aqueous environment. Light controllable switching property and extremely high solubility of spiropyran in the nematic liquid crystal, promise to elaborate a novel and reliable vehicles for the drug delivery systems. PMID- 26977354 TI - Discrimination of healthy and osteoarthritic articular cartilage by Fourier transform infrared imaging and Fisher's discriminant analysis. AB - Fourier transform infrared spectroscopic imaging (FTIRI) technique can be used to obtain the quantitative information of content and spatial distribution of principal components in cartilage by combining with chemometrics methods. In this study, FTIRI combining with principal component analysis (PCA) and Fisher's discriminant analysis (FDA) was applied to identify the healthy and osteoarthritic (OA) articular cartilage samples. Ten 10-MUm thick sections of canine cartilages were imaged at 6.25MUm/pixel in FTIRI. The infrared spectra extracted from the FTIR images were imported into SPSS software for PCA and FDA. Based on the PCA result of 2 principal components, the healthy and OA cartilage samples were effectively discriminated by the FDA with high accuracy of 94% for the initial samples (training set) and cross validation, as well as 86.67% for the prediction group. The study showed that cartilage degeneration became gradually weak with the increase of the depth. FTIRI combined with chemometrics may become an effective method for distinguishing healthy and OA cartilages in future. PMID- 26977355 TI - Assessing the imaging performance of light sheet microscopies in highly scattering tissues. AB - Light sheet microscopy (LSM) has emerged as an optical-imaging method for high spatiotemporal volumetric imaging of relatively transparent samples. While this capability has allowed the technique to be highly impactful in fields such as developmental biology, applications involving highly scattering thick tissues have been largely unexplored. Herein, we employ Monte Carlo simulations to explore the use of LSM for imaging turbid media. In particular, due to its similarity to dual-axis confocal (DAC) microscopy, we compare LSM performance to point-scanned (PS-DAC) and line-scanned (LS-DAC) dual-axis confocal microscopy techniques that have been previously shown to produce high-quality images at round-trip optical lengths of ~9 - 10 and ~3 - 4 respectively. The results of this study indicate that LSM using widefield collection (WF-LSM) provides comparable performance to LS-DAC in thick tissues, due to the fact that they both utilize an illumination beam focused in one dimension (i.e. a line or sheet). On the other hand, LSM using confocal line detection (CL-LSM) is more analogous to PS-DAC microscopy, in which the illumination beam is focused in two dimensions to a point. The imaging depth of LSM is only slightly inferior to DAC (~2 - 3 and ~6 - 7 optical lengths for WF-LSM and CL-LSM respectively) due to the use of a lower numerical aperture (NA) illumination beam for extended imaging along the illumination axis. Therefore, we conclude that the ability to image deeply is dictated most by the confocality of the microscope technique. In addition, we find that imaging resolution is mostly dependent on the collection NA, and is relatively invariant to imaging depth in a homogeneous scattering medium. Our results indicate that superficial imaging of highly scattering tissues using light sheet microscopy is possible. PMID- 26977356 TI - Model-free uncertainty estimation in stochastical optical fluctuation imaging (SOFI) leads to a doubled temporal resolution. AB - Stochastic optical fluctuation imaging (SOFI) is a super-resolution fluorescence imaging technique that makes use of stochastic fluctuations in the emission of the fluorophores. During a SOFI measurement multiple fluorescence images are acquired from the sample, followed by the calculation of the spatiotemporal cumulants of the intensities observed at each position. Compared to other techniques, SOFI works well under conditions of low signal-to-noise, high background, or high emitter densities. However, it can be difficult to unambiguously determine the reliability of images produced by any superresolution imaging technique. In this work we present a strategy that enables the estimation of the variance or uncertainty associated with each pixel in the SOFI image. In addition to estimating the image quality or reliability, we show that this can be used to optimize the signal-to-noise ratio (SNR) of SOFI images by including multiple pixel combinations in the cumulant calculation. We present an algorithm to perform this optimization, which automatically takes all relevant instrumental, sample, and probe parameters into account. Depending on the optical magnification of the system, this strategy can be used to improve the SNR of a SOFI image by 40% to 90%. This gain in information is entirely free, in the sense that it does not require additional efforts or complications. Alternatively our approach can be applied to reduce the number of fluorescence images to meet a particular quality level by about 30% to 50%, strongly improving the temporal resolution of SOFI imaging. PMID- 26977358 TI - Lock-in-photon-counting-based highly-sensitive and large-dynamic imaging system for continuous-wave diffuse optical tomography. AB - We implemented a novel lock-in photon-counting detection architecture that combines the ultra-high sensitivity of the photon-counting detection and the measurement parallelism of the lock-in technique. Based on this technique, a dual wavelength simultaneous measurement continuous wave diffuse optical tomography system was developed with a configuration of 16 sources and 16 detectors that works in a tandem serial-to-parallel fashion. Methodology validation and performance assessment of the system were conducted using phantom experiments that demonstrate excellent measurement linearity, moderate-term system stability, robustness to noise and negligible inter-wavelength crosstalk. 2-D imaging experiments further validate high sensitivity of the lock-in photon-counting methodology as well as high reliability of the proposed system. The advanced detection principle can be adapted to achieving a fully parallelized instrumentation for the extended applications. PMID- 26977357 TI - Scanning, non-contact, hybrid broadband diffuse optical spectroscopy and diffuse correlation spectroscopy system. AB - A scanning system for small animal imaging using non-contact, hybrid broadband diffuse optical spectroscopy (ncDOS) and diffuse correlation spectroscopy (ncDCS) is presented. The ncDOS uses a two-dimensional spectrophotometer retrieving broadband (610-900 nm) spectral information from up to fifty-seven source detector distances between 2 and 5 mm. The ncDCS data is simultaneously acquired from four source-detector pairs. The sample is scanned in two dimensions while tracking variations in height. The system has been validated with liquid phantoms, demonstrated in vivo on a human fingertip during an arm cuff occlusion and on a group of mice with xenoimplanted renal cell carcinoma. PMID- 26977359 TI - Dynamics of cell and tissue growth acquired by means of extended field of view lensfree microscopy. AB - In this paper, we discuss a new methodology based on lensfree imaging to perform wound healing assay with unprecedented statistics. Our video lensfree microscopy setup is a simple device featuring only a CMOS sensor and a semi coherent illumination system. Yet it is a powerful mean for the real-time monitoring of cultivated cells. It presents several key advantages, e.g. integration into standard incubator, compatibility with standard cell culture protocol, simplicity and ease of use. It can perform the follow-up in a large field of view (25 mm(2)) of several crucial parameters during the culture of cells i.e. their motility, their proliferation rate or their death. Consequently the setup can gather large statistics both in space and time. Here we uses this facility in the context of wound healing assay to perform label-free measurements of the velocities of the fronts of proliferation of the cell layer as a function of time by means of particle image velocimetry (PIV) processing. However, for such tissue growth experiments, the field of view of 25 mm(2) remains not sufficient and results can be biased depending on the position of the device with respect to the recipient of the cell culture. Hence, to conduct exhaustive wound healing assays, we propose to enlarge the field of view up to 10 cm(2) through a raster scan, by moving the source/sensor with respect to the Petri dish. We have performed acquisitions of wound healing assay (keratinocytes HaCaT) both in real-time (25 mm(2)) and in final point (10 cm(2)) to assess the combination of velocimetry measurements and final point wide field imaging. In the future, we aim at combining directly our extended field of view acquisitions (>10 cm(2)) with real time ability inside the incubator. PMID- 26977361 TI - Toward reliable retrieval of functional information of papillary dermis using spatially resolved diffuse reflectance spectroscopy. AB - Spatially resolved diffuse reflectance spectroscopy (SRDRS) has been employed to quantify tissue optical properties and its interrogation volume is majorly controlled by the source-to-detector separations (SDSs). To noninvasively quantify properties of dermis, a SRDRS setup that includes SDS shorter than 1 mm is required. It will be demonstrated in this study that Monte Carlo simulations employing the Henyey-Greenstein phase function cannot always precisely predict experimentally measured diffuse reflectance at such short SDSs, and we speculated this could be caused by the non-negligible backward light scattering at short SDSs that cannot be properly modeled by the Henyey-Greenstein phase function. To accurately recover the optical properties and functional information of dermis using SRDRS, we proposed the use of the modified two-layer (MTL) geometry. Monte Carlo simulations and phantom experiment results revealed that the MTL probing geometry was capable of faithfully recovering the optical properties of upper dermis. The capability of the MTL geometry in probing the upper dermis properties was further verified through a swine study, and it was found that the measurement results were reasonably linked to histological findings. Finally, the MTL probe was utilized to study psoriatic lesions. Our results showed that the MTL probe was sensitive to the physiological condition of tissue volumes within the papillary dermis and could be used in studying the physiology of psoriasis. PMID- 26977360 TI - Functional second harmonic generation microscopy probes molecular dynamics with high temporal resolution. AB - Second harmonic generation (SHG) microscopy is a powerful tool for label free ex vivo or in vivo imaging, widely used to investigate structure and organization of endogenous SHG emitting proteins such as myosin or collagen. Polarization resolved SHG microscopy renders supplementary information and is used to probe different molecular states. This development towards functional SHG microscopy is calling for new methods for high speed functional imaging of dynamic processes. In this work we present two approaches with linear polarized light and demonstrate high speed line scan measurements of the molecular dynamics of the motor protein myosin with a time resolution of 1 ms in mammalian muscle cells. Such a high speed functional SHG microscopy has high potential to deliver new insights into structural and temporal molecular dynamics under ex vivo or in vivo conditions. PMID- 26977362 TI - Second harmonic generation double stokes Mueller polarimetric microscopy of myofilaments. AB - The experimental implementation of double Stokes Mueller polarimetric microscopy is presented. This technique enables a model-independent and complete polarimetric characterization of second harmonic generating samples using 36 Stokes parameter measurements at different combinations of incoming and outgoing polarizations. The degree of second harmonic polarization and the molecular nonlinear susceptibility ratio are extracted for individual focal volumes of a fruit fly larva wall muscle. PMID- 26977363 TI - Early detection and differentiation of venous and arterial occlusion in skin flaps using visible diffuse reflectance spectroscopy and autofluorescence spectroscopy. AB - Our previous preclinical study demonstrated that both visible diffuse reflectance and autofluorescence spectroscopy, each of which yields a different set of physiological information, can predict skin flap viability with high accuracy in a MacFarlane rat dorsal skin flap model. In this report, we further evaluated our technique for the early detection and differentiation of venous occlusion and arterial occlusion in a rat groin flap model. We performed both diffuse reflectance and autofluorescence measurements on the skin flap model and statistically differentiated between flaps with and without occlusions as well as between flaps with venous occlusion and those with arterial occlusion based on these non-invasive optical measurements. Our preliminary results suggested that visible diffuse reflectance and autofluorescence spectroscopy can be potentially used clinically to detect both venous and arterial occlusion and differentiate one from the other accurately at an early time point. PMID- 26977364 TI - Automated geographic atrophy segmentation for SD-OCT images using region-based C V model via local similarity factor. AB - Age-related macular degeneration (AMD) is the leading cause of blindness among elderly individuals. Geographic atrophy (GA) is a phenotypic manifestation of the advanced stages of non-exudative AMD. Determination of GA extent in SD-OCT scans allows the quantification of GA-related features, such as radius or area, which could be of important value to monitor AMD progression and possibly identify regions of future GA involvement. The purpose of this work is to develop an automated algorithm to segment GA regions in SD-OCT images. An en face GA fundus image is generated by averaging the axial intensity within an automatically detected sub-volume of the three dimensional SD-OCT data, where an initial coarse GA region is estimated by an iterative threshold segmentation method and an intensity profile set, and subsequently refined by a region-based Chan-Vese model with a local similarity factor. Two image data sets, consisting on 55 SD-OCT scans from twelve eyes in eight patients with GA and 56 SD-OCT scans from 56 eyes in 56 patients with GA, respectively, were utilized to quantitatively evaluate the automated segmentation algorithm. We compared results obtained by the proposed algorithm, manual segmentation by graders, a previously proposed method, and experimental commercial software. When compared to a manually determined gold standard, our algorithm presented a mean overlap ratio (OR) of 81.86% and 70% for the first and second data sets, respectively, while the previously proposed method OR was 72.60% and 65.88% for the first and second data sets, respectively, and the experimental commercial software OR was 62.40% for the second data set. PMID- 26977365 TI - Fully distributed absolute blood flow velocity measurement for middle cerebral arteries using Doppler optical coherence tomography. AB - Doppler optical coherence tomography (DOCT) is considered one of the most promising functional imaging modalities for neuro biology research and has demonstrated the ability to quantify cerebral blood flow velocity at a high accuracy. However, the measurement of total absolute blood flow velocity (BFV) of major cerebral arteries is still a difficult problem since it is related to vessel geometry. In this paper, we present a volumetric vessel reconstruction approach that is capable of measuring the absolute BFV distributed along the entire middle cerebral artery (MCA) within a large field-of-view. The Doppler angle at each point of the MCA, representing the vessel geometry, is derived analytically by localizing the artery from pure DOCT images through vessel segmentation and skeletonization. Our approach could achieve automatic quantification of the fully distributed absolute BFV across different vessel branches. Experiments on rodents using swept-source optical coherence tomography showed that our approach was able to reveal the consequences of permanent MCA occlusion with absolute BFV measurement. PMID- 26977366 TI - Portable handheld diffuse reflectance spectroscopy system for clinical evaluation of skin: a pilot study in psoriasis patients. AB - Diffuse reflectance spectroscopy (DRS) has been utilized to study biological tissues for a variety of applications. However, many DRS systems are not designed for handheld use and/or relatively expensive which limit the extensive clinical use of this technique. In this paper, we report a handheld, low-cost DRS system consisting of a light source, optical switch, and a spectrometer, that can precisely quantify the optical properties of tissue samples in the clinical setting. The handheld DRS system was employed to determine the skin chromophore concentrations, absorption and scattering properties of 11 patients with psoriasis. The measurement results were compared to the clinical severity of psoriasis as evaluated by dermatologist using PASI (Psoriasis Area and Severity Index) scores. Our statistical analyses indicated that the handheld DRS system could be a useful non-invasive tool for objective evaluation of the severity of psoriasis. It is expected that the handheld system can be used for the objective evaluation and monitoring of various skin diseases such as keloid and psoriasis. PMID- 26977368 TI - Erratum: 0.5 gigapixel microscopy using a flatbed scanner: erratum. AB - When one uses USAF target to calibrate the resolution of an imaging system, the periodicity of the smallest resolvable line should be used to define the limit. However, in the original paper, the line width of the resolution target was used to characterize the resolution of our microscope system, resulting in an overestimation of the performance of the imaging system. In this erratum, we correct the parts that state incorrect resolution and also re-evaluate the performance of our micoscope.[This corrects the article on p. 1 in vol. 5, PMID: 24466471.]. PMID- 26977367 TI - Tissue thickness calculation in ocular optical coherence tomography. AB - Thickness measurements derived from optical coherence tomography (OCT) images of the eye are a fundamental clinical and research metric, since they provide valuable information regarding the eye's anatomical and physiological characteristics, and can assist in the diagnosis and monitoring of numerous ocular conditions. Despite the importance of these measurements, limited attention has been given to the methods used to estimate thickness in OCT images of the eye. Most current studies employing OCT use an axial thickness metric, but there is evidence that axial thickness measures may be biased by tilt and curvature of the image. In this paper, standard axial thickness calculations are compared with a variety of alternative metrics for estimating tissue thickness. These methods were tested on a data set of wide-field chorio-retinal OCT scans (field of view (FOV) 60 degrees x 25 degrees ) to examine their performance across a wide region of interest and to demonstrate the potential effect of curvature of the posterior segment of the eye on the thickness estimates. Similarly, the effect of image tilt was systematically examined with the same range of proposed metrics. The results demonstrate that image tilt and curvature of the posterior segment can affect axial tissue thickness calculations, while alternative metrics, which are not biased by these effects, should be considered. This study demonstrates the need to consider alternative methods to calculate tissue thickness in order to avoid measurement error due to image tilt and curvature. PMID- 26977369 TI - Multimodal 3D cancer-mimicking optical phantom. AB - Three-dimensional (3D) organ-mimicking phantoms provide realistic imaging environments for testing various aspects of optical systems, including for evaluating new probe designs, characterizing the diagnostic potential of new technologies, and assessing novel image processing algorithms prior to validation in real tissue. We introduce and characterize the use of a new material, Dragon Skin (Smooth-On Inc.), and fabrication technique, air-brushing, for fabrication of a 3D phantom that mimics the appearance of a real organ under multiple imaging modalities. We demonstrate the utility of the material and technique by fabricating the first 3D, hollow bladder phantom with realistic normal and multi stage pathology features suitable for endoscopic detection using the gold standard imaging technique, white light cystoscopy (WLC), as well as the complementary imaging modalities of optical coherence tomography and blue light cystoscopy, which are aimed at improving the sensitivity and specificity of WLC to bladder cancer detection. The flexibility of the material and technique used for phantom construction allowed for the representation of a wide range of diseased tissue states, ranging from inflammation (benign) to high-grade cancerous lesions. Such phantoms can serve as important tools for trainee education and evaluation of new endoscopic instrumentation. PMID- 26977370 TI - In vivo imaging of retinal hemodynamics with OCT angiography and Doppler OCT. AB - Retinal hemodynamics is important for early diagnosis and precise monitoring in retinal vascular diseases. We propose a novel method for measuring absolute retinal blood flow in vivo using the combined techniques of optical coherence tomography (OCT) angiography and Doppler OCT. Doppler values can be corrected by Doppler angles extracted from OCT angiography images. A three-dimensional (3D) segmentation algorithm based on dynamic programming was developed to extract the 3D boundaries of optic disc vessels, and Doppler angles were calculated from 3D vessel geometry. The accuracy of blood flow from the Doppler OCT was validated using a flow phantom. The feasibility of the method was tested on a subject in vivo. The pulsatile retinal blood flow and the parameters for retinal hemodynamics were successfully obtained. PMID- 26977371 TI - Comparison of reflectance confocal microscopy and two-photon second harmonic generation microscopy in fungal keratitis rabbit model ex vivo. AB - Fungal keratitis is an infection of the cornea by fungal pathogens. Diagnosis methods based on optical microscopy could be beneficial over the conventional microbiology method by allowing rapid and non-invasive examination. Reflectance confocal microscopy (RCM) and two-photon second harmonic generation microscopy (TPSHGM) have been applied to pre-clinical or clinical studies of fungal keratitis. In this report, RCM and TPSHGM were characterized and compared in the imaging of a fungal keratitis rabbit model ex vivo. Fungal infection was induced by using two strains of fungi: aspergillus fumigatus and candida albicans. The infected corneas were imaged in fresh condition by both modalities sequentially and their images were analyzed. Both RCM and TPSHGM could detect both fungal strains within the cornea based on morphology: aspergillus fumigatus had distinctive filamentous structures, and candida albicans had round structures superficially and elongated structures in the corneal stroma. These imaging results were confirmed by histology. Comparison between RCM and TPSHGM showed several characteristics. Although RCM and TPSHGM images had good correlation each other, their images were slightly different due to difference in contrast mechanism. RCM had relatively low image contrast with the infected turbid corneas due to high background signal. TPSHGM visualized cells and collagen in the cornea clearly compared to RCM, but used higher laser power to compensate low autofluorescence. Since these two modalities provide complementary information, combination of RCM and TPSHGM would be useful for fungal keratitis detection by compensating their weaknesses each other. PMID- 26977372 TI - Quantitative optical coherence elastography based on fiber-optic probe for in situ measurement of tissue mechanical properties. AB - We developed a miniature quantitative optical coherence elastography (qOCE) instrument with an integrated Fabry-Perot force sensor, for in situ elasticity measurement of biological tissue. The technique has great potential for biomechanics modeling and clinical diagnosis. We designed the fiber-optic qOCE probe that was used to exert a compressive force to deform tissue at the tip of the probe. Using the space-division multiplexed optical coherence tomography (OCT) signal detected by a spectral domain OCT engine, we were able to quantify the probe deformation that was proportional to the force applied, and to quantify the tissue deformation corresponding to the external stimulus. Simultaneous measurement of force and displacement allowed us to extract Young's modulus of biological tissue. We experimentally calibrated our qOCE instrument, and validated its effectiveness on tissue mimicking phantoms and biological tissues. PMID- 26977373 TI - Hollow optical-fiber based infrared spectroscopy for measurement of blood glucose level by using multi-reflection prism. AB - A mid-infrared attenuated total reflection (ATR) spectroscopy system employing hollow optical fibers and a trapezoidal multi-reflection ATR prism has been developed to measure blood glucose levels. Using a multi-reflection prism brought about higher sensitivity, and the flat and wide contact surface of the prism resulted in higher measurement reproducibility. An analysis of in vivo measurements of human inner lip mucosa revealed clear signatures of glucose in the difference spectra between ones taken during the fasting state and ones taken after ingestion of glucose solutions. A calibration plot based on the absorption peak at 1155 cm(-1) that originates from the pyranose ring structure of glucose gave measurement errors less than 20%. PMID- 26977374 TI - Comparing and Contrasting Consensus versus Empirical Domains. AB - BACKGROUND: Since the publication of the CFS case definition [1], there have been a number of other criteria proposed including the Canadian Consensus Criteria [2] and the Myalgic Encephalomyelitis: International Consensus Criteria. [3]. PURPOSE: The current study compared these domains that were developed through consensus methods to one obtained through more empirical approaches using factor analysis. METHODS: Using data mining, we compared and contrasted fundamental features of consensus-based criteria versus empirical latent factors. In general, these approaches found the domain of Fatigue/Post-exertional malaise as best differentiating patients from controls. RESULTS: Findings indicated that the Fukuda et al. criteria had the worst sensitivity and specificity. CONCLUSIONS: These outcomes might help both theorists and researchers better determine which fundamental domains to be used for the case definition. PMID- 26977375 TI - Molecular evidence for sediment nitrogen fixation in a temperate New England estuary. AB - Primary production in coastal waters is generally nitrogen (N) limited with denitrification outpacing nitrogen fixation (N2-fixation). However, recent work suggests that we have potentially underestimated the importance of heterotrophic sediment N2-fixation in marine ecosystems. We used clone libraries to examine transcript diversity of nifH (a gene associated with N2-fixation) in sediments at three sites in a temperate New England estuary (Waquoit Bay, Massachusetts, USA) and compared our results to net sediment N2 fluxes previously measured at these sites. We observed nifH expression at all sites, including a site heavily impacted by anthropogenic N. At this N impacted site, we also observed mean net sediment N2-fixation, linking the geochemical rate measurement with nifH expression. This same site also had the lowest diversity (non-parametric Shannon = 2.75). At the two other sites, we also detected nifH transcripts, however, the mean N2 flux indicated net denitrification. These results suggest that N2 fixation and denitrification co-occur in these sediments. Of the unique sequences in this study, 67% were most closely related to uncultured bacteria from various marine environments, 17% to Cluster III, 15% to Cluster I, and only 1% to Cluster II. These data add to the growing body of literature that sediment heterotrophic N2-fixation, even under high inorganic nitrogen concentrations, may be an important yet overlooked source of N in coastal systems. PMID- 26977376 TI - Effects of personal relevance and simulated darkness on the affective appraisal of a virtual environment. AB - This study investigated whether personal relevance influences the affective appraisal of a desktop virtual environment (VE) in simulated darkness. In the real world, darkness often evokes thoughts of vulnerability, threat, and danger, and may automatically precipitate emotional responses consonant with those thoughts (fear of darkness). This influences the affective appraisal of a given environment after dark and the way humans behave in that environment in conditions of low lighting. Desktop VEs are increasingly deployed to study the effects of environmental qualities and (architectural or lighting) interventions on human behaviour and feelings of safety. Their (ecological) validity for these purposes depends critically on their ability to correctly address the user's cognitive and affective experience. Previous studies with desktop (i.e., non immersive) VEs found that simulated darkness only slightly affects the user's behavioral and emotional responses to the represented environment, in contrast to the responses observed for immersive VEs. We hypothesize that the desktop VE scenarios used in previous studies less effectively induced emotional and behavioral responses because they lacked personal relevance. In addition, factors like signs of social presence and relatively high levels of ambient lighting may also have limited these responses. In this study, young female volunteers explored either a daytime or a night-time (low ambient light level) version of a desktop VE representing a deserted (no social presence) prototypical Dutch polder landscape. To enhance the personal relevance of the simulation, a fraction of the participants were led to believe that the virtual exploration tour would prepare them for a follow-up tour through the real world counterpart of the VE. The affective appraisal of the VE and the emotional response of the participants were measured through self-report. The results show that the VE was appraised as slightly less pleasant and more arousing in simulated darkness (compared to a daylight) condition, as expected. However, the fictitious follow-up assignment had no emotional effects and did not influence the affective appraisal of the VE. Further research is required to establish the qualities that may enhance the validity of desktop VEs for both etiological (e.g., the effects of signs of darkness on navigation behaviour and fear of crime) and intervention (e.g., effects of street lighting on feelings of safety) research. PMID- 26977377 TI - 3D solid supported inter-polyelectrolyte complexes obtained by the alternate deposition of poly(diallyldimethylammonium chloride) and poly(sodium 4 styrenesulfonate). AB - This work addresses the formation and the internal morphology of polyelectrolyte layers obtained by the layer-by-layer method. A multimodal characterization showed the absence of stratification of the films formed by the alternate deposition of poly(diallyldimethylammonium chloride) and poly(sodium 4 styrenesulfonate). Indeed the final organization might be regarded as three dimensional solid-supported inter-polyelectrolyte films. The growth mechanism of the multilayers, followed using a quartz crystal microbalance, evidences two different growth trends, which show a dependency on the ionic strength due to its influence onto the polymer conformation. The hydration state does not modify the multilayer growth, but it contributes to the total adsorbed mass of the film. The water associated with the polyelectrolyte films leads to their swelling and plastification. The use of X-ray photoelectron spectroscopy has allowed for deeper insights on the internal structure and composition of the polyelectrolyte multilayers. PMID- 26977378 TI - Characterisation of thin films of graphene-surfactant composites produced through a novel semi-automated method. AB - In this paper we detail a novel semi-automated method for the production of graphene by sonochemical exfoliation of graphite in the presence of ionic surfactants, e.g., sodium dodecyl sulfate (SDS) and cetyltrimethylammonium bromide (CTAB). The formation of individual graphene flakes was confirmed by Raman spectroscopy, while the interaction of graphene with surfactants was proven by NMR spectroscopy. The resulting graphene-surfactant composite material formed a stable suspension in water and some organic solvents, such as chloroform. Graphene thin films were then produced using Langmuir-Blodgett (LB) or electrostatic layer-by-layer (LbL) deposition techniques. The composition and morphology of the films produced was studied with SEM/EDX and AFM. The best results in terms of adhesion and surface coverage were achieved using LbL deposition of graphene(-)SDS alternated with polyethyleneimine (PEI). The optical study of graphene thin films deposited on different substrates was carried out using UV-vis absorption spectroscopy and spectroscopic ellipsometry. A particular focus was on studying graphene layers deposited on gold-coated glass using a method of total internal reflection ellipsometry (TIRE) which revealed the enhancement of the surface plasmon resonance in thin gold films by depositing graphene layers. PMID- 26977380 TI - Plasticity-mediated collapse and recrystallization in hollow copper nanowires: a molecular dynamics simulation. AB - We study the thermal stability of hollow copper nanowires using molecular dynamics simulation. We find that the plasticity-mediated structural evolution leads to transformation of the initial hollow structure to a solid wire. The process involves three distinct stages, namely, collapse, recrystallization and slow recovery. We calculate the time scales associated with different stages of the evolution process. Our findings suggest a plasticity-mediated mechanism of collapse and recrystallization. This contradicts the prevailing notion of diffusion driven transport of vacancies from the interior to outer surface being responsible for collapse, which would involve much longer time scales as compared to the plasticity-based mechanism. PMID- 26977379 TI - Mismatch detection in DNA monolayers by atomic force microscopy and electrochemical impedance spectroscopy. AB - BACKGROUND: DNA hybridization is at the basis of most current technologies for genotyping and sequencing, due to the unique properties of DNA base-pairing that guarantee a high grade of selectivity. Nonetheless the presence of single base mismatches or not perfectly matched sequences can affect the response of the devices and the major challenge is, nowadays, to distinguish a mismatch of a single base and, at the same time, unequivocally differentiate devices read-out of fully and partially matching sequences. RESULTS: We present here two platforms based on different sensing strategies, to detect mismatched and/or perfectly matched complementary DNA strands hybridization into ssDNA oligonucleotide monolayers. The first platform exploits atomic force microscopy-based nanolithography to create ssDNA nano-arrays on gold surfaces. AFM topography measurements then monitor the variation of height of the nanostructures upon biorecognition and then follow annealing at different temperatures. This strategy allowed us to clearly detect the presence of mismatches. The second strategy exploits the change in capacitance at the interface between an ssDNA functionalized gold electrode and the solution due to the hybridization process in a miniaturized electrochemical cell. Through electrochemical impedance spectroscopy measurements on extended ssDNA self-assembled monolayers we followed in real-time the variation of capacitance, being able to distinguish, through the difference in hybridization kinetics, not only the presence of single, double or triple mismatches in the complementary sequence, but also the position of the mismatched base pair with respect to the electrode surface. CONCLUSION: We demonstrate here two platforms based on different sensing strategies as sensitive and selective tools to discriminate mismatches. Our assays are ready for parallelization and can be used in the detection and quantification of single nucleotide mismatches in microRNAs or in genomic DNA. PMID- 26977381 TI - Influence of calcium on ceramide-1-phosphate monolayers. AB - Ceramide-1-phosphate (C1P) plays an important role in several biological processes, being identified as a key regulator of many protein functions. For instance, it acts as a mediator of inflammatory responses. The mediation of the inflammation process happens due to the interaction of C1P with the C2 domain of cPLA2alpha, an effector protein that needs the presence of submicromolar concentrations of calcium ions. The aim of this study was to determine the phase behaviour and structural properties of C1P in the presence and absence of millimolar quantities of calcium in a well-defined pH environment. For that purpose, we used monomolecular films of C1P at the soft air/liquid interface with calcium ions in the subphase. The pH was varied to change the protonation degree of the C1P head group. We used surface pressure versus molecular area isotherms coupled with other monolayer techniques as Brewster angle microscopy (BAM), infrared reflection-absorption spectroscopy (IRRAS) and grazing incidence X-ray diffraction (GIXD). The isotherms indicate that C1P monolayers are in a condensed state in the presence of calcium ions, regardless of the pH. At higher pH without calcium ions, the monolayer is in a liquid-expanded state due to repulsion between the negatively charged phosphate groups of the C1P molecules. When divalent calcium ions are added, they are able to bridge the highly charged phosphate groups, enhancing the regular arrangement of the head groups. Similar solidification of the monolayer structure can be seen in the presence of a 150 times larger concentration of monovalent sodium ions. Therefore, calcium ions have clearly a strong affinity for the phosphomonoester of C1P. PMID- 26977382 TI - Surface coating affects behavior of metallic nanoparticles in a biological environment. AB - Silver (AgNPs) and maghemite, i.e., superparamagnetic iron oxide nanoparticles (SPIONs) are promising candidates for new medical applications, which implies the need for strict information regarding their physicochemical characteristics and behavior in a biological environment. The currently developed AgNPs and SPIONs encompass a myriad of sizes and surface coatings, which affect NPs properties and may improve their biocompatibility. This study is aimed to evaluate the effects of surface coating on colloidal stability and behavior of AgNPs and SPIONs in modelled biological environments using dynamic and electrophoretic light scattering techniques, as well as transmission electron microscopy to visualize the behavior of the NP. Three dispersion media were investigated: ultrapure water (UW), biological cell culture medium without addition of protein (BM), and BM supplemented with common serum protein (BMP). The obtained results showed that different coating agents on AgNPs and SPIONs produced different stabilities in the same biological media. The combination of negative charge and high adsorption strength of coating agents proved to be important for achieving good stability of metallic NPs in electrolyte-rich fluids. Most importantly, the presence of proteins provided colloidal stabilization to metallic NPs in biological fluids regardless of their chemical composition, surface structure and surface charge. In addition, an assessment of AgNP and SPION behavior in real biological fluids, rat whole blood (WhBl) and blood plasma (BlPl), revealed that the composition of a biological medium is crucial for the colloidal stability and type of metallic NP transformation. Our results highlight the importance of physicochemical characterization and stability evaluation of metallic NPs in a variety of biological systems including as many NP properties as possible. PMID- 26977384 TI - Determination of Young's modulus of Sb2S3 nanowires by in situ resonance and bending methods. AB - In this study we address the mechanical properties of Sb2S3 nanowires and determine their Young's modulus using in situ electric-field-induced mechanical resonance and static bending tests on individual Sb2S3 nanowires with cross sectional areas ranging from 1.1.10(4) nm(2) to 7.8.10(4) nm(2). Mutually orthogonal resonances are observed and their origin explained by asymmetric cross section of nanowires. The results obtained from the two methods are consistent and show that nanowires exhibit Young's moduli comparable to the value for macroscopic material. An increasing trend of measured values of Young's modulus is observed for smaller thickness samples. PMID- 26977383 TI - Case studies on the formation of chalcogenide self-assembled monolayers on surfaces and dissociative processes. AB - This report examines the assembly of chalcogenide organic molecules on various surfaces, focusing on cases when chemisorption is accompanied by carbon-chalcogen atom-bond scission. In the case of alkane and benzyl chalcogenides, this induces formation of a chalcogenized interface layer. This process can occur during the initial stages of adsorption and then, after passivation of the surface, molecular adsorption can proceed. The characteristics of the chalcogenized interface layer can be significantly different from the metal layer and can affect various properties such as electron conduction. For chalcogenophenes, the carbon-chalcogen atom-bond breaking can lead to opening of the ring and adsorption of an alkene chalcogenide. Such a disruption of the pi-electron system affects charge transport along the chains. Awareness about these effects is of importance from the point of view of molecular electronics. We discuss some recent studies based on X-ray photoelectron spectroscopy that shed light on these aspects for a series of such organic molecules. PMID- 26977385 TI - High-bandwidth multimode self-sensing in bimodal atomic force microscopy. AB - Using standard microelectromechanical system (MEMS) processes to coat a microcantilever with a piezoelectric layer results in a versatile transducer with inherent self-sensing capabilities. For applications in multifrequency atomic force microscopy (MF-AFM), we illustrate that a single piezoelectric layer can be simultaneously used for multimode excitation and detection of the cantilever deflection. This is achieved by a charge sensor with a bandwidth of 10 MHz and dual feedthrough cancellation to recover the resonant modes that are heavily buried in feedthrough originating from the piezoelectric capacitance. The setup enables the omission of the commonly used piezoelectric stack actuator and optical beam deflection sensor, alleviating limitations due to distorted frequency responses and instrumentation cost, respectively. The proposed method benefits from a more than two orders of magnitude increase in deflection to strain sensitivity on the fifth eigenmode leading to a remarkable signal-to-noise ratio. Experimental results using bimodal AFM imaging on a two component polymer sample validate that the self-sensing scheme can therefore be used to provide both the feedback signal, for topography imaging on the fundamental mode, and phase imaging on the higher eigenmode. PMID- 26977386 TI - Functional fusion of living systems with synthetic electrode interfaces. AB - The functional fusion of "living" biomaterial (such as cells) with synthetic systems has developed into a principal ambition for various scientific disciplines. In particular, emerging fields such as bionics and nanomedicine integrate advanced nanomaterials with biomolecules, cells and organisms in order to develop novel strategies for applications, including energy production or real time diagnostics utilizing biomolecular machineries "perfected" during billion years of evolution. To date, hardware-wetware interfaces that sample or modulate bioelectric potentials, such as neuroprostheses or implantable energy harvesters, are mostly based on microelectrodes brought into the closest possible contact with the targeted cells. Recently, the possibility of using electrochemical gradients of the inner ear for technical applications was demonstrated using implanted electrodes, where 1.12 nW of electrical power was harvested from the guinea pig endocochlear potential for up to 5 h (Mercier, P.; Lysaght, A.; Bandyopadhyay, S.; Chandrakasan, A.; Stankovic, K. Nat. Biotech. 2012, 30, 1240 1243). More recent approaches employ nanowires (NWs) able to penetrate the cellular membrane and to record extra- and intracellular electrical signals, in some cases with subcellular resolution (Spira, M.; Hai, A. Nat. Nano. 2013, 8, 83 94). Such techniques include nanoelectric scaffolds containing free-standing silicon NWs (Robinson, J. T.; Jorgolli, M.; Shalek, A. K.; Yoon, M. H.; Gertner, R. S.; Park, H. Nat Nanotechnol. 2012, 10, 180-184) or NW field-effect transistors (Qing, Q.; Jiang, Z.; Xu, L.; Gao, R.; Mai, L.; Lieber, C. Nat. Nano. 2013, 9, 142-147), vertically aligned gallium phosphide NWs (Hallstrom, W.; Martensson, T.; Prinz, C.; Gustavsson, P.; Montelius, L.; Samuelson, L.; Kanje, M. Nano Lett. 2007, 7, 2960-2965) or individually contacted, electrically active carbon nanofibers. The latter of these approaches is capable of recording electrical responses from oxidative events occurring in intercellular regions of neuronal cultures (Zhang, D.; Rand, E.; Marsh, M.; Andrews, R.; Lee, K.; Meyyappan, M.; Koehne, J. Mol. Neurobiol. 2013, 48, 380-385). Employing monocrystalline gold, nanoelectrode interfaces, we have now achieved stable, functional access to the electrochemical machinery of individual Physarum polycephalum slime mold cells. We demonstrate the "symbionic" union, allowing for electrophysiological measurements, functioning as autonomous sensors and capable of producing nanowatts of electric power. This represents a further step towards the future development of groundbreaking, cell-based technologies, such as bionic sensory systems or miniaturized energy sources to power various devices, or even "intelligent implants", constantly refueled by their surrounding nutrients. PMID- 26977387 TI - Microscopy tools for the investigation of intracellular lipid storage and dynamics. AB - BACKGROUND: Excess storage of lipids in ectopic tissues, such as skeletal muscle, liver, and heart, seems to associate closely with metabolic abnormalities and cardiac disease. Intracellular lipid storage occurs in lipid droplets, which have gained attention as active organelles in cellular metabolism. Recent developments in high-resolution microscopy and microscopic spectroscopy have opened up new avenues to examine the physiology and biochemistry of intracellular lipids. SCOPE OF REVIEW: The aim of this review is to give an overview of recent technical advances in microscopy, and its application for the visualization, identification, and quantification of intracellular lipids, with special focus to lipid droplets. In addition, we attempt to summarize the probes currently available for the visualization of lipids. MAJOR CONCLUSIONS: The continuous development of lipid probes in combination with the rapid development of microscopic techniques can provide new insights in the role and dynamics of intracellular lipids. Moreover, in situ identification of intracellular lipids is now possible and promises to add a new dimensionality to analysis of lipid biochemistry, and its relation to (patho)physiology. PMID- 26977388 TI - Progress and prospects of long noncoding RNAs in lipid homeostasis. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) are a novel group of universally present, non-coding RNAs (>200 nt) that are increasingly recognized as key regulators of many physiological and pathological processes. SCOPE OF REVIEW: Recent publications have shown that lncRNAs influence lipid homeostasis by controlling lipid metabolism in the liver and by regulating adipogenesis. lncRNAs control lipid metabolism-related gene expression by either base-pairing with RNA and DNA or by binding to proteins. MAJOR CONCLUSIONS: The recent advances and future prospects in understanding the roles of lncRNAs in lipid homeostasis are discussed. PMID- 26977389 TI - High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring. AB - OBJECTIVES: Chronic and high consumption of fat constitutes an environmental stress that leads to metabolic diseases. We hypothesized that high-fat diet (HFD) transgenerationally remodels the epigenome of spermatozoa and metabolism of the offspring. METHODS: F0-male rats fed either HFD or chow diet for 12 weeks were mated with chow-fed dams to generate F1 and F2 offspring. Motile spermatozoa were isolated from F0 and F1 breeders to determine DNA methylation and small non coding RNA (sncRNA) expression pattern by deep sequencing. RESULTS: Newborn offspring of HFD-fed fathers had reduced body weight and pancreatic beta-cell mass. Adult female, but not male, offspring of HFD-fed fathers were glucose intolerant and resistant to HFD-induced weight gain. This phenotype was perpetuated in the F2 progeny, indicating transgenerational epigenetic inheritance. The epigenome of spermatozoa from HFD-fed F0 and their F1 male offspring showed common DNA methylation and small non-coding RNA expression signatures. Altered expression of sperm miRNA let-7c was passed down to metabolic tissues of the offspring, inducing a transcriptomic shift of the let-7c predicted targets. CONCLUSION: Our results provide insight into mechanisms by which HFD transgenerationally reprograms the epigenome of sperm cells, thereby affecting metabolic tissues of offspring throughout two generations. PMID- 26977391 TI - Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients. AB - OBJECTIVE: Epigenetic modifications contribute to the etiology of type 2 diabetes. METHOD: We performed genome-wide methylome and transcriptome analysis in liver from severely obese men with or without type 2 diabetes and non-obese men to discover aberrant pathways underlying the development of insulin resistance. Results were validated by pyrosequencing. RESULT: We identified hypomethylation of genes involved in hepatic glycolysis and insulin resistance, concomitant with increased mRNA expression and protein levels. Pyrosequencing revealed the CpG-site within ATF-motifs was hypomethylated in four of these genes in liver of severely obese non-diabetic and type 2 diabetic patients, suggesting epigenetic regulation of transcription by altered ATF-DNA binding. CONCLUSION: Severely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome, with hypomethylation of several genes controlling glucose metabolism within the ATF-motif regulatory site. Obesity appears to shift the epigenetic program of the liver towards increased glycolysis and lipogenesis, which may exacerbate the development of insulin resistance. PMID- 26977392 TI - Postnatal undernutrition delays a key step in the maturation of hypothalamic feeding circuits. AB - OBJECTIVE: Humans and animals exposed to undernutrition (UN) during development often experience accelerated "catch-up" growth when food supplies are plentiful. Little is known about the mechanisms regulating early growth rates. We previously reported that actions of leptin and presynaptic inputs to orexigenic NPY/AgRP/GABA (NAG) neurons in the arcuate nucleus of the hypothalamus are almost exclusively excitatory during the lactation period, since neuronal and humoral inhibitory systems do not develop until after weaning. Moreover, we identified a critical step that regulates the maturation of electrophysiological responses of NAG neurons at weaning - the onset of genes encoding ATP-dependent potassium (KATP) channel subunits. We explored the possibility that UN promotes subsequent catch-up growth, in part, by delaying the maturation of negative feedback systems to neuronal circuits driving food intake. METHODS: We used the large litter (LL) size model to study the impacts of postnatal UN followed by catch-up growth. We evaluated the maturation of presynaptic and postsynaptic inhibitory systems in NAG neurons using a combination of electrophysiological and molecular criteria, in conjunction with leptin's ability to suppress fasting-induced hyperphagia. RESULTS: The onset of KATP channel subunit expression and function, the switch in leptin's effect on NAG neurons, the ingrowth of inhibitory inputs to NAG neurons, and the development of homeostatic feedback to feeding circuits were delayed in LL offspring relative to controls. The development of functional KATP channels and the establishment of leptin-mediated suppression of food intake in the peri weaning period were tightly linked and were not initiated until growth and adiposity of LL offspring caught up to controls. CONCLUSIONS: Our data support the idea that initiation of KATP channel subunit expression in NAG neurons serves as a molecular gatekeeper for the maturation of homeostatic feeding circuits. PMID- 26977393 TI - Acyl CoA synthetase 5 (ACSL5) ablation in mice increases energy expenditure and insulin sensitivity and delays fat absorption. AB - OBJECTIVE: The family of acyl-CoA synthetase enzymes (ACSL) activates fatty acids within cells to generate long chain fatty acyl CoA (FACoA). The differing metabolic fates of FACoAs such as incorporation into neutral lipids, phospholipids, and oxidation pathways are differentially regulated by the ACSL isoforms. In vitro studies have suggested a role for ACSL5 in triglyceride synthesis; however, we have limited understanding of the in vivo actions of this ACSL isoform. METHODS: To elucidate the in vivo actions of ACSL5 we generated a line of mice in which ACSL5 expression was ablated in all tissues (ACSL5 (-/-) ). RESULTS: Ablation of ACSL5 reduced ACSL activity by ~80% in jejunal mucosa, ~50% in liver, and ~37% in brown adipose tissue lysates. Body composition studies revealed that ACSL5 (-/-) , as compared to control ACSL5 (loxP/loxP) , mice had significantly reduced fat mass and adipose fat pad weights. Indirect calorimetry studies demonstrated that ACSL5 (-/-) had increased metabolic rates, and in the dark phase, increased respiratory quotient. In ACSL5 (-/-) mice, fasting glucose and serum triglyceride were reduced; and insulin sensitivity was improved during an insulin tolerance test. Both hepatic mRNA (~16-fold) and serum levels of fibroblast growth factor 21 (FGF21) (~13-fold) were increased in ACSL5 (-/-) as compared to ACSL5 (loxP/loxP) . Consistent with increased FGF21 serum levels, uncoupling protein-1 gene (Ucp1) and PPAR-gamma coactivator 1-alpha gene (Pgc1alpha) transcript levels were increased in gonadal adipose tissue. To further evaluate ACSL5 function in intestine, mice were gavaged with an olive oil bolus; and the rate of triglyceride appearance in serum was found to be delayed in ACSL5 (-/-) mice as compared to control mice. CONCLUSIONS: In summary, ACSL5 ( /-) mice have increased hepatic and serum FGF21 levels, reduced adiposity, improved insulin sensitivity, increased energy expenditure and delayed triglyceride absorption. These studies suggest that ACSL5 is an important regulator of whole-body energy metabolism and ablation of ACSL5 may antagonize the development of obesity and insulin resistance. PMID- 26977394 TI - Impaired glucose metabolism and exercise capacity with muscle-specific glycogen synthase 1 (gys1) deletion in adult mice. AB - OBJECTIVE: Muscle glucose storage and muscle glycogen synthase (gys1) defects have been associated with insulin resistance. As there are multiple mechanisms for insulin resistance, the specific role of glucose storage defects is not clear. The aim of this study was to examine the effects of muscle-specific gys1 deletion on glucose metabolism and exercise capacity. METHODS: Tamoxifen inducible and muscle specific gys-1 KO mice were generated using the Cre/loxP system. Mice were subjected to glucose tolerance tests, euglycemic/hyperinsulinemic clamps and exercise tests. RESULTS: gys1-KO mice showed >=85% reduction in muscle gys1 mRNA and protein concentrations, 70% reduction in muscle glycogen levels, postprandial hyperglycaemia and hyperinsulinaemia and impaired glucose tolerance. Under insulin-stimulated conditions, gys1-KO mice displayed reduced glucose turnover and muscle glucose uptake, indicative of peripheral insulin resistance, as well as increased plasma and muscle lactate levels and reductions in muscle hexokinase II levels. gys1-KO mice also exhibited markedly reduced exercise and endurance capacity. CONCLUSIONS: Thus, muscle-specific gys1 deletion in adult mice results in glucose intolerance due to insulin resistance and reduced muscle glucose uptake as well as impaired exercise and endurance capacity. IN BRIEF: This study demonstrates why the body prioritises muscle glycogen storage over liver glycogen storage despite the critical role of the liver in supplying glucose to the brain in the fasting state and shows that glycogen deficiency results in impaired glucose metabolism and reduced exercise capacity. PMID- 26977390 TI - Interdependence of nutrient metabolism and the circadian clock system: Importance for metabolic health. AB - BACKGROUND: While additional research is needed, a number of large epidemiological studies show an association between circadian disruption and metabolic disorders. Specifically, obesity, insulin resistance, cardiovascular disease, and other signs of metabolic syndrome all have been linked to circadian disruption in humans. Studies in other species support this association and generally reveal that feeding that is not in phase with the external light/dark cycle, as often occurs with night or rotating shift workers, is disadvantageous in terms of energy balance. As food is a strong driver of circadian rhythms in the periphery, understanding how nutrient metabolism drives clocks across the body is important for dissecting out why circadian misalignment may produce such metabolic effects. A number of circadian clock proteins as well as their accessory proteins (such as nuclear receptors) are highly sensitive to nutrient metabolism. Macronutrients and micronutrients can function as zeitgebers for the clock in a tissue-specific way and can thus impair synchrony between clocks across the body, or potentially restore synchrony in the case of circadian misalignment. Circadian nuclear receptors are particularly sensitive to nutrient metabolism and can alter tissue-specific rhythms in response to changes in the diet. Finally, SNPs in human clock genes appear to be correlated with diet specific responses and along with chronotype eventually may provide valuable information from a clinical perspective on how to use diet and nutrition to treat metabolic disorders. SCOPE OF REVIEW: This article presents a background of the circadian clock components and their interrelated metabolic and transcriptional feedback loops, followed by a review of some recent studies in humans and rodents that address the effects of nutrient metabolism on the circadian clock and vice versa. We focus on studies in which results suggest that nutrients provide an opportunity to restore or, alternatively, can destroy synchrony between peripheral clocks and the central pacemaker in the brain as well as between peripheral clocks themselves. In addition, we review several studies looking at clock gene SNPs in humans and the metabolic phenotypes or tendencies associated with particular clock gene mutations. MAJOR CONCLUSIONS: Targeted use of specific nutrients based on chronotype has the potential for immense clinical utility in the future. Macronutrients and micronutrients have the ability to function as zeitgebers for the clock by activating or modulating specific clock proteins or accessory proteins (such as nuclear receptors). Circadian clock control by nutrients can be tissue-specific. With a better understanding of the mechanisms that support nutrient-induced circadian control in specific tissues, human chronotype and SNP information might eventually be used to tailor nutritional regimens for metabolic disease treatment and thus be an important part of personalized medicine's future. PMID- 26977395 TI - Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes. AB - OBJECTIVE: Although glucagon-secreting alpha-cells and insulin-secreting beta cells have opposing functions in regulating plasma glucose levels, the two cell types share a common developmental origin and exhibit overlapping transcriptomes and epigenomes. Notably, destruction of beta-cells can stimulate repopulation via transdifferentiation of alpha-cells, at least in mice, suggesting plasticity between these cell fates. Furthermore, dysfunction of both alpha- and beta-cells contributes to the pathophysiology of type 1 and type 2 diabetes, and beta-cell de-differentiation has been proposed to contribute to type 2 diabetes. Our objective was to delineate the molecular properties that maintain islet cell type specification yet allow for cellular plasticity. We hypothesized that correlating cell type-specific transcriptomes with an atlas of open chromatin will identify novel genes and transcriptional regulatory elements such as enhancers involved in alpha- and beta-cell specification and plasticity. METHODS: We sorted human alpha and beta-cells and performed the "Assay for Transposase-Accessible Chromatin with high throughput sequencing" (ATAC-seq) and mRNA-seq, followed by integrative analysis to identify cell type-selective gene regulatory regions. RESULTS: We identified numerous transcripts with either alpha-cell- or beta-cell-selective expression and discovered the cell type-selective open chromatin regions that correlate with these gene activation patterns. We confirmed cell type-selective expression on the protein level for two of the top hits from our screen. The "group specific protein" (GC; or vitamin D binding protein) was restricted to alpha-cells, while CHODL (chondrolectin) immunoreactivity was only present in beta-cells. Furthermore, alpha-cell- and beta-cell-selective ATAC-seq peaks were identified to overlap with known binding sites for islet transcription factors, as well as with single nucleotide polymorphisms (SNPs) previously identified as risk loci for type 2 diabetes. CONCLUSIONS: We have determined the genetic landscape of human alpha- and beta-cells based on chromatin accessibility and transcript levels, which allowed for detection of novel alpha- and beta-cell signature genes not previously known to be expressed in islets. Using fine mapping of open chromatin, we have identified thousands of potential cis regulatory elements that operate in an endocrine cell type-specific fashion. PMID- 26977396 TI - Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons. AB - OBJECTIVE: Obesity is one of the primary healthcare challenges of the 21st century. Signals relaying information regarding energy needs are integrated within the brain to influence body weight. Central among these integration nodes are the brain pro-opiomelanocortin (POMC) peptides, perturbations of which disrupt energy balance and promote severe obesity. However, POMC neurons are neurochemically diverse and the crucial source of POMC peptides that regulate energy homeostasis and body weight remains to be fully clarified. METHODS: Given that a 5-hydroxytryptamine 2c receptor (5-HT2CR) agonist is a current obesity medication and 5-HT2CR agonist's effects on appetite are primarily mediated via POMC neurons, we hypothesized that a critical source of POMC regulating food intake and body weight is specifically synthesized in cells containing 5-HT2CRs. To exclusively manipulate Pomc synthesis only within 5-HT2CR containing cells, we generated a novel 5-HT 2C R (CRE) mouse line and intercrossed it with Cre recombinase-dependent and hypothalamic specific reactivatable Pomc (NEO) mice to restrict Pomc synthesis to the subset of hypothalamic cells containing 5-HT2CRs. This provided a means to clarify the specific contribution of a defined subgroup of POMC peptides in energy balance and body weight. RESULTS: Here we transform genetically programed obese and hyperinsulinemic male mice lacking hypothalamic Pomc with increased appetite, reduced physical activity and compromised brown adipose tissue (BAT) into lean, healthy mice via targeted restoration of Pomc function only within 5-HT2CR expressing cells. Remarkably, the same metabolic transformation does not occur in females, who despite corrected feeding behavior and normalized insulin levels remain physically inactive, have lower energy expenditure, compromised BAT and develop obesity. CONCLUSIONS: These data provide support for the functional heterogeneity of hypothalamic POMC neurons, revealing that Pomc expression within 5-HT2CR expressing neurons is sufficient to regulate energy intake and insulin sensitivity in male and female mice. However, an unexpected sex difference in the function of this subset of POMC neurons was identified with regard to energy expenditure. We reveal that a large sex difference in physical activity, energy expenditure and the development of obesity is driven by this subpopulation, which constitutes approximately 40% of all POMC neurons in the hypothalamic arcuate nucleus. This may have broad implications for strategies utilized to combat obesity, which at present largely ignore the sex of the obese individual. PMID- 26977398 TI - Patterns of regional cerebellar atrophy in genetic frontotemporal dementia. AB - BACKGROUND: Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder with a strong genetic component. The cerebellum has not traditionally been felt to be involved in FTD but recent research has suggested a potential role. METHODS: We investigated the volumetry of the cerebellum and its subregions in a cohort of 44 patients with genetic FTD (20 MAPT, 7 GRN, and 17 C9orf72 mutation carriers) compared with 18 cognitively normal controls. All groups were matched for age and gender. On volumetric T1-weighted magnetic resonance brain images we used an atlas propagation and label fusion strategy of the Diedrichsen cerebellar atlas to automatically extract subregions including the cerebellar lobules, the vermis and the deep nuclei. RESULTS: The global cerebellar volume was significantly smaller in C9orf72 carriers (mean (SD): 99989 (8939) mm(3)) compared with controls (108136 (7407) mm(3)). However, no significant differences were seen in the MAPT and GRN carriers compared with controls (104191 (6491) mm(3) and 107883 (6205) mm(3) respectively). Investigating the individual subregions, C9orf72 carriers had a significantly lower volume than controls in lobule VIIa-Crus I (15% smaller, p < 0.0005), whilst MAPT mutation carriers had a significantly lower vermal volume (10% smaller, p = 0.001) than controls. All cerebellar subregion volumes were preserved in GRN carriers compared with controls. CONCLUSION: There appears to be a differential pattern of cerebellar atrophy in the major genetic forms of FTD, being relatively spared in GRN, localized to the lobule VIIa-Crus I in the superior-posterior region of the cerebellum in C9orf72, the area connected via the thalamus to the prefrontal cortex and involved in cognitive function, and localized to the vermis in MAPT, the 'limbic cerebellum' involved in emotional processing. PMID- 26977401 TI - Preface to the special issue of the International Congress on Parasites of Wildlife, 15-18 September 2014, Kruger National Park, South Africa. PMID- 26977399 TI - Spatial regression analysis of serial DTI for subject-specific longitudinal changes of neurodegenerative disease. AB - Quantitative measurement of localized longitudinal changes in brain abnormalities at an individual level may offer critical information for disease diagnosis and treatment. The voxel-wise permutation-based method SPREAD/iSPREAD, which combines resampling and spatial regression of neighboring voxels, provides an effective and robust method for detecting subject-specific longitudinal changes within the whole brain, especially for longitudinal studies with a limited number of scans. As an extension of SPREAD/iSPREAD, we present a general method that facilitates analysis of serial Diffusion Tensor Imaging (DTI) measurements (with more than two time points) for testing localized changes in longitudinal studies. Two types of voxel-level test statistics (model-free test statistics, which measure intra subject variability across time, and test statistics based on general linear model that incorporate specific lesion evolution models) were estimated and tested against the null hypothesis among groups of DTI data across time. The implementation and utility of the proposed statistical method were demonstrated by both Monte Carlo simulations and applications on clinical DTI data from human brain in vivo. By a design of test statistics based on the disease progression model, it was possible to apportion the true significant voxels attributed to the disease progression and those caused by underlying anatomical differences that cannot be explained by the model, which led to improvement in false positive (FP) control in the results. Extension of the proposed method to include other diseases or drug effect models, as well as the feasibility of global statistics, was discussed. The proposed statistical method can be extended to a broad spectrum of longitudinal studies with carefully designed test statistics, which helps to detect localized changes at the individual level. PMID- 26977397 TI - Subcortical neuromorphometry in schizophrenia spectrum and bipolar disorders. AB - BACKGROUND: Disorders within the schizophrenia spectrum genetically overlap with bipolar disorder, yet questions remain about shared biological phenotypes. Investigation of brain structure in disease has been enhanced by developments in shape analysis methods that can identify subtle regional surface deformations. Our study aimed to identify brain structure surface deformations that were common across related psychiatric disorders, and characterize differences. METHODS: Using the automated FreeSurfer-initiated Large Deformation Diffeomorphic Metric Mapping, we examined volumes and shapes of seven brain structures: hippocampus, amygdala, caudate, nucleus accumbens, putamen, globus pallidus and thalamus. We compared findings in controls (CON; n = 40), and those with schizophrenia (SCZ; n = 52), schizotypal personality disorder (STP; n = 12), psychotic bipolar disorder (P-BP; n = 49) and nonpsychotic bipolar disorder (N-BP; n = 24), aged 15-35. Relationships between morphometric measures and positive, disorganized and negative symptoms were also investigated. RESULTS: Inward deformation was present in the posterior thalamus in SCZ, P-BP and N-BP; and in the subiculum of the hippocampus in SCZ and STP. Most brain structures however showed unique shape deformations across groups. Correcting for intracranial size resulted in volumetric group differences for caudate (p < 0.001), putamen (p < 0.01) and globus pallidus (p < 0.001). Shape analysis showed dispersed patterns of expansion on the basal ganglia in SCZ. Significant clinical relationships with hippocampal, amygdalar and thalamic volumes were observed. CONCLUSIONS: Few similarities in surface deformation patterns were seen across groups, which may reflect differing neuropathologies. Posterior thalamic contraction in SCZ and BP suggest common genetic or environmental antecedents. Surface deformities in SCZ basal ganglia may have been due to antipsychotic drug effects. PMID- 26977403 TI - Morphological and molecular characterization of Eimeria purpureicephali n. sp. (Apicomplexa:Eimeriidae) in a red-capped parrot (Purpureicephalus spurius, Kuhl, 1820) in Western Australia. AB - A new Eimeria species is described from a red-capped parrot (Purpureicephalus spurius). Sporulated oocysts (n = 31) were spherical to subspherical, with a rough bilayered oocyst wall 0.8 MUm thick. Oocysts measured 24.0 * 22.8 (20.4 26.4 * 18.3-25.9) MUm, oocyst length/width ratio, 1.10. Oocyst residuum, polar granule and micropyle were absent. Sporocysts are elongate-ovoid, 11.0 * 7.3 (12.7-9.2 * 7.9-6.6) MUm, sporocyst length/width ratio, 1.51 (1.33-1.71). The thin convex Stieda body and indistinct substieda bodies were present and the sporocyst residuum was composed of numerous small granules less than 1.0 MUm in diameter dispersed randomly. Each sporocyst contained 2 sausage-shaped sporozoites in head-to-tail arrangement. The sporozoite nuclei were located centrally surrounded by refractile bodies. Molecular analysis was conducted at two loci; the 18S ribosomal RNA gene and the cytochrome c oxidase subunit I gene. At the18S locus, the new isolate shared 99.0% genetic similarity with Eimeria dispersa and Eimeria innocua from the turkey. At the cytochrome c oxidase subunit I gene locus, this new isolate was most closely related to E. dispersa and E. innocua, presented 99.0% and 98.0% genetic similarity, respectively. This new isolate and E. dispersa grouped together in the same clade. Based on the morphological and molecular data, this isolate is a new species of coccidian parasite, which is named Eimeria purpureicephali n. sp. after its host, the red capped parrot (Purpureicephalus spurius). PMID- 26977402 TI - Mussels (Perna perna) as bioindicator of environmental contamination by Cryptosporidium species with zoonotic potential. AB - Sources of contamination such as animal feces runoff, organic fertilizer application, and the release of partially treated or untreated sewage can lead to the contamination of aquatic environments by Cryptosporidium spp. The quality of mussels as food is closely related to the sanitary conditions of the marine environment where these bivalves are found. Marine mollusks are filter feeders that are able to retain Cryptosporidium oocysts in their tissue, thus functioning as bioindicators. A total of 72 pooled mussel samples of the species Perna perna were collected at two sites (A and B) in the municipality of Mangaratiba, Rio de Janeiro State, Brazil. Sampling involved removal of 30 mussels, from each collection site every month for one year. The 30 mussels from each sampling were then allocated into three groups of 10. Two Cryptosporidium spp. genes (18S and GP60) were targeted for DNA amplification from the samples obtained. After purification, all of the products obtained were sequenced and phylogenetic analyses were performed. Of the 72 samples analyzed using the nested-PCR for the 18S gene target, 29.2% were positive for the presence of Cryptosporidium spp. Of these samples, 52.4% were collected at site A (ie 11/21) and 47.6% at site B (ie 10/21). The 18S genes of all the samples considered positive for Cryptosporidium spp. were sequenced, and the following three species were identified: Cryptosporidium parvum, C. meleagridis, and C. andersoni. Three distinct C. parvum subtypes (IIaA19G2R2; IIaA20G2R2; IIaA20G3R2) were identified using the GP60 gene. More studies to evaluate the zoonotic potential of this species should be performed as both sampling locations contain human and/or animal fecal contaminants. PMID- 26977400 TI - Network analysis of functional brain connectivity in borderline personality disorder using resting-state fMRI. AB - Borderline personality disorder (BPD) is associated with symptoms such as affect dysregulation, impaired sense of self, and self-harm behaviors. Neuroimaging research on BPD has revealed structural and functional abnormalities in specific brain regions and connections. However, little is known about the topological organizations of brain networks in BPD. We collected resting-state functional magnetic resonance imaging (fMRI) data from 20 patients with BPD and 10 healthy controls, and constructed frequency-specific functional brain networks by correlating wavelet-filtered fMRI signals from 82 cortical and subcortical regions. We employed graph-theory based complex network analysis to investigate the topological properties of the brain networks, and employed network-based statistic to identify functional dysconnections in patients. In the 0.03-0.06 Hz frequency band, compared to controls, patients with BPD showed significantly larger measures of global network topology, including the size of largest connected graph component, clustering coefficient, small-worldness, and local efficiency, indicating increased local cliquishness of the functional brain network. Compared to controls, patients showed lower nodal centrality at several hub nodes but greater centrality at several non-hub nodes in the network. Furthermore, an interconnected subnetwork in 0.03-0.06 Hz frequency band was identified that showed significantly lower connectivity in patients. The links in the subnetwork were mainly long-distance connections between regions located at different lobes; and the mean connectivity of this subnetwork was negatively correlated with the increased global topology measures. Lastly, the key network measures showed high correlations with several clinical symptom scores, and classified BPD patients against healthy controls with high accuracy based on linear discriminant analysis. The abnormal topological properties and connectivity found in this study may add new knowledge to the current understanding of functional brain networks in BPD. However, due to limitation of small sample sizes, the results of the current study should be viewed as exploratory and need to be validated on large samples in future works. PMID- 26977404 TI - Sexual differences in prevalence of a new species of trypanosome infecting tungara frogs. AB - Trypanosomes are a diverse group of protozoan parasites of vertebrates transmitted by a variety of hematophagous invertebrate vectors. Anuran trypanosomes and their vectors have received relatively little attention even though these parasites have been reported from frog and toad species worldwide. Blood samples collected from tungara frogs (Engystomops pustulosus), a Neotropical anuran species heavily preyed upon by eavesdropping frog-biting midges (Corethrella spp.), were examined for trypanosomes. Our results revealed sexual differences in trypanosome prevalence with female frogs being rarely infected (<1%). This finding suggests this protozoan parasite may be transmitted by frog-biting midges that find their host using the mating calls produced by male frogs. Following previous anuran trypanosome studies, we examined 18S ribosomal RNA gene to characterize and establish the phylogenetic relationship of the trypanosome species found in tungara frogs. A new species of giant trypanosome, Trypanosoma tungarae n. sp., is described in this study. Overall the morphometric data revealed that the trypomastigotes of T. tungarae n. sp. are similar to other giant trypanosomes such as Trypanosoma rotatorium and Trypanosoma ranarum. Despite its slender and long cell shape, however, 18S rRNA gene sequences revealed that T. tungarae n. sp. is sister to the rounded-bodied giant trypanosome, Trypanosoma chattoni. Therefore, morphological convergence explains similar morphology among members of two non-closely related groups of trypanosomes infecting frogs. The results from this study underscore the value of coupling morphological identification with molecular characterization of anuran trypanosomes. PMID- 26977405 TI - Lungworm seroprevalence in free-ranging harbour seals and molecular characterisation of marine mammal MSP. AB - Harbour seals (Phoca vitulina) are frequently infected with the lungworms Otostrongylus circumlitus and Parafilaroides gymnurus. The infection is often accompanied by secondary bacterial infections and can cause severe bronchopneumonia and even death in affected animals. Hitherto, the detection of lungworm infections was based on post mortem investigations from animals collected within stranding networks and a valid detection method for live free ranging harbour seals was not available. Recently, an ELISA was developed for detecting lungworm antibodies in harbour seal serum, using major sperm protein (MSP) of the bovine lungworm, Dictyocaulus viviparus as recombinant diagnostic antigen. To determine lungworm seroprevalence in free-ranging harbour seals, serum was taken from four different seal age groups (n = 313) resulting in an overall prevalence of 17.9% (18.9% of males, 16.7% of females). 0.7% of harbour seals up to six weeks of age were seropositive, as were 89% of seals between six weeks and six months, 53.6% between six and 18 months and 24.2% of seals over 18 months of age. In the 18 months and over age group, seropositive animals showed statistically significant reductions in body weight (P = 0.003) and length (P < 0.001). Sera from lungworm infected harbour seals in rehabilitation (n = 6) revealed that duration of antibody persistence may be similar to that of lungworm infected cattle, but further studies are needed to confirm this. Phylogenetic analyses of MSP sequences of different marine and terrestrial mammal parasitic nematodes revealed that lungworm MSP of the genus Dictyocaulus (superfamily Trichostrongyloidea) is more closely related to metastrongylid marine mammal lungworms than to trichostrongylid nematodes of terrestrial hosts. PMID- 26977406 TI - Potential brain language reorganization in a boy with refractory epilepsy; an fNIRS-EEG and fMRI comparison. AB - As part of a presurgical investigation for a resection of a tumor located in the left temporal brain region, we evaluated pre- and postsurgical language lateralization in a right-handed boy with refractory epilepsy. In this study, we compared functional near infrared spectroscopy (fNIRS) results obtained while the participant performed expressive and receptive language tasks with those obtained using functional magnetic resonance imaging (fMRI). This case study illustrates the potential for NIRS to contribute favorably to the localization of language functions in children with epilepsy and cognitive or behavioral problems and its potential advantages over fMRI in presurgical assessment. Moreover, it suggests that fNIRS is sensitive in localizing an atypical language network or potential brain reorganization related to epilepsy in young patients. PMID- 26977408 TI - Surgical Management of Stuttering Ischemic Priapism: A Case Report and Concise Clinical Review. AB - Stuttering priapism is an extremely rare and poorly understood entity. We present a rare case of a 47-year-old Afro-Caribbean gentleman who required proximal shunt procedure to treat his ischemic stuttering priapism after he had failed medical management. We provided a concise review of the literature on the surgical management of ischemic priapism. This case highlighted the importance of prompt surgical intervention in prolonged stuttering priapism to avoid serious psychological and functional complications. PMID- 26977407 TI - Challenges in identifying Lennox-Gastaut syndrome in adults: A case series illustrating its changing nature. AB - The variable presentation and progression of Lennox-Gastaut syndrome (LGS) can make it difficult to recognize, particularly in adults. To improve diagnosis, a retrospective chart review was conducted on patients who were diagnosed as adults and/or were followed for several years after diagnosis. We present 5 cases that illustrate changes in LGS features over time. Cases 1 and 2 were diagnosed by age 8 with intractable seizures, developmental delay, and abnormal EEGs with 1.5-2 Hz SSW discharges. However, seizure type and frequency changed over time for both patients, and the incidence of SSW discharges decreased. Cases 3, 4, and 5 were diagnosed with LGS as adults based on current and past features and symptoms, including treatment-resistant seizures, cognitive and motor impairment, and abnormal EEG findings. While incomplete, their records indicate that an earlier LGS diagnosis may have been missed or lost to history. These cases demonstrate the need to thoroughly and continuously evaluate all aspects of a patient's encephalopathy, bearing in mind the potential for LGS features to change over time. PMID- 26977410 TI - Collecting Duct Carcinoma With Cardiac Metastases: A Case Report & Literature Review. AB - Collecting duct carcinoma (CDC), is a rare and aggressive form of renal cell carcinoma (RCC) accounting for around 1% of all renal malignancy. It affects younger patients and is associated with rapid progression, distant spread and poor prognosis. Cardiac metastases from all types of RCC, without involvement of the inferior vena cava are very rare. We present the case of a 54 year old man with a history of CDC, who presents with collapse and ventricular tachycardia secondary to multifocal cardiac metastases. We are not aware of any other reports in the literature of CDC and cardiac metastases. PMID- 26977409 TI - Lymphoepithelioma-like Carcinoma (LELC) of the Prostate. AB - Lymphoepithelioma-like carcinoma (LELC) is an aggressive tumor that rarely affects the prostate. Few cases are reported in the literature. We present a case report, pathologic description and review of the literature. PMID- 26977411 TI - Simple, fast, and accurate methodology for quantitative analysis using Fourier transform infrared spectroscopy, with bio-hybrid fuel cell examples. AB - The standard methodologies for quantitative analysis (QA) of mixtures using Fourier transform infrared (FTIR) instruments have evolved until they are now more complicated than necessary for many users' purposes. We present a simpler methodology, suitable for widespread adoption of FTIR QA as a standard laboratory technique across disciplines by occasional users.*Algorithm is straightforward and intuitive, yet it is also fast, accurate, and robust.*Relies on component spectra, minimization of errors, and local adaptive mesh refinement.*Tested successfully on real mixtures of up to nine components. We show that our methodology is robust to challenging experimental conditions such as similar substances, component percentages differing by three orders of magnitude, and imperfect (noisy) spectra. As examples, we analyze biological, chemical, and physical aspects of bio-hybrid fuel cells. PMID- 26977412 TI - Penis Allotransplantation in Beagle Dog. AB - This is an original research of penis allotransplantation. The paper presents an experiment allogenic penis transplantation model in Beagles, with a focus on recovery of blood supply and changes in tissue architecture. Twenty adult Beagles were allocated to 10 pairs for penile transplantation. After operation, the skin and glans were observed. If adverse symptoms occurred, the transplanted penis was resected and pathologically examined. Frequency of urination, urinary stream, and patency level were recorded 7 days after transplantation. Cystourethrography was performed on Day 10. The transplanted penises were resected on Day 14 for pathological examination. The research showed that transplanted penises survived after allotransplantation, and the dogs regained urination ability. Penis autotransplantation in Beagles is feasible. This preliminary study shows a potential for application of this new procedure for penis transplantation in humans. PMID- 26977413 TI - Energy Modulated Photon Radiotherapy: A Monte Carlo Feasibility Study. AB - A novel treatment modality termed energy modulated photon radiotherapy (EMXRT) was investigated. The first step of EMXRT was to determine beam energy for each gantry angle/anatomy configuration from a pool of photon energy beams (2 to 10 MV) with a newly developed energy selector. An inverse planning system using gradient search algorithm was then employed to optimize photon beam intensity of various beam energies based on presimulated Monte Carlo pencil beam dose distributions in patient anatomy. Finally, 3D dose distributions in six patients of different tumor sites were simulated with Monte Carlo method and compared between EMXRT plans and clinical IMRT plans. Compared to current IMRT technique, the proposed EMXRT method could offer a better paradigm for the radiotherapy of lung cancers and pediatric brain tumors in terms of normal tissue sparing and integral dose. For prostate, head and neck, spine, and thyroid lesions, the EMXRT plans were generally comparable to the IMRT plans. Our feasibility study indicated that lower energy (<6 MV) photon beams could be considered in modern radiotherapy treatment planning to achieve a more personalized care for individual patient with dosimetric gains. PMID- 26977414 TI - Advancements in RNASeqGUI towards a Reproducible Analysis of RNA-Seq Experiments. AB - We present the advancements and novelties recently introduced in RNASeqGUI, a graphical user interface that helps biologists to handle and analyse large data collected in RNA-Seq experiments. This work focuses on the concept of reproducible research and shows how it has been incorporated in RNASeqGUI to provide reproducible (computational) results. The novel version of RNASeqGUI combines graphical interfaces with tools for reproducible research, such as literate statistical programming, human readable report, parallel executions, caching, and interactive and web-explorable tables of results. These features allow the user to analyse big datasets in a fast, efficient, and reproducible way. Moreover, this paper represents a proof of concept, showing a simple way to develop computational tools for Life Science in the spirit of reproducible research. PMID- 26977415 TI - The Alternative Faces of Macrophage Generate Osteoclasts. AB - The understanding of how osteoclasts are generated and whether they can be altered by inflammatory stimuli is a topic of particular interest for osteoclastogenesis. It is known that the monocyte/macrophage lineage gives rise to osteoclasts (OCs) by the action of macrophage colony stimulating factor (M CSF) and receptor activator of nuclear factor-kB ligand (RANKL), which induce cell differentiation through their receptors, c-fms and RANK, respectively. The multinucleated giant cells (MGCs) generated by the engagement of RANK/RANKL are typical OCs. Nevertheless, very few studies have addressed the question of which subset of macrophages generates OCs. Indeed, two main subsets of macrophages are postulated, the inflammatory or classically activated type (M1) and the anti inflammatory or alternatively activated type (M2). It has been proposed that macrophages can be polarized in vitro towards a predominantly M1 or M2 phenotype with the addition of granulocyte macrophage- (GM-) CSF or M-CSF, respectively. Various inflammatory stimuli known to induce macrophage polarization, such as LPS or TNF-alpha, can alter the type of MGC obtained from RANKL-induced differentiation. This review aims to highlight the role of immune-related stimuli and factors in inducing macrophages towards the osteoclastogenesis choice. PMID- 26977416 TI - Increased Autoreactivity of the Complement-Activating Molecule Mannan-Binding Lectin in a Type 1 Diabetes Model. AB - BACKGROUND: Diabetic kidney disease is the leading cause of end-stage renal failure despite intensive treatment of modifiable risk factors. Identification of new drug targets is therefore of paramount importance. The complement system is emerging as a potential new target. The lectin pathway of the complement system, initiated by the carbohydrate-recognition molecule mannan-binding lectin (MBL), is linked to poor kidney prognosis in diabetes. We hypothesized that MBL activates complement upon binding within the diabetic glomerulus. METHODS: We investigated this by comparing complement deposition and activation in kidneys from streptozotocin-induced diabetic mice and healthy control mice. RESULTS: After 20 weeks of diabetes, glomerular deposition of MBL was significantly increased. Diabetic animals had 2.0-fold higher (95% CI 1.6-2.5) immunofluorescence intensity from anti-MBL antibodies compared with controls (P < 0.001). Diabetes and control groups did not differ in glomerular immunofluorescence intensity obtained by antibodies against complement factors C4, C3, and C9. However, the circulating complement activation product C3a was increased in diabetes as compared to control mice (P = 0.04). CONCLUSION: 20 weeks of diabetes increased MBL autoreactivity in the kidney and circulating C3a concentration. Together with previous findings, these results indicate direct effects of MBL within the kidney in diabetes. PMID- 26977418 TI - In Thyroidectomized Thyroid Cancer Patients, False-Positive I-131 Whole Body Scans Are Often Caused by Inflammation Rather Than Thyroid Cancer. AB - Objective. To show that I-131 false-positive results on whole-body scans (WBSs) after thyroidectomy for thyroid cancer may be a result of inflammation unassociated with the cancer. Methods. We performed a retrospective image analysis of our database of thyroid cancer patients who underwent WBS from January 2008 to January 2012 to identify and stratify false positives. Results. A total of 564 patients underwent WBS during the study period; 96 patients were referred for 99 I-131 single-photon emission computed tomography (SPECT/CT) scans to better interpret cryptic findings. Among them, 73 scans were shown to be falsely positive; 40/73 or 54.7% of false-positive findings were a result of inflammation. Of the findings, 17 were in the head, 1 in the neck, 4 in the chest, 3 in the abdomen, and 14 in the pelvis; 1 had a knee abscess. Conclusions. In our series, inflammation caused the majority of false-positive WBSs. I-131 SPECT/CT is powerful in the differentiation of inflammation from thyroid cancer. By excluding metastatic disease, one can properly prognosticate outcome and avoid unnecessary, potentially harmful treatment of patients with thyroid cancer. PMID- 26977417 TI - Systematic and Cell Type-Specific Telomere Length Changes in Subsets of Lymphocytes. AB - Telomeres, the protective DNA-protein complexes at the ends of linear chromosomes, are important for genome stability. Leukocyte or peripheral blood mononuclear cell (PBMC) telomere length is a potential biomarker for human aging that integrates genetic, environmental, and lifestyle factors and is associated with mortality and risks for major diseases. However, only a limited number of studies have examined longitudinal changes of telomere length and few have reported data on sorted circulating immune cells. We examined the average telomere length (TL) in CD4+, CD8+CD28+, and CD8+CD28- T cells, B cells, and PBMCs, cross-sectionally and longitudinally, in a cohort of premenopausal women. We report that TL changes over 18 months were correlated among these three T cell types within the same participant. Additionally, PBMC TL change was also correlated with those of all three T cell types, and B cells. The rate of shortening for B cells was significantly greater than for the three T cell types. CD8+CD28- cells, despite having the shortest TL, showed significantly more rapid attrition when compared to CD8+CD28+ T cells. These results suggest systematically coordinated, yet cell type-specific responses to factors and pathways contribute to telomere length regulation. PMID- 26977419 TI - Course Setting as a Prevention Measure for Overuse Injuries of the Back in Alpine Ski Racing: A Kinematic and Kinetic Study of Giant Slalom and Slalom. AB - BACKGROUND: A combination of frontal bending, lateral bending, and torsion in the loaded trunk has been suggested to be a mechanism leading to overuse injuries of the back in Alpine ski racing. However, there is limited knowledge about the effect of course setting on the aforementioned back-loading patterns. PURPOSE: To investigate the effect of increased gate offset on the skier's overall trunk kinematics and the occurring ground-reaction forces and to compare these variables between the competition disciplines giant slalom (GS) and slalom (SL). STUDY DESIGN: Controlled laboratory study. METHODS: Ten top-level athletes were divided into GS and SL groups. Both groups performed a total of 240 GS and 240 SL turns at 2 different course settings. The overall trunk movement components (frontal bending, lateral bending, and torsion angle) were measured using 2 inertial measurement units fixed on the sacrum and sternum. Total ground-reaction forces were measured by pressure insoles. RESULTS: In SL, ground-reaction force peaks were significantly lower when the gate offset was increased, while in GS, no differences between course settings were observed. During the turn phase in which the highest spinal disc loading is expected to occur, the back-loading patterns in both GS and SL included a combination of frontal bending, lateral bending, and torsion in the loaded trunk. SL was characterized by shorter turns, lower frontal and lateral bending angles after gate passage, and a trend toward greater total ground-reaction force peaks compared with GS. CONCLUSION: Course setting is a reasonable measure to reduce the skier's overall back loading in SL but not in GS. The distinct differences observed between GS and SL should be taken into account when defining discipline-specific prevention measures for back overuse injuries. CLINICAL RELEVANCE: To reduce the magnitude of the overall back loading, in SL, minimal gate offsets should be avoided. Prevention measures in GS might particularly need to control and/or reduce the magnitude of frontal and lateral bending in the loaded trunk, whereas prevention measures in SL might especially need to mitigate the short and high total ground-reaction force peaks. PMID- 26977421 TI - Assessment of Intraoperative Intra-articular Morphine and Clonidine Injection in the Acute Postoperative Period After Hip Arthroscopy. AB - BACKGROUND: Previous authors have suggested that intra-articular morphine and clonidine injections after knee arthroscopy have demonstrated equivocal analgesic effect in comparison with bupivacaine while circumventing the issue of chondrotoxicity. There have been no studies evaluating the effect of intra articular morphine after hip arthroscopy. PURPOSE: To evaluate the efficacy of intra-articular morphine in combination with clonidine on postoperative pain and narcotic consumption after hip arthroscopy surgery for femoroacetabular impingement. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective chart review was performed on 43 patients that underwent hip arthroscopy for femoroacetabular impingement at a single institution between September 2014 and May 2015. All patients received preoperative celecoxib and acetaminophen, and 22 patients received an additional intra-articular injection of 10 mg morphine and 100 MUg of clonidine at the conclusion of the procedure. Narcotic consumption, duration of anesthesia recovery, and perioperative pain scores were compared between the 2 groups. RESULTS: Patients who received intra articular morphine and clonidine used significantly less opioid analgesic (mEq) in the postanesthesia recovery (median difference, 17 mEq [95% CI, -32 to -2 mEq]; P = .02) compared with the control group. There were no differences in time spent in recovery before hospital discharge or in visual analog pain scores recorded immediately postoperatively and at 1 hour after surgery. CONCLUSION: Intraoperative intra-articular injection of morphine and clonidine significantly reduced the narcotic requirement during the postsurgical recovery period after hip arthroscopy. The reduction in postsurgical opioids may decrease adverse effects, improve overall pain management, and lead to better quality of recovery and improved patient satisfaction. PMID- 26977420 TI - Effect of Wedge Insertion Angle on Posterior Tibial Slope in Medial Opening Wedge High Tibial Osteotomy. AB - BACKGROUND: Medial opening wedge high tibial osteotomy (HTO) is a well established surgery for medial compartment knee osteoarthritis (OA) wherein the lower extremity is realigned to shift the load distribution from the medial compartment of the knee to the lateral compartment. However, this surgery is known to affect the posterior tibial slope angle (PTSA), which could lead to abnormal knee kinematics and instability, and eventually to knee OA. Although PTSA control is as important as coronal realignment, few appropriate measurements for this parameter have been reported. The placement of a wedge spacer might have an effect on PTSA. PURPOSE: To elucidate the relationship between the PTSA and the direction of insertion of a wedge spacer. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This study assessed 43 knees from 34 patients who underwent medial opening wedge HTO for knee OA. Pre- and postoperative lateral radiographs of the knee as well as postoperative computed tomography scans were performed to evaluate the relationship among PTSA, wedge insertion angle (WIA), and opening gap ratio (distance of the anterior opening gap/distance of the posterior opening gap at the osteotomy site). RESULTS: The PTSA significantly increased from 9.0 degrees +/- 2.8 degrees preoperatively to 13.2 degrees +/- 4.1 degrees postoperatively (P < .001), resulting in a mean DeltaPTSA of 4.7 degrees +/- 4.5 degrees . The mean opening gap ratio was 0.86 +/- 0.11, and the mean WIA was 25.9 degrees +/- 8.4 degrees . The WIA and opening gap ratio were both highly correlated with DeltaPTSA (r = 0.71 and 0.72, respectively), implying that a smaller WIA or smaller gap ratio leads to less increase in posterior slope. CONCLUSION: The direction of wedge insertion is highly correlated with PTSA increase, which suggests that the PTSA can be controlled for by adjusting the direction of wedge insertion during surgery. CLINICAL RELEVANCE: Study results suggest that it is possible to adjust the PTSA by controlling the WIA during surgery. Proper attention to WIA can avoid an iatrogenic increase in posterior tibial slope. PMID- 26977422 TI - Chao Yuanfang: Imperial Physician of the Sui Dynasty and an Early Pertussis Observer? AB - Early Chinese texts contain extensive disease descriptions, including various texts that contain descriptions of modern-day conditions. During the Sui Dynasty, a leading scholar, Chao Yuanfang, may have authored a leading treatise 1400 years ago. Although these texts are the subject of ongoing research, evidence suggests that a clinical syndrome consistent with pertussis was observed in ancient China. PMID- 26977425 TI - Data on in vitro and in vivo cell orientation on substrates with different topographies. AB - This data article contains data related to the research article entitled "Substrate topography: A valuable in vitro tool, but a clinical red herring for in vivo tenogenesis" [1]. We report measurements on tenocyte viability, metabolic activity and proliferation on substrates with different topographies. We also report the effect of substrates with different topographies on host cells in a subcutaneous model. PMID- 26977423 TI - Immunoadsorption therapy in autoimmune encephalitides. AB - OBJECTIVE: It was hypothesized that in encephalitides with autoantibodies directed to CNS surface antigens an antibody-removing intervention might speed up recovery. METHODS: The outcome of autoimmune encephalitis in 19 patients with antibodies against surface antigens (leucine-rich, glioma inactivated 1 [LGI1], n = 3; contactin-associated protein-2 [CASPR2], n = 4; NMDA receptor [NMDAR], n = 7) and intracellular antigens (glutamic acid decarboxylase [GAD], n = 5) after immunoadsorption in addition to corticosteroid therapy was evaluated retrospectively. Modified Rankin scale (mRS) scores and data on seizures, memory, and antibody titers directly after immunoadsorption (early follow-up) and after a median of 4 months (late follow-up) were compiled. RESULTS: Immediately after immunoadsorption, 9 of 14 patients with antibodies against LGI1, CASPR2, or NMDAR (64%), but none with GAD antibodies, had improved by at least one mRS point. Five of the 7 patients with LGI1 or CASRP2 antibodies had become seizure-free, and 2 patients with NMDAR antibodies had a memory improvement of more than 1 SD of a normal control population. At late follow-up, 12 of 14 patients with surface antibodies had improved (86%), and none of the patients with GAD antibodies. CONCLUSIONS: It is suggested that addition of immunoadsorption to immunosuppression therapy in patients with surface antibodies may accelerate recovery. This supports the pathogenic role of surface antibodies. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that immunoadsorption combined with immunosuppression therapy is effective in patients with autoimmune encephalitis with surface antibodies. PMID- 26977424 TI - Self-medication with sucrose. AB - For many individuals, stress promotes the consumption of sweet, high-sugar foods relative to healthier alternatives. Daily life stressors stimulate the overeating of highly-palatable foods through multiple mechanisms, including altered glucocorticoid, relaxin-3, ghrelin and serotonin signaling in brain. In turn, a history of consuming high-sugar foods attenuates the psychological (anxiety and depressed mood) and physiological (HPA axis) effects of stress. Together the metabolic and hedonic properties of sucrose contribute to its stress relief, possibly via actions in both the periphery (e.g., glucocorticoid receptor signaling in adipose tissue) and in the brain (e.g., plasticity in brain reward regions). Emerging work continues to reveal the bidirectional mechanisms that underlie the use of high-sugar foods as 'self-medication' for stress relief. PMID- 26977427 TI - Data in support of the negative influence of divalent cations on (-) epigallocatechin-3-gallate (EGCG)-mediated inhibition of matrix metalloproteinase 2 (MMP-2). AB - In this data article we have provided evidence for the negative influence of divalent cations on (-)-epigallocatechin-3-gallate (EGCG)-mediated inhibition of matrix metalloproteinase-2 (MMP-2) activity in cell-free experiments. Chelating agents, such as EDTA and sodium citrate alone, did not affect MMP-2 activity. While EDTA enhanced, excess of divalent cations interfered with EGCG-mediated inhibition of MMP-2. PMID- 26977426 TI - Corrigendum to "Data for proteomic analysis of murine cardiomyocytic HL-1 cells treated with siRNA against tissue factor" [Data Brief 3 (2015) 117-119]. AB - [This corrects the article DOI: 10.1016/j.dib.2015.02.005.]. PMID- 26977428 TI - Dataset for human sensitivity to chemicals during development of motor function. AB - The authors reviewed human data related to motor development following exposure to a subset of chemicals thoroughly reviewed in Agency for Toxic Substances and Disease Registry (ATSDR) Toxicological Profiles and Addenda. The resulting dataset includes the following variables and confounders: chemical name, exposure route, exposure duration and frequency, study design, cohort name and/or geographic location, sex of cohort subjects, NOAEL, and LOAEL. This data summary can help validate motor development outcomes observed in animal exposure studies; it can also aid in determining whether these outcomes and corresponding exposure windows are relevant to humans. PMID- 26977429 TI - Summary of clinical and laboratory data of study subjects with and without DCE MRI plaque measurements in the AIM-HIGH clinical trial. AB - This brief data article summarizes the clinical risk factors and laboratory data of a group of subjects recruited for the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes) and an associated magnetic resonance imaging (MRI) substudy. The sample is restricted to those on statin therapy at the time of enrollment and data are presented stratified by whether dynamic contrast enhanced MRI (DCE-MRI) markers of carotid plaque vascularity and inflammation were available or not. The data provided herein are directly related to the article "Longer Duration of Statin Therapy is Associated with Decreased Carotid Plaque Vascularity by Magnetic Resonance Imaging" [2]. PMID- 26977430 TI - Complementary characterization data in support of uniaxially aligned electrospun nanocomposites based on a model PVOH-epoxy system. AB - This paper presents complementary data corresponding to characterization tests done for our research article entitled "Uniaxially aligned electrospun fibers for advanced nanocomposites based on a model PVOH-epoxy system" (Karimi et al., 2016) [1]. Poly(vinyl alcohol) and epoxy resin were selected as a model system and the effect of electrospun fiber loading on polymer properties was examined in conjunction with two manufacturing methods. A novel electrospinning technology for production of uniaxially aligned nanofiber arrays was used. A conventional wet lay-up fabrication method is compared against a novel, hybrid electrospinning electrospraying approach. The structure and thermomechanical properties of resulting composite materials were examined using scanning electron microscopy, dynamic mechanical analysis, thermogravimetric analysis, differential scanning calorimetry, Fourier transform infrared spectroscopy, and tensile testing. For discussion of obtained results please refer to the research paper (Karimi et al., 2016) [1]. PMID- 26977431 TI - Proteomic analysis of the medicinal plant Artemisia annua: Data from leaf and trichome extracts. AB - This article contains raw and processed data related to research published by Bryant et al.[1]. Data was obtained by MS-based proteomics, analysing trichome enriched, trichome-depleted and whole leaf samples taken from the medicinal plant Artemisia annua and searching the acquired MS/MS data against a recently published contig database [2] and other genomic and proteomic sequence databases for comparison. The processed data shows that an order-of-magnitude more proteins have been identified from trichome-enriched Artemisia annua samples in comparison to previously published data. Proteins known to have a role in the biosynthesis of artemisinin and other highly abundant proteins were found which imply additional enzymatically driven processes occurring within the trichomes that are significant for the biosynthesis of artemisinin. PMID- 26977432 TI - Data on individual metabolites of synthetic cannabinoids JWH-018, JWH-073 and AM2201 by Cunninghamella elegans. AB - Synthetic cannabinoids JWH-018, JWH-073 and AM2201 were metabolised by the fungus Cunninghamella elegans. In this article, data on individual metabolites of their retention times, mass accuracies, major product ions and structures indicated by product ions are presented. The data in this article is related to "Biotransformation of synthetic cannabinoids JWH-018, JWH-073 and AM2201 by Cunninghamella elegans" [1]. PMID- 26977433 TI - Dataset of mouse hippocampus profiled by LC-MS/MS for label-free quantitation. AB - This dataset reports on the analysis of mouse hippocampus by LC-MS/MS, from mice fed a diet that was either deficient in n-3 FA (n-3 Def) or sufficient in n-3 FA (n-3 Adq). Label free quantitative (LFQ) analysis of the mass spectrometry data identified 1008 quantifiable proteins, 115 of which were found to be differentially expressed between the two dietary groups (n=8 per group). This data article refers to the research article "Omega-3 fatty acid deficiency disrupts endocytosis, neuritogenesis, and mitochondrial protein pathways in the mouse hippocampus" (English et al., 2013 [1]), in which a more comprehensive interpretation and analysis of the data is given. PMID- 26977435 TI - MS-analysis of SILAC-labeled MYC-driven B lymphoma cells overexpressing miR-17 19b. AB - Micro RNAs (miRNAs) are small non-coding RNAs, which dampen gene expression by repressing translation and/or inducing degradation of target-mRNAs. Although the role of miR-17-19b (a truncated version of miR-17-92 cluster) is well documented in MYC-driven B cell lymphomagenesis, little is known about the function of the cluster in the maintenance of full-blown lymphomas. We employed SILAC-based quantitative proteomics to identify miR-17-19b targets upon a mild overexpression of the cluster in B cell lymphomas, established from lambda-MYC transgenic mice. The proteomics data described in detail in this study, whose follow up analysis with MaxQuant algorithm is part of the recent publication (Mihailovich et al., 2015) [1], are deposited to the ProteomeXchange Consortium via the PRIDE partner repository, with the accession code PRIDE: PXD002810. PMID- 26977434 TI - Structure of the GAT domain of the endosomal adapter protein Tom1. AB - Cellular homeostasis requires correct delivery of cell-surface receptor proteins (cargo) to their target subcellular compartments. The adapter proteins Tom1 and Tollip are involved in sorting of ubiquitinated cargo in endosomal compartments. Recruitment of Tom1 to the endosomal compartments is mediated by its GAT domain's association to Tollip's Tom1-binding domain (TBD). In this data article, we report the solution NMR-derived structure of the Tom1 GAT domain. The estimated protein structure exhibits a bundle of three helical elements. We compare the Tom1 GAT structure with those structures corresponding to the Tollip TBD- and ubiquitin-bound states. PMID- 26977436 TI - Estimation of postmortem interval using the data of insulin level in the cadaver's blood. AB - An assessment of levels of Insulin in cadaveric fluids, to estimate the postmortem interval (PMI) was carried out. To profile postmortem changes of Insulin, it was extracted at different intervals i.e. (0, 3, 6, 12, 24 h), from the heart of 22 human cadavers. The cases included were the subjects of accidental deaths without any prior history of disease and their exact time of death was known. Immunoanalyzer Cobas e-411 instrument was used to detect the relationship between the amount of Insulin and PMI. Level of Insulin was measured in cardiac blood. Statically, significant correlations between levels of Insulin and PMI were studied and correlation coefficients were calculated. SPSS (version 12.0) was used for statistical analysis. Insulin levels in cadaver blood are correlated significantly with PMI with a p value of <0.001. When insulin level increases by 1 unit the duration decreases by 0.93 units. The least square regression line is: [Duration(Y)=22.71-0.93 Insulin level (X)]. PMID- 26977438 TI - Changes over lactation in breast milk serum proteins involved in the maturation of immune and digestive system of the infant. AB - Here we provide data from shot-gun proteomics, using filtered-aided sample preparation (FASP), dimethyl labeling and LC-MS/MS, to quantify the changes in the repertoire of human milk proteins over lactation. Milk serum proteins were analyzed at week 1, 2, 3 4, 8, 16, and 24 in milk from four individual mothers. A total of 247 proteins were identified, of which 200 proteins were quantified. The data supplied in this article supports the accompanying publication (Zhang et al., 2006) [1]. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (Vizcaino et al., 2016) [2] via the PRIDE partner repository with the dataset identifier PXD003465. PMID- 26977437 TI - The effect of statins therapy in aortic stenosis: Meta-analysis comparison data of RCTs and observationals. AB - Aortic stenosis has been shown to share the same risk factors as atherosclerosis which suggested a potential benefit from statins therapy. Fourteen studies which provided the effect of statins treatment on aortic stenosis (AS) were meta analyzed, including 5 randomized controlled trials (RCTs) and 9 observational studies. In the RCTs, statins did not have any influence on peak aortic valve velocity, peak valve gradient, mean valve gradient, aortic valve area and aortic calcification compared to controls. In the observational studies, the peak valve velocity, peak gradient and aortic valve area showed less progression in the statins group compared to controls. This article describes data related article title "The effect of statins on valve function and calcification in aortic stenosis: a meta-analysis" (Zhao et al., 2016) [1]. PMID- 26977439 TI - Behavioral data of thin-film single junction amorphous silicon (a-Si) photovoltaic modules under outdoor long term exposure. AB - Four years' behavioral data of thin-film single junction amorphous silicon (a-Si) photovoltaic (PV) modules installed in a relatively dry and sunny inland site with a Continental-Mediterranean climate (in the city of Jaen, Spain) are presented in this article. The shared data contributes to clarify how the Light Induced Degradation (LID) impacts the output power generated by the PV array, especially in the first days of exposure under outdoor conditions. Furthermore, a valuable methodology is provided in this data article permitting the assessment of the degradation rate and the stabilization period of the PV modules. Further discussions and interpretations concerning the data shared in this article can be found in the research paper "Characterization of degradation and evaluation of model parameters of amorphous silicon photovoltaic modules under outdoor long term exposure" (Kichou et al., 2016) [1]. PMID- 26977440 TI - Effects of glia metabolism inhibition on nociceptive behavioral testing in rats. AB - Fluoroacetate has been widely used to inhibit glia metabolism in vivo. It has yet to be shown what the effects of chronic intrathecal infusion of fluoroacetate on nociceptive behavioral testing are. The effects of chronic infusion of fluoroacetate (5 nmoles/h) for 2 weeks were examined in normal rats. Chronic intrathecal fluoroacetate did not alter mechanical threshold (von Frey filaments), responses to supra-threshold mechanical stimuli (von Frey filaments), responses to hot (hot plate) or cool (acetone test) stimuli and did not affect motor performance of the animals, which was tested with rotarod. This suggests that fluoroacetate at appropriate dose did not suppress neuronal activity in the spinal cord. PMID- 26977441 TI - Dataset of calcified plaque condition in the stenotic coronary artery lesion obtained using multidetector computed tomography to indicate the addition of rotational atherectomy during percutaneous coronary intervention. AB - Our data shows the regional coronary artery calcium scores (lesion CAC) on multidetector computed tomography (MDCT) and the cross-section imaging on MDCT angiography (CTA) in the target lesion of the patients with stable angina pectoris who were scheduled for percutaneous coronary intervention (PCI). CAC and CTA data were measured using a 128-slice scanner (Somatom Definition AS+; Siemens Medical Solutions, Forchheim, Germany) before PCI. CAC was measured in a non contrast-enhanced scan and was quantified using the Calcium Score module of SYNAPSE VINCENT software (Fujifilm Co. Tokyo, Japan) and expressed in Agatston units. CTA were then continued with a contrast-enhanced ECG gating to measure the severity of the calcified plaque condition. We present that both CAC and CTA data are used as a benchmark to consider the addition of rotational atherectomy during PCI to severely calcified plaque lesions. PMID- 26977442 TI - Supporting data for characterization of non-coding RNAs associated with the Neuronal growth regulator 1 (NEGR1) adhesion protein. AB - Long non-coding RNAs and microRNAs control gene expression to determine central nervous system development and function. Neuronal growth regulator 1 (NEGR1) is a cell adhesion molecule that plays an important role in neurite outgrowth during neuronal development and its precise expression is crucial for correct brain development. The data described here is related to the research article titled "A long non-coding RNA, BC048612 and a microRNA, miR-203 coordinate the gene expression of Neuronal growth regulator 1 (NEGR1) adhesion protein" [1]. This data article contains detailed bioinformatics analysis of genetic signatures at the Negr1 gene locus retrieved from the UCSC genome browser. This approach could be adopted to identify putative regulatory non-coding RNAs in other tissues and diseases. PMID- 26977444 TI - Data supporting the absence of FNR dynamic photosynthetic membrane recruitment in trol mutants. AB - In photosynthesis, the flavoenzyme ferredoxin:NADP(+) oxidoreductase (FNR) catalyses the final electron transfer from ferredoxin to NADP(+), which is considered as the main pathway of high-energy electron partitioning in chloroplasts (DOI: 10.1111/j.1365-313X.2009.03999.x[1], DOI: 10.1038/srep10085[2]). Different detergents and pH treatments of photosynthetic membranes isolated from the Arabidopsis wild-type (WT) and the loss-of-function mutants of the thylakoid rhodanase-like protein TROL (trol), pre-acclimated to either dark, growth-light, or high-light conditions, were used to probe the strength of FNR-membrane associations. Detergents beta-DM (decyl-beta-D maltopyranoside) or beta-DDM (n-dodecyl-beta-D-maltopyranoside) were used to test the stability of FNR binding to the thylakoid membranes, and to assess different membrane domains containing FNR. Further, the extraction conditions mimicked pH status of chloroplast stroma during changing light regimes. Plants without TROL are incapable of the dynamic FNR recruitment to the photosynthetic membranes. PMID- 26977443 TI - Dataset of liver proteins changed in eu- and hypothyroid female rats upon in vivo exposure to hexabromocyclododecane (HBCD). AB - Female Wistar rats with different thyroid status (eu-, hypothyroid) were exposed to 0, 3 or 30 mg/kg body weight of the flame retardant HBCD for 7 days. Changes in protein patterns obtained by 2D-DIGE were evaluated, and different animal groups compared taking into account their exposure and thyroid status. Proteins significantly altered in abundance in any of these comparisons were identified by mass spectrometry. These data, together with hormone data of the animals, are discussed in "Hexa-bromocyclododecane (HBCD) induced changes in the liver proteome of eu- and hypothyroid female rats" (Miller et al., 2016) [1]. PMID- 26977445 TI - Validation, optimisation, and application data in support of the development of a targeted selected ion monitoring assay for degraded cardiac troponin T. AB - Cardiac troponin T (cTnT) fragmentation in human serum was investigated using a newly developed targeted selected ion monitoring assay, as described in the accompanying article: "Development of a targeted selected ion monitoring assay for the elucidation of protease induced structural changes in cardiac troponin T" [1]. This article presents data describing aspects of the validation and optimisation of this assay. The data consists of several figures, an excel file containing the results of a sequence identity search, and a description of the raw mass spectrometry (MS) data files, deposited in the ProteomeXchange repository with id PRIDE: PXD003187. PMID- 26977446 TI - Data supporting the cardiac mitochondria calcium handling in female normotensive and spontaneously hypertensive rats. AB - In association with the published article "Mitochondrial calcium handling in normotensive and spontaneously hypertensive rats: correlation with systolic blood pressure levels" [1], this data article contains information about calcium handling of cardiac mitochondria isolated from female of both rats strains (WKY and SHR). Dataset of mitochondrial permeability transition pore (mPTP) resistance to opening Ca(2+)-mediated, Ca(2+) retention capacity (CRC), time constants and mitochondrial membrane potential (DeltaPsim) are showed. PMID- 26977447 TI - Data for global lysine-acetylation analysis in rice (Oryza sativa). AB - Rice is one of the most important crops for human consumption and is a staple food for over half of the world's population (Yu et al., 2002) [1]. A systematic identification of the lysine acetylome was performed by our research (Xiong et al., 2016) [2]. Rice plant samples were collected from 5 weeks old seedlings (Oryza sativa, Nipponbare). After the trypsin digestion and immunoaffinity precipitation, LC-MS/MS approach was used to identify acetylated peptides. After the collected MS/MS data procession and GO annotation, the InterProScan was used to annotate protein domain. Subcellular localization of the identified acetylated proteins was predicted by WoLF PSORT. The KEGG pathway database was used to annotate identified acetylated protein interactions, reactions, and relations. The data, supplied in this article, are related to "A comprehensive catalog of the lysine-acetylation targets in rice (O. sativa) based on proteomic analyses" by Xiong et al. (2016) [2]. PMID- 26977448 TI - SILAC based protein profiling data of MKK3 knockout mouse embryonic fibroblasts. AB - This data article reports changes in the phospho and total proteome of MKK3 knock out (MKK3(-) (/) (-)) mouse embryonic fibroblasts (MEFs). The dataset generated highlights the changes at protein level which can be helpful for understanding targets of the MAP kinase signaling pathway. Data was collected after TiO2-based phosphopeptide enrichment of whole cell lysate at baseline condition with bottom up SILAC-based LC MS/MS quantitative mass spectrometry. We report all the proteins and peptides identified and quantified in MKK3(-/-) and WT MEFs. The altered pathways in MKK3(-/-) MEFs were analyzed by Database for Annotation, Visualization and Integrated Discovery (DAVID, v6.7) and Ingenuity Pathway Analysis (IPA) and are presented as a table and graph, respectively. The data reported here is related to the published work [1]. All the associated mass spectrometry data has been deposited in the Yale Protein Expression Database (YPED) with the web-link to the data: http://yped.med.yale.edu/repository/ViewSeriesMenu.do;jsessionid=6A5CB07543D8B529 AE8C3FCFE29471D?series_id=5044&series_name=MMK3+Deletion+in+MEFs. PMID- 26977449 TI - Diagnostic Phase of Calcium Scoring Scan Applied as the Center of Acquisition Window of Coronary Computed Tomography Angiography Improves Image Quality in Minimal Acquisition Window Scan (Target CTA Mode) Using the Second Generation 320 Row CT. AB - OBJECTIVE: To compare the image quality of coronary computed tomography angiography (CCTA) acquired under two conditions: 75% fixed as the acquisition window center (Group 75%) and the diagnostic phase for calcium scoring scan as the center (CS; Group CS). METHODS: 320-row cardiac CT with a minimal acquisition window (scanned using "Target CTA" mode) was performed on 81 patients. In Group 75% (n = 40), CS was obtained and reconstructed at 75% and the center of the CCTA acquisition window was set at 75%. In Group CS (n = 41), CS was obtained at 75% and the diagnostic phase showing minimal artifacts was applied as the center of the CCTA acquisition window. Image quality was evaluated using a four-point scale (4-excellent) and the mean scores were compared between groups. RESULTS: The CCTA scan diagnostic phase occurred significantly earlier in CS (75.7 +/- 3.2% vs. 73.6 +/- 4.5% for Groups 75% and CS, resp., p = 0.013). The mean Group CS image quality score (3.58 +/- 0.63) was also higher than that for Group 75% (3.19 +/- 0.66, p < 0.0001). CONCLUSIONS: The image quality of CCTA in Target CTA mode was significantly better when the center of acquisition window is adjusted using CS. PMID- 26977450 TI - Intelligent Soft Computing on Forex: Exchange Rates Forecasting with Hybrid Radial Basis Neural Network. AB - This paper deals with application of quantitative soft computing prediction models into financial area as reliable and accurate prediction models can be very helpful in management decision-making process. The authors suggest a new hybrid neural network which is a combination of the standard RBF neural network, a genetic algorithm, and a moving average. The moving average is supposed to enhance the outputs of the network using the error part of the original neural network. Authors test the suggested model on high-frequency time series data of USD/CAD and examine the ability to forecast exchange rate values for the horizon of one day. To determine the forecasting efficiency, they perform a comparative statistical out-of-sample analysis of the tested model with autoregressive models and the standard neural network. They also incorporate genetic algorithm as an optimizing technique for adapting parameters of ANN which is then compared with standard backpropagation and backpropagation combined with K-means clustering algorithm. Finally, the authors find out that their suggested hybrid neural network is able to produce more accurate forecasts than the standard models and can be helpful in eliminating the risk of making the bad decision in decision making process. PMID- 26977452 TI - Universal Influenza Vaccines: To Dream the Possible Dream? AB - Influenza viruses are a significant public health threat, causing both annually circulating epidemics and unpredictable pandemics. Vaccination is the best means of control against individual cases of influenza and also for decreasing epidemic spread in the population. However, rapid influenza virus evolution requires continual reformulation of vaccines for annual influenza epidemics, and because pandemics cannot be accurately predicted, no current vaccine strategy can induce broad protection against all subtypes of influenza viruses. Recent work has suggested that such broadly protective, or "universal", influenza virus vaccines might be achievable using vaccine strategies that target conserved B- and T-cell epitopes. PMID- 26977451 TI - Analysis of Dental Enamel Surface Submitted to Fruit Juice Plus Soymilk by Micro X-Ray Fluorescence: In Vitro Study. AB - OBJECTIVE: This paper aimed to analyze the in vitro industrialized fruit juices effect plus soy to establish the erosive potential of these solutions. MATERIALS AND METHODS: Seventy bovine incisors were selected after being evaluated under stereomicroscope. Their crowns were prepared and randomly divided into 7 groups, using microhardness with allocation criteria. The crowns were submitted to the fruit juice plus soy during 15 days, twice a day. The pH values, acid titration, and Knoop microhardness were recorded and the specimens were evaluated using X ray microfluorescence (uXRF). RESULTS: The pH average for all juices and after 3 days was significantly below the critical value for dental erosion. In average, the pH value decreases 14% comparing initial time and pH after 3 days. Comparing before and after, there was a 49% microhardness decrease measured in groups (p < 0.05). Groups G1, G2, G5, and G6 are above this average. The analysis by MUXRF showed a decrease of approximately 7% Ca and 4% P on bovine crowns surface. Florida (FL) statistical analysis showed a statistically significant 1 difference between groups. Thus, a tooth chance to suffer demineralization due to industrialized fruit juices plus soy is real. PMID- 26977456 TI - Which "truths" will be proven false this year? AB - I continue to be amazed at the widespread changes in what we consider to be the correct approach to diagnosis and treatment of even common ailments. Several articles in this issue discuss new "truths, " or at least truths as we know them today. PMID- 26977454 TI - Altered Neural Processing to Social Exclusion in Young Adult Marijuana Users. AB - Previous studies have reported that peer groups are one of the most important predictors of adolescent and young adult marijuana use, and yet the neural correlates of social processing in marijuana users have not yet been studied. In the current study, marijuana-using young adults (n = 20) and non-using controls (n = 22) participated in a neuroimaging social exclusion task called Cyberball, a computerized ball-tossing game in which the participant is excluded from the game after a pre-determined number of ball tosses. Controls, but not marijuana users, demonstrated significant activation in the insula, a region associated with negative emotion, when being excluded from the game. Both groups demonstrated activation of the ventral anterior cingulate cortex (vACC), a region associated with affective monitoring, during peer exclusion. Only the marijuana group showed a correlation between vACC activation and scores on a self-report measure of peer conformity. This study indicates that marijuana users show atypical neural processing of social exclusion, which may be either caused by, or the result of, regular marijuana use. PMID- 26977457 TI - The solution to EHR woes: A team-based care model. PMID- 26977458 TI - What next when metformin isn't enough for type 2 diabetes? AB - This patient-centered case vignette offers insight into how best to choose among additional oral agents, basal insulin, or the newer GLP-1 receptor agonists. PMID- 26977453 TI - Sex and diagnosis specific associations between DNA methylation of the oxytocin receptor gene with emotion processing and temporal-limbic and prefrontal brain volumes in psychotic disorders. AB - BACKGROUND: The oxytocin (OT) system, including receptor epigenetic mechanisms, has been shown to influence emotion processing, especially in females. Whether OT receptor (OXTR) epigenetic alterations occur across psychotic disorders in relation to illness-related disturbances in social cognition and brain anatomy is unknown. METHODS: Participants with affective and nonaffective psychotic disorders (92 women, 75 men) and healthy controls (38 women, 37 men) from the Chicago site of the BSNIP study completed the Penn Emotion Recognition Test (ER 40), a facial emotion recognition task. We measured cytosine methylation at site 934 upstream of the OXTR start codon in DNA from whole blood, and for the first time their relationship with plasma OT levels assessed by enzyme-immunoassay. Volumes of brain regions supporting social cognition were measured from MRI scans using FreeSurfer. RESULTS: Patients with prototypic schizophrenia features showed higher levels of DNA methylation than those with prototypic bipolar features. Methylation was higher in women than men, and was associated with poorer emotion recognition only in female patients and controls. Greater methylation was associated with smaller volumes in temporal-limbic and prefrontal regions associated previously with social cognition, but only in healthy women and females with schizophrenia. CONCLUSION: DNA methylation of the OXTR site -934 was higher in schizophrenia spectrum than bipolar patients. Among patients, it was linked to behavioral deficits in social cognition and neuroanatomic structures known to support emotion processing only in schizophrenia spectrum individuals. PMID- 26977455 TI - Point-of-Care Technologies for Precision Cardiovascular Care and Clinical Research: National Heart, Lung, and Blood Institute Working Group. AB - Point-of-care technologies (POC or POCT) are enabling innovative cardiovascular diagnostics that promise to improve patient care across diverse clinical settings. The National Heart, Lung, and Blood Institute convened a working group to discuss POCT in cardiovascular medicine. The multidisciplinary working group, which included clinicians, scientists, engineers, device manufacturers, regulatory officials, and program staff, reviewed the state of the POCT field; discussed opportunities for POCT to improve cardiovascular care, realize the promise of precision medicine, and advance the clinical research enterprise; and identified barriers facing translation and integration of POCT with existing clinical systems. A POCT development roadmap emerged to guide multidisciplinary teams of biomarker scientists, technologists, health care providers, and clinical trialists as they: 1) formulate needs assessments; 2) define device design specifications; 3) develop component technologies and integrated systems; 4) perform iterative pilot testing; and 5) conduct rigorous prospective clinical testing to ensure that POCT solutions have substantial effects on cardiovascular care. PMID- 26977460 TI - Pulmonary nodule on x-ray: An algorithmic approach. AB - The best way to manage a pulmonary nodule depends on the patient's history, risk factors for cancer, and nodule characteristics. This review can guide you. PMID- 26977459 TI - Personality disorders: A measured response. AB - Improving your understanding of these disorders will help you identify specific diagnoses, ensure appropriate treatment, and reduce frustration during office visits. PMID- 26977461 TI - Knee pain . no popping . no previous trauma . Dx? AB - A 36-year-old man sought care at our family medicine clinic for knee pain that he'd had for the past year. He denied any previous injury or trauma to the knee. The pain affected the posterolateral left knee and was aggravated by squatting and deep flexion. Daily activities did not bother him, but skiing, golfing, mountain biking, and lifting weights worsened the pain. His pain had gradually become more severe and frequent. He denied any mechanical symptoms such as catching, popping, or locking. PMID- 26977462 TI - PURLs: Kidney stones? It's time to rethink those meds. AB - Despite being recommended for ureteral stone expulsion, tamsulosin or nifedipine are no more effective than placebo. PMID- 26977464 TI - Clinical Inquiry: Do corticosteroid injections improve carpal tunnel syndrome symptoms? AB - Yes. Injected corticosteroids reduce symptoms of carpal tunnel syndrome (CTS) more effectively than placebo or systemic steroids, but no better than anti inflammatory medication and splinting, from one to 12 weeks after therapy. PMID- 26977463 TI - Stiff hands and feet, facial deformities. AB - The appearance of the skin on this woman's face, hands, and feet helped us to recognize an advanced case of an autoimmune disease. PMID- 26977465 TI - Clinical Inquiry: Is lower BP worth it in higher-risk patients with diabetes or coronary disease? AB - There is no simple answer; the risk/benefit picture is complicated. Controlling blood pressure to a target of 130/80 mm Hg or lower produces mixed results in patients with diabetes and coronary disease equivalents. PMID- 26977466 TI - Spirituality can play a role in treating depression. PMID- 26977467 TI - Risk of a contaminated urine specimen linked to high BMI. PMID- 26977468 TI - These umbilical lesions weren't granulomas after all. AB - Consider a VID remnant as part of the differential diagnosis for any patient who has what appears to be a granulomatous umbilical lesion. Order ultrasonography to evaluate a suspected VID, especially for lesions that fail to respond to 2 or 3 silver nitrate treatments. Surgical excision of a VID remnant is usually curative. PMID- 26977476 TI - Modeling of band-3 protein diffusion in the normal and defective red blood cell membrane. AB - We employ a two-component red blood cell (RBC) membrane model to simulate lateral diffusion of band-3 proteins in the normal RBC and in the RBC with defective membrane proteins. The defects reduce the connectivity between the lipid bilayer and the membrane skeleton (vertical connectivity), or the connectivity of the membrane skeleton itself (horizontal connectivity), and are associated with the blood disorders of hereditary spherocytosis (HS) and hereditary elliptocytosis (HE) respectively. Initially, we demonstrate that the cytoskeleton limits band-3 lateral mobility by measuring the band-3 macroscopic diffusion coefficients in the normal RBC membrane and in a lipid bilayer without the cytoskeleton. Then, we study band-3 diffusion in the defective RBC membrane and quantify the relation between band-3 diffusion coefficients and percentage of protein defects in HE RBCs. In addition, we illustrate that at low spectrin network connectivity (horizontal connectivity) band-3 subdiffusion can be approximated as anomalous diffusion, while at high horizontal connectivity band-3 diffusion is characterized as confined diffusion. Our simulations show that the band-3 anomalous diffusion exponent depends on the percentage of protein defects in the membrane cytoskeleton. We also confirm that the introduction of attraction between the lipid bilayer and the spectrin network reduces band-3 diffusion, but we show that this reduction is lower than predicted by the percolation theory. Furthermore, we predict that the attractive force between the spectrin filament and the lipid bilayer is at least 20 times smaller than the binding forces at band-3 and glycophorin C, the two major membrane binding sites. Finally, we explore diffusion of band-3 particles in the RBC membrane with defects related to vertical connectivity. We demonstrate that in this case band-3 diffusion can be approximated as confined diffusion for all attraction levels between the spectrin network and the lipid bilayer. By comparing the diffusion coefficients measured in horizontal vs. vertical defects, we conclude that band-3 mobility is primarily controlled by the horizontal connectivity. PMID- 26977477 TI - From structures to functions: insights into exosomes as promising drug delivery vehicles. AB - Exosomes are small membrane vesicles secreted by most cell types, and appear ubiquitously in cell culture supernatants and body fluids. Increasing evidence supports that exosomes play important roles in intercellular communication, both locally and systemically, by transporting their contents such as proteins, lipids and RNAs between cells. Of particular interest for controlled drug delivery is that cell-derived exosomes offer the possibilities of overcoming biological barriers, thereby allowing the incorporated gene and drug to reach targeted tissue, which have been considerable challenges for synthetic carriers. Great research efforts have been dedicated to developing exosome-based drug delivery systems for the treatment of inflammatory diseases, degenerative disorders and cancer. In this review, we will describe the structural and functional properties of exosomes and emphasize current advances in the therapeutic applications of exosomes as drug delivery vehicles, followed by a discussion on current challenges and future perspectives. PMID- 26977478 TI - Direct organelle thermometry with fluorescence lifetime imaging microscopy in single myotubes. AB - We describe organelle thermometry using an endoplasmic reticulum-targeting small molecule dye and cytosolic mCherry, whose fluorescence lifetimes reduce with increasing temperature and can be monitored by fluorescence lifetime imaging microscopy. The results show that heat production in single myotubes is highly localized and is coupled to a Ca(2+) burst. PMID- 26977479 TI - The Genetic Evolution of Melanoma. PMID- 26977480 TI - Sexual science beyond the medical. PMID- 26977481 TI - Norman Edward Breslow. PMID- 26977482 TI - Paying for performance: money, motivation, and uncertainty. PMID- 26977483 TI - Alfred Goodman Gilman. PMID- 26977484 TI - [Irritated esophageal picture]. PMID- 26977485 TI - [Physicians seldom test for hepatitis C]. PMID- 26977486 TI - [HBV post-exposure prevention apparently still effective after 24 hours]. PMID- 26977487 TI - [Gender prevention: let us allow the man to be a man!]. PMID- 26977488 TI - [It is crucial with whom one eats!]. PMID- 26977489 TI - [What is better: rapid or slow weight loss?]. PMID- 26977490 TI - [Is the diabetic patient a victim of his genes?]. PMID- 26977491 TI - [Noise as a diabetes risk factor]. PMID- 26977492 TI - [Lowering blood glucose has little effect: myth or fact?]. PMID- 26977493 TI - [Mobilize your patients to prevent backache!]. PMID- 26977494 TI - [Statins for almost anyone but individualized]. PMID- 26977495 TI - [Western diet promotes acne development]. PMID- 26977497 TI - [Using the whole arsenal to prevent an attack]. PMID- 26977496 TI - [Photothermolysis for acne control]. PMID- 26977498 TI - [Audit bodies must provide concrete reasons]. PMID- 26977499 TI - [The general practitioner in charge in outpatient operations]. PMID- 26977500 TI - [Securing future reimbursement for palliative medicine]. PMID- 26977501 TI - [A high pressure talking young chatterbox]. PMID- 26977502 TI - [A contagious opera fever]. PMID- 26977503 TI - [Physician network tests collegial peer collaboration]. PMID- 26977504 TI - [Incontinence certificates are stressful!]. PMID- 26977505 TI - [Blood glucose test strips count as medications]. PMID- 26977506 TI - [The red line for intrusive patients]. PMID- 26977507 TI - [Testosterone supplementation can lead to better sex]. PMID- 26977508 TI - [Free choice of diet does not work better]. PMID- 26977509 TI - [Hypertension: adherence affects the prognosis]. PMID- 26977510 TI - [Asthmatic mothers tend to prematurity]. PMID- 26977511 TI - [Biliary pancreatitis: Remove Gallbladder immediately]. PMID- 26977513 TI - [Do not lower blood pressure too low in dementia]. PMID- 26977512 TI - [Coffee lowers in a study blood pressure]. PMID- 26977514 TI - [Diagnosis and therapy of bladder cancer]. PMID- 26977516 TI - [Graded compression stockings and deep vein thrombosis]. PMID- 26977515 TI - [Transcranial direct current stimulation (tDCS) for the treatment of depression]. PMID- 26977517 TI - [A red hand - getting worse by corticosteroids]. PMID- 26977518 TI - [Emergency checklist: Upper gastrointestinal bleeding]. PMID- 26977519 TI - [Asthma bronchiale and risk of infection. "Its now time to prepare patients for autumn and winter"]. PMID- 26977520 TI - [Nodules are frequent - cancer is rare]. PMID- 26977521 TI - [Good efficacy and safety profile in clinical practice]. PMID- 26977522 TI - [Endobronchial coils for better quality of life]. PMID- 26977523 TI - [An advanced course in doctor's latin]. PMID- 26977524 TI - [Doctor plus pharmacist plus patient care plus ... Simple addition or equation with many unknowns?]. PMID- 26977525 TI - Dual-Functional Antifogging/Antimicrobial Polymer Coating. AB - Dual-functional antifogging/antimicrobial polymer coatings were prepared by forming a semi-interpenetrating polymer network (SIPN) of partially quaternized poly(2-(dimethylamino)ethyl methacrylate-co-methyl methacrylate) and polymerized ethylene glycol dimethacrylate network. The excellent antifogging behavior of the smooth coating was mainly attributed to the hydrophilic/hydrophobic balance of the partially quaternized copolymer, while the covalently bonded, hydrophobic quaternary ammonium compound (5 mol % in the copolymer) rendered the coating strongly antimicrobial, as demonstrated by the total kill against both Gram positive Staphylococcus epidermidis and Gram-negative Escherichia coli. The antimicrobial action of the SIPN coating was based on contact killing, without leaching of bactericidal species, as revealed by a zone-of-inhibition test. This type of dual-functional coating may find unique applications where both antimicrobial and antifogging properties are desired. PMID- 26977526 TI - Rational Design of ZnO:H/ZnO Bilayer Structure for High-Performance Thin-Film Transistors. AB - The intriguing properties of zinc oxide-based semiconductors are being extensively studied as they are attractive alternatives to current silicon-based semiconductors for applications in transparent and flexible electronics. Although they have promising properties, significant improvements on performance and electrical reliability of ZnO-based thin film transistors (TFTs) should be achieved before they can be applied widely in practical applications. This work demonstrates a rational and elegant design of TFT, composed of poly crystalline ZnO:H/ZnO bilayer structure without using other metal elements for doping. The field-effect mobility and gate bias stability of the bilayer structured devices have been improved. In this device structure, the hydrogenated ultrathin ZnO:H active layer (~3 nm) could provide suitable carrier concentration and decrease the interface trap density, while thick pure-ZnO layer could control channel conductance. Based on this novel structure, a high field-effect mobility of 42.6 cm(2) V(-1) s(-1), a high on/off current ratio of 10(8) and a small subthreshold swing of 0.13 V dec(-1) have been achieved. Additionally, the bias stress stability of the bilayer structured devices is enhanced compared to the simple single channel layer ZnO device. These results suggest that the bilayer ZnO:H/ZnO TFTs have a great potential for low-cost thin-film electronics. PMID- 26977527 TI - Physicologically Based Toxicokinetic Models of Tebuconazole and Application in Human Risk Assessment. AB - A series of physiologically based toxicokinetic (PBTK) models for tebuconazole were developed in four species, rat, rabbit, rhesus monkey, and human. The developed models were analyzed with respect to the application of the models in higher tier human risk assessment, and the prospect of using such models in risk assessment of cumulative and aggregate exposure is discussed. Relatively simple and biologically sound models were developed using available experimental data as parameters for describing the physiology of the species, as well as the absorption, distribution, metabolism, and elimination (ADME) of tebuconazole. The developed models were validated on in vivo half-life data for rabbit with good results, and on plasma and tissue concentration-time course data of tebuconazole after i.v. administration in rabbit. In most cases, the predicted concentration levels were seen to be within a factor of 2 compared to the experimental data, which is the threshold set for the use of PBTK simulation results in risk assessment. An exception to this was seen for one of the target organs, namely, the liver, for which tebuconazole concentration was significantly underestimated, a trend also seen in model simulations for the liver after other nonoral exposure scenarios. Possible reasons for this are discussed in the article. Realistic dietary and dermal exposure scenarios were derived based on available exposure estimates, and the human version of the PBTK model was used to simulate the internal levels of tebuconazole and metabolites in the human body for these scenarios. By a variant of the models where the R(-)- and S(+)-enantiomers were treated as two components in a binary mixture, it was illustrated that the inhibition between the two tebuconazole enantiomers did not affect the simulation results for these realistic exposure scenarios. The developed models have potential as an important tool in risk assessment. PMID- 26977528 TI - Convenient One-Step Synthesis of Benzo[c]phenanthridines by Three-Component Reactions of Isochromenylium Tetrafluoroborates and Stilbenes in Acetonitrile. AB - A new type of three-component reaction of air-stable isochromenylium tetrafluoroborates with electron-rich stilbenes in acetonitrile has been developed under catalyst-free conditions in this work. This cascade multibond formation reaction is initiated by an intermolecular oxa [4 + 2]-cycloaddition, relayed with a nucleophilic addition of acetonitrile, and terminated by an intramolecular Friedel-Crafts reaction, affording the corresponding benzo[c]phenanthridine analogues in one step. PMID- 26977529 TI - Reversible Association of Nitro Compounds with p-Nitrothiophenol Modified on Ag Nanoparticles/Graphene Oxide Nanocomposites through Plasmon Mediated Photochemical Reaction. AB - Because localized surface plasmon resonance in nanostructures of noble metals is accompanied by interesting physical effects such as optical near-field enhancement, heat release, and the generation of hot electrons, it has been employed in a wide range of applications, including plasmon-assisted chemical reactions. Here, we use a composite of silver nanoparticles and graphene oxide (Ag@GO) as the catalytic as well as the analytic platform for plasmon-assisted chemical reactions. Through time-dependent surface-enhanced Raman scattering experiments, it is found that p-nitrothiophenol (pNTP) molecules on Ag@GO can be associated with nitro compounds such as nitrobenzene and 1-nitropropane to form azo compounds when aided by the plasmons. Furthermore, the reaction rate can be modulated by varying the wavelength and power of the excitation laser as well as the nitro compounds used. In addition, the aforementioned coupling reaction can be reversed. We demonstrate that the oxidation of azo compounds on Ag@GO using KMnO4 leads to the dissociation of the N?N double bond in the azo compounds and that the rate of bond dissociation can be accelerated significantly via laser irradiation. Furthermore, the pNTP molecules on Ag@GO can be recovered after the oxidation reaction. Finally, we demonstrate that the plasmon-assisted coupling reaction allows for the immobilization of nitro-group-containing fluorophores at specific locations on Ag@GO. PMID- 26977532 TI - Four-Component Damped Density Functional Response Theory Study of UV/Vis Absorption Spectra and Phosphorescence Parameters of Group 12 Metal-Substituted Porphyrins. AB - The influences of group 12 (Zn, Cd, Hg) metal-substitution on the valence spectra and phosphorescence parameters of porphyrins (P) have been investigated in a relativistic setting. In order to obtain valence spectra, this study reports the first application of the damped linear response function, or complex polarization propagator, in the four-component density functional theory framework [as formulated in Villaume et al. J. Chem. Phys. 2010 , 133 , 064105 ]. It is shown that the steep increase in the density of states as due to the inclusion of spin orbit coupling yields only minor changes in overall computational costs involved with the solution of the set of linear response equations. Comparing single frequency to multifrequency spectral calculations, it is noted that the number of iterations in the iterative linear equation solver per frequency grid-point decreases monotonously from 30 to 0.74 as the number of frequency points goes from one to 19. The main heavy-atom effect on the UV/vis-absorption spectra is indirect and attributed to the change of point group symmetry due to metal substitution, and it is noted that substitutions using heavier atoms yield small red-shifts of the intense Soret-band. Concerning phosphorescence parameters, the adoption of a four-component relativistic setting enables the calculation of such properties at a linear order of response theory, and any higher-order response functions do not need to be considered-a real, conventional, form of linear response theory has been used for the calculation of these parameters. For the substituted porphyrins, electronic coupling between the lowest triplet states is strong and results in theoretical estimates of lifetimes that are sensitive to the wave function and electron density parametrization. With this in mind, we report our best estimates of the phosphorescence lifetimes to be 460, 13.8, 11.2, and 0.00155 s for H2P, ZnP, CdP, and HgP, respectively, with the corresponding transition energies being equal to 1.46, 1.50, 1.38, and 0.89 eV. PMID- 26977531 TI - Biflorin, Isolated from the Flower Buds of Syzygium aromaticum L., Suppresses LPS Induced Inflammatory Mediators via STAT1 Inactivation in Macrophages and Protects Mice from Endotoxin Shock. AB - Two chromone C-glucosides, biflorin (1) and isobiflorin (2), were isolated from the flower buds of Syzygium aromaticum L. (Myrtaceae). Here, inhibitory effects of 1 and 2 on lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) in RAW 264.7 macrophages were evaluated, and 1 (IC50 = 51.7 and 37.1 MUM, respectively) was more potent than 2 (IC50 > 60 and 46.0 MUM). The suppression of NO and PGE2 production by 1 correlated with inhibition of iNOS and COX-2 protein expression. Compound 1 reduced inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) mRNA expression via inhibition of their promoter activities. Compound 1 inhibited the LPS-induced production and mRNA expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6. Furthermore, 1 reduced p-STAT1 and p-p38 expression but did not affect the activity of nuclear factor kappa light-chain enhancer of activated B cells (NF kappaB) or activator protein 1 (AP-1). In a mouse model of LPS-induced endotoxemia, 1 reduced the mRNA levels of iNOS, COX-2, and TNF-alpha, and the phosphorylation-mediated activation of the signal transducer and activator of transcription 1 (STAT1), consequently improving the survival rates of mice. Compound 1 showed a significant anti-inflammatory effect on carrageenan-induced paw edema and croton-oil-induced ear edema in rats. The collective data indicate that the suppression of pro-inflammatory gene expression via p38 mitogen activated protein kinase and STAT1 inactivation may be a mechanism for the anti inflammatory activity of 1. PMID- 26977530 TI - Activated Hippo/Yes-Associated Protein Pathway Promotes Cell Proliferation and Anti-apoptosis in Endometrial Stromal Cells of Endometriosis. AB - CONTEXT: The imbalance in cell proliferation and apoptosis is considered an important role in the pathogenesis of endometriosis, but the exact mechanisms remains unclear. A newly established signaling pathway-Hippo/Yes-associated protein (YAP) pathway plays a critical role in the proliferation and apoptosis processes. However, studies focusing on Hippo/YAP pathway and endometriosis are lacking. OBJECTIVE: The objective was to explore the function of the Hippo/YAP pathway in endometriosis. SETTING AND DESIGN: The expression of YAP was first investigated in endometrium of women with or without endometriosis. The role of YAP in cell proliferation and apoptosis is identified by transfection of endometrial stromal cells (ESCs) in vitro, subsequent Verteporfin treatments in eutopic ESCs in vitro, and endometriosis animal model of nude mice in vivo. RESULTS: Our results revealed that increased expression of YAP and decreased expression of p-YAP in ectopic and eutopic endometrium compared with normal endometrium. YAP knockdown in eutopic ESCs decreased cell proliferation and enhanced cell apoptosis companied with decreased expression of TEAD1, CTGF, and B cell lymphoma/leukemia (BCL)-2; whereas overexpression of YAP resulted in increased proliferation and decreased apoptosis of normal ESCs with increased expression of TEAD1, CTGF, and BCL-2. By chromatin immunoprecipitation qPCR CTGF and BCL-2 were identified as directly downstream target genes of YAP-TEAD1 active complex. Eutopic ESCs treated with Verteporfin revealed decreased proliferation and enhanced apoptosis whereas in endometriosis animal models of nude mice treated with Verteporfin, the size of endometriotic lesions was significantly reduced. CONCLUSIONS: Our study suggests that the Hippo/YAP-signaling pathway plays a critical role in the pathogenesis of endometriosis and should present a novel therapeutic method against endometriosis. PMID- 26977533 TI - Heterogeneity in the Small-Scale Deformation Behavior of Disordered Nanoparticle Packings. AB - Atomic force microscopy-based nanoindentation is used to image and probe the local mechanical properties of thin disordered nanoparticle packings. The probed region is limited to the size of a few particles, and an individual particle can be loaded and displaced to a fraction of a single particle radius. The results demonstrate heterogeneous mechanical response that is location-dependent. The weak locations may be analogous to the "soft spots" previously predicted in glasses and other disordered packings. PMID- 26977534 TI - Speciation Studies of Metals in Trace Concentrations: The Mononuclear Uranyl(VI) Hydroxo Complexes. AB - A direct luminescence spectroscopic experimental setup for the determination of complex stability constants of mononuclear uranyl(VI) hydrolysis species is presented. The occurrence of polynuclear species is prevented by using a low uranyl(VI) concentration of 10-8 M (2.4 ppb). Time-resolved laser-induced fluorescence spectra were recorded in the pH range from 3 to 10.5. Deconvolution with parallel factor analysis (PARAFAC) resulted in three hydrolysis complexes. A tentative assignment was based on thermodynamic calculations: UO22+, UO2(OH)+, UO2(OH)2, UO2(OH)3-. An implementation of a Newton-Raphson algorithm into PARAFAC allowed a direct extraction of complex stability constants during deconvolution yielding log(beta1M,1 degrees C)1:1 = -4.6, log(beta1M,1 degrees C)1:2 = -12.2, log(beta1M,1 degrees C)1:3 = -22.3. Extrapolation to standard conditions gave log(beta0)1:1 = -3.9, log(beta0)1:2 = -10.9, and log(beta0)1:3 = -20.7. Luminescence characteristics (band position, lifetime) of the individual mononuclear hydroxo species were derived to serve as a reference data set for further investigations. A correlation of luminescence spectroscopic features with Raman frequencies was demonstrated for the mononuclear uranyl(VI) hydroxo complexes for the first time. Thereby a signal-to-structure correlation was achieved and the complex assignment validated. PMID- 26977535 TI - Field data and numerical modeling: A multiple lines of evidence approach for assessing vapor intrusion exposure risks. AB - USEPA recommends a multiple lines of evidence approach to make informed decisions at vapor intrusion sites because the vapor intrusion pathway is notoriously difficult to characterize. Our study uses this approach by incorporating groundwater, soil gas, indoor air field measurements and numerical models to evaluate vapor intrusion exposure risks in a Metro-Boston neighborhood known to exhibit lower than anticipated indoor air concentrations based on groundwater concentrations. We collected and evaluated five rounds of field sampling data over the period of one year. Field data results show a steep gradient in soil gas concentrations near the groundwater surface; however as the depth decreases, soil gas concentration gradients also decrease. Together, the field data and the numerical model results suggest that a subsurface feature is limiting vapor transport into indoor air spaces at the study site and that groundwater concentrations are not appropriate indicators of vapor intrusion exposure risks in this neighborhood. This research also reveals the importance of including relevant physical models when evaluating vapor intrusion exposure risks using the multiple lines of evidence approach. Overall, the findings provide insight about how the multiple lines of evidence approach can be used to inform decisions by using field data collected using regulatory-relevant sampling techniques, and a well-established 3-D vapor intrusion model. PMID- 26977536 TI - Nutrient leaching and copper speciation in compost-amended bioretention systems. AB - Bioretention systems are designed to remove contaminants from stormwater; however, studies have shown that bioretention systems can export excess nitrogen, phosphorus, and copper when amended with compost. The objectives of this study were (1) to quantify removal of nitrates, phosphorus, copper, and dissolved organic matter (DOM) from compost-amended bioretention systems, and (2) to investigate the role of DOM on the leaching of copper. Simulated bioretention systems were irrigated with stormwater for seven storms in two-weeks intervals. Leachates were analyzed for nutrients, copper, and DOM. Visual MINTEQ was used to determine the speciation of copper and to quantify interactions of copper with DOM. Results showed that compost-amended bioretention systems were a source of nitrates, phosphorus, and DOM. Nitrate and phosphorus amounts were elevated up to three orders of magnitude in the leachate compared to the stormwater itself. Bioretention systems were a source for copper during the first 3-5 storms, but during later storms, they were a sink for copper. Copper speciation modeling indicated that the majority of dissolved copper was complexed with DOM. Dissolved organic matter thus helps to mobilize copper from the compost, particularly in the first few storms after compost application. However, since copper-DOM complexes are usually much less toxic than free copper ions, we expect that compost amendments may reduce harmful effects of copper on aquatic organisms. PMID- 26977537 TI - Influence of Ambient Humidity on the Voltage Response of Ionic Polymer-Metal Composite Sensor. AB - Electrical potential based on ion migration exists not only in natural systems but also in ionic polymer materials. In order to investigate the influence of ambient humidity on voltage response, classical Au-Nafion IPMC was chosen as the reference sample. Voltage response under a bending deformation was measured in two ways: first, continuous measurement of voltage response in the process of absorption and desorption of water to study the tendency of voltage variation at all water states; second, measurements at multiple fixed ambient humidity levels to characterize the process of voltage response quantitatively. Ambient humidity influences the voltage response mainly by varying water content in ionic polymer. Under a step bending, the amplitude of initial voltage peak first increases and then decreases as the ambient humidity and the inherent water content decrease. This tendency is explained semiquantitatively by mass storage capacity related to the stretchable state of the Nafion polymer network. Following the initial peak, the voltage shows a slow decay to a steady state, which is first characterized in this paper. The relative voltage decay during the steady state always decreases as the ambient humidity is lowered. It is ascribed to progressive increase of the ratio between the water molecules in the cation hydration shell to the free water. Under sinusoidal mechanical bending excitation in the range of 0.1-10 Hz, the voltage magnitude increases with frequency at high ambient humidity but decreases with frequency at low ambient humidity. The relationship is mainly controlled by the voltage decay effect and the response speed. PMID- 26977539 TI - Vascular Endothelial Function Assessed by Postischemic Diastolic Blood Pressure Is Associated with Acclimatization and Acute Mountain Sickness. AB - BACKGROUND: This study assessed whether the brachial diastolic blood pressure (DBP) decline induced by 5-minute arm ischemia is associated with acclimatization and acute mountain sickness (AMS). METHODS: Forty-two age- and body mass index matched young male residents at sea level (<400 m) or moderate altitude (1000 2000 m above sea level) were enrolled. All subjects had never been to 3200 m before. Brachial BP was measured at a station at 1380 m altitude before and 1, 5, and 10 minutes after right arm ischemia. AMS score was evaluated after 3-day training at a high altitude of 3200 m. RESULTS: In moderate altitude versus sea level residents: (1) systolic BP curves for both arms overlapped well; (2) mean right arm DBP decline post right arm ischemia was larger, while left arm, which was not subjected to ischemia, did not show DBP decline in either group; and (3) AMS scores were significantly lower (3.19 +/- 2.16 vs. 5.52 +/- 4.58, p = 0.043) in those residing at moderate altitude compared to those from low altitude. There was a low negative correlation between AMS score and right arm area between curves-DBP (r = -0.320, p = 0.039). CONCLUSION: Moderate altitude relative to sea level residents had a larger mean postischemic DBP decline in weak but significant association with lower mean AMS score at 3200 m. These data suggest that differences in vascular endothelial function related to altitude of residence persist during travel to high altitude and might contribute to AMS risk. PMID- 26977540 TI - The stress and workload of virtual reality training: the effects of presence, immersion and flow. AB - The present investigation evaluated the effects of virtual reality (VR) training on the performance, perceived workload and stress response to a live training exercise in a sample of Soldiers. We also examined the relationship between the perceptions of that same VR as measured by engagement, immersion, presence, flow, perceived utility and ease of use with the performance, workload and stress reported on the live training task. To a degree, these latter relationships were moderated by task performance, as measured by binary (Go/No-Go) ratings. Participants who reported positive VR experiences also tended to experience lower stress and lower workload when performing the live version of the task. Thus, VR training regimens may be efficacious for mitigating the stress and workload associated with criterion tasks, thereby reducing the ultimate likelihood of real world performance failure. Practitioner Summary: VR provides opportunities for training in artificial worlds comprised of highly realistic features. Our virtual room clearing scenario facilitated the integration of Training and Readiness objectives and satisfied training doctrine obligations in a compelling engaging experience for both novice and experienced trainees. PMID- 26977541 TI - Restricting Advertisements for High-Fat, High-Sugar Foods during Children's Television Programs: Attitudes in a US Population-Based Sample. AB - BACKGROUND: Children in the United States (US) are frequently exposed to advertisements for high-fat, high-sugar (HFHS) foods, which is linked to greater demand for and consumption of those foods. Restricting advertisements for HFHS foods may be a viable obesity prevention strategy-however, public support for policy change is unclear. METHODS: A secondary analysis of the 2012 Annenberg National Health Communication Survey was conducted. Respondents (N = 1838) were 53.2% female, mean age 50.0 +/- 16.5 years. Race/ethnic composition was 76.8% white, 7.4% black, 9.2% Hispanic, and 6.6% other. The percentage of respondents supporting and opposing the regulation was calculated and logistic regression models identified predictors of support. Potential predictors included sociodemographic variables, attitudes towards other health regulations (e.g., smoking bans in public places), and various health behaviors (e.g., fruit and vegetable intake). RESULTS: A total of 56.3% of respondents supported or strongly supported advertisement restrictions, while only 8.2% strongly opposed. Approximately 20% had no opinion. Greatest support was found among respondents who supported smoking bans in public settings (OR = 4.3), who supported banning trans fats in restaurants (OR = 1.7), and who were older (OR = 1.7). CONCLUSION: The US adult population appears to have an appetite for restricting HFHS advertising to children, with more than half the populace supporting such a policy in 2012. This may be an opportune time to implement and rigorously evaluate such childhood obesity prevention strategies. PMID- 26977542 TI - ToF-SIMS and XPS Characterization of Protein Films Adsorbed onto Bare and Sodium Styrenesulfonate-Grafted Gold Substrates. AB - The adsorption of single-component bovine serum albumin (BSA), bovine fibrinogen (Fgn), and bovine immunoglobulin G (IgG) films as well as multicomponent bovine plasma films onto bare and sodium styrenesulfonate (NaSS)-grafted gold substrates was characterized. The adsorption isotherms, measured via X-ray photoelectron spectroscopy, showed that at low solution concentrations all three single component proteins adsorb with higher affinity onto gold surfaces compared to NaSS surfaces. However, at higher concentrations, NaSS surfaces adsorb the same or more total protein than gold surfaces. This may be because proteins that adsorb onto NaSS undergo structural rearrangements, resulting in a larger fraction of irreversibly adsorbed species over time. Still, with the possible exception of BSA adsorbed onto gold, neither surface appeared to have saturated at the highest protein solution concentration studied. Principal component (PC) analysis of amino acid mass fragments from time-of-flight secondary ion mass spectra distinguished between the same protein adsorbed onto NaSS and gold surfaces, suggesting that proteins adsorb differently on NaSS and gold surfaces. Explored further using peak ratios for buried/surface amino acids for each protein, we found that proteins denature more on NaSS surfaces than on gold surfaces. Also, using peak ratios for asymmetrically distributed amino acids, potential structural differences were postulated for BSA and IgG adsorbed onto NaSS and gold surfaces. PC modeling, used to track changes in plasma adsorption with time, suggests that plasma films on NaSS and Au surfaces become more Fgn like with increasing adsorption time. However, the PC models included only three proteins, where plasma is composed of hundreds of proteins. Therefore, while both gold and NaSS appear to adsorb more Fgn with time, further study is required to confirm that this is representative of the final state of the plasma films. PMID- 26977544 TI - A Review of the Definitive Treatment of Pelvic Fractures. AB - Pelvic ring injuries can result in significant morbidity and mortality. New techniques, technologies, and research have led to the development of various algorithms to guide the initial diagnosis and management of these injuries. These include treatment with antibiotics and operative debridement in the case of open fractures and temporary stabilization in certain cases with sheets, binders, or external fixators. Yet even after successful completion of the initial treatment phase, identifying and implementing the optimal definitive treatment of pelvic ring injuries remains a challenge. Various classification schemes have been proposed and contribute in different ways to an understanding of pelvic ring injuries. The current paper will review the definitive management of pelvic ring injuries, ultimately using the Young and Burgess classification as a guide, with a focus on current practice and the supporting evidence. PMID- 26977543 TI - Association of Peripheral Membrane Proteins with Membranes: Free Energy of Binding of GRP1 PH Domain with Phosphatidylinositol Phosphate-Containing Model Bilayers. AB - Understanding the energetics of peripheral protein-membrane interactions is important to many areas of biophysical chemistry and cell biology. Estimating free-energy landscapes by molecular dynamics (MD) simulation is challenging for such systems, especially when membrane recognition involves complex lipids, e.g., phosphatidylinositol phosphates (PIPs). We combined coarse-grained MD simulations with umbrella sampling to quantify the binding of the well-explored GRP1 pleckstrin homology (PH) domain to model membranes containing PIP molecules. The experimentally observed preference of GRP1-PH for PIP3 over PIP2 was reproduced. Mutation of a key residue (K273A) within the canonical PIP-binding site significantly reduced the free energy of PIP binding. The presence of a noncanonical PIP-interaction site, observed experimentally in other PH domains but not previously in GRP1-PH, was also revealed. These studies demonstrate how combining coarse-grained simulations and umbrella sampling can unmask the molecular basis of the energetics of interactions between peripheral membrane proteins and complex cellular membranes. PMID- 26977545 TI - The Weak Link in Anterior Cruciate Ligament Reconstruction: What is the Evidence for Graft Fixation Devices? AB - Anterior cruciate ligament (ACL) rupture is a common injury that mostly affects young adults. The mechanisms of injury and surgical treatment have been extensively studied in both the laboratory and clinical arenas; however, great controversy still exists in regards to the best surgical technique, graft choice, and graft fixation device. In the area graft fixation, multiple breakthroughs have occurred in terms of fixation devices. These devices generally fall within the broad categories of interference screw, cross-pins, or cortical-based devices. Furthermore, some of these devices are available in either metal or bioabsorbable materials, which adds to the already great variety of options. Although biomechanically these devices have been shown to be able to withstand the typical forces experienced by the ACL graft during the early phases of rehabilitation before the graft has fully incorporated into the bone, little is known about the clinical outcomes. It is well recognized that graft fixation is the weakest link in the early postoperative period after ACL reconstruction. This review of the outcomes of ACL fixation devices explores some of the evidence available for the different devices. PMID- 26977547 TI - Osteochondritis Dissecans of the Capitellum: Diagnosis and Treatment. AB - Osteochondritis dissecans (OCD) of the capitellum is an articular cartilage lesion commonly affecting young adolescents. The exact mechanism for the development of these lesions is still uncertain; however, both traumatic and vascular etiologies have been described. Careful physical examination in conjunction with appropriate diagnostic studies helps the surgeon to classify these lesions as stable or unstable and leads to proper management. There is a diverse array of treatments available for OCD lesions of the capitellum, including fragment excision or fixation, bone marrow stimulation, and osteochondral autograft transplantation. This review helps the orthopaedic surgeon understand the diagnosis and management options available for OCD lesions of the capitellum. PMID- 26977546 TI - Bone Marrow Edema: Chronic Bone Marrow Lesions of the Knee and the Association with Osteoarthritis. AB - Bone marrow edema of the knee occurs secondary to a myriad of causes. The hallmark of a bone marrow lesion (BML) is an area of decreased signal intensity on T1 weighted MRI with a corresponding area of increased signal intensity on a T2 weighted MRI. Recently, chronic bone marrow lesions have been correlated with knee pain and progression of osteoarthritis. These lesions have also been associated with other degenerative conditions such as meniscal tears, cartilage deterioration, subchondral cyst formation, mechanical malalignment, and ultimately progression to arthroplasty. Medical treatments, such as prostacyclin and bisphosphonate therapy, have shown promise. Alignment procedures, as well as core decompression and subchondroplasty, have been used as surgical treatments for chronic BMLs. PMID- 26977548 TI - Anterior Cruciate Ligament Injuries in Females: Risk Factors, Prevention, and Outcome. AB - Anterior cruciate ligament (ACL) injuries are common among all participants in sports, occurring in approximately 1 in 3,000 individuals yearly in the USA. Epidemiological studies of ACL injuries have demonstrated that females are at higher risk for injury than males. When compared to male athletes participating in the same sports, the risk of ACL injury is two to eight times greater in females.1-3 A significant research effort has been directed at identifying risk factors that may predispose females to ACL injury. Female athletes likely have an increased incidence of ACL injury due to anatomic, hormonal, biomechanical, and neuromuscular differences between the sexes. Extrinsic factors may also play a role. As the number of girls and women participating in athletics continues to increase, understanding risk factors and developing prevention strategies will have profound physical, psychological, and financial implications for female athletes and the medical system. PMID- 26977549 TI - The Anterior Approach for Total Hip Replacement. AB - The anterior approach for total hip replacements has recently gained popularity. Some authors report faster recoveries and decreased dislocation rated with no increased risk of complications. However others claim no difference in outcomes when compared to other approaches yet an increase in complication rates. This paper provides a brief history of the approach, discusses various indications and contraindications, preoperative considerations, surgical techniques, and postoperative protocols. PMID- 26977550 TI - Endoscopic Treatment of Gluteus Medius Tears: A Review. AB - Greater trochanteric pain syndrome (GTPS) is a term used to describe disorders of the peritrochanteric region. This constellation of conditions includes greater trochanteric bursitis, gluteus medius (GM) tears, and external coxa saltans or snapping hip syndrome. Tears of the abductor mechanism, more specifically gluteus medius tears, have recently gained a considerable amount of interest in the orthopaedic literature. Abductor tears were first described by Bunker and Kagan in the late 1990s. They used the rotator cuff as an analogous structure to describe the pathological process associated with gluteus medius tears. Tears of the gluteus medius tendon can often be difficult to recognize. The clinical presentation is often attributed to trochanteric bursal inflammation, without any further workup. Provocative hip physical examination findings are an important key to proper diagnosis of abductor injuries. Depending on the size of the tear, patients with abductor tendon pathology may present with a Trendelenburg gait and reduced resisted abduction strength accompanied by pain. Initial noninvasive management of greater trochanteric pain syndrome includes oral or topical anti inflammatory medication and activity modification. Physical therapy or other treatment modalities can be considered, with a focus on core strengthening, truncal alignment, and iliotibial band stretching. Gluteus medius tears have historically been repaired in an open fashion; however, the advent of new endoscopic surgery techniques has allowed for a less invasive approach. Access to the peritrochanteric space affords the surgeon with access to pathology associated with the greater trochanter, iliotibial band, trochanteric bursa, sciatic nerve, short external-rota tors, iliopsoas tendon, and the gluteus medius and minimus tendon attachments. Over the last decade, we have seen rapid technological advances in hip arthroscopy, improved diagnostic imaging and interpretation, and an improved understanding of intra-articular and peritrochanteric hip pathology. As the emphasis on hip arthroscopy in residency and fellowship training programs continues to increase, the learning curve for endoscopic management of peritrochanteric disorders will continue to improve. PMID- 26977551 TI - Treatment of Pectoralis Major Muscle Ruptures. AB - Injuries to the pectoralis major muscle are relatively rare but result in pain, weakness, cosmetic deformity and in many cases, inability to return to previous levels of function. The most common cause of this injury is bench-pressing, as it places the muscle fibers in a position of mechanical disadvantage while under heavy load. The ability to detect and appropriately treat each patient with this injury is essential to restoring not only strength and function but also cosmesis. This article reviews the diagnostic workup of this injury and examines both the outcomes and techniques of non-operative and operative management. PMID- 26977552 TI - Pars Injuries in Athletes. AB - Pars injuries are common causes of low back pain in adolescent athletes. Workup traditionally has included lumbar radiographs with oblique views and single photon emission computed tomography (SPECT). However, recent literature has demonstrated the accuracy of MRI as a diagnostic modality. Acute injuries may be amenable to bracing with the goal of a healed lesion. Most cases of spondylolysis will result in asymptomatic non-union, though pars repair is an option for symptomatic pars defects without spondylolisthesis. PMID- 26977553 TI - Leg Length Discrepancy in Primary Total Hip Arthroplasty. AB - Leg length discrepancy (LLD) is one of the most common complications of total hip arthroplasty. It may cause pain and disability to the patient, and it is the number one reason for filing a lawsuit against an orthopaedic surgeon. This manuscript reviews the preparation for and execution of the operative plan with emphasis on avoiding pitfalls leading to LLD. It also considers the treatment of LLD in the postoperative period. PMID- 26977554 TI - Current Evidence of Minimally Invasive Spine Surgery in the Treatment of Lumbar Disc Herniations. AB - With the advent of new instrumentation and better imaging techniques that allowed less tissue trauma compared with traditional open procedures, while providing adequate or enhanced visualization of the pathologic site and based upon the successful experience of outpatient spine surgery to assist early ambulation, the trend and evolution toward ''minimal access'' or minimally invasive spine surgery began to develop with greater intensity. Many surgical techniques have flourished with the promise of delivering a safe and efficient alternative, including chemonucleolysis, manual percutaneous discectomy (MPD), automated percutaneous lumbar discectomy (APLD), and percutaneous lumbar laser discectomy (PLLD). Unfortunately, most of these techniques have been demonstrated to be inefficient with high complication rates. Only modifications of the original open discectomy in which direct visualization of the disc is obtained through either microscopic or endoscopic techniques have proven to be successful. This review outlines the historical journey that has inspired the development of these techniques and delineates the progressive clinical experience gained from their advent. PMID- 26977555 TI - Pediatric Thumb Flexion Deformities. AB - Pediatric trigger thumb and congenital clasped thumb are the two most common pediatric thumb flexion deformities. Both might appear similar, however, they are caused by varying etiologies, and treatment is vastly different. Pediatric trigger thumb is due to a size mismatch of the flexor tendon and the thumb pulley system, develops over time, typically manifests as a locked interphalangeal joint, and is treated with observation or surgical release. Congenital clasped thumb, although presenting in varying degrees of severity, is due to a congenital absence or hypoplasia of one or more of the thumb extensors and is treated with either splinting for supple deformities or surgery for more complex deformities. PMID- 26977556 TI - Dechlorination of Trichloroacetic Acid Using a Noble Metal-Free Graphene-Cu Foam Electrode via Direct Cathodic Reduction and Atomic H. AB - A three-dimensional graphene-copper (3D GR-Cu) foam electrode prepared by chemical vapor deposition method exhibited superior electrocatalytic activity toward the dechlorination of trichloroacetic acid (TCAA) as compared to the Cu foam electrode. The cyclic voltammetry and electrochemical impedance spectra analysis confirmed that GR accelerated the electron transfer from the cathode surface to TCAA. With the applied cathode potential of -1.2 V (vs SCE), 95.3% of TCAA (500 MUg/L) was removed within 20 min at pH 6.8. TCAA dechlorination at the Cu foam electrode was enhanced at acidic pH, while a slight pH effect was observed at the GR-Cu foam electrode with a significant inhibition for Cu leaching. The electrocatalytic dechlorination of TCAA was accomplished via a combined stepwise and concerted pathway on both electrodes, whereas the concerted pathway was efficiently promoted on the GR-Cu foam electrode. The direct reduction by electrons was responsible for TCAA dechlorination at Cu foam electrode, while at GR-Cu foam electrode, the surface-adsorbed atomic H* also contributed to TCAA dechlorination owing to the chemical storage of hydrogen in the GR structure. Finally, the potential applicability of GR-Cu foam was revealed by its stability in the electrocatalytic dechlorination over 25 cycles. PMID- 26977557 TI - Effect of Fiberoptic Collimation Technique on 808 nm Wavelength Laser Stimulation of Cochlear Neurons. AB - OBJECTIVE: The purpose of this study was to evaluate the effects of fiberoptic collimation technique on auditory neural stimulation in the cochlea with 808 nm wavelength lasers. BACKGROUND DATA: Recently, the pulsed near-infrared lasers in the 800-1000 nm wavelength range have been investigated as an emerging technique to trigger auditory neural response in the cochlea. A laser beam divergence in the optical stimulation pathway exists, which may affect stimulation efficiency and spatial selectivity. METHODS: The fiberoptic collimation technique was proposed for cochlear neuron stimulation, and the C-lens element was designed as the collimation structure. The spiral ganglion cells in deafened guinea pigs' cochlea were irradiated with collimated and uncollimated near-infrared lasers. Optically evoked auditory brainstem response (OABR) under the two laser output modes were recorded. RESULTS: Laser with the collimation technique evoked an average 58% higher OABR amplitude than the uncollimated laser output. In addition, the collimated laser setup consumed on average 35.2% of laser energy compared with the uncollimated laser when evoking the same OABR amplitude. CONCLUSIONS: The fiberoptic collimation technique improved stimulation efficiency and reduced stimulating energy consumption in near-infrared neural stimulation in cochlea. The positive effects of laser collimation technique could benefit further research in optically based cochlear implants. PMID- 26977558 TI - Factors Associated with Breast Milk Feeding of Very Preterm Infants from Birth to 6 Months Corrected Age. AB - OBJECTIVES: To investigate factors that may affect breast milk feeding (BMF) practices among very preterm infants. MATERIALS AND METHODS: This retrospective study included infants born before 32 weeks gestational age (GA) and monitored up to 6 months corrected age (CA). Feeding method was assessed at day 14 of life, 36 weeks GA, 6 weeks after home discharge, and 6 months CA. Multivariable logistic regression analysis was used to examine which factors were associated with BMF initiation at cessation. RESULTS: Of 181 infants who qualified for the study, 146 (81%) initiated BMF. Of these, 80% were mainly BMF (>=75% of daily nutrition volume). At 36 weeks GA, 6 weeks postdischarge, and 6 months CA, 130 (71.8%), 87 (48%), and 36 (19.9%) infants, respectively, continued to receive some BMF. Multivariate analysis revealed that initiation of BMF was more common with younger GA and higher level of maternal education. Infants whose mothers failed to supply >=75% of daily nutrition as BMF at day 14 were more likely to be exclusively formula fed 6 weeks after discharge. Cessation of BMF at 6 months CA was associated with birth at >28 weeks. CONCLUSIONS: Successful BMF can be commenced and maintained throughout hospitalization in the majority of very preterm infants. Despite a significant dropout rate occurring within several weeks after discharge, in this select cohort, infants with lower GA were more likely to be breastfed after discharge. PMID- 26977559 TI - [Focal infections in otorhinolaryngology]. AB - This publication is focused on the mechanisms underlying the clinical course of acute focal infections concomitant with ENT pathology, factors responsible for their chronization and the development of complications. Also discussed are the methods for the early adequate conservative and surgical treatment of these conditions. Special emphasis is placed on the principles of management of chronic tonsillitis. PMID- 26977560 TI - [The specific clinical features of acute sensorineural loss of hearing associated with vertigo]. AB - The objective of the present study was to estimate the prevalence of vertigo and to determine the type of the lesion of the vestibular analyzer in the patients presenting with acute sensorineural loss of hearing (ASNLH). The secondary objective was to evaluate the possibility of the restoration of the auditory thresholds. The results of the examination and treatment of 94 patients suffering from ASNLH are presented. It was shown that the development of acute sensorineural loss of hearing was accompanied by unilateral peripheral vestibulopathy in 22.3% of the patients. In 5.3% of these cases, dizziness could be attributed to benign paroxysmal positional vertigo and canalolythias is of the posterior semicircular canal on the side of hearing impairment. It is concluded that the presence of the clinical signs of lesions of the vestibular analyzer and peripheral vestibular dysfunction in the form of latent spontaneous nystagmus without gaze fixation and/or asymmetric nystagmus with unilateral weakness in the caloric test is a negative prognostic factor for the restoration of the auditory thresholds in the patients presenting with acute sensorineural loss of hearing. PMID- 26977561 TI - [The prevalence of hearing impairment in transport workers and peculiarities of management of occupational loss of hearing (as exemplified by the situation in the air and railway transport)]. AB - This article presents data on the prevalence of hearing impairment among the workers engaged in the main means of transportation(air and railway transport). They show that the relative frequency of occupational loss of hearing in the cockpit members of commercial aviation amounts to one third of all cases of analogous diseases in this country. The main professional groups of transport works suffering from hearing impairment are constituted by the representatives of the so-called elite specialities, such as flying crew personnel, locomotive engineers, and their assistants. This fact constitutes an important aspect (not only of medical but also of socio-economic significance) of the problem under consideration. The high prevalence of professional hearing impairment among the transport workers is attributable to the high noise level in the cabins of locomotives and aircraft cockpits as well as to the inadequate expert and diagnostic work or imperfection of the regulatory documentation. PMID- 26977562 TI - [The audiological analysis in the patients homozygous for the c.-23+1G>A mutation in the GJB2 gene presenting with the loss of hearing in Yakutiya]. AB - In the course of previous investigations carried out in the Republic of Sakha (Yakutiya), we have identified the main molecular-genetic factor responsible for the hereditary impairment of hearing among the indigenous population (mostly the Yakuts).The disease was shown to be attributable to the c.-23+1G>A mutation localized in the splice donor site (exon 1) of the GJB2 (Cx26) gene. The present study involved the comprehensive audiological analysis of the patients homozygous for the c.-23+1G>A mutation in the GJB2 gene based on the results of the study of a large sample of the patients residing in Yakutiya. All individuals with the GJB2 genotype c.-23+1G>A/c.-23-1G>A (n=108) at the mean age of 14.32+/-4.7 years (all ethnic Yakuts)were examined with the use oftonal threshold audiometry for air conduction testing at the frequencies of 0.25, 0.5, 1.0, 2.0, 4.0, and 8.0 kHz and bone conduction testing at the frequencies of 0.25, 0.5, 1.0, and 4.0 with a step of 5.0 dB.The results of the ASSR test were used whenever tonal threshold audiometry proved impracticable The data obtained in the study characterize the allelic form of the disease associated with the GJB2 genotype c. 23+1G>A/c.-23-1G>A as the congenital bilateral symmetric (90.1%), sensorineural (90.1%) form of hearing impairment of variable severity (from grade 1 to complete deafness) with the "flat" audiological profile (median slope not more than 5.0 dB in the extended frequency range (EFR) of 0.5, 1.0, 2.0, and 4.0, kHz). It is concluded that the results of the audiological analysis performed in the present study give evidence of relatively homogeneous but variable in terms of severity impairment of hearing in the patients homozygous for the c.-23+1G>A mutation in the GJB2 (Cx26) gene. It may serve as a positive prognostic sign to be used in the development and prescription of hearing aids. PMID- 26977563 TI - [Microanatomy of the cranial segment of the vestibulocochlear nerve. Possible correlations with the symptoms of neurovascular compression syndrome]. AB - The objective of the present study was to elucidate the topographic features of the nerve fibers belonging to the acoustic and vestibular analyzers located in the intracranial cranial segment of human vestibulocochlear nerve (VCN). A total of 16 samples of the intracranial cranial segment of the human vestibulocochlear nerve isolated from the region enclosed between the exit of VCN from the brainstem and its entrance into the internal acoustic meatus were available for the investigation. Prior to fixation of the samples, the VCN segments were marked in correspondence with their intravital anatomical location in the posterior cranial fossa. Cross sections of the PCN segments were stained with hematoxylin and eosin as well as according to the van-Hison method. The cross sections were made either at the exit of the nerve from the brainstem (N1), its entrance into the internal acoustic meatus (N3) or in-between these sites (N2). The morphometric analysis of the sections and the statistical treatment of the data obtained were performed with the use of the Diamfor hardware and software complex ("Diamfor", Russia). The digitized images of the PCN sections were prepared using amVizo 103 microvisor (Russia). It was shown that the intracranial segment of the human vestibulocochlear nerve consists of two isolated groups of nerve fibers differing in terms of staining density, size, and the degree of myelinization. The mutual location of the fibers forming the cochlear and vestibular nuclei (CN and VN respectively) varies. Namely, CN near the internal acoustic foramen occupies the antero-posterior position with respect to VN. In the middle part of VCN, CN-forming fibers are located at the anetro-inferoposterior surface of the nerve. The nerve fibers of both CN and VN are similarly arranged near the lateral surface of the brain stem. PMID- 26977564 TI - [The state of the larynx in the patients presenting with chronic obstructive pulmonary disease]. AB - The objective of the present study was to evaluate the clinical state of the larynx and its microbial population in 49 patients examined at the stage of stable condition of chronic obstructive pulmonary disease. Examination of the larynx was carried out with the use of a rigid laryngoscope having a visual angle of 70 degrees, videofibrolaryngoscopy, and stroboscopy using a "TelePac" videocomplex (Karl Storz, Germany). It was supplemented by the study of the bacteriological and mycological paysage. The acoustic analysis of the voice was performed with the help of the Specta PLUS computer program. It was shown that more than 70% of the examined patients presented with various forms of chronic laryngitis. Potentially pathogenic St. pyogenes and yeast-like fungi C. albicans were isolated from 59% and 29% of the patients respectively. PMID- 26977566 TI - [The influence of endogenous intoxication on the clinical picture of various forms of acute stenosinglaryngotracheitis in the children]. AB - The objective of the present study was to evaluate the influence of endogenous intoxication on the clinical picture of various forms of acute stenosinglaryngotracheitis in the children. The clinical and laboratory examination involved 275 patients presenting with this pathology. Special emphasis was laid on diagnostics of the character and severity of intoxication syndrome. To this effect, we carried out a dynamic study of variations in the blood levels of medium molecular weight peptides, the toxic blood factor, and circulating immune complexes (CIC). It is concluded that the parameters of endogenous intoxication in the children with acute stenosinglaryngotracheitis are directly related to the specific clinical features and severity of this disease. PMID- 26977565 TI - [Monitoring of microflora localized at the pharyngeal tonsil surface in the children residing in the city of Chelyabinsk and presenting with chronic adenoiditis]. AB - The objective of the present retrospective study based on the analysis of 791 medical cards was to investigate microflora localized at the pharyngeal tonsil surface in the children living in the city of Chelyabinsk and presenting with exacerbation of chronic adenoiditis. 66% of the patients with this condition were 4-6 year old children. The most commonly documented were the associations composed of resident species S. alpha-haemoliticus and S. epidermidis together with pathobiontic S. aureus. S. beta-haemoliticus and S. pneumoniae occurred most frequently whereas H. influenza and some representatives of the genus Enterobacteriaceae were less numerous. Fungi of the genus Candida were identified in 25.4% of the samples at a titer above 10^4. In 23.7% of the cases, these fungi were found in the associations with S. aureus which resulted in mutual potentiation of the pathogenicity factor. PMID- 26977567 TI - [The application of mastoidoplasty in repeated scanning operations on the ear]. AB - The objective of the present study was to evaluate the outcomes of mastoid obliteration with the use of the orthotopic bone tissue taken from the linea temporalis region. It was shown that this region is the optimal site at the temporal bone for the harvesting of the plastic bone material to be used in mastoidoplasty during secondary sanitizing surgical interventions on the patients with mastoid cavity problems after canal wall-down mastoidrctomy under conditions of the deficiency of the orthotopic bone tissue. The application of such tissue for the purpose of mastoid-obliteration surgery provides a number of advantages over other methods of mastoidoplasty, in the first place from the standpoint of tissue biocompatibility. Multispiral computed tomography (MSCT) of the temporal bones is a highly informative and non-invasive technique for the study and control of the patients' condition during the late postoperative period following a secondary sanitizing surgical intervention involving mastoidoplasty with the application of the orthotopic bone tissue. PMID- 26977568 TI - [Congenital parotid gland fistula in the children: diagnostics and surgical treatment]. AB - The objective of the present study was to improve diagnostics and surgical treatment of congenital parotid gland fistulae. It involved 86 children presenting with this defect at the age varying from 4 months to 17 years who were admitted to the Department of Otorhinolaryngology of the Morozovskaya City Children's Clinical Hospital during the period from 2010 till 2014. It was shown that parotid fistula suppuration is an absolute indication for the surgical treatment of such children regardless of their age. The proposed diaphanoscopic technique was shown to produce good results and can be recommended for both diagnostics an intraoperative visualization of the fistulous passage. PMID- 26977571 TI - [The dermoid cyst of the dorsum of the nose with intracranial invasion]. PMID- 26977570 TI - [The possibility of using soformulated intranasal drugs after surgical correction of nasal breathing]. AB - One of the major causes of chronic nasal obstruction is the nasal septum deformation and increase of the lower nasal turbinates. The number of septoplasty -operations ranges from 14% to 44,2% of all ENT-operations. The results of surgery are swelling of the tissues and damaged ciliar epithelium, that leads to the inparament of the mucociliar transport. In the postoperati e period the nasal cavity should be cleaned. Drugs, that are used, should reduce swelling, improve regeneration and should not supress ciliar activity. The results of supervisory, non-interventional study have shown, that application of Nasis after septoplasty and submucose vasotomy of inferior nasal turbinates increases reparative process and leads to more rapid recovery of respiratory function of nasal cavity. PMID- 26977569 TI - [Use of Myrtol standardized in the treatment of children with acute rhinosinusitis]. AB - The present study included 60 children at the age from 6 to 10 years undergoing a course of out-patient and in-patient treatment of acute rhinosinusitis (ARS). Thirty of these patients were given Myrtol standardised in the dose of 120 mg thrice daily for 7 days, in addition to traditional therapy.With convincing objective data for acute bacterial rhinosinusitis (in accordance with the criteria of EP3OS 2012), antibacterial preparations were prescribed to the children. The remaining patients received either conventional (symptomatic, irrigation) therapy or systemic antimicrobial agents. The analysis of characteristics of the visual-analog scale reflecting the severity of rhinorrhea, basal congestion, and coughing has demonstrated a significant (r<0,05) difference between the two groups of children in terms of manifestations of the clinical symptoms within days 7 and 14 after the onset of the treatment. For basal congestion, the difference was apparent as soon as day 3 after the beginning of therapy. The duration of the treatment with intranasal vasoconstrictive medications used for symptomatic therapy by the patients given Myrtol standardized was 2.2+/-0.4 days in comparison with 3.6+/-0.5 days in the control group. None of the patients treated with GeloMyrtol exhibited any adverse reaction attributable to the action of the medication in being studied. The study has demonstrated that using Myrtol standardized for the treatment of the uncomplicated forms of acute rhinosinusitis in children is clinically effective, safe, and convenient method for the management of ARS in children. And it can be recommended for the wide practical application. PMID- 26977572 TI - [The combination of laryngeal paresis in the patients presenting with systemic tick-borne borreliosis (Lyme disease)]. PMID- 26977573 TI - [Apical petrositis, osteomyelitis of the base of the skull bones and of the first cervical vertebra in a 5 year-old children following chicken pox]. AB - This publication was designed to describe a rare case of development of apicalpetrositis in a child presenting with acute otitis mediafollowing chicken pox experienced in the preceding period. We carried out the study with the use of computed tomography (CT) that demonstrated destruction of the temporal bone, bones of the base of the skull and of the first cervical vertebra. The treatment strategy chosen for the management of this condition that included antibiotic therapy and expectant observation proved justified and can be recommended as an algorithm of choice taking into consideration the difficulty of surgical approach to the apex of the petrous pyramid. However, this approach is associated with the high risk of disability arising from the potential injury to the craniocerebral nerves. PMID- 26977574 TI - [A large foreign body in the nose]. PMID- 26977575 TI - [The consensus view of the treatment of the retraction pockets of the tympanic membrane]. AB - The objective of the present study was to formulate the consensus document "The treatment of the retraction pockets (RP) of pars tensa and pars flaccida" as well as to estimate the situation in this country pertaining to the treatment of the retraction pockets of the tympanic membrane. We undertaken a pilot study that involved 91 practicing otorhinolaryngologists based at in-patient and out-patient healthcare facilities in different regions of the Russian Federation. M. Yung's questionnaire for otorhinolaryngologistswas used to gain relevant information. The Delphi technology was employed to process the data obtained. 30% of those who agreed to participate in the study answered to the proposed questions although some of them aroused a discord among the respondents. The results of this questionnaire study provided a basis for the pilot consensus document and allowed for the preliminary conclusion as regards prospects for the further exploration of both the problem in question and the instruments for this purpose with special reference to the awareness of the otorhinolaryngologists. PMID- 26977576 TI - [The remote post-graduate education in otorhinolaryngology: the first results and further prospects]. AB - The objective of the present work was the retrospective analysis of the efficiency of two courses of remote education of otorhinolaryngologists in the real-time mode based on the results of the on-line questionnaire study. We analyzed the data obtained during the implementation of the pilot project of the remote post-graduate education at the Department of Otorhinolaryngology,Russian Medical Academy of Post-Graduate Education making use of the independent Internet resource for the professional training of otorhinolaryngologists. The two programs of remote education realized in 2012 and 2013 involved 7.9% of all otorhinolaryngologists practicing in the Russian Federation. The fraction of those who passed through all stages of the learning process increased almost two fold, that is from 10% in 2012 up to 19% in 2013. About 14% of the participants made themselves familiar with all program modules; this result is in agreement with the data obtained in mass on-line remote teaching of the non-medical audience. It is concluded that the results of the present study provide a basis for the elaboration of the remote education programs for the training of specialists not only in otorhinolaryngology but also in other fields of medicine. PMID- 26977577 TI - Preterm birth in ancient Greece: a synopsis. AB - This report refers to preterm birth in Ancient Greece based on mythological, historical and archeological data. The two antique goddesses, patronesses of labor and birth, Artemis and Eileithyia, cared for full-term, as well as preterm infants, among them for the mythological preterms Dionysos and Eurystheus. The former was rapidly transported by Hermes and received special care by the nymphs Hyades in a mountain cave with "incubator" properties. Historical data are related to the nine months duration of a normal pregnancy, to the definition of "Elitomina" (preterms), the lower limit of viability, the causes for preterm birth, the existence of small for gestational age infants and relevant causes, the physical examination of neonates and postpartum care. Lastly, excavations in Athens and Astypalaia discovered burials - in wells or pots - of preterm infants with gestational age 24-37 weeks. PMID- 26977580 TI - How to decrease violence against doctors in China? PMID- 26977579 TI - Adopting a Uniform Approach to Site Assignment in Tubo-Ovarian High-Grade Serous Carcinoma: The Time has Come. AB - There is currently sufficient evidence that nonuterine high-grade serous carcinoma (HGSC) originates in the fallopian tube in the majority of cases, but this is not uniformly reflected in our diagnostic terminology. This is because there remains wide variation in awareness and acceptance of this evidence, which conflicts with traditional views on origin. Accurate disease classification is fundamental to routine clinical practice and research, particularly at a time when exciting new approaches to therapy, early detection, and prevention are appearing on the horizon. We feel the time has come to minimize individual and institutional variations in practice, and agree on an evidence-based approach to uniform terminology and primary site assignment. In this paper we put forward a proposal for a unified approach based on published research evidence and discuss the reasons why it is vital to agree on a uniform protocol. We propose the term "Tubo-ovarian HGSC" in preference to "pelvic" or "Mullerian," as it accurately reflects the origin of this disease in the vast majority of cases, and is unambiguous, distinguishing it clearly from uterine serous carcinoma and ovarian low-grade serous carcinomas. A detailed protocol for primary site assignment is presented for different scenarios, which is easy to follow and has been developed with a view to promoting a uniform approach worldwide. PMID- 26977578 TI - Determination of the Membrane Permeability to Water of Human Vaginal Mucosal Immune Cells at Subzero Temperatures Using Differential Scanning Calorimetry. AB - To study mucosal immunity and conduct HIV vaccine trials, it is important to be able to cryopreserve mucosal specimens and recover them in functional viable form. Obtaining a good recovery depends, in part, on cooling the cells at the appropriate rate, which is determined by the rate of water transport across the cell membrane during the cooling process. In this study, the cell membrane permeabilities to water at subzero temperatures of human vaginal mucosal T cells and macrophages were measured using the differential scanning calorimetry method proposed by Devireddy et al. in 1998. Thermal histograms were measured before and after cell lysis using a Slow-Fast-Fast-Slow cooling program. The difference between the thermal histograms of the live intact cells and the dead lysed cells was used to calculate the temperature-dependent cell membrane permeability at subzero temperatures, which was assumed to follow the Arrhenius relationship, [Formula: see text], where Lpg is the permeability to water at the reference temperature (273.15 K). The results showed that Lpg = 0.0209 +/- 0.0108 MUm/atm/min and Ea = 41.5 +/- 11.4 kcal/mol for T cells and Lpg = 0.0198 +/- 0.0102 MUm/atm/min and Ea = 38.2 +/- 10.4 kcal/mol for macrophages, respectively, in the range 0 degrees C to -40 degrees C (mean +/- standard deviation). Theoretical simulations predicted that the optimal cooling rate for both T cells and macrophages was about -3 degrees C/min, which was proven by preliminary immune cell cryopreservation experiments. PMID- 26977581 TI - Why should we abort the expression 'aborted sudden death'. PMID- 26977582 TI - Cardioembolism and takotsubo syndrome: A case report. PMID- 26977583 TI - Closed chest human aortic valve removal and replacement: Technical feasibility and one year follow-up. AB - BACKGROUND: Minimally invasive aortic valve replacement has so far required a minithoracotomy or a ministernotomy. We present here the first series of totally endoscopic aortic valve replacement (TEAVR). METHODS: Between June 2013 and April 2015, 14 consecutive patients (12 males, mean age=76 +/- 5.4 years) with a mean EuroSCORE II of 2.72 +/- 0.03% underwent TEAVR. A five trocar setting was used in all patients: after ablation of the native valve, a Nitinol stented sutureless 3f Enable Medtronic valve, compressed into the main working trocar, was introduced into the thorax and then expanded in the aortic root. RESULTS: Among the 14 patients, a thoracoscopic approach was successful in 13 (92.8%) and conversion into an open surgery using the right anterior minithoracotomy was necessary to close the aortotomy in one case. Mean cross-clamping and cardiopulmonary (CPB) times were 112 +/- 18 and 161 +/- 31 min, respectively. All patients left the surgical unit within 8 days after the operation without any paravalvular leakage. There was no paravalvular regurgitation, conductive block or any major adverse event at a mean follow-up of 10 +/- 4 months (range 2-16). CONCLUSIONS: TEAVR is feasible and safe in a selected subset of patients. Closed chest surgery has the potential to become the future approach of the isolated aortic valve replacement in low risk patients but further technical refinement and larger studies are necessary to reduce operative durations and enhance reproducibility. PMID- 26977584 TI - Health status of older patients with type 2 diabetes and screen-detected heart failure is significantly lower than those without. PMID- 26977585 TI - Ultra-high performance liquid chromatography coupled with quadrupole/time of flight mass spectrometry based chemical profiling approach for the holistic quality control of complex Kang-Jing formula preparations. AB - The Kang-Jing (KJ) formula is a compound preparation made from 12 kinds of herbs. So far, four different methods (M1-M4) have been documented for KJ preparation, but the influence of preparation methods on the holistic quality of KJ have remained unknown. In this study, a strategy was proposed to investigate the influence of different preparation methods on the holistic quality of KJ using ultra-high performance liquid chromatography coupled with quadrupole/time of flight mass spectrometry (UHPLC-QTOF-MS/MS) based chemical profiling. A total of 101 compounds mainly belonging to flavonoids, tanshinones, monoterpene glycosides, triterpenoid saponins, alkaloids, phenolic acids and volatile oils, were identified. Among these compounds, glaucine was detected only in M3/M4 samples, while two dehydrocorydaline isomers merely detected in M2/M3/M4 samples. Tetrahydrocolumbamine, ethylic lithospermic acid, salvianolic acid E and rosmarimic acid were only detected in M1/M3/M4 samples. In the subsequent quantitative analysis, 12 major compounds were determined by UHPLC-MS/MS. The proposed method was validated with respect to linearity, accuracy, precision and recovery. It was found that the contents of marker compounds varied significantly in samples prepared by different methods. These results demonstrated that preparation method does significantly affect the holistic quality of KJ. UHPLC QTOF-MS/MS based chemical profiling approach is efficient and reliable for comprehensive quality evaluation of KJ. Collectively, this study provide the chemical evidence for revealing the material basis of KJ, and establish a simple and accurate chemical profiling method for its quality control. PMID- 26977587 TI - Directional reflectance analysis for identifying counterfeit drugs: Preliminary study. AB - The WHO estimates that up to 10% of drugs on the market may be counterfeit. In order to prevent intensification of the phenomenon of drug counterfeiting, the methods for distinguishing genuine medicines from fake ones need to be developed. The aim of this study was to try to develop simple, reproducible and inexpensive method for distinguishing between original and counterfeit medicines based on the measurement of directional reflectance. The directional reflectance of 6 original Viagra((r)) tablets (Pfizer) and 24 (4 different batches) counterfeit tablets (imitating Viagra((r))) was examined in six spectral bands: from 0.9 to 1.1 MUm, from 1.9 to 2.6 MUm, from 3.0 to 4.0 MUm, from 3.0 to 5.0 MUm, from 4.0 to 5.0 MUm, from 8.0 to 12.0 MUm, and for two angles of incidence, 20 degrees and 60 degrees . Directional hemispherical reflectometer was applied to measure directional reflectance. Significant statistical differences between the directional reflectance of the original Viagra((r)) and counterfeit tablets were registered. Any difference in the value of directional reflectance for any spectral band or angle of incidence identifies the drug as a fake one. The proposed method of directional reflectance analysis enables to differentiate between the real Viagra((r)) and fake tablets. Directional reflectance analysis is a fast (measurement time under 5s), cheap and reproducible method which does not require expensive equipment or specialized laboratory staff. It also seems to be an effective method, however, the effectiveness will be assessed after the extension of research. PMID- 26977586 TI - Procedure optimization for extracting short-chain fatty acids from human faeces. AB - Short-chain fatty acids play an important role in the physiology and metabolism of the colon. Disturbed balance of such compounds in human gut can significantly contribute to etiological factors of various gastrointestinal disorders and it may also increase the risk of developing cancer or cardiovascular diseases. The aim of the study was to select the optimal parameters for acetic, propionic and butyric acids extraction from stool samples. The experimental conditions were optimized with respect to the solvent sample shacking time, sample ultrasounds (Ultrasound-Assisted Extraction, UAE) exposure time and the number of extractions from the particulate stool samples. The screening of experimental parameters was conducted with fractional factorial design of experiments, namely 3(3-1). The optimal conditions for UAE were found, namely ultrasound digestion time of 40 min (at 35 degrees C), shaking time of 4 min, and the three subsequent extractions. PMID- 26977588 TI - Does Subjective Rating Reflect Behavioural Coding? Personality in 2 Month-Old Dog Puppies: An Open-Field Test and Adjective-Based Questionnaire. AB - A number of studies have recently investigated personality traits in non-human species, with the dog gaining popularity as a subject species for research in this area. Recent research has shown the consistency of personality traits across both context and time for adult dogs, both when using questionnaire based methods of investigation and behavioural analyses of the dogs' behaviour. However, only a few studies have assessed the correspondence between these two methods, with results varying considerably across studies. Furthermore, most studies have focused on adult dogs, despite the fact that an understanding of personality traits in young puppies may be important for research focusing on the genetic basis of personality traits. In the current study, we sought to evaluate the correspondence between a questionnaire based method and the in depth analyses of the behaviour of 2-month old puppies in an open-field test in which a number of both social and non-social stimuli were presented to the subjects. We further evaluated consistency of traits over time by re-testing a subset of puppies. The correspondence between methods was high and test- retest consistency (for the main trait) was also good using both evaluation methods. Results showed clear factors referring to the two main personality traits 'extroversion,' (i.e. the enthusiastic, exuberant approach to the stimuli) and 'neuroticism,' (i.e. the more cautious and fearful approach to the stimuli), potentially similar to the shyness-boldness dimension found in previous studies. Furthermore, both methods identified an 'amicability' dimension, expressing the positive interactions the pups directed at the humans stranger, and a 'reservedness' dimension which identified pups who largely chose not to interact with the stimuli, and were defined as quiet and not nosey in the questionnaire. PMID- 26977591 TI - Impact of ERK activation on fly survival and Wolbachia-mediated protection during virus infection. AB - Elevated levels of reactive oxygen species (ROS) provide protection against virus induced mortality in Drosophila. In addition to contributing to oxidative stress, ROS are known to activate a number of signalling pathways including the extracellular signal-regulated kinases (ERK) signalling cascade. It was recently shown that ERK signalling is important for resistance against viral replication and invasion in cultured Drosophila cells and the gut epithelium of adult flies. Here, using a Drosophila loss-of-function ERK (rolled) mutant we demonstrated that ERK is important for fly survival during virus infection. ERK mutant flies subjected to Drosophila C virus (DCV) oral and systemic infection were more susceptible to virus-induced mortality as compared with wild-type flies. We have demonstrated experimentally that ERK activation is important for fly survival during oral and systemic virus infection. Given that elevated ROS correlates with Wolbachia-mediated antiviral protection, we also investigated the involvement of ERK in antiviral protection in flies infected by Wolbachia. The results indicate that ERK activation is increased in the presence of Wolbachia but this does not appear to influence Wolbachia-mediated antiviral protection, at least during systemic infection. PMID- 26977589 TI - Inducing amnesia through systemic suppression. AB - Hippocampal damage profoundly disrupts the ability to store new memories of life events. Amnesic windows might also occur in healthy people due to disturbed hippocampal function arising during mental processes that systemically reduce hippocampal activity. Intentionally suppressing memory retrieval (retrieval stopping) reduces hippocampal activity via control mechanisms mediated by the lateral prefrontal cortex. Here we show that when people suppress retrieval given a reminder of an unwanted memory, they are considerably more likely to forget unrelated experiences from periods surrounding suppression. This amnesic shadow follows a dose-response function, becomes more pronounced after practice suppressing retrieval, exhibits characteristics indicating disturbed hippocampal function, and is predicted by reduced hippocampal activity. These findings indicate that stopping retrieval engages a suppression mechanism that broadly compromises hippocampal processes and that hippocampal stabilization processes can be interrupted strategically. Cognitively triggered amnesia constitutes an unrecognized forgetting process that may account for otherwise unexplained memory lapses following trauma. PMID- 26977593 TI - Correction: Gradual Rewarming with Gradual Increase in Pressure during Machine Perfusion after Cold Static Preservation Reduces Kidney Ischemia Reperfusion Injury. PMID- 26977590 TI - N-acetyl-cysteine prevents age-related hearing loss and the progressive loss of inner hair cells in gamma-glutamyl transferase 1 deficient mice. AB - Genetic factors combined with oxidative stress are major determinants of age related hearing loss (ARHL), one of the most prevalent disorders of the elderly. Dwarf grey mice, Ggt1dwg/dwg, are homozygous for a loss of function mutation of the g-glutamyl transferase 1 gene, which encodes an important antioxidant enzyme critical for the resynthesis of glutathione (GSH). Since GSH reduces oxidative damage, we hypothesized that Ggt1dwg/dwg mice would be susceptible to ARHL. Surprisingly, otoacoustic emissions and cochlear microphonic potentials, which reflect cochlear outer hair cell (OHC) function, were largely unaffected in mutant mice, whereas auditory brainstem responses and the compound action potential were grossly abnormal. These functional deficits were associated with an unusual and selective loss of inner hair cells (IHC), but retention of OHC and auditory nerve fibers. Remarkably, hearing deficits and IHC loss were completely prevented by N-acetyl-L-cysteine, which induces de novo synthesis of GSH; however, hearing deficits and IHC loss reappeared when treatment was discontinued. Ggt1dwg/dwg mice represent an important new model for investigating ARHL, therapeutic interventions, and understanding the perceptual and electrophysiological consequences of sensory deprivation caused by the loss of sensory input exclusively from IHC. PMID- 26977592 TI - Activation of Endothelial Nitric Oxide (eNOS) Occurs through Different Membrane Domains in Endothelial Cells. AB - Endothelial cells respond to a large range of stimuli including circulating lipoproteins, growth factors and changes in haemodynamic mechanical forces to regulate the activity of endothelial nitric oxide synthase (eNOS) and maintain blood pressure. While many signalling pathways have been mapped, the identities of membrane domains through which these signals are transmitted are less well characterized. Here, we manipulated bovine aortic endothelial cells (BAEC) with cholesterol and the oxysterol 7-ketocholesterol (7KC). Using a range of microscopy techniques including confocal, 2-photon, super-resolution and electron microscopy, we found that sterol enrichment had differential effects on eNOS and caveolin-1 (Cav1) colocalisation, membrane order of the plasma membrane, caveolae numbers and Cav1 clustering. We found a correlation between cholesterol-induced condensation of the plasma membrane and enhanced high density lipoprotein (HDL) induced eNOS activity and phosphorylation suggesting that cholesterol domains, but not individual caveolae, mediate HDL stimulation of eNOS. Vascular endothelial growth factor (VEGF)-induced and shear stress-induced eNOS activity was relatively independent of membrane order and may be predominantly controlled by the number of caveolae on the cell surface. Taken together, our data suggest that signals that activate and phosphorylate eNOS are transmitted through distinct membrane domains in endothelial cells. PMID- 26977594 TI - Stance Postural Strategies in Patients with Chronic Inflammatory Demyelinating Polyradiculoneuropathy. AB - INTRODUCTION: Polyneuropathy leads to postural instability and an increased risk of falling. We investigated how impaired motor impairment and proprioceptive input due to neuropathy influences postural strategies. METHODS: Platformless bisegmental posturography data were recorded in healthy subjects and patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Each subject stood on the floor, wore a head and a hip electromagnetic tracker. Sway amplitude and velocity were recorded and the mean direction difference (MDD) in the velocity vector between trackers was calculated as a flexibility index. RESULTS: Head and hip postural sway increased more in patients with CIDP than in healthy controls. MDD values reflecting hip strategies also increased more in patients than in controls. In the eyes closed condition MDD values in healthy subjects decreased but in patients remained unchanged. DISCUSSION: Sensori-motor impairment changes the balance between postural strategies that patients adopt to maintain upright quiet stance. Motor impairment leads to hip postural strategy overweight (eyes open), and prevents strategy re-balancing when the sensory context predominantly relies on proprioceptive input (eyes closed). PMID- 26977597 TI - Diffusion Tensor Imaging Abnormalities in the Cerebral White Matter Correlate with Sex-Dependent Neurobehavioral Deficits in Adult Mice with Neonatal Ischemia. AB - BACKGROUND: Neonatal white matter injury (NWMI) is the leading cause of cerebral palsy in prematurely born children. In order to develop a test bed for therapeutics, we recently reported a mouse model of NWMI by using a modified Rice Vannucci model of neonatal ischemia on postnatal day 5 (P5) in CD-1 mice. We have previously shown that these mice illustrate initial neuroinflammation and oligodendroglial differentiation arrest followed by long-term dysmyelination, periventricular astrogliosis and axonal injury, resembling human NWMI. The objective of this study was to determine the sex-dependent long-term effects of neonatal brain injury on neurobehavioral and advanced in vivo neuroimaging indices in this mouse model, and to correlate these variables with histopathology. METHODS: After right common artery ligation on P5, in vivo T2 weighted imaging and diffusion tensor imaging (DTI) were performed on ligated and control animals at 4 and 8 weeks. Common sets of regions of interest were used to compare fractional anisotropy (FA) values between ischemic and control mice. Behavioral testing (open field, startle response and grip strength) was performed at adult age. Finally, the animals were sacrificed for immunohistochemical (IHC) assessment of major white matter tracts. RESULTS: DTI revealed significant sex dependent changes in FA values ipsi- and contralateral to the ligation. Behavioral testing showed decreased reaction to acoustic stimuli in males but not females. Similarly, increased number of rearings and lack of novelty-induced habituation in the open field were encountered only in the male subgroup. Several regional correlations were found between FA values and these behavioral alterations. IHC studies revealed degeneration of mature oligodendrocytes and damage of white matter tracts in ligated animals, as previously reported in this model, and showed regional correlation with in vivo FA values and behavioral alterations. CONCLUSIONS: Our findings suggest structural sex-dependent long-term abnormalities after neonatal ischemia. These changes lead to behavioral deficits resembling common problems of patients with cerebral palsy. PMID- 26977596 TI - Effects of Temperature on Bacterial Communities and Metabolites during Fermentation of Myeolchi-Aekjeot, a Traditional Korean Fermented Anchovy Sauce. AB - Myeolchi-aekjeot (MA) in Korea is produced outdoors without temperature controls, which is a major obstacle to produce commercial MA products with uniform quality. To investigate the effects of temperature on MA fermentation, pH, bacterial abundance and community, and metabolites were monitored during fermentation at 15 degrees C, 20 degrees C, 25 degrees C, and 30 degrees C. Initial pH values were approximately 6.0, and pH values increased after approximately 42 days, with faster increases at higher temperatures. Bacterial abundances increased rapidly in all MA samples after quick initial decreases during early fermentation and then they again steadily decreased after reaching their maxima, which were significantly greater at higher temperatures. Bacterial community analysis revealed that Proteobacteria and Tenericutes were predominant in all initial MA samples, but they were rapidly displaced by Firmicutes as fermentation progressed. Photobacterium and Mycoplasma belonging to Proteobacteria and Tenericutes, respectively, which may include potentially pathogenic strains, were dominant in initial MA, but decreased with the growth of Chromohalobacter, which occurred faster at higher temperatures--they were dominant until 273 and 100 days at 15 degrees C and 20 degrees C, respectively, but not detected after 30 days at 25 degrees C and 30 degrees C. Chromohalobacter also decreased with the appearance of subsequent genera belonging to Firmicutes in all MA samples. Tetragenococcus, halophilic lactic acid bacteria, appeared predominantly at 20 degrees C, 25 degrees C, and 30 degrees C; they were most abundant at 30 degrees C, but not detected at 15 degrees C. Alkalibacillus and Lentibacillus appeared as dominant genera with the decrease of Tetragenococcus at 25 degrees C and 30 degrees C, but only Lentibacillus was dominant at 15 degrees C and 20 degrees C. Metabolite analysis showed that amino acids related to tastes were major metabolites and their concentrations were relatively higher at high temperatures. This study suggests that high temperatures (approximately 30 degrees C) may be appropriate in MA fermentation, in the light of faster disappearance of potentially pathogenic genera, higher amino acids, growth of Tetragenococcus, and faster fermentation. PMID- 26977595 TI - CK19 and Glypican 3 Expression Profiling in the Prognostic Indication for Patients with HCC after Surgical Resection. AB - This retrospective study was designed to investigate the correlation between a novel immunosubtyping method for hepatocellular carcinoma (HCC) and biological behavior of tumor cells. A series of 346 patients, who received hepatectomy at two surgical centers from January 2007 to October 2010, were enrolled in this study. The expressions of cytokeratin 19 (CK19), glypican 3 (GPC3), and CD34 were detected by immunohistochemical staining. The clinical stage was assessed using the sixth edition tumor-node-metastasis (TNM) system (UICC/AJCC, 2010).Vascular invasion comprised both microscopic and macroscopic invasion. The tumor size, lymph node involvement, and metastasis were determined by pathological as well as imaging studies. Recurrence was defined as the appearance of new lesions with radiological features typical of HCC, seen by at least two imaging methods. Survival curves for the patients were plotted using the Kaplan-Meier method, and differences between the curves were assessed using the log-rank test. Significant differences in morphology, histological grading, and TNM staging were observed between groups. Based on the immunohistochemical staining, the enrolled cases were divided into CK19+/GPC3+, CK19-/GPC3+ and CK19-/GPC3- three subtypes. CK19+/GPC3+ HCC has the highest risk of multifocality, microvascular invasion, regional lymph node involvement, and distant metastasis, followed by CK19-/GPC3+ HCC, then CK19-/GPC3-HCC. CK19+/GPC3+ HCC has the shortest recurrence time compared to other immunophenotype HCCs. CK19 and GPC3 expression profiling is an independent prognostic indicator in patients with HCC, and a larger sample size is needed to further investigate the effect of this immunosubtyping model in stratifying the outcome of HCC patients. PMID- 26977598 TI - The Relationship between Body Mass Index and Post-Cessation Weight Gain in the Year after Quitting Smoking: A Cross-Sectional Study. AB - INTRODUCTION: There is wide variability in the amount of weight gained when quitting smoking, but little is known about key predictors of weight gain. We examined the impact of body mass index (BMI) category and sociodemographic variables on post-cessation weight gain. MATERIALS AND METHODS: We utilized National Health and Nutrition Examination Survey data from five consecutive cycles of data collection from 2003-2004 to 2011-2012 to estimate post-cessation weight gain by BMI category among recent quitters (n = 654). We analyzed data on their "current weight" and their "past year weight". We also compared the recent quitters with current smokers, in order to estimate the amount of weight that could be attributed to quitting smoking. RESULTS: Recent quitters gained 1.4 kg (95% CI: 0.8 to 2.0), while current smokers had a non-significant weight change ( 0.01 kg (95% CI: -0.3 to 0.2). Weight gain was significant for those in the normal weight (3.1 kg, 95% CI: 2.3 to 3.9) and overweight BMI categories (2.2 kg, 95% CI: 1.1 to 3.2). CONCLUSIONS: BMI category is a key factor in the extent of post-cessation weight gain, with normal and overweight recent quitters gaining significant amounts of weight. PMID- 26977599 TI - Falls and Fall-Related Injuries among Community-Dwelling Adults in the United States. AB - INTRODUCTION: Falls are the leading cause of unintentional injuries in the U.S.; however, national estimates for all community-dwelling adults are lacking. This study estimated the national incidence of falls and fall-related injuries among community-dwelling U.S. adults by age and gender and the trends in fall-related injuries across the adult life span. METHODS: Nationally representative data from the National Health Interview Survey (NHIS) 2008 Balance and Dizziness supplement was used to develop national estimates of falls, and pooled data from the NHIS was used to calculate estimates of fall-related injuries in the U.S. and related trends from 2004-2013. Costs of unintentional fall-related injuries were extracted from the CDC's Web-based Injury Statistics Query and Reporting System. RESULTS: Twelve percent of community-dwelling U.S. adults reported falling in the previous year for a total estimate of 80 million falls at a rate of 37.2 falls per 100 person-years. On average, 9.9 million fall-related injuries occurred each year with a rate of 4.38 fall-related injuries per 100 person-years. In the previous three months, 2.0% of older adults (65+), 1.1% of middle-aged adults (45 64) and 0.7% of young adults (18-44) reported a fall-related injury. Of all fall related injuries among community-dwelling adults, 32.3% occurred among older adults, 35.3% among middle-aged adults and 32.3% among younger adults. The age adjusted rate of fall-related injuries increased 4% per year among older women (95% CI 1%-7%) from 2004 to 2013. Among U.S. adults, the total lifetime cost of annual unintentional fall-related injuries that resulted in a fatality, hospitalization or treatment in an emergency department was 111 billion U.S. dollars in 2010. CONCLUSIONS: Falls and fall-related injuries represent a significant health and safety problem for adults of all ages. The findings suggest that adult fall prevention efforts should consider the entire adult lifespan to ensure a greater public health benefit. PMID- 26977600 TI - Spectroscopic Studies on Organic Matter from Triassic Reptile Bones, Upper Silesia, Poland. AB - Fossil biomolecules from an endogenous source were previously identified in Cretaceous to Pleistocene fossilized bones, the evidence coming from molecular analyses. These findings, however, were called into question and an alternative hypothesis of the invasion of the bone by bacterial biofilm was proposed. Herewith we report a new finding of morphologically preserved blood-vessel-like structures enclosing organic molecules preserved in iron-oxide-mineralized vessel walls from the cortical region of nothosaurid and tanystropheid (aquatic and terrestrial diapsid reptiles) bones. These findings are from the Early/Middle Triassic boundary (Upper Roetian/Lowermost Muschelkalk) strata of Upper Silesia, Poland. Multiple spectroscopic analyses (FTIR, ToF-SIMS, and XPS) of the extracted "blood vessels" showed the presence of organic compounds, including fragments of various amino acids such as hydroxyproline and hydroxylysine as well as amides, that may suggest the presence of collagen protein residues. Because these amino acids are absent from most proteins other than collagen, we infer that the proteinaceous molecules may originate from endogenous collagen. The preservation of molecular signals of proteins within the "blood vessels" was most likely made possible through the process of early diagenetic iron oxide mineralization. This discovery provides the oldest evidence of in situ preservation of complex organic molecules in vertebrate remains in a marine environment. PMID- 26977601 TI - [Not Available]. PMID- 26977603 TI - Invitation and a Warm Welcome to the 42nd Annual Meeting of the Society for Neuropediatrics. PMID- 26977602 TI - Qualitative Treatment-Subgroup Interactions in a Randomized Clinical Trial of Treatments for Adolescents with ADHD: Exploring What Cognitive-Behavioral Treatment Works for Whom. AB - OBJECTIVE: This study explored qualitative treatment-subgroup interactions within data of a RCT with two cognitive behavioral treatments (CBT) for adolescents with ADHD: a planning-focused (PML) and a solution-focused CBT (SFT). Qualitative interactions imply that which treatment is best differs across subgroups of patients, and are therefore most relevant for personalized medicine. METHODS: Adolescents with ADHD (N = 159) received either PML or SFT. Pre-, post- and three month follow-up data were gathered on parent-rated ADHD symptoms and planning problems. Pretreatment characteristics were explored as potential qualitative moderators of pretest to follow-up treatment effects, using an innovative analyses technique (QUINT; Dusseldorp & Van Mechelen, 2014). In addition, qualitative treatment-subgroup interactions for the therapeutic changes from pre- to posttest and from post- to follow-up test were investigated. RESULTS: For the entire time span from pretest to follow-up only a quantitative interaction was found, while from posttest to follow-up qualitative interactions were found: Adolescents with less depressive symptoms but more anxiety symptoms showed more improvement when receiving PML than SFT, while for other adolescents the effects of PML and SFT were comparable. DISCUSSION: Whereas subgroups in both treatments followed different trajectories, no subgroup was found for which SFT outperformed PML in terms of the global change in symptoms from pretest to three months after treatment. This implies that, based on this exploratory study, there is no need for personalized treatment allocation with regard to the CBTs under study for adolescents with ADHD. However, for a subgroup with comorbid anxiety symptoms but low depression PML clearly appears the treatment of preference. TRIAL REGISTRATION: Nederlands Trial Register NTR2142. PMID- 26977604 TI - The role of N-terminal pro-brain natriuretic peptide in prediction of postoperative atrial fibrillation. AB - AIM: To analyze prognostic value of different factors in postoperative atrial fibrillation prediction. MATERIAL AND METHODS: Study included 39 patients with coronary artery disease without previous paroxysmal atrial fibrillation. Multiple correlation, logistic regression and ROC-analysis were performed to create predictive model of postoperative atrial fibrillation prognosis. Authors have analyzed most of described in literature preoperative predictors of atrial fibrillation to define the role of different risk factors. Prognostic role of N terminal pro-brain natriuretic peptide (NT-proBNP) is assessed. RESULTS: We revealed high informativeness of NT-proBNP to predict postoperative atrial fibrillation after on-pump coronary artery bypass grafting. PMID- 26977605 TI - [Opportunities of endovideosurgical interventions in thoracic and abdominal trauma]. AB - AIM: To analyze the results of laparo- and thoracoscopy in patients with thoracic and abdominal trauma in conditions of emergency hospital. MATERIAL AND METHODS: For the period 2006-2013 we performed 56 laparoscopic and 15 thoracoscopic interventions in 67 patients with trauma. There were 80.6% of men and 19.4% of women aged 35+/-1.7 years. Abdominal, thoracic and thoraco-abdominal injuries were observed in 51 (76.1%), 14 (20.9%) and 2 (3%) patients. Abdominal or thoracic trauma alone was diagnosed in 41 (61.2%) cases and combined injury - in 26 (38.8%) patients. 37 (66%) interventions were performed laparoscopically. Conversion to laparotomy was observed in 19 (34%) cases. Mean volume of hemoperitoneum was 458 ml (range 100-1100 ml). In 11 (73.3%) patients thoracoscopic surgery was performed and conversion of access was applied in 4 (26.7%) cases. RESULTS: No injuries of internal organs were observed in 19.6% and 13.3% of patients using laparo- and thoracoscopy respectively. So inadvisable open surgery was prevented although formal indications for laparo- and thoracotomy were present. In 25% and 20% of abdominal and thoracic damages respectively we avoided relatively unjustified laparo- or thoracotomy because of injuries were cured endoscopically. No one missed injury was observed. Postoperative complications were diagnosed in 5.6% of cases. Mortality rate was 15.6% in case of severe combined trauma. Mean hospital stay was 23.2 days (range 3-105). CONCLUSION: Endoscopic techniques are perspective in treatment of thoracic and abdominal trauma. It allows to avoid inadvisable laparo- and thoracotomy in some cases and to improve results of treatment. PMID- 26977606 TI - [Computed tomography in diagnostics of extravasal influence of thyroid nodules]. AB - AIM: To estimate role of contrast-enhanced MDCT in diagnosis of common carotid arteries and internal jugular veins compression by thyroid nodules. MATERIAL AND METHODS: Contrast-enhanced MDCT of neck and mediastinum was performed in 15 patients with benign thyroid nodules in addition to conventional clinical survey and Doppler imaging of common carotid arteries and internal jugular veins. Thyroid volume ranged from 71.4 to 296 cm3. Cervical great vessels deviation, their dislocation and deformation because of compression were revealed in 14 patients. Partial and complete compression within transverse processes of cervical vertebrae was diagnosed in 7 cases. It was concluded that dislocated common carotid arteries per se can compress and deform internal jugular veins. Blood flow in veins is absent if they are compressed throughout. If jugular vein is compressed behind sternum only its ectasia may be observed. RESULTS: Vascular geometry was restored after extravasal compression elimination. Contrast-enhanced MDCT should be included into survey program of patients with thyroid nodules. PMID- 26977607 TI - [Analysis of reasons of "incomplete" colonoscopy]. AB - The objective of this study was to determine the reasons for incomplete colonoscopy, as well as evaluation of results preparation of patients for colonoscopy in a variety of ways, informative colonoscopy depending on the quality of preparation of the colon for examination. MATERIAL AND METHODS: The material of this study was the results 104 of colonoscopies drawn from daily clinical practice. To prepare the colon for the study used the most available ways: 1) lavage solutions, 2) castor oil, 2 enemas in the morning and 2 in the evening, 3) enema, which the patients were chosen after consulting a doctor. To assess the preparedness of the colon to the study used a Boston-scale of assessment of quality of preparation of the colon for a colonoscopy". Preparation of the colon was improved by using a water jet pump of the company "Olympus" AFU100. Statistical analysis was performed using IBM SPSS Statistics 19.0. RESULTS: Analysis of clinical specimens showed that in 13 (12.5%) of the observations to intubate the colon was not possible. The main reason is the poor preparation of the colon to the study, which failed to improve even with the aid of a water jet pump. PMID- 26977608 TI - [Rectosacropexy in rectal prolapse management]. AB - AIM: To compare results of rectosacropexy and posterior-loop rectopexy in rectal prolapse management. MATERIAL AND METHODS: Study included 122 patients operated for rectal prolapse for the period January 2007 to August 2014. Patients' age ranged from 19 to 85 years (mean 47.3+/-16.1). Main group consisted of 60 (49.2%) patients who underwent rectosacropexy (D'Hoore's procedure). Control group included 62 (50.8%) patients in whom posterior-loop rectopexy was applied (Wells's procedure). RESULTS: Long-term results were followed-up in 94 (77.0%) patients including 48 and 46 from main and control group respectively. Recurrent prolaple incidence after rectosacropexy and posterior-loop rectopexy was 2% and 8.7% respectively. Multivariant analysis statistically confirmed that postoperative impaired colon motility was independent risk factor of recurrence. Recurrent disease is observed 5.7 times more often in this case. Rectosacropexy does not significantly impair colon motility because of ileus occurs in 8.3% of operated patients. Impovement of anal continence does not depend on rectopexy method and occurs in all patients with degree 1-2 of anal sphincter failure. CONCLUSION: Rectosacropexy may be preferred in rectal prolapse. However, further highly significant studies are necessary to optimize rectal prolapse management. PMID- 26977609 TI - [The efficacy of endoscopic endosonography in diagnosis of benign and malignant stenoses of common bile duct]. AB - AIM: To define criteria and to estimate diagnostic significance of endosonography in differential diagnosis of benign and malignant stenoses of common bile duct. MATERIAL AND METHODS: We presented the results of survey and treatment of 57 patients with benign and malignant stenoses of common bile duct. The technique of endosonography is described. We have formulated major criteria of differential diagnostics of tumoral and non-tumoral lesion of extrahepatic bile ducts. Comparative analysis of endosonography, ultrasound, computed tomography and magnetic resonance cholangiopancreatography was performed. RESULTS: Sensitivity, specificity and accuracy of endosonography in diagnosis of stenosis cause is 97.7%, 100% and 98.2% respectively. So it exceeds the efficacy of other diagnostic X-ray methods. In modern surgical clinic endosonography should be mandatory performed. It is necessary for final diagnostics of cause of common bile duct stenosis especially in case of its low location. PMID- 26977610 TI - [Training curves for endosurgical interventions in neonates and infants]. AB - AIM: To demonstrate training curves for endosurgical interventions in neonates and infants. MATERIAL AND METHODS: It was analyzed duration of thoracoscopic reconstruction of esophageal atresia (31 patients) and laparoscopic Nissen fundoplication (61 patients) performed for the period from January 2005 to December 2012. Graphs and tables reflecting correlation between duration and number of operations were framed. RESULTS: Figures demonstrate reducing duration of surgery with increase of endosurgical interventions number. CONCLUSION: Our data revealed that time necessary for minimally invasive procedures in infants and neonates decreases in process of experience accumulation. PMID- 26977612 TI - [Transfusion supply optimization in multiple-discipline surgical hospital]. AB - AIM: To define optimal variant of transfusion supply of hospital by blood components and to decrease donor blood expense via application of blood preserving technologies. MATERIAL AND METHODS: Donor blood components expense, volume of hemotransfusions and their proportion for the period 2012-2014 were analyzed. RESULTS: Number of recipients of packed red cells, fresh-frozen plasma and packed platelets reduced 18.5%, 25% and 80% respectively. Need for donor plasma decreased 35%. Expense of autologous plasma in cardiac surgery was 76% of overall volume. Preoperative plasma sampling is introduced in patients with aortic aneurysm. Number of cardiac interventions performed without donor blood is increased 7-31% depending on its complexity. PMID- 26977613 TI - [Etiology of "difficult" laparoscopic cholecystectomy]. AB - AIM: To define causes of difficult situations in various forms of acute cholecystitis depending on terms of disease and clinico-morphological changes in gall bladder area and to justify differentiated application of laparoscopic surgery for acute cholecystitis. MATERIAL AND METHODS: It was reviewed 1132 medical records of patients with acute cholecystitis. It is found that morphological changes in gall bladder and surrounding tissues depend on duration of follow-up of patients with acute cholecystitis and type of inflammation. RESULTS: In acute catarrhal cholecystitis "complicated" intraoperative situations are observed in 37.5% due to "loose" tissues infiltration, in phlegmonous and gangrenous forms of inflammation - in 44.6% and 63.6% respectively due to "dense" infiltrates development. CONCLUSION: Technical variants of laparoscopic cholecystectomy for various "difficult" intraoperative situations are suggested. PMID- 26977611 TI - [Kidney allotransplantation from alive related donor in patients with Alport syndrome]. AB - AIM: To evaluate the results of kidney transplantation from alive related donor in patients with Alport syndrome and to compare with those in patients with kidney hypoplasia. MATERIAL AND METHODS: We have analyzed 8 and 27 medical records of patients with Alport syndrome and kidney hypoplasia respectively. Following parameters were used - Kaplan-Meier survival analysis, Wilcox overall risk, percentage of transplants loss and mortality (Fisher's exact test calculation). RESULTS: It is concluded that percentage of transplants loss and mortality rate as well as overall survival and risk were similar in both groups. CONCLUSION: Despite risk of anti-GBM nephritis development in patients with Alport syndrome results are comparable with those after transplatation for chronic renal failure caused by other reasons. PMID- 26977614 TI - [The combination of chondroitin sulfate and glucosamine (artra) for pain relief and to reduce the consumption of NSAIDs in patients with I-II stages of osteoarthritis of the knee]. AB - The analysis of the dynamics of pain and joint function on the background of the 3-month ARTRA.Study was conducted as a multicenter, with the inclusion of 3077 patients, 56.2% of whom received NSAIDs for pain relief. While taking after a month of therapy showed significant compared to the original value of reducing the intensity of pain. The therapeutic effect is increased with duration of dosing. It is shown that the drug reduces the need for arthritis NSAIDs after a month by 6.8%, after 3 months - by 37.3%, ie after the 3-month course of treatment with arthritis, the number of people taking NSAIDs fell by more than 3 times (up 18.9%). A significant reduction in consumption, coupled with the marked dynamics of the pain is regarded by us as a manifestation expressed anesthetic effect of the drug ARTRA. PMID- 26977616 TI - [A rare complication of necrotizing enterocolitis in newborn]. PMID- 26977615 TI - [Prevention and treatment of post-traumatic pancreatic necrosis in patients with blunt abdominal trauma]. AB - INTRODUCTION: High incidence of necrotic and suppurative complications is feature of acute post-traumatic pancreatitis. Severe trauma of the pancreas and post traumatic pancreatitis lead to depressurization of ductal system that requires adequate drainage of damaged area and retroperitoneal fat. MATERIAL AND METHODS: 95 patients in group 1 received standardized treatment. The victims of the 2nd group (44 patients) were treated using immunoreactive therapy (roncoleukin) and octreotide (the dose depended on the severity of pancreatitis) at early stages. The efficacy of treatment was assessed based on clinical, laboratory and instrumental parameters. RESULTS: Regardless severity of pancreatic injury overall mortality in groups 1 and 2 was 41% and 20.5% respectively. The main causes of adverse outcomes are severe destructive pancreatitis, postnecrotic suppurative complications. CONCLUSION: Adequacy rather radicalism of surgery should be preferred for blunt pancreatic trauma management. Minimally invasive surgical techniques and new methods of biological hemostasis may be applied. Timely use of anti-enzymatic and immunoactive therapy reduces the risk of severe post-traumatic pancreatitis, suppurative complications and improves outcomes in patients with blunt pancreatic trauma. PMID- 26977617 TI - Effect of Subthalamic Nucleus Stimulation on Pedunculopontine Nucleus Neural Activity. AB - BACKGROUND: The pedunculopontine nucleus has recently been proposed as an alternative target for deep brain stimulation for the treatment of medically intractable Parkinson's disease. The suggested indication for pedunculopontine nucleus deep brain stimulation is severe and medically intractable axial symptoms such as gait and postural impairment. OBJECTIVE: Our goal in this study was to describe the effects of subthalamic nucleus stimulation on pedunculopontine nucleus electrophysiological activity. METHODS: Fourteen male Wistar rats were divided into a sham stimulation group and an experimental group. In both groups, electrodes were implanted bilaterally into the subthalamic nucleus and into the right pedunculopontine nucleus. Microelectrode recordings were carried out in both groups prior to and during subthalamic nucleus stimulation. RESULTS: Subthalamic nucleus stimulation produced no clear inhibition of neuronal firing in the pedunculopontine nucleus. However, we found that stimulation of the subthalamic nucleus at 60 Hz produces some entrainment of pedunculopontine nucleus neuronal firing and a shift of subthalamic nucleus firing patterns to more tonic and random patterns. These results are consistent with the effects of deep brain stimulation on neuronal activity in the subthalamic nucleus and globus pallidus internus. CONCLUSION: The result of this study provides additional evidence to improve our understanding of the mechanism of subthalamic nucleus deep brain stimulation, and its physiological consequences. PMID- 26977618 TI - [Schizophrenia spectrum disorders in general medical practice]. AB - Based on the conception of correlations between independent endogenous factors (positive and negative disorders), the author present a psychopathological model of psychosomatic (hypochondriac) symptoms in deficit disturbances, comorbid with the changes of "verschroben" type, observed in general medical practice. The psychosomatic symptoms are represented by a wide range of symptom complexes (from idiopathic pain and conversions to restricted hypochondria, organ neuroses, encapsulated organ psychosis) and defined as a syndrome of endoform of somaticized disorders. The syndrome is interpreted beyond schizophrenia as "the second disease", a type of schizophrenia spectrum disorders, in which negative process changes have stopped while the other component (positive psychopathological symptoms) continues to develop. PMID- 26977619 TI - [Clinical manifestations of the onset and diagnostic problems in children with moyamoya disease]. AB - Moyamoya disease in children is a rarely diagnosed entity. Frequent headache is the first symptom of the disease. Headache associated with moya-moya disease (HAMD) is a separated entity reported in the literature. Variants of onset, a spectrum of primary diagnoses and diagnosis verification rate of moyamoya disease in 7 children are presented. A clinical case of moya-moya disease in a 9-year boy, who was primarily diagnosed with migraine with aura, is reported. The results presented by the authors as well as literature data indicate the necessity of using magnetic-resonance angiography in children with headache attacks and focal neurologic symptoms to identify this progressive vascular pathology and timely recommend a surgical treatment. PMID- 26977620 TI - [Brain function recovery after prolonged posttraumatic coma]. AB - OBJECTIVE: To explore the characteristics of brain function recovery in patients after prolonged posttraumatic coma and with long-unconscious states. MATERIAL AND METHODS: Eighty-seven patients after prolonged posttraumatic coma were followed up for two years. An analysis of a clinical/neurological picture after a prolonged episode of coma was based on the dynamics of vital functions, neurological status and patient's reactions to external stimuli. RESULTS AND CONCLUSION: Based on the dynamics of the clinical/neurological picture that shows the recovery of functions of the certain brain areas, three stages of brain function recovery after a prolonged episode of coma were singled out: brain stem areas, diencephalic areas and telencephalic areas. These functional/anatomic areas of brain function recovery after prolonged coma were compared to the present classifications. PMID- 26977621 TI - [Clinical and psychological mechanisms involved in the formation of syndromes of delusional and overvalued constructions]. AB - AIM: The identification of clinical-psychopathological and pathopsychological components involved in the formation of syndromes of delusional and overvalued constructions. MATERIAL AND METHODS: Authors examined 93 subjects using experimental psychological techniques for detection of cognitive styles. RESULTS AND CONCLUSION: A specific combination of phenomenological disorders and cognitive style characteristics in different types of delusional (sensual, imaginative and interpretive) and delusion-like (overvalued) states has been singled out. It has been shown that a specific combination of different cognitive motivational controllers of intellectual process underlies the mechanisms of these disorders. It is a basis for the formation of specific structures of pathological personal meanings with the dominance of imaginative or ideational patterns or deformations of the semantic significance of the stimuli. PMID- 26977622 TI - [A comparison of characteristics of pathologic hobbies in schizophrenic patients of different age]. AB - OBJECTIVE: To analyze age-related pathologic hobbies in patients with schizophrenia spectrum disorders. MATERIAL AND METHODS: Forty-three inpatients, aged from 4 to 16 years, and 31 patients, aged from 18 to 65 years, were studied. Clinical/psychopathological analysis, psychological experiment and clinical statistics were used. RESULTS AND CONCLUSION: Pathological hobbies substantially differed depending on the age (3-6, 7-15 and 18-65 years). In preschool age, hobbies were immature and infantile, arose autochthonously, their course was relatively stable and they had limited maladaptive effects. In junior school/teenager age, hobbies were more distinct and were associated with more diverse and mature realization patterns. Their origin was more depended on environmental factors, the course was persistent or attack-like with more pronounced and steady maladaptive effects. In some cases, there was a trend to pathological hobby progression. Abnormal hobbies in patients of mature age were the most diverse in their subjects and forms of realization as well as in their clinical variants and dynamic types. In the group of mature patients with schizophrenic spectrum disorders, there was a significantly higher percentage of psychotic forms of pathological hobbies. PMID- 26977623 TI - [Possibilities of preventive therapy in frequent episodic tension-type headache]. AB - OBJECTIVE: To study the efficacy and safety of tenoten in the preventive treatment of frequent episodic tension-type headache (FETHA) compared to patients treated with pain relievers. MATERIAL AND METHODS: A study included 60 patients with FETHA. Patients of the main group (n=30) received tenoten in addition to standard treatment. The study comprised 3 visits: beginning of treatment, after one month and after three months. All patients underwent physical and clinical/neurological examinations. In each visit, treatment efficacy was assessed according the following parameters: VAS scores (0-10) for assessment of pain and tension in pericranial muscles in 6 standard points, mean frequency and duration of the headache episode, quality of life indices, Beck depression scores, Spilberger trait and state anxiety, autonomic symptom severity, parameters of sleep disorders, frequency of adverse effects, CGI scores (0-7). RESULTS AND CONCLUSION: Tenoten as a preventive medication reduced the frequency of headache episodes that allowed to diagnose patients with rare episodic tension type headache in the end of treatment. At the same time, there was a significant reduction in headache intensity during the episode and decrease in amount of analgesics used by the patients. PMID- 26977624 TI - [The efficacy of remaxol addition in the treatment of alcohol withdrawal syndrome]. AB - OBJECTIVE: To study the efficacy of remaxol addition in the treatment scheme of alcohol withdrawal syndrome. MATERIAL AND METHODS: Eighty patients with alcohol dependence and physical symptoms of alcohol withdrawal syndrome were enrolled. All patients received basic therapy in accordance to the applicable standards of treatment. The patients were randomized to remaxol introduced intravenously 2 times a day (morning and afternoon) in dose of 400 ml for 7 days (n=40) and saline with 25%-magnesium sulfate (10 ml) and 4% potassium chloride (10 ml) (n=40). RESULTS: The effectiveness of the inclusion of remaxol was expressed in a more rapid relief of asthenic syndrome, reduction of phenomena such as tension, dysphoria, headache and impaired coordination of samples. Patients treated with remaxol demonstrated a trend towards a more rapid reduction of the affective (p=0.08) and behavioral components (p=0.09) of the syndrome of pathological craving for alcohol. Hepatoprotective and detoxification properties of the drug were confirmed by the significant decline in ALT and AST activity to the 20th day of treatment. Significant positive changes in lipid metabolism (HDL to the 7th day of treatment) and a normalizing effect on the processes of tissue respiration were shown as well. No adverse effects were noted. CONCLUSION: The data obtained allow to recommend the inclusion of remaxol in the complex treatment regimens of alcohol withdrawal syndrome to improve the treatment efficacy. PMID- 26977625 TI - [Comparative dynamics of EEG parameters in elderly depressive patients during monotherapy and combined therapy]. AB - OBJECTIVE: To compare the changes in brain functional state in combined antidepressive treatment (venlafaxine plus cerebrolysin) vs. monotherapy with the same antidepressant in elderly depressive patients using quantitative EEG methods. MATERIAL AND METHODS: Forty patients, aged 60-79 years, mean 67.1+/-5.7) were randomized to two groups. Patients of group 1 were treated with venlafaxine (4 weeks, in dose of 75-150 mg/day). Patients of group 2 were additionally treated with cerebrolysin (totally 20 i/v infusions during 4 weeks, 20.0 ml in 100 ml isotonic NaCl solution). RESULTS AND CONCLUSION: The significant improvement of clinical conditions was shown by the end of the treatment course using both clinical assessments and HAMD-17, CGI-S, CGI-I and MMSE scores in both groups. The combined treatment with venlafaxine and cerebrolysin in patients of group 2 led to more pronounced improvement of their brain functional state (seen as an increase of spectral power and normalization of frequency alpha band of parietal-occipital EEG) in comparison with patients of group 2 treated by the same antidepressant alone. PMID- 26977626 TI - [The efficacy of mexidol in carotid endarterectomy procedure in patients with cerebral atherosclerotic stenosis]. AB - OBJECTIVE: To determine the antihypoxic efficacy of mexidol in carotid endarterectomy (CE) procedure in patients with cerebral atherosclerotic stenosis using cerebral oximetry. MATERIAL AND METHODS: Clinical/psycho/neurological monitoring was performed in 109 patients with internal carotid artery stenosis of 69+/-7.0% and neurological symptoms of cerebral ischemia, 2-3 degree, in pre- and postoperative periods. Cerebral oximetry was carried out perioperatively. Fifty four patients were treated with mexidol in a dose of 1000 mg/day for 14-15 days and 55 patients did not received mexidol. RESULTS AND CONCLUSION: The difference in initial brain oxygenation (rSO2) between the main and comparison groups was shown (60.8+/-5.0 and 47.29+/-5.5%, respectively). During operation, the degree of blood oxygenation in these groups decreased by 57% and 41%, respectively. On day 7, sinificant differences in the Schulte test in two groups of patients with similar neurological status were found considering efficiency of work and mental stability before and after operation. No differences were found in the comparison group. Mexidol used for antihypoxic brain protection in carotid endarterectomy of patients with cerebral atherosclerotic stenosis significantly reduces the degree of cerebral hypoxia, decreases the duration of surgery, improves neurological status of patients and performance of psychological tests in postoperative period. PMID- 26977627 TI - [MRI-characteristics of epileptogenic supratentorial brain tumors in children]. AB - OBJECTIVE: To analyze MR-images in patients with symptomatic epilepsy associated with the brain tumor. MATERIAL AND METHODS: MRI results of 52 patients with symptomatic epilepsy operated for tumors of supratentorial localization were analyzed. The most epileptogenic tumors with atypical MRI signs and subtle clinical presentation were identified. All patients with tumors were operated using different methods of surgical intervention. RESULTS: Dysembryoplastic neuroepithelial tumors (DNET), diffuse astrocytomas (DA) and gangliogliomas (GG) were the most frequent epileptogenic tumors. In all the cases of DNET and in 4 patients with GG, epileptic seizures were the first, and in 4 of 5 cases of DIO were the only clinical sign of tumor presence. In DNET, DA and GG, there was an iso- or hypointensive signal on T1 WI and a signal varying in intensity from moderate to hyperintense in T2 and FLAIR WI, while in cases with DNET and GG, no mass effect and perifocal edema was practically seen. The so-called "spume-like" (multicystic) structure was most clearly observed in FLAIR WI. No significant changes in the dimensions of the DNET and GG were identified. The combination of DNET with focal cortical dysplasia was noted in one case. In DA, it was difficult to distinguish the perifocal edema from tumorous tissue and normal brain tissues, and the growth potential of malformation was slow. CONCLUSION: Epileptogenic tumors can imitate the x-ray characteristics of each other, and mimicry to gangliogliomas, oligodendrogliomas and astrocytomas Gr I, II, and others. They are the most frequent causes of symptomatic focal epilepsy. The presence of these malformations is necessary to exclude first of all in all cases of pharmacoresistant epilepsy. PMID- 26977628 TI - [Molecular genetic diagnosis and clinical features of hereditary neuropathy with liability to pressure palsies in Belarusian patients]. AB - OBJECTIVE: To analyze the molecular defect, a phenotype of hereditary neuropathy with liability to pressure palsies (HNPP, OMIM 162500), in patients with PMP22 gene mutation caused by 1.5 Mb deletion at 17p11.2. and present the principles of diagnosis and genetic counselling. MATERIAL AND METHODS: Patients were selected on the basis of the results of the clinical/genealogical analysis, neurological examination and ENMG study. Genomic DNA was isolated from peripheral blood leukocytes. RESULTS AND CONCLUSION: DNA diagnosis was performed in 5 families (the PMP22 deletion was found in 9 patients). The authors described clinical and electrophysiological characteristics and presented a diagnostic protocol. Identification of the mutation makes it possible to confirm the clinical diagnosis, assess genetic risks for the outcome and perform a prenatal DNA diagnosis in HNPP families. PMID- 26977629 TI - [Clinical/genetic characteristics of patients with congenital muscular dystrophy caused by mutations in the LMNA gene]. AB - OBJECTIVE: To study clinical/genetic characteristics of congenital muscular dystrophy caused by mutations in the LMNA gene in 5 patients from the Russian population. MATERIAL AND METHODS: DNA samples of 42 probands, aged from 2 months to 9 years, with characteristic signs of congenital muscular dystrophy from nonrelated families were studied. The diagnosis was based on the results of genealogical analysis, neurological examination, serum creatine phosphokinase activity, results of electroneuromyography. RESULTS AND CONCLUSION: In the Russian population, the frequency of congenital muscular dystrophy caused by mutations in the LMNA gene is not less than 12% of all cases of this group of diseases. The results indicate the presence of major mutation c.94_96delAAC in the LMNA gene. Specific phenotypic features of this form of congenital muscular dystrophy with symptoms of progressive flaccid paralysis with predominant lesions of axial muscles and plantar flexor muscles of the foot are described. PMID- 26977630 TI - [A role of Russian psychiatrists in the formation of forensic psychiatry in Russia in the beginning of XIX century]. AB - The formation of forensic psychiatry knowledge as a special area of concern was due to fundamental changes in the social, economic and political life of Russia society. It reflected public awareness of the urgent need in solving the problem of support, preserve and maintain the mental health of the people. Forensic psychiatry was based on the development of psychiatry, public health and community medicine. Author describes of the role of Russian psychiatrists in the formation of forensic psychiatry, their active particitpation in internation professional meetings and in the development of the problem of responsibility. PMID- 26977631 TI - [Neurological manifestations of giant cell arteritis]. AB - The article describes clinical, including neurological manifestations, of giant cell arteritis (GCA) - granulomatous vasculitis of large and medium-sized vessels, predominantly craniofacial, including precerebral and cerebral, arteries. Histopathological features of GCA are illustrated by the schemes of panarteritis and "postarteritis" (proliferative and fibrotic changes in the intima, underlying the development of cerebrovascular disorders). The main clinical manifestations of GCA are described as 3 groups of symptoms: general constitutional symptoms; manifestations of vasculitis of craniofacial, precerebral and cerebral arteries; polymyalgia rheumatica. The authors present their own version of the taxonomy of visual disturbances in patients with GCA. Diagnostic steps in patients with suggestive signs of GCA are described. Therapeutic regimens of use of glucocorticoids for suggestion/diagnosis of GCA are presented. PMID- 26977632 TI - [The phenomenon of attachment to parents, the duration of therapeutic remissions and autoaggressive behavior among inpatients with alcohol addiction]. AB - OBJECTIVE: To determine the role of phenomenon of attachment to parents in the formation of therapeutic remission and the relationship between attachment styles and autoaggressive behavior in patients with alcohol addiction (AA). MATERIAL AND METHODS: Sixty-two patients with AA and 30 controls were examined. RESULTS AND CONCLUSION: Insecure attachment styles were most frequents in AA patients that indicated a role of attachment pathology in the development of the disease. Higher frequency of secure and preoccupied styles were noted in patients with AA with the duration of therapeutic remissions more than one year compared to those with shorter duration. No effect of duration of therapeutic remission on autoaggressive behavior was found in patients who did not receive special treatment. In AA patients, avoidant style was correlated with autoaggression in family and professional spheres, and high-anxious style was correlated with classical autoaggression in the form of antisocial behavior. PMID- 26977634 TI - Deep brain stimulation for dystonia: review of the literature. AB - Deep brain stimulation (DBS) has become one of the major therapy options for movement disorders including dystonia. This article should give a review of the current literature from a neurosurgical perspective. Since dystonia is a rare disease, only few studies on larger cohorts have been published, and very few randomized controlled studies are avaialable in the international literature. Our experiences gained treating 134 patients with various types of dystonia, between 1999 and 2015, will serve a guide to interpret the current literature. Symptoms of dystonia are due to a variety of medical conditions. A careful and extensive neurological evaluation is mandatory before medical and surgical treatment options are considered, since the clinical benefits of more aggressive treatment e.g. by DBS depend to a large extent on the etiology of the disease. Diagnostic steps should include also magnetic resonance imaging (MRI) and possibly genetic evaluation. Therapy consists of physiotherapy, medical therapy including botulinum toxin injections in focal dystonia and DBS. This neurosurgical therapy is considered a highly effective therapy in well selected patients, which should be discussed, depending on the etiology, early in the patient's career. Patients with primary dystonia will benefit the most from DBS to the ventromediolateral part of the globus pallidus internus (GPi) with acceptable low complication rates; in order to optimize longterm results in these groups of patient, they will require an interdisciplinary individualized approach both pre- and postoperatively as well as longterm care adjusting to their needs. PMID- 26977635 TI - Motor cortex stimulation for movement disorders. AB - INTRODUCTION: Motor cortex stimulation (MCS) was introduced by Tsubokawa in 1991 1 for the treatment of thalamic pain, after coming to the conclusion that the hyperactivity of thalamic neurons after spino-thalamic tractotomy was inhibited by stimulation of the motor cortex. MCS has been reported not only to be effective on pain, but also to improve movement disorders such as Parkinson's disease, tremor, dystonia, poststroke movement disorders and hemiparesis. Most of these publications are case reports or small series, and the real impact of MCS on movement disorders remains to be determined. EVIDENCE ACQUISITION: In order to clarify this point, we conducted a PubMed search from 1991 to 2016 using established MeSH words. A total of 40 papers were selected and examined. Furthermore, personal experience with MCS for Parkinson's disease and akinesia, is reported. EVIDENCE SYNTHESIS: Only four studies were randomized controlled clinical trials: three out of four failed to demonstrate the efficacy of MCS at short term. CONCLUSIONS: At long term, MCS seems to show a clinical positive effect in the studies prolonged in an open observational trial. PMID- 26977636 TI - Inverted positioning of Leksell Frame G for very low posterior fossa and brain stem lesions biopsies. AB - BACKGROUND: The specificity of imaging alone in diagnosing posterior fossa lesions is insufficient, hence the importance of biopsy for diagnostic, therapeutic and prognostic purposes. Concerning the operative technique, many studies have demonstrated the superior safety of stereotactic biopsy over craniotomy and superior accuracy of frame-based systems over frameless ones as far as the posterior fossa is concerned; however versatile, frame-based instruments bear some intrinsic limitations in the positioning of frame in lower lesions mainly in short neck and kyphotic patients. For all these reasons, a more proficient technical bioptic approach to the posterior fossa and lower brainstem is sometimes required. METHODS: In order to obtain a specimen a Leksell System (Elekta(r)) constituted by the Leksell Coordinate G Frame (Article No: 014611), 4 adjustable posts (Article No: 1006476), 4 reusable screws (Article No: 1006581), an open indicator box (Article No: 1006559), a Leksell Multi-purpose Stereotactic Arc (Article No: 1008174) and a Sedan Needle (Article No: A2430-01) are required. RESULTS: This is a simple and reliable technique to obtain a brainstem/cerebellar specimen maintaining unchanged the know risks of the procedure, as well the morbidity and mortality. We otherwise recommend this procedure to be performed by a team of neurosurgeons trained in stereotaxy. CONCLUSIONS: If meticulously planned, our modified procedure provide a direct and precise access to deep seated areas of the posterior fossa and brainstem and is particularly helpful in those patients with short neck and kyphosis in which is crucial obtain an istopathologic diagnosis in lower posterior fossa. PMID- 26977637 TI - Quantitative fuel vapor/air mixing imaging in droplet/gas regions of an evaporating spray flow using filtered Rayleigh scattering. AB - This Letter demonstrates the application of filtered Rayleigh scattering (FRS) for quantitative two-dimensional fuel vapor/air mixing measurements in an evaporating hydrocarbon fuel spray flow. Using the FRS approach, gas-phase measurements are made in the presence of liquid-phase droplets without interference. Effective suppression of the liquid-phase droplet scattering using FRS is enabled by the high spectral purity of the current Nd:YAG laser system. Simultaneous Mie-scattering imaging is used to visualize the droplet field and illustrate the droplet loading under which the FRS imaging is applied in the current spray flows. The initial quantification of the FRS imaging is based on calibration measurements from a flow cell of known fuel vapor/air mixtures, while future work targets the utilization of a Rayleigh-Brillouin spectral model for quantification of the FRS signals. PMID- 26977638 TI - Piston and tilt interferometry for segmented wavefront sensing. AB - We present a novel interferometric technique dedicated to the measurement of relative phase differences (pistons) and tilts of a periodically segmented wavefront. Potential applications include co-phasing of segmented mirrors of Keck like telescopes as well as coherent laser beam combining. The setup only requires a holes mask selecting the center part of each element, a diffracting component, and a camera. Recorded interferogram is made of many subareas with sinusoidal fringe pattern. From each pattern, piston is extracted from fringe shift and tilts from fringe frequency and orientation. The pattern analysis is simple enough to enable kilohertz rate operation. The lambda ambiguities are solved by a two-wavelength measurement. This technique is compatible with a very high number of elements and can be operated in the presence of atmospheric turbulence. PMID- 26977633 TI - Molecular shifts in limb identity underlie development of feathered feet in two domestic avian species. AB - Birds display remarkable diversity in the distribution and morphology of scales and feathers on their feet, yet the genetic and developmental mechanisms governing this diversity remain unknown. Domestic pigeons have striking variation in foot feathering within a single species, providing a tractable model to investigate the molecular basis of skin appendage differences. We found that feathered feet in pigeons result from a partial transformation from hindlimb to forelimb identity mediated by cis-regulatory changes in the genes encoding the hindlimb-specific transcription factor Pitx1 and forelimb-specific transcription factor Tbx5. We also found that ectopic expression of Tbx5 is associated with foot feathers in chickens, suggesting similar molecular pathways underlie phenotypic convergence between these two species. These results show how changes in expression of regional patterning genes can generate localized changes in organ fate and morphology, and provide viable molecular mechanisms for diversity in hindlimb scale and feather distribution. PMID- 26977640 TI - Achieving cryogenic temperatures in deep space using a coating. AB - There is a current need to develop coatings that can reject more than 99% of the sun's irradiance to enable cryogenic storage and superconductor operation in space. Such a coating is proposed, composed of broadband scatterers on a metallic reflecting layer, yielding a surface that backscatters most of the solar spectrum yet still emits far-IR radiation. A model is presented with results, showing that a properly designed coating may potentially backscatter more than 99.9% of the sun's energy and allowing temperatures below 50 K to be achieved. PMID- 26977639 TI - Wavefront distortion optimized with volume Bragg gratings in photothermorefractive glass. AB - The wavefront characteristics in 2D angular filtering on the basis of two orthogonal transmitting volume Bragg gratings (VBGs) is presented. The experimental results show that middle-high frequency wavefront distortions are efficiently suppressed with VBGs. The peak-valley value of the beam at a wavelength of 1053 nm reduces from 2.075lambda to 0.209lambda, and the root mean square value reduces from 0.207lambda to 0.041lambda. The wavefront power spectrum density shows that the wavefront distribution of the beam in medium and high frequencies is corrected by the VBGs. Additionally, the far-field distribution and focusing properties of the beam are improved. The beam Strehl ratio increases from 0.43 to 0.96, and the encircled energy improves from 95% energy at 4.01 mrad to 95% energy at 1.26 mrad. PMID- 26977642 TI - Quantum telescope: feasibility and constraints. AB - The quantum telescope is a recent idea aimed at beating the diffraction limit of spaceborne telescopes and possibly other distant target imaging systems. There is no agreement yet on the best setup of such devices, but some configurations have already been proposed. In this Letter we characterize the predicted performance of quantum telescopes and their possible limitations. Our extensive simulations confirm that the presented model of such instruments is feasible and the device can provide considerable gains in the angular resolution of imaging in the UV, optical, and infrared bands. We argue that it is generally possible to construct and manufacture such instruments using the latest or soon to be available technology. We refer to the latest literature to discuss the feasibility of the proposed QT system design. PMID- 26977641 TI - Rayleigh scattering on the cavitation region emerging in liquids. AB - It is shown that the scattering of laser radiation off cavitation ruptures in fluids is similar to scattering by gas particles. When the characteristic dimensions of microscopic voids and bubbles are considerably smaller than the laser wavelength, the scattered light is in the Rayleigh regime, which allows for the detection of early stage cavitation. Simple estimates of the scattered radiation intensity and the dynamics of its changes in connection with the generation of cavitation in the test volume are obtained, allowing us to find the critical conditions for cavitation inception. PMID- 26977643 TI - Holographic liquid crystal polarization grating with Fabry-Perot structure. AB - A holographic liquid crystal polarization grating with a Fabry-Perot structure was developed. Because of its resonant structure, the device offers high levels of control of the diffraction properties of incident-polarized light beams, depending on the resonance conditions. The diffracted light beams are emitted in both the reflection and transmission directions, and the device thus works as a multibranch polarization grating with double optical paths, unlike a conventional polarization grating. These device features were experimentally demonstrated and were also explained theoretically. PMID- 26977644 TI - Design and analysis of frequency-independent reflectionless single-layer metafilms. AB - We develop a theory for realizing frequency-independent, reflectionless, single layer metafilms based on the Brewster effect. A designed metafilm based on the theory is numerically analyzed using a finite-difference time-domain method. The numerical analysis demonstrates that the reflectance of the metafilm vanishes independent of the frequency and that the metafilm behaves like an all-pass filter (with finite loss). An analysis based on an electrical circuit model of the reflectionless metafilm reveals that the energy of the suppressed reflection wave is not stored in the metafilm, but is radiated to the transmission direction. PMID- 26977646 TI - 40 GHz pulse source based on cross-phase modulation-induced focusing in normally dispersive optical fibers. AB - We theoretically and experimentally investigate the design of a high-repetition rate source delivering well-separated optical pulses due to the nonlinear compression of a dual-frequency beat signal within a cavity-less normally dispersive fiber-based setup. This system is well described by a set of two coupled nonlinear Schrodinger equations for which the traditional normally dispersive defocusing regime is turned in a focusing temporal lens through a degenerated cross-phase modulation process (XPM). More precisely, the temporal compression of the initial beating is performed by the combined effects of normal dispersion and XPM-induced nonlinear phase shift provided by an intense beat signal on its weak out-of-phase replica co-propagating with orthogonal polarizations. This adiabatic reshaping process allows us to experimentally demonstrate the generation of a 40 GHz well-separated 3.3 ps pulse train at 1550 nm in a 5 km long normally dispersive fiber. PMID- 26977645 TI - Fano resonance-based highly sensitive, compact temperature sensor on thin film lithium niobate. AB - In this Letter, we report a Fano resonance-based highly sensitive and compact temperature sensor fabricated on thin film lithium niobate (TFLN) Suzuki phase lattice (SPL) photonic crystal. The experimental sensitivity is estimated to be 0.77 nm/ degrees C with a photonic crystal size of only 25 MUm * 24 MUm. This sensitivity is 38 times larger than the intrinsic one of lithium niobate which is 0.02 nm/ degrees C. The demonstrated sharp and high extinction ratio characteristics of the Fano lineshape resonance could be an excellent candidate in developing a high sensitivity temperature sensor, electric field sensor, etc. PMID- 26977647 TI - Intracavity gain shaping in millijoule-level, high gain Ho:YLF regenerative amplifiers. AB - We demonstrate intracavity gain shaping inside a 2 MUm Ho:YLF regenerative amplifier with a spectral bandwidth of 2.9 nm broadened to 5.4 nm, corresponding to Fourier-limited pulses of 1 ps duration. The intracavity gain shaping is achieved by using a simple etalon, which acts as a frequency-selective filter. The output of the regenerative amplifier is amplified by a single-pass amplifier, and we achieve total energy of 2.2 mJ and pulse duration of 2.4 ps at 1 kHz with pulse fluctuations <1%. The amplifier chain is seeded by a home-built mode-locked holmium-doped fiber oscillator. PMID- 26977648 TI - Flexible RF filter using a nonuniform SCISSOR. AB - This work presents a flexible radiofrequency (RF) filter using an integrated microwave photonic circuit that comprises a nonuniform side-coupled integrated spaced sequence of resonators (N-SCISSOR). The filter passband can be reconfigured by varying the N-SCISSOR parameters. When employing a dual-parallel Mach-Zechnder modulator, the filter is also able to perform frequency down conversion. In the experiment, various filter response shapes are shown, ranging from a flat-top band-pass filter to a total opposite high-rejection (>40 dB) notch filter, with a frequency coverage of greater than two octaves. The frequency down-conversion function is also demonstrated. PMID- 26977649 TI - Nonlinear optical frequency mixing response of single and multilayer graphene. AB - It has been shown that graphene exhibits unique electronic, thermal, mechanical, and optical properties. In particular, due to its gapless band structure and linear dispersion relation around the Dirac points, graphene exhibits a strong nonlinear optical response, which has been theoretically predicted to depend on the number of graphene layers. In this Letter, we experimentally validate the theoretical predictions by probing multilayer graphene chi(3) nonlinearities. The intensity of the four-wave mixing signal is observed to grow monotonically as a function of the number of graphene layers, up to a maximum intensity corresponding to ~32 layers, after which it decreases, well in agreement with theoretical predictions. PMID- 26977650 TI - High-power, 1-ps, all-Yb:YAG thin-disk regenerative amplifier. AB - We report a 100 W, 20 mJ, 1-ps, all-Yb:YAG thin-disk regenerative amplifier seeded by a microjoule-level Yb:YAG thin-disk Kerr-lens mode-locked oscillator. The regenerative amplifier is implemented in a chirped pulse amplification system and operates at an ambient temperature in air, delivering ultrastable output pulses at a 5 kHz repetition rate and with a root mean square power noise value of less than 0.5%. Second harmonic generation of the amplifier's output in a 1.5 mm-thick BBO crystal results in more than 70 W at 515 nm, making the system an attractive source for pumping optical parametric chirped pulse amplifiers in the visible and near-infrared spectral ranges. PMID- 26977652 TI - Photo-resistive properties of LaAl0.6Cr0.4O3/SrTiO3 heterostructures: a comparative study with LaAlO3/SrTiO3. AB - We report photoconductivity measurements on LaAl(1-x)Cr(x)O3/SrTiO3 (x=0, 0.4) heterostructures. A polar layer modification of metallic LaAlO3/SrTiO3 heterostructure with Cr in the Al sites resulted in an increased photo-response (PR) and relaxation time, in addition to a distinct shift in the spectral weight toward the red end of the spectrum. The visible light photoconductivity is explained by d-d photoconductivity of Cr3+ valence states of the x=0.4 sample. Besides the established UV sensitivity, we observe a weak peak in PR around 690 nm possibly emanating from the mid-gap states arising from oxygen vacancies. PMID- 26977651 TI - Focusing light through scattering media by full-polarization digital optical phase conjugation. AB - Digital optical phase conjugation (DOPC) is an emerging technique for focusing light through or within scattering media such as biological tissue. Since DOPC systems are based on time reversal, they benefit from collecting as much information about the scattered light as possible. However, existing DOPC techniques record and subsequently phase-conjugate the scattered light in only a single-polarization state, limited by the operating principle of spatial light modulators. Here, we develop the first, to the best of our knowledge, full polarization DOPC system that records and phase-conjugates scattered light along two orthogonal polarizations. When focusing light through thick scattering media, such as 2 mm and 4 mm-thick chicken breast tissue, our full-polarization DOPC system on average doubles the focal peak-to-background ratio achieved by single polarization DOPC systems and improves the phase-conjugation fidelity. PMID- 26977654 TI - High-efficiency optical parametric chirped-pulse amplifier in BiB3O6 for generation of 3 mJ, two-cycle, carrier-envelope-phase-stable pulses at 1.7 MUm. AB - We produce a 3 mJ, two-cycle (11.4 fs), 1 kHz, carrier-envelope phase (CEP) stable laser source at 1.7 MUm via a three-stage Ti:sapphire-pumped optical parametric chirped-pulse amplifier in BiB3O6. We achieve a pump-to-signal conversion efficiency of 18% in the last stage, which is, to the best of our knowledge, the highest yet achieved for near-octave bandwidth amplification. A f to-2f measurement shows a CEP instability of 165 mrad over 1 h. This is an ideal light source for generating isolated attosecond pulses in the soft x-ray region. PMID- 26977653 TI - Multi-parameter sensor based on stimulated Brillouin scattering in inverse parabolic graded-index fiber. AB - We propose a unique multi-parameter optical fiber sensor based on intramodal stimulated Brillouin scattering of higher-order acoustic modes in inverse parabolic graded-index fiber (IPGIF) without a mode converter. Both optical modes and acoustic modes guided in the IPGIF are characterized and demonstrated theoretically and experimentally. Simulation analysis shows that the multi-peak feature in the Brillouin gain spectrum of the IPGIF is attributed to the couplings between the guided optical mode and the higher-order acoustic modes. Thanks to the distinct acoustic properties of the peaks induced by the sharp refractive index profile of the IPGIF, the different temperature and strain dependences of the first three Brillouin peaks enable the discrimination of the temperature and strain at an accuracy of 0.85 degrees C and 17.4 MUepsilon. PMID- 26977655 TI - Arithmetic with optical topological charges in stepwise-excited Rb vapor. AB - We report on experimentally observed addition, subtraction, and cancellation of orbital angular momentum (OAM) in the process of parametric four-wave mixing that results in frequency up- and down-converted emission in Rb vapor. Specific features of OAM transfer from resonant laser fields with different optical topological charges to the spatially and temporally coherent blue light (CBL) have been considered. We have observed the conservation of OAM in nonlinear wave mixing in a wide range of experimental conditions, including a noncollinear geometry of the applied laser beams, and furthermore, that the CBL accumulates the total OAM of the applied laser light. Spectral and power dependences of vortex and plane wavefront blue light beams have been compared. PMID- 26977656 TI - Gold nanobipyramids as saturable absorbers for passively Q-switched laser generation in the 1.1 MUm region. AB - We demonstrated that gold nanobipyramids (Au-NBPs) can be used as saturable absorbers for ultrafast pulsed-laser application, for the first time. Au-NBPs are prepared through a seed-mediated growth method, and performance is investigated in a passively Q-switched Nd:YVO4 laser. In the Q-switched operation the maximum average output power that can be achieved is 151 mW. The minimum pulse width is 396 ns at a pulse repetition rate of 90.6 kHz. PMID- 26977657 TI - Optically injected InAs/GaAs quantum dot laser for tunable photonic microwave generation. AB - We present an experimental investigation on the period-one dynamics of an optically injected InAs/GaAs quantum dot laser as a photonic microwave source. It is shown that the microwave frequency of the quantum dot laser's period-one oscillation is continuously tunable through the adjustment of the frequency detuning. The microwave power is enhanced by increasing the injection strength providing that the operation is away from the Hopf bifurcation, whereas the second-harmonic distortion of the electrical signal is well reduced by increasing the detuning frequency. Both strong optical injection and high detuning frequency are favorable for obtaining a single sideband optical signal. In addition, particular period-one oscillation points of low sensitivity to the frequency detuning are found close to the Hopf bifurcation line. PMID- 26977658 TI - High-frequency reverse-time chaos generation using an optical matched filter. AB - The optical reverse-time chaos is realized by modulating a binary pseudo-random bit sequence onto an optical carrier, and then driving an optical matched filter. The filter is demonstrated experimentally by using two fiber Bragg gratings and a Fourier-domain programmable optical processor. The complexity relationship between the binary input sequence and the output chaos signal is studied. This approach could be a novel way to generate a high speed repeatable and controllable optical chaos signal, which has the potential to be used in optical secure communication systems. PMID- 26977659 TI - Femtosecond laser written nanostructures in Ge-doped glasses. AB - We report on nanostructures induced by femtosecond laser pulses in the bulk of Germanium-doped silica glasses. For studying structural properties of the nanostructure constituents small-angle x-ray scattering and SEM served to map pore size, filling factor and periodicity. Our results show that with increasing the Ge doping concentration, the aspect ratio (transverse to inscribing laser) of nanometric pores rises while they arrange in a smaller period in contrast to nanogratings in pristine fused silica. Consequently, higher optical retardance can be obtained demonstrating the pronounced glass decomposition due to the changing network structure. PMID- 26977660 TI - Measuring different types of transverse momentum correlations in the biphoton's Fourier plane. AB - In this Letter, we present a theoretical and experimental study about the spatial correlations of paired photons generated by Type II spontaneous parametric down conversion. In particular, we show how these correlations can be positive or negative, depending on the direction in which the far-field plane is scanned and the polarization postselected. Our results provide a straightforward way to observe different kind of correlations that complement other well-known methods to tune the spatial correlations of paired photons. PMID- 26977661 TI - Coupled orbital angular momentum conversions in a quasi-periodically poled LiTaO3 crystal. AB - We experimentally demonstrate the orbital angular momentum (OAM) conversion by the coupled nonlinear optical processes in a quasi-periodically poled LiTaO3 crystal. In such a crystal, third-harmonic generation (THG) is realized by the coupled second-harmonic generation (SHG) and sum-frequency generation (SFG) processes, i.e., SHG is dependent on SFG and vice versa. The OAMs of the interacting waves are proved to be conserved in such coupled nonlinear optical processes. As we increase the input OAM in the experiment, the conversion efficiency decreases because of the reduced fundamental power density. Our results provide better understanding for the OAM conversions, which can be used to efficiently produce an optical OAM state at a short wavelength. PMID- 26977662 TI - Simultaneous real-time multicomponent fluorescence and reflectance imaging method for fluorescence-guided surgery. AB - Fluorescence-guided surgical procedures are employed in an increasing number of applications such as tumor delineation, blood perfusion, and sentinel lymph node detection. A new generation of fluorescent probes is expected to increase the number of applications and improve efficiency. Yet, there are no available imaging methods to take full advantage of the forthcoming targeting technologies. We present a novel concept for imaging multiple agents for fluorescence-guided surgery. The system operates without any moving parts and can resolve images of three different fluorochromes while simultaneously recording conventional reflectance images. PMID- 26977663 TI - Zero-static-power phase-change optical modulator. AB - This Letter presents an innovative design of an electro-optical modulator using germanium telluride (GeTe) phase change material with an integrated nano-heater. The refractive index and the electrical conductivity of GeTe significantly change as the GeTe goes though the crystallographic phase change. Amorphization and crystallization of GeTe is achieved using the Joule heating method by passing current through an array of metal gratings, where GeTe fills the slits between the metal lines. These metal slits also increase the contrast between the amorphous (on) and crystalline (off) phases of the modulator by having extraordinary transmission and reflection response based on interactions of surface plasmon polaritons (SPPs) with the incoming light. The modulator is designed for 1550 nm wavelength, where GeTe is transparent in the amorphous phase and provides high optical on/off contrast. The metal-insulator-metal (MIM) is designed in such a way to only support SPP excitation when GeTe is crystalline and slit resonance when it is amorphous to increase the modulation index. The modulator is stable in both phases with higher than 12 dB change in transmission with zero static power consumption at room temperature. PMID- 26977664 TI - Successive soliton explosions in an ultrafast fiber laser. AB - Soliton explosions, as one of the most fascinating nonlinear phenomena in dissipative systems, have been investigated in different branches of physics, including the ultrafast laser community. Herein, we reported on the soliton dynamics of an ultrafast fiber laser from steady state to soliton explosions, and to huge explosions by simply adjusting the pump power level. In particular, the huge soliton explosions show that the exploding behavior could operate in a sustained, but periodic, mode from one explosion to another, which we term as "successive soliton explosions." The experimental results will prove to be fruitful to the various communities interested in soliton explosions. PMID- 26977665 TI - Effect of dielectric claddings on the electro-optic behavior of silicon waveguides. AB - We fabricate silicon waveguides in silicon-on-insulator (SOI) wafers clad with either silicon dioxide, silicon nitride, or aluminum oxide and, by measuring their electro-optic behavior, we characterize the capacitively induced free carrier effect. By comparing our results with simulations, we confirm that the observed voltage dependences of the transmission spectra are due to changes in the concentrations of holes and electrons within the semiconductor waveguides and show how strongly these effects depend on the cladding material that comes into contact with the waveguide. Waveguide loss is additionally found to have a high sensitivity to the applied voltage, suggesting that these effects may find use in applications that require low- or high-loss propagation. These phenomena, which are present in all semiconductor waveguides, may be incorporated into more complex waveguide designs in the future to create high-efficiency electro-optic modulators and wavemixers. PMID- 26977666 TI - Resonant pumped erbium-doped waveguide lasers using distributed Bragg reflector cavities. AB - This Letter reports on an optical pumping scheme, termed resonant pumping, for an erbium-doped distributed feedback (DFB) waveguide laser. The scheme uses two mirrors on either side of the DFB laser, forming a pump cavity that recirculates the unabsorbed pump light. Symmetric distributed Bragg reflectors are used as the mirrors and are designed by matching the external and internal quality factors of the cavity. Experimental demonstration shows lasing at an optical communication wavelength of around 1560 nm and an improvement of 1.8 times in the lasing efficiency, when the DFB laser is pumped on-resonance. PMID- 26977667 TI - Confocal laser scanning microscopy with spatiotemporal structured illumination. AB - Confocal laser scanning microscopy (CLSM), which is widely utilized in the biological and biomedical sciences, is limited in spatial resolution due to diffraction to about half the light wavelength. Here we have combined structured illumination with CLSM to enhance its spatial resolution. To this end, we have used a spatial light modulator (SLM) to generate fringe patterns of different orientations and phase shifts in the excitation spot without any mechanical movement. We have achieved 1.8 and 1.7 times enhanced lateral and axial resolutions, respectively, by synthesizing the object spectrum along different illumination directions. This technique is thus a promising tool for high resolution morphological or fluorescence imaging, especially in deep tissue. PMID- 26977668 TI - On-chip integrated optofluidic complex refractive index sensing using silicon photonic crystal nanobeam cavities. AB - Complex refractive index sensing is proposed and experimentally demonstrated in optofluidic sensors based on silicon photonic crystal nanobeam cavities. The sensitivities are 58 and 139 nm/RIU, respectively, for the real part (n) and the imaginary part (kappa) of the complex refractive index, and the corresponding detection limits are 1.8*10(-5) RIU for n and 4.1*10(-6) RIU for kappa. Moreover, the capability of the complex refractive index sensing method to detect the concentration composition of the ternary mixture is demonstrated without the surface immobilization of functional groups, which is impossible to realize with the conventional refractive index sensing scheme. PMID- 26977669 TI - Off-axis ultraviolet-written fiber Bragg gratings for directional bending measurements. AB - Off-axis fiber Bragg gratings are inscribed by ultraviolet irradiation limited to expose only a portion of the fiber core cross section. The coupling to cladding modes is significantly increased, and the amplitude of the cladding mode resonances becomes sensitive to bending in magnitude and direction. Sensitivities ranging from +1.17 dB/m(-1) to -1.25 dB/m(-1) were obtained for bending in different directions relative to the offset direction of the grating, for curvatures from 0 to 1.1 m(-1), a range ideal for the shape sensing of large structures. The bending sensor response is also shown to be independent of temperature and the surrounding refractive index. PMID- 26977670 TI - Pupil filters for extending the field-of-view in light-sheet microscopy. AB - Pupil filters, represented by binary phase modulation, have been applied to extend the field of view of a light-sheet fluorescence microscope. Optimization has been used, first numerically to calculate the optimum filter structure and then experimentally, to scale and align the numerically synthesized filter in the microscope. A significant practical extension of the field of view has been observed, making the reported approach a valuable tool on the path to wide-field light-sheet microscopy. PMID- 26977671 TI - Suppression of nano-absorbing precursors and damage mechanism in optical coatings for 3omega mirrors. AB - Damage precursors in the 3omega (351 nm) mirror for a high-power laser system are investigated as well as the relevant damage mechanisms. The precursors are classified into two ensembles according to the different laser resistance and damage features. The former is nano-absorbing precursors, which are sensitive to the standing wave electric field and vulnerable to the laser irradiation. The latter is submicrometer nodular defects, which have higher laser resistance and are sensitive to the adhesion strength between the fluoride coatings and oxide coatings. The damage due to nano-absorbing precursors is efficiently suppressed with the double stack design that screens the electric field in the oxides. Currently, the nodular seed is major originating from the Al2O3/SiO2 stack. Even for the same defect type and mirror, the final damage features are dependent on the local mechanical properties at the irradiation location. The investigations of the damage mechanisms provide a direction to further improve the laser-induced damage threshold of the 3omega mirror. PMID- 26977673 TI - Enhanced light extraction and tunable chromaticity in white organic light emitting devices with ZnO nanopillars. AB - Robust ZnO nanopillars (NPs) with well-controlled morphology were directly prepared on the glass surface of a white organic light-emitting diode (WOLED) substrate using a hydrothermal process. The NPs can effectively recover light loss in the glass substrate and the current efficiency of the device increased by 20%. In addition, the chromaticity coordinates of the WOLED can be tuned by selecting the dimensions of the ZnO NPs. As a consequence, it is possible to produce a solar light spectrum using this technique. Furthermore, the nanotextured glass surface was superhydrophobic, which caused self-cleaning properties to the surface and help maintain maximum light output. PMID- 26977672 TI - Plasmonic metasurface for simultaneous detection of polarization and spectrum. AB - We present a new plasmonic metasurface for simultaneous detection of polarization and spectrum of incident light. The demonstrated metasurface is a rationally designed cluster of artificial atoms that are engineered to exhibit polarization and wavelength-selective optical transmission. The fundamental building block of this structure is periodically coupled subwavelength aperture arrays with different orientations and lattice constants. When integrated with pixelated photodetectors, the metasurface can be used to measure the polarization and spectral information of an optical input. In this Letter, simultaneous detection of the polarization and spectrum of polarized light was experimentally demonstrated by analyzing the transmitted intensity distribution through the metasurface. The demonstrated metasurface offers great potential for many applications, such as polarimetric multispectral imaging and polarization division multiplexing in optical communications. PMID- 26977674 TI - Developing carbon-nitride nanosheets for mode-locking ytterbium fiber lasers. AB - Graphitic carbon nitrides (CNs) have appeared as a new type of photocatalyst for water splitting, but their optical properties (e.g., nonlinear absorption), to the best of our knowledge, have been seldom explored. Here, we report the saturable absorption effects of novel 2D carbon-nitride-type nanosheets and use them as saturable absorbers to passively mode-lock Yb-doped fiber lasers. The CN based saturable absorber is manufactured by solution coating of 2D CN nanosheets on a gold mirror and has a modulation depth and saturation intensity of 12.5% and 7.5 MW/cm2, respectively. Two different output couplers are employed to construct ring laser cavities. With the 10% coupler, the mode-locked fiber laser produces pulses with duration of ~310 ps, average power of 1.24 mW, and repetition rate of 7.65 MHz. The laser spectrum is centered at 1066 nm with a bandwidth of 2.4 nm. Increasing the coupling ratio to 50% improves the output power to 2.58 mW but at the same time broadens the pulse width to 420 ps. As a new kind of 2D material with strong saturable absorption, CN nanosheets will open a new way for novel photonic and optoelectronic devices. PMID- 26977675 TI - Yb3+-doped large core silica fiber for fiber laser prepared by glass phase separation technology. AB - We report on the preparation and optical characteristics of an Yb(3+)-doped large core silica fiber with the active core prepared from nanoporous silica rod by the glass phase-separation technology. The measurements show that the fiber has an Yb(3+) concentration of 9811 ppm by weight, a low background attenuation of 0.02 dB/m, and absorption from Yb(3+) about 5.5 dB/m at 976 nm. The laser performance presents a high slope efficiency of 72.8% for laser emission at 1071 nm and a low laser threshold of 3 W within only 2.3 m fiber length. It is suggested that the glass phase-separation technology shows great potential for realizing active fibers with larger core and complex fiber designs. PMID- 26977676 TI - Adiabatic second-harmonic generation. AB - Adiabatic three-wave mixing processes enable broadband, efficient, and robust frequency conversion by slowly varying the phase mismatch between the interacting waves along the interaction region. Up until now, this method was mainly used in the case in which one of the waves was undepleted. Here we experimentally study fully nonlinear adiabatic processes by implementation in type I and type II second-harmonic generation processes, where the undepleted pump approximation does not hold. Using quasi-phase-matched interaction in chirped gratings, we obtain conversion efficiency approaching 60% and 80%, with corresponding wide thermal acceptance bandwidths of >100 degrees C and 30 degrees C, respectively. The transition between the depleted and undepleted pump regimes is also studied by varying the input polarization angle in the type II process; thus we also test current theory with arbitrary initial conditions. The results are in excellent agreement with analytic predictions for the fully nonlinear adiabatic process. PMID- 26977677 TI - Tunable band-stop plasmonic waveguide filter with symmetrical multiple-teeth shaped structure. AB - A nanometeric plasmonic filter with a symmetrical multiple-teeth-shaped structure is investigated theoretically and numerically. A tunable wide bandgap is achievable by adjusting the depth and number of teeth. This phenomenon can be attributed to the interference superposition of the reflected and transmitted waves from each tooth. Moreover, the effects of varying the number of identical teeth are also discussed. It is found that the bandgap width increases continuously with the increasing number of teeth. The finite difference time domain method is used to simulate and compute the coupling of surface plasmon polariton waves with different structures in this Letter. The plasmonic waveguide filter that we propose here may have meaningful applications in ultra-fine spectrum analysis and high-density nanoplasmonic integration circuits. PMID- 26977679 TI - Dynamic tuning of plasmon resonance in the visible using graphene. AB - We report active electrical tuning of plasmon resonance of silver nanoprisms (Ag NPs) in the visible spectrum. Ag NPs are placed in close proximity to graphene which leads to additional tunable loss for the plasmon resonance. The ionic gating of graphene modifies its Fermi level from 0.2 to 1 eV, which then affects the absorption of graphene due to Pauli blocking. Plasmon resonance frequency and linewidth of Ag NPs can be reversibly shifted by 20 and 35 meV, respectively. The coupled graphene-Ag NPs system can be classically described by a damped harmonic oscillator model. Atomic layer deposition allows for controlling the graphene-Ag NP separation with atomic-level precision to optimize coupling between them. PMID- 26977678 TI - High-slope-efficiency 2.06 MUm Ho: YLF laser in-band pumped by a fiber-coupled broadband diode. AB - We first demonstrate the laser performance of a compact 2.06 MUm Ho: YLF laser resonantly pumped by a broadband fiber-coupled diode. In continuous-wave (CW) operation, maximum output power of 1.63 W, corresponding to a slope efficiency of 89.2%, was obtained with a near diffraction-limited beam quality. In actively Q switched operation, maximum pulse energy of 1.1 mJ was achieved at the repetition frequency of 100 Hz. The minimum pulse duration was 43 ns. The performance in both the CW and Q-switched regimes indicates that the current fiber-coupled diode in-band pumped Ho: YLF laser has great potential in certain conditions that require several watts of output power or several millijoules of short pulse energy. PMID- 26977680 TI - 2.5 W continuous wave output at 665 nm from a multipass and quantum-well-pumped AlGaInP vertical-external-cavity surface-emitting laser. AB - An output power of 2.5 W at a wavelength of 665 nm was obtained from a quantum well (QW) and multipass-pumped AlGaInP-based vertical-external-cavity surface emitting laser operated at a heat sink temperature of 10 degrees C. Intracavity frequency doubling resulted in an output power of 820 mW at a wavelength of 333 nm. To the best of our knowledge, these are the highest continuous wave output powers from this type of laser both at the fundamental wavelength and in frequency-doubled operation. In fundamental wavelength operation, further power scaling by increasing the pump-spot size increased the output power to 3.3 W. However, at this power level, the laser was highly unstable. When the laser was operated at 50% pump duty cycle, a reproducible and stable peak output power of 3.6 W was obtained. These results demonstrate the potential of optical QW pumping combined with multipass pumping for the operation of AlGaInP-based semiconductor disk lasers. PMID- 26977681 TI - Compensation of the Kerr effect for transient optomechanically induced transparency in a silica microsphere. AB - We have studied the Kerr effect in silica microspheres and demonstrated compensation of the Kerr effect for transient optomechanically induced transparency (OMIT). Due to the Kerr effect of the temporal strong driving pulse, an asymmetric transparency dip is observed during the transient OMIT experiment when the laser frequency is locked at one mechanical frequency, omega(m), below the whispering gallery mode resonance using a weak locking pulse. For compensation of the Kerr effect, we lock the laser at a lower frequency and show the symmetric transparency window. These results are important for studying photon-phonon interconversion, especially in systems with strong driving power. PMID- 26977682 TI - Improving laser damage resistance of 355 nm high-reflective coatings by co evaporated interfaces. AB - 355 nm high-reflective multilayer coatings with or without coevaporated interfaces (CEIs) were prepared by electron beam evaporation under the same deposition condition. Their transmission spectra, surface roughness, and mechanical stress properties were evaluated. Elemental composition analysis of the multilayer interfaces was performed using x-ray photoelectron spectroscopy, and laser-induced damage thresholds were obtained in both 1-on-1 and 300-on-1 testing modes. The coatings with CEIs reveal a lower mechanical stress and a higher laser damage resistance when irradiated with high laser fluence, and the corresponding damage modeling indicates that CEIs can significantly decrease defect density. The resulting damage morphologies show that CEI coatings can significantly suppress coating delamination and exhibit a "bulk-like" damage behavior, demonstrating better damage performance against high-power lasers. PMID- 26977683 TI - Dispersion in silica microbubble resonators. AB - We explore the scope for engineering dispersion in whispering gallery mode silica microbubbles for nonlinear applications, such as optical frequency comb generation. In particular, the zero dispersion wavelength is shown to be highly tunable by changing the thickness of the shell. Using a small diameter and small wall thickness, dispersion equalization within the visible is predicted. This opens up the possibility of realizing visible frequency combs for a range of different applications. PMID- 26977684 TI - Frequency-multiplying microwave photonic phase shifter for independent multichannel phase shifting. AB - A frequency-multiplying microwave photonic phase shifter with independent multichannel phase shifting capability is proposed and demonstrated using an integrated polarization division multiplexing dual-parallel Mach-Zehnder modulator (PDM-DPMZM) and a polarizer. By building a proper power distribution network to drive the PDM-DPMZM, two sidebands along two orthogonal polarization directions are generated with a spacing of two or four times the frequency of the driving signal. Leading the signal to a polarizer and a photodetector, a frequency-doubled or frequency-quadrupled signal with its phase adjusted by the polarization direction of the polarizer is achieved. The magnitude of the signal remains almost unchanged when the phase is adjusted. The proposed approach features compact configuration, scalable independent phase-shift channels and wide bandwidth, which can find applications in beam forming and analog signal processing for millimeter-wave or terahertz applications. PMID- 26977685 TI - Noise induced in optical fibers by double Rayleigh scattering of a laser with a 1/fnu frequency noise. AB - We study, theoretically and experimentally, intensity noise induced by double Rayleigh scattering in long optical fibers. The results of the theoretical model are compared to experimental results performed with a high-coherence-length laser with a frequency noise spectrum that is dominated by 1/fnu noise. Excellent quantitative agreement between theoretical and experimental RF spectra were obtained for frequencies as low as 10 Hz and for fiber lengths between 4 and 45 km. Strong low-frequency intensity noise that is induced by 1/fnu frequency noise of the laser may limit the performance of interferometric fiber optic sensors that require high-coherence-length lasers. The intensity noise due to double Rayleigh backscattering can be suppressed by reducing the coherence length of the laser. Therefore, the intensity noise has a complex and non-monotonic dependence on the 1/fnu frequency noise amplitude of the laser. Stimulated Brillouin scattering will add a significant noise for input powers greater than about 7 mW for a 30 km length fiber. PMID- 26977686 TI - Cascaded-focus laser writing of low-loss waveguides in polymers. AB - Waveguide writing in poly (methyl methacrylate) (PMMA) with femtosecond laser radiation is presented. An adequate refractive index change is induced in the border area below the irradiated focal volume. It supports an almost symmetric fundamental mode with propagation losses down to 0.5 dB/cm, the lowest losses observed so far in this class of materials. The writing process with a cascaded focus is demonstrated to be highly reliable over a large parameter range. PMID- 26977687 TI - Analog optical computing primitives in silicon photonics. AB - Optical computing accelerators help alleviate bandwidth and power consumption bottlenecks in electronics. We show an approach to implementing logarithmic-type analog co-processors in silicon photonics and use it to perform the exponentiation operation and the recovery of a signal in the presence of multiplicative distortion. The function is realized by exploiting nonlinear absorption-enhanced Raman amplification saturation in a silicon waveguide. PMID- 26977688 TI - Complex direct comb spectroscopy with a virtually imaged phased array. AB - We demonstrate a simple interferometric technique to directly measure the complex optical transmittance over a large spectral range using a frequency-comb spectrometer based on a virtually imaged phased array. A Michelson interferometer encodes the phase deviations induced by a sample contained in one of its arms into an interferogram image. When combined with an additional image taken from each arm separately, along with a frequency-calibration image, this allows full reconstruction of the sample's optical transfer function. We demonstrate the technique with a vapor cell containing H13C14N, producing transmittance and phase spectra spanning 2.9 THz (~23 nm) with ~1 GHz resolution. PMID- 26977689 TI - Nanoparticle-polymer composite volume holographic gratings dispersed with ultrahigh-refractive-index hyperbranched polymer as organic nanoparticles. AB - We report on volume holographic recording at a wavelength of 532 nm in photopolymerizable polymer nanocomposites that are incorporated with new hyperbranched polymers (HBPs) acting as transporting organic nanoparticles. Since HBPs possess an ultrahigh index of refraction of 1.82 due to the inclusion of triazine and aromatic ring units, high-contrast transmission volume holographic gratings with refractive index modulation amplitudes as large as 2.2*10(-2) are recorded. This value enables us to realize a 10 MUm thick transmission volume grating with the diffraction efficiency near 100% in the green. PMID- 26977690 TI - Compact stereo endoscopic camera using microprism arrays. AB - This work reports a microprism array (MPA) based compact stereo endoscopic camera with a single image sensor. The MPAs were monolithically fabricated by using two step photolithography and geometry-guided resist reflow to form an appropriate prism angle for stereo image pair formation. The fabricated MPAs were transferred onto a glass substrate with a UV curable resin replica by using polydimethylsiloxane (PDMS) replica molding and then successfully integrated in front of a single camera module. The stereo endoscopic camera with MPA splits an image into two stereo images and successfully demonstrates the binocular disparities between the stereo image pairs for objects with different distances. This stereo endoscopic camera can serve as a compact and 3D imaging platform for medical, industrial, or military uses. PMID- 26977691 TI - Electrically tunable window device. AB - A device for controlling the transmittance of light over large areas, such as windows, is described. It is based on electrostatically induced surface deformation of soft dielectric elastomer sheets produced when a voltage is applied between two networks of electrically conducting nanowires on either side of the elastomer. Variations in the surface curvature are produced by the applied voltage refract light, decreasing the optical transmittance at all wavelengths. As the device relies on changes in the geometric propagation of light, rather than on chemical changes, it is color neutral. PMID- 26977692 TI - Optimal principal component analysis-based numerical phase aberration compensation method for digital holography. AB - In this Letter, an accurate and highly efficient numerical phase aberration compensation method is proposed for digital holographic microscopy. Considering that most parts of the phase aberration resides in the low spatial frequency domain, a Fourier-domain mask is introduced to extract the aberrated frequency components, while rejecting components that are unrelated to the phase aberration estimation. Principal component analysis (PCA) is then performed only on the reduced-sized spectrum, and the aberration terms can be extracted from the first principal component obtained. Finally, by oversampling the reduced-sized aberration terms, the precise phase aberration map is obtained and thus can be compensated by multiplying with its conjugation. Because the phase aberration is estimated from the limited but more relevant raw data, the compensation precision is improved and meanwhile the computation time can be significantly reduced. Experimental results demonstrate that our proposed technique could achieve both high compensating accuracy and robustness compared with other developed compensation methods. PMID- 26977693 TI - Influence of strong and weak hydrogen bonds in ices on stimulated Raman scattering. AB - Stimulated Raman scattering (SRS) in liquid water and ice Ih using Nd:YAG laser is investigated. The spectrum of backward SRS (BSRS) in water is acquired. The spectrum shows an unexpected SRS peak at around 3453 cm(-1) besides the normal peak, which is similar to the spontaneous Raman spectrum of ice VII. The ice VII phase will be formed by laser-induced shock compression in liquid water. Simultaneously, unlike the spontaneous Raman spectrum, the pre-resonance SRS of ice Ih at around 3110 and 3210 cm(-1) is observed. The Raman peaks appeared in liquid water and ice Ih are attributed to the effect of strong and weak hydrogen bonds (H bonds), which should be ubiquitous in other ice phases. PMID- 26977694 TI - Using an incoherent target return to adaptively focus through atmospheric turbulence. AB - A laser beam propagating to a remote target through atmospheric turbulence acquires intensity fluctuations. If the target is cooperative and provides a coherent return beam, the phase measured near the beam transmitter and adaptive optics, in principle, can correct these fluctuations. Generally, however, the target is uncooperative. In this case, we show that an incoherent return from the target can be used instead. Using the principle of reciprocity, we derive a novel relation between the field at the target and the returned field at a detector. We simulate an adaptive optics system that utilizes this relation to focus a beam through atmospheric turbulence onto a rough surface. PMID- 26977695 TI - Generation of integer and fractional vector beams with q-plates encoded onto a spatial light modulator. AB - We generate programmable vector beams with arbitrary q-plates encoded using a spatial light modulator system. Consequently, we can analyze new and exotic q plate designs without the difficulty of fabricating individual plates. We show experimental results for positive and negative integer and new fractional vector beam values. PMID- 26977697 TI - Journal Impact Factor: Do the Numerator and Denominator Need Correction? AB - To correct the incongruence of document types between the numerator and denominator in the traditional impact factor (IF), we make a corresponding adjustment to its formula and present five corrective IFs: IFTotal/Total, IFTotal/AREL, IFAR/AR, IFAREL/AR, and IFAREL/AREL. Based on a survey of researchers in the fields of ophthalmology and mathematics, we obtained the real impact ranking of sample journals in the minds of peer experts. The correlations between various IFs and questionnaire score were analyzed to verify their journal evaluation effects. The results show that it is scientific and reasonable to use five corrective IFs for journal evaluation for both ophthalmology and mathematics. For ophthalmology, the journal evaluation effects of the five corrective IFs are superior than those of traditional IF: the corrective effect of IFAR/AR is the best, IFAREL/AR is better than IFTotal/Total, followed by IFTotal/AREL, and IFAREL/AREL. For mathematics, the journal evaluation effect of traditional IF is superior than those of the five corrective IFs: the corrective effect of IFTotal/Total is best, IFAREL/AR is better than IFTotal/AREL and IFAREL/AREL, and the corrective effect of IFAR/AR is the worst. In conclusion, not all disciplinary journal IF need correction. The results in the current paper show that to correct the IF of ophthalmologic journals may be valuable, but it seems to be meaningless for mathematic journals. PMID- 26977696 TI - CDC Guideline for Prescribing Opioids for Chronic Pain--United States, 2016. AB - IMPORTANCE: Primary care clinicians find managing chronic pain challenging. Evidence of long-term efficacy of opioids for chronic pain is limited. Opioid use is associated with serious risks, including opioid use disorder and overdose. OBJECTIVE: To provide recommendations about opioid prescribing for primary care clinicians treating adult patients with chronic pain outside of active cancer treatment, palliative care, and end-of-life care. PROCESS: The Centers for Disease Control and Prevention (CDC) updated a 2014 systematic review on effectiveness and risks of opioids and conducted a supplemental review on benefits and harms, values and preferences, and costs. CDC used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework to assess evidence type and determine the recommendation category. EVIDENCE SYNTHESIS: Evidence consisted of observational studies or randomized clinical trials with notable limitations, characterized as low quality using GRADE methodology. Meta-analysis was not attempted due to the limited number of studies, variability in study designs and clinical heterogeneity, and methodological shortcomings of studies. No study evaluated long-term (>=1 year) benefit of opioids for chronic pain. Opioids were associated with increased risks, including opioid use disorder, overdose, and death, with dose-dependent effects. RECOMMENDATIONS: There are 12 recommendations. Of primary importance, nonopioid therapy is preferred for treatment of chronic pain. Opioids should be used only when benefits for pain and function are expected to outweigh risks. Before starting opioids, clinicians should establish treatment goals with patients and consider how opioids will be discontinued if benefits do not outweigh risks. When opioids are used, clinicians should prescribe the lowest effective dosage, carefully reassess benefits and risks when considering increasing dosage to 50 morphine milligram equivalents or more per day, and avoid concurrent opioids and benzodiazepines whenever possible. Clinicians should evaluate benefits and harms of continued opioid therapy with patients every 3 months or more frequently and review prescription drug monitoring program data, when available, for high-risk combinations or dosages. For patients with opioid use disorder, clinicians should offer or arrange evidence-based treatment, such as medication-assisted treatment with buprenorphine or methadone. CONCLUSIONS AND RELEVANCE: The guideline is intended to improve communication about benefits and risks of opioids for chronic pain, improve safety and effectiveness of pain treatment, and reduce risks associated with long-term opioid therapy. PMID- 26977698 TI - Interlinked multiphase Fe-doped MnO2 nanostructures: a novel design for enhanced pseudocapacitive performance. AB - Structure designing and morphology control can lead to high performance pseudocapacitive materials for supercapacitors. In this work, we have designed interlinked multiphase Fe-doped MnO2 nanostructures (alpha-MnO2/R-MnO2/epsilon MnO2) to enhance the electrochemical properties by a facile method. These hierarchical hollow microspheres assembled by interconnected nanoflakes, and with plenty of porous nanorods radiating from the spherical shells were hydrothermally obtained. The supercapacitor electrode prepared from the unique construction exhibits outstanding specific capacitance of 267.0 F g(-1) even under a high mass loading (~5 mg cm(-2)). Obviously improved performances compared to pure MnO2 are also demonstrated with a good rate capability, high energy density (1.30 mW h cm( 3)) and excellent cycling stability of 100% capacitance retention after 2000 cycles at 2 A g(-1). The synergistic effects of alternative crystal structures, appropriate crystallinity and optimal morphology are identified to be responsible for the observations. This rational multiphase composite strategy provides a promising idea for materials scientists to design and prepare scalable electrode materials for energy storage devices. PMID- 26977699 TI - Soft Regulation with Crowd Recommendation: Coordinating Self-Interested Agents in Sociotechnical Systems under Imperfect Information. AB - Regulating emerging industries is challenging, even controversial at times. Under regulation can result in safety threats to plant personnel, surrounding communities, and the environment. Over-regulation may hinder innovation, progress, and economic growth. Since one typically has limited understanding of, and experience with, the novel technology in practice, it is difficult to accomplish a properly balanced regulation. In this work, we propose a control and coordination policy called soft regulation that attempts to strike the right balance and create a collective learning environment. In soft regulation mechanism, individual agents can accept, reject, or partially accept the regulator's recommendation. This non-intrusive coordination does not interrupt normal operations. The extent to which an agent accepts the recommendation is mediated by a confidence level (from 0 to 100%). Among all possible recommendation methods, we investigate two in particular: the best recommendation wherein the regulator is completely informed and the crowd recommendation wherein the regulator collects the crowd's average and recommends that value. We show by analysis and simulations that soft regulation with crowd recommendation performs well. It converges to optimum, and is as good as the best recommendation for a wide range of confidence levels. This work sheds a new theoretical perspective on the concept of the wisdom of crowds. PMID- 26977701 TI - Reducing the Risks of Relief--The CDC Opioid-Prescribing Guideline. PMID- 26977702 TI - The Potential Impact on Children of the CDC Guideline for Prescribing Opioids for Chronic Pain: Above All, Do No Harm. PMID- 26977703 TI - Evolutionary Analysis of Dengue Serotype 2 Viruses Using Phylogenetic and Bayesian Methods from New Delhi, India. AB - Dengue fever is the most important arboviral disease in the tropical and sub tropical countries of the world. Delhi, the metropolitan capital state of India, has reported many dengue outbreaks, with the last outbreak occurring in 2013. We have recently reported predominance of dengue virus serotype 2 during 2011-2014 in Delhi. In the present study, we report molecular characterization and evolutionary analysis of dengue serotype 2 viruses which were detected in 2011 2014 in Delhi. Envelope genes of 42 DENV-2 strains were sequenced in the study. All DENV-2 strains grouped within the Cosmopolitan genotype and further clustered into three lineages; Lineage I, II and III. Lineage III replaced lineage I during dengue fever outbreak of 2013. Further, a novel mutation Thr404Ile was detected in the stem region of the envelope protein of a single DENV-2 strain in 2014. Nucleotide substitution rate and time to the most recent common ancestor were determined by molecular clock analysis using Bayesian methods. A change in effective population size of Indian DENV-2 viruses was investigated through Bayesian skyline plot. The study will be a vital road map for investigation of epidemiology and evolutionary pattern of dengue viruses in India. PMID- 26977704 TI - Critical Epitope of Anti-Rabbit Podoplanin Monoclonal Antibodies for Immunohistochemical Analysis. AB - Podoplanin (PDPN) is a type I transmembrane sialoglycoprotein, which is expressed in several normal cells, including lymphatic endothelial cells throughout the body, podocytes of the kidney, and lung type I alveolar cells of the lung. We have established many monoclonal antibodies (mAbs) against human PDPN, mouse PDPN, and rat PDPN. In addition, we recently produced an anti-rabbit PDPN mAb, PMab-32, which was established by immunizing mice with recombinant proteins of rabbit PDPN. Herein, we compared the reactivity of PMab-32 with that of newly established anti-rabbit PDPN mAbs, PMab-33 and PMab-21, against normal tissues in immunohistochemistry. PMab-32 reacted with podocytes, type I alveolar cells, and lymphatic endothelial cells, whereas PMab-33 detected only podocytes and type I alveolar cells but not lymphatic endothelial cells. PMab-21 was not useful in immunohistochemistry. We identified the epitope of PMab-32 and PMab-33 as Ser61 Ala68 of rabbit PDPN using western blot and flow cytometric analyses. In contrast, the epitope of PMab-21 was identified as Leu44-Glu48, which is corresponding to platelet aggregation-stimulating (PLAG) domain, indicating that Ser61-Ala68 of rabbit PDPN is a more appropriate epitope for immunohistochemistry compared with PLAG domain. PMab-32 could be useful for uncovering the function of rabbit PDPN. PMID- 26977706 TI - Older Adults' and Caregivers' Perspectives on In-Home Monitoring Technology. AB - In the past decade, there has been an increase in the application and investigation of in-home monitoring systems to support older adults with dementia and their caregivers. The current study focused on a monitoring system that included the use of motion sensors and Internet connections with one-way communication capabilities. Only a limited number of studies have explored and compared older adults' and caregivers' perspectives on such monitoring systems. The purpose of the current study was to explore older adults' and caregivers' perspectives on in-home monitoring systems using photo elicitation techniques. Three overarching themes emerged: (a) feeling cared for (which included two sub themes), (b) feeling cared about (which included three sub-themes), and (c) suggestions for change (which included four sub-themes). These results revealed the duality of care when using in-home monitoring. Clinical and other future implications are discussed. [Journal of Gerontological Nursing, 42(6), 43-50.]. PMID- 26977705 TI - Workplace Participatory Occupational Health/Health Promotion Program: Facilitators and Barriers Observed in Three Nursing Homes. AB - Nursing home employees experience high physical and psychosocial workloads, resulting in poor health outcomes. An occupational health/health promotion program, designed to facilitate employee participation, was initiated in three nursing homes. The aim of the current study was to evaluate facilitators and barriers of the program after 3-year implementation. Focus groups with employees and in-depth interviews with top and middle managers were conducted. The Social Ecological Model was used to organize the evaluation. Facilitators and barriers were reported from both managers' and employees' perspectives, and were categorized as intrapersonal, interpersonal, institutional, and corporate level. Management support, financial resources, and release time for participation were identified as the three most important factors. Supports from multiple levels including both human and environment, and managers and employees, are important for a successful participatory occupational health/health promotion program. [Journal of Gerontological Nursing, 42(6), 34-42.]. PMID- 26977707 TI - Assessment of Topical Skin Care Practices in Long-Term Institutional Nursing Care from a Health Service Perspective. AB - Skin aging is associated with increased skin vulnerability and susceptibility to ulcerations and dermatoses, making intensive skin care required, especially for older adults. As part of a nationwide prevalence study, data of 3,385 residents 60 and older were collected to analyze skin care practices in German long-term care facilities. The objective of the current study was to gain detailed insights into frequencies of leave-on skin care product applications by nursing care professionals for older adults. The 10 most frequently treated body parts accounted for >94% of all skin applications. Variations related to gender, age, and skin areas indicate differences in perceived skin care needs, although the evidence base supporting basic skin care interventions in this setting is weak. Gender, age, and clinical status seem to influence skin care practices. These factors must be taken into account to improve topical skin care and health in long-term care. [Journal of Gerontological Nursing, 42(6), 18-24.]. PMID- 26977709 TI - Protein-Style Dynamical Transition in a Non-Biological Polymer and a Non-Aqueous Solvent. AB - Temperature-dependent onset of apparent anharmonicity in the microscopic dynamics of hydrated proteins and other biomolecules has been known as protein dynamical transition for the last quarter of a century. Using neutron scattering and molecular dynamics simulation, techniques most often associated with protein dynamical transition studies, we have investigated the microscopic dynamics of one of the most common polymers, polystyrene, which was exposed to toluene vapor, mimicking the process of protein hydration from water vapor. Polystyrene with adsorbed toluene is an example of a solvent-solute system, which, unlike biopolymers, is anhydrous and lacks hydrogen bonding. Nevertheless, it exhibits the essential traits of the dynamical transition in biomolecules, such as a specific dependence of the microscopic dynamics of both solvent and host on the temperature and the amount of solvent adsorbed. We conclude that the protein dynamical transition is a manifestation of a universal solvent-solute dynamical relationship, which is not specific to either biomolecules as solute, or aqueous media as solvent, or even a particular type of interactions between solvent and solute. PMID- 26977708 TI - A C216-Nanographene Molecule with Defined Cavity as Extended Coronoid. AB - We describe the first coronoid nanographene C216-molecule. As an extended polycyclic aromatic hydrocarbon containing a defined cavity, our molecule can be seen as a model system to study the influence of holes on the physical and chemical properties of graphene. Along the pathway of an eight-step synthesis including Yamamoto-type cyclization followed by 6-fold Diels-Alder cycloaddition, C216 was obtained by oxidative cyclodehydrogenation in the final step. The defined molecular structure with a cavity was unambiguously validated by MALDI TOF mass spectrometry and FTIR, Raman, and UV-vis absorption spectroscopy coupled with DFT simulations. PMID- 26977711 TI - Correction to "Engaging Alkenyl Halides with Alkylsilicates via Photoredox Dual Catalysis". PMID- 26977710 TI - Controllable Multicompartmental Capsules with Distinct Cores and Shells for Synergistic Release. AB - A facile and flexible approach is developed for controllable fabrication of novel multiple-compartmental calcium alginate capsules from all-aqueous droplet templates with combined coextrusion minifluidic devices for isolated coencapsulation and synergistic release of diverse incompatible components. The multicompartmental capsules exhibit distinct compartments, each of which is covered by a distinct part of a heterogeneous shell. The volume and number of multiple compartments can be well-controlled by adjusting flow rates and device numbers for isolated and optimized encapsulation of different components, while the composition of different part of the heterogeneous shell can be individually tailored by changing the composition of droplet template for flexibly tuning the release behavior of each component. Two combined devices are first used to fabricate dual-compartmental capsules and then scaled up to fabricate more complex triple-compartmental capsules for coencapsulation. The synergistic release properties are demonstrated by using dual-compartmental capsules, which contain one-half shell with a constant release rate and the other half shell with a temperature-dependent release rate. Such a heterogeneous shell provides more flexibilities for synergistic release with controllable release sequence and release rates to achieve advanced and optimized synergistic efficacy. The multicompartmental capsules show high potential for applications such as drug codelivery, confined reactions, enzyme immobilizations, and cell cultures. PMID- 26977713 TI - Lithium-Air Batteries with Hybrid Electrolytes. AB - During the past decade, Li-air batteries with hybrid electrolytes have attracted a great deal of attention because of their exceptionally high capacity. Introducing aqueous solutions and ceramic lithium superionic conductors to Li-air batteries can circumvent some of the drawbacks of conventional Li-O2 batteries such as decomposition of organic electrolytes, corrosion of Li metal from humidity, and insoluble discharge product blocking the air electrode. The performance of this smart design battery depends essentially on the property and structure of the cell components (i.e., hybrid electrolyte, Li anode, and air cathode). In recent years, extensive efforts toward aqueous electrolyte-based Li air batteries have been dedicated to developing the high catalytic activity of the cathode as well as enhancing the conductivity and stability of the hybrid electrolyte. Herein, the progress of all aspects of Li-air batteries with hybrid electrolytes is reviewed. Moreover, some suggestions and concepts for tailored design that are expected to promote research in this field are provided. PMID- 26977712 TI - Pressed Paper-Based Dipstick for Detection of Foodborne Pathogens with Multistep Reactions. AB - This paper presents a pressed paper-based dipstick that enables detection of foodborne pathogens with multistep reactions by exploiting the delayed fluid flow and channel partition formation on nitrocellulose (NC) membrane. Fluid behaviors are easily modified by controlling the amount of pressure and the position of pressed region on the NC membrane. Detection region of the dipstick is optimized by controlling flow rate and delayed time based on Darcy's law. All the reagents required for assay are dried on the NC membrane and they are sequentially rehydrated at the prepartitioned regions when the device is dipped into sample solution. In this manner, multistep reactions can be facilitated by one-step dipping of the dipstick into the sample solution. As a proof of concept, we performed detection of two fatal foodborne pathogens (e.g., Escherichia coli O157:H7 and Salmonella typhimurium) with signal enhancement. In addition, we expanded the utilization of channel partitions by developing a pressed paper based dipstick into dual detection format. PMID- 26977714 TI - Expanding Thorium Hydride Chemistry Through Th2+, Including the Synthesis of a Mixed-Valent Th4+/Th3+ Hydride Complex. AB - The reactivity of the recently discovered Th(2+) complex [K(18-crown 6)(THF)2][Cp"3Th], 1 [Cp'' = C5H3(SiMe3)2-1,3], with hydrogen reagents has been investigated and found to provide syntheses of new classes of thorium hydride compounds. Complex 1 reacts with [Et3NH][BPh4] to form the terminal Th(4+) hydride complex Cp"3ThH, 2, a reaction that formally involves a net two-electron reduction. Complex 1 also reacts in the solid state and in solution with H2 to form a mixed-valent bimetallic product, [K(18-crown-6)(Et2O)][Cp"2ThH2]2, 3, which was analyzed by X-ray crystallography, electron paramagnetic resonance and optical spectroscopy, and density functional theory. The existence of 3, which formally contains Th(3+) and Th(4+), suggested that KC8 could reduce [(C5Me5)2ThH2]2. In the presence of 18-crown-6, this reaction forms an analogous mixed-valent product formulated as [K(18-crown-6)(THF)][(C5Me5)2ThH2]2, 4. A similar complex with (C5Me4H)(1-) ligands was not obtained, but reaction of (C5Me4H)3Th with H2 in the presence of KC8 and 2.2.2-cryptand at -45 degrees C produced two monometallic hydride products, namely, (C5Me4H)3ThH, 5, and [K(2.2.2 cryptand)]{(C5Me4H)2[eta(1):eta(5)-C5Me3H(CH2)]ThH]}, 6. Complex 6 contains a metalated tetramethylcyclopentadienyl dianion, [C5Me3H(CH2)](2-), that binds in a tuck-in mode. PMID- 26977715 TI - Quantum Dynamics in Phase Space using Projected von Neumann Bases. AB - We describe the mathematical underpinnings of the biorthogonal von Neumann method for quantum mechanical simulations (PvB). In particular, we present a detailed discussion of the important issue of nonorthogonal projection onto subspaces of biorthogonal bases, and how this differs from orthogonal projection. We present various representations of the Schrodinger equation in the reduced basis and discuss their relative merits. We conclude with illustrative examples and a discussion of the outlook and challenges ahead for the PvB representation. PMID- 26977716 TI - Characterization of Individual Magnetic Nanoparticles in Solution by Double Nanohole Optical Tweezers. AB - We study individual superparamagnetic Fe3O4 (magnetite) nanoparticles in solution using a double nanohole optical tweezer with magnetic force setup. By analysis of the trapping optical transmission signal (step size, autocorrelation, the root mean-square signal, and the distribution with applied magnetic field), we are able to measure the refractive index, magnetic susceptibility, remanence and size of each trapped nanoparticle. The size distribution is found to agree well with scanning electron microscopy measurements, and the permeability, magnetic susceptibility and remanence values are all in agreement with published results. Our approach demonstrates the versatility of the optical tweezer with magnetic field setup to characterize nanoparticles in fluidic mixtures with potential for isolation of desired particles and pick-and-place functionality. PMID- 26977717 TI - Cyclometalated Iridium(III) Complexes Containing 4,4'-pi-Conjugated 2,2' Bipyridine Derivatives as the Ancillary Ligands: Synthesis, Photophysics, and Computational Studies. AB - This article demonstrates a series of cyclometalated Ir(III) complexes of the type [Ir(III)(C^N)2(N^N)](PF6), where C^N is 2-phenylpyridine, and N^N corresponds to the 4,4'-pi-conjugated 2,2'-bipyridine ancillary ligands. All these compounds were synthesized through splitting of the binuclear dichloro bridged complex precursor, [Ir(C^N)2(MU-Cl)]2, with the appropriate bipyridine ligands followed by the anion exchange reaction. The linear and nonlinear absorption properties of the synthesized complexes were investigated. The absorption spectra of all the title complexes exhibit a broad structureless feature in the spectral region of 350-700 nm with two bands being well-resolved in most of the cases. The structures of all the compounds were modeled in dichloromethane using the density functional theory (DFT) algorithm. The nature of electronic transitions was further comprehended on the basis of time-dependent DFT analysis, which indicates that the origins of various bands are primarily due to intraligand charge transfer transitions along with mixed-metal and ligand centered transitions. The synthesized compounds are found to be nonemissive at room temperature because of probable nonradiative deactivation pathways of the T1 state that compete with the radiative (phosphorescence) decay modes. However, the frozen solutions of compounds Ir(MS 3) and Ir(MS 5) phosphoresce at the near-IR region, the other complexes remaining nonemissive up to 800 nm wavelength window. The two-photon absorption studies on the synthesized complexes reveal that values of the absorption cross-section are quite notable and lie in the range of 300 1000 GM in the picosecond case and 45-186 GM in the femtosecond case. PMID- 26977719 TI - I Want You to Be Fearless. PMID- 26977718 TI - Formulation of Acid-Sensitive Micelles for Delivery of Cabazitaxel into Prostate Cancer Cells. AB - We report the synthesis of an amphiphilic triblock copolymer composed of a hydrophilic poly(ethylene glycol) (PEG) block, a central poly(acrylic acid) (PAA) block, and a hydrophobic poly(methyl methacrylate) (PMMA) block using atom transfer radical polymerization technique. We examined the self-assembly of PEG-b PAA-b-PMMA copolymers in aqueous solutions forming nanosized micelles and their ability to encapsulate hydrophobic guest molecules such as Nile Red (NR) dye and cabazitaxel (CTX, an anticancer drug). We used 2,2beta'-(propane-2,2 diylbis(oxy))-diethanamine to react with the carboxylic acid groups of the central PAA block forming acid-labile, shell cross-linked micelles (SCLM). We investigated the loading efficiency and release of different guest molecules from non-cross-linked micelles (NSCLM) and shell cross-linked micelles (SCLM) prepared by reacting 50% (SCLM-50) and 100% (SCLM-100) of the carboxylic acid groups in the PAA in physiologic (pH 7.4) and acidic (pH 5.0) buffer solutions as a function of time. We examined the uptake of NR-loaded NSCLM, SCLM-50, and SCLM 100 micelles into PC-3 and C4-2B prostate cancer cells and the effect of different micelle compositions on membrane fluidity of both cell lines. We also investigated the effect of CTX-loaded NSCLM, SCLM-50, and SCLM-100 micelles on the viability of PC-3 and C4-2B cancer cells compared to free CTX as a function of drug concentration. Results show that PEG-b-PAA-b-PMMA polymers form micelles at concentrations >=11 MUg/mL with an average size of 40-50 nm. CTX was encapsulated in PEG-b-PAA-b-PMMA micelles with 55% loading efficiency in NSCLM. In vitro release studies showed that 30% and 85% of the loaded CTX was released from SCLM-50 micelles in physiologic (pH 7.4) and acidic (pH 5.0) buffer solutions over 30 h, confirming micelles' sensitivity to solution pH. Results show uptake of NSCLM and SCLM into prostate cancer cells delivering their chemotherapeutic cargo, which triggered efficient cancer cell death. PEG-b-PAA-b PMMA micelles were not hemolytic and did not cause platelet aggregation, which indicate their biocompatibility. PMID- 26977720 TI - [Light and scanning electron microscopy of anterior lens capsule following different capsulorhexis techniques]. AB - Aim - to assess the morphology of anterior lens capsules following circular capsulorhexis, for which capsulotomy was either manual or femtosecond (FS) laser produced. MATERIAL AND METHODS: A total of 30 capsular samples obtained during phacoemulsification surgery were studied by light and scanning electron microscopy. All the samples were divided into 3 groups of 10 according to the type of capsulotomy: group 1 - manual, groups 2 and 3 - FS laser produced (with the laser set at high or low energy level, respectively). RESULTS: In manual capsulorhexis, capsular disk edges were rather smooth all the way round. Rare notches and dents as well as fine burrs up to 4 um long could only be seen under high magnification. In FS laser capsulotomy groups, under low magnification already, capsular disk edges appeared stepped, stratified, and notched (some notches were up to 20 um deep). The said changes were more significant following low-energy laser treatment, while high-energy levels were notable for 'melted' disk edges. Regardless of the technique used, all the disks carried a zone of de epithelization of different width along the free edge. CONCLUSION: The differences revealed may result from several factors: 1) less accurate focusing of the laser due to fine torsional eye movements and minimal shape changes of the applanated cornea; 2) peculiarities of FS laser-tissue interaction, particularly, cavitation bubbles that are formed during tissue evaporation and tend to merge, subsequently producing the incision and demarcation line. Moreover, photothermal effects of laser radiation on epithelial cells within the anterior lens capsule cannot be excluded. PMID- 26977721 TI - [Functional loading test with caffeine as a detection method for hydrodynamic disturbances in patients with cataract and pseudoexfoliation syndrome]. AB - Different functional loading tests, with caffeine for example, can help reveal certain disturbances in ocular hydrodynamics and it would be interesting to investigate their diagnostic potential in eyes with pseudoexfoliation syndrome (PEX), which is a known trigger of glaucoma. Aim - to determine the value of caffeine loading test in the diagnosis of hydrodynamic disturbances in eyes with cataract and pseudoexfoliation syndrome. MATERIAL AND METHODS: A total of 98 patients (98 eyes) with cataract and PEX were examined. Intraocular pressure (IOP) measurements were taken using the Maklakov applanation tonometer every 15 min during the first hour after a 0.2 ml subcutaneous injection of 10% caffeine/sodium benzoate solution. RESULTS: Three types of intraocular pressure response to caffeine administration have been described in patients with cataract and PEX. The severity of hydrodynamic disturbances thus revealed has been also shown to correlate with PEX stage, IOP level, and the presence or absence of cardiovascular pathology, which allows to regard the latter sings as markers of hydrodynamic problems in the eye. PMID- 26977722 TI - [Retrospective analysis of clinical, radiological, and histopathological presentation of periocular dermoid cysts]. AB - Aim - to determine the contribution of clinical and radiological findings to proper diagnosis of dermoid cysts and treatment decision making and also, to identify their distinctive histopathological features. MATERIAL AND METHODS: This is a retrospective analysis of slinical signs, assessment RESULTS: and treatment outcomes in 52 patients with orbital dermoids. RESULTS: The patients enrolled mostly complained of painless non-inflammatory swelling of the upper eyelid that spatially corresponded to the cyst. None of the patients developed diplopia, exophthalmos, or change in refraction. Computed tomography revealed round or oval shapes with clear and smooth contours. CONCLUSION: Having analyzed clinical, radiological, and histopathological presentation of dermoid cysts, we conclude that, if interpreted correctly, clinical signs together with assessment results provide reliable diagnosis prior to surgery. PMID- 26977723 TI - [Evaluation of corneal biomechanics before and after up-to-date keratoplasty in patients with bullous keratopathy]. AB - Aim - to study biomechanical properties of the cornea in patients with bullous keratopathy before and after keratoplasty. MATERIAL AND METHODS: Ocular response analyzer (ORA, Reichert) indices were studied in 37 patients (37 eyes) with bullous keratopathy before and after surgery - in 1, 2, and 6 months and then in 1, 2, 3, and 5 years. The following keratoplasty modifications were performed: ultrathin Descemet's stripping automated endothelial keratoplasty (UTDSAEK) - in 17 cases, microkeratome-assisted posterior keratoplasty (MAPK) - in 13 cases, half top-hat penetrating keratoplasty (HTH PK) - in 7 cases. RESULTS: Corneal hysteresis (CH) and corneal resistance factor (CRF) values were significantly decreased in non-operated bullous keratopathy eyes as compared to healthy ones (p<0.05). By the 6-month follow-up these parameters have been found to be partially recovered and stabilized in all groups, however, still lower than normal (p<0.05). Differences between the groups were never statistically reliable, not at any time after surgery. Moreover, in eyes with bullous keratopathy, the mean corneal-compensated intraocular pressure (IOPcc) exceeded the mean Goldman-related IOP (IOPg) by 2.4 mmHg. One month after keratoplasty the difference between IOPcc and IOPg was 2.7, 4.3, and 3.6 mmHg in the MAPK, UTDSAEK, and HTH PK group, respectively; in 6 months - 2.6; 2.4 and 3.6 mmHg, respectively (p<0.05). In the fellow healthy eyes the two IOP measurements were not statistically different. CONCLUSION: Chronic edema of the cornea results in alteration of its viscoelastic properties. It has been shown that CH and CRF values decrease significantly in the eye involved as compared to the fellow healthy eye. After keratoplasty, regardless of the exact modification, these parameters partially recover, but remain lower than normal for at least 5 years as it was in our study. Neither before the surgery (when the cornea is chronically swollen), nor after, does corneal thickness correlate with its biomechanical indices. Postoperative reduction in corneal rigidity in eyes with bullous keratopathy may be confusing and lead to underestimation of the true level of IOP, thus, causing delays in diagnosis of concomitant glaucoma. PMID- 26977724 TI - [Novel approach to treatment of lagophthalmos-associated neuroparalytic keratitis]. AB - Aim - to develop effective treatment approaches to lagophthalmos-associated neuroparalytic keratitis. MATERIAL AND METHODS: A total of 34 patients (36 eyes) with neuroparalytic keratitis were enrolled. Group 1 consisted of 20 patients (21 eyes), in whom autoconjunctivoplasty was performed in combination with eyelid surgery. Group 2 consisted of 12 lagophthalmic patients (13 eyes) with purulent corneal ulcers, who additionally underwent corneal transplantation. Group 3 included 2 patients (2 eyes) with central corneal ulcer in the only seeing eye, who received, besides other things, upper sector iridectomy intended to serve as a pupil (RU 2299048 with priority date of 15.07.2005). RESULTS: In group 1, corneal re-epithelization and complete recovery was achieved in all patients within 3.00+/-0.69 weeks. Visual acuity (VA) has generally increased over the first year after treatment from 0.14+/-0.06 to 0.25+/-0.13 in group 1 and from 0.09+/-0.05 to 0.21+/-0.13 in group 2. In group 3, sector iridectomies also yielded an increase in VA - from 0.01 to 0.02 in one case and from 0.2 to 0.6 in the other. Autoconjunctivoplasty enabled rapid and stable re-epithelization of corneal defects in all cases. CONCLUSION: One-stage corneal and eyelid surgery has been shown to be more effective in treating lagophthalmos-associated neuroparalytic keratitis than previous methods. The novel approach ensures acute symptoms of keratitis resolve and the eye is saved, moreover, it allows to maintain visual acuity and prevent recurrences in 64% and 65% of patients, respectively. PMID- 26977725 TI - [Abnormal distribution of trace elements in keratoconic corneas]. AB - Our understanding of etiology and pathogenesis of many disorders, corneal included, greatly relies on existing knowledge in human biochemistry and biophysics. This study was aimed at chemical mapping of normal and keratoconic corneas. MATERIAL AND METHODS: Modern methods of analytical chemistry, such as X ray fluorescence and energy-dispersive X-ray spectroscopy on the basis of scanning electron microscopy, were adapted to the needs of cornea research. Normal human corneas obtained postmortem and corneal buttons obtained during penetrating keratoplasty were analyzed. RESULTS: In keratoconus, abnormal accumulation of iron, copper, and zinc was found in the periphery of the buttons, i.e. in the zone of visible pigmentation (Fleischer ring), while the center - the ectatic zone - demonstrated a total deficiency of trace elements. This data suggests that keratoconus pathogenesis is associated with impaired mineral metabolism and formation of a physicochemical barrier in corneal tissues with subsequent keratectasia. The authors discuss several possible vicious circles involved. PMID- 26977726 TI - [Custom-made artificial parts for improving functional and cosmetic results of ocular prosthetics]. AB - Aim - to justify the use of custom-made ocular prostheses aimed at better functional and cosmetic outcomes. MATERIAL AND METHODS: Cosmetic outcomes in 520 patients operated for either anophthalmia (89.1%), or ocular subatrophy (6.7%), or congenital micro-/anophthalmia have been analyzed. General and ophthalmic assessment was performed. RESULTS: Relationships were investigated between the results obtained in a particular patient, on the one hand, and primary etiology in his/her case, eye removal technique, postoperative management details, complications, treatments, and preventive measures, on the other. It has been found that, if aiming to avoid the development of anophthalmic syndrome, the choice of surgical technique should be done most carefully so that a muscle stump could be formed and primary prosthesis inserted. Indications for the use of complexly shaped ocular prostheses have been identified. We have also explored the possibilities for correction of cosmetic defects associated with the use of modified stock prostheses. Moreover, in this article particular attention is paid to the importance of cooperation between the oculoplastic surgeon and the ocularist in order to ensure timely orbital reconstruction. CONCLUSION: Indications for the use of custom-made ocular prostheses of complex shapes have been identified. The range of complications that may arise from their irrational use are discussed. PMID- 26977727 TI - [Retinal vein occlusion management algorithm. Part 1. Classification, diagnosis, and acute-stage treatment]. AB - Considering an upward global trend in cardiovascular disease rates, retinal vein occlusion (RVO) in particular, development of therapeutic guidelines is a pressing issue in ophthalmology. Risk factors for RVO include hypertension, atherosclerosis, diabetes mellitus, blood disorders, inflammatory disorders, and prescription drug use. Three stages of RVO have been identified. By location, the entity can be divided into three big groups: central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), and hemicentral retinal vein occlusion (HCRVO), each being either ischemic or nonischemic. Functional prognosis is better in nonischemic occlusions. Patient management comprises acute stage treatment (anticoagulants, fibrinolytic agents, and hemodilution) and struggling with ocular complications (intravitreal injections and laser coagulation). It is essential that primary assessment and follow-up of patients at any stage of RVO include optical coherence tomography and fluorescent angiography. PMID- 26977728 TI - [Retinal vein occlusion management algorithm. Part 2. Macular edema]. AB - Macular edema (ME) is the most common complication of both ischemic and nonischemic retinal vein occlusion (RVO). If the main trunk of the central retinal vein is involved, ME occurs in 100% of cases. According to the Central Vein Occlusion Study, in 65% of RVO and ME patients with baseline visual acuity (VA) of at least 0.5 (Golovin-Sivtsev chart) or higher, ME may resolve itself without treatment with subsequent VA improvement. Therefore, we recommend a 3 month treatment-free follow-up of nonischemic central RVO (CRVO) and ME patients with VA of 0.5 or higher. If no improvement is noted within this period, treatment is initiated. Immediate treatment is required in patients with cystic ME revealed by optical coherence tomography (OCT) and VA below 0.5. Ischemic maculopathy is extremely unpromising. Modified grid laser photocoagulation should not be used as monotherapy for macular edema. Repeated corticosteroid (Ozurdex) and/or anti-VEGF (ranibizumab, aflibercept) intravitreal injections are considered the first choice treatment for ME in CRVO patients. Efficiency assessments should include monthly OCT. For persistent ME, intravitreal therapy can be supplemented by laser retinal photocoagulation (panretinal or modified grid). Anti-VEGF treatment schemes should be adjusted in BRVO patients as most of their edemas are self-limiting. Of laser photocoagulation techniques, only modified grid is used. PMID- 26977729 TI - [Retinal vein occlusion management algorithm. Part 3. Neovascular complications]. AB - Neovascular complications severity in central/branch retinal vein occlusion (RVO) correlates with the level of occlusion and the degree of retinal perfusion disturbance. Large areas of retinal non-perfusion (more than half of the total retinal area) are associated with the risk for posterior segment neovascularization as high as 33% and for neovascular glaucoma - 45%. Over the past 30 years there has been an evident declining tendency of neovascular complications rates in the natural course of RVO. In ischemic RVO, anterior segment neovascularization is more aggressive than posterior. Neovascular glaucoma usually develops within the first 6 months of disease and correlates with uncontrolled arterial hypertension. Panretinal photocoagulation (PRP) is a standard treatment for anterior and posterior segment neovascularization in RVO patients. Anti-VEGF agents, if used as monotherapy, lead to rapid, however, short term remission. Combination therapy, that is anti-VEGF injections and PRP, is the most effective. Intravitreal steroids have demonstrated no effect on ocular neovascularization. If PRP cannot be performed and intraocular pressure levels remain high, one should consider glaucoma drainage implant surgery. Preventive measures for neovascular complications that have proved effective so far include regular follow-ups, individually scheduled intravitreal injections, and PRP for large zones of ischemia. PMID- 26977730 TI - [Rare case of primary orbital osteoma]. AB - We report a case of primary orbital osteoma originated from the sphenoid and notable for a mismatch between its giant size and mild clinical presentation. A lot of attention has been paid to the choice of surgical technique. PMID- 26977731 TI - [Occupational disability due to an eye injury (case report)]. AB - We report a long service driver with late onset bilateral cataract and unilateral retinal detachment following bilateral eye injury. The causal relationship between these pathological conditions and occupational injury has been convincingly established. The degree of patient's occupational disability has been determined by expert decision. PMID- 26977732 TI - [Assessment of microvascular bulbar conjunctiva in patients with type 1 diabetes]. AB - The aim was to study the state of microvascular bulbar conjunctiva in patients with type 1 diabetes. MATERIAL AND METHODS: A clinical study of 25 patients with DR in the type 1 diabetes and 20 healthy persons without ophthalmopathology. All patients in addition to conventional methods of ophthalmological conducted computer Capillaroscopy bulbar conjunctiva. RESULTS: Results of the study showed patients with DR in the type 1 diabetes tortuosity of capillaries (due to thickening of the basement membrane), the expansion of the department of venous capillaries and arterial narrowing department, the formation of aggregates, the phenomenon of sludge and slowing blood flow. After a course of treatment (Tanakan 2 months to 120 mg. per day) capillaroscopy showed a positive trend state bulbar conjunctiva microvessels: reduction in the incidence of the phenomenon of sludge and the duration of stasis, increased blood flow, which correlated with the positive dynamics ophthalmoscopic picture. CONCLUSION: The results indicate the informativeness capillaroscopy as a method of assessing the state of the microvasculature in patients with type 1 diabetes. PMID- 26977733 TI - [An experience with neuroprotective therapy of primary open-angle glaucoma based on the use of different dosage forms of Mexidol]. AB - Aim - to develop an algorithm to guide neuroprotective therapy in railway workers undergoing long-term follow-up for primary open-angle glaucoma (POAG) judging from the efficacy of sequential administration of intravenous dosage form of Mexidol and oral tablets. MATERIAL AND METHODS: All sorts of JSC Russian Railways employees with stage I-III POAG and well-controlled intraocular pressure were enrolled. Mexidol was first to be administered intravenously by a dropper in a day hospital (250 mg daily for 5 days) and then taken orally at home (125 mg t.i.d. for 3 months). A comprehensive ophthalmic examination with high-technology control was performed in all patients at their first, second, and third follow-up visits. RESULTS: Data from 58 patients (96 eyes) were analyzed. Statistically significant improvements in perimetry and optical coherence tomography results were only obtained at a third visit, i.e. at the end of the course of Mexidol tablets. The treatment effect was most pronounced in stage I-II patients. CONCLUSION: The results suggest that combination therapy with intravenous and oral Mexidol received sequentially as well as long-term (3-month) administration of Mexidol tablets can both be recommended in POAG patients. It has been also found that neuroprotective therapy with Mexidol performs best for early stages of the disease. PMID- 26977734 TI - Maliponia aquimaris gen. nov., sp. nov., isolated from seawater. AB - A Gram-stain-negative, coccoid- or oval-shaped and non-motile bacterial strain, designated MM-10T, belonging to the Alphaproteobacteria, was isolated from seawater of the Yellow Sea, Korea, and was subjected to a polyphasic taxonomic study. Strain MM-10T grew optimally at pH 7.0-8.0, at 30 degrees C and in the presence of 2-3 % (w/v) NaCl. Neighbour-joining, maximum-likelihood and maximum parsimony phylogenetic trees based on 16S rRNA gene sequences showed that strain MM-10T fell within the clade comprising members of the genera Mameliella, Sagittula, Antarctobacter and Ponticoccus. Strain MM-10T exhibited a 16S rRNA gene sequence similarity of 97.7 % with respect to the type strain of Mameliella alba. The DNA G+C content of strain MM-10T was 66.0 mol% and its mean level of DNA-DNA relatedness with M. alba LMG 24665T was 12.3+/-1.4 % . Strain MM-10T contained Q-10 as the predominant ubiquinone and C18 : 1omega7c as the major fatty acid. The major polar lipids were phosphatidylcholine, phosphatidylglycerol and phosphatidylethanolamine. Differential phenotypic properties, together with phylogenetic distinctiveness, demonstrate that strain MM-10T is distinguishable from recognized species of the genera Mameliella, Sagittula and Antarctobacter. On the basis of the data presented, strain MM-10T is considered to represent a novel species of a new genus, for which the name Maliponia aquimaris gen. nov., sp. nov. is proposed. The type strain of Maliponia aquimaris is MM-10T (=KCTC 42721T=CECT 8898T). PMID- 26977736 TI - The Combination of Biomarkers for Prognostication of Long-Term Outcome in Patients Treated with Mild Hypothermia After Out-of-Hospital Cardiac Arrest-A Pilot Study. AB - To explore if the brain biomarker neuron-specific enolase (NSE) in combination with a biomarker for stress; CT-proAVP (copeptin), oxidation; peroxiredoxin 4 (Prx4), inflammation; procalcitonin (PCT), or with biomarkers from the heart; midregional proatrial natriuretic peptide (MR-proANP), or troponin T (TnT) can improve the prognostic accuracy of long-term outcome after out-of-hospital cardiac arrest (OHCA). Serum samples from cardiac arrest patients, treated at 33 degrees C for 24 hours, were collected serially at 12, 24, and 48 hours after cardiac arrest. The concentration of the investigated biomarkers was measured using stored samples, and long-term outcome was evaluated by the cerebral performance category (CPC) at 6 months. Poor outcome was defined as CPC 3-5. Sixty-two patients with OHCA of presumed cardiac cause were included. NSE had best prognostic accuracy for poor outcome at 48 hours with a receiver operating characteristic area under curve (AUC) of 0.94 (95% confidence interval [CI] 0.87 1). The combination of NSE with TnT, both at 48 hours, increased the AUC to 0.98 (95% CI 0.95-1, likelihood ratio [LR] test p-value 0.07, net reclassification index [NRI] <0.001); NSE and MR-proANP, both at 12 hours, yielded an AUC of 0.91 (95% CI 0.80-1, LR test p-value 0.0014, NRI p-value 0.003); NSE at 48 hours with MR-proANP at 12 hours yielded an AUC of 0.97 (95% CI 0.92-1, LR test p-value 0.055, NRI p-value 0.04). This pilot study suggests that a combination of biomarkers with NSE could be beneficial for improving early prognostication of long-term outcome following OHCA. PMID- 26977738 TI - Observation of Skin-to-Skin Contact and Analysis of Factors Linked to Failure to Breastfeed Within 2 Hours After Birth. AB - BACKGROUND: Successful breastfeeding at birth seems to be associated with skin-to skin contact between mother and newborn and newborn suckling, both within the first 2 hours of life. In practice, knowledge about the number and cause of interruptions of this contact has to be increased. OBJECTIVE: To measure the actual time of skin-to-skin contact in the first 2 hours after birth, study the events that occur during this period, and search for factors linked to failure to breastfeed. MATERIALS AND METHODS: Thirty women wishing to breastfeed gave their consent for us to observe and analyze the first 2 hours of the baby's life during skin-to-skin contact. RESULTS: Mean total duration of skin-to-skin contact for the 30 newborns during the first 2 hours was 90.4 +/- 25.0 minutes; 17 (56.7%) were interrupted at least twice during this time, mainly for neonatal care. The first interruption took place before the first breastfeed in 60% of cases. Mean time before the first breastfeed was 44.6 +/- 21.1 minutes. Seven infants did not breastfeed in the first 2 hours (23.3%). The factors linked to this failure were nulliparity, lower umbilical arterial pH at birth, and early interruptions in skin-to-skin contact. Among them, only early interruptions of skin-to-skin contact appear to be modifiable. CONCLUSION: In the first 2 hours of life, early interruptions of skin-to-skin contact should be discouraged as they reduce the chances of early breastfeed. PMID- 26977740 TI - Efficacy of Low-Level Laser Therapy in the Management of Postoperative Pain in Children After Primary Teeth Extraction: A Randomized Clinical Trial. AB - OBJECTIVE: This study evaluated the effect of low-level laser therapy (LLLT) on postoperative pain in children undergoing primary molar extraction. MATERIALS AND METHODS: This randomized, controlled-crossover, double-blind clinical trial was conducted with 37 children requiring bilateral extraction of primary molars. In one tooth (LLLT group), a GaAlAs diode laser (wavelength, 810 nm; continuous mode, output power 0.3 W; 180 sec, 4 J/cm(2)) was applied intraorally 1 cm from the target tissue immediately following extraction. In the contralateral tooth (control group), the hand piece was applied, but without laser activation. Children and parents rated postoperative pain on the first three evenings following extraction using, respectively, the Wong-Baker FACES((r)) Pain Rating Scale (PRS) and the Visual Analogue Scale (VAS). Parents also reported if their children received analgesics. Data were analyzed using chi(2) and Mann-Whitney U tests. RESULTS: Mean VAS scores were higher for the control group than for the LLLT group on the first and second evenings, and PRS scores were higher for the control group than for the laser group on the first evening, but the differences were not statistically significant (p > 0.05). More analgesics were given to children in the control group on the first evening; however, both groups received equal amounts on the next two evenings (p > 0.05). CONCLUSIONS: Within the limitations of this study, LLLT application following primary molar extraction was not found to affect postoperative pain in children. PMID- 26977741 TI - Epidemiology of asthma. AB - PURPOSE OF REVIEW: This article reports the findings of recently published research articles and Centers for Disease Control (CDC) data on the epidemiology of asthma. Numerous otolaryngologic diseases are associated with asthma, such as allergic rhinitis, chronic rhinosinusitis, and obstructive sleep apnea. In addition, asthma causes a significant health burden and its prevalence is increasing. RECENT FINDINGS: Currently, 8.4% of persons in the United States have asthma as compared with 4.3% of the population worldwide, and both numbers are on the rise. The average annual asthma prevalence is higher in children (9.5%) than adults (7.7%). The prevalence of asthma is higher in black persons than white persons, and the ethnicity most affected is the Puerto Rican population. Asthma prevalence increases with each successive lower poverty level group. There are interesting relationships between asthma and certain otolaryngologic diseases. The impact of asthma on both morbidity and mortality is particularly noteworthy. SUMMARY: The prevalence of asthma is increasing both domestically and globally. The impact is most significant in the minority and lower socioeconomic populations. Future research should work to elucidate the reasons for this increase in asthma and promote better access to care for persons across all ethnic and socioeconomic classes. PMID- 26977739 TI - RemLogic plug-in enables clinical application of apnea-hypopnea index adjusted for severity of individual obstruction events. AB - Obstructive sleep apnea (OSA) is diagnosed based on obstruction event incidence, albeit individual obstruction event severity is connected to increased mortality rate. Adjusted-AHI parameter, incorporating number and severity of obstruction events, has shown good potential, but is calculated using custom-made MATLAB((r)) functions. To allow its clinical use, this study introduces the RemLogicTM plug in. It is tested comparing adjusted-AHI values calculated with the plug-in and MATLAB((r)) with a hundred patients. Furthermore, retrospective follow-up (mean +/- SD = 194.1 +/- 54.0 months) of 1128 working-age men was conducted to evaluate potential of adjusted-AHI to enhance diagnostic of OSA. Adjusted-AHI values were strongly correlated (r = 1.000, p < 0.001) and their average difference (mean +/- SD) was minimal (0.08 +/- 0.19%). Using adjusted-AHI to define OSA severity resulted in a higher hazard ratio of mortality in the severe OSA group and, for the first time, adjusted-AHI was found to explain independently the overall mortality and non-fatal cardiovascular events. Importantly, the present plug-in enables clinical use of adjusted-AHI, enhancing assessment of OSA severity. PMID- 26977742 TI - BIRDSHOT CHORIORETINITIS LESIONS ON INDOCYANINE GREEN ANGIOGRAPHY AS AN INDICATOR OF DISEASE ACTIVITY. AB - PURPOSE: To determine whether classical indocyanine green angiography lesions in patients with birdshot chorioretinitis can be used to monitor disease activity. METHODS: A retrospective case series was performed on 26 eyes in 26 consecutive patients with birdshot chorioretinitis who had at least one indocyanine green angiography performed during disease activity and another during disease quiescence. Using Photoshop, the mean number, area, and area per spot on indocyanine green angiography were compared between disease activity and quiescence using a paired ratio test. RESULTS: The mean total lesion number, area, and area per spot during disease activity were 75.27 spots, 24,525 pixels, and 364 pixels/spots, respectively. The mean total lesion number, area, and area per spot size during disease quiescence were 28.35 spots (P < 0.01), 7,411 pixels (P < 0.01), and 279 pixels/spot (P = 0.12), respectively. CONCLUSION: There was a statistically significant decrease in the mean total area and number of lesions between the time of disease activity and disease quiescence (P < 0.01). Our results suggest that indocyanine green angiography has a role not only in diagnosis but also in monitoring treatment effectiveness; lesions can be reversible with treatment and their reappearance may be an indicator of disease relapse. PMID- 26977743 TI - Diagnostic and Therapeutic Challenges. PMID- 26977737 TI - Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans. AB - RATIONALE: Obstructive sleep apnea is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. Although there is strong clinical and epidemiologic evidence supporting the importance of genetic factors in influencing obstructive sleep apnea, its genetic basis is still largely unknown. Prior genetic studies focused on traits defined using the apnea-hypopnea index, which contains limited information on potentially important genetically determined physiologic factors, such as propensity for hypoxemia and respiratory arousability. OBJECTIVES: To define novel obstructive sleep apnea genetic risk loci for obstructive sleep apnea, we conducted genome-wide association studies of quantitative traits in Hispanic/Latino Americans from three cohorts. METHODS: Genome-wide data from as many as 12,558 participants in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Starr County Health Studies population-based cohorts were metaanalyzed for association with the apnea-hypopnea index, average oxygen saturation during sleep, and average respiratory event duration. MEASUREMENTS AND MAIN RESULTS: Two novel loci were identified at genome-level significance (rs11691765, GPR83, P = 1.90 * 10-8 for the apnea-hypopnea index, and rs35424364; C6ORF183/CCDC162P, P = 4.88 * 10-8 for respiratory event duration) and seven additional loci were identified with suggestive significance (P < 5 * 10-7). Secondary sex-stratified analyses also identified one significant and several suggestive associations. Multiple loci overlapped genes with biologic plausibility. CONCLUSIONS: These are the first genome-level significant findings reported for obstructive sleep apnea-related physiologic traits in any population. These findings identify novel associations in inflammatory, hypoxia signaling, and sleep pathways. PMID- 26977744 TI - Correspondence. PMID- 26977745 TI - Timing of Linkage to Care After HIV Diagnosis and Time to Viral Suppression. PMID- 26977747 TI - Expenditures for Persons Living With HIV Enrolled in Medicaid, 2006-2010. AB - BACKGROUND: Costs of care for persons living with HIV have been high historically. Cost estimates based on data from 1 health care site may underestimate total expenditures; using insurance claims avoids this limitation. We used Medicaid claims data to comprehensively assess payments for care for persons living with HIV between 2006 and 2010. METHODS: Five sites from the HIV Research Network (HIVRN) provided information on patients with Medicaid coverage. Medicaid data were obtained from the sites' states (MD, NY, and MA) and 3 surrounding states and matched to HIVRN medical record-based data. Individuals less than 18, those with Medicare, and those in Medicaid managed care plans were excluded. Medicaid and HIVRN data were compared to ascertain concordance in capturing any inpatient event and any antiretroviral (ART) medication use. RESULTS: Of 6892 unique HIVRN identifiers, 6196 (90%) were linked to Medicaid data. The analytic sample included 11,341 person-years of Medicaid claims data from 3695 individuals in fee-for-service (FFS) programs. The mean annual FFS payment for all services was $47,434; mean annual FFS payment for only medical services was $38,311. Concordance between Medicaid and HIVRN data was excellent for ART use, but HIVRN data did not record a substantial proportion of years in which Medicaid recorded inpatient use. CONCLUSIONS: Estimated Medicaid payment amounts in this study are higher than some previous estimates. More complete capture of expensive inpatient hospitalizations in Medicaid data may partially explain this finding. Although inpatient care and ART medications contribute the most, expenditures for nonmedical services are substantial. PMID- 26977746 TI - Nucleoside-Sparing Regimens With Raltegravir and a Boosted Protease Inhibitor: An Unsettled Issue. PMID- 26977749 TI - Implementation and Operational Research: A Cost-Effective, Clinically Actionable Strategy for Targeting HIV Preexposure Prophylaxis to High-Risk Men Who Have Sex With Men. AB - BACKGROUND: Preexposure prophylaxis (PrEP) is effective at preventing HIV infection among men who have sex with men (MSM), but there is uncertainty about how to identify high-risk MSM who should receive PrEP. METHODS: We used a mathematical model to assess the cost-effectiveness of using the HIV Incidence Risk Index for MSM (HIRI-MSM) questionnaire to target PrEP to high-risk MSM. We simulated strategies of no PrEP, PrEP available to all MSM, and eligibility thresholds set to HIRI-MSM scores between 5 and 45, in increments of 5 (where a higher score predicts greater HIV risk). Based on the iPrEx, IPERGAY, and PROUD trials, we evaluated PrEP efficacies from 44% to 86% and annual costs from $5900 to 8700. We designate strategies with incremental cost-effectiveness ratio (ICER) <=$100,000/quality-adjusted life-year (QALY) as "cost-effective." RESULTS: Over 20 years, making PrEP available to all MSM is projected to prevent 33.5% of new HIV infections, with an ICER of $1,474,000/QALY. Increasing the HIRI-MSM score threshold reduces the prevented infections, but improves cost-effectiveness. A threshold score of 25 is projected to be optimal (most QALYs gained while still being cost-effective) over a wide range of realistic PrEP efficacies and costs. At low cost and high efficacy (IPERGAY), thresholds of 15 or 20 are optimal across a range of other input assumptions; at high cost and low efficacy (iPrEx), 25 or 30 are generally optimal. CONCLUSIONS: The HIRI-MSM provides a clinically actionable means of guiding PrEP use. Using a score of 25 to determine PrEP eligibility could facilitate cost-effective use of PrEP among high-risk MSM who will benefit from it most. PMID- 26977748 TI - Characteristics of Age-Discordant Partnerships Associated With HIV Risk Among Young South African Women (HPTN 068). AB - OBJECTIVE: Sexual liaisons between older men and younger women have been linked to greater risk of HIV acquisition. This study aims to (1) identify psychosocial and behavioral factors associated with age-discordant (partner >=5 years) versus age-concordant partnerships (-1< partner <5) and (2) examine the association between partner age discordance and young South African women's sexual behavior. METHODS: We used generalized estimating equations to analyze responses from 656 sexually experienced women (aged 13-20 years) from rural Mpumalanga province. RESULTS: Partner age discordance was associated with greater odds of reporting both more frequent sex [adjusted odd ratio (aOR) = 1.77; 95% confidence interval (CI): 1.20 to 2.60] and having a partner with concurrent partnerships (aOR = 1.77; 95% CI: 1.22 to 2.57). Age-discordant partnerships were associated with greater odds of casual partnerships (aOR = 1.50; 95% CI: 1.06 to 2.13), having a partner with concurrent partnerships (aOR = 1.71; 95% CI: 1.19 to 2.46), and more frequent intercourse (ie, having sex at least 2 or 3 times per month) (aOR = 2.04; 95% CI: 1.39 to 3.00). They were associated with lower odds of reporting condom use at last sex (aOR = 0.70; 95% CI: 0.50 to 0.98) and always using condoms (aOR = 0.53; 95% CI: 0.32 to 0.88) in age-discordant partnerships. CONCLUSIONS: Our findings suggest that a history of age-discordant partnerships, and to a lesser extent having an age-discordant partner, is linked to HIV risk among young South African women; however, the link between partner age discordance and HIV risk may be more strongly related to the characteristics of age-discordant partnerships than to the characteristics of young women who form such partnerships. PMID- 26977750 TI - One case of rare gastric cancer combined with lack of factor XI. AB - The patient, a 50-year-old woman, was admitted to hospital diagnosed with gastric cancer. While performing preoperative examination, we found that this patient had a lack of factor XI. This is the first case diagnosed with gastric cancer combined with lack of emitted factor XI, at least in China. We used only fresh frozen plasma to correct the blood coagulation disorder to perform an operation. Firstly, we think this is a rare case that should be reported. Secondly, what we have done to help this patient may help other doctors to make decisions when they meet any similar cases. PMID- 26977752 TI - [Test Your Knowledge]. PMID- 26977751 TI - Risk factors for central venous catheter-related thrombosis in children: a retrospective analysis. AB - Central venous catheter (CVC) placement is associated with increased risk of thrombosis in the paediatric population, particularly in relation to the type of catheter and the manner of its insertion. Here, we investigate risk factors associated with CVC-related thrombosis in children, with particular emphasis on positioning of the catheter tip. Patients aged 0-18 who underwent at least one CVC placement from 2008 to 2013 at a single centre with a subsequent follow-up echocardiogram were included for a total of 104 patients and 147 lines. Data on clinical and catheter-related risk factors were collected from patient charts. Statistical analysis using Pearson's chi tests, independent samples t-test, and odds ratios were used to assess potential risk factors for thrombosis. Neither insertion site (subclavian vein or otherwise), left- vs. right-sided insertion, nor catheter type were significant risk factors for thrombosis. There were no thrombotic events reported at the superior vena cava (SVC)-right atrium junction and no significant differences in thrombotic risk with initial tip placement in the SVC-right atrium junction vs. the SVC, right atrium, or inferior vena cava. Acute lymphoblastic leukaemia was a major clinical risk factor for thrombosis. Tip movement was common and may have been an important factor in the development of CVC-related thrombi. Prospective studies can yield insight into the role of follow-up imaging in the prevention of catheter-related thrombosis in children. PMID- 26977753 TI - [Case Report with Differential Diagnostic Aspects of Sarcoidosis]. AB - A 73-year-old non-atopic patient had developed at the age of 29 shortness of breath on exertion, general malaise, enlarged axillary lymph nodes and nodular cutaneous eruptions. Based on the presence of bihilar lymphadenopathy, the diagnosis of sarcoidosis was made at that time without any histological investigations and without taking detailed case history. Administration of systemic steroids resulted in remission. However, 12 years later, there was a relapse with alterations of lung parenchyma, followed by a more chronic course of the disorder. Since this relapse, an obstructive-restrictive ventilation defect requiring treatment has persisted till today. About five years ago and at the insistence of the patient, clarifying diagnostics were performed. The case shows the important role of a detailed case history including occupational history. Its failure not only led to disadvantages to the patient but also to incorrect social insurance handling and missing appropriate preventive measures with regard to co workers. PMID- 26977754 TI - Diagnostic Gain from Surgical Biopsy for Interstitial Lung Disease - When is it Worth the Risk? AB - BACKGROUND: History, clinical presentation, lung function testing, radiographs including HRCT and nonsurgical biopsy techniques in most cases provide sufficient information for classification of interstitial lung disease (ILD). However, in a small percentage it is not possible to establish the diagnosis so that lung biopsy may be required. We analyzed under which circumstances a reduction of invasive procedures is reasonable. METHODS: Between January 1997 and December 2009 we examined 3399 specimens from 1299 patients with benign inflammatory and granulomatous diseases in whom ILD was clinically hypothesized. We compared the probability of disease according to Bayes before and after surgery which corresponds to the clinical diagnosis (a priori probability) and the final diagnosis (a posteriori probability). Additionally, procedures, operation related complications and the patients' smoking habits were documented. RESULTS: In 111 patients (8.5 %) surgical evaluation was performed (14 mediastinoscopies, 97 thoracotomies/VATS biopsies). All mediastinoscopies substantiated a epitheloid cell granulomatosis. In 30 % of all VATS procedures a prolonged air leak of more than 4 days was observed. One patient died and one had to get a new chest tube after removal. Changes of a priori/a posteriori probabilities was shown for non smokers in Wegner's granulomatosis (0.6 vs. 2.2 %) and IPF (16.7 vs. 34.8 %), for smokers in Langerhans' cell histiocytosis (1.4 vs. 7.8 %) and IPF (16.7 vs. 33.3 %). In the majority of cases even a reduction of probability was seen. CONCLUSION: Considering complications and limited diagnostic gain, lung biopsies for diagnosis of ILD should be recommended only in selected patients. PMID- 26977755 TI - Non-Alcoholic Fatty Liver Disease in Early Pregnancy Predicts Dysglycemia in Mid Pregnancy: Prospective Study. AB - OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is mediated by insulin resistance, as is gestational diabetes mellitus (GDM). NAFLD has not been studied in relation to GDM. The objective of this study was to assess the association between first-trimester sonographic findings of NAFLD, and both dysglycemia and GDM in mid-pregnancy. METHODS: We followed a prospective cohort design at a large obstetrics clinic in Toronto, Ontario with 476 women enrolled in early pregnancy. NAFLD was assessed by ultrasound at 11-14 weeks gestation, and standardized images were independently scored by two ultrasonographers for the presence of hepatorenal contrast (one finding) and/or blurring of the intrahepatic vessels (one finding), relative to neither being present. Logistic regression analysis was used to generate odds ratios (ORs) and 95% confidence interval (CI) for the relation between 0, 1, or 2 sonographic findings of NAFLD and the composite outcome of impaired fasting glucose, impaired glucose tolerance, or GDM at 24-28 weeks gestation, determined by a fasting 75-g oral glucose tolerance test. ORs were adjusted (aOR) for maternal age, ethnicity, first-degree relative with type 2 DM, body mass index (BMI) at 11-14 weeks gestation, and change in BMI from 11 14 to 24-28 weeks gestation. RESULTS: Fifty out of 476 women (10.5%) developed the composite outcome. The presence of 1 (aOR 2.0, 95% CI: 1.0-4.1) or 2 (aOR 2.9, 95% CI: 1.0-18.4) sonographic features of NAFLD predicted the composite outcome. Limiting the analysis to >=1 feature vs. none, the aOR was 2.2 (95% CI: 1.1-4.3). CONCLUSIONS: Sonographic assessment of NAFLD is a semiquantitative measure, with limited ability to detect small amounts of hepatic steatosis, or to distinguish various stages of NAFLD. First-trimester sonographic evidence of NAFLD predicts dysglycemia in mid-pregnancy. PMID- 26977756 TI - Histology Grade Is Independently Associated With Relapse Risk in Patients With Ulcerative Colitis in Clinical Remission: A Prospective Study. AB - OBJECTIVES: Objective evidence of inflammation has been associated with the risk of relapse in patients with ulcerative colitis (UC) who are in clinical remission. We compared endoscopic and histologic grades for their ability to predict clinical relapse in this patient population. METHODS: Patients with UC in clinical remission were prospectively enrolled into an observational cohort. Baseline endoscopic scores (Mayo) and histological (Geboes) grades and blood markers were collected. All subjects were followed for 12 months and relapse determined using clinical indices. RESULTS: A total of 179 subjects were enrolled into the study and followed for 12 months. Clinical relapse occurred in 23%; 5% were hospitalized, and 2% underwent colectomy. In univariate analysis, the baseline Mayo endoscopy score and the Geboes histology grade were significantly associated with the later development of clinical relapse (P<0.001 for both), but only the histology grade remained significant in a multivariate model (P=0.006). The relative risk of clinical relapse was 3.5 (95% CI 1.9-6.4, P<0.0001) in subjects whose baseline Geboes grade was >=3.1. The area under the curve was 0.73 for the Geboes histology grade to identify subjects at risk of future clinical relapse. Of the patients in clinical, endoscopic, and histological remission at baseline (n=82), only 7% had a clinical relapse over the subsequent 12 months. CONCLUSIONS: Histology grade has the strongest association with the risk of clinical relapse in patients with UC who are in clinical remission. Consideration should be given to including this end point in evaluating therapy for UC. PMID- 26977758 TI - The Performance of Vibration Controlled Transient Elastography in a US Cohort of Patients With Nonalcoholic Fatty Liver Disease. AB - OBJECTIVES: Identification of patients with nonalcoholic fatty liver disease (NAFLD) who have advanced fibrosis is crucial. Vibration controlled transient elastography (VCTE) is an alternative to biopsy, although published experience with VCTE in a US population is limited. METHODS: We performed a prospective cohort of 164 biopsy-proven NAFLD patients evaluated with VCTE using an M probe and the NAFLD fibrosis score (NFS) at baseline and a repeat VCTE at 6 months. Reliable liver stiffness measurements (LSMs) were defined as 10 valid measurements and interquartile range <=30% of the median. RESULTS: A total of 120 (73.2%) patients had reliable LSM. The median LSMs for patients with and without F3-F4 (advanced) fibrosis were 6.6 kPA (5.3-8.9) and 14.4 kPA (12.1-24.3), respectively. The optimal LSM cutoff for advanced fibrosis was 9.9 kPA (sensitivity 95% and specificity 77%). In addition, 100% of patients with LSM<7.9 kPA did not have advanced fibrosis. A risk stratification strategy based on VCTE avoids the need for biopsy in at least the 74 (45.1%) patients correctly classified as low risk for advanced fibrosis. For the detection of F3-F4 fibrosis in patients with reliable VCTE, the area under the receiver operating curve (AUROC) is 0.93 (95% CI: 0.86-0.96). This is superior to the AUROC for the NFS (0.77), P=0.01. Patients who achieved a >=5% weight loss at 6-month follow-up experienced improved LSM (P=0.009), independent of the changes in aminotransferase levels. CONCLUSIONS: Reliable VCTE results can rule out advanced fibrosis and avoid the need for biopsy in at least 45% of US patients with NAFLD. However, 1 in 4 patients have uninterpretable studies using the M probe. PMID- 26977757 TI - Risk of Colorectal Neoplasia in Individuals With Self-Reported Family History: A Prospective Colonoscopy Study from 16 Asia-Pacific Regions. AB - OBJECTIVES: We tested the hypothesis that the risk of colorectal cancer (CRC), advanced colorectal neoplasia (ACN), and colorectal adenoma among screening participants with different first-degree relatives (FDRs) affected by CRC was similar. METHODS: A multi-center, prospective colonoscopy study involving 16 Asia Pacific regions was performed from 2008 to 2015. Consecutive self-referred CRC screening participants aged 40-70 years were recruited, and each subject received one direct optical colonoscopy. The prevalence of CRC, ACN, and colorectal adenoma was compared among subjects with different FDRs affected using Pearson's chi2 tests. Binary logistic regression analyses were performed to evaluate the risk of these lesions, controlling for recognized risk factors including age, gender, smoking habits, alcohol drinking, body mass index, and the presence of diabetes mellitus. RESULTS: Among 11,797 asymptomatic subjects, the prevalence of CRC was 0.6% (none: 0.6%; siblings: 1.1%; mother: 0.5%; father: 1.2%; >=2 members: 3.1%, P<0.001), that of ACN was 6.5% (none: 6.1%; siblings: 8.3%; mother: 7.7%; father: 8.7%; >=2 members: 9.3%, P<0.001), and that of colorectal adenoma was 29.3% (none: 28.6%; siblings: 33.5%; mother: 31.8%; father: 31.1%; >=2 members: 38.1%, P<0.001). In multivariate regression analyses, subjects with at least one FDR affected were significantly more likely to have CRC (adjusted odds ratio (AOR)=2.02-7.89), ACN (AOR=1.55-2.06), and colorectal adenoma (AOR=1.31-1.92) than those without a family history. The risk of CRC (AOR=0.90, 95% confidence interval (CI) 0.34-2.35, P=0.830), ACN (AOR=1.07, 95% CI 0.75 1.52, P=0.714), and colorectal adenoma (AOR=0.96, 95% CI 0.78-1.19, P=0.718) in subjects with either parent affected was similar to that of subjects with their siblings affected. CONCLUSIONS: The risk of colorectal neoplasia was similar among subjects with different FDRs affected. These findings do not support the need to discriminate proband identity in screening participants with affected FDRs when their risks of colorectal neoplasia were estimated. PMID- 26977762 TI - [Anesthetic management of reconstructive surgery on the respiratory tract]. AB - In the article provides an analysis of own of clinical experience peculiarities of carrying out of anesthesia, when performing 466 various tracheo-bronhoplastis of operations for the period from 1979 to 2014 the year a one team of surgeons. Preoperative preparation, anesthesia and postoperative management of patients are key to improving treatment outcomes. Full arsenal of modern methods of ventilation lets you choose for each stage of surgery is most convenient for the surgeon and patient-safe way to maintain gas exchange. Presented in this paper our anestiology experience allows you to discuss and elect the proposed management of patients through the selection and optimization of the method that best meets modern requirements. PMID- 26977761 TI - Boosting water oxidation layer-by-layer. AB - Electrocatalysis of water oxidation was achieved using fluorinated tin oxide (FTO) electrodes modified with layer-by-layer deposited films consisting of bilayers of negatively charged citrate-stabilized IrO2 NPs and positively charged poly(diallyldimethylammonium chloride) (PDDA) polymer. The IrO2 NP surface coverage can be fine-tuned by controlling the number of bilayers. The IrO2 NP films were amorphous, with the NPs therein being well-dispersed and retaining their as-synthesized shape and sizes. UV/vis spectroscopic and spectro electrochemical studies confirmed that the total surface coverage and electrochemically addressable surface coverage of IrO2 NPs increased linearly with the number of bilayers up to 10 bilayers. The voltammetry of the modified electrode was that of hydrous iridium oxide films (HIROFs) with an observed super Nernstian pH response of the Ir(III)/Ir(IV) and Ir(IV)-Ir(IV)/Ir(IV)-Ir(V) redox transitions and Nernstian shift of the oxygen evolution onset potential. The overpotential of the oxygen evolution reaction (OER) was essentially pH independent, varying only from 0.22 V to 0.28 V (at a current density of 0.1 mA cm(-2)), moving from acidic to alkaline conditions. Bulk electrolysis experiments revealed that the IrO2/PDDA films were stable and adherent under acidic and neutral conditions but degraded in alkaline solutions. Oxygen was evolved with Faradaic efficiencies approaching 100% under acidic (pH 1) and neutral (pH 7) conditions, and 88% in alkaline solutions (pH 13). This layer-by-layer approach forms the basis of future large-scale OER electrode development using ink-jet printing technology. PMID- 26977759 TI - Effect of Vagus Nerve Integrity on Short and Long-Term Efficacy of Antireflux Surgery. AB - OBJECTIVES: Vagus nerve injury is a feared complication of antireflux surgery (ARS) that may negatively affect reflux control. The aim of the present prospective study was to evaluate short-term and long-term impact of vagus nerve injury, evaluated by pancreatic polypeptide response to insulin-induced hypoglycemia (PP-IH), on the outcome of ARS. METHODS: In the period from 1990 until 2000, 125 patients with gastroesophageal reflux disease (GERD) underwent ARS at a single center. Before and 6 months after surgery, vagus nerve integrity testing (PP-IH), 24-h pH-monitoring, gastric emptying, and reflux-associated symptoms were evaluated. In 2014, 14-25 years after surgery, 110 patients were contacted again for evaluation of long-term symptomatic outcome using two validated questionnaires (Gastrointestinal Symptom Rating Scale (GSRS) and GERD Health Related Quality of Life (HRQL)). RESULTS: Short-term follow-up: vagus nerve injury (PP peak <=47 pmol/l) was observed in 23 patients (18%) 6 months after fundoplication. In both groups, a comparable decrease in reflux parameters and symptoms was observed at 6-month follow-up. Postoperative gastric emptying was significantly delayed in the vagus nerve injury group compared with the vagus nerve intact group. Long-term follow-up: patients with vagus nerve injury showed significantly less effective reflux control and a higher re-operation rate. CONCLUSIONS: Vagus nerve injury occurs in up to 20% of patients after ARS. Reflux control 6 months after surgery was not affected by vagus nerve injury. However, long-term follow-up showed a negative effect on reflux symptom control and re operation rate in patients with vagus nerve injury. PMID- 26977763 TI - [Video-assisted thoracoscopic anatomic lung resection: experience of 246 operations]. AB - AIM: To present one of the largest materials of video-assisted thoracoscopic (VATS) anatomic lung resections in Russia. MATERIAL AND METHODS: It is a retrospective analysis of treatment of 246 patients who underwent VATS anatomic lung resection for the period from 2010 to 2014 at the Center for Thoracic Surgery of St. Petersburg Clinical Hospital No122. One surgical team has operated 125 men and 121 women aged from 20 to 85 years (58.8+/-13.4 years). There were 216 (87.8%) lobectomies, 4 (1.6%) bilobectomies, 9 (3.7%) pneumonectomies, 10 (4.1%) segmentectomies and 7 (2.8%) trisegmentectomies. Upper right-side lobectomy was the most frequent in this group (87 (40.3%)). Most of operations was performed via 2 approaches (119 patients). Average length of the longest incision was 4.3+/-0.93 cm (range 2-6 cm). All patients were examined according to a single plan. FEV1 less than 70% was observed in 26% of patients; comorbidity index was 5 scores or more in 24% of cases; 23.2% of patients were older than 70 years. RESULTS: Non-small cell lung cancer (NSCLC) was diagnosed in 168 patients (68.3%), pulmonary tuberculosis - in 27 (11%), chronic suppurative lung disease - in 27 (11%) cases. Furthermore there were 9 cases of pulmonary metastases, 11 cases of carcinoid, 1 - MALT-lymphoma, 1 - leiomyoma, 2 - small cell lung cancer, as well as one case of IgG-associated pseudotumor. Among 168 cases of NSCLC operations were performed in 87 (51.8%) cases for cancer stage I, in 46 (27.3%) patients for stage II, in 27 patients for stage III (including 16 cases of stage IIIA and 11 cases of stage IIIB). 8 patients (4.7%) with lung cancer stage IV have been operated in radical surgery for solitary metastasis. Mean duration of surgery was 202.1+/-58.2 minutes (range 100-380). On the average 12.8+/-5.6 (range 9-32) mediastinal lymph nodes were excised during lymph node dissection in cancer patients. Mean number of nodes groups was 4.1+/-1.1. In 11 (4.5%) patients conversion to open surgery was made due to intraoperative bleeding (3 cases) and technical difficulties (8 cases). Mean duration of postoperative pleural drainage and hospital-stay were 5.1+/-4.3 (median - 3 days) and 7.9+/-4.7 days (median - 6 days) respectively. Complications which were not associated with perioperative deaths were observed in 66 patients (26.8%). Prolonged air vent was the most common complication. CONCLUSION: VATS anatomical lung resections are safe and effective in most of pulmonary surgical diseases. Such interventions may be recommended for wider introduction at the Thoracic Departments of Russia because of small number of complications and rapid rehabilitation. Bleeding or its risk associated with fibrotic changes in pulmonary root are the most frequent causes of conversion to open access. PMID- 26977764 TI - [Surgical interventions with tracheal bifurcation circular resection in bronchial cancer treatment]. AB - AIM: To evaluate results of circular resection and carina reconstruction in patients with bronchial cancer. MATERIAL AND METHODS: Study included 82 patients with bronchial malignant tumors operated for the period from 1998 to 2014. Mean age was 56+/-1.1 years (range 24-75). There were 75 men and 7 women. Squamous cell carcinoma, adenocarcinoma, dimorphic cancer, carcinoid, adenocystic cancer, small cell cancer and clear cell renal cancer were observed in 66, 9, 1, 3, 1, 1 and 1 patients respectively. Stages IIB, IIIA, IIIB and IV were determined in 5 (6.2%), 45 (56.3%), 28 (35%) and 2 (2.5%) patients respectively. Tracheal carina resection was combined with right-sided pneumonectomy in 62 (75.6%) patients, left-sided pneumonectomy - in 5 (6.1%) cases, right upper lobectomy - in 10 (12.2%) cases. 3 patients underwent carina resection alone. Plasty with bronchopulmonary segment of right upper lobe was applied in 2 cases. Since 2002 primary bronhomyoplasty using m.latiss.dorsi, m.intercostalis and m.serr.anterior flaps has been used in 64 patients. RESULTS: Postoperative complications occurred in 31.7% (26) of patients. In-hospital mortality was 10.1%. Use of primary bronhomyoplasty and head adduction reduced broncho-pleural fistula incidence and mortality (p<0.05). Long-term results in T3-T4N0 tumors were significantly better compared with T3-4N1-2 tumors (5-year survival 41.2 vs. 16.8%, p<0,05). CONCLUSION: Results of resection with carina reconstruction may be improved using primary bronhomyoplasty and is associated with satisfactory long-term results in patients with N0-tumors. PMID- 26977760 TI - Magnetic Resonance Elastography for the Evaluation of Liver Fibrosis in Chronic Hepatitis B and C by Using Both Gradient-Recalled Echo and Spin-Echo Echo Planar Imaging: A Prospective Study. AB - OBJECTIVES: Magnetic resonance elastography (MRE) with three-dimensional spin echo echo planar imaging (3D-SE-EPI) is a newly emerging noninvasive method for assessing liver fibrosis. We hypothesized that 3D-SE-EPI might have better diagnostic accuracy than conventional two-dimensional gradient-recalled echo (2D GRE). METHODS: We prospectively included 179 consecutive patients with chronic hepatitis B (CHB) or C (CHC) who underwent both MRE and liver biopsy. Liver stiffness was measured by both 3D-SE-EPI and 2D-GRE for staging biopsy-proven liver fibrosis (using METAVIR scores). A receiver-operating characteristic analysis using the area under the receiver-operating characteristic curve (AUC) was used to compare the diagnostic performance in predicting liver fibrosis between these two techniques, and compared them to serum markers of fibrosis. RESULTS: The technical failure rate of 3D-SE-EPI (2.2%, n=4/179) was lower compared with 2D-GRE (8.3%, n=15/179). The stiffness measured by 3D-SE-EPI was slightly lower compared with 2D-GRE, with the mean difference of 0.57 kPa (Bland and Altman plot, 95% limits of agreement: -0.32 and 1.45 kPa). AUCs for the characterization of >=F1, >=F2, >=F3, and F4 were 0.957 (95% confidence interval (CI): 0.913-0.983), 0.971 (0.932-0.991), 0.991 (0.961-0.999), and 0.979 (0.942 0.995) for 3D-SE-EPI, which was slightly higher compared with the AUCs for 2D-GRE at each fibrosis stage (0.948 (0.901-0.977), 0.959 (0.915-0.981), 0.979 (0.943 0.995), and 0.976 (0.938-0.994), respectively), although none reached statistical significance (P=0.160-0.585). In an "intention-to-diagnose" analysis, the diagnostic accuracy (the proportion of well-classified patients) by EPI (86.7 91.3%, n=169) was higher compared with GRE (80.9-82.1%, n=158) after applying optimal cutoffs. Both 3D-SE-EPI and 2D-GRE performed better than serum fibrosis markers. CONCLUSIONS: With respect to 2D-GRE, 3D-SE-EPI has the advantage of lower failure rate with equivalent high diagnostic performance for staging liver fibrosis in CHB/CHC patients, and thus more helpful for those challenging cases in 2D-GRE. PMID- 26977765 TI - [Analysis of postoperative complications after pneumo-n-ectomy using thoracic morbidity and mortality (tmm) system in nsclc patients for a 5-year period]. AB - AIM: Postoperative complications after pneumonectomy for NSCLC depend on the extension of surgery, comorbidities and accurate registration of any adverse event. The aim of the study was to evaluate the short-term results after standard and extended pneumonectomy in NSCLC patients according to the TMM grading system. MATERIAL AND METHODS: We included 216 NSCLC patients consecutively submitted to pneumonectomy at our institution from January 2009 to December 2013 in the retrospective study performed on data prospectively collected in an electronic clinical database. All patients were divided into two different groups: standard (n=142) and extended (n=74) pneumonectomy, where resection of adjacent organs was indicated. The patients undergone extended pneumonectomy were subdivided into single (n=49) and multi-organ resection (n=25) groups. Morbidity and mortality rate was analyzed according to the standard criteria and TMM classification system. RESULTS: Postoperative morbidity and mortality rate after standard pneumonectomy (23,9% and 3,5%) was significantly lower than extended procedure (43,2% and 10,8%) (p=0.02). Multi-organ resection was an independent prognostic factor of unfavourable outcome: morbidity and mortality was significantly higher in the multi-organ group (48,0% and 16,0%), while in the single-organ group it was 40,8% and 8,2% respectively (p=0.01). Major complications rate (grade IIIA and higher according to the TMM) was significantly higher in the multi-organ group (40,0%) than in the single-organ (28,6%) and standard (14,8%) group (p=0.01). CONCLUSION: TMM classification system is more accurate in grading and further analysis of postoperative complications after pneumonectomy in NSCLC patients in compare with standard criteria. Multi-organ resection should be carried out with caution due to unacceptable high morbidity and mortality rate. PMID- 26977766 TI - [Staged surgical treatment of subtotal tracheal cicatrical stenosis as an alternative to transplantation]. PMID- 26977768 TI - Five-year mortality in cardiac surgery patients with low cardiac output syndrome treated with levosimendan: prognostic evaluation of NT-proBNP and C-reactive protein. AB - BACKGROUND: To determine the clinical risk factors predictive of the 5-year mortality in patients with low cardiac output syndrome (LCOS) after cardiac surgery. In addition, to assess the influence of inflammation and myocardial dysfunction severity, as measured by C-reactive protein (CRP) and N-terminal pro brain natriuretic peptide (NT-proBNP) concentrations, on outcome. METHODS: We studied 30 patients who underwent cardiac surgery and developed postoperative LCOS requiring inotropic support for longer than 48 hours after intensive care unit (ICU) admission. All patients received a 24-hour infusion of levosimendan after study enrolment. We measured the following at baseline, 24 h, 48 h and 7 days: clinical data, serum NT-proBNP and serum CRP levels. Patients were followed up at 5 years for death by any cause. A risk-adjusted Cox proportional hazards regression model was used for statistical analysis. Hazard ratios and their 95% confidence intervals (CI) are presented. RESULTS: The 5-year mortality was 36.6% (n.=11). The predictors of 5-year mortality were the presence of dilated cardiomyopathy (HR=36.909; 95% CI: 1.901-716.747; P=0.017), a higher central venous pressure (CVP) at 48 hours (HR=2.686; 95% CI: 1.383-5.214; P=0.004), and lower CRP levels on day 7 (HR=0.963; 95% CI: 0.933-0.994; P=0.021). NT-proBNP levels showed a trend to higher initial levels in survivors without statistical significance, but were not associated with 5-year mortality. CONCLUSIONS: The presence of dilated cardiomyopathy, elevated CVP at 48 h and reduced CRP levels on day 7 predicted 5-year mortality in patients who developed postoperative LCOS after cardiac surgery. NT-proBNP levels in the first postoperative week were not predictors of long-term outcomes. PMID- 26977767 TI - Ring finger protein 10 is a novel synaptonuclear messenger encoding activation of NMDA receptors in hippocampus. AB - Synapses and nuclei are connected by bidirectional communication mechanisms that enable information transfer encoded by macromolecules. Here, we identified RNF10 as a novel synaptonuclear protein messenger. RNF10 is activated by calcium signals at the postsynaptic compartment and elicits discrete changes at the transcriptional level. RNF10 is enriched at the excitatory synapse where it associates with the GluN2A subunit of NMDA receptors (NMDARs). Activation of synaptic GluN2A-containing NMDARs and induction of long term potentiation (LTP) lead to the translocation of RNF10 from dendritic segments and dendritic spines to the nucleus. In particular, we provide evidence for importin-dependent long distance transport from synapto-dendritic compartments to the nucleus. Notably, RNF10 silencing prevents the maintenance of LTP as well as LTP-dependent structural modifications of dendritic spines. PMID- 26977771 TI - Expression Depression of CD300LG-gamma in Human Pulmonary Carcinoma. AB - The expression of CD300LG-gamma at mRNA and protein level was detected by semiquantitative reverse transcription-polymerase chain reaction (PCR), quantitative real-time PCR, and western blot, and compared by t-test analysis. The results of semiquantitative reverse transcription-PCR showed that the mRNA expression of CD300LG-gamma was significantly lower in pulmonary carcinoma tissues, compared to tumor-adjacent tissues. The results of quantitative real time PCR confirmed this finding. The mRNA level of CD300LG-gamma in pulmonary carcinoma tissues compared with tumor-adjacent tissues was 0.436-fold in a median. The results of western blot indicated that CD300LG-gamma protein was expressed in both pulmonary carcinoma and tumor-adjacent tissues, and the expression level was significantly lower in pulmonary carcinoma tissues compared with tumor-adjacent tissues. Both mRNA and protein levels of CD300LG-gamma in pulmonary carcinoma tissues were significantly lower than that in tumor-adjacent tissues, which might lead to inhibition of killing function of immunocytes, resulting in immune escape of lung cancer cells. PMID- 26977772 TI - A Significant but Constrained Geometry Pt->Al Interaction: Fixation of CO2 and CS2, Activation of H2 and PhCONH2. AB - Reaction of the geminal PAl ligand [Mes2PC(?CHPh)AltBu2] (1) with [Pt(PPh3)2(ethylene)] affords the T-shape Pt complex [(1)Pt(PPh3)] (2). X-ray diffraction analysis and DFT calculations reveal the presence of a significant Pt >Al interaction in 2, despite the strain associated with the four-membered cyclic structure. The Pt...Al distance is short [2.561(1) A], the Al center is in a pyramidal environment [Sigma(C-Al-C) = 346.6 degrees ], and the PCAl framework is strongly bent (98.3 degrees ). Release of the ring strain and formation of X->Al interactions (X = O, S, H) impart rich reactivity. Complex 2 reacts with CO2 to give the T-shape adduct 3 stabilized by an O->Al interaction, which is a rare example of a CO2 adduct of a group 10 metal and actually the first with eta(1) CO2 coordination. Reaction of 2 with CS2 affords the crystalline complex 4, in which the PPtP framework is bent, the CS2 molecule is eta(2)-coordinated to Pt, and one S atom interacts with Al. The Pt complex 2 also smoothly reacts with H2 and benzamide PhCONH2 via oxidative addition of H-H and H-N bonds, respectively. The ensuing complexes 5 and 7 are stabilized by Pt-H->Al and Pt-NH-C(Ph) = O->Al bridging interactions, resulting in 5- and 7-membered metallacycles, respectively. DFT calculations have been performed in parallel with the experimental work. In particular, the mechanism of reaction of 2 with H2 has been thoroughly analyzed, and the role of the Lewis acid moiety has been delineated. These results generalize the concept of constrained geometry TM->LA interactions and demonstrate the ability of Al-based ambiphilic ligands to participate in TM/LA cooperative reactivity. They extend the scope of small molecule substrates prone to such cooperative activation and contribute to improve our knowledge of the underlying factors. PMID- 26977774 TI - Synthesis of 1-Aryltetralins and 1-Arylnaphthalenes via (4 + 2) Annulation of beta-Ketosulfones with Styryl Bromides. AB - A novel route has been developed for the synthesis of various substituted 1 aryltetralins 6 and 1-arylnaphthalenes 8 via (1) K2CO3-mediated alpha-styrylation of beta-ketosulfones 3 with bromostyryl bromides 4 and (2) stereocontrolled NaBH4 promoted reduction of the resulting gamma-alkenones 5, followed by BF3.OEt2 catalyzed intramolecular annulation of the corresponding gamma-alkenols 7 under rt/5 h and reflux/10 h conditions, respectively. The key structures of 6 and 8 were confirmed by X-ray crystallographic analysis. A plausible mechanism has been proposed. PMID- 26977773 TI - Efficient and Selective Enrichment of Ultratrace Cytokinins in Plant Samples by Magnetic Perhydroxy-Cucurbit[8]uril Microspheres. AB - Cytokinins play a critical role in controlling plant growth and development, but it is difficult to be determined in plant samples due to the extremely low concentration level of picomole/gram. So it is important for efficient sample preparation with selective enrichment and rapid separation for accurate analysis of cytokinins. Herein, a supramolecular perhydroxy-cucurbit[8]uril (PCB[8]) was fabricated into the Fe3O4 magnetic particles via chemical bonding assembly and magnetic perhydroxy-cucurbit[8]uril (MPC) materials were obtained. The MPC had good enrichment capability to cytokinins and the enrichment factors were more than 208. The interaction of MPC and cytokinins was investigated by adsorption test and density functional theory (DFT) calculation, the results showed that the main drive forces were the host-guest interaction and hydrogen-bonding interaction between the perhydroxy-cucurbit[8]uril with analytes. Combined with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), the MPC was used as a sorbent of magnetic solid-phase extraction for the analysis of cytokinins in plant samples. A sensitive and selective UPLC-MS/MS method was developed with low detection limits of 0.14-0.32 ng/L for cytokinins analysis. Five cytokinins including zeatin riboside, meta-topolin, kinetin, kinetin riboside, and zip with 6.12-87.3 ng/kg were determined in the soybean sprout and Arabidopsis thaliana. The recoveries were in the range of 76.2-110% with relative standard deviations (n = 5) of 2.3-9.7%. On the basis of these results, magnetic perhydroxy-cucurbit[8]uril materials with selective enrichment capability have good potential on the analysis of ultratrace targets from complicated sample matrixes. PMID- 26977775 TI - Liquid-Infused Surfaces with Trapped Air (LISTA) for Drag Force Reduction. AB - Superhydrophobic (SHP) surfaces are known for their drag-reducing attributes thanks to their ability to trap air in their surface pores and thereby reduce the contact between water and the frictional solid area. SHP surfaces are prone to failure under elevated pressures or because of air-layer dissolution into the surrounding water. Slippery liquid-infused porous surfaces (SLIPS) or liquid infused surfaces (LIS) in which the trapped air is replaced with a lubricant have been proposed in the literature as a way of eliminating the air dissolution problem as well as improving the surface stability under pressure. While an LIS surface has been shown to reduce drag for flow of water-glycerol mixture (ref 18), no significant drag reduction has yet been reported for the flow of water (a lower viscosity fluid) over LIS. In this concern, we have designed a new surface in which a layer of air is trapped underneath the infused lubricant to reduce the frictional forces preventing the LIS to provide drag reduction for water or any fluid with a viscosity less than that of the lubricant. Drag reduction performance of such surfaces, referred to here as liquid-infused surfaces with trapped air (LISTA), is predicted by solving the biharmonic equation for the water-oil-air three-phase system in transverse grooves with enhanced meniscus stability thanks to double-reentry designs. For the arbitrary dimensions considered in our proof-of-concept study, LISTA designs showed 20-37% advantage over their LIS counterparts. PMID- 26977770 TI - A Jacob/Nsmf Gene Knockout Results in Hippocampal Dysplasia and Impaired BDNF Signaling in Dendritogenesis. AB - Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor cAMP-response-element binding protein (CREB). Several reports indicate that mutations in NSMF are related to Kallmann syndrome (KS), a neurodevelopmental disorder characterized by idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia or hyposmia. It has also been reported that a protein knockdown results in migration deficits of Gonadotropin-releasing hormone (GnRH) positive neurons from the olfactory bulb to the hypothalamus during early neuronal development. Here we show that mice that are constitutively deficient for the Nsmf gene do not present phenotypic characteristics related to KS. Instead, these mice exhibit hippocampal dysplasia with a reduced number of synapses and simplification of dendrites, reduced hippocampal long-term potentiation (LTP) at CA1 synapses and deficits in hippocampus-dependent learning. Brain-derived neurotrophic factor (BDNF) activation of CREB-activated gene expression plays a documented role in hippocampal CA1 synapse and dendrite formation. We found that BDNF induces the nuclear translocation of Jacob in an NMDAR-dependent manner in early development, which results in increased phosphorylation of CREB and enhanced CREB-dependent Bdnf gene transcription. Nsmf knockout (ko) mice show reduced hippocampal Bdnf mRNA and protein levels as well as reduced pCREB levels during dendritogenesis. Moreover, BDNF application can rescue the morphological deficits in hippocampal pyramidal neurons devoid of Jacob. Taken together, the data suggest that the absence of Jacob in early development interrupts a positive feedback loop between BDNF signaling, subsequent nuclear import of Jacob, activation of CREB and enhanced Bdnf gene transcription, ultimately leading to hippocampal dysplasia. PMID- 26977776 TI - Addition to "Achieving Reversible Sensing of Nitroxyl by Tuning the Ligand Environment of Azamacrocyclic Copper(II) Complexes". PMID- 26977777 TI - Competing Interactions between Various Entropic Forces toward Assembly of Pt3Ni Octahedra into a Body-Centered Cubic Superlattice. AB - Anisotropic nanocrystal assembled supercrystals with open superlattices (SLs) manifest novel and unique properties, but poor understanding of the nucleation/growth mechanisms limits their design and fabrication for practical applications. Using highly anisotropic Pt3Ni octahedral nanocrystals, we have grown large single supercrystals with an open body-centered cubic (bcc) superlattice that has a low filling factor of 26.8%. Synchrotron-based X-ray structural reconstruction fully revealed the coherence of translational and orientational orderings and determined that the constituent octahedra arrange themselves with the vertex-to-vertex and face-to-face configurations along the SL[100] and SL[111] directions, respectively. The large face-to-face separation and flexible vertex-to-vertex elastic contact provided the rattle space and supporting axis for local rotations of Pt3Ni octahedra within the bcc superlattice. Development of orientational disordering along with robust preservation of translational ordering during the heating process of a supercrystal in the oleic acid wetting environment confirmed the dominance of rotational entropy of hard octahedra in the formation of the open bcc superlattice. Ultimate achievement of dynamic equilibrium between the vertex oriented elastic repulsions and the face-oriented attractions of surface-coating ligands governs the structural and mechanical stability of the supercrystal. This discovery provides significant insights into the design and control of geometrical shapes for the fabrication of highly anisotropic nanocrystals into desired open superlattices with tailored optical and electronic properties. PMID- 26977778 TI - Electron Spectroscopy and Computational Studies of Dimethyl Methylphosphonate. AB - Dimethyl methylphosphonate (DMMP) is one of the most widely used molecules to simulate chemical warfare agents in adsorption experiments. However, the details of the electronic structure of the isolated molecule have not yet been reported. We have directly probed the occupied valence and core levels using gas phase photoelectron spectroscopy and the unoccupied states using near-edge X-ray absorption fine structure (NEXAFS) spectroscopy. Density functional theory (DFT) calculations were used to study the electronic structure, assign the spectral features, and visualize the molecular orbitals. Comparison with parent molecules shows that valence and core-level binding energies of DMMP follow trends of functional group substitution on the P center. The photoelectron and NEXAFS spectra of the isolated molecule will serve as a reference in studies of DMMP adsorbed on surfaces. PMID- 26977779 TI - Prediction of Loops in G Protein-Coupled Receptor Homology Models: Effect of Imprecise Surroundings and Constraints. AB - In the present study, we explored the extent to which inaccuracies inherent in homology models of the transmembrane helical cores of G protein-coupled receptors (GPCRs) can impact loop prediction. We demonstrate that loop prediction in homology models is much more difficult than loop reconstruction in crystal structures because of the imprecise positioning of loop anchors. Deriving information from 17 recently available GPCR crystal structures, we estimated all of the possible errors that could occur in loop anchors as the result of comparative modeling. Subsequently, we performed an exhaustive analysis to decipher the effect of these errors on loop modeling using ICM High Precision Sampling. The influence of the presence of other extracellular loops was also explored. Our results reveal that the error space of modeled loop residues is much larger than that of the anchor residues, although modeling a particular extracellular loop in the presence of other extracellular loops provides constraints that help in predicting near-native loop conformations observed in crystal structures. This implies that errors in loop anchor positions introduce increased uncertainty in the modeled loop coordinates. Therefore, for the success of any GPCR structure prediction algorithm, minimizing errors in the helical end points is likely to be critical for successful loop modeling. PMID- 26977781 TI - Immunotherapy: Antitumour T cells as peripheral biomarkers. PMID- 26977783 TI - Immunotherapy: PD-1 says goodbye, TIM-3 says hello. PMID- 26977785 TI - Pancreatic cancer: A problem quartered--new subtypes, new solutions? PMID- 26977787 TI - Amorphous Formulation and in Vitro Performance Testing of Instantly Disintegrating Buccal Tablets for the Emergency Delivery of Naloxone. AB - The aim of this study was to develop a freeze-dried buccal tablet for the rapid delivery of naloxone in opioid overdose. The tablet composition was optimized to produce an amorphous matrix, which was confirmed by the absence of peaks associated with crystallinity observed by differential scanning calorimetry and powder X-ray diffraction. Tablets with high gelatin content lacked adequate porosity. Mannitol was added to the formulation to bridge and intercalate gelatin's tight polymer aggregates, however sodium bicarbonate was also required to prevent crystallization within the tablets. A linear reduction in mannitol's recrystallization enthalpy was observed with increasing sodium bicarbonate concentration (DeltarecryH = -20.3[NaHCO3] + 220.9; r(2) = 0.9, n = 18). The minimum sodium bicarbonate concentration for full inhibition of mannitol crystallization was 10.9% w/w. Freeze-dried tablets with lower amounts of sodium bicarbonate possessed a crystalline fraction that PXRD identified as mannitol hemihydrate from the unique peak at 9.7 degrees 2theta. Mannitol's greater affinity for both ions and residual water rather than its affinity for self association was the mechanism for the inhibition of crystallization observed here. The optimized tablet (composition mannitol 24% w/w (4.26 mg), gelatin 65% w/w (11.7 mg), sodium bicarbonate 11% w/w (1.98 mg), and naloxone 800 MUg) formed predominantly amorphous tablets that disintegrated in less than 10 s. Optimized tablets were chemically and physically stable over 9 months storage at 25 degrees C. As speed of drug liberation is the critical performance attribute for a solid dosage form designed to deliver drug in an emergency, a novel imaging based in vitro disintegration assay for buccal tablets was developed. The assay was optimized with regard to conditions in the buccal cavity: i.e., temperature 33-37 degrees C, volume of medium (0.1-0.7 mL), and use of mucin-containing biorelevant medium. The disintegration assay was sensitive to temperature, medium volume, and medium composition; naloxone tablet disintegration was extremely rapid, with full disintegration ranging from 5 to 20 s. In conclusion, rapidly disintegrating tablets have been developed which are suitable for proof-of concept clinical trial in humans to determine the pharmacokinetics of naloxone delivered via the buccal route. PMID- 26977788 TI - Theoretical and Synthetic Study on the Existence, Structures, and Bonding of the Halide-Bridged [B2X7](-) (X = F, Cl, Br, I) Anions. AB - While hydrogen bridging is very common in boron chemistry, halogen bridging is rather rare. The simplest halogen-bridged boron compounds are the [B2X7](-) anions (X = F, Cl, Br, I), of which only [B2F7](-) has been reported to exist experimentally. In this paper a detailed theoretical and synthetic study on the [B2X7](-) anions is presented. The structures of [B2X7](-) anions have been calculated at the MP2/def2-TZVPP level of theory, and their local minima have been shown to be of C2 symmetry in all cases. The bonding situation varies significantly between the different anions. While in [B2F7](-) the bonding is mainly governed by electrostatics, the charge is almost equally distributed over all atoms in [B2I7](-) and additional weak iodine...iodine interactions are observed. This was shown by an atoms in molecules (AIM) analysis. The thermodynamic stability of the [B2X7](-) anions was estimated in all phases (gas, solution, and solid state) based on quantum-chemical calculations and estimations of the lattice enthalpies using a volume-based approach. In the gas phase the formation of [B2X7](-) anions from [BX4](-) and BX3 is favored in accord with the high Lewis acidity of the BX3 molecules. In solution and in the solid state only [B2F7](-) is stable against dissociation. The other three anions are borderline cases, which might be detectable under favorable conditions. However, experimental attempts to identify [B2X7](-) (X = Cl, Br, I) anions in solution by (11)B NMR spectroscopy and to prepare stable [PNP][B2X7] salts failed. PMID- 26977780 TI - The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. AB - In the past decade, advances in the use of monoclonal antibodies (mAbs) and adoptive cellular therapy to treat cancer by modulating the immune response have led to unprecedented responses in patients with advanced-stage tumours that would otherwise have been fatal. To date, three immune-checkpoint-blocking mAbs have been approved in the USA for the treatment of patients with several types of cancer, and more patients will benefit from immunomodulatory mAb therapy in the months and years ahead. Concurrently, the adoptive transfer of genetically modified lymphocytes to treat patients with haematological malignancies has yielded dramatic results, and we anticipate that this approach will rapidly become the standard of care for an increasing number of patients. In this Review, we highlight the latest advances in immunotherapy and discuss the role that it will have in the future of cancer treatment, including settings for which testing combination strategies and 'armoured' CAR T cells are recommended. PMID- 26977789 TI - [A correlation between diffusion kurtosis imaging and the proliferative activity of brain glioma]. AB - The aim of the study was to assess the capabilities of diffusion kurtosis imaging (DKI) in diagnosis of the glioma proliferative activity and to evaluate a relationship between the glioma proliferative activity index and diffusion parameters of the contralateral normal appearing white matter (CNAWM). MATERIAL AND METHODS: The study included 47 patients with newly diagnosed brain gliomas (23 low grade, 13 grade III, and 11 grade IV gliomas). We determined a relationship between absolute and normalized parameters of the diffusion tensor (mean (MD), axial (AD), and radial (RD) diffusivities; fractional (FA) and relative (RA) anisotropies) and diffusion kurtosis (mean (MK), axial (AK), and radial (RK) kurtosis; kurtosis anisotropy (KA)) and the proliferative activity index in the most malignant glioma parts (p<0.05). We also established a relationship between the tensor and kurtosis parameters of CNAWM and the glioma proliferative activity index (p<0.05). RESULTS: The correlation between all the absolute and normalized diffusion parameters and the glioma proliferative activity index, except absolute and normalized FA and RA values, was found to be statistically significant (p<0.05). Kurtosis (MK, AK, and RK) and anisotropy (KA, FA, RA) values increased, and diffusivity (MD, AD, RD) values decreased as the glioma proliferative activity index increased. A strong correlation between the proliferative activity index and absolute RK (r=0,71; p=0.000001) and normalized values of MK (r=0.8; p=0.000001), AK (r=0.71; p=0.000001), RK (r=0.81; p=0.000001), and RD (r=-0.71; p=0.000001) was found. A weak, but statistically significant correlation between the glioma proliferative activity index and diffusion values RK (r=-0.36; p=0.014), KA (r=-0.39; p=0.007), RD (r=0.35; p=0.017), FA (r=-0.42; p=0.003), and RA (r=-0.41; p=0.004) of CNAWM was found. CONCLUSION: DKI has good capabilities to detect immunohistochemical changes in gliomas. DKI demonstrated a high sensitivity in detection of microstructural changes in the contralateral normal appearing white matter in patients with brain gliomas. PMID- 26977790 TI - [Awake craniotomy: analysis of complicated cases]. AB - Awake craniotomy is recognized as method that can decrease the frequency of neurological complications after surgery for gliomas located near eloquent brain regions. Unfortunately good neurological outcome can't be ensured even by using of this technique. This paper discusses reasons and possible ways of prevention of such complications. MATERIAL AND METHODS: 162 awake craniotomies were performed in our clinic. RESULTS: 152 of patients were discharged from the clinic with good outcome. In 10 (6%) cases sustained severe neurological deficit was noted. These complications were associated with anatomic or ischemic injury of subcortical pathways and internal capsule. CONCLUSION: Awake craniotomy is effective instrument of brain language mapping and prevention of neurological deterioration. Severe neurological complications of awake craniotomy are associated with underestimate neurosurgical risks, especially in terms of blood vessel injury and depth of resection. The main way of prevention of such complications is meticulous planning of operation and adequate using of mapping facilities. PMID- 26977791 TI - [Comparative epidemiology of adult and pediatric intramedullary spinal cord tumors]. AB - Intramedullary spinal cord tumors (IMSCTs) are a rare pathology. They can be found at any age. Our experience with more than 507 surgeries for IMSCTs revealed some differences between pediatric and adult IMSCTs. AIM: We used a large surgical series to conduct comparative analysis of the main epidemiological characteristics of intramedullary tumors in children and adults and to identify possible differences. MATERIAL AND METHODS: Prospectively collected data from 224 pediatric and 242 adult patients operated by one surgeon (YK) for last 12 years were analyzed. RESULTS: Pediatric IMSCTs are more extensive and children undergo treatment in worse clinical condition than adults. There are age-related differences in the tumor localization. The astrocytoma/ependymoma ratio was 83/17 in children and 21/79 in adults. CONCLUSION: We confirmed differences in IMSCTs in different age groups. Late diagnosis is a problem in the pediatric subgroup of IMSCT patients. PMID- 26977792 TI - [Long-term outcomes of SDR in various groups of cerebral palsy (CP) patients]. AB - AIM: Long-term outcomes of selective dorsal rhizotomy (SDR) are not sufficiently summarized in the literature. The aim of this study was to systematize and evaluate long-term outcomes of SDR in various groups of cerebral palsy (CP) patients. MATERIAL AND METHODS: 47 patients with spastic CP were operated. In all cases, SDR of the L1-S1 roots was performed under EMG control. In all cases, laminoplasty was used as an approach. Outcomes of surgical treatment were estimated by the Ashworth scale and the GMFM 88 scale. The data were subjected to statistical analysis. The follow-up duration ranged from 12 months to 7 years. RESULTS: A significant reduction in spasticity from 4.34+/-0.53 points before surgery to 1.61+/-0.45 points after surgery (p<0.001) was observed in most cases. The dynamics of locomotor functions was maximal in the 3rd GMFM class: changing from 48+/-4% points before operation to 52+/-6% points 12 months after operation (p<0.042). The dynamics of locomotor functions amounted to 2% in the 4th GMFM class and 1% in the 5th GMFM class. The best functional outcomes were obtained in children under 10 years of age. A positive correlation only between the percentage of cut roots and a decrease in spasticity (r= 0.85) was found. No correlation between the amount of cut roots and the dynamics of locomotor functions was observed. No spinal cord deformities were observed during the follow-up period. CONCLUSION: A reduction in spasticity due to SDR depends on the amount of cut roots. The functional result of SDR is affected not only by a decrease in spasticity but also by the functional status and age of the patient at the time of surgery. In all cases, laminoplasty should be performed to prevent spinal cord deformities. PMID- 26977793 TI - [Electromyographic control of botulinum toxin a injections in the upper extremities in patients with spasticity of various etiology]. AB - AIM: The study was aimed at studying the efficacy of botulinum toxin A injections combined with EMG-control of the injections in patients with upper limb spasticity of various etiology for decreasing muscle tone and improving the passive limb function as well as at assessing the possibility of a botulinum toxin dose reduction under combination of these methods. MATERIAL AND METHODS: 61 patients with upper limb spasticity of different etiology were evaluated. The main group consisted of 29 patients who were injected with abobotulinum, the botulinum toxin A (500 U per vial), under EMG-control. The control group consisted of 32 patients who received BTA injections without EMG-control. A repeated BTA injection was performed on the 4th month of the study. Patients in both groups received standard rehabilitation therapy. The spasticity pattern was determined using the Arm Spasticity Pattern (ASP) scale. Evaluation of the treatment efficacy was performed using the modified Ashworth scale to determine upper limb spasticity and the modified Barthel Index scale to assess the quality of life as well as the Disability Assessment Scale (DAS) and Clinical Global Impression (CGI) scale. RESULTS: The main spasticity patterns were as follows: the type III was in 13 (44.8%) and 17 (53.1%) patients, the type I was in 9 (31.0%) and 9 (28.1%) patients, and the type VI was in 7 (24.2%) and 6 (18.8%) patients of the main and control groups, respectively. One month after BTA treatment, a significant improvement was observed in both groups, but the improvement in the main group was more pronounced compared to that in the control group (r<0.05). This difference persisted for the whole treatment period (r<0.05). The DAS score demonstrated improvement in both groups, but only patients of the main group had a statistically significant improvement in putting the arm through a sleeve (r<0.05). EMG-control enabled a reduction in the BTA dose by 50-300 U. CONCLUSION: BTA injections under EMG-control in upper limb spasticity patients may improve the treatment efficacy. PMID- 26977794 TI - [Results of motor cortex stimulation in the treatment of chronic pain syndromes]. AB - AIM: The article is aimed to demonstrate our experience in motor cortex stimulation (MCS) in patients with chronic neuropathic pain syndromes, assess the clinical efficacy of the technique in short-term and long-term follow-up, and analyze potential predictors of the MCS efficacy. MATERIAL AND METHODS: Twenty patients were implanted with MCS electrodes at the Burdenko Neurosurgical Institute in the period between 2004 and 2014. The mean age of patients was 52 years (26 to 74 years). The patients suffered from neuropathic pain syndromes of different genesis (post-stroke, multiple sclerosis, atypical facial pain, phantom limb pain, brachial plexus injury, spinal cord injury, complex regional pain syndrome I). All patients underwent neurological examination with verification of neuropathic pain (DN4, Pain Detect, LANSS). The pain intensity and its effect on quality of life were assessed before operation and during follow-up according to 10-point visual-analog scales (modified Brief Pain Inventory). Before surgery, all patients underwent several repetitive transcranial magnetic stimulation (rTMS) sessions. After implantation of epidural electrodes, test MCS was performed. RESULTS: Test stimulation was positive in 19 (95%) patients. All these patients were implanted with a chronic MCS system. The mean follow-up was 49.3 months (from 3 to 96 months). In short-term follow-up (fist 6 months), a positive result of MCS was observed in 17 patients, and a reduction in the pain intensity ranged from 37.5% to 90%. In long-term follow up (from 12 to 96 months), 14 patients had positive MCS RESULTS: and a reduction in the pain intensity amounted to 25% to 60%. All patients with positive MCS results received significantly decreased doses of opioids and tramadol. Two patients developed infectious complications, but there was no neurological deficit. Analysis of the factors affecting the efficacy of motor cortex stimulation did not reveal a statistically significant effect of rTMS and the presence and intensity of motor deficit. CONCLUSION: Chronic epidural MCS is an effective and safety method for the treatment of some chronic neurogenic medically-refractory pain syndromes. Further research is necessary to specify the patient selection criteria and the MCS efficacy predictors. PMID- 26977795 TI - [Cerebrovenous orthostatic reactivity in pathology of the craniovertebral junction (Chiari malformation)]. AB - AIM: Chiari malformation is characterized by herniation of the cerebellar tonsils into the foramen magnum, which leads to disturbance of CSF circulation through the craniovertebral junction. Orthostatic stress, which leads to the movement of SCF through the craniovertebral junction, is an adequate method to detect these disorders. It is accompanied by changes in the intracranial pressure, affecting the cerebrovenous orthostatic reactivity (CVOR), which is noninvasively assessed in patients with Chiari malformation. MATERIAL AND METHODS: The study involved 35 patients with Chiari malformation (26 patients with Chiari I and 9 patients with Chiari II) aged 4 to 58 years (of them 12 males). Hydrocephalus was diagnosed in 4 examined patients and myelosyringosis was diagnosed in 6 patients. Transcranial Doppler sonography was used to record the venous blood flow in the tentorial sinus of the brain while changing body position on the fracture table from +90 degrees to -30 degrees . RESULTS: There is significant CVOR abnormality in most patients with Chiari malformation (more than 90%), which is characterized by either increased CVOR (sometimes 5-6-fold compared to the upper normal level (considerable hyperreactivity) or complete absence of any changes during the orthostatic load (areactivity). Before surgical treatment, CVOR of patients with Chiari malformation is often characterized by areactivity, as well as a moderate or significant hyperreactivity. After surgical treatment (decompression of the foramen magnum), patients with Chiari malformation demonstrate significant normalization of the craniovertebral volumetric ratios and CVOR if often characterized by normoreactivity (in 63%) or, more rarely, moderate hyperreactivity. The rate of venous blood flow in the tentorial sinus of the brain in patients with Chiari malformation can be increased before the surgery and normalizes after surgery. CONCLUSION: The high incidence of disturbance of CVOR (over 90%) in patients with Chiari malformation was revealed. After surgical treatment, complete normalization of CVOR was observed in more than half of these patients (63%). PMID- 26977796 TI - [Experience of endoscopic removal of hypertensive intracerebral hemorrhage]. AB - AIM: This study was aimed at assessing the efficacy of endoscopic technique in surgery for hypertensive intracerebral hemorrhage. MATERIAL AND METHODS: This paper focus on our experience (11 cases) of endoscopic removal of hypertensive intracerebral hemorrhage. The paper presents examples of endoscopic removal of hematomas located in the basal ganglia (9 cases) and in the posterior fossa (2 cases), causing occlusion at the fourth ventricle. In 3 patients (27%) with intraventricular hemorrhage, the removal of acute hematomas from the ventricular system with simultaneous endoscopic triple ventriculostomy was performed. Intervention was carried out within the first 6 hours in patients with hemispheric hematomas (in 90% of cases) and within 3-5 hours in patients with PCF hematomas. RESULTS: The article analyzes the functional outcomes in the early and late postoperative period. Complete regression of neurological symptoms was achieved in 4 (36%) patients and the remaining 7 (64%) patients had a moderate disability at discharge. CONCLUSION: In our opinion, endoscopic removal of hypertensive intracerebral hemorrhage is a promising method that meets all existing aspects of modern neurosurgery. The combination of rigid and flexible endoscopy provides new capabilities in surgery of patients with intraventricular hemorrhage. PMID- 26977797 TI - [Surgical treatment of severe spondylogenic cervical myelopathy by laminoplasty]. AB - AIM: The objective of this study is to analyze the results of surgical treatment of patients with cervical myelopathy by laminoplasty. MATERIAL AND METHODS: The experience of surgical treatment of 30 patients (mean age 59.4) with cervical stenosis complicated with myelopathy was analyzed. Hirabayashi laminoplasty was performed in 26 patients and Kurokawa laminoplasty was performed in 4 patients. All patients were diagnosed with extended cervical spinal stenosis. Diagnosis was based on the survey RESULTS: including the dynamic clinical and neurological examination, x-ray study, CT, MRI, SSEP, and TMS. Nurick scale, the scale of the Japanese Orthopaedic Association (JOA), and the recovery rate scale were used to assess the severity of myelopathy. RESULTS: The long-term outcome of the clinical status, radiographic and neuroimaging parameters in patients with cervical myelopathy who underwent laminoplasty was evaluated. CONCLUSION: Laminoplasty is the method of choice in the treatment of extended spondylogenic cervical stenosis. Proper selection of patients based on clinical symptoms, assessment of the extent of stenosis, neurological examination and neuroimaging data leads to excellent results. PMID- 26977798 TI - [Endoscopic endonasal surgical treatment of large pituitary adenoma, spreading into the posterior fossa]. AB - AIM: The objective of the study was to develop the tactics of surgical treatment of large and giant pituitary adenomas, spreading into the posterior cranial fossa. MATERIAL AND METHODS: Patients with large hormonally inactive pituitary adenoma, extending to the right cavernous sinus and posterior cranial fossa. RESULTS: The endoscopic endonasal removal a large endo-supra-latero(D) retrosellar pituitary tumor was conducted. Control MRI shows that the tumor was removed radically. Oculomotor disturbances were observed in the early postoperative period, which significantly regressed within 6 months. The article provides detailed analysis of the world literature on the issue under discussion. Illustrative pre-, intra-, and post-operative photographs, as well as histological preparations are shown. CONCLUSION: Modern minimally invasive techniques make it possible to remove large pituitary adenomas (and other tumors) of the posterior cranial fossa using endoscopic endonasal approach. Such operations must be carried out at highly specialized institutions by the surgeons who have extensive experience in endoscopic transnasal surgery of skull base tumors. PMID- 26977799 TI - [Prx-monitoring based decision-making about decompressive craniectomy in a patient with severe traumatic brain injury. A case report]. AB - The presented case illustrates a new approach to making a decision about decompressive craniectomy in the patient with sever traumatic brain injury and intracranial hypertension. The approach is based on continuous assessment of cerebral autoregulation using Prx-monitoring in addition to monitoring of intracranial pressure and cerebral perfusion pressure. Prx-monitoring enables timely detection of autoregulation failure and provides the opportunity to make a decision about decompressive craniectomy before starting such aggressive methods of intensive care as hypothermia or barbiturate coma. PMID- 26977800 TI - [Guidelines for the management of severe head injury. Part 1. Neurotrauma system and neuroimaging]. AB - Traumatic brain injury is one of the main causes of mortality and disability in young and middle-aged individuals. The patients with severe traumatic brain injury who are in coma are the most difficult to deal with. Appropriate diagnosis of the primary brain injuries and early prevention and treatment of secondary damage mechanisms largely determine the possibility of reducing mortality and severe disabling consequences. The authors compiled these guidelines based on their experience in development of international and Russian recommendations on the diagnosis and treatment of mild traumatic brain injury, penetrating gunshot injury of the skull and brain, severe traumatic brain injury, and severe consequences of brain injuries, including a vegetative state. In addition, we used the materials of international and Russian recommendations on the diagnosis, intensive care, and surgical treatment of severe traumatic brain injury published in recent years. The proposed recommendations are related to organization of medical care and diagnosis of severe traumatic brain injury in adults and are primarily addressed to neurosurgeons, neurologists, neuroradiologists, anesthesiologists, and emergency room doctors, who are routinely involved in management of these patients. PMID- 26977801 TI - MKP1: Jekyll and Hyde for E1A. PMID- 26977803 TI - REPdenovo: Inferring De Novo Repeat Motifs from Short Sequence Reads. AB - Repeat elements are important components of eukaryotic genomes. One limitation in our understanding of repeat elements is that most analyses rely on reference genomes that are incomplete and often contain missing data in highly repetitive regions that are difficult to assemble. To overcome this problem we develop a new method, REPdenovo, which assembles repeat sequences directly from raw shotgun sequencing data. REPdenovo can construct various types of repeats that are highly repetitive and have low sequence divergence within copies. We show that REPdenovo is substantially better than existing methods both in terms of the number and the completeness of the repeat sequences that it recovers. The key advantage of REPdenovo is that it can reconstruct long repeats from sequence reads. We apply the method to human data and discover a number of potentially new repeats sequences that have been missed by previous repeat annotations. Many of these sequences are incorporated into various parasite genomes, possibly because the filtering process for host DNA involved in the sequencing of the parasite genomes failed to exclude the host derived repeat sequences. REPdenovo is a new powerful computational tool for annotating genomes and for addressing questions regarding the evolution of repeat families. The software tool, REPdenovo, is available for download at https://github.com/Reedwarbler/REPdenovo. PMID- 26977802 TI - Altered Spontaneous Activity in Patients with Persistent Somatoform Pain Disorder Revealed by Regional Homogeneity. AB - Persistent somatoform pain disorder (PSPD) is a mental disorder un-associated with any somatic injury and can cause severe somatosensory and emotional impairments in patients. However, so far, the neuro-pathophysiological mechanism of the functional impairments in PSPD is still unclear. The present study assesses the difference in regional spontaneous activity between PSPD and healthy controls (HC) during a resting state, in order to elucidate the neural mechanisms underlying PSPD. Resting-state functional Magnetic Resonance Imaging data were obtained from 13 PSPD patients and 23 age- and gender-matched HC subjects in this study. Kendall's coefficient of concordance was used to measure regional homogeneity (ReHo), and a two-sample t-test was subsequently performed to investigate the ReHo difference between PSPD and HC. Additionally, the correlations between the mean ReHo of each survived area and the clinical assessments were further analyzed. Compared with the HC group, patients with PSPD exhibited decreased ReHo in the bilateral primary somatosensory cortex, posterior cerebellum, and occipital lobe, while increased ReHo in the prefrontal cortex (PFC) and default mode network (including the medial PFC, right inferior parietal lobe (IPL), and left supramarginal gyrus). In addition, significant positive correlations were found between the mean ReHo of both right IPL and left supramarginal gyrus and participants' Self-Rating Anxiety Scale (SAS) scores, and between the mean ReHo of the left middle frontal gyrus and Visual Analogue Scale (VAS) scores. Our results suggest that abnormal spontaneous brain activity in specific brain regions during a resting state may be associated with the dysfunctions in pain, memory and emotional processing commonly observed in patients with PSPD. These findings help us to understand the neural mechanisms underlying PSPD and suggest that the ReHo metric could be used as a clinical marker for PSPD. PMID- 26977804 TI - Mechanical Ventilation and Clinical Outcomes in Patients with Acute Myocardial Infarction: A Retrospective Observational Study. AB - PURPOSE: Patients with acute myocardial infarction (AMI) and respiratory impairment may be treated with either invasive or non-invasive mechanical ventilation (MV). However, there has been little testing of non-invasive MV in the setting of AMI. Our objective was to evaluate the incidence and associated clinical outcomes of patients with AMI who were treated with non-invasive or invasive MV. METHODS: This was a retrospective observational study in which consecutive patients with AMI (n = 1610) were enrolled. The association between exclusively non-invasive MV, invasive MV and outcomes was assessed by multivariable models. RESULTS: Mechanical ventilation was used in 293 patients (54% invasive and 46% exclusively non-invasive). In-hospital mortality rates for patients without MV, with exclusively non-invasive MV, and with invasive MV were 4.0%, 8.8%, and 39.5%, respectively (P<0.001). The median lengths of hospital stay were 6 (5.8-6.2), 13 (11.2-4.7), and 28 (18.0-37.9) days, respectively (P<0.001). Exclusively non-invasive MV was not associated with in-hospital death (adjusted HR = 0.90, 95% CI 0.40-1.99, P = 0.79). Invasive MV was strongly associated with a higher risk of in-hospital death (adjusted HR = 3.07, 95% CI 1.79-5.26, P<0.001). CONCLUSIONS: In AMI setting, 18% of the patients required MV. Almost half of these patients were treated with exclusively non-invasive strategies with a favorable prognosis, while patients who needed to be treated invasively had a three-fold increase in the risk of death. Future prospective randomized trials are needed to compare the effectiveness of invasive and non invasive MV for the initial approach of respiratory failure in AMI patients. PMID- 26977805 TI - Early Afterdepolarizations with Growing Amplitudes via Delayed Subcritical Hopf Bifurcations and Unstable Manifolds of Saddle Foci in Cardiac Action Potential Dynamics. AB - Early afterdepolarizations (EADs) are pathological oscillations in cardiac action potentials during the repolarization phase and may be caused by drug side effects, ion channel disease or oxidative stress. The most widely observed EAD pattern is characterized by oscillations with growing amplitudes. So far, its occurence has been explained in terms of a supercritical Hopf bifurcation in the fast subsystem of the action potential dynamics from which stable limit cycles with growing amplitudes emerge. The novel contribution of this article is the introduction of two alternative explanations of EAD genesis with growing amplitudes that do not involve stable limit cycles in fast subsystems. In particular, we demonstrate that EAD patterns with growing amplitudes may alternatively arise due to a delayed subcritical Hopf bifurcation or an unstable manifold of a saddle focus fixed point in the full fast-slow system modelling the action potential. Our work extends the list of possible dynamical EAD mechanisms and may contribute to a classification of drug effects in preclinical cardiotoxicity testing. PMID- 26977806 TI - Interdependencies and Causalities in Coupled Financial Networks. AB - We explore the foreign exchange and stock market networks for 48 countries from 1999 to 2012 and propose a model, based on complex Hilbert principal component analysis, for extracting significant lead-lag relationships between these markets. The global set of countries, including large and small countries in Europe, the Americas, Asia, and the Middle East, is contrasted with the limited scopes of targets, e.g., G5, G7 or the emerging Asian countries, adopted by previous works. We construct a coupled synchronization network, perform community analysis, and identify formation of four distinct network communities that are relatively stable over time. In addition to investigating the entire period, we divide the time period into into "mild crisis," (1999-2002), "calm," (2003-2006) and "severe crisis" (2007-2012) sub-periods and find that the severe crisis period behavior dominates the dynamics in the foreign exchange-equity synchronization network. We observe that in general the foreign exchange market has predictive power for the global stock market performances. In addition, the United States, German and Mexican markets have forecasting power for the performances of other global equity markets. PMID- 26977807 TI - Using Random Forest to Improve the Downscaling of Global Livestock Census Data. AB - Large scale, high-resolution global data on farm animal distributions are essential for spatially explicit assessments of the epidemiological, environmental and socio-economic impacts of the livestock sector. This has been the major motivation behind the development of the Gridded Livestock of the World (GLW) database, which has been extensively used since its first publication in 2007. The database relies on a downscaling methodology whereby census counts of animals in sub-national administrative units are redistributed at the level of grid cells as a function of a series of spatial covariates. The recent upgrade of GLW1 to GLW2 involved automating the processing, improvement of input data, and downscaling at a spatial resolution of 1 km per cell (5 km per cell in the earlier version). The underlying statistical methodology, however, remained unchanged. In this paper, we evaluate new methods to downscale census data with a higher accuracy and increased processing efficiency. Two main factors were evaluated, based on sample census datasets of cattle in Africa and chickens in Asia. First, we implemented and evaluated Random Forest models (RF) instead of stratified regressions. Second, we investigated whether models that predicted the number of animals per rural person (per capita) could provide better downscaled estimates than the previous approach that predicted absolute densities (animals per km2). RF models consistently provided better predictions than the stratified regressions for both continents and species. The benefit of per capita over absolute density models varied according to the species and continent. In addition, different technical options were evaluated to reduce the processing time while maintaining their predictive power. Future GLW runs (GLW 3.0) will apply the new RF methodology with optimized modelling options. The potential benefit of per capita models will need to be further investigated with a better distinction between rural and agricultural populations. PMID- 26977808 TI - A Single 17D Yellow Fever Vaccination Provides Lifelong Immunity; Characterization of Yellow-Fever-Specific Neutralizing Antibody and T-Cell Responses after Vaccination. AB - INTRODUCTION: Prompted by recent amendments of Yellow Fever (YF) vaccination guidelines from boost to single vaccination strategy and the paucity of clinical data to support this adjustment, we used the profile of the YF-specific CD8+ T cell subset profiles after primary vaccination and neutralizing antibodies as a proxy for potentially longer lasting immunity. METHODS AND FINDINGS: PBMCs and serum were collected in six individuals on days 0, 3, 5, 12, 28 and 180, and in 99 individuals >10 years after YF-vaccination. Phenotypic characteristics of YF- tetramer+ CD8+ T-cells were determined using class I tetramers. Antibody responses were measured using a standardized plaque reduction neutralization test (PRNT). Also, characteristics of YF-tetramer positive CD8+ T-cells were compared between individuals who had received a primary- and a booster vaccination. YF tetramer+ CD8+ T-cells were detectable on day 12 (median tetramer+ cells as percentage of CD8+ T-cells 0.2%, range 0.07-3.1%). On day 180, these cells were still present (median 0.06%, range 0.02-0.78%). The phenotype of YF-tetramer positive CD8+ T-cells shifted from acute phase effector cells on day 12, to late differentiated or effector memory phenotype (CD45RA-/+CD27-) on day 28. Two subsets of YF-tetramer positive T-cells (CD45RA+CD27- and CD45RA+CD27+) persisted until day 180. Within all phenotypic subsets, the T-bet: Eomes ratio tended to be high on day 28 after vaccination and shifted towards predominant Eomes expression on day 180 (median 6.0 (day 28) vs. 2.2 (day 180) p = 0.0625), suggestive of imprinting compatible with long-lived memory properties. YF-tetramer positive CD8+ T-cells were detectable up to 18 years post vaccination, YF-specific antibodies were detectable up to 40 years after single vaccination. Booster vaccination did not increase titers of YF-specific antibodies (mean 12.5 vs. 13.1, p = 0.583), nor induce frequencies or alter phenotypes of YF-tetramer+ CD8+ T-cells. CONCLUSION: The presence of a functionally competent YF-specific memory T-cell pool 18 years and sufficient titers of neutralizing antibodies 35-40 years after first vaccination suggest that single vaccination may be sufficient to provide long-term immunity. PMID- 26977809 TI - A First Insight into the Genome of the Filter-Feeder Mussel Mytilus galloprovincialis. AB - Mussels belong to the phylum Mollusca, one of the largest and most diverse taxa in the animal kingdom. Despite their importance in aquaculture and in biology in general, genomic resources from mussels are still scarce. To broaden and increase the genomic knowledge in this family, we carried out a whole-genome sequencing study of the cosmopolitan Mediterranean mussel (Mytilus galloprovincialis). We sequenced its genome (32X depth of coverage) on the Illumina platform using three pair-end libraries with different insert sizes. The large number of contigs obtained pointed out a highly complex genome of 1.6 Gb where repeated elements seem to be widespread (~30% of the genome), a feature that is also shared with other marine molluscs. Notwithstanding the limitations of our genome sequencing, we were able to reconstruct two mitochondrial genomes and predict 10,891 putative genes. A comparative analysis with other molluscs revealed a gene enrichment of gene ontology categories related to multixenobiotic resistance, glutamate biosynthetic process, and the maintenance of ciliary structures. PMID- 26977810 TI - Interference and Inhibition in Bilingual Language Comprehension: Evidence from Polish-English Interlingual Homographs. AB - The main goal of the present study was to explore the involvement of inhibition in resolution of cross-language activation in bilingual comprehension and a possible modulatory effect of L2 proficiency. We used a semantic relatedness judgment task in L2 English that included Polish-English interlingual homographs and English translations of the Polish homographs' meanings. Based on previous studies using the same paradigm, we expected a strong homograph interference and inhibition of the homographs' Polish meanings translations. In addition, we predicted that participants with lower L2 proficiency would experience greater interference and stronger inhibitory effects. The reported results confirm a strong homograph interference effect. In addition, our results indicate that the scope of inhibition generalized from the homograph's irrelevant meaning to a whole semantic category, indicating the flexibility of the inhibitory mechanisms. Contrary to our expectations, L2 proficiency did not modulate the effects of interference and inhibition, possibly due to a relatively low variability in proficiency within our participant sample. PMID- 26977811 TI - Factors Contributing to the Delay in Diagnosis and Continued Transmission of Leprosy in Brazil--An Explorative, Quantitative, Questionnaire Based Study. AB - BACKGROUND: Leprosy is a leading cause of preventable disability worldwide. Delay in diagnosis of patients augments the transmission of infection, and allows progression of disease and more severe disability. Delays in diagnosis greater than ten years have been reported in Brazil. To reduce this delay, it is important to identify factors that hinder patients from presenting to doctors, and those that delay doctors from diagnosing patients once they have presented. This study aimed to explore factors associated with the delayed diagnosis of leprosy in Brazil. METHODOLOGY/ PRINCIPAL FINDINGS: This is an exploratory study using a self-constructed questionnaire delivered to patients attending three leprosy referral clinics across three states in Brazil. Data were analysed to determine associations between variables and the time taken for participants to present to the health-service, and between variables and the time taken for doctors to diagnose participants once they had presented. Participants who suspected they had leprosy but feared community isolation were 10 times more likely to wait longer before consulting a doctor for their symptoms (OR 10.37, 95% CI 2.18-49.45, p = 0.003). Participants who thought their symptoms were not serious had a threefold greater chance of waiting longer before consulting than those who did (OR 3.114, 95% CI 1.235-7.856, p = 0.016). Forty-two point six per cent of participants reported initially receiving a diagnosis besides leprosy. These had a three times greater chance of receiving a later diagnosis of leprosy compared to those not misdiagnosed or not given a diagnosis (OR 2.867, 95% CI 1.288-6.384, p = 0.010). CONCLUSIONS/ SIGNIFICANCE: This study implies a need for patient education regarding leprosy symptoms and the reduction of stigma to encourage patients to present. The high rate of misdiagnosis reported suggests a need to increase clinician suspicion of leprosy. Further education regarding disease symptoms in medical school curriculums may be advisable. PMID- 26977818 TI - Autoinducer-2 properties of kimchi are associated with lactic acid bacteria involved in its fermentation. AB - Bacteria use the cell density-dependent quorum signalling system to regulate particular gene expressions. In food microbiology, signalling is well known for its relation to (foodborne) pathogenicity, food spoilage, and biofilm formation. Quorum quenching and inhibition are thus being considered as a feasible approach in food preservation and safety. In the case of the luxS-mediated universal quorum sensing using autoinducer-2 (AI-2), however, it could be a different issue. Several studies have reported a luxS AI-2 synthase homologue in numerous bacteria, comprising both pathogens and beneficial strains. A recent study has shown the AI-2 signal to restore the balance of the major phyla of the gut microbiota in antibiotic-induced dysbiosis. We measured the AI-2 activity of the lactic fermented food, kimchi, and found different AI-2 signalling intensities. In order to trace the origin of the signal production, we obtained 229 lactic acid bacterial isolates from the kimchi samples, and detected the AI-2 properties of each isolate using a modified AI-2 bioluminescence assay. Our results showed isolates of dominant species of the genera Lactobacillus, Weissella and Leuconostoc which either produced or inhibited the AI-2 signal. No isolate of the dominant species Lactobacillus sakei (75 isolates) and Lactobacillus curvatus (28 isolates) showed AI-2 producing activity, while AI-2 inhibition could not be detected for any of the 31 Lactobacillus plantarum isolates. These results suggest the AI-2 activity of kimchi to result from the interaction of the associated microbial food cultures (MFCs) during fermentation. Thus far, only sparse information is available on AI-2 signalling interaction in fermented food, however, we suggest that fermented food may be a supplier of AI-2 signalling molecules via typical MFCs. PMID- 26977812 TI - Reshaping the Cone-Mosaic in a Rat Model of Retinitis Pigmentosa: Modulatory Role of ZO-1 Expression in DL-Alpha-Aminoadipic Acid Reshaping. AB - In S334ter-line-3 rat model of Retinitis Pigmentosa (RP), rod cell death induces the rearrangement of cones into mosaics of rings while the fibrotic processes of Muller cells remodel to fill the center of the rings. In contrast, previous work established that DL-alpha-aminoadipic-acid (AAA), a compound that transiently blocks Muller cell metabolism, abolishes these highly structured cone rings. Simultaneously, adherens-junction associated protein, Zonula occludens-1 (ZO-1) expression forms in a network between the photoreceptor segments and Muller cells processes. Thus, we hypothesized that AAA treatment alters the cone mosaic rings by disrupting the distal sealing formed by these fibrotic processes, either directly or indirectly, by down regulating the expression of ZO-1. Therefore, we examined these processes and ZO-1 expression at the outer retina after intravitreal injection of AAA and observed that AAA treatment transiently disrupts the distal glial sealing in RP retina, plus induces cones in rings to become more homogeneous. Moreover, ZO-1 expression is actively suppressed after 3 days of AAA treatment, which coincided with cone ring disruption. Similar modifications of glial sealing and cone distribution were observed after injection of siRNA to inhibit ZO-1 expression. These findings support our hypothesis and provide additional information about the critical role played by ZO-1 in glial sealing and shaping the ring mosaic in RP retina. These studies represent important advancements in the understanding of retinal degeneration's etiology and pathophysiology. PMID- 26977814 TI - Phenotypic and Genotypic Diversity of Salmonella in Finishing Swine. AB - Salmonella enterica (nontyphoidal) is one of the major causes of foodborne diseases in the United States and worldwide. Molecular typing methods are significant tools used to better understand the transmission and ecology of Salmonella in order to implement pre-harvest control measures. The objectives of this study were to describe the Salmonella genotypes, the distribution of isolate subtypes from different ecological niches (i.e., barn environment, nursery, and individual pigs) and their evolution over time in a longitudinal study conducted in three finishing sites (housing pigs from 10 weeks of age until slaughter at 24 26 weeks of age). Among the 107 Salmonella isolates submitted for pulsed-field gel electrophoresis (PFGE) analysis, there were 25 distinct subtypes. PFGE genotyping results were consistent with the serotype findings. A large number of distinguishable PFGE patterns (i.e., within the same serovar) were observed and different combinations of subtypes were identified within and across sites and cohorts. New subtypes may result of the introduction of new strains, genetic changes, or ongoing transmission of evolved strains within the production system. The same subtypes were detected intermittently during the study period, which suggests the persistence of indistinguishable subtypes in this production system. In addition, this study suggests persistence of the same subtype over several cohorts of pigs and potential residual contamination from the barn. Factors affecting adaptation and transmission of Salmonella within and among ecological systems (e.g., finishing pigs, nursery, and environment) should be further investigated. Understanding genotypic diversity of Salmonella in different ecological niches during pre-harvest may contribute to the development of more targeted and cost effective control programs during nursery and finishing phases. PMID- 26977819 TI - Endobronchial Involvement in Methotrexate-associated Lymphoproliferative Disease. PMID- 26977813 TI - Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction. AB - Type 2 diabetes mellitus (T2DM) is associated with a high incidence of non alcoholic fatty liver disease (NAFLD) related to obesity and insulin resistance. Currently, medical interventions for NAFLD have focused on diet control and exercise to reduce body weight, and there is a requirement for effective pharmacological therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. SGLT2 inhibitors lower blood glucose independent of insulin action and are expected to reduce body weight because of urinary calorie loss. Here we show that an SGLT2 inhibitor ipragliflozin improves hepatic steatosis in high-fat diet-induced and leptin-deficient (ob/ob) obese mice irrespective of body weight reduction. In the obese mice, ipragliflozin induced hyperphagia occurred to increase energy intake, attenuating body weight reduction with increased epididymal fat mass. There is an inverse correlation between weights of liver and epididymal fat in ipragliflozin-treated obese mice, suggesting that ipragliflozin treatment promotes normotopic fat accumulation in the epididymal fat and prevents ectopic fat accumulation in the liver. Despite increased adiposity, ipragliflozin ameliorates obesity-associated inflammation and insulin resistance in epididymal fat. Clinically, ipragliflozin improves liver dysfunction in patients with T2DM irrespective of body weight reduction. These findings provide new insight into the effects of SGLT2 inhibitors on energy homeostasis and fat accumulation and indicate their potential therapeutic efficacy in T2DM-associated hepatic steatosis. PMID- 26977820 TI - Antinociceptive activity of intraperitoneally administered novel and potent anticonvulsive compound, CY-PROLL-SS, in animal neuropathic pain models. AB - BACKGROUND: Neuropathic pain is still one of the most difficult pain states to be treated due to the lack of effective drugs. Although the mechanism of action of antiepileptic drugs in alleviating neuropathic pain is not fully understood, it is believed that the bases for both diseases are similar pathophysiologic disturbances. Therefore, in this article we explored the analgesic potential of a recently discovered compound CY-PROLL-SS (ADD 408003; 4-phenyl perhydropyrrole[1,2-a]pyrazine-1,3-dione) with proved anticonvulsant activity. METHODS: CY-PROLL-SS was delivered to animals systemically to assess the antinociceptive effects either in streptozocin (STZ)-induced diabetic or in chronic constriction injury (CCI) models of neuropathic pain after acute exposure to both thermal and mechanical stimulus. RESULTS: Examined here compound dose dependently reversed thermal and mechanical hyperalgesia induced by STZ single injection. Similar results were obtained for CCI-induced hyperalgesia; however, in this case an attenuation of thermal and reversal of mechanical hyperalgesia were observed. CONCLUSIONS: High doses of CY-PROLL-SS considerably alleviate peripheral neuropathic pain in model of STZ diabetic neuropathy and CCI. However, mechanisms remain to be elucidated. PMID- 26977823 TI - Parkinson's disease hand tremor detection system for mobile application. AB - Parkinson's disease currently affects millions of people worldwide and is steadily increasing. Many symptoms are associated with this disease, including rest tremor, bradykinesia, stiffness or rigidity of the extremities and postural instability. No cure is currently available for Parkinson's disease patients; instead most medications are for treatment of symptoms. This treatment depends on the quantification of these symptoms such as hand tremor. This work proposes a new system for mobile phone applications. The system is based on measuring the acceleration from the Parkinson's disease patient's hand using a mobile cell phone accelerometer. Recordings from 21 Parkinson's disease patients and 21 healthy subjects were used. These recordings were analysed using a two level wavelet packet analysis and features were extracted forming a feature vector of 12 elements. The features extracted from the 42 subjects were classified using a neural networks classifier. The results obtained showed an accuracy of 95% and a Kappa coefficient of 90%. These results indicate that a cell phone accelerometer can accurately detect and record rest tremor in Parkinson's disease patients. PMID- 26977821 TI - Modification of 5-methoxy-N,N-dimethyltryptamine-induced hyperactivity by monoamine oxidase A inhibitor harmaline in mice and the underlying serotonergic mechanisms. AB - BACKGROUND: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are indolealkylamine (IAA) drugs often abused together. Our recent studies have revealed the significant effects of co-administered harmaline, a monoamine oxidase inhibitor (MAOI), on 5-MeO-DMT pharmacokinetics and thermoregulation. This study was to delineate the impact of harmaline and 5-MeO-DMT on home-cage activity in mouse models, as well as the contribution of serotonin (5-HT) receptors. METHODS: Home-cage activities of individual animals were monitored automatically in the home cages following implantation of telemetry transmitters and administration of various doses of IAA drugs and 5-HT receptor antagonists. Area under the effect curve (AUEC) of mouse activity values were calculated by trapezoidal rule. RESULTS: High dose of harmaline (15mg/kg, ip) alone caused an early-phase (0-45min) hypoactivity in mice that was fully attenuated by 5-HT1A receptor antagonist WAY-100635, whereas a late-phase (45-180min) hyperactivity that was reduced by 5-HT2A receptor antagonist MDL-100907. 5-MeO-DMT (10 and 20mg/kg, ip) alone induced biphasic effects, an early-phase (0-45min) hypoactivity that was completely attenuated by WAY-100635, and a late-phase (45 180min) hyperactivity that was fully suppressed by MDL-100907. Interestingly, co administration of MAOI harmaline (2-15mg/kg) with a subthreshold dose of 5-MeO DMT (2mg/kg) induced excessive hyperactivities at late phase (45-180min) that could be abolished by either WAY-100635 or MDL-100907. CONCLUSIONS: Co administration of MAOI with 5-MeO-DMT provokes excessive late-phase hyperactivity, which involves the activation of both 5-HT1A and 5-HT2A receptors. PMID- 26977822 TI - An endomorphine analog ([d-Ala(2)]-Endomorphin 2, TAPP) lowers blood pressure and enhances tissue nitric oxide in anesthetized rats. AB - BACKGROUND: Activation of opioid receptors can alter cardiovascular function, an action possibly mediated by nitric oxide (NO). In this study we examined the effects of ([d-Ala(2)]-Endomorphin 2, TAPP), a synthetic opioid MU-receptor agonist, on blood pressure (MABP), tissue NO bioavailability and renal hemodynamics and excretion. METHODS: In acute experiments with anesthetized normotensive male Sprague-Dawley rats TAPP was given as a short iv infusion at a dose of 1.2 or 12mg/kg and then MABP, renal medullary NO signal (polarographic electrode), total renal blood flow (RBF, renal artery Transonic probe), renal regional perfusion (laser-Doppler fluxes) and renal excretion were simultaneously measured over 2h. RESULTS: After 1.2mg/kg dose MABP decreased progressively from 121+/-7 to 114+/-9mmHg (-6%, p<0.05) while kidney tissue NO signal increased from 29.1+/-2.7 to 31.7+/-3.1nA (6%, p<0.04). Both effects were prevented by Naloxone methiodide, a peripheral opioid receptor inhibitor. RBF and renal regional perfusion were not altered by either dose of TAPP; renal sodium excretion changes were highly variable and were not affected by Naloxone pretreatment. CONCLUSIONS: Briefly, we found that in anesthetized normotensive rats stimulation of peripheral opioid receptors with TAPP caused a prolonged decrease in arterial pressure, a change that was associated and probably causally related to an increase in tissue NO. The data suggest that synthetic opioids that do not penetrate the blood-brain barrier and are potentially non-addictive could be considered for antihypertensive therapy. PMID- 26977824 TI - Should spikes on post-resection ECoG guide pediatric epilepsy surgery? AB - PURPOSE: There is wide variation in clinical practice regarding the role of electrocorticography immediately after resection (post-resection ECoG) for pediatric epilepsy surgery. Results can guide further resection of potentially epileptogenic tissue. We hypothesized that post-resection ECoG spiking represents a biomarker of the epileptogenic zone and predicts seizure outcome in children undergoing epilepsy surgery. METHODS: We retrospectively identified 124 children with post-resection ECoG performed on the margins of resection. ECoG records were scored in a blinded fashion based on presence of frequent spiking. For patients identified as having additional resection based on clinical post-resection ECoG interpretation, these "second-look" ECoG results were re-reviewed for ongoing discharges or completeness of resection. Frequent spike populations were grouped using a standard scoring system into three ranges: 0.1-0.5Hz, 0.5-1Hz, >1Hz. Seizure outcomes were determined at minimum 12-month followup. RESULTS: Of 124 patients who met inclusion criteria, 60 (48%) had an identified spike population on post-resection ECoG. Thirty (50%) of these had further resection based on clinical interpretation. Overall, good outcome (ILAE 1) was seen in 56/124 (45%). Completeness of resection of spiking (absence of spiking on initial post resection ECoG or resolution of spiking after further resection) showed a trend toward good outcome (OR 2.03, p=0.099). Patients with completeness of resection had good outcome in 41/80 (51%) of cases; patients with continued spikes had good outcome in 15/44 (35%) of cases. CONCLUSIONS: Post-resection ECoG identifies residual epileptogenic tissue in a significant number of children. Lower frequency or absence of discharges on initial recording showed a trend toward good outcome. Completeness of resection demonstrated on final ECoG recording did not show a significant difference in outcome. This suggests that post-resection discharges represent a prognostic marker rather than a remediable biomarker of the epileptogenic zone in all patients. Resecting residual spike-generating cortex may be beneficial in selected patients, including children with tumors. PMID- 26977825 TI - Toward Global Biobank Integration by Implementation of the Minimum Information About BIobank Data Sharing (MIABIS 2.0 Core). AB - Biobanks are the biological back end of data-driven medicine, but lack standards and generic solutions for interoperability and information harmonization. The move toward a global information infrastructure for biobanking demands semantic interoperability through harmonized services and common ontologies. To tackle this issue, the Minimum Information About BIobank data Sharing (MIABIS) was developed in 2012 by the Biobanking and BioMolecular Resources Research Infrastructure of Sweden (BBMRI.se). The wide acceptance of the first version of MIABIS encouraged evolving it to a more structured and descriptive standard. In 2013 a working group was formed under the largest infrastructure for health in Europe, Biobanking and BioMolecular Resources Research Infrastructure (BBMRI ERIC), with the remit to continue the development of MIABIS (version 2.0) through a multicountry governance process. MIABIS 2.0 Core has been developed with 22 attributes describing Biobanks, Sample Collections, and Studies according to a modular structure that makes it easier to adhere to and to extend the standard. This integration standard will make a great contribution to the discovery and exploitation of biobank resources and lead to a wider and more efficient use of valuable bioresources, thereby speeding up the research on human diseases. Many within the European Union have accepted MIABIS 2.0 Core as the "de facto" biobank information standard. PMID- 26977828 TI - Foods Containing Saturated Fat: Dietary Limits Are Still Essential. PMID- 26977827 TI - Drug Combo Adds No Benefit in Patients with Type 2 Diabetes. PMID- 26977829 TI - Eating Less Meat: A Healthy and Environmentally Responsible Dietary Choice. PMID- 26977830 TI - Medications for Alcohol Use Disorder. AB - The U.S. Preventive Services Task Force recommends that clinicians screen adults for alcohol misuse and provide persons engaged in risky or hazardous drinking behaviors with brief behavioral counseling to reduce alcohol misuse. However, only a minority of American adults with high-risk alcohol use receive treatment. Three medications are approved by the U.S. Food and Drug Administration to treat alcohol use disorder: acamprosate, disulfiram, and naltrexone. Acamprosate and naltrexone reduce alcohol consumption and increase abstinence rates, although the effects appear to be modest. Disulfiram has been used for years, but evidence supporting its effectiveness is inconsistent. Other medications may be beneficial to reduce heavy alcohol use. The anticonvulsants topiramate and gabapentin may reduce alcohol ingestion, although long-term studies are lacking. Antidepressants do not decrease alcohol use in patients without mood disorders, but sertraline and fluoxetine may help depressed patients decrease alcohol ingestion. Ondansetron may reduce alcohol use, particularly in selected subpopulations. Further study is needed for genetically targeted or as-needed medications to reduce alcohol use. PMID- 26977831 TI - Diagnosis and Management of Endometrial Cancer. AB - Endometrial cancer is the most common gynecologic malignancy. It is the fourth most common cancer in women in the United States after breast, lung, and colorectal cancers. Risk factors are related to excessive unopposed exposure of the endometrium to estrogen, including unopposed estrogen therapy, early menarche, late menopause, tamoxifen therapy, nulliparity, infertility or failure to ovulate, and polycystic ovary syndrome. Additional risk factors are increasing age, obesity, hypertension, diabetes mellitus, and hereditary nonpolyposis colorectal cancer. The most common presentation for endometrial cancer is postmenopausal bleeding. The American Cancer Society recommends that all women older than 65 years be informed of the risks and symptoms of endometrial cancer and advised to seek evaluation if symptoms occur. There is no evidence to support endometrial cancer screening in asymptomatic women. Evaluation of a patient with suspected disease should include a pregnancy test in women of childbearing age, complete blood count, and prothrombin time and partial thromboplastin time if bleeding is heavy. Most guidelines recommend either transvaginal ultrasonography or endometrial biopsy as the initial study. The mainstay of treatment for endometrial cancer is total hysterectomy with bilateral salpingo-oophorectomy. Radiation and chemotherapy can also play a role in treatment. Low- to medium-risk endometrial hyperplasia can be treated with nonsurgical options. Survival is generally defined by the stage of the disease and histology, with most patients at stage I and II having a favorable prognosis. Controlling risk factors such as obesity, diabetes, and hypertension could play a role in the prevention of endometrial cancer. PMID- 26977832 TI - Diagnosis and Management of Nephrotic Syndrome in Adults. AB - Nephrotic syndrome (NS) consists of peripheral edema, heavy proteinuria, and hypoalbuminemia, often with hyperlipidemia. Patients typically present with edema and fatigue, without evidence of heart failure or severe liver disease. The diagnosis of NS is based on typical clinical features with confirmation of heavy proteinuria and hypoalbuminemia. The patient history and selected diagnostic studies rule out important secondary causes, including diabetes mellitus, systemic lupus erythematosus, and medication adverse effects. Most cases of NS are considered idiopathic or primary; membranous nephropathy and focal segmental glomerulosclerosis are the most common histologic subtypes of primary NS in adults. Important complications of NS include venous thrombosis and hyperlipidemia; other potential complications include infection and acute kidney injury. Spontaneous acute kidney injury from NS is rare but can occur as a result of the underlying medical problem. Despite a lack of evidence-based guidelines, treatment consisting of sodium restriction, fluid restriction, loop diuretics, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, and careful assessment for possible disease complications is appropriate for most patients. Renal biopsy is often recommended, although it may be most useful in patients with suspected underlying systemic lupus erythematosus or other renal disorders, in whom biopsy can guide management and prognosis. Immunosuppressive treatment, including corticosteroids, is often used for NS, although evidence is lacking. Routine prophylactic treatment to prevent infection or thrombosis is not recommended. A nephrologist should be consulted about use of anticoagulation and immunosuppressants, need for renal biopsy, and for other areas of uncertainty. PMID- 26977833 TI - Bell Palsy: A Frightening Symptom Can Lead to Unnecessary Testing. PMID- 26977834 TI - Electronic Cigarettes for Smoking Cessation. PMID- 26977835 TI - Chronic Anal Fissures. PMID- 26977836 TI - Screening for Depression in Children and Adolescents: Recommendation Statement. PMID- 26977837 TI - Screening for High Blood Pressure in Adults. PMID- 26977838 TI - Diffuse, Hyperpigmented Rash in an Adult. PMID- 26977839 TI - Preexposure Prophylaxis with Tenofovir/Emtricitabine Prevents HIV Infection In Men who Have Unprotected Anal Intercourse. PMID- 26977840 TI - Systolic BP of 120 instead of 140 in High-Risk Older Patients Without Diabetes Leads to Significant Benefits and Some Harms. PMID- 26977841 TI - DGAC Makes Food-Based Recommendations in the 2015-2020 Dietary Guidelines for Americans. PMID- 26977842 TI - American Academy of Pediatrics Releases Report on Infantile Hemangiomas. PMID- 26977843 TI - What You Need to Know About Medicine for Alcohol Use Disorder. PMID- 26977844 TI - Endometrial (Uterine) Cancer: What You Need to Know. PMID- 26977845 TI - Nephrotic Syndrome. PMID- 26977846 TI - Natural biology and management of nonmuscle invasive bladder cancer. AB - PURPOSE OF REVIEW: This article reviews the natural biology of noninvasive bladder cancer and its management strategies while summarizing the most recent advances in the field. RECENT FINDINGS: Nonmuscle invasive bladder cancer (NMIBC) has a tendency to recur and progress. Risk stratification has helped triage patients but improved tools, including biomarkers, are still needed. Enhanced endoscopy with photodynamic imaging, narrow band imaging, optical coherence tomography and confocal laser endomicroscopy show promise for diagnosis, risk stratification and disease monitoring. Attempts at better treatment, especially in refractory high-risk cases, include the addition of intravesical hyperthermia, combination and sequential therapy with existing agents and the use of novel agents such as mycobacterial cell wall extract. New data are emerging regarding the potential role of active surveillance in low-risk patients. SUMMARY: NMIBC represents a variety of disease states and continues to pose management challenges. As our understanding of tumor biology improves and technology advances, achieving better outcomes through individualized care may be possible. PMID- 26977847 TI - The evolving role of immunotherapy in prostate cancer. AB - PURPOSE OF REVIEW: In recent clinical trials, immunotherapeutic agents have demonstrated promising results for the treatment of prostate cancer. This review discusses emerging immunotherapies for prostate cancer and their evolving role in sequencing and combination therapy. RECENT FINDINGS: Therapeutic vaccines including PROSTVAC and DCVAC/PCa have completed promising phase 2 trials for the treatment of prostate cancer and phase 3 trials are underway. Recent evidence supports a synergistic relationship between immunotherapy agents themselves, antiandrogens and with cytotoxic chemotherapy. Prostate cancer patients with good prognostic factors, such as minimal disease burden, appear to achieve the optimal benefit from immunotherapy. SUMMARY: Therapeutic cancer vaccines and immunomodulating agents have demonstrated activity in the treatment of prostate cancer. Immunotherapies may alter the prostate tumor microenvironment and ongoing studies aim to provide guidance on effective sequencing and combination strategies. PMID- 26977848 TI - Structural Equation Model of Disability in Low Back Pain. AB - STUDY DESIGN: The effects of participant characteristics along with descriptions of pain and psychological involvement, such as fear avoidance, were assessed using structural equation modeling (SEM) to identify relationships between these factors and disability as a result of low back pain (LBP). OBJECTIVE: The aim of this study was to evaluate the relationship between factors related to pain description, participants' characteristics, psychological involvement, and disability through SEM. SUMMARY OF BACKGROUND DATA: LBP is a complex multifactorial condition that can lead to disability. Understanding which factors contribute to disability and how those factors interact is important for predicting and minimizing disability in patients with LBP. METHODS: We analyzed data from 156 participants (63% female) with LBP. A stepwise SEM was built with patient characteristics, pain intensity, depression, anxiety, and fear avoidance to predict disability in LBP. RESULTS: Participants were 23-84 years (49.7 +/- 15.1 yrs) of age and experienced 0.03 to 300 months duration (25.5 +/- 36.4 months) of current LBP. The final model explained 62% of the variance in disability and included female gender, full-time employment, depression, and fear avoidance beliefs as significant predictors. Full-time employment was the only significant predictor that reduced disability; all other significant predictors increased disability in the model. CONCLUSION: Understanding the relationship between these predictors and disability provides a foundation for predicting and managing disability for individual patients who suffer from LBP. LEVEL OF EVIDENCE: 3. PMID- 26977849 TI - Utilization of Lumbar Spinal Fusion in New York State: Trends and Disparities. AB - STUDY DESIGN: Retrospective review of an administrative database. OBJECTIVE: To observe New York statewide trends in lumbar spine surgery and to compare utilization of fusion according to hospital size and patient population. SUMMARY OF BACKGROUND DATA: Over the last 30 years, studies have indicated increasing rates of spinal fusion procedures performed each year in the United States. There is no study investigating potential variability in this trend according to hospital volume. METHODS: New York Statewide Planning and Research Cooperative System (SPARCS) administrative data were used to identify 228,882 lumbar spine surgery patients. New York State hospitals were categorized as low-, medium-, or high-volume and descriptive statistics were used to determine trends in spinal fusion. RESULTS: The number of fusions per year increased 55% from 2005 to 2014. The ratio of fusion to nonfusion surgery increased from 0.88 to 2.67 at high volume, from 0.84 to 2.30 at medium- volume, and from 0.66 to 1.52 at low-volume hospitals. In 2014, 22% of spine surgery patients at low-volume hospitals were either African Americans or Hispanics compared with 12% and 14% at high- and medium-volume hospitals, respectively. At high-volume hospitals, 33% of patients were privately insured and 3% had Medicare compared with 30% and 6% at low-volume hospitals. CONCLUSION: The annual number of lumbar spinal fusions continues to increase, especially at high- and medium-volume hospitals. The percentage of patients treated surgically for lumbar spinal stenosis that undergoes fusion ranges from 53.2 to 66.4% depending on hospital volume. Individual surgeon opinion, patient disease characteristics, and socioeconomic factors may affect surgical decision making. Caucasians and private insurance patients most often receive care at high-volume hospitals. Minorities and patients with Medicaid are over-represented at low-volume centers where fusions are less often performed. Accessibility to care at high-volume centers remains a major concern for these vulnerable populations. LEVEL OF EVIDENCE: 3. PMID- 26977850 TI - Posterior Only Approach for Lumbar Pyogenic Spondylitis With Short Instrumentation and Prolonged Suction Drainage. AB - STUDY DESIGN: A single-institution, single-surgeon retrospective review. OBJECTIVE: To assess the efficacy of posterior only approach with short instrumentation and prolonged suction drainage in managing lumbar pyogenic spondylitis. SUMMARY OF BACKGROUND DATA: Several methods of posterior surgical treatment for pyogenic spondylitis have been reported, there have been few reports regarding the efficacy of posterior only approach with short instrumentation including even inflamed segment. METHODS: Thirty-three patients with lumbar pyogenic spondylitis who underwent posterior decompression and lumbar interbody fusion with short instrumentation including the inflamed segment and catheter drainage were enrolled. Clinically infection control (erythrocyte sedimentation rate and C-reactive protein normalization time) and onset of ambulation were reviewed. Moreover, achievement of fusion and changes of sagittal alignment were investigated radiologically. RESULTS: In all 33 cases, infection was controlled successfully without any recurrence. There was no breakage of implant. Postoperative interval to normalization of erythrocyte sedimentation rate was average 69.4 days and C-reactive protein was 25.4 days, respectively. Ambulation was started at average 5.8 postoperative days. Successful interbody fusion was confirmed radiologically in all the cases at a mean of 5.4 months. Sagittal angle of fixed segment was average 6.9 degrees of lordosis before operation, which became more lordotic to 11.5 degrees just after operation, but decreased to 4.7 degrees of lordosis at the final follow up. Actually final sagittal alignment was almost same as preoperative status (P = 0.24). CONCLUSION: By achieving favorable clinical and radiological results, short instrumentation and prolonged suction drainage with posterior only approach seemed to be an effective method in managing lumbar pyogenic spondylitis. LEVEL OF EVIDENCE: 3. PMID- 26977851 TI - Food Costs Are Higher in Counties With Poor Health Rankings. AB - BACKGROUND: Poor dietary habits are associated with higher rates of cardiovascular disease. However, the cost of foods associated with lower risk of cardiovascular disease can be a significant barrier to healthy eating. OBJECTIVE: The aim of this study is to determine whether food prices per serving differed across Kentucky counties based on health ranking and overall nutritional quality. METHODS: Fifteen counties were randomly selected based on County Health Ranking. Overall Nutritional Quality Index and cost of 75 foods were assessed in all 15 counties in the same week. A generalized estimating equations model and post hoc analyses were used to assess differences in food cost by nutritional quality and health ranking. RESULTS: Food prices were significantly less in the most healthy counties compared with the least healthy (Z = 3.8; P < .001; $0.08 per serving). Prices were also significantly higher in least healthy counties (tertile 3) compared with moderately healthy counties (tertile 2) (Z = 2.3; P = .024; $0.05 per serving). CONCLUSIONS: Disproportionately higher food costs are associated with poor health outcomes in Kentucky counties. Community-based interventions can potentially improve access to affordable healthy foods. Current supplemental nutritional policies do not address disparate food costs. Health professionals should advocate for policy changes that are reflective of these food cost disparities. PMID- 26977852 TI - Early versus late tracheostomy in cardiovascular intensive care patients. AB - BACKGROUND: Benefits of tracheostomy have been well established. Most of the literature, refers these benefits to general intensive care population, excluding cardiac surgery or including only small number of these patients. On the other hand, there is no clear definition describing the proper time to perform the procedure and defining what are potential benefits of early compared to late tracheostomy. This retrospective cohort aims to assess the potential benefits of early tracheostomy on post-operative outcomes, length of stay and post tracheostomy complications within cardiac surgical population. METHODS: After obtaining REB approval, we conducted a retrospective chart review in a single, tertiary care institution, identifying patients who underwent tracheostomy after cardiac surgery from 1999 to 2006. Time-to-tracheostomy was defined as "early" if < 7 days or "late" if >= 7 days post-cardiac surgery). RESULTS: 14,101 patients underwent cardiac surgery over the 7-year study period; from those, 147 (1.36%) received tracheostomy. 32 (22%) patients underwent early tracheostomy and 115 (78%) late tracheostomy. Incidence of atrial fibrillation (31.2% vs 61.7%; P = 0.003), kidney dysfunction (6.3% vs 27.2%; P=0.015) and kidney failure 18.8% vs 43.5%; P = 0.013) were lower in the early tracheostomy group. There were no differences on post tracheostomy infection or presence of acute respiratory distress syndrome. Both the ICU and hospital length of stay were significantly shorter in early tracheostomy group, 21.5 (ET) vs 36.9 (LT) days and 37.5 (ET) vs 57.6 (LT) days respectively. There were no differences in mortality between groups. CONCLUSIONS: There are significant benefits in reduction of postoperative morbidities with overall shorter ICU and hospital stay. These benefits may promote faster patient rehabilitation with reduced healthcare costs. PMID- 26977853 TI - Hypersensitivity lo local anesthetics. AB - Using local anaesthetics in daily practice, particularly by anaesthetists and dentists, is connected with the risk of side effects. Therefore, the observation of side effects, carrying out detailed research (according to the chart proposed in this study) and conducting specialist examinations is of the highest importance. There is a variety of side effects that could occur during local anaesthesia procedures, with the intensity ranging from clinically unimportant to life threatening. Clinicians' major concerns are the appearance of various hypersensitivity reactions, including anaphylaxis. Healthcare providers responsible for the administration of local anaesthetics should be able to detect hypersensitivity reactions to implement appropriate treatment and then choose highly selected diagnostic procedures. The final diagnosis should be based on specific medical history; documentation, including a description of the case and measurement of tryptase activity; skin tests; and provocation trials. Screening tests are not recommended in populations without hypersensitivity to local anaesthestics in their medical history. PMID- 26977854 TI - Maternal Origin and Risk of Neonatal and Maternal ICU Admission. AB - OBJECTIVES: To evaluate maternal world region of birth, as well as maternal country of origin, and the associated risk of admission of 1) a mother to a maternal ICU, 2) her infant to a neonatal ICU, or 3) both concurrently to an ICU. DESIGN: Retrospective population-based cohort study. SETTING: Entire province of Ontario, Canada, from 2003 to 2012. PATIENTS: All singleton maternal-child pairs who delivered in any Ontario hospital. MEASUREMENTS AND MAIN RESULTS: We explored how maternal world region of birth, and specifically, maternal country of birth for the top 25 countries, was associated with the outcome of 1) neonatal ICU, 2) maternal ICU, and 3) both mother and newborn concurrently admitted to ICU. Relative risks were adjusted for maternal age, parity, income quintile, chronic hypertension, diabetes mellitus, obesity, dyslipidemia, drug dependence or tobacco use, and renal disease. Compared with infants of Canadian-born mothers (110.7/1,000), the rate of neonatal ICU admission was higher in immigrants from South Asia (155.2/1,000), Africa (140.4/1,000), and the Caribbean (167.3/1,000; adjusted relative risk, 1.41; 95% CI, 1.36-1.46). For maternal ICU, the adjusted relative risk was 1.79 (95% CI, 1.43-2.24) for women from Africa and 2.21 (95% CI, 1.78-2.75) for women from the Caribbean. Specifically, mothers from Ghana (adjusted relative risk, 2.71; 95% CI, 1.75-4.21) and Jamaica (adjusted relative risk, 2.74; 95% CI, 2.12-3.53) were at highest risk of maternal ICU admission. The risk of both mother and newborn concurrently admitted to ICU was even more pronounced for Ghana and Jamaica. CONCLUSIONS: Women from Africa and the Caribbean and, in particular, Ghana and Jamaica, are at higher risk of admission to ICU around the time of delivery, as are their newborns. PMID- 26977855 TI - Glycated Hemoglobin A1c Levels Are Not Affected by Critical Illness. AB - OBJECTIVES: Glycated hemoglobin A1c is used to estimate glycemic control. However, its value upon ICU admission may be altered by critical illness and not reflect true glycemic status. We assessed the relationship between ICU admission glycated hemoglobin A1c and premorbid glycated hemoglobin A1c levels. DESIGN: Retrospective observational cohort study. SETTING: Two tertiary ICUs in Australia. PATIENTS: Cohort of 69 critically ill patients with diabetes and glycated hemoglobin A1c levels measured upon ICU admission and during the month prior to admission. INTERVENTIONS: Measurement of glycated hemoglobin A1c. MEASUREMENTS AND MAIN RESULTS: Mean (SD) glycated hemoglobin A1c level was 7.5% (1.8%) upon ICU admission and 7.8% (2.0%) in previous measurements from the preceding 30 days. The change in glycated hemoglobin A1c did not correlate with time elapsed between the two measurements (r = 0.00005; p = 0.95), but there was a strong correlation between admission glycated hemoglobin A1c levels and premorbid glycated hemoglobin A1c levels (r = 0.89; p < 0.001). CONCLUSIONS: Glycated hemoglobin A1c levels are not altered by the onset of critical illness. Glycated hemoglobin A1c quantified at ICU admission can, therefore, be used to reliably estimate chronic glycemic control and guide acute glycemic therapy. PMID- 26977857 TI - Predictive value of mucinous histology in colon cancer: a population-based, propensity score matched analysis. AB - BACKGROUND: This investigation aimed to assess whether mucinous histology impacts overall (OS) and cancer-specific survival (CSS) in colon cancer. METHODS: Colon cancer patients who underwent surgery between 2004 and 2011 were identified in the Surveillance, Epidemiology, and End Results database. OS and CSS were assessed using Cox regression and propensity score methods. RESULTS: Out of 121 628 patients, 12 863 (10.6%) had a mucinous histology. Five-year OS and CSS for mucinous adenocarcinoma were 54.4% (95% CI: 53.4-55.5%) and 66.5% (95% CI: 65.5 67.5%) compared with 60.2% (95% CI: 59.8-60.5%) and 71.9% (95% CI: 71.5-72.2%) for non-mucinous adenocarcinoma (P<0.001). This survival disadvantage disappeared in multivariable analyses (hazard ratio (HR)=1.02, 95% CI: 0.99-1.05, P=0.269 and HR=1.03, 95% CI: 0.99-1.06, P=0.169), and after propensity score matching (OS: HR=0.99, 95% CI: 0.93-1.04, P=0.606 and CSS: HR=0.99, 95% CI:0.92-1.06, P=0.783). CONCLUSIONS: In this population-based investigation, a mucinous histology did not negatively impact survival. Hence, the present study does not provide evidence to change treatment strategies in patients with mucinous adenocarcinoma of the colon. PMID- 26977856 TI - Use of a 12 months' self-referral reminder to facilitate uptake of bowel scope (flexible sigmoidoscopy) screening in previous non-responders: a London-based feasibility study. AB - BACKGROUND: In March 2013, NHS England extended its national Bowel Cancer Screening Programme to include 'one-off' Flexible Sigmoidoscopy screening (NHS Bowel Scope Screening, BSS) for men and women aged 55. With less than one in two people currently taking up the screening test offer, there is a strong public health mandate to develop system-friendly interventions to increase uptake while the programme is rolling out. This study aimed to assess the feasibility of sending a reminder to previous BSS non-responders, 12 months after the initial invitation, with consideration for its potential impact on uptake. METHOD: This study was conducted in the ethnically diverse London Boroughs of Brent and Harrow, where uptake is below the national average. Between September and November 2014, 160 previous non-responders were randomly selected to receive a reminder of the opportunity to self-refer 12 months after their initial invitation. The reminder included instructions on how to book an appointment, and provided options for the time and day of the appointment and the gender of the endoscopist performing the test. To address barriers to screening, the reminder was sent with a brief locally tailored information leaflet designed specifically for this study. Participants not responding within 4 weeks were sent a follow-up reminder, after which there was no further intervention. Self-referral rates were measured 8 weeks after the delivery of the follow-up reminder and accepted as final. RESULTS: Of the 155 participants who received the 12 months' reminder (returned to sender, n=5), 30 (19.4%) self-referred for an appointment, of which 24 (15.5%) attended and were successfully screened. Attendance rates differed by gender, with significantly more women attending an appointment than men (20.7% vs 8.8%, respectively; OR=2.73, 95% CI=1.02-7.35, P=0.05), but not by area (Brent vs Harrow) or area-level deprivation. Of the 30 people who self-referred for an appointment, 27 (90%) indicated a preference for a same-sex practitioner, whereas three (10%) gave no preference. Preference for a same-sex practitioner was higher among women than men (chi(2)=7.78, P<0.05), with only 67% of men (six of nine) requesting a same-sex practitioner, compared with 100% of women (n=21). CONCLUSIONS: Sending previous non-responders a 12 months' reminder letter with a brief information leaflet is a feasible and efficacious intervention, which merits further investigation in a randomised controlled trial. PMID- 26977859 TI - Pregnancy in a Series of Dystonia Patients Treated with Deep Brain Stimulation: Outcomes and Management Recommendations. AB - BACKGROUND: Medically refractory dystonia affects children and young adults, and deep brain stimulation (DBS) can allow some patients to regain functional independence. Women with dystonia treated with DBS may wish to conceive a child, but there is limited published information on pregnancy and DBS. OBJECTIVE: To describe a series of dystonia patients treated with DBS who later became pregnant and provide guidelines for women treated with DBS considering conception. METHODS: We reviewed all dystonia DBS cases implanted at the University of California, San Francisco, and University of Alabama at Birmingham from 1998 to 2015 and identified patients who became pregnant. Patient records were reviewed and structured interviews were conducted. RESULTS: Six dystonia patients were identified [1 currently pregnant and 7 live births (including 1 twin pair)]. Patients (n = 5) with pre- and postoperative BFMDRS (Burke-Fahn-Marsden Dystonia Rating Scale) scores improved by 65.9% after DBS. All pregnancies and deliveries were uncomplicated (the delivery mode was not influenced by the presence of DBS), except for 1 child, who was born premature at 35 weeks' gestation. Stimulation remained on (n = 3) or off (n = 4) during deliveries. DBS neurostimulators did not hinder breastfeeding. CONCLUSIONS: In this small sample, pregnancy, delivery, and breastfeeding were safe in dystonia patients treated with DBS. The presence of DBS should not be a contraindication to pregnancy. PMID- 26977860 TI - Topical Application of Honey on Surgical Wounds: A Randomized Clinical Trial. AB - BACKGROUND: The antimicrobial and anti-inflammatory activity of honey and its ability to accelerate wound healing make it an attractive option in surgical wound care. We performed a randomized clinical trial to compare the efficacy of honey dressing with conventional dressing regarding the aesthetic outcome. PATIENTS AND METHODS: Bilateral symmetric incisions in randomly selected plastic surgical patients were randomly covered postoperatively with conventional dressing and honey dressing for five days. The aesthetic outcome of the two sides was rated on a Visual Analog Scale by the surgeon and the patient and compared at month three and six after surgery. RESULTS: Seventy two symmetrical incisions in 52 patients were evaluated during the study. The mean width of the scar after the third and the sixth month was 3.64 +/- 0.83 mm and 3.49 +/- 0.87 mm on the side that received honey dressing and 5.43 +/- 0.05 mm and 5.30+/- 1.35 mm in the control group. Wilcoxon signed-rank test showed significant difference between honey and conventional dressing outcomes at third and sixth month (p < 0.001). CONCLUSION: The healing process of the surgical wound and its final aesthetic result could be improved by using honey dressing. PMID- 26977861 TI - [Blunt abdominal trauma. Spleen injuries. Part 2]. PMID- 26977858 TI - Previous tonsillectomy modifies odds of tonsil and base of tongue cancer. AB - BACKGROUND: Tonsillectomy is a commonly performed surgical procedure that involves removal of the palatine tonsils. The purpose of this study is to examine the association between previous tonsillectomy and odds of oropharyngeal squamous cell carcinoma (OPSCC) in a large population-based case-control study. We hypothesise that previous tonsillectomy is associated with a decreased odds of tonsil cancer with no impact on the odds of developing base of tongue (BOT) cancer. METHODS: This was a population-based, frequency-matched case-control study with multinomial logistic regression, including 1378 controls, 108 BOT cancer cases, and 198 tonsil cancer cases. Demographic and risk factor data were collected using a structured questionnaire during an in-home visit conducted by trained nurse-interviewers. The human papillomavirus (HPV) tumour status was determined through Luminex-based multiplex PCR and p16 status by immunohistochemistry. RESULTS: Previous tonsillectomy was associated with a nearly two-fold increased odds of BOT cancer (OR=1.95, 95% CI 1.25-3.06, P=0.003) and a large decrease in the odds of tonsil cancer (OR=0.22, 95% CI 0.13-0.36, P<0.001). When HPV status was considered, tonsillectomy was associated with a decreased odds of HPV-positive tonsil cancer (OR=0.17, 95% CI 0.08-0.34, P<0.001) and an increased risk of HPV-positive BOT cancer (OR=2.46, 95% CI 1.22-4.95, P=0.012). When p16 status was considered, tonsillectomy was associated with an increased odds of p16-positive BOT cancer (OR=2.24, 95% CI 1.16-4.35, P=0.017) and a decreased odds of p16-positive tonsil cancer (OR=0.14, 95% CI 0.07-0.31, P<0.001). CONCLUSIONS: Previous tonsillectomy modifies the odds of both tonsil and BOT cancer, with decreased odds of tonsil cancer and increased odds of BOT cancer. A history of previous tonsillectomy may play a role in OPSCC risk stratification when considered along with other covariates such as sexual history, smoking status, and age. PMID- 26977862 TI - [Solid lesions of heart valves]. AB - AIM: To analyze clinical-diagnostic and surgical aspects of cardiac valve solid lesions as well as long-term results of surgical treatment. MATERIAL AND METHODS: Clinical, diagnostic and surgical aspects of treatment of 51 patients with tumorous and pseudotumorous lesions of cardiac valves were analyzed. RESULTS AND DISCUSSION: Hospital complications were observed in 17.7% of patients. Mortality rate was 3.9%. 1- and 28-year overall survival was 100% and 94.1% respectively. Quality of life was good, satisfactory and unsatisfactory in 73.5%, 20.4% and 6.1% of cases respectively. CONCLUSION: Timely diagnostics of tumorous and pseudotumorous lesions of cardiac valves is very difficult but possible based on short history, positional dependence of symptoms, embolic events without rhythm disturbances. Additional instrumental methods including TTE, TEE, CT and MRI are necessary to define diagnosis. Intraoperative diagnostics and immediate histological survey are useful to determine volume of surgery in each case. Successful surgical treatment implies urgency, hypothermic perfusion and pharmaco cold cardioplegia during operation. PMID- 26977863 TI - [Videolaparoscopic and morphological parallels in diagnosis of different forms of acute appendicitis]. AB - AIM: To compare results of macroscopic assessment and materials of histological examination of 1635 appendices removed using videolaparoscopy in patients with acute appendicitis. All patients have been treated in N.V.Sklifosovsky Research Institute of Emergency Care for the period from 2002 to 2014. MATERIAL AND METHODS: Intraoperative macroscopic assessment of appendix's inflammatory changes was performed using some conventional signs. Satarrhal, phlegmonous and gangrenous changes were suspected in 77 (4.7%), 1432 (87.5%) and 126 (7.7%) cases respectively. RESULTS: Histological examination revealed catarrhal, phlegmonous and gangrenous changes in 86 (5.3%), 1338 (81.8%) and 115 (7.0%) cases respectively. In 65 (4.0%) patients changes were estimated as chronic, 31 (1.9%) patients had not inflammation. Intraoperatively suspected diagnosis of different forms of appendicitis was confirmed by histological survey in 94.1%. Most cases of matched intraoperative and histological diagnosis were observed in case of phlegmonous appendicitis (88.2%). Only 5.9% of patients had not acute inflammation of appendix that may be explained by overdiagnosis and excess of indications for appendectomy. PMID- 26977865 TI - [Delayed coloesophagoplasty in difficult clinical situations]. AB - AIM: To improve immediate and long-term results of delayed coloesophagoplasty in cancer patients. MATERIAL AND METHODS: We presented three case reports of coloesophagoplasty in difficult clinical situations including technical impossibility of primary plasty, extraordinary anesthetic situation, transplant necrosis after primary plasty. RESULTS: Gastrointestinal tract integrity was restored in all cases and patients returned to nutrition per os, that provided good quality of life and compensated nutritional deficiencies. Only one patient had bleeding in postoperative period that required relaparotomy. There were no postoperative complications in two other patients. CONCLUSION: Delayed coloesophagoplasty should be performed in all patients who underwent esophagogastrectomy if progression of primary disease is absent. Graft placement and colic segment are chosen individually. However left half of colon with retrosternal location of transplant is preferable for plasty. PMID- 26977864 TI - [Comparison of Doppler-assisted dearterialization with mucopexy and hemorrhoidectomy]. AB - AIM: To compare two methods of hemorrhoid treatment. MATERIAL AND METHODS: This prospective study included 240 patients with hemorrhoids stage III-IVA. Stages III and IVA were diagnosed in 156 (65%) and 84 (35%) patients respectively. Randomization was performed using envelopes method in one to one distribution. In group 1 (n=120) Doppler-assisted dearterialization of internal hemorrhoids with mucopexy was performed (DDM), in group 2 (n=120) - hemorrhoidectomy using harmonic scalpel (HE). RESULTS: Duration of surgery was 17.9+/-6.1 and 34.5+/ 10.1 minutes in DDM and HE groups respectively (p<0.01). Postoperative pain severity was higher in group 2 (4.8 compared with 2.5 scores of the first group (p<0.01). Narcotic analgesics were used less often in DDM group (1.3 doses compared with 6.1 doses in HE group (p<0.01). Disability period was 14.4+/-5.2 and 30.3+/-5.4 days in both groups respectively (p<0.01). Immediate postoperative complications occurred in 9 (7.5%) and 19 (15.8%) patients of DDM and HE groups respectively. Recurrent prolapse of internal hemorrhoids was diagnosed in 2 (1.7%) patients of the 1st group in terms of up to 45 days. CONCLUSION: DDM is reliable minimally invasive method of hemorrhoids stage III-IVA treatment and has similar efficacy with HE. DDM reduces postoperative pain severity, hospital stay and disability period. PMID- 26977866 TI - [Vacuum-therapy for complicated anterior abdominal wall wounds and intestinal fistulas in children]. AB - AIM: To present results of VAC application in children with complicated wounds of anterior abdominal wall combined with intestinal and/or biliary fistulas. MATERIAL AND METHODS: For the last 7 years 8 patients aged from 1.5 months to 15 years with infected postoperative wounds of anterior abdominal wall complicated by intestinal fistulas (6), biliary and intestinal fistulas (1) and biliary fistula (1) have been treated at the surgical department No2 of Russian Children's Clinical Hospital. All patients received complex medical therapy and local VAC-therapy. RESULTS: Granulation and wound's size reduction were observed within first 7 days of VAC-therapy application in 5 (62.5%) children. In 4 (50%) patients at least 1 intestinal fistula has been closed in 15 days after VAC therapy initiation on the average (range 7--24). Closure of all fistulas and wounds healing were observed in all patients in 28 days (range 16--42) after VAC therapy initiation on the average. CONCLUSION: VAC-therapy is safe and effective treatment of complicated wounds of anterior abdominal wall combined with intestinal and/or biliary fistulas in children. PMID- 26977867 TI - [Endovascular arterial embolization for duodenal bleeding as an alternative to surgical approach]. AB - AIM: To present possibilities of transcatheter arterial embolization (TAE) in duodenal bleeding management. MATERIAL AND METHODS: Treatment of 212 patients with acute duodenal bleeding for the period from 2012 to 2014 was analyzed. In 32 (22.5%) patients of the study group bleeding recurrence or its high risk was indication for TAE. RESULTS: Change of surgical tactics for bleeding from upper gastrointestinal tract including endoscopic hemostasis optimization, wide introduction of TAE and sharp decrease of surgical activity reduced overall mortality to 1.6% in 2012--2014. CONCLUSION: TAE is effective to control bleeding and reduces mortality rate especially in high risk and elderly patients. PMID- 26977868 TI - [Analysis of dynamic implants use in surgical treatment of degenerative lumbar spine stenosis]. AB - AIM: To improve the results of surgical treatment of lumbar spine stenosis. MATERIAL AND METHODS: Surgical treatment of 84 patients was analyzed. There were 2 groups consisting of 48 and 36 patients respectively. Advanced decompression and fusion were performed in group 1, minimally invasive decompression (flavectomy, marginal arch resection, facetectomy) with implantstion of interspinous dynamic implants DIAM -- in group 2. Patients with isthmic spondylolisthesis were excluded. RESULTS AND DISCUSSION: Both methods did not show difference in efficacy of leg pain relief during follow-up (1.7--8.5 years). 16.7% of patients after fusion of more than 2 segments had pain above and below fusion area in long-term postoperative period. Such pain was not observed in group 2. One patient of the 1st group had fixation system destruction that required repeated intervention. Groups have not difference in back pain severity after surgery on 1 segment. Also less intraoperative blood loss and duration of surgery were established in group 2. CONCLUSION: Minimally invasive decompression with implantstion of interspinous dynamic implants is effective and safe alternative to advanced decompression and fusion in lumbar spine stenosis management. PMID- 26977869 TI - [Violations of oxygen transport function of hemoglobin in surgical endointoxication and their correction using remaxol]. AB - AIM: To study the effectiveness of remaxol in erythrocytes oxygen transport function correction in patients with surgical endotoxicosis. MATERIAL AND METHODS: Two groups of patients (main (n = 25) and comparison (n = 27) groups) with acute appendicitis complicated by peritonitis were compared. All patients underwent standard postoperative treatment including infusion therapy 1600--2000 ml/day, antibiotics as combination of semi-synthetic penicillins and aminoglycosides, anesthetic and desensitizing therapy. In the main group daily intravenous infusion of remaxol 400 ml for 5 days was used. The first dose was administered intraoperatively or immediately after surgery. Patients underwent emergency surgery and destructive forms of acute appendicitis accompanied by diffuse purulent or purulent-fibrinous peritonitis were diagnosed. Removal of appendix, debridement and drainage of the abdominal cavity were performed. Observation of clinical and laboratory tests were carried out at admission and in 1, 3, 5 days after surgery. CONCLUSION: Acute peritonitis leads to changes of hemoglobin conformation and its oxygen-binding capacity according to spectroscopy that is an important factor in the development of general hypoxia. The greatest changes in the hemoglobin molecule were found in the 1st day after surgery as a result of surgical aggression. It is proved that modified conformational state of hemoglobin is associated with processes of lipid peroxidation and endogenous intoxication. Combined therapy with remaxol is effective to correct oxygen transport function of hemoglobin in acute peritonitis. Pronounced positive effect of the drug weakening manifestations of surgical aggression is noted after the first administration. Therapeutic efficacy of the drug is explained by its ability to reduce lipid peroxidation. Rapid recovery of homeostasis including decrease of general hypoxia using remaxol resulted in a clinical benefit. PMID- 26977870 TI - [Ultrasound dynamics lysis apex thrombus as an objective criterion of effectiveness of anticoagulation therapy in venous thrombosis]. AB - OBJECTIVE OF THE STUDY: To assess the effectiveness of anticoagulant therapy (ACT) for the treatment of patients with deep venous thrombosis (DVT) of the lower extremities. MATERIAL AND METHODS: The study considered ultrasonic characteristics of lysis of the proximal part of thrombus: localization and nature of venous thrombosis, the length and diameter of the proximal floating part of the thrombus, and duration of the venous thrombosis. Depending on the ACT options patients were divided into 3 groups: Group 1 (18 patients) received rivaroxaban, group 2 (19 patients) received enoxaparin sodium with subsequent transition to warfarin, and 3 group (19 patietns) received enoxaparin sodium, followed by administration of rivaroxaban. RESULTS: Treatment with rivaroxaban was preferable over standard ACT with enoxaparin/warfarin with regards to the lysis of thrombus when duration of thrombosis did not exceed 10 days. In 10.5% of patients who received warfarin flotation of thrombi remained for 14 days; the length of the floating part of the thrombi did not exceed 3 cm. Such circumstances and inability to reach a therapeutic INR value required cava filter placement. Treatment with enoxaparin sodium followed by the administration of rivaroxaban was found to be the most efficient ACT regimen as there was no negative dynamics of ultrasound characteristics of lysis of thrombi at any duration of the disease. PMID- 26977871 TI - [Role of octreotide and prednisolone in prophylactic of poshepatectomy liver failure. Experimental study]. AB - AIM: Comparative morphologic assessment of the liver tissue response to the preoperative infusion of octreotide and prednisolon after the major hepatic resection was studied in rats. MATERIAL AND METHODS: 25 male Wistar rats weighing 230--280 g were used. All rats underwent 70--80% hepatectomy. The rats were divided into three groups according to the infusions before hepatectomy: group 1 (n=7) -- received octreotide, group 2 (n=8) -- prednisolone, group 3 (n=10) -- 0.9% saline solution as the control. Histologic features of the remnant liver were evaluated in the sacrificied rats after 72 hours post-hepatectomy. RESULTS: In the group 1 we observed more rapid decrease of edema and tendency to the accelerated regeneration process of hepatocytes. CONCLUSION: Octreotide infusion before the major hepatic resection may have protective effect on hepatocytes and accelerate the regeneration in the remnant liver. PMID- 26977872 TI - [Off-pump coronary artery bypass grafting and left atrium ligation]. PMID- 26977873 TI - CDK4/6 Inhibitors resTORe Therapeutic Sensitivity in HER2+ Breast Cancer. AB - CDK4/6 inhibitors have received approval for treating hormone-positive breast tumors, but whether other aggressive cancers respond to these molecules is not yet clear. In this issue of Cancer Cell, Goel et al. (2016) report an unexpected activity of CDK4/6 inhibitors in reducing mTOR function and re-sensitizing HER2 positive cancers to EGFR/HER2 blockade. PMID- 26977874 TI - HIV Drug to Aid Melanoma Therapies? AB - The HIV1 protease inhibitor nelfinavir is being investigated as a cancer therapeutic. In this issue of Cancer Cell, Smith et al. (2016) report that nelfinavir suppresses MITF expression induced by MAPK pathway inhibition in melanoma cells and sensitizes melanoma cells with NRAS or BRAF plus NRAS mutations to MEK inhibitors. PMID- 26977875 TI - KLF4 Initiates Acinar Cell Reprogramming and Is Essential for the Early Stages of Pancreatic Carcinogenesis. AB - Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and is minimally responsive to current chemotherapies. In this issue of Cancer Cell, Xie et al. (2016) identify the transcription factor KLF4 as essential for the early stages of pancreatic carcinogenesis, expanding the repertoire of targets for early intervention strategies. PMID- 26977876 TI - Mammary Ductal Environment Is Necessary for Faithful Maintenance of Estrogen Signaling in ER+ Breast Cancer. AB - In this issue of Cancer Cell, Sflomos et al. (2016) describe a robust preclinical animal model of ER+ breast cancer. The authors identify the critical role of the breast microenvironment in determining hormone response of ER+ breast cancer cells and in driving the luminal phenotype of breast cancer. PMID- 26977877 TI - Selective Targeting of the KRAS G12C Mutant: Kicking KRAS When It's Down. AB - Two recent studies evaluated a small molecule that specifically binds to and inactivates the KRAS G12C mutant. The new findings argue that the perception that mutant KRAS is persistently frozen in its active GTP-bound form may not be accurate. PMID- 26977878 TI - Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. AB - Using transgenic mouse models, cell line-based functional studies, and clinical specimens, we show that cyclin D1/CDK4 mediate resistance to targeted therapy for HER2-positive breast cancer. This is overcome using CDK4/6 inhibitors. Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC1 activity. This relieves feedback inhibition of upstream EGFR family kinases, resensitizing tumors to EGFR/HER2 blockade. Consequently, dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of TSC2 phosphorylation and hence mTORC1/S6K/S6RP activity. The suppression of both Rb and S6RP enhances G1 arrest and a phenotype resembling cellular senescence. In vivo, CDK4/6 inhibitors sensitize patient derived xenograft tumors to HER2-targeted therapies and delay tumor recurrence in a transgenic model of HER2-positive breast cancer. PMID- 26977879 TI - Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy. AB - Once melanomas have progressed with acquired resistance to mitogen-activated protein kinase (MAPK)-targeted therapy, mutational heterogeneity presents a major challenge. We therefore examined the therapy phase before acquired resistance had developed and discovered the melanoma survival oncogene MITF as a driver of an early non-mutational and reversible drug-tolerance state, which is induced by PAX3-mediated upregulation of MITF. A drug-repositioning screen identified the HIV1-protease inhibitor nelfinavir as potent suppressor of PAX3 and MITF expression. Nelfinavir profoundly sensitizes BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors. Moreover, nelfinavir is effective in BRAF and NRAS mutant melanoma cells isolated from patients progressed on MAPK inhibitor (MAPKi) therapy and in BRAF/NRAS/PTEN mutant tumors. We demonstrate that inhibiting a driver of MAPKi-induced drug tolerance could improve current approaches of targeted melanoma therapy. PMID- 26977880 TI - Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade. AB - Immune checkpoint blockade therapies fail to induce responses in the majority of cancer patients, so how to increase the objective response rate becomes an urgent challenge. Here, we demonstrate that sufficient T cell infiltration in tumor tissues is a prerequisite for response to PD-L1 blockade. Targeting tumors with tumor necrosis factor superfamily member LIGHT activates lymphotoxin beta receptor signaling, leading to the production of chemokines that recruit massive numbers of T cells. Furthermore, targeting non-T cell-inflamed tumor tissues by antibody-guided LIGHT creates a T cell-inflamed microenvironment and overcomes tumor resistance to checkpoint blockade. Our data indicate that targeting LIGHT might be a potent strategy to increase the responses to checkpoint blockades and other immunotherapies in non-T cell-inflamed tumors. PMID- 26977881 TI - A SIRT2-Selective Inhibitor Promotes c-Myc Oncoprotein Degradation and Exhibits Broad Anticancer Activity. AB - Targeting sirtuins for cancer treatment has been a topic of debate due to conflicting reports and lack of potent and specific inhibitors. We have developed a thiomyristoyl lysine compound, TM, as a potent SIRT2-specific inhibitor with a broad anticancer effect in various human cancer cells and mouse models of breast cancer. Mechanistically, SIRT2 inhibition promotes c-Myc ubiquitination and degradation. The anticancer effect of TM correlates with its ability to decrease c-Myc level. TM had limited effects on non-cancerous cells and tumor-free mice, suggesting that cancer cells have an increased dependency on SIRT2 that can be exploited for therapeutic benefit. Our studies demonstrate that SIRT2-selective inhibitors are promising anticancer agents and may represent a general strategy to target certain c-Myc-driven cancers. PMID- 26977882 TI - HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma. AB - Medulloblastoma (MB) is a highly malignant pediatric brain tumor. Despite aggressive therapy, many patients succumb to the disease, and survivors experience severe side effects from treatment. MYC-driven MB has a particularly poor prognosis and would greatly benefit from more effective therapies. We used an animal model of MYC-driven MB to screen for drugs that decrease viability of tumor cells. Among the most effective compounds were histone deacetylase inhibitors (HDACIs). HDACIs potently inhibit survival of MYC-driven MB cells in vitro, in part by inducing expression of the FOXO1 tumor suppressor gene. HDACIs also synergize with phosphatidylinositol 3-kinase inhibitors to inhibit tumor growth in vivo. These studies identify an effective combination therapy for the most aggressive form of MB. PMID- 26977884 TI - PITPNC1 Recruits RAB1B to the Golgi Network to Drive Malignant Secretion. AB - Enhanced secretion of tumorigenic effector proteins is a feature of malignant cells. The molecular mechanisms underlying this feature are poorly defined. We identify PITPNC1 as a gene amplified in a large fraction of human breast cancer and overexpressed in metastatic breast, melanoma, and colon cancers. Biochemical, molecular, and cell-biological studies reveal that PITPNC1 promotes malignant secretion by binding Golgi-resident PI4P and localizing RAB1B to the Golgi. RAB1B localization to the Golgi allows for the recruitment of GOLPH3, which facilitates Golgi extension and enhanced vesicular release. PITPNC1-mediated vesicular release drives metastasis by increasing the secretion of pro-invasive and pro angiogenic mediators HTRA1, MMP1, FAM3C, PDGFA, and ADAM10. We establish PITPNC1 as a PI4P-binding protein that enhances vesicular secretion capacity in malignancy. PMID- 26977887 TI - Medical treatment of Cushing's Disease. AB - Cushing's Syndrome (CS) is a serious endocrine disease that results from the adverse clinical consequences of chronic exposure to high levels of glucocorticoids. Most patients with endogenous CS have an adrenocorticotropin (ACTH)-secreting pituitary corticotroph adenoma, i.e. Cushing's Disease (CD). The first-line therapy for CD is transsphenoidal pituitary surgery. If tumor removal is incomplete or unsuccessful, persistent hypercortisolism will require further treatment. Repeat surgery, medical therapy, radiation and bilateral adrenalectomy are all second line therapy options; however, medical therapy can be also used as first line therapy in patients who cannot undergo surgery, or to decrease cortisol values and/or improve co-morbidities. Medications used in the treatment of CD, classified into three groups: pituitary directed drugs, adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers, are reviewed. Future 'on the horizon' treatment options are also discussed. PMID- 26977883 TI - KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis. AB - Understanding the molecular mechanisms of tumor initiation has significant impact on early cancer detection and intervention. To define the role of KLF4 in pancreatic ductal adenocarcinoma (PDA) initiation, we used molecular biological analyses and mouse models of klf4 gain- and loss-of-function and mutant Kras. KLF4 is upregulated in and required for acinar-to-ductal metaplasia. Klf4 ablation drastically attenuates the formation of pancreatic intraepithelial neoplasia induced by mutant Kras(G12D), whereas upregulation of KLF4 does the opposite. Mutant KRAS and cellular injuries induce KLF4 expression, and ectopic expression of KLF4 in acinar cells reduces acinar lineage- and induces ductal lineage-related marker expression. These results demonstrate that KLF4 induces ductal identity in PanIN initiation and may be a potential target for prevention of PDA initiation. PMID- 26977888 TI - Pregnancy and pituitary adenomas. AB - Infertility is frequent in patients harboring pituitary adenomas. The mechanisms involved include hypogonadism secondary to hormonal hypersecretion (prolactin, growth hormone and cortisol), stalk disconnection and pituitary damage. With the improvement of clinical and surgical treatment, pregnancy in women harboring pituitary adenomas turned into a reality. Pituitary hormonal hyper- and hyposecretion influences pregnancy outcomes, as well as pregnancy can interfere on pituitary tumors, especially in prolactinomas. We review literature about specific follow-up and management in pregnant women harboring prolactinomas, acromegaly, or Cushings disease and the impact of clinical and surgical treatment on each condition. PMID- 26977885 TI - Protein Kinase Ciota Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma. AB - We report that the protein kinase Ciota (PKCiota) oncogene controls expression of NOTCH3, a key driver of stemness, in KRAS-mediated lung adenocarcinoma (LADC). PKCiota activates NOTCH3 expression by phosphorylating the ELF3 transcription factor and driving ELF3 occupancy on the NOTCH3 promoter. PKCiota-ELF3-NOTCH3 signaling controls the tumor-initiating cell phenotype by regulating asymmetric cell division, a process necessary for tumor initiation and maintenance. Primary LADC tumors exhibit PKCiota-ELF3-NOTCH3 signaling, and combined pharmacologic blockade of PKCiota and NOTCH synergistically inhibits tumorigenic behavior in vitro and LADC growth in vivo demonstrating the therapeutic potential of PKCiota ELF3-NOTCH3 signal inhibition to more effectively treat KRAS LADC. PMID- 26977891 TI - Toward Plastic Smart Windows: Optimization of Indium Tin Oxide Electrodes for the Synthesis of Electrochromic Devices on Polycarbonate Substrates. AB - Plastic smart windows are becoming one of the key elements in view of the fabrication of inexpensive, lightweight electrochromic (EC) devices to be integrated in the new generation of high-energy-efficiency buildings and automotive applications. However, fabricating electrochromic devices on polymer substrates requires a reduction of process temperature, so in this work we focus on the development of a completely room-temperature deposition process aimed at the preparation of ITO-coated polycarbonate (PC) structures acting as transparent and conductive plastic supports. Without providing any substrate heating or surface activation pretreatments of the polymer, different deposition conditions are used for growing indium tin oxide (ITO) thin films by the radiofrequency magnetron sputtering technique. According to the characterization results, the set of optimal deposition parameters is selected to deposit ITO electrodes having high optical transmittance in the visible range (~90%) together with low sheet resistance (~8 ohm/sq). The as-prepared ITO/PC structures are then successfully tested as conductive supports for the fabrication of plastic smart windows. To this purpose, tungsten trioxide thin films are deposited by the reactive sputtering technique on the ITO/PC structures, and the resulting single electrode EC devices are characterized by chronoamperometric experiments and cyclic voltammetry. The fast switching response between colored and bleached states, together with the stability and reversibility of their electrochromic behavior after several cycling tests, are considered to be representative of the high quality of the EC film but especially of the ITO electrode. Indeed, even if no adhesion promoters, additional surface activation pretreatments, or substrate heating were used to promote the mechanical adhesion among the electrode and the PC surface, the observed EC response confirmed that the developed materials can be successfully employed for the fabrication of lightweight and inexpensive plastic EC devices. PMID- 26977890 TI - Fluorescence Immunoassay for Cocaine Detection. AB - A fluorescence immunoassay (FIA) has been developed for the detection of cocaine using norcocaine labeled with merocyanine dye and a monoclonal antibody specific to cocaine. Using this FIA, the detection range for cocaine was between 20.0 and 1700 MUg/L with a limit of detection of 20.0 MUg/L. Other cocaine derivatives did not interfere significantly with the detection when using this immunoassay technique with cross-reactivity values of less than 20%. Thus this FIA could be considered a useful tool for the detection of cocaine. PMID- 26977892 TI - A Terminally Bound Niobium Methylidyne. AB - Complex (PNP)Nb(CH3)2(OAr) (PNP = N[2-P(i)Pr2-4-methylphenyl]2(-), Ar = 2,6 (i)Pr2C6H3), prepared from treatment of (PNP)NbCl3 with NaOAr followed by 2 equiv of H3CMgCl, can be oxidized with [FeCp2][OTf] to afford (PNP)Nb(CH3)2(OAr)(OTf). While photolysis of the latter resulted in formation of a rare example of a niobium methylidene, (PNP)Nb?CH2(OAr)(OTf), treatment of the dimethyl triflate precursor with the ylide H2CPPh3 produced the mononuclear group 5 methylidyne complex, (PNP)Nb=CH(OAr). Adding a Bronsted base to (PNP)Nb?CH2(OAr)(OTf) also resulted in formation of the methylidyne. Solid-state structural analysis confirms both methylidene and methylidyne moieties to be terminal, having very short Nb-C distances of 1.963(2) and 1.820(2) A, respectively. It is also shown that methylidyne for nitride cross-metathesis between (PNP)Nb=CH(OAr) and NCR (R = tert-butyl or 1-adamantyl) results in formation of a neutral and mononuclear niobium nitride, (PNP)Nb=N(OAr), along with the terminal alkyne HC=CR. PMID- 26977886 TI - Genome-Wide Profiles of Extra-cranial Malignant Rhabdoid Tumors Reveal Heterogeneity and Dysregulated Developmental Pathways. AB - Malignant rhabdoid tumors (MRTs) are rare lethal tumors of childhood that most commonly occur in the kidney and brain. MRTs are driven by SMARCB1 loss, but the molecular consequences of SMARCB1 loss in extra-cranial tumors have not been comprehensively described and genomic resources for analyses of extra-cranial MRT are limited. To provide such data, we used whole-genome sequencing, whole-genome bisulfite sequencing, whole transcriptome (RNA-seq) and microRNA sequencing (miRNA-seq), and histone modification profiling to characterize extra-cranial MRTs. Our analyses revealed gene expression and methylation subgroups and focused on dysregulated pathways, including those involved in neural crest development. PMID- 26977893 TI - Opioid Prescribing for Chronic Pain: Not for the Faint of Heart. PMID- 26977895 TI - A Silver DNAzyme. AB - Silver is a very common heavy metal, and its detection is of significant analytical importance. DNAzymes are DNA-based catalysts; they typically recruit divalent and trivalent metal ions for catalysis. Herein, we report a silver specific RNA-cleaving DNAzyme named Ag10c obtained after six rounds of in vitro selection. Ag10c displays a catalytic rate of 0.41 min(-1) with 10 MUM Ag(+) at pH 7.5 with 200 mM NaNO3, while its activity is completely inhibited with the same concentration of NaCl. Ag10c is highly specific for Ag(+) among all the tested metals. A catalytic beacon biosensor is designed by labeling a fluorophore and a quencher on the DNAzyme. Fluorescence enhancement is observed in the presence of Ag(+) with a detection limit of 24.9 nM Ag(+). The sensor shows a similar analytical performance in Lake Huron water. This is the first monovalent transition metal dependent RNA-cleaving DNAzyme. Apart from its biosensor application, this study strengthens the idea of exploring beyond the traditional understanding of multivalent ion dependent DNAzyme catalysis. PMID- 26977896 TI - Characteristics of Teeth: A Review of Size, Shape, Composition, and Appearance of Maxillary Anterior Teeth. AB - Although digital technologies play an increasingly integral role in dentistry, there remains a need for dental professionals to understand the fundamentals of tooth anatomy, form, occlusion, and color science. In this article, the size, shape, composition, and appearance of maxillary anterior teeth will be discussed from esthetic and functional perspectives. A total of 600 extracted maxillary incisors were studied: 200 each of central incisors, lateral incisors, and cuspids. The purpose of the article is to exhibit and discuss factors that make teeth unique and diverse. Understanding these aspects of teeth aids dental professionals in more effectively creating realistic and highly esthetic restorations for patients. PMID- 26977897 TI - Diagnostic Value of Halitosis Examination Methods. AB - There are many methods and varied protocols for examining halitosis. Chemical and enzymatic tests determine the presence of bacterial species and their metabolic products or enzymes in the mouth, while halitometers precisely quantify gases but not halitosis itself. Examinations by the human nose (ie, self assessment, feedback from others, or organoleptic test by an examiner) directly target halitosis, however organoleptic examination alone is insufficient for a definitive diagnosis when the individual has no complaints about halitosis. The underlying reasons why patients seek consultation concerning halitosis are usually based on their own assessment and the opinion of others, even if those assessments are not correlated with oral odorous gas measurements. This article seeks to summarize findings and review methods of examining halitosis to determine their usefulness. PMID- 26977898 TI - Interdisciplinary Treatment Planning in Transitioning a Periodontally Hopeless Dentition: A Clinical Case Review. AB - Treating patients with advanced periodontal disease may require staged treatment that utilizes various modalities. In this case report, a patient with a high-risk periodontal condition lacked the financial means to receive optimal treatment immediately. The interdisciplinary team was able to provide a solution that addressed immediate needs and provide stability in the short term by retaining teeth that could be maintained for a limited amount of time until a long-term solution using implant-retained prostheses could be provided. PMID- 26977894 TI - S/HIC: Robust Identification of Soft and Hard Sweeps Using Machine Learning. AB - Detecting the targets of adaptive natural selection from whole genome sequencing data is a central problem for population genetics. However, to date most methods have shown sub-optimal performance under realistic demographic scenarios. Moreover, over the past decade there has been a renewed interest in determining the importance of selection from standing variation in adaptation of natural populations, yet very few methods for inferring this model of adaptation at the genome scale have been introduced. Here we introduce a new method, S/HIC, which uses supervised machine learning to precisely infer the location of both hard and soft selective sweeps. We show that S/HIC has unrivaled accuracy for detecting sweeps under demographic histories that are relevant to human populations, and distinguishing sweeps from linked as well as neutrally evolving regions. Moreover, we show that S/HIC is uniquely robust among its competitors to model misspecification. Thus, even if the true demographic model of a population differs catastrophically from that specified by the user, S/HIC still retains impressive discriminatory power. Finally, we apply S/HIC to the case of resequencing data from human chromosome 18 in a European population sample, and demonstrate that we can reliably recover selective sweeps that have been identified earlier using less specific and sensitive methods. PMID- 26977899 TI - CBCT-Aided Multidisciplinary Approach to Salvaging an Intruded Tooth. AB - Among the most severe types of traumatic dental injuries is intrusive luxation, which displaces the affected tooth deeper into the alveolus, causing significant damage to the pulp and all of the supporting structures. This article describes a unique case of intrusive luxation of the mature left maxillary central incisor in an 18-year-old male patient. The diagnosis was confirmed using cone-beam computed tomography (CBCT), after which the intruded tooth was successfully repositioned by endodontic and orthodontic management. This was followed by prosthodontic rehabilitation. This case report also discusses the role of CBCT in effectively diagnosing this type of injury. PMID- 26977900 TI - Proteolytic processing of mesonivirus replicase polyproteins by the viral 3C-like protease. AB - Mesoniviridae are a family of insect RNA viruses that diverged profoundly from other families of the Nidovirales. Mesonivirus replicative proteins are produced from large polyprotein (pp) precursors (pp1a and pp1ab) through proteolytic cleavage by the viral 3C-like protease (3CLpro) and, possibly, other proteases. Using recombinant forms of the Cavally virus 3CLpro and pp1a/pp1ab-derived substrates, we characterized 3CLpro cleavage sites in mesonivirus polyproteins. Our data lead us to suggest that 3CLpro cleaves the central and C-proximal regions of mesonivirus pp1a/pp1ab at 12 conserved sites. Compared to other nidovirus homologues, the mesonivirus 3CLpro features a distinct substrate specificity, with asparagine at P2 being a major specificity determinant. Furthermore, we provide evidence that expression of the ORF1b-encoded part of pp1ab involves a -1 ribosomal frameshift at a conserved GGAUUUU heptanucleotide sequence in the ORF1a/1b overlap region. Taken together, the study identifies critical steps in the expression and maturation of mesonivirus replicative proteins. PMID- 26977901 TI - Agromyces binzhouensis sp. nov., an actinobacterium isolated from a coastal wetland of the Yellow River Delta. AB - A Gram-stain-positive, heterotrophic, non-spore-forming, rod-shaped strain, designated OAct353T, belonging to the genus Agromyces was isolated from a soil sample collected from a coastal wetland of the Yellow River delta, PR China. The strain was identified using a polyphasic taxonomic approach. The strain grew in the presence of 0-10 % (w/v) NaCl (optimum 2-3 %), at pH 5.0-8.0 (optimum pH 7.0) and 12-36 degrees C (optimum 28 degrees C). The isolate contained 2,4 diaminobutyric acid, glutamic acid and glycine in its peptidoglycan. The acyl type of the cell-wall muramic acid was N-acetyl. The whole-cell sugars of this novel strain were glucose, xylose and rhamnose. The predominant menaquinones were MK-12 (74 %) and MK-11 (21 %). The major phospholipids were phosphatidylglycerol, one unknown phospholipid, three unknown glycolipids and three unknown polar lipids. The major fatty acids were iso-C16:0, anteiso-C15:0 and anteiso-C17:0. The DNA G+C content was 69.6 mol %. DNA-DNA relatedness clearly separated strain OAct353T from its closest relatives. On the basis of phenotypic, phylogenetic and chemotaxonomic data, a novel species, Agromyces binzhouensis sp. nov., is proposed. The type strain is OAct353T (=CGMCC4.7180T=DSM 28305T=NRRL B-59115T). PMID- 26977902 TI - Black Phosphorus Flexible Thin Film Transistors at Gighertz Frequencies. AB - Black phosphorus (BP) has attracted rapidly growing attention for high speed and low power nanoelectronics owing to its compelling combination of tunable bandgap (0.3 to 2 eV) and high carrier mobility (up to ~1000 cm(2)/V.s) at room temperature. In this work, we report the first radio frequency (RF) flexible top gated (TG) BP thin-film transistors on highly bendable polyimide substrate for GHz nanoelectronic applications. Enhanced p-type charge transport with low-field mobility ~233 cm(2)/V.s and current density of ~100 MUA/MUm at VDS = -2 V were obtained from flexible BP transistor at a channel length L = 0.5 MUm. Importantly, with optimized dielectric coating for air-stability during microfabrication, flexible BP RF transistors afforded intrinsic maximum oscillation frequency fMAX ~ 14.5 GHz and unity current gain cutoff frequency fT ~ 17.5 GHz at a channel length of 0.5 MUm. Notably, the experimental fT achieved here is at least 45% higher than prior results on rigid substrate, which is attributed to the improved air-stability of fabricated BP devices. In addition, the high-frequency performance was investigated through mechanical bending test up to ~1.5% tensile strain, which is ultimately limited by the inorganic dielectric film rather than the 2D material. Comparison of BP RF devices to other 2D semiconductors clearly indicates that BP offers the highest saturation velocity, an important metric for high-speed and RF flexible nanosystems. PMID- 26977903 TI - Reversible Hydrogen Uptake by BN and BC3 Monolayers Functionalized with Small Fe Clusters: A Route to Effective Energy Storage. AB - In an effort to design new functionalized nanostructures for clean energy storage, DFT calculations of Fen (n = 1-3) clusters on BC3 and BN monolayers are performed. The stability of the systems was considered by calculating the binding energies of the monolayers with Fen clusters on one or both sides. All the clusters bound strongly to both the monolayers and transferred electron density to the sheets. The cationic Fe clusters were then able to adsorb multiple H2 molecules through electrostatic and van der Waals interactions. The average adsorption energies per H2 in the case of maximum coverage were calculated to be 0.389 and -0.358 eV for systems with one Fe on both sides of BC3 and BN monolayers, respectively. In these cases four H2 molecules were adsorbed to the Fe atoms on both sides of the monolayer. These adsorption energies are such that there is potential for adsorption/desorption at ambient conditions. The results provide insights into an efficient and reversible storage of H2 by using Fen functionalized BC3 and BN monolayers. PMID- 26977905 TI - The Power Spectrum of Ionic Nanopore Currents: The Role of Ion Correlations. AB - We calculate the power spectrum of electric-field-driven ion transport through nanometer-scale membrane pores using both linearized mean-field theory and Langevin dynamics simulations. Remarkably, the linearized mean-field theory predicts a plateau in the power spectral density at low frequency omega, which is confirmed by the simulations at low ion concentration. At high ion concentration, however, the power spectral density follows a power law that is reminiscent of the 1/omega(alpha) dependence found experimentally at low frequency. On the basis of simulations with and without ion-ion interactions, we attribute the low frequency power-law dependence to ion-ion correlations. We show that neither a static surface charge density, nor an increased pore length, nor an increased ion valency have a significant effect on the shape of the power spectral density at low frequency. PMID- 26977906 TI - Knowledge-Based Optimization of Molecular Geometries Using Crystal Structures. AB - This paper describes a novel way to use the structural information contained in the Cambridge Structural Database (CSD) to drive geometry optimization of organic molecules. We describe how CSD structural information is transformed into objective functions for gradient-based optimization to provide good quality geometries for a large variety of organic molecules. Performance is assessed by minimizing different sets of organic molecules reporting RMSD movements for bond lengths, valence angles, torsion angles, and heavy atom positions. PMID- 26977904 TI - A large dataset of protein dynamics in the mammalian heart proteome. AB - Protein stability is a major regulatory principle of protein function and cellular homeostasis. Despite limited understanding on mechanisms, disruption of protein turnover is widely implicated in diverse pathologies from heart failure to neurodegenerations. Information on global protein dynamics therefore has the potential to expand the depth and scope of disease phenotyping and therapeutic strategies. Using an integrated platform of metabolic labeling, high-resolution mass spectrometry and computational analysis, we report here a comprehensive dataset of the in vivo half-life of 3,228 and the expression of 8,064 cardiac proteins, quantified under healthy and hypertrophic conditions across six mouse genetic strains commonly employed in biomedical research. We anticipate these data will aid in understanding key mitochondrial and metabolic pathways in heart diseases, and further serve as a reference for methodology development in dynamics studies in multiple organ systems. PMID- 26977907 TI - Magnetic Anisotropies in Rhombic Lanthanide(III) Complexes Do Not Conform to Bleaney's Theory. AB - We report a complete set of magnetic susceptibilities of lanthanide complexes with a macrocyclic ligand based on a 3,6,10,13-tetraaza-1,8(2,6) dipyridinacyclotetradecaphane platform containing four hydroxyethyl pendant arms (L(1)). The [LnL(1)](3+) complexes are isostructural along the lanthanide series from Ce(3+) to Yb(3+), with the only structural change observed along the series being the monotonous shortening of the Ln-donor distances due to lanthanide contraction. The (1)H NMR spectra point to a D2 symmetry of the [LnL(1)](3+) complexes in aqueous solution, which provides a unique opportunity for analysis of the rhombic magnetic anisotropies with an unequivocal location of the magnetic axes. The contact contributions for the observed paramagnetic shifts have been estimated with density functional theory calculations on the [GdL(1)](3+) complex. Subsequently, the pseudocontact shifts could be factored out, thereby giving access to the axial and rhombic contributions of the magnetic susceptibility tensor. Our results show that the calculated magnetic anisotropies do not follow the trends predicted by Bleaney's theory, particularly in the case of Ho(3+) and Er(3+) complexes. PMID- 26977908 TI - [Alexithymia in patients with left-hemispheric cerebral infarction in the late recovery period]. AB - AIM: To study emotional status, including alexithymia, anxiety and depression, in patients with cerebral infarction in the area of the middle cerebral artery (on the left side) in the late recovery period and to develop a method for correction of the damage. MATERIAL AND METHODS: The study included 30 patients with cerebral infarction in the area of the middle cerebral artery (on the left side). A comparison group consisted of 10 patients with chronic brain ischemia. RESULTS AND CONCLUSION: The results have demonstrated the correlation between the level of alexithymia and the severity of neurological deficit, sex-related level of anxiety and depression. The cerebral infarction impacts on the level of alexithymia. Alexithymia in patients with cerebral infarction affects the adequate self-esteem of physical and mental condition that may complicate the rehabilitation of these patients and demands correction as a combination of pharmacotherapy and psychotherapeutic intervention. PMID- 26977909 TI - [The relaxation time anisotropy as a method of assessment of physico-chemical activity of the cerebrospinal fluid in acute stroke]. AB - OBJECTIVE: To study the anisotropy relaxation time of the cerebrospinal fluid (CSF) in acute disorders of cerebral circulation compared by analyzing the kinetics of anisotropy relaxation of the dye "rhodamine 6G". MATERIAL AND METHODS: The study of the samples was performed using a laser confocal fluorescence microscope MicroTime 200 ("PicoQuant GmbH"). Authors used a laser operating at a wavelength of 470 nm with a time resolution of 8 PS with a pulse frequency of 10 MHz. RESULTS: Authors assessed this parameter in CSF of patients with different types of stroke. CONCLUSION: Confocal laser spectrometry can be considered as an objective method of studying CSF changes in patients with lesions of the central nervous system and control of patient status in a clinical setting. PMID- 26977911 TI - [A complex approach to the treatment of patients with chronic lumbalgia]. AB - The management of patients with chronic non-specific low-back pain (chronic lumbalgia) is an urgent problem of current medicine. We report two cases of patients with chronic lumbalgia and severe comorbid diseases who demonstrated good results after the complex treatment including pharmacotherapy, cognitive behavioral therapy and exercise treatment. PMID- 26977910 TI - [Cognitive impairment in amyotrophic lateral sclerosis]. AB - OBJECTIVE: To determine cognitive and emotional status in patients with amyotrophic lateral sclerosis (ALS). MATERIAL AND METHODS: One hundred sixteen patients were examined. RESULTS AND CONCLUSION: Frontotemporal cognitive changes (CC) were found in 35.3% of patients (medium log rank on the Frontotemporal dementia rating scale was 1.47 [1.92; 1.26], and 4.2% patients had frank dementia (medium log rank -0.4 [1.07; -3.09]). The average degree by the Montreal cognitive scale in patients with CC was 21.7+/-4.4. 48,9% patients had mixed (executive and speech) symptoms, 34% had frontal (executive) symptoms, 4.2% had temporal (visual and spatial) deficits, and 4.2% had isolated behavioral symptoms. There was no patients with isolated speech deficits. ALS patients with CC were significantly older than patients without CC (64.5+/-7.7 and 52.5+/-12.1 years, r=0,0001). ALS progressed more rapidly in patients with CC (13.5+/-9.3 and 10.4+/-9.1 ALSFRS-R scores per month, p=0.033). Patients with lumbar onset of ALS prevailed in the group without CC (17% and 36%, chi2=3.94; r=0.047), and patients with bulbar onset of ALS prevailed in the group with CC at the trend level. A comparison of estimates by different scores of emotional state and quality of life (the Hamilton depression scale, CNSLS, ALSAQ40) allows to conclude that CC had no influence on the emotional state of ALS patients and their total quality of life. PMID- 26977912 TI - [A comparative analysis of the efficacy of neuromidin and galantamine in Alzheimer's disease]. AB - OBJECTIVE: To evaluate the cognitive changes in patients with mild to moderate Alzheimer's disease after the treatment with acetylcholinesterase inhibitors - neuromidin and galantamine. MATERIAL AND METHODS: Fifty-eight patients with probable Alzheimer's disease, aged 60-84 years (mean 73.2+/-6.7), were enrolled in a 20-week double-blind parallel group study. All patients were randomized in 2 groups: group 1 (n=28) received neuromidin, group 2 (n=30) - galantamine. Treatment efficacy was evaluated with the ADAS-cog/11 scale. RESULTS: Both drugs significantly improved or stabilized cognitive function in the patients. The most marked changes were obtained in the group of patients treated with neuromidin (r<0.05). CONCLUSION: The results suggest that the effectiveness of anticholinesterase treatment of Alzheimer's disease could be determined not only by the central but also peripheral cholinergic action. PMID- 26977913 TI - [Current pharmacotherapy of the autonomic nervous system disorders]. AB - A state of the autonomic nervous system is known to play an important role in complex treatment of any somatic pathology. The drugs with complex anxiolytic, autonomic stabilizing and nootropic effects are used in treatment of autonomic disorders. These drugs stabilize as the general mental condition, including emotional state, as well as the autonomic condition of patients with somatic disorders. These notions are discussed in detail on the example of noofen and adaptol. PMID- 26977914 TI - [The measures of autonomic homeostasis as predictors of an individual risk of stroke and their dynamics during therapy with actovegin]. AB - OBJECTIVE: To evaluate an individual 10-year risk of stroke in patients with chronic cerebral ischemia, identify predictors of this risk and assess its dynamics during therapy with actovegin. MATERIAL AND METHODS: The measures of autonomic homeostasis were estimated in 54 patients with chronic brainstem ischemia. The dynamics of these indexes during therapy with actovegin was studied. RESULTS AND CONCLUSION: Chronic cerebral ischemia, mostly vertebrobasilar ischemia, is correlated with an increasing individual 10-year risk of stroke. A high positive pharmacologic effect of actovegin on the central and peripheral structures of the autonomic nervous system in chronic cerebral ischemia has been shown. A mediated hypotensive effect of actovegin due to humoral, metabolic and neurogenic influences on a vessel wall has been demonstrated. PMID- 26977915 TI - [A role of neuroprotective therapy in the rehabilitation of children with sensorineural hearing loss, IV degrees, after cochlear implanta-tion]. AB - OBJECTIVE: To study clinical/psychological characteristics in children with sensorineural hearing loss, IV degrees, before and after the cochlear implantation (CI) and to assess the dynamics of speech development during the rehabilitation using the neuroprotective drug cerebrolysin. MATERIAL AND METHODS: Authors examined 93 patients, aged from 5 to 8 years. The main group (n=46) received cerebrolysin, the control group was not treated with this drug. A diagnostic study included patient's history, neurological and neuropsychological examinations, auditory perception and sound reproduction. RESULTS AND CONCLUSION: According to the Meaningful Use of Speech Scale, 23% of children of the main group demonstrated the best results due to the better speech communication strategies. No significant between-group differences were found in the level of auditory perception 6 months after CI. The level of articulation was higher in the main group. Cognitive functioning was improved in children treated with cerebrolysin. PMID- 26977916 TI - [Melatonin in chronic pain syndromes]. AB - Melatonin, a neurohormone synthesized by the epiphysis and extrapineal structures, has several functions including chronobiotic, antioxidant, oncostatic, immunomodulating, normothymic and anxiolytic ones. It impacts on the cardiovascular system and the gastrointestinal tract and is involved in reproductive functions, metabolism and body mass regulation. Moreover, recent studies have demonstrated the efficacy of melatonin in pain syndromes. The authors present a literature review on the studies of melatonin in treatment of fibromyalgia, headache, irritated bowel syndrome, chronic back pain and rheumatoid arthritis. Possible mechanisms of analgesic properties of melatonin are discussed. On one hand, there is the improvement of sleep and activation of own adaptive potential of melatonin by normalizing circadian rhythms inevitably disturbed in chronic pain syndromes. On the other hand, there are the data on the analgesic effect of melatonin realized through melatonin receptors and several neurotransmitter systems. PMID- 26977917 TI - [Anxiety/depressive disorders and vitamin D status]. AB - OBJECTIVE: To search for the association between vitamin D status and anxiety and depression. MATERIAL AND METHODS: Authors examined 310 residents of St. Petersburg (137 men and 173 women). Anxiety and depression were measured with the HADS. RESULTS AND CONCLUSION: In people with vitamin D deficiency, anxiety and depression were noted in 32.5% and 11.0%, respectively. There were negative correlations between serum 25(OH)D level and anxiety (r= -0,11, p=0.03). Symptoms of depression were not correlated with vitamin D status (r= -0.08, p=0.09) but were correlated with the age (r=0.12, p=0.02). After excluding other risk factors for psychogenic disturbances (obesity, hypertension and impaired glucose metabolism) we concluded that serum 25(OH)D could be an independent risk factor for anxiety (R2=0.02, p=0.01) in the population studied. PMID- 26977918 TI - [A case report of bilateral trigeminal sensory neuropathy as one of the initial manifestation of systemic scleroderma (the difficulties of early diagnosis of the primary disease)]. AB - The article describes the case of a patient with bilateral trigeminal sensory neuropathy (TSN), as a possible neurological manifestation of systemic scleroderma (SS). In this patient, intense non-paroxysmal facial pain caused by TSN, subjectively dominated over other manifestations of SS, including Raynaud's syndrome, for at least 1.5 years, thus hampering the diagnosis of the primary disease. In addition to pain, which was not relieved by analgesic medication, TSN was manifested by marked sensory deficit on the face (hypoesthesia / anesthesia) and bilateral sensory deficits in the oral cavity, including the anterior third of the tongue. TSN was also combined with disorders of taste perception. The assumption of rheumatic origin of TSN occurred during a primary neurological examination: a standard examination revealed generalized sensory polyneuropathy with bilateral involvement of the trigeminal nerve; the additional study identified no neurological signs of rheumatic diseases, including Raynaud's phenomenon. SS met all the criteria for the diagnosis (2013), high titers of nuclear ribonucleoprotein were determined as well. Thus, TSN as early and subjectively dominant manifestation of SS can complicate the diagnosis of primary rheumatic diseases. Therefore, in cases of distal sensory polyneuropathy with bilateral involvement of the trigeminal nerve, it is necessary to conduct an additional survey to identify the signs of possible rheumatic diseases: signs of vascular lesion (Raynaud's syndrome), lesions of skin, joints and muscles. PMID- 26977919 TI - [The "Dialogue" or the "Conflict of interests" between psychiatrists and neurologists: results of a focus group interview]. AB - OBJECTIVE: To determine the characteristics of interdisciplinary interactions between neurologists and psychiatrists in treatment of anxiety and depressive disorders, including prognostic aspects, and the responsibility of the doctor. MATERIAL AND METHODS: A scenario of an interview included similar questions related to diagnosis, examination and the treatment of patients with anxiety and depressive disorders. Ten neurologists and 10 psychiatrists have completed the interview. RESULTS: The characteristics of the management of patients, the absence of the joint management and interactions, subjective adherence to definite drugs and methods were shown. CONCLUSION: The intersection of professional interests for both specialties because of the similarities of the groups of patients in the conditions of concurrent interdisciplinary interactions makes up the reason for the conflict between them. An introduction of an interdisciplinary model of interactions between the physicians and specified continual education in adjacent fields of medicine will resolve this situation. PMID- 26977920 TI - [Hypersalivation in Parkinson's disease: causes and treatment options]. AB - In average 50% of patients with Parkinson's disease complain on hypersalivation, subclinical sialorrhea can be objected in 90% of them by different methods. Hypersalivation causes negative implications for the patients for themselves as well as for the caregivers. Currently there are 3 main mechanisms of sialorrhea in Parkinson's disease are considered: saliva hypersecretion, inability of saliva retention in the oral cavity (hypomimia, involuntary mouth opening, declining posture or drooping head), salivary clearance deterioration (lingual bradykinesia, oropharyngeal dysphagia, upper esophageal sphincter dysfunction). Injections of botulinum toxins in the huge salivary glands and in cricopharingeal muscle are the most effective methods. PMID- 26977921 TI - [Back Pain: osteochondrosis or osteoarthritis?]. AB - The article considers a question of the differential diagnosis and treatment of back pain. The authors recommend the use of generally accepted term "spinal osteoarthritis" to describe changes in the spine, which in the Russian medical literature referred to as "osteochondrosis". The article describes the diagnosis and treatment of myogenic pain, pain due to facet syndrome, herniated disc, cervical and lumbar radiculopathy, spinal stenosis, interspinous bursitis. The authors recommend the use of dexketoprofen (flamadex) and adjuvants (baclofen, flupirtine) for the nociceptive back pain treatment. PMID- 26977922 TI - Reconciling simulated melting and ground-state properties of metals with a modified embedded-atom method potential. AB - We propose a modification of the embedded-atom method-type potential aiming at reconciling simulated melting and ground-state properties of metals by means of classical molecular dynamics. Considering titanium, magnesium, gold, and platinum as case studies, we demonstrate that simulations performed with the modified force field yield quantitatively correctly both the melting temperature of the metals and their ground-state properties. It is shown that the accounting for the long-range interatomic interactions noticeably affects the melting point assessment. The introduced modification weakens the interaction at interatomic distances exceeding the equilibrium one by a characteristic vibration amplitude defined by the Lindemann criterion, thus allowing for the correct simulation of melting, while keeping its behavior in the vicinity of the ground state minimum. The modification of the many-body potential has a general nature and can be applicable to metals with different characteristics of the electron structure as well as for many different molecular and solid state systems experiencing phase transitions. PMID- 26977923 TI - Joint Cognition: Thought Contagion and the Consequences of Cooperation when Sharing the Task of Random Sequence Generation. AB - Generating random number sequences is a popular psychological task often used to measure executive functioning. We explore random generation under "joint cognition" instructions; pairs of participants take turns to compile a shared response sequence. Across three studies, we point to six key findings from this novel format. First, there are both costs and benefits from group performance. Second, repetition avoidance occurs in dyadic as well as individual production settings. Third, individuals modify their choices in a dyadic situation such that the pair becomes the unit of psychological function. Fourth, there is immediate contagion of sequence stereotypy amongst the pairs (i.e., each contributor "owns" their partner's response). Fifth, dyad effects occur even when participants know their partner is not interacting with them (Experiment 2). Sixth, ironically, directing participants' efforts away from their shared task responsibility can actually benefit conjoint performance (Experiment 3). These results both constrain models of random generation and illuminate processes of joint cognition. PMID- 26977924 TI - Profound Effects of Aggregatibacter actinomycetemcomitans Leukotoxin Mutation on Adherence Properties Are Clarified in in vitro Experiments. AB - Leukotoxin (Ltx) is a prominent virulence factor produced by Aggregatibacter actinomycetemcomitans, an oral microorganism highly associated with aggressive periodontitis. Ltx compromises host responsiveness by altering the viability of neutrophils, lymphocytes, and macrophages. Previously, we developed a Rhesus (Rh) monkey colonization model designed to determine the effect of virulence gene mutations on colonization of A. actinomycetemcomitans. Unexpectedly, an A. actinomycetemcomitans leukotoxin (ltxA) mutant (RhAa-VS2) failed to colonize in the Rh model. No previous literature suggested that Ltx was associated with A. actinomycetemcomitans binding to tooth surfaces. These results led us to explore the broad effects of the ltxA mutation in vitro. Results indicated that LtxA activity was completely abolished in RhAa-VS2 strain, while complementation significantly (P<0.0001) restored leukotoxicity compared to RhAa-VS2 strain. RT PCR analysis of ltx gene expression ruled out polar effects. Furthermore, binding of RhAa-VS2 to salivary-coated hydroxyapatite (SHA) was significantly decreased (P<0.0001) compared to wild type RhAa3 strain. Real time RT-PCR analysis of the genes related to SHA binding in RhAa-VS2 showed that genes related to binding were downregulated [rcpA (P = 0.018), rcpB (P = 0.02), tadA (P = 0.002)] as compared to wild type RhAa3. RhAa-VS2 also exhibited decreased biofilm depth (P = 0.008) and exo-polysaccharide production (P<0.0001). Buccal epithelial cell (BEC) binding of RhAa-VS2 was unaffected. Complementation with ltxA restored binding to SHA (P<0.002) but had no effect on biofilm formation when compared to RhAa3. In conclusion, mutation of ltxA diminished hard tissue binding in vitro, which helps explain the previous in vivo failure of a ltxA knockout to colonize the Rh oral cavity. These results suggest that; 1) one specific gene knockout (in this case ltxA) could affect other seemingly unrelated genes (such as rcpA, rcpB tadA etc), and 2) some caution should be used when interpreting the effect attributed to targeted gene mutations when seen in a competitive in vivo environment. PMID- 26977925 TI - Immunological Properties of Corneal Epithelial-Like Cells Derived from Human Embryonic Stem Cells. AB - Transplantation of ex vivo expanded corneal limbal stem cells (LSCs) has been the main treatment for limbal stem cell deficiency, although the shortage of donor corneal tissues remains a major concern for its wide application. Due to the development of tissue engineering, embryonic stem cells (ESCs)-derived corneal epithelial-like cells (ESC-CECs) become a new direction for this issue. However, the immunogenicity of ESC-CECs is a critical matter to be solved. In the present study, we explored the immunological properties of ESC-CECs, which were differentiated from ESCs. The results showed that ESC-CECs had a similar character and function with LSCs both in vitro and in vivo. In ESC-CECs, a large number of genes related with immune response were down-regulated. The expressions of MHC-I, MHC-II, and co-stimulatory molecules were low, but the expression of HLA-G was high. The ESC-CECs were less responsible for T cell proliferation and NK cell lysis in vitro, and there was less immune cell infiltration after transplantation in vivo compared with LSCs. Moreover, the immunological properties were not affected by interferon-gamma. All these results indicated a low immunogenicity of ESC-CECs, and they can be promising in clinical use. PMID- 26977926 TI - SfDredd, a Novel Initiator Caspase Possessing Activity on Effector Caspase Substrates in Spodoptera frugiperda. AB - Sf9, a cell line derived from Spodoptera frugiperda, is an ideal model organism for studying insect apoptosis. The first notable study that attempted to identify the apoptotic pathway in Sf9 was performed in 1997 and included the discovery of Sf-caspase-1, an effector caspase of Sf9. However, it was not until 2013 that the first initiator caspase in Sf9, SfDronc, was discovered, and the apoptotic pathway in Sf9 became clearer. In this study, we report another caspase of Sf9, SfDredd. SfDredd is highly similar to insect initiator caspase Dredd homologs. Experimentally, recombinant SfDredd underwent autocleavage and exhibited different efficiencies in cleavage of synthetic caspase substrates. This was attributed to its caspase activity for the predicted active site mutation blocked the above autocleavage and synthetic caspase substrates cleavage activity. SfDredd was capable of not only cleaving Sf-caspase-1 in vitro but also cleaving Sf-caspase-1 and inducing apoptosis when it was co-expressed with Sf-caspase-1 in Sf9 cells. The protein level of SfDredd was increased when Sf9 cells were treated by Actinomycin D, whereas silencing of SfDredd reduced apoptosis and Sf-caspase-1 cleavage induced by Actinomycin D treatment. These results clearly indicate that SfDredd functioned as an apoptotic initiator caspase. Apoptosis induced in Sf9 cells by overexpression of SfDredd alone was not as obvious as that induced by SfDronc alone, and the cleavage sites of Sf-caspase-1 for SfDredd and SfDronc are different. In addition, despite sharing a sequence homology with initiator caspases and possessing weak activity on initiator caspase substrates, SfDredd showed strong activity on effector caspase substrates, making it the only insect caspase reported so far functioning similar to human caspase-2 in this aspect. We believe that the discovery of SfDredd, and its different properties from SfDronc, will improve the understanding of apoptosis pathway in Sf9 cells. PMID- 26977927 TI - A New Pharmacogenetic Algorithm to Predict the Most Appropriate Dosage of Acenocoumarol for Stable Anticoagulation in a Mixed Spanish Population. AB - There is a strong association between genetic polymorphisms and the acenocoumarol dosage requirements. Genotyping the polymorphisms involved in the pharmacokinetics and pharmacodynamics of acenocoumarol before starting anticoagulant therapy would result in a better quality of life and a more efficient use of healthcare resources. The objective of this study is to develop a new algorithm that includes clinical and genetic variables to predict the most appropriate acenocoumarol dosage for stable anticoagulation in a wide range of patients. We recruited 685 patients from 2 Spanish hospitals and 1 primary healthcare center. We randomly chose 80% of the patients (n = 556), considering an equitable distribution of genotypes to form the generation cohort. The remaining 20% (n = 129) formed the validation cohort. Multiple linear regression was used to generate the algorithm using the acenocoumarol stable dosage as the dependent variable and the clinical and genotypic variables as the independent variables. The variables included in the algorithm were age, weight, amiodarone use, enzyme inducer status, international normalized ratio target range and the presence of CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), VKORC1 (rs9923231) and CYP4F2 (rs2108622). The coefficient of determination (R2) explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R2 values were evaluated by pathology: atrial fibrillation, 57.4%; valve replacement, 56.3%; and venous thromboembolic disease, 51.5%. When the patients were classified into 3 dosage groups according to the stable dosage (<11 mg/week, 11-21 mg/week, >21 mg/week), the percentage of correctly classified patients was higher in the intermediate group, whereas differences between pharmacogenetic and clinical algorithms increased in the extreme dosage groups. Our algorithm could improve acenocoumarol dosage selection for patients who will begin treatment with this drug, especially in extreme-dosage patients. The predictability of the pharmacogenetic algorithm did not vary significantly between diseases. PMID- 26977928 TI - Assessing the Relationship between Lung Density and Function with Oxygen-Enhanced Magnetic Resonance Imaging in a Mouse Model of Emphysema. AB - PURPOSE: A magnetic resonance imaging method is presented that allows for the simultaneous assessment of oxygen delivery, oxygen uptake, and parenchymal density. The technique is applied to a mouse model of porcine pancreatic elastase (PPE) induced lung emphysema in order to investigate how structural changes affect lung function. METHOD: Nine-week-old female C57BL6 mice were instilled with saline or PPE at days 0 and 7. At day 19, oxygen delivery, oxygen uptake, and lung density were quantified from T1 and proton-density measurements obtained via oxygen-enhanced magnetic resonance imaging (OE-MRI) using an ultrashort echo time imaging sequence. Subsequently, the lungs were sectioned for histological observation. Blood-gas analyses and pulmonary functional tests via FlexiVent were performed in separate cohorts. PRINCIPAL FINDINGS: PPE-challenged mice had reduced density when assessed via MRI, consistent with the parenchyma loss observed in the histology sections, and an increased lung compliance was detected via FlexiVent. The oxygenation levels, as assessed via the blood-gas analysis, showed no difference between PPE-challenged animals and control. This finding was mirrored in the global MRI assessments of oxygen delivery and uptake, where the changes in relaxation time indices were matched between the groups. The heterogeneity of the same parameters however, were increased in PPE-challenged animals. When the oxygenation status was investigated in regions of varying density, a reduced oxygen-uptake was found in low-density regions of PPE challenged mice. In high-density regions the uptake was higher than that of regions of corresponding density in control animals. The oxygen delivery was proportional to the oxygen uptake in both groups. CONCLUSIONS: The proposed method allowed for the regional assessment of the relationship between lung density and two aspects of lung function, the oxygen delivery and uptake. When compared to global indices of lung function, an increased sensitivity for detecting heterogeneous lung disorders was found. This indicated that the technique has potential for early detection of lung dysfunction-before global changes occur. PMID- 26977931 TI - Minimal SNP overlap among multiple panels of ancestry informative markers argues for more international collaboration. AB - The century-old use of genetic markers to determine population relationships has morphed in modern forensics into use of markers to determine the ancestry of an individual from a DNA sample. Researchers have identified sets of SNPs that have frequency differences among populations and many sets of SNPs have been published for the purpose of inferring ancestry. Such inference also requires reference datasets for the particular set of SNPs selected. We have identified 21 largely independent published panels of ancestry informative SNPs (AISNPs) and examined their union of 1397 SNPs. No SNP occurs in more than 6 panels. The 1397 SNPs in 21 panels yield a largely empty matrix that is inhibiting progress on more refined ability to infer ancestry for a forensic sample. The most common set of reference populations is the HGDP set of 52 small population samples totaling a thousand individuals. Only 46 (3%) of the 1397 SNPs occur in three or more panels. We assembled a new dataset for 44 of those SNPs involving 4,559 individuals from 73 populations. Analyses of this dataset provided clear differentiation of only five biogeographic regions: sub-Saharan Africa, Europe and SW Asia, South Asia, East Asia, and the Americas. This is an inadequate level of biogeographic resolution already exceeded by other panels. We conclude that more such AISNP panels are not needed and that the forensic community must collaborate to develop a common set of highly differentiating AISNPs typed on a very large number of population samples. How that can be accomplished will be the subject of future discussion. PMID- 26977930 TI - Measuring the Burden of Hospitalization in Patients with Parkinson's Disease in Spain. AB - INTRODUCTION: This epidemiological survey estimates the hospitalization burden related to Parkinson's Disease in Spain. METHODS: This observational retrospective survey was performed by reviewing data from the National Surveillance System for Hospital Data, which includes more than 98% of Spanish hospitals. All hospitalizations of patients with Parkinson's disease that were reported from 1997-2012 were analyzed. Codes were selected using the 9th International Classification of Diseases: ICD-9-CM: 332.0. RESULTS: A total of 438,513 hospital discharges of patients with Parkinson's Disease were reported during the study period. The annual hospitalization rate was 64.2 cases per 100,000. The average length of hospital stay was 10 days. The trend for the annual hospitalization rate differed significantly depending on whether Parkinson's disease was the main cause of hospitalization (n = 23,086, 1.14% annual increase) or was not the main cause of hospitalization (n = 415,427, 15.37% annual increase). The overall case-fatality rate among hospitalized patients was 10%. The case fatality rate among patient's hospitalized with Parkinson's disease as the main cause of hospitalization was 2.5%. The hospitalization rate and case-fatality rate significantly increased with age. The primary causes of hospitalization when Parkinson's disease was not coded as the main cause of hospitalization were as follows: respiratory system diseases (24%), circulatory system diseases (19%), injuries and poisoning, including fractures (12%), diseases of the digestive system (10%) and neoplasms (5%). The annual average cost for National Health Care System was ? 120 M, with a mean hospitalization cost of ?4,378. CONCLUSIONS: Parkinson's disease poses a significant health threat in Spain, particularly in the elderly. While hospitalizations due to Parkinson's Disease are relatively stable over time, the number of patients presenting with Parkinson's disease as an important comorbidity has increased dramatically. Medical staff must be specifically trained to treat the particular needs of hospitalized patients suffering from Parkinson's disease as an important comorbidity. PMID- 26977932 TI - Observations of DNA transfer within an operational Forensic Biology Laboratory. AB - Advances in technology to both generate and interpret DNA profiles has seen the expansion of the ability to provide opinions about results obtained from very low levels of starting biological material. The response in court has been to question the mode by which the DNA came to be on an item, rather than questioning its presence. This brings into play a number of real-world aspects such as transfer of biological material, persistence of biological material on items, shedding ability of individuals, just to name a few. There have been a number of studies that investigate different aspects relating the mode of DNA deposition and transfer, mostly under tightly controlled conditions. We add to this knowledge pool by investigating the extent to which individuals at Forensic Science SA (FSSA) deposit their DNA on objects throughout the floor of the building where DNA examinations take place. We find that the results obtained in our minimally controlled study allow us to comment on a number of published concepts. PMID- 26977929 TI - Identification and Characterization of msf, a Novel Virulence Factor in Haemophilus influenzae. AB - Haemophilus influenzae is an opportunistic pathogen. The emergence of virulent, non-typeable strains (NTHi) emphasizes the importance of developing new interventional targets. We screened the NTHi supragenome for genes encoding surface-exposed proteins suggestive of immune evasion, identifying a large family containing Sel1-like repeats (SLRs). Clustering identified ten SLR-containing gene subfamilies, each with various numbers of SLRs per gene. Individual strains also had varying numbers of SLR-containing genes from one or more of the subfamilies. Statistical genetic analyses of gene possession among 210 NTHi strains typed as either disease or carriage found a significant association between possession of the SlrVA subfamily (which we have termed, macrophage survival factor, msf) and the disease isolates. The PittII strain contains four chromosomally contiguous msf genes. Deleting all four of these genes (msfA1-4) (KO) resulted in a highly significant decrease in phagocytosis and survival in macrophages; which was fully complemented by a single copy of the msfA1 gene. Using the chinchilla model of otitis media and invasive disease, the KO strain displayed a significant decrease in fitness compared to the WT in co-infections; and in single infections, the KO lost its ability to invade the brain. The singly complemented strain showed only a partial ability to compete with the WT suggesting gene dosage is important in vivo. The transcriptional profiles of the KO and WT in planktonic growth were compared using the NTHi supragenome array, which revealed highly significant changes in the expression of operons involved in virulence and anaerobiosis. These findings demonstrate that the msfA1-4 genes are virulence factors for phagocytosis, persistence, and trafficking to non mucosal sites. PMID- 26977933 TI - Foliar Essential Oil Glands of Eucalyptus Subgenus Eucalyptus (Myrtaceae) Are a Rich Source of Flavonoids and Related Non-Volatile Constituents. AB - The sub-dermal secretory cavities (glands) embedded within the leaves of Eucalyptus (Myrtaceae) were once thought to be the exclusive repositories of monoterpene and sesquiterpene oils. Recent research has debunked this theory and shown that abundant non-volatile compounds also occur within foliar glands. In particular, glands of four species in subgenus Eucalyptus contain the biologically active flavanone pinocembrin. Pinocembrin shows great promise as a pharmaceutical and is predominantly plant-sourced, so Eucalyptus could be a potential commercial source of such compounds. To explore this we quantified and assessed the purity of pinocembrin in glands of 11 species of E. subg. Eucalyptus using Electro-Spray Ionisation Liquid Chromatography Mass Spectrometry of acetonitrile extracts and Gas Chromatography Mass Spectrometry analyses of hexane extracts of isolated glands which were free from other leaf tissues. Our results showed that the glands of subgenus Eucalyptus contain numerous flavanones that are structurally related to pinocembrin and often present in much greater abundance. The maximum concentration of pinocembrin was 2 mg g-1 dry leaf found in E. stellulata, whereas that of dimethylpinocembrin (5,7-dimethoxyflavanone) was 10 mg g-1 in E. oreades and that of pinostrobin (5-hydroxy-7 methoxyflavanone) was 12 mg g-1 in E. nitida. We also found that the flavanones are exclusively located within the foliar glands rather than distributed throughout leaf tissues. The flavanones differ from the non-methylated pinocembrin in the degree and positions of methylation. This finding is particularly important given the attractiveness of methylated flavonoids as pharmaceuticals and therapeutics. Another important finding was that glands of some members of the subgenus also contain flavanone O-glucosides and flavanone beta-triketone conjugates. In addition, glands contain free beta-triketones, beta triketone heterodimers and chromone C-glucosides. Therefore, the foliar glands of this taxonomically distinct group of plants are a rich source of a range of flavonoids and other biologically active compounds with great commercial potential. PMID- 26977934 TI - Correction: Inflammatory Stress on Autophagy in Peripheral Blood Mononuclear Cells from Patients with Alzheimer's Disease during 24 Months of Follow-Up. PMID- 26977936 TI - Comparing a number line and audio prompts in supporting price comparison by students with intellectual disability. AB - BACKGROUND/AIMS/METHODS: Price comparison is an important and complex skill, but it lacks sufficient research attention in terms of educating secondary students with intellectual disability and/or autism spectrum disorder. This alternating treatment design study compared the use of a paper-based number line and audio prompts delivered via an audio recorder to support three secondary students with intellectual disability to independently and accuracy compare the price of three separate grocery items. PROCEDURES/OUTCOMES: The study consisted of 22 sessions, spread across baseline, intervention, best treatment, and two different generalization phases. Data were collected on the percent of task analysis steps completed independently, the type of prompts needed, students' accuracy selecting the lowest priced item, and task completion time. RESULTS/CONCLUSIONS: With both intervention conditions, students were able to independently complete the task analysis steps as well as accurately select the lowest priced item and decrease their task completion time. For two of the students, the audio recorder condition resulted in the greatest independence and for one the number line. For only one student was the condition with the greatest independence also the condition for the highest rate of accuracy. IMPLICATIONS: The results suggest both tools can support students with price comparison. Yet, audio recorders offer students and teachers an age-appropriate and setting-appropriate option. PMID- 26977935 TI - A Behavioral Measure of Costly Helping: Replicating and Extending the Association with Callous Unemotional Traits in Male Adolescents. AB - BACKGROUND: Some conduct-disordered youths have high levels of callous unemotional traits and meet the DSM-5's "with limited prosocial emotions" (LPE) specifier. These youths often do aggressive, self-benefitting acts that cost others. We previously developed a task, the AlAn's game, which asks participants to repeatedly decide whether to accept or reject offers in which they will receive money but a planned charity donation will be reduced. In our prior work, more "costly helping" (i.e., rejecting the offered money and protecting the donation) was associated with lower callous unemotional traits. Here we extend that prior work in a larger sample of adolescent male patients with serious conduct problems and controls, and test whether this association is mediated specifically by a Moral Elevation response (i.e., a positive emotional response to another's act of virtue). METHODS: The adolescent male participants were: 45 patients (23 with LPE) and 26 controls, who underwent an extensive phenotypic assessment including a measure of Moral Elevation. About 1 week later participants played the AlAn's game. RESULTS: All AlAn's game outcomes demonstrated significant group effects: (1) money taken for self (p = 0.02); (2) money left in the charitable donation (p = 0.03); and, (3) costly helping (p = 0.047). Controls took the least money and did the most costly helping, while patients with LPE took the most money and did the least costly helping. Groups also significantly differed in post-stimulus Moral Elevation scores (p = 0.005). Exploratory analyses supported that the relationship between callous unemotional traits and costly helping on the AlAn's game may be mediated in part by differences in Moral Elevation. CONCLUSIONS: The AlAn's game provides a standardized behavioral measure associated with callous unemotional traits. Adolescents with high levels of callous unemotional traits engage in fewer costly helping behaviors, and those differences may be related to blunting of positive emotional responses. PMID- 26977937 TI - Do inclusive work environments matter? Effects of community-integrated employment on quality of life for individuals with intellectual disabilities. AB - More individuals with an intellectual disability now possess prerequisite skills and supports necessary for successful work force integration than did previous generations. The current study compared quality of life of community-integrated workers with those participating in sheltered vocational workshops and adult day care programs. We considered numerous indices of quality of life, including inclusion and community participation; satisfaction within professional services, home life, and day activities; dignity, rights, and respect received from others; fear; choice and control; and family satisfaction. Our data revealed several important differences in quality of life across daytime activities; participants involved in community-integrated employment tended to be younger, indicated a greater sense of community integration, and reported more financial autonomy than did those who participated in adult day care programs and sheltered workshops. However, individuals reported no differences in overall satisfaction across daytime activities. We discuss generational differences across employment status as well as possible explanations to account for high levels of satisfaction across daytime activities. PMID- 26977938 TI - Fragile Sites of 'Valencia' Sweet Orange (Citrus sinensis) Chromosomes Are Related with Active 45s rDNA. AB - Citrus sinensis chromosomes present a morphological differentiation of bands after staining by the fluorochromes CMA and DAPI, but there is still little information on its chromosomal characteristics. In this study, the chromosomes in 'Valencia' C. sinensis were analyzed by fluorescence in situ hybridization (FISH) using telomere DNA and the 45S rDNA gene as probes combining CMA/DAPI staining, which showed that there were two fragile sites in sweet orange chromosomes co localizing at distended 45S rDNA regions, one proximally locating on B-type chromosome and the other subterminally locating on D-type chromosome. While the chromosomal CMA banding and 45S rDNA FISH mapping in the doubled haploid line of 'Valencia' C. sinensis indicated six 45S rDNA regions, four were identified as fragile sites as doubled comparing its parental line, which confirmed the cytological heterozygosity and chromosomal heteromorphisms in sweet orange. Furthermore, Ag-NOR identified two distended 45S rDNA regions to be active nucleolar organizing regions (NORs) in diploid 'Valencia' C. sinensis. The occurrence of quadrivalent in meiosis of pollen mother cells (PMCs) in 'Valencia' sweet orange further confirmed it was a chromosomal reciprocal translocation line. We speculated this chromosome translocation was probably related to fragile sites. Our data provide insights into the chromosomal characteristics of the fragile sites in 'Valencia' sweet orange and are expected to facilitate the further investigation of the possible functions of fragile sites. PMID- 26977939 TI - System impact research - increasing public health and health care system performance. AB - BACKGROUND: Interventions directed to system features of public health and health care should increase health and welfare of patients and population. AIMS: To build a new framework for studies aiming to assess the impact of public health or health care system, and to consider the role of Randomized Controlled Trials (RCTs) and of Benchmarking Controlled Trials (BCTs). METHODS: The new concept is partly based on the author's previous paper on the Benchmarking Controlled Trial. The validity and generalizability considerations were based on previous methodological studies on RCTs and BCTs. RESULTS: The new concept System Impact Research (SIR) covers all the studies which aim to assess the impact of the public health system or of the health care system on patients or on population. There are two kinds of studies in System Impact Research: Benchmarking Controlled Trials (observational) and Randomized Controlled Trials (experimental). The term impact covers in particular accessibility, quality, effectiveness, safety, efficiency, and equality. CONCLUSIONS: System Impact Research - creating the scientific basis for policy decision making - should be given a high priority in medical, public health and health economic research, and should also be used for improving performance. Leaders at all levels of health and social care can use the evidence from System Impact Research for the benefit of patients and population. Key messages The new concept of SIR is defined as a research field aiming at assessing the impacts on patients and on populations of features of public health and health and social care systems or of interventions trying to change these features. SIR covers all features of public health and health and social care system, and actions upon these features. The term impact refers to all effects caused by the public health and health and social care system or parts of it, with particular emphasis on accessibility, quality, effectiveness, adverse effects, efficiency, and equality of services. SIR creates the scientific basis for policy decisions. Leaders at all levels of health and social care can use the evidence from SIR for the benefit of the patients and the population. PMID- 26977940 TI - Characterization of Virulence-Associated Genes, Antimicrobial Resistance Genes, and Class 1 Integrons in Salmonella enterica serovar Typhimurium Isolates from Chicken Meat and Humans in Egypt. AB - Foodborne pathogens are leading causes of illness especially in developing countries. The current study aimed to characterize virulence-associated genes and antimicrobial resistance in 30 Salmonella Typhimurium isolates of chicken and human origin at Mansoura, Egypt. The results showed that invA, avrA, mgtC, stn, and bcfC genes were identified in all the examined isolates, while 96.7% and 6.7% were positive for sopB and pef genes, respectively. The highest resistance frequencies of the isolates were to chloramphenicol and trimethoprim sulfamethoxazole (73.3%, each), followed by streptomycin (56.7%), tetracycline and ampicillin (53.3%, each), and gentamicin (30%). However, only 2.7% of the isolates were resistant to cefotaxime and ceftriaxone each. Different resistance associated genes, including blaTEM, aadB, aadC, aadA1, aadA2, floR, tetA(A), tetA(B), and sul1, were identified in Salmonella Typhimurium isolates with the respective frequencies of 53.3%, 6.7%, 23.3%, 46.7%, 63.3%, 73.3%, 60%, 20%, and 96.7%. None of the isolates was positive for blaSHV, blaOXA, and blaCMY genes. The results showed that the intI1 gene was detected in 24 (80%) of the examined Salmonella Typhimurium isolates. Class 1 integrons were found in 19 (79.2%) isolates that were intI1 positive. Seven integron profiles (namely: P-I to P-VII) were identified with P-V (gene cassette dfrA15, aadA2), the most prevalent profile. To the best of our knowledge, this is the first study to characterize the unusual gene cassette array dfrA12-OrfF-aadA27 from Salmonella Typhimurium isolates in Egypt. PMID- 26977961 TI - Effects of different routes of application on ethylenediurea persistence in tobacco leaves. AB - Ethylenediurea (EDU) is a common research tool for investigating ozone impacts on vegetation, although the role of different application routes (foliar spray vs soil drench) on EDU persistence in the leaves is unknown. We quantified EDU concentrations in leaves of the O3-sensitive Bel-W3 cultivar of tobacco treated with EDU as either foliar spray or soil drench. Foliar EDU concentrations were measured by Q-TOF LC/MS. When EDU was applied as foliar spray, 1 h was enough for reaching a measurable concentration within the leaf. EDU concentration increased over the 21-day period when the leaf was not washed after the application (treatment #1), while it decreased when the leaf was washed after the application (treatment #2). These results suggest that: a) dry deposition of EDU onto the leaf surface was gradually absorbed into the unwashed leaf, although the mechanisms of such uptake were unclear; b) concentration of EDU was decreased quickly (-35%) during the first 24 h from application and more slowly during the following three days (-20%) in the washed leaves. Degradation did not involve enzymatic reactions and was not affected by the presence of ROS. When EDU was applied as soil drench, foliar concentrations increased over time, likely due to adsorption onto soil organic matter and gradual re-solubilization by irrigation water. An analysis of EDU concentration in protoplast and intercellular washing fluid showed that EDU did not enter the cells, but was retained in the apoplast only. Possible implications of EDU in the apoplast and recommendations for EDU application are discussed. PMID- 26977962 TI - Precision Medicine in Chronic Obstructive Pulmonary Disease. PMID- 26977963 TI - Now We Know Who You Are: A Clear Description of Mononuclear Phagocyte Subsets in the Human Lung. PMID- 26977964 TI - Asthma: Airways That Are Hyperactive by Design. PMID- 26977965 TI - Vitamin D in Asthma. Is the Golden Bullet Losing Its Luster? PMID- 26977966 TI - At the Checkpoint: Lung CD8(+) T Cells, Respiratory Viruses, and Chronic Obstructive Pulmonary Disease. PMID- 26977967 TI - Chronic Mucus Hypersecretion and the Natural History of Chronic Obstructive Pulmonary Disease. PMID- 26977968 TI - Pneumoconiosis Redux. Coal Workers' Pneumoconiosis and Silicosis Are Still a Problem. PMID- 26977969 TI - Access to Lung Transplantation. The Long and Short of It. PMID- 26977970 TI - Lipofibroblast Phenotype in Pulmonary Interstitial Glycogenosis. PMID- 26977972 TI - Duration of Hospitalization and Lung Function Deterioration as Predictors of Future Chronic Obstructive Pulmonary Disease Exacerbations. PMID- 26977971 TI - Controlled Mechanical Ventilation Attenuates the Systemic Inflammation of Severe Chronic Obstructive Pulmonary Disease Exacerbations. PMID- 26977974 TI - What is ECMO? PMID- 26977973 TI - Anticoagulant Therapy in Idiopathic Pulmonary Fibrosis and Its Potential Effects on Pathogenesis. PMID- 26977975 TI - Thyroid storm and early-onset proteinuric hypertension caused by a partial molar pregnancy. PMID- 26977976 TI - Uterine perforation of pyometra in a cervical cancer: A case report and literature review. PMID- 26977977 TI - Synthesis of functionalized gold nanoparticles capped with 3-mercapto-1 propansulfonate and 1-thioglucose mixed thiols and "in vitro" bioresponse. AB - The synthesis, characterization and assessment of biological behavior of innovative negatively charged functionalized gold nanoparticles is herein reported, for potential applications in the field of radiotherapy and drug delivery. Gold nanoparticles (AuNPs) functionalized with two capping agents, i.e., the 3-mercapto-1-propansulfonate (3-MPS) and 1-beta-thio-D-glucose (TG), have been on purpose synthesized and fully characterized. Advanced characterization techniques including X-Ray Photoelectron Spectroscopy (XPS) were applied to probe the chemical structure of the synthesized nanomaterials. Z potential and Dynamic Light Scattering measurements allowed assessing the nanodimension, dispersity, surface charge and stability of AuNPs. Transmission Electron Microscopy (TEM) and Flame Atomic Absorption Spectroscopy (FAAS) were applied to the "in vitro" HSG cell model, to investigate the nanoparticles-cells interaction and to evaluate the internalization efficiency, whereas short term cytotoxicity and long term cell killing were evaluated by means of MTT and SRB assays, respectively. In conclusion, in order to increase the amount of gold atoms inside the cell we have optimized the synthesis for a new kind of biocompatible and very stable negatively charged TG-functionalized nanoparticles, with diameters in a range that maximize the uptake in cells (i.e., ~15nm). Such particles are very promising for radiotherapy and drug delivery application. PMID- 26977978 TI - Unintended Pregnancy, Depression, and Hazardous Drinking in a Community-Based Sample of Sexual Minority Women. AB - CONTEXT: Unintended pregnancy is a stressful life event with important implications for women's health. Little research has examined sexual minority women's (SMW; lesbian, bisexual, mostly heterosexual) experiences of unintended pregnancy, and no studies have examined the relationship between unintended pregnancy, mental health, and negative coping behaviors in this population. METHODS: We used the Chicago Health and Life Experiences of Women (CHLEW) Study (n = 454), a diverse sample of SMW, to examine the relationship between self reported unintended pregnancy, depressive symptoms, and hazardous drinking. We used generalized linear model-building techniques and adjusted for key sociodemographic controls, as well as unintended pregnancy risk factors, including childhood physical and sexual abuse and age of sexual debut. RESULTS: Twenty-four percent of the sample reported an unintended pregnancy. SMW who reported unintended pregnancies also reported significantly more depressive symptoms and greater risk of hazardous drinking. Adjusting for childhood abuse explained the relationship between unintended pregnancy and depressive symptoms, but not the relationship between unintended pregnancy and hazardous drinking. CONCLUSIONS: Unintended pregnancy among SMW is an understudied topic. Our results suggest that unintended pregnancy is not uncommon among SMW and highlight the need for more research to investigate the mechanisms that link unintended pregnancy to depression and to hazardous drinking within this population. PMID- 26977980 TI - "We are our choices"--AIDS impact special issue Amsterdam 2015. PMID- 26977979 TI - Automated DBS microsampling, microscale automation and microflow LC-MS for therapeutic protein PK. AB - AIM: Reduce animal usage for discovery-stage PK studies for biologics programs using microsampling-based approaches and microscale LC-MS. METHODS & RESULTS: We report the development of an automated DBS-based serial microsampling approach for studying the PK of therapeutic proteins in mice. Automated sample preparation and microflow LC-MS were used to enable assay miniaturization and improve overall assay throughput. Serial sampling of mice was possible over the full 21-day study period with the first six time points over 24 h being collected using automated DBS sample collection. Overall, this approach demonstrated comparable data to a previous study using single mice per time point liquid samples while reducing animal and compound requirements by 14-fold. CONCLUSION: Reduction in animals and drug material is enabled by the use of automated serial DBS microsampling for mice studies in discovery-stage studies of protein therapeutics. PMID- 26977981 TI - Holy MACRA! Will Our Future Be Better or Worse? PMID- 26977982 TI - Beyond Work-Life "Balance". PMID- 26977983 TI - Medicare Payment Reform: Making Sense of MACRA. PMID- 26977984 TI - Screening Your Adult Patients for Depression. PMID- 26977985 TI - Lower Your Overhead With a Patient Portal. PMID- 26977986 TI - How to Start Your Workday. PMID- 26977988 TI - Coding bilateral procedures. PMID- 26977987 TI - Advance care planning. PMID- 26977989 TI - Data elements and medical decision-making. PMID- 26977991 TI - Injured extremity examination. PMID- 26977990 TI - Multiple digit procedures. PMID- 26977992 TI - Improve huddles with whiteboards. PMID- 26977993 TI - Compare job options using a simple tool. PMID- 26977994 TI - Diabetic foot exams and PQRS. PMID- 26977995 TI - Getting Your Notes Done on Time. PMID- 26977997 TI - Barcelona Consensus on Biomarker-Based Immunosuppressive Drugs Management in Solid Organ Transplantation. AB - With current treatment regimens, a relatively high proportion of transplant recipients experience underimmunosuppression or overimmunosuppression. Recently, several promising biomarkers have been identified for determining patient alloreactivity, which help in assessing the risk of rejection and personal response to the drug; others correlate with graft dysfunction and clinical outcome, offering a realistic opportunity for personalized immunosuppression. This consensus document aims to help tailor immunosuppression to the needs of the individual patient. It examines current knowledge on biomarkers associated with patient risk stratification and immunosuppression requirements that have been generally accepted as promising. It is based on a comprehensive review of the literature and the expert opinion of the Biomarker Working Group of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. The quality of evidence was systematically weighted, and the strength of recommendations was rated according to the GRADE system. Three types of biomarkers are discussed: (1) those associated with the risk of rejection (alloreactivity/tolerance), (2) those reflecting individual response to immunosuppressants, and (3) those associated with graft dysfunction. Analytical aspects of biomarker measurement and novel pharmacokinetic-pharmacodynamic models accessible to the transplant community are also addressed. Conventional pharmacokinetic biomarkers may be used in combination with those discussed in this article to achieve better outcomes and improve long-term graft survival. Our group of experts has made recommendations for the most appropriate analysis of a proposed panel of preliminary biomarkers, most of which are currently under clinical evaluation in ongoing multicentre clinical trials. A section of Next Steps was also included, in which the Expert Committee is committed to sharing this knowledge with the Transplant Community in the form of triennial updates. PMID- 26977998 TI - Regulatory T Cells as Biomarkers for Rejection and Immunosuppression Tailoring in Solid Organ Transplantation. AB - The use of biomarkers to tailor immunosuppression and to predict graft and patient outcomes using biological samples obtained by non-invasive tests is one of the main objectives in solid organ transplantation. Although biopsies give the most accurate information, they are clearly invasive and are associated with potentially adverse effects. To date, regulatory T cells have been shown to play a role in allograft protection; for this reason, extensive research has been performed to define them as biomarkers. However, studies of the measurement of these cells in peripheral blood as biomarkers in solid organ transplantation have been very limited and still not validated in prospective randomized large cohorts with the use of standardized methodology. Such poor evidence has been almost exclusively obtained in renal transplantation. Available data summarized here point for their use as biomarkers in different clinical settings with discordant data in many cases. PMID- 26977999 TI - Target Enzyme Activity and Phosphorylation of Pathway Molecules As Specific Biomarkers in Transplantation. AB - Therapeutic drug monitoring of immunosuppressants in the clinic is based on the measurement of blood concentration (pharmacokinetics). However, pharmacokinetic monitoring of immunosuppressants does not allow prediction of individual differences in pharmacological effects on immune cells. Pharmacodynamic (PD) monitoring via direct determination of target enzyme activity and phosphorylation of pathway molecules may enhance therapeutic drug monitoring and allow prediction of individual responses to immunosuppressants. This review discusses the clinical relevance of monitoring the activity of inosine-5'-monophosphate dehydrogenase (IMPDH), the target enzyme of mycophenolic acid, and of the phosphorylation of mechanistic target of rapamycin (mTOR) molecules. Significant progress regarding a robust and practicable assay for the determination of IMPDH activity as a specific PD parameter of mycophenolic acid activity has been achieved. The development of a rapid and reliable IMPDH assay system suitable for use in clinical practice was an important step that allowed thorough pharmacokinetics-PD investigations in large numbers of mycophenolic acid-treated patients. A reproducible and validated IMPDH assay was used in a few clinical trials by different research groups and is based on the chromatographic determination of newly generated xanthine monophosphate in mononuclear cell lysates. This assay requires only small volumes of blood and can be reliably used in multicenter trials; however, more clinical data from larger cohorts are needed to determine its clinical utility. Regarding monitoring of mTOR inhibitors (mTORis), the results of the first study that provided data on measurement of mTOR pathway molecules [p70 ribosomal protein S6 kinase (p70S6 kinase) and phosphorylated ribosomal protein S6] suggest that they are suitable targets for individualized PD monitoring of sirolimus and everolimus after organ transplantation. At present, only the phospho-flow phosphorylated ribosomal protein S6 assay has been validated in vitro and evaluated for confounding factors in vivo. The reported specific biomarkers for IMPDH activity and phosphorylation of mTOR molecules must be validated in clinical settings and multicenter studies to prove their clinical validity. PMID- 26977996 TI - Role of monocytes and macrophages in regulating immune response following lung transplantation. AB - PURPOSE OF REVIEW: Advances in the field of monocyte and macrophage biology have dramatically changed our understanding of their role during homeostasis and inflammation. Here we review the role of these important innate immune effectors in the lung during inflammatory challenges including lung transplantation. RECENT FINDINGS: Neutrophil extravasation into lung tissue and the alveolar space have been shown to be pathogenic during acute lung injury as well as primary graft dysfunction following lung transplantation. Recent advances in lung immunology have demonstrated the remarkable plasticity of both monocytes and macrophages and demonstrated their importance as mediators of neutrophil recruitment and transendothelial migration during inflammation. SUMMARY: Monocytes and macrophages are emerging as key players in mediating both the pathogen response and sterile lung inflammation, including that arising from barotrauma and ischemia-reperfusion injury. Ongoing studies will establish the mechanisms by which these monocytes and macrophages initiate a variety of immune response that lay the fundamental basis of injury response in the lung. PMID- 26978000 TI - Individual Health Management - A Comprehensive Lifestyle Counselling Programme for Health Promotion, Disease Prevention and Patient Education. AB - BACKGROUND: Epidemiological data shows globally increasing numbers of obesity and stress-related diseases. In this article, a comprehensive medical lifestyle modification programme - called Individual Health Management (IHM) - is described in detail and discussed as a promising tool to individually manage and reverse such negative health trends in patients. METHODS: The IHM programme is based on a blended learning concept. It comprises a 12-week basic training phase, followed by a 9-month maintenance phase, and includes the following key features: 1) web based and physician-led health screenings; 2) a structured 12-week basic training with a core curriculum providing tuition in behavioural self-management strategies for weight loss and stress reduction; 3) weekly supervised group sessions during the core curriculum; 4) tailoring of materials, strategies and lifestyle goals; 5) continuous self-monitoring and feedback of the achieved progress; 6) regular contact with physicians or health professionals based on either face-to-face or distant lifestyle counselling; 7) recurrent one-day health seminars to ensure the sustainability of obtained results. CONCLUSIONS: IHM is a multi-component lifestyle intervention programme to increase physical activity, to reduce calorie intake and to practice both self and stress management. Individual care, group support and a tailored web-based programme blend to achieve the desired goals. A randomised control study to evaluate IHM's effects on weight control is currently being conducted. PMID- 26978001 TI - Adrenal Adenoma and Pheochromocytoma: Comparison of Multidetector CT Venous Enhancement Levels and Washout Characteristics. AB - PURPOSE: The aim of the study was to compare multidetector CT venous enhancement level and washout characteristics of adrenal adenoma and pheochromocytoma, with the goal of defining a venous enhancement level predictive of pheochromocytoma. METHODS: Retrospective review of medical records between 2002 and 2012 was performed to identify adrenal masses measuring less than 4 cm. Inclusion criteria for adrenal adenomas was venous phase contrast-enhanced computed tomography (CT), confirmatory adrenal CT (precontrast +/- washout), 1 to 2 years stability, and absence of clinical indicators of pheochromocytoma. All pathologically proven pheochromocytomas with venous phase CT imaging were evaluated. Nodule size and attenuation (venous +/- precontrast, delayed) were recorded. Student t test analysis compared venous enhancement levels. RESULTS: One hundred eighty-three subjects with 200 adenomas were compared with 22 subjects with 26 pheochromocytomas. The mean (SD) venous enhancement level for all adenomas (58 [26] Hounsfield units [HU]) and lipid-poor adenomas (76 [25]) was lower than that of pheochromocytomas (111 [38] HU, P < 0.01). No adenomas enhanced greater than 130 HU, compared with 38% (10/26) of the pheochromocytomas. A threshold of 130 HU to identify pheochromocytoma was 38% sensitive and 100% specific for pheochromocytoma. Of the 17 pheochromocytomas with washout imaging, rapid washout was identified in all (10/10, 100%) that enhanced greater than 130 HU on the venous phase, compared with 43% (3/7) that enhanced less than 130 HU. CONCLUSIONS: An indeterminate adrenal lesion that enhances greater than 130 HU on multidetector CT cannot be assumed to be an adenoma. Hypervascular pheochromocytoma (>130 HU) mimics adenoma washout pattern; absolute venous phase enhancement level must be considered. PMID- 26978002 TI - Potential Utility of Visually AcceSAble Rembrandt Images Assessment in Brain Astrocytoma Grading. AB - OBJECTIVE: The aim of this study was to evaluate the predictive value of multivariate factors of Visually AcceSAble Rembrandt Images (VASARI) in brain astrocytoma grading. METHODS: Presurgical magnetic resonance images of 126 patients with brain astrocytomas (World Health Organization grade 2, n = 38; grade 3, n = 36; grade 4, n = 52) were rated by 2 neuroradiologists for tumor size, location, and tumor morphology by using a standardized imaging feature set VASARI. RESULTS: Significant differences were noted in 12 factors of VASARI including enhancement quality, enhancing proportion, noncontrast enhancing tumor proportion, necrosis proportion, edema proportion, hemorrhage, thickness of enhancing margin, definition of the enhancing margin, pial and ependymal invasion, enhanced tumor crossing midline, and satellites between brain astrocytoma grades (grades 1-IV, P < 0.05). On multivariate regression analysis, enhancement quality was an independent diagnostic factor for high-grade brain astrocytoma, whereas edema proportion was an independent diagnostic factor in differentiating grade 2 and grade 3. Noncontrast enhancing tumor proportion was a predictive factor in the diagnosis of grade 4 astrocytoma. Receiver operating characteristic analysis illustrates edema proportion score higher than 2 with sensitivity of 86.1% in differentiating grade 2 and grade 3 astrocytoma. Noncontrast enhancing tumor proportion scores 4 or lower has high sensitivity (92.3%) but moderate specificity (50.0%) in differentiating grade 3 and grade 4 astrocytoma. CONCLUSIONS: Our data illustrate that magnetic resonance features of VASARI especially enhancement quality, edema proportion, and noncontrast enhancing tumor proportion provided precise and detailed information of astrocytoma grading and suggested that prediction of astrocytoma grading is based on VASARI as an adjunct to biopsy. PMID- 26978003 TI - Clinicopathologic Analysis of Stable and Unstable Vitiligo: A Study of 66 Cases. AB - Vitiligo is an acquired skin disorder characterized by milky-white macules and absence of functioning melanocytes. The cornerstone of its management is the correct categorization of a case into its 2 broad types-stable and unstable vitiligo. This distinction is at present based mainly on clinical criteria because the histopathological features are not fully established. This study was thus undertaken to examine histopathological features of vitiligo and to come up with a reliable and systematic approach toward this diagnostic challenge. All patients presenting with clinical features of vitiligo at our institution were included in the study. A 3-mm punch biopsy was taken from 3 sites-lesional, perilesional, and normal skin. Histopathological examination was primarily focused on evaluating 5 histopathological variables-spongiosis, epidermal lymphocytes, basal cell vacuolation, dermal lymphocytes, and melanophages. A total number of 66 patients were included in the study. There were 30 patients in stable and 36 in unstable vitiligo groups. It was observed that all 5 histopathological pattens were associated with unstable vitiligo. All the cases were then scored using a scoring system devised by the authors and the scores obtained were correlated with clinical categorization. It was observed that while there is a definite overlap in histological findings in the 2 groups, adoption of a systematic reporting system brings more consistency and objectivity in the diagnosis. The authors have recommended diagnoses that should be reported for the various scores. This in turn will help us to more reliably and confidently manage these patients. PMID- 26978004 TI - Acquired Localized Longitudinal Pachyonychia and Onychomatrical Tumors: A Comparative Study to Onychomatricomas (5 Cases) and Onychocytic Matricomas (4 Cases). AB - BACKGROUND: Besides onychomatricoma (OM), which shows a clinical band pattern of nail plate thickening, 2 new onychomatrical tumors with this clinical feature have recently been described: onychocytic matricoma (OCM) and in situ onychocytic carcinoma. OBJECTIVE: The purpose of this study was to present 4 cases of OCMs and compare their clinical and histopathologic characteristics with usual OMs. METHODS: We studied 4 cases of OCMs with nail clipping in 3 cases and an extensive immunohistochemical study for hair-related keratins and epithelial keratins. Nail clipping of OCMs was compared with the distal nail plate of 5 cases of OMs. RESULTS: All cases showed an acquired localized longitudinal band pattern of a thickened nail plate with yellow discoloration in 2 cases and a black streak in 2 cases. All cases showed a V-shaped keratogenous epithelial tumor with a papillomatous pattern of growth. The nail plate was thickened with small holes in a honeycomb pattern. In contrast, the 5 OMs showed the classical pattern of a panonychoma fibropapilliferum. The nail plate showed large cavities in a honeycomb pattern. CONCLUSIONS: This case series raises awareness of the clinical value of longitudinal pachyonychia coupled with nail clipping in the early detection of onychomatrical tumors as generic diagnosis with a limited differential diagnosis and a simple therapeutic approach. Nail clipping could be an aid in the surgical planning of onychomatrical tumor. A diagnosis of a benign growth could be suggested when the average dimensions of cavities are superior to 0.15 mm sparing the patient from an excisional procedure with its risk of subsequent permanent nail dystrophy. In contrast, nail clipping with a honeycomb pattern of minute cavities with average dimension inferior to 0.10 mm should prompt a biopsy of the distal matrix to rule out a malignant lesion. PMID- 26978008 TI - Quantifying Head Impact Exposure in Collegiate Women's Soccer. AB - OBJECTIVE: The aim of this study was to quantify head impact exposure for a collegiate women's soccer team over the course of the 2014 season. DESIGN: Observational and prospective study. SETTING: Virginia Tech women's soccer games and practices. PARTICIPANTS: Twenty-six collegiate level women's soccer players with a mean player age of 19 +/- 1. INTERVENTIONS: Participating players were instrumented with head impact sensors for biomechanical analysis. Video recordings of each event were used to manually verify each impact sustained. MAIN OUTCOME MEASURES: Head impact counts by player position and impact situation. RESULTS: The sensors collected data from a total of 17 865 accelerative events, 8999 of which were classified as head impacts. Of these, a total of 1703 impacts were positively identified (19% of total real impacts recorded by sensor), 90% of which were associated with heading the ball. The average number of impacts per player per practice or game was 1.86 +/- 1.42. Exposure to head impact varied by player position. CONCLUSIONS: Head impact exposure was quantified through 2 different methods, which illustrated the challenges associated with autonomously collecting acceleration data with head impact sensors. Users of head impact data must exercise caution when interpreting on-field head impact sensor data. PMID- 26978006 TI - Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors. AB - BACKGROUND: The mTOR-inhibitor everolimus improves progression-free survival in advanced pancreatic neuroendocrine tumours (PNETs). However, adaptive resistance to mTOR inhibition is described. METHODS: QGP-1 and BON-1, two human PNET cell lines, were cultured with increasing concentrations of everolimus up to 22 weeks to reach a dose of 1 MUM everolimus, respectively, 1000-fold and 250-fold initial IC50. Using total DNA content as a measure of cell number, growth inhibitory dose response curves of everolimus were determined at the end of resistance induction and over time after everolimus withdrawal. Response to ATP-competitive mTOR inhibitors OSI-027 and AZD2014, and PI3K-mTOR inhibitor NVP-BEZ235 was studied. Gene expression of 10 PI3K-Akt-mTOR pathway-related genes was evaluated using quantitative real-time PCR (RT-qPCR). RESULTS: Long-term everolimus-treated BON 1/R and QGP-1/R showed a significant reduction in everolimus sensitivity. During a drug holiday, gradual return of everolimus sensitivity in BON-1/R and QGP-1/R led to complete reversal of resistance after 10-12 weeks. Treatment with AZD2014, OSI-027 and NVP-BEZ235 had an inhibitory effect on cell proliferation in both sensitive and resistant cell lines. Gene expression in BON-1/R revealed downregulation of MTOR, RICTOR, RAPTOR, AKT and HIF1A, whereas 4EBP1 was upregulated. In QGP-1/R, a downregulation of HIF1A and an upregulation of ERK2 were observed. CONCLUSIONS: Long-term everolimus resistance was induced in two human PNET cell lines. Novel PI3K-AKT-mTOR pathway-targeting drugs can overcome everolimus resistance. Differential gene expression profiles suggest different mechanisms of everolimus resistance in BON-1 and QGP-1. PMID- 26978005 TI - Antifibrinolytics (lysine analogues) for the prevention of bleeding in people with haematological disorders. AB - BACKGROUND: People with haematological disorders are frequently at risk of severe or life-threatening bleeding as a result of thrombocytopenia (reduced platelet count). This is despite the routine use of prophylactic platelet transfusions to prevent bleeding once the platelet count falls below a certain threshold. Platelet transfusions are not without risk and adverse events may be life threatening. A possible adjunct to prophylactic platelet transfusions is the use of antifibrinolytics, specifically the lysine analogues tranexamic acid (TXA) and epsilon aminocaproic acid (EACA). This is an update of a Cochrane review first published in 2013. OBJECTIVES: To determine the efficacy and safety of antifibrinolytics (lysine analogues) in preventing bleeding in people with haematological disorders. SEARCH METHODS: We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (The Cochrane Library 2016, Issue 3), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), the Transfusion Evidence Library (from 1950) and ongoing trial databases to 07 March 2016. SELECTION CRITERIA: We included RCTs involving participants with haematological disorders, who would routinely require prophylactic platelet transfusions to prevent bleeding. We only included trials involving the use of the lysine analogues TXA and EACA. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all electronically-derived citations and abstracts of papers, identified by the review search strategy, for relevancy. Two review authors independently assessed the full text of all potentially relevant trials for eligibility, completed the data extraction and assessed the studies for risk of bias using The Cochrane Collaboration's 'Risk of bias' tool. We requested missing data from one author but the data were no longer available. The outcomes are reported narratively: we performed no meta-analyses because of the heterogeneity of the available data. MAIN RESULTS: We identified three new studies in this update of the review. In total seven studies were eligible for inclusion, three were ongoing RCTs and four were completed studies. The four completed studies were included in the original review and the three ongoing studies were included in this update. We did not identify any RCTs that compared TXA with EACA.Of the four completed studies, one cross-over TXA study (eight participants) was excluded from the outcome analysis because it had very flawed study methodology. Data from the other three studies were all at unclear risk of bias due to lack of reporting of study methodology.Three studies (two TXA (12 to 56 participants), one EACA (18 participants) reported in four articles (published 1983 to 1995) were included in the narrative review. All three studies compared the drug with placebo. All three studies included adults with acute leukaemia receiving chemotherapy. One study (12 participants) only included participants with acute promyelocytic leukaemia. None of the studies included children. One of the three studies reported funding sources and this study was funded by a charity.We are uncertain whether antifibrinolytics reduce the risk of bleeding (three studies; 86 participants; very low-quality evidence). Only one study reported the number of bleeding events per participant and there was no difference in the number of bleeding events seen during induction or consolidation chemotherapy between TXA and placebo (induction; 38 participants; mean difference (MD) 1.70 bleeding events, 95% confidence interval (CI) -0.37 to 3.77: consolidation; 18 participants; MD -1.50 bleeding events, 95% CI -3.25 to 0.25; very low-quality evidence). The two other studies suggested bleeding was reduced in the antifibrinolytic study arm, but this was statistically significant in only one of these two studies.Two studies reported thromboembolism and no events occurred (68 participants, very low-quality evidence).All three studies reported a reduction in platelet transfusion usage (three studies, 86 participants; very low-quality evidence), but this was reported in different ways and no meta-analysis could be performed. No trials reported the number of platelet transfusions per participant. Only one study reported the number of platelet components per participant and there was a reduction in the number of platelet components per participant during consolidation chemotherapy but not during induction chemotherapy (consolidation; 18 participants; MD -5.60 platelet units, 95% CI -9.02 to -2.18: induction; 38 participants, MD -1.00 platelet units, 95% CI -9.11 to 7.11; very low-quality evidence).Only one study reported adverse events of TXA as an outcome measure and none occurred. One study stated side effects of EACA were minimal but no further information was provided (two studies, 74 participants, very low-quality evidence).None of the studies reported on the following pre-specified outcomes: overall mortality, adverse events of transfusion, disseminated intravascular coagulation (DIC) or quality of life (QoL). AUTHORS' CONCLUSIONS: Our results indicate that the evidence available for the use of antifibrinolytics in haematology patients is very limited. The trials were too small to assess whether or not antifibrinolytics decrease bleeding. No trials reported the number of platelet transfusions per participant. The trials were too small to assess whether or not antifibrinolytics increased the risk of thromboembolic events or other adverse events. There are three ongoing RCTs (1276 participants) due to be completed in 2017 and 2020. PMID- 26978007 TI - Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF mutated melanoma xenograft tumours. AB - BACKGROUND: Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the quantitative pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation. METHODS: A PK/biomarker model was developed to connect abemaciclib/vemurafenib concentrations to changes in MAPK and cell cycle pathway biomarkers in A375 BRAF mutated melanoma xenografts. Resultant tumour growth inhibition was described by relating (i) MAPK pathway inhibition to apoptosis, (ii) mitotic cell density to tumour growth and, under resistant conditions, (iii) retinoblastoma protein inhibition to cell survival. RESULTS: The model successfully described vemurafenib/abemaciclib-mediated changes in MAPK pathway and cell cycle biomarkers. Initial tumour shrinkage by vemurafenib, acquisition of resistance and subsequent abemaciclib-mediated efficacy were successfully captured and externally validated. Model simulations illustrate the benefit of intermittent vemurafenib therapy over continuous treatment, and indicate that continuous abemaciclib in combination with intermittent vemurafenib offers the potential for considerable tumour regression. CONCLUSIONS: The quantitative pharmacology of the abemaciclib/vemurafenib combination was successfully characterised and an optimised, clinically-relevant dosing strategy was identified. PMID- 26978011 TI - Low Threshold Quantum Dot Lasers. AB - Semiconductor quantum dots have replaced conventional inorganic phosphors in numerous applications. Despite their overall successes as emitters, their impact as laser materials has been severely limited. Eliciting stimulated emission from quantum dots requires excitation by intense short pulses of light typically generated using other lasers. In this Letter, we develop a new class of quantum dots that exhibit gain under conditions of extremely low levels of continuous wave illumination. We observe thresholds as low as 74 mW/cm(2) in lasers made from these materials. Due to their strong optical absorption as well as low lasing threshold, these materials could possibly convert light from diffuse, polychromatic sources into a laser beam. PMID- 26978009 TI - Structural complexes of the agonist, inverse agonist and antagonist bound C5a receptor: insights into pharmacology and signaling. AB - The C5a receptor (C5aR) is a pharmacologically important G-protein coupled receptor (GPCR) that interacts with (h)C5a, by recruiting both the "orthosteric" sites (site1 at the N-terminus and site2 at the ECS, extra cellular surface) on C5aR in a two site-binding model. However, the complex pharmacological landscape and the distinguishing chemistry operating either at the "orthosteric" site1 or at the functionally important "orthosteric" site2 of C5aR are still not clear, which greatly limits the understanding of C5aR pharmacology. One of the major bottlenecks is the lack of an experimental structure or a refined model structure of C5aR with appropriately defined active sites. The study attempts to understand the pharmacology at the "orthosteric" site2 of C5aR rationally by generating a highly refined full-blown model structure of C5aR through advanced molecular modeling techniques, and further subjecting it to automated docking and molecular dynamics (MD) studies in the POPC bilayer. The first series of structural complexes of C5aR respectively bound to a linear native peptide agonist ((h)C5a CT), a small molecule inverse agonist (NDT) and a cyclic peptide antagonist (PMX53) are reported, apparently establishing the unique pharmacological landscape of the "orthosteric" site2, which also illustrates an energetically distinct but coherent competitive chemistry ("cation-pi" vs. "pi-pi" interactions) involved in distinguishing the established ligands known for targeting the "orthosteric" site2 of C5aR. Over a total of 1 MUs molecular dynamics (MD) simulation in the POPC bilayer, it is evidenced that while the agonist prefers a "cation-pi" interaction, the inverse agonist prefers a "cogwheel/L-shaped" interaction in contrast to the "edge-to-face/T-shaped" type pi-pi interactions demonstrated by the antagonist by engaging the F275(7.28) of the C5aR. In the absence of a NMR or crystallographically guided model structure of C5aR, the computational model complexes not only provide valuable insights for understanding the C5aR pharmacology, but also emerge as a promising platform for the design and discovery of future potential drug candidates targeting the (h)C5a C5aR signaling axes. PMID- 26978012 TI - Bioapplications and biotechnologies of upconversion nanoparticle-based nanosensors. AB - Upconversion nanoparticles (UCNPs), which can emit ultraviolet/visible (UV/Vis) light under near-infrared (NIR) excitation, are regarded as a new generation of nanoprobes because of their unique optical properties, including a virtually zero auto-fluorescence background for the improved signal-to-noise ratio, narrow emission bandwidths and high resistance to photo-bleaching. These properties make UCNPs promising candidates as luminescent bioprobes in biomedicine and biotechnology. In this review, we focus on the recent progress in the development of UCNP-based nanoprobes for biosensing. Firstly, as the FRET process is a widely used method for biosensing to improve the sensitivity, we summarize recent research studies about UCNP-based nanocomposites utilizing the FRET process for biosensing. Different energy acceptors (organic dyes, noble metal nanoparticles, carbon nanomaterials and semiconductor nanomaterials) with their own advantages and limitations are well summarized in this review. Secondly, since UCNPs have been utilized for the detection of different kinds of analytes, we introduce recent research studies about UCNPs for ions, gas molecules, biomolecules and thermal sensing. Finally, we highlight the typical detection techniques and UCNP based devices for bioapplications. PMID- 26978013 TI - [The structure of the internal carotid artery wall in pathological tortuosity]. AB - OBJECTIVE: to study a change in the content of main components of the internal carotid artery (ICA) wall in pathological tortuosity (PT) resulting from fibromuscular dysplasia, using immunohistochemistry and confocal laser scanning microscopy. MATERIAL AND METHODS: Immunohistochemical (IHC) analysis using antibodies to elastin, collagen types I and III, and smooth muscle actin was made. The levels of elastin and matrix metalloproteinase 9 (MMP-9) were determined by confocal laser scanning microscopy. The relative area of expression and the area of co-location of these markers were measured. RESULTS: IHC examination of the expression of elastin revealed that the patients with PT of ICA had its higher content than the controls, but they were observed to have fiber fragmentation. Comparison of collagen types I and III expressions showed no significant differences between the groups. The found significantly lower smooth muscle actin expression in the patients with PT of ICA than in the controls was suggestive of the decreased levels of smooth muscle cells. Confocal microscopy analysis showed high elastin and low MMP-9 expressions in the control group and, on the contrary, low elastin and high proteinase levels in the PT group (r<0.05). CONCLUSION: One of the causes of PT is impairment in vascular elastic properties due to the destruction of elastic fibers and to their fragmentation, as well as to the decreased count of smooth muscle cells, which in turn causes enhanced MMP 9 activity and tissue matrix degradation. PMID- 26978014 TI - [Morphological pathology of vessels in granulomatosis with polyangiitis (Wegener's disease)]. AB - OBJECTIVE: to investigate the incidence of injuries in different vascular beds and the morphopathological changes in vessels in granulomatosis with polyangiitis. MATERIAL AND METHODS: The morphopathological features of vascular injuries were investigated in 11 dead patients aged 16--74 years with granulomatosis with polyangiitis. RESULTS: Proliferative and destructive angiitis with predominant involvement of microcirculatory vessels and with development of necrosis-prone granulomas in their walls and perivascularly was established to underlie the clinical manifestations of granulomatosis with polyangiitis. The most typical localization of the pathologic process is the vessels of the upper respiratory tract, lungs, and kidneys. Cardiopulmonary and renal failures are causes of death in the majority of cases. It should be noted that the vessels of the heart, liver, and gastrointestinal tract are frequently involved in the pathological process. Vascular changes in these organs determine the clinical features of granulomatosis with polyangiitis and lead to a number of fatal complications. CONCLUSION: Granulomatosis with polyangiitis is a systemic disease with polymorphism of clinical manifestations, which requires in-depth analysis based on current precision patient examination methods, including a histopathological study. PMID- 26978015 TI - [The mother-placenta-fetus system in diffuse toxic goiter: Morphopathological aspects]. AB - OBJECTIVE: to compare the clinical and morphological parallels of the mother placenta-fetus system in diffuse toxic goiter (DTG) through current morphological examinations. SUBJECTS AND METHODS: Sixty-five women whose pregnancy occurred with DTG were examined using both clinical and morphological studies (light, scanning electron, and atomic-force microscopies and macro- and microelement analysis); the placenta and uterus were investigated. RESULTS: Destructive changes and microrelief impairment, resulting from circulatory disorders (ischemia) and hemic hypoxia, were observed in the presence of DTG during pregnancy. Abnormal placental immaturity developed; the number of terminal villi decreased; sclerosis occurred. The magnitude of changes showed up to a greater extent in the myometrium, umbilical cord, and placenta of women, whose pregnancy occurred with DTG, and in patients with disease recurrence. In preeclampsia, plethora, stasis, and thrombosis were added to circulatory disorders. CONCLUSION: Not only the diagnosis itself of DTG, but also the type of its course and the pattern of obstetric disease, primarily preeclampsia, affect the state of structural components of the uteroplacental unit. PMID- 26978016 TI - [Morphological features of the myometrium in connective tissue dysplasia in women with uterine inertia]. AB - OBJECTIVE: to reveal the morphological features of the lower uterine segment myometrium in connective tissue dysplasia (CTD) in women with uterine inertia. MATERIAL AND METHODS: Histological, immunohistochemical (with antibodies against collagen types I and III, matrix metalloproteinases 1 and 9 (MMR-1, MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1), fibronectin; fibulin-5, connexin-43), electron microscopic, and electron immunocytochemical studies with morphometry of myometrial fragments from 15 parturient women with CTD and uterine inertia (a study group) and those from 10 women without CTD (a control group). RESULTS: The myometrium in CTD exhibited the decreased expression of connextin 43, fibulin-5, TIMP-1, collagens types I and III with collagen type III predominance and the unchanged levels of fibronectin and MMP-1 and MMP-9. Electron microscopy and immunocytochemistry showed fewer intercellular contacts and the dramatically lower expression of connexin-43 than in the control. CONCLUSION: A set of found myometrial changes in women with uterine inertia is a manifestation of CTD. PMID- 26978017 TI - [Prognostic values of the clinical, morphological and molecular biological characteristics of colon adenocarcinoma]. AB - OBJECTIVE: to estimate the predictive and prognostic factors using morphological studies in patients with colon cancer to increase survival rates. SUBJECTS AND METHODS: Immunohistochemical examination was made in 582 patients with colon adenocarcinoma, by determining 11 different indicators relating to the development of the tumor and its treatment. RESULTS: The simultaneous determination of the chemokine receptor CXCR4 and proliferative activity (Ki-67 expression) can define disease prognosis in view of relapse-survival rates in patients with Stage II colon cancer after radical surgical treatment. CONCLUSION: Thymidylate synthase and thymidine phosphorylase are of predictive value. The immunohistochemical examination of other markers, such as ALDH1, CCR10, ERCC-1, DYPD, topoisomerase II alpha, and class III beta-tubulin for the choice of treatment policy for patients with colon cancer has indicated that they are of no value. PMID- 26978018 TI - [Matrix metalloproteinases 2 and 9, their endogenous regulators, and angiotensin converting enzyme in cervical squamous cell carcinoma]. AB - OBJECTIVE: to investigate the specific features of the expression of matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), tissue inhibitor of metalloptoteinase 2 (TIMP-2), urokinase-type plasminogen activator (uPA), and angiotensin converting enzyme (ACE) in cervical squamous cell carcinoma (CSCC). MATERIAL AND METHODS: The samples of tumor tissue and morphologically normal tissue adjacent to the tumor were investigated. Enzymatic assays applying specific substrates, as well as zymographic and immunohistochemical studies were used. RESULTS: The invasive potential of CSCC has been established to be substantially influenced by the increased expression of MMP-9 and uPA and by the decreased expression of TIMP 2, as well as to a lesser extent by a change in MMP-2 expression. MMP-9 may serve as a marker for invasive growth. Enhanced ACE activity in cancer confirms the involvement of this enzyme in tumor progression. The morphologically normal tissue adjacent to the tumor shows the substantial expression of MMP-2 and MMP-9 and in some cases the enhanced activity of uPA and ACE, which makes an additional contribution to the increased invasive potential of tumor. CONCLUSION: The findings are important in understanding the mechanisms of cancer progression and may affect therapeutic strategies for the patient. PMID- 26978019 TI - [Diagnostic value of estimation of ERG expression in prostate adenocarcinoma and high-grade prostatic intraepithelial neoplasia]. AB - OBJECTIVE: to estimate the diagnostic and prognostic value of analyzing the abnormal overexpression of the chimeric protein ERG, encoded by the chimeric gene TMPRSS2/ERG, in prostatic neoplasias. MATERIAL AND METHODS: A total of 100 prostate adenocarcinoma samples were examined. The presence of tumor and high grade prostatic intraepithelial neoplasia (hPIN) was verified by immunohistochemical tests using anti-P504S and anti-34betaE12 antibodies in serial sections; RT-PCR was employed to analyze the chimeric transcript TMPRSS2/ERG in 30 prostate adenocarcinoma samples. RESULTS: ERG expression was noted in 46% of the adenocarcinomas and in 21% of hPIN. Eight (8%) patients were observed to have heterogeneous ERG expression: the marked reaction in some tumor portions was concurrent with its complete absence in others. Furthermore, there was ERG expression in all cases of intraductal (noninvasive) carcinoma (the foci of intraductal carcinoma were assessed as atypical cribriform lesions by light microscopy). The prognostic value of ERG expression could not be determined at the current stage of the investigation. CONCLUSION: The relatively low rate of ERG-positive hPIN counts in favor of the limited role of this marker in the differential diagnosis of hPIN. ERG in combination with P504S and 34betaE12 is an informative marker for the differential diagnosis of hPIN with intraductal carcinoma. PMID- 26978020 TI - [Use of the new 2013 ASCO/CAP guidelines to study HERS status by fluorescence in situ hybridization in patients with breast cancer]. AB - Despite the long-term history of HER2 testing in breast cancer (BC), the results of its study are frequently interpreted ambiguously. The introduction of the new 2013 ASCO/CAP guidelines is aimed to further optimize HERS testing in view of new scientific evidence for the biological characteristics of BC. OBJECTIVE: to study the results of assessing HERS2 status in patients with the questionable level of protein expression according to the 2007 versus 2013 ASCO/CAP criteria. SUBJECTS AND METHODS: Biopsy specimens from 572 patients diagnosed with BC after immunohistochemical examination, including HER2 status assessment, were investigated by fluorescence in situ hybridization. RESULTS: The use of the new 2013 ASCO/CAP criteria versus the previous criteria to determine intratumor heterogeneity, HER2 gene copy number, and the so-called chromosome 17 polysomy was ascertained to cause a statistically significant increase in HER2-positive cases from 25 to 42.5% (OR=2.2178; 95% CI, 1.8254-2.6950; r=0.0005). CONCLUSION: The use of the new guidelines additionally permits effective therapy in patients with BC, which may be another step to improve survival in this large patient group. PMID- 26978021 TI - [An observation of HELLP syndrome with fatal outcome]. AB - The paper describes the morphopathological changes found at autopsy of a 42-year old pregnant woman whose death was due to HELLP syndrome (Hemolysis, Elevated Liver enzymes, and Low Platelets) that is rarely encountered in autopsy practice and that is a type of preeclampsia. It considers the morphogenesis of these changes in the light of the pathophysiological mechanisms underlying the syndrome. PMID- 26978022 TI - [Optimization of the immunohistochemical diagnosis of AL amyloidosis using novel antibodies]. AB - OBJECTIVE: to improve the immunohistochemical diagnosis of AL amyloidosis, by generating novel peptide antibodies against the variable and constant regions of the kappa-light chains. MATERIAL AND METHODS: All amyloidogenic kappa-light chains were sought in the scientific literature and the database of the National Center for Biotechnology Information. On the basis of the findings, a chain was formed from the most common amino acid residues that were used to choose peptide regions for immunization. Four antibodies were generalized via immunization of rabbits with two peptides that corresponded to the variant or constant regions of kappa-light chains. RESULTS: The specificity of the obtained antibodies was confirmed using a series of 222 biopsy specimens from 193 patients with AL, AA, transthyretin, or insulin amyloidosis. All the novel polyclonal peptide antibodies produced positive staining in cases of ALkappa amyloidosis. CONCLUSION: The generated polyclonal peptide antibodies against the variable and constant regions of kappa-light chains are able to improve the immunohistochemical diagnosis of amyloidosis. PMID- 26978023 TI - In Vitro Antimicrobial Susceptibility of Pathogenic Leptospira Biofilm. AB - Pathogenic Leptospira spp. are the causative agent of leptospirosis. Biofilm formation in leptospires is a new area of study, and its role in pathogenesis is not fully explored. As in other biofilm-forming bacteria, Leptospira biofilm may play a significant role in antibiotic resistance. In this study, the antimicrobial susceptibility of Leptospira biofilm was investigated by 96-well plate assay using Alamar Blue. Leptospira biofilm showed five to sixfold increase in resistance in all the strains used. The range of minimal bactericidal concentrations for penicillin G, ampicillin, tetracycline, and doxycycline was 1,600 U/ml, 800-1,600 MUg/ml, 800-1,600 MUg/ml, and 800-1,600 MUg/ml, respectively. In agar substrate, the biofilm showed six- to sevenfold increase in resistance to antibiotics compared to planktonic cell. The present study emphasizes the importance of biofilm formation and its antibiotic susceptibility patterns. This could pave the way for devising appropriate strategy to prevent the occurrence of potential chronic leptospirosis in endemic areas and also during an outbreak situation. PMID- 26978025 TI - The cKit Inhibitor, Masitinib, Prevents Diabetes-Induced Retinal Vascular Leakage. AB - PURPOSE: Stem cell factor (SCF) has recently demonstrated activity as a novel endothelial permeability factor that contributes to the development of diabetes induced hyperpermeable retinal vasculature. This study investigated the therapeutic potential of masitinib, a pharmacologic inhibitor of the SCF receptor cKit, for prevention of diabetes-induced breakdown of blood retinal barrier (BRB). METHODS: Permeability assays were performed with human retinal microvascular endothelial cells (HRMECs) and murine retinal vasculature. Localization of vascular endothelial (VE)-cadherin and activation of SCF signaling pathway was determined by immunofluorescence and Western blotting assays. Mice and rats with streptozotocin (STZ)-induced diabetes were used to investigate the role of cKit and masitinib in diabetes-induced retinal vascular hyperpermeability. RESULTS: Masitinib substantially blocked SCF-induced phosphorylation of cKit in HRMECs. In vitro and in vivo vascular permeability assays showed that masitinib significantly inhibited SCF-induced endothelial hyperpermeability and junctional loss of VE-cadherin. Streptozotocin-induced diabetes was induced in cKit-mutant mice with low cKit expression in their endothelial cells. Although diabetic wild-type mice exhibited enhanced retinal vascular leakage, diabetic cKit-mutant mice showed no increase in retinal vascular leakage or alteration in the distribution of VE-cadherin; this indicates the crucial role of cKit in diabetes-induced breakdown of BRB. Moreover, in vivo prevention experiments showed that an intravitreal injection of masitinib substantially inhibited the development of hyperpermeable retinal vasculature. CONCLUSIONS: These results provide the first demonstration that cKit inhibitors, such as masitinib, might be promising therapeutics for prevention of diabetes induced breakdown of the BRB. PMID- 26978024 TI - Retinal Pigment Epithelium Atrophy 1 (rpea1): A New Mouse Model With Retinal Detachment Caused by a Disruption of Protein Kinase C, theta. AB - PURPOSE: Retinal detachments (RDs), a separation of the light-sensitive tissue of the retina from its supporting layers in the posterior eye, isolate retinal cells from their normal supply of nourishment and can lead to their deterioration and death. We identified a new, spontaneous murine model of exudative retinal detachment, nm3342 (new mutant 3342, also referred to as rpea1: retinal pigment epithelium atrophy 1), which we characterize herein. METHODS: The chromosomal position for the recessive nm3342 mutation was determined by DNA pooling, and the causative mutation was discovered by comparison of whole exome sequences of mutant and wild-type controls. The effects of the mutation were examined in longitudinal studies by clinical evaluation, electroretinography (ERG), light microscopy, and marker and Western blot analyses. RESULTS: New mutant 3342, nm3342, also referred to as rpea1, causes an early-onset, complete RD on the ABJ/LeJ strain background, and central exudative RD and late-onset RPE atrophy on the C57BL/6J background. The ERG responses were normal at 2 months of age but deteriorate as mice age, concomitant with progressive pan-retinal photoreceptor loss. Genetic analysis localized rpea1 to mouse chromosome 2. By high-throughput sequencing of a whole exome capture library of an rpea1/rpea1 mutant and subsequent sequence analysis, a splice donor site mutation in the Prkcq (protein kinase C, theta) gene, was identified, leading to a skipping of exon 6, frame shift and premature termination. Homozygotes with a Prkcq-targeted null allele (Prkcqtm1Litt) have similar retinal phenotypes as homozygous rpea1 mice. We determined that the PKCtheta protein is abundant in the lateral surfaces of RPE cells and colocalizes with both tight and adherens junction proteins. Phalloidin stained RPE whole mounts showed abnormal RPE cell morphology with aberrant actin ring formation. CONCLUSIONS: The homozygous Prkcqrpea1 and the null Prkcqtm1Litt mutants are reliable novel mouse models of RD and can also be used to study the effects of the disruption of PRKCQ (PKCtheta) signaling in RPE cells. PMID- 26978026 TI - Visualization of Intravital Immune Cell Dynamics After Conjunctival Surgery Using Multiphoton Microscopy. AB - PURPOSE: To visualize intravital immune cell dynamics in the subconjunctival tissue during the wound-healing process using multiphoton microscopy. METHODS: Gene-targeted mice expressing enhanced green fluorescent protein under the control of the endogenous lysozyme M promoter (LysM-eGFP mice) were anesthetized with isoflurane, and injured by a 10-0 nylon conjunctival suture. Vessels were visualized by intravenous injection of 70 kDa rhodamine-conjugated dextran. Using a multiphoton microscope, the three-dimensional images of the subconjunctival tissue were acquired every minute for 20 minutes before and 0.5, 3, 6, and 72 hours after injury. Raw imaging data were processed for four-dimensional images and analyzed for the number and the velocity of the LysM-eGFP-positive cells using Imaris software. RESULTS: The intravital LysM-eGFP-positive cells and the red-labeled vessels were successfully visualized using a multiphoton microscope. The conjunctival and scleral collagen fibers were detected as secondary harmonic generation signals, which were colored blue. Compared with mice without injury, the number of LysM-eGFP-positive cells in the subconjunctival tissue after conjunctival surgery increased in a time-dependent manner. The cell velocities significantly increased until 3 hours after surgery (5.9 +/- 3.2 MUm/min; P < 0.0001) and the elevated level was sustained until 72 hours after injury (5.9 +/- 3.3 MUm/min). CONCLUSION: This is the first report to visualize and evaluate intravital cellular dynamics during inflammation in the subconjunctival tissue using multiphoton microscopy. This technique may be a useful tool to characterize the molecular mechanisms of the wound-healing process after various ocular injuries, such as glaucoma surgery. PMID- 26978027 TI - Effect of Salicylic Acid on the Membrane Proteome and Virulence of Pseudomonas aeruginosa. AB - PURPOSE: This study aimed to determine the effect of salicylic acid on the membrane proteome, sensitivity to antibiotics, and production of microbial keratitis by Pseudomonas aeruginosa. METHODS: P. aeruginosa 6294 was grown in the presence or absence of 30 mM salicylic acid. Bacterial membrane proteins were extracted in carbonate buffer, separated using two-dimensional gel electrophoresis and identified by mass spectrometry. The minimum inhibitory concentration (MIC) of various antibiotics was determined using P. aeruginosa 6294 grown in presence or absence of salicylic acid. The scratch mouse model of microbial keratitis was used to determine whether treatment with 30 mM salicylic acid could improve the outcome of infection. RESULTS: Growth in salicylic acid altered the membrane proteome of P. aeruginosa 6294. Eighteen proteins, including OprF, OprD, MexA, OprG, PilQ, and flagellin-type A protein, were downregulated, six proteins, including OprM and OprB, were upregulated, and nine proteins were unaffected by growth in salicylic acid. Growth in salicylic acid slightly increased the resistance to carbapenem antibiotics but did not affect MICs of the other antibiotics tested. Salicylic acid treatment significantly reduced the clinical score of eyes and bacterial load in eyes during microbial keratitis but had no effect on numbers of infiltrating neutrophils. CONCLUSION: Salicylic acid altered the membrane proteins of P. aeruginosa, slightly increased the resistance of the bacterium to carbapenem antibiotics only, and was able to reduce the pathogenicity associated with P. aeruginosa infection of mouse corneas. Salicylic acid may be useful as an antimicrobial agent in the treatment of Pseudomonas keratitis. PMID- 26978029 TI - Enhanced Motion Aftereffects in Migraine Are Related to Contrast Sensitivity: Implications for Models of Differences in Precortical/Cortical Function. AB - PURPOSE: Visual tests can be used as noninvasive tools to test models of the pathophysiology underlying neurological conditions, such as migraine. For example, there are reports that the motion aftereffect, which involves neural processing in several cortical areas, is prolonged in migraine. There also are reports of impaired contrast sensitivity in migraine, however, attributed to a precortical dysfunction. This study explored associations between these two tests of visual function. Specifically, it aimed to clarify whether the magnitude of the motion aftereffect is affected by contrast and contrast sensitivity. METHODS: The motion aftereffect was elicited after observers viewed a coherently moving pattern for 45 seconds. The duration of the subsequent aftereffect was measured with three different test display contrasts (high, medium, low). Contrast sensitivity also was assessed. RESULTS: For each test display contrast, the motion aftereffect was prolonged in migraine compared to the control group. Contrast sensitivity was poorer in the migraine group and was a significant predictor of motion aftereffect duration. CONCLUSIONS: These results suggest an anomaly in early motion processing pathways in migraine that likely is linked with those pathways underlying contrast sensitivity. They provide further evidence for differences in visual processing that begin early, potentially starting at the retina, which have consequences for performance on tasks that putatively examine cortical processing. Differences in precortical and cortical visual pathways are implicated in the pathophysiology underlying migraine. PMID- 26978028 TI - Changes in Retinal Nerve Fiber Layer Reflectance Intensity as a Predictor of Functional Progression in Glaucoma. AB - PURPOSE: We determined whether longitudinal changes in retinal nerve fiber layer (RNFL) reflectance provide useful prognostic information about longitudinal changes in function in glaucoma. METHODS: The reflectance intensity of each pixel within spectral-domain optical coherence tomography (SD-OCT) circle scans was extracted by custom software. A repeatability cohort comprising 53 eyes of 27 participants (average visual field mean deviation [MD] -1.65 dB) was tested five times within a few weeks. To minimize test-retest variability in their data, a reflectance intensity ratio was defined as the mean reflectance intensity of pixels within the RNFL divided by the mean between the RNFL and RPE. This was measured in a separate longitudinal cohort comprising 310 eyes of 205 participants tested eight times at 6-month intervals (average MD, -0.99 dB; median rate of change, -0.09 dB/y). The rate of change of this ratio, together with the rate of RNFL thinning, and their interaction, were used to predict the rate of change of MD. RESULTS: In univariate analyses, the rate of RNFL thinning was predictive of the rate of MD change (P < 0.0001), but the rate of change of reflectance intensity ratio was not (P = 0.116). However, in a multivariable model, the interaction between these two rates significantly improved upon predictions of the rate of functional change made using RNFL thickness alone (P = 0.038). CONCLUSIONS: For a given rate of RNFL thinning, a reduction in the RNFL reflectance intensity ratio is associated with more rapid functional deterioration. Incorporating SD-OCT reflectance information may improve the structure-function relation in glaucoma. PMID- 26978030 TI - Seeking Balance Between Pain Relief and Safety: CDC Issues New Opioid-Prescribing Guidelines. PMID- 26978031 TI - Addition of Small Electrophiles to N-Heterocyclic-Carbene-Stabilized Disilicon(0): A Revisit of the Isolobal Concept in Low-Valent Silicon Chemistry. AB - Protonation and alkylation of (Idipp)Si?Si(Idipp) (1) afforded the mixed-valent disilicon(I)-borates [(Idipp)(R)Si(II)?Si(0)(Idipp)][B(Ar(F))4] (1R[B(Ar(F))4]; R = H, Me, Et; Ar(F) = C6H3-3,5-(CF3)2; Idipp = C[N(C6H3-2,6-iPr2)CH]2) as red to orange colored, highly air-sensitive solids, which were characterized by single crystal X-ray diffraction, IR spectroscopy and multinuclear NMR spectroscopy. Dynamic NMR studies in solution revealed a degenerate isomerization (topomerization) of the "sigma-bonded" tautomers of 1H[B(Ar(F))4], which proceeds according to quantum chemical calculations via a NHC-stabilized (NHC = N heterocyclic carbene) disilahydronium ion ("pi-bonded" isomer) and is reminiscent of the degenerate rearrangement of carbenium ions formed upon protonation of olefins. The topomerization of 1H[B(Ar(F))4] provides the first example of a reversible 1,2-H migration along a Si?Si bond observed in a molecular system. In contrast, 1Me[B(Ar(F))4] adopts a "rigid" structure in solution due to the higher energy required for the interconversion of the "sigma-bonded" isomer into a putative NHC-stabilized disilamethonium ion. Addition of alkali metal borates to 1 afforded the alkali metal disilicon(0) borates 1M[BAr4] (M = Li, Ar = C6F5; M = Na, Ar = Ar(F)) as brown, air-sensitive solids. Single-crystal X-ray diffraction analyses and NMR spectroscopic studies of 1M[BAr4] suggest in concert with quantum chemical calculations that encapsulation of the alkali metal cations in the cavity of 1 predominantly occurs via electrostatic cation-pi interactions with the Si?Si pi-bond and the peripheral NHC aryl rings. Displacement of the [Si(NHC)] fragments by the isolobal fragments [PR] and [SiR](-) interrelates the cations [(NHC)(R)Si?Si(NHC)](+) to a series of familiar, multiply bonded Si and P compounds as verified by analyses of their electronic structures. PMID- 26978033 TI - Genomic testing in oncology to improve clinical outcomes while optimizing utilization: the evolution of diagnostic testing. AB - Cancer care is costly, particularly when chemotherapy and its supportive costs are considered. Yet, chemotherapy is not the right course for every patient. Patients with cancer need appropriate treatment that will give them the best possible outcome. Personalized medicine has become an important area of oncology. In addition to genetic testing, genomic testing has become a useful tool in diagnostics. For genomic assays to be viable, they must have clinical validity, analytic validity, and clinical utility. Stakeholders are willing to provide coverage for such testing through medical policy when there is strong evidence the tests are effective. Genomic testing can be used in decision making to rule out chemotherapy or other treatment options that would not be effective for the care of an individual patient. The use of genomic testing to help eliminate ineffective or possible harmful treatment options and determine appropriate care will benefit the patient while reducing healthcare utiliztion and costs. PMID- 26978034 TI - Gritty Surface Sample Holder Invented To Obtain Correct X-ray Absorption Fine Structure Spectra for Concentrated Materials by Fluorescence Yield. AB - A gritty surface sample holder has been invented to obtain correct XAFS spectra for concentrated samples by fluorescence yield (FY). Materials are usually mixed with boron nitride (BN) to prepare proper concentrations to measure XAFS spectra. Some materials, however, could not be mixed with BN and would be measured in too concentrated conditions to obtain correct XAFS spectra. Consequently, XAFS spectra will be incorrect typically with decreased intensities of the peaks. We have invented the gritty surface sample holders to obtain correct XAFS spectra even for concentrated materials for FY measurements. Pure Cu and CuO powders were measured mounted on the sample holders, and the same spectra were obtained as transmission spectra of properly prepared samples. This sample holder is useful to measure XAFS for any concentrated materials. PMID- 26978035 TI - Prevalence and characterization of resistance genes with genetic clones among Staphylococcus aureus isolates obtained from various sources in China. PMID- 26978037 TI - Correction to "A General Strategy for the Discovery of Metabolic Pathways: D Threitol, L-Threitol, and Erythritol Utilization in Mycobacterium smegmatis". PMID- 26978036 TI - Kribbella pittospori sp. nov., an endophytic actinobacterium isolated from the surface-sterilized stem of an Australian native apricot tree, Pittosporum angustifolium. AB - An endophytic actinobacterium, strain PIP 158T, was isolated from the stem of a native apricot tree (Pittosporum angustifolium) collected from the grounds of Flinders University, Adelaide, Australia. As a result of a polyphasic taxonomic study, this strain was identified as a member of the genus Kribbella. This strain was a Gram-stain-positive, aerobic actinobacterium with well-developed substrate mycelia which were non-motile and with hyphae fragmenting into short to elongated rod-like elements. Phylogenetic evaluation based on 16S rRNA gene sequence analysis placed this isolate in the family Nocardioidaceae, being most closely related to Kribbella sandramycini ATCC 39419T and Kribbella albertanoniae BC640T which share a similarity of 99. 26 and 99.18 % with Kribbella hippodromi S1.4T, respectively. Chemotaxonomic data including cell-wall components, major menaquinones and major fatty acids confirmed the affiliation of strain PIP 158T to the genus Kribbella. The results of the phylogenetic analysis, including physiological and biochemical studies in combination with DNA-DNA hybridization, allowed the genotypic and phenotypic differentiation of strain PIP 158T from the closest related species with validly published names. The name proposed for the novel species is Kribbella pittospori sp. nov. The type strain is PIP 158T (=DSM 23717T=NRRL B-24813T). PMID- 26978032 TI - Protein Kinase A Activation Promotes Cancer Cell Resistance to Glucose Starvation and Anoikis. AB - Cancer cells often rely on glycolysis to obtain energy and support anabolic growth. Several studies showed that glycolytic cells are susceptible to cell death when subjected to low glucose availability or to lack of glucose. However, some cancer cells, including glycolytic ones, can efficiently acquire higher tolerance to glucose depletion, leading to their survival and aggressiveness. Although increased resistance to glucose starvation has been shown to be a consequence of signaling pathways and compensatory metabolic routes activation, the full repertoire of the underlying molecular alterations remain elusive. Using omics and computational analyses, we found that cyclic adenosine monophosphate Protein Kinase A (cAMP-PKA) axis activation is fundamental for cancer cell resistance to glucose starvation and anoikis. Notably, here we show that such a PKA-dependent survival is mediated by parallel activation of autophagy and glutamine utilization that in concert concur to attenuate the endoplasmic reticulum (ER) stress and to sustain cell anabolism. Indeed, the inhibition of PKA-mediated autophagy or glutamine metabolism increased the level of cell death, suggesting that the induction of autophagy and metabolic rewiring by PKA is important for cancer cellular survival under glucose starvation. Importantly, both processes actively participate to cancer cell survival mediated by suspension-activated PKA as well. In addition we identify also a PKA/Src mechanism capable to protect cancer cells from anoikis. Our results reveal for the first time the role of the versatile PKA in cancer cells survival under chronic glucose starvation and anoikis and may be a novel potential target for cancer treatment. PMID- 26978038 TI - Recombination Kinetics and Effects of Superacid Treatment in Sulfur- and Selenium Based Transition Metal Dichalcogenides. AB - Optoelectronic devices based on two-dimensional (2D) materials have shown tremendous promise over the past few years; however, there are still numerous challenges that need to be overcome to enable their application in devices. These include improving their poor photoluminescence (PL) quantum yield (QY) as well as better understanding of exciton-based recombination kinetics. Recently, we developed a chemical treatment technique using an organic superacid, bis(trifluoromethane)sulfonimide (TFSI), which was shown to improve the quantum yield in MoS2 from less than 1% to over 95%. Here, we perform detailed steady state and transient optical characterization on some of the most heavily studied direct bandgap 2D materials, specifically WS2, MoS2, WSe2, and MoSe2, over a large pump dynamic range to study the recombination mechanisms present in these materials. We then explore the effects of TFSI treatment on the PL QY and recombination kinetics for each case. Our results suggest that sulfur-based 2D materials are amenable to repair/passivation by TFSI, while the mechanism is thus far ineffective on selenium based systems. We also show that biexcitonic recombination is the dominant nonradiative pathway in these materials and that the kinetics for TFSI treated MoS2 and WS2 can be described using a simple two parameter model. PMID- 26978039 TI - Atomic Insight into the Lithium Storage and Diffusion Mechanism of SiO2/Al2O3 Electrodes of Lithium Ion Batteries: ReaxFF Reactive Force Field Modeling. AB - Atomically deposited layers of SiO2 and Al2O3 have been recognized as promising coating materials to buffer the volumetric expansion and capacity retention upon the chemo-mechanical cycling of the nanostructured silicon- (Si-) based electrodes. Furthermore, silica (SiO2) is known as a promising candidate for the anode of next-generation lithium ion batteries (LIBs) due to its superior specific charge capacity and low discharge potential similar to Si anodes. In order to describe Li-transport in mixed silica/alumina/silicon systems we developed a ReaxFF potential for Li-Si-O-Al interactions. Using this potential, a series of hybrid grand canonical Monte Carlo (GCMC) and molecular dynamic (MD) simulations were carried out to probe the lithiation behavior of silica structures. The Li transport through both crystalline and amorphous silica was evaluated using the newly optimized force field. The anisotropic diffusivity of Li in crystalline silica cases is demonstrated. The ReaxFF diffusion study also verifies the transferability of the new force field from crystalline to amorphous phases. Our simulation results indicates the capability of the developed force field to examine the energetics and kinetics of lithiation as well as Li transportation within the crystalline/amorphous silica and alumina phases and provide a fundamental understanding on the lithiation reactions involved in the Si electrodes covered by silica/alumina coating layers. PMID- 26978041 TI - Free-Standing Graphene Oxide-Palygorskite Nanohybrid Membrane for Oil/Water Separation. AB - Graphene oxide (GO) is an emerging kind of building block for advanced membranes with tunable passageway for water molecules. To synergistically manipulate the channel and surface structures/properties of GO-based membranes, the different building blocks are combined and the specific interfacial interactions are designed in this study. With vacuum-assisted filtration self-assembly, palygorskite nanorods are intercalated into adjacent GO nanosheets, and GO nanosheets are assembled into laminate structures through pi-pi stacking and cation cross-linking. The palygorskite nanorods in the free-standing GOP nanohybrid membranes take a 3-fold role, rendering enlarged mass transfer channels, elevating hydration capacity, and creating hierarchical nanostructures of membrane surfaces. Accordingly, the permeate fluxes from 267 L/(m(2) h) for GO membrane to 1867 L/(m(2) h) for GOP membrane. The hydration capacity and hierarchical nanostructures synergistically endow GOP membranes with underwater superoleophobic and low oil-adhesive water/membrane interfaces. Moreover, by rationally imparting chemical and physical joint defense mechanisms, the GOP membranes exhibit outstanding separation performance and antifouling properties for various oil-in-water emulsion systems (with different concentration, pH, or oil species). The high water permeability, high separation efficiency, as well as superior anti-oil-fouling properties of GOP membranes enlighten the great prospects of graphene-based nanostructured materials in water purification and wastewater treatment. PMID- 26978040 TI - A test-retest dataset for assessing long-term reliability of brain morphology and resting-state brain activity. AB - We present a test-retest dataset for evaluation of long-term reliability of measures from structural and resting-state functional magnetic resonance imaging (sMRI and rfMRI) scans. The repeated scan dataset was collected from 61 healthy adults in two sessions using highly similar imaging parameters at an interval of 103-189 days. However, as the imaging parameters were not completely identical, the reliability estimated from this dataset shall reflect the lower bounds of the true reliability of sMRI/rfMRI measures. Furthermore, in conjunction with other test-retest datasets, our dataset may help explore the impact of different imaging parameters on reliability of sMRI/rfMRI measures, which is especially critical for assessing datasets collected from multiple centers. In addition, intelligence quotient (IQ) was measured for each participant using Raven's Advanced Progressive Matrices. The data can thus be used for purposes other than assessing reliability of sMRI/rfMRI alone. For example, data from each single session could be used to associate structural and functional measures of the brain with the IQ metrics to explore brain-IQ association. PMID- 26978043 TI - A Hybrid Approach to Structure and Function Modeling of G Protein-Coupled Receptors. AB - The recent GPCR Dock 2013 assessment of serotonin receptor 5-HT1B and 5-HT2B, and smoothened receptor SMO targets, exposed the strengths and weaknesses of the currently used computational approaches. The test cases of 5-HT1B and 5-HT2B demonstrated that both the receptor structure and the ligand binding mode can be predicted with the atomic-detail accuracy, as long as the target-template sequence similarity is relatively high. On the other hand, the observation of a low target-template sequence similarity, e.g., between SMO from the frizzled GPCR family and members of the rhodopsin family, hampers the GPCR structure prediction and ligand docking. Indeed, in GPCR Dock 2013, accurate prediction of the SMO target was still beyond the capabilities of most research groups. Another bottleneck in the current GPCR research, as demonstrated by the 5-HT2B target, is the reliable prediction of global conformational changes induced by activation of GPCRs. In this work, we report details of our protocol used during GPCR Dock 2013. Our structure prediction and ligand docking protocol was especially successful in the case of 5-HT1B and 5-HT2B-ergotamine complexes for which we provide one of the most accurate predictions. In addition to a description of the GPCR Dock 2013 results, we propose a novel hybrid computational methodology to improve GPCR structure and function prediction. This computational methodology employs two separate rankings for filtering GPCR models. The first ranking is ligand-based while the second is based on the scoring scheme of the recently published BCL method. In this work, we prove that the use of knowledge-based potentials implemented in BCL is an efficient way to cope with major bottlenecks in the GPCR structure prediction. Thereby, we also demonstrate that the knowledge based potentials for membrane proteins were significantly improved, because of the recent surge in available experimental structures. PMID- 26978044 TI - From Minor Side Phases to Bulk Samples of Lanthanum Oxonitridosilicates: An Investigation with Microfocused Synchrotron Radiation. AB - Microcrystals of the oxonitridosilicate oxide La(11)Si(13)N(27.636)O(1.046):Ce(3+) were obtained by exploratory high temperature synthesis starting from La, La(NH2)3, Si(NH)2, BaH2, and CeF3. Owing to the small size of the crystals, microfocused synchrotron radiation was used for structure investigations (space group Cmc21 (No. 36), a = 9.5074(4) A, b = 32.0626(9) A, c = 18.5076(8) A, Z = 8, R1(all) = 0.0267). The crystal structure consists of an unprecedented interrupted three-dimensional network of vertex sharing SiN(4-x)O(x) tetrahedra that form channels of siebener rings along [100]. Moreover, the structure is characterized by layers of condensed sechser rings in a boat conformation and vierer rings, which are alternatingly stacked with layers of vierer and dreier rings. Several split positions indicate two different local structure variants. Infrared spectroscopy confirms the absence of N-H bonds. Powder X-ray diffraction data show that bulk samples contain only a small amount of La(11)Si(13)N(27.636)O1.046:Ce(3+). However, once the exact composition was determined from structure analysis, it was possible to optimize the synthesis using fluorides as starting materials. Thereby, bulk samples of the homeotypic compound La(11)Si(13)N(27.376)O(0.936)F were obtained and investigated. PMID- 26978042 TI - Telomere shortening leads to earlier age of onset in ALS mice. AB - Telomere shortening has been linked to a variety of neurodegenerative diseases. Recent evidence suggests that reduced telomerase expression results in shorter telomeres in leukocytes from sporadic patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls. Here, we have characterized telomere length in microglia, astroglia and neurons in human post mortem brain tissue from ALS patients and healthy controls. Moreover, we studied the consequences of telomerase deletion in a genetic mouse model for ALS. We found a trend towards longer telomeres in microglia in the brains of ALS patients compared to non neurologic controls. Knockout of telomerase leading to telomere shortening accelerated the ALS phenotype inSOD1G93A-transgenic mice. Our results suggest that telomerase dysfunction might contribute to the age-related risk for ALS. PMID- 26978045 TI - [Development of preclinical diagnosis and preventive treatment of neurodegenerative diseases]. AB - Neurodegenerative diseases (NDD) are serious fatal neurological and mental diseases that resulted in disability and fethal outcome. Based on the advances of basic sciences over the last two decades, new knowledge on the risk factors for NDD and molecular mechanisms of the pathogenesis are obtained. It has been shown that the accelerated process of neuronal death which is the main cause of NDD development begins long before the appearance of clinical symptoms. The first symptoms appeared only after the death of most specific regulatory neurons and exhaustion of brain compensatory reserve. Only at that time, one can make the diagnosis and start traditional treatment of patients that accounts for the extremely low efficacy of the latter. Currently, complex preclinical diagnosis based on the identification of relatively specific clinical precursors and peripheral biomarkers has been developing. Development of preclinical diagnosis and preventive treatment is a strategic issue of modern neurology and psychiatry. The resolution of this issue allows to consider NDD as cured, but not fatal, diseases. PMID- 26978046 TI - [Topochemistry of internuclear interneurons in the human brain stem in arterial hypertension]. AB - OBJECTIVE: To study the internuclear interneurons (IN) involved in the metabolism of nitric oxide, hydrogen sulfide and carbon monoxide in the caudal brainstem in healthy people and those with lifetime hypertension. MATERIAL AND METHODS: The study was performed on postmortem material of 8 healthy men and 19 men, aged 18 44 years, with lifetime arterial hypertension. Immunohistochemistry methods for nNOS, HO-2, CBS and histochemical method for NADPH-diaphorase were used to study IN groups located between the giant and small cell reticular nuclei (IN1), small cell reticular nucleus and the nucleus of the solitary tract (IN2) surrounded by the lateral reticular nucleus (IN3). RESULTS: IN differ in size, shape, length and structure of sprouts as well as the nature of relationships formed and intensity of immunohistochemical reaction. The intensity of MN response to the high blood pressure depends on the cell size: qualitative and quantitative changes among the most small MN are mild. In contrast, in many major MN, structural changes, a significant reduction in the proportion of these cells, concentration and reaction rate are noted. More significant changes in quantitative indicators are found among nNOS-positive neurons. The reduction in the quantitative indicators depends on the localization of cells. In IN1, where there are many large IN, changes are more pronounced than in IN3 and IN2, which do not contain so many such cells. CONCLUSION: Central mechanisms of hemodynamic control include, at least, two groups of interneurons: intranuclear and internuclear. However, among the latter, only large IN are responsive to increases in blood pressure that confirms their participation in the regulation of hemodynamics, Small IN maintain a relatively small organization and perform a stable, obviously, integrating function. PMID- 26978047 TI - [Mixed depression in the clinical presentation of attack-like schizophrenia]. AB - AIM: To explore the variants of attack-like schizophrenia with mixed depression and comorbid phobic, obsessive-compulsive disorders, pathological bodily sensations. MATERIAL AND METHODS: Authors studied 29 patients with attack-like schizophrenia using clinical-anamnestic and psychopathological methods as well as psychometric scales (PANSS, Salgary scale, social and mental functioning scale). RESULTS: Two main clinical groups of attack-like schizophrenia with mixed depression depending on the age of the active manifestations of the disease (adolescent/youth and adulthood) were identified. In accordance to the criteria for the diagnosis of mixed depression in the diagnostic category "Depressive Disorder" DSM-V, 6 manifestations of mania symptoms in the structure of mixed depression in patients with schizophrenia were determined. Their clinical features and frequency are presented. PMID- 26978048 TI - [Immune and oxygen disturbances in patients with chronic cerebral ischemia and their correction]. AB - OBJECTIVE: To determine the dynamics of immunometabolic characteristics in patients with chronic ischemia of the brain (discirculatory encephalopathy - DE) under the influence of various combinations of neuroprotective and antioxidant drugs and on this basis to identify the most effective therapeutic combinations. MATERIAL AND METHODS: Authors analyzed the results of treatment of 57 patients with DE, stage II, comorbid to hypertension, stage II, which were divided into 3 groups that received comprehensive basic and advanced therapy with paired combinations of neuroprotective and antioxidant drugs. Clinical examination and assessment of neuropsychiatric status were performed. Immune disorders were assessed by the level of plasma cytokines (TNF, IL-1beta, IL-6, IL-8, IL-18, IL 4, IL-10 receptor antagonist IL-1 (RAIL), INF-gamma, IL-2, IL-17), components of complement (C3, CA, C4, C5, CA), inhibitors (factor H, C1-inhibitor), immunoglobulin classes IgM, IgG, IgA, metabolic changes (concentrations of acylhydrazines, malondialdehyde, ceruloplasmin), C-reactive protein, neopterin concentrations, stable metabolites of nitric oxide, the activity of catalase, superoxide dismutase, total antioxidant activity of blood serum. RESULTS AND CONCLUSION: Laboratory and clinical efficacy of the combinations of neuroprotective and antioxidant drugs in DE reduced in the following order: actovegin and cereton -> emoxipine and piracetam -> cerebrolysin and mexidol. PMID- 26978049 TI - [Current possibilities in pharmacotherapy of anxiety disorders in children and adolescents]. AB - OBJECTIVE: To assess the efficacy and safety of children tenoten in the treatment of children and adolescents with anxiety disorders. MATERIAL AND METHODS: It was conducted a multicenter, double-blind, placebo-controlled trial of the drug tenoten children at a dose of 1 tablet 3 times a day for 12 weeks. The study included 98 patients (boys and girls from 5 to 15 years with a confirmed diagnosis of anxiety disorder), randomized into two groups: the first included 48 patients treated tenotenom children, in the second - 50 patients receiving placebo. RESULTS AND CONCLUSION: Tenoten children has a strong anti-anxiety effect both on the results of self-assessment of patients, and on the reports of parents. This anxiolytic activity of the drug manifested most significantly in children aged 5 to 7 years. In addition, in patients 8-15 years of treatment spent tenotenom children to regress the symptoms of anxiety disorders by anxiety subscales SCAS "Separation anxiety", "panic attacks and agoraphobia" and "social phobia". Throughout the course of treatment tenoten children have been no adverse events. PMID- 26978050 TI - [Plasma levels of antipsychotics and the severity of side-effects in the treatment of schizophrenia exacerbation]. AB - OBJECTIVE: To study a relationship between plasma levels of antipsychotics (AP) and severity of side-effects (SE) during the treatment of inpatients with exacerbation of schizophrenia. MATERIAL AND METHODS: The study included 39 patients treated with risperidone, haloperidol, zuclopenthixol, clozapine, aripiprazole or olanzapine as monotherapy or in combination of two AP. Blood sampling to measure the AP plasma level was performed twice (at 7-10 and 26-30 day from start of treatment), the levels of prolactin and glucose were determined once (at 26-30 day from start of treatment). Patients were assessed by psychometric scales PANSS and NSA and the side-effects scale UKU. RESULTS: The increased concentration of AP was noted in 33% of the patients. The high concentration of AP was significantly associated with akathisia and hyperkinesia (by UKU scale), NSA retardation factor and hyperprolactinemia. Patients with severe hyperprolactinemia were twice as likely to have a clinically significant depression. Increased blood glucose levels were observed in 18% of the patients, there was no significant association with AP plasma levels. Mental SE were most prominent, with a drift towards the neurological SE in the group with higher AP plasma levels. Chlorpromazine equivalent didn't significantly differ in the groups with normal, high and low AP concentrations. CONCLUSION: Elevated AP plasma levels, which were associated with some clinically significant SE and some negative symptoms, were found in most patients. In this regard, therapeutic drug monitoring is a promising method for the individualization of schizophrenia exacerbation treatment in routine clinical practice. PMID- 26978051 TI - [Clinical and therapeutic perspectives of agomelatine (valdoxan) in the treatment of anhedonia in patients with endogenous depressions]. AB - OBJECTIVE: To analyze the therapeutic effect of valdoxan on symptoms of anhedonia in patients with endogenous depressions and to develop indications for its use. MATERIAL AND METHODS: Authors examined 30 women, mean age 35,9 years with anhedonic depression (ICD-10 items F31.3-4, F33.1-2, F20.4). Valdoxan was administered in average daily dose from 25.8 to 45.8 mg during 30 days. Patient's status was assessed on 0, 7, 14 and 30th days, using clinical and psychometric (HAMD-21, HADS, SHAPS and UKU scales) methods. The reduction of scores was used as a measure of therapeutic effect designated as "mild", "moderate", "good" and "marked". RESULTS: Antianhedonic effect of valdoxan on 30th day was superior to thymoleptic and anxiolytic effects of this drug (91.5 versus 82.2 and 76.9%). The marked effect was identified already on 14th day and enhanced to 30th day. The best effect was seen in depression of moderate severity. Single autonomic side effects of the treatment were observed. CONCLUSION: The course treatment of anhedonic depressions with valdoxan should be considered as preferable and highly effective method that provides a dominative antianhedonic effect in the spectrum of antidepressive properties of the drug. Good and marked effects have been achieved in 96.7% of patients. The intensity and rate of its formation, good tolerability allow to tailor indications of valdoxan basing on the psychopathological characteristics of gedonic disorders. PMID- 26978052 TI - [Experience of the antidepressive therapy with valdoxan (agomelatine) in a psychogeriatric unit of the psychiatric hospital]. AB - OBJECTIVE: To assess therapeutic efficacy, tolerability and safety of valdoxan (agomelatine) in the treatment of depression in elderly inpatients of the psychiatric hospital. MATERIAL AND METHODS: The study included 20 patients, aged 60 years and older, with depression of varying severity. Patients received valdoxan in standard doses 25-50 mg/day during 42 days. RESULTS: Valdoxan showed a good balanced profile (in terms of indicators of depression, anxiety and anhedonia) of therapeutic response and tolerability in inpatients with mild to moderate depression. The use of valdoxan led to a significant reduction of depressive disorders and anxiety already in the early period of treatment. The severity of anhedonia decreased to the 14th day of treatment. A significant improvement in cognitive functioning of patients was noted to the end of treatment. CONCLUSION: Valdoxan can be recommended for treatment of mild and moderate depression in inpatients of psychiatric hospitals. PMID- 26978053 TI - [The use of spitomine (buspirone) in the combined therapy of panic disorder]. AB - OBJECTIVE: To explore the efficacy of spitomine (buspirone) in the combined therapy of panic disorder, we studied the dynamics of clinical parameters and personality traits associated with development and maintenance of panic disorder during the treatment. MATERIAL AND METHODS: Thirty patients of a treatment setting for out-patients with panic disorder were enrolled in the study. Patients received combined treatment with spitomine (buspirone) in the dose of 30 mg/daily (10 mg three times a day) during 6 weeks and individual short-term direct cognitive-behavioral therapy. Anxiety and panic symptoms were measured with HARS, CGI, MADRS and STAI-A. RESULTS: There was a significant reduction in panic and anxiety symptoms (by 50% on the HARS) that reached on average 9.73 scores to the end of the study. This finding indicates the absence of anxiety and, therefore, therapeutic efficacy of the treatment. Scores on state anxiety of STAI-A were significantly lower compared to baseline though the level of anxiety remained relatively high. The partial decrease in trait anxiety, though its level was high as well, was noted. CONCLUSION: The combined therapy of panic disorder with spitomine (buspirone) and cognitive-behavioral therapy is an optimal treatment, though not without the limitations of short-term methods. Good tolerability of the drug allowed all patients to complete the study. PMID- 26978054 TI - [Comprehensive early diagnosis of cognitive impairment]. AB - OBJECTIVE: To study cognitive function, CSF biochemical markers of amyloidosis and neurodegeneration, cerebral metabolism using PET, cerebral volumetric changes and metabolic content of the cingular gyrus using magnetic resonance spectroscopy (MRS) in patients with amnesic and neurodynamic variants of mild cognitive impairment (MCI). MATERIAL AND METHODS: Authors examined 369 patients with cognitive impairment of different severity. All patients underwent neuropsychological examination. To deter-mine the levels of beta-amyloid and tau protein,a lumbar puncture was performed in 125 patients and 20 controls. 18 Fluorine deoxyglucose positron emission tomography (FCSRT) was performed in 77 patients. Assessment of metabolite levels by MRS and volumetric parameters by magnetic resonance morphometry was done in 92 patients. RESULTS AND CONCLUSION: The "free and cued selective reminding test" and "trail making test" showed the best diagnostic value in the early differential diagnosis of amnesic and neurodynamic variants of MCI. A decrease in beta-amyloid-42 protein and an increase in tau-protein in CSF are early markers of neurodegenerative dementia as well as of the additional involvement of the neurodegeneration in cerebrovascular disease. Specific areas of glucose hypometabolism on preclinical stages of dementia were identified using FCSRT. Spectroscopy and morphometry based on magnetic resonance can predict neurodegeneration in the cingular cortex, frontal and temporal brain. PMID- 26978055 TI - [Association between pathological olfaction, immunological abnormalities and predisposition to substance use]. AB - OBJECTIVE: To reveal olfactory parameters of substance addiction formation through evaluation of predictive capability of olfactometry combined with laboratory-immunological methods. MATERIAL AND METHODS: Authors examined 156 people of both sexes aged 18-25 years. Three comparison groups with different attitudes towards psychoactive substances were formed as follows: people who do not use psychoactive substances (controls), episodic consumers (group at risk) and people with dependence syndrome. RESULTS: The occurrence of olfactory abnormalities in the anamnesis has immunological, psychological and behavioral correlates and is associated with earlier age of onset of substance consumption. The severity of aversive reactions to the test odorant is reduced already in the stage of episodic substance use and is associated with clinical signs of immune deficiency, suppression of cellular immunity and an increase in blood cortisol levels in substance abusers. CONCLUSION: Diagnostic and predictive modeling in the field of biological and clinical science of drug addiction is possible based on immunological and olfactory parameters. PMID- 26978056 TI - [Very low magnesium levels in red blood cells as a significant factor in the etiopathogenesis of borderline disorders]. AB - AIM: Basic studies indicate magnesium deficiency as one of the important, but often neglected, risk factors aggravating the course of borderline disorders (BD). A clinical verification of this notion has been conducted. MATERIAL AND METHODS: Authors studied 62 patients with BD, aged 25-65 years, of inpatient and outpatient settings. Contents of magnesium and other blood electrolytes were determined. RESULTS: Authors found an extremely high prevalence of very low levels of magnesium (Mg) in erythrocytes (<0.3 mmol/l) in patients with BD compared to controls (patients without BD, Mg (er.) 1.62+/-0.48 mmol/l). It has been shown that low Mg levels in the plasma and red blood cells are associated with a significantly increased risk of the following diagnoses: F07 "Personality and behavioral disorder due to brain disease, damage and dysfunction" (p<0.0016), F21 "Schizotypal disorder" (p<0.0005) and F34 "Persistent mood [affective] disorders" (p<0.0001). The use of Magne B6 Forte (4 tablets/day, 30 days, then 2 tablets/day for 1 year) resulted in a significant increase in the Mg levels in the plasma and erythrocytes, the compensation of anxiety and depressive symptoms, improvement of sleep and general health of the patients, reduced consumption of antidepressants (by 30%). CONCLUSION: Administration of the drugs based on organic salts of magnesium per os improves the condition of patients and reduces their need in pharmacotherapy. PMID- 26978057 TI - [The structure of mortality of patients under dispensary supervision diagnosed with alcohol-related mental and behavioral disorders]. AB - AIM: To identify the characteristics of mortality in patients under dispensary supervision with mental and behavioral disorders caused by alcohol (F10) in Arkhangelsk city. MATERIAL AND METHODS: Information obtained from certificates of death made out for people died in 2011-2012 who were registered in a regional psychoneurological dispensary was used. RESULTS: Mental and behavioral disorders caused by alcohol were diagnosed in 6,5% of patients, mean life longevity was 51,6 years while in others it was 67,8 years. Percentage of patients died from diseases of blood circulation system (40,6%) and tumors (13,8%) was relatively low while percentage of patients died from injuries, poisoning and other environmental factors was higher (28,6%). CONCLUSION: Alcohol abuse is a significant risk factor for population health of Arkhangelsk city. The structure of mortality of patients under dispensary supervision is characterized by the considerable prevalence of conditions that are potentially avertible. Differences in the approaches of forensic medicine experts and autopsists to the assessment of causes of death in these cases can lead to misrepresentation of statistical data on mortality structure. PMID- 26978058 TI - [The possibility of treatment of cognitive impairment in the complex therapy of patients with the consequences of cerebral infarction]. AB - AIM: To study neuropsychological status of inpatients with the consequences of cerebral infarction treated with cortexin and mexidol. MATERIAL AND METHODS: We carried out a neurological and neuropsychological examination of 62 patients with the consequences of cerebral infarction treated with cortexin in the dose of 10 mg and mexidol in the dose of 5 mL of 5% solution intravenously during 15 days. RESULTS AND CONCLUSION: It has been shown that the use of this drug combination decreasescomplaints and neurological symptoms and significantly improves cognitive and emotional status as well. The more positive changes are related to attention, speed of mental reactions, anxiety and verbal activity. The complex therapy with cortexin and mexidoldecreased neurological deficit and improve cognitive functioning and psychoemotional status thus increasing quality of life and rehabilitation potential of the patients. PMID- 26978059 TI - [On the question of the organization of brain function: cortical associations, "disconnection" syndrome and higher brain functions]. AB - The review considers the structural/functional brain organization, the disturbance of which is accompanied by the development of cognitive and behavioral disorders. The significance of the disruption of parallel circuits connecting frontal lobes with subcortical structures (the basal ganglia, thalamus, cerebellum) is highlighted. This disruption is clinically described as "disconnection" syndrome. The associations between the basal ganglia and the cortex of the large cerebral hemispheres responsible for motor, cognitive and emotional/behavioral functions do not restricted to these spheres and is characteristic not only of frontal brain areas. There are circuits connecting other brain compartments and the basal ganglia that provide perception, and are involved in decision making on the basis of input information of different modalities.The improvement of understanding of the pathophysiology and neurochemistry of these structures opens new possibilities for selective action on some or other circuit to achieve the best therapeutic result. PMID- 26978060 TI - [Frontotemporal degeneration: a clinical case and experience of using of diffusion tensor magnetic-resonance imaging tractography]. AB - Frontotemporal degeneration is a frequent cause of presenile dementia that makes up from 5 to 17% of autopsy-confirmed cases developed at the age of 70 years. Authors report a case of this disease, discuss the possible causes of its development and present the results of diffusion tensor magnetic resonance tractography. Clinical features of this case are practically isolated speech disturbance with the most likely domination of a semantic variant of primary progressive aphasia. Magnetic-resonance imaging has an important practical significance for this pathology due to the possibility of assessing atrophic zones. The use of DTI-tractography allows to extend diagnostic possibilities. PMID- 26978061 TI - Solution-processed photodetectors based on organic-inorganic hybrid perovskite and nanocrystalline graphite. AB - We present here solution-processed photodetectors based on a methyl ammonium lead iodide perovskite (MAPbI3) and nanocrystalline graphite (NCG) hybrid composite. The highest responsivity of the best MAPbI3/NCG photodetector was 795 mA W(-1) at 500 nm visible light, which is almost twice as high as that of the NCG-free MAPbI3 photodetector (408 mA W(-1)). The enhanced performance of the MAPbI3/NCG photodetector arises from the improved charge extraction at the MAPbI3/NCG interface. The dependence of photodetector performance on the mass percentage of NCG (the ratio of NCG to MAPbI3) in the hybrid materials is also reported here, and is correlated to the fabrication process. Moreover, by comparing the responsivity of the devices with different channel lengths, we show that the performance of hybrid photodetectors can be further tuned by tailoring the channel length. PMID- 26978063 TI - Correction: Medical and Obstetric Complications among Pregnant Women Aged 45 and Older. PMID- 26978062 TI - Bortezomib Inpatient Prescribing Practices in Free-Standing Children's Hospitals in the United States. AB - This study is a pharmacoepidemiologic description of pediatric bortezomib use. Exposure was identified through billing codes in patients admitted to US children's hospitals that participated with the Pediatric Health Information System between 2004 and 2013. Associated information on underlying diseases, demographics, institutional use, mortality, and physician type was collected. Exposure to bortezomib was identified in 314 patients. Hematologist/Oncologists prescribed half of the bortezomib used. Use increased during the study period. Inpatient volume was positively correlated with bortezomib utilization. Bortezomib use in pediatrics is increasing for a variety of diseases. Variation in use exists across institutions. Further studies are needed to characterize bortezomib's efficacy in pediatric diseases. PMID- 26978064 TI - Differentiation of Apical Bud Cells in a Newly Developed Apical Bud Transplantation Model Using GFP Transgenic Mice as Donor. AB - Rodent mandibular incisors have a unique anatomical structure that allows teeth to grow throughout the lifetime of the rodent. This report presents a novel transplantation technique for studying the apical bud differentiation of rodent mandibular incisors. Incisal apical end tissue with green fluorescent protein from transgenic mouse was transplanted to wild type mice, and the development of the transplanted cells were immunohistologically observed for 12 weeks after the transplantation. Results indicate that the green fluorescent apical end tissue replaced the original tissue, and cells from the apical bud differentiated and extended toward the incisal edge direction. The immunostaining with podoplanin also showed that the characteristics of the green fluorescent tissue were identical to those of the original. The green fluorescent cells were only found in the labial side of the incisor up to 4 weeks. After 12 weeks, however, they were also found in the lingual side. Here the green fluorescent cementocyte-like cells were only present in the cementum close to the dentin surface. This study suggests that some of the cells that form the cellular cementum come from the apical tissue including the apical bud in rodent incisors. PMID- 26978066 TI - Hendra virus ecology and transmission. AB - Hendra virus causes acute and highly fatal infection in horses and humans. Pteropid bats (flying-foxes) are the natural host of the virus, with age and species being risk factors for infection. Urine is the primary route of excretion in flying-foxes, with viral RNA more frequently detected in Pteropus alecto and P. conspicillatus than other species. Infection prevalence in flying-foxes can vary between and within years, with a winter peak of excretion occurring in some regions. Vertical transmission and recrudescing infection has been reported in flying-foxes, but horizontal transmission is evidently the primary mode of transmission. The most parsimonious mode of flying-fox to horse transmission is equine contact (oro-nasal, conjunctival) with infected flying-fox urine, either directly, or via urine-contaminated pasture or surfaces. Horse to horse transmission is inefficient, requiring direct contact with infected body fluids. Flying-fox to human transmission has not been recorded; all human cases have been associated with close and direct contact with infected horses. Canine cases (subclinical) have also been limited to equine case properties. Notwithstanding the recent availability of an effective vaccine for horses, a comprehensive understanding of Hendra virus ecology and transmission is essential to limit inter-species transmission. PMID- 26978065 TI - The Impact of Emotions and Empathy-Related Traits on Punishment Behavior: Introduction and Validation of the Inequality Game. AB - In the prevention and resolution of conflicts in social contexts, an important step is to understand how different emotions and empathic traits are linked to punishment behaviors. Unfortunately, few paradigms exist to study these phenomena. Here, we developed the Inequality Game (IG) as an economic and verbal interaction paradigm in which participants are faced with an "unfair other" as opposed to a "fair other" and subsequently have the opportunity to engage in a range of social behaviors. These social behaviors include cooperative or competitive economic choices and nice or derogatory verbal behavior toward the unfair and fair other. Participants could thus engage in punishment or forgiveness behavior toward the unfair other as well as in cooperative or aggressive behavior toward the fair other. We validated the IG through multimodal measures comprising the assessment of personality traits, emotions (by means of facial expressions and self-reports), arousal (by means of skin conductance responses), physical effort (force exertion), and behavioral reactions. Second, we examined the influence of emotions and empathy-related traits on punishment behavior. With regard to emotions, we observed a positive relation between malicious joy and punishment behavior. This result highlights the role of reward related mechanisms in favoring punishment behavior. In addition, different empathic traits had opposing effects on antisocial behavior. Whereas personal distress predicted aggressive verbal behavior, perspective taking and empathic concern predicted a reduction in punishment behavior. Empathic traits also modulated emotional experience and person evaluations, such that perspective taking was related to more positive affect (less frowning and more smiling) and a more favorable evaluation of the unfair other. The current data validate the IG, reveal that malicious joy is positively related to punishment behavior, and show that different types of empathic traits can have opposing effects on antisocial behavior as well as on related emotions and person evaluations. PMID- 26978067 TI - Prenatal Diagnosis and Evaluation of Sonographic Predictors for Intervention and Adverse Outcome in Congenital Pulmonary Airway Malformation. AB - OBJECTIVE: To describe antenatal findings and evaluate prenatal risk parameters for adverse outcome or need for intervention in fetuses with congenital pulmonary airway malformation (CPAM). METHODS: In our retrospective study all fetuses with a prenatal diagnosis of CPAM detected in our tertiary referral center between 2002 and 2013 were analyzed. Sonographic findings were noted and measurements of mass-to-thorax-ratio (MTR), congenital pulmonary airway malformation volume-ratio (CVR) and observed to expected lung-to head-ratio (o/e LHR) were conducted and correlated to fetal or neonatal morbidity and mortality and/or need for prenatal intervention. RESULTS: 67 fetuses with CPAM were included in the study. Hydropic fetuses were observed in 16.4% (11/67) of cases, prenatal intervention was undertaken in 9 cases; 7 pregnancies were terminated. The survival rate of non hydropic fetuses with conservatively managed CPAM was 98.0% (50/51), the survival rate for hydropic fetuses with intention to treat was 42.9% (3/7). 10 (18.2%) children needed respiratory assistance. Fetuses with a CVR of <0.91 were significantly less likely to experience adverse outcome or need for prenatal intervention with sensitivity, specificity and positive/negative predictive value of 0.89, 0.71, 0.62 and 0.93, respectively. A MTR (mass-to-thorax-ratio) of < 0.51 had a positive predictive value of 0.54 and a negative predictive value of 0.96 of adverse events with a sensitivity of 0.95 and a specificity of 0.63. The negative predictive value for o/e LHR of 45% was 0.84 with sensitivity, specificity and positive predictive value of 0.73, 0.68 and 0.52, respectively. CONCLUSIONS: The majority of cases with CPAM have a favorable outcome. MTR and CVR are able to identify fetuses at risk, the o/e LHR is less sensitive. PMID- 26978069 TI - Time-Resolved Visualisation of Nearly-Native Influenza A Virus Progeny Ribonucleoproteins and Their Individual Components in Live Infected Cells. AB - Influenza viruses are a global health concern because of the permanent threat of novel emerging strains potentially capable of causing pandemics. Viral ribonucleoproteins (vRNPs) containing genomic RNA segments, nucleoprotein oligomers, and the viral polymerase, play a central role in the viral replication cycle. Our knowledge about critical events such as vRNP assembly and interactions with other viral and cellular proteins is poor and could be substantially improved by time lapse imaging of the infected cells. However, such studies are limited by the difficulty to achieve live-cell compatible labeling of active vRNPs. Previously we designed the first unimpaired recombinant influenza WSN-PB2 GFP11 virus allowing fluorescent labeling of the PB2 subunit of the viral polymerase (Avilov et al., J.Virol. 2012). Here, we simultaneously labeled the viral PB2 protein using the above-mentioned strategy, and virus-encoded progeny RNPs through spontaneous incorporation of transiently expressed NP-mCherry fusion proteins during RNP assembly in live infected cells. This dual labeling enabled us to visualize progeny vRNPs throughout the infection cycle and to characterize independently the mobility, oligomerization status and interactions of vRNP components in the nuclei of live infected cells. PMID- 26978068 TI - Biofilm Morphotypes and Population Structure among Staphylococcus epidermidis from Commensal and Clinical Samples. AB - Bacterial species comprise related genotypes that can display divergent phenotypes with important clinical implications. Staphylococcus epidermidis is a common cause of nosocomial infections and, critical to its pathogenesis, is its ability to adhere and form biofilms on surfaces, thereby moderating the effect of the host's immune response and antibiotics. Commensal S. epidermidis populations are thought to differ from those associated with disease in factors involved in adhesion and biofilm accumulation. We quantified the differences in biofilm formation in 98 S. epidermidis isolates from various sources, and investigated population structure based on ribosomal multilocus typing (rMLST) and the presence/absence of genes involved in adhesion and biofilm formation. All isolates were able to adhere and form biofilms in in vitro growth assays and confocal microscopy allowed classification into 5 biofilm morphotypes based on their thickness, biovolume and roughness. Phylogenetic reconstruction grouped isolates into three separate clades, with the isolates in the main disease associated clade displaying diversity in morphotype. Of the biofilm morphology characteristics, only biofilm thickness had a significant association with clade distribution. The distribution of some known adhesion-associated genes (aap and sesE) among isolates showed a significant association with the species clonal frame. These data challenge the assumption that biofilm-associated genes, such as those on the ica operon, are genetic markers for less invasive S. epidermidis isolates, and suggest that phenotypic characteristics, such as adhesion and biofilm formation, are not fixed by clonal descent but are influenced by the presence of various genes that are mobile among lineages. PMID- 26978070 TI - Plant Tandem CCCH Zinc Finger Proteins Interact with ABA, Drought, and Stress Response Regulators in Processing-Bodies and Stress Granules. AB - Although multiple lines of evidence have indicated that Arabidopsis thaliana Tandem CCCH Zinc Finger proteins, AtTZF4, 5 and 6 are involved in ABA, GA and phytochrome mediated seed germination responses, the interacting proteins involved in these processes are unknown. Using yeast two-hybrid screens, we have identified 35 putative AtTZF5 interacting protein partners. Among them, Mediator of ABA-Regulated Dormancy 1 (MARD1) is highly expressed in seeds and involved in ABA signal transduction, while Responsive to Dehydration 21A (RD21A) is a well documented stress responsive protein. Co-immunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC) assays were used to confirm that AtTZF5 can interact with MARD1 and RD21A in plant cells, and the interaction is mediated through TZF motif. In addition, AtTZF4 and 6 could also interact with MARD1 and RD21A in Y-2-H and BiFC assay, respectively. The protein-protein interactions apparently take place in processing bodies (PBs) and stress granules (SGs), because AtTZF5, MARD1 and RD21A could interact and co-localize with each other and they all can co-localize with the same PB and SG markers in plant cells. PMID- 26978072 TI - Carvedilol nano lipid carriers: formulation, characterization and in-vivo evaluation. AB - The purpose of this study was to develop Carvedilol nanostructured lipid carriers (CAR-NLCs) using stearic acid and oleic acid as lipid, and to estimate the potential as oral delivery system for poorly water soluble drug. The particle size analysis revealed that all the developed formulations were within the nanometer range. The EE and loading were found to be between 69.45-88.56% and 9.58-12.56%, respectively. The CAR-NLCopt showed spherical morphology with smooth surface under transmission electron microscope (TEM). The crystallization of the drug in NLC was investigated by powder X-ray diffraction and differential scanning calorimetry (DSC) and revealed that the drug was in an amorphous state in the NLC matrix. The ex vivo gut permeation study showed many folds increment in the permeation of CAR-NLCs compared to Carvedilol suspension (CAR-S). The oral bioavailability study of CAR was carried out using Wistar rats and relative bioavailability of CAR-NLCopt was found to be 3.95 fold increased in comparison with CAR-S. In vivo antihypertensive study in Wistar rats showed significant reduction in mean systolic BP by CAR-NLCopt vis-a-vis CAR-S (p < 0.05) owing to the drug absorption through lymphatic pathways. In conclusion, the NLC formulation remarkably improved the oral bioavailability of CAR and demonstrated a promising perspective for oral delivery of poorly water-soluble drugs. The promising findings in this investigation suggest the practicability of these systems for the enhancement of bioavailability of CAR. PMID- 26978071 TI - Relative Importance of Sex, Pre-Starvation Body Mass and Structural Body Size in the Determination of Exceptional Starvation Resistance of Anchomenus dorsalis (Coleoptera: Carabidae). AB - In nature, almost all animals have to cope with periods of food shortage during their lifetimes. Starvation risks are especially high for carnivorous predatory species, which often experience long intervals between stochastic prey capturing events. A laboratory experiment using the common predatory carabid beetle Anchomenus dorsalis revealed an exceptional level of starvation resistance in this species: males survived up to 137 days and females up to 218 days without food at 20 degrees C. Individual starvation resistance was strongly positively affected by pre-starvation body mass but only slightly by beetle structural body size per se. Females outperformed males even when the effect of gender was corrected for the effects of structural body size and pre-starvation body mass. The better performance of females compared to males and of beetles with higher relative pre-starvation body mass could be linked to higher fat content and lean dry mass before starvation, followed by a greater decrease in both during starvation. There was also a difference between the sexes in the extent of body mass changes both during ad libitum feeding and following starvation; the body masses of females fluctuated more compared to males. This study stresses the need to distinguish between body mass and structural body size when investigating the ecological and evolutionary consequences of body size. Investigation of the net effects of body size and sex is necessary to disentangle the causes of differences in individual performances in studies of species with significant sexual size dimorphism. PMID- 26978073 TI - Physiological Responses and Hedonics During Prolonged Physically Interactive Videogame Play. AB - OBJECTIVE: This study was designed to assess physiologic responses and hedonics (i.e., liking) during prolonged physically interactive videogame play. MATERIALS AND METHODS: Participants (n = 24) completed three 30-minute videogame conditions on separate days in a random order. During two of the conditions participants played physically interactive videogames (Nintendo of America, Inc. [Redmond, WA] "WiiTM Fit" "Basic Run" and "Basic Step"). During the third condition participants played a traditional/sedentary game ("Tanks!"), which required minimal physical movement for gameplay. Oxygen consumption (VO2) was assessed using indirect calorimetry throughout each condition and averaged every 5 minutes. Liking was assessed via visual analog scale at the 15- and 30-minute time points during each condition. RESULTS: Mean VO2 was significantly (P < 0.001) greater during "Basic Run" (16.14 +/- 5.8 mL/kg/minute, 4.6 +/- 1.7 metabolic equivalents [METs]) than either "Basic Step" (11.4 +/- 1.7 mL/kg/minute, 3.3 +/- 0.5 METs) or the traditional/sedentary videogame (5.39 +/- 1.0 mL/kg/minute, 1.5 +/- 0.1 METs). "Basic Step" was also greater (P < 0.001) than the traditional/sedentary game. VO2 did not significantly (P = 0.25) fluctuate across the 30-minute session for any game. In other words, participants maintained a consistent physiologic intensity throughout each 30-minute condition. There were no differences (P >= 0.20) across gaming conditions or time for liking. CONCLUSIONS: Participants achieved and maintained moderate-intensity physical activity (>=3.0 METs) during both 30-minute physically interactive videogame conditions. Furthermore, because liking was similar across all gaming conditions, participants may be willing to substitute the physically interactive videogames in place of the traditional/sedentary game. PMID- 26978074 TI - Selective Influences of Precision and Power Grips on Speech Categorization. AB - Recent studies have shown that articulatory gestures are systematically associated with specific manual grip actions. Here we show that executing such actions can influence performance on a speech-categorization task. Participants watched and/or listened to speech stimuli while executing either a power or a precision grip. Grip performance influenced the syllable categorization by increasing the proportion of responses of the syllable congruent with the executed grip (power grip-[ke] and precision grip-[te]). Two follow-up experiments indicated that the effect was based on action-induced bias in selecting the syllable. PMID- 26978075 TI - BioSig3D: High Content Screening of Three-Dimensional Cell Culture Models. AB - BioSig3D is a computational platform for high-content screening of three dimensional (3D) cell culture models that are imaged in full 3D volume. It provides an end-to-end solution for designing high content screening assays, based on colony organization that is derived from segmentation of nuclei in each colony. BioSig3D also enables visualization of raw and processed 3D volumetric data for quality control, and integrates advanced bioinformatics analysis. The system consists of multiple computational and annotation modules that are coupled together with a strong use of controlled vocabularies to reduce ambiguities between different users. It is a web-based system that allows users to: design an experiment by defining experimental variables, upload a large set of volumetric images into the system, analyze and visualize the dataset, and either display computed indices as a heatmap, or phenotypic subtypes for heterogeneity analysis, or download computed indices for statistical analysis or integrative biology. BioSig3D has been used to profile baseline colony formations with two experiments: (i) morphogenesis of a panel of human mammary epithelial cell lines (HMEC), and (ii) heterogeneity in colony formation using an immortalized non transformed cell line. These experiments reveal intrinsic growth properties of well-characterized cell lines that are routinely used for biological studies. BioSig3D is being released with seed datasets and video-based documentation. PMID- 26978076 TI - Model Testing of PluriTest with Next-Generation Sequencing Data. PMID- 26978077 TI - Novel Approach to Simulate Sleep Apnea Patients for Evaluating Positive Pressure Therapy Devices. AB - Bench testing is a useful method to characterize the response of different automatic positive airway pressure (APAP) devices under well-controlled conditions. However, previous models did not consider the diversity of obstructive sleep apnea (OSA) patients' characteristics and phenotypes. The objective of this proof-of-concept study was to design a new bench test for realistically simulating an OSA patient's night, and to implement a one-night example of a typical female phenotype for comparing responses to several currently-available APAP devices. We developed a novel approach aimed at replicating a typical night of sleep which includes different disturbed breathing events, disease severities, sleep/wake phases, body postures and respiratory artefacts. The simulated female OSA patient example that we implemented included periods of wake, light sleep and deep sleep with positional changes and was connected to ten different APAP devices. Flow and pressure readings were recorded; each device was tested twice. The new approach for simulating female OSA patients effectively combined a wide variety of disturbed breathing patterns to mimic the response of a predefined patient type. There were marked differences in response between devices; only three were able to overcome flow limitation to normalize breathing, and only five devices were associated with a residual apnea hypopnea index of <5/h. In conclusion, bench tests can be designed to simulate specific patient characteristics, and typical stages of sleep, body position, and wake. Each APAP device behaved differently when exposed to this controlled model of a female OSA patient, and should lead to further understanding of OSA treatment. PMID- 26978119 TI - Psychometric properties of a short version of the Eating Attitudes Test (EAT-8) in a German representative sample. AB - PURPOSE: Disordered eating is common for all ages and sexes in the general population. However, only some individuals are known to develop clinically relevant eating disorders. There is a critical need of efficient, reliable and valid screening instruments to measure disordered eating for the general population. The Eating Attitudes Test was shortened into an 8-item-version to screen individuals at high risk of developing clinical eating disorders in a general population sample. METHODS: Psychometric properties (Cronbach's alpha, construct and concurrent validity and factor structure), cutoff scores (with sensitivity, specificity, positive and negative predictive value) and norms were determined in a representative sample of the German population (N=2527). Factorial validity was investigated using item response modeling. RESULTS: Results confirmed reliability and validity of the questionnaire. Internal consistency and convergent validity were good. Analysis revealed different cutoff points for male and female participants. Values for sensitivity and specificity were satisfying and the positive predictive value was higher compared to other short screening instruments for disordered eating. Factorial analysis revealed a one-factor solution with an excellent model fit. The elimination of one item was discussed. Gender- and age-specific norms are reported. CONCLUSIONS: Overall results indicated that the EAT-8 is an efficient instrument suitable for screening purposes in large general population samples. PMID- 26978120 TI - Decomposing contributions of absolute, relative and subjective deprivation: A commentary on "Relative deprivation and risk factors for obesity in Canadian adolescents". PMID- 26978121 TI - Discovery and modelling studies of natural ingredients from Gaultheria yunnanensis (FRANCH.) against phosphodiesterase-4. AB - Phosphodiesterase-4 (PDE4) is an anti-inflammatory target for treatment of asthma and chronic obstructive pulmonary disease (COPD). Here, we report the isolation and characterization of 13 compounds (G1-G13) by bioassay-guided fractionation of the ethyl acetate extraction of Gaultheria yunnanensis (FRANCH.), one of which pentacyclic triterpene (G1) has never been reported. Four of them (G1, G2, G4, and G5) inhibit PDE4 with the IC50 values < 20 MUM and G1 is the most potent ingredient with an IC50 of 245 nM and moderate selectivity over other PDE families. Molecular dynamics simulations suggest that G1 forms a hydrogen bond with Asn362, in addition to the hydrogen bond with Gln369 and pi-pi interactions with Phe372, which are commonly observed in the binding of most PDE4 inhibitors. The calculated binding free energies for the interactions of PDE4-G1 and PDE4-G2 are -19.4 and -18.8 kcal/mol, in consistence with the bioassay that G1 and G2 have IC50 of 245 nM and 542 nM, respectively. The modelling results of these active compounds may aid the rational design of novel PDE4 inhibitors as anti inflammatory agents. PMID- 26978123 TI - Putting Maternal Health in Perspective with a Life Course Approach to Women's Health. PMID- 26978122 TI - Inhibition of Lipolysis Ameliorates Diabetic Phenotype in a Mouse Model of Obstructive Sleep Apnea. AB - Obstructive sleep apnea (OSA) is associated with insulin resistance, glucose intolerance, and type 2 diabetes. Causal mechanisms mediating this association are not well defined; however, augmented lipolysis in adipose might be involved. Here, we investigated the effect of acipimox treatment (lipolysis inhibitor) on glucose tolerance and insulin sensitivity in mice exposed to intermittent hypoxia (IH). C57BL6/J mice were exposed for 14 days to IH or control conditions. IH was created by decreasing the fraction of inspired oxygen from 20.9 to 6.5%, 60 times/h. Control exposure was air (fraction of inspired oxygen, 20.9%) delivered at an identical flow rate. Acipimox was provided in drinking water (0.5 g/ml) during exposures. After exposures, intraperitoneal insulin (0.5 IU/kg) and glucose (1 g/kg) tolerance tests were performed, and primary adipocytes were isolated for lipolysis experiments. IH elevated fasting glucose by 51% and worsened glucose tolerance and insulin sensitivity by 33 and 102%, respectively. In parallel, IH increased spontaneous lipolysis by 264%, and reduced epididymal fat mass by 15% and adipocyte size by 8%. Acipimox treatment prevented IH-induced lipolysis and increased epididymal fat mass and adipocyte size by 19 and 10%, respectively. Acipimox fully prevented IH-induced impairments in fasting glycemia, glucose tolerance, and insulin sensitivity. For all reported results, P less than 0.05 was considered significant. Augmented lipolysis contributes to insulin resistance and glucose intolerance observed in mice exposed to IH. Acipimox treatment ameliorated the metabolic consequences of IH and might represent a novel treatment option for patients with obstructive sleep apnea. PMID- 26978124 TI - Adherence of Primary Care Physicians to Evidence-Based Recommendations to Reduce Ovarian Cancer Mortality. AB - Ovarian cancer is the deadliest gynecologic cancer. Receipt of treatment from a gynecologic oncologist is an evidence-based recommendation to reduce mortality from the disease. We examined knowledge and application of this evidence-based recommendation in primary care physicians as part of CDC gynecologic cancer awareness campaign efforts and discussed results in the context of CDC National Comprehensive Cancer Control Program (NCCCP). We analyzed primary care physician responses to questions about how often they refer patients diagnosed with ovarian cancer to gynecologic oncologists, and reasons for lack of referral. We also analyzed these physicians' knowledge of tests to help determine whether a gynecologic oncologist is needed for a planned surgery. The survey response rate was 52.2%. A total of 84% of primary care physicians (87% of family/general practitioners, 81% of internists and obstetrician/gynecologists) said they always referred patients to gynecologic oncologists for treatment. Common reasons for not always referring were patient preference or lack of gynecologic oncologists in the practice area. A total of 23% of primary care physicians had heard of the OVA1 test, which helps to determine whether gynecologic oncologist referral is needed. Although referral rates reported here are high, it is not clear whether ovarian cancer patients are actually seeing gynecologic oncologists for care. The NCCCP is undertaking several efforts to assist with this, including education of the recommendation among women and providers and assistance with treatment summaries and patient navigation toward appropriate treatment. Expansion of these efforts to all populations may help improve adherence to recommendations and reduce ovarian cancer mortality. PMID- 26978125 TI - Polar stir bars for isolation and preconcentration of perfluoroalkyl substances from human milk samples prior to UHPLC-MS/MS analysis. AB - BACKGROUND: A new method for the determination of four perfluoroalkyl carboxylic acids (from C5 to C8) and perfluorooctane sulfonate in human milk samples using stir-bar sorptive extraction-ultra-HPLC-MS/MS has been accurately optimized and validated. METHODOLOGY: Polydimethylsiloxane and polyethyleneglycol modified silicone materials were evaluated. DISCUSSION: Overall, polyethyleneglycol led to a better sensitivity. After optimizing experimental variables, the method was validated reaching detection limits in the range of 0.05-0.20 ng ml(-1); recovery rates from 81 to 105% and relative standard deviations fewer than 13% in all cases. The method was applied to milk samples from five randomly selected women. All samples were positive for at least one of the target compounds with concentrations ranging between 0.8 and 6.6 ng ml(-1), being the most abundant perfluorooctane sulfonate. PMID- 26978126 TI - A rare case of true carcinosarcoma of the breast. AB - BACKGROUND: True carcinosarcoma of the breast is an extremely rare condition, accounting for 0.08-0.2% of all breast malignancies. The correct definition of this tumor requires both a carcinomatous component and a malignant non-epithelial component of mesenchymal origin, without evidence of a transition zone between the two elements. CASE PRESENTATION: We present a case of a 49-year-old woman presenting with a 4cm mass at the level of her left breast upper-outer quadrant with a histologic diagnosis of true carcinosarcoma of the breast. DISCUSSION: The most appropriate therapeutic regimens for breast carcinosarcoma are still unclear because of the rarity of this condition, but Breast Conserving Treatment (BCT) followed by adjuvant chemotherapy seems to provide a prognosis equalling that of usual Invasive Ductal Carcinoma of the breast. PMID- 26978128 TI - A developmental study of latent absolute pitch memory. AB - The ability to recall the absolute pitch level of familiar music (latent absolute pitch memory) is widespread in adults, in contrast to the rare ability to label single pitches without a reference tone (overt absolute pitch memory). The present research investigated the developmental profile of latent absolute pitch (AP) memory and explored individual differences related to this ability. In two experiments, 288 children from 4 to12 years of age performed significantly above chance at recognizing the absolute pitch level of familiar melodies. No age related improvement or decline, nor effects of musical training, gender, or familiarity with the stimuli were found in regard to latent AP task performance. These findings suggest that latent AP memory is a stable ability that is developed from as early as age 4 and persists into adulthood. PMID- 26978129 TI - Rheumatoid arthritis management of early disease. AB - PURPOSE OF REVIEW: Early effective treatment has led to major improvements in patients with rheumatoid arthritis. This review aims to address the treatment of early rheumatoid arthritis, in particular the different therapeutic strategies evaluated in clinical trials to achieve optimal disease control. RECENT FINDINGS: The use of biological disease-modifying antirheumatic drugs (bDMARDs) has significantly improved patient outcomes. Overall, studies using bDMARD induction have shown early clinical improvements, with high proportions achieving remission with minimal radiographic progression. As these drugs are still relatively costly, conventional synthetic DMARDs, as monotherapy or in combination, remain the mainstay of treatment initiation. Good, albeit somewhat slower, responses can be achieved with these drugs. Strategies incorporating glucocorticoids and a treat-to-target approach (i.e. regular monitoring of disease activity and early treatment escalation with a conventional synthetic or b-DMARD, if needed) have shown additional benefit. In patients achieving low disease activity or remission, bDMARD dose reduction and withdrawal, and even drug-free remission have been possible in some. SUMMARY: In patients with early rheumatoid arthritis, conventional synthetic DMARDs and glucocorticoids used within a treat-to-target setting, and the addition of a bDMARD if required, outcomes have improved significantly. A proportion of patients are able to deescalate treatment after bDMARD therapy, with a significant minority achieving drug-free remission. PMID- 26978127 TI - Correlates of Subjective Caregiver Strain in Caregivers of Youth Evaluated in a Pediatric Psychiatric Emergency Room. AB - BACKGROUND: Although caregiver burden is relevant to the outcome for psychiatrically ill youth, most studies have focused on caregiver burden in the community or research settings. Therefore, we aimed at evaluating the subjective caregiver strain (SCS) at the time of presentation of youth to a pediatric psychiatric emergency room (PPER), assessing potential correlates to provide leads for improvements in formal support systems. METHODS: In this retrospective cohort study, the internalized, externalized, and total SCS were assessed in caregivers of youth <18 years of age consecutively evaluated at a PPER during a 1 year period using the Caregiver Strain Questionnaire. Sociodemographic and a broad range of clinical data were collected during the PPER visit using a 12-page semistructured institutional evaluation form. The Appropriateness of Pediatric Psychiatric Emergency Room Contact scale, incorporating acuity, severity and harm potential, was used to rate appropriateness of the visit. RESULTS: In caregivers of 444 youth, the internalized SCS was significantly higher than the externalized SCS (p < 0.001). Multivariable analyses indicated that higher total and externalized SCS were associated with disruptive behavior or substance abuse/dependent disorder diagnosis, presenting complaint of aggression, and discharge plan to the police. Higher total and internalized SCS were associated with lower child functioning, whereas total and internalized SCS were lower in adopted children. In addition, higher externalized SCS was associated with investigator-rated inappropriateness of the emergency visit, presenting complaint of defiance, and a lack of prior psychiatric ER visits. CONCLUSIONS: High levels of CS in PPER highlight the necessity to adhere to existing guidelines regarding the inclusion of caregivers' perceptions into comprehensive psychiatric assessments. The particularly high strain in caregivers of children with externalizing disorders and in families with low-functioning youth may need to prompt PPER staff to provide efficient information on appropriate treatment options for these children and on support facilities for the parents. PMID- 26978130 TI - Lupus and fractures. AB - PURPOSE OF REVIEW: The article reviews recent advances in the research of fractures in patients with systemic lupus erythematosus (SLE), highlighting their clinical, scientific, and economic impact. RECENT FINDINGS: Recent studies demonstrated an increased incidence of osteoporosis and symptomatic fractures in patients with SLE and age, disease duration, disease severity, and glucocorticoid use are important risk factors. A high prevalence of vertebral fractures was demonstrated, while one in three of these patients has normal bone density, which illustrates the multifactorial cause of fractures in SLE. Screening for vertebral fractures is important, as they often occur asymptomatically, but are associated with a reduced quality of life, increased future fracture risk, an increased mortality risk, and may have therapeutic implications. A recently developed Delphi consensus revealed the high economic burden of fractures as a glucocorticoid-related adverse event in SLE, whereas the majority of patients use glucocorticoids. SUMMARY: Recent studies revealed an increased incidence of symptomatic fractures and a relatively high prevalence of vertebral fractures in patients with SLE, and provided new insights into their multifactorial aetiology. The clinical consequences and high economic burden of fractures as glucocorticoid related adverse events underline the importance of reducing glucocorticoid therapy and use of steroid-sparing agents. PMID- 26978131 TI - Infection and Nonunion After Fasciotomy for Compartment Syndrome Associated With Tibia Fractures: A Matched Cohort Comparison. AB - OBJECTIVES: The objective was to compare the rates of union and infection in patients treated with and without fasciotomy for acute compartment syndrome (ACS) in operatively managed tibia fractures. DESIGN: This was a retrospective review. SETTING: The study was conducted at both a Level 1 and Level II trauma center. PATIENTS/PARTICIPANTS: Patients operated for tibial plateau fractures (group 1) and tibial shaft fractures (group 3) with ACS requiring fasciotomy were matched to patients without ACS (plateau: group 2, shaft: group 4) in a 1:3 ratio for age, sex, fracture pattern, and open/closed injury. INTERVENTION: Surgical treatment was provided with plates/screws (plateau fractures) or intramedullary rod (shaft fractures). Patients with ACS were treated with a 2-incision 4 compartment fasciotomy. MAIN OUTCOME MEASUREMENTS: Time to union and incidence of deep infection, nonunion, and delayed union. RESULTS: One hundred eighty-four patients were included-group 1: 23 patients, group 2: 69 patients, group 3: 23 patients, and group 4: 69 patients. Time to union averaged 26.8 weeks for groups 1 and 3 and 21.5 weeks for groups 2 and 4 (P > 0.05). Nonunion occurred in 20% for groups 1 and 3 and in 5% for groups 2 and 4 (P = 0.003). Deep infection developed in 20% for groups 1 and 3 and in 4% for groups 2 and 4 (P = 0.001). There was a significant increase in infection in group 1 versus group 2 and nonunion in group 3 versus group 4. There were significantly more smokers for those with fasciotomies (46%) than without (20%, P < 0.001), though all statistical results remained similar after a binary regression analysis. CONCLUSION: Four-compartment fasciotomies in patients with tibial shaft or plateau fractures is associated with a significant increase in infection and nonunion. LEVEL OF EVIDENCE: Prognostic level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 26978132 TI - Determinants of Functional Outcome in Distal Radius Fractures in High-Functioning Patients Older Than 55 Years. AB - OBJECTIVES: To determine the influence of treatment and radiographic parameters on patient-reported functional outcomes on a population of non-frail elderly with distal radius fractures. DESIGN: Prospective cohort study. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Patients older than 55 years presenting with a distal radius fracture and a Canadian Study of Health and Aging Clinical Frailty Scale score of 1 or 2. INTERVENTION: Closed reduction and casting or open reduction and internal fixation as per the treating surgeons' decision. MAIN OUTCOME MEASURES: Radiographic scores at baseline, 6 weeks, and 12 weeks, as well as Disabilities of the Arm, Shoulder and Hand, Short Form 36, and Patient Reported Wrist Evaluation scores up to 1 year after injury. Univariate analysis and linear regression analysis were performed on outcome measures. RESULTS: No difference exists in outcomes based on treatment choice. Patients with ulnar positivity greater than 2 mm at baseline, after treatment, and at final follow-up had worse patient-reported scores at 1 year. Persistent articular gaps and/or steps greater than 2 mm after treatment were also associated with worse patient reported outcomes. CONCLUSION: Even in high-functioning patients older than 55 years, there was no difference in patient-reported outcomes at 1 year in the open reduction group as compared with the closed reduction group. Instead, physicians should pay particular attention to radial shortening and persistent articular gaps following their chosen treatment plan for distal radial fractures. LEVEL OF EVIDENCE: Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 26978133 TI - "Fracturoscopy" is Superior to Fluoroscopy in the Articular Reconstruction of Complex Tibial Plateau Fractures-An Arthroscopy Assisted Fracture Reduction Technique. AB - OBJECTIVE: To analyze the anatomic accuracy of fracture reduction controlled by fluoroscopy as compared with arthroscopically assisted reduction ("fracturoscopy") in patients with complex tibial plateau fractures (AO/OTA 41 C). Quality of fracturoscopy-guided reduction was checked with postoperative computed tomography. DESIGN: Prospective observational study. SETTING: Urban level 1 trauma center. PATIENTS: Seventeen consecutive patients, with a complex, bicondylar tibial plateau fracture. INTERVENTION: The intraoperative, open insertion of an arthroscope (2.4-mm or 2.8-mm optics), to visualize the articular surface and fracture reduction. MAIN OUTCOME MEASUREMENTS: Ability to detect residual fracture depression or gap after previous open reduction under fluoroscopic guidance. RESULTS: An open fracture reduction with fluoroscopic guidance was performed in all cases. In 7 cases, open reduction and fluoroscopy resulted in satisfactory fracture reduction (fluoroscopy group). In 10 of 17 cases, subsequent "fracturoscopy" showed persistent fracture depression (>=2 mm, fracturoscopy group) with the need for intraoperative correction. Patients in the fracturoscopy group demonstrated significantly greater preoperative fragment depression (12.55 +/- 6.56 mm) and a larger preoperative fracture gap (7.83 +/- 5.49 mm) compared with patients with a satisfactory reduction under fluoroscopy (depression 4.97 +/- 4.02 mm, P = 0.016; gap 2.47 +/- 1.07 mm, P = 0.023). Fluoroscopy was not successful in achieving satisfactory reduction in cases in which the postero-latero-central region was affected (P = 0.004, chi test). Postoperative computed tomography demonstrated satisfactory articular reconstruction in all cases. CONCLUSIONS: Intraoperative fracturoscopy permitted a significantly improved visualization of fracture fragment displacement, specifically in the postero-latero-central region of the tibial plateau, as compared with fluoroscopy. Fracturoscopy is recommended for fractures involving the postero-latero-central region of the tibial plateau. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26978134 TI - Outcomes Over a Decade After Surgery for Unstable Ankle Fracture: Functional Recovery Seen 1 Year Postoperatively Does Not Decay With Time. AB - OBJECTIVES: To evaluate long-term clinical and radiographic outcomes after surgical fixation of unstable ankle fractures. DESIGN: Prospective follow-up study. SETTING: Academic medical center with 2 Level-I trauma centers and a tertiary care center. PATIENTS: One hundred forty-one patients who underwent surgical repair of an unstable ankle fracture. INTERVENTION: Open reduction internal fixation of an unstable ankle fracture. MAIN OUTCOME MEASUREMENTS: Short Musculoskeletal Function Assessment (SMFA) scores and radiographic outcomes based on the van Dijk criteria at a mean of 11.6 years follow-up. RESULTS: Of the 281 patients meeting the inclusion criteria for this study, follow-up data were obtained from 141 patients (50%), at a mean of 11.6 years after surgery. Overall, mean long-term SMFA scores were improved when compared with scores at 1 year. The American Society of Anesthesiologists class 1 or 2 was found to be a significant predictor of recovery based on SMFA scores. Sixty-three percent of follow-up radiographs demonstrated evidence of radiographic arthritis, including 31% with mild osteoarthritis, 22% with moderate osteoarthritis, and 10% with severe osteoarthritis. Fracture dislocation at injury was found to be a significant predictor of radiographic posttraumatic osteoarthritis at latest follow-up. One patient (0.7%) underwent a tibiotalar fusion secondary to symptomatic posttraumatic arthrosis. One patient (0.7%) underwent total ankle replacement due to severe osteoarthritis. CONCLUSIONS: Our data indicate that over a decade after ankle fracture fixation, most of the patients are doing well. Despite the presence of radiographic arthritis in 63% of patients, few experience pain or have restrictions in function, and mean long-term functional outcome scores are improved when compared with scores at 1 year. Patients undergoing operative fixation of unstable ankle fractures can anticipate functional outcomes that are maintained over time. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26978136 TI - Efficacy of Local Administration of Tranexamic Acid for Blood Salvage in Patients Undergoing Intertrochanteric Fracture Surgery. AB - OBJECTIVES: The primary aim of this study was to assess whether local administration of tranexamic acid (TXA) reduced the need for a blood transfusion in elderly patients treated with an intramedullary (IM) nail for an intertrochanteric fracture. DESIGN: Randomized prospective trial. SETTING: Academic level 1 trauma center. PATIENTS: Two hundred patients (200 fractures) over 65 years with an intertrochanteric fracture treated by IM nail between April 1, 2012, and March 31, 2014. INTERVENTION: Subfascial administration of 3 g of TXA around the fracture site at the end of the surgical procedure, versus a control group without TXA. Follow-up ranged from 12 to 24 months. MAIN OUTCOME MEASURES: Group differences in number of transfused packed red blood cell (PRBC) units, and hematocrit, hemoglobin, and platelet count. RESULTS: There was a 43% reduction in transfusion requirements in the TXA group (P < 0.01). Twenty-seven units of PRBC were transfused in 22/100 patients in the TXA group, whereas 48 PRBC units were transfused in 29/100 patients in control group. There was no difference between the 2 groups in terms of late complications and overall mortality rate. CONCLUSIONS: Subfascial administration of TXA around the fracture site in elderly patients undergoing IM nailing for intertrochanteric fractures is safe and cost-effective. A significant reduction in blood loss and transfused blood units, and health care cost can be achieved. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 26978135 TI - The 6-Hour Rule for Surgical Debridement of Open Tibial Fractures: A Systematic Review and Meta-Analysis of Infection and Nonunion Rates. AB - OBJECTIVES: The aim of this study was a systematic review and meta-analysis of studies comparing early (<6 hours) versus late (>6 hours) surgical debridement of open tibial fractures, with regards to infection and nonunion rates. METHODS: A systematic literature search of MEDLINE, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature (1961 to present), Allied and Complementary Medicine, and COCHRANE databases was conducted using any combination of the key words: "open," "tibial," and "fractures." After appropriate screening, 7 studies were included for analysis. Inclusion criteria were studies assessing the relation between time to debridement from injury and infection and/or nonunion rates. RESULTS: Three studies (n = 365) evaluated overall infection rates that varied from 7.7% to 8.9% in the early group versus 1%-18.5% in the late group. Three studies (n = 197) evaluated deep infection rates that varied from 13% to 18.5% in the early group versus 7.1%-18.6% in the late group. Four studies (n = 245) evaluated nonunion rates that varied from 13.2% to 26.1% in the early group versus 0%-32.6% in the late group. Meta analysis showed no statistical difference between groups with regards to overall infection rates (risk ratio = 1.32; 95% CI, 0.54-3.23; P = 0.55), deep infection rates (risk ratio = 0.99; 95% CI, 0.48-2.07; P = 0.98), and nonunion rates (risk ratio = 1.49; 95% CI, 0.64-3.49; P = 0.36). CONCLUSIONS: The available literature suggests that there is no obvious difference in the overall/deep infection and nonunion rates between open tibial fractures debrided within 6 hours and those debrided at more than 6 hours. The findings presented here would appear to indicate that judicious delays of greater than 6 hours may not result in a significantly increased risk of adverse events or peri-operative morbidity. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 26978137 TI - Biomechanical Contribution of Tension-Reducing Rotator Cuff Sutures in 3-Part Proximal Humerus Fractures. AB - OBJECTIVES: Using a cadaveric 3-part fracture model and cyclic loading protocol, our study objectives were to quantify the stabilizing effect of tension-reducing rotator cuff sutures in terms of fracture displacement across the surgical neck and greater tuberosity compared with a control group in which no sutures were used. METHODS: Six matched pairs of fresh frozen specimens underwent a standardized, 3-part, proximal humerus fracture and were split into 2 groups. The control group had the fracture fixed with a plate and screw construct only while the experimental group had additional suture fixation through the plate to each rotator cuff tendon. Active abduction through the rotator cuff was simulated for 100, 200, 300, and 400 cycles and to failure at 1000 N. A Mann-Whitney U test compared cyclic displacement of the greater tuberosity and surgical neck fracture gaps and load to failure between the 2 groups. RESULTS: There was no significant difference (P > 0.05) in fracture gap between fixation methods at the surgical neck at 100 (P = 0.13), 200 (P = 0.07), 300 (P = 0.49), and 400 (P = 0.07) cycles. There was no significant difference (P > 0.05) between fixation methods in the fracture gap at the greater tuberosity at 100 (P = 0.39), 200 (P = 1.00), 300 (P = 0.31), and 400 (P = 0.59) cycles. There was no significant difference (P > 0.5) at 1000 N at the surgical neck (P = 0.70) or the greater tuberosity (P = 0.39). CONCLUSIONS: Tension-relieving rotator cuff sutures do not add stability to the repair of 3-part proximal humerus fractures. Varus collapse and greater tuberosity displacement are common complications associated with 3-part fractures. No mechanical data exist to demonstrate benefit of adding suture to a plate and screw construct for limiting fracture displacement. PMID- 26978138 TI - Achieving Anatomic Acetabular Fracture Reduction-When is the Best Time to Operate? AB - OBJECTIVES: We hypothesize that earlier operative intervention for acetabular fractures improves the probability of achieving an anatomic reduction. DESIGN: Retrospective review. SETTING: Academic level I trauma center. PATIENTS/PARTICIPANTS: Six hundred fifty acetabular fractures treated through open reduction and internal fixation (ORIF) between September 2001 and February 2014. INTERVENTION: Acetabular fracture ORIF. MAIN OUTCOME MEASUREMENTS: Reduction quality was assessed through postoperative radiographs. Displacement of <=1 mm was considered an anatomic reduction, 2-3 mm imperfect, and >3 mm poor. RESULTS: Anatomic reductions were observed in 85% (n = 553) of cases, imperfect reductions in 11% (n = 74) of cases, and poor reductions in 4% (n = 23) of cases. Patients with anatomic reductions had significantly shorter times from injury to ORIF [odds ratio (OR) interval] (median, 3 d) when compared with either imperfect (median, 4.5 days, P = 0.02) or poor reductions (median, 7 days, P < 0.001) reductions. The OR interval of imperfect reductions was also significantly shorter than that of poor reductions (P = 0.02). Logistic regression analysis demonstrated that OR interval had an effect of -0.12, meaning that the log odds of anatomic reduction decreases by 0.12 with each day from injury to ORIF. CONCLUSION: The interval from injury to operative fixation of acetabular fractures affects reduction quality. Earlier intervention improves the probability of achieving an anatomic reduction; therefore, ORIF should be performed as early as possible, provided the patient is optimized for surgery. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 26978139 TI - Effect of Real-Time Feedback on Screw Placement Into Synthetic Cancellous Bone. AB - OBJECTIVES: The objective of this study is to evaluate whether real-time torque feedback may reduce the occurrence of stripping when inserting nonlocking screws through fracture plates into synthetic cancellous bone. METHODS: Five attending orthopaedic surgeons and 5 senior level orthopaedic residents inserted 8 screws in each phase. In phase I, screws were inserted without feedback simulating conventional techniques. In phase II, screws were driven with visual torque feedback. In phase III, screws were again inserted with conventional techniques. Comparison of these 3 phases with respect to screw insertion torque, surgeon rank, and perception of stripping was used to establish the effects of feedback. RESULTS: Seventy-three of 239 screws resulted in stripping. During the first phase, no feedback was provided and the overall strip rate was 41.8%; this decreased to 15% with visual feedback (P < 0.001) and returned to 35% when repeated without feedback. With feedback, a lower average torque was applied over a narrower torque distribution. Residents stripped 40.8% of screws compared with 20.2% for attending surgeons. Surgeons were poor at perceiving whether they stripped. CONCLUSIONS: Prevention and identification of stripping is influenced by surgeon perception of tactile sensation. This is significantly improved with utilization of real-time visual feedback of a torque versus roll curve. This concept of real-time feedback seems beneficial toward performance in synthetic cancellous bone and may lead to improved fixation in cancellous bone in a surgical setting. PMID- 26978140 TI - Ferdinand Hasbrouck's Nitrous Oxide Caper--Which One? PMID- 26978142 TI - Of Blurbs and Bromides--Gelett Burgess Asks, "Are You a Bromide?". PMID- 26978141 TI - When Seconds Count, Buy More Time: The Oxygen Reserve Index and its Promising Role in Patient Monitoring and Safety. PMID- 26978143 TI - Oxygen Reserve Index: A Novel Noninvasive Measure of Oxygen Reserve--A Pilot Study. AB - BACKGROUND: Pulse oximetry provides no indication of downward trends in PaO2 until saturation begins to decrease. The Oxygen Reserve Index (ORI) is a novel pulse oximeter-based nondimensional index that ranges from 1 to 0 as PaO2 decreases from about 200 to 80 mmHg and is measured by optically detecting changes in SvO2 after SaO2 saturates to the maximum. The authors tested the hypothesis that the ORI provides a clinically important warning of impending desaturation in pediatric patients during induction of anesthesia. METHODS: After preoxygenation, anesthesia induction, and tracheal intubation, the anesthesia circuit was disconnected and oxygen saturation was allowed to decrease to 90% before ventilation recommenced. The ORI and SpO2 values were recorded from a Masimo Pulse Co-Oximeter Sensor at the beginning of apnea, beginning and end of intubation, beginning and end of the ORI alarm, and 2 min after reoxygenation. RESULTS: Data from 25 healthy children, aged 7.6 +/- 4.6 yr, were included in the analysis. During apnea, the ORI slowly and progressively decreased over a mean of 5.9 +/- 3.1 min from 0.73 +/- 0.16 at the beginning of apnea to 0.37 +/- 0.11. SpO2 remained 100% throughout this initial period. Concurrently with alarm activation, the ORI began to decrease rapidly, and in median of 31.5 s (interquartile range, 19 to 34.3 s), saturation decreased to 98%. CONCLUSIONS: In this pilot study, the ORI detected impending desaturation in median of 31.5 s (interquartile range, 19-34.3 s) before noticeable changes in SpO2 occurred. This represents a clinically important warning time, which might give clinicians time for corrective actions. PMID- 26978145 TI - Advertising and Uncovering E. H. Neiman's "New Anaesthetic". PMID- 26978144 TI - Self-reported Mobility in Older Patients Predicts Early Postoperative Outcomes after Elective Noncardiac Surgery. AB - BACKGROUND: Specific geriatric assessment tools may complement traditional perioperative risk stratification. The aim of this study was to evaluate whether self-reported mobility is predictive of postoperative outcomes in older patients undergoing elective noncardiac surgery. METHODS: Patients aged 69 yr or older (n = 197) underwent (1) traditional risk assessments (American Society of Anesthesiologists physical status classification and Revised Cardiac Risk Index), (2) five-point frailty evaluation, (3) self-reported mobility assessment using the Mobility Assessment Tool-short form (range, 30.21 [poor] to 69.76 [excellent]), and (4) measurements of high-sensitivity C-reactive protein. Outcomes were postoperative complications, time to discharge, and nursing home placement (NHP). RESULTS: In the sample of this study (mean age, 75 +/- 5 yr; 51% women), 72% had intermediate- or high-risk surgery. Median time to discharge was 3 days (interquartile range, 1 to 4 days). Thirty patients (15%) developed postoperative complications, and 27 (13%) required NHP. After controlling for age, sex, body mass index, pain score, Revised Cardiac Risk Index, American Society of Anesthesiologist physical status, surgical risk, and high-sensitivity C-reactive protein, worse self-reported mobility (per 10-point decrease in Mobility Assessment Tool, which is equivalent to 1 SD) was associated with more postoperative complications (odds ratio [OR], 1.69; 95% CI, 1.05 to 2.73), later time to discharge (hazards ratio, 0.81; 95% CI, 0.68 to 0.96), and increased NHP (OR, 2.01; 95% CI, 1.13 to 3.56). By using the same model, intermediate frailty or frailty increased NHP (OR, 3.11; 95% CI, 1.02 to 9.54) but was not related to either postoperative complications or time to discharge. CONCLUSIONS: Preoperative self-reported mobility using a novel and brief assessment may help identify elderly patients at risk for adverse postoperative events. PMID- 26978146 TI - Down-regulation of MicroRNA-31 in CD4+ T Cells Contributes to Immunosuppression in Human Sepsis by Promoting TH2 Skewing. AB - BACKGROUND: Immunosuppression has been recognized as a major cause of sepsis related mortality. Currently, there is much interest in identifying central hubs controlling septic immunoparalysis. In this context, in this study, the authors investigate the role of microRNA-31 (miR-31) as a regulator of T cell functions. METHODS: Primary human T cells were separated from healthy volunteers (n = 16) and from sepsis patients by magnetic beads (n = 23). Expression of mRNA/microRNA (miRNA) was determined by real-time polymerase chain reaction. Gene silencing was performed by small interfering RNA transfection, and miRNA-binding sites were validated by reporter gene assays. Effects of miR-31 or anti-miR-31 transfection were analyzed by real-time polymerase chain reaction, Western blotting, and flow cytometry. RESULTS: Overexpression of miR-31 in stimulated CD4 T cells promoted a proinflammatory phenotype with increased levels of interferon-gamma (1.63 +/- 0.43; P = 0.001; means +/- SD) and reduced expression of interleukin (IL)-2 (0.66 +/- 0.19; P = 0.005) and IL-4 (0.80 +/- 0.2; P = 0.0001). In contrast, transfection of anti-miR-31 directed cells toward a TH2 phenotype. Effects on IL 2 and IL-4 were mediated by targeting of nuclear factor-kappa B-inducing kinase and factor-inhibiting hypoxia-inducible factor-1alpha. Interferon-gamma, however, was influenced via control of signaling lymphocytic activation molecule (SLAM) associated protein, an essential adaptor molecule of immunomodulatory SLAM receptor signaling, which was identified as a novel target gene of miR-31. In sepsis patients, an epigenetically driven down-regulation of miR-31 was found (0.44 +/- 0.25; P = 0.0001), associated with increased nuclear factor-kappa B inducing kinase, factor-inhibiting hypoxia-inducible factor-1alpha, SLAM associated protein expression, and a cytokine shift toward TH2. CONCLUSIONS: In this study, the authors provide novel evidence of miR-31 as an emerging key posttranscriptional regulator of sepsis-associated immunosuppression. The study results contribute to a further understanding of septic immunoparalysis and provide new perspectives on miRNA-based diagnostic approaches. PMID- 26978147 TI - Techniques to Minimize Posterior Wall Puncture during Internal Jugular Vein Cannulation. PMID- 26978148 TI - In Reply. PMID- 26978149 TI - One Size Does Not Fit All. PMID- 26978159 TI - Unraveling the Neurobiology of Consciousness: Anesthesia, Loss of Behavioral Response to Stimuli, and Functional Connectivity in the Brain. PMID- 26978150 TI - In Reply. PMID- 26978161 TI - Prevalence of Complementary and Alternative Medicine Use in the General Population in the Czech Republic. AB - BACKGROUND: Prevalence rates of complementary and alternative medicine (CAM) use are still missing for some European countries, especially in the East. Thus, we measured patterns and determinants of CAM use among a representative sample of the general population in the Czech Republic. METHODS: A cross-sectional survey was conducted. A sex-, age- and region-stratified sample of citizens aged 15 and older were randomly selected from voter registration lists (n = 8,639,375). RESULTS: Overall, 76.0% (n = 1,365) of the respondents reported use of one or more CAM modalities during the past 30 days. The top five CAM modalities used were vitamins/minerals (54.6%), herbal remedies (47.8%), massage (19.9%), relaxation techniques (9.5%), and dietary supplements excluding vitamins/minerals (9.2%). Prevention (82.0%) was the primary reason for CAM use. Only 15.9% of CAM users employed it for therapeutic purposes. The most commonly treated ailments were respiratory (35.0%) and musculoskeletal (33.6%) disorders. CONCLUSION: The prevalence of CAM use in the Czech Republic is high, especially among people who apply CAM for self-treatment prior to seeing a doctor. Half of the study population combined CAM with conventional medical treatment, which may result in potential harm to the patient. Healthcare providers as well as the public should be educated about effective and safe use of CAM. PMID- 26978160 TI - Tuberculous Prostatic Abscess with Prostatorectal Fistula after Intravesical Bacillus Calmette-Guerin Immunotherapy. AB - Intravesical bacillus Calmette-Guerin (BCG) immunotherapy is a common treatment modality for bladder cancer after transurethral resection of a bladder tumor. This therapy is generally safe, and development of a prostatic abscess with a prostatorectal fistula after intravesical BCG immunotherapy is a very rare complication. This finding was incidentally obtained by the authors, who examined a patient with colonoscopy for evaluation of abdominal pain. The patient was successfully treated with antitubercular drugs. To the authors' knowledge, this is the first report of a patient with a tuberculous prostatic abscess with prostatorectal fistula after BCG immunotherapy in South Korea. PMID- 26978162 TI - Pre-hospital versus in-hospital initiation of cooling for survival and neuroprotection after out-of-hospital cardiac arrest. AB - BACKGROUND: Targeted temperature management (also known under 'therapeutic hypothermia', 'induced hypothermia'", or 'cooling') has been shown to be beneficial for neurological outcome in patients who have had successful resuscitation from sudden cardiac arrest, but it remains unclear when this intervention should be initiated. OBJECTIVES: To assess the effects of pre hospital initiation of cooling on survival and neurological outcome in comparison to in-hospital initiation of cooling for adults with pre-hospital cardiac arrest. SEARCH METHODS: We searched CENTRAL, MEDLINE, EMBASE, CINAHL, BIOSIS, and three trials registers from inception to 5 March 2015, and carried out reference checking, citation searching, and contact with study authors to identify additional studies. SELECTION CRITERIA: We searched for randomized controlled trials (RCTs) in adults with out-of-hospital cardiac arrest comparing cooling in the pre-hospital setting to in-hospital cooling. Our primary outcomes were survival and neurological outcome; our secondary outcomes were adverse events, quality of life, and length of stay in the intensive care unit (ICU) and in the hospital. DATA COLLECTION AND ANALYSIS: We used Cochrane's standard methodological procedures. MAIN RESULTS: We included seven RCTs (2369 participants randomized) on the induction of pre-hospital cooling in comparison to in-hospital cooling. There was considerable methodological heterogeneity and risk of bias mainly due to deficits in the administration of cooling, therefore we refrained from pooling the results for survival and neurological outcome and we presented the results for each study separately. Adverse events were rare: based on four studies with 1713 adults pre-hospital induction of cooling may increase the risk of cardiac re-arrests. Risk of bias within the seven individual studies was generally moderate. Overall the quality of the evidence was very low. This was mainly driven by inconsistency and low precision. AUTHORS' CONCLUSIONS: Currently, there is no convincing evidence to clearly delineate beneficial or harmful effects of pre-hospital induction of cooling in comparison to in-hospital induction of cooling. This conclusion is based on very low quality evidence. PMID- 26978163 TI - Loss of Maspardin Attenuates the Growth and Maturation of Mouse Cortical Neurons. AB - BACKGROUND: Mast syndrome, an autosomal recessive, progressive form of hereditary spastic paraplegia, is associated with mutations in SPG21 loci that encode maspardin protein. Although SPG21-/- mice exhibit lower limb dysfunction, the role of maspardin loss in mast syndrome is unclear. OBJECTIVE: To test the hypothesis that loss of maspardin attenuates the growth and maturation of cortical neurons in SPG21-/- mice. METHODS AND RESULTS: In a randomized experimental design SPG21-/- mice demonstrated significantly less agility and coordination compared to wild-type mice in beam walk, ledge, and hind limb clasp tests for assessing neuronal dysfunction (p <= 0.05). The SPG21-/- mice exhibited symptoms of mast syndrome at 6 months which worsened in 12-month-old cohort, suggesting progressive dysfunction of motor neurons. Ex vivo, wild-type cortical neurons formed synapses, ganglia and aggregates at 96 h, whereas SPG21-/- neurons exhibited attenuated growth with markedly less axonal branches. Additionally, epidermal growth factor markedly promoted the growth and maturation of SPG21+/+ cortical neurons but not SPG21-/- neurons. Consequently, quantitative RT-PCR identified a significant reduction in the expression of a subset of EGF-EGFR signaling targets. CONCLUSIONS: Our current study uncovered a direct role for maspardin in normal and EGF-induced growth and maturation of primary cortical neurons. The loss of maspardin resulted in attenuated growth, axonal branching, and attenuation of EGF signaling. Reinstating the functions of maspardin may reverse hind limb impairment associated with neuronal dysfunction in mast syndrome patients. PMID- 26978164 TI - Rapid evolution of microbe-mediated protection against pathogens in a worm host. AB - Microbes can defend their host against virulent infections, but direct evidence for the adaptive origin of microbe-mediated protection is lacking. Using experimental evolution of a novel, tripartite interaction, we demonstrate that mildly pathogenic bacteria (Enterococcus faecalis) living in worms (Caenorhabditis elegans) rapidly evolved to defend their animal hosts against infection by a more virulent pathogen (Staphylococcus aureus), crossing the parasitism-mutualism continuum. Host protection evolved in all six, independently selected populations in response to within-host bacterial interactions and without direct selection for host health. Microbe-mediated protection was also effective against a broad spectrum of pathogenic S. aureus isolates. Genomic analysis implied that the mechanistic basis for E. faecalis-mediated protection was through increased production of antimicrobial superoxide, which was confirmed by biochemical assays. Our results indicate that microbes living within a host may make the evolutionary transition to mutualism in response to pathogen attack, and that microbiome evolution warrants consideration as a driver of infection outcome. PMID- 26978167 TI - [The metabolic memory phenomenon in predicting a risk for vascular complications in diabetes mellitus]. AB - The paper presents data on positive and negative metabolic memory phenomena in patients with type 1 and type 2 diabetes mellitus (DM) as exemplified by the long term randomized trials DCCT, UKPDS, ACCORD, VADT, and ADVANCE. It discusses the role of metabolic memory in predicting a risk for vascular complications in DM. Ideas on the mechanisms of this phenomenon, which are based on the activation of oxidative stress, the production of irreversible glycation products, and epigenetic disorders, are given. PMID- 26978166 TI - Physical Exam Risk Factors for Lower Extremity Injury in High School Athletes: A Systematic Review. AB - OBJECTIVE: A stated goal of the preparticipation physical evaluation (PPE) is to reduce musculoskeletal injury, yet the musculoskeletal portion of the PPE is reportedly of questionable use in assessing lower extremity injury risk in high school-aged athletes. The objectives of this study are: (1) identify clinical assessment tools demonstrated to effectively determine lower extremity injury risk in a prospective setting, and (2) critically assess the methodological quality of prospective lower extremity risk assessment studies that use these tools. DATA SOURCES: A systematic search was performed in PubMed, CINAHL, UptoDate, Google Scholar, Cochrane Reviews, and SportDiscus. Inclusion criteria were prospective injury risk assessment studies involving athletes primarily ages 13 to 19 that used screening methods that did not require highly specialized equipment. Methodological quality was evaluated with a modified physiotherapy evidence database (PEDro) scale. MAIN RESULTS: Nine studies were included. The mean modified PEDro score was 6.0/10 (SD, 1.5). Multidirectional balance (odds ratio [OR], 3.0; CI, 1.5-6.1; P < 0.05) and physical maturation status (P < 0.05) were predictive of overall injury risk, knee hyperextension was predictive of anterior cruciate ligament injury (OR, 5.0; CI, 1.2-18.4; P < 0.05), hip external:internal rotator strength ratio of patellofemoral pain syndrome (P = 0.02), and foot posture index of ankle sprain (r = -0.339, P = 0.008). CONCLUSIONS: Minimal prospective evidence supports or refutes the use of the functional musculoskeletal exam portion of the current PPE to assess lower extremity injury risk in high school athletes. Limited evidence does support inclusion of multidirectional balance assessment and physical maturation status in a musculoskeletal exam as both are generalizable risk factors for lower extremity injury. PMID- 26978165 TI - Evidence of horizontal gene transfer between obligate leaf nodule symbionts. AB - Bacteria of the genus Burkholderia establish an obligate symbiosis with plant species of the Rubiaceae and Primulaceae families. The bacteria, housed within the leaves, are transmitted hereditarily and have not yet been cultured. We have sequenced and compared the genomes of eight bacterial leaf nodule symbionts of the Rubiaceae plant family. All of the genomes exhibit features consistent with genome erosion. Genes potentially involved in the biosynthesis of kirkamide, an insecticidal C7N aminocyclitol, are conserved in most Rubiaceae symbionts. However, some have partially lost the kirkamide pathway due to genome erosion and are unable to synthesize the compound. Kirkamide synthesis is therefore not responsible for the obligate nature of the symbiosis. More importantly, we find evidence of intra-clade horizontal gene transfer (HGT) events affecting genes of the secondary metabolism. This indicates that substantial gene flow can occur at the early stages following host restriction in leaf nodule symbioses. We propose that host-switching events and plasmid conjugative transfers could have promoted these HGTs. This genomic analysis of leaf nodule symbionts gives, for the first time, new insights in the genome evolution of obligate symbionts in their early stages of the association with plants. PMID- 26978168 TI - [Cardiovascular autonomic neuropathy in patients with type 2 diabetes mellitus and coronary artery disease: Diagnosis and severity assessment]. AB - AIM: To study the nature and severity of heart rate variability (HRV) and heart rate turbulence (HRT) abnormalities in patients with coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) and to assess the prevalence of cardiovascular autonomic neuropathy (CAN) and its severity in patients with T2DM concurrent with CAD. MATERIAL AND METHODS: A total of 185 patients with T2DM and/or CAD were examined and divided into 3 groups: 1) 92 patients with CAD and T2DM; 2) 43 patients with CAD without T2DM; 3) 49 patients with T2DM without CAD. All the patients underwent 24-hour ECG monitoring with HRV and HRT analysis. RESULTS: CAN was identified and the severity of CAN was assessed based on the abnormal HRV and HRT parameters. CAN, especially severe one, was more common in Group 1 (the relative risk was 3.3 [95% CI 1.3-8.2]; p<0.05), than in Group 3. In Group 1, CAN was associated with the duration of T2DM and the level of glycated hemoglobin (p<0.05). The patients with severe CAN in Group 1 showed a 4-fold higher risk for multivessel coronary artery lesions than those without CAN (p<0.05). CONCLUSION: Glycemic control quality, T2DM duration, and obvious coronary atherosclerotic lesions were demonstrated to be associated with the presence and severity of CAN. The developed methods may be used in practice to detect and more accurately determine the severity of CAN and to predict cardiovascular risk in patients with T2DM and CAD. PMID- 26978169 TI - [Risk factors and glycation end products in patients with different forms of coronary heart disease and type 2 diabetes mellitus]. AB - AIM: To determine the levels of growth factors and glycation end products in patients with different forms of coronary heart disease (CHD) and type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS: A total of 134 patients with CHD and T2DM, including 38 patients with non-ST-elevation acute coronary syndrome (ACS), were examined. The arterial and venous serum levels of basic fibroblast growth factor beta (FGF-beta), transforming growth factor-beta (TGF-beta), placental growth factor (PlGF), advanced glycation end products (AGEs) and their receptors (RAGE) were estimated in all the patients. RESULTS: A direct correlation was found between the degree of arterial stenosis and the level of growth factors and AGEs in the patients with T2DM; there was also a direct correlation of the examined factors with lipid metabolic parameters. There was a significant two-fold increase in FGF-beta, PlGF, and RAGE levels in the patients with ACS. CONCLUSION: Hyperglycemia was found to negatively affect the progression of atherosclerotic changes in the vessel wall and on that of fibrotic processes. PMID- 26978170 TI - [The state of the great arteries in type 2 diabetes mellitus patients with obstructive sleep apnea syndrome]. AB - AIM: To evaluate the impact of hyperglycemia concurrent with obstructive sleep apnea syndrome (OSAS) on endothelial function (EF) and vessel remodeling in patients with Grade 1-2 hypertension. MATERIAL AND METHODS: A total of 101 patients with Grade 1-2 hypertension were examined. A study group (SG) consisted of 74 hypertensive patients with type 2 diabetes mellitus (T2DM). A control group (CG) comprised 27 persons with isolated blood pressure (BP) elevation. The patients with T2DM underwent cardiorespiratory sleep monitoring, the readings of which were used to divide SG into 2 subgroups: 1) patients with an apnea-hypopnea index of <30 episodes/h (SG-1); 2) those with an index of >30 episodes/h (SG-2). 24-hour BP and vascular stiffness monitoring was made; EF was evaluated; common carotid artery diameter (CCAD) and intima-media thickness (IMT) were determined. RESULTS: The diabetic patients showed lower central diastolic BP and higher aortic pulse BP. Unlike the comparison group, the diabetic patients with severe OSAS were found to have the highest central pulse wave propagation velocity at night. There was a preponderance of an average nocturnal arterial rigidity index, average daily and average nocturnal BP rising rates, and shorter reflected wave propagation time in the diabetic patients. The mean level of flow-mediated vasodilation was significantly reduced in SG-2. The diabetic patients, unlike the controls, were ascertained to have decreased absolute responsiveness index values. There were increases in IMT and CCAD in SG-2. CONCLUSION: OSAS worsens EF and vessel rigidity in patients with T2DM concurrent with hypertension. PMID- 26978171 TI - [Markers of visceral adipose tissue metabolic abnormalities in patients with coronary atherosclerosis in relation to the presence of type 2 diabetes mellitus]. AB - AIM: To assess the specific features of visceral adipose tissue metabolism in patients with coronary atherosclerosis, complicated or uncomplicated type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS: A cohort of 429 patients (325 men and 104 women; mean age, 61.3+/-9.4 years) with coronary atherosclerosis who had been admitted to the National Research Centre for Preventive Medicine, Ministry of Health of Russia, to undergo coronarography (CG) and to receive high-tech treatments and met the criteria for being included in and excluded from this investigation, was examined. The Gensini scoring scale was used to estimate the magnitude of coronary atherosclerosis from CG RESULTS: Carotid artery duplex ultrasound scanning estimating the intima-media thickness was performed in 48% of the patients. DM was diagnosed from examination results (fasting plasma glucose >=7.0 mmol/l and glycated hemoglobin >6.5%) and an endocrinologist's report. 94% of the patients took statins. RESULTS: Overall, 18% of the examinees had DM that was 2.5 times more common in the women than in the men (32.7 and 13.2%, respectively (p=0.000). The diabetic and non-diabetic patients showed no significant differences in age: 62.9+/-8.3 and 60.9+/-9.6 years, respectively (p=0.105). There were statistically significant differences in the magnitude of coronary artery atherosclerosis according to the Gensini scale in relation to the presence of T2DM; thus, the median Gensini score was 48 in the diabetic patients and 46 in the persons with no signs of the disease (Mann-Whitney test; p=0.03). Analysis of adipokine levels showed that the median leptin level was significantly higher than that in the male patients with T2DM than in the persons with no signs of the disease. In the patients with T2DM, the median adiponectin level turned out to be significantly lower in both men and women. CONCLUSION: The coronary atherosclerosis severity rated using the Gensini scale is shown to increase in the presence of T2DM. The probability of detecting obvious (>45%) carotid artery lesion is associated with the presence of DM in both men and women. The male patients with T2DM concurrent with coronary atherosclerosis are noted to have an elevated leptin level, but a lower adiponectin concentration was found in both the men and women. PMID- 26978172 TI - [Leptin, resistin, and hormonal and metabolic parameters in women with type 2 diabetes and in those with its concurrence with asthma]. AB - AIM: To investigate the relationship between resistin, adiponectin, leptin, and hormonal and metabolic parameters in patients with type 2 diabetes mellitus (T2DM) and in those with its concurrence with asthma. MATERIAL AND METHODS: Twenty-seven patients with T2DM and 26 patients with T2DM concurrent with asthma were examined. The examination data of 23 apparently healthy women served as a control. Anthropometric measurements, carbohydrate and lipid metabolic parameters, and leptin, resistin, adiponectin, interleukin (IL)-6 and IL-10 levels were studied. RESULTS: Hyperleptinemia, hyperresistinemia, and lower adiponectin concentrations were found in the patients with T2DM and in those with its concurrence with asthma. These changes in the patients from these groups occurred in the presence of subclinical inflammation. Obvious insulin resistance (IR) accompanied by compensatory hyperinsulinemia was identified in the examined women. The detected atherogenic dyslipidemia appeared as increases in the levels of total cholesterol (C), triglycerides, low-density lipoprotein C, and atherogenic index and as a decrease in those of high-density lipoprotein C. The women with the concurrence of the diseases showed a positive correlation of the level of resistin with insulin and the HOMA index. CONCLUSION: The patients with T2DM and those with its concurrence with asthma exhibited obvious IR accompanied by compensatory hyperinsulinemia. Hyperresistinemia plays a role in the development of IR in the concurrence of these diseases. The patients with T2DM and those with its concurrence with asthma were found to have hyperleptinemia, hyperresistinemia, and a trend for decreasing adiponectin values in the presence of subclinical inflammation. PMID- 26978173 TI - [Use of human insulin analogues in young patients with type 1 diabetes mellitus: Results of the RESULT observational program on the use of insulin glargine (Lantus) in combination with insulin glulisine (Apidra) as a basal-bolus regimen]. AB - AIM: To implement in 2009-2012 the RESULT observational program on the use of insulin glargine (Lantus) in combination with insulin glulisine (Apidra) as a basal-bolus regimen in patients with type 1 diabetes mellitus (DM) to evaluate the efficiency and safety of therapy with human insulin analogues. MATERIAL AND METHODS: The program covered 100 patients aged 19 to 25 years from 7 regions of the Russian Federation, who had had DM onset at the age of 9-13 years, were using human recombinant insulins as continuous insulin therapy, and had glycated hemoglobin (HbA1c) levels of 7 to 9%. The main inclusion criterion was switching to insulin therapy with the human insulin analogues Lantus and Apidra. RESULTS: A total 41 men and 59 women were followed up. Their mean baseline HbA1c level was 8.3+/-0.7%. After 24 months of therapy, HbA1c was significantly decreased to 7.7+/-0.7%; its change compared with that at Visit 1 was -0.6+/-0.6% (p<0.001). There was a significant reduction in fasting and postprandial blood glucose levels at 3 months of a follow-up. The number of symptomatic and asymptomatic glycemic episodes declined. No nocturnal or severe hypoglycemic episodes were recorded at 24 months of therapy. Microvascular complications did not progress during the follow-up. CONCLUSION: The use of human insulin analogues is effective and safe in treating young diabetic patients, improves their quality of life and confers no risk of asymptomatic or nocturnal hypoglycemic states. PMID- 26978175 TI - [Nonglycemic effects of incretins in patients with long-term type 1 diabetes mellitus and chronic kidney disease]. AB - AIM: To investigate the nonglycemic effects of incretins in patients with type 1 diabetes mellitus (DM1) of long duration (for more than 20 years) and chronic kidney disease. MATERIAL AND METHODS: Seventy-five patients with varying degrees of diabetic nephropathy (DN) and without this condition, including patients receiving renal replacement therapy with programmed hemodialysis and those who had undergone kidney transplantation were examined. The levels of phosphorus calcium metabolic indicators (calcium, phosphorus, parathyroid hormone, vitamin D, and fibroblast growth factor 23 (FGF-23)), the cardiac damage marker atrial natriuretic peptide, the proinflammatory markers monocyte chemoattractant protein 1 (MCP-1) and C-reactive protein (CRP) and the fibrotic marker transforming growth factor-beta, as well as those of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) were estimated in addition to conventional examination methods. All the patients underwent cardiac multislice spiral computed tomography, by calculating the Agatston index (calcium index (CI)) reflecting the degree of coronary artery calcification. RESULTS: The investigation revealed no relationship of GLP-1 and GIP levels to the presence and degree of DN in the patients of the study groups. GLP-1 was noted to be inversely related to patient age, indicating the diminished secretion of this peptide in older people. There was evidence that GLP-1 positively affected blood lipid composition (total cholesterol: r=-0,320; p<0.05) and the magnitude of coronary artery calcification (CI: r=-0.308; p<0.05). GIP showed a differently directed effect on the proinflammatory factors: fibrinogen (r=-0.264; p<0.05), CRP (r=-0.626; p<0.05), and FGF-23 (r=-0.341; p<0.05). CONCLUSION: The investigation has demonstrated the nonglycemic effects of incretins that favorably affect the pathogenetic processes underlying the late complications of DM1. The findings point to the potential efficacy of incretin-based drugs in preventing and treating the late complications of DM, which necessitates the conduction of larger investigations. PMID- 26978174 TI - [Intercurrent and autoimmune processes in type 1 diabetes mellitus]. AB - AIM: To estimate the prevalence of autoantibodies pathognomonic for autoimmune diseases of connective tissue and liver in patients with type 1 diabetes mellitus (DM1) and to study their clinical features in patients positive for these indicators. MATERIAL AND METHODS: A total of 84 patients (39 men and 45 women) with DM1 divided into 2 groups were examined. Biochemical, immunological, and instrumental examinations were performed. RESULTS: There was a high prevalence of markers of autoimmune diseases of connective tissue and liver in patients with DM1 and that of autoantibodies in those without its clinical symptoms or signs according to instrumental findings. CONCLUSION: The findings may suggest that patients with DM1 have a higher risk of concomitant autoimmune diseases with a probability of their asymptomatic course. PMID- 26978176 TI - [Urinary excretion of markers for podocyte injury in patients with diabetes mellitus]. AB - AIM: To estimate the urinary excretion of markers for podocyte injury, to specify their value for the early diagnosis of diabetic nephropathy (DN), and to access the risk of its progression in patients with diabetes mellitus (DM) with varying degrees of albuminuria/proteinuria. SUBJECT AND METHODS: Seventy-four diabetic patients (30 with type 1 DM and 44 with type 2 DM) were examined and divided into 3 groups according to the urinary concentration in one urinary portion: 1) 41 patients with normal albuminuria (NAU) (<20 mg/l); 2) 13 patients with microalbuminuria (MAU) (20-200 mg/l); 3) 20 patients with proteinuria (PU) (>200 mg/l). A control group included 10 healthy individuals. The urinary levels of the podocyte structural proteins nephrin and podocin were determined by enzyme immunoassay. RESULTS: Nephrinuria (NU) was detected in 63, 77, and 80% of the patients with NAU, MAU, and PU, respectively. Podocinuria (PDU) was found in 78, 54, and 83% of those with NAU, MAU, and PU, respectively. NU in DN with PU was significantly higher than that in DM with NAU. In the NAU, MAU, and PU subgroups, podocin excretion was equally higher and did not differ between the types of DM. There was a direct correlation of NU with albuminuria, which was stronger in the MAU subgroup. In the patients with DM with varying degrees of albuminuria, the values of NU and PDU correlated directly to serum creatinine levels and inversely with glomerular filtration rate. NU directly correlated with glycated hemoglobin levels in the patients with types 1 and 2 DM of less than 5 years' duration and a direct significant correlation of systolic blood pressure with NU was found in those with type 2 DM. CONCLUSION: Determination of urinary nephrin and podocin levels may be used for the early preclinical diagnosis of DN and the monitoring of the glomerular apparatus in DM. PMID- 26978177 TI - [Association of CTLA4 and TNF gene polymorphisms with endocrine ophthalmopathy in ethnic Russian patients with Graves' disease]. AB - AIM: To analyze the associations of the rs3087243 CTLA4 polymorphism and the rs1800629 TNF polymorphism with endocrine ophthalmopathy (EOP) in ethnic Russian patients with Graves' disease (GD). MATERIAL AND METHODS: The case-control study enrolled 205 patients with GD. The distribution of alleles and genotypes of the rs3087243 CTLA4 and rs1800629 TNF polymorphisms was studied in 141 patients with GD and EOP (a GD+EOP group) and 64 patients with GD without EOP (a GD-EOP group). The polymorphic alleles were identified by polymerase chain reaction-restriction fragment length analysis. RESULTS: The patients with GD in their history and EOP had significantly higher frequencies of A allele and AA genotype and a lower proportion of G allele and GG genotype of the rs3087243 CTLA4 polymorphism. Comparative analysis revealed no significant differences in the frequency of the alleles and genotypes of the rs1800629 TNF polymorphism. CONCLUSION: The rs3087243 CTLA4 polymorphism is associated with the risk of EOP in ethnic Russian patients with GD. PMID- 26978178 TI - [Impact of the local application of collagen on the activity of reparative processes in the lower extremity soft tissue of patients with diabetic foot syndrome]. AB - AIM: To estimate of the rate of reparative processes in the lower extremity (LE) soft tissues of patients with diabetic foot (DF) syndrome in the local application of collagen-containing dressings (CCD) versus standard medical therapy. MATERIAL AND METHODS: The clinical (sizes, tissue oxygenation), histological, and immunohistochemical markers of reparative processes in LE soft tissues were analyzed in patients with diabetes mellitus during the local application of collagen-containing wound dressings versus standard treatment. Forty-two patients with postrevascularization neuropathic and neuroischemic DF syndrome were examined after standard surgical wound treatment. In the perioperative period, 21 patients received local treatment using CCD and 21 patients had standard treatment. RESULTS: In the patients using CCD, the area and depth of wound defects could be decreased by 26.4+/-17.2 and 30.4+/-25.6%, respectively (p=0.002 vs baseline). In the control group, those were 17.0+/-19.4 and 16.6+/-21.6%, respectively (p=0.002). Percutaneous oximetry assessment indicated significantly higher local microhemodynamics in the local collagen treatment group (p<0.05). According to the data of histological examination of wound defect tissues, after 10-day treatment, Group 1 showed a 80% reduction in edema (p<0.05), a 90% disappearance of inflammatory infiltrates (p<0.05), and formation of mature granulation tissue (p<0.05). Immunohistochemical examination revealed a more pronounced rise in the count of macrophages in the derma (p<0.05). When CCD was applied, the level of matrix metalloproteinase tended to more markedly decrease as compared to that in the control group. CONCLUSION: The findings suggest that the activity of reparative processes in LE soft tissues is enhanced in diabetic patients receiving local collagen therapy versus those having standard treatment. This manifests itself as a decrease in both the area and depth of wounds, enhancement of local tissue perfusion, a reduction of inflammation and a rapider wound transfer from proliferation to the epithelialization phase, as supported by histological and immunohistochemical findings. PMID- 26978179 TI - [Adipokines and a risk for metabolic disturbances in different types of female obesity]. AB - AIM: To investigate the effects of adiponectin and leptin on the development of metabolic disturbances in women with android and gynoid fat distribution. MATERIAL AND METHODS: A total of 101 women aged 40 to 65 years were examined. Anthropometric measurements were made; overweight and obese women with a waist/hip (W/H) ratio of less than 0.83 were referred to as a gynoid fat distribution (GFD) group; and those with a W/H ratio of 0.83 or more were to an android fat distribution (AFD) group. The serum concentrations of triglycerides, high-density lipoprotein cholesterol, and glucose were measured; the levels of insulin, leptin, and adiponectin were determined by enzyme immunoassay. Insulin resistance (IR), HOMA IR, and visceral obesity index (VOI) were calculated. RESULTS: With the same excess adipose tissue accumulation, the women with GFD had a less magnitude of hormonal and metabolic disturbances than those with AFD, whose HOMA-IR also pointed to the presence of IR. VOI was insignificantly higher in the women with GFD and 2.4-fold greater than that in normal weight (NW) women. In the women with GFD and AFD, the concentration of leptin was higher than that in the NW women, which was characteristic of obesity, but the concentration of adiponectin proved to be significantly lower in the patients with AFD and to be unchanged in those with GFD as compared with that in the NW women. CONCLUSION: The women with AFD are typified by a high VOI, hypoadiponectinemia, IR, and metabolic disturbances, which determine a high risk for cardiovascular events and type 2 diabetes mellitus. In the women with GFD, obesity is associated with normal adiponectinemia and a low VOI and, in terms of hormonal and metabolic characteristics, may be characterized as metabolically healthy obesity. PMID- 26978180 TI - [Association of adiponectin gene G276T polymorphism with the development of metabolic syndrome in ethnic Kyrgyz patients]. AB - AIM: To study the association of adiponectin gene G276T (ADIPOQ) polymorphism with the development of metabolic syndrome (MS) in ethnic Kyrgyz patients. MATERIAL AND METHODS: A total of 171 patients with MS (a study group) and 117 patients without MS (a comparison group) were examined. MS was defined on the basis of the modified ATP III criteria. The genotypes of the G276T polymorphism in the adiponectin gene were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Dividing the MS and control groups by gender revealed statistically significant differences in the distribution of alleles and genotypes only among the women. There was a higher frequency of GT+TT genotypes (53% vs 34%; chi2=5.942; r=0.014) and T allele (30% vs 19%; chi2=4.489; r=0.0341) in the women with MS than in those without MS. Iin the ethnic Kyrgyz women, the T allele at the G276T polymorphic locus in the ADIPOQ gene was associated with the development of MS (odds ratio (OR)=1.82; 95% confidence interval (CI) 1.04-3.19) and type 2 diabetes mellitus (T2DM) (OR=2.63; 95% CI, 1.05-6.56 ) with the high levels of leptin (p<0.05), glucose (p<0.05), triglycerides (OR=3.06; 95% CI, 1.05-8.93), low-density lipoprotein cholesterol (OR=2.80; 95% CI, 1,07-7.31) and with the lower level of high-density lipoprotein cholesterol (OR=2.9; 95% CI, 1.15-7.24). CONCLUSION: The risk for MS, T2DM, hyperglycemia, and dyslipidemia is related to the carriage of the T allele of the G276T polymorphism in the ADIPOQ gene in ethnic Kyrgyz women. PMID- 26978181 TI - [Motor-evacuatory function of the gastrointestinal tract in metabolic syndrome]. AB - AIM: To investigate the motor-evacuatory function of the gastrointestinal tract (GIT) in metabolic syndrome (MS). MATERIAL AND METHODS: Fifty-eight patients with MS were examined. In addition to clinical findings, an integrated study of GIT motor function by peripheral electrogastroenterocolography was used. The specific features of lipid metabolism and hormonal and autonomic status were studied in patients with MS. RESULTS: The local and systemic clinical signs of small bowel lesions were noted in 82.9% of the patients with MS. There were elevated blood lipid levels in the presence of hypomotor dyskinesia of the upper GIT portions in the postprandial period. New pathogenetic trends in the role of hormones and hypersympatheticotonia in impairing the motor function of the small bowel were found in MS. CONCLUSION: The results of our investigations suggest that the found changes in GIT motor function are an important component of the complex pathogenesis of MS. PMID- 26978182 TI - 24-h activity rhythm and sleep in depressed outpatients. AB - Disturbances in sleep and circadian rest-activity rhythms are key features of depression. Actigraphy, a non-invasive method for monitoring motor activity, can be used to objectively assess circadian rest-activity rhythms and sleep patterns. While recent studies have measured sleep and daytime activity of depressed patients using wrist-worn actigraphy, the actigraphic 24-h rest-activity rhythm in depression has not been well documented. We aimed to examine actigraphically measured sleep and circadian rest-activity rhythms in depressed outpatients. Twenty patients with DSM-IV major depressive episode and 20 age- and sex-matched healthy controls participated in this study. Participants completed 7 consecutive days of all-day actigraphic activity monitoring while engaging in usual activities. For sleep parameters, total sleep time, wake after sleep onset, and sleep fragmentation index were determined. Circadian rhythms were estimated by fitting individual actigraphy data to a cosine curve of a 24-h activity rhythm using the cosinor method, which generated three circadian activity rhythm parameters, i.e., MESOR (rhythm-adjusted mean), amplitude, and acrophase. Subjective sleep was also assessed using a sleep diary and the Pittsburgh Sleep Quality Index. Patients showed significantly lower MESOR and more dampened amplitude along with significant sleep disturbances. Logistic regression analysis revealed that lower MESOR and more fragmented sleep emerged as the significant predictors of depression. Correlations between subjectively and actigraphically measured parameters demonstrated the validity of actigraphic measurements. These results indicate marked disturbances in sleep and circadian rest-activity rhythms of depression. By simultaneously measuring sleep and rest-activity rhythm parameters, actigraphy might serve as an objective diagnostic aid for depression. PMID- 26978183 TI - Implicit learning on a probabilistic classification task in adults and adolescents with Bulimia Nervosa. AB - BACKGROUND: Dysfunction in frontostriatal circuits likely contributes to impaired regulatory control in Bulimia Nervosa (BN), resulting in binge-eating and purging behaviors that resemble maladaptive habits. Less is known about the implicit learning processes of these circuits, which may contribute to habit formation. METHODS: We compared 52 adolescent and adult females with BN to 55 healthy matched-controls during performance of a probabilistic classification learning task, one form of implicit learning. Groups were compared in accuracy and response times, using mixed-models with block, age, and diagnosis as predictors, corrected for multiple comparisons with confounds covaried. RESULTS: BN participants showed differences in performance on a probabilistic classification learning task that varied by age. Adolescents with BN initially performed as accurately as healthy adolescents, but showed poorer perseverance over time. Adults with BN initially performed less accurately than healthy adults, but improved to perform equivalently. Symptom severity was associated with poorer accuracy in both adults and adolescents with BN. CONCLUSIONS: Frontostriatal dysfunction may underlie abnormalities in regulatory control and probabilistic classification learning in BN, likely contributing to the dysregulation of implicitly learned, maladaptive binge-eating and purging behaviors. Such dysfunction in BN may progress with increasing age, first manifesting in poor regulatory control over behaviors and then expanding to implicit learning processes that may underlie habitual behaviors. PMID- 26978184 TI - Exercise as a treatment for depression: A meta-analysis adjusting for publication bias. AB - The effects of exercise on depression have been a source of contentious debate. Meta-analyses have demonstrated a range of effect sizes. Both inclusion criteria and heterogeneity may influence the effect sizes reported. The extent and influence of publication bias is also unknown. Randomized controlled trials (RCTs) were identified from a recent Cochrane review and searches of major electronic databases from 01/2013 to 08/2015. We included RCTs of exercise interventions in people with depression (including those with a diagnosis of major depressive disorder (MDD) or ratings on depressive symptoms), comparing exercise versus control conditions. A random effects meta-analysis calculating the standardized mean difference (SMD, 95% confidence interval; CI), meta regressions, trim and fill and fail-safe n analyses were conducted. Twenty-five RCTs were included comparing exercise versus control comparison groups, including 9 examining participants with MDD. Overall, exercise had a large and significant effect on depression (SMD adjusted for publication bias = 1.11 (95% CI 0.79 1.43)) with a fail-safe number of 1057. Most adjusted analyses suggested publication bias led to an underestimated SMD. Larger effects were found for interventions in MDD, utilising aerobic exercise, at moderate and vigorous intensities, in a supervised and unsupervised format. In MDD, larger effects were found for moderate intensity, aerobic exercise, and interventions supervised by exercise professionals. Exercise has a large and significant antidepressant effect in people with depression (including MDD). Previous meta-analyses may have underestimated the benefits of exercise due to publication bias. Our data strongly support the claim that exercise is an evidence-based treatment for depression. PMID- 26978186 TI - Comprehensive Understanding of High Polar Polyacrylonitrile as an Effective Binder for Li-Ion Battery Nano-Si Anodes. AB - Well-defined polyacrylonitriles (PANs) with different molecular weights were synthesized through an activator regenerated by electron-transfer atom-transfer radical polymerization method and employed as binders in silicon negative electrode for lithium-ion batteries. Compared with poly(vinylidene fluoride) and carboxyl methyl cellulose as binders, the electrode performance of PANs is well improved. Specifically, at 100 mA g(-1) from 0.01 to 1.5 V, the initial discharge capacity of PAN100-based electrode is 4147.8 mA h g(-1) and still remains about 1639.6 mA h g(-1) over 50 cycles. A comprehensive understanding on the improvement mechanism is preliminarily discussed. The results indicate that the superior performance largely depends on the higher lithium ion diffusion efficiency in PAN which results from the weak interaction between lithium ions and PAN polymer chain, and the hydrogen bonds among the nitrile group (C=N) of PAN, Si nanoparticles, and the current collector, which will lead to an efficient coating of PAN with the Si particles and well-improved adhesion strength, synergistically depressing the structural deterioration of silicon electrodes. PMID- 26978187 TI - The squaramide-catalyzed asymmetric Michael/cyclization tandem reaction for the synthesis of chiral trifluoromethylated hydroxyimino tetrahydrobenzofuranones. AB - An enantioselective synthesis of trifluoromethylated hydroxyimino tetrahydrobenzofuranones has been developed. 1,3-Dicarbonyl carbocyclic compounds react with beta-CF3-beta-disubstituted nitroalkenes in the presence of a chiral squaramide catalyst, providing efficient access to diverse hydroxyimino tetrahydrobenzofuranones featuring a trifluoromethyl group at the C3-position of an all-carbon quaternary stereocenter with good yields (up to 81%) and enantioselectivities (up to 89% ee). PMID- 26978185 TI - Polygenic risk for type 2 diabetes mellitus among individuals with psychosis and their relatives. AB - BACKGROUND: An elevated prevalence of Type 2 diabetes (T2D) has been observed in people with psychotic disorders and their relatives compared to the general population. It is not known whether this population also has increased genetic risk for T2D. METHODS: Subjects included probands with schizophrenia, schizoaffective disorder, or psychotic bipolar I disorder, their first-degree relatives without psychotic disorders, and healthy controls, who participated in the Bipolar Schizophrenia Network for Intermediate Phenotypes study. We constructed sets of polygenic risk scores for T2D (PGRST2D) and schizophrenia (PGRSSCHIZ) using publicly available data from genome-wide association studies. We then explored the correlation of PGRST2D with psychiatric proband or relative status, and with self-reported diabetes. Caucasians and African-Americans were analyzed separately. We also evaluated correlations between PGRSSCHIZ and diabetes mellitus among Caucasian probands and their relatives. RESULTS: In Caucasians, PGRST2D was correlated with self-reported diabetes mellitus within probands, but was not correlated with proband or relative status in the whole sample. In African-Americans, a PGRST2D based on selected risk alleles for T2D in this population did not correlate with proband or relative status. PGRSSCHIZ was not correlated with self-reported diabetes within Caucasian probands. CONCLUSION: Differences in polygenic risk for T2D do not explain the increased prevalence of diabetes mellitus observed in psychosis probands and their relatives. PMID- 26978190 TI - Triplet Mediated C-N Dissociation versus Internal Conversion in Electronically Excited N-Methylpyrrole. AB - The photochemical and photophysical pathways operative in N-methylpyrrole, after excitation in the near part of its ultraviolet absorption spectrum, have been investigated by the combination of time-resolved total ion yield and photoelectron spectroscopies with high-level ab initio calculations. The results collected are remarkably different from the observations made for pyrrole and other aromatic systems, whose dynamics is dictated by the presence of pisigma* excitations on X-H (X: N, O, S, ...) bonds. The presence of a barrier along the C N dissociation coordinate that can not be tunneled triggers two alternative decay mechanisms for the S1 A" pisigma* state. While at low vibrational content the C-N dissociation occurs on the surface of a lower (3)pipi* state reached after efficient intersystem crossing, at higher excitation energies, the A" pisigma* directly internally converts to the ground state through a ring-twisted S1/S0 conical intersection. The findings explain previous observations on the molecule and may be relevant for more complex systems containing similar C-N bonds, such as the DNA nucleotides. PMID- 26978189 TI - Age-Related and Heteroplasmy-Related Variation in Human mtDNA Copy Number. AB - The mitochondrial (mt) genome is present in many copies in human cells, and intra individual variation in mtDNA sequences is known as heteroplasmy. Recent studies found that heteroplasmies are highly tissue-specific, site-specific, and allele specific, however the functional implications have not been explored. This study investigates variation in mtDNA copy numbers (mtCN) in 12 different tissues obtained at autopsy from 152 individuals (ranging in age from 3 days to 96 years). Three different methods to estimate mtCN were compared: shotgun sequencing (in 4 tissues), capture-enriched sequencing (in 12 tissues) and droplet digital PCR (ddPCR, in 2 tissues). The highest precision in mtCN estimation was achieved using shotgun sequencing data. However, capture enrichment data provide reliable estimates of relative (albeit not absolute) mtCNs. Comparisons of mtCN from different tissues of the same individual revealed that mtCNs in different tissues are, with few exceptions, uncorrelated. Hence, each tissue of an individual seems to regulate mtCN in a tissue-related rather than an individual-dependent manner. Skeletal muscle (SM) samples showed an age related decrease in mtCN that was especially pronounced in males, while there was an age-related increase in mtCN for liver (LIV) samples. MtCN in SM samples was significantly negatively correlated with both the total number of heteroplasmic sites and with minor allele frequency (MAF) at two heteroplasmic sites, 408 and 16327. Heteroplasmies at both sites are highly specific for SM, accumulate with aging and are part of functional elements that regulate mtDNA replication. These data support the hypothesis that selection acting on these heteroplasmic sites is reducing mtCN in SM of older individuals. PMID- 26978193 TI - The Lost Felice: Marsden Hartley. PMID- 26978200 TI - Does the Country of Origin Matter in Health Care Innovation Diffusion? PMID- 26978201 TI - Biomarkers and Surrogate Endpoints: Developing Common Terminology and Definitions. PMID- 26978203 TI - A PIECE OF MY MIND. Meeting the Organ Donor. PMID- 26978202 TI - Health Care Delivery Innovations That Integrate Care? Yes!: But Integrating What? PMID- 26978204 TI - The Enduring Evolution of the P Value. PMID- 26978205 TI - Toward High-Reliability Vaccination Efforts in the United States. PMID- 26978207 TI - Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial. AB - IMPORTANCE: Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies. OBJECTIVE: To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized. INTERVENTIONS: Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33 degrees C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group). MAIN OUTCOMES AND MEASURES: The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months. RESULTS: Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47 64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053). CONCLUSIONS AND RELEVANCE: Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00879892. PMID- 26978209 TI - Evolution of Reporting P Values in the Biomedical Literature, 1990-2015. AB - IMPORTANCE: The use and misuse of P values has generated extensive debates. OBJECTIVE: To evaluate in large scale the P values reported in the abstracts and full text of biomedical research articles over the past 25 years and determine how frequently statistical information is presented in ways other than P values. DESIGN: Automated text-mining analysis was performed to extract data on P values reported in 12,821,790 MEDLINE abstracts and in 843,884 abstracts and full-text articles in PubMed Central (PMC) from 1990 to 2015. Reporting of P values in 151 English-language core clinical journals and specific article types as classified by PubMed also was evaluated. A random sample of 1000 MEDLINE abstracts was manually assessed for reporting of P values and other types of statistical information; of those abstracts reporting empirical data, 100 articles were also assessed in full text. MAIN OUTCOMES AND MEASURES: P values reported. RESULTS: Text mining identified 4,572,043 P values in 1,608,736 MEDLINE abstracts and 3,438,299 P values in 385,393 PMC full-text articles. Reporting of P values in abstracts increased from 7.3% in 1990 to 15.6% in 2014. In 2014, P values were reported in 33.0% of abstracts from the 151 core clinical journals (n = 29,725 abstracts), 35.7% of meta-analyses (n = 5620), 38.9% of clinical trials (n = 4624), 54.8% of randomized controlled trials (n = 13,544), and 2.4% of reviews (n = 71,529). The distribution of reported P values in abstracts and in full text showed strong clustering at P values of .05 and of .001 or smaller. Over time, the "best" (most statistically significant) reported P values were modestly smaller and the "worst" (least statistically significant) reported P values became modestly less significant. Among the MEDLINE abstracts and PMC full-text articles with P values, 96% reported at least 1 P value of .05 or lower, with the proportion remaining steady over time in PMC full-text articles. In 1000 abstracts that were manually reviewed, 796 were from articles reporting empirical data; P values were reported in 15.7% (125/796 [95% CI, 13.2%-18.4%]) of abstracts, confidence intervals in 2.3% (18/796 [95% CI, 1.3%-3.6%]), Bayes factors in 0% (0/796 [95% CI, 0%-0.5%]), effect sizes in 13.9% (111/796 [95% CI, 11.6%-16.5%]), other information that could lead to estimation of P values in 12.4% (99/796 [95% CI, 10.2%-14.9%]), and qualitative statements about significance in 18.1% (181/1000 [95% CI, 15.8%-20.6%]); only 1.8% (14/796 [95% CI, 1.0%-2.9%]) of abstracts reported at least 1 effect size and at least 1 confidence interval. Among 99 manually extracted full-text articles with data, 55 reported P values, 4 presented confidence intervals for all reported effect sizes, none used Bayesian methods, 1 used false-discovery rates, 3 used sample size/power calculations, and 5 specified the primary outcome. CONCLUSIONS AND RELEVANCE: In this analysis of P values reported in MEDLINE abstracts and in PMC articles from 1990-2015, more MEDLINE abstracts and articles reported P values over time, almost all abstracts and articles with P values reported statistically significant results, and, in a subgroup analysis, few articles included confidence intervals, Bayes factors, or effect sizes. Rather than reporting isolated P values, articles should include effect sizes and uncertainty metrics. PMID- 26978212 TI - Liraglutide (Saxenda) for Weight Loss. PMID- 26978211 TI - Neck Pain, Stiffness, and Periorbital Edema in a Man With Diabetes. PMID- 26978208 TI - Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight. AB - IMPORTANCE: Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain. OBJECTIVE: To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. EXPOSURES: Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level. MAIN OUTCOME AND MEASURE: Offspring birth weight from 18 studies. RESULTS: Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 * 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP raising allele (P = 1*10(-5)), respectively. A 1-SD ( ~ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ~ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ~ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions. CONCLUSIONS AND RELEVANCE: In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight related birth outcomes. PMID- 26978210 TI - Association Between Vaccine Refusal and Vaccine-Preventable Diseases in the United States: A Review of Measles and Pertussis. AB - IMPORTANCE: Parents hesitant to vaccinate their children may delay routine immunizations or seek exemptions from state vaccine mandates. Recent outbreaks of vaccine-preventable diseases in the United States have drawn attention to this phenomenon. Improved understanding of the association between vaccine refusal and the epidemiology of these diseases is needed. OBJECTIVE: To review the published literature to evaluate the association between vaccine delay, refusal, or exemption and the epidemiology of measles and pertussis, 2 vaccine-preventable diseases with recent US outbreaks. EVIDENCE REVIEW: Search of PubMed through November 30, 2015, for reports of US measles outbreaks that have occurred since measles was declared eliminated in the United States (after January 1, 2000), endemic and epidemic pertussis since the lowest point in US pertussis incidence (after January 1, 1977), and for studies that assessed disease risk in the context of vaccine delay or exemption. FINDINGS: We identified 18 published measles studies (9 annual summaries and 9 outbreak reports), which described 1416 measles cases (individual age range, 2 weeks-84 years; 178 cases younger than 12 months) and more than half (56.8%) had no history of measles vaccination. Of the 970 measles cases with detailed vaccination data, 574 cases were unvaccinated despite being vaccine eligible and 405 (70.6%) of these had nonmedical exemptions (eg, exemptions for religious or philosophical reasons, as opposed to medical contraindications; 41.8% of total). Among 32 reports of pertussis outbreaks, which included 10,609 individuals for whom vaccination status was reported (age range, 10 days-87 years), the 5 largest statewide epidemics had substantial proportions (range, 24%-45%) of unvaccinated or undervaccinated individuals. However, several pertussis outbreaks also occurred in highly vaccinated populations, indicating waning immunity. Nine reports (describing 12 outbreaks) provided detailed vaccination data on unimmunized cases; among 8 of these outbreaks from 59% through 93% of unvaccinated individuals were intentionally unvaccinated. CONCLUSIONS AND RELEVANCE: A substantial proportion of the US measles cases in the era after elimination were intentionally unvaccinated. The phenomenon of vaccine refusal was associated with an increased risk for measles among people who refuse vaccines and among fully vaccinated individuals. Although pertussis resurgence has been attributed to waning immunity and other factors, vaccine refusal was still associated with an increased risk for pertussis in some populations. PMID- 26978213 TI - Suppression of Substance Abuse Claims in Medicaid Data and Rates of Diagnoses for Non-Substance Abuse Conditions. PMID- 26978214 TI - Dextromethorphan-Quinidine for Agitation in Alzheimer Disease. PMID- 26978215 TI - Dextromethorphan-Quinidine for Agitation in Alzheimer Disease--Reply. PMID- 26978216 TI - Preeclampsia and Congenital Heart Defects. PMID- 26978217 TI - Preeclampsia and Congenital Heart Defects--Reply. PMID- 26978218 TI - New Strategies to Treat High Cholesterol. PMID- 26978221 TI - Reducing Medical Facilities. PMID- 26978219 TI - New Strategies to Treat High Cholesterol--Reply. PMID- 26978223 TI - JAMA PATIENT PAGE. Dietary Guidelines for Americans--Eat Less Sugar. PMID- 26978226 TI - Gas-phase reactions of cyclopropenylidene with protonated alkyl amines. AB - Vinylidene carbenes (C3H2) are of high interest to interstellar, combustion, and organic chemistry. Due to their high instability, the direct experimental investigation of their chemical reactivity has rarely been achieved. Herein, we report a first study on the reactions of cyclopropenylidene (c-C3H2) with protonated alkyl amines in the gas phase using a home-built ion trap mass spectrometer. The high gas-phase basicity (GB) of ((1)A1) c-C3H2 (calculated as 920 kJ mol(-1)) facilitates the formation of a proton-bound dimer with protonated amines as the first step in the reaction. The dimer can stay as it is or rearrange to a covalent product. The formation of the covalent complex is highly exothermic and its yield is affected by the GB of alkyl amines. The highest yield (82%) was achieved when the GB of the amine was slightly lower but comparable to that of c-C3H2. Our results demonstrate a new reaction pathway of c-C3H2, which has long been considered as a "dead end" in interstellar carbon chemistry. PMID- 26978225 TI - Phenotypic and Molecular Antibiotic Resistance Determination of Airborne Coagulase Negative Staphylococcus spp. Strains from Healthcare Facilities in Southern Poland. AB - This study assessed the antimicrobial resistance of airborne Staphylococcus spp. strains isolated from healthcare facilities in southern Poland. A total of 55 isolates, belonging to 10 coagulase-negative staphylococci (CoNS) species, isolated from 10 healthcare facilities (including hospitals and outpatient units) were included in the analysis. The most frequently identified species were Staphylococcus saprophyticus and Staphylococcus warneri, which belong to normal human skin flora, but can also be the cause of common and even severe nosocomial infections. Disk diffusion tests showed that the bacterial strains were most frequently resistant to erythromycin and tetracycline and only 18% of strains were susceptible to all tested antimicrobials. Polymerase chain reaction amplification of specific gene regions was used to determine the presence of the Macrolide-Lincosamide-Streptogramin resistance mechanisms in CoNS. The molecular analysis, conducted using specific primer pairs, identified the msrA1 gene, encoding active efflux pumps in bacterial cells, as the most frequent resistance gene. As many as seven antibiotic resistance genes were found in one isolate, whereas the most common number of resistance genes per isolate was five (n = 17). It may be concluded that drug resistance was widely spread among the tested strains, but the resulting antimicrobial resistance profile indicates that in the case of infection, the use of antibiotics from the basic antibiogram group will be effective in therapy. However, before administering treatment, determination of the specific antimicrobial resistance should be conducted, particularly in the case of hospitalized patients. PMID- 26978224 TI - ClpXP and ClpAP control the Escherichia coli division protein ZapC by proteolysis. AB - The bacterial FtsZ-ring is an essential cytokinetic structure under tight spatiotemporal regulation. In Escherichia coli, FtsZ polymerization and assembly into the Z-ring is controlled on multiple levels through interactions with positive and negative regulators. Among these regulatory factors are ZapC, a Z ring stabilizer, and the conserved protease ClpXP, which has been shown to degrade FtsZ protofilaments in preference to FtsZ monomers. Here we report that ZapC and ClpX interact in a protein-protein interaction assay, and that ZapC is degraded in a ClpXP-dependent manner in vivo. The SspB adaptor protein is not required for targeting ZapC to the ClpXP proteolytic machinery. A mutation disrupting the zapC ssrA-like sequence (zapCDD) stabilizes ZapC consistent with a reduction in ClpXP-mediated ZapC degradation. ZapCDD retains the ability to interact with FtsZ and to promote bundling in vitro indicating that WT ZapC contains discrete FtsZ and ClpX recognition motifs. Additionally, ClpAP complexes are sufficient for degradation of ZapC in the absence of ClpX in vivo. Further, chromosomal expression of zapCDD suppresses filamentation of the temperature sensitive ftsZ84 mutant, confirming the role of ZapC as a Z-ring stabilizer. Lastly, changes in ClpXP and ZapC levels lead to cell division effects, likely through their roles in modulating FtsZ assembly dynamics. Taken together, our results indicate that the Z-ring stabilizer ZapC is a substrate of both ClpXP and ClpAP in vivo. Our data also point to a more complex regulatory circuit that integrates FtsZ, ClpXP and ZapC in achieving Z-ring stability in E. coli and related species. PMID- 26978227 TI - The CDC Guideline on Opioid Prescribing: Rising to the Challenge. PMID- 26978228 TI - Phenalenone Polyketide Cyclization Catalyzed by Fungal Polyketide Synthase and Flavin-Dependent Monooxygenase. AB - Phenalenones are polyketide natural products that display diverse structures and biological activities. The core of phenalenones is a peri-fused tricyclic ring system cyclized from a linear polyketide precursor via an unresolved mechanism. Toward understanding the unusual cyclization steps, the phn biosynthetic gene cluster responsible for herqueinone biosynthesis was identified from the genome of Penicillium herquei. A nonreducing polyketide synthase (NR-PKS) PhnA was shown to synthesize the heptaketide backbone and cyclize it into the angular, hemiketal containing naphtho-gamma-pyrone prephenalenone. The product template (PT) domain of PhnA catalyzes only the C4-C9 aldol condensation, which is unprecedented among known PT domains. The transformation of prephenalenone to phenalenone requires an FAD-dependent monooxygenase (FMO) PhnB, which catalyzes the C2 aromatic hydroxylation of prephenalenone and ring opening of the gamma-pyrone ring simultaneously. Density functional theory calculations provide insights into why the hydroxylated intermediate undergoes an aldol-like phenoxide-ketone cyclization to yield the phenalenone core. This study therefore unveiled new routes and biocatalysts for polyketide cyclization. PMID- 26978229 TI - [Specific features of reelin expression in the brain of fetuses and newborns with internal hydrocephalus]. AB - AIM: to study reelin expression in the neocortex of fetuses and newborns with internal hydrocephalus (HC) and to reveal its features in relation to the etiology of HC. MATERIAL AND METHODS: The brains of fetuses and newborn at 22-40 weeks' gestation with internal HC associated with Sylvian aqueduct malformation (n=9), post-inflammatory (n=4) and post-hemorrhagic (n=5) HC were examined. In a comparison group, the fragments of brain tissue with a slit-like lumen of the lateral ventricles were no more than 0.5 cm (n=20). A standard immunohistochemical method was used to reveal reelin expression in the neocortex of the anterior third of the precentral gyrus. RESULTS: HC associated with Sylvian aqueduct malformation is characterized by a negative reelin immunoexpression. In postinflammatory HC, the expression of reelin decreases significantly (p=0.025) with respect to the conditional norm and, in posthemorrhagic HC it is comparable with that in the comparison group. CONCLUSION: The features of reelin expression in the brain of fetuses and newborns at 22-40 weeks' gestation with internal HC should be considered as morphological differential and diagnostic criteria for the disease in relation to its etiology. PMID- 26978230 TI - [Immunomorphological aspects of miscarriage at late gestational ages]. AB - AIM: to reveal the morphological features of placentas and to define a role of the lectin pathway for activation of the complement system in the development of premature birth. MATERIAL AND METHODS: A complex morphological study was conducted to examine 37 placentas, 25 of which were obtained from women with clinical signs of threatened miscarriage and 12 placentas from apparently healthy pregnant women. RESULTS: Placental tissue CD59 expression was ascertained to be significantly less in the women with threatened miscarriage than in those having full-term babies. CONCLUSION: Decreased CD59 expression in threatened miscarriage at late gestational ages leads to additional activation of a maternal immune response and serves as a possible predictor for premature birth. PMID- 26978231 TI - [Histological hanges in the placenta and vascularization of its villi in early- and late-onset preeclampsia]. AB - AIM: to make a comparative histological study of the placenta and a morphometric analysis of its terminal villi in early- and late-onset preeclampsia. MATERIAL AND METHODS: Placentae from patients whose pregnancy had been complicated by the development of early- (n=26) or late-onset (n=84) preeclampsia were examined. A control group comprised placentae from 28 patients with physiological pregnancy and no extragenital diseases. The authors made a comparative histological study of placental tissue and a morphometric analysis of the terminal villi using the sections immunohistochemically stained for CD31. RESULTS: It was determined that there was a preponderance of branching angiogenesis in the preeclamptic chorionic villi and an increase in the number of syncytial nodules and microcysts in the septae in late-onset preeclampsia. Morphometric analysis of immunohistochemical placental specimens established a reduction in the sizes and vascularization indicators of terminal villi that determine the development of placental hypoxia and are more pronounced in cases of early-onset preeclampsia. PMID- 26978232 TI - [Somatostatin receptor expression in the ileal mucosa of patients with inflammatory bowel disease]. AB - AIM: to investigate the specific features of somatostatin receptor expression in the ileal mucosa of patients with inflammatory bowel disease (IBD). MATERIAL AND METHODS: Ileal biopsy specimens from 42 patients aged 22 to 55 years, including 16 patients with Crohn's disease (CD), 14 with indeterminate colitis of IBD unclassified (IBDU), and 12 with the unchanged ileal mucosa (a comparison group). Immunohistochemical examination was performed using anti-somatostatin receptor type 2 (SSTR-2) antibodies (Epitomics, USA). SSTR2-positively stained cells were counted per 100 epitheliocytes. RESULTS: There were three receptor expression types: predominantly membranous, cytoplasmic, and mixed (membranous-cytoplasmic). Calculation of cells with membranous expression indicated that the median was 1 in the patients with Crohn's disease (interquartile range (IQR) 0.5), 3 in those with IBDU (IQR 2.5), and 2 (IQR 2) in the comparison group. These indicators were 1 (IQR 2), 3 (IQR 2), and 2 (IQR 1) for cytoplasmic expression and 5 (IQR 4), 2 (IQR 3), and 3 (IQR 2) for membranous-cytoplasmic one. CONCLUSION: The number of SSTR-2-expressing cells was significantly smaller in the patients with Crohn's disease than that in those with the unchanged mucosa and in those with indeterminate (unclassified) colitis. There were three SSTR2 staining types: predominantly membranous, cytoplasmic, and mixed (membranous-cytoplasmic). The cells with membranous staining appeared to be neuroendocrine, those with cytoplasmic expression were intraepithelial T lymphocytes, and those with membranous-cytoplasmic expression were both neuroendocrine and epithelial. PMID- 26978233 TI - [Impact of preoperative drug therapy on the expression of apoptosis markers in colorectal liver metastases]. AB - AIM: to estimate the expression of p53 protein, effector caspases-3 and -7, and the antiapoptotic protein survivin in colorectal adenocarcinoma metastases to the liver in patients who have received preoperative cytotoxic and combined cytotoxic and target anti-VEGF therapies. SUBJECTS AND METHODS: Intraoperative samples from 122 patients with colorectal carcinoma metastases to the liver were immunohistologically examined. The investigation included patients who had received preoperative treatment with cytotoxic drugs, combined cytotoxic and targeted anti-VEGF therapy. A control group consisted of patients who had not received preoperative anti-tumor drug treatment. RESULTS: Expression of Caspase 3, including that of survivin, was significantly more frequently detected in the patients who had received combined cytotoxic and anti-VEGF therapy as compared to both those treated with only cytotoxic agents (p=0.00004) and the control group (p=0.0008) As compared to the latter, the women who had received cytotoxic therapy were found to have no survivin expression (p=0.015). Investigation of the expression of caspase-7 and p53 revealed no statistically significant differences between the three groups. CONCLUSION: Addition of bevacizumab to preoperative standard therapy regimens for colorectal adenocarcinoma metastases to the liver leads to activated apoptosis in tumor cells, by enhancing the expression of effector caspase 3. At the same time, standard cytotoxic chemotherapy regimens in women results in activated apoptosis, by decreasing the expression of the antiapoptotic protein survivin. PMID- 26978234 TI - [Unified requirements for the structure of the diagnosis to improving national morbidity ststistics and causes of death]. AB - The overall structure of the diagnosis should be presented underlying disease; complications of underlying disease and coexistent disease. If patient has other significant conditions contributing to the death (comorbidity), they should be included in the diagnosis after underlying disease as concurrent disease, polypathia or background diseases (condition). The category "underlying disease" should include only the disease (condition), which by itself or through the complications can lead to death and should be recorded in Part I of the medical certificate of cause of death. Other significant conditions contributing to the death (comorbidity) and defined as concurrent disease, polypathia or background diseases (condition), should be recorded in Part II of the medical certificate of cause of death. Coexistent diseases shall not be taken into account of the statistics of causes of death, and therefore they should not stand in a medical certificate of cause of death. PMID- 26978235 TI - [Von Hippel-Lindau disease type 2-related pancreatic neuroendocrine tumor and adrenal myelolipoma]. AB - The paper describes a case of von Hippel--Lindau-related pancreatic neuroendocrine tumor and adrenal myelolipoma in a 44-year-old woman. The pancreatic tumor and a left retroperitoneal mass were removed in the women in July 2014 and May 2015. Histological examination of the pancreatic tumor revealed that the latter consisted of clear cells forming tubular and tubercular structures showing the expression of chromogranin A, synaptophysin, and cytokeratins 18 and 19 and a negative response to CD10 and RCC. The adrenal medullary mass presented as clear-cell alveolar structures with inclusions of adipose tissue mixed with erythroid, myeloid, and lymphoid cells. The clear-cell component of the adrenal gland expressed neuroendocrine markers with a negative response to cytokeratins, CD10, and RCC. Molecular genetic examination yielded a signal corresponding to two copies of the VHL gene. No deletions or amplifications of the gene were detected. Cases of von Hippel--Lindau disease concurrent with adrenal pheochromocytoma and myelolipoma and simultaneous pancreatic involvement were not found in the literature. PMID- 26978236 TI - Thin Film Formation and Morphology of Electrosprayed Polydimethylsiloxane. AB - Low-voltage dielectric actuators (DEAs) can be fabricated using submicrometer thin polydimethylsiloxane (PDMS) films. The two established techniques, namely spin coating and molecular beam deposition, however, are inappropriate to produce multistack DEAs in an efficient way. Therefore, we propose an alternative deposition technique, i.e., the alternating current electrospray deposition (ACESD) of 5 vol % PDMS in ethyl acetate solution and subsequent ultraviolet light curing. Atomic force microscopy makes possible the three-dimensional analysis of cured droplet-like islands. These circular islands, prepared on 2 in. Si(100) wafers from four polymers with molecular masses between 800 and 62,700 g/mol, reveal a characteristic morphology with an increasing height-to-diameter ratio. Using the 6000 g/mol polymer for ACESD, the film morphology evolution was tracked by applying conventional optical microscopy and spectroscopic ellipsometry. When the deposition was terminated after 13 s, circular islands with a mean height of 30 nm were found, while terminating the deposition after about 155 s led to a confluent layer with a mean height of 91 +/- 10 nm. Potential electrostatic interactions between the droplets could not be identified through the analysis of spatial island distribution. Nevertheless, ACESD is a budget-priced and competitive deposition technique that can be employed to fabricate submicrometer-thin PDMS films with true nanometer roughness. PMID- 26978237 TI - LDL cholesterol response and statin adherence among high-risk patients initiating treatment. AB - OBJECTIVES: The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol treatment guideline recommends monitoring percent reduction in low-density lipoprotein cholesterol (LDL-C) among patients initiating statins as an indication of response and adherence. We examined LDL-C reduction and statin adherence among high-risk patients initiating statins in a real-world setting. STUDY DESIGN: Retrospective cohort study. METHODS: The study population included Kaiser Permanente Georgia members (n = 1066) with a history of coronary heart disease or risk equivalent(s) initiating statins in 2011. Percent change in LDL-C was defined using measurements before and 60 to 450 days after statin initiation. Statin adherence was defined by proportion of days covered, categorized as high (>=80%), intermediate (50%-79%), and low (< 50%). RESULTS: Overall, 58.4% of patients failed to achieve a >= 30% LDL-C reduction after statin initiation. The prevalences of high, intermediate, and low statin adherence were 41.3%, 23.2%, and 35.6%, respectively. Of patients with high adherence, 42.3% did not achieve a >= 30% reduction in LDL-C compared with 54.7% and 79.7% of those with intermediate and low statin adherence, respectively. After multivariable adjustment, and compared with those with high adherence, the risk ratios for not achieving a >= 30% LDL-C reduction were 1.31 (95% CI, 1.13 1.52) and 1.88 (95% CI, 1.67-2.11), for those with intermediate and low adherence. Women and African Americans were less likely to have high adherence, whereas having cardiologist visits was associated with high adherence. CONCLUSIONS: In a real-world setting, many patients did not achieve a 30% or larger LDL-C reduction. These data support the ACC/AHA recommendation to monitor LDL-C response among patients initiating statins. PMID- 26978238 TI - National estimates of price variation by site of care. AB - OBJECTIVES: Recently, researchers and policy makers have demonstrated growing interest in differences in payments across sites of care for the same healthcare service, such as in a hospital outpatient department (HOPD) versus a physician office (PO). Our objective was to examine the price differential for individuals with employer-sponsored insurance by site of care for 7 commonly performed services at the national and regional level. STUDY DESIGN: We analyzed 2008 to 2013 claims data from Truven Health MarketScan Commercial Claims and Encounters Database, containing administrative data for 44 to 53 million individuals covered by employer-sponsored health insurance. METHODS: We selected 7 services based on total payments from different clinical categories-categories in which differences in clinical quality and patient morbidity are less likely to be sources of the price differential. We calculated payment amounts at the visit level for each healthcare service by site of care, then calculated the price differential by site of care as a ratio of average HOPD price to the average PO price or average ambulatory surgery center price for the same service. RESULTS: Across all 7 services, prices at a HOPD were statistically significantly higher than payments to a PO, ranging in 2013 from 21% more for an office visit to 258% more for chest radiography. The increase in the price differentials, combined with a shift in volume in favor of hospital outpatient departments, was associated with a 44% increase in total spending between 2008 and 2013. CONCLUSIONS: Our study shows that price differentials by site of care exist at a national level, and that they are increasing over time. PMID- 26978239 TI - Organizational structure for chronic heart failure and chronic obstructive pulmonary disease. AB - OBJECTIVES: In contrast to chronic heart failure (CHF), measures of quality of care for chronic obstructive pulmonary disease (COPD) are poor. Our objective was to examine differences in organizational structure available to support quality of care for patients with CHF and COPD. STUDY DESIGN: We performed 2 nationwide surveys exploring organizational structure for the management of CHF and COPD. We surveyed the chief of medicine and the chief of cardiology and pulmonary medicine at 120 Veterans Affairs facilities in the United States. METHODS: Analogous questions about organizational structure that enhanced adherence to guideline based care were compared between CHF and COPD surveys. RESULTS: We found large and notable differences in the organizational structure for disease management, with systematically less attention given to COPD than CHF. These differences were evident in multiple processes of care. Key differences included fewer facilities: having COPD clinics than CHF clinics (12.7% vs 50.8%; P < .01), relating performance measures with COPD providers than CHF providers (17.1% vs 70%; P < .01), and having home monitoring programs for COPD than for CHF (50.5% vs 87.4%; P < .01). CONCLUSIONS: Despite the growing burden of COPD, less organizational structure existed for COPD than CHF. Lack of organizational structure for COPD likely impedes an organization's abilities to encourage high-quality care and avoid recently implemented hospital readmission penalties. Our results suggest the need to develop a systematic approach for healthcare systems to provide essential organizational structure based on the burden of disease in the population. PMID- 26978240 TI - Value of primary care diabetes management: long-term cost impacts. AB - OBJECTIVES: To estimate long-term cost savings associated with patients' exposure to an all-or-none bundle of measures for primary care management of diabetes. STUDY DESIGN: In 2006, Geisinger's primary care clinics implemented an all-or none diabetes system of care (DSC). Claims data from Geisinger Health Plan were used to identify those who met Healthcare Effectiveness Data and Information Set criteria for diabetes and had 2 or more diabetes-related encounters on different dates before 2006. A cohort of 1875 members exposed to the DSC was then compared against a propensity score matched non-DSC comparison cohort from January 1, 2006, through December 31, 2013. METHODS: A set of generalized linear models with log link and gamma distribution was estimated. The key explanatory variable was each member's bundle exposure measured in months. The dependent variables were inpatient and outpatient facility costs, professional cost, and total medical cost excluding prescription drugs measured on a per-member-per-month basis. RESULTS: Over the study period, the total medical cost saving associated with DSC exposure was approximately 6.9% (P < .05). The main source of the saving was reductions in inpatient facility cost, which showed approximately 28.7% savings (P < .01) over the study period. During the first year of the DSC exposure, however, there were significant increases in outpatient (13%; P < .05) and professional (9.7%; P < .05) costs. CONCLUSIONS: A system of care with an all-or none bundled measure used in primary care for patients with diabetes may reduce long-term cost of care while improving health outcomes. PMID- 26978242 TI - Nonlinear Terahertz Absorption of Graphene Plasmons. AB - Subwavelength graphene structures support localized plasmonic resonances in the terahertz and mid-infrared spectral regimes. The strong field confinement at the resonant frequency is predicted to significantly enhance the light-graphene interaction, which could enable nonlinear optics at low intensity in atomically thin, subwavelength devices. To date, the nonlinear response of graphene plasmons and their energy loss dynamics have not been experimentally studied. We measure and theoretically model the terahertz nonlinear response and energy relaxation dynamics of plasmons in graphene nanoribbons. We employ a terahertz pump terahertz probe technique at the plasmon frequency and observe a strong saturation of plasmon absorption followed by a 10 ps relaxation time. The observed nonlinearity is enhanced by 2 orders of magnitude compared to unpatterned graphene with no plasmon resonance. We further present a thermal model for the nonlinear plasmonic absorption that supports the experimental results. The model shows that the observed strong linearity is caused by an unexpected red shift of plasmon resonance together with a broadening and weakening of the resonance caused by the transient increase in electron temperature. The model further predicts that even greater resonant enhancement of the nonlinear response can be expected in high-mobility graphene, suggesting that nonlinear graphene plasmonic devices could be promising candidates for nonlinear optical processing. PMID- 26978241 TI - The budget impact of cervical cancer screening using HPV primary screening. AB - OBJECTIVES: This study assessed the clinical and budgetary impacts of human papillomavirus (HPV) primary screening with HPV16/18 genotyping, in contrast to current cervical cancer screening strategies. STUDY DESIGN: A decision-tree framework and Markov model were used to model clinical and cost implications of screening and diagnosis of disease. METHODS: A model was developed to compare the annual clinical and budgetary impact of HPV screening with genotyping versus cytology, and co-testing with and without genotyping. Epidemiology and test performance inputs are from the literature and the Addressing THE Need for Advanced HPV Diagnostics (ATHENA) trial. Costs are from a US payer perspective. Clinical impact was measured as the resulting incidence of cervical cancer, and budget impact is reported as annual cost per screened woman. The model considered the impact of patient noncompliance (loss to follow-up) at both the initial screen and re-test. RESULTS: Cytology was found to be inferior to both co-testing and HPV primary screening. Co-testing was inferior to co-testing with genotyping. Co-testing with genotyping every 3 years (incidence = 5.5 per 100,000 women; annual investment = $61) or 5 years (incidence = 7.4 per 100,000 women; annual investment = $37) was slightly more effective, but more costly than HPV primary screening every 3 years (incidence = 6.2 per 100,000 women; annual investment = $48) or 5 years (incidence = 8.1 per 100,000 women; annual investment = $30). Genotyping strategies were relatively stable to the effects of patient noncompliance. CONCLUSIONS: Primary HPV screening with genotyping represents a sensible combination of clinical effectiveness and costs, while reducing the risks associated with patient noncompliance. PMID- 26978243 TI - Palladium-Catalyzed Enantioselective Intermolecular Carboetherification of Dihydrofurans. AB - A novel enantioselective Pd-catalyzed intermolecular carboetherification of dihydrofurans is reported. The in situ generation of chiral bis-phosphine mono oxide ligands is crucial, and a general catalytic system has been identified based on this approach. It provides access to a variety of fused tetrahydrofurobenzofurans in consistently high yield and enantiomeric excess. PMID- 26978245 TI - Luteimonas arsenica sp. nov., an arsenic-tolerant bacterium isolated from arsenic contaminated soil. AB - A Gram-stain-negative, rod-shaped bacterium that formed yellow and viscous colonies was isolated from arsenic-contaminated soil of the Jianghan plain, Hubei Province, China, and it was designated 26-35T. This strain was capable of resisting arsenate and arsenite with MICs of 40 and 20 mM, respectively. The 16S rRNA gene of the novel isolate displayed 96.7-94.2 % sequence similarities to those of other known species of the genus Luteimonas. The respiratory quinone was ubiquinone-8 (Q-8). The DNA G+C content was 71.4 mol%. The predominant cellular fatty acids were iso-C15 : 0, iso-C16 : 0, iso-C17 : 0, iso-C11 : 0, iso-C11 : 0 3-OH and iso-C17 : 1omega9c. The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. Phylogenetic and physiological analysis indicated that the isolate represents a novel species of the genus Luteimonas, for which the name Luteimonas arsenica sp. nov. is proposed. The type strain is 26-35T (=KCTC 42824T=CCTCC AB 2014326T). PMID- 26978246 TI - Recent Advances in Dendritic Macromonomers for Hydrogel Formation and Their Medical Applications. AB - Hydrogels represent one of the most important classes of biomaterials and are of interest for various medical applications including wound repair, tissue engineering, and drug release. Hydrogels possess tunable mechanical properties, biocompatibility, nontoxicity, and similarity to natural soft tissues. The need for hydrogels with specific properties, based on the design requirements of the in vitro, in vivo, or clinical application, motivates researchers to develop new synthetic approaches and cross-linking methodologies to form novel hydrogels with unique properties. The use of dendritic macromonomers represents one elegant strategy for the formation of hydrogels with specific properties. Specifically, the uniformity of dendrimers combined with the control of their size, architecture, density, and surface groups make them promising cross-linkers for hydrogel formation. Over the last two decades, a large variety of dendritic-based hydrogels are reported for their potential use in the clinic. This review describes the state of the art with these different dendritic hydrogel formulations including their design requirements, the synthetic routes, the measurement and determination of their properties, the evaluation of their in vitro and in vivo performances, and future perspectives. PMID- 26978247 TI - Synthesis of Heavy Cyclodipnictadiphosphanes [ClE(MU-P-Ter)]2 [E = P, As, Sb, or Bi; Ter = 2,6-bis(2,4,6-trimethylphenyl)phenyl]. AB - A complete series of terphenyl-substituted 1,3-dichloro-1,3-dipnicta-2,4 diphosphanes {[ClE(MU-P-Ter)]2, where E = P, As, Sb, or Bi and Ter = 2,6 bis(2,4,6-trimethylphenyl)phenyl} was prepared and fully characterized. While the heavy derivatives with E = Sb or Bi can be accessed via conversion of silylated phosphanes with amino-dichloropnictanes and subsequent elimination of TerNH2, the lighter congeners could be prepared only by a metathesis reaction of [ClBi(MU-P Ter)]2 with PCl3 and AsCl3. Spectroscopic and structural data indicate the existence of cis and trans isomers of [ClP(MU-P-Ter)]2 in contrast to all heavier derivatives, for which only the trans isomer was obtained. PMID- 26978248 TI - [Schizophrenia in adolescence]. AB - AIM: Schizophrenia with childhood and adolescent onset is a serious clinical/social problem. It has been attempted to specify main clinical/dynamic sex-related characteristics of early onset schizophrenia, prognostic criteria and parameters of outcome. MATERIAL AND METHODS: The results of a long-term (1995 2014) clinical follow-up study of outpatients of a psychoneurological dispensary and inpatients of a Moscow Psychiatric Hospital No15, aged 15-17 years, were analyzed. RESULTS: There was the predominance of men over women (4:1). The evidence of poor outcome of childhood and adolescent onset schizophrenia was obtained. At the age of 18 years, no one patient had stable remission, more than 40% of the patients were disabled since childhood. Most of adolescents were disabled in one or another activity. At the same time, there was a relative stabilization of the early malignant variants of schizophrenia resulted in oligophrenia-like deficit. The delayed (for several years) and frequently mistaken diagnosis and the absence of adequate treatment are the most robust premises of the development of early disability, along with the severity of destructive potential of the disease. CONCLUSION: The more distinct qualification of early symptoms of schizophrenia with childhood and adolescent onset, search for social/therapeutic approaches directed to the prevention of exacerbations and prophylaxis of social incompetence of adolescents are needed. PMID- 26978244 TI - The FAIR Guiding Principles for scientific data management and stewardship. AB - There is an urgent need to improve the infrastructure supporting the reuse of scholarly data. A diverse set of stakeholders-representing academia, industry, funding agencies, and scholarly publishers-have come together to design and jointly endorse a concise and measureable set of principles that we refer to as the FAIR Data Principles. The intent is that these may act as a guideline for those wishing to enhance the reusability of their data holdings. Distinct from peer initiatives that focus on the human scholar, the FAIR Principles put specific emphasis on enhancing the ability of machines to automatically find and use the data, in addition to supporting its reuse by individuals. This Comment is the first formal publication of the FAIR Principles, and includes the rationale behind them, and some exemplar implementations in the community. PMID- 26978249 TI - [Youth-onset schizophrenia: psychopathology, clinical presentation and therapy]. AB - The paper reviews the clinical presentations and pathogenetic features of youth onset schizophrenia with onset at the age of 16-25 years old. The clinical presentation of the disease in young people is different in comparison to adult patients. Psychopathological and biological characteristics of the first episode, the course of "progressive" schizophrenia and "malignant youth schizophrenia" in the pubertal period are described. Early diagnosis and prevention of disease manifestation are discussed. Recommendations on therapeutic measures at different stages of the endogenous process in this age are presented. The most important future goals of research in this field are formulated. PMID- 26978250 TI - [Late-onset schizophrenia]. AB - OBJECTIVE: To verify clinical observations by the epidemiological method. MATERIAL AND METHODS: The data of the full investigation of 1781 schizophrenia cases, including 403 patients in the age of 60 and older were used. RESULTS AND CONCLUSION: A number of characteristics inherent for this group were fully consistent with clinical observations. These characteristics were connected with a few factors: probability to reach the old age for patients with young onset schizophrenia; probability to stay under psychiatric care for patients with long disease duration; characteristics of certain forms of schizophrenia and probability of the onset of some symptoms in elderly patients. A combined effect of these factors resulted in the development of some common features of schizophrenia with late-onset, i.e. the rarity of malignant schizophrenia and high frequency of depressive disorders. The author underlines the vagueness of the notion "late schizophrenia". PMID- 26978251 TI - [The role of deficit symptoms in the psychopathological picture of remission at the initial stage of schizophrenia]. AB - OBJECTIVE: To study the structure and dynamics of remission formation at the initial stage of schizophrenia. MATERIAL AND METHODS: The author examined 232 male inpatients with the first episode of juvenile endogenous attack-like psychosis at the stage getting to the first remission. RESULTS AND CONCLUSION: Remissions were stratified by the profile of deficit symptoms and influence of process/positive symptoms. Several variants of remission with the same profile of deficit symptoms were singled out. PMID- 26978252 TI - [Acute paraphrenic states in the clinical presentation of attack-like schizophrenia]. AB - OBJECTIVE: To study a psychopathological structure of the acute paraphrenic syndrome in different variants of schizophrenia course. MATERIAL AND METHODS: Sixty patients were examined. RESULTS AND CONCLUSION: Three variants of acute paraphrenic syndrome with the domination of sensitive delusions, Kandinsky Clerambault's syndrome or confabulatory disorders were singled out. Acute paraphrenic syndrome with sensitive delusions was characteristic of recurrent schizophrenia. Slow-progressive attack-like schizophrenia was characterized by the acute paraphrenic syndrome with sensitive delusions in the combination with interpretative delusions. Juvenile malignant schizophrenia was characterized by the acute paraphrenic syndrome with the domination of Kandinsky-Clerambault's syndrome and sensitive delusions. Acute paraphrenic syndrome with the domination of Kandinsky-Clerambault's syndrome and acute paraphrenic syndrome with confabulatory disorders were identified in patients with paranoid attack-like schizophrenia similar to chronic schizophrenia. The nosologic specificity of the acute paraphrenic syndrome for attack-like schizophrenia was confirmed. PMID- 26978253 TI - [Psychopathological features of chronic apathetic depressions in schizophrenia]. AB - OBJECTIVE: To study the features of apathetic phenomena developed in chronic depressions in patients with attack-like schizophrenia. MATERIAL AND METHODS: Psychopathological features of chronic apathetic depressions in schizophrenia (19 patients) were compared to attack-like depressions in affective disorders (n=25) and schizophrenia with distinct apathetic depressions (n=17). RESULTS AND CONCLUSION: Clinical features of the main cases and their differences from comparison groups have been identified. The influence of endogenous progressive disease on clinical and dynamic features of chronic apathetic depressions is discussed. PMID- 26978254 TI - [Clinical and pathopsychological aspects of forming negative disorders in remissions of shift-like schizophrenia treated with different generations of neuroleptics]. AB - OBJECTIVE: To determine clinical and pathopsychological parameters of negative personality changes, their diagnostic and predictive significance based on the variant of neuroleptic treatment in the dynamics of remissions in shift-like schizophrenia. MATERIAL AND METHODS: Twenty-nine female patients diagnosed with ICD-10 schizophrenia (items F20.01 and F20.02) were examined. The patients were treated with typical neuroleptics (TN) or atypical (ATN) neuroleptics in the hospital and then as outpatients. Patient's state was assessed clinically and psychometrically with the PANSS at admission, at the beginning of remission and after one and two years of remission. Mean score of positive (PS) and negative (NS) symptoms was determined differentially in the dynamics basing on the neuroleptic used. Twenty-seven patients underwent experimental/pathopsychological examination. RESULTS AND CONCLUSION: In different stages of the dynamics of shift like schizophrenia, NS had different capacity of "reversibility" and were distinctly associated with the illness-shaping influence of PS severity and activity and characteristics of psychotropic effect of the neuroleptics. The highest severity of NS was noted in the stage of active psychosis (up to 3.6 and 4.2 scores), with the following decrease in the beginning of remission (up to 2.3 and 2.8 scores). The most distinct trend towards the reduction of NS in the first and second years of remission (up to 2.0-1.0 scores), along with a trend to the complete reduction of PS, was identified in patients treated with ATN. In patients treated with TN, the severity of NS was relatively stable in all stages of remission, with a trend towards the increased severity (up to 2.8 and 3.2 scores) with the stable reduction of PS to1.6 scores. The distinct property of ATN to exert the reducing psychotropic effect on NS and the lack of antinegative effect in the antipsychotic spectrum of TN is discussed. PMID- 26978255 TI - [The recovery model of schizophrenia: could it be currently used?]. AB - The long-term antipsychotic treatment remains one of the main methods of treatment of schizophrenia. Drug choice is determined by a plethora of factors though two groups of antipsychotics (traditional neuroleptics and atypical antipsychotics) are currently the basic ones. The development of a new generation of atypical antipsychotics has given the possibility to improve significantly treatment RESULTS: The article presents the data on pharmacodynamics and pharmacokinetic properties of ziprasidone, its efficacy and safety in schizophrenia, including its treatment-refractory forms. PMID- 26978256 TI - [An experimental psychological study of sex/gender differences in patients with schizophrenia]. AB - OBJECTIVE: To perform an experimental psychological study of gender differences in patients with attack-like schizophrenia in the aspect of pathopsychological syndrome. MATERIAL AND METHODS: The study included 80 subjects: 40 men and 40 women, aged 18-30 years. The disease duration was <3 years. Patients were examined in remission. RESULTS AND CONCLUSION: The major gender differences are manifested in emotional and personal characteristics and self-concepts related with them, as well in the characteristics of communication. It can be assumed that these gender differences are due to a more pronounced presence of an affective component in the structure of endogenous disorders in women which slightly softens the manifestation of negative disorders during the endogenous process. PMID- 26978257 TI - [Memantine (akatinol) in the treatment of vascular dementia]. AB - The literature on the results of the therapeutic efficacy of memantine in treatment of cerebrovascular diseases with cognitive impairment of different severity is analyzed. The results of randomized and observational studies justified the wide use of memantine in clinical practice. PMID- 26978258 TI - [The pathomorphosis of schizophrenia]. AB - The author considers the problem of pathomorphosis, i.e. the changes in clinical presentation of endogenous mental diseases (schizophrenia, depression), since the time of its classical description. There is a general trend towards the development of forms with more favorable course in schizophrenia and the domination of prolonged and masked variants in depression. These changes are discussed in aspects of true (natural) pathomorphosis and therapeutic (induced) pathomorphosis. The relative character of this stratification and insufficient understanding of the problem in psychiatry in general are emphasized. PMID- 26978260 TI - Shaping and compositional modification of zinc oxide nanowires under energetic manganese ion irradiation. AB - For ZnO nanowires of 150 to 200 nm diameter standing on a flat substrate, the development of the surface contour/morphology and the local elemental composition under 175 keV Mn irradiation has been investigated both experimentally and by means of three-dimensional dynamic Monte Carlo computer simulation. The simulation results reveal a complex interplay of sputter erosion, implant incorporation, resputtering and atomic mixing, which is discussed in detail. The sputter-induced thinning of the wire is in good quantitative agreement with the experimental results obtained from pre- and post-irradiation scanning electron microscopy. The experiments also confirm the predicted sharpening of the tip, neck formation at the bottom interface, and ultimately the detachment of the nanowires from the substrate at high ion fluence. Additional good agreement with experimental results from nano-x-ray fluorescence is also obtained for the continuously increasing Mn/Zn atomic ratio within the nanowires as a function of ion fluence. The simulation yields a great deal of additional information that has not been accessible in the experiments. From this, preferential sputtering of O compared with Zn is deduced. A significant contamination of the wires with substrate material arises from ion mixing at the wire/substrate interface, rather than from redeposition of sputtered substrate atoms. Surprising hollow profiles are observed. Their formation is attributed to a special mechanism of collisional transport which is characteristic of the irradiation of nanowires at a suitable combination of wire diameter and ion energy. PMID- 26978259 TI - [Comorbidity of depression and nonaffective - schizophrenia spectrum disorders: the clinical-epidemiological study EDIP]. AB - AIM: To explore the association between depression and heterogenic nonaffective symptom complexes in the study EDIP (Epidemiology of Depression and nonaffective Psychiatric disorders). MATERIAL AND METHODS: The study consisted of two stages. The first stage (91 patients) aimed to resolve organizational and methodological issues, the second stage was performed in the epidemiological sample of 705 patients. RESULTS AND CONCLUSION: The heterogeneity (inequivalence and bidirectionality) of associations between depression and heteronomous nonaffective disorders have been identified. The associations are distinguished in three types: 1) affinity (agonism); 2) repulsion (antagonism); 3) lack of selective interaction (inertness) between depression and nonaffective disorders. The results obtained are discussed in a context of two conceptually polar psychopathological models of comorbidity between depression and nonaffective disorders: 1) based on a nosological dichotomy "affective disease - schizophrenia" and 2) denying the abovementioned dichotomy. The first model places depression among disorders of a mild psychiatric register. The second model supposes the integration of depression with syndromes typical for schizophrenia in a common "affect-symptoms" space and considers the increase of depression frequency proportionally to duration and severity of schizophrenia. Our own results have shown that depression is observed not only among disorders of mild psychiatric registers, but also in schizophrenia, though with a significantly lower frequency (as a nonobligatory compound of a syndrome). Thus, depression influence in comorbid delusional, schizophrenic and other severe nonaffective disorders is greatly diminished. PMID- 26978261 TI - Composition and Metabolic Activities of the Bacterial Community in Shrimp Sauce at the Flavor-Forming Stage of Fermentation As Revealed by Metatranscriptome and 16S rRNA Gene Sequencings. AB - The bacterial community and the metabolic activities involved at the flavor forming stage during the fermentation of shrimp sauce were investigated using metatranscriptome and 16S rRNA gene sequencings. Results showed that the abundance of Tetragenococcus was 95.1%. Tetragenococcus halophilus was identified in 520 of 588 transcripts annotated in the Nr database. Activation of the citrate cycle and oxidative phosphorylation, along with the absence of lactate dehydrogenase gene expression, in T. halophilus suggests that T. halophilus probably underwent aerobic metabolism during shrimp sauce fermentation. The metabolism of amino acids, production of peptidase, and degradation of limonene and pinene were very active in T. halophilus. Carnobacterium, Pseudomonas, Escherichia, Staphylococcus, Bacillus, and Clostridium were also metabolically active, although present in very small populations. Enterococcus, Abiotrophia, Streptococcus, and Lactobacillus were detected in metatranscriptome sequencing, but not in 16S rRNA gene sequencing. Many minor taxa showed no gene expression, suggesting that they were in dormant status. PMID- 26978262 TI - Validation Study: Response-Predictive Gene Expression Profiling of Glioma Progenitor Cells In Vitro. AB - BACKGROUND: In a previous publication we introduced a novel approach to identify genes that hold predictive information about treatment outcome. A linear regression model was fitted by using the least angle regression algorithm (LARS) with the expression profiles of a construction set of 18 glioma progenitor cells enhanced for brain tumor initiating cells (BTIC) before and after in vitro treatment with the tyrosine kinase inhibitor Sunitinib. Profiles from treated progenitor cells allowed predicting therapy-induced impairment of proliferation in vitro. Prediction performance was validated in leave one out cross validation. METHODS: In this study, we used an additional validation set of 18 serum-free short-term treated in vitro cell cultures to test the predictive properties of the signature in an independent cohort. We assessed proliferation rates together with transcriptome-wide expression profiles after Sunitinib treatment of each individual cell culture, following the methods of the previous publication. RESULTS: We confirmed treatment-induced expression changes in our validation set, but our signature failed to predict proliferation inhibition. Neither re calculation of the combined dataset with all 36 BTIC cultures nor separation of samples into TCGA subclasses did generate a proliferation prediction. CONCLUSION: Although the gene signature published from our construction set exhibited good prediction accuracy in cross validation, we were not able to validate the signature in an independent validation data set. Reasons could be regression to the mean, the moderate numbers of samples, or too low differences in the response to proliferation inhibition in the validation set. At this stage and based on the presented results, we conclude that the signature does not warrant further developmental steps towards clinical application. PMID- 26978264 TI - PHQ-9 and PHQ-2 for Screening Depression in Chinese Rural Elderly. AB - OBJECTIVES: This study aimed to explore cut-off scores of the 9-item Patient Health Questionnaire (PHQ-9) and 2-item Patient Health Questionnaire (PHQ-2) for depression screening in Chinese rural elderly. METHODS: A cross-sectional study was conducted on 839 residents aged 60 years and above in rural areas of Liuyang County. PHQ-9 was adopted to evaluate depression. The Structured Clinical Interview for DSM Disorders (SCID-I) was adopted to diagnose major depressive disorder (MDD) as a golden standard. Sensitivity, specificity, positive and negative predictive value, positive and negative likelihood ratio, Youden's index and the receiver operating characteristic (ROC) curve were analyzed on PHQ-9 and PHQ-2. RESULTS: The Cronbach's alphas of PHQ-9 and PHQ-2 were 0.82 and 0.76, respectively. The score of 8 of the PHQ-9 showed the highest Youden's index of 0.85, with a sensitivity of 0.97 and specificity of 0.89 respectively, and the area under the ROC curve (AUC) was 0.97 (95% CI: 0.96-0.98). The score of 3 of PHQ-2 showed the highest Youden's index of 0.79, with both sensitivity and specificity were 0.90 and the AUC was 0.94 (95% CI: 0.90-0.97). CONCLUSIONS: Both PHQ-9 and PHQ-2 are valid screening instruments for depression in the rural elderly in China, with recommended cut-off scores of 8 and 3 respectively. PMID- 26978263 TI - Impact of a Prospective Audit and Feedback Antimicrobial Stewardship Program at a Veterans Affairs Medical Center: A Six-Point Assessment. AB - BACKGROUND: Prospective audit and feedback is a core antimicrobial stewardship program (ASP) strategy; however its impact is difficult to measure. METHODS: Our quasi-experimental study measured the effect of an ASP on clinical outcomes, antimicrobial use, resistance, costs, patient safety (adverse drug events [ADE] and Clostridium difficile infection [CDI]), and process metrics pre- (9/10-10/11) and post-ASP (9/12-10/13) using propensity adjusted and matched Cox proportional hazards regression models and interrupted time series (ITS) methods. RESULTS: Among our 2,696 patients, median length of stay was 1 day shorter post-ASP (5, interquartile range [IQR] 3-8 vs. 4, IQR 2-7 days, p<0.001). Mortality was similar in both periods. Mean broad-spectrum (-11.3%), fluoroquinolone (-27.0%), and anti-pseudomonal (-15.6%) use decreased significantly (p<0.05). ITS analyses demonstrated a significant increase in monthly carbapenem use post-ASP (trend: +1.5 days of therapy/1,000 patient days [1000PD] per month; 95% CI 0.1-3.0). Total antimicrobial costs decreased 14%. Resistance rates did not change in the one-year post-ASP period. Mean CDI rates/10,000PD were low pre- and post-ASP (14.2 +/- 10.4 vs. 13.8 +/- 10.0, p = 0.94). Fewer patients experienced ADEs post ASP (6.0% vs. 4.4%, p = 0.06). CONCLUSIONS: Prospective audit and feedback has the potential to improve antimicrobial use and outcomes, and contain bacterial resistance. Our program demonstrated a trend towards decreased length of stay, broad-spectrum antimicrobial use, antimicrobial costs, and adverse events. PMID- 26978265 TI - Fast Pyrolysis of Tropical Biomass Species and Influence of Water Pretreatment on Product Distributions. AB - The fast pyrolysis behaviour of pretreated banagrass was examined at four temperatures (between 400 and 600 C) and four residence times (between ~1.2 and 12 s). The pretreatment used water washing/leaching to reduce the inorganic content of the banagrass. Yields of bio-oil, permanent gases and char were determined at each reaction condition and compared to previously published results from untreated banagrass. Comparing the bio-oil yields from the untreated and pretreated banagrass shows that the yields were greater from the pretreated banagrass by 4 to 11 wt% (absolute) at all reaction conditions. The effect of pretreatment (i.e. reducing the amount of ash, and alkali and alkali earth metals) on pyrolysis products is: 1) to increase the dry bio-oil yield, 2) to decrease the amount of undetected material, 3) to produce a slight increase in CO yield or no change, 4) to slightly decrease CO2 yield or no change, and 5) to produce a more stable bio-oil (less aging). Char yield and total gas yield were unaffected by feedstock pretreatment. Four other tropical biomass species were also pyrolyzed under one condition (450 degrees C and 1.4 s residence time) for comparison to the banagrass results. The samples include two hardwoods: leucaena and eucalyptus, and two grasses: sugarcane bagasse and energy-cane. A sample of pretreated energy-cane was also pyrolyzed. Of the materials tested, the best feedstocks for fast pyrolysis were sugarcane bagasse, pretreated energy cane and eucalyptus based on the yields of 'dry bio-oil', CO and CO2. On the same basis, the least productive feedstocks are untreated banagrass followed by pretreated banagrass and leucaena. PMID- 26978267 TI - A Novel Manno-Oligosaccharide Binding Protein Identified in Alkaliphilic Bacillus sp. N16-5 Is Involved in Mannan Utilization. AB - ManH, a novel substrate-binding protein of an ABC transporter, was identified from the mannan utilization gene cluster of Bacillus sp. N16-5. We cloned, overexpressed, and purified ManH and measured its binding affinity to different substrates by isothermal titration calorimetry. ManH binds to mannotriose, mannotetraose, mannopentose, and galactosyl-mannotriose with dissociation constants in the micromolar range. Deletion of manH led to decreased growth ability of the strain when cultivated in medium with manno-oligosaccharides or mannan as the carbon source. ManH belongs to a manno-oligosaccharide transporter and plays an important role in mannan utilization by Bacillus sp. N16-5. PMID- 26978266 TI - Rheumatoid Arthritis and Incidence of Twelve Initial Presentations of Cardiovascular Disease: A Population Record-Linkage Cohort Study in England. AB - INTRODUCTION: While rheumatoid arthritis is an established risk factor for cardiovascular disease (CVD), our knowledge of how the pattern of risk varies for different cardiovascular phenotypes is incomplete. The association between rheumatoid arthritis and the initial presentation of 12 types of CVDs were examined in a contemporary population of men and women of a wide age range. METHODS: CALIBER data, which links primary care, hospital and mortality data in England, was analysed. A cohort of people aged >=18 years and without history of CVD was assembled and included all patients with prospectively recorded rheumatoid arthritis from January 1997, until March 2010, matched with up to ten people without rheumatoid arthritis by age, sex and general practice. The associations between rheumatoid arthritis and the initial presentation of 12 types of CVDs were estimated using multivariable random effects Poisson regression models. RESULTS: The analysis included 12,120 individuals with rheumatoid arthritis and 121,191 comparators. Of these, 2,525 patients with and 18,146 without rheumatoid arthritis developed CVDs during a median of 4.2 years of follow-up. Patients with rheumatoid arthritis had higher rates of myocardial infarction (adjusted incidence ratio [IRR] = 1.43, 95%CI 1.21-1.70), unheralded coronary death (IRR = 1.60, 95%CI 1.18-2.18), heart failure (IRR = 1.61, 95%CI 1.43-1.83), cardiac arrest (HR = 2.26, 95%CI 1.69-3.02) and peripheral arterial disease (HR = 1.36, 95%CI 1.14-1.62); and lower rates of stable angina (HR = 0.83, 95%CI 0.73-0.95). There was no evidence of association with cerebrovascular diseases, abdominal aortic aneurysm or unstable angina, or of interactions with sex or age. CONCLUSIONS: The observed associations with some but not all types of CVDs inform both clinical practice and the selection of cardiovascular endpoints for trials and for the development of prognostic models for patients with rheumatoid arthritis. PMID- 26978268 TI - Graphene Functionalized Scaffolds Reduce the Inflammatory Response and Supports Endogenous Neuroblast Migration when Implanted in the Adult Brain. AB - Electroactive materials have been investigated as next-generation neuronal tissue engineering scaffolds to enhance neuronal regeneration and functional recovery after brain injury. Graphene, an emerging neuronal scaffold material with charge transfer properties, has shown promising results for neuronal cell survival and differentiation in vitro. In this in vivo work, electrospun microfiber scaffolds coated with self-assembled colloidal graphene, were implanted into the striatum or into the subventricular zone of adult rats. Microglia and astrocyte activation levels were suppressed with graphene functionalization. In addition, self assembled graphene implants prevented glial scarring in the brain 7 weeks following implantation. Astrocyte guidance within the scaffold and redirection of neuroblasts from the subventricular zone along the implants was also demonstrated. These findings provide new functional evidence for the potential use of graphene scaffolds as a therapeutic platform to support central nervous system regeneration. PMID- 26978269 TI - Bronchiectasis as a Comorbidity of Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Bronchiectasis revealed by chest computed tomography in COPD patients and its comorbid effect on prognosis have not been addressed by large-sized studies. Understanding the presence of bronchiectasis in COPD is important for future intervention and preventing disease progression. METHODS: Observational studies were identified from electronic literature searches in Cochrane library, PubMed, ScienceDirect databases, American Thoracic Society and European Respiratory Society meeting abstracts. A systematic review and meta-analysis of studies was performed to summarize the factors associated with bronchiectasis in COPD patients. Primary outcomes included the risks for exacerbation frequency, isolation of a potentially pathogenic microorganism, severe airway obstruction and mortality. Odds ratios (ORs) were pooled by random effects models. RESULTS: Fourteen observational studies were eligible for the study. Compared with COPD without bronchiectasis, comorbid bronchiectasis in COPD increased the risk of exacerbation (1.97, 95% CI, 1.29-3.00), isolation of a potentially pathogenic microorganism (4.11, 95%CI, 2.16-7.82), severe airway obstruction (1.31, 95% CI, 1.09-1.58) and mortality (1.96, 95% CI, 1.04-3.70). CONCLUSIONS: The presence of bronchiectasis in patients with COPD was associated with exacerbation frequency, isolation of a potentially pathogenic microorganism, severe airway obstruction and mortality. PMID- 26978270 TI - Income Related Inequality of Health Care Access in Japan: A Retrospective Cohort Study. AB - The purpose of this retrospective cohort study was to analyze the association between income level and health care access in Japan. Data from a total of 222,259 subjects (age range, 0-74 years) who submitted National Health Insurance claims in Chiba City from April 2012 to March 2014 and who declared income for the tax period from January 1 to December 31, 2012 were integrated and analyzed. The generalized estimating equation, in which household was defined as a cluster, was used to evaluate the association between equivalent income and utilization and duration of hospitalization and outpatient care services. A significant positive linear association was observed between income level and outpatient visit rates among all age groups of both sexes; however, a significantly higher rate and longer period of hospitalization, and longer outpatient care, were observed among certain lower income subgroups. To control for decreased income due to hospitalization, subjects hospitalized during the previous year were excluded, and the data was then reanalyzed. Significant inverse associations remained in the hospitalization rate among 40-59-year-old men and 60-69-year-old women, and in duration of hospitalization among 40-59 and 60-69-year-olds of both sexes and 70-74-year-old women. These results suggest that low-income individuals in Japan have poorer access to outpatient care and more serious health conditions than their higher income counterparts. PMID- 26978271 TI - High Frequency Hearing Loss and Hyperactivity in DUX4 Transgenic Mice. AB - Facioscapulohumeral muscular dystrophy (FSHD) is caused by mutations leading to ectopic expression of the transcription factor DUX4, and encompasses both muscle related and non-muscle phenotypes. Mouse models bearing this gene represent valuable tools to investigate which pathologies are due to DUX4 expression, and how DUX4 leads to these pathologies. The iDUX4(2.7) mouse contains an X-linked doxycycline-inducible DUX4 gene that shows low level basal expression in the absence of doxycycline, leading to male lethality, generally in embryo, but always before 8 weeks of age. Here, we describe additional non-muscle phenotypes in this animal model. We find that iDUX4(2.7) female carriers are extremely hyperactive, spending large amounts of time ambulating and much less time resting. Rare 3-week old males, although hypophagic, runted and extremely fragile, are capable of high activity, but show periods of catatonic torpor in which animals appear dead and respiration is virtually absent. We also examine a non-muscle phenotype of interest to FSHD, high frequency hearing loss. We find that young iDUX4(2.7) females are significantly impaired in their ability to hear at frequencies above 8 kHz. These phenotypes make the iDUX4(2.7) mouse an attractive model in which to study non-muscle activities of DUX4. PMID- 26978273 TI - A Preliminary Study on Sinus Fungus Ball with MicroCT and X-Ray Fluorescence Technique. AB - BACKGROUND: Sinus fungus ball, an accumulation of fungal dense concretions, is a common disease in practice, and might cause fatal complications or lead to death once converted into invasive type. Early preoperative diagnosis of this disease can lead to appropriate treatment for patients and prevent multiple surgical procedures. Up to now, the diagnostic criteria of sinus fungus ball have been defined and computed tomography (CT) scan was considered as a valuable preoperative diagnostic tool. However, the sensitivity of clinical CT is only about 62%. Thus, investigating the factors which influence sensitivity is necessary for clinical CT to be a more valuable preoperative diagnosis tool. Furthermore, CT scan usually presents micro-calcifications or spots with metallic density in sinus fungus ball. Previous literatures show that there are some metallic elements such as calcium and zinc in fungus ball, and they concluded that endodontic treatment has a strong correlation with the development of maxillary sinus fungus ball and zinc ion was an exogenous risk factor. But the pathogenesis of sinus fungus ball still remains unclear because fungus ball can also develop in other non-maxillary sinuses or the maxillary sinus without root canal treatment. Is zinc ion the endogenous factor? Study on this point might be also helpful for investigating the pathogenesis of sinus fungus ball. In this paper, we tried to investigate the factors which influence the sensitivity of clinical CT by imaging sinus fungus ball with microCT. The origin of zinc ion was also studied through elements test for different fungal ball samples using x-ray fluorescence technique. METHODS: Specimens including fungal ball material and sinus mucosa from patients confirmed by pathological findings were extracted after surgery. All fungal ball specimens came from sphenoid sinus, ethmoidal sinus and maxillary sinus with or without previous endodontic treatment respectively. All of them were imaged by microCT with spatial resolution up to 5MUm to acquire three-dimensional structure, and then the heavy metal elements were detected with x-ray fluorescence spectrometer analysis. RESULT: High concentration of zinc and calcium were detected in all fungal ball specimens compared to sinus mucosa membrane. Particles with different size varied from disperse to density, which have similar shape to the result of clinical CT but with different size, were found in three-dimensional reconstruction results of microCT. CONCLUSIONS: Spatial resolution is an influent factor of clinical CT sensitivity for sinus fungus ball. Improving the resolution of clinical CT will help to improve its sensitivity. Besides iatrogenic endodontic materials, endogenous metal elements of zinc and calcium might associate with the growth of fungal ball and the micro-calcifications or spots with metallic density of CT imaging. PMID- 26978274 TI - Performing mathematics activities with non-standard units of measurement using robots controlled via speech-generating devices: three case studies. AB - Purpose To examine how using a Lego robot controlled via a speech-generating device (SGD) can contribute to how students with physical and communication impairments perform hands-on and communicative mathematics measurement activities. This study was a follow-up to a previous study. Method Three students with cerebral palsy used the robot to measure objects using non-standard units, such as straws, and then compared and ordered the objects using the resulting measurement. Their performance was assessed, and the manipulation and communication events were observed. Teachers and education assistants were interviewed regarding robot use. Results Similar benefits to the previous study were found in this study. Gaps in student procedural knowledge were identified such as knowing to place measurement units tip-to-tip, and students' reporting revealed gaps in conceptual understanding. However, performance improved with repeated practice. Stakeholders identified that some robot tasks took too long or were too difficult to perform. Conclusions Having access to both their SGD and a robot gave the students multiple ways to show their understanding of the measurement concepts. Though they could participate actively in the new mathematics activities, robot use is most appropriate in short tasks requiring reasonable operational skill. Implications for Rehabilitation Lego robots controlled via speech-generating devices (SGDs) can help students to engage in the mathematics pedagogy of performing hands-on activities while communicating about concepts. Students can "show what they know" using the Lego robots, and report and reflect on concepts using the SGD. Level 1 and Level 2 mathematics measurement activities have been adapted to be accomplished by the Lego robot. Other activities can likely be accomplished with similar robot adaptations (e.g., gripper, pen). It is not recommended to use the robot to measure items that are long, or perform measurements that require high operational competence in order to be successful. PMID- 26978276 TI - Cerebral aspergillosis: a retrospective analysis of eight cases. AB - PURPOSE: Aspergillosis of the central nervous system is very rare. However with recent increases in the use of immunosuppressive agents and antibiotics, its incidence is increasing. We evaluated the demographics, clinical manifestations, laboratory findings, diagnosis, underlying conditions, treatment regimens and outcomes of patients with cerebral aspergillosis (CA). METHODS: We retrospectively reviewed data from eight patients with CA hospitalized at a Chinese general hospital from 1 January 2005 to 30 September 2015. RESULTS: Common clinical manifestations included headache and cranial nerve involvement. Four patients underwent biopsy and were pathologically diagnosed with Aspergillus hyphae. One patient was proved to have Aspergillus infection via autopsy. One patient had positive cerebrospinal fluid fungal cultures. The lesion locations were: the cavernous sinus (n = 5, 62.5%), frontal lobe (n = 1, 12.5%), temporosphenoid lobe (n = 1, 12.5%) and cerebellum (n = 1, 12.5%). At the end of follow-up, three patients were cured and five patients had died (mortality rate, 62.5%). CONCLUSIONS: Most patients with CA had no significant immunosuppression related conditions in our study. Aspergillus spp. can infect the central nervous system through several pathways and CA has an atypical clinical manifestation. The use of local tissue puncture, surgery or other invasive means to obtain diseased tissue containing higher levels of Aspergillus, followed by culture or histological examination, can contribute to an early diagnosis of CA and timely therapeutic intervention. The prognosis of CA is poor, but early and adequate use of antifungal drugs with high transfer across the blood-brain barrier and radical surgery to remove lesions can improve the survival rate. PMID- 26978275 TI - Nanostructured lipid carrier in photodynamic therapy for the treatment of basal cell carcinoma. AB - Topical photodynamic therapy (PDT) is a promising alternative for malignant skin diseases such as basal-cell carcinoma (BCC), due to its simplicity, enhanced patient compliance, and localization of the residual photosensitivity to the site of application. However, insufficient photosensitizer penetration into the skin is the major issue of concern with topical PDT. Therefore, the aim of the present study was to enable penetration of photosensitizer to the different strata of the skin using a lipid nanocarrier system. We have attempted to develop a nanostructured lipid carrier (NLC) for the topical delivery of second-generation photosensitizer, 5-amino levulinic acid (5-ALA), whose hydrophilicity and charge characteristic limit its percutaneous absorption. The microemulsion technique was used for preparing 5-ALA-loaded NLC. The mean particle size, polydispersity index, and entrapment efficiency of the optimized NLC of 5-ALA were found to be 185.2 +/- 1.20, 0.156 +/- 0.02, and 76.8 +/- 2.58%, respectively. The results of in vitro release and in vitro skin permeation studies showed controlled drug release and enhanced penetration into the skin, respectively. Confocal laser scanning microscopy and cell line studies respectively demonstrated that encapsulation of 5-ALA in NLC enhanced its ability to reach deeper skin layers and consequently, increased cytotoxicity. PMID- 26978272 TI - Cognitive Deficits Associated with Nav1.1 Alterations: Involvement of Neuronal Firing Dynamics and Oscillations. AB - Brain oscillations play a critical role in information processing and may, therefore, be essential to uncovering the mechanisms of cognitive impairment in neurological disease. In Dravet syndrome (DS), a mutation in SCN1A, coding for the voltage-gated sodium channel Nav1.1, is associated with severe cognitive impairment and seizures. While seizure frequency and severity do not correlate with the extent of impairment, the slowing of brain rhythms may be involved. Here we investigate the role of Nav1.1 on brain rhythms and cognition using RNA interference. We demonstrate that knockdown of Nav1.1 impairs fast- and burst firing properties of neurons in the medial septum in vivo. The proportion of neurons that fired phase-locked to hippocampal theta oscillations was reduced, and medial septal regulation of theta rhythm was disrupted. During a working memory task, this deficit was characterized by a decrease in theta frequency and was negatively correlated with performance. These findings suggest a fundamental role for Nav1.1 in facilitating fast-firing properties in neurons, highlight the importance of precise temporal control of theta frequency for working memory, and imply that Nav1.1 deficits may disrupt information processing in DS via a dysregulation of brain rhythms. PMID- 26978278 TI - Effects of Body Mass Index on Children's Physical Activity Levels in School-Based "Dance Dance Revolution". AB - OBJECTIVE: "Dance Dance Revolution" (DDR) (Konami Digital Entertainment, Inc., El Segundo, CA) has been recognized as an innovative approach to promote children's physical activity (PA). Previous works have described children's body mass index (BMI) status by group, but no studies have determined PA by category of BMI (underweight, normal weight, overweight, or obese). Therefore this study's purpose was to examine children's PA levels in DDR across different BMI groups. MATERIALS AND METHODS: Participants were 160 third through sixth grade urban children (79 girls; 115 white) who participated in a weekly 30-minute DDR program for 18 weeks. Children's BMI was calculated based on height and weight. Levels of PA and sedentary behavior in DDR were assessed by ActiGraph((r)) accelerometers (ActiGraph, LLC, Pensacola, FL) for three sessions. Outcome variables were percentages of time spent in sedentary behavior, light PA, and moderate-to vigorous PA (MVPA). RESULTS: Approximately one-third (32.5%) of children fell into the overweight (n = 26) or obese (n = 26) groups. One-way (overweight/obese versus normal weight) multivariate analysis of covariance with DDR skill level as covariate yielded a significant group effect (F3, 154 = 4.02, P < 0.01). Follow up tests indicated normal weight children accumulated significantly more MVPA (F = 8.94, P < 0.01) but less sedentary behavior (F = 3.27, P = 0.07) and light PA (F = 3.77, P = 0.054) while playing DDR than overweight/obese children. CONCLUSIONS: Overweight/obese children were less physically active than normal weight children during DDR. Consequently effective strategies are needed to stimulate these children to engage more actively in DDR experiences. PMID- 26978277 TI - Do my peers approve? Interest in injunctive norms feedback delivered online to college student drinkers. AB - Injunctive norms feedback is promising but understudied as a component of college drinking interventions. The aim of the present study was to demonstrate acceptability of injunctive norms feedback delivered to college drinkers via the web. We examined subjective interest in information reflecting peer approval of four sets of drinking behaviors and outcomes, and correlates of interest in the normative feedback. A sample of 221 young adults enrolled in a 2- or 4-year college or university (ages 18-25 years; 52% female) completed online surveys in which they were asked to rate their interest in each of 11 injunctive norms statements. Participants were randomly assigned to one of four sets of statements regarding peer approval of (a) intoxicated behaviors, (b) safe drinking strategies, (c) drinking-related consequences, and (d) drinking behaviors of potential partners. All items were framed to reflect disapproval of risky behaviors and approval of protective behaviors. Across norm sets, participants found the items to be moderately interesting and interest ratings did not differ across sets. Higher scores on the Alcohol Use Disorders Identification Test (AUDIT), stronger perceived approval of drinking in general (injunctive norms), stronger perceptions of drinking among peers (descriptive norms), and female gender were bivariately correlated with more interest. In a multiple regression, female gender, higher AUDIT (consequence subscale), and stronger general drinking injunctive norms remained significantly associated with interest in the pro moderation statements. An important future direction is to determine whether the presentation of specific types of injunctive norms feedback can result in downward changes in drinking behavior. PMID- 26978279 TI - Quantification of fumarate and investigation of endogenous and exogenous fumarate stability in rat plasma by LC-MS/MS. AB - BACKGROUND: Fumaric acid is a commonly used excipient in pharmaceutical products. It is not known if its presence may lead to fluctuation of endogenous fumarate levels. An LC-MS/MS method was developed and validated to quantify fumarate in support of a toxicokinetics study. RESULTS: Stability evaluation showed that endogenous fumarate was stable for 6 h at room temperature, while exogenously added fumaric acid was converted to malate within 1 h due to the presence of fumarase. Citric acid, a fumarase inhibitor, prevented the conversion of added fumaric acid in rat plasma. CONCLUSION: The method was validated in citric acid stabilized rat plasma using a surrogate matrix approach. A discrepancy in stability was observed between endogenous fumarate and exogenously added fumaric acid. PMID- 26978321 TI - The efficacy and tolerability of mirabegron in a non-trial clinical setting. AB - OBJECTIVES: Mirabegron is the first beta3-adrenoceptor selective agonist approved for the treatment of OAB. Many randomised controlled trials report outcomes that are difficult to interpret in usual clinical practice. The aim of our study is to evaluate the efficacy and tolerability of mirabegron as treatment option for OAB in an unselected patient population in daily clinical practice and to identify if any patient characteristics predicted patients response to therapy. STUDY DESIGN: A prospective consecutive cohort of patients was studied between February 2013 and July 2014. Patients were prescribed Mirabegron 50mg once daily for 6 weeks. They were assessed at the initial appointment and at 6 weeks using validated questionnaires. The primary outcome measure was defined using the Patient Global Impression of Improvement Scale (PGI-I). RESULTS: 317 women were prescribed mirabegron and 244 (77%) completed 6 weeks of drug therapy. Of those completing the course, 27 (11%) described themselves as "very much better" and a further 56 (23%) much better. There was significant symptom improvement based on the ICIQ FLUTS long form scores from 19.7 to 16.2 (p<0.001) and urinary distress inventory from 68.6 to 61.3 (p<0.005). Twenty-three (8.6%) patients discontinued mirabegron prematurely due to side-effects. Thirty one (10%) did not attend follow up and 19 (6%) decided against taking the medication and did not use their prescription. CONCLUSION: Mirabegron is a treatment option for patients with overactive bladder. Treatment benefits are modest but the discontinuation rate for side effects are low. PMID- 26978323 TI - Risky decision making in Attention-Deficit/Hyperactivity Disorder: A meta regression analysis. AB - ADHD has been associated with various forms of risky real life decision making, for example risky driving, unsafe sex and substance abuse. However, results from laboratory studies on decision making deficits in ADHD have been inconsistent, probably because of between study differences. We therefore performed a meta regression analysis in which 37 studies (n ADHD=1175; n Control=1222) were included, containing 52 effect sizes. The overall analysis yielded a small to medium effect size (standardized mean difference=.36, p<.001, 95% CI [.22, .51]), indicating that groups with ADHD showed more risky decision making than control groups. There was a trend for a moderating influence of co-morbid Disruptive Behavior Disorders (DBD): studies including more participants with co-morbid DBD had larger effect sizes. No moderating influence of co-morbid internalizing disorders, age or task explicitness was found. These results indicate that ADHD is related to increased risky decision making in laboratory settings, which tended to be more pronounced if ADHD is accompanied by DBD. We therefore argue that risky decision making should have a more prominent role in research on the neuropsychological and -biological mechanisms of ADHD, which can be useful in ADHD assessment and intervention. PMID- 26978324 TI - Associations between maternal and paternal parenting behaviors, anxiety and its precursors in early childhood: A meta-analysis. AB - In this meta-analysis we investigated differential associations between maternal and paternal parenting behaviors (overcontrol, overprotection, overinvolvement, autonomy granting, challenging parenting) and anxiety and its precursors (fearful temperament, behavioral inhibition, shyness) in children (0-5years). Two meta analyses were conducted, one for mothers (k=28, N=5,728), and one for fathers (k=12, N=1,019). In general, associations between parenting and child anxiety were small. Associations between child anxiety and overcontrol, overprotection, and overinvolvement did not differ for mothers and fathers. Maternal autonomy granting was not significantly related to child anxiety, and no studies examined fathers' autonomy granting. A significant difference was found for challenging parenting; mothers' challenging parenting was not significantly related to child anxiety, whereas fathers' challenging parenting was related to less child anxiety. Post-hoc meta-analyses revealed that mothers' and fathers' parenting was more strongly related to children's anxiety symptoms than to child anxiety precursors. Moreover, the association between parenting and child anxiety symptoms was stronger for fathers than for mothers. In conclusion, although parenting plays only a small role in early childhood anxiety, fathers' parenting is at least as important as mothers'. Paternal challenging behavior even seems more important than maternal challenging behavior. Research is needed to determine whether challenging fathering can prevent child anxiety development. PMID- 26978325 TI - Selective fractionation of Sugar Beet Pulp for release of fermentation and chemical feedstocks; optimisation of thermo-chemical pre-treatment. AB - The effect of time and pressure on the selective extraction of sugar beet pectin using steam pre-treatment on unprocessed Sugar Beet Pulp was evaluated using a design of experiments approach. This process gave the highest solubilisation of pectin oligomers at a relatively low pressure and longer time (5Bar, 24min), whilst leaving the majority of the cellulose fraction intact. This method of steam pre-treatment fits into the concept of a sugar beet biorefinery as it valorises an existing waste stream without requiring any further physical processing such as milling or dilution with water. The residual cellulose fraction was enriched in cellulose and could be effectively fermented into ethanol by yeast after enzymatic digestion, producing 0.48g ethanol per gram of glucose. PMID- 26978326 TI - Robotic Versus Thoracoscopic Resection for Lung Cancer: Early Results of a New Robotic Program. AB - BACKGROUND: Robot-assisted surgical techniques have been introduced in recent years as an alternative minimally invasive approach for lung surgery. While the advantage of video-assisted thoracoscopic surgery (VATS) over thoracotomy for anatomical lung resection has been extensively reported, the results of robotic video-assisted thoracoscopic surgery (RVATS) compared to VATS are still under investigation. METHODS: We performed a retrospective review of lung cancer patients, undergoing minimally invasive segmentectomy or lobectomy between December 2007 and May 2014. A robotic program was introduced in 2011. Relevant early surgical outcomes were compared between VATS and RVATS, including mortality, morbidity, conversion to thoracotomy, length of stay (LOS), and reoperation. RESULTS: Eighty (60.2%) patients underwent VATS resection, while 53 (39.8%) had a RVATS procedure. The two groups presented no meaningful differences at baseline, in terms of age, race, body mass index, and preoperative comorbidities. Adenocarcinoma was the most common histology in both groups. Patients in the RVATS group had significantly more segmentectomies (11.3% versus 1.2%, P = .016). There were no postoperative deaths. RVATS appeared to be associated with fewer conversions to open (13.2% versus 26.2%, P = .025) and more lymph nodes retrieved (9 versus 7, P = .049). We found no significant differences in terms of other individual complications, including tracheostomy, reintubation, pneumonia, pulmonary embolism, and cerebrovascular events. CONCLUSIONS: According to our results, the introduction of a robotic program did not negatively affect the early surgical outcomes of a well-established oncologic minimally invasive thoracic program. Potential advantages of RVATS still need to be explored in terms of long-term outcomes. PMID- 26978327 TI - Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo Controlled Study and Open-Label Extension. AB - OBJECTIVE: Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension. METHODS: A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day. RESULTS: There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks. CONCLUSIONS: This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications. PMID- 26978328 TI - Impact of Short and Moderate Rest Intervals on the Acute Immunometabolic Response to Exhaustive Strength Exercise: Part I. AB - The purpose of this study was to verify the influence of the short and moderate intervals of recovery in response to an acute bout of exhaustive strength exercise on performance, inflammatory, and metabolic responses in healthy adults. Eight healthy subjects (age = 24.6 +/- 4.1 years) performed 2 randomized sequences: short = 70% of 1 repetition maximum (1RM) with 30 seconds of rest between sets; moderate = 70% of 1RM with 90 seconds of rest between sets. All sequences of exercises were performed over 4 sets until movement failure in the squat and bench press exercises, respectively. The total number of repetitions performed was recorded for each set of each exercise for all sequences. The percentages of fat mass and fat-free mass were estimated by dual-energy x-ray absorptiometry. Glucose, tumor necrosis factor-alpha, interleukin (IL)-6, IL-10, and nonester fatty acid were assessed, at baseline, immediately after exercise, after 15 and 30 minutes. When compared with the maximum number of repetitions and the total weight lifted, there was a statistically significant decrease after both intervals. The only statistically significant decreases over time occurred at the post-15 minutes assessment of the IL-6 and glucose when a moderate interval of recovery was performed. When comparing the alterations between the pools (the mean of the cluster of all periods in each variable), there was a statistically significant increase on the IL-6 and IL-10 when a moderate interval of recovery was performed again, however, not considering a statistical difference on the IL-10. Thus, we concluded that different interval of recovery in response to exhaustive strength exercise decreases performance but in only moderate intervals, it is associated with inflammatory and metabolic response. PMID- 26978329 TI - Phosphorylation of Akt by SC79 Prevents Iron Accumulation and Ameliorates Early Brain Injury in a Model of Experimental Subarachnoid Hemorrhage. AB - Previous studies have demonstrated that activation of Akt may alleviate early brain injury (EBI) following subarachnoid hemorrhage (SAH). This study is undertaken to determine whether iron metabolism is involved in the beneficial effect of Akt activation after SAH. Therefore, we used a novel molecule, SC79, to activate Akt in an experimental Sprague-Dawley rat model of SAH. Rats were randomly divided into four groups as follows: sham, SAH, SAH + vehicle, SAH + SC79. The results confirmed that SC79 effectively enhanced the defense against oxidative stress and alleviated EBI in the temporal lobe after SAH. Interestingly, we found that phosphorylation of Akt by SC79 reduced cell surface transferrin receptor-mediated iron uptake and promoted ferroportin-mediated iron transport after SAH. As a result, SC79 administration diminished the iron content in the brain tissue. Moreover, the impaired Fe-S cluster biogenesis was recovered and loss of the activities of the Fe-S cluster-containing enzymes were regained, indicating that injured mitochondrial functions are restored to healthy levels. These findings suggest that disrupted iron homeostasis could contribute to EBI and Akt activation may regulate iron metabolism to relieve iron toxicity, further protecting neurons from EBI after SAH. PMID- 26978330 TI - Review on a Traditional Herbal Medicine, Eurycoma longifolia Jack (Tongkat Ali): Its Traditional Uses, Chemistry, Evidence-Based Pharmacology and Toxicology. AB - Eurycoma longifolia Jack (known as tongkat ali), a popular traditional herbal medicine, is a flowering plant of the family Simaroubaceae, native to Indonesia, Malaysia, Vietnam and also Cambodia, Myanmar, Laos and Thailand. E. longifolia, is one of the well-known folk medicines for aphrodisiac effects as well as intermittent fever (malaria) in Asia. Decoctions of E. longifolia leaves are used for washing itches, while its fruits are used in curing dysentery. Its bark is mostly used as a vermifuge, while the taproots are used to treat high blood pressure, and the root bark is used for the treatment of diarrhea and fever. Mostly, the roots extract of E. longifolia are used as folk medicine for sexual dysfunction, aging, malaria, cancer, diabetes, anxiety, aches, constipation, exercise recovery, fever, increased energy, increased strength, leukemia, osteoporosis, stress, syphilis and glandular swelling. The roots are also used as an aphrodisiac, antibiotic, appetite stimulant and health supplement. The plant is reported to be rich in various classes of bioactive compounds such as quassinoids, canthin-6-one alkaloids, beta-carboline alkaloids, triterpene tirucallane type, squalene derivatives and biphenyl neolignan, eurycolactone, laurycolactone, and eurycomalactone, and bioactive steroids. Among these phytoconstituents, quassinoids account for a major portion of the E. longifolia root phytochemicals. An acute toxicity study has found that the oral Lethal Dose 50 (LD50) of the alcoholic extract of E. longifolia in mice is between 1500-2000 mg/kg, while the oral LD50 of the aqueous extract form is more than 3000 mg/kg. Liver and renal function tests showed no adverse changes at normal daily dose and chronic use of E. longifolia. Based on established literature on health benefits of E. longifolia, it is important to focus attention on its more active constituents and the constituents' identification, determination, further development and most importantly, the standardization. Besides the available data, more evidence is required regarding its therapeutic efficacy and safety, so it can be considered a rich herbal source of new drug candidates. It is very important to conserve this valuable medicinal plant for the health benefit of future generations. PMID- 26978331 TI - Synthesis of New Functionalized Indoles Based on Ethyl Indol-2-carboxylate. AB - Successful alkylations of the nitrogen of ethyl indol-2-carboxylate were carried out using aq. KOH in acetone. The respective N-alkylated acids could be obtained without separating the N-alkylated esters by increasing the amount of KOH and water. The use of NaOMe in methanol led to transesterification instead of the alkylation, while the use of NaOEt led to low yields of the N-alkylated acids. Hydrazinolysis of the ester gave indol-2-carbohydrazide which then was allowed to react with different aromatic aldehydes and ketones in ethanol catalyzed by acetic acid. Indol-2-thiosemicarbazide was used in a heterocyclization reaction to form thiazoles. The new structures were confirmed using NMR, mass spectrometry and X-ray single crystal analysis. PMID- 26978332 TI - Quercetin-Rich Guava (Psidium guajava) Juice in Combination with Trehalose Reduces Autophagy, Apoptosis and Pyroptosis Formation in the Kidney and Pancreas of Type II Diabetic Rats. AB - We explored whether the combination of anti-oxidant and anti-inflammatory guava (Psidium guajava) and trehalose treatment protects the kidney and pancreas against Type II diabetes (T2DM)-induced injury in rats. We measured the active component of guava juice by HPLC analysis. T2DM was induced in Wistar rats by intraperitoneal administration of nicotinamide and streptozotocin and combination with high fructose diets for 8 weeks. The rats fed with different dosages of guava juice in combination with or without trehalose for 4 weeks were evaluated the parameters including OGTT, plasma insulin, HbA1c, HOMA-IR (insulin resistance) and HOMA-beta (beta cell function and insulin secretion). We measured oxidative and inflammatory degrees by immunohistochemistry stain, fluorescent stain, and western blot and serum and kidney reactive oxygen species (ROS) by a chemiluminescence analyzer. High content of quercetin in the guava juice scavenged H2O2 and HOCl, whereas trehalose selectively reduced H2O2, not HOCl. T2DM affected the levels in OGTT, plasma insulin, HbA1c, HOMA-IR and HOMA-beta, whereas these T2DM-altered parameters, except HbA1c, were significantly improved by guava and trehalose treatment. The levels of T2DM-enhanced renal ROS, 4 hydroxynonenal, caspase-3/apoptosis, LC3-B/autophagy and IL-1beta/pyroptosis were significantly decreased by guava juice and trehalose. The combination with trehalose and guava juice protects the pancreas and kidney against T2DM-induced injury. PMID- 26978333 TI - Role of Intestinal Microbiota in Baicalin-Induced Drug Interaction and Its Pharmacokinetics. AB - Since many glycoside compounds in natural products are hydrolyzed by intestinal microbiota when administered orally, it is of interest to know whether their pharmacological effects are derived from the glycoside itself or from the aglycone form in vivo. An interesting example is baicalin versus baicalein, the aglycone of baicalin, which is contained in some herbs from Labiatae including Scutellaria baicalensis Georgi and Scutellaria lateriflora Linne. The herbs have been extensively used for treatment of inflammatory diseases in Asia. Although there have been numerous reports regarding the pharmacological effects of baicalin and baicalein in vivo and in vitro, some reports indicated that the glycoside form would hardly be absorbed in the intestine and that it should be hydrolyzed to baicalein in advance for absorption. Therefore, the role of metabolism by intestinal microbiota should also be considered in the metabolism of baicalin. In addition, baicalin contains a glucuronide moiety in its structure, by which baicalin and baicalein show complex pharmacokinetic behaviors, due to the interconversion between them by phase II enzymes in the body. Recently, concerns about drug interaction with baicalin and/or baicalein have been raised, because of the co-administration of Scutellaria species with certain drugs. Herein, we reviewed the role of intestinal microbiota in pharmacokinetic characteristics of baicalin and baicalein, with regards to their pharmacological and toxicological effects. PMID- 26978335 TI - Investigation of the Pyridinium Ylide--Alkyne Cycloaddition as a Fluorogenic Coupling Reaction. AB - The cycloaddition of pyridinium ylides with alkynes was investigated under mild conditions. A series of 13 pyridinium salts was prepared by alkylation of 4 substituted pyridines. Their reactivity with propiolic ester or amide in various reaction conditions (different temperatures, solvents, added bases) was studied, and 11 indolizines, with three points of structural variation, were, thus, isolated and characterized. The highest yields were obtained when electron withdrawing groups were present on both the pyridinium ylide, generated in situ from the corresponding pyridinium salt, and the alkyne (X, Z = ester, amide, CN, carbonyl, etc.). Electron-withdrawing substituents, lowering the acid dissociation constant (pKa) of the pyridinium salts, allow the cycloaddition to proceed at pH 7.5 in aqueous buffers at room temperature. PMID- 26978334 TI - A Peptoid-Based Fluorescent Sensor for Cyanide Detection. AB - Peptoids, N-substituted glycine oligomers, are versatile peptidomimetics with diverse biomedical applications. However, strategies to the development of novel fluorescent peptoids as chemical sensors have not been extensively explored, yet. Here, we synthesized a novel peptoid-based fluorescent probe in which a coumarin moiety was incorporated via copper(I)-catalyzed azide-alkyne cycloaddition reaction. Fluorescence of the newly generated coumarin-peptoid was dramatically quenched upon coordination of the Cu(2+) ion, and the resulting peptoid-Cu(2+) complex exhibited significant Turn-ON fluorescence following the addition of CN( ). The rapid and reversible response, combined with cyanide selectivity of the synthesized peptoid, reflects a multistep photo-process and supports its utility as a new type of CN(-) sensor. PMID- 26978336 TI - Design, Synthesis and Antibacterial Evaluation of Some New 2-Phenyl-quinoline-4 carboxylic Acid Derivatives. AB - A series of new 2-phenyl-quinoline-4-carboxylic acid derivatives was synthesized starting from aniline, 2-nitrobenzaldehyde, pyruvic acid followed by Doebner reaction, amidation, reduction, acylation and amination. All of the newly synthesized compounds were characterized by 1H-NMR, (13)C-NMR and HRMS. The antibacterial activities of these compounds against Gram-negative (Escherichia coli, Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis), as well as one strain of methicillin-resistant Staphylococcus aureus (MRSA) bacteria were evaluated by the agar diffusion method (zone of inhibition) and a broth dilution method (minimum inhibitory concentration (MIC)), and their structure-activity relationships were obtained and discussed. The results revealed that some compounds displayed good antibacterial activity against Staphylococcus aureus, and Compounds 5a4 and 5a7 showed the best inhibition with an MIC value of 64 MUg/mL against Staphylococcus aureus and with an MIC value of 128 MUg/mL against Escherichia coli, respectively. The results of the MTT assay illustrated the low cytotoxicity of Compound 5a4. PMID- 26978337 TI - Coumarins, Xanthones and Related Compounds. PMID- 26978338 TI - Functionalization of a Triazine Dendrimer Presenting Four Maleimides on the Periphery and a DOTA Group at the Core. AB - A readily and rapidly accessible triazine dendrimer was manipulated in four steps with 23% overall yield to give a construct displaying four maleimide groups and DOTA. The maleimide groups of the dendrimer are sensitive to hydrolysis under basic conditions. The addition of up to four molecules of water can be observed via mass spectrometry and HPLC. The evolution in the alkene region of the 1H-NMR- the transformation of the maleimide singlet to the appearance of two doublets--is consistent with imide hydrolysis and not the Michael addition. The hydrolysis events that proceeded over hours are sufficiently slower than the desired thiol addition reactions that occur in minutes. The addition of thiols to maleimides can be accomplished in a variety of solvents. The thiols examined derived from cysteine and include the protected amino acid, a protected dipeptide, and native oligopeptides containing either 9 or 18 amino acids. The addition reactions were monitored with HPLC and mass spectrometry in most cases. Complete substitution was observed for small molecule reactants. The model peptides containing nine or eighteen amino acids provided a mixture of products averaging between 3 and 4 substitutions/dendrimer. The functionalization of the chelate group with gadolinium was also accomplished easily. PMID- 26978339 TI - Synthesis, Characterization and in Vitro Evaluation of Manganese Ferrite (MnFe2O4) Nanoparticles for Their Biocompatibility with Murine Breast Cancer Cells (4T1). AB - Manganese ferrite (MnFe2O4) magnetic nanoparticles were successfully prepared by a sol-gel self-combustion technique using iron nitrate and manganese nitrate, followed by calcination at 150 degrees C for 24 h. Calcined sample was systematically characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), and vibrational sample magnetometry (VSM) in order to identify the crystalline phase, functional group, morphology, particle size, shape and magnetic behavior. It was observed that the resultant spinal ferrites obtained at low temperature exhibit single phase, nanoparticle size and good magnetic behavior. The study results have revealed the existence of a potent dose dependent cytotoxic effect of MnFe2O4 nanoparticles against 4T1 cell lines at varying concentrations with IC50 values of 210, 198 and 171 MUg/mL after 24 h, 48 h and 72 h of incubation, respectively. Cells exposed to higher concentrations of nanoparticles showed a progressive increase of apoptotic and necrotic activity. Below 125 MUg/mL concentration the nanoparticles were biocompatible with 4T1 cells. PMID- 26978340 TI - Recent Advances in Volatiles of Teas. AB - Volatile compounds are important components of tea aroma, a key attribute of sensory quality. The present review examines the formation of aromatic volatiles of various kinds of teas and factors influencing the formation of tea volatiles, including tea cultivar, growing environment and agronomic practices, processing method and storage of tea. The determination of tea volatiles and the relationship of active-aroma volatiles with the sensory qualities of tea are also discussed in the present paper. PMID- 26978341 TI - Nanotechnology-Based Drug Delivery Systems for Photodynamic Therapy of Cancer: A Review. AB - Photodynamic therapy (PDT) is a promising alternative approach for improved cancer treatment. In PDT, a photosensitizer (PS) is administered that can be activated by light of a specific wavelength, which causes selective damage to the tumor and its surrounding vasculature. The success of PDT is limited by the difficulty in administering photosensitizers (PSs) with low water solubility, which compromises the clinical use of several molecules. Incorporation of PSs in nanostructured drug delivery systems, such as polymeric nanoparticles (PNPs), solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), gold nanoparticles (AuNPs), hydrogels, liposomes, liquid crystals, dendrimers, and cyclodextrin is a potential strategy to overcome this difficulty. Additionally, nanotechnology-based drug delivery systems may improve the transcytosis of a PS across epithelial and endothelial barriers and afford the simultaneous co delivery of two or more drugs. Based on this, the application of nanotechnology in medicine may offer numerous exciting possibilities in cancer treatment and improve the efficacy of available therapeutics. Therefore, the aim of this paper is to review nanotechnology-based drug delivery systems for photodynamic therapy of cancer. PMID- 26978343 TI - Chitosan and Its Derivatives as Highly Efficient Polymer Ligands. AB - The polyfunctional nature of chitosan enables its application as a polymer ligand not only for the recovery, separation, and concentration of metal ions, but for the fabrication of a wide spectrum of functional materials. Although unmodified chitosan itself is the unique cationic polysaccharide with very good complexing properties toward numerous metal ions, its sorption capacity and selectivity can be sufficiently increased and turned via chemical modification to meet requirements of the specific applications. In this review, which covers results of the last decade, we demonstrate how different strategies of chitosan chemical modification effect metal ions binding by O-, N-, S-, and P-containing chitosan derivatives, and which mechanisms are involved in binding of metal cation and anions by chitosan derivatives. PMID- 26978342 TI - Genetic and Epigenetic Approaches for the Possible Detection of Adulteration and Auto-Adulteration in Saffron (Crocus sativus L.) Spice. AB - Saffron (Crocus sativus L.) is very expensive and, because of this, often subject to adulteration. Modern genetic fingerprinting techniques are an alternative low cost technology to the existing chemical techniques, which are used to control the purity of food products. Buddleja officinalis Maxim, Gardenia jasminoides Ellis, Curcuma longa L., Carthamus tinctorius L. and Calendula officinalis L. are among the most frequently-used adulterants in saffron spice. Three commercial kits were compared concerning the ability to recover PCR-grade DNA from saffron, truly adulterated samples and possible adulterants, with a clear difference among them, mainly with the processed samples. Only one of the three kits was able to obtain amplifiable DNA from almost all of the samples, with the exception of extracts. On the recovered DNA, new markers were developed based on the sequence of the plastid genes matK and rbcL. These primers, mainly those developed on matK, were able to recognize saffron and the adulterant species and also in mixtures with very low percentages of adulterant. Finally, considering that the addition of different parts of saffron flowers is one of the most widespread adulterations, by analyzing the DNA of the different parts of the flower (styles, stamens and tepals) at the genetic and epigenetic level, we succeeded in finding differences between the three tissues that can be further evaluated for a possible detection of the kind of fraud. PMID- 26978345 TI - Erratum: Li, Y., et al. Mechanism of NO Photocatalytic Oxidation on g-C3N4 Was Changed by Pd-QDs Modification. Molecules, 2016, 21, 36. PMID- 26978344 TI - Regulation of Obesity and Metabolic Complications by Gamma and Delta Tocotrienols. AB - Tocotrienols (T3s) are a subclass of unsaturated vitamin E that have been extensively studied for their anti-proliferative, anti-oxidative and anti inflammatory properties in numerous cancer studies. Recently, T3s have received increasing attention due to their previously unrecognized property to attenuate obesity and its associated metabolic complications. In this review, we comprehensively evaluated the recent published scientific literature about the influence of T3s on obesity, with a particular emphasis on the signaling pathways involved. T3s have been demonstrated in animal models or human subjects to reduce fat mass, body weight, plasma concentrations of free fatty acid, triglycerides and cholesterol, as well as to improve glucose and insulin tolerance. Their mechanisms of action in adipose tissue mainly include (1) modulation of fat cell adipogenesis and differentiation; (2) modulation of energy sensing; (3) induction of apoptosis in preadipocytes and (4) modulation of inflammation. Studies have also been conducted to investigate the effects of T3s on other targets, e.g., the immune system, liver, muscle, pancreas and bone. Since deltaT3 and gammaT3 are regarded as the most active isomers among T3s, their clinical relevance to reduce obesity should be investigated in human trials. PMID- 26978346 TI - Botany in Molecular Era: A Modern Science with Ancient Roots. PMID- 26978348 TI - Spinal Glutamate Transporters Are Involved in the Development of Electroacupuncture Tolerance. AB - BACKGROUND: Electroacupuncture (EA) tolerance is a gradual decline in EA antinociception because of its repeated or prolonged use. This study aims to explore the role of spinal glutamate transporters (GTs) in EA tolerance (EAT). METHODS: Rats were treated with EA once per day for eight consecutive days, and their L4-5 spinal cords were collected at days 0, 2, 4, 6 and 8. The levels of three spinal GTs and their mRNAs were detected with Western blot and pPCR, respectively. Then, riluzole, a positive GT regulator, was administered intrathecally in order to observe its effect on EA analgesia after repeated EA. RESULTS: The expression levels of the spinal GTs increased at days 2 and 4, and gradually decreased as the times of EA increased. At day 8, no difference was observed in the spinal GTs between the sham treatment and the EA treatment. Intrathecal administration of riluzole dose-dependently attenuated the decreased EA analgesia. CONCLUSION: These results indicated the participation of the spinal GTs in EAT. PMID- 26978347 TI - Co-Expression and Co-Localization of Cartilage Glycoproteins CHI3L1 and Lubricin in Osteoarthritic Cartilage: Morphological, Immunohistochemical and Gene Expression Profiles. AB - Osteoarthritis is the most common human arthritis characterized by degeneration of articular cartilage. Several studies reported that levels of human cartilage glycoprotein chitinase 3-like-1 (CHI3L1) are known as a potential marker for the activation of chondrocytes and the progression of Osteoarthritis (OA), whereas lubricin appears to be chondroprotective. The aim of this study was to investigate the co-expression and co-localization of CHI3L1 and lubricin in normal and osteoarthritic rat articular cartilage to correlate their modified expression to a specific grade of OA. Samples of normal and osteoarthritic rat articular cartilage were analyzed by the Kellgren-Lawrence OA severity scores, the Kraus' modified Mankin score and the Histopathology Osteoarthritis Research Society International (OARSI) system for histomorphometric evaluations, and through CHI3L1 and lubricin gene expression, immunohistochemistry and double immuno-staining analysis. The immunoexpression and the mRNA levels of lubricin increased in normal cartilage and decreased in OA cartilage (normal vs. OA, p < 0.01). By contrast, the immunoexpression and the mRNA levels of CHI3L1 increased in OA cartilage and decreased in normal cartilage (normal vs. OA, p < 0.01). Our findings are consistent with reports suggesting that these two glycoproteins are functionally associated with the development of OA and in particular with grade 2/3 of OA, suggesting that in the future they could be helpful to stage the severity and progression of the disease. PMID- 26978349 TI - Probing the Ion Binding Site in a DNA Holliday Junction Using Forster Resonance Energy Transfer (FRET). AB - Holliday Junctions are critical DNA intermediates central to double strand break repair and homologous recombination. The junctions can adopt two general forms: open and stacked-X, which are induced by protein or ion binding. In this work, fluorescence spectroscopy, metal ion luminescence and thermodynamic measurements are used to elucidate the ion binding site and the mechanism of junction conformational change. Forster resonance energy transfer measurements of end labeled junctions monitored junction conformation and ion binding affinity, and reported higher affinities for multi-valent ions. Thermodynamic measurements provided evidence for two classes of binding sites. The higher affinity ion binding interaction is an enthalpy driven process with an apparent stoichiometry of 2.1 +/- 0.2. As revealed by Eu(3+) luminescence, this binding class is homogeneous, and results in slight dehydration of the ion with one direct coordination site to the junction. Luminescence resonance energy transfer experiments confirmed the presence of two ions and indicated they are 6-7 A apart. These findings are in good agreement with previous molecular dynamics simulations, which identified two symmetrical regions of high ion density in the center of stacked junctions. These results support a model in which site-specific binding of two ions in close proximity is required for folding of DNA Holliday junctions into the stacked-X conformation. PMID- 26978350 TI - Geranylgeraniol and Neurological Impairment: Involvement of Apoptosis and Mitochondrial Morphology. AB - Deregulation of the cholesterol pathway is an anomaly observed in human diseases, many of which have in common neurological involvement and unknown pathogenesis. In this study we have used Mevalonate Kinase Deficiency (MKD) as a disease-model in order to investigate the link between the deregulation of the mevalonate pathway and the consequent neurodegeneration. The blocking of the mevalonate pathway in a neuronal cell line (Daoy), using statins or mevalonate, induced an increase in the expression of the inflammasome gene (NLRP3) and programmed cell death related to mitochondrial dysfunction. The morphology of the mitochondria changed, clearly showing the damage induced by oxidative stress and the decreased membrane potential associated with the alterations of the mitochondrial function. The co-administration of geranylgeraniol (GGOH) reduced the inflammatory marker and the damage of the mitochondria, maintaining its shape and components. Our data allow us to speculate about the mechanism by which isoprenoids are able to rescue the inflammatory marker in neuronal cells, independently from the block of the mevalonate pathway, and about the fact that cell death is mitochondria related. PMID- 26978352 TI - Effects of Two Sublethal Concentrations of Mercury Chloride on the Morphology and Metallothionein Activity in the Liver of Zebrafish (Danio rerio). AB - Mercury (Hg) is a highly hazardous pollutant widely used in industrial, pharmaceutical and agricultural fields. Mercury is found in the environment in several forms, elemental, inorganic (iHg) and organic, all of which are toxic. Considering that the liver is the organ primarily involved in the regulation of metabolic pathways, homeostasis and detoxification we investigated the morphological and ultrastructural effects in Danio rerio liver after 96 h exposure to two low HgCl2 concentrations (7.7 and 38.5 MUg/L). We showed that a short-term exposure to very low concentrations of iHg severely affects liver morphology and ultrastructure. The main effects recorded in this work were: cytoplasm vacuolization, decrease in both lipid droplets and glycogen granules, increase in number of mitochondria, increase of rough endoplasmic reticulum and pyknotic nuclei. Pathological alterations observed were dose dependent. Trough immunohistochemistry, in situ hybridization and real-time PCR analysis, the induction of metallothionein (MT) under stressor conditions was also evaluated. Some of observed alterations could be considered as a general response of tissue to heavy metals, whereas others (such as increased number of mitochondria and increase of RER) may be considered as an adaptive response to mercury. PMID- 26978351 TI - Crosstalk between Long Noncoding RNAs and MicroRNAs in Health and Disease. AB - Protein-coding genes account for only a small part of the human genome; in fact, the vast majority of transcripts are comprised of non-coding RNAs (ncRNAs) including long ncRNAs (lncRNAs) and small ncRNAs, microRNAs (miRs). Accumulating evidence indicates that ncRNAs could play critical roles in regulating many cellular processes which are often implicated in health and disease. For example, ncRNAs are aberrantly expressed in cancers, heart diseases, and many other diseases. LncRNAs and miRs are therefore novel and promising targets to be developed into biomarkers for diagnosis and prognosis as well as treatment options. The interaction between lncRNAs and miRs as well as its pathophysiological significance have recently been reported. Mechanistically, it is believed that lncRNAs exert "sponge-like" effects on various miRs, which subsequently inhibits miR-mediated functions. This crosstalk between two types of ncRNAs frequently contributes to the pathogenesis of the disease. In this review, we provide a summary of the recent studies highlighting the interaction between these ncRNAs and the effects of this interaction on disease pathogenesis and regulation. PMID- 26978354 TI - A New Secondary Structure Assignment Algorithm Using Calpha Backbone Fragments. AB - The assignment of secondary structure elements in proteins is a key step in the analysis of their structures and functions. We have developed an algorithm, SACF (secondary structure assignment based on Calpha fragments), for secondary structure element (SSE) assignment based on the alignment of Calpha backbone fragments with central poses derived by clustering known SSE fragments. The assignment algorithm consists of three steps: First, the outlier fragments on known SSEs are detected. Next, the remaining fragments are clustered to obtain the central fragments for each cluster. Finally, the central fragments are used as a template to make assignments. Following a large-scale comparison of 11 secondary structure assignment methods, SACF, KAKSI and PROSS are found to have similar agreement with DSSP, while PCASSO agrees with DSSP best. SACF and PCASSO show preference to reducing residues in N and C cap regions, whereas KAKSI, P-SEA and SEGNO tend to add residues to the terminals when DSSP assignment is taken as standard. Moreover, our algorithm is able to assign subtle helices (310-helix, pi helix and left-handed helix) and make uniform assignments, as well as to detect rare SSEs in beta-sheets or long helices as outlier fragments from other programs. The structural uniformity should be useful for protein structure classification and prediction, while outlier fragments underlie the structure function relationship. PMID- 26978353 TI - Arginine Metabolism in Bacterial Pathogenesis and Cancer Therapy. AB - Antibacterial resistance to infectious diseases is a significant global concern for health care organizations; along with aging populations and increasing cancer rates, it represents a great burden for government healthcare systems. Therefore, the development of therapies against bacterial infection and cancer is an important strategy for healthcare research. Pathogenic bacteria and cancer have developed a broad range of sophisticated strategies to survive or propagate inside a host and cause infection or spread disease. Bacteria can employ their own metabolism pathways to obtain nutrients from the host cells in order to survive. Similarly, cancer cells can dysregulate normal human cell metabolic pathways so that they can grow and spread. One common feature of the adaption and disruption of metabolic pathways observed in bacterial and cancer cell growth is amino acid pathways; these have recently been targeted as a novel approach to manage bacterial infections and cancer therapy. In particular, arginine metabolism has been illustrated to be important not only for bacterial pathogenesis but also for cancer therapy. Therefore, greater insights into arginine metabolism of pathogenic bacteria and cancer cells would provide possible targets for controlling of bacterial infection and cancer treatment. This review will summarize the recent progress on the relationship of arginine metabolism with bacterial pathogenesis and cancer therapy, with a particular focus on arginase and arginine deiminase pathways of arginine catabolism. PMID- 26978355 TI - Molecular Selection, Modification and Development of Therapeutic Oligonucleotide Aptamers. AB - Monoclonal antibodies are the dominant agents used in inhibition of biological target molecules for disease therapeutics, but there are concerns of immunogenicity, production, cost and stability. Oligonucleotide aptamers have comparable affinity and specificity to targets with monoclonal antibodies whilst they have minimal immunogenicity, high production, low cost and high stability, thus are promising inhibitors to rival antibodies for disease therapy. In this review, we will compare the detailed advantages and disadvantages of antibodies and aptamers in therapeutic applications and summarize recent progress in aptamer selection and modification approaches. We will present therapeutic oligonucleotide aptamers in preclinical studies for skeletal diseases and further discuss oligonucleotide aptamers in different stages of clinical evaluation for various disease therapies including macular degeneration, cancer, inflammation and coagulation to highlight the bright commercial future and potential challenges of therapeutic oligonucleotide aptamers. PMID- 26978359 TI - Prediction of Military Vehicle's Drawbar Pull Based on an Improved Relevance Vector Machine and Real Vehicle Tests. AB - The scientific and effective prediction of drawbar pull is of great importance in the evaluation of military vehicle trafficability. Nevertheless, the existing prediction models have demonstrated lots of inherent limitations. In this framework, a multiple-kernel relevance vector machine model (MkRVM) including Gaussian kernel and polynomial kernel is proposed to predict drawbar pull. Nonlinear decreasing inertia weight particle swarm optimization (NDIWPSO) is employed for parameter optimization. As the relations between drawbar pull and its influencing factors have not been tested on real vehicles, a series of experimental analyses based on real vehicle test data are done to confirm the effective influencing factors. A dynamic testing system is applied to conduct field tests and gain required test data. Gaussian kernel RVM, polynomial kernel RVM, support vector machine (SVM) and generalized regression neural network (GRNN) are also used to compare with the MkRVM model. The results indicate that the MkRVM model is a preferable model in this case. Finally, the proposed novel model is compared to the traditional prediction model of drawbar pull. The results show that the MkRVM model significantly improves the prediction accuracy. A great potential of improved RVM is indicated in further research of wheel-soil interactions. PMID- 26978358 TI - Localization and Spectroscopic Analysis of the Cu(I) Binding Site in Wheat Metallothionein Ec-1. AB - The early cysteine-labeled metallothionein (MT) from Triticum aestivum (common wheat), denoted Ec-1, features two structurally well-defined domains, gamma and betaE, coordinating two and four Zn(II) ions, respectively. While the protein is currently assumed to function mainly in zinc homeostasis, a low amount of copper ions was also recently detected in a native Ec-1 sample. To evaluate the observed copper binding in more detail, the recombinant Zn6Ec-1 form was exposed to different amounts of Cu(I) ions and the resulting species characterized with spectroscopic methods. Data reveal that the first Cu(I) equivalent coordinates exclusively to the N-terminal gamma-domain of the protein and replaces one Zn(II) ion. To analyze the ability of the gamma-domain for coordination of monovalent metal ions in more detail, the gamma-Ec-1 peptide fragment was incubated with increasing amounts of Cu(I) and the process monitored with UV-VIS, circular dichroism, and luminescence spectroscopy. Closely similar spectra are observed regardless if the apo- or the metal ion-loaded and, hence, pre-folded forms, were used for the titration experiments with Cu(I). The results indicate that low amounts of Cu(I) ions displace the two metal ions subsequently and stoichiometrically, despite the different coordination geometry requirements of Cu(I) and Zn(II). PMID- 26978360 TI - XpertTrack: Precision Autonomous Measuring Device Developed for Real Time Shipments Tracker. AB - This paper proposes a software and hardware solution for real time condition monitoring applications. The proposed device, called XpertTrack, exchanges data through the GPRS protocol over a GSM network and monitories temperature and vibrations of critical merchandise during commercial shipments anywhere on the globe. Another feature of this real time tracker is to provide GPS and GSM positioning with a precision of 10 m or less. In order to interpret the condition of the merchandise, the data acquisition, analysis and visualization are done with 0.1 degrees C accuracy for the temperature sensor, and 10 levels of shock sensitivity for the acceleration sensor. In addition to this, the architecture allows increasing the number and the types of sensors, so that companies can use this flexible solution to monitor a large percentage of their fleet. PMID- 26978361 TI - AUV Positioning Method Based on Tightly Coupled SINS/LBL for Underwater Acoustic Multipath Propagation. AB - This paper researches an AUV (Autonomous Underwater Vehicle) positioning method based on SINS (Strapdown Inertial Navigation System)/LBL (Long Base Line) tightly coupled algorithm. This algorithm mainly includes SINS-assisted searching method of optimum slant-range of underwater acoustic propagation multipath, SINS/LBL tightly coupled model and multi-sensor information fusion algorithm. Fuzzy correlation peak problem of underwater LBL acoustic propagation multipath could be solved based on SINS positional information, thus improving LBL positional accuracy. Moreover, introduction of SINS-centered LBL locating information could compensate accumulative AUV position error effectively and regularly. Compared to loosely coupled algorithm, this tightly coupled algorithm can still provide accurate location information when there are fewer than four available hydrophones (or within the signal receiving range). Therefore, effective positional calibration area of tightly coupled system based on LBL array is wider and has higher reliability and fault tolerance than loosely coupled. It is more applicable to AUV positioning based on SINS/LBL. PMID- 26978357 TI - Postnatal High-Fat Diet Increases Liver Steatosis and Apoptosis Threatened by Prenatal Dexamethasone through the Oxidative Effect. AB - The objective of this study was to investigate cellular apoptosis in prenatal glucocorticoid overexposure and a postnatal high fat diet in rats. Pregnant Sprague-Dawley rats at gestational days 14 to 21 were administered saline (vehicle) or dexamethasone and weaned onto either a normal fat diet or a high fat diet for 180 days; in total four experimental groups were designated, i.e., vehicle treated group (VEH), dexamethasone treated group (DEX), vehicle treated plus high-fat diet (VHF), and dexamethasone treated plus high-fat diet (DHF). Chronic effects of prenatal liver programming were assessed at postnatal day 180. The apoptotic pathways involved proteins were analyzed by Western blotting for their expressions. Apoptosis and liver steatosis were also examined by histology. We found that liver steatosis and apoptosis were increased in the DHF, DEX, and VHF treated groups, and that the DHF treated group was increased at higher levels than the DEX and VHF treated groups. The expression of leptin was decreased more in the DHF treated group than in the DEX and VHF treated groups. Decreased peroxisome proliferator-activated receptor-gamma coactivator 1alpha, phosphoinositide-3-kinase, manganese superoxide dismutase and increased malondialdehyde expression levels were seen in DHF treated group relative to the DEX treated group. The DHF treated group exhibited higher levels of oxidative stress, apoptosis and liver steatosis than the DEX treated group. These results indicate that the environment of high-fat diet plays an important role in the development of liver injury after prenatal stress. PMID- 26978356 TI - Bidirectional Relationships and Disconnects between NAFLD and Features of the Metabolic Syndrome. AB - Non-alcoholic fatty liver disease (NAFLD) represents a wide spectrum of liver disease from simple steatosis, to steatohepatitis, (both with and without liver fibrosis), cirrhosis and end-stage liver failure. NAFLD also increases the risk of hepatocellular carcinoma (HCC) and both HCC and end stage liver disease may markedly increase risk of liver-related mortality. NAFLD is increasing in prevalence and is presently the second most frequent indication for liver transplantation. As NAFLD is frequently associated with insulin resistance, central obesity, dyslipidaemia, hypertension and hyperglycaemia, NAFLD is often considered the hepatic manifestation of the metabolic syndrome. There is growing evidence that this relationship between NAFLD and metabolic syndrome is bidirectional, in that NAFLD can predispose to metabolic syndrome features, which can in turn exacerbate NAFLD or increase the risk of its development in those without a pre-existing diagnosis. Although the relationship between NAFLD and metabolic syndrome is frequently bidirectional, recently there has been much interest in genotype/phenotype relationships where there is a disconnect between the liver disease and metabolic syndrome features. Such potential examples of genotypes that are associated with a dissociation between liver disease and metabolic syndrome are patatin-like phospholipase domain-containing protein-3 (PNPLA3) (I148M) and transmembrane 6 superfamily member 2 protein (TM6SF2) (E167K) genotypes. This review will explore the bidirectional relationship between metabolic syndrome and NAFLD, and will also discuss recent insights from studies of PNPLA3 and TM6SF2 genotypes that may give insight into how and why metabolic syndrome features and liver disease are linked in NAFLD. PMID- 26978362 TI - Lightweight CoAP-Based Bootstrapping Service for the Internet of Things. AB - The Internet of Things (IoT) is becoming increasingly important in several fields of industrial applications and personal applications, such as medical e-health, smart cities, etc. The research into protocols and security aspects related to this area is continuously advancing in making these networks more reliable and secure, taking into account these aspects by design. Bootstrapping is a procedure by which a user obtains key material and configuration information, among other parameters, to operate as an authenticated party in a security domain. Until now solutions have focused on re-using security protocols that were not developed for IoT constraints. For this reason, in this work we propose a design and implementation of a lightweight bootstrapping service for IoT networks that leverages one of the application protocols used in IoT : Constrained Application Protocol (CoAP). Additionally, in order to provide flexibility, scalability, support for large scale deployment, accountability and identity federation, our design uses technologies such as the Extensible Authentication Protocol (EAP) and Authentication Authorization and Accounting (AAA). We have named this service CoAP-EAP. First, we review the state of the art in the field of bootstrapping and specifically for IoT. Second, we detail the bootstrapping service: the architecture with entities and interfaces and the flow operation. Third, we obtain performance measurements of CoAP-EAP (bootstrapping time, memory footprint, message processing time, message length and energy consumption) and compare them with PANATIKI. The most significant and constrained representative of the bootstrapping solutions related with CoAP-EAP. As we will show, our solution provides significant improvements, mainly due to an important reduction of the message length. PMID- 26978363 TI - An SDR-Based Real-Time Testbed for GNSS Adaptive Array Anti-Jamming Algorithms Accelerated by GPU. AB - Nowadays, software-defined radio (SDR) has become a common approach to evaluate new algorithms. However, in the field of Global Navigation Satellite System (GNSS) adaptive array anti-jamming, previous work has been limited due to the high computational power demanded by adaptive algorithms, and often lack flexibility and configurability. In this paper, the design and implementation of an SDR-based real-time testbed for GNSS adaptive array anti-jamming accelerated by a Graphics Processing Unit (GPU) are documented. This testbed highlights itself as a feature-rich and extendible platform with great flexibility and configurability, as well as high computational performance. Both Space-Time Adaptive Processing (STAP) and Space-Frequency Adaptive Processing (SFAP) are implemented with a wide range of parameters. Raw data from as many as eight antenna elements can be processed in real-time in either an adaptive nulling or beamforming mode. To fully take advantage of the parallelism resource provided by the GPU, a batched method in programming is proposed. Tests and experiments are conducted to evaluate both the computational and anti-jamming performance. This platform can be used for research and prototyping, as well as a real product in certain applications. PMID- 26978364 TI - Sinabro: A Smartphone-Integrated Opportunistic Electrocardiogram Monitoring System. AB - In our preliminary study, we proposed a smartphone-integrated, unobtrusive electrocardiogram (ECG) monitoring system, Sinabro, which monitors a user's ECG opportunistically during daily smartphone use without explicit user intervention. The proposed system also monitors ECG-derived features, such as heart rate (HR) and heart rate variability (HRV), to support the pervasive healthcare apps for smartphones based on the user's high-level contexts, such as stress and affective state levels. In this study, we have extended the Sinabro system by: (1) upgrading the sensor device; (2) improving the feature extraction process; and (3) evaluating extensions of the system. We evaluated these extensions with a good set of algorithm parameters that were suggested based on empirical analyses. The results showed that the system could capture ECG reliably and extract highly accurate ECG-derived features with a reasonable rate of data drop during the user's daily smartphone use. PMID- 26978365 TI - Vision-Based Steering Control, Speed Assistance and Localization for Inner-City Vehicles. AB - Autonomous route following with road vehicles has gained popularity in the last few decades. In order to provide highly automated driver assistance systems, different types and combinations of sensors have been presented in the literature. However, most of these approaches apply quite sophisticated and expensive sensors, and hence, the development of a cost-efficient solution still remains a challenging problem. This work proposes the use of a single monocular camera sensor for an automatic steering control, speed assistance for the driver and localization of the vehicle on a road. Herein, we assume that the vehicle is mainly traveling along a predefined path, such as in public transport. A computer vision approach is presented to detect a line painted on the road, which defines the path to follow. Visual markers with a special design painted on the road provide information to localize the vehicle and to assist in its speed control. Furthermore, a vision-based control system, which keeps the vehicle on the predefined path under inner-city speed constraints, is also presented. Real driving tests with a commercial car on a closed circuit finally prove the applicability of the derived approach. In these tests, the car reached a maximum speed of 48 km/h and successfully traveled a distance of 7 km without the intervention of a human driver and any interruption. PMID- 26978366 TI - Measurement of 3-D Vibrational Motion by Dynamic Photogrammetry Using Least Square Image Matching for Sub-Pixel Targeting to Improve Accuracy. AB - This paper deals with an improved methodology to measure three-dimensional dynamic displacements of a structure by digital close-range photogrammetry. A series of stereo images of a vibrating structure installed with targets are taken at specified intervals by using two daily-use cameras. A new methodology is proposed to accurately trace the spatial displacement of each target in three dimensional space. This method combines the correlation and the least-square image matching so that the sub-pixel targeting can be obtained to increase the measurement accuracy. Collinearity and space resection theory are used to determine the interior and exterior orientation parameters. To verify the proposed method, experiments have been performed to measure displacements of a cantilevered beam excited by an electrodynamic shaker, which is vibrating in a complex configuration with mixed bending and torsional motions simultaneously with multiple frequencies. The results by the present method showed good agreement with the measurement by two laser displacement sensors. The proposed methodology only requires inexpensive daily-use cameras, and can remotely detect the dynamic displacement of a structure vibrating in a complex three-dimensional defection shape up to sub-pixel accuracy. It has abundant potential applications to various fields, e.g., remote vibration monitoring of an inaccessible or dangerous facility. PMID- 26978367 TI - Wireless Metal Detection and Surface Coverage Sensing for All-Surface Induction Heating. AB - All-surface induction heating systems, typically comprising small-area coils, face a major challenge in detecting the presence of a metallic vessel and identifying its partial surface coverage over the coils to determine which of the coils to power up. The difficulty arises due to the fact that the user can heat vessels made of a wide variety of metals (and their alloys). To address this problem, we propose and demonstrate a new wireless detection methodology that allows for detecting the presence of metallic vessels together with uniquely sensing their surface coverages while also identifying their effective material type in all-surface induction heating systems. The proposed method is based on telemetrically measuring simultaneously inductance and resistance of the induction coil coupled with the vessel in the heating system. Here, variations in the inductance and resistance values for an all-surface heating coil loaded by vessels (made of stainless steel and aluminum) at different positions were systematically investigated at different frequencies. Results show that, independent of the metal material type, unique identification of the surface coverage is possible at all freqeuncies. Additionally, using the magnitude and phase information extracted from the coupled coil impedance, unique identification of the vessel effective material is also achievable, this time independent of its surface coverage. PMID- 26978368 TI - Synthesis of Common Arabic Handwritings to Aid Optical Character Recognition Research. AB - Document analysis tasks such as pattern recognition, word spotting or segmentation, require comprehensive databases for training and validation. Not only variations in writing style but also the used list of words is of importance in the case that training samples should reflect the input of a specific area of application. However, generation of training samples is expensive in the sense of manpower and time, particularly if complete text pages including complex ground truth are required. This is why there is a lack of such databases, especially for Arabic, the second most popular language. However, Arabic handwriting recognition involves different preprocessing, segmentation and recognition methods. Each requires particular ground truth or samples to enable optimal training and validation, which are often not covered by the currently available databases. To overcome this issue, we propose a system that synthesizes Arabic handwritten words and text pages and generates corresponding detailed ground truth. We use these syntheses to validate a new, segmentation based system that recognizes handwritten Arabic words. We found that a modification of an Active Shape Model based character classifiers-that we proposed earlier-improves the word recognition accuracy. Further improvements are achieved, by using a vocabulary of the 50,000 most common Arabic words for error correction. PMID- 26978369 TI - Pressure Mapping Mat for Tele-Home Care Applications. AB - In this paper we present the development of a mat-like pressure mapping system based on a single layer textile sensor and intended to be used in home environments for monitoring the physical condition of persons with limited mobility. The sensor is fabricated by embroidering silver-coated yarns on a light cotton fabric and creating pressure-sensitive resistive elements by stamping the conductive polymer poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) ( PEDOT: PSS) at the crossing points of conductive stitches. A battery-operated mat prototype was developed and includes the scanning circuitry and a wireless communication module. A functional description of the system is presented together with a preliminary experimental evaluation of the mat prototype in the extraction of plantar pressure parameters. PMID- 26978370 TI - Design Methodology of a Dual-Halbach Array Linear Actuator with Thermal Electromagnetic Coupling. AB - This paper proposes a design methodology for linear actuators, considering thermal and electromagnetic coupling with geometrical and temperature constraints, that maximizes force density and minimizes force ripple. The method allows defining an actuator for given specifications in a step-by-step way so that requirements are met and the temperature within the device is maintained under or equal to its maximum allowed for continuous operation. According to the proposed method, the electromagnetic and thermal models are built with quasi static parametric finite element models. The methodology was successfully applied to the design of a linear cylindrical actuator with a dual quasi-Halbach array of permanent magnets and a moving-coil. The actuator can produce an axial force of 120 N and a stroke of 80 mm. The paper also presents a comparative analysis between results obtained considering only an electromagnetic model and the thermal-electromagnetic coupled model. This comparison shows that the final designs for both cases differ significantly, especially regarding its active volume and its electrical and magnetic loading. Although in this paper the methodology was employed to design a specific actuator, its structure can be used to design a wide range of linear devices if the parametric models are adjusted for each particular actuator. PMID- 26978371 TI - Experimental Validation of a Compound Control Scheme for a Two-Axis Inertially Stabilized Platform with Multi-Sensors in an Unmanned Helicopter-Based Airborne Power Line Inspection System. AB - A compound control scheme is proposed to achieve high control performance for a two-axis inertially stabilized platform (ISP) with multi-sensors applied to an unmanned helicopter (UH)-based airborne power line inspection (APLI) system. Compared with the traditional two closed-loop control scheme that is composed of a high-bandwidth rate loop and a lower bandwidth position loop, a new current loop inside rate loop is particularly designed to suppress the influences of voltage fluctuation from power supply and motor back electromotive force (BEMF) on control precision. In this way, the stabilization accuracy of the ISP is greatly improved. The rate loop, which is the middle one, is used to improve sensor's stability precision through compensating for various disturbances. To ensure the pointing accuracy of the line of sight (LOS) of multi-sensors, the position loop is designed to be the outer one and acts as the main feedback path, by which the accurate pointing angular position is achieved. To validate the scheme, a series of experiments were carried out. The results show that the proposed compound control scheme can achieve reliable control precision and satisfy the requirements of real APLI tasks. PMID- 26978372 TI - Three-Dimensional ISAR Imaging Method for High-Speed Targets in Short-Range Using Impulse Radar Based on SIMO Array. AB - This paper proposes a three-dimensional inverse synthetic aperture radar (ISAR) imaging method for high-speed targets in short-range using an impulse radar. According to the requirements for high-speed target measurement in short-range, this paper establishes the single-input multiple-output (SIMO) antenna array, and further proposes a missile motion parameter estimation method based on impulse radar. By analyzing the motion geometry relationship of the warhead scattering center after translational compensation, this paper derives the receiving antenna position and the time delay after translational compensation, and thus overcomes the shortcomings of conventional translational compensation methods. By analyzing the motion characteristics of the missile, this paper estimates the missile's rotation angle and the rotation matrix by establishing a new coordinate system. Simulation results validate the performance of the proposed algorithm. PMID- 26978374 TI - Deep Subseafloor Fungi as an Untapped Reservoir of Amphipathic Antimicrobial Compounds. AB - The evolving global threat of antimicrobial resistance requires a deep renewal of the antibiotic arsenal including the isolation and characterization of new drugs. Underexplored marine ecosystems may represent an untapped reservoir of novel bioactive molecules. Deep-sea fungi isolated from a record-depth sediment core of almost 2000 m below the seafloor were investigated for antimicrobial activities. This antimicrobial screening, using 16 microbial targets, revealed 33% of filamentous fungi synthesizing bioactive compounds with activities against pathogenic bacteria and fungi. Interestingly, occurrence of antimicrobial producing isolates was well correlated with the complexity of the habitat (in term of microbial richness), as higher antimicrobial activities were obtained at specific layers of the sediment core. It clearly highlights complex deep-sea habitats as chemical battlefields where synthesis of numerous bioactive compounds appears critical for microbial competition. The six most promising deep subseafloor fungal isolates were selected for the production and extraction of bioactive compounds. Depending on the fungal isolates, antimicrobial compounds were only biosynthesized in semi-liquid or solid-state conditions as no antimicrobial activities were ever detected using liquid fermentation. An exception was made for one fungal isolate, and the extraction procedure designed to extract amphipathic compounds was successful and highlighted the amphiphilic profile of the bioactive metabolites. PMID- 26978376 TI - Astaxanthin Inhibits Acetaldehyde-Induced Cytotoxicity in SH-SY5Y Cells by Modulating Akt/CREB and p38MAPK/ERK Signaling Pathways. AB - Excessive alcohol consumption can lead to brain tissue damage and cognitive dysfunction. Acetaldehyde, the most toxic metabolite of ethanol, mediates the brain tissue damage and cognitive dysfunction induced by chronic excessive alcohol consumption. In this study, the effect of astaxanthin, a marine bioactive compound, on acetaldehyde-induced cytotoxicity was investigated in SH-SY5Y cells. It was found that astaxanthin protected cells from apoptosis by ameliorating the effect of acetaldehyde on the expression of Bcl-2 family proteins, preventing the reduction of anti-apoptotic protein Bcl-2 and the increase of pro-apoptotic protein Bak induced by acetaldehyde. Further analyses showed that astaxanthin treatment inhibited acetaldehyde-induced reduction of the levels of activated Akt and cyclic AMP-responsive element binding protein (CREB). Astaxanthin treatment also prevented acetaldehyde-induced increase of the level of activated p38 mitogen-activated protein kinase (MAPK) and decrease of the level of activated extracellular signal-regulated kinases (ERKs). Activation of Akt/CREB pathway promotes cell survival and is involved in the upregulation of Bcl-2 gene. P38MAPK plays a critical role in apoptotic events while ERKs mediates the inhibition of apoptosis. Thus, astaxanthin may inhibit acetaldehyde-induced apoptosis through promoting the activation of Akt/CREB and ERKs and blocking the activation of p38MAPK. In addition, astaxanthin treatment suppressed the oxidative stress induced by acetaldehyde and restored the antioxidative capacity of SH-SY5Y cells. Therefore, astaxanthin may protect cells against acetaldehyde-induced cytotoxicity through maintaining redox balance and modulating apoptotic and survival signals. The results suggest that astaxanthin treatment may be beneficial for preventing neurotoxicity associated with acetaldehyde and excessive alcohol consumption. PMID- 26978378 TI - The Risk Implications of Globalisation: An Exploratory Analysis of 105 Major Industrial Incidents (1971-2010). AB - This paper revisits work on the socio-political amplification of risk, which predicts that those living in developing countries are exposed to greater risk than residents of developed nations. This prediction contrasts with the neoliberal expectation that market driven improvements in working conditions within industrialising/developing nations will lead to global convergence of hazard exposure levels. It also contradicts the assumption of risk society theorists that there will be an ubiquitous increase in risk exposure across the globe, which will primarily affect technically more advanced countries. Reviewing qualitative evidence on the impact of structural adjustment reforms in industrialising countries, the export of waste and hazardous waste recycling to these countries and new patterns of domestic industrialisation, the paper suggests that workers in industrialising countries continue to face far greater levels of hazard exposure than those of developed countries. This view is confirmed when a data set including 105 major multi-fatality industrial disasters from 1971 to 2000 is examined. The paper concludes that there is empirical support for the predictions of socio-political amplification of risk theory, which finds clear expression in the data in a consistent pattern of significantly greater fatality rates per industrial incident in industrialising/developing countries. PMID- 26978375 TI - Pseudopterosin A: Protection of Synaptic Function and Potential as a Neuromodulatory Agent. AB - Natural products have provided an invaluable source of inspiration in the drug discovery pipeline. The oceans are a vast source of biological and chemical diversity. Recently, this untapped resource has been gaining attention in the search for novel structures and development of new classes of therapeutic agents. Pseudopterosins are group of marine diterpene glycosides that possess an array of potent biological activities in several therapeutic areas. Few studies have examined pseudopterosin effects during cellular stress and, to our knowledge, no studies have explored their ability to protect synaptic function. The present study probes pseudopterosin A (PsA) for its neuromodulatory properties during oxidative stress using the fruit fly, Drosophila melanogaster. We demonstrate that oxidative stress rapidly reduces neuronal activity, resulting in the loss of neurotransmission at a well-characterized invertebrate synapse. PsA mitigates this effect and promotes functional tolerance during oxidative stress by prolonging synaptic transmission in a mechanism that differs from scavenging activity. Furthermore, the distribution of PsA within mammalian biological tissues following single intravenous injection was investigated using a validated bioanalytical method. Comparable exposure of PsA in the mouse brain and plasma indicated good distribution of PsA in the brain, suggesting its potential as a novel neuromodulatory agent. PMID- 26978377 TI - Discovery of Novel Antiangiogenic Marine Natural Product Scaffolds. AB - Marine natural products (MNPs) are recognized for their structural complexity, diversity, and novelty. The vast majority of MNPs are pharmacologically relevant through their ability to modulate macromolecular targets underlying human diseases. Angiogenesis is a fundamental process in cancer progression and metastasis. Targeting angiogenesis through selective modulation of linked protein kinases is a valid strategy to discover novel effective tumor growth and metastasis inhibitors. An in-house marine natural products mini-library, which comprises diverse MNP entities, was submitted to the Lilly's Open Innovation Drug Discovery platform. Accepted structures were subjected to in vitro screening to discover mechanistically novel angiogenesis inhibitors. Active hits were subjected to additional angiogenesis-targeted kinase profiling. Some natural and semisynthetic MNPs, including multiple members of the macrolide latrunculins, the macrocyclic oxaquinolizidine alkaloid araguspongine C, and the sesquiterpene quinone puupehenone, showed promising results in primary and secondary angiogenesis screening modules. These hits inhibited vascular endothelial growth factor (VEGF)-mediated endothelial tube-like formation, with minimal cytotoxicity at relevant doses. Secondary kinase profiling identified six target protein kinases, all involved in angiogenesis signaling pathways. Molecular modeling and docking experiments aided the understanding of molecular binding interactions, identification of pharmacophoric epitopes, and deriving structure-activity relationships of active hits. Marine natural products are prolific resources for the discovery of chemically and mechanistically unique selective antiangiogenic scaffolds. PMID- 26978380 TI - Erratum: Li, Z., et al. Smoking Prevalence and Associated Factors as well as Attitudes and Perceptions towards Tobacco Control in Northeast China. Int. J. Environ. Res. Public Health 2015, 12, 8606-8618. PMID- 26978379 TI - Association of Safe Disposal of Child Feces and Reported Diarrhea in Indonesia: Need for Stronger Focus on a Neglected Risk. AB - Indonesia still faces several challenges in the areas of water, sanitation, and hygiene (WASH). Diarrhea remains a major killer of children and it is important to understand the local diarrhea transmission pathways to prioritise appropriate WASH interventions to reduce diarrhea burden. This study used a cross-sectional data set from a recent national household survey (the 2012 Indonesia Demographic and Health Survey) to examine the associations between diarrhea in children aged less than 24 months with WASH interventions and population characteristics. Unsafe disposal of child feces was strongly associated with an increased odds of child diarrhea (OR: 1.46; 95% CI: 1.18-1.82, p = 0.001). However, other WASH practices were not found to be associated. The findings underline the dangers of unsafe disposal of child feces and highlight the need for strengthening the related policies and program strategies and their implementation. PMID- 26978373 TI - Potential Use of Antimicrobial Peptides as Vaginal Spermicides/Microbicides. AB - The concurrent increases in global population and sexually transmitted infection (STI) demand a search for agents with dual spermicidal and microbicidal properties for topical vaginal application. Previous attempts to develop the surfactant spermicide, nonoxynol-9 (N-9), into a vaginal microbicide were unsuccessful largely due to its inefficiency to kill microbes. Furthermore, N-9 causes damage to the vaginal epithelium, thus accelerating microbes to enter the women's body. For this reason, antimicrobial peptides (AMPs), naturally secreted by all forms of life as part of innate immunity, deserve evaluation for their potential spermicidal effects. To date, twelve spermicidal AMPs have been described including LL-37, magainin 2 and nisin A. Human cathelicidin LL-37 is the most promising spermicidal AMP to be further developed for vaginal use for the following reasons. First, it is a human AMP naturally produced in the vagina after intercourse. Second, LL-37 exerts microbicidal effects to numerous microbes including those that cause STI. Third, its cytotoxicity is selective to sperm and not to the female reproductive tract. Furthermore, the spermicidal effects of LL 37 have been demonstrated in vivo in mice. Therefore, the availability of LL-37 as a vaginal spermicide/microbicide will empower women for self-protection against unwanted pregnancies and STI. PMID- 26978382 TI - A Survey of Accidental Hypothermia Knowledge among Navy Members in China and the Implications for Training. AB - OBJECTIVES: Accidental hypothermia (AH) is a potentially life-threatening condition that can lead to significant morbidity and life-long effects. Navy personnel are always at a greater risk of AH due to frequent outdoor work, wilderness exposure, prolonged immobility and exhaustion. The purpose of the survey was to assess Chinese Navy members' awareness of AH and to make recommendations with regard to better measures for improving it. METHODS: 111 Navy members completed a written questionnaire that was subsequently analyzed. RESULTS: 30.6% of the respondents have experienced AH and 64.9% rated their knowledge of AH as "low" or "none". Over half of them identified the initial symptom of AH as obvious shivering (69.4%) and apathy (45.0%). As for the aggravate symptoms, 60.9% chose the wrong answer of more obvious shivering instead of the right one-absence of shivering (5.4%). In the case of the treatment of mild AH, more than half of the respondents chose the wrong answers. CONCLUSIONS: This study suggests that the basic skills of recognition and treatment of AH are inadequate in the Chinese Navy. Further work is required to develop a systematical, comprehensive and corresponding education method that would promote correct actions during AH. PMID- 26978381 TI - Greenness and Birth Outcomes in a Range of Pennsylvania Communities. AB - Living in communities with more vegetation during pregnancy has been associated with higher birth weights, but fewer studies have evaluated other birth outcomes, and only one has been conducted in the Eastern United States, in regions with a broad range, including high levels, of greenness. We evaluated associations between prenatal residential greenness and birth outcomes (term birth weight, small for gestational age, preterm birth, and low 5 min Apgar score) across a range of community types using electronic health record data from 2006-2013 from the Geisinger Health System in Pennsylvania. We assigned greenness based on mother's geocoded address using the normalized difference vegetation index from satellite imagery. We used propensity scores to restrict the study population to comparable groups among those living in green vs. less-green areas. Analyses were adjusted for demographic, clinical, and environmental covariates, and stratified by community type (city, borough, and township). In cities, higher greenness (tertiles 2-3 vs. 1) was protective for both preterm (OR = 0.78, 95% CI: 0.61 0.99) and small for gestational age birth (OR = 0.73, 95% CI: 0.58-0.97), but not birth weight or Apgar score. We did not observe associations between greenness and birth outcomes in adjusted models in boroughs or townships. These results add to the evidence that greener cities might be healthier cities. PMID- 26978383 TI - A Cross Section Study to Determine the Prevalence of Antibodies against HIV Infection among Hepatitis B and C Infected Individuals. AB - (1) BACKGROUND: There are limited data regarding human immunodeficiency virus (HIV) prevalence among hepatitis B virus (HBV) or hepatitis C virus (HCV) infected individuals. The aim of this cross-sectional study is to determine the prevalence of HBV and HCV infection among HIV individuals; (2) METHODS: A total of 409 patients (126 HBV+ and 283 HCV+) referred to the Brazilian Reference Laboratory for Viral Hepatitis from 2010 to 2013 donated serum samples. Anti-HIV, HBsAg, anti-HBc, anti-HBs, anti-HBcIgM, anti-HBe, HBeAg, and anti-HCV antibodies were measured, and anti-HCV positive samples were tested for viral RNA and genotype; (3) RESULTS: The anti-HIV antibody prevalence was 10.31% and 4.59% among HBV+ and HCV+ patients, respectively. The HCV mean (SD) viral load was log 5.14 +/- 1.64 IU/mL, and genotype I was most prevalent (163/283). Anti-HBs and anti-HBc were detected in 40% and 26% of HCV+ individuals, respectively. Among the HBV+ population, the presence of anti-HIV antibodies was associated with male gender, marital status (married), tattoo, sexual orientation, sexual practices (oral sex and anal sex), history of sexually transmitted diseases (STDs), history of viral hepatitis treatment, and a sexual partner with hepatitis or HIV. For the HCV+ group, the presence of anti-HIV antibodies was associated with female gender, marital status (married), anal intercourse, previous history of STDs, and number of sexual partners; (4) CONCLUSION: A high prevalence of anti-HIV antibodies was found among individuals with HBV and HCV, showing the importance of education programmes towards HIV infection among HBV- and HCV-infected individuals. PMID- 26978384 TI - Elevated Blood Lead Levels in Infants and Mothers in Benin and Potential Sources of Exposure. AB - Lead in childhood is well known to be associated with poor neurodevelopment. As part of a study on maternal anemia and offspring neurodevelopment, we analyzed blood lead level (BLL) with no prior knowledge of lead exposure in 225 mothers and 685 offspring 1 to 2 years old from Allada, a semi-rural area in Benin, sub Saharan Africa, between May 2011 and May 2013. Blood samples were analyzed by inductively coupled plasma mass spectrometry. Environmental assessments in households and isotopic ratio measurements were performed for eight children with BLL > 100 ug/L. High lead levels (BLL > 50 ug/L) were found in 44% of mothers and 58% of children. The median BLL was 55.1 (interquartile range 39.2-85.0) and 46.6 (36.5-60.1) ug/L, respectively. Maternal BLL was associated with offspring's consumption of piped water and animals killed by ammunition. Children's BLL was associated with presence of paint chips in the house and consumption of animals killed by ammunition. In this population, with 98% of children still breastfed, children's BLL was highly associated with maternal BLL on multivariate analyses. Environmental measures and isotopic ratios supported these findings. Offspring may be highly exposed to lead in utero and probably via breastfeeding in addition to lead paint exposure. PMID- 26978386 TI - Cellular microRNAs Repress Vesicular Stomatitis Virus but Not Theiler's Virus Replication. AB - Picornavirus' genomic RNA is a positive-stranded RNA sequence that also serves as a template for translation and replication. Cellular microRNAs were reported to interfere to different extents with the replication of specific picornaviruses, mostly acting as inhibitors. However, owing to the high error rate of their RNA dependent RNA-polymerases, picornavirus quasi-species are expected to evolve rapidly in order to lose any detrimental microRNA target sequence. We examined the genome of Theiler's murine encephalomyelitis virus (TMEV) for the presence of under-represented microRNA target sequences that could have been selected against during virus evolution. However, little evidence for such sequences was found in the genome of TMEV and introduction of the most under-represented microRNA target (miR-770-3p) in TMEV did not significantly affect viral replication in cells expressing this microRNA. To test the global impact of cellular microRNAs on viral replication, we designed a strategy based on short-term Dicer inactivation in mouse embryonic fibroblasts. Short-term Dicer inactivation led to a >10-fold decrease in microRNA abundance and strongly increased replication of Vesicular stomatitis virus (VSV), which was used as a microRNA-sensitive control virus. In contrast, Dicer inactivation did not increase TMEV replication. In conclusion, cellular microRNAs appear to exert little influence on Theiler's virus fitness. PMID- 26978385 TI - A Novel Vaccine Approach for Chagas Disease Using Rare Adenovirus Serotype 48 Vectors. AB - Due to the increasing amount of people afflicted worldwide with Chagas disease and an increasing prevalence in the United States, there is a greater need to develop a safe and effective vaccine for this neglected disease. Adenovirus serotype 5 (Ad5) is the most common adenovirus vector used for gene therapy and vaccine approaches, but its efficacy is limited by preexisting vector immunity in humans resulting from natural infections. Therefore, we have employed rare serotype adenovirus 48 (Ad48) as an alternative choice for adenovirus/Chagas vaccine therapy. In this study, we modified Ad5 and Ad48 vectors to contain T. cruzi's amastigote surface protein 2 (ASP-2) in the adenoviral early gene. We also modified Ad5 and Ad48 vectors to utilize the "Antigen Capsid-Incorporation" strategy by adding T. cruzi epitopes to protein IX (pIX). Mice that were immunized with the modified vectors were able to elicit T. cruzi-specific humoral and cellular responses. This study indicates that Ad48-modified vectors function comparable to or even premium to Ad5-modified vectors. This study provides novel data demonstrating that Ad48 can be used as a potential adenovirus vaccine vector against Chagas disease. PMID- 26978387 TI - A Brazilian Marseillevirus Is the Founding Member of a Lineage in Family Marseilleviridae. AB - In 2003, Acanthamoeba polyphaga mimivirus (APMV) was discovered as parasitizing Acanthamoeba. It was revealed to exhibit remarkable features, especially odd genomic characteristics, and founded viral family Mimiviridae. Subsequently, a second family of giant amoebal viruses was described, Marseilleviridae, whose prototype member is Marseillevirus, discovered in 2009. Currently, the genomes of seven different members of this family have been fully sequenced. Previous phylogenetic analysis suggested the existence of three Marseilleviridae lineages: A, B and C. Here, we describe a new member of this family, Brazilian Marseillevirus (BrMV), which was isolated from a Brazilian sample and whose genome was fully sequenced and analyzed. Surprisingly, data from phylogenetic analyses and comparative genomics, including mean amino acid identity between BrMV and other Marseilleviridae members and the analyses of the core genome and pan-genome of marseilleviruses, indicated that this virus can be assigned to a new Marseilleviridae lineage. Even if the BrMV genome is one of the smallest among Marseilleviridae members, it harbors the second largest gene content into this family. In addition, the BrMV genome encodes 29 ORFans. Here, we describe the isolation and genome analyses of the BrMV strain, and propose its classification as the prototype virus of a new lineage D within the family Marseilleviridae. PMID- 26978388 TI - Human Cytomegalovirus Nuclear Egress Proteins Ectopically Expressed in the Heterologous Environment of Plant Cells are Strictly Targeted to the Nuclear Envelope. AB - In all eukaryotic cells, the nucleus forms a prominent cellular compartment containing the cell's nuclear genome. Although structurally similar, animal and plant nuclei differ substantially in details of their architecture. One example is the nuclear lamina, a layer of tightly interconnected filament proteins (lamins) underlying the nuclear envelope of metazoans. So far no orthologous lamin genes could be detected in plant genomes and putative lamin-like proteins are only poorly described in plants. To probe for potentially conserved features of metazoan and plant nuclear envelopes, we ectopically expressed the core nuclear egress proteins of human cytomegalovirus pUL50 and pUL53 in plant cells. pUL50 localizes to the inner envelope of metazoan nuclei and recruits the nuclear localized pUL53 to it, forming heterodimers. Upon expression in plant cells, a very similar localization pattern of both proteins could be determined. Notably, pUL50 is specifically targeted to the plant nuclear envelope in a rim-like fashion, a location to which coexpressed pUL53 becomes strictly corecruited from its initial nucleoplasmic distribution. Using pUL50 as bait in a yeast two-hybrid screening, the cytoplasmic re-initiation supporting protein RISP could be identified. Interaction of pUL50 and RISP could be confirmed by coexpression and coimmunoprecipitation in mammalian cells and by confocal laser scanning microscopy in plant cells, demonstrating partial pUL50-RISP colocalization in areas of the nuclear rim and other intracellular compartments. Thus, our study provides strong evidence for conserved structural features of plant and metazoan nuclear envelops and identifies RISP as a potential pUL50-interacting plant protein. PMID- 26978389 TI - Characterization of Viral Communities of Biting Midges and Identification of Novel Thogotovirus Species and Rhabdovirus Genus. AB - More than two thirds of emerging viruses are of zoonotic origin, and among them RNA viruses represent the majority. Ceratopogonidae (genus Culicoides) are well known vectors of several viruses responsible for epizooties (bluetongue, epizootic haemorrhagic disease, etc.). They are also vectors of the only known virus infecting humans: the Oropouche virus. Female midges usually feed on a variety of hosts, leading to possible transmission of emerging viruses from animals to humans. In this context, we report here the analysis of RNA viral communities of Senegalese biting midges using next-generation sequencing techniques as a preliminary step toward the identification of potential viral biohazards. Sequencing of the RNA virome of three pools of Culicoides revealed the presence of a significant diversity of viruses infecting plants, insects and mammals. Several novel viruses were detected, including a novel Thogotovirus species, related but genetically distant from previously described tick-borne thogotoviruses. Novel rhabdoviruses were also detected, possibly constituting a novel Rhabdoviridae genus, and putatively restricted to insects. Sequences related to the major viruses transmitted by Culicoides, i.e., African horse sickness, bluetongue and epizootic haemorrhagic disease viruses were also detected. This study highlights the interest in monitoring the emergence and circulation of zoonoses and epizooties using their arthropod vectors. PMID- 26978391 TI - Sources of Caffeine in Diets of US Children and Adults: Trends by Beverage Type and Purchase Location. AB - New sources of caffeine, besides coffee and tea, have been introduced into the US food supply. Data on caffeine consumption age and purchase location can help guide public health policy. National Health and Nutrition Examination Surveys (NHANES) were used to estimate population-level caffeine intakes, using data from 24-h dietary recall. First, caffeine intakes by age-group and beverage type were estimated using the most recent 2011-2012 data (n = 7456). Second, fourteen years trends in caffeine consumption, overall and by beverage type, were evaluated for adults and children. Trend analyses were conducted by age groups. Last, trends in caffeine intakes by purchase location and beverage type were estimated. In 2011 2012, children aged four to eight years consumed the least caffeine (15 mg/day), and adults aged 51-70 years consumed the most (213 mg/day). The population mean (age >= four years) was 135 mg/day, driven largely by coffee (90 mg/day), tea (25 mg/day), and soda (21 mg/day). For the 14-19 years and 20-34 years age-groups, energy drinks contributed 6 mg/day (9.9%) and 5 mg/day (4.5%), respectively. The bulk of caffeine came from store-bought coffee and tea. Among both children and adults combined, caffeine intakes declined from 175 mg/day (1999-2000) to 142 mg/day (2011-2012), largely driven by a drop in caffeine from soda (41 mg/day to 21 mg/day). Store-bought coffee and tea remain principal drivers of caffeine intake in the US. Sodas and energy drinks make minor contributions to overall caffeine intakes. PMID- 26978390 TI - Liposome-Based Adjuvants for Subunit Vaccines: Formulation Strategies for Subunit Antigens and Immunostimulators. AB - The development of subunit vaccines has become very attractive in recent years due to their superior safety profiles as compared to traditional vaccines based on live attenuated or whole inactivated pathogens, and there is an unmet medical need for improved vaccines and vaccines against pathogens for which no effective vaccines exist. The subunit vaccine technology exploits pathogen subunits as antigens, e.g., recombinant proteins or synthetic peptides, allowing for highly specific immune responses against the pathogens. However, such antigens are usually not sufficiently immunogenic to induce protective immunity, and they are often combined with adjuvants to ensure robust immune responses. Adjuvants are capable of enhancing and/or modulating immune responses by exposing antigens to antigen-presenting cells (APCs) concomitantly with conferring immune activation signals. Few adjuvant systems have been licensed for use in human vaccines, and they mainly stimulate humoral immunity. Thus, there is an unmet demand for the development of safe and efficient adjuvant systems that can also stimulate cell mediated immunity (CMI). Adjuvants constitute a heterogeneous group of compounds, which can broadly be classified into delivery systems or immunostimulators. Liposomes are versatile delivery systems for antigens, and they can carefully be customized towards desired immune profiles by combining them with immunostimulators and optimizing their composition, physicochemical properties and antigen-loading mode. Immunostimulators represent highly diverse classes of molecules, e.g., lipids, nucleic acids, proteins and peptides, and they are ligands for pattern-recognition receptors (PRRs), which are differentially expressed on APC subsets. Different formulation strategies might thus be required for incorporation of immunostimulators and antigens, respectively, into liposomes, and the choice of immunostimulator should ideally be based on knowledge regarding the specific PRR expression profile of the target APCs. Here, we review state-of-the-art formulation approaches employed for the inclusion of immunostimulators and subunit antigens into liposome dispersion and their optimization towards robust vaccine formulations. PMID- 26978393 TI - Socioeconomic Indicators Are Independently Associated with Nutrient Intake in French Adults: A DEDIPAC Study. AB - Studies have suggested differential associations of specific indicators of socioeconomic position (SEP) with nutrient intake and a cumulative effect of these indicators on diet. We investigated the independent association of SEP indicators (education, income, occupation) with nutrient intake and their effect modification. This cross-sectional analysis included 91,900 French adults from the NutriNet-Sante cohort. Nutrient intake was estimated using three 24-h records. We investigated associations between the three SEP factors and nutrient intake using sex-stratified analysis of covariance, adjusted for age and energy intake, and associations between income and nutrient intake stratified by education and occupation. Low educated participants had higher protein and cholesterol intakes and lower fibre, vitamin C and beta-carotene intakes. Low income individuals had higher complex carbohydrate intakes, and lower magnesium, potassium, folate and vitamin C intakes. Intakes of vitamin D and alcohol were lower in low occupation individuals. Higher income was associated with higher intakes of fibre, protein, magnesium, potassium, beta-carotene, and folate among low educated persons only, highlighting effect modification. Lower SEP, particularly low education, was associated with lower intakes of nutrients required for a healthy diet. Each SEP indicator was associated with specific differences in nutrient intake suggesting that they underpin different social processes. PMID- 26978392 TI - Diagnosing and Treating Intolerance to Carbohydrates in Children. AB - Intolerance to carbohydrates is relatively common in childhood, but still poorly recognized and managed. Over recent years it has come to the forefront because of progresses in our knowledge on the mechanisms and treatment of these conditions. Children with intolerance to carbohydrates often present with unexplained signs and symptoms. Here, we examine the most up-to-date research on these intolerances, discuss controversies relating to the diagnostic approach, including the role of molecular analysis, and provide new insights into modern management in the pediatric age, including the most recent evidence for correct dietary treatment. PMID- 26978394 TI - Fruit Intake and Abdominal Aortic Calcification in Elderly Women: A Prospective Cohort Study. AB - Cardiovascular disease (CVD) is the leading cause of death worldwide. There is a consistent inverse relationship between fruit intake with CVD events and mortality in cross-sectional and prospective observational studies, but the relationship of fruit intake with measurements of atherosclerosis in humans is less clear. Nutritional effects on abdominal aortic calcification (AAC), a marker for subclinical intimal and medial atherosclerotic vascular disease, have not been studied previously. The aim of this study was to examine the cross-sectional relationship of total and individual fruit (apple, pear, orange and other citrus, and banana) intake with AAC, scored between 0 and 24. The current study assessed baseline data for a cohort of 1052 women over 70 years of age who completed both a food frequency questionnaire assessing fruit intake, and underwent AAC measurement using dual energy X-ray absorptiometry. AAC scores were significantly negatively correlated with total fruit and apple intakes (p < 0.05), but not with pear, orange or banana intakes (p > 0.25). In multivariable-adjusted logistic regression, each standard deviation (SD; 50 g/day) increase in apple intake was associated with a 24% lower odds of having severe AAC (AAC score >5) (odd ratio OR): 0.76 (0.62, 0.93), p = 0.009). Total and other individual fruit intake were not associated with increased odds of having severe AAC. Apple but not total or other fruit intake is independently negatively associated with AAC in older women. PMID- 26978397 TI - Validity of Bioelectrical Impedance Analysis to Estimation Fat-Free Mass in the Army Cadets. AB - BACKGROUND: Bioelectrical Impedance Analysis (BIA) is a fast, practical, non invasive, and frequently used method for fat-free mass (FFM) estimation. The aims of this study were to validate predictive equations of BIA to FFM estimation in Army cadets and to develop and validate a specific BIA equation for this population. METHODS: A total of 396 males, Brazilian Army cadets, aged 17-24 years were included. The study used eight published predictive BIA equations, a specific equation in FFM estimation, and dual-energy X-ray absorptiometry (DXA) as a reference method. Student's t-test (for paired sample), linear regression analysis, and Bland-Altman method were used to test the validity of the BIA equations. RESULTS: Predictive BIA equations showed significant differences in FFM compared to DXA (p < 0.05) and large limits of agreement by Bland-Altman. Predictive BIA equations explained 68% to 88% of FFM variance. Specific BIA equations showed no significant differences in FFM, compared to DXA values. CONCLUSION: Published BIA predictive equations showed poor accuracy in this sample. The specific BIA equations, developed in this study, demonstrated validity for this sample, although should be used with caution in samples with a large range of FFM. PMID- 26978395 TI - Lactobacillus fermentum Suo Attenuates HCl/Ethanol Induced Gastric Injury in Mice through Its Antioxidant Effects. AB - The purpose of the study was to determine the inhibitory effects of Lactobacillus fermentum Suo (LF-Suo) on HCl/ethanol induced gastric injury in ICR (Institute for Cancer Research) mice and explain the mechanism of these effects through the molecular biology activities of LF-Suo. The studied mice were divided into four groups: healthy, injured, LF-Suo-L and LF-Suo-H group. After the LF-Suo intragastric administration, the gastric injury area was reduced compared to the injured group. The serum MOT (motilin), SP (substance P), ET (endothelin) levels of LF-Suo treated mice were lower, and SS (somatostatin), VIP (vasoactive intestinal peptide) levels were higher than the injured group mice. The cytokine IL-6 (interleukin 6), IL-12 (interleukin 12), TNF-alpha (tumor necrosis factor alpha) and IFN-gamma (interferon-gamma) serum levels were decreased after the LF Suo treatment. The gastric tissues SOD (superoxide dismutase), GSH-Px (glutathione peroxidase), NO (nitric oxide) and activities of LF-Suo treated mice were increased and MDA (malondialdehyde) activity was decreased compared to the injured group mice. By the RT-PCR assay, LF-Suo raised the occludin, EGF (epidermal growth factor), EGFR (epidermal growth factor receptor), VEGF (vascular endothelial growth factor), Fit-1 (fms-like tyrosine kinase-1), IkappaB alpha (inhibitor kappaB-alpha), nNOS (neuronal nitric oxide synthase), eNOS (endothelial nitric oxide synthase), Mn-SOD, Cu/Zn-SOD, CAT (catalase) mRNA or protein expressions and reduced the COX-2, NF-kappaB (nuclear factor kappaB), and iNOS (inducible nitric oxide synthase) expressions in gastric tissues compared to the gastric injured group mice. A high concentration (1.0 * 108 CFU/kg b.w.) of LF-Suo treatment showed stronger anti-gastric injury effects compared to a low concentration of (0.5 * 108 CFU/kg b.w.) of LF-Suo treatment. LF-Suo also showed strong survival in pH 3.0 man-made gastric juice and hydrophobic properties. These results indicate that LF-Suo has potential use as probiotics for its gastric injury treatment effects. PMID- 26978396 TI - Dietary Natural Products for Prevention and Treatment of Liver Cancer. AB - Liver cancer is the most common malignancy of the digestive system with high death rate. Accumulating evidences suggests that many dietary natural products are potential sources for prevention and treatment of liver cancer, such as grapes, black currant, plum, pomegranate, cruciferous vegetables, French beans, tomatoes, asparagus, garlic, turmeric, ginger, soy, rice bran, and some edible macro-fungi. These dietary natural products and their active components could affect the development and progression of liver cancer in various ways, such as inhibiting tumor cell growth and metastasis, protecting against liver carcinogens, immunomodulating and enhancing effects of chemotherapeutic drugs. This review summarizes the potential prevention and treatment activities of dietary natural products and their major bioactive constituents on liver cancer, and discusses possible mechanisms of action. PMID- 26978398 TI - Pre-Pregnancy Weight Status Is Associated with Diet Quality and Nutritional Biomarkers during Pregnancy. AB - Although the positive association between pre-pregnancy overweight and obesity with excessive gestational weight gain is well known, it is not clear how pre pregnancy weight status is associated with gestational weight gain through maternal diet during pregnancy. This study aimed to examine the relationship between pre-pregnancy weight status and diet quality and maternal nutritional biomarkers during pregnancy. Our study included 795 U.S. pregnant women from the National Health and Nutrition Examination Survey, 2003-2012. Pre-pregnancy body mass index (BMI) was calculated based on self-reported pre-pregnancy weight and height. The cutoff points of <18.5 (underweight), 18.5-24.9 (normal), 25.0-29.9 (overweight), and 30 kg/m2 (obese) were used to categorize pregnant women's weight status. Diet quality during pregnancy was assessed by the Healthy Eating Index (HEI)-2010 based on a 24-h recall. Multivariable logistic regressions were used to estimate the odds ratios (OR) and 95% confidence intervals (CI). For all pregnant women included in this study, the mean HEI-2010 (+/-standard error of the mean (SEM)) was 50.7 (+/-0.9). Women with obese pre-pregnancy BMI demonstrated significantly lower HEI-2010 compared to those with underweight and normal pre-pregnancy BMI, respectively. In an unadjusted model, women with pre pregnancy obesity BMI had increased odds for being in the lowest tertile of HEI 2010 (33.4 +/- 0.5) compared to those with underweight pre-pregnancy BMI (OR 5.0; 95% CI 2.2-11.4). The inverse association between pre-pregnancy overweight and obesity status and diet quality during pregnancy persisted even after we controlled for physical activity levels (adjusted OR (AOR) 3.8; 95% CI 1.2-11.7, AOR 5.4; 95% CI 2.0-14.5, respectively). Serum folate concentration (ng/mL) was significantly higher in underweight women compared to overweight women (23.4 +/- 1.7 vs. 17.0 +/- 0.8, p < 0.05). Serum iron concentration (ng/dL) was significantly higher in normal weight women compared to overweight women (86.2 +/ 5.0 vs. 68.9 +/- 3.0, p < 0.05). An inverse association was found between pre pregnancy weight status and diet quality and maternal nutritional biomarkers during pregnancy. Poor diet quality as measured by HEI-2010 was shown among overweight and obese women. Nutrition education and interventions need to be targeted to those women entering pregnancy as overweight and obese. PMID- 26978399 TI - A Revised Australian Dietary Guideline Index and Its Association with Key Sociodemographic Factors, Health Behaviors and Body Mass Index in Peri-Retirement Aged Adults. AB - The Dietary Guideline Index, a measure of diet quality, was updated to reflect the 2013 Australian Dietary Guidelines. This paper describes the revision of the index (DGI-2013) and examines its use in older adults. The DGI-2013 consists of 13 components reflecting food-based daily intake recommendations of the Australian Dietary Guidelines. In this cross-sectional study, the DGI-2013 score was calculated using dietary data collected via an 111-item food frequency questionnaire and additional food-related behaviour questions. The DGI-2013 score was examined in Australian adults (aged 55-65 years; n = 1667 men; 1801 women) according to sociodemographics, health-related behaviours and BMI. Women scored higher than men on the total DGI-2013 and all components except for dairy. Those who were from a rural area (men only), working full-time (men only), with lower education, smoked, did not meet physical activity guidelines, and who had a higher BMI, scored lower on the DGI-2013, highlighting a group of older adults at risk of poor health. The DGI-2013 is a tool for assessing compliance with the Australian Dietary Guidelines. We demonstrated associations between diet quality and a range of participant characteristics, consistent with previous literature. This suggests that the DGI-2013 continues to demonstrate convergent validity, consistent with the original Dietary Guideline Index. PMID- 26978400 TI - Anti-Diabetic Activities of Gastrodia elata Blume Water Extracts Are Mediated Mainly by Potentiating Glucose-Stimulated Insulin Secretion and Increasing beta Cell Mass in Non-Obese Type 2 Diabetic Animals. AB - The brain is an important modulator of glucose metabolism, and is known to respond Gastrodia elata Blume water extract (GEB). Therefore, we examined whether long-term administration of GEB has hypoglycemic activity, and its action mechanism was explored in partially-pancreatectomized rats that exhibit similar characteristics as Asian type 2 diabetes, non-obese insulin-insufficient diabetes. The rats were provided high-fat diets supplemented with either of (1) 0.5% GEB (GEB-L), (2) 2% GEB (GEB-H), (3) 2% dextrin (control), or (4) 2% dextrin with rosiglitazone (20 mg/kg body weight; positive-control) for eight weeks. GEB dose-dependently improved hypothalamic insulin signaling, enhanced whole-body insulin sensitivity during hyperinsulinemic euglycemic clamp, and reduced hepatic glucose output in a hyperinsulinemic state. GEB dose-dependently increased the area under the curve of the serum insulin levels at the first and second phases during hyperglycemic clamp compared to the control, whereas the positive control had no effect. Insulin sensitivity during the hyperglycemic state also improved, dose-dependently, in response to GEB compared with that of the control, but was less than the positive control. GEB-H increased the mass of beta-cells by potentiating proliferation and decreasing apoptosis. In conclusion, GEB could be a therapeutic agent for treating Asian type 2 diabetes. PMID- 26978401 TI - Heart Alterations after Domoic Acid Administration in Rats. AB - Domoic acid (DA) is one of the best known marine toxins, causative of important neurotoxic alterations. DA effects are documented both in wildlife and experimental assays, showing that this toxin causes severe injuries principally in the hippocampal area. In the present study we have addressed the long-term toxicological effects (30 days) of DA intraperitoneal administration in rats. Different histological techniques were employed in order to study DA toxicity in heart, an organ which has not been thoroughly studied after DA intoxication to date. The presence of DA was detected by immunohistochemical assays, and cellular alterations were observed both by optical and transmission electron microscopy. Although histological staining methods did not provide any observable tissue damage, transmission electron microscopy showed several injuries: a moderate lysis of myofibrils and loss of mitochondrial conformation. This is the first time the association between heart damage and the presence of the toxin has been observed. PMID- 26978403 TI - PhTx3-4, a Spider Toxin Calcium Channel Blocker, Reduces NMDA-Induced Injury of the Retina. AB - The in vivo neuroprotective effect of PhTx3-4, a spider toxin N-P/Q calcium channel blocker, was studied in a rat model of NMDA-induced injury of the retina. NMDA (N-Methyl-D-Aspartate)-induced retinal injury in rats reduced the b-wave amplitude by 62% +/- 3.6%, indicating the severity of the insult. PhTx3-4 treatment increased the amplitude of the b-wave, which was almost equivalent to the control retinas that were not submitted to injury. The PhTx3-4 functional protection of the retinas recorded on the ERG also was observed in the neuroprotection of retinal cells. NMDA-induced injury reduced live cells in the retina layers and the highest reduction, 84%, was in the ganglion cell layer. Notably, PhTx3-4 treatment caused a remarkable reduction of dead cells in the retina layers, and the highest neuroprotective effect was in the ganglion cells layer. NMDA-induced cytotoxicity of the retina increased the release of glutamate, reactive oxygen species (ROS) production and oxidative stress. PhTx3-4 treatment reduced glutamate release, ROS production and oxidative stress measured by malondialdehyde. Thus, we presented for the first time evidence of in vivo neuroprotection from NMDA-induced retinal injury by PhTx3-4 (-ctenitoxin-Pn3a), a spider toxin that blocks N-P/Q calcium channels. PMID- 26978402 TI - The Ins and Outs of Anthrax Toxin. AB - Anthrax is a severe, although rather rare, infectious disease that is caused by the Gram-positive, spore-forming bacterium Bacillus anthracis. The infectious form is the spore and the major virulence factors of the bacterium are its poly gamma-D-glutamic acid capsule and the tripartite anthrax toxin. The discovery of the anthrax toxin receptors in the early 2000s has allowed in-depth studies on the mechanisms of anthrax toxin cellular entry and translocation from the endocytic compartment to the cytoplasm. The toxin generally hijacks the endocytic pathway of CMG2 and TEM8, the two anthrax toxin receptors, in order to reach the endosomes. From there, the pore-forming subunit of the toxin inserts into endosomal membranes and enables translocation of the two catalytic subunits. Insertion of the pore-forming unit preferentially occurs in intraluminal vesicles rather than the limiting membrane of the endosome, leading to the translocation of the enzymatic subunits in the lumen of these vesicles. This has important consequences that will be discussed. Ultimately, the toxins reach the cytosol where they act on their respective targets. Target modification has severe consequences on cell behavior, in particular on cells of the immune system, allowing the spread of the bacterium, in severe cases leading to host death. Here we will review the literature on anthrax disease with a focus on the structure of the toxin, how it enters cells and its immunological effects. PMID- 26978405 TI - Melanoma Cancer Stem Cells: Markers and Functions. AB - The discovery of cancer stem cells (CSCs) in human solid tumors has allowed a better understanding of the biology and neoplastic transformation of normal melanocytes, and the possible mechanisms by which melanoma cells acquire tumorigenicity. In this review I summarize the literature findings on the potential biomarkers of melanoma CSCs, their presence in the melanoma cell populations, the interaction with the immune system (with both T and NK cells) and the role of melanoma CSCs in the clinics. Given the extraordinary progress in the therapy of melanoma caused by immune checkpoint antibodies blockade, I discuss how these antibodies can work by the activation of melanoma infiltrating T cells specifically recognizing neo-antigens expressed even by melanoma CSCs. This is the mechanism that can induce a regression of the metastatic melanomas. PMID- 26978404 TI - Mast Cell Targeted Chimeric Toxin Can Be Developed as an Adjunctive Therapy in Colon Cancer Treatment. AB - The association of colitis with colorectal cancer has become increasingly clear with mast cells being identified as important inflammatory cells in the process. In view of the relationship between mast cells and cancer, we studied the effect and mechanisms of mast cells in the development of colon cancer. Functional and mechanistic insights were gained from ex vivo and in vivo studies of cell interactions between mast cells and CT26 cells. Further evidence was reversely obtained in studies of mast cell targeted Fcepsilon-PE40 chimeric toxin. Experiments revealed mast cells could induce colon tumor cell proliferation and invasion. Cancer progression was found to be related to the density of mast cells in colonic submucosa. The activation of MAPK, Rho-GTPase, and STAT pathways in colon cancer cells was triggered by mast cells during cell-to-cell interaction. Lastly, using an Fcepsilon-PE40 chimeric toxin we constructed, we confirmed the promoting effect of mast cells in development of colon cancer. Mast cells are a promoting factor of colon cancer and thus also a potential therapeutic target. The Fcepsilon-PE40 chimeric toxin targeting mast cells could effectively prevent colon cancer in vitro and in vivo. Consequently, these data may demonstrate a novel immunotherapeutic approach for the treatment of tumors. PMID- 26978407 TI - Polishing Step Purification of High-Strength Wastewaters by Nanofiltration and Reverse Osmosis. AB - This article reports findings on the use of nanofiltration (NF) and reverse osmosis (RO) for secondary treatment of high-strength rendering facility wastewaters following an ultrafiltration step. These wastewaters present significant challenges to classical treatment technologies. Constant-pressure, direct-flow membrane filtration experiments were done to screen for flux and effluent water permeate quality of ten commercial NF and RO membranes. All membranes tested were effective in reducing total dissolved salts (TDS) and chemical oxygen demand (COD); however, only two membranes (Koch MPF-34 and Toray 70UB) gave sufficiently stable flux values to warrant longer term cross-flow filtration studies. Cross-flow flux measurements, scanning electron microscopy (SEM), X-ray dispersive spectroscopy (EDS), and attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR) indicated that both membranes were eventually fouled by organic and inorganic foulants; however, the Toray 70UB RO membrane yielded a capacity of 1600 L/m2 prior to cleaning. A preliminary economic analysis compared the estimated costs of energy and consumables for a dual-stage UF/RO membrane process and dissolved air floatation (DAF) and found membrane process costs could be less than about 40% of the current DAF process. PMID- 26978406 TI - Hepatitis Vaccines. AB - Viral hepatitis is a serious health problem all over the world. However, the reduction of the morbidity and mortality due to vaccinations against hepatitis A and hepatitis B has been a major component in the overall reduction in vaccine preventable diseases. We will discuss the epidemiology, vaccine development, and post-vaccination effects of the hepatitis A and B virus. In addition, we discuss attempts to provide hepatitis D vaccine for the 350 million individuals infected with hepatitis B globally. Given the lack of a hepatitis C vaccine, the many challenges facing the production of a hepatitis C vaccine will be shown, along with current and former vaccination trials. As there is no current FDA-approved hepatitis E vaccine, we will present vaccination data that is available in the rest of the world. Finally, we will discuss the existing challenges and questions facing future endeavors for each of the hepatitis viruses, with efforts continuing to focus on dramatically reducing the morbidity and mortality associated with these serious infections of the liver. PMID- 26978408 TI - Cerebrospinal Fluid Oxaliplatin Contributes to the Acute Pain Induced by Systemic Administration of Oxaliplatin. AB - BACKGROUND: Systemic administration of oxaliplatin has no effect on the tumors in the central nervous system (CNS) due to the limited concentration of oxaliplatin in the cerebrospinal fluid (CSF), while it was clinically reported that oxaliplatin can induce acute encephalopathy. Currently, the impairment of neuronal functions in the CNS after systemic administration of oxaliplatin remains uninvestigated. METHODS: The von Frey test and the plantar test were performed to evaluate neuropathic pain behavior after a single intraperitoneal administration of oxaliplatin (4 mg/kg) in rats. Inductively coupled plasma-mass spectrometry, electrophysiologic recording, real-time quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, Western blot, immunohistochemistry, and small interfering RNA were applied to understand the mechanisms. RESULTS: Concentration of oxaliplatin in CSF showed a time dependent increase after a single administration of oxaliplatin. Spinal application of oxaliplatin at the detected concentration (6.6 nM) significantly increased the field potentials in the dorsal horn, induced acute mechanical allodynia (n = 12 each) and thermal hyperalgesia (n = 12 each), and enhanced the evoked excitatory postsynaptic currents and spontaneous excitatory postsynaptic currents in the projection neurokinin 1 receptor-expressing lamina I to II neurons. The authors further found that oxaliplatin significantly increased the nuclear factor-kappaB p65 binding and histone H4 acetylation in cx3cl1 promoter region. Thus, the upregulated spinal CX3CL1 markedly mediated the induction of central sensitization and acute pain behavior after oxaliplatin administration. CONCLUSIONS: The findings of this study suggested that oxaliplatin in CSF may directly impair the normal function of central neurons and contribute to the rapid development of CNS-related side effects during chemotherapy. This provides novel targets to prevent oxaliplatin-induced acute painful neuropathy and encephalopathy. PMID- 26978410 TI - Automated Detection of Uninformative Frames in Pulmonary Optical Endomicroscopy. AB - SIGNIFICANCE: Optical endomicroscopy (OEM) is a novel real-time imaging technology that provides endoscopic images at a microscopic level. The nature of OEM data, as acquired in clinical use, gives rise to the presence of uninformative frames (i.e., pure-noise and motion-artefacts). Uninformative frames can comprise a considerable proportion (up to > 25%) of a dataset, increasing the resources required for analyzing the data (both manually and automatically), as well as diluting the results of any automated quantification analysis. OBJECTIVE: There is, therefore, a need to automatically detect and remove as many of these uninformative frames as possible while keeping frames with structural information intact. METHODS: This paper employs Gray Level Cooccurrence Matrix texture measures and detection theory to identify and remove such frames. The detection of pure-noise and motion-artefacts frames is treated as two independent problems. RESULTS: Pulmonary OEM frame sequences of the distal lung are employed for the development and assessment of the approach. The proposed approach identifies and removes uninformative frames with a sensitivity of 93% and a specificity of 92.6%. CONCLUSION: The detection algorithm is accurate and robust in pulmonary OEM frame sequences. Conditional to appropriate model refinement, the algorithms can become applicable in other organs. PMID- 26978409 TI - Is Chemotherapy-induced Peripheral Neuropathy More Than Just a Peripheral Nervous System Disorder? PMID- 26978411 TI - [Four variants of the pathogenesis of diarrhea and its therapy]. AB - Diarrhea is a symptom of many diseases; its pathogenesis is associated with four main mechanisms: water and electrolyte secretion into the intestinal lumen, osmolarity of the chyme, exudation, and impaired intestinal motility. The clinical manifestations, diagnosis, and therapy of bowel diseases are discussed in terms of the pathogenesis of diarrhea. PMID- 26978412 TI - [Treatment motivation in patients with chronic cardiorenal syndrome]. AB - AIM: To study treatment motivation in patients with chronic heart failure (CHF) and in those with CHF concurrent with chronic kidney disease (CKD). SUBJECTS AND METHODS: A total of 203 patients (130 men and 73 women; mean age, 61.8+/-9.6 years) with CHF diagnosed and assessed in accordance with the National Guidelines of the All-Russian Research Society of Cardiology and the Heart Failure Society for the diagnosis and treatment of CHF (third edition, 2009) were examined. CKD was diagnosed according to the 2012 National Guidelines of the Research Nephrology Society of Russia. A group of patients with chronic cardiorenal syndrome (CRS) included those with CHF and CKD with a glomerular filtration rate (GFR) of <60 ml/min/1.73 m2. The clinical course of CHF, personality profile, and motivation for non-drug and drug treatments were assessed in patients with chronic CRS. RESULTS: CFR was 67.7+/-17.2 ml/min/1.73 m2; chronic CRS was observed in 89 (44%) patients. Psychological functioning assessment showed that the patients with chronic CRS as compared with those with CHF without CKD had high anxiety and maladaptive disease attitudes. CHF treatment motivation (compliance with lifestyle modification and medication) was proved inadequate and detected only in 31 (15.3%) patients with CHF regardless of the presence of CKD. The specific features of psychological functioning, which affected treatment motivation, were seen in patients with chronic CRS: those who were lowly motivated had a euphoric attitude towards their disease (p=0.03); those who were satisfactorily motivated showed an emotive accentuation of character (p=0.002). CONCLUSION: The presence of CKD aggravates the clinical course of CHF and negatively affects the psychological functioning of patients with CHF. The patients with chronic CRS are characterized by a low level of motivation for both drug and non-drug treatments, which should be taken into account when managing this cohort of patients. PMID- 26978413 TI - [Effect of nonsteroidal anti-inflammatory drugs on the indicators of cardiovascular risk in patients with acute nonspecific back pain]. AB - AIM: To evaluate the safety of etoricoxib in patients with acute nonspecific back pain associated with the high risk of cardiovascular events (CVE) in clinical practice. SUBJECTS AND METHODS: The open prospective follow-up by a simple randomization method included 80 patients, including 49 women and 31 men (mean 60.8+/-4.7 years). The patients were randomized into 4 groups of 20 persons each: 1) etoricoxib 90 mg/day; 2) nimesulide 100 mg/day; 3) diclofenac 100 mg/day; 4) meloxicam 15 mg/day. The investigation lasted 90+/-4.5 days. The interim evaluation criteria (study points) were pain changes using a visual analog scale (VAS); blood pressure (BP) changes; diurnal BP rhythm; and changes in coagulation hemostatic parameters and blood biochemical markers. The primary evaluation criteria (study endpoints) were the incidence of CVE in the use of nonsteroidal anti-inflammatory drugs (NSAIDs). RESULTS: The patients with acute back pain were shown to have a high incidence of comorbidities during outpatient care. The administration of NSAIDs resulted in a significant reduction in the magnitude and intensity of pain syndrome according to VAS in all the groups just on day 3 of therapy with a more marked analgesia in patients receiving etoricoxib and diclofenac. All the groups exhibited an increase in average daily systolic and diastolic BP with the most favorable profile in Group 1 patients. The intake of etoricoxib and other NSAIDs provided no evidence for changes in hemostatic parameters and biochemical markers during 10 weeks. The safety of etoricoxib was comparable with that of NSAIDs in its effect on the plasma hemostatic system. CONCLUSION: Unlike nimesulide, diclofenac, and meloxicam, etoricoxib was characterized by a rapid steady-state analgesic effect with a less pronounced action on diurnal BP rhythm. Within 3 months after treatment, no acute CVE was recorded in the patients taking etoricoxib. PMID- 26978414 TI - [Severe asthma: Characteristics of patients in clinical practice]. AB - AIM: To provide clinical characteristics of severe asthma (SA) patients encountered in clinical practice. SUBJECTS AND METHODS: A cross-sectional cohort study was performed to cover 119 outpatients aged 22-82 years. SA was diagnosed according to the ERS/ATS criteria (2014). Spirometry and bronchodilator reversibility testing were carried out; fractional exhaled nitric oxide (FeNO) was measured; inhalant allergen hypersensitivity (skin prick and blood specific IgE testing) and peripheral blood eosinophil counts were estimated. Asthma control and asthma-related quality of life were assessed. RESULTS: 77% of the patients were found to have allergic asthma; in this case, house dust mites were leading allergens in the spectrum of sensitization. 82% of the patients were observed to have uncontrolled asthma and 76% had incompletely reversible bronchial obstruction. The airway eosinophilic inflammation markers (FeNO more than 25 ppb and eosinophil counts of more than 150 cells/u) were elevated in 63% of the patients. Good compliance was noted in 61% of the patients. There were 27% of active smokers who had lower lung function and FeNO levels. The smokers showed a low compliance with inhaled glucocorticosteroid treatment. SA was concurrent with chronic obstructive pulmonary disease in 37% of the cases. CONCLUSION: SA is a heterogeneous disease. Traditional treatment is not always effective, as many patients, despite their treatment, have uncontrolled SA and continuously increased markers of airways eosinophilic inflammation. Monoclonal antibody therapy may promote success in treating this cohort of patients. PMID- 26978415 TI - [Vaccination in patients with chronic renal failure in the pre- and posttransplantation period]. AB - AIM: To clarify whether vaccination provokes renal graft rejection. SUBJECTS AND METHODS: A total of 131 vaccinations were performed in 92 patients with chronic kidney failure (CKF), including 7 and 85 patients vaccinated before and in different periods after kidney transplantation, respectively. The patients were examined using needle graft biopsy, measurement of proteinuria, and estimation of changes in blood creatinine levels and glomerular filtration rate. RESULTS: Vaccination was not fount to provoke rejection, as suggested by the results of needle biopsy of renal allografts and examination of their function. CONCLUSION: Vaccination is safe for patients with CKF as it causes no rejection episodes. PMID- 26978416 TI - [Matrix metalloproteinase 2, 3, and 9 gene polymorphisms in women with rheumatoid arthritis]. AB - AIM: To study the promoter regions of the matrix metalloproteinase (MMP)2, MMP3, and MMP9 genes to assess their associations with the risk of rheumatoid arthritis (RA) and with the types of its clinical course in women. SUBJECTS AND METHODS: 162 female patients with RA and 329 women without this condition were examined. Polymorphisms in the gene promoter region for MMP2 (-1306 S->T), MMP3 (-1171 5A >6A), and MMP9 (-1562 S->T) were studied. Genotyping was carried out using the restriction fragment length polymorphism method. RESULTS: In the RA group, the 1306TT genotype of MMP2 was significantly more frequently encountered and the 6A6A genotype was less frequently seen. In the seropositive RA group, the frequency of the -1306TT genotype of MMP2 was significantly higher than that in the healthy individuals. The significant differences shown for the entire group of patients with RA were preserved when they were divided into groups according to the presence or absence of rheumatoid nodules. Furthermore, the frequency of the homozygous -1306 genotypes of MMP2 was higher in both groups than in the healthy individuals. CONCLUSION: The presence of the allelic variants of the MMP genes may be one of the genetic factors that predispose to RA in women. PMID- 26978417 TI - [Correction of an inflammatory process with an interleukin-1 inhibitor in the combination treatment of secondary osteoarthritis in the presence of comorbid condition]. AB - AIM: To enhance the efficiency of treatment in patients with secondary osteoarthritis (OA) in the presence of comorbid condition, by using an interleukin-1 inhibitor (IL-1i) and laser therapy (LT). SUBJECTS AND METHODS: A total of 248 patients aged 38 to 65 years with RA and secondary OA who had predominantly Stage II in accordance with the Disease Activity Score 28 (DAS28) were examined. According to the received therapy, the patients were divided into 4 groups: 1) IL-1i + LT + mrthotrexate (MT); 2) IL-1i + MT; 3) LT + MT; 4) MT. The efficiency of treatment was evaluated from changes in the KOOS (Knee injury and Osteoarthritis Outcome Score), DAS 28, IL-1, and cartilage oligomeric matrix protein (COMP) 6 months later. RESULTS: There were statistically significant functional improvements in KOOS and DAS28 in Groups 1 and 2 patients with secondary OA in RA. Clinical efficacy was confirmed by positive changes in serum IL-1 and COMP levels. CONCLUSION: Incorporation of an IL-1i into a therapy regimen for secondary OA in RA patients during basic therapy could not only improve the functional status of patients, but also decrease activity of the underlying disease according to the DAS 28. PMID- 26978419 TI - [Trend in the prevalence of rheumatoid arthritis among the adult population in the Republic of Kazakhstan in 2011-2012]. AB - AIM: To analyze a trend in overall and new-onset rheumatoid arthritis morbidity among the adult population in the Republic of Kazakhstan in 2011-2012. SUBJECTS AND METHODS: The data of 2011-2012 annual statistical reports on "Population Health and Healthcare System" (Form 12) were analyzed. The indicators in the Republic of Kazakhstan were taken from the statistics digest "Population Health in the Republic of Kazakhstan and Activities of Healthcare Facilities". RESULTS: Comparative analysis of the indicators revealed an increment in overall morbidity by 1%, including that in the incidence of musculoskeletal diseases (MSD) by 3% (the increment rate per 100,000 was 2%). The rise in MSD prevalence was 20% among the adults (aged 18 years and older) and 21% among the women; the increase in the number of patients with a first established diagnosis of RA was 27% and that was 20% among the women. There was a higher rate of rises by 52 and 48% in the number of MSD patients aged 60 years and older and in that of women, respectively; the number of patients with a first established diagnosis of RA increased by 10% and that rose 12% in the women. The number of patients with a first established diagnosis of RA increased considerably by 27 and 20% among the adults aged 18 years and older) and by 10 and 12% among those aged 60 years or over, respectively. CONCLUSION: In the Republic of Kazakhstan, there is a high prevalence of MSD among people aged above 18 years and above 60 years and there is a preponderance of able-bodied persons aged 18 years or above with a first established diagnosis of RA. PMID- 26978418 TI - [Use of ARTRA MSM FORTE in patients with knee osteoarthritis: Results of a randomized open-label comparative study of the efficacy and tolerability of the drug]. AB - AIM: To study the clinical efficacy and safety of the combined medication ARTRA MSM FORTE (400 mg chondroitin sulfate, 500 mg glucosamine hydrochloride, 300 mg methylsulfonylmethane (MSM), and 10 mg sodium hyaluronate calculated with reference to hyaluronic acid) in patients with knee osteoarthritis (OA). SUBJECTS AND METHODS: The study enrolled 100 patients with Kellgren-Lawrence grades 2-3 knee OA with obvious pain syndrome (pain intensity scores on a visual analog scale (VAS)) equal or greater than 40 mm during walking. The patients were examined monthly; changes in WOMAC index scores, Get-Up and Go test results, the efficiency of therapy in the opinion of a physician and a patient, and quality of life according to the EQ-5D questionnaire were estimated. They were randomized into 2 groups: 1) 50 patients took ARTRA MSM as 2 tablets daily for one month, then 1 tablet daily; 2) 50 received ARTRA in accordance with the same scheme. Clinical examination was performed before and at 30, 60, 90 and 120 days of the study. RESULTS: All the 100 patients completed treatment. Analysis of the results showed a significant decrease in pain on VAS in both groups. Reduced pain intensity was observed by the end of the first month of therapy and remained throughout the follow-up. Both medications diminished stiffness just after a month of therapy. They alleviated joint function and reduced total WOMAC scores at Visit 2. Analysis of Get-Up and Go test results indicated significantly less spent time in both groups; however, these differences reached the statistical significance in the ARTRA MSM group just at Visit 2 and in the ARTRA group only at Visit 3. The effect ARTRA MSM occurred more rapidly. This was confirmed by the patient and physician evaluations of the efficiency of treatment, which indicated that its positive effect occurred more rapidly in the ARTRA MSM group (p=0.02). Estimation of EQ-5D scores also showed positive results: there was a significant improvement of these indicators in the two compared groups at Visit 3. Both medications were very well tolerated and caused no adverse reactions; therapy was not discontinued. CONCLUSION: ARTRA MSM is rapider in its effect: a significant improvement in Get-Up and Go test results and patient and physician evaluations of the efficiency of treatment. Additional interviews of the patients taking ARTRA MSM demonstrated that 36 (72%) of them reported a prompter pain relief than the ARTRA-treated patients. ARTRA MSM may be recommended for the treatment of OA in clinical practice. PMID- 26978420 TI - [Specific features of the enteric microbiota composition in patients with alcoholic liver cirrhosis]. AB - AIM: To establish the specific features of the taxonomic and functional composition of the enteric microbiota in patients with alcoholic liver cirrhosis (LC). SUBJECTS AND METHODS: Metagenomic analysis was used to study the taxonomic composition and functional potential of the enteric microbiota in 20 patients with alcoholic LC. Total DNA was isolated from the patients' fecal samples; thereafter full genome sequencing was carried out. The metagenomic analysis yielded the results of the relative taxonomic and functional abundance of microbial species in the test samples. These were comparatively analyzed with the previously published metagenomic datasets of healthy population cohorts in the Russian Federation, as well as in Denmark, China, and the USA. RESULTS: In the majority of patients, the dominant part of the intestinal community represented bacterial species constituting the normal human intestinal flora. At the same time, abnormal gut microbiota composition, which was suggestive of marked dysbacteriosis, was identified in a number of patients. In addition, pooled analysis of the data could identify a number of species with a statistically significantly increase and decrease in the relative abundance as compared to the control groups. Thus, the enteric microbiota of the patients with alcoholic LC showed a high proportion of bacteria characteristic of the oral cavity. Analysis of the pooled metabolic potential of the microbiota in these patients demonstrated the higher abundance of enzyme genes involved in alcohol metabolism. CONCLUSION: In the patients with alcoholic LC, the microbiota composition changes identified in individual bacterial species may be associated with gastrointestinal comorbidities, such as chronic erosive gastritis, chronic pancreatitis, and gastric ulcer. The alterations occurring in alcoholic cirrhosis promote the penetration and generation of oral cavity-specific microorganisms in the human intestine. This may a potential biomarker for the diagnosis of liver diseases. The bacterial enzyme genes involved in alcohol metabolism have an increased abundance in patients with alcoholic LC and healthy volunteers from the Russian Federation. PMID- 26978421 TI - [Fundamental bases for the use of silk fibroin-based bioresorbable microvehicles as an example of skin regeneration in therapeutic practice]. AB - AIM: To assess whether silk fibroin-based microvehicles (MVs) may be used to grow fibroblasts (FBs) and keratinocytes (KCs), key cellular components in skin regeneration after injury. SUBJECTS AND METHODS: Cryogrinding was applied to derive MVs from fibroin-based and fibroin- and 30% gelatin-containing composite matrices. To examine the structure of the matrices and MVs, confocal microscopy was used to conjugate the polymer with the dye tetramethylrhodamine isothiocyanate. Microparticle size distribution was estimated by granulometric analysis. 3T3 mouse FBs and cultured primary mouse KCs expressing green fluorescent protein (GFP) were used to study whether fibroin-based MVs might be suitable for growing the cells involved in skin regeneration. KC growth was analyzed by confocal laser scanning microscopy from cellular GFP expression. The proliferation rate of FBs and KCs was estimated by a MTT assay. RESULTS: There were two derived MV types: fibroin-based and fibroin and 30% gelatin-containing composite ones. On day 1, 3T3 mouse FBs on the fibroin-based gelatin-free MVs actively proliferated and the presence of gelatin in MVs diminished the proliferation of these cells. Fibroin-based MVs were shown to be suitable for the effective in vitro growth of KCs expressing cytokeratins 5 and 14, the major markers of KCs in the basal layer. Gelatin did not give rise to accelerated KC growth. The investigation has demonstrated that is possible to regulate FB proliferation on MVs, which is of great importance in delivering the cells into the site of injury since intensive proliferation of FBs may lead to the development of fibrosis and the formation of scar tissue. Balanced FB growth is essential to the creation of optimal conditions for KC growth in composite tissue engineering constructions. CONCLUSION: The use of fibroin-based MVs is promising for the design of novel therapeutic materials and injectable cell therapy for different diseases. PMID- 26978422 TI - [A case of irreversible cardiomyopathy induced by polychemotherapy]. AB - The paper describes a case of irreversible dilated cardiomyopathy in a young female patient receiving polychemotherapy for breast cancer. PMID- 26978423 TI - [IgG4-related disease and clonal B-cell lymphoid proliferation: Description of two clinical cases and a review of literature]. AB - IgG4-related disease (IgG4-RD) is a systemic immune-related disease that may involve the pancreas, liver, retroperitoneal space, biliary tract, salivary and lacrimal glands, eye socket, lung, and kidney. In term of pathomorphogenesis, it is a fibroinflammatory disease manifesting as a tumor-like lesion of organs, elevated serum IgG4 levels, and a morphofunctional substrate - the development of marked fibrosis and lymphoplasmacytic infiltration in the tissues with the high content of IgG4-positive plasma cells. The detection of a tumor-like nodule frequently leads to that the patients with IgG4-RD undergo major traumatic surgery for presumed cancer. At the same time, a number of investigations show the association of IgG4-RD with the development of cancer and lymphoproliferative diseases. The paper describes two clinical cases: Russia's first diagnosis of MALT lymphoma of the lacrimal gland, IgG4-positive and IgG4-RD with a rare onset with a destruction focus in the cervical vertebrae, multiple organ dysfunction, B cell clonality in salivary gland tissue and PIgMkappa secretion. It also reviews world literature on the development of lymphoproliferative diseases in the presence of IgG4-RD. PMID- 26978424 TI - [Minimal-change glomerulonephritis in chronic lymphocytic leukemia: A clinical case]. AB - Chronic lymphocytic leukemia (CLL) in association with glomerulonephritis (GN) and renal failure is a serious problem in terms of therapy. The paper reports a clinical case of a 64-year-old female patient with Binet stage C CLL accompanied by minimal-change GN complicated by nephrotic syndrome and the development of acute renal failure. GN was diagnosed on the basis of electron microscopic studies of renal biopsy specimens. It was treated with rituximab in combination with bendamustine. The former was intravenously injected in a dose of 375 mg/m2 on day 0 of the cycle; the latter was given in a dose of 70 mg/m2 within the first 2 days; the cycle was repeated 28 days after initiation of the previous cycle. Five cycles could result in complete CLL remission (the follow-up duration was 20 months); nephrotic syndrome was completely abolished and kidney function recovered. PMID- 26978426 TI - Growth of NiCo2O4@MnMoO4 Nanocolumn Arrays with Superior Pseudocapacitor Properties. AB - Three-dimensional heterostructured NiCo2O4@MnMoO4 nanocolumn arrays (NCAs) on Ni foam were first fabricated through an improved two-step hydrothermal process associated with a successive annealing treatment. The hybrid NiCo2O4@MnMoO4 electrode exhibited remarkable pseudocapacitor property with high initial mass specific capacitance of 1705.3 F g(-1) at 5 mA cm(-2), and retained 92.6% after 5000 cycles, compared to the bare NiCo2O4 electrode with 839.1 F g(-1) and 90.9%. The excellent capacitive property of the NiCo2O4@MnMoO4 hydrid was attributed to its high-electron/ion-transfer rate, large electrolyte infiltrate area, and more electroactive reaction sites. PMID- 26978425 TI - [FIP1L1-PDGFRA-positive myeloproliferative disease with eosinophilia: A rare case with multiple organ dysfunction and a response to tyrosine kinase inhibitor therapy]. AB - The described case of FIP1L1-PDGFRA-positive myeloproliferative disease is characterized by an atypical aggressive course to develop severe specific complications as injuries to the brain, heart, lung, and intestine. Pathogenetic therapy with imatinib could stabilize a patient's state, but failed to produce a complete hematological response. Switching from imatinib to dasatinib could produce sustained clinical, hematological, and molecular remissions. PMID- 26978427 TI - Acupoint Application for Asthma Therapy in Adults: A Systematic Review and Meta Analysis of Randomized Controlled Trials. AB - BACKGROUND: To evaluate the evidence available on the effects of acupuncture point (acupoint) application for asthma therapy in adults. METHODS: Six electronic databases were searched up to May 2014 to identify relevant studies. Randomized controlled trials, which assessed the effects of acupoint application for asthma treatment in adults, were included in our review. The methodological quality of eligible studies was assessed by the Cochrane Collaboration's tool. The standardized mean difference (SMD) and 95% confidence intervals (CI) of a random-effects model were calculated. The heterogeneity was assessed using I2 statistics. RESULTS: Eight studies were included in our review. The aggregated results indicated that acupoint application improved forced expiratory volume in 1 second (FEV1) (SMD, 0.32; 95% CI 0.04-0.60; p = 0.03), FEV1/forced vital capacity (SMD, 0.89; 95% CI 0.70-1.09; p < 0.00001), interleukin (SMD, -0.26; 95% CI -0.50 to -0.01; p = 0.04) and immunoglobulin E (SMD, -0.49; 95% CI -0.83 to 0.16; p = 0.004) in patients with asthma, but not eosinophilic cation protein (SMD, -0.58; 95% CI -1.42 to 0.26; p = 0.18). There was no sufficient evidence for the follow-up effects of acupoint application for asthma therapy in adults. CONCLUSIONS: Acupoint application may be a valid complementary and alternative therapy for asthma in adults. It contributes especially to improving pulmonary function and reducing the levels of interleukin and immunoglobulin E. However, more studies with longer follow-ups are warranted to confirm the current findings. PMID- 26978428 TI - Maltotriose-conjugation to a fluorinated chlorin derivative generating a PDT photosensitizer with improved water-solubility. AB - Photoactive molecules with the frameworks of chlorin and/or porphyrin possessing four perfluorinated aromatic rings were conjugated with maltotriose (Mal3) via the nucleophilic aromatic substitution reaction and subsequent deprotection reaction of the oligosaccharide moieties. The resulting oligosaccharide conjugated molecules are ultimately improved as compared to the previously reported monosaccharide-counterparts in terms of water-solubility. In particular, a water-soluble chlorin derivative surrounded by four Mal3 molecules showed an excellent biocompatibility, strong photoabsorption in the longer wavelength regions, and a very high photocytotoxicity. Thus, the present synthetic route combined with the use of an oligosaccharide was shown to be a straightforward strategy to develop a third generation photosensitizer for photodynamic therapy (PDT). PMID- 26978429 TI - FP-CIT- and IBZM-SPECT in Corticobasal Syndrome: Results from a Clinical Follow Up Study. AB - OBJECTIVE: To evaluate the striatal presynaptic dopamine transporter (FP-CIT SPECT) and postsynaptic D2 receptor (IBZM-SPECT) binding in patients with corticobasal syndrome (CBS). BACKGROUND: FP-CIT and IBZM are commercially available and approved SPECT tracers for in vivo molecular imaging of pre- and postsynaptic nigrostriatal neuronal degeneration, but only few data for CBS are available. METHODS: 23 patients meeting clinical criteria for early- to mid-stage CBS (disease duration <=4 years) were examined with SPECT radiotracers FP-CIT and IBZM. All suspected CBS patients underwent a clinical follow-up examination and were re-evaluated after 19.7 +/- 15.2 months (mean +/- SD). Postmortem diagnosis was available for 2 patients. In patients who met research criteria for probable CBS at the final follow-up visit (n = 19; disease duration: 1.95 +/- 0.91 years), SPECT binding values were compared to those of age- and gender-matched Parkinson's disease (PD) patients (n = 18, disease duration: 1.92 +/- 0.91 years; clinical follow-up: 32 +/- 29.6 months) and neurologically normal control subjects (n = 19). RESULTS: In comparison to the healthy control subjects, both patient groups showed significant and asymmetric reduction of the striatal presynaptic dopamine transporter binding, but PD patients had significantly lower FP-CIT binding ratios than probable-CBS patients. FP-CIT binding values of probable-CBS patients and healthy controls demonstrated marked overlaps, and in 7 patients (39%) scans revealed no dopaminergic deficit. IBZM uptake did not show significant between-group differences. CONCLUSION: Our data indicate that in the early- to mid-stage CBS the degree of nigrostriatal impairment is only mild with a significant proportion of preserved dopamine transporter binding. PMID- 26978430 TI - Application of (119)Sn CPMG MAS NMR for Fast Characterization of Sn Sites in Zeolites with Natural (119)Sn Isotope Abundance. AB - (119)Sn CPMG MAS NMR is demonstrated to be a fast and efficient method for characterization of Sn-sites in Sn-containing zeolites. Tuning of the CPMG echo train sequence decreases the experimental time by a factor of 5-40 in the case of as-synthesized and hydrated Sn-BEA samples and by 3 orders of magnitude in the case of dehydrated Sn-BEA samples as compared to conventional methods. In the latter case, the reconstruction of the quantitative spectrum without the loss of sensitivity is shown to be possible. The method proposed allows obtaining (119)Sn MAS NMR spectra with improved resolution for Sn-BEA zeolites with natural (119)Sn isotope abundance using conventional MAS NMR equipment. PMID- 26978456 TI - Planned Repeat Cesarean Section at Term and Adverse Childhood Health Outcomes: A Record-Linkage Study. AB - BACKGROUND: Global cesarean section (CS) rates range from 1% to 52%, with a previous CS being the commonest indication. Labour following a previous CS carries risk of scar rupture, with potential for offspring hypoxic brain injury, leading to high rates of repeat elective CS. However, the effect of delivery by CS on long-term outcomes in children is unclear. Increasing evidence suggests that in avoiding exposure to maternal bowel flora during labour or vaginal birth, offspring delivered by CS may be adversely affected in terms of energy uptake from the gut and immune development, increasing obesity and asthma risks, respectively. This study aimed to address the evidence gap on long-term childhood outcomes following repeat CS by comparing adverse childhood health outcomes after (1) planned repeat CS and (2) unscheduled repeat CS with those that follow vaginal birth after CS (VBAC). METHODS AND FINDINGS: A data-linkage cohort study was performed. All second-born, term, singleton offspring delivered between 1 January 1993 and 31 December 2007 in Scotland, UK, to women with a history of CS (n = 40,145) were followed up until 31 January 2015. Outcomes assessed included obesity at age 5 y, hospitalisation with asthma, learning disability, cerebral palsy, and death. Cox regression and binary logistic regression were used as appropriate to compare outcomes following planned repeat CS (n = 17,919) and unscheduled repeat CS (n = 8,847) with those following VBAC (n = 13,379). Risk of hospitalisation with asthma was greater following both unscheduled repeat CS (3.7% versus 3.3%, adjusted hazard ratio [HR] 1.18, 95% CI 1.05-1.33) and planned repeat CS (3.6% versus 3.3%, adjusted HR 1.24, 95% CI 1.09-1.42) compared with VBAC. Learning disability and death were more common following unscheduled repeat CS compared with VBAC (3.7% versus 2.3%, adjusted odds ratio 1.64, 95% CI 1.17 2.29, and 0.5% versus 0.4%, adjusted HR 1.50, 95% CI 1.00-2.25, respectively). Risk of obesity at age 5 y and risk of cerebral palsy were similar between planned repeat CS or unscheduled repeat CS and VBAC. Study limitations include the risk that women undergoing an unscheduled CS had intended to have a planned CS, and lack of data on indication for CS, which may confound the findings. CONCLUSIONS: Birth by repeat CS, whether planned or unscheduled, was associated with an increased risk of hospitalisation with asthma but no difference in risk of obesity at age 5 y. Greater risk of death and learning disability following unscheduled repeat CS compared to VBAC may reflect complications during labour. Further research, including meta-analyses of studies of rarer outcomes (e.g., cerebral palsy), are needed to confirm whether such risks are similar between delivery groups. PMID- 26978458 TI - Spatiotemporal multistage consensus clustering in molecular dynamics studies of large proteins. AB - The aim of this work is to find semi-rigid domains within large proteins as reference structures for fitting molecular dynamics trajectories. We propose an algorithm, multistage consensus clustering, MCC, based on minimum variation of distances between pairs of Calpha-atoms as target function. The whole dataset (trajectory) is split into sub-segments. For a given sub-segment, spatial clustering is repeatedly started from different random seeds, and we adopt the specific spatial clustering with minimum target function: the process described so far is stage 1 of MCC. Then, in stage 2, the results of spatial clustering are consolidated, to arrive at domains stable over the whole dataset. We found that MCC is robust regarding the choice of parameters and yields relevant information on functional domains of the major histocompatibility complex (MHC) studied in this paper: the alpha-helices and beta-floor of the protein (MHC) proved to be most flexible and did not contribute to clusters of significant size. Three alleles of the MHC, each in complex with ABCD3 peptide and LC13 T-cell receptor (TCR), yielded different patterns of motion. Those alleles causing immunological allo-reactions showed distinct correlations of motion between parts of the peptide, the binding cleft and the complementary determining regions (CDR)-loops of the TCR. Multistage consensus clustering reflected functional differences between MHC alleles and yields a methodological basis to increase sensitivity of functional analyses of bio-molecules. Due to the generality of approach, MCC is prone to lend itself as a potent tool also for the analysis of other kinds of big data. PMID- 26978457 TI - Heat shock response of thermophilic fungi: membrane lipids and soluble carbohydrates under elevated temperatures. AB - The heat shock (HS) response is an adaptation of organisms to elevated temperature. It includes substantial changes in the composition of cellular membranes, proteins and soluble carbohydrates. To protect the cellular macromolecules, thermophilic organisms have evolved mechanisms of persistent thermotolerance. Many of those mechanisms are common for thermotolerance and the HS response. However, it remains unknown whether thermophilic species respond to HS by further elevating concentrations of protective components. We investigated the composition of the soluble cytosol carbohydrates and membrane lipids of the thermophilic fungi Rhizomucor tauricus and Myceliophthora thermophilaat optimum temperature conditions (41-43 degrees S), and under HS (51-53 degrees S). At optimum temperatures, the membrane lipid composition was characterized by a high proportion of phosphatidic acids (PA) (20-35 % of the total), which were the main components of the membrane lipids, together with phosphatidylcholines (PC), phosphatidylethanolamines (PE) and sterols (St). In response to HS, the proportion of PA and St increased, and the amount of PC and PE decreased. No decrease in the degree of fatty acid desaturation in the major phospholipids under HS was detected. The mycelium of all fungi at optimum temperatures contained high levels of trehalose (8-10 %, w/w; 60-95 % of the total carbohydrates), which is a hallmark of thermophilia. In contrast to mesophilic fungi, heat exposure decreased the trehalose level and the fungi did not acquire thermotolerance to lethal HS, indicating that trehalose plays a key role in this process. This pattern of changes appears to be conserved in the studied filamentous thermophilic fungi. PMID- 26978460 TI - Zero Pain Is Not the Goal. PMID- 26978461 TI - Semifluorinated Alkanes at the Air-Water Interface: Tailoring Structure and Rheology at the Molecular Scale. AB - Semifluorinated alkanes form monolayers with interesting properties at the air water interface due to their pronounced amphi-solvophobic nature and the stiffness of the fluorocarbons. In the present work, using a combination of structural and dynamic probes, we investigated how small molecular changes can be used to control the properties of such an interface, in particular its organization, rheology, and reversibility during compression-expansion cycles. Starting from a reference system perfluor(dodecyl)dodecane, we first retained the linear structure but changed the linkage groups between the alkyl chains and the fluorocarbons, by introducing either a phenyl group or two oxygens. Next, the molecular structure was changed from linear to branched, with four side chains (two fluorocarbons and two hydrocarbons) connected to extended aromatic cores. Neutron reflectivity at the air-water interface and scanning force microscopy on deposited films show how the changes in the molecular structure affect molecular arrangement relative to the interface. Rheological and compression-expansion measurements demonstrate the significant consequences of these changes in molecular structure and interactions on the interfacial properties. Remarkably, even with these simple molecules, a wide range of surface rheological behaviors can be engineered, from viscous over viscoelastic to brittle solids, for very similar values of the surface pressure. PMID- 26978462 TI - [Accelerated postoperative rehabilitation: multidisciplinary issue. Part 2]. AB - AIM: To discuss the main aspects of multimodal method of accelerated postoperative rehabilitation (fast track surgery). MATERIAL AND METHODS: The program of accelerated rehabilitation consists of minimization of surgical treatment's stressful influence on patient's organism in all stages of perioperative period. The method implies use of efficient preoperative management, minimally invasive operations, regional anesthesia and short-acting anesthetics, early postoperative rehabilitation. RESULTS: The program improves the results of surgical treatment, reduces number of complications and cost of treatment, improves the "quality" of hospital stay and satisfaction of meeting with doctors. PMID- 26978463 TI - [Surgery of pancreatic injuries]. AB - AIM: To estimate different approaches to treatment of victims with pancreatic trauma with pancreatic trauma. MATERIAL AND METHODS: It was analyzedthe results of treatment of 342 victims with pancreatic trauma in N.V. Sklifosovskiy Research Institute of Emergency Care for the period 1991-2012. RESULTS: It was concluded that for the las decade curative and diagnostic tactics for pancreatic injury in victims with combined abdominal trauma has been changed; current diagnostic markers of pancreatic lesion and adequate intraoperative diagnosis are used. All of this together with timely specific therapy and adherence to guidelines of surgical treatment decreased mortality rate from 17.0 to 11.1% and suppurative complications incidence from 43.8 to 19.9%. PMID- 26978464 TI - [Nesidioblastosis (diagnosis, surgical treatment)]. AB - INTRODUCTION: Nesidioblastosis (NB) is rare disease with organic hyperinsulinism syndrome and caused by diffuse hyperplasia and/or hypertrophy of pancreatic islands of Langerhans. MATERIAL AND METHODS: The results of surgical treatment of 3 patients with NB are presented. In all patients the diagnosis was suspected at the preoperative stage and confirmed by histological examination later. Herewith in 2 patients NB was combined with insulinoma. All patients underwent corpora caudal pancreatectomy. RESULTS: In postoperative period one patient hadn't episodes of hypoglycemia for the entire follow-up period (5 months), in another patient hypoglycemic states occurred at 1.5 months after surgery. The third patient required pancreatic head extirpation at 11 days after surgery due to persistent severe course of organic hyperinsulinism. In immediate postoperative period in the same patient hyperinsular hypoglycemia was observed that pointed on extrapancreatic source of insulin secretion. However contrast-enhanced CT did not reveal any formations. CONCLUSION: Thus, corpora-caudal pancreatectomy is preferable as surgical treatment. Results of surgical management can provide a complete regression of the symptoms, but do not guarantee absence of recurrence and even any changes in frequency and severity of hypoglycemic states. PMID- 26978465 TI - [Endoscopic transpapillary lithoextraction in case of parapapillary diverticulum]. AB - AIM: To present the experience of endoscopic transpapillary procedures in patients with parapapillary diverticulum. MATERIAL AND METHODS: Endoscopic transpapillary treatment of choledocholithiasis was performed in 16.8% (423) of patients with suspected bile ducts stones for the period from August 2010 to January 2015. There were parapapillary diverticulum in all cases. Patients' age was from 29 to 92 years, there were 121 men and 302 women. Endoscopic transpapillary bile drainage was made in 407 (96.3%) cases. One-stage treatment was performed in 352 (83.2%) patients. The results of endoscopic transpapillary procedures in patients with parapapillary diverticulum were analyzed. RESULTS: We revealed high efficacy of transpapillary interventions in these patients. Herewith visualization of large duodenal papilla, determination of ducts' anatomic relations with diverticular and intestinal walls and adherence to main methodical and technical aspects of procedure are very important for successful treatment. PMID- 26978467 TI - [Multi-stage surgical treatment of woundeds with combined thermomechanic injuries in local armed conflict]. AB - AIM: To improve the results of surgical treatment of woundeds with combined thermomechanic injuries in local armed conflict. MATERIAL AND METHODS: It was analyzed treatment of 93 victims with thermomechanic injuries. In 29 (31.2%) aptients only Early Total Care protocol (ETC) was used up to 2001. These victims received complete surgical care. Since 2002 diffirentiated approach of multi stage surgical treatment (Damage Control Surgery) has been applied. ETC tactics was used if systolic blood pressure was more than 90 mm Hg (30 woundeds, 32.2%). DCS protocol was preferred in case of blood pressure less than 90 mm Hg or multiple-organ failure (34 patients, 36.6%). RESULTS: Diffirentiated surgical approach decreases mortality rate from 13.8% to 7.8% (p=0.453) compared with group of conventional one-stage care. PMID- 26978466 TI - [Correction of endotoxemia in patients with pancreatic necrosis]. AB - AIM: To study the results of deferoxamine (Deferal) administration in intensive therapy program of 63 patients with severe acute pancreatitis to decrease effect of oxidative stress and endotoxemia. MATERIAL AND METHODS: In deferoxamine group (31 patients) there were decrease of serum iron's level and inhibition of free radical oxidation that led to early relief of endotoxemia, reducing periods of organs' dysfunction. It was not observed in comparison group (32 patients). RESULTS: Deferoxamine decrease risk of pancreatic necrosis and pancreatogenic sepsis. It allows reducing ICU- and hospital-stay and number of extended surgical procedures. PMID- 26978468 TI - [Spleen-preserving D2 lymphodissection in gastrectomy]. AB - AIM: To analyze immediate and remote results of surgical treatment of 480 patients with gastric cancer who underwent total gastrectomy. MATERIAL AND METHODS: The study group included 371 patients who had spleen-preserving D2 lymphodissection during gastrectomy and control group consisted of 109 patients after D2 lymphodissection with splenectomy. Duration of surgery was 183.7+/-33.8 and 184.1+/-30.9 min in study and control groups respectively (p=0.72), blood loss - 330.2+/-33.7 and 351.8+/-28.8 ml (p=0.0001), incidence of postoperative complications - 6.7% (25 cases) and 4.6% (5 cases) respectively (p=0.5), mortality rate - 2.7% and 0.9% respectively (p=0.46). Number of excised regional lymph nodes of groups 10 and 11 was in most patients of the study group - 5.8 and 5.5 (p=0.92). Metastases in splenic hilus lymph nodes were diagnosed in 28 (7.5%) and 9 (8.2%) patients of the study and control groups respectively (p=0.30), metastases in lymph nodes along splenic vessels - in 24 (6.5%) and 7 (6.4%) patients respectively (p=0.90). RESULTS: 5-year survival in the study group was 40.3+/-3.0%, average life expectancy - 3.4+/-3.3 years, in the control groups - 33.1+/-5.6% and 2.7+/-2.5 years respectively. It was concluded that spleen preserving D2 lymphodissection decreases incidence of postoperative complications and has similar drastic nature as standard lymphodissection with splenectomy. PMID- 26978469 TI - [Diagnosis and surgical treatment of adrenocortical cancer with invasion into great veins]. AB - AIM: To estimate immediate and remote resaults of treatment of adrenocortical cancer with invasion into great veins. MATERIAL AND METHODS: It was analyzed survey and treatment results in 3 patients with adrenocortical cancer and invasion into renal veins and inferior vena cava. RESULTS: Radical surgery with tumoral thrombi removal from great vessels was performed in all cases. There were no complications and deaths in early postoperative period. Life expectancy after surgery was 6, 13 and over 58 months. CONCLUSION: At present time surgical intervention for adrenocortical cancer with invasion into great veins is single method to prolong patients' life. PMID- 26978470 TI - [Indications and surgical results of chronic colostasis treatment]. AB - AIM: To define the surgical indications in patients with chronic colostasis who were operated using original technique and to access obtained results. MATERIAL AND METHODS: It was analyzed the results of surgical treatment of 81 patients with chronic colostasis in remote postoperative period. We have proved that extended left-sided hemicolectomy with rectosigmoid resection, positive mesentery root rotation and transposition of right large bowel to left part of abdominal cavity, creation of new ligamentary apparatus provide favourable remote results and increase life's quality of operated patients. RESULTS: Complex analysis of clinical, morphological and functional results before and after medical therapy allowed to define indications and optimal period for surgical treatment in patients with chronic decompensated colostasis. PMID- 26978471 TI - [Surgical management of traumatic retroperitoneal hemor-rhage]. AB - AIM: To present the algorithm of management of victims using modern technologies including CT, laparoscopy, angiography, intraabdominal pressure monitoring, etc. MATERIAL AND METHODS: Treatment of 395 victims with traumatic retroperitoneal hemorrhage was analyzed. RESULTS: It was shown that the use of developed algorithm decreases mortality rate from 10.5 to 4.5% and postoperative complications incidence from 23 to 14.1% in reviewed patients. PMID- 26978472 TI - [Clinical cases of effective use of rivaroxaban in venous thromboembolic complications management in patients with cancer and collagen diseases]. PMID- 26978473 TI - [Extra-anatomic thoracic aortic bypass in patient with aortic arch hypoplasia and coarctation]. PMID- 26978474 TI - [Surgical treatment of descending aortic aneurysm with destruction of vertebral bodies]. PMID- 26978475 TI - [Bleeding giant duodenal ulcer caused by intake of non-steroidal anti inflammatory drugs]. PMID- 26978476 TI - [Again about sepsis: philosophy of dialectical unity of definition and clinical practice]. PMID- 26978477 TI - Fragment-Linking Approach Using (19)F NMR Spectroscopy To Obtain Highly Potent and Selective Inhibitors of beta-Secretase. AB - Fragment-based drug discovery (FBDD) has become a widely used tool in small molecule drug discovery efforts. One of the most commonly used biophysical methods in detecting weak binding of fragments is nuclear magnetic resonance (NMR) spectroscopy. In particular, FBDD performed with (19)F NMR-based methods has been shown to provide several advantages over (1)H NMR using traditional magnetization-transfer and/or two-dimensional methods. Here, we demonstrate the utility and power of (19)F-based fragment screening by detailing the identification of a second-site fragment through (19)F NMR screening that binds to a specific pocket of the aspartic acid protease, beta-secretase (BACE-1). The identification of this second-site fragment allowed the undertaking of a fragment linking approach, which ultimately yielded a molecule exhibiting a more than 360 fold increase in potency while maintaining reasonable ligand efficiency and gaining much improved selectivity over cathepsin-D (CatD). X-ray crystallographic studies of the molecules demonstrated that the linked fragments exhibited binding modes consistent with those predicted from the targeted screening approach, through-space NMR data, and molecular modeling. PMID- 26978479 TI - Low Trap Density in InAs/High-k Nanowire Gate Stacks with Optimized Growth and Doping Conditions. AB - In this paper, we correlate the growth of InAs nanowires with the detailed interface trap density (Dit) profile of the vertical wrap-gated InAs/high-k nanowire semiconductor-dielectric gate stack. We also perform the first detailed characterization and optimization of the influence of the in situ doping supplied during the nanowire epitaxial growth on the sequential transistor gate stack quality. Results show that the intrinsic nanowire channels have a significant reduction in Dit as compared to planar references. It is also found that introducing tetraethyltin (TESn) doping during nanowire growth severely degrades the Dit profile. By adopting a high temperature, low V/III ratio tailored growth scheme, the influence of doping is minimized. Finally, characterization using a unique frequency behavior of the nanowire capacitance-voltage (C-V) characteristics reveals a change of the dopant incorporation mechanism as the growth condition is changed. PMID- 26978478 TI - Novel Time-Resolved Fluorescence Europium Nanoparticle Immunoassay for Detection of Human Immunodeficiency Virus-1 Group O Viruses Using Microplate and Microchip Platforms. AB - Accurate detection and quantification of HIV-1 group O viruses have been challenging for currently available HIV assays. We have developed a novel time resolved fluorescence (TRF) europium nanoparticle immunoassay for HIV-1 group O detection using a conventional microplate enzyme-linked immunosorbent assay (ELISA) and a microchip platform. We screened several antibodies for optimal reactivity with several HIV-1 group O strains and identified antibodies that can detect all the strains of HIV-1 group O that were available for testing. The antibodies were used to develop a conventional ELISA format assay and an in-house developed europium nanoparticle-based assay for sensitivity. The method was evaluated on both microwell plate and microchip platforms. We identified two specific and sensitive antibodies among the six we screened. The antibodies, C65691 and ANT-152, were able to quantify 15 and detect all 17 group O viruses, respectively, as they were broadly cross-reactive with all HIV-1 group O strains and yielded better signals compared with other antibodies. We have developed a sensitive assay that reflects the actual viral load in group O samples by using an appropriate combination of p24 antibodies that enhance group O detection and a highly sensitive TRF-based europium nanoparticle for detection. The combination of ANT-152 and C65690M in the ratio 3:1 was able to give significantly higher signals in our europium-based assay compared with using any single antibody. PMID- 26978481 TI - Diaminopropionic Acid Reinforced Graphene Sponge and Its Use for Hemostasis. AB - 2,3-Diaminopropionic acid (DapA), a medicinal amino acid, is used for the first time to prepare a DapA cross-linked graphene sponge (DCGS) for hemostasis treatment. In a comparison with the reported ethanediamine (EDA) cross-linked graphene sponge (CGS), this carboxyl-functionalized DCGS can not only quickly absorb plasma, but also stimulate erythrocytes and platelets to change their normal form and structure at the interface, which largely affects a cell's metabolism and biofunction, thus further promoting blood coagulation. Whole blood clotting and rat-tail amputation tests indicated that on the basis of the additional interfacial stimulation, the hemostatic efficiency of the DCGS has been significantly improved in comparison with that of the CGS control (P < 0.05). In-depth insight revealed that the increased oxidation degree and the negative charge density play the crucial rule in the enhanced hemostatic performance. The chiral effect contributes mainly to the selective adhesion of erythrocytes and platelets rather than practical hemostasis. Nevertheless, this presentation demonstrated that, on the premise of keeping the fast absorbability, this is an effective method to improve the hemostatic efficiency by enhancing the cell/graphene interface interaction. PMID- 26978480 TI - Potentiometric Measurements of Semiconductor Nanocrystal Redox Potentials. AB - A potentiometric method for measuring redox potentials of colloidal semiconductor nanocrystals (NCs) is described. Fermi levels of colloidal ZnO NCs are measured in situ during photodoping, allowing correlation of NC redox potentials and reduction levels. Excellent agreement is found between electrochemical and optical redox-indicator methods. Potentiometry is also reported for colloidal CdSe NCs, which show more negative conduction-band-edge potentials than in ZnO. This difference is highlighted by spontaneous electron transfer from reduced CdSe NCs to ZnO NCs in solution, with potentiometry providing a measure of the inter NC electron-transfer driving force. Future applications of NC potentiometry are briefly discussed. PMID- 26978484 TI - Light-Controlled Radical Polymerization: Mechanisms, Methods, and Applications. AB - The use of light to mediate controlled radical polymerization has emerged as a powerful strategy for rational polymer synthesis and advanced materials fabrication. This review provides a comprehensive survey of photocontrolled, living radical polymerizations (photo-CRPs). From the perspective of mechanism, all known photo-CRPs are divided into either (1) intramolecular photochemical processes or (2) photoredox processes. Within these mechanistic regimes, a large number of methods are summarized and further classified into subcategories based on the specific reagents, catalysts, etc., involved. To provide a clear understanding of each subcategory, reaction mechanisms are discussed. In addition, applications of photo-CRP reported so far, which include surface fabrication, particle preparation, photoresponsive gel design, and continuous flow technology, are summarized. We hope this review will not only provide informative knowledge to researchers in this field but also stimulate new ideas and applications to further advance photocontrolled reactions. PMID- 26978483 TI - Evidence-Based Clinical Use of Nanoscale Extracellular Vesicles in Nanomedicine. AB - Recent research has demonstrated that all body fluids assessed contain substantial amounts of vesicles that range in size from 30 to 1000 nm and that are surrounded by phospholipid membranes containing different membrane microdomains such as lipid rafts and caveolae. The most prominent representatives of these so-called extracellular vesicles (EVs) are nanosized exosomes (70-150 nm), which are derivatives of the endosomal system, and microvesicles (100-1000 nm), which are produced by outward budding of the plasma membrane. Nanosized EVs are released by almost all cell types and mediate targeted intercellular communication under physiological and pathophysiological conditions. Containing cell-type-specific signatures, EVs have been proposed as biomarkers in a variety of diseases. Furthermore, according to their physical functions, EVs of selected cell types have been used as therapeutic agents in immune therapy, vaccination trials, regenerative medicine, and drug delivery. Undoubtedly, the rapidly emerging field of basic and applied EV research will significantly influence the biomedicinal landscape in the future. In this Perspective, we, a network of European scientists from clinical, academic, and industry settings collaborating through the H2020 European Cooperation in Science and Technology (COST) program European Network on Microvesicles and Exosomes in Health and Disease (ME-HAD), demonstrate the high potential of nanosized EVs for both diagnostic and therapeutic (i.e., theranostic) areas of nanomedicine. PMID- 26978482 TI - Genome-scale DNA methylome and transcriptome profiling of human neutrophils. AB - Methylation of DNA molecules is a key mechanism associated with human disease, altered gene expression and phenotype. Using reduced representation bisulphite sequencing (RRBS) technology we have analysed DNA methylation patterns in healthy individuals and identified genes showing significant inter-individual variation. Further, using whole genome transcriptome analysis (RNA-Seq) on the same individuals we showed a local and specific relationship of exon inclusion and variable DNA methylation pattern. For RRBS, 363 million, 100-bp reads were generated from 13 samples using Illumina GAII and HiSeq2000 platforms. Here we also present additional RRBS data for a female pair of monozygotic twins that was not described in our original publication. Further, We performed RNA-Seq on four of these individuals, generating 174 million, 51-bp high quality reads on an Illumina HiSeq2000 platform. The current data set could be exploited as a comprehensive resource for understanding the nature and mechanism of variable phenotypic traits and altered disease susceptibility due to variable DNA methylation and gene expression patterns in healthy individuals. PMID- 26978485 TI - The 22q11 PRODH/DGCR6 deletion is frequent in hyperprolinemic subjects but is not a strong risk factor for ASD. AB - The proline dehydrogenase (PRODH) gene maps to 22q11.2 in the region deleted in the velo-cardio-facial syndrome (VCFS). A moderate to severe reduction (>50%) in PRODH activity resulting from recessive deletions and/or missense mutations has been shown to cause type 1 hyperprolinemia (HPI). Autistic features have been reported as a common clinical manifestation of HPI. Here we studied the frequency of a recurrent small 22q11.2 deletion encompassing PRODH and the neighboring DGCR6 gene in three case-control studies, one comprising HPI patients (n = 83), and the other two comprising autism spectrum disorder (ASD) patients (total of n = 2800), analyzed with high-resolution microarrays. We found that the PRODH deletion is a strong risk factor for HPI (OR = 50.7; 95%CI = 7.5-2147) but not for ASD (P = 0.4, OR = 0.6-3.3). This result indicates either that the suggested association between ASD and HPI is spurious and results from a bias leading to the preferential inclusion of patients with autistic features in HPI series, or that HPI is present in only a very small subset of ASD patients. In this latter case, a very large sample size would be required to detect an association between the PRODH deletion and ASD in a case-control study. PMID- 26978487 TI - Coagulation Behavior of Graphene Oxide on Nanocrystallined Mg/Al Layered Double Hydroxides: Batch Experimental and Theoretical Calculation Study. AB - Graphene oxide (GO) has attracted considerable attention because of its remarkable enhanced adsorption and multifunctional properties. However, the toxic properties of GO nanosheets released into the environment could lead to the instability of biological system. In aqueous phase, GO may interact with fine mineral particles, such as chloridion intercalated nanocrystallined Mg/Al layered double hydroxides (LDH-Cl) and nanocrystallined Mg/Al LDHs (LDH-CO3), which are considered as coagulant molecules for the coagulation and removal of GO from aqueous solutions. Herein the coagulation of GO on LDHs were studied as a function of solution pH, ionic strength, contact time, temperature and coagulant concentration. The presence of LDH-Cl and LDH-CO3 improved the coagulation of GO in solution efficiently, which was mainly attributed to the surface oxygen containing functional groups of LDH-Cl and LDH-CO3 occupying the binding sites of GO. The coagulation of GO by LDH-Cl and LDH-CO3 was strongly dependent on pH and ionic strength. Results of theoretical DFT calculations indicated that the coagulation of GO on LDHs was energetically favored by electrostatic interactions and hydrogen bonds, which was further evidenced by FTIR and XPS analysis. By integrating the experimental results, it was clear that LDH-Cl could be potentially used as a cost-effective coagulant for the elimination of GO from aqueous solutions, which could efficiently decrease the potential toxicity of GO in the natural environment. PMID- 26978486 TI - Chania multitudinisentens gen. nov., sp. nov., an N-acyl-homoserine-lactone producing bacterium in the family Enterobacteriaceae isolated from landfill site soil. AB - Phylogenetic and taxonomic characterization was performed for bacterium RB-25T, which was isolated from a soil sample collected in a former municipal landfill site in Puchong, Malaysia. Growth occurred at 20-37 degrees C at pH 5-8 but not in the presence of 9 % (w/v) NaCl or higher. The principal fatty acids were C16:0, C18:1omega7c and summed feature 3 (C16:1omega7c and/or iso-C15:0 2-OH). Ubiquinone-8 was the only isoprenoid quinone detected. Polar lipid analysis revealed the presence of phospholipid, phosphoaminolipid, phosphatidylethanolamine, phosphatidylglycerol and one unidentified aminolipid. DNA G+C content was 50.9 mol% phylogenetic analysis based on 16S rRNA gene sequence showed that strain RB-25T formed a distinct lineage within the family Enterobacteriaceae of the class Gammaproteobacteria. It exhibited a low level of 16S rRNA gene sequence similarity with its phylogenetic neighbours Pantoea rwandensis LMG 26275T (96.6 %), Rahnella aquatilis CIP 78.65T (96.5 %), Pectobacterium betavasculorum ATCC 43762T (96.4 %), Pantoea rodasii LMG 26273T (96.3 %), Gibbsiella dentisursi NUM 1720T (96.3 %) and Serratia glossinae C1T (96.2 %). Multilocus sequence analyses based on fusA, pyrG, rplB, rpoB and sucA sequences showed a clear distinction of strain RB-25T from the most closely related genera. Isolate RB-25T could also be distinguished from members of these genera by a combination of the DNA G+C content, respiratory quinone system, fatty acid profile, polar lipid composition and other phenotypic features. Strain RB 25T represents a novel species of a new genus, for which the name Chaniamultitudinisentens gen. nov., sp. nov. is proposed. The type strain is RB 25T (=DSM 28811T=LMG 28304T). PMID- 26978488 TI - [Research Center of Neurology--the 70-anniversary]. PMID- 26978489 TI - [Repetitive transcranial magnetic stimulation in neurology and psychiatry]. AB - Transcranial magnetic stimulation (TMS) is a method based on the excitation of neurons in the brain cortex by an alternating magnetic field. Repetitive TMS (rTMS) is a kind of stimulation, in which a series of pulses are generated. rTMS can modulate different cortical area's activity and change their interactions using different protocols. The review shows the application of rTMS in treatment of various neurological (stroke, Parkinson's disease, dystonia, chronic pain syndromes, tinnitus, epilepsy, spasticity syndrome) and psychiatric (depression and anxiety) disorders. Authors collected all the main protocols, and gave recommendations for their use in clinical practice according to principles of evidence medicine. PMID- 26978490 TI - [Alarming signs and symptoms in the early diagnostics of late onset Pompe disease: super omnia clinica]. AB - Pompe disease (PD) is a rare autosomal recessive muscle lysosomal glycogenosis caused by a deficiency of acid-alpha-glucosidase. There are two main forms of the disease: aggressive infantile PD started within the first year of life with a severe enzyme deficiency and multiorgan involvement, and late onset PD (LOPD) with progressive signs and symptoms including predominant proximal, axial muscle weakness and respiratory insufficiency started at any time from 1 till 75 years and older. Usually due to physician's unawareness, most adults with PD are diagnosed with great delay. The typical features and early nonspecific signs in four patients, aged between 35 and 72 years, with confirmed LOPD are delineated and discussed in correspondence with the age of first signs, age development of muscle weakness, distribution and age of final diagnosis. The disorders for differential diagnosis and spectrum of conditions that expanded the possibility of PB are listed. The fluorometrically analyzed level of acid alpha-glucosidase from dried blood spots is considered to be the first choice diagnostic method for clinically suspected cases of LOPD. PMID- 26978491 TI - [Cognitive impairment in predialysis stages of chronic kidney disease]. AB - OBJECTIVE: To study the development and progression of cognitive impairment (CI), its risk factors and relationship with vascular-wall remodeling in patients with chronic kidney disease (CKD), stages I-IV. MATERIAL AND METHODS: Fifty-one patients, aged 53+/-10 years, including 20 with CKD, stages I-II, 20 with CKD, stage III, and 11 with CKD, stage IV, were enrolled. Frequency, severity and character of CI were studied using neuropsychological tests for assessment of global mental status, short-term and delayed memory, frontal lobe functions. Standard laboratory examinations, echocardiographic study, 24h arterial blood pressure monitoring, measurement of the thickness of carotid intima-media complex, pulse-wave velocity and augmentation index, brain MRI study were carried out. RESULTS: CI was found in 68% of patients, including 35% with CKD, stages I II, and 90.3% with CKD, stage IV. The severity of CI was higher in patients with CKD, stages III-IV, compared to those with stages I-II (p<0.001). CKD predicted the development of CI (OR 27.32, 95% CI 4.3-72.9, r<0.001). MRI revealed the focal lesions of the white matter in 30% of patients, leukoaraiosis in 23.3%, lateral ventricular dilatation in 50%, expressed dilatation in the sulci of brain hemispheres in 10%. There was a relationship between CI and male sex, hyperhomocysteinemia, anemia, abdominal obesity, left ventricular myocardial hypertrophy and age. The frequency and severity of CI was associated with the signs of atherosclerotic lesions of common carotid arteries and indices of arterial rigidity. CONCLUSION: The more increased the CKD severity, the higher the severity of CI. The dysfunction of frontal lobes plays a key role in the development of CI in patients with CKD, stages III-IV. CKD, stages III-IV, is an independent predictor of CI in people in predialysis stages. PMID- 26978492 TI - [The systematics of psychogenic depressions (reactions of complicated grief)]. AB - OBJECTIVE: Reactive depression provoked by the loss of loved ones is a controversial problem of modern psychiatry based on the diametrically opposite conceptions. The author suggests a clinical typology of these depressions based on a psychopathological analysis of trigger mechanisms and constitutional predisposition. MATERIAL AND METHODS: Fifty-five patients, aged from 31 to 65 years (mean age 46.9+/-13.9 years), were examined. The course of depression, including previous psychogenia, was followed up for 5-15 years (mean 11.5+/-3.6 years). RESULTS AND CONCLUSION: Three types of catathymic complexes (affective dissonance, affective resonance and affective imbalance) can be considered as a significant parameter responsible for trigger mechanisms of these psychogenias and their further dynamics. Each type determines not only the psychopathological structure of psychogenic depression but has a predictive validity thus allowing to predict the dynamics of depression and its nosological attribution. PMID- 26978494 TI - [Remote consequences of the long-term uncontrolled use of anxiolytic and hypnotic drugs by elderly patients: cognitive disorders]. AB - OBJECTIVE: Frequents cases (10-30% of the elderly population) of regular long term use of anxiolytic and hypnotic drugs, in particular, benzodiazepines, without control of the physician is an urgent problem of medicine worldwide. Severe and irreversible cognitive impairment is a frequent and severe consequence of this use. Authors studied cognitive impairment in these cases. MATERIAL AND METHODS: Patients were enrolled in the study from a psychiatric hospital. The study included 56 women, aged over 50 years, admitted to the hospital with the diagnosis of a mental disorder. Before admission, the patients regularly used benzodiazepines without a prescription for more than 2 months. Later on, anxiolytics were withdrawn during 1-5 days. The patients were studied during 4 weeks in the hospital. To assess the severity and dynamics of their condition, authors used MADRS, HAM-A, MMSE. RESULTS AND CONCLUSION: Severe cognitive impairment, achieving the level of dementia, was found in 57.2% of the patients, mild or moderate of cognitive impairment was in 32.1% and only 10.7% had normal level of cognitive functioning. After 4 weeks of benzodiazepine withdrawal, the percentage of patients with dementia reduced to 21.4%, the severity of cognitive impairment was estimated as mild or moderate. A number of patients without cognitive impairment increased to 37.5%. The old age of patients was a significant negative predictor of the dynamics. An impact of the high anxiolytic dose was shown on trend level. The duration of a mental disorder and duration of uncontrollable consumption of anxiolytics and hypnotics did not exert an effect on the development and reversibility of cognitive impairment. A combination of anxiolytics with alcohol increased the risk of dementia and did not reverse the cognitive pathology. PMID- 26978493 TI - [Pantogam activ (D-, L-hopantenic acid) in the treatment of cognitive and anxiety disorders in patients with arterial hypertension]. AB - OBJECTIVE: To evaluate the efficacy and safety of D-, L-hopantenic acid (pantogam active) on cognitive and anxiety disorders in patients with arterial hypertension. MATERIAL AND METHODS: Autors selected 80 inpatients of a cardiology department with the verified diagnosis of hypertension and comorbid cognitive and anxiety disorders (50 patients in the main group, 30 patients in the control one). All patients received standard cardiotropic hypotensive treatment. Patients of the main group received in addition pantogam active in the daily dose from 600 to 1200 mg. Psychopathological and psychometric examinations were conducted, the data were compared with the dynamics of physical parameters (ECG, ambulatory blood pressure monitoring, blood chemistry). The duration of treatment with pantogam activ was 28 days. RESULTS: There was a significant reduction in both cognitive and anxiety disorders in the main group compared with the controls and in patients with a history of stroke. The positive dynamics was observed during the treatment period. CONCLUSION: Authors support the possibility of using D-, L hopantenic acid (pantogam active) as a drug of choice with bimodal activity (nootropic and tranquilizing) in the treatment of cognitive and anxiety disorders in patients with arterial hypertension. A rapid (in the first week) significant reduction of cognitive and anxiety disorders during the treatment with pantogam activ was noted. PMID- 26978495 TI - [Emotional and personality disorders in atypical facial pain]. AB - OBJECTIVE: To investigate emotional and personality disorders in patients with atypical facial pain. MATERIAL AND METHODS: Forty-five patients (42 women, 3 men, mean age 50+/-16 years) were examined. Pain severity was assessed with the Visual Analogue Scale. Anxiety and depression levels were measured with the Zung Self Rating Depression Scale, the State-Trait Anxiety Inventory (Spilberg's tests), the Taylor Manifest Anxiety Scale, The Beck Depression Inventory. Thirty patients with atypical facial pain were treated with noophen. The clinical state of the patients was assessed with the Hamilton Depression Rating Scale (HAM-D). Noophen was administrated in daily dose of 500 mg, the course of the treatment was 8 weeks. RESULTS AND CONCLUSION: Anxiety and depression as well as the domination of functional neurologic symptoms were characteristic of patients with atypical facial pain. Anxiolytic and antidepressive effects of noophen were seen from the 21st day of treatment. A mild stimulation effect and sleep normalization were also observed. An improvement of the mental state was found in 70% patients with atypical facial pain in the end of treatment: 50% patients demonstrated a significant improvement. PMID- 26978496 TI - [Strategies on the improvement of chronic migraine treatment efficacy]. AB - OBJECTIVE: To determine the efficacy of type A botulinum toxin (lantox) in the treatment of chronic migraine. MATERIAL AND METHODS: Authors examined 22 patients with chronic migraine at baseline and 4 and 12 weeks after the introduction of 150 U of lantox in head and cervical muscles using "follow the pain method". The drug was introduced into the following muscles: m. corrugator, m. procerus, m. frontalis, m. temporalis and m. occipitalis. Clinical/neurological examinations, a study of the emotional sphere (anxiety and depression), daily activities, quality-of-life, patient's completion of questionnaires on the subjective satisfaction with treatment were carried out. RESULTS AND CONCLUSION: There was a significant positive effect of treatment on the frequency of headache attacks that was important for reverse transformation of chronic pain to episodic headache. Barriers in compliance may be overcome by solving psychological problems, in particular, overcoming depression. The prescription of the drug with no side-effects and fast results allows to support the adherence of the patient to treatment. PMID- 26978497 TI - [An effect of cytoprotective therapy on stress resistance and compensatory abilities of patients with chronic cerebral ischemia]. AB - OBJECTIVE: To study an effect of nonspecific cytoprotective therapy on clinical manifestations, disease course and indicators of stress system in patients with different stages of chronic cerebral ischemia (CCI). MATERIAL AND METHODS: Authors examined 266 patients with CCI, aged from 35 to 55 years. The patients received basic and nonspecific cytoprotective therapy. The dynamics of subjective and objective symptoms of encephalopathy, clinical outcomes after a year of observation, and the state of stress system were analyzed. An effect of therapy on stress was assessed by the dynamics of blood pressure reactions to stress. RESULTS AND CONCLUSION: An open randomized comparative study has shown that the inclusion of the drug with nonspecific cytoprotective actions (cytoflavin) in the therapeutic complex improves the therapeutic effect on the clinical manifestations of CCI. The higher frequency of favorable outcomes over one year of follow-up is associated with the optimization of stress system activity under nonspecific cytoprotective therapy and the increase in stress resistance. PMID- 26978498 TI - [Clinical experience of the use of agomelatine in the treatment of patients with depression and chronic brain ischemia]. AB - OBJECTIVE: To study the efficacy and tolerability of agomelatine (valdoxan) in treatment of mild depressive states in patients with chronic brain ischemia (CBI). MATERIAL AND METHODS: The study comprised 33 patients (23 women, 10 men, average age 54.5 years), including 12 people (36.4%) with CBI, stage I, and 21 (63.6%) with CBI, stage II. All patients had a single depressive episode of mild severity. Diagnosis of affective and cognitive impairment was carried out using clinical and neuropsychological methods (the Hamilton Depression Rating Scale (HDRS-17), the Hospital Anxiety and Depression Scale (HADS), the night sleep questionnaire developed by A.M. Vein, the Mini-mental state examination (MMSE), the modified Mini-Cog method, the Montreal Cognitive Assessment Scale (MoCA), the Clinical Global Impression scale (CGI-S, CGI-I) to assess the degree and dynamics of the disease, the Patient Global Impression (PGI) scale. The survey had been performed after 2,4 and 8 weeks of treatment. Agomelatine (valdoxan) was used 1 time per day in the evening in a dose of 25 mg (1 tablet). RESULTS AND CONCLUSION: Agomelatine improved sleep from the second week of treatment, reduced anxiety symptoms after six weeks and depressive symptoms after eight weeks. The improvement of cognitive functions was noted as well. No side-effects was observed. The results revealed the high antidepressive activity of the drug in treatment of mild depressive states in patients with chronic brain ischemia, the balanced spectrum of effects on anxiety, depression, insomnia, the positive effect on cognitive functions that allows to recommend agomelatine in treatment of patients with CBI. PMID- 26978499 TI - [The efficacy and safety of teraligen in patients with brain ischemia, stages I and II, and psychoautonomic syndrome]. AB - OBJECTIVE: To assess the efficacy and safety of teraligen in patients with psychoautonomic syndrome comorbid to brain ischemia. MATERIAL AND METHODS: Forty five patients, aged from 42 to 65 years (mean age 56 years), diagnosed with brain ischemia, stages I and II, with the signs of psychoautonomic syndrome were examined. Thirty-five patients received teraligen in the daily dose of 15 mg. The control group comprised 10 patients who were not treated with this drug. The duration of treatment was 60 days. Neurological status, autonomic changes, cognitive functions and mental state were assessed during the treatment. Neurophysiological examination (EEG and P300 event-related potential) were performed in the first and last visits. RESULTS AND CONCLUSION: The distinct positive dynamics of the decrease of psychoautonomic symptoms, cephalgic syndrome, sleep normalization as well as the improvement of cognitive function were noted. Good tolerability and no side-effects, in particular, those related to vascular disorders, were demonstrated. Clinical results were supported by the results of neurophysiological examinations. The drug can be recommended for treatment of psychoautonomic syndrome in elderly patients with brain ischemia, stages I and II. PMID- 26978500 TI - [Therapeutic possibilities of improvement of cognitive functions, psychoemotional condition and a quality of life in post-stroke patients]. AB - OBJECTIVE: To study an influence of cytoflavin on normalization of cognitive functions, psychoemotional condition and a quality of life in stroke patients. MATERIAL AND METHODS: It was analysed the results of treatment of 1450 stroke patients. The cognitive functions was followed up using MMSE and MoCA scales, psychoemotional condition--Beck Depression Questionnaire and Wakefield Depression Scale, Hamilton Scale of Anxiety, quality of life--Sickness Impact Profile. RESULTS AND CONCLUSION: The results of the study revealed that the use of cytoflavin was well founded in the treatment of stroke patients for improvement of cognitive functions, psychoemotional condition and the quality of life. PMID- 26978501 TI - [The multivector nature of relief of acute and chronic pain and necessity of using pain coping strategies]. AB - The paper is devoted to the urgent problem of pain syndromes of multimodal character developed in different pathologies. The diagnosis and treatment of pain is frequently complicated by nociceptive, neuropathic and dysfunctional components. Special attention is drawn to the dysfunctional component and its relation to depression. In this context, the authors consider psychological aspects of pain syndrome formation and methods of treatment using pharmacological medications and pain-coping strategies as well. Different coping strategies of active and passive pain-coping styles depending on sex, personality features, nosologic forms are presented. The necessity of using the active coping strategies to relieve pain of different genesis is highlighted. PMID- 26978503 TI - [The activity of blood serum cholinesterases and neprilysin as potential biomarkers of mild-cognitive impairment and Alzheimer's disease]. AB - OBJECTIVE: To analyze the activity of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and neprilysin (NEP) in the blood serum in elderly people with different types of cognitive impairment and evaluate the effect of ceraxon on the biochemical parameters. MATERIAL AND METHODS: Three groups of patients: without cognitive disorders (controls--CG), with amnestic mild cognitive impairment (a-MCI) and with Alzheimer's disease (AD were studied). RESULTS AND CONCLUSION: The activity of AChE, BChE and NEP was reduced in the blood serum of patients with a-MCI and, to the greater extent, in patients with AD compared to CG and correlated with the level of cognitive dysfunction evaluated by MMSE, ADAS-cog, and other tests. For the first time, it has been shown that treatment of a-MCI patients with ceraxon (citicolin) results in an increase of the activity of blood serum AChE, BChE and NEP to the values observed in the CG. Thus, the activities of blood serum AChE, BChE and NEP reflect the level of cognitive dysfunction and can be used as prognostic biomarkers of the level of dementia progression in patients with impaired memory. PMID- 26978502 TI - [The results of the multicenter pharmaco-epidemiological observational project on the use of mydocalm in the treatment of pain syndromes with the muscle spasm]. AB - The prospective multicenter open noncomparative pharmaco-epidemiological observational project on the use of mydocalm in real clinical practice has been completed in 2013. The project has been performed in 2090 clinical/rehabilitation settings in 284 cities of 13 countries using the results of 35,383 patients. The project aimed to assess the safety of treatment (percentage of patients with adverse-effects) and pain relieving efficacy as well as patient's satisfaction with the treatment. In total, 6603 (19%) adverse-effects were recorded. Their severity was evaluated as mild in 84,48%, no serious adverse-effects were noted. The high efficacy of mydocalm in the treatment of pain syndromes with the muscle spasm has been demonstrated. The high level of tolerability and absence of the clinically significant increase of adverse effects in the combination with nonsteroidal anti-inflammatory drugs have been confirmed. PMID- 26978504 TI - [A clinical efficacy of electrode pharmaphoresis in treatment of railway workers with low-back pain]. AB - OBJECTIVE: To evaluate clinical efficacy and tolerability of electrode pharmaphoresis using preparations xefocam and mydocalm-richter in railway workers with low-back pain. MATERIAL AND METHODS: Authors carried out an open prospective noncomparative study of 16 patients, aged 21-82 years, with spinal osteochondrosis with root syndrome and radiculopathia of the lumbar/sacral spine with pain syndrome regardless of its duration. Treatment efficacy was assessed by the dynamics of pain syndrome severity based on the scores of a self-rated scale completed by the patient and the McGill Pain Questionnaire. Quality-of-life was assessed with the Oswestry Disability Index before and in the end of treatment. Clinical outcome was evaluated with the modified Nurick scale. Electrode pharmaphoresis (the "Farma T.E.B. Trans Epidermal Barrier Physio" apparatus) was administered to all patients using xefocam (solution for injections 8 mg, 2 ml per procedure) and mydocalm-richter (solution for injections 100 mg, 2 ml per injection) in the lumbar/sacral spine. RESULTS AND CONCLUSION: The high clinical efficacy of electrode pharmaphoresis using xefocam and mydocalm-richter was shown. The complex restoration study resulted in the reduction of pain syndrome in all patients. Pain severity was reduced to mild grade in 68.8% to the middle of treatment and in 93.8% patients in the end of treatment. As a consequence of pain reduction, the functional activity (quality of self-service, daily activities) increased significantly in 68.8% of patients. Positive treatment effect was noted in 100% of patients, good tolerability of this medication in 87.5%. PMID- 26978505 TI - [Functional properties of dopaminergic neurons obtained from fibroblasts of a patient with PARK2 form of Parkinson's disease]. AB - OBJECTIVE: To carry out a functional analysis of dopamine transporter (DAT) in autosomal recessive Parkinson's disease caused by mutations in the PARK2 gene. MATERIAL AND METHODS: Cultures of dopaminergic neurons were obtained from fibroblasts of a patient with PARK2 form of Parkinson's disease and a healthy donor with the use of the cell reprogramming technology. DAT expression in both cell cultures was assessed at the RNA and protein levels, and DAT activity was tested with the use of the fluorescent dopamine analogue ASP+. RESULTS AND CONCLUSION: In the cells with PARK2 mutations, the level of DAT expression was significantly higher than in normal neurons, but the intensity of ASP+ capture by mutant dopaminergic neurons was 25% down from normal neurons. For the study of competitive inhibition of DAT, dopamine was added to the incubation medium containing ASP+: it was shown that dopamine binding by the normal cells was almost twice as much relative to PARK2 mutant neurons. Therefore, dopaminergic neurons carrying mutations in the PARK2 gene are characterized by functional failure of dopamine transport systems. One of cell mechanisms of compensation of this defect seems to be an early increase of expression of the DAT transporter protein. PMID- 26978507 TI - [Meige's syndrome or segmental craniocervical dystonia: terminology, history and contemporary view]. AB - The term "Meige's syndrome" or "Breughel's syndrome" is used by specialists for the description of blepharospasm with the involuntary movements in the lower part of the face and/or masseter muscle. These eponyms "Meige's syndrome" and "Breughel's syndrome" make some mess in the terminology. The term "segmental craniocervical dystonia" joins different blepharospam-plus phenotypes and reflects contemporary perceptions about its genetic and pathophysiological community. Botulinotherapy is in fact the only way of symptomathic treatment of craniocervical dystonias. PMID- 26978508 TI - [The 115-anniverssary of the department of neurology and neurosurgery of the Pavlov First Saint Petersburg State Medical University]. PMID- 26978506 TI - [The reduced level of antibodies to acetylcholine receptor alpha 7 fragment in the blood serum of patients with Alzheimer's disease]. AB - OBJECTIVE: Determination of antibodies to neuronal membrane proteins in the blood serum of patients is of interest for diagnosis and optimization of treatment of Alzheimer's disease (AD). Authors studied the level of antibodies to acetylcholine receptor alpha 7 protein fragment (AChR), prion protein (RrR) and glycation end-products (RAGE) as well as to intracellular proteins nucleophosmin (Nuc) and survivin (Sur) in the serum of AD patients. MATERIAL AND METHODS: Serum samples of 26 patients with probable AD and 13 healthy people were studied. Exposed sections of each protein were used for the choice of peptides for antibody visualization. ELIZA was a main method in this study. RESULTS AND CONCLUSION: Antibodies to several proteins were identified but significant differences were found only for AChR-(173-193). The results demonstrated the involvement of AChR and AChR-antibodies in the development of AD. Determination of antibodies to AChR-(173-193) may be a marker of AD and a method for specifying the diagnosis of AD. PMID- 26978509 TI - [Chronic insomnia: treatment methods based on the current "3P" model of insomnia]. AB - Authors consider one of the popular models of the pathogenesis of chronic insomnia--"3P" model. It explains the origin and course of insomnia on the basis of interaction of three factors: predisposing, precipitating and perpetuating. The role of each group of factors and its connection to the cerebral hyperarousal state is discussed. Different variants of cognitive-behavioral therapy and pharmacological treatment of chronic insomnia are described. PMID- 26978510 TI - [Neuronal plasticity and epilepsy: modern concepts and mechanisms of epilepsy and depression comorbidity]. PMID- 26978511 TI - [Cortical dysgenesis with epileptic syndromes and symptomatic epilepsy in children]. AB - Cortical dysgenesis (CD) is a frequent inherited brain malformation. CD is a key cause of epileptic syndrome in children. In this review, the author presents a current classification of CD, etiological factors of their development, including gene mutations and adverse effects of various toxins and perinatal factors. A spectrum of clinical symptoms of CD with epileptic seizures is discussed in details. A role of current MRI-regimes in the diagnosis, the management of patients and prognosis of the course of CD are highlighted. PMID- 26978512 TI - [Low back pain: possibilities of pathogenetic treatment]. AB - Intervertebral disc (IVD) degeneration is one of the major causes of low back pain (LBP). Due to the complexity of spinal pain syndromes, it is often difficult to determine the extent of the IVD's contribution to the genesis of spinal pain. Inflammatory response to IVD' injury has been acknowledged to be important in the process of disc degeneration and may play an important role in pain generation. In this article, the inflammatory mechanisms of LBP will be discussed with special focus on interactions between inflammatory mediators and IVD biomechanics. Tumor necrosis factor-alpha (TNF-alpha) is a key mediator of inflammatory reactions in the pathogenesis of degenerative disk disease. The role of TNF-alpha inhibitors as a potential target of therapeutic interventions in prevention of neuronal damage and neuroprotection in LBP is discussed. PMID- 26978513 TI - [The effect of childhood stress on the development of mental disorders in adults]. AB - There is evidence that not only severe stressful events, but also common low threat events, in particular chronic ones, may cause or provoke some mental disorders. The literature data on the degree of pathogenicity of stress factors are insufficient. Authors attempted to summarize the established facts in the following aspects: current conceptions on the physiology and pathology of stress in the frames of the problem of psychosomatic disorders, deprivation in childhood, neurobiological consequences of childhood stress, psychiatric consequences of stress in childhood. Authors believe that this problem demands further investigation to find possible predictors of mental disorders in patients who had experienced stressful life events in childhood. PMID- 26978514 TI - [Tanakan as a multimodal cytoprotective factor in general medicine (part II)]. AB - The second section of the review provides an update of the data on mechanisms of action of a standardized extract of Ginkgo biloba EGb761(r) (tanakan) and its efficacy in treatment of depression, pain, complications of diabetes, Parkinson disease, tinnitus and dizziness, reproductive dysfunction. Updated data enable to use EGb761(r) (tanakan) as a highly-effective cytoprotective agent in treatment of cardiovascular, degenerative and metabolic diseases of the nervous system, inner ear disturbances (tinnitus), dysfunction of reproductive system as well as in prevention and treatment of stress-induced disorders. PMID- 26978515 TI - Size-dependent magnetic transitions in CoFe0.1Cr1.9O4 nanoparticles studied by magnetic and neutron-polarization analysis. AB - Multiferroic, CoCr2O4 bulk material undergoes successive magnetic transitions such as a paramagnetic to collinear and non-collinear ferrimagnetic state at the Curie temperature (TC) and spiral ordering temperature (TS) respectively and finally to a lock-in-transition temperature (Tl). In this paper, the rich sequence of magnetic transitions in CoCr2O4 after mixing the octahedral site with 10% of iron are investigated by varying the size of the particle from 10 to 50 nm. With the increasing size, while the TC increases from 110 to 119 K which is higher than the TC (95 K) of pure CoCr2O4, the TS remains unaffected. In addition, a compensation of magnetization at 34 K and a lock-in transition at 10 K are also monitored in 50 nm particles. Further, we have examined the magnetic ordering temperatures through neutron scattering using a polarized neutron beam along three orthogonal directions after separating the magnetic scattering from nuclear-coherent and spin-incoherent contributions. While a sharp long-range ferrimagnetic ordering down to 110 K and a short-range spiral ordering down to 50 K are obtained in 50 nm particles, in 10 nm particles, the para to ferrimagnetic transition is found to be continuous and spiral ordering is diffused in nature. Frequency-dependent ac susceptibility (chi) data fitted with different phenomenological models such as the Neel-Arrhenius, Vogel-Fulcher and power law, while ruling out the canonical spin-glass, cluster-glass and interacting superparamagnetism, reveal that both particles show spin-glass behavior with a higher relaxation time in 10 nm particles than in 50 nm. The smaller spin flip time in 50 nm particles confirms that spin dynamics does not slow down on approaching the glass transition temperature (Tg). PMID- 26978516 TI - Overdose Intake of Curcumin Initiates the Unbalanced State of Bodies. AB - Curcumin is the major active component of turmeric and widely used as a spice and coloring agent in food. However, its safety evaluation has been little investigated. To evaluate the 90-day subchronic toxicity of curcumin in rats, its general observation, clinical biochemistry, pathology, and metabolomics were evaluated. The results showed that curcumin induced liver injury through the generation of the overexpression of reactive oxygen species (ROS) and pro inflammatory cytokines IL-6 and the decreases of the levels of antioxidant enzyme SOD and detoxified enzyme GST. Meanwhile, for the self-protection of rats, curcumin treatment activated the transcription of Nrf-2 and elevated the expression of HO-1 to reduce tissue damage. Furthermore, curcumin significantly increased key mRNA levels of HK2, PKM2, LDHA, CES, Cpt1, Cpt2, FASN, and ATP5b and decreased levels of GLUT2 and ACC1 to enhance glycolysis and inhibit lipid metabolism and TCA cycle. Therefore, overdose or long-term intake of curcumin could initiate the unbalanced state of bodies through oxidative stress, inflammation, and metabolic disorders, which induces liver injury. Intermittent administration of curcumin is necessary in our daily lives. PMID- 26978517 TI - Acute Middle Gastrointestinal Bleeding Risk Associated with NSAIDs, Antithrombotic Drugs, and PPIs: A Multicenter Case-Control Study. AB - BACKGROUND: Middle gastrointestinal bleeding (MGIB) risk has not been fully investigated due to its extremely rare occurrence and the need for multiple endoscopies to exclude upper and lower gastrointestinal bleeding. This study investigated whether MGIB is associated with the use of non-steroidal anti inflammatory drugs (NSAIDs), low-dose aspirin (LDA), thienopyridines, anticoagulants, and proton-pump inhibitors (PPIs), and whether PPI use affects the interactions between MGIB and antithrombotic drugs. METHODS: In this multicenter, hospital-based, case-control study, 400 patients underwent upper and lower endoscopy, 80 had acute overt MGIB and 320 had no bleeding and were matched for age and sex as controls (1:4). MGIB was additionally evaluated by capsule and/or double-balloon endoscopy, after excluding upper and lower GI bleeding. Adjusted odds ratios (AOR) for MGIB risk were calculated using conditional logistic regression. To estimate the propensity score, we employed a logistic regression model for PPI use. RESULTS: In patients with MGIB, mean hemoglobin level was 9.4 g/dL, and 28 patients (35%) received blood transfusions. Factors significantly associated with MGIB were chronic kidney disease (p<0.001), liver cirrhosis (p = 0.034), NSAIDs (p<0.001), thienopyridines (p<0.001), anticoagulants (p = 0.002), and PPIs (p<0.001). After adjusting for these factors, NSAIDs (AOR, 2.5; p = 0.018), thienopyridines (AOR, 3.2; p = 0.015), anticoagulants (AOR, 4.3; p = 0.028), and PPIs (AOR; 2.0; p = 0.021) were independently associated with MGIB. After adjusting for propensity score, the use of PPIs remained an independent risk factors for MGIB (AOR, 1.94; p = 0.034). No significant interactions were observed between PPIs and NSAIDs (AOR, 0.7; p = 0.637), LDA (AOR, 0.3; p = 0.112), thienopyridine (AOR, 0.7, p = 0.671), or anticoagulants (AOR, 0.5; p = 0.545). CONCLUSIONS: One-third of patients with acute small intestinal bleeding required blood transfusion. NSAIDs, thienopyridines, anticoagulants, and PPIs increased the risk of acute small intestinal bleeding. However, there were no significant interactions found between antithrombotic drugs and PPI use for bleeding risk. PMID- 26978518 TI - Selective Enrichment of Omega-3 Fatty Acids in Oils by Phospholipase A1. AB - Omega fatty acids are recognized as key nutrients for healthier ageing. Lipases are used to release omega-3 fatty acids from oils for preparing enriched omega-3 fatty acid supplements. However, use of lipases in enrichment of omega-3 fatty acids is limited due to their insufficient specificity for omega-3 fatty acids. In this study use of phospholipase A1 (PLA1), which possesses both sn-1 specific activity on phospholipids and lipase activity, was explored for hydrolysis of omega-3 fatty acids from anchovy oil. Substrate specificity of PLA1 from Thermomyces lenuginosus was initially tested with synthetic p-nitrophenyl esters along with a lipase from Bacillus subtilis (BSL), as a lipase control. Gas chromatographic characterization of the hydrolysate obtained upon treatment of anchovy oil with these enzymes indicated a selective retention of omega-3 fatty acids in the triglyceride fraction by PLA1 and not by BSL. 13C NMR spectroscopy based position analysis of fatty acids in enzyme treated and untreated samples indicated that PLA1 preferably retained omega-3 fatty acids in oil, while saturated fatty acids were hydrolysed irrespective of their position. Hydrolysis of structured triglyceride,1,3-dioleoyl-2-palmitoylglycerol, suggested that both the enzymes hydrolyse the fatty acids at both the positions. The observed discrimination against omega-3 fatty acids by PLA1 appears to be due to its fatty acid selectivity rather than positional specificity. These studies suggest that PLA1 could be used as a potential enzyme for selective concentrationof omega-3 fatty acids. PMID- 26978519 TI - In-Situ Observation of Membrane Protein Folding during Cell-Free Expression. AB - Proper insertion, folding and assembly of functional proteins in biological membranes are key processes to warrant activity of a living cell. Here, we present a novel approach to trace folding and insertion of a nascent membrane protein leaving the ribosome and penetrating the bilayer. Surface Enhanced IR Absorption Spectroscopy selectively monitored insertion and folding of membrane proteins during cell-free expression in a label-free and non-invasive manner. Protein synthesis was performed in an optical cell containing a prism covered with a thin gold film with nanodiscs on top, providing an artificial lipid bilayer for folding. In a pilot experiment, the folding pathway of bacteriorhodopsin via various secondary and tertiary structures was visualized. Thus, a methodology is established with which the folding reaction of other more complex membrane proteins can be observed during protein biosynthesis (in situ and in operando) at molecular resolution. PMID- 26978521 TI - Rates of intrauterine fetal demise and neonatal morbidity at term: determining optimal timing of delivery. AB - OBJECTIVE: To examine rates of unexplained intrauterine fetal demise (IUFD) and neonatal morbidity in uncomplicated term pregnancies to identify the optimal gestational age for delivery. METHODS: A retrospective case control study was performed with singleton pregnancies delivered between 37 0/7 weeks and 42 6/7 weeks. Exclusion criteria were "complicated pregnancies": emergency deliveries, maternal hypertension, diabetes, infection, fetal disease/malformations and placental abnormalities. RESULTS: Nineteen thousand two hundred and sixty-four maternal/infant pairs were examined. The overall rate of NICU admission was 2.7% and the rate of unexplained IUFD was 2.02 per 1000 births. The lowest rate of IUFD was found at 39 weeks (1.40 per 1000 births). Odds ratios adjusted for maternal smoking, ethnicity, age and mode of delivery showed 2.74 (95% CI 0.35 21.83) risk of IUFD at 42 versus 39 weeks, 2.09 (1.47-2.98) risk of NICU admission at 37 versus 38 weeks, 2.54 (1.62-3.97) risk of respiratory morbidity at 37 versus 38 weeks and 3.38 (1.84-6.18) risk of transient tachypnea of the newborn or respiratory distress syndrome at 37 versus 38 weeks. CONCLUSIONS: Neonatal respiratory morbidity was lowest for deliveries at 38-39 weeks. IUFD was 2.74 times more likely at 42 weeks versus 39 weeks. Our findings support current guidelines advising clinicians when to deliver term pregnancies. PMID- 26978520 TI - Immune Complexes Indirectly Suppress the Generation of Th17 Responses In Vivo. AB - The precise context in which the innate immune system is activated plays a pivotal role in the subsequent instruction of CD4+ T helper (Th) cell responses. Th1 responses are downregulated when antigen is encountered in the presence of antigen-IgG immune complexes. To assess if Th17 responses to antigen are subject to similar influences in the presence of immune complexes we utilized an inflammatory airway disease model in which immunization of mice with Complete Freund's Adjuvant (CFA) and ovalbumin (Ova) induces a powerful Ova-specific Th1 and Th17 response. Here we show that modification of that immunization with CFA to include IgG-Ova immune complexes results in the suppression of CFA-induced Th17 responses and a concurrent enhancement of Ova-specific Th2 responses. Furthermore, we show the mechanism by which these immune complexes suppress Th17 responses is through the enhancement of IL-10 production. In addition, the generation of Th17 responses following immunization with CFA and Ova were dependent on IL-1alpha but independent of NLRP3 inflammasome activation. Together these data represent a novel mechanism by which the generation of Th17 responses is regulated. PMID- 26978523 TI - SMARTbot: A Behavioral Analysis Framework Augmented with Machine Learning to Identify Mobile Botnet Applications. AB - Botnet phenomenon in smartphones is evolving with the proliferation in mobile phone technologies after leaving imperative impact on personal computers. It refers to the network of computers, laptops, mobile devices or tablets which is remotely controlled by the cybercriminals to initiate various distributed coordinated attacks including spam emails, ad-click fraud, Bitcoin mining, Distributed Denial of Service (DDoS), disseminating other malwares and much more. Likewise traditional PC based botnet, Mobile botnets have the same operational impact except the target audience is particular to smartphone users. Therefore, it is import to uncover this security issue prior to its widespread adaptation. We propose SMARTbot, a novel dynamic analysis framework augmented with machine learning techniques to automatically detect botnet binaries from malicious corpus. SMARTbot is a component based off-device behavioral analysis framework which can generate mobile botnet learning model by inducing Artificial Neural Networks' back-propagation method. Moreover, this framework can detect mobile botnet binaries with remarkable accuracy even in case of obfuscated program code. The results conclude that, a classifier model based on simple logistic regression outperform other machine learning classifier for botnet apps' detection, i.e 99.49% accuracy is achieved. Further, from manual inspection of botnet dataset we have extracted interesting trends in those applications. As an outcome of this research, a mobile botnet dataset is devised which will become the benchmark for future studies. PMID- 26978522 TI - PE_PGRS33 Contributes to Mycobacterium tuberculosis Entry in Macrophages through Interaction with TLR2. AB - PE_PGRS represent a large family of proteins typical of pathogenic mycobacteria whose members are characterized by an N-terminal PE domain followed by a large Gly-Ala repeat-rich C-terminal domain. Despite the abundance of PE_PGRS-coding genes in the Mycobacterium tuberculosis (Mtb) genome their role and function in the biology and pathogenesis still remains elusive. In this study, we generated and characterized an Mtb H37Rv mutant (MtbDelta33) in which the structural gene of PE_PGRS33, a prototypical member of the protein family, was inactivated. We showed that this mutant entered macrophages with an efficiency up to ten times lower than parental or complemented strains, while its efficiency in infecting pneumocytes remained unaffected. Interestingly, the lack of PE_PGRS33 did not affect the intracellular growth of this mutant in macrophages. Using a series of functional deletion mutants of the PE_PGRS33 gene to complement the MtbDelta33 strain, we demonstrated that the PGRS domain is required to mediate cell entry into macrophages, with the key domain encompassing position 140-260 amino acids of PE_PGRS33. PE_PGRS33-mediated entry into macrophages was abolished in TLR2 deficient mice, as well as following treatment with wortmannin or an antibody against the complement receptor 3 (CR3), indicating that PE_PGRS33-mediated entry of Mtb in macrophages occurs through interaction with TLR2. PMID- 26978525 TI - Soil Texture and Cultivar Effects on Rice (Oryza sativa, L.) Grain Yield, Yield Components and Water Productivity in Three Water Regimes. AB - The objective of this study was to determine the effects of water regime/soil condition (continuous flooding, saturated, and aerobic), cultivar ('Cocodrie' and 'Rondo'), and soil texture (clay and sandy loam) on rice grain yield, yield components and water productivity using a greenhouse trial. Rice grain yield was significantly affected by soil texture and the interaction between water regime and cultivar. Significantly higher yield was obtained in continuous flooding than in aerobic and saturated soil conditions but the latter treatments were comparable to each other. For Rondo, its grain yield has decreased with soil water regimes in the order of continuous flooding, saturated and aerobic treatments. The rice grain yield in clay soil was 46% higher than in sandy loam soil averaged across cultivar and water regime. Compared to aerobic condition, saturated and continuous flooding treatments had greater panicle numbers. In addition, panicle number in clay soil was 25% higher than in sandy loam soil. The spikelet number of Cocodrie was 29% greater than that of Rondo, indicating that rice cultivar had greater effect on spikelet number than soil type and water management. Water productivity was significantly affected by the interaction of water regime and cultivar. Compared to sandy loam soil, clay soil was 25% higher in water productivity. Our results indicated that cultivar selection and soil texture are important factors in deciding what water management option to practice. PMID- 26978527 TI - Strategies for optimizing polymer-lipid hybrid nanoparticle-mediated drug delivery. PMID- 26978524 TI - Associations among Erythroferrone and Biomarkers of Erythropoiesis and Iron Metabolism, and Treatment with Long-Term Erythropoiesis-Stimulating Agents in Patients on Hemodialysis. AB - BACKGROUND: We aimed to identify associations between erythroferrone (ERFE), a regulator of hepcidin 25, and biomarkers of erythropoiesis and iron metabolism. We also aimed to determine the effects of erythropoiesis-stimulating agents (ESA), continuous erythropoietin receptor activator (CERA) and darbepoetin-alpha (DA) on ERFE production in patients on hemodialysis (HD). METHODS: Blood samples were obtained from 59 patients before HD sessions on day 0 (baseline). Twenty patients who were injected with either CERA (N = 10) or DA (N = 10) at the end of the dialysis week (day 0), who had ferritin >= 100 ng/mL and/or transferrin saturation >= 20%, and hemoglobin > 9 g/dL were selected from among the 59 patients. Blood was sampled serially before HD sessions on days 3, 5, 7 from patients on DA and on the same days plus day 14 from those on CERA. RESULTS: Levels of ERFE correlated inversely with those of hepcidin 25 and ferritin, and positively with those of soluble transferrin receptor. The hepcidin 25: ERFE ratio and hepcidin 25 levels positively correlated with ferritin levels. Levels of ERFE significantly increased from day 3 of treatment with DA and CERA and decreased by days 7 and 14, respectively. Erythropoiesis-stimulating agents concomitantly decreased levels of hepcidin 25 as those of ERFE increased. CONCLUSION: We identified a novel association between ESA and ERFE in patients on HD. Both DA and CERA increased levels of ERFE that regulated hepcidin 25 and led to iron mobilization from body stores during erythropoiesis. PMID- 26978530 TI - Zika Virus Infection and Surgery. PMID- 26978526 TI - Impaired High-Density Lipoprotein Anti-Oxidant Function Predicts Poor Outcome in Critically Ill Patients. AB - INTRODUCTION: Oxidative stress affects clinical outcome in critically ill patients. Although high-density lipoprotein (HDL) particles generally possess anti-oxidant capacities, deleterious properties of HDL have been described in acutely ill patients. The impact of anti-oxidant HDL capacities on clinical outcome in critically ill patients is unknown. We therefore analyzed the predictive value of anti-oxidant HDL function on mortality in an unselected cohort of critically ill patients. METHOD: We prospectively enrolled 270 consecutive patients admitted to a university-affiliated intensive care unit (ICU) and determined anti-oxidant HDL function using the HDL oxidant index (HOI). Based on their HOI, the study population was stratified into patients with impaired anti-oxidant HDL function and the residual study population. RESULTS: During a median follow-up time of 9.8 years (IQR: 9.2 to 10.0), 69% of patients died. Cox regression analysis revealed a significant and independent association between impaired anti-oxidant HDL function and short-term mortality with an adjusted HR of 1.65 (95% CI 1.22-2.24; p = 0.001) as well as 10-year mortality with an adj. HR of 1.19 (95% CI 1.02-1.40; p = 0.032) when compared to the residual study population. Anti-oxidant HDL function correlated with the amount of oxidative stress as determined by Cu/Zn superoxide dismutase (r = 0.38; p<0.001). CONCLUSION: Impaired anti-oxidant HDL function represents a strong and independent predictor of 30-day mortality as well as long-term mortality in critically ill patients. PMID- 26978528 TI - CD24 Is Not Required for Tumor Initiation and Growth in Murine Breast and Prostate Cancer Models. AB - CD24 is a small, heavily glycosylated, GPI-linked membrane protein, whose expression has been associated with the tumorigenesis and progression of several types of cancer. Here, we studied the expression of CD24 in tumors of MMTV-PyMT, Apc1572/T+ and TRAMP genetic mouse models that spontaneously develop mammary or prostate carcinoma, respectively. We found that CD24 is expressed during tumor development in all three models. In MMTV-PyMT and Apc1572T/+ breast tumors, CD24 was strongly but heterogeneously expressed during early tumorigenesis, but decreased in more advanced stages, and accordingly was increased in poorly differentiated lesions compared with well differentiated lesions. In prostate tumors developing in TRAMP mice, CD24 expression was strong within hyperplastic lesions in comparison with non-hyperplastic regions, and heterogeneous CD24 expression was maintained in advanced prostate carcinomas. To investigate whether CD24 plays a functional role in tumorigenesis in these models, we crossed CD24 deficient mice with MMTV-PyMT, Apc1572T/+ and TRAMP mice, and assessed the influence of CD24 deficiency on tumor onset and tumor burden. We found that mice negative or positive for CD24 did not significantly differ in terms of tumor initiation and burden in the genetic tumor models tested, with the exception of Apc1572T/+ mice, in which lack of CD24 reduced the mammary tumor burden slightly but significantly. Together, our data suggest that while CD24 is distinctively expressed during the early development of murine mammary and prostate tumors, it is not essential for the formation of tumors developing in MMTV-PyMT, Apc1572T/+ and TRAMP mice. PMID- 26978529 TI - Turbulent Kinetic Energy Measurement Using Phase Contrast MRI for Estimating the Post-Stenotic Pressure Drop: In Vitro Validation and Clinical Application. AB - BACKGROUND: Although the measurement of turbulence kinetic energy (TKE) by using magnetic resonance imaging (MRI) has been introduced as an alternative index for quantifying energy loss through the cardiac valve, experimental verification and clinical application of this parameter are still required. OBJECTIVES: The goal of this study is to verify MRI measurements of TKE by using a phantom stenosis with particle image velocimetry (PIV) as the reference standard. In addition, the feasibility of measuring TKE with MRI is explored. METHODS: MRI measurements of TKE through a phantom stenosis was performed by using clinical 3T MRI scanner. The MRI measurements were verified experimentally by using PIV as the reference standard. In vivo application of MRI-driven TKE was explored in seven patients with aortic valve disease and one healthy volunteer. Transvalvular gradients measured by MRI and echocardiography were compared. RESULTS: MRI and PIV measurements of TKE are consistent for turbulent flow (0.666 < R2 < 0.738) with a mean difference of -11.13 J/m3 (SD = 4.34 J/m3). Results of MRI and PIV measurements differ by 2.76 +/- 0.82 cm/s (velocity) and -11.13 +/- 4.34 J/m3 (TKE) for turbulent flow (Re > 400). The turbulence pressure drop correlates strongly with total TKE (R2 = 0.986). However, in vivo measurements of TKE are not consistent with the transvalvular pressure gradient estimated by echocardiography. CONCLUSIONS: These results suggest that TKE measurement via MRI may provide a potential benefit as an energy-loss index to characterize blood flow through the aortic valve. However, further clinical studies are necessary to reach definitive conclusions regarding this technique. PMID- 26978531 TI - Infection in Burns. AB - BACKGROUND: Developments in critical care and surgical approaches to treating burn wounds, together with newer antimicrobial treatments, have significantly reduced the morbidity and mortality rates associated with this injury. METHODS: Review of the pertinent English-language literature. RESULTS: Several resistant organisms have emerged as the maleficent cause of invasive infection in burn patients, including methicillin-resistant Staphylococcus aureus, vancomycin resistant Enterococcus, Pseudomonas, Acinetobacter, non-albicans Candida spp., and Aspergillus. Advances in antimicrobial therapies and the release of new classes of antibiotics have certainly added to the armamentarium of therapeutic resources for the clinician. CONCLUSION: Strict infection control measures, constant wound surveillance with regular sampling of tissues for quantitative culture, and early excision and wound closure remain the principal adjuncts to control of invasive infections in burn patients. PMID- 26978532 TI - Continuous Multimodality Monitoring in Children after Traumatic Brain Injury Preliminary Experience. AB - INTRODUCTION: Multimodality monitoring is regularly employed in adult traumatic brain injury (TBI) patients where it provides physiologic and therapeutic insight into this heterogeneous condition. Pediatric studies are less frequent. METHODS: An analysis of data collected prospectively from 12 pediatric TBI patients admitted to Addenbrooke's Hospital, Pediatric Intensive Care Unit (PICU) between August 2012 and December 2014 was performed. Patients' intracranial pressure (ICP), mean arterial pressure (MAP), and cerebral perfusion pressure (CPP) were monitored continuously using brain monitoring software ICM+(r),) Pressure reactivity index (PRx) and 'Optimal CPP' (CPPopt) were calculated. Patient outcome was dichotomized into survivors and non-survivors. RESULTS: At 6 months 8/12 (66%) of the cohort survived the TBI. The median (+/-IQR) ICP was significantly lower in survivors 13.1+/-3.2 mm Hg compared to non-survivors 21.6+/-42.9 mm Hg (p = 0.003). The median time spent with ICP over 20 mm Hg was lower in survivors (9.7+9.8% vs 60.5+67.4% in non-survivors; p = 0.003). Although there was no evidence that CPP was different between survival groups, the time spent with a CPP close (within 10 mm Hg) to the optimal CPP was significantly longer in survivors (90.7+/-12.6%) compared with non-survivors (70.6+/-21.8%; p = 0.02). PRx provided significant outcome separation with median PRx in survivors being 0.02+/-0.19 compared to 0.39+/-0.62 in non-survivors (p = 0.02). CONCLUSION: Our observations provide evidence that multi-modality monitoring may be useful in pediatric TBI with ICP, deviation of CPP from CPPopt, and PRx correlating with patient outcome. PMID- 26978534 TI - Quantification of leucocytes, T-lymphocytes and macrophages in autoptical endomyocardial tissue from 56 normal human hearts during the first year of life. AB - This study evaluated the normal number of inflammatory cells in the heart in the first year of life using two methods to compare their ability to quantitate physiological myocardial infiltration. Eight endomyocardial samples from both ventricles were obtained at autopsy from 56 structurally normal hearts during the first year of life. In each sample the numbers of leucocytes, T-lymphocytes and macrophages were counted once in 20 randomly chosen high-power fields (400*) as well as in a 10mm(2) area of randomly chosen myocardial tissue (100*) by two independent investigators. Compared to the literature a greater representative proportion of myocardial tissue was analyzed. The results of the enumeration in mm(2) were converted into high-power-fields to compare both methods. The mean numbers and standard deviations for leucocytes, T-lymphocytes and macrophages were calculated. Both counting methods showed similar results with low inflammatory cell counts per single heart and staining. A greater understanding of the physiological myocardial infiltration by leucocytes, T-lymphocytes and macrophages is important for postmortem forensic cases, and for the interpretation of endomyocardial biopsies in infants. PMID- 26978533 TI - Paraoxonase 1 and 2 gene variants and the ischemic stroke risk in Gran Canaria population: an association study and meta-analysis. AB - PURPOSE OF THE STUDY: The present study aims to evaluate the relationship between rs662 (Gln(Q)192Arg(R)) and rs854560 (L55M) and the rs7493 (S311C) in the paraoxonase genes and ischemic stroke (IS) in the population of Gran Canaria (Canary Islands). The association with stroke was also evaluated using systematic review and meta-analysis. METHODS: A total of 129 IS patients and 176 age and gender matched controls were enrolled. For meta-analysis, eligible studies were identified through search in public databases. RESULTS: In multivariate regression analysis only the PON2 S311C variant showed to be an independent predictor of IS (OR = 0.093, 95% CI: 0.014-0.627). Overall, no significant association was found between L55M and IS when all studies were pooled nor by subgroup analysis by ethnicity. Gln192Arg showed a modest risk for IS in the global and in Asian population but with high heterogeneity among studies. A modest risk under a dominant inheritance model was found for the S311C variant with an overall random effect OR of 1.004 (95% CI: 1.00-1.35). There was strong evidence of heterogeneity among studies ( p = 0.0097, I2 = 25.35%) which did not disappear after stratification by ethnicity. CONCLUSIONS: The overall analysis shows a significant contribution of the rs662 variant to IS risk. We found that the CC genotype of the PON2 S311C polymorphism is a risk factor for IS. Results of the meta-analysis partially support this conclusion. PMID- 26978536 TI - 'Reckless policy' of senior nurse cuts could affect patient safety, RCN warns. AB - Almost 4,000 senior nursing posts have been lost in the NHS over the past three years, a situation which could have 'dire consequences' for patient safety, the RCN has warned. PMID- 26978535 TI - New cycloartane glycosides from the rhizomes of Cyperus rotundus and their antidepressant activity. AB - Two new cycloartane glycosides, cyprotusides A (1) and B (2), were isolated from the rhizomes of Cyperus rotundus. Their chemical structures were elucidated on the basis of IR, MS, NMR spectroscopic analyses coupled with chemical degradation. The potential antidepressant activity of the two compounds was evaluated. In the despair mice models, compounds 1 and 2 showed significant antidepressant activity. PMID- 26978537 TI - Terminally ill fail to receive suitable care at home. AB - People with terminal illnesses are not receiving access to suitable care in their own homes when they need it, according to a survey commissioned by charity Marie Curie Cancer Care. PMID- 26978538 TI - News digest March 11 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26978539 TI - Nurse's research highlights vital work of diabetes specialists. AB - Diabetes specialist nurses are highly valued by patients and can save the NHS money by keeping patients out of hospital, a nurse has found. PMID- 26978540 TI - More investment needed in advanced nurse practitioners to bolster emergency care. AB - NHS organisations must invest in sufficient numbers of advanced nurse practitioners to ease pressures on urgent and emergency care services, a report states. PMID- 26978541 TI - News digest March 10 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26978542 TI - Nurse awarded payout after sustaining injuries at work. AB - A hospice nurse whose career was cut short following an accident at work has been awarded a L765,992 payout from her former employers. PMID- 26978543 TI - Outpatient services not good enough, watchdog warns. AB - Patients are facing unacceptable delays at overcrowded outpatient clinics, the Care Quality Commission (CQC) has warned. PMID- 26978544 TI - News digest 07 March 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26978545 TI - Nurses call for overhaul of benefits assessments. AB - Nursing unions have called for an overhaul of the contentious benefit assessment system for people unable to work, after Atos Healthcare announced plans to exit its government contract early. PMID- 26978546 TI - More nurses could stop NHS 'failing older people'. AB - District and community nurse numbers need to be boosted to prevent older patients being failed by the NHS, the RCN has urged. PMID- 26978547 TI - News digest 06 March 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26978548 TI - New analytical application of antibody-based biosensor in estimation of thyroid stimulating hormone in serum. AB - BACKGROUND: Conventionally, ELISA is used to measure thyroid-stimulating hormone (TSH) for diagnosis of thyroid disease. In this study, an immunosensor-based, kinetic-exclusion analysis (KinExA) was used for TSH estimation. METHODOLOGY: A PMMA microbead column coated with TSH antigen is formed inside the flow cell. Samples consisting of mouse anti-TSH monoclonal antibody and TSH antigen complex in solution are passed over the beads and the unbound anti-TSH antibody is captured by the TSH-coated beads, followed by passing fluorescent-labeled antibody over the beads to generate signals for analysis. The limit of detection for the assay was 0.4 mIU l(-1) and the precision was acceptable. CONCLUSION: The developed sensor was advantageous due to the automated nature and its convenience, without compromising the sensitivity for estimation of TSH. PMID- 26978549 TI - Kinetics of ABTS derived radical cation scavenging by bucillamine, cysteine, and glutathione. Catalytic effect of Cu(2+) ions. AB - Kinetics of reduction of the stable radical cation derived from 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid (ABTS) in reaction with the anti-rheumatic drug bucillamine (BUC) and two reference thiols - cysteine (Cys) and glutathione (GSH) was followed spectrophotometrically in acidic medium with 10-fold molar excess of the reductant. Decay of the radical is governed by pseudo-first order kinetics with small deviation in the case of GSH. H(+) ions displayed second order inhibition of the reaction with all the studied compounds. The reaction of BUC exhibits zero order kinetics to the radical at lower acidities with a moderate acceleration of the reaction rate by H(+) ions. A significant catalytic effect of Cu(2+) ions on the reactions with all the reductants was observed. The most sensitive to Cu(2+)-catalysis was the reaction of BUC with the radical cation, while Cu(2+) ions showed much lower effect on the reaction with GSH. The presence of EDTA strongly inhibited the reactions and equalized the reaction rates for all the reductants. A Cu(I) selective chelator bathocuproine disulfonate reduced the reaction rate with Cys, but accelerated the reaction with BUC at the lower acidities. The experimental results were rationalized in the framework of the mechanism of reductive chelation. The conclusions may have important consequences for interpretation of antioxidant capacity assays, such as TEAC, utilizing the ABTS derived radical cation. PMID- 26978551 TI - Semi-Supervised Tensor-Based Graph Embedding Learning and Its Application to Visual Discriminant Tracking. AB - An appearance model adaptable to changes in object appearance is critical in visual object tracking. In this paper, we treat an image patch as a two-order tensor which preserves the original image structure. We design two graphs for characterizing the intrinsic local geometrical structure of the tensor samples of the object and the background. Graph embedding is used to reduce the dimensions of the tensors while preserving the structure of the graphs. Then, a discriminant embedding space is constructed. We prove two propositions for finding the transformation matrices which are used to map the original tensor samples to the tensor-based graph embedding space. In order to encode more discriminant information in the embedding space, we propose a transfer-learning- based semi supervised strategy to iteratively adjust the embedding space into which discriminative information obtained from earlier times is transferred. We apply the proposed semi-supervised tensor-based graph embedding learning algorithm to visual tracking. The new tracking algorithm captures an object's appearance characteristics during tracking and uses a particle filter to estimate the optimal object state. Experimental results on the CVPR 2013 benchmark dataset demonstrate the effectiveness of the proposed tracking algorithm. PMID- 26978550 TI - Cross reactivity of S. aureus to murine cytokine assays: A source of discrepancy. AB - Staphylococcus aureus is one of the versatile Gram positive bacteria causing a range of diseases. Upon challenge, host immune cells recognize S. aureus and mount diverse immune responses including production of pro-inflammatory cytokines such as IL-1beta and TNF-alpha. These cytokines are important mediators of inflammation which can be detected via various immunological methods such as enzyme linked immunosorbent assay (ELISA) and immunoblotting. In the current study, we found that a number of clinical isolates as well as laboratory strains of S. aureus exhibited cross reactivity with ELISA antibodies for murine IL-1beta and TNF-alpha assays. This cross reactivity generates exaggerated false positive signals which can be a source of discrepancy for the understanding of real immune responses against S. aureus infection by host immune cells. PMID- 26978552 TI - Blessing of Dimensionality: Recovering Mixture Data via Dictionary Pursuit. AB - This paper studies the problem of recovering the authentic samples that lie on a union of multiple subspaces from their corrupted observations. Due to the high dimensional and massive nature of today's data-driven community, it is arguable that the target matrix (i.e., authentic sample matrix) to recover is often low rank. In this case, the recently established Robust Principal Component Analysis (RPCA) method already provides us a convenient way to solve the problem of recovering mixture data. However, in general, RPCA is not good enough because the incoherent condition assumed by RPCA is not so consistent with the mixture structure of multiple subspaces. Namely, when the subspace number grows, the row coherence of data keeps heightening and, accordingly, RPCA degrades. To overcome the challenges arising from mixture data, we suggest to consider LRR in this paper. We elucidate that LRR can well handle mixture data, as long as its dictionary is configured appropriately. More precisely, we mathematically prove that LRR can weaken the dependence on the row-coherence, provided that the dictionary is well-conditioned and has a rank of not too high. In particular, if the dictionary itself is sufficiently low-rank, then the dependence on the row coherence can be completely removed. These provide some elementary principles for dictionary learning and naturally lead to a practical algorithm for recovering mixture data. Our experiments on randomly generated matrices and real motion sequences show promising results. PMID- 26978553 TI - A Sphere-Description-Based Approach for Multiple-Instance Learning. AB - Multiple-instance learning (MIL) is a generalization of supervised learning which addresses the classification of bags. Similar to traditional supervised learning, most of the existing MIL work is proposed based on the assumption that a representative training set is available for a proper learning of the classifier. That is to say, the training data can appropriately describe the distribution of positive and negative data in the testing set. However, this assumption may not be always satisfied. In real-world MIL applications, the negative data in the training set may not sufficiently represent the distribution of negative data in the testing set. Hence, how to learn an appropriate MIL classifier when a representative training set is not available becomes a key challenge for real world MIL applications. To deal with this problem, we propose a novel Sphere Description-Based approach for Multiple-Instance Learning (SDB-MIL). SDB-MIL learns an optimal sphere by determining a large margin among the instances, and meanwhile ensuring that each positive bag has at least one instance inside the sphere and all negative bags are outside the sphere. Enclosing at least one instance from each positive bag in the sphere enables a more desirable MIL classifier when the negative data in the training set cannot sufficiently represent the distribution of negative data in the testing set. Substantial experiments on the benchmark and real-world MIL datasets show that SDB-MIL obtains statistically better classification performance than the MIL methods compared. PMID- 26978554 TI - Multi-Timescale Collaborative Tracking. AB - We present the multi-timescale collaborative tracker for single object tracking. The tracker simultaneously utilizes different types of "forces", namely attraction, repulsion and support, to take advantage of their complementary strengths. We model the three forces via three components that are learned from the sample sets with different timescales. The long-term descriptive component attracts the target sample, while the medium-term discriminative component repulses the target from the background. They are collaborated in the appearance model to benefit each other. The short-term regressive component combines the votes of the auxiliary samples to predict the target's position, forming the context-aware motion model. The appearance model and the motion model collaboratively determine the target state, and the optimal state is estimated by a novel coarse-to-fine search strategy. We have conducted an extensive set of experiments on the standard 50 video benchmark. The results confirm the effectiveness of each component and their collaboration, outperforming current state-of-the-art methods. PMID- 26978556 TI - Geometric Calibration of Micro-Lens-Based Light Field Cameras Using Line Features. AB - We present a novel method for the geometric calibration of micro-lens-based light field cameras. Accurate geometric calibration is the basis of various applications. Instead of using sub-aperture images, we directly utilize raw images for calibration. We select appropriate regions in raw images and extract line features from micro-lens images in those regions. For the entire process, we formulate a new projection model of a micro-lens-based light field camera, which contains a smaller number of parameters than previous models. The model is transformed into a linear form using line features. We compute the initial solution of both the intrinsic and the extrinsic parameters by a linear computation and refine them via non-linear optimization. Experimental results demonstrate the accuracy of the correspondences between rays and pixels in raw images, as estimated by the proposed method. PMID- 26978555 TI - Active Clustering with Model-Based Uncertainty Reduction. AB - Semi-supervised clustering seeks to augment traditional clustering methods by incorporating side information provided via human expertise in order to increase the semantic meaningfulness of the resulting clusters. However, most current methods are passive in the sense that the side information is provided beforehand and selected randomly. This may require a large number of constraints, some of which could be redundant, unnecessary, or even detrimental to the clustering results. Thus in order to scale such semi-supervised algorithms to larger problems it is desirable to pursue an active clustering method-i.e., an algorithm that maximizes the effectiveness of the available human labor by only requesting human input where it will have the greatest impact. Here, we propose a novel online framework for active semi-supervised spectral clustering that selects pairwise constraints as clustering proceeds, based on the principle of uncertainty reduction. Using a first-order Taylor expansion, we decompose the expected uncertainty reduction problem into a gradient and a step-scale, computed via an application of matrix perturbation theory and cluster-assignment entropy, respectively. The resulting model is used to estimate the uncertainty reduction potential of each sample in the dataset. We then present the human user with pairwise queries with respect to only the best candidate sample. We evaluate our method using three different image datasets (faces, leaves and dogs), a set of common UCI machine learning datasets and a gene dataset. The results validate our decomposition formulation and show that our method is consistently superior to existing state-of-the-art techniques, as well as being robust to noise and to unknown numbers of clusters. PMID- 26978557 TI - Large-Scale Binary Quadratic Optimization Using Semidefinite Relaxation and Applications. AB - In computer vision, many problems can be formulated as binary quadratic programs (BQPs), which are in general NP hard. Finding a solution when the problem is of large size to be of practical interest typically requires relaxation. Semidefinite relaxation usually yields tight bounds, but its computational complexity is high. In this work, we present a semidefinite programming (SDP) formulation for BQPs, with two desirable properties. First, it produces similar bounds to the standard SDP formulation. Second, compared with the conventional SDP formulation, the proposed SDP formulation leads to a considerably more efficient and scalable dual optimization approach. We then propose two solvers, namely, quasi-Newton and smoothing Newton methods, for the simplified dual problem. Both of them are significantly more efficient than standard interior point methods. Empirically the smoothing Newton solver is faster than the quasi Newton solver for dense or medium-sized problems, while the quasi-Newton solver is preferable for large sparse/structured problems. PMID- 26978563 TI - Are Allopathic and Holistic Medicine Incommensurable? AB - The shift from the Aristotelian to the Newtonian scientific paradigm gave birth to progresses in the natural, hard sciences and contributed to the emergence of modernity. Allopathic medicine gradually implemented those progresses, transforming itself into contemporary biomedicine. In the early 20th century, replacement of Newtonian physics by quantum mechanics and Einstein's theory of relativity resulted in a new paradigm shift in the natural, hard sciences. This shift gave birth to post-modern perceptions, which attempt to put those changes in context. Within this new context, holistic therapeutic approaches are considered more compatible with the new paradigm. Different paradigms in the natural, hard sciences are considered to be incommensurable (in the Kuhnian sense). This incommensurability is also transferred to the different societal contexts, the different "Weltanschauungen" that rely on different scientific paradigms. However, drawing on arguments that range from historical and philosophical to practical and sociological ones, we argue that, although based on different scientific paradigms, allopathic and holistic medicine are not incommensurable, but rather complementary. This may be related to the inherent attributes of medicine, a fact that reinforces the debate on its epistemological status. PMID- 26978558 TI - Managing the female patient with hereditary angioedema. AB - Hereditary angioedema (HAE) is a rare disorder resulting from decreased functional levels of C1-inhibitor (C1-INH), which manifests as periodic episodes of localized edema which can be extremely painful, debilitating and even fatal if the swelling affects the larynx. HAE can complicate many aspects of obstetric/gynecologic care, and an awareness of the disease is critical for clinicians involved in the care of women because of potential HAE-related complications pertaining to pregnancy, labor and delivery, and other women's health issues. This article provides a review of published literature specific to HAE and its management in female patients, including important concerns regarding obstetric/gynecologic care. A growing body of relevant experience is presented to help guide the care of women with HAE. PMID- 26978564 TI - Clinicopathological Features and Prognosis of Sinonasal Mucosal Malignant Melanoma: A Retrospective Study of 83 Cases in a Chinese Population. AB - AIMS: Sinonasal mucosal malignant melanoma (SNMMM) is a rare disease. The aim of the present study was to describe its clinicopathological features and prognosis in a Chinese population. METHODS: Data on 83 SNMMM patients were collected and analyzed. A survival analysis was performed using the Kaplan-Meier method and a log-rank test. RESULTS: The most common presenting symptoms of SNMMM were nasal obstruction, epistaxis, and bloody rhinorrhea. Histopathologically, 38 cases (45.78%) were amelanotic. Five cell types (epithelioid, undifferentiated, plasmacytoid, spindle, and clear) were identified. Positive staining for human melanoma black-45 and Melan-A was diagnostic of SNMMM. Advanced age, multiple tumor sites, and amelanotic-type SNMMM indicated a worse outcome (p = 0.008, p = 0.009, and p = 0.013, respectively). Neither adjuvant therapy nor the tumor stage was associated with overall survival. CONCLUSIONS: SNMMM is an uncommon disease with atypical symptoms. Its histopathological appearance is variable, especially in the amelanotic type. Thus, immunohistochemistry is important in the diagnosis, and it should be performed according to the histology. PMID- 26978565 TI - Routine Pediatric Enterovirus 71 Vaccination in China: a Cost-Effectiveness Analysis. AB - BACKGROUND: China accounted for 87% (9.8 million/11.3 million) of all hand, foot, and mouth disease (HFMD) cases reported to WHO during 2010-2014. Enterovirus 71 (EV71) is responsible for most of the severe HFMD cases. Three EV71 vaccines recently demonstrated good efficacy in children aged 6-71 mo. Here we assessed the cost-effectiveness of routine pediatric EV71 vaccination in China. METHODS AND FINDINGS: We characterized the economic and health burden of EV71-associated HFMD (EV71-HFMD) in China using (i) the national surveillance database, (ii) virological surveillance records from all provinces, and (iii) a caregiver survey on the household costs and health utility loss for 1,787 laboratory-confirmed pediatric cases. Using a static model parameterized with these data, we estimated the effective vaccine cost (EVC, defined as cost/efficacy or simply the cost of a 100% efficacious vaccine) below which routine pediatric vaccination would be considered cost-effective. We performed the base-case analysis from the societal perspective with a willingness-to-pay threshold of one times the gross domestic product per capita (GDPpc) and an annual discount rate of 3%. We performed uncertainty analysis by (i) accounting for the uncertainty in the risk of EV71 HFMD due to missing laboratory data in the national database, (ii) excluding productivity loss of parents and caregivers, (iii) increasing the willingness-to pay threshold to three times GDPpc, (iv) increasing the discount rate to 6%, and (v) accounting for the proportion of EV71-HFMD cases not registered by national surveillance. In each of these scenarios, we performed probabilistic sensitivity analysis to account for parametric uncertainty in our estimates of the risk of EV71-HFMD and the expected costs and health utility loss due to EV71-HFMD. Routine pediatric EV71 vaccination would be cost-saving if the all-inclusive EVC is below US$10.6 (95% CI US$9.7-US$11.5) and would remain cost-effective if EVC is below US$17.9 (95% CI US$16.9-US$18.8) in the base case, but these ceilings could be up to 66% higher if all the test-negative cases with missing laboratory data are EV71-HFMD. The EVC ceiling is (i) 10%-14% lower if productivity loss of parents/caregivers is excluded, (ii) 58%-84% higher if the willingness-to-pay threshold is increased to three times GDPpc, (iii) 14%-19% lower if the discount rate is increased to 6%, and (iv) 36% (95% CI 23%-50%) higher if the proportion of EV71-HFMD registered by national surveillance is the same as that observed in the three EV71 vaccine phase III trials. The validity of our results relies on the following assumptions: (i) self-reported hospital charges are a good proxy for the opportunity cost of care, (ii) the cost and health utility loss estimates based on laboratory-confirmed EV71-HFMD cases are representative of all EV71-HFMD cases, and (iii) the long-term average risk of EV71-HFMD in the future is similar to that registered by national surveillance during 2010-2013. CONCLUSIONS: Compared to no vaccination, routine pediatric EV71 vaccination would be very cost effective in China if the cost of immunization (including all logistical, procurement, and administration costs needed to confer 5 y of vaccine protection) is below US$12.0-US$18.3, depending on the choice of vaccine among the three candidates. Given that the annual number of births in China has been around 16 million in recent years, the annual costs for routine pediatric EV71 vaccination at this cost range should not exceed US$192-US$293 million. Our results can be used to determine the optimal vaccine when the prices of the three vaccines are known. PMID- 26978566 TI - Two New Faces of Amifostine: Protector from DNA Damage in Normal Cells and Inhibitor of DNA Repair in Cancer Cells. AB - Amifostine protects normal cells from DNA damage induction by ionizing radiation or chemotherapeutics, whereas cancer cells typically remain uninfluenced. While confirming this phenomenon, we have revealed by comet assay and currently the most sensitive method of DNA double strand break (DSB) quantification (based on gammaH2AX/53BP1 high-resolution immunofluorescence microscopy) that amifostine treatment supports DSB repair in gamma-irradiated normal NHDF fibroblasts but alters it in MCF7 carcinoma cells. These effects follow from the significantly lower activity of alkaline phosphatase measured in MCF7 cells and their supernatants as compared with NHDF fibroblasts. Liquid chromatography-mass spectrometry confirmed that the amifostine conversion to WR-1065 was significantly more intensive in normal NHDF cells than in tumor MCF cells. In conclusion, due to common differences between normal and cancer cells in their abilities to convert amifostine to its active metabolite WR-1065, amifostine may not only protect in multiple ways normal cells from radiation-induced DNA damage but also make cancer cells suffer from DSB repair alteration. PMID- 26978568 TI - Post-discharge Follow-up Characteristics Associated With 30-Day Readmission After Heart Failure Hospitalization. AB - BACKGROUND: Readmission within 30 days after hospitalization for heart failure (HF) is a major public health problem. OBJECTIVE: To examine whether timing and type of post-discharge follow-up impacts risk of 30-day readmission in adults hospitalized for HF. DESIGN: Nested matched case-control study (January 1, 2006 June 30, 2013). SETTING: A large, integrated health care delivery system in Northern California. PARTICIPANTS: Hospitalized adults with a primary diagnosis of HF discharged to home without hospice care. MEASUREMENTS: Outpatient visits and telephone calls with cardiology and general medicine providers in non emergency department and non-urgent care settings were counted as follow-up care. Statistical adjustments were made for differences in patient sociodemographic and clinical characteristics, acute severity of illness, hospitalization characteristics, and post-discharge medication changes and laboratory testing. RESULTS: Among 11,985 eligible adults, early initial outpatient contact within 7 days after discharge was associated with lower odds of readmission [adjusted odds ratio (OR)=0.81; 95% CI, 0.70-0.94], whereas later outpatient contact between 8 and 30 days after hospital discharge was not significantly associated with readmission (adjusted OR=0.99; 95% CI, 0.82-1.19). Initial contact by telephone was associated with lower adjusted odds of 30-day readmission (adjusted OR=0.85; 95% CI, 0.69-1.06) but was not statistically significant. CONCLUSIONS: In adults discharged to home after hospitalization for HF, outpatient follow-up with a cardiology or general medicine provider within 7 days was associated with a lower chance of 30-day readmission. PMID- 26978567 TI - Dissecting the role of histidine kinase and HOG1 mitogen-activated protein kinase signalling in stress tolerance and pathogenicity of Parastagonospora nodorum on wheat. AB - The HOG1 mitogen-activated protein kinase (MAPK) pathway is activated through two component histidine kinase (HK) signalling. This pathway was first characterized in the budding yeast Saccharomyces cerevisiae as a regulator of osmotolerance. The fungus Parastagonospora nodorum is the causal agent of septoria nodorum blotch of wheat. This pathogen uses host-specific effectors in tandem with general pathogenicity mechanisms to carry out its infection process. Genes showing strong sequence homology to S. cerevisiae HOG1 signalling pathway genes have been identified in the genome of P. nodorum. In this study, we examined the role of the pathway in the virulence of P. nodorum on wheat by disrupting putative pathway component genes: HOG1 (SNOG_13296) MAPK and NIK1 (SNOG_11631) hybrid HK. Mutants deleted in NIK1 and HOG1 were insensitive to dicarboximide and phenylpyrrole fungicides, but not a fungicide that targets ergosterol biosynthesis. Furthermore, both Deltanik1 and Deltahog1 mutants showed increased sensitivity to hyperosmotic stress. However, HOG1, but not NIK1, is required for tolerance to elevated temperatures. HOG1 deletion conferred increased tolerance to 6-methoxy-2-benzoxazolinone, a cereal phytoalexin. This suggests that the HOG1 signalling pathway is not exclusively associated with NIK1. Both Deltanik1 and Deltahog1 mutants retained the ability to infect and cause necrotic lesions on wheat. However, we observed that the Deltahog1 mutation resulted in reduced production of pycnidia, asexual fruiting bodies that facilitate spore dispersal during late infection. Our study demonstrated the overlapping and distinct roles of a HOG1 MAPK and two-component HK signalling in P. nodorum growth and pathogenicity. PMID- 26978570 TI - Nationwide In-hospital Mortality Following Pancreatic Surgery in Germany is Higher than Anticipated. AB - OBJECTIVE: We aimed to determine the unbiased mortality rates for pancreatic surgery procedures at the national level through a comprehensive analysis of every inpatient case in Germany. SUMMARY OF BACKGROUND DATA: Several studies have proclaimed a general improvement of perioperative outcomes following pancreatic surgery. These results are challenged by recent analyses of large US databases that found strong volume-outcome relationships, with high mortality in low-volume facilities. METHODS: All inpatient cases with a pancreatic surgery procedure code in Germany from 2009 to 2013 were identified from nationwide administrative hospital data. We determined the absolute number of patients and the in-hospital death rate for crucial subcategories such as medical indications and types of surgical procedure. RESULTS: A total of 58,003 inpatient episodes of pancreatic surgery were identified between 2009 and 2013. Annual case numbers increased significantly, which was primarily attributed to patients aged 70 years and older. The overall in-hospital mortality rate (10.1%) did not significantly change during the study period. Major pancreatic resections were associated with mortality ranging from 7.3% (distal pancreatectomy) to 22.9% (total pancreatectomy). Postoperative interventions indicative of severe complications were documented frequently (eg, more than 6 blood transfusions in 20% of all patients and relaparotomy in 16%). Their occurrence was associated with a dramatic increase in mortality. CONCLUSION: At the national level in Germany, perioperative mortality is higher than anticipated from previous studies. The absence of a significant reduction in overall mortality challenges current health policies that aim to improve the outcomes of high-risk surgical procedures in Germany. PMID- 26978569 TI - Disparities in Discontinuing Rosiglitazone Following the 2007 FDA Safety Alert. AB - BACKGROUND: Responsiveness to the Food and Drug Administration (FDA) rosiglitazone safety alert, issued on May 21, 2007, has not been examined among vulnerable subpopulations of the elderly. OBJECTIVE: To compare time to discontinuation of rosiglitazone after the safety alert between black and white elderly persons, and across sociodemographic and economic subgroups. RESEARCH DESIGN: A cohort study. SUBJECTS: Medicare fee-for-service enrollees in 2007 who were established users of rosiglitazone identified from a 20% national sample of pharmacy claims. MEASURES: Outcome of interest was time to discontinuation of rosiglitazone after the May alert. We modeled the number of days following the warning to the end of the days' supply for the last rosiglitazone claim during the study period (May 21, 2007-December 31, 2007) using multivariable proportional hazards models. RESULTS: More than 67% of enrollees discontinued rosiglitazone within six months of the advisory. In adjusted analysis, white enrollees (hazard ratio=0.90; 95% confidence interval, 0.86-0.94) discontinued rosiglitazone later than the comparison group of black enrollees. Enrollees with a history of low personal income also discontinued later than their comparison group (hazard ratio=0.84; 95% confidence interval, 0.81-0.87). There were no observed differences across quintiles of area-level socioeconomic status. CONCLUSIONS: White race and a history of low personal income modestly predicted later discontinuation of rosiglitazone after the FDA's safety advisory in 2007. The impact of FDA advisories can vary among sociodemographic groups. Policymakers should continue to monitor whether risk management policies reach their intended populations. PMID- 26978574 TI - L-Rhamnose Enhances the Immunogenicity of Melanoma-Associated Antigen A3 for Stimulating Antitumor Immune Responses. AB - Vaccines based on melanoma-associated antigens (MAGEs) present a promising strategy for tumor immunotherapy, albeit with weak immunogenicity. In this study, the xenoantigen L-rhamnose (Rha) was chemically conjugated with truncated MAGE-A3 (tMAGE-A3) to generate Rha-tMAGE-A3. The product showed good antigenicity with anti-Rha antibodies purified from human serum. FITC-labeled Rha-tMAGE-A3 was detected in THP-1 human macrophage cells via the anti-Rha antibody-dependent antigen uptake process. Furthermore, peripheral blood mononuclear cells (PBMCs) stimulated with Rha-tMAGE-A3 in the presence of anti-Rha antibodies showed better cytotoxicity toward A375 human melanoma cells surfaced by MAGE-A3 antigen compared to PBMCs stimulated with tMAGE-A3. All data reveal that linking of Rha epitopes to MAGE enhances the immunogenicity of MAGE by harnessing the immune effector functions of human naturally existing anti-Rha antibodies. Rha epitopes could become immunogenicity enhancers of tumor associated antigens in the development of tumor immunotherapies. PMID- 26978575 TI - Spatial conservation studies of nucleobases in 10-23 DNAzyme by 2'-positioned isonucleotides and enantiomers for increased activity. AB - 2'-Positioned isonucleotides and enantiomers were used to evaluate the conservation of the spatial location of five adenines and two thymines in the catalytic core of 10-23 DNAzyme. The positive effect of isonucleotides at A15 and T8 along with inherent enzymatic resistance could be a tangible solution for the practical applications of 10-23 DNAzyme. PMID- 26978576 TI - Tailoring Charge Recombination in Photoelectrodes Using Oxide Nanostructures. AB - Optimizing semiconductor devices for solar energy conversion requires an explicit control of the recombination of photogenerated electron-hole pairs. Here we show how the recombination of charge carriers can be controlled in semiconductor thin films by surface patterning with oxide nanodisks. The control mechanism relies on the formation of dipole-like electric fields at the interface that, depending on the field direction, attract or repel minority carriers from underneath the disks. The charge recombination rate can be controlled through the choice of oxide material and the surface coverage of nanodisks. We provide proof-of principle demonstration of this approach by patterning the surface of Fe2O3, one of the most studied semiconductors for light-driven water splitting, with TiO2 and Cu2O nanodisks. We expect this method to be generally applicable to a range of semiconductor-based solar energy conversion devices. PMID- 26978577 TI - Structural Origins of Cholesterol Accelerated Lipid Flip-Flop Studied by Sum Frequency Vibrational Spectroscopy. AB - The unique structure of cholesterol and its role in modulating lipid translocation (flip-flop) were examined using sum-frequency vibrational spectroscopy (SFVS). Two structural analogues of cholesterol--cholestanol and cholestene--were examined to explore the influence of ring rigidity and amphiphilicity on controlling distearoylphosphocholine (DSPC) flip-flop. Kinetic rates for DSPC flip-flop were determined as a function of sterol concentration and temperature. All three sterols increased the rate of DSPC flip-flop in a concentration-dependent manner following the order cholestene > cholestanol > cholesterol. Rates of DSPC flip-flop were used to calculate the thermodynamic activation free energy barrier (DeltaG(?)) in the presence of cholesterol, cholestanol, and cholestene. The acyl chain gauche content of DSPC, mean lipid area, and membrane compressibility were correlated to observed trends in DeltaG(?). DeltaG(?) for DSPC flip-flop showed a strong positive correlation with the molar compression modulus (K*) of the membrane, influenced by the type and concentration of the sterol added. Interestingly, cholesterol is distinctive in maintaining invariant membrane compressibility over the range of 2-10 mol %. The results in this study demonstrate that the compression modulus of a membrane plays a significant role in moderating DeltaG(?) and the kinetics of native, protein-free, lipid translocation in membranes. PMID- 26978578 TI - Selection and Characterization of an alpha6beta4 Integrin blocking DNA Aptamer. AB - The heterodimeric laminin receptor alpha6beta4 integrin plays a central role in the promotion of tumor cell growth, invasion, and organotropic metastasis. As an overproduction of the integrin is often linked to a poor prognosis, the inhibition of integrin alpha6beta4 binding to laminin is of high therapeutical interest. Here, we report on the combination of a cell-systematic evolution of ligands by exponential enrichment and a bead-based selection resulting in the first aptamer inhibiting the interaction between alpha6beta4 integrin and laminin 332. This Integrin alpha6beta4-specific DNA Aptamer (IDA) inhibits the adhesion of prostate cancer cells (PC-3) to laminin-332 with an IC50 value of 149 nmol/l. The Kd value concerning the aptamer's interaction with PC-3 cells amounts to 137 nmol/l. Further characterization showed specificity to alpha6 integrins and a half-life in murine blood plasma of 6 hours. Two truncated versions of the aptamer retained their binding capacity, but lost their ability to inhibit the interaction between laminin-332 and PC-3 cells. Confocal laser scanning microscope studies revealed that the aptamer was internalized into PC-3-cells. Therefore, in addition to the adhesion-blocking function of this aptamer, IDA could also be applied for the delivery of siRNA, microRNA or toxins to cancer cells presenting the integrin alpha6beta4. PMID- 26978579 TI - A Tat-conjugated Peptide Nucleic Acid Tat-PNA-DR Inhibits Hepatitis B Virus Replication In Vitro and In Vivo by Targeting LTR Direct Repeats of HBV RNA. AB - Hepatitis B virus (HBV) infection is a major cause of chronic active hepatitis, cirrhosis, and primary hepatocellular carcinoma, all of which are severe threats to human health. However, current clinical therapies for HBV are limited by potential side effects, toxicity, and drug-resistance. In this study, a cell penetrating peptide-conjugated peptide nucleic acid (PNA), Tat-PNA-DR, was designed to target the direct repeat (DR) sequences of HBV. Tat-PNA-DR effectively inhibited HBV replication in HepG2.2.15 cells. Its anti-HBV effect relied on the binding of Tat-PNA-DR to the DR, whereby it suppressed the translation of hepatitis B e antigen (HBeAg), HBsAg, HBV core, hepatitis B virus x protein, and HBV reverse transcriptase (RT) and the reverse transcription of the HBV genome. Furthermore, Tat-PNA-DR administered by intravenous injection efficiently cleared HBeAg and HBsAg in an acute hepatitis B mouse model. Importantly, it induced an 80% decline in HBV DNA in mouse serum, which was similar to the effect of the widely used clinical drug Lamivudine (3TC). Additionally, a long-term hydrodynamics HBV mouse model also demonstrated Tat-PNA DR's antiviral effect. Interestingly, Tat-PNA-DR displayed low cytotoxicity, low mouse acute toxicity, low immunogenicity, and high serum stability. These data indicate that Tat-PNA-DR is a unique PNA and a promising drug candidate against HBV. PMID- 26978580 TI - Combination of microRNA-21 and microRNA-146a Attenuates Cardiac Dysfunction and Apoptosis During Acute Myocardial Infarction in Mice. AB - Recent studies have revealed the cytoprotective roles of microRNAs (miRNAs) miR 21 and miR-146a against ischemic cardiac injuries. While these studies investigated each of these miRNAs as an independent individual factor, our previous study has suggested the possible interaction between these two miRNAs. The present study was designed to investigate this possibility by evaluating the effects of miR-21 and miR-146a combination on cardiac ischemic injuries and the underlying mechanisms. MiR-21 and miR-146a synergistically decreased apoptosis under ischemia/hypoxic conditions in cardiomyocytes compared with either miR-21 or miR-146a alone. Mice coinjected with agomiR-21 and agomiR-146a had decreased infarct size, increased ejection fraction (EF), and fractional shortening (FS). These effects were greater than those induced by either of the two agomiRs. Furthermore, greater decreases in p38 mitogen-associated protein kinase phosphorylation (p-p38 MAPK) were observed with miR-21: miR-146a combination as compared to application of either of the miRNAs. These data suggest that combination of miR-21 and miR-146a has a greater protective effect against cardiac ischemia/hypoxia-induced apoptosis as compared to these miRNAs applied individually. This synergistic action is mediated by enhanced potency of inhibition of cardiomyocyte apoptosis by the miR-21-PTEN/AKT-p-p38-caspase-3 and miR-146a-TRAF6-p-p38-caspase-3 signal pathways. PMID- 26978581 TI - The prevalence, awareness, treatment and control of dyslipidemia among adults in China. AB - OBJECTIVES: To analyze the prevalence, awareness, treatment, control and epidemiological characteristics of dyslipidemia in Chinese adults. METHODS: In this cross-sectional study, we adopted a multi-stage, stratified sampling method to obtain representative samples of the general population aged >18 years from different urban and rural regions in China. All subjects completed a lifestyle and medical history questionnaire and were examined for risk factors. Dyslipidemia was defined according to criteria of the 2007 Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults. Continuous variables were compared using variance analysis. Multivariate logistic regression analysis was performed to explore the risk factors of dyslipidemia. RESULTS: The prevalence of dyslipidemia was 34.0% overall, and 35.1%, and 26.3% in urban and rural areas, respectively. The prevalence of dyslipidemia was significantly higher in men than women (41.9% vs 32.5%; P < 0.001). Rates of awareness, treatment, and control were 31.0%, 19.5%, and 8.9%, respectively. Increasing age (OR = 1.012; 95% CI:1.010, 1.014), male sex (OR = 1.411; 95% CI:1.318, 1.510), obesity (OR = 1.424; 95% CI:1.345, 1.507), cardiovascular disease (OR = 1.343; 95% CI:1.125, 1.603), diabetes (OR = 1.955; 95% CI:1.751, 2.182), hypertension (OR = 1.481; 95% CI:1.391, 1.577) and hyperuricemia (OR = 2.223; 95% CI:2.060, 2.399) were independent risk factors of dyslipidemia. CONCLUSION: The prevalence of dyslipidemia among Chinese adults was high but awareness, treatment, and control of dyslipidemia were low. Urban high income earners and rural medium income earners show higher prevalence. Low income earners in urban and rural population have the worst awareness treatment, and control rate. There is an increased need for closely monitoring and controlling high risk factors in the populations including postmenopausal women, unhealthy lifestyle peoples and patients with chronic non-communicable diseases. PMID- 26978582 TI - Possible roles of platelet-derived microparticles in atherosclerosis. AB - Platelets and platelet-derived microparticles (PMPs) play important roles in cardiovascular diseases, especially atherosclerosis. Continued research has revealed that PMPs have numerous functions in atherosclerosis, not only in thrombosis formation, but also by induction of inflammation. PMPs also induce formation of foam cells. Recent evidence strongly indicates a significant role of PMPs in atherosclerosis. Here, current research on the function of PMPs in atherosclerosis is reviewed. PMID- 26978583 TI - Up-regulation of Hnf1alpha gene expression in the liver of rats with experimentally induced chronic renal failure - A possible link between circulating PCSK9 and triacylglycerol concentrations. AB - BACKGROUND: The aim of this study was to verify if an increase in Hnf1alpha gene expression could be a possible link between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) and TAGs concentrations in chronic renal failure (CRF). METHODS: Rats underwent 5/6 nephrectomy or a sham surgery. Liver expressions of Pcsk9, Mttp, ApoB-100, Hnf1alpha, Hnf4alpha, lipogenic enzymes and beta-actin genes were quantified by qPCR. Liver levels of proteins coding by these genes were analyzed by Western blotting. Serum apoB-100 and PCSK9 concentration were estimated with an immunoassay. RESULTS: CRF rats showed an increase in circulating concentrations of TAGs, VLDL, apoB-100 and PCSK9, along with an enhanced liver VLDL-TAG secretion rate and a coordinated liver up regulation of genes coding: a) lipogenic enzymes; b) Mttp and ApoB-100; c) Pcsk9; d) Hnf1alpha and Hnf4alpha. Positive correlations were found between serum creatinine concentrations and: a) the liver levels of HNF1alpha mRNA (r = 0.79, p < 0.01) and HNF4alpha (r = 0.76, p < 0.01); b) the liver levels of PCSK9 mRNA (r = 0.88, p < 0.01) and serum PCSK9 concentrations (r = 0.73, p < 0.01); c) the liver levels of apoB-100 mRNA (r = 0.83, p < 0.01) and serum apoB-100 concentrations (r = 0.87, p < 0.01). Clofibrate treatment was shown to concomitantly decrease the liver levels of HNF1alpha, HNF4alpha and PCSK9 mRNA, as well as serum PCSK9, TAGs and total cholesterol concentrations in CRF rats. CONCLUSION: The results presented are consistent with a cause-effect relationship between the enhanced liver expression of Hnf1alpha gene and its target genes the products of which are involved in synthesis, assembly and secretion of VLDL, as well as Pcsk9 gene in CRF rats. This may at least in part explain an association between circulating PCSK9 and TAGs in CRF rats and possibly also in humans with chronic kidney disease (CKD). PMID- 26978584 TI - Effect of rosuvastatin on atherosclerotic plaque stability: An intravascular ultrasound elastography study. AB - OBJECTIVES: The present study aimed to investigate the effect of potent rosuvastatin therapy on plaque mechanical stabilization as seen on IVUSE. METHODS: 14 purebred New Zealand rabbits were fed a high-cholesterol diet; the abdominal aorta endothelium was balloon-injured after 2 weeks; at week 13, 7 rabbits received rosuvastatin (1.5 mg/kg/day), and the other 7 received an equal volume of saline. IVUS images of abdominal aortas were acquired, and 2 consecutive frames near the end-diastole images in situ were used to construct an IVUS elastogram. RESULTS: Control rabbits showed a significant increase in shear strain (SS) and area strain (AS) in total plaques. The rosuvastatin group showed no change in SS and AS, but serum TG and LDL-C levels were reduced, with less lipid deposition, macrophage infiltration, production of proinflammatory cytokines and apoptosis in plaques. The changes in SS and AS from baseline between groups significantly differed (SS: 1.15 (1.96) % vs. -0.99 +/- 2.83%, p = 0.013; AS: 1.25 (2.29) % vs. -1.67 +/- 5.05%, p = 0.022). At follow-up, for controls, strain values were increased in the shoulder of eccentric plaques (SS: 2.66 +/- 1.31% vs. 4.86 +/- 1.93%, p = 0.016; AS: 4.45 +/- 2.33% vs. 7.91 +/- 2.74%, p = 0.009) but not the plaque body. Changes in SS and AS in the plaque shoulder differed between the control and rosuvastatin groups (SS: 2.20 +/- 2.17% vs. -0.87 +/- 3.31%, p = 0.028; AS: 2.10 (4.61) % vs. -2.75 +/- 5.97%, p = 0.009). CONCLUSION: Rosuvastatin therapy in rabbits with atherosclerotic plaques led to less vulnerable plaque features. IVUSE is a very sensitive technique for detecting pharmacologically-induced mechanical changes in rabbit atherosclerotic plaques. PMID- 26978585 TI - Are Second Trimester Apparent Diffusion Coefficient Values of the Short Uterine Cervix Associated with Impending Preterm Delivery? AB - Purpose To prospectively determine whether the apparent diffusion coefficient (ADC) of the cervix is associated with preterm delivery in asymptomatic patients with a sonographic cervical length of 15 mm or less and positive fetal fibronectin test results between 23 and 28 weeks of gestation. Materials and Methods The institutional review board approved this prospective hypotheses generating study. A total of 30 pregnant women (mean gestational age, 26 weeks) with a sonographic short cervix (<=15 mm) underwent pelvic 1.5-T magnetic resonance (MR) imaging. Oblique sagittal diffusion-weighted images were obtained with b values of 0, 400, and 800 sec/mm(2). ADC values at MR imaging of the subglandular and stromal cervix and the difference between both were correlated to the interval to delivery. Receiver operating characteristic curve analysis was performed to obtain sensitivity and specificity of ADC values in association with delivery within 7 days. Results Eight (27%) of 30 patients delivered within 6 or 7 days after MR imaging (impending delivery group), and 22 (73%) of 30 patients delivered between 18 and 89 days after imaging (mean, 55 days) (late delivery group). Mean subglandular ADC and mean ADC difference were higher (P < .001) in patients with impending delivery than in those with late delivery ([2406.3 +/- 166.0] * 10(-6) mm(2)/sec vs [1708.9 +/- 108.1] * 10(-6) mm(2)/sec and [657.3 +/- 129.9] * 10(-6) mm(2)/sec vs [69.2 +/- 70.2] * 10(-6) mm(2)/sec, respectively). Subglandular ADC inversely correlated with the interval between MR imaging and delivery (r = -0.75). Receiver operating characteristic curve analysis of subglandular ADC revealed 100% sensitivity (95% confidence interval: 63.1, 100) and 100% specificity (95% confidence interval: 84.6, 100) in association with impending delivery with a 1921 * 10(-6) mm(2)/sec threshold. Stromal ADC and sonographic cervical length showed no difference between groups (P = .072 and P = .511, respectively). Conclusion Cervical subglandular ADC at MR imaging is associated with impending preterm birth in patients with a short sonographic cervix. ((c)) RSNA, 2016. PMID- 26978586 TI - Postoperative shoulder pain after laparoscopic hysterectomy with deep neuromuscular blockade and low-pressure pneumoperitoneum. PMID- 26978587 TI - Enhancement of motor coordination by applying high frequency repetitive TMS on the sensory cortex. AB - The sensory function plays an important role for successful motor performance. We investigated the modulating effects of high frequency repetitive transcranial magnetic stimulation (rTMS) on sensory discrimination and motor coordination. Twenty healthy participants were assigned into two random groups; the real- and sham-rTMS group. Total of 900 rTMS pulses at a frequency of 10Hz (stimulus intensity of 90% RMT) were given over deltoid representational areas of the somatosensory cortex. Sensory discrimination ability was evaluated using two point discrimination test. Motor coordination was measured by the latency difference between the synchronized contraction of deltoid and abductor pollicis brevis muscles before and after rTMS. The sensory discrimination was significantly increased only in the deltoid area and the difference in the latency of synchronized contraction of two muscles was significantly shortened after real-rTMS compared sham condition, which had tendency of negative correlation following real-rTMS condition. The results of this study demonstrated rTMS-induced enhancement of sensorimotor integration, which may contribute to develop effective therapeutic strategies for rehabilitation of various sensorimotor disorders in the clinical setting. PMID- 26978589 TI - Full Spectrum Visible LED Light Activated Antibacterial System Realized by Optimized Cu2O Crystals. AB - Assisted by three-dimensional printing technology, we proposed and demonstrated a full spectrum visible light activated antibacterial system by using a combination of 500 nm sized Cu2O crystals and light-emitting diode (LED) lamps. Further improved antibacterial ratios were achieved, for the first time, with pure Cu2O for both Gram-positive bacteria and Gram-negative bacteria among all of the six different color LED lamps. For practical antibacterial applications, we revealed that the nonwoven fabric could act as excellent carrier for Cu2O crystals and provide impressive antibacterial performance. Furthermore, integrated with our self-developed app, the poly(ethylene terephthalate) film loaded with Cu2O crystals also showed significant antibacterial property, thus making it possible to be applied in field of touch screen. The present research not only provided a healthier alternative to traditional ultraviolet-based sterilization but also opened an auto-response manner to decrease the rate of microbial contamination on billions of touch screen devices. PMID- 26978590 TI - Weight Loss Mediated Reduction in Xanthine Oxidase Activity and Uric Acid Clearance in Adolescents with Severe Obesity. AB - BACKGROUND: Increased xanthine oxidase (XO) activity and uric acid levels are known to be associated with obesity and hypertension; however, it is not known if obesity is directly responsible for these associations in youth. This study investigated the effect of weight loss on XO activity, uric acid, and their relationship to blood pressure change in obese youth to provide greater insight on how obesity increases cardiovascular risk. METHODS: This was an ancillary study in which 16 adolescents (mean age 15 +/- 2 years) received meal replacement therapy over a period of four weeks. Outcomes measured at baseline and after intervention included weight, blood pressure, XO activity, plasma uric acid, uric acid clearance, and creatinine clearance. RESULTS: After the meal replacement intervention, participants experienced reductions in body weight (109.2 +/- 16 kg vs. 105.2 +/- 14 kg, p < 0.0001) and BMI (38.7 +/- 4 kg vs. 37.4 +/- 3 kg, p < 0.0001). Plasma XO activity was reduced by 9.8% (p = 0.016). Uric acid clearance was decreased by 39% (p = 0.006). SBP (systolic blood pressure) and plasma uric acid concentrations were reduced but did not achieve statistical significance (p = 0.34 and 0.38, respectively). DBP (diastolic blood pressure) was unchanged (p = 0.86). No significant relationships were found between changes in blood pressure and changes in either XO activity or plasma uric acid levels. CONCLUSION: Weight loss led to decreases in uric acid production by lowering XO activity and decreases in uric acid clearance by reducing glomerular filtration (GF) and increasing reabsorption. Changes in XO activity and uric acid levels did not correlate with changes in blood pressure. PMID- 26978591 TI - Anesthesia for pregnant women with pulmonary hypertension. AB - PURPOSE OF REVIEW: Purpose of review is to summarize and highlight recent advances in the management of pregnant patients with pulmonary hypertension. RECENT FINDINGS: Despite recent advances in the therapy of pulmonary hypertension, prognosis for pregnant patients with pulmonary hypertension remains poor with high maternal mortality. Pregnancy is still considered contraindicated in these patients. If pregnancy occurs, referral to a tertiary hospital and a multidisciplinary approach ensure the best possible outcome. All pregnant patients with pulmonary hypertension should be counseled for a termination of pregnancy. If the patient wants to continue the pregnancy despite strong recommendations for therapeutic interruption, specific pulmonary hypertension therapy has to be initiated, adjusted, and/or augmented. A close clinical follow up of the mother throughout the entire pregnancy is of utmost importance. Elective caesarean section in week 34-36 is recommended as preferred mode of delivery, preferentially under epidural or low-dose combined spinal-epidural anesthesia. Because of an acute increase in pulmonary vascular resistance and delivery-associated acute volume overload, the immediate postpartum period carries the highest risk for acute right ventricular failure necessitating close monitoring and treatment on an ICU. SUMMARY: Anesthesiologists involved in the management of pregnant patients with pulmonary hypertension must have detailed knowledge of pathophysiological alterations in pregnancy and during birth, cardiac (patho)physiology, cardiovascular and obstetric pharmacology, hemodynamic monitoring, and echocardiography. Both regional and general anesthesia have typical adverse effects that can severely jeopardize the cardiovascular system in patients with pulmonary hypertension, and should therefore be anticipated/prevented/rapidly treated by the attending anesthesiologist. PMID- 26978592 TI - The patient with chronic heart failure undergoing surgery. AB - PURPOSE OF REVIEW: Congestive heart failure (CHF) is one of the most common diseases of the elderly patient. The underlying pathophysiology varies considerably and approximately 50% of the patients suffer from CHF with reduced left ventricular ejection fraction. Mortality in the perioperative period is increased in patients with CHF and this holds true for both minor and major surgeries. This review will summarize recent literature in the field of CHF and perioperative outcome in patients undergoing surgery with a special emphasis on actual guidelines, preoperative assessment and appropriate perioperative therapy. RECENT FINDINGS: In the past 18 months, new insights in the short and long-term effects of CHF in the perioperative period have been published. The role of left ventricular ejection fraction has been studied in noncardiac surgical patients and it has been demonstrated that an ejection fraction less than 30% is associated with a significant increase in mortality and myocardial infarctions. Moreover, in 25% of patients, acute exacerbation of heart failure takes place in the perioperative period. The European Society of Anesthesiology published new guidelines on the preoperative evaluation of patients with CHF. The role of adequate preoperative evaluation and preparation of patients with CHF is discussed widely. It becomes clear that parameters like brain natriuretic peptide play a crucial role in risk stratification and prediction of outcome. Also, the treatment of patients with low cardiac output was a topic, and it became clear that established therapies including the use of beta-mimetics and PDE-III inhibitors should only be initiated in very selected patient groups. However, adequately powered studies in patients with CHF are still missing and the majority of knowledge is based on patient undergoing cardiac surgery. SUMMARY: CHF is a source of considerable perioperative morbidity and mortality and in contrast to coronary artery disease, knowledge is very limited and additional research urgently needed. PMID- 26978593 TI - Catalytic Difluorination of Olefins. AB - Molecular editing with fluorine is a validated strategy for modulating the structure and function of organic systems. In the current arsenal of catalytic dihalogenation technologies, the direct generation of the vicinal difluoride moiety from simple olefins without a prefunctionalization step remains conspicuously absent. Herein we report a catalytic, vicinal difluorination of olefins displaying broad functional group tolerance, using inexpensive p iodotoluene as the catalyst. Preliminary efforts toward the development of an enantioselective variant are also disclosed. PMID- 26978594 TI - Laparoscopic Three-Port Sleeve Gastrectomy: A Single Institution Case Series. AB - BACKGROUND: Further minimization of abdominal wall trauma during laparoscopic bariatric surgery is a topic of great interest. Reducing the number of trocars may provide superior cosmetic results with less pain and shorter length of stay (LOS). However, it remains unclear if this approach compromises safety or effectiveness of weight loss. The aim of this study is to report initial safety and feasibility results using a three-port minimally invasive sleeve gastrectomy technique. MATERIALS AND METHODS: A retrospective review of patients who underwent laparoscopic three-port sleeve gastrectomy (3PSG) at our institution was conducted. Patient demographics, intraoperative parameters, and perioperative outcomes were extracted and analyzed. Postoperative data were obtained from routine follow-up history and physical examination. RESULTS: From May 2013 to April 2014, 45 morbidly obese patients underwent 3PSG. The cohort had a male-to female ratio of 20:25, mean age of 47.4 +/- 11.6 years, and a mean preoperative body mass index (BMI) of 47.6 +/- 9.7 kg/m(2). The mean number of comorbidities was 4 (range 0-8), and the mean American Society of Anesthesiologists score was 2.82 (range 1-4). Mean procedural duration and blood loss were 165 +/- 31.9 minutes and 27.0 +/- 31.8 mL, respectively. Eight patients (17%) required one additional trocar. Two cases (4.4%) had an intraoperative complication (staple line bleeding and splenic capsule laceration). Two (4.4%) postoperative complications were encountered (wound infection and axillary vein thrombosis). The mean LOS was 2.7 (range 2-7) days. At a mean follow-up of 5 (range 0.4-11.7) months, the cohort had a mean BMI of 40.0 +/- 9.26 kg/m(2), which corresponded to a mean excess weight loss of 36.0% +/- 18.1%. There were no trocar site hernias. All patients were highly satisfied with the final cosmetic result. CONCLUSION: Laparoscopic 3PSG appears to be a safe and feasible technique for performing sleeve gastrectomy. While further long-term research is needed, it appears to have significant benefits, mainly patient satisfaction and potentially less pain. PMID- 26978595 TI - Gas-Phase Spectroscopic Signatures of Carboxylate-Li(+) Contact Ion Pairs: New Benchmarks For Characterizing Ion Pairing in Solution. AB - The coexistence of several types of ion pairs in solution together with their elusive nature hampers their experimental characterization, which relies in practice on theoretical models resorting to numerous approximations. In this context, a series of isolated contact ion pairs between a lithium cation and phenyl-tagged carboxylate anions of various lengths (Ph-(CH2)n-COO(-), n = 1-3) has been investigated in a conformer-selective manner by IR and UV laser spectroscopy, in conjunction with quantum chemistry calculations. The typical gas phase IR signature of the bidentate structure formed between the carboxylate moiety and Li(+) has thus been obtained in the CO2(-) stretch region. In addition to the cation-anion interaction, a cation-pi interaction occurs simultaneously in the largest system investigated (n = 3). The resulting distorted ion pair structure has been evidenced from both the IR signature of the CO2(-) stretches and the unique vibrationally resolved UV spectroscopy of a phenyl ring interacting with a cation. Such specific spectroscopic signatures of contact ion pairs provide experimental benchmarks, alternative to theoretical predictions, that can assist the assignment of vibrational spectra in solution. PMID- 26978597 TI - Elucidating the Phase Transformation of Li4Ti5O12 Lithiation at the Nanoscale. AB - This work provides insight regarding the fundamental lithiation and delithiation mechanism of the popular lithium ion battery anode material, Li4Ti5O12 (LTO). Our results quantify the extent of reaction between Li4Ti5O12 and Li7Ti5O12 at the nanoscale, during the first cycle. Lithium titanate's discharge (lithiation) and charge (delithiation) reactions are notoriously difficult to characterize due to the zero-strain transition occurring between the end members Li4Ti5O12 and Li7Ti5O12. Interestingly, however, the latter compound is electronically conductive, while the former is an insulator. We take advantage of this critical property difference by using conductive atomic force microscopy (c-AFM) to locally monitor the phase transition between the two structures at various states of charge. To do so, we perform ex situ characterization on electrochemically cycled LTO thin-films that are never exposed to air. We provide direct confirmation of the manner in which the reaction occurs, which proceeds via percolation channels within single grains. We complement scanning probe analyses with an X-ray photoelectron spectroscopy (XPS) study that identifies and explains changes in the LTO surface structure and composition. In addition, we provide a computational analysis to describe the unique electronic differences between LTO and its lithiated form. PMID- 26978596 TI - Activation of AMPK Prevents Monocrotaline-Induced Extracellular Matrix Remodeling of Pulmonary Artery. AB - BACKGROUND: The current study was performed to investigate the effect of adenosine monophosphate (AMP) - activated protein kinase (AMPK) activation on the extracellular matrix (ECM) remodeling of pulmonary arteries in pulmonary arterial hypertension (PAH) and to address its potential mechanisms. MATERIAL AND METHODS: PAH was induced by a single intraperitoneal injection of monocrotaline (MCT) into Sprague-Dawley rats. Metformin (MET) was administered to activate AMPK. Immunoblotting was used to determine the phosphorylation and expression of AMPK and expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). Gelatin zymography was performed to determine the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9. RESULTS: Activation of AMPK by MET significantly reduced the right ventricle systolic pressure and the right ventricular hypertrophy in MCT induced rat PAH model, and partially inhibited the ECM remodeling of pulmonary arteries. These effects were coupled with the decrease of MMP-2/9 activity and TIMP-1 expression. CONCLUSIONS: This study suggests that activation of AMPK benefits PAH by inhibiting ECM remodeling of pulmonary arteries. Enhancing AMPK activity might have potential value in clinical treatment of PAH. PMID- 26978599 TI - Mass-Transfer-Controlled Dynamic Interfacial Tension in Microfluidic Emulsification Processes. AB - Varied interfacial tension caused by the unsaturated adsorption of surfactants on dripping droplet surfaces is experimentally studied. The mass transfer and adsorption of surfactants, as well as the generation of fresh interfaces, are considered the main factors dominating the surfactant adsorption ratio on droplet surfaces. The diffusion and convective mass transfer of the surfactants are first distinguished by comparing the adsorption depth and the mass flux boundary layer thickness. A characterized mass transfer time is then calculated by introducing an effective diffusion coefficient. A time ratio is furthermore defined by dividing the droplet generation time by the characteristic mass transfer time, t/tm, in order to compare the rates of surfactant mass transfer and droplet generation. Different control mechanisms for different surfactants are analyzed based on the range of t/t(m), and a criterion time ratio using a simplified characteristic mass transfer time, t(m)*, is finally proposed for predicting the appearance of dynamic interfacial tension. PMID- 26978598 TI - Proinflammatory isoforms of IL-32 as novel and robust biomarkers for control failure in HIV-infected slow progressors. AB - HIV-infected slow progressors (SP) represent a heterogeneous group of subjects who spontaneously control HIV infection without treatment for several years while showing moderate signs of disease progression. Under conditions that remain poorly understood, a subgroup of these subjects experience failure of spontaneous immunological and virological control. Here we determined the frequency of SP subjects who showed loss of HIV control within our Canadian Cohort of HIV(+) Slow Progressors and identified the proinflammatory cytokine IL-32 as a robust biomarker for control failure. Plasmatic levels of the proinflammatory isoforms of IL-32 (mainly beta and gamma) at earlier clinic visits positively correlated with the decline of CD4 T-cell counts, increased viral load, lower CD4/CD8 ratio and levels of inflammatory markers (sCD14 and IL-6) at later clinic visits. We present here a proof-of-concept for the use of IL-32 as a predictive biomarker for disease progression in SP subjects and identify IL-32 as a potential therapeutic target. PMID- 26978600 TI - Photochemical hydrogen production and cobaloximes: the influence of the cobalt axial N-ligand on the system stability. AB - We report on the first systematic study of cobaloxime-based hydrogen photoproduction in mixed pH 7 aqueous/acetonitrile solutions and demonstrate that H2 evolution can be tuned through electronic modifications of the axial cobalt ligand or through introduction of TiO2 nanoparticles. The photocatalytic systems consist of various cobaloxime catalysts [Co(dmgH)2(L)Cl] (L = nitrogen-based axial ligands) and a water soluble porphyrin photosensitizer. They were assayed in the presence of triethanolamine as a sacrificial electron donor. Optimal turnover numbers related to the photosensitizer are obtained with electron-rich axial ligands such as imidazole derivatives (1131 TONs with N-methyl imidazole). Lower stabilities are observed with various pyridine axial ligands (443 TONs for para-methylpyridine), especially for those containing electron-acceptor substituents. Interestingly, when L is para-carboxylatopyridine the activity of the system is increased from 40 to 223 TONs in the presence of TiO2 nanoparticles. PMID- 26978601 TI - Opioid Prescribing After Surgical Extraction of Teeth in Medicaid Patients, 2000 2010. PMID- 26978602 TI - [Recent trends in and new data on the epidemiology and prevention of non communicable diseases]. AB - Mortality from non-communicable diseases (NCDs) in the country varies considerably among its regions and social strata of the population. The main reason for providing inadequate conditions for a healthy lifestyle is that the state and municipal authorities and employers pay insufficient attention to the role of socioeconomic risk factors for NCDs. Only an analysis of the reasons for changing mortality rates allows the correct course of actions to reduce mortality to be chosen and a national plan for the control of NCDs to be worked out. The important mechanisms for improving the prevention of NCDs are to make better cardiovascular risk stratification systems, to introduce telemonitoring the status of the patients followed up, and to interface the prophylactic medical examination of elderly patients with a geriatric service. The design of long acting drugs is a promising way to increase the patients' motivation to control blood pressure and blood cholesterol levels. PMID- 26978603 TI - [A rank-order method for the integrated assessment of trends in all-cause and cardiovascular mortality rates in the subjects of the Russian Federation in 2006 2012]. AB - AIM: To rank the subjects of the Russian Federation by the trend direction in all cause and cardiovascular mortality (including mortality from coronary heart disease and cerebrovascular diseases) as a whole and at able-bodied age. SUBJECTS AND METHODS: The investigation used mortality rates from to the 2006 and 2012 data available in the Federal State Statistics Service on 81 subjects of the Russian Federation. According to mortality rates, each region was assigned a rank in 2006 and 2012. Trends in rank changes in the Russian Federation's regions were analyzed. A cluster analysis was used to group the subjects of the Russian Federation by trends in rank changes. RESULTS: The cluster analysis of rank changes from 2006 to 2012 could combine the Russian Federation's regions into 10 groups showing the similar trends in all-cause and circulatory disease mortality rates. Overall, the results of the ranking and further clusterization of the regions of the Russian Federation correspond to the trends in all-cause and cardiovascular mortality rates according to the data of other Russian investigations, by qualitatively complementing them. CONCLUSION: The trend rank order method permits a comprehensive comparative analysis of changes in all-cause and cardiovascular mortality in the subjects of the Russian Federation both as a whole and at able-bodied age, which provides qualitatively new information complementing the universally accepted approaches to studying the population's mortality. PMID- 26978604 TI - [The stages of development of cardiovascular diseases and the evolution of their pattern in the veterans of the Great Patriotic War (according to the 1946-2015 records of the Saint Petersburg War Veterans Hospital)]. AB - AIM: To determine the stages of development of cardiovascular diseases and the evolution of their pattern in the veterans of the Great Patriotic War during 70 postwar years. SUBJECTS AND METHODS: The investigation used the 1946-2014 annual reports on the hospital's work; analysis of the pattern of therapeutic and cardiovascular diseases over time; the results of laboratory and functional tests in 148 patients who developed in-hospital myocardial infarction (cardiospecific enzymes, electrocardiography, echocardiography (EchoCG), and, if clinically indicated, coronary angiography) and in 112 cardiopulmonary patients who were detected to have a chronic multimorbid heart phenomenon (EchoCG, radiological examination, blood gas tests, and statistical processing of the findings). RESULTS: The postwar evolution of therapeutic and cardiovascular diseases was ascertained to consist of 5 stages, each of which averaged about 15 years. At the same time, the nosological entities typical of the subsequent stage developed in the pattern of those at the preceding stage and gradually became predominant. The form of in-hospital myocardial infarction, as well as the chronic multimorbid heart phenomenon in the presence of comorbidity (chronic obstructive pulmonary disease and hypertensive disease) at Stage IV was described. CONCLUSION: With allowance made for the stages of development of therapeutic diseases and evolution of its pattern in the veterans of the Great Patriotic War, the clinical departments of the hospital, its laboratory and functional diagnosis departments have been reorganized for 70 postwar years in order to render adequate specialized medical care to the patients. PMID- 26978605 TI - [Results of endovascular revascularization in elderly patients with ST-segment elevation myocardial infarction in multivessel disease in relation to the degree of coronary atherosclerosis]. AB - AIM: To investigate the impact of the degree of coronary atherosclerosis evaluated by the SYNTAX scale on the early and late results of endovascular revascularization in elderly and middle-aged patients with ST-segment elevation myocardial infarction (STEMI). SUBJECTS AND METHODS: The investigation enrolled 327 consecutively admitted patients with STEMI and multivessel coronary bed disease, who had received revascularization within the first 12 hours after disease onset via primary percutaneous coronary interventions (PCI). The clinical, demographic, and angiographic characteristics of the patients, as well as the specific features of chosen revascularization strategies and treatment outcomes were compared in two groups of 103 elderly patients (>=65 years of age) and 224 middle-aged patients (<=64 years) in relation to the severity of coronary bed lesion according to the SYNTAX scale. RESULTS: By and large, severe coronary atherosclerosis (>=23 SYNTAX scores) was related to reduced left ventricular ejection fraction and clinical manifestations of acute heart failure in all the analyzed patients regardless of their age and this was most markedly associated with the risk factors of cardiovascular events in the elderly patients. The elderly patients with severe coronary atherosclerosis (>=23 SYNTAX scores) were noted to have the lowest frequency of successful PCIs and higher 30-day mortality rates after primary PCI. CONCLUSION: The SYNTAX scale is of high prognostic value in the patients with STEMI, by determining the results of endovascular revascularization in elderly and middle-aged patients. The elderly patients with STEMI and severe coronary atherosclerosis are at very high risk for poor outcome within 30 days of follow-up after primary CPI, which necessitates a search for optimal revascularization strategies for this category of patients. PMID- 26978606 TI - [Impact of the dosing of basic drugs on the risk of rehospitalization in patients with chronic heart failure]. AB - AIM: To investigate the impact of doses of the drugs, which have been achieved during adjustment and account for less or more than 50% of the maximal therapeutic ones on the risk of rehospitalization. SUBJECTS AND METHODS: The data of the Pavlov Register were used to assess the treatment of patients with chronic heart failure. To assess the risk of rehospitalization in relation of the dose of a drug, all the doses were represented in percentage terms depending on the maximum therapeutic one. RESULTS: The risk of hospitalization during 6 months in the patients receiving angiotensin-converting enzyme inhibitors at a dose of 25% or less of the therapeutic one was 21.18% (odds ratio (OR), 1.41; 95% confidence interval (CI), 1.13-1.76), that at doses of 50 and 100% of the therapeutic one was 16% (OR, 0.71; 95% CI, 0.56-0.88) and 34% (OR, 0.51; 95% CI, 0.43-0.60), respectively. The risk of rehospitalization in the patients taking beta-blockers at doses of 25, 50, and 100% of the therapeutic one was 26% (OR, 1.05; 95% CI, 0.94-1.17), 23% (OR, 0.902; 95% CI, 0.75-1.07), and 6.25% (OR, 0.19; 95% CI, 0.07 0.56), respectively. The combined analysis of the dose and use frequency of diuretics showed that the highest risk of rehospitalization turned was noted in the patients using a single dose of 100 mg of furosemide (4.2% of cases) once weekly and was as high as 39% (OR, 0.45; 95% CI, 1.04-1.98). CONCLUSION: The risk of rehospitalization is largely determined by the dosing factor in outpatient settings. Increasing the doses during adjustment reduces the risk of rehospitalization. PMID- 26978607 TI - [A change in adrenal responsiveness in sotalol-treated patients with paroxysmal atrial fibrillation depending on autonomic nervous system tone]. AB - AIM: To evaluate the efficacy of sotalol depending on the magnitude of changes in adrenal responsiveness and autonomic nervous system tone in patients with paroxysmal atrial fibrillation (AF). SUBJECTS AND METHODS: Twenty-six patients with paroxysmal AF in the presence of coronary heart disease (CHD) and hypertension were examined. Sinus rhythm variability and sympathicotonic and vagotonic disorders were studied in patients with paroxysmal AF before and during sotalol treatment. A commercial Beta-ARM-Agat kit was used to estimate the adrenal responsiveness of erythrocyte membranes (beta-APM), which can judge the body's individual sensitivity to beta-adrenoblockers. RESULTS: Sotalol used in the average therapeutic doses of 160-240 mg did not reduce ejection fraction or increase atrioventricular conduction up to abnormal values. In patients with borderline and mild hypertension, the drug lowered blood pressure statistically significantly (p=0.01) and was well tolerated. The drug increased the sensitivity of beta-adrenoblockers in patients with adrenergic AF. CONCLUSION: The effect of sotalol on the autonomic nervous system manifested in the higher power of a high frequency spectral component of heart rate variability than in that of a low frequency one. Long-term sotalol administration significantly reduced beta-APM, increasing the sensitivity of adrenoceptors. PMID- 26978608 TI - [Features of polymorbidity in cardiac and gastroenterologic patients from a therapeutic clinic]. AB - AIM: To examine the incidence of polymorbidity (PM) and changes in its rates in 2003 to 2011 in cardiac and gastroenterologic patients living in the Novosibirsk Region and the Republic of Sakha (Yakutia) in accordance with gender, occupation, and residence. SUBJECTS AND METHODS: The dynamics of PM rates was analyzed in 13 496 patients who had been examined and treated at the Cardiology and Gastroenterology Departments, Therapeutic Clinic, Research Institute of Experimental and Clinical Medicine (Novosibirsk), 2003-2011. The study used an archival research method and a statistical analysis of all nosological entities, groups, and classes in ICD-10, regardless of whether the diagnosis was primary or concurrent. RESULTS: There was an increase in PM rates among the therapeutic clinic's patients of regardless of their gender and occupation. There were gender differences in the incidence of PM: its higher rates were noted in the women than those in the men among both the residents of the Novosibirsk Region and those of the Republic of Sakha (Yakutia). More significantly higher PM rates were registered in the male inhabitants of the Novosibirsk Region. There were also regional differences in the incidence of PM: its rates proved to be higher in the patients in the Republic of Sakha (Yakutia) than in those in the Novosibirsk Region in 2003-2007. At the same time, the growth rates for PM were more marked in the patients in the Novosibirsk region than in those in the Republic of Sakha (Yakutia); these differences levelled off in subsequent years. CONCLUSION: The findings indicate a pronounced increase in the incidence of PM in cardiac and gastroentorologic patients and determine a need to keep in mind the influence of gender, social, and regional factors on its development in order to create and improve a primary and secondary prevention, diagnosis and treatment system. PMID- 26978609 TI - [Results of circulatory disease detection during prophylactic medical examination of the adult population: the first two years' experience]. AB - AIM: To estimate circulatory diseases (CD) detection rates during prophylactic medical examination of the adult population and to define their association with mortality rates and the spread of risk factors. MATERIAL AND METHODS: The results of the 2013-2014 prophylactic medical examinations for CD in the adult population of the Russian Federation as a whole and its subjects were comparatively analyzed using the data of statistical reports and official medical statistics on morbidity and mortality in the adult population. RESULTS: The data of official statistical reports on the results of prophylactic medical examinations in 2013 (19.4 million) and 2014 (22.2 million) were analyzed. In 2013 and 2014, there were 85.9 and 82.7 CD cases per 1000 examinees, respectively. These years were marked by the detection of 50.0 and 46.2 hypertensive patients, 17.1 and 16.1 coronary heart disease (CHD) cases, and 11.5 and 11.2 cerebrovascular diseases (CVD) ones, respectively. In 2013 and 2014, most CD cases were caused by hypertension (58.4 and 57%, respectively). The proportion of CHD was 19.9 and 19.4% and that of CVD was 13.4 and 13.6%, respectively. CONCLUSION: The analysis carried out could provide evidence for the importance of continuous monitoring of prophylactic medical examination at the level of each specific healthcare facility for primary health care to improve its quality and completeness of diagnostic examination. The found interregional differences in the detection rate of CD call for detailed analysis and determination of their causes, which will ensure the preventive direction of a medical examination that is inextricably entwined with further active follow-up measures for patients having the identified diseases and a risk for their development. PMID- 26978610 TI - [The role and place of high-dose immunosuppressive therapy and autologous transplantation of hematopoietic stem cells for autoimmune diseases]. AB - AIM: To determine the possible boundaries of high-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HDIT-autoHSCT) for autoimmune diseases (AUDs), such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). SUBJECTS AND METHODS: A long-term trial was conducted at one center to evaluate the efficiency and safety of HDIT-autoHSCT in patients with AUDs. The previous standard therapy was noted to be resistant or lowly effective. The age of 10 patients with systemic connective tissue diseases was 27.6+/-2.8 years; the pre-HDIT-autoHSCT disease duration was 5.9+/-1.3 years; the median posttransplantation follow-up was 39.3 months. The age of 49 patients with MS reached 34.9+/-1.33 years; the pretransplantation disease duration was 8.4+/-0.69 years; the median post-HDIT autoHSCT follow-up was 42 months. The efficiency of transplantation was evaluated on the basis of clinical findings, by using scales, laboratory tests, and magnetic resonance imaging. Pretransplantation conditioning was carried out according to the protocols: a) BEAM + antilymphocyte globulin (ALG); b) fludarabine + melphalan + ALG. No fatal outcomes due to a transplant procedure were observed. RESULTS: Overall 5-year survival after transplantation was 80% for systemic connective tissue diseases and 95% for MS; 5-year progression-free survival rates were 30% in the RA and SLE groups and 45% in the MS group. HDIT autoHSCT turned out safe and reduced the activity of the process and further disease progression for a long period of time, as confirmed by regression of clinical symptoms and/or status stabilization in 9 patients with SLE or RA and in all patients with MS. CONCLUSION: The favorable factors associated with the results of transplantation are age younger than 35 years in collagenoses with their short-term duration and moderate signs; age younger than 40 years in MS with a disease duration of less than 10 years and expanded disability status scale scores of not more than 6.5. Of importance are functional system scores, duration of first remission, and an index of disease progression in different types of MS. PMID- 26978611 TI - [Results of malignancy detection during prophylactic medical examinations in 2013 2014]. AB - AIM: To analyze the efficiency of prophylactic medical examination for malignancies that considerably contributes to adult mortality. MATERIAL AND METHODS: The data of the national health statistics (Form 131/o, 7, 35) were used to make an expert analytical assessment of the results of prophylactic medical examinations for cancer in certain adult population groups in Russia in 2013 2014. RESULTS: Medical examinations covered 20.5 and 22.5 million people in 2013 and 2014, respectively. The proportion of 21-36-, 39-60-, and over 60-year olds was 36, 42, and 22%, respectively. All the age groups showed a preponderance of women with their larger proportion in the older age groups (55, 58, and 64%, respectively). In 2013 and 2014 there were 27,173 and 34,638 detected patients with malignances, including 17,095 (62.9%) and 20,944 (60.5%) women and 10,078 (37.1%) and 13,694 (39.5%) men, respectively. In these years, the breast (28 and 30.5%), prostate (13.9 and 18.5%), rectum (6.5 and 7.5%), stomach (6.3% and 7.8%), lung (6.1 and 7.3%) ranked fifth in cancer sites. There was a 17.6% increase in the detection rate of malignancy among the first identified patients during prophylactic medical examinations and and a 10.2% increase among all actively detected patients in 2014 versus 2013. The older age groups exhibited a rise in cancer detection rates, the most significant (11.8%) increase being in the women older than 60 years of age. CONCLUSION: The malignancy detection rates were noted to be on the rise, although there are defects in organizing prophylactic medical examination, ensuring the complete scope of necessary investigations, and interpreting the findings. The measures methodically supported a by regional cancer may provide a guide to solving these problems. At the same time, efforts are needed to actively attract citizens in the participation in prophylactic medical examination and in the development of behavioral attitudes associated with the higher responsibility for maintaining personal and public health. PMID- 26978612 TI - [Influence of smoking cessation on the microcirculatory bed in apparently healthy young people]. AB - AIM: To study the influence of smoking cessation on the microcirculatory bed (MCB) in 33 healthy young people. SUBJECTS AND METHODS: The investigation enrolled 33 healthy young people (male/female (M/F) ratio, 20:13; mean age, 21.6+/-0.5 years) who had quit smoking 1 month to 10 years (mean age 2.5+/-0.5 years) before. Comparable groups consisted of 15 smokers (M/F ratio, 5:10; mean age, 21.5+/-0.8 years) and 18 nonsmokers (M/F ratio, 6:12; mean age, 21+/-0.3 years). Computer-assisted video-biomicroscopy of the bulbar conjunctiva was carried out. When assessing the RESULTS: attention was focused on microvessel diameter changes in the patients who had quit smoking compared to the smokers and nonsmokers. RESULTS: As compared to the smokers, those who had quit smoking showed a significant increase in the mean diameters of arterioles (13.01+/-0.41 and 18.33+/-0.65 um; r<0.001) and capillaries (9.2+/-0.23 and 9.89+/-0.19 um; r<0.05). The number of functioning capillaries per mm2 of the conjunctival surface did not differ from that in the nonsmokers (8.01+/-0.21 and 8.25+/-0.44; r>0.05). Thus, the rarefication phenomenon reflecting the influence of smoking on the MCB vessels at a young age undergoes rapidly regression. There are increases in the diameter of arterioles and the number of functioning capillaries just in the first months of smoking cessation (r<0.01). CONCLUSION: The considerably increased diameters of arterioles and capillaries and the larger number of functioning capillaries per mm2 of the conjunctival surface suggest that smoking cessation at a young age have a positive impact on MCB vessels. PMID- 26978613 TI - [The incidence of respiratory symptoms and their associations with serum cotinine levels as a marker of tobacco smoking in 25-45-year-old Novosibirsk dwellers]. AB - AIM: To study the incidence of respiratory symptoms and to reveal their associations with serum cotinine levels (SCL) in 25-45-year-old Novosibirsk dwellers. SUBJECTS AND METHODS: The WHO respiratory symptom questionnaire and the ECRHS screening questionnaire were used for a population-based survey conducted in Novosibirsk to identify respiratory symptoms; 545 people replied to the questions available in the questionnaires. SCL was determined by enzyme immunoassay on a random subsample of 182 examinees. RESULTS: The incidence of respiratory symptoms was determined among the 25-45-year-old Novosibirsk dwellers: cough (27.7%), more than 3-month cough per year (22%), sputum discharge (25%), forced respiration/wheezing in the past year (22.6%), suffocation fits in the past year (5.3%), and cough/forced respiration/stertor bouts by breathing cold air (14.9%) or contacting animals, plants, or chemical agents (16.5%). There was a significant positive correlation between SCL and the presence of cough, more than 3-month cough per year, sputum discharge, forced respiration/wheezing in the past year (compared to the examinees who did not report these symptoms). The median SCL proved to be significantly higher in the people who complained of cough, more than 3-month cough per year, sputum discharge, and forced respiration/wheezing in the past year (compared to the examinees who did not report these symptoms). The people who had a SCL of more than 3 ng/ml were ascertained to be at higher risk of cough, more than 3-month cough per year, sputum discharge, and forced respiration/wheezing in the past year than those who had a SCL of less than 3 ng/ml. CONCLUSION: The incidence of respiratory symptoms was determined among the 25-45-year-old Novosibirsk dwellers; SCL was found to be associated with the symptoms characteristic of bronchial obstructive diseases; the expediency of using the SCL threshold of 3 ng/ml as a marker of tobacco smoking was confirmed. PMID- 26978614 TI - [Typical management practice in outpatients with type 2 diabetes mellitus in cities, towns, and villages]. AB - AIM: To analyze one-year typical management practice in outpatients with type 2 diabetes mellitus (T2DM) in cities, towns, and villages. SUBJECTS AND METHODS: 438 records of T2DM outpatients regularly visiting their physicians during 2009 were retrospectively analyzed. Group 1 included 221 outpatients from 7 polyclinics of the Kirov Regional Center; Group 2 consisted of 227 patients from 36 districts of the Kirov Region. VEN-, ABC-, and frequency analyses were made; the costs of drug therapy and hospitalization for the included patients were calculated. RESULTS: The investigation revealed the low efficiency of sugar lowering therapy (SLT), insufficient glycated hemoglobin testing rates (15% in Group 2 during a year), inadequate correction of SLT. During one year the number of patients with fixed target office blood pressure levels in Group 1 increased from 16.6 to 34.1% (r<0.001) and that in Group 2 was statistically significantly unchanged (21.6% vs 25.1%; p=0.05). In Group 2, the use frequency of statins was lower (20.3% by the end of the year versus 49.3% in Group 1; r<0.001); the examination quality was worse; the drugs with unproven efficacy, the cost of which was higher than that of statins/disaggregants, were used more often. In Groups 1 and 2, there were 50 (23.7%) and 95 (41.9%) patients who were more commonly hospitalized for T2DM-related causes; Group 2 patients had a higher rate of hospitalizations and longer inpatient treatment. CONCLUSION: The worse outpatient care quality in the towns and villages was followed by increases in a need for inpatient treatment and in direct drug (2.36-fold) and non-drug direct and indirect (2.77-fold) costs. PMID- 26978615 TI - [Associations of lipoproteins with bone mass in postmenopausal women]. AB - AIM: To study an association between blood lipid composition and bone mass in Russian postmenopausal women. SUBJECTS AND METHODS: The cross-sectional study included 373 postmenopausal women aged 45-80 years who were examined to diagnose osteoporosis in outpatient settings. Height, body weight, and waist and hip circumferences (WC and HC) were measured before densitometry. Quetelet's index was calculated as a ratio of weight (kg) to height (m2). The concentration of lipids and apolipoproteins (apo) AI and B were measured by enzyme immunoassay. Bone mineral density (BMD) in the spine and proximal femur (PF) was estimated by dual-energy X-ray absorptiometry. RESULTS: According to bone mass, the patients were divided into three groups: 1) osteoporosis (OP); 2) osteopenia; 3) normal BMD. The levels of total cholesterol and high-density lipoprotein (HDL) cholesterol were significantly higher in the postmenopausal women with OP than in those with normal bone mass. There was a negative correlation of cholesterol and HDL cholesterol levels with lumbar spine BMD and that of HDL levels with BMD in the femoral neck (FN) and entire PF. The level of lipoprotein (a) (LPa) was significantly lower in the group of patients with OP and positively correlated with BMD in FN and entire PF. After adjustment for age, the duration of menopause, Quetelet's index, and WC/HC association remained only between LPa and FN BMD. CONCLUSION: Multivariate regression analysis failed to confirm a trend towards decreased BMD and increased HDL cholesterol. This suggests that the association of HDL cholesterol with bone mass is apparently mediated by other factors and, above all, with age, postmenopausal hormonal status and body weight. PMID- 26978616 TI - [Experience in treating portal thromboses in patients with chronic myeloproliferative diseases]. AB - Patients with myeloproliferative diseases (MPD) are noted to be at high risk for portal thromboses. This problem gives rise to disability if it is untimely treated or resistant to therapy. The paper gives the experience of the Outpatient Department of the Hematology Research Center, Ministry of Health of the Russian Federation, in using antithrombin III in MPD patients (3 patients with primary myelofibrosis, 3 with essential thrombocythemia) and acute and subacute portal vein thromboses resistant to therapy with direct anticoagulants. In all 5 cases, the use of antithrombin III in combination with low-molecular-weight heparin showed a positive clinical effect as rapid relief of pain syndrome and comparatively early (3-week to 1.5-2-month) recanalization of thrombosed vessels. Three clinical cases are described in detail. PMID- 26978618 TI - [Immediate results of off-pump coronary artery bypass grafting]. AB - AIM: To present an experience of off-pump coronary artery bypass surgery in the department of cardiac surgery of I.M. Sechenov First Moscow State Medical University for the period 2009-2014. MATERIAL AND METHODS: It was performed 32 off-pump interventions. We established indications for off-pump myocardial revascularization, surgical technique and intraoperative and postoperative complications. RESULTS: Off-pump coronary artery bypass grafting is successfully reproducible method associated with favourable immediate results. PMID- 26978617 TI - Involvement of Daphnia pulicaria Sir2 in regulating stress response and lifespan. AB - The ability to appropriately respond to proteotoxic stimuli is a major determinant of longevity and involves induction of various heat shock response (HSR) genes, which are essential to cope with cellular and organismal insults throughout lifespan. The activity of NAD+-dependent deacetylase Sir2, originally discovered in yeast, is known to be essential for effective HSR and longevity. Our previous work on HSR inDaphnia pulicaria indicated a drastic reduction of the HSR in older organisms. In this report we investigate the role of Sir2 in regulating HSR during the lifespan of D. pulicaria. We cloned Daphnia Sir2 open reading frame (ORF) to characterize the enzyme activity and confirmed that the overall function of Sir2 was conserved in Daphnia. The Sir2 mRNA levels increased while the enzyme activity declined with age and considering that Sir2 activity regulates HSR, this explains the previously observed age-dependent decline in HSR. Finally, we tested the effect of Sir2 knockdown throughout adult life by using our new RNA interference (RNAi) method by feeding. Sir2 knockdown severely reduced both the median lifespan as well as significantly increased mortality following heat shock. Our study provides the first characterization and functional study of Daphnia Sir2. PMID- 26978619 TI - Surgical and combined treatment of patients with cholangiocellular carcinoma. AB - INTRODUCTION: Liver resection is the essential method of cholangiocellular carcinoma treatment. However due to low resectability and high incidence of recurrences search for additional curative methods is necessary. AIM: To improve the results of surgical treatment of patients with cholangiocellular carcinoma especially with complications and poor prognosis. MATERIAL AND METHODS: A total of 95 surgical procedures for intrahepatic cholangiocarcinoma have been performed in the department of liver andpancreatic tumors at N.N. Blokhin Russian Cancer Research Center since 1998 to 2014. 11 patients had obstructive jaundice as the first symptom of the disease. Extended liver resections were done in most cases (84.2%). Preoperative treatment was performed in 3 patients. Adjuvant chemotherapy after R0-resection was applied in 15 patients. RESULTS: The postoperative mortality rate was 4.2%. Postoperative complications were observed in 51 (53.7%) patients. Complication grade III after adjuvant chemotherapy was observed in one (6.7%) patient. Median survival after liver resection was 25 months, 5-year survival rate - 25.3%. In stage I-II five-year survival reached 66.7%. In patients with obstructive jaundice 5-year survival rate was 26.7%, median survival - 37 months. There was no improvement of survival in case of adjuvant therapy. CONCLUSION: Liver resection remains essential treatment of cholangiocellular carcinoma including patients with obstructive jaundice. Additional curative methods are necessary to increase resectability and decrease the risk of recurrence. PMID- 26978620 TI - [Features of severe surgical infections of soft tissues]. AB - AIM: To analyze clinical and microbiological examinations in severe soft tissues infections and their significance in predictors of outcomes. MATERIAL AND METHODS: Treatment of 19 patients with severe suppurative infection and suspected non-clostridial anaerobic flora with different causes of soft tissues infection was analyzed. All patients were treated in N.V. Sklifosovskiy Research Institute of Emergency Care for the period 2010-2012. Diagnosis was based on X-ray survey, sonography and CT data. Multicomponent management included surgery, intensive therapy, proteinic and water-electrolyte balance correction, deintoxication, nutritive support and immune therapy.Microbiological diagnosis was performed using Bactec-9050, Multiscan and WalkAway-40 analyzers. Culture mediums and microanaerostats to detect aerobic and obligately-anaerobic pathogens certified in Russia were used. Of 19 patients bacteriological examination was performed in 11 patients. So 107 specimens from wounds predominantly and blood were studied. 91 strains were revealed and identified. RESULTS: 8 of 11 patients in group 1 were operated. Three patients were inoperable due to severe condition and endotoxic shock. Despite complex treatment inflammation progressed in 5 of 8 patients followed by death. The second group consisted of 8 survivors. Staphylococcus aureus played leading role. There were no significant differences related to obligately-anaerobic pathogens. Mixed populations of aerobic and facultative anaerobic pathogens were diagnosed in 45% of specimens sampled from deads that is significantly greater than from survivors (8.7%). Leading pathogens of severe suppurative infections of soft tissues were more frequent revealed in mono-culture. Early diagnosis of tissue infections caused by nonsporeforming microorganisms should be based on clinical instrumental data, microbiological and morphological examinations. PMID- 26978621 TI - [Risk of hypocalcemia after thyroid surgery]. AB - AIM: To reveal calcium metabolism disorders that frequently occur after thyroid surgery. MATERIAL AND METHODS: The study included 202 patients who underwent thyroid surgery for different diseases and had normal calcium level in peripheral blood at baseline. RESULTS: Based on laboratory data postoperative hypocalcemia was diagnosed in 57 (28.8%) patients. It was not always accompanied by clinical symptoms. Clinical picture depended on degree of hypocalcemia. Symptoms was diagnosed more frequently if calcium concentration was less than 2.1 mmol/l. Clinical manifestations were absent in 64.9% of cases on background of hypocalcemia. Incidence of hypocalcemia was higher after thyroidectomy compared to organ-preserving surgery. Symptoms of hypocalcemia occurred after thyroidectomy only. Casual parathyroidectomy does not always cause hypocalcemia. Only in 14% of patients with hypocalcemia excised parathyroid was identified in specimen. At the same time 7.6% of patients with postoperative normocalcaemia also had excised parathyroids in specimens. Symptoms of hypocalcemia does not always occur at 1 day after surgery. They can appear later, for example at 5 days postoperatively and depend on severity of hypocalcemia. Thyroidectomy has high risk of postoperative hypocalcemia with clinical symptoms (19.6%) that is transient in 15.5% of cases and permanent in 4.1% of patients. PMID- 26978622 TI - [Management of perforative gastroduodenal ulcer]. AB - AIM: To study the immediate results of surgical treatment of patients with perforative gastroduodenal ulcer. MATERIAL AND METHODS: It was analyzed immediate results of surgical treatment of 646 patients with perforative gastroduodenal ulcer. Ulcer suturing predominated as surgical technique (358 patients, 55.5%), in other observations there were different types of vagotomy (215 cases, 33.3%), partial gastrectomy in 73 (11.2%) patients. RESULTS: In early postoperative period 36 (5.62%)patients died, incidence of complications was 6.2%. Following aspects effect on choice of surgical techbique including laoarotomy or minimally invasive approach, conventional suturing, vagotomy, partial gastrectomy: 1. presence of shock or unstable hemodynamics; 2. life-threating comorbidities (ASA class 3 and higher); 3. degree of abdominal bacterial contamination; 4. pre hospital duration of disease; 5. dimension and type of ulcer; 6. ulcerative history or intraoperative evidence of chronic ulcer. Implementation or absolute predominance of surgery of the same type (suturing of perforative ulcer) leads to great number of poor long-term results (up to 60-70%) and requires repeated interventions. PMID- 26978623 TI - [Latex ligation in treatment of chronic hemorrhoids]. AB - We analyzed the results of treatment of 432 patients with chronic hemorrhoids using different variants of latex ligation. New technique including ligation of mucosa and submucosa of low-ampullar rectum providing ligation of hemorrhoidalvessels, lifting and recto-anal repair is developed and suggested. This method is advisable to use in case of chronic internal hemorrhoids stages I and II. The authors recommend simultaneous combined ligation of mucosa of low ampullar rectum and internal hemorrhoids for stages III and IV. Different variants of latex ligation with external hemorrhoids excision were used in 103 patients. Pointed variants of latex ligation preserve important advantages including mini-invasiveness, simplicity and wide availability, low cost. Good remote results were obtained after these procedures in 87.3% of observations. Suggested tactics extends use of latex ligation and increases its effectiveness in treatment of different stages and forms of chronic hemorrhoids. PMID- 26978624 TI - [Performance evaluation of comprehensive treatment of patients with infectious complications of bullet-extremity fractures]. AB - The objective of the study was to examine the effectiveness of complex treatment of patients with infectious complications of gunshot fractures of limb bones using advanced minimally invasive surgical technologies phased osteosynthesis and new approaches of drug therapy. A prospective, comparative study of the results of examination and treatment of 60 patients with infectious complications of gunshot diaphyseal fractures of the long bones of the limbs treated in hospital Almutavakel (Sana'a, Republic of Yemen) in the period 2009-2011. Patients were randomized and divided into groups depending on the treatment regimen: a comparison (30 patients) received traditional scheme in which only apply external fixation devices or metal obsolete models and basic (30 patients), received treatment for advanced techniques include minimally invasive surgical sanitation of infected fracture zone followed by differentiated (depending on the size of the existing bone defect) tactics of consistent and gradual minimally invasive functionally stable osteosynthesis with modern APS and implants on a background of conservative therapy consisting of Cycloferon. The study showed a high clinical and cost-effectiveness of improved methods compared to traditional, that allows to recommend it for the provision of specialized medical care in the treatment of patients with infectious and complicated gunshot fractures of the long bones of the limbs. PMID- 26978626 TI - [Surgical treatment of patient with thoracoabdominal aneurysm and dissection combined with left kidney tumor]. PMID- 26978625 TI - [Analysis of the short-term and long-term results in surgical treatment of the chronic cystic pancreatitis]. AB - INTRODUCTION: In recent years, the practice of abdominal surgery marked increase in the number of patients with pancreatic cysts. Tactics of treatment of this disease is still disputable. MATERIAL AND METHODS: The article analyzes the treatment of 128 patients with formed pancreatic cysts. They were divided into three groups: 1) external drainage - 44 (34.4%); 2) internal drainage - 41 (32.0%); 3) resection surgery - 43 (33.6%). RESULTS: The duodenum resections were introduced for the treatment of the pancreatic head cysts - 21 (48.8%). Resection methods in the number of postoperative complications (23.3%) could be compared with the operations of the internal drainage of pancreatic cysts (19.5%), although the resection methods are technically more difficult and traumatic. 66 (51.6%) patients were observed in the long-term period. The number of postoperated disease recurrences was more in group 1 (28.6%). Quality of life indicators (SF-36) were higher in group 3. We marked the best results after resection operations. CONCLUSION: So this type of operation can be recommended for the treatment of patients with formed pancreatic cysts as the most radical method. PMID- 26978627 TI - [To the question of left renal vein intersection to improve exposure of juxtarenal abdominal aorta]. PMID- 26978628 TI - [Disseminated peritoneal lesion after laparoscopic removal of renal hydatid cyst]. PMID- 26978629 TI - [Pancreatic localization of hydatid cyst]. PMID- 26978630 TI - [Lipoma of Bauhin's valve - rare cause of large bowel obstruction]. PMID- 26978631 TI - [Treatment of patient with cholangiocarcinoma complicated by jaundice after previous surgery in terms of municipal clinic]. PMID- 26978632 TI - [Increase of relaparotomy efficacy in peritonitis management]. PMID- 26978633 TI - [New risk factors of stroke in young adults]. AB - According to the modern point of view, up to 75% stroke cases may be associated with conventional (basic) risk factors such as hypertension, atherosclerosis, cardiac arrhythmia, diabetes, and others. However, up to 25% of stroke cases are associated with the influence of other risk factors, especially among young people. In this review, an analysis and evaluation of the most significant new stroke risk factors in young adults, such as genetic predisposition, "small" vessels disease, hyperhomocysteinemia, thrombophilia, "silent" brain infarction and others was made. Attention was paid to a role of new stroke risk factors in women. In this review, criteria for clinical evaluation of new stroke risk factors and pattern of laboratory tests to determine the stroke risk were defined based on current literature and personal observations. PMID- 26978634 TI - [Characteristics of risk factors in young and middle-aged patients with first hemispheric ischemic stroke]. AB - AIM: To compare risk factors of the first hemispheric ischemic stroke in young, middle and old age groups. MATERIAL AND METHODS: One hundred and thirteen patients with first hemispheric ischemic stroke confirmed by CT/MRI were examined. The patients were divided into 2 groups: young and middle-aged (51 patients, 24 women, 27 men, mean age 49.8+/-5.2) and advanced-aged (62 patients, 30 women, 32 men, mean age 76.4+/-7.5). The frequency and duration of the following risk factors for ischemic stroke, including arterial hypertension, ischemic heart disease and arrhythmias, diabetes, smoking, family history of myocardial infarction and/or stroke, body mass index, acute emotional stress before the onset of the disease, were compared. Results of echocardiography, Holter and blood pressure monitoring, total cholesterol, low and high-density lipoproteins, triglycerides and blood glucose were analyzed. RESULTS: In young and middle-aged patients, an increased variability of blood pressure, acute emotional stress before the onset of stroke, a family history of cardiovascular and/or cerebrovascular disease, a decreased level of high-density lipoproteins, silent myocardial ischemia on Holter monitoring, mitral and tricuspid valve prolapse, minor abnormalities of the heart were more frequent than in the advanced age group. CONCLUSION: There are age-related differences in the spectrum and frequency of risk factors in patients with first hemispheric ischemic stroke. This fact should be taken into account in stroke prevention programs in various age groups. PMID- 26978635 TI - [Internal carotid artery dissection as a cause of severe ischemic stroke with lethal outcome]. AB - We present a medical history of a 30-year old male patient with fatal ischemic stroke, resulting from the right internal carotid artery (ICA) dissection provoked by repeated head tilts and verified by magnetic resonance imaging and pathomorphological examination. At admission, the high level of creatine phosphokinase (5284 un/ml, normal level<171) in the blood was found, the coagulation parameters were normal. Autopsy revealed intramural hematoma (IMH), which was located between the media and adventitia of the arterial wall, began at 3 cm above the common carotid artery bifurcation and extended to the base of the skull. The lumen of the ICA at the level of the IMG and intracranial parts as well as of the middle cerebral artery was occluded by the thrombus. The histological examination of the right ICA wall found splitting, thinning, fragmentation, disrupters of internal elastic membrane, severe media fibrosis, myocyte necrosis at the site of the dissection with the surrounding leukocyte infiltration, as well as lymphocytic infiltrates, clusters of eosinophils in adventitia. Similar changes, except myocyte necrosis, were also found in intact (non-dissected) brain supplying arteries. In general, they were similar to those in fibromuscular dysplasia (FMD). Histochemical and electron microscopic studies of skeletal muscles showed signs of mitochondrial cytopathy. The authors discuss the relationship between the dissection, FMD and mitochondrial pathology. PMID- 26978636 TI - [Associations between quality of life and lifestyle peculiarities in stroke survivors: the results of the EROS study]. AB - OBJECTIVE: To determine relations between quality of life and characteristics of lifestyle in stroke patients and control groups. MATERIAL AND METHODS: The case group consisted of 508 Kaunas citizens, aged 25-84, who had survived their first stroke. The control group consisted of 508 randomly chosen healthy Kaunas citizens age- and sex-matched to the cases. SF-12 questionnaire on the quality of life has been used for the study. The characteristics of lifestyle (alcohol use, smoking, nutrition) were studied. RESULTS: The effect size of alcohol use in the stroke patients was not large (Cohen's d=0.41) compared to the control group (Cohen's d=0.87). Patients who did not use alcohol had lower estimations in the physical health domain of quality of life compared to those who used alcohol. The number of smoking men was significantly higher (p=0.0005) in the stroke patients (29.0%) than in the control group (19.6%). The physical health was best assessed by men belonging to the control group who never smoked compared to men who had quit smoking (p=0.0005) and in the stroke group - by smoking men compared to men who had quit smoking (p=0.049). Nutrition status had significant effect only on the physical health in the control group: the estimate of physical health of obese individuals was lower when compared to the rest participants (p<0.001). CONCLUSION: The number of men who used excessive amounts of alcohol and smoked or had quit smoking was higher in the stroke patients group than in the control group. In the stroke patient group, the effect size of alcohol use was not large. Men who had quit smoking prior to stroke presented poorer evaluations of the quality of life in the general health and mental health domains than did those who had smoked before stroke onset. PMID- 26978637 TI - [Risk factors of stroke in men exposed to environmental factors at workplace]. AB - OBJECTIVE: To explore risk factors of stroke in men of different age groups exposed to adverse environmental factors at work. MATERIAL AND METHODS: Four hundred and eleven men after stroke, aged from 30 to 65 years, including 335 patients, who had been exposed to adverse environmental factors at work, were compared to 76 patients who had not been exposed to adverse environmental factors. RESULTS: The distribution of the frequencies of risk factors of stroke depending on the character of adverse factors was shown. PMID- 26978638 TI - [Prognostic factors of recurrent acute cerebrovascular incidents in patients with ischemic stroke]. AB - OBJECTIVE: To establish prognostic factors of recurrent acute cerebrovascular complications after ischemic stroke. MATERIAL AND METHODS: A prospective observational study on the 21-22nd day of the acute stage of ischemic stroke included 148 patients, aged 60 [5; 68] years. Following the discharge, a unified telephone survey of patients or their relatives was performed every 3 months. Recurrent strokes, including those with fatal outcome, and transient ischemic attacks (TIA) were recorded. RESULTS AND CONCLUSION: The long-term prospective follow-up duration was 35 [28; 40] months. In 26 (18%) patients, 31 cerebral complications, including 24 recurrent ischemic strokes, 6 TIA, 1 hypertensive intracerebral hemorrhage were registered. Recurrent cerebral complications found to be associated with age older 67 years, ischemic heart disease, multiple focal brain lesions, supraventricular arrhythmias more 46/day, bradyarrhythmias, ventricular arrhythmias. The use of thiazide and thiazide-liked diuretics as part of antihypertensive therapy was associated with a reduced risk of cerebral complications. PMID- 26978639 TI - [The lipid profile and psychometric assessments in patients with psychosomatic illnesses and chronic cerebral ischemia]. AB - OBJECTIVE: To explore the correlations between plasma cholesterol and triglyceride levels and psychometric assessments in patients with psychosomatic illnesses and chronic cerebral ischemia (CCI). MATERIAL AND METHODS: One hundred and ten patients (51% women, 49% men), aged from 46 to 76 years (mean 65.1 years) with CCI were examined. The study included cholesterol and triglyceride tests and a battery of tests for assessment of cognitive functions and neurotization level. RESULTS: Cholesterol levels were higher in patients with post-infarct cardiosclerosis (PICS) compared to the comparison group but did not differ from those of patients with peptic ulcer disease (PUD). Triglyceride levels were high in both psychosomatic groups, with higher levels in the patients with PICS compared to the patients with PUD. Plasma cholesterol and triglyceride levels were not correlated with assessments of cognitive functions in patients of different age. CONCLUSION: Cognitive impairment and higher level of neurotization were characteristic of patients with psychosomatic illnesses. Regression analysis has demonstrated that plasma cholesterol and triglyceride levels may be a prognostic factor for cognitive impairment. PMID- 26978640 TI - [Characteristics of immune response and inflammatory reaction in atherothrombotic stroke and myocardial infarction]. AB - AIM: To study characteristics of ischemic tissue damage basing on the assessment of the correlations between markers of immune response, inflammation and apoptosis in patients with myocardial infarction (MI) and atherothrombotic stroke (AS). MATERIAL AND METHODS: Concentrations of matrix metalloproteinase-9 (MMP-9), immune complexes with cryogenic properties, soluble Fas-ligand, tumor necrosis factor alpha, interleukin-10 measured with ELISA as well as the activity of spontaneous apoptosis of mononuclear cells and surface expression of Toll-like receptors-4 and intracellular heat shock proteins measured with flow cytofluorometry were determined in the blood of 93 patients with the first AS and 94 patients with MI without concomitant inflammation in the 1st and 7th day of the disease. RESULTS AND CONCLUSION: Increased levels of the markers of immune response, inflammation, apoptosis and destruction of the extracellular matrix were identified at the beginning of MI and AS. The results provide the evidence that similar mechanisms may be involved in ischemic tissue damage. Multivariate analysis conducterd by of principal component analysis correlation matrix revealed the specificity of the relationships between all of these markers. This is the completely new approach to assessin the role and importance of defined parameters in the acute period of the myocardial ischemia and brain. PMID- 26978641 TI - [Impairment of attention in post-stroke fatigue and depression]. AB - OBJECTIVE: To study the relationship between impairment of attention and development of pathological fatigue and depression after non-disabling stroke. MATERIAL AND METHODS: Thirty patients were examined. Attention was assessed by the Attention Network Test (ANT). Pathological fatigue and depression were assessed by the Fatigue assessment scale and depression subscale of the Hospital Anxiety and Depression Scale, respectively. RESULTS AND CONCLUSION: The association between the severity of depression and fatigue after stroke and reduction of mean reaction time in ANT was found. A decrease in the reaction time may be one of the factors reducing working ability in patients with post-stroke fatigue and depression even in the absence of severe neurological deficit. This has to be taken into account when planning rehabilitation. PMID- 26978643 TI - [The efficacy of transcranial magnetic stimulation in acute ischemic stroke]. AB - OBJECTIVE: To study an effect of the course treatment with transcranial magnetic stimulation (TMS) on cognitive functions, movement deficit, daily activity and cerebral hemodynamics in the acute ischemic stroke. MATERIAL AND METHODS: Ninety two patients, including 32 patients treated with TMS (the main group), 30 patients who received placebo (comparison group 1) and 30 patients who received low intensity magnetic stimulation and basic complex therapy during 10 days once a day (the comparison group 2), were examined. RESULTS AND CONCLUSION: A significant improvement of cognitive processes, restoration of motor functions, increase in daily activities, normalization of the cerebral hemodynamics were observed. Based on these RESULTS: the inclusion of TMS in the complex rehabilitation system of post-stroke patients is recommended. PMID- 26978642 TI - [A protective role of the nitrite/nitrate reductase system in ischemic stroke]. AB - OBJECTIVE: To reveal a protective role of the nitrite/nitrate reductase system in NO- synthase (NOS) inhibition in ischemic stroke. MATERIAL AND METHODS: An effect of the non-selective NOS inhibitor Nomega-nitro-L-arginine (L-NNA) introduced in dose of 25 mg/kg and nitrates (KNO3, NaNO3, Mg(NO3)2, Ca(NO3) in doses of 5 mg/kg) on ischemic stroke induced by the occlusion of carotid arteries in an experimental model was studied. The animals (Wistar rats) were stratified into 20 experimental groups (n=480) and 4 control groups (n=96). One of nitrates or L-NNA along with one of nitrates or L-NNA alone were administered to experimental groups 1h before brain ischemia or 5s after carotid artery occlusion. 0.9% NaCl was used in the control rats. RESULTS: L-NNA increases neurological deficit and lethality in brain ischemia. Depending on a cation, the nitrite/nitrate reductase system may play a protective role in the inhibition of NOS-system in brain ischemia. CONCLUSION: In brain ischemia and NOS inhibition, Mg(NO3)2 has the greatest protective effect. PMID- 26978644 TI - [Interview with prof. V.V. Shprakh]. PMID- 26978645 TI - [Mexidol in the rehabilitation of patients in the acute ischemic stroke]. AB - Research objective - studying of results of a comprehensive neuro-rehabilitation patients in the acute ischemic stroke (according to the Samara regional vascular centre). MATERIAL AND METHODS: A review of the work of RVC on the main indicators for 2014, detailed analysis of 20 patients in the acute period of ischemic stroke, in which treatment was used the drug mexidol with the dynamics on standardized assessment scales (NIHSS, Rankin, Rivermead, MoCA, HADS). RESULTS AND DISCUSSION: The use of "Mexidol" in the treatment of stroke leads to a significant statistically and clinically significant improvement in cognitive, motor, sensory functions, reduction of fatigue, anxiety, improved adaptation to physical loads. PMID- 26978646 TI - Efficient Absorption of X-Hydroxyproline (Hyp)-Gly after Oral Administration of a Novel Gelatin Hydrolysate Prepared Using Ginger Protease. AB - Recent studies have reported that oral intake of gelatin hydrolysate has various beneficial effects, such as reduction of joint pain and lowering of blood sugar levels. In this study, we produced a novel gelatin hydrolysate using a cysteine type ginger protease having unique substrate specificity with preferential peptide cleavage with Pro at the P2 position. Substantial amounts of X hydroxyproline (Hyp)-Gly-type tripeptides were generated up to 2.5% (w/w) concomitantly with Gly-Pro-Y-type tripeptides (5%; w/w) using ginger powder. The in vivo absorption of the ginger-degraded gelatin hydrolysate was estimated using mice. The plasma levels of collagen-derived oligopeptides, especially X-Hyp-Gly, were significantly high (e.g., 2.3-fold for Glu-Hyp-Gly, p < 0.05) compared with those of the control gelatin hydrolysate, which was prepared using gastrointestinal proteases and did not contain detectable X-Hyp-Gly. This study demonstrated that orally administered X-Hyp-Gly was effectively absorbed into the blood, probably due to the high protease resistance of this type of tripeptide. PMID- 26978647 TI - Marinicella pacifica sp. nov., isolated from seawater. AB - A Gram-stain-negative, strictly aerobic, non-motile, non-gliding, oxidase positive, catalase-positive, rod-shaped bacterium, designated strain sw153T, was isolated from surface seawater of the South Pacific Gyre (39 degrees 19' S 139 degrees 48' W) during Integrated Ocean Drilling Program Expedition 329. Growth occurred at 10-42 degrees C (optimum 28 degrees C), in the presence of 1-8 % (w/v) NaCl (optimum 2 %) and at pH 6.0-10.0 (optimum pH 7.5-8.5). The major fatty acids (>10 %) were iso-C15:0 and summed feature 3 (C16:1omega6c and/or C16:1omega7c). The major polar lipids comprised phosphatidylethanolamine, phosphatidylmonomethylethanolamine, phosphatidylcholine, phosphatidylglycerol, an unidentified polar lipid and an unidentified phospholipid. The major respiratory quinone was ubiquinone-8 (Q-8). The DNA G+C content of strain sw153T was 44.5 mol%. Phylogenetic analysis based on 16S rRNA gene sequences placed strain sw153T within the genus Marinicella, class Gammaproteobacteria. The most closely related species was Marinicella litoralis KMM 3900T (96.6 % 16S rRNA gene sequence similarity). Based on the polyphasic analyses in this study, strain sw153T is considered to represent a novel species of the genus Marinicella, for which the name Marinicella pacifica sp. nov. is proposed. The type strain is sw153T (=JCM 18208T=CGMCC 1.12181T). PMID- 26978648 TI - Life-Cycle Costing of Food Waste Management in Denmark: Importance of Indirect Effects. AB - Prevention has been suggested as the preferred food waste management solution compared to alternatives such as conversion to animal fodder or to energy. In this study we used societal life-cycle costing, as a welfare economic assessment, and environmental life-cycle costing, as a financial assessment combined with life-cycle assessment, to evaluate food waste management. Both life-cycle costing assessments included direct and indirect effects. The latter are related to income effects, accounting for the marginal consumption induced when alternative scenarios lead to different household expenses, and the land-use-changes effect, associated with food production. The results highlighted that prevention, while providing the highest welfare gains as more services/goods could be consumed with the same income, could also incur the highest environmental impacts if the monetary savings from unpurchased food commodities were spent on goods/services with a more environmentally damaging production than that of the (prevented) food. This was not the case when savings were used, e.g., for health care, education, and insurances. This study demonstrates that income effects, although uncertain, should be included whenever alternative scenarios incur different financial costs. Furthermore, it highlights that food prevention measures should not only demote the purchase of unconsumed food but also promote a low-impact use of the savings generated. PMID- 26978649 TI - Effects of Sildenafil Citrate and Heparin Treatments on Placental Cell Morphology in a Murine Model of Pregnancy Loss. AB - Lipopolysaccharide (LPS) injections during pregnancy are well established as models for pregnancy complications, including fetal growth restriction (FGR), thrombophilia, preterm labor and abortion. Indeed, inflammation, as induced by LPS injection has been described as a pivotal factor in cases of miscarriage related to placental tissue damage. The phosphodiesterase-5 inhibitor sildenafil (Viagra(r)) is currently used to treat FGR cases in women, while low-molecular weight heparin (Fragmin(r)) is a standard treatment for recurrent miscarriage (RM). However, the pathways and cellular dynamics involved in RM are not completely understood. The aim of this study was to evaluate the protective effect of sildenafil and dalteparin in a mouse model of LPS-induced abortion. Histopathology, ultrastructural analysis and immunofluorescence for P-selectin were studied in two different placental cell types: trophoblast cells and labyrinth endothelial cells. Treatment with sildenafil either alone or in combination with heparin showed the best response against LPS-induced injury during pregnancy. In conclusion, our results support the use of these drugs as future therapeutic agents that may protect the placenta against inflammatory injury in RM events. Analyses of the ultrastructure and placental immunophysiology are important to understand the mechanism underlying RM. These findings may spark future studies and aid in the development of new therapies in cases of RM. PMID- 26978650 TI - Serial amnioinfusions for fetal pulmonary palliation in fetuses with renal failure. AB - Fetal lower urinary tract obstruction (LUTO) encompasses a heterogeneous group of congenital pathologies and generally results in oligohydramnios. Fetal intervention (e.g. vesicoamniotic shunting, fetal cystoscopy) has traditionally been reserved for cases with a favorable renal profile, while those with unfavorable renal function have been offered termination or expectant management with the latter leading to high incidence of marked pulmonary hypoplasia, neonatal morbidity and mortality. Here, we describe two cases, which were not candidates for traditional intervention based on abnormal fetal renal function, who elected to proceed with serial amnioinfusions for fetal pulmonary palliation to attenuate the risk of pulmonary hypoplasia. PMID- 26978651 TI - Fibronectin Modulates Cell Adhesion and Signaling to Promote Single Cell Migration of Highly Invasive Oral Squamous Cell Carcinoma. AB - Cell migration is regulated by adhesion to the extracellular matrix (ECM) through integrins and activation of small RhoGTPases, such as RhoA and Rac1, resulting in changes to actomyosin organization. During invasion, epithelial-derived tumor cells switch from laminin-enriched basal membrane to collagen and fibronectin enriched connective tissue. How this switch affects the tumor migration is still unclear. We tested the hypothesis that ECM dictates the invasiveness of Oral Squamous Cell Carcinoma (OSCC). We analyzed the migratory properties of two OSCC lines, a low invasive cell line with high e-cadherin levels (Linv/HE-cad) or a highly invasive cell line with low e-cadherin levels (Hinv/LE-cad), plated on different ECM components. Compared to laminin, fibronectin induced non directional collective migration and decreased RhoA activity in Linv/HE-cad OSCC. For Hinv/LE-cad OSCC, fibronectin increased Rac1 activity and induced smaller adhesions, resulting in a fast single cell migration in both 2D and 3D environments. Consistent with these observations, human OSCC biopsies exhibited similar changes in cell-ECM adhesion distribution at the invasive front of the tumor, where cells encounter fibronectin. Our results indicate that ECM composition might induce a switch from collective to single cell migration according to tumor invasiveness due to changes in cell-ECM adhesion and the resulting signaling pathways that alter actomyosin organization. PMID- 26978652 TI - Inactivation of the WNT5A Alternative Promoter B Is Associated with DNA Methylation and Histone Modification in Osteosarcoma Cell Lines U2OS and SaOS-2. AB - WNT5A is a secreted ligand involved in Wnt pathway signaling and has a role in cell movement and differentiation. Altered WNT5A expression is associated with various cancers, although in most studies the focus has been on only one of the known WNT5A isoforms. In this study, we analyzed expression from two of the major WNT5A promoters, termed promoter A and promoter B, in normal human osteoblasts, SaOS-2 and U2OS osteosarcoma cell lines, and osteosarcoma tumor tissue. We found that both promoters A and B are active in normal osteoblasts with nearly 11-fold more promoter B than A transcripts. Promoter B but not promoter A transcripts are decreased or nearly undetectable in the SaOS-2 and U2OS cell lines and osteosarcoma tumor tissues. Transient transfection of promoter A and promoter B reporter constructs confirmed that SaOS-2 cells have the necessary factors to transcribe both promoters. Bisulfite sequencing analysis revealed that three CpG enriched regions upstream of the promoter B exon 1betaare highly methylated in both SaOS-2 and U2OS cells. The CpG island sub-region R6 located in promoter B exon 1beta was approximately 51% methylated in SaOS-2 and 25% methylated in U2OS. Region 3 was approximately 28% methylated in normal osteoblasts, whereas the others were unmethylated. Promoter B was re-activated by treatment of SaOS-2 cells with 1 MUM 5-azacytidine, which was associated with only a small insignificant change in methylation of sub-region R6. ChIP analysis of U2OS and SaOS-2 cells indicated that the promoter B region is less enriched in the active histone mark H3K4me3, in comparison to promoter A and that there is increased enrichment of the repressive mark H3K27me3 in association with the promoter B genomic region in the cell line SaOS-2. These findings show that epigenetic inactivation of the WNT5A promoter B involves both DNA methylation and histone modifications and suggest that differential expression of the WNT5A alternative promoters A and B is a characteristic of osteosarcomas. PMID- 26978653 TI - Information Limited Oligonucleotide Amplification Assay for Affinity-Based, Parallel Detection Studies. AB - Molecular communication systems encounter similar constraints as telecommunications. In either case, channel crosstalk at the receiver end will result in information loss that statistical analysis cannot compensate. This is because in any communication channel there is a physical limit to the amount of information that can be transmitted. We present a novel and simple modified end amplification (MEA) technique to generate reduced and defined amounts of specific information in form of short fragments from an oligonucleotide source that also contains unrelated and redundant information. Our method can be a valuable tool to investigate information overflow and channel capacity in biomolecular recognition systems. PMID- 26978654 TI - Development of Microsatellite Markers and Analysis of Genetic Diversity and Population Structure of Colletotrichum gloeosporioides from Ethiopia. AB - Twenty three polymorphic microsatellite markers were developed for citrus plant pathogenic fungus, Colletotrichum gloeosporioides, and were used to analyze genetic diversity and population structure of 163 isolates from four different geographical regions of Ethiopia. These loci produced a total of 118 alleles with an average of 5.13 alleles per microsatellite marker. The polymorphic information content values ranged from 0.104 to 0.597 with an average of 0.371. The average observed heterozygosity across all loci varied from 0.046 to 0.058. The gene diversity among the loci ranged from 0.106 to 0.664. Unweighted Neighbor-joining and population structure analysis grouped these 163 isolates into three major groups. The clusters were not according to the geographic origin of the isolates. Analysis of molecular variance showed 85% of the total variation within populations and only 5% among populations. There was low genetic differentiation in the total populations (FST = 0.049) as evidenced by high level of gene flow estimate (Nm = 4.8 per generation) among populations. The results show that Ethiopian C. gloeosporioides populations are generally characterized by a low level of genetic diversity. The newly developed microsatellite markers were useful in analyzing the genetic diversity and population structure of the C. gloeosporioides populations. Information obtained from this study could be useful as a base to design strategies for better management of leaf and fruit spot disease of citrus in Ethiopia. PMID- 26978655 TI - Defining Feasibility and Pilot Studies in Preparation for Randomised Controlled Trials: Development of a Conceptual Framework. AB - We describe a framework for defining pilot and feasibility studies focusing on studies conducted in preparation for a randomised controlled trial. To develop the framework, we undertook a Delphi survey; ran an open meeting at a trial methodology conference; conducted a review of definitions outside the health research context; consulted experts at an international consensus meeting; and reviewed 27 empirical pilot or feasibility studies. We initially adopted mutually exclusive definitions of pilot and feasibility studies. However, some Delphi survey respondents and the majority of open meeting attendees disagreed with the idea of mutually exclusive definitions. Their viewpoint was supported by definitions outside the health research context, the use of the terms 'pilot' and 'feasibility' in the literature, and participants at the international consensus meeting. In our framework, pilot studies are a subset of feasibility studies, rather than the two being mutually exclusive. A feasibility study asks whether something can be done, should we proceed with it, and if so, how. A pilot study asks the same questions but also has a specific design feature: in a pilot study a future study, or part of a future study, is conducted on a smaller scale. We suggest that to facilitate their identification, these studies should be clearly identified using the terms 'feasibility' or 'pilot' as appropriate. This should include feasibility studies that are largely qualitative; we found these difficult to identify in electronic searches because researchers rarely used the term 'feasibility' in the title or abstract of such studies. Investigators should also report appropriate objectives and methods related to feasibility; and give clear confirmation that their study is in preparation for a future randomised controlled trial designed to assess the effect of an intervention. PMID- 26978656 TI - Proteinuria during Follow-Up Period and Long-Term Renal Survival of Childhood IgA Nephropathy. AB - BACKGROUND: Proteinuria is the most important risk factor for IgA nephropathy progression. The purpose of this study is to evaluate the long-term outcome and risk factors for poor prognosis in childhood IgA nephropathy. METHODS: Patients who were diagnosed with IgA nephropathy between 1972 and 1992 at the Tokyo Metropolitan Kiyose Children's Hospital were included. We analyzed risk factors for progression to end-stage kidney disease (ESKD) and chronic renal insufficiency (CRI) using Kaplan-Meier method and multivariate analyses of Cox proportional hazard model. RESULTS: One hundred patients were included and the median observation period was 11.8 years. Twelve and 17 patients progressed to ESKD and CRI, respectively. The survival probabilities were 90.0% at 10 years and 79.8% at 20 years for ESKD, and 86.1% at 10 years and 72.3% at 20 years for CRI. Notably, patients with heavy proteinuria with hypoalbuminemia during follow-up period showed extremely poor prognosis. In this group, the survival rate at 10 years from ESKD and CRI was 40.6% and 20.8%, respectively. By multivariate analysis, proteinuria at diagnosis and proteinuria during follow-up period were risk factors for ESKD, whereas glomeruli showing mesangial proliferation >=50% and proteinuria during follow-up period were risk factors for CRI. Patients without heavy proteinuria during follow-up period did not develop CRI and 63% of patients with mild proteinuria during follow-up period showed no proteinuria at the last observation. CONCLUSIONS: The degree of proteinuria during follow-up period is the strongest risk factor for ESKD and CRI. PMID- 26978658 TI - Genetic Diversity of NHE1, Receptor for Subgroup J Avian Leukosis Virus, in Domestic Chicken and Wild Anseriform Species. AB - J subgroup avian leukosis virus (ALV-J) infects domestic chicken, jungle fowl, and turkey and enters the host cell through a receptor encoded by tvj locus and identified as Na+/H+ exchanger 1 (NHE1). The resistance to ALV-J in a great majority of examined galliform species was explained by deletions or substitutions of the critical tryptophan 38 in the first extracellular loop of NHE1, and genetic polymorphisms around this site predict the susceptibility or resistance of a given species or individual. In this study, we examined the NHE1 polymorphism in domestic chicken breeds and documented quantitative differences in their susceptibility to ALV-J in vitro. In a panel of chicken breeds assembled with the aim to cover the maximum variability encountered in domestic chickens, we found a completely uniform sequence of NHE1 extracellular loop 1 (ECL1) without any source of genetic variation for the selection of ALV-J-resistant poultry. In parallel, we studied the natural polymorphisms of NHE1 in wild ducks and geese because of recent reports on ALV-J positivity in feral Asian species. In anseriform species, we demonstrate a specific and highly conserved critical ECL1 sequence without any homologue of tryptophan 38 in accordance with the resistance of duck cells to prototype ALV-J. Last, we demonstrated that the new Asian strains of ALV-J have not evolved their envelope glycoprotein to the entry the duck cells. Our results contribute substantially to the current discussion of possible heterotransmission of ALV-J and its spill-over into the wild ducks and geese. PMID- 26978659 TI - Relative Preference and Localized Food Affect Predator Space Use and Consumption of Incidental Prey. AB - Abundant, localized foods can concentrate predators and their foraging efforts, thus altering both the spatial distribution of predation risk and predator preferences for prey that are encountered incidentally. However, few investigations have quantified the spatial scale over which localized foods affect predator foraging behavior and consumption of incidental prey. In spring 2010, we experimentally tested how point-source foods altered how generalist predators (white-footed mice, Peromyscus leucopus) utilized space and depredated two incidental prey items: almonds (Prunus dulcis; highly profitable) and maple seeds (Acer saccharum; less profitable). We estimated mouse population densities with trapping webs, quantified mouse consumption rates of these incidental prey items, and measured local mouse activity with track plates. We predicted that 1) mouse activity would be elevated near full feeders, but depressed at intermediate distances from the feeder, 2) consumption of both incidental prey would be high near feeders providing less-preferred food and, 3) consumption of incidental prey would be contingent on predator preference for prey relative to feeders providing more-preferred food. Mouse densities increased significantly from pre- to post experiment. Mean mouse activity was unexpectedly greatest in control treatments, particularly <15 m from the control (empty) feeder. Feeders with highly preferred food (sunflower seeds) created localized refuges for incidental prey at intermediate distances (15 to 25m) from the feeder. Feeders with less-preferred food (corn) generated localized high risk for highly preferred almonds <10 m of the feeder. Our findings highlight the contingent but predictable effects of locally abundant food on risk experienced by incidental prey, which can be positive or negative depending on both spatial proximity and relative preference. PMID- 26978657 TI - Mechanosensory and ATP Release Deficits following Keratin14-Cre-Mediated TRPA1 Deletion Despite Absence of TRPA1 in Murine Keratinocytes. AB - Keratinocytes are the first cells that come into direct contact with external tactile stimuli; however, their role in touch transduction in vivo is not clear. The ion channel Transient Receptor Potential Ankyrin 1 (TRPA1) is essential for some mechanically-gated currents in sensory neurons, amplifies mechanical responses after inflammation, and has been reported to be expressed in human and mouse skin. Other reports have not detected Trpa1 mRNA transcripts in human or mouse epidermis. Therefore, we set out to determine whether selective deletion of Trpa1 from keratinocytes would impact mechanosensation. We generated K14Cre Trpa1fl/fl mice lacking TRPA1 in K14-expressing cells, including keratinocytes. Surprisingly, Trpa1 transcripts were very poorly detected in epidermis of these mice or in controls, and detection was minimal enough to preclude observation of Trpa1 mRNA knockdown in the K14Cre-Trpa1fl/fl mice. Unexpectedly, these K14Cre Trpa1fl/fl mice nonetheless exhibited a pronounced deficit in mechanosensitivity at the behavioral and primary afferent levels, and decreased mechanically-evoked ATP release from skin. Overall, while these data suggest that the intended targeted deletion of Trpa1 from keratin 14-expressing cells of the epidermis induces functional deficits in mechanotransduction and ATP release, these deficits are in fact likely due to factors other than reduction of Trpa1 expression in adult mouse keratinocytes because they express very little, if any, Trpa1. PMID- 26978660 TI - Social Use of Facial Expressions in Hylobatids. AB - Non-human primates use various communicative means in interactions with others. While primate gestures are commonly considered to be intentionally and flexibly used signals, facial expressions are often referred to as inflexible, automatic expressions of affective internal states. To explore whether and how non-human primates use facial expressions in specific communicative interactions, we studied five species of small apes (gibbons) by employing a newly established Facial Action Coding System for hylobatid species (GibbonFACS). We found that, despite individuals often being in close proximity to each other, in social (as opposed to non-social contexts) the duration of facial expressions was significantly longer when gibbons were facing another individual compared to non facing situations. Social contexts included grooming, agonistic interactions and play, whereas non-social contexts included resting and self-grooming. Additionally, gibbons used facial expressions while facing another individual more often in social contexts than non-social contexts where facial expressions were produced regardless of the attentional state of the partner. Also, facial expressions were more likely 'responded to' by the partner's facial expressions when facing another individual than non-facing. Taken together, our results indicate that gibbons use their facial expressions differentially depending on the social context and are able to use them in a directed way in communicative interactions with other conspecifics. PMID- 26978662 TI - Convolutional Neural Networks for Medical Image Analysis: Full Training or Fine Tuning? AB - Training a deep convolutional neural network (CNN) from scratch is difficult because it requires a large amount of labeled training data and a great deal of expertise to ensure proper convergence. A promising alternative is to fine-tune a CNN that has been pre-trained using, for instance, a large set of labeled natural images. However, the substantial differences between natural and medical images may advise against such knowledge transfer. In this paper, we seek to answer the following central question in the context of medical image analysis: Can the use of pre-trained deep CNNs with sufficient fine-tuning eliminate the need for training a deep CNN from scratch? To address this question, we considered four distinct medical imaging applications in three specialties (radiology, cardiology, and gastroenterology) involving classification, detection, and segmentation from three different imaging modalities, and investigated how the performance of deep CNNs trained from scratch compared with the pre-trained CNNs fine-tuned in a layer-wise manner. Our experiments consistently demonstrated that 1) the use of a pre-trained CNN with adequate fine-tuning outperformed or, in the worst case, performed as well as a CNN trained from scratch; 2) fine-tuned CNNs were more robust to the size of training sets than CNNs trained from scratch; 3) neither shallow tuning nor deep tuning was the optimal choice for a particular application; and 4) our layer-wise fine-tuning scheme could offer a practical way to reach the best performance for the application at hand based on the amount of available data. PMID- 26978661 TI - The Role of Metformin Response in Lipid Metabolism in Patients with Recent-Onset Type 2 Diabetes: HbA1c Level as a Criterion for Designating Patients as Responders or Nonresponders to Metformin. AB - BACKGROUND: In this study, we investigated whether response to metformin, the most frequently drug for diabetes treatment, influences the therapeutic effects of antilipidemic medication in newly diagnosed patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 150 patients with T2DM were classified into two groups following 3 months of metformin therapy (1000 mg twice daily): responders (patients showing >=1% reduction in HbA1c from baseline) and nonresponders (patients showing <1% reduction in HbA1c from baseline). The patients received atorvastatin 20 mg, gemfibrozil 300 mg, or atorvastatin 20 mg and gemfibrozil 300 mg daily. PRINCIPAL FINDINGS: HbA1c and fasting glucose levels were significantly different between baseline and 3 months among responders receiving atorvastatin; however, these differences were not statistically significant in nonresponders. Atherogenic ratios of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL-C/HDL-C; p = 0.002), total cholesterol to HDL-C (TC/HDL-C; p<0.001) and AIP (the atherogenic index of plasma; p = 0.004) decreased significantly in responders receiving atorvastatin than in nonresponders. Moreover, responders receiving atorvastatin showed a significant increase in HDL-C levels but nonresponders receiving atorvastatin did not (p = 0.007). The multivariate model identified a significant association between metformin response (as the independent variable) and TG, TC, HDL-C and LDL-C (dependent variables; Wilk's lambda = 0.927, p = 0.036). CONCLUSIONS: Metformin response affects therapeutic outcomes of atorvastatin on atherogenic lipid markers in patients newly diagnosed with T2DM. Metformin has a greater impact on BMI in responders of metformin compared to nonresponders. Adoption of better therapeutic strategies for reducing atherogenic lipid markers may be necessary for metformin nonresponders. PMID- 26978663 TI - Cryo-Balloon Catheter Localization Based on a Support-Vector-Machine Approach. AB - Cryo-balloon catheters have attracted an increasing amount of interest in the medical community as they can reduce patient risk during left atrial pulmonary vein ablation procedures. As cryo-balloon catheters are not equipped with electrodes, they cannot be localized automatically by electro-anatomical mapping systems. As a consequence, X-ray fluoroscopy has remained an important means for guidance during the procedure. Most recently, image guidance methods for fluoroscopy-based procedures have been proposed, but they provide only limited support for cryo-balloon catheters and require significant user interaction. To improve this situation, we propose a novel method for automatic cryo-balloon catheter detection in fluoroscopic images by detecting the cryo-balloon catheter's built-in X-ray marker. Our approach is based on a blob detection algorithm to find possible X-ray marker candidates. Several of these candidates are then excluded using prior knowledge. For the remaining candidates, several catheter specific features are introduced. They are processed using a machine learning approach to arrive at the final X-ray marker position. Our method was evaluated on 75 biplane fluoroscopy images from 40 patients, from two sites, acquired with a biplane angiography system. The method yielded a success rate of 99.0% in plane A and 90.6% in plane B, respectively. The detection achieved an accuracy of 1.00 mm+/-0.82 mm in plane A and 1.13 mm+/-0.24 mm in plane B. The localization in 3-D was associated with an average error of 0.36 mm+/-0.86 mm. PMID- 26978664 TI - Design Features and Mutual Compatibility Studies of the Time-of-Flight PET Capable GE SIGNA PET/MR System. AB - A recent entry into the rapidly evolving field of integrated PET/MR scanners is presented in this paper: a whole body hybrid PET/MR system (SIGNA PET/MR, GE Healthcare) capable of simultaneous acquisition of both time-of-flight (TOF) PET and high resolution MR data. The PET ring was integrated into an existing 3T MR system resulting in a (patient) bore opening of 60 cm diameter, with a 25 cm axial FOV. PET performance was evaluated both on the standalone PET ring and on the same detector integrated into the MR system, to assess the level of mutual interference between both subsystems. In both configurations we obtained detector performance data. PET detector performance was not significantly affected by integration into the MR system. The global energy resolution was within 2% (10.3% versus 10.5%), and the system coincidence time resolution showed a maximum change of < 3% (385 ps versus 394 ps) when measured outside MR and during simultaneous PET/MRI acquisitions, respectively. To evaluate PET image quality and resolution, the NEMA IQ phantom was acquired with MR idle and with MR active. Impact of PET on MR IQ was assessed by comparing SNR with PET acquisition on and off. B0 and B1 homogeneities were acquired before and after the integration of the PET ring inside the magnet. In vivo brain and whole body head-to-thighs data were acquired to demonstrate clinical image quality. PMID- 26978665 TI - Geometrical Calibration of X-Ray Imaging With RGB Cameras for 3D Reconstruction. AB - We present a methodology to recover the geometrical calibration of conventional X ray settings with the help of an ordinary video camera and visible fiducials that are present in the scene. After calibration, equivalent points of interest can be easily identifiable with the help of the epipolar geometry. The same procedure also allows the measurement of real anatomic lengths and angles and obtains accurate 3D locations from image points. Our approach completely eliminates the need for X-ray-opaque reference marks (and necessary supporting frames) which can sometimes be invasive for the patient, occlude the radiographic picture, and end up projected outside the imaging sensor area in oblique protocols. Two possible frameworks are envisioned: a spatially shifting X-ray anode around the patient/object and a moving patient that moves/rotates while the imaging system remains fixed. As a proof of concept, experiences with a device under test (DUT), an anthropomorphic phantom and a real brachytherapy session have been carried out. The results show that it is possible to identify common points with a proper level of accuracy and retrieve three-dimensional locations, lengths and shapes with a millimetric level of precision. The presented approach is simple and compatible with both current and legacy widespread diagnostic X-ray imaging deployments and it can represent a good and inexpensive alternative to other radiological modalities like CT. PMID- 26978667 TI - Techniques and issues in breath and clinical sample headspace analysis for disease diagnosis. AB - Analysis of volatile organic compounds (VOCs) from breath or clinical samples for disease diagnosis is an attractive proposition because it is noninvasive and rapid. There are numerous studies showing its potential, yet there are barriers to its development. Sampling and sample handling is difficult, and when coupled with a variety of analytical instrumentation, the same samples can give different results. Background air and the environment a person has been exposed to can greatly affect the VOCs emitted by the body; however, this is not an easy problem to solve. This review investigates the use of VOCs in disease diagnosis, the analytical techniques employed and the problems associated with sample handling and standardization. It then suggests the barriers to future development. PMID- 26978666 TI - Identification QTLs Controlling Genes for Se Uptake in Lentil Seeds. AB - Lentil (Lens culinaris Medik.) is an excellent source of protein and carbohydrates and is also rich in essential trace elements for the human diet. Selenium (Se) is an essential micronutrient for human health and nutrition, providing protection against several diseases and regulating important biological systems. Dietary intake of 55 MUg of Se per day is recommended for adults, with inadequate Se intake causing significant health problems. The objective of this study was to identify and map quantitative trait loci (QTL) of genes controlling Se accumulation in lentil seeds using a population of 96 recombinant inbred lines (RILs) developed from the cross "PI 320937" * "Eston" grown in three different environments for two years (2012 and 2013). Se concentration in seed varied between 119 and 883 MUg/kg. A linkage map consisting of 1,784 markers (4 SSRs, and 1,780 SNPs) was developed. The map spanned a total length of 4,060.6 cM, consisting of 7 linkage groups (LGs) with an average distance of 2.3 cM between adjacent markers. Four QTL regions and 36 putative QTL markers, with LOD scores ranging from 3.00 to 4.97, distributed across two linkage groups (LG2 and LG5) were associated with seed Se concentration, explaining 6.3-16.9% of the phenotypic variation. PMID- 26978668 TI - Anxiety sensitivity class membership moderates the effects of pre-quit reduction in anxiety sensitivity on quit-day tobacco craving. AB - BACKGROUND: Although anxiety sensitivity has been primarily conceptualized as a dimensional latent construct, empirical evidence suggests that it also maintains a latent class structure, reflecting low-, moderate-, and high-risk underlying classes. The present study sought to explore whether these anxiety sensitivity classes moderated the relations between the degree of pre-quit reductions in anxiety sensitivity and the severity of nicotine withdrawal symptoms and craving experienced on quit-day. METHODS: Participants included 195 adult smokers (47% female; Mage=39.4) participating in a larger "anxiety sensitivity reduction smoking cessation" intervention trial. RESULTS: Anxiety sensitivity class significantly moderated relations between pre-quit reduction in anxiety sensitivity and quit-day craving. Specifically, smokers within the anxiety sensitivity high-risk class, who also demonstrated lesser pre-quit reductions in anxiety sensitivity, experienced the highest levels of craving on quit-day. CONCLUSIONS: These findings highlight the importance of 'high-risk' classes of anxiety sensitivity to better understand the experience of craving on quit day. PMID- 26978669 TI - Chemical constituents from rhizome of Anemone amurensis. AB - Phytochemical investigation of the 70% EtOH extract of the rhizome of Anemone amurensis led to the isolation of two new oleanane-type triterpenoid saponins 1 and 2. Their structures were elucidated on the basis of chemical and spectral analysis, including 1D, 2D NMR data, and HR-ESI-MS. Compounds 1 and 2 were tested for cytotoxicities against two human cancer cell lines (A549 and Hep-G2). Compound 2 showed potent cytotoxicity with IC50 values of 38.53 and 66.17 MUM, respectively, while compound 1 with IC50 > 100 MUM. PMID- 26978681 TI - Transforming growth factor-beta1 SMAD effectors and medial cell number in ascending aorta diseases. AB - In ascending aorta aneurysms and dissections, the extracellular matrix is degraded. Transforming growth factor (TGF)-beta1 modulates its synthesis. The production and presence of SMADs, intracellular effectors of TGF-beta1 signaling, were analyzed in patients with these diseases. To verify whether medial cells are lost, their total numbers were computed. Ascending aorta samples from 19 patients and 18 controls underwent immunoperoxidase reactions to SMADs 2, 3, 4, and 7. Positive and negative cells were counted, and total numbers of cells and positive/total ratios were calculated. Samples from other 14 patients and 7 normal controls were used for the quantification of SMAD3, SMAD4, and SMAD7 mRNA. For SMAD4, both mRNA (2.36 vs. 0.37, P=.03) and ratio of positive cells (0.94 vs. 0.73, P=.02) are increased in patients with ascending aortic diseases. SMAD3 mRNA was also increased (1.19 vs. 0.20, P=.05). The cell ratios of this and the other SMADs, SMAD7 mRNA, and the total cell count did not differ between groups. In conclusion, in ascending aortic aneurysms and dissections, there is an increase in SMAD4, implicated in extracellular matrix production, possibly as an attempt to compensate for extracellular matrix deficiency. Lost medial cells are replaced, since their number is not diminished. PMID- 26978682 TI - Atypical Teratoid Rhabdoid Tumor Diagnosis after Partial Resection of Dysembryoplastic Neuroepithelial Tumor: Case Report and Review of the Literature. AB - Dysembryoplastic neuroepithelial tumors (DNETs) are generally considered benign, slow-growing epilepsy-associated lesions. While rare cases of malignant transformation of DNET to high-grade glial tumors have been reported, to our knowledge there have been no reports of transformation/emergence of DNET to atypical teratoid rhabdoid tumor (AT/RT), a highly aggressive embryonal brain tumor. Here, we report the case of an 8-year-old boy who presented with an incidental finding of a small right insular lesion which grew slowly over 3 years. The patient first underwent surgery with subtotal tumor resection at age 11. Pathology was consistent with DNET. Following surgery, further tumor growth was evident, requiring fractionated radiotherapy and eventually chemotherapy, but continued tumor growth was witnessed. Three years after radiation, imaging showed dramatic further tumor growth, and the patient underwent a second debulking surgery. The pathology revealed a malignant tumor with BAF47-negative cells, suggestive of AT/RT. This report adds to our knowledge about the poorly understood behavior and natural history of DNETs and emphasizes the importance of lifelong clinical and neuroimaging follow-up of these lesions. PMID- 26978684 TI - Direct fascia lata reconstruction to reduce donor site morbidity in endoscopic endonasal extended surgery: a pilot study. AB - OBJECTIVE: Fascia lata is a validated source of autologous grafts, adopted by many surgical figures throughout different types of reconstructive procedures. Postoperative pain and muscle prolapse are frequent complications after harvesting fascia lata; donor site morbidity causes delayed mobilization and increased lenght of hospital stay. In our department fascia lata is used as autologous graft in reconstruction of skull base after extended endoscopic transsphenoidal surgery (EETS) and the thigh defect is usually repaired with allograft to restore tissue continuity and avoid muscle prolapse. Our aim was to evaluate the post-operative pain and muscle prolapse in a group of patients who underwent EETS with fascia lata reconstruction with allograft. METHODS: We retrospectively analyzed clinical data of 11 patients who underwent harvesting and reconstruction of fascia lata during EETS, collected in our department of Neurosurgery between January 2012 and September 2015. "Pain on rest" and "pain on walking" data were collected daily according to the Numerical Rating Scale (NRS) system, during hospital stay until sutures removal and 1 month after surgery. Furthermore, the degree of muscle prolapse was analyzed at the time of sutures removal and 1 month following surgery. RESULTS: 11 patients were studied between January 2012 and September 2015: 4 men and 7 women (1:1.75). Mean age 53.6+/ 11.1years. During the post-operative stay, "pain on rest" and "pain on walking" values of all patients did not exceed grade 4 of NRS. While removing sutures, "pain on rest" resulted grade 1 of NRS in 27.3% (3/11) patients, while "pain on walking" was grade 1 of NRS in 18.2% (2/11) and grade 2 in 9.1% (1/11). After a month of surgery "pain on rest" reduced to NRS grade 1 in 9.1% (1/11), while patients NRS results for "pain on walking" were the same as the previous evaluation. Mean duration of hospital stay was 5.7+/-2.28 days. 10 patients were discharged home, only 1 patient was transferred to a rehabilitation ward. No visible nor palpable muscle prolapse was found in our group of patients during the entire assessment. CONCLUSION: Findings show how fascia lata reconstruction with allograft reduced post-operative discomfort and muscle prolapse in our serie; it also permitted their early mobilization and discharge. These are promising results. However further studies are needed to see this technique approved. PMID- 26978683 TI - Expanding the Oncofertility Workforce: Training Allied Health Professionals to Improve Health Outcomes for Adolescents and Young Adults. AB - As cancer survivors live longer, fertility and reproductive health become important health concerns. Like other secondary effects of cancer treatment, these anticipated health risks should be addressed before the initiation of cancer treatment. While existing and emerging technologies may prevent or reduce risk of infertility (e.g., sperm, oocyte, embryo, or tissue banking), the lack of a trained workforce knowledgeable about oncology and reproductive health poses a barrier to care. The allied health professional (AHP) is a target of opportunity because of the direct and sustained patient relationships. Thus, developing tailored educational programs for nurses, social workers, psychologists, and physician assistants is an urgent unmet need toward field building. In this report, we outline results from a pilot study evaluating AHP perceptions of an oncology and reproductive health curriculum originally developed for nurses and adapted to meet the needs of several other AHP groups. PMID- 26978685 TI - [Not Available]. PMID- 26978686 TI - An Uninformative Truth: The Logic of Amarin's Off-Label Promotion. AB - Spencer Phillips Hey and Aaron Kesselheim propose that informativeness-asserting scientific facts-rather than truthfulness ought to be the standard for regulating commercial speech about pharmaceuticals. PMID- 26978692 TI - [Not Available]. AB - OBJECTIVES: Over the past twenty years, numerous community social pediatrics centres (CSPCs) have been established in Quebec. Because the needs of the children followed are so complex, collaboration with organizations in social services and public and community health networks is paramount. The purpose of this study is to document CSPCs'level of integration into these networks and the issues and challenges involved in such collaborations. METHOD: Telephone surveys were conducted with 75 respondents from public and community networks and with representatives from CSPCs that have been open for at last one year. Two questionnaires were used to document the depth and quality of connections and an open question helped identify certain collaboration-related issues and challenges. RESULTS: CSPCs perceive a higher level of collaboration with the social services and public health network than with the community network. Similarly, CSPCs want to collaborate more with the public network than with the community network. With respect to the quality of collaborations, the climate is more positive and the level of joint coordination is higher between CSPCs and the public network. Although they are similar, the issues related to collaboration can be seen differently in terms of challenges, depending on the stakeholders' network. CONCLUSION: Results are discussed in light of challenges that characterize the collaborations between CSPCs and the networks, which include the recognition of their identity and the funding of the organizations. PMID- 26978693 TI - [Not Available]. AB - OBJECTIVES: Describe the preschool education of children in educational services. Study the effects of components of preschool educational service attendance on the development of kindergarten children, based on income. METHOD: A sample of 1,184 children was extracted from a survey frame that included Montreal children assessed in the 2012 Quebec Survey of Child Development in Kindergarten (2012 QSCDK). Data collected from the parents of these children allowed us to document the following components of educational service attendance (independent variables): longitudinal profile of the service used; age at entry; duration; average weekly attendance; and cumulative time. Linking QSCDK data provided a measure of development of children in kindergarten (dependent variable). Various logistic regression models using different combinations of components of educational service attendance were tested. Akaike information criterion enabled us to select the model that best explains the data. RESULTS: Children from low income families are proportionately fewer to attend a preschool educational service than children from better-off families (79.6% vs. 90.5%; chi-square test (1df), p < 0.001). Children from low-income families who attended only an early childhood centre (centre de la petite enfance) are less likely to be vulnerable in two or more domains of development compared to their peers who did not attend educational services (OR 0.23; CI: 0.06 -0.92). Children who started attending an educational service before the age of 12 months are less likely to be vulnerable in two or more domains of development (OR: 0.38; CI: 0.18-0.81). CONCLUSION: Attending an early childhood centre (centre de la petite enfance) is beneficial to the development of children from low-income families. PMID- 26978694 TI - Quebec Incidence Study on the situations investigated by child protective services: Major findings for 2008 and comparison with 1998. AB - OBJECTIVE: The Quebec Incidence Study on situations investigated by child protective services (QIS) has been conducted in 5-year cycles since 1998 in collaboration with all 16 Quebec child protection agencies. It provides reliable estimates of the incidence and characteristics of investigated children. The aim of this paper is to discuss major findings from the QIS-2008 and to compare them with the findings from QIS-1998. METHODS: Two representative samples of children who were investigated by child protection services during the same three-month time frame in 1998 (N = 4,771) and in 2008 (N = 3,079) were constituted. Caseworkers were asked to complete the QIS data collection form for each sampled child. Annual estimates of the number of children investigated with different characteristics were computed and compared across both cycles. Statistical tests were performed to identify significant differences. RESULTS: While the rate of children investigated increased between 1998 and 2008, the rate of substantiated cases remained stable at 12 and 11 per 1,000 children in the population respectively. Furthermore, substantiated cases in 2008 were less severe than in 1998 along several dimensions, such as co-occurrence, emotional harm and duration. CONCLUSION: Combined with the stability in the rate of substantiated cases, the decline in the severity of the situations seems encouraging but questions the necessity of a CPS intervention for some of these families. These findings are consistent with the ones reported in other countries, but Quebec rates are below the rates estimated for Canada, where substantiated maltreatment almost doubled during the same time frame. Aspects of social policies in Quebec may play a role in this situation and need to be examined in future research. PMID- 26978695 TI - [Not Available]. AB - OBJECTIVES: The Main dans la main initiative relies on collaboration between child protection and hospital-based social workers to help substance-abusing expectant mothers maximize their chances of caring for their newborn. The article describes the positive outcomes of this initiative for the women, based on the experiences and perception of the participants and social workers involved. METHOD: A case study was conducted with 21 participants using three data sources: 1) a semi-structured interview with the mothers at two points in time; 2) a semi structured interview with social workers; and 3) the tools of the initiative. The data were analyzed based on content condensation and data presentation. RESULTS: A majority of participants experienced changes in their various spheres of life: personal (positive changes in substance-abuse habits), parental (improved self confidence as a parent, reduced stress due to the fear of losing custody of their newborn), and social/relational (improved relationships with social support network and support services). CONCLUSION: The results confirm the relevance and potential for change of a short intervention model during the perinatal period based on inter-professional collaboration with substance-abusing expectant mothers. Further research is needed to validate the hypothesis on the effectiveness of this initiative. PMID- 26978696 TI - [Not Available]. AB - OBJECTIVES: The objectives of this study were to 1) map the geographic distribution of rates of children reported to Montreal child protective services by ethnocultural group (Black, other visible minorities, not from visible minorities) and 2) estimate the relative contribution of different territorial characteristics to the rates for those groups. METHOD: The study covered the 505 Montreal-area census tracts for which complete data were available. The reporting rates by group (dependent variables) and various territorial characteristics such as poverty (independent variables) were mapped and subjected to multiple linear regression and geographically weighted regression. The results of the geographically weighted regression were then mapped. RESULTS: The geographic distribution and reporting rates varied greatly by group, with the Black children having the highest rates. Although territorial characteristics explained 51% of variance for the children who were not members of visible minorities, they were clearly less effective in predicting rates in the case of Black children (18%) and other minorities (18%). CONCLUSION: Already well-known territorial risk factors are at work in Montreal, but their influence is not equally strong in all census tracts nor, especially, in all ethnocultural groups. Therefore, when only the distribution and prediction of reports for all children as a whole are examined, important differences are underestimated. Access to and appropriateness of services offered to vulnerable families, including those of visible minorities, could, however, be improved with a better understanding of local dynamics. PMID- 26978697 TI - Review of child maltreatment in immigrant and refugee families. AB - OBJECTIVES: Study results on child maltreatment based on general population samples cannot be extrapolated with confidence to vulnerable immigrant or refugee families because of the specific characteristics and needs of these families. The aims of this paper are 1) to conduct an evidence review of the prevalence, risk factors and protective factors for child maltreatment in immigrant and refugee populations, and 2) to integrate the evidence in an analytical ecosystemic framework that would guide future research. METHODS: We used a 14-step process based on guidelines from Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Canadian Collaboration for Immigrant and Refugee Health. We searched major databases from "the oldest date available to July 2014". The eligibility criteria for paper selection included qualitative or quantitative methodologies; papers written in English or French; papers that describe, assess or review prevalence, risk and protection factors for child maltreatment; and a studied population of immigrants or refugees. SYNTHESIS: Twenty-four articles met the criteria for eligibility. The results do not provide evidence that immigrant or refugee children are at higher risk of child maltreatment. However, recently settled immigrants and refugees experience specific risk factors related to their immigration status and to the challenges of settlement in a new country, which may result in high risk of maltreatment. CONCLUSION: Future research must incorporate more immigrant and refugee samples as well as examine, within an ecosystemic framework, the interaction between migratory and cultural factors with regard to the prevalence, consequences and treatment of child maltreatment for the targeted groups. PMID- 26978698 TI - Prevalence, co-occurrence and decennial trends of family violence toward children in the general population. AB - OBJECTIVES: In Quebec, three population-based surveys have documented the prevalence of psychological aggression, and minor and severe physical violence toward children. This paper aims to present 1) the results of the 2012 survey with regard to the frequency and annual prevalence of violence, and 2) the trends in all three forms of violence between 1999 and 2012 according to children's age. METHODS: The three independent surveys were all conducted through telephone interviews in 1999, 2004 and 2012 by the Institut de la Statistique du Quebec and reached a total sample of 9,646 children living with a mother figure. Psychological aggression, and minor and severe physical violence were measured using the Parent Child Conflict Tactics Scales. RESULTS: The results show that repeated psychological aggression, after having increased between 1999 (48%) and 2004 (53%), slightly decreased in 2012 (49%). Minor physical violence decreased steadily between 1999 and 2012, from 48% to 35%, and severe physical violence remained stable (6%). These three forms of violence varied by the age category of the children. Finally, the results show that the co-occurrence of the use of physical and psychological violence remained high in all three surveys. CONCLUSION: The results are consistent with trends in North America and are discussed in terms of services to support families. PMID- 26978700 TI - Twenty years of research and action for the well-being of children. PMID- 26978699 TI - [Not Available]. AB - OBJECTIVES: MAP (mothers with power) is a program that proposes a comprehensive approach to promote social and professional integration of low income single mothers with children under six years old. Using the results of a qualitative evaluation of the program 's outcomes and the contextual factors that produced them, this article aims to identify the aspects of the program that are the most promising for practise. METHOD: To assess the program's outcomes, the study uses two monitoring tools and an information sheet on each participant. An in-depth analysis of the connections between the program's outcomes and the contextual factors that produced them is conducted using 16 case studies, a case being defined as the integration path of each participant during the participation in the program. For each case, four data sources were used: in addition to the monitoring tools, semi-structured interviews were conducted with the participants and the case workers at two points in time. RESULTS: Data show positive outcomes of this program. After three years, a majority of participants went back to school, finished high school, started collegial studies or found a job. These outcomes resulted from a set of factors: structuring actions on the life environment, support from an intervention team working closely with the participants and personalized references to programs and services in the community. CONCLUSION: The results support the relevance of an integrated and comprehensive approach to the social and professional integration of low-income single mothers. PMID- 26978703 TI - The Red Light District and Its Effects on Zebrafish Reproduction. AB - Light-dark cycles mimicking natural settings in a zebrafish facility are crucial for maintaining fish with an entrained circadian clock making them an ideal vertebrate model to study such rhythms. However, failure to provide optimal conditions to include complete darkness can lead to a disturbed circadian pacemaker affecting physiology and behavior in zebrafish. To meet building code requirements, the aquatics facility in use was outfitted with EXIT signs emitting a constant light. To determine if light radiating from the EXIT sign has an effect on zebrafish embryo production, 100 fish (1:1 m/f ratio) were split and housed at 10 fish/L. Half were housed directly in front of the EXIT sign, whereas the other half (control) were housed under a true 14-h light-10-h dark cycle. Reproductive success was evaluated by recording fecundity and viability from 10 weekly matings under two light colors: red (640 nm) and green (560 nm). On average the control group spawned twice as many embryos compared to those housed in front of a red EXIT sign, whereas green EXIT sign showed no difference. This suggests the importance of providing a complete dark environment within the night cycle and a recommendation toward dim green EXIT signs to avoid a decline in reproductive performance. PMID- 26978706 TI - Exertional Angina Due To Fused Aortic Bioprosthesis During Left Ventricular Assist Device Support: Two Cases and Review of the Literature. AB - We present the case of two patients with idiopathic dilated cardiomyopathy and moderate aortic valve regurgitation that were treated with a bioprosthetic valve at the time of the left ventricular assist device (LVAD) implantation. A few months later, patients revealed partial recovery in the left ventricle systolic function. Both patients, during the LVAD turndown protocol, reported the onset of chest pain. The transthoracic echocardiography revealed the presence of a new transaortic pressure gradient. We confirmed the presence of a fused bioprosthetic valve by further performing a transesophageal echocardiogram and a left and right heart catheterization. Replacement of aortic valve at the time of an LVAD implantation constitutes a challenging case. Although a mechanical valve is contraindicated due to the increased thromboembolic risk, selecting a bioprosthetic valve increases the risk of valve leaflets fusion. The consequences of this phenomenon should be acknowledged in LVAD patients undergoing aortic valve replacement with a bioprosthetic, especially under the view of LVAD explantation for those revealing myocardial recovery under mechanical unloading. PMID- 26978705 TI - Organochlorine pesticides (OCPs) in the Indus River catchment area, Pakistan: Status, soil-air exchange and black carbon mediated distribution. AB - Organochlorine pesticides (OCPs) were investigated in passive air and soil samples from the catchment area of the Indus River, Pakistan. ?15OCPs ranged between 0.68 and 13.47 ng g(-1) in soil and 375.1-1975 pg m-(3) in air. HCHs and DDTs were more prevalent in soil and air compartments. Composition profile indicated that beta-HCH and p,p'-DDE were the dominant of all metabolites among HCHs and DDTs respectively. Moreover, fBC and fTOC were assessed and evaluated their potential role in the distribution status of OCPs. The fTOC and fBC ranged between 0.77 and 2.43 and 0.04-0.30% respectively in soil. Regression analysis showed the strong influence of fBC than fTOC on the distribution of OCPs in the Indus River catchment area soil. Equilibrium status was observed for beta-HCH, delta-HCH, p,p'-DDD, o,p'-DDT, TC, HCB and Heptachlor with ff ranged between 0.3 and 0.59 while assessing the soil-air exchange of OCPs. PMID- 26978704 TI - Widely used pharmaceuticals present in the environment revealed as in vitro antagonists for human estrogen and androgen receptors. AB - A considerable amount of scientific evidence indicates that a number of pharmaceuticals that could be detected in the environment can contribute towards the development of problems associated with human reproductive systems, as well as those of wildlife. We investigated the estrogenic and androgenic effects of select pharmaceuticals with high production volume and environmental relevance. We examined the receptor-binding activities of these pharmaceuticals in the T47D human cell line using altered secretion of cytokine CXCL12. Functional yeast luciferase reporter gene assays were also employed to confirm the mechanism of receptor binding by estrogen and androgen. Non-steroidal anti-inflammatory drugs, namely ibuprofen, diclofenac and antiarrhythmic agent amiodarone showed strong anti-estrogenic effects in the T47D cell line. In the yeast-luciferase assay, these anti-inflammatory drugs also demonstrated anti-estrogenic potency and inhibited the E2 response in a concentration-dependent manner. Amiodarone did not exhibit any response in the yeast-luciferase assay; therefore, the endocrine disruption presumably occurred at a different level without directly involving the receptor. All the anti-inflammatory drugs considered in this study, including ketoprofen, naproxen and clofibrate, exhibited a dose-dependent antagonism towards the androgen receptor in the yeast-luciferase assays. Several other drugs, including the stimulant caffeine, did not show any response in the tests that were employed. A risk assessment analysis using 'Hazard Quotient' suggested a potential risk, especially in the cases of ibuprofen, ketoprofen, diclofenac and clofibrate. The results reveal the intrinsic endocrine disrupting nature of several pharmaceuticals and thus could contribute towards explaining a number of adverse health effects on humans and wildlife. PMID- 26978707 TI - Full-Support LVAD Implantation in a C-Pulse Heart Assist System Recipient with Deteriorating Chronic Heart Failure: Is It Feasible and Safe? AB - Heart failure is a progressive disease with limited treatment options. The C Pulse Heart Assist System (Eden Prairie, MN) is an extravascular, diastolic counterpulsation circulatory support device for patients with refractory NHYA Class III/ambulatory class IV heart failure. It comprises a balloon-cuff which is implanted around the ascending aorta that is synchronised to inflate during ventricular diastole. The system eliminates the need for systemic anticoagulation and significantly reduces the risk of bleeding and overcomes the problem of device thrombosis. However, clinical efficacy is dependent on maintenance of residual myocardial function. We describe a case of a patient who presented with ischemic cardiomyopathy in end-stage heart failure and received the C-Pulse System. Due to deterioration in cardiac function, the system had to be upgraded to a full-support left ventricular assist device (LVAD) after 4 months. However, the aorta ascendens was short and the outflow graft of the HeartWare LVAD had to be anastomosed to the cuff balloon region of the aorta. Our experience showed in this case that the inflatable cuff action did not compromise the structural integrity of the aortic wall. PMID- 26978708 TI - Duration of ECMO Is an Independent Predictor of Intracranial Hemorrhage Occurring During ECMO Support. AB - We assessed the incidence and predictors of intracranial hemorrhage (ICH) occurring during extracorporeal membrane oxygenation (ECMO) support. Of 154 patients who received ECMO, 12 (7.8%) developed ICH. Patients with ICH had a longer ECMO duration (9.41 vs. 5.37 days, p = 0.007), and higher activated clotting time (activated clotting time, p= 0.016). They also experienced higher frequency of bleeding at other sites (p = 0.017) and required more platelet transfusion (p = 0.016). Multivariate analysis showed that a longer ECMO duration (odds ratio [OR] = 1.074, 95% confidence interval [CI] = 1.005-1.148, p = 0.035) is independently associated with the risk of ICH. We recommend routine neurological checks, monitoring of coagulation parameters, and attempt earlier rather than late weaning from ECMO whenever feasible. PMID- 26978709 TI - Noncardiac Surgical Procedures After Left Ventricular Assist Device Implantation. AB - As left ventricular assist devices (LVADs) are increasingly used for patients with end-stage heart failure, the need for noncardiac surgical procedures (NCSs) in these patients will continue to rise. We examined the various types of NCS required and its outcomes in LVAD patients requiring NCS. The National Inpatient Sample Database was examined for all patients implanted with an LVAD from 2007 to 2010. Patients requiring NCS after LVAD implantation were compared to all other patients receiving an LVAD. There were 1,397 patients undergoing LVAD implantation. Of these, 298 (21.3%) required 459 NCS after LVAD implantation. There were 153 (33.3%) general surgery procedures, with abdominal/bowel procedures (n = 76, 16.6%) being most common. Thoracic (n = 141, 30.7%) and vascular (n = 140, 30.5%) procedures were also common. Patients requiring NCS developed more wound infections (9.1 vs. 4.6%, p = 0.004), greater bleeding complications (44.0 vs. 24.8%, p < 0.001) and were more likely to develop any complication (87.2 vs. 82.0%, p = 0.001). On multivariate analysis, the requirement of NCSs (odds ratio: 1.45, 95% confidence interval: 0.95-2.20, p = 0.08) was not associated with mortality. Noncardiac surgical procedures are commonly required after LVAD implantation, and the incidence of complications after NCS is high. This suggests that patients undergoing even low-risk NCS should be cared at centers with treating surgeons and LVAD specialists. PMID- 26978710 TI - First Implantation of Silicon Nanopore Membrane Hemofilters. AB - An implantable hemofilter for the treatment of kidney failure depends critically on the transport characteristics of the membrane and the biocompatibility of the membrane, cartridge, and blood conduits. A novel membrane with slit-shaped pores optimizes the trade-off between permeability and selectivity, enabling implanted therapy. Sustained (3-8) day function of an implanted parallel-plate hemofilter with minimal anticoagulation was achieved by considering biocompatibility at the subnanometer scale of chemical interactions and the millimeter scale of blood fluid dynamics. A total of 400 nm-thick polysilicon flat sheet membranes with 5-8 nm * 2 micron slit-shaped pores were surface-modified with polyethylene glycol. Hemofilter cartridge geometries were refined based on computational fluid dynamics models of blood flow. In an uncontrolled pilot study, silicon filters were implanted in six class A dogs. Cartridges were connected to the cardiovascular system by anastamoses to the aorta and inferior vena cava and filtrate was drained to collection pouches positioned in the peritoneum. Pain medicine and acetylsalicylic acid were administered twice daily until the hemofilters were harvested on postoperative days 3 (n = 2), 4 (n = 2), 5 (n = 1), and 8 (n = 1). No hemofilters were thrombosed. Animals treated for 5 and 8 days had microscopic fractures in the silicon nanopore membranes and 20-50 ml of transudative (albumin sieving coefficient thetaalb ~ 0.5 - 0.7) fluid in the collection pouches at the time of explant. Shorter experimental durations (3-4 days) resulted in filtration volumes similar to predictions based on mean arterial pressures and membrane hydraulic permeability and (thetaalb ~ 0.2 - 0.3), similar to preimplantation measurements. In conclusion, a detailed mechanistic and materials science attention to blood-material interactions allows implanted hemofilters to resist thrombosis. Additional testing is needed to determine optimal membrane characteristics and identify limiting factors in long term implantation. PMID- 26978712 TI - Erratum: "Development of a Gravid Uterus Model for the Study of Road Accidents Involving Pregnant Women" [ASME J. Biomech. Eng., 2016, 138(1), p. 011009]. PMID- 26978711 TI - OSWG Recommendations for Genotoxicity Testing of Novel Oligonucleotide-Based Therapeutics. AB - The Oligonucleotide Safety Working Group subcommittee on genotoxicity testing considers therapeutic oligonucleotides (ONs) unlikely to be genotoxic based on their properties and on the negative results for ONs tested to date. Nonetheless, the subcommittee believes that genotoxicity testing of new ONs is warranted because modified monomers could be liberated from a metabolized ON and incorporated into DNA and could hypothetically cause chain termination, miscoding, and/or faulty replication or repair. The standard test battery as described in Option 1 of International Conference on Harmonisation S2(R1) is generally adequate to assess such potential. However, for the in vitro assay for gene mutations, mammalian cells are considered more relevant than bacteria for most ONs due to their known responsiveness to nucleosides and their greater potential for ON uptake; on the other hand, bacterial assays may be more appropriate for ONs containing non-ON components. Testing is not recommended for ONs with only naturally occurring chemistries or for ONs with chemistries for which there is documented lack of genotoxicity in systems with demonstrated cellular uptake. Testing is recommended for ONs that contain non-natural chemical modifications and use of the complete drug product (including linkers, conjugates, and liposomes) is suggested to provide the most clinically relevant assessment. Documentation of uptake into cells comparable to those used for genotoxicity testing is proposed because intracellular exposure cannot be assumed for these large molecules. ONs could also hypothetically cause mutations through triple helix formation with genomic DNA and no tests are available for detection of such sequence-specific mutations across the entire genome. However, because the potential for triplex formation by therapeutic ONs is extremely low, this potential can be assessed adequately by sequence analysis. PMID- 26978714 TI - Long-term follow-up after LeFort colpocleisis: patient satisfaction, regret rate, and pelvic symptoms. AB - OBJECTIVE: The aim of the study was to evaluate long-term patient satisfaction, regret rate, and pelvic symptoms in older women who underwent LeFort colpocleisis. METHODS: A retrospective cohort study of women who underwent LeFort colpocleisis at least 3 years before was conducted. Records were reviewed for participant characteristics, comorbid conditions, and complications. The Patient Global Impression of Change (PGI-C) questionnaire and the Chinese version of the Pelvic Floor Distress Inventory-short form 20 (PFDI-20) were used to evaluate self-perceived quality of life. Regret was assessed by one additional question: "Do you regret choosing to have vaginal closure surgery for prolapse (Yes/No)?" RESULTS: LeFort colpocleisis accounted for 7.3% (42/572) of all the prolapse surgeries. Thirty-five of the women (83.3%) who responded were considered for statistical evaluation. Twenty-nine (82.9%) had at least one comorbid condition. After a median 5-year (range 3-7) follow-up period, no woman had experienced prolapse recurrence requiring a second surgery. No woman regretted having had the surgery. The satisfaction rate was 94.3%, with postoperative overactive bladder syndrome accounting for one "neither satisfied nor dissatisfied" woman and vaginal hematoma for another. Pelvic symptoms improved significantly from baseline (PFDI-20, preoperative 60.5 +/- 29.5) to postoperative (14.1 +/- 20.0, P < 0.001). CONCLUSIONS: After long-term follow-up, LeFort colpocleisis still had a high satisfaction rate, a low regret rate, and a positive impact on pelvic symptoms. PMID- 26978715 TI - Physical activity and healthy aging. PMID- 26978716 TI - Coagulation and oxidation for controlling ultrafiltration membrane fouling in drinking water treatment: Application of ozone at low dose in submerged membrane tank. AB - Coagulation prior to ultrafiltration (UF) is widely applied for treating contaminated surface water sources for potable supply. While beneficial, coagulation alone is unable to control membrane fouling effectively in many cases, and there is continuing interest in the use of additional, complementary methods such as oxidation in the pre-treatment of raw water prior to UF. In this study, the application of ozone at low dose in the membrane tank immediately following coagulation has been evaluated at laboratory-scale employing model raw water. In parallel tests with and without the application of ozone, the impact of applied ozone doses of 0.5 mg L(-1) and 1.5 mg L(-1) (approximately 0.18 mg L(-1) and 0.54 mg L(-1) consumed ozone, respectively) on the increase of trans-membrane pressure (TMP) was evaluated and correlated with the quantity and nature of membrane deposits, both as a cake layer and within membrane pores. The results showed that a dose of 0.5 mgO3 L(-1) gave a membrane fouling rate that was substantially lower than without ozone addition, while a dose of 1.5 mgO3 L(-1) was able to prevent fouling effects significantly (no increase in TMP). Ozone was found to decrease the concentration of bacteria (especially the concentration of bacteria per suspended solid) in the membrane tank, and to alter the nature of dissolved organic matter by increasing the proportion of hydrophilic substances. Ozone decreased the concentration of extracellular polymeric substances (EPS), such as polysaccharides and proteins, in the membrane cake layer; the reduced EPS and bacterial concentrations resulted in a much thinner cake layer, although the suspended solids concentration was much higher in the ozone added membrane tank. Ozone also decreased the accumulation and hydrophobicity of organic matter within the membrane pores, leading to minimal irreversible fouling. Therefore, the application of low-dose ozone within the UF membrane tank is a potentially important approach for fully mitigating membrane fouling. PMID- 26978717 TI - Persistence of naturally occurring antibiotic resistance genes in the bacteria and bacteriophage fractions of wastewater. AB - The emergence and prevalence of antibiotic resistance genes (ARGs) in the environment is a serious global health concern. ARGs from bacteria can be mobilized by mobile genetic elements, and recent studies indicate that phages and phage-derived particles, among others, could play a role in the spread of ARGs through the environment. ARGs are abundant in the bacterial and bacteriophage fractions of water bodies and for successful transfer of the ARGs, their persistence in these environments is crucial. In this study, three ARGs (blaTEM, blaCTX-M and sul1) that naturally occur in the bacterial and phage fractions of raw wastewater were used to evaluate the persistence of ARGs at different temperatures (4 degrees C, 22 degrees C and 37 degrees C) and pH values (3, 7 and 9), as well as after various disinfection treatments (thermal treatment, chlorination and UV) and natural inactivation in a mesocosm. Gene copies (GC) were quantified by qPCR; then the logarithmic reduction and significance of the differences between their numbers were evaluated. The ARGs persisted for a long time with minimal reductions after all the treatments. In general, they showed greater persistence in the bacteriophage fraction than in the bacterial fraction. Comparisons showed that the ARGs persisted under conditions that reduced culturable Escherichia coli and infectious coliphages below the limit of detection. The prevalence of ARGs, particularly in the bacteriophage fraction, poses the threat of the spread of ARGs and their incorporation into a new bacterial background that could lead to the emergence of new resistant clones. PMID- 26978718 TI - Enantiomeric fractionation as a tool for quantitative assessment of biodegradation: The case of metoprolol. AB - An efficient chiral liquid chromatography high resolution mass spectrometry method has been developed for the determination of metoprolol (MTP) and three of its major metabolites, namely O-desmethylmetoprolol (O-DMTP), alpha hydroxymetoprolol (alpha-HMTP) and metoprolol acid (MTPA) in wastewater treatment plant (WWTP) influents and effluents. The optimized analytical method has been validated with good quality parameters including resolution >1.3 and method quantification limits down to the ng/L range except for MTPA. On the basis of this newly developed analytical method, the stereochemistry of MTP and its metabolites was studied over time in effluent/sediment biotic and sterile microcosms under dark and light conditions and in influents and effluents of 5 different WWTPs. MTP stereoselective degradation was exclusively observed under biotic conditions, confirming the specificity of enantiomeric fraction variations to biodegradation processes. MTP was always biotransformed into MTPA with a (S) enantiomer enrichment. The results of enantiomeric enrichment pointed the way for a quantitative assessment of in situ biodegradation processes due to a good fit (R(2) > 0.98) of the aerobic MTP biodegradation to the Rayleigh dependency in all the biotic microcosms and in WWTPs because both MTP enantiomers followed the same biodegradation kinetic profiles. These results demonstrate that enantiomeric fractionation constitutes a very interesting quantitative indicator of MTP biodegradation in WWTPs and probably in the environment. PMID- 26978719 TI - Understanding congested travel in urban areas. AB - Rapid urbanization and increasing demand for transportation burdens urban road infrastructures. The interplay of number of vehicles and available road capacity on their routes determines the level of congestion. Although approaches to modify demand and capacity exist, the possible limits of congestion alleviation by only modifying route choices have not been systematically studied. Here we couple the road networks of five diverse cities with the travel demand profiles in the morning peak hour obtained from billions of mobile phone traces to comprehensively analyse urban traffic. We present that a dimensionless ratio of the road supply to the travel demand explains the percentage of time lost in congestion. Finally, we examine congestion relief under a centralized routing scheme with varying levels of awareness of social good and quantify the benefits to show that moderate levels are enough to achieve significant collective travel time savings. PMID- 26978720 TI - Photophysics and Electrochemiluminescence of Bright Cyclometalated Ir(III) Complexes in Aqueous Solutions. AB - A family of neutral bis-cyclometalated iridium complexes [Ir(C^N)2(LX)] has been investigated as ECL labels under immunoassay conditions. Among them, the complex based on phenylphenanthridine (pphent) as the C^N ligand, exhibits outstanding performance and it is a candidate to substitute the commercially available Ru based label in diagnostics. PMID- 26978721 TI - Attachment representations among substance-abusing women in transition to motherhood: implications for prenatal emotions and mother-infant interaction. AB - We studied how attachment representations contribute to central components of transition to motherhood, prenatal emotion processing (EP) and emotional availability (EA) of mother-infant interaction, and whether there are group specific differences. Participants were 51 treatment-enrolled substance-abusing (SA) mothers and their infants and 50 non-using comparison dyads with obstetric risk. Mother's attachment representations (AAI) and EP were assessed prenatally and EA when infants were four months. Results showed that autonomous attachment only had a buffering effect on prenatal EP among comparisons. All SA mothers showed more dysfunctional EP than comparisons and, contrary to comparisons, autonomous SA mothers reported more negative cognitive appraisals and less meta evaluation of emotions than dismissing SA mothers. Preoccupied SA mothers showed high negative cognitive appraisals, suggesting under-regulation of emotions. Attachment representations were not associated with EA in either group; rather, SA status contributed to global risk in the relationship. Surprisingly, autonomous SA mothers showed a tendency towards intrusiveness. We propose that obstetric risk among comparisons and adverse relational experiences among almost all SA mothers might override the protective role of mother's autonomous representations for dyadic interaction. We conclude that prenatal emotional turbulence and high interaction risk of all SA mothers calls for holistic treatment for the dyad. PMID- 26978723 TI - Thiopurine Metabolism in the Era of Combotherapy. AB - 6-thioguanine nucleotides levels are associated with clinical remission in patients with inflammatory bowel disease (IBD) on thiopurine monotherapy. Recently, few studies investigated the interaction between thiopurine metabolism and anti-tumor necrosis factor therapy among patients with IBD on combotherapy. Two studies demonstrated that infliximab therapy increases 6-thioguanine nucleotides level, while such effect could not be observed with adalimumab. Three studies showed that a Delta mean corpuscular volume >7 and high 6-thioguanine nucleotides levels are associated with favorable outcomes, i.e., greater mucosal healing rates, and have a positive impact on the pharmacokinetics of infliximab. These results suggest a synergistic effect between thiopurine metabolism and anti tumor necrosis factor therapy, especially with infliximab. We propose here some algorithms for clinical practice integrating thiopurine metabolism in patients with IBD on combotherapy. Further randomized controlled trials are needed to further investigate the relationships between thiopurine metabolism and anti tumor necrosis factor therapy and to establish the clinical utility of measuring thiopurines' metabolites in these patients in clinical practice. Whether measuring thiopurine metabolism can be used to guide decision-making in patients with IBD on combotherapy when considering drug de-escalation or discontinuation will require further investigation. PMID- 26978722 TI - Clinical Factors Associated with the Development of Crohn's Disease in Inflammatory Bowel Disease-unclassified Patients Undergoing Ileal Pouch-anal Anastomosis. AB - BACKGROUND: Patients with inflammatory bowel disease-unclassified (IBDU) undergoing ileal pouch-anal anastomosis (IPAA) are at the risk of developing Crohn's disease (CD) after surgical procedure. In these patients, a clinically centered set of preoperative risk factors has not been prospectively defined. We report a single-center analysis of clinical factors associated with the development of CD after IPAA. METHODS: Consecutive IBDU patients undergoing IPAA were identified. The diagnosis of IBDU was based on the presence of atypical disease distribution, presence of granulomas on endoscopic biopsy, and/or perianal disease. The diagnosis of CD after IPAA included the presence of afferent limb inflammation on pouchoscopy in the absence of nonsteroidal anti inflammatory drug use and/or the development of pouch fistulizing disease more than 3 months after ileostomy closure. RESULTS: Of the 149 study patients, 33 (22%) were diagnosed with CD after IPAA at a median of 37 months (interquartile range, 11-83 mo) after ileostomy closure. CD was diagnosed by mucosal inflammation above the pouch (n = 23; 70%), pouch fistulizing disease (n = 4; 12%), anorectal septic complications (n = 2; 6%), or the presence of >=2 of the above complications (n = 4; 12%). The sole clinical predictor for the development of CD after IPAA was younger age at disease onset even after controlling for relevant clinical factors in a multivariate analysis. The odds of developing CD increased by 4% for each year that IBDU was diagnosed at a younger age. CONCLUSIONS: Younger age at disease onset is the only clinical factor associated with the development of CD after IPAA for IBDU. Patients with IBDU undergoing IPAA with young age at disease onset should be counseled about the potentially higher risk of developing CD. PMID- 26978724 TI - Performance of Common Disease Activity Markers as a Reflection of Inflammatory Burden in Ulcerative Colitis. AB - BACKGROUND: The inflammatory burden influences therapeutic decisions in patients with ulcerative colitis (UC). We aimed to study which commonly used markers of disease activity correlate best with inflammatory burden in patients with UC using leukocyte scintigraphy (single-photon emission computed tomography [SPECT CT]) as the gold standard. METHODS: Patients with different severity of UC underwent colonoscopy with biopsies and leukocyte SPECT-CT scintigraphy. Serum C reactive protein (CRP), fecal calprotectin, and clinical questionnaires were collected. The maximum uptake of technetium-labeled leukocytes was calculated as a SPECT score for each colon segment and a summed activity score for 5 colonic segments combined. RESULTS: Thirty patients with UC were included; 14 of 30 (47%) had left-sided colitis, and 16 of 30 (53%) had pancolitis. One patient (3%) had inactive UC, 5 of 30 (17%) had mild, 11 of 30 (37%) had moderate, and 13 of 30 (43%) had severe disease activity based on the endoscopic Mayo score. The endoscopic Mayo score correlated better with the SPECT score than with the ulcerative colitis endoscopic index of severity (UCEIS) (r = 0.50; P < 0.01 and r = 0.32; P = 0.08, respectively). The Geboes UC histologic score correlated equally well as the Mayo score (r = 0.50; P < 0.01). We found a significant correlation between scintigraphy and fecal calprotectin (r = 0.44; P = 0.02) but not with serum CRP (r = 0.25; P = 0.18). Fecal calprotectin reflected inflammatory burden significantly better in left-sided colitis (r = 0.80; P = 0.001) than in pancolitis (r = 0.22; P = 0.41). CONCLUSIONS: The inflammatory burden in patients with UC, measured by SPECT-CT, is better reflected by the endoscopic Mayo score and the Geboes histologic score than by the UCEIS. Fecal calprotectin is a more accurate inflammatory marker than CRP, predominantly in patients with left-sided colitis. REGISTRATION: This study was approved by the Ethics Committee Review at October 22, 2012 and, in accordance with Dutch legislation, prospectively registered at the CCMO (Dutch central commission for human research) https://www.toetsingonline.nl with NL39801.018.12. PMID- 26978726 TI - Can Radiologic Evaluation Before Capsule Endoscopy Predict Capsule Retention? PMID- 26978725 TI - Medication Utilization and the Impact of Continued Corticosteroid Use on Patient reported Outcomes in Older Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Older individuals with inflammatory bowel disease (IBD) require ongoing medications. We aimed to describe (1) medication use in older and younger IBD patients and (2) medication associations with patient reported outcomes (PROs) in older patients. METHODS: We conducted cross-sectional and longitudinal analyses within CCFA Partners internet-based cohort of patients with self reported IBD. We assessed medication use by disease sub-type and age. We used bivariate analyses to (1) compare medication use in older and younger patients and (2) determine associations between continued steroid use and patient reported outcomes in older patients. RESULTS: We included 5382 participants with IBD; 1004 were older (>=age 60). Older patients with Crohn's disease (CD) had lower antitumor necrosis factor alpha (anti-TNF) use at baseline (29.1% versus 44.3%, P < 0.001), comparable steroid use (16.0% versus 16.5%, P = 0.77), and higher aminosalicylate use (40.3% versus 33.9%, P = 0.003) versus younger patients. Older ulcerative colitis (UC) patients had similar anti-TNF use (16.0% versus 19.2%, P = 0.16), lower steroid use (9.6% versus 15.4%, P = 0.004), and higher aminosalicylate use (73.8% versus 68.2%, P = 0.04) at baseline. In longitudinal analyses, older CD patients had higher continued steroid use (11.6% versus 7.8%, P = 0.002); which was associated with worsened anxiety (P = 0.02), sleep (P = 0.01), and fatigue (P = 0.001) versus nonuse. Older CD patients on steroids, versus anti-TNF or immunomodulators, had increased depression (P = 0.04) and anxiety (P = 0.03). CONCLUSIONS: Medication utilization differs in older patients with IBD. Older CD patients have higher continued steroid use associated with worsened patient reported outcomes. As in younger IBD populations, continued steroid use should be limited in older patients. PMID- 26978727 TI - The Possible Link Between Artificial Sweeteners Such as Saccharin and Sucralose and Inflammatory Bowel Disease Deserves Further Study. PMID- 26978728 TI - Reply to: Can Radiologic Evaluation Before Capsule Endoscopy Predict Capsule Retention? PMID- 26978729 TI - Is Colonic Crohn's Disease More Closely Related to Ulcerative Colitis or Crohn's Disease by Nature? PMID- 26978732 TI - A laboratory investigation into the influence of a rigid vegetation on the evolution of a round turbulent jet discharged within a cross flow. AB - The study of buoyant jets, those between pure jets and plumes, has been carried out with ever greater frequency over recent years due to its application in different practical engineering fields, i.e. appropriate design of outfalls for the disposal of municipal and industrial waste waters. The dispersion of waste and the related dilution of pollutants are governed by the mean-flow and turbulence characteristics of the resulting jets, which themselves depend on environmental conditions. The present study deals with how a uniform cross-stream with a channel bed surface covered by rigid emergent stems affects the behaviour of a circular turbulent buoyant jet. The time-averaged temperature and velocity fields are investigated in order to understand jet diffusion and penetration within the ambient fluid. The examination and comparison of the measured scalar and vector quantities show that the presence of emergent vegetation in the receiving environment affects both the average flow field and the jet structure, reducing the mean channel velocity, with a notable increase in jet penetration height and dilution compared to the test case without vegetation. This result is confirmed by the several vertical profiles of the mean scalar concentration and the normalized vertical velocity component along the channel centre plane. Moreover, the rigid emergent vegetation and its driven instabilities promote a distortion of the mean concentration and normalized axial velocity component profiles in the trajectory-based coordinate system. PMID- 26978730 TI - Sleep Duration and Media Time Have a Major Impact on Insulin Resistance and Metabolic Risk Factors in Obese Children and Adolescents. AB - BACKGROUND: Lifestyle factors sleep duration and media time during childhood differ between countries. This study examined whether sleep duration and media time affect metabolic risk factors insulin resistance (IR), blood lipid profile, and liver enzymes, and whether there is a relationship between sleep time and media time in Turkish obese children and adolescents. METHODS: Subjects included 108 obese children and adolescents (aged 10-15 years) whose lifestyle factors were assessed using a survey containing questions about sleep durations, television viewing, media use, and demographic factors. Metabolic risk factors were compared among groups categorized according to sleep and media duration. RESULTS: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and triglyceride (TG) levels and homeostasis model assessment of insulin resistance (HOMA-IR) values were higher in subjects who spent >5 hours/day on media. Children 10-13 years old who slept <9 hours/day were more likely to have higher insulin and HOMA-IR (p < 0.05) levels and lower high-density lipoprotein cholesterol (HDL-C) levels compared with subjects who slept 9-10 hours/day and >10 hours/day. Correlation analysis revealed a negative relationship between sleep time and media time (r = -0.471, p = 0.000). CONCLUSIONS: Short sleep duration was associated with IR and an elevated plasma lipoprotein profile in children and adolescents. Our results suggest that insufficient sleep and excessive media exposure may contribute to metabolic risk in the context of obesity, and therefore, working to improve sleep duration and limit media time could help reduce metabolic risk in obese children and adolescents. PMID- 26978731 TI - Pyrolysis of wetland biomass waste: Potential for carbon sequestration and water remediation. AB - Management of biomass waste is crucial to the efficiency and sustainable operation of constructed wetlands. In this study, biochars were prepared using the biomass of 22 plant species from constructed wetlands and characterized by BET-N2 surface area analysis, FTIR, TGA, SEM, EDS, and elemental compositions analysis. Biochar yields ranged from 32.78 to 49.02%, with mesopores dominating the pore structure of most biochars. The biochars had a R50 recalcitrance index of class C and the carbon sequestration potential of 19.4-28%. The aquatic plant biomass from all the Chinese constructed wetlands if made into biochars has the potential to sequester 11.48 Mt carbon yr(-1) in soils over long time periods, which could offset 0.4% of annual CO2 emissions from fossil fuel combustion in China. In terms of adsorption capacity for selected pollutants, biochar derived from Canna indica plant had the greatest adsorption capacity for Cd(2+) (98.55 mg g(-1)) and NH4(+) (7.71 mg g(-1)). Whereas for PO4(3-), Hydrocotyle verticillata derived biochar showed the greatest adsorption capacities (2.91 mg g(-1)). The results from this present study demonstrated that wetland plants are valuable feedstocks for producing biochars with potential application for carbon sequestration and contaminant removal in water remediation. PMID- 26978733 TI - Novel mechanism-based therapeutics for androgen axis blockade in castration resistant prostate cancer. AB - PURPOSE OF REVIEW: Understanding the mechanisms by which castration-resistant prostate cancer (CRPC) progresses provides an opportunity to identify novel therapeutic strategies to treat this disease. This understanding has led to approaches to attack prostate cancer's androgen axis in unique ways. This review will examine the classes of novel therapies for androgen axis blockade in CRPC, with a particular focus on the unique characteristics of drugs in various stages of clinical development. RECENT FINDINGS: The success of abiraterone and enzalutamide has stimulated multiple investigations into novel approaches to attack the androgen-signaling pathway. Drugs under development include cytochrome P17 inhibitors with 17,20-lyase specificity, androgen receptor antagonists that are active against mutated and constitutively active splice variant forms of the protein, androgen receptor degraders, and bromodomain/bromodomain extra-terminal inhibitors that prevent chromatin binding of activated receptors. The clinical development of several of these experimental agents is reviewed. SUMMARY: Given the unique mechanisms of action for drugs in development, and the possibility that the novel agents may be active in the setting of common resistance mechanisms, treatment options for patients are likely to expand greatly in the coming years. Future studies should prioritize combinations of agents with unique mechanisms of action to optimize outcomes for patients, and should rely on precision-medicine approaches to target known molecular alterations. PMID- 26978734 TI - Preparation of Monoclonal Antibodies and a Simple Myeloperoxidase-Immunosorbent Assay for Detecting Human Myeloperoxidase. AB - Myeloperoxidase (MPO), a leukocyte hemoprotein released from neutrophils, is thought to be a potential participant in plaque formation and plaque rupture. Therefore, MPO is regarded as an early marker predicting the risk for atherosclerosis, especially for coronary artery disease and acute coronary syndrome. We generated hybridoma clones 1E3 and 3E8 secreting monoclonal antibodies (mAbs) specific to human MPO. BALB/c mice were immunized with MPO protein purified from human neutrophils. Splenocytes from these mice were fused with the mouse myeloma cell line SP2/0. Based on isotyping of the mAbs, both clones 1E3 and 3E8 were referred to the IgG1 subclass. The specificities of 1E3 and 3E8 were assessed by enzyme-linked immunosorbent assay (ELISA), and only 3E8 was confirmed by western blot. We developed a simple MPO-immunosorbent assay (MPO ISA) on microplate based on both the immune activity and peroxidase activity of MPO. The mAb secreted by clone 3E8 was chosen as coating antibody to capture the plasma MPO without interfering with the peroxidase activity of MPO. Then, tetramethylbenzidine substrate was added to the microwell directly, catalyzed by captured MPO, and a colored product was formed. The simple MPO-ISA test has a sensitivity of 3.68 ng/mL. The linear concentration of MPO-ISA for commercial MPO standard ranged to 250 ng/mL. The average recovery rate is 101.02%. The imprecision within-day was <10% at three different MPO levels. The imprecision between-day was <10% at low and middle MPO levels and varied to 14.61% at the high MPO level. We found that the established MPO-ISA can detect the plasma MPO from human and cavy, but not from mouse and rat. Compared with the commercial human MPO ELISA assay, the MPO-ISA can be used to detect the natural human MPO protein, but not recombinant MPO polypeptides. The generated mAbs and MPO-ISA test may be useful tools to assess risk for inflammation and cardiac events. PMID- 26978736 TI - Ultrasensitive detection of microbial cells using magnetic focus enhanced lateral flow sensors. AB - We report on an improved lateral flow immunoassay (LFIA) sensor with a magnetic focus for ultrasensitive naked-eye detection of pathogenic microorganisms at a near single cell limit without any pre-enrichment steps, by allowing the magnetic probes to focus the labelled pathogens to the target zone of the LF strip. PMID- 26978735 TI - Potential Diagnostic and Prognostic Value of Plasma Circulating MicroRNA-182 in Human Glioma. AB - BACKGROUND: Previous studies showed the aberrant expression of microRNA-182 (miR 182) in glioma tissue. However, the exact role of circulating miR-182 in glioma remains unclear. Here, we confirmed the expression of plasma circulating miR-182 in glioma patients, and further explored its potential diagnostic and prognostic value. MATERIAL/METHODS: Real-time quantitative PCR (RT-PCR) was used to measure circulating cell-free miR-182 from 112 glioma patients and 54 healthy controls. RESULTS: Our findings showed that the level of circulating miR-182 in glioma patients was higher than that in healthy controls (P<0.001), which was significantly associated with KPS score (P=0.025) and WHO grade (P<0.001). The area under the receiver operating characteristic (ROC) curve (AUC) was 0.778. The optimal cut-off value was 1.56, and the sensitivity and specificity were 58.5% and 85.2%, respectively. Interestingly, a high predictive value of circulating miR-182 was observed in high-grade glioma (AUC=0.815). However, the AUC was lower in low-grade glioma (AUC=0.621). Kaplan-Meier analysis demonstrated that the cumulative 5-year overall survival rate in the high miR-182 group was significantly lower than that in the low miR-182 group in both overall survival (OS) (P=0.003) and disease-free survival (DFS) (P=0.006). Moreover, multivariate Cox analysis revealed that circulating miR-182 was an independent prognostic indicator for OS (P=0.034) and DFS (P=0.013). CONCLUSIONS: These results suggest that circulating miR-182 may be a potential noninvasive biomarker for the diagnosis and prognosis of human glioma. PMID- 26978737 TI - Impulsivity-based thrifty eating phenotype and the protective role of n-3 PUFAs intake in adolescents. AB - The goal of the present study was to investigate whether intrauterine growth restriction (IUGR) affects brain responses to palatable foods and whether docosahexaenoic acid (DHA, an omega-3 fatty acid that is a primary structural component of the human brain) serum levels moderate the association between IUGR and brain and behavioral responses to palatable foods. Brain responses to palatable foods were investigated using a functional magnetic resonance imaging task in which participants were shown palatable foods, neutral foods and non-food items. Serum DHA was quantified in blood samples, and birth weight ratio (BWR) was used as a proxy for IUGR. The Dutch Eating Behavior Questionnaire (DEBQ) was used to evaluate eating behaviors. In the contrast palatable food > neutral items, we found an activation in the right superior frontal gyrus with BWR as the most important predictor; the lower the BWR (indicative of IUGR), the greater the activation of this region involved in impulse control/decision making facing the viewing of palatable food pictures versus neutral items. At the behavioral level, a general linear model predicting external eating using the DEBQ showed a significant interaction between DHA and IUGR status; in IUGR individuals, the higher the serum DHA, the lower is external eating. In conclusion, we suggest that IUGR moderates brain responses when facing stimuli related to palatable foods, activating an area related to impulse control. Moreover, higher intake of n-3 PUFAs can protect IUGR individuals from developing inappropriate eating behaviors, the putative mechanism of protection would involve decreasing intake in response to external food cues in adolescents/young adults. PMID- 26978738 TI - Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder. AB - Omega-3 polyunsaturated fatty acid (PUFA) supplementation has been proposed as (adjuvant) treatment for major depressive disorder (MDD). In the present meta analysis, we pooled randomized placebo-controlled trials assessing the effects of omega-3 PUFA supplementation on depressive symptoms in MDD. Moreover, we performed meta-regression to test whether supplementation effects depended on eicosapentaenoic acid (EPA) or docosahexaenoic acid dose, their ratio, study duration, participants' age, percentage antidepressant users, baseline MDD symptom severity, publication year and study quality. To limit heterogeneity, we only included studies in adult patients with MDD assessed using standardized clinical interviews, and excluded studies that specifically studied perinatal/perimenopausal or comorbid MDD. Our PubMED/EMBASE search resulted in 1955 articles, from which we included 13 studies providing 1233 participants. After taking potential publication bias into account, meta-analysis showed an overall beneficial effect of omega-3 PUFAs on depressive symptoms in MDD (standardized mean difference=0.398 (0.114-0.682), P=0.006, random-effects model). As an explanation for significant heterogeneity (I(2)=73.36, P<0.001), meta-regression showed that higher EPA dose (beta=0.00037 (0.00009-0.00065), P=0.009), higher percentage antidepressant users (beta=0.0058 (0.00017-0.01144), P=0.044) and earlier publication year (beta=-0.0735 (-0.143 to 0.004), P=0.04) were significantly associated with better outcome for PUFA supplementation. Additional sensitivity analyses were performed. In conclusion, present meta analysis suggested a beneficial overall effect of omega-3 PUFA supplementation in MDD patients, especially for higher doses of EPA and in participants taking antidepressants. Future precision medicine trials should establish whether possible interactions between EPA and antidepressants could provide targets to improve antidepressant response and its prediction. Furthermore, potential long term biochemical side effects of high-dosed add-on EPA supplementation should be carefully monitored. PMID- 26978739 TI - MiR-582-5p/miR-590-5p targeted CREB1/CREB5-NF-kappaB signaling and caused opioid induced immunosuppression in human monocytes. AB - Chronic opioid abusers are more susceptible to bacterial and viral infections, but the molecular mechanism underlying opioid-induced immunosuppression is unknown. MicroRNAs (miRNAs) are emerging as key players in the control of biological processes, and may participate in immune regulation. In this study, we investigated the molecular mechanisms in opioid-induced and miRNA-mediated immunosuppression, in the context of miRNA dysregulation in opioid abusers. Blood samples of heroin abusers were collected and analyzed using miRNA microarray analysis and quantitative PCR validation. The purified primary human monocytes were cultured in vitro to explore the underlying mechanism. We found that morphine and its derivative heroin significantly decreased the expression levels of miR-582-5p and miR-590-5p in monocytes. cAMP response element-binding protein 1 (CREB1) and CREB5 were detected as direct target genes of miR-582-5p and miR 590-5p, respectively, by using dual-luciferase assay and western bolt. Functional studies showed that knockdown of CREB1/CREB5 increased tumor necrosis factor alpha (TNF-alpha) level and enhanced expression of phospho-NF-kappaB p65 and NF kappaB p65. Our results demonstrated that miR-582-5p and miR-590-5p play important roles in opioid-induced immunosuppression in monocytes by targeting CREB1/CREB5-NF-kappaB signaling pathway. PMID- 26978740 TI - A common NTRK2 variant is associated with emotional arousal and brain white matter integrity in healthy young subjects. AB - Dysregulation of emotional arousal is observed in many psychiatric diseases such as schizophrenia, mood and anxiety disorders. The neurotrophic tyrosine kinase receptor type 2 gene (NTRK2) has been associated with these disorders. Here we investigated the relation between genetic variability of NTRK2 and emotional arousal in healthy young subjects in two independent samples (n1=1171; n2=707). In addition, diffusion tensor imaging (DTI) data in a subgroup of 342 participants were used to identify NTRK2-related white-matter structure differences. After correction for multiple testing, we identified a NTRK2 single nucleotide polymorphism associated with emotional arousal in both samples (n1: Pnominal=0.0003, Pcorrected=0.048; n2: Pnominal=0.0141, Pcorrected=0.036). DTI revealed significant, whole-brain corrected correlations between emotional arousal and brain white-matter mean diffusivity (MD), as well as significant, whole-brain corrected NTRK2 genotype-related differences in MD (PFWE<0.05). Our study demonstrates that genetic variability of NTRK2, a susceptibility gene for psychiatric disorders, is related to emotional arousal and-independently-to brain white-matter properties in healthy individuals. PMID- 26978743 TI - [Photodynamic therapy. The fields of applications and prospects for the further development in otorhinolaryngology]. AB - This article presents a review of the modern specialized medical literature concerned with the applications of photodynamic therapy (PDT) in otorhinolaryngology and medicine at large. The necessity of such a review of the available possibilities provided by PDT is dictated by the ever increasing interest of otorhinolaryngologists and specialists of other medical disciplines in the use of this method for the treatment of tumours and inflammatory diseases as well as their pyogenic complications. The author offers the critical assessment of the experience gained with the application of the known PDT technologies for the management of various pathological conditions. Especially much attention is given to the treatment of acute and chronic inflammation in the otorhinolaryngological practice with special reference to the yet unresolved problems. PMID- 26978744 TI - [The silent sinus syndrome in the patients presenting with the uncinate process apposed to the orbital wall]. AB - The objective of the present study was to analyze the frequency of the silent sinus syndrome (SSS) based on the results of computed tomography of the paranasal sinuses (PNS) in the patients presenting with the uncinate process (UP) apposed to the orbital wall. The study included 35 patients with the uncinate process apposed to the orbital wall who had been operated in the Clinic of ENT Diseases of I.M. Sechenov First Moscow State Medical University. The examination of the nasal cavity with the use of computed tomography and PNS endoscopy revealed the silent sinus syndrome in 14 patients. Ten of them had endoscopically confirmed type 2 hypoplasia of maxillary sinuses (MS). This finding suggests the necessity of computed tomography of paranasal sinuses in the patients with this condition in order to exclude the diagnosis of silent sinus syndrome even in the absence of exophthalmos. All the patients included in the present study underwent endoscopic surgery on maxillary sinuses that resulted in the adequate widening of the ostium and comprehensive sanation of the sinuses. PMID- 26978741 TI - Is increased antidepressant exposure a contributory factor to the obesity pandemic? AB - Major depressive disorder (MDD) and obesity are both common heterogeneous disorders with complex aetiology, with a major impact on public health. Antidepressant prescribing has risen nearly 400% since 1988, according to data from the Centers for Disease Control and Prevention (CDC). In parallel, adult obesity rates have doubled since 1980, from 15 to 30 percent, while childhood obesity rates have more than tripled. Rising obesity rates have significant health consequences, contributing to increased rates of more than thirty serious diseases. Despite the concomitant rise of antidepressant use and of the obesity rates in Western societies, the association between the two, as well as the mechanisms underlying antidepressant-induced weight gain, remain under explored. In this review, we highlight the complex relationship between antidepressant use, MDD and weight gain. Clinical findings have suggested that obesity may increase the risk of developing MDD, and vice versa. Hypothalamic-pituitary-adrenal (HPA) axis activation occurs in the state of stress; concurrently, the HPA axis is also dysregulated in obesity and metabolic syndrome, making it the most well understood shared common pathophysiological pathway with MDD. Numerous studies have investigated the effects of different classes of antidepressants on body weight. Previous clinical studies suggest that the tricyclics amitriptyline, nortriptyline and imipramine, and the serotonin norepinephrine reuptake inhibitor mirtazapine are associated with weight gain. Despite the fact that selective serotonin reuptake inhibitor (SSRI) use has been associated with weight loss during acute treatment, a number of studies have shown that SSRIs may be associated with long-term risk of weight gain; however, because of high variability and multiple confounds in clinical studies, the long-term effect of SSRI treatment and SSRI exposure on body weight remains unclear. A recently developed animal paradigm shows that the combination of stress and antidepressants followed by long-term high-fat diet results, long after discontinuation of antidepressant treatment, in markedly increased weight, in excess of what is caused by high-fat diet alone. On the basis of existing epidemiological, clinical and preclinical data, we have generated the testable hypothesis that escalating use of antidepressants, resulting in high rates of antidepressant exposure, might be a contributory factor to the obesity epidemic. PMID- 26978745 TI - [The evaluation of the hearing function in the premature infants with intrauterine growth retardation during the third and sixth months of life by recording auditory steady-state response]. AB - The objective of the present work was to study the function of the retrocochlear auditory pathway in the premature infants with intrauterine growth retardation (IGR) in comparison to that of the normotrophics of a similar gestational age during the third and sixth months of life by recording auditory steady-state responses (ASSR). The audiological examination by the method of auditory steady state response (ASSR) involved 127 children at the 3d month of life and in 97 children at the 6th month of life. It was shown that the ASSR thresholds at certain frequencies during the 3d and 6th months of life of the children born after the 32d week of pregnancy were significantly higher than in the children born after 32 weeks gestation. The comparison of the two objective audiological methods, viz. distortion-product otoacoustic emission (DPOAE) and ASSR, indicates that both should be used to evaluate the hearing function during the third and sixth months of life to compensate for the discrepancy between the results obtained by either technique. PMID- 26978742 TI - 11beta-hydroxysteroid dehydrogenase inhibition as a new potential therapeutic target for alcohol abuse. AB - The identification of new and more effective treatments for alcohol abuse remains a priority. Alcohol intake activates glucocorticoids, which have a key role in alcohol's reinforcing properties. Glucocorticoid effects are modulated in part by the activity of 11beta-hydroxysteroid dehydrogenases (11beta-HSD) acting as pre receptors. Here, we tested the effects on alcohol intake of the 11beta-HSD inhibitor carbenoxolone (CBX, 18beta-glycyrrhetinic acid 3beta-O-hemisuccinate), which has been extensively used in the clinic for the treatment of gastritis and peptic ulcer and is active on both 11beta-HSD1 and 11beta-HSD2 isoforms. We observed that CBX reduces both baseline and excessive drinking in rats and mice. The CBX diastereomer 18alpha-glycyrrhetinic acid 3beta-O-hemisuccinate (alphaCBX), which we found to be selective for 11beta-HSD2, was also effective in reducing alcohol drinking in mice. Thus, 11beta-HSD inhibitors may be a promising new class of candidate alcohol abuse medications, and existing 11beta-HSD inhibitor drugs may be potentially re-purposed for alcohol abuse treatment. PMID- 26978746 TI - [The state of the nasal cavity and paranasal sinuses in the children presenting with congenital cleft of upper lip and palate]. AB - The objective of the present study was to evaluate the state of the nasal cavity and paranasal sinuses in the children presenting with congenital cleft of upper lip and palate (CLP). A total of 23 children at the age from 9 to 16 years who had undergone the surgical treatment of the above malformations during the first year of life were examined. The comprehensive study including routine ENT examination, endoscopic examination of the nasal cavity and nasopharynx, and computed tomography has demonstrated that 50% of the patients with congenital cleft of upper lift and palate suffered the deflection of the nasal septum associated with hyperplasia of inferior turbinal bones. The children with congenital cleft of upper lip and palate were characterized by enhanced pneumatization of the anterior end of the middle turbinate despite the absence of well apparent differences between their paranasal sinuses and those of the healthy children, with the degree of pneumatization being consistent with the patient's age in both groups. PMID- 26978747 TI - [Peculiar features of immunological and metabolic status associated with polypous rhinosinusitis]. AB - The objective of the present work was to study peculiar features of immunological and metabolic status associated with polypous rhinosinusitis (PRS). We determined the population and subpopulation composition of blood lymphocytes, concentration of cytokines in blood sera and nasal secretion as well as the level of intracellular enzymes in blood lymphocytes of the patients presenting with polypous rhinosinusitis and of the control subjects. It was shown that PRS was associated with activation of Th1-lymphocytes and determined the character of the immune response largely of the cell-mediated type. The study has demonstrated the differently directed changes in the activation of the intracellular processes in blood lymphocytes. Specifically, the intensity of the aerobic processes and lipid anabolism was increased while that of the anaerobic processes and amino acid metabolism (NAD-GDG and NADH-GDG) was suppressed. PMID- 26978748 TI - [The methodological approaches to the evaluation of the risk of developing pathology of the upper respiratory tract in the employees engaged in the dust producing industries]. AB - The objective of the present work was to develop the scientifically sound criteria for the evaluation of the occupational risks bearing in mind the high frequency of pathological changes in the ciliary epithelium of the upper respiratory tract in the employees engaged in the dust-producing industries. It was proposed to consider an increase of the SIgA level, alkaline shift in nasal secretion pH, elevation of body temperature, slowdown of the mucociliary transport, disintegration of the epithelial mucous membrane, and high frequency of its inflammatory and dystrophic changes as the criteria for early diagnostics of developing pathology of the upper respiratory tract. We have developed the method for the score-based evaluation of the risk of formation of pathological changes in the upper respiratory tract of the employees engaged in the dust producing industries. This method can be used to enhance the effectiveness of the preventive and health-promoting measures. PMID- 26978749 TI - [The modern epidemiological characteristics of oto- and rhinosinusogenic intracranial complications]. AB - The objective of the present study was to survey epidemiology of oto- and rhinosinusogenic intracranial complications that are currently diagnosed at the territory of the Russian Federation. The work was based on the analysis of the official statistical reports together with the data obtained from the chief specialists responsible for the otorhinolaryngological services in 32 subjects of the Russian Federation during the period from 2009 to 2014. It was shown that the state of the otorhinolaryngological service in the period covered by the study was characterized by the reduction in the number of beds available for the patients presenting with ENT pathology by 14.0% and the lowering of the hospitalization rate for the general population by 6.3%. The frequency of oto- and rhinosinusogenic intracranial complications among the patients hospitalized to occupy the beds intended for the care of the patients suffering from ENT diseases was estimated at 0.03% and intrahospital lethality at 21.2%. The prevalence of pyogenic intracranial complications associated with the inflammatyory pathology affecting ENT was 0.61 per 100.000 population per year, with the mortality rate amounting to 0.17 fatal outcomes per 100.000 population per year. The study revealed significant correlation of the principal medico statistical characteristics of high-frequency oscillatory ventilation (HFOV)---?? between themselves and with the parameters of ENT morbidity and activities of the otorhinolaryngological services at the territory of a given administrative territory. It is concluded that the improvement of the quality of healthcare for the population presenting with intracranial complications and inflammatory ENT diseases is possible only on the baseis of the combined and interdisciplinary approach to the solution of the problem. PMID- 26978750 TI - [Oral cavity and pharynx cancer in the region of Siberia and Far East]. AB - The objective of the present work was to study the prevalence of malignant oral cavity and pharynx neoplasms among the population of the region of Siberia and Far East. These neoplasms are the ninth most frequent conditions in the structure of malignant tumours among the male population and rank the eighteenth among the women. On the whole, the morbidity rate of oral cavity and pharyngeal cancer (3.80/000 and 2.00/000 respectively) was consistent with the mean morbidity levels in Russia. The risk of the development of these conditions among the men is significantly higher than among the women. The highest morbidity is recorded among the subjects at the age of 65-69 years. It increases in the subjects of either sex at a rate that is 3.4 times higher in the women than in the men. The study revealed the territories characterized ether by the enhanced or by the reduced risk of oral cavity and pharyngeal cancer development. The prevalence of this pathology was estimated at 28.4 per 100,000 population, with the overall active detectability being 11.8%, that of stage 1 an 2 disease 7.8% and 19.3% respectively. One-year lethality was 35.6%. The radical treatment was completed in 41.1% of the patients; 45.8% of them were followed up during 5 years. It is concluded that the increasing oral cavity and pharyngeal cancer morbidity and the insufficient volume of preventive measures taken together suggest the necessity of closer cooperation of general practitioners and dental surgeons with oncologists. PMID- 26978751 TI - [Prophylaxis of chronic adenoiditis in the children]. AB - This study was undertaken with the purpose of improving the effectiveness of the preventive treatment of chronic adenoiditis in the children. The open randomized comparative study included 219 children aged from 6 to 7 years presenting with clinical and anamnestic signs of chronic adenoiditis. The study group was comprised of 113 patients given the Streptococcus salivarius K12-based probiotic complex during 30 days in combination with the nasal-douche. The control group consisted of 106 patients treated with the nasal douche alone. The analysis of the results of the study has demonstrated that episodes of exacerbation of adenoiditis on day 30 after the onset of the treatment occurred in 56 (49.6%) children of the study group compared with 95 (88.7%) patients of the control group. Three months later, acute sinusitis was diagnosed in 4 (3.5%) children of the study group compared with 14 (13.2%) ones in the control group. Acute otitis media was documented in 2 (1.8%) and 5 (4.7%) children of the study and control groups respectively. It is concluded that the treatment with the use of the Streptococcus salivarius K12-based probiotic complex permits to decrease the frequency of exacerbations of chronic adenoiditis and its complications in the children and reduces the requirement for medication therapy. PMID- 26978752 TI - [Enlarged vestibular aqueduct syndrome: etiology, clinical features, diagnostics, and rehabilitation of the patients]. AB - This publication was designed to describe the clinical manifestations of the enlarged vestibular aqueduct syndrome (EVAS), the currently employed methods for its diagnostics, and the strategy for the rehabilitation of the patients presenting with this pathological condition. In addition, the article provides information about the topographic anatomy and X-ray anatomy of the vestibular aqueduct, the specific clinical features of EVAS, the modern algorithm of its diagnostics, and the facilities for hearing rehabilitation in this group of patients. PMID- 26978753 TI - [The clinical effectiveness of azithromycin antimicrobial therapy used for the treatment of acute bacterial sinusitis in the patients presenting with concomitant pathology]. AB - The objective of the present publication was to report the result of the evaluation of the clinical effectiveness of azithromycin (Sumamed) antimicrobial therapy used for the treatment of bacterial acute rhinsinusitis (ARS) in the patients presenting with concomitant pathology of the respiratory and cardiovascular systems. Dynamics of the reversal of the clinical symptoms of bacterial ARS in the patients of the study group is described. Neither adverse side effects nor complications in response to the treatment were documented. 98.6% of the patients recovered from the disease within 7 days after the onset of the treatment. It is concluded that antimicrobial therapy with the use of azithromycin (Sumamed) based at the outpatient settings provides a highly efficient tool for the treatment of the patients presenting with concomitant pathology of the respiratory and cardiovascular systems. PMID- 26978754 TI - [The follow up observation of an 11 year exploitation of the domestically produced voice prosthesis in the patient who underwent laryngectomy with the use of the tracheoesophageal shunt and the endoprosthetic correction]. PMID- 26978755 TI - [A clinical case of osteoma of the maxillary sinus]. PMID- 26978757 TI - [Closed abdominal trauma. Liver injuries. Part 1]. PMID- 26978756 TI - Opioids Prescribed After Low-Risk Surgical Procedures in the United States, 2004 2012. PMID- 26978758 TI - [Streptococcal infection in surgery]. AB - INTRODUCTION: Despite the advances of modern medicine purulent-inflammatory diseases of soft tissues continue to occupy a leading position in surgical practice. Streptococcal surgical infection does not refer to specific category, but it has a number of significant features and its definition as separate type is necessary. MATERIAL AND METHODS: Based on the results of treatment of 312 patients with streptococcal infection of soft tissues we studied the prevalence of this disease in overall structure of surgical infection of soft tissue, main clinical courses are defined. We performed molecular genetic typing of pathogens that allows to predict the course of pathological process taking into account microorganism's characteristics. RESULTS AND DISCUSSION: On the basis of obtained data basic medical and diagnostic concept of surgical care for these patients depending on clinical course of disease was formulated. It allowed to improve significantly the results of treatment of such patients. PMID- 26978759 TI - [Abdominal sepsis and oxidative stress]. AB - INTRODUCTION: Oxidative stress deserves special attention in the pathogenesis of sepsis. MATERIAL AND METHODS: The study included 96 patients with abdominal sepsis caused by advanced suppurative peritonitis and destructive pancreatitis. All patients were divided into 3 groups depending on the severity of sepsis. Level of malondialdehyde (MDA) was determined to evaluate the intensity of lipid peroxidation (LPO). Proteins oxidative modification was assessed according to level of sulfhydryl groups (SH-groups) and carbonyls in proteins. State of anti oxidant system (AOS) was defined based on activity of catalase, peroxidase, superoxide dismutase and glutathione peroxidase in erythrocytes. RESULTS AND DISCUSSION: There was no relationship between severity of multiple organ failure, MDA concentration, SH-groups and anti-oxidant enzymes levels. At the same time positive correlation between severity of multiple organ failure and carbonyls content in proteins was revealed. CONCLUSION: In surgical patients sepsis develops on background of oxidative stress. Significant reduction of SH-groups in proteins by the moment of sepsis diagnosis is an unfavorable factor for outcome. The degree of multiple organ failure in patients with abdominal sepsis correlates with oxidative injury of proteinic structures. PMID- 26978760 TI - [The difficulties of diagnosis and treatment of non-occlusive mesenteric circulatory disorders]. AB - AIM: To review one of actual problems of emergency surgery - diagnosis and treatment of patients with non-occlusive mesenteric circulatory disorders. MATERIAL AND METHODS: The article presents the clinical observations showing the ambiguity of clinical picture, features and challenges of diagnosis, treatment of disease and opportunities for positive outcomes. Diagnostic methods are x-ray, abdominal ultrasonography according to which acute abdominal ischemia may be assumed. However, in all unclear cases diagnostic videolaparoscopy is mandatory to determine further tactics. Unfortunately diagnostic videolaparoscopy is not always interpreted comprehensively and not a definitive method of diagnosis. Wide surgical access is usually necessary for non-occlusal acute violation of mesenteric circulation and volume of surgery varies from segmental to subtotal intestinal and colic resection with obligatory enteral intubation and decompression. Thus, complex pre- and postoperative treatment is required. PMID- 26978761 TI - [Surgical treatment of thoracoabdominal aortic aneurysms]. AB - INTRODUCTION: Surgical treatment of patients with thoracoabdominal aneurysm is still actual problem in cardiovsacular surgery. MATERIAL AND METHODS: We have retrospectively analyzed 344 treated patients. Thoracoabdominal aneurysms Crawford I-IV and descending aortic aneurysms were diagnosed in 186 (54,1%) and 158 (45,9%) patients respectively. RESULTS: For the follow-up period surgical mortality in case of thoracoabdominal aneurysms has been decreased to 8.9%. According to our opinion major predictors of adverse events are extended reconstruction (r=0.0086), intraoperative blood loss over 4.5 liters (r=0.003) and postoperative renal failure (r=0.0005). 2-fold decrease of blood loss was observed if "bag handle" technique introduced by us was applied (r=0.0042). Organs protection is provided by using of active selective blood perfusion as well as "Custodiol" infusion. Herewith safe period of absolute ischemia ranges from 30 to 50 minutes in normothermia. Development of "hybrid" methods significantly reduced incidence of complications. We consider that patients with thoracoabdominal aneurysm and dissection are candidates for "hybrid treatment". PMID- 26978763 TI - [The ways to improve the efficiency of surgical care service]. AB - AIM: To examine the work of surgical service in the Central Federal District and to define the main directions to improve the efficacy of surgical care in case of acute abdominal diseases. MATERIAL AND METHODS: The results of surgical service of the Central Federal District for the period 2011-2014 in treatment of 2.5 millions patients were analyzed. RESULTS: Parameters in elective and emergency surgery persuasively prove stable work of surgical service of the Central Federal District for recent years. Obtained results were compared with the indicators of emergency surgical care in Moscow for objective assessment. It was revealed 2-4 fold decrease of overall and postoperative mortality in Moscow. CONCLUSION: Conditions for all-day diagnostic and medical assistance for emergency abdominal diseases should be created to improve the effectiveness of surgical service of the Central Federal District. PMID- 26978762 TI - [Postoperative bleeding in tracheal surgery]. AB - AIM: Tracheal surgery became relatively safe with development of thoracic surgery, endoscopy and anesthesia. However, life-threatening vascular complications especially arrosive bleeding from great vessels play important role in the structure of postoperative complications. It is a major cause of hospital mortality after tracheal surgery. MATERIAL AND METHODS: Since 1963 to 2013 867 patients with cicatrical tracheal stenosis were treated. Their age ranged from 8 to 77 years. Bleeding was the main cause of death after tracheal surgery. It occurs in 31 patients among whom 22 died. 9 patients are alive. There was bleeding from small cervical vessels and carotid artery in 5 and 2 patients respectively. All patients with bleeding from brachiocephalic trunk died except 2 patients who underwent complex vascular reconstructions and recurrent complications were prevented. Vascular complications occurred after both circular tracheal resection with the anastomosis (19 patients) and tracheoplasty followed by airway lumen formation on T-shaped tube (in 11 cases) or endoscopic treatment (in 1 patient). Postoperative complications were predominantly arrosive and accompanied by wound infection or severe purulent tracheobronchitis. Blood loss was relatively small in all patients and asystole was caused by blood asphyxia in died patients. Therefore, firstly respiratory tract lumen should be isolated from source of bleeding. 22 patients were urgently operated. Intraoperative death was observed in 6 cases, 7 patients died within 2-31 days. In 7 other patients cervical soft tissues, thyroid artery collaterals and carotid artery were origin of bleeding. RESULTS: Final bleeding stop was performed with good immediate and long-term results in all cases. Final bleeding stop usually requires complex vascular reconstructions and it is difficult to predict their outcomes. It is necessary to prevent intraoperative bleeding because of unsatisfactory results of vascular complications management. So careful manipulations with vessels and their isolation from the tracheal anastomosis and tracheostomy channel with patient's own tissues are obligatory. PMID- 26978764 TI - [The results of endoscopic gastroduodenal, enteral and colorectal stenting for blastomatous stenosis: 8-year experience]. AB - INTRODUCTION: Gastroduodenal, enteral and colorectal stenting of blastomatous stenosis is a reasonable alternative to operative treatment of unresectable tumors. Moreover in some cases it allows to gain time and to prepare the patient for radical surgery. MATERIAL AND METHODS: For the period from 2007 to 2015 in endoscopic department of acad. B.V. Petrovskiy Russian Research Center for Surgery 76 patients with piloroduodenal, enteral and colic stenoses successfully underwent self-expanding metal stents installation. There were 21 patients with malignant stenosis of the stomach and pilorobulbar area, 17 with secondary duodenal stenosis, 17 after gastrectomy and distal gastric resection; 2 with stenosing colorectal cancer, 4 patients with rectal cancer involving rectosigmoid junction, 7 with rectosigmoid junction cancer and 8 with sigmoid cancer. RESULTS: Ambulatory and hospital interventions were performed in 35.5% and 64.5% of cases respectively. Hospital-stay did not exceed 2 days. The total complication rate was 11.8% (9/76), 3 of 9 patients required surgical intervention. The attention is given to important technical aspects of intervention as well as to those clinical situations when stenting is inappropriate because of absence of favourable functional outcome. CONCLUSION: Stenting should be more actively implemented in clinical practice, especially in emergency surgical hospitals. However it requires adequate technical support of hospitals with different endoprostheses, because it provides simultaneous diagnostic survey and remedial procedure. PMID- 26978765 TI - The role of prognostic models in metastatic colorectal liver cancer surgery. AB - INTRODUCTION: Patients with metastatic colorectal liver cancer differ from each other by some characteristics which affect on the prognosis of disease. Long-term results and, consequently, the prognosis depend on not one but group of factors which may be incorporated into mathematical models allowing to classify patients according to their risk of recurrence or prognosis of survival. AIM: To calculate survival in patients with metastatic colorectal liver cancer and to evaluate the most popular models of 3- and 5-year survival rate prognosis after liver resection. MATERIAL AND METHODS: We analyzed the results of treatment of 342 patients with metastatic colorectal cancer who underwent different resections since 1991 to 2014. The effectiveness of prognostic models was estimated according to the most popular scales that were developed based on groups of more than 200 patients. RESULTS: Long-term results were followed in 312 (91.2%) patients. Median life in the total group of patients was 24 months in 3-, 5- and 10-year survival of 56.3%, 36.1% and 18.1% respectively. The most accurate stratification of patients into groups was obtained using preoperative Rees scale for 5-year and 3-year survival (C-statistics - 0.73 and 0.69, respectively). Analysis of Iwatsuki and Fong scales for 5-year survival prediction (C-statistics - 0.68 and 0.62) and postoperative Rees scale for 3-year survival (C-statistics - 0.63) also showed relatively good results. None of models showed C-statistics level over 0.8. CONCLUSION: Stratification of patients according to prognostic scales should not affect on monitoring of patients with high risk of recurrence and poor prognosis of survival. PMID- 26978766 TI - [Survival rate after D3-lymphadenectomy for right-sided colic cancer: case-match study]. AB - The aim of the study was to compare the effectiveness of D3-lymphadenectomy in compliance with "no-touch" principle and mesocolectomy with traditional hemicolectomy in patients with right-sided colon cancer. MATERIAL AND METHODS: It is retrospective-prospective comparative case-match study. From prospectively collected database patients with right-sided colon cancer stage I-III treated in 2009-2013 without adjuvant chemotherapy were selected. Patients who underwent conventional right-sided hemicolectomy with D2-lymphadenectomy in the regional oncologic dispensary formed the first group. The second group included patients after right-sided hemicolectomy with D3-lymphadenectomy, "no-touch" principle and mesocolectomy performed in academic hospital of the third level. From both groups 'case-match' patients by gender, age, stage and location of primary tumor were selected. Each group consisted of 50 patients. RESULTS: Overall and cancer related 5-year survival was significantly higher in the second group - 80.9% vs. 56.0% (p=0.01) and 93.4% vs. 59.8% (p=0.01), respectively. CONCLUSION: D3 lymphadenectomy and mesocolectomy for right-sided colon cancer stage I-III without adjuvant chemotherapy provides significantly better overall and cancer related 5-year survival compared with conventional right-sided hemicolectomy. Thus, D3-lymphadenectomy and mesocolectomy in compliance with "no-touch" principle for right-sided colon cancer is reproducible and effective in Russian conditions. PMID- 26978767 TI - [Is there a place for single laparoscopic approach in colic surgery?]. AB - INTRODUCTION: This prospective randomized study was performed to determine the place of surgery via single laparoscopic access in modern coloproctology. MATERIAL AND METHODS: The results of right-sided hemicolectomy using multiport laparoscopic-assisted technique (n=48) or single laparoscopic access (n=47) in case of cancer were analyzed. RESULTS AND DISCUSSION: There were no significant differences in the incidence of complications, severity of pain, postoperative rehabilitation and quality of life. Surgery via single access were characterized by better cosmetic effect, less need for analgesics compared with multiport interventions. However, according to surgeons' opinion operations with single laparoscopic access are more laborious. CONCLUSION: Thus, single laparoscopic access can't be recommended for routine use in daily practice because of absence of significant advantages in colon resection compared with multiport technique. PMID- 26978768 TI - [Surgical treatment of patients with enteric fistulae]. AB - AIM: To create multidisciplinary diagnostic and curative approach to patients with intestinal fistulae. MATERIAL AND METHODS: Additional nutritive support was applied in all patients preoperatively. 35 patients with intestinal fistulae were operated. Unformed and formed intestinal fistulae were observed in 10 and 25 patients respectively. Radical one-stage surgery was performed in 30 cases, two stage - in 3 patients. Unformed fistulae opened into granulating wound were not eliminated in 2 patients. RESULTS: Postoperative complications were observed in 10 patients. 2 of them required re-intervention. There were no deaths. PMID- 26978769 TI - [Radical removal of parasitic twin in 29-years-old patient]. PMID- 26978770 TI - [First experience of ultrasound-assisted percutaneous microwave ablation of insulin-producing pancreatic tumor]. PMID- 26978772 TI - Wave Propagation Direction and c-Axis Tilt Angle Influence on the Performance of ScAlN/Sapphire-Based SAW Devices. AB - Some previously reported surface acoustic wave (SAW) devices using bulk piezoelectric substrates showed higher acoustic power radiated in either forward or backward wave propagation direction depending on their crystal orientations and are called natural single-phase unidirectional transducers (NSPUDT). While these reports were based on bulk piezoelectric substrates, we report directionality in the c-axis tilted 44% scandium doped aluminum nitride thin piezoelectric film-based SAW devices on sapphire. It is worth noting that our observance of directionality is specifically in Sezawa mode. We produced a c-axis tilt up to 5.5 degrees over the single wafer and examined the directionality by comparing the forward and backward insertion loss utilizing split finger electrodes as a receiver. The wave propagation direction and c-axis tilt angle influence on the performance of SAW devices is evaluated. Furthermore, return loss and insertion loss data are presented for various SAW propagation directions and c-axis tilt angles. Finally, the comparison for both acoustic modes, i.e., Rayleigh and Sezawa, is reported. PMID- 26978771 TI - Bacillusurumqiensis sp. nov., a moderately haloalkaliphilic bacterium isolated from a salt lake. AB - A Gram-stain-positive, rod-shaped, aerobic and moderately haloalkaliphilic bacterium, designated BZ-SZ-XJ18T, was isolated from the mixed water and sediment of a saline-alkaline lake located in the Xinjiang Uyghur Autonomous Region of China. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain BZ-SZ-XJ18T was a member of the genus Bacillus. The closest phylogenetic relatives were Bacillus saliphilus 6AGT (96.7 % 16S rRNA gene sequence similarity), 'Bacillusdaqingensis' X10-1 (96.6 %), Bacillus luteus JC167T (96.5 %), Bacillus daliensis DLS13T (96.2 %), Bacillus chagannorensis CG-15T (95.2 %) and Bacillus polygoni YN-1T (95.0 %). DNA-DNA relatedness between strain BZ-SZ XJ18T and the reference type strains of the related species of the genus Bacillus was lower than 27 %. The isolate formed yellow pigment and grew in the presence of 0.22-4.32 M Na+ (equivalent to 1.3-25.3 %, w/v, NaCl) (optimum 1.08 M Na+, equivalent to 6.3 %, w/v, NaCl), at pH 6.5-10.0 (optimum pH 8.5-9.5) and at 8-41 oC (optimum 37 oC). The major cellular fatty acids were anteiso-C15:0 (43.0 %), C16:0 (18.1 %), iso-C15:0 (11.3 %), anteiso-C17:0 (8.0 %) and iso-C16:0 (7.0 %). The major polar lipids consisted of diphosphatidylglycerol and phosphatidylglycerol. The main respiratory quinone was menaquinone-7 (MK-7), and the peptidoglycan type of the cell wall was A1gamma based on meso-diaminopimelic acid as the diagnostic diamino acid. The genomic DNA G+C content was 42.3 mol% (HPLC) or 41.4 mol% (Tm). On the basis of phenotypic, chemotaxonomic and phylogenetic features, strain BZ-SZ-XJ18T is proposed to represent a novel species, Bacillusurumqiensis within the genus Bacillus. The type strain is BZ-SZ XJ18T (=DSM 29145T=JCM 30195T). PMID- 26978775 TI - Topical Nasal Anesthesia in Flexible Bronchoscopy--A Cross-Over Comparison between Two Devices. AB - INTRODUCTION: Topical airway anesthesia is known to improve tolerance and patient satisfaction during flexible bronchoscopy (FB). Lidocaine is commonly used, delivered as an atomized spray. The current study assesses safety and patient satisfaction for nasal anesthesia of a new atomization device during outpatient bronchoscopy in lung transplant recipients. METHODS: Using a prospective, non blinded, cross-over design, patients enrolled between 01-10-2014 and 24-11-2014 received 2% lidocaine using the standard reusable nasal atomizer (CRNA). Those enrolled between 25-11-2014 and 30-01-2015, received a disposable intranasal mucosal atomization device (DIMAD). After each procedure, the treating physician, their assistant and the patient independently rated side-effects and satisfaction, basing their responses on visual analogue scales (VAS). At their next scheduled bronchoscopy during the study period, patients then received the alternative atomizer. Written consent was obtained prior to the first bronchoscopy, and the study approved by the institutional ethics committee. RESULTS: Of the 252 patients enrolled between 01-10-2014 and 30-01-2015, 80 (32%) received both atomizers. Physicians reported better efficacy (p = 0.001) and fewer side effects (p< = 0.001) for DIMAD in patients exposed to both procedures. Among patients with one visit, physicians and their assistants reported improved efficacy (p = 0.018, p = 0.002) and fewer side effects (p< = 0.001, p = 0.029) for the disposable atomizer, whereas patients reported no difference in efficacy or side effects (p = 0.72 and p = 0.20). No severe adverse events were noted. The cost of the reusable device was 4.08? per procedure, compared to 3.70? for the disposable device. DISCUSSION: Topical nasal anesthesia via a disposable intranasal mucosal atomization device (DIMAD) offers comparable safety and patient comfort, compared to conventional reusable nasal atomizers (CRNA) in lung transplant recipients. Procedural costs were reduced by 0.34? per procedure. TRIAL REGISTRATION: clinicaltrials.gov NCT02237651. PMID- 26978773 TI - Vascular Endothelial Growth Factor (VEGF) Bioavailability Regulates Angiogenesis and Intestinal Stem and Progenitor Cell Proliferation during Postnatal Small Intestinal Development. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is a highly conserved, master regulatory molecule required for endothelial cell proliferation, organization, migration and branching morphogenesis. Podocoryne carnea and drosophila, which lack endothelial cells and a vascular system, express VEGF homologs, indicating potential roles beyond angiogenesis and vasculogenesis. The role of VEGF in the development and homeostasis of the postnatal small intestine is unknown. We hypothesized regulating VEGF bioavailability in the postnatal small intestine would exhibit effects beyond the vasculature and influence epithelial cell stem/progenitor populations. METHODS: VEGF mutant mice were created that overexpressed VEGF in the brush border of epithelium via the villin promotor following doxycycline treatment. To decrease VEGF bioavailability, sFlt 1 mutant mice were generated that overexpressed the soluble VEGF receptor sFlt-1 upon doxycycline administration in the intestinal epithelium. Mice were analyzed after 21 days of doxycycline administration. RESULTS: Increased VEGF expression was confirmed by RT-qPCR and ELISA in the intestine of the VEGF mutants compared to littermates. The VEGF mutant duodenum demonstrated increased angiogenesis and vascular leak as compared to littermate controls. The VEGF mutant duodenum revealed taller villi and increased Ki-67-positive cells in the transit amplifying zone with reduced Lgr5 expression. The duodenum of sFlt-1 mutants revealed shorter villi and longer crypts with reduced proliferation in the transit-amplifying zone, reduced expression of Dll1, Bmp4 and VE-cadherin, and increased expression of Sox9 and EphB2. CONCLUSIONS: Manipulating VEGF bioavailability leads to profound effects on not only the intestinal vasculature, but epithelial stem and progenitor cells in the intestinal crypt. Elucidation of the crosstalk between VEGF signaling in the vasculature, mesenchyme and epithelial stem/progenitor cell populations may direct future cell therapies for intestinal dysfunction or disease. PMID- 26978774 TI - Phenylpropanoid Defences in Nicotiana tabacum Cells: Overlapping Metabolomes Indicate Common Aspects to Priming Responses Induced by Lipopolysaccharides, Chitosan and Flagellin-22. AB - Plants have evolved both constitutive and inducible defence strategies to cope with different biotic stimuli and stresses. Exposure of a plant to a challenging stress can lead to a primed state that allows it to launch a more rapid and stronger defence. Here we applied a metabolomic approach to study and compare the responses induced in Nicotiana tabacum cells by microbe-associated molecular pattern (MAMP) molecules, namely lipopolysaccharides (LPS), chitosan (CHT) and flagellin-22 (FLG22). Early response metabolites, extracted with methanol, were analysed by UHPLC-MS/MS. Using multivariate statistical tools the metabolic profiles induced by these elicitors were analysed. In the metabolic fingerprint of these agents a total of 19 cinnamic acid derivatives conjugated to quinic acids (chlorogenic acids), shikimic acid, tyramine, polyamines or glucose were found as discriminant biomarkers. In addition, treatment with the phytohormones salicylic acid (SA), methyljasmonic acid (MJ) and abscisic acid (ABA) resulted in differentially-induced phenylpropanoid pathway metabolites. The results indicate that the phenylpropanoid pathway is activated by these elicitors while hydroxycinnamic acid derivatives are commonly associated with the metabolic response to the MAMPs, and that the activated responses are modulated by both SA and MJ, with ABA not playing a role. PMID- 26978776 TI - Sarcopenia and Hearing Loss in Older Koreans: Findings from the Korea National Health and Nutrition Examination Survey (KNHANES) 2010. AB - Age-related hearing impairment (ARHI) is becoming a more significant issue as geriatric population increases. Sarcopenia in older people is known to have a diverse health problem in various circumstances in recent studies. We assessed whether the decrease in muscle mass is related to ARHI. We used the 2010 data of the Korea National Health and Nutrition Examination Survey (KNHANES) to examine the associations between sarcopenia and ARHI. A total number of participants was 1,622 including 746 males and 876 females aged 60 years or older. Muscle mass was assessed as an appendicular skeletal muscle mass, and hearing loss was defined as the pure-tone averages (PTA) of test frequencies 0.5, 1, 2, 4 kHz at a threshold of 40 dB or higher in worse hearing side of the ear. Among 1,622 participants, 298 men and 256 women had hearing loss. Appendicular muscle mass (ASM), expressed as kg, was categorized in tertiles. In female population, after adjusting for age, smoking, drinking, amount of exercise, total body fat, education level, income level, and tinnitus, the odds ratio (OR) for hearing loss was 1.57 (95% confidence interval (CI) = 0.92-2.68) in the middle tertile and 1.79 (1.03-3.08) in the lowest tertile, compared with the highest tertile. P for trend in this model was 0.036. Controlling further for hypertension, diabetes mellitus, chronic kidney disease, and three types of noise exposure did not change the association. Larger muscle mass is associated with lower prevalence of hearing loss in elderly Korean females. PMID- 26978777 TI - Machine Learning Classification of Cirrhotic Patients with and without Minimal Hepatic Encephalopathy Based on Regional Homogeneity of Intrinsic Brain Activity. AB - Machine learning-based approaches play an important role in examining functional magnetic resonance imaging (fMRI) data in a multivariate manner and extracting features predictive of group membership. This study was performed to assess the potential for measuring brain intrinsic activity to identify minimal hepatic encephalopathy (MHE) in cirrhotic patients, using the support vector machine (SVM) method. Resting-state fMRI data were acquired in 16 cirrhotic patients with MHE and 19 cirrhotic patients without MHE. The regional homogeneity (ReHo) method was used to investigate the local synchrony of intrinsic brain activity. Psychometric Hepatic Encephalopathy Score (PHES) was used to define MHE condition. SVM-classifier was then applied using leave-one-out cross-validation, to determine the discriminative ReHo-map for MHE. The discrimination map highlights a set of regions, including the prefrontal cortex, anterior cingulate cortex, anterior insular cortex, inferior parietal lobule, precentral and postcentral gyri, superior and medial temporal cortices, and middle and inferior occipital gyri. The optimized discriminative model showed total accuracy of 82.9% and sensitivity of 81.3%. Our results suggested that a combination of the SVM approach and brain intrinsic activity measurement could be helpful for detection of MHE in cirrhotic patients. PMID- 26978778 TI - Risk Perceptions of Wastewater Use for Urban Agriculture in Accra, Ghana. AB - Poor food hygiene is a significant risk to public health globally, but especially in low and middle-income countries where access to sanitation, and general hygiene remain poor. Food hygiene becomes even more pertinent when untreated, or poorly treated wastewater is used in agriculture. In such circumstances the WHO recommends the adoption of a multiple-barrier approach that prescribes health protective measures at different entry points along the food chain. This study sought to assess the knowledge and awareness of wastewater use for crop production, its related health risks, and adoption of health protective measures by farmers, market salespersons and consumers using questionnaires and focus group discussions. In the period from September 2012 to August 2013, 490 respondents were interviewed during two cropping seasons. The study found that awareness of the source of irrigation water was low among consumers and street food vendors, though higher among market vendors. In contrast, health risk awareness was generally high among salespersons and consumers, but low among farmers. The study found that consumers did not prioritize health indicators when buying produce from vendors but were motivated to buy produce, or prepared food based on taste, friendship, cost, convenience and freshness of produce. Similarly, farmers' awareness of health risk did not influence their adoption of safer farm practices. The study recommends the promotion of interventions that would result in more direct benefits to both producers and vendors, together with hygiene education and enforcement of food safety byelaws in order to influence behaviour change, and increase the uptake of the multiple-barrier approach. PMID- 26978779 TI - Disentangle the Causes of the Road Barrier Effect in Small Mammals through Genetic Patterns. AB - Road barrier effect is among the foremost negative impacts of roads on wildlife. Knowledge of the factors responsible for the road barrier effect is crucial to understand and predict species' responses to roads, and to improve mitigation measures in the context of management and conservation. We built a set of hypothesis aiming to infer the most probable cause of road barrier effect (traffic effect or road surface avoidance), while controlling for the potentially confounding effects road width, traffic volume and road age. The wood mouse Apodemus sylvaticus was used as a model species of small and forest-dwelling mammals, which are more likely to be affected by gaps in cover such as those resulting from road construction. We confront genetic patterns from opposite and same roadsides from samples of three highways and used computer simulations to infer migration rates between opposite roadsides. Genetic patterns from 302 samples (ca. 100 per highway) suggest that the highway barrier effect for wood mouse is due to road surface avoidance. However, from the simulations we estimated a migration rate of about 5% between opposite roadsides, indicating that some limited gene flow across highways does occur. To reduce highway impact on population genetic diversity and structure, possible mitigation measures could include retrofitting of culverts and underpasses to increase their attractiveness and facilitate their use by wood mice and other species, and setting aside roadside strips without vegetation removal to facilitate establishment and dispersal of small mammals. PMID- 26978781 TI - Correction: Renal Function Outcomes and Risk Factors for Risk Factors for Stage 3B Chronic Kidney Disease after Urinary Diversion in Patients with Muscle Invasive Bladder Cancer. PMID- 26978780 TI - Social Contact Networks and Mixing among Students in K-12 Schools in Pittsburgh, PA. AB - Students attending schools play an important role in the transmission of influenza. In this study, we present a social network analysis of contacts among 1,828 students in eight different schools in urban and suburban areas in and near Pittsburgh, Pennsylvania, United States of America, including elementary, elementary-middle, middle, and high schools. We collected social contact information of students who wore wireless sensor devices that regularly recorded other devices if they are within a distance of 3 meters. We analyzed these networks to identify patterns of proximal student interactions in different classes and grades, to describe community structure within the schools, and to assess the impact of the physical environment of schools on proximal contacts. In the elementary and middle schools, we observed a high number of intra-grade and intra-classroom contacts and a relatively low number of inter-grade contacts. However, in high schools, contact networks were well connected and mixed across grades. High modularity of lower grades suggests that assumptions of homogeneous mixing in epidemic models may be inappropriate; whereas lower modularity in high schools suggests that homogenous mixing assumptions may be more acceptable in these settings. The results suggest that interventions targeting subsets of classrooms may work better in elementary schools than high schools. Our work presents quantitative measures of age-specific, school-based contacts that can be used as the basis for constructing models of the transmission of infections in schools. PMID- 26978783 TI - Fine-Scale Vertical Stratification and Guild Composition of Saproxylic Beetles in Lowland and Montane Forests: Similar Patterns despite Low Faunal Overlap. AB - OBJECTIVE: The finer scale patterns of arthropod vertical stratification in forests are rarely studied and poorly understood. Further, there are no studies investigating whether and how altitude affects arthropod vertical stratification in temperate forests. We therefore investigated the fine-scale vertical stratification of diversity and guild structure of saproxylic beetles in temperate lowland and montane forests and compared the resulting patterns between the two habitats. METHODS: The beetles were sampled with flight intercept traps arranged into vertical transects (sampling heights 0.4, 1.2, 7, 14, and 21 m). A triplet of such transects was installed in each of the five sites in the lowland and in the mountains; 75 traps were used in each forest type. RESULTS: 381 species were collected in the lowlands and 236 species in the mountains. Only 105 species (21%) were found at both habitats; in the montane forest as well as in the lowlands, the species richness peaked at 1.2 m, and the change in assemblage composition was most rapid near the ground. The assemblages clearly differed between the understorey (0.4 m, 1.2 m) and the canopy (7 m, 14 m, 21 m) and between the two sampling heights within the understorey, but less within the canopy. The stratification was better pronounced in the lowland, where canopy assemblages were richer than those near the forest floor (0.4 m). In the mountains the samples from 14 and 21 m were more species poor than those from the lower heights. The guild structure was similar in both habitats. CONCLUSIONS: The main patterns of vertical stratification and guild composition were strikingly similar between the montane and the lowland forest despite the low overlap of their faunas. The assemblages of saproxylic beetles were most stratified near ground. The comparisons of species richness between canopy and understorey may thus give contrasting results depending on the exact sampling height in the understorey. PMID- 26978785 TI - The spectroscopic analysis of the v2=1, v5=1, and v3=v6=1 infrared vibration system of H3SiI. AB - The nu2 (A1)/nu5 (E)/nu3+nu6 (E) band system of H3(28)SiI was investigated using Fourier transform infrared spectra recorded from 820 to 1100 cm(-1) at a resolution of 2.0*10(-3) cm(-1). In total, 11,903 transitions were assigned. Additional 1466 transitions reaching the v3=v6=1 state were obtained from the nu3+nu6-nu6 and nu3+nu6-nu3 hot bands near 360 and 590 cm(-1), respectively. Moreover, 30 highly accurate CO2 laser sideband transitions of the (r)Q0 branch of nu5 (J.M. Frye, W. Schupita, and G. Magerl, J. Mol. Spectrosc. 128, 427 (1988)) were implemented in the data set with J(max)"=140 and K(max)"=21. To adequately reproduce the complex pattern of interacting levels the Hamiltonian employed included 14 off-diagonal terms. These comprise x,y Coriolis ro-vibration resonances, between nu2/nu5, nu2/nu3+nu6 and nu5/nu3+nu6, and the anharmonic Fermi resonance between nu5/nu3+nu6. All these resonances strongly perturb the v2=1, v5=1, and v3=v6=1 excited states whose rounded deperturbed vibrational term values are 904.5, 941.1, and 953.7 cm(-1), respectively. In addition, the Deltal=Deltak=+/-2 l-resonance was found to be active within the v3=v6=1 state and between v5=1 and v3=v6=1; the Deltal=+/-2,Deltak=?1 l-resonance within the v5=1 state and between v5=1 and v3=v6=1 was established, as well as the Deltal=+/ 1,Deltak=?2 alpha resonance between v2=1 and v5=1. A standard deviation of the fit, 0.48*10(-3) cm(-1), resulted which is ca. three times the estimated precision of experimental wavenumbers. Improved J-dependent ground state parameters of H3SiI were obtained by fitting 5420 combination differences, sigma(fit)=0.22*10(-3) cm(-1). PMID- 26978782 TI - When Breathing Interferes with Cognition: Experimental Inspiratory Loading Alters Timed Up-and-Go Test in Normal Humans. AB - Human breathing stems from automatic brainstem neural processes. It can also be operated by cortico-subcortical networks, especially when breathing becomes uncomfortable because of external or internal inspiratory loads. How the "irruption of breathing into consciousness" interacts with cognition remains unclear, but a case report in a patient with defective automatic breathing (Ondine's curse syndrome) has shown that there was a cognitive cost of breathing when the respiratory cortical networks were engaged. In a pilot study of putative breathing-cognition interactions, the present study relied on a randomized design to test the hypothesis that experimentally loaded breathing in 28 young healthy subjects would have a negative impact on cognition as tested by "timed up-and-go" test (TUG) and its imagery version (iTUG). Progressive inspiratory threshold loading resulted in slower TUG and iTUG performance. Participants consistently imagined themselves faster than they actually were. However, progressive inspiratory loading slowed iTUG more than TUG, a finding that is unexpected with regard to the known effects of dual tasking on TUG and iTUG (slower TUG but stable iTUG). Insofar as the cortical networks engaged in response to inspiratory loading are also activated during complex locomotor tasks requiring cognitive inputs, we infer that competition for cortical resources may account for the breathing-cognition interference that is evidenced here. PMID- 26978786 TI - An experimental and theoretical investigation of free Oxazole in conjunction with the DFT analysis of Oxazole?(H2O)n complexes. AB - The mid-IR spectrum of Oxazole (Oxa) is recorded. This spectrum is interpreted with the help of B3LYP/6-311++G(d,p) calculations and potential energy distribution (PED) analysis. The experimental spectrum is concordant with the theoretical data. Geometrical parameters and the atomic charges are also theoretically obtained and presented. Solvent effects on the geometrical parameters, vibrational frequencies, and electronic properties of Oxa are analyzed theoretically in chloroform, ethanol, and water. Besides, hydrogen bonded Oxa?(H2O)n (n=1, 2,..., 10) complexes are investigated within the PCM solvation model. It is found that the interaction energies in Oxa?(H2O)n complexes are influenced by the number of water molecules, and by the arrangement of water molecules. PMID- 26978784 TI - Knocking on Heaven's Door: Are Novel Invaders Necessarily Facing Naive Native Species on Islands? AB - The impact of alien predator species on insular native biota has often been attributed to island prey naivete (i.e. lack of, or inefficient, anti-predator behavior). Only rarely, however, has the concept of island prey naivete been tested, and then only a posteriori (i.e. hundreds or thousands of years after alien species introduction). The presence of native or anciently introduced predators or competitors may be crucial for the recognition and development of adaptive behavior toward unknown predators or competitors of the same archetype (i.e. a set of species that occupy a similar ecological niche and show similar morphological and behavioral traits when interacting with other species). Here, we tested whether two squamates endemic to New Caledonia, a skink, Caledoniscincus austrocaledonicus, and a gecko, Bavayia septuiclavis, recognized and responded to the odor of two major invaders introduced into the Pacific islands, but not yet into New Caledonia. We chose one predator, the small Indian mongoose Herpestes javanicus and one competitor, the cane toad Rhinella marina, which belong respectively to the same archetype as the following two species already introduced into New Caledonia in the nineteenth century: the feral cat Felis catus and the golden bell frog Litoria aurea. Our experiment reveals that geckos are naive with respect to the odors of both an unknown predator and an unknown competitor, as well as to the odors of a predator and a competitor they have lived with for centuries. In contrast, skinks seem to have lost some naivete regarding the odor of a predator they have lived with for centuries and seem "predisposed" to avoid the odor of an unknown potential competitor. These results indicate that insular species living in contact with invasive alien species for centuries may be, although not systematically, predisposed toward developing adaptive behavior with respect to species belonging to the same archetype and introduced into their native range. PMID- 26978787 TI - Conjugation of cytochrome c with ferrocene-terminated hyperbranched polymer and its influence on protein structure, conformation and function. AB - Interaction mechanism of a new hyperbranched polyurethane-based ferrocene (HPU Fc) with cytochrome c (cyt c) and cyt c structure and conformation change induced by HPU-Fc were investigated using cyclic voltammogram(CV), differential pulse voltammetry (DPV), circular dichroism (CD), fluorescence, synchronous fluorescence and absorbance spectroscopy technique. The peroxidase activity of cyt c in the presence of HPU-Fc was also studied. The structure and conformation of protein are relatively stable at moderate concentration of HPU-Fc without obvious perturbation of the heme pocket and significant changes in protein secondary structure. Conjugation of cyt c with excessive HPU-Fc (over about 3 times of cyt c) slightly changed the alpha-helix structure in protein, disturbed the microenvironment around heme as well as away from the heme crevice, which caused the changes of the electrochemical behavior and the absorption spectra. Reasonable amount of HPU-Fc has no significant influence on the protein enzymatic activity, while excess HPU-Fc may cause a conformation not suitable for H2O2 activation and guaiacol oxidation. The interaction of HPU-Fc with cyt c and the conservation of protein function at suitable HPU-Fc amount make prepared complex promising for the synergistic anticancer therapy. PMID- 26978788 TI - A sensitive and selective resonance Rayleigh scattering method for quick detection of avidin using affinity labeling Au nanoparticles. AB - Avidin is a glycoprotein with antinutritional property, which should be limited in daily food. We developed an affinity biosensor system based on resonance Rayleigh scattering (RRS) and using affinity biotin labeling Au nanoparticles (AuNPs). This method was selective and sensitive for quick avidin detection due to the avidin-biotin affinitive interaction. Under optimal conditions, RRS intensity of biotin-AuNPs increase linearly with an increasing concentration of avidin from 5 to 160 ng/mL. The lower limit of detection was 0.59 ng/mL. This rapid and selective avidin detection method was used in synthetic samples and egg products with recoveries of between 102.97 and 107.92%, thereby demonstrating the feasible and practical application of this assay. PMID- 26978789 TI - Imaging Assessment of Re-Exploratory Repair of an Occipital Bone Defect Associated Tectocerebellar Dysraphism via Hybrid Cranioplasty. PMID- 26978790 TI - Electrochemiluminescent detection of methamphetamine and amphetamine. AB - Direct detection of amphetamine type stimulants (ATSs) including methylamphetamine (MA) in street samples and biological matrices without the need for pretreatment or extraction is a great challenge for forensic drug analysis. Electrochemical techniques, such as electrochemiluminescence (ECL), are promising tools for this area of analysis. This contribution focuses on the electrochemical and photochemical properties of [Ru(bpy)3](2+) Nafion composite films and their subsequent use for the detection of ATS in particular MA. Under optimised conditions, the response linearly increased with the concentration over the concentration range 50pM<=[MA]<=1mM while an equivalent dynamic range was obtained for amphetamine with a correlation coefficient of 0.9903 and 0.9948 respectively. The ECL signal was monitored at ~620nm, representing the lambdamax for the [Ru(bpy)3](2+) Nafion composite films. This wavelength is shifted by approximately 15nm compared to the photoexcited lambdamax for the same system. The modified films were formed by direct interaction with the electrode surface without the need for surface modification or chain linkers. This is a major advantage for the fabrication of any sensor as it reduces the synthesis times resulting in more economically and cheaper production costs. This technique is simple, rapid, selective and sensitive, and shows potential for the high throughput quantitation of ATS as well as possibilities for adaptation with other techniques such as FIA or LC systems. PMID- 26978791 TI - Studying illicit drug trafficking on Darknet markets: Structure and organisation from a Canadian perspective. AB - Cryptomarkets are online marketplaces that are part of the Dark Web and mainly devoted to the sale of illicit drugs. They combine tools to ensure anonymity of participants with the delivery of products by mail to enable the development of illicit drug trafficking. Using data collected on eight cryptomarkets, this study provides an overview of the Canadian illicit drug market. It seeks to inform about the most prevalent illicit drugs vendors offer for sale and preferred destination countries. Moreover, the research gives an insight into the structure and organisation of distribution networks existing online. In particular, we provide information about how vendors are diversifying and replicating across marketplaces. We inform on the number of listings each vendor manages, the number of cryptomarkets they are active on and the products they offer. This research demonstrates the importance of online marketplaces in the context of illicit drug trafficking. It shows how the analysis of data available online may elicit knowledge on criminal activities. Such knowledge is mandatory to design efficient policy for monitoring or repressive purposes against anonymous marketplaces. Nevertheless, trafficking on Dark Net markets is difficult to analyse based only on digital data. A more holistic approach for investigating this crime problem should be developed. This should rely on a combined use and interpretation of digital and physical data within a single collaborative intelligence model. PMID- 26978792 TI - A bacteriophage endolysin that eliminates intracellular streptococci. AB - PlyC, a bacteriophage-encoded endolysin, lyses Streptococcus pyogenes (Spy) on contact. Here, we demonstrate that PlyC is a potent agent for controlling intracellular Spy that often underlies refractory infections. We show that the PlyC holoenzyme, mediated by its PlyCB subunit, crosses epithelial cell membranes and clears intracellular Spy in a dose-dependent manner. Quantitative studies using model membranes establish that PlyCB interacts strongly with phosphatidylserine (PS), whereas its interaction with other lipids is weak, suggesting specificity for PS as its cellular receptor. Neutron reflection further substantiates that PlyC penetrates bilayers above a PS threshold concentration. Crystallography and docking studies identify key residues that mediate PlyCB-PS interactions, which are validated by site-directed mutagenesis. This is the first report that a native endolysin can traverse epithelial membranes, thus substantiating the potential of PlyC as an antimicrobial for Spy in the extracellular and intracellular milieu and as a scaffold for engineering other functionalities. PMID- 26978793 TI - A simple generative model of the mouse mesoscale connectome. AB - Recent technological advances now allow for the collection of vast data sets detailing the intricate neural connectivity patterns of various organisms. Oh et al. (2014) recently published the most complete description of the mouse mesoscale connectome acquired to date. Here we give an in-depth characterization of this connectome and propose a generative network model which utilizes two elemental organizational principles: proximal attachment - outgoing connections are more likely to attach to nearby nodes than to distant ones, and source growth - nodes with many outgoing connections are likely to form new outgoing connections. We show that this model captures essential principles governing network organization at the mesoscale level in the mouse brain and is consistent with biologically plausible developmental processes. PMID- 26978797 TI - Organ Failure, Hypoperfusion, and Pressure Ulcers Are Not the Same as Skin Failure: A Case for a New Definition. PMID- 26978798 TI - 2016 Update: Cellular and/or Tissue-Based Products for Wounds. PMID- 26978794 TI - Cooperation between distinct viral variants promotes growth of H3N2 influenza in cell culture. AB - RNA viruses rapidly diversify into quasispecies of related genotypes. This genetic diversity has long been known to facilitate adaptation, but recent studies have suggested that cooperation between variants might also increase population fitness. Here, we demonstrate strong cooperation between two H3N2 influenza variants that differ by a single mutation at residue 151 in neuraminidase, which normally mediates viral exit from host cells. Residue 151 is often annotated as an ambiguous amino acid in sequenced isolates, indicating mixed viral populations. We show that mixed populations grow better than either variant alone in cell culture. Pure populations of either variant generate the other through mutation and then stably maintain a mix of the two genotypes. We suggest that cooperation arises because mixed populations combine one variant's proficiency at cell entry with the other's proficiency at cell exit. Our work demonstrates a specific cooperative interaction between defined variants in a viral quasispecies. PMID- 26978799 TI - A Multimodality Imaging and Software System for Combining an Anatomical and Physiological Assessment of Skin and Underlying Tissue Conditions. AB - OBJECTIVE: The timely and accurate assessment of skin and underlying tissue is crucial for making informed decisions relating to wound development and existing wounds. The study objective was to determine within- and between-reader agreement of Scout Visual-to-Thermal Overlay (WoundVision LLC, Indianapolis, Indiana) placement (moving the wound edge trace from the visual image onto the wound edge signature of the infrared image). MATERIALS AND METHODS: For establishing within- and between-reader agreement of the Scout Visual-to-Thermal Overlay feature, 5 different readers overlaid a wound edge trace from the visual image and placed it onto the congruent thermal representation of the wound on a thermal image 3 independent times. Forty different wound image pairs were evaluated by each reader. All readers were trained by the same trainer on the operation of the Scout prior to using the software features. The Scout Visual-to-Thermal Overlay feature allows clinicians to use an anatomical measurement of the wound on the visual image (area and perimeter) to extract a congruent physiological measurement of the wound on the thermal image (thermal intensity variation data) by taking the wound edge trace from the visual image and overlaying it onto the corresponding thermal signature of the same wound edge. RESULTS: The results are very similar both within- and between-readers. The coefficient of variation (CV) for the mean PV both within- and between-readers averages less than 1%, 0.89 and 0.77 respectively. When converted into degrees Celsius across all 5 readers and all 3 wound replicates, the average temperature differential is 0.28 degrees C (). The largest difference observed was 0.63 degrees C and the smallest difference observed was 0.04 degrees C. CONCLUSIONS: The Scout software's Visual to-Thermal Overlay procedure, as implemented in this study, is very precise. This study demonstrates that the thermal signature of wounds may be delineated repeatedly by the same operator and reproducibly by different operators. Thus, clinicians can integrate a criterion standard visual (anatomical) assessment with a congruent physiological assessment to provide them with knowledge relating to the presence or absence of blood flow, perfusion, and metabolic activity in the wound, periwound, and wound site. PMID- 26978800 TI - The Use of a Novel Canister-free Negative-Pressure Device in Chronic Wounds: A Retrospective Analysis. AB - OBJECTIVE: Negative-pressure wound therapy (NPWT) is a mainstay in the treatment of acute and chronic wounds. Following the success of the Vacuum-Assisted Closure system (Kinetic Concepts Inc [KCI], an Acelity Company, San Antonio, Texas), many similar systems were developed with minor variations. However, these systems are best suited to wounds with soft-tissue defects. Moreover, the need for a canister to collect wound exudate adds to the size and weight of the device. A canister free (CF) NPWT device was cleared by the FDA for the treatment of chronic wounds (Kalypto Medical, Mendota Heights, Minnesota). A retrospective study was designed to evaluate the effectiveness of the CF-NPWT device in promoting wound healing. METHODS: The authors examined the records of 51 patients treated with the CF-NPWT device over a 21-month period. Study participants were treated in an outpatient setting, had at least 30 days of prior treatment, and carried insurance coverage through Medicare or Medicaid. The comparison of time to heal between groups was conducted using the log-rank, Breslow, and Tarone-Ware tests in conjunction with a Kaplan-Meier analysis. RESULTS: In the study population, 65% of the wounds achieved complete closure. For unhealed wounds, the mean wound area reduction was 31.9%, and the mean wound depth reduction was 57.5%. The mean time to heal was 56.9 days (95% confidence interval, 46.4-67.4 days). CONCLUSIONS: The results show that the CF-NPWT system meets or exceeds healing rates previously reported in the literature for canister-based systems. This CF device offers a more portable NPWT option, particularly effective in the treatment of shallow wounds. PMID- 26978795 TI - Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration. AB - Photoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease. RPE dysfunction or death is a primary event in AMD, but the combination(s) of cellular stresses that affect the function and survival of RPE are incompletely understood. Here, using mouse models in which hypoxia can be genetically triggered in RPE, we show that hypoxia-induced metabolic stress alone leads to photoreceptor atrophy. Glucose and lipid metabolism are radically altered in hypoxic RPE cells; these changes impact nutrient availability for the sensory retina and promote progressive photoreceptor degeneration. Understanding the molecular pathways that control these responses may provide important clues about AMD pathogenesis and inform future therapies. PMID- 26978802 TI - Risk Factors for Pressure Ulcers Including Suspected Deep Tissue Injury in Nursing Home Facility Residents: Analysis of National Minimum Data Set 3.0. AB - PURPOSE: To provide information on risk factors associated with pressure ulcers (PrUs), including suspected deep tissue injury (sDTI), in nursing home residents in the United States. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to:1. Examine the literature related to risk factors for the development of PrUs.2. Compare risk factors associated with the prevalence of PrUs and sDTI from the revised Minimum Data Set 3.0 2012 using a modified Defloor's conceptual model of PrUs as a theoretical framework. ABSTRACT: OBJECTIVE: This study aims to characterize and compare risk factors associated with pressure ulcers (PrUs), including suspected deep tissue injury (sDTI), in nursing home (NH) residents in the United States. DESIGN: Secondary analysis of the 2012 Minimum Data Set (MDS 3.0). SETTING: Medicare- or Medicaid-certified NHs in the United States. PARTICIPANTS: Nursing home residents (n = 2,936,146) 18 years or older with complete PrU data, who received comprehensive assessments from January to December 2012. MEASUREMENTS: Pressure ulcer by stage was the outcome variable. Explanatory variables (age, gender, race and ethnicity, body mass index, skin integrity, system failure, disease, infection, mobility, and cognition) from the MDS 3.0 were aligned with the 4 elements of Defloor's conceptual model: compressive forces, shearing forces, tissue tolerance for pressure, and tissue tolerance for oxygen. RESULTS: Of 2,936,146 NH residents who had complete data for PrU, 89.9% had no PrU; 8.4% had a Stage 2, 3, or 4 or unstagable PrU; and 1.7% had an sDTI. The MDS variables corresponding to the 4 elements of Defloor's model were significantly predictive of both PrU and sDTI. Black residents had the highest risk of any-stage PrU, and Hispanic residents had the highest risk of sDTI. Skin integrity, system failure, infection, and disease risk factors had larger effect sizes for sDTI than for other PrU stages. CONCLUSIONS: The MDS data support Defloor's model and inform clinicians, educators, researchers, and policymakers on risk factors associated with PrUs and sDTI in NH residents in the United States participating in Medicare and Medicaid. PMID- 26978801 TI - Effects of Lidocaine, Bupivacaine, and Ropivacaine on Calcitonin Gene-Related Peptide and Substance P Levels in the Incised Rat Skin. AB - OBJECTIVE: To evaluate the effect of 2% lidocaine, 0.5% bupivacaine, and 0.75% ropivacaine on the release of substance P (SP) and calcitonin gene-related peptide (CGRP) in skin wounds. DESIGN: A primary, experimental, analytical, prospective, self-controlled, blinded study. SETTING: The study is set in a university research center. INTERVENTIONS: Twenty-eight Wistar rats were randomly divided into 4 groups: lidocaine, bupivacaine, ropivacaine, and the control. After general anesthesia, a local anesthetic or 0.9% saline (control) was injected subdermally along a 2-cm line on the dorsal midline of each rat; 30 minutes later, an incision (nociceptive stimulus) was made along this line. The animals were euthanized, and skin samples were collected from the center of the incision line and sent for CGRP and SP quantification. MAIN OUTCOME MEASURES: Quantification of CGRP and SP by Western blotting. RESULTS: Substance P levels were similar in the lidocaine and ropivacaine groups but were significantly lower than those of the control group (P = .002); no significant difference in SP levels was found between the bupivacaine and control groups. Procalcitonin gene related peptide levels were significantly lower in the experimental groups than those in control subjects (P = .009), with no significant differences among the experimental groups. No significant differences in CGRP levels were found among all groups. Lidocaine and ropivacaine inhibited SP release. All 3 local anesthetics inhibited the release of procalcitonin gene-related peptide, but not the release of CGRP in rat skin. CONCLUSIONS: Lidocaine and ropivacaine may inhibit neurogenic inflammation by biochemical pathways activated by SP, whereas bupivacaine seems to have no influence on this process. PMID- 26978803 TI - The Strategic View of Modified Stage 2 Meaningful Use: Part 4: Objective 8: Patient Electronic Access. PMID- 26978805 TI - [Not Available]. PMID- 26978806 TI - [Not Available]. AB - Acute-on-chronic liver failure (ACLF) is a condition that may develop in up to one third of patients with chronic liver disease who exhibit clinical signs of acute decompensation, i.e. ascites, gastrointestinal bleeding, hepatic encephalopathy or bacterial infection. ACLF implies the combination of acute hepatic decompensation with organ failure in kidney, brain, liver, lungs, circulation and/or coagulation. The prognosis worsens with the number of failing organs, renal involvement, advanced age and elevated leukocyte blood count. ACLF is caused by a systemic inflammation. Cultures from blood, urine and ascites should be drawn, and rapid antibiotic treatment is essential to prevent ACLF development. Renal function must be monitored and renal failure treated promptly. Acute alcoholic hepatitis may be considered a specific case of ACLF, which may be treated with corticosteroids in cases having high score in prognostic indices (GAHS, MELD or ABIC), and after bacterial infections have been ruled out or treated. PMID- 26978807 TI - [Not Available]. PMID- 26978808 TI - [Not Available]. PMID- 26978809 TI - [Not Available]. AB - Hepatic encephalopathy causes significant impairment and morbidity. Hepatic encephalopathy is just one of many causes for altered mental status in patients with cirrhosis of the liver. The initial management at admission to hospital includes a search for differential diagnoses and precipitating factors. A structured description of the type, cause, time course and clinical severity is essential for achieving medically safe communication and care of the HE patient. Lactulose and correction of any precipitating factors is the basis for initial therapy. A post-discharge management which includes frequent monitoring, preventive measures as well as education of patient and caregivers may ameliorate the often very high readmission rate. PMID- 26978810 TI - [Not Available]. AB - Ascites is a common complication of liver cirrhosis and is associated with a poor prognosis. The main pathophysiology is an increased portal pressure with compensatory activation of neurohumoral systems. A patient history, proper physical exam and adequate examination of ascitic fluid will reveal the aetiology in most cases. Complications such as spontaneous bacterial peritonitis and thrombosis of hepatic vessel should be excluded in cases of first episode of ascites or deterioration of ascites. A moderate salt restriction and treatment with diuretics is the mainstay of treatment. Potentially nephrotoxic drugs such as NSAID and ACE inhibitors should be avoided in patients with cirrhosis. PMID- 26978811 TI - [Not Available]. AB - Patients with acute and chronic liver disease have a rebalanced hemostasis, i.e. these patients have an increased tendency for both bleeding and thrombosis.Bleeding is primarily related to portal hypertension, rather than a defective hemostasis. There are well-established clinical guidelines for the management of patients with liver cirrhosis and variceal bleeding.Epidemiological studies have demonstrated an increased risk of venous thromboembolism in patients with liver cirrhosis. The treatment of patients with liver cirrhosis and venous thrombosis is not well documented. Treatment with anticoagulants should be considered in patients with symptomatic, extensive or progressive thrombosis of the portal system, as well as in patients who are being considered for liver transplantation. PMID- 26978812 TI - [Not Available]. PMID- 26978813 TI - [Not Available]. PMID- 26978814 TI - [Alcoholism - Malcolm Lowrys deadly disease and literary theme]. PMID- 26978815 TI - [Zika virus - ancient virus gets new life in a new ecosystem. Microcephaly and Guillain-Barre syndrome are possible consequences when there is no background herd immunity in the population]. AB - Zika virus is a mosquito-borne flavivirus transmitted by Aedes mosquitos. The virus was discovered in 1947 in the Zika forest in Uganda. Symptomatic disease is usually mild and is characterized by maculopapular rash, headache, fever, arthralgia and conjunctivitis. Fatalities are rare. There is neither vaccine nor curative treatment available. In May 2015, the first observation of local virus transmission was reported from Brazil. During the expanding outbreak in the Americas, Zika virus infection has been associated with microcephaly in newborn and fetal losses in women infected with Zika virus during pregnancy. The main reason for the current epidemic in the Americas is the introduction of an Old World virus into a new ecosystem, with no background herd immunity in the population. It is likely that the spread of Zika virus will continue, affecting all countries in the Americas except for Chile and Canada. PMID- 26978817 TI - [Not Available]. PMID- 26978816 TI - [Lack of evidence for the result of "active health management"]. PMID- 26978818 TI - [Responsibility is to choose feasible ways]. PMID- 26978819 TI - [Reply to Carl-Gustaf Elinder: Active health management - neither new nor unknown intervention]. PMID- 26978821 TI - Multi-Modal Clique-Graph Matching for View-Based 3D Model Retrieval. AB - Multi-view matching is an important but a challenging task in view-based 3D model retrieval. To address this challenge, we propose an original multi-modal clique graph (MCG) matching method in this paper. We systematically present a method for MCG generation that is composed of cliques, which consist of neighbor nodes in multi-modal feature space and hyper-edges that link pairwise cliques. Moreover, we propose an image set-based clique/edgewise similarity measure to address the issue of the set-to-set distance measure, which is the core problem in MCG matching. The proposed MCG provides the following benefits: 1) preserves the local and global attributes of a graph with the designed structure; 2) eliminates redundant and noisy information by strengthening inliers while suppressing outliers; and 3) avoids the difficulty of defining high-order attributes and solving hyper-graph matching. We validate the MCG-based 3D model retrieval using three popular single-modal data sets and one novel multi-modal data set. Extensive experiments show the superiority of the proposed method through comparisons. Moreover, we contribute a novel real-world 3D object data set, the multi-view RGB-D object data set. To the best of our knowledge, it is the largest real-world 3D object data set containing multi-modal and multi-view information. PMID- 26978820 TI - Estimation of Virtual View Synthesis Distortion Toward Virtual View Position. AB - We propose an analytical model to estimate the depth-error-induced virtual view synthesis distortion (VVSD) in 3D video, taking the distance between reference and virtual views (virtual view position) into account. In particular, we start with a comprehensive preanalysis and discussion over several possible VVSD scenarios. Taking intrinsic characteristic of each scenario into consideration, we specifically classify them into four clusters: 1) overlapping region; 2) disocclusion and boundary region; 3) edge region; and 4) infrequent region. We propose to model VVSD as the linear combination of the distortion under different scenarios (DDSs) weighted by the probability under different scenarios (PDSs). We show analytically that DDS and PDS can be related to the virtual view position using quadratic/biquadratic models and linear models, respectively. Experimental results verify that the proposed model is capable of estimating the relationship between VVSD and the distance between reference and virtual views. Therefore, our model can be used to inform a reference view setup for capturing, or distortion at certain virtual view positions, when depth information is compressed. PMID- 26978822 TI - Non-Iterative Rigid 2D/3D Point-Set Registration Using Semidefinite Programming. AB - We describe a convex programming framework for pose estimation in 2D/3D point-set registration with unknown point correspondences. We give two mixed-integer nonlinear program (MINLP) formulations of the 2D/3D registration problem when there are multiple 2D images, and propose convex relaxations for both the MINLPs to semidefinite programs that can be solved efficiently by interior point methods. Our approach to the 2D/3D registration problem is non-iterative in nature as we jointly solve for pose and correspondence. Furthermore, these convex programs can readily incorporate feature descriptors of points to enhance registration results. We prove that the convex programs exactly recover the solution to the MINLPs under certain noiseless condition. We apply these formulations to the registration of 3D models of coronary vessels to their 2D projections obtained from multiple intra-operative fluoroscopic images. For this application, we experimentally corroborate the exact recovery property in the absence of noise and further demonstrate robustness of the convex programs in the presence of noise. PMID- 26978823 TI - Online Nonparametric Bayesian Activity Mining and Analysis From Surveillance Video. AB - A method for online incremental mining of activity patterns from the surveillance video stream is presented in this paper. The framework consists of a learning block in which Dirichlet process mixture model is employed for the incremental clustering of trajectories. Stochastic trajectory pattern models are formed using the Gaussian process regression of the corresponding flow functions. Moreover, a sequential Monte Carlo method based on Rao-Blackwellized particle filter is proposed for tracking and online classification as well as the detection of abnormality during the observation of an object. Experimental results on real surveillance video data are provided to show the performance of the proposed algorithm in different tasks of trajectory clustering, classification, and abnormality detection. PMID- 26978824 TI - Non-Local Auto-Encoder With Collaborative Stabilization for Image Restoration. AB - Deep neural networks have been applied to image restoration to achieve the top level performance. From a neuroscience perspective, the layerwise abstraction of knowledge in a deep neural network can, to some extent, reveal the mechanisms of how visual cues are processed in human brain. A pivotal property of human brain is that similar visual cues can stimulate the same neuron to induce similar neurological signals. However, conventional neural networks do not consider this property, and the resulting models are, as a result, unstable regarding their internal propagation. In this paper, we develop the (stacked) non-local auto encoder, which exploits self-similar information in natural images for stability. We propose that similar inputs should induce similar network propagation. This is achieved by constraining the difference between the hidden representations of non local similar image blocks during training. By applying the proposed model to image restoration, we then develop a collaborative stabilization step to further rectify forward propagation. To obtain a reliable deep model, we employ several strategies to simplify training and improve testing. Extensive image restoration experiments, including image denoising and super-resolution, demonstrate the effectiveness of the proposed method. PMID- 26978825 TI - JAMA PATIENT PAGE. Opioids for Chronic Pain. PMID- 26978827 TI - Fast, Memory-Efficient Construction of Voxelized Shadows. AB - We present a fast and memory efficient algorithm for generating Compact Precomputed Voxelized Shadows. By performing much of the common sub-tree merging before identical nodes are ever created, we improve construction times by several orders of magnitude for large data structures, and require much less working memory. To further improve performance, we suggest two new algorithms with which the remaining common sub-trees can be merged. We also propose a new set of rules for resolving undefined regions, which significantly reduces the final memory footprint of the already heavily compressed data structure. Additionally, we examine the feasibility of using CPVS for many local lights and present two improvements to the original algorithm that allow us to handle hundreds of lights with high-quality, filtered shadows at real-time frame rates. PMID- 26978829 TI - Energetic Passivity of the Human Ankle Joint. AB - Understanding the passive or nonpassive behavior of the neuromuscular system is important to design and control robots that physically interact with humans, since it provides quantitative information to secure coupled stability while maximizing performance. This has become more important than ever apace with the increasing demand for robotic technologies in neurorehabilitation. This paper presents a quantitative characterization of passive and nonpassive behavior of the ankle of young healthy subjects, which provides a baseline for future studies in persons with neurological impairments and information for future developments of rehabilitation robots, such as exoskeletal devices and powered prostheses. Measurements using a wearable ankle robot actuating 2 degrees-of-freedom of the ankle combined with curl analysis and passivity analysis enabled characterization of both quasi-static and steady-state dynamic behavior of the ankle, unavailable from single DOF studies. Despite active neuromuscular control over a wide range of muscle activation, in young healthy subjects passive or dissipative ankle behavior predominated. PMID- 26978830 TI - Extension of Stability Radius to Neuromechanical Systems With Structured Real Perturbations. AB - The ability of humans to maintain balance about an unstable position in a continuously changing environment attests to the robustness of their balance control mechanisms to perturbations. A mathematical tool to analyze robust stabilization of unstable equilibria is the stability radius. Based on the pseudo spectra, the stability radius gives a measure to the maximum change of the system parameters without resulting in a loss of stability. Here, we compare stability radii for a model for human frontal plane balance controlled by a delayed proportional-derivative feedback to two types of perturbations: unstructured complex and weighted structured real. It is shown that: 1) narrow stance widths are more robust to parameter variation; 2) stability is maintained for larger structured real perturbations than for unstructured complex perturbations; and 3) the most robust derivative gain to weighted structured real perturbations is located near the stability boundary. It is argued that stability radii can effectively be used to compare different control concepts associated with human motor control. PMID- 26978831 TI - Nanowire-Based Sensors for Biological and Medical Applications. AB - Nanomaterials such as nanowires, carbon nanotubes, and nanoparticles have already led to breakthroughs in the field of biological and medical sensors. The quantum size effects of the nanomaterials and their similarity in size to natural and synthetic nanomaterials are anticipated to improve sensor sensitivity dramatically. Nanowires are considered as key nanomaterials because of their electrical controllability for accurate measurement, and chemical-friendly surface for various sensing applications. This review covers the working principles and fabrication of silicon nanowire sensors. Furthermore, we review their applications for the detection of viruses, biomarkers, and DNA, as well as for drug discovery. Advances in the performance and functionality of nanowire sensors are also surveyed to highlight recent progress in this area. These advances include the improvements in reusability, sensitivity in high ionic strength solvent, long-term stability, and self-powering. Overall, with the advantages of ultra-sensitivity and the ease of fabrication, it is expected that nanowires will contribute significantly to the development of biological and medical sensors in the immediate future. PMID- 26978833 TI - Neural Network Control-Based Adaptive Learning Design for Nonlinear Systems With Full-State Constraints. AB - In order to stabilize a class of uncertain nonlinear strict-feedback systems with full-state constraints, an adaptive neural network control method is investigated in this paper. The state constraints are frequently emerged in the real-life plants and how to avoid the violation of state constraints is an important task. By introducing a barrier Lyapunov function (BLF) to every step in a backstepping procedure, a novel adaptive backstepping design is well developed to ensure that the full-state constraints are not violated. At the same time, one remarkable feature is that the minimal learning parameters are employed in BLF backstepping design. By making use of Lyapunov analysis, we can prove that all the signals in the closed-loop system are semiglobal uniformly ultimately bounded and the output is well driven to follow the desired output. Finally, a simulation is given to verify the effectiveness of the method. PMID- 26978832 TI - A Mixed-Signal VLSI System for Producing Temporally Adapting Intraspinal Microstimulation Patterns for Locomotion. AB - Neural pathways can be artificially activated through the use of electrical stimulation. For individuals with a spinal cord injury, intraspinal microstimulation, using electrical currents on the order of 125 MU A, can produce muscle contractions and joint torques in the lower extremities suitable for restoring walking. The work presented here demonstrates an integrated circuit implementing a state-based control strategy where sensory feedback and intrinsic feed forward control shape the stimulation waveforms produced on-chip. Fabricated in a 0.5 MU m process, the device was successfully used in vivo to produce walking movements in a model of spinal cord injury. This work represents progress towards an implantable solution to be used for restoring walking in individuals with spinal cord injuries. PMID- 26978834 TI - Action and Event Recognition in Videos by Learning From Heterogeneous Web Sources. AB - In this paper, we propose new approaches for action and event recognition by leveraging a large number of freely available Web videos (e.g., from Flickr video search engine) and Web images (e.g., from Bing and Google image search engines). We address this problem by formulating it as a new multi-domain adaptation problem, in which heterogeneous Web sources are provided. Specifically, we are given different types of visual features (e.g., the DeCAF features from Bing/Google images and the trajectory-based features from Flickr videos) from heterogeneous source domains and all types of visual features from the target domain. Considering the target domain is more relevant to some source domains, we propose a new approach named multi-domain adaptation with heterogeneous sources (MDA-HS) to effectively make use of the heterogeneous sources. In MDA-HS, we simultaneously seek for the optimal weights of multiple source domains, infer the labels of target domain samples, and learn an optimal target classifier. Moreover, as textual descriptions are often available for both Web videos and images, we propose a novel approach called MDA-HS using privileged information (MDA-HS+) to effectively incorporate the valuable textual information into our MDA-HS method, based on the recent learning using privileged information paradigm. MDA-HS+ can be further extended by using a new elastic-net-like regularization. We solve our MDA-HS and MDA-HS+ methods by using the cutting plane algorithm, in which a multiple kernel learning problem is derived and solved. Extensive experiments on three benchmark data sets demonstrate that our proposed approaches are effective for action and event recognition without requiring any labeled samples from the target domain. PMID- 26978835 TI - $?mu $ -Stability of Nonlinear Positive Systems With Unbounded Time-Varying Delays. AB - The stability of the zero solution plays an important role in the investigation of positive systems. In this brief, we discuss the MU -stability of positive nonlinear systems with unbounded time-varying delays. The system is modeled by the continuous-time ordinary differential equation. Under some assumptions on the nonlinear functions, such as homogeneous, cooperative, and nondecreasing, we propose a novel transform, by which the nonlinear system reduces to a new system. Thus, we analyze its dynamics, which can simplify the nonlinear homogenous functions with respect to the arbitrary dilation map to those with respect to the standard dilation map. We finally get some new criteria for the global MU stability taking the degree into consideration. A numerical example is given to demonstrate the validity of obtained results. PMID- 26978836 TI - Holographic Graph Neuron: A Bioinspired Architecture for Pattern Processing. AB - In this paper, we propose a new approach to implementing hierarchical graph neuron (HGN), an architecture for memorizing patterns of generic sensor stimuli, through the use of vector symbolic architectures. The adoption of a vector symbolic representation ensures a single-layer design while retaining the existing performance characteristics of HGN. This approach significantly improves the noise resistance of the HGN architecture, and enables a linear (with respect to the number of stored entries) time search for an arbitrary subpattern. PMID- 26978837 TI - Sequential Nonlinear Learning for Distributed Multiagent Systems via Extreme Learning Machines. AB - We study online nonlinear learning over distributed multiagent systems, where each agent employs a single hidden layer feedforward neural network (SLFN) structure to sequentially minimize arbitrary loss functions. In particular, each agent trains its own SLFN using only the data that is revealed to itself. On the other hand, the aim of the multiagent system is to train the SLFN at each agent as well as the optimal centralized batch SLFN that has access to all the data, by exchanging information between neighboring agents. We address this problem by introducing a distributed subgradient-based extreme learning machine algorithm. The proposed algorithm provides guaranteed upper bounds on the performance of the SLFN at each agent and shows that each of these individual SLFNs asymptotically achieves the performance of the optimal centralized batch SLFN. Our performance guarantees explicitly distinguish the effects of data- and network-dependent parameters on the convergence rate of the proposed algorithm. The experimental results illustrate that the proposed algorithm achieves the oracle performance significantly faster than the state-of-the-art methods in the machine learning and signal processing literature. Hence, the proposed method is highly appealing for the applications involving big data. PMID- 26978838 TI - Robust Object Tracking via Key Patch Sparse Representation. AB - Many conventional computer vision object tracking methods are sensitive to partial occlusion and background clutter. This is because the partial occlusion or little background information may exist in the bounding box, which tends to cause the drift. To this end, in this paper, we propose a robust tracker based on key patch sparse representation (KPSR) to reduce the disturbance of partial occlusion or unavoidable background information. Specifically, KPSR first uses patch sparse representations to get the patch score of each patch. Second, KPSR proposes a selection criterion of key patch to judge the patches within the bounding box and select the key patch according to its location and occlusion case. Third, KPSR designs the corresponding contribution factor for the sampled patches to emphasize the contribution of the selected key patches. Comparing the KPSR with eight other contemporary tracking methods on 13 benchmark video data sets, the experimental results show that the KPSR tracker outperforms classical or state-of-the-art tracking methods in the presence of partial occlusion, background clutter, and illumination change. PMID- 26978839 TI - Task Sensitive Feature Exploration and Learning for Multitask Graph Classification. AB - Multitask learning (MTL) is commonly used for jointly optimizing multiple learning tasks. To date, all existing MTL methods have been designed for tasks with feature-vector represented instances, but cannot be applied to structure data, such as graphs. More importantly, when carrying out MTL, existing methods mainly focus on exploring overall commonality or disparity between tasks for learning, but cannot explicitly capture task relationships in the feature space, so they are unable to answer important questions, such as what exactly is shared between tasks and what is the uniqueness of one task differing from others? In this paper, we formulate a new multitask graph learning problem, and propose a task sensitive feature exploration and learning algorithm for multitask graph classification. Because graphs do not have features available, we advocate a task sensitive feature exploration and learning paradigm to jointly discover discriminative subgraph features across different tasks. In addition, a feature learning process is carried out to categorize each subgraph feature into one of three categories: (1) common feature; (2) task auxiliary feature; and (3) task specific feature, indicating whether the feature is shared by all tasks, by a subset of tasks, or by only one specific task, respectively. The feature learning and the multiple task learning are iteratively optimized to form a multitask graph classification model with a global optimization goal. Experiments on real world functional brain analysis and chemical compound categorization demonstrate the algorithm's performance. Results confirm that our method can be used to explicitly capture task correlations and uniqueness in the feature space, and explicitly answer what are shared between tasks and what is the uniqueness of a specific task. PMID- 26978840 TI - A Robust and Fast Method for Sidescan Sonar Image Segmentation Using Nonlocal Despeckling and Active Contour Model. AB - Sidescan sonar image segmentation is a very important issue in underwater object detection and recognition. In this paper, a robust and fast method for sidescan sonar image segmentation is proposed, which deals with both speckle noise and intensity inhomogeneity that may cause considerable difficulties in image segmentation. The proposed method integrates the nonlocal means-based speckle filtering (NLMSF), coarse segmentation using k -means clustering, and fine segmentation using an improved region-scalable fitting (RSF) model. The NLMSF is used before the segmentation to effectively remove speckle noise while preserving meaningful details such as edges and fine features, which can make the segmentation easier and more accurate. After despeckling, a coarse segmentation is obtained by using k -means clustering, which can reduce the number of iterations. In the fine segmentation, to better deal with possible intensity inhomogeneity, an edge-driven constraint is combined with the RSF model, which can not only accelerate the convergence speed but also avoid trapping into local minima. The proposed method has been successfully applied to both noisy and inhomogeneous sonar images. Experimental and comparative results on real and synthetic sonar images demonstrate that the proposed method is robust against noise and intensity inhomogeneity, and is also fast and accurate. PMID- 26978843 TI - All It Takes Is Vision: Synthetic Biology Opens the Doors to Vast Possibilities: "Ideas Just Pop Into Your Head". AB - Traditional genetic engineering has for several decades enabled the cutting and pasting of DNA from one place to another, allowing for all kinds of developments: giving bacteria the ability to make insulin, making crops pesticide-resistant, and increasing the size of food animals, to name but a few. PMID- 26978841 TI - Modeled Perfluorooctanoic Acid (PFOA) Exposure and Liver Function in a Mid-Ohio Valley Community. AB - BACKGROUND: Perfluorooctanoic acid (PFOA or C8) has hepatotoxic effects in animals. Cross-sectional epidemiologic studies suggest PFOA is associated with liver injury biomarkers. OBJECTIVES: We estimated associations between modeled historical PFOA exposures and liver injury biomarkers and medically validated liver disease. METHODS: Participants completed surveys during 2008-2011 reporting demographic, medical, and residential history information. Self-reported liver disease, including hepatitis, fatty liver, enlarged liver and cirrhosis, was validated with healthcare providers. Alanine aminotransferase (ALT), gamma glutamyltransferase (GGT) and direct bilirubin, markers of liver toxicity, were obtained from blood samples collected in the C8 Health Project (2005-2006). Historically modeled PFOA exposure, estimated using environmental fate and transport models and participant residential histories, was analyzed in relation to liver biomarkers (n = 30,723, including 1,892 workers) and liver disease (n = 32,254, including 3,713 workers). RESULTS: Modeled cumulative serum PFOA was positively associated with ALT levels (p for trend < 0.0001), indicating possible liver toxicity. An increase from the first to the fifth quintile of cumulative PFOA exposure was associated with a 6% increase in ALT levels (95% CI: 4, 8%) and a 16% increased odds of having above-normal ALT (95% CI: odds ratio: 1.02, 1.33%). There was no indication of association with either elevated direct bilirubin or GGT; however, PFOA was associated with decreased direct bilirubin. We observed no evidence of an effect of cumulative exposure (with or without a 10 year lag) on all liver disease (n = 647 cases), nor on enlarged liver, fatty liver, and cirrhosis only (n = 427 cases). CONCLUSION: Results are consistent with previous cross-sectional studies showing association between PFOA and ALT, a marker of hepatocellular damage. We did not observe evidence that PFOA increases the risk of clinically diagnosed liver disease. CITATION: Darrow LA, Groth AC, Winquist A, Shin HM, Bartell SM, Steenland K. 2016. Modeled perfluorooctanoic acid (PFOA) exposure and liver function in a Mid-Ohio Valley community. Environ Health Perspect 124:1227-1233; http://dx.doi.org/10.1289/ehp.1510391. PMID- 26978844 TI - The Engineer?s Take on Biology : The Godfather of Synthetic Biology Watched the Field Evolve and Continues to Expect Big Things. AB - Tom Knight may laugh when someone calls him the ?godfather of synthetic biology,? but his ideas have helped spur a worldwide movement to look at biology with an engineer?s eye. PMID- 26978845 TI - Cell Break: How Cell-Free Biology Is Finally Putting the Engineering Back in Bioengineering. AB - In 2011, the California-based company Genomatica reported its success in rigging Escherichia coli microbes to convert sugar into the industrial chemical 1,4 butanediol (BDO). It was a feat of metabolic engineering: BDO is a key ingredient in the production of goods like running shoes, solvents, and spandex. At the time of the company?s announcement, 2.8 billion tons of BDO were produced every year in a multistep, fossil fuel-based process. Genomatica?s system neatly reduced all of that into a cheap, sustainable, one-step fermentation process. The company spent another year refining its technique and finally went commercial with the platform in late 2012. From start to commercialization, the process took about five years. PMID- 26978842 TI - Prioritizing Environmental Chemicals for Obesity and Diabetes Outcomes Research: A Screening Approach Using ToxCastTM High-Throughput Data. AB - BACKGROUND: Diabetes and obesity are major threats to public health in the United States and abroad. Understanding the role that chemicals in our environment play in the development of these conditions is an emerging issue in environmental health, although identifying and prioritizing chemicals for testing beyond those already implicated in the literature is challenging. This review is intended to help researchers generate hypotheses about chemicals that may contribute to diabetes and to obesity-related health outcomes by summarizing relevant findings from the U.S. Environmental Protection Agency (EPA) ToxCastTM high-throughput screening (HTS) program. OBJECTIVES: Our aim was to develop new hypotheses around environmental chemicals of potential interest for diabetes- or obesity-related outcomes using high-throughput screening data. METHODS: We identified ToxCastTM assay targets relevant to several biological processes related to diabetes and obesity (insulin sensitivity in peripheral tissue, pancreatic islet and beta cell function, adipocyte differentiation, and feeding behavior) and presented chemical screening data against those assay targets to identify chemicals of potential interest. DISCUSSION: The results of this screening-level analysis suggest that the spectrum of environmental chemicals to consider in research related to diabetes and obesity is much broader than indicated by research papers and reviews published in the peer-reviewed literature. Testing hypotheses based on ToxCastTM data will also help assess the predictive utility of this HTS platform. CONCLUSIONS: More research is required to put these screening-level analyses into context, but the information presented in this review should facilitate the development of new hypotheses. CITATION: Auerbach S, Filer D, Reif D, Walker V, Holloway AC, Schlezinger J, Srinivasan S, Svoboda D, Judson R, Bucher JR, Thayer KA. 2016. Prioritizing environmental chemicals for obesity and diabetes outcomes research: a screening approach using ToxCastTM high-throughput data. Environ Health Perspect 124:1141-1154; http://dx.doi.org/10.1289/ehp.1510456. PMID- 26978846 TI - The CRISPR Conundrum: As Millions of Dollars Flow into Developing the Gene Editing Tool, Scientists Continue to Discover the Technology's Potential and Pitfalls. AB - We are in the midst of a CRISPR craze. The last five years have seen the publication of over 1,000 scientific papers, the allocation of millions of research dollars, and the establishment of four start-up companies in the United States alone. Internationally, the genome-editing market, fueled by CRISPR technology, is expected to be worth more than US$3,000 million by 2019. PMID- 26978847 TI - Organs-on-Chips: How Microsystems Technology Can Transform the Drug Development Process. AB - The drug development pipeline, once one of the most successful and lucrative commercial sectors in the United States, is now strained by a combination of factors: increased development costs, lengthy time lines, and the poor predictive power of preclinical studies, among others. These factors, in combination with the need to respond to newly evolving demands?including the trend toward personalized or precision medicine, rising rates for many chronic diseases, and continued threats from emerging infectious diseases?are placing extraordinary pressure on an already strained development process. PMID- 26978848 TI - The Clinical Utility of Circulationg Tumor Cells: Analysis of These Cells May Have the Potential to Assist with Screening and Diagnosing Cancer. AB - Clinicians have long sought rapid and accurate methods to screen for and track the progression of cancer. Current technologies include the use of blood tests to screen for certain biomarkers such as PSA level as an indication of prostate cancer (although there are often problems with the sensitivity and specificity of such tests), along with imaging methods such as computed tomography or magnetic resonance imaging (imaging tests however, often require patients to have tumors above a certain size?usually about 1 cm?to yield positive results). PMID- 26978849 TI - Putting a Number on Pain: Technology Has an Increased Role in Measuring Subjective Symptoms in Clinical Trials. AB - Will new technologies substantially change the way subjective complaints are measured in clinical trials, and, if so, by how much? Depending on the expert consulted, the answer ranges from a little to a lot. PMID- 26978850 TI - New Trends in Clinical Trials: A Conversation with Pfizer's Craig Lipset. AB - Technological advances, such as electronic data capture and the prevalence of Wi Fi connectivity, are driving changes in how clinical trials are conducted and analyzed. As the power to track and analyze data expands, clinical trials are becoming more efficient and objective, and patient experiences are improved. PMID- 26978851 TI - The Problem of False Discovery: Many Scientific Results Can't Be Replicated, Leading to Serious Questions about What's True and False in the World of Research. AB - Is there a Cheshire Cat in science? One might believe so, given the many published scientific discoveries that cannot be independently reproduced. The ?replication crisis? in science has become a widely discussed issue among scientists and the lay media and even has its own entry in Wikipedia. PMID- 26978853 TI - Brain-Inspired Machines: What, Exactly, Are We Looking For? AB - In the computing community, people look at the brain as the ultimate computer. Brain-inspired machines are believed to be more efficient than the traditional Von Neumann computing paradigm, which has been the dominant computing model since the dawn of computing. More recently, however, there have been many claims made regarding attempts to build brain-inspired machines. But one question, in particular, needs to be thoroughly considered before we embark on creating these so-called brain-inspired machines: Inspired by what, exactly? Do we want to build a full replica of the human brain, assuming we have the required technology? PMID- 26978852 TI - What Is the Distance Between Objects in a Data Set?: A Brief Review of Distance and Similarity Measures for Data Analysis. AB - Digitally recorded data have become another critical natural resource in our current research environment. This reality is one of the tremendous victories for decades of research in computer engineering, computer science, electronics, and communications. While this scenario will continue to be the case in the future, our current era has also marked the beginning of another unstoppable activity that is intimately related to digitally stored data: extracting knowledge and information from such data. Digital data are recorded in different forms and at unprecedented scales. Examples include database tables in every business entity; Tweets; e-mails and text documents; audio and speech signals; seismic data (recorded as temporal multidimensional tensors); video data (possibly stored with other modalities such as audio and captions); graphs representing relations and interactions among different entities (links among web documents, users on social networks, devices on computer networks, or gene interaction networks); and images, including functional magnetic resonance imaging (fMRI) and more. Because of their different forms and structures, throughout this article, each datum in a data set will be referred to as an object.Digitally recorded data have become another critical natural resource in our current research environment. This reality is one of the tremendous victories for decades of research in computer engineering, computer science, electronics, and communications. While this scenario will continue to be the case in the future, our current era has also marked the beginning of another unstoppable activity that is intimately related to digitally stored data: extracting knowledge and information from such data. Digital data are recorded in different forms and at unprecedented scales. Examples include database tables in every business entity; Tweets; e-mails and text documents; audio and speech signals; seismic data (recorded as temporal multidimensional tensors); video data (possibly stored with other modalities such as audio and captions); graphs representing relations and interactions among different entities (links among web documents, users on social networks, devices on computer networks, or gene interaction networks); and images, including functional magnetic resonance imaging (fMRI) and more. Because of their different forms and structures, throughout this article, each datum in a data set will be referred to as an object. PMID- 26978854 TI - Could Al-Zahrawi Be Considered a Biomedical Engineer? [Retrospectroscope]. AB - In one?s career, it is good to look back at the predecessors in the field. Biomedical engineering history is full of hidden treasures, one of whom is Al Zahrawi, a Muslim surgeon who had a wide reputation in Europe during the Middle Ages. Herein, besides recalling that he was a surgeon, the intent is to spotlight his talent in biomedical engineering. Important contributions in surgical instruments come up readily in a review of his work, contradicting the view some have maintained of him as a mere compiler. He was a true inventor, creating many surgical instruments that were not known in the Greco-Roman era. Quite early, he produced contributions influencing surgical procedures in Europe from the 14th to the 18th centuries. As a problem solver, he was aware of anatomical and physiological problems, and he moved through design, methods of manufacturing, and practical applications. The illustrations of such instruments in his encyclopedic work, Al-Tasrif, reflect his willingness to teach. PMID- 26978855 TI - Calling All Nursing Students: How Much Wound Care is in Your Future? AB - This month, more than 2,000 student nurses and nursing faculty will attend the National Student Nurses Association Annual Convention in Orlando, FL. Thinking about this event presents the perfect time for student nurses, faculty, clinical instructors, and preceptors--anyone involved in wound prevention and care practice or education--to look ahead and ponder the future of nursing in general and wound care nursing in particular. PMID- 26978856 TI - A Prospective, Descriptive Study to Assess the Clinical Benefits of Using Calendula officinalis Hydroglycolic Extract for the Topical Treatment of Diabetic Foot Ulcers. AB - Diabetic foot ulcers (DFUs) have a significant impact on patient quality of life. A prospective, descriptive pilot study was conducted between May 2012 and December 2013 through the dermatology outpatient unit in a Brazilian hospital to evaluate the clinical benefits of using Calendula officinalis hydroglycolic extract in the treatment of DFUs. Patients diagnosed with a stable neuropathic ulcer of >3 months' duration; ranging in size from 0.5-40 cm(2); without osteomyelitis, gangrene, bone exposure, cancer, or deep tissue infection; ages 18 90 years; with adequate glycemic control and no history of an allergy to C. officinalis were enrolled. Patients provided demographic and diabetes-related information and were evaluated biweekly for 30 weeks or until healing (ie, full epithelialization with no wound drainage). DFUs were measured and clinically examined for microbiological flora and presence of odor, tissue type (eg, granulation, fibrin sloth, necrosis), exudate, and retraction rate using planimetry images. Patients' blood tests and neuropathic pain assessment (the latter by clinician-directed questionnaire) were performed at baseline and the end of treatment; pain also was assessed during dressing changes using a 10-point rating scale. Patients' ulcers were treated twice daily with C. officinalis hydroglycolic extract spray solution and covered with saline-moistened, sterile, nonadherent gauze and bandages followed by foot offloading with adequate protective footwear. Patients received their first treatment in the clinic then performed care at home. From a potential population of 109 patients, 25 did not meet the inclusion criteria. Of the remaining 84 participants enrolled, 43 withdrew before study completion; cited reasons included lost to follow-up (16), medical judgment (2), failure to attend >3 scheduled visits (17), protocol violation (5), and death (3). Forty-one (41) - 17 women, average age 62 years (range 44-82 years), average glycemic level 153 mg/dL (range 82-395 mg/dL), most (34) with Wagner type 1 ulcers--completed the study. The proportions of patients who achieved complete wound closure after 11, 20, and 30 weeks of treatment was 54%, 68%, and 78%, respectively; mean healing time was 15.5 +/- 6.7 weeks. When individual weekly healing rates (the percentage reduction in wound area per week) were corrected for variability in initial DFU area, the values were nearly 6-fold higher for complete wound closure (7.8% +/- 3.6%) than for incomplete wound closure (1.4% +/- 0.7%) (Student t-test; P = 0.001). After 30 weeks of treatment, the number of colonized wounds decreased from 29 at baseline to 5, and the number of odorous wounds decreased from 19 to 1. Ulcer bed planimetry data showed a significant reduction in the amount of exudate, fibrin slough, and necrotic tissue after the treatment with C. officinalis hydroglycolic extract (chi(2) test; P = 0.001). No adverse events were observed during treatment. The study findings suggest C. officinalis extract is safe and has a beneficial effect on DFU healing. Randomized, controlled studies using C. officinalis hydroglycolic extract are warranted to confirm its safety and establish its clinical efficacy and effectiveness for the topical treatment of DFUs. PMID- 26978857 TI - The Effects of Argan Oil in Second-degree Burn Wound Healing in Rats. AB - Argan oil, produced from the kernels of the argan tree (Argania spinosa), has been shown to have antioxidant properties. To examine the effect of argan oil in second-degree burn wound healing, an in vivo experiment was conducted among 30 adult male Wistar rats divided into 5 equal groups: a sham group, a control group (burned but no topical agent), a group in which argan oil was applied once a day, a group in which argan oil was applied twice a day, and a group treated with 1% silver sulfadiazine once a day. Second-degree burns were created by scalding hot water (85 C for 15 seconds). Treatment began 24 hours after the burn injury; in the argan oil groups, 1 mL of argan oil was administered via syringe to the wound. The rate of wound healing was quantified by wound measurements on days 1, 7, and 14 after burn injury. Tissues were analyzed for molecular and histologic changes in TGF-beta expression and fibroblast activity. Percent contraction of burned skin tissue was determined using the stereo investigator program, which calculated the burn field to the millimeter. Means (SD) were calculated and compared using Duncan's multiple comparison test. The group receiving argan oil twice daily showed significantly increased mRNA levels of TGF-beta1 from 39.66- to 58.70-fold compared to the burn control group on day 14 (P less than 0.05). Both argan oil-treated groups showed significantly increased contraction compared to the burn control group at all 3 timepoints; the group receiving argan oil twice daily had a greater contraction rate (31% on day 7, 76% on day 14) than the silver sulfadiazine group (22% on day 7, 69% on day 14), (P less than 0.05). Histopathological assessments on days 3, 7, and 14 showed greater healing/contraction in both argan oil and silver sulfadiazine groups compared to the control group. These results suggest argan oil is effective in healing experimentally created second-degree burns in rats. Prospective, randomized, controlled clinical studies are needed to evaluate the safety, efficacy, and effectiveness of this treatment modality for patients with second-degree burn wounds. PMID- 26978858 TI - Silver-Collagen Dressing and High-voltage, Pulsed-current Therapy for the Treatment of Chronic Full-thickness Wounds: A Case Series. AB - Research suggests high-voltage, pulsed-current electric therapy (HVPC) is safe and effective for treating chronic wounds, and some data suggest silver- and collagen-based dressings may facilitate healing. A combination therapy utilizing both HVPC and silver-collagen dressing may present clinical advantages. To explore the effect of the combined therapy for chronic full-thickness wounds, a prospective, consecutive case series study was conducted. All participants were adults with wounds of at least 6 weeks' duration. After obtaining informed consent, patient and wound characteristics were obtained, wounds were assessed and measured, and patients received 2 to 3 HVPC treatments per week followed by application of the silver- and collagen-based dressing for a period of 2 weeks. Data were analyzed descriptively, and changes in wound size and volume from baseline were analyzed using Wilcoxon Signed Rank Test. The dressings were saturated with normal saline, used simultaneously during the 45-minute HVPC treatment, and left on top of the wound after treatment. The HVPC electro pads (stainless steel electrodes with a sponge interface) also were moistened with normal saline and the cathode placed on top of the wound. If the patient had more than 1 wound on the same leg, the anode was placed on the additional wound (otherwise over the intact skin nearby). Secondary dressings (eg, foam and/ or gauze) were used as clinically appropriate, and a 4-layer compression wrap was used, if indicated, for patients with venous ulcers. Ten (10) patients (3 women, 7 men, 57.30 +/- 9.70 years old with 14 wounds of 273.10 +/- 292.03 days' duration before study) completed the study and were included in the final analyses. Average wound surface area decreased from 13.78 +/- 21.35 cm(2) to 9.07 +/- 16.81 cm(2) (42.52% +/- 34.16% decrease, P = 0.002) and wound volume decreased from 3.39 +/- 4.31 cm(3) to 1.28 +/- 2.25 cm(3) (66.84% +/- 25.07% decrease, P = 0.001). One (1) patient was discharged with complete wound closure. No serious adverse events were noted, but a diagnosis of osteomyelitis in 1 patient and increased pain in a patient with significant Reynaud's syndrome suggest clinicians should be cautious using HVPC in these instances. The combined intervention utilizing both HVPC and silver-collagen dressing was effective in the treatment of chronic fullthickness wounds in this patient population. Controlled clinical studies of longer duration are needed to further explore the safety, effectiveness, and efficacy of this treatment. PMID- 26978859 TI - Salmonella Abscess of the Anterior Chest Wall in a Patient With Type 2 Diabetes and Poor Glycemic Control: A Case Report. AB - Salmonella can cause extra-intestinal focal infections as well as gastrointestinal problems. A few cases of Salmonella skin and soft tissue infection have been documented in immunocompromised patients such as persons with type 2 diabetes and poor glycemic control. A case study is presented of a 30-year old man with a 10-year history of poorly controlled (HbA1C 11.7%) diabetes mellitus who presented with a ruptured nodule resulting in a wound with signs of infection over his anterior chest region of 1-month duration. He had been taking amoxycillin/clavulanate for the week previous to presentation at the authors' facility. Following sharp debridement, the ulcerative wound deteriorated and a chest wall abscess developed. Bacterial culture results were positive for Salmonella group D, resistant to ampicillin and susceptible to ceftriaxone and ciprofloxacin. The patient underwent surgical debridement, resulting in a wound 7 cm x 4 cm, and was provided ceftriaxone 2.0 g intravenously daily along with insulin therapy. After surgical debridement, a local rotational flap was created for wound closure and reconstruction. The patient was discharged 1 week later on oral antibiotic therapy for 1 week. His wound was completely healed without recurrence at his 4-month follow-up. For this patient, addressing glycemic issues, identifying the infectious organism, and providing appropriate therapy, radical debridement, and flap surgery helped heal an advanced soft tissue infection. In immunocompromised patients with skin or soft tissue infections, the presence of Salmonella should be considered. PMID- 26978860 TI - A Prospective, Randomized, Multicenter, Controlled Evaluation of the Use of Dehydrated Amniotic Membrane Allograft Compared to Standard of Care for the Closure of Chronic Diabetic Foot Ulcer. AB - Delayed closure of foot ulcers is a primary factor leading to lower extremity amputation in patients with diabetes, creating great demand for products or therapies to accelerate the rate of wound closure in this population. This study (ClinicalTrials.gov Identifier: NCT02209051) was designed to evaluate dehydrated amniotic membrane allograft (DAMA) (AMNIOEXCEL, Derma Sciences Inc, Princeton, NJ) plus standard of care (SOC) compared to SOC alone for the closure of chronic diabetic foot ulcers (DFUs). MATERIALS AND METHODS: This prospective, open-label, randomized, parallel group trial was implemented at 8 clinical sites in the United States. Eligibility criteria included adults with type 1 or type 2 diabetes mellitus who have 1 or more ulcers with a Wagner classification of grade 1 or superficial 2 measuring between 1 cm2 and 25 cm2 in area, presenting for more than 1 month with no signs of infection/osteomyelitis; ABI > 0.7; HbA1c Less than 12%; and serum creatinine less than 3.0 mg/dL. Eligible subjects were randomized (1:1) to receive either SOC alone (n = 14) or DAMA+SOC (n = 15) until wound closure or 6 weeks, whichever occurred first. The endpoint was the proportion of subjects with complete wound closure (defined as complete reepithelialization without drainage or need for dressings). RESULTS: Thirty-five percent of subjects in the DAMA+SOC cohort achieved complete wound closure at or before week 6, compared with 0% of the SOC alone cohort (intent-to-treat population, P = 0.017). There was a more robust response noted in the per protocol population, with 45.5% of subjects in the DAMA+SOC cohort achieving complete wound closure, while 0% of SOC-alone subjects achieved complete closure (P = 0.0083). No treatment-related adverse events were reported. CONCLUSION: The results suggest DAMA is safe and effective in the management of DFUs, but additional research is needed. PMID- 26978861 TI - Hyaluronic Acid in Inflammation and Tissue Regeneration. AB - Hyaluronic acid (HA), the main component of extracellular matrix, is considered one of the key players in the tissue regeneration process. It has been proven to modulate via specific HA receptors, inflammation, cellular migration, and angiogenesis, which are the main phases of wound healing. Studies have revealed that most HA properties depend on its molecular size. High molecular weight HA displays anti-inflammatory and immunosuppressive properties, whereas low molecular weight HA is a potent proinflammatory molecule. In this review, the authors summarize the role of HA polymers of different molecular weight in tissue regeneration and provide a short overview of main cellular receptors involved in HA signaling. In addition, the role of HA in 2 major steps of wound healing is examined: inflammation and the angiogenesis process. Finally, the antioxidative properties of HA are discussed and its possible clinical implication presented. PMID- 26978862 TI - Diabetic Foot Infection in Morocco: Microbiological Profile. AB - OBJECTIVE: The objective of this work is to describe the microbiology of diabetic foot infections (DFIs). MATERIALS AND METHODS: The authors included all samples of infected diabetic foot ulcers between January 2009 and June 2014 at the Mohammed Vth Military Teaching Hospital of Rabat, Morocco. RESULTS: The researchers collected 199 samples corresponding to 157 patients. The mean age of the patients was 59 years +/- 12 years. Of the collected samples, deep samples represented 41% and swab samples 59%. Direct examination indicated anaerobic infection in 32% of the cases. There were 307 bacteria isolates from both deep and swab samples. There was no statistically significant association between the sampling method and isolate species (P = 0.237). Enterobacteriaceae, Staphylococcus aureus, Streptococcus sp, nonfermenting gram-negative bacilli (NFGNB), and Enterococcus sp represented 31.8%, 12.6 %, 12.3%, 11.7%, and 8.7% of the isolates, respectively. Methicillin-resistant S. aureus represented 4.7% of S. aureus isolates. Enterobacteriaceae and NFGNB-producing extended spectrum beta lactamases represented 14.1% and 5.1%, respectively, with isolates producing carabapenemase representing 3.8% and 38.5%. Piperacillin-tazobactam, imipenem, and ciprofloxacin resistance concerned 7.5%, 4.7%, and 25.5%, respectively, of isolated Enterobacteriaceae, and 35.9%, 30.7%, and 35.9% of NFGNB. Low susceptibility to beta-lactams was found in 4.9% of Streptococcus sp isolates and 4.9% of Streptococcus sp isolates were resistant to moxifloxacin. CONCLUSION: Gram-negative bacilli are responsible for 43% of DFIs, and multidrug-resistant GNB is a challenging issue in DFI management. The sampling method doesn't seem to impact the bacteriological profile; however, this finding must be confirmed with further study. PMID- 26978863 TI - Comparison of the Effects of Plateletrich Plasma Prepared in Various Forms on the Healing of Dermal Wounds in Rats. AB - OBJECTIVE: This study was designed to evaluate the effects of 3 different forms of platelet-rich plasma (PRP) on the healing process, wound healing rate, and histopathological changes that occur during recovery of open dermal wounds. MATERIALS AND METHODS: A 2 cm x 1 cm full-thickness skin defect was made on the backs of 40 Wistar female rats that were divided into 4 groups of 10. In group 1 (control group), the wounds were cleaned with saline; in group 2, the wounds were covered with PRP gel obtained by single centrifugation; in group 3, the wounds were covered with liquid PRP obtained by double centrifugation; and in group 4, PRP gel obtained by double centrifugation with added thrombin was applied on the dermal wounds. All treatments were applied on postoperative days 1, 4, 7, and 10. RESULTS: In all PRP groups, the wound closure was almost complete on day 14 while the wound contraction progressed more slowly in the control group. The mean histopathological scores of epithelialization, inflammation, and fibrosis were significantly better in all PRP groups than the scores in the control group. CONCLUSION: In conclusion, although all PRP preparations had positive effects on dermal wound healing, double centrifuged PRP topical treatments (with or without thrombin activation) are more effective than single centrifuged PRP, and double centrifugation methods should be preferred for the preparation of PRP. PMID- 26978864 TI - Estrogenic properties of spices of the traditional Cameroonian dish "Nkui" in ovariectomized Wistar rats. AB - BACKGROUND: Besides the basic role to flavor and color foods, several health benefits have been attributed to spices. The traditional Cameroonian food "Nkui" is prepared using several spices (Afrostyrax lepidophyllus Mildbr., Capsicum frutescens Linn., Fagara leprieurii Guill. et Perr., Fagara tessmannii Engl., Mondia whitei Hook. F. Skell., Pentadiplandra brazzeana Baill., Solanum gilo Raddi., Tetrapleura tetraptera Taub. and Xylopia parviflora A. Rich. Benthane) that are believed to have a positive impact on the female reproductive physiology. Aiming to determine the potential effect of this food on the female reproductive tract, we evaluated the estrogenic properties of aqueous and ethanol extracts of Nkui using a 3-day uterotrophic assay in ovariectomized (OVX) rats. METHODS: OVX female Wistar rats were randomly separated in several groups of five animals each and submitted to a 3-day uterotrophic assay (per os). At the end of treatment, animals were sacrificed and uterus, vagina and mammary gland collected and fixed in 10 % formalin for histological analysis. RESULTS: These extracts increased the uterine wet weight, the uterine and vaginal epithelial heights, and the lumen and diameter of alveoli in the mammary glands. They also altered the estradiol-induced increase of uterine wet weight. The dichloromethane and methanol fractions of the ethanol extract exhibited estrogenic properties as well by increasing uterine and vaginal endpoints. CONCLUSIONS: These results suggest that the spices of "Nkui" contain estrogenic phytoconstituents and this traditional food may be considered as functional. PMID- 26978865 TI - AGE-RELATED MACULAR DEGENERATION. AB - OBJECTIVES: The objective of our study was to review the current knowledge on Age Related Macular Degeneration, including pathogenesis, ocular manifestations, diagnosis and ancillary testing. SYSTEMATIC REVIEW METHODOLOGY: Relevant publications on Age-Related Macular Degeneration that were published until 2014. CONCLUSIONS: Age-related macular degeneration (AMD) is a common macular disease affecting elderly people in the Western world. It is characterized by the appearance of drusen in the macula, accompanied by choroidal neovascularization (CNV) or geographic atrophy. PMID- 26978866 TI - NOVELTIES IN MEDICAL TREATMENT OF GLAUCOMA. AB - The purpose of this study is to review the current medical treatment and the new and better alternatives for patients with glaucoma. Glaucoma refers to a group of related eye disorders that have in common an optic neuropathy associated with visual function loss. It is one of the leading causes of irreversible blindness worldwide. Glaucoma can damage vision gradually so it may not be noticed until the disease is at an advanced stage. Early diagnosis and treatment can minimize or prevent optic nerve damage and limit glaucoma-related vision loss. Nowadays, research continues for the improvement of current medical treatment. PMID- 26978868 TI - THE LIABILITY FORMS OF THE MEDICAL PERSONNEL. AB - Current legislation, namely Law no. 95/2006 on healthcare reform in the medical malpractice domain stipulates that medical staff can be held accountable in the following forms: disciplinary liability, administrative liability, civil liability and criminal liability. Each form of legal liability presents its features, aspects that are found mainly in the procedural rules. However, the differences between the various legal forms of liability are not met only in the procedural rules but also in their effects and consequences. It is necessary to know what the procedure for disciplinary responsibility, administrative liability, civil liability, or criminal liability is. In addition to the differentiation determined by the consequences that may arise from the different forms of legal liability, it is important to know the competent authorities to investigate a case further and the solutions which various public institutions can take regarding the medical staff. Depending on the type of legal liability, authorities have a specialized authority. If the Disciplinary Committee is encountered at the College of Physicians, it may not intervene in cases before the monitoring and competence for malpractice cases Committee. The latter two committees cannot intervene directly in the legal assessment of civil or criminal cases, as no criminal investigation authorities cannot intervene in strictly civilian cases. Therefore, the importance of knowing the competent institutions is imperative. PMID- 26978867 TI - THE PATHOGENY OF PROLIFERATIVE VITREORETINOPATHY. AB - Proliferative vitreoretinopathy (PVR) is the most important complication of rhegmatogenous retinal detachment (RRD) and the main cause of RRD surgery failure. This is a review of recent literature data, which concerns PVR pathogeny and risk factors. The occurrence of pre- and subretinal membranes is a consequence of retinal pigment epithelial cells activation and migration, with concomitant participation of inflammatory cells. The newly synthesized extracellular matrix interacts with cells promoting membrane contraction. Photoreceptor apoptosis limits functional recovery--but there is ongoing research for neuroprotective mechanisms. A lot of evidence has been accumulated about the role of growth factors (PDGF, VEGF, HGF, EGF, TGF alpha and beta, G-CSF, FGF, IGF 1,CTGF), cytokines (interleukins IL-1, -6, -8, -10 and interferon gamma), matrix metalloproteinases and chemokines, by measuring their concentrations in the vitreous or the subretinal fluid of PVR patients. A list of risk factors (common or more controversial) may help the surgeon make the best approach for the management of individual cases. Adjuvant therapies tested for PVR prevention (steroids, heparin, 5 fluorouracil, daunomycin, colchicine and 13-cis retinoic acid) did not enter current practice, but there are numerous research directions currently being developed. PMID- 26978869 TI - REFRACTIVE SURGERY FOR HIGH AMETROPIES, A FEW CONCLUSIONS. AB - This paper presents a few clinical cases of patients with high ametropies and/or anisometropia, who underwent one or two surgical procedures in our clinic, in order to obtain independence of glasses or contact lenses. Twenty cases of high ametropies were included in our study, with or without astigmatism, with transparent lenses, who presented in our clinic for surgical treatment to correct their refractive errors. Postoperatively, we analyzed the results and took decisions for each case in particular; sometimes a second surgical procedure was needed. PMID- 26978870 TI - COMPARATION OF REFRACTIVE RESULTS WITH BIFOCAL IMPLANTS AT LISA 809 AND TRIFOCAL AT LISA TRI839. AB - The purpose of this paper is to make a comparison between the results obtained with AT LISA 809 bifocal IOL and trifocal AT LISA 839. Interest was represented especially by the evaluation of intermediate vision for the 2 implants. 18 patients (36 eyes) operated in Gauss Clinic in 2014 were included in the study: 9 patients (18 eyes) with bifocal implant AT LISA 809 and 9 patients (18 eyes) with bilateral implantation AT LISA 839 trifocal lens. Results showed that implant trifocal provided better visual results for intermediate vision to bifocal implant, as there were not significant differences between the two, in terms of distance vision and near vision. PMID- 26978871 TI - GRAVES OPHTHALMOPATHY--TERAPEUTICAL ALTERNATIVES. AB - Graves disease associates thyroid and non-thyroid symptoms and signs with autoimmune pathogeny, including the ophthalmopathy. The treatment of Graves ophthalmopathy consists of medical immunosuppressive therapy, retrobulbar injections and general treatment. Recently, Somatostatin injections have proved their efficiency. PMID- 26978872 TI - MY EXPERIENCE OF TEACHING PHACOSURGERY ON VISALIS 100 IN SUDAN AND NIGERIA. AB - At the invitation of the director of The National Eye Center, Kaduna, Nigeria and The Makkah Eye Hospital of Khartoum, Sudan I visited both these institutions to teach phacoemulsification surgery to their aspiring surgeons on Visalis 100 (Carl Zeiss Meditec, Germany). This article highlights the experience of teaching phacoemulsification surgery in foreign African countries like Nigeria and Sudan. In Nigeria I had the opportunity to give training in both wet lab and live surgery settings whereas in Sudan only hands-on live surgery. Sudan being an Islamic nation pigs are not slaughtered there and hence no pig eyes. Goat eyes differ significantly from human eyes and hence have almost no value in wet lab teaching. The training program included theoretical discussions, wet lab, surgery and finally discussions related to the days' surgery. It became clear that quality of learning depends on three main factors. Thorough understanding of theory and observation of senior surgeons in operation room Good wet lab and finally doing the surgery oneself in step by step manner. Dedicated teachers and instructors can make all the difference. The learning curve also significantly shortens if the trainees are exposed to all types of cataract surgery like ECCE, SICS and phacoemulsification surgery. The main problem faced by those surgeons who have done only ECCE/SICS is that they are not used to handling microscope and instruments in both hands at the same time. Hence I strongly recommend them wet lab where they can sit and practice using both hands and feet and microscope simultaneously and in coordinated fashion. PMID- 26978873 TI - IMPORTANCE OF DEMOGRAPHIC RISK FACTORS FOR PRIMARY ANGLE CLOSURE. AB - According to the Guidelines of the European Glaucoma Society (fourth edition), the family history in the closing angle is an important factor that makes the family screening vital in these families. It is present in the clinical case in which two twin patients in different circumstances show the same symptoms of angle closure. PMID- 26978874 TI - TRANSITORY CONSECUTIVE ESOTROPIA AFTER AMITRIPTYLINE TREATMENT FOR NOCTURNAL ENURESIS -CASE REPORT. AB - We report the case of a 9-year-old child operated for intermittent exotropia and V-pattern with a good result 2 months after bilateral Lateral Rectus Muscle Recession. The binocular vision was restored in primary position and down-gaze with excellent stereopsis at near and distance and a deviation of +4 PD in primary position. Three months later, the patient developed a consecutive esotropia of + 18 PD in primary position with diplopia in all gazes triggered by Amitriptyline treatment prescribed one month earlier for nocturnal enuresis. Diplopia was solved in time after anticholinergic medication cessation. During the recovery period, Fresnell prisms have been used in order to eliminate diplopia. Three months after diplopia onset, the binocular vision was restored showing a transitory and reversible effect of the Amitriptyline treatment. Fusion vulnerability can be a possible risk factor in developing diplopia and esotropia in patients treated with anticholinergic drugs. PMID- 26978875 TI - ICE SYNDROME--CASE REPORT. AB - Iridocorneal endothelial (ICE) syndrome encompasses a group of rare ocular pathologies with unilateral involvement, frequently affecting young women. The disease complex includes essential iris atrophy, Chandler's syndrome, and Cogan Reese syndrome. In the following article, we present a case of Iridocorneal endothelial syndrome in which a late diagnosis was made and who underwent surgery for advanced glaucoma. PMID- 26978876 TI - OCULAR AND OSTEOARTICULAR TUBERCULOSIS IN A YOUNG PATIENT. CASE REPORT. AB - CASE REPORT: A young healthy patient, health-care worker in a state hospital, presented in the eye department complaining of pain and blurred vision in the left eye for approx. 2 weeks. Examination revealed a VA of 12/20 in the left eye, an interstitial keratitis, some signs of vitreal inflammation and two chorioretinal mass lesions (at echography appearing cystic) in the affected eye. She also mentioned a chronic pain in the right wrist. No systemic association was found. Based on the orthopaedic examination, biopsy, and surgical intervention, a strong suspicion of ocular tuberculosis was made and the patient was advised to start tuberculostatic treatment for 12 months and ocular steroidian treatment for 4 months. The ocular manifestations regressed totally after 3 months of treatment, the VA of the left eye improving at 20/ 20. CONCLUSION: Tuberculosis can present many manifestations, with multi systemic involvement. Ocular tuberculosis is a difficult diagnosis and thus requires thorough multi disciplinary investigations. PMID- 26978877 TI - EBOD--The european standard examination in Ophthalmology. PMID- 26978878 TI - ASSESSMENT OF CLINICAL AND IMAGISTIC STRUCTURAL PROGRESSION IN GLAUCOMA. AB - Glaucoma is a progressive optic neuropathy, characterized by loss of retinal ganglion cells and retinal nerve fiber layer as well as visual field loss. Therefore, in glaucoma, the correlation between structure and function is important, since it can be useful for tracking glaucomatous changes and for following the progression of the disease. PMID- 26978879 TI - DIABETIC MACULAR EDEMA. AB - Diabetic macular edema (DME) remains the most common cause of vision loss among diabetic patients. New understanding of the underlying pathophysiology has interest in the potential benefits of the specific pharmacologic therapy, such as treatment with intraocular steroids, anti-vascular endothelial growth factor (VEGF), and protein kinase C-beta (PKCbeta) inhibition. At the last time, laser photocoagulation, according to the guidelines of the Early Treatment of Diabetic Retinopathy Study (ETDRS), continues to be primary standard care treatment in most communities. Optical coherence tomography (OCT) is very useful in monitoring macular edema progression and response to treatment. PMID- 26978880 TI - ANOMALOUS HEAD POSTURES IN STRABISMUS AND NYSTAGMUS DIAGNOSIS AND MANAGEMENT. AB - Abnormal head positions are adopted in order to improve visual acuity, to avoid diplopia or to obtain a more comfortable binocular vision. The head can be turned or tilted toward right or left, with the chin rotated up or downwards or combination of these positions. The ophthalmologic examination including the assessment of versions leads to the diagnosis. When versions are free, the cause may be congenital nystagmus or strabismus with large angle. When versions are limited we suspect paralytic or restrictive strabismus. The head tilted to one shoulder suggests cyclotropia (IV Nerve Palsy) or congenital nystagmus. We present few of the above cases. An adequate surgical treatment can improve or correct the ocular deviation, diplopia and the abnormal head posture. CONCLUSIONS: The abnormal head posture must be assessed and treated early in order to correct the ocular position and head posture. All patient presenting abnormal head position HAD TO BE investigated by an ophthalmologist. PMID- 26978882 TI - SELECTIVE LASER TRABECULOPLASTY--SHORT TERM EFFICACY AND SAFETY PROFILE IN OPEN ANGLE GLAUCOMA OR OCULAR HYPERTENSION TREATMENT. AB - Selective laser trabeculoplasty--medium term efficacy and safety profile in open anlgle glaucoma or ocular hypertension treatment: SLT effect in reducing the intraocular pressure (IOP) in patients with open angle glaucoma or ocular hypertension. MATERIAL AND METHOD: 70 eyes from 70 patients were included in the study in 2014 (12 months); the established design for this research was prospective and interventional. Patients received indication for SLT treatment as initial procedure or as adjuvant method in reducing the intraocular pressure when insufficient control with topical medication was noted. A single laser procedure was performed on 360 degrees. The result was verified and compared with baseline values of IOP at 1 month, 3 months respectively. RESULTS: IOP decreased at 1 month with 22.47% vs. baseline IOP and with 26.58% at 3 months. The IOP dynamics showed an additional 5.30% decrease between the intermediate and final values, with statistical significance for all the measured parameters (p = 0.001). CONCLUSION: SLT applied on 360 degrees in a single session represents a safe and efficient procedure. The IOP decrease is marked at 1 month, but the effect continues until later, at 3 months interval after treatment. The higher the initial IOP was, the greater effect SLT has in decreasing the IOP level. Most frequently LST helps control the IOP, but rarely allows reducing or eliminating the glaucoma medication. PMID- 26978881 TI - THE ROLE OF SYSTEMIC BLOOD PRESSURE IN GLAUCOMA PROGRESSION. AB - The present paper aims to highlight the role of arterial hypotension in the progression of glaucoma. The data analyzed in this study was collected in a prospective manner for a period of one year, from september 2013 to august 2014. It includes newly diagnosed glaucoma patients treated with prostaglandin analogues and who have presented within normal range values of intraocular pressure during the study. In spite of good control of intraocular pressure, there was recorded a progression of glaucoma lesions documented using the visual field . All patients were evaluated through 24 h outpatient holter monitoring of systemic blood pressure (BP) and were consequently divided into three groups: Group A--non-dipper (within normal range of both diurnal and nocturnal BP values and no significant drop during the night). Group B--dipper (patients with nocturnal hypotension recording BP drops of more the X mmHg). Group C--patients with arterial hypertension (defined as diurnal values of more than 150 mmHg for systolic BP and 110 mmHg for dyastolic BP). After through statistical analysis of the patients data, we noticed that the most important progression of glaucoma changes objectified by visual field and OCT examinations was recorded in group B, which illustrates the importance of careful monitoring and strict control of blood pressure in order to eliminate this risk factor in the progress of glaucoma. PMID- 26978883 TI - CLINICAL IMPACT IN THE MANAGEMENT OF NEOVASCULAR GLAUCOMA. AB - INTRODUCTION: Neovascular glaucoma (NVG), participates in the group of secondary glaucoma causing the-increase of intraocular pressure (IOP) as a result of iridocorneal angle enclosure with the development of neovase derived from the retinal ischemic and other inflamatory diseases. PURPOSE OF THE STUDY: Is to show the incidence, etiopathogenesis, clinical development and the management of NVG by comparing the contemporary and referring literature to other clinics. METHODS: In this study there were presented the results of NVG treatment for the 2010- 2014 interval. The data processing were conducted using statistically package SPSS 22. RESULTS: In this scientific study were included 61 patients with NVG containing 4.3% of all cases with glaucoma and 14% of cases with secondary glaucoma, aged 22-79. The mean age of the patients was 60.9 year (SD + 10.6 year), 39 cases or 63.9% were of masculine gender and 22 cases or 36.1% of feminine gender, as it seems there is a differentiation with a statistical significance (X2 = 4.74, P = 0.03, therefore P < 0.05). The most frequent cause of NVG was PDR in 55 cases or 55.6% of them, then, ischemic CRVO with 11 cases or 11.1%. The most frequent complications to the NVG were hemophthalmos, cataract and absolute glaucoma. CONCLUSION: In many aspects our results were in line with the results of other authors. Therefore we should focus on the adequate treatment of ocular ischemic in time, as it is only prevention method of NVG. PMID- 26978884 TI - FUCHS ENDOTHELIAL CORNEAL DYSTROPHY: IS FEMTOSECOND LASER-ASSISTED CATARACT SURGERY THE RIGHT APPROACH? AB - INTRODUCTION: Femtosecond Laser-assisted cataract surgery represents a modern technology that hopes to lower the risk of complications for patients suffering from Fuchs endothelial dystrophy by using a reduced level of energy that causes less damage to the endothelium, the main concern for patients with Fuchs endothelial dystrophy. The femtosecond laser performs 3 important steps in cataract surgery: corneal incisions, capsulorhexis and nucleus fragmentation without intraocular instrument manipulation. PURPOSE: The purpose of this study is to determine the efficiency of Femtosecond Laser-assisted cataract surgery in Fuchs endothelial dystrophy. MATERIAL AND METHODS: 5 patients with 6 eyes underwent cataract surgery assisted by Femtosecond Laser LensX at Laser Optisan Clinic. Corneal changes before and after surgery and cumulative dissipated energy (CDE) were analyzed. RESULTS: Before surgery, our patients presented BCVA between 0.16-0.4, Pachymetry between 450-590 Lm, endothelial cells between 789-2008 mm2. The medium cumulative dissipated energy (CDE) used was 4.58 seconds. After surgery, BCVA improved in all patients and none of them developed corneal decompensation so far. CONCLUSIONS: Femtosecond Laser-assisted cataract surgery represents a safe alternative in patients with Fuchs endothelial dystrophy and has a low risk of corneal decompensation. PMID- 26978885 TI - ANTERIOR CHAMBER SYNCHYSIS SCINTILLANS: A CASE REPORT. AB - Synchysis scintillans is a vitreous condition in which multiple golden brown opacities are formed as a result of chronic vitreous hemorrhage. Anterior chamber synchysis scintillans was described in patients with afakia or lens subluxation. We report a case of a 63-year-old man with a history of left eye trauma and complete loss of vision, who presented for left eye discomfort. The slit lamp examination revealed crystals of synchysis scintillans and rare inflammatory cells in the anterior chamber, stromal iris atrophy, circumferential posterior iris synechiae, and complete lens opacity. Total retinal detachment was observed on ocular ultrasonography. Intraocular pressure value was in normal range. The distinctiveness of this case is the mechanism of vitreous crystals mobilization into the anterior chamber through an atrophic iris while intraocular pressure remains normal. PMID- 26978886 TI - RETINAL ANGIOMATOUS PROLIFERATION CASE REPORT. AB - The diagnosis of RAP is similar with the diagnosis of the AMD, but PED, exudate and superficial hemorrhages are more common in RAP. A 75-year-old male presented himself at the Ophthalmology Department of the Emergency County Hospital in Craiova in January 2015, with a 4 months history of vision loss. In his right eye the visual acuity was 4/50 eye non-optical correctable and 5/5 with optical correction in the left eye. According to the FA and OCT that were performed in both eyes, in the right eye was found intraretinal neovascularization and sub and intraretinal fluid. A normal aspect was found in the left eye. After the investigations we decided to start the treatment consisting in one single intravitreal injection with Triamcinolone Acetonide (IVTA) in the right eye. The VA improved 1 week after the treatment from 4/50 to 5/30. In comparison with the improved VA, the macular edema gradually resorbed 1 month after the IVTA injection. In spite of the late presentation of the patient in the Ophthalmology Department, the VA and OCT outcome after a single dose of IVTA injection was very good. PMID- 26978887 TI - NONICHEMIC CENTRAL RETINAL VEIN OCCLUSION ASSOCIATED WITH HEREDITARY THROMBOPHYLIA. AB - Retinal vein occlusion (RVO) is the second most common retinal vein disease with significant visual loss via thrombus or compression of vein wall. Thrombophilia is the predisposition to vascular thrombosis with the existence of genetic defect that leads to blood hypercoagulability. This report describes the case of a 55 year old male patient, with an active life who presented himself at the emergency room with acute visual lose, insidious and progressive visual field constriction, without any known history of neurological or vascular diseases. The examinations revealed unilateral optic nerve head edema, the fluorescein angiography was specific for nonischemic central retinal vein occlusion CRVO complicated with macular edema. Blood examinations has emphasized the presence of the heterozygous mutation A1298C in the methylenetetrahydrofolate reductase gene (MTHFR), the only one presented from the thrombophilia screen panel and a slightly elevated cholesterol level. During the follow-up period, the patient received anti-VEGF treatment (Bevacizumab, 3x 0.1 ml intravitreal injections) with improved visual acuity and amendment of macular edema. The complex etiology calls for interdisciplinary approach to determine better the cause of this ophthalmological disease. Although studies have found a correlation between some thrombophilia mutations and retinal vein occlusion, more studies that contain a larger number of patients are necessary in order to determine the final role of these gene variants. PMID- 26978888 TI - A RARER FORM OF ANGLE-CLOSURE GLAUCOMA--DIAGNOSIS AND TREATMENT. AB - PURPOSE: to show how we diagnosed and treated a rarer form of angle-closure glaucoma; the pathogenic mechanism was angle crowding through thick peripheral iris roll. METHODS: we show the investigations: biomicroscopy of the fundus, tonometry, pachymetry, gonioscopy, perimetry, ultrasound biomicroscopy, optical coherence tomography of the anterior segment--that helped us to diagnose the angle-closure glaucoma and its pathogenic mechanism; we also show our choice for surgery--lens extraction--and our arguments for this choice. RESULTS: first postoperative day--intraocular pressure was 14 mmHg; a week postoperatively- intraocular pressure was 13 mmHg; three months postoperatively--intraocular pressure was 13 mmHg. CONCLUSIONS: lens extraction may be a very good choice in several forms of angle-closure glaucoma. PMID- 26978889 TI - PERSISTENT PUPILLARY MEMBRANE OR ACCESSORY IRIS MEMBRANE?. AB - Frequently, in literature and curent practice, accessory iris membrane (AIM) and persistant pupillary membrane (PPM) are confused. Both AIM and PPM are congenital iris anomalies in which fine or thick iris strands arrise form the collarette and obscure the pupil. AIM, which is also called iris duplication, closely resembles the normal iris tissue in color and thickness and presents a virtual second pseudopupil aperture in the centre while PPM even in its extreme forms presents as a translucent or opaque membranous structure that extends across the pupil and has no pseudopupil. Mydriatiscs, laser treatment or surgery is used to clear the visual axis and optimize visual development. Surgical intervention is reserved for large, dense AIMs and PPMs. Our patient, a 29 year old male, has come with bilateral dense AIM, bilateral compound hyperopic astigmatism, BCVA OD = 0.6, BCVA OS = 0.4, IOP OU = 17 mmHg. To improve the visual acuity of the patient we decided to do a bilateral membranectomy, restoring in this way transparency of the visual axis. After surgery, the visual acuity improved to BCVA OD= 0.8, BCVA OS=0.8. PMID- 26978890 TI - PLATEAU IRIS SYNDROME--CASE SERIES. AB - Plateau iris is characterized by closing the anterior chamber angle due to a large ciliary body or due to its anterior insertion that alters the position of iris periphery in respect to the trabecular meshwork. There are two aspects that need to be differentiated: plateau iris configuration and plateau iris syndrome. The first describes a situation when the iris root is flat and the anterior chamber is not shallow, the latter refers to a post laser iridotomy condition in which a patent iridotomy has removed the relative pupillary block, but goniscopically confirmed angle closure recurs without central shallowing of the anterior chamber. Isolated plateau iris syndrome is rare compared to plateau iris configuration. We hereby present two case reports of plateau iris syndrome in young patients who came to an ophthalmologic consult by chance. PMID- 26978892 TI - [Radiance Simulation of BUV Hyperspectral Sensor on Multi Angle Observation, and Improvement to Initial Total Ozone Estimating Model of TOMS V8 Total Ozone Algorithm]. AB - New hyperspectral sensor to detect total ozone is considered to be carried on geostationary orbit platform in the future, because local troposphere ozone pollution and diurnal variation of ozone receive more and more attention. Sensors carried on geostationary satellites frequently obtain images on the condition of larger observation angles so that it has higher requirements of total ozone retrieval on these observation geometries. TOMS V8 algorithm is developing and widely used in low orbit ozone detecting sensors, but it still lack of accuracy on big observation geometry, therefore, how to improve the accuracy of total ozone retrieval is still an urgent problem that demands immediate solution. Using moderate resolution atmospheric transmission, MODT-RAN, synthetic UV backscatter radiance in the spectra region from 305 to 360 nm is simulated, which refers to clear sky, multi angles (12 solar zenith angles and view zenith angles) and 26 standard profiles, moreover, the correlation and trends between atmospheric total ozone and backward scattering of the earth UV radiation are analyzed based on the result data. According to these result data, a new modified initial total ozone estimation model in TOMS V8 algorithm is considered to be constructed in order to improve the initial total ozone estimating accuracy on big observation geometries. The analysis results about total ozone and simulated UV backscatter radiance shows: Radiance in 317.5 nm (R317.5) decreased as the total ozone rise. Under the small solar zenith Angle (SZA) and the same total ozone, R317.5 decreased with the increase of view zenith Angle (VZA) but increased on the large SZA. Comparison of two fit models shows: without the condition that both SZA and VZA are large (> 80 degrees ), exponential fitting model and logarithm fitting model all show high fitting precision (R2 > 0.90), and precision of the two decreased as the SZA and VZA rise. In most cases, the precision of logarithm fitting mode is about 0.9% higher than exponential fitting model. With the increasing of VZA or SZA, the fitting precision gradually lower, and the fall is more in the larger VZA or SZA. In addition, the precision of fitting mode exist a plateau in the small SZA range. The modified initial total ozone estimating model (ln(I) vs. Omega) is established based on logarithm fitting mode, and compared with traditional estimating model (I vs. ln(Omega)), that shows: the RMSE of ln(I) vs. Omega and I vs. ln(Omega) all have the down trend with the rise of total ozone. In the low region of total ozone (175-275 DU), the RMSE is obvious higher than high region (425-525 DU), moreover, a RMSE peak and a trough exist in 225 and 475 DU respectively. With the increase of VZA and SZA, the RMSE of two initial estimating models are overall rise, and the upraising degree is ln(I) vs. Omega obvious with the growing of SZA and VZA. The estimating result by modified model is better than traditional model on the whole total ozone range (RMSE is 0.087%-0.537% lower than traditional model), especially on lower total ozone region and large observation geometries. Traditional estimating model relies on the precision of exponential fitting model, and modified estimating model relies on the precision of logarithm fitting model. The improvement of the estimation accuracy by modified initial total ozone estimating model expand the application range of TOMS V8 algorithm. For sensor carried on geostationary orbit platform, there is no doubt that the modified estimating model can help improve the inversion accuracy on wide spatial and time range This modified model could give support and reference to TOMS algorithm update in the future. PMID- 26978893 TI - [Detection of Atmospheric HONO and NO2 by Incoherent Broadband Cavity Enhanced Spectroscopy]. AB - We report on the development of an optical instrument based on LED-IBBCEAS for simultaneous measurements of nitrous acid (HONO) and nitrogen dioxide (NO2) in ambient air. The light emitting from the LED centered at 365 nm was directly focused into the cavity formed with two high reflectivity mirrors, separated by a distance of 1. 76 m. The light output of the cavity was received with a portable spectrometer. The mirror reflectivity was calibrated by absorption spectra of NO2 and O2-O2. In the spectral range of 353-376 nn, the maximum mirror reflectivity was found to be 0.999 17. Detection limits (1sigma) of 0.6 ppbv for HONO and 1.8 ppbv for NO2 were achieved with an acquisition time of 120 s. In order to test the accuracy of measured results by present setup, concentrations of NO2 were recorded during continuous 56 hours and compared with data from a NOX analyzer equipped with a blue light converter. The least-square fit lines give gradients of 1. 09 and respective intercepts of 3.45, with a linear correction factor of 0.89. The concentrations of HONO and NO2 in indoor air were monitored, the concentrations of HONO varied from near 0 to 5.3 ppbv in 24 hours, the averaged concentration was 1. 8 ppbv, and the concentrations of NO2 varied from 5 to 51 ppbv at the same time, the averaged concentration was 21.9 ppbv. PMID- 26978891 TI - CURRENT OPTIONS FOR SURGICAL TREATMENT OF GLAUCOMA. AB - The purpose of this study is to review current surgical treatment and new and better alternatives for patients with glaucoma. Glaucoma refers to a group of related eye disorders that have in common an optic neuropathy associated with visual function loss. It is one of the leading causes of irreversible blindness worldwide. Optic nerve damage and glaucoma-related vision loss can be prevented or limited by early diagnosis and treatment. Surgery offers a better control of the intraocular pressure then medical therapy. Nowadays, research continues for improving current surgical alternatives for treatment. PMID- 26978894 TI - [Quantitative Measurement of Equivalence Ratios of Methane/Air Mixture by Laser Induced Breakdown Spectroscopy: the Effects of Detector Gated Mode and Laser Wavelength]. AB - Laser-induced breakdown spectroscopy (LIBS) has been increasingly used in combustion diagnostics as a novel spectral analysis method in recent years. The quantitative local equivalence ratio of methane/air mixture is determined by LIBS using different emission intensity ratios of H/O and H/N. The comparison between calibration curves of H656/O777 and H656/N746 is performed in gated mode, which shows that H656/O777 can achieve better prediction accuracy and higher sensitivity. More spectral intensity ratios (H656/O777, H656/N500+, H656/N567 and H656/N746) can be used to make calibration measurements in ungated mode and H656/O777 is also tested best among them. The comparison between gated and ungated detection modes shows that gated mode offers better accuracy and precision. In addition, the effects of different laser wavelengths (1064, 532 and 355 nm) on LIBS spectra and calibration curves are investigated with laser focal point size and laser fluence kept constant. The results show that with longer laser wavelength, the peak intensity and SNR of H, O and N lines increase, as well as the slope of calibration curve of H656/O777. Among these three wavelengths, 1064 nm laser is best suited to measure the equivalence ratio of CH4/air mixture by LIBS. The experimental results are explained in terms of plasma electron density and temperature, which have a significant impact on the emission intensity and the partition function of hydrogen and oxygen, respectively. PMID- 26978895 TI - [Laser Raman Spectroscopy and Its Application in Gas Hydrate Studies]. AB - Gas hydrates are important potential energy resources. Microstructural characterization of gas hydrate can provide information to study the mechanism of gas hydrate formation and to support the exploitation and application of gas hydrate technology. This article systemly introduces the basic principle of laser Raman spectroscopy and summarizes its application in gas hydrate studies. Based on Raman results, not only can the information about gas composition and structural type be deduced, but also the occupancies of large and small cages and even hydration number can be calculated from the relative intensities of Raman peaks. By using the in-situ analytical technology, laser Raman specstropy can be applied to characterize the formation and decomposition processes of gas hydrate at microscale, for example the enclathration and leaving of gas molecules into/from its cages, to monitor the changes in gas concentration and gas solubility during hydrate formation and decomposition, and to identify phase changes in the study system. Laser Raman in-situ analytical technology has also been used in determination of hydrate structure and understanding its changing process under the conditions of ultra high pressure. Deep-sea in-situ Raman spectrometer can be employed for the in-situ analysis of the structures of natural gas hydrate and their formation environment. Raman imaging technology can be applied to specify the characteristics of crystallization and gas distribution over hydrate surface. With the development of laser Raman technology and its combination with other instruments, it will become more powerful and play a more significant role in the microscopic study of gas hydrate. PMID- 26978896 TI - [Research on Real-Time Trace Gas Detection System Based on QEPAS]. AB - Quartz-enhanced photoacoustic spectroscopy (QEPAS) technology was invented lately. Therefore it's an innovative method for trace gas detection compared with other existed technologies. In this paper, we studied the trace gas detection system based on QEPAS, and the atmospheric H2O was selected as the target analyte. In theory, the principles of laser wavelength modulation and signal harmonic detection were analyzed firstly, and the realizing solutions for the gas concentration retrieving and laser wavelength locking were obtained. Furthermore, the selection principle of absorption line for high sensitivity gas detection was discussed. In experiments, a continuous-wave distributed feedback(DFB) single mode diode laser emitting at 1.39 um was used as the exciting source for the H2O vapor measurement. Using wavelength modulation spectroscopy and 2nd harmonic detection, the influence of laser wavelength modulation depth on QEPAS signal level was investigated, and the acoustic wave enhancement of the addition of micro-resonator in the acoustic detection module was analyzed as well. After optimization of the QEPAS system, a detection limit of 5.9 ppm for H2O vapor was obtained. We measured the H2O vapor with different concentrations, and the R Square of 0.98 was achieved after the experimental data was linear fitted, indicated that the QEPAS system had an excellent linear response ability. Finally, continuous monitoring of atmospheric H2O concentration levels for a period of 12 hours was performed when the line locking mode was employed with the help of 3rd harmonic detection. The experimental results showed that this QEPAS scheme had a stable performance and outstanding continuous measuring capacity, and it can be widely used in high sensitivity on-line measurement for other trace gases detection fields. PMID- 26978898 TI - [The Effect of Hydrogen Bonding on the Spectrum of HPAM in Various Systems]. AB - IR and UV-Vis was employed to analyzed the spectrum effect of hydrogen bonding on the partially hydrolyzed polyacrylamide polymer(HPAM). The study reveals that, the characteristic absorption peak of free amino group moves to the low frequency due to the formation of intramolecular hydrogen bonding between amide group and carboxyl group. In the water solution, intramolecular hydrogen bonding is the main factor that shifted maximal absorption towards long wavelength. Intramolecular hydrogen bonding and intermolecular hydrogen bonds exist at the same time in the water solution contains intermediate sodium and calcium ions. While in the high concentration solution, the main form between amide group and carboxyl group is intermolecular hydrogen bonding. The effect of hydrogen bonding on the spectrum of HPAM demonstrates different extent in various systems. In the water solution, the maximum absorption wavelength red shifts 8 nm. In the system contains sodium ions, this shift is 4 nm. And this shift is only 2 nm in the solution contains both sodium ions and calcium ions. PMID- 26978897 TI - [Optical Spectroscopy for High-Pressure Microwave Plasma Chemical Vapor Deposition of Diamond Films]. AB - Polycrystalline diamond growth by microwave plasma chemical vapor deposition (MPCVD) at high-pressure (34.5 kPa) was investigated. The CH4/H2/O2plasma was detected online by optical emission spectroscopy (OES), and the spatial distribution of radicals in the CH4/H2/O2plasma was studied. Raman spectroscopy was employed to analyze the properties of the diamond films deposited in different oxygen volume fraction. The uniformity of diamond films quality was researched. The results indicate that the spectrum intensities of C2, CH and Halpha decrease with the oxygen volume fraction increasing. While the intensity ratios of C2, CH to Halpha also reduced as a function of increasing oxygen volume fraction. It is shown that the decrease of the absolute concentration of carbon radicals is attributed to the rise volume fraction of oxygen, while the relative concentration of carbon radicals to hydrogen atom is also reducing, which depressing the growth rate but improving the quality of diamond film. Furthermore, the OH radicals, role of etching, its intensities increase with the increase of oxygen volume fraction. Indicated that the improvement of OH concentration is also beneficial to reduce the content of amorphous carbon in diamond films. The spectrum space diagnosis results show that under high deposition pressure the distribution of the radicals in the CH4/H2/O2plasma is inhomogeneous, especially, that of radical C2 gathered in the central region. And causing a rapid increase of non-diamond components in the central area, eventually enable the uneven distribution of diamond films quality. PMID- 26978899 TI - [Comparative Study on the Molecular Structures and Spectral Properties of Ponceau 4R and Amaranth]. AB - The Edinburgh FLS920P steady-instantaneous fluorescence spectrometer was applied on the detection of the absorption and the emission spectra of ponceau 4R and amaranth, which are isomers to each other. After that, the spectral parameters of them were compared. Then, the density functional theory (DFT) and time-dependent density functional theory (TD-DFT) were used on the optimization of ponceau 4R and amaranth under the ground and excited state, respectively, in order to compare the differences in configurations of them under different states. On the base of the results above, the absorption and emission spectra of the two isomers were calculated with TD-DFT, and the polarized continuum model (PCM) was applied on the base of 6-311++G (d, p). The fluorescence mechanism, the relationships between the properties of fluorescence spectra and the molecular geometry were all analyzed. The results shows that, the structures of the two molecules are non planar, these two naphthalene rings are not co-planar, respectively, and there's hydrogen bond in amaranth. When the two isomers were on the ground state, the planarity of the naphthalene ring which exists the hydrogen bond mentioned above in amaranth is better than the corresponding part of ponceau 4R. The two isomers are nearly co-planar when they're on the excited state. The molecular structures of ponceau 4R and amaranth optimized above are basically reasonable, for the quantum chemistry calculation spectral results are agree with the experiments. The planarity of the naphthalene rings on the right side in ponceau 4R is worse than that in amaranth, the ponceau 4R molecule experienced more vibration and rotation from the excited to the ground state, lost more energy, which lead to the reduction of energy for emitting fluorescent photons. So ponceau 4R has longer fluorescence emission wave- length than amaranth. In this paper, the molecular structure information of ponceau 4R and amaranth were obtained, and the differences of the spectral characteristics between them were found out. The results can provide references for the study of the relationship between the spectral properties and the configuration of isomers. PMID- 26978900 TI - [Endpoint Temperature Prediction of the Basic Oxygen Furnace Based on the Flame Temperature Measurement at the Converter Mouth]. AB - In the basic oxygen steelmaking process, the endpoint temperature of the molten steel is one of the key factors whether the molten steel is qualified for tapping. Currently, it mainly relies on the experienced operators to control the endpoint temperature of the molten steel, and the prediction precision may vary among different operators. In order to realize the effectively end-point steel temperature prediction of the basic oxygen furnace as well as to meet the requirement of different sizes of the converter mouth, a new method based on the flame temperature measurement at the converter mouth was proposed in this paper. Firstly, a fiber-optic spectrometer system in the visible and near infrared spectral range was designed which can real-timely and effectively realize the collection of the flame radiation information at the converter mouth. Secondly, in consideration of the actual temperature of the flame and the distance between the converter and the designed system, an improved calibration method instead of the halogen lamp was adopted, and the two-color method was employed for the flame temperature measurement. Then a regression model based on the support vector machine was built with the flame temperature and several other parameters of the steel-making process as the input variables of the model. Verification experiment was carried out on 68 industrial data collected in the steel-making workshop. The results show that the prediction accuracy of this method is superior to the experienced operators, and close to the sub-lance based method. As a result, the proposed method can provide a feasible and effective solution to the end-point steel temperature prediction for those small-sized and medium-sized converters. PMID- 26978901 TI - [Preparation and Luminescent Properties of Blue Emitting Phosphor of Sr3 (PO4)2: Eu2+ for White LED]. AB - A series of Sr3 (PO4)2: Eu2+ blue phosphors were synthesized by high temperature solid state method under N2-H2 reducing atmosphere. The crystal structures, excitation and emission spectra were characterized by X-ray diffraction (XRD) and Photoluminescence (PL), respectively. The results show that the Sr3 (PO4)2: Eu2+ phosphor can be efficiently excited by the wavelengths ranging from 310 to 390 nm, and the excitation peak wavelength locates at 359 nm. A wide emission spectrum (~150 nm, originating from the 4f 5d1-->4f of the Eu2+) with a peaking wavelength of 438 nm was obtained. Through the Gaussian fitting, we found that the emission band formed by two luminescence centers(430 and 459 nm), which indicated that the Eu2+ occupied two different Sr2+ sites in the substrate of Sr3(PO4)2. As the Eu2+ doping concentration is 7%, the maximum luminous intensity was obtained. With the increasing of the doping concentration of the Eu2+, the concentration quenching effect occurred, and the emission peak wavelength has a red shift. The PL intensity of the Sr3 (PO4)2: Eu2+ phosphor is about 1.3 times than that of the blue emitting phosphor BaMgAl10O17: Eu2+ (BAM) which means that it is a promising candidate for the blue phosphor material for white LED. PMID- 26978902 TI - [Spectroscopic Properties of CeO2: Eu3+ for White LEDs]. AB - Under different Eu3+ concentration, Eu3+ doped CeO2 was prepared by co precipitation method, and the structure and luminescent properties were studied through XRD, excitation and emission spectra. The PLE spectrum shows a broad charge- transfer band from 300-400 nm, and a week excitation line at 467 arise from 7F0--5D2 transition in Eu3+. The red emission arise from 5D0--7F1 (592 nm) and 5D0--7F2 transitions of Eu3+ has a great increase by high concentration doping under 467 nm excitation. The wavelength at 467 nm is nicely fitting in with the widely applied emission wavelengths of blue LED chips. It is indicated that the CeO2:Eu3+ phosphor emits efficiently red emission under the blue light which makes it possible to create white light from a combination of a blue LED chip. PMID- 26978903 TI - [Preparation and Photoluminescent Properties of Ce3+-Activated LaPO4 Nanocrystals and Core/Shell Structure]. AB - Hydrophobic, monodisperse LaPO4: Ce3+ nanoparticles, LaPO4:Ce3+/LaPO4 and LaPO4:Ce3+/LaPO4: Ce3+/ LaPO4 core/shell structure nanocrystals were synthesized via a high-temperature organic solution approach. The as-synthesized samples were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR) and photoluminescence spectroscopy (PL). The results show that: all the samples are a monoclinic phase, Because of the size small nanoparticles, the diffraction peaks of the sample occurs width phenomenon. The LaPO4:Ce3+ nano- crystals exhibits the characteristic emission of Ce3+ ions, the photoluminescence intensity increases first and then decreases with the increasing doping concentration of Ce3+ ions, and the best doping amount is 6 at %, with the increasing doping amount, the photoluminescence intensity decreases which may caused by the concentration quenching. Compared to LaPO4:Ce3+ nanoparti- cles, the photoluminescence intensity of LaPO4:Ce3+/LaPO4 and LaPO4: Ce3+/LaPO4: Ce3+/LaPO4 core/shell structure nanocrystals improves about 41% and 95% respectively, this may be a synergy of larger particle size of nanocrystals and surface passivation effect. FTIR spectra data shows that the absorption peak at 1545 and 1461 cm-1 corresponded to the asymmetric and symmetric stretching vibration of --COO-, the separation, Delta, between the two peaks is 84 cm-1, The mechanism of the sample surface modification by the organics might be that the oxygen atoms of the carboxyl are coordinated with the lanthunum ions by a bidentate mode. PMID- 26978904 TI - [Identification of Six Isomers of Dimethylbenzoic Acid by Using Terahertz Time Domain Spectroscopy Technique]. AB - In this paper, the absorption spectra of 6 isomers of dimethylbenzoic acid, which were widely used in chemical and pharmaceutical production as intermediate substance, were measured by using the terahertz time-domain spectroscopy (THz TDS) system in the range 0.2-2.2 THz at room temperature. The experimental results show that the six measured isomers present apparent different spectral response. However, the results of using infrared spectroscopy indicates that different isomers show high similarity in absorption spectra in the range 1450 1700 cm-1. The vibrational frequencies are calculated by using the density functional theory (DFT), and identification of vibrational modes are given. It is clear that the absorption peaks of the 6 isomers in the range 1450-1700 cm-1 come from the stretching vibration of benzene ring and C==O, while the absorption peaks in the terahertz range are caused by the relative wagging of benzene ring and all the chains out of plane, which lead to the different absorption characteristics of the 6 isomers in the range 0.2-2.2 THz. The results suggest that the difference and similarity of the absorption spectra observed in the two different frequency range are resulted from the difference and similarity of the molecular structures of the six isomers. By using the different absorption characteristics, we can identify the six isomers of dimethylbenzoic acid effectively. Our study indicates that it is feasible to distinguish the isomers by using terahertz and infrared spectroscopy technique. It provides an effective way to identify different isomers and test the purity of the intermediate substance in the process of production quickly and accurately. PMID- 26978906 TI - [A Double Split Ring Terahertz Filter on Ploymide Substrate]. AB - Metamaterials are artificial composites that acquire their electromagnetic properties from embeded subwavelength metalic structure. With proper design of metamaterials, numerrous intriguing phenomena that not exhibited naturally can be realized, such as invisible cloaking, perfect absorption, negative refractive index and so on. In recent years, With the development of THz technology, the extensive research onTHz metamaterials devices areattracting more and more attentions. Since silicon (Si) has a higher transmittance for THz wave, it is usually selected as substrate in metamaterials structure. However, Si has the shortcomings of hardness, not easy to bend, and fragile, which limit the application of THz metamaterials. In this work, we use polyimide as the substrate to overcome the shortcomings of the Si substrate. Polyimide is flexible, smooth, suitable for conventional lithography process and the THz transmittance can compete with that of the Si. Frist, we test the THz optical properties of polymide, and get the refractive index of 1.9, and the transmittance of 80%. Second, we design a double splits ring resonators (DSRRs), and study the properties of transmission by changing the THz incidence angle and curvature of the sample. We find the resonant amplitude and resonant frequencies are unchanged. Fabricating metamaterials structures on a thin plastic substrate is a possible way to extend plane surface filtering to curved surface filtering. Third, we try to make a broadband filter by stacking two samples, and the 181GHz bandwidth at 50% has been achieved. By stacking several plane plastic metamaterial layers with different resonance responses into a multi-layer structure, a broadband THz filter can be built. The broadband filter has the advantages of simple manufacture, obvious filtering effect, which provides a new idea for the production of terahertz band filter. PMID- 26978905 TI - [Reseach on THz Time Domain Spectrum of Photo-Induced Insulator-Metal Phase Transition of VO2 Films]. AB - Vanadium dioxide (VO2) film will be phase-transitioned from insulator into metal, accompanied with dramatic change on conductivity, which is named as photo-induced insulator-metal phase transition. Such phase transition of VO2 film has important application potentials in modulators or other functional devices for terahertz waves. In this paper, the transmission spectrum variations before and after the photo-induced insulator-metal phase transition of vanadium dioxide film are investigated, and the phase transition properties in terahertz(THz) region are analyzed. In the experiment, the phase transition of the VO2 film was induced by a continuous wave (CW) laser source and a femtosecond (fs) laser source, respectively. Obvious changes on the THz waveforms were observed for the both mentioned means of excitation, and the amplitude attenuation, as well as the signal distortion, was intensified with the increase of the impinging optical power. The fast Fourier transform (FFT) spectra of the transmitted THz time domain signals were analyzed and it was found that the amplitude of the transmitted spectrum decreased synchronously with the increase of the optical power, accompanied with deformation of the spectrum line shape at the same time. The reason was that the macroscopic dielectric properties of the VO2 film approached gradually to that of a metal as laser power was increased. A parameter, transmission modulation function, was defined in the paper as the amplitude difference between the transmission spectra of the VO2 film before and after the laser excitation, to describe the dispersivity of the photo-induced phase transition more clearly. From the curve of the transmission modulation function, strong frequency-dependent properties at THz frequencies were found to vary regularly with the incident light power. After furthermore comparison, it was found that, though the insulator-metal phase transition could be trigged by both CW laser source and fs laser source, the corresponding impinging optical power values were obviously alternative for the equivalent transmission modulation function. At the end of the paper, the difference of the phase transition efficiency between the two excitation methods was analyzed and discussed. PMID- 26978907 TI - [The Study on the Far-FTIR and THz Spectra of Azitromycin Drugs with Different Physical Forms]. AB - Far Fourier transform infrared spectroscopy (Far-FTIR) and terahertz time-domain spectroscopy (THz-TDS) were used to measure the fingerprint spectra of Azitromycin suspension, capsule, tablet and dispersible tablet under vacuum and nitrogen conditions, respectively. In the frequency range of 0.2-15 THz, highly resolved spectral features for Azitromycin suspension were measured and some minor differences were observed between domestic and exotic Azitromycin Suspension, such as linewidth broadening and additional peaks. As same time, for the domestic Azitromycin capsule, tablet and dispersible tablet, the absorption baselines in the range of 0.2-2.7 THz rise with the increase of frequency while absorption peaks become weaker due to the scattering of bigger particles and smaller amount of Azitromycin. Also, the additional peaks are caused by the absorption of filling materials. In parallel with the qualitative measurement, the THz absorption spectra for mixtures of polyethylene (PE) powders and exotic Azithomycin suspension with different concentrations were also measured. According to the linear correlation between the concentration and the absorption intensity, the concentration of effective component can be evaluated accurately. This means that THz-TDS method is suitable for the quality inspection and evaluation of the mixed Azithromycin system. PMID- 26978908 TI - [Infrared Spectrum Analysis of Propolis and Tree Gum Collected from Different Areas]. AB - Propolis possesses functions of antibacterial, antiviral, anticancer, and liver protection, and is known as the "purple gold", however, the phenomenon which making and selling of counterfeit are growing in intensity. In order to establish a authenticity and quality of propolis evaluation model, in this paper, forty-one Chinese propolis, one proplis from United States and two tree gums were used for experimental materials. The infrared spectrum collection was performed by Fourier transform infrared spectrometer, and principal component analysis (PCA) was used for data analysis. The result showed that, the intrared spectrum of propolis and tree gum were significantly different. The propolis characteristic peak only appeared in 2500-3500 and 400-1800 cm-1. All propolis had two frequency region of characteristic peaks, 2849.08-2848.53 and 2917.74- 2916.76 cm-1, but tree gum did not have characteristic peak in this region. The characteristic peaks of gum were in 1150-1300 and 1550-1650 cm-1. Differences in these aspects can be used to distinguish propolis and gum, and can be used to identify true and false propolis. We use Qinghai propolis as a standard sample, in 42 samples, the matching degree of other propolis is > 80%. In addition, the result of PCA shows that tree gum and the propolis from different climate zone, or with different colors could be distinguished well. This paper firstly performed analysis on different propolis and gum by infrared spectrum, and a new method, for authenticity and quality of propolis identification, could be developed. PMID- 26978909 TI - [A Study of FTIR Spectrometry Based on a Long Optical Path on the Emission Rules of Nitrous Oxide from Soil]. AB - The excessive emission of N2O (Nitrous oxide) will destroy the ozone layer, reasonable fertilization and adopting measures of emission reduction of N2O are of great significance to slowing down the greenhouse effect. The article studied the impact of fertilization and water on the emission of N2 0 from the cabbage farmland using FTIR spectrometry. To enhance the sensitivity of the measuring system, we used multi-reflecting mirrors to increase the optical pathlength. By comparing the infrared spectra between the before and after fertilizer application and the NIST spectral library, finally, the band at 2160-2225 cm-1 was chosen as the spectral characteristics band of quantitative calculation of N2O through analyzing. The research found that fertilization and water could promote the emission of N2 0 from the cabbage farmland soil, which could supply theory bases for emission reduction of N2O and slowing down the greenhouse effect. Finally, we also studied the diurnal emission rules of N2O from the fertilized soil; the results showed that the emission of N2O was lower at night and the results were compared with that of previous' studies, which verifies the feasibility of this method. The results proved that FTIR with long optical path was a rapid and effective method to measure the emission rules of N2O from the cabbage farmland soil, which can measure the gas emissions of N2O from the fertilized cabbage farmland soil and compared with other traditional measuring methods, it had the advantages such as rapidness and convenience. PMID- 26978910 TI - [A Novel Method of Infrared Radiative Parameters Calculation in High Temperature Flow Field]. AB - Infrared radiative parameters under high temperature was calculated using RJMCMC method under Bayesian framework presumed Smeared Rotational Band model (SRB), in order to solve the problem of radiation calculation for high speed vehicle infrared signature research. The process of calculation does not need any database of parameter or priors about transition. The experiment from simulation and measured data demonstrates that the position of vibrational transition have been estimated precisely. Simultaneously, the change law of parameter estimation was consistent with theoretic SRB model, from which the integration of radiative parameters under different temperature approximated the line by line calculation (LBL) result very well. PMID- 26978912 TI - [Evaluation of Sugar Content of Huanghua Pear on Trees by Visible/Near Infrared Spectroscopy]. AB - A method of ambient light correction was proposed to evaluate the sugar content of Huanghua pears on tree by visible/near infrared diffuse reflectance spectroscopy (Vis/NIRS). Due to strong interference of ambient light, it was difficult to collect the efficient spectral of pears on tree. In the field, covering the fruits with a bag blocking ambient light can get better results, but the efficiency is fairly low, the instrument corrections of dark and reference spectra may help to reduce the error of the model, however, the interference of the ambient light cannot be eliminated effectively. In order to reduce the effect of ambient light, a shutter was attached to the front of probe. When opening shutter, the spot spectrum were obtained, on which instrument light and ambient light acted at the same time. While closing shutter, background spectra were obtained, on which only ambient light acted, then the ambient light spectra was subtracted from spot spectra. Prediction models were built using data on tree (before and after ambient light correction) and after harvesting by partial least square (PLS). The results of the correlation coefficient (R) are 0.1, 0.69, 0.924; the root mean square error of prediction (SEP) are 0. 89 degrees Brix, 0.42 degrees Brix, 0.27 degrees Brix; ratio of standard deviation (SD) to SEP (RPD) are 0.79, 1.69, 2.58, respectively. The results indicate that, method of background correction used in the experiment can reduce the effect of ambient lighting on spectral acquisition of Huanghua pears in field, efficiently. This method can be used to collect the visible/near infrared spectrum of fruits in field, and may give full play to visible/near-infrared spectroscopy in preharvest management and maturity testing of fruits in the field. PMID- 26978911 TI - [Differentiation and Identification of Alicyclobacillus Strains by Fourier Transform Near-Infrared Spectroscopy]. AB - Fourier transform near-infrared spectroscopy (FT-NIR) can reflect the overall molecular composition of microbial cells to identify different types of microorganisms. To establish an accurate, effective method about the differentiation and identification of Alicyclobacillus strains between different species, the present research performed the following studies by FT-NIR: (1) The FT-NIR spectra about seven type stains was clustered for data analysis. After preprocessing, reduction of data was performed by Principal Component Analysis (PCA) and Linear Discriminant Analysis(LDA), exploring the feasibility of differentiation and identification between different species, the result suggested that the PCA model can cluster the seven species of Alicyclobacillus strains correctly and the LDA model I can predict the unknown species with 100% accuracy. It evidenced that the method could identify different species of Alicyclobacillus strains preliminary. (2)In order to improve the robustness and practicability of the model, a total of 41 Alicyclobacillus strains including type and isolated strains were prepared for LDA model II, using the same methods as mentioned before. The result indicated that the LDA model validated by fifteen sample with 86.67% accuracy. It was more perfect and more comprehensive. As a result, the FT-NIR technology combined with chemometrics method can accurately and effectively identify Alicyclobacillus strains between different microbial species. PMID- 26978913 TI - [Study of Surface Enhanced Raman Spectroscopy on Copper Films Modified by Ion Beam]. AB - Surface-enhanced Raman Spectroscopy (SERS) was a rapid non-destructive testing. It was based on detecting molecule vibrational spectrum which was adsorbed on the metallic surface. Now it was widely used in surface adsorption, electrochemical catalysis, sensors, bio-medical testing, trace amount analysis and other fields. In our experiment, copper metallic films were deposited 50 nm on BK7 glass substrates by direct current magnetron sputtering. And then the films were employed for the Ar ion beam etching modification. The structure, morphology and optical properties was characterized by X-ray diffraction (XRD), Atomic Force Microscope (AFM), spectrophotometer and Raman spectroscopy. In the XRD graph, the peak value of modify copper film were the same with the untreated film. So the structure of copper film was not change. With increasing the power of Ar ion, the surface roughness was changed, and scattered spectrum intensity was increased by surface roughness added. With Rhodamine B (Rh B) as a probe molecule, Raman scattered spectrum was detected on modify copper film. Compared with the different samples, we can find the Raman signal was enhanced by surface roughness added. It will have some value on study the principles of SERS. PMID- 26978914 TI - [Raman Enhancement of a Dipolar Molecule on CVD Graphene]. AB - The CVD graphene was chosen as the Raman enhancement substrate, graphene-enhanced Raman scattering(GERS) of dipolar molecule DREP were explored with a laser wavelength lambda = 532 nm of micro-Raman spectroscopy. Upon comparison of the raman signal of DREP molecular latched to a graphene/SiO2 substrate and to a bare SiO2substrate, we found that the Raman signal of pure DREP molecule basically does not exist at low concentrations, until it reaches a certain concentration of 1 x 10-5 mol . L-1, its Raman signal emerging and as the increasing of the concentration, Raman signal and fluorescence signal all increase. However, the raman signal of DREP molecular on the grapheme occur at the concentration of 1 x 10-7 mol . L-1 and as the increasing of concentration, the raman signal increasing quickly but the fluorescence signal is not obvious. The studies were shown that graphene can achieve the Raman signal of DREP molecule enhancement, and can quench fluorescent backing off, increase the ratio of Raman signal and fluorescence signals. Comparing the GERS of DREP and DR1P molecules with different molecular dipole moment, indicating that the greater the dipole moment, the greater the enhancement factor, the degree of enhancement is stronger. Finally, we analyze the mechanism of Raman enhancement about DREP molecule on the grapheme. The dipole molecular is a pyrene terminal tethered a azobenzene molecular that was modified. There will happen the electron transfer of the pyrene terminal on the graphene interface through pi-pi interactions, changing the energy level of grapheme and leading to a p-doping. The mechanism of Raman enhancement are chemical mechanisms. The study of GERS of DREP molecular can help the comprehension of grapheme and the mechanism of grapheme enhanced raman scattering, for example the transfer of grapheme electron, the theory of chemical enhancement mechanism and how to separate the chemical enhancement mechanism from electromagnetic enhancement mechanism. PMID- 26978915 TI - [Preparation of Gold Nano-Particles as Surface-Enhanced Raman Scattering Sensors for Analysis of Banned Food Dye Chrysoidin in Yuba]. AB - Chrysoidin is a kind of banned food dye, and it has been illegally used for coloring food. A rapid detection and quantification method is developed and applied in analysis chrysoidin in yuba. Gold nanoparticles are synthesized by using hexadecyl trimethyl ammonium bromide (CTAB) as the bifunctional ligand to link the solid substrate and the AuNPs. The laser wavelength used for quantitative is 1594 cm-1. Significant differences between different concentrations of chrysoidin are verified by multiple variable analysis. A relationship between the logarithm of the concentrations and the intensity of laser is proved using univariate analysis method. The calibration curves showed good linearity in the range of 0.001-0.5 mmol . L-1 with correlation coefficients r = 0.995. The method is successfully applied to the determination of chrysoidin in yuba. The average recoveries of the drugs spiked at 50 and 500 ug . g-1 levels are 82.4% and 116.9%, and the relative standard deviations (RSD) are 3.8% and 4.0%. The method is simple, rapid, sensitive and accurate in the determination of chrysoidin. PMID- 26978916 TI - [Development of Fluorescence Resonance Energy Transfer Sensor for Determination of Adenosine Monophosphate in Biological Drug]. AB - The biological drug of the calf-blood dialysate has various pharmacological effects. It can promote the oxygen and glucose uptake for the hypoxia cells, and has beneficial effects on the malfunction of the blood circulation and trophic disturbances in the brain, and the impairment of peripheral blood circulation. Furthermore, it is favorable to wound healing and can regulate the central nervous system. Adenosine monophosphate (AMP) is a main active ingredient of the biological drug. In this report, a fluorescence resonance energy transfer (FRET) sensor has been developed with beta-CD-capped ZnS QDs as energy donor and 3 hydroxyflavone (3-HF) as energy acceptor. The results showed that AMP can lead to the fluorescence quenching of the FRET sensor at 526 nm, and the Stern-Volmer curve between the fluorescence quenching and the concentrations of AMP present a satisfactory linearity with the correlation coefficient of 0.996. The developed sensor has successfully applied for determination of the AMP in the biological drug. PMID- 26978917 TI - [Fluoroimmunoassay and Magnetic Lateral Flow Immunoassay for the Detection of Ractopamine]. AB - A fluoroimmunoassay based on quantum dots (QDs) and a lateral flow immunoassay system based on the magnetic beads (MB) were constructed to detect ractopamine (RAG) in urine samples. The monoclonal antibody (Ab1) against RAC was conjugated with QDs or MB as detector reagent, respectively. They apply a competitive format using an immobilized RAC conjugate and free RAC present in samples. That is to say, the concentration of RAC in the sample was negative related to the fluorescense intensity of QDs or the color density of MB. Results showed that the limit of detection (LOD) of fluorescence immunoassay method is 1 ng . mL-1 and analysis time is 4 h, while the visual LOD was 10 ng . mL-1 and analysis time was 15 min in magnetic lateral flow immunoassay system (MFLIS). Taken into consideration of the advantages and disadvantages of the two methods, it was suitable for the trace detection of RAC using fluoroimmunoassay while it was appropriate for point-of-care tesing of RAC by MFLIS. PMID- 26978918 TI - [Fluorescent and Magnetic Relaxation Switch Immunosensor for the Detecting Foodborne Pathogen Salmonella enterica in Water Samples]. AB - Fluoroimmunoassay based on quantum dots (QDs) and magnetic relaxation switch (MRS) immunoassay based on superparamagnetic nanoparticles (SMN) were constructed to detect Salmonella enterica (S. enterica) in water samples. In fluoroimmunoassay, magnetic beads was conjugated with S. enterica capture antibody (MB-Ab2) to enrich S. enterica from sample solution, then the QDs was conjugated with the S. enterica detection antibody (QDs-Ab1) to detect S. enterica based on sandwich immunoassay format. And the fluorescence intensity is positive related to the bacteria concentration of the sample. Results showed that the limit of detection (LOD) of this method was 102 cfu . mL-1 and analysis time was 2 h. In MRS assay, magnetic nanoparticle-antibody conjugate (MN-Ab1) can switch their dispersed and aggregated state in the presence of the target. This state of change can modulate the spin-spin relaxation time (T2) of the neighboring water molecule. The change in T2(DeltaT2) positively correlates with the amount of the target in the sample. Thus, AT can be used as a detection signal in MRS immunosensors. Results showed that LOD of MRS sensor for S. enterica was 103 cfu . mL-1 and analysis time was 0.5 h. Two methods were compared in terms of advantages and disadvantages in detecting S. enterica. PMID- 26978919 TI - [The Thiacalix [4] arene-Coumarin Fluorescence Probe Recognition for Fe3+ and Bovine Hemoglobin]. AB - 1,3-alternate coumarin substituted thiacalix[4]arene fluorescent probe 1 was synthesised from 1,3-alternate diethyl thiacalix[4]arene and 7-hydroxycoumarin by step reactions. In DMSO/H2O (phi, 3/7, pH 7) solution, the strong fluorescence emission and UV absorption of probe 1 can be selectively quenched or significantly enhanced by Fe3+ ion. The probe 1 showed high Fe3+ selective fluorescence quenching or absorption enhancement over commonly coexistent metal ions in neutral aqueous media, and the limit of detections were obtained as low as 10-8 mol . L-1 of Fe3+ by fluorescence and absorption spectrometry. Spectral titration, isothermal titration calorimetry and mass spectrometry were showed that probe and Fe3+ form 1:1 complexes, the constant up to 105 L . mol-1 and coordinate process was spontaneous by the mole binding free energy and entropy of probe with Fe3+. In addition, the probe can identification bovine hemoglobin (BHb) over other proteins through quenched its fluorescence in DMSO/H2O (phi, 1/9, Tris-HCl, pH 7, 0.1 mol . L-1 NaCl) media. The limit of detection was obtained as 0. 12 ug . mL-1 of BHb, as well as a linearity of 0.2-3.0 ug . mL-1, indicating the probe of high sensitivity and quantitation range. It can be used as a selective recognition Fe3+ and BHb of thiacalix[4] arene fluorescent probe. PMID- 26978920 TI - [Effect of Temperatures and Lead Ions on 3D-EEMs of Dissolved Organic Matter (DOM) Derived from Straw Humification]. AB - Straw incorporation is significant for straw reduction and reutilization, and is clearly required in the twelfth five-year-plan for national economic and social development of the People's Republic of China. The incorporated straw will naturally decompose and release the component of dissolved organic matter (DOM). At present, it lacks the research on straw humification behavior controlled by environmental factors and complexation effect between humification component and metal ions with fluorescence spectrometry in the representative region of loess. The fluorescence spectrometry was used to reveal the 3D-EEMs characteristics of DOM affected by temperatures and lead ions in the straw humification process, and the modified Stern-Volmer equation and Van't Hoff equation were applied to indicate the complexation parameters and thermodynamic constants between lead ions and DOM. The results showed: the humification temperatures affected little on fluorescence peaks of DOM and no peaks were obviously found to appear or disappear from the 3D-EEMs results. The fluorescence intensity decreased gradually at higher temperatures and in the presence of lead ions, the quenching effect might work in the process. The binding ability was more significant between lead ions and visible fulvic-like component shown from modified Stern Volmer equation, and the values of f revealed the complexation effect of lead ions and functional groups in DOM. Static quenching was the primary mechanism during the reaction process. The constants in Van't Hoff equation suggested the reaction was spontaneous and endothermic, and the disordered degree and the complexity were relatively low in the reaction system. The 3D-EEMs were acceptable to illustrate the variation of DOM characteristics under different temperatures and in the presence of lead ions in the straw humification process. PMID- 26978921 TI - [Study of Retrieving the Sandy Surface Roughness Land Based on the Bidirectional Reflectance Model]. AB - In the semiarid area, the structural nature of sandy land is changed due to wind erosion. Furthermore, assessing the changes in the composition and surface roughness in several spatial and temporal scales is significant for the wind erosion model calculations. As a noninvasive approach, remote sensing can be used to improve the study of sandy surface in time and space. In order to characterize the surface structure using the reflectance of sandy land, we analysis the effects of the changes of sandy surface structure on the bidirectional reflectance distribution basing on the multi-angular and hyperspectral measurements in the field; the measured sandy land samples are taken from nature, but the surface structures are artificial: one type is the direction of sand furrows is parallel to the incident direction, the other is the direction of sand furrows is perpendicular to the incident direction. At the same time, we analyzed the effects of surface structure on the bidirectional reflectance factor of sand land and we also retrieve the sandy surface roughness using the reflectance model parameter. The results suggest that both types of sand furrows will influence the distribution of reflectance of sandy land surface, for example, the backward scattering of sandy land increased when the direction of sand furrows is perpendicular to the incident direction, and the range of backward scattering of sandy land expended when the direction of sand furrows is parallel to the incident direction. When we compared the measured reflectance with the modeled results basing on the reflectance model, it is found that the reflectance model can be used to simulate the reflectance property of sandy land surface and prove that the parameter of model is useful for retrieving the surface roughness. This research not only presents the sample for quantifying the structural information of sandy land by the reflectance measurements, but also shows valuable reference for the research of intrinsic optical property of sandy land and the reversion of the texture of sandy land. In other words, this paper can also help the scientists understand the effect of the structural information on the optical properties of sandy land. PMID- 26978922 TI - [A Novel Method of Soil Moisture Content Monitoring by Land Surface Temperature and LAI]. AB - Land surface temperature (Ts) is influenced by soil background and vegetation growing conditions, and the combination of Ts and vegetation indices (Vis) can indicate the status of surface soil moisture content (SMC). In this study, Advanced Temperature Vegetation Dryness Index (ATVDI) used for monitoring SMC was proposed on the basis of the simulation results with agricultural climate model CUPID. Previous studies have concluded that Normalized Difference Vegetation Index (NDVI) easily reaches the saturation point, andLeaf Area Index (LAI) was then used instead of NDVI to estimate soil moisture content in the paper. With LAI-Ts scatter diagram established by the simulation results of CUPID model; how Ts varied with LAI and SMC was found. In the case of the identical soil background, the logarithmic relations between Ts and LAI were more accurate than the linear relations included in Temperature Vegetation Dryness Index (TVDI), based on which ATVDI was then developed. LAI-Ts scatter diagram with satellite imagery were necessary for determining the expression of the upper and lower logarithmic curves while ATVDI was used for monitoring SMC. Ts derived from satellite imagery were then transformed to the Ts-value which has the same SMC and the minimum LAI in study area with look-up table. The measured SMC from the field sites in Weihe Plain, Shanxi Province, China, and the products of LAI and Ts (MOD15A2 and MOD11A2, respectively) produced by the image derived from Moderate Resolution Imaging Spectrometer (MODIS) were collected to validate the new method proposed in this study. The validation results shown that ATVDI (R2 = 0.62) was accurate enough to monitor SMC, and it achieved better result than TVDI. Moreover, ATVDI-derived result were Ts values with some physical meanings, which made it comparative in different periods. Therefore, ATVDI is a promising method for monitoring SMC in different time-spatial scales in agricultural fields. PMID- 26978923 TI - [Interaction of Cucurbit[8]uril with beta-Indoleacetic Acid and Methylviologen]. AB - The interaction between Q[8] with beta-indoleacetic acid and the methylviologen was studied in aqueous solution with electronic absorption spectroscopy (UV-Vis), fluorescence spectroscopy, 1H NMR spectroscopy and isothermal titration calorimetry (ITC) in details. The authors explored the mode of action, action site and thermodynamic properties of the host-guest system. The electronic absorption and fluorescence spectroscopy data showed that the Q[8]/IAA system and Q[8]/MV2+ system informed 1:1 inclusion complexes in aqueous solution. ITC results showed that the changes of Gibbs free energy and enthalpy are all negative, it suggested that complex formation was spontaneous and exothermic reaction. Moreover, ITC results for the Q [8] and IAA with MV2+ indicate that the association constants of the Q[8]-IAA and Q[8]-MV2+ complexes were (3.22 +/- 0.96) x 105 L . mol-1 and (3.90 +/- 0.91) x 106 L . mol-1, respectively. Therefore, the interaction between Q[8] and IAA with the MV2+ was a competitive process. This likely occurs because the MV2+ and IAA molecules attempt to occupy the Q[8] cavity, which reduces the fluorescence and absorption spectra intensity of Q[8]-IAA because of the formation of a new inclusion complex between Q[8] and IAA with MV2+. In addition, with the addition of MV2+ to a Q[8]/IAA complex, 1H NMR results showed that the indole moieties of beta-indoleacetic acid and bipyridyl group of methylviologen can be incorporated into Q[8] cavities because of electronic transfer MV2+ with PQ in a Q[8] cavity with ternary complexes. These results provides the potential applications for the supramolecular self assembly in cucurbit[n]urils field. PMID- 26978924 TI - [Prediction of Cadmium Content in the Leaves of Navel Orange in Heavy Metal Contaminated Soil Using VIS-NIR Reflectance Spectroscopy]. AB - Visual and Near-infrared (VIS-NIR) reflectance spectroscopy had been used widely in monitoring agricultural pollution in recent years, however, it was rarely applied in monitoring the contamination of heavy metal in orchards. In the present paper, Newhall navel orange (Citrus sinensis [L.] Osbeck cv. Newhall) were cultivated in the potted soil contaminated with cadmium (Cd) at different levels, and the spectral reflectance and Cd content in the leaves were measured simultaneously at different growing seasons, which then were used to establish the prediction model by partial least squares regression (PLSR) based on spectral reflectance and by linear regression based on spectral index. The results showed that Cd was more easily transferred to and cumulated in the new leaves, and this phenomenon was more obvious in heavily contaminated soils with Cd. Blue shift in red edge was found in the band of 700-730 nm in the new leaves, however, no such phenomenon was found in the old leaves. The coefficient of determination (R2) of linear regression model based on spectral index was nearly 0. 8, while the PLSR model had a better result in predicting Cd content in the new leaves than the linear regression with R2CV of approximately 0.9. Furthermore, the standard normal variate transformation(SNV) in spectral preprocessing can improve the precision significantly in PLSR model. These results suggest that the VIS-NIR method has a great potential in monitoring heavy metal pollution in the navel orange. PMID- 26978925 TI - [Influence Mechanism of Dissolved Organic Matter (DOM) from Straw Humification on Chemical Speciation of Lead in Loess Region]. AB - Heavy metal is regarded as one of the most representative contaminants in soil, and the chemical speciation is greatly related to the toxicity and transformation behavior, which attracts the attention of researchers for years. The environmental factors could change the speciation of heavy metals, plus to the complexity of soil system, and the transformation variation of speciation might occasional existed under similar conditions. At present, the different viewpoints of related issues are urgent to be investigated. The characteristics of DOM from straw humification were revealed with UV spectra, 3D-EEMs spectra and FTIR spectra, and the Tessier Sequential Extraction Procedure was used to study the speciation transformation behavior of lead affected by DOM. The linear relationship of the contents between DOC and lead bound to organic matter was indicated to further discuss the influence mechanism of lead speciation using FTIR. The results showed: the absorbance peak of DOM located in 229 nm in UV spectra, and the fluorescence peaks appeared around the regions of lambda(ex)/em = 250/350 nm, lambda(em) = 250/450 nm and lambda(ex) = 330/450 nm, referred as UV fulvic-like fluorescence, and visible humic-like fluorescence, respectively. The dominant functional groups of DOM included--OH, C==O and N--H. The three fractions contents of lead (exchangeable, bound to iron and manganese oxides, residual) decreased, while that of lead bound to carbonates varied little. The contents of DOC and lead bound to organic matter appeared positive correlation (r == 0.691 8), indicating the effective complexation between DOM and lead ions. The functional groups of -OH, C==O and --COOH played an important role for the speciation transformation of lead, suggested from the FTIR spectra. PMID- 26978926 TI - [Sensing of Cu2+ Based on Fenton Reaction and Unmodified Gold Nanoparticles]. AB - Heavy metal pollution has received great attentions in recent years. The traditional methods for heavy metal detection rely on the expensive laboratory instruments and need time-consuming preparation steps; therefore, it is urgent to develop quick and highly sensitive new technologies for heavy metal detection. The colorimetric method based on the gold nanoparticles (AuNPs) features with simple operation, high sensitivity and low cost, therefore, enabling it widely concerned and used in the environmental monitoring, food safety and chemical and biological sensing fields. This work developed a simple, rapid and highly sensitive strategy based on the Fenton reaction and unmodified AuNPs for the detection of Cu2+ in water samples. The hydroxyl radical ( . OH) generated by the Fenton reaction between the Cu2+ and sodium ascorbate (SA) oxidized the single stranded DNA (ssDNA) attached on the AuNPs surface into variable sequence fragments. The cleavage of ssDNA induced the aggregation of AuNPs in a certain salt solution, therefore, resulting in the changes on the absorbance of solution. The assay conditions were optimized to be pH value of 7.9, 11 mg . L-1 ssDNA, 8 mmol . L-1 SA and 70 mmol . L-1 NaCl. Results showed that the absorbance ratio values at the wavelengths of 700 and 525 nm (A700/A525) were linearly correlated with the Cu2+ concentrations. The linear detection range was 0.1-10.0 umol . L-1 with a detection limit of 24 nmol . L-1 (3sigma). Spiked recoveries ranged from 87%-120% in three sorts of water, including drinking water, tap water and lake water, which confirmed that the potentials of the proposed assay for Cu2+ detection in reality. PMID- 26978927 TI - [Optimized Spectral Indices Based Estimation of Forage Grass Biomass]. AB - As an important indicator of forage production, aboveground biomass will directly illustrate the growth of forage grass. Therefore, Real-time monitoring biomass of forage grass play a crucial role in performing suitable grazing and management in artificial and natural grassland. However, traditional sampling and measuring are time-consuming and labor-intensive. Recently, development of hyperspectral remote sensing provides the feasibility in timely and nondestructive deriving biomass of forage grass. In the present study, the main objectives were to explore the robustness of published and optimized spectral indices in estimating biomass of forage grass in natural and artificial pasture. The natural pasture with four grazing density (control, light grazing, moderate grazing and high grazing) was designed in desert steppe, and different forage cultivars with different N rate were conducted in artificial forage fields in Inner Mongolia. The canopy reflectance and biomass in each plot were measured during critical stages. The result showed that, due to the influence in canopy structure and biomass, the canopy reflectance have a great difference in different type of forage grass. The best performing spectral index varied in different species of forage grass with different treatments (R2 = 0.00-0.69). The predictive ability of spectral indices decreased under low biomass of desert steppe, while red band based spectral indices lost sensitivity under moderate-high biomass of forage maize. When band combinations of simple ratio and normalized difference spectral indices were optimized in combined datasets of natural and artificial grassland, optimized spectral indices significant increased predictive ability and the model between biomass and optimized spectral indices had the highest R2 (R2 = 0.72) compared to published spectral indices. Sensitive analysis further confirmed that the optimized index had the lowest noise equivalent and were the best performing index in estimating biomass. In conclusion, optimizing wave-bands combination was a promising algorithm for improving prediction abilities of biomass for forage grass. PMID- 26978928 TI - [Spectral Analysis of CdZnSe Ternary Quantum Dots Sensitized TiO2 Tubes and Its Application in Visible-Light Photocatalysis]. AB - In this work, cadmium nitrate hexahydrate [Cd(NO3)2 . 6H2O] is as a source of cadmium, zinc nitrate [Zn(NO3)2] as a source of zinc source, and NaHSe as a source of selenium which was prepared through reducing the elemental selenium with sodium borohydride (NaBH4). Then water-soluble Cd1-xZnxSe ternary quantum dots with different component were prepared by colloid chemistry. The as-prepared Cd1-xZnx Se ternary quantum dots exhibit stable fluorescent property in aqueous solution, and can still maintain good dispersivity at room temperature for four months. Powder X-ray diffraction (XRD) and high resolution transmission electron microscope (HRTEM) were used to analyze crystal structure and morphology of the prepared Cd1-xZnxSe. It is found that the as-prepared ternary quantum dots are cubic phase, show as sphere, and the average of particle size is approximate 4 nm. The spectral properties and energy band structure of the as-prepared ternary quantum dots were modulated through changing the atom ratio of elements Zn and Cd. Compared with binary quantum dots CdSe and ZnSe, the ultraviolet-visible (UV Visible) absorption spectrum and fluorescence (FL) emission spectrum of ternary quantum dots are both red-shift. The composites (Cd0.5 Zn0.5 Se@TNTs) of Cd0.5 Zn0.5 Se ternary quantum dots and TiO2 nanotubes (TNTs) were prepared by directly immerging TNTs into quantum dots dispersive solution for 5 hours. TEM image shows that the Cd0.5 Zn0.5 Se ternary quantum dots were closely combined to nanotube surface. The infrared spectra show that the Ti-Se bond was formed between Cd0.5 Zn0.5 Se ternary quantum dots and TiO2 nanotubes, which improve the stability of the composite. Compared to pristine TNTs, UV-Visible absorption spectrum of the composites is significantly enhanced in the visible region of light. And the absorption band edge of Cd0.5Zn0.5 Se@TNTs red-shift from 400 to 700 nm. The recombination of the photogenerated electron-hole pairs was restrained with the as-prepared ternary quantum dots. Therefore, the visible-light photocatalytic efficiency was greatly improved. After visible-light irradiation for 60 min, the degradation of Cd0.5 Zn0.5 Se@TNTs photocatalysts for RhB is nearly 100%, which is about 3. 3 times of that of pristine TNTs and 2. 5 times of that of pure Cd0.5 Zn0.5 Se ternary quantum dots, respectively. PMID- 26978929 TI - [Detection of Hawthorn Fruit Defects Using Hyperspectral Imaging]. AB - Hyperspectral imaging technology covered the range of 380-1000 nm was employed to detect defects (bruise and insect damage) of hawthorn fruit. A total of 134 samples were collected, which included damage fruit of 46, pest fruit of 30, injure and pest fruit of 10 and intact fruit of 48. Because calyx . s-1 tem-end and bruise/insect damage regions offered a similar appearance characteristic in RGB images, which could produce easily confusion between them. Hence, five types of defects including bruise, insect damage, sound, calyx, and stem-end were collected from 230 hawthorn fruits. After acquiring hyperspectral images of hawthorn fruits, the spectral data were extracted from region of interest (ROI). Then, several pretreatment methods of standard normalized variate (SNV), savitzky golay (SG), median filter (MF) and multiplicative scatter correction (MSC) were used and partial least squares method(PLS) model was carried out to obtain the better performance. Accordingly to their results, SNV pretreatment methods assessed by PLS was viewed as best pretreatment method. Lastly, SNV was chosen as the pretreatment method. Spectral features of five different regions were combined with Regression coefficients(RCs) of partial least squares-discriminant analysis (PLS-DA) model was used to identify the important wavelengths and ten wavebands at 483, 563, 645, 671, 686, 722, 777, 819, 837 and 942 nm were selected from all of the wavebands. Using Kennard-Stone algorithm, all kinds of samples were randomly divided into training set (173) and test set (57) according to the proportion of 3:1. And then, least squares-support vector machine (LS-SVM) discriminate model was established by using the selected wavebands. The results showed that the discriminate accuracy of the method was 91.23%. In the other hand, images at ten important wavebands were executed to Principal component analysis (PCA). Using "Sobel" operator and region growing algrorithm "Regiongrow", the edge and defect feature of 86 Hawthorn could be recognized. Lastly, the detect precision of bruised, insect damage and two-defect samples is 95.65%, 86.67% and 100%, respectively. This investigation demonstrated that hyperspectral imaging technology could detect the defects of bruise, insect damage, calyx, and stem-end in hawthorn fruit in qualitative analysis and feature detection which provided a theoretical reference for the defects nondestructive detection of hawthorn fruit. PMID- 26978930 TI - [Study on the Geochemical Anomalies Identification of REE Based on HJ-1A-HSI]. AB - The characteristic spectral bands of REE do not vary with the occurrence state, cannot be used to identify mineral species, but can prove the existence of its own. Here we report the spectrum characteristics of REE and their compounds by remote sensing wave band from visible light-near infrared, with the quantitative relationship between the contents of REE and absorption index of characteristic spectral bands. The experimental study was carried out in Bayan Obo area, Inner Mongolia. Spectrums and Nd contents of typical rock and ore samples were gathered and analyzed. There is positive correlation between the Nd content, the absorption depth and absorption index of different spectrum characteristics (correlation coefficient > 0.778). Moreover, the correlation between absorption index of 726-772 nm band and Nd content is the best, at 0. 937. As mentioned above, the quantitative model and the inversion information remote sensing geochemical anomaly of Nd were built by the band of HJ-1A-HIS hyperspectral remote sensing data. Our results consistent with 1:200,000 stream sediment geochemical anomalies of Nd. The model provides a new means for rapid extract regional geochemical anomalies of REE. PMID- 26978931 TI - [Retrieval of Copper Pollution Information from Hyperspectral Satellite Data in a Vegetation Cover Mining Area]. AB - Heavy metal mining activities have caused the complex influence on the ecological environment of the mining regions. For example, a large amount of acidic waste water containing heavy metal ions have be produced in the process of copper mining which can bring serious pollution to the ecological environment of the region. In the previous research work, bare soil is mainly taken as the research target when monitoring environmental pollution, and thus the effects of land surface vegetation have been ignored. It is well known that vegetation condition is one of the most important indictors to reflect the ecological change in a certain region and there is a significant linkage between the vegetation spectral characteristics and the heavy metal when the vegetation is effected by the heavy metal pollution. It means the vegetation is sensitive to heavy metal pollution by their physiological behaviors in response to the physiological ecology change of their growing environment. The conventional methods, which often rely on large amounts of field survey data and laboratorial chemical analysis, are time consuming and costing a lot of material resources. The spectrum analysis method using remote sensing technology can acquire the information of the heavy mental content in the vegetation without touching it. However, the retrieval of that information from the hyperspectral data is not an easy job due to the difficulty in figuring out the specific band, which is sensitive to the specific heavy metal, from a huge number of hyperspectral bands. Thus the selection of the sensitive band is the key of the spectrum analysis method. This paper proposed a statistical analysis method to find the feature band sensitive to heavy metal ion from the hyperspectral data and to then retrieve the metal content using the field survey data and the hyperspectral images from China Environment Satellite HJ-1. This method selected copper ion content in the leaves as the indicator of copper pollution level, using stepwise multiple linear regression and cross validation on the dataset which is consisting of 44 groups of copper ion content information in the polluted vegetation leaves from Dexing Copper Mine in Jiangxi Province to build up a statistical model by also incorporating the HJ-1 satellite images. This model was then used to estimate the copper content distribution over the whole research area at Dexing Copper Mine. The result has shown that there is strong statistical significance of the model which revealed the most sensitive waveband to copper ion is located at 516 nm. The distribution map illustrated that the copper ion content is generally in the range of 0-130 mg . kg-1 in the vegetation covering area at Dexing Copper Mine and the most seriously polluted area is located at the South-east corner of Dexing City as well as the mining spots with a higher value between 80 and 100 mg . kg-1. This result is consistent with the ground observation experiment data. The distribution map can certainly provide some important basic data on the copper pollution monitoring and treatment. PMID- 26978932 TI - [Prediction of Encapsulation Temperatures of Copolymer Films in Photovoltaic Cells Using Hyperspectral Imaging Techniques and Chemometrics]. AB - A novel method of combination of the chemometrics and the hyperspectral imaging techniques was presented to detect the temperatures of Ethylene-Vinyl Acetate copolymer (EVA) films in photovoltaic cells during the thermal encapsulation process. Four varieties of the EVA films which had been heated at the temperatures of 128, 132, 142 and 148 degrees C during the photovoltaic cells production process were used for investigation in this paper. These copolymer encapsulation films were firstly scanned by the hyperspectral imaging equipment (Spectral Imaging Ltd. Oulu, Finland). The scanning band range of hyperspectral equipemnt was set between 904.58 and 1700.01 nm. The hyperspectral dataset of copolymer films was randomly divided into two parts for the training and test purpose. Each type of the training set and test set contained 90 and 10 instances, respectively. The obtained hyperspectral images of EVA films were dealt with by using the ENVI (Exelis Visual Information Solutions, USA) software. The size of region of interest (ROI) of each obtained hyperspectral image of EVA film was set as 150 x 150 pixels. The average of reflectance hyper spectra of all the pixels in the ROI was used as the characteristic curve to represent the instance. There kinds of chemometrics methods including partial least squares regression (PLSR), multi-class support vector machine (SVM) and large margin nearest neighbor (LMNN) were used to correlate the characteristic hyper spectra with the encapsulation temperatures of of copolymer films. The plot of weighted regression coefficients illustrated that both bands of short- and long-wave near infrared hyperspectral data contributed to enhancing the prediction accuracy of the forecast model. Because the attained reflectance hyperspectral data of EVA materials displayed the strong nonlinearity, the prediction performance of linear modeling method of PLSR declined and the prediction precision only reached to 95%. The kernel-based forecast models were introduced to eliminate the impact of nonlinear hyperspectral data to some extent through mapping the original nonlinear hyperspectral data to the high dimensional linear feature space, so the relationship between the nonlinear hyperspectral data and the encapsulation temperatures of EVA films was fully disclosed finally. Compared with the prediction results of three proposed models, the prediction performance of LMNN was superior to the other two, whose final recognition accuracy achieved 100%. The results indicated that the methods of combination of LMNN model with the hyperspectral imaging techniques was the best one for accurately and rapidly determining the encapsulation temperatures of EVA films of photovoltaic cells. In addition, this paper had created the ideal conditions for automatically monitoring and effectively controlling the encapsulation temperatures of EVA films in the photovoltaic cells production process. PMID- 26978933 TI - [Analysis of X-Ray Fluorescence Spectroscopy and Plasma Mass Spectrometry of Pangxidong Composite Granitoid Pluton and Its Implications for Magmatic Differentiation]. AB - Pangxidong composite granitoid pluton located in the southwestern margin of Yunkai massif. The metamorphic grade of this pluton increases from outside to inside, that is, banded-augen granitic gneisses, gneissoid granites and granites distribute in order from edge to core. X-Ray Fluorescence Spectroscopy and Plasma Mass Spectrometry are conducted to study the geochemical characteristics of the three types of rocks. The result shows that all the three types of rocks are peraluminous rocks and their contents of main elements and rare earth elements change gradually. From granitic gneisses to granites, the contents of Al2O3, CaO, MgO, TiO2, total rare earth elements and light rare earth elements increase, but the contents of SiO2 and heavy rare earth elements decrease. It is suggested that the phylogenetic relationship exists between granitic gneisses, gneissoid granites and granites during the multi-stage tectonic evolution process. Furthermore, the remelting of metamorphosed supracrustal rocks in Yunkai massif is probably an important cause of granitoid rocks forming. The evolutionary mechanism is probably that SiO2 and heavy rare earth elements were melt out from the protolith and gradually enriched upward, but Al2O3, CaO, MgO, TiO2 and light rare earth elements enriched downward. PMID- 26978935 TI - [Application of ICP-MS to Detect Rare Earth Elements in Three Economic Macroalgaes in China]. AB - In order to investigate the content and distribution of rare earth elements (REE) in main economic macroalgaes in our country, fifteen rare earth elements in three economic macroalgaes (including 30 samples of kelp, 30 samples of laver and 15 samples of Enteromorpha) were detected using ICP-MS method. Results showed that the total content of REE in different species of macroalgaes was different. The highest total content of REE was in Enteromorpha (16,012.0 ng . g-1), while in kelp and laver, the total REE was similar for two macroalgaes (3887.4 and 4318.1 ng . g-1 respectively). The content of fifteen rare earth elements in kelp ranged from 7.9 to 1496.4 ng . g-1; in laver, it ranged from 8.2 to 1836.6 ng . g-1. For Enteromorpha, the concentration of 15 rare earth elements were between 19.2 and 6014.5 ng . g-1. In addition, the content and distribution of different rare earth elements in different macroalgaes was also different. For kelp, the highest content of REE was Ce (1 496.4 ng . g-1), and the second was La (689.1 ng . g-1). For laver, the highest was Y (1836.6 ng . g-1), and the second was Ce (682.2 ng . g-1). For Enteromorpha, the highest was Ce (6014.5 ng . g-1), and the second was La (2902.9 ng . g-1). Present results also showed that three macroalgaes accumulated the light rare earth elements much more than the high rare earth elements. The light rare earth elements occupied 90.9%, 87.3% and 91.1% for kelp, laver and Enteromorpha respectively. The result that the Enteromorpha had high content of rare earth elements could provide important support for opening new research directions for the utilization of Enteromorpha. PMID- 26978934 TI - [Determination of Heavy Metal Elements in Diatomite Filter Aid by Inductively Coupled Plasma Mass Spectrometry]. AB - This study established a method for determining Be, Cr, Ni, As, Cd, Sb, Sn, Tl, Hg and Pb, total 10 heavy metals in diatomite filter aid. The diatomite filter aid was digested by using the mixture acid of HNO3 + HF+ H3PO4 in microwave system, 10 heavy metals elements were determined by inductively coupled plasma mass spectrometry (ICP-MS). The interferences of mass spectrometry caused by the high silicon substrate were optimized, first the equipment parameters and isotopes of test metals were selected to eliminate these interferences, the methane was selected as reactant gas, and the mass spectral interferences were eliminated by dynamic reaction cell (DRC). Li, Sc, Y, In and Bi were selected as the internal standard elements to correct the interferences caused by matrix and the drift of sensitivity. The results show that the detection limits for analyte is in the range of 3.29-15.68 ng . L-1, relative standard deviations (RSD) is less than 4.62%, and the recovery is in the range of 90.71%-107.22%. The current method has some advantages such as, high sensitivity, accurate, and precision, which can be used in diatomite filter aid quality control and safety estimations. PMID- 26978936 TI - [Study on Leaching Characteristic of Heavy Metal in the Manure-Amended Soil Using ICP-MASS]. AB - Based on an 11-year fertilizer field trial (located at the lower liaohe river plain), the effects of different organic manure application rates on the accumulations of heavy metals (Cu, Zn, Cd and Cr) in surface soil (0-20 cm), and the leaching characteristic and vertical migration pattern of heavy metal have been investigated in this rainfed agro-ecosystem using undisturbed soil columns. The result showed that the content of heavy metal in surface soil was elevated with the increase of manure application. The increasing magnitude was in the order of Cd>Cu>Zn>Cr. According to the Chinese soil quality standard (GB15618 1995), the application of manure (not exceeding 50 t . ha-1) did not result in serious heavy metal pollution in the surface soil. Chromium met the Grade I , and Cu and Zn met the Grade II; whereas, Cd was almost exceeded the threshold of Grade III. The potential risk of Cd in soil should be paid more attentions in future research. According to the National water quality standard (GB/T14848-93), the Cu and Cd concentrations in leachate samples were up to the Grade II except only a few samples that fell in Grade III. Furthermore, Cr in the leachate all matched Grade I water quality standard. These results indicated long-term application of manure (not exceeding 50 t . ha-1) in our site had not induced contaminant risks of heavy metals in underground water. In addition, the Cu, Zn and Cd (except Cr) in leachate all declined with the increase of soil depth, indicating the low capacity of vertical migration of heavy metal. Among the four heavy metals, Zn and Cr tended to be leached into deep soil, whereas Cu and Cd were more prone to be accumulated in surface soil. PMID- 26978937 TI - [Automatic Measurement of the Stellar Atmospheric Parameters Based Mass Estimation]. AB - We have collected massive stellar spectral data in recent years, which leads to the research on the automatic measurement of stellar atmospheric physical parameters (effective temperature Teff, surface gravity log g and metallic abundance [Fe/ H]) become an important issue. To study the automatic measurement of these three parameters has important significance for some scientific problems, such as the evolution of the universe and so on. But the research of this problem is not very widely, some of the current methods are not able to estimate the values of the stellar atmospheric physical parameters completely and accurately. So in this paper, an automatic method to predict stellar atmospheric parameters based on mass estimation was presented, which can achieve the prediction of stellar effective temperature Teff, surface gravity log g and metallic abundance [Fe/H]. This method has small amount of computation and fast training speed. The main idea of this method is that firstly it need us to build some mass distributions, secondly the original spectral data was mapped into the mass space and then to predict the stellar parameter with the support vector regression (SVR) in the mass space. we choose the stellar spectral data from the United States SDSS-DR8 for the training and testing. We also compared the predicted results of this method with the SSPP and achieve higher accuracy. The predicted results are more stable and the experimental results show that the method is feasible and can predict the stellar atmospheric physical parameters effectively. PMID- 26978938 TI - [Fourier Transform Spectrometer Based on Rotating Parallel-Mirror-Pair]. AB - In the temporally-modulated Fourier transform spectroscopy, the translational moving mirror is difficult to drive accurately, causing tilt and shear problems. While, a rotational moving mirror can solve these problems. A rotary Fourier transform spectrometer is recommanded in this paper. Its principle is analyzed and the optical path difference is deduced. Also, the constrains for engineering realization are presented. This spectrometer consists of one beamsplitter, two fixed mirrors, one rotating parallel mirror pair, a collimating lens, a collecting lens, and one detector. From it's principle, this spectrometer show a simple structure, and it is assembled and adjustmented easily because the two split light are interfered with each other after reflected through the same plane mirror; By calculating the expression of it's optical path difference, the spectrometer is easy to realize large optical path difference, meaning high spectral resolution; Through analyzing it's engineering design constraints and computer simulation, it is known that the spectrometer should get the high resolution sample by high-speed spinning motor, so it is easy to achieve precise motion control, good stability, fast measurement speed. PMID- 26978939 TI - [Optical Path Difference Analysis and Simulation of Four Typical Rotary Type Interferometer]. AB - The four kinds of the structure characteristics of rotary type interferometer are mainly analyzed from the classical Michelson interferometer structure in the paper. The Optical path difference between the interferometer and the rotation angle is also analyzed. By setting parameters, the four kinds of rotary type optical path difference of the interferometer are simulated based on the optical path difference formula. The rotation velcocity of the four kinds of interferometers is also simulated. By simulation and contrast of the optical path difference, the relationship is intuitively reflect by figure between the optical path difference and the rotation angle. The scope of the rotation angle is discussed within 3% of the velocity errors. It is the very good reference significance to study the structure and properties of the interferometer by analyzing and simulating the optical path difference discussed in the paper. PMID- 26978940 TI - [Dynamic Wavelength Characteristics of Semiconductor Laser in Electric Current Tuning Process]. AB - In order to measure the dynamic wavelength of semiconductor lasers under current tuning, an improved method of fi- ber delay self-heterodyne interferometer was proposed. The measurement principle, as well the beat frequency and dynamic wavelength of recursive relations are theoretically analyzed. The application of the experimental system measured the dynamic wavelength characteristics of distributed feedback semiconductor laser and the static wavelength characteristics measurement by the spectrometer. The comparison between the two values indicates that both dynamic and static wavelength characteristic with the current tuning are the similar non-linear curve. In 20-100 mA current tuning range, the difference of them is less than 0.002 nm. At the same time, according to the absorption lines of CO2 gas, and HITRAN spectrum library, we can identify the dynamic wavelength of the laser. Comparing it with dynamic wavelength calculated by the beat signal, the difference is only 0.001 nm, which verifies the reliability of the experimental system to measure the dynamic wavelength. PMID- 26978941 TI - [A New Method for Eliminating Background Signal Drift to Improve the Detection Precision in Continuous Harmonic Detection]. AB - To overcome the second harmonic background signal drift in gas continuous detection based on tunable diode laser absorption spectroscopy(TDLAS), a new method of background elimination was proposed by changing center current of the laser. This method can eliminated the effects of background signal drifting on concentration inversion. Based on the wavelength modulation theory, the theoretical expression of the second harmonic of the background signal is derived. In addition, the second harmonic background signal components and the factors that affect it are described. In different working temperatures, the relationship curve between thelaser current and output light intensity. In the process of continuous detection, we analyzes the feasibility ofchangingthe laser center current extraction of background signal. Combined with the principle of the background signal searching, the LabView flow chart was designed to search background center current. Ammonia (NH3) was detected by the TDLAS experimental system, which demonstrated the feasibility of the new method. The range of experiment parameters and the range of background center current searches were determined, in the situation that there was only one absorption line in the full laser workspace. The experimental results showed that this method realizes background signal extraction, reduces the error of concentration inversion and the effects of concentration inversion bybackground signal. Thus it improved the detection accuracy of the concentration. In the continuous detection experiment, the standarddeviation of inversion concentration reduced from 2.688 3 to 1.856 1, which demonstrated. that the degree of dispersion of detected concentration is reduced, even eliminate the effects of background signal drifting on concentration inversion and the accuracy of detection is improved. This method provides an effective background drifting elimination approach for improving the detection accuracy of the concentration. PMID- 26978942 TI - [The Study of Characteristics of Cladding-Reduced Coated Long-Period Fiber Grating Based on Mode Transition and Dual Peak Resonance]. AB - Based on coupled-mode theory, the mode transition of the high-order cladding modes in a coated long-period tiber grating (LPFG) has been studied firstly; the mode transition region and non-mode transition region of high-order cladding modes are divided. The response characteristic of cladding mode effective index with increasing the overlay thickness is analyzed; the shift of resonant wavelength in the mode transition region will be larger than that in the non-mode transition region. Further, the changes of the resonant wavelength of some high order cladding modes with grating period are investigated when the cladding radius are different, the shift between two resonant wavelengths of dual peak in the mode transition region is bigger than that in non-mode transition region when the cladding radius are uniform. And the shift between two resonant wavelengths of dual peak will be increased by the decrease of the cladding radius in both mode transition and non-mode transition regions. Finally, the response characteristics of film refractive index of coated LPFG are investigated for a high-order cladding mode while the cladding radius are different and the overlay thickness is located in mode transition region and non-transition mode region, then the optimized design scheme is come up with. The higher sensitivity dual peak sensor of coated LPFG than the traditional dual-peak sensor will be obtained when the overlay thickness and refractive index is located in the mode transition region and the grating period close to the phase matching turning points. Further, the resolution power of coated LPFG sensor will further be improved by the appropriate reducing of the cladding radius. PMID- 26978943 TI - A Quantum Dot Fluorescence Sensor System Design for Hg2+ Trace Detection. AB - The detection of Hg2+ ions usually requires large laboratory equipment, which encounters difficulties for rapid field test in most applications. In this paper, we design a reflective sensor for trace Hg2+ analysis based on the fluorescent quenching of Quantum dots, which contains two major modules, i. e. the fluorescent sensing module and the signal processing module. The fluorescence sensing module is composed of a laser source, a light collimated system and a photo-detector, which enables the realization of the fluorescence excitation as well as its detection. The signal processing module realized the further amplification of the detected signal and hereafter the filtering of noises. Furthermore, the Hg2+ concentration will displayed on the QT interface using a Linux embedded system. The sensor system is low cost and small, which makes it available for rapid field test or portable applications. Experimental results show that the sensor has a good linear relationship for the Hg2+ concentration range from 15.0 x 10-9 to 1.8 x 10-6 mol . L-1. The regression equation is V0/V = 1.309 13 + 3.37c, where c is Hg2+ concentration, and V0 is the voltage value for the blank case. In our work, the linearity is determined as 0. 989 26. The experiments exhibit that Ca2+, Mn2+ and Pb2+ ions have small influence on the Hg2+ detection, and the interfere of other common ions can be neglected, which indicates a good selectivity of the sensor. Finally, it shows that our sensor has a rapid response time of 35 s and a good repeatability, thus it is potential for field test of trace Hg2+. PMID- 26978944 TI - High-Frequency Observation of Water Spectrum and Its Application in Monitoring of Dynamic Variation of Suspended Materials in the Hangzhou Bay. AB - In situ measurement of water spectrum is the basis of the validation of the ocean color remote sensing. The traditional method to obtain the water spectrum is based on the shipboard measurement at limited stations, which is difficult to meet the requirement of validation of ocean color remote sensing in the highly dynamic coastal waters. To overcome this shortage, continuously observing systems of water spectrum have been developed in the world. However, so far, there are still few high-frequency observation systems of the water spectrum in coastal waters, especially in the highly turbid and high-dynamic waters. Here, we established a high-frequency water-spectrum observing system based on tower in the Hangzhou Bay. The system measures the water spectrum at a step of 3 minutes, which can fully match the satellite observation. In this paper, we primarily developed a data processing method for the tower-based high-frequency water spectrum data, to realize automatic judgment of clear sky, sun glint, platform shadow, and weak illumination, etc. , and verified the processing results. The results show that the normalized water-leaving radiance spectra obtained through tower observation have relatively high consistency with the shipboard measurement results, with correlation coefficient of more than 0. 99, and average relative error of 9.96%. In addition, the long-term observation capability of the tower based high-frequency water-spectrum observing system was evaluated, and the results show that although the system has run for one year, the normalized water leaving radiance obtained by this system have good consistency with the synchronously measurement by Portable spectrometer ASD in respect of spectral shape and value, with correlation coefficient of more than 0.90 and average relative error of 6.48%. Moreover, the water spectra from high-frequency observation by the system can be used to effectively monitor the rapid dynamic variation in concentration of suspended materials with tide. The tower-based high frequency water-spectrum observing system provided rich in situ spectral data for the validation of ocean color remote sensing in turbid waters, especially for validation of the high temporal-resolution geostationary satellite ocean color remote sensing. PMID- 26978945 TI - The Extraction Model of Paddy Rice Information Based on GF-1 Satellite WFV Images. AB - In the present, using the characteristics of paddy rice at different phenophase to identify it by remote sensing images is an efficient way in the information extraction. According to the remarkably properties of paddy rice different from other vegetation, which the surface of paddy fields is with a large number of water in the early stage, NDWI (normalized difference water index) which is used to extract water information can reasonably be applied in the extraction of paddy rice at the early stage of the growth. And using NDWI ratio of two phenophase can expand the difference between paddy rice and other surface features, which is an important part for the extraction of paddy rice with high accuracy. Then using the variation of NDVI (normalized differential vegetation index) in different phenophase can further enhance accuracy of paddy rice information extraction. This study finds that making full advantage of the particularity of paddy rice in different phenophase and combining two indices (NDWI and NDVI) associated with paddy rice can establish a reasonable, accurate and effective extraction model of paddy rice. This is also the main way to improve the accuracy of paddy rice extraction. The present paper takes Lai'an in Anhui Province as the research area, and rice as the research object. It constructs the extraction model of paddy rice information using NDVI and NDWI between tillering stage and heading stage. Then the model was applied to GF1-WFV remote sensing image on July 12, 2013 and August 30, 2013. And it effectively extracted out of paddy rice distribution in Lai'an and carried on the mapping. At last, the result of extraction was verified and evaluated combined with field investigation data in the study area. The result shows that using the extraction model can quickly and accurately obtain the distribution of rice information, and it has the very good universality. PMID- 26978946 TI - Degradation Ability of Modified Polyvinyl Alcohol Film for Coating of Fertilizer. AB - Using outdoor exposure and cinnamon soil incubation test, by quality changes, infrared spectroscopy and electron microscopic scanning technology, to research the degradation ability of self-developed coated fertilizer films. The results of outdoor exposure and cinnamon soil incubation test showed that all films had certain degradation ability, and the degradation rate increased with the increase of time. Under two kinds of test conditions, the highest degradation rate could reach above 35%. The degradation ability of film citric acid/ PVA was much stronger than epoxy resin/PVA. The degradation ability of citric acid/PVA/diatomite composite film materials was further enhanced because of the addition of diatomite. The epoxy resin/PVA composite film materials, although they had certain degradability, compared to the contrast, the difference was not significant, and adding diatomite can't obviously increase the degradation rate. The results of IR spectroscopy showed that some major functional groups, such as C==O, C==C, ==C--H would be reduced after degradation, and the transmission rate also increased, which showed that the degradation of composite film materials must be happened Scanning electron microscopy showed that the surface becomes rough and uneven, and it also meant the films have some degradation. The results of IR spectroscopy and scanning electron microscopy were consistent with the results of quality change test, and could more objectively represent the degradability of film material. Modified film materials can effectively control nutrient release without causing harm to the soil environment, so it is suitable for the film materials of coated fertilizer. PMID- 26978947 TI - Discrimination of Maize Haploid Seeds from Hybrid Seeds Using Vis Spectroscopy and Support Vector Machine Method. AB - Doubled haploid (DH) lines are routinely applied in the hybrid maize breeding programs of many institutes and companies for their advantages of complete homozygosity and short breeding cycle length. A key issue in this approach is an efficient screening system to identify haploid kernels from the hybrid kernels crossed with the inducer. At present, haploid kernel selection is carried out manually using the"red-crown" kernel trait (the haploid kernel has a non pigmented embryo and pigmented endosperm) controlled by the R1-nj gene. Manual selection is time-consuming and unreliable. Furthermore, the color of the kernel embryo is concealed by the pericarp. Here, we establish a novel approach for identifying maize haploid kernels based on visible (Vis) spectroscopy and support vector machine (SVM) pattern recognition technology. The diffuse transmittance spectra of individual kernels (141 haploid kernels and 141 hybrid kernels from 9 genotypes) were collected using a portable UV-Vis spectrometer and integrating sphere. The raw spectral data were preprocessed using smoothing and vector normalization methods. The desired feature wavelengths were selected based on the results of the Kolmogorov-Smirnov test. The wavelengths with p values above 0. 05 were eliminated because the distributions of absorbance data in these wavelengths show no significant difference between haploid and hybrid kernels. Principal component analysis was then performed to reduce the number of variables. The SVM model was evaluated by 9-fold cross-validation. In each round, samples of one genotype were used as the testing set, while those of other genotypes were used as the training set. The mean rate of correct discrimination was 92.06%. This result demonstrates the feasibility of using Vis spectroscopy to identify haploid maize kernels. The method would help develop a rapid and accurate automated screening-system for haploid kernels. PMID- 26978948 TI - Determination of Beryllium in Soil and Sediment by Graphite Furnace Atomic Absorption with a Microwave-Acid Digestion Method. AB - A method for determination of beryllium in soils and sediments by microwave-acid digestion/graphite furnace atomic absorption (GFAA) is described. In this paper, the working conditions of the instrument are optimized, the drawing of calibration curve is expounded, the pretreatment process of soil and sediments (including microwave heating process and the selection of digestion system) is discussed, and the interference of coexisting elements is examined. The sample was pretreated by microwave digestion parameters using HNO3/ HCl/HF mixed acid system. The method is fast and simple without matrix modifier, and has no interference by coexisting ions, and has high repeatability and reproducibility. Under the optimal experimental conditions, the limit of detection (LOD) is 0.004 9 mg . kg-1 (sample quantity 0.200 0 g, sample volume 25 mL), and the limits of quantitation (LOQ) is 0.20 mg . kg-1. This method is used to measure the standard samples and actual samples, whether in the laboratory, or between laboratories, has good accuracy and precision. PMID- 26978949 TI - Cost versus investment: how does the C-suite view the security function? AB - Is security an investment or a cost? Since the preventative value of security is difficult to prove, each professional security practitioner must do his or her best to take existing data and translate it into a language that the C-Suite will understand, the author says. In this article he describes ways that appropriate resourcesfor security in the healthcare environment can be validated. PMID- 26978950 TI - Adapting healthcare security officer training to changing times. AB - The need to conduct field training programs of new officers instead of "learning by doing" has become essential as violent incidents in hospitals keep increasing, the author says. In this article he outlines the elements of a successful field training program. PMID- 26978952 TI - Total quality leadership tactics for healthcare security teams. AB - Leading a large staff of individuals with different personality traits can be a challenge, the authors state, but understanding that each team member is a unique person with thoughts and feelings that may differ from a leader's preconceived notions allows healthcare security officers to celebrate diversity and work together to create positive change. A high functioning team, they add, accepts personality differences and knows that each individual is a value-contributing member of the team. PMID- 26978951 TI - IAHSS certification rollout: helping officers succeed. AB - After determining that security staff should obtain IAHSS certification on every level to help reduce the risk for mishandling of incidents and enhance the health system's reputation for being a "best practice" organization, security managers, working with Human Resources, developed a special training program designed to maximize the chances of an individual officer and supervisor attaining such certification. In this article, the author reviews this training program. PMID- 26978953 TI - Shared governance team develops standard onboarding process. AB - Standardizing the hiring and onboarding of security officers in a diverse and comprehensive healthcare system has been attained, according to the author, by the employment of Shared Governance, a staff-leader partnership designed to improve department outcomes. In this article, he describes how Shared Government was employed, how different issues were identified, and how benefits were achieved. PMID- 26978954 TI - Resources available for applying metrics in security and safety programming. AB - Incorporating metrics into security surveys has been championed as a better way of substantiating program-related effectiveness and expenditures. Although security surveys have been aroundfor well over 40 years, rarely, if ever, have metric-related strategies been part of the equation, the author says. In this article, he cites several published articles and research findings available to security professionals and their surveyors that may give them the expertise and confidence they need to make use of this valuable tool. PMID- 26978955 TI - Critical partners in domestic violence advocacy- a unique collaboration. AB - Recognizing the reality of domestic violence and its impact on the workplace, the Police and Security Staff of a leading hospital launched a team effort to protect and empower abused employees and break the cycle of violence. In this article, the author describes how the team was formed, how it operates, and the results it has achieved. PMID- 26978956 TI - What every healthcare facility should do now to reduce the potential for workplace violence. AB - The prevalence and growth of violence in healthcare facilities has now been recognized by government and regulatory agencies, the author reports, but there continues to be a general lack of understanding and support of security and safety by some hospital administrators. In this article he presents the options that should be considered for reducing violence and outlines the steps which can be taken to reduce the number of violent incidents and effectively respond if they do occur. PMID- 26978957 TI - The value of prevention: managing the risks associated with targeted violence and active shooters. AB - Every time we turn on the news, or open our Internet browsers, a story about an active shooter--at a school, house of worship, public place and even in our workplace--spills onto the page, the author reports. In this article he focuses on how we can prevent these incidents from occurring. What exactly is "targeted violence"--and why is what experts call "behavioral threat assessment" one of the single most effective ways to prevent the next active shooter incident in any organization? PMID- 26978958 TI - Workplace violence mitigation: the three-year model. AB - In presenting a three-year model for workplace violence mitigation in this article, the author sees it as providing a way to gauge the maturity of the program. This model, he says, functions similarly to a high performing security awareness program where certain themes need to be repeated on a routine basis just so situational awareness does not fall by the wayside. While the program outlined here is not a guaranteed formula for success, it is a framework to work within to ensure you have a roadmap upon which to build success. PMID- 26978959 TI - Hospital incident command system: tool for a TJC accreditation survey. AB - The unannounced Joint Commission (TJC) accreditation survey can prove just as unpredictable and challenging as any other incident. In this article, the authors describe a plan developed by a hospital emergency response team that has proven successful in dealing with TJC and other surveys. PMID- 26978960 TI - NFPA 99 Chapter 13 and healthcare security management. AB - The new NFPA 99 Security Management Standard for healthcare facilities requires a Security Vulnerability Analysis be conducted annually, the author reports. This will usually uncover little change from year to year, he says, but by using the right model the analysis can be used to win back security additions that had previously been rejected by the C-Suite. PMID- 26978961 TI - Light at the end of the rabbit hole: how to determine appropriate lighting levels as part of a total security program. AB - Appropriate lighting coupled with additional security meth- ods has been shown to reduce the occurrence of crime, the author reports in this article which describes the characteristics of lighting, how to decide how much light to use, and how and when to conduct lighting assessments. PMID- 26978962 TI - Teaching EHRs security with simulation for non-technical healthcare professionals. AB - This paper intends to simplify challenging concepts through role-play demonstrations and serve as a foundation for understanding the basis of securing healthcare data. Disparity exists between the rising need for security of electronic healthcare information and the number of healthcare leaders who understand the concepts behind ensuring privacy and accuracy of such data. Healthcare managers with a basic understanding of data encryption and how it safeguards health information are vital to the success of Electronic Health Records. They often are responsible for proper oversight of such systems and should instill confidence in medical providers and patients that electronic medical data is safe and accurate. However, data security and privacy are complex concepts and remain foreign to many healthcare managers. This paper reviews the benefits of simulation learning and outlines a workshop and simulation game developed in response to difficulties teaching the technology of encryption. The simulation has been successfully tested with graduate health administration students, as well as members of the technical, academic, and teaching community. PMID- 26978963 TI - Tourniquet use by security officers. AB - The need for equipping healthcare security officers with tourniquets may seem far fetched, but it is not, according to the author, because such officers in their role of first responders may well face situations where they have to administer such first aid to save lives and limbs. In this article, he describes how training in tourniquet use by officers can be given. PMID- 26978964 TI - The need for patrol rifles in a hospital setting. AB - This article is based on a proposal to management by the police chief of a hospital for equipping police officers with patrol rifles. According to the IHSSF 2014 research report on Weapons Use Among Hospital Security Personnel, handguns are available in 52% of hospitals, but there were no reports of the availability of patrol rifles. Recognizing that such a proposal is highly controversial, the author maintains that in view of the nature of today's security threats, the use of such weapons should be given serious consideration. PMID- 26978965 TI - Predicting violent behavior in clinical settings: a case-control study of a mental health inpatient unit. AB - In order to assist staff in recognizing patients prone to violence and guide their clinical decision-making, this study summarizes mental health inpatient unit incidents over a one-year period. Results describe demographic and clinical information for patients, and evaluate risk assessment tools currently used to predict risk. A retrospective analysis included data on patients involved in incidents and frequency matched controls. There were a total of 44 incidents, caused by 38 unique patients. A constructed model to estimate patient characteristics and risk of violent incidents included involuntary admittance (OR 2.07, 95% CI 1.05-6.11, p = 0.039), more than one admission at the facility (OR 4.18, 95% CI 1.71-10.22, p = 0.002) and Global Subjective Irritability on day one (OR 4.24, 95% CI 1.77-10.16, p = 0.001). Violent incidents on the mental inpatient unit threaten safety and disrupt the therapeutic environment. The findings may be useful in aiding clinicians to quickly recognize patients that are prone to violence. PMID- 26978966 TI - Use of K9 units in healthcare: a history. AB - The use of K9 units within healthcare facilities will continue to increase as the violence within healthcare increases. K9s are a wise investment and are cost effective. K9 units deter and prevent crime and violence at facilities. The typical K9 will be utilized for eight to ten years. The research demonstrates that facilities that have deployed K9 units have seen a reduction in crime and violence. A well trained K9 can not only patrol the exterior of a healthcare facility but also the patient care and service areas. As more hospitals and healthcare facilities look at non-lethal weapons to protect their officers, staff and guests, the use of K9 within healthcare will continue to rise. PMID- 26978967 TI - [Twenty years' review and prospect of modernization research on traditional Chinese medicine]. AB - The modernization strategy of traditional Chinese medicine (TCM) has been implemented for 20 years, which has provided a strong impetus to the development of TCM and gained remarkable achievements in scientific research platform, research result, industry scale, clinical evaluation, internationalization and professionals training as well. The achievements of TCM modernization greatly improved the clinical service ability and level of TCM, broadened the scope of service, become the important foundation of the big health industry. TCM has played an irreplaceable role in the health care reform, benefiting people's livelihood, promoting industrial structure adjustment and cultivating strategic emerging industries. This article summarized the main achievements of the modernization of TCM and prospected the direction and tasks in the next 20 years in order to further promote the modernization process of TCM. PMID- 26978968 TI - [Essentials of pharmacophylogeny: knowledge pedigree, epistemology and paradigm shift]. AB - Chinese materia medica resource (CMM resource) is the foundation of the development of traditional Chinese medicine. In the study of sustainable utilization of CMM resource, adopting innovative theory and method to find new CMM resource is one of hotspots and always highlighted. Pharmacophylogeny interrogates the phylogenetic relationship of medicinal organisms (especially medicinal plants), as well as the intrinsic correlation of morphological taxonomy, molecular phylogeny, chemical constituents, and therapeutic efficacy (ethnopharmacology and pharmacological activity). This new discipline may have the power to change the way we utilize medicinal plant resources and develop plant-based drugs. Phylogenomics is the crossing of evolutionary biology and genomics, in which genome data are utilized for evolutionary reconstructions. Phylogenomics can be integrated into the flow chart of drug discovery and development, and extends the field of pharmacophylogeny at the omic level, thus the concept of pharmacophylogenomics could be redefined in the context of plant pharmaceutical resources. This contribution gives a brief discourse of knowledge pedigree of pharmacophylogeny, epistemology and paradigm shift, highlighting the theoretical and practical values of pharmacophylogenomics. Many medicinally important tribes and genera, such as Clematis, Pulsatilla, Anemone, Cimicifugeae, Nigella, Delphinieae, Adonideae, Aquilegia, Thalictrum, and Coptis, belong to Ranunculaceae family. Compared to other plant families, Ranunculaceae has the most species that are recorded in China Pharmacopoeia (CP) 2010. However, many Ranunculaceae species, e. g., those that are closely related to CP species, as well as those endemic to China, have not been investigated in depth, and their phylogenetic relationship and potential in medicinal use remain elusive. As such, it is proposed to select Ranunculaceae to exemplify the utility of pharmacophylogenomics and to elaborate the new concept empirically. It is argued that phylogenetic and evolutionary relationship of medicinally important tribes and genera within Ranunculaceae could be elucidated at the genomic, transcriptomic, and metabolomic levels, from which the intrinsic correlation between medicinal plant genotype and metabolic phenotype, and between genetic diversity and chemodivesity of closely related taxa, could be revealed. This proof-of-concept study regards pharmacophylogenomics as the updated version of pharmacophylogeny and would enrich the intension and spread the extension of pharmacophylogeny. The interdisciplinary knowledge and techniques will be integrated in the proposed study to promote development of CMM resource discipline and to boost sustainable development of Chinese medicinal plant resources. PMID- 26978969 TI - [On Chinese medicine quality precision in expectation]. AB - According to the correlative analyses on Chinese medicine essence, dosage forms and quality control level, it expounds the precise concept of Chinese medicine, and its quality advantages and characteristics in this paper, furthermore discusses how to achieve the ideal drugs and Chinese medicine quality precision in expectation. Base on the Chinese medicine essence, using the concept of nature medicine and its drug system to construct Chinese medicine effective material basis and its drugs, with the correlative analyses of whole view and reductionism, the problems of uncertainty quality of original natural medicinal resources and preparations may well be solved, and further with the macroscopic to microcosmic construction of drug system, the precision in expectations of Chinese medicine quality and higher production lever may well be achieved. PMID- 26978970 TI - [Two new polyesters from wetland soil-derived fungus Talaromyces flavus]. AB - Two new polyesters, talapolyesters G-H (1-2) were isolated from the wetland soil derived fungus Talaromyces flavus BYD07-13, and their structures were determined by NMR and MS spectroscopic data. The absolute configurations of the residues were determined by alkaline hydrolysis. The cytotoxicity against five tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480) of 1-2 was examined. PMID- 26978971 TI - [Academician Li Lianda talking about doctors doing scientific research]. AB - At present, Chinese medical field faces with an important problem of how to correctly handle the relationship between medical and scientific research. Academician Li Lianda advocates doctors doing scientific research under the premise of putting the medical work first. He points out that there are many problems in the process of doctors doing scientific research at present such as paying more attention to scientific research than medical care, excessively promoting building scientific research hospital, only paying attention to training scientific talents, research direction be flashy without substance, the medical evaluation system should be improved and so on. Medical, scientific research and teaching are inseparable because improving medical standards depends on scientific research and personnel training. But not all doctors need to take into account of medical treatment, scientific research and teaching in the same degree while not all hospitals need to turn into three-in-one hospital, scientific research hospital or teaching hospital. It must be treated differently according to the actual situation. PMID- 26978972 TI - [Analysis and outlook on teaching status of Molecular Pharmacognosy]. AB - The teaching status of Molecular Pharmacognosy in 28 institutions in China was investigated by questionnaire and the survey data was analyzed by SPSS. Research contents included course beginning years, majors, class hours, characteristics of the course, teaching ways, the theory and practice contents, evaluation modes, selection of teaching material, teaching achievements, teachers and so on for undergraduates and graduates. Research results showed that with 20 years' development, Molecular Pharmacognosy had been offered for both undergraduate and graduate students in at least 20 colleges and universities and Molecular Pharmacognosy education in China showed good development momentum. At the same time, to promote the development of Molecular Pharmacognosy further, investment for it should be increased and practical teaching condition should be improved. PMID- 26978973 TI - [Ecological agriculture: future of Good Agriculture Practice of Chinese materia medica]. AB - Based on the ecological and economic problems in Good Agriculture Practice (GAP) of Chinese material medica, we introduced the origin, concept, features and operative technology of eco-agriculture worldwide, emphasizing its modes on different biological levels of landscape, ecosystem, community, population, individual and gene in China. And on this basis, we analyzed the background and current situation of eco-agriculture of Chinese materia medica, and proposed its development ideas and key tasks, including: (1) Analysis and planning of the production pattern of Chinese material medica national wide. (2) Typical features extraction of regional agriculture of Chinese materia medica. (3) Investigation of the interaction and its mechanism between typical Chinese materia medica in each region and the micro-ecology of rhizosphere soil. (4) Study on technology of eco-agriculture of Chinese materia medica. (5) Extraction and solidification of eco-agriculture modes of Chinese materia medica. (6) Study on the theory of eco agriculture of Chinese materia medica. Also we pointed out that GAP and eco agriculture of Chinese material medica are both different and relative, but they are not contradictory with their own features. It is an irresistible trend to promote eco-agriculture in the GAP of Chinese material medica and coordinate ecological and economic development. PMID- 26978974 TI - [Cropping system and research strategies in Panax ginseng]. AB - Panax ginseng is the king of herbs and plays important roles in the traditional Chinese medicine industry. In this paper, we summarized the development of ginseng cultivation in China and other main countries, analyzed the effects of ecological factors of soil and climate on ginseng distribution, and investigated the characteristic of main cultivation patterns (conversion of forest to cultivate ginseng soils, cultivated ginseng in the farmland and wild nursery). Aimed at the serious issues in the cultivation, research strategies have been provided to guarantee the sustainable development of the ginseng industry. The patterns of cultivated ginseng in the farmland should be strive to develop; pollution-free cultivation and studies of continuous cropping obstacles should be carried out; ginseng varieties suited to ecological environment of farmland should be bred using modern biotechnology. PMID- 26978975 TI - [The technological innovation strategy for quality control of Chinese medicine based on Big Data]. AB - The evolution of the quality control concepts of medical products within the global context and the development of the quality control technology of Chinese medicine are briefly described. Aimed at the bottlenecks in the regulation and quality control of Chinese medicine, using Big Data technology to address the significant challenges in Chinese medicine industry is proposed. For quality standard refinements and internationalization of Chinese medicine, a technological innovation strategy encompassing its methodology, and the R&D direction of the subsequent core technology are also presented. PMID- 26978976 TI - [Characteristics and innovation in projects of ethnomedicine and ethnopharmacology funded by National Natural Science Foundation of China]. AB - The overall situation of projects of ethnomedicine and ethnopharmacology funded by the National Natural Science Foundation of China (NSFC) since 2008 has been presented in this paper. The main source of characteristics and innovation of the funded projects were summarized, which may come from several aspects, such as the ethnomedical theories, the dominant diseases of ethnomedicine, special diseases in ethnic minorities inhabited areas, unique ethnomedical therapy, special methods for applying medication, endemic medicinal materials in ethnic minorities inhabited areas, same medicinal materials with different applications. Examples have been provided to give references to the applicants in the fields of ethnomedicine and ethnopharmacology. PMID- 26978977 TI - [Inheritance and innovation of traditional Chinese medicinal authentication]. AB - Chinese medicinal authentication is fundamental for the standardization and globalization of Chinese medicine. The discipline of authentication addresses difficult issues that have remained unresolved for thousands of years, and is essential for preserving safety. Chinese medicinal authentication has both scientific and traditional cultural connotations; the use of scientific methods to elucidate traditional experience-based differentiation carries the legacy of Chinese medicine forward, and offers immediate practical significance and long term scientific value. In this paper, a path of inheritance and innovation is explored through the scientific exposition of Chinese medicinal authentication, featuring a review of specialized publications, the establishment of a Chinese medicine specimen center and Chinese medicinal image databases, the expansion of authentication technologies, and the formation of a cultural project dedicated to the Compedium of Materia Medica. PMID- 26978978 TI - [Retrospect and prospect of medicinal plants cultivation in China]. AB - There is time-honored history and culture of medicinal plant cultivation in China. In the present review, the medicinal plant cultivation history in china was summarized, its current situation and question were analyzed, and the prospects of medicinal plant cultivation research were pointed out, with the purpose of accelerating the growth of medicinal plant cultivation research. PMID- 26978979 TI - [Research on resources chemistry of Chinese medicinal materials and resources recycling utilization ways and goals and tasks]. AB - The objects of research on the resources chemistry of Chinese medicinal materials (RCCMM) are promotion of efficient production, rational utilization and improving quality of CMM and natural products. The development of TCM cause depends on the efficient utilization and sustainable development of CMM, hinges on the technologies and methods for using and discovering medicinal biological resources, stand or fall on the extension of industy chains, detailed utilizaion of resource chemical components by multi-way, multi-level. All of these may help to the recycling utilization and sound development of RCMM. In this article, five respects were discussed to the RCCMM researches and resources recycling utilization ways and goals and tasks. First, based on the principle of resource scarcity, discovering or replacing CMM resources, protecting the rare or endangered species or resources. Second, based on the multifunctionality of CMM, realizing the value-added and value compensation, and promoting the utilization efficiency through systermatic and detailed exploitation and utilization. Third, based on the resource conservation and environment-friendly, reducing raw material consumption, lowering cost, promoting recycling utilization and elevating utilization efficiency. Fourth, based on the stratege of turning harm into good, using the invasive alien biological resources by multi-ways and enriching the medicial resources. Fifth, based on the method of structure modification of chemical components, exploring and enhancing the utility value of resouces chemical substances. These data should provide references and attention for improving the utilization efficiency, promoting the development of recycling economy, and changing the mode of economic growth of agriculture and industry of CMM fundamentally. PMID- 26978980 TI - [Promoting development of new traditional Chinese medicine by combination disease syndrome and multi-objective optimization research in prevention and treatment of cardiovascular disease]. AB - Differences in theories, application forms and evaluation standards about curative effect between traditional Chinese medicine and modern medicine lead to not only question safty and effectiveness but also hinder development and internationalization of traditional Chinese medicine. Combination of common problems in traditional Chinese new drug registration with experiences in research on traditional Chinese new drugs of prevention and treatment of coronary heart disease elucidate application value about theory of disease-syndrome combination and multi-objective optimization in several ways such as the indications positioning, preparation process optimization, preclinical efficacy evaluating and clinical assessmenting of efficacy and analysis development prospect. PMID- 26978981 TI - [Progress of serum pharmacochemistry of traditional Chinese medicine and further development of its theory and method]. AB - Serum pharmacochemistry of traditional Chinese medicine (TCM) is designed to screen the efficacy material base of TCMs from the constituents absorbed into the blood after oral administration. The theory and method is in accordance with the effect characteristics of TCMs, and reflects the interaction between the body and the drugs, has become an effective pathway for researching the efficacy material base of TCMs which has been recognized and used widely. In the paper, the previous research contents and methods of the serum pharmacochemistry of TCM were reviewed, and on the basis of the further validity of the special administration form of the TCM formula and the corresponding property to TCM syndrome, the new strategy of serum pharmacochemistry of TCM integrating the metabonomics technologies was put forward. According to the strategy, we take the biological characters of TCM syndrome as a research starting point, taking TCM formula as object, using the metabolic biomarkers of syndromes or disease to evaluate the therapeutic effect of formula and screen the compounds of TCMs in serum which are highly correlated with the metabolic biomarkers through the correlation analysis, and by further biological validation to finally confirm the efficacy material basis of TCMs. Integrating with the systems biology technologies, the theory and method of serum pharmacochemistry of TCM will further develop, and open a new chapter in the interpretation of the theory of TCM. PMID- 26978982 TI - [Drug design ideas and methods of Chinese herb prescriptions]. AB - The new drug of Chinese herbal prescription, which is the best carrier for the syndrome differentiation and treatment of Chinese medicine and is the main form of the new drug research and development, plays a very important role in the new drug research and development. Although there are many sources of the prescriptions, whether it can become a new drug, the necessity, rationality and science of the prescriptions are the key to develop the new drug. In this article, aiming at the key issues in prescriptions design, the source, classification, composition design of new drug of Chinese herbal prescriptions are discussed, and provide a useful reference for research and development of new drugs. PMID- 26978983 TI - [Current topics on cancer biology and research strategies for anti-cancer traditional Chinese medicine]. AB - Cancer, an abnormal cell proliferation resulted from multi-factors,has the highest morbidity and mortality among all the serious diseases. Considerable progress has been made in cancer biology in recent years. Tumor immunology, cancer stem cells (CSCs), autophagy, and epithelial-mesenchymal transition (EMT) have become hot topics of interests in this area. Detailed dissection of these biological processes will provide novel directions, targets, and strategies for the pharmacological evaluation, mechanism elucidation, and new drug development of traditional Chinese medicine. PMID- 26978984 TI - [Discovery, research and development for innovative drug of traditional Chinese medicine under new situations]. AB - Referring to the rapid developed life science and the higher requirements for the approval of innovative Chinese drugs in recent years, this paper described systematically the discovery, research and development (R&D) approaches for the innovative Chinese drugs under the new situation from the following five aspects, i. e., active components discovered from TCMs, the discovery of effective fractions of TCMs and their formulae, the R&D of TCM innovative drugs based on famous classic prescriptions and famous Chinese patent drugs, and the transformation of clinical effective prescriptions, on the basis of analysing the advantages of innovative drugs derived from natural products based on TCM theories and the problems existed in current R&D of new TCM drugs. Moreover, five suggestions are also given for the rapid development of TCM innovative drugs in China. All these will provide reference for the R&D of TCM innovative drugs. PMID- 26978985 TI - [Substance basis research on Chinese materia medica is one of key scientific problems of inheriting, development and innovation of Chinese materia medica]. AB - The compound Chinese materia medica is the medication pattern of the traditional Chinese medicine for the disease prevention and treatment. The single Chinese materia medica (mostly in decoction pieces) is the prescription composition of the compound Chinese materia medica. The study of the effective substance basis of Chinese materia medica should be based on the chemical compositions of the compound Chinese materia medica as an entry point considering the different status of "Monarch, Minister, Assistant, and Guide" for a certain single Chinese materia medica in the different compound Chinese materia medica while substance basis research of a certain single Chinese materia medica should be a full component analysis as well as both stable and controllable quality. Substance basis research on Chinese materia medica is one of key scientific problems of inheriting, development and innovation of Chinese materia medica. PMID- 26978986 TI - ["Efficacy Theory" may help to explain characteristic advantages of traditional Chinese medicines]. AB - This article proposes the "Efficacy Theory" hypothesis of the traditional Chinese medicines (TCMs): TCMs take effects and weaken toxicities through the additive effects of numerous effective forms (including their constituents or/and metabolites) on a same target, the synergistic effects based on the overall action of the additive effects on individual targets and their toxicities scattering effects. A TCM may include approximately 1000 constituents and each constituent may produce about 100 metabolites in vivo after oral administration. Numerous effective forms of incalculable constituents and their metabolites could work like a "army group" together. When the quantity of a specific target molecule is larger than the pharmaceutical molecules, the molecules of different kinds of effective forms could combine with the target molecules successively, to exert the additive effects. When the target molecules are mostly occupied ("target most spaces occupied"), this TCM begins to work. The additive effects maybe exert not only in concentration but also in a time order way, which gives a sustained efficacy of TCM. The additive effects and the toxicities scattering effects are resulted from the same effective groups and not identical toxic groups among different effective form molecules. The "toxicities scattering effect" can be used to explain the non-toxic TCMs, but not fit for toxic TCMs. The efficacy theory showed that the variety of constituents and metabolites may participate in the process of pharmacodynamic actions, including the additive effects, synergy effects and toxicities scattering effects, which may be useful for explaining and developing the characteristic advantage of the TCMs. The questions we need to study or confirm are as follows: What are the TCMs' pharmacodynamic substance basis and mechanism made up of Why are toxicities of most TCMs' smaller How is the TCMs' "Efficacy Theory" which reflects characteristic advantage of TCMs applied in the research and development of new drugs. PMID- 26978987 TI - [Pharmacology research on PXR as a potential target in screening bioactive components of Chinese material medica]. AB - Pregnane X receptor (PXR) is key transcription factors which mainly regulate the expression of CYP3A genes. At the molecular level, PXR has been revealed the protection mechanism of the body against xenochemicals and a major mode of the drug-drug interactions. Besides playing an important role in drug metabolism and interactions, PXR and its target genes also play an important role in maintaining normal physiological function and homeostasis. Therefore, it is necessary to study the regulation of PXR and its related pharmacological effects of TCM and natural products, and to provide new clues for the new pharmacological pathway. PMID- 26978988 TI - [Progress of mesoporous silica nanoparticles in targeting drug delivery system of antitumor drug]. AB - Currently, chemotherapy is one of the main therapy for cancer. But the traditional antitumor drugs are systemic distribution in vivo, they are difficult to achieve an effective drug concentration in the tumor tissue and don't have the ability to distinguish normal cells and tumor cells by themselves, that cause systemic toxicity easily and can not meet the clinical needs. With the research on mesoporous silica nanoparticles (MSNs) deepening, more and more attention in the drug delivery system have been payed to in recent years, because of its unique physicochemical structure characteristics, it has the effect on specific targets, directly inhibits the tumor cell growth, reduces the side effects to normal cells, tissues and organs and can be long-term medication, etc. It is expected to be excellent carriers of antitumor drugs. MSNs application in the field of cancer treatment has now become a hot research field of medicine. In this paper, the latest research about MSNs in antitumor drugs targeting delivery system from 2008 to 2015 is summarized, including the application of MSNs separately in antitumor drug targeting, passive targeting, active targeting, physical or chemical conditions response targeting and other compound targeting drug delivery system. We expect it to provide a reference to the toxicity reducing and efficacy enhancing and further development of chemical medicine, natural medicine and monomeric compound of chinese herbal medicine. PMID- 26978989 TI - [Main progress on intranasal administration of traditional Chinese medicine]. AB - Traditional Chinese medicine has a long history of intranasal administration. Compared with the other administration routes, intranasal administration has the benefits of fast absorption, high bioavailability, high brain-targeting and non invasive. In the past few years we take "Xingnaojing" and "Tongqiao Sanyu formula" as model drug and studied pharmacokinetics of effective components of different polarities. MDCK/MDCK-MDR1 cells were used to simulate blood brain barrier to study the permeate behaviors of different drug and the mechanism of enhancing effects of aromatic medicine. Then a microemulsion (modified by mPEG2000-PLA) was prepared for intranasal administration, and the pharmacokinetics and investigated tissue distribution were studied by fluorescence imaging. The irritation of the drug and different preparations were studied on human nasal epithelial cell (HNEC) cell and living animals. In this paper, we reviewed the achievements and hope that it can provide constructive suggestions for the future research. PMID- 26978990 TI - [Traightened on Chinese endemic seed plant species of medicine plants used in Tibetan medicine]. AB - This paper is in order to discussion with the composition and characteristics of Tibetan medicine plant resources, and promote the reasonable protection and utilization of the resources of Tibetan materia medica. Statistical analysis of species, distributions, and others of Chinese endemic seed plant from Tibetan medicine plants and usually used in the clinic of Tibetan medicine. The results showed that there are 523 species (25%) of Chinese endemic seed plant, belonging to 65 families and 162 genera, in about 2 000 varieties of Tibetan medicine plants recorded in relevant literatures. There are 180 Chinese endemic seed plant species (28%) belonging to 42 families and 72 genera from 625 medicine plants usually used in the clinic of Tibetan medicine. Specifically, the most of these Chinese endemic seed plant species are characteristic crude drug used in Tibetan medicine, and mainly or only distributed in Qinghai-Tibet Plateau. And a few species of them were intersected with traditional Chinese medicines (TCM) and other ethnic medicines. In addition, about 10% are listed in China Species Red List. The Qinghai-Tibet Plateau is the most abundant areas of Areal-types of the Chinese endemic seed plant. This is the biological and ecological reason formation the characteristics of Tibetan medicine plant resources. Therefore, strengthen the research of Chinese endemic seed plants used in Tibetan medicine is great significance for the reasonable protection and utilization of Tibetan medicine plant resources. PMID- 26978991 TI - [Studies on genetic relationship of Dioscorea]. AB - Based on the results of the morphologic studies on genus Dioscorea, the paper summarized the entire chemical constituent that isolated from this genus and analyzed it with the methods of chemotaxonomy. The rules of the chemical constituent and pharmacodynamic effects were analyzed. Seventeen species which belong to Sect. Stenophora Uline of Dioscorea contain steroidal sapogenin. Other species with different main components such as polysaccharide and tannin have have different effects. This chemotaxonomic view point will conduce to establish a phylogeny of the genus Dioscorea. PMID- 26978992 TI - [Structure and biological action on cardiovascular systems of saponins from Panax notoginseng]. AB - Notoginseng Radix et Rhizoma (Sanqi), the underground part of Panax notoginseng (Burk.) F. H. Chen (Araliaceae) is commonly used in Chinese medicine for treatment of haemorrhage, haemostasis, swelling, etc. The aerial part including leaves, flowers and fruits are also applied for similar functions. Triterpenoid saponins are considered to be responsible for the biological activities of Sanqi. Up to date, more than 100 saponins have been isolated from theroots, rhizomes, leaves, flowers and fruits of P. notoginseng. The reported saponins can be classified into protopanaxadiol (PPD), protopanaxatriol (PPT), C17 side-chain varied and other types, according to the skeletons of the aglycons. The present review summarizes the saponins isolated from P. notoginseng and their distribution in different medicinal organs, as well as the pharmacological actions on cardiovascular system. PMID- 26978993 TI - [Development of Fuzi precision decoction pieces (PDP) (I): Specification and quality uniformity]. AB - The specification of decoction pieces and quality uniformity are the important factors to influence the efficacy of clinical medicine. Considering the deficiency of diversity, poor quality uniformity and confusion of decoction pieces specifications, we first propose a new idea of precision decoction pieces (PDP) based on clinical demands and fresh-processed technology. In order to explain the idea, a study case of aconite SUP is provided, including the optimized specification design, processing technology, extraction effects, quality uniformity, and toxic and efficacy variation and so on. The results showed that preparing 5 mm PDP by fresh-cutting is rather simple and practicable, with high efficiency and large yield; then, this technology could significantly decrease the ingredients loss and increase the efficacy components; moreover, it was helpful for achieving the quality uniformity and best extraction effects. This work revealed the quality superiority of PDP, and provided a good strategy and example for the standard of decoction pieces specification and modernization of processing technology. PMID- 26978994 TI - [Studies on chemical constituents of aqueous extract of Lonicera japonica flower buds]. AB - From an aqueous extract of Lonicera japonica flower buds, sixteen compounds were isolated by a combination of various chromatographic techniques including column chromatography over macroporous resin, MCI gel, silica gel, and sephadex LH-20 and reversed-phase HPLC. Their structures were elucidated by spectroscopic data analysis as 6'-O-acetylvogeloside (1), 6'-O-acetylsecoxyloganin (2), dichlorogelignate (3), guanosinyl-(3' --> 5')-adenosine monophosphate(GpA,4) , 5' O-methyladenosine (5), 2'-O-methyladenosine (6), adenosine (7), syringin (8), methyl 4-O-beta-D-glucopyranosyl caffeate (9), (-)-dihydrophaseic acid 4'-O-beta D-glucopyranoside (10), ketologanin (11), 7alpha-morroniside (12), 7beta morroniside (13), kingiside (14), cryptochlorogenic acid methyl ester (15), and 6 hydroxymethyl-3-pyridinol (16). All the compounds were obtained from this plant for the first time, compounds 1 and 2 are new compounds, 3 and 5 are new natural products, and 4 is the first example of dinucleoside monophosphate isolated from a plant extract. PMID- 26978996 TI - Psychiatric Collaboration Models in Israel. AB - We present a literature review of collaborative enterprises between psychiatrists and primary care physicians in Israel and other countries. Also described are local psychiatric liaison initiatives in Israel, as well as landmark studies of collaborative psychiatric care. These studies demonstrate the superiority of community psychiatric liaison models in the treatment of patients suffering from depressive anxiety disorders and somatization disorder. In light of the mental health reform process currently underway in Israel, it is important to develop, implement and assess such liaison models. PMID- 26978995 TI - [Saccharide mapping and its application in quality control of polysaccharides from Chinese medicines]. AB - Polysaccharides with multiple biological activities are usually considered as one of the major bioactive compounds in Chinese medicines (CMs). At present, the development of drug and functional foods related to polysaccharides have attracted a great deal of attention due to their great potential effects and diverse action mechanisms. However, quality control of polysaccharides is the bottleneck and a challenge due to their complexity and chemical diversity. Actually, the bioactivities of polysaccharides are closely related to their molecular structures. In order to ensure their safety and efficacy, the development of novel approaches based on the molecular structures for the improvement of quality control of polysaccharides is significantly important. Therefore, in this article, the relationship between biological activities and chemical structures, as well as the action mechanisms of polysaccharides from CMs were summarized first. Furthermore, saccharide mapping, a novel strategy for quality control of bioactive polysaccharides from CMs, was introduced and the application and perspectives were also discussed. PMID- 26978997 TI - Yield of Non-Invasive Phase 1 Presurgical Evaluation in Drug-Resistant Epilepsy Patients. AB - BACKGROUND: Resective epilepsy surgery is an accepted treatment option for patients with drug-resistant epilepsy (DRE). Presurgical evaluation consists of a phase 1 non-invasive evaluation and a phase 2 invasive evaluation, when necessary. OBJECTIVES: To assess the results of phase 1 evaluation in patients with focal DRE. METHODS: This observational retrospective study was performed in all consecutive DRE patients admitted to our clinic from January 2001 to July 2010, and who underwent a presurgical evaluation which included at least magnetic resonance imaging (MRI) scan and long-term video EEG monitoring (LTVEM). RESULTS: A total of 253 consecutive patients with a diagnosis of DRE (according to the ILAE recommendations) who underwent presurgical evaluation were extracted from our clinic and department registry. In 45 of these patients either imaging or ictal video EEG data were missing; the final analysis therefore involved 208 patients. The combined result of the LTVEM and the MRI scan were as follows: 102 patients (49% of the cohort) had a lesion on the MRI scan, in 77 patients (37% of the cohort) the LTVEM results were localizing and congruent with the MRI findings, and in 25 patients (12% of the cohort) the LTVEM results were either non-localizing or incongruent with the MRI findings. In 106 patients (51% of the cohort) the MRI scan was normal or had a non-specific lesion. The LTVEM was localizing in 66 of these patients (31.7% of the cohort) and non-localizing in 40 (19.2% of the cohort). CONCLUSIONS: Although some of the patients with focal DRE can be safely treated with resective surgery based solely on the findings of phase 1 evaluation, a substantial percent of patients do need to undergo a phase 2 evaluation before a final surgical decision is made. PMID- 26978998 TI - Variance in Biomarker Usefulness as Indicators for Carotid and Coronary Atherosclerosis. AB - BACKGROUND: Atherosclerosis is a systemic disease. Nevertheless, the role of specific biomarkers as indicators for both coronary and carotid diseases is debatable. OBJECTIVES: To evaluate the association of biomarkers with coronary and carotid disease. METHODS: We studied 522 consecutive patients with stable angina. All underwent coronary angiography and carotid duplex study on the same day. Patients with no apparent carotid plaques were evaluated for carotid intima media thickness (CIMT) using an automated system that sampled over 100 samples in each carotid artery. Biochemical markers of cardiovascular disease risk were obtained at the time of coronary angiography, including serum lipid levels, hemoglobin A1C (HbA1c), white blood cell count, fibrinogen and high sensitivity C reactive protein (hs-CRP). RESULTS: The mean age of the patients was 66 +/- 11; 73% were males. Significant carotid stenosis was associated with higher hs-CRP (9.4 +/- 17 vs. 6.3 +/- 13 mg/L, P = 0.001), while high HbA1c (6.7 +/- 1.6 vs. 5.8 +/- 0.8%, P 0.001) and low high density lipoprotein levels (40 +/- 9 vs. 47 +/- 14 mg/dl, P < 0.001) were linked with advanced coronary artery disease severity. In contrast, CIMT was not related to any of the biomarkers evaluated. CONCLUSIONS: Although atherosclerosis is considered a systemic disease, different biomarkers are associated with coronary and carotid artery disease. Identifying the specific biomarkers for each disease is important for both prevention and for exposing the underlying pathophysiologic mechanism. PMID- 26978999 TI - Injuries in a Developing Sport, Cachibol (Newcomb Ball). AB - BACKGROUND: Cachibol (known as kadureshet in Hebrew) is a team ball game whose characteristics are similar to those of volleyball. The game is becoming increasingly popular, particularly among adult women and is the fastest growing female sport in Israel. Despite its growing popularity, data on the epidemiology of injuries incurred from this sport are sparse. OBJECTIVES: To investigate the incidence and severity of injuries among adult female cachibol players. METHODS: We conducted a cross-sectional survey and observational cohort study of 612 amateur female cachibol players participating in a 3 day national tournament; 355 players completed questionnaires relating to traumatic injuries incurred during previous cachibol activity (58% response rate). All injuries sustained during the tournament were reported. RESULTS: Fingers were the most commonly injured part of the body, mostly due to a direct hit by the ball. Finger injuries, though considered mild, may have long-term implications: over 50% of the injured players reported long-term finger discomfort. After finger injuries, ankles and knees were the second most commonly injured parts of the body, with a higher rate of absence from sports activity and work and for a longer time compared to finger injuries. CONCLUSIONS: Due to the unique characteristics of cachibol, the rate of finger injuries is higher than in volleyball. Injuries are a growing cause for concern in view of the rapidly increasing number of cachibol players. Our findings may be useful for developing effective injury prevention programs for cachibol players. PMID- 26979000 TI - Radiation-Induced Well-Differentiated Thyroid Cancer: Disease Characteristics and Survival. AB - BACKGROUND: Radiation exposure is a well-known risk factor for well differentiated thyroid cancer (WDTC). However, disease characteristics, optimal treatment, time from exposure to disease appearance, and the effect of age at initial exposure on the outcome have yet to be determined. OBJECTIVES: To identify the characteristics of radiation-induced thyroid carcinoma. METHODS: We retrieved the charts of all patients previously exposed to radiation who were diagnosed with WDTC between the years 1985 and 2013 in a tertiary referral center. RESULTS: Forty-four patients were reviewed. Median time from radiation exposure to diagnosis was 23 years. These patients had higher rates of aerodigestive symptoms and distant metastases on presentation than seen in non radiated patients. Patients who were exposed to radiation before age 15 years tended to develop the disease at a younger age but had a longer latency period (34.7 +/- 15.3 vs. 16.3 +/- 10 years, P < 0.001) and none had significantly higher rates of vocal cord palsy, hoarseness on presentation, or aggressive variants on histology compared to patients exposed to radiation at an older age. Disease-specific survival (DSS) was the same for both groups and were similar to that seen in the general population (95% 20 year DSS). CONCLUSIONS: Radiation induced thyroid cancer has a more aggressive presentation and the age at exposure affects the presentation of disease. Nonetheless, appropriate treatment leads to a favorable prognosis. PMID- 26979001 TI - Hypernatremic Dehydration in Young Children: Is There a Solution? AB - BACKGROUND: Hypernatremic dehydration is a common and potentially life threatening condition in children. There is currently no consensus as to the optimal strategy for fluid management. OBJECTIVES: To describe the relationship between the type, route and rate of fluids administered and the rate of decline in serum sodium (Na+) concentration. METHODS: We reviewed the medical records of all children under the age of 2 years who were hospitalized with hypernatremic dehydration (serum Na+ >= 155 mEq/L) in Shaare Zedek Medical Center during the period 2001-2010. Collected data of 62 subjects included initial and subsequent serum Na+ levels, and rate and Na+ concentration of all intravenous and oral fluids administered until the serum Na+ reached <= 150 mEq/L. RESULTS: Median initial serum Na+ was 159.5 mEq/L (IQR 157-163, maximal value 170). The median rate of decline in serum Na+ until serum Na+ reached 150 mEq/L was 0.65 mEq/L/hr (IQR 0.45-0.95). Forty-two children received hypotonic oral fluids which accounted for approximately one-quarter of all fluids they received. There was no significant difference in the rate of decline in serum Na+ between those who consumed oral fluids and those who did not. Neither was there a correlation between the rate of IV fluids, receipt of oral fluids or the degree of dehydration, with the rate of decline in serum Na+. No child experienced an apparent short-term adverse outcome. CONCLUSIONS: A cumulative rate of 5.9 mI/kg/hr of IV fluid administration may reduce the serum Na+ by an acceptable rate (0.65 mEq/L/hr). Fluid therapy comprising up to 25% hypotonic oral fluids and 75% IV fluids high in Na+ concentration was not associated with any short term adverse outcome in our patient population. PMID- 26979002 TI - Prevalence of Carotid Artery Disease among Ambulatory Patients with Coronary Artery Disease. AB - BACKGROUND: Concomitant carotid artery disease (CaAD) in patients with coronary artery disease (CAD) is associated with worse cardiac and neurologic outcomes. The reported prevalence and risk factors for concomitant CaAD in CAD patients varied among previous studies. OBJECTIVES: To examine these factors in ambulatory patients with CAD and well-documented cholesterol levels treated with cholesterol lowering medications. METHODS: We retrospectively analyzed prospectively collected data from 325 unselected patients with CAD (89 women, mean age 68.8 +/- 9.9 years) undergoing routine evaluation at the coronary clinic of our hospital. RESULTS: The low density lipoprotein-cholesterol (LDL-C) was < 100 mg/dl in 292 patients (90%). Age at onset of CAD symptoms was 59.4 +/- 10.8 years. Carotid stenosis >= 50% was seen in 83 patients (25.5%) and between 30% and 49% in 55 patients (17%) (duplex method). Carotid stenosis was significantly associated with hypertension (P = 0.032), peripheral arterial disease (P = 0.002) and number of coronary arteries with >= 50% stenosis (P = 0.002), and showed a borderline association with age at CAD onset (P = 0.062) and diabetes mellitus (P = 0.053). On linear regression analysis, independent predictors of CaAD were peripheral vascular disease (OR 3.186, 95% CI 1.403-7.236, P = 0.006), number of coronary arteries with >= 50% stenosis (OR 1.543, 95% CI 1.136-2.095, P = 0.005), and age at CAD onset (OR 1.028, 95% CI 1.002-1.054, P = 0.003). None of the variables studied predicted freedom from CaAD. CONCLUSIONS: Carotid atherosclerosis is very common in stable ambulatory patients with CAD regularly taking statins. The risk is higher in patients with peripheral arterial disease, a greater number of involved coronary arteries, and older age at onset of CAD. PMID- 26979003 TI - Retrievable Inferior Vena Cava Filters: Indications, Indwelling Time, Removal, Success and Complication Rates. AB - BACKGROUND: Various vena cava filters (VCF) are designed with the ability to be retrieved percutaneously. Yet, despite this option most of them remain in the inferior vena cava (IVC). OBJECTIVES: To report our experience in the placement and retrieval of three different types of VCFs, and to compare the indications for their insertion and retrieval as reported in the literature. METHODS: During a 5 year period three types of retrievable VCF (ALN, OptEase, and Celect) were inserted in 306 patients at the Rabin Medical Center (Beilinson and Hasharon hospitals). Indications, retrieval rates, median time to retrieval, success and complication rates were viewed and assessed in the three groups of filter types and were compared with the data of similar studies in the literature. RESULTS: Of the 306 VCFs inserted, 31 (10.1%) were retrieved with equal distribution in the three groups. In most patients the reason for filter insertion was venous thromboembolic events (VTE) and contraindications to anticoagulant therapy. Mean age was 68.38 +/- 17.5 years (range 18-99) and was noted to be significantly higher compared to similar studies (53-56 years) (P < 0.0001). Multi-trauma patients were significantly older (71.11 +/- 14.99 years) than post-pulmonary embolism patients (48.03 +/- 20.98 years, P < 0.0001) and patients with preventive indication (26.00 +/- 11.31, P < 0.0001). The mean indwelling time was 100.6 +/- 103.399 days. Our results are comparable with the results of other studies, and there was no difference in percentage of retrieval or complications between patients in each of the three groups. CONCLUSIONS: In 1 of 10 patients filters should be removed after an average of 3.5 months. All three IVC filter types used are safe to insert and retrieve. PMID- 26979004 TI - Anti-Factor Xa Activity of Prophylactic Enoxaparin Regimens in Critically Ill Patients. AB - BACKGROUND: Enoxaparin is frequently used as prophylaxis for deep venous thrombosis in critically ill patients. OBJECTIVES: To evaluate three enoxaparin prophylactic regimens in critical care patients with and without administration of a vasopressor. METHODS: Patients admitted to intensive care units (general and post-cardiothoracic surgery) without renal failure received, once daily, a subcutaneous fixed dose of 40 mg enoxaparin, a subcutaneous dose of 0.5 mg/kg enoxaparin, or an intravenous dose of 0.5 mg/kg enoxaparin. Over 5 days anti activated factor X levels were collected before the daily administration and 4 hours after the injection. RESULTS: Overall, 16 patients received the subcutaneous fixed dose, 15 received the subcutaneous weight-based dosage, and 8 received the dose intravenously. Around two-fifths (38%) of the patients received vasopressors. There was no difference between anti-activated factor X levels regarding vasopressor administration. However, in all three groups the levels were outside the recommended range of 0.1 IU/ml and 0.3 IU/ml. CONCLUSIONS: Although not influenced by vasopressor administration, the enoxaparin regimens resulted in blood activity levels outside the recommended range. PMID- 26979005 TI - Left Ventricular Outflow Tract Arrhythmias: Clinical Characteristics and Site of Origin. AB - BACKGROUND: Left ventricular outflow tract (LVOT) arrhythmias are increasingly recognized. Data regarding the distribution of the sites of origin (SOO) of the arrhythmias are sparse. OBJECTIVES: To describe the clinical characteristics of patients with LVOT arrhythmias and the distribution of their SOO. METHODS: All 42 consecutive patients with LVOT arrhythmias who underwent radiofrequency (RF) ablation during the period 2000-2014 were included. SOO identification was based on mapping activation, pace mapping and a 3D mapping system in eight patients. RESULTS: The study group comprised 28 males (66.7%) and 14 females, the mean age was 55 +/- 15.4 years. Most patients (76%) were symptomatic. All suffered from high grade ventricular arrhythmias. Left ventricular (LV) dysfunction (ejection fraction <= 50%) was observed in 15 patients (35.7%), of whom 14 (93.3%) were males. The left coronary cusp (LCC) was the most common arrhythmia SOO (64.3%). Other locations were the right coronary cusp (RCC), the junction of the RCC-LCC commissure, aortic-mitral continuity, endocardial-LVOT, and a coronary sinus branch. Acute successful ablation was achieved in 29 patients (69%) and transient arrhythmia abolition in 40 (95.2%). There was a trend for a higher success rate using cooled tip ablation catheters as compared to standard catheters. The ablation procedure significantly improved LV function in all patients with tachycardiomyopathy. CONCLUSIONS: LVOT arrhythmias mostly originate from the LCC and are associated with LV dysfunction in 36% of patients. Knowledge regarding the prevalence of the anatomic origin of the LVOT arrhythmias may help achieve successful ablation. The use of cooled tip ablation catheters might have beneficial effects on the success rate of the procedure. PMID- 26979006 TI - Sutureless Aortic Valve: Early and Mid-Term Results at a Single Center. AB - Background: Prolonged life expectancy has increased the number of elderly high risk patients referred for surgical aortic valve replacement (AVR). These referred high risk patients may benefit from sutureless bioprosthesis procedures which reduce mortality and morbidity. OBJECTIVES: To present our initial experience with sutureless aortic bioprotheses, including clinical and echocardiographic results, in elderly high risk patients referred for AVR. METHODS: Forty patients (15 males, mean age 78 +/- 7 years) with symptomatic severe aortic stenosis underwent AVR with the 3F Enable or Perceval sutureless bioprosthesis during the period December 2012 to May 2014. Mean logistic EuroScore was 10 +/- 3%. Echocardiography was performed preoperatively, intraoperatively, at discharge and at follow-up. RESULTS: There was no in hospital mortality. Nine patients (22%) underwent minimally invasive AVR via a right anterior mini-thoracotomy and one patient via a J-incision. Four patients underwent concomitant coronary aortic bypass graft, two needed intraoperative repositioning of the valve, one underwent valve exchange due to inappropriate sizing, three (7.5%) had a perioperative stroke with complete resolution of neurologic symptoms, and one patient (2.5%) required permanent pacemaker implantation due to complete atrioventricular block. Mean preoperative and postoperative gradients were 44 +/- 14 and 13 +/- 5 mmHg, respectively. At follow up, 82% of patients were in New York Heart Association functional class I and II. CONCLUSIONS: Sutureless AVR can be used safely in elderly high risk patients with relatively low morbidity and mortality. The device can be safely implanted via a minimally invasive incision. Mid-term hemodynamic results are satisfactory, demonstrating significant clinical improvement. PMID- 26979007 TI - Integrating Mental Health into Primary Care. PMID- 26979008 TI - Merkel Cell Carcinoma of the Eyelid. PMID- 26979009 TI - Listeria Peritonitis in a Patient Treated with Peritoneal Dialysis. PMID- 26979010 TI - [To treat is to resist]. PMID- 26979011 TI - [Fibrates: their prescription must be restricted]. PMID- 26979012 TI - [Treatment of type 2 diabetes with metformin]. PMID- 26979013 TI - [What's new in hysterical conversion?]. PMID- 26979014 TI - [The procedure for controlling professional incompetence]. PMID- 26979015 TI - [SCHOOL HEALTH IN FRANCE]. AB - On average, French children spend 18.5 years n schools. Improving the effectiveness of interventions in school setting aiming at promoting children's health and reducing health inequities is critical in public health. Evidence shows that a whole school approach, where there is coherence between the school's policies and practices that promote social inclusion and commitment to education, actually facilitates improved learning outcomes, increases emotional wellbeing and reduces health risk behaviours. Many factors govern the ways in which school health education is implemented and within these factors, staff commitment and partnership with local health professionals play a crucial role. The effectiveness of health promotion in schools is directly linked to the way in which school environment is supportive. There is a need to improve school organisation, ethos and environment as well as to invest in partnerships with local organisations and services especially the health professionals who are in charge of children's health. PMID- 26979016 TI - [Obesity and overweight of children and adolescents]. PMID- 26979017 TI - [Early assessment of overweight for preventing obesity]. AB - The overweight child should be detected as soon as possible to avoid the occurrence of a more severe obesity, source of early complications. Thus, it is essential to carefully follow the BMI curve in all children with particular attention to the age of the early adiposity rebound (between 1 and 5 years). Early rebound indicates predisposition, and represents a risk factor for later obesity. The announcement is not harmless and should avoid unnecessary judging or blaming the family outside rare situations of abuse. Overweight results from an energy imbalance favored by many risk factors often entangled. These predisposing factors are specific to the child (especially genetic and epigenetic origin) and environmental. Among these environmental factors, those occurring during pregnancy and the nutritional education (too permissive or too restrictive) represent targets for primary prevention. PMID- 26979018 TI - [Epidemiology of pediatric obesity: stabilizing after 20 years of strong increase in prevalence]. PMID- 26979019 TI - [Hypothalamus and behavior: the model Prader-Willi syndrome]. PMID- 26979020 TI - [WHAT IS THE RISK FOR CHILDHOOD OBESITY?]. AB - The complications of obesity may be observed during childhood. They include multiple and varied anomalies that are found in all major organ systems. These abnormalities occur in the more or less long term. In this context, the question of the impact of early development of obesity on overall health status and mortality is asked. The most frequent comorbidities are described and the different clinical and para-clinical indicators that allow to detect them. PMID- 26979021 TI - [PRIMARY CARE INTERVENTIONS FOR PEDIATRIC OVERWEIGHT OR OBESITY]. AB - Obesity is a slow progressive chronic disease, for the complications as well as efficacy of the care. A long-term success requires a comprehensive educational diagno- sis that explores the various dimensions of the child and his family, thus allowing to define the care project. Both the motivational Interviewing that is based on the technics of therapeutic patient education and the parents' implication are the key factors for the success of the care. They allow, from the assessment of competencies of parents and child to propose, according to child's situation, the best targeted management. The follow up will be step by step, in long-term concerted interdisciplinarity, with in each visit the possibility of choosing a new objective or reinforcing some objectives suitable for the child, in combination with strategies that frequently involve the parents. Negotiation between caregiver(s), the child and his family are suitable. The greatest flexibility on both sides will allow to go forward together to reach the chosen aim. PMID- 26979022 TI - [Organization of care for obese children and teenagers]. PMID- 26979023 TI - [Henna tattoo]. PMID- 26979024 TI - [Spontaneous isolated dissection of the superior mesenteric artery]. PMID- 26979025 TI - [Poorly controlled arterial blood pressure]. PMID- 26979026 TI - [Living with . . . macular degeneration]. PMID- 26979027 TI - [What is new in . . . Infectious diseases: Advancements and setbacks]. PMID- 26979028 TI - [CELIAC DISEASE]. AB - Celiac disease is an inflammatory enteropathy, autoimmune-like, due to gluten intake in genetically predisposed persons with HLA-DQ2/DQ8 genotyping. Prevalence rates are approaching 1% of population in Europe and USA. Clinical expression of celiac disease is extremely various. Screening is based on detection of serum celiac antibodies and diagnosis is confirmed with duodenal biopsy. Treatment relies on gluten free diet (GFD) with eviction of wheat, barley and rye. GFD allows prevention of osteopenia, autoimmune diseases and malignant complications. The main cause of resistance to GFD because is its bad observance. PMID- 26979029 TI - [IRON OVERLOAD: BETTER UNDERSTANDING, BETTER CARE]. AB - Chronic iron overload, either of genetic (hemochromatoses) or acquired (transfusions) origin, leads to frequent disorders, affecting both the quality of life and life expectancy. Major recent advances in the knowledge of iron metabolism, together with advances in biology, imaging and drug design have already significantly improved the diagnostic and therapeutic approaches. These conceptual and technological ameliorations should, in the near future, continue to benefit the clinical management of iron overloaded patients. PMID- 26979030 TI - [Diffuse interstitial lung disease: What is the role of bronchoalveolar lavage?]. AB - Bonchoalveolar lavage is a safe and poorly invasive tool with a great diagnostic value particularly in diffuse infiltrative pulmonary diseases (IPD). In specific instances, it allows for a definite diagnosis (alveolar hemorrhage; alveolar proteinosis, lipidoses, infiltrative malignant diseases, opportunistic infections), obviating the need to perform more invasive diagnostic procedures like video-assisted surgical biopsy. In inflammatory IPD, either idiopathic, diagnostic or associated with inhaled antigens or with collagen vascular diseases for instance, it represents a crucial orientation diagnostic tool, considerably narrowing the spectrum of potential differential diagnosis. PMID- 26979031 TI - [Visceral mycoses]. PMID- 26979032 TI - [EPIDEMIOLOGY OF VISCERAL FUNGAL INFECTION IN FRANCE AND IN THE WORLD]. AB - Invasive fungal infections are severe infections and constantly rising in developed countries. Indeed, advances in hematology, oncology, transplantation and intensive care medicine, are responsible for a longer and deeper immunodepression, in patients which are increasingly older. Only HIV-associated cryptococcosis and Pneumocystis pneumonia are decreasing, in countries where HAART are available and have been able to restore immunity. An increase in the antifungal therapies exposure lead to the emergence of less susceptible species/isolates to usual treatments, and other fungi (Mucorales, Scedosporium, Fusarium). However, in developing countries where access to HAART is limited, cryptococcosis remains a major public health. To a lesser degree, some endemic mycoses are on the rise. PMID- 26979033 TI - [Genetic susceptibility to invasive fungal infections]. PMID- 26979034 TI - [The challenge of nosocomial fungal infections]. PMID- 26979035 TI - [NEW STRATEGIES FOR THE MICROBIOLOGICAL DIAGNOSIS OF VISCERAL MYCOSES]. AB - The recent improvements of the diagnosis of invasive mycoses have included the shortening of the species identification time for a rapid adaptation of the antifungal treatment, and the anticipation of the diagnosis thanks to biomarkers. Species identification is now achieved using MALDI-TOF 24 hours earlier than with the previous phenotypic tests. The aim is now to identify directly on positive blood bottle either using MALDI-TOF or molecular methods. The biomarkers are dominated by antigens (mannan, galactomanan, glucan) with available commercial kits. These antigens are mainly used as screening tests in patients at risk of invasive mycoses. Their main limitation is their weak specificity rather than their sensitivity. For circulating DNA, the quantitative real-time PCR format and the publication of recommendations for validation of diagnostic assays suggest they should be implemented soon in a diagnostic strategy. PMID- 26979036 TI - [Diagnostic and monitoring contribution of imaging of visceral mycoses]. PMID- 26979037 TI - [Cryptococcosis: mass diagnosis is possible in Sub-Saharan Africa]. PMID- 26979039 TI - [Hygienic recommendations for preventing visceral mycoses]. PMID- 26979038 TI - [NEW ANTIFUNGAL DRUGS FOR PREVENTION AND TREATMENT OF VISCERAL MYCOSES]. AB - Invasive fungal infections are increasing due to the increase in the number of at risk patients. The antifungal armamentarium has been improved the last few years with new galenic for ampoetericin B, the widening of the azole spectrum with voriconazole, poscaonazole and isavuconazole and the launch of a new antifungal class, the eschinocandins, currently represented by casoefungin and micftungin. The aim of this work is to provide an update in new antifungal drugs available. PMID- 26979040 TI - [Indications for surgical management of visceral fungal infections]. PMID- 26979042 TI - [ANTI-TUBERCULOSIS THERAPY AND PARADOXICAL RESPONSE WHEN TUBERCULOSIS DEVELOPS UNDER THE INFLUENCE OF BIOLOGICS FOR RHEUMATOID ARTHRITIS]. AB - A paradoxical response is designated as the clinical or radiological worsening of pre-existing TB lesions or the development of new lesions during appropriate anti TB treatment. Tuberculosis bacilli have no toxin and the organism apparently does not produce any toxins, so the virulence depends on a response to the host immune reaction. According to our report, the annual reported numbers of tuberculosis cases and death did not decrease during biologics treatment in Japan. We have been monitoring and analyzing all the TB cases activated during adalimumab treatments in Japan. According to the analysis, there was no TB related death and severe sequelae in patients with lung tuberculosis without extra pulmonary TB; TB related deaths were caused not by delays of diagnosis and therapy but by the paradoxical response following miliary TB. Paradoxical response after abrupt cessation of anti-TB treatment is caused by immune activation to cell components despite TB bacilli are alive or dead. So, we concluded that the abrupt cessation of anti-TNF agents after TB development could activate immune response causing paradoxical response, which lead to severe sequelae and death, and that continuation of anti-TNF therapy for rheumatoid arthritis in patients with active tuberculosis reactivated during anti-TNF medication is more beneficial than its cessation concerning not only clinical and radiological but also bacteriological outcomes. PMID- 26979041 TI - [COMBINED USE OF INTERFERON-GAMMA RELEASE ASSAY AND LOW-DOSE COMPUTED TOMOGRAPHY FOR TUBERCULOSIS SCREENING PROGRAM OF HEALTH CARE WORKERS]. AB - OBJECTIVE: To evaluate the value of the interferon-gamma release assays and low dose computed tomography for the pulmonary tuberculosis screenings program of health care workers. DESIGN: For the pulmonary tuberculosis (TB) screenings program, T-SPOT.TB (one of interferon-gamma release assays: IGRA) were performed on 332 health care workers (HCWs) with normal chest roentgenogram and without the history of TB treatment. Low-dose computed tomography (LDCT) was also performed on IGRA positive HCWs. RESULTS: Ten of 332 subjects were positive IGRA. LDCT was performed on IGRA positive 10 subjects. Abnormal findings were noted in 2 of 10 subjects by LDCT. One had CT findings compatible with active TB and finally diagnosed as active TB. Another had scarring shadow at right S5 and lingular segment. Nine of 10 IGRA positive subjects were judged as latent tuberculosis infection (LTBI). Three hundred twenty-one subjects with negative and borderline IGRA of 332 HCWs were judged as not infected with TB. CONCLUSION: Combined use of IGRA and LDCT for tuberculosis screening program of HCWs was found to be effective for early diagnosis of TB, accurate diagnosis of LTBI and judgment of non-infective subjects. PMID- 26979043 TI - [IMPORTANCE OF HEALTH CARE FOR THE ERADICATION OF TUBERCULOSIS--Efforts Implemented in Nishinari Ward, Osaka City]. AB - 1) Changes in the incidence rate of tuberculosis in Osaka City and Nishinari Ward. The incidence rate of tuberculosis among people living in Osaka City (per 100,000 people) was 41.5 (number of patients: 1,109) in 2011--an approximately 50% decrease from 82.6 in 2001. However, the figure is 2.3 times higher than the national incidence rate of tuberculosis (17.7), and the highest of all ordinance designated cities and prefectures. Osaka City consists of 24 wards, and the incidence rate of tuberculosis varies from ward to ward. Although the incidence rate of tuberculosis in Nishinari Ward in 2011 was 199.6 (number of patients: 242) and the highest by far in the city, the figure is approximately 50% of the incidence rate in 2001 (405.9). There were two other wards with the incidence rate of 50.0 or higher, and the lowest incidence rate was 22.4. The incidence rate of tuberculosis in the Airin area of Nishinari Ward is particularly high. Although the number of newly registered patients decreased from 336 to 128 over the past ten years, and the incidence rate significantly decreased from 1,120.0 to 426.7 (when the population of the area was estimated to be 30,000), it is still 24.1 times higher than the national incidence rate. 2) Basic guidelines for tuberculosis strategy developed by Osaka City. Osaka City has developed basic guidelines for tuberculosis strategy to address patients with tuberculosis and eradicate the disease. The first and second periods of the basic guidelines for tuberculosis strategy were ten years from 2001 and 2011, respectively. The overall objective of these basic guidelines was to significantly reduce the incidence rate of tuberculosis, and numerical targets related to basic policies and specific activities were set to accomplish the goal. The basic guidelines allow Osaka City, including its public health centers, to implement measures against tuberculosis as a municipal project. 3) Assessment of the City's efforts. The measures were assessed on a regular basis at the committee on the assessment of measures for tuberculosis and analysis assessment review meetings, and, as the results, problems were identified and activities were further promoted and reviewed based on scientific evidence. 4) Important measures for patients with tuberculosis living in Nishinari Ward, Osaka City. In addition to the measures implemented by Osaka City, Nishinari Ward plans to improve the measures for the prevention of tuberculosis. 1. Although tuberculosis screening tests conducted in the Airin area have been effective for its early detection to some extent, the rate of identification of patients from 2007 to 2011 was still high (163/18,378). It is necessary to further promote tuberculosis screening. 2. Although the outcomes in general were improved by emphasizing drug administration guidance, there are still many homeless people with tuberculosis and patients who may stop taking drugs. The outcomes of these patients are poor, and, therefore, it is necessary to provide them with improved support. PMID- 26979044 TI - Cleveland hospitals increase capacity, hire additional staff to help end ambulance diversion. AB - With pressure from EMS to curb ambulance diversion, the four hospital systems serving metropolitan Cleveland have made a pact to bring diversion to an end. The agreement is voluntary, but all sides were determined to make the ban on diversion stick as of mid-February 2016. To get there, the health systems are increasing capacity, adding staff, and taking steps to tackle deeper hospital throughput issues. In 2015, reports noted that University Hospitals logged more than 550 hours on diversion, and MetroHealth closed its doors to new ambulance traffic for more than 400 hours. The Cleveland Clinic went on diversion for only 10 hours last year. To prepare for the ban on diversions, MetroHealth is adding more inpatient and ED beds, and it is also hiring additional staff. University Hospitals is taking similar steps while also building on the success of its medical access clinic, a lower-cost setting where patients can be screened, stabilized, and connected with primary care for future low-acuity needs. Hanging over the effort in Cleveland: Voluntary efforts to ban ambulance diversion in Boston failed repeatedly. However, once regulators mandated a ban on diversion statewide in 2009, the hospitals all fell into line with few signs of any adverse consequences. The city has now operated diversion-free for seven years. PMID- 26979045 TI - CMS proposes prioritizing patient preferences, linking patients to follow-up care in discharge planning process. AB - Hospital providers voice concerns about a proposed rule by the Centers for Medicare and Medicaid Services (CMS) that would require providers to devote more resources to discharge planning. The rule would apply to inpatients as well as emergency patients requiring comprehensive discharge plans as opposed to discharge instructions. CMS states that the rule would ensure the prioritization of patient preferences and goals in the discharge planning process, and also would prevent avoidable complications and readmissions. However, hospital and emergency medicine leaders worry that community resources are not yet in place to facilitate the links and follow-up required in the proposed rule, and that the costs associated with implementation would be prohibitive. The proposed rule would apply to acute care hospitals, EDs, long-term care facilities, inpatient rehabilitation centers, and home health agencies. Regardless of the setting, though, CMS is driving home the message that patient preferences should be given more weight during the discharge planning process. Under the rule, hospitals or EDs would need to develop a patient-centered discharge plan within 24 hours of admission or registration, and complete the plan prior to discharge or transfer to another facility. Under the rule, emergency physicians would determine which patients require a comprehensive discharge plan. Both the American Hospital Association and the American College of Emergency Physicians worry that hospitals will have to take on more staff, invest in training, and make changes to their electronic medical record systems to implement the provisions in the proposed rule. PMID- 26979046 TI - New policy changes regarding observation are boon to emergency medicine. PMID- 26979047 TI - Using swarm intelligence to boost the root cause analysis process and enhance patient safety. AB - In an effort to strengthen patient safety, leadership at the University of Kentucky HealthCare (UKHC) decided to replace its traditional approach to root cause analysis (RCA) with a process based on swarm intelligence, a concept borrowed from other industries. Under this process, when a problem or error is identified, staff quickly hold a swarm--a meeting in which all those involved in the incident or problem quickly evaluate why the issue occurred and identify potential solutions for implementation. A pillar of the swarm concept is a mandate that there be no punishments or finger-pointing during the swarms. The idea is to encourage staff to be forthcoming to achieve effective solutions. Typically, swarms last for one hour and result in action plans designed to correct problems or deficiencies within a specific period of time. The ED was one of the first areas where UKHC applied swarms. For example, hospital administrators note that the approach has been used to address issues involving patient flow, triage protocols, assessments, overcrowding, and boarding. After seven years, incident reporting at UKHC has increased by 52%, and the health system has experienced a 37% decrease in the observed-to-expected mortality ratio. PMID- 26979048 TI - Decalcification using ethylenediaminetetraacetic acid for clear microstructure imaging of cochlea through optical coherence tomography. AB - The aim of this study was to analyze the effectiveness of decalcification using ethylenediaminetetraacetic acid (EDTA) as an optical clearing method to enhance the depth visibility of internal soft tissues of cochlea. Ex vivo mouse and guinea pig cochlea samples were soaked in EDTA solutions for decalcification, and swept source optical coherence tomography (OCT) was used as imaging modality to monitor the decalcified samples consecutively. The monitored noninvasive cross sectional images showed that the mouse and guinea pig cochlea samples had to be decalcified for subsequent 7 and 14 days, respectively, to obtain the optimal optical clearing results. Using this method, difficulties in imaging of internal cochlea microstructures of mice could be evaded. The obtained results verified that the depth visibility of the decalcified ex vivo samples was enhanced. PMID- 26979049 TI - Lean body mass change over 6 years is associated with dietary leucine intake in an older Danish population. AB - Higher protein intake, and particularly higher leucine intake, is associated with attenuated loss of lean body mass (LBM) over time in older individuals. Dietary leucine is thought to be a key mediator of anabolism. This study aimed to assess this relationship over 6 years among younger and older adult Danes. Dietary leucine intake was assessed at baseline and after 6 years in men and women, aged 35-65 years, participating in the Danish cohort of the WHO-MONICA (Multinational MONItoring of trends and determinants in CArdiovascular disease) study (n 368). Changes in LBM over the 6 years were measured by bioelectrical impedance using equations developed for this Danish population. The association between leucine and LBM changes was examined using multivariate linear regression and ANCOVA analyses adjusted for potential confounders. After adjustment for baseline LBM, sex, age, energy intake and physical activity, leucine intake was associated with LBM change in those older than 65 years (n 79), with no effect seen in those younger than 65 years. Older participants in the highest quartile of leucine intake (7.1 g/d) experienced LBM maintenance, whereas lower intakes were associated with LBM loss over 6 years (for trend: beta=0.434, P=0.03). Sensitivity analysis indicated no effect modification of sex or the presence of CVD. Greater leucine intake in conjunction with adequate total protein intake was associated with long-term LBM retention in a healthy older Danish population. This study corroborates findings from laboratory investigations in relation to protein and leucine intakes and LBM change. A more diverse and larger sample is needed for confirmation of these results. PMID- 26979050 TI - Trading new neurons for status: Adult hippocampal neurogenesis in eusocial Damaraland mole-rats. AB - Diversity in social structures, from solitary to eusocial, is a prominent feature of subterranean African mole-rat species. Damaraland mole-rats are eusocial, they live in colonies that are characterized by a reproductive division of labor and a subdivision into castes based on physiology and behavior. Damaraland mole-rats are exceptionally long lived and reproductive animals show delayed aging compared to non-reproductive animals. In the present study, we described the hippocampal architecture and the rate of hippocampal neurogenesis of wild-derived, adult Damaraland mole-rats in relation to sex, relative age and social status or caste. Overall, Damaraland mole-rats were found to have a small hippocampus and low rates of neurogenesis. We found no correlation between neurogenesis and sex or relative age. Social status or caste was the most prominent modulator of neurogenesis. An inverse relationship between neurogenesis and social status was apparent, with queens displaying the lowest neurogenesis while the worker mole rats had the most. As there is no natural progression from one caste to another, social status within a colony was relatively stable and is reflected in the level of neurogenesis. Our results correspond to those found in the naked mole-rat, and may reflect an evolutionary and environmentally conserved trait within social mole-rat species. PMID- 26979051 TI - Altered metabolic activity in the developing brain of rats predisposed to high versus low depression-like behavior. AB - Individual differences in human temperament can increase the risk of psychiatric disorders like depression and anxiety. Our laboratory utilized a rat model of temperamental differences to assess neurodevelopmental factors underlying emotional behavior differences. Rats selectively bred for low novelty exploration (Low Responders, LR) display high levels of anxiety- and depression-like behavior compared to High Novelty Responder (HR) rats. Using transcriptome profiling, the present study uncovered vast gene expression differences in the early postnatal HR versus LR limbic brain, including changes in genes involved in cellular metabolism. These data led us to hypothesize that rats prone to high (versus low) anxiety/depression-like behavior exhibit distinct patterns of brain metabolism during the first weeks of life, which may reflect disparate patterns of synaptogenesis and brain circuit development. Thus, in a second experiment we examined activity of cytochrome C oxidase (COX), an enzyme responsible for ATP production and a correlate of metabolic activity, to explore functional energetic differences in the HR/LR early postnatal brain. We found that HR rats display higher COX activity in the amygdala and specific hippocampal subregions compared to LRs during the first 2 weeks of life. Correlational analysis examining COX levels across several brain regions and multiple early postnatal time points suggested desynchronization in the developmental timeline of the limbic HR versus LR brain during the first two postnatal weeks. These early divergent COX activity levels may reflect altered circuitry or synaptic activity in the early postnatal HR/LR brain, which could contribute to the emergence of their distinct behavioral phenotypes. PMID- 26979054 TI - Risk assessment of polychlorinated biphenyls (PCBs) and trace metals in River Nile up- and downstream of a densely populated area. AB - Cairo city is the largest populated area along the whole course of River Nile with a wide range of anthropogenic activities. Efforts to restore fish habitat and recreational use of the river have raised concerns about its water, sediment and biota quality. This study provides a baseline data on the levels of PCBs and trace metals in River Nile along Cairo sector and implements the formulation of monitoring activities of the river's pollution status. Water, sediment and Nile tilapia (Oreochromis niloticus) samples were collected during summer season, 2013 from two sites, up- and downstream, for detection and determination of 11 PCB congeners (PCBs 28, 44, 52, 70, 101, 105, 118, 138, 152, 180 and 192) as well as six trace metals (Cu, Zn, Mn, Cd, Pb and Fe). Evidences of long- or short-term exposures to these contaminants as well as its accumulation tendency were assessed by integrating the obtained analytical results of biotic and abiotic components of this aquatic ecosystem. All calculated lifetime cancer risk values for PCBs showed unacceptable risk of cancer for human consumers at both normal and subsistence fish consumption rates. The calculated hazard index for total PCBs indicates that fish are not safe for human consumption except in site 1 at normal consumption rate. Meanwhile, trace metals do not pose unacceptable risks at both consumption rates except for Pb in site 1 at subsistence consumption rate. PMID- 26979053 TI - Prenatal fat-rich diet exposure alters responses of embryonic neurons to the chemokine, CCL2, in the hypothalamus. AB - Maternal consumption of a high-fat diet (HFD) during pregnancy is found to stimulate the genesis of hypothalamic orexigenic peptide neurons in the offspring, while HFD intake in adult animals produces a systemic low-grade inflammation which increases neuroimmune factors that may affect neurogenesis and neuronal migration. Building on this evidence and our recent study showing that the inflammatory chemokine, CCL2, stimulates the migration of hypothalamic neurons and expression of orexigenic neuropeptides, we tested here the possibility that prenatal exposure to a HFD in rats affects this chemokine system, both CCL2 and its receptors, CCR2 and CCR4, and alters its actions on hypothalamic neurons, specifically those expressing the neuropeptides, enkephalin (ENK) and galanin (GAL). Using primary dissociated hypothalamic neurons extracted from embryos on embryonic day 19, we found that prenatal HFD exposure compared to chow control actually reduces the expression of CCL2 in these hypothalamic neurons, while increasing CCR2 and CCR4 expression, and also reduces the sensitivity of hypothalamic neurons to CCL2. The HFD abolished the dose dependent, stimulatory effect of CCL2 on the number of migrated neurons and even shifted its normal stimulatory effect on migrational velocity and distance traveled by control neurons to an inhibition of migration. Further, it abolished the dose-dependent, stimulatory effect of CCL2 on neuronal expression of ENK and GAL. These results demonstrate that prenatal HFD exposure greatly disturbs the functioning of the CCL2 chemokine system in embryonic hypothalamic neurons, reducing its endogenous levels and ability to promote the migration of neurons and their expression of orexigenic peptides. PMID- 26979055 TI - Hydrogeochemical controls on mobilization of arsenic and associated health risk in Nagaon district of the central Brahmaputra Plain, India. AB - In recent years, elevated concentration of arsenic (As) in groundwater in the northeastern states of India has become a major cause of concern. Since many regions of the Brahmaputra plains are reported with groundwater As contamination, an attempt was made to study the As contamination and factors governing its release in the Nagaon district in Brahmaputra floodplain, based on various water types, relation of As with other major ions and with various depth profiles. The origin of groundwater mineralization and the processes responsible for As enrichment in groundwater was determined by calculating saturation index using PHREEQC code. Multivariate statistical analysis was carried out for identification of As-releasing mechanism based on rock-water interaction. Principle component analysis of physicochemical parameters revealed the association of As with SiO2 and Cl- in pre-monsoon and the fact that alkaline condition favors release of As. The relation between As and Fe shows that reductive dissolution of solid Fe oxide and hydroxide phases could be the source of As in Nagaon district. The result of hierarchical cluster analysis indicates that As release could also be associated with the agrochemicals application. Health risk assessment revealed that children are more susceptible to carcinogenic as well as non-carcinogenic health impact with consumption of As contaminated drinking water. The male population is more susceptible to cancer as compared to females as the average water consumption is higher in case of male. Overall, the study highlights the health risk assessment is a matter of chief concern in this study as the younger generation are at higher risk. PMID- 26979056 TI - Fluorescent Polyamide-Based Rhodamine Hydrazide Moieties with Oxethyl as Spacer for Detection of Cr(3+), Fe(3+), and Hg(2+) Ions in Water. AB - An acrylic monomer bearing xanthene group, N-oxethyl acrylate-N'-rhodamine B hydrazide (ARBHE) was synthesized from N-hydroxyl ethyl-N'-rhodamine hydrazide (RBHE) and acryloyl chloride (Ac) in the presence of triethylamine in dry dichloromethane (CH2Cl2) at room temperature. The synthesized ARBHE was identified by FTIR, (1)H NMR spectra and elementary analysis. Copolymer poly(AM ARBHE) of ARBHE and AM was synthesized with thermal initiator by free radical precipitation polymerization and it was characterized by the method of FTIR and (1)H NMR. Its molecular weights (Meta) was 7.03 * 10(3) g mol(-1) and the content of rhodamine units in the polymer chains was 1.44 % in mole fraction. The ability of the poly(AM-ARBHE) to detect different metal cations (Ag(+), Ba(2+), Cd(2+) Co(2+), Cr(3+), Cu(2+), Co(2+) K(+), La(3+), Mg(2+), Na(+), Ni(2+), Pb(2+), Fe(2+), Fe(3+), Hg(2+) and Zn(2+)) in water was investigated. Upon addition of Cr(3+), Fe(3+) or Hg(2+) ions to the aqueous solution, visual color change and fluorescence enhancement were observed. Moreover, other metal ions did not induce obvious changes to the fluorescence spectra except to Fe(2+). The detection limit of poly(AM-ARBHE) was less than 1 * 10(-11) M. The results suggest that this copolymer may offer potential as a polymeric sensor for Cr(3+), Fe(3+) and Hg(2+) ions in water. PMID- 26979052 TI - The neural basis of reversal learning: An updated perspective. AB - Reversal learning paradigms are among the most widely used tests of cognitive flexibility and have been used as assays, across species, for altered cognitive processes in a host of neuropsychiatric conditions. Based on recent studies in humans, non-human primates, and rodents, the notion that reversal learning tasks primarily measure response inhibition, has been revised. In this review, we describe how cognitive flexibility is measured by reversal learning and discuss new definitions of the construct validity of the task that are serving as a heuristic to guide future research in this field. We also provide an update on the available evidence implicating certain cortical and subcortical brain regions in the mediation of reversal learning, and an overview of the principal neurotransmitter systems involved. PMID- 26979057 TI - Determination of Montelukast in Plasma Using beta - Cyclodextrins Coated on CoFe2O4 Magnetic Nanoparticles in Luminol-H2O2 Chemiluminescence System Optimized by Doehlert Design. AB - A novel chemiluminescence method using beta - cyclodextrins coated on CoFe2O4 magnetic nanoparticles is proposed for the chemiluminometric determination of montelukast in plasma. The effect of coated beta - cyclodexterinon CoFe2O4 magnetic nanoparticles in the chemiluminescence of luminol-H2O2 system was investigated. It was found that beta - cyclodexterin coated on CoFe2O4 magnetic nanoparticles could greatly enhance the chemiluminescence of the luminol-H2O2 system. Doehlert design was applied in order to optimize the number of experiments to be carried out to ascertain the possible interactions between the parameters and their effects on the chemiluminescence emission intensity. This design was selected because the levels of each variable may vary in a very efficient way with few experiments. Doehlert design and response surface methodology have been employed for optimization pH and concentrations of the components. Results showed under the optimized experimental conditions, the relative CL intensity (DeltaI) is increased linearly in the concentration range of 0.003-0.586 MUgml(-1) of montelukast with limit of detection (LOD) 1.09 * 10( 4) MUgml(-1) at S/N ratio of 3, limit of quantitative (LOQ) 3.59 * 10(-4) MUgml( 1) and the relative standard deviation 2.63 %. The method has been successfully applied to the determination of montelukast in plasma of human body. Results specified that relative chemiluminescence intensity (DeltaI) has good proportional with the montelukast concentration with R(2) = 0.99979. The test of the recovery efficiency for known amounts of montelukast was also performed, the recoveries range obtained from 98.2 to 103.3 %, with RSDs of <4 % indicated that the proposed method was reliable. PMID- 26979058 TI - Awareness of cytomegalovirus and risk factors for susceptibility among pregnant women, in Montreal, Canada. AB - BACKGROUND: Advances in diagnostic and therapeutic modalities for congenital cytomegalovirus (CMV) infection have generated a mounting interest in identifying mothers susceptible to CMV. The objectives of this study were to evaluate the prevalence and socio-demographic determinants of CMV susceptibility and CMV awareness, among pregnant women, in Montreal, Quebec. METHODS: Between April and December 2012, women delivering at Centre Hospitalier Universitaire Sainte Justine were recruited for the study. Stored serum from the first trimester of pregnancy was tested for CMV IgG. Knowledge about CMV and socio-demographic characteristics were collected via standardized questionnaire. RESULTS: Four hundred and ninety one women were enrolled in the study. Overall, 225 mothers (46%) were seronegative for CMV, and 85% (n = 415) were unaware of CMV or the associated risks in pregnancy. Significant risk factors for CMV seronegative status included Canadian vs. foreign born (aOR 6.88, 95% CI 4.33-10.94), and high vs. low family income (aOR 4.68, 95% CI 2.09-10.48). Maternal employment status was the only significant predictor of CMV unawareness, with unemployed mothers at the highest risk (aOR 85.6, 95% CI 17.3-421.3). CONCLUSIONS: Nearly half of pregnant women studied were at risk of primary infection, and yet, the majority was unaware of potential risks associated with CMV. Canadian born mothers and those with a high socioeconomic status were more likely to be CMV seronegative. Increased education about CMV infection, through public health interventions and obstetrician/pediatric counseling, is needed for all pregnant women. PMID- 26979061 TI - Further New Highly Oxidative Cembranoids from the Hainan Soft Coral Sarcophyton trocheliophorum. AB - Three new highly oxidative cembranoids, sarcophytrols D-F (1-3), were obtained from the South China Sea soft coral Sarcophyton trocheliophorum, along with two known related ones (4 and 5). Their structures were elucidated by extensive spectroscopic analyses and by comparison with literature data. The discovery of these new secondary metabolites enriched the family of cembranoids deduced from the title animal. PMID- 26979059 TI - Multifaceted functions and roles of HBZ in HTLV-1 pathogenesis. AB - Human T cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus responsible for the development of adult T-cell leukemia (ATL). Although HTLV-1 harbors an oncogene, tax, that transforms T cells in vitro and induces leukemia in transgenic mice, tax expression is frequently disrupted in ATL, making the oncogenesis of ATL a bit mysterious. The HTLV-1 bZIP factor (HBZ) gene was discovered in 2002 and has been found to promote T-cell proliferation and cause lymphoma in transgenic mice. Thus HBZ has become a novel hotspot of HTLV-1 research. This review summarizes the current findings on HBZ with a special focus on its potential links to the oncogenesis of ATL. We propose viewing HBZ as a critical contributing factor in ATL development. PMID- 26979062 TI - Predictive and prognostic value of FDG-PET/CT imaging and different response evaluation criteria after primary systemic therapy of breast cancer. AB - OBJECTIVES: (1) To predict pathological complete remission (pCR) and survival after primary systemic therapy (PST) in patients diagnosed with breast cancer by using two different PET/CT based scores: a simplified PERCIST-based PET/CT score (Method 1) and a combined PET/CT score supplemented with the morphological results of the RECIST system (Method 2) and (2) to assess the effect of different breast carcinoma subtypes on tumor response and its evaluation. METHODS: Eighty eight patients were enrolled in the study who underwent PET/CT imaging before and after PST. PET/CTs were evaluated by changes in maximum Standardized Uptake Value (SUVmax) and tumor size. Method 1 and 2 were applied to predict pathological complete remission (pCR). Kaplan-Meier analyses for survival were performed. Classification into biological subtypes was performed based on the pre therapeutic tumor characteristics. RESULTS: A total of 30/88 patients showed pCR (34.1 %). Comparing pCR/non-pCR patient groups, significant differences were detected by changes in SUVmax (p < 0.001) and tumor size (p < 0.001) regarding the primary breast lesions. To predict pCR, Method 2 had higher sensitivity (72.4 % vs. 44.8 %) and negative predictive value (57.9 % vs. 45.8 %) with lower false negativity rate (16 vs. 32) than Method 1. pCR rate was higher in Her2-positive and triple negative tumors. Despite the significant differences detected between the biological subtypes regarding changes in primary tumor SUVmax (p = 0.007) and size (p = 0.015), the subtypes only had significant impact on response evaluation with Method 2 and not with Method 1. In our study, neither clinical nor pathological CR were predictors of longer progression-free survival. CONCLUSIONS: Our results suggest that combined PET/CT criteria are more predictive of pCR. The effect of biological subtypes is significant on pCR rate as well as on the changes in FDG-uptake and morphological tumor response. Response evaluation with combined criteria was also able to reflect the differences between the biological behavior of breast tumor subtypes. PMID- 26979060 TI - The effects of storage temperature on PBMC gene expression. AB - BACKGROUND: Cryopreservation of peripheral blood mononuclear cells (PBMCs) is a common and essential practice in conducting research. There are different reports in the literature as to whether cryopreserved PBMCs need to only be stored <= 150 degrees C or can be stored for a specified time at -80 degrees C. Therefore, we performed gene expression analysis on cryopreserved PBMCs stored at both temperatures for 14 months and PBMCs that underwent temperature cycling 104 times between these 2 storage temperatures. Real-time RT-PCR was performed to confirm the involvement of specific genes associated with identified cellular pathways. All cryopreserved/stored samples were compared to freshly isolated PBMCs and between storage conditions. RESULTS: We identified a total of 1,367 genes whose expression after 14 months of storage was affected >3 fold in PBMCs following isolation, cryopreservation and thawing as compared to freshly isolated PBMC aliquots that did not undergo cryopreservation. Sixty-six of these genes were shared among two or more major stress-related cellular pathways (stress responses, immune activation and cell death). Thirteen genes involved in these pathways were tested by real-time RT-PCR and the results agreed with the corresponding microarray data. There was no significant change on the gene expression if the PBMCs experienced brief but repetitive temperature cycling as compared to those that were constantly kept <= -150 degrees C. However, there were 18 genes identified to be different when PBMCs were stored at -80 degrees C but did not change when stored < -150 degrees C. A correlation was also found between the expressions of 2'-5'- oligoadenylate synthetase (OAS2), a known interferon stimulated gene (IFSG), and poor PBMC recovery post-thaw. PBMC recovery and viability were better when the cells were stored <= -150 degrees C as compared to -80 degrees C. CONCLUSIONS: Not only is the viability and recovery of PBMCs affected during cryopreservation but also their gene expression pattern, as compared to freshly isolated PBMCs. Different storage temperature of PBMCs can activate or suppress different genes, but the cycling between -80 degrees C and -150 degrees C did not produce significant alterations in gene expression when compared to PBMCs stored <= -150 degrees C. Further analysis by gene expression of various PBMC processing and cryopreservation procedures is currently underway, as is identifying possible molecular mechanisms. PMID- 26979063 TI - Use of a knowledge broker to establish healthy public policies in a city district: a developmental evaluation. AB - BACKGROUND: Public health is to a large extent determined by non-health-sector policies. One approach to address this apparent paradox is to establish healthy public policies. This requires policy makers in non-health sectors to become more aware of the health impacts of their policies, and more willing to adopt evidence informed policy measures to improve health. We employed a knowledge broker to set the agenda for health and to specify health-promoting policy alternatives. This study aimed at gaining in-depth understanding of how this knowledge broker approach works. METHODS: In the context of a long-term partnership between the two universities in Amsterdam and the municipal public health service, we employed a knowledge broker who worked part-time at a university and part-time for an Amsterdam city district. When setting an agenda and specifying evidence informed policy alternatives, we considered three individual policy portfolios as well as the policy organization of the city district. We evaluated and developed the knowledge broker approach through action research using participant observation. RESULTS: Our knowledge brokering strategy led to the adoption of several policy alternatives in individual policy portfolios, and was especially successful in agenda-setting for health. More specifically, health became an issue on the formal policy agenda as evidenced by its uptake in the city district's mid-term review and the appointment of a policy analyst for health. Our study corroborated the importance of process factors such as building trust, clearly distinguishing the knowledge broker role, and adequate management support. We also saw the benefits of multilevel agenda-setting and specifying policy alternatives at appropriate policy levels. Sector-specific responsibilities hampered the adoption of cross-sectoral policy alternatives, while thematically designed policy documents offered opportunities for including them. Further interpretation revealed three additional themes in knowledge brokering: boundary spanning, a ripple effect, and participant observation. CONCLUSIONS: The employment of a knowledge broker who works simultaneously on both agenda-setting for health as well as the specification of health-promoting policy alternatives seems to be a promising first step in establishing local healthy public policies. Future studies are needed to explore the usefulness of our approach in further policy development and policy implementation. PMID- 26979065 TI - Heterotopic ovarian transplantation results in less apoptosis than orthotopic transplantation in a minipig model. AB - BACKGROUND: Ovarian autotransplantation has shown increasing promise as a clinical method for the preservation of fertility and hormonal function. However, information regarding the success rate of this type of transplantation is limited. We hypothesized that results vary according to the site of the ovarian transplantation. To test this hypothesis, fresh or cryopreserved ovarian strips were autotransplanted to orthotopic or heterotopic sites. The strips were later collected, and the morphology and expression of selected markers of apoptosis were evaluated. We compared the Bax, Bcl-2 and cleaved caspase-3 staining levels and the morphometric aspects of autotransplanted fresh and cryopreserved ovarian strips placed at orthotopic and heterotopic sites in minipigs. METHODS: Forty female minipigs were allocated to the following five groups: group 1 (control), ovarian tissue removed during oophorectomy; group 2, transplantation of fresh ovarian strips to a heterotopic site; group 3, transplantation of fresh ovarian strips to an orthotopic site; group 4, transplantation of cryopreserved ovarian strips to a heterotopic site; and group 5, transplantation of ovarian trips to an orthotopic site. On day 7 after transplantation, ovarian strips were collected, and the morphology and expression of apoptosis markers were evaluated. RESULTS: In all groups, follicles across all stages of development were detected. The numbers of primordial, primary and secondary follicles were similar in all groups, but the numbers of antral follicles were lower in the cryopreserved groups in comparison with freshly derived ovarian tissue, with no significant differences observed between fresh and cryopreserved transplants. In all transplanted groups, Bcl-2 expression was lower and Bax expression was higher than in the control group. Furthermore, increased expression of apoptosis markers was detected in fresh intraperitoneal transplants. Lastly, the expression of cleaved caspase-3 was higher in the cryopreserved orthotopic group compared with the heterotopic group. CONCLUSIONS: Orthotopic and heterotopic ovarian strip transplantations are feasible options using these techniques. Importantly, we found that heterotopic transplantation preserves ovarian follicle integrity to a greater degree (i.e., lower expression of apoptosis markers) than orthotopic transplantation, and cryopreservation does not exacerbate expression of apoptosis's markers. These findings have major clinical applications and enhance the discussion regarding the heterotopic transplantation of ovarian tissue. PMID- 26979064 TI - A novel-type phosphatidylinositol phosphate-interactive, Ca-binding protein PCaP1 in Arabidopsis thaliana: stable association with plasma membrane and partial involvement in stomata closure. AB - The Ca(2+)-binding protein-1 (PCaP1) of Arabidopsis thaliana is a new type protein that binds to phosphatidylinositol phosphates and Ca(2+)-calmodulin complex as well as free Ca(2+). Although biochemical properties, such as binding to ligands and N-myristoylation, have been revealed, the intracellular localization, tissue and cell specificity, integrity of membrane association and physiological roles of PCaP1 are unknown. We investigated the tissue and intracellular distribution of PCaP1 by using transgenic lines expressing PCaP1 linked with a green fluorescence protein (GFP) at the carboxyl terminus of PCaP1. GFP fluorescence was obviously detected in most tissues including root, stem, leaf and flower. In these tissues, PCaP1-GFP signal was observed predominantly in the plasma membrane even under physiological stress conditions but not in other organelles. The fluorescence was detected in the cytosol when the 25-residue N terminal sequence was deleted from PCaP1 indicating essential contribution of N myristoylation to the plasma membrane anchoring. Fluorescence intensity of PCaP1 GFP in roots was slightly decreased in seedlings grown in medium supplemented with high concentrations of iron for 1 week and increased in those grown with copper. In stomatal guard cells, PCaP1-GFP was strictly, specifically localized to the plasma membrane at the epidermal-cell side but not at the pore side. A T DNA insertion mutant line of PCaP1 did not show marked phenotype in a life cycle except for well growth under high CO2 conditions. However, stomata of the mutant line did not close entirely even in high osmolarity, which usually induces stomata closure. These results suggest that PCaP1 is involved in the stomatal movement, especially closure process, in leaves and response to excessive copper in root and leaf as a mineral nutrient as a physiological role. PMID- 26979067 TI - Erratum to: Web searching for systematic reviews: a case study of reporting standards in the UK Health Technology Assessment programme. PMID- 26979066 TI - Generation of Plasmodium falciparum parasite-inhibitory antibodies by immunization with recombinantly-expressed CyRPA. AB - BACKGROUND: The pathogenesis of malaria is primarily associated with blood-stage infection and there is strong evidence that antibodies specific for parasite blood-stage antigens can control parasitaemia. This provides a strong rationale for incorporation of asexual blood-stage antigen components into an effective multivalent malaria subunit vaccine. On the basis of available genome-wide transcriptomic and proteomic data, previously uncharacterized Plasmodium falciparum open reading frames were screened for new blood stage vaccine candidates. This has led to the identification of the cysteine-rich protective antigen (PfCyRPA), which forms together with PfRH5 and PfRipr a multiprotein complex that is crucial for erythrocyte invasion. METHODS: Glycosylated and non glycosylated variants of recombinant PfCyRPA were expressed and produced as secreted protein in mammalian cells. Adjuvanted formulations of purified PfCyRPA were tested to assess whether they can effectively elicit parasite inhibitory antibodies, and to investigate whether or not the glycosylation status affects antibody binding. For this purpose, two sets of PfCyRPA-specific mouse monoclonal antibodies (mAbs) have been raised and evaluated for functional activity. RESULTS: Generated PfCyRPA-specific mAbs, irrespective of the immunogen's glycosylation status, showed substantial parasite in vitro growth-inhibitory activity due to inhibition of erythrocyte invasion by merozoites. Furthermore, passive immunization experiments in P. falciparum infected NOD-scid IL2Rgamma (null) mice engrafted with human erythrocytes demonstrated potent in vivo growth inhibitory activity of generated mAbs. CONCLUSIONS: Recombinantly expressed PfCyRPA tested as adjuvanted vaccine formulations in mice elicited antibodies that significantly inhibit P. falciparum asexual blood stage parasite growth both in vitro and in vivo. These findings render PfCyRPA a promising blood-stage candidate antigen for inclusion into a multicomponent malaria subunit vaccine. PMID- 26979069 TI - Perception of Stand-on-ability: Do Geographical Slants Feel Steeper Than They Look? AB - Past research has shown that haptically perceived surface slant by foot is matched with visually perceived slant by a factor of 0.81. Slopes perceived visually appear shallower than when stood on without looking. We sought to identify the sources of this discrepancy by asking participants to judge whether they would be able to stand on an inclined ramp. In the first experiment, visual perception was compared to pedal perception in which participants took half a step with one foot onto an occluded ramp. Visual perception closely matched the actual maximal slope angle that one could stand on, whereas pedal perception underestimated it. Participants may have been less stable in the pedal condition while taking half a step onto the ramp. We controlled for this by having participants hold onto a sturdy tripod in the pedal condition (Experiment 2). This did not eliminate the difference between visual and haptic perception, but repeating the task while sitting on a chair did (Experiment 3). Beyond balance requirements, pedal perception may also be constrained by the limited range of motion at the ankle and knee joints while standing. Indeed, when we restricted range of motion by wearing an ankle brace pedal perception underestimated the affordance (Experiment 4). Implications for ecological theory were offered by discussing the notion of functional equivalence and the role of exploration in perception. PMID- 26979070 TI - Ws-2 Introgression in a Proportion of Arabidopsis thaliana Col-0 Stock Seed Produces Specific Phenotypes and Highlights the Importance of Routine Genetic Verification. PMID- 26979071 TI - A Novel Method for Achievement of Vascular Closure After Misdeployment of an Angio-SealTM Device. PMID- 26979068 TI - Clinical efficiency of Helicobacter pylori eradication in the treatment of patients with acute central serous chorioretinopathy. AB - BACKGROUND: Although the majority of cases of acute central serous chorioretinopathy are self-limited, resolving spontaneously after a number of weeks, the recurrence rate is estimated to be 20-50 %, and some cases will be chronic, lasting 6 months or longer. The evidence of Helicobacter pylori infection appears more often in patients with central serous chorioretinopathy. The purpose of this work was to estimate the efficiency of H. pylori infection eradication in treatment of patients with acute central serous chorioretinopathy. METHODS: Ninety-three patients with acute central serous chorioretinopathy participated in this study. Patients were divided into an experimental group (33 Helicobacter pylori-positive patients who received eradication treatment) and two control groups who did not receive eradication treatment: 29 H. pylori-positive patients and 31 H. pylori-negative patients. Research methods were best-corrected Snellen visual acuity, optical coherence tomography, fluorescein angiography. Research methods were best-corrected Snellen visual acuity, optical coherence tomography, static perimetry, and Amsler grid. The follow-up period was 2 years. RESULTS: Helicobacter pylori eradication caused a decrease of disease duration at 3 months (p = 0.04) and recurrence frequency of 45.6 % (p = 0.03) as well as improvement of distant prognosis. After 2 years, visual acuity increased from 0.91 +/- 0.07 to 0.99 +/- 0.02 (p = 0.01), scotoma frequency decreased from 100 % eyes to 27.2 % (p = 0.001), and metamorphopsia frequency decreased from 57.6 % eyes to 39.4 % (p = 0.04). CONCLUSIONS: Helicobacter pylori eradication is effective in the treatment of H. pylori-positive patients with acute central serous chorioretinopathy. PMID- 26979072 TI - Cancer care team. PMID- 26979073 TI - Long Non-coding RNA HOTAIR Promotes Parkinson's Disease Induced by MPTP Through up-regulating the Expression of LRRK2. AB - Homeobox (HOX) transcript antisense RNA (HOTAIR), as a long intergenic noncoding RNA (lincRNA), is known to be overexpressed in several cancers. However, the role of HOTAIR in Parkinson's disease (PD) remains unclear. A mouse model of PD was developed by intraperitoneal injection of MPTP (N-methyl-4-phenyl-1,2,3,6- tetrahydropyridine). The expression of HOTAIR and LRRK2 (leucine-rich repeat kinase 2) were detected in the PD mice and in Human neuroblastoma cell lines SH SY5Y pretreated with MPP+ (N-methyl-4-phenylpyridinium). The effect of HOTAIR on the expression of LRRK2 was examined in SH-SY5Y cells through overexpressing HOTAIR. A MTT (3- (4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay was performed to measure the cell viability of SH-SY5Y cells. si HOTAIR (siRNA-HOTAIR) was utilized to investigate the effect of HOTAIR on the expression of LRRK2 in vivo. In this study, upregulation of HOTAIR and LRRK2 were found in the midbrain of PD mice induced by MPTP and in SH-SY5Y cells pretreated with MPP+. With the presence of HOTAIR overexpression in SH-SY5Y cells, the expression of LRRK2 was increased compared with that in the control. HOTAIR knockdown showed a protective effect on the cell viability of SH-SY5Y cells pretreated with MPP+, which was abrogated by overexpression of LRRK2. In mouse model of PD treated with si-HOTAIR, the expression of LRRK2 was decreased. In conclusion, high expression of HOTAIR promoted the onset of PD induced by MPTP. Moreover, the finding that HOTAIR promoted PD induced by MPTP through regulating LRRK2 expression could add our understanding of the molecular mechanisms in PD. PMID- 26979074 TI - Plasma Level of D-dimer is an Independent Diagnostic Biomarker for Deep Venous Thrombosis in Patients with Ischemic Stroke. AB - This study was to determine the clinical diagnostic value of D-dimer for DVT in patients with ischemic stroke. During July 2013 to December 2014, a cohort study of ischemic stroke patients who presented with symptoms of DVT in upper or lower extremities was performed, with a total of 255 patients at baseline. D-dimer levels were measured from each patient using Colour Doppler Ultrasonography (CDUS), and all patients underwent venous duplex examinations. In ours study, 56 patients were diagnosed as DVT (22.0%). When compared to the patients without DVT, a significantly increased trend of plasma D-dimer levels was found in stroke patients with DVT [3.07 (IQR, 2.26-4.05)mg/L VS. 0.54 (IQR, 0.27-1.14) mg/L; P<0.0001]. From the analysis results of the ROC curve, optimal cutoff value was 1.51 mg/L for diagnosing of DVT (sensitivity: 91.1 %; specificity: 85.4%; the AUC: 0.914 [95%CI, 0.878-0.950; P<0.001]). If cut-off value of 0.5 mg/L, the diagnosis sensitivity was 100%, the specificity was 46.2%, and the positive predictive value was 34.3%. In addition, 36.1% (92/255) stroke patients who suspected with DVT did not need perform CDUS, and those patients could be excluded by plasma D-dimer tested. Collectively, plasma D-dimer level may have a guiding meaning for diagnosing DVT in ischemic stroke patients, and the D-dimer assay is a reliable method for ruling out DVT. PMID- 26979075 TI - Medicine, belief, witchcraft and demonic possession in late seventeenth-century Ulster. AB - Ireland's only published witchcraft pamphlet, written by Daniel Higgs, The Wonderful and True Relation of the Bewitching of a Young Girle in Ireland, What Ways she was Tormented, and a Receipt of the Ointment that she was Cured with (1699), works within the confines of late seventeenth-century demonology, while upholding the patriarchy of the fledgling Protestant Ascendancy. More importantly, it provides rare insight into early modern Protestant witchcraft beliefs, highlights the limits of contemporary medical care and provision and details the pathways of self-medication people resorted to. Higgs' method of promoting self-medication as a cure to bewitchment and demonic possession was based on a remedy described in an obscure Renaissance magical text. To promote his 'cure' the pamphlet included a particularly vitriolic critique of the established Irish medical profession, as self-regarding and incompetent witchcraft deniers. This article uses Higgs' pamphlet to explore the limits to/of medical knowledge in early modern Ireland and Europe. PMID- 26979077 TI - Potential roles for calcium-sensing receptor (CaSR) and transient receptor potential ankyrin-1 (TRPA1) in murine anorectic response to deoxynivalenol (vomitoxin). AB - Food contamination by the trichothecene mycotoxin deoxynivalenol (DON, vomitoxin) has the potential to adversely affect animal and human health by suppressing food intake and impairing growth. In mice, the DON-induced anorectic response results from aberrant satiety hormone secretion by enteroendocrine cells (EECs) of the gastrointestinal tract. Recent in vitro studies in the murine STC-1 EEC model have linked DON-induced satiety hormone secretion to activation of calcium sensing receptor (CaSR), a G-coupled protein receptor, and transient receptor potential ankyrin-1 (TRPA1), a TRP channel. However, it is unknown whether similar mechanisms mediate DON's anorectic effects in vivo. Here, we tested the hypothesis that DON-induced food refusal and satiety hormone release in the mouse are linked to activation of CaSR and TRPA1. Oral treatment with selective agonists for CaSR (R-568) or TRPA1 (allyl isothiocyanate (AITC)) suppressed food intake in mice, and the agonist's effects were suppressed by pretreatment with corresponding antagonists NPS-2143 or ruthenium red (RR), respectively. Importantly, NPS-2143 or RR inhibited both DON-induced food refusal and plasma elevations of the satiety hormones cholecystokinin (CCK) and peptide YY3-36 (PYY3 36); cotreatment with both antagonists additively suppressed both anorectic and hormone responses to DON. Taken together, these in vivo data along with prior in vitro findings support the contention that activation of CaSR and TRPA1 contributes to DON-induced food refusal by mediating satiety hormone exocytosis from EEC. PMID- 26979076 TI - Fluid shear stress modulation of hepatocyte-like cell function. AB - Freshly isolated human adult hepatocytes are considered to be the gold standard tool for in vitro studies. However, primary hepatocyte scarcity, cell cycle arrest and the rapid loss of cell phenotype limit their widespread deployment. Human embryonic stem cells and induced pluripotent stem cells provide renewable sources of hepatocyte-like cells (HLCs). Despite the use of various differentiation methodologies, HLCs like primary human hepatocytes exhibit unstable phenotype in culture. It has been shown that the functional capacity can be improved by adding back elements of human physiology, such as cell co-culture or through the use of natural and/or synthetic surfaces. In this study, the effect of fluid shear stress on HLC performance was investigated. We studied two important liver functions, cytochrome P450 drug metabolism and serum protein secretion, in static cultures and those exposed to fluid shear stress. Our study demonstrates that fluid shear stress improved Cyp1A2 activity by approximately fivefold. This was paralleled by an approximate ninefold increase in sensitivity to a drug, primarily metabolised by Cyp2D6. In addition to metabolic capacity, fluid shear stress also improved hepatocyte phenotype with an approximate fourfold reduction in the secretion of a foetal marker, alpha-fetoprotein. We believe these studies highlight the importance of introducing physiologic cues in cell-based models to improve somatic cell phenotype. PMID- 26979078 TI - Empathy among undergraduate medical students: A multi-centre cross-sectional comparison of students beginning and approaching the end of their course. AB - BACKGROUND: Although a core element in patient care the trajectory of empathy during undergraduate medical education remains unclear. Empathy is generally regarded as comprising an affective capacity: the ability to be sensitive to and concerned for, another and a cognitive capacity: the ability to understand and appreciate the other person's perspective. The authors investigated whether final year undergraduate students recorded lower levels of empathy than their first year counterparts, and whether male and female students differed in this respect. METHODS: Between September 2013 and June 2014 an online questionnaire survey was administered to 15 UK, and 2 international medical schools. Participating schools provided both 5-6 year standard courses and 4 year accelerated graduate entry courses. The survey incorporated the Jefferson Scale of Empathy-Student Version (JSE-S) and Davis's Interpersonal Reactivity Index (IRI), both widely used to measure medical student empathy. Participation was voluntary. Chi squared tests were used to test for differences in biographical characteristics of student groups. Multiple linear regression analyses, in which predictor variables were year of course (first/final); sex; type of course and broad socio-economic group were used to compare empathy scores. RESULTS: Five medical schools (4 in the UK, 1 in New Zealand) achieved average response rates of 55 % (n = 652) among students starting their course and 48 % (n = 487) among final year students. These schools formed the High Response Rate Group. The remaining 12 medical schools recorded lower response rates of 24.0 % and 15.2 % among first and final year students respectively. These schools formed the Lower Response Rate Group. For both male and female students in both groups of schools no significant differences in any empathy scores were found between students starting and approaching the end of their course. Gender was found to significantly predict empathy scores, with females scoring higher than males. CONCLUSIONS: Participant male and female medical students approaching the end of their undergraduate education, did not record lower levels of empathy, compared to those at the beginning of their course. Questions remain concerning the trajectory of empathy after qualification and how best to support it through the pressures of starting out in medical practice. PMID- 26979079 TI - Ranolazine: A Contemporary Review. PMID- 26979081 TI - Clipping the Wings of Glioblastoma: Modulation of WNT as a Novel Therapeutic Strategy. AB - Glioblastoma (GBM) is the most malignant brain tumor and has a dismal prognosis. Aberrant WNT signaling is known to promote glioma cell growth and dissemination and resistance to conventional radio- and chemotherapy. Moreover, a population of cancer stem-like cells that promote glioma growth and recurrence are strongly dependent on WNT signaling. Here, we discuss the role and mechanisms of aberrant canonical and noncanonical WNT signaling in GBM. We present current clinical approaches aimed at modulating WNT activity and evaluate their clinical perspective as a novel treatment option for GBM. PMID- 26979080 TI - Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent for Percutaneous Coronary Revascularization: 2 Year Results of the BIOSCIENCE Trial. AB - BACKGROUND: No data are available on the long-term performance of ultrathin strut biodegradable polymer sirolimus-eluting stents (BP-SES). We reported 2-year clinical outcomes of the BIOSCIENCE (Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent for Percutaneous Coronary Revascularisation) trial, which compared BP-SES with durable-polymer everolimus-eluting stents (DP-EES) in patients undergoing percutaneous coronary intervention. METHODS AND RESULTS: A total of 2119 patients with minimal exclusion criteria were assigned to treatment with BP-SES (n=1063) or DP-EES (n=1056). Follow-up at 2 years was available for 2048 patients (97%). The primary end point was target-lesion failure, a composite of cardiac death, target-vessel myocardial infarction, or clinically indicated target-lesion revascularization. At 2 years, target-lesion failure occurred in 107 patients (10.5%) in the BP-SES arm and 107 patients (10.4%) in the DP-EES arm (risk ratio [RR] 1.00, 95% CI 0.77-1.31, P=0.979). There were no significant differences between BP-SES and DP-EES with respect to cardiac death (RR 1.01, 95% CI 0.62 1.63, P=0.984), target-vessel myocardial infarction (RR 0.91, 95% CI 0.60-1.39, P=0.669), target-lesion revascularization (RR 1.17, 95% CI 0.81-1.71, P=0.403), and definite stent thrombosis (RR 1.38, 95% CI 0.56-3.44, P=0.485). There were 2 cases (0.2%) of definite very late stent thrombosis in the BP-SES arm and 4 cases (0.4%) in the DP-EES arm (P=0.423). In the prespecified subgroup of patients with ST-segment elevation myocardial infarction, BP-SES was associated with a lower risk of target-lesion failure compared with DP-EES (RR 0.48, 95% CI 0.23-0.99, P=0.043, Pinteraction=0.026). CONCLUSIONS: Comparable safety and efficacy profiles of BP-SES and DP-EES were maintained throughout 2 years of follow-up. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01443104. PMID- 26979083 TI - Studies drawing on qualitative research are funded by the most prestigious research funders in the UK. PMID- 26979082 TI - Altered Proteins in the Aging Brain. AB - We assessed the prevalence of common altered brain proteins in 296 cognitively unimpaired subjects ranging from age 50 to 102 years. The incidence and the stage of hyperphosphorylated-tau (HPtau), beta-amyloid, alpha-synuclein (alphaS), and transactive response DNA (TDP) binding protein 43 (TDP43)-immunoreactivity (-IR) increased with age. HPtau-IR was observed in 98% of the subjects; the locus coeruleus was solely affected in 46%, and 79% of the subjects were in Braak stages a to II. beta-Amyloid was seen in 47% of subjects and the Thal phase correlated with the HPtau Braak stage and age. Intermediate Alzheimer disease related pathology (ADRP) was seen in 12%; 52% of the subjects with HPtau-IR fulfilled criteria for definite primary age-related tauopathy (PART). The incidence of concomitant pathology (alphaS, TDP43) did not differ between those with PART and those with ADRP but the former were younger. TDP43-IR was observed in 36%; the most frequently affected region was the medulla; alphaS-IR was observed in 19% of subjects. In 41% of the subjects from 80 to 89 years at death, 3 altered proteins were seen in the brain. Thus, altered proteins are common in the brains of cognitively unimpaired aged subjects; this should be considered while developing diagnostic biomarkers, particularly for identifying subjects at early stages of neurodegenerative diseases. PMID- 26979084 TI - Intense Exercise and Native Collateral Function in Stable Moderate Coronary Artery Disease: Incidental, Causal, or Clinically Important? PMID- 26979085 TI - Coronary Collateral Growth Induced by Physical Exercise: Results of the Impact of Intensive Exercise Training on Coronary Collateral Circulation in Patients With Stable Coronary Artery Disease (EXCITE) Trial. AB - BACKGROUND: A well-developed coronary collateral circulation provides a potential source of blood supply in coronary artery disease. However, the prognostic importance and functional relevance of coronary collaterals is controversial with the association between exercise training and collateral growth still unclear. METHODS AND RESULTS: This prospective, open-label study randomly assigned 60 patients with significant coronary artery disease (fractional flow reserve <=0.75) to high-intensity exercise (group A, 20 patients) or moderate-intensity exercise (group B, 20 patients) for 4 weeks or to a control group (group C, 20 patients). The primary end point was the change of the coronary collateral flow index (CFI) after 4 weeks. Analysis was based on the intention to treat. After 4 weeks, baseline CFI increased significantly by 39.4% in group A (from 0.142+/ 0.07 at beginning to 0.198+/-0.09 at 4 weeks) in comparison with 41.3% in group B (from 0.143+/-0.06 to 0.202+/-0.09), whereas CFI in the control group remained unchanged (0.7%, from 0.149+/-0.09 to 0.150+/-0.08). High-intensity exercise did not lead to a greater CFI than moderate-intensity training. After 4 weeks, exercise capacity, Vo2 peak and ischemic threshold increased significantly in group A and group B in comparison with group C with no difference between group A and group B. CONCLUSIONS: A significant improvement in CFI was demonstrated in response to moderate- and high-intensity exercise performed for 10 hours per week. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01209637. PMID- 26979086 TI - Moraxella catarrhalis decreases antiviral innate immune responses by down regulation of TLR3 via inhibition of p53 in human bronchial epithelial cells. AB - Chronic obstructive pulmonary disease (COPD) is complicated by infectious exacerbations with acute worsening of respiratory symptoms. Coinfections of bacterial and viral pathogens are associated with more severe exacerbations. Moraxella catarrhalis is one of the most frequent lower respiratory tract pathogens detected in COPD. We therefore studied the impact of M. catarrhalis on the antiviral innate immune response that is mediated via TLR3 and p53. Molecular interactions between M. catarrhalis and normal human bronchial epithelial (NHBE) cells as well as Beas-2B cells were studied using flow cytometry, quantitative PCR analysis, chromatin immunoprecipitation, RNA interference, and ELISA. M. catarrhalis induces a significant down-regulation of TLR3 in human bronchial epithelial cells. In M. catarrhalis-infected cells, expression of p53 was decreased. We detected a reduced binding of p53 to the tlr3 promoter, resulting in reduced TLR3 gene transcription. M. catarrhalis diminished the TLR3-dependent secretion of IFN-beta, IFN-lambda, and chemokine (C-X-C motif) ligand 8. In addition in M. catarrhalis infected cells, expression of rhinovirus type 1A RNA was increased compared with uninfected cells. M. catarrhalis reduces antiviral defense functions of bronchial epithelial cells, which may increase susceptibility to viral infections.-Heinrich, A., Haarmann, H., Zahradnik, S., Frenzel, K., Schreiber, F., Klassert, T. E., Heyl, K. A., Endres, A.-S., Schmidtke, M., Hofmann, J., Slevogt, H. Moraxella catarrhalis decreases antiviral innate immune responses by down-regulation of TLR3 via inhibition of p53 in human bronchial epithelial cells. PMID- 26979088 TI - Mishearing, In Its Many Forms. PMID- 26979089 TI - A gold(i)-catalyzed substituent-controlled cycloisomerization of propargyl vinyl ethers to multi-substituted furofuran and furopyran derivatives. AB - A gold(i)-catalyzed substituent-controlled strategy for the stereoselective synthesis of bicyclic furan and pyran derivatives has been developed. The mechanisms of the reactions have been studied thoroughly by deuterium labelling experiments. The applications of the methodologies were demonstrated by evaluating the preliminary anti-fungal activity of the synthetic compounds. PMID- 26979087 TI - ECL1i, d(LGTFLKC), a novel, small peptide that specifically inhibits CCL2 dependent migration. AB - CC chemokine receptor type 2 (CCR2) is a key molecule in inflammatory diseases and is an obvious drug target for the treatment of inflammation. A number of nonpeptidic, competitive CCR2 antagonists have been developed, but none has yet been approved for clinical use. Our aim was to identify a short peptide that showed allosteric antagonism against human and mouse CCR2. On the basis of sequence analysis and 3-dimensional modeling, we identified an original 7-d-amino acid peptidic CCR2 inhibitor that we have called extracellular loop 1 inverso (ECL1i), d(LGTFLKC). In vitro, ECL1i selectively and potently inhibits CC chemokine ligand type 2 (CCL2)-triggered chemotaxis (IC50, 2 uM) but no other conventional CCL2-associated events. We used the classic competitive CCR2 antagonist, BMS22 {2-[(isopropylaminocarbonyl)amino]-N-[2-[[cis-2-[[4 (methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5 (trifluoromethyl)benzamide}, as positive control and inhibited CCL2-dependent chemotaxis with an IC50 of 18 nM. As negative control, we used a peptide with the same composition as ECL1i, but in a different sequence, d(FKLTLCG). In vivo, ECL1i (4 mg/kg) interfered with CCR2-positive cell recruitment and attenuated disease progression in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. This study establishes ECL1i as the first allosteric inhibitor of CCR2 with functional selectivity. ECL1i is a promising new agent in therapeutic development, and it may, by its selective effect, increase our understanding of CCR2 signaling pathways and functions.-Auvynet, C., Baudesson de Chanville, C., Hermand, P., Dorgham, K., Piesse, C., Pouchy, C., Carlier, L., Poupel, L., Barthelemy, S., Felouzis, V., Lacombe, C., Sagan, S., Salomon, B., Deterre, P., Sennlaub, F., Combadiere, C. ECL1i, d(LGTFLKC), a novel, small peptide that specifically inhibits CCL2-dependent migration. PMID- 26979090 TI - Negative-index gratings formed by femtosecond laser overexposure and thermal regeneration. AB - We demonstrate a method for the preparation of negative-index fibre Bragg gratings (FBGs) using 800 nm femtosecond laser overexposure and thermal regeneration. A positive-index type I-IR FBG was first inscribed in H2-free single-mode fibre using a femtosecond laser directed through a phase mask, and then a highly polarization dependant phase-shifted FBG (P-PSFBG) was fabricated from the type I-IR FBG by overexposure to the femtosecond laser. Subsequently, the P-PSFBG was thermally annealed at 800 degrees C for 12 hours. Grating regeneration was observed during thermal annealing, and a negative-index FBG was finally obtained with a high reflectivity of 99.22%, an ultra-low insertion loss of 0.08 dB, a blueshift of 0.83 nm in the Bragg wavelength, and an operating temperature of up to 1000 degrees C for more than 10 hours. Further annealing tests showed that the thermal stability of the negative-index FBG was lower than that of a type II-IR FBG, but much higher than that of a type I-IR FBG. Moreover, the formation of such a negative-index grating may result from thermally regenerated type IIA photosensitivity. PMID- 26979091 TI - Health burden of serious road injuries in the Netherlands. AB - BACKGROUND: The consequences of injuries in terms of disabilities and health burden are relevant for policy making. This article provides an overview of the current knowledge on this topic and discusses the health burden of serious road injuries in The Netherlands. METHODS: The overview of current knowledge on disabilities following a road crash is based on a literature review. The health burden of serious road injuries is quantified in terms of years lived with disability (YLD), by combining incidence data from the Dutch hospital discharge register with information about temporary and lifelong disability. RESULTS: Literature shows that road traffic injuries can have a major impact on victims' physical and psychological well-being and functioning. Reported proportions of people with disability vary between 11 and 80% depending on the type of casualties, time elapsed since the crash, and the health impacts considered. Together, all casualties involving serious injuries in The Netherlands in 2009 account for about 38,000 YLD, compared to 25,000 years of life lost (YLL) of fatalities. Ninety percent of the burden of injury is due to lifelong consequences that are experienced by 20% of all those seriously injured in road accidents. Lower leg injuries and head injuries represent a high share in the total burden of injury as have cyclists that are injured in a crash without a motorized vehicle. Pedestrians and powered 2-wheeler users show the highest burden of injury per casualty. CONCLUSION: Given their major impacts and contribution to health burden, road policy making should also be aimed at reducing the number of serious road injuries and limiting the resulting health impacts. PMID- 26979092 TI - Universal limiting shape of worn profile under multiple-mode fretting conditions: theory and experimental evidence. AB - We consider multiple-mode fretting wear in a frictional contact of elastic bodies subjected to a small-amplitude oscillation, which may include in-plane and out-of plane translation, torsion and tilting ("periodic rolling"). While the detailed kinetics of wear depends on the particular loading history and wear mechanism, the final worn shape, under some additional conditions, occurs to be universal for all types and loading and wear mechanisms. This universal form is determined solely by the radius of the permanent stick region and the maximum indentation depth during the loading cycle. We provide experimental evidence for the correctness of the theoretically predicted limiting shape. The existence of the universal limiting shape can be used for designing joints which are resistant to fretting wear. PMID- 26979093 TI - Cellulose Acetate Based Nanocomposites for Biomedical Applications: A Review. AB - The development of polymer nanocomposites by incorporating variable nanofillers has attracted attention of scientists, researchers and industrial sectors due to their dramatic improvement in various properties. Cellulose acetate (CA) based nanocomposites have interesting history in the field of medical applications because CA meets a wide range of biomedical implant properties. Since cellulose acetate is considered as a biodegradable, renewable, non-corrosive, non-toxic and biocompatible material, it raised up the unique advantages over many other materials. This review is designed to provide a broad overview of cellulose acetate nanocomposites in the field of medical applications and medical devices. PMID- 26979094 TI - Asthma 2015: The Year in Review. AB - Between January 1, 2015, and the end of October, there were >6,500 peer-reviewed papers listed in PubMed on asthma. Of necessity, those that have been selected for inclusion for this Year in Review represent a few that have caught the reviewer's interest, organized by themes. Not unexpectedly, some of these papers are in conflict with each other, whereas others raise more questions then they appear to answer. All in all, it has been a busy year in the asthma world and with new medications reaching the market in coming years, it is unlikely that this interest will abate. PMID- 26979095 TI - Year in Review 2015: Neonatal Respiratory Care. AB - Neonatal respiratory care practices have changed with breathtaking speed in the past few years. It is critical for the respiratory therapist and others caring for neonates to be up to date with current recommendations and evolving care practices. The purpose of this article is to review papers of particular note that were published in 2015 and address important aspects of newborn respiratory care. PMID- 26979096 TI - Estimating the Prevalence of Sleep-Disordered Breathing Among Collegiate Football Players. AB - BACKGROUND: Obstructive sleep apnea is a clinical disorder characterized by loud snoring, apneic episodes, and chronic sleep disruption. Collegiate football players exhibit several risk factors for OSA, including large neck circumference and high body mass index, although the prevalence of OSA in this cohort is unknown. METHODS: The STOP-BANG questionnaire was administered at random to members of a collegiate football team and used to stratify the players into high and low risk for sleep-disordered breathing (SDB). Those who completed the questionnaire were then evaluated for SDB during preseason camp using a single channel (finger pulse oximetry) photoplethysmography-based device. SDB was defined as an apnea-hypopnea index of >=5. RESULTS: Of 56 players who underwent overnight photoplethysmography monitoring, valid results were available for 51. Forty-eight percent of the players were high-risk (neck size = 44.6 +/- 2.2 cm, body mass index = 33.0 +/- 5.4) versus low-risk (neck size = 41.4 +/- 2.8 cm, body mass index = 27.6 +/- 3.6) (both P values <.001). An apnea-hypopnea index of >=5 was found in 2 (8.3%, 95% CI 1.0-20.0%) high-risk and 2 (7.7, 95% CI 1.0 18.4%) low-risk players. Two offensive linemen, a linebacker, and a tight end accounted for the positive cases. CONCLUSIONS: Based on our sample, we estimate the prevalence of SDB among collegiate football players to be 8%, regardless of risk stratification. Given the strong link between SDB and cardiovascular disease, these data underscore the importance of screening and subsequent treatment of SDB in this highly conditioned yet potentially vulnerable group of athletes. PMID- 26979097 TI - Early-Onset Multiple Sclerosis in Isfahan, Iran: Report of the Demographic and Clinical Features of 221 Patients. AB - It is estimated that early-onset multiple sclerosis multiple sclerosis (early onset multiple sclerosis) approximately incorporates 3-5% of the multiple sclerosis population. In this report on early-onset multiple sclerosis, the authors aimed to define demographic, clinical and imaging features in a case series of true-childhood multiple sclerosis and to compare its characteristics with juvenile multiple sclerosis. The authors inspected the records of multiple sclerosis patients who were registered by Isfahan MS Society. Clinical and demographic data of children with less than 16 years of age were reviewed retrospectively. Out of 4536 multiple sclerosis patients referred to the authors' center, 221 patients (4.8%) had multiple sclerosis starting at the age of 16 or less (11 true-childhood multiple sclerosis vs 210 juvenile-onset multiple sclerosis); the female to male ratio was 4.81:1. In the mean follow-up period of 6.2 years, 22 patients (10.5%) had positive family history of multiple sclerosis, 196 (88.6%) patients were classified as relapsing-remitting multiple sclerosis, the mean (+/- SD Expanded Disability Status Scale) was 1.5 +/- 1.1 at the last evaluation. The most common initial presentation was optic nerve involvement (36.1%) and cerebellar sign and symptoms (14.6%). In all, 13 patients (5.8%) had experienced seizure in the course of multiple sclerosis. This study indicated that early-onset multiple sclerosis is not rare condition and overwhelmingly affects girls even at prepubertal onset. Physicians should consider multiple sclerosis in suspicious pediatric cases. PMID- 26979098 TI - Autism Spectrum Disorders in Africa: Current Challenges in Identification, Assessment, and Treatment: A Report on the International Child Neurology Association Meeting on ASD in Africa, Ghana, April 3-5, 2014. AB - Prevalence of autism spectrum disorders has increased over recent years, however, little is known about the identification and management of autism spectrum disorder in Africa. This report summarizes a workshop on autism spectrum disorder in Africa under the auspices of the International Child Neurology Association and the African Child Neurology Association through guided presentations and working group reports, focusing on identification, diagnosis, management, and community support. A total of 47 delegates participated from 14 African countries. Although there was a huge variability in services across the countries represented, numbers of specialists assessing and managing autism spectrum disorder was small relative to populations served. Strategies were proposed to improve identification, diagnosis, management and support delivery for individuals with autism spectrum disorder across Africa in these culturally diverse, low-resource settings. Emphasis on raising public awareness through community engagement and improving access to information and training in autism spectrum disorder. Special considerations for the cultural, linguistic, and socioeconomic factors within Africa are discussed. PMID- 26979099 TI - Weight loss associated with exenatide in an obese man with diabetes commenced on clozapine. PMID- 26979100 TI - Depression or personality disorder: Autopsy of a mass-homicide. PMID- 26979101 TI - Associations of 5HTTLPR polymorphism with major depressive disorder and alcohol dependence: A systematic review and meta-analysis. AB - OBJECTIVE: The neurotransmitter serotonin is understood to control mood and drug response. Carrying a genetic variant in the serotonin transporter gene (5HTT) may increase the risk of major depressive disorder and alcohol dependence. Previous estimates of the association of the S allele of 5HTTLPR polymorphism with major depressive disorder and alcohol dependence have been inconsistent. METHODS: For the systematic review, we used PubMed MEDLINE and Discovery of The University of Melbourne to search for all relevant case-control studies investigating the associations of 5HTTLPR polymorphism with major depressive disorder and alcohol dependence. Summary odds ratios (OR) and their 95% confidence intervals (CI) were estimated. To investigate whether year of publication, study population or diagnostic criteria used were potential sources of heterogeneity, we performed meta-regression analyses. Publication bias was assessed using Funnel plots and Egger's statistical tests. RESULTS: We included 23 studies of major depressive disorder without alcohol dependence containing 3392 cases and 5093 controls, and 11 studies of alcohol dependence without major depressive disorder containing 2079 cases and 2273 controls. The summary OR for homozygote carriers of the S allele of 5HTTLPR polymorphism compared with heterozygote and non-carriers combined (SS vs SL+LL genotype) was 1.33 (95% CI = [1.19, 1.48]) for major depressive disorder and 1.18 (95% CI = [1.01, 1.38]) for alcohol dependence. The summary OR per S allele of 5HTTLPR polymorphism was 1.16 (95% CI = [1.08, 1.23]) for major depressive disorder and 1.12 (95% CI = [1.01, 1.23]) for alcohol dependence. Meta-regression models showed that the associations did not substantially change after adjusting for year of publication, study population and diagnostic criteria used. There was no evidence for publication bias of the studies included in our meta-analysis. CONCLUSIONS: Our meta-analysis confirms that individuals with the homozygous S allele of 5HTTLPR polymorphism are at increased risks of major depressive disorder as well as alcohol dependence. Further studies are required to investigate the association between 5HTTLPR polymorphism and the comorbidity of major depressive disorder and alcohol dependence as well as gene * environmental interactions. PMID- 26979102 TI - Natural weight loss supplements - Are they psychoactive? PMID- 26979103 TI - Hirschsprung's disease - Postsurgical intestinal dysmotility. AB - OBJECTIVE: To describe the case of an infant with Hirschsprung's disease presenting as total colonic aganglionosis, which, after surgical resection of the aganglionic segment persisted with irreversible functional intestinal obstruction; discuss the difficulties in managing this form of congenital aganglionosis and discuss a plausible pathogenetic mechanism for this case. CASE DESCRIPTION: The diagnosis of Hirschsprung's disease presenting as total colonic aganglionosis was established in a two-month-old infant, after an episode of enterocolitis, hypovolemic shock and severe malnutrition. After colonic resection, the patient did not recover intestinal motor function that would allow enteral feeding. Postoperative examination of remnant ileum showed the presence of ganglionic plexus and a reduced number of interstitial cells of Cajal in the proximal bowel segments. At 12 months, the patient remains dependent on total parenteral nutrition. COMMENTS: Hirschsprung's disease presenting as total colonic aganglionosis has clinical and surgical characteristics that differentiate it from the classic forms, complicating the diagnosis and the clinical and surgical management. The postoperative course may be associated with permanent morbidity due to intestinal dysmotility. The numerical reduction or alteration of neural connections in the interstitial cells of Cajal may represent a possible physiopathological basis for the condition. PMID- 26979105 TI - Flare in axial spondyloarthritis. The dark side of the outcome. PMID- 26979104 TI - Association between rheumatoid arthritis disease activity, progression of functional limitation and long-term risk of orthopaedic surgery: combined analysis of two prospective cohorts supports EULAR treat to target DAS thresholds. AB - OBJECTIVES: To examine the association between disease activity in early rheumatoid arthritis (RA), functional limitation and long-term orthopaedic episodes. METHODS: Health Assessment Questionnaire (HAQ) disability scores were collected from two longitudinal early RA inception cohorts in routine care; Early Rheumatoid Arthritis Study and Early Rheumatoid Arthritis Network from 1986 to 2012. The incidence of major and intermediate orthopaedic surgical episodes over 25 years was collected from national data sets. Disease activity was categorised by mean disease activity score (DAS28) annually between years 1 and 5; remission (RDAS<=2.6), low (LDAS>2.6-3.2), low-moderate (LMDAS>=3.2-4.19), high-moderate (HMDAS 4.2-5.1) and high (HDAS>5.1). RESULTS: Data from 2045 patients were analysed. Patients in RDAS showed no HAQ progression over 5 years, whereas there was a significant relationship between rising DAS28 category and HAQ at 1 year, and the rate of HAQ progression between years 1 and 5. During 27 986 person-years follow-up, 392 intermediate and 591 major surgeries were observed. Compared with the RDAS category, there was a significantly increased cumulative incidence of intermediate surgery in HDAS (OR 2.59 CI 1.49 to 4.52) and HMDAS (OR 1.8 CI 1.05 to 3.11) categories, and for major surgery in HDAS (OR 2.48 CI 1.5 to 4.11), HMDAS (OR 2.16 CI 1.32 to 3.52) and LMDAS (OR 2.07 CI 1.28 to 3.33) categories. There was no significant difference in HAQ progression or orthopaedic episodes between RDAS and LDAS categories. CONCLUSIONS: There is an association between disease activity and both poor function and long-term orthopaedic episodes. This illustrates the far from benign consequences of persistent moderate disease activity, and supports European League Against Rheumatism treat to target recommendations to secure low disease activity or remission in all patients. PMID- 26979106 TI - Changes in gene expression of histone modification enzymes in rat granulosa cells undergoing luteinization during ovulation. AB - BACKGROUND: The ovulatory LH surge rapidly alters the expression of steroidogenesis-related genes such as steroidogenic acute regulatory protein (StAR) in granulosa cells (GCs) undergoing luteinization. We recently reported that histone modifications contribute to these changes. Histone modifications are regulated by a variety of histone modification enzymes. This study investigated the changes in gene expression of histone modification enzymes in rat GCs undergoing luteinization after the induction of ovulation. The extracellular regulated kinase (ERK)-1/2 is a mediator in the intracellular signaling pathway stimulated by the ovulatory LH surge and regulates the expression of a number of genes in GCs. We further investigated whether ERK-1/2 is involved in the regulation of the histone modification at the StAR promoter region in GCs undergoing luteinization. RESULTS: GCs were obtained from rats treated with equine chorionic gonadotropin (CG) before (0 h) and after human (h) CG injection. The expressions of 84 genes regulating histone modifications or DNA methylation were measured using a PCR array. Five genes (HDAC4, HDAC10, EZH2, SETDB2, and CIITA) were identified as histone acetylation- or histone methylation-related genes, and were significantly altered after hCG injection. None of the genes were related to DNA methylation. mRNA levels of EZH2, SETDB2, HDAC4, and HDAC10 decreased and CIITA mRNA levels increased 4 or 12 h after hCG injection. GCs isolated after eCG injection were incubated with hCG for 4 h to induce luteinization. StAR mRNA levels were significantly increased by hCG accompanied by the increase in H3K4me3 of the StAR promoter region. StAR mRNA expression was inhibited by the ERK inhibitor with the significant decrease of H3K4me3. These results suggest that hCG increases StAR gene expression through the ERK-1/2 mediated signaling which is also associated with histone modification of the promoter region. CONCLUSIONS: Gene expressions of histone modification enzymes change in GCs undergoing luteinization after ovulation induction. This change may play important roles in regulating the expression of various genes during the early stage of luteinization, which may be critical for the subsequent corpus luteum formation. PMID- 26979108 TI - Medical students' creative projects on a third year pediatrics clerkship: a qualitative analysis of patient-centeredness and emotional connection. AB - BACKGROUND: Increasingly, medical educators are incorporating reflective writing and original creative work into educational practices with the goals of stimulating student self-awareness, appreciation of multiple perspectives, and comfort with ambiguity and uncertainty. This study investigated students' creative projects to assess the extent to which they adopted a patient/relationship-centered, emotionally connected position toward patients and families. METHODS: Over a 10 year period, students on a required third year pediatrics clerkship individually or in groups completed either a reflection or an education project using a creative medium. 520 projects (representing 595 students, 74.7 % of total eligible students) were qualitatively analyzed according to various thematic and emotion-based dimensions. RESULTS: The majority of projects were personal narrative essays and poetry. The largest number of project themes related to the importance of patient/relationship-centered medicine with patients. The next largest number of projects focused on health education of parents, patients, or classmates. In telling their stories, students were more likely to use a personal voice representing either their or the patient's perspective than an objective, impersonal one. In terms of emotional tone, projects were more likely to be serious than humorous. The largest number of students' emotions expressed an empathic tone. Students identified a large number and wide range of both negative and positive feelings in themselves and their patients. The majority of student emotions were positive, while the majority of patient and family emotions were negative. CONCLUSIONS: Students' preference for patient-centered, relational themes, as well as their tendency to favor the first voice, empathic tone, and willingness to express a range of positive and negative emotions in presenting their projects, suggests that they valued emotional connection with patients and families during the pediatrics clerkship experience. PMID- 26979107 TI - Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer. AB - BACKGROUND: Nanomedicine is a very promising field and nanomedical drugs have recently been used as therapeutic agents against cancer. In a previous study, we showed that Nanoceria (NCe), nanoparticles of cerium oxide, significantly inhibited production of reactive oxygen species, cell migration and invasion of ovarian cancer cells in vitro, without affecting cell proliferation and significantly reduced tumor growth in an ovarian cancer xenograft nude model. Increased expression of folate receptor-alpha, an isoform of membrane-bound folate receptors, has been described in ovarian cancer. To enable NCe to specifically target ovarian cancer cells, we conjugated nanoceria to folic acid (NCe-FA). Our aim was to investigate the pre-clinical efficacy of NCe-FA alone and in combination with Cisplatin. METHODS: Ovarian cancer cell lines were treated with NCe or NCe-FA. Cell viability was assessed by MTT and colony forming units. In vivo studies were carried in A2780 generated mouse xenografts treated with 0.1 mg/Kg NCe, 0.1 mg/Kg; NCe-FA and cisplatinum, 4 mg/Kg by intra peritoneal injections. Tumor weights and burden scores were determined. Immunohistochemistry and toxicity assays were used to evaluate treatment effects. RESULTS: We show that folic acid conjugation of NCe increased the cellular NCe internalization and inhibited cell proliferation. Mice treated with NCe-FA had a lower tumor burden compared to NCe, without any vital organ toxicity. Combination of NCe-FA with cisplatinum decreased the tumor burden more significantly. Moreover, NCe-FA was also effective in reducing proliferation and angiogenesis in the xenograft mouse model. CONCLUSION: Thus, specific targeting of ovarian cancer cells by NCe-FA holds great potential as an effective therapeutic alone or in combination with standard chemotherapy. PMID- 26979109 TI - Mitochondrial DNA homeostasis is essential for nigrostriatal integrity. AB - Mitochondrial involvement in the pathogenesis of Parkinson's disease has been suggested by multiple studies, but the mechanisms involved remain unresolved. Here, we sought to identify which mitochondrial defects are associated with degeneration of the nigrostriatal system. Nigrostriatal integrity was assessed in vivo by dopamine transporter (DAT) imaging in twenty-one patients with mitochondrial disorders of different molecular aetiology including: maternally inherited mitochondrial DNA (mtDNA) point mutations, primary single mtDNA deletions, nuclear-encoded disorders of mtDNA replication and maintenance due to mutations in POLG or C10orf2 (Twinkle), and mutations in other nuclear mitochondrial genes including the mitochondrial aspartyl-tRNA synthetase (DARS2) and ADCK3 genes. Patients with mitochondrial disease were compared with twenty patients with Parkinson's disease and eighteen controls. Nigrostriatal degeneration occurred exclusively in patients with defective mtDNA replication and maintenance. In these patients, nigrostriatal degeneration was progressive and at least as severe as in patients with advanced Parkinson's disease. None of the patients with other mitochondrial defects showed evidence of nigral involvement. Our findings demonstrate that dopaminergic neurons of the substantia nigra are specifically vulnerable to defective mtDNA replication/repair or quality control and not to primary point mutations of mtDNA. These results support the hypothesis that accumulating somatic mtDNA damage plays an important role in neurodegeneration. PMID- 26979112 TI - [Focus on the clinical application of the first artificial bioengineered cornea in China]. AB - Corneal disease ranks second among blinding diseases in China, with the corneal blindness taking up one fourth of the blind population. It has a high incidence and a low rate of sight rehabilitation. The lack of cornea donors and the shortage of corneal specialists have become the bottleneck that hampers the development in curing corneal disease. It is of primal importance to find sufficient donor sources in order to alleviate the current situation. In 2015, the world's first artificial bioengineered cornea was approved by CFDA to be applied clinically as a substitute for human cornea in lamellar keratoplasty. It will not only relieve the cornea donor shortage, but will also spur the training and practices of corneal specialists. The application and clinical trials of such an innovative product will significantly boost fundamental and clinical researches in corneal disease in our country, helping more patients with corneal blindness to recover their sights. PMID- 26979110 TI - Investigating a holobiont: Microbiota perturbations and transkingdom networks. AB - The scientific community has recently come to appreciate that, rather than existing as independent organisms, multicellular hosts and their microbiota comprise a complex evolving superorganism or metaorganism, termed a holobiont. This point of view leads to a re-evaluation of our understanding of different physiological processes and diseases. In this paper we focus on experimental and computational approaches which, when combined in one study, allowed us to dissect mechanisms (traditionally named host-microbiota interactions) regulating holobiont physiology. Specifically, we discuss several approaches for microbiota perturbation, such as use of antibiotics and germ-free animals, including advantages and potential caveats of their usage. We briefly review computational approaches to characterize the microbiota and, more importantly, methods to infer specific components of microbiota (such as microbes or their genes) affecting host functions. One such approach called transkingdom network analysis has been recently developed and applied in our study. (1) Finally, we also discuss common methods used to validate the computational predictions of host-microbiota interactions using in vitro and in vivo experimental systems. PMID- 26979113 TI - [Clinical manifestations of 172 patients with blepharokeratoconjunctivitis]. AB - OBJECTIVE: To summarize the clinical characteristics, diagnosis, and treatment of blepharokeratoconjunctivitis (BKC). METHODS: Retrospective analysis. One hundred and seventy-two patients were diagnosed as BKC between January 2012 and December 2014 at Beijing Tongren Hospital. The clinical characteristics, the degrees of blepharitis and BKC, and the therapeutic effect were evaluated. RESULTS: The patients were aged from 2 to 78 years (mean, 27+/-18 years). Forty-nine patients (28.5%) were males, and 123 patients (71.5%) were females. One hundred and five patients had photograph records of lid margin, cornea, and conjunctiva. BKC was unilateral in 28 (26.7%) of them, and bilateral in 68 (64.8%) with similar degrees and in 9 (8.6%) with different degrees. The disease was mild in 39 patients (40.6%), moderate in 24 patients (25.0%), and severe in 33 patients (34.4%). There was no significant difference in the degree of BKC between males and females (chi(2)=1.022, P=0.600). A total of 1 875 patients were diagnosed as blepharitis during the same period, and 172 patients (9.2%) were complicated by BKC. Female patients with blepharitis were more susceptible to BKC (chi(2)=8.355, P<0.05). Among the children patients with blepharitis, the incidence of BKC was significantly higher than that in the other groups (chi(2)=224.566, P< 0.05), but in the degree of BKC, there was no significant difference among groups. Typical clinical findings consisted of punctuate epithelial and subepithelial haze, stromal infiltrates, corneal ulcer, corneal scar, and corneal pannus. The patients were followed up for 1 to 80 months (mean, 7 months). According to the different degrees of BKC, the patients were given treatment for 1 month. Sixty nine patients (71.9%) had clinical recovery, and the other cases were improved obviously. Nine patients (15 eyes) had recurred BKC during the follow-up period, and the recurrence rate was 9.2%. CONCLUSIONS: BKC is not uncommon in patients suffering blepharitis, with a variety of clinical characteristics. Female and children patients with blepharitis are more susceptible to BKC. It is vital to perform standardized diagnosis and treatment for improvement of therapeutic effect. PMID- 26979114 TI - [Preliminary results of femtosecond laser-assisted Descemet stripping endothelial keratoplasty for bullous keratopathy]. AB - OBJECTIVE: To evaluate the preliminary results of femtosecond laser-assisted Descemet stripping endothelial keratoplasty (FS-DSEK) for the treatment of bullous keratopathy. METHODS: In the nonrandomized, prospective, consecutive case series, 7 eyes with bullous keratopathy induced by cataract surgery received FS DSEK surgery between September and December 2013. Standard Descemet stripping endothelial keratoplasty procedure was performed. The Descemet membrane and abnormal endothelial layer were stripped from the central recipient posterior surface in a diameter of 7.75 mm. The graft was fixed to the edge of recipient cornea with one single stitch. The donor lenticule was produced by Intralase 150 femtosecond laser with a diameter of 7.75 mm. The adherence of donor lenticule to the recipient posterior stroma and postoperative donor lenticule dislocation were monitored in the early stage after surgery. Best spectacle-corrected visual acuity, refraction, endothelial cell density and thickness of grafts were measured preoperatively, and at 1 week, 1, 3, 6 and 12 months after FS-DSEK. RESULTS: Two eyes had graft dislocation, with a gap between the graft and recipent posterior stroma at 2 days after surgery. The grafts were repositioned after bubbles were added into the anterior chamber. All grafts were well adherent to the recipent posterior stromal surface at 1 week postoperatively. One graft failed at 3 months postoperatively, and penetrating keratoplasty was performed. At 12 months, the best spectacle-corrected visual acuity was 0.04 to 0.7, the mean endothelial cell density was (1 698.0+/-251.8) cells/mm(2), and the mean thickness of grafts was (124.2 +/- 11.4) MUm. CONCLUSION: Femtosecond laser assisted Descemet stripping endothelial keratoplasty was effective in treating bullous keratopathy. Stitching the graft to the recipent cornea can prevent postoperative graft dislocation effectively. PMID- 26979111 TI - Medication use and the risk of motor vehicle collision in West Virginia drivers 65 years of age and older: a case-crossover study. AB - BACKGROUND: The current generation of older adults reports a higher lifetime prevalence of prescription, over-the-counter, and recreational drug use. The purpose of this analysis is to characterize the drug usage and determine the risk of motor vehicle collision associated with individual medications in a population of drivers >= 65 years. METHODS: A case-crossover study was conducted at West Virginia University Healthcare's facilities using data obtained from the electronic health records (n = 611) of drivers >= 65 years admitted for medical treatment following a motor vehicle collision which occurred between Jan. 1, 2009 and June 30, 2014. Patients' medication usage 14 days before collision were matched and compared to their medication usage during four control periods prior to collision. Odds ratios were then calculated for the most prevalent individual medications and pharmaceutical sub-classes using conditional logistic regression. RESULTS: Analgesic, cardiovascular and gastrointestinal medicines were common. Few drivers tested positive for either licit or illicit drugs. Of those testing positive for drugs, benzodiazepines and opiates were prevalent. Drivers consuming Tramadol (adjusted OR 11.41; 95% CI 1.27, 102.15) were at a significantly increased risk of motor vehicle collision. CONCLUSIONS: Older adult drivers who have a prescription for this medication may need to be aware of the potential risk. Further research is necessary in a larger, more nationally representative population. PMID- 26979115 TI - [Quantitative analysis of the corneal subbasal nerves in different degrees of dry eye with AutoCAD]. AB - OBJECTIVE: To evaluate the practical value of AutoCAD in quantitative analysis of corneal subbasal epithelial nerves with different degrees of dry eye. METHODS: Ninety patients were divided into groups of mild, moderate, and severe dry eye, 30 patients (60 eyes) in each group. And 30 healthy volunteers were recruited as the normal control group. Confocal microscopy was used to observe the length of the subbasal epithelial nerve plexus. The images were analyzed by AutoCAD software to determine the density (mm/mm(2)), the number of branches, and the curvature score of the subbasal epithelial nerves. These data of patients with dry eye and the controls were statistically compared, by analysis of variance(ANOV). RESULTS: By AutoCAD software, quantitative analysis of the corneal subbasal epithelial nerves was successfully performed. The nerve density in the patients with mild dry eye[(16.70+/-3.43) mm/mm(2)] was not significantly different from the controls[(15.87 +/- 2.75) mm/mm(2)] (P=0.880), but the number of nerval branches 13.43+/-2.46 and the curvature 3.10+/-0.80 increased significantly (P<0.001). The nerve density in the patients with moderate and severe dry eye was significantly different from that in the normal control group (F=114.739, P<0.001). The neural density was significantly lower in the patients with severe dry eye than the controls, but there was no significant difference in the curvature scores between the two groups (P= 0.557). CONCLUSIONS: AutoCAD software is useful in the quantitative analysis of corneal nerve images under a confocal microscope. The corneal subbasal epithelial nerve density, the number of branches, and the curvature of the nerves are related to the degree of dry eye, and may be used as clinical indicators. PMID- 26979116 TI - [An experimental study of mesenchymal stem cells in tissue engineering scaffolds implanted in rabbit corneal lamellae to increase keratoprosthesis biointegration]. AB - OBJECTIVE: To complete a preliminary evaluation of the feasibility of implanting the complex of mouse bone marrow mesenchymal stem cells (BMSC) and a tissue engineering scaffold into rabbit corneal lamellae, based on which a solution may be proposed to consolidate the keratoprosthesis and the recipient surface, and to reduce the risk of complications. METHODS: This experimental study was composed of two parts. (1) In vitro: some mouse BMSC were marked with red fluorescent proteins (RFP) and integrated with a decellularized pig articular cartilage extracellular matrix (ECM) scaffold. The cell survival was observed under a fluorescence microscope at 4 and 8 weeks. The cell distribution was examined by toluidine blue staining. The pore structure and the cell adhesion were observed under a scanning electron microscope. (2) in vivo: the complex of mouse BMSC and a decellularized scaffold was implanted into the lamellar cornea of 8 rabbit eyes with the fellow eyes as the controls. The eyes were sampled for observation using HE staining under a light microscope at 2, 4 and 8 weeks, respectively. The cell survival was examined under a fluorescence microscope, and the intracorneal cell survival at 8 weeks was observed using in vivo imaging. The conditions of ocular anterior segment of all the experimental animals were recorded. RESULTS: (1) Under the scanning electron microscope, the ECM scaffolds showed satisfactory porosity required for the adhesion and growth of cells and tissues, and the cell distribution over the cell-scaffold complex can be observed by toluidine blue staining. (2) Under the immunofluorescence microscope, cell proliferation was observed in vitro and in the interlamellar space (the maximum observation time was 8 weeks) after the RFP-marked mouse BMSC were integrated in vitro with ECM scaffolds. (3) Under the light microscope (HE staining), the stromal cells were detected to increase at each timepoint. A small number of monocytes and some mouse BMSC were observed in the superficial layer of corneal stroma, with sparsely and orderly arranged collagenous fibers and no neovascularization. All the epithelial cells appeared as mononuclear, columnar and undamaged, and the shape of ECM scaffolds, which were fused with the collagens, became unclear. (4) By in vivo imaging, it was found that the mouse BMSC survived for 8 weeks after being integrated with scaffolds and implanted into the interlamellar space of rabbit cornea. (5) After the implantation of cell-scaffold complex, severe postoperative inflammatory reactions, obvious conjunctival congestion and neovascularization were not observed. The corneal tissues surrounding the recipient area were transparent. One week later, mild inflammatory reactions were barely observed, and the cornea was transparent enough to observe the scaffold in the stromal layers. Four weeks later, the scaffolds became thinner. Eight weeks later, the scaffolds became extremely thin with normal vascular system in the corneal limbus. CONCLUSIONS: The ECM scaffold is a solid and biocompatible carrier for the growth and proliferation of BMSC. The mouse BMSC can grow and proliferate in the microenvironment of the interlamellar space of cornea. PMID- 26979117 TI - [Femtosecond lenticule extraction for correction of myopia: clinical results and recovery of subbasal nerves]. AB - OBJECTIVE: To investigate the clinical efficacy, safety, predictability, corneal sensitivity, tear function and recovery of subbasal nerves after femtosecond lenticule extraction (FLEx) and laser in situ keratomileusis (LASIK). METHODS: In this prospective, nonrandomized, comparative clinical study, 49 patients (98 eyes) were divided into two groups. FLEx was performed to treat myopia by Visumax femtosecond laser system, and LASIK was performed by Allegretto Wave laser system. The patients were followed up for 6 months. Visual acuity, manifest refraction, intraocular pressure, slit-lamp examination, corneal topography by Pentacam, tear break-up time, Schirmer test, corneal sensitivity and confocal microscopy were assessed. RESULTS: Forty-four patients (88 eyes) completed the 6 month follow-up. Best corrected visual acuity (BCVA) was 0.89+/-0.14 in eyes with FLEx and 0.98+/-0.08 in eyes with LASIK at 1 day after surgery. After 10 days, BCVA was 0.98+/-0.09 and 1.02+/-0.09, respectively. At the final follow-up visit, the efficacy index was 1.09 in the FLEx group and 1.07 in the LASIK group, and the safety index was 1.12 and 1.07, respectively, in the two groups. Mean Schirmer score was (16.92+/-7.58) mm and (15.03+/-5.89) mm (t=1.316, P=0.192), mean tear break-up time was (8.94+/-2.57) s and (8.00+/-2.39) s (t=1.759, P=0.082), and corneal sensitivity was (56.46+/-4.49) mm and (51.38+/-8.16) mm (t=1.316, P=0.001) in the groups of FLEx and LASIK, respectively. At 10 days after surgery, the number of subbasal nerves was significantly decreased in the FLEx group, and in the LASIK group the subbasal nerve fibers were hardly observed. At 6 months, regenerated nerve fibers were evident in the subbasal area, which recovered faster in eyes with FLEx than in those with LASIK. CONCLUSIONS: Femtosecond lenticule extraction appears to be efficient, safe and predictable for myopia. FLEx surgery is superior over LASIK in less reduction of corneal sensation and lower risk of harm to the subbasal nerve fibers. PMID- 26979118 TI - [TSLPR/STAT5 signaling modulates innate immunity in corneal fibroblasts triggered by Aspergillus fumigatus]. AB - OBJECTIVE: To study the primary role of TSLPR/STAT5 signaling in inflammatory responses triggered by Aspergillus fumigatus(AF) in telomerase-immortalized human stromal fibroblasts (THSF). METHODS: Experimental study. Baseline expression of TSLPR in THSF was assessed by immunofluorescence analysis. Human recombinant TSLP was added. At 5, 15, 30 and 60 min after incubation, cells were harvested for Western blot to assess the protein levels of p-STAT5 and STAT5. After stimulated with AF hyphae for 1, 3, 6, 12, 24 and 48 h, cells were collected for measurement of mRNA of TSLPR and IL-7Ralpha. After incubated with AF hyphae for 12, 24 and 48 h, cells were harvested for Western blot to assess the protein levels of TSLPR, p STAT5 and STAT5. Incubation with anti-TSLPR antibody was performed for 4 h, and at 24 h after AF hyphae were added, cells were harvested to assess the protein levels of p-STAT5 and STAT5. RESULTS: Immunofluorescence staining evidenced that expression of TSLPR was visualized in THSF. Western blot assay showed that p STAT5 protein was increased and peaked at 30 min after stimulation with hTSLP (AF group: 8.87+/-0.75; control group: 1.00+/-0.14; P<0.01). RT-PCR revealed that the expression levels of TSLPR mRNA were increased after incubation with AF hyphae for 3, 6, 12 and 24 h (AF group: 0.000 50+/-0.000 07, 0.001 20+/-0.000 11, 0.002 30+/-0.000 25 and 0.001 70+/-0.000 17; control group: 0.000 20+/-0.000 03, 0.000 20+/-0.000 05, 0.000 20+/-0.000 03 and 0.000 20+/-0.000 04; t=-9.955, -17.329, 16.735 and -18.214, P<0.01), but the expression levels of IL-7Ralpha mRNA were not increased significantly (t=-0.684,-0.029,-0.319,-1.034, P>0.05). In comparison with the control group, after being challenged with AF hyphae for 24 h, both TSLPR and p-STAT5 protein were increased significantly (p-STAT5: 9.46+/ 2.08 vs. 1.00+/-0.06; TSLPR: 1.80+/-0.27 vs. 1.00+/-0.34; t=-7.055, -3.170, P<0.01). Western blot showed that the elevated p-STAT5 expression levels observed after AF hyphae stimulation can be inhibited by TSLPR antibody (anti-TSLPR-AF: 0.55 +/- 0.20; CTR Ab-AF: 1.00 +/- 0.08; t=3.506, P<0.05). CONCLUSION: TSLP/TSLPR/STAT5 signaling pathway plays an important role in inflammatory responses triggered by AF in THSF. PMID- 26979119 TI - [Evaluate the prevalence of trachoma in high risk area of China]. AB - OBJECTIVE: To determine the prevalence of trachoma in urban and rural area in China. To provide the data evidence for the strategies of eliminating trachoma in China. METHODS: Survey was conducted in 13 suspect trachoma high prevalence provinces according to the World Health Organization trachoma grading system and Trachoma Rapid Assessment(TRA). RESULTS: From 2004 to 2007, a total number of examined children which were younger than 10 years old was 59 630. The prevalence of TF was 0.94%. To sum up the data of 2004 and 2005, the prevalence of active trachoma was 1.71% for children.TT and CO was not reported. The results for subjects older than 50 years old showed that the prevalence of TT was 0.34%. We examined 26 857 adults in both 2004 and 2005.The prevalence of TF, TI, TS and CO was 0.03%,0.08%,0.88% and 0.05% respectively. CONCLUSIONS: The prevalence of active trachoma of younger children was under 5%. However,the prevalence of TT of the adults was not reached the target. PMID- 26979120 TI - [Antibody-based agents as experimental therapeutic interventions for corneal allograft rejection]. AB - The corneal allograft rejection is the primary reason for graft failure, but the existing agents are of limited efficacy and may be accompanied by unacceptable morbidity. Recently, antibody-based agents have received great attention and have become an important part of therapeutic intervention for organ transplantation, which is also a research focus in the field of corneal transplantation. This review summarizes the history, current situation and mechanism of antibody-based agents in corneal transplantation. PMID- 26979121 TI - [The research advances of psychological disorder in patients with dry eye]. AB - In clinical practice, dry eye disease (DED) is recognized as one of the most frequent reasons for chronic ocular surface disorder, which can cause the damage to the ocular surface and some symptoms associated with ocular discomfort and impaired visual quality. This common ocular problem is characterized by high incidence and difficulty in treatment. DED can make the visual disturbance and degrade the quality of everyday life and social activities in different levels. Some patients with DED often report psychological changes because of the symptoms of ocular discomfort. This article mainly summarizes the characteristics and mechanism of psychological disorder in patients with DED. PMID- 26979122 TI - [The progress of study about endoplasmic reticulum stress in glaucoma]. AB - In eukaryotic cells, the most secreted proteins and membrane proteins are compounded, modified and folded into the correct structure in the endoplasmic reticulum. Only correctly folded proteins can be transported to the golgi apparatus for further processing. If the endoplasmic reticulum is insufficient to deal with the accumulation of unfolded or misfolded proteins, balance will be broken, and endoplasmic reticulum stress (ERS) will be started. To eliminate the unfolded proteins, cells will activate unfolded protein response (UPR) immediately for self-protection. If the induced ERS is strong or persistent, the UPR could not maintain the balance of homeostasis in endoplasmic reticulum. Then the ERS will lead to C/EBP homologous protein activation and initiate cell apoptosis. The continuous ERS may participate in the occurrence and development of many diseases, such as neurodegenerative diseases and type 2 diabetes. In this article, the research progress of ERS and its relationship with glaucoma is reviewed. PMID- 26979123 TI - Precipitation of a new platelet phase during the quenching of an Al-Zn-Mg-Cu alloy. AB - A previously undescribed high aspect ratio strengthening platelet phase, herein named the Y-phase, has been identified in a commercial Al-Zn-Mg-Cu alloy. Differential scanning calorimetry indicates that this phase only precipitates at temperature and cooling rate of about 150-250 degrees C and 0.05-300 K/s, respectively. This precipitate is shown to be responsible for a noticeable improvement in mechanical properties. Aberration corrected scanning transmission electron microscopy demonstrates the minimal thickness (~1.4 nm) precipitate plates are isostructural to those of the T1 (Al2CuLi) phase observed in Al-Cu-Li alloys. Low voltage chemical analysis by energy dispersive X-ray spectroscopy and electron energy loss spectroscopy gives evidence of the spatial partitioning of the Al, Cu and Zn within the Y-phase, as well as demonstrating the incorporation of a small amount of Mg. PMID- 26979125 TI - A study of the depth and size of concave cube Au nanoparticles as highly sensitive SERS probes. AB - High and uniform near fields are localized at the eight similar sharp corners of cubic gold nanoparticles. Moreover, by introducing concavity in the particle lateral planes, such field intensities can be further increased and tuned in the near infrared region without altering the overall size of the nanoparticles. Herein, we perform a thorough investigation of the morphological, crystallographic and plasmonic properties of concave gold nanocubes (GNCs) in the sub-70 nm size range, for their potential application as highly efficient SERS substrates in size-limiting cases. Theoretical calculations indicate that the highest increment of the near-field is located at the eight sharp tips and, interestingly, a medium near-field increment is also activated over the volume next to the concave surface. Remarkably, the plasmonic response of the concave cubic morphology showed great sensitivity to the concavity degree. Experimental SERS analysis nicely matches the outcome of the theoretical model, confirming that medium-sized concave GNCs (35 nm side length) possess the highest SERS activity upon excitation with a 633 nm laser, whereas larger 61 nm side concave GNCs dominate the optical response at 785 nm. Due to their size-intensity trade off, we envision that such small concave gold nanocubes can provide a highly active and efficient SERS platform for size-limiting applications, especially when near infrared excitations are required. PMID- 26979124 TI - In vivo risk evaluation of carbon-coated iron carbide nanoparticles based on short- and long-term exposure scenarios. AB - BACKGROUND: While carbon-encapsulated iron carbide nanoparticles exhibit strong magnetic properties appealing for biomedical applications, potential side effects of such materials remain comparatively poorly understood. Here, we assess the effects of iron-based nanoparticles in an in vivo long-term study in mice with observation windows between 1 week and 1 year. MATERIALS & METHODS: Functionalized (PEG or IgG) carbon-encapsulated platinum-spiked iron carbide nanoparticles were injected intravenously in mice (single or repeated dose administration). RESULTS: One week after administration, magnetic nanoparticles were predominantly localized in organs of the reticuloendothelial system, particularly the lung and liver. After 1 year, particles were still present in these organs, however, without any evident tissue alterations, such as inflammation, fibrosis, necrosis or carcinogenesis. Importantly, reticuloendothelial system organs presented with normal function. CONCLUSION: This long-term exposure study shows high in vivo compatibility of intravenously applied carbon-encapsulated iron nanoparticles suggesting continuing investigations on such materials for biomedical applications. PMID- 26979126 TI - "This is the way we were raised": Alcohol beliefs and acculturation in relation to alcohol consumption among Native Americans. AB - Native Americans have the highest rates of alcohol use in comparison to other ethnic groups, placing them at risk for experiencing alcohol-related problems. The present study examined the beliefs that some Native Americans may have related to alcohol use; specifically, the belief that alcohol is a key component in Native American cultures. To assess these beliefs, we developed the Stereotypical Alcohol Beliefs Scale for Native Americans (SABSNA). The new 20 item measure was administered to 144 individuals who identified as Native American along with a measure of acculturation and other drinking-related measures, including perceived norms, alcohol expectancies, and drinking motives. An exploratory factor analysis revealed that the measure is unidimensional in structure and has excellent internal consistency. SABSNA scores were found to be positively associated with typical week drinking, alcohol expectancies, and drinking motives (social, coping, enhancement, and conformity). Hierarchical regression analyses revealed that level of acculturation moderated the association between alcohol beliefs and weekly drinking. Native Americans who identified less with mainstream culture demonstrated a positive association between their cultural alcohol beliefs and their weekly drinking. The findings suggest that alcohol beliefs would be an appropriate additional target for interventions for individuals who are not oriented to the mainstream culture. PMID- 26979127 TI - Estimating repetitive spatiotemporal patterns from resting-state brain activity data. AB - Repetitive spatiotemporal patterns in spontaneous brain activities have been widely examined in non-human studies. These studies have reported that such patterns reflect past experiences embedded in neural circuits. In human magnetoencephalography (MEG) and electroencephalography (EEG) studies, however, spatiotemporal patterns in resting-state brain activities have not been extensively examined. This is because estimating spatiotemporal patterns from resting-state MEG/EEG data is difficult due to their unknown onsets. Here, we propose a method to estimate repetitive spatiotemporal patterns from resting state brain activity data, including MEG/EEG. Without the information of onsets, the proposed method can estimate several spatiotemporal patterns, even if they are overlapping. We verified the performance of the method by detailed simulation tests. Furthermore, we examined whether the proposed method could estimate the visual evoked magnetic fields (VEFs) without using stimulus onset information. The proposed method successfully detected the stimulus onsets and estimated the VEFs, implying the applicability of this method to real MEG data. The proposed method was applied to resting-state functional magnetic resonance imaging (fMRI) data and MEG data. The results revealed informative spatiotemporal patterns representing consecutive brain activities that dynamically change with time. Using this method, it is possible to reveal discrete events spontaneously occurring in our brains, such as memory retrieval. PMID- 26979128 TI - Spectrum of ocular manifestations in cobalamin C and cobalamin A types of methylmalonic acidemia. AB - BACKGROUND: Cobalamin C disease (cblC), which leads to methylmalonic acidemia with homocystinuria, is the most common inherited disorder of vitamin B12 metabolism. Reported ocular findings associated with cblC have been maculopathy, pigmentary retinopathy, and optic nerve atrophy. Cobalamin A disease (cblA) which causes an isolated methylmalonic acidemia without homocystinuria is rarer than cblC. This is the first detailed report of the ocular findings associated with cblA. We also describe the spectrum of ocular findings in our cblC patients. MATERIALS AND METHODS: A case series describing the ophthalmologic clinical course of six patients with a diagnosis of cobalamin C type and one patient with cobalamin A type of methylmalonic acidemia. Patients were diagnosed through biochemical laboratory testing and genetic analysis was conducted on most patients. Longitudinal fundus findings, optical coherence tomography (OCT), autofluorescence, and electrophysiology were followed in the patients. RESULTS: The cblA patient demonstrated a relatively mild ocular phenotype with late-onset and slowly progressing temporal disc pallor and peripapillary atrophy in the second decade of life. The patient maintained good visual acuity and central vision, without evidence of maculopathy. The six cblC patients demonstrated a range of ocular findings from unremarkable and mild phenotypes to significant retinopathy, including bull's eye maculopathy, severe maculopathy with punched out chorioretinal atrophy, peripheral bone spicules, and optic nerve atrophy. CONCLUSIONS: The spectrum of ocular manifestations seen with inherited disorders of cobalamin metabolism is wide, ranging from mild optic nerve atrophy to severe macular or retinal degeneration. This heterogeneity may in part reflect the associated biochemical phenotype, such as that observed between our cblA and cblC patients. We also observed heterogeneity within the cblC type in agreement with previous reports. PMID- 26979129 TI - Self-Organizing Maps-based ocean currents forecasting system. AB - An ocean surface currents forecasting system, based on a Self-Organizing Maps (SOM) neural network algorithm, high-frequency (HF) ocean radar measurements and numerical weather prediction (NWP) products, has been developed for a coastal area of the northern Adriatic and compared with operational ROMS-derived surface currents. The two systems differ significantly in architecture and algorithms, being based on either unsupervised learning techniques or ocean physics. To compare performance of the two methods, their forecasting skills were tested on independent datasets. The SOM-based forecasting system has a slightly better forecasting skill, especially during strong wind conditions, with potential for further improvement when data sets of higher quality and longer duration are used for training. PMID- 26979130 TI - Role of CD20 expression and other pre-treatment risk factors in the development of infusion-related reactions in patients with CLL treated with obinutuzumab. PMID- 26979131 TI - Assessment of medical waste management in seven hospitals in Lagos, Nigeria. AB - BACKGROUND: Medical waste (MW) can be generated in hospitals, clinics and places where diagnosis and treatment are conducted. The management of these wastes is an issue of great concern and importance in view of potential public health risks associated with such wastes. The study assessed the medical waste management practices in selected hospitals and also determined the impact of Lagos Waste Management Authority (LAWMA) intervention programs. A descriptive cross-sectional survey method was used. METHODS: Data were collected using three instrument (questionnaire, site visitation and in -depth interview). Two public (hospital A, B) and five private (hospital C, D, E, F and G) which provide services for low, middle and high income earners were used. Data analysis was done with SPSS version 20. Chi-squared test was used to determine level of significance at p < 0.05. RESULTS: The majority 56 (53.3%) of the respondents were females with mean age of 35.46 (+/-1.66) years. The hospital surveyed, except hospital D, disposes both general and medical waste separately. All the facilities have the same process of managing their waste which is segregation, collection/on-site transportation, on-site storage and off-site transportation. Staff responsible for collecting medical waste uses mainly hand gloves as personal protective equipment. The intervention programs helped to ensure compliance and safety of the processes; all the hospitals employ the services of LAWMA for final waste disposal and treatment. Only hospital B offered on-site treatment of its waste (sharps only) with an incinerator while LAWMA uses hydroclave to treat its wastes. There are no policies or guidelines in all investigated hospitals for managing waste. CONCLUSIONS: An awareness of proper waste management amongst health workers has been created in most hospitals through the initiative of LAWMA. However, hospital D still mixes municipal and hazardous wastes. The treatment of waste is generally done by LAWMA using hydroclave, to prevent environmental hazards except hospital B that treats its sharp with an incinerator. In order to enhance uniform and appropriate waste management practices in the entire State, there is need for capacity building at all levels and also policies and guidelines formulations. PMID- 26979132 TI - Neuropsychological assessment of a veteran with a large arachnoid cyst. AB - Arachnoid cysts are benign, congenital masses that are believed to form when the arachnoid membrane splits or is duplicated and the resulting space fills with fluid. Despite their potentially alarming appearance on brain imaging, congenital cysts discovered in adulthood are usually silent and do not result in functional impairment. A left-handed male veteran with mild memory complaints was discovered to have a large (16.4 cm * 7.7 cm), left-sided arachnoid cyst. Magnetic resonance imaging (MRI) revealed significant displacement of brain structures including the hippocampus, Sylvan fissure, and splenium. Viewing brain MRI images in only 1 plane was misleading and could have erroneously resulted in assuming some structures were absent. Viewing multiple planes of section revealed significant structural displacement and provided a better 3-dimensional conceptualization of an abnormal brain. A clinical interview indicated excellent premorbid functioning, and neuropsychological test results were within the normal range with the exception of mildly impaired scores on tests reliant on processing speed and lower-than-expected visual memory scores. Results were consistent with previous research noting retained verbal abilities and low-average visual skills. Low-average and mildly impaired scores were potentially secondary to microvascular changes, slowed visual scanning, psychiatric conditions, and testing base rates. PMID- 26979134 TI - Pyrolysis of the Simplest Carbohydrate, Glycolaldehyde (CHO-CH2OH), and Glyoxal in a Heated Microreactor. AB - Both glycolaldehyde and glyoxal were pyrolyzed in a set of flash-pyrolysis microreactors. The pyrolysis products resulting from CHO-CH2OH and HCO-CHO were detected and identified by vacuum ultraviolet (VUV) photoionization mass spectrometry. Complementary product identification was provided by argon matrix infrared absorption spectroscopy. Pyrolysis pressures in the microreactor were about 100 Torr, and contact times with the microreactors were roughly 100 MUs. At 1200 K, the products of glycolaldehyde pyrolysis are H atoms, CO, CH2?O, CH2?C?O, and HCO-CHO. Thermal decomposition of HCO-CHO was studied with pulsed 118.2 nm photoionization mass spectrometry and matrix infrared absorption. Under these conditions, glyoxal undergoes pyrolysis to H atoms and CO. Tunable VUV photoionization mass spectrometry provides a lower bound for the ionization energy (IE)(CHO-CH2OH) >= 9.95 +/- 0.05 eV. The gas-phase heat of formation of glycolaldehyde was established by a sequence of calorimetric experiments. The experimental result is DeltafH298(CHO-CH2OH) = -75.8 +/- 1.3 kcal mol(-1). Fully ab initio, coupled cluster calculations predict DeltafH0(CHO-CH2OH) of -73.1 +/- 0.5 kcal mol(-1) and DeltafH298(CHO-CH2OH) of -76.1 +/- 0.5 kcal mol(-1). The coupled-cluster singles doubles and noniterative triples correction calculations also lead to a revision of the geometry of CHO-CH2OH. We find that the O-H bond length differs substantially from earlier experimental estimates, due to unusual zero-point contributions to the moments of inertia. PMID- 26979133 TI - Centenarians' offspring as a model of healthy aging: a reappraisal of the data on Italian subjects and a comprehensive overview. AB - Within the scenario of an increasing life expectancy worldwide it is mandatory to identify determinants of healthy aging. Centenarian offspring (CO) is one of the most informative model to identify trajectories of healthy aging and their determinants (genetic and environmental), being representative of elderly in their 70th whose lifestyle can be still modified to attain a better health. This study is the first comprehensive investigation of the health status of 267 CO (mean age: 70.2 years) and adopts the innovative approach of comparing CO with 107 age-matched offspring of non-long-lived parents (hereafter indicated as NCO controls), recruited according to strict inclusion demographic criteria of Italian population. We adopted a multidimensional approach which integrates functional and cognitive assessment together with epidemiological and clinical data, including pro- and anti-inflammatory cytokines and adipokines, lipid profile, and insulin resistance. CO have a lower prevalence of stroke, cerebral thrombosis-hemorrhage, hypertension, hypercholesterolemia, and other minor diseases, lower BMI and waist circumference, a better functional and cognitive status and lower plasma level of FT4 compared to NCO controls. We conclude that a multidimensional approach is a reliable strategy to identify the health status of elderly at an age when interventions to modify their health trajectory are feasible. PMID- 26979135 TI - Status of vaccine research and development for Shigella. AB - Shigella are gram-negative bacteria that cause severe diarrhea and dysentery. In 2013, Shigella infections caused an estimated 34,400 deaths in children less than five years old and, in 2010, an estimated 40,000 deaths in persons older than five years globally. New disease burden estimates from newly deployed molecular diagnostic assays with increased sensitivity suggest that Shigella-associated morbidity may be much greater than previous disease estimates from culture-based methods. Primary prevention of this disease should be based on universal provision of potable water and sanitation methods and improved personal and food hygiene. However, an efficacious and low-cost vaccine would complement and accelerate disease reduction while waiting for universal access to water, sanitation, and hygiene improvements. This review article provides a landscape of Shigella vaccine development efforts. No vaccine is yet available, but human and animal challenge-rechallenge trials with virulent Shigella as well as observational studies in Shigella-endemic areas have shown that the incidence of disease decreases following Shigella infection, pointing to biological feasibility of a vaccine. Immunity to Shigella appears to be strain-specific, so a vaccine that covers the most commonly detected strains (i.e., S. flexneri 2a, 3a, 6, and S. sonnei) or a vaccine using cross-species conserved antigens would likely be most effective. Vaccine development and testing may be accelerated by use of animal models, such as the guinea pig keratoconjunctivitis or murine pneumonia models. Because there is no correlate of protection, however, human studies will be necessary to evaluate vaccine efficacy prior to deployment. A diversity of Shigella vaccine constructs are under development, including live attenuated, formalin-killed whole-cell, glycoconjugate, subunit, and novel antigen vaccines (e.g., Type III secretion system and outer membrane proteins). PMID- 26979136 TI - Randomized, double-blind, active-controlled study evaluating the safety and immunogenicity of three vaccination schedules and two dose levels of AV7909 vaccine for anthrax post-exposure prophylaxis in healthy adults. AB - AV7909 vaccine being developed for post-exposure prophylaxis of anthrax disease may require fewer vaccinations and reduced amount of antigen to achieve an accelerated immune response over BioThrax((r)) (Anthrax Vaccine Adsorbed). A phase 2, randomized, double-blind, BioThrax vacccine-controlled study was conducted to evaluate the safety and immunogenicity of three intramuscular vaccination schedules and two dose levels of AV7909 in 168 healthy adults. Subjects were randomized at a 4:3:2:4:2 ratio to 5 groups: (1) AV7909 on Days 0/14; (2) AV7909 on Days 0/28; (3) AV7909 on Days 0/14/28; (4) half dose AV7909 on Days 0/14/28; and (5) BioThrax vaccine on Days 0/14/28. Vaccinations in all groups were well tolerated. The incidences of adverse events (AEs) were 79% for AV7909 subjects and 65% for BioThrax subjects; 92% of AV7909 subjects and 87% of BioThrax subjects having AEs reported Grade 1-2 AEs. No serious AEs were assessed as potentially vaccine-related, and no AEs of potential autoimmune etiology were reported. There was no discernible pattern indicative of a safety concern across groups in the incidence or severity of reactogenicity events. Groups 2-4 achieved success for the primary endpoint, demonstrated by a lower 95% confidence limit of the percentage of subjects with protective toxin neutralizing antibody NF50 values (>=0.56) to be >=40% at Day 63. Group 1 marginally missed the criterion (lower bound 95% confidence limit of 39.5%). Immune responses were above this threshold for Groups 1, 3 and 4 at Day 28 and all groups at Day 42. Further study of an AV7909 two-dose schedule given 2 weeks apart is warranted in light of the favorable tolerability profile and immunogenicity response relative to three doses of BioThrax vaccine, as well as preliminary data from nonclinical studies indicating similar immune responses correlate with higher survival for AV7909 than BioThrax vaccine. PMID- 26979137 TI - Acceptability of financial incentives or quasi-mandatory schemes to increase uptake of immunisations in preschool children in the United Kingdom: Qualitative study with parents and service delivery staff. AB - INTRODUCTION: Since the 1990 s strenuous attempts have been made to rebuild trust in childhood immunisations. This study aimed to understand if financial incentives (FI) or quasi-mandatory schemes (QMS), e.g. mandating immunisations for entry to universal services such as day care or school, might be acceptable interventions to increase immunisations uptake for preschool children. MATERIAL AND METHODS: Parents and carers of preschool children (n=91); health and other professionals (n=18); and those responsible for developing and commissioning immunisation services (n=6) took part in the study. Qualitative methods were employed to explore the acceptability of FI/QMS with stakeholders. Framework analysis was used to develop a coding framework that was applied to the whole dataset. Interpretations of the emergent themes were verified between researchers and presented to the project's Parent Reference Group to ensure coherence and relevance. RESULTS: (1) FI: parents and professionals felt introducing FI was inappropriate. It was acknowledged FI may encourage families living in disadvantage to prioritise immunisation, but unintended consequences could outweigh any advantage. FI essentially changes behaviour into a cash transaction which many equated to bribery that could inadvertently create inequalities. (2) QMS: parents and professionals highlighted the positives of introducing QMS, stating it felt natural, fair and less likely to create inequality. Despite QMS' potential to positively impact on uptake there were concerns about the implementation and workability of such schemes. DISCUSSION AND CONCLUSION: FI for preschool immunisation may not be acceptable, within a UK context. Introducing FI could have detrimental effects on uptake if it were associated with bribery and coercion. Quasi-mandatory schemes, mandating immunisation for universal service entry, was the most acceptable option and could contribute to the normalising of immunisation. Future work would be needed to assess how this could be successfully implemented and if it did indeed increase uptake. PMID- 26979138 TI - CAPECO: Cost evaluation of community acquired pneumonia managed in primary care. AB - BACKGROUND: Estimating the economic burden of community acquired pneumonia (CAP) managed in ambulatory setting is needed in France since no data are available. METHOD: A retrospective study (CAPECO) was conducted based on a prospective French study describing patients with suspected CAP managed in primary care (CAPA). The aim of the CAPECO study was to estimate and explain medical costs of a disease episode in CAP patients only followed in ambulatory care and in hospitalised patients. Primary endpoints were the direct medical costs, impact on productivity and costs of incident CAP over one year. Secondary endpoint was to describe predictive factors of costs, hospital admission and stay length. RESULTS: In this cohort of 886 patients, resulting in an incidence of CAP of 400 per 100,000 inhabitants per year, the mean direct medical cost of a disease episode of CAP was ? 118.8 for strictly ambulatory patients with an equal weight for medical time, drugs, diagnostic procedures and tests. This direct cost was ? 102.1 before admission for patients who were finally hospitalised. The mean cost of hospital admissions was ? 3522.9. Main predictive factors of hospital admission and stay length were respectively a history of chronic respiratory disease and older age. Factors of direct medical cost were prescribing X-ray examination and having a positive X-ray. The impact of a disease episode on productivity was ? 1980 (sd 1400) per ambulatory episode and ? 5425 (sd 4760) per episode leading to hospital admission. CONCLUSION: Costs per ambulatory episode were modest but increased substantially in hospitalised patients, who were more numerous when chronic respiratory disorders were present and in the elderly. Indirect costs were significant. Deciders should thus consider both direct and indirect costs when assessing preventive interventions in the context of this disease. PMID- 26979139 TI - The application of exfoliated graphite electrode in the electrochemical degradation of p-nitrophenol in water. AB - We report the application of exfoliated graphite (EG) as an electrode material in the electrochemical degradation of p-nitrophenol in water. Bulk electrolysis (degradation) of p-nitrophenol was carried out at a potential of 2.0 V (vs. Ag/AgCl) in the presence of 0.1 M Na2SO4 supporting electrolyte, while UV-Vis spectrophotometry was used to monitor the degradation efficiency. An initial p nitrophenol load concentration of 0.2 mM for 3 h electrolysis time was studied under the optimized conditions of pH 7, and 10 mAcm(-2) current density. The electro-degradation reaction displayed a pseudo-first-order kinetic behavior with a rate constant (k(r)) of 11*10(-3) min(-1). The removal efficiency was found to be 91.5%. Chromatography coupled with time of flight mass spectrometry revealed p benzoquinone as a major intermediate product. These results demonstrate the potential and viability of electrochemical technology as an alternative approach to water treatment using a low cost graphite electrode. PMID- 26979140 TI - A contemporary review of paediatric heart transplantation and mechanical circulatory support. AB - Improvements in the care of children with cardiomyopathy, CHDs, and acquired heart disease have led to an increased number of children surviving with advanced heart failure. In addition, the advent of more durable mechanical circulatory support options in children has changed the outcome for many patients who otherwise would have succumbed while waiting for heart transplantation. As a result, more children with end-stage heart failure are being referred for heart transplantation, and there is increased demand for a limited donor organ supply. A review of important publications in the recent years related to paediatric heart failure, transplantation, and mechanical circulatory support show a trend towards pushing the limits of the current therapies to address the needs of this growing population. There have been a number of publications focussing on previously published risk factors perceived as barriers to successful heart transplantation, including elevated pulmonary vascular resistance, medication non adherence, re-transplantation, transplantation of the failed Fontan patient, and transplantation in an infant or child bridged with mechanical circulatory support. This review will highlight some of these key articles from the last 3 years and describe recent advances in the understanding, diagnosis, and management of children with end-stage heart disease. PMID- 26979142 TI - PGX: Pharmacogenomics During Generation X. PMID- 26979143 TI - It is all About "ADME". PMID- 26979141 TI - Linalool isomerase, a membrane-anchored enzyme in the anaerobic monoterpene degradation in Thauera linaloolentis 47Lol. AB - BACKGROUND: Thauera linaloolentis 47Lol uses the tertiary monoterpene alcohol (R,S)-linalool as sole carbon and energy source under denitrifying conditions. The conversion of linalool to geraniol had been observed in carbon-excess cultures, suggesting the presence of a 3,1-hydroxyl-Delta(1)-Delta(2)-mutase (linalool isomerase) as responsible enzyme. To date, only a single enzyme catalyzing such a reaction is described: the linalool dehydratase/isomerase (Ldi) from Castellaniella defragrans 65Phen acting only on (S)-linalool. RESULTS: The linalool isomerase activity was located in the inner membrane. It was enriched by subcellular fractionation and sucrose gradient centrifugation. MALDI-ToF MS analysis of the enriched protein identified the corresponding gene named lis that codes for the protein in the strain with the highest similarity to the Ldi. Linalool isomerase is predicted to have four transmembrane helices at the N terminal domain and a cytosolic domain. Enzyme activity required a reductant for activation. A specific activity of 3.42 +/- 0.28 nkat mg * protein(-1) and a kM value of 455 +/- 124 MUM were determined for the thermodynamically favored isomerization of geraniol to both linalool isomers at optimal conditions of pH 8 and 35 degrees C. CONCLUSION: The linalool isomerase from T. linaloolentis 47Lol represents a second member of the enzyme class 5.4.4.4, next to the linalool dehydratase/isomerase from C. defragrans 65Phen. Besides considerable amino acid sequence similarity both enzymes share common characteristics with respect to substrate affinity, pH and temperature optima, but differ in the dehydratase activity and the turnover of linalool isomers. PMID- 26979144 TI - Drug Disposition Issues in CKD: Implications for Drug Discovery and Regulatory Approval. AB - Patients with chronic kidney disease (CKD) have several comorbidities that require pharmacologic intervention including hypertension, diabetes, anemia, and cardiovascular disease. Advanced CKD patients (eg, treated with hemodialysis) take an average of 12 medications concurrently and are known to suffer from an increased number of medication-related adverse drug events. Recent basic and clinical research has identified altered renal and nonrenal drug clearance in CKD as one mediator of the increased adverse drug events observed in this patient population. This review will briefly describe pharmacokinetic considerations in CKD, review the Food and Drug Administration guidelines for performing pharmacokinetic studies in CKD patients, and outline the roles of academia, industry, and regulatory agencies in improving drug safety in CKD patients. PMID- 26979146 TI - Drug Transporter Function--Implications in CKD. AB - Drug transporters typically move substrates, including drugs, in an intracellular to extracellular direction and thus are efflux transporters. There is a small subset of transporters that move substrates in the opposite direction and are classified as influx transporters. Collectively, drug transporters contribute to the pharmacokinetic profile of a wide variety of drugs and other molecules including xenobiotics, metabolites, and endogenous solutes. Identification of genetic variants in the genes that encode these transporters is an emerging area of pharmacogenomics. Many polymorphisms of the multitude of genes that code for the transporters within the 2 major superfamilies (ATP-binding cassette transporters and solute carrier transporters) have been identified. Studies have shown that many single-nucleotide polymorphisms are associated with changes in protein expression, functionality, and drug exposure; however, there are limited data for most single-nucleotide polymorphisms and impact on clinical end points. Preliminary data suggest that patients with CKD may have reduced transporter function that may have effects on exposure and toxicity profiles. Additional research translating the functional significance of polymorphisms on clinical pharmacokinetics and relevant disease-specific end points will provide further understanding of the role of genetic variations in transporter genes. PMID- 26979145 TI - The Effects of CKD on Cytochrome P450-Mediated Drug Metabolism. AB - CKD affects a significant proportion of the world's population, and the prevalence of CKD is increasing. Standard practice currently is to adjust the dose of renally eliminated medications as kidney function declines in effort to prevent adverse drug reactions. It is increasingly becoming recognized that CKD also impacts nonrenal clearance mechanisms such as hepatic and intestinal cytochrome P450 (CYP) enzymes and drug transport proteins, the latter of which is beyond the scope of this review. CYPs are responsible for the metabolism of many clinically used drugs. Genetics, patient factors (eg, age and disease) and drug interactions are well known to affect CYP metabolism resulting in variable pharmacokinetics and responses to medications. There now exists an abundance of evidence demonstrating that CKD can impact the activity of many CYP isoforms either through direct inhibition by circulating uremic toxins and/or by reducing CYP gene expression. Evidence suggests that reductions in CYP metabolism in ESRD are reversed by kidney transplantation and temporarily restored via hemodialysis. This review summarizes the current understanding of the effects that CKD can have on CYP metabolism and also discusses the impact that CYP metabolism phenotypes can have on the development of kidney injury. PMID- 26979148 TI - A Physiologic Approach to the Pharmacogenomics of Hypertension. AB - Hypertension is a multifactorial condition with diverse physiological systems contributing to its pathogenesis. Individuals exhibit significant variation in their response to antihypertensive agents. Traditional markers, such as age, gender, diet, plasma renin level, and ethnicity, aid in drug selection. However, this review explores the contribution of genetics to facilitate antihypertensive agent selection and predict treatment efficacy. The findings, reproducibility, and limitations of published studies are examined, with emphasis placed on candidate genetic variants affecting drug metabolism, the renin-angiotensin system, adrenergic signalling, and renal sodium reabsorption. Single-nucleotide polymorphisms identified and replicated in unbiased genome-wide association studies of hypertension treatment are reviewed to illustrate the evolving understanding of the disease's complex and polygenic pathophysiology. Implementation efforts at academic centers seek to overcome barriers to the broad adoption of pharmacogenomics in the treatment of hypertension. The level of evidence required to support the implementation of pharmacogenomics in clinical practice is considered. PMID- 26979149 TI - Role of Pharmacogenomics in Kidney Disease and Injury. AB - There has been considerable excitement in the kidney community surrounding the research findings on the genetic contributions to kidney diseases. However, positive outcomes of personalized therapeutic interventions can be circumvented by unpredictable pharmacokinetics of prescribed drugs. Furthermore, unpredictable drug disposition can result in toxicities such as kidney injury. Patient covariates, disease covariates, and pharmacogenetics all contribute to variability in drug disposition. Further treatment personalization and avoidance of drug- and biologic- induced kidney injury will require extensive knowledge and expertise in renal clinical pharmacology. The current review will focus on the pharmacogenetics of drugs and biologics used in the treatment of glomerular kidney diseases and drugs implicated in inducing kidney injury phenotypes. PMID- 26979147 TI - Cardiovascular Pharmacogenomics--Implications for Patients With CKD. AB - CKD is an independent risk factor for cardiovascular disease (CVD). Thus, patients with CKD often require treatment with cardiovascular drugs, such as antiplatelet, antihypertensive, anticoagulant, and lipid-lowering agents. There is significant interpatient variability in response to cardiovascular therapies, which contributes to risk for treatment failure or adverse drug effects. Pharmacogenomics offers the potential to optimize cardiovascular pharmacotherapy and improve outcomes in patients with CVD, although data in patients with concomitant CKD are limited. The drugs with the most pharmacogenomic evidence are warfarin, clopidogrel, and statins. There are also accumulating data for genetic contributions to beta-blocker response. Guidelines are now available to assist with applying pharmacogenetic test results to optimize warfarin dosing, selection of antiplatelet therapy after percutaneous coronary intervention, and prediction of risk for statin-induced myopathy. Clinical data, such as age, body size, and kidney function have long been used to optimize drug prescribing. An increasing number of institutions are also implementing genetic testing to be considered in the context of important clinical factors to further personalize drug therapy for patients with CVD. PMID- 26979151 TI - Comparison of fitness traits and their plasticity on multiple plants for Sitobion avenae infected and cured of a secondary endosymbiont. AB - Regiella insecticola has been found to enhance the performance of host aphids on certain plants, but its functional role in adaptation of host aphids to plants is still controversial. Here we evaluate the impacts of R. insecticola infections on vital life-history traits of Sitobion avenae (Fabricius), and their underlying genetic variation and phenotypic plasticity on three plants. It was shown that effects of R. insecticola on S. avenae's fitness (i.e., developmental time and fecundity) were neutral on oat or wheat, but negative on rye. Infections of R. insecticola modified genetic variation that underlies S. avenae's life-history traits. This was demonstrated by comparing life-history trait heritabilities between aphid lines with and without R. insecticola. Moreover, there were enhanced negative genetic correlations between developmental time and fecundity for R. insecticola infected lines, and structural differences in G-matrices of life-history traits for the two types of aphid lines. In R. insecticola-infected aphid lines, there were increases in plasticities for developmental times of first and second instar nymphs and for fecundity, showing novel functional roles of bacterial symbionts in plant-insect interactions. The identified effects of R. insecticola infections could have significant implications for the ecology and evolution of its host populations in natural conditions. PMID- 26979150 TI - Genomics in CKD: Is This the Path Forward? AB - Recent advances in genomics and sequencing technology have led to a better understanding of genetic risk in CKD. Genetics could account in part for racial differences in treatment response for medications including antihypertensives and immunosuppressive medications due to its correlation with ancestry. However, there is still a substantial lag between generation of this knowledge and its adoption in routine clinical care. This review summarizes the recent advances in genomics and CKD, discusses potential reasons for its underutilization, and highlights potential avenues for application of genomic information to improve clinical care and outcomes in this particularly vulnerable population. PMID- 26979153 TI - Advances in and hope for the treatment of parasitosis. PMID- 26979152 TI - Analysis of the mechanical properties of wild type and hyperstable mutants of the HIV-1 capsid. AB - BACKGROUND: The human immunodeficiency virus (HIV-1) capsid is a self-assembled protein shell that contains the viral genome. During the stages between viral entry into a host cell and nuclear import of the viral DNA, the capsid dissociates in a process known as uncoating, which leads to the release of the viral genetic material. Mutations that alter the stability of the capsid affect the uncoating rate and impair HIV-1 infectivity. RESULTS: To gain further insight into the role of capsid stability during uncoating, we used atomic force spectroscopy to quantify the stiffness of the capsid. Empty in vitro assemblies of wild type (WT) and mutant recombinant HIV-1 capsid protein (CA) as well as isolated WT and mutant HIV-1 cores (i.e., filled capsids) were analyzed. We find that hyperstable CA mutant assemblies (A204C, A14C/E45C, E45A and E45A/R132T) are significantly stiffer than WT assemblies. However, the hardening effect of disulfide crosslinking (A204C and A14C/E45C) is lower than that of hydrophobic interactions (E45A and E45A/R132T). CONCLUSIONS: Our results demonstrate that mutations that increase the intrinsic stability of the HIV-1 capsid have an increased stiffness of their lattice. PMID- 26979154 TI - Differential effects of a short-term high-fat diet in an animal model of depression in rats treated with the 5-HT3 receptor antagonist, ondansetron, the 5 HT3 receptor agonist, 2-methyl-5-HT, and the SSRI, fluoxetine. AB - Investigation into the effects of a high-fat diet on depression in the context of 5-HT3 receptor function is important given 5-HT3 antagonism may represent a novel candidate for drug discovery. To more fully understand the relationship between the 5-HT3 receptor system, depression, and high-fat intake, our main interest was to study the short-term effects of a high-fat diet on the 5-HT3 receptor antagonist, ondansetron, and the 5-HT3 receptor agonist, 2-methyl-5-HT, as well as the SSRI, fluoxetine, in an animal model of depression. Male Sprague Dawley rats were fed either a standard diet (11% fat) or a high-fat diet (32.5% fat) for seven days then treated with either fluoxetine (10mg/kg, ip), ondansetron (1mg/kg, ip), 2-methyl-5-HT (3mg/kg, ip), fluoxetine+ondansetron or, 2-methyl-5 HT+ondansetron prior to the Forced Swim Test. In the standard diet group, treatment with the 5HT3 receptor agonist, 2-methyl-5-HT, served to significantly decrease time of immobility as compared to controls thus showing anti-depressive like effects. Treatment with the 5-HT3 receptor antagonist, ondansetron, served to enhance the anti-depressive like effects of the SSRI, fluoxetine, as treatment with both the SSRI and 5-HT3 receptor antagonist dramatically decreased immobility. Importantly, in the high-fat diet groups, a week of high-fat intake served to: 1) counteract the anti-depressive-like effect of the SSRI, fluoxetine, 2) reverse the anti-depressive-like effect of the 5HT3 receptor agonist, 2-methyl 5-HT and 3) provide protection against the depressive-like effects induced by the Forced Swim Test as rats fed a high-fat diet displayed the lowest amounts of immobility. In the aggregate, these data suggest that both SSRIs and the 5HT3 receptor system are affected by short-term high-fat intake and that a short-term high-fat diet protects against depressive-like effects in an animal model of depression. PMID- 26979155 TI - Design and synthesis of natural product derivatives with selective and improved cytotoxicity based on a sesquiterpene scaffold. AB - Brasilamide E (1) is a bisabolane sesquiterpenoid isolated from the solid substrate fermentation cultures of a plant endophytic fungus Paraconiothyrium brasiliense. The compound specifically inhibited proliferation of the MCF-7 cells, but did not show cytotoxicity towards the negative controls HaCaT and NIH3T3 cells (IC50>50 MUM). To improve its potency while maintain selectivity, a total of 27 derivatives of 1 were designed, synthesized, and evaluated for in vitro cytotoxicity against six tumor cell lines and the negative control NIH3T3 cells. Among these compounds, compound 12b showed significantly improved potency against the MCF-7, HeLa, and HO8910 cells with IC50 values of 0.13-0.25 MUM compared to 1 (IC50 8.47-18.00 MUM), and remained nontoxic to the NIH3T3 cells. PMID- 26979156 TI - Rational modification of the lead molecule: Enhancement in the anticancer and dihydrofolate reductase inhibitory activity. AB - By using molecular docking studies, the practice of fragment based drug discovery is conceptualized by introducing oxindole and iso-propanol moieties in our previous lead molecule 1. The resulting compound 2 exhibited competitive inhibition and favorable Ka and Ki for hDHFR. The screening of compound 2 at 60 cell line panel of human tumor cell lines showed its considerably better efficacy than compound 1 and hence put the candidature of 2 on stronghold for further studies. PMID- 26979157 TI - Design and synthesis of novel 3-sulfonylpyrazol-4-amino pyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors. AB - Anaplastic lymphoma kinase (ALK) is a highly attractive therapeutic target for the treatment of some non-small cell lung cancer patients. This Letter describes the further SAR exploration on the novel 3-sulfonylpyrazol-4-amino pyrimidine scaffold. This work identified a compound 53 with very good in vitro/in vivo efficacies, good DMPK properties together with better hERG tolerability and it is currently being profiled for the evaluation as a potential pre-clinical candidate. PMID- 26979159 TI - Synthesis, in vitro and in vivo evaluation of novel substituted N-(4-(2-(4 benzylpiperazin-1-yl)ethoxy)phenyl)-N-methyl-quinazolin-4-amines as potent antitumor agents. AB - A novel series of substituted N-(4-(2-(4-benzylpiperazin-1-yl)ethoxy)phenyl)-N methylquinazolin-4-amines were synthesized and evaluated for their in vitro antiproliferative activity. Among them, compound 7a exhibited the best potency, with IC50 values of 0.029-0.147 MUM against four types of cancer cell lines. In addition, 7a was confirmed that it could arrest the cell cycle at G2/M phase and trigger apoptosis. Indirect immunofluorescence staining revealed its anti-tubulin property. Importantly, 7a significantly inhibited tumor growths in HepG2 xenograft models without causing significant loss of body weight, suggesting that 7a is a promising new anticancer agent to be developed. PMID- 26979158 TI - Synthesis and evaluation of (S)-[(18)F]fesetron in the rat brain as a potential PET imaging agent for serotonin 5-HT3 receptors. AB - Serotonin 5-HT3 receptors are involved in various brain functions including as an emesis target during cancer chemotherapy. We report here the development of (S) 2,3-dimethoxy-5-(3'-[(18)F]fluoropropyl)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide ([(18)F]fesetron) as a potential PET imaging agent for serotonin 5-HT3 receptors. By radiolabeling((S)-2,3-dimethoxy-5-(3'-tosyloxypropyl)-N-(1 azabicyclo[2.2.2]oct-3-yl)benzamide) with fluorine-18, (S)-[(18)F]fesetron was obtained in 5 to 10% decay-corrected yields and with specific activities >74GBq/MUmol at the end of radiosynthesis. PET imaging in rats showed low uptake of [(18)F]fesetron in the brain with retention of binding in the striatal and cerebellar regions. Using colliculi as a reference region, ratios were 3.4 for striata and 2.5 for cerebellum. Ex vivo brain PET analysis displayed binding of [(18)F]fesetron in the hippocampus, striatum and cerebellar regions. Cerebellar regions corresponded to area postrema and nucleus tract solitaris known to contain 5-HT3 receptors. Dorsal hippocampus showed the highest uptake with ratio of >17 with respect to colliculi, while area postrema and striata had ratios of >10. Thus, [(18)F]fesetron exhibited a unique binding profile to rat brain regions known to contain significant amounts of serotonin 5-HT3 receptors. However, the very low brain uptake limits its usefulness as a PET radiotracer in this animal model. PMID- 26979160 TI - A reliable method for quantification of splice variants using RT-qPCR. AB - BACKGROUND: The majority of protein isoforms arise from alternative splicing of the encoding primary RNA transcripts. To understand the significance of single splicing events, reliable techniques are needed to determine their incidence. However, existing methods are labour-intensive, error-prone or of limited use. RESULTS: Here, we present an improved method to determine the relative incidence of transcripts that arise from alternative splicing at a single site. Splice variants were quantified within a single sample using one-step reverse transcription quantitative PCR. Amplification products obtained with variant specific primer pairs were compared to those obtained with primer pairs common to both variants. The identities of variant specific amplicons were simultaneously verified by melt curve analysis. Independent calculations of the relative incidence of each variant were performed. Since the relative incidences of variants have to add upto 100%, the method provides an internal control to monitor experimental errors and uniform reverse transcription. The reliability of the method was tested using mixtures of cDNA templates as well as RNA samples from different sources. CONCLUSION: The method described here, is easy to set up and does not need unrelated reference genes and time consuming, error-prone standard curves. It provides a reliable and precise technique to distinguish small differences of the relative incidence of two splice variants. PMID- 26979161 TI - Misplaced "bear claw" in a bleeding gastric ulcer: What next? PMID- 26979162 TI - Perceptual, durational and tongue displacement measures following articulation therapy for rhotic sound errors. AB - Outcomes of articulation therapy for rhotic errors are usually assessed perceptually. However, our understanding of associated changes of tongue movement is limited. This study described perceptual, durational and tongue displacement changes over 10 sessions of articulation therapy for /r/ in six children. Four of the participants also received ultrasound biofeedback of their tongue shape. Speech and tongue movement were recorded pre-therapy, after 5 sessions, in the final session and at a one month follow-up. Perceptually, listeners perceived improvement and classified more productions as /r/ in the final and follow-up assessments. The durations of VrV syllables at the midway point of the therapy were longer. Cumulative tongue displacement increased in the final session. The average standard deviation was significantly higher in the middle and final assessments. The duration and tongue displacement measures illustrated how articulation therapy affected tongue movement and may be useful for outcomes research about articulation therapy. PMID- 26979163 TI - Effect of mild medical hypothermia on in vitro growth of Plasmodium falciparum and the activity of anti-malarial drugs. AB - BACKGROUND: Cerebral malaria remains a medical emergency with high mortality. Hypo-perfusion due to obstructed blood vessels in the brain is thought to play a key role in the pathophysiology of cerebral malaria leading to neurological impairment, long-term neuro-cognitive sequelae and, potentially, death. Due to the rapid reversibility of vascular obstruction caused by sequestered Plasmodium falciparum, it is hypothesized that mild medical hypothermia--a standard intervention for other medical emergencies--may improve clinical outcome. This preclinical in vitro study was performed to assess the impact of mild hypothermia on parasite growth and the intrinsic activity of anti-malarials drugs. METHODS: Three laboratory-adapted clones and two clinical isolates were used for growth assays and standardized drug sensitivity assessments using the standard HRP2 assay. All assays were performed in parallel under normothermic (37 degrees C), mild hypothermic (32 degrees C), and hyperthermic (41 degrees C) conditions. RESULTS: Parasite growth was higher under standard temperature condition than under hypo- or hyperthermia (growth ratio 0.85; IQR 0.25-1.06 and 0.09; IQR 0.05 0.32, respectively). Chloroquine and mefloquine had comparable in vitro activity under mild hypothermic conditions (ratios for IC50 at 37 degrees C/32 degrees C: 0.88; 95% CI 0.25-1.50 and 0.86; 95% CI 0.36-1.36, respectively) whereas dihydroartemisinin was more active under mild hypothermic conditions (ratio for IC50 at 37 degrees C/32 degrees C: 0.27; 95% CI 0.19-0.27). Hyperthermia led by itself to almost complete growth inhibition and precluded further testing of the activity of anti-malarial drugs. CONCLUSION: This preclinical evaluation demonstrates that mild medical hypothermia inhibits in vitro growth of P. falciparum and enhances the pharmacodynamic activity of artemisinin derivatives. Based on these preclinical pharmacodynamic data, the further clinical development of mild medical hypothermia as adjunctive treatment to parenteral artesunate for cerebral malaria is warranted. PMID- 26979164 TI - Disruption of spermatogenesis in the liver fluke, Fasciola hepatica by two artemisinin derivatives, artemether and artesunate. AB - An in vivo study in the laboratory rat model has been carried out to monitor changes to the spermatogenic cells in the testis tubules of adult Fasciola hepatica following treatment with the artemisinins, artemether and artesunate. Rats infected with the triclabendazole (TCBZ)-resistant Sligo isolate were dosed orally with artemether at a concentration of 200 mg/kg and flukes recovered at 24, 48 and 72 h post treatment (pt). Rats infected with the TCBZ-resistant Oberon isolate were dosed orally with artesunate at a concentration of 200 mg/kg and flukes recovered 24, 48, 72 and 96 h pt. The flukes were processed for histological and transmission electron microscope (TEM) examination. Changes to the spermatogenic cells were evident at 24 h pt with artemether. The spermatogonial and spermatocyte cells contained abnormal mitochondria, there were fewer spermatids and spermatozoa in the tubules than normal, and a number of cells showed signs of apoptosis. There was a further decline in cell numbers at 48 h pt and the organization of the spermatocyte and spermatid rosettes was atypical. Sperm formation had become abnormal and those spermatozoa present possessed only a single axoneme. By 72 h pt, the testis tubules were vacuolated and filled with abnormal cells and cell debris. Only spermatogonial cells could be identified and there was widespread evidence of apoptosis in the cells. Distinct cellular changes following artesunate treatment did not become apparent until 48 h pt. The changes seen were similar to those described for artemether, but were generally less severe at matching time-periods. The fine structural changes occurring in the spermatogenic cells were compared to those observed in other cell types and fluke tissues and the overall information was collated to identify the cellular targets for artemisinin action and to establish the time line for drug action. PMID- 26979167 TI - Self-Efficacy, Health Literacy, and Nutrition and Exercise Behaviors in a Low Income, Hispanic Population. AB - Public health goals have emphasized healthy nutrition and exercise behaviors, especially in underserved populations. According to social cognitive theory (SCT), self-efficacy and capability (e.g., health literacy) may interact to predict preventative behaviors. We surveyed 100 low-income, native Spanish speakers living in the United States who were low in English proficiency and predominantly of Mexican heritage. Participants reported their nutritional and exercise self-efficacy, Spanish health literacy, and nutrition and physical activity behaviors. Consistent with SCT, the interaction of self-efficacy and health literacy significantly predicted fruit and vegetable consumption and weekly exercise, and marginally predicted avoidance of high fat foods. For all three interactions, higher health literacy levels strengthened the positive relationship between self-efficacy and health behaviors. The results offer support for the tenets of SCT and suggest-for low-income, Spanish-speaking adults that a combination of behavioral confidence and literacy capability are necessary to enact appropriate health behaviors. PMID- 26979169 TI - Men from Sub-Saharan Africa Living in Worker Hostels in France: A Hidden Population with Poor Access to HIV Testing. AB - Delayed presentation to care among HIV-infected individuals continued to be frequent in France. Migrants are at high risk for late presentation. This cross sectional study investigated barriers to HIV testing in the specific population of men from sub-Saharan Africa living in four migrant worker hostels in Paris, France. Factors associated with never having been tested for HIV were examined using logistic regression. In all, 550 men participated, coming mainly from Mali and Senegal, with 31 % having lived in France for less than 5 years, and 25 % without any health insurance. Only 37 % have ever been tested for HIV. Not having health insurance was the main risk factor for never-testing [adjusted odds ratio (aOR) 2.4; 95 % confidence interval (CI) 1.4-4.0]. Despite free and anonymous HIV testing available at dedicated public screening centers, 63 % of men living in migrant worker hostels had never been tested for HIV. PMID- 26979168 TI - A Pilot Examination of a Mosque-Based Physical Activity Intervention for South Asian Muslim Women in Ontario, Canada. AB - Low levels of physical activity have been reported in South Asian Muslim women. Mosques could be beneficial in providing physical activity opportunities for Muslim women. This study examined the feasibility, acceptability and effectiveness of a mosque-based physical activity program for South Asian Muslim women in Canada. Sixty-two South Asian Muslim women participated in a 24-week mosque-based exercise intervention. Feasibility, acceptability and effectiveness of the program was evaluated by pre-post survey questions from the Duke Activity Status Index (DASI) and International Physical Activity Questionnaire among 28 women who consented to the research data collection. Nineteen women were assessed pre-and post-intervention. The women demonstrated increase in median scores of self-efficacy (90 pre vs. 100 post; p = 0.004) and the importance of engaging in regular physical activity (90 pre vs. 100 post; p = 0.01). Fewer participants were classified as inactive at the end of the intervention (42 % pre vs. 10 % post; p = 0.006). There was a mean increase in DASI scores (39.2 pre vs. 44.6 post; p = 0.06) reflecting an improvement in peak aerobic capacity and functional quality of life. Culturally relevant structured networks such as mosques are important assets when designing healthy lifestyle interventions for South Asian Muslim women. PMID- 26979170 TI - Continuous molecular remission and regression of side effects after discontinuation of salvage therapy with sorafenib and donor lymphocyte infusions in a young patient with relapsed AML. PMID- 26979171 TI - Correlation between indexes of autonomic maneuvers and heart rate variability in hemodialysis patients. AB - PURPOSE: The autonomic maneuvers are simple methods to evaluate autonomic balance, but the association between autonomic maneuvers and heart rate variability (HRV) in hemodialysis patients remains unknown. This study aimed to evaluate the correlation between HRV and respiratory sinus arrhythmia (RSA) and Valsalva maneuver (VM) indexes in hemodialysis patients and to compare two methods for RSA indexes acquisitions. METHODS: Forty-eight volunteers on hemodialysis (66.7 % men) were evaluated by VM, RSA, and 24 h Holter monitoring. At the VM, the Valsalva index (VI) was the variable considered. In the RSA, the ratio and difference between the RR intervals of inspiratory and expiratory phase (E:I and E-I, respectively) were considered by traditional form (average of respiratory cycles) and independent respiratory cycles (E:Iindep and E-Iindep). The HRV indexes evaluated were standard deviation of all normal RR intervals (SDNN), standard deviation of sequential 5-min RR interval means (SDANN), root mean square of the successive differences (rMSSD) and percentage of adjacent RR intervals with difference of duration greater than 50 ms (pNN50). RESULTS: The SDNN, SDANN showed significant correlation with all classic indexes of RSA (E:I: r = 0.62, 0.55, respectively, E-I: r = 0.64, 0.57, respectively), E:Iindep (r = 0.59, 0.54, respectively), E-Iindep (r = 0.47, 0.43, respectively) and VI (r = 0.42, 0.34, respectively). Significant correlation of rMSSD with E:I (r = 0.37), E-I (r = 0.41) and E:Iindep (r = 0.34) was also observed. There was no association of any variable with pNN50. Have been show high values for all variables of independent cycles method (p < 0.05). CONCLUSION: The autonomic maneuvers, especially RSA, are useful methods to evaluate cardiac autonomic function in hemodialysis patients. The acquisition of the RSA index by independent cycles should not be used in this population. PMID- 26979173 TI - Indirect Treatment Comparison of Talimogene Laherparepvec Compared with Ipilimumab and Vemurafenib for the Treatment of Patients with Metastatic Melanoma. AB - INTRODUCTION: Few randomized controlled trials have compared new treatments for metastatic melanoma. We sought to examine the relative treatment effect of talimogene laherparepvec compared with ipilimumab and vemurafenib. METHODS: A systematic literature review of treatments for metastatic melanoma was undertaken but a valid network of evidence could not be established because of a lack of comparative data or studies with sufficient common comparators. A conventional adjusted indirect treatment comparison via network meta-analysis was, therefore, not feasible. Instead, a meta-analysis of absolute efficacy was undertaken, adjusting overall survival (OS) data for differences in prognostic factors between studies using a published algorithm. RESULTS: Four trials were included in the final indirect treatment comparison: two of ipilimumab, one of vemurafenib, and one of talimogene laherparepvec. Median OS for ipilimumab and vemurafenib increased significantly when adjustment was applied, demonstrating that variation in disease and patient characteristics was biasing OS estimates; adjusting for this made the survival data more comparable. For both ipilimumab and vemurafenib, the adjustments improved Kaplan-Meier OS curves; the observed talimogene laherparepvec OS curve remained above the adjusted OS curves for ipilimumab and vemurafenib, showing that long-term survival could differ from the observed medians. CONCLUSION: Even with limited data, talimogene laherparepvec, ipilimumab, and vemurafenib could be compared following adjustments, thereby providing a more reliable understanding of the relative effect of treatment on survival in a more comparable patient population. The results of this analysis suggest that OS with talimogene laherparepvec is at least as good as with ipilimumab and vemurafenib and improvement was more pronounced in patients with no bone, brain, lung or other visceral metastases. FUNDING: Amgen Inc. PMID- 26979172 TI - Impacts of forest harvesting on mobilization of Hg and MeHg in drained peatland forests on black schist or felsic bedrock. AB - Forest harvesting, especially when intensified harvesting method as whole-tree harvesting with stump lifting (WTHs) are used, may increase mercury (Hg) and methylmercury (MeHg) leaching to recipient water courses. The effect can be enhanced if the underlying bedrock and overburden soil contain Hg. The impact of stem-only harvesting (SOH) and WTHs on the concentrations of Hg and MeHg as well as several other variables in the ditch water was studied using a paired catchment approach in eight drained peatland-dominated catchments in Finland (2008-2012). Four of the catchments were on felsic bedrock and four on black schist bedrock containing heavy metals. Although both Hg and MeHg concentrations increased after harvesting in all treated sites according to the randomized intervention analyses (RIAs), there was only a weak indication of a harvest induced mobilization of Hg and MeHg into the ditches. Furthermore, no clear differences between WTHs and SOH were found, although MeHg showed a nearly significant difference (p = 0.06) between the harvesting regimes. However, there was a clear bedrock effect, since the MeHg concentrations in the ditch water were higher at catchments on black schist than at those on felsic bedrock. The pH, suspended solid matter (SSM), dissolved organic carbon (DOC), and iron (Fe) concentrations increased after harvest while the sulfate (SO4-S) concentration decreased. The highest abundances of sulfate-reducing bacteria (SRB) were found on the sites with high MeHg concentrations. The biggest changes in ditch water concentrations occurred first 2 years after harvesting. PMID- 26979174 TI - Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): a randomised controlled trial with cost-effectiveness analysis. AB - BACKGROUND: Carotid artery stenting (CAS) is an alternative to carotid endarterectomy (CEA) for the treatment of carotid stenosis, but safety and long term efficacy were uncertain. OBJECTIVE: To compare the risks, benefits and cost effectiveness of CAS versus CEA for symptomatic carotid stenosis. DESIGN: International, multicentre, randomised controlled, open, prospective clinical trial. SETTING: Hospitals at 50 centres worldwide. PARTICIPANTS: Patients older than 40 years of age with symptomatic atheromatous carotid artery stenosis. INTERVENTIONS: Patients were randomly allocated stenting or endarterectomy using a computerised service and followed for up to 10 years. MAIN OUTCOME MEASURES: The primary outcome measure was the long-term rate of fatal or disabling stroke, analysed by intention to treat (ITT). Disability was assessed using the modified Rankin Scale (mRS). A cost-utility analysis estimating mean costs and quality adjusted life-years (QALYs) was calculated over a 5-year time horizon. RESULTS: A total of 1713 patients were randomised but three withdrew consent immediately, leaving 1710 for ITT analysis (853 were assigned to stenting and 857 were assigned to endarterectomy). The incidence of stroke, death or procedural myocardial infarction (MI) within 120 days of treatment was 8.5% in the CAS group versus 5.2% in the CEA group (72 vs. 44 events) [hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.16 to 2.45; p = 0.006]. In the analysis restricted to patients who completed stenting, age independently predicted the risk of stroke, death or MI within 30 days of CAS (relative risk increase 1.17% per 5 years of age, 95% CI 1.01% to 1.37%). Use of an open-cell stent conferred higher risk than a closed-cell stent (relative risk 1.92, 95% CI 1.11 to 3.33), but use of a cerebral protection device did not modify the risk. CAS was associated with a higher risk of stroke in patients with an age-related white-matter changes score of 7 or more (HR 2.98, 95% CI 1.29 to 6.93; p = 0.011). After completion of follow-up with a median of 4.2 years, the number of patients with fatal or disabling stroke in the CAS and CEA groups (52 vs. 49), and the cumulative 5-year risk did not differ significantly (6.4% vs. 6.5%) (HR 1.06, 95% CI 0.72 to 1.57; p = 0.776). Stroke of any severity was more frequent in the CAS group (15.2% vs. 9.4% in the CEA group) (HR 1.712, 95% CI 1.280 to 2.300; p < 0.001). There was no significant difference in long-term rates of severe carotid restenosis or occlusion (10.8% in the CAS group vs. 8.6% in the CEA group) (HR 1.25, 95% CI 0.89 to 1.75; p = 0.20). There was no difference in the distribution of mRS scores at 1-year, 5-year or final follow-up. There were no differences in costs or QALYs between the treatments. LIMITATIONS: Patients and investigators were not blinded to treatment allocation. Interventionists' experience of stenting was less than that of surgeons with endarterectomy. Data on costs of managing strokes were not collected. CONCLUSIONS: The functional outcome after stenting is similar to endarterectomy, but stenting is associated with a small increase in the risk of non-disabling stroke. The choice between stenting and endarterectomy should take into account the procedural risks related to individual patient characteristics. Future studies should include measurement of cognitive function, assessment of carotid plaque morphology and identification of clinical characteristics that determine benefit from revascularisation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN25337470. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 20. See the NIHR Journal Library website for further project information. Further funding was provided by the Medical Research Council, Stroke Association, Sanofi-Synthelabo and the European Union. PMID- 26979166 TI - Modulatory effects of alpha7 nAChRs on the immune system and its relevance for CNS disorders. AB - The clinical development of selective alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists has hitherto been focused on disorders characterized by cognitive deficits (e.g., Alzheimer's disease, schizophrenia). However, alpha7 nAChRs are also widely expressed by cells of the immune system and by cells with a secondary role in pathogen defense. Activation of alpha7 nAChRs leads to an anti-inflammatory effect. Since sterile inflammation is a frequently observed phenomenon in both psychiatric disorders (e.g., schizophrenia, melancholic and bipolar depression) and neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, and multiple sclerosis), alpha7 nAChR agonists might show beneficial effects in these central nervous system disorders. In the current review, we summarize information on receptor expression, the intracellular signaling pathways they modulate and reasons for receptor dysfunction. Information from tobacco smoking, vagus nerve stimulation, and cholinesterase inhibition is used to evaluate the therapeutic potential of selective alpha7 nAChR agonists in these inflammation-related disorders. PMID- 26979175 TI - Variable ventilation from bench to bedside. AB - This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901. PMID- 26979176 TI - ADN-1184, a monoaminergic ligand with 5-HT6/7 receptor antagonist action, exhibits activity in animal models of anxiety. AB - Behavioral and psychological symptoms of dementia (BPSD) include apathy, sleep problems, irritability, wandering, elation, agitation/aggression, and mood disorders such as depression and/or anxiety. Elderly patients are usually treated with second-generation antipsychotics; however, they present not enough efficacy against all symptoms observed. Hence, there still is an unmet need for novel pharmacotherapeutic agents targeted BPSD. A novel arylsulfonamide derivative ADN 1184 has been developed that possesses a preclinical profile of activity corresponding to criteria required for treatment of both psychosis and depressive symptoms of BPSD without exacerbating cognitive impairment or inducing motor disturbances. To broaden its pharmacological efficacy toward anxiety symptoms, its anxiolytic properties have been examined in common animal preclinical models in rats and mice. ADN-1184 significantly increased the number of entries into open arms measured in the elevated plus-maze test; however, it simultaneously increased parameters of exploratory activity. In the Vogel conflict drinking test, ADN-1184 dose-dependently and significantly increased the number of shocks accepted and the number of licks. Moreover, in mice, it also had specific anxiolytic-like activity in the four-plate test, and only negligible one at a specific mid-range dose measured in the spontaneous marble burying test. The obtained findings reveal that ADN-1184 displays anxiolytic-like activity in animal models of anxiety which employed punished stimuli. In its unusual combination of some anxiolytic action with already proven antipsychotic and antidepressant properties, and lack of any disruptive impact on learning and memory processes and motor coordination, ADN-1184 displays a profile that would be desired for a novel therapeutic for BPSD. PMID- 26979177 TI - Does simulated walking cause gapping of meniscal repairs? AB - BACKGROUND: The objective of rehabilitation following meniscal repair is to promote healing by limiting stresses on repairs, while simultaneously preserving muscle strength and joint motion. Both protective protocols limiting weight bearing and accelerated which do not, have shown clinical success. This study assesses the effects of physiologic gait loading on the kinematic behavior of a repaired medial meniscus. METHODS: The medial menisci of eight fresh cadaveric knees were implanted with arrays of six 0.8-1.0 mm beads. Pneumatic actuators delivered muscle loads and forces on the knee as each specimen was subjected to a simulated stance phase of gait. Meniscus motion was measured at loading response, mid stance, and toe-off positions. Measurements were performed using biplanar radiography and RSA, with each knee: (a) intact, (b) with posterior longitudinal tear, and (c) after inside-out repair. RESULTS: The tissue spanning the site of the longitudinal tear underwent compression rather than gapping open in all states (intact [I], torn [T] and repaired [R] states). Average compression at three sites along the posterior half of the meniscus was: posterior horn -0.20 +/ 0.08 mm [I], -0.39 +/- 0.10 mm [T], and -0.20 +/- 0.06 mm [R] (p = 0.15); junction of posterior horn and body -0.11 +/- 0.12 mm [I], -0.21 +/- 12 mm [T], 0.17 +/- 0.09 mm [R] (p = 0.87); and adjacent to the medial collateral ligament 0.07 +/- 0.06 mm [I], -0.29 +/- 0.13 mm [T], -0.07 +/- 0.17 mm [R] (p = 0.35). The entire meniscus translated posteriorly from mid-stance to toe off. Displacement was greatest in the torn state compared to intact, but was not restored to normal levels after repair. CONCLUSION: The edges of a repaired longitudinal medial meniscal tear undergo compression, not gapping, during simulated gait. PMID- 26979178 TI - Aware, Yet Ignorant: Exploring the Views of Early Career Researchers About Funding and Conflicts of Interests in Science. AB - This study investigates the level of awareness about funding influences and potential conflicts of interests (COI) among early career researchers. The sample for this study included users of one or more of the 14 U.S. laboratories associated with the National Nanotechnology Infrastructure Network. To be eligible, respondents must have been either still completing graduate work or <5 years since graduation. In total, 713 early career researchers completed the web survey, with about half still in graduate school. Results indicate that although respondents were aware of potential funding and COI influences on their work, they remained largely ignorant of their role in addressing or managing these issues. Respondents often attributed the responsibility of addressing these issues to their supervisors. Respondents who had received some training around these issues, however, were more likely to assume more personal responsibility. Overall, this study points out that ignorance among early career researchers is less about awareness of funding and COI issues and more about taking personal responsibility for addressing these issues. PMID- 26979180 TI - Peroneal nerve entrapment neuropathy induced by playing the drum. PMID- 26979179 TI - Combined surgical intervention with vagus nerve stimulation following corpus callosotomy in patients with Lennox-Gastaut syndrome. AB - BACKGROUND: Lennox-Gastaut syndrome (LGS) is a drug-resistant pediatric epilepsy characterized by multiple seizure types, including drop attacks (DAs). Palliative procedures such as corpus callosotomy (CC) and vagus nerve stimulation (VNS) may be effective for adequate seizure control in LGS patients who are not candidates for resective surgery. We evaluated the efficacy of the combination of these two procedures for LGS-related seizures. METHOD: Ten patients with LGS (age 3-30 years at VNS implantation) underwent CC and subsequent VNS. We evaluated surgical outcomes, particularly with respect to the efficacy of VNS on seizure reduction rates for different residual seizure types after CC. We compared clinical parameters, including sex, age, seizure duration, history, MRI findings, extent of CC, number of antiepileptic drugs, and neuropsychological states, between VNS responders and non-responders to predict satisfactory seizure outcomes with respect to residual seizures after CC. FINDINGS: VNS was effective for residual seizures regardless of seizure type (except for DAs) after CC in patients with LGS. Six of ten (60%) patients had a satisfactory seizure outcome (>=50% seizure reduction) for all residual seizure types after VNS. Two of ten (20%) patients were seizure-free at 12 months post-VNS. Even those patients that were non responders, with respect to all seizures including DAs, after prior CC showed favorable responses to subsequent VNS. Compared to VNS, excellent seizure outcomes for DAs were achieved after CC in seven of nine (77.8%) patients with DAs. Among the clinical parameters, only conversation ability before VNS was significantly different between responders and non-responders (p = 0.033). CONCLUSION: Combined VNS and prior CC produced satisfactory seizure outcomes in LGS patients with different seizure types, including DAs. Even non-responders to prior CC responded to subsequent VNS for residual seizures, except for DAs. There is a greater likelihood that these procedures may be more feasible in patients who possess conversation ability prior to VNS. PMID- 26979181 TI - Percutaneous radiofrequency thermocoagulation of dorsal ramus branches as a treatment of "lumbar facet syndrome"--How I do it. AB - BACKGROUND: Low back pain is an extremely common and often chronic condition. In some cases, this is due to an irritative arthropathy of zygapophyseal joint involving the medial branch of the dorsal ramus of the spinal nerve. Percutaneous radiofrequency thermocoagulation appears to be the most effective treatment to date, among a range of different treatments. In this paper, the technique is described as performed at out institution. METHODS: In supine position and under fluoroscopic control, a radiofrequency electrode is inserted into different articular zygapophyseal complexes to thermocoagulate ramifications of the medial branch of the dorsal primary ramus of the spinal nerve. CONCLUSIONS: Fluoroscopic guided percutaneous radiofrequency thermocoagulation of dorsal rami branches is a safe and reliable technique for the treatment of lumbar facet syndrome. Careful selection of patients based on clinical presentation and positive anesthetic block test are key points for an optimum outcome. PMID- 26979182 TI - Treatment of complete facial palsy in adults: comparative study between direct hemihypoglossal-facial neurorrhaphy, hemihipoglossal-facial neurorrhaphy with grafts, and masseter to facial nerve transfer. AB - BACKGROUND: The hypoglossal (with or without grafts) and masseter nerves are frequently used as axon donors for facial reinnervation when no proximal stump of the facial nerve is available. We report our experience treating facial nerve palsies via hemihypoglossal-to-facial nerve transfers either with (HFG) or without grafts (HFD), comparing these outcomes against those of masseteric-to facial nerve transfers (MF). METHOD: A total of 77 patients were analyzed retrospectively, including 51 HFD, 11 HFG, and 15 MF nerve transfer patients. Both the House-Brackmann (HB) scale and our own, newly-designed scale to rate facial reanimation post nerve transfer (quantifying symmetry at rest and when smiling, eye occlusion, and eye and mouth synkinesis when speaking) were used to enumerate the extent of recovery. RESULTS: With both the HB and our own facial reanimation scale, the HFD and MF procedures yielded better outcome scores than HFG, though only the HGD was statistically superior. HGD produced slightly better scores than MF for everything but eye synkinesis, but these differences were generally not statistically significant. Delaying surgery beyond 2 years since injury was associated with appreciably worse outcomes when measured with our own but not the HB scale. The only predictors of outcome were the surgical technique employed and the duration of time between the initial injury and surgery. CONCLUSIONS: HFD appears to produce the most satisfactory facial reanimation results, with MF providing lesser but still satisfactory outcomes. Using interposed grafts while performing hemihypoglossal-to-facial nerve transfers should likely be avoided, whenever possible. PMID- 26979183 TI - [More harmful in diabetics]. PMID- 26979185 TI - [Benign nodule or malignant tumor?]. PMID- 26979186 TI - [E-health - what is changing in medical practice?]. PMID- 26979187 TI - [Increasing costs caused by multiresistant pathogens in the nursing home]. PMID- 26979188 TI - [Migraine experts often suffer from migraine as well]. PMID- 26979189 TI - [Vertigo - a fatal illness?]. PMID- 26979190 TI - [With herbal wraps for knee pain control]. PMID- 26979191 TI - [They can be recognized by their smocks]. PMID- 26979192 TI - [Difficult decisions regarding patients with dementia]. PMID- 26979193 TI - ["Being relegated to an illusory world due to a diagnosis is unacceptable"]. PMID- 26979194 TI - [Three new early summer meningoencephalitis risk areas]. PMID- 26979195 TI - [Sports are health - also with an endoprosthesis]. PMID- 26979196 TI - [Not always must a surgeon be called immediately]. PMID- 26979197 TI - [Naturopathy in common cold season]. PMID- 26979198 TI - [Attractive but error prone?]. PMID- 26979199 TI - [Almost all patients can be healed]. PMID- 26979200 TI - [How long will the patient be anticoagulated?]. PMID- 26979201 TI - [Remedy regresses become significantly more difficult starting in 2017]. PMID- 26979203 TI - [Girl with mysterious genital mycosis]. PMID- 26979202 TI - [Does number 01435 exclude all other services?]. PMID- 26979204 TI - [Involuntary commitment? The patient turns the table]. PMID- 26979205 TI - [Total amnesia after only 10 years in the practice?]. PMID- 26979206 TI - [When cleaning out please note the deadlines!]. PMID- 26979207 TI - [Unfortunately still unequal]. PMID- 26979208 TI - [With 52 the family physician's life is just starting!]. PMID- 26979209 TI - [BGH deals with unfavorable online evaluations]. PMID- 26979210 TI - [All for the patient]. PMID- 26979211 TI - [Despite cultural difference to the correct diagnosis]. PMID- 26979212 TI - [Evaluating the etiology of dyspnea more rapidly]. PMID- 26979213 TI - [A correct lousy diagnosis]. PMID- 26979214 TI - [Central sleep apnea warns of heart failure]. PMID- 26979215 TI - [After 2 days the source of the pain is revealed]. PMID- 26979216 TI - [For diabetics sports are more strenuous]. PMID- 26979217 TI - [Simultaneous onset of primary and secondary syphilis]. PMID- 26979218 TI - [A new remedy for diarrheal irritable bowel syndrome]. PMID- 26979219 TI - [Madelung disease: accumulation of fat deposits]. PMID- 26979220 TI - [Backache: early physical therapy has little effect]. PMID- 26979221 TI - [ECG guides the way to diagnosis of Wellens' syndrome]. PMID- 26979222 TI - [Replacement or repair of degenerative heart valves. Focus on minimal invasive strategies]. PMID- 26979223 TI - [Interventional therapy for aortic valve stenosis]. PMID- 26979224 TI - [Modern interventional procedures for mitral valve in sufficiency]. PMID- 26979225 TI - [Redo surgery in patients with pacemakers and internal cardioverter defibrillators]. PMID- 26979227 TI - [Back to the earlier GOLD classification I-IV?]. PMID- 26979226 TI - [Anogenital diseases caused by human papillomavirus - A modern pandemia]. PMID- 26979228 TI - [Micronutrients are essential for brain function]. PMID- 26979229 TI - [Empagliflozin improves cardiovascular prognosis]. PMID- 26979230 TI - [New fixed dose combination for initial control of hypertension]. PMID- 26979231 TI - [Drug reduction of uric acid not just when symptoms appear]. PMID- 26979232 TI - [Combination with Iceland moss shows effectiveness in a study]. PMID- 26979233 TI - [First new oral anticoagulant with specific antidote]. PMID- 26979234 TI - [Expert panel recommends mustard oils as causation oriented therapy]. PMID- 26979235 TI - [Good bronchial dilatation helps keep patients physically active]. PMID- 26979238 TI - Correction: Absolute stereochemistry and preferred conformations of urate degradation intermediates from computed and experimental circular dichroism spectra. AB - Correction for 'Absolute stereochemistry and preferred conformations of urate degradation intermediates from computed and experimental circular dichroism spectra' by Silvio Pipolo et al., Org. Biomol. Chem., 2011, 9, 5149-5155. PMID- 26979236 TI - Wilfully out of sight? A literature review on the effectiveness of cancer-related decision aids and implementation strategies. AB - BACKGROUND: There is evidence to suggest that decision aids improve a number of patient outcomes. However, little is known about the progression of research effort in this area over time. This literature review examined the volume of research published in 2000, 2007 and 2014 which tested the effectiveness of decision aids in improving cancer patient outcomes, coded by cancer site and decision type being targeted. These numbers were compared with the volume of research examining the effectiveness of strategies to increase the adoption of decision aids by healthcare providers. METHODS: A literature review of intervention studies was undertaken. Medline, Embase, PsychInfo and Cochrane Database of Systematic Reviews were searched. The search was limited to human studies published in English, French, or German. Abstracts were assessed against eligibility criteria by one reviewer and a random sample of 20 % checked by a second. Eligible intervention studies in the three time periods were categorised by: i) whether they tested the effectiveness of decision aids, coded by cancer site and decision type, and ii) whether they tested strategies to increase healthcare provider adoption of decision aids. RESULTS: Over the three time points assessed, increasing research effort has been directed towards testing the effectiveness of decision aids in improving patient outcomes (p < 0.0001). The number of studies on decision aids for cancer screening or prevention increased statistically significantly (p < 0.0001) whereas the number of studies on cancer treatment did not (p = 1.00). The majority of studies examined the effectiveness of decision aids for prostate (n = 10), breast (n = 9) or colon cancer (n = 7). Only two studies assessed the effectiveness of implementation strategies to increase healthcare provider adoption of decision aids. CONCLUSIONS: While the number of studies testing the effectiveness of decision aids has increased, the majority of research has focused on screening and prevention decision aids for only a few cancer sites. This neglects a number of cancer populations, as well as other areas of cancer care such as treatment decisions. Also, given the apparent effectiveness of decision aids, more effort needs to be made to implement this evidence into meaningful benefits for patients. PMID- 26979237 TI - Self-sampling in cervical cancer screening: comparison of a brush-based and a lavage-based cervicovaginal self-sampling device. AB - BACKGROUND: High coverage and attendance is essential for cervical cancer screening success. We investigated whether the previous positive experiences on increasing screening attendance by self-sampling in Finland are sampler device dependent. METHODS: All women identified to cervical cancer screening in 2013 in 28 Finnish municipalities were randomised to receive a lavage- (n = 6030) or a brush type of self-sampling device (n = 6045) in case of non-attendance after two invitation letters. Seven hundred seventy non-attending women in the lavage device group and 734 in the brush group received the self-sampling offer. Women's experiences were enquired with an enclosed questionnaire. RESULTS: Total attendance in the lavage group increased from 71.0 to 77.7% by reminder letters and further to 80.5% by self-sampling. Respective increase in the brush group was from 72.2 to 78.6% and then to 81.5%. The participation by self-sampling was 21.7% (95% CI 18.8-24.6) in the lavage group and 23.8% (95% CI 20.8-26.9) in the brush group. Women's self-sampling experiences were mainly positive and the sampler devices were equally well accepted by the women. CONCLUSION: Our study shows that the lavage device and brush device perform similarly in terms of uptake by non-attending women and user comfort. If self-sampling is integrated to the routine screening program in Finland, either of the devices can be chosen without the fear of losing participants due to a less acceptable device. PMID- 26979239 TI - Social networks help to infer causality in the tumor microenvironment. AB - BACKGROUND: Networks have become a popular way to conceptualize a system of interacting elements, such as electronic circuits, social communication, metabolism or gene regulation. Network inference, analysis, and modeling techniques have been developed in different areas of science and technology, such as computer science, mathematics, physics, and biology, with an active interdisciplinary exchange of concepts and approaches. However, some concepts seem to belong to a specific field without a clear transferability to other domains. At the same time, it is increasingly recognized that within some biological systems--such as the tumor microenvironment--where different types of resident and infiltrating cells interact to carry out their functions, the complexity of the system demands a theoretical framework, such as statistical inference, graph analysis and dynamical models, in order to asses and study the information derived from high-throughput experimental technologies. RESULTS: In this article we propose to adopt and adapt the concepts of influence and investment from the world of social network analysis to biological problems, and in particular to apply this approach to infer causality in the tumor microenvironment. We showed that constructing a bidirectional network of influence between cell and cell communication molecules allowed us to determine the direction of inferred regulations at the expression level and correctly recapitulate cause-effect relationships described in literature. CONCLUSIONS: This work constitutes an example of a transfer of knowledge and concepts from the world of social network analysis to biomedical research, in particular to infer network causality in biological networks. This causality elucidation is essential to model the homeostatic response of biological systems to internal and external factors, such as environmental conditions, pathogens or treatments. PMID- 26979240 TI - Effects of tensile strain on the peculiarities of PEO penetration into the nanoporous structure of PET deformed via the crazing mechanism. AB - Solvent crazing involves the development of a highly dispersed fibrillar-porous structure with dimensions of pores and craze fibrils of about 2-20 nm, and crazing by itself can be treated as a universal method for the development of nanoscale porosity. The penetration and release of poly(ethylene oxide) macromolecules into and from the crazes during the development of the nanoporous structure of poly(ethylene terephthalate) have been studied. In particular, PET has been deformed in dilute or semidilute (unentangled as well as entangled) solutions of PEO (a Mw of 4 and 40 kDa) via the mechanism of solvent crazing. Hydrodynamic coil radii Rh, blob sizes xi, and concentration ranges (crossover and entanglement concentrations) have been determined for the PEO solutions. The evolution of the craze structure (change in porosity W and pore diameters d) has been described as a function of the tensile strain of PET during its drawing in an adsorption-active medium and in the PEO solutions. PEO has been shown to penetrate into the nanoporous structure of the crazes under the conditions corresponding to Rh<=d and xi < d. It has been shown that coagulation processes in the structure of crazed PET, PEO adsorption at the highly developed surface of PET, and the mechanism of PEO transport in the nanopores are equally important factors affecting the direction of the macromolecule mass transfer in the nanopores (penetration or release) and PEO content variation as a function of PET tensile strain. PMID- 26979241 TI - Knowledge and perception about climate change and human health: findings from a baseline survey among vulnerable communities in Bangladesh. AB - BACKGROUND: Bangladesh is one of the countries most vulnerable to climate change (CC). A basic understanding of public perception on vulnerability, attitude and the risk in relation to CC and health will provide strategic directions for government policy, adaptation strategies and development of community-based guidelines. The objective of this study was to collect community-based data on peoples' knowledge and perception about CC and its impact on health. METHODS: In 2012, a cross-sectional survey was undertaken among 6720 households of 224 enumeration areas of rural villages geographically distributed in seven vulnerable districts of Bangladesh, with total population of 19,228,598. Thirty households were selected randomly from each enumeration area using the household listing provided by the Bangladesh Bureau of Statistics (BBS). Information was collected from all the 6720 research participants using a structured questionnaire. An observation checklist was used by the interviewers to collect household- and community-related information. In addition, we selected the head of each household as the eligible participant for an interview. Evidence of association between sociodemographic variables and knowledge of CC was explored by cross-tabulation and measured using chi-square tests. Logistic regression models were used to further explore the predictors of knowledge. RESULTS: The study revealed that the residents of the rural communities selected for this study largely come from a low socioeconomic background: only 9.6% had postsecondary education or higher, the majority worked as day labourer or farmer (60%), and only 10% earned a monthly income above BDT 12000 (equivalent to US $150 approx.). The majority of the participants (54.2%) had some knowledge about CC but 45.8% did not (p < 0.001). The majority of knowledgeable participants (n = 3645) felt excessive temperature as the change of climate (83.2%). Among all the respondents (n = 6720), 94.5% perceived change in climate and extreme weather events. Most of them (91.9%) observed change in rainfall patterns in the last 10 years, and 97.8% people think their health care expenditure increased after the extreme weather events. Age, educational qualification, monthly income, and occupation were significantly associated with the knowledge about climate change (p < 0.001). People with higher educational level or who live near a school were more knowledgeable about CC and its impact on health. CONCLUSIONS: The knowledge level about CC in our study group was average but the perception and awareness of CC related events and its impact on health was high. The most influential factor leading to understanding of CC and its impact on health was education. School based intervention could be explored to increase peoples' knowledge about CC and necessary health adaptation at community level. PMID- 26979242 TI - The diagnostic value of plasma N-terminal connective tissue growth factor levels in children with heart failure. AB - OBJECTIVE: The aim of this study was to assess the diagnostic value of plasma N terminal connective tissue growth factor in children with heart failure. Methods and results Plasma N-terminal connective tissue growth factor was determined in 61 children, including 41 children with heart failure, 20 children without heart failure, and 30 healthy volunteers. The correlations between plasma N-terminal connective tissue growth factor levels and clinical parameters were investigated. Moreover, the diagnostic value of N-terminal connective tissue growth factor levels was evaluated. Compared with healthy volunteers and children without heart failure, plasma N-terminal connective tissue growth factor levels were significantly elevated in those with heart failure (p0.05), but it obviously improved the ability of diagnosing heart failure in children, as demonstrated by the integrated discrimination improvement (6.2%, p=0.013) and net re classification improvement (13.2%, p=0.017) indices. CONCLUSIONS: Plasma N terminal connective tissue growth factor is a promising diagnostic biomarker for heart failure in children. PMID- 26979243 TI - Safety of combination treatment with imatinib mesylate, carboplatin, and cetuximab in a patient with multiple cancers: a case report. AB - PURPOSE: Therapies directed against multiple signaling pathways have been validated in the clinical setting as effective anticancer treatments. The combination of different agents is particularly helpful in patients with multiple cancer diagnoses, while data on cross-toxicity are frequently missing, as for imatinib and cetuximab plus platinum drugs. METHODS: We present the case of a 76 year-old man with advanced laryngeal squamous cell carcinoma and chronic myeloid leukemia (CML). Combined treatment with imatinib mesylate and cetuximab plus carboplatin was well-tolerated by the patient, who did not develop neutropenia. By an interdisciplinary approach with hematology specialists, the anticipated neutropenia was managed by the temporary interruption of imatinib treatment when the white blood cell (WBC) count nadir was expected to occur. RESULTS: Although treatment with imatinib, carboplatin, and cetuximab can be associated with hematologic toxicities, a combination regimen based on the concomitant administration of these 3 drugs and on the discontinuation of imatinib at the predicted nadir of WBC count was feasible and well-tolerated in a patient with concomitant CML and locally advanced laryngeal squamous cell carcinoma. CONCLUSIONS: Our report indicates the feasibility of combination imatinib and cetuximab plus carboplatin in a case of multiple cancer diagnoses, provided that the treatment with imatinib is modulated according to the expected bone marrow depression. PMID- 26979244 TI - Peripapillary retinal leukemic infiltration associated with papilledema in a T ALL patient without cranial or optic nerve involvement. AB - PURPOSE: To present a rare case of bilateral peripapillary retinal leukemic infiltration associated with papilledema without retrobulbar optic nerve involvement in a patient with acute lymphoblastic leukemia (ALL). METHODS: This was a retrospective case report. RESULTS: A 24-year-old man with T-cell ALL and 2 month history of papilledema presented to our department with reduction of visual acuity in the left eye. Visual acuity was 20/60 in the right eye and hand movements in the left eye. Fundus examination revealed grade 3 papilledema, bilateral peripapillary leukemic infiltration, and intraretinal hemorrhages. Cranial magnetic resonance imaging did not show any sign of cranial mass or optic nerve involvement. Pulse steroid therapy and oral acetazolamide was started. At day 18, visual acuity improved to 20/40 in the right eye and 20/60 in the left eye, while papilledema improved to grade 1 and hemorrhages regressed. CONCLUSIONS: To our knowledge, there is no other report of peripapillary leukemic infiltration in the absence of retrobulbar optic nerve involvement. We suspect that papilledema might have facilitated peripapillary retinal infiltration due to altered vascular permeability. The reverse could also be possible: leukemic infiltration leading to increase in vascular permeability may also contribute to papilledema. PMID- 26979246 TI - Is the chemotherapy era in advanced non-small cell lung cancer really over? Maybe not yet. AB - Lung cancer is one of the most frequently diagnosed tumors in both the male and female population. In Italy it is the leading cause of cancer deaths in men and the third in women. Although the 5-year survival rate has moderately increased in the last years, the diagnosis remains associated with a very poor prognosis. However, in the last decade significant progress has been made, also in the treatment of advanced-stage non-small cell lung cancer. The advent of targeted therapies and the recent explosion of immunotherapy seem to have limited the role of chemotherapy. But is this completely true? The aim of this editorial is to discuss some of the most controversial aspects of the therapeutic scenario in non small cell lung cancer, with particular attention to the role that chemotherapy still plays. PMID- 26979245 TI - Polymorphism rs144848 in BRCA2 may reduce lung cancer risk in women: a case control study in southeast China. AB - PURPOSE: Whereas lung cancer incidence among men has declined in recent years, the incidence rate among women has increased rapidly. Sex could affect DNA repair capacity. Although BRCA2 is important in DNA repair, few data are available on the association between BRCA2 polymorphisms and lung cancer in women. Therefore, we investigated this in a case-control study among Chinese women. METHODS: We enrolled 226 women with lung cancer and 269 age-matched healthy controls in our study. Polymorphisms studied were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. RESULTS: Unconditional logistic regression showed no association between rs1799943 or rs1799944 and cancer risk. However, the AC and CC genotypes of rs144848 were significantly associated with reduced risk after adjustment for age and education, with adjusted odds ratios (ORs) of 0.66 (95% confidence interval [CI] 0.45-0.97) and 0.37 (95% CI 0.16-0.78), respectively. The adjusted OR of carriers with the C allele was 0.62 (95% CI 0.44-0.81) compared with the A allele. CONCLUSIONS: The rs144848 mutation may have a protective effect against lung cancer among women. PMID- 26979247 TI - Secondary bone marrow malignancies after adjuvant chemotherapy for breast cancer: a report of 2 cases and a review of the literature. AB - PURPOSE: Secondary malignancies are new cancers occurring in patients previously treated with radiation or chemotherapy for a primary tumor. Secondary cancers are not related to the primary tumor, and may develop months or years after cancer treatment: they are usually a result of the first cancer therapy. Chemotherapy and radiotherapy may increase the risk of second cancers, such as skin tumors (basal or squamous cell carcinoma) or acute leukemia. METHODS: A patient with B lymphoma and a patient with multiple myeloma, previously treated for breast cancer, are presented. RESULTS: We report the cases of 2 patients treated with adjuvant therapy for breast cancer who developed secondary bone marrow malignancies 15 years after primary treatment. CONCLUSIONS: By literature review, these 2 cases do not support the relationship between primary tumor treatment and secondary cancer, but strongly suggest the need for histologic samples when bone metastasis occurred after years from diagnosis of breast cancer. In this setting, the oncologist should take into account a secondary bone marrow tumor before starting treatment for breast cancer. PMID- 26979248 TI - Validation and Cross-Cultural Adaptation of a Chinese Version of the Emotional and Social Dysfunction Questionnaire in Stroke Patients. AB - The objectives of this study were to develop a cross-cultural Chinese version of the Emotional and Social Dysfunction Questionnaire (ESDQ-C) and test its validity and reliability among Chinese-speaking stroke patients. Various methods were used to develop the ESDQ-C. A cross-sectional study was used to examine the validity and reliability of the developed questionnaire, which consists of 28 items belonging to six factors, anger, helplessness, emotional dyscontrol, indifference, inertia and fatigue, and euphoria. Satisfactory convergence and known-group validities were confirmed by significant correlations of the ESDQ-C with the Profile of Mood States-Short Form ( p < .05) and with the Hospital Anxiety and Depression Scale ( p < .05). The internal consistency was represented by Cronbach's alpha, which was .96 and .79 to .92 for the entire scale and subscales, respectively. Appropriate application of the ESDQ-C will be helpful to identify critical adjustment-related types of distress and patients who experience difficulty coping with such distress. PMID- 26979249 TI - Value of 24-hour Delayed Film of Barium Enema for Evaluation of Colon Transit Function in Young Children with Constipation. AB - BACKGROUND/AIMS: A colon transit time test using radio-opaque markers (CTTRM) is considered the gold standard for evaluating colon transit function. A 24-hour delayed film of barium enema (BE) has been used as a supplementary method in structural evaluations. The aim of this study was to evaluate the utility of a 24 hour delayed BE film for assessing colon transit function in young children with constipation. METHODS: In total, 93 children with constipation who performed both single-contrast BE and CTTRM were enrolled in this study. Of these, the data from 70 children were analyzed (males 33, females 37; mean age [range], 5.63 +/- 2.94 [2-14] years). The basic principle of the study is "velocity = distance/time". Time values were identified in both studies, and the colon length and distance of barium movement were measured on the 24-hour delayed BE film. Thus, colon transit velocity values could be calculated using both methods. The correlation between colon transit velocity using a 24-hour delayed BE film versus CTTRM was analyzed statistically. RESULTS: Median value (interquartile range) of colon transit velocity using CTTRM was 1.57 (1.07-2.89) cm/hr, and that using BE of that was 1.58 (0.94-2.07) cm/hr. The Spearman correlation coefficient was 0.438 (P < 0.001) for the overall group. The correlation was strongest in children younger than 4 years (r= 0.537, P = 0.032). CONCLUSIONS: Although the correlation between BE and CTTRM was not very strong, the 24-hour delayed BE film could provide broad information about colon transit function in young children, especially those under 4 years who usually cannot undergo CTTRM. PMID- 26979251 TI - WHAT ARE 'BEST INTERESTS'? A CRITICAL EVALUATION OF 'BEST INTERESTS' DECISION MAKING IN CLINICAL PRACTICE. AB - Obtaining the patient's consent is usually a prerequisite of any clinical intervention. However, some cognitively impaired patients may not be able to give valid consent. Following years of consultation and legislative review, the Mental Capacity Act 2005 (MCA) provides a statutory framework of 'best interests' decision-making on behalf of incapacitated individuals. However, confusion over the meaning and application of the 'best interests' standard persists. This paper explores the variation in judicial interpretation of the standard and the complexities of best interests decision-making in clinical practice. Prevailing confusion and risk-aversive practices mean that the rights and interests of cognitively impaired individuals continue to be compromised, with evidence to suggest that 'best interests' may be conflated with the clinician's evaluation of 'best medical interests'. PMID- 26979253 TI - Shaken baby witness was dishonest about her expertise, finds tribunal. PMID- 26979250 TI - Safe and effective pharmacotherapy in infants and preschool children: importance of formulation aspects. AB - Safe and effective paediatric pharmacotherapy requires careful evaluation of the type of drug substance, the necessary dose and the age-appropriateness of the formulation. Generally, the younger the child, the more the attention that is required. For decades, there has been a general lack of (authorised) formulations that children are able to and willing to take. Moreover, little was known on the impact of pharmaceutical aspects on the age-appropriateness of a paediatric medicine. As a result of legislative incentives, such knowledge is increasingly becoming available. It has become evident that rapidly dissolving tablets with a diameter of 2 mm (mini-tablets) can be used in preterm neonates and non-rapidly dissolving 2 mm mini-tablets in infants from 6 months of age. In addition, uncoated 4 mm mini-tablets can be used in infants from the age of 1 year. Also, there is some evidence that children prefer mini-tablets over a powder, suspension or syrup. Other novel types of age-appropriate oral formulations such as orodispersible films may further add to the treatment possibilities. This review provides an overview of the current knowledge on oral formulations for infants and preschool children, the advantages and disadvantages of the different types of dosage forms and the age groups by which these can likely be used. PMID- 26979252 TI - The plasmid-mediated evolution of the mycobacterial ESX (Type VII) secretion systems. AB - BACKGROUND: The genome of Mycobacterium tuberculosis contains five copies of the ESX gene cluster, each encoding a dedicated protein secretion system. These ESX secretion systems have been defined as a novel Type VII secretion machinery, responsible for the secretion of proteins across the characteristic outer mycomembrane of the mycobacteria. Some of these secretion systems are involved in virulence and survival in M. tuberculosis; however they are also present in other non-pathogenic mycobacteria, and have been identified in some non-mycobacterial actinomycetes. Three components of the ESX gene cluster have also been found clustered in some gram positive monoderm organisms and are predicted to have preceded the ESX gene cluster. RESULTS: This study used in silico and phylogenetic analyses to describe the evolution of the ESX gene cluster from the WXG-FtsK cluster of monoderm bacteria to the five ESX clusters present in M. tuberculosis and other slow-growing mycobacteria. The ancestral gene cluster, ESX 4, was identified in several nonmycomembrane producing actinobacteria as well as the mycomembrane-containing Corynebacteriales in which the ESX cluster began to evolve and diversify. A novel ESX gene cluster, ESX-4EVOL, was identified in some non-mycobacterial actinomycetes and M. abscessus subsp. bolletii. ESX-4EVOL contains all of the conserved components of the ESX gene cluster and appears to be a precursor of the mycobacterial ESX duplications. Between two and seven ESX gene clusters were identified in each mycobacterial species, with ESX-2 and ESX-5 specifically associated with the slow growers. The order of ESX duplication in the mycobacteria is redefined as ESX-4, ESX-3, ESX-1 and then ESX-2 and ESX-5. Plasmid-encoded precursor ESX gene clusters were identified for each of the genomic ESX-3, -1, -2 and -5 gene clusters, suggesting a novel plasmid-mediated mechanism of ESX duplication and evolution. CONCLUSIONS: The influence of the various ESX gene clusters on vital biological and virulence-related functions has clearly influenced the diversification and success of the various mycobacterial species, and their evolution from the non-pathogenic fast-growing saprophytic to the slow-growing pathogenic organisms. PMID- 26979254 TI - The influence of harpagoside and harpagide on TNFalpha-secretion and cell adhesion molecule mRNA-expression in IFNgamma/LPS-stimulated THP-1 cells. AB - Inflammation does not only lead to pain and functio laesa in the affected tissue but is also implicated in the onset and progression of cardiovascular diseases and cancer. Many medicinal plants show anti-inflammatory properties yet plant constituents and their effect on molecular pathways involved in the attenuation of inflammation as well as cell migration are only poorly understood. Harpagophytum procumbens DC. ex MEISN. is a potent plant used as an immune modulator in traditional herbal medicine. Aim of this study was to investigate the influence of harpagoside and harpagide on TNFalpha-secretion in undifferentiated and differentiated THP-1 cells under inflammatory conditions as well as their implication in cellular migration into inflamed tissue. We found that both iridoids decrease TNFalpha-secretion in PMA-differentiated THP-1 cells whereas undifferentiated cells were poorly affected. Yet, in undifferentiated cells harpagoside and harpagide induced mRNA-expression of certain proteins involved in leukocyte transmigration. Especially TNFalpha and ICAM-1 mRNA expression was positively affected after 3h and expression could be maintained on high levels even after 48h. L-selectin and PSGL-1 were strongly induced after 48h of stimulation. This ambiguous effect of harpagoside and harpagide highlights their immune modulatory function by facilitating cell migration into the inflamed tissue, whereby in consequence the anti-inflammatory activity of the resident macrophages was also found to be promoted. PMID- 26979255 TI - Synthesis, characterization, and evaluation of the antimicrobial potential of copper(II) coordination complexes with quinolone and p-xylenyl-linked quinolone ligands. AB - The antimicrobial properties of copper have been known to mankind since the ancient times. In a coordination chemistry approach to develop novel antimicrobial agents, the quinolone antimicrobial agents ciprofloxacin (Hcipro) and pipemidic acid (Hpia), as well as dimers thereof (piperazinyl-linked with a p xylenyl moiety) were complexed with copper(II). The synthesis and antimicrobial evaluation of bis(ciprofloxacino)copper(II) [Cu(cipro)2], bis(pipemido)copper(II) [Cu(pia)2], and the corresponding dimer complexes, [Cu2(ciproXcipro)2] and [Cu2(piaXpia)2], are reported. No combinational or synergistic effect between copper(II) and the respective quinolone ligands was observed in vitro. PMID- 26979257 TI - Recurrent KRAS G12V pathogenic mutation in adenomatoid odontogenic tumours. PMID- 26979256 TI - Refugee migration and risk of schizophrenia and other non-affective psychoses: cohort study of 1.3 million people in Sweden. AB - OBJECTIVE: To determine whether refugees are at elevated risk of schizophrenia and other non-affective psychotic disorders, relative to non-refugee migrants from similar regions of origin and the Swedish-born population. DESIGN: Cohort study of people living in Sweden, born after 1 January 1984 and followed from their 14th birthday or arrival in Sweden, if later, until diagnosis of a non affective psychotic disorder, emigration, death, or 31 December 2011. SETTING: Linked Swedish national register data. PARTICIPANTS: 1,347,790 people, including people born in Sweden to two Swedish-born parents (1,191,004; 88.4%), refugees (24,123; 1.8%), and non-refugee migrants (132,663; 9.8%) from four major refugee generating regions: the Middle East and north Africa, sub-Saharan Africa, Asia, and Eastern Europe and Russia. MAIN OUTCOME MEASURES: Cox regression analysis was used to estimate adjusted hazard ratios for non-affective psychotic disorders by refugee status and region of origin, controlling for age at risk, sex, disposable income, and population density. RESULTS: 3704 cases of non-affective psychotic disorder were identified during 8.9 million person years of follow-up. The crude incidence rate was 38.5 (95% confidence interval 37.2 to 39.9) per 100,000 person years in the Swedish-born population, 80.4 (72.7 to 88.9) per 100,000 person years in non-refugee migrants, and 126.4 (103.1 to 154.8) per 100,000 person years in refugees. Refugees were at increased risk of psychosis compared with both the Swedish-born population (adjusted hazard ratio 2.9, 95% confidence interval 2.3 to 3.6) and non-refugee migrants (1.7, 1.3 to 2.1) after adjustment for confounders. The increased rate in refugees compared with non-refugee migrants was more pronounced in men (likelihood ratio test for interaction chi(2) (df=2) z=13.5; P=0.001) and was present for refugees from all regions except sub Saharan Africa. Both refugees and non-refugee migrants from sub-Saharan Africa had similarly high rates relative to the Swedish-born population. CONCLUSIONS: Refugees face an increased risk of schizophrenia and other non-affective psychotic disorders compared with non-refugee migrants from similar regions of origin and the native-born Swedish population. Clinicians and health service planners in refugee receiving countries should be aware of a raised risk of psychosis in addition to other mental and physical health inequalities experienced by refugees. PMID- 26979258 TI - Knot Security- How is it Affected by Suture Technique, Material, Size, and Number of Throws? AB - PURPOSE: To measure knot security in relation to different surgical knotting techniques, suture materials, suture sizes, and number of throws commonly used in oral and maxillofacial surgery. MATERIALS AND METHODS: Three surgical tying techniques were tested: square, surgeon's, and sliding knots. Suture materials included chromic gut, nylon, silk, and Vicryl (polyglycolic acid). Suture diameter sizes 3-0, 4-0, and 5-0 were tested. Ten trials were undertaken for each combination of material, size, and technique using 2, 3, 4, 5, and 6 throws (ties). Suture materials were presoaked in 0.9% saline solution for 15 minutes to simulate the environment of the oral cavity. A standard knot-tying force for each throw was applied to each combination. Knot security satisfaction was set from pilot experimental trials at less than 1.8-mm slippage from the center of the knot while testing. The dichotomous outcome of knot slippage (stable or unstable) was analyzed using logistic regression analysis and odds ratios with Tukey adjusted 95% confidence intervals. RESULTS: Knot security depended on suture technique, material, and number of throws but did not depend on suture size. In general, 4 throws were required for surgeon's and square knots, whereas 5 throws were required for sliding knots. After 5 throws, tying an additional throw did not contribute to knot security. Surgeon's knots were stronger than square knots and sliding knots (P < .0001 and P < .0001). Square knots were stronger than sliding knots (P = .01). Vicryl had the greatest knot security, followed by chromic gut, nylon, and silk. CONCLUSION: This study showed that knot security depends on suture material, tying technique, and number of throws, but is independent of suture size. Surgeon's knot security was greater than that for square and sliding knots when using sutures commonly used in the oral cavity. Vicryl had the greatest knot security and silk had the least. For surgeon's and square knots, at least 4 throws were generally indicated to achieve knot security; for sliding knots, at least 5 throws were generally indicated. Knot security did not increase after 5 throws and 2 throws are never indicated. PMID- 26979259 TI - A flexible pressure sensor could correctly measure the depth of chest compression on a mattress. AB - BACKGROUND: Feedback devices are used to improve the quality of chest compression (CC). However, reports have noted that accelerometers substantially overestimate depth when cardiopulmonary resuscitation (CPR) is performed on a soft surface. Here, we determined whether a flexible pressure sensor could correctly evaluate the depth CC performed on a mannequin placed on a mattress. METHODS: Chest compression was performed 100 times/min by a compression machine on the floor or a mattress, and the depth of CC was monitored using a flexible pressure sensor (Shinnosukekun) and CPRmeter(TM). The depth of machine-performed CC was consistently 5cm. We compared data from the feedback sensor with the true depth of CC using dual real-time auto feedback system that incorporated an infrared camera (CPR evolution(TM)). RESULTS: On the floor, the true depth of CC was 5.0+/ 0.0cm (n=100), or identical to the depth of CC performed by the machine. The Shinnosukekun(TM) measured a mean (+/-SD) CC depth of 5.0+/-0.1cm (n=100), and the CPRmeter(TM) measured a depth of 5.0+/-0.2cm (n=100). On the mattress, the true depth of CC was 4.4+/-0.0cm (n=100). The Shinnosukekun(TM) measured a mean CC depth of 4.4+/-0.0cm (n=100), and the CPRmeter(TM) measured a depth of 4.7+/ 0.1cm (n=100). The data of CPRmeter(TM) were overestimated (P<.0001 between the true depth and the CPRmeter(TM)-measured depth). CONCLUSION: The Shinnosukekun(TM) could correctly measure the depth of CC on a mattress. According to our present results, the flexible pressure sensor could be a useful feedback system for CC performed on a soft surface. PMID- 26979260 TI - Comparison of the VivaSight single lumen endotracheal tube and the Macintosh laryngoscope for emergency intubation by experienced paramedics in a standardized airway manikin with restricted access: a randomized, crossover trial. PMID- 26979261 TI - Prospective, randomized, double-blind controlled trial comparing vapocoolant spray vs placebo spray in adults undergoing venipuncture. AB - INTRODUCTION: Topical anesthetics are used to decrease procedural pain such as venipuncture. Advantages of vapocoolants include rapid onset, ease of application, low cost, and lack of associated pain of injection and other needlestick-related risks. We hypothesized that the pain of venipuncture would be reduced by at least 1.8 points on a 10-point numerical rating scale after application of a vapocoolant compared with placebo. METHODS: We conducted a prospective, randomized, double-blind controlled trial of vapocoolant vs placebo spray in 100 adults (ages 18-80) requiring venipuncture in a hospital emergency department or observation unit. The primary efficacy outcome was the difference in pain scores immediately after venipuncture, measured on a 10-point verbal numeric rating scale from 0 (none) to worst (10). Safety outcomes included local adverse effects (edema, erythema, blanching) and changes in vital signs (VS). RESULTS: Patient characteristics and venipuncture procedure were not significantly different for the 2 groups. The median (interquartile range) pain of venipuncture was 3 (1.2-5) in the placebo group and 1 (0-3) in the vapocoolant group, P < .001. Skin checklist revealed the following: vapocoolant-minimal blanching 4%, minimal erythema 18% which resolved within 5 minutes; placebo-no visible skin changes. Photographs at 5 to 10 minutes revealed no visible skin changes in any patient. There were 2 complaints: "very wet and cold on skin" (placebo) and "felt burning on skin" (vapocoolant). CONCLUSION: The vapocoolant significantly decreased venipuncture pain in adults compared with placebo and was well tolerated with minor adverse effects that resolved quickly. There were no significant differences in VS and no visible skin changes documented at the site by photographs taken within 5 to 10 minutes postspray/venipuncture. PMID- 26979262 TI - Macroevolutionary dynamics in the early diversification of Asteraceae. AB - Spatial and temporal differences in ecological opportunity can result in disparity of net species diversification rates and consequently uneven distribution of taxon richness across the tree of life. The largest eudicotyledonous plant family Asteraceae has a global distribution and at least 460 times more species than its South American endemic sister family Calyceraceae. In this study, diversification rate dynamics across Asteraceae are examined in light of the several hypothesized causes for the family's evolutionary success that could be responsible for rate change. The innovations of racemose capitulum and pappus, and a whole genome duplication event occurred near the origin of the family, yet we found the basal lineages of Asteraceae that evolved in South America share background diversification rates with Calyceraceae and their Australasian sister Goodeniaceae. Instead we found diversification rates increased gradually from the origin of Asteraceae approximately 69.5Ma in the late Cretaceous through the Early Eocene Climatic Optimum at least. In contrast to earlier studies, significant rate shifts were not strongly correlated with intercontinental dispersals or polyploidization. The difference is due primarily to sampling more backbone nodes, as well as calibrations placed internally in Asteraceae that resulted in earlier divergence times than those found in most previous relaxed clock studies. Two clades identified as having transformed rate processes are the Vernonioid Clade and a clade within the Heliantheae alliance characterized by phytomelanic fruit (PF Clade) that represents an American radiation. In Africa, subfamilies Carduoideae, Pertyoideae, Gymnarrhenoideae, Cichorioideae, Corymbioideae, and Asteroideae diverged in a relatively short span of only 6.5millionyears during the Middle Eocene. PMID- 26979263 TI - Was Gondwanan breakup the cause of the intercontinental distribution of Osteoglossiformes? A time-calibrated phylogenetic test combining molecular, morphological, and paleontological evidence. AB - The intercontinental distribution of living freshwater osteoglossiform fishes (Osteoglossomorpha, Teleostei) was hypothesized to predominantly represent the vicariant result of the fragmentation of Gondwana based on physiological and phylogenetic evidence. The fossil record, however, challenges this hypothesis by making transoceanic dispersal plausible because it provides post-fragmentation minimum ages of intercontinental clades and it includes several marine forms. The aim of this study was to test whether the divergence of Osteoglossiformes was compatible with the breakup of Gondwana using newly reconstructed time-calibrated phylogenetic trees based on a large dataset combining extant and fossil taxa and molecular and morphological characters. Bayesian tip-dating and node-dating approaches with different Teleostei age calibrations were employed. The results of the divergence tests are largely dependent on the a priori calibrated age of crown-group Teleostei, with two of the three specific vicariance hypotheses tested in this study not being rejected only when the age of the Teleostei was constrained to be as old as the early Permian. Molecules consistently push the age of crown-group Teleostei back to the Paleozoic, while the fossil record, which is considered informative, does not support such an ancient origin. Reconciling molecular and paleontological estimates of the age of crown-group Teleostei is central to determining the role of Gondwanan breakup in the intercontinental distribution of freshwater teleosts, including Osteoglossiformes. PMID- 26979264 TI - Apnea-like suppression of respiratory motion: First evaluation in radiotherapy. AB - BACKGROUND AND PURPOSE: Compensation for respiratory motion is needed while administering radiotherapy (RT) to tumors that are moving with respiration to reduce the amount of irradiated normal tissues and potentially decrease radiation induced collateral damages. The purpose of this study was to test a new ventilation system designed to induce apnea-like suppression of respiratory motion and allow long enough breath hold durations to deliver complex RT. MATERIAL AND METHODS: The High Frequency Percussive Ventilation system was initially tested in a series of 10 volunteers and found to be well tolerated, allowing a median breath hold duration of 11.6 min (range 3.9-16.5 min). An evaluation of this system was subsequently performed in 4 patients eligible for adjuvant breast 3D conformal RT, for lung stereotactic body RT (SBRT), lung volumetric modulated arc therapy (VMAT), and VMAT for palliative pleural metastases. RESULTS: When compared to free breathing (FB) and maximal inspiration (MI) gating, this Percussion Assisted RT (PART) offered favorable dose distribution profiles in 3 out of the 4 patients tested. PART was applied in these 3 patients with good tolerance, without breaks during the "beam on time period" throughout the overall courses of RT. The mean duration of the apnea-like breath hold that was necessary for delivering all the RT fractions was 7.61 min (SD=2.3). CONCLUSIONS: This first clinical implementation of PART was found to be feasible, tolerable and offers new opportunities in the field of RT for suppressing respiratory motion. PMID- 26979265 TI - An Update on Neurofibromatosis Type 1: Not Just Cafe-au-Lait Spots, Freckling, and Neurofibromas. An Update. Part I. Dermatological Clinical Criteria Diagnostic of the Disease. AB - Neurofibromatosis type 1 (NF1) is the most common neurocutaneous syndrome and probably the one best known to dermatologists, who are generally the first physicians to suspect its diagnosis. Although the genetic locus of NF1 was identified on chromosome 17 in 1987, diagnosis of the disease is still mainly based on clinical observations and the diagnostic criteria of the National Institute of Health, dating from 1988. Cutaneous manifestations are particularly important because cafe-au-lait spots, freckling on flexural areas, and cutaneous neurofibromas comprise 3 of the 7 clinical diagnostic criteria. However, cafe-au lait spots and freckling can also be present in other diseases. These manifestations are therefore not pathognomonic and are insufficient for definitive diagnosis in the early years of life. NF1 is a multisystemic disease associated with a predisposition to cancer. A multidisciplinary follow-up is necessary and dermatologists play an important role. PMID- 26979266 TI - A genome-wide survey of expansive NLR-C subfamily in miiuy croaker and characterization of the NLR-B30.2 genes. AB - NOD-like receptors (NLRs) are essential intracellular pattern-recognition receptors that respond to pathogens and regulate innate immunity. NLRs include three distinct subfamilies: NLR-A, NLR-B and NLR-C, thereinto, NLR-C as a large subfamily is unique to bony fish and little research about it has been done. In the current study, we identified the members of NLR-B and NLR-C subfamilies containing 2 and 48 genes respectively in miiuy croaker. Compared with other teleosts except for zebrafish, NLR-C subfamily genes occurred expansion in miiuy croaker. The gene expansions of NLR-C subfamily may illustrate adaptive genome evolution in response to specific aquatic environments. Structural analysis showed that the N-terminus of NLR-C subfamily receptors has different characteristics of the domains including RING domain, FISNA domain or PYRIN domain. Interestingly, the C-terminus of 18 NLR-C subfamily members contains an extra B30.2 domain (named NLR-B30.2 genes) which plays an important role in antiviral immune recognition. Simultaneously, molecular evolutionary analysis indicated that the positively sites in miiuy croaker are mainly located in NACHT domain which was the vital region for signal transduction in immune response. Significantly, pathogens challenge in spleen and macrophages demonstrated that NLR-B30.2 genes exhibited more sensitive response to virus than bacteria, suggesting these genes play enhanced roles in innate antiviral immunity, which may represent a new family used for antiviral infection. PMID- 26979267 TI - A closer study of methanol adsorption and its impact on solute retentions in supercritical fluid chromatography. AB - Surface excess adsorption isotherms of methanol on a diol silica adsorbent were measured in supercritical fluid chromatography (SFC) using a mixture of methanol and carbon dioxide as mobile phase. The tracer pulse method was used with deuterium labeled methanol as solute and the tracer peaks were detected using APCI-MS over the whole composition range from neat carbon dioxide to neat methanol. The results indicate that a monolayer (4A) of methanol is formed on the stationary phase. Moreover, the importance of using the set or the actual methanol fractions and volumetric flows in SFC was investigated by measuring the mass flow respective pressure and by calculations of the actual volume fraction of methanol. The result revealed a significant difference between the value set and the actually delivered volumetric methanol flow rate, especially at low modifier fractions. If relying only on the set methanol fraction in the calculations, the methanol layer thickness should in this system be highly overestimated. Finally, retention times for a set of solutes were measured and related to the findings summarized above concerning methanol adsorption. A strongly non-linear relationship between the logarithms of the retention factors and the modifier fraction in the mobile phase was revealed, prior to the established monolayer. At modifier fractions above that required for establishment of the methanol monolayer, this relationship turns linear which explains why the solute retention factors are less sensitive to changes in modifier content in this region. PMID- 26979269 TI - NO adsorption on Cu(110) and O(2 * 1)/Cu(110) surfaces from density functional theory calculations. AB - In a recent study [M. Feng, et al., ACS Nano, 2011, 5, 8877], it was shown that CO molecules adsorbed on the quasi-one-dimensional O(2 * 1)/Cu(110) surface reconstruction tend to form highly-ordered single-molecule-wide rows along the direction perpendicular to the Cu-O chains. This stems from the peculiar tilted adsorption configuration of CO on this substrate, which gives rise to short-range attractive dipole-dipole interactions. Motivated by this observation, here we study the adsorption of nitric oxide (NO) on O(2 * 1)/Cu(110) and Cu(110) using density functional theory, with the aim of elucidating whether a similar behaviour can be expected for this molecule. We first study NO adsorption on a clean Cu(110) surface, where the role of short-range attractions between molecules has already been pointed out by the observation of the formation of NO dimers by scanning tunnelling microscopy [A. Shiotari, et al., Phys. Rev. Lett., 2011, 106, 156104]. On the clean Cu(110), the formation of dimers along the [110] direction is favourable, in agreement with published experimental results. However, the formation of extended NO rows is found to be unstable. Regarding the O(2 * 1)/Cu(110) substrate, we observe that NO molecules adsorb in between the Cu O chains, causing a substantial disruption of the surface structure. Although individual molecules can be tilted with negligible energetic cost along the direction of the Cu-O chains, the interaction among neighbouring molecules was found to be repulsive along all directions and, consequently, the formation of dimers unfavourable. PMID- 26979270 TI - Hysteretic memory in pH-response of water contact angle on poly(acrylic acid) brushes. AB - We investigated the pH-dependent response of flat polyacid brushes of varying length and dispersity in the extended brush regime. Our model system consisted of poly(acrylic acid) brushes, which change from hydrophobic and neutral at low pH to hydrophilic and negatively charged at high pH, synthesized on silicon substrates using a grafting-from approach at constant grafting density. We observed three trends in the pH-response: first, the dry brush thickness increased as the pH was increased for brushes above a critical length, and this effect was magnified as the dispersity increased; second, the water contact angle measured at low pH was larger for brushes of greater dispersity; and third, brushes of sufficient dispersity exhibited hysteretic memory behavior in the pH dependence of the contact angle, in which the contact angle upon increasing and decreasing pH differed. As a consequence, the pKa of the brushes measured upon increasing pH was consistently higher than that measured upon decreasing pH. The observed pH response is consistent with proposed changes in the conformation and charge distribution of the polyelectrolyte brushes that depend on the direction of pH change and the dispersity of the brushes. PMID- 26979268 TI - Pre-column dilution large volume injection ultra-high performance liquid chromatography-tandem mass spectrometry for the analysis of multi-class pesticides in cabbages. AB - Pre-column dilution large volume injection (PD-LVI), a novel sample injection technique for reverse phase ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), was developed in this study. The PD-LVI UHPLC MS/MS system was designed by slightly modifying the commercial UHPLC-MS/MS equipment with a mixer chamber. During the procedure of PD-LVI, sample solution of 200MUL was directly carried by the organic mobile phase to the mixer and diluted with the aqueous mobile phase. After the mixture was introduced to the UHPLC column in a mobile phase of acetonitrile-water (15/85, v/v), the target analytes were stacked on the head of the column until following separation. Using QuEChERS extraction, no additional steps such as solvent evaporation or residue redissolution were needed before injection. The features of PD-LVI UHPLC-MS/MS system were systematically investigated, including the injection volume, the mixer volume, the precondition time and the gradient elution. The efficiency of this approach was demonstrated by direct analysis of 24 pesticides in cabbages. Under the optimized conditions, low limits of detection (0.00074-0.8 ng/kg) were obtained. The recoveries were in the range of 63.3-109% with relative standard deviations less than 8.1%. Compared with common UHPLC-MS/MS technique, PD-LVI UHPLC-MS/MS showed significant advantages such as excellent sensitivity and reliability. The mechanism of PD-LVI was demonstrated to be based on the column head stacking effect with pre-column dilution. Based on the results, PD-LVI as a simple and effective sample injection technique of reverse phase UHPLC-MS/MS for the analysis of trace analytes in complex samples showed a great promising prospect. PMID- 26979271 TI - Autoimmune atherosclerosis in 3D: How it develops, how to diagnose and what to do. AB - Autoimmune-inflammatory rheumatic diseases, such as rheumatoid arthritis (RA) have been associated with autoimmune atherosclerosis leading to increased cardiovascular risk. Traditional risk factors, genetics, as well as the role of systemic inflammation including inflammatory cells, cytokines, chemokines, proteases, autoantibodies, adhesion receptors and others have been implicated in the development of these vascular pathologies. Cardiovascular risk may be determined by the use of currently available tools. In addition, non-invasive assessment of vascular pathophysiology by imaging, as well as laboratory biomarkers can help to refine risk assessment. With respect to prevention and therapy, traditional vasculoprotection using statins, ACE inhibitors, aspirin should be applied to patients at risk. Non-steroidal antiinflammatory drugs and corticosteroids may be pro-atherogenic, on the other hand, they may also be beneficial due to their anti-inflammatory nation. Traditional and biologic DMARDs may have significant vascular and metabolic effects. Decreasing inflammatory activity by any of these agents may lead to better CV outcome. The official EULAR recommendations on the assessment and management of cardiovascular disease in arthritides may guide the rheumatologist during the process of CV screening, prevention and treatment. PMID- 26979272 TI - Flexible and static wrist units in upper limb prosthesis users: functionality scores, user satisfaction and compensatory movements. AB - BACKGROUND: The current study examines the relevance of prosthetic wrist movement to facilitate activities of daily living or to prevent overuse complaints. Prosthesis hands with wrist flexion/extension capabilities are commercially available, but research on the users' experiences with flexible wrists is limited. METHODS: In this study, eight transradial amputees using a myoelectric prosthesis tested two prosthesis wrists with flexion/extension capabilities, the Flex-wrist (Otto Bock) and Multi-flex wrist (Motion Control), in their flexible and static conditions. Differences between the wrists were assessed on the levels of functionality, user satisfaction and compensatory movements after two weeks use. RESULTS: No significant differences between flexible and static wrist conditions were found on activity performance tests and standardized questionnaires on satisfaction. Inter-individual variation was remarkably large. Participants' satisfaction tended to be in favour of flexible wrists. All participants but one indicated that they would choose a prosthesis hand with wrist flexion/extension capabilities if allowed a new prosthesis. Shoulder joint angles, reflecting compensatory movements, showed no clear differences between wrist conditions. CONCLUSIONS: Overall, positive effects of flexible wrists are hard to objectify. Users seem to be more satisfied with flexible wrists. A person's needs, work and prosthesis skills should be taken into account when prescribing a prosthesis wrist. TRIAL REGISTRATION: Nederlands Trial Register NTR3984 . PMID- 26979274 TI - Transition to Retirement and Use of Private Health Care. AB - Associations between retirement and changes in health care use have not been shown in a longitudinal setting. In the Finnish universal health care system, transition into retirement from employment entails loss of access to occupational health care that provides easily accessible primary health care services, which may cause changes in utilization of other health care sectors. The aim of this study was to find out whether transition into old-age retirement is associated with change in utilization of private health care. The panel data consist of a 30% random sample of the Finnish population aged 62-75 in 2006-2011. Register data on National Health Insurance compensation were linked to socio-demographic covariates. Fixed-effects logistic and Poisson regression models were used. Adjusted for changes in covariates, retirement from employment was associated especially with private general practitioner visits but also with specialist visits among both women and men. Interaction analyses showed that retirement was associated with an increase in private care use only among those with higher-than median income. The results may indicate preferences for quick access to care, mistrust toward the universal system, and problems of the public system in delivering needed services. PMID- 26979273 TI - The Association Between Income Inequality and Oral Health in Canada: A Cross Sectional Study. AB - Societies exhibiting higher levels of economic inequality experience poorer health outcomes, and the proposed pathways used to explain these patterns are also relevant to oral health. This study therefore examines the relationship between the level of income inequality and the oral health and dental care services utilization of residents from eleven Canadian metropolitan areas. We calculated Pearson correlation coefficients (r) between each metropolitan area's Gini coefficient (used as a proxy for income inequality, calculated from 2006 Canadian census data) and each area's experience of dental pain, self-reported oral health, and use of dental care services (provided by data from the 2003 Canadian Community Health Survey). Greater levels of income inequality in the selected metropolitan areas were related to an increased likelihood of residents self-reporting their oral health as poor/fair and reporting a prolonged absence from visiting a dentist. There was, however, no relationship between the level of income inequality and the likelihood of respondents reporting a recent toothache, tooth sensitivity, or jaw pain. Policies designed to improve the oral health of the population, and Canadians' access to dental care generally, may therefore work best when supported by policies that promote greater economic equality within Canada. PMID- 26979275 TI - Identification of putative regulatory region of insulin-like androgenic gland hormone gene (IAG) in the prawn Macrobrachium nipponense and proteins that interact with IAG by using yeast two-hybrid system. AB - Insulin-like androgenic gland hormone gene (IAG) is a sex regulator specifically expressed in male crustaceans, controlling the male sexual differentiation, spermatogenesis and reproductive strategy. Our previous study reported the cloning and characterization of the prawn Macrobrachium nipponense IAG (MnIAG). In this study, we further identified a 2214-bp MnIAG 5'-flanking region, and analyzed its transcription factor binding sites and transcriptional activity. The results showed that there were two potential promoter core sequences, three TATA boxes and one CAAT box existing in the MnIAG 5'-flanking region as well as many potential transcription factor binding sites, such as SRY, Sox-5, GATA-1, etc. Notably, the transcriptional activity was weak in this region, and a negative regulatory region was found in -604 to -231bp. In addition, we constructed M. nipponense yeast libraries and identified proteins interacting with the MnIAG protein by yeast two hybridization assay. The yeast two-hybrid screening yielded ten positive clones, of which five were annotated by NCBI database, namely heat shock protein 21, NADH dehydrogenase, zinc finger protein, beta-N acetylglucosaminidase and a hypothetical protein. The identification of MnIAG putative regulatory region and proteins that interact with IAG will facilitate our understanding of the regulatory role of MnIAG and provide a foundation for deep insight into the prawn sex differentiation mechanism and signaling transduction pathways. PMID- 26979276 TI - Leptin receptor gene in the European sea bass (Dicentrarchus labrax): Cloning, phylogeny, tissue distribution and neuroanatomical organization. AB - In this study, we report the cloning of three transcripts for leptin receptor in the European sea bass, a marine teleost of economic interest. The two shortest variants, generated by different splice sites, encode all functional extracellular and intracellular domains but missed the transmembrane domain. The resulting proteins are therefore potential soluble binding proteins for leptin. The longest transcript (3605bp), termed sblepr, includes all the essential domains for binding and transduction of the signal. Thus, it is proposed as the ortholog for the human LEPR gene, the main responsible for leptin signaling. Phylogenetic analysis shows the sblepr clustered within the teleost leptin receptor group in 100% of the bootstrap replicates. The neuroanatomical localization of sblepr expressing cells has been assessed by in situ hybridization in brains of sea bass of both sexes during their first sexual maturation. At histological level, the distribution pattern of sblepr expressing cells in the brain shows no clear differences regarding sex or reproductive season. Transcripts of the sblepr have a widespread distribution throughout the forebrain and midbrain until the caudal portion of the hypothalamus. A high hybridization signal is detected in the telencephalon, preoptic area, medial basal and caudal hypothalamus and in the pituitary gland. In a more caudal region, sblepr expressing cells are identified in the longitudinal torus. The expression pattern observed for sblepr suggests that in sea bass, leptin is very likely to be involved in the control of food intake, energy reserves and reproduction. PMID- 26979277 TI - Similarities and differences between molecular order in the nematic and twist bend nematic phases of a symmetric liquid crystal dimer. AB - The order parameter, Szz, where z is the para axis of the difluoroterphenyl groups in DTC5C9, has been obtained from chemical shift anisotropies measured by (13)C - {(1)H} NMR experiments at temperatures throughout the nematic, NU, and twist-bend nematic, NTB, phases shown by this compound. The order parameter temperature profiles are unusual in having a maximum value in the NU phase and then decreasing until the NTB phase is reached. There is a small discontinuity (~2%) in Szz at TNNTB and then a gradual decrease until a new phase appears. This behaviour is interpreted as revealing a temperature-dependent tilting of local directors in both phases away from the applied magnetic field direction. In the enantiomorphic twist-bend phase this tilt is consistent with the structure of the phase as a helical arrangement of local directors, whilst in the high-temperature non-chiral nematic the tilt must involve a non-chiral arrangement. It is proposed that in both phases the tilting of directors has a common origin in the bent shape of the molecules. PMID- 26979278 TI - The i6A37 tRNA modification is essential for proper decoding of UUX-Leucine codons during rpoS and iraP translation. AB - The translation of rpoS(sigma(S)), the general stress/stationary phase sigma factor, is tightly regulated at the post-transcriptional level by several factors via mechanisms that are not clearly defined. One of these factors is MiaA, the enzyme necessary for the first step in theN(6)-isopentyl-2-thiomethyl adenosinemethyl adenosine 37 (ms(2)i(6)A37) tRNA modification. We tested the hypothesis that an elevated UUX-Leucine/total leucine codon ratio can be used to identify transcripts whose translation would be sensitive to loss of the MiaA dependent modification. We identified iraPas another candidate MiaA-sensitive gene, based on the UUX-Leucine/total leucine codon ratio. AniraP-lacZ fusion was significantly decreased in the abse nce of MiaA, consistent with our predictive model. To determine the role of MiaA in UUX-Leucine decoding in rpoS and iraP, we measured beta-galactosidase-specific activity of miaA(-)rpo Sandira P translational fusions upon overexpression of leucine tRNAs. We observed suppression of the MiaA effect on rpoS, and notira P, via overexpression of tRNA(LeuX)but not tRNA(LeuZ) We also tested the hypothesis that the MiaA requirement for rpoS and iraP translation is due to decoding of UUX-Leucine codons within the rpoS and iraP transcripts, respectively. We observed a partial suppression of the MiaA requirement for rpoS and iraP translational fusions containing one or both UUX-Leucine codons removed. Taken together, this suggests that MiaA is necessary for rpoS and iraP translation through proper decoding of UUX-Leucine codons and that rpoS and iraP mRNAs are both modification tunable transcripts (MoTTs) via the presence of the modification. PMID- 26979279 TI - Topology of RNA-protein nucleobase-amino acid pi-pi interactions and comparison to analogous DNA-protein pi-pi contacts. AB - The present work analyzed 120 high-resolution X-ray crystal structures and identified 335 RNA-protein pi-interactions (154 nonredundant) between a nucleobase and aromatic (W, H, F, or Y) or acyclic (R, E, or D) pi-containing amino acid. Each contact was critically analyzed (including using a visual inspection protocol) to determine the most prevalent composition, structure, and strength of pi-interactions at RNA-protein interfaces. These contacts most commonly involve F and U, with U:F interactions comprising one-fifth of the total number of contacts found. Furthermore, the RNA and protein pi-systems adopt many different relative orientations, although there is a preference for more parallel (stacked) arrangements. Due to the variation in structure, the strength of the intermolecular forces between the RNA and protein components (as determined from accurate quantum chemical calculations) exhibits a significant range, with most of the contacts providing significant stability to the associated RNA-protein complex (up to -65 kJ mol(-1)). Comparison to the analogous DNA-protein pi interactions emphasizes differences in RNA- and DNA-protein pi-interactions at the molecular level, including the greater abundance of RNA contacts and the involvement of different nucleobase/amino acid residues. Overall, our results provide a clearer picture of the molecular basis of nucleic acid-protein binding and underscore the important role of these contacts in biology, including the significant contribution of pi-pi interactions to the stability of nucleic acid protein complexes. Nevertheless, more work is still needed in this area in order to further appreciate the properties and roles of RNA nucleobase-amino acid pi interactions in nature. PMID- 26979281 TI - Approximation of Resting Energy Expenditure in Intensive Care Unit Patients Using the SenseWear Bracelet: A Comparison With Indirect Calorimetry. AB - BACKGROUND AND AIMS: Indirect calorimetry (IC) is the gold standard for determining energy expenditure in patients requiring mechanical ventilation. Metabolic armbands using data derived from dermal measurements have been proposed as an alternative to IC in healthy subjects, but their utility during critical illness is unclear. The aim of this study was to determine the level of agreement between the SenseWear armband and the Deltatrac Metabolic Monitor in mechanically ventilated intensive care unit (ICU) patients. METHODS: Adult ICU patients requiring invasive ventilator therapy were eligible for inclusion. Simultaneous measurements were performed with the SenseWear Armband and Deltatrac under stable conditions. Resting energy expenditure (REE) values were registered for both instruments and compared with Bland-Altman plots. RESULTS: Forty-two measurements were performed in 30 patients. The SenseWear Armband measured significantly higher REE values as compared with IC (mean bias, 85 kcal/24 h; P = .027). Less variability was noted between individual SenseWear measurements and REE as predicted by the Harris-Benedict equation (2 SD, +/-327 kcal/24 h) than when IC was compared with SenseWear and Harris-Benedict (2 SD, +/-473 and +/-543 kcal/24 h, respectively). CONCLUSIONS: The systematic bias and large variability of the SenseWear armband when compared with gas exchange measurements confer limited benefits over the Harris Benedict equation in determining caloric requirements of ICU patients. PMID- 26979280 TI - Presence of Polycyclic Aromatic Hydrocarbons in Rubber Packaging Materials and in Parenteral Formulations Stored in Bottles With Rubber Stoppers. AB - BACKGROUND: Rubber closures are the primary packaging material for sterile preparations intended for repeated use. Important features of rubber closures are achieved after additives are added to the elastomeric material that compounds the rubber. Among these additives is carbon black. Because of its origin, carbon black may contain polycyclic aromatic hydrocarbons (PAHs). The U.S. Environmental Protection Agency has identified 16 priority PAHs on the basis of concerns that they cause or might cause cancer in animals and humans. Regulatory agencies impose carbon black purity specifications based on limits for total PAHs (0.5 mg/kg) and benzo[a]pyrene (5 MUg/kg) or benzo[a]pyrene only (250 MUg/kg). PAHs in rubber packaging used for pharmaceutical formulations and in parenteral products stored in containers with rubber stoppers were investigated. METHODS: To this end, the method proposed by the National Institute for Occupational Safety and Health-based on high-performance liquid chromatography with ultraviolet and fluorescence detection-was adapted to determine the levels of PAHs in rubber stoppers (gray and red) and in lipid emulsions and amino acid solutions stored in bottles with rubber stoppers. RESULTS: The rubber materials were shown to contain 12 PAHs, in concentrations ranging from 0.25-3.31 ug/g. Only 1 of 18 samples (11 amino acid solutions and 7 lipid emulsions) was uncontaminated. The most prevalent contaminants were pyrene, benzo[a]pyrene, and fluoranthene. The total PAH concentrations in the samples ranged from 0.11-5.96 ug/mL. CONCLUSION: Components of parenteral nutrition may be contaminated with PAHs, and rubber stoppers represent a potential source of these contaminants. PMID- 26979283 TI - Superhigh moduli and tension-induced phase transition of monolayer gamma-boron at finite temperatures. AB - Two dimensional (2D) gamma-boron (gamma-B28) thin films have been firstly reported by the experiments of the chemical vapor deposition in the latest study. However, their mechanical properties are still not clear. Here we predict the superhigh moduli (785 +/- 42 GPa at 300 K) and the tension-induced phase transition of monolayer gamma-B28 along a zigzag direction for large deformations at finite temperatures using molecular dynamics (MD) simulations. The new phase can be kept stable after unloading process at these temperatures. The predicted mechanical properties are reasonable when compared with our results from density functional theory. This study provides physical insights into the origins of the new phase transition of monolayer gamma-B28 at finite temperatures. PMID- 26979282 TI - Methods for conducting systematic reviews of risk factors in low- and middle income countries. AB - BACKGROUND: Rates of youth violence are disproportionately high in many low- and middle-income countries [LMICs] but existing reviews of risk factors focus almost exclusively on high-income countries. Different search strategies, including non English language searches, might be required to identify relevant evidence in LMICs. This paper discusses methodological issues in systematic reviews aiming to include evidence from LMICs, using the example of a recent review of risk factors for child conduct problems and youth violence in LMICs. METHODS: We searched the main international databases, such as PsycINFO, Medline and EMBASE in English, as well as 12 regional databases in Arabic, Chinese, English, French, Spanish, Portuguese and Russian. In addition, we used internet search engines and Google Scholar, and contacted over 200 researchers and organizations to identify potentially eligible studies in LMICs. RESULTS: The majority of relevant studies were identified in the mainstream databases, but additional studies were also found through regional databases, such as CNKI, Wangfang, LILACS and SciELO. Overall, 85% of eligible studies were in English, and 15% were reported in Chinese, Spanish, Portuguese, Russian or French. Among eligible studies in languages other than English, two-thirds were identified only by regional databases and one-third was also indexed in the main international databases. CONCLUSIONS: There are many studies on child conduct problems and youth violence in LMICs which have not been included in prior reviews. Most research on these subjects in LMICs has been produced in the last two-three decades and mostly in middle-income countries, such as China, Brazil, Turkey, South Africa and Russia. Based on our findings, it appears that many studies of child conduct problems and youth violence in LMICs are reported in English, Chinese, Spanish and Portuguese, but few such studies are published in French, Arabic or Russian. If non-English language searches and screening had not been conducted in the current review, 15% of eligible studies would have been missed. Although there are benefits to non English language searches and the inclusion of non-English studies in meta analyses, systematic reviewers also need to consider the resources required to incorporate multi-lingual research. PMID- 26979284 TI - Realization of magnetostructural coupling by modifying structural transitions in MnNiSi-CoNiGe system with a wide Curie-temperature window. AB - The magnetostructural coupling between structural and magnetic transitions leads to magneto-multifunctionalities of phase-transition alloys. Due to the increasing demands of multifunctional applications, to search for the new materials with tunable magnetostructural transformations in a large operating temperature range is important. In this work, we demonstrate that by chemically alloying MnNiSi with CoNiGe, the structural transformation temperature of MnNiSi (1200 K) is remarkably decreased by almost 1000 K. A tunable magnetostructural transformation between the paramagnetic hexagonal and ferromagnetic orthorhombic phase over a wide temperature window from 425 to 125 K is realized in (MnNiSi)1-x(CoNiGe)x system. The magnetic-field-induced magnetostructural transformation is accompanied by the high-performance magnetocaloric effect, proving that MnNiSi CoNiGe system is a promising candidate for magnetic cooling refrigerant. PMID- 26979285 TI - Relationship between personality and psychopathology in a longitudinal community study: a test of the predisposition model. AB - BACKGROUND: Mounting evidence supports the notion that personality is crucial in the aetiopathology of common mental disorders, but studies that allow for aetiological conclusions are lacking. The aim of the present study was thus to provide a test of the predisposition model. METHOD: We analysed data from the Zurich Cohort Study, a 30-year longitudinal epidemiological community study of an adult cohort (n = 591) from 1979 to 2008. Personality was assessed in 1988 with an established personality questionnaire, and psychopathology through seven semi structured interviews between 1979 and 2008. RESULTS: On the basis of personality assessment from 1988, used as predictor of subsequent psychopathology (1993 2008), while adjusting for sex and prior mental disorders (1979-1988), neuroticism related significantly with future major depression episodes [odds ratio (OR) = 1.41], anxiety disorders (OR = 1.32) and depression treatment use (OR = 1.41). When participants with a past 10-year history (i.e. 1979-1988) of either major depression, anxiety disorder or depression treatment use were excluded, neuroticism in 1988 still significantly predicted first incidence (i.e. 1993-2008) of major depression episodes (OR = 1.53) and depression treatment use (OR = 1.84). CONCLUSIONS: The present study provides compelling evidence that the personality trait of neuroticism constitutes an independent risk factor for subsequent major depression episodes and use of respective professional treatments, which serves as a proxy for particularly severe and impairing depression episodes. We therefore advocate that personality traits could provide clinically useful prognostic information when considered carefully. PMID- 26979288 TI - Delayed signatures of underground nuclear explosions. AB - Radionuclide signals from underground nuclear explosions (UNEs) are strongly influenced by the surrounding hydrogeologic regime. One effect of containment is delay of detonation-produced radioxenon reaching the surface as well as lengthening of its period of detectability compared to uncontained explosions. Using a field-scale tracer experiment, we evaluate important transport properties of a former UNE site. We observe the character of signals at the surface due to the migration of gases from the post-detonation chimney under realistic transport conditions. Background radon signals are found to be highly responsive to cavity pressurization suggesting that large local radon anomalies may be an indicator of a clandestine UNE. Computer simulations, using transport properties obtained from the experiment, track radioxenon isotopes in the chimney and their migration to the surface. They show that the chimney surrounded by a fractured containment regime behaves as a leaky chemical reactor regarding its effect on isotopic evolution introducing a dependence on nuclear yield not previously considered. This evolutionary model for radioxenon isotopes is validated by atmospheric observations of radioxenon from a 2013 UNE in the Democratic People's Republic of Korea (DPRK). Our model produces results similar to isotopic observations with nuclear yields being comparable to seismic estimates. PMID- 26979289 TI - Unique trapping of paddlewheel copper(ii) carboxylate by ligand-bound {Cu2} fragments for [Cu6] assembly. AB - The bridging nature of in situ generated hydroxide ions and carboxylates (RCOO( ); R = CH3, C2H5, CH2Ph) has been utilized to design a new family of [Cu6] coordination complexes: [Cu6(MU3-OH)2(MU-H2L)2(MU1,1,3-O2CCH3)2(MU1,3-O2CCH3)2(MU ClO4)2](ClO4)2.H2O (), [Cu6(MU3-OH)2(MU-H2L)2(MU1,1,3-O2CC2H5)4(MU ClO4)2](ClO4)2.2H2O () and [Cu6(MU3-OH)2(MU-H2L)2(MU1,3 O2CCH2Ph)4(ClO4)2](ClO4)2.2H2O (). Tetracarboxylate bridged {Cu2} core units are trapped between two ligand-bound {Cu2(MU-H2L)(MU-OH)}(2+) subunits forming the [Cu6] complexes. The hexanuclear {Cu6(MU3-OH)2(H2L)2(MU-O2CR)4}(4+) cores having six interconnected Cu(II) ions assume a hitherto unknown dumbbell-shaped topology. Detailed characterizations have been done using X-ray crystallography and variable temperature magnetic measurements. For complexes , the dominant coupling constant (J') values between carboxylate bridged copper centers are 36.2 to -45.2 cm(-1) for short CuCu separations of 2.540-2.578 A. In MeCN solutions all three complexes showed catalytic oxidation of 3,5-di-tert-butyl catechol (3,5-DTBCH2) in air. PMID- 26979286 TI - Health workers' compliance to rapid diagnostic tests (RDTs) to guide malaria treatment: a systematic review and meta-analysis. AB - BACKGROUND: The World Health Organization recommends malaria to be confirmed by either microscopy or a rapid diagnostic test (RDT) before treatment. The correct use of RDTs in resource-limited settings facilitates basing treatment onto a confirmed diagnosis; contributes to speeding up considering a correct alternative diagnosis, and prevents overprescription of anti-malarial drugs, reduces costs and avoids unnecessary exposure to adverse drug effects. This review aims to evaluate health workers' compliance to RDT results and factors contributing to compliance. METHODS: A PROSPERO-registered systematic review was conducted to evaluate health workers' compliance to RDTs in sub-Saharan Africa, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies published up to November 2015 were searched without language restrictions in Medline/Ovid, Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, Biosis Previews and the African Index Medicus. The primary outcome was health workers treating patients according to the RDT results obtained. RESULTS: The literature search identified 474 reports; 14 studies were eligible and included in the quantitative analysis. From the meta analysis, health workers' overall compliance in terms of initiating treatment or not in accordance with the respective RDT results was 83% (95% CI 80-86%). Compliance to positive and negative results was 97% (95% CI 94-99%) and 78% (95% CI 66-89%), respectively. Community health workers had higher compliance rates to negative test results than clinicians. Patient expectations, work experience, scepticism of results, health workers' cadres and perceived effectiveness of the test, influenced compliance. CONCLUSIONS: With regard to published data, compliance to RDT appears to be generally fair in sub-Saharan Africa; compliance to negative results will need to improve to prevent mismanagement of patients and overprescribing of anti-malarial drugs. Improving diagnostic capacity for other febrile illnesses and developing local evidence-based guidelines may help improve compliance and management of negative RDT results. TRIAL REGISTRATION: CRD42015016151 (PROSPERO). PMID- 26979287 TI - Identification of early myeloid progenitors as immunosuppressive cells. AB - Growing evidence suggests that hematopoietic stem/progenitor cells (HSPCs), precursors of mature immune cells, may play a direct role in immunosurveillance. Early myeloid progenitors are the major components of HSPCs and they often undergo extensive expansion in stress as a result of myeloid-biased hematopoiesis. Yet, the precise function of early myeloid progenitors remains unclear. Here we show that during tumor progression, mouse granulocyte/macrophage progenitors (GMPs) but not common myeloid progenitors (CMPs) are markedly expanded within the bone marrow and blood of mice. Interestingly, both GMPs and CMPs freshly isolated from either tumor-bearing or naive animals are capable of inhibiting polyclonal stimuli- and alloantigen-induced T cell proliferation, with tumor host-derived cells having elevated activities. Strikingly, these early myeloid progenitor cells even display much stronger suppressive capacity than the classical myeloid-derived suppressive cells. Analysis of GMPs indicates that they express iNOS and can secrete high levels of NO. Further studies unusing iNOS specific inhibitors reveal that the immunosuppression of GMPs is, to a large extent, NO-dependent. GMPs can also efficiently induce regulatory T cell development. These studies demonstrate that early myeloid progenitors can act as immunosuppressive cells. This finding provides novel insights into the functional diversity and plasticity of early myeloid progenitor cells. PMID- 26979291 TI - Emotions Related to Bodily Organs/Parts. PMID- 26979290 TI - Does the rise in eating disorders lead to increasing risk of orthorexia nervosa? Correlations with gender, education, and body mass index. AB - Investigating eating disorders and orthorexia nervosa, especially in the young population, is an important step in taking protective precautions and identifying disease. This study was carried out to determine the relationship of eating disorders and orthorexia nervosa to gender, BMI, and field of study in a population of university students in Turkey. In all, 900 university students aged 17-23 years participated in this study. EAT-40 and ORTO-15, which are validated instruments for the screening of participants with anormal eating behaviors and orthorexia nervosa, respectively, were used. There was not a significant difference in EAT-40 scores according to gender and BMI classification. However, EAT-40 scores were high among the students in social science. The number of orthorectic participants among women is higher than that among men, and ORTO-15 scores were not associated with BMI classification and field of study. A significant negative correlation was found between EAT-40 and ORTO-15 scores. PMID- 26979292 TI - Photoconductive terahertz generation from textured semiconductor materials. AB - Photoconductive (PC) terahertz (THz) emitters are often limited by ohmic loss and Joule heating-as these effects can lead to thermal runaway and premature device breakdown. To address this, the proposed work introduces PC THz emitters based on textured InP materials. The enhanced surface recombination and decreased charge carrier lifetimes of the textured InP materials reduce residual photocurrents, following the picosecond THz waveform generation, and this diminishes Joule heating in the emitters. A non-textured InP material is used as a baseline for studies of fine- and coarse-textured InP materials. Ultrafast pump-probe and THz setups are used to measure the charge-carrier lifetimes and THz response/photocurrent consumption of the respective materials and emitters. It is found that similar temporal and spectral characteristics can be achieved with the THz emitters, but the level of photocurrent consumption (yielding Joule heating) is greatly reduced in the textured materials. PMID- 26979293 TI - Perceived environmental barriers to outdoor mobility and changes in sense of autonomy in participation outdoors among older people: a prospective two-year cohort study. AB - OBJECTIVE: The aim was to study whether perceived environmental barriers to outdoor mobility affect changes in sense of autonomy in participation outdoors among community-dwelling older people over a two-year period. METHODS: Community dwelling people aged 75-90 years (n = 848) in central Finland were interviewed on two occasions, face-to-face at baseline and over the telephone two years later. Perceived environmental barriers to outdoor mobility were assessed using a 15 item structured questionnaire, and the sum scores categorized into tertiles (0, 1 and 2 or more barriers). Autonomy in participation outdoors was assessed with the 'Impact on Participation and Autonomy' (IPA) questionnaire using the autonomy outdoors subscale (score range 0-20, higher scores indicating more restricted autonomy). RESULTS: Scores for autonomy in participation outdoors were available for 848 participants at baseline (mean 6.2, SD = 3.8) and for 748 participants at the two-year follow-up (mean 6.7, SD = 3.9). At baseline, those reporting multiple environmental barriers had the most restricted autonomy, while those reporting no environmental barriers had the least restricted autonomy (p < .001). Over the follow-up, autonomy in participation outdoors declined more among those reporting multiple environmental barriers compared to those reporting none (age- and sex-adjusted group*time beta = .629, s.e. = .277, p = .023). Adjustment for cognitive functioning, education, number of chronic conditions and change in walking difficulty did not influence the association. CONCLUSION: Perceived environmental barriers to outdoor mobility accelerate the decline in autonomy in participation outdoors among older community-dwelling people. Understanding factors affecting autonomy can help in finding ways to support the sense of autonomy as people age. PMID- 26979294 TI - Drug-Paired Contextual Stimuli Increase Dendritic Spine Dynamics in Select Nucleus Accumbens Neurons. AB - Repeated exposure to amphetamine leads to both associative conditioning and nonassociative sensitization. Here we assessed the contribution of neuronal ensembles in the nucleus accumbens (NAcc) to these behaviors. Animals exposed to amphetamine IP or in the ventral tegmental area (VTA) showed a sensitized locomotor response when challenged with amphetamine weeks later. Both exposure routes also increased DeltaFosB levels in the NAcc. Further characterization of these DeltaFosB+ neurons, however, revealed that amphetamine had no effect on dendritic spine density or size, indicating that these neurons do not undergo changes in dendritic spine morphology that accompany the expression of nonassociative sensitization. Additional experiments determined how neurons in the NAcc contribute to the expression of associative conditioning. A discrimination learning procedure was used to expose rats to IP or VTA amphetamine either Paired or Unpaired with an open field. As expected, compared with Controls, Paired rats administered IP amphetamine subsequently showed a conditioned locomotor response when challenged with saline in the open field, an effect accompanied by an increase in c-Fos+ neurons in the medial NAcc. Further characterization of these c-Fos+ cells revealed that Paired rats showed an increase in the density of dendritic spines and the frequency of medium-sized spines in the NAcc. In contrast, Paired rats previously exposed to VTA amphetamine showed neither conditioned locomotion nor conditioned c-Fos+ expression. Together, these results suggest a role for c-Fos+ neurons in the medial NAcc and rapid changes in the morphology of their dendritic spines in the expression of conditioning evoked by amphetamine-paired contextual stimuli. PMID- 26979296 TI - Could the use of nanowire structures overcome some of the current limitations of brain electrode implants? PMID- 26979297 TI - Understanding the Thermodynamics of Hydrogen Bonding in Alcohol-Containing Mixtures: Cross-Association. AB - The thermodynamics of hydrogen bonding in 1-alcohol + water binary mixtures is studied using molecular dynamic (MD) simulation and the polar and perturbed chain form of the statistical associating fluid theory (polar PC-SAFT). The fraction of free monomers in pure saturated liquid water is computed using both TIP4P/2005 and iAMOEBA simulation water models. Results are compared to spectroscopic data available in the literature as well as to polar PC-SAFT. Polar PC-SAFT models hydrogen bonds using single bondable association sites representing electron donors and electron acceptors. The distribution of hydrogen bonds in pure alcohols is computed using the OPLS-AA force field. Results are compared to Monte Carlo (MC) simulations available in the literature as well as to polar PC-SAFT. The analysis shows that hydrogen bonding in pure alcohols is best predicted using a two-site model within the SAFT framework. On the other hand, molecular simulations show that increasing the concentration of water in the mixture increases the average number of hydrogen bonds formed by an alcohol molecule. As a result, a transition in association scheme occurs at high water concentrations where hydrogen bonding is better captured within the SAFT framework using a three site alcohol model. The knowledge gained in understanding hydrogen bonding is applied to model vapor-liquid equilibrium (VLE) and liquid-liquid equilibrium (LLE) of mixtures using polar PC-SAFT. Predictions are in good agreement with experimental data, establishing the predictive power of the equation of state. PMID- 26979295 TI - Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors. AB - Previous studies have identified potential antidepressant effects of buprenorphine (BPN), a drug with high affinity for mu opioid receptor (MORs) and kappa opioid receptors (KORs) and some affinity at delta opioid receptor (DOR) and opioid receptor-like 1 (ORL-1) receptors. Therefore, these studies examined which opioid receptors were involved in BPN's effects on animal behavior tests sensitive to antidepressant drugs. The acute effects of BPN were tested in the forced swim test (FST) using mice with genetic deletion of individual opioid receptors or after pharmacological blockade of receptors. For evaluating the effects of BPN on chronic stress, separate groups of mice were exposed to unpredictable chronic mild stress (UCMS) for 3 weeks and treated with BPN for at least 7 days before behavioral assessment and subsequent measurement of Oprk1, Oprm1, and Pdyn mRNA expression in multiple brain regions. BPN did not reduce immobility in mice with KOR deletion or after pretreatment with norbinaltorphimine, even though desipramine remained effective. In contrast, BPN reduced immobility in MOR and DOR knockout mice and in mice pretreated with the ORL-1 antagonist JTC-801. UCMS reduced sucrose preference, decreased time in the light side of the light/dark box, increased immobility in the FST and induced region-specific alterations in Oprk1, Oprm1, and PDYN mRNA expression in the frontal cortex and striatum. All of these changes were normalized following BPN treatment. The KOR was identified as a key player mediating the effects of BPN in tests sensitive to antidepressant drugs in mice. These studies support further development of BPN as a novel antidepressant. PMID- 26979298 TI - ADP-Ribose Pyrophosphatase Reaction in Crystalline State Conducted by Consecutive Binding of Two Manganese(II) Ions as Cofactors. AB - Adenosine diphosphate ribose pyrophosphatase (ADPRase), a member of the Nudix family proteins, catalyzes the metal-induced and concerted general acid-base hydrolysis of ADP ribose (ADPR) into AMP and ribose-5'-phosphate (R5P). The ADPR hydrolysis reaction of ADPRase from Thermus thermophilus HB8 (TtADPRase) requires divalent metal cations such as Mn(2+), Zn(2+), or Mg(2+) as cofactors. Here, we report the reaction pathway observed in the catalytic center of TtADPRase, based on cryo-trapping X-ray crystallography at atomic resolutions around 1.0 A using Mn(2+) as the reaction trigger, which was soaked into TtADPRase-ADPR binary complex crystals. Integrating 11 structures along the reaction timeline, five reaction states of TtADPRase were assigned, which were ADPRase alone (E), the ADPRase-ADPR binary complex (ES), two ADPRase-ADPR-Mn(2+) reaction intermediates (ESM, ESMM), and the postreaction state (E'). Two Mn(2+) ions were inserted consecutively into the catalytic center of the ES-state and ligated by Glu86 and Glu82, which are highly conserved among the Nudix family, in the ESM- and ESMM states. The ADPR-hydrolysis reaction was characterized by electrostatic, proximity, and orientation effects, and by preferential binding for the transition state. A new reaction mechanism is proposed, which differs from previous ones suggested from structure analyses with nonhydrolyzable substrate analogues or point-mutated ADPRases. PMID- 26979299 TI - Perceived racial discrimination, heavy episodic drinking, and alcohol abstinence among African American and White college students. AB - Previous research has demonstrated that White college students are more likely to drink alcohol at a greater frequency and quantity compared to their African American counterparts. Examining race-related factors that structure alcohol use among college students remains an important area of research. In this study, we specifically examine perceived discrimination and its association with both heavy episodic drinking (HED) and alcohol abstinence among college students. Items that measured perceived racial discrimination in alcohol use contexts and demographic characteristics were used as independent and control variables. African American students were more likely to abstain from alcohol and less likely to engage in HED compared to their White counterparts. Results also suggest that students who believe their drinking will solicit race-based police bias have lower odds of engaging in HED and greater odds of alcohol abstention. We conclude that unsolicited policing, experienced by African Americans generally, and White Americans on campuses, explains effect sizes. PMID- 26979300 TI - Caution warranted in extrapolating from Boston Naming Test item gradation construct. AB - The Boston Naming Test (BNT) was designed to present items in order of difficulty based on word frequency. Changes in word frequencies over time, however, would frustrate extrapolation in clinical and research settings based on the theoretical construct because performance on the BNT might reflect changes in ecological frequency of the test items, rather than performance across items of increasing difficulty. This study identifies the ecological frequency of BNT items at the time of publication using the American Heritage Word Frequency Book and determines changes in frequency over time based on the frequency distribution of BNT items across a current corpus, the Corpus of Contemporary American English. Findings reveal an uneven distribution of BNT items across 2 corpora and instances of negligible differentiation in relative word frequency across test items. As BNT items are not presented in order from least to most frequent, clinicians and researchers should exercise caution in relying on the BNT as presenting items in increasing order of difficulty. A method is proposed for distributing confrontation-naming items to be explicitly measured against test items that are normally distributed across the corpus of a given language. PMID- 26979301 TI - 2D measurements of cup orientation are less reliable than 3D measurements (Acta Orthop 2015; 86 (4): 485-90.). PMID- 26979303 TI - Metals in agricultural produce associated with acid-mine drainage in Mount Morgan (Queensland, Australia). AB - Acid-mine drainage (AMD) into the Dee River from the historic gold and copper mine in Mount Morgan, Queensland (Australia) has been of concern to farmers in the area since 1925. This study sought to determine the levels of AMD-related metals and sulfur in agricultural produce grown near the mine-impacted Dee River, compare these with similar produce grown in reference fields (which had no known AMD influence), and assess any potential health risk using relevant Australian or US guidelines. Analyses of lucerne (Medicago sativa; also known as alfalfa) from five Dee fields showed the following average concentrations (mg/kg dry basis): Cd < 1, Cu 11, Fe 106, Mn 52, Pb < 5, Zn 25 and S 3934; similar levels were found in lucerne hay (used as cattle feed) from two Dee fields. All lucerne and lucerne hay data were generally comparable with levels found in the lucerne reference fields, suggesting no AMD influence; the levels were within the US National Research Council (US NRC) guidelines for maximum tolerable cattle dietary intake. Pasture grass (also cattle feed) from two fields in the Dee River floodplains gave mean concentrations (mg/kg dry) of Cd 0.14, Cu 12, Fe 313, Mn 111, Pb 1.4, Zn 86 and S 2450. All metal levels from the Dee and from reference sites were below the US NRC guidelines for maximum tolerable cattle dietary intake; however, the average Cd, Cu and Fe levels in Dee samples were significantly greater than the corresponding levels in the pasture grass reference sites, suggesting AMD influence in the Dee samples. The average levels in the edible portions of mandarin oranges (Citrus reticulata) from Dee sites (mg/kg wet weight) were Cd 0.011, Cu 0.59, Fe 2.2, Mn 0.56, Pb 0.18, S 91 and Zn 0.96. Cd and Zn were less than or close to, average Fe and Mn levels were at most twice, Cd 1.8 or 6.5 times, and Pb 8.5 or 72 times the maximum levels in raw oranges reported in the US total diet study (TDS) or the Australian TDS, respectively. Average Cd, Fe, Mn, Pb and Zn levels in the citrus reference samples were found to exceed the maximum reported in one or both TDS surveys. Cu, Fe, Mn, Pb and Zn plant-soil transfer factor (TF) values were < 1 for all agricultural samples from both Dee and reference sites, suggesting relatively poor transfer of these metals from soil to plant. In the case of Cd, TF values for Dee pasture grass and citrus fruit samples were 0.14 and 0.73, respectively; lucerne and lucerne hay from both Dee and reference sites gave TF = 10, suggesting some potential risk to cattle, although this conclusion is tentative because Cd levels were close to or less than the detection limit. TF values for S in lucerne, lucerne hay, pasture grass and mandarin oranges from Dee sites were 18, 14, 3 and 3.6, respectively, indicating that S in soil was readily available to plant or fruit. Sulfur in pasture grass and citrus fruit (TF = 11 for both) was apparently more bioavailable at the reference sites than at the Dee sites (TF = 3.0 for pasture grass; TF = 3.6 for citrus fruit). PMID- 26979304 TI - Decomposing socioeconomic inequalities in the use of preventive eye screening services among individuals with diabetes in Korea. AB - OBJECTIVES: The aim of this study was to assess the socioeconomic inequalities in the use of preventive eye screening services among individuals with diabetes in Korea. METHODS: Using nationally representative survey data, the concentration index (CI) and decomposition of the CI were used to capture and quantify income related inequalities. RESULTS: The results show income-related inequality in the use of eye screening services among individuals with diabetes, suggesting that services were concentrated among individuals with higher incomes. After adjusting for need factors, such as sex, age and self-rated health, the inequality still persisted as observed horizontal inequity in the services, indicating that unequal care was provided for equal need. The decomposition approach revealed that the largest contributions to the observed inequality were higher education and higher income levels. Having private insurance and residing in non-Seoul metro areas also contributed to the observed pro-rich inequality. CONCLUSIONS: These findings suggest that income- and education-related barriers to the use of preventive eye screening services for individuals with diabetes should be targeted for removal at the national level to achieve the goal of equal care for equal need in diabetes management. PMID- 26979302 TI - Human rights protections and HIV prevalence among MSM who sell sex: Cross-country comparisons from a systematic review and meta-analysis. AB - Laws and policies can affect the HIV risk of key populations through a number of direct and indirect pathways. We investigated the association between HIV prevalence among men who engage in transactional sex and language in the penal code protecting sexual minorities, including men who have sex with men (MSM), and sex workers. HIV prevalence among men who engage in transactional sex was assessed through meta-analysis of published literature and country surveillance reports. Meta-regression was used to determine the association between HIV prevalence and protective laws for sexual minorities and sex workers. Sixty-six reports representing 28 countries and 31,924 individuals were included in the meta-analysis. Controlling for multiple study- and country-level variables, legal protection for sexual minorities was associated with a 10.9% (95% CI: 3.8-18.0%) and sex workers associated with a 7.0% (95% CI: 1.3-12.8%) decrease in country level HIV prevalence among men who engage in transactional sex. Laws that seek to actively protect sex workers and MSM may be necessary to decrease HIV risk for this key population. PMID- 26979305 TI - Epigenetic Alterations and Canonical Pathway Disruption in Papillary Thyroid Cancer: A Genome-wide Methylation Analysis. AB - BACKGROUND: Alterations in DNA methylation have been demonstrated in a variety of malignancies, including papillary thyroid cancer (PTC). The full extent of dysregulation in PTC and the downstream affected pathways remains unclear. Here we report a genome-wide analysis of PTC methylation, the dysregulation of various canonical pathways, and assess its potential as a diagnostic test. METHODS: A discovery set utilized 49 PTCs and matched normal controls from The Cancer Genome Atlas. Another set of 16 PTCs and 13 normal controls were used as a replication set. Genome-wide methylation analysis was done using Illumina 450 K methylation chips. Differentially methylated loci (DML) were identified by comparing PTC and matched normal tissues. DML were defined as false-discovery rate p < 0.05 and absolute Deltabeta >= 0.2. DML were then analyzed for pathway and disease commonalities using Qiagen Ingenuity Pathway Analysis. RESULTS: Of 485,577 CpG sites analyzed, 1226 DML were identified in our discovery and replication sets, and 1061 (86.5 %) DML showed hypomethylation when comparing tumor with normal tissue. Support vector machine classification was able to differentiate benign from malignant tissue in 107 (94.7 %) of 113 tested samples, including 15 (83.3 %) of 18 samples lacking a clearly deleterious mutation. Statistically significant associations with multiple canonical pathways, diseases, and biofunctions were observed including PI3K, PTEN, wnt/beta-catenin, and p53. CONCLUSIONS: Epigenetic dysregulation of multiple canonical pathways are associated with the development of PTC. This methylation signature shows promise as a future adjunctive screening test for thyroid nodules. PMID- 26979306 TI - Value-Based Breast Cancer Care: A Multidisciplinary Approach for Defining Patient Centered Outcomes. AB - PURPOSE: Value in healthcare-i.e., patient-centered outcomes achieved per healthcare dollar spent-can define quality and unify performance improvement goals with health outcomes of importance to patients across the entire cycle of care. We describe the process through which value-based measures for breast cancer patients and dynamic capture of these metrics via our new electronic health record (EHR) were developed at our institution. METHODS: Contemporary breast cancer literature on treatment options, expected outcomes, and potential complications was extensively reviewed. Patient perspective was obtained via focus groups. Multidisciplinary physician teams met to inform a 3-phase process of (1) concept development, (2) measure specification, and (3) implementation via EHR integration. RESULTS: Outcomes were divided into 3 tiers that reflect the entire cycle of care: (1) health status achieved, (2) process of recovery, and (3) sustainability of health. Within these tiers, 22 patient-centered outcomes were defined with inclusion/exclusion criteria and specifications for reporting. Patient data sources will include the Epic Systems EHR and validated patient reported outcome questionnaires administered via our institution's patient portal. CONCLUSIONS: As healthcare costs continue to rise in the United States and around the world, a value-based approach with explicit, transparently reported patient outcomes will not only create opportunities for performance improvement but will also enable benchmarking across providers, healthcare systems, and even countries. Similar value-based breast cancer care frameworks are also being pursued internationally. PMID- 26979307 TI - An assessment of the safety, hemodynamic response, and diagnostic accuracy of commonly used vasodilator stressors in patients with severe aortic stenosis. AB - BACKGROUND: Increasing numbers of patients are undergoing transcatheter aortic valve replacement, which often involves assessment of coronary artery disease ischemic burden. The safety and diagnostic accuracy of vasodilator stress agents in patients with severe aortic stenosis (AS) undergoing SPECT myocardial perfusion imaging (MPI) has not been established. METHODS: Patients with severe AS (valve area <1 cm2) on echocardiography who underwent vasodilator stress SPECT MPI at two centers were identified. Patients with aortic valve intervention prior to MPI or who underwent concurrent exercise during stress testing were excluded. AS patients were matched to controls without AS based on age, gender, BMI, ejection fraction, and stress agent. Symptoms, serious adverse events, hemodynamic response, and correlation to invasive angiography were assessed. RESULTS: A total of 95 cases were identified with 45% undergoing regadenoson, 31% dipyridamole, and 24% adenosine stress. A significant change in systolic blood pressure (BP), cases vs controls, was observed with adenosine [-17.9 +/- 20.1 vs 2.6 +/- 24.9 P = .03)], with a trend toward significance with regadenoson [-16.8 +/- 20.3 vs -9.4 +/- 17.9 (P = .08)] and dipyridamole [-17.8 +/- 20.6 vs -9.0 +/- 12.1 (P = .05)]. The change in heart rate was significantly different only for adenosine [5.3 +/- 16.8 vs 14.2 +/- 10.8 (P = .04)]. Overall, 45% of cases vs 24% of controls (P = .004) had a >20 mmHg decrease in systolic BP. Age, BMI, and resting systolic BP were related to a >20 mmHg decrease in systolic BP on univariate analysis, although only higher resting systolic BP was a predictor on multivariate analysis. In 33 patients who underwent angiography, the sensitivity, specificity, and diagnostic accuracy of vasodilator stress MPI was 77%, 69%, and 73%, respectively. No serious adverse events occurred in the severe AS patients. CONCLUSION: Severe AS patients are more likely to have a hemodynamically significant decrease in systolic BP with vasodilator stress. There were no serious adverse events in this severe AS cohort with good diagnostic performance of MPI compared to angiography. PMID- 26979308 TI - Impact of cardiac reverse remodeling after cardiac resynchronization therapy assessed by myocardial perfusion imaging on ventricular arrhythmia. AB - BACKGROUND: Although cardiac resynchronization therapy (CRT) has been a useful treatment of heart failure, patients with CRT are still in risk of sudden cardiac death due to ventricular arrhythmia. The aim of this study was to investigate the impact of cardiac reverse remodeling after CRT on the prevalence of ventricular tachycardia or fibrillation (VT/VF). METHODS AND RESULTS: Forty-one heart failure patients (26 men, age 66 +/- 10 years), who were implanted with CRT for at least 12 months, were enrolled. All patients received myocardial perfusion imaging (MPI) under CRT pacing to evaluate left ventricle (LV) function, dyssynchrony, and scar. VT/VF episodes during the follow-up period after MPI were recorded by the CRT devices. Sixteen patients (N = 16/41, 39%) were found to have VT/VF. Multivariate Cox regression analysis and receiver operating characteristic curve analysis showed that five risk factors were significant predictors of VT/VF, including increased left ventricle ejection fraction (LVEF) by <=7% after CRT, low LVEF after CRT (<=30%), change of intrinsic QRS duration (iQRSd) by <=7 ms, wide iQRSd after CRT (>=121 ms), and high systolic dyssynchrony after CRT (phase standard deviation >=45.6 degrees ). For those patients with all of the 5 risk factors, 85.7% or more developed VT/VF. CONCLUSIONS: The characteristics of cardiac reverse remodeling after CRT as assessed by MPI are associated with the prevalence of ventricular arrhythmia. PMID- 26979309 TI - Phoma glomerata D14: An Endophytic Fungus from Salvia miltiorrhiza That Produces Salvianolic Acid C. AB - In recent years, more and more researches focus on endophytic fungi derived from important medicinal plants, which can produce the same bioactive metabolites as their host plants. Salvia miltiorrhiza Bunge is a traditional medicinal plant with versatile pharmacological effects. But the wild plant resource has been in short supply due to the overcollection for bioactive metabolites. Our study was therefore conducted to isolate endophytic fungi from S. miltiorrhiza and get candidate strains that produce the same bioactive compounds as the plant. As a result, an endophyte that produces salvianolic acid C was obtained and identified as Phoma glomerata D14 based on its morphology and internal transcribed spacer analysis. Salvianolic acid C was found present in both the mycelia and fermentation broth. Our study indicates that the endophytic fungus has significant industrial potential to meet the pharmaceutical demands for salvianolic acid C in a cost-effective, easily accessible, and reproducible way. PMID- 26979311 TI - The Self-Compassion Scale is Not Validated in a Buddhist Sample. AB - The concept of self-compassion originated from Buddhism, but very little is known about the utility and functions of this concept among Buddhists. Four hundred and eleven individuals (179 Buddhists and 232 non-Buddhists) completed the survey packages using the self-compassion scale (SCS; Neff in Self Identity 2(3):223 250, 2003a. doi: 10.1080/15298860309027 ). Confirmatory factor analysis showed that the original six dimensions of the SCS were not replicated by both samples, and further analysis of the intra-correlations within dimensions of SCS and relationships between SCS and other variables showed unexpected results specific to Buddhists. Among Buddhists, the dimensions of self-kindness and common humanity neither showed negative correlations with their opposite dimensions nor were associated with better emotional outcomes. In addition, these two dimensions were not predicted by the regular practice of loving-kindness meditation. This study argued that the ideas of self-compassion reflected in the SCS are theoretically different from the ideas of Buddhism, and further implications for measuring and clinically applying self-compassion were discussed. PMID- 26979310 TI - Molecular evolution and gene expression differences within the HD-Zip transcription factor family of Zea mays L. AB - Homeodomain-leucine zipper (HD-Zip) transcription factors regulate developmental processes and stress responses in plants, and they vary widely in gene number and family structure. In this study, 55 predicted maize HD-Zip genes were systematically analyzed with respect to their phylogenetic relationships, molecular evolution, and gene expression in order to understand the functional diversification within the family. Phylogenetic analysis of HD-Zip proteins from Zea mays, Oryza sativa, Arabidopsis thaliana, Vitis vinifera, and Physcomitrella patens showed that they group into four classes. We inferred that the copy numbers of classes I and III genes were relatively conserved in all five species. The 55 maize HD-Zip genes are distributed randomly on the ten chromosomes, with 15 segmental duplication and 4 tandem duplication events, suggesting that segmental duplications were the major contributors in the expansion of the maize HD-Zip gene family. Expression analysis of the 55 maize HD-Zip genes in different tissues and drought conditions revealed differences in the expression levels and patterns between the four classes. Promoter analysis revealed that a number of stress response-, hormone response-, light response-, and development-related cis acting elements were present in their promoters. Our results provide novel insights into the molecular evolution and gene expression within the HD-Zip gene family in maize, and provide a solid foundation for future functional study of the HD-Zip genes in maize. PMID- 26979314 TI - Emergency control system based on the analytical hierarchy process and coordinated development degree model for sudden water pollution accidents in the Middle Route of the South-to-North Water Transfer Project in China. AB - Water transfer projects are important for realizing reasonable allocation of water resources, but once a water pollution accident occurs during such a project, the water environment is exposed to enormous risks. Therefore, it is critical to determine an appropriate emergency control system (ECS) for sudden water pollution accidents that occur in water transfer projects. In this study, the analytical hierarchy process (AHP) integrated with the coordinated development degree model (CDDM) was used to develop the ECS. This ECS was developed into two parts, including the emergency risk assessment and the emergency control. Feasible emergency control targets and control technology were also proposed for different sudden water pollution accidents. A demonstrative project was conducted in the Fangshui to Puyang channel, which is part of the Beijing-Shijiazhuang Emergency Water Supply Project (BSP) in the Middle Route of the South-to-North Water Transfer Project (MR-SNWTP) in China. However, we could not use an actual toxic soluble pollutant to validate our ECS, so we performed the experiment with sucrose to test the ECS based on its concentration variation. The relative error of peak sucrose concentration was less than 20 %. PMID- 26979312 TI - Phase 1b/2a study of trastuzumab emtansine (T-DM1), paclitaxel, and pertuzumab in HER2-positive metastatic breast cancer. AB - BACKGROUND: In pre-clinical studies, the anti-tumor activity of T-DM1 was enhanced when combined with taxanes or pertuzumab. This phase 1b/2a study evaluated the safety/tolerability of T-DM1 + paclitaxel +/- pertuzumab in HER2 positive advanced breast cancer. METHODS: In phase 1b (n = 60), a 3 + 3 dose escalation approach was used to determine the maximum tolerated dose (MTD) of T DM1 + paclitaxel +/- pertuzumab. The primary objective of phase 2a was feasibility, with 44 patients randomized to T-DM1 + paclitaxel +/- pertuzumab at the MTD identified in phase 1b. RESULTS: The MTD was T-DM1 3.6 mg/kg every three weeks (q3w) or 2.4 mg/kg weekly + paclitaxel 80 mg/m(2) weekly +/- pertuzumab 840 mg loading dose followed by 420 mg q3w. Phase 2a patients had received a median of 5.0 (range: 0-10) prior therapies for advanced cancer. In phase 2a, 51.2 % received >=12 paclitaxel doses within 15 weeks, and 14.0 % received 12 paclitaxel doses by week 12. Common all-grade adverse events (AEs) were peripheral neuropathy (90.9 %) and fatigue (79.5 %). A total of 77.3 % experienced grade >=3 AEs, most commonly neutropenia (25.0 %) and peripheral neuropathy (18.2 %). Among the 42 phase 2a patients with measurable disease, the objective response rate (ORR) was 50.0 % (95 % confidence interval (CI) 34.6-65.4); the clinical benefit rate (CBR) was 56.8 % (95 % CI 41.6-71.0). No pharmacokinetic interactions were observed between T-DM1 and paclitaxel. CONCLUSIONS: This regimen showed clinical activity. Although there is potential for paclitaxel to be added to T-DM1 +/- pertuzumab, peripheral neuropathy was common in this heavily pretreated population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00951665 . Registered August 3, 2009. PMID- 26979315 TI - Electrochemical detection of malathion pesticide using acetylcholinesterase biosensor based on glassy carbon electrode modified with conducting polymer film. AB - Acetylcholinesterase (AChE) biosensor based on conducting poly([2,2';5' 2"] terthiophene-3-carbaldehyde) (PTT) modified glassy carbon electrode (GCE) was constructed. AChE was immobilized on PTT film surface through the covalent bond between aldehyde and amino groups. The properties of PTT modified GCE were studied using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and scanning electron microscopy (SEM). The biosensor showed an oxidation peak at +0.83 V related to the oxidation of thiocholine, hydrolysis product of acetylthiocholine iodide (ATCI), catalyzed by AChE. The optimum current response of the biosensor was observed at pH 7.5-8.0, 40 degrees C and 120 U/cm(2) of AChE concentration. The biosensor showed a high sensitivity (183.19 MUA/mM), a linear range from 0.015 to 1.644 mM, and a good reproducibility with 1.7 % of relative standard deviation (RSD). The biosensor showed a good stability. The interference of glycin, ascorbic acid, histidine, uric acid, dopamine, and arginine on the biosensor response was studied. An important analytical response from these inteferents that overlaps the biosensor response was not observed. The inhibition rate of malathion as a model pesticide was proportional to its concentrations from 9.99 to 99.01 nM. The detection limit was 4.08 nM. PMID- 26979316 TI - Immobilization of Mn and NH4 (+)-N from electrolytic manganese residue waste. AB - The objective of this work was the immobilization of soluble manganese (Mn) and ammonium nitrogen (NH4 (+)-N) leached from electrolytic manganese residue (EMR). Immobilization of Mn was investigated via carbonation using carbon dioxide (CO2) and alkaline additives. NH4 (+)-N immobilization was evaluated via struvite precipitation using magnesium and phosphate sources. Results indicated that the immobilization efficiency of Mn using CO2 and quicklime (CaO) was higher than using CO2 and sodium hydroxide (NaOH). This higher efficiency was likely due to the slower release of OH(-) during CaO hydrolysis. The immobilization efficiency of Mn was >99.99 % at the CaO:EMR mass ratio of 0.05:1 for 20-min reaction time. The struvite precipitation of NH4 (+)-N was conducted in the carbonated EMR slurry and the immobilization efficiency was 89 % using MgCl2 . 6H2O + Na3PO4 . 12H2O at the Mg:P:N molar ratio of 1.5:1.5:1 for 90-min reaction time. A leaching test showed that the concentrations of Mn and NH4 (+)-N in the filtrate of the treated EMR were 0.2 and 9 mg/L, respectively. The combined immobilization of Mn and NH4 (+)-N was an effective pretreatment method in the harmless treatment of the EMR. PMID- 26979318 TI - A new estimation of the total flavonoids in silkworm cocoon sericin layer through aglycone determination by hydrolysis-assisted extraction and HPLC-DAD analysis. AB - BACKGROUND: Silk sericin and a few non-protein components isolated from the cocoon layer including two silk proteins in silkworm Bombyx mori has many bioactivities. The dietary sericin possess antinatural oxidation, anticancer, antihyperlipidemic, and antidiabetic activities. The non-protein components surrounding the sericin layer involve in wax, pigments mainly meaning flavonoids, sugars, and other impurities. However, very few investigations have reported the estimation of the total flavonoids derived from the cocoon layer. The flavonoids are commonly present in their glycosylated forms and mostly exist as quercetin glycosides in the sericin layers of silkworm cocoons. OBJECTIVE: The aim of this study was to find a more accurate method to estimate the level of the total flavonoids in silkworm cocoons. DESIGN: An efficient procedure of hydrolysis assisted extraction (HAE) was first established to estimate the level of the total flavonoids through the determination of their aglycones, quercetin, and kaempferol. Then, a comparison was made between traditional colorimetric method and our method. In addition, the antioxidant activities of hydrolysis-assisted extract sample were determined. RESULTS: The average contents of quercetin and kaempferol were 1.98 and 0.42 mg/g in Daizo cocoon. Their recoveries were 99.56 and 99.17%. The total sum of quercetin and kaempferol was detected to be 2.40+/ 0.07 mg/g by HAE-HPLC, while the total flavonoids (2.59+/-0.48 mg/g) estimated by the traditional colorimetric method were only equivalent to 1.28+/-0.04 mg/g of quercetin. The HAE sample also exhibits that IC50 values of scavenging ability of diphenyl picryl hydrazinyl (DPPH) radical and hydroxyl radical (HO.) are 243.63 ug/mL and 4.89 mg/mL, respectively. CONCLUSIONS: These results show that the HAE HPLC method is specificity of cocoon and far superior to the colorimetric method. Therefore, this study has profound significance for the comprehensive utilization of silkworm cocoon and also may be applied to the estimation of total flavonoids in other functional foods. PMID- 26979317 TI - Gamma radiolytic decomposition of endosulfan in aerated solution: the role of carbonate radical. AB - The present study elaborates the removal of endosulfan, an emerging water pollutant and potential carcinogenic, in aerated solution. The influence of Cl( ), NO3 (-), NO2 (-), CO3 (2-), HCO3 (-), SO3 (2-), and humic acid was assessed on the radiolytic degradation of endosulfan. A strong inhibition on the radiolytic degradation of endosulfan was observed in the presence of NO3 (-), NO2 (-), and SO3 (2-). Instead, a slight increase in the removal efficiency of endosulfan was observed at high concentrations of CO3 (2-) and HCO3 (-). The formation of CO3 (* ) in radiolytic degradation of endosulfan in the presence of CO3 (2-) and HCO3 ( ) was demonstrated by adding SO3 (2-) that rapidly react with CO3 (*-). The results indicate that CO3 (*-) formed from the reactions of CO3 (2-) and HCO3 (-) and commonly found in natural water can play an important role in the degradation of endosulfan and other sulfur containing electron-rich compounds. The study showed faster degradation of endosulfan at lower concentration compared to high concentration and removal was found to follow pseudo-first-order kinetic. Endosulfan ether was found as the main degradation product and degradation pathway was found to be initiated at the S=O bond of endosulfan. The efficiency of gamma irradiation in the removal of endosulfan was examined in terms of formation of short chain organic acids and chloride ion accumulation. PMID- 26979319 TI - CORR Insights((r)): Can Vascular Injury be Appropriately Assessed With Physical Examination After Knee Dislocation? PMID- 26979320 TI - Digital X-ray radiogrammetry and its sensitivity and specificity for the identification of rheumatoid arthritis-related cortical hand bone loss. AB - Digital X-ray radiogrammetry (DXR) is a computer-assisted diagnosis technique for quantifying cortical hand bone mineral density (BMD) as well as the metacarpal index (MCI) in the metacarpal bones from radiographs. The objective was to compare DXR-BMD and DXR-MCI between healthy individuals and patients with rheumatoid arthritis (RA) and verify the sensitivity and specificity of this technique for the identification of cortical hand bone loss as an additional diagnostic approach in RA. 618 patients were enrolled and divided into two groups: those with RA (n = 309) and a healthy control group (n = 309) as a reference database. DXR-BMD and the DXR-MCI were measured by DXR using hand radiographs. The severity of RA was evaluated by the modified Larsen score. Mean values for DXR-BMD and DXR-MCI in RA patients were significantly lower compared to healthy subjects (-20.7 and -21.1 %, respectively). Depending on the severity of RA-related joint damage, DXR-BMD revealed a significant reduction of -28.1 % and DXR-MCI -28.2 %, comparing score 1 and score 5 of the modified Larsen score. Both DXR-BMD and DXR-MCI had a high sensitivity (DXR-BMD 91 %, DXR-MCI 87 %) and a moderate specificity (DXR-BMD 47 %, DXR-MCI 49 %) to identify RA-related cortical hand bone loss. The DXR technique seems to be able to quantify RA related periarticular bone loss as a characteristic feature in the course of RA. Consequently, periarticular osteoporosis seems to function as a reliable diagnostic approach comparable to erosions and joint space narrowing in the diagnosis of RA and as a surrogate marker for the progression of bone loss in RA. PMID- 26979322 TI - Erratum to: Quantitative proteomics analysis reveals that S-nitrosoglutathione reductase (GSNOR) and nitric oxide signaling enhance poplar defense against chilling stress. PMID- 26979321 TI - Depurinating estrogen-DNA adducts, generators of cancer initiation: their minimization leads to cancer prevention. AB - Estrogens can initiate cancer by reacting with DNA. Specific metabolites of endogenous estrogens, the catechol estrogen-3,4-quinones, react with DNA to form depurinating estrogen-DNA adducts. Loss of these adducts leaves apurinic sites in the DNA, generating mutations that can lead to the initiation of cancer. A variety of endogenous and exogenous factors can disrupt estrogen homeostasis, which is the normal balance between estrogen activating and protective enzymes. In fact, if estrogen metabolism becomes unbalanced and generates excessive catechol estrogen 3,4-quinones, formation of depurinating estrogen-DNA adducts increases and the risk of initiating cancer is greater. The levels of depurinating estrogen-DNA adducts are high in women diagnosed with breast cancer and those at high risk for the disease. High levels of depurinating estrogen-DNA adducts before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Women with thyroid or ovarian cancer also have high levels of estrogen-DNA adducts, as do men with prostate cancer or non-Hodgkin lymphoma. Depurinating estrogen-DNA adducts are initiators of many prevalent types of human cancer. These findings and other discoveries led to the recognition that reducing the levels of estrogen-DNA adducts could prevent the initiation of human cancer. The dietary supplements N-acetylcysteine and resveratrol inhibit formation of estrogen-DNA adducts in cultured human breast cells and in women. These results suggest that the two supplements offer an approach to reducing the risk of developing various prevalent types of human cancer. Graphical abstract Major metabolic pathway in cancer initiation by estrogens. PMID- 26979323 TI - Structural modelling and transcriptional responses highlight a clade of PpKAI2 LIKE genes as candidate receptors for strigolactones in Physcomitrella patens. AB - MAIN CONCLUSION: A set of PpKAI2 - LIKE paralogs that may encode strigolactone receptors in Physcomitrella patens were identified through evolutionary, structural, and transcriptional analyses, suggesting that strigolactone perception may have evolved independently in basal land plants in a similar manner as spermatophytes. Carotenoid-derived compounds known as strigolactones are a new class of plant hormones that modulate development and interactions with parasitic plants and arbuscular mycorrhizal fungi. The strigolactone receptor protein DWARF14 (D14) belongs to the alpha/beta hydrolase family. D14 is closely related to KARRIKIN INSENSITIVE2 (KAI2), a receptor of smoke-derived germination stimulants called karrikins. Strigolactone and karrikin structures share a butenolide ring that is necessary for bioactivity. Charophyte algae and basal land plants produce strigolactones that influence their development. However phylogenetic studies suggest that D14 is absent from algae, moss, and liverwort genomes, raising the question of how these basal plants perceive strigolactones. Strigolactone perception during seed germination putatively evolved in parasitic plants through gene duplication and neofunctionalization of KAI2 paralogs. The moss Physcomitrella patens shows an increase in KAI2 gene copy number, similar to parasitic plants. In this study we investigated whether P. patens KAI2-LIKE (PpKAI2L) genes may contribute to strigolactone perception. Based on phylogenetic analyses and homology modelling, we predict that a clade of PpKAI2L proteins have enlarged ligand-binding cavities, similar to D14. We observed that some PpKAI2L genes have transcriptional responses to the synthetic strigolactone GR24 racemate or its enantiomers. These responses were influenced by light and dark conditions. Moreover, (+)-GR24 seems to be the active enantiomer that induces the transcriptional responses of PpKAI2L genes. We hypothesize that members of specific PpKAI2L clades are candidate strigolactone receptors in moss. PMID- 26979326 TI - Columnar propeller-like 1,3,5-triphenylbenzenes: the missing link of shape persistent hekates. AB - Triphenylbenzenes with different substitution patterns at the outer phenyl rings have been successfully synthesised. Sixfold n-alkoxy substitution was insufficient for mesomorphism, but already increasing the number of side chains by three methoxy groups led to liquid crystalline behaviour and mesophase formation. Symmetrical triphenylbenzenes with nine n-alkoxy side chains (>=C9) formed broad enantiotropic mesophases. The symmetry of the liquid crystalline phases was unambiguously determined by X-ray diffraction measurements as Colh and Colho for symmetry-reduced methoxy-alkoxy derivatives and symmetrical nona-alkoxy triphenylbenzenes, respectively. Based on X-ray diffraction data a stacking model was proposed in which the single molecules aggregate to helical columns forming a mesophase. PMID- 26979327 TI - Elevated birth prevalence of conotruncal heart defects in a population with high consanguinity rate. AB - BACKGROUND: The aetiology of conotruncal heart defects is poorly understood and the birth prevalence varies geographically. The known risk factors for developing conotruncal heart defects are as follows: CHD in siblings, genetic chromosomal abnormalities, paternal age >30 years, high parity, low birth weight, prematurity, and maternal diabetes. OBJECTIVE: The aim of this study was to characterise conotruncal heart defects, birth prevalence, mortality, and morbidity in the population of southern Israel, of whom 75% are Jewish and the rest are mostly Bedouin Arabs. METHODS: The data were obtained from Soroka University Medical Center database of births and newborns. Conotruncal heart defects cases were identified by ICD9 codes. RESULTS: During 1991-2011, there were 247,290 singleton live births and 393 conotruncal heart defects in Soroka University Medical Center. The birth prevalence per 10,000 live births of tetralogy of Fallot, transposition of the great arteries, and truncus arteriosus was 9.5, 5, and 1.8, respectively. In the multivariate analysis, Bedouin descent (adjusted odds ratio 2.40, p35 years (1.66, p=0.004), and siblings with congenital heart defects (1.98, p=0.005) were associated with tetralogy of Fallot, and Bedouin descent (1.61, p=0.05), siblings with congenital heart defects (2.19, p=0.004), and diabetes mellitus (7.15, p<0.001) were associated with transposition of the great arteries. In a univariate analysis, Bedouin descent (p=0.004) and congenital heart defects in siblings (p<0.001) were associated with truncus arteriosus. CONCLUSION: We observed higher birth prevalence of conotruncal heart defects compared with the birth prevalence reported worldwide, specifically among the Bedouins, a population characterised with high consanguinity rate. Therefore, genetic counselling and early fetal echocardiograms should be encouraged, especially in high consanguinity rate populations. Naturally, further educational efforts are needed in order to decrease consanguinity and its related consequences. PMID- 26979324 TI - Down-regulation of nitrogen/carbon metabolism coupled with coordinative hormone modulation contributes to developmental inhibition of the maize ear under nitrogen limitation. AB - MAIN CONCLUSION: Developmental inhibition of the maize ear by nitrogen limitation is due to overall down-regulation of nitrogen/carbon metabolism, coordinative hormonal modulation, and probable early senescence. The kernel number is primarily determined from 2 weeks pre-silking to 3 weeks post-silking, largely depending on dynamic nitrogen (N) and carbohydrate metabolism and accumulation in the maize ear. Underlying physiological and molecular mechanisms of kernel abortion caused by N limitation needs to be further investigated. Using a widely grown maize hybrid ZD958, we found that the N deficient ear was shorter, with less biomass accumulation, lower N concentrations, and overall lower concentrations of N assimilates and soluble sugars at 1- or 2-week after silking. Such negative alterations were probably due to significant decreases in activities of nitrate reductase, glutamine synthetase, sucrose phosphate synthetase, and sucrose synthetase in the N deficient maize ear especially after silking. Compensatory up-regulation of corresponding gene expression, together with co-downregulation of gene expression and enzyme activities in certain circumstances, suggested regulatory complexity and mechanistic differentiation from gene expression to functioning at physiological and molecular levels in quickly developing maize ear in counteracting N deficiency. Importantly, auxin, gibberellin, cytokinin, and abscisic acid may act in a coordinative manner to negatively modulate ear development under N limitation, as indicated by their concentration variations and substantial up-regulation of IAA14, GA2-ox1, and CKX12. Lastly, early senescence may occur in the low-N ear driven by interplay of hormone functioning and senescence-related gene regulation. PMID- 26979325 TI - Case-finding for common mental disorders of anxiety and depression in primary care: an external validation of routinely collected data. AB - BACKGROUND: The robustness of epidemiological research using routinely collected primary care electronic data to support policy and practice for common mental disorders (CMD) anxiety and depression would be greatly enhanced by appropriate validation of diagnostic codes and algorithms for data extraction. We aimed to create a robust research platform for CMD using population-based, routinely collected primary care electronic data. METHODS: We developed a set of Read code lists (diagnosis, symptoms, treatments) for the identification of anxiety and depression in the General Practice Database (GPD) within the Secure Anonymised Information Linkage Databank at Swansea University, and assessed 12 algorithms for Read codes to define cases according to various criteria. Annual incidence rates were calculated per 1000 person years at risk (PYAR) to assess recording practice for these CMD between January 1(st) 2000 and December 31(st) 2009. We anonymously linked the 2799 MHI-5 Caerphilly Health and Social Needs Survey (CHSNS) respondents aged 18 to 74 years to their routinely collected GP data in SAIL. We estimated the sensitivity, specificity and positive predictive value of the various algorithms using the MHI-5 as the gold standard. RESULTS: The incidence of combined depression/anxiety diagnoses remained stable over the ten year period in a population of over 500,000 but symptoms increased from 6.5 to 20.7 per 1000 PYAR. A 'historical' GP diagnosis for depression/anxiety currently treated plus a current diagnosis (treated or untreated) resulted in a specificity of 0.96, sensitivity 0.29 and PPV 0.76. Adding current symptom codes improved sensitivity (0.32) with a marginal effect on specificity (0.95) and PPV (0.74). CONCLUSIONS: We have developed an algorithm with a high specificity and PPV of detecting cases of anxiety and depression from routine GP data that incorporates symptom codes to reflect GP coding behaviour. We have demonstrated that using diagnosis and current treatment alone to identify cases for depression and anxiety using routinely collected primary care data will miss a number of true cases given changes in GP recording behaviour. The Read code lists plus the developed algorithms will be applicable to other routinely collected primary care datasets, creating a platform for future e-cohort research into these conditions. PMID- 26979328 TI - Turnabout Is Fair Play: Herbivory-Induced Plant Chitinases Excreted in Fall Armyworm Frass Suppress Herbivore Defenses in Maize. AB - The perception of herbivory by plants is known to be triggered by the deposition of insect-derived factors such as saliva and oral secretions, oviposition materials, and even feces. Such insect-derived materials harbor chemical cues that may elicit herbivore and/or pathogen-induced defenses in plants. Several insect-derived molecules that trigger herbivore-induced defenses in plants are known; however, insect-derived molecules suppressing them are largely unknown. In this study, we identified two plant chitinases from fall armyworm (Spodoptera frugiperda) larval frass that suppress herbivore defenses while simultaneously inducing pathogen defenses in maize (Zea mays). Fall armyworm larvae feed in enclosed whorls of maize plants, where frass accumulates over extended periods of time in close proximity to damaged leaf tissue. Our study shows that maize chitinases, Pr4 and Endochitinase A, are induced during herbivory and subsequently deposited on the host with the feces. These plant chitinases mediate the suppression of herbivore-induced defenses, thereby increasing the performance of the insect on the host. Pr4 and Endochitinase A also trigger the antagonistic pathogen defense pathway in maize and suppress fungal pathogen growth on maize leaves. Frass-induced suppression of herbivore defenses by deposition of the plant-derived chitinases Pr4 and Endochitinase A is a unique way an insect can co opt the plant's defense proteins for its own benefit. It is also a phenomenon unlike the induction of herbivore defenses by insect oral secretions in most host herbivore systems. PMID- 26979329 TI - A JUMONJI Protein with E3 Ligase and Histone H3 Binding Activities Affects Transposon Silencing in Arabidopsis. AB - Transposable elements (TEs) make up a large proportion of eukaryotic genomes. As their mobilization creates genetic variation that threatens genome integrity, TEs are epigenetically silenced through several pathways, and this may spread to neighboring sequences. JUMONJI (JMJ) proteins can function as antisilencing factors and prevent silencing of genes next to TEs Whether TE silencing is counterbalanced by the activity of antisilencing factors is still unclear. Here, we characterize JMJ24 as a regulator of TE silencing. We show that loss of JMJ24 results in increased silencing of the DNA transposon AtMu1c, while overexpression of JMJ24 reduces silencing. JMJ24 has a JumonjiC (JmjC) domain and two RING domains. JMJ24 autoubiquitinates in vitro, demonstrating E3 ligase activity of the RING domain(s). JMJ24-JmjC binds the N-terminal tail of histone H3, and full length JMJ24 binds histone H3 in vivo. JMJ24 activity is anticorrelated with histone H3 Lys 9 dimethylation (H3K9me2) levels at AtMu1c Double mutant analyses with epigenetic silencing mutants suggest that JMJ24 antagonizes histone H3K9me2 and requires H3K9 methyltransferases for its activity on AtMu1c Genome-wide transcriptome analysis indicates that JMJ24 affects silencing at additional TEs Our results suggest that the JmjC domain of JMJ24 has lost demethylase activity but has been retained as a binding domain for histone H3. This is in line with phylogenetic analyses indicating that JMJ24 (with the mutated JmjC domain) is widely conserved in angiosperms. Taken together, this study assigns a role in TE silencing to a conserved JmjC-domain protein with E3 ligase activity, but no demethylase activity. PMID- 26979330 TI - Phosphate Treatment Strongly Inhibits New Arbuscule Development But Not the Maintenance of Arbuscule in Mycorrhizal Rice Roots. AB - Phosphorus (P) is a crucial nutrient for plant growth, but its availability to roots is limited in soil. Arbuscular mycorrhizal (AM) symbiosis is a promising strategy for improving plant P acquisition. However, P fertilizer reduces fungal colonization (P inhibition) and compromises mycorrhizal P uptake, warranting studies on the mechanistic basis of P inhibition. In this study, early morphological changes in P inhibition were identified in rice (Oryza sativa) using fungal cell wall staining and live-cell imaging of plant membranes that were associated with arbuscule life cycles. Arbuscule density decreased, and aberrant hyphal branching was observed in roots at 5 h after P treatment. Although new arbuscule development was severely inhibited, preformed arbuscules remained intact and longevity remained constant. P inhibition was accelerated in the rice pt11-1 mutant, which lacks P uptake from arbuscule branches, suggesting that mature arbuscules are stabilized by the symbiotic P transporter under high P condition. Moreover, P treatment led to increases in the number of vesicles, in which lipid droplets accumulated and then decreased within a few days. The development of new arbuscules resumed within by 2 d. Our data established that P strongly and temporarily inhibits new arbuscule development, but not intraradical accommodation of AM fungi. PMID- 26979331 TI - Xylans Provide the Structural Driving Force for Mucilage Adhesion to the Arabidopsis Seed Coat. AB - Arabidopsis (Arabidopsis thaliana) seed coat epidermal cells produce large amounts of mucilage that is released upon imbibition. This mucilage is structured into two domains: an outer diffuse layer that can be easily removed by agitation and an inner layer that remains attached to the outer seed coat. Both layers are composed primarily of pectic rhamnogalacturonan I (RG-I), the inner layer also containing rays of cellulose that extend from the top of each columella. Perturbation in cellulosic ray formation has systematically been associated with a redistribution of pectic mucilage from the inner to the outer layer, in agreement with cellulose-pectin interactions, the nature of which remained unknown. Here, by analyzing the outer layer composition of a series of mutant alleles, a tight proportionality of xylose, galacturonic acid, and rhamnose was evidenced, except for mucilage modified5-1 (mum5-1; a mutant showing a redistribution of mucilage pectin from the inner adherent layer to the outer soluble one), for which the rhamnose-xylose ratio was increased drastically. Biochemical and in vitro binding assay data demonstrated that xylan chains are attached to RG-I chains and mediate the adsorption of mucilage to cellulose microfibrils. mum5-1 mucilage exhibited very weak adsorption to cellulose. MUM5 was identified as a putative xylosyl transferase recently characterized as MUCI21. Together, these findings suggest that the binding affinity of xylose ramifications on RG-I to a cellulose scaffold is one of the factors involved in the formation of the adherent mucilage layer. PMID- 26979334 TI - Acceptability of study procedures (self-collected introital swabs, blood draws and stool sample collection) by students 10-16 years for an HPV vaccine effectiveness study: a pilot study. AB - BACKGROUND: A cohort study was planned to evaluate vaccine immunogenicity and effect of malaria and helminth co-infections on the bivalent Human papilloma virus (HPV) vaccine. The study would involve self collected introital swabs, blood draws and stool sample collection. We therefore conducted a pilot study to assess the acceptability of these procedures among the students and their parents. RESULTS: A cross-sectional study among forty four students from two purposively selected primary schools of Western Uganda. Exit interviews and two focus group discussions (FGD) (for parents) were conducted. Acceptability was measured by willingness to undergo the procedures again, recommending the procedures to others as well as proportion of introital swabs positive for beta globulin. FGD determined acceptability of the parents and explored opinions and perceptions that would influence their decisions. HPV-16/18 and beta globulin deoxyribonucleic acid (DNA) were analysed using a polymerase chain reaction (PCR) kit. All the students (100%) in the study were willing to provide a self- collected introital swab and a stool sample as well as recommending their friends while (86.3%) were willing for blood draws. There were 40/44 (90.1%) self collected introital swabs that had positive result for human beta globulin though none of them was positive for HPV-16/18. In the FGD, it emerged that parents concerns were on the blood draws and introital swab collection which were addressed. CONCLUSIONS: The study procedures were highly acceptable among this study population of students and their parents. Follow-up to assess HPV vaccine effectiveness and factors that may influence the vaccine in this age group is feasible. PMID- 26979332 TI - Arabidopsis CALCINEURIN B-LIKE10 Functions Independently of the SOS Pathway during Reproductive Development in Saline Conditions. AB - The accumulation of sodium in soil (saline conditions) negatively affects plant growth and development. The Salt Overly Sensitive (SOS) pathway in Arabidopsis (Arabidopsis thaliana) functions to remove sodium from the cytosol during vegetative development preventing its accumulation to toxic levels. In this pathway, the SOS3 and CALCINEURIN B-LIKE10 (CBL10) calcium sensors interact with the SOS2 protein kinase to activate sodium/proton exchange at the plasma membrane (SOS1) or vacuolar membrane. To determine if the same pathway functions during reproductive development in response to salt, fertility was analyzed in wild type and the SOS pathway mutants grown in saline conditions. In response to salt, CBL10 functions early in reproductive development before fertilization, while SOS1 functions mostly after fertilization when seed development begins. Neither SOS2 nor SOS3 function in reproductive development in response to salt. Loss of CBL10 function resulted in reduced anther dehiscence, shortened stamen filaments, and aborted pollen development. In addition, cbl10 mutant pistils could not sustain the growth of wild-type pollen tubes. These results suggest that CBL10 is critical for reproductive development in the presence of salt and that it functions in different pathways during vegetative and reproductive development. PMID- 26979335 TI - Evidence for multi-polymorphic islands during epitaxial growth of ZnO on Ag(1 1 1). AB - A range of models of free standing and Ag(1 1 1)-supported stoichiometric ZnO films with coverages between 2-3 monolayers are studied using density functional calculations. Following experimental observations we focus on stoichiometric hexagonal and triangular ad-layer islands grown on top of two complete ZnO monolayers. The adlayer islands display distinct edge and corner reconstructions and are found to induce a structural transition extending from the island core to the layered phase below. Based on our results we propose a general model of ad layer triangular island structure based on seven regions exhibiting four distinct polymorphs. PMID- 26979333 TI - Correlation between EGFR gene mutation, cytologic tumor markers, 18F-FDG uptake in non-small cell lung cancer. AB - BACKGROUND: EGFR mutation-induced cell proliferation causes changes in tumor biology and tumor metabolism, which may reflect tumor marker concentration and 18F-FDG uptake on PET/CT. Direct aspirates of primary lung tumors contain different concentrations of tumor markers than serum tumor markers, and may correlate better with EGFR mutation than serum tumor markers. The purpose of this study is to investigate an association between cytologic tumor markers and FDG uptake with EGFR mutation status in non-small cell lung cancer (NSCLC). METHODS: We prospectively collected tumor aspirates of 61 patients who underwent EGFR mutation analysis. Serum and cytologic CYFRA 21-1, CEA, and SCCA levels were measured and correlated with EGFR gene mutations. FDG PET/CT was performed on 58 patients for NSCLC staging, and SUV was correlated with EGFR mutation status. RESULTS: Thirty (50%) patients had EGFR mutation and 57 patients had adenocarcinoma subtype. Univariate analysis showed that female gender, never smoker, high levels of cytologic CYFRA 21-1 (c-CYFRA) and lower maximum standard uptake value (SUVmax) were correlated with EGFR mutations. ROC generated cut-off values of 20.8 ng/ml for c-CYFRA and SUVmax of 9.6 showed highest sensitivity for EGFR mutation detection. Multivariate analysis revealed that female gender [hazard ratio (HR): 18.15, p = 0.025], higher levels of c-CYFRA (HR: 7.58, and lower SUVmax (HR: 0.08, p = 0.005) were predictive of harboring EGFR mutation. CONCLUSIONS: The cytologic tumor marker c-CYFRA was positively associated with EGFR mutations in NSCLC. EGFR mutation-positive NSCLCs have relatively lower glycolysis compared with NSCLCs without EGFR mutation. PMID- 26979336 TI - How are the employed and unemployed affected by the economic crisis in Spain? Educational inequalities, life conditions and mental health in a context of high unemployment. AB - BACKGROUND: Despite an increasing number of studies on the factors mediating the impact of the economic recession on mental health, research beyond the individual employment status is scarce. Our objectives were to investigate in which ways the mental health of employed and unemployed populations is differently affected by the current economic recession along the educational scale and to examine whether financial strain and social support explain these effects of the crisis. METHODS: A repeated cross-sectional study, using two waves of the Andalusian Health Survey in 2007 (pre-crisis) and 2011-2012 (crisis). A population aged between 19 and 64 years was selected. The dependent variable was the Mental Component Summary of the SF-12 questionnaire. We performed Poisson regression models stratified by working status, with period, educational level, financial strain and social support as independent variables. We examined interactions between period and educational level. Age, sex, main earner, cohabitation and partner's working status were considered as covariates. RESULTS: The study included 3210 individuals (1185 women) in 2007 and 3633 individuals (1486 women) in 2011-2012. In working individuals the prevalence of poor mental health increased for secondary and complete primary studies groups during crisis compared to the pre crisis period, while it decreased significantly in the university study group (PR = 0.76, 95% CI: 0.58-0.99). However, in unemployed individuals prevalence ratios for poor mental health increased significantly only in the secondary studies group (PR = 1.73, 95% CI: 1.06-2.83). Financial strain and social support yielded consistent associations with mental health in all subgroups. Only financial strain could partly explain the crisis effect on mental health among the unemployed. CONCLUSIONS: Our study supports the finding that current economic recession is associated with poorer mental health differentially according to labour market status and educational level. Those with secondary studies may be at risk in times of economic recession. In connection with this, emerging educational inequalities in mental health among the employed population were observed. Our research also suggests a partial mediating role of financial strain for the effects of crisis on poor mental health among the unemployed. Good social support appears to buffer poor mental health in all subgroups but not specifically during crisis period. PMID- 26979338 TI - The in vivo effects of a fraction from Dioscorea spongiosa on glucocorticoid induced osteoporosis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicines, osteoporosis was considered to be induced by the deficiency of kidney's function. The Rhizoma of Dioscorea spongiosa was one of the kidney tonifying and bone strengthening agent in the traditional usage and previous study had shown that its 90% ethanol fraction was effective on anti-osteoporosis using the ovariectomized (OVX) rats. However, for the secondary osteoporosis, like glucocorticoid-induced osteoporosis (GIO), its effect was still unknown. MATERIALS AND METHODS: The GIO model was established by injecting dexamethasone into the muscles of rats. The 90% ethanol extraction of Dioscorea spongiosa (DSE) were administrated to rats in three different dosages, 125, 250 and 500mg/Kg/d, respectively. After the administration, the rats were sacrificed to measure different kinds of indicators, including the biochemical indexes in urine and serum, the bone tissue metrology, BMC and BMD, biomechanical indicators and histological changes. RESULTS: DSE could significantly reduce the content of BGP, ALT, TRAcP, HOP/Cr and Ca/Cr, increase the content of P/Cr compared with the control group, suggesting that DSE is effective on controlling the excessive transition of bones and inhibiting the bone resorption. By the administration of DSE, the dry bone weight/volume, ash weight/volume, the content of Ca, BMD and BMC were also obviously increased, suggesting that DSE could increase the bone mass by increasing its Ca content. Besides, the flexure strength and maximum bending force could be improved by DSE, suggesting that it could strengthen the hardness and strength of bones. In the histological investigation, DSE could repair the broken of cancellous bones and bone trabecular with the similar activity with XLGB. CONCLUSIONS: The results showed that DSE is effective on inhibiting GIO in rats by improving the bone tissue metrology, BMC and BMD as well as biomechanical indicators, and also repairing the microscopic changes of cancellous bones and trabecular bones. The mechanism was related to the inhibition of excessive bone transition and bone resorption according to the changes of biochemical indexes. PMID- 26979337 TI - Chronic obstructive pulmonary disease is not a risk factor for polyneuropathy: A prospective controlled study. AB - Polyneuropathy has been observed in patients with chronic obstructive pulmonary disease (COPD). If polyneuropathy occurs as a complication or extrapulmonary manifestation of COPD, one would expect an increased prevalence among patients with a cryptogenic axonal polyneuropathy. This case-control study aimed to investigate the association between COPD and polyneuropathy. We prospectively included 345 patients with cryptogenic axonal polyneuropathy and 465 controls. A standardized questionnaire assessed the presence of COPD and we verified this diagnosis by contacting the family physician. The severity of COPD was based on the Global Initiative for Chronic Obstructive Lung Disease classification. The prevalence of COPD did not differ between patients with polyneuropathy and controls (15/345 vs. 12/465 respectively; odds ratio (OR) 1.7; 95% confidence interval (CI) [0.8-3.7]). Adjusting for age, gender and possible confounders did not affect these results (adjusted OR 1.7, 95% CI 0.7-4.1). The severity of COPD was similar between patients with polyneuropathy and controls. This study does not support the hypothesis that COPD is a risk factor for polyneuropathy. PMID- 26979339 TI - The aqueous extract of rhizome of Gastrodia elata Blume attenuates locomotor defect and inflammation after traumatic brain injury in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traumatic brain injury (TBI) has an incident rate of 200-300 people per 100,000 annually in the developed countries. TBI has relatively high incidence at an early age and may cause long-term physical disability. Patients suffered from severe TBI would have motor and neuropsychological malfunctions, affecting their daily activities. Traditionally, Gastrodia elata Blume is a Chinese Medicines which was used for the head diseases, while their efficiency on reducing brain damage was still largely unknown. In the present study, we aimed to examine the effect of water extract of G. elata Blume (GE) against TBI and elucidate its underlying mechanism. MATERIALS AND METHODS: Sprague-Dawley rats were treated with GE for 7 days, immediately after controlled cortical impact-induced TBI. Impaired neurobehavioral functioning was measured on day 3 and 6 after TBI. Histology of TBI was examined to assess the extent of inflammation, and the expressions of pro-inflammatory cytokines were examined by immunofluorescence study on day 7. RESULTS: GE treatment significantly improved the impaired locomotor functions induced by TBI. GE treatment reduced inflammation and gliosis in the penumbral area. The increase in brain levels of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha observed in non-GE treated TBI rats were also reversed. CONCLUSIONS: GE treatment attenuated the locomotor deficit caused by TBI. The anti inflammatory activity might be mediated by inhibition of pro-inflammatory cytokines responses in the TBI-brain. PMID- 26979341 TI - Paeoniflorin protects Schwann cells against high glucose induced oxidative injury by activating Nrf2/ARE pathway and inhibiting apoptosis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Paeoniflorin (PF) is the principal bioactive component of Paeonia lactiflora Pall., which an included in Tang Luo Ning recipe, a traditional Chinese herbal medicine based on Huangqi Guizhi Wuwu decoction. PF is also widely used in Traditional Chinese Medicine for the treatment of blood arthralgia disease including diabetic peripheral neuropathy (DPN), but its underlying molecular mechanism of neuroprotective effects is not yet well understood. Diabetic hyperglycemia induced oxidative stress in Schwann cells, an important component of the peripheral nervous system, has been proposed as a unifying mechanism for DPN. The objective of this study is to determine the effects of PF on Schwann cells oxidative stress and apoptosis induced by high glucose. MATERIALS AND METHODS: RSC96 cells, a Schwann cell line, were treated with high glucose (150mM) and PF (1, 10 and 100MUM). Subsequently, MTT assay was performed. The level of apoptosis was examined by flow cytometry and the oxidative stress was reflected by reactive oxygen species (ROS), malondialdehyde (MDA), glutathione S-transferases (GST) and glutathione peroxidase (GPX) levels. The mRNA expressions of Nuclear factor-E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) were detected by qRT-PCR. The levels of Kelch-like ECH associating protein 1 (Keap1), Nrf2, HO-1, gamma-glutamylcysteine synthetase (gammaGCS), B-cell CLL/lymphoma 2 (Bcl-2), Bax and Caspase 3 were detected by High content analysis and/or Western blot. RESULTS: The role of PF markedly suppressed high glucose induced Schwann cells oxidative stress by decreasing ROS and MDA levels and increasing GST and GPX activity. Western blot analysis showed that PF induced nuclear translocation of Nrf2. High content analysis showed that PF promoted Nrf2 dissociation from Keap1 and upregulating the Nrf2/ antioxidant response element (ARE) pathway. Furthermore, PF reduced Schwann cells apoptosis by increasing Bcl-2 and inhibiting Bax and Caspase-3 expressions. CONCLUSIONS: PF in the management of Schwann cells oxidative stress induced by high glucose may be associated with activation of Nrf2/ARE pathway and Bcl-2-related apoptotic pathway. PMID- 26979340 TI - Quantitative evaluation of Oryeongsan and its action on water regulation in renal inner medullary collecting duct cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Oryeongsan (ORS, Wulingsan) has been reported to possess renal protective effects from renal diseases such as diabetes-induced renal damage, and nephrocalcinosis. AIM OF THE STUDY: This study was conducted to evaluate the quantitative analysis and the inhibitory effect of ORS on hypertonic stress-induced water channel and apoptosis in murine inner medullary collecting duct cell line (mIMCD-3). MATERIALS AND METHODS: Chromatographic and NMR spectroscopic analysis were performed and water balance regulation was determined by Western blot, RT-PCR, and immunofluorescnece. RESULTS: Seven active principles (5-hydroxymethylfurfural, alismoxide, methyl(-)trans-cinnamate, adenine, guanosine, adenosine, and ferulic acid) in ORS were isolated and the structures were identified mainly by NMR spectroscopic analysis. In addition, contents of these metabolites in ORS were evaluated by HPLC analysis. Pretreatment with ORS significantly attenuated the hypertonic stress (175mM NaCl)-induced increase in protein levels of AQP2 and apical membrane insertion. ORS also attenuated osmolyte sodium-myo-inositol transporter (SMIT) expression and tonicity responsive enhancer binding protein (TonEBP) mRNA under hypertonic stress. Those actions of ORS presented the similar effect of PKA inhibitor which AQP2 expression throughout the inhibition of vasopressin-mediated cAMP/PKA signal pathway. On the other hand, pretreatment with ORS attenuated hypertonic stress induced cell death. Hypertonic stress-induced Bax or caspase-3 expression was decreased by ORS, resulting in anti-apoptotic effect. CONCLUSIONS: The present data suggest that the beneficial effect of ORS in water balance and apoptosis against hypertonic stress of renal collecting ducts. PMID- 26979343 TI - Differentiation signalobody: Demonstration of antigen-dependent osteoclast differentiation from a progenitor cell line. AB - A "cytokine-less" in vitro differentiation method would be promising for cost effective mass production of cells used for regenerative medicine. In this study, we developed a differentiation signalobody S-RANK, in which the extracellular domain of receptor activator of nuclear factor kappa-B (RANK) is replaced with a single-chain variable fragment (scFv) to attain signaling in response to an inexpensive antigen. A murine macrophage cell line RAW264, which is known to differentiate into an osteoclast by RANK ligand (RANKL), was lentivirally transduced with S-RANK. When the resultant cells were cultured with a specific antigen, the cells differentiated into multinucleated tartrate-resistant acid phosphatase-positive osteoclasts. The differentiation efficiency was almost comparable to those induced by RANKL. In addition, the signaling analysis demonstrated that nuclear factor kappa-B and mitogen-activated protein kinase signaling pathways, which are the major signaling pathways downstream of wild type RANK, were also activated by S-RANK. These results demonstrate that S-RANK sufficiently mimics signal transduction of wild-type RANK. Differentiation signalobodies may be applied for controlling differentiation of other cell types by using appropriate signaling domains. PMID- 26979342 TI - The genetic diversity and structure of indica rice in China as detected by single nucleotide polymorphism analysis. AB - BACKGROUND: Rice (Oryza sativa L.) is the staple food of more than half of the world's population. The identification of genetic diversity in local varieties of rice compared with that of improved or introduced varieties is important in breeding elite varieties for sustainable agriculture. Array-based single nucleotide polymorphism (SNP) detection is a useful technique for such studies and breeding applications. RESULTS: We developed a 5291-SNP genome-wide array and used it to genotype 471 indica rice accessions in China using Illumina's Infinium technology. Local, introduced, and improved rice varieties were clustered into three sub-groups, with some overlapping shown in principal component analysis and neighbor-joining tree, also confirmed by model-based structure. A minor allele frequency >= 0.2 was observed in 72% of polymorphic SNPs in local rice varieties, which was higher than that in other sub-groups. Local rice varieties also had the highest mean polymorphism information content (PIC) and genetic diversity. Analysis of molecular variance showed that 90.61% of genetic variation was a result of differences within sub-groups. CONCLUSIONS: Our results revealed that SNP analysis clustered local varieties, introduced varieties, and improved varieties into three clear sub-groups. The distribution of parameter PIC values on sub-group genomes revealed that genetic differentiation among them might not be on a genome-wide scale, but rather on selected loci or chromosomal intervals. The result of Gene Ontology enrichment analysis showed that genes nearby those selected SNPs associated different molecular functions or various traits among sub-groups. PMID- 26979346 TI - Two in five consultant posts were unfilled last year. PMID- 26979344 TI - In vitro steroid profiling system for the evaluation of endocrine disruptors. AB - Endocrine disruptors (ED) are chemicals that affect various aspects of the endocrine system, often leading to the inhibition of steroidogenesis. Current chemical safety policies that restrict human exposure to such chemicals describe often time-consuming and costly methods for the evaluation of ED effects. We aimed to develop an effective tool for accurate phenotypic chemical toxicology studies. We developed an in vitro ED evaluation system using gas chromatography/mass spectrometry (GC/MS/MS) methods for metabolomic analysis of multi-marker profiles. Accounting for sample preparation and GC/MS/MS conditions, we established a screening method that allowed the simultaneous analysis of 17 steroids with good reproducibility and a linear calibration curve. Moreover, we applied the developed system to H295R human adrenocortical cells exposed to forskolin and prochloraz in accordance with the Organization for Economic Cooperation and Development (OECD) guidelines and observed dose-dependent variations in steroid profiles. While the OECD guidelines include only testosterone and 17beta-estradiol, our system enabled a comprehensive and highly sensitive analysis of steroid profile alteration due to ED exposure. The application of our ED evaluation screen could be economical and provide novel insights into the hazards of ED exposure to the endocrine system. PMID- 26979345 TI - Fiber degradation potential of natural co-cultures of Neocallimastix frontalis and Methanobrevibacter ruminantium isolated from yaks (Bos grunniens) grazing on the Qinghai Tibetan Plateau. AB - Several natural anaerobic fungus-methanogen co-cultures have been isolated from rumen and feces source of herbivores with strong fiber degrading ability. In this study, we isolated 7 Neocallimastix with methanogen co-cultures from the rumen of yaks grazing on the Qinghai Tibetan Plateau. Based on morphological characteristics and internal transcribed spacer 1 sequences (ITS1), all the fungi were identified as Neocallimastix frontalis. The co-cultures were confirmed as the one fungus - one methanogen pattern by the PCR-denatured gradient gel electrophoresis (DGGE) assay. All the methanogens were identified as Methanobrevibacter ruminantium by 16s rRNA gene sequencing. We investigated the biodegrading capacity of the co-culture (N. frontalis + M. ruminantium) Yaktz1 on wheat straw, corn stalk and rice straw in a 7 days-incubation. The in vitro dry matter digestibility (IVDMD), acid detergent fiber digestibility (ADFD) and neural detergent fiber digestibility (NDFD) values of the substrates in the co culture were significantly higher than those in the mono-culture N. frontalis Yaktz1. The co-culture exhibited high polysaccharide hydrolase (xylanase and FPase) and esterase activities. The xylanase in the co-culture reached the highest activity of 12500 mU/ml on wheat straw at the day 3 of the incubation. At the end of the incubation, 3.00 mmol-3.29 mmol/g dry matter of methane were produced by the co-culture. The co-culture also produced high level of acetate (40.00 mM-45.98 mM) as the end-product during the biodegradation. Interestingly, the N. frontalis Yaktz1 mono-culture produced large amount of lactate (8.27 mM 11.60 mM) and ethanol (163.11 mM-242.14 mM), many times more than those recorded in the previously reported anaerobic fungi. Our data suggests that the (N. frontalis + M. ruminantium) Yaktz1 co-culture and the N. frontalis Yaktz1 mono culture both have great potentials for different industrial use. PMID- 26979348 TI - Taking up the proposal of allocating one slot a month for a year to qualitative research. PMID- 26979347 TI - Utility of Procedural Sedation as a Marker for Quality Assurance in Emergency Medicine. AB - BACKGROUND: The Joint Commission requires health care organizations to monitor and evaluate procedural sedation. However, the utility of mandatory review of procedural sedation in evaluating health care quality is unknown. OBJECTIVE: To determine whether procedural sedation is a useful marker for evaluating error in the emergency department (ED). METHODS: We prospectively collected data for patients presenting to an urban, tertiary care, academic medical center ED between October 2013 and June 2015. We used an automated, electronic tracking system to identify patients who underwent procedural sedation. We randomly assigned cases to physician reviewers. Reviewers used a structured tool to determine the presence of error and adverse events. If a reviewer felt that the case had an error or adverse event, it was referred to a quality assurance (QA) committee, which made a final determination as to whether or not an error or adverse event occurred. RESULTS: There were 166 cases of procedural sedation reviewed. Two errors were identified, for an error rate of 1.2% (95% confidence interval [CI] 0.003-0.043). Both errors occurred during the use of propofol to facilitate upper gastrointestinal endoscopy. Neither error resulted in an adverse event. One adverse event was identified that was unrelated to physician error (0.6%; 95% CI 0.001-0.033). CONCLUSION: Routine review of procedural sedation performed in the ED offers little advantage over existing QA markers. Directed review of high-risk cases, such as those involving endoscopy or other longer duration procedures, may be more useful. Future studies focusing quality review on projected high-risk sedation cases may establish more valuable markers for QA review. PMID- 26979349 TI - Incidental bronchography. PMID- 26979350 TI - Laryngeal myoclonus. PMID- 26979352 TI - Wound healing and treating wounds: Differential diagnosis and evaluation of chronic wounds. AB - Wounds are an excellent example of how the field of dermatology represents a cross-section of many medical disciplines. For instance, wounds may be caused by trauma, vascular insufficiency, and underlying medical conditions, such as diabetes, hypertension, and rheumatologic and inflammatory disease. This continuing medical education article provides an overview of wound healing and the pathophysiology of chronic wounds and reviews the broad differential diagnosis of chronic wounds. It also describes the initial steps necessary in evaluating a chronic wound and determining its underlying etiology. PMID- 26979351 TI - The possible role of asbestos exposure in the pathogenesis of a thoracic non Hodgkin lymphoma. PMID- 26979353 TI - Wound healing and treating wounds: Chronic wound care and management. AB - In the United States, chronic ulcers--including decubitus, vascular, inflammatory, and rheumatologic subtypes--affect >6 million people, with increasing numbers anticipated in our growing elderly and diabetic populations. These wounds cause significant morbidity and mortality and lead to significant medical costs. Preventative and treatment measures include disease-specific approaches and the use of moisture retentive dressings and adjunctive topical therapies to promote healing. In this article, we discuss recent advances in wound care technology and current management guidelines for the treatment of wounds and ulcers. PMID- 26979355 TI - What's new: Management of venous leg ulcers: Treating venous leg ulcers. AB - Venous leg ulcers account for approximately 70% of all leg ulcers and affect 2.2 million Americans annually. After a comprehensive patient and wound assessment, compression therapy remains the cornerstone of standard care. Adjuvant care with topical or systemic agents is used for wounds that do not heal within 4 weeks. Once healed, long-term compression therapy with stockings or surgical intervention will reduce the incidence of recurrence. This continuing medical education article aims to outline optimal management for patients with venous leg ulcers, highlighting the role of a multidisciplinary team in delivering high quality care. PMID- 26979354 TI - What's new: Management of venous leg ulcers: Approach to venous leg ulcers. AB - Leg ulcerations are a common problem, with an estimated prevalence of 1% to 2% in the adult population. Venous leg ulcers are primarily treated in outpatient settings and often are managed by dermatologists. Recent advances in the diagnosis and treatment of leg ulcers combined with available evidence-based data will provide an update on this topic. A systematized approach and the judicious use of expensive advanced therapeutics are critical. Specialized arterial and venous studies are most commonly noninvasive. The ankle brachial pressure index can be performed with a handheld Doppler unit at the bedside by most clinicians. The vascular laboratory results and duplex Doppler findings are used to identify segmental defects and potential operative candidates. Studies of the venous system can also predict a subset of patients who may benefit from surgery. Successful leg ulcer management requires an interdisciplinary team to make the correct diagnosis, assess the vascular supply, and identify other modifiable factors to optimize healing. The aim of this continuing medical education article is to provide an update on the management of venous leg ulcers. Part I is focused on the approach to venous ulcer diagnostic testing. PMID- 26979357 TI - Sharps injuries among US dermatology trainees: A cross-sectional study. PMID- 26979356 TI - The cost of applying to dermatology residency: 2014 data estimates. PMID- 26979358 TI - Does biopsy accurately assess basal cell carcinoma (BCC) subtype? PMID- 26979359 TI - Surgical treatment of pyoderma gangrenosum with negative pressure wound therapy and split thickness skin grafting under adequate immunosuppression is a valuable treatment option: Case series of 15 patients. PMID- 26979360 TI - "Pretend you didn't hear that"--managing ethical dilemmas from the bottom of a medical hierarchy. PMID- 26979361 TI - Inpatient dermatology consultative programs: A continued need, tools for needs assessment for curriculum development, and a call for new methods of teaching. PMID- 26979363 TI - The cost of applying to dermatology residency. PMID- 26979362 TI - Recognizing that the microbiome is part of the human immune system will advance treatment of both cancer and infections. PMID- 26979367 TI - Halo and pseudo-halo melanoma. PMID- 26979368 TI - Optimized dermatopathologic imaging by a smartphone camera. PMID- 26979369 TI - Reconstruction of the central anthelix using a novel double chondrocutaneous island flap. PMID- 26979370 TI - Superior Antia-Buch flap for reconstruction of helical rim defects. PMID- 26979371 TI - Failure of photodynamic therapy (PDT) in 3 patients with folliculitis decalvans. PMID- 26979372 TI - Reply: Treatment of folliculitis decalvans with photodynamic therapy. PMID- 26979373 TI - Finasteride is of uncertain utility in treating frontal fibrosing alopecia. PMID- 26979374 TI - Further research needed if finasteride is to become standard of care for frontal fibrosing alopecia (FFA). PMID- 26979375 TI - Antiandrogenic drugs, a therapeutic option for frontal fibrosing alopecia patients. PMID- 26979376 TI - Reply to: '"Pretend you didn't hear that"--managing ethical dilemmas from the bottom of a medical hierarchy.' Attitude toward pregnancy and motherhood in our dermatology workplace. PMID- 26979377 TI - Reply to: "What's in a name?". PMID- 26979378 TI - Secukinumab versus ustekinumab: "CLEAR" conclusions are needed. PMID- 26979379 TI - Does the presence of a mutation at position V179 impact on virological outcome in patients receiving antiretroviral medication? PMID- 26979380 TI - Insufficient evidence to support the use of laser therapy for peri-implantitis. PMID- 26979381 TI - Delineation of QRS offset by instantaneous changes in ECG vector angle can improve detection of acute inferior myocardial infarctions. AB - We developed an automated new method for determining QRS offset, based on angular velocity (AV) changes around the QRS loop, and compared the method's performance to that of manual and more established automated methods for determining QRS offset in both healthy subjects and patients with acute myocardial infarction (AMI). Specifically, using Frank leads reconstructed from standard 12-lead ECGs, we determined AV in the direction of change raised to the 4th power, d(t). We found that the d(t)-determined AV transition (DeltaAV) nearly coincided with manually determined QRS offset in healthy subjects, and in 27 patients with anterior AMI. However, in 31 patients with inferior AMI, DeltaAV typically preceded that of QRS offset determined by the established automated methods, and by more than 10ms in 32% of cases. While this "DeltaAV precedence" coincided with diagnostic ST elevation in only a minority of patients with recent inferior AMI, the use of DeltaAV precedence as a complement to traditional determination of ST elevation increased the sensitivity for detecting inferior AMIs from 23 to 42%. PMID- 26979382 TI - Three-dimensional knee kinematics in patients with a discoid lateral meniscus during gait. AB - BACKGROUND: To date, the knee kinematics of a discoid lateral meniscus (DLM) has not been elucidated. The aim was to investigate the three-dimensional knee kinematics in knees with a DLM using gait analysis. METHODS: Ten patients (mean: 14years) diagnosed with bilateral DLM and unilaterally symptomatic snapping as well as 10 healthy controls (mean: 23years) participated in the study. Each patient with a DLM had unilaterally snapping knee in full extension and deep flexion. The three-dimensional gait analysis was performed with the point cluster technique. All subjects were asked to walk on a level floor at the speed of their choice. In the sagittal plane, knee excursion was separately evaluated during the weight acceptance phase and the mid-stance phase. In the axial plane, knee excursion during the stance phase was assessed. Finally, knee excursion during the whole gait cycle was evaluated in the frontal plane. Statistical comparison was conducted between groups, and between both sides in the DLM group. RESULTS: In the sagittal plane, knee excursions during the weight acceptance phase and the mid-stance phase were significantly smaller in the DLM group than in the control group; in addition, these were smaller on the symptomatic side than on the asymptomatic side in the DLM group. In the axial plane, knee excursion was also significantly smaller on the symptomatic side than on the asymptomatic side in the DLM group, whereas the frontal knee motion did not differ significantly. CONCLUSION: Less knee motion in the sagittal plane may prevent snapping during extension and flexion in patients with a DLM. LEVEL OF EVIDENCE: III. PMID- 26979385 TI - Lithium storage on carbon nitride, graphenylene and inorganic graphenylene. AB - We present results of density functional theory calculations on the lithium (Li) ion storage capacity of three different two dimensional porous graphene-like membranes. The graphitic carbon nitride membrane, g-CN, is found to have a large Li storage capacity of at least 813 mA h g(-1) (LiCN). However, it is also found that the Li interacts very strongly with the membrane indicating that this is most likely irreversible. According to the calculations, graphenylene or biphenylene carbon (BPC) has a storage capacity of 487 mA h g(-1) (Li1.5C6) which is higher than that for graphite. We also find that Li is very mobile on these materials and does not interact as strongly with the membrane making it a more suitable anode material. Inorganic graphenylene, which is a boron nitride analog of graphenylene, shows very low binding energies, much lower than the cohesive energy of lithium, and it appears to be unsuitable as an anode material for lithium ion batteries. We discuss how charge transfer leads to the very different behaviour observed in these three similar materials. PMID- 26979383 TI - The Arabidopsis Protein CGLD11 Is Required for Chloroplast ATP Synthase Accumulation. AB - ATP synthases in chloroplasts (cpATPase) and mitochondria (mtATPase) are responsible for ATP production during photosynthesis and oxidative phosphorylation, respectively. Both enzymes consist of two multisubunit complexes, the membrane-bound coupling factor O and the soluble coupling factor 1. During cpATPase biosynthesis, several accessory factors facilitate subunit production and orchestrate complex assembly. Here, we describe a new auxiliary protein in Arabidopsis thaliana, which is required for cpATPase accumulation. AtCGLD11 (CONSERVED IN THE GREEN LINEAGE AND DIATOMS 11) is a protein without any known functional domain and shows dual localization to chloroplasts and mitochondria. Loss of AtCGLD11 function results in reduced levels of cpATPase and impaired photosynthetic performance with lower rates of ATP synthesis. In yeast two-hybrid experiments, AtCGLD11 interacts with the beta subunits of the cpATPase and mtATPase. Our results suggest that AtCGLD11 functions in F1 assembly during cpATPase biogenesis, while its role in mtATPase biosynthesis may not, or not yet, be essential. PMID- 26979384 TI - Sperm viability and gene expression in honey bee queens (Apis mellifera) following exposure to the neonicotinoid insecticide imidacloprid and the organophosphate acaricide coumaphos. AB - Honey bee population declines are of global concern. Numerous factors appear to cause these declines including parasites, pathogens, malnutrition and pesticides. Residues of the organophosphate acaricide coumaphos and the neonicotinoid insecticide imidacloprid, widely used to combat Varroa mites and for crop protection in agriculture, respectively, have been detected in wax, pollen and comb samples. Here, we assess the effects of these compounds at different doses on the viability of sperm stored in the honey bee queens' spermatheca. Our results demonstrate that sub-lethal doses of imidacloprid (0.02ppm) decreased sperm viability by 50%, 7days after treatment. Sperm viability was a downward trend (about 33%) in queens treated with high doses of coumaphos (100ppm), but there was not significant difference. The expression of genes that are involved in development, immune responses and detoxification in honey bee queens and workers exposed to chemicals was measured by qPCR analysis. The data showed that expression levels of specific genes were triggered 1day after treatment. The expression levels of P450 subfamily genes, CYP306A1, CYP4G11 and CYP6AS14 were decreased in honey bee queens treated with low doses of coumaphos (5ppm) and imidacloprid (0.02ppm). Moreover, these two compounds suppressed the expression of genes related to antioxidation, immunity and development in queens at day 1. Up-regulation of antioxidants by these compounds in worker bees was observed at day 1. Coumaphos also caused a repression of CYP306A1 and CYP4G11 in workers. Antioxidants appear to prevent chemical damage to honey bees. We also found that DWV replication increased in workers treated with imidacloprid. This research clearly demonstrates that chemical exposure can affect sperm viability in queen honey bees. PMID- 26979386 TI - Improving stand-to-sit maneuver for individuals with spinal cord injury. AB - BACKGROUND: Users of neuroprostheses employing electrical stimulation (ES) generally complete the stand-to-sit (STS) maneuver with high knee angular velocities, increased upper limb support forces, and high peak impact forces at initial contact with the chair. Controlling the knee during STS descent is challenging in individuals with spinal cord injury (SCI) due to the decreasing joint moment available with increased knee angle in response to ES. METHODS: The goal of this study was to investigate the effects of incorporating either (1) a coupling mechanism that coordinates hip and knee flexion or (2) a mechanism that damps knee motion to keep the knee angular velocity constant during the STS transition. The coupling and damping were achieved by hydraulic orthotic mechanisms. Two subjects with SCI were enrolled and each served as their own controls when characterizing the performance of each mechanism during STS as compared to stimulation alone. Outcome measures such as hip-knee angle, knee angular velocity, upper limb support force, and impact force were analyzed to determine the effectiveness of the two mechanisms in providing controlled STS. RESULTS: The coordination between the hip and knee joints improved with each orthotic mechanism. The damping and hip-knee coupling mechanisms caused the hip and knee joint ratios of 1:1.1 and 1:0.99, respectively, which approached the 1:1 coordination ratio observed in nondisabled individuals during STS maneuver. The knee damping mechanism provided lower (p < 0.001) and a more constant knee angular velocity than the hip-knee coupling mechanism over the knee range of motion. Both the coupling and damping mechanisms were similarly effective at reducing upper limb support forces by 70 % (p < 0.001) and impact force by half (p <= 0.001) as compared to sitting down with stimulation alone. CONCLUSIONS: Orthoses imposing simple kinematic constraints, such as 1:1 hip-knee coupling or knee damping, can normalize upper limb support forces, peak knee angular velocity, and peak impact force during the STS maneuvers. PMID- 26979390 TI - Unplugging JAK/STAT in Chronic Myelomonocytic Leukemia. AB - The proliferative component of chronic myelomonocytic leukemia, related to an increased sensitivity of myeloid progenitors to granulocyte macrophage-colony stimulating factor, suggests dedicated therapeutic approaches. In this issue, ruxolitinib, a JAK1 and -2 inhibitory drug, is shown to induce objective responses in chronic myelomonocytic leukemia patients. Clin Cancer Res; 22(15); 3707-9. (c)2016 AACRSee related article by Padron et al., p. 3746. PMID- 26979389 TI - Mutual antagonism between hepatitis B viral mRNA and host microRNA let-7. AB - The interplay between viral and host factors plays a major role in viral pathogenesis. Hepatitis B virus (HBV) infection is a global health problem that leads to liver cirrhosis and hepatocellular carcinoma (HCC). Although HBV proteins have been studied extensively about their implication in hepatocarcinogenesis, the molecular mechanisms of oncogenesis are still largely unknown. A recent concept in gene regulation, in which competitive endogenous RNAs compete for common microRNAs (miRNAs), suggests that mRNA targets are key elements in the regulation of miRNA availability. Here, we show that HBV mRNA in the preS2 region can be targeted by host miRNA let-7 g. This leads to the sequestration of let-7 g and inhibition of let-7 g function. The expression of HBV transcripts, including the preS2 region, de-repressed let-7 g targets, which may contribute to long-term oncogenesis. HBV transcript-expressing transgenic mice, but not non-targeted transcript-expressing mice, were more prone to chemically induced hepatoocarcinogenesis. Let-7 target protein expression was upregulated in human HCC tissues derived from HBV-infected patients. On the other hand, let-7 g inhibited HBV preS2 protein expression and viral products. These results suggest that the interplay between viral intermediate transcripts during HBV replication and host miRNAs is crucial to the pathogenesis of chronic viral infection. PMID- 26979388 TI - Recurrent Gene Duplication Diversifies Genome Defense Repertoire in Drosophila. AB - Transposable elements (TEs) comprise large fractions of many eukaryotic genomes and imperil host genome integrity. The host genome combats these challenges by encoding proteins that silence TE activity. Both the introduction of new TEs via horizontal transfer and TE sequence evolution requires constant innovation of host-encoded TE silencing machinery to keep pace with TEs. One form of host innovation is the adaptation of existing, single-copy host genes. Indeed, host suppressors of TE replication often harbor signatures of positive selection. Such signatures are especially evident in genes encoding the piwi-interacting-RNA pathway of gene silencing, for example, the female germline-restricted TE silencer, HP1D/Rhino Host genomes can also innovate via gene duplication and divergence. However, the importance of gene family expansions, contractions, and gene turnover to host genome defense has been largely unexplored. Here, we functionally characterize Oxpecker, a young, tandem duplicate gene of HP1D/rhino We demonstrate that Oxpecker supports female fertility in Drosophila melanogaster and silences several TE families that are incompletely silenced by HP1D/Rhino in the female germline. We further show that, like Oxpecker, at least ten additional, structurally diverse, HP1D/rhino-derived daughter and "granddaughter" genes emerged during a short 15-million year period of Drosophila evolution. These young paralogs are transcribed primarily in germline tissues, where the genetic conflict between host genomes and TEs plays out. Our findings suggest that gene family expansion is an underappreciated yet potent evolutionary mechanism of genome defense diversification. PMID- 26979391 TI - Poly (ADP-Ribose) Polymerase Inhibitor Hypersensitivity in Aggressive Myeloproliferative Neoplasms. AB - PURPOSE: DNA repair defects have been previously reported in myeloproliferative neoplasms (MPN). Inhibitors of PARP have shown activity in solid tumors with defects in homologous recombination (HR). This study was performed to assess MPN sensitivity to PARP inhibitors ex vivo EXPERIMENTAL DESIGN: HR pathway integrity in circulating myeloid cells was evaluated by assessing the formation of RAD51 foci after treatment with ionizing radiation or PARP inhibitors. Sensitivity of MPN erythroid and myeloid progenitors to PARP inhibitors was evaluated using colony formation assays. RESULTS: Six of 14 MPN primary samples had reduced formation of RAD51 foci after exposure to ionizing radiation, suggesting impaired HR. This phenotype was not associated with a specific MPN subtype, JAK2 mutation status, or karyotype. MPN samples showed increased sensitivity to the PARP inhibitors veliparib and olaparib compared with normal myeloid progenitors. This hypersensitivity, which was most pronounced in samples deficient in DNA damage induced RAD51 foci, was observed predominantly in samples from patients with diagnoses of chronic myelogenous leukemia, chronic myelomonocytic leukemia, or unspecified myelodysplastic/MPN overlap syndromes. CONCLUSIONS: Like other neoplasms with HR defects, MPNs exhibit PARP inhibitor hypersensitivity compared with normal marrow. These results suggest that further preclinical and possibly clinical study of PARP inhibitors in MPNs is warranted. Clin Cancer Res; 22(15); 3894-902. (c)2016 AACR. PMID- 26979392 TI - Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine Models and Spontaneous Canine Malignancies. AB - PURPOSE: Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically upregulate immunosuppressive pathways, a phenomenon we term "rebound immune suppression," limiting clinical responses. We further hypothesized that the immunosuppressive enzyme indolamine-2,3-dioxygenase (IDO) is a mechanism of rebound immune suppression and that IDO blockade would improve immunotherapy efficacy. EXPERIMENTAL DESIGN: We examined the efficacy and immunologic effects of a novel triple therapy consisting of local radiotherapy, intratumoral CpG, and systemic IDO blockade in murine models and a pilot canine clinical trial. RESULTS: In murine models, we observed marked increase in intratumoral IDO expression after treatment with radiotherapy, CpG, or other immunotherapies. The addition of IDO blockade to radiotherapy + CpG decreased IDO activity, reduced tumor growth, and reduced immunosuppressive factors, such as regulatory T cells in the tumor microenvironment. This triple combination induced systemic antitumor effects, decreasing metastases, and improving survival in a CD8(+) T-cell dependent manner. We evaluated this novel triple therapy in a canine clinical trial, because spontaneous canine malignancies closely reflect human cancer. Mirroring our mouse studies, the therapy was well tolerated, reduced intratumoral immunosuppression, and induced robust systemic antitumor effects. CONCLUSIONS: These results suggest that IDO maintains immune suppression in the tumor after therapy, and IDO blockade promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation. Clin Cancer Res; 22(17); 4328-40. (c)2016 AACR. PMID- 26979393 TI - Molecular Pathways: Immunosuppressive Roles of IRE1alpha-XBP1 Signaling in Dendritic Cells of the Tumor Microenvironment. AB - The endoplasmic reticulum (ER) is a massive cytoplasmic membrane network that functions primarily to ensure proper folding and posttranslational modification of newly synthesized secreted and transmembrane proteins. Abnormal accumulation of unfolded proteins in this organelle causes a state of "ER stress," which is a hallmark feature of various diseases, including cancer, neurodegeneration, and metabolic dysfunction. Cancer cells exploit the IRE1alpha-XBP1 arm of the ER stress response to efficiently adjust their protein-folding capacity and ensure survival under hostile tumor microenvironmental conditions. However, we recently found that dendritic cells (DC) residing in the ovarian cancer microenvironment also experience sustained ER stress and demonstrate persistent activation of the IRE1alpha-XBP1 pathway. This previously unrecognized process disrupts metabolic homeostasis and antigen-presenting capacity in DCs, thereby crippling their natural ability to support the protective functions of infiltrating antitumor T cells. In this review, we briefly discuss some of the mechanisms that fuel ER stress in tumor-associated DCs, the biologic processes altered by aberrant IRE1alpha-XBP1 signaling in these innate immune cells, and the unique immunotherapeutic potential of targeting this pathway in cancer hosts. Clin Cancer Res; 22(9); 2121-6. (c)2016 AACR. PMID- 26979394 TI - Lack of Immunomodulatory Interleukin-27 Enhances Oncogenic Properties of Mutant p53 In Vivo. AB - PURPOSE: p53 is mutated in about 50% of human cancers, mostly through missense mutations. Expression of mutant p53 is associated with poor clinical outcomes or metastasis. Although mutant p53 is inherently instable, various stressors such as DNA damage or expression of the oncogenic Kras or c-myc affect the oncogenic properties of mutant p53. However, the effects of inflammation on mutant p53 are largely unknown. IL27 is an important immunomodulatory cytokine, but its impact on mutant p53-driven tumorigenesis has not been reported. EXPERIMENTAL DESIGN: IL27RA(-/-) mice were bred with mutant p53 heterozygous (p53(R172H/+)) mice to obtain IL27RA(-/-)p53(H/+) and IL27RA(-/-)p53(H/H) mice. Mouse survival and tumor spectra for the cohort were analyzed. Stability of p53 protein was analyzed via IHC and Western blot analysis. RESULTS: This study unraveled that lack of IL27 signaling significantly shortened the survival duration of mice with tumors expressing both copies of the mutant p53 gene (Li-Fraumeni mouse model). Interestingly, in mice that were heterozygous for mutant p53, lack of IL27 signaling not only significantly shortened survival time but also doubled the incidence of osteosarcomas. Furthermore, lack of IL27 signaling is closely associated with increased mutant p53 stability in vivo from early age. CONCLUSIONS: These results suggest that IL27 signaling modulates the oncogenic properties of mutant p53 in vivo Clin Cancer Res; 22(15); 3876-83. (c)2016 AACR. PMID- 26979395 TI - Effectiveness of Prophylactic Surgeries in BRCA1 or BRCA2 Mutation Carriers: A Meta-analysis and Systematic Review. AB - PURPOSE: To systematically investigate the effectiveness of prophylactic surgeries (PS) implemented in women carrying BRCA1/2 mutations. EXPERIMENTAL DESIGN: The PubMed database was searched till August 2014 and 15 studies met the inclusion criteria. Fixed- or random-effects models were conducted according to study heterogeneity. We calculated the pooled relative risks (RR) for cancer risk or mortality along with 95% confidence intervals (CI). RESULTS: Prophylactic bilateral salpingo-oophorectomy (PBSO) and bilateral prophylactic mastectomy (BPM) were both associated with a decreased breast cancer risk in BRCA1/2 mutation carriers (RR, 0.552; 95% CI, 0.448-0.682; RR, 0.114; 95% CI, 0.041 0.317, respectively). Similar findings were observed in BRCA1 and BRCA2 mutation carriers separately. Moreover, contralateral prophylactic mastectomy (CPM) significantly decreased contralateral breast cancer incidence in BRCA1/2 mutation carriers (RR, 0.072; 95% CI, 0.035-0.148). Of note, PBSO was associated with significantly lower all-cause mortality in BRCA1/2 mutation carriers without breast cancer (HR, 0.349; 95% CI, 0.190-0.639) and those with breast cancer (HR, 0.432; 95% CI, 0.318-0.588). In addition, all-cause mortality was significantly lower for patients with CPM than those without (HR, 0.512; 95% CI, 0.368-0.714). However, BPM was not significantly associated with reduced all-cause mortality. Data were insufficient to obtain separate estimates of survival benefit with PS in BRCA1 or BRCA2 mutation carriers. CONCLUSIONS: BRCA1/2 mutation carriers who have been treated with PS have a substantially reduced breast cancer incidence and mortality. Clin Cancer Res; 22(15); 3971-81. (c)2016 AACR. PMID- 26979397 TI - Is There a Future for AKT Inhibitors in the Treatment of Cancer? AB - An AKT inhibitor plus an antiestrogen exhibited no significant clinical activity in patients with ER(+)/HER2(-) breast cancer despite laboratory studies supporting an antitumor effect for both drugs combined. These results raise concerns about the development of AKT inhibitors in unselected patients whose tumors have unknown dependence on the PI3K/AKT pathway. Clin Cancer Res; 22(11); 2599-601. (c)2016 AACRSee related article by Ma et al., p. 2650. PMID- 26979398 TI - Development of a stage-dependent prognostic model to predict psychosis in ultra high-risk patients seeking treatment for co-morbid psychiatric disorders. AB - BACKGROUND: Current ultra-high-risk (UHR) criteria appear insufficient to predict imminent onset of first-episode psychosis, as a meta-analysis showed that about 20% of patients have a psychotic outcome after 2 years. Therefore, we aimed to develop a stage-dependent predictive model in UHR individuals who were seeking help for co-morbid disorders. METHOD: Baseline data on symptomatology, and environmental and psychological factors of 185 UHR patients (aged 14-35 years) participating in the Dutch Early Detection and Intervention Evaluation study were analysed with Cox proportional hazard analyses. RESULTS: At 18 months, the overall transition rate was 17.3%. The final predictor model included five variables: observed blunted affect [hazard ratio (HR) 3.39, 95% confidence interval (CI) 1.56-7.35, p < 0.001], subjective complaints of impaired motor function (HR 5.88, 95% CI 1.21-6.10, p = 0.02), beliefs about social marginalization (HR 2.76, 95% CI 1.14-6.72, p = 0.03), decline in social functioning (HR 1.10, 95% CI 1.01-1.17, p = 0.03), and distress associated with suspiciousness (HR 1.02, 95% CI 1.00-1.03, p = 0.01). The positive predictive value of the model was 80.0%. The resulting prognostic index stratified the general risk into three risk classes with significantly different survival curves. In the highest risk class, transition to psychosis emerged on average ?8 months earlier than in the lowest risk class. CONCLUSIONS: Predicting a first episode psychosis in help-seeking UHR patients was improved using a stage dependent prognostic model including negative psychotic symptoms (observed flattened affect, subjective impaired motor functioning), impaired social functioning and distress associated with suspiciousness. Treatment intensity may be stratified and personalized using the risk stratification. PMID- 26979396 TI - Identification of Mithramycin Analogues with Improved Targeting of the EWS-FLI1 Transcription Factor. AB - PURPOSE: The goal of this study was to identify second-generation mithramycin analogues that better target the EWS-FLI1 transcription factor for Ewing sarcoma. We previously established mithramycin as an EWS-FLI1 inhibitor, but the compound's toxicity prevented its use at effective concentrations in patients. EXPERIMENTAL DESIGN: We screened a panel of mithralogs to establish their ability to inhibit EWS-FLI1 in Ewing sarcoma. We compared the IC50 with the MTD established in mice to determine the relationship between efficacy and toxicity. We confirmed the suppression of EWS-FLI1 at the promoter, mRNA, gene signature, and protein levels. We established an improved therapeutic window by using time lapse microscopy to model the effects on cellular proliferation in Ewing sarcoma cells relative to HepG2 control cells. Finally, we established an improved therapeutic window using a xenograft model of Ewing sarcoma. RESULTS: EC-8105 was found to be the most potent analogue and was able to suppress EWS-FLI1 activity at concentrations nontoxic to other cell types. EC-8042 was substantially less toxic than mithramycin in multiple species but maintained suppression of EWS-FLI1 at similar concentrations. Both compounds markedly suppressed Ewing sarcoma xenograft growth and inhibited EWS-FLI1 in vivo CONCLUSIONS: These results provide a basis for the continued development of EC-8042 and EC-8105 as EWS-FLI1 inhibitors for the clinic. Clin Cancer Res; 22(16); 4105-18. (c)2016 AACR. PMID- 26979387 TI - Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. AB - The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change. PMID- 26979399 TI - Prevalence of gastro-esophageal reflux disease and its risk factors in a community-based population in southern India. AB - BACKGROUND: The prevalence of gastro-esophageal reflux disease (GERD) varies widely around the world. This study aimed to investigate the prevalence and risk factors of GERD in a general population of southern India. METHODS: An interview based observational study was carried out in southern India during 2010 and early 2011 using a GERD questionnaire (GerdQ). In total 1072 participants were enrolled using a multi-stage cluster sampling method. Presence of GERD was defined as a score of >= 8. Logistic regression models were used to derive odds ratios (ORs) with 95 % confidence intervals (CIs). RESULTS: The prevalence of GERD was 22.2 % (238/1072) in southern India, and was more common among older subjects and men. Overweight and obese subjects had a dose-dependent increased risk of GERD, compared to those with body mass index less than 25 (multivariate-adjusted OR = 1.4, 95 % CI 1.0-2.0; OR = 2.3, 95 % CI 1.3-4.1, respectively). People residing in urban community were more vulnerable to GERD than those in rural community (multivariate-adjusted OR = 1.8, 95 % CI 1.3-2.5). Similarly, those with a lower educational level appeared to have an increased risk of GERD. Further, those with a habit of pan masala chewing were more likely to develop GERD compared with those abstained from the habit (multivariate-adjusted OR = 2.0, 95 % CI 1.2-3.2). CONCLUSIONS: GERD is highly prevalent in southern India. Increasing age and BMI, an urban environment, lower educational level, and pan masala chewing appear to be risk factors of GERD symptoms for the studied population. PMID- 26979403 TI - Quantifying the binding strength of salicylaldoxime-uranyl complexes relative to competing salicylaldoxime-transition metal ion complexes in aqueous solution: a combined experimental and computational study. AB - The design of new ligands and investigation of UO2(2+) complexations are an essential aspect of reducing the cost of extracting uranium from seawater, improving the sorption efficiency for uranium and the selectivity for uranium over competing ions (such as the transition metal cations). The binding strengths of salicylaldoxime-UO2(2+) complexes were quantified for the first time and compared with the binding strengths of salicylic acid-UO2(2+) and representative amidoxime-UO2(2+) complexes. We found that the binding strengths of salicylaldoxime-UO2(2+) complexes are ~2-4 log beta2 units greater in magnitude than their corresponding salicylic acid-UO2(2+) and representative amidoxime UO2(2+) complexes; moreover, the selectivity of salicylaldoxime towards the UO2(2+) cation over competing Cu(2+) and Fe(3+) cations is far greater than those reported for salicylic acid and glutarimidedioxime in the literature. The higher UO2(2+) selectivity can likely be attributed to the different coordination modes observed for salicylaldoxime-UO2(2+) and salicylaldoxime-transition metal complexes. Density functional theory calculations indicate that salicylaldoxime can coordinate with UO2(2+) as a dianion species formed by eta(2) coordination of the aldoximate and monodentate binding of the phenolate group. In contrast, salicylaldoxime coordinates with transition metal cations as a monoanion species via a chelate formed between phenolate and the oxime N; the complexes are stabilized via hydrogen bonding interactions between the oxime OH group and phenolate. By coupling the experimentally determined thermodynamic constants and the results of theoretical computations, we are able to derive a number of ligand design principles to further improve the UO2(2+) cation affinity, and thus further increase the selectivity of salicylaldoxime derivatives. PMID- 26979400 TI - Exosomal miR-10a derived from amniotic fluid stem cells preserves ovarian follicles after chemotherapy. AB - Chemotherapy (CTx)-induced premature ovarian failure (POF) in woman remains clinically irreversible. Amniotic fluid stem cells (AFSCs) have shown the potential to treat CTx-induced POF; however, the underlying mechanism is unclear. Here we demonstrate that AFSC-derived exosomes recapitulate the anti-apoptotic effect of AFSCs on CTx-damaged granulosa cells (GCs), which are vital for the growth of ovarian follicles. AFSC-derived exosomes prevent ovarian follicular atresia in CTx-treated mice via the delivery of microRNAs in which both miR-146a and miR-10a are highly enriched and their potential target genes are critical to apoptosis. The down-regulation of these two miRNAs in AFSC-derived exosomes attenuates the anti-apoptotic effect on CTx-damaged GCs in vitro. Further, the administration of these miRNAs recapitulates the effects both in vitro and in vivo, in which miR-10a contributes a dominant influence. Our findings illustrate that miR-10a has potential as a novel therapeutic agent for the treatment of POF. PMID- 26979402 TI - High phylogenetic diversity is preserved in species-poor high-elevation temperate moth assemblages. AB - Understanding the diversity and composition of species assemblages and identifying underlying biotic and abiotic determinants represent great ecological challenges. Addressing some of these issues, we investigated the alpha-diversity and phylogenetic composition of species-rich geometrid moth (Lepidoptera: Geometridae) assemblages in the mature temperate forest on Changbai Mountain. A total of 9285 geometrid moths representing 131 species were collected, with many species displaying wide elevational distribution ranges. Moth alpha-diversity decreased monotonously, while the standardized effect size of mean pairwise phylogenetic distances (MPD) and phylogenetic diversity (PD) increased significantly with increasing elevation. At high elevations, the insect assemblages consisted largely of habitat generalists that were individually more phylogenetically distinct from co-occurring species than species in assemblages at lower altitudes. This could hint at higher speciation rates in more favourable low-elevation environments generating a species-rich geometrid assemblage, while exclusion of phylogenetically closely related species becomes increasingly important in shaping moth assemblages at higher elevations. Overall, it appears likely that high-elevation temperate moth assemblages are strongly resilient to environmental change, and that they contain a much larger proportion of the genetic diversity encountered at low-elevation assemblages in comparison to tropical geometrid communities. PMID- 26979401 TI - Ion-Doped Silicate Bioceramic Coating of Ti-Based Implant. AB - Titanium and its alloy are known as important load-bearing biomaterials. The major drawbacks of these metals are fibrous formation and low corrosion rate after implantation. The surface modification of biomedical implants through various methods such as plasma spray improves their osseointegration and clinical lifetime. Different materials have been already used as coatings on biomedical implant, including calcium phosphates and bioglass. However, these materials have been reported to have limited clinical success. The excellent bioactivity of calcium silicate (Ca-Si) has been also regarded as coating material. However, their high degradation rate and low mechanical strength limit their further coating application. Trace element modification of (Ca-Si) bioceramics is a promising method, which improves their mechanical strength and chemical stability. In this review, the potential of trace element-modified silicate coatings on better bone formation of titanium implant is investigated. PMID- 26979406 TI - Implementation of a Psychiatric Nurse-led Outreach Service for Adults Residing at Subvented Old Age Homes: A Hong Kong Experience. AB - This paper reports on the implementation of a pioneering psychiatric nurse-led service that was designed to address the unmet mental healthcare needs of adults residing at subvented old age homes. It also describes features of potentially wider relevance to nurses interested in developing healthcare service for other underserved populations. We highlight the view that the crux of developing a successful service involves understanding existing service gaps; grasping the pulse of changing healthcare service policies; involving relevant stakeholders in the planning process; validating service outcomes; and seeking support from management. A central goal of the service was to enhance the accessibility of mental healthcare services to the needy. The data was collected over a 5-year period. Our study suggests that this model of service is preferred by service users (both the care providers and the residents in the old age homes); is efficient in terms of providing prompt psychiatric nursing interventions; is able to supply primary care advisors with practical advice in response to enquiries; and helps primary care providers to detect and manage the mental healthcare needs of older adults. PMID- 26979404 TI - Comparative performance of three experimental hut designs for measuring malaria vector responses to insecticides in Tanzania. AB - BACKGROUND: Experimental huts are simplified, standardized representations of human habitations that provide model systems to evaluate insecticides used in indoor residual spray (IRS) and long-lasting insecticidal nets (LLINs) to kill disease vectors. Hut volume, construction materials and size of entry points impact mosquito entry and exposure to insecticides. The performance of three standard experimental hut designs was compared to evaluate insecticide used in LLINs. METHODS: Field studies were conducted at the World Health Organization Pesticide Evaluation Scheme (WHOPES) testing site in Muheza, Tanzania. Three East African huts, three West African huts, and three Ifakara huts were compared using Olyset((r)) and Permanet 2.0((r)) versus untreated nets as a control. Outcomes measured were mortality, induced exophily (exit rate), blood feeding inhibition and deterrence (entry rate). Data were analysed using linear mixed effect regression and Bland-Altman comparison of paired differences. RESULTS: A total of 613 mosquitoes were collected in 36 nights, of which 13.5% were Anopheles gambiae sensu lato, 21% Anopheles funestus sensu stricto, 38% Mansonia species and 28% Culex species. Ifakara huts caught three times more mosquitoes than the East African and West African huts, while the West African huts caught significantly fewer mosquitoes than the other hut types. Mosquito densities were low, very little mosquito exit was measured in any of the huts with no measurable exophily caused by the use of either Olyset or Permanet. When the huts were directly compared, the West African huts measured greater exophily than other huts. As unholed nets were used in the experiments and few mosquitoes were captured, it was not possible to measure difference in feeding success either between treatments or hut types. In each of the hut types there was increased mortality when Permanet or Olyset were present inside the huts compared to the control, however this did not vary between the hut types. CONCLUSIONS: Both East African and Ifakara huts performed in a similar way although Ifakara huts allowed more mosquitoes to enter, increasing data power. The work convincingly demonstrates that the East African huts and Ifakara huts collect substantially more mosquitoes than the West African huts. PMID- 26979408 TI - Control of Nanomaterial Self-Assembly in Ultrasonically Levitated Droplets. AB - We demonstrate that acoustic trapping can be used to levitate and manipulate droplets of soft matter, in particular, lyotropic mesophases formed from self assembly of different surfactants and lipids, which can be analyzed in a contact less manner by X-ray scattering in a controlled gas-phase environment. On the macroscopic length scale, the dimensions and the orientation of the particle are shaped by the ultrasonic field, while on the microscopic length scale the nanostructure can be controlled by varying the humidity of the atmosphere around the droplet. We demonstrate levitation and in situ phase transitions of micellar, hexagonal, bicontinuous cubic, and lamellar phases. The technique opens up a wide range of new experimental approaches of fundamental importance for environmental, biological, and chemical research. PMID- 26979407 TI - Impact of mooring activities on carbon stocks in seagrass meadows. AB - Boating activities are one of the causes that threaten seagrass meadows and the ecosystem services they provide. Mechanical destruction of seagrass habitats may also trigger the erosion of sedimentary organic carbon (Corg) stocks, which may contribute to increasing atmospheric CO2. This study presents the first estimates of loss of Corg stocks in seagrass meadows due to mooring activities in Rottnest Island, Western Australia. Sediment cores were sampled from seagrass meadows and from bare but previously vegetated sediments underneath moorings. The Corg stores have been compromised by the mooring deployment from 1930s onwards, which involved both the erosion of existing sedimentary Corg stores and the lack of further accumulation of Corg. On average, undisturbed meadows had accumulated ~6.4 Kg Corg m(-2) in the upper 50 cm-thick deposits at a rate of 34 g Corg m(-2) yr(-1). The comparison of Corg stores between meadows and mooring scars allows us to estimate a loss of 4.8 kg Corg m(-2) in the 50 cm-thick deposits accumulated over ca. 200 yr as a result of mooring deployments. These results provide key data for the implementation of Corg storage credit offset policies to avoid the conversion of seagrass ecosystems and contribute to their preservation. PMID- 26979409 TI - Iron oxide nanoparticles and the mechanisms of immune recognition of nanomedicines. PMID- 26979410 TI - Charged Polymer Membranes for Environmental/Energy Applications. AB - Ion exchange membranes are used in various membrane-based processes (e.g., electrodialysis, fuel cells). Charged solute transport is largely governed by the charged groups on the polymer backbone. In this review, fundamental relationships describing salt permeability and ionic conductivity, as well as water permeability, in charged polymers are developed within the framework of the Nernst-Planck and solution-diffusion models. The influence of fixed charge groups and polymer structure on water sorption and diffusion is discussed. Current understanding of ion partitioning in charged polymers, focusing on the use of thermodynamic models (i.e., Donnan theory) to describe such phenomena, is summarized. Ion diffusivity data from the literature are interpreted using a model developed by Mackie and Meares to assess relative and absolute effects of the polymer and fixed charge groups on ion diffusivity. Furthermore, membrane requirements for several important technologies are listed. Knowledge gaps and opportunities for fundamental research are also discussed. PMID- 26979405 TI - Lessons from HeLa Cells: The Ethics and Policy of Biospecimens. AB - Human biospecimens have played a crucial role in scientific and medical advances. Although the ethical and policy issues associated with biospecimen research have long been the subject of scholarly debate, the story of Henrietta Lacks, her family, and the creation of HeLa cells captured the attention of a much broader audience. The story has been a catalyst for policy change, including major regulatory changes proposed in the United States surrounding informed consent. These proposals are premised in part on public opinion data, necessitating a closer look at what such data tell us. The development of biospecimen policy should be informed by many considerations-one of which is public input, robustly gathered, on acceptable approaches that optimize shared interests, including access for all to the benefits of research. There is a need for consent approaches that are guided by realistic aspirations and a balanced view of autonomy within an expanded ethical framework. PMID- 26979411 TI - The Evolution of Process Safety: Current Status and Future Direction. AB - The advent of the industrial revolution in the nineteenth century increased the volume and variety of manufactured goods and enriched the quality of life for society as a whole. However, industrialization was also accompanied by new manufacturing and complex processes that brought about the use of hazardous chemicals and difficult-to-control operating conditions. Moreover, human-process equipment interaction plus on-the-job learning resulted in further undesirable outcomes and associated consequences. These problems gave rise to many catastrophic process safety incidents that resulted in thousands of fatalities and injuries, losses of property, and environmental damages. These events led eventually to the necessity for a gradual development of a new multidisciplinary field, referred to as process safety. From its inception in the early 1970s to the current state of the art, process safety has come to represent a wide array of issues, including safety culture, process safety management systems, process safety engineering, loss prevention, risk assessment, risk management, and inherently safer technology. Governments and academic/research organizations have kept pace with regulatory programs and research initiatives, respectively. Understanding how major incidents impact regulations and contribute to industrial and academic technology development provides a firm foundation to address new challenges, and to continue applying science and engineering to develop and implement programs to keep hazardous materials within containment. Here the most significant incidents in terms of their impact on regulations and the overall development of the field of process safety are described. PMID- 26979412 TI - Design of Responsive and Active (Soft) Materials Using Liquid Crystals. AB - Liquid crystals (LCs) are widely known for their use in liquid crystal displays (LCDs). Indeed, LCDs represent one of the most successful technologies developed to date using a responsive soft material: An electric field is used to induce a change in ordering of the LC and thus a change in optical appearance. Over the past decade, however, research has revealed the fundamental underpinnings of potentially far broader and more pervasive uses of LCs for the design of responsive soft material systems. These systems involve a delicate interplay of the effects of surface-induced ordering, elastic strain of LCs, and formation of topological defects and are characterized by a chemical complexity and diversity of nano- and micrometer-scale geometry that goes well beyond that previously investigated. As a reflection of this evolution, the community investigating LC based materials now relies heavily on concepts from colloid and interface science. In this context, this review describes recent advances in colloidal and interfacial phenomena involving LCs that are enabling the design of new classes of soft matter that respond to stimuli as broad as light, airborne pollutants, bacterial toxins in water, mechanical interactions with living cells, molecular chirality, and more. Ongoing efforts hint also that the collective properties of LCs (e.g., LC-dispersed colloids) will, over the coming decade, yield exciting new classes of driven or active soft material systems in which organization (and useful properties) emerges during the dissipation of energy. PMID- 26979413 TI - The Modern Temperature-Accelerated Dynamics Approach. AB - Accelerated molecular dynamics (AMD) is a class of MD-based methods used to simulate atomistic systems in which the metastable state-to-state evolution is slow compared with thermal vibrations. Temperature-accelerated dynamics (TAD) is a particularly efficient AMD procedure in which the predicted evolution is hastened by elevating the temperature of the system and then recovering the correct state-to-state dynamics at the temperature of interest. TAD has been used to study various materials applications, often revealing surprising behavior beyond the reach of direct MD. This success has inspired several algorithmic performance enhancements, as well as the analysis of its mathematical framework. Recently, these enhancements have leveraged parallel programming techniques to enhance both the spatial and temporal scaling of the traditional approach. We review the ongoing evolution of the modern TAD method and introduce the latest development: speculatively parallel TAD. PMID- 26979414 TI - STIM and Orai Proteins in Calcium Signaling: an AJP-Cell Physiology series of Themed Reviews. PMID- 26979416 TI - Outcome Expectancy and Sexual Compulsivity Among Men Who Have Sex with Men Living with HIV. AB - Sexual compulsivity is operationalized by engaging in repetitive sexual acts, having multiple sexual partners and/or the excessive use of pornography. Outcome expectancy refers to the beliefs about the consequences of engaging in a given behavior. Research examining the relationship between outcome expectancy and sexual compulsivity is limited. The aim of this study was to assess the association between outcome expectancy and sexual compulsivity among men who have sex with men (MSM) living with HIV. Data were obtained from 338 MSM. Simple and multiple linear regression models were used to assess the association between outcome expectancy and sexual compulsivity. After adjusting for age, race/ethnicity, income, education, and employment status, for every one point increase in outcome expectancies for condom use, HIV disclosure and negotiation of safer sex practices, there was, on average, an approximate one point decrease in sexual compulsivity score. Prevention and intervention programs geared towards reducing sexual compulsivity among MSM should focus on increasing outcome expectancies for condom use, HIV disclosure and negotiation of safer sex practices. PMID- 26979417 TI - Actor-Partner Effects of Male Couples Substance Use with Sex and Engagement in Condomless Anal Sex. AB - Few studies have examined actor-partner effects about male couples' substance use with sex. Dyadic data from 361 male couples were used to examine these effects regarding engagement in condomless anal sex (CAS) by type of partner and substance. Couples with one or both partners reported using marijuana, amyl nitrates, party drugs, and/or stimulants with sex in their relationship was positively associated with them having had CAS. Actor-partner effects for stimulant use with sex with the main partner were associated with CAS with a casual MSM partner. Only an actor effect for stimulant use with sex with a casual MSM partner was associated with CAS with that partner type, and an actor effect for marijuana use with sex for both partner types was associated with CAS with both partner types. These findings illuminate the need for further inquiry about male couples' substance use with sex for HIV prevention. PMID- 26979418 TI - Investigating HIV Infection and HIV Incidence Among Chinese Men Who Have Sex with Men with Recent Sexual Debut, Chongqing, China, 2011. AB - HIV among men who have sex with men (MSM) with recent male-male sexual debut, such as within the past 5 years, may be a proxy for recent HIV infection. Using this definition, we explored factors associated with HIV infection in this group to understand the evolving HIV epidemic among MSM in Chongqing. We conducted a cross-sectional respondent-driven sampling survey among Chongqing MSM in 2011. Computer-assisted, self-administered questionnaires were used and blood specimens were collected for HIV and syphilis testing. Three hundred and ninety-one unique MSM were recruited of which 65.7 % (257) had their sexual debut with another man in the past 5 years. HIV prevalence among men with recent sexual debut was 18.7 % suggesting a possible HIV incidence of 3.7 %. Multivariable analysis among men with recent sexual debut suggests that lower education, having more than one male partner, and currently being infected with syphilis are associated with HIV among men with recent sexual debut. HIV prevalence is high among MSM with recent sexual debut in Chongqing, which may be a proxy a high incidence rate. HIV prevention efforts should focus on STD reduction among those MSM with lower educational attainment. PMID- 26979421 TI - Sputtering Deposition of Sandwich-Structured V2O5/Metal (V, W)/V2O5 Multilayers for the Preparation of High-Performance Thermally Sensitive VO2 Thin Films with Selectivity of VO2 (B) and VO2 (M) Polymorph. AB - For specific application to an uncooled infrared detector, VO2 thin films should have a series of characteristics including purposefully chosen polymorphs, accurate stoichiometry, phase stabilization, a high temperature-coefficient of resistance (TCR), and suitable square-resistance. This work reports controllable preparation of high-performance VO2 films via post annealing of a sandwich structured V2O5/metal (V, W)/V2O5 multilayer precursor, which was deposited by RF magnetron sputtering. This sandwich structure can dynamically regulate oxygen contents and doping element levels in the films, enabling us to achieve accurate regulation of stoichiometry and polymorphs. The precursor films undergo a B to M phase transition depending on the quantity of the metal layers. At the thickness of the metal layer below a limitation, the resulting film after heat treatment was VO2 (B), and above the limitation, the product was VO2 (M). The optical modulation of the VO2 (M) in the near-infrared region can be tuned from 1.2 to 39.8% (DeltaT2000 nm). TCR values can range from -1.89 to -4.29%/K and the square resistances at room temperature (R0) from 69.68 to 12.63 kOmega. The simplicity in phase regulation of the present method and the superior optical and electrical properties of the films may allow its wide applications in thermo-opto-electro sensing devices. PMID- 26979419 TI - HIV Transmission Risk Behavior in a Cohort of HIV-Infected Treatment-Naive Men and Women in the United States. AB - Antiretroviral therapy (ART) can minimize HIV transmission. Prevention benefits may be compromised by barriers to virologic suppression, and by increased condomless sex among those initiating ART. We evaluated condomless sex in a cohort of HIVinfected US individuals poised to initiate ART in a clinical trial. We assessed partner and sex act type, condom use, and perception of infectiousness. Six percent of participants reported as not infectious; men who have sex with men were more likely to perceive high infectivity. Prevalence of condomless sex was 44 %; 74 % of those also reported homosexual acquisition of HIV. Predictors of increased risk of condomless sex included greater numbers of lifetime partners, recent stimulant drug use and an HIV-positive or unknown serostatus partner. In the context of serodifferent partners, lower perception of infectiousness was also associated with a higher risk of condomless sex. Results highlight opportunities for prevention education for HIV infected individuals at ART initiation. PMID- 26979422 TI - Differences in neurocognitive functioning associated with alcohol consumption in a multiethnic rural cohort: A Project FRONTIER study. AB - The current study assessed if a neuroprotective effect on cognition from mild alcohol consumption occurs in multiethnic rural communities and if effect differences occur due to gender or ethnicity. Participants were drawn from Project FRONTIER (Facing Rural Obstacles to healthcare Now Through Intervention, Education & Research), a community-based participatory research study assessing aging in a rural, West Texas, multiethnic cohort of participants aged 40 years and older. Alcohol consumption patterns were determined from Alcohol Use Disorders Identification Test responses. Cognitive measures included the Repeatable Battery for the Assessment of Neuropsychological Status. Because few participants had greater than a mild alcohol consumption pattern, only abstinent participants and those with mild consumption were compared (N = 1,004 1st observation; N = 256 2nd observation). Multivariate analysis of covariance revealed main effects for alcohol consumption pattern, gender, and ethnicity. Attention was most affected by alcohol consumption pattern followed by verbal memory. Mild alcohol consumption was associated with better performance in these areas. Gender and ethnicity had broad effects on cognitive abilities but inconsistent attention effects. Overall, mild alcohol consumption was associated with better attentional and other abilities compared with abstinence in a rural multiethnic sample. These findings are consistent with previous research and suggest ethnicity and gender are uninvolved in any alcohol neuroprotective effects. PMID- 26979420 TI - Mapping the dynamics and nanoscale organization of synaptic adhesion proteins using monomeric streptavidin. AB - The advent of super-resolution imaging (SRI) has created a need for optimized labelling strategies. We present a new method relying on fluorophore-conjugated monomeric streptavidin (mSA) to label membrane proteins carrying a short, enzymatically biotinylated tag, compatible with SRI techniques including uPAINT, STED and dSTORM. We demonstrate efficient and specific labelling of target proteins in confined intercellular and organotypic tissues, with reduced steric hindrance and no crosslinking compared with multivalent probes. We use mSA to decipher the dynamics and nanoscale organization of the synaptic adhesion molecules neurexin-1beta, neuroligin-1 (Nlg1) and leucine-rich-repeat transmembrane protein 2 (LRRTM2) in a dual-colour configuration with GFP nanobody, and show that these proteins are diffusionally trapped at synapses where they form apposed trans-synaptic adhesive structures. Furthermore, Nlg1 is dynamic, disperse and sensitive to synaptic stimulation, whereas LRRTM2 is organized in compact and stable nanodomains. Thus, mSA is a versatile tool to image membrane proteins at high resolution in complex live environments, providing novel information about the nano-organization of biological structures. PMID- 26979423 TI - Psychological Resources Are Independently Associated with Markers of Inflammation in a Middle-Aged Community Sample. AB - PURPOSE: To elucidate possible independent associations of psychological resources with inflammatory markers, all linked with coronary heart disease (CHD). METHOD: In a middle-aged general population (n = 944), psychological resources (coping, self-esteem, and sense of coherence (SOC)), a global measure of quality of life (Cantril's self-anchoring ladder, also called "ladder of life"), and psychological risk factors (hopelessness, vital exhaustion, and depressive symptoms) were used in linear regression models to evaluate associations with the inflammatory markers interleukin (IL)-6, C-reactive protein (CRP), and matrix metalloproteinase (MMP)-9. Adjustments were done for age, sex, medical conditions, and cardiovascular risk factors. RESULTS: After full adjustments, self-esteem was independently associated with all three biomarkers. Ladder of life was associated with IL-6 and log-CRP; coping, vital exhaustion, and depressive symptoms with IL-6; and SOC with MMP-9 (p < 0.05 for all associations). CONCLUSION: Numerous significant associations of psychological resources and risk factors with IL-6, CRP, and MMP-9 were found in a community based sample. The associations of psychological resources were mostly independent, while the psychological risk factors seemed preferentially dependent on lifestyle factors as smoking, physical activity, and body mass index (BMI). This suggests that the psychological resources' (in particular self-esteem) protective effects on CHD are linked to inflammatory markers. PMID- 26979425 TI - Stress Underestimation and Mental Health Outcomes in Male Japanese Workers: a 1 Year Prospective Study. AB - PURPOSE: Being appropriately aware of the extent of stress experienced in daily life is essential in motivating stress management behaviours. Excessive stress underestimation obstructs this process, which is expected to exert adverse effects on health. We prospectively examined associations between stress underestimation and mental health outcomes in Japanese workers. METHODS: Web based surveys were conducted twice with an interval of 1 year on 2359 Japanese male workers. Participants were asked to complete survey items concerning stress underestimation, depressive symptoms, sickness absence, and antidepressant use. RESULTS: Multiple logistic regression analysis revealed that high baseline levels of 'overgeneralization of stress' and 'insensitivity to stress' were significantly associated with new-onset depressive symptoms (OR = 2.66 [95 % CI, 1.54-4.59], p < .01) and antidepressant use (OR = 4.91 [95 % CI, 1.22-19.74], p < .05), respectively, during the 1-year follow-up period. CONCLUSIONS: This study clearly demonstrated that stress underestimation, including stress insensitivity and the overgeneralization of stress, could exert adverse effects on mental health. PMID- 26979424 TI - Lifestyle and Addictive Behaviors Among Chinese Adolescents in Hong Kong, Macau, Taipei, Wuhan, and Zhuhai-a First Cross-subculture Assessment. AB - PURPOSE: This study aimed at assessing the differences in prevalence rates of common health behavior among adolescents in the five Chinese cities and the influential factors at the contextual and individual levels. METHOD: We compared the standardized rates of three lifestyle behaviors (sedentary, dietary, and physical activity) and three addictive behaviors (cigarette smoking, alcohol consumption, and participation in gambling) among a sample of 13,950 adolescents. The sample was randomly selected from five cities, including Hong Kong, Macau, Taipei, Zhuhai, and Wuhan. Population size, GDP per capita, and literacy at the city level as well as parental monitoring and school performance at the student's level were assessed. Multi-level mixed effect models were used to examine the interaction of individual level factors with study sites. RESULTS: The six health behaviors differed significantly across sites with the highest rates of alcohol consumption in Hong Kong (39.5 %), of cigarette smoking in Macau (9.8 %), and of gambling in Taipei (37.1 %) and Hong Kong (35.9 %). The city-level measures were associated with only a few behavioral measures. Relative to Hong Kong, parental monitoring had stronger association with the three addictive behaviors in the other sites. CONCLUSION: Findings suggest that although the study sites share similar Chinese culture, students in the five cities differed from each other with regard to levels of health behaviors. Relative to the broad socioeconomic development, differences in parental monitoring played a significant role in explaining the observed difference. PMID- 26979426 TI - Spatial distribution of lead in soils of Pb-Zn mining and smelting area of the Mitrovica Region, Republic of Kosovo. AB - An area of 301 km(2) in the Mitrovica region, Republic of Kosovo, was selected in order to evaluate the lead distribution in the soil. In total, 156 surface soil samples (0 to 5 cm) were collected. The lead content was determined by inductively coupled plasma-mass spectrometry (ICP-MS). It was found that the average content of lead in the surface soil is 450 mg/kg (with a range of 35 35000 mg/kg). For the entire study area 93% of the samples had lead levels above 100 mg/kg, eight samples below 100 mg/kg and only one sample had lead levels at 30 mg/kg. The effects of mining and metallurgical activities were further assessed using the enrichment factor (EF) value. The lead average exceeded the optimum value specified in the New Dutchlist by five times, while EU average value exceeded it up to 20 times. An area of 113 km(2) of the study area was enriched with Pb higher than the action value (530 mg/kg) while 287 km(2) had significant concentration levels with Pb (358 mg/kg) higher than the optimal value (85 mg/kg), according to New Dutchlist. PMID- 26979427 TI - [Hereditary renal tumors: More common than expected?]. AB - Renal cell carcinomas are associated with hereditary tumor syndromes in approximately 5 % of cases. In patients with a hereditary predisposition, tumors show an earlier age of onset, often with a multicentric and bilateral manifestation. While some patients with renal cell carcinoma can be classified into well-characterized kidney cancer syndromes others have a genetic background which is still poorly understood. Most of the specific tumor syndromes are associated with a histopathologically distinct renal cell tumor phenotype. The recognition of patients with hereditary renal cell carcinoma and the identification of individual family members with a higher risk of development of renal tumors is important for early tumor detection and treatment. This manuscript reviews the clinical pathological and molecular findings of hereditary renal cell carcinoma syndromes. PMID- 26979428 TI - [Succinate dehydrogenase (SDH)-deficient renal cell carcinoma]. AB - Succinate dehydrogenase (SDH) represents a type II mitochondrial complex related to the respiratory chain and Krebs cycle. The complex is composed of four major subunits, SDHA, SDHB, SDHC and SDHD. The oncogenic role of this enzyme complex has only recently been recognized and the complex is currently considered an important oncogenic signaling pathway with tumor suppressor properties. In addition to the familial paraganglioma syndromes (types 1-5) as prototypical SDH related diseases, many other tumors have been defined as SDH-deficient, in particular a subset of gastrointestinal stromal tumors (GIST), rare hypophyseal adenomas, a subset of pancreatic neuroendocrine neoplasms (recently added) and a variety of other tumor entities, the latter mainly described as rare case reports. As a central core subunit responsible for the integrity of the SDH complex, the expression of SDHB is lost in all SDH-deficient neoplasms irrespective of the specific SDH subunit affected by a genetic mutation in addition to concurrent loss of the subunit specifically affected by genetic alteration. Accordingly, all SDH-deficient neoplasms are by definition SDHB deficient. The SDH-deficient renal cell carcinoma (RCC) has only recently been well-characterized and it is included as a specific subtype of RCC in the new World Health Organization (WHO) classification published in 2016. In this review, the major clinicopathological, immunohistochemical and genetic features of this rare disease entity are presented and discussed in the context of the broad differential diagnosis. PMID- 26979429 TI - [Barrett's esophagus and carcinoma: Recommendations of the S2k guideline 2014 and the S3 guideline 2015]. AB - In the current S2k guideline for gastroesophageal reflux disease and the new S3 guideline for esophageal cancer, histopathological evaluation of Barrett's esophagus has been revised and supplemented. The histological diagnosis of Barrett's esophagus still requires the proof of a specialized intestinal metaplastic epithelium (columnar epithelium with goblet cells). Barrett mucosa must be classified as negative, unclear/doubtful, and positive concerning the intraepithelial neoplasia (IEN)/dysplasia according to the current WHO guideline. Each IEN should be confirmed by an external second opinion due to poor interobserver variability. The pathological classification is of decisive importance here, since the recommended monitoring intervals are based solely on the ground of proved IEN. Risk factors in endoscopic resection specimens such as depth of infiltration (m1-m4; sm1-sm3; distance in um); angioinvasion (L, V); grading and lateral/basal resection margin have to be reported. In surgical specimens, the reference of the tumor center to the gastroesophageal junction and in the neoadjuvant situation the tumor regression should be documented. PMID- 26979430 TI - What benefits does team sport hold for the workplace? A systematic review. AB - Physical inactivity is proven to be a risk factor for non-communicable diseases and all-cost mortality. Public health policy recommends community settings worldwide such as the workplace to promote physical activity. Despite the growing prevalence of workplace team sports, studies have not synthesised their benefits within the workplace. A systematic review was carried out to identify articles related to workplace team sports, including intervention, observational and qualitative studies. Eighteen studies met the inclusion criteria. The findings suggest team sport holds benefits not only for individual health but also for group cohesion and performance and organisational benefits such as the increased work performance. However, it is unclear how sport is most associated with these benefits as most of the studies included poorly described samples and unclear sports activities. Our review highlights the need to explore and empirically understand the benefits of workplace team sport for individual, group and organisational health outcomes. Researches carried out in this field must provide details regarding their respective samples, the sports profile and utilise objective measures (e.g., sickness absence register data, accelerometer data). PMID- 26979431 TI - Burden and Unmet Needs of Caregivers of Chronic Obstructive Pulmonary Disease Patients: A Systematic Review of the Volume and Focus of Research Output. AB - Caregivers of individuals with chronic obstructive pulmonary disease (COPD) experience significant burden. To develop effective interventions to support this vulnerable group, it is necessary to understand how this burden varies as a function of patient well-being and across the illness trajectory. This systematic review aimed to identify the number and type of data-based publications exploring the burden and unmet needs of caregivers of individuals with COPD. Medline, Embase, PsycINFO and Cochrane databases were searched for studies published between January 2000 and February 2014. Studies were eligible if they were quantitative studies examining unmet needs of, or burden on, adult caregivers of individuals with COPD. Eligible papers were categorised according to (i) type (i.e. descriptive, measurement and intervention studies); (ii) whether they measured associations between patient and caregiver burden and (iii) whether they measured caregiver burden longitudinally. Twenty-seven data-based papers met criteria for inclusion. There was a significant increase in the total number of publications over time. The majority of publications were descriptive studies (n = 25), with one measurement and one intervention study identified. Fourteen descriptive studies measured the relationship between patient or caregiver factors and caregiver burden. Only two studies measured caregiver burden over time. There are a number of gaps in the body of research examining burden and unmet needs of caregivers of individuals with COPD that preclude the development of effective interventions for this population. Greater research effort should be directed towards identifying rigorous measurement tools which more accurately characterise caregiver burden, so that evidence-based interventions can be developed. PMID- 26979432 TI - Sialylation of vitronectin regulates stress fiber formation and cell spreading of dermal fibroblasts via a heparin-binding site. AB - Vitronectin (VN) plays an important role in tissue regeneration. We previously reported that VN from partial hepatectomized (PH) rats results in a decrease of sialylation of VN and de-sialylation of VN decreases the cell spreading of hepatic stellate cells. In this study, we analyzed the mechanism how sialylation of VN regulates the properties of mouse primary cultured dermal fibroblasts (MDF) and a dermal fibroblast cell line, Swiss 3T3 cells. At first, we confirmed that VN from PH rats or de-sialylated VN also decreased cell spreading in MDF and Swiss 3T3 cells. The de-sialylation suppressed stress fiber formation in Swiss 3T3 cells. Next, we analyzed the effect of the de-sialylation of VN on stress fiber formation in Swiss 3T3 cells. RGD peptide, an inhibitor for a cell binding site of VN, did not affect the cell attachment of Swiss 3T3 cells on untreated VN but significantly decreased it on de-sialylated VN, suggesting that the de sialylation attenuates the binding activity of an RGD-independent binding site in VN. To analyze a candidate RGD-independent binding site, an inhibition experiment of stress fiber formation for a heparin binding site was performed. The addition of heparin and treatment of cells with heparinase decreased stress fiber formation in Swiss 3T3 cells. Furthermore, de-sialylation increased the binding activity of VN to heparin, as detected by surface plasmon resonance (SPR). These results demonstrate that sialylation of VN glycans regulates stress fiber formation and cell spreading of dermal fibroblast cells via a heparin binding site. PMID- 26979433 TI - Beneficial effect of xylose consumption on postprandial hyperglycemia in Korean: a randomized double-blind, crossover design. AB - BACKGROUND: Previous studies have reported that xylose selectively inhibited the activity of sucrase. Xylose supplementation may have a beneficial effect on the postprandial glycemic response. However, no studies have investigated patients with IFG or the effectivity of a dose of D-xylose less than 10 % (w/w). METHODS: The present study determined the effect of xylose consumption on postprandial hyperglycemia in normal (n = 25) and hyperglycemic subjects (n = 50). Subjects in this double-blind crossover design study were randomly assigned to consume a sucrose drink (Control, sucrose 50 g + deionized water 100 g) or a sucrose drink additionally containing 5 g (Test 1, sucrose:xylose = 10:1), 3.33 g (Test 2, sucrose:xylose = 15:1), or 2.5 g (Test 3, sucrose:xylose = 20:1) of D-xylose separated by a one-week interval. RESULTS: Normal subjects in all test groups exhibited a significant decrease in serum glucose levels 15 min and 30 min after consuming the xylose-containing drinks compared to the control group. Significantly lower serum levels of insulin were observed at 15 min and 30 min after consuming the xylose-containing drinks compared to the control group. The test 1 group also exhibited a significantly lower insulin area under the curve than the control group. Hyperglycemic subjects (n = 50) in all test groups exhibited a significant decrease in serum glucose levels at 30 min compared to the control group. However, the test 1 group exhibited a significant increase in serum glucose levels at 120 min compared to the control group. Glucose-related markers did not significantly differ in each group. CONCLUSION: Xylose supplementation may exert a beneficial effect on postprandial glycemic responses in subjects with normal glucose levels and prediabetes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02654301 . Registered 12 January 2016. PMID- 26979434 TI - Atranorin and lecanoric acid antagonize TCDD-induced xenobiotic response element driven activity, but not xenobiotic response element-independent activity. AB - Lichens are symbiotic organisms that consist of fungi and photosynthetic symbionts (algae and/or cyanobacteria). Previous studies of their constituents suggested lichens produce many kinds of aromatic secondary metabolites, such as depsides, quinones, and dibenzofurans. In this study, we evaluated the aryl hydrocarbon receptor (AhR) antagonistic activity of 17 lichen substances and demonstrated that atranorin (1) and lecanoric acid (2), isolated from Parmotrema tinctorum Hale, showed an inhibitory effect on luciferase activity increased by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), using an XRE-driven pX4TK-Luc reporter gene assay. In addition, CYP1A1 mRNA and protein levels increased by TCDD were also suppressed by 1 and 2. Conversely, neither 1 nor 2 antagonized the suppressive effect of TCDD on interleukin (IL)-1beta-induced acute-phase response (APR) gene expression. Thus, we concluded that 1 and 2 were selective AhR modulators that antagonize XRE-dependent activity, but not XRE-independent activity. However, 1 has different characteristics to 2 in that 1 alone showed a suppressive effect on IL-1beta-induced APR gene expression in a similar fashion to TCDD. PMID- 26979435 TI - Brain activation is related to smoothness of upper limb movements after stroke. AB - It is unclear whether additionally recruited sensorimotor areas in the ipsilesional and contralesional hemisphere and the cerebellum can compensate for lost neuronal functions after stroke. The objective of this study was to investigate how increased recruitment of secondary sensorimotor areas is associated with quality of motor control after stroke. In seventeen patients (three females, fourteen males; age: 59.9 +/- 12.6 years), cortical activation levels were determined with functional magnetic resonance imaging (fMRI) in 12 regions of interest during a finger flexion-extension task in weeks 6 and 29 after stroke. At the same time points and by using 3D kinematics, the quality of motor control was assessed by smoothness of the grasp aperture during a reach-to grasp task, quantified by normalized jerk. Ipsilesional premotor cortex, insula and cerebellum, as well as the contralesional supplementary motor area, insula and cerebellum, correlated significantly and positively with the normalized jerk of grasp aperture at week 6 after stroke. A positive trend towards this correlation was observed in week 29. This study suggests that recruitment of secondary motor areas at 6 weeks after stroke is highly associated with increased jerk during reaching and grasping. As jerk represents the change in acceleration, the recruitment of additional sensorimotor areas seems to reflect a type of control in which deviations from an optimal movement pattern are continuously corrected. This relationship suggests that additional recruitment of sensorimotor areas after stroke may not correspond to restitution of motor function, but more likely to adaptive motor learning strategies to compensate for motor impairments. PMID- 26979436 TI - Automatic adjustments toward unseen visual targets during grasping movements. AB - We investigated whether control of hand movements can be driven by visual information that is not consciously perceived. Subjects performed reach-to-grasp movements toward 2D virtual objects that were projected onto a rigid surface. On perturbed trials, the target object was briefly presented at a different orientation (+/-20 degrees rotation) or different size (+/-20 % scaling) during movement. The perturbed objects were presented for 33 ms, followed by a 200-ms mask and reappearance of the original target object. Subjects perceived only the mask and were not aware of the preceding perturbed stimuli. Unperturbed trials were identical except that there was no change in the target object before the mask. Despite being unaware of the brief perturbed stimuli, subjects showed corrective adjustments to their movements: rotation of the grip axis in response to orientation perturbations, and scaling of grip aperture in response to size perturbations. Responses were detectable 250-300 ms after the perturbation onset and began to reduce 250-300 ms after the reappearance of the original target. Our results demonstrate that the visuomotor system can utilize visual information for control of grasping even when this information is not available for conscious perception. We suggest that this dissociation is due to different temporal resolution of visual processing mechanisms underlying conscious perception and control of actions. PMID- 26979437 TI - Target position relative to the head is essential for predicting head movement during head-free gaze pursuit. AB - Gaze pursuit is the coordinated movement of the eyes and head that allows humans and other foveate animals to track moving objects. The control of smooth pursuit eye movements when the head is restrained is relatively well understood, but how the eyes coordinate with concurrent head movements when the head is free remains unresolved. In this study, we describe behavioral tasks that dissociate head and gaze velocity during head-free pursuit in monkeys. Existing models of gaze pursuit propose that both eye and head movements are driven only by the perceived velocity of the visual target and are therefore unable to account for these data. We show that in addition to target velocity, the positions of the eyes in the orbits and the retinal position of the target are important factors for predicting head movement during pursuit. When the eyes are already near their limits, further pursuit in that direction will be accompanied by more head movement than when the eyes are centered in the orbits, even when target velocity is the same. The step-ramp paradigm, often used in pursuit tasks, produces larger or smaller head movements, depending on the direction of the position step, while gaze pursuit velocity is insensitive to this manipulation. Using these tasks, we can reliably evoke head movements with peak velocities much faster than the target's velocity. Under these circumstances, the compensatory eye movements, which are often called counterproductive since they rotate the eyes in the opposite direction, are essential to maintaining accurate gaze velocity. PMID- 26979438 TI - Boredom, sustained attention and the default mode network. AB - Boredom is a ubiquitous human experience that can best be described as an inability to engage with one's environment despite the motivation to do so. Boredom is perceived as a negative experience and demonstrates strong associations with other negatively valenced states including depression and aggression. Although boredom has been shown to be elevated in neurological and psychiatric illnesses, little is known about the neural underpinnings of the state. We scanned the brains of healthy participants under four separate conditions: a resting state scan, a sustained attention task and two video-based mood inductions, one known to produce boredom and another we validated to produce a state of interest or engagement. Using independent components analyses, results showed common regions of correlated activation in posterior regions of the so called default mode network (DMN) of the brain across all four conditions. The sustained attention and boredom induction scans were differentiated from the resting state scan by the presence of anticorrelated activity-i.e. when DMN regions were active, this region was deactivated-in the anterior insula cortex. This same region demonstrated correlated activity with both the DMN and the regions associated with attentional control during the interest mood induction. We interpret these findings to suggest that boredom represents a failure to engage executive control networks when faced with a monotonous task-in other words, when the task demands some level of engagement (watch the movie, search for infrequent targets), but is so mundane that attempts to do so fail. PMID- 26979439 TI - The violation of Fitts' Law: an examination of displacement biases and corrective submovements. AB - Fitts' Law holds that, to maintain accuracy, movement times of aiming movements must change as a result of varying degrees of movement difficulty. Recent evidence has emerged that aiming to a target located last in an array of placeholders results in a shorter movement time than would be expected by the Fitts' equation-a violation of Fitts' Law. It has been suggested that the violation emerges because the performer adopts an optimized movement strategy in which they partially pre-plan an action to the closest placeholder (undershoot the last placeholder) and rely on a secondary acceleration to propel the limb toward the last location when it is selected as the target (Glazebrook et al. in Hum Mov Sci 39:163-176, 2015). In the current study, we examine this proposal and further elucidate the processes underlying the violation by examining limb displacement and corrective submovements that occur when performers aim to different target locations. For our Main Study, participants executed discrete aiming movements in a five-placeholder array. We also reanalyzed data from a previously reported study in which participants aimed in placeholder and no placeholder conditions (Blinch et al. in Exp Brain Res 223:505-515, 2012). The results showed the violation of Fitts' Law unfolded following peak velocity (online control). Further, the analysis showed that movements to the last target tended to overshoot and had a higher proportion of secondary submovements featuring a reversal than other categories of submovement (secondary accelerations, discontinuities). These findings indicate that the violation of Fitts' Law may, in fact, result from a strategic bias toward planning farther initial displacements of the limb which accommodates a shorter time in online control. PMID- 26979441 TI - Fracture load and failure types of different veneered polyetheretherketone fixed dental prostheses. AB - OBJECTIVE: The aim of this study is to investigate the fracture load of different veneered PEEK 3-unit fixed dental prosthesis (FDPs) after different aging regimens. METHODS: Congruently anatomically shaped 3-unit FDPs were milled using a master stl-data set and randomly divided into four groups (N = 120, n = 30 per veneering group), which were veneered using different veneering methods: (i) digital veneering with breCAM.HIPC, (ii) conventional veneering with crea.lign, (iii) conventional with crea.lign paste, and (iv) using pre-manufactured veneers visio.lign. The FDPs were then adhesively cemented on a metal abutment and fracture loads were measured in a universal testing machine (1 mm/min) before and after aging (10,000 thermal cycles, 5/55 degrees C). Two- and one-way ANOVA followed by post hoc Scheffe tests were used for data analysis (p < 0.05). RESULTS: This investigation showed an influence of the veneering method on the fracture load results independent of the aging level. The highest fracture load was measured for the FDPs with digital veneering (1882 +/- 152 N at baseline, 2021 +/- 184 N after thermocycling). The remaining groups showed comparable results, and no impact of thermal aging was observed. Digital and conventional veneers showed cracks in the pontic region starting from the connector area as a main failure type after loading, while the pre-manufactured veneers showed predominantly adhesive failures. CONCLUSIONS: The digital veneering method showed the highest fracture load resistance. Thermal aging showed no impact on the fracture load of all tested veneered PEEK 3-unit FDPs. CLINICAL RELEVANCE: According to this study results, reliable veneering of PEEK FDPs can be achieved with digital veneering. PMID- 26979440 TI - Self-prioritization in vision, audition, and touch. AB - To investigate self-prioritization independently of stimulus familiarity, Sui et al. (J Exp Psychol Hum Percept Perform 38:1105-1117, 2012. doi: 10.1037/a0029792 ) introduced a new paradigm in which different geometric shapes are arbitrarily associated with self-relevant (e.g., "I") and neutral labels (e.g., "stranger"). It has now been repeatedly demonstrated that in a subsequently presented matching task, this association leads to faster and more accurate verifications of self relevant shape-label pairings than neutral shape-label pairings. In order to assess whether this self-prioritization effect represents a general selection mechanism in human information processing, we examined whether it is limited to the visual modality. Therefore, besides visual stimuli, auditory and vibrotactile stimuli were also associated either to self-relevant or to neutral labels. The findings demonstrate that self-prioritization represents a general tendency influencing human information processing, one that operates across the senses. Our results also highlight a top-down component to self-prioritization. PMID- 26979442 TI - Evaluation of a regional German interdisciplinary oral health programme for children from birth to 5 years of age. AB - OBJECTIVES: The aim of this prospective birth cohort study was to evaluate the effect of the interdisciplinary oral health programme (OHP) for early childhood caries (ECC) in 5-year-old German children. MATERIAL AND METHODS: All parents of newborns (n = 1162; born 2009/2010) were visited after birth by the communal newborn visiting service of Jena, Thuringia, and advised on general and dental health. In the first year of life, children were invited to attend a dental examination in the Jena University Hospital. Participating children were included in a caries-risk-related recall system with continuous oral care over 5 years. The caries-risk assessment tool of the AAPD was used to determine the likelihood of carious lesion development and to categorize the children at low, moderate or high risk for caries. High-risk children received fluoride varnish. Families (n = 563) who gave their approval for final examination after 5 years were invited again and examined by a blinded clinician. Dental caries was scored using WHO diagnostic criteria expanded to d1-level without radiography. Children were allocated to prevention (PG) and control group (CG) and matched on the basis of age, sex, ethnicity and socio-economic status (SES). RESULTS: Two hundred and eighty-nine children (mean age 5.2 +/- 0.7 years; 46.7 % female) were examined. Children in the PG (n = 174) showed significantly lower caries prevalence and experience (10.9 %, 0.2 +/- 0.7 d3-4mft) than children in the CG (57.4 %, 2.9 +/- 3.8 d3-4mft). Multivariate analysis found that low SES, early start of tooth brushing, supervision/regular second brush by parent, regular dental visits and duration of breast-/bottle-feeding >1 year were significantly related to d3-4mft. CONCLUSIONS: The OHP was an effective approach for preventing early childhood caries in preschool children. CLINICAL RELEVANCE: A programme consisting of early maternal counselling, establishment of a dental home, and inclusion of the children in a caries-risk-related recall system with continuous dental care and fluoride varnish application can prevent ECC. TRIAL REGISTRATION: German Clinical Trials Register DRKS00003438, https://drks-neu.uniklinik freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00003438. PMID- 26979443 TI - The Use of Reverse Vaccinology and Molecular Modeling Associated with Cell Proliferation Stimulation Approach to Select Promiscuous Epitopes from Schistosoma mansoni. AB - Schistosomiasis remains an important parasitic disease that affects millions of individuals worldwide. Despite the availability of chemotherapy, the occurrence of constant reinfection demonstrates the need for additional forms of intervention and the development of a vaccine represents a relevant strategy to control this disease. With the advent of genomics and bioinformatics, new strategies to search for vaccine targets have been proposed, as the reverse vaccinology. In this work, computational analyses of Schistosoma mansoni membrane proteins were performed to predict epitopes with high affinity for different human leukocyte antigen (HLA)-DRB1. Ten epitopes were selected and along with murine major histocompatibility complex (MHC) class II molecule had their three dimensional structures optimized. Epitope interactions were evaluated against murine MHC class II molecule through molecular docking, electrostatic potential, and molecular volume. The epitope Sm141290 and Sm050890 stood out in most of the molecular modeling analyses. Cellular proliferation assay was performed to evaluate the ability of these epitopes to bind to murine MHC II molecules and stimulate CD4+ T cells showing that the same epitopes were able to significantly stimulate cell proliferation. This work showed an important strategy of peptide selection for epitope-based vaccine design, achieved by in silico analyses that can precede in vivo and in vitro experiments, avoiding excessive experimentation. PMID- 26979444 TI - Tonic Seizure Status Epilepticus Triggered by Valproate in a Child with Doose Syndrome. AB - Antiepileptic drugs may occasionally increase seizure frequency or eliciting de novo seizure occurrence; the underlying mechanism of these effects is not known. The potential adverse effects of valproic acid in myoclonic astatic epilepsy have been noted by experienced clinicians in various different regions of the world, but this important observation has not been sufficiently reported. We present the case of tonic status epilepticus in an 8-year-old boy with Doose syndrome related to valproic acid. Valproic acid, such as others antiepileptic drugs, is liable to produce paradoxical effects such as the atypical seizures we report. We emphasize the importance for the management of acute seizures in an intensive care unit setting and increase awareness of the acute toxic effects of antiepileptic drugs. PMID- 26979445 TI - The Enduring Significance of Skin Tone: Linking Skin Tone, Attitudes Toward Marriage and Cohabitation, and Sexual Behavior. AB - Past evidence has documented that attitudes toward marriage and cohabitation are related to sexual behavior in adolescence and young adulthood. This study extends prior research by longitudinally testing these associations across racial/ethnic groups and investigating whether culturally relevant variations within racial/ethnic minority groups, such as skin tone (i.e., lightness/darkness of skin color), are linked to attitudes toward marriage and cohabitation and sex. Drawing on family and public health literatures and theories, as well as burgeoning skin tone literature, it was hypothesized that more positive attitudes toward marriage and negative attitudes toward cohabitation would be associated with less risky sex, and that links differed for lighter and darker skin individuals. The sample included 6872 respondents (49.6 % female; 70.0 % White; 15.8 % African American; 3.3 % Asian; 10.9 % Hispanic) from the National Longitudinal Study of Adolescent to Adult Health. The results revealed that marital attitudes had a significantly stronger dampening effect on risky sexual behavior of lighter skin African Americans and Asians compared with their darker skin counterparts. Skin tone also directly predicted number of partners and concurrent partners among African American males and Asian females. We discuss theoretical and practical implications of these findings for adolescence and young adulthood. PMID- 26979446 TI - Participation in Organized Activities Protects Against Adolescents' Risky Substance Use, Even Beyond Development in Conscientiousness. AB - Adolescents are at a significant risk for binge drinking and illicit drug use. One way to protect against these behaviors is through participation in extracurricular activities. However, there is a debate about whether highly conscientious adolescents are more likely to participate in activities, which raises the concern of a confound. To disentangle these relationships, we tested the latent trajectories of substance use and personality across 3 years, with participation in activities and sports as time-varying predictors. We surveyed 687 adolescents (55 % female, 85.4 % Caucasian) in Western Australia schools across 3 years. At Time 1, the students were in Year 10 1 (mean age 15 years). The results showed that participation in activities and conscientiousness are related, but each uniquely predicts slower growth in substance use. Across waves, participation in activities predicted less risky substance use a year later, over and above conscientiousness development. These results suggest that there may be unique benefits of participation in activities that protect against risky substance use. PMID- 26979450 TI - Commentary on: Objective Sensory Changes Following Subfascial Breast Augmentation. PMID- 26979448 TI - Is it About Me, You, or Us? Stress Reactivity Correlates of Discrepancies in We Talk Among Parents and Preadolescent Children. AB - An emerging literature suggests that not only do parent and child perceptions of parent-child relationship quality independently predict children's adjustment, but also that the discrepancy between parent and child perceptions of the relationship also carries predictive power. In the current study, we examine discrepancies in mother and children's we-talk, which is thought to reveal the degree to which members of a dyad conceive of problems affecting just one of the members as shared. We anticipate that discrepancies in which the mother expresses a greater sense of we-ness than the child would be particularly toxic during this developmental phase, when youth's strivings for independence ought to near their apex. Using an ethnically and socioeconomically diverse sample of school-aged children and their mothers (N = 106, 49.1 % female; 43 % Non-Hispanic White, 21 % African American, 21 % Hispanic, 10 % Asian, and 5 % of another ethnic category or mixed race; 48 % reported an annual income of <$60,000), we expose children to a standardized failure task that their mothers observe and then interview both members of the dyad regarding the task-we-talk is derived from these interviews. We examine the discrepancy between child and mother we-talk as a predictor of children's cortisol reactivity and mothers' behavioral overcontrol during the failure task. We also examine whether the discrepancy in mother-child we-talk predicts children's trait rumination. The interaction between child and mother we talk was significantly associated with all three outcomes. Children's cortisol reactivity and rumination were highest when mothers used high and children used low levels of we-talk. A three-way interaction of children's we-talk, mothers' we talk and child age emerged, suggesting that the association of discrepancies in we-talk with maternal overcontrol depended on child age, with significant effects emerging among older children. We discuss our results in terms of their implications for preadolescent development and emotion regulation. PMID- 26979449 TI - A momentary biomarker for depressive mood. AB - Many biomarkers from genetic, neuroimaging, and biological/biochemical measures have been recently developed in order to make a shift toward the objective evaluation of psychiatric disorders. However, they have so far been less successful in capturing dynamical changes or transitions in pathological states, such as those occurring during the course of clinical treatments or pathogenic processes of disorders. A momentary biomarker is now required for objective monitoring of such dynamical changes. The development of ecological momentary assessment (EMA) allows the assessment of dynamical aspects of diurnal/daily clinical conditions and subjective symptoms. Furthermore, a variety of validation studies on momentary symptoms assessed by EMA using behavioral/physiological/biochemical measures have demonstrated the possibility of evaluating momentary symptoms from such external objective measures. In this review, we introduce physical activity as a candidate biobehavioral biomarker for psychiatric disorders. We also mention its potential as a momentary biomarker for depressive mood. Finally, we address the continuous monitoring of the pathogenic processes and pathological states of depressive disorders based on physical activity, as well as its application in pharmacological animal studies. PMID- 26979451 TI - Commentary on: Effects of Abdominoplasty on Intra-Abdominal Pressure and Pulmonary Function. PMID- 26979452 TI - Commentary on: Does Implant Insertion with a Funnel Decrease Capsular Contracture? A Preliminary Report. PMID- 26979453 TI - Earlobe Rejuvenation: A Fat Grafting Technique. AB - BACKGROUND: The earlobe demonstrates stereotypical signs of aging, including wrinkles and volume depletion. OBJECTIVES: The purpose of this study is to review the outcome of the earlobe rejuvenation developed by the senior author. METHODS: We describe our earlobe rejuvenation technique refined over 10 years that uses fat grafting to the earlobe. Three raters assessed preoperative and postoperative photographs of 40 earlobes in 20 patients. Each earlobe was evaluated for volume deficiency, number of deep creases, depth of creases, and number of fine wrinkles. Inter-rater reliability was calculated. Earlobe length was also measured. RESULTS: Seventeen females and 3 males with average age of 63 years were followed for an average of 26 months. Postoperative improvements were observed in earlobe volume deficiency and number of fine wrinkles (P < .05). Improvements were seen in number and depth of creases and the earlobe height, but these were not significant (P > .05). No complications relating to the earlobe were observed in these patients. CONCLUSIONS: Fat grafting can be an effective means for earlobe rejuvenation. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 26979454 TI - Abdominoplasty with Scarpa's Fascia Advancement Flap to Enhance the Waistline. PMID- 26979455 TI - Commentary on: Safety of Aesthetic Surgery in the Overweight Patient: Analysis of 127,961 Patients. PMID- 26979456 TI - Biomarkers Provide Clues to Early Events in the Pathogenesis of Breast Implant Associated Anaplastic Large Cell Lymphoma. AB - Almost 200 women worldwide have been diagnosed with breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). The unique location and specific lymphoma type strongly suggest an etio-pathologic link between breast implants and BIA-ALCL. It is postulated that chronic inflammation via bacterial infection may be an etiological factor. BIA-ALCL resembles primary cutaneous ALCL (pcALCL) in morphology, activated T-cell phenotype, and indolent clinical course. Gene expression array analysis, flow cytometry, and immunohistochemistry were used to study pcALCL and BIA-ALCL cell lines. Clinical samples were also studied to characterize transcription factor and cytokine profiles of tumor cells and surrounding lymphocytes. BIA-ALCL and pcALCL were found to have common expression of transcription factors SOCS3, JunB, SATB1, and a cytokine profile suggestive of a Th1 phenotype. Similar patterns were observed in a CD30+ cutaneous lymphoproliferative disorder (LPD). The patterns of cytokine and transcription factor expression suggest that BIA-ALCL is likely to arise from chronic bacterial antigen stimulation of T-cells. Further analysis of cytokine and transcription factor profiles may allow early detection and treatment of BIA-ALCL leading to better prognosis and survival. LEVEL OF EVIDENCE 5: Risk. PMID- 26979457 TI - OnabotulinumtoxinA for Treatment of Moderate to Severe Crow's Feet Lines: A Review. AB - Lateral canthal lines or crow's feet lines (CFL) may be treated with onabotulinumtoxinA. We identified several key concepts important to understanding the use of onabotulinumtoxinA for treatment of moderate-to-severe CFL. To contextualize and integrate data on the recommended dose and injection patterns of onabotulinumtoxinA for treatment of CFL, we summarized data from pivotal clinical studies in the development of onabotulinumtoxinA for treatment of CFL. Data from key studies of onabotulinumtoxinA for CFL are presented. The efficacy and safety of onabotulinumtoxinA treatment of moderate-to-severe CFL were evaluated in 2 randomized, controlled phase 3 studies comprising 1362 patients. The 24U total dose of onabotulinumtoxinA used in these studies was based on a phase 2 dose-ranging trial. Two injection patterns were available to investigators; each involved 3 injection sites per side in the lateral orbicularis oculi muscle. A cross-sectional analysis of photographs from the phase 3 trials provided detailed information on the frequency of 4 distinct CFL patterns. In the primary efficacy analysis for each phase 3 trial, CFL responder rates were significantly greater with onabotulinumtoxinA vs placebo at day 30 (P< .001). Eyelid edema (1%) was the only adverse event reported in >= 1% of patients receiving onabotulinumtoxinA, occurring more frequently with onabotulinumtoxinA than with placebo. The studies showed that onabotulinumtoxinA is effective and generally well-tolerated for CFL treatment. Additionally, 2 different injection patterns allow physicians to tailor treatment based on a patient's CFL pattern. PMID- 26979458 TI - Patient satisfaction with the healthcare system: Assessing the impact of socio economic and healthcare provision factors. AB - BACKGROUND: Patient satisfaction is an important measure of healthcare quality as it offers information on the provider's success at meeting clients' expectations and is a key determinant of patients' perspective behavioral intention. The aim of this paper is first to assess the degree of patient satisfaction, and second, to study the relationship between patient satisfaction of healthcare system and a set of socio-economic and healthcare provision indicators. METHODS: This empirical analysis covers 31 countries for the years 2007, 2008, 2009 and 2012. The dependent variable, the satisfaction index, is defined as the patient satisfaction of their country's health system. We first construct an index of patient satisfaction and then, at a second stage, this index is related to socio economic and healthcare provision variables. RESULTS: Our findings support that there is a strong positive association between patient satisfaction level and healthcare provision indicators, such as nurses and physicians per 100,000 habitants, with the latter being the most important contributor, and a negative association between patient satisfaction level and number of hospital beds. Among the socio-economic variables, public health expenditures greatly shape and positive relate to patient satisfaction, while private spending on health relates negatively. Finally, the elder a patient is, the more satisfied with a country's healthcare system appears to be. CONCLUSIONS: We conclude that there is a strong positive association between patient satisfaction and public health expenditures, number of physicians and nurses, and the age of the patient, while there is a negative evidence for private health spending and number of hospital beds. PMID- 26979459 TI - Different Array CGH profiles within hereditary breast cancer tumors associated to BRCA1 expression and overall survival. AB - BACKGROUND: Array CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease. Moreover, specific genomic alterations may contribute to the identification of potential therapeutic targets and offer a more personalized treatment to breast cancer patients. METHODS: Forty seven tumors from hereditary breast cancer cases, previously analyzed for BRCA1 expression, and screened for germline BRCA1 and 2 mutations, were analyzed by Array based Comparative Genomic Hybridization (aCGH) using Agilent 4x44K arrays. Overall survival was established for tumors in different clusters using Log-rank (Mantel-Cox) Test. Gene lists obtained from aCGH analysis were analyzed for Gene Ontology enrichment using GOrilla and DAVID tools. RESULTS: Genomic profiling of the tumors showed specific alterations associated to BRCA1 or 2 mutation status, and BRCA1 expression in the tumors, affecting relevant cellular processes. Similar cellular functions were found affected in BRCA1 not expressing and BRCA1 or 2 mutated tumors. Hierarchical clustering classified hereditary breast tumors in four major, groups according to the type and amount of genomic alterations, showing one group with a significantly poor overall survival (p = 0.0221). Within this cluster, deletion of PLEKHO1, GDF11, DARC, DAG1 and CD63 may be associated to the worse outcome of the patients. CONCLUSIONS: These results support the fact that BRCA1 lack of expression in tumors should be used as a marker for BRCAness and to select these patients for synthetic lethality approaches such as treatment with PARP inhibitors. In addition, the identification of specific alterations in breast tumors associated with poor survival, immune response or with a BRCAness phenotype will allow the use of a more personalized treatment in these patients. PMID- 26979461 TI - Exploring synergistic interactions and catalysts in complex interventions: longitudinal, mixed methods case studies of an optimised multi-level suicide prevention intervention in four european countries (Ospi-Europe). AB - BACKGROUND: The Medical Research Council (MRC) Framework for complex interventions highlights the need to explore interactions between components of complex interventions, but this has not yet been fully explored within complex, non-pharmacological interventions. This paper draws on the process evaluation data of a suicide prevention programme implemented in four European countries to illustrate the synergistic interactions between intervention levels in a complex programme, and to present our method for exploring these. METHODS: A realist evaluation approach informed the process evaluation, which drew on mixed methods, longitudinal case studies. Data collection consisted of 47 semi-structured interviews, 12 focus groups, one workshop, fieldnoted observations of six programme meetings and 20 questionnaires (delivered at six month intervals to each of the four intervention sites). Analysis drew on the framework approach, facilitated by the use of QSR NVivo (v10). Our qualitative approach to exploring synergistic interactions (QuaSIC) also developed a matrix of hypothesised synergies that were explored within one workshop and two waves of data collection. RESULTS: All four implementation countries provided examples of synergistic interactions that added value beyond the sum of individual intervention levels or components in isolation. For instance, the launch ceremony of the public health campaign (a level 3 intervention) in Ireland had an impact on the community-based professional training, increasing uptake and visibility of training for journalists in particular. In turn, this led to increased media reporting of OSPI activities (monitored as part of the public health campaign) and also led to wider dissemination of editorial guidelines for responsible reporting of suicidal acts. Analysis of the total process evaluation dataset also revealed the new phenomenon of the OSPI programme acting as a catalyst for externally generated (and funded) activity that shared the goals of suicide prevention. CONCLUSIONS: The QuaSIC approach enabled us to develop and refine our definition of synergistic interactions and add the innovative concept of catalytic effects. This represents a novel approach to the evaluation of complex interventions. By exploring synergies and catalytic interactions related to a complex intervention or programme, we reveal the added value to planned activities and how they might be maximised. PMID- 26979460 TI - Cognitive and affective theory of mind in dementia with Lewy bodies and Alzheimer's disease. AB - BACKGROUND: Theory of mind (ToM) refers to the ability to attribute mental states, thoughts (cognitive component) or feelings (affective component) to others. This function has been studied in many neurodegenerative diseases; however, to our knowledge, no studies investigating ToM in dementia with Lewy bodies (DLB) have been published. The aim of our study was to assess ToM in patients with DLB and to search for neural correlates of potential deficits. METHODS: Thirty-three patients with DLB (DLB group) and 15 patients with Alzheimer's disease (AD group), all in the early stage of the disease, as well as 16 healthy elderly control subjects (HC group), were included in the study. After a global cognitive assessment, we used the Faux Pas Recognition (FPR) test, the Reading the Mind in the Eyes (RME) test and Ekman's Facial Emotion Recognition test to assess cognitive and affective components of ToM. Patients underwent cerebral 3-T magnetic resonance imaging, and atrophy of grey matter was analysed using voxel-based morphometry. We performed a one-sample t test to investigate the correlation between each ToM score and grey matter volume and a two-sample t test to compare patients with DLB impaired with those non-impaired for each test. RESULTS: The DLB group performed significantly worse than the HC group on the FPR test (P = 0.033) and the RME test (P = 0.015). There was no significant difference between the AD group and the HC group or between the DLB group and the AD group. Some brain regions were associated with ToM impairments. The prefrontal cortex, with the inferior frontal cortex and the orbitofrontal cortex, was the main region, but we also found correlations with the temporoparietal junction, the precuneus, the fusiform gyrus and the insula. CONCLUSIONS: This study is the first one to show early impairments of ToM in DLB. The two cognitive and affective components both appear to be affected in this disease. Among patients with ToM difficulties, we found atrophy in brain regions classically involved in ToM, which reinforces the neuronal network of ToM. Further studies are now needed to better understand the neural basis of such impairment. PMID- 26979464 TI - Government has no credible plan to plug NHS funding "black hole," MPs warn. PMID- 26979462 TI - Gene-based SNP discovery in tepary bean (Phaseolus acutifolius) and common bean (P. vulgaris) for diversity analysis and comparative mapping. AB - BACKGROUND: Common bean (Phaseolus vulgaris) is an important grain legume and there has been a recent resurgence in interest in its relative, tepary bean (P. acutifolius), owing to this species' ability to better withstand abiotic stresses. Genomic resources are scarce for this minor crop species and a better knowledge of the genome-level relationship between these two species would facilitate improvement in both. High-throughput genotyping has facilitated large scale single nucleotide polymorphism (SNP) identification leading to the development of molecular markers with associated sequence information that can be used to place them in the context of a full genome assembly. RESULTS: Transcript based SNPs were identified from six common bean and two tepary bean accessions and a subset were used to generate a 768-SNP Illumina GoldenGate assay for each species. The tepary bean assay was used to assess diversity in wild and cultivated tepary bean and to generate the first gene-based map of the tepary bean genome. Genotypic analyses of the diversity panel showed a clear separation between domesticated and cultivated tepary beans, two distinct groups within the domesticated types, and P. parvifolius was confirmed to be distinct. The genetic map of tepary bean was compared to the common bean genome assembly to demonstrate high levels of collinearity between the two species with differences limited to a few intra-chromosomal rearrangements. CONCLUSIONS: The development of the first set of genomic resources specifically for tepary bean has allowed for greater insight into the structure of this species and its relationship to its agriculturally more prominent relative, common bean. These resources will be helpful in the development of efficient breeding strategies for both species and will facilitate the introgression of agriculturally important traits from one crop into the other. PMID- 26979463 TI - Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting. AB - BACKGROUND: Extracellular vesicles (EVs) are attractive candidate drug delivery systems due to their ability to functionally transport biological cargo to recipient cells. However, the apparent lack of target cell specificity of exogenously administered EVs limits their therapeutic applicability. In this study, we propose a novel method to equip EVs with targeting properties, in order to improve their interaction with tumour cells. METHODS: EV producing cells were transfected with vectors encoding for anti-epidermal growth factor receptor (EGFR) nanobodies, which served as targeting ligands for tumour cells, fused to glycosylphosphatidylinositol (GPI) anchor signal peptides derived from decay accelerating factor (DAF). EVs were isolated using ultrafiltration/size-exclusion liquid chromatography and characterized using western blotting, Nanoparticle Tracking Analysis, and electron microscopy. EV-tumour cell interactions were analyzed under static conditions using flow cytometry and under flow conditions using a live-cell fluorescence microscopy-coupled perfusion system. RESULTS: EV analysis showed that GPI-linked nanobodies were successfully displayed on EV surfaces and were highly enriched in EVs compared with parent cells. Display of GPI-linked nanobodies on EVs did not alter general EV characteristics (i.e. morphology, size distribution and protein marker expression), but greatly improved EV binding to tumour cells dependent on EGFR density under static conditions. Moreover, nanobody-displaying EVs showed a significantly improved cell association to EGFR-expressing tumour cells under flow conditions. CONCLUSIONS: We show that nanobodies can be anchored on the surface of EVs via GPI, which alters their cell targeting behaviour. Furthermore, this study highlights GPI-anchoring as a new tool in the EV toolbox, which may be applied for EV display of a variety of proteins, such as antibodies, reporter proteins and signaling molecules. PMID- 26979465 TI - Role of anxiety and depression in adolescents with chest pain referred to a cardiology clinic. AB - BACKGROUND: We carried out this study in order to evaluate the causes of chest pain in teenagers and the role of anxiety and depression in this age group compared with the normal population. METHODS: In this prospective case-control study, all patients aged 11-18 years with chest pain and no history of trauma and referred to a paediatric cardiology clinic from March, 2009-April, 2010 were selected. A chest pain protocol including a detailed history, full physical examination, required blood tests, electrocardiography, and echocardiography was performed for all. The presence of depression and anxiety and their severity were assessed by Beck questionnaires. The patients were compared with age- and sex matched, randomly selected healthy controls. RESULTS: In total, 194 patients with a mean age of 14+/-2 years were selected. The most frequent presentation was idiopathic chest pain (43.3%), followed by the psychological group (29.9%). These groups had no abnormal points in history, physical, and para-clinical tests. Moderate-to-severe depression was found in 45.9% in the patients group, compared with 17.6% of controls, which was statistically significant (p=0.016). Moreover, anxiety was detected in 67.5% of patients versus 15.4% in controls, which is a statistically significant difference (p=0.009). Cardiac chest pain with 9.27% was the most common type of organic causes. CONCLUSION: Chest pain during teenage is more prevalent, but not risky. Undergoing a detailed history and full physical examination can help diagnose the causes in the majority of cases. Given the prevalence of a psychological group as well as role of anxiety and depression in most patients, referring to a psychiatrist is suggested. PMID- 26979466 TI - The BMJ editors respond. PMID- 26979467 TI - Assessment of structural, optical and conduction properties of ZnO thin films in the presence of acceptor impurities. AB - The structural, optical and electrical conduction properties of (Li/Cu,N):ZnO codoped thin films synthesized by the sol-gel method were investigated by field emission scanning electron microscopy (FESEM), x-ray diffraction (XRD), transmission and absorption, photoluminescence (PL) and I-V measurements in order to bring evidence of the formation of acceptor centers by dual-acceptor codoping processes. The (Li 3%,N 5%):ZnO films consist of crystallites with average size of 15 nm, show 95% transmission in the visible region, and an optical band gap of 3.22 eV. The PL spectra show emission maxima at 3.21 and 2.96 eV which are related to the emission of acceptor centers and the presence of defects, respectively. Li occupies interstitial sites and may form Lii-N(O) defect complexes that act as acceptor centers. The (Cu 3%,N 5%):ZnO films consist of crystallites with average size of 12 nm, and exhibit 90% transmission in the visible region. The PL spectra reveal band edge emission at 3.23 eV and defect related emission at 2.74 eV. In the (Cu,N) codoped films, copper substitutes zinc and adopts mainly the Cu(1+) state. A possible defect complex involving Cu and N determines the transition from n- to p-type conductivity. These findings are in agreement with results of electronic structure calculations at the GGA-PBE level. PMID- 26979469 TI - Out-of-hospital Cardiac Arrest Patient Characteristics: Comparing ventricular arrhythmia and Pulseless Electrical Activity. AB - BACKGROUND: The proportion of patients suffering out-of-hospital cardiac arrest presenting with ventricular arrhythmias/ventricular fibrillation (VT/VF) is decreasing, while the proportion presenting with pulseless electrical activity (PEA) is increasing. Cardiac arrest interventions target VT/VF and survival rates from PEA are much lower. The aim of this study was to compare clinical characteristics of those suffering PEA and VT/VF. METHODS: We examined the past medical history of all patients suffering cardiac arrest in the Wellington region between 2008-2012 and compared clinical features of those with PEA to VT/VF. RESULTS: We identified 749 cardiac arrests in the study period, and were able to obtain detailed medical histories in 735 (98%) cases. The presenting rhythm was VF/VT in 337 (46%) cases, PEA in 127 (17%), and asystole in 271 (37%). Patients with PEA were older (68+/-14 versus 63+/-15 years, p=0.003), a higher proportion were female (35% versus 22%, p=0.002) and were less likely to have prior cardiovascular disease than those with VT/VF (48% versus 59%, p=0.03). Respiratory disease was more common in those with PEA (35% versus 23%, p=0.008). CONCLUSION: The population suffering PEA differs from the VT/VF cohort in a number of ways, and PEA is associated with significantly worse outcomes. PMID- 26979468 TI - Electroanatomic Mapping and Transoesophageal Echocardiography for near Zero Fluoroscopy during Complex Left Atrial Ablation. AB - BACKGROUND: We evaluated Carto 3, transoesophageal echocardiography (TOE) and contact force (CF) sensing catheter in atrial fibrillation (AF) ablation. METHODS: Unselected consecutive ablations performed under general anaesthesia (GA) were studied with modified protocol (cases, n=11) and compared to retrospective consecutive controls (n=10). Patent foramen ovale (PFO) or single transseptal puncture enabled left atrial (LA) access; ablation strategy was stepwise approach. Modified protocol utilised right atrial (RA) electrograms, CF and TOE to localise SmartTouch and create RA and CS electroanatomic map (EAM) without fluoroscopy. Transseptal puncture was performed with fluoroscopy in absence of PFO. Fluoroless pulmonary vein and LA EAM was created using TOE to locate circular-mapping catheter. RESULTS: Mean age of cases was 57+/-11 years with 64% male compared with 60+/-11 (70% male) for controls. Patent foramen ovale was identified in four cases (36%) and two controls (20%). No early complications occurred. Shorter fluoroscopy time (median 36 vs 390seconds; p=0.038) and trend to lower radiation dose (median 17 vs 165 cGym2; p=0.053) was seen in cases, with no increase in total procedure time (p=0.438). CONCLUSIONS: General anaesthesia, TOE and CF mapping catheters facilitate minimised fluoroscopy for catheter ablation of LA arrhythmias. Zero fluoroscopy is possible in a majority of cases with PFO. PMID- 26979471 TI - Editorial overview: Viral immunology. PMID- 26979470 TI - No additional effect of different types of physical activity on 10-hour muscle protein synthesis in elderly men on a controlled energy- and protein-sufficient diet. AB - PURPOSE: The elderly lose skeletal muscle mass with age, which may be detrimental for function and quality of life. Both inactivity and heavy resistance exercise are known to have marked but opposite effects upon muscle mass. However, the potential effects of daily physical activity upon muscle protein synthesis (MPS) are less investigated. The aim of this study was to determine the effects of daily physical activities upon MPS in elderly individuals. METHODS: A total of 24 elderly men (70+/-1year) were recruited and randomly assigned: inactivity in form of bed-rest (IA), daily physical activities (DA), or heavy resistance exercise (RE). All groups undertook a normal eating routine containing carbohydrates (52 E%), fat (32 E%), and protein (16 E%). Ingestion of labeled milk protein ([1 (13)C]leucine-labeled whey and caseinate) served to maintain tracer enrichment for determination of 10-hour myofibrillar protein fractional synthesis rates (FSR), and typical prerequisites for calculating FSR were fulfilled. Physical activities were monitored, and venous blood and muscle biopsies collected. RESULTS: Physical activity was highest in the DA compared to both the IA and RE groups. Nutrient ingestion increased insulin, leucine, and phenylalanine plasma concentrations in all groups. [1-(13)C]leucine enrichment was stable throughout the 10-hour FSR period. Myofibrillar protein FSR were similar for IA, DA, and RE groups, 0.055+/-0.003%/h, 0.058+/-0.006%/h, and 0.065+/-0.008%/h, respectively (means+/-SE, P=0.44). CONCLUSIONS: In elderly males, inactivity, daily activities, and resistance exercise interventions result in equal 10-hour, whole day MPS during an energy- and protein-sufficient diet regimen. PMID- 26979472 TI - 2,3 Butanediol production in an obligate photoautotrophic cyanobacterium in dark conditions via diverse sugar consumption. AB - Cyanobacteria are under investigation as a means to utilize light energy to directly recycle CO2 into chemical compounds currently derived from petroleum. Any large-scale photosynthetic production scheme must rely on natural sunlight for energy, thereby limiting production time to only lighted hours during the day. Here, an obligate photoautotrophic cyanobacterium was engineered for enhanced production of 2,3-butanediol (23BD) in continuous light, 12h:12h light dark diurnal, and continuous dark conditions via supplementation with glucose or xylose. This study achieved 23BD production under diurnal conditions comparable to production under continuous light conditions. The maximum 23BD titer was 3.0gL(-1) in 10d. Also achieving chemical production under dark conditions, this work enhances the feasibility of using cyanobacteria as industrial chemical producing microbes. PMID- 26979474 TI - Training primary care physicians in cognitive behavioral therapy: A review of the literature. AB - OBJECTIVE: Patients often seek mental health treatment through primary care. Training primary care physicians (PCPs) in approaches to address common mental health concerns may be a useful method for narrowing gaps in care. Cognitive Behavioral Therapy (CBT) is especially applicable in medical settings given its brief, skill-based approach and strong evidence for a number of presenting problems. This paper reviews the current literature on training PCPs in CBT with a focus on PCP-level outcomes. METHODS: We reviewed studies that described and evaluated CBT training programs for PCPs. Of 652 records identified and screened, 33 full-text articles were assessed for eligibility, resulting in 9 articles identified for inclusion. RESULTS: We extracted and report information about study design, participants, intervention and dose, training content, and outcomes (PCP reaction, learning, and performance; patient outcomes). CONCLUSION: There was substantial variability in sample size, methodology, training content and design, and assessment of outcomes, which translated into mixed findings across studies. In order to best assess effectiveness and allow replicability, future studies should provide adequate information about training curricula and assess multiple levels of learning outcomes. PRACTICE IMPLICATIONS: Additional studies are needed to determine whether PCPs effectively implement skills within routine practice after CBT training. PMID- 26979473 TI - Establishment of a highly efficient virus-inducible CRISPR/Cas9 system in insect cells. AB - Although current antiviral strategies can inhibit baculovirus infection and decrease viral DNA replication to a certain extent, novel tools are required for specific and accurate elimination of baculovirus genomes from infected insects. Using the newly developed clustered regularly interspaced short palindromic repeats/associated protein 9 nuclease (CRISPR/Cas9) technology, we disrupted a viral genome in infected insect cells in vitro as a defense against viral infection. We optimized the CRISPR/Cas9 system to edit foreign and viral genome in insect cells. Using Bombyx mori nucleopolyhedrovirus (BmNPV) as a model, we found that the CRISPR/Cas9 system was capable of cleaving the replication key factor ie-1 in BmNPV thus effectively inhibiting virus proliferation. Furthermore, we constructed a virus-inducible CRISPR/Cas9 editing system, which minimized the probability of off-target effects and was rapidly activated after viral infection. This is the first report describing the application of the CRISPR/Cas9 system in insect antiviral research. Establishment of a highly efficient virus-inducible CRISPR/Cas9 system in insect cells provides insights to produce virus-resistant transgenic strains for future. PMID- 26979475 TI - Methods for using microblogs for health communication with a pharmacist-based account. AB - OBJECTIVE: To implement and assess the effectiveness of using microblogging for health communication with a pharmacist-based account. METHODS: We created a private and public "iPharmacist" account on the Weibo microblogging platform using the "Brief, Evidence-based, Ethical, and Plain-language (BEEP)" principle to post messages and to interact with patients. From November 2012 to November 2013, a content analysis was performed of the original microposts by iPharmacist, as well as original messages directed to iPharmacist by other accounts, and private messages received by iPharmacist. RESULTS: A total of 598 original messages were posted by iPharmacist, which were reposted 34442 times with 6013 comments received; while 310 messages were posted by other Weibo users directed to the iPharmacist alone with 131 private messages. CONCLUSIONS: The use of iPharmacist account allowed the provision of quality microposts to educate the Chinese public. The public messages were well disseminated. PRACTICE IMPLICATIONS: Microblogging could be an effective tool for patient education and health communication. PMID- 26979476 TI - Assessing patients' experiences with communication across the cancer care continuum. AB - OBJECTIVE: To evaluate the relevance, performance and potential usefulness of the Patient Assessment of cancer Communication Experiences (PACE) items. METHODS: Items focusing on specific communication goals related to exchanging information, fostering healing relationships, responding to emotions, making decisions, enabling self-management, and managing uncertainty were tested via a retrospective, cross-sectional survey of adults who had been diagnosed with cancer. Analyses examined response frequencies, inter-item correlations, and coefficient alpha. RESULTS: A total of 366 adults were included in the analyses. Relatively few selected Does Not Apply, suggesting that items tap relevant communication experiences. Ratings of whether specific communication goals were achieved were strongly correlated with overall ratings of communication, suggesting item content reflects important aspects of communication. Coefficient alpha was >=.90 for each item set, indicating excellent reliability. Variations in the percentage of respondents selecting the most positive response across items suggest results can identify strengths and weaknesses. CONCLUSION: The PACE items tap relevant, important aspects of communication during cancer care, and may be useful to cancer care teams desiring detailed feedback. PRACTICE IMPLICATIONS: The PACE is a new tool for eliciting patients' perspectives on communication during cancer care. It is freely available online for practitioners, researchers and others. PMID- 26979477 TI - A microporous silk carbon-ionic liquid composite for the electrochemical sensing of dopamine. AB - Porous silk carbon (Silk C) was obtained through carbonization and KOH activation of natural silk cocoons. The as-prepared Silk C presented the good characteristics of a large surface area (SBET: 2854.53 m(2) g(-1)) and a high volume of pores (1.54 cm(3) g(-1)) with uniform micropores (2.5 nm) and multiple defects. The metal-free silk carbon-ionic liquid (Silk C-IL) composite, synthesized by modifying Silk C with ionic liquid through non-covalent (pi-pi) interactions under grinding conditions, was prepared for electrochemical determination of dopamine (DA). The detection limit of DA was 79 nM (S/N = 3) with a linear range from 0.6 MUM to 140 MUM. Meanwhile, the as-made Silk C-IL/GCE presented good selectivity for DA detection from other possible interferences, such as ascorbic acid, glucose and uric acid. Furthermore, the Silk C-IL/GCE was also successfully used for the detection of DA in fetal bovine serum and dopamine hydrochloride injection samples. PMID- 26979478 TI - Increased Lipocalin-2 Contributes to the Pathogenesis of Psoriasis by Modulating Neutrophil Chemotaxis and Cytokine Secretion. AB - Psoriasis is characterized by resistance to infections, which is regulated by antimicrobial proteins. Whether antimicrobial proteins play a pathogenic role in psoriasis remains unclear. In this study, we aimed to elucidate the role of lipocalin-2 (Lcn2), an antimicrobial protein, in the pathogenesis of psoriasis. Our results showed that Lcn2 was highly expressed in the lesional skin of psoriatic patients. The neutralization of Lcn2 alleviated epidermal hyperplasia, inflammation, and especially neutrophil infiltration in an imiquimod-induced psoriasis-like murine model. In vitro, Lcn2 stimulated human neutrophils to produce vital proinflammatory mediators, such as IL-6, IL-8, tumor necrosis factor-alpha, and IL-1alpha via a specific receptor, 24p3R, on neutrophils, which consequently activated the downstream extracellular signal-regulated kinase-1/2 and p38-mitogen-activated protein kinase signaling pathways. Moreover, Lcn2 induced neutrophil chemotaxis was concentration dependent and mediated by the extracellular signal-regulated kinase-1/2 and p38-mitogen-activated protein kinase signaling pathways in vitro. Furthermore, we demonstrated that both keratinocytes and neutrophils were the sources of Lcn2 in the lesional skin of psoriatic patients. Taken together, these results suggest that Lcn2 is involved in the pathogenesis of psoriasis by modulating neutrophil function, and that it could serve as a potential target for treating psoriasis. PMID- 26979479 TI - Usefulness of Fragmented QRS Complex to Predict Arrhythmic Events and Cardiovascular Mortality in Patients With Noncompaction Cardiomyopathy. AB - We aimed to evaluate the prevalence and prognostic role of fragmented QRS complex (fQRS) in predicting arrhythmic events and cardiovascular mortality in patients with noncompaction cardiomyopathy (NCC). A total of 88 patients (64.8% men, mean age 38.6 +/- 17.7 years) with the diagnosis of NCC were enrolled. Median follow up time was 42.4 months. The fQRS was defined as the presence of >=1 additional R wave (R') or notch on the R/S waves in >=2 contiguous leads representing anterior (V1 to V5), inferior (II, III, and aVF), or lateral (I, aVL, and V6) myocardial segments. Compared to patients without fQRS group, patients with fQRS (fQRS (+) group) showed higher rates for total arrhythmic events, ventricular tachycardia, bradyarrhythmia requiring pacemaker, sudden cardiac death, cardiovascular mortality, and all-cause mortality. The cut-off point of >=3 leads for the fQRS was the optimal point discriminating an arrhythmic event and cardiovascular mortality. In Kaplan-Meier survival analysis, total arrhythmic events and cardiovascular mortality occurred more frequently in the fQRS (+) group. In multivariate Cox proportional hazard regression analysis, after adjusting for other confounding factors, the presence of fQRS were found to be as an independent predictor of arrhythmic events (hazard ratio 3.850, 95% CI 1.062 to 9.947, p = 0.002) and cardiovascular mortality (hazard ratio 2.719, 95% CI 1.494 to 9.262, p = 0.005). In conclusion, the presence of fQRS complex, as a simple and feasible electrocardiographic marker, seems to be a novel predictor of arrhythmic events and cardiovascular mortality in patients with NCC. This simple parameter may be used in identifying patients at high risk for arrhythmic events and so individualization of specific therapies can be applied. PMID- 26979480 TI - Low Young's modulus Ti-based porous bulk glassy alloy without cytotoxic elements. AB - A new a biocompatible Ti42Zr40Ta3Si15 (atomic %) porous bulk glassy alloy was produced by combination of rapid solidification and powder metallurgy techniques. Amorphous alloy ribbons were fabricated by melt spinning, i.e. extremely fast quenching the molten alloy with 10(6)K/s from T=1973K down to room temperature. The ribbons were then cryo-milled at liquid nitrogen temperature in order to produce powder, which was subsequently hot pressed. The resulting thick pellets have a porosity of about 14vol%, a high compression strength of 337MPa and a Young's modulus of about E=52GPa, values very close to those characteristic of cortical bone. Moreover, the morphology of the samples is very similar to that of cortical bone. The biocompatibility, which is due to the absence of any toxic element in the chemical composition, together with the suitable mechanical behavior, make these samples promising for orthopedic and dentistry applications. STATEMENT OF SIGNIFICANCE: Ti-based alloys are nowadays the standard solution for biomedical implants. However, both the conventional crystalline and amorphous alloys have higher rigidity as the human bone, leading to the damage of the bone at the interface, and contains harmful elements like vanadium, aluminum, nickel or beryllium. The hierarchical porous structures based on glassy alloys with biocompatible elements is a much better alternative. This work presents for the first time the manufacturing of such porous bodies starting from Ti-based amorphous alloy ribbons, which contains only non-harmful elements. The morphology and the compressive mechanical properties of these new products are analyzed in regard with those characteristic to the cortical bone. PMID- 26979481 TI - Testing the relation between percentage change and baseline value. AB - Testing the relation between percentage change and baseline value has been controversial, but it is not clear why this practice may yield spurious results. In this paper, we first explained why the usual testing of the relation between percentage change and baseline value is inappropriate and then demonstrated how the appropriate null hypothesis could be formulated. We also proposed a simple procedure for testing the appropriate null hypothesis based on the assumption that when there is no relation between percentage change and baseline value, the coefficients of variation for repeated measurements of a random variable should remain unchanged. Two examples were used to demonstrate how the usual testing gave rise to misleading results, whilst results from our simple test were in general consistent with those from simulations. We also undertook simulations to investigate the impact of measurement errors on the performance of the proposed test. Results suggested the type-I error rates increased with the magnitude of measurement errors, whilst the statistical power to detect a genuine relation decreased. The usual approach to testing the relation between percentage change and baseline value tended to yield misleading results and should be avoided. PMID- 26979482 TI - Erratum. AB - Erratum to Twelve-year follow-up of a randomized controlled trial of comprehensive physiotherapy following disc herniation operation Owing to errors made at SAGE, the name of one of the authors of the following article was printed incorrectly.Ebenbichler GR, Inschlag S, Pfluger V, et al. Twelve-year follow-up of a randomized controlled trial of comprehensive physiotherapy following disc herniation operation Clinical Rehabilitation 2015; 29: 548-560 DOI: 10.1177/0269215514552032. PMID- 26979483 TI - Effect of course length and corridor width on the 2-minute walk test performance in geriatric patients. AB - OBJECTIVE: To evaluate the effect of course length and corridor width on 2-minute walk test results in older adults. DESIGN: Cross-sectional and experimental study with different test conditions. SETTING: Geriatric rehabilitation clinic. SUBJECTS: A total of 21 patients (median age 81 years). MAIN MEASURES: Patients walked two minutes on a 20 m and 40 m course with a 2 m or 1 m corridor width and on a continuous course without any turning in a corridor of 2 m width, five walks in total. The distance traveled within the 2 minutes was recorded. RESULTS: Compared with the 20 m course length, median walking distances measured by the 2 minute walk test in a walk way 2 m broad were better on the continuous corridor without any turn (136.9 m vs. 129.3 m, p = 0.002) and on the 40 m course (131.8 m vs. 129.3 m, p = 0.003). Walking distance on a 20 m course length was longer in a corridor of 2 m width compared with the 1 m corridor width (129.3 m vs. 119.2 m, p = 0.005). The walking distance was not affected by corridor width on the 40 m course length. CONCLUSIONS: Performance of elderly patients on the 2-minute walk test is influenced by the width of the corridor and the length of the course used. PMID- 26979484 TI - Seroprevalence and risk factors of herpes simplex virus-2 among pregnant women attending antenatal care at health facilities in Wolaita zone, Ethiopia. AB - BACKGROUND: Herpes simplex virus type-2 is the common cause of genital ulcer disease worldwide. Genital herpes infection is a major concern in pregnancy due to the risk of neonatal transmission. METHOD: A Cross-sectional survey was conducted from December 2013 to September 2014 in randomly selected 28 health centers to assess the seroprevalence and risk factors of herpes simplex virus type-2 infection among pregnant women attending antenatal care in Wolaita zone, Southern Ethiopia. After taking written consent socio demographic, behavioral, obstetric history and family planning data along with blood samples were collected from 252 pregnant women using pre-structured questionnaire. Sera were tested using HerpeSelect-2 ELISA IgG. Data entry and analysis was done using Epi info 3.5.4 and SPSS 21.00 respectively. Binary logistic regression was performed to identify the risk factors associated with HSV-2 seropositivity. P-values less than 0.05 were considered statistically significant. RESULTS: The overall seroprevalence of HSV-2 infection was 32.1 % (81/252) among pregnant women in Wolaita zone. Independent predictors of HSV-2 infection includes daily laborer (AOR 1.293, 95 % CI: 1.033-1.739; p = 0.022), having one sexual partners (AOR 0.476, 95 % CI: 0 .250 -0.904; p = 0.023), history of STDs (AOR 2.822, 95 % CI: 1.50-5.289; p = 0.001) and use of contraceptive (AOR 2.602, 95 % CI: 1.407-4.812; p = 0.002). CONCLUSION: Overall seroprevalence of HSV-2 infection among pregnant women of Wolaita Zone is high. Awareness creation among high risk groups like women who have history of STD should be strengthened. Strengthening the quality of health service delivery and expansion of health service coverage is mandatory. PMID- 26979486 TI - Theory of mind as a predictor of maternal sensitivity in women with severe mental illness. AB - BACKGROUND: Research has shown that maternal mental illness can affect mother infant interactions with implications for infant outcomes. Severe and chronic mental illness (SMI), particularly schizophrenia, is associated with the greatest risk. Schizophrenia is also associated with impairments in attribution of mental states, 'theory of mind' (ToM). Recent attachment research has suggested that maternal mentalizing skills are strongly associated with attachment outcome in infants. To date, no research has explored the relationship between ToM and maternal sensitivity in mothers with SMI using standard tests of ToM. The present study was designed as an exploratory study in order to investigate this. METHOD: A total of 40 women with SMI in the postpartum period were administered a battery of ToM tasks and general neuropsychological tasks. The women were also filmed in an unstructured play session with their infants, which was coded for maternal sensitivity using the Crittenden CARE-Index. RESULTS: One ToM task, the Frith Happe Animations, predicted maternal sensitivity across all diagnoses. There was also an effect of diagnosis, with lower sensitivity observed in women with schizophrenia. ToM impairments did not fully explain the effect of diagnosis on sensitivity. Mothers of girls were rated as being more sensitive than mothers of boys. CONCLUSIONS: The results suggest that ToM is a significant predictor of maternal sensitivity across all mental health diagnoses, extending the results of studies focusing on healthy populations. Clinical interventions emphasizing the importance of understanding the perspective of the infant may enhance maternal sensitivity. PMID- 26979485 TI - Synthesis and biological evaluation of quinoline derivatives as potential anti prostate cancer agents and Pim-1 kinase inhibitors. AB - In this work, a series of quinoline derivatives were designed and synthesized as antitumor agents. Most quinolines showed potent anti-proliferative activity against human prostatic cancer PC-3 cell line. Among which, 9d, 9f and 9g were the most effective compounds with GI50 values of 2.60, 2.81 and 1.29 MUM, respectively. Structure-activity relationship analysis indicated that the secondary amine linked quinoline and pyridine ring played an important role in the anti-proliferative effects. Mechanistic studies revealed that 9g was a potential Pim-1 kinase inhibitor with abilities of cell cycle arrest and apoptosis induction. Considering of the increased activity of Pim-1 in prostate cancer, such compounds have potential to be developed as anti-prostate cancer agents. PMID- 26979488 TI - Fipronil application on rice paddy fields reduces densities of common skimmer and scarlet skimmer. AB - Several reports suggested that rice seedling nursery-box application of some systemic insecticides (neonicotinoids and fipronil) is the cause of the decline in dragonfly species noted since the 1990s in Japan. We conducted paddy mesocosm experiments to investigate the effect of the systemic insecticides clothianidin, fipronil and chlorantraniliprole on rice paddy field biological communities. Concentrations of all insecticides in the paddy water were reduced to the limit of detection within 3 months after application. However, residuals of these insecticides in the paddy soil were detected throughout the experimental period. Plankton species were affected by clothianidin and chlorantraniliprole right after the applications, but they recovered after the concentrations decreased. On the other hand, the effects of fipronil treatment, especially on Odonata, were larger than those of any other treatment. The number of adult dragonflies completing eclosion was severely decreased in the fipronil treatment. These results suggest that the accumulation of these insecticides in paddy soil reduces biodiversity by eliminating dragonfly nymphs, which occupy a high trophic level in paddy fields. PMID- 26979489 TI - Hydrothermal synthesis and characterization under dynamic conditions of cobalt oxide nanoparticles supported over magnesium oxide nano-plates. AB - A nano-catalyst comprised of oxidized Co NPs supported on MgO nano-plates was synthesized via a hydrothermal co-precipitation strategy and calcination in O2 and subsequently in H2 at 250 degrees C. Spectro-microscopy characterization was performed by scanning transmission electron microscopy, electron energy loss spectroscopy and scanning X-ray transmission microscopy. Surface measurements under H2 and H2 + CO atmospheres were obtained by ambient pressure X-ray photoelectron spectroscopy and in situ X-ray absorption spectroscopy in the 225 480 degrees C range. These measurements at the atomic and microscopic levels demonstrated that the oxidized Co nanoparticles uniformly decorated the MgO nano plates. The surfaces are enriched with Co, and with a mixture of Co(OH)2 and CoO under H2 and H2 + CO atmospheres. Under a H2 atmosphere, the outermost surfaces were composed of (lattice) O(2-), CO3(2-) and OH(-). No inorganic carbonates were observed in the bulk. Chemisorbed CO, likely on the oxidized Co surfaces, was observed at the expense of O(2-) under 300 mTorr H2 + CO (2 : 1) at 225 degrees C. Gas phase CO2 was detected under 32 Torr H2 + CO (2 : 1) at 225 degrees C upon prolonged reaction time, and was attributed to a surface chemical reaction between O(2-) and chemisorbed CO. Furthermore, sp(3) like carbon species were detected on the otherwise carbon free surface in H2 + CO, which remained on the surface under the subsequent reaction conditions. The formation of sp(3) like hydrocarbons was ascribed to a surface catalytic reaction between the chemisorbed CO and OH(-) as the apparent hydrogen source. PMID- 26979487 TI - Graviola inhibits hypoxia-induced NADPH oxidase activity in prostate cancer cells reducing their proliferation and clonogenicity. AB - Prostate cancer (PCa) is the leading malignancy among men. Importantly, this disease is mostly diagnosed at early stages offering a unique chemoprevention opportunity. Therefore, there is an urgent need to identify and target signaling molecules with higher expression/activity in prostate tumors and play critical role in PCa growth and progression. Here we report that NADPH oxidase (NOX) expression is directly associated with PCa progression in TRAMP mice, suggesting NOX as a potential chemoprevention target in controlling PCa. Accordingly, we assessed whether NOX activity in PCa cells could be inhibited by Graviola pulp extract (GPE) that contains unique acetogenins with strong anti-cancer effects. GPE (1-5 MUg/ml) treatment strongly inhibited the hypoxia-induced NOX activity in PCa cells (LNCaP, 22Rv1 and PC3) associated with a decrease in the expression of NOX catalytic and regulatory sub-units (NOX1, NOX2 and p47(phox)). Furthermore, GPE-mediated NOX inhibition was associated with a strong decrease in nuclear HIF 1alpha levels as well as reduction in the proliferative and clonogenic potential of PCa cells. More importantly, GPE treatment neither inhibited NOX activity nor showed any cytotoxicity against non-neoplastic prostate epithelial PWR-1E cells. Overall, these results suggest that GPE could be useful in the prevention of PCa progression via inhibiting NOX activity. PMID- 26979490 TI - A new lupane-type triterpenoid fatty acid ester and other isolates from Ophiorrhiza shendurunii. AB - A new pentacyclic triterpenoid fatty acid ester, lupan-20-ol-3(beta)-yl hexadecanoate (1), together with lupan-20-ol-3(beta)-yl acetate (2), olean-18-en 3(beta)-yl hexadecanoate (3), dotriacontanoic acid (4), stigmasterol (5), rubiadin (6), nonadecanoic acid (7), palmitic acid (8) and camptothecin (9) were isolated from the hexane and chloroform extracts of Ophiorrhiza shendurunii from South India. Structures of the isolates were determined by (1)H, (13)C, (13)C DEPT, (1)H-(1)H COSY, HMBC, HSQC, NOESY NMR, FT-IR, DART-MS, ESI-MS, alkaline hydrolysis, derivatisation, GC-MS and HPTLC analyses. O. shendurunii hexane and chloroform extracts showed significant activities against Candida albicans and Fusarium oxysporum. Compounds 1 to 3 showed only moderate antiyeast/antifungal activities. PMID- 26979492 TI - Unearthing the Theoretical Underpinnings of "Green Care" in Mental Health and Substance Misuse Care: Theoretical Underpinnings and Contemporary Clinical Examples. AB - The concept of "Green Care" can increasingly be found in mental health and addictions literature and some Psychiatric/Mental Health Nurses are practicing in facilities that base their approach on some or all of the underpinning theoretical elements of Green Care. However, Green Care is not yet widely considered to be part of mainstream psychiatry. Unearthing and articulating its theoretical underpinnings and clinical applications may further advance its legitimacy. Accordingly, this article identifies four principal theoretical elements of Green Care: Connectedness; Contact with Nature; Benefits of Exercise; and Occupation/Work as Therapeutic, each of which is explored and articulated by drawing on relevant literature. PMID- 26979491 TI - Evidence of surgical outcomes fluctuates over time: results from a cumulative meta-analysis of laparoscopic versus open appendectomy for acute appendicitis. AB - BACKGROUND: In surgical trials, complex variables such as equipment development and surgeons' learning curve are involved. The evidence obtained in these trials can thus fluctuate over time. We explored the stability of the evidence obtained during surgery by conducting a cumulative meta-analysis of randomized controlled trials for open and laparoscopic appendectomy. METHODS: We conducted a cumulative meta-analysis of randomized controlled trials comparing laparoscopic appendectomy with open appendectomy for acute appendicitis, a topic with the greatest number of trials in the gastroenterological surgical field. We searched the MEDLINE (PubMed), EMBASE, and CINAHL databases up to September 2014 and reviewed the bibliographies. Outcomes were the incidence of intra-abdominal abscess, incidence of wound infection, operative time, and length of hospital stay. We used the 95 % confidence interval (95 % CI) of effect size for the significance test. RESULTS: Sixty-four trials were included in this analysis. Of the 51 trials addressing intra-abdominal abscesses, our cumulative meta-analysis of trials published up to and including 2001 demonstrated statistical significance in favor of open appendectomy (cumulative odds ratio [OR] 2.35, 95 % CI 1.30-4.25). The effect size in favor of open procedures began to disappear after 2001, leading to an insignificant result with an overall cumulative OR of 1.32 (95 % CI 0.84-2.10) when laparoscopic appendectomy was compared with open appendectomy. CONCLUSIONS: The evidence regarding treatment effectiveness changed over time, after treatment effectiveness became significant in trials comparing laparoscopic and open appendectomy. Observing only the 95 % confidence interval of effect size from a meta-analysis may not provide conclusive results. PMID- 26979493 TI - Extraction, Enrichment, Solubilization, and Digestion Techniques for Membrane Proteomics. AB - The importance of membrane proteins in biological systems is indisputable; however, their amphipathic nature makes them difficult to analyze. In this study, the most popular techniques for extraction, enrichment, solubilization, and digestion are compared, resulting in an overall improved workflow for the insoluble portion of Saccharomyces cerevisiae cell lysate. Yeast cells were successfully lysed using a French press pressure cell at 20 000 psi, and resulting proteins were fractionated prior to digestion to reduce sample complexity. The proteins were best solubilized with the addition of ionic detergent sodium deoxycholate (1%) and through the application of high-frequency sonication prior to a tryptic digestion at 37 degrees C. Overall, the improved membrane proteomic workflow resulted in a 26% increase in membrane protein identifications for baker's yeast. In addition, more membrane protein identifications were unique to the improved protocol. When comparing membrane proteins that were identified in the improved protocol and the standard operating procedure (176 proteins), 93% of these proteins were present in greater abundance (higher intensity) when using the improved method. PMID- 26979494 TI - Transcriptome analysis of different developmental stages of amphioxus reveals dynamic changes of distinct classes of genes during development. AB - Vertebrates diverged from other chordates approximately 500 million years ago and have adopted several modifications of developmental processes. Amphioxus is widely used in evolutionary developmental biology research, such as on the basic patterning mechanisms involved in the chordate body plan and the origin of vertebrates. The fast development of next-generation sequencing has advanced knowledge of the genomic organization of amphioxus; however, many aspects of gene regulation during amphioxus development have not been fully characterized. In this study, we applied high-throughput sequencing on the transcriptomes of 13 developmental stages of Chinese amphioxus to gain a comprehensive understanding of transcriptional processes occurring from the fertilized egg to the adult stage. The expression levels of 3,423 genes were significantly changed (FDR <= 0.01). All of these genes were included in a clustering analysis, and enrichment of biological functions associated with these clusters was determined. Significant changes were observed in several important processes, including the down-regulation of the cell cycle and the up-regulation of translation. These results should build a foundation for identifying developmentally important genes, especially those regulatory factors involved in amphioxus development, and advance understanding of the developmental dynamics in vertebrates. PMID- 26979496 TI - The enduring impact of violence against children. AB - More than one billion children - half of all children in the world - are exposed to violence every year. The violence children are exposed to includes both direct experiences of physical, sexual, and emotional abuse, as well as indirectly witnessing violence in their homes, schools, and communities. What these various forms of violence share, based on a review of the literature, is their enduring potential for life-long consequences. These consequences include increases in the risks of injury, HIV, sexually transmitted infections, mental health problems, reproductive health problems, and non-communicable diseases, including cardiovascular disease, cancer, chronic lung disease, and diabetes. Studies addressing biologic underpinnings of such consequences demonstrate that violence associated toxic stress may cause damage to the nervous, endocrine, circulatory, musculo-skeletal, reproductive, respiratory, and immune systems. Furthermore, rigorous economic evaluations suggest that costs associated with the consequences of violence against children exceed $120 billion in the U.S. and account for up to 3.5% of the GDP in sub-regions of East Asia. The expanding literature confirming the mechanisms of consequences and the associated costs of violence against children has been accompanied by growing evidence on effective approaches to prevention. Moreover, the expanding evidence on prevention has been accompanied by a growing determination on the part of global leaders to accelerate action. Thus, as part of the Post-2015 Sustainable Development agenda, the UN has issued a call-to-action: to eliminate violence against children. This unprecedented UN call may foster new investments, to fuel new progress for protecting children around the world from violence and its preventable consequences. PMID- 26979495 TI - Bioinspired negatively charged calcium phosphate nanocarriers for cardiac delivery of MicroRNAs. AB - AIM: To develop biocompatible and bioresorbable negatively charged calcium phosphate nanoparticles (CaP-NPs) as an innovative therapeutic system for the delivery of bioactive molecules to the heart. MATERIALS & METHODS: CaP-NPs were synthesized via a straightforward one-pot biomineralization-inspired protocol employing citrate as a stabilizing agent and regulator of crystal growth. CaP-NPs were administered to cardiac cells in vitro and effects of treatments were assessed. CaP-NPs were administered in vivo and delivery of microRNAs was evaluated. RESULTS: CaP-NPs efficiently internalized into cardiomyocytes without promoting toxicity or interfering with any functional properties. CaP-NPs successfully encapsulated synthetic microRNAs, which were efficiently delivered into cardiac cells in vitro and in vivo. CONCLUSION: CaP-NPs are a safe and efficient drug-delivery system for potential therapeutic treatments of polarized cells such as cardiomyocytes. PMID- 26979499 TI - Gene expression: Buffering newly replicated DNA. PMID- 26979500 TI - RNA: Expanding the mRNA epitranscriptome. PMID- 26979497 TI - Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style. AB - Biologists have long been intrigued by the possibility that cells can change their identity, a phenomenon known as cellular plasticity. The discovery that terminally differentiated cells can be experimentally coaxed to become pluripotent has invigorated the field, and recent studies have demonstrated that changes in cell identity are not limited to the laboratory. Specifically, certain adult cells retain the capacity to de-differentiate or transdifferentiate under physiological conditions, as part of an organ's normal injury response. Recent studies have highlighted the extent to which cell plasticity contributes to tissue homeostasis, findings that have implications for cell-based therapy. PMID- 26979502 TI - Metabolomics: beyond biomarkers and towards mechanisms. AB - Metabolomics, which is the profiling of metabolites in biofluids, cells and tissues, is routinely applied as a tool for biomarker discovery. Owing to innovative developments in informatics and analytical technologies, and the integration of orthogonal biological approaches, it is now possible to expand metabolomic analyses to understand the systems-level effects of metabolites. Moreover, because of the inherent sensitivity of metabolomics, subtle alterations in biological pathways can be detected to provide insight into the mechanisms that underlie various physiological conditions and aberrant processes, including diseases. PMID- 26979505 TI - Sexual Violence Against Female and Male Children in the United Republic of Tanzania. AB - During a household survey in Tanzania, a nationally representative sample of females and males aged 13-24 years reported any experiences of sexual violence that occurred before the age of 18 years. The authors explore the prevalence, circumstances, and health outcomes associated with childhood sexual violence. The results suggest that violence against children in Tanzania is pervasive, with roughly three in 10 females and one in eight males experiencing some form of childhood sexual violence, and its health consequences are severe. Results are being used by the Tanzanian government to implement a National Plan of Action. PMID- 26979506 TI - Processing-Induced Electrically Active Defects in Black Silicon Nanowire Devices. AB - Silicon nanowires (Si NWs) are widely investigated nowadays for implementation in advanced energy conversion and storage devices, as well as many other possible applications. Black silicon (BSi)-NWs are dry etched NWs that merge the advantages related to low-dimensionality with the special industrial appeal connected to deep reactive ion etching (RIE). In fact, RIE is a well established technique in microelectronics manufacturing. However, RIE processing could affect the electrical properties of BSi-NWs by introducing deep states into their forbidden gap. This work applies deep level transient spectroscopy (DLTS) to identify electrically active deep levels and the associated defects in dry etched Si NW arrays. Besides, the successful fitting of DLTS spectra of BSi-NWs-based Schottky barrier diodes is an experimental confirmation that the same theoretical framework of dynamic electronic behavior of deep levels applies in bulk as well as in low dimensional structures like NWs, when quantum confinement conditions do not occur. This has been validated for deep levels associated with simple pointlike defects as well as for deep levels associated with defects with richer structures, whose dynamic electronic behavior implies a more complex picture. PMID- 26979504 TI - Tying malaria and microRNAs: from the biology to future diagnostic perspectives. AB - Symptoms caused by bacterial, viral and malarial infections usually overlap and aetiologic diagnosis is difficult. Patient management in low-resource countries with limited laboratory services has been based predominantly on clinical evaluation and syndromic approaches. However, such clinical assessment has limited accuracy both for identifying the likely aetiological cause and for the early recognition of patients who will progress to serious or fatal disease. Plasma-detectable biomarkers that rapidly and accurately diagnose severe infectious diseases could reduce morbidity and decrease the unnecessary use of usually scarce therapeutic drugs. The discovery of microRNAs (miRNAs) has opened exciting new avenues to identify blood biomarkers of organ-specific injury. This review assesses current knowledge on the relationship between malaria disease and miRNAs, and evaluates how future research might lead to the use of these small molecules for identifying patients with severe malaria disease and facilitate treatment decisions. PMID- 26979510 TI - Molecular-Scale Electronics: From Concept to Function. AB - Creating functional electrical circuits using individual or ensemble molecules, often termed as "molecular-scale electronics", not only meets the increasing technical demands of the miniaturization of traditional Si-based electronic devices, but also provides an ideal window of exploring the intrinsic properties of materials at the molecular level. This Review covers the major advances with the most general applicability and emphasizes new insights into the development of efficient platform methodologies for building reliable molecular electronic devices with desired functionalities through the combination of programmed bottom up self-assembly and sophisticated top-down device fabrication. First, we summarize a number of different approaches of forming molecular-scale junctions and discuss various experimental techniques for examining these nanoscale circuits in details. We then give a full introduction of characterization techniques and theoretical simulations for molecular electronics. Third, we highlight the major contributions and new concepts of integrating molecular functionalities into electrical circuits. Finally, we provide a critical discussion of limitations and main challenges that still exist for the development of molecular electronics. These analyses should be valuable for deeply understanding charge transport through molecular junctions, the device fabrication process, and the roadmap for future practical molecular electronics. PMID- 26979508 TI - Colchicine in addition to conventional therapy for pericarditis recurrence : An update meta-analysis. AB - BACKGROUND: Randomized controlled trials (RCTs) have investigated the use of colchicine and conventional therapy for reducing the recurrence of pericarditis in patients with acute pericarditis or post-pericardiotomy syndrome. However, the benefits of these treatments are variable. METHODS: Studies were retrieved from PubMed, the Cochrane Library, and the EMBASE database. RESULTS: We identified nine RCTs with 1832 patients and a mean follow-up of 13.1 months. Overall, colchicine therapy significantly decreased the risk of pericarditis recurrence (odds ratio, OR 0.42; 95 % confidence interval, CI 0.33-0.52; P < 0.001; I2 = 17.0 %). Colchicine therapy was associated with significantly lower rates of pericarditis-associated rehospitalization (OR 0.29; 95 % CI 0.16-0.53; P < 0.0001; I2 = 0.0 %) and persistence of symptoms (OR 0.29; 95 % CI, 0.21-0.41; P = 0.000; I2 = 0.0 %) at 72 h. Adverse events were higher in the colchicine group (relative risk, RR 1.48; 95 % CI, 1.06-2.07; P = 0.02; I2 = 0.0 %). Subgroup analysis showed that recurrence of pericarditis was significantly lower in the colchicine therapy group, irrespective of prednisone use and the cause of pericarditis. CONCLUSION: Colchicine significantly decreases the rate of pericarditis recurrence, regardless of prednisone use and the cause of pericarditis. Larger studies are needed to confirm this effect. PMID- 26979509 TI - [Thrombus aspiration in patients with acute myocardial infarction : Scientific evidence and guideline recommendations]. AB - Recent advances in percutaneous coronary intervention and antiplatelet therapy as well as faster door-to-balloon times have markedly improved the therapy of patients with acute myocardial infarction. However, impaired myocardial perfusion despite revascularization of the infarcted vessel remains an ongoing problem with high prognostic relevance. In initial clinical trials thrombus aspiration in addition to conventional percutaneous coronary intervention demonstrated benefits regarding coronary flow and myocardial perfusion and was therefore recommended in practice guidelines. These improvements in surrogate endpoints did not translate into a favorable clinical outcome in recent large-scale multicenter randomized trials investigating the routine use of thrombus aspiration in patients with acute myocardial infarction. Furthermore, an increased risk of stroke after thrombus aspiration raises safety concerns. Therefore, thrombus aspiration has been downgraded in the recent guideline updates. The current article reviews the evidence from clinical trials and the recommendations in practice guidelines regarding thrombus aspiration in acute myocardial infarction. PMID- 26979511 TI - Paenibacillus salinicaeni sp. nov., isolated from saline silt sample. AB - A novel facultatively anaerobic bacterium, designated strain LAM0A28(T), was isolated from a saline silt sample collected from the Chinese Sea of Death located in Suining city, Sichuan province, China. Cells of strain LAM0A28(T) were observed to be Gram-stain positive, motile, endospore-forming and straight-rod shaped. Strain LAM0A28(T) was found to be able to grow at 15-45 degrees C (optimum: 30-35 degrees C), pH 5.0-10.0 (optimum: 7.5) and 0-5 % NaCl (w/v) (optimum: 0.5 %). The 16S rRNA gene sequence similarity analysis showed that strain LAM0A28(T) is closely related to Paenibacillus jilunlii DSM 23019(T) (97.5 %) and Paenibacillus graminis DSM 15220(T) (97.2 %). The DNA-DNA hybridization values between the isolate and P. jilunlii DSM 23019(T), P. graminis DSM 15220(T) were 30.2 +/- 1.6 % and 44.7 +/- 2.1 %, respectively. The DNA G+C content was found to be 51.2 mol% as determined by the T m method. The major cellular fatty acids were identified as anteiso-C15:0, C16:0, iso-C16:0 and C14:0. The major isoprenoid quinone was identified as MK-7. The cell wall peptidoglycan was found to contain meso-diaminopimelic acid. The major polar lipids were found to be diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, two aminophospholipids and six unidentified lipids. Based on the phylogenetic, phenotypic and chemotaxonomic characteristics, strain LAM0A28(T) is concluded to represent a novel species within the genus Paenibacillus, for which the name Paenibacillus salinicaeni sp. nov. is proposed. The type strain is LAM0A28(T) (=ACCC 00741(T) = JCM 30850(T)). PMID- 26979507 TI - PX-RICS-deficient mice mimic autism spectrum disorder in Jacobsen syndrome through impaired GABAA receptor trafficking. AB - Jacobsen syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood. PX-RICS is located in the chromosomal region commonly deleted in JBS patients with autistic-like behaviour. Here we report that PX-RICS-deficient mice exhibit ASD-like social behaviours and ASD-related comorbidities. PX-RICS deficient neurons show reduced surface gamma-aminobutyric acid type A receptor (GABAAR) levels and impaired GABAAR-mediated synaptic transmission. PX-RICS, GABARAP and 14-3-3zeta/theta form an adaptor complex that interconnects GABAAR and dynein/dynactin, thereby facilitating GABAAR surface expression. ASD-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABAAR agonist. Our findings demonstrate a critical role of PX-RICS in cognition and suggest a causal link between PX-RICS deletion and ASD-like behaviour in JBS patients. PMID- 26979512 TI - Performance of the major semiempirical, ab initio, and DFT methods for isomerization enthalpies of linear to branched heptanes. AB - The gas phase standard state (298.15 K, 1 atm) isomerization enthalpy (Delta(isom)H degrees (g)) prediction performance of the major semiempirical, ab initio, and density functional levels of theory for environmentally relevant transformations was investigated using the linear to branched heptanes as a representative case study. The M062X density functional, MP2 (and higher) levels of Moller-Plesset perturbation theory, and the CBS and Gaussian-n composite methods are well suited for investigating the thermodynamic properties of environmentally interesting isomerizations, although the M062X functional may not be appropriate for all systems. Where large molecular systems prohibit the use of higher levels of theory, the PM6 and PDDG semiempirical methods may offer an appropriate computational cost-accuracy compromise. PMID- 26979513 TI - Process change evaluation framework for allogeneic cell therapies: impact on drug development and commercialization. AB - AIMS: Some allogeneic cell therapies requiring a high dose of cells for large indication groups demand a change in cell expansion technology, from planar units to microcarriers in single-use bioreactors for the market phase. The aim was to model the optimal timing for making this change. MATERIALS & METHODS: A development lifecycle cash flow framework was created to examine the implications of process changes to microcarrier cultures at different stages of a cell therapy's lifecycle. RESULTS: The analysis performed under assumptions used in the framework predicted that making this switch earlier in development is optimal from a total expected out-of-pocket cost perspective. From a risk-adjusted net present value view, switching at Phase I is economically competitive but a post approval switch can offer the highest risk-adjusted net present value as the cost of switching is offset by initial market penetration with planar technologies. CONCLUSION: The framework can facilitate early decision-making during process development. PMID- 26979515 TI - MoCps1 is important for conidiation, conidial morphology and virulence in Magnaporthe oryzae. AB - Conidia play important roles in primary and secondary infections of airborne fungal pathogens. In this study, an insertional mutant with reduced capacity for conidiation was isolated from the rice blast fungus Magnaporthe oryzae. The mutant has a T-DNA insertion that disrupts a gene named MoCPS1. The deduced MoCps1 protein contains three AMP-binding domains. Gene complementation and gene knockout assays confirmed that MoCPS1 is important for conidiation. Conidia produced by the MoCPS1 deletion mutants are much more slender and longer than those produced by the wild-type strain. The Mocps1 mutants are less efficient in both appressorial penetration and invasive growth of infection hyphae, resulting in attenuated virulence toward host plants. MoCPS1 is highly expressed in a mature appressorium. Interestingly, the expression levels of several genes related to conidiation and pathogenicity have been significantly altered in the MoCPS1 deletion mutants. Taken together, our results indicated that MoCPS1 is important for conidiogenesis, conidial morphogenesis, and pathogenesis in the rice blast fungus. PMID- 26979514 TI - Neuronal circuits and physiological roles of the basal ganglia in terms of transmitters, receptors and related disorders. AB - The authors have reviewed recent research advances in basal ganglia circuitry and function, as well as in related disorders from multidisciplinary perspectives derived from the results of morphological, electrophysiological, behavioral, biochemical and molecular biological studies. Based on their expertise in their respective fields, as denoted in the text, the authors discuss five distinct research topics, as follows: (1) area-specific dopamine receptor expression of astrocytes in basal ganglia, (2) the role of physiologically released dopamine in the striatum, (3) control of behavioral flexibility by striatal cholinergic interneurons, (4) regulation of phosphorylation states of DARPP-32 by protein phosphatases and (5) physiological perspective on deep brain stimulation with optogenetics and closed-loop control for ameliorating parkinsonism. PMID- 26979516 TI - The transcription factor GCN4 regulates PHM8 and alters triacylglycerol metabolism in Saccharomyces cerevisiae. AB - PHM8 is a very important enzyme in nonpolar lipid metabolism because of its role in triacylglycerol (TAG) biosynthesis under phosphate stress conditions. It is positively regulated by the PHO4 transcription factor under low phosphate conditions; however, its regulation has not been explored under normal physiological conditions. General control nonderepressible (GCN4), a basic leucine-zipper transcription factor activates the transcription of amino acids, purine biosynthesis genes and many stress response genes under various stress conditions. In this study, we demonstrate that the level of TAG is regulated by the transcription factor GCN4. GCN4 directly binds to its consensus recognition sequence (TGACTC) in the PHM8 promoter and controls its expression. The analysis of cells expressing the P PHM8 -lacZ reporter gene showed that mutations (TGACTC GGGCCC) in the GCN4-binding sequence caused a significant increase in beta galactosidase activity. Mutation in the GCN4 binding sequence causes an increase in PHM8 expression, lysophosphatidic acid phosphatase activity and TAG level. PHM8, in conjunction with DGA1, a mono- and diacylglycerol transferase, controls the level of TAG. These results revealed that GCN4 negatively regulates PHM8 and that deletion of GCN4 causes de-repression of PHM8, which is responsible for the increased TAG content in gcn4? cells. PMID- 26979517 TI - Potential movement of transposable elements through DNA circularization. AB - The generation of circular DNAs is a relatively unrecognized type of genomic structural variation, but recent findings point to a possible role of circular DNAs in the movement of transposable elements. Circularization of genomic DNA is observed across eukaryotic species, in a range of different cell types, and from all parts of the genome. A recent study on circular DNAs in yeast found that transposable element sequence residing in circular structures mostly corresponded to full-length transposable elements. Transposable elements are mobile genetic elements scattered across eukaryotic genomes. Different classes of transposable elements move either through a copy-and-paste or a cut-and-paste. As circular DNA structures may recombine with the genome and re-integrate into a novel genomic locus, transposable elements could move through circularization. In yeast, the predominant type of transposable element is a so-called LTR (long terminal repeats) retrotransposable element that moves through a copy-and-paste mechanism. The observed circularization of this element means it potentially could move through a cut-and-paste mechanism as well. Although further experimental evidence is needed to establish the extent to which movement of transposable elements through DNA circularization takes place, such movement is likely to have a functional impact on the genomic context. PMID- 26979518 TI - Identification of a Tsal152-75 salivary synthetic peptide to monitor cattle exposure to tsetse flies. AB - BACKGROUND: The saliva of tsetse flies contains a cocktail of bioactive molecules inducing specific antibody responses in hosts exposed to bites. We have previously shown that an indirect-ELISA test using whole salivary extracts from Glossina morsitans submorsitans was able to discriminate between (i) cattle from tsetse infested and tsetse free areas and (ii) animals experimentally exposed to low or high numbers of tsetse flies. In the present study, our aim was to identify specific salivary synthetic peptides that could be used to develop simple immunoassays to measure cattle exposure to tsetse flies. METHODS: In a first step, 2D-electrophoresis immunoblotting, using sera from animals exposed to a variety of bloodsucking arthropods, was performed to identify specific salivary proteins recognised in cattle exposed to tsetse bites. Linear epitope prediction software and Blast analysis were then used to design synthetic peptides within the identified salivary proteins. Finally, candidate peptides were tested by indirect-ELISA on serum samples from tsetse infested and tsetse free areas, and from exposure experiments. RESULTS: The combined immunoblotting and bioinformatics analyses led to the identification of five peptides carrying putative linear epitopes within two salivary proteins: the tsetse salivary gland protein 1 (Tsal1) and the Salivary Secreted Adenosine (SSA). Of these, two were synthesised and tested further based on the absence of sequence homology with other arthropods or pathogen species. IgG responses to the Tsal152-75 synthetic peptide were shown to be specific of tsetse exposure in both naturally and experimentally exposed hosts. Nevertheless, anti-Tsal152-75 IgG responses were absent in animals exposed to high tsetse biting rates. CONCLUSIONS: These results suggest that Tsal152-75 specific antibodies represent a biomarker of low cattle exposure to tsetse fly. These results are discussed in the light of the other available tsetse saliva based-immunoassays and in the perspective of developing a simple serological tool for tsetse eradication campaigns to assess the tsetse free status or to detect tsetse reemergence in previously cleared areas. PMID- 26979519 TI - Emergency Department Visits for Homelessness or Inadequate Housing in New York City before and after Hurricane Sandy. AB - Hurricane Sandy struck New York City on October 29, 2012, causing not only a large amount of physical damage, but also straining people's health and disrupting health care services throughout the city. In prior research, we determined that emergency department (ED) visits from the most vulnerable hurricane evacuation flood zones in New York City increased after Hurricane Sandy for several medical diagnoses, but also for the diagnosis of homelessness. In the current study, we aimed to further explore this increase in ED visits for homelessness after Hurricane Sandy's landfall. We performed an observational before-and-after study using an all-payer claims database of ED visits in New York City to compare the demographic characteristics, insurance status, geographic distribution, and health conditions of ED patients with a primary or secondary ICD-9 diagnosis of homelessness or inadequate housing in the first week after Hurricane Sandy's landfall versus the baseline weekly average in 2012 prior to Hurricane Sandy. We found statistically significant increases in ED visits for diagnosis codes of homelessness or inadequate housing in the week after Hurricane Sandy's landfall. Those accessing the ED for homelessness or inadequate housing were more often elderly and insured by Medicare after versus before the hurricane. Secondary diagnoses among those with a primary ED diagnosis of homelessness or inadequate housing also differed after versus before Hurricane Sandy. These observed differences in the demographic, insurance, and co-existing diagnosis profiles of those with an ED diagnosis of homelessness or inadequate housing before and after Hurricane Sandy suggest that a new population cohort potentially including those who had lost their homes as a result of storm damage was accessing the ED for homelessness or other housing issues after the hurricane. Emergency departments may serve important public health and disaster response roles after a hurricane, particularly for people who are homeless or lack adequate housing. Further, tracking ED visits for homelessness may represent a novel surveillance mechanism to assess post-disaster infrastructure impact and to prepare for future disasters. PMID- 26979520 TI - The effect of dipyridamole on the pharmacokinetics of metformin: a randomized crossover study in healthy volunteers. AB - PURPOSE: Concomitant treatment with the glucose-lowering drug metformin and the platelet aggregation inhibitor dipyridamole often occurs in patients with type 2 diabetes mellitus who have suffered a cerebrovascular event. The gastrointestinal uptake of metformin is mediated by the human equilibrative nucleoside transporter 4 (ENT4), which is inhibited by dipyridamole in preclinical studies. We hypothesized that dipyridamole lowers the plasma exposure to metformin. METHODS: Eighteen healthy volunteers (mean age 23 years; 9 male) were randomized in an open-label crossover study. Subjects were allocated to treatment with metformin 500 mg twice daily in combination with dipyridamole slow-release 200 mg twice daily or to metformin alone for 4 days. After a washout period of 10 days, the volunteers were crossed over to the alternative treatment arm. Blood samples were collected during a 10-h period after intake of the last metformin dose. The primary endpoint was the area under the plasma concentration-time curve (AUC0 12h) and the maximum plasma metformin concentration (C max). RESULTS: In healthy subjects, dipyridamole did not significantly affect Cmax nor AUC0-12h of metformin under steady-state conditions. CONCLUSIONS: Previous in vitro studies report that dipyridamole inhibits the ENT4 transporter that mediates gastrointestinal uptake of metformin. In contrast, co-administration of dipyridamole at therapeutic dosages to healthy volunteers does not have a clinically relevant effect on metformin plasma steady-state exposure. This observation is reassuring for patients who are treated with this combination of drugs. PMID- 26979521 TI - Processing fragile matter: effect of polymer graft modification on the mechanical properties and processibility of (nano-) particulate solids. AB - The effect of polymer modification on the deformation characteristics and processibility of particle assembly structures is analyzed as a function of particle size and degree of polymerization of surface-tethered chains. A pronounced increase of the fracture toughness (by approximately one order of magnitude) is observed as the degree of polymerization exceeds a threshold value that increases with particle size. The threshold value is interpreted as being related to the transition of tethered chains from stretched-to-relaxed conformation (and the associated entanglement of tethered chains) and agrees with predictions from scaling theory. The increase in toughness is reduced with increasing particle size - this effect is rationalized as a consequence of the decrease of entanglement density with increasing dimension of interstitial (void) space in particle array structures. The increased fracture toughness of particle brush materials (with sufficient degree of polymerization of tethered chains) enables the fabrication of ordered colloidal films and even complex 3D shapes by scalable polymer processing techniques, such as spin coating and micromolding. The results, therefore, suggest new opportunities for the processing of colloidal material systems that could find application in the economical fabrication of functional components or systems compromised of colloidal materials. PMID- 26979522 TI - Neuregulin-1beta promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes. AB - Nrg1beta is critically involved in cardiac development and also maintains function of the adult heart. Studies conducted in animal models showed that it improves cardiac performance under a range of pathological conditions, which led to its introduction in clinical trials to treat heart failure. Recent work also implicated Nrg1beta in the regenerative potential of neonatal and adult hearts. The molecular mechanisms whereby Nrg1beta acts in cardiac cells are still poorly understood. In the present study, we analyzed the effects of Nrg1beta on glucose uptake in neonatal rat ventricular myocytes and investigated to what extent mTOR/Akt signaling pathways are implicated. We show that Nrg1beta enhances glucose uptake in cardiomyocytes as efficiently as IGF-I and insulin. Nrg1beta causes phosphorylation of ErbB2 and ErbB4 and rapidly induces the phosphorylation of FAK (Tyr(861)), Akt (Thr(308) and Ser(473)), and its effector AS160 (Thr(642)). Knockdown of ErbB2 or ErbB4 reduces Akt phosphorylation and blocks the glucose uptake. The Akt inhibitor VIII and the PI3K inhibitors LY-294002 and Byl-719 abolish Nrg1beta-induced phosphorylation and glucose uptake. Finally, specific mTORC2 inactivation after knockdown of rictor blocks the Nrg1beta induced increases in Akt-p-Ser(473) but does not modify AS160-p-Thr(642) or the glucose uptake responses to Nrg1beta. In conclusion, our study demonstrates that Nrg1beta enhances glucose uptake in cardiomyocytes via ErbB2/ErbB4 heterodimers, PI3Kalpha, and Akt. Furthermore, although Nrg1beta activates mTORC2, the resulting Akt-Ser(473) phosphorylation is not essential for glucose uptake induction. These new insights into pathways whereby Nrg1beta regulates glucose uptake in cardiomyocytes may contribute to the understanding of its regenerative capacity and protective function in heart failure. PMID- 26979525 TI - Extract of Ginkgo biloba for Tardive Dyskinesia: Meta-analysis of Randomized Controlled Trials. AB - OBJECTIVE: Free radicals may be involved in the pathogenesis of tardive dyskinesia (TD). We conducted this meta-analysis to systematically examine the efficacy of extract of Ginkgo biloba (EGb), a potent antioxidant possessing free radical-scavenging properties, as a treatment for TD in schizophrenia using randomized controlled trial (RCT) data. METHOD: Drawn from English and Chinese databases, 3 RCTs of EGb augmentation of antipsychotics (APs) vs. AP plus placebo or AP monotherapy were identified. 2 evaluators extracted data. The primary outcome measure was the severity of TD symptoms assessed by the Abnormal Involuntary Movement Scale (AIMS). Weighted mean difference (WMD) and risk ratio (RR) +/-95% confidence intervals (CI) were calculated. Statistical analyses were performed using Review Manager (version 5.1.7.0) and STATA (version 12.0). RESULTS: The 3 RCTs (n=299) from China, of 12 weeks duration, involved schizophrenia patients with TD of 55.9+/-13.4 years old. EGb (240 mg/day) outperformed the control group in reducing the severity of TD and clinical symptoms as measured by the AIMS (trials=3, n=299, WMD: -2.30 (95%CI: - 3.04, 1.55), P<0.00001) and the adverse drug reactions as assessed by the Treatment Emergent Symptom Scale (TESS) (trials=2, n=142, WMD: -2.38 (95%CI: -4.01, -0.74), P=0.004). Both the Positive and Negative Syndrome Scale (PANSS) total score (trials=2, n=239, P=0.87) and all-cause discontinuation (trials=3, n=299, P=0.21) were similar between the EGb and control group. CONCLUSION: This meta-analysis suggests that adjunctive EGb appeared to be an effective and safe option for improving TD in the treatment of schizophrenia patients. However, better RCTs are needed to demonstrate its efficacy and safety especially on cognitive function in TD. TRIAL REGISTRATION: PROSPERO: CRD42015024930. PMID- 26979523 TI - The incretin effect in obese adolescents with and without type 2 diabetes: impaired or intact? AB - The incretin effect reflects the actions of enteral stimuli to promote prandial insulin secretion. Impairment of this measure has been proposed as an early marker of beta-cell dysfunction and described in T2D, IGT, and even obesity without IGT. We sought to determine the effects of obesity and diabetes on the incretin effect in young subjects with short exposures to metabolic abnormalities and a few other confounding medical conditions. Subjects with T2D (n = 10; 18.0 +/- 0.4 yr) or NGT, either obese (n = 11; 17.7 +/- 0.4 yr) or lean (n = 8; 26.5 +/- 2.3 yr), had OGTT and iso-iv. The incretin effect was calculated as the difference in insulin secretion during these tests and was decreased ~50% in both the NGT-Ob and T2D subjects relative to the NGT-Ln group. The T2D group had impaired glucose tolerance and insulin secretion during the OGTT, whereas the lean and obese NGT subjects had comparable glucose excursions and beta-cell function. During the iso-iv test, the NGT-Ob subjects had significantly greater insulin secretion than the NGT-Ln and T2D groups. These findings demonstrate that in young subjects with early, well-controlled T2D the incretin effect is reduced, similar to what has been described in diabetic adults. The lower incretin effect calculated for the obese subjects with NGT is driven by a disproportionately greater insulin response to iv glucose and does not affect postprandial glucose regulation. These findings confirm that the incretin effect is an early marker of impaired insulin secretion in persons with abnormal glucose tolerance but suggest that in obese subjects with NGT the incretin effect calculation can be confounded by exaggerated insulin secretion to iv glucose. PMID- 26979524 TI - Validity of proposed DSM-5 ADHD impulsivity symptoms in children. AB - The American Psychiatric Association (APA) working group on Attention Deficit/Hyperactivity Disorder (ADHD) proposed the inclusion of four new impulsivity symptoms. However, they were not included in DSM-5 due to the lack of sufficient evidence. The aim of this study is to investigate the performance of the proposed four ADHD impulsivity symptoms with respect to: (a) ADHD factor structure; (b) performance in predicting clinical impairment; (c) specificity for ADHD diagnosis and (d) best symptomatic threshold to predict clinical impairment. The sample comprised 416 children (31 ADHD subjects according to both DSM-IV and proposed DSM-5, 20 ADHD subjects according to just one diagnostic system and 365 controls) from 12 schools. Diagnoses were derived using semi-structured interviews and ADHD rating scales. Results from confirmatory factor analysis indicate that addition of the four new impulsivity items provided a slightly better factor structure if compared to models including only 18 items. Regression analyses showed that only one of the new impulsivity symptoms (impatient) was part of the list of best predictors of impairment. None of the four new impulsivity items was specifically associated with ADHD diagnosis. The best cutoff point in the hyperactivity/impulsivity dimension for predicting impairment did not change significantly. Overall, our findings suggest that the determination on how to best capture impulsivity dimension as part of the ADHD construct needs more investigation and that there is not enough evidence to include these four assessed impulsivity symptoms as part of the ADHD criteria. PMID- 26979527 TI - Afamelanotide: A Review in Erythropoietic Protoporphyria. AB - Afamelanotide (SCENESSE((r))) is a synthetic alpha-melanocyte stimulating hormone analogue and first-in-class melanocortin-1 receptor agonist that is approved in the EU for the prevention of phototoxicity in adults with erythropoietic protoporphyria (EPP). It is administered subcutaneously as a biodegradable, controlled-release implant containing 16 mg of afamelanotide. This article reviews the clinical efficacy and tolerability of afamelanotide in EPP and summarizes its pharmacological properties. In the phase III trial, CUV039, afamelanotide treatment improved light tolerance in patients with EPP. Compared with placebo, afamelanotide treatment enabled patients to spend more time in direct sunlight without pain and increased the time to the appearance of the first symptoms of phototoxicity provoked by a standardized light source. Afamelanotide was generally well tolerated in this trial, with no drug-related serious adverse events reported. Commonly occurring adverse reactions included headache and implant-site reactions. Efficacy and safety data from earlier phase III trials are consistent with those from the CUV039 trial. Afamelanotide, approved in the EU for the prevention of EPP phototoxicity, represents a useful addition to the management of the disorder. PMID- 26979526 TI - Diet-induced obesity and prenatal undernutrition lead to differential neuroendocrine gene expression in the hypothalamic arcuate nuclei. AB - Previously we reported that prenatal undernutrition (UN) leads to a dysregulation of appetite suppression through alterations in hypothalamic neuropeptide gene expression. In the current study, we expand our observations and investigate neuroendocrine transcriptional responses and central leptin sensitivity within the arcuate nucleus of rats exposed to prenatal UN or a postnatal high-fat diet (HF). Pregnant Wistar rats were fed a standard chow diet either ad libitum (AD) or at 30 % of AD intake throughout gestation (UN) resulting in either control or intrauterine growth-restricted female offspring. At weaning, AD offspring were fed either a chow (C) or a HF (30 % fat wt/wt) diet ad libitum for the remainder of the study, whereas UN offspring were fed a chow diet only. At ~142 days, AD and UN offspring received either recombinant rat leptin (L) or saline (S) subcutaneously for 14 days. Prenatal UN had a significant effect on hypothalamic NPY (P < 0.0001), AgRP (P < 0.01) and ObRb (P < 0.02) mRNA expression compared to AD chow-fed offspring. A postnatal HF diet had a significant effect on AgRP mRNA expression (P < 0.001), compared to AD chow-fed offspring, but no effect on NPY and ObRb expression. Leptin treatment, in both UN and HF offspring, was ineffective in reducing NPY and AgRP mRNA expression, and had no effect on ObRb expression. These findings suggest that prenatal UN and a postnatal HF diet lead to differential neuroendocrine gene expression in the hypothalamic arcuate nuclei and reduced sensitivity to leptin's anorexigenic effects. PMID- 26979528 TI - Disease-specific clinical trials networks: the example of cystic fibrosis. AB - This article describes the steps of the development and the structure of a disease-specific clinical trials network for cystic fibrosis in Europe. Activities such as reviewing study protocols, feasibility assessments, training and standardizing of procedures, and outcome measurements help to bring high quality clinical trials to the patients. Cooperation with the pharmaceutical industry, other research networks, patient organizations, and regulatory agencies is very important throughout all activities. CONCLUSION: The European Cystic Fibrosis Society-Clinical Trials Network facilitates the development of new treatments for a rare disease and could be a prototype for other diseases. WHAT IS KNOWN: * Clinical research has led to the first approved treatments targeting the basic Cystic Fibrosis defect. * For a rare disease like Cystic Fibrosis, multicenter international collaboration is needed to obtain solid evidence when testing possible new treatments. What is New: * The Clinical Trials Network established by the European Cystic Fibrosis Society has grown to a fully operational network with well-defined structures, procedures and partnerships. * Standardization of outcome parameters, protocol review, feasibility assessment and other activities help to develop high quality, efficient, relevant and feasible clinical trials, with the aim to bring new treatments to the patients. PMID- 26979529 TI - More than fetal urine: enteral uptake of amniotic fluid as a major predictor for fetal growth during late gestation. AB - The purpose of our study was to investigate the importance of amniotic fluid (AF) for fetal growth during late gestation using esophageal atresia (EA) patients as a model. In this retrospective cohort study, we compared the z-scores adapted for birth weights (BW z-scores) for each of 517 European newborns with congenital pre gastric intestinal atresia, i.e., EA, to a European reference population. To account for the influence of the intestinal atresia on fetal growth per se, we compared adapted birth weights for each of 504 European newborns with post colonic intestinal atresia (anorectal malformation (ARM) with atresia of the anus) to the same European reference population. Analysis of the complete cohort showed (i) a significantly higher rate of small for gestational age newborns among EA compared to ARM newborns (p < 0.001) and (ii) significantly lower BW z scores among EA compared to ARM newborns (p < 0.001). BW z-scores of EA newborns were significantly lower in term compared to preterm newborns with an inverse correlation with gestational age (GA) (Spearman correlation coefficient, r = 0.185, p < 0.001). CONCLUSIONS: Enteral uptake of AF seems to play a pivotal role in fetal growth during late gestation. WHAT IS KNOWN: * Peak velocity of fetal weight gain occurs at 33 weeks of gestation and continues until birth. During this period, fetal growth is mainly characterized by cellular hypertrophy. * Amniotic fluid (AF) comprises large amounts of hormones and growth regulators. What is New: * A significantly higher rate of small for gestational age and lower birth weights and z-scores are observed among newborn infants with congenital pre gastric intestinal atresia. * These findings suggest that enteral uptake of AF is a major predictor for fetal growth during late gestation. PMID- 26979530 TI - Elevated ratio of MMP2/MMP9 activity is associated with poor response to chemotherapy in osteosarcoma. AB - BACKGROUND: Matrix metalloproteinases (MMPs) are crucially involved in the regulation of multiple stages of cancer progression. Elevated MMP levels have been associated with the development of metastases and poor prognosis in several types of cancer. However, the role of MMPs in osteosarcoma and their prognostic value is still unclear. Available data are conflicting, most likely due to different technical approaches. We hypothesized that in contrast to total mRNA or protein levels frequently analyzed in previous studies the enzymatic activities of MMPs and their inhibitors the tissue inhibitors of matrix metalloproteinases (TIMPs) are closer related to their biological functions. We therefore aimed to evaluate the reliability of different zymography techniques for the quantification of MMP and TIMP activities in osteosarcoma biopsies in order to investigate their distribution, possible regulation and prognostic value. METHODS: All analyses were done using cryo-conserved osteosarcoma pretreatment biopsies (n = 18). Gene and protein expression of MMPs and TIMPs were analyzed by RT-qPCR and western blot analysis, respectively. Overall MMP activity was analyzed by in situ zymography, individual MMP activities were analyzed by gelatin zymography. Reverse zymography was used to detect and quantify TIMP activities. RESULTS: Strong overall MMP activities could be detected in osteosarcoma pretreatment biopsies with MMP2 and MMP9 as predominant active MMPs. In contrast to total RNA or protein expression MMP2 and MMP9 activities showed significant quantitative differences between good and poor responders. While MMP9 activity was high in the good responder group and significantly decreased in the poor responder group, MMP2 activity showed a reverse distribution. Likewise, significant differences were detected concerning the activity of TIMPs resulting in a negative correlation of TIMP1 activity with MMP2 activity (p = 0.044) and negative correlations of TIMP2 and TIMP3 with MMP9 activity (p = 0.007 and p = 0.006). CONCLUSION: In contrast to mRNA or protein levels MMP and TIMP activities showed significant differences between the analyzed good and poor responder groups. A shift from MMP9 to predominant MMP2 activity is associated with poor response to chemotherapy suggesting that the ratio of MMP2/MMP9 activity might be a valuable and easily accessible marker to predict the response to chemotherapy in osteosarcoma. PMID- 26979531 TI - Barriers and facilitators of dental service utilization by children aged 8 to 11 years in Enugu State, Nigeria. AB - BACKGROUND: Multiple factors influence a child's ability to access oral health care. The aim of this study was to identify factors that facilitated and served as barriers to children's utilization of oral health care services in Enugu, Nigeria. METHODS: The study recruited 1406 primary school pupils aged 8 to 11 years. All the children received oral health education, with the aid of an oral health education curriculum appropriate for their age. After this, referral letters were given to the children. Twelve months later, the study participants were revisited in their schools to obtain information on their reasons for utilizing, or not utilizing an oral health care service in the last 12 months. The association between socio-economic status; form of parenthood; number of siblings, birth rank and reasons for utilization and non-utilization of dental services were assessed. Influence on the child's predisposition to oral health service utilization on dental visit was also assessed. RESULTS: Only 116 (14.7 %) of the 791 children accessible during the 12 months follow-up visit had visited the dental clinic and the main reason for utilization was the desire to fulfill the dentist's request for dental visit (41.9 %) while parents' inability to make out time for a dental visit (43.3 %) was the main reason for non-utilization. The odds of utilizing oral health care services for study participants from the middle (AOR: 0.50; CI: 0.31-0.79; P = 0.003) and low (AOR: 0.24; CI: 0.13-0.45; p = <0.001) socioeconomic strata, and those living with guardians/relatives (AOR: 0.08; CI: 0.01-0.60; p = 0.01) were decreased when compared to those living with both parents, respectively. Respondents with positive perception about dental service utilization had increased odds of utilizing oral health care (AOR: 2.96; CI: 1.48-5.90; p = 0.002). CONCLUSION: Dentists can be strong motivators for children to utilize oral health care. Time is a significant barrier for the utilization of dental services. The programs designed to address barriers to oral health care utilization for children should be geared towards overcoming the possible threats that socio-economic status and type of parents they have may pose, to reduce inequity in dental service utilization. PMID- 26979532 TI - Trends and determinants of discretionary salt use: National Health and Nutrition Examination Survey 2003-2012. AB - OBJECTIVE: To examine temporal trends and determinants of discretionary salt use in the USA. DESIGN: Multiple logistic regression was used to assess temporal trends in discretionary salt use at the table and during home cooking/preparation, adjusting for demographic characteristics, using data from the National Health and Nutrition Examination Survey 2003-2012. Prevalence and determinants of discretionary salt use in 2009-2012 were also examined. SETTING: Participants answered salt use questions after completing a 24 h dietary recall in a mobile examination centre. SUBJECTS: Nationally representative sample of non institutionalized US children and adults, aged >=2 years. RESULTS: From 2003 to 2012, the proportion of the population who reported using salt 'very often' declined; from 18 % to 12 % for use at the table (P<0.01) and from 42 % to 37 % during home cooking (P<0.02). While one-third of the population reported never adding salt at the table, most used it during home cooking/preparation (93 %). Use of discretionary salt was least commonly reported among young children and older adults and demographic and health subgroups at risk of CVD. CONCLUSIONS: While most people reported using salt during home cooking/preparation, a minority reported use at the table. Reported 'very often' discretionary salt use has declined. That discretionary salt use is less common among those at risk of CVD suggests awareness of messages to limit Na intake. PMID- 26979533 TI - Intraspinal bone-marrow cell therapy at pre- and symptomatic phases in a mouse model of amyotrophic lateral sclerosis. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease that selectively affects the motor neurons. The details of the mechanisms of selective motor-neuron death remain unknown and no effective therapy has been developed. We investigated the therapy with bone-marrow mononuclear cells (BMMC) in a mouse model of ALS (SOD1(G93A) mice). METHODS: We injected 10(6) BMMC into the lumbar portion of the spinal cord of SOD1(G93A) mice in presymptomatic (9 weeks old) and symptomatic (14 weeks old) phases. In each condition, we analyzed the progression of disease and the lifespan of the animals. RESULTS: We observed a mild transitory delay in the disease progression in the animals injected with BMMC in the presymptomatic phase. However, we observed no increase in the lifespan. When we injected BMMC in the symptomatic phase, we observed no difference in the animals' lifespan or in the disease progression. Immunohistochemistry for NeuN showed a decrease in the number of motor neurons during the course of the disease, and this decrease was not affected by either treatment. Using different strategies to track the BMMC, we noted that few cells remained in the spinal cord after transplantation. This observation could explain why the BMMC therapy had only a transitory effect. CONCLUSION: This is the first report of intraspinal BMMC therapy in a mouse model of ALS. We conclude this cellular therapy has only a mild transitory effect when performed in the presymptomatic phase of the disease. PMID- 26979534 TI - Railway suicide in England and Wales 2000-2013: a time-trends analysis. AB - BACKGROUND: In 2010, the "Tackling Suicide on the Railways" programme was launched as a joint initiative among Network Rail, the Samaritans and other key organisations such as the British Transport Police and train operators to achieve a 20% reduction in railway suicides from 2010 to 2015 in Great Britain. We report the most recent age and sex specific trends in railway suicide in England and Wales from 2000 to 2013 and examine whether the initiative's target reduction in railway suicides is likely to be achieved. METHODS: Population data and suicide mortality data (all methods combined and railway) for England and Wales were obtained from the Office for National Statistics (ONS) and used to calculate age and gender specific rates for deaths registered from 2000 to 2013. Data on railway suicides were also obtained from the Rail Safety and Standards Board (RSSB) and compared with ONS data. We used joinpoint regression to identify changes in suicide trends across the study period. RESULTS: The railway was used in 4.1% of all suicides in England and Wales (RSSB data were similar to ONS data for most years). Suicides in all persons from all causes decreased from 2000 to 2007, with small increases from 2008 until 2013; this rise was entirely due to an increase in male suicides. Railway suicide rates increased over the entire study period; the proportion of railway suicides in all persons increased from 3.5 to 4.9% during the study period. This trend was also mainly driven by increases in male suicides as female railway suicide rates remained steady over time. The highest age specific railway suicide rates were observed in middle aged men and women. Although there was no conclusive evidence of an increase in ONS railway suicides, RSSB data showed a statistically significant increase in railway suicides in males from 2009 onwards. CONCLUSION: The continued rise in male railway suicide in England and Wales is concerning, particularly due to the high economic costs and psychological trauma associated with these deaths. The initiative's target of a 20% reduction in railway suicide is unlikely to be achieved. PMID- 26979535 TI - Prevalence of hepatitis B and C viruses in HIV-positive patients in China: a cross-sectional study. AB - INTRODUCTION: Liver disease related to hepatitis B (HBV) and hepatitis C (HCV) may temper the success of antiretroviral therapy (ART) in China. Limited data exist on their prevalence in HIV-positive Chinese. A multi-centre, cross sectional study was carried out to determine the prevalence and disease characteristics of HBV and HCV co-infection in HIV-positive patients across 12 provinces. METHODS: HIV-positive ART-naive patients were recruited from two parent cohorts established during November 2008-January 2010 and August 2012 September 2014. Hepatitis B surface antigen (HBsAg), hepatitis B e antigen and HCV antibody (anti-HCV) status were retrieved from parent databases at the visit prior to ART initiation. HBV DNA was then determined in HBsAg+ patients. HCV RNA was quantified in anti-HCV+ patients. Aspartate aminotransferase-to-platelet ratio index (APRI) and the fibrosis-4 (FIB4) were calculated. Chi-square test, Kruskal-Wallis test and logistic regression were used for statistical analysis, as appropriate. RESULTS: Of 1944 HIV-positive patients, 186 (9.5%) were HIV-HBV co-infected and 161 (8.3%) were HIV-HCV co-infected. The highest HIV-HBV prevalence (14.5%) was in Eastern China while the highest HIV-HCV prevalence was in the Central region (28.2%). HIV-HBV patients had lower median CD4 + T cell count (205 cells/MUL) than either HIV monoinfected (242 cells/MUL, P = 0.01) or HIV-HCV patients (274 cells/MUL, P = 0.001). Moderate-to-significant liver disease was present in > 65% of the HIV-HCV, ~ 35% of the HIV-HBV and ~ 20% of the HIV monoinfected patients. Independent associations with moderate-to significant liver disease based on APRI included HBV (Odds ratio, OR 2.37, P < 0.001), HCV (OR 9.64, P < 0.001), CD4 count <= 200 cells/MUL (OR 2.55, P < 0.001) and age >= 30 years (OR 1.80, P = 0.001). CONCLUSIONS: HBV and HCV prevalence is high in HIV-positive Chinese and differs by geographic region. HBV and HCV co infection and HIV monoinfection are risks for moderate-to-significant liver disease. Only HIV-HBV is associated with greater HIV-related immunosuppression. Incorporating screening and management of hepatitis virus infections into Chinese HIV programmes is needed. PMID- 26979537 TI - Sudden unexpected death in epilepsy: basic mechanisms and clinical implications for prevention. AB - Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with intractable epilepsy. The substantial lifetime risk of SUDEP and the lack of a clear pathophysiological connection between epilepsy itself and sudden death have fuelled increased attention to this phenomenon. Understanding the mechanisms underlying SUDEP is paramount to developing preventative strategies. In this review, we discuss SUDEP population studies, case-control studies, witnessed and monitored cases, as well as human seizure cardiorespiratory findings related to SUDEP, and SUDEP animal models. We integrate these data to suggest the most probable mechanisms underlying SUDEP. Understanding the modifiable risk factors and pathophysiology allows us to discuss potential preventative strategies. PMID- 26979538 TI - Magnetic resonance spectroscopy and imaging for the study of fossils. AB - Computed tomography (CT) has long been used for investigating palaeontological specimens, as it is a nondestructive technique which avoids the need to dissolve or ionize the fossil sample. However, magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) have recently gained ground as analytical tools for examination of palaeontological samples, by nondestructively providing information about the structure and composition of fossils. While MRI techniques are able to reveal the three-dimensional geometry of the trace fossil, MRS can provide information on the chemical composition of the samples. The multidimensional nature of MR (magnetic resonance) signals has potential to provide rich three-dimensional data on the palaeontological specimens and also to help in elucidating paleopathological and paleoecological questions. In this work the verified applications and the emerging uses of MRI and MRS in paleontology are reviewed, with particular attention to fossil spores, fossil plants, ambers, fossil invertebrates, and fossil vertebrate studies. PMID- 26979539 TI - Magnetic resonance imaging for the study of mummies. AB - Nondestructive diagnostic imaging for mummies study has a long tradition and high resolution images of the samples morphology have been extensively acquired by using computed tomography (CT). However, although in early reports no signal or image was obtained because of the low water content, mummy magnetic resonance imaging (MRI) was demonstrated able to generate images of such ancient specimens by using fast imaging techniques. Literature demonstrated the general feasibility of nonclinical MRI for visualizing historic human tissues, which is particularly interesting for archeology. More recently, multinuclear magnetic resonance spectroscopy (MRS) was demonstrated able to detect numerous organic biochemicals from such remains. Although the quality of these images is not yet comparable to that of clinical magnetic resonance (MR) images, and further research will be needed for determining the full capacity of MR in this topic, the information obtained with MR can be viewed as complementary to the one provided by CT and useful for paleoradiological studies of mummies. This work contains an overview of the state of art of the emerging uses of MRI in paleoradiology. PMID- 26979536 TI - Genomic structure and marker-derived gene networks for growth and meat quality traits of Brazilian Nelore beef cattle. AB - BACKGROUND: Nelore is the major beef cattle breed in Brazil with more than 130 million heads. Genome-wide association studies (GWAS) are often used to associate markers and genomic regions to growth and meat quality traits that can be used to assist selection programs. An alternative methodology to traditional GWAS that involves the construction of gene network interactions, derived from results of several GWAS is the AWM (Association Weight Matrices)/PCIT (Partial Correlation and Information Theory). With the aim of evaluating the genetic architecture of Brazilian Nelore cattle, we used high-density SNP genotyping data (~770,000 SNP) from 780 Nelore animals comprising 34 half-sibling families derived from highly disseminated and unrelated sires from across Brazil. The AWM/PCIT methodology was employed to evaluate the genes that participate in a series of eight phenotypes related to growth and meat quality obtained from this Nelore sample. RESULTS: Our results indicate a lack of structuring between the individuals studied since principal component analyses were not able to differentiate families by its sires or by its ancestral lineages. The application of the AWM/PCIT methodology revealed a trio of transcription factors (comprising VDR, LHX9 and ZEB1) which in combination connected 66 genes through 359 edges and whose biological functions were inspected, some revealing to participate in biological growth processes in literature searches. CONCLUSIONS: The diversity of the Nelore sample studied is not high enough to differentiate among families neither by sires nor by using the available ancestral lineage information. The gene networks constructed from the AWM/PCIT methodology were a useful alternative in characterizing genes and gene networks that were allegedly influential in growth and meat quality traits in Nelore cattle. PMID- 26979542 TI - Hunt rejects claim that no plan exists to tackle NHS funding "black hole". PMID- 26979540 TI - Gd-EOB-DTPA-enhanced-MR imaging in the inflammation stage of nonalcoholic steatohepatitis (NASH) in mice. AB - OBJECTIVE: The purpose of this study is to investigate the correlation between the liver kinetics of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) and liver histopathology in a mouse model of NASH by using dynamic contrast-enhanced MRI. MATERIALS AND METHODS: Twenty male C57/BL6 mice aged 8weeks were fed a methionine-choline-deficient (MCD) diet for 2, 4 and 6weeks (MCD groups: MCD 2w, 4w, or 6w). Gd-EOB-DTPA-enhanced MR imaging of the liver was performed at 2, 4 and 6weeks after the MCD feeding. The signal intensity of the liver was obtained from dynamic MR images and relative enhancement (RE), and the time to maximum RE (Tmax) and half-life of elimination RE (T1/2) were calculated. After MRI scan, histopathological scores of hepatic steatosis and inflammation and blood biochemistry data, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, were obtained. RESULTS: Plasma AST and ALT levels were significantly increased in mice fed MCD. Histopathological scores indicated that steatohepatitis progressed with the MCD feeding period from 2 to 6weeks, but significant fibrosis was observed only in mice fed MCD for 6weeks. Gd-EOB-DTPA enhanced MRI showed that Tmax was significantly prolonged in the livers of the 6 week group compared to the control group (control, 4.0+/-0.7min; MCD 6w, 12.1+/ 1.6min), although there was no alteration in the 2- and 4-week groups. T1/2 was significantly prolonged in mice fed MCD for 4 and 6weeks compared to the control group (control, 19.9+/-2.0min; MCD 4w, 46.7+/-8.7min; MCD 6w, 65.4+/-8.8min). The parameters of Gd-EOB-DTPA kinetics (Tmax and T1/2) in the liver were positively correlated with the liver histopathological score (steatosis vs Tmax, rho=0.69, P=0.0007; inflammation vs Tmax, rho=0.66, P=0.00155; steatosis vs T1/2, rho=0.77, P<0.0001; inflammation vs T1/2, rho=0.73, P=0.0003). CONCLUSIONS: The liver kinetics of Gd-EOB-DTPA correlated well with the inflammation score in the mouse model of NASH, suggesting the possibility of detecting the steatohepatitis stage without fibrosis by Gd-EOB-DTPA-enhanced MR imaging. PMID- 26979541 TI - CNR improvement of MP2RAGE from slice encoding directional acceleration. AB - PURPOSE: While MP2RAGE shows the potential to generate B1 insensitive T1 contrast, the long TR of MP2RAGE (>=6s at 7T) is essential to provide the large dynamic range of apparent T1 relaxation for dual inversion time acquisitions. We present a 2 direction (2D) accelerated MP2RAGE, which provides an increased flip angle while maintaining similar dynamic recovery as 1D accelerated MP2RAGE. METHOD: Simulations were conducted to optimize 2D accelerated MP2RAGE parameters and healthy subjects were scanned with 1D and 2D accelerated MP2RAGE at 7T. Images were compared visually and contrast to noise (CNR) between brain tissues was measured. RESULT: Simulations showed that CNR is primarly determined by the TR, followed by the number of the first partition encoding steps in MP2RAGE. Keeping TR constant, a smaller number of partition encoding steps increases the achievable maximal CNR. In-vivo 2D MP2RAGE improves CNR between white and gray matters by 9% when compared to 1D accelerated MP2RAGE with identical voxel size. CONCLUSION: We presented 2D accelated MP2RAGE at 7T with the increased flip angle. We show that this leads to CNR improvement, and consequently a reduction of scan time to be compared to 1D accelerated MP2RAGE. PMID- 26979543 TI - Our Year on Twitter: Science in #SocialMedia. AB - Information is now available in real time from a multitude of sources. Twitter provides one effective means to broadcast images with short captions instantly and everywhere. Last year we began using Twitter to convey our excitement with the biological sciences, and discovered a new means to contribute, connect, and conference with a broader global scientific community and beyond. Here we share this experience, and invite you to join in the conversation. PMID- 26979544 TI - The role of elective nodal irradiation for esthesioneuroblastoma patients with clinically negative neck. AB - PURPOSE: Although adjuvant radiation to the tumor bed has been reported to improve the clinic outcomes of esthesioneuroblastoma (ENB) patients, the role of elective neck irradiation (ENI) in clinically node-negative (N0) patients remains controversial. Here, we evaluated the effects of ENI on neck nodal relapse risk in ENB patients treated with radiation therapy as a component of multimodality treatment. METHODS AND MATERIALS: Seventy-one N0 ENB patients irradiated at the University of Texas MD Anderson Cancer Center between 1970 and 2013 were identified. ENI was performed on 22 of these patients (31%). Survival analysis was performed with focus on comparative outcomes of those patients who did and did not receive ENI. RESULTS: The median follow-up time for our cohort is 80.8 months (range, 6-350 months). Among N0 patients, 13 (18.3%) developed neck nodal relapses, with a median time to progression of 62.5 months. None of these 13 patients received prophylactic neck irradiation. ENI was associated with significantly improved regional nodal control at 5 years (regional control rate of 100% for ENI vs 82%, P < .001), but not overall survival or disease-free survival. Eleven patients without ENI developed isolated neck recurrences. All had further treatment for their neck disease, including neck dissection (n = 10), radiation (n = 10), or chemotherapy (n = 5). Six of these 11 patients (54.5%) demonstrated no evidence of further recurrence with a median follow-up of 55.5 months. CONCLUSION: ENI significantly reduces the risk of cervical nodal recurrence in ENB patients with clinically N0 neck, but this did not translate to a survival benefit. Multimodality treatment for isolated neck recurrence provides a reasonable salvage rate. The greatest benefit for ENI appeared to be among younger patients who presented with Kadish C disease. Further studies are needed to confirm these findings. PMID- 26979545 TI - Cholangiocarcinoma size on magnetic resonance imaging versus pathologic specimen: Implications for radiation treatment planning. AB - PURPOSE: The accuracy of abdominal magnetic resonance imaging (MRI) in measuring gross tumor volume in patients with resectable cholangiocarcinoma (CC) is unknown. CC is a highly difficult tumor to visualize and treatment with dose escalated radiation therapy requires clear tumor delineation. We aim to investigate the concordance between imaging and pathologic size in patients with resected CC to determine the usefulness of MRI for image guided treatment modalities. METHODS AND MATERIALS: The records of 51 patients with resected CC who underwent preoperative MRI were evaluated. Each preoperative MRI was individually reviewed by a diagnostic radiologist (P.M.), who was blinded to pathologic measurements. A combination of dynamic multiphase contrast-enhanced T1 and T2-weighted images, original imaging reports, and pathologic reports were reviewed for greatest tumor dimensions. A general linear regression model was used to examine the outcome MRI minus pathology using MRI report, T1-weighted measurement, or T2-weighted measurement. A multivariable regression model was fit to assess the association of other factors with pathologic underestimation. RESULTS: The median age was 69 years. Eleven tumors were categorized distal/extrahepatic, 17 hilar, and 23 intrahepatic CC. The median tumor size on pathology report was 3.00 cm (range, 0.3-19). The median tumor size from the MRI report was 3 cm (range, 0.80-16.20) and median tumor size on independent radiological review was 3 cm (range, 0.90-17) on the T1-weighted and 3 cm (range, 0.90-17) on the T2-weighted MRI sequences. When compared with pathologic tumor size, the MRI report dimension was found to underestimate tumor size by 4.1 mm (P = .04). On multivariable analysis, pathologic size underestimation was influenced by increasing tumor size (slope, -0.20; P < .001); however, underestimation was not affected by tumor location or MRI sequence. CONCLUSIONS: MRI underestimates tumor size, which was more pronounced with larger tumors, but not influenced by tumor location. The potential for gross tumor volume underestimation should be considered when planning highly conformal radiation therapy treatment of CC. PMID- 26979546 TI - Application of an automated natural language processing (NLP) workflow to enable federated search of external biomedical content in drug discovery and development. AB - External content sources such as MEDLINE((r)), National Institutes of Health (NIH) grants and conference websites provide access to the latest breaking biomedical information, which can inform pharmaceutical and biotechnology company pipeline decisions. The value of the sites for industry, however, is limited by the use of the public internet, the limited synonyms, the rarity of batch searching capability and the disconnected nature of the sites. Fortunately, many sites now offer their content for download and we have developed an automated internal workflow that uses text mining and tailored ontologies for programmatic search and knowledge extraction. We believe such an efficient and secure approach provides a competitive advantage to companies needing access to the latest information for a range of use cases and complements manually curated commercial sources. PMID- 26979547 TI - Transcriptional response networks for elucidating mechanisms of action of multitargeted agents. AB - Drug discovery is moving away from the single target-based approach towards harnessing the potential of polypharmacological agents that modulate the activity of multiple nodes in the complex networks of deregulations underlying disease phenotypes. Computational network pharmacology methods that use systems-level drug-response phenotypes, such as those originating from genome-wide transcriptomic profiles, have proved particularly effective for elucidating the mechanisms of action of multitargeted compounds. Here, we show, via the case study of the natural product pinosylvin, how the combination of two complementary network-based methods can provide novel, unexpected mechanistic insights. This case study also illustrates that elucidating the mechanism of action of multitargeted natural products through transcriptional response-based approaches is a challenging endeavor, often requiring multiple computational-experimental iterations. PMID- 26979549 TI - Beta-cell mitochondrial carriers and the diabetogenic stress response. AB - Mitochondria play a central role in pancreatic beta-cells by coupling metabolism of the secretagogue glucose to distal events of regulated insulin exocytosis. This process requires transports of both metabolites and nucleotides in and out of the mitochondria. The molecular identification of mitochondrial carriers and their respective contribution to beta-cell function have been uncovered only recently. In type 2 diabetes, mitochondrial dysfunction is an early event and may precipitate beta-cell loss. Under diabetogenic conditions, characterized by glucotoxicity and lipotoxicity, the expression profile of mitochondrial carriers is selectively modified. This review describes the role of mitochondrial carriers in beta-cells and the selective changes in response to glucolipotoxicity. In particular, we discuss the importance of the transfer of metabolites (pyruvate, citrate, malate, and glutamate) and nucleotides (ATP, NADH, NADPH) for beta-cell function and dysfunction. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou. PMID- 26979548 TI - The impact of communicating genetic risks of disease on risk-reducing health behaviour: systematic review with meta-analysis. AB - OBJECTIVE: To assess the impact of communicating DNA based disease risk estimates on risk-reducing health behaviours and motivation to engage in such behaviours. DESIGN: Systematic review with meta-analysis, using Cochrane methods. DATA SOURCES: Medline, Embase, PsycINFO, CINAHL, and the Cochrane Central Register of Controlled Trials up to 25 February 2015. Backward and forward citation searches were also conducted. STUDY SELECTION: Randomised and quasi-randomised controlled trials involving adults in which one group received personalised DNA based estimates of disease risk for conditions where risk could be reduced by behaviour change. Eligible studies included a measure of risk-reducing behaviour. RESULTS: We examined 10,515 abstracts and included 18 studies that reported on seven behavioural outcomes, including smoking cessation (six studies; n=2663), diet (seven studies; n=1784), and physical activity (six studies; n=1704). Meta analysis revealed no significant effects of communicating DNA based risk estimates on smoking cessation (odds ratio 0.92, 95% confidence interval 0.63 to 1.35, P=0.67), diet (standardised mean difference 0.12, 95% confidence interval 0.00 to 0.24, P=0.05), or physical activity (standardised mean difference -0.03, 95% confidence interval -0.13 to 0.08, P=0.62). There were also no effects on any other behaviours (alcohol use, medication use, sun protection behaviours, and attendance at screening or behavioural support programmes) or on motivation to change behaviour, and no adverse effects, such as depression and anxiety. Subgroup analyses provided no clear evidence that communication of a risk conferring genotype affected behaviour more than communication of the absence of such a genotype. However, studies were predominantly at high or unclear risk of bias, and evidence was typically of low quality. CONCLUSIONS: Expectations that communicating DNA based risk estimates changes behaviour is not supported by existing evidence. These results do not support use of genetic testing or the search for risk-conferring gene variants for common complex diseases on the basis that they motivate risk-reducing behaviour. SYSTEMATIC REVIEW REGISTRATION: This is a revised and updated version of a Cochrane review from 2010, adding 11 studies to the seven previously identified. PMID- 26979550 TI - Key Questions in Marine Megafauna Movement Ecology. AB - It is a golden age for animal movement studies and so an opportune time to assess priorities for future work. We assembled 40 experts to identify key questions in this field, focussing on marine megafauna, which include a broad range of birds, mammals, reptiles, and fish. Research on these taxa has both underpinned many of the recent technical developments and led to fundamental discoveries in the field. We show that the questions have broad applicability to other taxa, including terrestrial animals, flying insects, and swimming invertebrates, and, as such, this exercise provides a useful roadmap for targeted deployments and data syntheses that should advance the field of movement ecology. PMID- 26979551 TI - The Relationship Between Non-Medical Use of Prescription Opioids and Sex Work Among Adults in Residential Substance Use Treatment. AB - High rates of substance use (e.g., alcohol, cocaine, heroin) have been documented among individuals who engage in sex work (SW), and adults seeking substance use disorder (SUD) treatment frequently report prior engagement in SW. Non-medical use of prescription opioids (NMUPO) has increased over the last decade, but little is known about the relationship between NMUPO with sex exchange. The purpose of this study was to describe the prevalence of recent SW among patients at a large residential SUD treatment center and examine the association between NMUPO and SW. Approximately 14% of 588 adults reported involvement in SW in the month prior to treatment. NMUPO was more common among those with a history of SW (95% of sex workers vs. 74% of non-sex-workers), and this association remained statistically significant after controlling for demographic factors, other substance use and psychiatric symptom severity (odds ratio=3.38). SW is relatively common among patients in residential SUD treatment, and is associated with greater psychiatric severity and more extensive substance use, including alarming rates of NMUPO. Addiction treatment for individuals involved in SW may benefit from the addition of content related to NMUPO. PMID- 26979554 TI - On-line chiral analysis using the kinetic method. AB - Chiral analysis of constituents in solution-phase reaction mixtures can be performed by tandem mass spectrometry using the kinetic method to determine the enantiomeric excess (ee). Simply diluting an aliquot of a reaction mixture, adjusting the pH, and adding reagents necessary to form a chiral cluster ion allows chiral analysis. The product of a stereospecific N-selective alkylation reaction, 2-(3-(2-methoxyethoxy)-5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid, was monitored for ee during the course of reaction, and it showed the expected inversion without ee erosion. Base-catalyzed racemization of the reaction product showed the expected decrease in ee as the reaction proceeded. The base-catalyzed racemization of ibuprofen was monitored on-line, providing near real-time data on ee. PMID- 26979552 TI - Barriers to Quitting Smoking Among Substance Dependent Patients Predict Smoking Cessation Treatment Outcome. AB - For smokers with substance use disorders (SUD), perceived barriers to quitting smoking include concerns unique to effects on sobriety as well as usual concerns. We expanded our Barriers to Quitting Smoking in Substance Abuse Treatment (BQS SAT) scale, added importance ratings, validated it, and then used the importance scores to predict smoking treatment response in smokers with substance use disorders (SUD) undergoing smoking treatment in residential treatment programs in two studies (n=184 and 340). Both components (general barriers, weight concerns) were replicated with excellent internal consistency reliability. Construct validity was supported by significant correlations with pretreatment nicotine dependence, smoking variables, smoking self-efficacy, and expected effects of smoking. General barriers significantly predicted 1-month smoking abstinence, frequency and heaviness, and 3-month smoking frequency; weight concerns predicted 1-month smoking frequency. Implications involve addressing barriers with corrective information in smoking treatment for smokers with SUD. PMID- 26979555 TI - Interplay between seven secondary metal uptake systems is required for full metal resistance of Cupriavidus metallidurans. AB - The beta-proteobacterium Cupriavidus metallidurans is able to grow in metal contaminated environments due to having sophisticated metal efflux systems. Here, the contribution of all seven known secondary metal uptake systems (ZupT, PitA, CorA1, CorA2, CorA3, ZntB, HoxN) to metal resistance is characterized. In a strategic deletion approach, all ten double deletion mutants, a variety of triple and quadruple mutants, and from the Delta4 mutant (DeltazupT DeltacorA1 DeltacorA2 DeltacorA3) the mutants Delta5 (=Delta4 DeltapitA), Delta6 (=Delta4 DeltapitA DeltazntB), and finally Delta7 (DeltazupT DeltacorA1 DeltacorA2 DeltacorA3 DeltapitA DeltazntB DeltahoxN) were constructed. Metal resistance, metal content, and regulation of expression of these genes were characterized in these mutants. The DeltazupT single deletion strain exhibited an extended lag phase in Tris-buffered liquid mineral salts medium (TMM) compared to its parent strain AE104, indicating a decreased fitness level. Further deletions up to Delta6 did not influence growth in TMM without added metals but fitness of the Delta7 strain dropped to a lower level compared to Delta6, Delta5 and DeltazupT. The cells of the Delta7 multiple deletion strain still contained all essential metals, demonstrating that additional metal import systems must exist in C. metallidurans. PitA was an important contributor of metal:phosphate complexes to C. metallidurans. Up to Delta5 no evidence was found for increased expression of the transporter genes to recruit substitutes for the deleted importers. Only the hoxN-lacZ reporter gene fusion displayed a changed expression pattern in the Delta6 strain, indicating recruitment of HoxN. Metal resistance of the deletion strains decreased along the deletion series although all strains still contained metal efflux systems: up to the Delta6 mutant the overall fitness was kept at the DeltazupT mutant strain level at the cost of a diminished competence to handle MUM concentrations of transition metals. Together, these data demonstrated an important contribution of the seven secondary metal import systems to metal homeostasis in this bacterium. PMID- 26979556 TI - Detection of trapped charges in the blend films of polystyrene/SFDBAO electrets by electrostatic and Kelvin probe force microscopy. AB - The charge trapping properties of the blend of polystyrene (PS) and a sterically hindered organic semiconductor SFDBAO (spiro[fluorene-9,7-dibenzo[c,h]acridin-5 one]) are investigated by electrostatic and Kelvin probe force microscopy (EFM and KPFM). EFM signals of trapped charge spots injected with controllable tip biases, which are recorded with different dissipation times t, the percent of SFDBAO in blends, and the scanning tip bias, have been measured. By the quantitative analysis, the excellent trapped charge density of PS/SFDBAO blend films for the holes (~*10(-5) C m(-2)) is much higher than that of the SFDBAO film (~*10(-6) C m(-2)) and the PS film (~*10(-7) C m(-2)). However, the trapped charge density of electrons (~*10(-7) C m(-2)) has the same order magnitude for SFDBAO, PS and the blend films. The results indicate that the blend of PS and SFDBAO enhances the high-density storage and retention abilities of the holes to a larger extent, but the endurance improvement of the electrons is not that obvious. By the KPFM measurement, we further verify the different diffusion rates of the trapped holes and electrons in the PS/SFDBAO blend films, and discuss the possible physical mechanism. The qualitative and quantitative determination of charge trapping properties in this work can be very useful for the characterization of PS/SFDBAO based charge trapping memory devices. PMID- 26979557 TI - The RNA Response to DNA Damage. AB - Multicellular organisms must ensure genome integrity to prevent accumulation of mutations, cell death, and cancer. The DNA damage response (DDR) is a complex network that senses, signals, and executes multiple programs including DNA repair, cell cycle arrest, senescence, and apoptosis. This entails regulation of a variety of cellular processes: DNA replication and transcription, RNA processing, mRNA translation and turnover, and post-translational modification, degradation, and relocalization of proteins. Accumulated evidence over the past decades has shown that RNAs and RNA metabolism are both regulators and regulated actors of the DDR. This review aims to present a comprehensive overview of the current knowledge on the many interactions between the DNA damage and RNA fields. PMID- 26979558 TI - Allometric scaling of intraspecific space use. AB - Allometric scaling relationships enable exploration of animal space-use patterns, yet interspecific studies cannot address many of the underlying mechanisms. We present the first intraspecific study of home range (HR) allometry relative to energetic requirements over several orders of magnitude of body mass, using as a model the predatory fish, pike Esox lucius. Analogous with interspecific studies, we show that space use increases more rapidly with mass (exponent = 1.08) than metabolic scaling theories predict. Our results support a theory that suggests increasing HR overlap with body mass explains many of these differences in allometric scaling of HR size. We conclude that, on a population scale, HR size and energetic requirement scale allometrically, but with different exponents. PMID- 26979559 TI - Selection is stronger in early-versus-late stages of divergence in a Neotropical livebearing fish. AB - How selection acts to drive trait evolution at different stages of divergence is of fundamental importance in our understanding of the origins of biodiversity. Yet, most studies have focused on a single point along an evolutionary trajectory. Here, we provide a case study evaluating the strength of divergent selection acting on life-history traits at early-versus-late stages of divergence in Brachyrhaphis fishes. We find that the difference in selection is stronger in the early-diverged population than the late-diverged population, and that trait differences acquired early are maintained over time. PMID- 26979560 TI - Do female Nicrophorus vespilloides reduce direct costs by choosing males that mate less frequently? AB - Sexual conflict occurs when selection to maximize fitness in one sex does so at the expense of the other sex. In the burying beetle Nicrophorus vespilloides, repeated mating provides assurance of paternity at a direct cost to female reproductive productivity. To reduce this cost, females could choose males with low repeated mating rates or smaller, servile males. We tested this by offering females a dichotomous choice between males from lines selected for high or low mating rate. Each female was then allocated her preferred or non-preferred male to breed. Females showed no preference for males based on whether they came from lines selected for high or low mating rates. Pairs containing males from high mating rate lines copulated more often than those with low line males but there was a negative relationship between female size and number of times she mated with a non-preferred male. When females bred with their preferred male the number of offspring reared increased with female size but there was no such increase when breeding with non-preferred males. Females thus benefited from being choosy, but this was not directly attributable to avoidance of costly male repeated mating. PMID- 26979561 TI - Differential scaling within an insect compound eye. AB - Environmental and genetic influences cause individuals of a species to differ in size. As they do so, organ size and shape are scaled to available resources whilst maintaining function. The scaling of entire organs has been investigated extensively but scaling within organs remains poorly understood. By making use of the structure of the insect compound eye, we show that different regions of an organ can respond differentially to changes in body size. Wood ant (Formica rufa) compound eyes contain facets of different diameters in different regions. When the animal body size changes, lens diameters from different regions can increase or decrease in size either at the same rate (a 'grade' shift) or at different rates (a 'slope' shift). These options are not mutually exclusive, and we demonstrate that both types of scaling apply to different regions of the same eye. This demonstrates that different regions within a single organ can use different rules to govern their scaling, responding differently to their developmental environment. Thus, the control of scaling is more nuanced than previously appreciated, diverse responses occurring even among homologous cells within a single organ. Such fine control provides a rich substrate for the diversification of organ morphology. PMID- 26979562 TI - Debunking the viper's strike: harmless snakes kill a common assumption. AB - To survive, organisms must avoid predation and acquire nutrients and energy. Sensory systems must correctly differentiate between potential predators and prey, and elicit behaviours that adjust distances accordingly. For snakes, strikes can serve both purposes. Vipers are thought to have the fastest strikes among snakes. However, strike performance has been measured in very few species, especially non-vipers. We measured defensive strike performance in harmless Texas ratsnakes and two species of vipers, western cottonmouths and western diamond backed rattlesnakes, using high-speed video recordings. We show that ratsnake strike performance matches or exceeds that of vipers. In contrast with the literature over the past century, vipers do not represent the pinnacle of strike performance in snakes. Both harmless and venomous snakes can strike with very high accelerations that have two key consequences: the accelerations exceed values that can cause loss of consciousness in other animals, such as the accelerations experienced by jet pilots during extreme manoeuvres, and they make the strikes faster than the sensory and motor responses of mammalian prey and predators. Both harmless and venomous snakes can strike faster than the blink of an eye and often reach a target before it can move. PMID- 26979564 TI - Superconductivity in Ca-doped graphene laminates. AB - Despite graphene's long list of exceptional electronic properties and many theoretical predictions regarding the possibility of superconductivity in graphene, its direct and unambiguous experimental observation has not been achieved. We searched for superconductivity in weakly interacting, metal decorated graphene crystals assembled into so-called graphene laminates, consisting of well separated and electronically decoupled graphene crystallites. We report robust superconductivity in all Ca-doped graphene laminates. They become superconducting at temperatures (Tc) between ~4 and ~6 K, with Tc's strongly dependent on the confinement of the Ca layer and the induced charge carrier concentration in graphene. We find that Ca is the only dopant that induces superconductivity in graphene laminates above 1.8 K among several dopants used in our experiments, such as potassium, caesium and lithium. By revealing the tunability of the superconducting response through doping and confinement of the metal layer, our work shows that achieving superconductivity in free-standing, metal decorated monolayer graphene is conditional on an optimum confinement of the metal layer and sufficient doping, thereby bringing its experimental realization within grasp. PMID- 26979563 TI - Differential gene expression in seasonal sympatry: mechanisms involved in diverging life histories. AB - In an era of climate change, understanding the genetic and physiological mechanisms underlying flexibility in phenology and life history has gained greater importance. These mechanisms can be elucidated by comparing closely related populations that differ in key behavioural and physiological traits such as migration and timing of reproduction. We compared gene expression in two recently diverged dark-eyed Junco ( Junco hyemalis) subspecies that live in seasonal sympatry during winter and early spring, but that differ in behaviour and physiology, despite exposure to identical environmental cues. We identified 547 genes differentially expressed in blood and pectoral muscle. Genes involved in lipid transport and metabolism were highly expressed in migrant juncos, while genes involved in reproductive processes were highly expressed in resident breeders. Seasonal differences in gene expression in closely related populations residing in the same environment provide significant insights into mechanisms underlying variation in phenology and life history, and have potential implications for the role of seasonal timing differences in gene flow and reproductive isolation. PMID- 26979565 TI - Psychiatric outcomes of bullying victimization: a study of discordant monozygotic twins. AB - BACKGROUND: Bullying victimization in childhood is associated with a broad array of serious mental health disturbances, including anxiety, depression, and suicidal ideation and behavior. The key goal of this study was to evaluate whether bullying victimization is a true environmental risk factor for psychiatric disturbance using data from 145 bully-discordant monozygotic (MZ) juvenile twin pairs from the Virginia Twin Study of Adolescent Behavioral Development (VTSABD) and their follow-up into young adulthood. METHOD: Since MZ twins share an identical genotype and familial environment, a higher rate of psychiatric disturbance in a bullied MZ twin compared to their non-bullied MZ co twin would be evidence of an environmental impact of bullying victimization. Environmental correlations between being bullied and the different psychiatric traits were estimated by fitting structural equation models to the full sample of MZ and DZ twins (N = 2824). Environmental associations were further explored using the longitudinal data on the bullying-discordant MZ twins. RESULTS: Being bullied was associated with a wide range of psychiatric disorders in both children and young adults. The analysis of data on the MZ-discordant twins supports a genuine environmental impact of bullying victimization on childhood social anxiety [odds ratio (OR) 1.7], separation anxiety (OR 1.9), and young adult suicidal ideation (OR 1.3). There was a shared genetic influence on social anxiety and bullying victimization, consistent with social anxiety being both an antecedent and consequence of being bullied. CONCLUSION: Bullying victimization in childhood is a significant environmental trauma and should be included in any mental health assessment of children and young adults. PMID- 26979568 TI - Non-directed, carbonate-mediated C-H activation and aerobic C-H oxygenation with Cp*Ir catalysts. AB - The effect of oxidatively stable L- and X-type additives on the activity of Cp*Ir catalyst precursors in the C-H activation of arenes has been studied. Turnover numbers for C-H activation of up to 65 can thus be achieved, as determined by H/D exchange in MeOH-D4. In particular, carbonate additives are found to enhance the C-H activation reactivity of Cp*Ir(H2O)3(OTf)2 () more significantly than L-type ligands investigated in this study. Based on these studies, Cp*Ir/carbonate systems are developed that catalyze the aerobic Csp(3)-H oxygenation of alkyl arenes, employing air as oxidant. PMID- 26979566 TI - Silencing of the olfactory co-receptor gene in Dendroctonus armandi leads to EAG response declining to major host volatiles. AB - In this study, a polymerase chain reaction (PCR) based on homology genes of Orco was utilized to identify DarmOrco, which is essential for olfaction in D. armandi. The results showed that DarmOrco shares significant sequence homology with Orco proteins had known in other insects. Quantitative real-time PCR (qRT PCR) analysis suggested that DarmOrco was abundantly expressed in adult D. armandi; by contrast, DarmOrco showed trace amounts of expression level in other stages. Of different tissues, DarmOrco expression level was the highest in the antennae. In order to understand the functional significance of Orco, we injected siRNA of DarmOrco into the conjunctivum between the second and third abdominal segments, and evaluated its expression after siRNA injected for 24 h, 48 h and 72 h. The results of qRT-PCR demonstrated that the reduction of mRNA expression level was significant (~80%) in DarmOrco siRNA-treated D. armandi than in water injected and non-injected controls. The electroantennogram responses of females and males to 11 major volatiles of its host, were also reduced (30~68% for females; 16~70% for males) in siRNA-treated D. armandi compared with the controls. These results suggest that DarmOrco is crucial in mediating odorant perception. PMID- 26979567 TI - Insights into mutualism mechanism and versatile metabolism of Ketogulonicigenium vulgare Hbe602 based on comparative genomics and metabolomics studies. AB - Ketogulonicigenium vulgare has been widely used in vitamin C two steps fermentation and requires companion strain for optimal growth. However, the understanding of K. vulgare as well as its companion strain is still preliminary. Here, the complete genome of K. vulgare Hbe602 was deciphered to provide insight into the symbiosis mechanism and the versatile metabolism. K. vulgare contains the LuxR family proteins, chemokine proteins, flagellar structure proteins, peptides and transporters for symbiosis consortium. Besides, the growth state and metabolite variation of K. vulgare were observed when five carbohydrates (D sorbitol, L-sorbose, D-glucose, D-fructose and D-mannitol) were used as carbon source. The growth increased by 40.72% and 62.97% respectively when K. vulgare was cultured on D-mannitol/D-sorbitol than on L-sorbose. The insufficient metabolism of carbohydrates, amino acids and vitamins is the main reason for the slow growth of K. vulgare. The combined analysis of genomics and metabolomics indicated that TCA cycle, amino acid and nucleotide metabolism were significantly up-regulated when K. vulgare was cultured on the D-mannitol/D-sorbitol, which facilitated the better growth. The present study would be helpful to further understand its metabolic structure and guide the engineering transformation. PMID- 26979571 TI - Application of nitrogen sufficiency conversion strategy for microalgae-based ammonium-rich wastewater treatment. AB - Ammonium ([Formula: see text]-N)-rich wastewater, a main cause for eutrophication, can serve as a promising medium for fast microalgae cultivation with efficient [Formula: see text]-N removal. To achieve this goal, a well controlled three-stage treatment process was developed. Two trophic modes (mixotrophy and heterotrophy) in Stage 1 and Stage 2, with two nitrogen availability conditions (N sufficient and N deprived) in Stage 2, and different [Formula: see text]-N concentrations in Stage 3 were compared to investigate the effects of nitrogen sufficiency conversion on indigenous strain UMN266 for [Formula: see text]-N removal. Results showed that mixotrophic cultures in the first two stages with N deprivation in Stage 2 was the optimum treatment strategy, and higher [Formula: see text]-N concentration in Stage 3 facilitated both microalgal growth and [Formula: see text]-N removal, with average and maximum biomass productivity of 55.3 and 161.0 mg L(-1) d(-1), and corresponding removal rates of 4.2 and 15.0 mg L(-1) d(-1), respectively, superior to previously published results. Observations of intracellular compositions confirmed the optimum treatment strategy, discovering excellent starch accumulating property of strain UMN266 as well. Combination of bioethanol production with the proposed three-stage process using various real wastewater streams at corresponding stages was suggested for future application. PMID- 26979570 TI - Online discussion effects on intention to participate in genetic research: A longitudinal experimental study. AB - OBJECTIVE: The National Human Genome Research Institute has emphasised community engagement and public dialogue in the U.S. on issues related to genetics. This study examines how online discussions among the U.S. public directly or indirectly influence psychosocial constructs of the Theory of Planned Behavior, including intention to take part in genetic research. DESIGN: After completing the baseline questionnaire, participants (n = 3754) were randomly assigned to one of the following three groups: the discussion group, the pre-/post-only group and the End-of-Project group. The discussion group (n = 1824) was invited and participated in up to three online discussions, which were held from November 2008 to May 2009. MAIN OUTCOME MEASURES: Behavioural intention, beliefs, attitudes, subjective norm and perceived behavioural control variables were assessed. RESULTS: The most interesting finding was that those participating in online discussions had fewer negative beliefs about volunteering for genetic research, which in turn contributed to more positive attitudes, increased injunctive and descriptive norms and enhanced behavioural control. These relationships, then, were associated with higher intention to participate in genetic research. CONCLUSION: These findings suggest that continuous public discussions seem to positively affect volunteer intention for genetic research through ameliorating fears of negative consequences. PMID- 26979569 TI - Evolutionary development of embryonic cerebrospinal fluid composition and regulation: an open research field with implications for brain development and function. AB - Within the consolidated field of evolutionary development, there is emerging research on evolutionary aspects of central nervous system development and its implications for adult brain structure and function, including behaviour. The central nervous system is one of the most intriguing systems in complex metazoans, as it controls all body and mind functions. Its failure is responsible for a number of severe and largely incurable diseases, including neurological and neurodegenerative ones. Moreover, the evolution of the nervous system is thought to be a critical step in the adaptive radiation of vertebrates. Brain formation is initiated early during development. Most embryological, genetic and evolutionary studies have focused on brain neurogenesis and regionalisation, including the formation and function of organising centres, and the comparison of homolog gene expression and function among model organisms from different taxa. The architecture of the vertebrate brain primordium also reveals the existence of connected internal cavities, the cephalic vesicles, which in fetuses and adults become the ventricular system of the brain. During embryonic and fetal development, brain cavities and ventricles are filled with a complex, protein rich fluid called cerebrospinal fluid (CSF). However, CSF has not been widely analysed from either an embryological or evolutionary perspective. Recently, it has been demonstrated in higher vertebrates that embryonic cerebrospinal fluid has key functions in delivering diffusible signals and nutrients to the developing brain, thus contributing to the proliferation, differentiation and survival of neural progenitor cells, and to the expansion and patterning of the brain. Moreover, it has been shown that the composition and homeostasis of CSF are tightly controlled in a time-dependent manner from the closure of the anterior neuropore, just before the initiation of primary neurogenesis, up to the formation of functional choroid plexuses. In this review, we draw together existing literature about the formation, function and homeostatic regulation of embryonic cerebrospinal fluid, from the closure of the anterior neuropore to the formation of functional fetal choroid plexuses, from an evolutionary perspective. The relevance of these processes to the normal functions and diseases of adult brain will also be discussed. PMID- 26979573 TI - Tracking neighbours promotes the coexistence of large carnivores. AB - The study of competition and coexistence among similar interacting species has long been considered a cornerstone in evolutionary and community ecology. However, understanding coexistence remains a challenge. Using two similar and sympatric competing large carnivores, Eurasian lynx and wolverines, we tested the hypotheses that tracking among heterospecifics and reactive responses to potential risk decreases the probability of an agonistic encounter when predators access shared food resources, thus facilitating coexistence. Lynx and wolverines actively avoided each other, with the degree of avoidance being greater for simultaneous than time-delayed predator locations. Wolverines reacted to the presence of lynx at relatively short distances (mean: 383 m). In general, lynx stayed longer, and were more stationary, around reindeer carcasses than wolverines. However, when both predators were present at the same time around a carcass, lynx shortened their visits, while wolverine behavior did not change. Our results support the idea that risk avoidance is a reactive, rather than a predictive, process. Since wolverines have adapted to coexist with lynx, exploiting lynx-killed reindeer carcasses while avoiding potential encounters, the combined presence of both predators may reduce wolverine kill rate and thus the total impact of these predators on semi-domestic reindeer in Scandinavia. Consequently, population management directed at lynx may affect wolverine populations and human-wolverine conflicts. PMID- 26979574 TI - Nanosized, peptide-based multicomponent DNA delivery systems: optimization of endosome escape activity. AB - AIM: Endosome escape is essential for developing effective nonviral gene delivery systems. Herein, three endosome-disrupting peptides (HA2(1-20), GALA and KALA) were incorporated into a multicomponent oligonucleotide delivery system to identify which peptide imparted the most favorable endosome escape and toxicity profile. MATERIALS & METHODS: Copper (I)-catalyzed azide-alkyne cycloaddition was used to construct multicomponent delivery vectors. The systems were evaluated for size, toxicity, cellular uptake and endosome escape activity. RESULTS: Each system condensed plasmid DNA to form nanosized particles. The highest cellular uptake and endosome escape were associated with GALA and KALA containing systems, with KALA incorporation correlating with greater toxicity. CONCLUSION: GALA was selected as the most promising endosome-disrupting peptide for incorporation into the nanosized oligonucleotide delivery system. PMID- 26979572 TI - Coping with Depression in Single Black Mothers. AB - Very little information exists in the literature about what black women do when they experience symptoms of depression. The purpose of this descriptive study was to analyze the responses of 208 community-residing black single mothers, aged 18 to 45, to an open-ended question asking, "What do you do to feel better when you are feeling down in the dumps?" The theoretical bases of the Ways of Coping Checklist, were used to facilitate categorizing their responses into a coping scale and then a particular coping profile. Percentages were used to categorize the frequency of the responses into the respective coping scale and to categorize the frequency of the combined responses of each woman into a respective coping profile. Of the 333 responses that the women provided, 327 were useable. Findings indicated that a majority of responses fell into the Escape-Avoidance category (n = 206; 63%), followed by the Seeking Social Support (n = 60, 18.3%), Positive Reappraisal (n = 40; 12.2%), Planful Problem Solving (n = 12; 3.7%), Distancing (n = 3; 1%), and Self-Controlling (n = 6; 1.8%) categories. No responses fit the Confrontive Coping or Accepting Responsibility categories and none of the responses indicated that the women sought professional help. Of the 176 women who provided answers to the study question, more than half (64.2%; n = 113) gave only emotion-focused responses, 2.8% (n = 5) gave only problem-focused responses, 2.8% (n = 5) gave mixed responses, and 30.2% (n = 53) reported social support seeking. Implications for future research, cultural theory, and nursing practice are addressed. PMID- 26979575 TI - Transurethral Pneumatic Cystolithotripsy: A Novel Approach. AB - OBJECTIVE: Various endoscopic instruments used in treating renal stones have been used in managing bladder calculi. Our aim is to evaluate the use of transurethral ureteroscopic pneumatic cystolithotripsy for the management of large bladder calculi. PATIENTS AND METHODS: In a retrospective study conducted between May 2005 and July 2011, 53 patients with solitary bladder stones were subjected to our technique, transurethral ureteroscopic pneumatic cystolithotripsy. The mean patient age was 54.3 years. The mean stone size was 4.8 cm. Diagnostic cystoscopy was performed first. A semirigid ureteroscope with a pneumatic probe was introduced through the cystoscope sheath, and pneumatic lithotripsy was performed. The cystoscope sheath works as a draining channel, allowing bladder evacuation. The bladder collapses over the stone and, subsequently, prevents stone migration, which shortens the lithotripsy's duration. Stone immobilization allows the transmission of full pneumatic power to the stone. The stone fragments were removed through periodic bladder irrigation using an Ellick evacuation irrigation system, and a 16F Foley catheter was placed at the end of the procedure. RESULTS: Our technique was effective in all cases, including stone free bladders. No surgical complications were detected. The mean operative time was 83 +/- 21.0 minutes, which is comparable to that of standard management. The mean duration of lithotripsy and evacuation was 29.7 +/- 18.4 minutes. In the postoperative period, patients were followed up for 18 months, with no urethral stricture being reported in any case. CONCLUSION: The transurethral ureteroscopic pneumatic cystolithotripsy procedure is a safe technique for the management of large bladder calculi. It allows the bladder to collapse over the stone, leading to stone immobilization and, subsequently, decreasing lithotripsy duration. Our procedure is associated with a minimal chance of postoperative urethral injury because all stone fragments are evacuated through the cystoscope sheath, without contact with the urethral urothelium. PMID- 26979576 TI - A Delphi process to address medication appropriateness for older persons with multiple chronic conditions. AB - BACKGROUND: Frameworks exist to evaluate the appropriateness of medication regimens for older patients with multiple medical conditions (MCCs). Less is known about how to translate the concepts of the frameworks into specific strategies to identify and remediate inappropriate regimens. METHODS: Modified Delphi method involving iterative rounds of input from panel members. Panelists (n = 9) represented the disciplines of nursing, medicine and pharmacy. Included among the physicians were two geriatricians, one general internist, one family practitioner, one cardiologist and two nephrologists. They participated in 3 rounds of web-based anonymous surveys. RESULTS: The panel reached consensus on a set of markers to identify problems with medication regimens, including patient/caregiver report of non-adherence, medication complexity, cognitive impairment, medications identified by expert opinion as inappropriate for older persons, excessively tight blood sugar and blood pressure control among persons with diabetes mellitus, patient/caregiver report of adverse medication effects or medications not achieving desired outcomes, and total number of medications. The panel also reached consensus on approaches to address these problems, including endorsement of strategies to discontinue medications with known benefit if necessary because of problems with feasibility or lack of alignment with patient goals. CONCLUSIONS: The results of the Delphi process provide the basis for an algorithm to improve medication regimens among older persons with MCCs. The algorithm will require assessment not only of medications and diagnoses but also cognition and social support, and it will support discontinuation of medications both when risks outweigh benefits and when regimens are not feasible or do not align with goals. PMID- 26979577 TI - Simultaneous determination of 8-oxo-2'-deoxyguanosine and 8-oxo-2'-deoxyadenosine in human retinal DNA by liquid chromatography nanoelectrospray-tandem mass spectrometry. AB - Age-related macular degeneration (AMD) is the leading cause of blindness among older adults in the developed world. Oxidative damage to mitochondrial DNA (mtDNA) in the retinal pigment epithelium (RPE) may play a key role in AMD. Measurement of oxidative DNA lesions such as 8-oxo-2'-deoxyguanosine (8-oxo-dG) and 8-oxo-2'-deoxyadenosine (8-oxo-dA) in diseased RPE could provide important insights into the mechanism of AMD development. We have developed a liquid chromatography-nanoelectrospray ionization-tandem mass spectrometry method for simultaneous analysis of 8-oxo-dG and 8-oxo-dA in human retinal DNA. The developed method was applied to the analysis of retinal DNA from 5 donors with AMD and 5 control donors without AMD. In mtDNA, the levels of 8-oxo-dG in controls and AMD donors averaged 170 and 188, and 8-oxo-dA averaged 11 and 17 adducts per 10(6) bases, respectively. In nuclear DNA, the levels of 8-oxo-dG in controls and AMD donors averaged 0.54 and 0.96, and 8-oxo-dA averaged 0.04 and 0.05 adducts per 10(6) bases, respectively. This highly sensitive method allows for the measurement of both adducts in very small amounts of DNA and can be used in future studies investigating the pathophysiological role of 8-oxo-dG and 8-oxo dA in AMD and other oxidative damage-related diseases in humans. PMID- 26979580 TI - Guest editorial: Deconstructing disorder: An ordered reaction to a disordered environment. PMID- 26979578 TI - Intrauterine growth restriction - part 2. AB - Small for gestational age (SGA) infants have been classically defined as having birth weight less than two standard deviations below the mean or less than the 10th percentile of a population-specific birth weight for specific gestational age, whereas intrauterine growth restriction (IUGR) has been defined as a rate of foetal growth that is less than normal for the population and for the growth potential of a specific infant. SGA infants have more frequent problems such as perinatal asphyxia, hypothermia, hypoglycaemia, polycythaemia and many more when compared with their appropriate for gestational age counterpart. They too have growth retardation and various major and subtle neurodevelopmental handicaps, with higher rates of perinatal and neonatal mortality. With the advent of newer technologies, even though the perinatal diagnosis of these SGA/IUGR foetuses has increased, but still perinatal morbidity and mortality rates are higher than normal foetuses and infants. In this part, we have covered neonatal IUGR classification, postnatal diagnosis, short-term and long-term complications faced by these IUGR infants. PMID- 26979581 TI - Towards the end of life: An in-depth exploration of the role of Admiral Nursing in dementia care (Innovative practice). AB - There are approximately 150 Admiral Nurses in the UK who work alongside other health and social care professionals to support people with dementia and their family carers. However, the stigma of the disease and the lack of recognition that dementia is a life limiting illness have led to neglect in addressing the end of life challenges. The small in-depth study reported here aimed to add to an extremely limited formal evidence base for the effectiveness of this approach and to develop a greater understanding of the range of knowledge and skills required of them in ensuring they are better able to support families in the later stages of the illness. Findings focus on the experiences of family carers, the impact of performing the Admiral Nurse role and the use of qualitative measures in this setting. PMID- 26979582 TI - Evaluation of 'Dementia Friends' programme for undergraduate nursing students: Innovative practice. AB - The 'dementia friends' programme was launched by the Alzheimer's Society in the UK two years ago with the purpose of educating members of the public about the things they can do which can enhance the lives of people living with dementia. The aim of this project was to deliver a two-hour 'Dementia Friendly Community Workshop' written by the Alzheimer's Society, to an entire cohort of first-year undergraduate nursing students in one Higher Education Institutions in Northern Ireland. Following delivery of the programme, students were asked to complete a short questionnaire on their knowledge and confidence in relation to dementia care before and after the Dementia Friendly Community programme. A total of 322 undergraduate first-year nursing students took part in the Dementia Friendly Community programme. Of these, 304 returned questionnaires; 31.25% of students stated their perceived improvement in dementia knowledge was 'good' while 49.01% stated their perceived improvement in dementia knowledge was 'very good' and 13.49% stated their perceived improvement in dementia knowledge was 'excellent'. In relation to confidence in engaging with people with dementia, 31.91% stated 'good' improvement, 40.79% stated 'very good' improvement and 11.84% stated 'excellent' improvement. The Dementia Friendly Community programme was positively reviewed by the undergraduate students as it enhanced knowledge and confidence in relation to care of someone living with dementia. PMID- 26979584 TI - [Internal mammary node irradiation in early node-positive breast cancer: Improved survival]. PMID- 26979583 TI - Postprandial changes in cardiometabolic disease risk in young Chinese men following isocaloric high or low protein diets, stratified by either high or low meal frequency - a randomized controlled crossover trial. AB - BACKGROUND: Cardio-Metabolic Disease (CMD) is the leading cause of death globally and particularly in Asia. Postprandial elevation of glycaemia, insulinaemia, triglyceridaemia are associated with an increased risk of CMD. While studies have shown that higher protein intake or increased meal frequency may benefit postprandial metabolism, their combined effect has rarely been investigated using composite mixed meals. We therefore examined the combined effects of increasing meal frequency (2-large vs 6-smaller meals), with high or low-protein (40 % vs 10 % energy from protein respectively) isocaloric mixed meals on a range of postprandial CMD risk markers. METHODS: In a randomized crossover study, 10 healthy Chinese males (Age: 29 +/- 7 years; BMI: 21.9 +/- 1.7 kg/m(2)) underwent 4 dietary treatments: CON-2 (2 large Low-Protein meals), CON-6 (6 Small Low Protein meals), PRO-2 (2 Large High-Protein meals) and PRO-6 (6 Small High Protein meals). Subjects wore a continuous glucose monitor (CGM) and venous blood samples were obtained at baseline and at regular intervals for 8.5 h to monitor postprandial changes in glucose, insulin, triglycerides and high sensitivity C reactive protein (hsCRP). Blood pressure was measured at regular intervals pre- and post- meal consumption. Urine was collected to measure excretion of creatinine and F2-isoprostanes and its metabolites over the 8.5 h postprandial period. RESULTS: The high-protein meals, irrespective of meal frequency were beneficial for glycaemic health since glucose incremental area under the curve (iAUC) for PRO-2 (185 +/- 166 mmol.min.L(-1)) and PRO-6 (214 +/- 188 mmol.min.L( 1)) were 66 and 60 % lower respectively (both p < 0.05), compared with CON-2 (536 +/- 290 mmol.min.L(-1)). The iAUC for insulin was the lowest for PRO-6 (13.7 +/- 7.1 U.min.L(-1)) as compared with CON-2 (28.4 +/- 15.6 U.min.L(-)1), p < 0.001. There were no significant differences in postprandial responses in other measurements between the dietary treatments. CONCLUSIONS: The consumption of composite meals with higher protein content, irrespective of meal frequency appears to be beneficial for postprandial glycemic and insulinemic responses in young, healthy Chinese males. Implications of this study may be useful in the Asian context where the consumption of high glycemic index, carbohydrate meals is prevalent. TRIAL REGISTRATION: NCT02529228 . PMID- 26979586 TI - Life cycle of the taiga tick Ixodes persulcatus (Acari: Ixodidae) in the North West of Russia. AB - The life cycle of Ixodes persulcatus lasts 3 years in the conditions of the Leningrad province (North-West Russia), the development of each phase taking a year. The normal age of the taiga tick is 3 years. The calendar age of larvae and nymphs reaches 11-12 months under favorable abiotic and biotic factors, while the calendar age of adults does not exceed 11 months. At the preimaginal phases of development the ticks that breed in August can feed before or after winter. However, their metamorphosis begins and reaches completion within the same timeframes (from late June to early August) and lasts for about 30-50 (60) days. The survival rate of hungry and engorged larvae and nymphs after wintering is quite high (88.6-100 %). We explain the low activity of larvae and nymphs in late summer and autumn by incomplete development. Morphogenetic diapause of engorged larvae and nymphs interrupts digestion but not metamorphosis which starts only in late June and July after the complete absorption of blood from the gut cavity. PMID- 26979585 TI - Esterase mediated resistance in deltamethrin resistant reference tick colony of Rhipicephalus (Boophilus) microplus. AB - Monitoring of acaricide resistance is considered as one of the important facets of integrated tick management. In an attempt of development of resistance monitoring indicators, in the present study two reference tick lines of Rhipicephalus (Boophilus) microplus maintained in the Entomology laboratory, Indian Veterinary Research Institute (IVRI), Izatnagar, India, were studied to determine the possible contributing factors involved in development of resistance to deltamethrin. Electrophoretic profiling of esterase enzymes detected high activities of EST-1 in reference resistant tick colony designated as IVRI-IV whereas it was not detectable in reference susceptible IVRI-I line of R. (B.) microplus. Esterases were further characterized as carboxylesterase or acetylcholinesterase based on inhibitor study using PMSF, eserine sulphate, malathion, TPP and copper sulphate. It was concluded that an acetylcholinesterase, EST-1, possibly plays an important role for development of deltamethrin resistance in IVRI-IV colony of R. (B.) microplus. PMID- 26979587 TI - Decreased mental time travel to the past correlates with default-mode network disintegration under lysergic acid diethylamide. AB - This paper reports on the effects of LSD on mental time travel during spontaneous mentation. Twenty healthy volunteers participated in a placebo-controlled crossover study, incorporating intravenous administration of LSD (75 MUg) and placebo (saline) prior to functional magnetic resonance imaging (fMRI). Six independent, blind judges analysed mentation reports acquired during structured interviews performed shortly after the functional magnetic resonance imaging (fMRI) scans (approximately 2.5 h post-administration). Within each report, specific linguistic references to mental spaces for the past, present and future were identified. Results revealed significantly fewer mental spaces for the past under LSD and this effect correlated with the general intensity of the drug's subjective effects. No differences in the number of mental spaces for the present or future were observed. Consistent with the previously proposed role of the default-mode network (DMN) in autobiographical memory recollection and ruminative thought, decreased resting-state functional connectivity (RSFC) within the DMN correlated with decreased mental time travel to the past. These results are discussed in relation to potential therapeutic applications of LSD and related psychedelics, e.g. in the treatment of depression, for which excessive reflection on one's past, likely mediated by DMN functioning, is symptomatic. PMID- 26979588 TI - Colour correct: the interactive effects of food label nutrition colouring schemes and food category healthiness on health perceptions. AB - OBJECTIVE: The purpose of the present study was to examine the effects of food label nutrition colouring schemes in interaction with food category healthiness on consumers' perceptions of food healthiness. Three streams of colour theory (colour attention, colour association and colour approach-avoidance) in interaction with heuristic processing theory provide consonant predictions and explanations for the underlying psychological processes. DESIGN: A 2 (food category healthiness: healthy v. unhealthy)*3 (food label nutrient colouring schemes: healthy=green, unhealthy=red (HGUR) v. healthy=red, unhealthy=green (HRUG) v. no colour (control)) between-subjects design was used. SETTING: The research setting was a randomised-controlled experiment using varying formats of food packages and nutritional information colouring. SUBJECTS: Respondents (n 196) sourced from a national consumer panel, USA. RESULTS: The findings suggest that, for healthy foods, the nutritional colouring schemes reduced perceived healthiness, irrespective of which nutrients were coloured red or green (healthinesscontrol=4.86; healthinessHGUR=4.10; healthinessHRUG=3.70). In contrast, for unhealthy foods, there was no significant difference in perceptions of food healthiness when comparing different colouring schemes against the control. CONCLUSIONS: The results make an important qualification to the common belief that colour coding can enhance the correct interpretation of nutrition information and suggest that this incentive may not necessarily support healthier food choices in all situations. PMID- 26979589 TI - High resolution scanning near field mapping of enhancement on SERS substrates: comparison with photoemission electron microscopy. AB - The need for a dedicated spectroscopic technique with nanoscale resolution to characterize SERS substrates pushed us to develop a proof of concept of a functionalized tip-surface enhanced Raman scattering (FTERS) technique. We have been able to map hot spots on semi-continuous gold films; in order to validate our approach we compare our results with photoemission electron microscopy (PEEM) data, the complementary electron microscopy tool to map hot spots on random metallic surfaces. Enhanced Raman intensity maps at high spatial resolution reveal the localisation of hotspots at gaps for many neighboring nanostructures. Finally, we compare our findings with theoretical simulations of the enhancement factor distribution, which confirms a dimer effect as the dominant origin of hot spots. PMID- 26979590 TI - Incidence and risk factors for morbidity and mortality in elderly head and neck cancer patients undergoing major oncological surgery. AB - PURPOSE: Cancer incidence in the elderly population has been continuously rising, and their treatment is an increasing concern among oncologists. This study aimed to evaluate the incidence and risk factors for morbidity and mortality after major oncological surgery in elderly patients with head and neck squamous cell carcinoma (HNSCC). METHODS: The 196 HNSCC patients aged 55 and older who underwent major curative surgery. Patients were categorized into three groups: far-old (>=75 years; n = 41); old (65-74 years; n = 72); or middle-aged (55-64 years; n = 83). The rates of early and late postoperative complications, hospital stays, and mortality were compared among groups. Univariate and multivariate analyses were performed to identify the factors associated with early postoperative complications. RESULTS: No study patients had mortality during surgery or within 3-month postoperation. Karnofsky performance status, frail functional status, comorbidity, and index cancer and noncancer mortality were the poorest in the far-old group. The far-old group demonstrated significantly higher rates of early overall complications, readmission within 1 month, and recurrence rates (P < 0.05 each). Multivariate analysis showed that age, postoperative hemoglobin, and C-reactive protein are independent predictors of early postoperative complications (P < 0.05 each). CONCLUSIONS: In elderly patients, chronological age affects the increased risk of early postoperative morbidity and later mortality following major HNSCC surgery. In combination with these risk factors, older patients who are diagnosed with HNSCC should be carefully monitored in order to determine the potential occurrence of postsurgical complications. PMID- 26979591 TI - Reporting transparency: making the ethical mandate explicit. AB - Improving the transparency and quality of reporting in biomedical research is considered ethically important; yet, this is often based on practical reasons such as the facilitation of peer review. Surprisingly, there has been little explicit discussion regarding the ethical obligations that underpin reporting guidelines. In this commentary, we suggest a number of ethical drivers for the improved reporting of research. These ethical drivers relate to researcher integrity as well as to the benefits derived from improved reporting such as the fair use of resources, minimizing risk of harms, and maximizing benefits. Despite their undoubted benefit to reporting completeness, questions remain regarding the extent to which reporting guidelines can influence processes beyond publication, including researcher integrity or the uptake of scientific research findings into policy or practice. Thus, we consider investigation on the effects of reporting guidelines an important step in providing evidence of their benefits. PMID- 26979592 TI - Media and Sexualization: State of Empirical Research, 1995-2015. AB - Sexually objectifying portrayals of women are a frequent occurrence in mainstream media, raising questions about the potential impact of exposure to this content on others' impressions of women and on women's views of themselves. The goal of this review was to synthesize empirical investigations testing effects of media sexualization. The focus was on research published in peer-reviewed, English language journals between 1995 and 2015. A total of 109 publications that contained 135 studies were reviewed. The findings provided consistent evidence that both laboratory exposure and regular, everyday exposure to this content are directly associated with a range of consequences, including higher levels of body dissatisfaction, greater self-objectification, greater support of sexist beliefs and of adversarial sexual beliefs, and greater tolerance of sexual violence toward women. Moreover, experimental exposure to this content leads both women and men to have a diminished view of women's competence, morality, and humanity. Limitations with the existing research approaches and measures are discussed, and suggestions for future research directions are provided. PMID- 26979594 TI - Tumour Risk with Once-Weekly Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes Mellitus Patients: A Systematic Review. AB - BACKGROUND AND OBJECTIVE: Once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a novel class of injectable antidiabetic drugs. Previous studies indicated that GLP-1RAs (exenatide and liraglutide) might increase the incidence of pancreatitis and pancreatic cancer. Here, we evaluated the clinical safety of once-weekly GLP-1RAs with respect to tumour risk. METHODS: Relevant studies were selected from ClinicalTrials.gov. Randomized controlled trials that reported the incidences of neoplasms were included in our research. Outcomes were calculated as the risk ratio using the Mantel-Haenszel method and fixed-effects model. RESULTS: Our analysis included 26 randomized controlled trials with 16,090 patients. Once-weekly GLP-1RAs did not increase the risk for tumours compared with other antidiabetic drugs [risk ratio (RR), 1.02; 95 % confidence interval (CI), 0.74-1.41; p = 0.91]; this finding was independent of the type of GLP-1RA administered (albiglutide, exenatide extended-release and dulaglutide) and duration of the trials (limited to >=52 weeks). Subgroup analyses revealed that once-weekly GLP-1RAs did not increase tumour risk compared with placebos, exenatide and liraglutide, insulin or oral drugs. Additionally, once-weekly GLP 1RAs did not increase tumour risk in any tissue. CONCLUSIONS: Compared with other antidiabetic drugs, once-weekly GLP-1RAs did not increase the risk for any tumour, and this finding was independent of the type of GLP-1RA administered and treatment duration. However, our study had many limitations, and further longer term trials with larger samples should be conducted in future to confirm our results. PMID- 26979595 TI - Expression and characterization of tissue inhibitor of metalloproteinase 4 from complex canine mammary carcinomas. AB - All four members of the tissue inhibitors of metalloproteinase (TIMP) family have been reported to be over-expressed in breast cancer cells in vitro. Dysregulation of TIMP-4 expression predicts poor prognosis in cancers. The present study evaluated the association of the expression levels of TIMP-4 with mammary tumor development in dogs, measured by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Mammary tissue samples were collected from healthy canine mammary gland and from tumor subjects. TIMP-4 expression was found to be upregulated (5.856 times) in complex canine mammary carcinomas. Also, TIMP 4 mature peptide was expressed heterologously in E. coli. The recombinant protein was purified by Ni- NTA affinity chromatography and further confirmed by western blotting. The rTIMP-4 was found to be functionally active and could inhibit matrix metalloproteinase 11(MMP-11) activity. Immunization of mice with rTIMP-4 resulted in increased antigen specific serum antibody titer, and this serum could be suitably used to detect and quantify the protein in sera of dogs with mammary tumors. TIMP-4 could act as a marker of canine mammary tumors. To the best of our knowledge, this is the first report of heterologous expression of TIMP-4 from complex canine mammary carcinomas. PMID- 26979593 TI - Health-Related Quality of Life During Routine Treatment with the SQ-Standardised Grass Allergy Immunotherapy Tablet: A Non-Interventional Observational Study. AB - BACKGROUND AND OBJECTIVE: Allergy immunotherapy (AIT) with the SQ((r)) grass sublingual immunotherapy (SLIT)-tablet has been shown to be efficacious, well tolerated and to improve disease-specific health-related quality of life (HRQoL) in controlled clinical trials. The aim of our study was to investigate HRQoL in patients with allergic rhinoconjunctivitis routinely treated with the SLIT-tablet and taking symptomatic medication as needed compared with patients treated only with symptomatic medication. METHODS: In a non-interventional, open-label study, patients treated with the SLIT-tablet were observed for about 12 months compared with patients only symptomatically treated. Patients assessed their HRQoL with the 12-Item Short Form Health Survey (SF-12) and the Rhinitis Quality of Life Questionnaire (RQLQ) in the grass pollen seasons (GPS) at baseline (GPS1, HRQoL1), after GPS1 (HRQoL2) and in the following GPS (GPS2, HRQoL3). Tolerability, compliance, symptoms and medication use were assessed in the SLIT tablet group by the physician. RESULTS: Overall, data were analysed in 576 patients. Mean differences (+/-SD) in overall scores for HRQoL3 versus HRQoL1 (186 patients) of SF-12 were +11.4 +/- 16.8 (SLIT-tablet) and -3.4 +/- 15.7 (symptomatic medication), (p < 0.0001), and of RQLQ -1.31 +/- 1.07 and +0.10 +/- 0.74 (p < 0.001), and for HRQoL3 versus HRQoL2 (238 patients) of SF-12 -1.6 +/- 15.3 and -10.0 +/- 14.1 (p = 0.0003), and of RQLQ +0.22 +/- 1.29 and +1.24 +/- 1.30 (p < 0.0001). Tolerability and adherence for the SLIT-tablet were comparable with data of other non-interventional studies. CONCLUSIONS: Routine treatment with the SQ((r)) grass SLIT-tablet resulted in clear improvements in disease specific and general quality of life, while no improvements were observed in patients treated only symptomatically. PMID- 26979598 TI - Combined experimental and density functional theory studies of an organic inorganic hybrid perovskite. AB - Single crystals of [C6H5-C2H4-NH3]2ZnCl4 were obtained by slow evaporation at room temperature. Single-Crystal X-Ray Diffraction (SCXRD), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA) and UV-Visible spectroscopy were used to characterize the crystal structure, and thermal and optical properties, respectively. At 293 K, PEA-ZnCl4 crystallizes in a monoclinic unit cell in the P21/c space group a = 7.449(2) A, b = 24.670(3) A, c = 11.187(2) A and beta = 91.762(5) degrees , V = 2054.8(2) A(3) and Z = 4. The DSC and TGA analyses show respectively the presence of two first order reversible phase transitions and a sample thermal stability below 541 K. The optical study reveals that the compound undergoes a direct optical transition and an energy gap about of Eg = 4.46 eV. In parallel, ab initio DFT calculations are performed to study the electronic band structure, to examine electronic density and to calculate the gap energy value. The calculated values are in good agreement with the experimental data. PMID- 26979599 TI - Very long-term clinical and angiographic outcomes after sirolimus- and paclitaxel eluting stent placement for ST-elevation myocardial infarction: a propensity score-matched comparison. AB - We conducted a retrospective examination of the very long-term outcomes of placing sirolimus (SES) and paclitaxel (PES)-eluting stents in patients with ST elevation myocardial infarction (STEMI). This was a nonrandomized, retrospective, single-center study that included 872 first STEMI patients who underwent successful placement of either SES (n = 547) or PES from November 2004 to April 2012. The primary end point was the incidence of severe cardiac events comprising cardiac death, nonfatal recurrent myocardial infarction, and definite stent thrombosis (ST). The frequency of target lesion revascularization (TLR) was also compared. A propensity score-matched analysis was used to adjust the 29 baseline variables. In the baseline-adjusted cohorts in 231 STEMI patients in each arm, the frequency of the primary end point in the SES group (5.6 %) during the follow up duration of 2583 +/- 806 days was not significantly different from that in the PES group (6.1 %, follow-up: 1866 +/- 699 days). The cumulative primary end point free ratio in the SES group was not significantly different from that in the PES group (p = 0.503). The frequency of TLR in the SES group (7.5 %) was significantly lower than that in the PES group (16.9 %, p = 0.005), with and the significantly higher cumulative TLR-free ratio in the SES group than that in the PES group (p < 0.001). The very long-term clinical outcomes after SES or PES placement for STEMI patients were statistically equivalent. SES showed the better angiographic outcomes for STEMI compared to PES. PMID- 26979596 TI - Nephrotoxicity of cisplatin combination chemotherapy in thoracic malignancy patients with CKD risk factors. AB - BACKGROUND: Nephrotoxicity is the major side effect that limits the dose of cisplatin that can be safely administered, and it is a clinical problem in cancer patients who received cisplatin combination chemotherapy. Recent evidence has demonstrated that patients with chronic kidney disease (CKD) have an increased risk of developing acute kidney injury (AKI). The present study was conducted to evaluate the prevalence of CKD risk factors in patients who received cisplatin and to assess the correlation between CKD risk factors and cisplatin-induced AKI. METHODS: We retrospectively analyzed 84 patients treated with cisplatin combination chemotherapy for thoracic malignancies. AKI was defined as a decrease in the estimated glomerular filtration rate (eGFR) > 25% from base line, an increase in the serum creatinine (sCre) level of > 0.3 mg/dl or >= 1.5 times the baseline level. RESULTS: Eighty of the 84 patients (95.2%) had at least one risk factor for CKD. All enrolled patients received cisplatin with hydration, magnesium supplementation and mannitol. Cisplatin-induced AKI was observed in 18 patients (21.4%). Univariate analysis revealed that cardiac disease and use of non-steroidal anti-inflammatory drugs (NSAIDs) were associated with cisplatin induced nephrotoxicity (odds ratios [OR] 6 and 3.56, 95% confidence intervals [CI] 1.21-29.87 and 1.11-11.39, p = 0.04 and p = 0.04, respectively). Multivariate analysis revealed that cisplatin nephrotoxicity occurred significantly more often in patients with both risk factors (OR 13.64, 95% CI 1.11-326.83, p = 0.04). Patients with more risk factors for CKD tended to have a greater risk of developing cisplatin-induced AKI. CONCLUSIONS: We should consider avoiding administration of cisplatin to patients with CKD risk factors, particularly cardiac disease and NSAID use. PMID- 26979597 TI - Genome-wide gene expression analyses reveal unique cellular characteristics related to the amenability of HPC/HSCs into high-quality induced pluripotent stem cells. AB - BACKGROUND: Transcription factor-mediated reprogramming can efficiently convert differentiated cells into induced pluripotent stem cells (iPSCs). Furthermore, many cell types have been shown to be amenable to reprogramming into iPSCs, such as neural stem cells, hematopoietic progenitor and stem cells (HPC/HSCs). However, the mechanisms related to the amenability of these cell types to be reprogrammed are still unknown. METHODS: Herein, we attempt to elucidate the mechanisms of HPC/HSC reprogramming using the sequential reprogramming system that we have previously established. RESULTS: We found that HPC/HSCs were amenable to transcription factor-mediated reprogramming, which yielded a high frequency of fully reprogrammed HPC/HSC-iPSCs. Genome-wide gene expression analyses revealed select down-regulated tumor suppressor and mesenchymal genes as well as up-regulated oncogenes in HPC/HSCs compared with mouse embryonic fibroblasts (MEFs), indicating that these genes may play important roles during the reprogramming of HPC/HSCs. Additional studies provided insights into the contribution of select tumor suppressor genes (p21, Ink4a and Arf) and an epithelial-to-mesenchymal transition (EMT) factor (Snail1) to the reprogramming process of HPC/HSCs. CONCLUSIONS: Our findings demonstrate that HPC/HSCs carry unique cellular characteristics, which determine the amenability of HPC/HSCs to be reprogrammed into high-quality iPSCs. PMID- 26979600 TI - A case of subacute stent thrombosis after drug-coated balloon coronary angioplasty for in-stent restenosis under single anti-platelet therapy. AB - This report describes a case of subacute stent thrombosis (SAT) after drug-coated balloon (DCB). A 79-year-old male was investigated for stable angina. An in-stent restenosis (ISR) lesion was detected by coronary angiography. A skin reaction related to the anti-platelet agent thienopyridine was also observed at this time. Therefore, DCB was used to treat the ISR lesion under single anti-platelet therapy (aspirin). However, 3 days after percutaneous coronary intervention, SAT occurred. OCT did not reveal the underlying cause of SAT. Further data are needed to clarify the optimal duration of dual anti-platelet therapy after DCB. PMID- 26979601 TI - A review on B-type natriuretic peptide monitoring: assays and biosensors. AB - Since its discovery in 1988, B-type natriuretic peptide (BNP) has been recognized as a powerful cardiovascular biomarker for a number of disease states, specifically heart failure. Concurrent with such a discovery, much effort has been allocated to the precise monitoring of physiological BNP levels. Thus, it can be used to guide the therapy of heart failure and determine the patient's stage of disease. Thus, we discuss in this article BNP as a potent biomarker. Subsequently, we will review the progress of biosensing devices as they could be applied to monitor BNP levels as assays, benchtop biosensors and implantable biosensors. The analytical characteristics of commercially available BNP assays are presented. Still emerging as a field, we define four obstacles that present opportunity for the future development of implantable biosensor: foreign body response, sensor renewability, sensitivity and selectivity. PMID- 26979602 TI - Recent advances in ChIP-seq analysis: from quality management to whole-genome annotation. AB - Chromatin immunoprecipitation followed by sequencing (ChIP-seq) analysis can detect protein/DNA-binding and histone-modification sites across an entire genome. Recent advances in sequencing technologies and analyses enable us to compare hundreds of samples simultaneously; such large-scale analysis has potential to reveal the high-dimensional interrelationship level for regulatory elements and annotate novel functional genomic regions de novo. Because many experimental considerations are relevant to the choice of a method in a ChIP-seq analysis, the overall design and quality management of the experiment are of critical importance. This review offers guiding principles of computation and sample preparation for ChIP-seq analyses, highlighting the validity and limitations of the state-of-the-art procedures at each step. We also discuss the latest challenges of single-cell analysis that will encourage a new era in this field. PMID- 26979603 TI - Clinical features and long-term outcomes of systemic lupus erythematosus: comparative data of childhood, adult and late-onset disease in a national register. AB - Systemic lupus erythematosus (SLE) affects predominantly women at reproductive age but may present at any age. Age at disease onset has a modulating effect on presentation and course of disease, but controversies persist regarding its impact on long-term outcome. Our aims were to characterize clinical features, co morbidities and cumulative damage in childhood-onset, adult-onset and late-onset SLE. Patients with childhood-onset SLE fulfilling ACR 1997 criteria were identified in a nationwide register-Reuma.pt/SLE (N = 89) and compared with adult onset and late-onset counterparts matched 1:1:1 for disease duration. 267 SLE patients with mean disease duration of 11.9 +/- 9.3 years were analyzed. Skin (62 %), kidney (58 %), neurological (11 %) and hematologic involvement (76 %) were significantly more common in childhood-onset SLE and disease activity was higher in this subset than in adult- and late-onset disease (SLEDAI-2K 3.4 +/- 3.8 vs. 2.2 +/- 2.7 vs. 1.6 +/- 2.8, respectively; p = 0.004). Also, more childhood-onset patients received cyclophosphamide (10 %) and mycophenolate mofetil (34 %). A greater proportion of women (96 %), prevalence of arthritis (89 %) and anti-SSA antibodies (34 %) were noted in the adult-onset group. There was a significant delay in the diagnosis of SLE in older ages. Co-morbidities such as hypertension, diabetes and thyroid disease were significantly more frequent in late-onset SLE, as well as the presence of irreversible damage evaluated by the SLICC/ACR damage index (20 vs. 26 vs. 40 %; p < 0.001). Greater organ involvement as well as the frequent need for immunosuppressants supports the concept of childhood-onset being a more severe disease. In contrast, disease onset is more indolent but co morbidity burden and irreversible damage are greater in late-onset SLE, which may have implications for patients' management. PMID- 26979605 TI - Quantifying fat and lean muscle in the lower legs of women with knee osteoarthritis using two different MRI systems. AB - Decreased muscle mass and increased fat mass are commonly seen in the thighs of individuals with knee osteoarthritis (OA). Despite the role of calf muscles in activities of daily living and knee mechanics, little work has investigated calf changes in knee OA. Unlike the thigh, muscle and fat in the lower leg can be imaged using a peripheral magnetic resonance imaging (MRI) scanner. We aimed to assess agreement between subcutaneous fat, intermuscular fat (IMF), intramuscular fat (intraMF), and lean muscle volumes acquired using a peripheral 1.0T as compared to a reference whole-body 3.0T MRI scanner. A calf MRI scan from each scanner was acquired from twenty women >55 years with knee OA. The different tissues were segmented on each of ten axial slices for every participant using SliceOmatic 5.0 (Tomovision, Magog, QC). Tissue volumes were determined for each outcome. Agreement between tissue volumes from the two scanners was assessed using intraclass correlation (ICC(2,1)) coefficients, standard error, and Bland Altman plots. Agreement between tissue volumes was strong to very strong, with ICCs ranging from 0.842 to 0.991 for all outcomes. However, wide confidence intervals for IMF and intraMF suggest there is less confidence in agreement with segmentation of images from the 1.0T scanner generally underestimating fat volume relative to the 3.0T scanner. The 3.0T's superior between-tissue contrast likely resulted in more accurate segmentation of IMF and intraMF compared to the 1.0T scanner. Comparisons of tissue volume between studies using different scanners/sequences should be interpreted cautiously. PMID- 26979604 TI - To walk or not to walk: insights from a qualitative description study with women suffering from fibromyalgia. AB - Walking improves health outcomes in fibromyalgia; however, there is low adherence to this practice. The aim of this research was to explore the beliefs of women suffering from fibromyalgia toward walking, and the meaning that they attribute to the behavior of walking as part of their fibromyalgia treatment. This study is a qualitative description research. Forty-six (46) women suffering from fibromyalgia and associated with local fibromyalgia associations located in four different Spanish cities (Elche, Alicante, Madrid, and Talavera de la Reina) participated in focus group discussions in the summer 2012. Thematic content analysis was performed in transcribed verbatim from interviews. Participants perceived several inhibitors for walking even when they had positive beliefs toward its therapeutic value. Whereas participants believed that walking can generate improvement in their disease and their health in general, they did not feel able to actually do so given their many physical impediments. Furthermore, participants struggled with social isolation and stigma, which was lessened through the conscious support of family. Advice from family doctors was also a very important facilitator to participants. In a health care delivery context that favors person-centered care, and in order to foster adherence to walking based fibromyalgia treatments, it is recommended that therapeutic walking programs be tailored to each woman' individual circumstances, and developed in close collaboration with them to help them increase control over their health and their condition. PMID- 26979607 TI - Methane activation on nickel oxide clusters with a concerted mechanism: a density functional theory study of the effect of silica support. AB - The support effect is an important issue in heterogeneous catalysis. A systematic density functional theory (DFT) study was performed to investigate the support effect of a silica model on the initial step of methane activation on NixOx (x =2,3) clusters with a concerted mechanism. Four reactions were examined by exploring their potential energy surfaces (PES): CH4 reacting with unsupported Ni2O2, with silica-supported Ni2O2, with unsupported Ni3O3, and with silica supported Ni3O3. For each reaction, PES with different spin states were explored. For CH4 activation taking place via a concerted mechanism, the reaction barriers in terms of free energy and reaction free energy increased with the involvement of the model silica support. Only one PES made a major contribution to the overall reaction rate of all four reactions examined. No spin transition process was required for the reactions to undergo their most-favorable pathway from their starting reactants. These results provide a deeper insight into the support effect on C-H bond activation of small alkanes in general, and of methane in particular, on supported transition metal catalysts. PMID- 26979606 TI - Matrix-assisted laser desorption/ionization time of flight mass spectrometry for comprehensive indexing of East African ixodid tick species. AB - BACKGROUND: The tick population of Africa includes several important genera belonging to the family Ixodidae. Many of these ticks are vectors of protozoan and rickettsial pathogens including Theileria parva that causes East Coast fever, a debilitating cattle disease endemic to eastern, central and southern Africa. Effective surveillance of tick-borne pathogens depends on accurate identification and mapping of their tick vectors. A simple and reproducible technique for rapid and reliable differentiation of large numbers of closely related field-collected ticks, which are often difficult and tedious to discriminate purely by morphology, will be an essential component of this strategy. Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) is increasingly becoming a useful tool in arthropod identification and has the potential to overcome the limitations of classical morphology-based species identification. In this study, we applied MALDI-TOF MS to a collection of laboratory and field ticks found in Eastern Africa. The objective was to determine the utility of this proteomic tool for reliable species identification of closely related afrotropical ticks. METHODS: A total of 398 ixodid ticks from laboratory maintained colonies, extracted from the hides of animals or systematically collected from vegetation in Kenya, Sudan and Zimbabwe were analyzed in the present investigation. The cytochrome c oxidase I (COI) genes from 33 specimens were sequenced to confirm the tentatively assigned specimen taxa identity on the basis of morphological analyses. Subsequently, the legs of ticks were homogenized and analyzed by MALDI-TOF MS. A collection of reference mass spectra, based on the mass profiles of four individual ticks per species, was developed and deposited in the spectral database SARAMISTM. The ability of these superspectra (SSp.) to identify and reliably validate a set of ticks was demonstrated using the remaining individual 333 ticks. RESULTS: Ultimately, ten different tick species within the genera Amblyomma, Hyalomma, Rhipicephalus and Rhipicephalus (Boophilus) based on molecular COI typing and morphology were included into the study analysis. The robustness of the 12 distinct SSp. developed here proved to be very high, with 319 out of 333 ticks used for validation identified correctly at species level. Moreover, these novel SSp. allowed for diagnostic specificity of 99.7 %. The failure of species identification for 14 ticks was directly linked to low quality mass spectra, most likely due to poor specimen quality that was received in the laboratory before sample preparation. CONCLUSIONS: Our results are consistent with earlier studies demonstrating the potential of MALDI-TOF MS as a reliable tool for differentiating ticks originating from the field, especially females that are difficult to identify after blood feeding. This work provides further evidence of the utility of MALDI-TOF MS to identify morphologically and genetically highly similar tick species and indicates the potential of this tool for large-scale monitoring of tick populations, species distributions and host preferences. PMID- 26979608 TI - Molecular modeling of zinc paddlewheel molecular complexes and the pores of a flexible metal organic framework. AB - A new all-atom first-principles force field (FF) is constructed for the bimetallic, four-bladed zinc paddlewheel (ZPW) motif. Zinc-ligand interactions are described via Morse functions and the angular geometry at the metal centers is modeled with a pure ligand-ligand repulsion term. The ZPW-FF is principally based on 15 DFT-optimized model systems of general formula ZnPR.nL, where ZnP is the base Zn2(O2CR)4 unit, R = H, CH3 or CF3, L = NH3 or pyridine, and n = 0, 1 or 2. It correctly generates the distorted tetrahedral coordination of the uncapped [Zn2(O2CR)4] species in their ground states as well as giving reasonable structures and energies for the higher symmetry D4h transition state conformations. The zinc-ligand Morse function reference distance, r 0 , is further refined against 30 complexes located in the Cambridge Structural Database and this FF is applied to pore models of the flexible metal-organic framework (MOF) [Zn(bdc)2(dabco)]n (bdc = 1,4-benzendicarboxylate; dabco = 1,4 diazabicyclo(2.2.2)octane). A single pore model reproduces the unit cell of the evacuated MOF system while a 3*3 grid model is necessary to provide good agreement with the observed pronounced structural changes upon adsorption of either dimethylformamide or benzene. PMID- 26979609 TI - Suppression of Bm-Caspase-1 Expression in BmN Cells Enhances Recombinant Protein Production in a Baculovirus Expression Vector System. AB - Baculovirus expression vector systems (BEVSs) have been widely used for recombinant protein production. Many studies have tried to improve the recombinant protein production by either modification of BEVSs vectors or by cell line selection. In this study, using a modified shRNA vector, we established a stable Bombyx mori cell line that significantly inhibits expression of caspase-1 after selection. We further compared cell proliferation and viability between caspase-1-suppressed cells and control cells, and found that there is no significant difference in these stable cell lines. We utilized these cell lines to analyze recombinant protein production after infection with recombinant baculovirus. We found that both intracellular and extracellular recombinant protein production significantly increased when expression of caspase-1 is inhibited in BmN cells. These data indicate that blocking the apoptotic pathway is a promising way to enhance recombinant protein production in BEVSs. PMID- 26979610 TI - The Interacting Domains of PREP1 and p160 are Endowed with a Remarkable Structural Stability. AB - PREP1/p160 is a protein complex with relevant physiopathological roles in vivo. p160 regulates PREP1 transcriptional activity by preventing the formation of other PREP1-containing complexes, whereas PREP1 regulates p160 activity by increasing its stability. This induces the repression of the insulin-regulated glucose transporter GLUT4 dampening insulin sensitivity. In spite of the considerable amount of functional studies performed on the PREP1/p160 complex in vivo, a biochemical and structural characterization of this complex has not been so far undertaken, given the poor stability of the recombinant full-length proteins. Here, we report the design and preparation of PREP1 and p160 domains together with preliminary structural and binding studies. PREP1, residues 45-155, and p160, residues 20-160, have been expressed and purified as folded, monomeric domains. The two domains show both all-alpha secondary structures, as demonstrated by CD studies and are endowed with unusually high thermal stabilities. We have also estimated for the first time the PREP1-p160 interaction strength finding that the two recombinant domains interact with a KD ranging between about 0.3 and 1 MUM. Altogether, data suggest that the selected PREP1 and p160 domains are structurally independent and that their structure is underlined by high stability and a prevailing alpha-helical organization. PMID- 26979611 TI - Group Prenatal Care Results in Medicaid Savings with Better Outcomes: A Propensity Score Analysis of CenteringPregnancy Participation in South Carolina. AB - Objectives This study was undertaken to determine the cost savings of prevention of adverse birth outcomes for Medicaid women participating in the CenteringPregnancy group prenatal care program at a pilot program in South Carolina. Methods A retrospective five-year cohort study of Medicaid women was assessed for differences in birth outcomes among women involved in CenteringPregnancy group prenatal care (n = 1262) and those receiving individual prenatal care (n = 5066). The study outcomes examined were premature birth and the related outcomes of low birthweight (LBW) and neonatal intensive care unit (NICU) visits. Because women were not assigned to the CenteringPregnancy group, a propensity score analysis ensured that the inference of the estimated difference in birth outcomes between the treatment groups was adjusted for nonrandom assignment based on age, race, Clinical Risk Group, and plan type. A series of generalized linear models were run to estimate the difference between the proportions of individuals with adverse birth outcomes, or the risk differences, for CenteringPregnancy group prenatal care participation. Estimated risk differences, the coefficient on the CenteringPregnancy group indicator variable from identity-link binomial variance generalized linear models, were then used to calculate potential cost savings due to participation in the CenteringPregnancy group. Results This study estimated that CenteringPregnancy participation reduced the risk of premature birth (36 %, P < 0.05). For every premature birth prevented, there was an average savings of $22,667 in health expenditures. Participation in CenteringPregnancy reduced the incidence of delivering an infant that was LBW (44 %, P < 0.05, $29,627). Additionally, infants of CenteringPregnancy participants had a reduced risk of a NICU stay (28 %, P < 0.05, $27,249). After considering the state investment of $1.7 million, there was an estimated return on investment of nearly $2.3 million. Conclusions Cost savings were achieved with better outcomes due to the participation in CenteringPregnancy among low-risk Medicaid beneficiaries. PMID- 26979613 TI - Ethnic Differences in Gestational Weight Gain: A Population-Based Cohort Study in Norway. AB - Objectives To explore ethnic differences in gestational weight gain (GWG). Methods This was a population-based cohort study conducted in primary care child health clinics in Groruddalen, Oslo, Norway. Participants were healthy pregnant women (n = 632) categorised to six ethnic groups (43 % were Western European women, the reference group). Body weight was measured at 15 and 28 weeks' gestation on average. Data on pre-pregnancy weight and total GWG until delivery were self-reported. The main method of analysis was linear regression adjusting for age, weeks' gestation, pre-pregnancy body mass index, education and severe nausea. Results No ethnic differences were observed in GWG by 15 weeks' gestation. By 28 weeks' gestation, Eastern European women had gained 2.71 kg (95 % confidence interval, CI 1.10-4.33) and Middle Eastern women 1.32 kg (95 % CI 0.14-2.50) more weight on average than the Western European women in the fully adjusted model. Among Eastern European women, the total adjusted GWG was 3.47 kg (95 % CI 1.33-5.61) above the reference group. Other ethnic groups (South Asian, East Asian and African) did not differ from the reference group. When including non-smokers (n = 522) only, observed between-group differences increased and Middle Eastern women gained more weight than the reference group by all time points. Conclusions Eastern European and Middle Eastern women had higher GWG on average than Western European women, especially among the non-smokers. Although prevention of excessive GWG is important for all pregnant women, these ethnic groups might need special attention during pregnancy. PMID- 26979612 TI - Women's Autonomy and Skilled Attendance During Pregnancy and Delivery in Nepal. AB - Objectives This study aims to explore the association between women's autonomy and skilled attendance during pregnancy and delivery in Nepal. Methods We adopt data from the Nepal Demographic and Health Survey (NDHS, 2011). We include only married women who gave birth in the 5 years preceding the survey (N = 4148). Women's autonomy was assessed on the basis of four indicators of decision making: healthcare, visiting friends or relatives, household purchases and spending earned money. Each indicator was dichotomized (yes/no) and then summarized into a single variable to measure overall autonomy. Next, we measured health attendance (skilled vs. unskilled) during antenatal and delivery care. The association between women's autonomy and skilled attendance was analysed using a logistic regression model. Results Most women had a medium (40 %) and high (35 %) level of overall autonomy. The proportion of women accessing skilled providers during antenatal and delivery care was 51 and 36 %. Women with autonomy in healthcare, visiting friends or relatives, making household purchases and spending money earned were associated with a higher likelihood of receiving care from skilled providers during antenatal care and delivery. An elevated probability of access to skilled attendance during antenatal (aOR 1.33; 95 % CI 1.10-1.59) and delivery care (aOR 1.38; 95 % CI 1.12-1.70) was reported among women with higher levels of overall autonomy. Conclusion Women's autonomy was significantly associated with the maternal health care utilization by skilled attendants. This study will provide insights for policy makers to develop strategies in improving maternal health. PMID- 26979614 TI - Birth Weight and Birth Weight for Gestational Age in Relation to Risk of Hospitalization with Primary Hypertension in Children and Young Adults. AB - Introduction Low birth weight has been associated with an increased risk of hypertension in children. Less clear is whether high birth weight is also associated with risk. We evaluated overall and age-specific risks of primary hypertension in children and young adults associated with birth weight and birth weight for gestational age. Methods We conducted a population-based case-control study using linked Washington State birth certificate and hospital discharge data from 1987 to 2003. Cases were persons hospitalized with primary hypertension at 8 24 years of age (n = 533). Controls were randomly selected among those born in the same years who were not hospitalized with hypertension (n = 25,966). Results Birth weight was not related to risk of primary hypertension overall, except for a suggestion of an increased risk associated with birth weight >=4500 g relative to 3500-3999 g (odds ratio (OR) 1.55; 95 % confidence interval (CI) 0.96-2.49). Compared to children born appropriate weight for gestational age, those born small (SGA) (OR 1.32; 95 % CI 1.02-1.71) and large for gestational age (LGA) (OR 1.30; 95 % CI 1.00-1.71) had increased risks of primary hypertension. These overall associations were due to increased risks of hypertension at 15-24 years of age; no associations were observed with risk at 8-14 years of age. Discussion In this study, both SGA and LGA were associated with increased risks of primary hypertension. Our findings suggest a possible nonlinear (U-shaped) association between birth weight for gestational age and primary hypertension risk in children and young adults. PMID- 26979615 TI - The Relation of Neighborhood Income to the Age-Related Patterns of Preterm Birth Among White and African-American Women: The Effect of Cigarette Smoking. AB - Objectives We investigated the contributions of cigarette smoking to the age related patterns of preterm (<37 weeks) birth (PTB) rates among African-American and White women within the context of lifelong neighborhood income. Methods Stratified and multilevel logistic regression analyses were performed on an Illinois transgenerational dataset of non-Hispanic White and African-American infants (1989-1991) and their mothers (1956-1976) with appended US census income information. RESULTS: Among non-smoking African-American women (n = 20,107) with a lifelong residence in lower income neighborhoods, PTB rates decreased from 18.5 % for teens to 15.0 % for 30-35 year-olds, p < 0.0001. The opposite pattern occurred among African-American women smokers (n = 5936) with a lifelong residence in lower income neighborhoods, p < 0.01. Among upwardly mobile African American women smokers (n = 756), PTB rates increased from 11.1 % for teens to 24.9 % for 30-35 year-olds, p < 0.05. Cigarette smoking was not associated with an age-related increase in PTB rates among African-American women with a lifelong residence in upper income neighborhoods. No subgroup of White women, even cigarette smokers with a lifelong residence in lower income neighborhoods, exhibited weathering with regard to PTB. Conclusions A weathering pattern of rising PTB rates with advancing age occurs only among African-American women cigarette smokers with an early-life or lifelong residence in lower income neighborhoods, underscoring the public health policy importance of targeted smoking cessation programs in eliminating the racial disparity in the age-related patterns of PTB rates. PMID- 26979617 TI - Robotic-Assisted Endovascular Pulmonary Artery Foreign Body Retrieval: A Case Report. AB - As intravascular robotics technology continues to evolve, so do the potential applications. The present case describes the use of the Magellan Robotic System within the pulmonary artery. A 61-year-old female was referred for retrieval of a transected port catheter, which had embolized into the pulmonary artery. After a failed attempt using a conventional technique, retrieval was ultimately successful with assistance of the Magellan system. The unique navigational capabilities and stability of the system may make it a valuable tool in pulmonary artery interventions. PMID- 26979616 TI - Endovascular Treatment of Traumatic Pseudoaneurysm of the Superficial Temporal Artery. AB - Pseudoaneurysms of the superficial temporal artery (STA) are rare vascular lesions that mainly occur after blunt head trauma. Diagnosis can be made on clinical grounds and is confirmed by ultrasonography. They are usually treated by open surgery procedures, but when the aneurysm is located in inaccessible areas, catheter embolization can be an alternative therapeutic option. We describe a case of a traumatic pseudoaneurysm of the STA which was treated with the vascular plug embolization. We conclude that endovascular embolization can be an option in the treatment of STA pseudoaneurysms. PMID- 26979618 TI - A valid model for predicting responsible nerve roots in lumbar degenerative disease with diagnostic doubt. AB - OBJECTIVE: To construct and validate a model to predict responsible nerve roots in lumbar degenerative disease with diagnostic doubt (DD). METHODS: From January 2009-January 2013, 163 patients with DD were assigned to the construction (n = 106) or validation sample (n = 57) according to different admission times to hospital. Outcome was assessed according to the Japanese Orthopedic Association (JOA) recovery rate as excellent, good, fair, and poor. The first two results were considered as effective clinical outcome (ECO). Baseline patient and clinical characteristics were considered as secondary variables. A multivariate logistic regression model was used to construct a model with the ECO as a dependent variable and other factors as explanatory variables. The odds ratios (ORs) of each risk factor were adjusted and transformed into a scoring system. Area under the curve (AUC) was calculated and validated in both internal and external samples. Moreover, calibration plot and predictive ability of this scoring system were also tested for further validation. RESULTS: Patients with DD with ECOs in both construction and validation models were around 76 % (76.4 and 75.5 % respectively). RISK FACTORS: more preoperative visual analog pain scale (VAS) score (OR = 1.56, p < 0.01), stenosis levels of L4/5 or L5/S1 (OR = 1.44, p = 0.04), stenosis locations with neuroforamen (OR = 1.95, p = 0.01), neurological deficit (OR = 1.62, p = 0.01), and more VAS improvement of selective nerve route block (SNRB) (OR = 3.42, p = 0.02). VALIDATION: the internal area under the curve (AUC) was 0.85, and the external AUC was 0.72, with a good calibration plot of prediction accuracy. Besides, the predictive ability of ECOs was not different from the actual results (p = 0.532). CONCLUSIONS: We have constructed and validated a predictive model for confirming responsible nerve roots in patients with DD. The associated risk factors were preoperative VAS score, stenosis levels of L4/5 or L5/S1, stenosis locations with neuroforamen, neurological deficit, and VAS improvement of SNRB. A tool such as this is beneficial in the preoperative counseling of patients, shared surgical decision making, and ultimately improving safety in spine surgery. PMID- 26979619 TI - Changes in gene methylation patterns in neonatal murine hearts: Implications for the regenerative potential. AB - BACKGROUND: The neonatal murine heart is able to regenerate after severe injury; this capacity however, quickly diminishes and it is lost within the first week of life. DNA methylation is an epigenetic mechanism which plays a crucial role in development and gene expression regulation. Under investigation here are the changes in DNA methylation and gene expression patterns which accompany the loss of regenerative potential. RESULTS: The MeDIP-chip (methylated DNA immunoprecipitation microarray) approach was used in order to compare global DNA methylation profiles in whole murine hearts at day 1, 7, 14 and 56 complemented with microarray transcriptome profiling. We found that the methylome transition from day 1 to day 7 is characterized by the excess of genomic regions which gain over those that lose DNA methylation. A number of these changes were retained until adulthood. The promoter genomic regions exhibiting increased DNA methylation at day 7 as compared to day 1 are significantly enriched in the genes critical for heart maturation and muscle development. Also, the promoter genomic regions showing an increase in DNA methylation at day 7 relative to day 1 are significantly enriched with a number of transcription factors binding motifs including those of Mfsd6l, Mef2c, Meis3, Tead4, and Runx1. CONCLUSIONS: The results indicate that the extensive alterations in DNA methylation patterns along the development of neonatal murine hearts are likely to contribute to the decline of regenerative capabilities observed shortly after birth. This conclusion is supported by the evidence that an increase in DNA methylation in the neonatal murine heart from day 1 to day 7 occurs in the promoter regions of genes playing important roles in cardiovascular system development. PMID- 26979620 TI - The Forgotten Syndrome? Four Cases of Gradenigo's Syndrome and a Review of the Literature. AB - BACKGROUND: Gradenigo's Syndrome (GS) is defined as the clinical triad of acute otitis media, ipsilateral sixth nerve palsy, and pain in the distribution of the first and the second branches of the fifth nerve. The purpose of this study is to review the literature and report 4 cases of GS. METHODS: The study is a retrospective case series and a review of the literature. Four consecutive patients (aged 5-70 years) treated by otolaryngologists and ophthalmologists for GS in the Capital region of Denmark from 2003 to 2015 are presented. Diagnosis is based on the clinical triad, and in 3 of 4 patients, neuroimaging supports the diagnosis. Follow-up was continued until both the sixth nerve palsy and the ear infection had resolved. Diagnostic work-up and treatment profile are described. RESULTS: In 3 of our 4 reported patients, the presentation of GS was classic with a history of acute otitis media and ipsilateral sixth nerve palsy. One case presented as a chronic case with a sixth nerve palsy secondary to chronic suppurative otitis media (CSOM), with a relapse 6 years later. CONCLUSION: GS is a rare and potentially life-threatening complication to otitis media. GS can present in an acute and chronic form, and should be a differential diagnosis in the workup of unexplained sixth nerve palsy. PMID- 26979621 TI - Pay-for-performance pricing for a breakthrough heart drug: learnings for cell and gene therapies. PMID- 26979624 TI - Pharmacological Management of Bronchorrhea in Malignant Disease: A Systematic Literature Review. AB - CONTEXT: Malignant respiratory tract tumors can lead to massive fluid production, known as bronchorrhea. This symptom can be very distressing itself, and it can lead to or aggravate other symptoms such as dyspnea and cough. Pharmacological treatment options have been reported in the literature. However, no systematic evaluation of their effectiveness has been conducted so far. OBJECTIVES: To systematically identify, appraise, and evaluate the effectiveness of symptomatic pharmacological treatment of bronchorrhea in malignant disease in palliative care. METHODS: A systematic literature review in Medline, Embase, and the Cochrane Database, as well as citation tracking, hand searches of selected journals, and reference lists of retrieved articles, was performed. For the purpose of this review, only symptomatic treatments were considered. RESULTS: No controlled clinical studies could be identified. Twenty of 48 retrieved references were analyzed in detail. These 20 case reports and case series dealt with the symptomatic pharmacological management of bronchorrhea in malignant disease; the other 28 had to be excluded for various reasons. The majority of patients suffered from bronchioloalveolar carcinoma. Reported treatments comprise corticosteroids, macrolide antibiotics, inhaled indomethacin, octreotide, and tyrosine-kinase inhibitors. For some drugs, significant clinical impact on distressing symptoms associated with bronchorrhea was reported. CONCLUSION: There are only very limited data on the pharmacological management of bronchorrhea in malignant disease. Because of the distressing nature of the symptom, a pragmatic management strategy is essential. This can include promising treatment options reported in the literature but should also take into account availability, individual tolerability, and costs. Further research is needed. PMID- 26979625 TI - ATM and ATR signaling at a glance. PMID- 26979623 TI - [A Measure of Participation and Social Inclusion for Use in People with a Chronic Mental Disorder (F-INK)]. AB - Objective To develop and test the psychometric properties of a measure of participation and social inclusion for individuals with a chronic mental disorder - the F-INK. Methods Within a cross-sectional design, mental health patients from different institutional settings (n = 106) and adults from the general population (n = 19) completed the questionnaire in an individual interview with a researcher. To estimate the reliability of two sum-scores on social inclusion and participation, Cronbach's alpha was computed. To appraise the validity, mean scale scores were compared across different study groups. Results For both scales, reliability was qualified as substantial (alpha > 0.70). Study groups showed expected differences in mean scores. Conclusion Preliminary findings suggest that the F-INK may be a useful tool for the assessment of social inclusion and social participation in individuals with a chronic mental disorder. However, further testing of the psychometric properties on a larger population is needed. PMID- 26979626 TI - Orthodontic extrusion for pre-implant site enhancement: Principles and clinical guidelines. AB - PURPOSE: The aim of this paper is to provide a concise overview about the principles of pre-implant orthodontic extrusion, describe methods and techniques available and provide the clinicians with guidelines about its application. STUDY SELECTION: A number of reports describe orthodontic extrusion as a reliable method for pre-implant site enhancement. However, no standard protocols have been provided about the application of this technique. The literature database was searched for studies involving implant site enhancement by means of orthodontic extrusion. Information about the principles, indications and contraindications of this method, type of anchorage, force and time were obtained from the literature. RESULT: Despite that the scarce data is largely limited to case reports and case series, implant site enhancement by means of orthodontic extrusion seems to be a promising option to improve soft and hard tissue conditions prior to implant placement. CONCLUSION: Orthodontic extrusion is being implemented as a treatment alternative to enhance hard and soft tissue prior to implant placement. While the current literature does not provide clear guidelines, the decision making for a specific approach seems to be based on the clinician's preferences. Clinical studies are needed to verify the validity of this treatment option. PMID- 26979627 TI - Isolation and co-cultivation of human macrophages and neutrophils with Plasmodium falciparum-parasitized erythrocytes: An optimized system to study the phagocytic activity to malarial parasites. AB - Macrophages and neutrophils are our front line of defense against invading pathogens. They are professional phagocytic cells that play a key role in the clearance of Plasmodium falciparum-parasitized erythrocytes from the host circulation. A stable in vitro culture system for these cells and parasitized erythrocytes would provide the means to study their immunological responses to infection, potentially revealing important clues for new therapeutic interventions for malaria. Here, we present an optimized protocol for cultivating human peripheral blood monocyte-derived macrophages and neutrophils with Plasmodium falciparum-parasitized erythrocytes. PMID- 26979622 TI - A phosphotyrosine switch regulates organic cation transporters. AB - Membrane transporters are key determinants of therapeutic outcomes. They regulate systemic and cellular drug levels influencing efficacy as well as toxicities. Here we report a unique phosphorylation-dependent interaction between drug transporters and tyrosine kinase inhibitors (TKIs), which has uncovered widespread phosphotyrosine-mediated regulation of drug transporters. We initially found that organic cation transporters (OCTs), uptake carriers of metformin and oxaliplatin, were inhibited by several clinically used TKIs. Mechanistic studies showed that these TKIs inhibit the Src family kinase Yes1, which was found to be essential for OCT2 tyrosine phosphorylation and function. Yes1 inhibition in vivo diminished OCT2 activity, significantly mitigating oxaliplatin-induced acute sensory neuropathy. Along with OCT2, other SLC-family drug transporters are potentially part of an extensive 'transporter-phosphoproteome' with unique susceptibility to TKIs. On the basis of these findings we propose that TKIs, an important and rapidly expanding class of therapeutics, can functionally modulate pharmacologically important proteins by inhibiting protein kinases essential for their post-translational regulation. PMID- 26979628 TI - Pulmonary Macrophages: A New Therapeutic Pathway in Fibrosing Lung Disease? AB - Pulmonary fibrosis (PF) is a growing clinical problem which can result in breathlessness or respiratory failure and has an average life expectancy of 3 years from diagnosis. Therapeutic options for PF are limited and there is therefore a significant unmet clinical need. The recent resurgent interest in macrophage biology has led to a new understanding of lung macrophage origins, biology, and phenotypes. In this review we discuss fibrotic mechanisms and focus on the role of macrophages during fibrotic lung disease. Data from both human and murine studies are reviewed, highlighting novel macrophage-orientated biomarkers for disease diagnosis and potential targets for future anti-fibrotic therapies. PMID- 26979629 TI - Prenatal diethylstilbestrol exposure and high-grade squamous cell neoplasia of the lower genital tract. AB - BACKGROUND: Prenatal diethylstilbestrol (DES) exposure is associated with an excess risk of clear-cell adenocarcinoma of the vagina and cervix, and of high grade squamous neoplasia. OBJECTIVE: We explored whether neoplasia risk remains elevated among DES-exposed women as they age. STUDY DESIGN: In all, 4062 DES exposed and 1837 unexposed daughters were followed for approximately 30 years (1982 through 2013) for pathology-confirmed diagnoses of cervical intraepithelial neoplasia grade >=2 (CIN2+) of the lower genital tract (n = 178). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated adjusting for birth year and individual study cohort. RESULTS: The cumulative incidence of CIN2+ in the DES-exposed group was 5.3% (95% CI, 4.1-6.5%) and in the unexposed group was 2.6% (95% CI, 1.5-3.7%). The HR for DES and CIN2+ was 1.98 (95% CI, 1.33-2.94), and was similar with further adjustment for frequency of cervical cancer screening (HR, 1.97; 95% CI, 1.33-2.93). The HR was 2.10 (95% CI, 1.41-3.13) with additional adjustment for other potential confounders. The HR for DES exposure was elevated through age 44 years (age <45 years HR, 2.47; 95% CI, 1.55-3.94), but not in women age >=45 years (HR, 0.91; 95% CI, 0.39-2.10). In exposed women, HRs for DES were 1.74 (95% CI, 1.09-2.79) among those who had earlier evidence of vaginal epithelial changes (VEC), presumably reflecting glandular epithelium undergoing transformation to normal, adult-type squamous epithelium, and 1.24 (95% CI, 0.75-2.06) among those without VEC, compared with unexposed women. The HRs for DES and CIN2+ were higher among women with earlier intrauterine exposure (HR, 2.64; 95% CI, 1.64-4.25 for <8 weeks' gestation and HR, 1.41; 0.88-2.25 for >=8 weeks' gestation), and lowest when exposure began >15th week (HR, 1.14; 95% CI, 0.59-2.20). CONCLUSION: CIN2+ incidence was higher among the DES exposed, particularly those with early gestational exposure and VEC. The HR for DES and CIN2+ remained positive and significant until the mid-40s, confirming that the recommendation of annual cytological screening among these women is appropriate. Whether those >=45 years of age continue to require increased screening is unclear, and would require a careful weighing of possible risks and benefits. PMID- 26979630 TI - A new minimally invasive treatment for cesarean scar pregnancy and cervical pregnancy. AB - BACKGROUND: Cesarean scar pregnancy and cervical pregnancy are unrelated forms of pathological pregnancies carrying significant diagnostic and treatment challenges, with a wide range of treatment effectiveness and complication rates ranging from 10% to 62%. At times, life-saving hysterectomy and uterine artery embolization are required to treat complications. Based on our previous success with using a single-balloon catheter for the treatment of cesarean scar pregnancy after local injection of methotrexate, we evaluated the use of a double-balloon catheter to terminate the pregnancy while preventing bleeding without any additive treatment. This was a retrospective study. OBJECTIVES: The objective of the study was to describe the placement of a cervical ripening double-balloon catheter as a novel, minimally invasive treatment in patients with cesarean scar and cervical pregnancies to terminate the pregnancy and at the same time prevent bleeding by compressing the blood supply of the gestational sac. STUDY DESIGN: Patients with diagnosed, live cervical pregnancy and cesarean scar pregnancy between 6 and 8 weeks' gestation were considered for the office-based treatment. Paracervical block with 1% lidocaine was administered in 3 patients for pain control. Insertion of the catheter and inflation of the upper balloon were done under transabdominal ultrasound guidance. The lower (pressure) balloon was inflated opposite the gestational sac under transvaginal ultrasound guidance. After an hour, the area of the sac was scanned. When fetal cardiac activity was absent and no bleeding was noted, patients were discharged. After 2-3 days, a follow-up appointment was scheduled for possible catheter removal. Serial ultrasound (US) and serum human chorionic gonadotropin were followed weekly or as needed. RESULTS: Three live cervical pregnancies and 7 live cesarean scar pregnancies were successfully treated. Median gestational age at treatment was 6 6/7 weeks (range 6 1/7 through 7 4/7 weeks). Patients' acceptance for the double balloon treatment was high in spite of the initial low abdominal pressure felt at the inflation of the balloons. All but 1 patient noted vaginal spotting at the follow-up appointment. Only 1 patient experienced bleeding of dark blood. The balloons were in place for a median of 3 days (range, 1-5 days). Median time from treatment to the total drop of human chorionic gonadotropin was 49 days (range, 28-97 days). CONCLUSION: The double balloon is a successful, minimally invasive and well-tolerated single treatment for cervical pregnancy and cesarean scar pregnancy. This simple treatment method has 4 main advantages: it effectively stops embryonic cardiac activity, prevents bleeding complications, does not require any additional invasive therapies, and is familiar to obstetricians gynecologists who use the same cervical ripening catheters for labor induction. Its wider application, however, has to be validated on a larger patient population. PMID- 26979633 TI - An Unsusual Case of Lower Gastrointestinal Bleeding. AB - BACKGROUND: Amyloidosis is a multisystem disease, and can present with multitude of nonspecific symptoms. Gastrointestinal amyloidosis is common, and gastrointestinal (GI) bleeding in these patients has a wide differential diagnosis. The present case features the distinctive endoscopic finding of submucosal hematoma as a clue to immunoglobin light chain (AL) amyloid involvement of the gastrointestinal tract. CASE REPORT: An 81-year-old woman with AL amyloidosis was transferred to the intensive care unit (ICU) for evaluation of GI bleeding. Prior to the bleeding episode, the patient had undergone paracentesis for management of her ascites related to restrictive cardiomyopathy. Initial evaluation was negative for any intra-abdominal catastrophe related to her recent paracentesis. Upper gastrointestinal endoscopy was negative for any source of bleeding. However, colonoscopy showed a ruptured submucosal hematoma, which is a rare but classical finding in patients with amyloidosis. The patient was managed conservatively and did not have any further episodes of bleeding in the hospital. She unfortunately died due to her primary illness 6 weeks after discharge from the hospital. CONCLUSIONS: The finding of submucosal hematoma on endoscopy is a rare but sentinel sign for amyloidosis involvement in the GI tract. PMID- 26979631 TI - Genetic variation associated with preterm birth in African-American women. AB - BACKGROUND: Preterm birth is considered a multifactorial condition; however, emerging evidence suggests that genetic variation among individuals may have an important role. Prior studies have suggested that single-nucleotide polymorphisms associated with genes related to the immune system, and particularly the maternal inflammatory response, may be associated with an increased risk of preterm delivery. OBJECTIVE: The objective of the study was to identify single-nucleotide polymorphisms associated with spontaneous preterm birth <37 weeks within a cohort of African-American women. STUDY DESIGN: This is a secondary analysis of a randomized trial that evaluated periodontal disease and preterm birth. Women were enrolled between 6 and 20 weeks' gestation at 3 prenatal care clinics between 2004 and 2007. Maternal DNA samples were collected and analyzed using a custom 1536 single-nucleotide polymorphismgenotyping array designed to assess genes involved in inflammation. Women were included in this study if they self identified as African American. We excluded women with a multiple gestation or an indicated preterm delivery. We performed allele- and genotype-based analyses to evaluate the association between spontaneous preterm birth and tag single nucleotide polymorphisms. We used a logistic regression to adjust for prior preterm birth in our genotype-based analysis. In a subgroup analysis, we compared women who delivered at <34 weeks' gestation to women who delivered at term. Within the microarray, we identified ancestry informative markers and compared global ancestry estimates among women who delivered preterm with those who delivered at term. RESULTS: Of the 833 African-American women in the study with genotype data, 77 women (9.2%) had a spontaneous preterm birth, whereas 756 women delivered at term. In an allele-based analysis, 4 single-nucleotide polymorphisms related to the genes for protein kinase C-alpha (PRKCA) were associated with increased risk of spontaneous preterm birth <37 weeks, whereas a single single nucleotide polymorphism related to fms-related tyrosine kinase 1 (FLT1) was associated with spontaneous preterm birth <34 weeks. A genotype-based analysis revealed similar associations between single-nucleotide polymorphisms related to the PRKCA genes and spontaneous premature delivery. Additionally, single nucleotide polymorphisms related to matrix metalloproteinase-2 (MMP2), tissue inhibitor of matrix metalloproteinase-2 (TIMP2), and interleukin 16 (IL16) genes were associated with spontaneous preterm birth <37 weeks in genotype-based analysis. Genetic variants related to MMP2, matrix metalloproteinase-1 (MMP1), and leukemia inhibitory factor receptor antisense RNA 1 (LIFR-AS1) genes were associated with higher rates of preterm birth <34 weeks. Ancestry estimates were similar between the women who had a spontaneous preterm birth and those who delivered at term. CONCLUSION: We identified tag single-nucleotide polymorphisms related to 7 genes that are critical to inflammation, extracellular remodeling, and cell signaling that were associated with spontaneous preterm birth in African American women. Specifically, we found a strong association with the PRKCA gene. Genetic variation in these regions of the genome may be important in the pathogenesis of preterm birth. Our results should be considered in the design of future genomic studies in prematurity. PMID- 26979634 TI - Is there a justification for hysterectomy in patients with borderline ovarian tumors? AB - OBJECTIVE: To determine the frequency of uterine involvement in patients with borderline ovarian tumors (BOT) and to evaluate the recurrence risk and survival after hysterectomy. MATERIALS AND METHODS: In two French hospitals: A tertiary referral centre (University hospital centre of Tours, France) and the Alliance community hospital of Tours (France), we reviewed data of consecutive women undergoing surgery for presumed stage I BOT between January 1997 and December 2012. Patients were divided into two groups: patients treated with fertility sparing surgery (group 1) and those treated with radical surgery (group 2). RESULTS: A total of 135 patients were evaluated. 35 had fertility sparing surgery, 81 had radical surgery with hysterectomy and 19 had previous hysterectomy for other reasons. There were more recurrent borderline ovarian disease and more ovarian invasive disease developed in group 1 (p = 0.02, p = 0.04, respectively). Hysterectomy affected favorably borderline disease-free survival, OR = 0.09 95%CI (0.005-0.69), p = 0.04, but perceived benefits may be related to bilateral salpingo-oophorectomy and not hysterectomy directly. PMID- 26979632 TI - The green tea polyphenol EGCG alleviates maternal diabetes-induced neural tube defects by inhibiting DNA hypermethylation. AB - BACKGROUND: Maternal diabetes increases the risk of neural tube defects in offspring. Our previous study demonstrated that the green tea polyphenol, Epigallocatechin gallate, inhibits high glucose-induced neural tube defects in cultured embryos. However, the therapeutic effect of Epigallocatechin gallate on maternal diabetes-induced neural tube defects is still unclear. OBJECTIVE: We aimed to examine whether Epigallocatechin gallate treatment can reduce maternal diabetes-induced DNA methylation and neural tube defects. STUDY DESIGN: Nondiabetic and diabetic pregnant mice at embryonic day 5.5 were given drinking water with or without 1 or 10 MUM Epigallocatechin gallate. At embryonic day 8.75, embryos were dissected from the visceral yolk sac for the measurement of the levels and activity of DNA methyltransferases, the levels of global DNA methylation, and methylation in the CpG islands of neural tube closure essential gene promoters. embryonic day 10.5 embryos were examined for neural tube defect incidence. RESULTS: Epigallocatechin gallate treatment did not affect embryonic development because embryos from nondiabetic dams treated with Epigallocatechin gallate did not exhibit any neural tube defects. Treatment with 1 MUM Epigallocatechin gallate did not reduce maternal diabetes-induced neural tube defects significantly. Embryos from diabetic dams treated with 10 MUM Epigallocatechin gallate had a significantly lower neural tube defect incidence compared with that of embryos without Epigallocatechin gallate treatment. Epigallocatechin gallate reduced neural tube defect rates from 29.5% to 2%, an incidence that is comparable with that of embryos from nondiabetic dams. Ten micromoles of Epigallocatechin gallate treatment blocked maternal diabetes increased DNA methyltransferases 3a and 3b expression and their activities, leading to the suppression of global DNA hypermethylation. Additionally, 10 MUM Epigallocatechin gallate abrogated maternal diabetes-increased DNA methylation in the CpG islands of neural tube closure essential genes, including Grhl3, Pax3, and Tulp3. CONCLUSION: Epigallocatechin gallate reduces maternal diabetes-induced neural tube defects formation and blocks the enhanced expression and activity of DNA methyltransferases, leading to the suppression of DNA hypermethylation and the restoration of neural tube closure essential gene expression. These observations suggest that Epigallocatechin gallate supplements could mitigate the teratogenic effects of hyperglycemia on the developing embryo and prevent diabetes-induced neural tube defects. PMID- 26979635 TI - Complications after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis: Risk factors for ICU admission and morbidity prognostic score. AB - BACKGROUND AND OBJECTIVES: For patients suffering from peritoneal carcinomatosis, cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is the only curative option. We focused on severe complications in the postoperative course of HIPEC. METHODS: We studied perioperative data from patients who underwent HIPEC between January 2010 and August 2011. Our primary objective was to identify perioperative risk factors for ICU admission. Our secondary objective was to identify patient that may be re-admitted to the ICU thanks to a prognostic score. RESULTS: 122 patients underwent HIPEC. 32 presented severe adverse events (26.2%) and 7 died (5.7%). Reasons for ICU admission were septic shock in 28.1% of patients, hemorrhagic shock for 21.9%, hemodynamic instability for 15.6%, respiratory causes for 6.2% and post-operative acidosis for 6.2%. Vasopressors were required for 34% and 40.6% were mechanically ventilated. CONCLUSION: Peritoneal cancer index, diaphragmatic peritonectomy, the need of vasopressive therapy, total volume of fluid leakage collected in drains and total volume of fluid therapy administered at day 1 reported on ideal body weight were the 5 significant variables that we combined to build a morbidity prognostic score. One patient over 4 is likely to present severe complications. A predictive morbidity score provide informative data for clinicians. PMID- 26979638 TI - Making cancer visible--Dyes in surgical oncology. AB - Dyes share an intricate relationship with oncology. Dyes can cause cancer as chemical carcinogens, but can also be harnessed against cancer when used as diagnostic and therapeutic agents. Histopathology, imaging, and newer molecular diagnostics all rely on dyes, and their use in sentinel lymph node biopsies and intra-operative imaging has helped drive a paradigm shift in cancer surgery towards minimally-invasive and organ sparing approaches with enhanced resection accuracy. As therapeutic agents, the cytotoxicity of specific dyes can be employed in direct chemo-ablation or in photodynamic therapy. The same agent can have dual functionalities in cancer detection and treatment, in a novel field known as theranostics. This is facilitated by newer generation dyes conjugated with tumour-targeting probes such as antibodies, and these bio-conjugate agents can also incorporate nanotechnology or radio-isotopes. Further advances will be closely aligned with our increasing understanding of molecular oncology, and will form a new generation of cancer detection and treatment agents that promote precision medicine for cancer. Dyes and their roles have evolved and been reinvented, but they remain relevant as ever. This review explores the fascinating history of dyes, and their place in the state-of-the-art of oncology. PMID- 26979637 TI - Risk factors and patterns of early recurrence after curative hepatectomy for hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) often recurs after curative hepatectomy; and early recurrence after hepatectomy (ERAH) is associated with poor prognosis. This study aimed to clarify risk factors and disease patterns for ERAH. METHODS: We retrospectively analyzed clinicopathological factors of 232 patients who underwent initial curative hepatectomies for HCC between April 2000 and March 2013, and examined associated risk factors and early recurrence patterns by liver function status (as indicated by indocyanine green retention rate at 15 min [ICGR15]). RESULTS: Patients who experienced recurrence within 6 months after hepatectomy (i.e., ERAH) had significantly shorter survival than those with longer disease-free intervals (P < 0.001). In multivariate analysis, microvascular invasion (mVI; P = 0.034) and ICGR15 >= 16% (P = 0.010) were independent risk factors for ERAH. In the ICGR1<16% subgroup, positive L3-AFP (P = 0.04), tumor size >= 5 cm (P = 0.011), surgical margin = 0 (P = 0.0103), mVI (P = 0.034), and extrahepatic recurrence were significant predictors of ERAH; in the ICGR15 >= 16%, subgroup, multiple tumors (P = 0.046) were identified as a risk factor for ERAH; however, this group did not experience much extrahepatic recurrence. CONCLUSIONS: ERAH was associated with mVI and ICGR15 >= 16%. Recurrence patterns and risk factors vary by liver function status, which should be considered in forming management strategies for early recurrence of HCC after curative hepatectomy. PMID- 26979636 TI - A systematic review of optimal treatment strategies for localized Ewing's sarcoma of bone after neo-adjuvant chemotherapy. AB - OBJECTIVE: To perform a systematic review to investigate the optimal treatment strategy among the options of surgery alone, radiotherapy (RT) alone, and the combination of RT plus surgery in the management of localized Ewing's sarcoma of bone following neo-adjuvant chemotherapy. METHODS: MEDLINE and EMBASE (1999 to February 2015), the Cochrane Library, and relevant conferences were searched. RESULTS: Two systematic reviews and eight full texts met the pre-planned study selection criteria. When RT was compared with surgery, a meta-analysis combining two papers showed that surgery resulted in a higher event-free survival (EFS) than RT in any location (HR = 1.50, 95% CI 1.12-2.00; p = 0.007). However another paper did not find a statistically significant difference in patients with pelvic disease, and no papers identified a significant difference in overall survival. When surgery plus RT was compared with surgery alone, a meta-analysis did not demonstrate a statistically significant difference for EFS between the two groups (HR = 1.21, 95% CI 0.90-1.63). Both surgical morbidities and radiation toxicities were reported. CONCLUSIONS: The existing evidence is based on very low aggregate quality as assessed by the GRADE approach. In patients with localized Ewing's sarcoma, either surgery alone (if complete surgical excision with clear margin can be achieved) or RT alone may be a reasonable treatment option. The optimal local treatment for an individual patient should be decided through consideration of patient characteristics, the potential benefit and harm of the treatment options, and patient preference. PMID- 26979639 TI - Comparison of long-term oncological outcomes of appendiceal cancer and colon cancer: A multicenter retrospective study. AB - BACKGROUND: There has been no comparative study of the long-term oncological outcomes of appendiceal cancer and colon cancer. We hypothesized that the oncological outcome is worse in appendiceal cancer because perforation is more frequent than in colon cancer. METHODS: Patients with stage I-III were selected from 5046 patients with appendiceal or colon cancer, between September 2001 and June 2010. The 5-year disease-free survival (DFS) was the primary endpoint. Multivariate analyses with Cox proportional hazards model for DFS and logistic regression model for perforation were conducted. A matching model was used to compensate for the heterogeneity between groups. RESULTS: The perforation rate was 44.7% in appendiceal cancer (n = 47), but 1.1% in colon cancer (n = 2828) (p = 0.001). The 5-year DFS rate was lower in appendiceal cancer than in colon cancer (57.9% vs. 85.2%, p = 0.001; matching model, 54.2% vs. 78.4%, p = 0.038), with a higher rate of peritoneal seeding (25.5% vs. 2.5%, p = 0.001; matching model, 24.0% vs. 4.0%, p = 0.007). Multivariate Cox regression showed that appendiceal cancer was an independent prognostic factor for poor DFS (hazard ratio = 2.602, 95% confidence interval = 1.26-5.35, p = 0.009), and logistic regression confirmed that appendiceal cancer was the risk factor associated with perforation (odds ratio = 66.265, 95% confidence interval = 28.21-155.61, p = 0.001). CONCLUSIONS: This study suggested that the long-term oncological outcomes are worse for appendiceal cancer than for colon cancer, attributed to higher perforation rate in appendiceal cancer. PMID- 26979640 TI - Clinical application of a color map pattern on shear-wave elastography for invasive breast cancer. AB - PURPOSE: The aim of this study was to classify the color map pattern on shear wave elastography (SWE) and to determine its association with clinicopathological factors for clinical application in invasive breast cancer. METHODS: From June to December 2014, 103 invasive breast cancers were imaged by B-mode ultrasonography (US) and SWE just before surgery. The color map pattern identified on the SWE could be classified into three main categories: type 1 (diffuse pattern), increased stiffness in the surrounding stroma and the interior lesion itself; type 2 (lateral pattern), marked peri-tumoral stiffness at the anterior and lateral portions with no or minor stiffness at the posterior portion; and type 3 (rim-off pattern), marked peri-tumoral stiffness at the anterior and posterior portion with no or minor stiffness at both lateral portions. RESULTS: High-grade density on mammography (grade 3-4) was more frequent in the type 1 pattern than the other pattern types (80.5% in high-grade density vs. 19.5% in low-grade density). For type 1 tumors, the extent of synchronous non-invasive cancers (pT0), ductal carcinoma in situ (DCIS), was 1.8-2.0 times wider than that measured by US or magnetic resonance imaging (MRI). For type 2 tumors, the invasive tumor components (pT size) size was 1.3 times greater than measured by MRI (p = 0.049). On the other hand, the pT size and pT0 extent of type 3 tumors were almost equal to the preoperative US and MRI measurements. In terms of immunohistochemical (IHC) profiles, type 3 tumors showed a high histologic grade (p = 0.021), poor differentiation (p = 0.009), presence of necrosis (p = 0.018), and high Ki-67 (p = 0.002). The percentage of HER2-positive cancers was relatively high within the type 2 group, and the percentage of triple negative breast cancer was relatively high in the type 3 group (p = 0.011). CONCLUSIONS: We expect that assessments of the SWE color map pattern will prove useful for surgical or therapeutic plan decisions and to predict prognosis in invasive breast cancer patients. PMID- 26979642 TI - Reinventing qualitative research. PMID- 26979641 TI - "The impact of debulking surgery in patients with node-positive epithelial ovarian cancer: Analysis of prognostic factors related to overall survival and progression-free survival after an extended long-term follow-up period". AB - OBJECTIVE: to estimate the prognostic factors associated with survival and progression free survival (PFS) in patients with node-positive epithelial ovarian cancer (EOC) after an extended long-term follow-up period. METHODS: Data was provided by the Tumor Registry of the Mayo Clinic, Scottsdale, Arizona on 116 node-positive EOC patients who underwent primary cytoreductive surgery observed over the period 1996-2014. RESULTS: At censoring date, 21 patients were alive (18%), 95 dead (82%), 18 without evidence of disease (NED) (15 alive, 3 dead) and 76 with evidence of disease (ED) (2 alive, 74 dead). Twenty-nine ED patients (38.2%) experienced a recurrence within 2 years, 53 patients (69.7%) before 5 years. No recurrences were recorded after 10 years. The median follow-up in alive patients was 169.8 months (1.20-207.9 months), 34.9 months (0.30-196.2 months) in dead patients, 128.4 months for NED patients (72.8-202.5 months) and 34.6 months (0.1-106.9 months) in ED patients. Multivariate analysis showed an increased risk of dead in patients with age >= 60 years (HR: 3.20; p < 0.002), stage IVA/B (compared with stage IIIA1/2, HR: 4.31; p < 0.001 and stage IIIB/C, HR: 5.31; p < 0.010) and incomplete surgery (compared with complete surgery, HR: 3.10; 95% CI, 1.41-6.77; p < 0.003) and a decreased PFS in stage IVA/B (compared with stages IIIB/C; p = 0.003 and stage IIIA; p = 0.000) and residual volume after surgery >0.6 cm (compared with residual disease <0.5 cm; p < 0.023). CONCLUSIONS: prognostic factors for an extended long-term PFS are similar as those for survival, because after 17-year follow-up period, the majority of alive patients are NED patients. PMID- 26979643 TI - Regulatory effect of paraprobiotic Lactobacillus gasseri CP2305 on gut environment and function. AB - BACKGROUND: Lactobacillus gasseri CP2305 (CP2305) is a strain of Lactobacillus isolated from a stool sample from a healthy adult that showed beneficial effects on health as a paraprobiotic. In a previous study, we demonstrated that CP2305 fermented heat-treated milk modified gut functions more than artificially acidified sour milk. Thus, the regulatory activity of the former beverage was attributed to the inactivated CP2305 cells. OBJECTIVE: The aim of this study was to elucidate the contribution of non-viable paraprobiotic CP2305 cells to regulating human gut functions. We thus conducted a randomized, placebo controlled, double-blinded parallel group trial. DESIGN: The trial included 118 healthy participants with relatively low or high stool frequencies. The test beverage was prepared by adding 1*10(10) washed, heat-treated, and dried CP2305 cells directly to the placebo beverage. The participants ingested a bottle of the assigned beverage daily for 3 weeks and answered daily questionnaires about defecation and quality of life. Fecal samples were collected and the fecal characteristics, microbial metabolite contents of the feces and composition of fecal microbiota were evaluated. RESULTS: The number of evacuations and the scores for fecal odors were significantly improved in the group that consumed the CP2305-containing beverage compared with those of the group that consumed the placebo (p=0.035 and p=0.040, respectively). Regarding the fecal contents of microbial metabolites, the level of fecal p-cresol was significantly decreased in the CP2305 group relative to that of the placebo group (p=0.013). The Bifidobacterium content of the intestinal microbiota was significantly increased in the CP2305 group relative to that of the placebo group (p<0.008), whereas the content of Clostridium cluster IV was significantly decreased (p<0.003). The parasympathetic nerve activity of the autonomic nervous system became dominant and the total power of autonomic activity was elevated in the CP2305 group (p=0.0401 and p=0.011, respectively). CONCLUSIONS: The continuous ingestion of heat-treated CP2305 cells clearly affected intestinal functionality. This is the first report of sterilized Lactobacillus cells having a significant impact on the environment and functions of the intestinal tract. The observed effects might be due, at least in part, to the brain-gut interaction. PMID- 26979644 TI - Development of a lateral flow immunochromatographic assay for rapid detection of Mycoplasma pneumoniae-specific IgM in human serum specimens. AB - Early diagnosis of Mycoplasma pneumoniae (MP) infection is crucial for prompt treatment and good patient outcome. However, serological tests to detect MP rapidly and conveniently are still lacking. This study aimed to use the fluorescent dye Alexa Fluor(r) 647 as the detection marker to develop a lateral flow immunochromatographic assay (LFIA) for detection of MP-specific IgM in serum specimen. Monoclonal mouse antibody against human IgM (MU-chain specific) and goat anti-rabbit IgG were labeled with Alexa Fluor(r) 647 (anti-IgM-AF647 and anti-IgG-AF647). A mixture of natural MP antigen and recombinant P1 antigen was coated as the test line (T line) and rabbit IgG was coated as the control line (C line) on a nitrocellulose (NC) membrane. The MP antigens captured IgM-anti-IgM AF647 complex on the T line. Rabbit IgG captured anti-IgG-AF647 on the C line. The fluorescence intensity on the T line and C line was measured. Sartorius CN140 NC membrane showed higher sensitivity than CN95. The optimal reaction time for the LFIA was 10min. The area under the receiver operating characteristic curve based on 34 MP positive and 166 MP negative serum samples was 0.986 (p<0.001). The cutoff value of T/C area ratio was 0.3830. The LFIA strips did not react with serum from patients infected with non-MP pathogens including influenza viruses and bacteria causing respiratory tract infection. The intra-assay and inter-assay coefficients of variation were between 3.28% and 10.14%. The shelf life was calculated to be 2years at room temperature. The LFIA strips and the commercial EUROIMMUN kit showed consistent results on 372 serum specimens. The overall consistency rate was 96.37% with a Kappa value of 0.842 (p<0.001). The LFIA in the current study may be a sensitive and specific approach to detect early MP infection rapidly and conveniently. PMID- 26979645 TI - Confocal microscopy imaging of the biofilm matrix. AB - The extracellular matrix is an integral part of microbial biofilms and an important field of research. Confocal laser scanning microscopy is a valuable tool for the study of biofilms, and in particular of the biofilm matrix, as it allows real-time visualization of fully hydrated, living specimens. Confocal microscopes are held by many research groups, and a number of methods for qualitative and quantitative imaging of the matrix have emerged in recent years. This review provides an overview and a critical discussion of techniques used to visualize different matrix compounds, to determine the concentration of solutes and the diffusive properties of the biofilm matrix. PMID- 26979646 TI - Editorial. PMID- 26979647 TI - The use of onestep nucleic acid amplification (OSNA) and tumour related factors in the treatment of axillary breast cancer: A predictive model. AB - AIMS: We aimed to determine the effectiveness of CK19 mRNA copy number and tumour related factors in predicting non-sentinel axillary nodal involvement, in order to facilitate the formulation of local treatment guidelines for axillary clearance (ANC) following intra-operative analysis of the sentinel node biopsy (SNB) using one-step nucleic acid amplification (OSNA). METHODS: Patients due to have (SNB) at our institution for breast cancer as well as patients with high grade ductal carcinoma in situ with pre-operative negative assessment of the axilla were included. Alternate slices of each node were sent for assessment by either OSNA or histopathology. Immediate ANC was performed if OSNA was positive. The CK19 mRNA nodal copy number, the total tumour load (TTL) measured by summation of mRNA copy numbers of all positive nodes, the nodal status at ANC and tumour characteristics for each patient were recorded. A model of risk probability was constructed using TTL and tumour related factors. RESULTS: 664 nodes were analysed from 425 patients who had SNB performed between 2011 and 2014. ANC was performed on 105 of these patients. The concordance between OSNA and histology was 91.4% and negative predictive value (NPV) was 97%. TTL (p = 0.003) and LVI (p = 0.04) were identified as risk factors for non-sentinel nodal involvement. The risk probability model identified all patients with pN2 disease for ANC. CONCLUSION: In the future a decision to perform ANC will be based on a risk stratification model based on TTL and tumour related factors. PMID- 26979649 TI - Consequences of Correcting Intelligence Quotient for Prematurity at Age 5 Years. AB - OBJECTIVES: To determine the effects of correcting for prematurity on full scale IQ (FSIQ), verbal IQ (VIQ), performance IQ (PIQ), and processing speed quotient (PSQ) scores, and to investigate whether differences between corrected and uncorrected FSIQ are associated with gestational age (GA), FSIQ, and age at assessment. STUDY DESIGN: Single-center consecutive cohort study. Data were analyzed from 275 very preterm children (GA <30 weeks), born between January 2006 and December 2009 and assessed at 5 years corrected age as part of the neonatal long-term follow-up program, at the Emma Children's Hospital in Amsterdam, The Netherlands. Outcome measures were FSIQ, VIQ, PIQ, and PSQ, calculated for uncorrected and corrected age. Paired sample t tests, repeated measures ANOVA, and ANCOVA were performed to explore differences between corrected and uncorrected IQ. RESULTS: Differences between corrected and uncorrected FSIQ, VIQ, PIQ, and PSQ ranged from 0-15 IQ points. All corrected IQ scores were significantly higher than uncorrected IQ scores (all P values <.001). Differences were larger at lower GAs, for higher IQ scores, and if time of assessment lay near the starting point of a 3-month age band of the Wechsler Preschool and Primary Scale of Intelligence-Third Edition-Dutch Version. CONCLUSIONS: Given the great variation observed in differences between corrected and uncorrected IQ scores, an international standard as to what age correction is appropriate should be pursued. PMID- 26979648 TI - Quantitative imaging of 2 nm monolayer-protected gold nanoparticle distributions in tissues using laser ablation inductively-coupled plasma mass spectrometry (LA ICP-MS). AB - Functionalized gold nanoparticles (AuNPs) have unique properties that make them important biomedical materials. Optimal use of these materials, though, requires an understanding of their fate in vivo. Here we describe the use of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to image the biodistributions of AuNPs in tissues from mice intravenously injected with AuNPs. We demonstrate for the first time that the distributions of very small (~2 nm core) monolayer-protected AuNPs can be imaged in animal tissues at concentrations in the low parts-per-billion range. Moreover, the LA-ICP-MS images reveal that the monolayer coatings on the injected AuNPs influence their distributions, suggesting that the AuNPs remain intact in vivo and their surface chemistry influences how they interact with different organs. We also demonstrate that quantitative images of the AuNPs can be generated when the appropriate tissue homogenates are chosen for matrix matching. Overall, these results demonstrate the utility of LA-ICP-MS for tracking the fate of biomedically-relevant AuNPs in vivo, facilitating the design of improved AuNP-based therapeutics. PMID- 26979650 TI - Outcomes of Adolescent-Onset Postural Orthostatic Tachycardia Syndrome. AB - OBJECTIVES: To determine the clinical course of adolescent-onset postural orthostatic tachycardia syndrome (POTS) and to assess health-related quality of life, 2-10 years after diagnosis. STUDY DESIGN: Pediatric patients, 13-18 years of age, diagnosed with POTS at Mayo Clinic, Rochester, from 2003 to 2010 were mailed a questionnaire if they were at least 18 years of age at the time of the mailing. The primary outcome measures were norm-based, age- and sex-adjusted, 36 Item Short Form Health Survey physical composite score and mental composite score. RESULTS: The survey was mailed to 502 patients with a response rate of 34% (n = 172). The mean duration from diagnosis to survey completion was 5.4 (SD, 1.9) years; the mean age of the respondents at the time of the survey was 21.8 (2.2) years. The responders were predominantly females (84% vs 68% of nonresponders; P < .001). Only 33 (19%) respondents reported complete resolution of symptoms, and an additional 51% reported persistent but improved symptoms, and 28 (16%) had only intermittent symptoms. The majority (71%) consider their health at least "good." The mean physical composite score was significantly lower than the population norm (mean [SD], 36.6 [15.8] vs 50; P < .001), however, the corresponding mean mental composite score was normal (50.1 [11.2]). CONCLUSIONS: Overall, 86% of adolescents with POTS report resolved, improved, or just intermittent symptoms, when assessed via questionnaire at an average of 5 years after initial treatment. Patients with persistent symptoms have more physical than mental health concerns. PMID- 26979651 TI - The BMJ should not narrowly confine publication to positivist quantitative studies. PMID- 26979653 TI - 24-Hour Urinary Parameters in Overweight and Obese Children with Urolithiasis. AB - PURPOSE: The increasing incidence of pediatric nephrolithiasis is a growing concern and its association with obesity continues to be an area of debate. We present data on urine chemistries of overweight/obese children compared to those with a normal body mass index and history of urolithiasis treated at a single institution in the United States, and assess risk factors. MATERIALS AND METHODS: We retrospectively identified 110 stone forming patients who underwent 24-hour urine collection and stratified them according to the Centers for Disease Control and Prevention definitions of overweight/obese (body mass index above 85th/95th percentile). Absolute urine collection quantities were compared between groups. Stone risk factors were analyzed according to Litholink(r) specified reference ranges. RESULTS: Compared to patients with low or normal body mass index, overweight and obese patients had lower body surface area adjusted citrate (242 mg/1.73 m(2) vs 315 mg/1.73 m(2), p = 0.03), lower urine phosphate (12 mg/kg vs 14 mg/kg, p = 0.04), lower urine magnesium (1.2 mg/kg vs 1.6 mg/kg, p = 0.01) and increased incidence of hypercalciuria (31% vs 11%, p = 0.02). Differences in urine citrate, phosphate and magnesium were not apparent when analyzing stone risk factors. There was no association between body mass index and urine pH. CONCLUSIONS: Overweight and obese stone forming children have decreased levels of urine citrate, phosphate and magnesium compared to patients with normal body mass index. The incidence of hypercalciuria is increased in overweight/obese patients. In contrast to findings in adults, there is no association between urine pH and body mass index. PMID- 26979652 TI - Serial Percent Free Prostate Specific Antigen in Combination with Prostate Specific Antigen for Population Based Early Detection of Prostate Cancer. AB - PURPOSE: We characterized the diagnostic properties of serial percent free prostate specific antigen in relation to prostate specific antigen in a multiethnic, multiracial cohort of healthy men. MATERIALS AND METHODS: A total of 6,982 percent free prostate specific antigen and prostate specific antigen measurements were obtained from participants in a greater than 12-year Texas screening study comprising 1,625 men who never underwent biopsy, 497 who underwent 1 or more biopsies negative for prostate cancer and 61 diagnosed with prostate cancer. We evaluated the ROC AUC of percent free prostate specific antigen and the proportion of patients with fluctuating values across multiple visits determined according to 2 thresholds (less than 15% vs 25%). The proportion of cancer cases in which percent free prostate specific antigen indicated a positive test before prostate specific antigen greater than 4 ng/ml did and the number of negative biopsies that would have been spared by negative percent free prostate specific antigen test results were calculated. RESULTS: Percent free prostate specific antigen fluctuated around its threshold of less than 25% (less than 15%) in 38.3% (78.1%), 42.2% (20.9%), and 11.4% (25.7%) of patients never biopsied, and with negative and positive biopsies, respectively. At the same thresholds, percent free prostate specific antigen tested positive earlier than prostate specific antigen in 71.4% and 34.2% of cancer cases, respectively. Among men with multiple negative biopsies and PSA greater than 4 ng/ml, percent free PSA would have tested negative in 31.6% and 65.8%, respectively. CONCLUSIONS: Percent free prostate specific antigen should accompany prostate specific antigen testing to potentially spare unnecessary biopsies or detect cancer earlier. When near the threshold, both tests should be repeated due to commonly observed fluctuation. PMID- 26979654 TI - A neurocutaneous phenotype with paired hypo- and hyperpigmented macules, microcephaly and stunted growth as prominent features. AB - Neurocutaneous disorders represent a heterogeneous group of conditions affecting the skin (with pigmentary/vascular abnormalities, hamartomas or tumors) and the central and peripheral nervous systems. In recent years, besides the well-known neurocutaneous diseases (e.g., the different forms of neurofibromatosis, tuberous sclerosis complex, Sturge-Weber syndrome and mosaic pigmentary/hamartomatous disorders), new distinctive syndromes have been characterized, extending our knowledge on the spectrum of these conditions. The concurrent presence of pigmentary abnormalities (both of the hypo- and hyperpigmented type), and primary microcephaly has not been commonly reported. We report on a 4.5-year-old girl with primary microcephaly, who had in addition moderate to severe developmental delay, behavioral and stereotypic abnormalities and a cutaneous pattern of paired hypo- and hyperpigmented lesions variously distributed over the body, particularly on the trunk. Failure to thrive and mild facial dysmorphic features were also present. To our knowledge, this complex malformation (neurocutaneous) phenotype has not been previously reported. PMID- 26979655 TI - Minimal access mitral valve repair in a patient with a right pneumonectomy for Scimitar syndrome. AB - A 61-year old man known with chronic atrial fibrillation was referred to our unit via the multidisciplinary team meeting, with severe mitral regurgitation secondary to prolapse of anterior mitral leaflet. In 1968, he had undergone right pneumonectomy due to Scimitar syndrome. Dense adhesions due to previous interventions, such as thoracotomy, make it difficult to insert ports, and this is therefore considered a relative contraindication to port access approach to the mitral valve. The anatomical position of the heart in the mediastinum was completely distorted due to the shift of the mediastinum to the right following previous surgery. Our report illustrates the operative success that can be achieved in such complex situations. Computed tomography scanning and on table transoesophageal and transthoracic echocardiography were the tools used in conjunction to achieve the best possible approach. This case promotes the use of minimal access approach in the experienced hands so that such complex procedures can be carried out without any complication and yield good results. PMID- 26979657 TI - Towards manipulating relativistic laser pulses with micro-tube plasma lenses. AB - Efficient coupling of intense laser pulses to solid-density matter is critical to many applications including ion acceleration for cancer therapy. At relativistic intensities, the focus has been mainly on investigating various laser beams irradiating initially overdense flat interfaces with little or no control over the interaction. Here, we propose a novel approach that leverages recent advancements in 3D direct laser writing (DLW) of materials and high contrast lasers to manipulate the laser-matter interactions on the micro-scales. We demonstrate, via simulations, that usable intensities >=10(23) Wcm(-2) could be achieved with current tabletop lasers coupled to micro-engineered plasma lenses. We show that these plasma optical elements act as a lens to focus laser light. These results open new paths to engineering light-matter interactions at ultra relativistic intensities. PMID- 26979658 TI - The cells that mediate innate immune memory and their functional significance in inflammatory and infectious diseases. AB - Immunological memory mediated by antigen-specific T and B cells is the foundation of adaptive immunity and is fundamental to the heightened and rapid protective immune response induced by vaccination or following re-infection with the same pathogen. While the innate immune system has classically been considered to be non-specific and devoid of memory, it now appears that it can be trained following exposure to microbes or their products and that this may confer a form of memory on innate immune cells. The evidence for immunological memory outside of T and B cells has been best established for natural killer (NK) cells, where it has been known for decades that NK cells have heighten responses following immunological re-challenge. Furthermore, recent studies have demonstrated that monocyte/macrophages, and probably dendritic cells, can be re-programmed through epigenetic modification, following exposure to pathogens or their products, resulting in heighted responses following a second stimulation. Unlike antigen specific memory of the adaptive immune system, the second stimulation does not have to be with the same pathogen or antigen. Indirect evidence for this comes from reports on the non-specific beneficial effect of certain live vaccines, such as Bacillus Calmette Guerin (BCG) against unrelated childhood infectious diseases. It also appears that certain pathogen or pathogen-derived molecules can prime immune cells, especially macrophages, to secrete more anti-inflammatory and less pro-inflammatory cyokines, thus opening up the possibility of exploiting innate immune training as a new therapeutic approach for inflammatory diseases. PMID- 26979656 TI - Results of surgical aortic valve replacement and transapical transcatheter aortic valve replacement in patients with previous coronary artery bypass grafting. AB - OBJECTIVES: To evaluate the results of aortic valve replacement through sternotomic approach in redo scenarios (RAVR) vs transapical transcatheter aortic valve replacement (TAVR), in patients in the eighth decade of life or older already undergone previous coronary artery bypass grafting (CABG). METHODS: One hundred and twenty-six patients undergoing RAVR were compared with 113 patients undergoing TaTAVR in terms of 30-day mortality and Valve Academic Research Consortium-2 outcomes. The two groups were also analysed after propensity matching. RESULTS: TaTAVR patients demonstrated a higher incidence of 30-day mortality (P = 0.03), stroke (P = 0.04), major bleeding (P = 0.03), worse 'early safety' (P = 0.04) and lower permanent pacemaker implantation (P = 0.03). TaTAVR had higher follow-up hazard in all-cause mortality [hazard ratio (HR) 3.15, 95% confidence interval (CI) 1.28-6.62; P < 0.01] and cardiovascular mortality (HR 1.66, 95% CI 1.02-4.88; P = 0.04). Propensity-matched patients showed comparable 30-day outcome in terms of survival, major morbidity and early safety, with only a lower incidence of transfusions after TaTAVR (10.7% vs RAVR: 57.1%; P < 0.01). A trend towards lower Acute Kidney Injury Network Classification 2/3 (3.6% vs RAVR 21.4%; P = 0.05) and towards a lower freedom from all-cause mortality at follow-up (TaTAVR: 44.3 +/- 21.3% vs RAVR: 86.6 +/- 9.3%; P = .08) was demonstrated after TaTAVR, although cardiovascular mortality was comparable (TaTAVR: 86.5 +/- 9.7% vs RAVR: 95.2 +/- 4.6%; P = 0.52). Follow-up freedom from stroke, acute heart failure, reintervention on AVR and thrombo-embolisms were comparable (P = NS). EuroSCORE II (P = 0.02), perioperative stroke (P = 0.01) and length of hospitalization (P = 0.02) were the determinants of all-cause mortality at follow-up, whereas perioperative stroke (P = 0.03) and length of hospitalization (P = 0.04) impacted cardiovascular mortality at follow-up. CONCLUSIONS: Reported differences in mortality and morbidity after TaTAVR and RAVR reflect differences in baseline risk profiles. Given the lower trend for renal complications, patients at higher perioperative renal risk might be better served by TaTAVR. PMID- 26979660 TI - Load partitioning between the bcc-iron matrix and NiAl-type precipitates in a ferritic alloy on multiple length scales. AB - An understanding of load sharing among constituent phases aids in designing mechanical properties of multiphase materials. Here we investigate load partitioning between the body-centered-cubic iron matrix and NiAl-type precipitates in a ferritic alloy during uniaxial tensile tests at 364 and 506 degrees C on multiple length scales by in situ neutron diffraction and crystal plasticity finite element modeling. Our findings show that the macroscopic load transfer efficiency is not as high as that predicted by the Eshelby model; moreover, it depends on the matrix strain-hardening behavior. We explain the grain-level anisotropic load-partitioning behavior by considering the plastic anisotropy of the matrix and elastic anisotropy of precipitates. We further demonstrate that the partitioned load on NiAl-type precipitates relaxes at 506 degrees C, most likely through thermally-activated dislocation rearrangement on the microscopic scale. The study contributes to further understanding of load partitioning characteristics in multiphase materials. PMID- 26979659 TI - Neurobiological correlates of distinct post-traumatic stress disorder symptom profiles during threat anticipation in combat veterans. AB - BACKGROUND: Previous research in post-traumatic stress disorder (PTSD) has identified disrupted ventromedial prefrontal cortex (vmPFC) function in those with v. without PTSD. It is unclear whether this brain region is uniformly affected in all individuals with PTSD, or whether vmPFC dysfunction is related to individual differences in discrete features of this heterogeneous disorder. METHOD: In a sample of 51 male veterans of Operation Enduring Freedom/Operation Iraqi Freedom, we collected functional magnetic resonance imaging data during a novel threat anticipation task with crossed factors of threat condition and temporal unpredictability. Voxelwise regression analyses related anticipatory brain activation to individual differences in overall PTSD symptom severity, as well as individual differences in discrete symptom subscales (re-experiencing, emotional numbing/avoidance, and hyperarousal). RESULTS: The vmPFC showed greater anticipatory responses for safety relative to threat, driven primarily by deactivation during threat anticipation. During unpredictable threat anticipation, increased PTSD symptoms were associated with relatively greater activation for threat v. SAFETY: However, simultaneous regression on individual symptom subscales demonstrated that this effect was driven specifically by individual differences in hyperarousal symptoms. Furthermore, this analysis revealed an additional, anatomically distinct region of the vmPFC in which re experiencing symptoms were associated with greater activation during threat anticipation. CONCLUSIONS: Increased anticipatory responses to unpredictable threat in distinct vmPFC subregions were uniquely associated with elevated hyperarousal and re-experiencing symptoms in combat veterans. These results underscore the disruptive impact of uncertainty for veterans, and suggest that investigating individual differences in discrete aspects of PTSD may advance our understanding of underlying neurobiological mechanisms. PMID- 26979662 TI - Evidence for 5d-sigma and 5d-pi covalency in lanthanide sesquioxides from oxygen K-edge X-ray absorption spectroscopy. AB - The electronic structure in the complete series of stable lanthanide sesquioxides, Ln2O3 (Ln = La to Lu, except radioactive Pm), has been evaluated using oxygen K-edge X-ray absorption spectroscopy (XAS) with a scanning transmission X-ray microscope (STXM). The experimental results agree with recent synthetic, spectroscopic and theoretical investigations that provided evidence for 5d orbital involvement in lanthanide bonding, while confirming the traditional viewpoint that there is little Ln 4f and O 2p orbital mixing. However, the results also showed that changes in the energy and occupancy of the 4f orbitals can impact Ln 5d and O 2p mixing, leading to several different bonding modes for seemingly identical Ln2O3 structures. On moving from left to right in the periodic table, abrupt changes were observed for the energy and intensity of transitions associated with Ln 5d and O 2p antibonding states. These changes in peak intensity, which were directly related to the amounts of O 2p and Ln 5d mixing, were closely correlated to the well-established trends in the chemical accessibility of the 4f orbitals towards oxidation or reduction. The unique insight provided by the O K-edge XAS is discussed in the context of several recent theoretical and physical studies on trivalent lanthanide compounds. PMID- 26979661 TI - Identification and characterisation of Dof transcription factors in the cucumber genome. AB - Cucumber is vulnerable to many foliage diseases. Recent studies reported cloning of candidate genes for several diseases in cucumber; however, the exact defence mechanisms remain unclear. Dof genes have been shown to play significant roles in plant growth, development, and responses to biotic and abiotic stresses. Dof genes coding for plant-specific transcription factors can promote large-scale expression of defence-related genes at whole genome level. The genes in the family have been identified and characterized in several plant species, but not in cucumber. In the present study, we identified 36 CsDof members from the cucumber draft genomes which could be classified into eight groups. The proportions of the CsDof family genes, duplication events, chromosomal locations, cis-elements and miRNA target sites were comprehensively investigated. Consequently, we analysed the expression patterns of CsDof genes in specific tissues and their response to two biotic stresses (watermelon mosaic virus and downy mildew). These results indicated that CsDof may be involved in resistance to biotic stresses in cucumber. PMID- 26979663 TI - Correlation of Motor Abilities and Executive Functions in Children With ADHD. AB - Children with attention-deficit hyperactivity disorder (ADHD) commonly experience issues with both cognitive and motor abilities. This study aimed to determine whether a correlation exists between these 2 domains in children with ADHD. Tasks assessing executive function and motor performance were carried out with a sample of 50 children. The data demonstrated significant correlations between performance in motor activities and working memory. Performance in working memory was explained predominantly by manual dexterity and catching and aiming. These results support the hypothesis that training of these motor tasks could improve executive functioning in children with ADHD. PMID- 26979664 TI - Disintegration impact on sludge digestion process. AB - The anaerobic sludge digestion is a widely used method for sludge stabilization in wastewater treatment plant. This process can be improved by applying the sludge disintegration methods. As the sludge disintegration is not investigated enough, an analysis of how the application of thermal hydrolysis affects the sludge digestion process based on full-scale data was conducted. The results showed that the maximum volatile suspended solids (VSS) destruction reached the value of 65% independently on the application of thermal hydrolysis. The average VSS destruction increased by 14% when thermal hydrolysis was applied. In order to have the maximum VSS reduction and biogas production, it is recommended to keep the maximum defined VSS loading of 5.7 kg VSS/m(3)/d when the thermal hydrolysis is applied and to keep the VSS loading between 2.1-2.4 kg VSS/m(3)/d when the disintegration of sludge is not applied. The application of thermal hydrolysis leads to an approximately 2.5 times higher VSS loading maintenance comparing VSS loading without the disintegration; therefore, digesters with 1.8 times smaller volume is required. PMID- 26979665 TI - The Effect of a Resourcefulness Training Intervention on Relocation Adjustment and Adaptive Functioning among Older Adults in Retirement Communities. AB - The population of older adults is increasing rapidly and is expected to reach 83.7 million by the year 2050. Previous research demonstrates that greater resourcefulness is associated with better quality of life and life satisfaction. The purpose of this pilot study was to evaluate the effects of a resourcefulness training intervention on positive cognitions, resourcefulness, relocation adjustment, and adaptive functioning among older adults who have relocated to retirement communities. Resourcefulness theory provided the theoretical framework for this study. Forty older adults who relocated to three retirement communities in Milwaukee, WI were randomly assigned to either a diversional activity group or to a resourcefulness training (RT) intervention group. Two older adults dropped out of the study (one from the diversional activity group and one from the RT group), leaving 38 elders. The results of the study indicated that there were slight increases (a trend) in the mean of positive cognitions, relocation adjustment, adaptive functioning, and personal resourcefulness in the expected direction for the RT intervention group as compared to the diversional group. Recommendations for future research include the use of larger and more diverse samples over a longer periods of time (6 weeks and 12 weeks post-intervention) as well as the use of cut scores on the resourcefulness scale so that the RT training intervention is taught to those who need it. PMID- 26979666 TI - TiO2-catalyzed synthesis of sugars from formaldehyde in extraterrestrial impacts on the early Earth. AB - Recent synthetic efforts aimed at reconstructing the beginning of life on our planet point at the plausibility of scenarios fueled by extraterrestrial energy sources. In the current work we show that beyond nucleobases the sugar components of the first informational polymers can be synthesized in this way. We demonstrate that a laser-induced high-energy chemistry combined with TiO2 catalysis readily produces a mixture of pentoses, among them ribose, arabinose and xylose. This chemistry might be highly relevant to the Late Heavy Bombardment period of Earth's history about 4-3.85 billion years ago. In addition, we present an in-depth theoretical analysis of the most challenging step of the reaction pathway, i.e., the TiO2-catalyzed dimerization of formaldehyde leading to glycolaldehyde. PMID- 26979668 TI - On the convergence of nanotechnology and Big Data analysis for computer-aided diagnosis. AB - An overview is provided of the challenges involved in building computer-aided diagnosis systems capable of precise medical diagnostics based on integration and interpretation of data from different sources and formats. The availability of massive amounts of data and computational methods associated with the Big Data paradigm has brought hope that such systems may soon be available in routine clinical practices, which is not the case today. We focus on visual and machine learning analysis of medical data acquired with varied nanotech-based techniques and on methods for Big Data infrastructure. Because diagnosis is essentially a classification task, we address the machine learning techniques with supervised and unsupervised classification, making a critical assessment of the progress already made in the medical field and the prospects for the near future. We also advocate that successful computer-aided diagnosis requires a merge of methods and concepts from nanotechnology and Big Data analysis. PMID- 26979669 TI - Death after cessation of treatment by cystic fibrosis patients: An international survey of clinicians. AB - BACKGROUND: Little is known about cystic fibrosis patients, who are not considered to be terminally ill, and who die after voluntary cessation of treatment. AIM: This study was undertaken to provide an international snapshot of this issue. DESIGN: An online survey was distributed across three continents. SETTING: Distribution to the medical directors of the cystic fibrosis centres affiliated with the US Cystic Fibrosis Foundation, Cystic Fibrosis Australia (inclusion of New Zealand) and to every clinician member of the European Cystic Fibrosis Society. RESULTS: More than 200 cystic fibrosis patients not considered to be terminally ill and, who voluntarily ceased treatment, were reported by the clinicians surveyed. Detailed data were reported in 102 patients (4 children, 25 adolescents and 73 adults). Only one child, six adolescents and one adult were judged by clinicians not to be competent to make the decision to stop treatment. Time-consuming and low immediate-impact therapies, such as respiratory physiotherapy, were most frequently discontinued. Resignation was the main reported reason for discontinuing treatment, followed by reactive depression and lack of familial support. A total of 69% of the patients received palliative care and 72% died in the 6 months following cessation of treatment. CONCLUSION: Death of cystic fibrosis patients, not considered to be terminally ill, is reported in Europe, the United States and Australia due to voluntary cessation of treatment. PMID- 26979667 TI - Nano-risk Science: application of toxicogenomics in an adverse outcome pathway framework for risk assessment of multi-walled carbon nanotubes. AB - BACKGROUND: A diverse class of engineered nanomaterials (ENMs) exhibiting a wide array of physical-chemical properties that are associated with toxicological effects in experimental animals is in commercial use. However, an integrated framework for human health risk assessment (HHRA) of ENMs has yet to be established. Rodent 2-year cancer bioassays, clinical chemistry, and histopathological endpoints are still considered the 'gold standard' for detecting substance-induced toxicity in animal models. However, the use of data derived from alternative toxicological tools, such as genome-wide expression profiling and in vitro high-throughput assays, are gaining acceptance by the regulatory community for hazard identification and for understanding the underlying mode-of-action. Here, we conducted a case study to evaluate the application of global gene expression data in deriving pathway-based points of departure (PODs) for multi-walled carbon nanotube (MWCNT)-induced lung fibrosis, a non-cancer endpoint of regulatory importance. METHODS: Gene expression profiles from the lungs of mice exposed to three individual MWCNTs with different physical chemical properties were used within the framework of an adverse outcome pathway (AOP) for lung fibrosis to identify key biological events linking MWCNT exposure to lung fibrosis. Significantly perturbed pathways were categorized along the key events described in the AOP. Benchmark doses (BMDs) were calculated for each perturbed pathway and were used to derive transcriptional BMDs for each MWCNT. RESULTS: Similar biological pathways were perturbed by the different MWCNT types across the doses and post-exposure time points studied. The pathway BMD values showed a time-dependent trend, with lower BMDs for pathways perturbed at the earlier post-exposure time points (24 h, 3d). The transcriptional BMDs were compared to the apical BMDs derived by the National Institute for Occupational Safety and Health (NIOSH) using alveolar septal thickness and fibrotic lesions endpoints. We found that regardless of the type of MWCNT, the BMD values for pathways associated with fibrosis were 14.0-30.4 MUg/mouse, which are comparable to the BMDs derived by NIOSH for MWCNT-induced lung fibrotic lesions (21.0-27.1 MUg/mouse). CONCLUSIONS: The results demonstrate that transcriptomic data can be used to as an effective mechanism-based method to derive acceptable levels of exposure to nanomaterials in product development when epidemiological data are unavailable. PMID- 26979671 TI - In situ Transmission Electron Microscopy observation of Ag nanocrystal evolution by surfactant free electron-driven synthesis. AB - The study of the interaction of electron irradiation with matter and the response of the material to the passage of electrons is a very challenging problem. However, the growth mechanism observed during nanostructural evolution appears to be a broad and promising scientific field in nanotechnology. We report the in situ TEM study of nanostructural evolution of electron-driven silver (Ag) nanocrystals through an additive-free synthetic procedure. Observations revealed the direct effect of the electron beam on the morphological evolution of Ag nanocrystals through different mechanisms, such as mass transport, site-selective coalescence, and an appropriate structural configuration after coalescence leading to a more stable configuration. A fundamental understanding of the growth and formation mechanisms of Ag nanocrystals, which interact with the electron beam, is essential to improve the nanocrystal shape-control mechanisms as well as the future design and study of nanomaterials. PMID- 26979672 TI - Neonatal magnetic resonance imaging in double aortic arch diagnosed prenatally by ultrasound. AB - Congenital double aortic arch (DAA) is an uncommon vascular anomaly; however, its prenatal detection is associated with congenital heart defects and chromosomal abnormalities, including 22q11 deletion. We present a case of DAA diagnosed prenatally. DAA can be diagnosed by prenatal ultrasound in the transverse three vessel-trachea view, which shows a trident image formed by a complete vascular ring and the ductus arteriosus. Postnatal magnetic resonance images in this view correlate well with prenatal ultrasound images and help in confirmation of diagnosis, evaluation of the risk of airway or esophageal compression, and planning of surgery. PMID- 26979673 TI - Communication: Methane dissociation on Ni(111) surface: Importance of azimuth and surface impact site. AB - Understanding the role of reactant ro-vibrational degrees of freedom (DOFs) in reaction dynamics of polyatomic molecular dissociation on metal surfaces is of great importance to explore the complex chemical reaction mechanism. Here, we present an expensive quantum dynamics study of the dissociative chemisorption of CH4 on a rigid Ni(111) surface by developing an accurate nine-dimensional quantum dynamical model including the DOF of azimuth. Based on a highly accurate fifteen dimensional potential energy surface built from first principles, our simulations elucidate that the dissociation probability of CH4 has the strong dependence on azimuth and surface impact site. Some improvements are suggested to obtain the accurate dissociation probability from quantum dynamics simulations. PMID- 26979670 TI - Retrospective evaluation of palliative care and hospice utilization in hospitalized patients with metastatic breast cancer. AB - BACKGROUND: Hospitalizations in patients with metastatic cancer occur commonly at the end of life but have not been well-described in individuals with metastatic breast cancer. AIM: To describe the reasons for admission and frequency of palliative care and hospice utilization in hospitalized patients with metastatic breast cancer. DESIGN: This was a retrospective chart review of patients who had their first hospitalization with a diagnosis of metastatic breast cancer between 1 January 2009 and 31 December 2010. To standardize follow-up time, we collected data for 3 years post the index hospitalization. SETTING/PARTICIPANTS: We identified 123 consecutive patients who were hospitalized for the first time with a diagnosis of metastatic breast cancer at a single, tertiary care center. RESULTS: Uncontrolled symptoms accounted for half (50%, 62/123) of index admissions. The majority of patients died during the follow-up period (76%, 94/123), and the median time from index admission to death was 6 months (range: 0 34 months). Approximately half (53%, 50/94) died in the hospital or within 14 days of last hospital discharge, and less than one-third (29%, 27/94) were referred to hospice after their last hospitalization. The inpatient palliative care team evaluated 57% (54/94) of those who died at least once during an admission, but only 17% (16/94) of patients attended an outpatient palliative care appointment. CONCLUSIONS: Hospitalized patients with metastatic breast cancer are commonly admitted for uncontrolled symptoms and have a poor prognosis. However, only a minority receive outpatient palliative care or are referred to hospice during their last hospitalization prior to death. PMID- 26979674 TI - Communication: GAIMS--Generalized Ab Initio Multiple Spawning for both internal conversion and intersystem crossing processes. AB - Full multiple spawning is a formally exact method to describe the excited-state dynamics of molecular systems beyond the Born-Oppenheimer approximation. However, it has been limited until now to the description of radiationless transitions taking place between electronic states with the same spin multiplicity. This Communication presents a generalization of the full and ab initio multiple spawning methods to both internal conversion (mediated by nonadiabatic coupling terms) and intersystem crossing events (triggered by spin-orbit coupling matrix elements) based on a spin-diabatic representation. The results of two numerical applications, a model system and the deactivation of thioformaldehyde, validate the presented formalism and its implementation. PMID- 26979675 TI - Relaxation of hot and massive tracers using numerical solutions of the Boltzmann equation. AB - A numerical method using B-splines is used to solve the linear Boltzmann equation describing the energy relaxation of massive tracer particles moving through a dilute bath gas. The smooth and rough hard sphere and Maxwell molecule models are used with a variety of mass ratios and initial energies to test the capability of the numerical method. Massive tracers are initialized with energies typically found in energy loss experiments in mass spectrometry using biomolecules. The method is also used to examine the applicability of known expressions for the kinetic energy decay from the Fokker-Planck equation for the Rayleigh gas, where we find that results are generally good provided that the initial energy is properly bounded. Otherwise, the energy decay is not constant and a more complex behaviour occurs. The validity of analytical expressions for drag coefficients for spherical particles under specular and diffuse scattering is also tested. We find such expressions are generally good for hard spheres but cannot account, as expected, for the softer repulsive walls of the Maxwell (and real) molecules. Overall, the numerical method performed well even when tracers more than 400 times as massive as the bath were initialized with energies very far from equilibrium. This is a range of applicability beyond many of the standard methods for solving the Boltzmann equation. PMID- 26979676 TI - Breaking the bottleneck: Use of molecular tailoring approach for the estimation of binding energies at MP2/CBS limit for large water clusters. AB - A pragmatic method based on the molecular tailoring approach (MTA) for estimating the complete basis set (CBS) limit at Moller-Plesset second order perturbation (MP2) theory accurately for large molecular clusters with limited computational resources is developed. It is applied to water clusters, (H2O)n (n = 7, 8, 10, 16, 17, and 25) optimized employing aug-cc-pVDZ (aVDZ) basis-set. Binding energies (BEs) of these clusters are estimated at the MP2/aug-cc-pVNZ (aVNZ) [N = T, Q, and 5 (whenever possible)] levels of theory employing grafted MTA (GMTA) methodology and are found to lie within 0.2 kcal/mol of the corresponding full calculation MP2 BE, wherever available. The results are extrapolated to CBS limit using a three point formula. The GMTA-MP2 calculations are feasible on off-the shelf hardware and show around 50%-65% saving of computational time. The methodology has a potential for application to molecular clusters containing ~100 atoms. PMID- 26979677 TI - Guiding ab initio calculations by alchemical derivatives. AB - We assess the concept of alchemical transformations for predicting how a further and not-tested change in composition would change materials properties. This might help to guide ab initio calculations through multidimensional property composition spaces. Equilibrium volumes, bulk moduli, and relative lattice stability of fcc and bcc 4d transition metals Zr, Nb, Mo, Tc, Ru, Rh, Pd, and Ag are calculated using density functional theory. Alchemical derivatives predict qualitative trends in lattice stability while equilibrium volumes and bulk moduli are predicted with less than 9% and 28% deviation, respectively. Predicted changes in equilibrium volume and bulk moduli for binary and ternary mixtures of Rh-Pd-Ag are in qualitative agreement even for predicted bulk modulus changes as large as +100% or -50%. Based on these results, it is suggested that alchemical transformations could be meaningful for enhanced sampling in the context of virtual high-throughput materials screening projects. PMID- 26979678 TI - Spin density and orbital optimization in open shell systems: A rational and computationally efficient proposal. AB - The present work describes a new method to compute accurate spin densities for open shell systems. The proposed approach follows two steps: first, it provides molecular orbitals which correctly take into account the spin delocalization; second, a proper CI treatment allows to account for the spin polarization effect while keeping a restricted formalism and avoiding spin contamination. The main idea of the optimization procedure is based on the orbital relaxation of the various charge transfer determinants responsible for the spin delocalization. The algorithm is tested and compared to other existing methods on a series of organic and inorganic open shell systems. The results reported here show that the new approach (almost black-box) provides accurate spin densities at a reasonable computational cost making it suitable for a systematic study of open shell systems. PMID- 26979679 TI - State-specific tunneling lifetimes from classical trajectories: H-atom dissociation in electronically excited pyrrole. AB - A trajectory method of calculating tunneling probabilities from phase integrals along straight line tunneling paths, originally suggested by Makri and Miller [J. Chem. Phys. 91, 4026 (1989)] and recently implemented by Truhlar and co-workers [Chem. Sci. 5, 2091 (2014)], is tested for one- and two-dimensional ab initio based potentials describing hydrogen dissociation in the (1)B1 excited electronic state of pyrrole. The primary observables are the tunneling rates in a progression of bending vibrational states lying below the dissociation barrier and their isotope dependences. Several initial ensembles of classical trajectories have been considered, corresponding to the quasiclassical and the quantum mechanical samplings of the initial conditions. It is found that the sampling based on the fixed energy Wigner density gives the best agreement with the quantum mechanical dissociation rates. PMID- 26979680 TI - Coupled-cluster based basis sets for valence correlation calculations. AB - Novel basis sets are generated that target the description of valence correlation in atoms H through Ar. The new contraction coefficients are obtained according to the Atomic Natural Orbital (ANO) procedure from CCSD(T) (coupled-cluster singles and doubles with perturbative triples correction) density matrices starting from the primitive functions of Dunning et al. [J. Chem. Phys. 90, 1007 (1989); ibid. 98, 1358 (1993); ibid. 100, 2975 (1993)] (correlation consistent polarized valence X-tuple zeta, cc-pVXZ). The exponents of the primitive Gaussian functions are subject to uniform scaling in order to ensure satisfaction of the virial theorem for the corresponding atoms. These new sets, named ANO-VT-XZ (Atomic Natural Orbital Virial Theorem X-tuple Zeta), have the same number of contracted functions as their cc-pVXZ counterparts in each subshell. The performance of these basis sets is assessed by the evaluation of the contraction errors in four distinct computations: correlation energies in atoms, probing the density in different regions of space via ?r(n)? (-3 <= n <= 3) in atoms, correlation energies in diatomic molecules, and the quality of fitting potential energy curves as measured by spectroscopic constants. All energy calculations with ANO VT-QZ have contraction errors within "chemical accuracy" of 1 kcal/mol, which is not true for cc-pVQZ, suggesting some improvement compared to the correlation consistent series of Dunning and co-workers. PMID- 26979681 TI - Efficient estimators for likelihood ratio sensitivity indices of complex stochastic dynamics. AB - We demonstrate that centered likelihood ratio estimators for the sensitivity indices of complex stochastic dynamics are highly efficient with low, constant in time variance and consequently they are suitable for sensitivity analysis in long time and steady-state regimes. These estimators rely on a new covariance formulation of the likelihood ratio that includes as a submatrix a Fisher information matrix for stochastic dynamics and can also be used for fast screening of insensitive parameters and parameter combinations. The proposed methods are applicable to broad classes of stochastic dynamics such as chemical reaction networks, Langevin-type equations and stochastic models in finance, including systems with a high dimensional parameter space and/or disparate decorrelation times between different observables. Furthermore, they are simple to implement as a standard observable in any existing simulation algorithm without additional modifications. PMID- 26979682 TI - Development of multi-mode diabatic spin-orbit models at arbitrary order. AB - The derivation of diabatic spin-orbit (SO) Hamiltonians is presented, which are expanded in terms of nuclear coordinates to arbitrary order including the treatment of multi-mode systems, having more than one mode of the same symmetry. The derivation is based on the microscopic Breit-Pauli SO operator and the consequent utilization of time reversal and spatial symmetry transformation properties of basis functions and coordinates. The method is demonstrated for a set of (2)E and (2)A1 states in C(3v)* (double group) symmetry, once for a 3D case of one a1 and one e mode and once for a 9D case of three a1 and three e coordinates. It is shown that the general structure of the diabatic SO Hamiltonian only depends on the basis states and is strictly imposed by time reversal symmetry. The resulting matrix can be expressed easily by a power series using six parametrized structure matrices as expansion coefficients multiplied by the associated monomials in terms of symmetrized coordinates. The explicit example presented here provides a full-dimensional diabatic SO model for methyl halide cations, which will be studied in the future. PMID- 26979683 TI - Iterative diagonalization of the non-Hermitian transcorrelated Hamiltonian using a plane-wave basis set: Application to sp-electron systems with deep core states. AB - We develop an iterative diagonalization scheme in solving a one-body self consistent-field equation in the transcorrelated (TC) method using a plane-wave basis set. Non-Hermiticity in the TC method is well handled with a block-Davidson algorithm. We verify that the required computational cost is efficiently reduced by our algorithm. In addition, we apply our plane-wave-basis TC calculation to some simple sp-electron systems with deep core states to elucidate an impact of the pseudopotential approximation to the calculated band structures. We find that a position of the deep valence bands is improved by an explicit inclusion of core states, but an overall band structure is consistent with a regular setup that includes core states into the pseudopotentials. This study offers an important understanding for the future application of the TC method to strongly correlated solids. PMID- 26979684 TI - Nuclear spatial delocalization silences electron density oscillations in 2-phenyl ethyl-amine (PEA) and 2-phenylethyl-N,N-dimethylamine (PENNA) cations. AB - We simulate electron dynamics following ionization in 2-phenyl-ethyl-amine and 2 phenylethyl-N,N-dimethylamine as examples of systems where 3 coupled cationic states are involved. We study two nuclear effects on electron dynamics: (i) coupled electron-nuclear motion and (ii) nuclear spatial delocalization as a result of the zero-point energy in the neutral molecule. Within the Ehrenfest approximation, our calculations show that the coherent electron dynamics in these molecules is not lost as a result of coupled electron-nuclear motion. In contrast, as a result of nuclear spatial delocalization, dephasing of the oscillations occurs on a time scale of only a few fs, long before any significant nuclear motion can occur. The results have been rationalized using a semi quantitative model based upon the gradients of the potential energy surfaces. PMID- 26979685 TI - Focal construct geometry for high intensity energy dispersive x-ray diffraction based on x-ray capillary optics. AB - We presented a focal construct geometry (FCG) method for high intensity energy dispersive X-ray diffraction by utilizing a home-made ellipsoidal single-bounce capillary (ESBC) and a polycapillary parallel X-ray lens (PPXRL). The ESBC was employed to focus the X-rays from a conventional laboratory source into a small focal spot and to produce an annular X-ray beam in the far-field. Additionally, diffracted polychromatic X-rays were confocally collected by the PPXRL attached to a stationary energy-resolved detector. Our FCG method based on ESBC and PPXRL had achieved relatively high intensity diffraction peaks and effectively narrowed the diffraction peak width which was helpful in improving the potential d-spacing resolution for material phase analysis. PMID- 26979687 TI - Rovibrational energy transfer and dissociation in O2-O collisions. AB - A set of state-specific transition rates for each rovibrational level is generated for the O2(X(3)Sigma(g)(-))-O(3)P system using the quasi-classical trajectory method at temperatures observed in hypersonic flows. A system of master equations describes the relaxation of the rovibrational ensemble to thermal equilibrium under ideal heat bath conditions at a constant translational temperature. Vibrational and rotational relaxation times, obtained from the average internal energies, exhibit a pattern inherent in a chemically reactive collisional pair. An intrinsic feature of the O3 molecular system with a large attractive potential is a weak temperature dependence of the rovibrational transition rates. For this reason, the quasi-steady vibrational and rotational temperatures experience a maximum at increasing translational temperature. The energy rate coefficients, that characterize the average loss of internal energy due to dissociation, quickly diminish at high temperatures, compared to other molecular systems. PMID- 26979686 TI - High-resolution nuclear magnetic resonance measurements in inhomogeneous magnetic fields: A fast two-dimensional J-resolved experiment. AB - High spectral resolution in nuclear magnetic resonance (NMR) is a prerequisite for achieving accurate information relevant to molecular structures and composition assignments. The continuous development of superconducting magnets guarantees strong and homogeneous static magnetic fields for satisfactory spectral resolution. However, there exist circumstances, such as measurements on biological tissues and heterogeneous chemical samples, where the field homogeneity is degraded and spectral line broadening seems inevitable. Here we propose an NMR method, named intermolecular zero-quantum coherence J-resolved spectroscopy (iZQC-JRES), to face the challenge of field inhomogeneity and obtain desired high-resolution two-dimensional J-resolved spectra with fast acquisition. Theoretical analyses for this method are given according to the intermolecular multiple-quantum coherence treatment. Experiments on (a) a simple chemical solution and (b) an aqueous solution of mixed metabolites under externally deshimmed fields, and on (c) a table grape sample with intrinsic field inhomogeneity from magnetic susceptibility variations demonstrate the feasibility and applicability of the iZQC-JRES method. The application of this method to inhomogeneous chemical and biological samples, maybe in vivo samples, appears promising. PMID- 26979688 TI - Infrared spectroscopic studies on the cluster size dependence of charge carrier structure in nitrous oxide cluster anions. AB - We report infrared photodissociation spectra of nitrous oxide cluster anions of the form (N2O)(n)O(-) (n = 1-12) and (N2O)n(-) (n = 7-15) in the region 800-1600 cm(-1). The charge carriers in these ions are NNO2(-) and O(-) for (N2O)(n)O(-) clusters with a solvation induced core ion switch, and N2O(-) for (N2O)n(-) clusters. The N-N and N-O stretching vibrations of N2O(-) (solvated by N2O) are reported for the first time, and they are found at (1595 +/- 3) cm(-1) and (894 +/- 5) cm(-1), respectively. We interpret our infrared spectra by comparison with the existing photoelectron spectroscopy data and with computational data in the framework of density functional theory. PMID- 26979689 TI - Ab initio calculation of the cross sections for electron impact vibrational excitation of CO via the (2)Pi shape resonance. AB - The stabilization method is used to calculate the complex potential energy curve of the (2)Pi state of CO(-) as a function of bond length, with the refinement that separate potentials are determined for p-wave and d-wave attachment and detachment of the excess electron. Using the resulting complex potentials, absolute vibrational excitation cross sections are calculated as a function of electron energy and scattering angle. The calculated cross sections agree well with experiment. PMID- 26979691 TI - A coarse-grain force field for RDX: Density dependent and energy conserving. AB - We describe the development of a density-dependent transferable coarse-grain model of crystalline hexahydro-1,3,5-trinitro-s-triazine (RDX) that can be used with the energy conserving dissipative particle dynamics method. The model is an extension of a recently reported one-site model of RDX that was developed by using a force-matching method. The density-dependent forces in that original model are provided through an interpolation scheme that poorly conserves energy. The development of the new model presented in this work first involved a multi objective procedure to improve the structural and thermodynamic properties of the previous model, followed by the inclusion of the density dependency via a conservative form of the force field that conserves energy. The new model accurately predicts the density, structure, pressure-volume isotherm, bulk modulus, and elastic constants of the RDX crystal at ambient pressure and exhibits transferability to a liquid phase at melt conditions. PMID- 26979690 TI - The transition from the open minimum to the ring minimum on the ground state and on the lowest excited state of like symmetry in ozone: A configuration interaction study. AB - The metastable ring structure of the ozone 1(1)A1 ground state, which theoretical calculations have shown to exist, has so far eluded experimental detection. An accurate prediction for the energy difference between this isomer and the lower open structure is therefore of interest, as is a prediction for the isomerization barrier between them, which results from interactions between the lowest two (1)A1 states. In the present work, valence correlated energies of the 1(1)A1 state and the 2(1)A1 state were calculated at the 1(1)A1 open minimum, the 1(1)A1 ring minimum, the transition state between these two minima, the minimum of the 2(1)A1 state, and the conical intersection between the two states. The geometries were determined at the full-valence multi-configuration self-consistent-field level. Configuration interaction (CI) expansions up to quadruple excitations were calculated with triple-zeta atomic basis sets. The CI expansions based on eight different reference configuration spaces were explored. To obtain some of the quadruple excitation energies, the method of Correlation Energy Extrapolation by Intrinsic Scaling was generalized to the simultaneous extrapolation for two states. This extrapolation method was shown to be very accurate. On the other hand, none of the CI expansions were found to have converged to millihartree (mh) accuracy at the quadruple excitation level. The data suggest that convergence to mh accuracy is probably attained at the sextuple excitation level. On the 1(1)A1 state, the present calculations yield the estimates of (ring minimum-open minimum) ~45-50 mh and (transition state-open minimum) ~85-90 mh. For the (2(1)A1 (1)A1) excitation energy, the estimate of ~130-170 mh is found at the open minimum and 270-310 mh at the ring minimum. At the transition state, the difference (2(1)A1-(1)A1) is found to be between 1 and 10 mh. The geometry of the transition state on the 1(1)A1 surface and that of the minimum on the 2(1)A1 surface nearly coincide. More accurate predictions of the energy differences also require CI expansions to at least sextuple excitations with respect to the valence space. For every wave function considered, the omission of the correlations of the 2s oxygen orbitals, which is a widely used approximation, was found to cause errors of about +/-10 mh with respect to the energy differences. PMID- 26979692 TI - Effect of simple solutes on the long range dipolar correlations in liquid water. AB - Intermolecular correlations in liquid water at ambient conditions have generally been characterized through short range density fluctuations described through the atomic pair distribution functions. Recent numerical and experimental results have suggested that such a description of order or structure in liquid water is incomplete and there exist considerably longer ranged orientational correlations in water that can be studied through dipolar correlations. In this study, using large scale classical, atomistic molecular dynamics simulations using TIP4P-Ew and TIP3P models of water, we show that salts such as sodium chloride (NaCl), potassium chloride (KCl), caesium chloride (CsCl), and magnesium chloride (MgCl2) have a long range effect on the dipolar correlations, which cannot be explained by the notion of structure making and breaking by dissolved ions. Observed effects are explained through orientational stratification of water molecules around ions and their long range coupling to the global hydrogen bond network by virtue of the sum rule for water. The observations for single hydrophilic solutes are contrasted with the same for a single methane (CH4) molecule. We observe that even a single small hydrophobe can result in enhancement of long range orientational correlations in liquid water, contrary to the case of dissolved ions, which have been observed to have a reducing effect. The observations from this study are discussed in the context of hydrophobic effect. PMID- 26979693 TI - Optimization of classical nonpolarizable force fields for OH(-) and H3O(+). AB - We optimize force fields for H3O(+) and OH(-) that reproduce the experimental solvation free energies and the activities of H3O(+) Cl(-) and Na(+) OH(-) solutions up to concentrations of 1.5 mol/l. The force fields are optimized with respect to the partial charge on the hydrogen atoms and the Lennard-Jones parameters of the oxygen atoms. Remarkably, the partial charge on the hydrogen atom of the optimized H3O(+) force field is 0.8 +/- 0.1|e|--significantly higher than the value typically used for nonpolarizable water models and H3O(+) force fields. In contrast, the optimal partial charge on the hydrogen atom of OH(-) turns out to be zero. Standard combination rules can be used for H3O(+) Cl(-) solutions, while for Na(+) OH(-) solutions, we need to significantly increase the effective anion-cation Lennard-Jones radius. While highlighting the importance of intramolecular electrostatics, our results show that it is possible to generate thermodynamically consistent force fields without using atomic polarizability. PMID- 26979694 TI - Theoretical study of ionic liquids based on the cholinium cation. Ab initio simulations of their condensed phases. AB - We have explored by means of ab initio molecular dynamics the homologue series of 11 different ionic liquids based on the combination of the cholinium cation with deprotonated amino acid anions. We present a structural analysis of the liquid states of these compounds as revealed by accurate ab initio computations of the forces. We highlight the persistent structural motifs that see the ionic couple as the basic building block of the liquid whereby a strong hydrogen bonding network substantially determines the short range structural behavior of the bulk state. Other minor docking features of the interaction network are also discovered and described. Special cases along the series such as Cysteine and Phenylalanine are discussed in the view of their peculiar properties due to zwitterion formation and additional long-range structural organization. PMID- 26979695 TI - Dielectric relaxation in ionic liquid/dipolar solvent binary mixtures: A semi molecular theory. AB - A semi-molecular theory is developed here for studying dielectric relaxation (DR) in binary mixtures of ionic liquids (ILs) with common dipolar solvents. Effects of ion translation on DR time scale, and those of ion rotation on conductivity relaxation time scale are explored. Two different models for the theoretical calculations have been considered: (i) separate medium approach, where molecularities of both the IL and dipolar solvent molecules are retained, and (ii) effective medium approach, where the added dipolar solvent molecules are assumed to combine with the dipolar ions of the IL, producing a fictitious effective medium characterized via effective dipole moment, density, and diameter. Semi-molecular expressions for the diffusive DR times have been derived which incorporates the effects of wavenumber dependent orientational static correlations, ion dynamic structure factors, and ion translation. Subsequently, the theory has been applied to the binary mixtures of 1-butyl-3-methylimidazolium tetrafluoroborate ([Bmim][BF4]) with water (H2O), and acetonitrile (CH3CN) for which experimental DR data are available. On comparison, predicted DR time scales show close agreement with the measured DR times at low IL mole fractions (x(IL)). At higher IL concentrations (x(IL) > 0.05), the theory over-estimates the relaxation times and increasingly deviates from the measurements with x(IL), deviation being the maximum for the neat IL by almost two orders of magnitude. The theory predicts negligible contributions to this deviation from the x(IL) dependent collective orientational static correlations. The drastic difference between DR time scales for IL/solvent mixtures from theory and experiments arises primarily due to the use of the actual molecular volume (V(mol)(dip)) for the rotating dipolar moiety in the present theory and suggests that only a fraction of V(mol)(dip) is involved at high x(IL). Expectedly, nice agreement between theory and experiments appears when experimental estimates for the effective rotational volume (V(eff)(dip)) are used as inputs. The fraction, V(eff)(dip)/V(mol)(dip), sharply decreases from ~1 at pure dipolar solvent to ~0.01 at neat IL, reflecting a dramatic crossover from viscosity-coupled hydrodynamic angular diffusion at low IL mole fractions to orientational relaxation predominantly via large angle jumps at high x(IL). Similar results are obtained on applying the present theory to the aqueous solution of an electrolyte guanidinium chloride (GdmCl) having a permanent dipole moment associated with the cation, Gdm(+). PMID- 26979696 TI - Carbon dioxide in an ionic liquid: Structural and rotational dynamics. AB - Ionic liquids (ILs), which have widely tunable structural motifs and intermolecular interactions with solutes, have been proposed as possible carbon capture media. To inform the choice of an optimal ionic liquid system, it can be useful to understand the details of dynamics and interactions on fundamental time scales (femtoseconds to picoseconds) of dissolved gases, particularly carbon dioxide (CO2), within the complex solvation structures present in these uniquely organized materials. The rotational and local structural fluctuation dynamics of CO2 in the room temperature ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (EmimNTf2) were investigated by using ultrafast infrared spectroscopy to interrogate the CO2 asymmetric stretch. Polarization selective pump probe measurements yielded the orientational correlation function of the CO2 vibrational transition dipole. It was found that reorientation of the carbon dioxide occurs on 3 time scales: 0.91 +/- 0.03, 8.3 +/- 0.1, 54 +/- 1 ps. The initial two are attributed to restricted wobbling motions originating from a gating of CO2 motions by the IL cations and anions. The final (slowest) decay corresponds to complete orientational randomization. Two-dimensional infrared vibrational echo (2D IR) spectroscopy provided information on structural rearrangements, which cause spectral diffusion, through the time dependence of the 2D line shape. Analysis of the time-dependent 2D IR spectra yields the frequency-frequency correlation function (FFCF). Polarization-selective 2D IR experiments conducted on the CO2 asymmetric stretch in the parallel- and perpendicular-pumped geometries yield significantly different FFCFs due to a phenomenon known as reorientation-induced spectral diffusion (RISD), revealing strong vector interactions with the liquid structures that evolve slowly on the (independently measured) rotation time scales. To separate the RISD contribution to the FFCF from the structural spectral diffusion contribution, the previously developed first order Stark effect RISD model is reformulated to describe the second order (quadratic) Stark effect--the first order Stark effect vanishes because CO2 does not have a permanent dipole moment. Through this analysis, we characterize the structural fluctuations of CO2 in the ionic liquid solvation environment, which separate into magnitude-only and combined magnitude and directional correlations of the liquid's time dependent electric field. This new methodology will enable highly incisive comparisons between CO2 dynamics in a variety of ionic liquid systems. PMID- 26979697 TI - Insight into the Li2CO3-K2CO3 eutectic mixture from classical molecular dynamics: Thermodynamics, structure, and dynamics. AB - We use molecular dynamics simulations to study the thermodynamics, structure, and dynamics of the Li2CO3-K2CO3 (62:38 mol. %) eutectic mixture. We present a new classical non-polarizable force field for this molten salt mixture, optimized using experimental and first principles molecular dynamics simulations data as reference. This simple force field allows efficient molecular simulations of phenomena at long time scales. We use this optimized force field to describe the behavior of the eutectic mixture in the 900-1100 K temperature range, at pressures between 0 and 5 GPa. After studying the equation of state in these thermodynamic conditions, we present molecular insight into the structure and dynamics of the melt. In particular, we present an analysis of the temperature and pressure dependence of the eutectic mixture's self-diffusion coefficients, viscosity, and ionic conductivity. PMID- 26979698 TI - Intermolecular electron transfer from intramolecular excitation and coherent acoustic phonon generation in a hydrogen-bonded charge-transfer solid. AB - Organic materials that produce coherent lattice phonon excitations in response to external stimuli may provide next generation solutions in a wide range of applications. However, for these materials to lead to functional devices in technology, a full understanding of the possible driving forces of coherent lattice phonon generation must be attained. To facilitate the achievement of this goal, we have undertaken an optical spectroscopic study of an organic charge transfer material formed from the ubiquitous reduction-oxidation pair hydroquinone and p-benzoquinone. Upon pumping this material, known as quinhydrone, on its intermolecular charge transfer resonance as well as an intramolecular resonance of p-benzoquinone, we find sub-cm(-1) oscillations whose dispersion with probe energy resembles that of a coherent acoustic phonon that we argue is coherently excited following changes in the electron density of quinhydrone. Using the dynamical information from these ultrafast pump-probe measurements, we find that the fastest process we can resolve does not change whether we pump quinhydrone at either energy. Electron-phonon coupling from both ultrafast coherent vibrational and steady-state resonance Raman spectroscopies allows us to determine that intramolecular electronic excitation of p benzoquinone also drives the electron transfer process in quinhydrone. These results demonstrate the wide range of electronic excitations of the parent of molecules found in many functional organic materials that can drive coherent lattice phonon excitations useful for applications in electronics, photonics, and information technology. PMID- 26979699 TI - Coverage induced structural transformations of tetracene on Ag(110). AB - Self-assembly of tetracene on an anisotropic surface of Ag(110) has been investigated using scanning tunneling microscopy and low-energy electron diffraction. We observe multistage structural transformations of the self assembled tetracene on Ag(110) as a function of molecular coverages, which are accompanied by the changes in molecular orientations. They are analyzed by a balance between multiple molecule-molecule and anisotropic substrate-molecule interactions. PMID- 26979700 TI - Kinetic Monte Carlo simulations for birefringence relaxation of photo-switchable molecules on a surface. AB - Recent experiments have demonstrated that in a dense monolayer of photo switchable dye methyl-red molecules the relaxation of an initial birefringence follows a power-law decay, typical for glass-like dynamics. The slow relaxation can efficiently be controlled and accelerated by illuminating the monolayer with circularly polarized light, which induces trans-cis isomerization cycles. To elucidate the microscopic mechanism, we develop a two-dimensional molecular model in which the trans and cis isomers are represented by straight and bent needles, respectively. As in the experimental system, the needles are allowed to rotate and to form overlaps but they cannot translate. The out-of-equilibrium rotational dynamics of the needles is generated using kinetic Monte Carlo simulations. We demonstrate that, in a regime of high density and low temperature, the power-law relaxation can be traced to the formation of spatio-temporal correlations in the rotational dynamics, i.e., dynamic heterogeneity. We also show that the nearly isotropic cis isomers can prevent dynamic heterogeneity from forming in the monolayer and that the relaxation then becomes exponential. PMID- 26979701 TI - Ag2ZnSn(S,Se)4: A highly promising absorber for thin film photovoltaics. AB - The growth in efficiency of earth-abundant kesterite Cu2ZnSn(S,Se)4 (CZTSSe) solar cells has slowed, due in part to the intrinsic limitations imposed by the band tailing attributed primarily to I-II antisite exchange. In this study, density functional theory simulations show that when Ag is substituted for Cu to form kesterite Ag2ZnSnSe4 (AZTSe), the I-II isolated antisite formation energy becomes 3.7 times greater than in CZTSSe, resulting in at least an order of magnitude reduction in I-II antisite density. Experimental evidence of an optoelectronically improved material is also provided. Comparison of the low temperature photoluminescence (PL) structure of Cu(In,Ga)Se2 (CIGSe), CZTSSe, and AZTSe shows that AZTSe has a shallow defect structure with emission significantly closer to the band edge than CZTSe. Existence of suppressed band tailing is found in the proximity of the room-temperature PL peak of AZTSe to its measured band gap. The results are consistent with AZTSe being a promising alternative to CZTSSe and CIGSe for thin film photovoltaics. PMID- 26979702 TI - Ab initio parameterization of a charge optimized many-body forcefield for Si SiO2: Validation and thermal transport in nanostructures. AB - In an effort to extend the reach of current ab initio calculations to simulations requiring millions of configurations for complex systems such as heterostructures, we have parameterized the third-generation Charge Optimized Many-Body (COMB3) potential using solely ab initio total energies, forces, and stress tensors as input. The quality and the predictive power of the new forcefield are assessed by computing properties including the cohesive energy and density of SiO2 polymorphs, surface energies of alpha-quartz, and phonon densities of states of crystalline and amorphous phases of SiO2. Comparison with data from experiments, ab initio calculations, and molecular dynamics simulations using published forcefields including BKS (van Beest, Kramer, and van Santen), ReaxFF, and COMB2 demonstrates an overall improvement of the new parameterization. The computed temperature dependence of the thermal conductivity of crystalline alpha-quartz and the Kapitza resistance of the interface between crystalline Si(001) and amorphous silica is in excellent agreement with experiment, setting the stage for simulations of complex nanoscale heterostructures. PMID- 26979703 TI - Nanopore gating with an anchored polymer in a switching electrolyte bias. AB - In this work, we theoretically study the interaction between a solid state membrane equipped with a nanopore and a tethered, negatively charged polymer chain subjected to a time-dependent applied electrolyte bias. In order to describe the movement of the chain in the biomolecule-membrane system immersed in an electrolyte solution, Brownian dynamics is used. We show that we can control the polymer's equilibrium position with various applied electrolyte biases: for a sufficiently positive bias, the chain extends inside the pore, and the removal of the bias causes the polymer to leave the pore. Corresponding to a driven process, we find that the time it takes for a biomolecular chain to enter and extend into a nanopore in a positive bias almost increases linearly with chain length while the amount of time it takes for a polymer chain to escape the nanopore is mainly governed by diffusion. PMID- 26979704 TI - Effect of excluded volume on the force-extension of wormlike chains in slit confinement. AB - We use pruned-enriched Rosenbluth method simulations to develop a quantitative phase diagram for the stretching of a real wormlike chain confined in a slit. Our simulations confirm the existence of a "confined Pincus" regime in slit confinement, analogous to the Pincus regime in free solution, where excluded volume effects are sensible. The lower bound for the confined Pincus regime in the force-molecular weight plane, as well as the scaling of the extension with force and slit size, agree with an existing scaling theory for this regime. The upper bound of the confined Pincus regime depends on the strength of the confinement. For strong confinement, the confined Pincus regime ends when the contour length in the Pincus blob is too short to have intrablob excluded volume. As a result, the chain statistics become ideal and the confined Pincus regime at low forces is connected directly to ideal chain stretching at large forces. In contrast, for weak confinement, the confined Pincus regime ends when the Pincus blobs no longer fit inside the slit, even though there is sufficient contour length to have excluded volume inside the Pincus blob. As a result, weak confinement leads to a free-solution Pincus regime intervening between the confined Pincus regime for weak forces and ideal chain stretching at strong forces. Our results highlight shortcomings in existing models for the stretching of wormlike chains in slits. PMID- 26979705 TI - Coarse-grained molecular simulations of allosteric cooperativity. AB - Interactions between a protein and a ligand are often accompanied by a redistribution of the population of thermally accessible conformations. This dynamic response of the protein's functional energy landscape enables a protein to modulate binding affinities and control binding sensitivity to ligand concentration. In this paper, we investigate the structural origins of binding affinity and allosteric cooperativity of binding two Ca(2+) ions to each domain of Calmodulin (CaM) through simulations of a simple coarse-grained model. In this model, the protein's conformational transitions between open and closed conformational ensembles are simulated explicitly and ligand binding and unbinding are treated implicitly within the grand canonical ensemble. Ligand binding is cooperative because the binding sites are coupled through a shift in the dominant conformational ensemble upon binding. The classic Monod-Wyman Changeux model of allostery with appropriate binding free energies to the open and closed ensembles accurately describes the simulated binding thermodynamics. The simulations predict that the two domains of CaM have distinct binding affinity and cooperativity. In particular, the C-terminal domain binds Ca(2+) with higher affinity and greater cooperativity than the N-terminal domain. From a structural point of view, the affinity of an individual binding loop depends sensitively on the loop's structural compatibility with the ligand in the bound ensemble, as well as the conformational flexibility of the binding site in the unbound ensemble. PMID- 26979706 TI - Comparing allosteric transitions in the domains of calmodulin through coarse grained simulations. AB - Calmodulin (CaM) is a ubiquitous Ca(2+)-binding protein consisting of two structurally similar domains with distinct stabilities, binding affinities, and flexibilities. We present coarse grained simulations that suggest that the mechanism for the domain's allosteric transitions between the open and closed conformations depends on subtle differences in the folded state topology of the two domains. Throughout a wide temperature range, the simulated transition mechanism of the N-terminal domain (nCaM) follows a two-state transition mechanism while domain opening in the C-terminal domain (cCaM) involves unfolding and refolding of the tertiary structure. The appearance of the unfolded intermediate occurs at a higher temperature in nCaM than it does in cCaM consistent with nCaM's higher thermal stability. Under approximate physiological conditions, the simulated unfolded state population of cCaM accounts for 10% of the population with nearly all of the sampled transitions (approximately 95%) unfolding and refolding during the conformational change. Transient unfolding significantly slows the domain opening and closing rates of cCaM, which can potentially influence its Ca(2+)-binding mechanism. PMID- 26979707 TI - Dynamics of the entropic insertion of a large sphere into a cylindrical vessel. AB - Insertion of a solute into a vessel comprising biopolymers is a fundamental function in a biological system. The entropy originating from the translational displacement of solvent particles plays an essential role in the insertion. Here we study the dynamics of entropic insertion of a large spherical solute into a cylindrical vessel. The solute and the vessel are immersed in small spheres forming the solvent. We develop a theoretical method formulated using the Fokker Planck equation. The spatial distribution of solute-vessel entropic potential, which is calculated by the three-dimensional integral equation theory combined with rigid-body models, serves as input data. The key quantity analyzed is the density of the probability of finding the solute at any position at any time. It is found that the solute is inserted along the central axis of the vessel cavity and trapped at a position where the entropic potential takes a local minimum value. The solute keeps being trapped without touching the vessel inner surface. In a significantly long time tau, the solute transfers to the position in contact with the vessel bottom possessing the global potential minimum along the central axis. As the solute size increases, tau becomes remarkably longer. We also discuss the relevance of our result to the functional expression of a chaperonin/cochaperonin in the assistance of protein folding. PMID- 26979708 TI - An implicit divalent counterion force field for RNA molecular dynamics. AB - How to properly account for polyvalent counterions in a molecular dynamics simulation of polyelectrolytes such as nucleic acids remains an open question. Not only do counterions such as Mg(2+) screen electrostatic interactions, they also produce attractive intrachain interactions that stabilize secondary and tertiary structures. Here, we show how a simple force field derived from a recently reported implicit counterion model can be integrated into a molecular dynamics simulation for RNAs to realistically reproduce key structural details of both single-stranded and base-paired RNA constructs. This divalent counterion model is computationally efficient. It works with existing atomistic force fields, or coarse-grained models may be tuned to work with it. We provide optimized parameters for a coarse-grained RNA model that takes advantage of this new counterion force field. Using the new model, we illustrate how the structural flexibility of RNA two-way junctions is modified under different salt conditions. PMID- 26979709 TI - Erratum: "Influence of grain size on optical properties of Sr2CeO4 nanocrystals" [J. Chem. Phys. 142, 184701 (2015)]. PMID- 26979710 TI - Early detection of novel Leishmania species DNA in the saliva of two HIV-infected patients. AB - BACKGROUND: Leishmaniasis caused by two new species of Leishmania; L. siamensis and L. martiniquensis have been recently described in Thailand. The disease has mainly been documented in AIDS patients from southern Thailand. In this study, polymerase chain reaction (PCR) was used to determine HIV-Leishmania co-infection in southern Thailand. METHODS: One ml of saliva and 3 ml of EDTA blood were collected from HIV-infected patients for PCR detection of Leishmania DNA, cloning and sequencing. The positive PCR samples were then cultured on Schneider's insect medium. RESULTS: Three out of 316 saliva samples collected from HIV-infected patients were found to be positive for Leishmania DNA (0.95%). Among the positive samples, one patient was observed with disseminated cutaneous lesions and also tested positive via saliva, whole blood and buffy coat in PCR. The second case presenting with nodular lesions also gave a positive saliva test via PCR two months prior to buffy coat. This diagnosis was confirmed by microscopic examination and a culture of biopsy samples from a nodule. The last case was an asymptomatic Leishmania infection which tested PCR positive only in saliva with a consecutive sample collection conducted for three months. CONCLUSIONS: The prevalence of Leishmania infection in HIV infected patients within this study is 0.95%. Leishmania DNA was detected in saliva by PCR prior to blood and buffy coat of two HIV infected patients. Early detection of Leishmania DNA in saliva would be beneficial for the follow up of asymptomatic Leishmania infected patients, the early treatment of leishmaniasis and for surveillance survey purpose. However, full evaluation of sensitivity and specificity of this technique with a large cohort of patients is required before deployment. PMID- 26979713 TI - Does Mode of Transport Confer a Mortality Benefit in Trauma Patients? Characteristics and Outcomes at an Ontario Lead Trauma Hospital. AB - OBJECTIVES: Evidence-based guidelines regarding the optimal mode of transport for trauma patients from scene to trauma centre are lacking. The purpose of this study was to investigate the relationship between trauma patient outcomes and mode of transport at a single Ontario Level I Trauma Centre, and specifically to investigate if the mode of transport confers a mortality benefit. METHODS: A historical, observational cohort study was undertaken to compare rotor-wing and ground transported patients. Captured data included demographics, injury severity, temporal and mortality variables. TRISS-L analysis was performed to examine mortality outcomes. RESULTS: 387 rotor-wing transport and 2,759 ground transport patients were analyzed over an 18-year period. Rotor-wing patients were younger, had a higher Injury Severity Score, and had longer prehospital transport times. Mechanism of injury was similarly distributed between groups. After controlling for heterogeneity with TRISS-L analysis, the mortality of rotor-wing patients was found to be lower than predicted mortality, whereas the converse was found with ground patients. CONCLUSION: Rotor-wing and ground transported trauma patients represent heterogeneous populations. Accounting for these differences, rotor-wing patients were found to outperform their predicted mortality, whereas ground patients underperformed predictions. PMID- 26979711 TI - Chemotherapy-Induced Inflammatory Gene Signature and Protumorigenic Phenotype in Pancreatic CAFs via Stress-Associated MAPK. AB - Pancreatic ductal adenocarcinoma (PDAC) has a characteristically dense stroma comprised predominantly of cancer-associated fibroblasts (CAF). CAFs promote tumor growth, metastasis, and treatment resistance. This study aimed to investigate the molecular changes and functional consequences associated with chemotherapy treatment of PDAC CAFs. Chemoresistant immortalized CAFs (R-CAF) were generated by continuous incubation in gemcitabine. Gene expression differences between treatment-naive CAFs (N-CAF) and R-CAFs were compared by array analysis. Functionally, tumor cells (TC) were exposed to N-CAF- or R-CAF conditioned media and assayed for migration, invasion, and viability in vitro Furthermore, a coinjection (TC and CAF) model was used to compare tumor growth in vivo R-CAFs increased TC viability, migration, and invasion compared with N-CAFs. In vivo, TCs coinjected with R-CAFs grew larger than those accompanied by N-CAFs. Genomic analysis demonstrated that R-CAFs had increased expression of various inflammatory mediators, similar to the previously described senescence-associated secretory phenotype (SASP). In addition, SASP mediators were found to be upregulated in response to short duration treatment with gemcitabine in both immortalized and primary CAFs. Inhibition of stress-associated MAPK signaling (P38 MAPK or JNK) attenuated SASP induction as well as the tumor-supportive functions of chemotherapy-treated CAFs in vitro and in vivo These results identify a negative consequence of chemotherapy on the PDAC microenvironment that could be targeted to improve the efficacy of current therapeutic regimens. IMPLICATIONS: Chemotherapy treatment of pancreatic cancer-associated fibroblasts results in a proinflammatory response driven by stress-associated MAPK signaling that enhances tumor cell growth and invasiveness. Mol Cancer Res; 14(5); 437-47. (c)2016 AACR. PMID- 26979714 TI - Berberine activates Nrf2 nuclear translocation and inhibits apoptosis induced by high glucose in renal tubular epithelial cells through a phosphatidylinositol 3 kinase/Akt-dependent mechanism. AB - Apoptosis of tubular epithelial cells is a major feature of diabetic kidney disease, and hyperglycemia triggers the generation of free radicals and oxidant stress in tubular cells. Berberine (BBR) is identified as a potential anti diabetic herbal medicine due to its beneficial effects on insulin sensitivity, glucose metabolism and glycolysis. In this study, the underlying mechanisms involved in the protective effects of BBR on high glucose-induced apoptosis were explored using cultured renal tubular epithelial cells (NRK-52E cells) and human kidney proximal tubular cell line (HK-2 cells). We identified the pivotal role of phosphatidylinositol 3-kinase (PI3K)/Akt in BBR cellular defense mechanisms and revealed the novel effect of BBR on nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2) and heme oxygenase (HO)-1 in NRK-52E and HK-2 cells. BBR attenuated reactive oxygen species production, antioxidant defense (GSH and SOD) and oxidant-sensitive proteins (Nrf2 and HO-1), which also were blocked by LY294002 (an inhibitor of PI3K) in HG-treated NRK-52E and HK-2 cells. Furthermore, BBR improved mitochondrial function by increasing mitochondrial membrane potential. BBR-induced anti-apoptotic function was demonstrated by decreasing apoptotic proteins (cytochrome c, Bax, caspase3 and caspase9). All these findings suggest that BBR exerts the anti-apoptosis effects through activation of PI3K/Akt signal pathways and leads to activation of Nrf2 and induction of Nrf2 target genes, and consequently protecting the renal tubular epithelial cells from HG-induced apoptosis. PMID- 26979712 TI - Acute effects of coffee consumption on self-reported gastrointestinal symptoms, blood pressure and stress indices in healthy individuals. AB - BACKGROUND: It has been suggested that coffee may affect the gut-brain axis with conflicting outcomes. Moreover, there is insufficient evidence to determine whether the type or temperature of coffee consumed will have a different impact on the gut-brain axis. The purpose of this study was to investigate the effects of acute coffee consumption on the following: 1. self-reported GI symptoms and salivary gastrin, 2. stress indices [salivary cortisol and alpha-amylase (sAA)] and psychometric measures, and 3. blood pressure (BP), in healthy, daily coffee consuming individuals in non-stressful conditions. METHODS: This was a randomized, double blind, crossover clinical trial, in which 40 healthy individuals (20 men, 20 women), 20-55 years of age, randomly consumed four 200 ml coffee beverages containing 160 mg caffeine (hot and cold instant coffee, cold espresso, hot filtered coffee), 1 week apart. Salivary samples and psychometric questionnaires were collected at baseline and post-coffee consumption at 15,30, and 60 min for salivary gastrin and sAA measurements and at 60,120, and 180 min for cortisol measurements. BP was measured at beginning and end of each intervention. ClinicalTrials.gov ID: NCT02253628 RESULTS: Coffee consumption significantly increased sAA activity (P = 0.041), with significant differences only between cold instant and filter coffee at 15 and 30 min post-consumption (P < 0.05). Coffee temporarily increased salivary gastrin, without differences between coffee types. Coffee did not affect salivary cortisol or self-reported anxiety levels. Coffee consumption significantly increased BP, within the healthy physiological levels, in a gender specific manner at the end of the experimental periods, without differences between coffee types. CONCLUSION: Acute coffee consumption in non-stressful conditions activated sAA and BP but not salivary cortisol, indicating activation of the sympathetic nervous system. Post-coffee sAA increase without a concomitant cortisol increase may also indicate that coffee may have some anti-stress properties. PMID- 26979715 TI - [Progress due to networking structures. Challenges for the Competence Network Malignant Lymphomas in the Era of Precision Medicine]. AB - The Competence Network Malignant Lymphomas (KML), founded in 1999 at the initiative of the Federal Ministry of Education and Research (BMBF), brings together interdisciplinary medical and scientific expertise in research on malignant lymphomas. The network helps to release synergies in evidence-based clinical research and contributes to the accelerated transfer of advances in knowledge gained from therapeutic studies for the health care of lymphoma patients. During the regular BMBF funding period (1999-2009) individual sub projects were hived off, such as the Cochrane Haematological Malignancies Group (CHMG) or the Scientific Institute of Haematologists and Oncologists in Private Practice (WINHO GmbH). At the end of BMBF funding, pivotal KML projects such as the reference diagnostic panel for KML lymphoma study groups, site management support, health care management and the information and communication section could be continued in the scientific association "Kompetenznetz Maligne Lymphome e. V." which was founded in 2005. Due to the recent in-depth understanding of the molecular and genetic mechanisms of lymphomagenesis and the consequent transformation to precision medicine targeting specialised groups of patients, the KML is currently facing the challenge of developing modern study, health-care and information concepts in ever shorter periods of time. PMID- 26979716 TI - [AFNET. A translational research network develops into an academic research organization]. AB - "The whole is greater than the sum of its parts" (Aristotle).Atrial fibrillation (AF) is the most common sustained arrhythmia and affects 1-2 % of the population in developed countries, especially the elderly. We expect that the prevalence of AF will double in the next few decades. The last decades have seen important improvements in the management of atrial fibrillation, but many questions remain regarding the optimal diagnosis and management of the condition. The German Atrial Fibrillation NETwork (AFNET) was one of three cardiovascular competence networks in medicine funded by the German Ministry of Education and Research between 2003-2014. AFNET has contributed to the understanding of atrial fibrillation, and AFNET-led studies have led to improved clinical practices and practice guidelines in Germany and in Europe. This work has been expanded and is continuing in the AFNET association (AFNET e. V.). The AFNET association, founded in 2010 and continuing to this day, has developed into a small but fully formed academic research organisation that conducts investigator-initiated clinical trials as the responsible sponsor in Germany, Europe, and beyond. The AFNET association currently cooperates with EHRA (The European Heart Rhythm Association), ESC (The European Society of Cardiology) and DZHK (The German Centre for Cardiovascular Research) and receives funding from the European Union to generate evidence that can in the future lead to better prevention and management of AF. PMID- 26979717 TI - [Dementia Competence Network. Results and outlook]. AB - BACKGROUND: The Dementia Competence Network (DCN) is represented by academic memory clinics and has three major aims: (1) To facilitate the development of diagnostic tools including neuropsychology, biomarkers, imaging and genetics. (2) To implement clinical trials in mild cognitive impairment and dementia and (3) to improve standard care for dementia in Germany. AIMS: This article summarizes the achievements of the DCN so far and highlights future perspectives. METHODS: The DCN has built up two multicentre cohorts. Within the first cohort, patients with mild cognitive impairment or mild dementia were examined longitudinally using multiple neuropsychological assessments and numerous different biomarkers. In a subgroup of the first cohort, patients were treated with antidementive drugs in two placebo-controlled clinical trials. The second cohort included cognitively healthy older people and examined repetitively clinical, neuropsychological and psychosocial parameters for ten years. RESULTS AND DISCUSSION: The DCN has generated a large data and biomaterial bank. Numerous publications have helped to develop further diagnostic procedures and treatment of cognitive disorders and dementia. The DCN has contributed to end stigmatisation of dementia. PMID- 26979718 TI - [Competence Network Heart Failure (CNHF). Together against heart failure]. AB - Heart failure is one of the most urgent medical and socio-economic challenges of the 21(st) century. Up to three million people are affected in Germany; this means one in ten people over the age of 65 live with heart failure. The current demographic changes will accentuate the importance of this grave health problem. The care of patients with heart failure, as well as the associated research mandates a comprehensive, multidisciplinary approach. The Competence Network Heart Failure (CNHF) pursues this objective. CNHF is a research alliance with 11 sites in Germany and was funded by the Federal Ministry of Research (BMBF) from 2003 through 2014. Since January 2015, the network has been an associate cooperating partner of the German Centre for Cardiovascular Research (DZHK). During the 12-year funding period by the BMBF, scientists in the field of heart failure from 30 university hospitals, 5 research institutes, 7 heart centers, 17 cardiovascular clinics, over 200 general practitioners, 4 rehabilitation clinics, as well as numerous organizations and associations were involved in cooperative CNHF research. In the context of 22 projects, the CNHF covered basic, clinical, and health care research, and generated numerous groundbreaking insights into disease mechanisms, as well as diagnosis and treatment of heart failure, which are documented in more than 350 publications. With its central study database and bank of biomaterials, the network has set up a Europe-wide unique research resource, which can be used in the future for national and international cooperations with the DZHK and other partners. Furthermore, the CNHF strongly promotes nation- and Europe-wide public relations and heart failure awareness activities. PMID- 26979721 TI - Interface properties between a low band gap conjugated polymer and a calcium metal electrode. AB - Interfaces between metal electrodes and pi-conjugated polymers play an important role in the organic optoelectronic devices. In this paper, the molecular orientation of the pristine poly[(9,9-dioctylfluorenyl-2,7-diyl)-alt-5,5-(4',7' di-2-thienyl-2',1',3'-benzothiadiazole)] (APFO3) films, chemical reactions and the electronic structure during the interface formation of Ca/APFO3 have been investigated in detail using synchrotron radiation photoemission spectroscopy (SRPES), X-ray photoemission spectroscopy (XPS) and near-edge X-ray absorption fine structure (NEXAFS) spectroscopy. It is shown that the APFO3 film has a high degree of orientational ordering with its aromatic ring tilted at an angle of 43 degrees from the substrate, and the 9,9-dioctyl fluorene unit (F8) is almost in the same plane as the benzothiazole unit (BT). Upon vapor-deposition of Ca onto APFO3 at room temperature, Ca dopes electrons into APFO3 and induces the downward band bending of APFO3. Moreover, Ca can diffuse into the APFO3 subsurface and react with N, S and C atoms of APFO3. Finally, the barrier of electron injection at the Ca/APFO3 interface is derived by the energy level alignment diagram. These results enable us to gain comprehensive insights into APFO3 and will facilitate the reasonable design of high performance devices based on APFO3. PMID- 26979719 TI - [Leukemia research in Germany: the Competence Network Acute and Chronic Leukemias]. AB - The Competence Network "Acute and Chronic Leukemias" was founded in 1997 by the consolidation of the leading leukemia study groups in Germany. Key results are the development of new trials and cooperative studies, the setup of patient registries and biobanking facilities, as well as the improvement of study infrastructure. In 2003, the concept of the competence network contributed to the foundation of the European LeukemiaNet (ELN). Synergy with the ELN resulted in cooperation on a European and international level, standardization of diagnostics and treatment, and recommendations for each leukemia and interdisciplinary specialty. The ultimate goal of the network is the cure of leukemia through cooperative research. PMID- 26979722 TI - Hybridization of Surface Plasmon Polariton and Photonic Crystal Modes in Bragg Mirror with Periodically Profiled Metal Film. AB - The hybridization of the plasmonic and guided modes in the case of one-dimension photonic crystal based on Bragg mirror terminated by a corrugated metal film has been demonstrated theoretically. The simulations have showed that the hybrid plasmonic-photonic mode is characterized by low broadening due to redistribution of the electric field intensity between photonic mode and surface plasmon polariton. It was found that the Q-factor and the polarisation sensitivity of these modes are about 144 and 25, respectively, that is 3 times greater than for surface plasmon polariton exciting in similar structure without Bragg mirror. PMID- 26979720 TI - Citicoline retards myopia progression following form deprivation in guinea pigs. AB - The retinal dopaminergic system is involved in the myopic shift following form deprivation. Citicoline has been demonstrated to stimulate the dopaminergic system in the brain and retina. Furthermore, citicoline has been used in many neurogenic diseases, such as senile cognitive impairment, stroke and Parkinson's disease as well as in amblyopia and glaucoma. Our aim was to investigate the effect of citicoline on the refractive state and retinal dopamine level in form deprivation myopia of guinea pigs. Guinea pigs, at an age of four weeks, were randomly divided into normal control, deprivation, deprived + citicoline and deprived + vehicle groups. Form deprivation myopia was induced by a translucent eye shield covering the right eye. Citicoline was injected intraperitoneally twice a day (500 mg/kg, 9 am and 9 pm) for 10 days. In vitro, retinal explants were cultured with citicoline for 24 h, with a final citicoline concentration of 100 umol/L. The ocular refractive parameters and retinal dopamine content were measured. After occlusion for 10 days, the form-deprived eyes became myopic with an increase in axial length and a decrease in retinal dopamine content. The intraperitoneal injection of citicoline reduced the myopic degree (from -3.25 +/- 0.77D to -0.62 +/- 0.47D, P < 0.001) and partially raised retinal dopamine levels (from 0.55 +/- 0.21 ng to 0.81 +/- 0.24 ng, P < 0.01) in the form-deprived eyes. After 24 h of culturing retinal explants with citicoline, retinal dopamine content increased significantly (from 0.42 +/- 0.14 ng to 0.62 +/- 0.21 ng, P < 0.05). These results demonstrated that an intraperitoneal injection of citicoline could retard the myopic shift induced by form deprivation in guinea pigs, which was mediated by an increase in the retinal dopamine levels. PMID- 26979723 TI - Endothelialization of TiO2 Nanorods Coated with Ultrathin Amorphous Carbon Films. AB - Carbon plasma nanocoatings with controlled fraction of sp(3)-C bonding were deposited on TiO2 nanorod arrays (TNAs) by DC magnetic-filtered cathodic vacuum arc deposition (FCVAD). The cytocompatibility of TNA/carbon nanocomposites was systematically investigated. Human umbilical vein endothelial cells (HUVECs) were cultured on the nanocomposites for 4, 24, and 72 h in vitro. It was found that plasma-treated TNAs exhibited excellent cell viability as compared to the untreated. Importantly, our results show that cellular responses positively correlate with the sp(3)-C content. The cells cultured on high sp(3)-C-contented substrates exhibit better attachment, shape configuration, and proliferation. These findings indicate that the nanocomposites with high sp(3)-C content possessed superior cytocompatibility. Notably, the nanocomposites drastically reduced platelet adhesion and activation in our previous studies. Taken together, these findings suggest the TNA/carbon scaffold may serve as a guide for the design of multi-functionality devices that promotes endothelialization and improves hemocompatibility. PMID- 26979724 TI - Annealing Effects on Structure and Optical Properties of Diamond-Like Carbon Films Containing Silver. AB - In the present study, diamond-like carbon films with embedded Ag nanoparticles (DLC:Ag) were deposited by reactive magnetron sputtering. Structure of the films was investigated by Raman scattering spectroscopy. Atomic force microscopy was used to define thickness of DLC:Ag films as well as to study the surface morphology and size distribution of Ag nanoparticles. Optical absorbance and reflectance spectra of the films were studied in the 180-1100-nm range. Air annealing effects on structure and optical properties of the DLC:Ag were investigated. Annealing temperatures were varied in the 180-400 degrees C range. Changes of size and shape of the Ag nanoclusters took place due to agglomeration. It was found that air annealing of DLC:Ag films can result in graphitization following destruction of the DLC matrix. Additional activation of surface enhanced Raman scattering (SERS) effect in DLC:Ag films can be achieved by properly selecting annealing conditions. Annealing resulted in blueshift as well as significant narrowing of the plasmonic absorbance and reflectance peaks. Moreover, quadrupole surface plasmon resonance peaks appeared. Modeling of absorption spectra of the nanoclusters depending on the shape and surrounding media has been carried out. PMID- 26979725 TI - Crossbar Nanoscale HfO2-Based Electronic Synapses. AB - Crossbar resistive switching devices down to 40 * 40 nm(2) in size comprising 3 nm-thick HfO2 layers are forming-free and exhibit up to 10(5) switching cycles. Four-nanometer-thick devices display the ability of gradual switching in both directions, thus emulating long-term potentiation/depression properties akin to biological synapses. Both forming-free and gradual switching properties are modeled in terms of oxygen vacancy generation in an ultrathin HfO2 layer. By applying the voltage pulses to the opposite electrodes of nanodevices with the shape emulating spikes in biological neurons, spike-timing-dependent plasticity functionality is demonstrated. Thus, the fabricated memristors in crossbar geometry are promising candidates for hardware implementation of hybrid CMOS neuron/memristor-synapse neural networks. PMID- 26979726 TI - Microstructure and Phase Composition of Cold Isostatically Pressed and Pressureless Sintered Silicon Nitride. AB - The microstructure and physical properties of new Y2O3 and Al2O3 oxide-doped silicon nitride ceramics fabricated by cold isostatic pressing and free sintering were investigated. The phase composition of produced material was also studied by X-ray diffraction at room and elevated temperature. The fabricated ceramics featured a microstructure of Si5AlON7 grains with a fine-grained alpha-Si3N4 with a small amount of Y2SiAlON5. Described ceramics is attractive for many high temperature structural applications due to beneficial combination of fine-grained structure with improved mechanical properties and small weight loss. PMID- 26979727 TI - Solid-Phase Spectrophotometric Analysis of 1-Naphthol Using Silica Functionalized with m-Diazophenylarsonic Acid. AB - The m-aminophenylarsonic acid (m-APAA) was immobilized onto the silica gel surface with covalently grafted quaternary ammonium groups via ion exchange. The diazotization of ion-bonded m-APAA resulted in a new solid-phase spectrophotometric reagent for detection of 1-naphtol in environmental water samples. The procedure of solid-phase spectrophotometric analysis is characterized by 20 MUg L(-1) limit of detection (LOD) of 1-naphtol, up to 2000 concentration factor, and insensitivity to the presence of natural water components as well as to 30-fold excess of phenol, resorcinol, and catechol. PMID- 26979728 TI - Stochastic Formation of Fibrillar and Amorphous Superoxide Dismutase Oligomers Linked to Amyotrophic Lateral Sclerosis. AB - Recent reports suggest that the nucleation and propagation of oligomeric superoxide dismutase-1 (SOD1) is effectively stochastic in vivo and in vitro. This perplexing kinetic variability-observed for other proteins and frequently attributed to experimental error-plagues attempts to discern how SOD1 mutations and post-translational modifications linked to amyotrophic lateral sclerosis (ALS) affect SOD1 aggregation. This study used microplate fluorescence spectroscopy and dynamic light scattering to measure rates of fibrillar and amorphous SOD1 aggregation at high iteration (ntotal = 1.2 * 10(3)). Rates of oligomerization were intrinsically irreproducible and populated continuous probability distributions. Modifying reaction conditions to mimic random and systematic experimental error could not account for kinetic outliers in standard assays, suggesting that stochasticity is not an experimental artifact, rather an intrinsic property of SOD1 oligomerization (presumably caused by competing pathways of oligomerization). Moreover, mean rates of fibrillar and amorphous nucleation were not uniformly increased by mutations that cause ALS; however, mutations did increase kinetic noise (variation) associated with nucleation and propagation. The stochastic aggregation of SOD1 provides a plausible statistical framework to rationalize how a pathogenic mutation can increase the probability of oligomer nucleation within a single cell, without increasing the mean rate of nucleation across an entire population of cells. PMID- 26979729 TI - Molecular differentiation of Sarcocystis buffalonis and Sarcocystis levinei in water buffaloes (Bubalus bubalis) from Sarcocystis hirsuta and Sarcocystis cruzi in cattle (Bos taurus). AB - The purpose of the present study was to obtain sarcocysts of Sarcocystis buffalonis and Sarcocystis levinei from water buffaloes and characterize the isolates by molecular methods in order to determine whether the two species were genetically different from Sarcocystis hirsuta and Sarcocystis cruzi, respectively, from cattle, which had been characterized before. About 35 macroscopically visible (3-4 * 1-2 mm) and 20 barely visible (1-3 * 0.2 mm) sarcocysts were excised from the esophagus of 18 naturally infected and freshly slaughtered adult water buffaloes at three slaughterhouses in Egypt. Genomic DNA was extracted from the sarcocysts, and all isolates were first characterized at the mitochondrial cytochrome c oxidase subunit I gene (cox1) gene through PCR amplification and direct sequencing. Selected isolates were subsequently further characterized at the 18S and 28S ribosomal (r) RNA genes and the internal transcribed spacer 1 (ITS1) region of the nuclear rDNA unit by direct sequencing or cloning. Only six of the isolated macroscopic sarcocysts belonged to S. buffalonis, whereas the others belonged to Sarcocystis fusiformis. Twelve of the smaller cysts belonged to S. levinei and seven to Sarcocystis sinensis. The characterization of the sarcocysts of S. sinensis and some of the sarcocysts of S. fusiformis have been reported before. Fifteen additional sarcocyst isolates of S. fusiformis were characterized at cox1 in the present study and found to be identical or closely similar to previous isolates. At cox1, the sequence identity between the six isolates of S. buffalonis was 99.8-100 % (two haplotypes), whereas the identity between the 12 isolates of S. levinei was 99.0-100 % (10 haplotypes). The identity between cox1 sequences of S. buffalonis and S. hirsuta (n = 56) was 92.9-93.6 % (on average 93.4 %), and the identity between cox1 sequences of S. levinei and S. cruzi (n = 22) was 92.9-94.0 % (on average 93.5 %). The phylogenetic analyses placed with high support the cox1 sequences of S. buffalonis and S. hirsuta into two monophyletic sister groups, and the same was true for the cox1 sequences of S. levinei and S. cruzi. Hence, the study established that S. buffalonis and S. levinei are distinct species different from S. hirsuta and S. cruzi, respectively. Nucleotide sequences of S. buffalonis could be distinguished from those of S. hirsuta also at the 28S rRNA gene (clearly different) and the ITS1 region (small and uncertain difference) but not at the 18S rRNA gene. Sequences of S. levinei could be distinguished from those of S. cruzi both at the 18S and 28S rRNA genes (ITS1 region not examined). However, the cox1 gene was superior to the 18S and 28S rRNA genes as regards the ability to unambiguously delimit the species within each species pair, since at the latter markers, the number of consistent nucleotide differences between the species was low and there was a slight overlap between the intraspecific and interspecific sequence divergence. Comparison of the newly generated 18S rRNA gene sequences of S. levinei from water buffaloes with similar sequences deposited in GenBank suggested that S. levinei and S. cruzi are not strictly intermediate host specific but might occasionally infect cattle and water buffaloes, respectively. PMID- 26979730 TI - Occurrence of Leishmania infantum and associated histological alterations in the genital tract and mammary glands of naturally infected dogs. AB - The objectives of this study were to evaluate the occurrence of Leishmania infantum in the male and female genital tract and female mammary glands of dogs and the parasite burden and to identify histological alterations associated with this protozoan. Twenty male and 20 female Leishmania-seropositive dogs with isolation of L. infantum were examined. Tissue samples of the prepuce, glans, epididymis, testes, prostate, vulva, vagina, uterus, uterine tubes, and mammary glands were analyzed by immunohistochemistry and histopathology. For parasitological culture and in situ hybridization, samples were collected from the testis, epididymis, and uterus. Additionally, seminal fluid was aspirated from the epididymis for parasitological culture. In the genital tract, 34 (85 %) dogs, including 18 males and 16 females, were positive for Leishmania. Of these, 27 (79 %) animals were symptomatic. Leishmania was detected in the mammary glands of 13 (65 %) females. L. infantum was isolated for the first time from the seminal fluid and uterus of naturally infected dogs. The parasite burden and intensity of the inflammatory reaction were greater in the prepuce and glans of males and in the vulva and mammary glands of females. In addition to inflammation, testicular degeneration, atrophy, absence of spermatogenesis, and necrosis were observed. Detection of amastigote forms in the mammary gland lumen indicates possible elimination of this parasite in milk. The frequent parasitism observed in the genital tract of infected males and females and the viability of L. infantum in seminal fluid and uterus suggest the possibility of bidirectional venereal and vertical transmission. PMID- 26979735 TI - Inhibition of Glycogen Synthase Kinase-3: An Emerging Target in the Treatment of Traumatic Brain Injury. AB - Although traumatic brain injury (TBI) has been a major public health concern for decades, the pathophysiological mechanism of TBI is not clearly understood, and an effective medical treatment of TBI is not available at present. Of particular concern is sustained TBI, which has a strong tendency to take a deteriorating neurodegenerative course into chronic traumatic encephalopathy (CTE) and dementia, including Alzheimer's disease. Tauopathy and beta amyloid (Abeta) plaques are known to be the key pathological markers of TBI, which contribute to the progressive deterioration associated with TBI such as CTE and Alzheimer's disease. The multiple lines of evidence strongly suggest that the inhibition of glycogen synthase kinase-3 (GSK-3) is a potential target in the treatment of TBI. GSK-3 constitutively inhibits neuroprotective processes and promotes apoptosis. After TBI, GSK-3 is inhibited through the receptor tyrosine kinase (RTK) and canonical Wnt signaling pathways as an innate neuroprotective mechanism against TBI. GSK-3 inhibition via GSK-3 inhibitors and drugs activating RTK or Wnt signaling is likely to reinforce the innate neuroprotective mechanism. GSK-3 inhibition studies using rodent TBI models demonstrate that GSK-3 inhibition produces diverse neuroprotective actions such as reducing the size of the traumatic injury, tauopathy, Abeta accumulation, and neuronal death, by releasing and activating neuroprotective substrates from GSK-3 inhibition. These effects are correlated with reduced TBI-induced behavioral and cognitive symptoms. Here, we review studies on the therapeutic effects of GSK-3 inhibition in TBI rodent models, and critically discuss the issues that these studies address. PMID- 26979731 TI - Carbonic anhydrase enzyme as a potential therapeutic target for experimental trichinellosis. AB - Trichinellosis is a globally distributed helminthic infection. There is a considerable interest in developing new anti-helminthic drugs affecting all the developmental stages of Trichinella. Acetazolamide (carbonic anhydrase (CA) inhibitor) involves a novel mechanism of action by inhibiting such an essential enzyme for parasite metabolism. This work aimed to study the effect of acetazolamide against different stages of T. spiralis in experimental animals. Mice were divided into three groups: group I: infected and treated with acetazolamide on day 2 post infection (P.I.), group II: infected and treated with acetazolamide on day 12 P.I., and group III: infected non-treated. From each group, small intestine and muscles were removed for histopathological and immunohistochemical studies. Also, total adult and muscle larval count were estimated. We found that acetazolamide was effective in reduction of both adult and muscle larval counts. When given early, the effect was more pronounced on the adults (62.7 %). However, the efficacy of the drug against muscle larvae was increased when given late (63 %). Improvement of the intestinal histopathological changes was observed in all the treated groups. Degeneration of encysted larvae with minimal pathologic changes of infected skeletal muscle was observed in the treated groups. Expression of matrix metalloproteinase-9 showed a statistically significant decrease in the intestinal and muscle tissues in all treated groups as compared to the control group. In conclusion, the present study revealed that acetazolamide, carbonic anhydrase inhibitor, could be a promising drug against both adults and larvae of T. spiralis. PMID- 26979738 TI - Prague Congress Abstracts. PMID- 26979737 TI - Availability and affordability of essential medicines for children in the Western part of Ethiopia: implication for access. AB - BACKGROUND: Essential medicines (EMs) are those medicines which satisfy the priority health care needs of the population. Although it is a fundamental human right, access to essential medicines has been a big challenge in developing countries particularly for children. WHO recommends assessing the current situations on availability and affordability of EMs as the first step towards enhancing access to them. Therefore, the aim of this study was to assess access to EMs for children based on availability, affordability, and price. METHODS: We adapted the WHO and Health Action International tools to measure availability, affordability, and prices of EMs. We collected data on 22 EMs for children from 15 public to 40 private sectors' drug outlets in east Wollega zone. Availability was expressed as percentage of drug outlets per sector that stocked surveyed medicines on the day of data collection, and prices were expressed as median price ratio. Affordability was measured as the number of daily wages required for the lowest-paid government unskilled worker (1.04 US $per day) to purchase one standard treatment of an acute condition or treatment for a chronic condition for a month. RESULTS: The average availability of essential medicines was 43 % at public and 42.8 % at private sectors. Lowest priced medicines were sold at median of 1.18 and 1.54 times their international reference prices (IRP) in the public and private sectors, respectively. Half of these medicines were priced at 0.90 to 1.3 in the public sector and 1.23 to 2.07 in the private sector times their respective IRP. Patient prices were 36 % times higher in the private sector than in the public sector. Medicines were unaffordable for treatment of common conditions prevalent in the zone at both public and private sectors as they cost a day or more days' wages for the lowest paid government unskilled worker. CONCLUSIONS: Access to EMs to children is hampered by low availability and high price which is unaffordable. Thus, further study on larger scale is critical to identify acute areas for policy interventions such as price and or supply, and to enhance access to EMs to children. PMID- 26979736 TI - Pediatric Clinical Pharmacology of Voriconazole: Role of Pharmacokinetic/Pharmacodynamic Modeling in Pharmacotherapy. AB - Voriconazole is a potent antifungal agent used for the treatment of invasive fungal infections caused by Aspergillus and Candida species in adult and pediatric patients. Voriconazole has a narrow therapeutic index and a large intra and inter-individual pharmacokinetics (PK) variability. Several factors including non-linear PK, age, body weight, cytochrome P450 2C19 genotype, concomitant drugs, liver function, and food are responsible for the large variability in voriconazole PK. A combination of a narrow therapeutic index with a large PK variability results in treatment failure in many patients at clinically recommended doses. There is an urgent need to establish an optimal dosing regimen for pediatric patients <2 years of age because of a lack of recommended dosing guidelines and high (>60 %) treatment failure rates. Therapeutic drug monitoring is commonly used in clinical practice to optimize the voriconazole dosing regimens in pediatric patients, but it is associated with several practical limitations. Implementation of a PK model-guided individualized dose selection will help in reducing the PK variability and will improve therapeutic outcomes. In this review, we have summarized the covariates influencing the PK of voriconazole in adult and pediatric patients, emphasizing that the clearance of voriconazole is significantly different between adult and pediatric patients owing to developmental changes in the major clearance pathways. Moreover, we have provided the limitations of the current dosing regimens and have proposed a new dosing method using a PK model-guided dose individualization of voriconazole in pediatric patients. PMID- 26979739 TI - Subchondral bone density distribution of the talus in clinically normal Labrador Retrievers. AB - BACKGROUND: Bones continually adapt their morphology to their load bearing function. At the level of the subchondral bone, the density distribution is highly correlated with the loading distribution of the joint. Therefore, subchondral bone density distribution can be used to study joint biomechanics non invasively. In addition physiological and pathological joint loading is an important aspect of orthopaedic disease, and research focusing on joint biomechanics will benefit veterinary orthopaedics. This study was conducted to evaluate density distribution in the subchondral bone of the canine talus, as a parameter reflecting the long-term joint loading in the tarsocrural joint. RESULTS: Two main density maxima were found, one proximally on the medial trochlear ridge and one distally on the lateral trochlear ridge. All joints showed very similar density distribution patterns and no significant differences were found in the localisation of the density maxima between left and right limbs and between dogs. CONCLUSIONS: Based on the density distribution the lateral trochlear ridge is most likely subjected to highest loads within the tarsocrural joint. The joint loading distribution is very similar between dogs of the same breed. In addition, the joint loading distribution supports previous suggestions of the important role of biomechanics in the development of OC lesions in the tarsus. Important benefits of computed tomographic osteoabsorptiometry (CTOAM), i.e. the possibility of in vivo imaging and temporal evaluation, make this technique a valuable addition to the field of veterinary orthopaedic research. PMID- 26979740 TI - Maternal obesity alters endoplasmic reticulum homeostasis in offspring pancreas. AB - The prevalence of non-alcoholic fatty pancreas disease (NAFPD) is increasing in parallel with obesity rates. Stress-related alterations in endoplasmic reticulum (ER), such as the unfolded protein response (UPR), are associated with obesity. The aim of this study was to investigate ER imbalance in the pancreas of a mice model of adult and perinatal diet-induced obesity. Twenty female C57BL/6J mice were assigned to control (Con) or obesogenic (Ob) diets prior to and during pregnancy and lactation. Their offspring were weaned onto Con or Ob diets up to 6 months post-partum. Then, after sacrifice, plasma biochemical analyses, gene expression, and protein concentrations were measured in pancreata. Offspring of Ob-fed mice had significantly increased body weight (p < 0.001) and plasma leptin (p < 0.001) and decreased insulin (p < 0.01) levels. Maternal obesogenic diet decreased the total and phosphorylated Eif2alpha and increased spliced X-box binding protein 1 (XBP1). Pancreatic gene expression of downstream regulators of UPR (EDEM, homocysteine-responsive endoplasmic reticulum-resident (HERP), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP)) and autophagy-related proteins (LC3BI/LC3BII) were differently disrupted by obesogenic feeding in both mothers and offspring (from p < 0.1 to p < 0.001). Maternal obesity and Ob feeding in their offspring alter UPR in NAFPD, with involvement of proapoptotic and autophagy-related markers. Upstream and downstream regulators of PERK, IRE1alpha, and ATF6 pathways were affected differently following the obesogenic insults. PMID- 26979743 TI - Environmental-Impact Assessment of Natural Radioactivity Around a Traditional Mining Area in Al-Ibedia, Sudan. AB - Recently, in the Sudan, traditional gold mining has been growing rapidly and has become a very attractive and popular economic activity. Mining activity is recognized as one of the sources of radioactivity contamination. Hence, the radioactivity concentration and radiological hazard due to exposure of radionuclides (226)Ra, (232)Th, and (40)K were evaluated. The measurements were performed using gamma-ray spectrometry with an NaI (Tl) detector. The results show that (226)Ra, (232)Th, and (40)K activity concentration ranged from 2.66 to 18.47, 9.20 to 51.87, and 0.17 to 419.77 Bq/kg with average values of 7.54 +/- 4.91, 20.74 +/- 11.29, and 111.87 +/- 136.84 Bq/kg, respectively. In contrast, (222)Rn in soil, (222)Rn in air, and (226)Ra in vegetables along with radiation dose were computed and compared with the international recommended levels. Potential radiological effects to miners and the public due to (226)Ra, (232)Th, (40)K, and (222)Rn are insignificant. (226)Ra transferred to vegetables appears to be negligible compared with the allowable limit 1.0 mSv/year set by United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). The average value of the annual gonadal dose equivalent (AGDE) is lower than the global average of 300 uSv/year (UNSCEAR 2000). However, some locations exhibit values >300 uSv/year. To the best of our knowledge, so far there seems to be no data regarding radioactivity monitoring in traditional mining areas in the Sudan. PMID- 26979741 TI - The "bioregulatory effect of exercise" on the innate/inflammatory responses. AB - The effects of exercise on the innate response are primarily mediated by the SNS (sympathetic nervous system) and/or the HPA (hypothalamic-pituitary-adrenal) axis and by stress proteins such as Hsp72. Regular exercise can induce immuno neuroendocrine stabilization in persons with deregulated inflammatory and stress feedback by reducing the presence of stress hormones and inflammatory cytokines. Anti-inflammatory and "anti-stress" responses seem also to be induced (paradoxically, opposite to the effects in healthy persons) after sessions of exercise, being a promising strategy for treating certain inflammatory pathologies. Nevertheless, the biomedical side effects of exercise are also needed to be considered. This article defines the "Bioregulatory Effect of Exercise" to be one that reduces or prevents any excessive effect of inflammatory mediators and stimulates (or at least does not impair) the innate defences (i.e. chemotaxis, phagocytosis, and microbicidal activities) against pathogens. It also generates immunophysiological adaptations through an optimal balance between the pro- and the anti-inflammatory responses. These effects are mediated via immuno neuroendocrine interactions. This review analyses concepts and conclusions related to how exercise affects the innate and/or inflammatory responses and discusses some paradoxical interpretations relevant for the practical use of exercise in treating infectious and inflammatory diseases. A potential role of exercise as hormesis strategy and the concept of exercise immunization are also discussed. PMID- 26979742 TI - Metal Concentrations in Sediment And Biota of the Huludao Coast in Liaodong Bay and Associated Human and Ecological Health Risks. AB - This study assessed the contamination extent and potential ecological and human health impacts for chromium (Cr), manganese (Mn), nickel (Ni), copper (Cu), zinc (Zn), cadmium (Cd), and lead (Pb) in sediments and indigenous benthic organisms along the coastal area of Huludao, China. We analyzed a total of eight species: two benthic fish species, two bivalves, two snails, and two decapod crustaceans. Cu, Zn, and Cd levels in sediment exceeded the Chinese marine sediment quality criteria. The geoaccumulation index was highest for Cd followed in a decreasing order by Zn, Pb, Cu, Ni, and Cr. Metal levels were highest in the four mollusk species. The oyster and veined rapa whelk had the highest bioaccumulation factors, indicating that these two species would be well suited for monitoring the metal pollution in this area. Our comparison of estimated daily intake values for human consumption of the seafood species to the Food and Agricultural Organization-recommended daily dietary allowances indicate potential health risks from the intake of Cd from all shellfish other than our crab species and Zn intake from oyster consumption. An analysis of target hazard quotients identified noncarcinogenic health risks from Cd (in all shellfish analyzed except for our crab species), Cu, and Zn (in oysters and veined rapa whelks). Moreover, an analysis of cancer risk from Pb ingestion detected an increased risk for consumption of all shellfish except for the crab species. Health risks seem especially pronounced for the consumption of oysters and the veined rapa whelks; a seafood advisory may be warranted for these mollusks. PMID- 26979744 TI - Are we ready to inject? Individualized LC-CUSUM training in ICSI. AB - PURPOSE: The objective of this prospective, single center study was to develop a personalized training scheme for intracytoplasmic sperm injection (ICSI) through the use of learning curve-cumulative summation (LC-CUSUM), which allows to tailor training to the trainee performance, and to validate it against the performance of experienced embryologists. METHODS: Five trainees microinjected latex microspheres (LM) into vitro matured oocytes. A microinjection was considered successful when the oocyte did not lyse in the 24 h following the injection. RESULTS: Each trainee became proficient at ICSI after a variable number of injections, ranging from 35 to 80. Trainees that achieved proficiency went on to perform ICSI with human gametes in a clinical setting with proficiency comparable to that of experienced embryologists. CONCLUSIONS: We show that LC-CUSUM based personalized ICSI training is feasible and allows trainees to be as proficient as trained embryologists when treating actual patients. PMID- 26979745 TI - The effects of psychosocial interventions on the mental health, pregnancy rates, and marital function of infertile couples undergoing in vitro fertilization: a systematic review. AB - PURPOSE: The purpose of this study was to examine the effects of psychosocial interventions on the mental health, pregnancy rates, and marital function of infertile couples undergoing in vitro fertilization (IVF), as determined through RCT studies. METHODS: Using the electronic databases PubMed, EMBase, Cochrane Library, CINAHL, PsycInfo, and CAJ, a systematic literature search was conducted in July 2015. MeSH terms, key words, and free words such as "infertility," "fertilization in vitro," "psychotherapy," "intervention," "anxiety," "depression," and "marital satisfaction" were used to identify all potential studies. The quality of the studies that were included was assessed using the risk of bias assessment tool developed by the Cochrane Back Review Group. Descriptive analysis was adopted to synthesize the results. RESULTS: A total of 20 randomized controlled trials were included in this review. There were reports of positive effects on the anxiety levels, pregnancy rates, or marital function of infertile couples in six studies that adopted different psychosocial approaches, including mind body intervention (Eastern body-mind-spirit, Integrative body-mind-spirit, and Mind/body intervention), cognitive behavioral therapy, group psychotherapy, and harp therapy. However, there were methodological or practical issues related to measurement points and attrition rates in these studies. None of these interventions were found to be efficacious in relieving the depression or stress of individuals or couples undergoing IVF treatment. None of the included studies tackled or measured the mental health status of the couples during the most stressful time of waiting for the pregnancy results of their treatment. CONCLUSIONS: A complex intervention, based on sound evidence, should be developed targeting both females and males of infertile couples undergoing IVF treatment, particularly during the stressful period of waiting for the results of the pregnancy test result and after failed cycles. PMID- 26979746 TI - Risk factors in transient osteoporosis: a retrospective study on 23 cases. AB - The aim of this study is to verify the prevalence of risk factors for transient osteoporosis (TO) in a cohort of patients selected by strict diagnostic criteria. Retrospective observational cohort study on outpatients' data. Inclusion criteria were: (1) acute onset of pain at a lower limb joint exacerbated by weight bearing; (2) no history of trauma, tumors, rheumatic diseases, or infection; (3) presence bone marrow edema on MRI in a weight bearing joint without signs of intraarticular lesions; (4) no hyperesthesia and/or allodynia and/or sweeting changes. The following risk factors were search for in all patients: (1) previous episode of TO; (2) disorders of bone metabolism; (3) cigarette smoke; (4) sudden lower limb overuse; (5) presence of osteoporosis/osteopenia. Twenty-three patients (8 females, 15 males, mean age 48.4 years) fulfilled the inclusion criteria. An average of 1.96 risk factors for TO was present in the cohort. The most frequent risk factor was overuse (in 15 patients, 65.2 %) and the second risk factor was bone metabolism disorders (in 10 patients, 43.5 %). Seven patients (30.4 %) were heavy smokers (more than 20 cigarettes per day) and seven patients showed a previous episode of TO. Six patients (26.1 % of the overall cohort but 60 % of those investigated with DEXA) resulted osteoporotic or osteopenic. Our results suggest there are risk factors that must be investigated in these patients. The presence of these risk factors might support the thesis that their disorder is tied to a decoupling between microdamage accumulation and self-reparative ability of bone tissue. The identification of risk factors with a precise diagnostic pathway can accelerate the diagnostic process and reduce recurrences. PMID- 26979747 TI - Genetic and biochemical mechanisms of rice resistance to planthopper. AB - KEY MESSAGE: This article presents a comprehensive review on the genetic and biochemical mechanisms governing rice-planthopper interactions, aiming to contribute substantial planthopper control and facilitate breeding for resistance to planthoppers in rice. The rice planthopper is the most destructive pest of rice and a substantial threat to rice production. The brown planthopper (BPH), white-backed planthopper (WBPH) and small brown planthopper (SBPH) are three species of delphacid planthoppers and important piercing-sucking pests of rice. Host-plant resistance has been recognized as the most practical, economical and environmentally friendly strategy to control planthoppers. Until now, at least 30, 14 and 34 major genes/quantitative trait loci for resistance to BPH, WBPH and SBPH have been identified, respectively. Recent inheritance and molecular mapping of gene analysis showed that some planthopper-resistance genes in rice derived from different donors aggregate in clusters, while resistance to these three species of planthoppers in a single donor is governed not by any one dominant gene but by multiple genes. Notably, Bph14, Bph26, Bph3 and Bph29 were successfully identified as BPH-resistance genes in rice. Biological and chemical studies on the feeding of planthoppers indicate that rice plants have acquired various forms of defence against planthoppers. Between the rice-planthopper interactions, rice plants defend against planthoppers through activation the salicylic acid-dependent systemic acquired resistance but not jasmonate-dependent hormone response pathways. Transgenic rice for the planthopper-resistance mechanism shows that jasmonate and its metabolites function diversely in rice's resistance to planthopper. Understanding the genetic and biochemical mechanisms underlying resistance in rice will contribute to the substantial control of such pests and facilitate breeding for rice's resistance to planthopper more efficiently. PMID- 26979748 TI - Why, when and how to update a meta-ethnography qualitative synthesis. AB - BACKGROUND: Meta-ethnography is a unique, systematic, qualitative synthesis approach widely used to provide robust evidence on patient and clinician beliefs and experiences and understandings of complex social phenomena. It can make important theoretical and conceptual contributions to health care policy and practice. RESULTS: Since beliefs, experiences, health care contexts and social phenomena change over time, the continued relevance of the findings from meta ethnographies cannot be assumed. However, there is little guidance on whether, when and how meta-ethnographies should be updated; Cochrane guidance on updating reviews of intervention effectiveness is unlikely to be fully appropriate. This is the first in-depth discussion on updating a meta-ethnography; it explores why, when and how to update a meta-ethnography. Three main methods of updating the analysis and synthesis are examined. Advantages and disadvantages of each method are outlined, relating to the context, purpose, process and output of the update and the nature of the new data available. Recommendations are made for the appropriate use of each method, and a worked example of updating a meta ethnography is provided. CONCLUSIONS: This article makes a unique contribution to this evolving area of meta-ethnography methodology. PMID- 26979750 TI - Putting pressure on aromaticity along with in situ experimental electron density of a molecular crystal. AB - When pressure is applied, the molecules inside a crystal undergo significant changes of their stereoelectronic properties. The most interesting are those enhancing the reactivity of systems that would be otherwise rather inert at ambient conditions. Before a reaction can occur, however, a molecule must be activated, which means destabilized. In aromatic compounds, molecular stability originates from the resonance between two electronic configurations. Here we show how the resonance energy can be decreased in molecular crystals on application of pressure. The focus is on syn-1,6:8,13-Biscarbonyl[14]annulene, an aromatic compound at ambient conditions that gradually localizes one of the resonant configurations on compression. This phenomenon is evident from the molecular geometries measured at several pressures and from the experimentally determined electron density distribution at 7.7 GPa; the observations presented in this work are validated by periodic DFT calculations. PMID- 26979749 TI - High genetic diversity in the Culex pipiens complex from a West Nile Virus epidemic area in Southern Europe. AB - BACKGROUND: The Culex pipiens complex includes the most widespread mosquito species in the world. Cx. pipiens is the primary vector of the West Nile Virus (WNV) in Europe and North America. Cases of WNV have been recorded in Italy since 1998. In particular, wet areas along the Po River are considered some of the most WNV affected areas in Italy. Here, we analyzed the genetic structure of ten Cx. pipiens populations collected in the last part of the Po River including the Delta area. METHODS: We assessed the genetic variability of two mitochondrial markers, cytochrome oxidase 1 (COI) and 2 (COII), for a total of 1200 bp, and one nuclear marker, a fragment of acetylcholinesterase-2 (ace-2), 502 bp long. The effect of the landscape features was evaluated comparing haplotype and nucleotide diversity with the landscape composition. RESULTS: The analysis showed a high genetic diversity in both COI and COII gene fragments mainly shared by the populations in the Delta area. The COI-COII network showed that the set of haplotypes found was grouped into three main supported lineages with the higher genetic variability gathered in two of the three lineages. By contrast, ace-2 fragment did not show the same differentiation, displaying alleles grouped in a single clade. Finally, a positive correlation between mitochondrial diversity and natural wetland areas was found. CONCLUSIONS: The high mitochondrial genetic diversity found in Cx. pipiens populations from the Po River Delta contrasts with the low variability of inland populations. The different patterns of genetic diversity found comparing mitochondrial and nuclear markers could be explained by factors such as differences in effective population size between markers, sex biased dispersal or lower fitness of dispersing females. Moreover, the correlation between genetic diversity and wetland areas is consistent with ecosystem stability and lack of insecticide pressure characteristic of this habitat. The mtDNA polymorphism found in the Po River Delta is even more interesting due to possible linkages between the mitochondrial lineages and different biting behaviors of the mosquitoes influencing their vector ability of arboviral infections. PMID- 26979751 TI - Dendritic Cell-Secreted Cytotoxic T-Lymphocyte-Associated Protein-4 Regulates the T-cell Response by Downmodulating Bystander Surface B7. AB - The remarkable functional plasticity of professional antigen-presenting cells (APCs) allows the adaptive immune system to respond specifically to an incredibly diverse array of potential pathogenic insults; nonetheless, the specific molecular effectors and mechanisms that underpin this plasticity remain poorly characterized. Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), the target of the blockbuster cancer immunotherapeutic ipilimumab, is one of the most well known and well-studied members of the B7 superfamily and negatively regulates T cell responses by a variety of known mechanisms. Although CTLA-4 is thought to be expressed almost exclusively among lymphoid lineage hematopoietic cells, a few reports have indicated that nonlymphoid APCs can also express the CTLA-4 mRNA transcript and that transcript levels can be regulated by external stimuli. In this study, we substantially build upon these critical observations, definitively demonstrating that mature myeloid lineage dendritic cells (DC) express significant levels of intracellular CTLA-4 that they constitutively secrete in microvesicular structures. CTLA-4(+) microvesicles can competitively bind B7 costimulatory molecules on bystander DC, resulting in downregulation of B7 surface expression with significant functional consequences for downstream CD8(+) T-cell responses. Hence, the data indicate a previously unknown role for DC derived CTLA-4 in immune cell functional plasticity and have significant implication for the design and implementation of immunomodulatory strategies intended to treat cancer and infectious disease. PMID- 26979753 TI - Comparative Influence of Imidafenacin and Oxybutynin on Voiding Function in Rats with Functional Urethral Obstruction. AB - An antimuscarinic therapy may increase the risk of voiding dysfunction. However, it is unclear whether the relative risk of voiding dysfunction is different among antimuscarinics. Therefore we determined the potencies both in enhancing the bladder capacity (BC), effectiveness, and in decreasing the maximum urinary flow rate (Qmax), voiding dysfunction, to compare their therapeutic indices.Under urethane anesthesia, urinary flow rate was measured at distal urethra using an ultrasonic flow meter in female Sprague-Dawley rats with functional urethral obstruction induced by a continuous i. v. infusion of alpha1-adrenoceptor agonist A-61603 (0.03 MUg/kg/min). In a separate group of urethane-anesthetized rats without urethral obstruction, an intermittent cystometry was performed to determine BC.Intravenous imidafenacin and oxybutynin produced a significant dose dependent decrease in Qmax with the minimum doses of 0.03 and 1 mg/kg, respectively. Imidafenacin and oxybutynin markedly increased BC, with minimum doses of 0.01 and 3 mg/kg, respectively. At the minimum dose to increase BC, oxybutynin caused a significant increase in residual urine volume with a significant decrease in voiding efficiency, whereas imidafenacin had no influence on these values. The relative influence index, which is the ratio of the minimum influence dose between in decreasing of Qmax and in increasing of BC, of imidafenacin was 10 fold higher than that of oxybutynin.This study suggests that imidafenacin has a lower relative risk of voiding difficulty compared with oxybutynin in rats. These results provide new information that antimuscarinics may have varying degrees of impact on voiding difficulty. PMID- 26979752 TI - HLA-A2 Alleles Mediate Alzheimer's Disease by Altering Hippocampal Volume. AB - HLA-A is a locus of the major histocompatibility complex situated on chromosome 6p21.3. HLA-A has been shown to be associated with susceptibility to Alzheimer's disease (AD). In this study, we firstly investigated the association of gene variants in HLA-A and brain structures on MRI in a large sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to explore the effects of HLA A on AD pathogenesis. We selected the hippocampus, parahippocampus, posterior cingulate, precuneus, middle temporal, entorhinal cortex, and amygdala as regions of interest (ROIs). In hybrid population analysis, our results showed a marginally significant association between rs9260168 and the atrophy of the left parahippocampus (P = 0.007, Pc = 0.054), rs3823342 and the atrophy of the left parahippocampus (P = 0.014, Pc = 0.054), rs76475517, which only exists in Caucasians with HLA-A23 or HLA-A24 alleles, and the atrophy of the right amygdala (P = 0.010, Pc = 0.085) at baseline. In particular, the haplotype (TGACAAGG), as a surrogate marker of HLA-A2, was founded to be positively associated with the atrophy of the right hippocampus (P = 0.047) at baseline. Furthermore, we detected the above four associations in mild cognitive impairment (MCI) subpopulation analysis. Our study provided preliminary evidences supporting HLA A2 in Caucasians contribute to the risk of AD by modulating the alteration of hippocampal volume and HLA-A gene variants appear to play a role in altering AD related brain structures on MRI. PMID- 26979754 TI - Identification of antigen-specific human monoclonal antibodies using high throughput sequencing of the antibody repertoire. AB - High-throughput sequencing of the antibody repertoire provides a large number of antibody variable region sequences that can be used to generate human monoclonal antibodies. However, current screening methods for identifying antigen-specific antibodies are inefficient. In the present study, we developed an antibody clone screening strategy based on clone dynamics and relative frequency, and used it to identify antigen-specific human monoclonal antibodies. Enzyme-linked immunosorbent assay showed that at least 52% of putative positive immunoglobulin heavy chains composed antigen-specific antibodies. Combining information on dynamics and relative frequency improved identification of positive clones and elimination of negative clones. and increase the credibility of putative positive clones. Therefore the screening strategy could simplify the subsequent experimental screening and may facilitate the generation of antigen-specific antibodies. PMID- 26979756 TI - Digital anatomical measurements and crucial bending areas of the fixation route along the inferior border of the arcuate line for pelvic and acetabular fractures. AB - BACKGROUND: Better understanding of three-dimensional (3D) morphology of the pelvis at the area of inferior border of the arcuate line is very important, which could guide the surgeons to treat pelvic and acetabular fractures more efficiently. The objective of this study is to provide references for screw placement and design of anatomical internal fixators for the fixation route along the pelvic inferior border of the arcuate line. METHODS: Seventy five cases of computed tomography (CT) scan data were collected using Medical Image Database in Shanghai General Hospital between December 2009 and November 2010. 44 males and 31 females, aging from 21 to 91 years (average: 57.8 years) were enrolled. Using MIMICS 13.0, these data were used for three dimensional (3D) reconstructions of pelvic model. A curve from the pubic tubercle, along the inferior border of the arcuate line, to the sacroiliac joint was depicted and then divided into 11 equal parts. The measurements of whole length of the curve, the radius of the curvature and the thickness of bone at each decile point were performed, respectively. RESULTS: The thinnest bone thickness at acetabular area was 17.24 +/- 2.90 mm and 9.94 +/- 2.69 mm for male and female, respectively. The radius of curvature at the decile points 1, 8 and 10 were smaller compared with the surrounding points. CONCLUSIONS: Using a screw shorter than 10 mm perpendicular to the bone surface along the inferior border of the arcuate line can avoid intra-articular screw penetration. There should be more recontouring of the plate at the areas of pubic tubercle and posterior edge of the acetabulum when placing a fixator along this fixation route. This study provides solid guidance for pelvic and acetabular surgeries as well as designing of anatomical fixators along inferior border fixation route at this area. PMID- 26979755 TI - Rapid genomic changes in Drosophila melanogaster adapting to desiccation stress in an experimental evolution system. AB - BACKGROUND: Experimental evolution studies, coupled with whole genome resequencing and advances in bioinformatics, have become a powerful tool for exploring how populations respond to selection at the genome-wide level, complementary to genome-wide association studies (GWASs) and linkage mapping experiments as strategies to connect genotype and phenotype. In this experiment, we analyzed genomes of Drosophila melanogaster from lines evolving under long term directional selection for increased desiccation resistance in comparison with control (no-selection) lines. RESULTS: We demonstrate that adaptive responses to desiccation stress have exerted extensive footprints on the genomes, manifested through a high degree of fixation of alleles in surrounding neighborhoods of eroded heterozygosity. These patterns were highly convergent across replicates, consistent with signatures of 'soft' selective sweeps, where multiple alleles present as standing genetic variation become beneficial and sweep through the replicate populations at the same time. Albeit much less frequent, we also observed line-unique sweep regions with zero or near-zero heterozygosity, consistent with classic, or 'hard', sweeps, where novel rather than pre-existing adaptive mutations may have been driven to fixation. Genes responsible for cuticle and protein deubiquitination seemed to be central to these selective sweeps. High divergence within coding sequences between selected and control lines was also reflected by significant results of the McDonald Kreitman and Ka/Ks tests, showing that as many as 347 genes may have been under positive selection. CONCLUSIONS: Desiccation stress, a common challenge to many organisms inhabiting dry environments, proves to be a very potent selecting factor having a big impact on genome diversity. PMID- 26979759 TI - The role of triacylglycerol in cardiac energy provision. AB - Triacylglycerols (TAGs) constitute the main energy storage resource in mammals, by virtue of their high energy density. This in turn is a function of their highly reduced state and hydrophobicity. Limited water solubility, however, imposes specific requirements for delivery and uptake mechanisms on TAG-utilising tissues, including the heart, as well as intracellular disposition. TAGs constitute potentially the major energy supply for working myocardium, both through blood-borne provision and as intracellular TAG within lipid droplets, but also provide the heart with fatty acids (FAs) which the myocardium cannot itself synthesise but are required for glycerolipid derivatives with (non-energetic) functions, including membrane phospholipids and lipid signalling molecules. Furthermore they serve to buffer potentially toxic amphipathic fatty acid derivatives. Intracellular handling and disposition of TAGs and their FA and glycerolipid derivatives similarly requires dedicated mechanisms in view of their hydrophobic character. Dysregulation of utilisation can result in inadequate energy provision, accumulation of TAG and/or esterified species, and these may be responsible for significant cardiac dysfunction in a variety of disease states. This review will focus on the role of TAG in myocardial energy provision, by providing FAs from exogenous and endogenous TAG sources for mitochondrial oxidation and ATP production, and how this can change in disease and impact on cardiac function. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk. PMID- 26979757 TI - Association Between Polymorphism rs678653 in Human Cyclin D1 Gene (CCND1) and Susceptibility to Cancer: A Meta-Analysis. AB - BACKGROUND: To assess the association between polymorphism rs678653 in human Cyclin D1 gene (CCND1) and the risk of cancer. MATERIAL/METHODS: Multiple biomedical databases were systematically searched. Pooled odds ratios (OR) and 95% confidence intervals (95% CIs) were calculated in the appropriate model. RESULTS: In total, 17 case-control studies from 14 articles were included. When combing all available data, no significant association of rs678653 with cancer risk was observed under different genetic models. Stratification by ethnicity also indicated that rs678653 was not correlated with cancer risk in Taiwanese or Indian populations. When stratified by cancer type, no significant association was found between polymorphism rs678653 and digestive tract cancer, head and neck cancer, and gynecological cancer risk. CONCLUSIONS: Our comprehensive meta analysis suggests that the polymorphism rs678653 in CCND1 has no association with cancer risk in different population and disease contexts, indicating that CCND1 rs678653 does not serve a significant biological function in predicting cancer risk. PMID- 26979758 TI - Assessing in-vitro estrogenic effects of currently-used flame retardants. AB - Flame retardants are chemicals that are added to nearly all manufactured materials. Additionally, there has been a steady increase in diseases resulting from endocrine-disruption with an aligned increase in use of chemicals. Given the persistence, potential bioaccumulation, limited toxicological understanding, and vast use of flame retardants, there is a need to investigate potential endocrine disruptive activity associated with these compounds in an effort for better risk assessment. We therefore used the MCF-7 flow-cytometric proliferation assay in an effort to establish potential estrogen-disrupting effects of twelve currently used flame retardants. Triphenyl phosphate, tris(1,3-dichloro-2-propyl) phosphate, tris(butyl) phosphate, hexabromocyclododecane, and tetrabromobisphenol A showed statistically significant estrogenic activity, with hexabromocyclododecane being the most potent of the five (EC20 of 5.5 MUM). Tris(2-butoxyethyl) phosphate, tris(1,3-dichloro-2-propyl) phosphate, tri(2 chloroethyl) phosphate, tris(butyl) phosphate, hexabromocyclododecane, tetrabromobisphenol A, and tris(2,3,-dibromopropyl) isocyanurate harboured anti estrogenic activity when co-treating with 17beta-estradiol, with hexabromocyclododecane showing the highest potency (IC20 of 17.6 MUM). Interestingly, some compounds showed both estrogenic and anti-estrogenic effects, indicating both receptor-dependant and -independent mechanisms attributed to some of these compounds, in line with other studies. Multiple currently-used flame retardants may therefore act as xenoestrogens and anti-estrogens, or alter estrogen homeostasis, which could affect endocrine function. PMID- 26979761 TI - Performance monitoring in autism spectrum disorders: A systematic literature review of event-related potential studies. AB - Autism spectrum disorder (ASD) is marked by impairments in social-emotional situations, executive functioning, and behavioral regulation. These symptoms may be related to deficits in performance monitoring, i.e., the ability to observe and evaluate one's own behavior and performance which is necessary for the regulation of future behavior. The present literature review investigated electroencephalic correlates of performance monitoring in ASD. Event-related potentials (ERPs) considered in this review included internal performance monitoring components (error-related negativity, error positivity), external performance monitoring components (feedback-related negativity, feedback-P3), and observational performance monitoring components (observer error-related negativity, observer feedback-related negativity). The majority of studies point to reduced internal performance monitoring in ASD. External performance monitoring in reward-processing paradigms, where rewards are independent of performance, seems to be intact in ASD. So far, no studies have investigated the observer error-related negativity in ASD. Available data on the observer feedback related negativity are inconclusive, since only two studies with differential study results investigated this construct in ASD. In general, results suggest that individuals with ASD have problems with internal performance monitoring and with learning from external, abstract feedback. In contrast, the processing of external, concrete feedback seems to be largely intact in ASD. PMID- 26979760 TI - Digalactosyldiacylglycerol is essential in Synechococcus elongatus PCC 7942, but its function does not depend on its biosynthetic pathway. AB - Digalactosyldiacylglycerol (DGDG) is a major component of thylakoid membranes, occupying approximately 20% of the membrane system. This lipid composition is conserved from cyanobacteria to the chloroplasts of terrestrial plants, suggesting that DGDG is important for the function of photosynthetic membranes. Here we isolated the gene for DGDG synthase in the cyanobacterium Synechococcus elongatus PCC 7942 (7942dgdA) and found that this gene is essential for this species. 7942dgdA could be knocked out only when genes for cyanobacterial or plant DGDG synthases were expressed, indicating that the important factor was not the specific synthetic pathway but the lipid product. Lack of DGDG could not be compensated by the other membrane lipids in S. elongatus PCC 7942 or by glucosylgalactosyldiacylglycerol synthesized by the beta-GlcT gene of Chloroflexus aurantiacus. These results reveal that DGDG has an indispensable role in S. elongatus PCC 7942 and that the second galactose molecule is key. Conservation and distribution of the galactolipid synthetic pathway among oxygenic phototrophs is discussed. This article is part of a Special Issue entitled: Plant Lipid Biology edited by Kent D. Chapman and Ivo Feussner. PMID- 26979762 TI - Sonic hedgehog is a chemotactic neural crest cell guide that is perturbed by ethanol exposure. AB - Our aim was to understand the involvement of Sonic hedgehog (Shh) morphogen in the oriented distribution of neural crest cells (NCCs) toward the optic vesicle and to look for potential disorders of this guiding mechanism after ethanol exposure. In vitro directional analysis showed the chemotactic response of NCCs up Shh gradients and to notochord co-cultures (Shh source) or to their conditioned medium, a response inhibited by anti-Shh antibody, receptor inhibitor cyclopamine and anti-Smo morpholino (MO). Expression of the Ptch-Smo receptor complex on in vitro NCCs was also shown. In whole embryos, the expression of Shh mRNA and protein was seen in the ocular region, and of Ptch, Smo and Gli/Sufu system on cephalic NCCs. Anti-Smo MO or Ptch-mutated plasmid (Ptch1(Deltaloop2)) impaired cephalic NCC migration/distribution, with fewer cells invading the optic region and with higher cell density at the homolateral mesencephalic level. Beads embedded with cyclopamine (Smo-blocking) or Shh (ectopic signal) supported the role of Shh as an in vivo guide molecule for cephalic NCCs. Ethanol exposure perturbed in vitro and in vivo NCC migration. Early stage embryos treated with ethanol, in a model reproducing Fetal Alcohol Syndrome, showed later disruptions of craniofacial development associated with abnormal in situ expression of Shh morphogen. The results show the Shh/Ptch/Smo-dependent migration of NCCs toward the optic vesicle, with the support of specific inactivation with genetic and pharmacological tools. They also help to understand mechanisms of accurate distribution of embryonic cells and of their perturbation by a commonly consumed teratogen, and demonstrate, in addition to its other known developmental functions, a new biological activity of cellular guidance for Shh. PMID- 26979763 TI - Conserved mechanism of action of a phosphate analogue in cultured cells. AB - The present study was undertaken to further examine a model for the mechanism of action of thio-phosphate in cells using the cultured human cell line HEK 293 and the bacterium E. coli. Previous work has shown that thio-phosphate is incorporated into the nucleic acids of all types of cells and that this modification leads to the stabilization and accumulation of mRNA in vivo. Evidently, competition for translation occurs between cellular mRNAs, due to the limited number of ribosomes in the cell, which impacts the proteins synthesized. In both E. coli and HEK 293 cells, a global shift in the distribution of proteins on 2D gels was observed when cells were grown in the presence of thio-phosphate. In both cases, a significant fraction of the proteins were impacted, namely 17 % in E. coli and 28 % in HEK 293 cells. In general, those proteins originally expressed at lower levels were enhanced while those at higher levels were reduced. In addition, a correlation was observed between the % initial mass and the fold change observed, supporting the idea of a global shift. Furthermore, the potential identity of some proteins spots was obtained by comparisons with computed MW and pI values for known genes. The candidates were cross-referenced with known mRNA half-lives when available. The analysis supports the idea that a preferential accumulation of proteins derived from mRNAs with half-lives less than the cellular mRNA average occurred, at the expense of those proteins derived from mRNAs with half-lives greater than the cellular average. In summary, thio phosphate is shown to be a useful tool for predictably shifting the distribution of proteins in a variety of cell types. The fold enhancement is typically 5- to 10-fold. Interestingly, there were some proteins elevated more than 20-fold, identifying potential regulatory responses. Some of these were further characterized using LC-MS/MS. PMID- 26979764 TI - Clinical decision rules for epilepsy care: The case for thinking big. PMID- 26979765 TI - Knee Extensor Strength and Gait Characteristics After Minimally Invasive Unicondylar Knee Arthroplasty vs Minimally Invasive Total Knee Arthroplasty: A Nonrandomized Controlled Trial. AB - BACKGROUND: In light of the existing lack of evidence, it was the aim of this study to compare gait characteristics and knee extensor strength after medial unicondylar knee arthroplasty (MUKA) with those after total knee arthroplasty (TKA), given the same standardized minimally invasive surgery (MIS) approach in both groups. METHODS: Patients scheduled for MIS-MUKA or MIS-TKA as part of clinical routine were invited to participate. A posterior cruciate ligament retaining total knee design was used for all MIS-TKA. A 3-dimensional gait analysis was performed preoperatively with a VICON system and at 8 weeks postoperative to determine temporospatial parameters, ground reaction forces, joint angles, and joint moments. At the same 2 times, isokinetic tests were performed to obtain peak values of knee extensor torque. A multivariate analysis of variance was conducted and included the main effects time (before and after surgery) and surgical group and the group-by-time interaction effect. RESULTS: Fifteen MIS-MUKA patients and 17 MIS-TKA patients were eligible for the final analysis. The groups showed no differences regarding age, body mass index, sex, side treated, or stage of osteoarthritis. We determined neither intergroup differences nor time * group interactions for peak knee extensor torque or any gait parameters (temporospatial, ground reaction forces, joint angles, and joint moments). CONCLUSION: It is concluded that MUKA is not superior to TKA with regard to knee extensor strength or 3-dimensional gait characteristics at 8 weeks after operation. As gait characteristics and knee extensor strength are only 2 of the various potential outcome parameters (knee scores, activity scores...) and quadriceps strength might take a longer time to recover, our findings should be interpreted with caution. PMID- 26979766 TI - Changes in Acute Coronary Syndrome Treatment and Prognosis After Implementation of the Infarction Code in a Hospital With a Cardiac Catheterization Unit. AB - INTRODUCTION AND OBJECTIVES: Emergency care systems have been created to improve treatment and revascularization in myocardial infarction but they may also improve the management of all patients with acute coronary syndrome. METHODS: A comparative study of all patients admitted with acute coronary syndrome before and after implementation of an infarction protocol. RESULTS: The study included 1210 patients. While the mean age was the same in both periods, the patient group admitted after implementation of the protocol had a lower prevalence of diabetes mellitus and hypertension but more active smokers and higher GRACE scores. The percentage of ST-segment elevation acute coronary syndrome (29.8%-39.5%) and coronary revascularizations (82.1%-90.1%) significantly increased among patients admitted with acute coronary syndrome, and primary angioplasty became routine (51.9%-94.9%); there was also a reduction in time to catheterization and an increase in early revascularization. The mean hospital stay was significantly shorter after implementation of the infarction protocol. In-hospital mortality was unchanged, except in high-risk patients (38.8%-22.4%). After discharge, no differences were observed between the 2 periods in cardiovascular mortality, all cause mortality, reinfarction, or major cardiovascular complications. CONCLUSIONS: After implementation of the infarction protocol, the percentage of patients admitted with ST-segment elevation acute coronary syndrome and the mean GRACE score increased among patients admitted with acute coronary syndrome. Hospital stay was reduced, and primary angioplasty use increased. In-hospital mortality was reduced in high-risk patients, and prognosis after discharge was the same in both periods. PMID- 26979768 TI - Towards universal ambient ionization: direct elemental analysis of solid substrates using microwave plasma ionization. AB - A microwave plasma was used for direct ambient ionization mass spectrometry of solid substrates, rapidly yielding atomic spectra without sample digestion or pre treatment. Further, molecular spectra for the organic components of the substrate were obtained simultaneously, in an ambient ionization format. Initial characterization of the microwave plasma coupling to an ion trap mass spectrometer was carried out using solution standards and a microwave plasma torch (MPT) configuration. The configuration of the microwave plasma was then optimized for ambient ionization. The atomic and organic composition for samples applicable to nuclear and conventional forensic screening, including explosive/radionuclide mixtures and inorganic/organic gunshot residue component mixtures were successfully determined. The technologies employed are readily fieldable; the feasibility of a multimode ion source that could be coupled with a portable ion trap mass spectrometer for rapid, on-site, elemental, isotopic, and molecular screening of samples is demonstrated. PMID- 26979767 TI - Prevalence, Diagnosis, Treatment, and Control of Hypertension in Spain. Results of the Di@bet.es Study. AB - INTRODUCTION AND OBJECTIVES: Di@bet.es is a national study designed to estimate the prevalence of diabetes mellitus and other cardiovascular risk factors in the Spanish adult population. The prevalence of hypertension and the degree to which it is recognized, treated, and controlled are described. METHODS: The study included a sample of the Spanish population with 5048 adults aged >= 18 years. Patients were questioned and examined, with 3 blood pressure readings while seated and at rest to calculate the mean of the 3 readings. Hypertension was defined as systolic blood pressure >= 140 mmHg and/or diastolic blood pressure >= 90 mmHg and/or prescription for antihypertensive drug therapy. RESULTS: Hypertension was found in 42.6% of the Spanish adult population aged >= 18 years and was more common among men (49.9%) than women (37.1%). The prevalence was higher among prediabetics (67.9%) and diabetics (79.4%). Undiagnosed hypertension was identified in 37.4% of patients and was more common in men (43.3%) than in women (31.5%). Among patients with known hypertension, 88.3% were receiving drug therapy. Well-controlled blood pressure was found in only 30% and was more common among women (24.9%) than men (16%). CONCLUSIONS: The prevalence of hypertension in Spain is high, and a considerable percentage of hypertensive patients have still not been diagnosed. Hypertension is associated with diabetes and prediabetes, and although drug therapy is increasingly common, the degree of control has not improved and remains low. Population campaigns should be developed and promoted for hypertension prevention, detection, and treatment. PMID- 26979769 TI - Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-beta in orbital fibroblasts. AB - During the course of Graves' orbitopathy (GO), orbital fibroblasts are exposed to factors that lead to proliferation and extracellular matrix (ECM) overproduction. Increased levels of tissue plasminogen activator inhibitor type 1 (PAI-1 (SERPINE1)) might promote the accumulation of ECM components. PAI-1 expression is regulated by cell density and various cytokines and growth factors including transforming growth factorbeta(TGF-beta). We examined the effects of increasing cell densities and TGF-beta on orbital fibroblasts obtained from GO patients and controls. Responses were evaluated by the measurement of proliferation, PAI-1 expression, and ECM production. There was an inverse correlation between cell density and the per cell production of PAI-1. GO orbital, normal orbital, and dermal fibroblasts behaved similarly in this respect. Proliferation rate also declined with increasing cell densities. Hyaluronan (HA) production was constant throughout the cell densities tested in all cell lines. In both GO and normal orbital fibroblasts, but not in dermal fibroblasts, TGF-beta stimulated PAI-1 production in a cell density-dependent manner, reaching up to a five-fold increase above baseline. This has been accompanied by increased HA secretion and pericellular HA levels at high cell densities. Increasing cell density is a negative regulator of proliferation and PAI-1 secretion both in normal and GO orbital fibroblasts; these negative regulatory effects are partially reversed in the presence of TGF-beta. Cell density-dependent regulation of PAI-1 expression in the orbit, together with the local cytokine environment, may have a regulatory role in the turnover of the orbital ECM and may contribute to the expansion of orbital soft tissue in GO. PMID- 26979770 TI - Meningoencephalitis due to the amoeboflagellate Naegleria fowleri in ruminants in Algeria. AB - Primary amoebic meningoencephalitis (PAM) is a fatal infection in most cases, caused by the amoeba flagellate Naegleria fowleri. This report describes the first cases of PAM in Algeria, in a cow and a ewe from Batna, north-eastern Algeria. The death of both ruminants occurred a week after the first clinical manifestations. The cerebrospinal fluid, after staining with May-Grunwald-Giemsa, showed the presence of amoebae cells. Histological sections revealed numerous amoebae in all parts of the brain. The presence of N. fowleri was confirmed using a species-specific real-time PCR in histological tissue sections. The two PAM cases were reported during the hot season, and the source of infection is very likely the water where the cattle came to drink. Particular attention should be focused on this type of infection in aquatic environments when the temperature is high and preventive measures must be taken to avoid the proliferation of N. fowleri. PMID- 26979771 TI - Preconditioning at a distance: Involvement of endothelial vasoactive substances in cardioprotection against ischemia-reperfusion injury. AB - There is growing preclinical as well as clinical evidence supporting remote ischemic preconditioning (RIPC), in which short cycles of non-fatal ischemia followed by reperfusion to an organ or tissue distant from the heart elicits cardioprotection. It is the most practical, non-invasive, cost-free, and clinically compatible, secure procedure for reducing ischemia-reperfusion induced injury. The use of a conventional blood pressure cuff on the upper or lower limb in eliciting cardioprotection has expedited its clinical applicability. Endothelium has been documented to respond very quickly to blood flow and hypoxia by releasing different humoral factors such as endothelium derived releasing factor, endothelium derived contracting factor, endothelium derived hyperpolarizing factor. In recent years, there have been studies suggesting the key role of endothelial derived factors in RIPC induced cardioprotection. The signaling cascade involves nitric oxide, gap junctions, epoxyeicosatrienoic (EETs) acids, Ca-activated K(+) channels, angiotensin II, thromboxane A2, superoxide anions and prostacyclin. The present review describes the role of these endothelial derived factors in RIPC induced cardioprotection with possible mechanisms. PMID- 26979772 TI - Pulsed magnetic therapy increases osteogenic differentiation of mesenchymal stem cells only if they are pre-committed. AB - AIM: Pulsed electromagnetic field (PEMF) therapy has been documented to be an effective, non-invasive, safe treatment method for a variety of clinical conditions, especially in settings of recalcitrant healing. The underlying mechanisms on the different biological components of tissue regeneration are still to be elucidated. The aim of the present study was to characterize the effects of extremely low frequency (ELF)-PEMFs on commitment of mesenchymal stem cell (MSCs) culture system, through the determination of gene expression pattern and cellular morphology. MAIN METHODS: Human MSCs derived from adipose tissue (ADSCs) were cultured in presence of adipogenic, osteogenic, neural, or glial differentiative medium and basal medium, then exposed to ELF-PEMFs daily stimulation for 21days. Control cultures were performed without ELF-PEMFs stimulation for all cell populations. Effects on commitment were evaluated after 21days of cultures. KEY FINDINGS: The results suggested ELF-PEMFs does not influence ADSCs commitment and does not promote adipogenic, osteogenic, neural or glial differentiation. However, ELF-PEMFs treatment on ADSCs cultured in osteogenic differentiative medium markedly increased osteogenesis. SIGNIFICANCE: We concluded that PEMFs affect the osteogenic differentiation of ADSCs only if they are pre-commitment and that this therapy can be an appropriate candidate for treatment of conditions requiring an acceleration of repairing process. PMID- 26979773 TI - Fermented papaya preparation modulates the progression of N-methyl-N-nitrosourea induced hepatocellular carcinoma in Balb/c mice. AB - AIM AND MAIN METHOD: The medicinal properties of fermented papaya preparation (FPP) derived from Carica papaya fruit was investigated in order to determine its ability to modulate the progression of N-methyl-N-nitrosourea induced hepatocellular carcinoma in Balb/c mice. KEY FINDINGS: As well as reducing the physical symptoms associated with N-methyl-N-nitrosourea (MNU)-induced hepatocellular carcinoma, supplementation of Balb/c mice with 500mg FPP/kg BW for 92days normalized the blood cell count, led to an increased activity of several key antioxidant enzymes (SOD: +20%, CAT: +81%, GPx: +66.1%, GR: +54.4%; P<0.001 vs. MNU control), increased the ferrous reducing antioxidant potential (+36.7%, P<0.001 vs. MNU control) and reduced the extent of lipid peroxidation in the liver by 44.3% (P<0.001 vs. MNU control). SIGNIFICANCE: Results demonstrated the ability of FPP to preserve the integrity of liver against oxidative damage and protect hepatocytes against irreversible DNA structural modifications induced by MNU, highlighting its potential role as an immune-defense modulator during hepatocarcinoma. PMID- 26979774 TI - Effect of retinoic acid on human adrenal corticosteroid synthesis. AB - AIMS: Retinoic acid has recently yielded promising results in the treatment of Cushing's disease, i.e., excess cortisol secretion due to a pituitary corticotropin (ACTH)-secreting adenoma. In addition to its effect on the tumoral corticotrope cell, clinical results suggest an additional adrenal site of action. Aim of this study was to evaluate whether retinoic acid modulates cortisol synthesis and secretion by human adrenals in vitro. MAIN METHODS: Primary cultures from 10 human adrenals specimens were incubated with 10nM, 100nM and 1MUM retinoic acid with and without 10nM ACTH for 24h. Cortisol levels were measured by radioimmunoassay and CYP11A1, STAR and MC2R gene expression analyzed by real-time PCR. KEY FINDINGS: Retinoic acid increased cortisol secretion (149.5+/-33.01%, 151.3+/-49.45% and 129.3+/-8.32% control secretion for 10nM, 100nM and 1MUM respectively, p<0.05) and potentiated STAR expression (1.51+/ 0.22, 1.56+/-0.15 and 1.59+/-0.14 fold change over baseline, for 10nM, 100nM and 1MUM respectively, p<0.05). Concurrently, retinoic acid markedly blunted constitutional and ACTH-induced MC2R expression (0.66+/-0.11, 0.62+/-0.08 and 0.53+/-0.07 fold change over baseline, for 10nM, 100nM and 1MUM respectively, p<0.05; 0.71+/-0.10, 0.51+/-0.07 and 0.51+/-0.08 fold change over ACTH alone, for 10nM, 100nM and 1MUM respectively, p<0.05). No effect on CYP11A1 was observed. SIGNIFICANCE: Retinoic acid stimulates cortisol synthesis and secretion in human adrenals and at the same time markedly blunts ACTH receptor transcription. These results reveal a novel, adrenal effect of retinoic acid which may contribute to its efficacy in patients with Cushing's disease. PMID- 26979775 TI - Oxidative stress upregulates zinc uptake activity via Zrt/Irt-like protein 1 (ZIP1) in cultured mouse astrocytes. AB - AIMS: Zinc released from glutamatergic boutons and astrocytes acts as neuro- and glio-transmitters, and thus its extracellular level has to be strictly regulated. We previously revealed that uptake of zinc by astrocytes plays a critical role in its clearance, and zinc transporter Zrt/Irt-like protein 1 (ZIP1) is the molecule responsible for the uptake. However, it is unknown whether or not the functionality of the zinc clearance system is altered under oxidative stress loaded conditions. Here, we characterized zinc uptake by oxidative stress-loaded astrocytes. MAIN METHODS: Cultured mouse astrocytes were treated with hydrogen peroxide (H2O2) to load oxidative stress. Functional expression of ZIP1 in astrocytes was evaluated by means of (65)Zn uptake, Western blotting and immunocytochemical analysis. KEY FINDINGS: Treatment of astrocytes with 0.4mM H2O2 for 24h increased the expression levels of glial fibrillary acidic protein and 4-hydroxynonenal without significant decreases in their viability, indicating that induction of oxidative stress in astrocytes. Under oxidative stress-loaded conditions, astrocytes exhibited increased (65)Zn uptake activity, and the maximum uptake velocity for the uptake was significantly increased compared to that in the control group, while there was no change in the Michaelis constants, which were almost identical to that of mouse ZIP1. In the H2O2-treated astrocytes, the expression levels of ZIP1 were significantly increased in the cellular and plasma membrane fractions. SIGNIFICANCE: It appears that under oxidative stress-loaded conditions, astrocytes exhibit increased zinc clearance activity and this is due, at least in part, to increased ZIP1 expression. PMID- 26979777 TI - Electroacupunctre improves motor impairment via inhibition of microglia-mediated neuroinflammation in the sensorimotor cortex after ischemic stroke. AB - AIMS: Electroacupuncture (EA) is one of the safety and effective therapies for improving neurological and sensorimotor impairment via blockade of inappropriate inflammatory responses. However, the mechanisms of anti-inflammation involved is far from been fully elucidated. MAIN METHODS: Focal cerebral ischemic stroke was administered by the middle cerebral artery occlusion and reperfusion (MCAO/R) surgery. The MCAO/R rats were accepted EA treatment at the LI 11 and ST 36 acupoints for consecutive 3days. The neurological outcome, animal behaviors test and molecular biology assays were used to evaluate the MCAO/R model and therapeutic effect of EA. KEY FINDINGS: EA treatment for MCAO rats showed a significant reduction in the infarct volumes accompanied by functional recovery in mNSS outcomes, motor function performances. The possible mechanisms that EA treatment attenuated the over-activation of Iba-1 and ED1 positive microglia in the peri-infract sensorimotor cortex. Simultaneously, both tissue and serum protein levels of the tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) were decreased by EA treatment in MCAO/R injured rats. The levels of inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) were decreased in the peri-infract sensorimotor cortex and blood serum of MCAO/R injured rats after EA treatment. Furthermore, we found that EA treatment prevented from the nucleus translocation of NF-kappaB p65 and suppressed the expression of p38 mitogen activated protein kinase (p38 MAPK) and myeloid differentiation factor 88 (MyD88) in the peri-infract sensorimotor cortex. SIGNIFICANCE: The findings from this study indicated that EA improved the motor impairment via inhibition of microglia mediated neuroinflammation that invoked NF-kappaB p65, p38 MAPK and MyD88 produced proinflammatory cytokine in the peri-infract sensorimotor cortex of rats following ischemic stroke. PMID- 26979778 TI - A novel bisindole-PBD conjugate inhibits angiogenesis by regulating STAT3 and VEGF in breast cancer cells. AB - AIMS: Breast cancer is highly resistant to chemotherapeutic approach and hence, alternative strategies have been developed to fight against this heterogeneous group of disease. In particular, many studies have demonstrated about various drugs for the treatment of breast cancer. In our study, we assessed the anti angiogenenic activities of Bisindole-PBD (5b) in MCF-7 and MDA-MB-231 cell lines. MAIN METHODS: In vitro Endothelial Cell (HUVEC) Tube Formation Assay was performed to show inhibitory role of 5b along with its role upon wound healing process in breast cancer cells in vitro. Semi-quantitative reverse transcription PCR (RT-PCR) was also done to examine the expression of VEGF in response to 5b in breast cancer cells and in HUVEC cells. siRNA transfection study explored STAT3 mediated VEGF transcription in breast cancer cells MCF-7 and MDA-MB-231. CAM assay was performed to see the role of 5b on vessel formation in chicken embryo. KEY FINDINGS: From in vitro data we have demonstrated that 5b played a role in regulation of breast cancer cell proliferation by inhibiting angiogenesis. Test drug 5b suppressed the expression VEGF at both transcriptional and post transcriptional levels. Apart from this, there was significant down regulation in STAT3 level after drug treatment, which was found to be involved in the VEGF transcription. Metastasis related MMP-2 and MMP-9 expressions were also modulated by 5b. In vivo study by Chick Chorioallantoic Membrane (CAM) Assay also showed anti-angiogenesis role of the test drug which was consistent with the in vitro data. SIGNIFICANCE: Altogether, our data demonstrated 5b as potent small molecule with anti-angiogenic activities. PMID- 26979776 TI - Attenuated allergic inflammatory response in the lungs during lactation. AB - AIMS: To evaluate the influence of lactation on lung immune function during allergic inflammation. MAIN METHODS: Female rats, 60-90days old, were divided into three groups: no lung allergy virgins (N group), ovalbumin (OVA)-immunized and sensitized virgins (V group), and OVA-immunized and sensitized lactating females (L group). On gestation day (GD) 10, all animals in L group received a subcutaneous injection of 0.1mg.kg(-1) OVA plus aluminum hydroxide. On GD17, the L group received a subcutaneous booster injection of 10MUg OVA plus 10mg aluminum hydroxide. After 7days, an inhalatory challenge with 1% OVA was given in 15min sessions for 3 consecutive days. Animals from the V group received the same treatment, meaning both tests and time intervals between OVA treatment and inhalatory challenge were the same as in the L group. Twenty-four hours after the last inhalation session, the animals were euthanized, and the following tests were performed: total and differential bronchoalveolar lavage (BAL) and femoral marrow lavage (FML) leukocyte counts, quantification of tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) levels in BAL fluid, and quantification of plasma corticosterone and catecholamine levels. KEY FINDINGS: The L group presented lower BAL total leukocyte counts and decreases in the number of eosinophils and macrophages compared with the V group. They also expressed higher BAL IFN-gamma and lower plasma corticosterone levels. Plasma norepinephrine levels were higher in the L group than in the N and V groups. SIGNIFICANCE: Lactating female rats presented less intense allergic lung inflammation. Our findings suggest that lactation may protect females from asthmatic crises. PMID- 26979779 TI - Infant Sleep and Parent Health Literacy. AB - OBJECTIVE: Child sleep problems are prevalent and have been linked to poor behavior, worse school performance, and obesity. Low health literacy (HL) is associated with suboptimal parenting practices and worse health outcomes, but the relationship between parent HL and child sleep-related issues is not known. We examined the association between parent HL and child sleep-related issues. METHODS: This was a cross-sectional analysis of data from caregivers enrolled in a cluster randomized trial of a primary care-based child obesity prevention program in 4 pediatric clinics. Parent HL was assessed using the Short Test of Functional Health Literacy in Adults. At the 9-month well-child visit, sleep related factors were assessed: presence of TV in room where child sleeps, regular naptimes and bedtimes (>=5 days/wk), low daytime and nighttime sleep duration (>1 SD below mean on the basis of national data). Multiple logistic regression analyses were performed. RESULTS: We enrolled 557 caregivers of 9-month-old children (49.7% Hispanic, 26.9% black, 56.2% <$20,000 annual income); 49.6% reported having a TV in the room where their child sleeps; 26.6% did not have regular naptimes norbedtimes. Median sleep duration was 2.3 (interquartile range, 1.5-3.0) hours (daytime), and 9.0 (interquartile range, 8.0-10.0) hours (night) (30.2% low daytime; 20.3% low nighttime sleep duration). Children of parents with low HL were more likely to have a bedroom TV (66.7% vs 47.7%, P = .01; adjusted odds ratio, 2.2; 95% confidence interval, 1.1-4.3) and low night-time sleep (37.0% vs 18.5%; P = .002; adjusted odds ratio, 2.4; 95% confidence interval, 1.2 4.8). CONCLUSIONS: Low parent HL is associated with TV in the bedroom and low night sleep duration. Additional study is needed to further explore these associations and intervention strategies to address child sleep problems. PMID- 26979780 TI - Communication Challenges: A Qualitative Look at the Relationship Between Pediatric Hospitalists and Primary Care Providers. AB - OBJECTIVE: Primary care providers (PCPs) and hospitalists endorse the importance of effective communication yet studies illustrate critical communication problems between these 2 provider types. Our objective was to develop deeper insight into the dimensions of and underlying reasons for communication issues and determine ways to improve communication and remove barriers by eliciting the perspectives of pediatric PCPs and hospitalists. METHODS: Using qualitative methods, 2 sets of focus groups were held: 1) mix of local PCPs serving diverse populations, and 2) hospitalists from a free-standing, pediatric institution. The open-ended, semistructured question guides included questions about communication experiences, patient care responsibilities, and suggestions for improvement. Using inductive thematic analysis, investigators coded the transcripts, and resolved differences through consensus. RESULTS: Six PCP (n = 27) and 3 hospitalist (n = 15) focus groups were held. Fifty-six percent of PCPs and 14% of hospitalists had been practicing for >10 years. Five major themes were identified: problematic aspects of communication, perceptions of provider roles, push-pull, postdischarge responsibilities/care, and proposed solutions. Aspects of communication included specific problem areas with verbal and written communication. Perceptions of provider roles highlighted the issue of PCPs feeling devalued. Push-pull described conflicting expectations about a counterpart's role and responsibilities. Postdischarge responsibilities/care addressed unclear responsibilities related to patient follow-up. Proposed solutions were suggested for ways to improve communication. CONCLUSIONS: Deficiencies in communication hinder successful collaboration and can cause tension between providers in inpatient and outpatient settings. Understanding specific issues that contribute to poor communication like perceptions about provider roles is critical to improving relationships and facilitating combined efforts to improve patient care. PMID- 26979782 TI - Norovirus as the cause of medically attended gastroenteritis: a hospital-based experience. AB - Gastroenteritis remains an important cause of morbidity and mortality worldwide. With the introduction of vaccines against rotavirus, interest has shifted to understanding the epidemiology of norovirus (NoV). While the importance of NoV in gastroenteritis outbreaks is well established, its role in sporadic gastroenteritis is less known. To better define the role of NoV as a cause of sporadic gastroenteritis we investigated its prevalence in the patients seen in our paediatric hospital with special emphasis on its seasonal and age distribution. Over a 12-month period discarded stool specimens submitted to our paediatric hospital for testing of an infectious aetiology were retrieved and additionally tested for NoV by real-time reverse transcriptase-polymerase chain reaction; demographical and clinical information were also obtained. Overall, NoV was the single most commonly identified pathogen and found in 68/892 (7.6%) total specimens or 68/258 (26%) of pathogen-positive specimens. The highest rates of NoV were detected in children aged 6 months to 4 years (50/332, 15.1%) and presenting between October and January (46/314, 14.7%). NoV has become the main cause of gastroenteritis in our paediatric population. PMID- 26979781 TI - The DmtA methyltransferase contributes to Aspergillus flavus conidiation, sclerotial production, aflatoxin biosynthesis and virulence. AB - DNA methylation is essential for epigenetic regulation of gene transcription and development in many animals, plants and fungi. We investigated whether DNA methylation plays a role in the development and secondary metabolism of Aspergillus flavus, identified the DmtA methyltransferase from A. flavus, and produced a dmtA knock-out mutant by replacing the dmtA coding sequence with the pyrG selectable marker. The A. flavus dmtA null mutant lines produced white fluffy mycelium in liquid medium, and displayed a slightly flavescent conidial pigmentation compared with the normal yellow of the wild-type strain when grown on agar. The DeltadmtA lines exhibited decreased conidiation and aflatoxin (AF) biosynthesis, compared with the wild-type line, suggesting that the DmtA knock out affected the transcriptional level of genes in the AF cluster. In particular, sclerotia development and host colonization were altered in the dmtA null mutants. Green fluorescent protein tagging at the C-terminus of DmtA showed that DmtA localized to the nucleus and cytoplasm. DNA methylation content measurements in the dmtA mutants revealed no widespread DNA methylation in the mutants or wild type lines. Thus, our findings suggest that DmtA, apart from being a C-5 cytosine methyltransferase in A. flavus, contributes to asexual development, aflatoxin biosynthesis, sclerotial production and virulence. PMID- 26979783 TI - Ongoing effects of burns. PMID- 26979784 TI - The pursuit of ignorance. PMID- 26979786 TI - Electrochemical and chemical routes to hydride loss from an iridium dihydride. AB - With a view towards replacing sacrificial hydrogen acceptors in alkane dehydrogenation catalysis, electrochemical methods for oxidative activation of a pincer-ligated iridium hydride intermediate were explored. A 1H(+)/2e(-) oxidation process was observed in THF solvent, with net hydride loss leading to a reactive cationic intermediate that can be trapped by chloride. Analogous reactivity was observed with the concerted hydride transfer reagent Ph3C(+), connecting chemical and electrochemical hydride loss pathways. PMID- 26979787 TI - Phonon Transport at Crystalline Si/Ge Interfaces: The Role of Interfacial Modes of Vibration. AB - We studied the modal contributions to heat conduction at crystalline Si and crystalline Ge interfaces and found that more than 15% of the interface conductance arises from less than 0.1% of the modes in the structure. Using the recently developed interface conductance modal analysis (ICMA) method along with a new complimentary methodology, we mapped the correlations between modes, which revealed that a small group of interfacial modes, which exist between 12-13 THz, exhibit extremely strong correlation with other modes in the system. It is found that these interfacial modes (e.g., modes with large eigen vectors for interfacial atoms) are enabled by the degree of anharmonicity near the interface, which is higher than in the bulk, and therefore allows this small group of modes to couple to all others. The analysis sheds light on the nature of localized vibrations at interfaces and can be enlightening for other investigations of localization. PMID- 26979789 TI - Commentary on Thomas and Epstein: "Bone Marrow Transplantation in Acute Leukemia". PMID- 26979790 TI - Intensive Combination Chemotherapy and X-Irradiation in Hodgkin's Disease. PMID- 26979785 TI - Identification of protein secretion systems in bacterial genomes. AB - Bacteria with two cell membranes (diderms) have evolved complex systems for protein secretion. These systems were extensively studied in some model bacteria, but the characterisation of their diversity has lagged behind due to lack of standard annotation tools. We built online and standalone computational tools to accurately predict protein secretion systems and related appendages in bacteria with LPS-containing outer membranes. They consist of models describing the systems' components and genetic organization to be used with MacSyFinder to search for T1SS-T6SS, T9SS, flagella, Type IV pili and Tad pili. We identified ~10,000 candidate systems in bacterial genomes, where T1SS and T5SS were by far the most abundant and widespread. All these data are made available in a public database. The recently described T6SS(iii) and T9SS were restricted to Bacteroidetes, and T6SS(ii) to Francisella. The T2SS, T3SS, and T4SS were frequently encoded in single-copy in one locus, whereas most T1SS were encoded in two loci. The secretion systems of diderm Firmicutes were similar to those found in other diderms. Novel systems may remain to be discovered, since some clades of environmental bacteria lacked all known protein secretion systems. Our models can be fully customized, which should facilitate the identification of novel systems. PMID- 26979793 TI - Correction: p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis. PMID- 26979792 TI - Correction: Hydrogen Peroxide-Mediated Cytosolic Acidification Is a Signal for Mitochondrial Translocation of Bax during Drug-Induced Apoptosis of Tumor Cells. PMID- 26979791 TI - A Chimeric Switch-Receptor Targeting PD1 Augments the Efficacy of Second Generation CAR T Cells in Advanced Solid Tumors. AB - Chimeric antigen receptor (CAR)-modified adoptive T-cell therapy has been successfully applied to the treatment of hematologic malignancies, but faces many challenges in solid tumors. One major obstacle is the immune-suppressive effects induced in both naturally occurring and genetically modified tumor-infiltrating lymphocytes (TIL) by inhibitory receptors (IR), namely PD1. We hypothesized that interfering with PD1 signaling would augment CAR T-cell activity against solid tumors. To address this possibility, we introduced a genetically engineered switch receptor construct, comprising the truncated extracellular domain of PD1 and the transmembrane and cytoplasmic signaling domains of CD28, into CAR T cells. We tested the effect of this supplement, "PD1CD28," on human CAR T cells targeting aggressive models of human solid tumors expressing relevant tumor antigens. Treatment of mice bearing large, established solid tumors with PD1CD28 CAR T cells led to significant regression in tumor volume due to enhanced CAR TIL infiltrate, decreased susceptibility to tumor-induced hypofunction, and attenuation of IR expression compared with treatments with CAR T cells alone or PD1 antibodies. Taken together, our findings suggest that the application of PD1CD28 to boost CAR T-cell activity is efficacious against solid tumors via a variety of mechanisms, prompting clinical investigation of this potentially promising treatment modality. PMID- 26979794 TI - Correction: The Tyrosine Phosphatase Shp2 Interacts with NPM-ALK and Regulates Anaplastic Lymphoma Cell Growth and Migration. PMID- 26979795 TI - Functional Divergence in Teleost Cardiac Troponin Paralogs Guides Variation in the Interaction of TnI Switch Region with TnC. AB - Gene duplication results in extra copies of genes that must coevolve with their interacting partners in multimeric protein complexes. The cardiac troponin (Tn) complex, containing TnC, TnI, and TnT, forms a distinct functional unit critical for the regulation of cardiac muscle contraction. In teleost fish, the function of the Tn complex is modified by the consequences of differential expression of paralogs in response to environmental thermal challenges. In this article, we focus on the interaction between TnI and TnC, coded for by genes that have independent evolutionary origins, but the co-operation of their protein products has necessitated coevolution. In this study, we characterize functional divergence of TnC and TnI paralogs, specifically the interrelated roles of regulatory subfunctionalization and structural subfunctionalization. We determined that differential paralog transcript expression in response to temperature acclimation results in three combinations of TnC and TnI in the zebrafish heart: TnC1a/TnI1.1, TnC1b/TnI1.1, and TnC1a/TnI1.5. Phylogenetic analysis of these highly conserved proteins identified functionally divergent residues in TnI and TnC. The structural and functional effect of these Tn combinations was modeled with molecular dynamics simulation to link divergent sites to changes in interaction strength. Functional divergence in TnI and TnC were not limited to the residues involved with TnC/TnI switch interaction, which emphasizes the complex nature of Tn function. Patterns in domain-specific divergent selection and interaction energies suggest that substitutions in the TnI switch region are crucial to modifying TnI/TnC function to maintain cardiac contraction with temperature changes. This integrative approach introduces Tn as a model of functional divergence that guides the coevolution of interacting proteins. PMID- 26979797 TI - Maintenance of Species Boundaries Despite Ongoing Gene Flow in Ragworts. AB - The role of hybridization between diversifying species has been the focus of a huge amount of recent evolutionary research. While gene flow can prevent speciation or initiate species collapse, it can also generate new hybrid species. Similarly, while adaptive divergence can be wiped out by gene flow, new adaptive variation can be introduced via introgression. The relative frequency of these outcomes, and indeed the frequency of hybridization and introgression in general are largely unknown. One group of closely-related species with several documented cases of hybridization is the Mediterranean ragwort (genus: Senecio) species complex. Examples of both polyploid and homoploid hybrid speciation are known in the clade, although their evolutionary relationships and the general frequency of introgressive hybridization among them remain unknown. Using a whole genome gene space dataset comprising eight Senecio species we fully resolve the phylogeny of these species for the first time despite phylogenetic incongruence across the genome. Using a D-statistic approach, we demonstrate previously unknown cases of introgressive hybridization between multiple pairs of taxa across the species tree. This is an important step in establishing these species as a study system for diversification with gene flow, and suggests that introgressive hybridization may be a widespread and important process in plant evolution. PMID- 26979796 TI - Whole-Genome Identification, Phylogeny, and Evolution of the Cytochrome P450 Family 2 (CYP2) Subfamilies in Birds. AB - The cytochrome P450 (CYP) superfamily defends organisms from endogenous and noxious environmental compounds, and thus is crucial for survival. However, beyond mammals the molecular evolution of CYP2 subfamilies is poorly understood. Here, we characterized the CYP2 family across 48 avian whole genomes representing all major extant bird clades. Overall, 12 CYP2 subfamilies were identified, including the first description of the CYP2F, CYP2G, and several CYP2AF genes in avian genomes. Some of the CYP2 genes previously described as being lineage specific, such as CYP2K and CYP2W, are ubiquitous to all avian groups. Furthermore, we identified a large number of CYP2J copies, which have been associated previously with water reabsorption. We detected positive selection in the avian CYP2C, CYP2D, CYP2H, CYP2J, CYP2K, and CYP2AC subfamilies. Moreover, we identified new substrate recognition sites (SRS0, SRS2_SRS3, and SRS3.1) and heme binding areas that influence CYP2 structure and function of functional importance as under significant positive selection. Some of the positively selected sites in avian CYP2D are located within the same SRS1 region that was previously linked with the metabolism of plant toxins. Additionally, we find that selective constraint variations in some avian CYP2 subfamilies are consistently associated with different feeding habits (CYP2H and CYP2J), habitats (CYP2D, CYP2H, CYP2J, and CYP2K), and migratory behaviors (CYP2D, CYP2H, and CYP2J). Overall, our findings indicate that there has been active enzyme site selection on CYP2 subfamilies and differential selection associated with different life history traits among birds. PMID- 26979799 TI - Formation of chukanovite in simulated groundwater containing [Formula: see text]. AB - Chukanovite (Fe2(OH)2CO3) is one of the secondary mineral precipitates on the surfaces of zero-valent iron (ZVI) barriers in groundwater containing carbonates. Synthesizing experiments were conducted in FeCl2, NaOH, and Na2CO3 solutions to investigate the effect of carbonate concentration on the formation of Fe2(OH)2CO3 and estimate the stability field of Fe2(OH)2CO3 on the potential-pH diagram. Results revealed that Fe2(OH)2CO3 is a unique product based on X-ray diffraction. The [Formula: see text], OH-, and Fe2+ concentrations and the ratios (R = [Fe2+]/[OH-] and R' = [[Formula: see text]]/[OH-]) are important parameters in the formation of the Fe2(OH)2CO3. Fe2(OH)2CO3 was better formed in the R = 1.1, R' = 0.9 system than in the R = 1.1, R' = 0.7 system. The crystallization of Fe2(OH)2CO3was increased with the concentration of [Formula: see text] increased from 0.018 to 0.18 mol/L. The standard Gibbs free energy of the formation of Fe2(OH)2CO3 was -1151.1 +/- 5.3 kJ/mol from the equilibrium conditions between Fe2(OH)2CO3 and Fe2+, [Formula: see text]. Potential-pH diagram of iron, including Fe2(OH)2CO3, was drawn in the Fe-C-H2O system. In this diagram, the stable domain of Fe2(OH)2CO3 was 7.87 < pH < 10.34, -740 mV < Eh < -400 mV, which can be converted into FeCO3 in low pH value in the 0.18mol/L carbonate solution. This work will aid in predicting the potential for mineral precipitation, as well as estimating the reactivity, porosity, and hydraulic performance of ZVI permeable reactive barriers. PMID- 26979798 TI - Genetic Evidence of Human Adaptation to a Cooked Diet. AB - Humans have been argued to be biologically adapted to a cooked diet, but this hypothesis has not been tested at the molecular level. Here, we combine controlled feeding experiments in mice with comparative primate genomics to show that consumption of a cooked diet influences gene expression and that affected genes bear signals of positive selection in the human lineage. Liver gene expression profiles in mice fed standardized diets of meat or tuber were affected by food type and cooking, but not by caloric intake or consumer energy balance. Genes affected by cooking were highly correlated with genes known to be differentially expressed in liver between humans and other primates, and more genes in this overlap set show signals of positive selection in humans than would be expected by chance. Sequence changes in the genes under selection appear before the split between modern humans and two archaic human groups, Neandertals and Denisovans, supporting the idea that human adaptation to a cooked diet had begun by at least 275,000 years ago. PMID- 26979800 TI - Predictors and Correlates of Inattentive/Overactive Behaviors in Internationally Adopted Children. AB - Children adopted internationally following deprived early care have an elevated risk for difficulties with inattention/overactivity (Kreppner et al., 2001 ). The current study sought to identify predictors of inattention/overactivity and child and adoptive family challenges that co-occur with inattention/overactivity difficulties in a sample of internationally adopted children. Forty-eight children (mean age at adoption = 57.98 months, SD = 47.7 months) were examined at 3 yearly assessments, which included semistructured interviews, parent ratings, and neuropsychological assessment with children. Results revealed that older age at adoption, longer time in the adoptive home, and smaller family size were associated with greater parent-rated difficulties with inattention/overactivity. Additionally, greater inattention/overactivity difficulties were associated with poorer expressive language and reading performance, poorer child emotional behavioral outcomes, and poorer adoptive family functioning. Given the increase in difficulties over time in the adoptive home, longer-term follow-up may be helpful to ensure appropriate intervention. Additionally, interventions may need to be more comprehensive given the connection between inattentive/overactive behaviors and other areas of functioning. PMID- 26979801 TI - Emotional Reactions to War: What's in a Name? PMID- 26979802 TI - Nanoparticle transport across the placental barrier: pushing the field forward! AB - The human placenta is a multifunctional organ constituting the barrier between maternal and fetal tissues. Nanoparticles can cross the placental barrier, and there is increasing evidence that the extent of transfer is dependent on particle characteristics and functionalization. While translocated particles may pose risks to the growing fetus particles may also be engineered to enable new particle-based therapies in pregnancy. In both cases, a comprehensive understanding of nanoparticle uptake, accumulation and translocation is indispensable and requires predictive placental transfer models. We examine and evaluate the current literature to draw first conclusions on the possibility to steer translocation of nanoparticles. In addition, we discuss if current placental models are suitable for nanoparticle transfer studies and suggest strategies to improve their predictability. PMID- 26979804 TI - CURRENT STATUS OF INDIVIDUAL DOSIMETRIC MONITORING IN UKRAINE. AB - About 50 000 workers are being occupationally exposed to radiation in Ukraine. Individual dosimetric monitoring (IDM) is provided by 77 dosimetry services and laboratories of very different scale with a number of monitored workers ranging from several persons to ~9000. In the present work, the current status of personal dosimetry in Ukraine was studied. The First National Intercomparison (FNI) of the IDM labs was accompanied by a survey of the laboratory operation in terms of coverage, types of dosimetry provided, instrumentation and methodologies used, metrological support, data recording, etc. Totally, 34 laboratories responded to the FNI call, and 18 services with 19 different personal dosimetry systems took part in the intercomparison exercise providing 24 dosimeters each for blind irradiation to photons of 6 different qualities (ISO N-series X-rays, S Cs and S-Co sources) in a dose range of 5-60 mSv. Performance of the dosimetry labs was evaluated according to ISO 14146 criteria of matching trumpet curves with H0 = 0.2 mSv. The test revealed that 8 of the 19 systems meet ISO 14146 criteria in full, 5 other labs show marginal performance and 6 laboratories demonstrated catastrophic quality of dosimetric results. Altogether, 18 participating labs provide dosimetric monitoring to 37 477 workers (about three fourths of all occupationally exposed workers), usually on monthly (nuclear industry) or quarterly (rest of applications) basis. Of this number, 20 664 persons (55 %) receive completely adequate individual monitoring, and the number of personnel receiving IDM of inadequate quality counts 3054 persons. PMID- 26979805 TI - THREE-YEAR RETENTION OF RADIOACTIVE CAESIUM IN THE BODY OF TEPCO WORKERS INVOLVED IN THE FUKUSHIMA DAIICHI NUCLEAR POWER STATION ACCIDENT. AB - Direct measurements of seven highly exposed workers at the Tokyo Electric Power Company Fukushima Daiichi Nuclear Power Station accident have been performed continuously since June 2011. Caesium clearance in the monitored workers is in agreement with the biokinetic models proposed by the International Commission on Radiological Protection. After 500 d from the initial measurement, however, the caesium clearance slowed. It was thought to be unlikely that additional Cs intake had occurred after the initial intake, as activity in foods was kept low. And, the contribution from the detector over the chest was enhanced with time. This indicates that insoluble Cs particles were inhaled and a long metabolic rate showed. PMID- 26979803 TI - Chromatin interactions and candidate genes at ten prostate cancer risk loci. AB - Genome-wide association studies have identified more than 100 common single nucleotide polymorphisms (SNPs) that are associated with prostate cancer risk. However, the vast majority of these SNPs lie in noncoding regions of the genome. To test whether these risk SNPs regulate their target genes through long-range chromatin interactions, we applied capture-based 3C sequencing technology to investigate possible cis-interactions at ten prostate cancer risk loci in six cell lines. We identified significant physical interactions between risk regions and their potential target genes including CAPG at 2p11.2, C2orf43 at 2p24.1, RFX6 at 6q22.1, NFASC at 1q32.1, MYC at 8q24.1 and AGAP7P at 10q11.23. Most of the interaction peaks were co-localized to regions of active histone modification and transcription factor binding sites. Expression quantitative trait locus (eQTL) analysis showed suggestive eQTL signals at rs1446669, rs699664 and rs1078004 for CAPG (p < 0.004), rs13394027 for C2orf43 (p = 2.25E-27), rs10993994 and rs4631830 for AGAP7P (p < 8.02E-5). Further analysis revealed an enhancer activity at genomic region surrounding rs4631830 which was expected to disrupt HOXB-like DNA binding affinity. This study identifies a set of candidate genes and their potential regulatory variants, and provides additional evidence showing the role of long-range chromatin interactions in prostate cancer etiology. PMID- 26979806 TI - RESPONSE OF DOSEMETERS IN FIELDS GENERATED BY LASER-ACCELERATED PROTONS. AB - In laser-driven acceleration, ultra-short and intense laser pulses are focussed on targets to generate beams of ionising radiation. One of the most important issues to be addressed is personal monitoring. While traditional dosemeters were designed primarily for measurements in continuous fields, dosemeters for laser laboratories must be capable of working in pulsed fields of pulse length below 1 ps, in a single-shot regime up to the repetition rate of 1 kHz. Responses of conventional dosemeters (films, polyallyldiglycol carbonate, electronic personal dosemeter) to proton bunches of up to 30 MeV energy produced by South Korean PW laser system at the Advanced Photonics Research Institute, Gwangju Institute of Science and Technology were studied, both by means of Monte Carlo simulations and experimentally. PMID- 26979807 TI - AN ANALYSIS OF THE POTENTIAL ROLE OF CHEST TOMOSYNTHESIS IN OPTIMISING IMAGING RESOURCES IN THORACIC RADIOLOGY. AB - The aim of the study was to investigate the potential role of chest tomosynthesis (CTS) at a tertiary referral centre by exploring to what extent CTS could substitute chest radiography (CXR) and computed tomography (CT). The study comprised 1433 CXR, 523 CT and 216 CTS examinations performed 5 years after the introduction of CTS. For each examination, it was decided if CTS would have been appropriate instead of CXR (CXR cases), if CTS could have replaced the performed CT (CT cases) or if CT would have been performed had CTS not been available (CTS cases). It was judged that (a) CTS had been appropriate in 15 % of the CXR examinations, (b) CTS could have replaced additionally 7 % of the CT examinations and (c) CT would have been carried out in 63 % of the performed CTS examinations, had CTS not been available. In conclusion, the potential role for CTS to substitute other modalities during office hours at a tertiary referral centre may be in the order of 20 and 25 % of performed CXR and chest CT, respectively. PMID- 26979808 TI - THE VALIDITY OF USING ROC SOFTWARE FOR ANALYSING VISUAL GRADING CHARACTERISTICS DATA: AN INVESTIGATION BASED ON THE NOVEL SOFTWARE VGC ANALYZER. AB - The purpose of the present work was to investigate the validity of using single reader-adapted receiver operating characteristics (ROC) software for analysis of visual grading characteristics (VGC) data. VGC data from four published VGC studies on optimisation of X-ray examinations, previously analysed using ROCFIT, were reanalysed using a recently developed software dedicated to VGC analysis (VGC Analyzer), and the outcomes [the mean and 95 % confidence interval (CI) of the area under the VGC curve (AUCVGC) and the p-value] were compared. The studies included both paired and non-paired data and were reanalysed both for the fixed reader and the random-reader situations. The results showed good agreement between the softwares for the mean AUCVGC For non-paired data, wider CIs were obtained with VGC Analyzer than previously reported, whereas for paired data, the previously reported CIs were similar or even broader. Similar observations were made for the p-values. The results indicate that the use of single-reader-adapted ROC software such as ROCFIT for analysing non-paired VGC data may lead to an increased risk of committing Type I errors, especially in the random-reader situation. On the other hand, the use of ROC software for analysis of paired VGC data may lead to an increased risk of committing Type II errors, especially in the fixed-reader situation. PMID- 26979810 TI - Foetal fibular hemimelia with focal femoral deficiency following prenatal misoprostol use: A case report. AB - Misoprostol is a well known abortifacient. It can cause teratogenicity like Mobius sequence and terminal transverse limb defects. We report a rare case of proximal focal femoral deficiency with fibular hemimelia in a woman who had attempted abortion with self-administered misoprostol and later continued the pregnancy. Though the absolute risk of congenital malformations with its use is low ~1%, this should be clearly communicated to the women requesting abortion to help them make fully informed reproductive health decisions. PMID- 26979813 TI - Opposing inequity in medical publishing: Care for quality and cherish diversity. PMID- 26979811 TI - In vivo acoustic and photoacoustic focusing of circulating cells. AB - In vivo flow cytometry using vessels as natural tubes with native cell flows has revolutionized the study of rare circulating tumor cells in a complex blood background. However, the presence of many blood cells in the detection volume makes it difficult to count each cell in this volume. We introduce method for manipulation of circulating cells in vivo with the use of gradient acoustic forces induced by ultrasound and photoacoustic waves. In a murine model, we demonstrated cell trapping, redirecting and focusing in blood and lymph flow into a tight stream, noninvasive wall-free transportation of blood, and the potential for photoacoustic detection of sickle cells without labeling and of leukocytes targeted by functionalized nanoparticles. Integration of cell focusing with intravital imaging methods may provide a versatile biological tool for single cell analysis in circulation, with a focus on in vivo needleless blood tests, and preclinical studies of human diseases in animal models. PMID- 26979817 TI - Heredity, evolution and development in their (epistemic) environment at the turn of the nineteenth century. AB - During the early 1870s a young zoologist who worked as a Privatdozent delivering lectures at different Prussian universities invested much of his family wealth and solicited his fellows' contributions to establish a research facility by the sea. The young zoologist happened to be called Anton Dohrn. From the time it opened its doors, the Anton Dohrn Zoological Station - or Naples Zoological Station, as it was originally called - played a crucial role in shaping life sciences as it facilitated research aimed at explaining the mechanics of inheritance. During the last quarter of the nineteenth century and the first decades of the twentieth, zoologists attempted to explain how evolutionary changes occur within a population and become stabilized. In so doing, they looked at developmental processes as well as environmental pressure, coming up with different hypotheses to explain inheritance. In some cases, their research was highly speculative, whereas in other cases they conducted cytological observations to identify the material basis of heredity. Research on evolution and development has been carried out in different places, and zoological stations like the one in Naples have played a major role in this story. However, numerous biological institutions active at the turn of the twentieth century have not received much attention from historians. PMID- 26979816 TI - Finite element model-based evaluation of tissue stress variations to fabricate corrective orthosis in feet with neutral subtalar joint. AB - BACKGROUND: The subtalar joint position during static stance is a crucial determinant of the peak plantar pressures and forms ideal reference point for any intervention in foot-related problems for leprosy-affected patients. OBJECTIVES: The study pursued the hypothesis through a three-dimensional model that stress will be minimal in the distal joints of the foot when the subtalar joint is in neutral static stance position. STUDY DESIGN: Finite element model. METHODS: The computed tomography images of the feet for five patients suffering from Hansen's disease having no muscle weakness and joint restriction were acquired. The gray intensities corresponding to the bones of the foot from the computed tomography images were three-dimensionally reconstructed. The three-dimensional model of the human foot, incorporating the realistic geometry, and the material properties of the hard tissues were then analyzed using a finite element solver for the stress distribution on bones of the foot. RESULTS: The results demonstrate that the position of the calcaneum in the static stance position does contribute to the varying stress in the foot. CONCLUSION: The stresses in the bones of the foot are minimal while the subtalar is in neutral position; this position will be suitable for foot orthotic fabrication. Clinical relevance The clinicians, therapists, and podiatrists having less engineering skills can quickly assess the patient and get optimal results on the stress associated with the joints of the foot. PMID- 26979812 TI - Neuropsychological and neurophysiological benefits from white noise in children with and without ADHD. AB - BACKGROUND: Optimal stimulation theory and moderate brain arousal (MBA) model hypothesize that extra-task stimulation (e.g. white noise) could improve cognitive functions of children with attention-deficit/hyperactivity disorder (ADHD). We investigate benefits of white noise on attention and inhibition in children with and without ADHD (7-12 years old), both at behavioral and at neurophysiological levels. METHODS: Thirty children with and without ADHD performed a visual cued Go/Nogo task in two conditions (white noise or no-noise exposure), in which behavioral and P300 (mean amplitudes) data were analyzed. Spontaneous eye-blink rates were also recorded and participants went through neuropsychological assessment. Two separate analyses were conducted with each child separately assigned into two groups (1) ADHD or typically developing children (TDC), and (2) noise beneficiaries or non-beneficiaries according to the observed performance during the experiment. This latest categorization, based on a new index we called "Noise Benefits Index" (NBI), was proposed to determine a neuropsychological profile positively sensitive to noise. RESULTS: Noise exposure reduced omission rate in children with ADHD, who were no longer different from TDC. Eye-blink rate was higher in children with ADHD but was not modulated by white noise. NBI indicated a significant relationship between ADHD and noise benefit. Strong correlations were observed between noise benefit and neuropsychological weaknesses in vigilance and inhibition. Participants who benefited from noise had an increased Go P300 in the noise condition. CONCLUSION: The improvement of children with ADHD with white noise supports both optimal stimulation theory and MBA model. However, eye-blink rate results question the dopaminergic hypothesis in the latter. The NBI evidenced a profile positively sensitive to noise, related with ADHD, and associated with weaker cognitive control. PMID- 26979819 TI - Male Prison Inmates With Gender Dysphoria: When Is Sex Reassignment Surgery Appropriate? AB - Gender dysphoria (GD), a feeling of persistent discomfort with one's biologic sex or assigned gender, is estimated to be more prevalent in male prison inmates than in nonincarcerated males; there may be 3000-4000 male inmates with GD in prisons in the United States. An increasing number of U.S. prison systems now offer gender dysphoric inmates diagnostic evaluation, psychotherapy, cross-sex hormone therapy, and opportunities, albeit limited, to enact their preferred gender role. Sex reassignment surgery (SRS), however, has not been offered to inmates except in response to litigation. In the first case of its kind, the California Department of Corrections and Rehabilitation recently agreed to provide SRS to an inmate and developed policy guidelines for its future provision. In other recent cases, U.S. courts have ruled that male inmates with GD are entitled to SRS when it is medically necessary. Although these decisions may facilitate the provision of SRS to inmates in the future, many U.S. prison systems will probably remain reluctant to offer SRS unless legally compelled to do so. In this review, we address the medical necessity of SRS for male inmates with GD. We also discuss eligibility criteria and the practical considerations involved in providing SRS to inmates. We conclude by offering recommendations for physicians, mental health professionals, and prison administrators, designed to facilitate provision of SRS to inmates with GD in a manner that provides humane treatment, maximizes the likelihood of successful outcomes, minimizes risk of regret, and generates data that can help inform future decisions. PMID- 26979820 TI - Multiscale structural characterizations of mixed U(iv)-An(iii) oxalates (An(iii) = Pu or Am) combining XAS and XRD measurements. AB - Mixed actinide(III,IV) oxalates of the general formula M2.2UAn(C2O4)5.nH2O (An = Pu or Am and M = H3O(+) and N2H5(+)) have been quantitatively precipitated by oxalic precipitation in nitric acid medium (yield >99%). Thorough multiscale structural characterization using XRD and XAS measurements confirmed the existence of mixed actinide oxalate solid solutions. The XANES analysis confirmed that the oxidation states of the metallic cations, tetravalent for uranium and trivalent for plutonium and americium, are maintained during the precipitation step. EXAFS measurements show that the local environments around U(+IV), Pu(+III) and Am(+III) are comparable, and the actinides are surrounded by ten oxygen atoms from five bidentate oxalate anions. The mean metal-oxygen distances obtained by XAS measurements are in agreement with those calculated from XRD lattice parameters. PMID- 26979821 TI - [Not Available]. PMID- 26979818 TI - Engineered nanomaterials: toward effective safety management in research laboratories. AB - BACKGROUND: It is still unknown which types of nanomaterials and associated doses represent an actual danger to humans and environment. Meanwhile, there is consensus on applying the precautionary principle to these novel materials until more information is available. To deal with the rapid evolution of research, including the fast turnover of collaborators, a user-friendly and easy-to-apply risk assessment tool offering adequate preventive and protective measures has to be provided. RESULTS: Based on new information concerning the hazards of engineered nanomaterials, we improved a previously developed risk assessment tool by following a simple scheme to gain in efficiency. In the first step, using a logical decision tree, one of the three hazard levels, from H1 to H3, is assigned to the nanomaterial. Using a combination of decision trees and matrices, the second step links the hazard with the emission and exposure potential to assign one of the three nanorisk levels (Nano 3 highest risk; Nano 1 lowest risk) to the activity. These operations are repeated at each process step, leading to the laboratory classification. The third step provides detailed preventive and protective measures for the determined level of nanorisk. CONCLUSIONS: We developed an adapted simple and intuitive method for nanomaterial risk management in research laboratories. It allows classifying the nanoactivities into three levels, additionally proposing concrete preventive and protective measures and associated actions. This method is a valuable tool for all the participants in nanomaterial safety. The users experience an essential learning opportunity and increase their safety awareness. Laboratory managers have a reliable tool to obtain an overview of the operations involving nanomaterials in their laboratories; this is essential, as they are responsible for the employee safety, but are sometimes unaware of the works performed. Bringing this risk to a three band scale (like other types of risks such as biological, radiation, chemical, etc.) facilitates the management for occupational health and safety specialists. Institutes and school managers can obtain the necessary information to implement an adequate safety management system. Having an easy-to-use tool enables a dialog between all these partners, whose semantic and priorities in terms of safety are often different. PMID- 26979822 TI - Negative attitude and low intention to vaccinate universally against varicella among public health professionals and parents in the Netherlands: two internet surveys. AB - BACKGROUND: Prior to introduction of universal varicella vaccination, it is crucial to gain insight into the willingness to vaccinate among the population. This is because suboptimal national vaccination coverage might increase the age of infection in children, which will lead to higher complication rates. We studied the attitude and intention to vaccinate against varicella among Dutch public health professionals who execute the National Immunisation Programme (NIP), and parents. METHODS: Medical doctors and nurses of regional public health services (RPHS) and child health clinics (CHC), and a random sample of parents received an internet survey on varicella vaccination. Separate logistic regression models were used to identify determinants for a positive attitude (professionals) or a positive intention (parents) to vaccinate against varicella within the NIP (free of charge). RESULTS: The questionnaire was completed by 181 RPHS professionals (67%), 260 CHC professionals (46%), and 491 parents (33%). Of professionals, 21% had a positive attitude towards universal varicella vaccination, while 72% preferred to limit vaccination to high-risk groups only. Of parents, 28% had a positive intention to vaccinate their child against varicella within the NIP. The strongest determinant for a positive attitude or intention to vaccinate against varicella among professionals and parents was the belief that varicella is a disease serious enough to vaccinate against. CONCLUSIONS: We showed that a majority of the Dutch public health professionals and parents in this study have a negative attitude or low intention to vaccinate universally against varicella, as a result of the perceived low severity of the disease. Most participating professionals support selective vaccination to prevent varicella among high-risk groups. PMID- 26979826 TI - Depression Trajectories during the First Year after Traumatic Brain Injury. AB - Major depression is prevalent after traumatic brain injury (TBI) and associated with poor outcomes. Little is known about the course of depression after TBI. Participants were 559 consecutively admitted patients with mild to severe TBI recruited from inpatient units at Harborview Medical Center, a Level I trauma center in Seattle, WA. Participants were assessed with the Patient Health Questionnaire-9 (PHQ-9) depression measure at months 1-6, 8, 10, and 12 post injury. We used linear latent class growth mixture modeling (LCGMM) of PHQ-9 total scores to identify homogeneous subgroups with distinct longitudinal trajectories. A four-class LCGMM had good fit indices and clinical interpretability. Trajectory groups were: low depression (70.1%), delayed depression (13.2%), depression recovery (10.4%), and persistent depression (6.3%). Multinomial logistic regression analyses were used to distinguish trajectory classes based on baseline demographic, psychiatric history, and clinical variables. Relative to the low depression group, the other three groups were consistently more likely to have a pre-injury history of other mental health disorders or major depressive disorder, a positive toxicology screen for cocaine or amphetamines at the time of injury, and a history of alcohol dependence. They were less likely to be on Medicare versus commercial insurance. Trajectories based on LCGMM are an empirical and clinically meaningful way to characterize distinct courses of depression after TBI. When combined with baseline predictors, this line of research may improve our ability to predict prognosis and target groups who may benefit from treatment or secondary prevention efforts (e.g., proactive telephone counseling). PMID- 26979823 TI - Untangling the Web: Toxic and Protective Effects of Neuroinflammation and PGE2 Signaling in Alzheimer's Disease. AB - The neuroinflammatory response has received increasing attention as a key factor in the pathogenesis of Alzheimer's disease (AD). Microglia, the innate immune cells and resident phagocytes of the brain, respond to accumulating Abeta peptides by generating a nonresolving inflammatory response. While this response can clear Abeta peptides from the nervous system in some settings, its failure to do so in AD accelerates synaptic injury, neuronal loss, and cognitive decline. The complex molecular components of this response are beginning to be unraveled, with identification of both damaging and protective roles for individual components of the neuroinflammatory response. Even within one molecular pathway, contrasting effects are often present. As one example, recent studies of the inflammatory cyclooxygenase-prostaglandin pathway have revealed both beneficial and detrimental effects dependent on the disease context, cell type, and downstream signaling pathway. Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenases, are associated with reduced AD risk when taken by cognitively normal populations, but additional clinical and mouse model studies have added complexities and caveats to this finding. Downstream of cyclooxygenase activity, prostaglandin E2 signaling exerts both damaging pro-inflammatory and protective anti-inflammatory effects through actions of specific E-prostanoid G protein coupled receptors on specific cell types. These complexities underscore the need for careful study of individual components of the neuroinflammatory response to better understand their contribution to AD pathogenesis and progression. PMID- 26979827 TI - Power Day: Addressing the Use and Abuse of Power in Medical Training. AB - PROBLEM: Medical student mistreatment, as well as patient and staff mistreatment by all levels of medical trainees and faculty, is still prevalent in U.S. clinical training. Largely missing in interventions to reduce mistreatment is acknowledgement of the abuse of power produced by the hierarchical structure in which medicine is practiced. APPROACH: Beginning in 2001, Yale School of Medicine has held annual "Power Day" workshops for third year medical students and advanced practice nursing students, to define and analyse power dynamics within the medical hierarchy and hidden curriculum using literature, guest speakers, and small groups. During rotations, medical students write narratives about the use of power witnessed in the wards. In response to student and small group leader feedback, workshop organizers have developed additional activities related to examining and changing the use of power in clinical teams. OUTCOME: Emerging narrative themes included the potential impact of small acts and students feeling "mute" and "complicit" in morally distressing situations. Small groups provided safe spaces for advice, support, and professional identity formation. By 2005, students recognized residents that used power positively with Power Day awards and alumni served as keynote speakers on the use of power in medicine. By 2010, departments including OB/GYN, surgery, psychiatry, and paediatrics, had added weekly team Power Hour discussions. NEXT STEPS: The authors highlight barriers, benefits, and lessons learned. Barriers include the notion of clinical irrelevance and resistance to the word "power" due to perceived accusation of abuse. Benefits include promoting open dialogue about power, fostering inter professional collaboration, rewarding positive role modelling by residents and faculty, and creating a network of trainee empowerment and leadership. Furthermore, faculty have started to ask that issues of power be addressed in a more transparent way at their level of the hierarchy as well. PMID- 26979828 TI - The presence of LC3B puncta and HMGB1 expression in malignant cells correlate with the immune infiltrate in breast cancer. AB - Several cell-intrinsic alterations have poor prognostic features in human breast cancer, as exemplified by the absence of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta)-positive puncta in the cytoplasm (which indicates reduced autophagic flux) or the loss of nuclear HMGB1 expression by malignant cells. It is well established that breast cancer is under strong immunosurveillance, as reflected by the fact that scarce infiltration of the malignant lesion by CD8(+) cytotoxic T lymphocytes or comparatively dense infiltration by immunosuppressive cell types (such as FOXP3(+) regulatory T cells or CD68(+) tumor-associated macrophages), resulting in low CD8(+):FOXP3(+) or CD8(+):CD68(+) ratios, has a negative prognostic impact. Here, we reveal the surprising finding that cell-intrinsic features may influence the composition of the immune infiltrate in human breast cancer. Thus, the absence of LC3B puncta is correlated with intratumoral (but not peritumoral) infiltration by fewer CD8(+) cells and more FOXP3(+) or CD68(+) cells, resulting in a major drop in the CD8(+):FOXP3(+) or CD8(+):CD68(+) ratios. Moreover, absence of HMGB1 expression in nuclei correlated with a general drop in all immune effectors, in particular FOXP3(+) and CD68(+) cells, both within the tumor and close to it. Combined analysis of LC3B puncta and HMGB1 expression allowed for improved stratification of patients with respect to the characteristics of their immune infiltrate as well as overall and metastasis-free survival. It can be speculated that blocked autophagy in, or HMGB1 loss from, cancer cells may favor tumor progression due to their negative impact on anticancer immunosurveillance. PMID- 26979829 TI - Mesenchymal-epithelial signalling in tumour microenvironment: role of high mobility group Box 1. AB - Glucose deprivation, hypoxia and acidosis are characteristic features of the central core of most solid tumours. Myofibroblasts are stromal cells present in many such solid tumours, including those of the colon, and are known to be involved in all stages of tumour progression. HMGB1 is a nuclear protein with an important role in nucleosome stabilisation and gene transcription; it is also released from immune cells and is involved in the inflammatory process. We report that the microenvironmental condition of glucose deprivation is responsible for the active release of HMGB1 from various types of cancer cell lines (HT-29, MCF-7 and A549) under normoxic conditions. Recombinant HMGB1 (10 ng/ml) triggered proliferation in myofibroblast cells via activation of PI3K and MEK1/2. Conditioned medium collected from glucose-deprived HT-29 colon cancer cells stimulated the migration and invasion of colonic myofibroblasts, and these processes were significantly inhibited by immunoneutralising antibodies to HMGB1, RAGE and TLR4, together with specific inhibitors of PI3K and MEK1/2. Our data suggest that HMGB1 released from cancer cells under glucose deprivation is involved in stimulating colonic myofibroblast migration and invasion and that this occurs through the activation of RAGE and TLR4, resulting in the activation of the MAPK and PI3K signalling pathways. Thus, HMGB1 might be released by cancer cells in areas of low glucose in solid tumours with the resulting activation of myofibroblasts and is a potential therapeutic target to inhibit solid tumour growth. PMID- 26979831 TI - Long-Term Outcomes of Short-Term Statin Use in Healthy Adults: A Retrospective Cohort Study. AB - INTRODUCTION: Data suggest that the beneficial cardiovascular effects of statins are maximized after the first year of statin use; yet, the timeline of statin associated adverse events is not well delineated. OBJECTIVE: To examine the associations of short-term statin use (<=1 year) with short- and long-term adverse events and beneficial cardiovascular outcomes in a 'healthy' cohort. PARTICIPANTS AND METHODS: A cohort study of a healthy Tricare population (fiscal year [FY] 2002 through FY 2011) who have no cardiovascular disease, major comorbidities requiring medications, or functional limitations. Statin users used statins for 90-365 days during FY 2005 as their only prescription medication. Nonusers had medical encounters but did not receive prescription medications during FY 2005, and did not receive any statins throughout the study period from FY 2002 to FY 2011. Outcomes were the occurrence of major acute cardiovascular events, diabetes mellitus and its complications, kidney diseases, musculoskeletal diseases, obesity, cataracts, malignancy, and death. RESULTS: We matched 1525 statin users to 1525 nonusers. During the follow-up period (FY 2006 to FY 2011), statin users had significantly higher odds of developing diabetes and diabetic complications that persisted throughout follow-up (odds ratio [OR] 1.93, 95 % confidence interval [CI] 1.55-2.41 and OR 2.15, 95 % CI 1.20-3.86, respectively). Short-term statin use was not associated with decreased odds of major acute cardiovascular events (OR 1.17, 95 % CI 0.72-1.92). There were no differences in risks of kidney diseases, musculoskeletal diseases, or malignancy. CONCLUSIONS: Short-term statin use for primary prevention in this healthy cohort was associated with an increased risk of long-term diabetes and diabetic complications without cardiovascular benefits. Further study using pragmatic studies and prospective observational studies appropriately equipped to eliminate unidentified confounders are urgently needed. PMID- 26979832 TI - The large contribution of twins to neonatal and post-neonatal mortality in The Gambia, a 5-year prospective study. AB - BACKGROUND: A high twinning rate and an increased risk of mortality among twins contribute to the high burden of infant mortality in Africa. This study examined the contribution of twins to neonatal and post-neonatal mortality in The Gambia, and evaluated factors that contribute to the excess mortality among twins. METHODS: We analysed data from the Basse Health and Demographic Surveillance System (BHDSS) collected from January 2009 to December 2013. Demographic and epidemiological variables were assessed for their association with mortality in different age groups. RESULTS: We included 32,436 singletons and 1083 twins in the analysis (twining rate 16.7/1000 deliveries). Twins represented 11.8 % of all neonatal deaths and 7.8 % of post-neonatal deaths. Mortality among twins was higher than in singletons [adjusted odds ratio (AOR) 4.33 (95 % CI: 3.09, 6.06) in the neonatal period and 2.61 (95 % CI: 1.85, 3.68) in the post-neonatal period]. Post-neonatal mortality among twins increased in girls (P for interaction = 0.064), being born during the dry season (P for interaction = 0.030) and lacking access to clean water (P for interaction = 0.042). CONCLUSION: Mortality among twins makes a significant contribution to the high burden of neonatal and post-neonatal mortality in The Gambia and preventive interventions targeting twins should be prioritized. PMID- 26979835 TI - Detecting MLC errors in stereotactic radiotherapy plans with a liquid filled ionization chamber array. AB - Quality assurance of stereotactic radiotherapy demands the use of equipment with the highest resolution and sensitivity available. This study examines the sensitivity of a commercially available liquid-filled ionization chamber array- the Octavius 1000 SRS (PTW, Frieburg, Germany) for detecting small (sub millimetre) multi-leaf collimator (MLC) alignment errors in static square fields (side length 16-40 mm). Furthermore, the effectiveness of detecting small MLC errors in clinical stereotactic radiotherapy patient plans using the device was also evaluated. The commonly used gamma pass rate metric (of the measurements compared with treatment planning system generated results) was used. The gamma pass rates were then evaluated as a function of MLC position error (MLC error size 0.1-2.5 mm). The detector array exhibited a drop in pass rate between plans without error and those which had MLC errors induced. For example a drop in pass rate of 4.5% (gamma criteria 3%, 1 mm) was observed when a 0.8 mm error was introduced into a 16 mm square field. Furthermore the drop in pass rate increased as the MLC position error increased. This study showed that the Octavius 1000 SRS array could be a useful tool for applications requiring the detection of small geometric delivery uncertainties. PMID- 26979833 TI - Formative research to identify perceptions of e-cigarettes in college students: Implications for future health communication campaigns. AB - OBJECTIVE: This formative study examined perceptions of e-cigarettes in college students with the goal of informing future health communication campaigns. Differences between e-cigarette users and nonusers were also examined. PARTICIPANTS: Thirty undergraduate students were recruited from a large southwestern public university (15 users, 15 nonusers). METHODS: Structured interviews were conducted and transcripts were coded for themes. RESULTS: Although users had more favorable attitudes toward e-cigarettes, both users and nonusers believed that e-cigarettes produce water vapor and reported that e cigarettes were less harmful than conventional cigarettes. Potential health consequences and addiction concerns were the most common perceived threats for both users and nonusers. Both nonusers and users cited social stigma as a perceived disadvantage of e-cigarette use. CONCLUSIONS: Ultimately, themes with particular relevance to future health communication campaigns included negative perceptions of e-cigarette users and social stigma, as well as harm perceptions and potential health consequences associated with e-cigarette use. PMID- 26979830 TI - A Phase II Dose-Ranging Study Evaluating the Efficacy and Safety of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Primary Insomnia. AB - BACKGROUND: Filorexant (MK-6096) is an orexin receptor antagonist; here, we evaluate the efficacy of filorexant in the treatment of insomnia in adults. METHODS: A double-blind, placebo-controlled, randomized, two 4-week-period, adaptive crossover polysomnography study was conducted at 51 sites worldwide. Patients (18 to <65 years) with insomnia received 1 of 4 doses of oral filorexant (2.5, 5, 10, 20mg) once daily at bedtime during one period and matching placebo in the other period in 1 of 8 possible treatment sequences. Polysomnography was performed on night 1 and end of week 4 of each period. The primary endpoint was sleep efficiency at night 1 and end of week 4. Secondary endpoints included wakefulness after persistent sleep onset and latency to onset of persistent sleep. RESULTS: A total of 324 patients received study treatment, 315 received >=1 dose of placebo, and 318 >=1 dose of filorexant (2.5mg, n=79; 5mg, n=78; 10mg, n=80; 20mg, n=81). All filorexant doses (2.5/5/10/20mg) were significantly superior to placebo in improving sleep among patients with insomnia as measured by sleep efficiency and wakefulness after persistent sleep onset on night 1 and end of week 4. The 2 higher filorexant doses (10/20mg) were also significantly more effective than placebo in improving sleep onset as measured by latency to onset of persistent sleep at night 1 and end of week 4. Filorexant was generally well tolerated. CONCLUSIONS: Orexin receptor antagonism by filorexant significantly improved sleep efficiency in nonelderly patients with insomnia. Dose-related improvements in sleep onset and maintenance outcomes were also observed with filorexant. PMID- 26979836 TI - Buried iceberg scours reveal reduced North Atlantic Current during the stage 12 deglacial. AB - Reconstructing past ocean-climate environments and heat transport requires proxies from which these conditions can be quantified. This is particularly important for the evaluation of numerical palaeoclimate models. Here we present new evidence for a reduced North Atlantic Current (NAC) at the termination of the third last glacial, for which palaeocurrent information was previously unavailable. This is based on an exquisitely preserved set of buried iceberg scours seen in three-dimensional seismic reflection images from the mid-Norwegian slope. The scours were formed ~430 ka during the transition from glacial to interglacial conditions. The spiral geometry of the scours suggests that they were carved by grounded icebergs influenced by tidal and geostrophic ocean currents. Using the ratio between the estimated tidal and geostrophic current velocities and comparing them with velocities from the Last Glacial Maximum and the present, we show that the stage 12 NAC velocities may have been ~50% slower than the present. PMID- 26979837 TI - A simplified vector system for visualization of localized RNAs in Schizosaccharomyces pombe. AB - RNA localization is an important event that is essential for the polarization and differentiation of a cell. Although several methods are currently used to detect localized RNAs, a simplified detection system has not yet been developed for Schizosaccharomyces pombe. In the present study, we describe a new vector system for the visualization of localized RNAs in S. pombe using a U1A-tag-GFP system. A pREP1-U1A-tag vector plasmid to express U1A-tagged RNA and a pREP2-U1AGFP plasmid to produce a U1A-GFP fusion protein were constructed for this system. Since the U1A-GFP protein binds U1A-tagged RNA, fluorescence is observed at the location of U1A-tagged RNA in cells expressing both of these. The nucleolar localization of U3 snoRNA was successfully detected using this system, and a novel RNA localized at the DNA region of the nucleus was found by screening localized RNAs. This system will accelerate the study of localized RNAs in S. pombe. PMID- 26979838 TI - Effects of Hypoxia on the Phylogenetic Composition and Species Distribution of Protists in a Subtropical Harbor. AB - Tolo Harbor, a subtropical semi-enclosed coastal water body, is surrounded by an expanding urban community, which contributes to large concentrations of nutrient runoff, leading to algal blooms and localized hypoxic episodes. Present knowledge of protist distributions in subtropical waters during hypoxic conditions is very limited. In this study, therefore, we combined parallel 454 pyrosequencing technology and denaturing gradient gel electrophoresis (DGGE) fingerprint analyses to reveal the protist community shifts before, during, and after a 2 week hypoxic episode during the summer of 2011. Hierarchical clustering for DGGE demonstrated similar grouping of hypoxic samples separately from oxic samples. Dissolved oxygen (DO) concentration and dissolved inorganic nitrogen:phosphate (DIN:PO4) concentrations significantly affected OTU distribution in 454 sequenced samples, and a shift toward a ciliate and marine alveolate clade II (MALV II) species composition occurred as waters shifted from oxic to hypoxic. These results suggest that protist community shifts toward heterotrophic and parasitic tendencies as well as decreased diversity and richness in response to hypoxic outbreaks. PMID- 26979839 TI - The mechanism of mitral regurgitation assessed by preprocedural echocardiography is associated with the outcome of catheter ablation in patients with paroxysmal atrial fibrillation. AB - BACKGROUND: Mitral regurgitation (MR) is generally classified as either primary (organic) or secondary (functional). Although patients with atrial fibrillation (AF) often exhibit MR, the relation between the etiology of MR and the outcome of catheter ablation (CA) remains unknown. We conducted this study in order to elucidate this association. METHODS: Among 1330 consecutive paroxysmal AF patients who underwent initial catheter ablation in our institution, 92 patients (62 men, mean age 65 +/- 7 years) who had moderate or severe MR were included in this study; 46 were classified to have primary and the remaining 46 to have secondary MR by preoperative echocardiography. These patients were prospectively monitored after the CA. RESULTS: During a mean follow-up period of 27.9 +/- 28.8 months, AF recurred in 26/46 (56.6 %) of primary MR patients and in 15/46 (32.6 %) of those with secondary MR (P < 0.02). Although univariate analysis found that diabetes, left atrial volume indexed by body surface area (LAVI), and primary MR were significantly associated with AF recurrence, primary MR (hazard ratio (HR), 2.47; 95 % confidence interval (CI), 1.30-4.88; P = 0.006) and LAVI (HR, 1.03/1 mL/m(2) increase; 95 % CI, 1.00-1.06; P = 0.03) remained significant predictors on multivariate analysis. The AF recurrence-free rate was lower in patients with primary MR after both the initial and final CA. CONCLUSION: In patients with paroxysmal AF and moderate or severe MR, primary MR may increase the risk of AF recurrence after the initial and final CA. PMID- 26979841 TI - High-resolution ultrasound may depict pseudomeningocele. PMID- 26979840 TI - Can dietary saturated fat be beneficial in prevention of stroke risk? A meta analysis. AB - We conducted a meta-analysis to summarize available evidence regarding the relation between saturated fatty acid (SFA) intake and stroke risk. We searched multiple electronic databases through February 2016. Log relative risks (RRs) with 95 % confidence intervals (CIs) of the highest versus the lowest for cohort studies were weighed by the inverse variance method to obtain combined RRs. 15 prospective studies including 476,569 individuals and 11,074 strokes were included. Higher SFA intake was associated with reduced overall stroke risk [RR = 0.89 (95 % CI 0.82-0.96)] and fatal stroke risk [RR = 0.75 (95 % CI 0.59-0.94)]. Subgroup analysis indicated that higher SFA intake was associated with reduced stroke risks for East-Asians [RR = 0.79 (95 % CI 0.69-0.90)], for dose <25 g/day [RR = 0.81 (95 % CI 0.71-0.92)], for males [RR = 0.85 (95 % CI 0.75-0.96)], and for individuals with body mass index (BMI) <24 [RR = 0.75 (95 % CI 0.65-0.87)], but not for non East-Asians, females, and individuals with dose >=25 g/day and BMI >=24. This meta-analysis reveals that higher SFA intake is inversely associated with risk of stroke morbidity and mortality with race, sex, and BMI as key factors influencing this risk. There seems to be a threshold of SFA intake for inverse relation of SFA intake with stroke. However, the stroke-reducing or increasing effects for specific subtypes and specific food sources of SFA can be concealed. Functions of specific subtypes of SFA (e.g. lignoceric acid) and specific food sources of SFA (i.e. plant vs. animal) in relation to stroke need to be clarified in further studies. PMID- 26979843 TI - Incisura Morphology as a Risk Factor for Syndesmotic Malreduction. AB - BACKGROUND: The goal of this study was to objectively assess if rotational or translational syndesmotic malreduction is associated with certain syndesmotic morphologies. Prior studies based on subjective assessment of syndesmotic morphology and reduction have not shown any difference between groups. METHODS: Thirty-five prospectively recruited patients with operatively treated syndesmotic injuries were recruited at an Urban Level I Trauma Center. Patients underwent postoperative bilateral computed tomographic (CT) scans of the ankle to assess incisura depth and syndesmotic reduction. The uninjured extremity was used as a control. Side-to-side differences of syndesmotic reduction were measured at several anatomic points and compared to the incisura depth. RESULTS: There was a significant correlation between more shallow syndesmoses and increased anterior translation of the fibula in the incisura (r = -0.63, P <= .001). Six of 8 patients with "shallow" (<=2.5 mm) incisura were anteriorly malreduced greater than or equal to 1.5 mm compared to the contralateral ankle. The anterior malreduction rate in those with a shallow incisura was significantly greater than in the "non-shallow" patients (P < .001). There were 9 patients with incisurae greater than or equal to 4.5 mm deep. Five of the "deep" patients had posterior malreductions greater than or equal to 1.5 mm. The posterior malreduction rate in the "deep" group was significantly greater than the "non-deep" patients (P = .02). There was a significant correlation between increasing syndesmotic depth and increased malrotation (r = .46, P = .01). CONCLUSION: Syndesmotic morphology was found to be associated with specific malreduction patterns. Shallow syndesmoses were correlated with anterior fibular malreduction, and were less likely to be malrotated. Conversely, deep syndesmoses predisposed to posterior sagittal plane and rotational malalignment. Preoperative CT scans that assess the syndesmosis morphology may allow surgeons to alter reduction strategies to avoid syndesmotic malreduction. LEVEL OF EVIDENCE: Level III, retrospective cohort study. PMID- 26979842 TI - Mapping hyper-susceptibility to colitis-associated colorectal cancer in FVB/NJ mice. AB - Inbred strains of mice differ in susceptibility to colitis-associated colorectal cancer (CA-CRC). We tested 10 inbred strains of mice for their response to azoxymethane/dextran sulfate sodium-induced CA-CRC and identified a bimodal inter strain distribution pattern when tumor multiplicity was used as a phenotypic marker of susceptibility. The FVB/NJ strain was particularly susceptible showing a higher tumor burden than any other susceptible strains (12.5-week post treatment initiation). FVB/NJ hyper-susceptibility was detected as early as 8 week post-treatment initiation with FVB/NJ mice developing 5.5-fold more tumors than susceptible A/J or resistant B6 control mice. Linkage analysis by whole genome scan in informative (FVB/NJ*C3H/HeJ)F2 mice identified a novel susceptibility locus designated as C olon c ancer s usceptibility 6 (Ccs6) on proximal mouse chromosome 6. When gender was used as a covariate, a LOD score of 5.4 was computed with the peak marker being positioned at rs13478727, 43.8 Mbp. Mice homozygous for FVB/NJ alleles at this locus had increased tumor multiplicity compared to homozygous C3H/HeJ mice. Positional candidates in this region of chromosome 6 were analyzed with respect to a possible role in carcinogenesis and a role in inflammatory response using a new epigenetic gene scoring tool (Myeloid Inflammation Score). PMID- 26979844 TI - Total Arthroplasty of the Metatarsophalangeal Joint of the Hallux. AB - BACKGROUND: The current gold standard in the treatment of severe hallux rigidus is arthrodesis of the first metatarsophalangeal (MTP-I) joint. We present the results of a new 3-component MTP-I prosthesis. We determined (1) the intraoperative and perioperative complications; (2) survivorship of prosthesis components and rate of secondary surgeries for any reason; (3) prosthetic component stability and radiographic alignment; (4) the degree of pain relief; and (5) the midterm functional outcomes including radiographic range of motion (ROM). METHODS: From 2008 to 2010, we prospectively included 29 MTP-I prostheses in 25 patients. The average age of the patients was 63.1 years (range, 48-87 years). The average follow-up was 49.5 months (range, 36-62 months). We observed complications and reoperations. A visual analog scale for pain and the American Orthopaedic Foot & Ankle Society (AOFAS) forefoot score were obtained pre- and postoperation. Component stability and alignment were assessed using weight bearing radiographs. Fluoroscopy was used to determine radiographic MTP-I ROM. RESULTS: Seven (24.1%) patients underwent 1 or more secondary surgeries. Four cases (13.7%) eventually had a conversion to MTP-I arthrodesis. Two patients (3 cases) died from causes not related to the procedure. This left 22 feet in 19 patients for final follow-up. All but 3 remaining prostheses showed stable osteointegration and no migration, but MTP-I alignment showed high variability. The average pain score decreased from 5.9 (range, 3-9) to 1.2 (range, 0-5). The average AOFAS forefoot score increased from 55 (range, 0-80) to 83.5 (range, 58 95). Range of motion initially increased from 37.8 degrees (range, 0-60 degrees) to 88.6 degrees (range, 45-125 degrees) intraoperatively and decreased to 29.0 degrees (range, 11-52 degrees) at latest follow-up. CONCLUSION: Our data suggest that total arthroplasty of MTP-I leads to a high amount of revision surgeries, but the remaining patients had significant pain relief at midterm follow-up. However, we observed high variability regarding the prosthesis component alignment and poor range of motion. LEVEL OF EVIDENCE: Level IV, prospective cohort study. PMID- 26979845 TI - Is caffeine intake a risk factor leading to infertility? A protocol of an epidemiological systematic review of controlled clinical studies. AB - BACKGROUND: Previous studies showed that high dose of caffeine intake may induce some specific human reproductive system diseases, even lead to infertility. OBJECTIVES: In consideration of the high consumption of caffeine according to the latest population-based survey, this review is aimed to systematically review the evidence from all controlled clinical studies of caffeine intake for infertility. DESIGNS: Relevant randomized/quasi-randomized controlled trials, non-randomized clinical studies, cohort studies, and case-control studies will be included in this review. Participants will be either those without a history of infertility who are willing to have a baby (for prospective studies) or infertile patients with confirmed diagnosis (for retrospective studies). Caffeine or caffeine containing beverage will be observed as the exposure factor. The key outcome will be the diagnosis of infertility in participants. All relevant published/unpublished or ongoing studies will be searched from seven databases and four online systems until December 2015. Two authors will screen the literatures and extract the data independently. Methodological quality of the included studies will be assessed by two authors according to either Risk of Bias Assessment or Newcastle-Ottawa Scale. We will use R software to analyze the data. Dose of caffeine will be quantified on a daily basis, and relative risk with their 95 % confidence interval will be measured. If data permit, meta-analysis and dose-response analysis will be conducted. Summary of findings tables will be generated using Guideline Development Tool online. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015015714. PMID- 26979848 TI - [About diagnoses that come and go]. PMID- 26979847 TI - Spatial analysis of visceral leishmaniasis in the oases of the plains of Kashi Prefecture, Xinjiang Uygur Autonomous Region, China. AB - BACKGROUND: Kashi Prefecture of Xinjiang is one of the most seriously affected areas with anthroponotic visceral leishmaniasis in China. A better understanding of space distribution features in this area was needed to guide strategies to eliminate visceral leishmaniasis from highly endemic areas. We performed a spatial analysis using the data collected in Bosh Klum Township in Xinjiang China. METHODS: Based on the report of endemic diseases between 1990 and 2005, three villages with a high number of visceral leishmaniasis cases in Bosh Klum Township were selected. We conducted a household survey to collect the baseline data of kala-azar patients using standard case definitions. The geographical information was recorded with GIS equipment. A binomial distribution fitting test, runs test, and Scan statistical analysis were used to assess the space distribution of the study area. RESULTS: The result of the binomial distribution fitting test showed that the distribution of visceral leishmaniasis cases in local families was inconsistent (chi(2) = 53.23, P < 0.01). The results of runs test showed that the distribution of leishmaniasis infected families along the channel was not random in the group of more than five infected families. The proportion of this kind of group in all infected families was 63.84 % (113 of 177). In the Scan statistical analysis, spatial aggregation was analyzed by poisson model, which found 3 spatial distribution areas 1) Zone A was located in a center point of 76.153447 degrees E, 39.528477 degrees N within its 1.11 mile radius, where the cumulative life-incidence of leishmaniasis was 1.95 times as high as that in surrounding areas (P < 0.05); 2) Zone B was located in a center point of 76.111968 degrees E, 39.531895 degrees N within its 0.54 mile radius, where the cumulative life-incidence of leishmaniasis was 1.82 times as high as that in surrounding areas (P < 0.01); and 3) Zone C was located in a center point of 76.195427 degrees E, 39.563835 degrees N within its 0.68 mile radius, where the cumulative life-incidence of leishmaniasis was 1.31 times as high as that in surrounding areas (P < 0.05). CONCLUSIONS: The spatial distribution of visceral leishmaniasis-infected families was clustered. Thus, the proper use of this finding would be an improvement in highly endemic areas, which could help identify the types of endemic areas and population at high risk and carry out appropriate measures to prevent and control VL in this area as well. PMID- 26979849 TI - [Working effectively towards rehabilitation goals: long-term outcome of a randomised controlled trial of the Boston psychiatric rehabilitation approach]. AB - BACKGROUND: In the Netherlands the Boston psychiatric rehabilitation approach (bpr) is one of the most widely implemented rehabilitation methods. So far, little research has been done on the efficacy of this approach. AIM: To investigate the effect of bpr on the attainment of personal rehabilitation goals, social functioning and empowerment and on care requirements and quality of life in persons with severe mental illness (smi) in the Netherlands. METHOD: In a multicentre randomised controlled trial (rct: CLINICAL TRIAL REGISTRATION NUMBER: isrctn73683215) patients with smi were randomly assigned to bpr (n = 80) or 'care as usual' (cau; n = 76). The primary outcome was the attainment of the rehabilitation goal as formulated by the patient. The secondary outcomes were a change in the work situation and in the degree of independent living, in care requirements (Camberwell Assessment of Needs), in empowerment (Personal Empowerment Scale) and in the quality of life (who-qol). The effects were tested at 12 and 24 months. RESULTS: The degree of goal attainment was substantially higher in bpr at both 12 months (adjusted risk difference: 16%; 95%ci, 2 to 31; nnt = 7) and 24 months (adjusted risk difference: 21%, 95%ci, 4% to 38%; nnt = 5). The approach was also more effective in the area of societal participation (bpr: 21% adjusted increase, cau: 0% adjusted increase; nnt = 5), but not in the other secondary outcome measures. CONCLUSION: The results suggest that bpr is effective in supporting patients with smi to reach self-formulated rehabilitation goals and in enhancing their societal participation. PMID- 26979850 TI - [The general practitioner in charge of treatment of patients with bipolar disorder: an exploratory study]. AB - BACKGROUND: The role of the general practitioner (gp) in the treatment of severe psychiatric disorders, including bipolar disorder (bd), is under discussion. AIM: To investigate how many patients with a recognised bd are being treated for their illness exclusively in the setting of primary care and to find out how many patients are registrated as having bd on their gp's file. METHOD: We made an exploratory study in a gp's database containing data for 14,254 Dutch adult patients in the Amsterdam over a period of 3.5 years (2010-2013). RESULTS: We found that the gp was in charge of the treatment of bd in less than one patient per practice. The percentage of patients officially recognised as having bd in the database we studied was 0.15%, a percentage that is much lower than the percentage of bd in the Dutch population as a whole. There are several possible explanations for this discrepancy. CONCLUSION: Given these low numbers, it is unlikely that the gps can have adequate experience of giving their bd patients the latest type of treatment. In view of the increasing role played by gps in the treatment of bd, it is important that there is strong collaboration with specialised mental health care, and that a low threshold prevails for consultation and referral. PMID- 26979851 TI - [Mindfulness-based cognitive therapy for patients with somatoform disorders]. AB - BACKGROUND The daily lives of patients with somatoform disorders are often severely impaired by the symptoms of their illness. Cognitive behavioural therapy has proved to be an effective treatment for somatoform disorders. However, patients with these disorders are often reluctant to consult a psychologist for their physical symptoms. Mindfulness-based cognitive therapy (mbct) might be a useful form of treatment because it gives explicit attention to physical experiences and because it has a strong focus on acceptance of symptoms. AIM: To measure the effectiveness and cost-effectiveness of mbct for patients with somatoform disorders and to provide insight into how the therapy can gradually bring about behavioural change. METHOD: In this randomised controlled trial (rct), half of the participants (n=61) received mbct and the other half (n=56) received usual care. Participants belonged to the 10% of patients who visited primary care practitioners the most frequently; they had unexplained medical symptoms for at least six months. The primary outcomes were health status and mental and physical functioning. Measurements were taken at baseline, after 3 months and one year after baseline. In addition, records were kept of the costs involved so that we could obtain insight into health care use. Twelve patients were interviewed extensively at three points in time. RESULTS: Although the health status and the physical functioning were almost the same in the two conditions, the mental functioning improved in the patients who had attended mbct with an effect size of 0.3. At three months past baseline vitality and social functioning were significantly higher in the mindfulness condition than in the control condition. There was no significant difference between the total healthcare costs in the two conditions. The use of hospital care was lower in the mbct condition. At the same time, however, greater use was made of mental health care in the mbct condition. The interview study enabled us to establish a process of change. As a result of this process, patients focused less on short-term symptom reduction and more on the acceptance of their symptoms and on self-care. CONCLUSION: With the improvement that occurred in patients' mental functioning, we conclude that mbct is a meaningful therapy for patients with somatoform disorders. The fact that patients increased their use of mental health care after mbct could indicate that patients with somatoform disorders become more willing to receive mental health care. PMID- 26979852 TI - [Moral case deliberation: time for ethical reflection in the daily practice of mental health care]. AB - BACKGROUND: Nowadays, reflecting on ethics, which we choose to call moral case deliberation, is occurring more and more frequently in psychiatric institutions. We have personal experience of organising and supervising moral case deliberation in a large psychiatric institute and we can confirm the positive effects of moral case deliberation which have been reported in the literature. AIM: To describe a structured method for moral case deliberation which enables care-givers in health care and/or addiction care to reflect on moral dilemmas. METHOD: We refer to the main findings in relevant literature and describe how we developed a structured method for implementing moral case deliberation. RESULTS: Our studies of the literature indicate that systematic reflection about ethical dilemmas can improve the quality of care and make care-givers more satisfied with their work. This is why we have developed our own method which is applicable particularly to psychiatric and/or addition care and which can be used systematically in discussions of moral dilemmas. CONCLUSION: Our method for discussing ethical issues works well in clinical practice, particularly when it is embedded in a multidisciplinary context. Of course, to ensure the continuity of the system, deliberation about moral and ethical issues needs to be financially safeguarded and embedded in the organisation. Discussion of moral issues improves the quality of care and increases care-givers' satisfaction with their work. PMID- 26979853 TI - [The neurotrophic hypothesis of depression]. AB - BACKGROUND: The neurotrophic hypothesis of depression postulates that neuronal plasticity is a key factor in the development of depression and in the clinical response to antidepressants. Brain-derived neurotrophic factor (BDNF) is an important protein in this process. AIM: To provide a survey of the current scientific view regarding the neurotrophic hypothesis of depression. METHOD: We studied the literature using PubMed. RESULTS: The serum bdnf level was found to be consistently lower in depressed patients compared to healthy controls. In short open-label antidepressant treatment trials the bdnf levels were found to be higher post-treatment than pre-treatment. Longitudinal analysis of a large naturalistic cohort study revealed that it was more likely that bdnf serum levels were lower as a result of depression than that they represented an etiological factor for the illness. CONCLUSION: These findings show that the neurotrophic hypothesis of depression is more complex than previously assumed. Animal studies have shown a correlation between stress, diminished bdnf expression in the brain and depressive-like behavior. Studies in humans, on the other hand, particularly those with a longitudinal design, suggest that the decrease in serum bdnf is a consequence of the depression rather than vice versa. This is in sharp contrast to the original assumptions of the neurotrophic hypothesis. PMID- 26979854 TI - [Young adult with psychotic disorders have problems relating to sexuality, intimacy and relationships. An explanatory study based on focus group]. AB - BACKGROUND: Research has shown that young adults with psychotic disorders frequently have problems relating to sexuality, intimacy and relationships. Such problems are often neglected in clinical practice. AIM: To perform a study that explores, on the basis of focus groups, how issues such as sexuality, intimacy and relationships can be addressed as part of the treatment of adolescents suffering from a psychotic disorder. METHOD: We created eight focus groups consisting of clients attending the department of psychotic disorders and caregivers who worked there. The meetings of each focus group were fully transcribed and analysed by means of Nvivo. RESULTS: Clients indicated they wanted to address the topics of sexuality, intimacy and relationships in a group setting. They expressed the wish to have mixed gender groups and decided that in the group discussions the main focus should be on the exchange of personal experiences. CONCLUSION: In our view, it is desirable that psychiatry should pay more attention to the subject of sexuality. By giving adolescents suffering from psychotic disorders the opportunity to discuss their experiences, problems and feelings of insecurity in a group setting and in a low-threshold environment, psychiatrists can greatly improve the quality of care that they provide for their patients. PMID- 26979855 TI - [A girl with foetal valproate syndrome and autism spectrum disorder]. AB - We study the case of a 12-year-old girl who, following intra-uterine exposure to valproate, was diagnosed with foetal valproate syndrome, characterised at birth by dysmorphic features. The use of valproate during pregnancy (because of epilepsy or bipolar disorder) can cause not only structural defects in the growing foetus, but also problems in cognitive development and in adaptive and emotional/behavioural functioning in later life. We evaluate these domains of development in our discussion and suggest several other drugs, less harmful than valproate, which can be used to treat epilepsy or bipolar disorder during pregnancy. PMID- 26979856 TI - [A case-report on catatonia: a prevalent but under-recognised psychiatric illness]. AB - We describe the case of a 63-year-old female patient with schizoaffective disorder who spent more than two months in two different psychiatric wards because of an unrecognised psychiatric illness. Ultimately, the patient was referred to the psychiatric ward of the university hospital where she was treated for catatonia with electroconvulsive therapy (ect). Three treatments with ect led to a full recovery of the patient. PMID- 26979857 TI - [Psyche, psychiatric and 'psycho-']. PMID- 26979859 TI - Characterization and Application of BiLA, a Psychrophilic alpha-Amylase from Bifidobacterium longum. AB - In this study, a novel alpha-amylase was cloned from Bifidobacterium longum and named BiLA. The enzyme exhibited optimal activity at 20 degrees C and a pH value of 5.0. Kinetic analysis using various carbohydrate substrates revealed that BiLA had the highest k(cat/)K(m) value for amylose. Interestingly, analysis of the enzymatic reaction products demonstrated that BiLA specifically catalyzed the hydrolysis of oligosaccharides and starches up to G5 from the nonreducing ends. To determine whether BiLA can be used to generate slowly digestible starch (SDS), starch was treated with BiLA, and the kinetic parameters were analyzed using porcine pancreatic alpha-amylase (PPA) and amyloglucosidase (AMG). Compared to normal starch, BiLA-treated starch showed lower k(cat)/K(m) values with PPA and AMG, suggesting that BiLA is a potential candidate for the production of SDS. PMID- 26979858 TI - [Reaction on 'Functional remission of people with serious mental illness' and 'Functional recovery and self-regulation']. PMID- 26979860 TI - Species differences in the pharmacokinetics of cefadroxil as determined in wildtype and humanized PepT1 mice. AB - PepT1 (SLC15A1) is a high-capacity low-affinity transporter that is important in the absorption of digested di/tripeptides from dietary protein in the small intestine. PepT1 is also crucial for the intestinal uptake and absorption of therapeutic agents such as the beta-lactam aminocephalosporins and antiviral prodrugs. Species differences, however, have been observed in PepT1-mediated intestinal absorption and pharmacokinetics, thereby, making it more difficult to predict systemic drug exposure. In the present study, we evaluated the in situ intestinal permeability of the PepT1 substrate cefadroxil in wildtype and humanized PepT1 (huPepT1) mice, and the in vivo absorption and disposition of drug after escalating oral doses. The in situ perfusions indicated that cefadroxil had a twofold higher affinity (i.e., twofold lower Km) for jejunal PepT1 in huPepT1 mice, lower but substantial permeability in all regions of the small intestine, and low but measureable permeability in the colon as compared to wildtype animals. The in vivo experiments indicated almost superimposable pharmacokinetic profiles between the two genotypes after intravenous bolus dosing of cefadroxil. In contrast, after oral dose escalation, the systemic exposure of cefadroxil was reduced in huPepT1 mice as compared to wildtype animals. Moreover, the AUC and Cmax versus dose relationships were nonlinear for huPepT1 but not wildtype mice, and similar to that observed from human subjects. In conclusion, our findings indicate that huPepT1 mice may provide a valuable tool in the drug discovery process by better predicting the oral pharmacokinetic profiles of PepT1 substrates in humans. PMID- 26979863 TI - Early Fiber Number Ratio Is a Surrogate of Corticospinal Tract Integrity and Predicts Motor Recovery After Stroke. AB - BACKGROUND AND PURPOSE: The contribution of imaging metrics to predict poststroke motor recovery needs to be clarified. We tested the added value of early diffusion tensor imaging (DTI) of the corticospinal tract toward predicting long term motor recovery. METHODS: One hundred seventeen patients were prospectively assessed at 24 to 72 hours and 1 year after ischemic stroke with diffusion tensor imaging and motor scores (Fugl-Meyer). The initial fiber number ratio (iFNr) and final fiber number ratio were computed as the number of streamlines along the affected corticospinal tract normalized to the unaffected side and were compared with each other. The prediction of motor recovery (DeltaFugl-Meyer) was first modeled using initial Fugl-Meyer and iFNr. Multivariate ordinal logistic regression models were also used to study the association of iFNr, initial Fugl Meyer, age, and stroke volume with Fugl-Meyer at 1 year. RESULTS: The iFNr correlated with the final fiber number ratio at 1 year (r=0.70; P<0.0001). The initial Fugl-Meyer strongly predicted motor recovery (~73% of initial impairment) for all patients except those with initial severe stroke (Fugl-Meyer<50). For these severe patients (n=26), initial Fugl-Meyer was not correlated with motor recovery (R(2)=0.13; p=ns), whereas iFNr showed strong correlation (R(2)=0.56; P<0.0001). In multivariate analysis, the iFNr was an independent predictor of motor outcome (beta=2.601; 95% confidence interval=0.304-5.110; P=0.031), improving prediction compared with using only initial Fugl-Meyer, age, and stroke volume (P=0.026). CONCLUSIONS: Early measurement of FNr at 24 to 72 hours poststroke is a surrogate marker of corticospinal tract integrity and provides independent prediction of motor outcome at 1 year especially for patients with severe initial impairment. PMID- 26979862 TI - Does Diffusion Lesion Volume Above 70 mL Preclude Favorable Outcome Despite Post Thrombolysis Recanalization? AB - BACKGROUND AND PURPOSE: Whether to withhold recanalization treatment when the diffusion-weighted imaging (DWI) lesion exceeds a given volume is unsettled. Our aim was to assess the impact of recanalization on outcome in patients with baseline DWI lesion >=70 mL (DWI>=70 mL) treated <=4.5 hours from onset. We hypothesized that recanalization is beneficial in a sizeable fraction of these patients and that this is associated with a larger DWI lesion reversal. METHODS: We analyzed 267 consecutive patients treated with intravenous recombinant tissue type plasminogen activator for middle cerebral artery territory stroke in whom an occlusion was present on magnetic resonance angiography and 24-hour recanalization and 90-day clinical outcome could be assessed. After stratification relative to the 70-mL DWI lesion cut point, we calculated the odds ratio for recanalization of the primary arterial occlusive lesion (AOL score >=2) to predict favorable outcome (modified Rankin scale score <=2). DWI lesion reversal was compared between recanalizers with DWI>=70 mL with favorable and unfavorable outcomes. RESULTS: Median (interquartile range) DWI lesion volume was 22 mL (10-60), and median onset time to imaging was 116 minutes (86-151). Twelve (22%) of the 54 patients with DWI>=70 mL experienced favorable outcome, of which 9 had recanalized. In patients with DWI>=70 mL, recanalization was significantly associated with favorable outcome after adjustment for age and National Institutes of Health Stroke Scale (odds ratio =4.72 [1.09-20.32]; P=0.0375). Among recanalizers with DWI>=70 mL, absolute and relative DWI reversal volumes were larger in those with favorable as compared with unfavorable outcome (18.8 mL [12.2-47.6] versus 8.5 mL [4.3-31.1]; P=0.17; and 19.6% [10.9-62.8] versus 8.7% [3.9-16.5], respectively; P=0.049). CONCLUSIONS: Patients with DWI lesion volume >=70 mL can benefit from recanalization after intravenous recombinant tissue-type plasminogen activator. This may partly reflect a larger amount of DWI lesion reversal. PMID- 26979861 TI - Hepatitis B virus receptors and molecular drug targets. AB - Chronic hepatitis B virus (HBV) infection is a leading cause of liver disease worldwide. Virus-induced diseases include cirrhosis, liver failure and hepatocellular carcinoma. Current therapeutic strategies may at best control infection without reaching cure. Complementary antiviral strategies aimed at viral cure are therefore urgently needed. HBV entry is the first step of the infection cycle, which leads to the formation of cccDNA and the establishment of chronic infection. Viral entry may thus represent an attractive target for antiviral therapy. This review summarizes the molecular virology and cell biology of HBV entry, including the discovery and development of new HBV entry inhibitors, and discusses their potential in future treatment of HBV infection. PMID- 26979866 TI - Sumoylation of LYS590 of NCX3 f-Loop by SUMO1 Participates in Brain Neuroprotection Induced by Ischemic Preconditioning. AB - BACKGROUND AND PURPOSE: The small ubiquitin-like modifier (SUMO), a ubiquitin like protein involved in posttranslational protein modifications, is activated by several conditions, such as heat stress, hypoxia, and hibernation and confers neuroprotection. Sumoylation enzymes and substrates are expressed also at the plasma membrane level. Among the numerous plasma membrane proteins controlling ionic homeostasis during cerebral ischemia, 1 of the 3 brain sodium/calcium exchangers (NCX3), exerts a protective role during ischemic preconditioning. In this study, we evaluated whether NCX3 is a target for sumoylation and whether this posttranslational modification participates in ischemic preconditioning induced neuroprotection. To test these hypotheses, we analyzed (1) SUMO1 conjugation pattern after ischemic preconditioning; (2) the effect of SUMO1 knockdown on the ischemic damage after transient middle cerebral artery occlusion and ischemic preconditioning, (3) the possible interaction between SUMO1 and NCX3 and (4) the molecular determinants of NCX3 sequence responsible for sumoylation. METHODS: Focal brain ischemia and ischemic preconditioning were induced in rats by middle cerebral artery occlusion. SUMOylation was evaluated by western blot and immunohistochemistry. SUMO1 and NCX3 interaction was analyzed by site directed mutagenesis and immunoprecipitation assay. RESULTS: We found that (1) SUMO1 knockdown worsened ischemic damage and reduced the protective effect of preconditioning; (2) SUMO1 bound to NCX3 at lysine residue 590, and its silencing increased NCX3 degradation; and (3) NCX3 sumoylation participates in SUMO1 protective role during ischemic preconditioning. Thus, our results demonstrate that NCX3 sumoylation confers additional neuroprotection in ischemic preconditioning. CONCLUSIONS: Finally, this study suggests that NCX3 sumoylation might be a new target to enhance ischemic preconditioning-induced neuroprotection. PMID- 26979865 TI - Exendin-4 Inhibits Matrix Metalloproteinase-9 Activation and Reduces Infarct Growth After Focal Cerebral Ischemia in Hyperglycemic Mice. AB - BACKGROUND AND PURPOSE: Admission hyperglycemia is an independent risk factor for poor outcome of ischemic stroke. Amelioration of hyperglycemia by insulin has not been shown to improve the poststroke outcome. Glucagon-like peptide 1 receptor agonists, which modulate glucose levels by stimulating insulin secretion, have been shown to exert cytoprotective effects by inhibiting inflammation and oxidative stress. This study aimed to evaluate whether the glucagon-like peptide 1 receptor agonist exendin-4 could reduce glucose levels and exert protective effects after acute focal ischemia in hyperglycemic mice. METHODS: Hyperglycemia was induced by intraperitoneal injection of dextrose 15 minutes before transient middle cerebral artery occlusion was performed for 60 minutes using an intraluminal thread. We assessed 4 groups: (1) normal glucose (vehicle control), (2) induced hyperglycemia, (3) induced hyperglycemia with insulin treatment, and (4) induced hyperglycemia with exendin-4 treatment. Neurovascular injuries in brains from each group were evaluated 24 hours and 7 days post ischemia. RESULTS: Hyperglycemia significantly increased infarct volume (36.3+/-1.20 versus 26.9+/ 1.28; P<0.001), brain edema (P<0.05), and hemorrhagic transformation compared with control (P<0.001). This increase in infarct volume was associated with increased blood-brain barrier disruption and matrix metalloproteinase-9 activation. Exendin-4, but not insulin, attenuated matrix metalloproteinase-9 activation, proinflammatory cytokine (tumor necrosis factor-alpha) release, and biomarkers of oxidative stress and showed significant inhibition of infarct growth at 24 hours (23.6+/-0.97 versus 36.3+/-1.20; P<0.001) and at 7 days after ischemia (21.0+/-0.92 versus 29.3+/-1.41; P<0.001). CONCLUSIONS: Treatment with exendin-4 could be a potentially useful therapeutic option for treatment of acute ischemic stroke with transient hyperglycemia. PMID- 26979864 TI - Paracetamol, Ibuprofen, and Recurrent Major Cardiovascular and Major Bleeding Events in 19 120 Patients With Recent Ischemic Stroke. AB - BACKGROUND AND PURPOSE: The presumed safety of paracetamol in high-cardiovascular risk patients has been questioned. We determined whether paracetamol or ibuprofen use is associated with major cardiovascular events (MACE) or major bleeding in 19 120 patients with recent ischemic stroke or transient ischemic attack of mainly atherothrombotic origin included in the Prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) trial. METHODS: We performed 2 nested case-control analysis (2153 cases with MACE during trial follow-up and 4306 controls matched on Essen stroke risk score; 809 cases with major bleeding matched with 1616 controls) and a separate time-varying analysis. RESULTS: 12.3% were prescribed paracetamol and 2.5% ibuprofen. Median duration of treatment was 14 (interquartile range 5-145) days for paracetamol and 9 (5-30) days for ibuprofen. Paracetamol, but not ibuprofen, was associated with increased risk of MACE (odds ratio 1.21, 95% confidence interval [CI] 1.04-1.42) or a major bleeding (odds ratio 1.60, 95% CI 1.26-2.03), with no impact of daily dose and duration of paracetamol treatment. Time-varying analysis found an increased risk of MACE with both paracetamol (hazard ratio 1.22, 95% CI 1.05-1.43) and ibuprofen (hazard ratio 1.47, 95% CI 1.06-2.03) and of major bleeding with paracetamol (hazard ratio 1.95, 95% CI 1.45-2.62). CONCLUSIONS: There was a weak and inconsistent signal for association between paracetamol or ibuprofen and MACE or major bleeding, which may be related to either a genuine but modest effect of these drugs or to residual confounding. CLINICAL TRIAL REGISTRATION: http://www.isrctn.com. Unique identifier: ISRCTN66157730. PMID- 26979867 TI - Retinal Microvascular Calibers Are Associated With Enlarged Perivascular Spaces in the Brain. AB - BACKGROUND AND PURPOSE: Perivascular enlargement in the brain is a putative imaging marker for microvascular brain damage, but this link has not yet been confirmed using direct in vivo visualization of small vessels. We investigated the relation between microvascular calibers on retinal imaging and enlarged perivascular spaces (ePVSs) on brain magnetic resonance imaging. METHODS: We included 704 participants from the Rotterdam study. Retinal arteriolar and venular calibers were measured semiautomatically on fundus photographs. ePVSs were counted in the centrum semiovale, basal ganglia, hippocampus, and mesencephalon, using a standardized rating method. We determined the association between retinal microvascular calibers and ePVSs with negative binomial regression models, adjusting for age, sex, the other vascular caliber, structural brain magnetic resonance imaging markers, and cardiovascular risk factors. RESULTS: Both narrower arteriolar and wider venular calibers were associated with more ePVSs in the centrum semiovale and hippocampal region. Rate ratios (95% confidence interval) for arterioles in the centrum semiovale and hippocampus were 1.07 (1.01-1.14) and 1.13 (1.04-1.22), respectively, and for venules 1.08 (1.01 1.16) and 1.09 (1.00-1.18), respectively. These associations were independent from other brain magnetic resonance imaging markers and cardiovascular risk factors. CONCLUSIONS: Retinal microvascular calibers are related to ePVSs, confirming the putative link between microvascular damage and ePVSs. PMID- 26979868 TI - Role of the blood smear in febrile returning travelers: Beyond malaria. PMID- 26979872 TI - epic3: revised recommendation for intravenous catheter and catheter site care. PMID- 26979869 TI - Multiple inflammasome complexes are activated in autistic spectrum disorders. AB - BACKGROUND: Inflammasomes are multimeric protein platforms involved in the regulation of inflammatory responses whose activity results in the production of proinflammatory cytokines. Because neuroinflammation is observed in autistic spectrum disorders (ASD), a neurologic condition of childhood resulting in a complex behavioural impairment, we analyzed the inflammasomes activity in ASD. Additionally we verified whether alterations of the gastrointestinal (GI) barriers might play a role in inflammasomes activation. METHODS: The activity of the inflammasomes, the concentration of the inflammasomes-derived proinflammatory cytokines interleukin (IL)-1beta and IL-18, and serum parameters of GI damage were analyzed in 25 ASD children, 23 healthy siblings (HS) and 30 unrelated age matched healthy controls (HC). RESULTS: A significant upregulation of the AIM2 and the NLRP3 inflammasomes and an increased production of IL-1beta and IL-18 that was associated with a consistent reduction of IL-33, an anti inflammation cytokine were observed in ASD alone. Notably, in a possible immune-mediated attempt to dampen inflammation, IL-37, a suppressor of innate inflammatory responses, was significantly augmented in these same children. Finally, intestinal fatty acid binding protein (IFABP), an index of altered GI permeability, was significantly increased in serum of ASD and HS. CONCLUSIONS: These results show that the inflammasomes are activated in ASD and shed light on the molecular mechanisms responsible for ASD-associated neuroinflammation. The observation that GI alterations could be present as well in ASD offers a possible link between such alterations and neuroinflammation. Therapeutic strategies targeting inflammasome activation could be useful in ASD. PMID- 26979871 TI - Transcriptional profiling of Klebsiella pneumoniae defines signatures for planktonic, sessile and biofilm-dispersed cells. AB - BACKGROUND: Surface-associated communities of bacteria, known as biofilms, play a critical role in the persistence and dissemination of bacteria in various environments. Biofilm development is a sequential dynamic process from an initial bacterial adhesion to a three-dimensional structure formation, and a subsequent bacterial dispersion. Transitions between these different modes of growth are governed by complex and partially known molecular pathways. RESULTS: Using RNA seq technology, our work provided an exhaustive overview of the transcriptomic behavior of the opportunistic pathogen Klebsiella pneumoniae derived from free living, biofilm and biofilm-dispersed states. For each of these conditions, the combined use of Z-scores and principal component analysis provided a clear illustration of distinct expression profiles. In particular, biofilm-dispersed cells appeared as a unique stage in the bacteria lifecycle, different from both planktonic and sessile states. The K-means cluster analysis showed clusters of Coding DNA Sequences (CDS) and non-coding RNA (ncRNA) genes differentially transcribed between conditions. Most of them included dominant functional classes, emphasizing the transcriptional changes occurring in the course of K. pneumoniae lifestyle transitions. Furthermore, analysis of the whole transcriptome allowed the selection of an overall of 40 transcriptional signature genes for the five bacterial physiological states. CONCLUSIONS: This transcriptional study provides additional clues to understand the key molecular mechanisms involved in the transition between biofilm and the free-living lifestyles, which represents an important challenge to control both beneficial and harmful biofilm. Moreover, this exhaustive study identified physiological state specific transcriptomic reference dataset useful for the research community. PMID- 26979875 TI - Multiscale entropy identifies differences in complexity in postural control in women with multiple sclerosis. AB - Loss of postural center-of-pressure complexity (COP complexity) has been associated with reduced adaptability that accompanies disease and aging. The aim of this study was to identify if COP complexity is reduced: (1) in those with Multiple Sclerosis (MS) compared to controls; (2) when vision is limited compared to remaining intact; and (3) during more demanding postural conditions compared to quiet standing. Additionally, we explored the relationship between the COP complexity and disease severity, fatigue, cutaneous sensation and central motor drive. Twelve women with MS and 12 age-matched controls were tested under quiet standing and postural maximal lean conditions with normal and limited vision. The key dependent variable was the complexity index (CI) of the center of pressure. We observed a lower CI in the MS group compared to controls in both anterior posterior (AP) and medio-lateral (ML) directions (p's<0.002), during the performance of maximal self-regulated leans (AP: p<0.001; ML: p=0.018), and under limited vision (AP: p=0.001; ML: p=0.006). No group-by-vision interaction (p>0.05) was observed, indicating that limiting vision did not impact COP complexity differently in the two groups. Decreased cutaneous sensitivity was associated with lower CI values in the AP direction among those with MS (r(2)=0.57); all other measures did not exhibit significant relationships. The findings reported here suggest that (1) MS is associated with diminished COP complexity under both normal and challenging postures, and (2) complexity is strongly correlated with cutaneous sensitivity, suggesting the unique contribution of impaired somatosensation on postural control deficits in persons with MS. PMID- 26979870 TI - Systemic delivery of siRNA by actively targeted polyion complex micelles for silencing the E6 and E7 human papillomavirus oncogenes. AB - Human papillomavirus (HPV) E6 and E7 oncogenes are essential for the immortalization and maintenance of HPV-associated cancer and are ubiquitously expressed in cervical cancer lesions. Small interfering RNA (siRNA) coding for E6 and E7 oncogenes is a promising approach for precise treatment of cervical cancer, yet a delivery system is required for systemic delivery to solid tumors. Here, an actively targeted polyion complex (PIC) micelle was applied to deliver siRNAs coding for HPV E6/E7 to HPV cervical cancer cell tumors in immune incompetent tumor-bearing mice. A cell viability assay revealed that both HPV type 16 and 18 E6/E7 siRNAs (si16E6/E7 and si18E6/E7, respectively) interfered with proliferation of cervical cancer cell lines in an HPV type-specific manner. A fluorescence imaging biodistribution analysis further revealed that fluorescence dye-labeled siRNA-loaded PIC micelles efficiently accumulated within the tumor mass after systemic administration. Ultimately, intravenous injection of si16E6/E7 and si18E6/E7-loaded PIC micelles was found to significantly suppress the growth of subcutaneous SiHa and HeLa tumors, respectively. The specific activity of siRNA treatment was confirmed by the observation that p53 protein expression was restored in the tumors excised from the mice treated with si16E6/E7- and si18E6/E7-loaded PIC micelles for SiHa and HeLa tumors, respectively. Therefore, the actively targeted PIC micelle incorporating HPV E6/E7-coding siRNAs demonstrated its therapeutic potential against HPV-associated cancer. PMID- 26979874 TI - Biomechanical and perceived differences between overground and treadmill walking in children with cerebral palsy. AB - The treadmill is widely used as an instrument for gait training and analysis. The primary purpose of this study was to compare biomechanical variables between overground and treadmill walking in children with cerebral palsy (CP). Perceived differences between the two walking modes were also investigated by comparing self-selected walking speeds. Twenty children with CP performed both overground and treadmill walking at a matched speed for biomechanical comparison using a 3-D motion analysis system. In addition, they were asked to select comfortable and fastest walking speeds under each walking condition to compare perceived differences. Significant differences in spatiotemporal variables were found including higher cadence and shorter stride length during treadmill walking at a matched speed (for all, P<.003). The comparison of joint kinematics demonstrated significant differences between overground and treadmill walking, which showed increases in peak angles of ankle dorsi-flexion, knee flexion/extension, and hip flexion (for all, P<.001), increases in ankle and hip excursions and a decrease in pelvic rotation excursion while walking on treadmill (for all, P<.002). Comparison of perceived difference revealed that children with CP chose significantly slower speeds when asked to select their comfortable and fastest walking speeds on the treadmill as compared to overground (for both, P<.001). Our results suggest that these biomechanical and perceived differences should be considered when using a treadmill for gait intervention or assessment. PMID- 26979873 TI - Healing of rotator cuff tendons using botulinum toxin A and immobilization in a rat model. AB - BACKGROUND: We evaluated effects of botulinum toxin A (Botox) and cast immobilization on tendon healing in a rat model. Injection of Botox into rat supraspinatus was hypothesized to reduce muscle active force and improved healing. METHODS: Eighty-four supraspinatus tendons were surgically transected and repaired in 42 Sprague-Dawley rats (transosseous technique). After repair, supraspinatus muscle was injected with saline or Botox (3 or 6 U/kg). Half the shoulders were cast-immobilized for the entire postoperative period; half were allowed free cage activity. Histology was examined at 2, 4, 8, and 12 weeks. A healing zone cross-sectional area was measured, and biomechanical testing of repair strength and tendon viscoelastic properties was conducted at 4 and 12 weeks. RESULTS: Botox alone and cast immobilization alone exhibited increased ultimate load compared with controls (saline injection, no immobilization) at 4 weeks. No difference in ultimate load occurred between Botox-only and cast-only groups. At 12 weeks, the Botox (6 U/kg) plus cast immobilization group was significantly weakest (p < 0.05). A trend was shown toward decreased healing zone cross-sectional areas in casted groups. CONCLUSIONS: Supraspinatus Botox injection after rotator cuff repair might help protect the repair. However, cast immobilization plus Botox administration is harmful to rotator cuff healing in a rat tendon model. PMID- 26979877 TI - Threat-induced changes in attention during tests of static and anticipatory postural control. AB - Postural threat, manipulated through changes in surface height, influences postural control. Evidence suggests changes in attention may contribute to this relationship. However, limited research has explored where and how attention is reallocated when threatened. The primary aim of this study was to describe changes in attention when presented with a postural threat, while a secondary aim was to explore associations between changes in attention and postural control. Eighty-two healthy young adults completed tests of static (quiet standing) and anticipatory (rise to toes) postural control under threatening and non threatening conditions. Participants completed an open-ended questionnaire after each postural task which asked them to list what they thought about or directed their attention toward. Each item listed was assigned a percentage value reflecting how much attention it occupied. Exit interviews were completed to help confirm where attention was directed. Five attention categories were identified: movement processes, threat-relevant stimuli, self-regulatory strategies, task objectives, and task-irrelevant information. For both postural tasks, the percentage values and number of items listed for movement processes, threat relevant stimuli, and self-regulatory strategies increased under threatening compared to non-threatening conditions, while the percentage values and number of items listed for task objectives and task-irrelevant information decreased. Changes in attention related to movement processes and self-regulatory strategies were associated with changes in static postural control, while changes in attention related to threat-relevant stimuli were associated with changes in anticipatory postural control. These results suggest that threat-induced changes in attention are multidimensional and contribute to changes in postural control. PMID- 26979878 TI - Reductions in knee joint forces with weight loss are attenuated by gait adaptations in class III obesity. AB - A consensus exists that high knee joint forces are a precursor to knee osteoarthritis and weight loss reduces these forces. Because large weight loss also leads to increased step length and walking velocity, knee contact forces may be reduced less than predicted by the magnitude of weight loss. The purpose was to determine the effects of weight loss on knee muscle and joint loads during walking in Class III obese adults. We determined through motion capture, force platform measures and biomechanical modeling the effects of weight loss produced by gastric bypass surgery over one year on knee muscle and joint loads during walking at a standard, controlled velocity and at self-selected walking velocities. Weight loss equaling 412 N or 34% of initial body weight reduced maximum knee compressive force by 824 N or 67% of initial body weight when walking at the controlled velocity. These changes represent a 2:1 reduction in knee force relative to weight loss when walking velocity is constrained to the baseline value. However, behavioral adaptations including increased stride length and walking velocity in the self-selected velocity condition attenuated this effect by ~50% leading to a 392 N or 32% initial body weight reduction in compressive force in the knee joint. Thus, unconstrained walking elicited approximately 1:1 ratio of reduction in knee force relative to weight loss and is more indicative of walking behavior than the standard velocity condition. In conclusion, massive weight loss produces dramatic reductions in knee forces during walking but when patients stride out and walk faster, these favorable reductions become substantially attenuated. PMID- 26979876 TI - Effect of calendar age on physical performance: A comparison of standard clinical measures with instrumented measures in middle-aged to older adults. AB - BACKGROUND: Decline in physical performance is highly prevalent during aging. Identification of sensitive markers of age-related changes in physical performance is important for early detection, development of therapeutic strategies and insight into underlying mechanisms. We studied the association of calendar age and familial longevity with standard clinical and instrumented measures of physical performance in a cohort of healthy middle-aged to older adults. METHODS: Cross-sectional analysis within the Leiden Longevity Study consisting of offspring of nonagenarian siblings and their partners (n=300, mean age (SD) 65.3 (6.7) years). Standard clinical measures were 25-meter walking speed and total duration of the chair stand test (CST). Instrumented measures were determined using a body fixed sensor. Dependence of physical performance on calendar age and familial longevity (offspring versus partner status) was analyzed using linear and logistic regression, respectively, adjusted for gender and height. RESULTS: Higher calendar age was associated with slower walking speed and longer duration of the CST (standardized beta (95% CI) -.024 (-.042; -.006) and .035 (.014;.056), respectively). Instrumented measures showed similar effect sizes with strongest associations for gait stability and symmetry in mediolateral direction and for the extension and flexion phase of sit-to-stand and stand-to sit transfers, respectively. No differences were observed between offspring of nonagenarian siblings and their partners. CONCLUSIONS: Standard clinical and instrumented measures of physical performance are associated with similar effect size to age-related changes in physical performance observable from middle age. The potential added value of instrumented measures for understanding underlying mechanisms requires further attention. PMID- 26979879 TI - Vestibular asymmetry increases double support time variability in a counter balanced study on elderly fallers. AB - Vestibular asymmetry is a common cause of dizziness in the elderly, for whom it precipitates the risk of falling. Previous studies have shown that those with vestibular asymmetry displayed an altered variability in double support time (DST) compared to controls. However, swing time (SwT) variability findings are conflicting. In this study, we investigated if vestibular asymmetry might be causally connected to increased DST variability. We studied a group of eight elderly fallers with wrist fractures across three months, during which time four of them regained vestibular symmetry while four others developed an asymmetry. We evaluated the variability of DST and SwT, both when the participants suffered from vestibular asymmetry and when they did not. On average, variability in DST was significantly greater by 2.38%CV (coefficient of variation) when participants scored positive for vestibular asymmetry compared to when not, t(5)=4.39, p=0.01, xi=1.67. In contrast, SwT variability differed non-significantly by 0.44%CV when participants had tested positive versus negative for vestibular asymmetry, t(5)= 0.87, p=0.39, xi=-0.29. As a possible rationale for our results, we propose that increased DST variability may be the result of a re-stabilization strategy. Further research on DST variability and its correlation to the duration of vestibular asymmetry is recommended. PMID- 26979881 TI - Variability of gait, bilateral coordination, and asymmetry in women with fibromyalgia. AB - PURPOSE: To analyze how fibromyalgia affected the variability, asymmetry, and bilateral coordination of gait walking at comfortable and fast speeds. METHODS: 65 fibromyalgia (FM) patients and 50 healthy women were analyzed. Gait analysis was performed using an instrumented walkway (GAITRite system). Average walking speed, coefficient of variation (CV) of stride length, swing time, and step width data were obtained and bilateral coordination and gait asymmetry were analyzed. RESULTS: FM patients presented significantly lower speeds than the healthy group. FM patients obtained significantly higher values of CV_StrideLength (p=0.04; p<0.001), CV_SwingTime (p<0.001; p<0.001), CV_StepWidth (p=0.004; p<0.001), phase coordination index (p=0.01; p=0.03), and p_CV (p<0.001; p=0.001) than the control group, walking at comfortable or fast speeds. Gait asymmetry only showed significant differences in the fast condition. CONCLUSION: FM patients walked more slowly and presented a greater variability of gait and worse bilateral coordination than healthy subjects. Gait asymmetry only showed differences in the fast condition. The variability and the bilateral coordination were particularly affected by FM in women. Therefore, variability and bilateral coordination of gait could be analyzed to complement the gait evaluation of FM patients. PMID- 26979884 TI - The effect of weight-bearing asymmetry on dynamic postural stability in healthy young individuals. AB - BACKGROUND: In people with lateralized disorders, such as stroke, Weight-Bearing Asymmetry (WBA) is common. It is associated with postural instability, however, WBA is one of several abnormalities that may affect postural stability in these disorders. Therefore, we investigated the isolated effects of WBA on dynamic postural stability in healthy individuals. METHODS: Ten young participants were subjected to multidirectional stance perturbations by support surface translations at three levels of WBA (0, 10 and 20% of body weight unloading of one leg). The stepping threshold was determined iteratively for each condition and in four perturbation directions (forward, backward, leftward and rightward). The stepping threshold was defined as the highest perturbation intensity recovered from with a feet-in-place response. The Margin of Stability (MOS) at the stepping threshold was defined as the smallest distance between the vertical projection of the Extrapolated Center of Mass (XCOM) and the edge of the base of support. RESULTS: WBA decreased the stepping threshold (stability decreased) for perturbations towards the loaded side (translations towards the unloaded side), whereas it increased stepping thresholds for perturbations towards the unloaded side. No significant effects of WBA were found on the MOS. WBA increased the frequency of stepping with the unloaded leg upon forward and backward perturbations. CONCLUSION: WBA increased dynamic stability towards the unloaded leg following external balance perturbations and resulted in a greater probability of stepping with this leg. Future studies are needed to evaluate the functional significance of these WBA-related effects on postural stability in people with lateralized disorders. PMID- 26979880 TI - Ankle muscle coactivation during gait is decreased immediately after anterior weight shift practice in adults after stroke. AB - Increased ankle muscle coactivation during gait has frequently been observed as an adaptation strategy to compensate for postural instability in adults after stroke. However, it remains unclear whether the muscle coactivation pattern increases or decreases after balance training. The aim of this study was to investigate the immediate effects of balance practice on ankle muscle coactivation during gait in adults after stroke. Standing balance practice performed to shift as much weight anteriorly as possible in 24 participants after stroke. The forward movement distance of the center of pressure (COP) during anterior weight shifting, gait speed, and ankle muscle activities during 10-m walking tests were measured immediately before and after balance practice. Forward movement of the COP during anterior weight shifting and gait speed significantly increased after balance practice. On the paretic side, tibialis anterior muscle activity significantly decreased during the single support and second double support phases, and the coactivation index at the ankle joint during the first double support and single support phases significantly decreased after balance practice. However, there were no significant relationships between the changes in gait speed, forward movement of the COP during anterior weight shifting, and ankle muscle coactivation during the stance phase. These results suggested that ankle muscle coactivation on the paretic side during the stance phase was decreased immediately after short-term anterior weight shift practice, which was not associated with improved gait speed or forward movement of the COP during anterior weight shifting in adults after stroke. PMID- 26979882 TI - In-shoe plantar pressure measurements for the evaluation and adaptation of foot orthoses in patients with rheumatoid arthritis: A proof of concept study. AB - OBJECTIVES: Improving foot orthoses (FOs) in patients with rheumatoid arthritis (RA) by using in-shoe plantar pressure measurements seems promising. The objectives of this study were to evaluate (1) the outcome on plantar pressure distribution of FOs that were adapted using in-shoe plantar pressure measurements according to a protocol and (2) the protocol feasibility. METHODS: Forty-five RA patients with foot problems were included in this observational proof-of concept study. FOs were custom-made by a podiatrist according to usual care. Regions of Interest (ROIs) for plantar pressure reduction were selected. According to a protocol, usual care FOs were evaluated using in-shoe plantar pressure measurements and, if necessary, adapted. Plantar pressure-time integrals at the ROIs were compared between the following conditions: (1) no-FO versus usual care FO and (2) usual care FO versus adapted FO. Semi-structured interviews were held with patients and podiatrists to evaluate the feasibility of the protocol. RESULTS: Adapted FOs were developed in 70% of the patients. In these patients, usual care FOs showed a mean 9% reduction in pressure-time integral at forefoot ROIs compared to no-FOs (p=0.01). FO adaptation led to an additional mean 3% reduction in pressure-time integral (p=0.05). The protocol was considered feasible by patients. Podiatrists considered the protocol more useful to achieve individual rather than general treatment goals. A final protocol was proposed. CONCLUSIONS: Using in-shoe plantar pressure measurements for adapting foot orthoses for patients with RA leads to a small additional plantar pressure reduction in the forefoot. Further research on the clinical relevance of this outcome is required. PMID- 26979885 TI - Dynamically adjustable foot-ground contact model to estimate ground reaction force during walking and running. AB - Human dynamic models have been used to estimate joint kinetics during various activities. Kinetics estimation is in demand in sports and clinical applications where data on external forces, such as the ground reaction force (GRF), are not available. The purpose of this study was to estimate the GRF during gait by utilizing distance- and velocity-dependent force models between the foot and ground in an inverse-dynamics-based optimization. Ten males were tested as they walked at four different speeds on a force plate-embedded treadmill system. The full-GRF model whose foot-ground reaction elements were dynamically adjusted according to vertical displacement and anterior-posterior speed between the foot and ground was implemented in a full-body skeletal model. The model estimated the vertical and shear forces of the GRF from body kinematics. The shear-GRF model with dynamically adjustable shear reaction elements according to the input vertical force was also implemented in the foot of a full-body skeletal model. Shear forces of the GRF were estimated from body kinematics, vertical GRF, and center of pressure. The estimated full GRF had the lowest root mean square (RMS) errors at the slow walking speed (1.0m/s) with 4.2, 1.3, and 5.7% BW for anterior posterior, medial-lateral, and vertical forces, respectively. The estimated shear forces were not significantly different between the full-GRF and shear-GRF models, but the RMS errors of the estimated knee joint kinetics were significantly lower for the shear-GRF model. Providing COP and vertical GRF with sensors, such as an insole-type pressure mat, can help estimate shear forces of the GRF and increase accuracy for estimation of joint kinetics. PMID- 26979887 TI - Temporal-spatial gait parameters and neurodevelopment in very-low-birth-weight preterm toddlers at 18-22 months. AB - Children born preterm with very-low birth-weight (VLBW) have increased risk of motor impairment. Early identification of impairment guides treatment to improve long-term function. Temporal-spatial gait parameters are an easily-recorded assessment of gross motor function. The objective of this study was to characterize preterm toddlers' gait and its relationship with neurodevelopment. Velocity, cycle time, step width, step length and time asymmetry, %stance, %single-limb support, and %double-limb support were calculated for 81 VLBW preterm and 43 typically-developing (TD) toddlers. Neurodevelopment was assessed with Bayley Scales of Infant Development-3rd Edition (BSID-III) motor composite and gross motor scores. Mean step width (p=.009) was wider in preterm compared to TD toddlers. Preterm toddlers with <85 BSID-III motor composite scores, indicating mild-to-moderate delay, had significantly increased step width, step length asymmetry, and step time compared to TD toddlers. Step time was also significantly longer for lower-scoring compared to higher-scoring (>=85 BSID-III motor composite scores) preterm toddlers, suggesting that step time may be particularly sensitive to gradations of motor performance. Velocity, cycle time, step length asymmetry, %stance, step length, and step time significantly correlated with BSID-III gross motor scores, suggesting that these parameters may be revealing of gross motor function. The differences in gait between lower scoring preterm toddlers and TD toddlers, together with the correlations between gait and BSID-III motor scores, suggest that temporal-spatial gait parameters may be useful in building a clinically-relevant, easily-conducted assessment of toddler gross motor development. PMID- 26979888 TI - Load distribution and postural changes in young adults when wearing a traditional backpack versus the BackTpack. AB - Backpacks lead to poor posture due to the posterior placement of the load, which overtime may contribute to low back pain and musculoskeletal complications. This study examined postural and load distribution differences between a traditional backpack (BP) and a nontraditional backpack (BTP) in a young adult population. Using a 3D motion analysis system, 24 healthy young adults (22.5 +/- 2.5 years, 12 male) completed both static stance and walking trials on a treadmill with No Load and with 15% and 25% of their body weight using the two different backpacks. There was a significant difference in trunk angle, head angle, and lower extremity joint mechanics between the backpack and load conditions during walking (p<.05). Notably, relative to the No Load condition, trunk angle decreased approximately 14 degrees while head angle increased approximately 13 degrees for the BP 25% state on average. In contrast, average trunk and head angle differences for the BTP 25% state were approximately 7.5 degrees and 7 degrees , respectively. There was also a significant difference in head angle from pre- to post-walk (p<.05) across backpacks, loads, and time. Taken together, the results indicate that the BTP more closely resembled the participants' natural stance and gait patterns as determined by the No Load condition. The more upright posture supported by the BTP may help reduce characteristics of poor posture and, ideally, help to reduce low back pain while carrying loads. PMID- 26979889 TI - A new approach of the Star Excursion Balance Test to assess dynamic postural control in people complaining from chronic ankle instability. AB - The purpose of this study was to quantitatively and qualitatively assess dynamic balance with accuracy in individuals with chronic ankle instability (CAI). To this aim, a motion capture system was used while participants performed the Star Excursion Balance Test (SEBT). Reached distances for the 8 points of the star were automatically computed, thereby excluding any dependence to the experimenter. In addition, new relevant variables were also computed, such as absolute time needed to reach each distance, lower limb ranges of motion during unipodal stance, as well as absolute error of pointing. Velocity of the center of pressure and range of variation of ground reaction forces have also been assessed during the unipodal phase of the SEBT thanks to force plates. CAI group exhibited smaller reached distances and greater absolute error of pointing than the control group (p<0.05). Moreover, the ranges of motion of lower limbs joints, the velocity of the center of pressure and the range of variation of the ground reaction forces were all significantly smaller in the CAI group (p<0.05). These reduced quantitative and qualitative performances highlighted a lower dynamic postural control. The limited body movements and accelerations during the unipodal stance in the CAI group could highlight a protective strategy. The present findings could help clinicians to better understand the motor strategies used by CAI patients during dynamic balance and may guide the rehabilitation process. PMID- 26979883 TI - Influence of non-spatial working memory demands on reach-grasp responses to loss of balance: Effects of age and fall risk. AB - Reactive balance recovery strategies following an unexpected loss of balance are crucial to the prevention of falls, head trauma and other major injuries in older adults. While a longstanding focus has been on understanding lower limb recovery responses, the upper limbs also play a critical role. However, when a fall occurs, little is known about the role of memory and attention shifting on the reach to grasp recovery strategy and what factors determine the speed and precision of this response beyond simple reaction time. The objective of this study was to compare response time and accuracy of a stabilizing grasp following a balance perturbation in older adult fallers compared to non-fallers and younger adults while loading the processing demands of non-spatial, verbal working memory. Working memory was engaged with a progressively challenging verb generation task that was interrupted by an unexpected sideways platform perturbation and a pre-instructed reach to grasp response. Results revealed that the older adults, particularly those at high fall risk, demonstrated significantly increased movement time to handrail contact and grasping errors during conditions in which non-spatial memory was actively engaged. These findings provide preliminary evidence of the cognitive deficit in attention shifting away from an ongoing working memory task that underlies delayed and inaccurate protective reach to grasp responses in older adult fallers. PMID- 26979886 TI - Runners with patellofemoral pain have altered biomechanics which targeted interventions can modify: A systematic review and meta-analysis. AB - Patellofemoral pain (PFP) is the most prevalent running pathology and associated with multi-level biomechanical factors. This systematic review aims to guide treatment and prevention of PFP by synthesising prospective, observational and intervention studies that measure clinical and biomechanical outcomes in symptomatic running populations. Medline, Web of Science and CINAHL were searched from inception to April 2015 for prospective, case-control or intervention studies in running-related PFP cohorts. Study methodological quality was scored by two independent raters using the modified Downs and Black or PEDro scales, with meta-analysis performed where appropriate. 28 studies were included. Very limited evidence indicates that increased peak hip adduction is a risk factor for PFP in female runners, supported by moderate evidence of a relationship between PFP and increased peak hip adduction, internal rotation and contralateral pelvic drop, as well as reduced peak hip flexion. Limited evidence was also identified that altered peak force and time to peak at foot level is a risk factor for PFP development. Limited evidence from intervention studies indicates that both running retraining and proximal strengthening exercise lead to favourable outcomes in both pain and function, but only running retraining significantly reduces peak hip adduction, suggesting a possible kinematic mechanism. Put together, these findings highlight limited but coherent evidence of altered biomechanics which interventions can alter with resultant symptom change in females with PFP. There is a clear need for high quality prospective studies of intervention efficacy with measurement of explanatory mechanisms. PMID- 26979890 TI - Biomechanical risk factors for tripping during obstacle--Crossing with the trailing limb in patients with type II diabetes mellitus. AB - People with type II diabetes mellitus (DM) are at a high risk of falling especially during more challenging locomotor tasks such as obstacle-crossing. The current study aimed to identify the risk factors for tripping in these patients during trailing-limb obstacle-crossing. Fourteen patients with type II DM with or without mild peripheral neuropathy (PN) and 14 healthy controls walked and crossed obstacles of three different heights while their motion data were measured using a motion capture system and two forceplates. The DM group was found to cross obstacles with significantly reduced trailing toe clearance (p<0.05), increasing the probability of the foot hitting the obstacle, and thus the risk of tripping. This altered end-point control was associated with significantly reduced knee flexion and hip adduction of the trailing swing limb (p<0.05), as well as significantly increased ankle plantarflexor moments in the leading stance limb (p<0.05). Therefore, reduced knee flexion and hip adduction of the swing limb are identified as risk factors for tripping during obstacle crossing. Increased mechanical demands on the ankle plantarflexors suggest that weakness of these muscles may further reduce the already compromised performance of obstacle-crossing in these patients. The current results showed that obstacle crossing can be used to detect gait deviations and to identify the associated risk of tripping in patients with type II DM without or at an early stage of PN. PMID- 26979891 TI - Estimation of foot trajectory during human walking by a wearable inertial measurement unit mounted to the foot. AB - To establish a supportive technology for reducing the risk of falling in older people, it is essential to clarify gait characteristics in elderly individuals that are possibly linked to the risk of falling during actual daily activities. In this study, we developed a system to monitor human gait in an outdoor environment using an inertial measurement unit consisting of a tri-axial accelerometer and tri-axial gyroscope. Step-by-step foot trajectories were estimated from the sensor unit attached to the dorsum of the foot. Specifically, stride length and foot clearance were calculated by integrating the gravity compensated translational acceleration over time during the swing phase. Zero vertical velocity and displacement corrections were applied to obtain the final trajectory, assuming the slope of the walking surface is negligible. Short, normal, and long stride-length walking of 10 healthy participants was simultaneously measured using the proposed system and a conventional motion capture system to evaluate the accuracy of the estimated foot trajectory. Mean accuracy and precision were approximately 20 +/- 50 mm, for stride length, and 2 +/- 7 mm for foot clearance, indicating that the swing phase trajectory of the sensor unit attached to the foot was reconstructed more accurately and precisely using the proposed system than with previously published methods owing to the flat floor assumption. Although some methodological limitations certainly apply, this system will serve as a useful tool to monitor human walking during daily activities. PMID- 26979892 TI - Knee contact forces are not altered in early knee osteoarthritis. AB - OBJECTIVE: This study calculated knee contact forces (KCF) and its relations with knee external knee adduction moments (KAM) and/or flexion moments (KFM) during the stance phase of gait in patients with early osteoarthritis (OA), classified based on early joint degeneration on Magnetic Resonance Imaging (MRI). We aimed at assessing if altered KCF are already present in early structural degeneration. DESIGN: Three-dimensional motion and ground reaction force data in 59 subjects with medial compartment knee OA (N=23 established OA, N=16 early OA, N=20 controls) were used as input for a musculoskeletal model. KAM and KFM, and KCF were estimated using OpenSim software. RESULTS: No significant differences were found between controls and subjects with early OA. In early OA patients, KAM significantly explained 69% of the variance associated with the first peaks KCF but only KFM contributed to the second peaks KCF. The multiple correlation, combining KAM and KFM, showed to be higher. However, only 20% of the variance of second peak KCF was explained by both moments in established OA. CONCLUSION: KCF are not increased in patients with early OA, suggesting that knee joint overload is more a consequence of further joint degeneration in more advanced stages of OA. Additionally, our results clearly show that KAM is not sufficient to predict joint loading at the end of the stance, where KFM contributes substantially to the loading, especially in early OA. PMID- 26979893 TI - Sagittal plane momentum control during walking in elderly fallers. AB - OBJECTIVE: The purpose of this study was to examine sagittal plane momentum control during walking with the use of center of mass (COM) velocity and acceleration. METHODS: COM control in the antero-posterior direction during walking of healthy young and elderly adults, and elderly fallers (n=15/group) was examined. Using a single-link-plus-foot inverted pendulum model, boundaries for the region of stability were determined based on the COM position at toe-off and its instantaneous velocity or the peak acceleration prior to toe-off (ROSv or ROSa, respectively). RESULTS: Although no significant difference in forward COM velocity was detected between healthy young and elderly subjects, the peak forward COM acceleration differed significantly, suggesting age-related differences in momentum control during walking. Elderly fallers demonstrated significantly slower forward COM velocities and accelerations and placed their COM significantly more anterior than healthy young and elderly subjects at toe off, which resulted in their COM position-velocity combination located within the ROSv. Similar results were obtained in the ROSa, where elderly fallers demonstrated a larger stability margin than healthy young and elderly subjects. INTERPRETATIONS: Significantly slower peak COM accelerations could be indicative of a poor momentum control ability, which was more pronounced in elderly fallers. Examining COM acceleration, in addition to its velocity, would provide a greater understanding of person's momentum control, which would allow us to better reveal underlying mechanisms of gait imbalance or falls. PMID- 26979894 TI - Repeatability of muscle synergies within and between days for typically developing children and children with cerebral palsy. AB - Muscle synergies are typically calculated from electromyographic (EMG) signals using nonnegative matrix factorization. Synergies identify weighted groups of muscles that are commonly activated together during a task, such as walking. Synergy analysis has become an emerging tool to evaluate neuromuscular control; however, the repeatability of synergies between trials and days has not been evaluated. The goal of this study was to evaluate the repeatability of synergy complexity and structure in unimpaired individuals and individuals with cerebral palsy (CP). EMG data were collected from eight lower-limb muscles during gait for six typically developing (TD) children and five children with CP on two separate days, over three walking speeds. To evaluate synergy complexity, we calculated the total variance accounted for by one synergy (tVAF1). On a given day, the average range in tVAF1 between gait cycles was 18.2% for TD and 19.1% for CP. The average standard deviation in tVAF1 between gait cycles was 4.9% for TD and 5.0% for CP. Average tVAF1 calculated across gait cycles was not significantly different between days for TD or CP participants. Comparing synergy structure, the average (standard deviation) within day correlation coefficients of synergy weights for two or more synergies were 0.89 (0.15) for TD and 0.88 (0.15) for CP. Between days, the average correlation coefficient of synergy weights for two or more synergies was greater than 0.89 for TD and 0.74 for CP. These results demonstrate that synergy complexity and structure averaged over multiple gait cycles are repeatable between days in both TD and CP groups. PMID- 26979895 TI - Is adult gait less susceptible than paediatric gait to hip joint centre regression equation error? AB - Hip joint centre (HJC) regression equation error during paediatric gait has recently been shown to have clinical significance. In relation to adult gait, it has been inferred that comparable errors with children in absolute HJC position may in fact result in less significant kinematic and kinetic error. This study investigated the clinical agreement of three commonly used regression equation sets (Bell et al., Davis et al. and Orthotrak) for adult subjects against the equations of Harrington et al. The relationship between HJC position error and subject size was also investigated for the Davis et al. set. Full 3-dimensional gait analysis was performed on 12 healthy adult subjects with data for each set compared to Harrington et al. The Gait Profile Score, Gait Variable Score and GDI kinetic were used to assess clinical significance while differences in HJC position between the Davis and Harrington sets were compared to leg length and subject height using regression analysis. A number of statistically significant differences were present in absolute HJC position. However, all sets fell below the clinically significant thresholds (GPS <1.6 degrees , GDI-Kinetic <3.6 points). Linear regression revealed a statistically significant relationship for both increasing leg length and increasing subject height with decreasing error in anterior/posterior and superior/inferior directions. Results confirm a negligible clinical error for adult subjects suggesting that any of the examined sets could be used interchangeably. Decreasing error with both increasing leg length and increasing subject height suggests that the Davis set should be used cautiously on smaller subjects. PMID- 26979896 TI - Lower limb joint forces during walking on the level and slopes at different inclinations. AB - Sloped walking is associated with an increase of lower extremity joint loading compared to level walking. Therefore, the aim of this study was to analyse lower limb joint compression forces as well as tibiofemoral joint shear forces during sloped walking at different inclinations. Eighteen healthy male participants (age: 27.0 +/- 4.7 years, height: 1.80 +/- 0.05 m, mass: 74.5 +/- 8.2 kg) were asked to walk at a pre-set speed of 1.1m/s on a ramp (6 m * 1.5 m) at the slopes of -18 degrees , -12 degrees , -6 degrees , 0 degrees , 6 degrees , 12 degrees and 18 degrees . Kinematic data were captured with a twelve-camera motion capture system (Vicon). Kinetic data were recorded with two force plates (AMTI) imbedded into a ramp. A musculoskeletal model (AnyBody) was used to compute lower limb joint forces. Results showed that downhill walking led to significantly increased hip, tibiofemoral and patellofemoral joint compression forces (p<0.05) and to significantly decreased ankle joint compression forces (p<0.05). Uphill walking significantly increased all lower limb joint compression forces with increasing inclination (p<0.05). Findings that downhill walking is a stressful task for the anterior cruciate ligament could not be supported in the current study, since anterior tibiofemoral joint shear forces did not increase with the gradient. Due to diverse tibiofemoral joint shear force patterns in the literature, results should be treated with caution in general. Finally, lower limb joint force analyses provided more insight in the structure loading conditions during sloped walking than joint moment analyses. PMID- 26979897 TI - Whole-brain grey matter density predicts balance stability irrespective of age and protects older adults from falling. AB - Functional and structural imaging studies have demonstrated the involvement of the brain in balance control. Nevertheless, how decisive grey matter density and white matter microstructural organisation are in predicting balance stability, and especially when linked to the effects of ageing, remains unclear. Standing balance was tested on a platform moving at different frequencies and amplitudes in 30 young and 30 older adults, with eyes open and with eyes closed. Centre of pressure variance was used as an indicator of balance instability. The mean density of grey matter and mean white matter microstructural organisation were measured using voxel-based morphometry and diffusion tensor imaging, respectively. Mixed-effects models were built to analyse the extent to which age, grey matter density, and white matter microstructural organisation predicted balance instability. Results showed that both grey matter density and age independently predicted balance instability. These predictions were reinforced when the level of difficulty of the conditions increased. Furthermore, grey matter predicted balance instability beyond age and at least as consistently as age across conditions. In other words, for balance stability, the level of whole brain grey matter density is at least as decisive as being young or old. Finally, brain grey matter appeared to be protective against falls in older adults as age increased the probability of losing balance in older adults with low, but not moderate or high grey matter density. No such results were observed for white matter microstructural organisation, thereby reinforcing the specificity of our grey matter findings. PMID- 26979899 TI - Development of adaptive sensorimotor control in infant sitting posture. AB - A reliable and adaptive relationship between action and perception is necessary for postural control. Our understanding of how this adaptive sensorimotor control develops during infancy is very limited. This study examines the dynamic visual postural relationship during early development. Twenty healthy infants were divided into 4 developmental groups (each n=5): sitting onset, standing alone, walking onset, and 1-year post-walking. During the experiment, the infant sat independently in a virtual moving-room in which anterior-posterior oscillations of visual motion were presented using a sum-of-sines technique with five input frequencies (from 0.12 to 1.24 Hz). Infants were tested in five conditions that varied in the amplitude of visual motion (from 0 to 8.64 cm). Gain and phase responses of infants' postural sway were analyzed. Our results showed that infants, from a few months post-sitting to 1 year post-walking, were able to control their sitting posture in response to various frequency and amplitude properties of the visual motion. Infants showed an adult-like inverted-U pattern for the frequency response to visual inputs with the highest gain at 0.52 and 0.76 Hz. As the visual motion amplitude increased, the gain response decreased. For the phase response, an adult-like frequency-dependent pattern was observed in all amplitude conditions for the experienced walkers. Newly sitting infants, however, showed variable postural behavior and did not systemically respond to the visual stimulus. Our results suggest that visual-postural entrainment and sensory re-weighting are fundamental processes that are present after a few months post sitting. Sensorimotor refinement during early postural development may result from the interactions of improved self-motion control and enhanced perceptual abilities. PMID- 26979900 TI - Immediate and 1 week effects of laterally wedge insoles on gait biomechanics in healthy females. AB - It is estimated that approximately 45% of the U.S. population will develop knee osteoarthritis, a disease that creates significant economic burdens in both direct and indirect costs. Laterally wedged insoles have been frequently recommended to reduce knee abduction moments and to manage knee osteoarthritis. However, it remains unknown whether the lateral wedge will reduce knee abduction moments over a prolonged period of time. Thus, the purposes of this study were to (1) examine the immediate effects of a laterally wedged insole in individuals normally aligned knees and (2) determine prolonged effects after the insole was worn for 1 week. Gait analysis was performed on ten women with and without a laterally wedged insole. After participants wore the wedges for a week, a second gait analysis was performed with and without the insole. The wedged insole did not affect peak knee abduction moment, although there was a significant increase in knee abduction angular impulse after wearing the insoles for 1 week. Furthermore, there was a significant increase in vertical ground reaction force at the instance of peak knee abduction moment with the wedges. While the laterally wedged insole used in the current study did not alter knee abduction moments as expected, other studies have shown alterations. Future studies should also examine a longer acclimation period, the influence of gait speed, and the effect of different shoe types with the insole. PMID- 26979901 TI - Multiple sclerosis influences the precision of the ankle plantarflexon muscular force production. AB - OBJECTIVE: To quantify the precision of the steady-state isometric control of the ankle plantarflexors musculature of individuals with multiple sclerosis (MS), and to evaluate if the precision is related to the mobility impairments. METHODS: Individuals with MS and healthy adults performed a submaximal steady-state isometric contraction with the ankle plantarflexors. The coefficient of variation was used to assess the amount of variability or error in the precision of the torques generated by the ankle plantarflexor musculature. The participants also walked across a digital mat at their preferred and fast-as-possible walking speeds, which recorded their spatiotemporal gait kinematics. RESULTS: The individuals with MS: (1) had reduced maximal voluntary torques at the ankle, (2) a greater amount of variability in the precision of the isometric ankle torques, (3) altered and more variable spatiotemporal gait kinematics, and (4) a greater amount of variability in the isometric ankle torques were related to a slower walking speed and cadence, shorter step length and a greater amount of gait variability. CONCLUSIONS: These results further fuels the impression that a reduction in control of the ankle joint musculature may be a key factor in the mobility and balance impairments seen in individuals with MS. PMID- 26979903 TI - Walking at the preferred stride frequency minimizes muscle activity. AB - This study determined whether walking at the preferred stride frequency minimizes muscle activity compared with other cadences at the same speed. Anthropometric measurements were recorded from 10 subjects and used to estimate their predicted resonant stride frequency. The preferred walking speed and stride frequency were determined from freely adopted walking on a treadmill. For the experimental trials the treadmill was set at each individual's preferred walking speed. Participants walked for 6 min at eight cadences prescribed by an auditory metronome: preferred stride frequency and -35, -25, -15, 0, +15, +25, +35% of predicted resonant stride frequency. Oxygen consumption was measured via gas analysis. Muscle activity of the right leg gastrocnemius (GA), tibialis anterior (TA), biceps femoris (BF) and rectus femoris (RF) muscles was recorded via electromyography (EMG). On average, participants preferred to walk with a stride frequency .07 Hz lower than their predicted resonant stride frequency, however a strong positive correlation was observed between these variables. Stride frequency had a significant and large quadratic effect on VO2 (RLR(2)=.76), and activity of the GA (RLR(2)=.66), TA (RLR(2)=.83), BF (RLR(2)=.70) and RF (RLR(2)=.78) muscles. VO2, GA and TA activity were all minimal at the preferred stride frequency and increased for faster or slower cadences. BF and RF activity were minimal across a broad range of slow frequencies including the preferred stride frequency and increased for faster frequencies. The preferred stride frequency that humans readily adopt during walking minimizes the activation of the GA, TA, BF and RF muscles, which in turn minimizes the overall metabolic cost. PMID- 26979902 TI - Effects of emotional videos on postural control in children. AB - The link between emotions and postural control has been rather unexplored in children. The objective of the present study was to establish whether the projection of pleasant and unpleasant videos with similar arousal would lead to specific postural responses such as postural freezing, aversive or appetitive behaviours as a function of age. We hypothesized that postural sway would similarly increase with the viewing of high arousal videos in children and adults, whatever the emotional context. 40 children participated in the study and were divided into two groups of age: group 7-9 years (n=23; mean age=8 years +/- 0.7) and group 10-12 years (n=17; mean age=11 years +/- 0.7). 19 adults (mean age=25.8 years +/- 4.4) also took part in the experiment. They viewed emotional videos while standing still on a force platform. Centre of foot pressure (CoP) displacements were analysed. Antero-posterior, medio-lateral mean speed and sway path length increased similarly with the viewing of high arousal movies in the younger, older children, and adults. Our findings suggest that the development of postural control is not influenced by the maturation of the emotional processing. PMID- 26979905 TI - Light finger contact concurrently reduces postural sway and enhances signal detection performance in children with developmental coordination disorder. AB - The current study examined the effects of light finger touch on postural sway and signal detection performance in children with developmental coordination disorder (DCD). Children with DCD (n=30; 18 boys, 12 girls; age=11.87 +/- 0.48 years) and typically developing children (n=30; 14 boys, 16 girls; age=11.73 +/- 0.52 years) were recruited from schools in Pintung County, Taiwan. Participants completed a signal detection task under no finger touch (NT) and light finger touch (LT) conditions, while postural sway in both anteroposterior (AP) and mediolateral (ML) axes was recorded. In both conditions, children with DCD exhibited significantly higher levels of postural sway (p<0.05) and lower signal detection performances (p<0.05) than TDC. Additionally, both groups significantly reduced postural sway (p<0.05) and enhanced signal detection performance (p<0.05) when engaged in light finger touch compared with no finger touch. While the effect of LT on postural sway was greater among TDC relative to children with DCD (p<0.05), the effect of LT on signal detection was greater in children with DCD compared with TDC (p<0.05). These results suggest that light finger touch is effective in concurrently reducing postural sway and enhancing signal detection in both groups. PMID- 26979904 TI - Unilateral hip osteoarthritis: Its effects on preoperative lower limb muscle activation and intramuscular coordination patterns. AB - The objective of this study was to test if patients with unilateral hip osteoarthritis (OA) show greater muscle activity asymmetry between their affected and non-affected limbs than healthy controls between their left and right limbs. Seventeen patients with unilateral hip OA (7 females, 10 males) and 17 age matched healthy controls (7 females, 10 males) participated in this study. Both groups performed instrumented gait analysis at comparable speeds. Muscle activity was recorded simultaneously for the tibialis anterior (TA), gastrocnemius medialis (GM), vastus lateralis (VL), semitendinosus (ST), tensor fasciae latae (TFL), and gluteus medius (GLM) muscles. In hip OA patients, EMG data showed greater activity of the TA muscle in the non-affected limb, and greater TFL muscle activity in the affected limb. Compared to healthy controls, greater asymmetries between paired limbs were observed for the TA and GM muscles. Finally, the TFL muscle of the affected limb contributed more to the total limb muscle activity than did the non-affected limb. The observed alterations in TA and GM muscle activity in hip OA patients may be due to the greater peak braking and peak vertical forces measured in the non-affected limb. Contrary to this, greater TLF muscle activity of the affected limb indicates the demands put on stabilizing the hip during stance phase. Further studies are necessary to test whether leg length discrepancy affects muscle activation alterations between the affected and non-affected limb in unilateral hip OA patients. PMID- 26979909 TI - Calibration of an instrumented treadmill using a precision-controlled device with artificial neural network-based error corrections. AB - Instrumented treadmills (ITs) are used to measure reaction forces (RF) and center of pressure (COP) movements for gait and balance assessment. Regular in situ calibration is essential to ensure their accuracy and to identify conditions when a factory re-calibration is needed. The current study aimed to develop and calibrate in situ an IT using a portable, precision-controlled calibration device with an artificial neural network (ANN)-based correction method. The calibration device was used to apply static and dynamic calibrating loads to the surface of the IT at 189 and 25 grid-points, respectively, at four belt speeds (0, 4, 6 and 8 km/h) without the need of a preset template. Part of the applied and measured RF and COP were used to train a threelayered, back-propagation ANN model while the rest of the data were used to evaluate the performance of the ANN. The percent errors of Fz and errors of the Px and Py were significantly decreased from a maximum of -1.15%, -1.64 mm and -0.73 mm to 0.02%, 0.02 mm and 0.03 mm during static calibration, respectively. During dynamic calibration, the corresponding values were decreasing from -3.65%, 2.58 mm and -4.92 mm to 0.30%, 0.14 mm and -0.47 mm, respectively. The results suggest that the calibration device and associated ANN will be useful for correcting measurement errors in vertical loads and COP for ITs. PMID- 26979898 TI - Identification of trunk and pelvis movement compensations in patients with transtibial amputation using angular momentum separation. AB - Patients with unilateral dysvascular transtibial amputation (TTA) have a higher risk of developing low back pain than their healthy counterparts, which may be related to movement compensations used in the absence of ankle function. Assessing components of segmental angular momentum provides a unique framework to identify and interpret these movement compensations alongside traditional observational analyses. Angular momentum separation indicates two components of total angular momentum: (1) transfer momentum and (2) rotational momentum. The objective of this investigation was to assess movement compensations in patients with dysvascular TTA, patients with diabetes mellitus (DM), and healthy controls (HC) by examining patterns of generating and arresting trunk and pelvis segmental angular momenta during gait. We hypothesized that all groups would demonstrate similar patterns of generating/arresting total momentum and transfer momentum in the trunk and pelvis in reference to the groups (patients with DM and HC). We also hypothesized that patients with amputation would demonstrate different (larger) patterns of generating/arresting rotational angular momentum in the trunk. Patients with amputation demonstrated differences in trunk and pelvis transfer angular momentum in the sagittal and transverse planes in comparison to the reference groups, which indicates postural compensations adopted during walking. However, patients with amputation demonstrated larger patterns of generating and arresting of trunk and pelvis rotational angular momentum in comparison to the reference groups. These segmental rotational angular momentum patterns correspond with high eccentric muscle demands needed to arrest the angular momentum, and may lead to consequential long-term effects such as low back pain. PMID- 26979906 TI - Accuracy and concurrent validity of a sensor-based analysis of sit-to-stand movements in older adults. AB - Body-fixed motion sensors have been applied for the assessment of sit-to-stand (STS) performance. However, the accuracy and concurrent validity of sensor-based estimations of the body's center of mass (CoM) motion during STS are unclear. Therefore, this study investigated the accuracy and concurrent validity of sensor based measures of CoM motion during STS in older adults. Accuracy and concurrent validity were investigated by comparing the sensor-based method to a force plate method. Twenty-seven older adults (20 females, 7 males; age: 72-94 years) performed five STS movements while data were collected with force plates and motion sensors on the hip and chest. Hip maximal acceleration provided an accurate estimation of the center of mass (CoM) maximal acceleration (limits of agreement (LOA) smaller than 5% of the CoM maximal acceleration; estimated and real CoM maximal acceleration did not differ (p=0.823)). Other hip STS measures and the chest STS measures did not provide accurate estimations of CoM motion (LOA ranged from -155.6% to 333.3% of the CoM value; sensor-based measures overestimated CoM motion (range p: <0.001 to 0.01)). However, the hip sensor did not overestimate maximal jerk of the CoM (p=0.679). Moderate to very strong associations were observed between sensor-based estimations and actual CoM motion (range r=0.64-0.94, p<0.001). Hence, sensor-based estimations of CoM motion during STS are possible, but accuracy is limited. The sensor-based method cannot replace laboratory methods for a mechanical analysis of CoM motion during STS but it may be a practical alternative for the clinical assessment of STS performance in older persons. PMID- 26979908 TI - Defining the medial-lateral axis of an anatomical femur coordinate system using freehand 3D ultrasound imaging. AB - Hip rotation from gait analysis informs clinical decisions regarding correction of femoral torsional deformities. However, it is among the least repeatable due to discrepancies in determining the medial-lateral axis of the femur. Conventional or functional calibration methods may be used to define the axis but there is no benchmark to evaluate these methods. Freehand 3D ultrasound, the coupling of ultrasound with 3D motion capture, may provide such a benchmark. We measured the accuracy in vitro and repeatability in vivo of determining the femur condylar axis from freehand 3D ultrasound. The condylar axis provided the reference medial-lateral axis of the femur and was used to evaluate one conventional method and three functional calibration methods, applied to three calibration movements. Ten healthy subjects (20 limbs) underwent 3D gait analysis and freehand 3D ultrasound. The functional calibration methods were a transformation technique, a geometrical method and a method that minimises variance of knee varus-valgus kinematics (DynaKAD). The conventional method used markers over the femoral epicondyles. The condylar axis determined by 3D ultrasound showed good accuracy in vitro, 1.6 degrees (SD: 0.3 degrees ) and good repeatability in vivo, 0.2 degrees (RSMD: 2.3 degrees ). The DynaKAD method applied to the walking calibration movement determined the medial-lateral axis closest to the ultrasound reference. The average angular difference in the transverse plane was 3.1 degrees (SD: 6.1 degrees ). Freehand 3D ultrasound offers an accurate, non-invasive and relatively fast method to locate the medial lateral axis of the femur for gait analysis. PMID- 26979912 TI - Computed tomography confirms a reduction in diaphragm thickness in mechanically ventilated patients. AB - PURPOSE: Patients who require mechanical ventilation (MV) may experience diaphragm atrophy, which may delay the discontinuation of MV. Here, we used computed tomographic (CT) scans to confirm this phenomenon. METHOD AND MATERIALS: Patients who underwent two chest CT scans while on MV were retrospectively evaluated. Diaphragm thickness was measured using a three-dimensional CT image processing program. RESULTS: Thirteen patients, including 8 men, who underwent 26 CT scans were assessed. The mean age was 67.8 +/- 7.5 years. The interval between CT scans was 18.4 +/- 14.9 days. The first CT scans revealed that the mean thicknesses of the left and right sides of the diaphragm were 3.8 +/- 0.6 and 3.9 +/- 0.8 mm, respectively (total: 7.7 +/- 1.4 mm). These values were significantly reduced to 3.4 +/- 0.6 and 3.5 +/- 0.9 mm, respectively, (total: 6.9 +/- 1.5 mm) after the second scan (P < .01). No significant change in body weight (57.3 +/- 12.6 vs. 56.7 +/- 11.6 kg) or body mass index (21.8 +/- 5.1 vs. 21.6 +/- 4.8 kg/m(2)) was observed. CONCLUSION: Computed tomography confirmed that diaphragm thickness was reduced in critically ill patients who underwent MV. PMID- 26979907 TI - Are flexible flat feet associated with proximal joint problems in children? AB - The role of flexible flat feet (FF) in the development of musculoskeletal symptoms at joints proximal to the ankle is unclear. We undertook an observational study to investigate the relationship between foot posture and the proximal joints in children. It was hypothesised that reduced arch height would be associated with proximal joint symptoms and altered gait kinematics and kinetics particularly in the transverse plane at the hip and knee. Ninety-five children between the ages of 8-15 were recruited into this ethically approved study. Foot posture was classified using the arch height index (AHI). The frequency of knee and hip/back pain was documented, and each child underwent three dimensional gait analysis. Reduced arch height was associated with increased odds of knee symptoms (p<0.01) and hip/back symptoms (p=0.01). A flat foot posture was also significantly associated with a reduction in the second peak of the vertical ground reaction force (p=0.03), which concomitantly affected late stance hip and knee moments. A reduced AHI was also associated with increased pelvic retraction and increased knee valgus in midstance. No kinematic and kinetic parameter associated with a flat foot posture related to increased proximal joint symptoms in the FF group. Children with a flatter foot posture are more likely to have pain or discomfort at the knee, hip and back; however, the mechanisms by which this occurs remain unclear. Treating FF without explicit understanding of how it relates to symptoms is difficult, and further work in this area is required. PMID- 26979910 TI - Is proprioception diminished in patients with patellar tendinopathy? AB - PURPOSE: Patellar tendinopathy is a highly prevalent overuse injury, and most treatments are only effective to some extent. This persistence of complaints could be linked to changed proprioception. One study showed diminished proprioception in athletes with lateral epicondylitis. Aim of this study was to determine differences in proprioception, by measuring threshold to detect passive motion (TTDPM) between recreational athletes diagnosed with patellar tendinopathy and healthy controls. METHOD: The TTDPM as measure of proprioception was determined in 22 recreational athletes with patellar tendinopathy and 22 healthy recreational athletes using a validated instrument. Amount of knee flexion and extension before the movement was noticed by the subject was determined. 80 measurements per athlete (left and right leg, towards extension and flexion and with two starting angles of 20 degrees and 40 degrees flexion) were performed. Mean TTDPM was compared between groups and among the injured recreational athletes between the affected and unaffected knee. RESULTS: No significant difference in TTDPM was found between recreational athletes with patellar tendinopathy and healthy controls. We did find a significant difference between the injured and non-injured knee in recreational athletes with patellar tendinopathy; mean TTDPM was 0.02 degrees higher in the injured knee (p=0.044). CONCLUSION: No difference was found in proprioception between recreational athletes with patellar tendinopathy and healthy recreational athletes. It is unclear whether such a small difference in TTDPM between affected and unaffected knee is important in clinical setting. PMID- 26979911 TI - Unplanned intensive care unit admission following trauma. AB - BACKGROUND: The prevalence and outcomes of trauma patients requiring an unplanned return to the intensive care unit (ICU) and those initially admitted to a step down unit or floor and subsequently upgraded to the ICU, collectively termed unplanned ICU (UP-ICU) admission, are largely unknown. METHODS: A retrospective review of the trauma registry of a suburban regional trauma center was conducted for adult patients who were admitted between 2007 and 2013, focusing on patients requiring ICU admission. Prehospital or emergency department intubations and patients undergoing surgery immediately after emergency room evaluation were excluded. RESULTS: Of 5411 admissions, there were 212 UP-ICU admissions, 541 planned ICU (PL-ICU) admissions, and 4658 that were never admitted to the ICU (NO ICU). Of the 212 UP-ICU admits, 19.8% were unplanned readmissions to the ICU. Injury Severity Score was significantly different between PL-ICU (16), UP-ICU (13), and NO-ICU (9) admits. UP-ICU patients had significantly more often major (Abbreviated Injury Score >= 3) head/neck injury (46.7%) and abdominal injury (9.0%) than the NO-ICU group (22.5%, 3.4%), but significantly less often head/neck (59.5%) and abdominal injuries (17.9%) than PL-ICU patients. Major chest injury in the UP-ICU group (27.8%) occurred at a statistically comparable rate to PL-ICU group (31.6%) but more often than the NO-ICU group (14.7%). UP-ICU patients also significantly more often underwent major neurosurgical (10.4% vs 0.7%), thoracic (0.9% vs 0.1%), and abdominal surgery (8.5% vs 0.4%) than NO-ICU patients. Meanwhile, the PL-ICU group had statistically comparable rates of neurosurgical (6.8%) and thoracic surgical (0.9%) procedures but lower major abdominal surgery rate (2.0%) than the UP-ICU group. UP-ICU admission occurred at a median of 2 days following admission. UP-ICU median hospital LOS (15 days), need for mechanical ventilation (50.9%), and in-hospital mortality (18.4%) were significantly higher than those in the PL-ICU (9 days, 13.9%, 5.4%) and NO-ICU (5 days, 0%, 0.5%) groups. CONCLUSIONS: UP-ICU admission, although infrequent, was associated with significantly greater hospital length of stay, rate of major abdominal surgery, need for mechanical ventilation, and mortality rates than PL ICU and NO-ICU admission groups. PMID- 26979914 TI - Is there a preferred diuretic class for patients with renal impairment and hypertension? AB - It is widely believed that "high-ceiling" loop diuretics are required in patients with renal impairment and that "low-ceiling" thiazides are not sufficiently potent to cause meaningful natriuresis and diuresis. If this statement is true, at what level of renal function do thiazides lose their punch? Another related issue is the enlightened use of diuretic combinations. Use of diuretics in chronic kidney disease and hypertension has been addressed in the many guidelines, but further insight is provided in this installment of the "Controversies" series by two well-known authorities, William Elliott, M.D. Ph.D. and Rajiv Agarwal, M.D. PMID- 26979913 TI - Oxaliplatin Immune-Induced Syndrome Occurs With Cumulative Administration and Rechallenge: Single Institution Series and Systematic Review Study. AB - Oxaliplatin immune-induced syndrome (OIIS) is an uncommon, potentially life threatening, side effect associated with oxaliplatin-based chemotherapy. The present study reports 5 original cases of OIIS and systematically reviewed the available published cases. We retrospectively analyzed the clinical archives of the Niguarda Cancer Center from 2009 to 2015 and conducted a search for OIIS using the PubMed database, followed by deeper investigation of the references of the recorded studies. We pooled our series with other reported cases for systematic review in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement using only English language as the selection criterion. A total of 61 OIIS cases were analyzed, the largest series reported to date. Of the 61 patients, 56 (91.8%) had received oxaliplatin for metastatic colorectal cancer. In 32 of the 61 patients (52.5%), OIIS was associated with grade 4 thrombocytopenia and in 4 (6.6%) with grade 4 anemia. OIIS was fatal in 4 patients. In 49 patients, oxaliplatin-induced immune system activation was tested using the Coombs test or by detection of antiplatelet antibodies and was positive in 87.7% of the patients. The average number of oxaliplatin cycles until the onset of OIIS was 16.7, and the number was significantly lower when oxaliplatin was administered as a rechallenge after a period of vacancy of treatment with this agent (4.6 cycles as rechallenge vs. 13.6 as first-time exposure; P < .00001). OIIS is triggered by cumulative administration of oxaliplatin, characteristically with a threefold earlier onset when the drug is administered as a rechallenge. Prompt identification of OIIS can be expected to reduce the risk of iatrogenic morbidity and mortality. PMID- 26979917 TI - Certification in cardiothoracic surgical critical care: A distinction for some or for all? PMID- 26979918 TI - Finding the truth in the guidelines and gospels. PMID- 26979920 TI - A novel DNA tetrahedron-hairpin probe for in situ"off-on" fluorescence imaging of intracellular telomerase activity. AB - A novel three-dimensionally structured DNA probe is reported to realize in situ"off-on" imaging of intracellular telomerase activity. The probe consists of a DNA tetrahedron and a hairpin DNA on one of the vertices of the DNA tetrahedron. It is composed of four modified DNA segments: S1-Au nanoparticle (NP) inserting a telomerase strand primer (TSP) and S2-S4, three Cy5 dye modified DNA segments. Fluorescence of Cy5 at three vertices of the DNA tetrahedron is quenched by the Au NP at the other vertex due to the effective fluorescence resonance energy transfer (FRET) ("off" state). When the probe meets telomerase, the hairpin structure changes to rod-like through complementary hybridization with the telomerase-triggered stem elongation product, resulting in a large distance between the Au NP and Cy5 and the recovery of Cy5 fluorescence ("on" state). The molar ratio of 3 : 1 between the reporter (Cy5) and the target related TSP makes the probe show high sensitivity and recovery efficiency of Cy5 in the presence of telomerase extracted from HeLa cells. Given the functional and compact nanostructure, the mechanically stable and noncytotoxic nature of the DNA tetrahedron, this FRET-based probe provides more opportunities for biosensing, molecular imaging and drug delivery. PMID- 26979919 TI - Clinical assessment of diastolic retrograde flow in the descending aorta for high flow systemic-to-pulmonary artery shunting. AB - OBJECTIVE: To investigate whether echocardiographic characteristics in the descending aorta of patients with cyanotic congenital heart disease who have received a systemic-to-pulmonary artery (SP) shunt can indicate shunt flow volume and predict postoperative adverse events related to high-flow shunting. METHODS: Among the 73 consecutive patients who received an SP shunt between 2010 and 2014, data for 53 patients who underwent postoperative Doppler echocardiographic assessment of diastolic retrograde flow in the descending aorta (dAo-RF) were reviewed retrospectively. RESULTS: The mean dAo-RF ratio was 0.50 +/- 0.15 at intensive care unit admission and reached its peak level (0.56 +/- 0.12) at 24 hours after surgery. All of the patients with a maximal dAo-RF ratio of >=0.80 had experienced acute heart failure or cardiogenic shock due to postoperative high-flow shunting and required emergent surgical interventions to reduce pulmonary blood flow. Pulse oximetry-measured oxygen saturation and serum lactate level were significantly correlated with dAo-RF ratio, but they had some clinical dispersion to match the postoperative adverse events. CONCLUSIONS: The dAo-RF ratio is a simple, repeatable, and noninvasive index for postoperative assessment of SP shunt flow volume. A high dAo-RF ratio is a significant predictor of postoperative adverse events of high-flow shunting. PMID- 26979916 TI - Extracellular matrix fiber microarchitecture is region-specific in bicuspid aortic valve-associated ascending aortopathy. AB - OBJECTIVE: Ascending thoracic aortic aneurysm (ATAA) in patients with bicuspid aortic valve (BAV) commonly dilate asymmetrically compared with patients with tricuspid aortic valve (TAV). This discrepancy in aneurysm geometry led us to hypothesize that microarchitectural differences underlie the observed asymmetric dilatation pattern. The purpose of this study was to characterize the microarchitectural distinctions of the extracellular matrix of the 2 phenotypes with a focus on the proportion of radially oriented elastin and collagen fibers in different circumferential aortic regions. METHODS: Aortic tissue rings were obtained just distal to the sinotubular junction from patients with BAV or TAV undergoing elective aneurysm repair. They were sectioned into three circumferentially based regions according to adjacent aortic sinus segment (left coronary sinus [L], right coronary sinus [R], or noncoronary sinus [N]). Multiphoton microscopy was used to quantify and characterize the number of radially oriented elastin and collagen fibers. RESULTS: There were fewer radially oriented fibers in medial region N and medial-intimal region R of BAV-ATAAs when compared with TAV-ATAAs (medial region N, amplitude of angular undulation of elastin = 10.67 degrees +/- 1.35 degrees vs 15.58 degrees +/- 1.91 degrees ; P = .041; medial-intimal region R, amplitude of angular undulation of elastin = 9.83 degrees +/- 0.83 degrees vs 14.72 degrees +/- 1.64 degrees ; P = .015). Conversely, fibers became more radially oriented in the medial-intimal region L of BAV-ATAA when compared with TAV-ATAA (amplitude of angular undulation of collagen = 18.67 degrees +/- 0.95 degrees vs 14.56 degrees +/- 1.37 degrees ; P = .041). CONCLUSIONS: The differential pattern of fiber orientation noted between L and N-R regions help explain the unique pattern of greater curvature dilatation of BAV-ATAA. The distinctions noted in matrix microarchitecture may form the basis of differing aneurysm geometries and aortic wall integrities in ATAAs arising in these different valve morphologies. PMID- 26979915 TI - Seizures in patients with primary brain tumors: what is their psychosocial impact? AB - Seizures occur in most patients with primary malignant tumors and are associated with poor quality of life. To our knowledge, no previous studies have sought descriptions of quality of life in patients' own words. Patients with a history of a malignant primary brain tumor and seizures participated in semi-structured interviews, which were analyzed with qualitative methodology. Twenty-seven patients participated, most with high grade brain tumors. Most were receiving anti-seizure medication. Three distinct themes emerged: (1) the first seizure as a sentinel event, as manifested in part by how patients described their first seizure in remarkable detail ("I clearly remember the date..."); (2) seizures as inextricably tied to the brain tumor itself; for example, one patient explained how he "always wondered what was happening with my brain tumor" with each seizure; and (3) adaptation and acceptance-or lack therefore-to seizures. With respect to this third theme, patients conveyed frustration from an inability to work, to drive, and to take care of their children ("It's like you are 15 all over again.") Others described frustration with taking antiseizure medications ("I felt like an 80 year old, now taking her pills every day"). However, some patients had adapted or resigned themselves ("...so much of life is out of control-you just gotta take what you get."). These findings have future research implications but should also serve to make healthcare providers more aware of the heavy emotional burden that seizures thrust upon brain tumor patients. PMID- 26979922 TI - Better Height Restoration, Greater Kyphosis Correction, and Fewer Refractures of Cemented Vertebrae by Using an Intravertebral Reduction Device: a 1-Year Follow up Study. AB - PURPOSE: This study compared the radiologic and clinical outcomes of kyphoplasty with intravertebral reduction device (IRD) and vertebroplasty (VP) in treating osteoporotic vertebral compression fractures (OVCFs). MATERIALS AND METHODS: We enrolled 75 patients with OVCFs who were aged >60 years and treated them through VP or kyphoplasty with IRD. The radiologic outcomes, namely the anterior and middle body heights (ABH and MBH, respectively) and kyphotic angle (KA), were measured preoperatively and at postoperative 1 week, 3 months, 6 months, and 1 year. The refracture was identified on the basis of a decrease in ABH, MBH, or KA compared with those at postoperative 1 week. Visual analog scale (VAS) for pain and complications were recorded. The incidence of adjacent and nonadjacent fractures was also recorded. RESULTS: We treated 36 patients with kyphoplasty with IRD (IRD group) and 39 through VP (VP group). The patient characteristics were comparable in both groups. The KA and its restoration were more favorable after IRD than after VP. Although ABHs were not different in either group, their restoration was more efficient after IRD than after VP. MBHs, their restoration, and their refracture rates were better after IRD than after VP. VAS pain scores and complication rates were not different between the groups. The incidences of adjacent or nonadjacent fractures were not different between the 2 groups. CONCLUSION: Our findings reveal significantly more efficient height restoration and kyphosis correction and fewer refractures in the IRD group. IRD may not increase the risk of adjacent or nonadjacent fractures. PMID- 26979924 TI - Frontal Sinus Morphometry in Relation to Surgically Relevant Landmarks in the United States Population. AB - BACKGROUND: Knowledge of frontal sinus morphometry is important in bifrontal, pterional, orbitozygomatic, and supraorbital craniotomies. Inadvertent frontal sinus violation can lead to infection, cerebrospinal fluid fistula, and mucocele formation. In particular, knowledge of anatomy in relation to surgically relevant landmarks can help surgeons perform these procedures more precisely and safely. We performed a descriptive radiographic analysis to better understand variations in frontal sinus anatomy. METHODS: Using 3-dimensional reconstructive software, we analyzed 162 normal cranial computerized tomographic angiograms (from 80 men and 82 women). A line between the supraorbital notches (SONs) was used as a horizontal reference line (HRL). We recorded the maximum sinus height and width from the HRL and midline, respectively. In addition, sinus width was measured in relation to the SON at 0, 1, and 2 cm above the HRL. RESULTS: The mean maximal sinus height from the HRL was 1.8 cm. The mean maximum sinus width was 2.6 cm (right and left) from midline and 0.46 cm (right) and 0.49 cm (left) from the SON. Less than 11% of sinuses were lateral to the SON at 2.0 cm above the HRL and <6% of sinuses were >1.5 cm lateral to the SON at 1.0 cm above the HRL. CONCLUSIONS: Planned surgical corridors >1.5 cm lateral to the SON and/or >3.0 cm above the HRL are most likely to avoid the frontal sinus based on our radiographic measurements of normal sinus anatomy. Careful radiographic study and appropriate planning for more medial and/or inferior corridors is suggested. PMID- 26979923 TI - Indocyanine Green Videoangiography Transoptic Visualization and Clipping Confirmation of an Optic Splitting Ophthalmic Artery Aneurysm. AB - OBJECTIVE: Ophthalmic artery aneurysms with medial and superior projection in exceptionally rare cases can split the optic nerve. Treatment of these aneurysms is challenging, because the aneurysm dome is hidden from the optic nerve, rendering its visualization and clipping confirmation difficult. In addition, optic nerve function should be preserved during surgical maneuvers. Preoperative detection of this growing feature is usually missing. CASE DESCRIPTION: We illustrate the first case of indocyanine green videoangiography (ICG-VA) application in an optic penetrating ophthalmic artery aneurysm treatment. A 57 year-old woman presented with temporal hemianopsia, slight right visual acuity deficit, and new onset of headache. The cerebral angiography detected a right ophthalmic artery aneurysm medially and superiorly projecting. The A1 tract of the ipsilateral anterior cerebral artery was elevated and curved, being suspicious for an under optic aneurysm growth. Surgery was performed. Initially the aneurysm was not visible. ICG-VA permitted the transoptic aneurysm visualization. After optic canal opening, the aneurysm was clipped and transoptic ICG-VA confirmed the aneurysm occlusion. ICG-VA showed also the slight improvement of the optic nerve pial vascularization. Postoperatively, the visual acuity was 10/10 and the hemianopsia did not worsen. CONCLUSIONS: The elevation and curve of the A1 tract in medially and superiorly projecting ophthalmic aneurysms may be an indirect sign of under optic growth, or optic splitting aneurysms. ICG-VA transoptic aneurysm detection and occlusion confirmation reduces the surgical maneuvers on the optic nerve, contributing to function preservation. PMID- 26979921 TI - The need for new approaches in CNS drug discovery: Why drugs have failed, and what can be done to improve outcomes. AB - An important goal of biomedical research is to translate basic research findings into useful medical advances. In the field of neuropharmacology this requires understanding disease mechanisms as well as the effects of drugs and other compounds on neuronal function. Our hope is that this information will result in new or improved treatment for CNS disease. Despite great progress in our understanding of the structure and functions of the CNS, the discovery of new drugs and their clinical development for many CNS disorders has been problematic. As a result, CNS drug discovery and development programs have been subjected to significant cutbacks and eliminations over the last decade. While there has been recent resurgence of interest in CNS targets, these past changes in priority of the pharmaceutical and biotech industries reflect several well-documented realities. CNS drugs in general have higher failure rates than non-CNS drugs, both preclinically and clinically, and in some areas, such as the major neurodegenerative diseases, the clinical failure rate for disease-modifying treatments has been 100%. The development times for CNS drugs are significantly longer for those drugs that are approved, and post-development regulatory review is longer. In this introduction we review some of the reasons for failure, delineating both scientific and technical realities, some unique to the CNS, that have contributed to this. We will focus on major neurodegenerative disorders, which affect millions, attract most of the headlines, and yet have witnessed the fewest successes. We will suggest some changes that, when coupled with the approaches discussed in the rest of this special volume, may improve outcomes in future CNS-targeted drug discovery and development efforts. This article is part of the Special Issue entitled "Beyond small molecules for neurological disorders". PMID- 26979927 TI - Time-series analysis of monthly age-specific numbers of newly registered cases of active tuberculosis in Japan from 1998 to 2013. AB - We investigated the seasonality of age-specific tuberculosis (TB) in Japan. To allow the development of TB control strategies for different age groups we used a time-series analysis, including a spectral analysis and least squares method, to analyse the monthly age-specific numbers of newly registered cases of all forms of active TB in Japan from January 1998 to December 2013. The time-series data are reported in 10-year age groups: 0-9, 10-19, ..., 70-79, and ?80 years. We defined the contribution ratio of the 1-year cycle, Q 1, as the contribution of the amplitude of a 1-year cycle to the whole amplitude of the time-series data. The Q 1 values in the age groups corresponding to adolescence and middle life (10 39 years) and old age (?70 years) were high. The peaks in the active TB epidemics for the ?70 years age group occurred in August and September, 1-2 months behind the peaks for the 10-39 years age group (June and July). An active TB epidemic might be attributable to travel by public transport and irregular employment in the 10-39 years age group and immune system suppression by low winter temperatures in the ?70 years age group. PMID- 26979929 TI - Plasmofluidic Disk Resonators. AB - Waveguide-coupled silicon ring or disk resonators have been used for optical signal processing and sensing. Large-scale integration of optical devices demands continuous reduction in their footprints, and ultimately they need to be replaced by silicon-based plasmonic resonators. However, few waveguide-coupled silicon based plasmonic resonators have been realized until now. Moreover, fluid cannot interact effectively with them since their resonance modes are strongly confined in solid regions. To solve this problem, this paper reports realized plasmofluidic disk resonators (PDRs). The PDR consists of a submicrometer radius silicon disk and metal laterally surrounding the disk with a 30-nm-wide channel in between. The channel is filled with fluid, and the resonance mode of the PDR is strongly confined in the fluid. The PDR coupled to a metal-insulator-silicon insulator-metal waveguide is implemented by using standard complementary metal oxide semiconductor technology. If the refractive index of the fluid increases by 0.141, the transmission spectrum of the waveguide coupled to the PDR of radius 0.9 MUm red-shifts by 30 nm. The PDR can be used as a refractive index sensor requiring a very small amount of analyte. Plus, the PDR filled with liquid crystal may be an ultracompact intensity modulator which is effectively controlled by small driving voltage. PMID- 26979931 TI - Removal characteristics and fluctuation of norovirus in a pilot-plant by an ultrafiltration membrane for the reclamation of treated sewage. AB - When ultrafiltration (UF) membrane processes that are able to effectively reduce viruses are installed in a waste water reclamation system, the security of sanitation safety for water-borne diseases is essential. It is important to understand the behaviour of enteric viruses such as Adenovirus, Rotavirus and Norovirus (NV), the detection rate of which is relatively high in sewage. This study focused on the UF membrane process for the reclaimed water treatment process, and investigated the removal performance in NV type GI and GII in the UF membrane process by performing coagulation and sedimentation as the pre-treatment process in a pilot-plant by considering the concentration fluctuation of the influent. The removal ratio of GI and GII by the UF membrane process alone was 3.3 +/- 0.7 Log in GI and 3.6 +/- 1.0 Log in GII, and no clear difference in the removal ratio by NV species type was observed. The removal ratio of NV GII was increased by about 0.6 Log on average (4.2 +/- 1.1 Log) compared with the UF membrane process only when the coagulation and sedimentation process were conducted as pre-treatment. However, there was no significant difference in the removal of NV GI by conducting the coagulation and sedimentation process. PMID- 26979930 TI - Are There Subconcussive Neuropsychological Effects in Youth Sports? An Exploratory Study of High- and Low-Contact Sports. AB - This exploratory study was designed to examine the neuropsychological effects of sports-related head trauma-specifically, repetitive subconcussive impacts or head blows that do not result in a diagnosable concussion. The researchers compared the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) neurocognitive test scores of 2 groups of nonconcussed youth athletes (n = 282), grouped according to the frequency of concussions in their respective sports, with the assumption that more subconcussive impacts occur in sports in which there are more reported concussions. The results indicated that high-contact sport (football) athletes had significantly poorer performance in processing speed and reaction time compared with athletes in low-contact sports (wrestling, soccer, baseball, judo, and basketball). This study into the effects of repetitive subconcussive head trauma tentatively raises concern that participation in high-contact sports, even without evidence of a diagnosable concussion, could result in lowered neuropsychological functioning among high school athletes. Limitations of this exploratory research effort are discussed. PMID- 26979926 TI - The State of Cancer Care in America, 2016: A Report by the American Society of Clinical Oncology. PMID- 26979925 TI - Safety and Efficacy of Trastuzumab Emtansine in Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: a Meta-analysis. AB - Advanced or metastatic breast cancer is an incurable disease with high mortality rate worldwide and about 20% of breast cancers overexpress and amplify the human epidermal growth factor receptor 2 (HER2). Achievements in targeted therapy have benefited people during the past decades. Trastuzumab emtansine (T-DM1), a novel antibody-drug conjugate playing a powerful role in anti-tumor activity, not only blocks the HER2 signaling pathways, but also disturbs the microtubule dynamics. To access the efficacy and safety of T-DM1, we analyzed 9 clinical trials on T DM1. Results showed that fatigue (0.604, 95% CI 0.551, 0.654), nausea (0.450, 95% CI 0.365, 0.537), increased transaminases (0.425, 95% CI 0.353, 0.500) and thrombocytopenia (0.383, 95% CI 0.322, 0.448) occurred more frequently in participants with single T-DM1. In controlled trials, increased transaminases (OR = 4.040, 95% CI 1.429, 11.427), thrombocytopenia (OR = 8.500, 95% CI 3.964, 18.226) and fatigue (OR = 1.288, 95% CI 1.041, 1.593) were statistically significant. Only thrombocytopenia appeared as severe adverse event (grade >= 3) in single-arm and control-arm studies. Meanwhile, T-DM1 stabilized cancer and prolonged life with notable improved progression-free survival (PFS) and overall survival (OS). In conclusion, it is a safe and effective agent in advanced or metastatic breast cancer, but should be carefully applied on patients with severe hepatic and neurological disease. PMID- 26979932 TI - A New Perspective on Mental Illness: From Nigeria to SW United States. PMID- 26979934 TI - Red-light activated photoCORMs of Mn(i) species bearing electron deficient 2,2' azopyridines. AB - The realization of CO releasing molecules triggered by light (photoCORMs) within the phototherapeutic window (lambda > 600 nm) constitutes an important goal for potential therapeutic applications of the molecules. The activation of photoCORMs with red/NIR light would enable exploiting the higher depth of penetration of this radiation with respect to higher energy photons. In this article we report a family of carbonyl Mn(i) complexes capable of releasing CO when triggered with red light (>=625 nm). Such complexes are based on 2,2'-azopyridine ligands modified by the introduction of electron-donating or electron-withdrawing substituents. Our results indicate that electron deficient ligands induce a gradual decrease of the HOMO-1/LUMO gap of the species (i.e. of the orbitals involved in the lowest energy transition), thus enabling a fine tuning of their visible absorption maxima between 630 and 693 nm. The synthesis of the complexes and their photodecomposition behaviour towards CO release are described. We suggest that this approach could be generalized for further development of low energy activated photoCORMs. PMID- 26979928 TI - RNA-dependent RNA polymerase 1 in potato (Solanum tuberosum) and its relationship to other plant RNA-dependent RNA polymerases. AB - Cellular RNA-dependent RNA polymerases (RDRs) catalyze synthesis of double stranded RNAs that can serve to initiate or amplify RNA silencing. Arabidopsis thaliana has six RDR genes; RDRs 1, 2 and 6 have roles in anti-viral RNA silencing. RDR6 is constitutively expressed but RDR1 expression is elevated following plant treatment with defensive phytohormones. RDR1 also contributes to basal virus resistance. RDR1 has been studied in several species including A. thaliana, tobacco (Nicotiana tabacum), N. benthamiana, N. attenuata and tomato (Solanum lycopersicum) but not to our knowledge in potato (S. tuberosum). StRDR1 was identified and shown to be salicylic acid-responsive. StRDR1 transcript accumulation decreased in transgenic potato plants constitutively expressing a hairpin construct and these plants were challenged with three viruses: potato virus Y, potato virus X, and tobacco mosaic virus. Suppression of StRDR1 gene expression did not increase the susceptibility of potato to these viruses. Phylogenetic analysis of RDR genes present in potato and in a range of other plant species identified a new RDR gene family, not present in potato and found only in Rosids (but apparently lost in the Rosid A. thaliana) for which we propose the name RDR7. PMID- 26979933 TI - Naming it 'nano': Expert views on 'nano' terminology in informed consent forms of first-in-human nanomedicine trials. AB - BACKGROUND: Obtaining valid informed consent (IC) can be challenging in first-in human (FIH) trials in nanomedicine due to the complex interventions, the hype and hope concerning potential benefits, and fear of harms attributed to 'nano' particles. AIM: We describe and analyze the opinions of expert stakeholders involved in translational nanomedicine regarding explicit use of 'nano' terminology in IC documents. METHODS: We draw on content analysis of 46 in-depth interviews with European and North American stakeholders. RESULTS: We received a spectrum of responses (reluctance, ambivalence, absolute insistence) on explicit mention of 'nano' in IC forms with underlying reasons. CONCLUSION: We conclude that consistent, clear and honest communication regarding the 'nano' dimension of investigational product is critical in IC forms of FIH trials. PMID- 26979935 TI - US health officials press Congress for Zika funds. PMID- 26979936 TI - By not publishing good qualitative research The BMJ is not fulfilling its values. PMID- 26979941 TI - Newly diagnosed hyperthyroidism in the 25th gestational week of pregnancy presenting with systolic arterial hypertension only. AB - We present a case of a 30-year-old woman diagnosed with arterial hypertension in the 25th week of pregnancy. Our search for secondary causes of arterial hypertension revealed hyperthyroid Hashimoto's thyroiditis (HT), which was treated with propilthiouracil. Three weeks after delivery, she was normotensive without medication. In the next four months, she developed hypothyroidism and treatment with L-thyroxine was started. In conclusion, in the second half of pregnancy, a hyperthyroid HT can occur - in spite of the well-known amelioration of autoimmune thyroid disorders in that period, and can be the only cause of arterial hypertension. PMID- 26979939 TI - Altered expression of acetylcholinesterase gene in rice results in enhancement or suppression of shoot gravitropism. AB - Acetylcholinesterase (AChE), an acetylcholine-hydrolyzing enzyme, exists widely in plants, although its role in plant signal transduction is still unclear. We have hypothesized that the plant AChE regulates asymmetric distribution of hormones and substrates due to gravity stimulus, based on indirect pharmacological experiments using an AChE inhibitor. As a direct evidence for this hypothesis, our recent study has shown that AChE overexpression causes an enhanced gravitropic response in rice seedlings and suggested that the function of the rice AChE relates to the promotion of shoot gravitropism in the seedlings. Here, we report that AChE suppression inhibited shoot gravitropism in rice seedlings, as supportive evidence demonstrating the role of AChE as a positive regulator of shoot gravitropic response in plants. PMID- 26979937 TI - Cysteinyl leukotriene 1 receptor influences intestinal polyp incidence in a gender-specific manner in the ApcMin/+ mouse model. AB - There is emerging literature emphasizing the role of inflammatory eicosanoids, including prostaglandins and leukotrienes, in cancer development. Increased expression of both the cysteinyl leukotriene receptor 1 (CysLTR1) and the enzyme responsible for the production of leukotrienes, 5-lipoxygenase, is associated with poor prognosis in patients with colorectal adenocarcinomas. Apc mutation is an early event in the development of sporadic and hereditary (familial adenomatous polyposis) colorectal cancer. We utilized the Apc(Min/+) mouse model of familial adenomatous polyposis/sporadic colorectal cancer to investigate the role of CysLTR1 in intestinal tumorigenesis by crossing Apc(Min/+) mice with mice lacking the Cysltr1 gene. We could observe a reduced tumor burden in the small intestine of double-mutant female (Cysltr1 (-/-) Apc (Min/+) ) but not double mutant male mice, compared with gender-matched single-mutant (Cysltr1 (+/+) Apc (Min/+) ) mice. This reduction was in a Cysltr1-dependent manner, female double mutant mice having significantly reduced tumor formation compared with control littermates. The female double-mutant phenotype was accompanied with decreased systemic inflammation, as evidenced by significantly reduced serum levels of prostaglandin E2 and CysLTs, as well as increased CD3(+)CD8(+) T-cell tumor infiltration. Furthermore, the reduced formation of polyps in double-mutant (Cysltr1 (-/-) Apc (Min/+) ) female mice could in part be explained by the cytotoxic action of CD3(+)CD8(+) T cells in the polyp and reduced nuclear accumulation of beta-catenin in the epithelium of small intestinal polyps. Our results stress the important role that CysLTR1 plays in colorectal cancer and its potential as a therapeutic target in cancer therapy. PMID- 26979943 TI - Effect of IGF-I and TNF-alpha on intensification of steroid pathways in women with PCOS phenotypes are not identical. Enhancement of progesterone pathway in women with PCOS increases the concentration of TNF-alpha. AB - OBJECTIVE: The aim of this study was to determine the correlations between the concentration of tumor necrosis factor (TNF-alpha) and insulin-like growth factor I (IGF-I) in each woman with polycystic ovary syndrome (PCOS) phenotypes based on the levels of androgen. METHODS: Two groups of women with PCOS differing in their levels of androgens. The test group composed of 39 women with PCOS according to the Rotterdam criteria in their reproductive age. The hormonal levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid stimulating hormone (TSH), prolactin (PRL), androstenedione, testosterone (T), estradiol (E2) and sex hormone binding globulin (SHBG) were measured. Correlations analysis were performed calculating Spearman's rank correlation coefficient of hormones with relation to TNF-alpha and IGF-I. RESULTS: There was a medium positive correlation of IGF-1 with LH levels (p < 0.05) and negative medium correlation of TNF-alpha with of dehydroepiandrosterone (DHEA)-SO4 levels (p < 0.05) only in group of PCOS women with elevated androgens. CONCLUSION: Analysis of TNF-alpha showed that women with high testosterone negative correlation between level of TNF-alpha and the concentration of DHEA-SO4. Inflammatory state involving TNF-alpha in women with PCOS and high concentration of androgens is caused by intensified Delta4 (progesterone) pathway and omitted or limited Delta5 (dehydroepiandrosterone) pathway of testosterone biosynthesis. PMID- 26979945 TI - Probiotics in early life: a preventative and treatment approach. AB - Microbial colonization of the infant gut plays a key role in immunological and metabolic pathways impacting human health. Since the maturation of the gut microbiota coincides with early life development, failure to develop a health compatible microbiota composition may result in pathology and disease in later life. Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. Maternal transfer of microorganisms is possible during pregnancy and lactation, and the mother's diet and microbiota can influence that of her offspring. Furthermore, pre-term birth, Caesarean section birth, formula feeding, antibiotic use, and malnutrition have been linked to dysbiosis, which in turn is associated with several pathologies such as necrotizing enterocolitis, inflammatory bowel diseases, antibiotic associated diarrhea, colic, and allergies. Thus, early life should represent a preferred stage of life for probiotic interventions. In this context, they could be regarded as a means to 'program' the individual for health maintenance, in order to prevent pathologies associated with dysbiosis. In order to elucidate the mechanisms underlying the benefits of probiotic administration, pre-clinical studies have been conducted and found an array of positive results such as improved microbial composition, intestinal maturation, decreased pathogenic load and infections, and improved immune response. Moreover, specific probiotic strains administered during the perinatal period have shown promise in attenuating severity of necrotizing enterocolitis. The mechanisms elucidated suggest that probiotic interventions in early life can be envisaged for disease prevention in both healthy offspring and offspring at risk of chronic disease. PMID- 26979949 TI - Systematic Review and Meta-Analysis: Is Pre-Injury Antiplatelet Therapy Associated with Traumatic Intracranial Hemorrhage? AB - The objective of this systematic review and meta-analysis is to evaluate whether the pre-injury use of antiplatelet therapy (APT) is associated with increased risk of traumatic intracranial hemorrhage (tICH) on CT scan. PubMed, Medline, Embase, Cochrane Central, reference lists, and national guidelines on traumatic brain injury were used as data sources. Eligible studies were cohort studies and case-control studies that assessed the relationship between APT and tICH. Studies without control group were not included. The primary outcome of interest was tICH on CT. Two reviewers independently selected studies, assessed methodological quality, and extracted outcome data. This search resulted in 10 eligible studies with 20,247 patients with head injury that were included in the meta-analysis. The use of APT in patients with head injury was associated with significant increased risk of tICH compared with control (odds ratio [OR] 1.87, 95% confidence interval [CI]1.27-2.74). There was significant heterogeneity in the studies (I2 84%), although almost all showed an association between APT use and tICH. This association could not be established for patients receiving aspirin monotherapy. When considering only patients with mild traumatic brain injury (mTBI), the OR is 2.72 (95% CI 1.92-3.85). The results were robust to sensitivity analysis on study quality. In summary, APT in patients with head injury is associated with increased risk of tICH; this association is most relevant in patients with mTBI. Whether this association is the result of a causal relationship and whether this relationship also exists for patients receiving aspirin monotherapy cannot be established with the current review and meta analysis. PMID- 26979944 TI - Challenges for the implementation of World Health Organization guidelines for acute stress, PTSD, and bereavement: a qualitative study in Uganda. AB - BACKGROUND: In 2013, the World Health Organization (WHO) published new guidelines for the management of conditions specifically related to stress, including symptoms of acute stress, bereavement, and post-traumatic stress disorder (PTSD). It is important to evaluate potential challenges for the implementation of these guidelines in low-resource settings, however, there is a dearth of research in this area. The current qualitative study aimed to assess perspectives on the feasibility and acceptability of the new guidelines in four clinics that provide mental health services in post-conflict northern Uganda. METHODS: In-depth interviews were conducted with 19 mental health-care providers and program developers in northern Uganda to address three major research objectives: (1) describe the current standard practices and guidelines used for treating conditions related to stress in Uganda; (2) identify barriers and challenges associated with implementing the new WHO guidelines; and (3) identify and describe potential strategies for overcoming these barriers and challenges. An emergent thematic analysis was used to develop a coding scheme for the transcribed interviews. RESULTS: Practices for managing conditions related to stress included group psychological interventions, psychoeducation, and medication for clients with severe signs and symptoms. Several themes were identified from the interviews on barriers to guideline implementation. These included (1) a lack of trained and qualified mental health professionals to deliver WHO-recommended psychological interventions; (2) a perception that psychological interventions developed in high-income countries would not be culturally adaptable in Uganda; and (3) reluctance about blanket statements regarding medication for the management of acute stress symptoms and PTSD. Identified strategies for overcoming these barriers included (1) training and capacity building for current mental health staff; (2) a stepped care approach to mental health services; and (3) cultural modification of psychological interventions to improve treatment acceptability by clients. CONCLUSIONS: Guidelines were viewed positively by mental health professionals in Uganda, but barriers to implementation were expressed. Recommendations for implementation include (1) strengthening knowledge on effectiveness of existing cultural practices for improving mental health; (2) improving supervision capacity of current mental health staff to address shortage in human resources; and (3) increasing awareness of help-seeking clients on the potential effectiveness of psychological vs. pharmacological interventions. PMID- 26979950 TI - Health-related quality of life in children with chronic immune thrombocytopenia in China. AB - BACKGROUND: The concept of health-related quality of life (HRQoL) was brought up decades ago and has been well utilized in many different areas. Regarding immune thrombocytopenia (ITP) management, much work has been done to emphasize the necessity of taking HRQoL into consideration. However, data on HRQoL of children with chronic ITP remain rare. METHODS: This is a cross-sectional study. Children with chronic ITP aged from 2 to 18 and their parents were recruited. Participants completed the Pediatric Quality of Life InventoryTM (PedsQLTM) and Kids' ITP Tools (KIT) questionnaires at only one time. The Pearson's correlation was examined between these measures for the pooled samples. RESULTS: A total of 42 families participated. Mean child self-report scores of KIT and PedsQLTM were 78.60 (SD = 12.40) and 85.13 (SD = 14.12), respectively, corresponding to parent proxy report scores, which were 73.40 (SD = 19.96) and 85.10 (SD = 13.56), respectively. Mean score of KIT parent impact report was only 40.39 (SD = 19.96). Significantly higher KIT scores (self-report and parent proxy) were observed in children with PLT more than 30 * 10*9/L compared to others, and this difference was even more noticeable in the PedsQLTM parent proxy report group (p < 0.001). As with intravenous immunoglobulin, the statistics difference appeared only in KIT child self-report group (p = 0.03), while for bone marrow examination, the difference appeared only in PedsQLTM parent proxy report group (p = 0.01). A negative relationship was apparent between duration of disease and scores. Gender and use of corticosteroids had no impact on the KIT and PedsQLTM scores here. Internal consistency reliability was demonstrated with Cronbach's alpha for all scales above the acceptable level of 0.89 (range from 0.88 to 0.97). There was a substantial concordance (p < 0.001) between the child and parent proxy scores (ICC for KIT is 0.59, ICC for PedsQLTM is 0.85). Meanwhile, KIT scores are correlated with PedsQLTM (r = 0.75 for child self report, r = 0.61 for parent proxy report). CONCLUSIONS: ITP affects HRQoL of children and parents. Parents are much more concerned with the disease than their children, which seriously influence their HRQoL as a result. The cross-culture translated KIT is reliable and valid with acceptable correlation to the PedsQLTM. KIT provides valuable information of childhood ITP and will be a reliable outcome measure for further clinical research on HRQoL. PMID- 26979940 TI - Principles of dynamical modularity in biological regulatory networks. AB - Intractable diseases such as cancer are associated with breakdown in multiple individual functions, which conspire to create unhealthy phenotype-combinations. An important challenge is to decipher how these functions are coordinated in health and disease. We approach this by drawing on dynamical systems theory. We posit that distinct phenotype-combinations are generated by interactions among robust regulatory switches, each in control of a discrete set of phenotypic outcomes. First, we demonstrate the advantage of characterizing multi-switch regulatory systems in terms of their constituent switches by building a multiswitch cell cycle model which points to novel, testable interactions critical for early G2/M commitment to division. Second, we define quantitative measures of dynamical modularity, namely that global cell states are discrete combinations of switch-level phenotypes. Finally, we formulate three general principles that govern the way coupled switches coordinate their function. PMID- 26979951 TI - Biosynthetic investigation of phomopsins reveals a widespread pathway for ribosomal natural products in Ascomycetes. AB - Production of ribosomally synthesized and posttranslationally modified peptides (RiPPs) has rarely been reported in fungi, even though organisms of this kingdom have a long history as a prolific source of natural products. Here we report an investigation of the phomopsins, antimitotic mycotoxins. We show that phomopsin is a fungal RiPP and demonstrate the widespread presence of a pathway for the biosynthesis of a family of fungal cyclic RiPPs, which we term dikaritins. We characterize PhomM as an S-adenosylmethionine-dependent alpha-N-methyltransferase that converts phomopsin A to an N,N-dimethylated congener (phomopsin E), and show that the methyltransferases involved in dikaritin biosynthesis have evolved differently and likely have broad substrate specificities. Genome mining studies identified eight previously unknown dikaritins in different strains, highlighting the untapped capacity of RiPP biosynthesis in fungi and setting the stage for investigating the biological activities and unknown biosynthetic transformations of this family of fungal natural products. PMID- 26979938 TI - C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. AB - The expansion of a hexanucleotide (GGGGCC) repeat in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both the function of C9ORF72 and the mechanism by which the repeat expansion drives neuropathology are unknown. To examine whether C9ORF72 haploinsufficiency induces neurological disease, we created a C9orf72-deficient mouse line. Null mice developed a robust immune phenotype characterized by myeloid expansion, T cell activation, and increased plasma cells. Mice also presented with elevated autoantibodies and evidence of immune-mediated glomerulonephropathy. Collectively, our data suggest that C9orf72 regulates immune homeostasis and an autoimmune response reminiscent of systemic lupus erythematosus (SLE) occurs in its absence. We further imply that haploinsufficiency is unlikely to be the causative factor in C9ALS/FTD pathology. PMID- 26979952 TI - Biotic homogenization can decrease landscape-scale forest multifunctionality. AB - Many experiments have shown that local biodiversity loss impairs the ability of ecosystems to maintain multiple ecosystem functions at high levels (multifunctionality). In contrast, the role of biodiversity in driving ecosystem multifunctionality at landscape scales remains unresolved. We used a comprehensive pan-European dataset, including 16 ecosystem functions measured in 209 forest plots across six European countries, and performed simulations to investigate how local plot-scale richness of tree species (alpha-diversity) and their turnover between plots (beta-diversity) are related to landscape-scale multifunctionality. After accounting for variation in environmental conditions, we found that relationships between alpha-diversity and landscape-scale multifunctionality varied from positive to negative depending on the multifunctionality metric used. In contrast, when significant, relationships between beta-diversity and landscape-scale multifunctionality were always positive, because a high spatial turnover in species composition was closely related to a high spatial turnover in functions that were supported at high levels. Our findings have major implications for forest management and indicate that biotic homogenization can have previously unrecognized and negative consequences for large-scale ecosystem multifunctionality. PMID- 26979953 TI - Exploring the surfaceome of Ewing sarcoma identifies a new and unique therapeutic target. AB - The cell surface proteome of tumors mediates the interface between the transformed cells and the general microenvironment, including interactions with stromal cells in the tumor niche and immune cells such as T cells. In addition, the cell surface proteome of individual cancers defines biomarkers for that tumor type and potential proteins that can be the target of antibody-mediated therapy. We have used next-generation deep RNA sequencing (RNA-seq) coupled to an in-house database of genes encoding cell surface proteins (herein referred to as the surfaceome) as a tool to define a cell surface proteome of Ewing sarcoma compared with progenitor mesenchymal stem cells. This subtractive RNA-seq analysis revealed a specific surfaceome of Ewing and showed unexpectedly that the leucine rich repeat and Ig domain protein 1 (LINGO1) is expressed in over 90% of Ewing sarcoma tumors, but not expressed in any other somatic tissue apart from the brain. We found that the LINGO1 protein acts as a gateway protein internalizing into the tumor cells when engaged by antibody and can carry antibody conjugated with drugs to kill Ewing sarcoma cells. Therefore, LINGO1 is a new, unique, and specific biomarker and drug target for the treatment of Ewing sarcoma. PMID- 26979942 TI - Structure and Activation of Soluble Guanylyl Cyclase, the Nitric Oxide Sensor. AB - SIGNIFICANCE: Soluble guanylyl/guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) and is central to the physiology of blood pressure regulation, wound healing, memory formation, and other key physiological activities. sGC is increasingly implicated in disease and is targeted by novel therapeutic compounds. The protein displays a rich evolutionary history and a fascinating signal transduction mechanism, with NO binding to an N-terminal heme containing domain, which activates the C-terminal cyclase domains. Recent Advances: Crystal structures of individual sGC domains or their bacterial homologues coupled with small-angle x-ray scattering, electron microscopy, chemical cross-linking, and Forster resonance energy transfer measurements are yielding insight into the overall structure for sGC, which is elongated and likely quite dynamic. Transient kinetic measurements reveal a role for individual domains in lowering NO affinity for heme. New sGC stimulatory drugs are now in the clinic and appear to function through binding near or directly to the sGC heme domain, relieving inhibitory contacts with other domains. New sGC-activating drugs show promise for recovering oxidized sGC in diseases with high inflammation by replacing lost heme. CRITICAL ISSUES: Despite the many recent advances, sGC regulation, NO activation, and mechanisms of drug binding remain unclear. Here, we describe the molecular evolution of sGC, new molecular models, and the linked equilibria between sGC NO binding, drug binding, and catalytic activity. FUTURE DIRECTIONS: Recent results and ongoing studies lay the foundation for a complete understanding of structure and mechanism, and they open the door for new drug discovery targeting sGC. Antioxid. Redox Signal. 26, 107-121. PMID- 26979954 TI - Circadian clock, nutrient quality, and eating pattern tune diurnal rhythms in the mitochondrial proteome. PMID- 26979956 TI - Rapid evolution of a Y-chromosome heterochromatin protein underlies sex chromosome meiotic drive. AB - Sex chromosome meiotic drive, the non-Mendelian transmission of sex chromosomes, is the expression of an intragenomic conflict that can have extreme evolutionary consequences. However, the molecular bases of such conflicts remain poorly understood. Here, we show that a young and rapidly evolving X-linked heterochromatin protein 1 (HP1) gene, HP1D2, plays a key role in the classical Paris sex-ratio (SR) meiotic drive occurring in Drosophila simulans Driver HP1D2 alleles prevent the segregation of the Y chromatids during meiosis II, causing female-biased sex ratio in progeny. HP1D2 accumulates on the heterochromatic Y chromosome in male germ cells, strongly suggesting that it controls the segregation of sister chromatids through heterochromatin modification. We show that Paris SR drive is a consequence of dysfunctional HP1D2 alleles that fail to prepare the Y chromosome for meiosis, thus providing evidence that the rapid evolution of genes controlling the heterochromatin structure can be a significant source of intragenomic conflicts. PMID- 26979955 TI - Detection, phenotyping, and quantification of antigen-specific T cells using a peptide-MHC dodecamer. AB - Here we report a peptide-MHC (pMHC) dodecamer as a "next generation" technology that is a significantly more sensitive and versatile alternative to pMHC tetramers for the detection, isolation, and phenotypic analysis of antigen specific T cells. In particular, dodecamers are able to detect two- to fivefold more antigen-specific T cells in both human and murine CD4(+)and CD8(+)alphabeta T-cell compartments compared with the equivalent tetramers. The low-affinity, tetramer-negative, dodecamer-positive T cells showed comparable effector cytokine responses as those of high-affinity, tetramer-positive T cells. Dodecamers are able to detect early stage CD4(+)CD8(+)double-positive thymocytes on which T-cell receptors are 10- to 30-fold less dense than mature T cells. Dodecamers also show utility in the analysis of gammadelta T cells and in cytometry by time-of-flight applications. This construct has a simple structure with a central scaffold protein linked to four streptavidin molecules, each having three pMHC ligands or other molecules. The dodecamer is straightforward and inexpensive to produce and is compatible with current tetramer technology and commercially available streptavidin conjugates. PMID- 26979957 TI - Snapshot of sequential SNARE assembling states between membranes shows that N terminal transient assembly initializes fusion. AB - Many prominent biological processes are driven by protein assembling between membranes. Understanding the mechanisms then entails determining the assembling pathway of the involved proteins. Because the intermediates are by nature transient and located in the intermembrane space, this determination is generally a very difficult, not to say intractable, problem. Here, by designing a setup with sphere/plane geometry, we have been able to freeze one transient state in which the N-terminal domains of SNARE proteins are assembled. A single camera frame is sufficient to obtain the complete probability of this state with the transmembrane distance. We show that it forms when membranes are 20 nm apart and stabilizes by further assembling of the SNAREs at 8 nm. This setup that fixes the intermembrane distance, and thereby the transient states, while optically probing the level of molecular assembly by Forster resonance energy transfer (FRET) can be used to characterize any other transient transmembrane complexes. PMID- 26979958 TI - Intramolecular allosteric communication in dopamine D2 receptor revealed by evolutionary amino acid covariation. AB - The structural basis of allosteric signaling in G protein-coupled receptors (GPCRs) is important in guiding design of therapeutics and understanding phenotypic consequences of genetic variation. The Evolutionary Trace (ET) algorithm previously proved effective in redesigning receptors to mimic the ligand specificities of functionally distinct homologs. We now expand ET to consider mutual information, with validation in GPCR structure and dopamine D2 receptor (D2R) function. The new algorithm, called ET-MIp, identifies evolutionarily relevant patterns of amino acid covariations. The improved predictions of structural proximity and D2R mutagenesis demonstrate that ET-MIp predicts functional interactions between residue pairs, particularly potency and efficacy of activation by dopamine. Remarkably, although most of the residue pairs chosen for mutagenesis are neither in the binding pocket nor in contact with each other, many exhibited functional interactions, implying at-a-distance coupling. The functional interaction between the coupled pairs correlated best with the evolutionary coupling potential derived from dopamine receptor sequences rather than with broader sets of GPCR sequences. These data suggest that the allosteric communication responsible for dopamine responses is resolved by ET-MIp and best discerned within a short evolutionary distance. Most double mutants restored dopamine response to wild-type levels, also suggesting that tight regulation of the response to dopamine drove the coevolution and intramolecular communications between coupled residues. Our approach provides a general tool to identify evolutionary covariation patterns in small sets of close sequence homologs and to translate them into functional linkages between residues. PMID- 26979959 TI - Inbreeding depression across the lifespan in a wild mammal population. AB - Inbreeding depression is of major concern for the conservation of threatened species, and inbreeding avoidance is thought to be a key driver in the evolution of mating systems. However, the estimation of individual inbreeding coefficients in natural populations has been challenging, and, consequently, the full effect of inbreeding on fitness remains unclear. Genomic inbreeding coefficients may resolve the long-standing paucity of data on inbreeding depression in adult traits and total fitness. Here we investigate inbreeding depression in a range of life history traits and fitness in a wild population of red deer (Cervus elaphus) in Scotland using individual inbreeding coefficients derived from dense Single Nucleotide Polymorphism (SNP) data (Fgrm). We find associations between[Formula: see text]and annual breeding success in both sexes, and between maternal inbreeding coefficient and offspring survival. We also confirm previous findings of inbreeding depression in birth weight and juvenile survival. In contrast, inbreeding coefficients calculated from a deep and comparatively complete pedigree detected inbreeding depression in juvenile survival, but not in any adult fitness component. The total effect of inbreeding on lifetime breeding success (LBS) was substantial in both sexes: for Fgrm = 0.125, a value resulting from a half-sib mating, LBS declined by 72% for females and 95% for males. Our results demonstrate that SNP-based estimates of inbreeding provide a powerful tool for evaluating inbreeding depression in natural populations, and suggest that, to date, the prevalence of inbreeding depression in adult traits may have been underestimated. PMID- 26979960 TI - TFE and Spt4/5 open and close the RNA polymerase clamp during the transcription cycle. AB - Transcription is an intrinsically dynamic process and requires the coordinated interplay of RNA polymerases (RNAPs) with nucleic acids and transcription factors. Classical structural biology techniques have revealed detailed snapshots of a subset of conformational states of the RNAP as they exist in crystals. A detailed view of the conformational space sampled by the RNAP and the molecular mechanisms of the basal transcription factors E (TFE) and Spt4/5 through conformational constraints has remained elusive. We monitored the conformational changes of the flexible clamp of the RNAP by combining a fluorescently labeled recombinant 12-subunit RNAP system with single-molecule FRET measurements. We measured and compared the distances across the DNA binding channel of the archaeal RNAP. Our results show that the transition of the closed to the open initiation complex, which occurs concomitant with DNA melting, is coordinated with an opening of the RNAP clamp that is stimulated by TFE. We show that the clamp in elongation complexes is modulated by the nontemplate strand and by the processivity factor Spt4/5, both of which stimulate transcription processivity. Taken together, our results reveal an intricate network of interactions within transcription complexes between RNAP, transcription factors, and nucleic acids that allosterically modulate the RNAP during the transcription cycle. PMID- 26979962 TI - The Bulletin of Environmental Contamination and Toxicology: The Next Chapter. PMID- 26979961 TI - Cytonuclear interactions affect adaptive traits of the annual plant Arabidopsis thaliana in the field. AB - Although the contribution of cytonuclear interactions to plant fitness variation is relatively well documented at the interspecific level, the prevalence of cytonuclear interactions at the intraspecific level remains poorly investigated. In this study, we set up a field experiment to explore the range of effects that cytonuclear interactions have on fitness-related traits in Arabidopsis thaliana To do so, we created a unique series of 56 cytolines resulting from cytoplasmic substitutions among eight natural accessions reflecting within-species genetic diversity. An assessment of these cytolines and their parental lines scored for 28 adaptive whole-organism phenotypes showed that a large proportion of phenotypic traits (23 of 28) were affected by cytonuclear interactions. The effects of these interactions varied from slight but frequent across cytolines to strong in some specific parental pairs. Two parental pairs accounted for half of the significant pairwise interactions. In one parental pair, Ct-1/Sha, we observed symmetrical phenotypic responses between the two nuclear backgrounds when combined with specific cytoplasms, suggesting nuclear differentiation at loci involved in cytonuclear epistasis. In contrast, asymmetrical phenotypic responses were observed in another parental pair, Cvi-0/Sha. In the Cvi-0 nuclear background, fecundity and phenology-related traits were strongly affected by the Sha cytoplasm, leading to a modified reproductive strategy without penalizing total seed production. These results indicate that natural variation in cytoplasmic and nuclear genomes interact to shape integrative traits that contribute to adaptation, thereby suggesting that cytonuclear interactions can play a major role in the evolutionary dynamics ofA. thaliana. PMID- 26979963 TI - Potential Implications of Approaches to Climate Change on the Clean Water Rule Definition of "Waters of the United States". AB - The 1972 Clean Water Act was passed to protect chemical, physical, and biological integrity of United States' waters. The U.S. Environmental Protection Agency and U.S. Army Corps of Engineers codified a new "waters of the United States" rule on June 29, 2015, because several Supreme Court case decisions caused confusion with the existing rule. Climate change could affect this rule through connectivity between groundwater and surface waters; floodplain waters and the 100-year floodplain; changes in jurisdictional status; and sea level rise on coastal ecosystems. Four approaches are discussed for handling these implications: (1) "Wait and see"; (2) changes to the rule; (3) use guidance documents; (4) Congress statutorily defining "waters of the United States." The approach chosen should be legally defensible and achieved in a timely fashion to provide protection to "waters of the United States" in proactive consideration of scientifically documented effects of climate change on aquatic ecosystems. PMID- 26979964 TI - Impact of chronic hepatitis C on mortality in cirrhotic patients admitted to intensive-care unit. AB - BACKGROUND: Cirrhosis and severe sepsis are factors associated with increased mortality in intensive care unit (ICU), but chronic hepatitis C (CHC) has been less studied in ICU. The aim of this study was to analyze the impact of CHC on the mortality of cirrhotic patients admitted to ICU according to severe sepsis and decompensated cirrhosis. METHODS: We carried out a retrospective study based on CHC-cirrhotic patients (CHC-group) admitted to ICU (n = 1138) and recorded in the Spanish Minimum Basic Data Set (2005-2010). A control-group (randomly selected cirrhotic patients without HIV, HBV, or HCV infections) was also included (n = 4127). The primary outcome variable was ICU mortality. The cumulative mortality rate on days 7, 30, and 90 in patients admitted to the ICUs was calculated by dividing the number of deaths by the number of patients admitted to the ICU. The adjusted hazard ratio (aHR) for death in the ICU was estimated through a semi-parametric Bayesian model of competing risk. RESULTS: The CHC-group had a higher cumulative incidence of severe sepsis than the control group in compensated cirrhosis (37.4 vs. 31.1%; p = 0.024), but no differences between the CHC-group and the control-group in decompensated cirrhosis were found. Moreover, a higher cumulative incidence of severe sepsis was associated with decompensated cirrhosis compared to compensated cirrhosis in the control group (40.1 vs. 31.1%; p < 0.001) whereas this was not observed in the CHC group (38.1 vs. 37.4%; p = 0.872). The CHC-group had higher cumulative mortality than the control-group by days 7 (47 vs. 41.3%; p < 0.001), 30 (78.5 vs. 73.5%; p < 0.001), and 90 (96.3 vs. 95.9%; p < 0.001). In a competitive risk model, the CHC group had a higher risk of dying if the ICU course was complicated by severe sepsis (adjusted hazard ratio (aHR) = 1.19; p = 0.003), but no significant values in patients with absence of severe sepsis were found (aHR = 1.09; p= 0.068). When patients were stratified by cirrhosis stage and severe sepsis, CHC patients with compensated cirrhosis had the higher risk of death if they had severe sepsis (aHR = 1.35; p = 0.002). Moreover, the survival was low in patients with decompensated cirrhosis and severe sepsis but we did not find significant differences between CHC-group and control-group. CONCLUSIONS: CHC was associated with an increased risk of death in cirrhotic patients admitted to ICUs, particularly in patients with compensated cirrhosis and severe sepsis. PMID- 26979965 TI - Neural mechanisms linking social status and inflammatory responses to social stress. AB - Social stratification has important implications for health and well-being, with individuals lower in standing in a hierarchy experiencing worse outcomes than those higher up the social ladder. Separate lines of past research suggest that alterations in inflammatory processes and neural responses to threat may link lower social status with poorer outcomes. This study was designed to bridge these literatures to investigate the neurocognitive mechanisms linking subjective social status and inflammation. Thirty-one participants reported their subjective social status, and underwent a functional magnetic resonance imaging scan while they were socially evaluated. Participants also provided blood samples before and after the stressor, which were analysed for changes in inflammation. Results showed that lower subjective social status was associated with greater increases in inflammation. Neuroimaging data revealed lower subjective social status was associated with greater neural activity in the dorsomedial prefrontal cortex (DMPFC) in response to negative feedback. Finally, results indicated that activation in the DMPFC in response to negative feedback mediated the relation between social status and increases in inflammatory activity. This study provides the first evidence of a neurocognitive pathway linking subjective social status and inflammation, thus furthering our understanding of how social hierarchies shape neural and physiological responses to social interactions. PMID- 26979967 TI - The Improvement of Gastroesophageal Reflux Disease and Barrett's after Bariatric Surgery. AB - Obesity and gastroesophageal reflux disease (GERD) are prevalent in Western populations. In obese patients, high-resolution manometry often shows altered gastroesophageal pressure gradients, promoting retrograde gastric content flow into the esophagus and esophagogastric junction disruption, leading to a hiatal hernia. Hernia recurrence is higher in the obese, and recurrence is seen regardless of the operative approach used. Bariatric surgery is the gold-standard treatment for GERD in obese patients, and symptom improvement varies depending on the specific bariatric procedure performed, Roux-en-Y (RYGB), laparoscopic adjustable gastric banding (LAGB), or sleeve gastrectomy (SG). Studies have shown these surgeries significantly improve GERD, but RYGB had the greatest effect. Limited data is available examining the progression or regression of Barrett's following bariatric surgery. We currently recommend RYGB for morbidly obese patients with Barrett's esophagus. PMID- 26979966 TI - Primary somatosensory contribution to action observation brain activity-combining fMRI and cTBS. AB - Traditionally the mirror neuron system (MNS) only includes premotor and posterior parietal cortices. However, somatosensory cortices, BA1/2 in particular, are also activated during action execution and observation. Here, we examine whether BA1/2 and the parietofrontal MNS integrate information by using functional magnetic resonance imaging (fMRI)-guided continuous theta-burst stimulation (cTBS) to perturb BA1/2. Measuring brain activity using fMRI while participants are under the influence of cTBS shows local cTBS effects in BA1/2 varied, with some participants showing decreases and others increases in the BOLD response to viewing actions vs control stimuli. We show how measuring cTBS effects using fMRI can harness this variance using a whole-brain regression. This analysis identifies brain regions exchanging action-specific information with BA1/2 by mapping voxels away from the coil with cTBS-induced, action-observation-specific BOLD contrast changes that mirror those under the coil. This reveals BA1/2 exchanges action-specific information with premotor, posterior parietal and temporal nodes of the MNS during action observation. Although anatomical connections between BA1/2 and these regions are well known, this is the first demonstration that these connections carry action-specific signals during observation and hence, that BA1/2 plays a causal role in the human MNS. PMID- 26979968 TI - Administering Probiotics in Duodenal-Jejunal Bypass Surgery Induces More Weight Loss in Sprague-Dawley Rats. PMID- 26979969 TI - Author's Reply to Dayal: "Therapies to Preserve beta-Cell Function in Type 1 Diabetes". PMID- 26979970 TI - Comment on: "Therapies to Preserve beta-Cell Function in Type 1 Diabetes". PMID- 26979971 TI - Conducting Real-Time Videofluoroscopic Swallow Study via Telepractice: A Preliminary Feasibility and Reliability Study. AB - A small number of studies have examined the feasibility of conducting videofluoroscopic swallow studies (VFSS) via telepractice. While the results have confirmed this potential, the systems tested to date have either reported issues that impacted the ability to analyze/interpret the VFSS recordings in real time, or they were not designed to enable real-time interpretation. Further system design is needed to establish a telepractice model that enables the VFSS assessment to be both guided and interpreted live in real time. The aim of this study was to test the feasibility and reliability of using a telepractice system to enable live VFSS assessment. Twenty adult patients underwent a VFSS assessment directed by a telepractice SLP with competency in VFSS located in another room of the hospital. The telepractice clinician led the sessions using a C20 Cisco TelePresence System. This was linked in real time via a secure telehealth network (at 4 megabits per second (Mbit/s)) to a C60 Cisco TelePresence System located in a fluoroscopy suite, connected to the digital fluoroscopy system. Levels of agreement were calculated between the telepractice clinician and a face-to-face clinician who simultaneously rated the VFSS in real time. High levels of agreement for swallowing parameters (range = 75-100 %; k = -0.34 to 1.0) and management decisions (range = 70-100 %, k = 0.64-1.0) were found. A post-session questionnaire revealed clinicians agreed that the telepractice system enabled successful remote assessment of VFSS. The findings support the potential to conduct live VFSS assessment via a telepractice model. PMID- 26979972 TI - Experiences and attitudes of residents regarding a community-based genome cohort study in Japan: a population-based, cross-sectional study. AB - BACKGROUND: Because of the rapid development in genomics, more research findings have emerged. However, the association between society and research results remains controversial. This article examines the experiences and attitudes of residents regarding a community-based genomic cohort study. METHODS: This study was conducted as a part of the health survey of the City Health Promotion section. At the conclusion of the first stage of the project, a self-administered questionnaire was mailed to a random sample of 2,500 residents in 2012. RESULTS: The response rate was 59 % (n = 1477/2500). The findings show that 70 % of males and 50 % of females knew nothing about the project. Females and elderly people were more likely to have knowledge of the study, indicating that self-rated understanding of the terminology is statistically associated with the level of awareness regarding the project. In addition, those who were aware of the project were also aware of the benefits of research utilizing genetic information, whereas unaware respondents, particularly males, believed that unexpected negative effects may occur. Those with higher self-rated understanding of the terminology and higher awareness of benefit of the research utilizing genetic information had more positive attitudes toward undergoing drug susceptibility genetic testing, indicating that the awareness of project in females and concerns toward genetic research are not statistically associated with the willingness to undergo. CONCLUSIONS: This study suggests that a community-based genome cohort project helps raise awareness of benefit of genetic research and that knowledge, however, does not directly affect the willingness to participate in related activities, such as drug susceptibility genetic testing. Therefore, additional research that focuses on the circular relationship between risk and action must be conducted in the future. PMID- 26979973 TI - Photoacoustics of single laser-trapped nanodroplets for the direct observation of nanofocusing in aerosol photokinetics. AB - Photochemistry taking place in atmospheric aerosol droplets has a significant impact on the Earth's climate. Nanofocusing of electromagnetic radiation inside aerosols plays a crucial role in their absorption behaviour, since the radiation flux inside the droplet strongly affects the activation rate of photochemically active species. However, size-dependent nanofocusing effects in the photokinetics of small aerosols have escaped direct observation due to the inability to measure absorption signatures from single droplets. Here we show that photoacoustic measurements on optically trapped single nanodroplets provide a direct, broadly applicable method to measure absorption with attolitre sensitivity. We demonstrate for a model aerosol that the photolysis is accelerated by an order of magnitude in the sub-micron to micron size range, compared with larger droplets. The versatility of our technique promises broad applicability to absorption studies of aerosol particles, such as atmospheric aerosols where quantitative photokinetic data are critical for climate predictions. PMID- 26979974 TI - An analysis of volumes, prices and pricing trends of the pediatric antiretroviral market in developing countries from 2004 to 2012. AB - BACKGROUND: The pediatric antiretroviral (ARV) market is poorly described in the literature, resulting in gaps in understanding treatment access. We analyzed the pediatric ARV market from 2004 to 2012 and assessed pricing trends and associated factors. METHODS: Data on donor funded procurements of pediatric ARV formulations reported to the Global Price Reporting Mechanism database from 2004 to 2012 were analyzed. Outcomes of interest were the volume and mean price per patient-year ARV formulation based on WHO ARV dosing recommendations for a 10 kg child. Factors associated with the price of formulations were assessed using linear regression; potential predictors included: country income classification, geographical region, market segment (originator versus generic ARVs), and number of manufacturers per formulation. All analyses were adjusted for type of formulations (single, dual or triple fixed-dose combinations (FDCs)) RESULTS: Data from 111 countries from 2004 to 2012 were included, with procurement of 33 formulations at a total value of USD 204 million. Use of dual and triple FDC formulations increased substantially over time, but with limited changes in price. Upon multivariate analysis, prices of originator formulations were found to be on average 72 % higher than generics (p < 0.001). A 10 % increase in procurement volume was associated with a 1 % decrease (p < 0.001) in both originator and generic prices. The entry of one additional manufacturer producing a formulation was associated with a decrease in prices of 2 % (p < 0.001) and 8 % (p < 0.001) for originator and generic formulations, respectively. The mean generic ARV price did not differ by country income level. Prices of originator ARVs were 48 % (p < 0.001) and 14 % (p < 0.001) higher in upper-middle income and lower-middle income countries compared to low income countries respectively, with the exception of South Africa, which had lower prices despite being an upper middle income country. CONCLUSIONS: The donor funded pediatric ARV market as represented by the GPRM database is small, and lacks price competition. It is dominated by generic drugs due to the lower prices offered and the practicality of FDC formulations. This market requires continued donor support and the current initiatives to protect it are important to ensure market viability, especially if new formulations are to be introduced in the future. PMID- 26979975 TI - Frequency of Lipohypertrophy and Associated Risk Factors in Young Patients with Type 1 Diabetes: A Cross-Sectional Study. AB - INTRODUCTION: The objective of this study was to investigate the frequency of lipohypertrophy (LH) and the associated risk factors in young patients with type 1 diabetes mellitus (T1DM). METHODS: This cross-sectional study was conducted on a sample of 174 patients with T1DM (aged 13-18 years) treated with multiple daily insulin injections for a minimum duration of 1 year. The study was performed at the Diabetes Treatment Center, Prince Sultan Military Medical City (Riyadh, Saudi Arabia), between July 2015 and September 2015. Information regarding patients' age, weight, height, adjusted body mass index (BMI), period of the diabetic condition, length of needle used, number of injections per day, injection locations, insulin regimen, and glycosylated hemoglobin (HbA1c) were recorded. LH was assessed using the palpation technique. RESULTS: Nearly 46% of patients were found to reuse needles, while 42.5% failed to alternate the injection site and 23% revealed unexplained hypoglycemic events. A substantial percentage of patients (approximately 47%) showed grade 1 LH, followed by 33.7% with grade 2 and 19.3% with grade 3 LH. A higher frequency of LH was observed in the thigh region (n = 28, 33.7%) than in the arm, which was second highest (n = 23, 27.7%). Patients aged >=16 years showed a higher frequency of LH than those aged <16 years. Patients with uncontrolled diabetes mellitus had a greater likelihood of having LH (59.5%) than those with controlled diabetes (20.8%). Significant differences in LH were observed based on needle length, needle reuse, and rotation of the injection sites. On performing regression analysis, the independent risk factors for LH were found to be as follows: higher BMI, higher HbA1c, a higher number of injection sites, a higher rate of needle reuse and failed to alternate the injection site. CONCLUSION: As the frequency of LH was found to be high in Saudi patients with T1DM, it is essential to educate patients on the risk factors for LH and on diabetic control. PMID- 26979976 TI - Prolongation of the degradation period and improvement of the angiogenesis of zein porous scaffolds in vivo. AB - Zein porous scaffolds modified with fatty acids have shown great improvement in mechanical properties and good cell compatibility in vitro, indicating the potential application as a bone tissue engineering substitute. The present study was conducted to systematically investigate whether the addition of fatty acids affects the short-term (up to 12 weeks) and long-term (up to 1 year) behaviors of scaffolds in vivo, mainly focusing on changes in the degradation period and inflammatory responses. Throughout the implantation period, no abnormal signs occurred and zein porous scaffolds modified with oleic acid showed good tolerance in rabbits, characterized by the growth of relatively more blood vessels in the scaffolds and only a slight degree of fibrosis histology. Moreover, the degradation period was prolonged from 8 months to 1 year as compared to the control. These results affirmed further that zein could be used as a new kind of natural biomaterial suitable for bone tissue engineering. PMID- 26979977 TI - Evolutionary study of leporid CD4 reveals a hotspot of genetic variability within the D2 domain. AB - CD4 is the major receptor on T helper cells involved in the uptake of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) into their host cells. Evolutionary studies of CD4 in primates revealed signatures of positive selection in the D1 domain that interacts with primate exogenous lentivirus gp120 proteins. Here, we studied the evolution of CD4 in lagomorphs by comparing sequences obtained for the genera Oryctolagus, Sylvilagus, Lepus, and Ochotona. Our results reveal an overall higher divergence in lagomorphs compared to primates with highest divergence in the D2 domain. A detailed analysis of a small fragment of 33 nucleotides coding for amino acids 169 to 179 in the D2 domain showed dramatic amino acid alterations with a dN/dS value of 3.2 for lagomorphs, suggesting that CD4 is under strong positive selection in this particular region. Within each leporid genus, no significant amino acid changes were observed for the D2 domain which indicates that the genetic differentiation occurred in the ancestor of each genus before the species radiation. The rabbit endogenous lentivirus type K (RELIK) found in leporids shares high structural similarity with HIV which suggests a possible interaction between RELIK and CD4. The presence of RELIK in the studied leporids, the high structural similarity to modern-day exogenous lentiviruses and the absence of exogenous lentiviruses in leporids, allows us to hypothesize that this endogenous retrovirus, that was most probably exogenous in the past, drove the divergent evolution of leporid CD4. PMID- 26979978 TI - Myocutaneous transpelvic flaps do improve quality of life and help to reduce wound healing complications in patients receiving abdominoperineal resection in the real world. PMID- 26979979 TI - Disease pattern in Danish patients with Peutz-Jeghers syndrome. AB - PURPOSE: In this paper, we aimed to collect genetic and medical information on all Danish patients with Peutz-Jeghers syndrome (PJS), in order to contribute to the knowledge of phenotype and genotype. Peutz-Jeghers syndrome is a hereditary syndrome characterized by multiple hamartomatous polyps in the GI tract, mucocutaneous pigmentations, and an increased risk of cancer in the GI tract and at extraintestinal sites. Over 90 % of patients harbour a pathogenic mutation in STK11. METHODS: Based on the Danish Pathology Data Bank, the Danish National Patient Register, as well as information from relevant departments at Danish hospitals, we identified patients and collected clinical and genetic information. RESULTS: We identified 43 patients of which 14 were deceased. The prevalence was estimated to be ~1 in 195,000 individuals. The median age at first symptom was 27.5 with invagination of the small bowel as the most frequent presenting symptom. We noted 18 occurrences of cancer at various anatomical sites, including a case of thyroid cancer and penile cancer. Eight of the deceased patients had died of cancer. Eighteen different mutations in STK11 had been detected in 28 patients. CONCLUSION: This is the first comprehensive study of patients with Peutz-Jeghers syndrome in the Danish population identified from nationwide registers and databases. We have demonstrated that the expressivity of Peutz Jeghers syndrome varies greatly among the patients, even within the same families, underlining the great phenotypic spectrum. Patients with PJS should be offered surveillance from childhood in order to prevent morbidity and reduce mortality. PMID- 26979980 TI - Total caseload of a colorectal surgical unit: baseline measurement and identification of areas for efficiency gains. AB - PURPOSE: Resource limitations are a concern in most modern public hospital systems. The aim of this study is to prospectively quantify the total caseload of a tertiary colorectal surgery unit to identify areas of redundancy. METHODS: Data was collected prospectively at all points of clinical care (outpatient clinic, inpatient referrals, operating theatre and endoscopy) between March 2014 and March 2015 using specifically designed templates. The final data was analysed using descriptive statistics. RESULTS: During the study period, 4012 patient episodes were recorded: 2871 in outpatient clinic, 186 as emergency patient referrals, 541 at colonoscopy and 414 at surgery. The largest component of the caseload was made up primarily of colonoscopy results follow-up, protocol review for previous cancer or polyps and post-operative review. Sixty-eight percent of these episodes did not result in any active intervention such as further tests or surgery. Most new outpatient referrals were undifferentiated, with the most common indications being minor rectal bleeding, non-specific gastrointestinal symptoms, and minor non-bleeding anorectal problems. Of the new referrals, 56 % were booked for a colonoscopy, and only 13.3 % were booked directly for elective surgery. CONCLUSION: A large component of the caseload of a tertiary colorectal surgery unit is made up of post-colonoscopy, post-operative, and surveillance protocol follow-up, with a significant proportion of patients not requiring any active intervention. The majority of new referrals are undifferentiated and result in a low rate of direct booking for operative intervention. Rationalisation of this resource using evidence-based methods could reduce redundancy, workload, and cost. PMID- 26979981 TI - Laparoscopy for bowel obstruction--a contradiction? Results of a multi institutional survey in Germany. AB - PURPOSE: The purpose of the present study was to investigate on the acceptance and frequency of laparoscopic surgery for the management of acute and chronic bowel obstruction in a general patient population in German hospitals. METHODS: To receive an authoritative opinion on laparoscopic treatment of bowel obstruction in Germany, a cross-sectional online study was conducted. We designed an online-based survey, supported by the German College of Surgeons (Berufsverband der Deutschen Chirurgen, BDC) to get multi-institutional-based data from various level providers of patient care. RESULTS: Between January and February 2014, we received completed questionnaires from 235 individuals (16.7 %). The participating surgeons were a representative sample of German hospitals with regard to hospital size, level of center size, and localization. A total of 74.9 % (n = 176) of all responders stated to use laparoscopy as the initial step of exploration in expected bowel obstruction. This procedure was highly statistically associated with the frequency of overall laparoscopic interventions and laparoscopic experience. The overall conversion rate was reported to be 29.4 %. CONCLUSIONS: This survey, investigating on the use of laparoscopic exploration or interventions in bowel obstruction, was able to show that by now, a majority of the responding surgeons accept laparoscopy as an initial step for exploration of the abdomen in the case of bowel obstruction. Laparoscopy was considered to be at least comparable to open surgery in an emergency setting. Furthermore, data analysis demonstrated generally accepted advantages and disadvantages of the laparoscopic approach. Indications for or against laparoscopy are made after careful consideration in each individual case. PMID- 26979983 TI - "Things I did not know": Retrospectives on a Canadian rural male youth suicide using an instrumental photovoice case study. AB - In Canada, it is young, rural-based men who are at the greatest risk of suicide. While there is no consensus on the reasons for this, evidence points to contextual social factors including isolation, lack of confidential services, and pressure to uphold restrictive norms of rural masculinity. In this article, we share findings drawn from an instrumental photovoice case study to distil factors contributing to the suicide of a young, Canadian, rural-based man. Integrating photovoice methods and in-depth qualitative, we conducted interviews with seven family members and close friends of the deceased. The interviews and image data were analyzed using constant comparative methods to discern themes related to participants' reflections on and perceptions about rural male suicide. Three inductively derived themes, "Missing the signs," "Living up to his public image," and "Down in Rural Canada," reflect the challenges that survivors and young rural men can experience in attempting to be comply with restrictive dominant ideals of masculinity. We conclude that community-based suicide prevention efforts would benefit from gender-sensitive and place-specific approaches to advancing men's mental health by making tangibly available and affirming an array of masculinities to foster the well-being of young, rural-based men. PMID- 26979982 TI - A computer-assisted motivational social network intervention to reduce alcohol, drug and HIV risk behaviors among Housing First residents. AB - BACKGROUND: Individuals transitioning from homelessness to housing face challenges to reducing alcohol, drug and HIV risk behaviors. To aid in this transition, this study developed and will test a computer-assisted intervention that delivers personalized social network feedback by an intervention facilitator trained in motivational interviewing (MI). The intervention goal is to enhance motivation to reduce high risk alcohol and other drug (AOD) use and reduce HIV risk behaviors. METHODS/DESIGN: In this Stage 1b pilot trial, 60 individuals that are transitioning from homelessness to housing will be randomly assigned to the intervention or control condition. The intervention condition consists of four biweekly social network sessions conducted using MI. AOD use and HIV risk behaviors will be monitored prior to and immediately following the intervention and compared to control participants' behaviors to explore whether the intervention was associated with any systematic changes in AOD use or HIV risk behaviors. DISCUSSION: Social network health interventions are an innovative approach for reducing future AOD use and HIV risk problems, but little is known about their feasibility, acceptability, and efficacy. The current study develops and pilot-tests a computer-assisted intervention that incorporates social network visualizations and MI techniques to reduce high risk AOD use and HIV behaviors among the formerly homeless. CLINICALTRIALS. GOV IDENTIFIER: NCT02140359. PMID- 26979984 TI - Effects of overexpression of PKAc genes on expressions of lignin-modifying enzymes by Pleurotus ostreatus. AB - We studied the role of genes encoding the cAMP-dependent protein kinase A catalytic subunit (PKAc) in the ligninolytic system in Pleurotus ostreatus. The wild-type P. ostreatus strain PC9 has two PKAc-encoding genes: PKAc1 and PKAc2 (protein ID 114122 and 85056). In the current study, PKAc1 and PKAc2 were fused with a beta-tubulin promoter and introduced into strain PC9 to produce the overexpression strains PKAc1-97 and PKAc2-69. These strains showed significantly higher transcription levels of isozyme genes encoding lignin-modifying enzymes than strain PC9, but the specific gene expression patterns differed between the two recombinant strains. Both recombinants showed 2.05-2.10-fold faster degradation of beechwood lignin than strain PC9. These results indicate that PKAc plays an important role in inducing the wood degradation system in P. ostreatus. PMID- 26979985 TI - The case test-negative design for studies of the effectiveness of influenza vaccine in inpatient settings. AB - Background: The test-negative design (TND) to evaluate influenza vaccine effectiveness is based on patients seeking care for acute respiratory infection, with those who test positive for influenza as cases and the test-negatives serving as controls. This design has not been validated for the inpatient setting where selection bias might be different from an outpatient setting. Methods: We derived mathematical expressions for vaccine effectiveness (VE) against laboratory-confirmed influenza hospitalizations and used numerical simulations to verify theoretical results exploring expected biases under various scenarios. We explored meaningful interpretations of VE estimates from inpatient TND studies. Results: VE estimates from inpatient TND studies capture the vaccine-mediated protection of the source population against laboratory-confirmed influenza hospitalizations. If vaccination does not modify disease severity, these estimates are equivalent to VE against influenza virus infection. If chronic cardiopulmonary individuals are enrolled because of non-infectious exacerbation, biased VE estimates (too high) will result. If chronic cardiopulmonary disease status is adjusted for accurately, the VE estimates will be unbiased. If chronic cardiopulmonary illness cannot be adequately be characterized, excluding these individuals may provide unbiased VE estimates. Conclusions: The inpatient TND offers logistic advantages and can provide valid estimates of influenza VE. If highly vaccinated patients with respiratory exacerbation of chronic cardiopulmonary conditions are eligible for study inclusion, biased VE estimates will result unless this group is well characterized and the analysis can adequately adjust for it. Otherwise, such groups of subjects should be excluded from the analysis. PMID- 26979986 TI - Leisure-time physical inactivity and association with body mass index: a Finnish Twin Study with a 35-year follow-up. AB - Background: We investigated the stability and change of leisure-time physical inactivity in adult men and women during a 35-year follow-up. We also analysed the impact of long-term physical inactivity on the development of body mass index (BMI). Methods: : In this population-based cohort study, 5254 Finnish twin individuals (59% women) participated in four surveys in 1975, 1981, 1990 and 2011. Mean age at baseline was 23.9 years. Individual long-term leisure-time physical activity (LTPA) was categorized into seven classes varying from 'persistently inactive' to 'persistently active'. We used the multivariate multilevel mixed-effects linear regression model and paired-sample t-test in the analyses. Co-twin control design was used for examining within-pair associations. Results: : Of men 11%, and of women 8%, were persistently inactive. Among both sexes, the mean BMI slope trajectories were steeper among the persistently inactive and those who became inactive than among those who were persistently active. Overall, the inactive participants gained 1.4 kg/m 2 [95% confidence interval (CI) 1.2 to 1.7] more in weight than did the active participants from 1975 to 2011. Among twin pairs discordant for LTPA, the corresponding difference was 1.4 kg/m 2 (95% CI 0.83 to 2.0) in dizygotic pairs and 0.68 kg/m 2 (95% CI 0.05 to1.3) in monozygotic pairs. Conclusions: Over a 35-year time span from young adulthood, persistently inactive participants and those who had become inactive had greater weight increases than those who were persistently active. This association was also found in twin-pair analyses, although attenuated in monozygotic pairs. This may support the importance of LTPA in weight management, although further causal inference is required. PMID- 26979987 TI - Combined body mass index with high-sensitivity C-reactive protein as independent predictors for chronic kidney disease in a relatively healthy population in Taiwan. AB - BACKGROUND/OBJECTIVES: Obesity, a chronic inflammatory state, increases risk of cardiovascular disease and insulin resistance, which are the leading cause of end stage renal disease (ESRD). We evaluated the relationship between body mass index (BMI) and high-sensitivity C-reactive protein (hsCRP) level and impaired kidney function to determine the predictive value of both markers for estimating chronic kidney disease (CKD) risk in a healthy adult population in Taiwan. SUBJECTS/METHODS: In a retrospective cross-sectional study of 4100 subjects ?18 years, a multivariate logistic regression model was used to assess the relationship among BMI, high hsCRP levels and CKD. Receiver-operating characteristic curve and Youden index were developed to define the discrimination power of combining BMI with hsCRP for CKD prediction and to determine the best predictive index. RESULTS: Overweight/obese subjects with high hsCRP levels had the highest odds ratio for CKD (P=0.048). In females, combining BMI with hsCRP for CKD prediction was superior to that of males (0.890 vs 0.623, respectively; both P<0.001). For females, the Youden index was 25.65 kg/m(2) for BMI and 1.04 MUg/ml for hsCRP. CONCLUSIONS: Overweight/obesity with higher hsCRP levels is associated with reduced renal function and increased risk for CKD. BMI and hsCRP levels can be used as surrogate markers for CKD risk, especially for females. PMID- 26979988 TI - Different effects of living conditions on the variation in BMI and height in children before the onset of puberty. AB - BACKGROUND/OBJECTIVES: Biological indicators of children's growth, such as the mean values for both height and weight, are often used as markers of change in living conditions. However, little is known about how the quality of life affects the variation in height and weight. Therefore, the aim of this study was to assess the variation in height and body mass index (BMI) in Polish children between 1966 and 2012. During this period, Poland underwent vast political and socioeconomic changes. SUBJECTS/METHODS: The study included 5597 boys and 5479 girls aged 7-8 years of age. Socioeconomic status (SES) was defined in three categories: high, medium and low. RESULTS: Between 1966 and 2012, the mean values for height and BMI significantly increased in both sexes (P<0.001). The variation of these two parameters, however, showed a different pattern. Whereas the variation in Z-values for height remained unchanged in both sexes, the variation in BMI increased in boys (P<0.01) but not in girls. SES affected the variation in Z-BMI in 1978 in both sexes (P<0.001), whereas variation in Z-height between SES categories remained unchanged across all years of surveys in boys. Before the political transformation, significant regional differences were observed in the variances of Z-BMI (P<0.05) but not of Z-height. This pattern changed after the political transformation, when regional differences in variances of Z-BMI disappeared. CONCLUSIONS: It is concluded that the mean values and the variation of BMI are affected by a changing quality of life, whereas the variation in height is usually independent of living conditions. PMID- 26979989 TI - Association of serum selenium with thyroxin in severely iodine-deficient young children from the Amhara region of Ethiopia. AB - BACKGROUND/OBJECTIVES: Selenium (Se) as part of glutathione peroxidase and iodothyronine deiodinase enzymes influences thyroid metabolism. This study investigated the association of serum Se levels with thyroid metabolism of severely iodine-deficient young children from the Amhara region of Ethiopia. SUBJECTS/METHODS: In a cross-sectional study, Se, thyroid-stimulating hormone, total thyroxin, total triiodothyronine and thyroglobulin in serum of children (N=628) 54-60 months of age from the Amhara region, Ethiopia, were analyzed. In addition, iodine in urine and household salt was analyzed, and the presence of goiter was assessed. RESULTS: The median serum Se concentration was 61.4 MUg/l (10.7-290.9 MUg/l). Selenium deficiency (serum Se <70 MUg/l) was detected in 57.8% (N=349) of the children. The median urinary iodine concentration (UIC) was 9.8 MUg/l. The majority (86.6%, N=449) of children had UIC below the recommended value (100 MUg/l). In addition, 59.8% (N=310) of children were severely iodine deficient (UIC<20 MUg/l). Only 12.7% of salt samples had iodine. Goiter was present in 44.6% (N=280) of the children. Selenium-deficient children had higher serum thyroxin (T4) than children with normal serum Se concentration (P<0.001). CONCLUSIONS: Serum Se was negatively associated with T4 level in young children from the Amhara region of Ethiopia and may endanger the effectiveness of the salt iodization program. PMID- 26979990 TI - Vitamin D and incident urinary incontinence in older adults. AB - BACKGROUND/OBJECTIVES: The aim of this study is to determine whether vitamin D status is associated with incident urinary incontinence (UI) among community dwelling older adults. SUBJECTS/METHODS: The University of Alabama at Birmingham Study of Aging is a prospective cohort study of community-dwelling Medicare enrollees. Standardized assessment of UI was conducted using the validated Incontinence Severity Index. The analysis of 25-hydroxyvitamin D [25(OH)D] levels was performed on stored baseline sera. UI was assessed every 6-12 months for up to 42 months. The analyses included multivariable logistic regression and Cox proportional hazard models. RESULTS: Of 350 participants (175 male, 147 black, mean age 73.6+/-5.8), 54% (189/350) were vitamin D deficient (25(OH)D <20 ng/ml) and 25% (87/350) were vitamin D insufficient (25(OH)D: 20 ng/ml to <30 ng/ml). Among the 187 subjects with no UI at baseline, 57% (107/187) were vitamin D deficient and 24% (45/187) were vitamin D insufficient. A total of 175 of the 187 subjects had follow-up evaluation for incident UI over 42 months, and incident UI occurred in 37% (65/175). After adjustment, cumulative incident UI at 42 months was associated with baseline vitamin D insufficiency (P=0.03) and demonstrated a trend association with deficiency (P=0.07). There was no association between baseline vitamin D status and the time to incident UI. CONCLUSIONS: These preliminary results support an association between vitamin D and incident UI in community-dwelling older adults. Future studies may target specific at-risk groups, such as men with BPH or women with pelvic floor disorders for evaluation of the impact of vitamin D supplementation on urinary symptoms. PMID- 26979991 TI - The power of the kashrut: older but shorter. The impact of religious nutritional and hygienic rules on stature and life expectancy of Jewish conscripts in the early 19th century. AB - BACKGROUND/OBJECTIVES: We test the impact of several demographic, economic and social factors on stature in an early nineteenth century environment. SUBJECTS/METHODS: We use a database of conscripts from the period 1818-1860 of a rural province in The Netherlands (Drenthe). This area had a rather high biological standard of living. This database of 413 conscripts contains information about family structure, family rank order, height, tax income, occupation and age of death. Conscripts came from two communities: one from a particular village (Oosterhesselen) and the other was Jewish conscripts that came from the countryside of the province. RESULTS: Our statistical analysis shows a positive significant relationship between family size and height, which confirms the resource dilution theory. Remarkably, the sign of the relation between family size and life expectancy is inverse. Other factors such as the potato crisis and income had the expected effect on conscript heights. The community effect was strong. Jewish conscripts were much shorter than their counterparts. Access to nutrition, the specific food laws and other factors can explain this difference. CONCLUSIONS: An increasing sibship size had a negative impact on body height but positive effects on life expectancy when adulthood was reached. Specifically for the Jewish community was the positive effect of the death of the father on conscript height. The mechanisms behind this phenomenon are unclear and open for further research. PMID- 26979994 TI - Histological and immunohistochemical effects of L-arginine and silymarin on TNBS induced inflammatory bowel disease in rats. AB - Inflammatory bowel disease (IBD) is a chronic disease that affects quality of life. Various mediators are involved in IBD pathogenesis including inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NF-kappaB), cytochrome c, heat shock protein 70 (HSP70) and tumor necrosis factor (TNF)-alpha. L-Arginine (L-Arg) can be depleted in IBD, and silymarin inhibits neutrophil infiltration, NF-kappaB, and TNF-alpha, which have crucial roles in inducing IBD. This study aimed to investigate whether silymarin and L-Arg supplementation decreases IBD progression in trinitrobenzine-sulfonic acid (TNBS)-induced colitis. Fifty adult male albino rats were randomized into five groups (10 animals per group): Group I rats orally received 100 mg silymarin/kg body weight once daily; Group II rats orally received 2 mg L-Arg/100 g body weight in 5 mL distilled water once daily; Group III rats rectally received 0.85 mL TNBS in 50% ethanol to induce colitis; Group IV rats were treated similar to group III and, on recovery from anesthesia, received silymarin as described for group I; and Group V rats were treated similar to group III and, on recovery from anesthesia, received L-Arg as described for group II. On day 7, the rats were anesthetized, and blood samples were collected to determine the serum concentrations of TNF-alpha. Laparotomy and total colectomy were performed for macroscopic, histological, and immunohistochemical investigations. The results showed that silymarin and L-Arg macroscopically and microscopically ameliorated TNBS-induced colitis; significantly decreased the serum levels of TNF-alpha; inhibited the colonic expression of iNOS, NF-kappaB, and cytochrome c; and increased expression of HSP70. Our results suggest that these complementary medicines could be used to supplement current treatments for IBD. PMID- 26979993 TI - Immunoprecipitation and mass spectrometry defines an extensive RBM45 protein protein interaction network. AB - The pathological accumulation of RNA-binding proteins (RBPs) within inclusion bodies is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). RBP aggregation results in both toxic gain and loss of normal function. Determining the protein binding partners and normal functions of disease-associated RBPs is necessary to fully understand molecular mechanisms of RBPs in disease. Herein, we characterized the protein-protein interactions (PPIs) of RBM45, a RBP that localizes to inclusions in ALS/FTLD. Using immunoprecipitation coupled to mass spectrometry (IP-MS), we identified 132 proteins that specifically interact with RBM45 within HEK293 cells. Select PPIs were validated by immunoblot and immunocytochemistry, demonstrating that RBM45 associates with a number of other RBPs primarily via RNA-dependent interactions in the nucleus. Analysis of the biological processes and pathways associated with RBM45-interacting proteins indicates enrichment for nuclear RNA processing/splicing via association with hnRNP proteins and cytoplasmic RNA translation via eiF2 and eiF4 pathways. Moreover, several other ALS-linked RBPs, including TDP-43, FUS, Matrin-3, and hnRNP-A1, interact with RBM45, consistent with prior observations of these proteins within intracellular inclusions in ALS/FTLD. Taken together, our results define a PPI network for RBM45, suggest novel functions for this protein, and provide new insights into the contributions of RBM45 to neurodegeneration in ALS/FTLD. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease. PMID- 26979995 TI - Correction to Protein-Protein Multilayer Oil-in-Water Emulsions for the Microencapsulation of Flaxseed Oil: Effect of Whey and Fish Gelatin Concentration. PMID- 26979996 TI - EPAC1 promotes adaptive responses in human arterial endothelial cells subjected to low levels of laminar fluid shear stress: Implications in flow-related endothelial dysfunction. AB - Blood flow-associated fluid shear stress (FSS) dynamically regulates the endothelium's ability to control arterial structure and function. While arterial endothelial cells (AEC) subjected to high levels of laminar FSS express a phenotype resistant to vascular insults, those exposed to low levels of laminar FSS, or to the FSS associated with oscillatory blood flow, are less resilient. Despite numerous reports highlighting how the cAMP-signaling system controls proliferation, migration and permeability of human AECs (HAECs), its role in coordinating HAEC responses to FSS has received scant attention. Herein we show that the cAMP effector EPAC1 is required for HAECs to align and elongate in the direction of flow, and for the induction of several anti-atherogenic and anti thrombotic genes associated with these events. Of potential therapeutic importance, EPAC1 is shown to play a dominant role the in response of HAECs to low levels of laminar FSS, such as would be found within atherosclerosis-prone areas of the vasculature. Moreover, we show that EPAC1 promotes these HAEC responses to flow by regulating Vascular Endothelial Growth Factor Receptor-2 and Akt activation, within a VE-cadherin (VECAD)/PECAM1-based mechanosensor. We submit that these findings are consistent with the novel proposition that promoting EPAC1-signaling represents a novel means through which to promote expression of an adaptive phenotype in HAECs exposed to non-adaptive FSS-encoded signals as a consequence of vascular disease. PMID- 26979997 TI - A Role for Behavior in the Relationships Between Depression and Hostility and Cardiovascular Disease Incidence, Mortality, and All-Cause Mortality: the Prime Study. AB - BACKGROUND: Behavioral factors are important in disease incidence and mortality and may explain associations between mortality and various psychological traits. PURPOSE: These analyses investigated the impact of behavioral factors on the associations between depression, hostility and cardiovascular disease(CVD) incidence, CVD mortality, and all-cause mortality. METHODS: Data from the PRIME Study (N = 6953 men) were analyzed using Cox proportional hazards models, following adjustment for demographic and biological CVD risk factors, and other psychological traits, including social support. RESULTS: Following initial adjustment, both depression and hostility were significantly associated with both mortality outcomes (smallest SHR = 1.24, p < 0.001). Following adjustment for behavioral factors, all relationships were attenuated both when accounting for and not accounting for other psychological variables. Associations with all-cause mortality remained significant (smallest SHR = 1.14, p = 0.04). Of the behaviors included, the most significant contribution to outcomes was found for smoking, but a role was also found for fruit and vegetable intakes and high alcohol consumption. CONCLUSIONS: These findings demonstrate well-known associations between depression, hostility, and mortality and suggest the potential importance of behaviors in explaining these relationships. PMID- 26980000 TI - A multicentre randomized controlled trial of moderate hypothermia to prevent intracranial hypertension in acute liver failure. AB - BACKGROUND & AIMS: Animal models and human case series of acute liver failure (ALF) suggest moderate hypothermia (MH) to have protective effects against cerebral oedema (CO) development and intracranial hypertension (ICH). However, the optimum temperature for patient management is unknown. In a prospective randomized controlled trial we investigated if maintenance of MH prevented development of ICH in ALF patients at high risk of the complication. METHODS: Patients with ALF, high-grade encephalopathy and intracranial pressure (ICP) monitoring in specialist intensive care units were randomized by sealed envelope to targeted temperature management (TTM) groups of 34 degrees C (MH) or 36 degrees C (control) for a period of 72h. Investigators were not blinded to group assignment. The primary outcome was a sustained elevation in ICP >25mmHg, with secondary outcomes the occurrence of predefined serious adverse effects, magnitude of ICP elevations and cerebral and all-cause hospital mortality (with or without transplantation). RESULTS: Forty-six patients were randomized, of whom forty-three were studied. There was no significant difference between the TTM groups in the primary outcome during the study period (35% vs. 27%, p=0.56), for the MH (n=17) or control (n=26) groups respectively, relative risk 1.31 (95% CI 0.53-3.2). Groups had similar incidence of adverse events and overall mortality (41% vs. 46%, p=0.75). CONCLUSIONS: In patients with ALF at high risk of ICH, MH at 33-34 degrees C did not confer a benefit above management at 36 degrees C in prevention of ICH or in overall survival. This study did not confirm advantage of its prophylactic use. (ISRCTN registration number 74268282; no funding.) LAY SUMMARY: Studies in animals with acute liver failure (ALF) have suggested that cooling (hypothermia) could prevent or limit the development of brain swelling, a dangerous complication of the condition. There is limited data on its effects in humans. In a randomized controlled trial in severely ill patients with ALF we compared the effects of different temperatures and found no benefit on improving survival or preventing brain swelling by controlling temperature at 33-34 degrees C against 36 degrees C. PMID- 26979998 TI - Dorsal Root Ganglion Infiltration by Macrophages Contributes to Paclitaxel Chemotherapy-Induced Peripheral Neuropathy. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a disruptive and persistent side effect of cancer treatment with paclitaxel. Recent reports showed that paclitaxel treatment results in the activation of Toll-like receptor 4 (TLR4) signaling and increased expression of monocyte chemoattractant protein 1 (MCP-1) in dorsal root ganglion cells. In this study, we sought to determine whether an important consequence of this signaling and also a key step in the CIPN phenotype was the recruitment and infiltration of macrophages into dorsal root ganglia (DRG). Here, we show that macrophage infiltration does occur in a time course that matches the onset of the behavioral CIPN phenotype in Sprague-Dawley rats. Moreover, depletion of macrophages by systemic administration of liposome encapsulated clodronate (clophosome) partially reversed behavioral signs of paclitaxel-induced CIPN as well as reduced tumor necrosius factor alpha expression in DRG. Intrathecal injection of MCP-1 neutralizing antibodies reduced paclitaxel-induced macrophage recruitment into the DRG and also blocked the behavioral signs of CIPN. Intrathecal treatment with the TLR4 antagonist lipopolysaccharide-RS (LPS-RS) blocked mechanical hypersensitivity, reduced MCP-1 expression, and blocked the infiltration of macrophages into the DRG in paclitaxel-treated rats. The inhibition of macrophage infiltration into DRG after paclitaxel treatment with clodronate or LPS-RS prevented the loss of intraepidermal nerve fibers (IENFs) observed after paclitaxel treatment alone. These results are the first to indicate a mechanistic link such that activation of TLR4 by paclitaxel leads to increased expression of MCP-1 by DRG neurons resulting in macrophage infiltration to the DRG that express inflammatory cytokines and the combination of these events results in IENF loss and the development of behavioral signs of CIPN. PERSPECTIVE: This paper shows that activation of innate immunity by paclitaxel results in a sequence of signaling events that results in the infiltration of the dorsal root ganglia by activated macrophages. Macrophages appear to drive the development of behavioral hypersensitivity and the loss of distal epidermal nerve fibers, and hence play an important role in the mechanism of paclitaxel-related neuropathy. PMID- 26979999 TI - Perceived function and physical performance are associated with pain and fatigue in women with fibromyalgia. AB - BACKGROUND: Fibromyalgia is a condition characterized by chronic widespread muscle pain and fatigue and associated with significant impairment in perceived function and reduced physical performance. The purpose of this study was to determine the degree to which pain and fatigue are associated with perceived function and physical performance in women with fibromyalgia. METHODS: Hierarchical linear regression determined the contribution of pain and fatigue (Numeric Rating Scale (NRS) for resting, movement and combined) to perceived function (Fibromyalgia Impact Questionnaire Revised - Function Subscale, FIQR Function), Multidimensional Assessment of Fatigue - Activities of Daily Living (MAF-ADL) and SF-36 Physical Function Subscale (SF-36-PF) and physical performance (6-Minute Walk Test, 6MWT and Five Time Sit To Stand, 5TSTS) while controlling for age, body mass index, pain catastrophizing, fear of movement, anxiety, and depression in women with fibromyalgia (N = 94). RESULTS: For perceived function, movement pain and movement fatigue together better predicted FIQR-function (adjusted R(2) = 0.42, p <= 0.001); MAF-ADL (adjusted R(2) = 0.41, p <= 0.001); and SF-36-PF function (adjusted R(2) = 0.34, p <= 0.001). For physical performance measures, movement pain and fatigue together predicted 6MWT distance (adjusted R(2) = 0.42, p <= 0.001) and movement fatigue alone predicted performance time on the 5TSTS (adjusted R(2) = 0.20, p <= 0.001). CONCLUSIONS: Pain and fatigue are significantly associated with and explain more than one third of the variance in perceived function and physical performance in women with fibromyalgia. TRIAL REGISTRATION: NIH Clinicaltrials.gov REGISTRATION: NCT01888640 . Registered 13 June 2013. PMID- 26980001 TI - Rapid gene identification in sugar beet using deep sequencing of DNA from phenotypic pools selected from breeding panels. AB - BACKGROUND: The combination of bulk segregant analysis (BSA) and next generation sequencing (NGS), also known as mapping by sequencing (MBS), has been shown to significantly accelerate the identification of causal mutations for species with a reference genome sequence. The usual approach is to cross homozygous parents that differ for the monogenic trait to address, to perform deep sequencing of DNA from F2 plants pooled according to their phenotype, and subsequently to analyze the allele frequency distribution based on a marker table for the parents studied. The method has been successfully applied for EMS induced mutations as well as natural variation. Here, we show that pooling genetically diverse breeding lines according to a contrasting phenotype also allows high resolution mapping of the causal gene in a crop species. The test case was the monogenic locus causing red vs. green hypocotyl color in Beta vulgaris (R locus). RESULTS: We determined the allele frequencies of polymorphic sequences using sequence data from two diverging phenotypic pools of 180 B. vulgaris accessions each. A single interval of about 31 kbp among the nine chromosomes was identified which indeed contained the causative mutation. CONCLUSIONS: By applying a variation of the mapping by sequencing approach, we demonstrated that phenotype-based pooling of diverse accessions from breeding panels and subsequent direct determination of the allele frequency distribution can be successfully applied for gene identification in a crop species. Our approach made it possible to identify a small interval around the causative gene. Sequencing of parents or individual lines was not necessary. Whenever the appropriate plant material is available, the approach described saves time compared to the generation of an F2 population. In addition, we provide clues for planning similar experiments with regard to pool size and the sequencing depth required. PMID- 26980002 TI - Biomechanical response of lumbar facet joints under follower preload: a finite element study. AB - BACKGROUND: Facet joints play a significant role in providing stability to the spine and they have been associated with low back pain symptoms and other spinal disorders. The influence of a follower load on biomechanics of facet joints is unknown. A comprehensive research on the biomechanical role of facets may provide insight into facet joint instability and degeneration. METHOD: A nonlinear finite element (FE) model of lumbar spine (L1-S1) was developed and validated to study the biomechanical response of facets, with different values of follower preload (0 N,500 N,800 N,1200 N), under loadings in the three anatomic planes. In this model, special attention was paid to the modeling of facet joints, including cartilage layer. The asymmetry in the biomechanical response of facets was also discussed. A rate of change (ROC) and an average asymmetry factor (AAF) were introduced to explore and evaluate the preload effect on these facet contact parameters and on the asymmetry under different loading conditions. RESULTS: The biomechanical response of facets changed according to the loading condition. The preload amplified the facet force, contact area and contact pressure in flexion extension; the same effect was observed on the ipsilateral facet while an opposite effect could be seen on the contralateral facet during lateral bending. For torsion loading, the preload increased contact area, decreased the mean contact pressure, but had almost no effect on facet force. However, all the effects of follower load on facet response became weaker with the increase of preload. The greatest asymmetry of facet response could be found on the ipsilateral side during lateral bending, followed by flexion, bending (contralateral side), extension and torsion. This asymmetry could be amplified by preload in the bending (ipsilateral), torsion loading group, while being reduced in the flexion group. CONCLUSIONS: An analysis combining patterns of contact pressure distribution, facet load, contact area and contact pressure can provide more insight into the biomechanical role of facets under various moment loadings and follower loads. The effect of asymmetry on facet joint response should be fully considered in biomechanical studies of lumbar spine, especially in post structures subjected to physiological loadings. PMID- 26980003 TI - A highly sensitive and simply operated protease sensor toward point-of-care testing. AB - Protease sensors for point-of-care testing (POCT) require simple operation, a detection period of less than 20 minutes, and a detection limit of less than 1 ng mL(-1). However, it is difficult to meet these requirements with protease sensors that are based on proteolytic cleavage. This paper reports a highly reproducible protease sensor that allows the sensitive and simple electrochemical detection of the botulinum neurotoxin type E light chain (BoNT/E-LC), which is obtained using (i) low nonspecific adsorption, (ii) high signal-to-background ratio, and (iii) one-step solution treatment. The BoNT/E-LC detection is based on two-step proteolytic cleavage using BoNT/E-LC (endopeptidase) and l-leucine-aminopeptidase (LAP, exopeptidase). Indium-tin oxide (ITO) electrodes are modified partially with reduced graphene oxide (rGO) to increase their electrocatalytic activities. Avidin is then adsorbed on the electrodes to minimize the nonspecific adsorption of proteases. Low nonspecific adsorption allows a highly reproducible sensor response. Electrochemical-chemical (EC) redox cycling involving p-aminophenol (AP) and dithiothreitol (DTT) is performed to obtain a high signal-to-background ratio. After adding a C-terminally AP-labeled oligopeptide, DTT, and LAP simultaneously to a sample solution, no further treatment of the solution is necessary during detection. The detection limits of BoNT/E-LC in phosphate buffered saline are 0.1 ng mL(-1) for an incubation period of 15 min and 5 fg mL( 1) for an incubation period of 4 h. The detection limit in commercial bottled water is 1 ng mL(-1) for an incubation period of 15 min. The developed sensor is selective to BoNT/E-LC among the four types of BoNTs tested. These results indicate that the protease sensor meets the requirements for POCT. PMID- 26980004 TI - Potential identification of a claudicant group vulnerable to acute kidney injury. AB - This observational study aimed to investigate the relationship between renal injury, endothelial function and oxidative stress in claudicants undergoing maximal treadmill exercise. Twenty patients with claudication were identified in whom the urinary N-acetyl-beta-D-glucosaminidase (beta-NAG)/creatinine ratio, plasma oxidative state and endothelial function were tested pre- and post-maximal treadmill walking exercise. Of the 20 participants in this study, the urinary NAG/creatinine (Cr) rose from a pre-exercise level of 8.9, 6.7 to 14.3 (MUmol/L/mmol Cr; median, IQR) to 12.9, 9.1 to 17.7 post exercise (p = 0.0003, Mann Whitney U test). Of the 20 participants, eight participants had a rise of the NAG/Cr ratio post exercise whereas 12 did not. Participants with a rise in the NAG/Cr ratio post exercise had a greater ability to increase endothelial reactivity (%; median, IQR; 2.56, 0.1 to 3.7) cf. (0.1, -4.8 to 0.9, p = 0.03); they also walked further (metres; median, IQR; 415, 208 to 908) cf. (170, 100 to 315, p = 0.04), had a lower pre-exercise H2O2 (median, IQR; 1.9, 1.4 to 2.3 cf. 2.7, 2.1 to 3.3; p = 0.04) and a greater rise in H2O2 post exercise (18.8, -1.5 to 129.7 cf., -7.7, -13.9 to -2.0, p = 0.04). The mechanism by which the phenotypically distinct sub-group of patients with intermittent claudication who experience a NAG/Cr rise involves complex interactions between systemic oxidative stress and endothelial function. Implications on cardiovascular risk in this group requires further investigation. PMID- 26980005 TI - Agreement between ACT and aPTT during extracorporeal membrane oxygenation shows intra- and inter-individual variation. AB - AIM: We explored the relationship between activated clotting time (ACT) and activated partial thromboplastin time (aPTT) when used to monitor anticoagulation in patients undergoing extracorporeal membrane oxygenation (ECMO) support. METHODS: Data obtained in patients undergoing ECMO support between October 2012 and August 2013 in a single centre were reviewed. Clinical data were extracted from our Clinical Information System and ECMO database. ACT and aPTT values were paired when taken from the same patient, with the ACT preceding the aPTT and the heparin infusion rate was kept constant between samples. The aPTT and ACT were normalized by dividing by the mean of their respective reference ranges and are referred to as APR and N-ACT, respectively. Bivariate analysis and Bland-Altman plots were used to assess correlation and agreement. Mixed effects regression was used to model the effects of variables, including platelet count, creatinine and urea levels, plasma free haemoglobin, white cell count and ECMO flow rate on concordance between APR and N-ACT measurements. RESULTS: The Pearson product moment correlation coefficient in 15 patients was calculated as r=0.55. The Bland Altman plot shows a mean difference between the APR and the N-ACT of -0.08. The 95% limits of agreement were -0.67 to 0.51. Results from mixed effects regression analysis on data from the 15 patients identified platelet count (and thrombocytopenia) and urea as significant independent predictors of concordance between APR and N-ACT. CONCLUSION: We report a moderate degree of positive correlation between APR and N-ACT. We conclude that there is poor agreement between the ACT and aPTT for the heparin concentrations in patients supported with ECMO. Our results indicate that platelet count and urea are significant independent variables affecting concordance between ACT and aPTT measurements. PMID- 26980006 TI - Puncture and wiring of extracorporeal circuit for cannula safe removal or exchange. AB - A previously undescribed technique for removing a cannula used in extracorporeal life support (ECLS) is proposed, using an over-the-wire technique by puncturing the circuit and continuing with a pre-close technique for access site closure. PMID- 26980007 TI - The Effects of Granulocyte-Colony Stimulating Factor on Regeneration in Nerve Crush Injuries in Rats. AB - Granulocyte-colony stimulating factor (G-CSF) is widely known to have a neuroprotective effect, but its effects on function and morphology in mechanical nerve injury are not well understood. The aim of this study was to confirm the time course of the functional changes and morphological effects of G-CSF in a rat model of nerve crush injury. Twelve-eight rats were divided into three group: sham-operated control group, G-CSF-treated group, and saline treated group. 2 weeks after the nerve crush injury, G-CSF was injected for 5 days. After 4 weeks, functional tests such as motor nerve conduction velocity (MNCV), mechanical and cold allodynia tests, and morphological studies were performed. G-CSF-treated rats had significantly improved nerve function including MNCV and mechanical and cold allodynia. In addition, G-CSF-treated rats had significantly higher the density of myelinated fibers than saline-treated rats. In conclusion, we found that 100 MUg/kg administration of G-CSF promoted long-term functional recovery in a rat model of nerve crush injury. PMID- 26980008 TI - Altered Expression of Human Mitochondrial Branched Chain Aminotransferase in Dementia with Lewy Bodies and Vascular Dementia. AB - Cytosolic and mitochondrial human branched chain aminotransferase (hBCATc and hBCATm, respectively) play an integral role in brain glutamate metabolism. Regional increased levels of hBCATc in the CA1 and CA4 region of Alzheimer's disease (AD) brain together with increased levels of hBCATm in frontal and temporal cortex of AD brains, suggest a role for these proteins in glutamate excitotoxicity. Glutamate toxicity is a key pathogenic feature of several neurological disorders including epilepsy associated dementia, AD, vascular dementia (VaD) and dementia with Lewy bodies (DLB). To further understand if these increases are specific to AD, the expression profiles of hBCATc and hBCATm were examined in other forms of dementia including DLB and VaD. Similar to AD, levels of hBCATm were significantly increased in the frontal and temporal cortex of VaD cases and in frontal cortex of DLB cases compared to controls, however there were no observed differences in hBCATc between groups in these areas. Moreover, multiple forms of hBCATm were observed that were particular to the disease state relative to matched controls. Real-time PCR revealed similar expression of hBCATm mRNA in frontal and temporal cortex for all cohort comparisons, whereas hBCATc mRNA expression was significantly increased in VaD cases compared to controls. Collectively our results suggest that hBCATm protein expression is significantly increased in the brains of DLB and VaD cases, similar to those reported in AD brain. These findings indicate a more global response to altered glutamate metabolism and suggest common metabolic responses that might reflect shared neurodegenerative mechanisms across several forms of dementia. PMID- 26980009 TI - Blocking B7-1/CD28 Pathway Diminished Long-Range Brain Damage by Regulating the Immune and Inflammatory Responses in a Mouse Model of Intracerebral Hemorrhage. AB - Acute brain injuries can activate bidirectional crosstalk between the injured brain and the immune system. The immune system, particularly T lymphocytes and cytokines, has been implicated in the progression of brain injury after intracerebral hemorrhage (ICH). Co-stimulatory molecules B7-1 (CD80)/B7-2 (CD86) binding cognate receptor provides a secondary signaling to T cell activation. The aim of our study was to explore the effects of anti-B7-1 antibody on the development and prognosis of cerebral hemorrhage and to investigate the possible underlying mechanism. Mice were inner canthus veniplex administered with anti-B7 1 antibody at 10 min and 24 h after ICH and sacrificed on the third day after ICH. Immune function was assessed via splenocyte proliferation assay and organism index, respectively. IFN-gamma and IL-4 were detected by enzyme-linked immuno sorbent assay. The cerebral edema was evaluated via brain water content. The levels of autophagy and apoptosis related proteins were measured by western blotting analysis. In addition, functional outcome was studied with pole-climbing test and morris water maze. The mice were weighed on 0, 1, 3, 14 and 21 days after ICH. The treatment with anti-B7-1 antibody significantly lowered immune function, and reduced the latency of water maze on 18 and 20 days, the ratio of IFN-gamma/IL-4 as well as body weight on day 3 after cerebral hemorrhage. Our study suggests that in the cerebral hemorrhage mice brain anti-B7-1 antibody may reduce long-range brain damage by reversing immune imbalance. PMID- 26980010 TI - Obstructive sleep apnoea and frequency of occupational injury. AB - We sought to determine whether patients with obstructive sleep apnoea (OSA) are at increased risk of occupational injury (OI). Patients referred to the University of British Columbia Hospital Sleep Laboratory for suspected OSA (May 2003 to July 2011 were recruited and rates and types of validated OI (that caused at least 1 day of disability) in the 5 years prior to polysomnography were calculated. In a sample of 1236, patients with OSA were twice as likely (OR=1.93, 95% CI 1.06 to 3.50, p=0.03) to suffer at least one OI compared with patients without OSA. This association was attenuated (OR=1.76, CI 0.86 to 3.59, p=0.12) after controlling for confounders. In a secondary analysis, patients with OSA were almost three times more likely (OR=2.88, CI 1.02 to 8.08, p=0.05) to suffer from an injury more likely related to reduced vigilance (eg, a fall or commercial motor vehicle crash) when compared with patients without OSA, and this again was attenuated after controlling for confounders (OR=2.42, CI 0.085 to 6.93, p=0.10). PMID- 26980011 TI - Lung cancer tissue diagnosis in poor lung function: addressing the ongoing percutaneous lung biopsy FEV1 paradox using Heimlich valve. AB - Many centres continue to decline percutaneous lung biopsy (PLB) in patients with poor lung function (particularly FEV1 <1 L) due to the theoretically increased risk of pneumothorax. This practice limits access to novel lung cancer therapies and minimally invasive surgical techniques. Our retrospective single-centre analysis of 212 patients undergoing PLB, all performed prospectively and blinded to lung function, demonstrates that using ambulatory Heimlich valve chest drain (HVCD) to treat significant postbiopsy pneumothorax facilitates safe, diagnostic, early discharge lung biopsy irrespective of lung function with neither FEV1 <1 L nor transfer coefficient for carbon monoxide (TLCO) <40% predicted shown to be independent predictors of HVCD insertion or pneumothorax outcomes. Incorporating ambulatory HVCD into standard PLB practice thereby elegantly bridges the gap that currently exists between tissue diagnosis in patients with poor lung function and the advanced therapeutic options available for this cohort. PMID- 26980012 TI - Galectin-1 is a useful marker for detecting neoplastic squamous cells in oral cytology smears. AB - Cytologic diagnoses in the oral region are very difficult due to the small amount of cells in smears, which are also exposed to many stimulating factors and often show atypical changes. Galectin-1 (Gal1) is a beta-galactoside binding protein that modulates tumor progression. Gal1 is very weakly expressed in normal cells, but is often overexpressed in neoplastic lesions. The aim of the present study was to determine whether it is possible to differentiate reactive changes from neoplastic changes in oral cytology smears based on the expression of Gal1. A total of 155 tissue biopsy specimens and 61 liquid-based cytology specimens were immunostained by an anti-Gal1 antibody, and Gal1 expression levels were subsequently evaluated. These samples consisted of oral squamous cell carcinomas, epithelial dysplasia, and oral mucosal diseases. The positive and negative expressions of Gal1 were examined in 37 specimens collected by scalpel and cytobrush biopsy. The sensitivity, specificity, and positive predictive value of Gal1 were also evaluated in smears. In tissue sections, the positive ratio of Gal1 in neoplastic lesions was high (72.3%). In cytology specimens, the positive ratio of Gal1 was higher in neoplastic lesions (79.0%) than in those negative for intraepithelial lesion or malignancy (22.2%). A correlation was found between immunocytochemical Gal1 expression and immunohistochemical Gal1 expression (P < .001). The sensitivity (75.0%), specificity (75.0%), and positive predictive value (91.3%) of Gal1 were also high in smears. In conclusion, Gal1 may be a useful marker for determining whether morphologic changes in cells are reactive or neoplastic. PMID- 26980014 TI - Use of short tandem repeat analysis in unusual presentations of trophoblastic tumors and their mimics. AB - Gestational trophoblastic tumors can be difficult to distinguish from nongestational neoplasms. Somatic and germ cell tumors can mimic gestational choriocarcinoma, and epithelioid trophoblastic tumor (ETT) is known for its histologic, and sometimes clinical, resemblance to squamous cell carcinoma. Short tandem repeat (STR) analysis can separate gestational from nongestational neoplasms and can provide useful information about the type of causative conceptus. We present a series of cases which demonstrate the utility of STR analysis in the evaluation of gestational choriocarcinoma, epithelioid trophoblastic tumor, and their mimics. Samples from normal tissue and tumor were microdissected. DNA was extracted, and STR analysis was performed. Five cases were identified in which there was clinical and/or histologic concern for a gestational trophoblastic neoplasm. Case 1 is a choriocarcinoma presenting concurrently with a 16-week gestation. STR testing on the tumor, mother, and fetus showed that the tumor arose from a previous occult complete hydatidiform mole. Case 2 is an ETT presenting as multiple masses in bilateral kidneys, initially diagnosed as urothelial carcinoma. However, because of an elevated human chorionic gonadotropin, additional workup was performed which showed that the tumor was most likely an ETT. STR analysis showed that the tumor arose from a nonmolar pregnancy. Cases 3-5 illustrate somatic carcinomas mimicking gestational neoplasia. In those cases, STR confirmed a somatic origin. STR can be useful in distinguishing gestational from nongestational neoplasms, particularly in unusual settings. Also, STR analysis can add clinically useful information that is not available from clinical or histologic evaluation. PMID- 26980013 TI - SMYD3 stimulates EZR and LOXL2 transcription to enhance proliferation, migration, and invasion in esophageal squamous cell carcinoma. AB - Epigenetic alterations, including DNA methylation and histone modifications, are involved in the regulation of cancer initiation and progression. SET and MYND domain-containing protein 3 (SMYD3), a methyltransferase, plays an important role in transcriptional regulation during human cancer progression. However, SMYD3 expression and its function in esophageal squamous cell carcinoma (ESCC) remain unknown. In this study, SMYD3 expression was studied by immunohistochemistry in a tumor tissue microarray from 131 cases of ESCC patients. Statistical analysis showed that overall survival of patients with high SMYD3 expressing in primary tumors was significantly lower than that of patients with low SMYD3-expressing tumors (P = .008, log-rank test). Increased expression of SMYD3 was found to be associated with lymph node metastasis in ESCC (P = .036) and was an independent prognostic factor for poor overall survival (P = .025). RNAi-mediated knockdown of SMYD3 suppressed ESCC cell proliferation, migration, and invasion in vitro and inhibited local tumor invasion in vivo. SMYD3 regulated transcription of EZR and LOXL2 by directly binding to the sequences of the promoter regions of these target genes, as demonstrated by a chromatin immunoprecipitation assay. Immunohistochemical staining of ESCC tissues also confirmed that protein levels of EZR and LOXL2 positively correlated with SMYD3 expression, and the Spearman correlation coefficients (rs) were 0.78 (n = 81; P < .01) and 0.637 (n = 103; P < .01), respectively. These results indicate that SMYD3 enhances tumorigenicity in ESCC through enhancing transcription of genes involved in proliferation, migration, and invasion. PMID- 26980015 TI - Fluorescent and chromogenic in situ hybridization of CEN17q as a potent useful diagnostic marker for Birt-Hogg-Dube syndrome-associated chromophobe renal cell carcinomas. AB - Birt-Hogg-Dube syndrome (BHD) is a familial disorder associated with a germline mutation of FLCN that is a tumor suppressor gene. Patients with BHD have high risks for developing multiple renal cell carcinomas (RCCs). The frequent histological types are hybrid oncocytic/chromophobe tumors (HOCTs) and chromophobe RCCs. The morphology of HOCTs could alert pathologists to the possibility of BHD. On the other hand, chromophobe RCCs occurring in BHD patients demonstrate positive immunostaining for cytokeratin-7, CD82, and Ksp-cadherin similar to their sporadic counterparts. Highly reliable markers for BHD associated chromophobe RCCs have not been identified. In the present study, we analyzed the state of chromosome 17 in 18 renal tumors composed of 8 chromophobe RCCs, 7 HOCTs, and 3 papillary RCCs obtained from BHD patients using fluorescent and chromogenic in situ hybridization probes for the centromeric region of chromosome 17 long arm. All chromophobe RCCs and HOCTs were disomic except for 1 chromophobe RCC that showed monosomy. On the other hand, 12 of 14 sporadic chromophobe RCCs were monosomic (P = .0008). The state of chromosomes 2 and 6 were also statistically different (P = .0074 and P = .0007, respectively). Three BHD-associated papillary RCCs demonstrated either trisomy (n = 2) or disomy (n = 1). Three of 5 sporadic papillary RCCs showed trisomy. The results indicate that fluorescent and chromogenic in situ hybridization of the centromeric region of chromosome 17 long arm should be a potent useful marker for chromophobe RCCs in patients who have not been diagnosed with BHD and thereby help to determine whether the cases should be considered for genetic testing. PMID- 26980017 TI - Round cell pattern of prostatic stromal tumor of uncertain malignant potential: a subtle newly recognized variant. AB - Prostatic stromal tumor of uncertain malignant potential (STUMP) is a distinct entity which includes several different patterns. Four patterns of STUMP have been described including stroma with (1) degenerative atypia, (2) hypercellular spindle cells, (3) myxoid spindle cells, and (4) phyllodes-like pattern. The current study identified a novel round cell pattern. We searched our database from 1999 to 2015 and identified 7 patients with round cell pattern out of a total number of 98 patients with STUMP. All 7 cases showed mildly increased stromal cellularity with rounded nuclei, diagnosed on core biopsies in 5 cases, transurethral resection in 1 case, and radical prostatectomy in 1 case. Some degree of glandular displacement was observed in 4 cases. In 2 of the cases, STUMP was not recognized histologically by the referring pathologists and was initially diagnosed as benign prostatic hyperplasia. As has been described with other patterns of STUMP, several cases showed associated epithelial proliferations that in some instances masked the neoplastic stromal process. The round cell pattern of STUMP is a new deceptively subtle pattern that may not be recognized as a neoplasm and may be misdiagnosed as benign prostatic hyperplasia. Although there was no direct evidence in our study that the round cell pattern of STUMP has the same behavior as other variants of STUMPs, increased recognition of this entity will hopefully lead to additional studies to further understand its malignant potential. PMID- 26980016 TI - MAGI-2 in prostate cancer: an immunohistochemical study. AB - Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 (MAGI-2) is a scaffolding protein that links cell adhesion molecules, receptors, and signaling molecules to the cytoskeleton and maintains the architecture of cell junctions. MAGI-2 gene rearrangements have recently been described in prostate cancer. We studied the immunohistochemical expression of MAGI-2 protein in prostate tissue. Seventy-eight radical prostatectomies were used to construct 3 tissue microarrays consisting of 512 cores, including benign tissue, benign prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia (HGPIN), and adenocarcinoma, Gleason patterns 3 to 5. Immunohistochemistry for phosphatase and tensin homologue (PTEN) and double-stain MAGI-2/p63 was performed and analyzed by visual and image analysis, the latter as percent of analyzed area (%AREA), and mean optical density multiplied by %AREA (STAIN). By visual and image analysis, MAGI-2 was significantly higher in adenocarcinoma and HGPIN compared with benign (benign versus HGPIN P < .001; benign versus adenocarcinoma, P < .001). HGPIN and adenocarcinoma did not significantly differ by either modality. Using visual intensity to distinguish benign tissue and adenocarcinoma, a receiver operating curve yielded an area under the curve of 0.902. A STAIN threshold of 1470 yielded a sensitivity of 0.66 and specificity of 0.96. There was a significant correlation between PTEN and MAGI-2 staining for normal and benign prostatic hyperplasia, but this was lost in HGPIN and cancer. We conclude that MAGI-2 immunoreactivity is elevated in prostate cancer and HGPIN compared with normal tissue, and suggest that MAGI-2 may contribute to prostate carcinogenesis. This is the first report of MAGI-2 staining by immunohistochemistry in prostate cancer. PMID- 26980018 TI - Secondary malignancies diagnosed using kidney needle core biopsies: a clinical and pathological study of 75 cases. AB - Involvement of the kidney by secondary malignancies is uncommon. Differentiating secondary malignancies from primary kidney/urothelial tumors can be challenging, especially on limited biopsy material. A retrospective search of our institutional archive from January 2002 to May 2015 identified 1572 cases of imaging-guided needle core biopsies of the kidney. Of these, 75 (5%) cases revealed a secondary malignancy; 48 (64%) patients had undergone the biopsy with a primary kidney tumor favored clinically. There were 39 male and 36 female patients with a mean age of 59.4 years (range, 21-83 years). The majority of the cases (n = 55, 73%) were metastases from solid tumors, with lung being the most common primary site (n = 22, 29%). Diffuse large B-cell lymphoma was the most common hematological malignancy (n = 6) secondarily involving the kidney. Radiographically, 58 (77%) cases presented as a solitary kidney mass. The primary malignancy was known prior to the kidney biopsy in 66 (88%) cases. The mean interval between diagnoses of the primary tumor and secondary involvement of the kidney was 4.5 years. Immunohistochemical stains were performed in 65 (87%) cases. Follow-up information was available for 73 patients; mean survival was 19.4 months, with 43 patients dead of their disease (mean, 12 months) and 30 patients alive at last follow-up (21 with and 9 without disease; mean, 30 months). Secondary malignancy in the kidney may clinically and pathologically mimic primary kidney tumors. Accurate diagnosis can be rendered by correlating pathological features with clinical and radiographic findings and judicious use of ancillary studies. PMID- 26980019 TI - SOX9 expression predicts relapse of stage II colon cancer patients. AB - The aim of this study was to investigate if the protein expression of sex determining region y-box 9 (SOX9) in primary tumors could predict relapse of stage II colon cancer patients. One hundred forty-four patients with stage II primary colon cancer were retrospectively enrolled in the study. SOX9 expression was evaluated by immunohistochemistry, and mismatch repair status was assessed by both immunohistochemistry and promoter hypermethylation assay. High SOX9 expression at the invasive front was significantly associated with lower risk of relapse when including the SOX9 expression as a continuous variable (from low to high expression) in univariate (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.56-0.94; P = .01) and multivariate Cox proportional hazards analyses (HR, 0.75; 95% CI, 0.58-0.96; P = .02), adjusting for mismatch repair deficiency and histopathologic risk factors. Conversely, low SOX9 expression at the invasive front was significantly associated with high risk of relapse, when including SOX9 expression as a dichotomous variable, in univariate (HR, 2.32; 95% CI, 1.14-4.69; P = .02) and multivariate analyses (HR, 2.32; 95% CI, 1.14-4.69; P = .02), adjusting for histopathologic risk factors and mismatch repair deficiency. In conclusion, high levels of SOX9 of primary stage II colon tumors predict low risk of relapse, whereas low levels of SOX9 predict high risk of relapse. SOX9 may have an important value as a biomarker when evaluating risk of relapse for personalized treatment. PMID- 26980020 TI - Acidophil bodies in nonalcoholic steatohepatitis. AB - The significance of the quantity of acidophil bodies (AB) in nonalcoholic steatohepatitis (NASH) is not certain. We quantified AB in liver biopsies and examined the association with the diagnosis of NASH and other histologic features. We reviewed 157 liver biopsies from the NASH Clinical Research Network Database collected in 2006. One hundred twenty-seven biopsies were from adult patients. Diagnoses were 94 definite NASH, 40 borderline NASH, and 23 definitely not NASH. The total length and average width of the core biopsies were measured, and the biopsy areas were calculated (mm(2)). Total AB were counted, and mean AB count per mm(2) was calculated (AB/mm(2)) to derive acidophil body index (ABI). ABI was 0.04 (+/-0.08) in definite NASH and 0.02 (+/-0.05) in borderline/definitely not NASH groups combined (P = .02) in all 157 biopsies; similar findings were present in the 127 adult-only biopsies (0.04 +/- 0.05 and 0.02 +/- 0.05, respectively; P = .05). In all 157 biopsies, increased ABI was associated with greater lobular inflammation (P = .01) and many ballooned hepatocytes (P = .048). There was a positive relationship between ABI and high nonalcoholic fatty liver disease activity scores, but this association was not statistically significant. There was no association between ABI and steatosis or fibrosis stage either in the entire cohorts or in the subset of adult patients. In conclusion, the density of AB is associated with lobular inflammation, ballooned hepatocytes, and the diagnosis of NASH in adult and pediatric liver biopsies, suggesting the implication of the apoptotic pathway in NASH-associated liver cell injury. PMID- 26980021 TI - BRAF and MAP2K1 mutations in Langerhans cell histiocytosis: a study of 50 cases. AB - Langerhans cell histiocytosis (LCH) is a proliferation of Langerhans cells, often associated with lymphocytes, eosinophils, macrophages, and giant cells. BRAF mutations, usually V600E, have been reported in 40%-70% of cases, and recently, MAP2K1 mutations have been reported in BRAF-negative cases. We assessed 50 cases of LCH for BRAF mutations and assessed a subset of cases for MAP2K1 mutations. The study group included 28 men and 22 women (median age, 36.5 years; range, 1-78 years). BRAF V600E mutation was detected in 8 (16%) cases including 3 (30%) skin, 2 (11%) bone, 1 (50%) colon, 1 (20%) lung, and 1 (33%) extradural, intracranial mass. MAP2K1 mutations were detected in 6 of 13 (46%) BRAF-negative cases including 2 (100%) lymph node, 2 (50%) bone, 1 (25%) skin, and 1 (100%) orbit. Patients with BRAF mutation were younger than patients with wild-type BRAF (median age, 28 versus 38 years; P = .026). The median age of MAP2K1-mutated patients was 34.5 years, similar to patients without MAP2K1 mutation (41 years; P = .368). In agreement with 2 recent studies, we showed a high frequency of MAP2K1 mutations in BRAF-negative LCH cases. Unlike other studies, the overall frequency of BRAF mutation in this cohort is substantially lower than what has been reported in pediatric patients, perhaps because most patients in this study were adults. Moreover, we showed a high concordance between mutational and immunohistochemical analysis for BRAF mutation. There was no statistically significant association between BRAF or MAP2K1 mutation and anatomic site, unifocal versus multifocal presentation, or clinical outcome. PMID- 26980022 TI - Ring finger protein 43 expression is associated with genetic alteration status and poor prognosis among patients with intrahepatic cholangiocarcinoma. AB - Ring finger E3 ligases have roles in processes central to maintenance of genomic integrity and cellular homeostasis. Many ring finger E3 ligases are implicated in malignancy. Ring finger protein 43 (RNF43) is a ring finger E3 ligase that negatively regulates the Wnt/beta-catenin signaling pathway. RNF43 is frequently mutated in several types of malignancy, including intrahepatic cholangiocarcinoma (ICC). The significance of its expression in ICC has not, however, been reported. We determined RNF43 expression and identified RNF43 polymorphisms in ICC tissues. We also investigated the correlation between RNF43 expression and RNF43 mutation status, RNF43 polymorphisms, clinicopathological features, and prognosis of ICC patients. RNF43 reduced expression in ICC, and the reduction of RNF43 messenger RNA expression was significantly correlated with the presence of rs2257205 and RNF43 somatic mutations, confirming that all RNF43 somatic mutations in ICC are inactivating. Overall survival was worst in patients with down-regulation of RNF43. Univariate and multivariate analyses revealed that RNF43 expression was an independent prognostic factor. There was no statistically significant association between RNF43 messenger RNA and protein expression nor any clinicopathological features or RNF43 polymorphisms. The results imply that RNF43 is down-regulated in ICC and may play a crucial role during development of ICC. PMID- 26980023 TI - A single EBUS-TBNA procedure can support a large panel of immunohistochemical stains, specific diagnostic subtyping, and multiple gene analyses in the majority of non-small cell lung cancer cases. AB - Targeted therapies for pulmonary adenocarcinoma (ACA) necessitate specific subtyping and molecular testing of non-small cell lung carcinomas (NSCLC). However, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) has decreased the tissue available for these assessments. While EBUS-TBNA specimens have previously been reported to successfully subtype NSCLC, allow immunohistochemistry (IHC), and support molecular diagnostics, no studies have documented the extent to which all objectives are possible in a single sample. Of 107 consecutive EBUS-TBNA specimens that were eligible for molecular testing, 98.8% had enough tissue for IHC, 80.2% received a definitive subtype, and 71.0% had both sufficient tissue to attempt molecular testing and technical success on multigene next-generation sequencing and ALK fluorescence in situ hybridization assays. Both subtyping and molecular diagnostics were possible in 57.9% of patients. The mean number of immunostains performed did not differ between patients with or without successful molecular testing (4.4 versus 4.6, P = .88). Only 40% of patients with insufficient tissue underwent repeat sampling. These findings indicate that a majority of EBUS-TBNA specimens provide sufficient tissue for subtyping pulmonary NSCLC, performing IHC, and completing multiple gene analyses. Although priorities must be assessed for each case individually, performance of IHC does not detract from completion of molecular diagnostics in general. Because most patients never undergo repeat sampling, the tissue yield of EBUS-TBNA should be improved to maximize evaluation for targeted therapies. PMID- 26980024 TI - BRAF and epithelial-mesenchymal transition in primary cutaneous melanoma: a role for Snail and E-cadherin? AB - In vitro studies in melanoma indicate that up-regulation of the transcriptional repressor Snail occurs with a concomitant decrease of its target E-cadherin, both hallmarks of epithelial-mesenchymal transition-an association not established in vivo. We sought to elucidate the relationship between BRAF, Snail, E-cadherin, and established histopathologic prognosticators in primary cutaneous melanoma. Archived annotated samples with a diagnosis of primary cutaneous melanoma were retrieved (n = 68 cases; 34 BRAF mutant and 34 BRAF wild type) and immunohistochemically stained for Snail and E-cadherin protein expression. A semiquantitative scoring system was used. Multivariate logistic analysis was used to control confounders of BRAF. Snail expression was significantly associated only with ulceration (42% versus 13%; P = .02). E-cadherin expression was present in 26% of BRAF mutant and 71% of BRAF wild-type cases (P = .0003). Loss of E cadherin expression was associated with female sex (60% versus 34%; P = .05), BRAF mutation (74% versus 29%; P = .0003), thickness greater than or equal to 1 mm (68% versus 32%; P = .004), mitosis (63% versus 25%; P = .007), and ulceration (75% versus 44%; P = .05). BRAF mutation was associated with male sex (60% versus 30%; P = .02), Breslow thickness (P = .007), thickness greater than or equal to 1 mm (68% versus 29%; P = .002), and ulceration (75% versus 42%; P = .02). Snail expression did not correlate with loss of E-cadherin expression (47% versus 53%; P = .79). After controlling for potential confounding, BRAF mutation was associated with loss of E-cadherin (adjusted odds ratio, 8.332; 95% confidence interval, 2.257-30.757; P = .0015) and Breslow thickness greater than 1 mm (adjusted odds ratio, 7.360; 95% confidence interval, 1.534-35.318; P = .0126). Our findings, indicating that mutant BRAF represses E-cadherin expression, implicating a catalytic role for BRAF in epithelial-mesenchymal transition. PMID- 26980025 TI - A favorable role of prolactin in human breast cancer reveals novel pathway-based gene signatures indicative of tumor differentiation and favorable patient outcome. AB - Prolactin (PRL) hormone is known to play a key role in mammary gland development allowing for successful lactation. The role of this hormone in breast tumorigenesis is still controversial. Here, we evaluated PRL protein and gene expression levels in human breast cancer using tissue microarray of 100 breast cancer cases, as well as different publically available human breast cancer gene profiling databases. Interestingly, our results showed a significant downregulation of PRL expression in breast cancer compared to normal adjacent tissue. Moreover, expression of PRL was associated with more differentiated tumors, early stage, smaller tumor size and absence of distant metastasis. Importantly, our results indicate that higher PRL mRNA levels are significantly associated with prolonged relapse-free survival (RFS) in breast cancer patients (P=3.7 x 10(-9)). Additionally, examining expression of PRL pathway-based gene signature composed of PRL, PRLR, Jak2 and Stat5a showed a significant association with more differentiated tumors (P<.00001), prolonged RFS (P=1.8 x 10(-6)) as well as overall survival (OS) (P=.0026). As well, our results indicate that PRL directed differentiation program in mammary epithelial cells offer good prognosis in human breast cancer. Indeed, expression of a gene signature composed of PRL upregulated genes showed a significant association with well-differentiated tumors (P<.00001). Whereas expression of a gene signature composed of PRL downregulated genes showed a significant association with shortened distant metastasis-free survival (DMFS) (P=.0086). Altogether our results highlight that PRL hormone and its signaling pathway may play an important role in maintaining tumor differentiation state and in turn better patient outcome. PMID- 26980026 TI - Serous carcinomatous component championed by heparin-binding EGF-like growth factor (HB-EGF) predisposing to metastasis and recurrence in stage I uterine malignant mixed mullerian tumor. AB - The stage I uterine malignant mixed mullerian tumor (MMMT) shows different potential for progression. We reason that MMMTs with high-grade carcinomatous component and positivity for HB-EGF are prone to recurrence/metastasis in the early stage. A retrospective clinical and histopathologic review with immunohistochemical staining for HB-EGF, EGFR, and integrin-alpha5 was performed for 62 surgically staged MMMT cases. Recurrence/metastasis (RM) is 6/18 (33%) in stage I disease. Of all the clinicopathologic variables and biomarkers analyzed for stage I MMMT, serous carcinomatous component (83% [5/6] versus 17% [1/12], P = .0015) and HB-EGF expression (100% [6/6] versus 50% [6/12], P=.0339) were significantly different between groups with RM and without RM. The presence of serous carcinoma in all stages was 83% (5/6) in stage I with RM, 8% (1/12) in stage I without RM, 20% (1/5) in stage II, 36.4% (8/22) in stage III and 64.7% (11/17) in stage IV; this was paralleled by HB-EGF expression of 100% (6/6), 50% (6/12), 40% (2/5), 50% (11/22) and 71% (12/17) with a correlation coefficient r=0.9131 (P=.027). HB-EGF and integrin-alpha5 were highly expressed in MMMTs bearing serous carcinoma component, compared to endometrioid and unclassifiable/miscellaneous subtypes (84.6%/47.6%/33.3%, P=.025 for HB-EGF; and 61.5%/42.9%/20.0%, P=.021 for integrin-alpha5). The EGFR positivity was comparable among the three subtypes (48.1%, 47.6% and 26.7%, P=.326). This study indicates that serous carcinomatous component championed by expression of HB-EGF predisposes to recurrence/metastasis in stage I MMMT. This process might involve integrin-alpha5 and does not seem to require overexpression of EGFR. Further study is required. PMID- 26980027 TI - Translocation t(7;12) as the sole chromosomal abnormality resulting in ACTB-GLI1 fusion in pediatric gastric pericytoma. AB - We hereby report an unusual gastric tumor arising from the pyloric wall of the stomach in a 9-year-old child harboring the exceptionally rare translocation t(7;12) resulting in ACTB-GLI1 gene fusion. This tumor has been previously classified as pericytoma with t(7;12) and described in 6 patients, 2 of them children. We discuss the challenges in recognizing this rare entity and the importance of the molecular studies in establishing the correct diagnosis. Our case is the first report of this type arising in the stomach of a child. PMID- 26980028 TI - Detection of TERT promoter mutations in primary adenocarcinoma of the urinary bladder. AB - TERT promoter mutations (TERT-mut) have been detected in 60% to 80% of urothelial carcinomas. A molecular urine-based screening assay for the detection of TERT-mut is currently being pursued by our group and others. A small but significant number of bladder carcinomas are adenocarcinoma. The current study assesses the incidence of TERT-mut in primary adenocarcinomas of urinary bladder. A retrospective search of our institutional pathology records identified 23 cystectomy specimens with a diagnosis of adenocarcinoma (2000-2014). All slides were reviewed by a senior urologic pathologist to confirm tumor type and select a representative formalin-fixed, paraffin-embedded block for mutational analysis. Adequate material for DNA testing was available in 14 cases (7 enteric type and 7 not otherwise specified). TERT-mut sequencing analysis was performed using previously described SafeSeq technique. Overall, 28.5% of primary adenocarcinoma harbored TERT-mut. Interestingly, 57% of nonenteric adenocarcinomas were mutation positive, whereas none of the enteric-type tumors harbored mutations. Similar to urothelial carcinoma, we found a relatively higher rate of TERT-mut among nonenteric-type adenocarcinomas further supporting the potential utility of TERT mut urine-based screening assay for bladder cancer. PMID- 26980029 TI - Prevalence and distribution of 15 high-risk human papillomavirus types in squamous cell carcinoma of the scrotum. AB - Which subtype(s) of high-risk human papillomavirus (hrHPV) are involved in squamous cell carcinoma (SCC) of the scrotum is unknown. Twenty-seven cases of SCC of the scrotum were retrieved, and all 15 subtypes of hrHPV and their viral loads were assessed using multiplex real-time polymerase chain reaction. The results were correlated with the histopathologic features, p16 expression, and in situ hybridization for hrHPV. hrHPV was identified in 18 (67%) of 27 of the cases, including HPV16 (n=8), HPV35 (n=7), HPV31 (n=5), HPV59 (n=5), HPV33 (n=3), HPV18 (n=2), HPV51 (n=2), HPV39 (n=1), HPV56 (n=1), and HPV82 (n=1). Of the 18 cases, 10 (56%) were infected by multiple hrHPV subtypes. In situ carcinomas had higher viral loads than invasive (50M versus 2M in average). The average age of HPV-positive and -negative cases was similar, 55 and 51, respectively. Of 11 cases of invasive carcinoma, 5 (45%) were positive for hrHPV versus 13 of 16 (81%) of in situ carcinomas. The highest proportion of hrHPV-positive cases was seen in basaloid type (7/7; 100%) and warty type (4/4; 100%), followed by usual type (7/16; 44%). Of 18 of the HPV-positive cases, 9 (50%) were also positive for p16 by immunohistochemistry and 6 of 18 (33%) were positive by in situ hybridization. Similar to SCC of the vulva and penis, the most frequently HPV positive tumors are basaloid and warty types. However, a proportion of SCC usual type are also positive for hrHPV. Our results show that 8 (44%) of 18 of cases are associated with hrHPV subtypes other than 16 and 18. Additionally, 7 (70%) of 10 of hrHPV16/18-positive cases are coinfected with other subtypes. PMID- 26980030 TI - Neurofibromin protein loss in desmoplastic melanoma subtypes: implicating NF1 allelic loss as a distinct genetic driver? AB - Loss of the NF1 allele, coding for the protein neurofibromin, and polymorphism in the proto-oncogene RET (RETp) are purportedly common in desmoplastic melanoma (DM). DM is categorized into pure (PDM) and mixed (MDM) subtypes, which differ in prognosis. Most NF1 mutations result in a truncated/absent protein, making immunohistochemical screening for neurofibromin an ideal surrogate for NF1 allelic loss. Using antineurofibromin, our aims were to ascertain the incidence of neurofibromin loss in DM subtypes and to evaluate the relationship with RET, perineural invasion (PNI) and established histopathologic prognosticators. A total of 78 archival samples of DM met criteria for inclusion (54 cases of non-DM serving as controls). Immunohistochemistry was performed for neurofibromin, whereas direct DNA sequencing was used for RETp and BRAF mutation status. Statistical analyses included chi(2) test as well as Fisher exact test. Neurofibromin loss was more common in DM than non-DM (69% versus 54%; P=.02). In DM, significant differences in neurofibromin loss were noted in the following: non-head and neck versus head and neck biopsy site (88% versus 55%) and PDM versus MDM variants (80% versus 56%). No significant associations were noted with sex, presence of a junctional component, Breslow depth, ulceration, mitoses, host response, RETp, BRAF status, or PNI. RETp was marginally associated with PNI positive DM versus PNI-negative DM (36 versus 18%; P=.08). Our findings, the largest to date investigating neurofibromin in DM, validate the incidence of NF1 mutations/allelic loss in DM and suggest that the DM subtypes have distinct genetic drivers. PMID- 26980031 TI - Comparison of the methods for measuring the Ki-67 labeling index in adrenocortical carcinoma: manual versus digital image analysis. AB - Adrenocortical carcinoma (ACC) is a rare, highly malignant neoplasm harboring marked histologic heterogeneity. The Ki-67 labeling index (LI) is one of the most effective diagnostic and prognostic markers in ACC. However, its assessment has by no means been standardized. Therefore, in this study, we analyzed the Ki-67 LI in 18 ACC cases both by seven pathologists using microscopes (MA; manual analysis) and with digital image analysis (DIA) and also compared the Ki-67 LI obtained by selecting "hot spots" and formulating the "average" reading of the whole tumor specimen. In addition, we performed statistical analysis of the association between Ki-67 LI and the clinical and pathologic features of individual cases. The DIA was significantly correlated with MA in hot spots but not in the average fields. The Ki-67 LI in hot spots was significantly and consistently higher than that in average areas by both MA and DIA, indicating intratumoral heterogeneity. The Ki-67 LI was significantly correlated with the Weiss criteria (eosinophilic cytoplasm, nuclear atypia, atypical mitoses, and sinusoidal invasion) by any mode of evaluation. The clinical outcome was significantly better in the patients with a Ki-67 < 10% than in those with a Ki 67 > 10% by MA in hot spots. The Ki-67 LI in hot spots measured by MA best reflected the clinical and pathologic features of ACC. Employment of DIA to obtain the Ki-67 LI in ACC requires further improvement, including correction of its overestimation of the value by counting non-tumorous cells and nuclear segmentation in areas of high cell density. PMID- 26980033 TI - Diffuse large B-cell lymphoma occurring in an ovarian cystic teratoma: expanding the spectrum of large B-cell lymphoma associated with chronic inflammation. PMID- 26980032 TI - Immunohistochemical detection of NRAS(Q61R) protein in follicular-patterned thyroid tumors. AB - The NRAS(A182G) mutation, which results in the NRAS(Q61R) protein, is a major driver mutation in follicular-patterned thyroid neoplasms. Although new immunohistochemistry (IHC) for NRAS(Q61R) is now available, its sensitivity, specificity, and diagnostic utility for thyroid tumors are not yet established. We performed IHC for NRAS(Q61R) and direct sequencing for NRAS codon 61 in 4 thyroid cancer-derived cell lines and 98 follicular-patterned thyroid tumors that included 22 follicular thyroid adenomas (FTAs), 35 follicular thyroid carcinomas (FTCs), and 41 cases of nodular hyperplasia (NH). In the tumors with NRAS(Q61R), the expression of BRAF(V600E) was further evaluated immunohistochemically. Two cell lines with NRAS(A182G) showed selective immunoreactivity for NRAS(Q61R). In tumor tissues, NRAS(Q61R) IHC was positive in 18% (4/22), 29% (10/35), and 2% (1/41) of FTAs, FTCs, and NH samples, respectively. The frequencies of the NRAS(Q61R) in FTAs and FTCs were significantly higher than that in NH (P=.046 and P=.001, respectively). All tumors with NRAS(Q61R) expression exhibited uniform cytoplasmic positivity with or without accumulation in their cell membranes. Of the 15 tumors with NRAS(Q61R) expression, 13 cases showed NRAS(A182G) in direct sequencing, whereas all of the tumors without NRAS(Q61R) expression were negative for the mutation. There were no tumors with overlapping expression of NRAS(Q61R) and BRAF(V600E). In reference to the direct sequencing, sensitivity and specificity of the NRAS(Q61R) IHC were 100% and 98%, respectively. In conclusion, NRAS(Q61R) IHC is a highly sensitive and specific tool that is useful for differentiating follicular-patterned thyroid tumors. PMID- 26980034 TI - Expression and prognostic roles of PIK3CA, JAK2, PD-L1, and PD-L2 in Epstein-Barr virus-associated gastric carcinoma. AB - As a special subtype of gastric carcinoma, Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) has distinct clinicopathological features. The Cancer Genome Atlas Research Network revealed that EBVaGC also has distinct molecular features: PIK3CA mutations, DNA hypermethylation, and JAK2, PD-L1, and PD-L2 amplification. Here, we evaluated PIK3CA, JAK2, PD-L1, and PD-L2 expression in 59 EBVaGC and 796 EBV-negative gastric carcinoma (EBVnGC) cases using immunohistochemistry and found that PIK3CA, JAK2, PD-L1, and PD-L2 were highly expressed in 75.9% and 48.8% (P<.001), 81.8% and 71.1% (P=.091), 92.5% and 84.8% (P=.132), and 98.1% and 89.7% (P=.049) of the EBVaGC and EBVnGC cases, respectively. However, the expression of PIK3CA, JAK2, PD-L1, or PD-L2 was not significantly associated with clinicopathological features or patient outcomes in EBVaGC. In contrast, in EBVnGC, high PIK3CA expression was significantly associated with indolent clinicopathological features and independently predicted better 5-year overall survival (57.8% versus 33.4%, P<.001). Our study indicated that the protein expression of the 4 characteristic molecules of EBVaGC was basically consistent with their genetic alterations, making them potential characteristic protein biomarkers and therapeutic targets of EBVaGC. The favorable impact of PIK3CA overexpression on survival found in this study gives us new insight into the clinical significance of PIK3CA in EBVnGC. PMID- 26980035 TI - Anti-CD8 (SP57) rabbit monoclonal antibody is a useful tool for detecting Toxoplasma gondii on formalin-fixed, paraffin-embedded tissue sections. PMID- 26980036 TI - TGFBR3 and MGEA5 rearrangements are much more common in "hybrid" hemosiderotic fibrolipomatous tumor-myxoinflammatory fibroblastic sarcomas than in classical myxoinflammatory fibroblastic sarcomas: a morphological and fluorescence in situ hybridization study. AB - Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare low-grade sarcoma that most often involves the distal extremities of adults. Some MIFSs have been reported to show TGFBR3 and MGEA5 rearrangements. TGFBR3 and MGEA5 rearrangements have also been reported in hemosiderotic fibrolipomatous tumor (HFLT), in pleomorphic hyalinizing angiectatic tumor (PHAT), and in rare tumors allegedly showing features of both HFLT and MIFS (hybrid HFLT-MIFS). These findings have led to speculation that HFLT, MIFS, PHAT, and hybrid HFLT-MIFS are closely related; however, areas resembling HFLTs are only very rarely encountered in previous series of MIFSs. We studied classic examples of these tumors with the goal of clarifying the relationship between MIFS and HFLT-MIFS. Cases of MIFS (n=31), hybrid HFLT-MIFS (n=8), PHAT (n=2), HFLT (n=1), and undifferentiated pleomorphic sarcoma (n=4) were retrieved from our archives, and the diagnoses were verified by 5 soft tissue pathologists. Using previously validated break apart fluorescence in situ hybridization probes, we analyzed for TGFBR3 and MGEA5 rearrangements. Only 2 of 31 MIFSs harbored MGEA5 rearrangements; all lacked TGFBR3 rearrangements. Six of 8 hybrid HFLT-MIFSs harbored rearrangements of TGFBR3 and/or MGEA5. Both PHATs were positive for rearrangements of TGFBR3 and/or MGEA5. The HFLT was positive for rearrangements of both TGFBR3 and MGEA5. All undifferentiated pleomorphic sarcomas with focal myxoid change were negative. We conclude that (1) TGFBR3 and/or MGEA5 rearrangements are much more common in hybrid HFLT-MIFSs than in classic MIFSs, (2) HFLTs and MIFSs may be unrelated lesions, and (3) hybrid HFLT-MIFSs most likely represent HFLTs with sarcomatous progression, rather than tumors strictly related to classic MIFSs. PMID- 26980037 TI - ARID1A expression in early stage colorectal adenocarcinoma: an exploration of its prognostic significance. AB - ARID1A is a chromatin remodeling gene that is mutated in a number of cancers including colorectal carcinoma (CRC). Loss of ARID1A has been associated with an adverse outcome in some types of cancer. However, literature data have not been consistent. Major limitations of some outcome studies include small sample size and heterogeneous patient population. In this study, we evaluated the prognostic value of ARID1A in a homogeneous group of early stage CRC patients, a population where prognostic markers are particularly relevant. We collected a retrospective series of 578 stage I or II CRCs. All patients underwent surgery with curative intent and without neoadjuvant or adjuvant therapy. ARID1A expression was analyzed by immunohistochemistry using tissue microarray. We found ARID1A loss in 49 of 552 analyzable tumors (8.9%). Compared with the ARID1A-retained group, cases with ARID1A loss were associated with female sex (P<.001), mismatch-repair protein deficiency (P<.001), poor differentiation (P<.001), lymphovascular invasion (P=.001), and higher pT stage (P=.047). However, at a median follow-up of 49months, ARID1A loss did not correlate with overall, disease-specific, or recurrence-free survival. This is the first systematic analysis to evaluate the prognostic significance of ARID1A in stage I/II CRCs, and our data indicate that ARID1A loss lacks prognostic significance in this population despite its association with other adverse features. Such data are clinically relevant, as efforts are ongoing in identifying markers that can detect the small but significant subset of early stage CRCs that will have a poor outcome. PMID- 26980038 TI - Could prominent airway-centered fibroblast foci in lung biopsies predict underlying chronic microaspiration in idiopathic pulmonary fibrosis patients? AB - Chronic occult aspiration of small droplets (microaspiration) due to gastroesophageal reflux disease (GERD) and/or hiatal hernia is postulated to be a contributing factor in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Usual interstitial pneumonia (UIP) is the histopathologic correlate of IPF. We hypothesized that chronic microaspiration may manifest as prominent airway centered fibroblastic foci (FFs) in IPF. UIP cases diagnosed by wedge biopsies over a 6-year period (2006-2011) were identified and scored (1-3) for the prominence of airway-centered FFs by 2 authors blinded for clinical history. Relevant clinical information was obtained. Thirty-seven patients (22 men) were diagnosed with IPF by multidisciplinary approach. Thirteen cases (35.1%) demonstrated high airway-centered FF score (score 3). Twenty (54.1%) patients carried a clinical diagnosis of GERD, and 3 patients (8.1%) had hiatal hernia. High airway-centered FF score was significantly associated with hiatal hernia diagnosis (P=.037) but not with a diagnosis of GERD or the use of proton pump inhibitors/histamine-2 receptor antagonists. High airway-centered FF score was associated with airway-centered acute inflammation (P=.028) and peribronchiolar granulomas (P=.042). In summary, IPF cases with hiatal hernia were more likely to have a prominent airway-centered FF. Given the strong association between hiatal hernia and GERD and their risk for developing chronic microaspiration, the prominent airway-centered FF in UIP might predict the presence of chronic microaspiration, acknowledging that GERD and proton pump inhibitor/histamine-2 receptor antagonist use failed to demonstrate a significant association. Larger studies are warranted for further investigation. PMID- 26980039 TI - A morphological and immunophenotypic map of the immune response in Merkel cell carcinoma. AB - The susceptibility of Merkel cell carcinoma to the host immune response has prompted a search for effective immunotherapy. CD8-positive T lymphocytes are considered key effectors of this response, but the cellular infiltrates also harbor tumor-protective agents. By developing a comprehensive morphological and immunophenotypic map of tumor-infiltrating lymphocytes (TILS) in Merkel cell carcinoma, we aimed to establish a useful template for future studies. Twenty-two cases (mean age, 79years [range, 52-95]; male-female ratio, 10:12) were studied. TILS were categorized as brisk (7), nonbrisk (9), and absent(6). Merkel cell polyomavirus (MCPyV)-positive (16) and -negative (6) cases were included, as were those with pure (18) and combined (4) morphologies. One MCPyV+ case had undergone spontaneous regression. Immunohistochemical markers included CD3, CD4, CD8, CD20, CD68, FoxP3, PD-1, and CD123. Statistical analysis used Fisher exact tests and Spearman correlations. There was a significant correlation between brisk TILs and MCPyV+ status (P=.025). CD8+ T lymphocytes predominated, were present in significantly higher proportions in brisk infiltrates (P=.003), and showed a significant predilection for the intratumoral environment (P=.003). Immune inhibitors including T regulatory cells (FOXP3+) and PD-1+ "exhausted" immunocytes were present in lower proportions. Our findings support (1) the link between a brisk immune response and MCPyV positivity, (2) the supremacy of CD8+ cells in effecting immunity, and (3) the incorporation of immune inhibitors within the global infiltrate. Efforts to therapeutically arm the "effectors" and disarm the "detractors" are well focused. These will likely have the greatest impact on MCPyV-positive cases. PMID- 26980040 TI - Biologic effect of neurogenesis in pancreatic cancer. AB - Pancreatic cancer (PaCA) is a deadly disease with few systemic therapeutic options. The head of the pancreas is the most innervated part and most common location of cancer. However, little is known about the contribution of the nerve cancer interaction to facilitate pancreatic progression. To quantify PaCA axonogenesis, we used a 3-dimensional in vitro neurogenesis model. In addition, neurogenesis in human PaCA was analyzed using PGP9.5 immunohistochemistry, deconvolution imaging, and image segmentation and analysis. There was a significant increase of the total area of neurites in the in vitro coculture with dorsal root ganglia group than control. The nerve density in PaCA tissue was significantly higher than normal pancreatic tissue. To study the functional role of nerves in PaCA, male athymic nude (Nu-Nu) mice were divided into 3 groups: (A) animals were coinjected with MIA PaCa-2 cells and 20U/kg weight units of Botulinum toxin (Botox) (n=10); (B) first injected with Botox and 6weeks later MIA PaCa-2 cancer cells (n=4); and (C) control animals were injected with equivalent amounts of saline fluid (n=9). Animals were sacrificed 6weeks later. Tumor size and apoptotic count (terminal deoxynucleotidyl transferase dUTP nick end labeling) were measured. Tumor size was decreased and apoptotic rate increased in Botox-treated PaCA. Our data indicate that neural microenvironment may play an important role in the progression of PaCA. It may lead to novel nerve targeted coadjuvant therapies for PaCA. PMID- 26980041 TI - The role of Alix in the proliferation of human glioma cells. AB - Apoptosis-linked-gene-2-interacting protein 1 (Alix) is involved in the endosome lysosome system in the cytoplasm. The normal function of Alix may be altered by ALG-2 toward a destructive role during active cell death. Alix also may play a role in regulation of cell proliferation. However, the role of Alix in human glioma has not been elucidated yet. This study intended to clarify the relationship between Alix and glioma pathologic grades and its role in the proliferation of glioma cells. Our findings showed that Alix protein concentrations were significantly elevated in high-grade glioma tissue compared with low-grade glioma (P < .0001). Immunohistochemical study revealed that Alix was overexpressed in 75 resected glioma tissues and may forecast poor survival. Alix expression was increased in resting serum-stimulated glioma cells. Additionally, we reduced Alix expression in U251MG cells and then found that cell viability was decreased significantly when p21 expression increased. Colony formation assay and flow cytometry analysis demonstrated that reduced Alix expression may lead to growth inhibition and cell cycle arrest. In summary, our findings suggest that Alix plays an important role in the proliferation of glioma cells and may be a novel therapeutic target. PMID- 26980042 TI - Brain biopsy in atypical dementia and primary angiitis of the central nervous system. PMID- 26980043 TI - Brain biopsy in atypical dementia and primary angiitis of the central nervous system--reply. PMID- 26980044 TI - PAX8, auseful biomarker for ovarianserous tumors. PMID- 26980045 TI - Physician scientist research pathway leading to certification by the American Board of Pathology. AB - In 2014, the American Board of Pathology, in response to the pathology community, approved a physician scientist research pathway (PSRP). This brief report summarizes the history of and objectives for creating the physician scientist research pathway and the requirements of the American Board of Pathology for the certification of physician scientist research pathway trainees. PMID- 26980046 TI - Impact of peritumoral and intratumoral budding in esophageal adenocarcinomas. AB - Tumor budding has prognostic significance in many carcinomas and is defined as the presence of detached isolated single cells or small cell clusters up to 5 cells at the invasion front (peritumoral budding [PTB]) or within the tumor (intratumoral budding [ITB]). For esophageal adenocarcinomas (EACs), there are currently only few data about the impact of this morphological feature. We investigated tumor budding in a large collective of 200 primarily resected EACs. Pancytokeratin staining was demonstrated to be superior to hematoxylin and eosin staining for the detection of buds with substantial to excellent interobserver agreement and used for subsequent analysis. PTB and ITB were scored across 10 high-power fields (HPFs). The median count of tumor buds was 130/10 HPFs for PTB (range, 2-593) and 80/10 HPFs for ITB (range, 1-656). PTB and ITB correlated significantly with each other (r = 0.9; P < .001). High PTB and ITB rates were seen in more advanced tumor categories (P < .001 each); tumors with lymph node metastases (P < .001/P = .002); and lymphatic, vascular, and perineural invasion and higher tumor grading (P < .001 each). Survival analysis showed an association with worse survival for high-grade ITB (P = .029) but not PTB (P = .385). However, in multivariate analysis, lymph node and resection status, but not ITB, were independent prognostic parameters. In conclusion, PTB and ITB can be observed in EAC to various degrees. High-grade budding is associated with aggressive tumor phenotype. Assessment of tumor budding, especially ITB, may provide additional prognostic information about tumor behavior and may be useful in specific cases for risk stratification of EAC patients. PMID- 26980047 TI - The predictive value of kidney biopsy in renal vasculitis: a multicenter cohort study. AB - The histopathologic classification of antineutrophil cytoplasmic antibody associated vasculitis has been demonstrated to have prognostic value in small cohorts of patients with pauci-immune extracapillary glomerulonephritis. We aimed to validate this histologic subgrouping system in a large cohort of patients with renal vasculitis from 3 Spanish centers. The additional value of several histologic parameters for predicting renal outcome was investigated. A total of 151 biopsies of patients with renal vasculitis were reviewed and classified as follows: 41% crescentic, 24% mixed, 21% focal, and 14% sclerotic. The cumulative proportions of renal survival at 5 years were 83.2%, 81.2%, 60.5%, and 50.7% for the focal, mixed, crescentic, and sclerotic categories, respectively (P < .05). In the crescentic category, patients with less than 75% of glomeruli showing crescents had better survival at 1 and 5 years compared with those having greater than or equal to 75% of crescents (77.9% and 70.6% versus 51.3% and 45.6%; P = .02). When adjusted by renal function and other histologic parameters, the percentage of extracapillary proliferation and glomerulosclerosis remained as significant predictors for renal survival (hazard ratio, 1.03; 95% confidence interval, 1.01-1.05; P = .001, and hazard ratio, 1.03; 95% confidence interval, 1.01-1.05; P = .002, respectively). In conclusion, patients with pauci-immune crescentic glomerulonephritis experienced different outcomes depending on the percentage of crescents observed, so that extensive extracapillary proliferation was associated with the poorest renal survival. These findings validate the prognostic utility of the histologic classification scheme in antineutrophil cytoplasmic antibody positive and negative patients and suggest a subdivision of crescentic category (<75% and >=75% of crescents) based on the different survival rates observed among these subgroups. PMID- 26980048 TI - Aberrant activation-induced cytidine deaminase expression in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia. AB - Activation-induced cytidine deaminase (AID) is expressed in germinal center B cells and plays a critical role in somatic hypermutation and class-switch recombination of immunoglobulin genes. Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) carries a poor prognosis and is specifically treated with tyrosine kinase inhibitors. Interestingly, AID has been shown to be aberrantly expressed and functional in Ph+ ALL and is thought to contribute to genetic instability. We hypothesized that AID might be detectable in routinely processed bone marrow biopsies by immunohistochemistry (IHC) and assist in identifying Ph+ ALL. We found that AID was expressed in 26 (70%) of 37 cases of Ph+ ALL but only 1 (2.9%) of 38 cases of Ph- ALL cases. There was a significant difference in AID expression between these 2 ALL groups (P < .001, Fisher exact test). The expression of AID was confirmed by RT-PCR (reverse-transcriptase polymerase chain reaction) and correlated with IHC scoring. AID protein is expressed in a large proportion of Ph+ ALL cases at levels detectable by IHC in clinical samples and might be useful to rapidly identify cases likely to have a BCR/ABL1 fusion. PMID- 26980049 TI - Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas. AB - Malignant pleural mesothelioma (MPM) is an aggressive tumor with no effective therapy. However PD-L1/PD-1 immunity checkpoint therapies gave encouraging results; TLR3 is a programmed death factor, which triggering up-regulates PD-L1. As PD-1/PD-L1 blocking antibodies could restore antitumor immune responses alone or in combination with TLR3 agonists, we investigated PD-L1/PD-1 and TLR3 expressions in MPM to select patients for immunotherapy. Sixty-eight pleural surgical specimens, including 58 MPM (epithelioid, n = 34; biphasic, n = 11; sarcomatoid, n = 13) and 10 benign lesions, were studied. PD-L1 expression was assessed using E1L3N and SP142 clones in tumor cells (TCs) and in tumor infiltrating lymphocytes (TILs) (positivity threshold of 1%), and compared with overall survival. PD-1, CD3 and CD8 expression by TILs, and TLR3 expression by TCs were analyzed concomitantly. PD-L1 was more expressed by sarcomatoid subtype than by other MPM (62% versus 23% and 9% for E1L3N; 38% versus 11% for SP142) (P = .01 and .04, respectively). Specificity and sensitivity of E1L3N and SP142 were of 53% and 98%, and 90% and 86%, respectively. PD-L1 expression by TILs and TCs correlated for SP142 (P = .023), and PD-L1 SP142 expression by TCs was associated with shorter overall survival (P = .016). TLR3 was expressed in most MPM, but weakly in sarcomatoid MPM. We confirm by comparing two commercially available antibodies that PD-L1 expression is higher in sarcomatoid MPM and correlates with a shorter survival. Whereas TLR3 agonists could be tested in MPM expressing TLR3, the sarcomatoid subtype could benefit from anti-PD-L1/PD-1 therapies alone or in combination. PMID- 26980050 TI - High IFIT1 expression predicts improved clinical outcome, and IFIT1 along with MGMT more accurately predicts prognosis in newly diagnosed glioblastoma. AB - Interferon-induced protein with tetratricopeptide repeat 1 (IFIT1) plays a key role in growth suppression and apoptosis promotion in cancer cells. Interferon was reported to induce the expression of IFIT1 and inhibit the expression of O-6 methylguanine-DNA methyltransferase (MGMT).This study aimed to investigate the expression of IFIT1, the correlation between IFIT1 and MGMT, and their impact on the clinical outcome in newly diagnosed glioblastoma. The expression of IFIT1 and MGMT and their correlation were investigated in the tumor tissues from 70 patients with newly diagnosed glioblastoma. The effects on progression-free survival and overall survival were evaluated. Of 70 cases, 57 (81.4%) tissue samples showed high expression of IFIT1 by immunostaining. The chi(2) test indicated that the expression of IFIT1 and MGMT was negatively correlated (r = 0.288, P = .016). Univariate and multivariate analyses confirmed high IFIT1 expression as a favorable prognostic indicator for progression-free survival (P = .005 and .017) and overall survival (P = .001 and .001), respectively. Patients with 2 favorable factors (high IFIT1 and low MGMT) had an improved prognosis as compared with others. The results demonstrated significantly increased expression of IFIT1 in newly diagnosed glioblastoma tissue. The negative correlation between IFIT1 and MGMT expression may be triggered by interferon. High IFIT1 can be a predictive biomarker of favorable clinical outcome, and IFIT1 along with MGMT more accurately predicts prognosis in newly diagnosed glioblastoma. PMID- 26980051 TI - Reduced MUTYH, MTH1, and OGG1 expression and TP53 mutation in diffuse-type adenocarcinoma of gastric cardia. AB - The effects of oxidative stress in adenocarcinomas of gastric cardia (AGCs) have not been fully elucidated. With a strict definition of AGC, we examined the immunohistochemical expressions of inducible nitric oxide synthase; 8-hydroxy deoxyguanosine; and the base excision repair enzymes such as MUTYH, MTH1, and OGG1, and TP53 mutational status. Sixty-three cases of AGC were characterized by younger patient age (P = .0227) and more frequent venous invasion (P = .0106) compared with the adenocarcinomas of pylorus (APs). 8-hydroxy-deoxyguanosine was accumulated (P = .0011), whereas MUTYH (P = .0325) and OGG1 (P = .0007) were decreased, in the AGCs compared with the adjacent mucosa, but these differences were not detected in the APs. Among the AGCs, lower expressions of MUTYH (P = .0013) and MTH1 (P = .0059) were each significantly associated with diffuse-type histology. A lower expression of OGG1 was correlated with higher T-stage (P = .0011), lymphatic invasion (P = .004), and lymph node metastasis (P = .0094). In addition, the presence of TP53 mutation was associated with diffuse-type histology (P = .0153) and a lower level of MUTYH (P = .0221). The AGCs also showed a relatively high rate of a transversion-type mutation of TP53 (50%), whereas all TP53 mutations in the APs were transition type. Age 62years or older (P = .0073), diffuse-type histology (P = .0020), and TP53 mutation (P = .0066) were each associated with worse survival in the AGC patients. Our results indicate that oxidative stress accumulation and a downregulation of base excision repair enzymes may play an important role in the pathogenesis of AGC, in particular diffuse-type AGCs. Diffuse-type AGC might involve molecular pathways different from those of other subsets of gastric cancer. PMID- 26980052 TI - Increased resting state connectivity between ipsilesional motor cortex and contralesional premotor cortex after transcranial direct current stimulation with physical therapy. AB - Non-invasive stimulation of the brain using transcranial direct current stimulation (tDCS) during motor rehabilitation can improve the recovery of movements in individuals with stroke. However, the neural substrates that underlie the clinical improvements are not well understood. In this proof-of principle open-label pilot study, five individuals with stroke received 10 sessions of tDCS while undergoing usual care physical/occupational therapy for the arm and hand. Motor impairment as indexed by the Upper Extremity Fugl Meyer assessment was significantly reduced after the intervention. Resting state fMRI connectivity increased between ipsilesional motor cortex and contralesional premotor cortex after the intervention. These findings provide preliminary evidence that the neural underpinnings of tDCS coupled with rehabilitation exercises, may be mediated by interactions between motor and premotor cortex. The latter, of which has been shown to play an important role in the recovery of movements post-stroke. Our data suggest premotor cortex could be tested as a target region for non-invasive brain-stimulation to enhance connectivity between regions that might be beneficial for stroke motor recovery. PMID- 26980053 TI - Association of cardiac autonomic modulation with physical and clinical features of young people with type 1 diabetes. AB - OBJECTIVE: The objective of this study was to verify possible associations between heart rate variability indices and physical activity, body composition, and metabolic and cardiovascular parameters in individuals with type 1 diabetes. METHOD: A total of 39 young patients with type 1 diabetes were included. Body composition, physical activity, cardiovascular parameters, and metabolic parameters were assessed. For the heart rate variability analysis, heart rate was recorded beat-by-beat using a Polar S810i heart rate monitor for 30 minutes, with the volunteers in the supine position; subsequently, the following indices were considered: standard deviation of all normal RR intervals; root-mean square of differences between adjacent normal RR intervals in a time interval; percentage of adjacent RR intervals with a difference of duration >50 ms; high frequency component in milliseconds squared; high frequency component in normalised units; standard deviation of the instantaneous variability beat-to-beat; and standard deviation of the long-term variability. The association between the heart rate variability indices and independent variables was verified through linear regression in unadjusted and adjusted models (considering gender and age). The statistical significance was set at 5% and the confidence interval at 95%. RESULTS: High values of at-rest heart rate were associated with reduced parasympathetic activity and global heart rate variability, and higher values of waist-to-hip ratio were related to lower parasympathetic activity, independent of age or gender. CONCLUSION: For young patients with type 1 diabetes, increases in at-rest heart rate values are associated with reduced parasympathetic activity and global heart rate variability, whereas higher waist-to-hip ratio values are related to lower parasympathetic activity, both independent of age and gender. PMID- 26980054 TI - Targeted proteomics identify metabolism-dependent interactors of yeast cytochrome c peroxidase: implications in stress response and heme trafficking. AB - Recently we discovered that cytochrome c peroxidase (Ccp1) functions primarily as a mitochondrial H2O2 sensor and heme donor in yeast cells. When cells switch their metabolism from fermentation to respiration mitochondrial H2O2 levels spike, and overoxidation of its polypeptide labilizes Ccp1's heme. A large pool of heme-free Ccp1 exits the mitochondria and enters the nucleus and vacuole. To gain greater insight into the mechanisms of Ccp1's H2O2-sensing and heme-donor functions during the cell's different metabolic states, here we use glutathione-S transferase (GST) pulldown assays, combined with 1D gel electrophoresis and mass spectrometry to probe for interactors of apo- and holoCcp1 in extracts from 1 d fermenting and 7 d stationary-phase respiring yeast. We identified Ccp1's peroxidase cosubstrate Cyc1 and 28 novel interactors of GST-apoCcp1 and GST holoCcp1 including mitochondrial superoxide dismutase 2 (Sod2) and cytosolic Sod1, the mitochondrial transporter Pet9, the three yeast isoforms of glyceraldehyde-3-phosphate dehydrogenase (Tdh3/2/1), heat shock proteins including Hsp90 and Hsp70, and the main peroxiredoxin in yeast (Tsa1) as well as its cosubstrate, thioreoxin (Trx1). These new interactors expand the scope of Ccp1's possible roles in stress response and in heme trafficking and suggest several new lines of investigation. Furthermore, our targeted proteomics analysis underscores the limitations of large-scale interactome studies that found only 4 of the 30 Ccp1 interactors isolated here. PMID- 26980055 TI - One-dimensional ionic self-assembly in a fluorous solution: the structure of tetra-n-butylammonium tetrakis[3,5-bis(perfluorohexyl)phenyl]borate in perfluoromethylcyclohexane by small-angle neutron scattering (SANS). AB - Fluorous liquids are the least polarizable condensed phases known, and their nonpolar members form solutions with conditions the closest to being in vacuo. A soluble salt consisting of a large fluorophilic anion, tetrakis[3,5 bis(perfluorohexyl)phenyl]borate, and its counterion, tetra-n-butylammonium, dissolved in perfluoromethylcyclohexane produces ionic solutions with extremely low conductivity. These solutions were subjected to small-angle neutron scattering (SANS) to ascertain the solute structure. At concentrations of 9% mass fraction, the fluorophilic electrolyte forms straight, long (>160 A) self assembled structures that are, in essence, long, homogeneous cylinders. Molecular models were made assuming a requirement for electroneutrality on the shortest length scale possible. This shows a structure formed from a stack of alternating anions and cations, and the structures fit the experimental scattering well. At the lower concentration of 1%, the stacks of ion pairs are shorter and eventually break up to form solitary ion pairs in the solution. These characteristics suggest such conditions provide an interesting new way to form long, self assembling ionic nanostructures with single-molecule diameters in free solution onto which various moieties could be attached. PMID- 26980056 TI - Flat Feet and the U.S. Army Through 1918. PMID- 26980057 TI - Characterization of Brain-Penetrant Pyrimidine-Containing Molecules with Differential Microtubule-Stabilizing Activities Developed as Potential Therapeutic Agents for Alzheimer's Disease and Related Tauopathies. AB - The microtubule (MT)-stabilizing protein tau disengages from MTs and forms intracellular inclusions known as neurofibrillary tangles in Alzheimer's disease and related tauopathies. Reduced tau binding to MTs in tauopathies may contribute to neuronal dysfunction through decreased MT stabilization and disrupted axonal transport. Thus, the introduction of brain-penetrant MT-stabilizing compounds might normalize MT dynamics and axonal deficits in these disorders. We previously described a number of phenylpyrimidines and triazolopyrimidines (TPDs) that induce tubulin post-translational modifications indicative of MT stabilization. We now further characterize the biologic properties of these small molecules, and our results reveal that these compounds can be divided into two general classes based on the cellular response they evoke. One group composed of the phenylpyrimidines and several TPD examples showed a bell-shaped concentration response effect on markers of MT stabilization in cellular assays. Moreover, these compounds induced proteasome-dependent degradation of alpha- and beta tubulin and caused altered MT morphology in both dividing cells and neuron cultures. In contrast, a second group comprising a subset of TPD molecules (TPD+) increased markers of stable MTs in a concentration-dependent manner in dividing cells and in neurons without affecting total tubulin levels or disrupting MT architecture. Moreover, an example TPD+ compound was shown to increase MTs in a neuron culture model with induced tau hyperphosphorylation and associated MT deficits. Several TPD+ compounds were shown to be both brain penetrant and orally bioavailable, and a TPD+ example increased MT stabilization in the mouse brain, making these compounds potential candidate therapeutics for neurodegenerative tauopathies such as Alzheimer's disease. PMID- 26980058 TI - An Ethylene-responsive Factor BpERF11 Negatively Modulates Salt and Osmotic Tolerance in Betula platyphylla. AB - Ethylene responsive factors (ERFs) play important roles in the abiotic stress; however, only a few ERF genes from woody plants have been functionally characterized. In the present study, an ERF gene from Betula platyphylla (birch), BpERF11, was functionally characterized in response to abiotic stress. BpERF11 is a nuclear protein, which could specifically bind to GCC boxes and DRE motifs. BpERF11-overexpressing and BpERF11 RNA interference (RNAi) knockdown plants were generated for gain- and loss-of-function analysis. BpERF11 negatively regulates resistance to salt and severe osmotic stress, and the transgenic birch plants overexpressing BpERF11 shows increased electrolyte leakage and malondialdehyde (MDA) contents. BpERF11 inhibits the expression of an AtMYB61 homologous gene, resulting in increased stomatal aperture, which elevated the transpiration rate. Furthermore, BpERF11 downregulates the expression of P5CS, SOD and POD genes, but upregulates the expression of PRODH and P5CDH, which results in reduced proline levels and increased reactive oxygen species (ROS) accumulation. BpERF11 also significantly inhibits the expression of LEA and dehydrin genes that involve in abiotic stress tolerance. Therefore, BpERF11 serves as a transcription factor that negatively regulates salt and severe osmotic tolerance by modulating various physiological processes. PMID- 26980059 TI - Computerized Working-Memory Training for Children Following Arterial Ischemic Stroke: A Pilot Study With Long-Term Follow-Up. AB - Cognitive deficits in the domains of working memory (WM) and executive function are well documented following childhood arterial ischemic stroke (AIS). However, there are currently no evidence-based cognitive interventions for this population. Computerized, implicit WM training has been demonstrated to generate generalized cognitive gains for children with WM and attention deficits and for adults following brain injury. This study used a pilot design to investigate the efficacy and feasibility of such an intervention program (Cogmed WM Training) for a childhood AIS population. Outcomes were measured via psychometric assessment at preintervention and postintervention and again at 1-year follow-up. At longitudinal follow-up, participants were found to have significant and persistent cognitive difficulties, particularly with attention and response inhibition. Following the computerized, implicit WM intervention, a significant improvement in phonological-loop WM was seen; however, this improvement was not maintained after 12 months. No additional significant improvements on standardized psychometric outcome measures were seen either immediately or at 12 month follow-up. Findings of this pilot study therefore do not currently support Cogmed as an effective intervention for children with AIS but highlight the need for further research, including randomized, controlled trials, to investigate cognitive interventions for the childhood AIS population. PMID- 26980060 TI - High applicability of two-dimensional phosphorous in Kagome lattice predicted from first-principles calculations. AB - A new semiconducting phase of two-dimensional phosphorous in the Kagome lattice is proposed from first-principles calculations. The band gaps of the monolayer (ML) and bulk Kagome phosphorous (Kagome-P) are 2.00 and 1.11 eV, respectively. The magnitude of the band gap is tunable by applying the in-plane strain and/or changing the number of stacking layers. High optical absorption coefficients at the visible light region are predicted for multilayer Kagome-P, indicating potential applications for solar cell devices. The nearly dispersionless top valence band of the ML Kagome-P with high density of states at the Fermi level leads to superconductivity with Tc of ~9 K under the optimal hole doping concentration. We also propose that the Kagome-P can be fabricated through the manipulation of the substrate-induced strain during the process of the sample growth. Our work demonstrates the high applicability of the Kagome-P in the fields of electronics, photovoltaics, and superconductivity. PMID- 26980062 TI - FDA Approval of Gefitinib for the Treatment of Patients with Metastatic EGFR Mutation-Positive Non-Small Cell Lung Cancer. AB - On July 13, 2015, the FDA approved gefitinib (Iressa; AstraZeneca UK Limited) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Concurrently, a labeling expansion of the therascreen EGFR RGQ PCR Kit (Qiagen) as a companion diagnostic test was approved. The approval was based on the results of a multicenter, single-arm, open-label clinical study of 106 treatment-naive patients with metastatic EGFR mutation-positive NSCLC who received gefitinib, 250 mg daily, until disease progression or intolerable toxicity. The major efficacy outcome was RECIST v1.1 objective response rate (ORR). The blinded independent central review (BICR) ORR was 50% [95% confidence interval (CI), 41-59] with a median duration of response (DoR) of 6.0 months. Efficacy results were supported by a retrospective exploratory analysis of a subset of a randomized, multicenter, open-label trial on 1,217 patients with metastatic NSCLC. Of the patients randomized, 186 (15%) were retrospectively determined to be EGFR positive and evaluable for a BICR assessment. The HR for progression-free survival (PFS) was 0.54 (95% CI, 0.38 0.79), favoring gefitinib over platinum-doublet chemotherapy. The most common (>=20%) adverse reactions were skin reactions, increased aspartate and alanine aminotransferase, proteinuria, and diarrhea. Approximately 5% of patients discontinued treatment due to an adverse reaction. Given the safety profile and clinically meaningful ORR, DoR, and PFS, the benefit-risk analysis was deemed favorable for FDA approval. PMID- 26980063 TI - Yawning, Why and When? PMID- 26980064 TI - Magnetic nanoparticles: novel options for vascular repair? PMID- 26980065 TI - In vitro extraction and fermentation of polyphenols from grape seeds (Vitis vinifera) by human intestinal microbiota. AB - The effects of several parameters on the extraction yield of total polyphenols from grape seeds by pressurized liquid extraction were investigated. The highest recovery of total polyphenols occurred at 80 degrees C within 5 min, and a single extraction allowed a recovery of more than 97% of total polyphenols. Following the purification with macroporous resin, the effects of grape polyphenols (>94.8%) on human intestinal microbiota were monitored over 36 h incubation by fluorescence in situ hybridization, and short-chain fatty acids (SCFAs) were measured by HPLC. The result showed that the grape polyphenols promoted the changes in the relevant microbial populations and shifted the profiles of SCFAs. Fermentation of grape polyphenols resulted in a significant increase in the numbers of Bifidobacterium spp. and Lactobacillus-Enterococcus group and inhibition in the growth of the Clostridium histolyticum group and the Bacteroides-Prevotella group, with no significant effect on the population of total bacteria. The findings suggest that grape polyphenols have potential prebiotic effects on modulating the gut microbiota composition and generating SCFAs that contribute to the improvements of host health. PMID- 26980066 TI - The Hippo pathway member YAP enhances human neural crest cell fate and migration. AB - The Hippo/YAP pathway serves as a major integrator of cell surface-mediated signals and regulates key processes during development and tumorigenesis. The neural crest is an embryonic tissue known to respond to multiple environmental cues in order to acquire appropriate cell fate and migration properties. Using multiple in vitro models of human neural development (pluripotent stem cell derived neural stem cells; LUHMES, NTERA2 and SH-SY5Y cell lines), we investigated the role of Hippo/YAP signaling in neural differentiation and neural crest development. We report that the activity of YAP promotes an early neural crest phenotype and migration, and provide the first evidence for an interaction between Hippo/YAP and retinoic acid signaling in this system. PMID- 26980068 TI - Variability in biofilm formation correlates with hydrophobicity and quorum sensing among Vibrio parahaemolyticus isolates from food contact surfaces and the distribution of the genes involved in biofilm formation. AB - Vibrio parahaemolyticus is one of the leading foodborne pathogens causing seafood contamination. Here, 22 V. parahaemolyticus strains were analyzed for biofilm formation to determine whether there is a correlation between biofilm formation and quorum sensing (QS), swimming motility, or hydrophobicity. The results indicate that the biofilm formation ability of V. parahaemolyticus is positively correlated with cell surface hydrophobicity, autoinducer (AI-2) production, and protease activity. Field emission scanning electron microscopy (FESEM) showed that strong-biofilm-forming strains established thick 3-D structures, whereas poor-biofilm-forming strains produced thin inconsistent biofilms. In addition, the distribution of the genes encoding pandemic clone factors, type VI secretion systems (T6SS), biofilm functions, and the type I pilus in the V. parahaemolyticus seafood isolates were examined. Biofilm-associated genes were present in almost all the strains, irrespective of other phenotypes. These results indicate that biofilm formation on/in seafood may constitute a major factor in the dissemination of V. parahaemolyticus and the ensuing diseases. PMID- 26980067 TI - Actin3 promoter reveals undulating F-actin bundles at shanks and dynamic F-actin meshworks at tips of tip-growing pollen tubes. AB - The dynamic actin cytoskeleton of pollen tubes is both the driver of the tip growth and the organizer of cell polarity. In order to understand this fast re arranging cytoskeletal system, we need reliable constructs expressed under relevant promoters. Here we are reporting that the Lifeact reporter, expressed under the pollen-specific Actin3 promoter, visualizes very dynamic F-actin elements both in germinating pollen grains and tip-growing pollen tubes. Importantly, we have documented very active actin polymerization at the cell periphery, especially in the bulging area during pollen germination and in the apical clear zone. Expression of the Lifeact reporter under control of the pollen specific Actin3 promoter revealed 2 new aspects: (i) long F-actin bundles in pollen tube shanks are dynamic, showing undulating movements, (ii) subapical 'actin collars' or 'fringes' are absent. PMID- 26980069 TI - Response to ibrutinib in a patient with IgG lymphoplasmacytic lymphoma carrying the MYD88 L265P gene mutation. PMID- 26980070 TI - Global functional diversity of freshwater fish is concentrated in the Neotropics while functional vulnerability is widespread. AB - Worldwide biodiversity assessments have mainly focused on species richness but little is known about the diversity of species roles, i.e. functional diversity, while this is a key facet to understanding the consequences of global changes on the ecosystem services to human societies. Here, we report the world pattern of functional diversity of freshwater fish using a database encompassing morphological characteristics of more than 9,000 species. The Neotropical realm hosts more than 75% of global functional diversity while other realms each host less than 25%. This discrepancy is mediated by high functional uniqueness in some diversified Neotropical fish orders. Surprisingly, functional diversity patterns were weakly related to functional vulnerability. In the Neotropics the loss of threatened species will cause a limited loss of functional diversity (<10%) whereas in the Nearctic and Palearctic realms, decline of the functional diversity will reach 43% and 33%, respectively, conferring a high functional vulnerability to these realms. Conservation of the Neotropical fish diversity is a key target to maintain world fish functional diversity, but this should not hide the pressing need to conserve the vulnerable fish faunas of the rest of the world, in which functional diversity is to a large extent supported by threatened species. PMID- 26980071 TI - Pharmacodynamics of Dimethyl Fumarate Are Tissue Specific and Involve NRF2 Dependent and -Independent Mechanisms. AB - AIMS: Gastro-resistant dimethyl fumarate (DMF) is an oral therapeutic indicated for the treatment of relapsing multiple sclerosis. Recent data suggest that a primary pharmacodynamic response to DMF treatment is activation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway; however, the gene targets modulated downstream of NRF2 that contribute to DMF-dependent effects are poorly understood. RESULTS: Using wild-type and NRF2 knockout mice, we characterized DMF transcriptional responses throughout the brain and periphery to understand DMF effects in vivo and to explore the necessity of NRF2 in this process. Our findings identified tissue-specific expression of NRF2 target genes as well as NRF2-dependent and -independent gene regulation after DMF administration. Furthermore, using gene ontology, we identified common biological pathways that may be regulated by DMF and contribute to in vivo functional effects. INNOVATION: Together, these data suggest that DMF modulates transcription through multiple pathways, which has implications for the cytoprotective, immunomodulatory, and clinical properties of DMF. CONCLUSION: These findings provide further understanding of the DMF mechanism of action and propose potential therapeutic targets that warrant further investigation for treating neurodegenerative diseases. Antioxid. Redox Signal. 24, 1058-1071. PMID- 26980072 TI - BMA calls for changes to end of life care. PMID- 26980073 TI - The effect of orthotic devices on knee adduction moment, pain and function in medial compartment knee osteoarthritis: a literature review. AB - Background Knee braces and foot orthoses are commonly used to improve knee adduction moment, pain and function in subjects with knee osteoarthritis (OA). However, no literature review has been performed to compare the effects of foot orthoses and knee braces in this group of patients. Purpose The aim of this review was to evaluate the effects of foot orthoses and knee braces on knee adduction moment, pain and function in individuals with knee OA. Study design Literature review. Method The search strategy was based on the Population Intervention Comparison Outcome method. A search was performed in PubMed, Science Direct, Google Scholar and ISI web of knowledge databases using the PRISMA method and based on selected keywords. Thirty-one related articles were selected for final evaluation. Results The results of the analysis of these studies demonstrated that orthotic devices reduce knee adduction moment and also improve pain and function in individuals with knee OA. Conclusion Foot orthoses may be more effective in improving pain and function in subjects with knee OA. Both knee braces and foot orthoses reduce the knee adduction moment in knee OA and consequently patients typically do not need to use knee braces for a long period of time. Also, foot orthoses and knee braces may be more effective for medial compartment knee OA patients due to the fact that this treatment helps improve pain and function. Implications for Rehabilitation Knee braces and foot orthoses are commonly used for improving knee adduction moment, pain and function in subjects with knee osteoarthritis (OA). Orthotic devices can reduce knee adduction moment, pain and improve function in knee OA. The combined use of a knee braces and foot orthoses can provide more improvement in knee adduction moment, reduced pain and increased function. PMID- 26980074 TI - Mechanical phenotyping of primary human skeletal stem cells in heterogeneous populations by real-time deformability cytometry. AB - Skeletal stem cells (SSCs) are a sub-population of mesenchymal stromal cells (MSCs) present in bone marrow with multipotent differentiation potential. A current unmet challenge hampering their clinical translation remains the isolation of homogeneous populations of SSCs, in vitro, with consistent regeneration and differentiation capacities. Cell stiffness has been shown to play an important role in cell separation using microfluidic techniques such as inertial focusing or deterministic lateral displacement. Here we report that the mechanical properties of SSCs, and of a surrogate human osteosarcoma cell line (MG-63), differ significantly from other cell populations found in the bone marrow. Using real-time deformability cytometry, a recently introduced method for cell mechanical characterization, we demonstrate that both MG-63 and SSCs are stiffer than the three primary leukocyte lineages (lymphocytes, monocytes and granulocytes) and also stiffer than HL-60, a human leukemic progenitor cell line. In addition, we show that SSCs form a mechanically distinct sub-population of MSCs. These results represent an important step towards finding the bio-physical fingerprint of human SSCs that will allow their label-free separation from bone marrow with significant physiological and therapeutic implications. PMID- 26980075 TI - Dermatology team. PMID- 26980076 TI - Implementation of an intraoperative electron radiotherapy in vivo dosimetry program. AB - BACKGROUND: Intraoperative electron radiotherapy (IOERT) is a highly selective radiotherapy technique which aims to treat restricted anatomic volumes during oncological surgery and is now the subject of intense re-evaluation. In vivo dosimetry has been recommended for IOERT and has been identified as a risk reduction intervention in the context of an IOERT risk analysis. Despite reports of fruitful experiences, information about in vivo dosimetry in intraoperative radiotherapy is somewhat scarce. Therefore, the aim of this paper is to report our experience in developing a program of in vivo dosimetry for IOERT, from both multidisciplinary and practical approaches, in a consistent patient series. We also report several current weaknesses. METHODS: Reinforced TN-502RDM-H mobile metal oxide semiconductor field effect transistors (MOSFETs) and Gafchromic MD-55 2 films were used as a redundant in vivo treatment verification system with an Elekta Precise fixed linear accelerator for calibrations and treatments. In vivo dosimetry was performed in 45 patients in cases involving primary tumors or relapses. The most frequent primary tumors were breast (37 %) and colorectal (29 %), and local recurrences among relapses was 83 %. We made 50 attempts to measure with MOSFETs and 48 attempts to measure with films in the treatment zones. The surgical team placed both detectors with supervision from the radiation oncologist and following their instructions. RESULTS: The program was considered an overall success by the different professionals involved. The absorbed doses measured with MOSFETs and films were 93.8 +/- 6.7 % and 97.9 +/- 9.0 % (mean +/- SD) respectively using a scale in which 90 % is the prescribed dose and 100 % is the maximum absorbed dose delivered by the beam. However, in 10 % of cases we experienced dosimetric problems due to detector misalignment, a situation which might be avoided with additional checks. The useful MOSFET lifetime length and the film sterilization procedure should also be controlled. CONCLUSIONS: It is feasible to establish an in vivo dosimetry program for a wide set of locations treated with IOERT using a multidisciplinary approach according to the skills of the professionals present and the detectors used; oncological surgeons' commitment is key to success in this context. Films are more unstable and show higher uncertainty than MOSFETs but are cheaper and are useful and convenient if real-time treatment monitoring is not necessary. PMID- 26980077 TI - Psychometric evaluation of the Sinhalese version of MacNew Heart Disease Health Related Quality of Life Questionnaire in patients with stable angina. AB - BACKGROUND: A Sinhalese version of a validated, disease-specific patient-reported heart disease health related quality of life instrument is lacking. The purpose of this study was to validate the interviewer-administered Sinhalese version of the MacNew Heart Disease Health-related Quality of Life Questionnaire (MacNew) in patients with clinically diagnosed stable angina. METHODS: The Sinhalese translation of the MacNew was carried using standard forward- backward translation technique. In this validation study, the MacNew was administered to 200 patients with stable angina. Reliability was assessed by internal consistency and test-retest reliability. Construct validity was explored by exploratory factor analysis using principal component analysis and confirmed by confirmatory factor analysis using the robust maximum likelihood method and known group comparison. The correlation between compatible domain scores of MacNew and the World Health Organization's quality of life -brief questionnaire was used to assess concurrent validity. RESULTS: The original 3-factor model (Physical, Emotional and Social) of the MacNew with cross-loadings was confirmed: principal component analysis with 53.42 % of the explained variance and confirmatory factor analysis with adequate fit for each of the three model fit criteria considered [root mean square error of approximation = 0.044 (90 % CI = 0.031 to 0.056); comparative fit index = 0.99; chi(2)/df = 1.39]. Internal consistency of the MacNew was acceptable with Cronbach's alpha of 0.92 on the Global scale and on the domain scales ranging from 0.85-0.91. Test-retest reliability was also found to be satisfactory with intraclass correlation coefficients of >0.9 for total and domain scores. A satisfactory level of concurrent validity was demonstrated with statistically significant correlations between compatible domain scores of MacNew and the World Health Organization's quality of life questionnaire (Pearson correlation ranging from 0.36-0.79). CONCLUSIONS: The interviewer-administered Sinhalese MacNew is a valid and reliable patient-reported outcome measure to assess disease specific health-related quality of life among Sinhalese patients with stable angina. PMID- 26980078 TI - Reduction in Bladder-Related Autonomic Dysreflexia after OnabotulinumtoxinA Treatment in Spinal Cord Injury. AB - Bladder-related events, including neurogenic detrusor overactivity, are the leading cause of autonomic dysreflexia in spinal cord injured individuals. Self reported autonomic dysreflexia is reduced following onabotulinumtoxinA treatment for neurogenic detrusor overactivity; however, none of these trials have assessed autonomic dysreflexia events using the clinical cutoff of an increase in systolic blood pressure >=20 mm Hg. This study used a prospective, open-labelled design from 2013 to 2014 to quantitatively assess the efficacy of one cycle 200 U intradetrusor-injected onabotulinumtoxinA (20 sites) on reducing the severity and frequency of bladder-related autonomic dysreflexia events and improving quality of life. Twelve men and five women with chronic, traumatic spinal cord injuries at or above the sixth thoracic level, and concomitant autonomic dysreflexia and neurogenic detrusor overactivity, underwent blood pressure monitoring during urodynamics and over a 24 h period using ambulatory blood pressure monitoring pre and 1 month post-treatment. Post-onabotulinumtoxinA, autonomic dysreflexia severity was reduced during urodynamics (systolic blood pressure increase: 42 +/- 23 mm Hg vs. 20 +/- 10 mm Hg, p < 0.001) and during bladder-related events across the 24 h period (systolic blood pressure increase: 49 +/- 2 mm Hg vs. 26 +/- 22 mm Hg, p = 0.004). Frequency of 24 h bladder-related autonomic dysreflexia events was also decreased post-onabotulinumtoxinA (4 +/- 2 events vs. 1 +/- 1 events, p < 0.001). Autonomic dysreflexia and incontinence quality of life indices were also improved post-onabotulinumtoxinA (p < 0.05). Intradetrusor injections of onabotulinumtoxinA for the management of neurogenic detrusor overactivity in individuals with high level spinal cord injuries decreased the severity and frequency of bladder-related episodes of autonomic dysreflexia, and improved bladder function and quality of life. PMID- 26980079 TI - Fast-crawling cell types migrate to avoid the direction of periodic substratum stretching. AB - To investigate the relationship between mechanical stimuli from substrata and related cell functions, one of the most useful techniques is the application of mechanical stimuli via periodic stretching of elastic substrata. In response to this stimulus, Dictyostelium discoideum cells migrate in a direction perpendicular to the stretching direction. The origins of directional migration, higher migration velocity in the direction perpendicular to the stretching direction or the higher probability of a switch of migration direction to perpendicular to the stretching direction, however, remain unknown. In this study, we applied periodic stretching stimuli to neutrophil-like differentiated HL-60 cells, which migrate perpendicular to the direction of stretch. Detailed analysis of the trajectories of HL-60 cells and Dictyostelium cells obtained in a previous study revealed that the higher probability of a switch of migration direction to that perpendicular to the direction of stretching was the main cause of such directional migration. This directional migration appears to be a strategy adopted by fast-crawling cells in which they do not migrate faster in the direction they want to go, but migrate to avoid a direction they do not want to go. PMID- 26980080 TI - Worker, workplace, and community/environmental risk factors for workplace violence in emergency departments. AB - Workplace violence committed by patients and visitors has high propensity to occur against emergency department employees. This article reports the association of worker, workplace, and community/environmental factors with violence risks. A cross-sectional research design was used with 280 employees from six emergency departments in the Midwest United States. Respondents completed the Survey of Violence Experienced by Staff and a 10-item demographic questionnaire. Data were analyzed using frequencies, percentages, Chi-square tests, and adjusted relative risks with 95% confidence intervals. Over 80% of respondents experienced at least one type of workplace violence with their current employer and approximately 40% experienced all three types. Risks for workplace violence were significantly higher for registered nurses and hospital based emergency departments. Workplace violence can impact all employees in the emergency department regardless of worker, workplace, and community/environmental factors. PMID- 26980082 TI - [Not Available]. PMID- 26980081 TI - Primary nasopharyngeal tuberculosis: a case report. AB - BACKGROUND: The occurrence of nasopharyngeal tuberculosis is rare even in areas where tuberculosis is endemic. Here, we report a case of rare primary nasopharyngeal tuberculosis, promptly evaluated by nasolaryngoscopy. CASE PRESENTATION: A 78-year-old woman presented with postnasal drip and a cough of 1 month duration. Endoscopic examination of the nasopharynx revealed irregular mucosal thickening of the right lateral and posterior wall of the naso (epi) pharynx, which was covered with yellow discharge presenting as postnasal drip. Computed tomography (CT) demonstrated enhanced soft tissue area in the right lateral and posterior wall of the nasopharynx. Bacteriological examination from a nasopharyngeal swab revealed that staining for acid-fast bacilli was positive and the quenching probe PCR test was positive for Mycobacterium tuberculosis. Histopathological examination from the thickening nasopharyngeal mucosa revealed granulomatous formation with caseous necrosis. Ziehl-Nielsen staining directly could detect acid-fast bacilli. Chest X-ray and CT scan ruled out the pulmonary tuberculosis. Base on these findings, we diagnosed it as primary nasopharyngeal tuberculosis. After six months anti-tuberculous therapy, the patient's symptoms had completely disappeared. Nasolaryngoscopic examination and CT image after 6 months post therapy revealed a normal nasopharynx with complete resolution of the lesion. CONCLUSION: We recommend endoscopic examination for patients suffering from chronic postnasal drips to avoid inappropriate diagnosis. PMID- 26980083 TI - GP contact with patients after treatment for hip fracture: frequency and determinants. AB - BACKGROUND: Patients with hip fracture have complex medical issues, both at the time of admission and after discharge from hospital. We have observed a surge in patient-initiated and carer-initiated contacts with general physicians (GPs) for periods longer than those usually reported, in a series of patients sustaining fractures from July 2008 to September 2013. OBJECTIVES: To establish (1) the frequency of contact with GPs (primary outcome) and (2) the factors influencing the frequency of different modes of contact. METHODS: Ten GP practices in West Northumberland were asked to retrospectively identify patients sustaining hip fractures, and to provide data on the number of GP contacts (patient visits to GP, telephone consultations, GP visits to patient's home) up to 1 year before and 1 year after fracture. Generalised linear models (GLM) were constructed using number of postfracture GP contacts as response variable; age, gender, residential status, number of prefracture contacts and days to contact postfracture were covariates. RESULTS: Each patient recorded cumulative 8.4 GP contacts before and 10.79 contacts after fracture. There were significantly more telephone contacts with GPs and GP home visits, but significantly fewer patient visits to GP clinics. In the GLM analysis, patient age and number of prefracture GP contacts predicted all types of postfracture contacts, while gender was not. Patients discharged home visited their GPs five times more frequently than those discharged to institutional care. CONCLUSIONS: After hip fractures, telephone contacts and GP visits to patients' homes increase, but patient visits to GP clinics decrease, influenced by age and residential status. PMID- 26980084 TI - Contrasting scaling properties of interglacial and glacial climates. AB - Understanding natural climate variability is essential for assessments of climate change. This is reflected in the scaling properties of climate records. The scaling exponents of the interglacial and the glacial climates are fundamentally different. The Holocene record is monofractal, with a scaling exponent H~0.7. On the contrary, the glacial record is multifractal, with a significantly higher scaling exponent H~1.2, indicating a longer persistence time and stronger nonlinearities in the glacial climate. The glacial climate is dominated by the strong multi-millennial Dansgaard-Oeschger (DO) events influencing the long-time correlation. However, by separately analysing the last glacial maximum lacking DO events, here we find the same scaling for that period as for the full glacial period. The unbroken scaling thus indicates that the DO events are part of the natural variability and not externally triggered. At glacial time scales, there is a scale break to a trivial scaling, contrasting the DO events from the similarly saw-tooth-shaped glacial cycles. PMID- 26980085 TI - In silico tools and transcriptomics analyses in the mutagenicity assessment of cosmetic ingredients: a proof-of-principle on how to add weight to the evidence. AB - Prior to the downstream development of chemical substances, including pharmaceuticals and cosmetics, their influence on the genetic apparatus has to be tested. Several in vitro and in vivo assays have been developed to test for genotoxicity. In a first tier, a battery of two to three in vitro tests is recommended to cover mutagenicity, clastogenicity and aneugenicity as main endpoints. This regulatory in vitro test battery is known to have a high sensitivity, which is at the expense of the specificity. The high number of false positive in vitro results leads to excessive in vivo follow-up studies. In the case of cosmetics it may even induce the ban of the particular compound since in Europe the use of experimental animals is no longer allowed for cosmetics. In this article, an alternative approach to derisk a misleading positive Ames test is explored. Hereto we first tested the performance of five existing computational tools to predict the potential mutagenicity of a data set of 132 cosmetic compounds with a known genotoxicity profile. Furthermore, we present, as a proof-of-principle, a strategy in which a combination of computational tools and mechanistic information derived from in vitro transcriptomics analyses is used to derisk a misleading positive Ames test result. Our data shows that this strategy may represent a valuable tool in a weight-of-evidence approach to further evaluate a positive outcome in an Ames test. PMID- 26980086 TI - Effect of thromboprophylaxis with anticoagulant drugs on the incidence of arterial thrombotic events in medical inpatients: a systematic review. AB - Pharmacological prophylaxis of venous thromboembolism (VTE) is recommended for medical inpatients. Since arterial thrombosis (AT) shares some risk factors with VTE, it would be reasonable to assess the efficacy of thromboprophylaxis by considering both VTE and AT as outcome events. We performed a systematic review and meta-analysis of phase III RCTs on thromboprophylaxis in medical inpatients, to evaluate the quality of reporting and the incidence of AT, and the effect of thromboprophylaxis with anticoagulants on AT incidence. Studies were identified by a combined search strategy until May 2015. Differences in outcomes among groups were expressed as pooled odds ratios (OR) and 95 % confidence intervals (CI). Statistical heterogeneity was assessed by I (2) statistic. Twenty phase III RCTs, encompassing 54,742 patients, were included; of these, 3 (15 %) reported on AT as a pre-defined secondary outcome and 8 (40 %) on at least one AT outcome. Raw-unweighed incidence of fatal MI in the three RCTs is 0.37 % in patients receiving unfractionated heparin or enoxaparin, and 0.38 % in controls (OR 0.97, 95 % CI 0.62-1.52; I (2) = 0 %). A non-statistically significant increase in AT is reported in patients on enoxaparin compared to control (OR 1.95, 95 % CI 0.89 4.27; I (2) = 13 %). AT is underreported in RCTs on VTE prophylaxis in medical inpatients. Published data suggest that incidence of fatal MI in these patients may be clinically relevant. Insufficient data are available to draw firm conclusions on the effects of thromboprophylaxis with anticoagulants on AT incidence in this setting. PMID- 26980087 TI - Biological rhythms are independently associated with quality of life in bipolar disorder. AB - BACKGROUND: Evidence suggests that patients with bipolar disorder (BD) experience biological rhythm disturbances; however, no studies have examined the impact of this disruption on quality of life (QOL). The aim of this study is to investigate the influence of biological rhythm, depressive symptoms, sleep quality, and sleep medication use on QOL in BD. METHODS: Eighty BD subjects (44 depressed and 36 euthymic) completed questionnaires assessing QOL (WHOQOL-BREF), biological rhythm disruption (BRIAN), depressive symptoms (MADRS), and sleep quality (PSQI). The impact of biological rhythm disturbance, depressive symptoms severity, sleep quality, and sleep medication use on QOL was determined with multiple regression analyses. RESULTS: BRIAN (beta = -0.31, t = -2.73, p < 0.01), MADRS (beta = 0.30, t = -2.93, p < 0.01), and sleep medication use (beta = -0.45, t = -2.55, p < 0.05) were significant predictors of QOL in this model (F 4, 75 = 20.28; p < 0.0001). The relationship of these factors with subdomains of QOL showed that poorer social QOL was associated with greater biological rhythm disturbance (beta = -0.43, t = -3.66, p < 0.01) and sleep medication use (beta = -0.49, t = -2.35, p < 0.01), providing support for the social rhythm theory of BD. Physical QOL was associated with depression (beta = -0.30, t = -2.93, p < 0.01) and biological rhythm disruption (beta = -0.31, t = -2.73, p < 0.01). Main limitations include the cross-sectional assessment and the lack of objective measures of biological rhythms in relation to QOL. CONCLUSIONS: Disruption in biological rhythm is associated with poor QOL in BD, independent of sleep disturbance, sleep medication use, and severity of depression. Treatment strategies targeting regulation of biological rhythms, such as sleep/wake cycles, eating patterns, activities, and social rhythms, are likely to improve QOL in this population. PMID- 26980088 TI - An unusual cause of hypertension with hematuria and proteinuria: Questions. PMID- 26980089 TI - An unusual cause of hypertension with hematuria and proteinuria: Answers. PMID- 26980090 TI - Yeast-based assays for screening 11beta-HSD1 inhibitors. AB - BACKGROUND: Intracellular metabolism of glucocorticoid hormones plays an important role in the pathogenesis of metabolic syndrome and regulates, among many physiological processes, collagen metabolism in skin. At the peripheral level the concentration of active glucocorticoids is mainly regulated by the 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) enzyme, involved in the conversion of cortisone into the biologically active hormone cortisol. Cortisol interacts with the glucocorticoid receptor and regulates the expression of different classes of genes within the nucleus. Due to its implication in glucocorticoid metabolism, the inhibition of 11beta-HSD1 activity has become a dominant strategy for the treatment of metabolic syndrome. Moreover, inhibitors of this target enzyme can be used for development of formulations to counteract skin ageing. Here we present the construction of two yeast cell based assays that can be used for the screening of novel 11beta-HSD1 inhibitors. RESULTS: The yeast Saccharomyces cerevisiae is used as a host organism for the expression of human 11beta-HSD1 as well as a genetically encoded assay system that allows intracellular screening of molecules with 11beta-HSD1 inhibitory activity. As proof of concept the correlation between 11beta-HSD1 inhibition and fluorescent output signals was successfully tested with increasing concentrations of carbenoxolone and tanshinone IIA, two known 11beta-HSD1 inhibitors. The first assay detects a decrease in fluorescence upon 11beta-HSD1 inhibition, whereas the second assay relies on stabilization of yEGFP upon inhibition of 11beta-HSD1, resulting in a positive read-out and thus minimizing the rate of false positives sometimes associated with read-outs based on loss of signals. Specific inhibition of the ABC transporter Pdr5p improves the sensitivity of the assay strains to cortisone concentrations by up to 60 times. CONCLUSIONS: Our yeast assay strains provide a cost-efficient and easy to handle alternative to other currently available assays for the screening of 11beta-HSD1 inhibitors. These assays are designed for an initial fast screening of large numbers of compounds and enable the selection of cell permeable molecules with target inhibitory activity, before proceeding to more advanced selection processes. Moreover, they can be employed in yeast synthetic biology platforms to reconstitute heterologous biosynthetic pathways of drug-relevant scaffolds for simultaneous synthesis and screening of 11beta-HSD1 inhibitors at intracellular level. PMID- 26980091 TI - Minimally invasive approach to colorectal cancer: an evidence-based analysis. AB - Minimally invasive surgery (MIS) was initially used for the treatment of colorectal benign disease. However, the indications for MIS techniques have progressively been expanded to include cancers. Nowadays, the indications for MIS are almost the same as those for open surgery. The scientific validation of MIS for colorectal cancer has favorably evolved. The advantages awaited for the short term outcome were confirmed, although at the cost of longer operating time and higher costs. In parallel, tangible evidence of oncologic safety was demonstrated, and long-term results of MIS have been found comparable to those of open surgery. In the current state of MIS short-term superiority and log-term equality, less surgical injury, lower immune function depression and better postoperative outcome make MIS particularly suitable for delicate and difficult patients, such as elderly or obese; on the contrary, the lower costs have led to still consider open surgery as a valid alternative for low-impact resections (such as right colectomy). The continuous development in the field of MIS has recently led to the introduction of the single-port (SILS) and natural-orifice (NOTES) techniques, which allow better esthetic results, even if the their validation has not yet reached scientific evidence. PMID- 26980092 TI - Associations between delayed completion of high school and educational attainment and symptom levels of anxiety and depression in adulthood. AB - BACKGROUND: There is a higher prevalence of anxiety and depression among adults with lower educational attainment. Delayed completion of high school (HS) is common and represents a potentially complicating factor in the relationship between educational attainment and anxiety and depression. This study aims to investigate whether delayed HS completion is associated with symptom levels of anxiety and depression in adulthood and whether it interacts with later educational attainment in predicting symptom-levels of anxiety and depression in adulthood. METHODS: The sample consisted of 10 149 participants from the Nord Trondelag Health Survey (HUNT 3) between 30 and 46 years of age in 2006. The outcome variables were symptoms of anxiety and depression as measured by the HADS scale. Variables measuring educational attainment were obtained from the National Educational Database in Norway. We used linear regression to estimate associations between educational attainment, delayed HS completion and symptom levels of anxiety and depression in adulthood. RESULTS: We found delayed HS completion to be associated with higher symptom levels of both anxiety and depression. There was a dose-response association suggesting that each additional year of delay in HS was associated with higher symptom levels for both anxiety and depression. Mean symptom levels of both anxiety and depression were significantly lower among individuals who completed HS within a normative timeframe vs those who were substantially delayed in their HS completion. For anxiety symptoms, we found a statistically significant interaction between delayed HS completion and later educational attainment. This interaction suggested that individuals with a combination of being delayed in HS and having no higher educational attainment had significantly higher levels of anxiety symptoms than all other combinations of later educational attainment and normative/delayed HS completion. For depression, associations between predictors and symptom levels were additive. CONCLUSIONS: Delayed HS completion is associated with symptom levels of both depression and anxiety and interacts with later educational attainment in predicting symptom levels of anxiety. Individuals with a combination of delayed HS completion and lower educational attainment had particularly high symptom levels of anxiety. PMID- 26980093 TI - Streptococcus suis in invasive human infections in Poland: clonality and determinants of virulence and antimicrobial resistance. AB - The purpose of this study was to perform an analysis of Streptococcus suis human invasive isolates, collected in Poland by the National Reference Centre for Bacterial Meningitis. Isolates obtained from 21 patients during 2000-2013 were investigated by phenotypic tests, multilocus sequence typing (MLST), analysis of the TR9 locus from the multilocus variable number tandem repeat (VNTR) analysis (MLVA) scheme and pulsed-field gel electrophoresis (PFGE) of SmaI-digested DNA. Determinants of virulence and antimicrobial resistance were detected by polymerase chain reaction (PCR) and analysed by sequencing. All isolates represented sequence type 1 (ST1) and were suggested to be serotype 2. PFGE and analysis of the TR9 locus allowed the discrimination of four and 17 types, respectively. Most of the isolates were haemolysis- and DNase-positive, and around half of them formed biofilm. Genes encoding suilysin, extracellular protein factor, fibronectin-binding protein, muramidase-released protein, surface antigen one, enolase, serum opacity factor and pili were ubiquitous in the studied group, while none of the isolates carried sequences characteristic for the 89K pathogenicity island. All isolates were susceptible to penicillin, cefotaxime, imipenem, moxifloxacin, chloramphenicol, rifampicin, gentamicin, linezolid, vancomycin and daptomycin. Five isolates (24 %) were concomitantly non susceptible to erythromycin, clindamycin and tetracycline, and harboured the tet(O) and erm(B) genes; for one isolate, lsa(E) and lnu(B) were additionally detected. Streptococcus suis isolated in Poland from human invasive infections belongs to a globally distributed clonal complex of this pathogen, enriched in virulence markers. This is the first report of the lsa(E) and lnu(B) resistance genes in S. suis. PMID- 26980094 TI - Influenza A and B co-infection: a case-control study and review of the literature. AB - Influenza virus infection remains a major cause of morbidity and mortality during winter seasons. Bacterial and virus co-infection is a commonly described situation in these patients. However, data on co-infection by influenza A and B viruses are lacking. In this study, we present the cases of co-infection by influenza A and B viruses during the winter season of 2014-2015 in our institution. We analyzed 2759 samples from 2111 patients and found that 625 samples corresponding to 609 patients were positive for influenza A or B virus. A total of 371 patients had influenza A, 228 had influenza B, and 10 (1.6 %) had influenza A and B virus detection in the same sample. The median age of co infected patients was 78.6 years, and only one of the co-infected patients died because of the infection. Comparison with a control group of mono-infected patients revealed that co-infection was significantly associated with nosocomial acquisition [odds ratio (OR) = 4.5, 95 % confidence interval (CI) = 1.05-19.25, p = 0.042]. However, co-infection was not associated with worse outcome, previous underlying condition, or vaccination status. Multivariate analysis revealed that co-infection was not an independent risk factor for death and that no single risk factor could predict co-infection. PMID- 26980096 TI - Pre-operative templating in total elbow arthroplasty: not useful. AB - PURPOSE: Total elbow arthroplasty (TEA) is a definitive surgical procedure for treating rheumatoid arthritis and (posttraumatic) osteoarthritis of the elbow and is also useful in comminuted elbow fractures. Pre-operative digital templating may theoretically improve the surgical implantation of TEA, but reliability and predictive values of templating are unknown. The aim of this study was to determine the intra- and inter-observer reliability and the validity of pre operative digital templating for TEA. MATERIALS AND METHODS: All pre-operative plain anterior-posterior and lateral calibrated elbow radiographs from patients who underwent TEA in our center from 2008 to June 2014 were reviewed. Two independent assessors templated implant sizes using digital overlays twice. Intra and inter-observer reliability were evaluated with Cohen's kappa. Two experienced elbow surgeons reviewed post-operative radiographs for evaluation. The predictive value of templating was the percentage of the correctly templated sizes, with the optimal implant size as the reference standard. RESULTS: Twenty one cases were included. Intra-observer reliability was substantial to almost perfect (kappa = 0.61 and kappa = 0.90) for humeral implants, moderate to substantial (kappa = 0.54 and kappa = 0.73) for ulnar implants. Inter-observer reliability was substantial (kappa = 0.67) for humeral implants and moderate (kappa = 0.60) for ulnar implants. The predictive value was 53 % for both implants. CONCLUSIONS: Pre-operative digital templating for TEA is a reliable method to plan implant sizes. However, the predictive value is low. PMID- 26980095 TI - Light-sensitive brain pathways and aging. AB - Notwithstanding its effects on the classical visual system allowing image formation, light acts upon several non-image-forming (NIF) functions including body temperature, hormonal secretions, sleep-wake cycle, alertness, and cognitive performance. Studies have shown that NIF functions are maximally sensitive to blue wavelengths (460-480 nm), in comparison to longer light wavelengths. Higher blue light sensitivity has been reported for melatonin suppression, pupillary constriction, vigilance, and performance improvement but also for modulation of cognitive brain functions. Studies investigating acute stimulating effects of light on brain activity during the execution of cognitive tasks have suggested that brain activations progress from subcortical regions involved in alertness, such as the thalamus, the hypothalamus, and the brainstem, before reaching cortical regions associated with the ongoing task. In the course of aging, lower blue light sensitivity of some NIF functions has been reported. Here, we first describe neural pathways underlying effects of light on NIF functions and we discuss eye and cerebral mechanisms associated with aging which may affect NIF light sensitivity. Thereafter, we report results of investigations on pupillary constriction and cognitive brain sensitivity to light in the course of aging. Whereas the impact of light on cognitive brain responses appears to decrease substantially, pupillary constriction seems to remain more intact over the lifespan. Altogether, these results demonstrate that aging research should take into account the diversity of the pathways underlying the effects of light on specific NIF functions which may explain their differences in light sensitivity. PMID- 26980097 TI - Which frailty measure is a good predictor of early post-operative complications in elderly hip fracture patients? AB - INTRODUCTION: Current pre-operative assessment using, e.g., American Society of Anaesthesiologists score does not accurately predict post-operative outcomes following hip fracture. The multidimensional aspect of frailty syndrome makes it a better predictor of post-operative outcomes in hip fracture patients. We aim to discover which frailty measure is more suitable for prediction of early post operative outcomes in hip fracture patients. METHODS: Hundred consecutive hip fracture patients seen by the orthogeriatric service were included. We collected baseline demographic, functional and comorbidity data. In addition to ASA, a single blinded rater measured frailty using two scales (i) modified fried criteria (MFC) and (ii) reported edmonton frail scale (REFS). The MFC adopted a surrogate gait speed measure with two questions: (i) Climbing one flight of stairs and (ii) Ability to walk 1 km in the last 2 weeks. Immediate post operative complications during the inpatient stay were taken as the primary outcome measure. RESULTS: Subjects had mean age of 79.1 +/- 9.6 years. Sixty six percent were female and 87 % of Chinese ethnicity. Eighty two percent had surgery, of which 37.8 % (n = 31) had post-operative complications. Frailty, measured by MFC (OR 4.46, p = 0.04) and REFS (OR 6.76, p = 0.01) were the only significant predictors of post-operative complications on univariate analyses. In the hierarchical logistic regression model, only REFS (OR 3.42, p = 0.04) predicted early post-operative complications. At 6 months follow-up, REFS significantly predicted [basic activities of daily living (BADL)] function on the multivariable logistic regression models. (BADL, OR 6.19, p = 0.01). CONCLUSIONS: Frailty, measured by the REFS is a good predictor of early post-operative outcomes in our pilot study of older adults undergoing hip surgery. It is also able to predict 6 months BADL function. We intend to review its role in longer term post-operative outcomes and validate its potential role in pre-operative assessment of older adults undergoing hip surgery. PMID- 26980098 TI - Self-management of chronic illness: the role of 'habit' versus reflective factors in exercise and medication adherence. AB - Non-adherence to health behaviors required for chronic illness self-management is pervasive. Advancing health-behavior theory to include behavioral initiation and maintenance factors, including reflective (e.g., belief- and feedback-based) and automatic (e.g., habit-based) mechanisms of adherence to different treatment related behaviors could improve non-adherence prediction and intervention efforts. To test behavioral initiation and maintenance factors from an extended common sense self-regulation theoretical framework for predicting medication adherence and physical activity among patients with Type 2 diabetes. Patients (n = 133) in an in-person (n = 80) or online (n = 53) version of the study reported treatment-related (1) barriers, (2) beliefs and experiential feedback (reflective mechanisms of treatment-initiation and short-term repetition), and (3) habit strength (automatic mechanism of treatment-maintenance) for taking medication and engaging in regular physical activity at baseline. Behaviors were assessed via self-reports (n = 133) and objectively (electronic monitoring pill bottles, accelerometers; n = 80) in the subsequent month. Treatment-specific barriers and habit strength predicted self-reported and objective adherence for both behaviors. Beliefs were inconsistently related to behavior, even when habits were "weak". Experiential feedback from behavior was not related to adherence. Among patients with Type 2 diabetes diagnosis, medication and physical activity adherence were better predicted by their degree of automatic behavioral repetition than their beliefs/experiences with the treatment-actions. Habit strength should be an intervention target for chronic illness self-management; assessing it in practice settings may effectively detect non-adherence to existing treatment-regimens. However, future research and further refining of CS SRM theory regarding the processes required for such habit development are needed. PMID- 26980099 TI - Fisetin yeast-based bio-capsules via osmoporation: effects of process variables on the encapsulation efficiency and internalized fisetin content. AB - Osmoporation is an innovative method that can be used with food-grade yeast cells of Saccharomyces cerevisiae as natural encapsulating matrices. This technique overcomes barriers that difficult encapsulation and enables the internalization of fragile bioactive molecules such as fisetin into yeasts. In the present study, we assessed the effects of concentration, osmotic pressure, and temperature on the encapsulation efficiency (EE) and internalized fisetin content (IF). Two different quantification strategies were investigated: direct extraction (DE) without cell washing or freeze-drying steps and indirect extraction (IE) performed after washings with ethanol and freeze-drying. Our results showed that osmoporation improved EE (33 %) and IF (1.199 mg). The best experimental conditions were found by using DE. High-resolution images showed that the yeast cell envelope was preserved during osmoporation at 30 MPa and 84 % of yeast cells remained viable after treatment. Washing cells with organic solvent led to decreased EE (0.65 %) and IF (0.023 mg). This was probably due to either damages caused to yeast cell envelope or fisetin dragged out of cell. Overall, the results demonstrated the adequacy and relevant biotechnological potential of yeasts as encapsulating matrices for hydrophobic compounds. This fresh biotechnological approach has proven to be a promising tool for the production of bioactive-rich food products. PMID- 26980100 TI - Microbial profiling of South African acid mine water samples using next generation sequencing platform. AB - This study monitored changes in bacterial and fungal structure in a mine water in a monthly basis over 4 months. Over the 4-month study period, mine water samples contained more bacteria (91.06 %) compared to fungi (8.94 %). For bacteria, mine water samples were dominated by Proteobacteria (39.14 to 65.06 %) followed by Firmicutes (26.34 to 28.9 %) in summer, and Cyanobacteria (27.05 %) in winter. In the collected samples, 18 % of bacteria could not be assigned to a phylum and remained unclassified suggesting hitherto vast untapped microbial diversity especially during winter. The fungal domain was the sole eukaryotic microorganism found in the mine water samples with unclassified fungi (68.2 to 91 %) as the predominant group, followed by Basidiomycota (6.9 to 27.8 %). The time of collection, which was linked to the weather, had higher impact on bacterial community than fungal community. The bacterial operational taxonomic units (OTUs) ranged from 865 to 4052 over the 4-month sampling period, while fungal OTUs varied from 73 to 249. The diversity indices suggested that the bacterial community inhabiting the mine water samples were more diverse than the fungal community. The canonical correspondence analysis (CCA) results highlighted that the bacterial community variance had the strongest relationship with water temperature, conductivity, pH, and dissolved oxygen (DO) content, as compared to fungi and water characteristics, had the greatest contribution to both bacterial and fungal community variance. The results provided the relationships between microbial community and environmental variables in the studied mining sites. PMID- 26980101 TI - Toe-Sparing Surgery for Neuropathic Toe Ulcers With Exposed Bone or Joint in an Outpatient Setting: A Retrospective Study. AB - The purpose of this study was to review the results of aggressive surgical debridement of neuropathic toe ulcers with exposed bone or joint. We identified patients with a single toe ulcer with exposed bone or joint that had been operated on in an outpatient setting. The surgery had included aggressive debridement and was performed using a small curette and rongeur, followed by oral antibiotic treatment at home. Success was defined as complete healing with no recurrence 6 months after full wound closure and epitheliazation was achieved. Twenty-five patients with neuropathic toe ulcers (72% male) had a total of 26 primary operations. Their mean age was 60 +/- 12 years. In 22 patients, the neuropathy resulted from diabetes mellitus of 17 +/- 9 years' duration. The mean ulcer duration was 6 weeks (range 1-24). The mean number of visits per patient was 6.5 (range 3-20). The ulcers closed in a median of 5 weeks (8 +/- 6 weeks, range 3-24 weeks, Q1-Q3 4-10 weeks). At 6 months, 3 (11.5%) patients had needed a toe amputation for infection or necrosis that could not be controlled. None needed a major amputation or hospitalization related to the ulcer. Toe-sparing surgery is feasible and in a select population can have a high success rate (88%), even though it does dictate more dedicated patient care. PMID- 26980102 TI - Association of G22A and A4223C ADA1 gene polymorphisms and ADA activity with PCOS. AB - Adenosine deaminase-1 (ADA1) regulates the concentration of adenosine as the main modulator of oocyte maturation. There is compelling evidence for the association of ADA1 gene polymorphisms with many diseases but the importance of ADA1 polymorphisms in polycystic ovary syndrome (PCOS) has not been studied before. This study investigates serum total ADA activity (tADA), ADA1 and ADA2 isoenzyme activities, and genotype and allele frequencies of G22A and A4223C polymorphisms in healthy and PCOS women. In this case-control study 200 PCOS patients and 200 healthy women were enrolled. Genomic DNA was extracted from whole blood and the PCR-RFLP technique was used to determine the G22A and A4223C variants. The genotype frequencies were calculated and the association between polymorphic genotypes and enzyme activities were determined. tADA activity was significantly lower in the PCOS group compared with the control group (27.76+/-6.0 vs. 39.63+/ 7.48, respectively). PCOS patients also showed reduced activity of ADA1 and ADA2. PCOS was not associated with G22A polymorphism whereas AA, AC, and CC genotypes of A4223C polymorphism were found distributed differently between the control and the PCOS women where the C allele showed a strong protective role for PCOS (odds ratio=1.876, p=0.033). The present study for the first time showed that lower ADA activity may be involved in pathogenesis of PCOS by maintaining a higher concentration of adenosine affecting follicular growth. As a novel finding, we also showed great differences in genotype distribution and allele frequencies of A4223C polymorphism between groups indicating a protective role for C allele against PCOS. AbbreviationsADA: adenosine deaminase PCOS: polycystic ovary syndrome PCR-RFLP: polymerase chain reaction-restriction fragment length polymorphism tADA: total adenosine deaminase. PMID- 26980103 TI - Design, synthesis, molecular docking studies and anti-HBV activity of phenylpropanoid derivatives. AB - In this work, a series of phenylpropanoid derivatives were synthesized, and their anti-hepatitis B virus (HBV) activity was evaluated. Most of the synthesized derivatives showed effective anti-HBV activity. And compound 4d-3 showed the most effective anti-HBV activity, performing strong potent inhibitory not only on the secretion of HBsAg (IC50 = 58.28 MUM, SI = 23.26) and HBeAg (IC50 = 97.21 MUM, SI = 13.95), but also on the HBV DNA replication (IC50 = 42.28 MUM, SI = 32.06). The structure-activity relationships (SARs) of the derivatives had been discussed, which were useful for developing phenylpropanoid derivatives as novel anti-HBV agents. Moreover, the docking study of all synthesized compounds inside the HLA-A protein (PDB ID: 3OX8) active site was carried out to explore the molecular interactions and a molecular target for activity and a modified assay method measuring the interaction between our derivatives and HBcAg was investigated, indicating that the HBV core protein might be their potential target for anti HBV. This study identified a new class of potent non-nucleoside anti-HBV agents. PMID- 26980104 TI - Substantial decrease in cell wall alpha-1,3-glucan caused by disruption of the kexB gene encoding a subtilisin-like processing protease in Aspergillus oryzae. AB - Disruption of the kexB encoding a subtilisin-like processing protease in Aspergillus oryzae (DeltakexB) leads to substantial morphological defects when the cells are grown on Czapek-Dox agar plates. We previously found that the disruption of kexB causes a constitutive activation of the cell wall integrity pathway. To understand how the disruption of the kexB affects cell wall organization and components, we analyzed the cell wall of DeltakexB grown on the plates. The results revealed that both total N-acetylglucosamine content, which constitutes chitin, and chitin synthase activities were increased. Whereas total glucose content, which constitutes beta-1,3-glucan and alpha-1,3-glucan, was decreased; this decrease was attributed to a remarkable decrease in alpha-1,3 glucan. Additionally, the beta-1,3-glucan in the alkali-insoluble fraction of the DeltakexB showed a high degree of polymerization. These results suggested that the loss of alpha-1,3-glucan in the DeltakexB was compensated by increases in the chitin content and the average degree of beta-1,3-glucan polymerization. PMID- 26980108 TI - MicroRNA-10 modulates Hox genes expression during Nile tilapia embryonic development. AB - Hox gene clusters encode a family of transcription factors that govern anterior posterior axis patterning during embryogenesis in all bilaterian animals. The time and place of Hox gene expression are largely determined by the relative position of each gene within its cluster. Furthermore, Hox genes were shown to have their expression fine-tuned by regulatory microRNAs (miRNAs). However, the mechanisms of miRNA-mediated regulation of these transcription factors during fish early development remain largely unknown. Here we have profiled three highly expressed miR-10 family members of Nile tilapia at early embryonic development, determined their genomic organization as well as performed functional experiments for validation of target genes. Quantitative analysis during developmental stages showed miR-10 family expression negatively correlates with the expression of HoxA3a, HoxB3a and HoxD10a genes, as expected for bona fide miRNA-mRNA interactions. Moreover, luciferase assays demonstrated that HoxB3a and HoxD10a are targeted by miR-10b-5p. Overall, our data indicate that the miR-10 family directly regulates members of the Hox gene family during Nile tilapia embryogenesis. PMID- 26980105 TI - Responsible implementation of expanded carrier screening. AB - This document of the European Society of Human Genetics contains recommendations regarding responsible implementation of expanded carrier screening. Carrier screening is defined here as the detection of carrier status of recessive diseases in couples or persons who do not have an a priori increased risk of being a carrier based on their or their partners' personal or family history. Expanded carrier screening offers carrier screening for multiple autosomal and X linked recessive disorders, facilitated by new genetic testing technologies, and allows testing of individuals regardless of ancestry or geographic origin. Carrier screening aims to identify couples who have an increased risk of having an affected child in order to facilitate informed reproductive decision making. In previous decades, carrier screening was typically performed for one or few relatively common recessive disorders associated with significant morbidity, reduced life-expectancy and often because of a considerable higher carrier frequency in a specific population for certain diseases. New genetic testing technologies enable the expansion of screening to multiple conditions, genes or sequence variants. Expanded carrier screening panels that have been introduced to date have been advertised and offered to health care professionals and the public on a commercial basis. This document discusses the challenges that expanded carrier screening might pose in the context of the lessons learnt from decades of population-based carrier screening and in the context of existing screening criteria. It aims to contribute to the public and professional discussion and to arrive at better clinical and laboratory practice guidelines. PMID- 26980106 TI - CAG repeat size in Huntingtin alleles is associated with cancer prognosis. AB - The abnormal expansion of a >=36 CAG unit tract in the Huntingtin gene (HTT) leads to Huntington's disease (HD), but has also been associated with cancer: the incidence of cancer is lower in HD patients than in age-matched controls, but HD causing variants of HTT accelerate the progression of breast tumors and the development of metastases in mouse models of breast cancer. To investigate the relationship between HTT CAGs and cancer, data concerning 2407 women with BRCA1 or BRCA2 mutations that predispose to breast and ovarian cancers and 431 patients with breast cancer without family histories were studied; the size of the CAG expansions on both HTT alleles was determined in each subject. The proportion of individuals carrying a CAG expansion in a pathological range for HD was 10 times more frequent than previously reported in the literature. In carriers of BRCA2 mutations, the length of the HTT CAG tract was correlated with lower incidence of ovarian cancer. Among carriers of BRCA1 mutations who developed a breast cancer, its onset occurred 2.4 years earlier in individuals with intermediate HTT alleles (>=27) than in those with a CAG tract <27. Finally, in patients with sporadic HER2 breast cancer, metastasis increased by a factor of 11.10 per 10 additional CAG repeats in HTT. We concluded that whereas long CAG length could be associated with lower cancer incidence, it could also be paradoxically associated with cancer severity (age of apparition and metastasis development). PMID- 26980109 TI - 2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kdelta Selective Inhibitors. AB - Inhibition of phosphoinositide 3-kinase delta (PI3Kdelta) is an appealing target for several hematological malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kdelta inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism. This medicinal chemistry effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kdelta that demonstrates efficacy in a rat model of arthritis. PMID- 26980110 TI - Reply to: Eye disorders in children with celiac disease. PMID- 26980111 TI - Eye disorders in children with celiac disease. PMID- 26980112 TI - Consistency of corneal sublayer thickness measurements using Fourier-domain optical coherence tomography after phacoemulsification. AB - PURPOSE: To assess the reliability of corneal epithelial thickness (CET), nonepithelial central corneal thickness (NECCT), and central corneal thickness (CCT) measurements using Cirrus high-definition optical coherence tomography (HD OCT) in patients who did and did not undergo cataract surgery. METHODS: Forty patients who underwent uneventful phacoemulsification and 40 healthy participants were recruited to evaluate the intraobserver repeatability and interobserver reproducibility of CET, NECCT, and CCT measurements using Cirrus HD-OCT. To analyze repeatability, one examiner obtained 5 consecutive scans in each participant; for interobserver reproducibility, another examiner randomly obtained another scan. Within-subject standard deviation, coefficient of variation (CV), limits of agreement, and intraclass correlation coefficient (ICC) data were obtained. RESULTS: For intraobserver repeatability, the intrasession CV (CVw) and ICC values of the CET in the operated and nonoperated groups were 3.7% and 0.80 and 3.8% and 0.73, respectively; for NECCT, 0.7% and 0.98 and 0.8% and 0.97; and for CCT, 0.6% and 0.99 and 0.7% and 0.98. For interobserver reproducibility, the CVw and ICC values for the CET in the operated and nonoperated groups were 2.6% and 0.82 and 2.3% and 0.62, respectively; for NECCT, 0.7% and 0.98 and 0.5% and 0.98; and for CCT, 0.5% and 0.99 and 0.4% and 0.99. CONCLUSIONS: The corneal sublayer thickness can be measured reliably using Cirrus HD-OCT in patients who underwent cataract surgery and elderly participants; however, the CET consistency is poorer than the NECCT. Corneal epithelial thickness modifications exceeding 4% reflect true thickness changes instead of random error variations using HD-OCT. PMID- 26980113 TI - Glyphosate-based herbicide exposure causes antioxidant defence responses in the fruit fly Drosophila melanogaster. AB - Glyphosate is a non-selective and post-emergent herbicide that affects plant growth. Animal exposure to this herbicide can lead to adverse effects, such as endocrine disruption, oxidative stress and behavioural disorders. Drosophilids have been utilized previously as an effective tool in toxicological tests. In the present study, the effects of a glyphosate-based herbicide (Roundup [Original]) were investigated regarding oxidative stress, the antioxidant defence system and acetylcholinesterase (AChE) activity in Drosophila melanogaster. Flies (of both genders) that were 1 to 3days old were exposed to different glyphosate concentrations (0.0g/L=control, 1.0g/L, 2.0g/L, 5.0g/L and 10.0g/L) [corrected] in the diet for 24h and 96h. After the exposure periods, reactive oxygen species (ROS) levels, antioxidant capacity against peroxyl radicals (ACAP) and lipid peroxidation (LPO) levels were quantified. In addition, the mRNA expression of antioxidant genes (i.e., keap1, sod, sod2, cat, irc, gclc, gclm, gss, trxt, trxr 1 and trxr-2) was evaluated via RT-PCR. Additionally, AChE activity was evaluated only after the 96h exposure period. The results indicated that Roundup exposure leads to a reduction in ROS levels in flies exposed for 96h. ACAP levels and gene expression of the antioxidant defence system exhibited an increase from 24h, while LPO did not show any significant alterations in both exposure periods. AChE activity was not affected following Roundup exposure. Our data suggest that Roundup exposure causes an early activation of the antioxidant defence system in D. melanogaster, and this can prevent subsequent damage caused by ROS. PMID- 26980114 TI - Lipovitellin as an antigen to improve the precision of sandwich ELISA for quantifying zebrafish (Danio rerio) vitellogenin. AB - Vitellogenin (Vtg) in zebrafish (Danio rerio) is a core biomarker for screening environmental estrogens in test guidelines of the Organization for Economic Cooperation and Development. To accurately quantify zebrafish Vtg, lipovitellin (Lv), the main Vtg-derived yolk protein, was used as the antigen to establish a sandwich enzyme-linked immunosorbent assay (ELISA). The purified Lv was a phospholipoglycoprotein with apparent molecular weight of ~445kDa, and separated into three polypeptides corresponding to ~117, ~102, and ~23.8kDa by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Immunological analysis confirmed the specificity of the anti-Lv antibody for Vtg and the immunological similarity between Vtg and Lv. Using the purified Lv and anti-Lv antibody, a sandwich ELISA with a detection limit of 4.3ng/mL and a detection range from 7.8 to 250ng/mL was developed. The intra- and inter-assay coefficients of variation were both below 10%. Moreover, the Lv standard curve was nearly identical to the Vtg standard curve, and paralleled serial whole-body homogenate dilutions of male zebrafish exposed to 17beta-estradiol, demonstrating that the Lv-based ELISA could be used for quantification of zebrafish Vtg. Zebrafish Lv showed high stability during purification process, heat treatment, -80 degrees C storage, and repeated freeze/thaw cycles. Additionally, the standard curve of Lv stored at -80 degrees C for 3months exhibited higher robustness than that of Vtg stored under the same conditions. Finally, the usefulness of the ELISA for detecting estrogenic activity was verified by quantifying Vtg inductions in zebrafish exposed to monocrotophos. PMID- 26980115 TI - Preparing national health systems to cope with the impending tsunami of ageing and its associated complexities: Towards more sustainable health care. AB - Healthcare systems across the world are experiencing increased financial, organizational and social pressures attributable to a range of critical issues including the challenge of ageing populations. Health systems need to adapt, in order to sustainably provide quality care to the widest range of patients, particularly those with chronic and complex diseases, and especially those in vulnerable and low-income groups. We report on a workshop designed to tackle such issues under the auspices of ISQua, with representatives from Argentina, Australia, Canada, Columbia, Denmark, Emirates, France, Ireland, Jordan, Qatar, Malaysia, Norway, Oman, UK, South Africa and Switzerland. We discuss some of the challenges facing healthcare systems in countries ageing rapidly, to those less so, and touch on current and future reform options. PMID- 26980116 TI - How food marketers can sell smaller portions: Consumer insights and product innovation. AB - Food portion size has been shown to be an important driver of energy intake. Despite the well acknowledged role of portion control in weight management, large portion sizes remain ubiquitous in the marketplace. Moving consumers towards consumption of smaller portion sizes will require changes in consumer behavior as well as changes in products available to consumers in a variety of settings. This special supplement presents cutting edge research aimed at understanding consumer behavior around portion size and innovations in product design that may promote the selection and consumption of smaller portion sizes. We identify further research that will be needed to translate basic behavioral findings into real world settings and to viable product development. PMID- 26980117 TI - [Frailty and long term mortality, disability and hospitalisation in Spanish older adults. The FRADEA Study]. AB - INTRODUCTION: The objective of this study was to analyse whether frailty is related to long-term mortality, incident disability in basic activities of daily living (BADL), and hospitalisation. MATERIAL AND METHODS: A concurrent cohort study conducted on 993 participants over age 70 from the FRADEA Study. Frailty was determined with Fried frailty phenotype. Data was collected on mortality, hospitalisation and incident disability in BADL (bathing, grooming, dressing, toileting, eating or transferring) during the follow-up period. The risk of adverse events was determined by logistic regression, Kaplan-Meier analysis, and Cox proportional hazard analysis adjusted for age, sex, Barthel index, comorbidity and institutionalization. RESULTS: Mean follow-up was 952 days (SD 408), during which 182 participants (18.4%) died. Frail participants had an increased adjusted risk of death (HR 4.5, 95%CI: 1.8-11.1), incident disability in BADL (OR 2.7, 95%CI: 1.3-5.9) and the combined event mortality or incident disability (OR 3.0, 95%CI: 1.5-6.1). Pre-frail subjects had an increased adjusted risk of death (HR 2.9, 95%CI: 1.2-6.5), incident disability in BADL (OR 2.1, 95%CI: 1.2-3.6), and the combined event mortality or incident disability (OR 2.2, 95%CI: 1.3-3.6). There was a positive association between frailty and hospitalisation, which almost reached statistical significance (OR 1.7, 95%CI: 1.0-3.0). CONCLUSIONS: Frailty is long-term associated with mortality and incident disability in BADL in a Spanish cohort of older adults. PMID- 26980118 TI - Differentiation of Mouse Embryonic Stem Cells toward Functional Pancreatic beta Cell Surrogates through Epigenetic Regulation of Pdx1 by Nitric Oxide. AB - Pancreatic and duodenal homeobox 1 (Pdx1) is a transcription factor that regulates the embryonic development of the pancreas and the differentiation toward beta cells. Previously, we have shown that exposure of mouse embryonic stem cells (mESCs) to high concentrations of diethylenetriamine nitric oxide adduct (DETA-NO) triggers differentiation events and promotes the expression of Pdx1. Here we report evidence that Pdx1 expression is associated with release of polycomb repressive complex 2 (PRC2) and P300 from its promoter region. These events are accompanied by epigenetic changes in bivalent markers of histones trimethylated histone H3 lysine 27 (H3K27me3) and H3K4me3, site-specific changes in DNA methylation, and no change in H3 acetylation. On the basis of these findings, we developed a protocol to differentiate mESCs toward insulin-producing cells consisting of sequential exposure to DETA-NO, valproic acid, and P300 inhibitor (C646) to enhance Pdx1 expression and a final maturation step of culture in suspension to form cell aggregates. This small molecule-based protocol succeeds in obtaining cells that express pancreatic beta-cell markers such as PDX1, INS1, GCK, and GLUT2 and respond in vitro to high glucose and KCl. PMID- 26980120 TI - Adverse Childhood Experiences, Resilience and Mindfulness-Based Approaches: Common Denominator Issues for Children with Emotional, Mental, or Behavioral Problems. AB - US children with emotional, mental, or behavioral conditions (EMB) have disproportionate exposure to adverse childhood experiences (ACEs). There are theoretic and empirical explanations for early and lifelong physical, mental, emotional, educational, and social impacts of the resultant trauma and chronic stress. Using mindfulness-based, mind-body approaches (MBMB) may strengthen families and promote child resilience and success. This paper examines associations between EMB, ACEs, and protective factors, such as child resilience, parental coping/stress, and parent-child engagement. Findings encourage family centered and mindfulness-based approaches to address social and emotional trauma and potentially interrupt cycles of ACEs and prevalence of EMB. PMID- 26980119 TI - Knee instability scores for ACL reconstruction. AB - Despite abundant biological, biomechanical, and clinical research, return to sport after anterior cruciate ligament (ACL) injury remains a significant challenge. Residual rotatory knee laxity has been identified as one of the factors responsible for poor functional outcome. To improve and standardize the assessment of knee instability, a variety of instability scoring systems is available. Recently, devices to objectively quantify static and dynamic clinical exams have been developed to complement traditional subjective grading systems. These devices enable an improved evaluation of knee instability and possible associated injuries. This additional information may promote the development of new treatment algorithms and allow for individualized treatment. In this review, the different subjective laxity scores as well as complementary objective measuring systems are discussed, along with an introduction of injury to an individualized treatment algorithm. PMID- 26980121 TI - Child Maltreatment Prevention and the Scope of Child and Adolescent Psychiatry. AB - Child maltreatment is one of the most deleterious known influences on the mental health and development of children. This article briefly reviews a complement of methods that are ready to incorporate into child and adolescent psychiatric practice, by having been validated either with respect to the prevention of child maltreatment or with respect to adverse outcomes associated with maltreatment (and primarily focused on enhancing the caregiving environment); they are feasible for integration into clinical decision making, and most importantly, can be included in the training of the next generation of clinicians. PMID- 26980122 TI - The Vermont Family Based Approach: Family Based Health Promotion, Illness Prevention, and Intervention. AB - All health is tied to emotional and behavioral health. To improve population health, we need innovative approaches to healthcare that target emotional and behavioral health. The Vermont Family Based Approach (VFBA) is a healthcare paradigm that aims to improve population health by improving emotional and behavioral health. Because the family is a powerful health-promoting social institution, the VFBA also aims to shift the delivery of healthcare to the family level. This article introduces the VFBA, and presents the main empirical findings that informed the approach in the context of the early childhood period. PMID- 26980124 TI - Prevention of Depression in Childhood and Adolescence. AB - This article discusses strategies and programs used to prevent depression in children and adolescents. It describes the rationale for depression prevention and discusses prevention approaches in schools and other settings, highlighting examples of programs that have been empirically evaluated. Prevention effects are small but significant, comparable or greater in magnitude than adolescent prevention programs for other issues, including substance use and human immunodeficiency virus. Future research should include rigorous design features, including attention control groups, allocation concealment, larger sample sizes, longer follow-up assessments, and theory-driven tests of moderation and mediation, and should test larger-scale implementation of prevention programs. PMID- 26980125 TI - Suicide Prevention Strategies for Improving Population Health. AB - Suicide is a public health problem that accounts for more than 1 million deaths annually worldwide. This article addresses evidence-based and promising youth suicide prevention approaches at the primary, secondary, and tertiary levels. Coordinated, developmentally timed, evidence-based suicide prevention approaches at all intervention levels are likely to reduce youth suicide. For most youth who die by suicide, there are opportunities for intervention before imminent risk develops. Current research in suicide prevention points to the value of investing in "upstream" universal interventions that build skills and resilience as well as policies that enable access to care and protection from lethal means. PMID- 26980126 TI - Bullying. AB - Bullying refers to aggressive behavior that is repetitive and intentional in which a power differential exists between the victim and bully. The negative effects of bullying on an individual's mental and physical health are substantial and in line with other major forms of child maltreatment. Efforts to increase detection of bullying are indicated, especially among youth presenting with school phobia, depression, anxiety, and declining school performance. Several antibullying efforts have been developed and promoted at the school and community level. Research indicates that many of these programs are effective and share some common elements that can help reduce the prevalence and impact of bullying. PMID- 26980127 TI - Prevention of Youth Violence: A Public Health Approach. AB - The causes of youth violence are multifactorial and include biological, individual, familial, social, and economic factors. The influence of parents, family members, and important adults can shape the beliefs of the child toward violence in a significant manner. However, the influence of school and the neighborhood also have an important role in attitudes and behaviors of children toward violence. The complexity of factors related to violence requires a comprehensive public health approach. This article focuses on evidence-based models of intervention to reduce violence while emphasizing collective impact as a guiding principle. PMID- 26980123 TI - The Neurobiological Impact of Postpartum Maternal Depression: Prevention and Intervention Approaches. AB - The lasting negative impact of postpartum depression (PPD) on offspring is well established. PPD seems to have an impact on neurobiological pathways linked to socioemotional regulation, cognitive and executive function, and physiologic stress response systems. This review focus on examining the current state of research defining the effect of universal, selected, and indicated interventions for PPD on infant neurodevelopment. Given the established lasting, and potentially intergenerational, negative implications of maternal depression, enhanced efforts targeting increased identification and early intervention approaches for PPD that have an impact on health outcomes in both infants and mothers represent a critical public health concern. PMID- 26980128 TI - Empirically Based Strategies for Preventing Juvenile Delinquency. AB - Juvenile crime is a serious public health problem that results in significant emotional and financial costs for victims and society. Using etiologic models as a guide, multiple interventions have been developed to target risk factors thought to perpetuate the emergence and persistence of delinquent behavior. Evidence suggests that the most effective interventions tend to have well-defined treatment protocols, focus on therapeutic approaches as opposed to external control techniques, and use multimodal cognitive-behavioral treatment strategies. Moving forward, there is a need to develop effective policies and procedures that promote the widespread adoption of evidence-based delinquency prevention practices across multiple settings. PMID- 26980129 TI - Child Obesity and Mental Health: A Complex Interaction. AB - Prevalence rates of childhood obesity have risen steeply over the last 3 decades. Given the increased national focus, the frequency of this clinical problem, and the multiple mental health factors that coexist with it, make obesity a public health concern. The complex relationships between mental health and obesity serve to potentiate the severity and interdependency of each. The purpose of this review is to create a contextual connection for the 2 conditions as outlined by the research literature and consider treatment options that affect both health problems. PMID- 26980130 TI - Human Immunodeficiency Virus Prevention. AB - Human immunodeficiency virus (HIV) is the virus that causes AIDS. Surveillance data from 2012 indicate an estimated 1.2 million people aged 13 years and older were living with HIV infection in the United States, and 12.8% do not know their status. There are approximately 50,000 new HIV infections annually. With no available cure for HIV, primary prevention to reduce incident cases of HIV is essential. Strategies to prevent HIV transmission include reducing sexual risk behavior and needle sharing. The Centers for Disease Control and Prevention has multiple resources available for primary and secondary prevention to reduce disease transmission and severity. PMID- 26980131 TI - Substance Abuse Prevention. AB - Substance use disorders account for approximately 6% of deaths worldwide and cost about $700 billion in the United States. Approximately 80% of drug users begin using during adolescence, underscoring the public health importance of effective substance prevention programs for youth and families. Prevention science designates 3 intervention categories: (1) universal prevention, targeting all individuals in the population, (2) selective interventions, targeting high-risk groups, and (3) indicated prevention interventions for youth with risk-taking behaviors. School-based and non-school-based interventions are reviewed, as well as the limitations of existing research, gaps in access and availability, and directions for future research and development. PMID- 26980132 TI - A Population Health Approach to System Transformation for Children's Healthy Development. AB - What if the goal of child health services was not "merely" treating, or even preventing, childhood diseases and disorders, but was expanded to that of promoting children's optimal healthy development? Pediatrics has evolved from an exclusive focus on the treatment of illness to the opportunity to promote children's healthy development. This evolution has profound implications for the content of child health services and programs, for system transformation, and for public policy. Enhanced understanding of the impact of social determinants on children's health and developmental outcomes underscores the importance of an evolving framework for system transformation with key policy implications. PMID- 26980133 TI - Appendix. AB - This article is designed to serve as a reference for researchers and clinicians interested in extant evidence-based programs designed to promote healthy youth development. This article begins with a review of 2 freely available online registries of evidence-based youth development programs. Both registries compile information on healthy youth development programs and rate such programs on pre established criteria. This article also outlines several specific model programs, which intervene on a variety of targets to promote healthy youth development. Lastly, this article also outlines emerging youth development programs. The model and emerging programs reviewed have resulted in myriad positive outcomes. PMID- 26980134 TI - Prevention of Mental Health Disorders: Principles and Implementation. PMID- 26980135 TI - Generation mechanism of RANKL(+) effector memory B cells: relevance to the pathogenesis of rheumatoid arthritis. AB - BACKGROUND: The efficacy of B cell-depleting therapies for rheumatoid arthritis underscores antibody-independent functions of effector B cells such as cognate T B interactions and production of pro-inflammatory cytokines. Receptor activator of nuclear factor kappaB ligand (RANKL) is a key cytokine involved in bone destruction and is highly expressed in synovial fluid B cells in patients with rheumatoid arthritis. In this study we sought to clarify the generation mechanism of RANKL(+) effector B cells and their impacts on osteoclast differentiation. METHODS: Peripheral blood and synovial fluid B cells from healthy controls and patients with rheumatoid arthritis were isolated using cell sorter. mRNA expression of RANKL, osteoprotegerin, tumor necrosis factor (TNF)-alpha, and Blimp-1 was analyzed by quantitative real-time polymerase chain reaction. Levels of RANKL, CD80, CD86, and CXCR3 were analyzed using flow cytometry. Functional analysis of osteoclastogenesis was carried out in the co-culture system using macrophage RAW264 reporter cells. RESULTS: RANKL expression was accentuated in CD80(+)CD86(+) B cells, a highly activated B-cell subset more abundantly observed in patients with rheumatoid arthritis. Upon activation via B-cell receptor and CD40, switched-memory B cells predominantly expressed RANKL, which was further augmented by interferon-gamma (IFN-gamma) but suppressed by interleukin-21. Strikingly, IFN-gamma also enhanced TNF-alpha expression, while it strongly suppressed osteoprotegerin expression in B cells. IFN-gamma increased the generation of CXCR3(+)RANKL(+) effector B cells, mimicking the synovial B cell phenotype in patients with rheumatoid arthritis. Finally, RANKL(+) effector B cells in concert with TNF-alpha facilitated osteoclast differentiation in vitro. CONCLUSIONS: Our current findings have shed light on the generation mechanism of pathogenic RANKL(+) effector B cells that would be an ideal therapeutic target for rheumatoid arthritis in the future. PMID- 26980136 TI - Bad splits in bilateral sagittal split osteotomy: systematic review and meta analysis of reported risk factors. AB - An unfavourable and unanticipated pattern of the bilateral sagittal split osteotomy (BSSO) is generally referred to as a 'bad split'. Patient factors predictive of a bad split reported in the literature are controversial. Suggested risk factors are reviewed in this article. A systematic review was undertaken, yielding a total of 30 studies published between 1971 and 2015 reporting the incidence of bad split and patient age, and/or surgical technique employed, and/or the presence of third molars. These included 22 retrospective cohort studies, six prospective cohort studies, one matched-pair analysis, and one case series. Spearman's rank correlation showed a statistically significant but weak correlation between increasing average age and increasing occurrence of bad splits in 18 studies (rho=0.229; P<0.01). No comparative studies were found that assessed the incidence of bad split among the different splitting techniques. A meta-analysis pooling the effect sizes of seven cohort studies showed no significant difference in the incidence of bad split between cohorts of patients with third molars present and concomitantly removed during surgery, and patients in whom third molars were removed at least 6 months preoperatively (odds ratio 1.16, 95% confidence interval 0.73-1.85, Z=0.64, P=0.52). In summary, there is no robust evidence to date to show that any risk factor influences the incidence of bad split. PMID- 26980137 TI - Parasite fauna of Epinephelus coioides (Hamilton, 1822) (Epinephelidae) as environmental indicator under heavily polluted conditions in Jakarta Bay, Indonesia. AB - The objective of this study was to assess the environmental conditions of a heavily polluted marine habitat using descriptors of fish parasites. Epinephelus coioides from Jakarta Bay as well as off Jakarta Bay was studied for metazoan parasites. Based on 70 fish and considering previous studies (230 fish), an environmental indicator system was designed. Including the recent study, a total of 51 parasite species have been recorded for E. coioides in Indonesian waters. Seven of them combined with five parasitological indices are useful descriptors for the environmental status of marine ecosystems. The results are visualized in a star graph. A significant different parasite infection between nine analyzed localities demonstrates the negative influence of the megacity Jakarta onto the coastal environment. We herewith complete a parasite based indicator system for Indonesian coastal waters, and suggest that it can be used in other marine habitats as well as for further epinephelids. PMID- 26980138 TI - Microplastic contamination in natural mussel beds from a Brazilian urbanized coastal region: Rapid evaluation through bioassessment. AB - Microplastic pollution (particles <5mm) is a widespread marine threat and a trigger for biological effects, especially if ingested. The mussel Perna perna, an important food resource, was used as bioindicator to investigate the presence of microplastic pollution on Santos estuary, the most urbanized area of the coast of Sao Paulo State, Brazil. A simple and rapid assessment showed that 75% of sampled mussels had ingested microplastics, an issue of human and environmental concern. All sampling points had contaminated mussels and this contamination had no clear pattern of distribution along the estuary. This was the first time that microplastic bioavailability was assessed in nature for the southern hemisphere and that wild P. perna was found contaminated with this pollutant. This is an important issue that should be better assessed due to an increase in seafood consumption and culture in Brazil and worldwide. PMID- 26980139 TI - Systematic identification of phenotypically enriched loci using a patient network of genomic disorders. AB - BACKGROUND: Network medicine is a promising new discipline that combines systems biology approaches and network science to understand the complexity of pathological phenotypes. Given the growing availability of personalized genomic and phenotypic profiles, network models offer a robust integrative framework for the analysis of "omics" data, allowing the characterization of the molecular aetiology of pathological processes underpinning genetic diseases. METHODS: Here we make use of patient genomic data to exploit different network-based analyses to study genetic and phenotypic relationships between individuals. For this method, we analyzed a dataset of structural variants and phenotypes for 6,564 patients from the DECIPHER database, which encompasses one of the most comprehensive collections of pathogenic Copy Number Variations (CNVs) and their associated ontology-controlled phenotypes. We developed a computational strategy that identifies clusters of patients in a synthetic patient network according to their genetic overlap and phenotype enrichments. RESULTS: Many of these clusters of patients represent new genotype-phenotype associations, suggesting the identification of newly discovered phenotypically enriched loci (indicative of potential novel syndromes) that are currently absent from reference genomic disorder databases such as ClinVar, OMIM or DECIPHER itself. CONCLUSIONS: We provide a high-resolution map of pathogenic phenotypes associated with their respective significant genomic regions and a new powerful tool for diagnosis of currently uncharacterized mutations leading to deleterious phenotypes and syndromes. PMID- 26980140 TI - Electrochemical detection of protein glycosylation using lectin and protein-gold affinity interactions. AB - We report a new method for the electrochemical detection of glycosylation on proteins, which relies on lectin-protein interaction on a bare gold electrode. The target protein isolated by immunoaffinity is directly adsorbed onto a gold surface and its glycosylation status is retrieved by subsequent addition of specific lectins. The adsorption and subsequent recognition process is monitored electrochemically in the presence of [Fe(CN)6](3-/4-) redox system. By decoupling target protein capture from glycosylation read-out steps, this approach circumvents unwanted antibody-lectin crosstalk while enabling specific glycosylation detection of a glycoprotein in serum-spiked samples in less than 1 h. PMID- 26980141 TI - A qualitative study of patients' perspectives on collaboration to support self management in routine rheumatology consultations. AB - BACKGROUND: Self-management of inflammatory arthritis (IA) requires patients to address the impact of symptoms, treatment, and the psychosocial consequences of a long term condition. There are several possible mechanisms for facilitating self management, including patient-clinician interactions in routine consultations. This requires patients to collaborate in their healthcare, and clinicians to specifically encourage and help patients to do so. To design training that enables clinicians to support patients to be actively involved and self-manage requires understanding both patients' and clinicians' perspectives about what is important and feasible. Previous research explored the perspectives of clinicians who had undertaken brief training which they were putting into practice in their routine consultations. This study explored the perspectives of patients attending those routine consultations to identify aspects of the interaction that influenced collaboration and self-management. METHODS: Nineteen patients with IA who had attended a routine consultation with a rheumatology clinician at one of four hospitals in England took part in semi-structured interviews. Interviews were transcribed, anonymised and analysed using inductive thematic analysis. RESULTS: Three themes encompass participants' thoughts about interactions that facilitated collaboration in consultations and their ability to self-manage their IA: first, patients and clinicians viewing care as a shared endeavour, including patients responding actively to their IA and clinicians exploring and negotiating with patients; second, the need for clinicians to understand the challenges faced by patients, appreciate the impact of IA and focus on patients' priorities; and third, clinicians using an open communication style, including the use of non didactic, patient-centred approaches. A fourth theme was perceived benefits of actively engaging in consultations, including increased confidence to deal with the impact of IA and greater acceptance of a long term condition. CONCLUSIONS: Patients perceive that self-management can be facilitated when clinicians and patients view healthcare as a shared responsibility, underpinned by clinicians as experts in the disease and patients as experts in living with it. Clinicians can support patients' self-management by using non-didactic communication skills to identify patients' priorities, and to prompt patients to problem-solve and share in setting the consultation agenda. This should inform skills-training for rheumatology clinicians. PMID- 26980142 TI - Diagnostic Stability of ICD/DSM First Episode Psychosis Diagnoses: Meta-analysis. AB - BACKGROUND: Validity of current International Classification of Disease/Diagnostic and Statistical Manual of Mental Disorders (ICD/DSM) first episode psychosis diagnoses is essential in clinical practice, research, training and public health. METHOD: We provide a meta-analytical estimate of prospective diagnostic stability and instability in ICD-10 or DSM-IV first episode diagnoses of functional psychoses. Independent extraction by multiple observers. Random effect meta-analysis conducted with the "metaprop," "metaninf," "metafunnel," "metabias," and "metareg" packages of STATA13.1. Moderators were tested with meta regression analyses. Heterogeneity was assessed with the I 2 index. Sensitivity analyses tested robustness of results. Publication biases were assessed with funnel plots and Egger's test. FINDINGS: 42 studies and 45 samples were included, for a total of 14 484 first episode patients and an average follow-up of 4.5 years. Prospective diagnostic stability ranked: schizophrenia 0.90 (95% CI 0.85 0.95), affective spectrum psychoses 0.84 (95% CI 0.79-0.89), schizoaffective disorder 0.72 (95% CI 0.61-0.73), substance-induced psychotic disorder 0.66 (95% CI 0.51-0.81), delusional disorder 0.59 (95% CI 0.47-0.71), acute and transient psychotic disorder/brief psychotic disorder 0.56 (95% CI 0.62-0.60), psychosis not otherwise specified 0.36 (95% CI 0.27-0.45, schizophreniform disorder 0.29 (95% CI 0.22-0.38). Diagnostic stability within schizophrenia spectrum psychoses was 0.93 (95% CI 0.89-0.97); changes to affective spectrum psychoses were 0.05 (95% CI 0.01-0.08). About 0.10 (95% CI 0.05-0.15) of affective spectrum psychoses changed to schizophrenia spectrum psychosis. Across the other psychotic diagnoses there was high diagnostic instability, mostly to schizophrenia. INTERPRETATION: There is meta-analytical evidence for high prospective diagnostic stability in schizophrenia spectrum and affective spectrum psychoses, with no significant ICD/DSM differences. These results may inform the development of new treatment guidelines for early psychosis and impact drug licensing from regulatory agencies. PMID- 26980143 TI - Cortical Gene Expression After a Conditional Knockout of 67 kDa Glutamic Acid Decarboxylase in Parvalbumin Neurons. AB - In the cortex of subjects with schizophrenia, expression of glutamic acid decarboxylase 67 (GAD67), the enzyme primarily responsible for cortical GABA synthesis, is reduced in the subset of GABA neurons that express parvalbumin (PV). This GAD67 deficit is accompanied by lower cortical levels of other GABA associated transcripts, including GABA transporter-1, PV, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B, somatostatin, GABAA receptor alpha1 subunit, and KCNS3 potassium channel subunit mRNAs. In contrast, messenger RNA (mRNA) levels for glutamic acid decarboxylase 65 (GAD65), another enzyme for GABA synthesis, are not altered. We tested the hypothesis that this pattern of GABA-associated transcript levels is secondary to the GAD67 deficit in PV neurons by analyzing cortical levels of these GABA-associated mRNAs in mice with a PV neuron-specific GAD67 knockout. Using in situ hybridization, we found that none of the examined GABA-associated transcripts had lower cortical expression in the knockout mice. In contrast, PV, BDNF, KCNS3, and GAD65 mRNA levels were higher in the homozygous mice. In addition, our behavioral test battery failed to detect a change in sensorimotor gating or working memory, although the homozygous mice exhibited increased spontaneous activities. These findings suggest that reduced GAD67 expression in PV neurons is not an upstream cause of the lower levels of GABA-associated transcripts, or of the characteristic behaviors, in schizophrenia. In PV neuron-specific GAD67 knockout mice, increased levels of PV, BDNF, and KCNS3 mRNAs might be the consequence of increased neuronal activity secondary to lower GABA synthesis, whereas increased GAD65 mRNA might represent a compensatory response to increase GABA synthesis. PMID- 26980144 TI - Defeatist Performance Beliefs, Negative Symptoms, and Functional Outcome in Schizophrenia: A Meta-analytic Review. AB - Negative symptoms are a strong predictor of poor functional outcome in people with schizophrenia. Unfortunately there are few effective interventions for either negative symptoms or functional outcome, despite the identification of potential mechanisms. Recent research, however, has elucidated a new potential mechanism for negative symptoms and poor functional outcome: defeatist performance beliefs (DPB), or negative thoughts about one's ability to successfully perform goal-directed behavior that can prevent behavior initiation and engagement. We conducted 2 meta-analyses examining the relationship between DPB and both negative symptoms (n = 10 studies) and functional outcome (n = 8 studies) in people with schizophrenia. We found a small effect size for the relationship between DPB and negative symptoms, regardless of how negative symptoms were measured. We also found a small effect size for the relationship between DPB and functional outcome, which was significantly moderated by the method of assessing DPB and moderated by the sex composition of the study at a trend level. These findings highlight the potential of targeting DPB in psychosocial interventions for both negative symptoms and functional outcome. PMID- 26980145 TI - Effects of acrolein on aldosterone release from zona glomerulosa cells in male rats. AB - A positive correlation between smoking and hypertension has been well established. Acrolein is a major toxic volatile compound found in cigarette smoke. Human exposure to low levels of acrolein is unavoidable due to its production in daily activities, such as smoke from industrial, hot oil cooking vapors, and exhaust fumes from vehicles. The toxicity and the action mechanism of acrolein to induce apoptosis have been extensively studied, but the effects of acrolein on hypertension are still unknown. The present study aimed to examine the effects of acrolein on aldosterone release both in vivo and in vitro. Male rats were divided into three groups, and intraperitoneally injected with normal saline, or acrolein (2mg/kg) for 1 (group A-1) or 3 (group A-3) days, respectively. After sacrificing, rat blood samples were obtained to measure plasma aldosterone and angiotensin II (Ang II) levels. Zona glomerulosa (ZG) cells were prepared from rat adrenal cortex, and were incubated with or without stimulants. We found that the serum aldosterone was increased by 1.2-fold (p<0.05) in A-3 group as compared to control group. Basal aldosterone release from ZG cells in A-3 group was also increased significantly. Moreover, acrolein enhanced the stimulatory effects of Ang II and 8-bromo-cyclic AMP on aldosterone secretion from ZG cells prepared in both A-1 and A-3 groups. Furthermore, the enzyme activity of P450scc, the rate-limiting step of aldosterone synthesis, was elevated after acrolein injection. Plasma level of Ang II was increased in both A 1 and A-3 groups. These results suggested that acrolein exposure increased aldosterone production, at least in part, through elevating the level of plasma Ang II and stimulating steroidogenesis pathways. PMID- 26980146 TI - The combination of tetraiodothyroacetic acid and cetuximab inhibits cell proliferation in colorectal cancers with different K-ras status. AB - Thyroid hormone induces cancer cell proliferation through its cell surface receptor integrin alphavbeta3. Acting via integrin alphavbeta3, the deaminated T4 analog tetraiodothyroacetic acid (tetrac), and its nanoparticle formulation nano diamino-tetrac (NDAT) could inhibit cell proliferation and xenograft growth. In this study, we investigated the T4 effects on proliferation in colorectal cancer cell lines based on the proliferation marker expressions at both mRNA and protein levels. The effects of tetrac/NDAT, the monoclonal anti-EGFR antibody cetuximab, and their combinations on colorectal cancer cell proliferation were examined according to the relevant gene expression profiles and cell count analysis. The results showed that T4 significantly enhanced PCNA, Cyclin D1 and c-Myc levels in both K-ras wild type HT-29 and mutant HCT 116 cells. In HCT 116 cells, the combination of NDAT and cetuximab significantly suppressed the mRNA expressions of proliferative genes PCNA, Cyclin D1, c-Myc and RRM2 raised by T4 compared to cetuximab alone. In addition, T4-suppressed mRNA expressions of pro-apoptotic genes p53 and RRM2B could be significantly elevated by the combination of NDAT and cetuximab compared to cetuximab alone. In the K-ras mutant HCT 116 cells, but not in the K-ras wild type COLO 205 cells, the combinations of tetrac/NDAT and cetuximab significantly reduced cell proliferation compared to cetuximab alone. In conclusion, T4 promoted colorectal cancer cell proliferation which could be repressed by tetrac and NDAT. The combinations of tetrac/NDAT and cetuximab potentiated cetuximab actions in K-ras mutant colorectal cancer cells. PMID- 26980147 TI - Including Online-Recruited Seeds: A Respondent-Driven Sample of Men Who Have Sex With Men. AB - BACKGROUND: Technology has changed the way men who have sex with men (MSM) seek sex and socialize, which may impact the implementation of respondent-driven sampling (RDS) among this population. Initial participants (also known as seeds) are a critical consideration in RDS because they begin the recruitment chains. However, little information is available on how the online-recruited seeds may effect RDS implementation. OBJECTIVE: The objectives of this study were to compare (1) online-recruited versus offline-recruited seeds and (2) subsequent recruitment chains of online-recruited versus offline-recruited seeds. METHODS: Between 2012 and 2014, we recruited MSM using RDS in Vancouver, Canada. RDS weights were used with logistic regression to address each objective. RESULTS: A total of 119 seeds were used, 85 of whom were online-recruited seeds, to recruit an additional 600 MSM. Compared with offline-recruited seeds, online-recruited seeds were less likely to be HIV-positive (OR 0.34, 95% CI 0.13-0.88), to have attended a gay community group (AOR 0.33, 95% CI 0.12-0.90), and to feel gay community involvement was "very important" (AOR 0.16, 95% CI 0.03-0.93). Online recruited seeds were more likely to ask a sexual partner's HIV status always versus <50% of the time (AOR 5.21, 95% CI 1.17-23.23), to have watched the Pride parade (AOR 6.30, 95% CI 1.69-23.45), and to have sought sex online (AOR 4.29, 95% CI 1.53-12-12.05). Further, compared with recruitment chains started by offline-recruited seeds, recruits from chains started by online-recruited seeds (283/600, 47.2%) were less likely to be HIV-positive (AOR 0.25, 95% CI 0.16 0.40), to report "versatile" versus "bottom" sexual position preference (AOR 0.56, 95% CI 0.35-0.88), and to be in a relationship lasting >1 year (AOR 1.65, 95% CI 1.06-2.56). Recruits of online seeds were more likely to be out as gay for longer (eg, 11-21 vs 1-4 years, AOR 2.22, 95% CI 1.27-3.88) and have fewer Facebook friends (eg, 201-500 vs >500, AOR 1.69, 95% CI 1.02-2.80). CONCLUSIONS: Online-recruited seeds were more prevalent, recruited fewer participants, but were different from those recruited offline. This may therefore help create a more diverse overall sample. Our work has shown the value of geosocial networking apps for aiding RDS recruitment efforts, especially when faced with slow participation uptake by other means. Understanding the degree to which networks interact will be an important next step in confirming the efficacy of online RDS recruitment strategies. PMID- 26980149 TI - A 'bottom up', ab initio computational approach to understanding fundamental photophysical processes in nitrogen containing heterocycles, DNA bases and base pairs. AB - The availability of non-radiative decay mechanisms by which photoexcited molecules can revert to their ground electronic state, without experiencing potentially deleterious chemical transformation, is fundamental to molecular photostability. This Perspective Article combines results of new ab initio electronic structure calculations and prior experimental data in an effort to systematise trends in the non-radiative decay following UV excitation of selected families of heterocyclic molecules. We start with the prototypical uni- and bicyclic molecules phenol and indole, and explore the structural and photophysical consequences of incorporating progressively more nitrogen atoms within the respective ring structures en route to the DNA bases thymine, cytosine, adenine and guanine. For each of the latter, we identify low energy non radiative decay pathways via conical intersections with the ground state potential energy surface accessed by out-of-plane ring deformations. This is followed by summary descriptions and illustrations of selected rival (electron driven H atom transfer) non-radiative excited state decay processes that demand consideration once the nucleobases are merely components in larger biomolecular systems like nucleosides, and both individual and stacked base-pairs. PMID- 26980148 TI - Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis. AB - The bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) plays a key role in sialic acid production. It is different from the non-hydrolyzing enzymes for bacterial cell wall biosynthesis, and it is feed-back inhibited by the downstream product CMP-Neu5Ac. Here the complex crystal structure of the N terminal epimerase part of human GNE shows a tetramer in which UDP binds to the active site and CMP-Neu5Ac binds to the dimer-dimer interface. The enzyme is locked in a tightly closed conformation. By comparing the UDP-binding modes of the non-hydrolyzing and hydrolyzing UDP-GlcNAc epimerases, we propose a possible explanation for the mechanistic difference. While the epimerization reactions of both enzymes are similar, Arg113 and Ser302 of GNE are likely involved in product hydrolysis. On the other hand, the CMP-Neu5Ac binding mode clearly elucidates why mutations in Arg263 and Arg266 can cause sialuria. Moreover, full-length modelling suggests a channel for ManNAc trafficking within the bifunctional enzyme. PMID- 26980150 TI - Comparison of a rapid point-of-care and two laboratory-based CYP2C19*2 genotyping assays for personalisation of antiplatelet therapy. AB - BACKGROUND: A quick CYP2C19*2 genotyping assay can be useful in personalised antiplatelet-therapy. OBJECTIVE: To apply a rapid point-of-care (POC) CYP2C19*2 genotyping assay for personalisation of antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) and to compare this POC assay to two laboratory-based CYP2C19*2 genotyping assays. SETTING: Cardiac Catheterisation Suite and Molecular Diagnostics Unit in a general hospital. METHODS: A buccal sample was collected for POC CYP2C19*2 genotyping with the SpartanTM RX system (Spartan Bioscience). A whole blood sample was collected from the same patients for laboratory-based CYP2C19*2 genotyping with a TaqMan(r) allelic discrimination assay (Life Technologies) using real-time quantitative PCR and with the GenID(r) reverse dot-blot hybridisation assay (Autoimmun Diagnostika GmbH). Each patient was genotyped as a non-carrier of CYP2C19*2 (*1/*1), a carrier of one CYP2C19*2 allele (*1/*2), or a carrier of two CYP2C19*2 alleles (*2/*2). Genotyping, interpretation and communication of genotype results (*1/*2, *2/*2) to the consultant cardiologist was undertaken by a clinical pharmacist researcher. Quantitative and qualitative comparison between the three assays was carried out. MAIN OUTCOME MEASURES: Application of a rapid POC CYP2C19*2 genotyping assay for antiplatelet therapy individualisation; comparison of the POC CYP2C19*2 genotyping assay to two laboratory-based assays. RESULTS: The total sample consisted of 34 Caucasian patients. With the POC assay, 21 patients were genotyped as non-carriers of CYP2C19*2, 12 patients as carriers of one CYP2C19*2 allele and one patient as a carrier of two CYP2C19*2 alleles. With both laboratory-based assays, the same 21 patients were genotyped as non-carriers of CYP2C19*2, however 13 patients were genotyped as carriers of one CYP2C19*2 allele and no patients were genotyped as carriers of two CYP2C19*2 alleles. Agreement in genotype results was 97 % (kappa = 0.939) between the POC assay and both laboratory-based assays and 100 % (kappa = 1.000) between the two laboratory based assays. CONCLUSION: Compared to both laboratory-based genotyping assays, the POC assay is accurate and reliable, provides rapid results, can process single samples, is portable and more operator-friendly, however the tests are more expensive. PMID- 26980151 TI - Mining social media data for opinion polarities about electronic cigarettes. AB - BACKGROUND: There is an ongoing debate about harm and benefit of e-cigarettes, usage of which has rapidly increased in recent years. By separating non commercial (organic) tweets from commercial tweets, we seek to evaluate the general public's attitudes towards e-cigarettes. METHODS: We collected tweets containing the words 'e-cig', 'e-cigarette', 'e-liquid', 'vape', 'vaping', 'vapor' and 'vaporizer' from 23 July to 14 October 2015 (n=757 167). A multilabel Naive Bayes model was constructed to classify tweets into 5 polarities (against, support, neutral, commercial, irrelevant). We further analysed the prevalence of e-cigarette tweets, geographic variations in these tweets and the impact of socioeconomic factors on the public attitudes towards e-cigarettes. RESULTS: Opinions from organic tweets about e-cigarettes were mixed (against 17.7%, support 10.8% and neutral 19.4%). The organic-against tweets delivered strong educational information about the risks of e-cigarette use and advocated for the general public, especially youth, to stop vaping. However, the organic-against tweets were outnumbered by commercial tweets and organic-support tweets by a ratio of over 1 to 3. Higher prevalence of organic tweets was associated with states with higher education rates (r=0.60, p<0.0001), higher percentage of black and African-American population (r=0.34, p=0.01), and higher median household income (r=0.33, p=0.02). The support rates for e-cigarettes were associated with states with fewer persons under 18 years old (r=-0.33, p=0.02) and a higher percentage of female population (r=0.3, p=0.02). CONCLUSIONS: The organic-against tweets raised public awareness of potential health risks and could aid in preventing non-smokers, adolescents and young adults from using e-cigarettes. Opinion polarities about e-cigarettes from social networks could be highly influential to the general public, especially youth. Further educational campaigns should include measuring their effectiveness. PMID- 26980152 TI - Health-related quality of life of patients with pulmonary arterial hypertension associated with CHD: the multicentre cross-sectional ACHILLE study. AB - BACKGROUND: The aim of this study was to assess health-related quality of life in patients with pulmonary arterial hypertension associated with CHD and correlations with clinical status. METHODS: This prospective cross-sectional observational study included CHD patients with pulmonary arterial hypertension in 14 tertiary-care centres in France. We used two health-related quality of life questionnaires - SF-36 and Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) - and one anxiety/depression Hospital Anxiety and Depression Scale (HADS) questionnaire. RESULTS: Clinical data were collected for the 208 included patients (mean age: 42.6 years, range from 15.1 to 85.8 years, 69.7% female). Most patients were in NYHA functional class II (48.1%) and III (37.5%). Patients' phenotype was classified as Eisenmenger syndrome (70.7%), pulmonary arterial hypertension associated with systemic-to-pulmonary shunts (12.0%), with small defects (3.4%), or after corrective cardiac surgery (13.9%). In total, 76.4% of the patients were receiving pulmonary arterial hypertension-specific treatments. SF-36 scores showed impairment compared with normalised data. Health-related quality of life scores were significantly lower in females than in males for most dimensions of both questionnaires and were independent of the patients' phenotype, even after gender adjustment - except for CAMPHOR functioning - but significantly depended on NYHA functional class. The Hospital Anxiety and Depression Scale (HADS) scores suggested anxiety and depression associated with increasing NYHA functional class but independent of patients' phenotype. NYHA functional class, 6-minute walk distance, HADS, gender, and recent stressful event significantly affected quality of life in the multivariate analysis. CONCLUSIONS: This study showed impairment of quality of life in a large cohort of patients with pulmonary arterial hypertension associated with CHD with both generic and specific questionnaires. NYHA functional class and HADS scores were predictive of most quality of life scores. PMID- 26980153 TI - Secure Infant-Mother Attachment Buffers the Effect of Early-Life Stress on Age of Menarche. AB - Prior research indicates that being reared in stressful environments is associated with earlier onset of menarche in girls. In this research, we examined (a) whether these effects are driven by exposure to certain dimensions of stress (harshness or unpredictability) during the first 5 years of life and (b) whether the negative effects of stress on the timing of menarche are buffered by secure infant-mother attachment. Results revealed that (a) exposure to greater harshness (but not unpredictability) during the first 5 years of life predicted earlier menarche and (b) secure infant-mother attachment buffered girls from this effect of harsh environments. By connecting attachment research to its evolutionary foundations, these results illuminate how environmental stressors and relationships early in life jointly affect pubertal timing. PMID- 26980154 TI - Is Seeing Gesture Necessary to Gesture Like a Native Speaker? AB - Speakers of all languages gesture, but there are differences in the gestures that they produce. Do speakers learn language-specific gestures by watching others gesture or by learning to speak a particular language? We examined this question by studying the speech and gestures produced by 40 congenitally blind adult native speakers of English and Turkish (n = 20/language), and comparing them with the speech and gestures of 40 sighted adult speakers in each language (20 wearing blindfolds, 20 not wearing blindfolds). We focused on speakers' descriptions of physical motion, which display strong cross-linguistic differences in patterns of speech and gesture use. Congenitally blind speakers of English and Turkish produced speech that resembled the speech produced by sighted speakers of their native language. More important, blind speakers of each language used gestures that resembled the gestures of sighted speakers of that language. Our results suggest that hearing a particular language is sufficient to gesture like a native speaker of that language. PMID- 26980155 TI - Word Retrieval Ability on Phonemic Fluency in Typically Developing Children. AB - Verbal fluency tasks are simple behavioral measures useful in assessing word retrieval abilities. Among the verbal fluency tasks, the utility of the Phonemic Fluency Task in children has received less attention. As the task is dependent on phonemic characteristics of each language, there is a great need for understanding its developmental trend. The present study, therefore, aims to delineate the performance on phonemic fluency in typically developing Malayalam speaking children. Verbal fluency performance on 2 tasks of phonemic fluency was tested using a cross-sectional study design among 1,015 school-going Malayalam speaking typically developing children aged 5 to 15 years old. Performance with respect to word productivity and clustering-switching measures was analyzed. The effect of age, gender, and tasks on the outcome measures were investigated in the present study. Study findings revealed a positive influence of age with no statistically significant gender effects. Children employed both task-discrepant and task-consistent organizational strategies during tasks of phonemic fluency, dependent purely on the Malayalam language. Future research focusing on developmental trends across different languages is vital for enhancing the task's clinical sensitivity and specificity among childhood disorders. PMID- 26980156 TI - Longitudinal association between toenail zinc levels and the incidence of diabetes among American young adults: The CARDIA Trace Element Study. AB - Data on primary prevention of zinc status and diabetes risk are sparse and inconsistent. Of note, the previous studies measured either dietary zinc intake with questionnaire or zinc status in serum or hair. Toenail zinc levels are reliable biomarkers of a relatively long-term exposure. A total of 3,960 American young adults, aged 20-32 years, free of diabetes at baseline in 1987 when toenail clippings were collected, were examined for incident diabetes through 2010. Toenail zinc levels were measured with an inductively-coupled-plasma mass spectroscopy method. Incident diabetes cases were identified by fasting or non fasting plasma glucose levels, oral glucose tolerance tests, hemoglobin A1C levels, and/or antidiabetic medications. During the 23-year follow-up, 418 incident diabetes occurred. After adjusted for age, sex, ethnicity, study center, body mass index, education, smoking status, alcohol consumption, physical activity, family history of diabetes, homeostasis model assessment of insulin resistance, and other dietary and non-dietary potential confounders, the hazard ratio of incident diabetes comparing the highest to the lowest quartile of toenail zinc levels was 1.21 (95% CI: 0.90-1.63; Ptrend = 0.20). Findings from this study do not support the hypothesis that zinc status is inversely and longitudinally associated with the incidence of diabetes in American young adults. PMID- 26980157 TI - Mycobacterial escape from macrophage phagosomes to the cytoplasm represents an alternate adaptation mechanism. AB - Survival of Mycobacterium tuberculosis (Mtb) within the host macrophage is mediated through pathogen-dependent inhibition of phagosome-lysosome fusion, which enables bacteria to persist within the immature phagosomal compartment. By employing ultrastructural examination of different field isolates supported by biochemical analysis, we found that some of the Mtb strains were in fact poorly adapted for subsistence within endocytic vesicles of infected macrophages. Instead, through a mechanism involving activation of host cytosolic phospholipase A2, these bacteria rapidly escaped from phagosomes, and established residence in the cytoplasm of the host cell. Interestingly, by facilitating an enhanced suppression of host cellular autophagy, this translocation served as an alternate virulence acquisition mechanism. Thus, our studies reveal plasticity in the adaptation strategies employed by Mtb, for survival in the host macrophage. PMID- 26980158 TI - Resourcefulness Training for Women Dementia Caregivers: Acceptability and Feasibility of Two Methods. AB - Almost 10 million women in the United States are caregivers for elders with dementia and many experience extreme stress that compromises their health. Acceptable and feasible interventions to teach them resourcefulness skills for managing stress may improve their health and facilitate continued caregiving. This study examined two commonly used methods for practicing skills taught during resourcefulness training (RT) to women caregivers of elders with dementia (n=63): journaling and digital voice recording. It also explored whether providing caregivers a choice between the two methods made it more acceptable or feasible. Qualitative and quantitative data were collected before, during, and after RT. Caregivers who recorded used more words (M=5446) but recorded fewer days (M=17) than those who journaled (M=2792 words and M=27 days). Similar concerns in relation to time management and practice method were expressed by women caregivers irrespective of practice method (journal versus recorder) or random versus choice condition. While journaling was more frequent than recording, more words were expressed during recordings. Perceived stress and depressive symptoms were unrelated to the number of practice days or word counts, suggesting RT acceptability and feasibility even for highly stressed or depressed caregivers. Because intervention feasibility is important for RT effectiveness testing, alternatives to the journaling and recording methods for practicing RT skills should be considered. PMID- 26980159 TI - Direct 3D-printing of cell-laden constructs in microfluidic architectures. AB - Microfluidic platforms have greatly benefited the biological and medical fields, however standard practices require a high cost of entry in terms of time and energy. The utilization of three-dimensional (3D) printing technologies has greatly enhanced the ability to iterate and build functional devices with unique functions. However, their inability to fabricate within microfluidic devices greatly increases the cost of producing several different devices to examine different scientific questions. In this work, a variable height micromixer (VHM) is fabricated using projection 3D-printing combined with soft lithography. Theoretical and flow experiments demonstrate that altering the local z-heights of VHM improved mixing at lower flow rates than simple geometries. Mixing of two fluids occurs as low as 320 MUL min(-1) in VHM whereas the planar zigzag region requires a flow rate of 2.4 mL min(-1) before full mixing occurred. Following device printing, to further demonstrate the ability of this projection-based method, complex, user-defined cell-laden scaffolds are directly printed inside the VHM. The utilization of this unique ability to produce 3D tissue models within a microfluidic system could offer a unique platform for medical diagnostics and disease modeling. PMID- 26980160 TI - Nonalcoholic Fatty Liver Disease: Pathogenesis and Disease Spectrum. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction in the Western world and is increasing owing to its close association with obesity and insulin resistance. NAFLD represents a spectrum of liver disease that, in a minority of patients, can lead to progressive nonalcoholic steatohepatitis (NASH), fibrosis, and ultimately hepatocellular carcinoma and liver failure. NAFLD is a complex trait resulting from the interaction between environmental exposure and a susceptible polygenic background and comprising multiple independent modifiers of risk, such as the microbiome. The molecular mechanisms that combine to define the transition to NASH and progressive disease are complex, and consequently, no pharmacological therapy currently exists to treat NASH. A better understanding of the pathogenesis of NAFLD is critical if new treatments are to be discovered. PMID- 26980161 TI - Gliomas Genomics and Epigenomics: Arriving at the Start and Knowing It for the First Time. AB - Gliomas are the most common primary human brain tumors and occur in both adults and children. Over the past few years, systematic large-scale genomic and epigenomic profiling has provided unprecedented insight into their pathogenesis, uncovering alterations in an unanticipated number of genes and regulatory elements. In this review, we discuss recent discoveries about the genomics and epigenomics of adult and pediatric gliomas and highlight how some of the founding genetic mutations reshape the cancer epigenome. These studies provide an in-depth view of the molecular routes leading to glioma development, offer insight into the cancer stem cell model, help refine classifications, and should lay the foundation for improved clinical care. PMID- 26980162 TI - Bronchiectasis: Current Concepts in Pathogenesis, Immunology, and Microbiology. AB - Bronchiectasis is a disorder of persistent lung inflammation and recurrent infection, defined by a common pathological end point: irreversible bronchial dilatation arrived at through diverse etiologies. This suggests an interplay between immunogenetic susceptibility, immune dysregulation, bacterial infection, and lung damage. The damaged epithelium impairs mucus removal and facilitates bacterial infection with increased cough, sputum production, and airflow obstruction. Lung infection is caused by respiratory bacterial and fungal pathogens, including Pseudomonas aeruginosa, Haemophilus, Aspergillus fumigatus, and nontuberculous mycobacteria. Recent studies have highlighted the relationship between the lung microbiota and microbial-pathogen niches. Disease may result from environments favoring interleukin-17-driven neutrophilia. Bronchiectasis may present in autoimmune disease, as well as conditions of immune dysregulation, such as combined variable immune deficiency, transporter associated with antigen processing-deficiency syndrome, and hyperimmunoglobulin E syndrome. Differences in prevalence across geography and ethnicity implicate an etiological mix of genetics and environment underpinning susceptibility. PMID- 26980163 TI - Effects of intervalley scattering on the transport properties in one-dimensional valleytronic devices. AB - Based on a one-dimensional valley junction model, the effects of intervalley scattering on the valley transport properties are studied. We analytically investigate the valley transport phenomena in three typical junctions with both intervalley and intravalley scattering included. For the tunneling between two gapless valley materials, different from conventional Klein tunneling theory, the transmission probability of the carrier is less than 100% while the pure valley polarization feature still holds. If the junction is composed of at least one gapped valley material, the valley polarization of the carrier is generally imperfect during the tunneling process. Interestingly, in such circumstance, we discover a resonance of valley polarization that can be tuned by the junction potential. The extension of our results to realistic valley materials are also discussed. PMID- 26980164 TI - Custom sizing of lower limb exoskeleton actuators using gait dynamic modelling of children with cerebral palsy. AB - The use of exoskeletons as an aid for people with musculoskeletal disorder is the subject to an increasing interest in the research community. These devices are expected to meet the specific needs of users, such as children with cerebral palsy (CP) who are considered a significant population in pediatric rehabilitation. Although these exoskeletons should be designed to ease the movement of people with physical shortcoming, their design is generally based on data obtained from healthy adults, which leads to oversized components that are inadequate to the targeted users. Consequently, the objective of this study is to custom-size the lower limb exoskeleton actuators based on dynamic modeling of the human body for children with CP on the basis of hip, knee, and ankle joint kinematics and dynamics of human body during gait. For this purpose, a multibody modeling of the human body of 3 typically developed children (TD) and 3 children with CP is used. The results show significant differences in gait patterns especially in knee and ankle with respectively 0.39 and -0.33 (Nm/kg) maximum torque differences between TD children and children with CP. This study provides the recommendations to support the design of actuators to normalize the movement of children with CP. PMID- 26980165 TI - Off-label prescription of drugs at hospital. AB - OBJECTIVES: To develop a procedure for management of off-label medications, and to analyze the treatments, indications, and hospital units which will request them more frequently, as well as which variables will have an impact on the authorization decision, and its economic impact. METHODS: A procedure was designed where clinicians would complete request forms and the Hospital Unit would prepare reports assessing their efficacy, safety, convenience, and cost. The request forms for the past five years were analyzed. RESULTS: A total of 834 applications were received, and 88.1% of these were accepted. The authorization rates were higher for Paediatric Units (95.7% vs. 86.6%; p<0.05). The reasons for considering prescriptions as off-label were: different indication (73.2%), different combination (10.2%), different line of treatment (8.6%) and different age (8%). A 73.4% of requests were for antineoplastic drugs, and the most frequently prescribed were rituximab (120) and bevacizumab (103). The quality of evidence supporting the prescriptions was moderate-low, though no direct relationship with the likelihood of approval was demonstrated (p = 0.413). The cost of the approved medications was 8,567,537 ?, and the theoretical savings for those drugs rejected was of 2,268,642 ?. There was a statistically significant decrease in the authorization rate (p < 0.05, Student's t test) when spending increased. CONCLUSIONS: The responsibility for assessing off-label prescriptions has fallen on the Pharmacy Unit. It has not been demonstrated that the quality of evidence represents a decisive variable for approval of treatment; on the other hand, age and cost have demonstrated a significant impact. PMID- 26980166 TI - Assessment of the quality of sample labelling for clinical research. AB - OBJECTIVE: To assess the quality of the labels for clinical trial samples through current regulations, and to analyze its potential correlation with the specific characteristics of each sample. METHOD: A transversal multicenter study where the clinical trial samples from two third level hospitals were analyzed. The eleven items from Directive 2003/94/EC, as well as the name of the clinical trial and the dose on the label cover, were considered variables for labelling quality. The influence of the characteristics of each sample on labelling quality was also analyzed. OUTCOME: The study included 503 samples from 220 clinical trials. The mean quality of labelling, understood as the proportion of items from Appendix 13, was of 91.9%. Out of these, 6.6% did not include the name of the sample in the outer face of the label, while in 9.7% the dose was missing. The samples with clinical trial-type samples presented a higher quality (p < 0.049), blinding reduced their quality (p = 0.017), and identification by kit number or by patient increased it (p < 0.01). The promoter was the variable which introduced the highest variability into the analysis. CONCLUSIONS: The mean quality of labelling is adequate in the majority of clinical trial samples. The lack of essential information in some samples, such as the clinical trial code and the period of validity, is alarming and might be the potential source for dispensing or administration errors. PMID- 26980167 TI - Influence of pharmacotherapy complexity on compliance with the therapeutic objectives for HIV+ patients on antiretroviral treatment concomitant with therapy for dyslipidemia. INCOFAR Project. AB - OBJECTIVES: To analyze the relationship between pharmacotherapeutical complexity and compliance of therapeutic objectives in HIV+ patients on antiretroviral treatment and concomitant dyslipidemia therapy. MATERIALS AND METHODS: A retrospective observational study including HIV patients on stable antiretroviral treatment during the past 6 months, and dyslipidemia treatment between January and December, 2013. The complexity index was calculated with the tool developed by McDonald et al. Other variables analyzed were: age, gender, risk factor of HIV, smoking, alcoholism and drugs, psychiatric disorders, adherence to antiretroviral treatment and lipid lowering drugs, and clinical parameters (HIV viral load, CD4 count, plasma levels of total cholesterol, LDL, HDL, and triglycerides). In order to determine the predictive factors associated with the compliance of therapeutic objectives, univariate analysis was conducted through logistical regression, followed by a multivariate analysis. RESULTS: The study included 89 patients; 56.8% of them met the therapeutic objectives for dyslipidemia. The complexity index was significantly higher (p = 0.02) in those patients who did not reach the objective values (median 51.8 vs. 38.9). Adherence to lipid lowering treatment was significantly associated with compliance of the therapeutic objectives established for dyslipidemia treatment. A 67.0% of patients met the objectives for their antiretroviral treatment; however, the complexity index was not significantly higher (p = 0.06) in those patients who did not meet said objectives. CONCLUSIONS: Pharmacotherapeutical complexity represents a key factor in terms of achieving health objectives in HIV+ patients on treatment for dyslipidemia. PMID- 26980168 TI - Use of closed systems in the Hospital Pharmacy. AB - OBJECTIVE: In the setting of the increasing use of closed systems for reconstitution and preparation of these drugs, we intend to analyze the correct use of these systems in the Hospital Pharmacy, with the objective to minimize the risks of exposure not only for those professionals directly involved, but also for all the staff in the unit, taking also into account efficiency criteria. METHOD: Since some systems protect against aerosol formation but not from vapours, we decided to review which cytostatics should be prepared using an awl with an air inlet valve, in order to implement a new working procedure. We reviewed the formulations available in our hospital, with the following criteria: method of administration, excipients, and potential hazard for the staff handling them. We measured the diameters of the vials. We selected drugs with Level 1 Risk and also those including alcohol-based excipients, which could generate vapours. OUTCOMES: Out of the 66 reviewed formulations, we concluded that 11 drugs should be reconstituted with this type of awl: busulfan, cabazitaxel, carmustine, cyclophosphamide, eribulin, etoposide, fotemustine, melphalan, paclitaxel, temsirolimus and thiotepa; these represented an 18% of the total volume of formulations. CONCLUSIONS: The selection of healthcare products must be done at the Hospital Pharmacy, because the use of a system with an air valve inlet only for those drugs selected led to an outcome of savings and a more efficient use of materials. In our experience, we confirmed that the use of the needle could only be avoided when the awl could adapt to the different formulations of cytostatics, and this is only possible when different types of awls are available. Besides, connections were only really closed when a single awl was used for each vial. The change in working methodology when handling these drugs, as a result of this study, will allow us to start different studies about environmental contamination as a future line of work. PMID- 26980169 TI - [Design of a computer program for the registration of implantable medical device, field safety corrective action and advers events, as a tool for medical device surveillance]. AB - OBJECTIVE: To describe the features of computer program to support the activity of the responsible for surveillance of medical devices. To evaluate their use after one year of implementation in a hospital. METHOD: The stages of the process were: description of the activities of medical devices surveillance and implant registration, definition of functionality and data processing, creation of databases, implementation in a private hospital which manages PS, validation of the program and analysis of their usefulness. RESULTS: SIVIPS was developed using Acces. Main variables were described for all the activities of the responsible for medical device surveillance (implants, alert, medical device incidents, including for in vitro diagnostics) and all the functionalities of the computer program. SIVIPS was introduced in a pharmacy service with one pharmacist for the management of medical devices. One year after its implementation we had registered 564 implants with a description by type of implant, 31 alerts and 6 incidents. SIVIPS allow monitoring of the actions taken in these cases. CONCLUSIONS: SIVIPS is the first tool to support the activity of medical device surveillance. It is an easy tool that allows the registration of alerts and medical device related incidents, and registration of implants performed in the center, which will improve the traceability of the PS. PMID- 26980170 TI - Hazardous drugs: new challenges, new opportunities. AB - Occupational exposure to hazardous drugs can cause harmful effects on health professionals and several protective measures must be taken. Nevertheless, classification of hazardous drugs is not the same in all the published repertoires and the terminology is still confusing: hazardous drugs, biohazardous drugs or risky drugs are terms improperly described and can define very different drugs with a very different hazard profiles. In Spain, there is not an updated official list of hazardous drugs, and healthcare professionals must consider and follow other published lists. In our opinion, it is mandatory to do a consensus among these professionals, administration and labor union organizations in order to clarify some conflictive questions not only in healthcare settings but in investigational and academic scenarios too. These multidisciplinary groups should be involved also in teaching new and non-experienced personnel and in the knowledge reinforcement for the experienced ones. PMID- 26980171 TI - Oral formulation of pyridoxine for the treatment of pyridoxinedependent epilepsy in a paediatric patient. PMID- 26980172 TI - [Hepatic toxicity in HER-2(+) breast cancer patient under treatment with capecitabine and lapatinib]. PMID- 26980173 TI - [Pernicious anaemia in a young patient: what is the best route of administration of vitammin B12?]. PMID- 26980174 TI - [Roberto Marin Gil (1979-2016)]. PMID- 26980175 TI - Pre- and post-treatment serum ferritin levels in patients with higher risk myelodysplastic syndromes receiving azacitidine. PMID- 26980177 TI - SELEX Modifications and Bioanalytical Techniques for Aptamer-Target Binding Characterization. AB - The quest to improve the detection of biomolecules and cells in health and life sciences has led to the discovery and characterization of various affinity bioprobes. Libraries of synthetic oligonucleotides (ssDNA/ssRNA) with randomized sequences are employed during Systematic Evolution of Ligands by Exponential Enrichment (SELEX) to select highly specific affinity probes called aptamers. With much focus on the generation of aptamers for a variety of target molecules, conventional SELEX protocols have been modified to develop new and improved SELEX protocols yielding highly specific and stable aptamers. Various techniques have been used to analyze the binding interactions between aptamers and their cognate molecules with associated merits and limitations. This article comprehensively reviews research advancements in the generation of aptamers, analyses physicochemical conditions affecting their binding characteristics to cellular and biomolecular targets, and discusses various field applications of aptameric binding. Biophysical techniques employed in the characterization of the molecular and binding features of aptamers to their cognate targets are also discussed. PMID- 26980176 TI - Improving Low-dose Cardiac CT Images based on 3D Sparse Representation. AB - Cardiac computed tomography (CCT) is a reliable and accurate tool for diagnosis of coronary artery diseases and is also frequently used in surgery guidance. Low dose scans should be considered in order to alleviate the harm to patients caused by X-ray radiation. However, low dose CT (LDCT) images tend to be degraded by quantum noise and streak artifacts. In order to improve the cardiac LDCT image quality, a 3D sparse representation-based processing (3D SR) is proposed by exploiting the sparsity and regularity of 3D anatomical features in CCT. The proposed method was evaluated by a clinical study of 14 patients. The performance of the proposed method was compared to the 2D spares representation-based processing (2D SR) and the state-of-the-art noise reduction algorithm BM4D. The visual assessment, quantitative assessment and qualitative assessment results show that the proposed approach can lead to effective noise/artifact suppression and detail preservation. Compared to the other two tested methods, 3D SR method can obtain results with image quality most close to the reference standard dose CT (SDCT) images. PMID- 26980178 TI - Integrated Practice Improvement Solutions-Practical Steps to Operating Room Management. AB - Perioperative productivity is a vital concern for surgeons, anesthesiologists, and administrators as the OR is a major source of hospital elective admissions and revenue. Based on elements of existing Practice Improvement Methodologies (PIMs), "Integrated Practice Improvement Solutions" (IPIS) is a practical and simple solution incorporating aspects of multiple management approaches into a single open source framework to increase OR efficiency and productivity by better utilization of existing resources. MATERIALS AND METHODS: OR efficiency was measured both before and after IPIS implementation using the total number of cases versus room utilization, OR/anesthesia revenue and staff overtime (OT) costs. Other parameters of efficiency, such as the first case on-time start and the turnover time (TOT) were measured in parallel. RESULTS: IPIS implementation resulted in increased numbers of surgical procedures performed by an average of 10.7%, and OR and anesthesia revenue increases of 18.5% and 6.9%, respectively, with a simultaneous decrease in TOT (15%) and OT for anesthesia staff (26%). The number of perioperative adverse events was stable during the two-year study period which involved a total of 20,378 patients. CONCLUSION: IPIS, an effective and flexible practice improvement model, was designed to quickly, significantly, and sustainably improve OR efficiency by better utilization of existing resources. Success of its implementation directly correlates with the involvement of and acceptance by the entire OR team and hospital administration. PMID- 26980179 TI - Monitoring of chromosome dynamics of single yeast cells in a microfluidic platform with aperture cell traps. AB - Chromosome movement plays important roles in DNA replication, repair, genetic recombination, and epigenetic phenomena during mitosis and meiosis. In particular, chromosome movement in the nuclear space is essential for the reorganization of the nucleus. However, conventional methods for analyzing the chromosome movements in vivo have been limited by technical constraints of cell trapping, cell cultivation, oxygenation, and in situ imaging. Here, we present a simple microfluidic platform with aperture-based cell trapping arrays to monitor the chromosome dynamics in single living cells for a desired period of time. Under the optimized conditions, our microfluidic platform shows a single-cell trapping efficiency of 57%. This microfluidic approach enables in situ imaging of intracellular dynamics in living cells responding to variable input stimuli under the well-controlled microenvironment. As a validation of this microfluidic platform, we investigate the fundamental features of the dynamic cellular response of the individual cells treated with different stimuli and drug. We prove the basis for dynamic chromosome movement in single yeast cells to be the telomere and nuclear envelope ensembles that attach to and move in concert with nuclear actin cables. Therefore, these results illustrate the monitoring of cellular functions and obtaining of dynamic information at a high spatiotemporal resolution through the integration of a simple microfluidic platform. PMID- 26980180 TI - The potential for nanotechnology to improve delivery of therapy to the acute ischemic heart. AB - Treatment of acute cardiac ischemia remains an area in which there are opportunities for therapeutic improvement. Despite significant advances, many patients still progress to cardiac hypertrophy and heart failure. Timely reperfusion is critical in rescuing vulnerable ischemic tissue and is directly related to patient outcome, but reperfusion of the ischemic myocardium also contributes to damage. Overproduction of reactive oxygen species, initiation of an inflammatory response and deregulation of calcium homeostasis all contribute to injury, and difficulties in delivering a sufficient quantity of drug to the affected tissue in a controlled manner is a limitation of current therapies. Nanotechnology may offer significant improvements in this respect. Here, we review recent examples of how nanoparticles can be used to improve delivery to the ischemic myocardium, and suggest some approaches that may lead to improved therapies for acute cardiac ischemia. PMID- 26980181 TI - Electrochemical Platform for the Detection of Transmembrane Proteins Reconstituted into Liposomes. AB - The development of new methods and strategies for the investigation of membrane proteins is limited by poor solubility of these proteins in an aqueous environment and hindered by a number of other problems linked to the instability of the proteins outside lipid bilayers. Therefore, current research focuses on an analysis of membrane proteins incorporated into model lipid membrane, most frequently liposomes. In this work, we introduce a new electrochemical methodology for the analysis of transmembrane proteins reconstituted into a liposomal system. The proposed analytical approach is based on proteoliposomal sample adsorption on the surface of working electrodes followed by analysis of the anodic and cathodic signals of the reconstituted proteins. It works based on the fact that proteins are electroactive species, in contrast to the lipid components of the membranes under the given experimental conditions. Electroanalytical experiments were performed with two transmembrane proteins; the Na(+)/K(+)ATPase that contains transmembrane as well as large extramembraneous segments and the mitochondrial uncoupling protein 1, which is a transmembrane protein essentially lacking extramembraneous segments. Electrochemical analyses of proteoliposomes were compared with analyses of both proteins solubilized with detergents (C12E8 and octyl-PoE) and supported by the following complementary methods: microscopy techniques, protein activity testing, molecular model visualizations, and immunochemical identification of both proteins. The label free electrochemical platform presented here enables studies of reconstituted transmembrane proteins at the nanomolar level. Our results may contribute to the development of new electrochemical sensors and microarray systems applicable within the field of poorly water-soluble proteins. PMID- 26980182 TI - Frizzled-1 receptor regulates adult hippocampal neurogenesis. AB - BACKGROUND: In the adult hippocampus new neurons are continuously generated from neural stem cells (NSCs) present at the subgranular zone of the dentate gyrus. This process is controlled by Wnt signaling, which plays a complex role in regulating multiple steps of neurogenesis including maintenance, proliferation and differentiation of progenitor cells and the development of newborn neurons. Differential effects of Wnt signaling during progression of neurogenesis could be mediated by cell-type specific expression of Wnt receptors. Here we studied the potential role of Frizzled-1 (FZD1) receptor in adult hippocampal neurogenesis. RESULTS: In the adult dentate gyrus, we determined that FZD1 is highly expressed in NSCs, neural progenitors and immature neurons. Accordingly, FZD1 is expressed in cultured adult hippocampal progenitors isolated from mouse brain. To evaluate the role of this receptor in vivo we targeted FZD1 in newborn cells using retroviral-mediated RNA interference. FZD1 knockdown resulted in a marked decrease in the differentiation of newborn cells into neurons and increased the generation of astrocytes, suggesting a regulatory role for the receptor in cell fate commitment. In addition, FZD1 knockdown induced an extended migration of adult-born neurons within the granule cell layer. However, no differences were observed in total dendritic length and dendritic arbor complexity between control and FZD1-deficient newborn neurons. CONCLUSIONS: Our results show that FZD1 regulates specific stages of adult hippocampal neurogenesis, being required for neuronal differentiation and positioning of newborn neurons into the granule cell layer, but not for morphological development of adult-born granule neurons. PMID- 26980183 TI - Does duration of physical activity bouts matter for adiposity and metabolic syndrome? A cross-sectional study of older British men. AB - BACKGROUND: Older adults have low physical activity(PA) and high sedentary behaviour(SB) levels. We investigate how total volume and specific patterns of moderate to vigorous PA(MVPA), light PA(LPA) and SB are related to adiposity and metabolic syndrome (MS). Then, with reference to physical activity guidelines which encourage MVPA in bouts > =10 min and avoiding "long" sedentary bouts, we investigate whether accumulating PA and SB in bouts of different defined durations are differently associated with these outcomes. METHODS: Cross sectional study of men (71-91 years) recruited in UK primary care centres. Nurses made physical measures (weight, height, bio-impedance, blood pressure) and took fasting blood samples. 1528/3137 (49%) surviving men had >=3 valid days (>=600 min) accelerometer data. 450 men with pre-existing chronic disease were excluded. 1009/1078 (93.6%) had complete covariate data. RESULTS: Men (n = 1009, mean age 78.5(SD 4.7) years) spent 612(SD 83), 202(SD 64) and 42(SD 33) minutes in SB, LIPA and MVPA respectively. Each additional 30 min/day of SB and MVPA were associated with 0.32 (95% CI 0.23, 0.40)Kg/m(2) higher Body Mass Index (BMI) and 0.72(-0.93, -0.51) lower BMI Kg/m(2) respectively. Patterns for waist circumference (WC), fat mass index (FMI), fasting insulin and MS were similar. MVPA in bouts lasting <10 min or >=10 min duration were not associated differently with outcomes. In models adjusted for total MVPA, each minute accumulated in SB bouts lasting 1-15 min was associated with lower BMI -0.012 kg/m(2), WC -0.029 cm, and OR 0.989 for MS (all p < 0.05), and coefficients for LPA bouts 1-9 min were very similar in separate models adjusted for total MVPA. Minutes accumulated in SB bouts 1-15 min and LPA bouts 1-9 min were correlated, r = 0.62. CONCLUSIONS: Objectively measured MVPA, LPA and SB were all associated with lower adiposity and metabolic risk. The beneficial associations of LPA are encouraging for older adults for whom initiating MVPA and maintaining bouts lasting >=10 min may be particularly challenging. Findings that short bouts of LPA (1-9 min) and SB (1-15 min), but that all MVPA, not just MVPA accumulated in bouts >=10 min were associated with lower adiposity and better metabolic health could help refine older adult PA guidelines. PMID- 26980185 TI - The chronic disease explosion: artificial bang or empirical whimper? PMID- 26980184 TI - Global prevalence of antibiotic resistance in paediatric urinary tract infections caused by Escherichia coli and association with routine use of antibiotics in primary care: systematic review and meta-analysis. AB - OBJECTIVES: To systematically review studies investigating the prevalence of antibiotic resistance in urinary tract infections caused by Escherichia coli in children and, when appropriate, to meta-analyse the relation between previous antibiotics prescribed in primary care and resistance. DESIGN AND DATA ANALYSIS: Systematic review and meta-analysis. Pooled percentage prevalence of resistance to the most commonly used antibiotics in children in primary care, stratified by the OECD (Organisation for Economic Co-operation and Development) status of the study country. Random effects meta-analysis was used to quantify the association between previous exposure to antibiotics in primary care and resistance. DATA SOURCES: Observational and experimental studies identified through Medline, Embase, Cochrane, and ISI Web of Knowledge databases, searched for articles published up to October 2015. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies were eligible if they investigated and reported resistance in community acquired urinary tract infection in children and young people aged 0-17. Electronic searches with MeSH terms and text words identified 3115 papers. Two independent reviewers assessed study quality and performed data extraction. RESULTS: 58 observational studies investigated 77,783 E coli isolates in urine. In studies from OECD countries, the pooled prevalence of resistance was 53.4% (95% confidence interval 46.0% to 60.8%) for ampicillin, 23.6% (13.9% to 32.3%) for trimethoprim, 8.2% (7.9% to 9.6%) for co-amoxiclav, and 2.1% (0.8 to 4.4%) for ciprofloxacin; nitrofurantoin was the lowest at 1.3% (0.8% to 1.7%). Resistance in studies in countries outside the OECD was significantly higher: 79.8% (73.0% to 87.7%) for ampicillin, 60.3% (40.9% to 79.0%) for co-amoxiclav, 26.8% (11.1% to 43.0%) for ciprofloxacin, and 17.0% (9.8% to 24.2%) for nitrofurantoin. There was evidence that bacterial isolates from the urinary tract from individual children who had received previous prescriptions for antibiotics in primary care were more likely to be resistant to antibiotics, and this increased risk could persist for up to six months (odds ratio 13.23, 95% confidence interval 7.84 to 22.31). CONCLUSIONS: Prevalence of resistance to commonly prescribed antibiotics in primary care in children with urinary tract infections caused by E coli is high, particularly in countries outside the OECD, where one possible explanation is the availability of antibiotics over the counter. This could render some antibiotics ineffective as first line treatments for urinary tract infection. Routine use of antibiotics in primary care contributes to antimicrobial resistance in children, which can persist for up to six months after treatment. PMID- 26980186 TI - Building up the nucleus: nuclear organization in the establishment of totipotency and pluripotency during mammalian development. AB - In mammals, epigenetic reprogramming, the acquisition and loss of totipotency, and the first cell fate decision all occur within a 3-d window after fertilization from the one-cell zygote to the formation of the blastocyst. These processes are poorly understood in molecular detail, yet this is an essential prerequisite to uncover principles of stem cells, chromatin biology, and thus regenerative medicine. A unique feature of preimplantation development is the drastic genome-wide changes occurring to nuclear architecture. From studying somatic and in vitro cultured embryonic stem cells (ESCs) it is becoming increasingly established that the three-dimensional (3D) positions of genomic loci relative to each other and to specific compartments of the nucleus can act on the regulation of gene expression, potentially driving cell fate. However, the functionality, mechanisms, and molecular characteristics of the changes in nuclear organization during preimplantation development are only now beginning to be unraveled. Here, we discuss the peculiarities of nuclear compartments and chromatin organization during mammalian preimplantation development in the context of the transition from totipotency to pluripotency. PMID- 26980187 TI - A decade of the anaphase-promoting complex in the nervous system. AB - Control of protein abundance by the ubiquitin-proteasome system is essential for normal brain development and function. Just over a decade ago, the first post mitotic function of the anaphase-promoting complex, a major cell cycle-regulated E3 ubiquitin ligase, was discovered in the control of axon growth and patterning in the mammalian brain. Since then, a large number of studies have identified additional novel roles for the anaphase-promoting complex in diverse aspects of neuronal connectivity and plasticity in the developing and mature nervous system. In this review, we discuss the functions and mechanisms of the anaphase-promoting complex in neurogenesis, glial differentiation and migration, neuronal survival and metabolism, neuronal morphogenesis, synapse formation and plasticity, and learning and memory. We also provide a perspective on future investigations of the anaphase-promoting complex in neurobiology. PMID- 26980188 TI - Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice. AB - The Fan1 endonuclease is required for repair of DNA interstrand cross-links (ICLs). Mutations in human Fan1 cause karyomegalic interstitial nephritis (KIN), but it is unclear whether defective ICL repair is responsible or whether Fan1 nuclease activity is relevant. We show that Fan1 nuclease-defective (Fan1(nd/nd)) mice develop a mild form of KIN. The karyomegalic nuclei from Fan1(nd/nd) kidneys are polyploid, and fibroblasts from Fan1(nd/nd) mice become polyploid upon ICL induction, suggesting that defective ICL repair causes karyomegaly. Thus, Fan1 nuclease activity promotes ICL repair in a manner that controls ploidy, a role that we show is not shared by the Fanconi anemia pathway or the Slx4-Slx1 nuclease also involved in ICL repair. PMID- 26980189 TI - Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction. AB - Deficiency of FANCD2/FANCI-associated nuclease 1 (FAN1) in humans leads to karyomegalic interstitial nephritis (KIN), a rare hereditary kidney disease characterized by chronic renal fibrosis, tubular degeneration, and characteristic polyploid nuclei in multiple tissues. The mechanism of how FAN1 protects cells is largely unknown but is thought to involve FAN1's function in DNA interstrand cross-link (ICL) repair. Here, we describe a Fan1-deficient mouse and show that FAN1 is required for cellular and organismal resistance to ICLs. We show that the ubiquitin-binding zinc finger (UBZ) domain of FAN1, which is needed for interaction with FANCD2, is not required for the initial rapid recruitment of FAN1 to ICLs or for its role in DNA ICL resistance. Epistasis analyses reveal that FAN1 has cross-link repair activities that are independent of the Fanconi anemia proteins and that this activity is redundant with the 5'-3' exonuclease SNM1A. Karyomegaly becomes prominent in kidneys and livers of Fan1-deficient mice with age, and mice develop liver dysfunction. Treatment of Fan1-deficient mice with ICL-inducing agents results in pronounced thymic and bone marrow hypocellularity and the disappearance of c-kit(+) cells. Our results provide insight into the mechanism of FAN1 in ICL repair and demonstrate that the Fan1 mouse model effectively recapitulates the pathological features of human FAN1 deficiency. PMID- 26980190 TI - Stepwise and dynamic assembly of the earliest precursors of small ribosomal subunits in yeast. AB - The eukaryotic ribosomal RNA (rRNA) is associated cotranscriptionally with numerous factors into an enormous 90S preribosomal particle that conducts early processing of small ribosomal subunits. The assembly pathway and structure of the 90S particle is poorly understood. Here, we affinity-purified and analyzed the constituents of yeast 90S particles that were assembled on a series of plasmid encoded 3'-truncated pre-18S RNAs. We determined the assembly point of 65 proteins and the U3, U14, and snR30 small nucleolar RNAs (snoRNAs), revealing a stepwise and dynamic assembly map. The 5' external transcribed spacer (ETS) alone can nucleate a large complex. When the 18S rRNA is nearly complete, the 90S structure undergoes a dramatic reorganization, releasing U14, snR30, and 14 protein factors that bind earlier. We also identified a reference state of 90S that is fully assembled yet has not undergone 5'ETS processing. The assembly map present here provides a new framework to understand small subunit biogenesis. PMID- 26980191 TI - Tuberculosis infection control measures in health care facilities offering tb services in Ikeja local government area, Lagos, South West, Nigeria. AB - BACKGROUND: Tuberculosis infection among health care workers is capable of worsening the existing health human resource problems of low--and middle-income countries. Tuberculosis infection control is often weakly implemented in these parts of the world therefore, understanding the reasons for poor implementation of tuberculosis infection control guidelines are important. This study was aimed at assessing tuberculosis infection control practices and barriers to its implementation in Ikeja, Nigeria. METHODS: A cross-sectional study in 20 tuberculosis care facilities (16 public and 4 private) in Ikeja, Lagos was conducted. The study included a facility survey to assess the availability of tuberculosis infection control guidelines, the adequacy of facilities to prevent transmission of tuberculosis and observations of practices to assess the implementation of tuberculosis infection control guidelines. Four focus group discussions were carried out to highlight HCWs' perceptions on tuberculosis infection control guidelines and barriers to its implementation. RESULTS: The observational study showed that none of the clinics had a tuberculosis infection control plan. No clinic was consistently screening patients for cough. Twelve facilities (60%) consistently provided masks to patients who were coughing. Ventilation in the waiting areas was assessed to be adequate in 60% of the clinics while four clinics (20%) possessed N-95 respirators. Findings from the focus group discussions showed weak managerial support, poor funding, under staffing, lack of space and not wanting to be seen as stigmatizing against tuberculosis patients as barriers that hindered the implementation of TB infection control measures. CONCLUSION: Tuberculosis infection control measures were not adequately implemented in health facilities in Ikeja, Nigeria. A multi pronged approach is required to address the identified barriers to the implementation of tuberculosis infection control guidelines. PMID- 26980192 TI - The Hand Motor Hotspot is not Always Located in the Hand Knob: A Neuronavigated Transcranial Magnetic Stimulation Study. AB - The hand motor hot spot (hMHS) is one of the most salient parameters in transcranial magnetic stimulation (TMS) practice, notably used for targeting. It is commonly accepted that the hMHS corresponds to the hand representation within the primary motor cortex (M1). Anatomical and imaging studies locate this representation in a region of the central sulcus called the "hand knob". The aim of this study was to determine if the hMHS location corresponds to its expected location at the hand knob. Twelve healthy volunteers and eleven patients with chronic neuropathic pain of various origins, but not related to a brain lesion, were enrolled. Morphological magnetic resonance imaging of the brain was normal in all participants. Both hemispheres were studied in all participants except four (two patients and two healthy subjects). Cortical mapping of the hand motor area was conducted using a TMS-dedicated navigation system and recording motor evoked potentials (MEPs) in the contralateral first dorsal interosseous (FDI) muscle. We then determined the anatomical position of the hMHS, defined as the stimulation site providing the largest FDI-MEPs. In 45 % of hemispheres of normal subjects and 25 % of hemispheres of pain patients, the hMHS was located over the central sulcus, most frequently at the level of the hand knob. However, in the other cases, the hMHS was located outside M1, most frequently anteriorly over the precentral or middle frontal gyrus. This study shows that the hMHS does not always correspond to the hand knob and M1 location in healthy subjects or patients. Therefore, image-guided navigation is needed to improve the anatomical accuracy of TMS targeting, even for M1. PMID- 26980193 TI - Electrical impedance tomography to monitor lung sampling during broncho-alveolar lavage. PMID- 26980194 TI - The ten studies that should be done in ARDS. PMID- 26980195 TI - What's new in mechanical ventilation in patients without ARDS: lessons from the ARDS literature. PMID- 26980196 TI - Ganetespib radiosensitization for liver cancer therapy. AB - Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancer cell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, gammaH2AX foci kinetics and client protein expression in pathways important for liver cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined ganetespib-radiation treatment on tumor cell proliferation in a HepG2 hind-flank tumor graft model. Nanomolar levels of ganetespib alone exhibited liver cancer cell anti-cancer activity in vitro as shown by decreased clonogenic survival that was associated with increased apoptotic cell death, prominent G2-M arrest and marked changes in PI3K/AKT/mTOR and RAS/MAPK client protein activity. Ganetespib caused a supra additive radiosensitization in all liver cancer cell lines at low nanomolar doses with enhancement ratios between 1.33-1.78. These results were confirmed in vivo, where the ganetespib-radiation combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in HepG2 tumor grafts. Our data suggest that combined ganetespib-radiation therapy exhibits promising activity against liver cancer cells, which should be investigated in clinical studies. PMID- 26980198 TI - The Assisted Decision-Making (Capacity) Act 2015: what it is and why it matters. AB - BACKGROUND: Ireland's Assisted Decision-Making (Capacity) Act 2015 was signed by President Higgins in December 2015 and scheduled for commencement in 2016. AIMS: To explore the content and implications of the 2015 Act. METHODS: Review of the 2015 Act and related literature. RESULTS: The 2015 Act places the "will and preferences" of persons with impaired mental capacity at the heart of decision making relating to "personal welfare" (including healthcare) and "property and affairs". Capacity is to be "construed functionally" and interventions must be "for the benefit of the relevant person". The Act outlines three levels of decision-making assistance: "decision-making assistant", "co-decision-maker" (joint decision-maker) and "decision-making representative" (substitute decision maker). There are procedures relating to "enduring power of attorney" and "advance healthcare directives"; in the case of the latter, a "refusal of treatment" can be legally binding, while a "request for a specific treatment" must "be taken into consideration". CONCLUSIONS: The 2015 Act is considerably more workable than the 2013 Bill that preceded it. Key challenges include the subtle decision-making required by patients, healthcare staff, Circuit Court judges and the director of the Decision Support Service; implementation of "advance healthcare directives", especially if they do not form part of a broader model of advance care planning (incorporating the flexibility required for unpredictable future circumstances); and the over-arching issue of logistics, as very many healthcare decisions are currently made in situations where the patient's capacity is impaired. A key challenge will lie in balancing the emphasis on autonomy with principles of beneficence, mutuality and care. PMID- 26980197 TI - C1, a highly potent novel curcumin derivative, binds to tubulin, disrupts microtubule network and induces apoptosis. AB - We have synthesized a curcumin derivative, 4-{5-(4-hydroxy-3-methoxy-phenyl)-2-[3 (4-hydroxy-3-methoxy-phenyl)-acryloyl]-3-oxo-penta-1,4-dienyl}-piperidine-1 carboxylic acid tert-butyl ester (C1) that displays much stronger antiproliferative activity against various types of cancer cells including multidrug resistance cells than curcumin. C1 depolymerized both interphase and mitotic microtubules in MCF-7 cells and also inhibited the reassembly of microtubules in these cells. C1 inhibited the polymerization of purified tubulin, disrupted the lattice structure of microtubules and suppressed their GTPase activity in vitro The compound bound to tubulin with a dissociation constant of 2.8+/-1 MUM and perturbed the secondary structures of tubulin. Further, C1 treatment reduced the expression of Bcl2, increased the expression of Bax and down regulated the level of a key regulator of p53, murine double minute 2 (Mdm2) (S166), in MCF-7 cells. C1 appeared to induce p53 mediated apoptosis in MCF-7 cells. Interestingly, C1 showed more stability in aqueous buffer than curcumin. The results together showed that C1 perturbed microtubule network and inhibited cancer cells proliferation more efficiently than curcumin. The strong antiproliferative activity and improved stability of C1 indicated that the compound may have a potential as an anticancer agent. PMID- 26980199 TI - Stresses in the midpalatal suture in the maxillary protraction therapy: a 3D finite element analysis. AB - BACKGROUND: The aim of the present work was to evaluate the stress magnitudes and directions along the midpalatal suture in the maxillary protraction therapy. METHODS: The geometry of the maxilla and teeth were digitally reconstructed based on computer tomography images obtained from the skull of a girl in a mixed dentition stage with skeletal and dental class III malocclusion. An appliance commonly used for rapid palatal expansion (RPE) was also digitally modeled for anchorage of the protraction force and meshed for finite element analysis. The maxillary protraction was simulated applying 600 cN (300 cN for each side) directed 30 degrees forward and downward to the maxillary occlusal plane. RESULTS: The principal stresses, through the force application, exhibited similar distribution patterns. A higher stress area was observed in the region of the midpalatal suture located in front of the incisive canal. All the sections showed vectors of compressive nature. CONCLUSIONS: Because of the compressive nature of the stresses distributed along the midpalatal suture in the maxillary protraction therapy simulation, which is opposite to the natural growth transversal tendency, maxillary expansion is advisable in clinical cases. PMID- 26980200 TI - Effect of molar intrusion with temporary anchorage devices in patients with anterior open bite: a systematic review. AB - OBJECTIVE: The objective of the study is to assess the effect of molar intrusion with temporary anchorage devices on the vertical facial morphology and mandibular rotation during open bite treatment in the permanent dentition. METHODS: We performed a systematic review of the published data in seven electronic databases up to September 2015. We considered studies for inclusion if they were examining the effects of posterior teeth intrusion on the vertical facial morphology with open bite malocclusion in the permanent dentition. Study selection, risk of bias assessment, and data-extraction were performed in duplicate. Meta-analysis was not possible due to dissimilarity and heterogeneity among the included studies. RESULTS: Out of the 42 articles that met the initial eligibility criteria, 12 studies were finally selected. Low level of scientific evidence was identified after risk of bias assessment of the included studies with no relevant randomized controlled trial performed. Out of the 12 selected studies, five studies used miniplates and seven studies used miniscrews. Mandibular counterclockwise rotation was found to be between 2.3 degrees and 3.9 degrees in six studies (as sassed by mandibular plane angle, between MeGo or GoGn and SN or FH plane) while it was less than 2 degrees in the remaining studies. CONCLUSIONS: Current weak evidence suggests that molar intrusion with temporary anchorage devices may cause mandibular counterclockwise autorotation. Future well-conducted and clearly reported multicenter randomized controlled trials that include a non-treatment control group are needed to make robust recommendations regarding the amount of mandibular rotation during open bite treatments. PMID- 26980201 TI - Converting ICD-9 to ICD-10. AB - Implementing the International Classification of Diseases, Ninth Revision (ICD-9) to International Classification of Diseases, Tenth Revision (ICD-10) conversion on October 1, 2015, in the United States has been a long-term goal. While most countries in the world converted more than 10 years ago, the United States was still using ICD-9. Many countries in the world have a single-payer healthcare system, while there are thousands of different healthcare organizations (providers and payers) that presently exist in the United States. With so many different software platforms for healthcare providers and payers, the conversion had become that much more complicated and capital intensive for all healthcare organizations in the country. A few of the present delay reasons to the ICD-10 conversion in past years were the concurrent timelines for meeting meaningful use requirements for the electronic health record, testing with external payers and upgrades from vendors which added complexities and extra costs. The authors examine the reasoning behind the conversion as well as the delays, before making the conversion on October 1, 2015, and review the question regarding whether the government's decision to push the date back a year would have been helpful. PMID- 26980202 TI - The Impact of a Pay-for-Performance Program on Central Line-Associated Blood Stream Infections in Pennsylvania. AB - Healthcare associated infections have significantly contributed to the rising cost of hospital care in the United States. The implementation of pay-for performance (P4P) programs has been one approach to improve quality at a reduced cost. We quantify the impact of Highmark's Quality Blue (QB) hospital P4P program on central line-associated blood stream infections (CLABSI) in Pennsylvania. The impact of years of participation in QB on CLABSI is also evaluated. Data from 149 Pennsylvania hospitals on CLABSI from 2008-2013 are used. Negative binomial regression and fixed effects panel regression are performed. Hospitals participating in QB have 0.727 times the CLABSI as those hospitals that do not participate. Hospitals participating for four or more years have on average 3.13 fewer CLABSI per year compared to those participating for less than four years. Highmark's P4P program has shown improved outcomes with regards to CLABSI, but further research is needed to determine if QB is cost effective. PMID- 26980203 TI - Physician Recommendation of Diabetes Clinical Protocols. AB - The authors examined the responses of 63 primary care physicians to diabetes clinical protocols (DCPs) for the management of type II diabetes (T2DM). We measured physician demographics, current diabetes patient loads, and responses to DCPs (physician attitudes, physician familiarity, and physician recommendation of DCPs) using a 20-question electronic survey. Results of the survey indicate that primary care physicians may be unfamiliar with the benefits of diabetes clinical protocols for the self-management of T2DM. Given the importance of diabetes self management education in controlling T2DM, those interested in implementing DCPs should address the beliefs and attitudes of primary care physicians. PMID- 26980204 TI - Human PCSK9 promotes hepatic lipogenesis and atherosclerosis development via apoE and LDLR-mediated mechanisms. AB - AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of hepatic low-density lipoprotein (LDL) receptors (LDLR), thereby, decreasing hepatocyte LDL-cholesterol (LDL-C) uptake. However, it is unknown whether PCSK9 has effects on atherogenesis that are independent of lipid changes. The present study investigated the effect of human (h) PCSK9 on plasma lipids, hepatic lipogenesis, and atherosclerotic lesion size and composition in transgenic mice expressing hPCSK9 (hPCSK9tg) on wild-type (WT), LDLR-/-, or apoE /- background. METHODS AND RESULTS: hPCSK9 expression significantly increased plasma cholesterol (+91%), triglycerides (+18%), and apoB (+57%) levels only in WT mice. The increase in plasma lipids was a consequence of both decreased hepatic LDLR and increased hepatic lipid production, mediated transcriptionally and post-transcriptionally by PCSK9 and dependent on both LDLR and apoE. Despite the lack of changes in plasma lipids in mice expressing hPCSK9 and lacking LDLR (the main target for PCSK9) or apoE (a canonical ligand for the LDLR), hPCSK9 expression increased aortic lesion size in the absence of apoE (268 655 +/- 97 972 um2 in hPCSK9tg/apoE-/- vs. 189 423 +/- 65 700 um(2) in apoE-/-) but not in the absence of LDLR. Additionally, hPCSK9 accumulated in the atheroma and increased lesion Ly6C(hi) monocytes (by 21%) in apoE-/- mice, but not in LDLR-/- mice. CONCLUSIONS: PCSK9 increases hepatic lipid and lipoprotein production via apoE- and LDLR-dependent mechanisms. However, hPCSK9 also accumulate in the artery wall and directly affects atherosclerosis lesion size and composition independently of such plasma lipid and lipoprotein changes. These effects of hPCSK9 are dependent on LDLR but are independent of apoE. PMID- 26980205 TI - Exosomes induce and reverse monocrotaline-induced pulmonary hypertension in mice. AB - AIMS: Extracellular vesicles (EVs) from mice with monocrotaline (MCT)-induced pulmonary hypertension (PH) induce PH in healthy mice, and the exosomes (EXO) fraction of EVs from mesenchymal stem cells (MSCs) can blunt the development of hypoxic PH. We sought to determine whether the EXO fraction of EVs is responsible for modulating pulmonary vascular responses and whether differences in EXO-miR content explains the differential effects of EXOs from MSCs and mice with MCT-PH. METHODS AND RESULTS: Plasma, lung EVs from MCT-PH, and control mice were divided into EXO (exosome), microvesicle (MV) fractions and injected into healthy mice. EVs from MSCs were divided into EXO, MV fractions and injected into MCT-treated mice. PH was assessed by right ventricle-to-left ventricle + septum (RV/LV + S) ratio and pulmonary arterial wall thickness-to-diameter (WT/D) ratio. miR microarray analyses were also performed on all EXO populations. EXOs but not MVs from MCT-injured mice increased RV/LV + S, WT/D ratios in healthy mice. MSC-EXOs prevented any increase in RV/LV + S, WT/D ratios when given at the time of MCT injection and reversed the increase in these ratios when given after MCT administration. EXOs from MCT-injured mice and patients with idiopathic pulmonary arterial hypertension (IPAH) contained increased levels of miRs-19b,-20a,-20b, and -145, whereas miRs isolated from MSC-EXOs had increased levels of anti inflammatory, anti-proliferative miRs including miRs-34a,-122,-124, and -127. CONCLUSION: These findings suggest that circulating or MSC-EXOs may modulate pulmonary hypertensive effects based on their miR cargo. The ability of MSC-EXOs to reverse MCT-PH offers a promising potential target for new PAH therapies. PMID- 26980206 TI - Engineering and systems-level analysis of Saccharomyces cerevisiae for production of 3-hydroxypropionic acid via malonyl-CoA reductase-dependent pathway. AB - BACKGROUND: In the future, oil- and gas-derived polymers may be replaced with bio based polymers, produced from renewable feedstocks using engineered cell factories. Acrylic acid and acrylic esters with an estimated world annual production of approximately 6 million tons by 2017 can be derived from 3 hydroxypropionic acid (3HP), which can be produced by microbial fermentation. For an economically viable process 3HP must be produced at high titer, rate and yield and preferably at low pH to minimize downstream processing costs. RESULTS: Here we describe the metabolic engineering of baker's yeast Saccharomyces cerevisiae for biosynthesis of 3HP via a malonyl-CoA reductase (MCR)-dependent pathway. Integration of multiple copies of MCR from Chloroflexus aurantiacus and of phosphorylation-deficient acetyl-CoA carboxylase ACC1 genes into the genome of yeast increased 3HP titer fivefold in comparison with single integration. Furthermore we optimized the supply of acetyl-CoA by overexpressing native pyruvate decarboxylase PDC1, aldehyde dehydrogenase ALD6, and acetyl-CoA synthase from Salmonella enterica SEacs (L641P). Finally we engineered the cofactor specificity of the glyceraldehyde-3-phosphate dehydrogenase to increase the intracellular production of NADPH at the expense of NADH and thus improve 3HP production and reduce formation of glycerol as by-product. The final strain produced 9.8 +/- 0.4 g L(-1) 3HP with a yield of 13% C-mol C-mol(-1) glucose after 100 h in carbon-limited fed-batch cultivation at pH 5. The 3HP-producing strain was characterized by (13)C metabolic flux analysis and by transcriptome analysis, which revealed some unexpected consequences of the undertaken metabolic engineering strategy, and based on this data, future metabolic engineering directions are proposed. CONCLUSIONS: In this study, S. cerevisiae was engineered for high-level production of 3HP by increasing the copy numbers of biosynthetic genes and improving flux towards precursors and redox cofactors. This strain represents a good platform for further optimization of 3HP production and hence an important step towards potential commercial bio-based production of 3HP. PMID- 26980208 TI - Regulation of the Phosphatidylinositide 3-Kinase Pathway by the Lipid Phosphatase PTEN. PMID- 26980207 TI - Developing a clinical translational neuroscience taxonomy for anxiety and mood disorder: protocol for the baseline-follow up Research domain criteria Anxiety and Depression ("RAD") project. AB - BACKGROUND: Understanding how brain circuit dysfunctions relate to specific symptoms offers promise for developing a brain-based taxonomy for classifying psychopathology, identifying targets for mechanistic studies and ultimately for guiding treatment choice. The goal of the Research Domain Criteria (RDoC) initiative of the National Institute of Mental Health is to accelerate the development of such neurobiological models of mental disorder independent of traditional diagnostic criteria. In our RDoC Anxiety and Depression ("RAD") project we focus trans-diagnostically on the spectrum of depression and anxiety psychopathology. Our aims are a) to use brain imaging to define cohesive dimensions defined by dysfunction of circuits involved in reactivity to and regulation of negatively valenced emotional stimulation and in cognitive control, b) to assess the relationships between these dimension and specific symptoms, behavioral performance and the real world capacity to function socially and at work and c) to assess the stability of brain-symptom-behavior-function relationships over time. METHODS AND DESIGN: Here we present the protocol for the "RAD" project, one of the first RDoC studies to use brain circuit functioning to define new dimensions of psychopathology. The RAD project follows baseline-follow up design. In line with RDoC principles we use a strategy for recruiting all clients who "walk through the door" of a large community mental health clinic as well as the surrounding community. The clinic attends to a broad spectrum of anxiety and mood-related symptoms. Participants are unmedicated and studied at baseline using a standardized battery of functional brain imaging, structural brain imaging and behavioral probes that assay constructs of threat reactivity, threat regulation and cognitive control. The battery also includes self-report measures of anxiety and mood symptoms, and social and occupational functioning. After baseline assessments, therapists in the clinic apply treatment planning as usual. Follow-up assessments are undertaken at 3 months, to establish the reliability of brain-based subgroups over time and to assess whether these subgroups predict real-world functional capacity over time. First enrollment was August 2013, and is ongoing. DISCUSSION: This project is designed to advance knowledge toward a neural circuit taxonomy for mental disorder. Data will be shared via the RDoC database for dissemination to the scientific community. The clinical translational neuroscience goals of the project are to develop brain behavior profile reports for each individual participant and to refine these reports with therapist feedback. Reporting of results is expected from December 2016 onward. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02220309 . Registered: August 13, 2014. PMID- 26980209 TI - Diagnosis and Monitoring of Cystinosis Using Immunomagnetically Purified Granulocytes. AB - BACKGROUND: Cystine determination is a critical biochemical test for the diagnosis and therapeutic monitoring of the lysosomal storage disease cystinosis. The classical mixed-leukocyte cystine assay requires prompt specialized recovery/isolation following blood drawing, providing cystine concentrations normalized to total protein from assorted types of white blood cells, each with varying cystine content. METHODS: We present a new workflow for cystine determination using immunomagnetic granulocyte purification, and new reference ranges established from 47 patient and 27 obligate heterozygote samples assayed. Samples were collected in acid-citrate dextrose tubes and their stability was proven to allow for overnight shipping before analysis. Cystine was quantified by LC-MS/MS. RESULTS: The new method was reproducible (<15% root mean square error) and specific, assaying purified granulocytes from blood samples that no longer required immediate preparation and therefore allowing for up to 30 h before processing. There was a nearly a 2-fold increase in the therapeutic target (1.9 nmol half-cystine/mg protein) range, established using distributions of patient, obligate heterozygote, and control samples. The 2.5-97.5 percentile ranges (-2 SD to +2 SD around mean) for these cohorts were 0.67-6.05 nmol/mg protein for patients, 0.33-1.35 nmol/mg protein for obligate heterozygotes, and 0.09-0.35 nmol/mg protein for controls. CONCLUSIONS: The intracellular cystine determination method using immunopurified granulocytes followed by LC-MS/MS analysis improves the inherent variability of mixed leukocyte analysis and eliminates the need for immediate sample preparation following blood draw. PMID- 26980210 TI - Prospective Associations of Systemic and Urinary Choline Metabolites with Incident Type 2 Diabetes. AB - BACKGROUND: Several compounds in the choline oxidation pathway are associated with insulin resistance and prevalent diabetes; however, prospective data are scarce.We explored the relationships between systemic and urinary choline-related metabolites and incident type 2 diabetes in an observational prospective study among Norwegian patients. METHODS: We explored risk associations by logistic regression among 3621 nondiabetic individuals with suspected stable angina pectoris, of whom 3242 provided urine samples. Reclassification of patients was investigated according to continuous net reclassification improvement (NRI >0). RESULTS: After median (25th to 75th percentile) follow-up of 7.5 (6.4-8.7) years, 233 patients (6.4%) were registered with incident type 2 diabetes. In models adjusted for age, sex, and fasting status, plasma betaine was inversely related to new-onset disease [odds ratio (OR) per 1 SD, 0.72; 95% CI, 0.62-0.83; P < 0.00001], whereas positive associations were observed for urine betaine (1.25; 1.09-1.43; P = 0.001), dimethylglycine (1.22; 1.06-1.40; P = 0.007), and sarcosine (1.30; 1.13-1.49; P < 0.001). The associations were maintained in a multivariable model adjusting for body mass index, hemoglobin A1c, urine albumin to-creatinine ratio, estimated glomerular filtration rate, C-reactive protein, HDL cholesterol, and medications. Plasma betaine and urine sarcosine, the indices most strongly related to incident type 2 diabetes, improved reclassification [NRI >0 (95% CI) 0.33 (0.19-0.47) and 0.16 (0.01-0.31), respectively] and showed good within-person reproducibility. CONCLUSIONS: Systemic and urinary concentrations of several choline metabolites were associated with risk of incident type 2 diabetes, and relevant biomarkers may improve risk prediction. PMID- 26980211 TI - The Importance of Reagent Lot Registration in External Quality Assurance/Proficiency Testing Schemes. AB - BACKGROUND: Providers of external quality assurance (EQA)/proficiency testing schemes have traditionally focused on evaluation of measurement procedures and participant performance and little attention has been given to reagent lot variation. The aim of the present study was to show the importance of reagent lot registration and evaluation in EQA schemes. METHODS: Results from the Noklus (Norwegian Quality Improvement of Primary Care Laboratories) urine albumin/creatinine ratio (ACR) and prothrombin time international normalized ratio (INR) point-of-care EQA schemes from 2009-2015 were used as examples in this study. RESULTS: The between-participant CV for Afinion ACR increased from 6% 7% to 11% in 3 consecutive surveys. This increase was caused by differences between albumin reagent lots that were also observed when fresh urine samples were used. For the INR scheme, the CoaguChek INR results increased with the production date of the reagent lots, with reagent lot medians increasing from 2.0 to 2.5 INR and from 2.7 to 3.3 INR (from the oldest to the newest reagent lot) for 2 control levels, respectively. These differences in lot medians were not observed when native patient samples were used. CONCLUSIONS: Presenting results from different reagent lots in EQA feedback reports can give helpful information to the participants that may explain their deviant EQA results. Information regarding whether the reagent lot differences found in the schemes can affect patient samples is important and should be communicated to the participants as well as to the manufacturers. EQA providers should consider registering and evaluating results from reagent lots. PMID- 26980212 TI - Comparison between surgery and definitive chemoradiotherapy for patients with resectable esophageal squamous cell carcinoma: a propensity score analysis. AB - PURPOSE: Our intent was to compare survival following neoadjuvant chemotherapy followed by surgery versus chemoradiotherapy (CRT) among patients with potentially resectable esophageal squamous cell carcinoma. METHODS: Information about 406 consecutive esophageal cancer patients with resectable disease who underwent surgery with neoadjuvant chemotherapy consisting of cisplatin plus 5 fluorouracil or who underwent definitive CRT was reviewed. The survival outcomes were analyzed using the Kaplan-Meier method and propensity score-adjusted Cox proportional hazards models. Relevant variables were included in the propensity score model. RESULTS: Overall, 206 patients planned to undergo surgery (S group) and 200 patients planned to undergo CRT (CRT group). In the unadjusted situation, progression-free survival and overall survival did not differ statistically between the groups. After matching, both survival outcomes were better in the S group compared to the CRT group. Subanalysis showed both survival outcomes were better in the S group for patients with only stage III disease. However, survival outcomes for stages I, II, and IV were not significantly different between treatment groups. CONCLUSIONS: Among patients with resectable disease, survival outcomes in the S group were favored over those of the CRT group. These results indicate that different therapeutic strategies should be used for stage III esophageal cancer than for other stages. PMID- 26980214 TI - Loeffler endocarditis: silent right ventricular myocardium! AB - We present the case of a 54-year-old male patient with Loeffler endocarditis. It is a rare disorder characterized by fibrous thickening of the endocardium leading to apical obliteration and restrictive cardiomyopathy resulting in heart failure, thromboembolic events or atrial fibrillation. To the best of our knowledge, this is the first case reporting the electrical silence of the right ventricular (RV) apex caused by fibrothrombotic thickening of this area. Under these circumstances RV apical implantation of an implantable cardioverter defibrillator (ICD) or pacemaker electrode may lead to unsuccessful stimulation of these devices. PMID- 26980213 TI - Association of cytomegalovirus infection with hypertension risk: a meta-analysis. AB - BACKGROUND: Information regarding association between cytomegalovirus (CMV) infection and essential hypertension (EH) risk is not consistent across studies. Therefore, we conducted a meta-analysis to investigate the association in detail. METHODS: We comprehensively searched the published literature from the PubMed and Embase databases for any study analyzing the association between CMV and EH risk. A random-effects model was used to calculate the pooled odds ratio (OR) with 95 % confidence interval (CI). RESULTS: Three studies involving 9657 patients were included in the meta-analysis, and the results showed a significantly increased risk of EH in patients with CMV infection. Overall, 79.3 % of the hypertension patients were CMV-positive, which was significantly higher than the percentage for controls (OR = 1.39, 95 % CI = 0.95-2.05, P = 0.017). There was significant heterogeneity among the studies included (I(2) = 70.5 %). The funnel plot and Egger's test also indicated no publication bias. CONCLUSIONS: The results showed a significant association between CMV and EH, which indicates that CMV infection is a possible cause of EH. PMID- 26980215 TI - Cardiovagal and adrenergic function tests in unilateral carotid artery stenosis patients-a Valsalva manoeuvre tool to show an autonomic dysfunction? AB - BACKGROUND: The stability of an arterial baroreflex depends also upon the integrity of the afferent limb. For its quantification, we can use a noninvasive test such as baroreceptor sensitivity estimation during Valsalva manoeuvre. The aim of this study was to evaluate potential autonomic dysfunction in patients with unilateral severe carotid disease and compare the results to the results obtained from an age and gender matched group of healthy volunteers. METHODS: We evaluated dynamic changes during Valsalva manoeuvre (Valsalva ratio, cardiovagal and adrenergic baroreceptor sensitivity, sympathetic indexes and its dynamic ranges) in 41 patients (29 males; 62.9 +/- 7.4 years) and compared the results to results obtained from volunteers (62.8 +/- 7.0 years). RESULTS: Valsalva ratio between the patients and control group revealed no significant difference, as well as cardiovagal and adrenergic baroreceptor sensitivity. Sympathetic indexes, except for sympathetic index 2, reflecting the sympathetic vasoconstrictor baroreceptor response in late phase 2 of Valsalva manoeuvre (7.1 +/- 13.1 mmHg in patients vs. 11.4 +/- 10.2 mmHg in control group; p = 0.012) showed no significant differences between the studied groups. The most prominent dynamic range between the groups was within the sympathetic index 2. CONCLUSION: With some Valsalva manoeuvre test results, we were not able to show severe autonomic dysfunction in unilateral severe carotid stenosis patients except for lower vasoconstriction response within the late phase 2 of the manoeuvre. PMID- 26980216 TI - Percutaneous instillation of physiological saline solution for the treatment of femoral pseudoaneuryms. AB - OBJECTIVE: To investigate the efficacy of para-aneurysmal saline injection for closure of postcatheterization pseudo-aneurysm (PA) at the vascular access site. METHODS: Fifty-one consecutive patients with postcatheterization PA at the vascular access site were included to undergo percutaneous para-aneurysmal saline injection. In case of technical failure the day after, PA were treated by bovine thrombin injection. Anatomical properties of the PA were recorded as were details to injection. RESULTS: Initially all patients exhibited success which was reduced to 43 % at day one. A saline volume of median 7 ml (interquartile range 6-8 ml) has been injected. The amount of injected saline was not different in patients with and without treatment success at day one (P = 0.6). Several anatomical properties of the PA exhibited marked differences in patients with or without success. The length (10.3 mm (7.8-12.0) vs. 12.5 mm (10.3-15.0); P = 0.009) and the angulation (110 degrees (100-118) vs. 140 degrees (129-146); P < 0.001) of the fistula/vessel axis was statistically different between groups. The peak systolic velocity failed to show significance with a tendency to higher values in the ineffective study group (P = 0.07). No peripheral complications occurred. CONCLUSION: Para-aneurysmal saline injection may be a therapeutic alternative to percutaneous thrombin injection in patients exhibiting favorable anatomical properties. PMID- 26980218 TI - Commentary: How do haematopoietic cell transplants cure leukaemia? PMID- 26980219 TI - "Imatinib-induced gastric antral vascular ectasia" in a reporting system of the Japanese Adverse Drug Event Report database. PMID- 26980217 TI - Characterization and pharmacological potential of Lactobacillus sakei 1I1 isolated from fresh water fish Zacco koreanus. AB - BACKGROUND: There are still a large variety of microorganisms among aquatic animals which have not been explored for their pharmacological potential. Hence, present study was aimed to isolate and characterize a potent lactic acid bacterium from fresh water fish sample Zacco koreanus, and to confirm its pharmacological potential. METHODS: Isolation of lactic acid bacteria (LAB) from fresh water fish samples was done using serial dilution method. Biochemical identification and molecular characterization of selected LAB isolate 1I1, based on its potent antimicrobial efficacy, was accomplished using API kit and 16S rRNA gene sequencing analysis. Further, 1I1 was assessed for alpha-glucosidase and tyrosinase inhibitory potential as well as antiviral efficacy against highly pathogenic human influenza virus H1N1 using MDCK cell line in terms of its pharmacological potential. RESULTS: Here, we first time report isolation as well as biochemical and molecular characterization of a lactic acid bacterium Lactobacillus sakei 1I1 isolated from the intestine of a fresh water fish Z. koreanus. As a result, L. sakei 1I1 exhibited potent antimicrobial effect in vitro, and diameter of zones of inhibition of 1I1 against the tested pathogens was found in the range of 13.32 +/- 0.51 to 23.16 +/- 0.32 mm. Also L. sakei 1I1 at 100 mg/ml exhibited significant (p < 0.05) alpha-glucosidase and tyrosinase inhibitory activities by 60.69 and 72.59%, in terms of its anti-diabetic and anti melanogenic potential, respectively. Moreover, L. sakei 1I1 displayed profound anti-cytopathic effect on MDCK cell line when treated with its ethanol extract (100 mg/ml), confirming its potent anti-viral efficacy against H1N1 influenza virus. CONCLUSIONS: These findings reinforce the suggestions that L. sakei 1I1 isolated from the intestine of fresh water fish Z. koreanus might be a candidate of choice for using in pharmacological preparations as an effective drug. PMID- 26980220 TI - Signet ring cell "lymphoma": mimicking the appearance of signet ring cell carcinoma. PMID- 26980221 TI - Successful treatment of TAFRO syndrome, a variant type of multicentric Castleman disease with thrombotic microangiopathy, with anti-IL-6 receptor antibody and steroids. AB - TAFRO syndrome is a rare variant type of multicentric Castleman disease, which is characterized by thrombocytopenia, anasarca, reticulin fibrosis of bone marrow, renal dysfunction and organomegaly. Here, we report a case of TAFRO syndrome that was successfully treated with tocilizumab. A 50-year-old man, who presented with fever, epigastric pain, abdominal fullness, and massive edema of the extremities, was admitted to our hospital. Computed tomography revealed bilateral pleural effusions, ascites, and lymphadenopathy. Laboratory data showed renal dysfunction, anemia, and thrombocytopenia. Examination of bone marrow and cervical lymph nodes led to a diagnosis of hyaline vascular-type Castleman disease. The level of serum interleukin (IL)-6 was extremely high. TAFRO syndrome was finally diagnosed. The patient was treated weekly with tocilizumab, an anti IL-6 receptor antibody and steroids. In 4 weeks, all symptoms disappeared and serum IL-6 level returned to normal. Activity of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which was significantly decreased (9.9 %) prior to treatment, increased after treatment with tocilizumab. The present case suggests that tocilizumab is an effective therapeutic agent for TAFRO syndrome. We suggest that hypercytokinemia in TAFRO syndrome inhibits ADAMTS13 activity, thereby inducing thrombotic microangiopathy. PMID- 26980222 TI - Miscarriage and recurrent miscarriage in patients with congenital factor V deficiency: a report of six cases in Iran. AB - Miscarriage and recurrent miscarriage have not been reported in women with congenital factor V (FV) deficiency. Here we describe cases of both miscarriage and recurrent miscarriage in women with congenital FV deficiency (FVD). We investigated six women with FVD from the southeast of Iran who had experienced miscarriage and recurrent miscarriage. Consequent diagnosis was made by routine coagulation tests as well as FV activity and antigen assays. To evaluate the presence of an inhibitor, a mixing study via prothrombin time (PT) assay was performed. All patients were investigated, and found to be negative for antiphospholipid syndrome. Demographic data and clinical presentations were obtained by standard questionnaire. The factor assays determined that all six women were suffering from moderate FVD. One had experienced eight miscarriages, while the others experienced two (two patients), three, and four episodes. Only one patient had a single miscarriage. Three of the women experienced successful delivery without medical intervention. Miscarriage and recurrent miscarriage should be considered as possible presentations of FVD to prevent its life threatening consequences. PMID- 26980223 TI - Roles of IDH1/2 and TET2 mutations in myeloid disorders. AB - Mutations of the epigenetic enzymes isocitrate dehydrogenase (IDH) 1 and 2, and the methylcytosine dioxygenase 'ten-eleven translocation 2' (TET2), are common in human myeloid malignancies and drivers of these disorders but the underlying mechanisms remain obscure. This review examines mutant IDH1/2 and TET2 enzymes in the context of responses to DNA damage and their potential involvement in age related genomic instability. The clinical relevance of these findings and their potential application in novel therapeutic strategies is also discussed. PMID- 26980225 TI - Tunable quasiparticle trapping in Meissner and vortex states of mesoscopic superconductors. AB - Nowadays, superconductors serve in numerous applications, from high-field magnets to ultrasensitive detectors of radiation. Mesoscopic superconducting devices, referring to those with nanoscale dimensions, are in a special position as they are easily driven out of equilibrium under typical operating conditions. The out of-equilibrium superconductors are characterized by non-equilibrium quasiparticles. These extra excitations can compromise the performance of mesoscopic devices by introducing, for example, leakage currents or decreased coherence time in quantum devices. By applying an external magnetic field, one can conveniently suppress or redistribute the population of excess quasiparticles. In this article, we present an experimental demonstration and a theoretical analysis of such effective control of quasiparticles, resulting in electron cooling both in the Meissner and vortex states of a mesoscopic superconductor. We introduce a theoretical model of quasiparticle dynamics, which is in quantitative agreement with the experimental data. PMID- 26980224 TI - Secondary Antibody Deficiency in Glucocorticoid Therapy Clearly Differs from Primary Antibody Deficiency. AB - PURPOSE: The aim of this study was to identify characteristics of hypogammaglobulinemia secondary to glucocorticoid therapy and their value in the differential diagnosis to primary forms of antibody deficiency. METHODS: We investigated prevalence and character of hypogammaglobulinemia in a cohort of 36 patients with giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) on glucocorticoid therapy in comparison to a gender- and age-matched cohort of hospital controls. We therefore determined serum immunoglobulin levels as well as B- and T cell-subsets in the peripheral blood of all participants. In addition, prior serum immunoglobulin levels and clinical data of the GCA and PMR patients were extracted from the electronic patient data-base. RESULTS: 21/36 GCA/PMR patients on glucocorticoid treatment developed antibody deficiency. In 19 patients this included IgG and in 13 patients IgG was the only affected isotype. The reduction of IgG was persistent in nearly 50 % of these patients during the observed period. GCA/PMR patients had reduced circulating naive and transitional B cells (p = 0.0043 and p = 0.0002 respectively) while IgM, IgG and IgA memory B cells were preserved. Amongst T-cell subsets, we found a reduction of CD4 memory T cells (p < 0.0001), CD4 regulatory T cells (p = 0.0002) and few CD8 memory T cell subtypes. CONCLUSION: Persistent humoral immunodeficiency occurs in about a quarter of GCA/PMR patients under glucocorticoid therapy. Because most patients have isolated IgG deficiency, preserved IgA production and class-switched memory B cells, by these markers this form of secondary hypogammaglobulinemia can be clearly distinguished from common variable immunodeficiency (CVID). PMID- 26980226 TI - ECU tendon "dislocation" in asymptomatic volunteers. AB - OBJECTIVE: Assess extensor carpi ulnaris (ECU) tendon position in the ulnar groove, determine the frequency of tendon "dislocation" with the forearm prone, neutral, and supine, and determine if an association exists between ulnar groove morphology and tendon position in asymptomatic volunteers. MATERIALS AND METHODS: Axial proton density-weighted MR was performed through the distal radioulnar joint with the forearm prone, neutral, and supine in 38 asymptomatic wrists. The percentage of the tendon located beyond the ulnar-most border of the ulnar groove was recorded. Ulnar groove depth and length was measured and ECU tendon signal was assessed. RESULTS: 15.8 % of tendons remained within the groove in all forearm positions. In 76.3 %, the tendon translated medially from prone to supine. The tendon "dislocated" in 0, 10.5, and 39.5 % with the forearm prone, neutral and supine, respectively. In 7.9 % prone, 5.3 % neutral, and 10.5 % supine exams, the tendon was 51-99 % beyond the ulnar border of the ulnar groove. Mean ulnar groove depth and length were 1.6 and 7.7 mm, respectively, with an overall trend towards greater degrees of tendon translation in shorter, shallower ulnar grooves. CONCLUSIONS: The ECU tendon shifts in a medial direction when the forearm is supine; however, tendon "dislocation" has not been previously documented in asymptomatic volunteers. The ECU tendon medially translated or frankly dislocated from the ulnar groove in the majority of our asymptomatic volunteers, particularly when the forearm is supine. Overall greater degrees of tendon translation were observed in shorter and shallower ulnar grooves. PMID- 26980227 TI - Manubrial stress fractures diagnosed on MRI: report of two cases and review of the literature. AB - In contrast to widely-reported sternal insufficiency fractures, stress fractures of the sternum from overuse are extremely rare. Of the 5 cases of sternal stress fracture published in the English-language medical literature, 3 were in the sternal body and only 2 were in the manubrium. We describe two cases of manubrial stress fracture related to golf and weightlifting, and present the first report of the MR findings of this injury. In each of these cases, the onset of pain was atraumatic, insidious, and associated with increased frequency of athletic activity. Imaging was obtained because of clinical diagnostic uncertainty. On MRI, each patient had a sagittally oriented stress fracture of the lateral manubrium adjacent to the first rib synchondrosis. Both patients had resolution of pain after a period of rest, with subsequent successful return to their respective activities. One patient had a follow-up MRI, which showed resolution of the manubrial marrow edema and fracture line. Based on the sternal anatomy and MR findings, we hypothesize that this rare injury might be caused by repetitive torque of the muscle forces on the first costal cartilage and manubrium, and propose that MRI might be an effective means of diagnosing manubrial stress fracture. PMID- 26980228 TI - Voriconazole-induced periostitis: beyond post-transplant patients. AB - Voriconazole-induced periostitis (VIP) is a rare but increasingly encountered entity since Food and Drug Administration (FDA) approval of the second generation antifungal medication in 2002. Literature reports most commonly include transplant recipients on immunosuppressive therapy simultaneously requiring antifungal therapy. Nontransplant patients receiving long-term voriconazole have an equal risk of developing the disease, but may experience a delay in diagnosis due to a lack of familiarity with the process outside of the post-transplant and/or immunosuppressed population. We present a case of VIP in a nontransplant, immunocompetent patient on suppressive antifungal therapy for prior abdominal aortic stent graft fungal infection. Radiologist review of current medications and recognition of periostitis on multiple imaging modalities may hasten the diagnosis and lead to earlier treatment and resolution of symptoms. PMID- 26980229 TI - Back to "once a caesarean: always a caesarean"? A trend analysis in Switzerland. AB - PURPOSE: Caesarean sections (CS) have significantly increased worldwide and a previous CS is nowadays an important and increasingly reported indication to perform a repeat CS. There is a paucity of information in Switzerland on the incidence of repeat CS after previous CS and relationship between the rates of vaginal birth after CS (VBAC). The aim of this study was to analyse the actual trend in VBAC in Switzerland. METHODS: We performed a retrospective cohort study to analyse the proportion of VBAC among all pregnant women with previous sections which give birth during two time periods (group 1:1998/1999 vs. group 2:2004/2005) in our tertiary care referral hospital and in the annual statistics of Swiss Women's Hospitals (ASF-Statistics). In addition, the proportion of induction of labour after a previous caesarean and its success was analysed. RESULTS: In both cohorts studied, we found a significant decrease of vaginal births (p < 0.05) and a significant increase of primary elective repeat caesarean section (p < 0.05) from the first to the second time period, while there was a decrease of secondary repeat caesarean sections. The prevalence of labour induction did not decrease. CONCLUSION: Our study shows that vaginal birth after a prior caesarean section has decreased over time in Switzerland. There was no significant change in labour induction during the study period. While this trend might reflect an increasing demand for safety in pregnancy and childbirth, it concomitantly increases maternal risks of further pregnancies, and women need to be appropriately informed about long-term risks. PMID- 26980230 TI - Intramuscular versus intravenous prophylactic oxytocin for postpartum hemorrhage after vaginal delivery: a randomized controlled study. AB - PURPOSE: Prevention of postpartum haemorrhage (PPH) is essential in the pursuit of improved health care for women. Oxytocin, the most commonly used uterotonic agent to prevent PPH, has no established the route of administration. In this study we aimed to compare whether the mode of oxytocin administration, i.e., intravenous and intramuscular administration, has an effect on the potential benefits and side effects. MATERIALS AND METHODS: A total of 256 women were randomised into two groups: intramuscular group (128) or intravenous group (128). RESULTS: Estimated blood loss during the third stage of labour was similar between the two groups (p = 0.572). Further there were no statistically significant difference was noted between the two groups in terms of the mean duration of labor, duration of the third stage of labor, manual removal of the placenta, need for instrumental delivery, need for blood transfusion, PPH >=500 mL, PPH >=1000 mL, or length of hospital stay. CONCLUSION: Using oxytocin by intravenous and intramuscular route has a similar efficacy and adverse effects. PMID- 26980231 TI - The Effects of Perceptions of Organizational Structure on Job Involvement, Job Satisfaction, and Organizational Commitment Among Indian Police Officers. AB - Successful police organizations rely on involved, satisfied, and committed workers. The concepts of job involvement (i.e., connection with the job), job satisfaction (i.e., affective feeling toward the job), and organizational commitment (i.e., bond with the employing organization) have been shown to significantly affect intentions and behaviors of employees. The current study used multivariate ordinary least squares (OLS) regression analysis on survey results from a sample of 827 Indian police officers to explore how perceptions of work environment factors affect officers' job involvement, job satisfaction, and organizational commitment. Organizational support, formalization (i.e., level of codified written rules and guidelines), promotional opportunities, institutional communication (i.e., salient work information is transmitted), and input into decision-making (i.e., having a voice in the process) significantly influenced the job involvement, job satisfaction, and organizational commitment of Indian police officers. Specifically, in the multivariate analysis, perceptions of formalization and instrumental communication had a positive relationship with job involvement; perceptions of organizational support, promotional opportunities, instrumental communication, and input into decision-making had positive associations with job satisfaction; and perceptions of organizational support, formalization, promotional opportunities, instrumental communication, and input into decision-making had positive relationships with organizational commitment. PMID- 26980232 TI - Considerations on antiviral treatment of suspected influenza infections in hospitalised children. PMID- 26980233 TI - [Geohelminths]. AB - Millions of people in in rural areas and deprived tropical and subtropical regions are infected by soil-transmitted helminths: Ascaris lumbricoides, Trichuris trichiura, hookworms (Ancylostoma duodenale and Necator americanus), and Strongyloides stercoralis. Large migratory flows have made their worldwide distribution easier. Besides being debilitating and producing a significant mortality, they cause high morbidity, leading to physical and intellectual impairment in millions of children who live in poverty. Along with the use of benzimidazoles (albendazole and mebendazole), large-scale international campaigns for treatment and prevention have decreased the number of affected individuals. However, re-infestations and benzimidazole-resistance are frequent, so there needs to be awareness about the importance and consequences of these neglected parasites. PMID- 26980234 TI - Fuhrman Grade and Neutrophil-To-Lymphocyte Ratio Influence on Survival in Patients With Metastatic Renal Cell Carcinoma Treated With First-Line Tyrosine Kinase Inhibitors. AB - BACKGROUND: The present study investigated the various features that might influence the overall survival (OS) of patients with metastatic renal cell carcinoma (RCC) treated with first-line tyrosine kinase inhibitors (TKIs). PATIENTS AND METHODS: A retrospective analysis was performed of consecutive patients with metastatic RCC, in whom treatment with a first-line TKI was initiated from January 2010 to December 2014, at the Department of Oncology, Military Institute of Medicine (Warsaw, Poland). Cox proportional hazards regression was used to construct a prognostic model that included independent factors for OS. We validated the model using 2 bootstrap procedures and calculation of the bias-corrected concordance index. RESULTS: Of the 266 patients included in the study, 201, 45, and 20 received sunitinib, pazopanib, and sorafenib, respectively. The median OS for the whole cohort was 24.8 months (95% confidence interval, 20.2-29.4 months). Six factors were independently associated with poor survival: Eastern Cooperative Oncology Group performance status > 0 (P < .0001), Fuhrman grade 3 to 4 (P < .0001), hemoglobin less than the lower limit of normal (P < .0001), lactate dehydrogenase greater than the upper limit of normal (P = .0011), neutrophil-to-lymphocyte ratio >= 4 (P < .0001), and > 2 metastatic sites (P = .0012). The bias-corrected concordance index was 0.751. CONCLUSION: Fuhrman grade and neutrophil-to-lymphocyte ratio are potential factors that affect the survival of patients with metastatic RCC treated with first-line TKIs. The presented prognostic model demonstrated satisfactory performance but requires external validation with a larger data set. PMID- 26980235 TI - Predicting colorectal surgical complications using heterogeneous clinical data and kernel methods. AB - OBJECTIVE: In this work, we have developed a learning system capable of exploiting information conveyed by longitudinal Electronic Health Records (EHRs) for the prediction of a common postoperative complication, Anastomosis Leakage (AL), in a data-driven way and by fusing temporal population data from different and heterogeneous sources in the EHRs. MATERIAL AND METHODS: We used linear and non-linear kernel methods individually for each data source, and leveraging the powerful multiple kernels for their effective combination. To validate the system, we used data from the EHR of the gastrointestinal department at a university hospital. RESULTS: We first investigated the early prediction performance from each data source separately, by computing Area Under the Curve values for processed free text (0.83), blood tests (0.74), and vital signs (0.65), respectively. When exploiting the heterogeneous data sources combined using the composite kernel framework, the prediction capabilities increased considerably (0.92). Finally, posterior probabilities were evaluated for risk assessment of patients as an aid for clinicians to raise alertness at an early stage, in order to act promptly for avoiding AL complications. DISCUSSION: Machine-learning statistical model from EHR data can be useful to predict surgical complications. The combination of EHR extracted free text, blood samples values, and patient vital signs, improves the model performance. These results can be used as a framework for preoperative clinical decision support. PMID- 26980236 TI - Graphic and haptic simulation for transvaginal cholecystectomy training in NOTES. AB - BACKGROUND: Natural Orifice Transluminal Endoscopic Surgery (NOTES) provides an emerging surgical technique which usually needs a long learning curve for surgeons. Virtual reality (VR) medical simulators with vision and haptic feedback can usually offer an efficient and cost-effective alternative without risk to the traditional training approaches. Under this motivation, we developed the first virtual reality simulator for transvaginal cholecystectomy in NOTES (VTESTTM). METHODS: This VR-based surgical simulator aims to simulate the hybrid NOTES of cholecystectomy. We use a 6DOF haptic device and a tracking sensor to construct the core hardware component of simulator. For software, an innovative approach based on the inner-spheres is presented to deform the organs in real time. To handle the frequent collision between soft tissue and surgical instruments, an adaptive collision detection method based on GPU is designed and implemented. To give a realistic visual performance of gallbladder fat tissue removal by cautery hook, a multi-layer hexahedral model is presented to simulate the electric dissection of fat tissue. RESULTS: From the experimental results, trainees can operate in real time with high degree of stability and fidelity. A preliminary study was also performed to evaluate the realism and the usefulness of this hybrid NOTES simulator. CONCLUSIONS: This prototyped simulation system has been verified by surgeons through a pilot study. Some items of its visual performance and the utility were rated fairly high by the participants during testing. It exhibits the potential to improve the surgical skills of trainee and effectively shorten their learning curve. PMID- 26980237 TI - Comparison of metoprolol tartrate multiple-unit lipid matrix systems produced by different technologies. AB - The aim of this study was to develop, evaluate and compare extended release mini matrices based on metoprolol tartrate (MPT) and either glyceryl behenate (GB) or glyceryl palmitostearate (GPS). Mini-matrices were produced by three different techniques: hot melt extrusion, compression of melt granulates and prilling. Hot melt extrusion and compression of granules obtained from melted material proved to be reliable, robust and reproducible techniques with aim of obtaining extended release matrices. Prilling tended to be susceptible to increased melt viscosity. Direct compression was not applicable for mini-matrix production due to poor powder flow. In general MPT release from all matrices was affected by its loading and the size of the units/particles. Processing of GB-MPT mixtures by different techniques did not lead to different drug release rates and patterns, while in case of GPS differently obtained matrices provided diverse MPT release outcomes. Matrices based on GB tended to have higher porosity compared to ones composed of GPS and thus most of the GB-based formulations showed faster drug delivery. FT-IR analysis revealed no interactions between primary components used for matrix production and Raman mapping outlined uniform MPT distribution throughout the units. DSC and X-ray studies revealed significant changes in the crystallinity of glycerides after storage under room conditions (GPS samples) and at increased temperature (GB and GPS samples), which was correlated to the changes seen in drug release rate and pattern after storage. Media composition in general tended to insignificantly affect GB matrices, while in case of GPS matrices increasing the pH and presence of biorelevant compounds induced faster drug release. PMID- 26980238 TI - Wewakazole B, a Cytotoxic Cyanobactin from the Cyanobacterium Moorea producens Collected in the Red Sea. AB - A mass spectrometry (MS)-guided isolation has led to the purification of a new cyanobactin, wewakazole B (1), along with the known compound curacin D from a Red Sea Moorea producens. The planar structure of 1 was elucidated using a combination of NMR and MS techniques. After ozonolysis and acid hydrolysis, the absolute configurations of the amino acid components of 1 were determined by chiral-phase LC-MS and HPLC analyses. Notably, compound 1 exhibited cytotoxic activity toward human MCF7 breast cancer cells (IC50 = 0.58 MUM) and human H460 lung cancer cells (IC50 = 1.0 MUM) and was also found to be inactive in a siderophore assay. PMID- 26980240 TI - Longevity(r) constrained cup: an operative technical tip for prevention of metallic ring disassembly. AB - Constrained liners are a salvage procedure for treating or preventing recurrent dislocations. The Longevity(r) constrained liner (Zimmer) has a special design with cut-outs on its circumference for avoiding impingement in certain areas and a metallic constraining ring that has to be impacted. The ring impaction may be technical demanding. We recommend preassembly with the head component prior to seating into the acetabular cup, thus avoiding the soft tissue or cement interference and malposition due to bad angle of incidence of impaction force. PMID- 26980239 TI - Comparative genomic analysis of pre-epidemic and epidemic Zika virus strains for virological factors potentially associated with the rapidly expanding epidemic. AB - Less than 20 sporadic cases of human Zika virus (ZIKV) infection were reported in Africa and Asia before 2007, but large outbreaks involving up to 73% of the populations on the Pacific islands have started since 2007, and spread to the Americas in 2014. Moreover, the clinical manifestation of ZIKV infection has apparently changed, as evident by increasing reports of neurological complications, such as Guillain-Barre syndrome in adults and congenital anomalies in neonates. We comprehensively compared the genome sequences of pre-epidemic and epidemic ZIKV strains with complete genome or complete polyprotein sequences available in GenBank. Besides the reported phylogenetic clustering of the epidemic strains with the Asian lineage, we found that the topology of phylogenetic tree of all coding regions is the same except that of the non structural 2B (NS2B) coding region. This finding was confirmed by bootscan analysis and multiple sequence alignment, which suggested the presence of a fragment of genetic recombination at NS2B with that of Spondweni virus. Moreover, the representative epidemic strain possesses one large bulge of nine bases instead of an external loop on the first stem-loop structure at the 3' untranslated region just distal to the stop codon of the NS5 in the 1947 pre epidemic prototype strain. Fifteen amino acid substitutions are found in the epidemic strains when compared with the pre-epidemic strains. As mutations in other flaviviruses can be associated with changes in virulence, replication efficiency, antigenic epitopes and host tropism, further studies would be important to ascertain the biological significance of these genomic changes. PMID- 26980241 TI - Subspine impingement: 2 case reports of a previously unreported cause of instability in total hip arthroplasty. AB - BACKGROUND: Instability is a common cause of revision hip arthroplasty and is frequently due to improper component placement and subsequent component impingement. Impingement of the greater trochanter upon the anterior inferior iliac spine (AIIS) has been described as a cause of symptomatic femoroacetabular impingement (FAI), but has never been described as a cause of instability following total hip arthroplasty (THA). CASE REVIEW: We present 2 cases of patients undergoing THA. Each patient was evaluated preoperatively and found to have a prominent AIIS, which was concerning due to it overhanging the anterolateral acetabular lip. Both patients had intraoperative posterior instability of their THA, the cause of which was determined to be impingement of the greater trochanter upon a prominent AIIS. Open resection of the AIIS was performed with subsequent resolution of impingement. LITERATURE REVIEW: AIIS impingement has been reported as a cause of symptomatic FAI. In these case reports, open or arthroscopic resection of the AIIS resulted in resolution of symptoms. Morphologically distinct subtypes of the AIIS have been previously described based upon computed tomography, and some subtypes are associated with a high risk of impingement in the native hip. No previous studies have described this phenomenon in the setting of THA. CLINICAL RELEVANCE: Instability is a common cause of revision THA. Impingement of the greater trochanter upon a prominent AIIS is a previously unreported cause of THA instability which can be addressed with intraoperative resection of the AIIS with good result. PMID- 26980242 TI - Development of an experimental rat model of hyperammonemic encephalopathy and evaluation of the effects of rifaximin. AB - Hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with hepatic dysfunction. However, the precise mechanism of HE is unclear. To elucidate the mechanism, we developed a new rat model of HE with coma using a combination of subcutaneous splenic transposition, partial hepatectomy and portal vein stenosis. In this model, blood ammonia levels increase in the postcaval vein over time and markedly increase in the cerebrospinal fluid (CSF). The distribution of ammonia in the various blood vessels in the HE model suggests that the origin of peripheral blood and CSF ammonia is the mesenteric veins that drain blood from the gastrointestinal tract. Behavioral analysis revealed decreased pain response, increased passivity, and decreased pinna and corneal reflexes, followed by the development of coma. The development of coma in this model was frequent and reproducible. Increased S100 calcium-binding protein B (S100B: a biomarker for brain injury) in venous blood, as well as damaged brain tissue, increased intracranial pressure and cerebral edema were observed in rats with coma. A very high correlation was observed between the blood ammonia concentration in the postcaval vein and the onset of coma. Rifaximin, a poorly absorbed antibiotic that targets gut flora, significantly improved symptoms of HE. Based on these results, our rat model appears to reflect the pathological state of HE associated with acute liver failure and may be a useful model for analysis of hyperammonemic encephalopathy. PMID- 26980244 TI - Hepatoprotective effects of polymethoxyflavones against acute and chronic carbon tetrachloride intoxication. AB - In the present study, we explore the protective effects of Citrus aurantium L. extract (CAE) against acute and chronic CCl4-induced hepatotoxicity. The quantitative analysis of CAE was performed using HPLC-UV to determine the nobiletin content was approximately 27%. For the acute model, the male ICR mice were orally treated with water, silymarin (positive control, 200 mg/kg) and CAE (50 and 200 mg/kg) for 3 days prior to CCl4 (1 mL/kg, 50% v/v in olive oil) IP injection. For the chronic model (n = 6/group), the mice were treated with each treatment for 28 consecutive days and CCl4 (1 mL/kg, 20%) was injected twice a week. In both the acute and chronic models, the CCl4 alone treated group showed histopathologic alterations with a significantly increase in serum hepatic enzyme levels together with a disrupted anti-oxidative status. In contrast, the CAE treatments restored pathologic alterations and recovered the oxidative status by enhancing antioxidant enzymes and reducing lipid peroxidation levels. Furthermore, CAE enhanced nuclear factor E2-related factor 2 (Nrf2) and its related cytoprotective signals, including NAD(P)H quinone oxidoreductase 1, UDP glucuronosyltransferase, and gamma-glutamylcysteine synthetase. Taken together, the present study demonstrates that CAE exerts a protective effect against CCl4 induced hepatotoxicity with its anti-oxidant, anti-inflammatory, and anti apoptotic activity. PMID- 26980245 TI - A case report of lethal post-viral lymphocytic myocarditis with exclusive location in the right ventricle. AB - The inflammatory involvement of vital organs may represent a dangerous and life threatening situation: in particular, the inflammation of the myocardial tissue of the heart may lead to severe consequences since the clinical history of the disease may be completely asymptomatic, any clinical sign may be lacking, thus preventing correct diagnosis and treatment. This may occur even in the case of myocarditis and may lead to unexpected death whose cause can be assessable only by means of a thorough histopathological examination. The article reports the case of 61-year old female who developed a flu-like syndrome with very few symptoms, followed by sudden death in three weeks. The autopsy and following histopathological investigations identified the cause of death in a post-viral lymphocytic myocarditis, probably related to the previous infectious disease, and alternative causes (as arrhythmic ventricular dysplasia, vasculitis, sarcoidosis and giant cell myocarditis) were excluded. The exclusive location in the right ventricle was a peculiar finding. The case highlights the importance of the myocardium of the right ventricle, a tissue which is often less considered even in histopathological surveys. The exclusive location of myocarditis in the right ventricle is a rare event but in this case fully responsible for death. PMID- 26980243 TI - Cartilage-specific deletion of ephrin-B2 in mice results in early developmental defects and an osteoarthritis-like phenotype during aging in vivo. AB - BACKGROUND: Ephrins and their related receptors have been implicated in some developmental events. We have demonstrated that ephrin-B2 (EFNB2) could play a role in knee joint pathology associated with osteoarthritis (OA). Here, we delineate the in vivo role of EFNB2 in musculoskeletal growth, development, and in OA using a cartilage-specific EFNB2 knockout (EFNB2(Col2)KO) mouse model. METHODS: EFNB2(Col2)KO was generated with Col2a1-Cre transgenic mice. The skeletal development was evaluated using macroscopy, immunohistochemistry, histomorphometry, radiology, densitometry, and micro-computed tomography. Analyses were performed at P0 (birth) and on postnatal days P15, P21, and on 8 week- and 1-year-old mice. RESULTS: EFNB2(Col2)KO mice exhibited significant reduction in size, weight, length, and in long bones. At P0, the growth plates of EFNB2(Col2)KO mice displayed increased type X collagen, disorganized hyphertrophic zone, and decreased mineralization. At P15, mutant mice demonstrated a significant reduction in VEGF and TRAP at the chondro-osseous junction and a delay in the secondary ossification, including a decrease in bone volume and trabecular thickness. At P21 and 8 weeks old, EFNB2(Col2)KO mice exhibited reduced bone mineral density in the total skeleton, femur and spine. One-year-old EFNB2(Col2)KO mice demonstrated OA phenotypic features in both the knee and hip. By P15, 27 % of the EFNB2(Col2)KO mice developed a hip locomotor phenotype, which further experiments demonstrated reflected the neurological midline abnormality involving the corticospinal tract. CONCLUSION: This in vivo study demonstrated, for the first time, that EFNB2 is essential for normal long bone growth and development and its absence leads to a knee and hip OA phenotype in aged mice. PMID- 26980247 TI - Experimental drowning lung images on postmortem CT - Difference between sea water and fresh water. AB - PURPOSE: Experimental drowning models were prepared to investigate the time related course of lung changes using postmortem CT. This study was approved by our institutional animal ethics committee. MATERIALS AND METHODS: Fifteen NZW rabbits (female fifteen, 2.6-4.3 (mean 3.3)kg) were divided into 3 groups: fresh water drowning (FRESH), sea water drowning (SEA), and sea water drowning with anterior chest compression (ACC). All individuals were examined by CT (Aquilion CX, Toshiba, Japan) on postmortem time course. The rabbit's head was submerged in a water bath for a total of 10 min. In ACC, cardiopulmonary resuscitation was performed for 2 min, additionally. The percentage of aerated lung volumes (%ALV=100 (aerated lung volume/total lung volume)) were statistically evaluated and the lung CT image patterns and pleural fluid appearance time were investigated. RESULTS: All lungs had decreased their %ALV within 24h, and there were no statistical differences in and among the 3 groups. After 36 h, %ALV tended to increase in all groups, and only ACC presented a statistical difference between 1h and 36 h (p<0.005). On postmortem lung CT, all lungs presented ground glass opacity with interstitial thickening spread pattern (100%) and no pattern change during the follow-up period. After presenting pleural space fluid collection, the %ALV tended to increase. CONCLUSION: There were no differences among FRESH, SEA, and ACC in %ALV within 24h. Only ground-glass opacity could be detected on postmortem lung CT, experimentally. PMID- 26980246 TI - Hair analysis of an unusual case of Chloroquine intoxication. AB - A dead body of middle aged man was exhumed from 6.5 month earth-grave. Autopsy findings were non-specific as the body was completely putrefied. Deceased's scalp hair and kidney was sent for toxicological analysis. Hair sample (50mg) was incubated with 1M NaOH (2 ml). Chloroquine was detected in hair and kidney during basic drug screen performed on GC/MS. For confirmation and quantitation, chloroquine was extracted using Hypersep verify CX SPE cartridges while mass detector was operated in SIM mode using the ions of m/z 245.0, 290.1, 319.0 for chloroquine while ions of m/z 260 and 455 were monitored for nalorphine (internal standard). Chloroquine was present in high concentration in hair (211 ng/mg) as well as in kidney (37.3mg/kg). Moreover, chloroquine was not detected in the wash solvents, suggesting ingestion of the drug rather than an external contamination of hair. These findings strongly suggested the acute exposure of higher doses of chloroquine to the deceased before death. PMID- 26980248 TI - New stutter ratio distribution for DNA mixture interpretation based on a continuous model. AB - In forensic science, DNA mixture interpretation is traditionally based on a binary model, which does not account for peak-height information in DNA profiles. In recent years, some countries have adopted a continuous model in which peak heights are used and stochastic effects are considered to enable rigorous calculation of likelihood ratios. However, this model requires certain biological parameters which affect the expected allelic and stutter peak heights. In this paper, we focused on estimating the distribution of the stutter ratio (SR) in 15 short tandem repeat loci in relation to the allele repeat number. We estimated the SR values of 234 single-source DNA samples by using a commercially available kit. In all loci except for D8S1179, D21S11, and D2S1338, a simple log-normal distribution model was fitted to the variability of SR. For D21S11, we developed a new distribution model in which distinct log-normal distributions between complete and incomplete repeat units are used (a separate log-normal distribution model). For D8S1179 and D2S1338, we developed another new distribution model that mixes two log-normal distributions to explain two types of repeat structures appearing within the same number of allele repeats. These two models were fitted to the observed SR values more accurately than the simple log-normal distribution model. We expected these new SR models to be applied to DNA mixture interpretation based on a continuous model. PMID- 26980249 TI - Frontal sinus parameters in computed tomography and sex determination. AB - The frontal sinus is a sturdy part of the skull that is likely to be retrieved for forensic investigations. We evaluated frontal sinus parameters in paranasal sinus computed tomography (CT) images for sex determination. The study was conducted on 200 normal paranasal sinus CT images of 100 men and 100 women of Persian origin. We categorized the studied population into three age groups of 20 34, 35-49 and ? 50 years. The number of partial septa in the right frontal sinus and the maximum height and width were significantly different between the two sexes. The highest precision for sex determination was for the maximum height of the left frontal sinus (61.3%). In the 20-34 years age-group, height and width of the frontal sinus were significantly different between the two sexes and the height of the left sinus had the highest precision (60.8%). In the 35-49 years age-group, right anterior-posterior diameter had a sex determination precision of 52.3%. No frontal sinus parameter reached a statistically significant level for sex determination in the ? 50 years age-group. The number of septa and scallopings were not useful in sex determination. Frontal sinus parameters did not have a high precision in sex determination among Persian adults. PMID- 26980250 TI - The art of traditional native PAGE: The APLP 48-ID assay for human identification. AB - When full STR profiles cannot be obtained, further DNA analyses targeting single nucleotide polymorphisms (SNPs) may occasionally yield valuable information. Although the discrimination power of each SNP is relatively low, combined analysis of many SNPs can improve the personal identification ability to a level as high as that of commercial STR typing kits. In this study, we developed a new SNP typing method, named the amplified-product length polymorphism (APLP) 48-ID assay, for genotyping of 47 autosomal SNPs and two X and Y chromosomal markers for sex typing. Forty-seven SNPs were selected from all 22 autosomes, showing high diversity in European, Nigerian, Han Chinese, and Japanese population in the HapMap data. PCR primers were designed to generate amplicons 40-100 bp in length to increase the robustness of the PCR. The APLP 48-ID assay consisted of four independent PCR reactions followed by electrophoretic run on four lanes in a polyacrylamide gel. Complete profiles were obtained when more than 1.2 ng of DNA was used. We applied this assay for genotyping of 236 Japanese individuals. The random matching probability was 3.3E-20, and the power of exclusion was greater than 0.9999999. This method is a rapid, robust, and cost-effective approach for human identification and paternity testing. PMID- 26980252 TI - Rectal temperature-based death time estimation in infants. AB - In determining the time of death in infants based on rectal temperature, the same methods used in adults are generally used. However, whether the methods for adults are suitable for infants is unclear. In this study, we examined the following 3 methods in 20 infant death cases: computer simulation of rectal temperature based on the infinite cylinder model (Ohno's method), computer-based double exponential approximation based on Marshall and Hoare's double exponential model with Henssge's parameter determination (Henssge's method), and computer based collinear approximation based on extrapolation of the rectal temperature curve (collinear approximation). The interval between the last time the infant was seen alive and the time that he/she was found dead was defined as the death time interval and compared with the estimated time of death. In Ohno's method, 7 cases were within the death time interval, and the average deviation in the other 12 cases was approximately 80 min. The results of both Henssge's method and collinear approximation were apparently inferior to the results of Ohno's method. The corrective factor was set within the range of 0.7-1.3 in Henssge's method, and a modified program was newly developed to make it possible to change the corrective factors. Modification A, in which the upper limit of the corrective factor range was set as the maximum value in each body weight, produced the best results: 8 cases were within the death time interval, and the average deviation in the other 12 cases was approximately 80min. There was a possibility that the influence of thermal isolation on the actual infants was stronger than that previously shown by Henssge. We conclude that Ohno's method and Modification A are useful for death time estimation in infants. However, it is important to accept the estimated time of death with certain latitude considering other circumstances. PMID- 26980251 TI - A case of fatal sigmoid volvulus visualized on postmortem radiography: The importance of image optimization with multidetector computed tomography. AB - This report describes the case of a man who developed fatal sigmoid volvulus that was identified on postmortem radiography before forensic autopsy. Postmortem radiography is useful for visualizing the body prior to autopsy. We discuss postmortem multidetector computed tomography that was tailored for optimum image quality to allow reconstruction of the fatal findings in multiple axes and in three dimensions, helping to pinpoint the anatomical sites of interest. This involves techniques such as manipulation of the scanning beam pitch and overlapping CT section acquisition. These techniques are best performed by personnel with CT technology training. PMID- 26980253 TI - Detection of a novel X-chromosomal short tandem repeat marker in Xq28 in four ethnic groups. AB - DNA testing of X-chromosomal short tandem repeat (X-STR) polymorphisms has been the focus of attention in several studies, mainly due to its applicability in the investigation of complex kinship cases. Studies of X-STR in analyses of DNA sequences, population studies and DNA testing applications have been reported. We performed detection and population genetic study of a novel tetranucleotide X-STR locus in the present study. We identified a unique X-STR locus consisting of two tetranucleotides in Xq28. Although the STR is a simple tetranucleotide, its polymorphism was comparatively high [polymorphism information content (PIC)=0.7140] in Japanese subjects. In addition, the STR varied in structure among ethnic groups. We conclude that this locus will be useful for forensic DNA testing and anthropological studies. PMID- 26980254 TI - Use of postmortem coronary computed tomography angiography with water-insoluble contrast medium to detect stenosis of the left anterior descending artery in a case of sudden death. AB - A 40-year-old man was found dead on a sidewalk in an expressway parking area one hour after he had entered the area on a motorcycle. A medicolegal autopsy was performed to reveal the cause of this sudden and unexpected death. Postmortem coronary CT angiography after introduction of 5% gelatin-barium emulsion as a radiopaque contrast medium into the heart demonstrated a significant arterial luminal filling defect in the left anterior descending (LAD) coronary artery. Macroscopic and microscopic examinations revealed that a thrombus had become deposited on ruptured plaque within the LAD artery, and that a small amount of the contrast medium was present between the thrombus and the vessel endothelium. These histological findings were consistent with incomplete occlusion of the LAD artery in the 3D reconstructed image. The cause of death in this case was definitively determined to be ischemic heart disease. Postmortem angiography played a role in screening of a vascular lesion that was subsequently verified by histology to have been responsible for sudden and unexpected death. PMID- 26980255 TI - The identification of living persons on images: A literature review. AB - Personal identification in the forensic context commonly concerns unknown decedents. However, recently there has been an increase in cases which require identification of living persons, especially from surveillance systems. These cases bring about a relatively new challenge for forensic anthropologists and pathologists concerning the selection of the most suitable methodological approaches with regard to the limitations of the photographic representation of a given person for individualization and identity. Facial features are instinctively the primary focus for identification approaches. However, other body parts (e.g. hands), and body height and gait (on videos) have been considered in cases of personal identification. This review aims at summarizing the state-of-the-art concerning the identification of the living on images and videos, including a critical evaluation of the advantages and limitations of different methods. Recommendations are given in order to aid forensic practitioners who face cases of identification of living persons. PMID- 26980256 TI - Body height estimation from post-mortem CT femoral F1 measurements in a contemporary Swiss population. AB - PURPOSE: The present study aimed at the comparison of body height estimations from cadaver length with body height estimations according to Trotter and Gleser (1952) and Penning and Riepert (2003) on the basis of femoral F1 section measurements in post-mortem computed tomography (PMCT) images. METHODS: In a post mortem study in a contemporary Swiss population (226 corpses: 143 males (mean age: 53 +/- 17 years) and 83 females (mean age: 61 +/- 20 years)) femoral F1 measurements (403 femora: 199 right and 204 left; 177 pairs) were conducted in PMCT images and F1 was used for body height estimation using the equations after Trotter and Gleser (1952, "American Whites"), and Penning and Riepert (2003). RESULTS: The mean observed cadaver length was 176.6 cm in males and 163.6 cm in females. Mean measured femoral length F1 was 47.5 cm (males) and 44.1cm (females) respectively. Comparison of body height estimated from PMCT F1 measurements with body height calculated from cadaver length showed a close congruence (mean difference less than 0.95 cm in males and less than 1.99 cm in females) for equations both applied after Penning and Riepert and Trotter and Gleser. CONCLUSIONS: Femoral F1 measurements in PMCT images are very accurate, reproducible and feasible for body height estimation of a contemporary Swiss population when using the equations after Penning and Riepert (2003) or Trotter and Gleser (1952). PMID- 26980257 TI - Detection of toluene in a body buried for years with a fatal cardiac contusion. AB - This report aimed to present the postmortem finding of toluene in a homicide victim buried under the ground for six years. The bones of the skull and limbs were exposed, and the remainder of the subcutaneous tissues, brain and heart had formed into adipocere. There were numerous fractures in the skull and the anterior side of the ribs. A cardiac contusion extending into the cavity of the right ventricle was also observed. No other obvious injuries were identified on the body. The concentration of toluene in the bone marrow within the head of the humerus was 58.4 MUg/g. The cause of death was suspected as heart rupture, possibly from a forceful impact or compression of the anterior chest under toluene intoxication. This report presents a rare case where toluene intake by a human was disclosed by autopsy even after several years of death. PMID- 26980258 TI - Aggressive angiomyxoma. A rare mesenchymal pelvic tumor. PMID- 26980259 TI - Locally advanced rectal cancer: Preliminary results of rectal preservation after neoadjuvant chemoradiotherapy. AB - INTRODUCTION: The standard treatment for locally advanced rectal cancer is total mesorectal excision. However, organ preservation has been proposed for tumors with good response to neoadjuvant treatment. The aim of this study was to evaluate the oncologic results of this strategy. METHODS: This is a retrospective cohort study (2005-2014) including a consecutive series of patients with rectal adenocarcinoma with complete or almost complete clinical response after preoperative chemo-radiotherapy, that were treated according to a strategy of preservation of the rectum. RESULTS: A total of 204 patients with rectal cancer received neoadjuvant therapy. Thirty (14.7%) had a good response and were treated with rectal preservation (23 "Watch and Wait" and 7 local resections). Median follow-up was 46 months (interquartile range: 30-68). In the group of "Watch & Wait", 4 patients had local recurrence before 12 months (actuarial local recurrence rate=18.5%). All of them underwent salvage surgery (2 with radical surgery and 2 local resections) without any further recurrence. Disease-free survival actuarial rate at 3 years follow-up was 94.1% (95% CI 82.9-100). None of the 7 patients that were treated by local excision had local recurrence. The organ preservation rate for the whole group was 93%. CONCLUSION: The strategy of organ preservation in locally advanced rectal cancer is feasible in cases with good response to neoadjuvant therapy. When implemented in a highly selected group of patients this strategy is associated with satisfactory oncologic results. PMID- 26980260 TI - Subcapsular splenic hematoma due to metastatic squamous cell anal carcinoma. PMID- 26980261 TI - Structural features and molecular aggregations of designed triple-stranded beta sheets in single crystals. AB - Design, synthesis and single-crystal conformations of hybrid triple-stranded beta sheets composed of E-vinylogous residues are reported. Restricting conformational flexibility of beta-strands through the insertion of carbon-carbon double bonds at facing positions leads to increased peptide crystallinity, which allowed unambiguous structural characterization of three-stranded beta-sheets. This strategy can be further explored for the design of functional beta-sheets. PMID- 26980262 TI - Histone retention, protein carbonylation, and lipid peroxidation in spermatozoa: Possible role in recurrent pregnancy loss. AB - Contribution from a defective paternal genome has been attributed to be an important cause for spontaneous recurrent pregnancy loss (RPL). Increased oxidative stress results in decreased detoxification and is a cause for damage to chromatin, proteins, and membrane lipids. The present study aimed to explore if there is a significant relationship between retained histones due to defective packaging of DNA in spermatozoa and oxidative stress. RPL patients (n=16) with a history of >=2 embryo losses before the 20th week of gestation and no female factor abnormality, and fertile healthy volunteers (n=20) as controls were included in the study. A significant difference in the levels of protein carbonylation and lipid peroxidation together with an increased retention of histones in the experimental groups was noticed. Histone carrying sites for oxidative modification such as arginine and lysine might be responsible for disturbing the paternal epigenomic control during early stages of embryonic differentiation leading to abortion. PMID- 26980264 TI - Topical diltiazem for pain after closed hemorrhoidectomy. AB - BACKGROUND: Anal sphincter spasm contributes to the appearance of postoperative pain following hemorrhoidectomy. AIM: To determine the efficacy of topical diltiazem in the control of post-hemorrhoidectomy pain. MATERIAL AND METHODS: A randomized, prospective, experimental, double-blind study was conducted on 2 groups of patients in the postoperative period of closed hemorrhoidectomy. Each group consisted of 17 patients. Group A received topical diltiazem in the anal region 3 times a day and group B received a placebo. Ketorolac was administered to both groups as rescue therapy. RESULTS: In group A, the mean score on the visual analog scale was 2.97+/-1.18cm at 24h, 1.51+/-1.18cm at 48h, and 0.84+/ 0.92cm at 72h. In group B, it was 6.82+/-1.9cm at 24h, 5.3+/-1.66cm at 48h, and 4.32+/-2.13cm at 72h (P<.001, 95% CI). The mean number of analgesic doses in group A was 2.41+/-0.87 at 24h, 1.11+/-0.85 at 48h, and 0.94+/-0.96 at 72h. In group B, it was 3.82+/-0.52 at 24h, 3.64+/-0.70 at 48h, and 2.88+/-1.26 at 72h (P<.001, 95% CI). CONCLUSIONS: In this study, topical administration of diltiazem resulted in a statistically significant reduction of postoperative pain in patients that underwent closed hemorrhoidectomy. PMID- 26980265 TI - Three-dimensional ultrasonography and power Doppler for discrimination between benign and malignant endometrium in premenopausal women with abnormal uterine bleeding. AB - BACKGROUND: Ultrasonography has been extensively used in women suspected of having a gynecological malignancy. The aim of this study is to evaluate the efficacy of 3D ultrasonography and power Doppler for discrimination between benign and malignant endometrium in premenopausal women with abnormal uterine bleeding. METHODS: This cross-sectional study included 78 premenopausal women with abnormal uterine bleeding scheduled for hysteroscopy and endometrial curettage. The endometrial thickness (ET), uterine artery pulsatility index (PI) and resistance index (RI), and endometrial volume (EV) and 3D power Doppler vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were measured and compared with hysteroscopic and histopathologic findings. RESULTS: The ET (P <0.001), EV (P <0.001), and endometrial VI (P <0.001) and VFI (P = 0.043) were significantly increased in patients with atypical endometrial hyperplasia and endometrial carcinoma (n = 10) than those with benign endometrium (n = 68); whereas, the uterine artery PI and RI and endometrial FI were not significantly different between the two groups. The best marker for discrimination between benign and malignant endometrium was the VI with an area under the ROC curve of 0.88 at a cutoff value of 0.81%. CONCLUSION: 3D ultrasonography and power Doppler, especially endometrial VI, may be useful for discrimination between benign and malignant endometrium in premenopausal women with abnormal uterine bleeding. PMID- 26980266 TI - Genome-wide identification and functional prediction of novel and fungi responsive lincRNAs in Triticum aestivum. AB - BACKGROUND: Stripe rust (Puccinia striiformis f. sp. tritici; Pst) and powdery mildew (Blumeria graminis f. sp. tritici; Bgt) are important diseases of wheat (Triticum aestivum) worldwide. Increasingly evidences suggest that long intergenic ncRNAs (lincRNAs) are developmentally regulated and play important roles in development and stress responses of plants. However, identification of lincRNAs in wheat is still limited comparing with functional gene expression. RESULTS: The transcriptome of the hexaploid wheat line N9134 inoculated with the Chinese Pst race CYR31 and Bgt race E09 at 1, 2, and 3 days post-inoculation was recapitulated to detect the lincRNAs. Here, 283 differential expressed lincRNAs were identified from 58218 putative lincRNAs, which account for 31.2% of transcriptome. Of which, 254 DE-LincRNAs responded to the Bgt stress, and 52 lincRNAs in Pst. Among them, 1328 SnRNP motifs (sm sites) were detected and showed RRU4-11RR sm site element and consensus RRU1-9VU1-7RR SnRNP motifs, where the total number of uridine was more than 3 but less than 11. Additionally, 101 DE-lincRNAs were predicted as targets of miRNA by psRNATarget, while 5 target mimics were identified using target mimicry search in TAPIR. CONCLUSIONS: Taken together, our findings indicate that the lincRNA of wheat responded to Bgt and Pst stress and played important roles in splicesome and inter-regulating with miRNA. The sm site of wheat showed a more complex construction than that in mammal and model plant. The mass sequence data generated in this study provide a cue for future functional and molecular research on wheat-fungus interactions. PMID- 26980267 TI - Human Neural Stem Cell Transplantation-Mediated Alteration of Microglial/Macrophage Phenotypes after Traumatic Brain Injury. AB - Neural stem cells (NSCs) promote recovery from brain trauma, but neuronal replacement is unlikely the sole underlying mechanism. We hypothesize that grafted NSCs enhance neural repair at least partially through modulating the host immune response after traumatic brain injury (TBI). C57BL/6 mice were intracerebrally injected with primed human NSCs (hNSCs) or vehicle 24 h after a severe controlled cortical impact injury. Six days after transplantation, brain tissues were collected for Western blot and immunohistochemical analyses. Observations included indicators of microglia/macrophage activation, M1 and M2 phenotypes, axonal injury detected by amyloid precursor protein (APP), lesion size, and the fate of grafted hNSCs. Animals receiving hNSC transplantation did not show significant decreases of brain lesion volumes compared to transplantation procedures with vehicle alone, but did show significantly reduced injury-dependent accumulation of APP. Furthermore, intracerebral transplantation of hNSCs reduced microglial activation as shown by a diminished intensity of Iba1 immunostaining and a transition of microglia/macrophages toward the M2 anti inflammatory phenotype. The latter was represented by an increase in the brain M2/M1 ratio and increases of M2 microglial proteins. These phenotypic switches were accompanied by the increased expression of anti-inflammatory interleukin-4 receptor alpha and decreased proinflammatory interferon-gamma receptor beta. Finally, grafted hNSCs mainly differentiated into neurons and were phagocytized by either M1 or M2 microglia/macrophages. Thus, intracerebral transplantation of primed hNSCs efficiently leads host microglia/macrophages toward an anti inflammatory phenotype that presumably contributes to stem cell-mediated neuroprotective effects after severe TBI in mice. PMID- 26980268 TI - State of science: Choroidal thickness and systemic health. AB - The choroid is a highly vascular structure; therefore, a wide range of systemic conditions can affect it. Conversely, choroid health may also give us insight into systemic health. With the emergence of optical coherence tomography, there has been a surge in the research on choroidal thickness and factors affecting it. Studies regarding the effect of systemic health on the choroid have largely been in the form of cross-sectional, prospective, and case studies. We offer a summary of recent findings on the topic. PMID- 26980269 TI - Mass spectrometric analysis of accumulated TDP-43 in amyotrophic lateral sclerosis brains. AB - TDP-43 is the major disease-associated protein involved in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions linked to TDP-43 pathology (FTLD TDP). Abnormal phosphorylation, truncation and cytoplasmic mis-localization are known to be the characteristics for the aggregated forms of TDP-43, and gain of toxic abnormal TDP-43 or loss of function of physiological TDP-43 have been suggested as the cause of neurodegeneration. However, most of the post translational modifications or truncation sites in the abnormal TDP-43 in brains of patients remain to be identified by protein chemical analysis. In this study, we carried out a highly sensitive liquid chromatography-mass spectrometry analysis of Sarkosyl-insoluble pathological TDP-43 from brains of ALS patients and identified several novel phosphorylation sites, deamidation sites, and cleavage sites. Almost all modifications were localized in the Gly-rich C terminal half. Most of the cleavage sites identified in this study are novel and are located in N-terminal half, suggesting that these sites may be more accessible to proteolytic enzymes. The data obtained in this study provide a foundation for the molecular mechanisms of TDP-43 aggregation and ALS pathogenesis. PMID- 26980270 TI - Health Information Technology: Meaningful Use and Next Steps to Improving Electronic Facilitation of Medication Adherence. AB - BACKGROUND: The use of health information technology (HIT) may improve medication adherence, but challenges for implementation remain. OBJECTIVE: The aim of this paper is to review the current state of HIT as it relates to medication adherence programs, acknowledge the potential barriers in light of current legislation, and provide recommendations to improve ongoing medication adherence strategies through the use of HIT. METHODS: We describe four potential HIT barriers that may impact interoperability and subsequent medication adherence. Legislation in the United States has incentivized the use of HIT to facilitate and enhance medication adherence. The Health Information Technology for Economic and Clinical Health (HITECH) was recently adopted and establishes federal standards for the so called "meaningful use" of certified electronic health record (EHR) technology that can directly impact medication adherence. RESULTS: The four persistent HIT barriers to medication adherence include (1) underdevelopment of data reciprocity across clinical, community, and home settings, limiting the capture of data necessary for clinical care; (2) inconsistent data definitions and lack of harmonization of patient-focused data standards, making existing data difficult to use for patient-centered outcomes research; (3) inability to effectively use the national drug code information from the various electronic health record and claims datasets for adherence purposes; and (4) lack of data capture for medication management interventions, such as medication management therapy (MTM) in the EHR. Potential recommendations to address these issues are discussed. CONCLUSION: To make meaningful, high quality data accessible, and subsequently improve medication adherence, these challenges will need to be addressed to fully reach the potential of HIT in impacting one of our largest public health issues. PMID- 26980271 TI - Molecular simulations of cytochrome c adsorption on positively charged surfaces: the influence of anion type and concentration. AB - Contradictory results have been reported regarding cytochrome c (Cyt-c) adsorption onto the positively charged SAMs, and the role of small anions in the adsorption is still unclear. In this work, the adsorption of Cyt-c on the amino terminated SAM (NH2-SAM) and the effect of chloride and phosphate ions on the adsorption were studied using molecular dynamics simulations. The results reveal that Cyt-c could not stably adsorb onto the surface even at a relatively high ionic strength when chloride ions were added, while phosphate ions could promote its adsorption. At a low phosphate concentration, Cyt-c can adsorb on the NH2-SAM mainly with two opposite orientations. One is similar to that characterized in the experiments for Cyt-c adsorbed on the NH2-SAMs, in which the heme group points far away from the surface. The other orientation is similar to that for Cyt-c on the carboxyl-terminated SAMs. In the latter case, phosphate ions formed a distinct counterion layer near the surface and overcompensated the positive charge of the surface. Further analysis shows that chloride ions have no significant tendency to aggregate near the NH2-SAM surface and cannot shield the electrostatic repulsion between Cyt-c and the surface, while the phosphate ions can easily adsorb onto the surface and bind specifically to certain lysine residues of Cyt-c, which mediate its adsorption. At a high phosphate concentration, the phosphate and sodium ions will aggregate to form clusters, which results in random adsorption orientation. This work may provide some guidance for the design of Cyt-c-based bioelectronic devices and controlled enzyme immobilization. PMID- 26980272 TI - Sudden cardiac arrest following ventricular fibrillation attributed to anabolic steroid use in an adolescent. AB - Anabolic androgenic steroids are synthetic derivatives of testosterone that promote the growth of skeletal muscles and have many recognised cardiovascular effects. We report the clinical presentation and pathological findings of an adolescent male whose sudden cardiac arrest following ventricular fibrillation was attributed to anabolic androgenic steroid use. The age of our patient reflects the usage of anabolic androgenic steroids among younger athletes and highlights the need for increased awareness among practitioners. PMID- 26980273 TI - A relationship between three-dimensional surface hydration structures and force distribution measured by atomic force microscopy. AB - Hydration plays important roles in various solid-liquid interfacial phenomena. Very recently, three-dimensional scanning force microscopy (3D-SFM) has been proposed as a tool to visualise solvated surfaces and their hydration structures with lateral and vertical (sub) molecular resolution. However, the relationship between the 3D force map obtained and the equilibrium water density, rho(r), distribution above the surface remains an open question. Here, we investigate this relationship at an interface of an inorganic mineral, fluorite, and water. The force maps measured in pure water are directly compared to force maps generated using the solvent tip approximation (STA) model and from explicit molecular dynamics simulations. The results show that the simulated STA force map describes the major features of the experimentally obtained force image. The agreement between the STA data and the experiment establishes the correspondence between the water density used as an input to the STA model and the experimental hydration structure and thus provides a tool to bridge the experimental force data and atomistic solvation structures. Further applications of this method should improve the accuracy and reliability of both interpretation of 3D-SFM force maps and atomistic simulations in a wide range of solid-liquid interfacial phenomena. PMID- 26980274 TI - The chlorophyll a fluorescence induction curve in the green microalga Haematococcus pluvialis: further insight into the nature of the P-S-M fluctuation and its relationship with the "low-wave" phenomenon at steady-state. AB - Chlorophyll fluorescence is an information-rich signal which provides an access to the management of light absorbed by PSII. A good example of this is the succession of fast fluorescence fluctuations during light-induced photosynthetic induction after dark-adaptation. During this period, the fluorescence trace exhibits several inflexion points: O-J-I-P-S-M-T. Whereas the OJIP part of this kinetics has been the subject of many studies, the processes that underly the PSMT transient are less understood. Here, we report an analysis of the PSMT phase in the green microalga Haematococcus pluvialis in terms of electron acceptors and light use by photochemistry, fluorescence and non-photochemical quenching (NPQ). We identify additional sub-phases between P and S delimited by an inflexion point, that we name Q, found in the second time scale. The P-Q phase expresses a transient photochemical quenching specifically due to alternative electron transport to oxygen. During the transition from Q to S, the NPQ increases and then relaxes during the S-M phase in about 1 min. It is suggested that this transient NPQ observed during induction is a high energy state quenching (qE) dependent on the alternative electron transport to molecular oxygen. We further show that this NPQ is of the same nature than the NPQ, known as the low-wave phenomenon, which is transiently observed after a saturating light pulse given at steady-state. In both cases, the NPQ is oxygen-dependent. This NPQ is observed at external pH 6.0, but not at pH 7.5, which seems correlated with faster saturation of the PQ pool at pH 6.0. PMID- 26980277 TI - Cognitive Development and the Immediate Postconcussion Assessment and Cognitive Testing: A Case for Separate Norms in Preadolescents. AB - With youth sports participation and concern about sports-related concussions both on the rise, it is important to properly measure cognitive function to ensure the clinical utility of baseline testing. Computerized testing batteries are often employed as baseline and postinjury measures of cognitive function, with the Immediate Postconcussion Assessment and Cognitive Testing (ImPACT) being the most used of all the current testing platforms. The current study compared 10- to 12 year-old children across the composite scores yielded by the ImPACT and provided normative data on each of the subtests used to calculate the composite scores. Normative data are separated by gender for athletes aged 10 to 12 years old, as this is the current age bracket used by the ImPACT. These norms may be helpful in the interpretation of the ImPACT clinical report and further delineation of areas of neurocognitive dysfunction. PMID- 26980276 TI - miR-33-5p, a novel mechano-sensitive microRNA promotes osteoblast differentiation by targeting Hmga2. AB - MicroRNAs (miRNAs) interfere with the translation of specific target mRNAs and are thought to thereby regulate many cellular processes. However, the role of miRNAs in osteoblast mechanotransduction remains to be defined. In this study, we investigated the ability of a miRNA to respond to different mechanical environments and regulate mechano-induced osteoblast differentiation. First, we demonstrated that miR-33-5p expressed by osteoblasts is sensitive to multiple mechanical environments, microgravity and fluid shear stress. We then confirmed the ability of miR-33-5p to promote osteoblast differentiation. Microgravity or fluid shear stress influences osteoblast differentiation partially via miR-33-5p. Through bioinformatics analysis and a luciferase assay, we subsequently confirmed that Hmga2 is a target gene of miR-33-5p that negatively regulates osteoblast differentiation. Moreover, miR-33-5p regulates osteoblast differentiation partially via Hmga2. In summary, our findings demonstrate that miR-33-5p is a novel mechano-sensitive miRNA that can promote osteoblast differentiation and participate in the regulation of differentiation induced by changes in the mechanical environment, suggesting this miRNA as a potential target for the treatment of pathological bone loss. PMID- 26980278 TI - Molecular dynamics simulations reveal the balance of forces governing the formation of a guanine tetrad-a common structural unit of G-quadruplex DNA. AB - G-quadruplexes (G4) are nucleic acid conformations of guanine-rich sequences, in which guanines are arranged in the square-planar G-tetrads, stacked on one another. G4 motifs formin vivoand are implicated in regulation of such processes as gene expression and chromosome maintenance. The structure and stability of various G4 topologies were determined experimentally; however, the driving forces for their formation are not fully understood at the molecular level. Here, we used all-atom molecular dynamics to probe the microscopic origin of the G4 motif stability. By computing the free energy profiles governing the dissociation of the 3'-terminal G-tetrad in the telomeric parallel-stranded G4, we examined the thermodynamic and kinetic stability of a single G-tetrad, as a common structural unit of G4 DNA. Our results indicate that the energetics of guanine association alone does not explain the overall stability of the G-tetrad and that interactions involving sugar-phosphate backbone, in particular, the constrained minimization of the phosphate-phosphate repulsion energy, are crucial in providing the observed enthalpic stabilization. This enthalpic gain is largely compensated by the unfavorable entropy change due to guanine association and optimization of the backbone topology. PMID- 26980280 TI - f-divergence cutoff index to simultaneously identify differential expression in the integrated transcriptome and proteome. AB - The ability to integrate 'omics' (i.e. transcriptomics and proteomics) is becoming increasingly important to the understanding of regulatory mechanisms. There are currently no tools available to identify differentially expressed genes (DEGs) across different 'omics' data types or multi-dimensional data including time courses. We present fCI (f-divergence Cut-out Index), a model capable of simultaneously identifying DEGs from continuous and discrete transcriptomic, proteomic and integrated proteogenomic data. We show that fCI can be used across multiple diverse sets of data and can unambiguously find genes that show functional modulation, developmental changes or misregulation. Applying fCI to several proteogenomics datasets, we identified a number of important genes that showed distinctive regulation patterns. The package fCI is available at R Bioconductor and http://software.steenlab.org/fCI/. PMID- 26980279 TI - Using structural-based protein engineering to modulate the differential inhibition effects of SAUGI on human and HSV uracil DNA glycosylase. AB - Uracil-DNA glycosylases (UDGs) are highly conserved proteins that can be found in a wide range of organisms, and are involved in the DNA repair and host defense systems. UDG activity is controlled by various cellular factors, including the uracil-DNA glycosylase inhibitors, which are DNA mimic proteins that prevent the DNA binding sites of UDGs from interacting with their DNA substrate. To date, only three uracil-DNA glycosylase inhibitors, phage UGI, p56, and Staphylococcus aureus SAUGI, have been determined. We show here that SAUGI has differential inhibitory effects on UDGs from human, bacteria, Herpes simplex virus (HSV; human herpesvirus 1) and Epstein-Barr virus (EBV; human herpesvirus 4). Newly determined crystal structures of SAUGI/human UDG and a SAUGI/HSVUDG complex were used to explain the differential binding activities of SAUGI on these two UDGs. Structural-based protein engineering was further used to modulate the inhibitory ability of SAUGI on human UDG and HSVUDG. The results of this work extend our understanding of DNA mimics as well as potentially opening the way for novel therapeutic applications for this kind of protein. PMID- 26980281 TI - Oxidized dNTPs and the OGG1 and MUTYH DNA glycosylases combine to induce CAG/CTG repeat instability. AB - DNA trinucleotide repeat (TNR) expansion underlies several neurodegenerative disorders including Huntington's disease (HD). Accumulation of oxidized DNA bases and their inefficient processing by base excision repair (BER) are among the factors suggested to contribute to TNR expansion. In this study, we have examined whether oxidation of the purine dNTPs in the dNTP pool provides a source of DNA damage that promotes TNR expansion. We demonstrate that during BER of 8 oxoguanine (8-oxodG) in TNR sequences, DNA polymerase beta (POL beta) can incorporate 8-oxodGMP with the formation of 8-oxodG:C and 8-oxodG:A mispairs. Their processing by the OGG1 and MUTYH DNA glycosylases generates closely spaced incisions on opposite DNA strands that are permissive for TNR expansion. Evidence in HD model R6/2 mice indicates that these DNA glycosylases are present in brain areas affected by neurodegeneration. Consistent with prevailing oxidative stress, the same brain areas contained increased DNA 8-oxodG levels and expression of the p53-inducible ribonucleotide reductase. Our in vitro and in vivo data support a model where an oxidized dNTPs pool together with aberrant BER processing contribute to TNR expansion in non-replicating cells. PMID- 26980283 TI - De novo reconstruction of DNA origami structures through atomistic molecular dynamics simulation. AB - The DNA origami method has brought nanometer-precision fabrication to molecular biology labs, offering myriads of potential applications in the fields of synthetic biology, medicine, molecular computation, etc. Advancing the method further requires controlling self-assembly down to the atomic scale. Here we demonstrate a computational method that allows the equilibrium structure of a large, complex DNA origami object to be determined to atomic resolution. Through direct comparison with the results of cryo-electron microscopy, we demonstrate de novo reconstruction of a 4.7 megadalton pointer structure by means of fully atomistic molecular dynamics simulations. Furthermore, we show that elastic network-guided simulations performed without solvent can yield similar accuracy at a fraction of the computational cost, making this method an attractive approach for prototyping and validation of self-assembled DNA nanostructures. PMID- 26980284 TI - Controllable Hysteresis and Threshold Voltage of Single-Walled Carbon Nano-tube Transistors with Ferroelectric Polymer Top-Gate Insulators. AB - Double-gated field effect transistors have been fabricated using the SWCNT networks as channel layer and the organic ferroelectric P(VDF-TrFE) film spin coated as top gate insulators. Standard photolithography process has been adopted to achieve the patterning of organic P(VDF-TrFE) films and top-gate electrodes, which is compatible with conventional CMOS process technology. An effective way for modulating the threshold voltage in the channel of P(VDF-TrFE) top-gate transistors under polarization has been reported. The introduction of functional P(VDF-TrFE) gate dielectric also provides us an alternative method to suppress the initial hysteresis of SWCNT networks and obtain a controllable ferroelectric hysteresis behavior. Applied bottom gate voltage has been found to be another effective way to highly control the threshold voltage of the networked SWCNTs based FETs by electrostatic doping effect. PMID- 26980282 TI - Arabidopsis DNA polymerase epsilon recruits components of Polycomb repressor complex to mediate epigenetic gene silencing. AB - Arabidopsis ESD7 locus encodes the catalytic subunit of the DNA Pol epsilon involved in the synthesis of the DNA leading strand and is essential for embryo viability. The hypomorphic allele esd7-1 is viable but displays a number of pleiotropic phenotypic alterations including an acceleration of flowering time. Furthermore, Pol epsilon is involved in the epigenetic silencing of the floral integrator genes FT and SOC1, but the molecular nature of the transcriptional gene silencing mechanisms involved remains elusive. Here we reveal that ESD7 interacts with components of the PRC2 such as CLF, EMF2 and MSI1, and that mutations in ESD7 cause a decrease in the levels of the H3K27me3 mark present in the chromatin of FT and SOC1 We also demonstrate that a domain of the C-terminal region of ESD7 mediates the binding to the different PRC2 components and this interaction is necessary for the proper recruitment of PRC2 to FT and SOC1 chromatin. We unveil the existence of interplay between the DNA replication machinery and the PcG complexes in epigenetic transcriptional silencing. These observations provide an insight into the mechanisms ensuring that the epigenetic code at pivotal loci in developmental control is faithfully transmitted to the progeny of eukaryotic cells. PMID- 26980285 TI - Classification of Human Pregnane X Receptor (hPXR) Activators and Non-Activators by Machine Learning Techniques: A Multifaceted Approach. AB - The Human Pregnane X Receptor (hPXR) is a regulator of drug metabolising enzymes (DME) and efflux transporters (ET). The prediction of hPXR activators and non activators has pharmaceutical importance to predict the multiple drug resistance (MDR) and drug-drug interactions (DDI). In this study, we developed and validated the computational prediction models to classify hPXR activators and non activators. We employed four machine learning methods support vector machine (SVM), k-nearest neighbour (k-NN), random forest (RF) and naive bayesian (NB). These methods were used to develop molecular and fingerprint based descriptors for the prediction of hPXR activators and non-activators. Total 529 molecules consitsting of 317 activators and 212 non-activators were used for model development. The overall prediction accuracy of models was 69% to 99% to classify hPXR activators and nonactivators using RDkit descriptors. In case of 5 and 10 fold cross validation the prediction accuracy for training set is 74% to 82% and 79% to 83% for hPXR activators respectively and 50% to 62% and 49% to 65% non activators, respectively. The external test prediction is between 59% to 73% for hPXR activators and 55% to 68% for hPXR non-activators. In addition, consensus models were developed in which the best model shows overall 75% to 83% accuracy for fingerprint and RDkit descriptors, respectively. The best developed model will be utilized for the prediction of hPXR activators and non-activators. PMID- 26980286 TI - Characterization of Seven New Polystyrene Plates Binding Peptides from a Phage Displayed Random 12-Peptide Library. AB - A random 12-peptide library was screened against Erysipelothrix rhusiopthiae and porcine circovirus 2 recombinant Cap protein and the selected peptides were used for detecting the corresponding pathogens quickly and effectively. To our surprise, seven peptides, P1 (WHWNAP WWNGVY), P2 (FHWTWQFPYTST), P3 (GAMHLPWHMGTL), P4 (HWNIWWQHHPSP), P5 (HFFKWHTRTNDQ), P6 (HFFRWHPSAHLG) and P7 (HFAYWWNGVRGP) with the characteristics of polystyrene plate (PS) binding target unrelated peptides (TUPs), were selected from the library. It has been found that P2 and P4 shared common motif of plastic binding peptide, moreover, P2, P3, P5 and P7 have been isolated repeatedly in other research groups using different targets. Then, the seven peptide phage clones were identified as the PS binding TUP phages by phage-ELISA and elution titration, particularly, P1 and P2 showed strong PS binding affinity which can not be inhibited by usual blocking buffers. In addition, all of the phages were not propagation-related TUP, but P3 showed the similar propagation rate with M13KE (vector phage). We also found that the seven PS-TUPs are rich in W, H, F, P and G, particularly, both W and H are contained in all PS-TUPs. It deduced that they may play a potential role in peptide binding to plastic. Although it is difficult to eliminate the TUP phages in phage display completely, these PS-TUPs can be used to exclude the false positive peptides rapidly and effectively and help us to obtain truly interesting peptides more accurately. PMID- 26980287 TI - Test-retest reproducibility of the Assessment of Motor and Process Skills for school-aged children with acquired brain injuries. AB - Background Persistent impairments resulting from childhood acquired brain injury (ABI) can impact performance of activities of daily living (ADL). Objective and reliable measures of ADL skills are required for treatment planning and research. Aim To evaluate test-retest reproducibility of the Assessment of Motor and Process Skills (AMPS) for children with ABI. Methods Twenty-eight children with ABI (mean age 11 years 7 months, SD 2 years 4 months; males = 11) were recruited. Two AMPS tasks were performed over two consecutive days, as per standardized AMPS procedures. Intraclass correlation coefficients (ICC; 2,1), standard error of measurement (SEM), smallest detectable difference (SDD), and 95% limits of agreement (Bland-Altman) were calculated. Results Test-retest reliability was fair to good for AMPS ADL motor (ICC 0.55) and ADL process (ICC 0.58) measures. The SEM was 0.36 and 0.34 logits for AMPS ADL motor and ADL process measures respectively. The SDD was 1.0 (motor) and 0.93 logits (process) measures. A learning effect was evident. Conclusion Test-retest reproducibility of the AMPS was fair to good for children with ABI, which is poorer than previously published data. Administration of the AMPS in an unfamiliar environment, fatigue, and the small time interval between testing sessions may have contributed to poorer results. The AMPS remains a useful measure of ADL, contributing to our understanding of task execution processes. PMID- 26980288 TI - Synergistic cytotoxicity of busulfan, melphalan, gemcitabine, panobinostat, and bortezomib in lymphoma cells. AB - DNA alkylators busulfan (B) and melphalan (M) act synergistically with gemcitabine (G) against lymphoma cells. To further improve the cytotoxicity, we combined them with the histone deacetylase inhibitor panobinostat (P) and proteasome inhibitor bortezomib (V). Lymphoma cell lines U937 and J45.01, and patient-derived cell samples were exposed to these drugs and the effects on cell proliferation and apoptosis were quantified. The combination BMGPV was found to exert strong synergistic cytotoxicity. Drug exposure to these cells activated the ATM pathway and modified histones at the epigenetic level. Cell death was triggered by the production of reactive oxygen species (ROS), permeabilization of the mitochondrial membrane, upregulation of proapoptotic factors, and activation of caspases. Downregulation of anti-apoptotic proteins c-MYC, MCL-1, and BCL-2 and inhibition of the prosurvival PI3K-AKT-mTOR pathway, culminated in apoptosis. The results of this study support a clinical trial using BMGPV as a possible pre transplant conditioning regimen for relapsed/refractory lymphoma patients. PMID- 26980289 TI - A comparison of no-slip, stress-free and inviscid models of rapidly rotating fluid in a spherical shell. AB - We investigate how the choice of either no-slip or stress-free boundary conditions affects numerical models of rapidly rotating flow in Earth's core by computing solutions of the weakly-viscous magnetostrophic equations within a spherical shell, driven by a prescribed body force. For non-axisymmetric solutions, we show that models with either choice of boundary condition have thin boundary layers of depth E(1/2), where E is the Ekman number, and a free-stream flow that converges to the formally inviscid solution. At Earth-like values of viscosity, the boundary layer thickness is approximately 1 m, for either choice of condition. In contrast, the axisymmetric flows depend crucially on the choice of boundary condition, in both their structure and magnitude (either E(-1/2) or E(-1)). These very large zonal flows arise from requiring viscosity to balance residual axisymmetric torques. We demonstrate that switching the mechanical boundary conditions can cause a distinct change of structure of the flow, including a sign-change close to the equator, even at asymptotically low viscosity. Thus implementation of stress-free boundary conditions, compared with no-slip conditions, may yield qualitatively different dynamics in weakly-viscous magnetostrophic models of Earth's core. We further show that convergence of the free-stream flow to its asymptotic structure requires E <= 10(-5). PMID- 26980290 TI - The reaction times of drivers aged 20 to 80 during a divided attention driving. AB - OBJECTIVE: Many studies addressing age-related changes in driving performance focus on comparing young vs. older drivers, which might lead to the biased conclusion that driving performance decreases only after the age of 65. The main aim of the study was to show that changes in driving performance are progressive throughout the adult years. METHODS: A sample of 351 drivers aged 20 to 80 was assessed for their reaction times while driving between road cones. The drivers were exposed to 2 conditions varying according to task complexity. In single task conditions, the drivers performed a full stopping maneuver at a given signal; in dual task conditions, the drivers were distracted before the signal for stopping maneuver was triggered. Reaction times were compared across conditions and age groups. RESULTS: The results showed that both reaction times and variability of driving performance increased progressively between the ages of 20 and 80. The increase in both reaction times and variability was greater in the complex task condition. The high-performing quarter of elderly drivers performed equally well or better than younger drivers did. CONCLUSIONS: The data clearly supported the claim that driving performance changes steadily across age groups: both mean reaction time and interindividual variability progressively increase with age. In addition, a significant group of older drivers was identified who did not show the expected age-related decrease in performance. The findings have important implications, suggesting that in relation to driving, aging is a progressive phenomenon and may lead to variety of driving performance; age-related studies of driving performance should put more emphasis on investigating changes across the whole driver age range rather than only comparing younger and older drivers. PMID- 26980291 TI - Fetuin A is a Predictor of Liver Fat in Preoperative Patients with Nonalcoholic Fatty Liver Disease. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are frequent comorbidities in perioperative patients. However, the predictive role of the hepatokine fetuin A was not evaluated in this collective. OBJECTIVE: To study fetuin A as predictor of NAFLD/NASH in preoperative patients. METHODS: 58 subjects were included. Fetuin A was studied in patients undergoing open abdominal surgery and in a subset with acute liver failure. Blood and liver specimens were sampled. NAFLD was histologically evaluated. Liver fat was additionally analyzed by an enzymatic approach, circulating fetuin A by enzyme linked-immunosorbent assay, fetuin A mRNA by reverse-transcription PCR. RESULTS: Univariate correlation studies linked fetuin A to liver steatosis (r = 0.40, p = .029) and hepatocellular ballooning degeneration (r = 0.34, p = .026). Compared to non-NAFLD subjects fetuin A was increased in NAFLD (p = .009) and in NASH (p = .029). However, when corrected for main confounders by linear modeling, fetuin A remained related to hepatic steatosis, but not to ballooning degeneration or other NAFLD features. In support of this, biochemically analyzed liver lipids correlated with fetuin A in plasma (r = 0.34, p = .033) and with hepatic fetuin A mRNA (r = 0.54, p < .001). In addition, plasma fetuin A was related to hepatic mRNA (r = 0.32, p = .036), while circulating levels were reduced by 64% with acute liver failure (p < .001), confirming the liver as main fetuin A source. CONCLUSION: Fetuin A is suggested as noninvasive biomarker of hepatic steatosis in preoperative settings. PMID- 26980294 TI - David Oliver: Resuscitation orders and reality. PMID- 26980293 TI - Advantages of pure platelet-rich plasma compared with leukocyte- and platelet rich plasma in promoting repair of bone defects. AB - BACKGROUND: High levels of pro-inflammatory cytokines in leukocyte- and platelet rich plasma (L-PRP) may activate the nuclear factor kappaB (NF-kappaB) pathway to counter the beneficial effect of the growth factors on bone regeneration. However, to date, no relevant studies have substantiated this. METHODS: L-PRP and pure platelet-rich plasma (P-PRP) were isolated. The in vitro effects of L-PRP and P-PRP on the proliferation, viability and migration of human bone marrow derived mesenchymal stem cells (HBMSCs) and EaHy926, tube formation of EaHy926, and osteogenic differentiation of HBMSCs were assessed by cell counting, flow cytometry, scratch assay, tube formation assay, and real-time quantitative polymerase chain reaction (RT-PCR), western blotting and Alizarin red staining, respectively. The in vitro effects of L-PRP and P-PRP on the nuclear translocation of NF-kappaB p65, mRNA expression of inducible nitric oxide synthase and cyclooxygenase-2, and production of prostaglandin E2 and nitric oxid were assessed by western blotting, RT-PCR, enzyme-linked immunosorbent assay and Griess reaction, respectively. The in vivo effects of L-PRP or P-PRP preprocessed beta-tricalcium phosphate (beta-TCP) on the calvarial defects in rats were assessed by histological and immunofluorescence examinations. RESULTS: P-PRP, which had similar platelet and growth factors concentrations but significantly lower concentrations of leukocytes and pro-inflammatory cytokines compared with L PRP, promoted the proliferation, viability and migration of HBMSCs and EaHy926, tube formation of EaHy926 and osteogenic differentiation of HBMSCs in vitro, compared with L-PRP. The implantation of P-PRP preprocessed beta-TCP also yielded better histological results than the implantation of L-PRP preprocessed beta-TCP in vivo. Moreover, L-PRP treatment resulted in the activation of the NF-kappaB pathway in HBMSCs and EaHy926 in vitro while the postoperative delivery of caffeic acid phenethyl ester, an inhibitor of NF-kappaB activation, enhanced the histological results of the implantation of L-PRP preprocessed beta-TCP in vivo. CONCLUSIONS: Leukocytes in L-PRP may activate the NF-kappaB pathway via the increased pro-inflammatory cytokines to induce the inferior effects on bone regeneration of L-PRP compared with P-PRP. Hence, P-PRP may be more suitable for bone regeneration compared with L-PRP, and the combined use of P-PRP and beta-TCP represents a safe, simple, and effective alternative option for autogenous bone graft in the treatment of bone defects. PMID- 26980296 TI - Targeted next-generation sequencing identification of mutations in patients with disorders of sex development. AB - BACKGROUND: The identification of causative mutations is important for treatment decisions and genetic counseling of patients with disorders of sex development (DSD). Here, we designed a new assay based on targeted next-generation sequencing (NGS) to diagnose these genetically heterogeneous disorders. METHODS: All coding regions and flanking sequences of 219 genes implicated in DSD were designed to be included on a panel. A total of 45 samples were used for sex chromosome dosage validation by targeted sequencing using the NGS platform. Among these, 21 samples were processed to find the causative mutation. RESULTS: The sex chromosome dosages of all 45 samples in this assay were concordant with their corresponding karyotyping results. Among the 21 DSD patients, a total of 11 mutations in SRY, NR0B1, AR, CYP17A1, GK, CHD7, and SRD5A2 were identified, including five single nucleotide variants, three InDels, one in-frame duplication, one SRY-positive 46,XX, and one gross duplication with an estimated size of more than 427,038 bp containing NR0B1 and GK. We also identified six novel mutations: c.230_231insA in SRY, c.7389delA in CHD7, c.273C>G in NR0B1, and c.2158G>A, c.1825A>G, and c.2057_2065dupTGTGTGCTG in AR. CONCLUSIONS: Our assay was able to make a genetic diagnosis for eight DSD patients (38.1%), and identified variants of uncertain clinical significance in the other three cases (14.3%). Targeted NGS is therefore a comprehensive and efficient method to diagnose DSD. This work also expands the pathogenic mutation spectrum of DSD. PMID- 26980295 TI - Impact of conditioning intensity in T-replete haplo-identical stem cell transplantation for acute leukemia: a report from the acute leukemia working party of the EBMT. AB - BACKGROUND: Increasing numbers of patients are receiving haplo-identical stem cell transplantation (haplo-SCT) for treatment of acute leukemia with reduced intensity (RIC) or myeloablative (MAC) conditioning regimens. The impact of conditioning intensity in haplo-SCT is unknown. METHODS: We performed a retrospective registry-based study comparing outcomes after T-replete haplo-SCT for patients with acute myeloid (AML) or lymphoid leukemia (ALL) after RIC (n = 271) and MAC (n = 425). Regimens were classified as MAC or RIC based on published criteria. RESULTS: A combination of post-transplant cyclophosphamide (PT-Cy) with one calcineurin inhibitor and mycophenolate mofetil (PT-Cy-based regimen) for graft-versus-host disease (GVHD) prophylaxis was used in 66 (25%) patients in RIC and 125 (32%) in MAC groups. Patients of RIC group were older and had been transplanted more recently and more frequently for AML with active disease at transplant. Percentage of engraftment (90 vs. 92%; p = 0.58) and day 100 grade II to IV acute GVHD (24 vs. 29%, p = 0.23) were not different between RIC and MAC groups. Multivariable analyses, run separately in AML and ALL, showed a trend toward higher relapse incidence with RIC in comparison to MAC in AML (hazard ratio (HR) 1.34, p = 0.09), and no difference in both AML and ALL in terms of non relapse mortality (NRM) chronic GVHD and leukemia-free survival. There was no impact of conditioning regimen intensity in overall survival (OS) in AML (HR = 0.97, p = 0.79) but a trend for worse OS with RIC in ALL (HR = 1.44, p = 0.10). The main factor impacting outcomes was disease status at transplantation (HR >= 1.4, p <= 0.01). GVHD prophylaxis with PT-Cy-based regimen was independently associated with reduced NRM (HR 0.63, p = 0.02) without impact on relapse incidence (HR 0.99, p = 0.94). CONCLUSIONS: These data suggest that T-replete haplo-SCT with both RIC and MAC, in particular associated with PT-Cy, are valid options in first line treatment of high risk AML or ALL. PMID- 26980297 TI - [An unusual outcome in a patient with acute tonsillitis]. PMID- 26980298 TI - Genomic Alterations of Anaplastic Thyroid Carcinoma Detected by Targeted Massive Parallel Sequencing in a BRAF(V600E) Mutation-Prevalent Area. AB - BACKGROUND: Anaplastic thyroid carcinoma (ATC), the most aggressive type of thyroid cancer, has no effective therapy. Due to its dismal prognosis, it is vital to understand the genetic alterations of ATC and identify effective molecular targets. Targeted next-generation sequencing was performed to investigate the mutational profile of ATC using a massive parallel sequencing approach. METHODS: DNA from formalin-fixed, paraffin-embedded archival samples of 11 ATCs and normal matched pairs were used. A total of 48 genetic alterations were identified by targeted exome sequencing. These alterations were validated by mass spectrometric genotyping and direct Sanger sequencing. RESULTS: The most commonly mutated gene was BRAF, identified in 10 samples (91%), all showing the V600E point mutation. A KRAS point mutation was observed in the one sample (9%) without the BRAF(V600E) mutation. All 11 ATCs harbored BRAF or RAS mutations, reflecting the possibility that differentiated thyroid carcinomas progress to ATCs after the accumulation of mutations. A loss of function mutation of TP53 was observed in eight samples (73%), a PIK3CA mutation was observed in two samples (18%), and a frameshift mutation of PTEN was observed in one sample (9%). Twenty eight novel mutated genes were found that had not previously been associated with ATC. Of these, loss of function mutations of NF2, KMT2D, and PKHD1 were repeatedly seen in three samples (27%), two samples (18%), and two samples (18%), respectively. Using direct Sanger sequencing, two samples (18%) were also found with a RASAL1 mutation. KMT2D and RASAL1 mutations were significantly associated with shorter ATC patient survival. CONCLUSIONS: This comprehensive analysis of ATCs using targeted massive parallel sequencing identified several novel mutations in ATCs, such as loss of function mutations of NF2 or KMT2D. Future studies are needed to confirm the role of these novel mutations as independent drivers of ATC development. PMID- 26980299 TI - Incidence of Hip Fracture in U.S. Nursing Homes. AB - BACKGROUND: Hip fractures are associated with significant morbidity and mortality in the nursing home. Our objective was to describe the incidence rate (IR) of hip fracture according to age, sex, and race in a nationwide sample of long-stay nursing home residents. METHODS: Using 2007-2010 Medicare claims data linked with the Minimum Data Set, we identified 892,837 long-stay residents (>=100 days in the same nursing facility) between May 1, 2007 and April 30, 2008. Hip fractures were defined using Part A diagnostic codes (ICD-9). Residents were followed from the date they became a long-stay resident until the first event of death, discharge, hip fracture, or 2 years of follow-up. RESULTS: Mean age was 84 years (range 65-113 years), and 74.5% were women. 83.9% were white and 12.0% were black. The overall IR of hip fracture was 2.3/100 person years. The IR was similar in men and women across age groups. The IR of hip fracture was highest in Native Americans aged 85 years or older (3.7/100 person years), in whites (2.6/100 person years), and during the first 100 days of institutionalization (2.7/100 person years). IRs of hip fracture were lowest in blacks (1.3/100 person years). CONCLUSIONS: In nursing home residents surviving 100 days or more in a facility, the incidence of hip fracture is high, particularly among older white, Native American, and newly admitted residents. This is the first nationwide study to provide sex- and age-specific estimates among U.S. nursing home residents, and it underscores the magnitude of the problem. PMID- 26980301 TI - High gamma-aminobutyric acid production from lactic acid bacteria: Emphasis on Lactobacillus brevis as a functional dairy starter. AB - gamma-Aminobutyric acid (GABA) and GABA-rich foods have shown anti-hypertensive and anti-depressant activities as the major functions in humans and animals. Hence, high GABA-producing lactic acid bacteria (LAB) could be used as functional starters for manufacturing novel fermented dairy foods. Glutamic acid decarboxylases (GADs) from LAB are highly conserved at the species level based on the phylogenetic tree of GADs from LAB. Moreover, two functionally distinct GADs and one intact gad operon were observed in all the completely sequenced Lactobacillus brevis strains suggesting its common capability to synthesize GABA. Difficulties and strategies for the manufacture of GABA-rich fermented dairy foods have been discussed and proposed, respectively. In addition, a genetic survey on the sequenced LAB strains demonstrated the absence of cell envelope proteinases in the majority of LAB including Lb. brevis, which diminishes their cell viabilities in milk environments due to their non-proteolytic nature. Thus, several strategies have been proposed to overcome the non-proteolytic nature of Lb. brevis in order to produce GABA-rich dairy foods. PMID- 26980302 TI - Tipping the Balance: Hepatotoxicity and the 4 Apical Key Events of Hepatic Steatosis. AB - Hepatic steatosis is a condition were fat accumulates in the liver and it is associated with extra-hepatic diseases related to metabolic syndrome and systemic energy metabolism. If not reversed, steatosis can progress to steatohepatitis and irreversible stages of liver disease including fibrosis, cirrhosis, hepatocellular carcinoma, and death. From a public health standpoint, identifying chemical exposures that may be factors in steatosis etiology are important for preventing hepatotoxicity and liver disease progression. It is therefore important to identify the biological events that are key for steatosis pathology mediated by chemical exposure. In this review, we give a current overview of the complex biological cascades that can disrupt lipid homeostasis in hepatocytes in the context of 4 apical key events central to hepatic lipid retention: hepatic fatty acid (FA) uptake,de novoFA and lipid synthesis, FA oxidation, and lipid efflux. Our goal is to review these key cellular events and visually summarize them using a network for application in pathway-based toxicity testing. This effort provides a foundation to improve next-generation chemical screening efforts that may be used to prevent and ultimately reverse the growing incidence of fatty liver disease in our population. PMID- 26980300 TI - Proteome distribution between nucleoplasm and nucleolus and its relation to ribosome biogenesis in Arabidopsis thaliana. AB - Ribosome biogenesis is an essential process initiated in the nucleolus. In eukaryotes, multiple ribosome biogenesis factors (RBFs) can be found in the nucleolus, the nucleus and in the cytoplasm. They act in processing, folding and modification of the pre-ribosomal (r)RNAs, incorporation of ribosomal proteins (RPs), export of pre-ribosomal particles to the cytoplasm, and quality control mechanisms. Ribosome biogenesis is best established for Saccharomyces cerevisiae. Plant ortholog assignment to yeast RBFs revealed the absence of about 30% of the yeast RBFs in plants. In turn, few plant specific proteins have been identified by biochemical experiments to act in plant ribosome biogenesis. Nevertheless, a complete inventory of plant RBFs has not been established yet. We analyzed the proteome of the nucleus and nucleolus of Arabidopsis thaliana and the post translational modifications of these proteins. We identified 1602 proteins in the nucleolar and 2544 proteins in the nuclear fraction with an overlap of 1429 proteins. For a randomly selected set of proteins identified by the proteomic approach we confirmed the localization inferred from the proteomics data by the localization of GFP fusion proteins. We assigned the identified proteins to various complexes and functions and found about 519 plant proteins that have a potential to act as a RBFs, but which have not been experimentally characterized yet. Last, we compared the distribution of RBFs and RPs in the various fractions with the distribution established for yeast. PMID- 26980303 TI - Sulfur Dioxide Contributes to the Cardiac and Mitochondrial Dysfunction in Rats. AB - Epidemiological studies have demonstrated an association between sulfur dioxide (SO2) and an increase of morbidity and mortality of cardiovascular diseases, such as ischemic heart disease, heart failure, and arrhythmia. Mitochondrion is the most sensitive organelle in myocardium of animals exposed to SO2 Here we study the molecular characterization of mitochondrial dysfunction in cardiac muscles of rat after SO2 exposure. We found that the cytochrome c oxidase (COX) activity, mitochondrial membrane potential (DeltaPsim), ATP contents, mitochondrial DNA (mtDNA) contents, and mRNA expression of complexes IV and V subunits encoded by mtDNA were decreased after NaHSO3 treatment in vitro or SO2 inhalation in vivo The mitochondrial dysfunctions were accompanied by depressions of co-activator of peroxisome proliferator activated receptor gamma (PGC-1alpha), nuclear respiratory factor 1, and mitochondrial transcription factor A (TFAM) mRNA and protein. We observed swollen mitochondria and lower amounts of cristae in hearts of rats after 3.5 mg/m(3) SO2 inhalation for 30 days. Interestingly, NaHSO3 induced mitochondrial dysfunctions marked by DeltaPsim and ATP reduction could be inhibited by an antioxidant N-acetyl-L-cysteine (NALC), accompanied by the restoration of transcriptional factors expressions. The cardiac mitochondrial dysfunctions could also be alleviated by overexpression of TFAM. SO2 induced abnormal left ventricular function was restored by NALC in vivo Our findings demonstrate that SO2 induces cardiac and mitochondrial dysfunction. And inhibition of reactive oxygen species and enhancing the transcriptional network controlling mitochondrial biogenesis can mitigate the SO2-induced mitochondrial dysfunction. PMID- 26980304 TI - Enhancing Important Fluctuations: Rare Events and Metadynamics from a Conceptual Viewpoint. AB - Atomistic simulations play a central role in many fields of science. However, their usefulness is often limited by the fact that many systems are characterized by several metastable states separated by high barriers, leading to kinetic bottlenecks. Transitions between metastable states are thus rare events that occur on significantly longer timescales than one can simulate in practice. Numerous enhanced sampling methods have been introduced to alleviate this timescale problem, including methods based on identifying a few crucial order parameters or collective variables and enhancing the sampling of these variables. Metadynamics is one such method that has proven successful in a great variety of fields. Here we review the conceptual and theoretical foundations of metadynamics. As demonstrated, metadynamics is not just a practical tool but can also be considered an important development in the theory of statistical mechanics. PMID- 26980305 TI - Recent Advances in Quantum Dynamics of Bimolecular Reactions. AB - In this review, we survey the latest advances in theoretical understanding of bimolecular reaction dynamics in the past decade. The remarkable recent progress in this field has been driven by more accurate and efficient ab initio electronic structure theory, effective potential-energy surface fitting techniques, and novel quantum scattering algorithms. Quantum mechanical characterization of bimolecular reactions continues to uncover interesting dynamical phenomena in atom-diatom reactions and beyond, reaching an unprecedented level of sophistication. In tandem with experimental explorations, these theoretical developments have greatly advanced our understanding of key issues in reaction dynamics, such as microscopic reaction mechanisms, mode specificity, product energy disposal, influence of reactive resonances, and nonadiabatic effects. PMID- 26980306 TI - Gas-Phase Femtosecond Particle Spectroscopy: A Bottom-Up Approach to Nucleotide Dynamics. AB - We summarize how gas-phase ultrafast charged-particle spectroscopy has been used to provide an understanding of the photophysics of DNA building blocks. We focus on adenine and discuss how, following UV excitation, specific interactions determine the fates of its excited states. The dynamics can be probed using a systematic bottom-up approach that provides control over these interactions and that allows ever-larger complexes to be studied. Starting from a chromophore in adenine, the excited state decay mechanisms of adenine and chemically substituted or clustered adenine are considered and then extended to adenosine mono-, di-, and trinucleotides. We show that the gas-phase approach can offer exquisite insight into the dynamics observed in aqueous solution, but we also highlight stark differences. An outlook is provided that discusses some of the most promising developments in this bottom-up approach. PMID- 26980307 TI - Geochemical Insight from Nonlinear Optical Studies of Mineral-Water Interfaces. AB - The physics and chemistry of mineral-water interfaces are complex, even in idealized systems. Our need to understand this complexity is driven by both pure and applied sciences, that is, by the need for basic understanding of earth systems and for the knowledge to mitigate our influences upon them. The second order nonlinear optical techniques of second-harmonic generation and sum frequency generation spectroscopy have proven adept at probing these types of interfaces. This review focuses on the contributions to geochemistry made by nonlinear optical methods. The types of questions probed have included a basic description of the structure adopted by water molecules at the mineral interface, how flow and porosity affect this structure, adsorption of trace metal and organic species, and dissolution mechanisms. We also discuss directions and challenges that lie ahead and the outlook for the continued use of nonlinear optical methods for studies of mineral-water boundaries. PMID- 26980308 TI - Interfacial Charge Transfer States in Condensed Phase Systems. AB - Intermolecular charge transfer (CT) states at the interface between electron donating (D) and electron-accepting (A) materials in organic thin films are characterized by absorption and emission bands within the optical gap of the interfacing materials. CT states efficiently generate charge carriers for some D A combinations, and others show high fluorescence quantum efficiencies. These properties are exploited in organic solar cells, photodetectors, and light emitting diodes. This review summarizes experimental and theoretical work on the electronic structure and interfacial energy landscape at condensed matter D-A interfaces. Recent findings on photogeneration and recombination of free charge carriers via CT states are discussed, and relations between CT state properties and optoelectronic device parameters are clarified. PMID- 26980309 TI - Charge-Carrier Dynamics in Organic-Inorganic Metal Halide Perovskites. AB - Hybrid organic-inorganic metal halide perovskites have recently emerged as exciting new light-harvesting and charge-transporting materials for efficient photovoltaic devices. Yet knowledge of the nature of the photogenerated excitations and their subsequent dynamics is only just emerging. This article reviews the current state of the field, focusing first on a description of the crystal and electronic band structure that give rise to the strong optical transitions that enable light harvesting. An overview is presented of the numerous experimental approaches toward determining values for exciton binding energies, which appear to be small (a few milli-electron volts to a few tens of milli-electron volts) and depend significantly on temperature because of associated changes in the dielectric function. Experimental evidence for charge carrier relaxation dynamics within the first few picoseconds after excitation is discussed in terms of thermalization, cooling, and many-body effects. Charge carrier recombination mechanisms are reviewed, encompassing trap-assisted nonradiative recombination that is highly specific to processing conditions, radiative bimolecular (electron-hole) recombination, and nonradiative many-body (Auger) mechanisms. PMID- 26980310 TI - Vibrational Control of Bimolecular Reactions with Methane by Mode, Bond, and Stereo Selectivity. AB - Vibrational motions of a polyatomic molecule are multifold and can be as simple as stretches or bends or as complex as concerted motions of many atoms. Different modes of excitation often possess different capacities in driving a bimolecular chemical reaction, with distinct dynamic outcomes. Reactions with vibrationally excited methane and its isotopologs serve as a benchmark for advancing our fundamental understanding of polyatomic reaction dynamics. Here, some recent progress in this area is briefly reviewed. Particular emphasis is placed on the key concepts developed from those studies. The interconnections among mode and bond selectivity, Polanyi's rules, and newly introduced vibrational-induced steric phenomena are highlighted. PMID- 26980311 TI - Vacuum Ultraviolet Photoionization of Complex Chemical Systems. AB - Tunable vacuum ultraviolet (VUV) radiation coupled to mass spectrometry is applied to the study of complex chemical systems. The identification of novel reactive intermediates and radicals is revealed in flame, pulsed photolysis, and pyrolysis reactors, leading to the elucidation of spectroscopy, reaction mechanisms, and kinetics. Mass-resolved threshold photoelectron photoion coincidence measurements provide unprecedented access to vibrationally resolved spectra of free radicals present in high-temperature reactors. Photoionization measurements in water clusters, nucleic acid base dimers, and their complexes with water provide signatures of proton transfer in hydrogen-bonded and pi stacked systems. Experimental and theoretical methods to track ion-molecule reactions and fragmentation pathways in intermolecular and intramolecular hydrogen-bonded systems in sugars and alcohols are described. Photoionization of laser-ablated molecules, clusters, and their reaction products inform thermodynamics and spectroscopy that are relevant to astrochemistry and catalysis. New directions in coupling VUV radiation to interrogate complex chemical systems are discussed. PMID- 26980312 TI - Real-Time Probing of Electron Dynamics Using Attosecond Time-Resolved Spectroscopy. AB - Attosecond science has paved the way for direct probing of electron dynamics in gases and solids. This review provides an overview of recent attosecond measurements, focusing on the wealth of knowledge obtained by the application of isolated attosecond pulses in studying dynamics in gases and solid-state systems. Attosecond photoelectron and photoion measurements in atoms reveal strong-field tunneling ionization and a delay in the photoemission from different electronic states. These measurements applied to molecules have shed light on ultrafast intramolecular charge migration. Similar approaches are used to understand photoemission processes from core and delocalized electronic states in metal surfaces. Attosecond transient absorption spectroscopy is used to follow the real time motion of valence electrons and to measure the lifetimes of autoionizing channels in atoms. In solids, it provides the first measurements of bulk electron dynamics, revealing important phenomena such as the timescales governing the switching from an insulator to a metallic state and carrier-carrier interactions. PMID- 26980313 TI - Qualitative research can inform clinical practice. PMID- 26980314 TI - Moderating Effects of Relational Interdependence on the Association Between Peer Victimization and Depressive Symptoms. AB - This short-term longitudinal study examined the association between relational and physical victimization and subsequent depressive symptoms together with the roles of social cognitive processes (i.e., relational interdependence) and gender in this association. A total of 580 Japanese adolescents in the seventh and eighth grades (52 % girls; age range 12-14) participated in this study across an academic year. Results of structural equation modeling demonstrated that relational and physical victimization, which was assessed via self- and teacher- reports, was concurrently associated with greater depressive symptoms, regardless of the gender of the youth and the level of relational interdependence. Furthermore, after controlling for the stability and co-occurrence between each construct, relational victimization (not physical victimization) was predictive of elevated depressive symptoms only for boys who exhibited relatively higher relational interdependence. The findings are discussed from developmental, gender, and cultural perspectives. PMID- 26980315 TI - An integrated miRNA functional screening and target validation method for organ morphogenesis. AB - The relative ease of identifying microRNAs and their increasing recognition as important regulators of organogenesis motivate the development of methods to efficiently assess microRNA function during organ morphogenesis. In this context, embryonic organ explants provide a reliable and reproducible system that recapitulates some of the important early morphogenetic processes during organ development. Here we present a method to target microRNA function in explanted mouse embryonic organs. Our method combines the use of peptide-based nanoparticles to transfect specific microRNA inhibitors or activators into embryonic organ explants, with a microRNA pulldown assay that allows direct identification of microRNA targets. This method provides effective assessment of microRNA function during organ morphogenesis, allows prioritization of multiple microRNAs in parallel for subsequent genetic approaches, and can be applied to a variety of embryonic organs. PMID- 26980316 TI - Recent Developments in Gene Therapy for Homozygous Familial Hypercholesterolemia. AB - Homozygous familial hypercholesterolemia (HoFH) is a life-threatening Mendelian disorder with a mean life expectancy of 33 years despite maximally tolerated standard lipid-lowering therapies. This disease is an ideal candidate for gene therapy, and in the last few years, a number of exciting developments have brought this approach closer to the clinic than ever before. In this review, we discuss in detail the most advanced of these developments, a recombinant adeno associated virus (AAV) vector carrying a low-density lipoprotein receptor (LDLR) transgene which has recently entered phase 1/2a testing. We also review ongoing development of approaches to enhance transgene expression, improve the efficiency of hepatocyte transduction, and minimize the AAV capsid-specific adaptive immune response. We include a summary of key gene therapy approaches for HoFH in pre clinical development, including RNA silencing of t he gene encoding HMG-CoA reductase (HMGCR) and induced pluripotent stem cell transplant therapy. PMID- 26980318 TI - Are K-12 school environments harming students with obesity? A qualitative study of classroom teachers. AB - PURPOSE: Weight bias can negatively impact health, and schools may be risky environments for students with obesity. We aimed to explore teachers' perceptions of the school experiences and academic challenges of students with obesity. METHODS: We conducted interviews with 22 teachers in the Northeast, mid-Atlantic, and Midwest in July-August 2014. All interviews were transcribed verbatim, coded, and analyzed for important themes by two researchers using the immersion/crystallization approach. RESULTS: Most teachers felt that students with obesity were more likely to have academic difficulties. Two main perceptions of the reasons for these difficulties emerged: (1) obesity led to lower self esteem that caused students to participate less, and (2) poorer nutrition, increased screen time, and reduced physical activity were simultaneously causing obesity and poorer academic performance. A few teachers described colleagues who felt students with obesity were not as motivated to work hard in school as their peers. Many teachers described school health promotion efforts focused on weight reduction that could exacerbate weight stigma and risk of disordered eating. CONCLUSIONS: Students with obesity, particularly girls, may be at risk for negative social and academic experiences in K-12 schools and may be perceived as struggling academically by their teachers. PMID- 26980317 TI - Cardiac MRI and Ischemic Heart Disease: Role in Diagnosis and Risk Stratification. AB - Cardiac magnetic resonance imaging (CMRI) has been under development for the past four decades and has more recently become an essential tool in the evaluation of ischemic heart disease (IHD). It is the reference standard for quantification of both right and left ventricular volume and function and, after landmark work published in the New England Journal of Medicine in 2000, has proven effective in identifying hibernating myocardium, or hypokinetic myocardium that will recover after revascularization. More recent literature continues to support both delayed enhancement imaging and CMRI stress perfusion as essential tools in evaluating IHD. This review will briefly address the basics of CMRI and the scientific literature supporting the use of CMRI in IHD. It will then address more recent clinical studies establishing the clinical utility of CMRI in IHD, followed by a discussion of future directions in CMRI. PMID- 26980319 TI - A comprehensive review of psychodynamic treatments for eating disorders. AB - PURPOSE: To comprehensively review the existing literature on the effectiveness of psychodynamic psychotherapies in eating disorders (EDs) and to stimulate both debate and research on this topic. METHODS: Online and hand searches were conducted to identify papers published between 1980 and 2015 on psychodynamic treatments delivered to adults with anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). RESULTS: A total of 47 studies were finally included in this review. Fifteen studies were available for AN, 9 for BN, 12 for BED, and 11 for samples with mixed diagnoses. Several methodological flaws emerged, but overall psychodynamic interventions showed promising results at the end of treatment and follow-up, when available. CONCLUSIONS: The body of literature on psychodynamic treatments is sparse and sometimes methodologically questionable; nevertheless, current data provide support to the effectiveness of these interventions, particularly for AN. However, both a defined approach (focus, themes, and techniques) and randomized controlled trials (RCTs) are warranted to clarify the effectiveness of psychodynamic psychotherapies. PMID- 26980320 TI - Integrating multidimensional omics data for cancer outcome. AB - In multidimensional cancer omics studies, one subject is profiled on multiple layers of omics activities. In this article, the goal is to integrate multiple types of omics measurements, identify markers, and build a model for cancer outcome. The proposed analysis is achieved in two steps. In the first step, we analyze the regulation among different types of omics measurements, through the construction of linear regulatory modules (LRMs). The LRMs have sound biological basis, and their construction differs from the existing analyses by modeling the regulation of sets of gene expressions (GEs) by sets of regulators. The construction is realized with the assistance of regularized singular value decomposition. In the second step, the proposed cancer outcome model includes the regulated GEs, "residuals" of GEs, and "residuals" of regulators, and we use regularized estimation to select relevant markers. Simulation shows that the proposed method outperforms the alternatives with more accurate marker identification. We analyze the The Cancer Genome Atlas data on cutaneous melanoma and lung adenocarcinoma and obtain meaningful results. PMID- 26980321 TI - Risk of venous thromboembolism in patients undergoing surgery for pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: We sought to determine the incidence of venous thromboembolism (VTE) in patients undergoing surgery for pelvic organ prolapse (POP) based on surgical approach. METHODS: The American College of Surgeons National Quality Improvement Program (NSQIP) database was used to select all surgeries performed for POP from 2005 to 2013. CPT-4 codes were grouped based on surgical approach: vaginal (VAG), laparoscopic sacrocolpopexy (LSC), or open abdominal sacrocolpopexy (ASC). Patient demographics, preoperative American Society of Anesthesiologists (ASA) classification system scores, and 30-day postoperative complications were obtained. RESULTS: Of the 26,103 women who underwent surgery for POP, 21,311 (81.7 %) underwent VAG, 3,346 (12.8 %) LSC, and 1,426 (5.5 %) ASC. VTE occurred in 36 patients (0.17 %) in the VAG group, 8 (0.24 %) in the LSC group, and 9 (0.63 %) in the ASC group. The ASC group had a significantly higher incidence of VTE compared with the VAG group (p < 0.01). Upon multivariate analysis, factors associated with a greater incidence of VTE included BMI greater than 30 kg/m(2) (p = 0.048), ASA score of 3, 4, or 5 (p = 0.027), and length of stay above the 75th percentile (p < 0.01). The procedure group did not retain statistical significance in multivariate modeling. CONCLUSIONS: Venous thromboembolism is rare following surgery for POP. Although differences in VTE rates between procedure groups failed to maintain statistical significance after multivariate analysis, we were able to identify risk factors associated with an increased VTE risk in surgery for POP. Women with obesity, an increased length of stay, or ASA score of 3 or higher are at an increased risk for developing VTE after undergoing surgery for POP. PMID- 26980322 TI - Bare and Polymer-Coated Indium Tin Oxide as Working Electrodes for Manganese Cathodic Stripping Voltammetry. AB - Though an essential metal in the body, manganese (Mn) has a number of health implications when found in excess that are magnified by chronic exposure. These health complications include neurotoxicity, memory loss, infertility in males, and development of a neurologic psychiatric disorder, manganism. Thus, trace detection in environmental samples is increasingly important. Few electrode materials are able to reach the negative reductive potential of Mn required for anodic stripping voltammetry (ASV), so cathodic stripping voltammetry (CSV) has been shown to be a viable alternative. We demonstrate Mn CSV using an indium tin oxide (ITO) working electrode both bare and coated with a sulfonated charge selective polymer film, polystyrene-block-poly(ethylene-ran-butylene)-block polystyrene-sulfonate (SSEBS). ITO itself proved to be an excellent electrode material for Mn CSV, achieving a calculated detection limit of 5 nM (0.3 ppb) with a deposition time of 3 min. Coating the ITO with the SSEBS polymer was found to increase the sensitivity and lower the detection limit to 1 nM (0.06 ppb). This polymer modified electrode offers excellent selectivity for Mn as no interferences were observed from other metal ions tested (Zn(2+), Cd(2+), Pb(2+), In(3+), Sb(3+), Al(3+), Ba(2+), Co(2+), Cu(2+), Ni(3+), Bi(3+), and Sn(2+)) except Fe(2+), which was found to interfere with the analytical signal for Mn(2+) at a ratio 20:1 (Fe(2+)/Mn(2+)). The applicability of this procedure to the analysis of tap, river, and pond water samples was demonstrated. This simple, sensitive analytical method using ITO and SSEBS-ITO could be applied to a number of electroactive transition metals detectable by CSV. PMID- 26980323 TI - The effect of a family-based mindfulness intervention on children with attention deficit and hyperactivity symptoms and their parents: design and rationale for a randomized, controlled clinical trial (Study protocol). AB - BACKGROUND: About 4 % of children in Hong Kong have attention deficit hyperactivity disorder (ADHD). The parents of children with ADHD report higher levels of stress and show more negative parenting behavior. Medication and behavior training are evidence-based treatments, but both show significant limitations. In short, medical treatment is not suitable for preschool children and would suppress growth, whereas parents under stress may not be capable of consistently applying behavior management skills. Mindfulness training can improve attention and facilitate cognitive development and overall functioning. It has been widely adopted as a treatment option in health care, but its application in a family context is limited. In this context, a family-based mindfulness intervention (FBMI) has been developed to promote the attention and mental health of children with attention symptoms and to reduce the stress experienced by their parents. This article describes the design and conduct of the trial. METHODS/DESIGN: A multicenter, 8-week, waitlist, randomized controlled trial of FBMI is currently being conducted in Hong Kong (from mid-2015 to mid 2016). Its effectiveness will be examined by comparing the participants who receive treatment to those in a waitlist control group. The study population consists of one hundred twenty children with ADHD, or with symptoms of inattention and hyperactivity, between 5 and 7 years of age and their parents. To be included in the study, the children are required to meet or exceed the borderline cutoff score of the Chinese version of the Strengths and Weaknesses of ADHD Symptoms and Normal Behaviors Rating Scale (SWAN-C). The primary outcome measures are the children's ADHD symptoms and behavior and the parents' stress. The secondary outcome measures include the children's overall behavioral problems and performance on the Attention Network Test, the parents' ADHD symptoms, the parents' mindful parenting scores, and heart rate variability of parents. DISCUSSION: This study is probably the first randomized controlled trial of FBMI for young children and their caregivers. A rigorous design and multiple outcome measures are used to examine the effectiveness of FBMI. If the hypotheses are confirmed, FBMI may serve as an additional treatment option for children with ADHD. TRIAL REGISTRATION: This study is registered with the Chinese Clinical Trial Registry (reference number: ChiCTR-IOR-15007292 ). Registered 28 October 2015. PMID- 26980324 TI - Single-step synthesis of heparin-doped polypyrrole nanoparticles for delivery of angiogenic factor. AB - AIM: To perform one-pot synthesis of heparin-immobilized polypyrrole (PPy) nanoparticles and evaluate the use of these nanoparticles for the delivery of VEGF. MATERIALS & METHODS: Heparin-stabilized synthesis of PPy nanoparticles was performed via oxidative polymerization. VEGF-bound PPy-heparin nanoparticles were delivered to endothelial cells and bioactivity of VEGF was assessed by Matrigel tube formation. RESULTS: Size-controllable synthesis of heparin-doped PPy nanoparticles was achieved, and heparin promoted the conjugation of VEGF. Angiogenic activity of the VEGF-conjugated PPy nanoparticles was verified. CONCLUSION: Heparin-doped PPy nanoparticles can be synthesized using one-pot reaction and provide a delivery platform by which VEGF can be conjugated onto. PMID- 26980325 TI - Digital diffraction detection of protein markers for avian influenza. AB - Rapid pathogen testing is expected to play a critical role in infection control and in limiting epidemics. Smartphones equipped with state-of-the-art computing and imaging technologies have emerged as new point-of-use (POU) sensing platforms. We herein report a new assay format for fast, sensitive and portable detection of avian influenza-associated antibodies. PMID- 26980326 TI - Larval habitats of the Anopheles farauti and Anopheles lungae complexes in the Solomon Islands. AB - BACKGROUND: There is an urgent need for vector control tools to supplement long lasting insecticidal nets (LLINs) and indoor residual spraying; particularly in the Solomon Islands where the primary vector, Anopheles farauti, is highly anthropophagic and feeds mainly outdoors and early in the evening. Currently, the only supplementary tool recommended by the World Health Organization is larval source management (LSM). The feasibility and potential effectiveness of LSM requires information on the distribution of anophelines, the productivity of larval habitats and the potential impacts of larval control on adult fitness. METHODS: The distribution of anophelines in Central and Western Provinces in the Solomon Islands was mapped from cross-sectional larval habitat surveys. The composition and micro-distribution of larval instars within a large permanent river-mouth lagoon was examined with a longitudinal survey. Density-dependent regulation of An. farauti larvae was investigated by longitudinally following the development and survival of different densities of first instars in floating cages in a river-mouth lagoon. RESULTS: Five anopheline species were molecularly identified from a range of fresh and brackish water habitats: An. farauti s.s., An. hinesorum, An. lungae, An. nataliae and An. solomonis. The most common habitats used by the primary malaria vector, An. farauti, were coastal lagoons and swamps. In the detailed study of lagoon micro-productivity, An. farauti was non-uniformly distributed with highest densities found at collections sites most proximal and distal to the mouth of the lagoon. The survival of An. farauti larvae was more than twofold lower when larvae were held at the highest experimental density (1 larva per 3.8 cm(2)) when compared with the lowest density (1 larva per 38 cm(2)). CONCLUSIONS: The only documented major malaria vector collected in larval surveys in both Central and Western Provinces was An. farauti. Lagoons and swamps, the most common, largest and (potentially) most productive larval sites of this malaria vector, were "few, fixed and findable" and theoretically, therefore, amenable to successful LSM. However, the immense scale and complexity of these ecosystems in which An. farauti larvae are found raises questions regarding the ability to effectively control the larvae, as incomplete larviciding could trigger density dependent effects resulting in increased larval survivorship. While LSM has the potential to significantly contribute to malaria control of this early and outdoor biting vector, more information on the distribution of larvae within these extensive habitats is required to maximize the effectiveness of LSM. PMID- 26980327 TI - Charge localization in a diamine cation provides a test of energy functionals and self-interaction correction. AB - Density functional theory (DFT) is widely applied in calculations of molecules and materials. Yet, it suffers from a well-known over-emphasis on charge delocalization arising from self-interaction error that destabilizes localized states. Here, using the symmetric diamine N,N'-dimethylpiperazine as a model, we have experimentally determined the relative energy of a state with positive charge localized on one of the two nitrogen atoms, and a state with positive charge delocalized over both nitrogen atoms. The charge-localized state was found to be 0.33 (0.04) eV higher in energy than the charge-delocalized state. This provides an important test of theoretical approaches to electronic structure calculations. Calculations with all DFT functionals commonly used today, including hybrid functionals with exact exchange, fail to predict a stable charge localized state. However, the application of an explicit self-interaction correction to a semi-local functional identifies both states and gives relative energy in excellent agreement with both experiment and CCSD(T) calculations. PMID- 26980328 TI - Early attentional bias for negative words when competition is induced. AB - Previous research (Zeelenberg, Wagenmakers, & Rotteveel, 2006) revealed that emotionally meaningful words were identified significantly better than neutral words, with no difference between positive and negative words. Since in that study only a single target word was displayed at a time, we hypothesized that the equivalent performances for positive and negative words were due to a lack of competition. To test this, in our Experiment 1, we replicated Zeelenberg and colleagues' finding, using emotion-laden Chinese words and the identical data limited method, which measured the accuracy of a briefly shown target. We then introduced competition in Experiment 2 by simultaneously presenting two words during the target frame, and found evidence for an early attentional bias to negative words. In Experiment 3, we confirmed that the bias in Experiment 2 was not due to the inevitable repetition of stimuli. Taken together, these results support our hypothesis that, in the presence of competition, negative words receive attentional priority and consequently have enhanced perceptual representations. PMID- 26980329 TI - Stapled hemorrhoidopexy complicated by rectourethral fistula. PMID- 26980330 TI - Results from the LIDO anemia survey: adherence to EORTC guidelines in cancer patients in France. AB - PURPOSE: The aim of the LIDOanemia surveys was to assess how anemia in cancer patients is managed by oncologists and hematologists according to the key messages of the EORTC guidelines. METHODS: LIDO 1 and LIDO 2 (Leaning upon International Directives for Optimization: Anemia) were declarative web-based surveys conducted in France. LIDO 1 specifically focused on clinical features triggering the decision to treat anemia, biological indicators of anemia, the hemoglobin (Hb) threshold for initiating treatment and blood transfusion, and the Hb treatment target. In LIDO 2, participants were presented the main messages of the EORTC guidelines and were asked four questions to assess the impact of the guideline's broadcast on their practice. RESULTS: A total of 133 and 319 physicians took part in the LIDO 1 and 2 surveys, respectively. The majority were oncologists (65 and 61 %, respectively). Responses from LIDO 1 showed practice habits that differed from those recommended in the EORTC guidelines. However, LIDO 2 showed that an average of 18 % of the participating physicians were willing to amend their clinical practice after receiving a summary of the EORTC recommendations for anemia management. CONCLUSION: These findings raise the questions of how often and how to most effectively disseminate key guideline messages. With the best interests of patients in mind, the ultimate objective is to improve the understanding of consensus recommendations and to close the gap between them and actual clinical practice. PMID- 26980331 TI - Cancer and fertility preservation in Puerto Rico: a qualitative study of healthcare provider perceptions. AB - PURPOSE: This study aims to examine healthcare provider perceptions of cancer related infertility and fertility preservation (FP) in an underserved population and to highlight cognitive and structural barriers to use. METHODS: In-depth, semi-structured interviews were conducted with a sample of 16 healthcare providers participating in a larger ethnographic study on cancer survivorship and cancer-related infertility in Puerto Rico, an unincorporated US territory. Interviews were conducted in-person, audio-recorded, transcribed verbatim, and coded using the constant comparative method. RESULTS: Providers identified several barriers to FP in Puerto Rico: high cost in relation to income levels, lack of insurance coverage, gaps in provider knowledge of fertility clinics and financial assistance, lower prioritization of quality-of-life needs leading to inconsistent physician disclosure of fertility risks, geographical location of fertility clinics, and logistical challenges to maintaining FP offerings. Two factors act as facilitators: a high value placed on patient-provider communication and relationships and the formation of local alliances between the oncology and reproductive medicine fields, potentially leading to increased cross specialty communication and referral. CONCLUSIONS: Infertility is a continuing source of distress for cancer patients and survivors, and barriers to FP vary cross-culturally. In Puerto Rico, context-specific factors indicate potential areas of intervention. Greater awareness of fertility risks and options can be fostered through physician training in conjunction with organizational measures targeting cost barriers. PMID- 26980332 TI - Prediction of skeletal-related events in patients with non-small cell lung cancer. AB - PURPOSE: Advanced lung cancer frequently causes bone metastasis which can be associated with skeletal-related events (SREs) that may cause significant deterioration of the patient's quality of life (QoL). The Spinal Instability Neoplastic Score (SINS) can be used to assist in standardizing evaluations of neoplastic spinal instability between spinal and non-spine surgeons. This research investigated the association between SREs and SINS for patients with non small cell lung cancer (NSCLC). METHODS: Between 2009 and 2013, 47 patients with NSCLC who were diagnosed with bone metastasis were classified using SINS into either a stable group (SINS, 0-6 points) or unstable group (SINS, 7-18 points). The primary endpoint was time from diagnosis of metastasis to SREs. Secondary endpoints included tumor type and epidermal growth factor receptor (EGFR) mutational status. SREs were defined as spinal compression, pathologic fracture, spinal surgery, and hypercalcemia. RESULTS: Patients included 37 cases of adenocarcinoma and 10 cases of squamous cell carcinoma. Mean follow-up time was 10.2 +/- 13.7 months. SRE incidence was 15.0 % (3/20) in the stable group versus 44.4 % (12/27) in the unstable group (p = 0.048). A Cox regression model revealed that an EGFR-positive mutational status (hazard ratio [HR] = 0.15, 95 % CI, 0.030.71; p = 0.017) or good spinal stability (HR = 0.49; 0.08-0.99; p = 0.049) were favorable prognostic factors. CONCLUSION: The incidence of SREs was significantly lower in NSCLC patients with better spinal stability as determined by SINS, which was a good prediction tool for SREs from bone metastasis. The lower incidence of SREs in EGFR-positive patients suggests tumor biology should be considered when predicting SREs. PMID- 26980333 TI - Lysine residues K66, K109, and K110 in the bovine foamy virus transactivator protein are required for transactivation and viral replication. AB - Bovine foamy virus (BFV) is a complex retrovirus that infects cattle. Like all retroviruses, BFV encodes a transactivator Tas protein (BTas) that increases gene transcription from viral promoters. BFV encodes two promoters that can interact with BTas, a conserved promoter in the 5' long terminal repeat (LTR) and a unique internal promoter (IP). Our previous study showed that BTas is acetylated by p300 at residues K66, K109, and K110, which markedly enhanced the ability of BTas to bind to DNA. However, whether these residues are important for BFV replication was not determined. Therefore, in this study we provide direct evidence that BTas is required for BFV replication and demonstrate that residues K66, K109, and K110 are critical for BTas function and BFV replication. Full-length infectious clones were generated, which were BTas deficient or contained lysine to arginine (K->R) mutations at position 66, 109, and/or 110. In vivo data indicated that K->R mutations at positions 66, 109, and 110 in BTas impaired transactivation of both the LTR and IP promoters. In addition, the K->R mutations in full-length infectious clones reduced expression of viral proteins, and the triple mutant and BTas deletion completely abrogated viral replication. Taken together, these results indicate that lysine residues at positions 66, 109, and 110 in the BTas protein are crucial for BFV replication and suggest a potential role for BTas acetylation in regulating the viral life cycle. PMID- 26980334 TI - Recombinant Newcastle disease virus expressing African swine fever virus protein 72 is safe and immunogenic in mice. AB - African swine fever (ASF) is a lethal hemorrhagic disease that affects wild and domestic swine. The etiological agent of ASF is African swine fever virus (ASFV). Since the first case was described in Kenya in 1921, the disease has spread to many other countries. No commercial vaccines are available to prevent ASF. In this study, we generated a recombinant Newcastle disease virus (rNDV) expressing ASFV protein 72 (p72) by reverse genetics and evaluated its humoral and cellular immunogenicity in a mouse model. The recombinant virus, rNDV/p72, replicated well in embryonated chicken eggs and was safe to use in chicks and mice. The p72 gene in rNDV/p72 was stably maintained through ten passages. Mice immunized with rNDV/p72 developed high titers of ASFV p72 specific IgG antibody, and had higher levels of IgG1 than IgG2a. Immunization also elicited T-cell proliferation and secretion of IFN-gamma and IL-4. Taken together, these results indicate that rNDV expressing ASFV p72 might be a potential vaccine candidate for preventing ASF. PMID- 26980335 TI - Utilization of antihypertensive drugs in obesity-related hypertension: a retrospective observational study in a cohort of patients from Southern Italy. AB - BACKGROUND: Although the pathophysiological mechanisms of arterial hypertension are different in obese and lean patients, hypertension guidelines do not include specific recommendations for obesity-related hypertension and, therefore, there is a considerable uncertainty on which antihypertensive drugs should be used in this condition. Moreover, studies performed in general population suggested that some antihypertensive drugs may increase body weight, glycemia and LDL cholesterol but it is unclear how this impact on drug choice in clinical practice in the treatment of obese hypertensive patients. Therefore, in order to identify current preferences of practitioners for obesity-related hypertension, in the present work we evaluated antihypertensive drug therapy in a cohort of 129 pharmacologically treated obese hypertensive patients (46 males and 83 females, aged 51.95 +/- 10.1 years) that came to our observation for a nutritional consultation. METHODS: Study design was retrospective observational. Differences in the prevalence of use of the different antihypertensive drug classes among groups were evaluated with chi(2) square analysis. Threshold for statistical significance was set at p < 0.05. RESULTS: 41.1 % of the study sample was treated with one, 36.4 % with two and the remaining 22.5 % with three or more antihypertensive drugs. In patients under single drug therapy, beta-blockers, ACEIs and ARBs accounted each for about 25 % of prescriptions. The prevalence of use of beta-blockers was about sixfold higher in females than males. Diuretics were virtually never used in monotherapy regimens but were used in more than 60 % of patients on dual antihypertensive therapy and in all patients assuming three or more drugs. There was no significant difference in the prevalence of use of any of the aforementioned drugs among patients with obesity of type I, II and III or between patients with or without metabolic syndrome. CONCLUSIONS: Our data show that no first choice protocol seems to be adopted in clinical practice for the treatment of obesity-related hypertension. Importantly, physicians do not seem to differentiate drug use according to the severity of obesity or to the presence of metabolic syndrome or to avoid drugs known to detrimentally affect body weight and metabolic profile in general population. PMID- 26980336 TI - A Rare Case of Chronic Diarrhea and Weight Loss. PMID- 26980337 TI - Head and neck cutaneous leishmania: clinical characteristics, microscopic features and molecular analysis in a cohort of 168 cases. AB - Lebanon, an underendemic area for cutaneous leishmania (CL), is suffering from a CL outbreak brought by the massive population influx from endemic Syria. CL affects mainly exposed areas; therefore, the head and neck (HN) region is highly susceptible. Individuals diagnosed and speciated with CL (n = 168) using molecular and microscopic analysis on punch biopsy/scrapings were studied. Clinical data, parasitic index (PI) and Ridley's Pattern (RP) were recorded. The HN was divided into 11 anatomic locations. Of 168 patients, 96 patients (57.1 %) had HN involvement and 72 (42.9 %) had no HN involvement. Lesions from the HN were significantly more common in younger patients and were more prone for ulceration, had larger size, higher PI and more advanced RP (p < 0.05). There was no difference in the anatomic distribution of lesions among age groups and genders in the HN group. The cheek area was the most HN involved location. Lesions were less commonly encountered in the veiled area in women. In the community we studied, HN is commonly involved by CL. Lesions with HN involvement were encountered more in pediatric age group and showed more extensive features. PMID- 26980338 TI - Head position and increased head velocity to optimize video head impulse test sensitivity. AB - This study investigated the effects of head position on gain values during video head impulse tests (vHITs). Different head positions were used for vHIT of the horizontal semicircular canals of 20 healthy controls and 18 patients with unilateral vestibular loss (UVL), with head velocities ranging from 150 degrees /s to 200 degrees /s. Differences in vestibulo-ocular reflex gain in the control and patient groups according to head position (0 degrees and 30 degrees downward pitch) were analyzed. In the unaffected control group, the 30 degrees pitched-down position resulted in a mean gain increase of up to 1.0 in both ears (right ear: 0.85 +/- 0.26 for head-up and 1.05 +/- 0.12 for head-down, p = 0.004; left ear: 0.75 +/- 0.18 for head-up and 0.98 +/- 0.16 for head-down, p < 0.001). In patients with UVL, the mean gains on the diseased side were 0.92 +/- 0.16 in the head-up position and 0.82 +/- 0.2 in the head-down position, at similar head velocities (p = 0.046). The pitched-down position also increased the asymmetry between ears in patients with UVL, at the same head velocity. A 30 degrees head down position can increase vHIT sensitivity, which resulted in increased mean gain in unaffected people and decreased mean gain in most of the patients with UVL in this study. This method may more effectively stimulate the horizontal semicircular canal. This vHIT modification may be helpful for more precisely evaluating vestibular function, thus reducing false-negative findings. PMID- 26980339 TI - Antileukotrienes in adenotonsillar hypertrophy: a review of the literature. AB - We assessed the use of antileukotrienes for treating adenotonsillar hypertrophy. We reviewed the current literature on the anatomy of adenotonsillar tissue, adenotonsillar hypertrophy/hyperplasia (and the associated pathophysiology and symptoms), and the effects of antileukotrienes used to treat adenotonsillar hypertrophy. Leukotrienes (LTs) are inflammatory mediators produced by a number of cell types, including mast cells, eosinophils, basophils, macrophages, and monocytes. There are several types (e.g., LTA4, LTB4, LTC4, LTD4, and LTE4). By competitive binding to the cysLT1 receptor, LT-receptor antagonist drugs such as montelukast, zafirlukast, and pranlukast block the effects of cySHLTs, improving the symptoms of some chronic respiratory diseases. High numbers of LT receptors have been found in the tonsils of children with obstructive sleep apnea. Antileukotrienes reduce the apnea-hypopnea index and adenotonsillar inflammation. Antileukotrienes may be useful for children with adenotonsillar hypertrophy due to their anti-inflammatory effects, which help to reduce adenotonsillar inflammation. PMID- 26980340 TI - Celecoxib versus diclofenac for the treatment of ankylosing spondylitis: 12-week randomized study in Norwegian patients. AB - OBJECTIVE: To compare the efficacy and safety of two different doses of celecoxib and diclofenac in the treatment of Norwegian patients with ankylosing spondylitis. METHODS: In this 12-week, double-blind, non-inferiority trial patients were randomized to 200 mg once daily (qd) celecoxib, 400 mg qd celecoxib, or 50 mg three times daily (tid) diclofenac. The primary objective compared patients' assessments of Global Pain Intensity, measured on a visual analogue scale. RESULTS: A total of 330 patients were randomized (200 mg celecoxib, n = 107; 400 mg celecoxib, n = 108; diclofenac, n = 115). Least squares mean changes in Global Pain Intensity at 12 weeks were -25.8 mm, -30.6 mm and -28.2 mm, respectively. Both celecoxib treatment groups were non-inferior to diclofenac. More patients in the 400 mg celecoxib group met the Assessments in Ankylosing Spondylitis 20 responder criteria at Week 12 (60.2%) than in the celecoxib 200 mg (51.4%) and the diclofenac 50 mg (57.4%) groups. Adverse events were mild-to-moderate in severity, with dyspepsia and diarrhoea the most commonly reported. CONCLUSIONS: Celecoxib and diclofenac both provided pain reduction, in addition to improvements in disease activity and functional capacity, in patients with ankylosing spondylitis. PMID- 26980341 TI - Mammalian X homolog acts as sex chromosome in lacertid lizards. AB - Among amniotes, squamate reptiles are especially variable in their mechanisms of sex determination; however, based largely on cytogenetic data, some lineages possess highly evolutionary stable sex chromosomes. The still very limited knowledge of the genetic content of squamate sex chromosomes precludes a reliable reconstruction of the evolutionary history of sex determination in this group and consequently in all amniotes. Female heterogamety with a degenerated W chromosome typifies the lizards of the family Lacertidae, the widely distributed Old World clade including several hundreds of species. From the liver transcriptome of the lacertid Takydromus sexlineatus female, we selected candidates for Z-specific genes as the loci lacking single-nucleotide polymorphisms. We validated the candidate genes through the comparison of the copy numbers in the female and male genomes of T. sexlineatus and another lacertid species, Lacerta agilis, by quantitative PCR that also proved to be a reliable technique for the molecular sexing of the studied species. We suggest that this novel approach is effective for the detection of Z-specific and X-specific genes in lineages with degenerated W, respectively Y chromosomes. The analyzed gene content of the Z chromosome revealed that lacertid sex chromosomes are not homologous with those of other reptiles including birds, but instead the genes have orthologs in the X-conserved region shared by viviparous mammals. It is possible that this part of the vertebrate genome was independently co-opted for the function of sex chromosomes in viviparous mammals and lacertids because of its content of genes involved in gonad differentiation. PMID- 26980342 TI - Evolution in situ: hybrid origin and establishment of willows (Salix L.) on alpine glacier forefields. AB - Little attention has been paid to the evolutionary consequences of the colonizing dynamics and succession processes following glacier retreat. Here we studied hybrid populations that have recently formed and established on glacier forefields of the European Alps owing to secondary contact of a lowland colonizer with a subalpine species. We analyzed the composition of two hybrid populations between Salix purpurea and Salix helvetica with nine microsatellite markers by using Bayesian methods (structure and NewHybrids), and simulations. We also studied niche differentiation between the hybrids and the parental species based on indicator values, soil pH and water retention potential measurements. Allelic structure of hybrids confirms the assumed parentage and in situ origin of the crosses on two independent sites within the last decades. Both hybrid populations comprised F1 and later generation hybrids (F2 and backcrosses), confirming hybrid fertility. The parental species showed significant differences in niche characteristics for temperature, soil pH, nutrients and moisture. Remarkably, the hybrids exhibited a higher tolerance to cold temperatures, nutrient-poor and acidic soils than either parent. Our results show that willow hybrids originated after glacier retreat and have established persistent populations within a few decades. One factor contributing to hybrid establishment in sympatry with their parents is their ability to occupy more extreme niches than either parental species within a mosaic-like pattern of microhabitats on the forefield. Introgression and/or transgressive segregation may have resulted in novel genotypes that are able to expand the ecological spectrum of either parent. PMID- 26980343 TI - Interspecific Y chromosome variation is sufficient to rescue hybrid male sterility and is influenced by the grandparental origin of the chromosomes. AB - Y chromosomes display population variation within and between species. Co evolution within populations is expected to produce adaptive interactions between Y chromosomes and the rest of the genome. One consequence is that Y chromosomes from disparate populations could disrupt harmonious interactions between co evolved genetic elements and result in reduced male fertility, sterility or inviability. Here we address the contribution of 'heterospecific Y chromosomes' to fertility in hybrid males carrying a homozygous region of Drosophila mauritiana introgressed in the Drosophila simulans background. In order to detect Y chromosome-autosome interactions, which may go unnoticed in a single-species background of autosomes, we constructed hybrid genotypes involving three sister species: Drosophila simulans, D. mauritiana, and D. sechellia. These engineered strains varied due to: (i) species origin of the Y chromosome (D. simulans or D. sechellia); (ii) location of the introgressed D. mauritiana segment on the D. simulans third chromosome, and (iii) grandparental genomic background (three genotypes of D. simulans). We find complex interactions between the species origin of the Y chromosome, the identity of the D. mauritiana segment and the grandparental genetic background donating the chromosomes. Unexpectedly, the interaction of the Y chromosome and one segment of D. mauritiana drastically reduced fertility in the presence of Ysim, whereas the fertility is partially rescued by the Y chromosome of D. sechellia when it descends from a specific grandparental genotype. The restoration of fertility occurs in spite of an autosomal and X-linked genome that is mostly of D. simulans origin. These results illustrate the multifactorial basis of genetic interactions involving the Y chromosome. Our study supports the hypothesis that the Y chromosome can contribute significantly to the evolution of reproductive isolation and highlights the conditional manifestation of infertility in specific genotypic combinations. PMID- 26980344 TI - A novel study on the mechanisms of drug release in PLGA-mPEG microspheres with fluorescent drug. AB - The purpose of this research was to proof the microspheres release mechanism by a novel method-detecting and comparing the drugs fluorescent changes on the microspheres surface. Fluorescein sodium (FS, 0.4 kDa) and fluorescein isothiocyanate-bovine serum albumin (FITC-BSA, 66.8 kDa) were employed as model drugs. FS and FITC-BSA were encapsulated into PLGA-mPEG microspheres through double emulsion evaporation method, and the drug-loaded microspheres in vitro degradation and release behaviors were evaluated by scanning electron microscope, gel permeation chromatography, confocal laser scanning microscopy (CLSM), BCA assay kit, and UV-vis spectrophotometry. FS-loaded microspheres revealed a severe initial burst release, followed by a sustained release, and we could observe a bright fluorescent on the microspheres surface during the early release period under the CLSM. The bright fluorescent gradually faded out in the later period as only 1~2% FS was remained after 14 days release. FITC-BSA-loaded microspheres revealed a typical tri-phase release profile, and we observed a weak fluorescent on the microspheres surface after the initial burst release, and the fluorescent came bright again after an obvious erosion appeared on the microspheres surface. In the later release stage, the fluorescent gradually faded out as the fast release of FITC-BSA. PMID- 26980345 TI - IL-10-producing regulatory B-cells suppressed effector T-cells but enhanced regulatory T-cells in chronic HBV infection. AB - Non-specific immune responses to antigens have been demonstrated as being enhanced during chronic hepatitis B virus (HBV) infection. Here, we evaluated the role of interleukin-10 (IL-10)-producing regulatory B-cells (Bregs) in the pathogenesis of HBV-related liver fibrosis (HBV-LF) and assessed their immunoregulatory effects. Sixty-seven patients diagnosed with chronic hepatitis B (CHB) were enrolled in this study. Numbers and frequencies of peripheral B-cells (memory CD19(+)CD24(hi)CD27(+) cells, immature/transitional CD19(+)CD24(hi)CD38(hi) cells, mature CD19(+)CD24(int)CD38(int) cells) were tested and analysed. Flow cytometry-sorted CD4(+)T cells were cultured with autologous Bregs to elucidate the effects of Bregs on CD4(+)T cells, including effector T and regulatory T-cells (Tregs). The potential immunoregulatory mechanism of Bregs was also investigated. The numbers of total B-cells and Bregs were enriched in CHB patients. The frequency of Bregs was negatively correlated with elevated alanine aminotransferase (ALT) and histological inflammation grades (G), but positively correlated with advanced histological fibrosis stages (S) and enhanced HBV replication. The phenotype of Bregs was predominantly characterized as CD19(+)CD24(hi)CD38(hi) In co-culture with Bregs, CD4(+)CD25(-)T cells from CHB patients produced less interferon-gamma (IFN-gamma) and IL-17 but more IL-4 than CD4(+)CD25(-)T cells alone, whereas their conversions into Tregs and IL 10(+)T cells were enhanced. In addition, Breg depletion in CHB samples dramatically decreased Treg numbers and expression of cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), IL-10 and transforming growth factor-beta (TGF beta). Moreover, the observed regulatory effect was partly dependent on IL-10 release and cell-to-cell contact. Elevated Bregs can suppress effector T but enhance Treg functions, which might influence immune tolerance in chronic HBV infection. PMID- 26980347 TI - RhinoChill((r))-more than an "ice-cream headache (1)" serious adverse event related to transnasal evaporative cooling. PMID- 26980346 TI - Impaired glucose tolerance after brief heat exposure: a randomized crossover study in healthy young men. AB - A high demand on thermoregulatory processes may challenge homoeostasis, particularly regarding glucose regulation. This has been understudied, although it might concern millions of humans. The objective of this project was to examine the isolated and combined effects of experimental short-term mild heat exposure and metabolic level on glucoregulation. Two experimental randomized crossover studies were conducted. Ten healthy young men participated in study A, which comprises four sessions in a fasting state at two metabolic levels [rest and exercise at 60% of maximal oxygen uptake (O2) for 40 min] in two environmental temperatures (warm: 31 degrees C and control: 22 degrees C). Each session ended with an ad libitum meal, resulting in similar energy intake across sessions. In study B, 12 healthy young men underwent two 3 h oral glucose tolerance tests (OGTTs) in warm and control environmental temperatures. Venous blood was sampled at several time points. In study A, repeated measure ANOVAs revealed higher postprandial serum glucose and insulin levels with heat exposure. Glycaemia following the OGTT was higher in the warm temperature compared with control. The kinetics of the serum glucose response to the glucose load was also affected by the environmental temperature (temperature-by-time interaction, P=0.030), with differences between the warm and control conditions observed up to 90 min after the glucose load (all P<0.033). These studies provide evidence that heat exposure alters short-term glucoregulation. The implication of this environmental factor in the physiopathology of Type 2 diabetes has yet to be investigated. PMID- 26980348 TI - Cardiopulmonary arrest is the most frequent cause of the unresponsive wakefulness syndrome: A prospective population-based cohort study in Austria. AB - BACKGROUND: The "Unresponsive wakefulness syndrome" (UWS) or previously termed vegetative state is a possible consequence of severe brain damage where individuals just open their eyes but show no conscious behavioural reaction. While head trauma has previously been considered the prevailing cause, clinical experience suggests shows that cardiopulmonary arrest plays an increasingly important role. We therefore attempted to study this hypothesis in a well-defined region of Austria. METHODS: Prospective population-based cohort study to calculate the incidence and aetiologies of the UWS. All facilities in the state of Styria (n=38), which are involved in the medical care of patients with brain damage, participated. Among the adult population of Styria (n=1010,164) we identified all individuals who developed UWS over a one year period. The diagnosis was based on a formal neurologic evaluation at least 4 weeks after the brain damage and had to be in line with the criteria of the "Multi-society Task Force on Persistent Vegetative State". RESULTS: We identified 19 individual with UWS which correspond to an annual incidence of 1.88/100,000 people. Male gender predominated (78.9%) and the mean age was 57.8 years (age range 18-78 years). The most frequent cause of UWS was cerebral hypoxia in the wake of cardiopulmonary resuscitation (63%), cerebral bleeding (21%) and brain trauma (16%). CONCLUSIONS: Cardiopulmonary resuscitation has become the major cause of UWS which leads to an increasing incidence with age. These aspects may become even more prominent with the ageing of our population and need to be considered in the organisation of care. PMID- 26980349 TI - National population size estimation of illicit drug users through the network scale-up method in 2013 in Iran. AB - BACKGROUND: For a better understanding of the current situation of drug use in Iran, we utilized the network scale-up approach to estimate the prevalence of illicit drug use in the entire country. METHODS: We implemented a self administered, street-based questionnaire to 7535 passersby from the general public over 18 years of age by street based random walk quota sampling (based on gender, age and socio-economic status) from 31 provinces in Iran. The sample size in each province was approximately 400, ranging from 200 to 1000. In each province 75% of sample was recruited from the capital and the remaining 25% was recruited from one of the large cities of that province through stratified sampling. The questionnaire comprised questions on demographic information as well as questions to measure the total network size of participants as well as the network size in each of seven drug use groups including Opium, Shire (combination of Opium residue and pure opium), Crystal Methamphetamine, heroin/crack (which in Iranian context is a cocaine-free drug that mostly contains heroin, codeine, morphine and caffeine with or without other drugs), Hashish, Methamphetamine/LSD/ecstasy, and injecting drugs. The estimated size for each group was adjusted for transmission and barrier ratios. RESULTS: The most common type of illicit drug used was opium with the prevalence of 1500 per 100,000 population followed by shire (660), crystal methamphetamine (590), hashish (470), heroin/crack (350), methamphetamine, LSD and ecstasy (300) and injecting drugs (280). All types of substances were more common among men than women. The use of opium, shire and injecting drugs was more common in individuals over 30 whereas the use of stimulants and hashish was largest among individuals between 18 and 30 years of age. CONCLUSION: It seems that younger individuals and women are more desired to use new synthetic drugs such as crystal methamphetamine. Extending the preventive programs especially in youth as like as scaling up harm reduction services would be the main priorities in prevention and control of substance use in Iran. Because of poor service coverage and high stigma in women, more targeted programs in this affected population are needed. PMID- 26980350 TI - Neutralization of IL-23 depresses experimental ocular neovascularization. AB - Interleukin-23 (IL-23) is a heterodimeric cytokine that consists of p19, a novel subunit, and p40, which is shared by IL-12. IL-23 has been demonstrated to play an important role in autoimmunity and tumor growth. However, the role of IL-23 in ocular neovascularization (NV) diseases remains unclear. In this study, we explored the role of IL-23 in the processing of retinal and choroidal neovascularization (RNV and CNV). We found a significantly higher expression of IL-23 in the retinas with oxygen-induced retinopathy (OIR), and after neutralizing IL-23, the mRNA and protein levels of the angiogenic factors vascular endothelial growth factor receptor (VEGFR)1/FLT-1, VEGFR2/FLK-1, placental growth factor (PIGF), endothelial-specific receptor tyrosine kinase (Tie2), inducible nitric-oxide synthase (iNOS), matrix metalloproteinase (MMP) 2 and MMP9 were significantly down regulated, while the opposite trend was found for the anti-angiogenic molecules chemokine (C-X-C motif) ligand (CXCL) 9 and CXCL10. IL-23 blockade caused less NV in both the RNV and CNV mouse models. In addition, our in vitro assay showed that IL-23 alone is able to increase the ability of endothelial cells to form tubes. Our findings suggest that targeting IL-23 could be a potential therapy for RNV and CNV diseases. PMID- 26980351 TI - Plication for the treatment of a radio-cephalic fistula with ulnar artery steal. AB - PURPOSE: Generally the steal syndrome occurs in proximal arterial-venous fistulas and only exceptionally with distal vascular access because of the high number of arteries supplying the hand. We describe a rare case of steal syndrome of a proximalized distal radio-cephalic fistula stealing from both the radial and ulnar artery through the palmar arch. METHODS: An 86 year old man was admitted because of a cyanotic, swollen left hand with trophic lesions at the third finger. He had a latero-terminal radio-cephalic fistula performed in 2006 with subsequent proximalization performed four years later after failure of the first one. Duplex ultrasound examination showed a high flow within the fistula (2080 mL/min) and a retrograde perfusion of the radial artery from the ulnar artery through the palmar arch and an angiography excluded stenosis along the radial artery. RESULTS: We treated the steal syndrome through a plication technique that was performed with careful flow variations measurement, under duplex evaluation, during the surgical procedure. That procedure was effective to maintain the fistula flow and obtain the symptoms relief. The patient was evaluated the day after the intervention and after 10 weeks. The clinical examination highlighted the resolution of hand ischemia. The Duplex Ultrasound examination showed a lower flow within the fistula (1060 mL/min) and a retrograde perfusion of the radial artery from the ulnar artery through the palmar arch with a three-phase flow. dialysis access from the fistula was never interrupted from immediately after surgery to the present date. CONCLUSIONS: Plication is an effective technique for treatment of steal syndrome requiring a short operative time and it is related to satisfying post-operative results. PMID- 26980352 TI - Bonding strategies of resin cement to Er,Cr:YSGG lased dentin: micro-CT evaluation and microshear bond strength testing. AB - AIMS: Pretreatment of the tooth surface is essential for establishing effective micromechanical retention between it and the restoration. The purpose of this study was to evaluate the bond strength between the resin and the Er,Cr:YSGG laser irradiated dentin and to examine morphologic characterization of the dentin resin interface. In addition, the study evaluated the quantity of opened and closed dentinal tubules. SUBJECTS AND METHODS: Thirty extracted human molars were sectioned into samples of 1 mm thickness. The samples were randomly assigned to two groups containing 15 specimens each. Surface treatments were not applied to the samples in the control group and the samples in the experimental group were irradiated with an Er,Cr:YSGG laser. Two resin cement samples were polymerized on the surface of each sliced dentin. The microshear bond strength (MUSBS) between dentin and cement (n = 30 for each group) was measured with a universal testing machine. The topography and morphology of the resin-dentin interface were evaluated by micro-CT (n = 20 for each group). The areas of closed tubular space, closed porosity, area of open tubular space, open porosity, total area of tubular space and fractal dimension were investigated by micro-CT. STATISTICAL ANALYSIS USED: The data for each parameter were analyzed by Shapiro-Wilk and Student's t test (p<0.05). RESULTS: uSBS values for control group were higher than experimental group. Dentin surfaces in the control group revealed less closed and more opened dentin tubules compared to the experimental group. Total area of tubular space was found to have decreased due to the laser ablation. There was no significant difference between the fractal dimensions of the control and experimental groups. CONCLUSIONS: The lased dentin surface was not favorable for the bonding mechanism due to alterations in the dentinal structure. PMID- 26980353 TI - Does information overload prevent chronic patients from reading self-management educational materials? AB - BACKGROUND: Self-care management is becoming an important part of care for chronic patients. However, various kinds of self-management educational materials which government or healthcare institutions provide for patients may not achieve the expected outcome. One of the critical reasons affecting patients' use intention could be patients' perceived information overload regarding the self management educational materials. PURPOSE: This study proposed an extended model of the Theory of Planned Behavior (TPB), which incorporated perceived information overload, to explore if information overload will prevent chronic patients from reading educational materials for self-care management. The independent variables are attitude, subject norm, perceived behavior control and perceived information overload while the dependent variable is behavior intention to use the self management educational materials. Perceived information overload is also referred to as an antecedent variable which may has impacts on attitude and perceived behavior control. METHODS: The cross-sectional study interviewed newly diagnosed chronic patients with coronary artery disease, who are the potential users of the self-management educational materials, in a medical center in Taiwan. Data were analyzed using descriptive statistics of the basic information distribution of the respondents, and structural equation modeling to study the reliability and validity for testing hypotheses. RESULTS: A total of 110 respondents were enrolled in this study and successful interview data were collected from 106 respondents. The result indicates that the patients' perceived information overload of self-management educational materials was validated to have impacts on attitude and perceived behavioral control constructs of the TPB as well as contributing a direct impact on patients' intentions to use self-management educational materials. Besides, subjective norm and perceived behavioral control constructs were validated to have significant impacts on behavioral intentions, whereas the attitude construct was not. Finally, the relationships between information overload and attitude, information overload and intention, subjective norm and intention, as well as perceived behavioral control and intention varied significantly between highly- and less-educated respondents. Differing self management educational materials for respondents of various educational levels could be formulated to substantially boost the use of self-management educational materials. CONCLUSIONS: This study demonstrated a comprehensive framework, which extended perceived information overload into the TPB model, to predict patients' behavioral intention of using self-management educational materials. We expect the results of this study will provide useful insights for studying self management educational materials usage and information overload from the perspectives of academia, governments, and healthcare providers. PMID- 26980355 TI - OMARC: An online multimedia application for training health care providers in the assessment of respiratory conditions. AB - OBJECTIVES: OMARC, a multimedia application designed to support the training of health care providers for the identification of common lung sounds heard in a patient's thorax as part of a health assessment, is described and its positive contribution to user learning is assessed. The main goal of OMARC is to effectively help health-care students become familiar with lung sounds as part of the assessment of respiratory conditions. In addition, the application must be easy to use and accessible to students and practitioners over the internet. SYSTEM DESCRIPTION: OMARC was developed using an online platform to facilitate access to users in remote locations. OMARC's unique contribution as an educational software tool is that it presents a narrative about normal and abnormal lung sounds using interactive multimedia and sample case studies designed by professional health-care providers and educators. Its interface consists of two distinct components: a sounds glossary and a rich multimedia interface which presents clinical case studies and provides access to lung sounds placed on a model of a human torso. OMARC's contents can be extended through the addition of sounds and case studies designed by health-care educators and professionals. VALIDATION AND RESULTS: To validate OMARC and determine its efficacy in improving learning and capture user perceptions about it, we performed a pilot study with ten nursing students. Participants' performance was measured through an evaluation of their ability to identify several normal and adventitious/abnormal sounds prior and after exposure to OMARC. Results indicate that participants are able to better identify different lung sounds, going from an average of 63% (S.D. 18.3%) in the pre-test evaluation to an average of 90% (S.D. of 11.5%) after practising with OMARC. Furthermore, participants indicated in a user satisfaction questionnaire that they found the application helpful, easy to use and that they would recommend it to other persons in their field. CONCLUSIONS: OMARC is an online multimedia application for training health care students in the assessment of respiratory conditions. The software integrates multimedia technology and health-care education concepts to facilitate learning, while being useful and easy to use. Results from a pilot study indicate that OMARC significantly helps to improve the capacity of the users to correctly identify lung sounds for different respiratory conditions. In addition, participants' opinions about OMARC were quite positive: users were likely to recommend the application to other persons in their field and found the application easy to use and helpful to better identify lung sounds. PMID- 26980354 TI - Behavior and attitudes of residents and general practitioners in searching for health information: From intention to practice. AB - BACKGROUND: Physicians are increasingly encouraged to practice evidence-based medicine (EBM), and their decisions require evidence based on valid research. Existing literature shows a mismatch between general practitioners' (GPs) information needs and evidence available online. The aim of this study was to explore the attitudes and behavior of residents in general medicine and GPs when seeking medical information online. METHODS: Five focus groups (FGs) involving residents in general medicine and GPs were conducted between October 2013 and January 2014. The overall number of participants recruited was 35. The focus group discussion guide focused on participants' experiences in searching for health information on the Internet, perceived barriers and possible solutions for improving the quality of their own search processes. Descriptive analysis was performed by three researchers. RESULTS: Participants described a wide range of research topics, covering all general medicine core competencies, and especially patient-oriented topics. They used a limited list of websites. Participants were not confident about their ability to assess the quality of the information they found. Their assessment of data quality was based on intuition, and they mainly sought concordance with their existing knowledge. The way the data were exposed was considered very important. Participants were looking for information that was directly linked to their clinical practice. Information seeking processes varied among participants. They felt they had not mastered query building for conducting searches, and were aware of the impact this shortcoming had on the quality of their search for information. CONCLUSIONS: Residents in general medicine and GPs understood the importance of EBM and the need for objective and reliable information. The present study highlights the difficulties in identifying this kind of information, and suggests ideas for improvement. Available search tools should change in order to fill the gap with real-world clinical practice, for example by integrating a patient-centred approach. PMID- 26980356 TI - Distributed clinical data sharing via dynamic access-control policy transformation. AB - BACKGROUND: Data sharing in electronic health record (EHR) systems is important for improving the quality of healthcare delivery. Data sharing, however, has raised some security and privacy concerns because healthcare data could be potentially accessible by a variety of users, which could lead to privacy exposure of patients. Without addressing this issue, large-scale adoption and sharing of EHR data are impractical. The traditional solution to the problem is via encryption. Although encryption can be applied to access control, it is not applicable for complex EHR systems that require multiple domains (e.g. public and private clouds) with various access requirements. OBJECTIVES: This study was carried out to address the security and privacy issues of EHR data sharing with our novel access-control mechanism, which captures the scenario of the hybrid clouds and need of access-control policy transformation, to provide secure and privacy-preserving data sharing among different healthcare enterprises. METHODS: We introduce an access-control mechanism with some cryptographic building blocks and present a novel approach for secure EHR data sharing and access-control policy transformation in EHR systems for hybrid clouds. RESULTS: We propose a useful data sharing system for healthcare providers to handle various EHR users who have various access privileges in different cloud environments. A systematic study has been conducted on data sharing in EHR systems to provide a solution to the security and privacy issues. CONCLUSIONS: In conclusion, we introduce an access-control method for privacy protection of EHRs and EHR policy transformation that allows an EHR access-control policy to be transformed from a private cloud to a public cloud. This method has never been studied previously in the literature. Furthermore, we provide a protocol to demonstrate policy transformation as an application scenario. PMID- 26980357 TI - Assessing and comparing the usability of Chinese EHRs used in two Peking University hospitals to EHRs used in the US: A method of RUA. AB - OBJECTIVES: The objective of this study was to investigate the usability level of Chinese hospital Electronic Health Records (EHRs) by assessing the completion times of EHRs for seven "meaningful use (MU)" relevant tasks conducted at two Chinese tertiary hospitals and comparing the results to those of relevant research conducted in US EHRs. METHODS: Using Rapid Usability Assessment (RUA) developed by the National Center for Cognitive Informatics and Decision Making (NCCD), the usability of EHRs from two Peking University hospitals was assessed using a three-step Keystroke Level Model (KLM) in a laboratory environment. RESULTS: (1) The total EHR task completion time for 7 MU relevant test tasks showed no significant differences between the two Chinese EHRs and their US counterparts, in which the time for thinking was relatively large and comprised 35.6% of the total time. The time for the electronic physician order was the largest. (2) For specific tasks, the mean completion times of the 2 hospital EHR systems spent on recording, modifying and searching (RMS) the medication orders were similar to those for the RMS radioactive tests; the mean time spent on the RMS laboratory test orders were much less. (3) There were 85 usability problems identified in the 2 hospital EHR systems. DISCUSSION: In Chinese EHRs, a substantial amount of time is required to complete tasks relevant to MU targets and many preventable usability problems can be discovered. The task completion time of the 2 Chinese EHR systems was a little shorter than in the 5 reported US EHR systems, while the differences in smoking status and CPOE tasks were obvious; one main reason for these differences was the use of structured data entry. CONCLUSIONS: The efficiency of Chinese and US EHRs was not significantly different. The key to improving the efficiency of both systems lies in expediting the Computerized physician order entry (CPOE) task. Many usability problems can be identified using heuristic assessments and improved by corresponding actions. PMID- 26980358 TI - Evaluating Model-Driven Development for large-scale EHRs through the openEHR approach. AB - PURPOSE: In healthcare, the openEHR standard is a promising Model-Driven Development (MDD) approach for electronic healthcare records. This paper aims to identify key socio-technical challenges when the openEHR approach is put to use in Norwegian hospitals. More specifically, key fundamental assumptions are investigated empirically. These assumptions promise a clear separation of technical and domain concerns, users being in control of the modelling process, and widespread user commitment. Finally, these assumptions promise an easy way to model and map complex organizations. METHODS: This longitudinal case study is based on an interpretive approach, whereby data were gathered through 440h of participant observation, 22 semi-structured interviews and extensive document studies over 4 years. RESULTS: The separation of clinical and technical concerns seemed to be aspirational, because both designing the technical system and modelling the domain required technical and clinical competence. Hence developers and clinicians found themselves working together in both arenas. User control and user commitment seemed not to apply in large-scale projects, as modelling the domain turned out to be too complicated and hence to appeal only to especially interested users worldwide, not the local end-users. Modelling proved to be a complex standardization process that shaped both the actual modelling and healthcare practice itself. CONCLUSION: A broad assemblage of contributors seems to be needed for developing an archetype-based system, in which roles, responsibilities and contributions cannot be clearly defined and delimited. The way MDD occurs has implications for medical practice per se in the form of the need to standardize practices to ensure that medical concepts are uniform across practices. PMID- 26980359 TI - Reasons for intentional guideline non-adherence: A systematic review. AB - BACKGROUND: Reasons for intentional non-adherence to guidelines are largely unknown. The objective of this systematic review was to gain insight into and categorize reasons for intentional non-adherence and their validity. Non adherence might be a conscious choice by either the clinician or the patient, and is not influenced by external factors (e.g. lack of knowledge or resources). We use the term intentional non-adherence to describe this class of reasons for not following guideline recommendations. METHODS: Two independent reviewers examined MEDLINE citations for studies that investigated reasons for guideline non adherence. The obtained articles were assessed for relevance and quality. Our search yielded 2912 articles, of which 16 matched our inclusion criteria and quality requirements. We planned to determine an overall ranking of categories of non-adherence. RESULTS: Seven studies investigated clinical reasons and performed adjudication, while nine studies did not perform adjudication. Non-adherence varied between 8.2% and 65.3%. Meta-analysis proved unfeasible due to heterogeneity of study methodologies. The percentage of reasons deemed valid by adjudication ranged from 6.6% to 93.6%. Guideline non-adherence was predominantly valid; contra-indications and patient preference were most often reported as reasons for intentional non-adherence. CONCLUSION: We found a wide range of rates of non-adherence to clinical guidelines. This non-adherence is often supported by valid reasons, mainly related to contra-indications and patient preference. Therefore, we submit that many guideline deviations are intentional and these deviations do not necessarily impact quality of care. PMID- 26980360 TI - Highly grafted polystyrene/polyvinylpyridine polymer gold nanoparticles in a good solvent: effects of chain length and composition. AB - In this work, the structural features of spherical gold nanoparticles (NPs) decorated with highly grafted poly(styrene) (PS), poly(vinylpyridine) (PVP) and PS-PVP diblock copolymer brushes immersed in a good solvent are investigated by means of Dissipative Particle Dynamics (DPD) simulations as a function of grafted chain length and of homopolymer and copolymer chain composition. For NPs grafted either by PS or PVP homopolymer brushes (selected as a proof of concept), good agreement between the Daoud-Cotton theory, experimental evidence, and our DPD simulations is observed in the scaling behavior of single chain properties, especially for longer grafted chains, and in brush thickness prediction. On the other hand, for grafted chain lengths comparable to NP dimensions parabolic-like profiles of the end-monomer distributions are obtained. Furthermore, a region of high concentration of polymer segments is observed in the monomer density distribution for long homopolymers. In the case of copolymer-decorated NPs, the repulsion between PS and PVP blocks is found to substantially influence the radius of gyration and the shape of the end-monomer distribution of the relevant polymer shell. Moreover, for diblock chains, the un-swollen region is observed to be thinner (and, correspondingly, the swollen layer thicker) than that of a NP modified with a homopolymer of the same length. Finally, the lateral segregation of PS and PVP blocks is evidenced by our calculations and a detailed analysis of the corona behavior is reported, thus revealing the key parameters in controlling the surface properties and the response of diblock copolymer modified nanoparticles. PMID- 26980361 TI - The importance of transmission electron microscopy analysis of spermatozoa: Diagnostic applications and basic research. AB - This review is aimed at discussing the role of ultrastructural studies on human spermatozoa and evaluating transmission electron microscopy as a diagnostic tool that can complete andrology protocols. It is clear that morphological sperm defects may explain decreased fertilizing potential and acquire particular value in the field of male infertility. Electron microscopy is the best method to identify systematic or monomorphic and non-systematic or polymorphic sperm defects. The systematic defects are characterized by a particular anomaly that affects the vast majority of spermatozoa in a semen sample, whereas a heterogeneous combination of head and tail defects found in variable percentages are typically non-systematic or polymorphic sperm defects. A correct diagnosis of these specific sperm alterations is important for choosing the male infertility's therapy and for deciding to turn to assisted reproduction techniques. Transmission electron microscopy (TEM) also represents a valuable method to explore the in vitro effects of different compounds (for example drugs with potential spermicidal activity) on the morphology of human spermatozoa. Finally, TEM used in combination with immunohistochemical techniques, integrates structural and functional aspects that provide a wide horizon in the understanding of sperm physiology and pathology. ABBREVIATIONS: transmission electron microscopy: TEM; World Health Organization: WHO; light microscopy: LM; motile sperm organelle morphology examination: MSOME; intracytoplasmic morphologically selected sperm injection: IMSI; intracytoplasmic sperm injection: ICSI; dysplasia of fibrous sheath: DFS; primary ciliary dyskinesia: PCD; outer dense fibers: ODF; assisted reproduction technologies: ART; scanning electron microscopy: SEM; polyvinylpirrolidone: PVP; tert-butylhydroperoxide: TBHP. PMID- 26980362 TI - Exercise: An Important Key to Prevent Physical and Cognitive Frailty. PMID- 26980364 TI - Frailty Across Age Groups. AB - BACKGROUND: The implementation of an aging biomarker into clinical practice is under debate. The Frailty Index is a model of deficit accumulation and has shown to accurately capture frailty in older adults, thus bridging biological with clinical practice. OBJECTIVES: To describe the association of socio-demographic characteristics and the Frailty Index in different age groups (from 20 to over one hundred years) in a representative sample of Mexican subjects. DESIGN: Cross sectional analysis. SETTING: Nationwide and population-representative survey. PARTICIPANTS: Adults 20-years and older interviewed during the last Mexican National Health and Nutrition Survey (2012). MEASUREMENTS: A 30-item Frailty Index following standard construction was developed. Multi-level regression models were performed to test the associations of the Frailty Index with multiple socio-demographic characteristics across age groups. RESULTS: A total of 29,504 subjects was analyzed. The 30-item Frailty Index showed the highest scores in the older age groups, especially in women. No sociodemographic variable was associated with the Frailty Index in all the studied age groups. However, employment, economic income, and smoking status were more consistently found across age groups. CONCLUSIONS: To our knowledge, this is the first report describing the Frailty Index in a representative large sample of a Latin American country. Increasing age and gender were closely associated with a higher score. PMID- 26980365 TI - Association between Berg Balance, Physiological Profile Assessment and Physical Activity, Physical Function and Body Composition: A Cross-sectional Study. AB - BACKGROUND: Falls are of great concern to older adults and costly to the health system. In addition the relationship between falls risk and falls risk predictor characteristics is complex. OBJECTIVE: This study aimed to explore the relationship between two objective fall-risk measures tools, the Physiological Profile Assessment and the Berg Balance Scale and to determine how an individual's sex, level of physical function, health-related and body composition characteristics impact these objective falls risk measures. DESIGN: A cross sectional, observational study. PARTICIPANTS: 245 community-dwelling older adults (M age=68.12 years, SD=6.21; 69.8% female). MEASUREMENTS: Participants were assessed for falls-risk (Physiological Profile Assessment and the Berg Balance Scale), physical activity, physical functional and body composition characteristics. Pearson product-moment correlation coefficients were calculated to examine bivariate relationships and hierarchical multiple linear regression modelling was used to estimate the contribution of each predictor in explaining variance in falls-risk. RESULTS: In females, there was a weak association between the two objective falls-risk measures (r =-0.17 p <0.05). The number of falls in the previous 12 months explained 6% of variance in Physiological Profile Assessment scores, with bone density of the lumbar spine contributing a further 1%. In males and females, variance in the Berg Balance Scale showed that age (25%) and physical function (16% for females, 28% for males) contributed significantly to the explaining variance in the falls-risk measure. CONCLUSION: Sex differences are apparent and as such males and females should be assessed (and potentially treated) differently with regards to falls risk. Results indicate that both falls risk assessment tools measure aspects of balance but are not interchangeable. The Berg Balance Scale may be more discriminative in older, less functioning adults and the Physiological Profile Assessment is more useful in assessing falls risk in females. PMID- 26980366 TI - Validity and Reliability of the Polish Version of the Tilburg Frailty Indicator (TFI). AB - BACKGROUND: In the last decade, studies on frailty have become increasingly frequent in the literature on aging, and also the number of available questionnaires regarding frailty has increased over the years. Therefore, the choice of which questionnaire to use is becoming more difficult. OBJECTIVE: The aim of this study was to assess the psychometric properties of the Polish version of the Tilburg Frailty Indicator (TFI), an instrument that identifies frailty in the elderly population. DESIGN: Setting, and Participants. The study was carried out in a community-based setting in Wroclaw, Poland. Nurses and doctors (general practitioners) administered the TFI in primary care facilities. Participants included a sample of 212 community dwelling elderly aged 60 or older (mean age:70.6 SD>=7.16). MEASUREMENTS: The validation (assessment of face validity, content validity) was carried out in accordance with the literature. The Tilburg Frailty Indicator (TFI) consists of two different parts. One part addresses the potential determinants of frailty and the other specifically addresses the components of frailty, covering its physical, psychological and social domains. Scale reliability was estimated using two methods: Cronbach's alpha, measuring the scale's internal consistency, and the test-retest method, determining the scale's absolute stability. To assess test-retest reliability, the same group was re-interviewed by the same observer within 10-14 days of the first interview. RESULTS: The test-retest reliability showed a high level of agreement for all items of the instrument, with values ranging from 96 to 100%. The Cronbach's Alpha internal consistency was 0.74. CONCLUSION: The Polish version of the TFI proved to be a valid and reproducible tool for assessment of Frailty Syndrome for the Polish population. We would recommend to be used as the screening tool to assess frailty. PMID- 26980363 TI - Genetic Moderators of the Impact of Physical Activity on Depressive Symptoms. AB - BACKGROUND: Converging evidence suggests that physical activity is an effective intervention for both clinical depression and sub-threshold depressive symptoms; however, findings are not always consistent. These mixed results might reflect heterogeneity in response to physical activity, with some subgroups of individuals responding positively, but not others. OBJECTIVES: 1) To examine the impact of genetic variation and sex on changes in depressive symptoms in older adults after a physical activity (PA) intervention, and 2) to determine if PA differentially improves particular symptom dimensions of depression. DESIGN: Randomized controlled trial. SETTING: Four field centers (Cooper Institute, Stanford University, University of Pittsburgh, and Wake Forest University). PARTICIPANTS: 396 community-dwelling adults aged 70-89 years who participated in the Lifestyle Interventions and Independence for Elders Pilot Study (LIFE-P). INTERVENTION: 12-month PA intervention compared to an education control. MEASUREMENTS: Polymorphisms in the serotonin transporter (5-HTT), brain-derived neurotrophic factor (BDNF), and apolipoprotein E (APOE) genes; 12-month change in the Center for Epidemiologic Studies Depression Scale total score, as well as scores on the depressed affect, somatic symptoms, and lack of positive affect subscales. RESULTS: Men randomized to the PA arm showed the greatest decreases in somatic symptoms, with a preferential benefit in male carriers of the BDNF Met allele. Symptoms of lack of positive affect decreased more in men compared to women, particularly in those possessing the 5-HTT L allele, but the effect did not differ by intervention arm. APOE status did not affect change in depressive symptoms. CONCLUSIONS: Results of this study suggest that the impact of PA on depressive symptoms varies by genotype and sex, and that PA may mitigate somatic symptoms of depression more than other symptoms. The results suggest that a targeted approach to recommending PA therapy for treatment of depression is viable. PMID- 26980367 TI - Muscle Disuse as a Pivotal Problem in Sarcopenia-related Muscle Loss and Dysfunction. AB - An age-associated loss of muscle mass and strength--sarcopenia--begins at around the fifth decade of life, with mass being lost at ~0.5-1.2% per year and strength at ~3% per year. Sarcopenia can contribute to a variety of negative health outcomes, including an increased risk for falls and fractures, the development of metabolic diseases like type 2 diabetes mellitus, and increase the chance of requiring assisted living. Linear sarcopenic declines in muscle mass and strength are, however, punctuated by transient periods of muscle disuse that can accelerate losses of muscle and strength, which could result in increased risk for the aforementioned conditions. Muscle disuse is recognizable with bed rest or immobilization (for example, due to surgery or acute illness requiring hospitalization); however, recent work has shown that even a relative reduction in ambulation (reduced daily steps) results in significant reductions in muscle mass, strength and possibly an increase in disease risk. Although reduced ambulation is a seemingly "benign" form of disuse, compared to bed rest and immobilization, reports have documented that 2-3 weeks of reduced daily steps may induce: negative changes in body composition, reductions in muscle strength and quality, anabolic resistance, and decrements in glycemic control in older adults. Importantly, periods of reduced ambulation likely occur fairly frequently and appear more difficult to fully recover from, in older adults. Here we explore the consequences of muscle disuse due to reduced ambulatory activity in older adults, with frequent comparisons to established models of disuse: bed rest and immobilization. PMID- 26980369 TI - Dietary Protein to Maintain Muscle Mass in Aging: A Case for Per-meal Protein Recommendations. AB - It is well accepted that daily protein intake is an important dietary consideration to limit and treat age-related declines in muscle mass, strength, and function. Furthermore, we propose that there is a growing appreciation for the need to consider protein intake on a per-meal basis rather than simply focusing on the total daily protein intake. The existence of a saturable dose response relationship between muscle protein synthesis (MPS) and the quantity of protein consumed in a single meal/bolus provides the rationale for promoting an even/balanced pattern of daily protein intake. We hypothesize that a balanced/even protein intake pattern with the ingestion a quantity of protein shown to optimally stimulate MPS at each meal may be an effective strategy to alleviate sarcopenic muscle loss. In this review we examine the available evidence supporting the influence of dietary protein intake pattern on muscle protein turnover, muscle mass, and muscle function. We present several practical considerations that, it is proposed, should be taken into account when translating a per-meal protein recommendation into dietary advice for older adults. PMID- 26980368 TI - Frailty and Constellations of Factors in Aging HIV-infected and Uninfected Women- The Women's Interagency HIV Study. AB - BACKGROUND: Biological similarities are noted between aging and HIV infection. Middle-aged adults with HIV infection may present as elderly due to accelerated aging or having more severe aging phenotypes occurring at younger ages. OBJECTIVES: We explored age-adjusted prevalence of frailty, a geriatric condition, among HIV+ and at risk HIV- women. DESIGN: Cross-sectional. SETTING: The Women's Interagency HIV Study (WIHS). PARTICIPANTS: 2028 middle-aged (average age 39 years) female participants (1449 HIV+; 579 HIV-). MEASUREMENTS: The Fried Frailty Index (FFI), HIV status variables, and constellations of variables representing Demographic/health behaviors and Aging-related chronic diseases. Associations between the FFI and other variables were estimated, followed by stepwise regression models. RESULTS: Overall frailty prevalence was 15.2% (HIV+, 17%; HIV-, 10%). A multivariable model suggested that HIV infection with CD4 count<200; age>40 years; current or former smoking; income <=$12,000; moderate vs low fibrinogen-4 (FIB-4) levels; and moderate vs high estimated glomerular filtration rate (eGFR) were positively associated with frailty. Low or moderate drinking was protective. CONCLUSIONS: Frailty is a multidimensional aging phenotype observed in mid-life among women with HIV infection. Prevalence of frailty in this sample of HIV-infected women exceeds that for usual elderly populations. This highlights the need for geriatricians and gerontologists to interact with younger 'at risk' populations, and assists in the formulation of best recommendations for frailty interventions to prevent early aging, excess morbidities and early death. PMID- 26980370 TI - Association between Chronic Pain and Frailty in Mexican Elders. AB - Chronic pain is defined as pain lasting longer than six weeks and is one of the main complaints in elderly subjects. Frailty is a pathological condition that increases an individual's vulnerability by diminishing their homeostatic reserve, and it is considered a mortality risk factor. We examined the association between chronic pain and frailty in subjects who were recruited from a check-up clinic in Mexico City. Chronic pain and frailty were evaluated in 131 subjects through validated questionnaires. Descriptive and analytical statistics were performed. Of the participants, 41.9% presented with chronic pain, and 12.2% were frail. The unadjusted OR for the presence of frailty in subjects with chronic pain was 14.3 (95%CI 3.0-67.8), and the phi coefficient showed a weak positive correlation between the variables (Phi=0.352, p<0.001). In conclusion, chronic pain is associated with a higher risk of frailty. Well-timed diagnosis and treatment of chronic pain can help prevent dependency in these individuals. PMID- 26980371 TI - A Phase 2 Randomized Study Investigating the Efficacy and Safety of Myostatin Antibody LY2495655 versus Placebo in Patients Undergoing Elective Total Hip Arthroplasty. AB - BACKGROUND: Total hip arthroplasty relieves joint pain in patients with end stage osteoarthritis. However, postoperative muscle atrophy often results in suboptimal lower limb function. There is a need to improve functional recovery after total hip arthroplasty. OBJECTIVES: To assess safety and efficacy of LY2495655, a humanized monoclonal antibody targeting myostatin, in patients undergoing elective total hip arthroplasty. DESIGN: Phase 2, randomized, parallel, double blind, 12-week clinical trial with a 12-week follow-up period. SETTING: Forty-two sites in 11 countries. PARTICIPANTS: Individuals (N=400) aged >=50 years scheduled for elective total hip arthroplasty for osteoarthritis within 10 +/- 6 days after randomization. INTERVENTION: Placebo or LY2495655 (35 mg, 105 mg, or 315 mg) subcutaneous injections at weeks 0 (randomization date), 4, 8, and 12 with follow up until week 24. MEASUREMENTS: Primary endpoint: probability that LY2495655 increases appendicular lean mass (operated limb excluded) by at least 2.5% more than placebo at week 12, using dual-energy x-ray absorptiometry. Exploratory endpoints: muscle strength, performance based and self-reported measures of physical function, and whole body composition over time. RESULTS: Participants: 59% women, aged 69 +/- 8 years, BMI 29 +/- 5 kg/m2. Groups were comparable at baseline. The primary objective was not reached as LY2495655 changes in lean mass did not meet the superiority threshold at week 12. However, LY2495655 105 and LY2495655 315 experienced progressive increases in appendicular lean mass that were statistically significant versus placebo at weeks 8 and 16. Whole body fat mass decreased in LY2495655 315 versus placebo at weeks 8 and 16. No meaningful differences were detected between groups in other exploratory endpoints. Injection site reactions occurred more often in LY2495655 patients than in placebo patients. No other safety signals were detected. CONCLUSION: Dose dependent increases in appendicular lean body mass and decreases in fat mass were observed, although this study did not achieve the threshold of its primary objective. PMID- 26980373 TI - Nickel-catalyzed ortho-halogenation of unactivated (hetero)aryl C-H bonds with lithium halides using a removable auxiliary. AB - The first example of Ni-catalyzed halogenation of (hetero)aryl C-H bonds with lithium halides (LiX, X = Br, I, Cl) using PIP as a removable directing group is reported. This protocol provides an efficient access to ortho-halogenated (hetero)arenes with operational simplicity, good functional group tolerance, and large-scale synthesis. PMID- 26980372 TI - Investigation of agreement between wastewater-based epidemiology and survey data on alcohol and nicotine use in a community. AB - BACKGROUND/AIMS: Alcohol and nicotine are the two most used substances world-wide and associated with increased burden of disease. Since surveys on substance use may be difficult due to response biases, wastewater-based epidemiology (WBE) was developed as a more objective measure of nicotine and alcohol use. This study compares estimates of nicotine and alcohol use from a wastewater sampling campaign in a medium-sized Belgian city with a concurrently executed population survey. METHODS: 29,083 letters about participation in an online survey study on weekly alcohol and tobacco use were sent to the inhabitants of Lier, Belgium. Wastewater samples were collected from the associated treatment plant in four bi weekly periods. Samples were analyzed using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Ethylsulfate was used as alcohol biomarker and cotinine and trans-3'-hydroxycotinine as nicotine biomarker. RESULTS: 263 (1%) surveys were filled out on average per week. According to survey data, alcohol and nicotine were used less than in the rest of Belgium and this was matched by the wastewater data. Nicotine use, but not alcohol use, showed a significant variation over the sampling periods. Both nicotine and alcohol showed increase use during the weekend while only alcohol showed a different use pattern throughout the week. CONCLUSION: No correlation between WBE and survey data could be demonstrated, possibly due to small sample sizes. However, this study shows that weekly trends in alcohol and nicotine use can be quickly detected from wastewater analysis and the occurrence of major events such as festivals can be identified. PMID- 26980374 TI - CD271(+) stromal cells expand in arthritic synovium and exhibit a proinflammatory phenotype. AB - BACKGROUND: CD271(+) stromal cells (SCs) with multipotent stem cell capacity have been identified in synovial tissues, but their functional significance is unknown. We analyzed the distribution of CD271(+) cells in inflammatory synovial tissues as well as their ex vivo immunomodulatory and inflammatory phenotypes. METHODS: CD271 expression was analyzed by immunohistochemistry in synovial tissues and by flow cytometry in primary adherent synovial cell cultures from rheumatoid arthritis (RA), osteoarthritis (OA), and non-inflammatory control tissues. Isolation of CD271(+) synovial SCs was carried out by magnetic cell sorting. Allogeneic T-cell/SC cocultures were performed to analyze the regulatory capacity of these cells on T-cell proliferation and cytokine production. The production of inflammatory mediators was analyzed in cultures of sorted CD271(+)/(-) SCs. The capacity of CD271(+)/(-) SCs to induce inflammatory cell recruitment in vivo was evaluated in subcutaneous implants in immunodeficient mice. RESULTS: CD271(+) SC were detected in non-inflammatory as well as in arthritic synovial tissues with a specific perivascular distribution. CD271(+) SC density was increased in RA and OA compared with normal synovial tissues. T-cell proliferation and cytokine synthesis were similarly modified by CD271(+) and CD271(-) SCs. Sorted CD271(+) SCs from OA synovial tissues released significantly more interleukin (IL)-6, matrix metalloproteinase (MMP)-1, and MMP-3 than CD271( ) SCs. In immunodeficient mice, implants of CD271(+) SCs induced significantly higher myeloid cell infiltration than CD271(-) SCs. CONCLUSIONS: Our results demonstrate that CD271(+) perivascular SCs expand in RA and OA synovial tissues. CD271(+) cells showed enhanced proinflammatory properties ex vivo and in vivo, whereas immunoregulatory properties were equivalent in CD271(+) and CD271(-) SC. PMID- 26980375 TI - The contribution of the body and motion to whole person recognition. AB - While the importance of faces in person recognition has been the subject of many studies, there are relatively few studies examining recognition of the whole person in motion even though this most closely resembles daily experience. Most studies examining the whole body in motion use point light displays, which have many advantages but are impoverished and unnatural compared to real life. To determine which factors are used when recognizing the whole person in motion we conducted two experiments using naturalistic videos. In Experiment 1 we used a matching task in which the first stimulus in each pair could either be a video or multiple still images from a video of the full body. The second stimulus, on which person recognition was performed, could be an image of either the full body or face alone. We found that the body contributed to person recognition beyond the face, but only after exposure to motion. Since person recognition was performed on still images, the contribution of motion to person recognition was mediated by form-from-motion processes. To assess whether dynamic identity signatures may also contribute to person recognition, in Experiment 2 we presented people in motion and examined person recognition from videos compared to still images. Results show that dynamic identity signatures did not contribute to person recognition beyond form-from-motion processes. We conclude that the face, body and form-from-motion processes all appear to play a role in unfamiliar person recognition, suggesting the importance of considering the whole body and motion when examining person perception. PMID- 26980376 TI - Step down Vascular Calcification Analysis using State-of-the-Art Nanoanalysis Techniques. AB - New insights into the architecture and formation mechanisms of calcific lesions down to the nanoscale open a better understanding of atherosclerosis and its pathogenesis. Scanning electron - and atomic force microscope based nano analytical characterization techniques were adapted to the assessment of an ex vivo calcified coronary artery. Human atherosclerotic tissue and bone tissue reside a typical chemistry of Magnesium and Sodium rich Calcium phosphates, identified as whitlockite and Calcium apatite, respectively. Despite the obvious similarities in both chemistry and crystallography, there are also clear differences between calcified vascular tissue and bone such as the highly oriented growth in bone, revealing meso-crystal character, as opposed to the anisotropic character of calcified vascular lesions. While the grain size in vascular calcified plaques is in the range of nanometers, the grain size in bone appears larger. Spherical calcific particles present in both the coronary artery wall and embedded in plaques reveal concentric layers with variations in both organic content and degree of hydration. PMID- 26980378 TI - Chronic rhinosinusitis and extraesophageal reflux: Who is the candidate for antireflux treatment? AB - BACKGROUND: During the past decade, extraesophageal reflux (EER) has been hypothesized to be one of the possible factors that contribute to the worsening of chronic rhinosinusitis (CRS). However, the relationship remains indeterminate due to its complexity, and it is not clear whether antireflux treatment is indicated for patients with recurrent CRS and who would benefit from it. OBJECTIVE: The aim of the study was to determine the severity of EER in patients with variable durations of CRS and different numbers of previous endoscopic endonasal surgeries (EES). METHODS: Ninety patients with CRS were recruited for the prospective case series. The age, sex, body mass index, reflux symptom index, duration of treatment of CRS with corticosteroids, and the number of ESS within the previous 5 years were ascertained. The severity of EER was evaluated by oropharyngeal pH monitoring by using the Restech system (the presence of EER, value of the RYAN score) and compared among the groups with varying durations of treatment of CRS (<=10 years, 11-20 years, >20 years) and different numbers of ESS within the previous 5 years (no ESS, 1-2 ESS, >2 ESS). RESULTS: Pathologic EER was present significantly more often in patients with CRS treated for >10 years (p = 0.0054) and in patients who underwent >2 ESS within the previous 5 years (p = 0.0001). CONCLUSION: Patients with CRS treated for >10 years and those who had undergone >2 ESS within the previous 5 years had significant EER. Antireflux therapy (e.g., proton pump inhibitors) can be recommended for these patients. However, its effect has to be confirmed in further studies. PMID- 26980377 TI - In vivo and in vitro evaluation of the effects of Urtica dioica and swimming activity on diabetic factors and pancreatic beta cells. AB - BACKGROUND: Urtica dioica (UD) has been identified as a traditional herbal medicine. This study aimed to investigate the effect of UD extract and swimming activity on diabetic parameters through in vivo and in vitro experiments. METHODS: Adult WKY male rats were randomly distributed in nine groups: intact control, diabetic control, diabetic + 625 mg/kg, 1.25 g/kg UD, diabetic + 100 mg/kg Metformin, diabetic + swimming, diabetic + swimming 625 mg/kg, 1.25 g/kg UD, and diabetic +100 mg/kg Metformin + swimming. The hearts of the animals were punctured, and blood samples were collected for biochemical analysis. The entire pancreas was exposed for histologic examination. The effect of UD on insulin secretion by RIN-5F cells in 6.25 or 12.5 mM glucose dose was examined. Glucose uptake by cultured L6 myotubes was determined. RESULTS: The serum glucose concentration decreased, the insulin resistance and insulin sensitivity significantly increased in treated groups. These changes were more pronounced in the group that received UD extract and swimming training. Regeneration and less beta cell damage of Langerhans islets were observed in the treated groups. UD treatment increased insulin secretion in the RIN-5F cells and glucose uptake in the L6 myotubes cells. CONCLUSIONS: Swimming exercises accompanied by consuming UD aqueous extracts effectively improved diabetic parameters, repaired pancreatic tissues in streptozotocin-induced diabetics in vivo, and increased glucose uptake or insulin in UD-treated cells in vitro. PMID- 26980380 TI - Nasal septal deviation with obstructive symptoms: Association found with asthma but not with other general health problems. AB - BACKGROUND: Nasal septal deviation (NSD) is a very common deformity. Because it may induce chronic upper airway obstruction in the nose, clinicians encounter some patients who have concerns about whether this can be a risk factor for general health. However, the influence of NSD on general health has rarely been studied. OBJECTIVE: To determine associations between NSD, especially NSD with nasal obstructive symptom, and general health problems in an adult Korean population. METHODS: This nationwide study analyzed data from the Korea National Health and Nutritional Examination Survey, 2008-2009. NSD was evaluated by using a nasal endoscope, and a nasal obstructive symptom was assessed via individual interviews. The survey also investigated general health problems, such as medical comorbidity, mental health status, and quality of life. Medical conditions included neurocardiovascular, respiratory, metabolic, musculoskeletal, gastrointestinal, and malignant diseases. To eliminate the effect of combined nasal problems in otorhinolaryngology, subjects with rhinosinusitis and allergic rhinitis were excluded. This study focused on obstructive NSD, which is defined as an anatomic NSD with a chronic nasal obstructive symptom. RESULTS: We enrolled 8865 participants, and the prevalence of NSD was 44.8%. No general health problems showed a significant association with NSD. However, the prevalence of NSD with an obstructive symptom was 2.1%. Obstructive NSD had no association with all the general health problems, except asthma. A significant association was found between obstructive NSD and asthma (odds ratio 2.648 [95% confidence interval, 1.211-5.791]). CONCLUSION: Among various general health problems, our study found that NSD was associated with asthma only when NSD was accompanied by a chronic nasal obstructive symptom. PMID- 26980379 TI - Systematic review of the effectiveness of perioperative prophylactic antibiotics for skull base surgeries. AB - BACKGROUND: Perioperative antibiotics are commonly used in endoscopic skull base surgeries as prophylaxis for infectious complications, e.g., meningitis. The role of perioperative prophylactic antibiotics in endoscopic sinus surgery is unclear, and the routine use of prophylactic antibiotics in endoscopic skull base surgery is also highly debated. Currently, there is no formal recommendation for perioperative antibiotic use in skull base surgery, and regimens vary greatly from one institution to the next. OBJECTIVE: To assess perioperative antibiotics as prophylaxis against infectious complications in patients who underwent endoscopic skull base surgery. DATA SOURCES: PubMed, Ovid EMBASE, and the Cochrane Library. METHODS: A systematic review that examined perioperative antibiotic use in endoscopic skull base and craniofacial surgeries was conducted. Inclusion criteria were prospective or retrospective study design and clinical trials related to the use of antibiotics within 30 days of skull base surgery. End points included infectious complications such as (1) meningitis and (2) sinusitis. RESULTS: A total of 2543 articles were identified by the initial search, and 5 articles met inclusion criteria. The five eligible trials were all observational and involved different types of skull base surgical procedures and antibiotic regimens. CONCLUSIONS: Despite institutional variability in antibiotic regimens, meningitis rarely occurs after skull base procedures and seems to be encountered most frequently in open craniofacial surgeries. A systematic review revealed a limited number of published studies, all observational in study design, which precluded a formal meta-analysis. A novel large-scale randomized controlled clinical trial is needed to evaluate antibiotic selection and need in endoscopic skull base surgery. PMID- 26980381 TI - Evaluation of the eosinophil-to-lymphocyte ratio in pediatric patients with allergic rhinitis. AB - BACKGROUND: Allergic rhinitis is a type 1 hypersensitivity reaction of the nasal mucosa, the primary mediator of which is immunoglobulin E. Allergic rhinitis occurs in children and adolescents. OBJECTIVE: This study examined the relationship between allergies and the eosinophil-to-lymphocyte ratio in children with allergic rhinitis with a positive skin-prick test. STUDY DESIGN: This study was planned and performed as a case-control study. METHODS: There were 695 patients who presented to our clinic who were enrolled in the study. Only group 4 fit the criteria for allergic rhinitis. Group 1 (nonsensitized asymptomatic [control group]), group 2 (nonsensitized symptomatic), group 3 (sensitized asymptomatic), and group 4 (sensitized symptomatic). The patients' allergy symptoms and skin test results were assessed and compared. The eosinophil-to lymphocyte ratio for each patient was calculated. The eosinophil and lymphocyte counts and the eosinophil-to-lymphocyte ratio were calculated for each group. RESULTS: The eosinophil-to-lymphocyte ratio and eosinophil counts in groups 3 and 4 were significantly higher (p < 0.001 and p < 0.001, respectively) than those in groups 1 and 2. The lymphocyte counts in groups 3 and 4 were significantly lower (p = 0.046) than those of groups 1 and 2. CONCLUSIONS: The eosinophil-to lymphocyte ratio may be used in conjunction with skin-prick testing in pediatric patients with allergic rhinitis. This parameter is inexpensive to measure and easy to use and calculate. PMID- 26980382 TI - Prevalence of allergic rhinitis symptoms and positive skin-prick test results in patients with dry eye. AB - BACKGROUND: Dry eye is characterized by decreased tear production and/or increased evaporation rates of the tear film barrier. Allergic rhinitis is an inflammatory disease that develops through immunoglobulin E in the rhino-ocular mucosa due to allergens. To investigate the prevalence of allergic rhinitis symptoms and positive skin-prick test results in patients with dry eye. METHODS: This is a case-control study. The study included 57 patients with dry eye and 48 healthy subjects. The prevalence of allergic symptoms and skin-prick test results were assessed and compared with the control group. RESULTS: With regard to positive reactions to allergens in skin-prick tests, Dermatophagoides pteronyssinus allergy (p = 0.0003), Dermatophagoides farinae allergy (p = 0.0003), grass-mix allergy (p = 0.049), Salicaces allergy (p = 0.006), and Compositae allergy (p = 0.019) were significantly observed to be higher in the group with dry eye. Nasal obstruction (p = 0.027), discharge (p = 0.0001), sneeze (p = 0.0003), itching (p = 0.0001), and postnasal drainage (p = 0.001) symptoms were observed to be significantly higher in the group with dry eye. CONCLUSIONS: Our study revealed that there was a significant association between dry eye and allergic rhinitis with positive skin-prick test results. There may be a possible link between dry eye and allergy. PMID- 26980383 TI - Quality-of-life outcomes after sinus surgery in allergic fungal rhinosinusitis versus nonfungal chronic rhinosinusitis. AB - BACKGROUND: Given the differences in pathophysiology between allergic fungal rhinosinusitis (AFRS) and other chronic rhinosinusitis (CRS) subgroups, it remains unclear about whether these patients respond differently to a combination of surgical and medical treatments. OBJECTIVE: To evaluate differences in quality of-life (QoL) outcomes for a cohort of patients who underwent endoscopic sinus surgery (ESS) for CRS. METHODS: This retrospective review included patients with CRS who underwent ESS between 2010 and 2013. QoL was measured by using the 22 item Sino-Nasal Outcome Test (SNOT-22). Variables collected included baseline demographics, SNOT-22 scores before ESS and at 1, 3, 6, 9, and 12 months after ESS. Groups tested were CRS with nasal polyposis, CRS without nasal polyposis (CRSsNP), and patients with AFRS. A linear mixed- effects regression model was used to calculate the adjusted mean QoL differences. RESULTS: Among the 250 patients included, 61.6% had CRS with nasal polyposis (n = 154), 28.8% had CRSsNP (n = 72), and 9.6% had AFRS (n = 24). Significant differences were seen in SNOT 22 scores between pre- and postoperative visits and between the etiologic subgroups (p < 0.001). Multivariate analysis revealed significantly greater improvement in QoL for patients with AFRS in comparison with those with CRSsNP at the 9-month follow-up (change in SNOT-22 score, 22.6 [95% confidence interval, 1.2-44.1]; p < 0.0) and the 12-month follow-up (change in SNOT-22 score, 20.2 [95% confidence interval, 0.5-39.9]; p < 0.04). CONCLUSIONS: Patients with AFRS experienced a more-prolonged QoL benefit from surgical and targeted medical intervention compared with those with CRSsNP, which may reflect the severity of inflammation that they presented with compared with other CRS subtypes. PMID- 26980384 TI - Evaluation of residual symptoms: A method to assess surgical outcomes for nasal polyposis. AB - BACKGROUND: The assessment of residual symptoms after endoscopic sinus surgery for nasal polyposis (NP) could be an accurate way to evaluate surgical outcomes. OBJECTIVE: To assess the residual symptoms and their severity at 6 weeks and 7 months after radical ethmoidectomy for NP. METHODS: Sixty-five patients who had surgery for NP were included in this prospective study. Six residual symptoms (nasal obstruction, anterior rhinorrhea, postnasal discharge, olfactory disturbances, facial pain, and cough) were assessed by using the validated Dysfonctionnement Nasal Chronique (French) or Chronic Nasal Dysfunction (English) questionnaire at 6 weeks and 7 months after surgery. Olfactory measurements were performed with the Sniffin' Stick test. A self-rating score of >=1 was considered as "having a complaint." RESULTS: Radical ethmoidectomy for NP improved not only the number of symptoms but also the intensity of symptoms. Before surgery, 64 of 65 patients (98.46%) reported at least three of the six symptoms, whereas 26 patients (40%) reported six symptoms, 16 (24.62%) reported five symptoms, and 14 (21.54%) reported four symptoms. At 6 weeks and at 7 months after surgery, one third of the patients had fewer than three symptoms. Olfactory disturbance remained the most mentioned postoperative disabling problem. Posterior discharge tended to become more pronounced at 7 months than at 6 weeks after surgery but remained considerably improved compared with the preoperative state. CONCLUSION: This information is useful to warn patients about the difficulty of getting rid of all symptoms and that there is a chance that some symptoms remain or even reappear after NP surgery. PMID- 26980385 TI - Septoplasty in children. AB - OBJECTIVES: Physicians have long had concerns about the potential harmful effects of pediatric septoplasties on the nasoseptal growth process because septal cartilage is important for the growth and development of the face. METHODS: In this review article, pediatric septoplasty and its indications are discussed, together with a literature survey. In addition, overviews of development of the nasal skeleton from neonate to adult, nasal growth, and cartilaginous septum are presented. Important issues and comments on pediatric septoplasties are provided. RESULTS: During septoplasty procedures, elevation of the mucoperichondrium unilaterally or bilaterally does not negatively affect growth of the face. Stabilization of the septum may be easier when mucosal elevation is performed unilaterally. The nasal floor mucosa should not be elevated so to avoid damage to the incisive nerves. Corrections and limited excisions may be done from the cartilaginous septum. Separation of the septal cartilage from the perpendicular plate, especially at the dorsal part, should not be performed because this area is important for the length and height of the nasal septum and nasal dorsum. Incisions or excisions should not be performed through the growing and supporting zones, especially at the sphenoethmoid dorsal zone. CONCLUSION: If there are severe breathing problems related to the septal deviation, septoplasty should be performed. In the majority of cases, septal surgery may be conducted in 6-year old children. However, if necessary, septal surgery may be performed in younger children and even at birth. PMID- 26980386 TI - The association between serum lead and total immunoglobulin E levels according to allergic sensitization. AB - BACKGROUND: Results of several studies showed that blood lead concentration is positively associated with total immunoglobulin E (IgE) value. However, no study has investigated whether allergic sensitization could be responsible for the association between lead exposure and total IgE value. OBJECTIVE: We investigated whether there was difference in the association between lead exposure and the total IgE value, depending on the presence or absence of Dermatophagoides farinae sensitization. METHODS: We used data obtained from the Korea National Health and Nutrition Examination Survey. Serum levels of heavy metals, such as mercury, cadmium, and lead, were measured. Total and D. farinae specific IgE levels were measured, and the urinary cotinine level was investigated. Information about sex, age, body mass index, and household income were also obtained. We analyzed the association between serum lead and total IgE levels, after adjusting other variables. RESULTS: In an multivariate linear regression analysis, only the serum concentration of lead among the three heavy metals was positively associated with logarithmic transformed total IgE (coefficient [B], 0.026 [95% confidence interval {CI}], 0.008-0.044). When we performed the same analysis on groups divided by allergic D. farinae sensitization status, we found a significant positive association between serum lead and logarithmic transformed total IgE values in subjects with D. farinae sensitization (B, 0.043 [95% CI, 0.014-0.071]) but not in subjects without D. farinae sensitization (B, 0.015 [95% CI, -0.008 to 0.039]). CONCLUSIONS: A positive association between the serum lead and total IgE levels was statistically significant in subjects with D. farinae sensitization, which indicated that the immunologic effects of lead exposure may be greater in people with allergic sensitization. PMID- 26980387 TI - Inverted papilloma: The stubbornly persistent tumor of the sinonasal cavity. PMID- 26980388 TI - Smoking, not human papilloma virus infection, is a risk factor for recurrence of sinonasal inverted papilloma. AB - BACKGROUND: The recurrence rate of sinonasal inverted papillomas (SNIP) is 15 20%. However, few studies have investigated patient-dependent factors related to recurrence of SNIPs. OBJECTIVE: To analyze risk factors, including human papilloma virus (HPV) infection and smoking, as well as other factors, for recurrence of SNIPs. METHODS: Fifty-four patients who were diagnosed with SNIP and underwent surgery were enrolled: 39 men and 15 women, with the mean age of 54.0 years. Their mean follow-up was 40.6 months. Demographics and information about the history of smoking, previous surgery, tumor extent, follow-up, and recurrence were reviewed retrospectively. Those patients whose tumors were associated with malignant transformation were excluded in this study. HPV detection and genotyping in the tumor specimens were performed with the HPV DNA chip, a polymerase chain reaction-based DNA microarray system. RESULTS: Seven patients (13.0%) had recurrence, with a mean time to recurrence of 39.8 months. Recurrence rates in T1, T2, T3, and T4 of the Krouse staging system were 0% (0/4), 8.3% (2/24), 17.4% (4/23), and 33.3% (1/3), respectively (p > 0.5). Eight patients (14.8%) were positive for HPV DNA. All of these patients belonged to the group without recurrence (p > 0.5). However, recurrence rates according to HPV DNA positivity were not statistically different (0% versus 15.2%). Three (42.9%) in the group with recurrence and four (8.5%) in the group without recurrence were smokers (p < 0.5). CONCLUSION: Smoking was associated with recurrence of SNIP. However, HPV infection is not a recurrence of SNIP risk factor. PMID- 26980389 TI - Cytofunctional changes in nasal ciliated cells in patients treated with hyaluronate after nasal surgery. AB - BACKGROUND: Hyaluronic acid (HA) plays a significant role in tissue repair of mucosal surfaces and, consequently, in surgical injury remodelling of nasal mucosa. OBJECTIVE: To assess the effect of high-molecular-weight HA administered by aerosol on the morphofunctional recovery of ciliated cells damaged by surgical trauma. METHODS: A single-blind, prospective, randomized trial was carried out with 94 patients who were randomly assigned, after endoscopic turbinoplasty, either to treatment with nasal saline solution irrigation (control group, n = 47) or to treatment with nasal douches based on high concentration (9 mg) and high molecular-weight sodium hyaluronate (active treatment group, n = 47). All the patients were evaluated by using nasal fiberendoscopy, mucociliary transport time, nasal cytologic test, and a visual analog scale in terms of symptoms before and at 2 and 4 weeks after surgery. RESULTS: Visual analog scale values were significantly lower in the active treatment (AT) group at week 2 regarding each individual symptom. Mucociliary transport time was significantly reduced in patients in the AT group but only 1 month after surgery. Both the percentage of cellular impairments and the number of cells with hyperchromatic supranuclear stria showed significant improvements in the AT group in all postsurgery evaluations (p < 0.05). CONCLUSION: Intranasal use of sodium hyaluronate in patients who underwent functional nasal surgery improved both mucociliary clearance and nasal mucosa regeneration due to a faster recovery of the impaired ciliated cells. PMID- 26980390 TI - Spleen tyrosine kinase induces MUC5AC expression in human airway epithelial cell. AB - BACKGROUND: MUC5AC, a major secreted mucin, is increased in chronic inflammatory airway disease. Spleen tyrosine kinase (SYK) is a mediator, which acts as an important regulator of intracellular signal transduction in the inflammatory response. SYK was originally identified in hematopoietic cells, and its expression in some nonhematopoietic cells, including respiratory epithelial cells, was recently demonstrated. However, the effects of SYK on mucin secretion in human airway epithelial cells have not been studied. The objective of this study was to investigate the effect and brief signaling pathways of SYK on MUC5AC expression in human airway epithelial cells. METHODS: In mucin-producing human NCI-H292 cells and primary cultures of human nasal epithelial cells, the effects and signaling pathways of SYK on MUC5AC expression were investigated by reverse transcriptase-polymerase chain reaction, real-time polymerase chain reaction, enzyme immunoassay, and immunoblot analysis with several specific inhibitors and small interfering RNA (siRNA). RESULTS: SYK induced MUC5AC expression. SYK activated significant phosphorylation of extracellular signal-related kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) signaling pathways. SYK induced MUC5AC expression was significantly attenuated by pretreatment with U0126 (ERK1/2 MAPK inhibitor) and SB203580 (p38 MAPK inhibitor). In addition, the knockdown of ERK2 and p38 MAPK by ERK2 and p38 MAPK siRNA significantly blocked SYK-induced MUC5AC expression. CONCLUSION: These results indicated that SYK increased MUC5AC expression via ERK2 and p38 MAPK signaling pathways in human airway epithelial cells. PMID- 26980391 TI - Differences in the Sino-Nasal Outcome Test 22 and visual analog scale symptom scores in chronic rhinosinusitis with and without nasal polyps. AB - BACKGROUND: Chronic rhinosinusitis (CRS) with and without polyps has a high impact on health-related quality of life (HRQL), but the difference in HRQL and symptom presentation between two clinical phenotypes of CRS has not been specifically evaluated before now. OBJECTIVE: To evaluate patterns of symptoms and HRQL disease-specific domains affected in patients with CRS by comparing differences between two clinical phenotypes, adjusted for demographics, major risk factors, comorbidities, current medical treatment, and previous surgery. METHODS: A group of 251 patients with CRS completed the visual analog scale (VAS) symptom severity score and the Sino-Nasal Outcome Test 22 (SNOT-22) questionnaire. Data sets were analyzed by using principal component analysis (PCA) to identify a set of symptom components, together with the items excluded from PCA, which were then analyzed for differences between patients with CRS with nasal polyps (CRSwNP) and patients with CRS without nasal polyps (CRSsNP). RESULTS: PCA of SNOT-22 items identified six components, three referred to CRS specific symptoms termed "nasal"; "extranasal, rhinologic"; and "olfactory/cough"; and three referred to HRQL impairment termed "sleep disturbance," "functional disturbance," and "emotional disturbance." Nasal obstruction, ear pain, ear fullness, and fatigue were excluded from PCA and treated as separate outcomes. Patients with CRSwNP had significantly worse nasal symptoms, olfactory/cough symptoms, and nasal obstruction. Patients with CRSsNP scored significantly worse with regard to fatigue and to sleep and functional disturbances. The PCA results for VAS scores identified three symptom components: pain, nasal symptoms, and pharyngeal symptoms. Patients with CRSwNP had significantly worse VAS nasal symptoms but less pronounced VAS pain symptoms than patients with CRSsNP. The total SNOT-22 score between the groups was not significantly different. CONCLUSION: With controlling of covariates that may influence the severity of the disease, this study showed significant differences in symptom patterns and different aspects of HRQL impairment between patients with CRSwNP and patients with CRSsNP, however, with no difference in the total HRQL score. PMID- 26980392 TI - Problem-based learning discussion: Medical treatment of pediatric chronic rhinosinusitis. AB - This problem-based learning case focused on the approach to evaluation and management of a 5-year old girl who was "always sick" with sinus infections. The discussion unfolds in a "real life" scenario, i.e., based on information available to the clinician initially and after the acquisition of laboratory data, and, ultimately, after sinus surgery. Emphasis is placed on the differential diagnosis of the patient's symptoms, discussion of the initial management strategy for chronic rhinosinusitis (CRS), evolution from acute rhinosinusitis to CRS, the prevalence of and differential diagnosis of nasal polyps in children, treatment considerations specific for CRS with nasal polyps, the significance of Pseudomonas aeruginosa sinus infection, the significance of an abnormal sweat chloride test in a young child with nasal polyposis, special considerations in children with CRS who have cystic fibrosis, treatment considerations after endoscopic sinus surgery, and, finally, prognostic factors that impact the outcomes of endoscopic sinus surgery. This problem-based learning case highlights many facets of managing refractory CRS in children. PMID- 26980394 TI - Chronic rhinosinusitis: Epidemiology and burden of disease. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is based on sinonasal symptoms coupled with sinonasal tissue inflammation. Establishing the epidemiology and prevalence of CRS, therefore, is challenging given that confirming objective evidence of sinonasal inflammation on a large scale is not feasible. Although the sinonasal symptoms are well documented at the sinonasal level, analysis of emerging data indicates that the impact on the general-health-related domains of health are the symptoms that are most bothersome to patients' quality of life. OBJECTIVE: To review the literature on the epidemiology and the societal and individual burdens of CRS. METHODS: A literature review. RESULTS: A refinement of questionnaire based surveys coupled with sampling of respondents for accuracy likely provides the most accurate assessment of prevalence. There is geographic variation, but, in North American and European countries, the rates range from 4.5 to 12%. Although CRS is marked by sinonasal symptoms, the most problematic symptoms for patients seem to be the symptoms that affect general-health-related domains. Diminished sleep, productivity, cognition, mood, and fatigue are associated with the decision to elect surgical intervention and are associated with diminished healthy utility values. Direct costs of CRS have been well documented, but new data on the indirect costs of decreased productivity surpass direct costs, at $12.8 billion dollars per year in the United States. CONCLUSION: CRS is a common disease with a large and vast symptom burden with high indirect costs. Although clinicians are focused by guidelines on sinus-specific symptoms, patients seem to be most impacted by the general-health-related consequences of CRS. An expanded understanding of the extent and costs of these symptoms will allow for a cost effective allocation of limited health care resources. PMID- 26980393 TI - Depression in chronic rhinosinusitis: A controlled cohort study. AB - BACKGROUND: Depression in patients with chronic rhinosinusitis (CRS) is underdiagnosed but significantly impacts treatment outcomes and health care utilization. OBJECTIVE: To compare undiagnosed depression in a CRS cohort with a healthy, non-CRS control cohort. METHODS: A case-control study of patients with symptomatic CRS and a non-CRS control cohort was performed. Demographic and comorbidity factors were correlated to depression-specific outcomes by using the Beck Depression Inventory II (BDI). RESULTS: We enrolled 42 patients with CRS and 88 control patients with no history of CRS. Physician-diagnosed depression was equivalent in CRS and control patients (6% and 9%, respectively). BDI-detected depression was higher among patients with CRS compared with controls (31% versus 14.8%, respectively; p = 0.031). BDI scores were higher in patients with CRS even when controlling for comorbid asthma, allergy, and aspirin sensitivity. When examined by polyp status, the patients without polyps had more depression than did the controls (38% versus 14.8%; p = 0.048). The somatic subscale scores of the BDI were worse in patients with CRS (p = 0.004), whereas the cognitive subscale trended toward significance (p = 0.081). CONCLUSION: Depression may be more common in CRS than previously recognized, especially in patients without polyps. Somatic subscale scores of the BDI are increased in CRS and may impact future treatment outcomes. PMID- 26980395 TI - Bleeding risk associated with resection of the middle turbinate during functional endoscopic sinus surgery. AB - BACKGROUND: The decision to resect the middle turbinate (MT) during functional endoscopic sinus surgery is controversial. Although there have been a variety of studies that examined the functional outcome related to this maneuver, very few studies evaluated the potential for complications, in particular, epistaxis. OBJECTIVE: We sought to determine if resection of the MT during functional endoscopic sinus surgery leads to an increased risk for postoperative bleeding. METHODS: Patients who underwent functional endoscopic sinus surgery for chronic sinusitis or nasal polyposis between 2004 and 2014 at a single institution were analyzed for bleeding and other complications after resection of the MT. RESULTS: Between 2004 and 2014, 1185 sinus surgeries were performed by 18 surgeons. A propensity matched set of 228 patients who underwent turbinate resection, and 228 controls were selected based on predicted probabilities from a logistic regression that predicted turbinate resection and that was adjusted for age, sex, and procedure. There were 89 patients with bilateral turbinates removed and 139 with unilateral turbinates removed. There was no significant difference in major bleeding or other complication rates between the two groups. Patients who underwent resection of at least one MT were 3.95 times more likely to have minor bleeding compared with those who did not; this risk increased with the number of turbinates resected (trend p = 0.008). Patients on anticoagulation medications were at a significant risk of bleeding if their MT was removed (p = 0.007), whereas patients on aspirin or antiplatelet therapy were not at a significant risk. CONCLUSION: There was no increased risk of major bleeding or other complication associated with resection of the MT. However, there was a significantly increased minor bleeding rate associated with MT resection, particularly if the patient was on anticoagulants. PMID- 26980396 TI - Extensive versus functional endoscopic sinus surgery for chronic rhinosinusitis with nasal polyps and asthma: A 1-year study. AB - BACKGROUND: Functional endoscopic sinus surgery (FESS) is considered to be the standard procedure for chronic rhinosinusitis with nasal polyps (CRSwNP). However, for CRSwNP that accompanies asthma, the results are not satisfying. Extensive endoscopic sinus surgery (EESS) aimed at reducing the inflammatory load has been indicated as a viable option for refractory chronic rhinosinusitis. OBJECTIVE: To evaluate the clinical outcomes and safety of EESS (middle turbinate and superior turbinate resection and total ethmoidectomy) for patients with CRSwNP and with asthma. METHODS: This was a prospective, single-institute cohort study conducted in a tertiary teaching hospital. Patients with CRSwNP and with asthma who were proceeding to surgery were enrolled. There were 23 patients in the EESS group and 24 patients in the FESS group. The preoperative disease severity was evaluated by the visual analog scale (VAS), Lund-Kennedy (L-K) endoscopy score, computed tomography Lund-Mackay score, asthma control test (ACT), and pulmonary function test. Clinical outcomes were comparatively evaluated between the two groups after a 1-year follow-up by using the VAS score, the postoperative endoscopic score (E score), L-K score, ACT score, and pulmonary function test. RESULTS: The disease severity (general VAS score, endoscopic L-K score, computed tomography score, ACT score) showed no significant differences between the two groups before surgery (p > 0.05). One year after surgery, both groups achieved significant improvement in the VAS score and endoscopic L-K score. The EESS group showed better improvement in the olfactory VAS score and E score compared with the FESS group (mean [standard deviation] change of olfactory VAS, 6.00 +/- 3.67 versus 3.30 +/- 3.44, p = 0.015; mean [standard deviation] E score, 0.31 +/- 0.18 versus 0.66 +/- 0.26, p < 0.001). No significant differences were found in the change of general nasal symptom VAS score, other individual VAS scores (nasal congestion, discharge, headache and/or facial pain), L-K score, ACT score, and pulmonary function between the two groups (p > 0.05). CONCLUSION: EESS for patients with CRSwNP and with asthma may help to improve the subjective olfaction and endoscopic appearance. PMID- 26980397 TI - Atypical presentations of sinonasal inverted papilloma: Surgical management and influence on the recurrence rate. AB - BACKGROUND: Sinonasal inverted papilloma (SNIP), classically, is a unilateral benign tumor of the nasal lateral wall. Numerous variations have been observed, depending on location, bilateral presentation, or association with nasal polyposis. OBJECTIVE: The aim of this work was to describe atypical presentations of SNIPs with their management specificities and to assess their influence on the recurrence rate in a large case series. METHODS: A retrospective single center study of 110 patients treated for SNIP. Atypical inverted papillomas were identified according to the following criteria: (1) unusual location (frontal, posterior, anterior), (2) bilateral involvement, and (3) association with nasal polyposis. Surgical management was detailed, and the influence of each atypical group on recurrence was assessed by using Kaplan-Meier survival curves and the log-rank test. RESULTS: Distribution of atypical presentations was as follows: frontal sinus localization (10.9%); posterior localization, including sphenoid sinus (9%); nasal anterior localization (3.6%); bilateral involvement (3.6%); and nasal polyposis association (10%). The surgical approach was endoscopic (74.5%), external (5.5%), or combined endoscopic and external (20%). Except for nasal anterior localization, all the groups were associated with a higher recurrence rate, without reaching statistical significance. CONCLUSION: Recurrence rates for these atypical presentations arise from their specific surgical challenges. The choice of the surgical technique is guided by tumor location and extension, and by the surgeon's experience; the main objective is a complete resection. The endoscopic endonasal approach is the most frequent procedure. PMID- 26980399 TI - De novo transcriptomic assembly and profiling of Rigidoporus microporus during saprotrophic growth on rubber wood. AB - BACKGROUND: The basidiomycete Rigidoporus microporus is a fungus that causes the white rot disease of the tropical rubber tree, Hevea brasiliensis, the major source of commercial natural rubber. Besides its lifestyle as a pathogen, the fungus is known to switch to saprotrophic growth on wood with the ability to degrade both lignin and cellulose. There is almost no genomic or transcriptomic information on the saprotrophic abilities of this fungus. In this study, we present the fungal transcriptomic profiles during saprotrophic growth on rubber wood. RESULTS: A total of 266.6 million RNA-Seq reads were generated from six libraries of the fungus growing either on rubber wood or without wood. De novo assembly produced 34, 518 unigenes with an average length of 2179 bp. Annotation of unigenes using public databases; GenBank, Swiss-Prot, Kyoto Encyclopedia of Genes and Genomes (KEGG), Cluster of Orthologous Groups (COG) and Gene Ontology (GO) produced 25, 880 annotated unigenes. Transcriptomic profiling analysis revealed that the fungus expressed over 300 genes encoding lignocellulolytic enzymes. Among these, 175 genes were up-regulated in rubber wood. These include three members of the glycoside hydrolase family 43, as well as various glycosyl transferases, carbohydrate esterases and polysaccharide lyases. A large number of oxidoreductases which includes nine manganese peroxidases were also significantly up-regulated in rubber wood. Several genes involved in fatty acid metabolism and degradation as well as natural rubber degradation were expressed in the transcriptome. Four genes (acyl-CoA synthetase, enoyl-CoA hydratase, 3 hydroxyacyl-CoA dehydrogenase and acyl-CoA acetyltransferase) potentially involved in rubber latex degradation pathway were also induced. A number of ATP binding cassette (ABC) transporters and hydrophobin genes were significantly expressed in the transcriptome during saprotrophic growth. Some genes related to energy metabolism were also induced. CONCLUSIONS: The analysed data gives an insight into the activation of lignocellulose breakdown machinery of R. microporus. This study also revealed genes with relevance in antibiotic metabolism (e.g. cephalosporin esterase) as well as those with potential applications in fatty acid degradation. This is the first study on the transcriptomic analysis of R. microporus on rubber wood and should serve as a pioneering resource for future studies of the fungus at the genomic or transcriptomic level. PMID- 26980401 TI - Density and structural anomalies in soft-repulsive dimeric fluids. AB - We report Monte Carlo results for the fluid structure of a system of dimeric particles interacting via a core-softened potential. More specifically, dimers interact through a repulsive pair potential of an inverse-power form, modified in such a way that the repulsion strength is softened for a given range of distances. The aim of such a study is to investigate how both the elongation of the dimers and the softness of the potential affect some features of the model. Our results show that the dimeric fluid exhibits both density and structural anomalies, even if the interaction is not characterized by two length scales. Upon increasing the aspect ratio of the dimers, such anomalies are progressively hindered, with the structural anomaly surviving even after the disappearance of the density anomaly. These results shed light on the peculiar behaviour of molecular systems of non-spherical shape, showing how geometrical and interaction parameters play a fundamental role in determining the presence of anomalies. PMID- 26980400 TI - Ecological Momentary Assessment of Illicit Drug Use Compared to Biological and Self-Reported Methods. AB - BACKGROUND: The use of mHealth methods for capturing illicit drug use and associated behaviors have become more widely used in research settings, yet there is little research as to how valid these methods are compared to known measures of capturing and quantifying drug use. OBJECTIVE: We examined the concordance of ecological momentary assessment (EMA) of drug use to previously validated biological and audio-computer assisted self-interview (ACASI) methods. METHODS: The Exposure Assessment in Current Time (EXACT) study utilized EMA methods to assess drug use in real-time in participants' natural environments. Utilizing mobile devices, participants self-reported each time they used heroin or cocaine over a 4-week period. Each week, PharmChek sweat patch samples were collected for measurement of heroin and cocaine and participants answered an ACASI-based questionnaire to report behaviors and drug using events during the prior week. Reports of cocaine and heroin use captured through EMA were compared to weekly biological or self-report measures through percent agreement and concordance correlation coefficients to account for repeated measures. Correlates of discordance were obtained from logistic regression models. RESULTS: A total of 109 participants were a median of 48.5 years old, 90% African American, and 52% male. During 436 person-weeks of observation, we recorded 212 (49%) cocaine and 103 (24%) heroin sweat patches, 192 (44%) cocaine and 161 (37%) heroin ACASI surveys, and 163 (37%) cocaine and 145 (33%) heroin EMA reports. The percent agreement between EMA and sweat patch methods was 70% for cocaine use and 72% for heroin use, while the percent agreement between EMA and ACASI methods was 77% for cocaine use and 79% for heroin use. Misreporting of drug use by EMA compared to sweat patch and ACASI methods were different by illicit drug type. CONCLUSIONS: Our work demonstrates moderate to good agreement of EMA to biological and standard self-report methods in capturing illicit drug use. Limitations occur with each method and accuracy may differ by type of illicit drugs used. PMID- 26980402 TI - Fabrication of FeOOH hollow microboxes for purification of heavy metal contaminated water. AB - FeOOH, a frequently used adsorbent, has been widely applied in purifying aqueous heavy metals, and its performance can be greatly improved by enlarging the number of surface active sites. To this end, we fabricated FeOOH hollow microboxes constructed from numerous 2D nanosheets via a template-engaged reaction between Prussian blue (PB) and NaOH solution. With combined observations from X-ray powder diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS), we confirmed that the hollow microboxes corroded from PB were composed of ample frizzy FeOOH nanosheets, which ensured extensive exposure of the surface active sites. Moreover, the FeOOH microboxes were utilized as an adsorbent in the removal of heavy metals (As(III), As(V) and Se(IV)) from water and the maximum adsorption capacities were reached up to 192.19 mg g(-1), 250.0 mg g(-1) and 169.9 mg g(-1) at pH = 7.0, 4.0 and 5.0, respectively. The superior adsorptive performance of the FeOOH microboxes was derived from their large content of reactive exposed hydroxyl groups, which was unambiguously confirmed by X-ray adsorption fine structure spectroscopy (XAFS), as well as by surface site density analysis. PMID- 26980403 TI - Aortic coarctation, aneurysm, and ventricular dysfunction in an asymptomatic infant. AB - Aortic arch coarctation with post-coarctation aneurysm is rare in infants. We present the case of an asymptomatic 3-month-old infant with severe left ventricular dysfunction in this setting. The patient underwent surgical repair, and the left ventricular ejection fraction improved to recovery the 4th post operative month. PMID- 26980404 TI - Nanostructured conducting polymers for energy applications: towards a sustainable platform. AB - Recently, there has been tremendous progress in the field of nanodimensional conducting polymers with the objective of tuning the intrinsic properties of the polymer and the potential to be efficient, biocompatible, inexpensive, and solution processable. Compared with bulk conducting polymers, conducting polymer nanostructures possess a high electrical conductivity, large surface area, short path length for ion transport and superior electrochemical activity which make them suitable for energy storage and conversion applications. The current status of polymer nanostructure fabrication and characterization is reviewed in detail. The present review includes syntheses, a deeper understanding of the principles underlying the electronic behavior of size and shape tunable polymer nanostructures, characterization tools and analysis of composites. Finally, a detailed discussion of their effectiveness and perspectives in energy storage and solar light harvesting is presented. In brief, a broad overview on the synthesis and possible applications of conducting polymer nanostructures in energy domains such as fuel cells, photocatalysis, supercapacitors and rechargeable batteries is described. PMID- 26980406 TI - NMR Evidence for the Topologically Nontrivial Nature in a Family of Half-Heusler Compounds. AB - Spin-orbit coupling (SOC) is expected to partly determine the topologically nontrivial electronic structure of heavy half-Heusler ternary compounds. However, to date, attempts to experimentally observe either the strength of SOC or how it modifies the bulk band structure have been unsuccessful. By using bulk-sensitive nuclear magnetic resonance (NMR) spectroscopy combined with first-principles calculations, we reveal that (209)Bi NMR isotropic shifts scale with relativity in terms of the strength of SOC and average atomic numbers, indicating strong relativistic effects on NMR parameters. According to first-principles calculations, we further claim that nuclear magnetic shieldings from relativistic p1/2 states and paramagnetic contributions from low-lying unoccupied p3/2 states are both sensitive to the details of band structures tuned by relativity, which explains why the hidden relativistic effects on band structure can be revealed by (209)Bi NMR isotropic shifts in topologically nontrivial half-Heusler compounds. Used in complement to surface-sensitive methods, such as angle resolved photon electron spectroscopy and scanning tunneling spectroscopy, NMR can provide valuable information on bulk electronic states. PMID- 26980407 TI - Attention-Deficit Hyperactivity Disorder Status and Baseline Neurocognitive Performance in High School Athletes. AB - Approximately 136,000 concussions occur annually in American high school sports. Neuropsychological data indicate that children with preexisting cognitive difficulties, such as attention-deficit hyperactivity disorder (ADHD), may have protracted recovery from concussion. ADHD, with an estimated prevalence of 11% in youth, may increase an athlete's vulnerability to sustaining sports-related traumatic brain injury (TBI). The preponderance of evidence focusing on TBI and ADHD has derived from motor vehicle accidents rather than sports-related incidents. Thus, it is paramount to explore how ADHD may relate to injury in the sports concussion context, as well as to assess how ADHD may affect baseline neurocognitive testing. Adolescent athletes with ADHD (n = 256) demonstrated significantly reduced Verbal Memory, Visual Motor, and Impulse Control index scores compared with their peers without ADHD (n = 256). Athletes with ADHD were nearly twice as likely to have sustained a prior concussion (ADHD, 14.1%; non ADHD, 7.8%). Knowledge regarding the unique neurocognitive profile of athletes with ADHD may enhance clinical management decisions. PMID- 26980409 TI - Austerity and ecology. PMID- 26980410 TI - Worrying tonsillectomy. PMID- 26980411 TI - The NHS is no longer an attractive option. PMID- 26980408 TI - miR-27a-3p suppresses tumor metastasis and VM by down-regulating VE-cadherin expression and inhibiting EMT: an essential role for Twist-1 in HCC. AB - Twist-1 and miRNAs have been reported to be associated with tumor metastasis and angiogenesis. However, the relationship between Twist-1 and miRNAs and the function of miRNAs remain largely undefined. We aimed to reveal the Twist-1 related miRNA expression profile and to determine whether Twist-1 functions in tumor metastasis and vasculogenic mimicry (VM) by regulating miRNA expression in hepatocellular carcinoma (HCC). Results showed that the expression of miR-27a-3p was consistently down-regulated in HCC cell lines and tissue samples displaying high expression of Twist-1. Both loss- and gain-of-function assays revealed suppressive effects of miR-27a-3p. Low miR-27a-3p expression was significantly associated with early metastasis in HCC. Subsequent investigations revealed that miR-27a-3p mediated the inhibition of epithelial-mesenchymal transition (EMT). Additional experiments showed that VE-cadherin is a direct target of miR-27a-3p and further demonstrated the critical role of miR-27a-3p in suppressing tumor metastasis and VM. CONCLUSIONS: Twist-1 up-regulation in HepG2 cells resulted in the differential expression of 18 miRNAs. Among them, miR-27a-3p deregulation contributed to VM and metastasis. The miR-27a-3p-mediated down-regulation of VE cadherin and inhibition of EMT may be essential for Twist-1 to induce tumor metastasis and VM. Our findings highlight the importance of miR-27a-3p and suggest a promising new strategy for anti-HCC therapy. PMID- 26980412 TI - Austerity and old-age mortality in England: a longitudinal cross-local area analysis, 2007-2013. AB - OBJECTIVE: There has been significant concern that austerity measures have negatively impacted health in the UK. We examined whether budgetary reductions in Pension Credit and social care have been associated with recent rises in mortality rates among pensioners aged 85 years and over. DESIGN: Cross-local authority longitudinal study. SETTING: Three hundred and twenty-four lower tier local authorities in England. MAIN OUTCOME MEASURE: Annual percentage changes in mortality rates among pensioners aged 85 years or over. RESULTS: Between 2007 and 2013, each 1% decline in Pension Credit spending (support for low income pensioners) per beneficiary was associated with an increase in 0.68% in old-age mortality (95% CI: 0.41 to 0.95). Each reduction in the number of beneficiaries per 1000 pensioners was associated with an increase in 0.20% (95% CI: 0.15 to 0.24). Each 1% decline in social care spending was associated with a significant rise in old-age mortality (0.08%, 95% CI: 0.0006-0.12) but not after adjusting for Pension Credit spending. Similar patterns were seen in both men and women. Weaker associations observed for those aged 75 to 84 years, and none among those 65 to 74 years. Categories of service expenditure not expected to affect old-age mortality, such as transportation, showed no association. CONCLUSIONS: Rising mortality rates among pensioners aged 85 years and over were linked to reductions in spending on income support for poor pensioners and social care. Findings suggest austerity measures in England have affected vulnerable old-age adults. PMID- 26980413 TI - Astley Cooper's dramatically effective treatment of deafness. PMID- 26980417 TI - Clinical significance of physical symptom severity in standardized assessments of patient reported outcomes. AB - PURPOSE: Standardized measures of physical symptoms predict mortality and healthcare utilization, but clinicians remain uncertain about how to apply them in routine clinical care. Recognizing the tendency for physician documentations to routinely underestimate symptom burden, we assessed whether or not severity was an important dimension of symptom assessments that may determine their usefulness in clinical encounters. METHODS: Retrospective cohort study using data from audio computer-assisted self-interviews augmented by chart review of patients from a primary care clinic of an urban health system. RESULTS: We sampled 145 patients who completed the Memorial Symptom Assessment Scale (MSAS) short form-physical symptom severity measurement-before their primary care visit. Most were women (60 %), and non-Hispanic black (59 %), and many responded in Spanish (19 %). All but three reported > 1 symptom. Overall, 79 % of elicited symptoms were not documented in physician notes from the same day. Severe symptoms were more likely to be documented [MSAS mean (95 % confidence interval): documented 2.2 (1.9, 2.4) vs. undocumented 1.8 (1.7, 1.9)]. CONCLUSION: Documentations reflect usual patient-clinician communications that prioritize severe symptoms, while standardized instruments target their comprehensive assessments. Among the many validated instruments, those eliciting the severity of physical symptoms may simultaneously help clinicians with prioritization and risk assessments. PMID- 26980418 TI - Quality of life in older individuals with joint contractures in geriatric care settings. AB - PURPOSE: The purpose of this study was to analyze the association between functioning and disability and quality of life (QoL) in older individuals with joint contractures in the geriatric care setting. More specifically, this study aimed to identify determinants of QoL out of a defined set of contracture-related categories of the International Classification of Functioning, Disability and Health (ICF). METHODS: Participants for this multicenter cross-sectional survey were recruited from acute geriatric rehabilitation hospitals, nursing homes, and community nursing facilities in Germany between February and October 2013. QoL was assessed using the validated German version of the EQ-5D index score and the EQ-5D visual analog scale (VAS). Manual and automatic variable selection methods were used to identify the most relevant variables out of 125 contracture-related ICF categories. RESULTS: A total of 241 eligible participants (34.9 % male, mean age 80.1 years) were included. The final models contained 14 ICF categories as predictors of the EQ-5D index score and 15 categories as predictors of the EQ-5D VAS. The statistically significant ICF categories from both models were 'muscle power functions (b730),' 'memory functions (b144),' 'taking care of plants (d6505),' 'recreation and leisure (d920),' 'religion and spirituality (d930),' 'drugs (e1101),' and 'products and technology for personal use in daily living (e115).' CONCLUSIONS: We identified the most relevant ICF categories for older individuals with joint contractures and their health-related quality of life. These items describe potential determinants of QoL which may provide the basis for future health interventions aiming to improve QoL for the patients with joint contractures. PMID- 26980419 TI - Phase 1 in the development of a patient-reported measure to quantify perceived inconvenience of radiotherapy: generation of issues. AB - AIMS: Current patient-reported measures (PROMs) do not specifically address radiotherapy (RT) related inconvenience. We conducted, as per guidelines of the European Organization for Research and Treatment of Cancer (EORTC), the initial (issue generation) phase of development of a RT inconvenience PROM. Specifically, we aimed to develop a conceptual framework for RT inconvenience and generate a comprehensive list of issues pertaining to it. METHODS: We reviewed existing PROMs and literature and gathered qualitative and quantitative data from consumers and health professionals, in order to generate a comprehensive list of issues pertaining to RT inconvenience. A framework for the consideration of RT inconvenience was defined and used to ensure all possible issues were explored and to list the issues into conceptual domains. RESULTS: Qualitative data from 26 consumers and 30 health professionals, and quantitative data from 1191 consumers and 253 health professionals resulted in the identification of 38 issues grouped into five conceptual domains: (1) inconvenience of RT opportunity, (2) inconvenience of decision-making, (3) inconvenience of treatment, (4) inconvenience of side effects, and (5) inconvenience of follow-up. CONCLUSIONS: This list of RT inconvenience issues will, in future work, be operationalized into a set of items for pretesting and then large-scale field testing as per the EORTC guidelines. PMID- 26980421 TI - Income-related inequality in perceived oral health among adult Finns before and after a major dental subsidization reform. AB - Objectives In Finland, a dental subsidization reform, implemented in 2001-2002, abolished age restrictions on subsidized dental care. The aim of this study was to investigate income-related inequality in the perceived oral health and its determinants among adult Finns before and after the reform. Materials and methods Three identical cross-sectional nationally representative postal surveys, concerning perceived oral health and the use of dental services among people born before 1971, were conducted in 2001 (n = 2157), in 2004 (n = 1814) and in 2007 (n = 1671). Three measures of perceived oral health were used: toothache or oral discomfort during the past 12 months, current need for dental care and self reported oral health status. Concentration index was used to analyse the income related inequalities. Its decomposition was used to study factors related to the inequalities. Results The proportion of respondents reporting need for dental care decreased from 2001 to 2007, while no changes were seen in reports of toothache or self-reported oral health status. Income-related inequalities in reports of toothache and perceived need for care widened, while the inequality in self-reported oral health remained stable. Most of the inequalities were related to income itself, perceived general health and the time since the last visit to dental care. Conclusions It seems that the income-related inequalities in perceived oral health remained or even widened after the reform. PMID- 26980420 TI - Validity and reliability of the 19-item Audit of Diabetes-Dependent Quality of Life (ADDQoL-19) questionnaire in Chinese patients with type 2 diabetes mellitus in primary care. AB - BACKGROUND: This study aimed to determine the psychometric properties of the 19 item Audit of Diabetes-Dependent Quality of Life (ADDQoL-19) in Chinese patients with type 2 diabetes mellitus (T2DM) in primary care setting. METHODS: The ADDQoL 19 and SF-12v2 were administered to 386 Chinese patients with T2DM in public primary outpatient clinic in Hong Kong. Internal consistency reliability was determined by Cronbach's alpha, whereas construct validity was assessed by the Spearman's correlations between the scores of the ADDQoL-19 and SF-12v2. Independent t tests were used in known-group comparisons to identify the differences in the ADDQoL-19 scores between respondents with different duration of diabetes, treatment modalities, body mass index and glycemic control. RESULTS: The ADDQoL-19 had a moderate to weak correlation with SF-12v2 in convergent validity but with statistically significant results in known-group comparisons. Good internal consistency was generated with an acceptable value of 0.81, which was comparable to original English version. Construct validity was proven except the convergent validity is found to be weak with the generic SF-12v2, which was similar to the results in prior psychometric studies. CONCLUSIONS: Despite weak convergent validity, the ADDQoL-19 was found to have a satisfactory psychometric property, especially known-group comparisons and internal consistency reliability in the primary care setting. PMID- 26980422 TI - Efficacy and toxicity of a rituximab and methotrexate based regimen (GMALL B ALL/NHL 2002 protocol) in high risk diffuse large cell B-cell lymphoma patients as a first line treatment. PMID- 26980423 TI - Effects of acute intra-abdominal hypertension on multiple intestinal barrier functions in rats. AB - Intra-abdominal hypertension (IAH) is a common and serious complication in critically ill patients for which there is no well-defined treatment strategy. Here, we explored the effect of IAH on multiple intestinal barriers and discussed whether the alteration in microflora provides clues to guide the rational therapeutic treatment of intestinal barriers during IAH. Using a rat model, we analysed the expression of tight junction proteins (TJs), mucins, chemotactic factors, and Toll-like receptor 4 (TLR4) by immunohistochemistry. We also analysed the microflora populations using 16S rRNA sequencing. We found that, in addition to enhanced permeability, acute IAH (20 mmHg for 90 min) resulted in significant disturbances to mucosal barriers. Dysbiosis of the intestinal microbiota was also induced, as represented by decreased Firmicutes (relative abundance), increased Proteobacteria and migration of Bacteroidetes from the colon to the jejunum. At the genus level, Lactobacillus species and Peptostreptococcaceae incertae sedis were decreased, whereas levels of lactococci remained unchanged. Our findings outline the characteristics of IAH-induced barrier changes, indicating that intestinal barriers might be treated to alleviate IAH, and the microflora may be an especially relevant target. PMID- 26980424 TI - MicroRNAs provide a novel pathway toward combinatorial immune checkpoint blockade. PMID- 26980425 TI - Analyzing injury severity factors at highway railway grade crossing accidents involving vulnerable road users: A comparative study. AB - OBJECTIVE: The main objective of this study is to identify the main factors associated with injury severity of vulnerable road users (VRUs) involved in accidents at highway railroad grade crossings (HRGCs) using data mining techniques. METHODS: This article applies an ordered probit model, association rules, and classification and regression tree (CART) algorithms to the U.S. Federal Railroad Administration's (FRA) HRGC accident database for the period 2007-2013 to identify VRU injury severity factors at HRGCs. RESULTS: The results show that train speed is a key factor influencing injury severity. Further analysis illustrated that the presence of illumination does not reduce the severity of accidents for high-speed trains. In addition, there is a greater propensity toward fatal accidents for elderly road users compared to younger individuals. Interestingly, at night, injury accidents involving female road users are more severe compared to those involving males. CONCLUSIONS: The ordered probit model was the primary technique, and CART and association rules act as the supporter and identifier of interactions between variables. All 3 algorithms' results consistently show that the most influential accident factors are train speed, VRU age, and gender. The findings of this research could be applied for identifying high-risk hotspots and developing cost-effective countermeasures targeting VRUs at HRGCs. PMID- 26980426 TI - Effects of mTOR Inhibitors in Prevention of Abdominal Adhesions. AB - PURPOSE OF THE STUDY: Postsurgical adhesions can occur after laparotomy and can cause morbidity. Local delivery of sirolimus prevented adhesion formation in various experiments. We analyzed the impact of orally dosed mammalian target of rapamycin inhibitors on abdominal adhesion formation and wound tensile strength in an experimental model. MATERIALS AND METHODS: Wistar albino rats were divided into sirolimus, everolimus, and control groups (n = 6 per group). Experimental animals underwent midline laparotomy and adhesion induction procedure which included cecum abrasion and mesh implantation. Animals were administered oral sirolimus (4 mg/kg), everolimus (3 mg/kg), or placebo starting on postoperative day 1. Treatments were given until postoperative day 7. At postoperative day 21, adhesions were scored. Meshes were resected with the attached abdominal wall and cecal segment and stained with Sirius red for collagen density analysis. Midline scars were excised for tensile strength measurement. Effects of sirolimus and everolimus on fibroblast proliferation were also assessed. RESULTS: Mean adhesion score of the everolimus group (7.83 +/- 1.17) was significantly lower compared to sirolimus (11.00 +/- 0.63) and control (11.66 +/- 0.51) groups. Mean collagen density of the everolimus group (33.5 +/- 7.8) was significantly lower compared to sirolimus (50.7 +/- 9.69) and control (53.8 +/- 12.4) groups. Mean tensile strength of the control group (26.41 +/- 2.10) was significantly higher compared to sirolimus (17.89 +/- 1.9) and everolimus (21.37 +/- 1.25) groups. It was significantly lower in sirolimus group than everolimus group. Both sirolimus and everolimus treated media inhibited fibroblast proliferation significantly compared to media alone. CONCLUSIONS: Everolimus effectively reduced adhesions. Nevertheless, it also reduced wound tensile strength: an effect which seemed to be due to inhibition of fibroblast proliferation. PMID- 26980427 TI - Promote Recurrent Aphthous Ulcer Healing with Low Dose Prednisolone Bilayer Mucoadhesive Buccal Film. AB - BACKGROUND: Recurrent aphthous ulcer (RAU) is one of the most common ulcerative diseases of the oral mucosa which is recurrent, painful and slow to heal. Treatment is primarily for pain relief and promotion of healing to shorten the disease duration or reduce the rate of recurrence. OBJECTIVE: Development of a new design of topical buccal bilayer mucoadhesive films containing sodium alginate and gellan gum loaded with low dose of 1 mg prednisolone sodium phosphate to reduce the treatment period and decrease side effects of systemic treatment. METHODS: Films were prepared by solvent casting technique and evaluated to ensure optimum film characteristics, and in vivo efficiency. RESULTS: The bilayer films were thin, flexible with good water uptake, mucoadhesive and mechanical properties. In vitro drug release was sustained and showed anomalous non-Fickian kinetics. SEM confirmed the development of bilayer formation. Fourier Transform Infrared Spectroscopy and Differential Scanning Calorimetery indicated no chemical interaction between the layers. In vivo study in rabbits with induced oral ulceration showed complete ulcer healing within 4-5 days by once daily treatment of the studied film. Histological examination indicated no inflammation on treatment sites compared to inflamed tissue on the control sites. CONCLUSION: The results suggested that buccal application of the developed bilayer mucoadhesive films loaded with only 1mg of prednisolone provided mucoadhesive and convenient application and was able to promote RAU healing with shorter treatment duration. PMID- 26980429 TI - Celastrol, an NF-kappaB inhibitor, ameliorates hypercalciuria and articular cartilage lesions in a mouse model of secondary osteoporosis. AB - Notwithstanding compelling contribution of NF-kappaB to the progression of osteoporosis has been reported, little is known regarding direct inhibition of NF kappaB benefiting osteoporosis. In this study, therefore, we evaluated the role of celastrol, an NF-kappaB inhibitor, in a mouse model of secondary osteoporosis. Animals were divided into three groups as Sham (control), SO (secondary osteoporosis) and SO + CA (secondary osteoporosis treated with celastrol). Significant decreases in body weight and body fat were observed following celastrol treatment in SO group, but leptin levels were much higher. Celastrol also exhibited a significant decrease in urinary calcium excretion. Moreover, other important events were observed after celastrol treatment, covering substantial decrements in serum concentrations of PTH, TRAP-5b, CTX and DPD, improved structure of articular cartilage and cancellous bone (revealed by H&E and safranin-O staining), and significant decline in levels of NF-kappaB (P65), MMP-1, and MMP-9. These findings demonstrated that celastrol treatment not only improved abnormal lipid metabolism and hypercalciuria in mice subjected to secondary osteoporosis, but also ameliorated articular cartilage lesions. Our results provided evidence of targeted therapy for NF-kappaB in the clinical treatment of secondary osteoporosis. PMID- 26980430 TI - Antihistamines suppress upregulation of histidine decarboxylase gene expression with potencies different from their binding affinities for histamine H1 receptor in toluene 2,4-diisocyanate-sensitized rats. AB - Antihistamines inhibit histamine signaling by blocking histamine H1 receptor (H1R) or suppressing H1R signaling as inverse agonists. The H1R gene is upregulated in patients with pollinosis, and its expression level is correlated with the severity of nasal symptoms. Here, we show that antihistamine suppressed upregulation of histidine decarboxylase (HDC) mRNA expression in patients with pollinosis, and its expression level was correlated with that of H1R mRNA. Certain antihistamines, including mepyramine and diphenhydramine, suppress toluene-2,4-diisocyanate (TDI)-induced upregulation of HDC gene expression and increase HDC activity in TDI-sensitized rats. However, d-chlorpheniramine did not demonstrate any effect. The potencies of antihistamine suppressive effects on HDC mRNA elevation were different from their H1R receptor binding affinities. In TDI sensitized rats, the potencies of antihistamine inhibitory effects on sneezing in the early phase were related to H1R binding. In contrast, the potencies of their inhibitory effects on sneezing in the late phase were correlated with those of suppressive effects on HDC mRNA elevation. Data suggest that in addition to the antihistaminic and inverse agonistic activities, certain antihistamines possess additional properties unrelated to receptor binding and alleviate nasal symptoms in the late phase by inhibiting synthesis and release of histamine by suppressing HDC gene transcription. PMID- 26980431 TI - Initial Detection and Molecular Characterization of Namaycush Herpesvirus (Salmonid Herpesvirus 5) in Lake Trout. AB - A novel herpesvirus was found by molecular methods in samples of Lake Trout Salvelinus namaycush from Lake Erie, Pennsylvania, and Lake Ontario, Keuka Lake, and Lake Otsego, New York. Based on PCR amplification and partial sequencing of polymerase, terminase, and glycoprotein genes, a number of isolates were identified as a novel virus, which we have named Namaycush herpesvirus (NamHV) salmonid herpesvirus 5 (SalHV5). Phylogenetic analyses of three NamHV genes indicated strong clustering with other members of the genus Salmonivirus, placing these isolates into family Alloherpesviridae. The NamHV isolates were identical in the three partially sequenced genes; however, they varied from other salmonid herpesviruses in nucleotide sequence identity. In all three of the genes sequenced, NamHV shared the highest sequence identity with Atlantic Salmon papillomatosis virus (ASPV; SalHV4) isolated from Atlantic Salmon Salmo salar in northern Europe, including northwestern Russia. These results lead one to believe that NamHV and ASPV have a common ancestor that may have made a relatively recent host jump from Atlantic Salmon to Lake Trout or vice versa. Partial nucleotide sequence comparisons between NamHV and ASPV for the polymerase and glycoprotein genes differ by >5% and >10%, respectively. Additional nucleotide sequence comparisons between NamHV and epizootic epitheliotropic disease virus (EEDV/SalHV3) in the terminase, glycoprotein, and polymerase genes differ by >5%, >20%, and >10%, respectively. Thus, NamHV and EEDV may be occupying discrete ecological niches in Lake Trout. Even though NamHV shared the highest genetic identity with ASPV, each of these viruses has a separate host species, which also implies speciation. Additionally, NamHV has been detected over the last 4 years in four separate water bodies across two states, which suggests that NamHV is a distinct, naturally replicating lineage. This, in combination with a divergence in nucleotide sequence from EEDV, indicates that NamHV is a new species in the genus Salmonivirus. Received April 20, 2015; accepted October 11, 2015. PMID- 26980432 TI - Identification, cDNA Cloning, and Characterization of Luteinizing Hormone Beta Subunit (lhb) Gene in Catla catla. AB - Reproductive hormones play a significant role in the gonadal development and gametogenesis process of animals. In the present study luteinizing hormone beta, (lhb) subunit gene was cloned and characterized from the brain of Catla catla. The lhb full-length of cDNA sequence is 629 bp which consists of 43bp 5'-UTR (untranslated region) 447bp, ORF(open reading frame) and 139 bp of 3'-UTR respectively. The coding region of lhb gene encoded a peptide of 148 amino acids. The coding sequence of lhb gene consist of a single N-linked glycosylation site (NET) and 12 cysteine knot residues. Phylogenetic analysis of C. catla Lhbeta deduced amino acid sequence showed high similarity with Carassius auratus followed by Gobiocypris rarus. 3D structure Lhbeta protein comprises of five beta sheets and six coils/loops. The qPCR results revealed lhb mRNA is mainly expressed in the pituitary, ovary while moderate expression was observed in brain and testis. To best our knowledge, this is the first report on the identification, molecular characterization and structural information regarding luteinizing hormone in Indian major carp. PMID- 26980434 TI - Maillard reaction in food allergy: Pros and cons. AB - Food allergens have a notable potential to induce various health concerns in susceptible individuals. The majority of allergenic foods are usually subjected to thermal processing prior to their consumption. However, during thermal processing and long storage of foods, Maillard reaction (MR) often takes place. The MR is a non-enzymatic glycation reaction between the carbonyl group of reducing sugars and compounds having free amino groups. MR may sometimes be beneficial by damaging epitope of allergens and reducing allergenic potential, while exacerbation in allergic reactions may also occur due to changes in the motifs of epitopes or neoallergen generation. Apart from these modulations, non enzymatic glycation can also modify the food protein(s) with various type of advance glycation end products (AGEs) such as Nepsilon-(carboxymethyl-)lysine (CML), pentosidine, pyrraline, and methylglyoxal-H1 derived from MR. These Maillard products may act as immunogen by inducing the activation and proliferation of various immune cells. Literature is available to understand pathogenesis of glycation in the context of various diseases but there is hardly any review that can provide a thorough insight on the impact of glycation in food allergy. Therefore, present review explores the pathogenesis with special reference to food allergy caused by non-enzymatic glycation as well as AGEs. PMID- 26980433 TI - The lack of aspirin resistance in patients with coronary artery disease. AB - BACKGROUND: Aspirin resistance established by different laboratory methods is still a debated problem. Using COX1 specific methods no aspirin resistance was detected among healthy volunteers. Here we tested the effect of chronic aspirin treatment on platelets from patients with stable coronary artery disease. The expression of COX2 mRNA in platelets and its influences on the effect of aspirin was also investigated. METHODS: One hundred and forty four patients were enrolled in the study. The direct measurement of COX1 acetylation was carried out by monoclonal antibodies specific to acetylated and non-acetylated COX1 (acCOX1 and nacCOX1) using Western blotting technique. Arachidonic acid (AA) induced TXB2 production by platelets was measured by competitive immunoassay. AA induced platelet aggregation, ATP secretion and VerifyNow Aspirin Assay were also performed. COX2 and COX1 mRNA expression in platelets were measured in 56 patients by RT-qPCR. RESULTS: In 138 patients only acCOX1 was detected, in the remaining six patients nacCOX1 disappeared after a compliance period. AA induced TXB2 production by platelets was very low in all patients including the 6 patients after compliance. AA induced platelet aggregation, secretion and with a few exceptions the VerifyNow Assay also demonstrated the effect of aspirin. Smoking, diabetes mellitus and inflammatory conditions did not influence the results. The very low amount of COX2 mRNA detected in 39 % of the investigated platelets did not influence the effect of aspirin. CONCLUSIONS: No aspirin resistance was detected among patients with stable coronary artery disease. COX2 expression in platelets did not influence the effect of aspirin. PMID- 26980435 TI - Modulation of anti-cancer drug sensitivity through the regulation of mitochondrial activity by adenylate kinase 4. AB - BACKGROUND: Adenylate kinase is a key enzyme in the high-energy phosphoryl transfer reaction in living cells. An isoform of this enzyme, adenylate kinase 4 (AK4), is localized in the mitochondrial matrix and is believed to be involved in stress, drug resistance, malignant transformation in cancer, and ATP regulation. However, the molecular basis for the AK4 functions remained to be determined. METHODS: HeLa cells were transiently transfected with an AK4 small interfering RNA (siRNA), an AK4 short hairpin RNA (shRNA) plasmid, a control shRNA plasmid, an AK4 expression vector, and a control expression vector to examine the effect of the AK4 expression on cell proliferation, sensitivity to anti-cancer drug, metabolome, gene expression, and mitochondrial activity. RESULTS: AK4 knockdown cells treated with short hairpin RNA increased ATP production and showed greater sensitivity to hypoxia and anti-cancer drug, cis-diamminedichloro-platinum (II) (CDDP). Subcutaneous grafting AK4 knockdown cells into nude mice revealed that the grafted cells exhibited both slower proliferation and reduced the tumor sizes in response to CDDP. AK4 knockdown cell showed a increased oxygen consumption rate with FCCP treatment, while AK4 overexpression lowered it. Metabolome analysis showed the increased levels of the tricarboxylic acid cycle intermediates, fumarate and malate in AK4 knockdown cells, while AK4 overexpression lowered them. Electron microscopy detected the increased mitochondrial numbers in AK4 knockdown cells. Microarray analysis detected the increased gene expression of two key enzymes in TCA cycle, succinate dehydrogenase A (SDHA) and oxoglutarate dehydrogenease L (OGDHL), which are components of SDH complex and OGDH complex, supporting the metabolomic results. CONCLUSIONS: We found that AK4 was involved in hypoxia tolerance, resistance to anti-tumor drug, and the regulation of mitochondrial activity. These findings provide a new potential target for efficient anticancer therapies by controlling AK4 expression. PMID- 26980436 TI - Acute interstitial nephritis due to flecainide therapy in the 38(th) week of pregnancy. AB - BACKGROUND: Acute interstitial nephritis (AIN) represents a frequent cause of acute kidney injury. While many etiologies of AIN have been recognized, the majority (60-70 %) are due to allergic reactions or drug exposure. Many different classes of drugs and several agents within a class can cause drug induced AIN. Flecainide, a class Ic antiarrhythmic drug, had thus far not been associated with the occurrence of AIN. CASE PRESENTATION: Here we describe a case of biopsy proven AIN after flecainide therapy in a pregnant patient. The 24-year old Caucasian woman was admitted to our university hospital for a planned c-section. She had been put on flecainide at a dose of 200 mg/d for supraventricular tachyarrhythmia of the fetus ten days earlier. The only fleaainide drug level was obtained 24 h after the last dose. At this time point the serum level was still in the therapeutic range (392 ng/mL). After hospital admission the patient underwent uneventful c-section and delivered a 3095 g baby girl with mild insufficiency of the tricuspid valve. In the hours following the c-section, a single dose of the non-steroidal anti-inflammatory drug (NSAID) ibuprofen (600 mg) as well as single dose of diclofenac (100 mg) was administered. Within 5 days after c-section her baseline creatinine of 30 MUmol/L increased to 277 MUmol/L. The serum creatinine continued to rise to 411 MUmol/L on hospital day # 7. On renal ultrasound kidneys were enlarged and swollen. Urinary sediment at this point only revealed slight proteinuria (506 mg/g creatinine). A renal biopsy was performed showing acute interstitial nephritis. Within four days the renal function improved after discontinuation of flecainide and NSAIDs even without steroid therapy and the patient was discharged with a creatinine of 88 MUmol/L after 13 days in the hospital. CONCLUSION: This case suggests that flecainide, at least in combination with NSAIDs, can cause AIN. PMID- 26980437 TI - Dietary Patterns and Plasma Sex Hormones, Prolactin, and Sex Hormone-Binding Globulin in Premenopausal Women. AB - BACKGROUND: Sex hormones are important for breast cancer, but it is unclear whether dietary patterns influence hormone concentrations. METHODS: Dietary pattern adherence scores for the alternate Mediterranean diet (aMED), Dietary Approaches to Stop Hypertension (DASH), and Alternative Healthy Eating Index (AHEI) were calculated from semiquantitative food frequency questionnaires administered in 1995 and 1999. Premenopausal plasma concentrations of sex hormones were measured in samples collected in 1996 to 1999. We used generalized linear models to calculate geometric mean hormone concentrations across quartiles of dietary pattern scores among 1,990 women in the Nurses' Health Study II. RESULTS: We did not observe significant associations between sex hormone concentrations and the DASH pattern and only one suggestive association between follicular estrone concentrations and the aMED pattern [top vs. bottom quartile 4.4%, 95% confidence interval (CI), -10.6% to 2.1%; Ptrend = 0.06]. However, women in the top versus bottom quartile of AHEI score had lower concentrations of follicular (-9.1%; 95% CI, -16.1% to -1.4%; Ptrend = 0.04) and luteal (-7.5%; 95% CI, -13.6% to -0.9%; Ptrend = 0.01) estrone, luteal-free (-9.3%; 95% CI, -16.8% to -1.1%; Ptrend = 0.01) and total (-6.7 %; 95% CI, -14.3% to 1.5%; Ptrend = 0.04) estradiol, follicular estradiol (-14.2%; 95% CI, -24.6% to -2.4%; Ptrend = 0.05), and androstenedione (-7.8%; 95% CI, -15.4% to 0.4%; Ptrend = 0.03). CONCLUSION: Diet quality measured by the AHEI is inversely associated with premenopausal estrogen concentrations. Given that we did not observe similar associations with the aMED or DASH patterns, our findings should be interpreted with caution. IMPACT: Given the role of estrogens in breast cancer etiology, our findings add to the substantial evidence on the benefits of adhering to a healthy diet. Cancer Epidemiol Biomarkers Prev; 25(5); 791-8. (c)2016 AACR. PMID- 26980438 TI - Evolution to low-dose NSAID therapy. AB - All NSAIDs are to varying degrees associated with gastrointestinal, cardiovascular and renal adverse effects (AEs). Differences in selectivity for inhibition of the COX isozymes (COX-1/COX-2) have been used as an indicator of the likelihood of experiencing an AE, but the measure of 'selectivity' commonly used is less than desirable, and selectivity has not yielded unequivocal superior safety. Recent guidelines recommend that NSAIDs be used at the lowest effective dose and for the shortest period of time. In response, 'low-dose' NSAID formulations have been developed. Such formulations may help by reducing overall systemic exposure, thereby reducing the frequency or severity of AEs. It seems timely to review the need, rationale and application of such an approach. PMID- 26980439 TI - Prescription for antibiotics at drug shops and strategies to improve quality of care and patient safety: a cross-sectional survey in the private sector in Uganda. AB - OBJECTIVES: The main objective of this study was to assess practices of antibiotic prescription at registered drug shops with a focus on upper respiratory tract infections among children in order to provide data for policy discussions aimed at improving quality of care and patient safety in the private health sector in Uganda. METHODS: A survey was conducted within 57 parishes from August to October 2014 in Mukono District, Uganda. Data was captured on the following variables: drug shop characteristics, training of staff in management of pneumonia, availability of guidelines and basic equipment, available antibiotics, knowledge on treatment of pneumonia in children aged <5 years. The main study outcome was the proportion of private health facilities prescribing an antibiotic. RESULTS: A total of 170 registered drug shops were surveyed between August and October 2014. The majority of drug shops, 93.5% were prescribing antibiotics, especially amoxicillin and trimethoprim-sulfamethoxazole (septrin). The professional qualification of a provider was significantly associated with this practice, p=0.04; where lower cadre staff (nursing assistants and enrolled nurses) overprescribed antibiotics. A third, 29.4% of drug shop providers reported that antibiotics were the first-line treatment for children with diarrhoea; yet the standard guideline is to give oral rehydration salts and zinc tablets. Only few providers, 8.2%, had training on antibiotics, with 10.6% on pneumonia case management. Further to this, 7.1% drug shops had WHO-Integrated Management of Childhood Illness guidelines, and a negligible proportion (<1%) had respiratory timers and baby weighing scales. Although the majority of providers, 82.4%, knew severe signs and symptoms of pneumonia, few, 17.6%, knew that amoxicillin was the first-line drug for treatment of pneumonia in children according to the guidelines. CONCLUSIONS: There is urgent need to regulate drug shop practices of prescribing and selling antibiotics, for the safety of patients seeking care at these outlets. PMID- 26980440 TI - Exploring the glycan interaction in vivo: Future prospects of neo-glycoproteins for diagnostics. AB - Herein the biodistributions and in vivo kinetics of chemically prepared neoglycoproteins are reviewed. Chemical methods can be used to conjugate various mono- and oligosaccharides onto a protein surface. The kinetics and organ specific accumulation profiles of these glycoconjugates, which are introduced through intravenous injections, have been analyzed using conventional dissection studies as well as noninvasive methods such as single photon emission computed tomography, positron emission tomography and fluorescence imaging. These studies suggest that glycan-dependent protein distribution kinetics may be useful for pharmacological and diagnostic applications. PMID- 26980441 TI - Identification of IL-23p19 as an endothelial proinflammatory peptide that promotes gp130-STAT3 signaling. AB - Interleukin-23 (IL-23), a heterodimeric cytokine composed of the unique p19 peptide (IL-23p19) and a peptide called IL-12p40, which is shared with IL-12, is implicated in Crohn's disease, rheumatoid arthritis, psoriasis, and other immune mediated inflammatory diseases. Endothelial cells produce the IL-23p19 peptide in the absence of the IL-12p40 chain and thus do not make heterodimeric IL-23. We found that intercellular IL-23p19 increased the cell surface abundances of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells, which enhanced the attachment of leukocytes and increased their transendothelial migration. Intracellular p19 associated with the cytokine receptor subunit gp130 and stimulated the gp130-dependent activation of signal transducer and activator of transcription 3 (STAT3) signaling. Proinflammatory factors promoted the generation of IL-23p19 in endothelial cells. The adventitial capillaries of inflamed temporal arteries in patients with giant cell arteritis (GCA) had endothelial p19 protein associated with gp130, but did not contain the IL-12p40 chain. Because adventitial capillaries are essential for the entry of inflammatory cells into arterial walls, these data suggest that p19 may contribute to GCA disease and could represent a therapeutic target. Our results provide evidence that IL-23p19 is a previously unrecognized endothelial proinflammatory peptide that promotes leukocyte transendothelial migration, advancing our current understanding of the complexities of inflammatory responses. PMID- 26980442 TI - Loss of Reelin protects against atherosclerosis by reducing leukocyte-endothelial cell adhesion and lesion macrophage accumulation. AB - The multimodular glycoprotein Reelin controls neuronal migration and synaptic transmission by binding to apolipoprotein E receptor 2 (Apoer2) and very low density lipoprotein receptor (Vldlr) on neurons. In the periphery, Reelin is produced by the liver, circulates in blood, and promotes thrombosis and hemostasis. To investigate if Reelin influences atherogenesis, we studied atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice in which we inducibly deleted Reelin either ubiquitously or only in the liver, thus preventing the production of circulating Reelin. In both types of Reelin deficient mice, atherosclerosis progression was markedly attenuated, and macrophage content and endothelial cell staining for vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were reduced at the sites of atherosclerotic lesions. Intravital microscopy revealed decreased leukocyte-endothelial adhesion in the Reelin-deficient mice. In cultured human endothelial cells, Reelin enhanced monocyte adhesion and increased ICAM1, VCAM1, and E-selectin expression by suppressing endothelial nitric oxide synthase (eNOS) activity and increasing nuclear factor kappaB (NF-kappaB) activity in an Apoer2 dependent manner. These findings suggest that circulating Reelin promotes atherosclerosis by increasing vascular inflammation, and that reducing or inhibiting circulating Reelin may present a novel approach for the prevention of cardiovascular disease. PMID- 26980443 TI - Mouse redox histology using genetically encoded probes. AB - Mapping the in vivo distribution of endogenous oxidants in animal tissues is of substantial biomedical interest. Numerous health-related factors, including diet, physical activity, infection, aging, toxins, or pharmacological intervention, may cause redox changes. Tools are needed to pinpoint redox state changes to particular organs, tissues, cell types, and subcellular organelles. We describe a procedure that preserves the in vivo redox state of genetically encoded redox biosensors within histological tissue sections, thus providing "redox maps" for any tissue and comparison of interest. We demonstrate the utility of the technique by visualizing endogenous redox differences and changes in the context of tumor growth, inflammation, embryonic development, and nutrient starvation. PMID- 26980444 TI - Optimizing matching and analysis combinations for estimating causal effects. AB - Matching methods are common in studies across many disciplines. However, there is limited evidence on how to optimally combine matching with subsequent analysis approaches to minimize bias and maximize efficiency for the quantity of interest. We conducted simulations to compare the performance of a wide variety of matching methods and analysis approaches in terms of bias, variance, and mean squared error (MSE). We then compared these approaches in an applied example of an employment training program. The results indicate that combining full matching with double robust analysis performed best in both the simulations and the applied example, particularly when combined with machine learning estimation methods. To reduce bias, current guidelines advise researchers to select the technique with the best post-matching covariate balance, but this work finds that such an approach does not always minimize mean squared error (MSE). These findings have important implications for future research utilizing matching. To minimize MSE, investigators should consider additional diagnostics, and use of simulations tailored to the study of interest to identify the optimal matching and analysis combination. PMID- 26980445 TI - A drug safety evaluation of mirabegron in the management of overactive bladder. AB - INTRODUCTION: Overactive Bladder (OAB) is a clinical syndrome describing the symptom complex of urgency, with or without urgency incontinence and is usually associated with frequency and nocturia. Antimuscarinics are currently the most widely prescribed drugs for OAB although persistence with medication is often limited due to lack of efficacy or intolerable adverse effects. Mirabegron is beta3 adrenoreceptor agonist that is the first new drug licensed for the management of overactive bladder (OAB) in over 30 years. AREAS COVERED: This review provides a comprehensive overview of the mirabegron clinical trials programme, including Phase II, III and IV studies with a particular focus on tolerability and safety. A literature search was performed in Pubmed using the key words 'mirabegron', 'overactive bladder', 'beta3 adrenoceptor agonist' and 'detrusor overactivity' with no restriction on dates. EXPERT OPINION: The extensive clinical trial programme has shown mirabegron to be safe and efficacious in the treatment of OAB symptoms and the evidence would suggest that it offers an effective alternative to antimuscarinic therapy. PMID- 26980446 TI - GP accused of fraudulently conducting a clinical trial. PMID- 26980447 TI - Treatment of vitamin A deficiency retinopathy with sublingual vitamin A palmitate. AB - PURPOSE: To report treatment of vitamin A deficiency retinopathy with sublingual vitamin A drops. METHODS: Case report with review of the literature. RESULTS: A 69-year-old Caucasian woman with a history of small bowel resection presented with progressive symptoms of bilateral nyctalopia and decreased visual acuity. Ophthalmic examination revealed bilateral conjunctival xerosis and fine white granular deposits in the midperipheral retina suggestive of vitamin A deficiency. Full-field electroretinogram (ERG), multifocal ERG (mfERG), and two-color dark adaptometry revealed significant impairment of rod and cone photoreceptor function. Kinetic perimetry demonstrated depressed macular sensitivity with constriction of the finer isopters. After 5 months of treatment with sublingual vitamin A drops, the patient's vision, ERG, mfERG, dark adaptometry, and perimetry normalized. A review of the literature summarizing the electrophysiologic testing in vitamin A deficiency is also discussed. CONCLUSIONS: This case highlights novel observations on the effects of sublingual vitamin A supplementation for acquired vitamin A deficiency retinopathy. Sublingual vitamin A may represent a viable and efficacious treatment modality for vitamin A deficiency. PMID- 26980448 TI - Quenching of Unincorporated Amplification Signal Reporters in Reverse Transcription Loop-Mediated Isothermal Amplification Enabling Bright, Single Step, Closed-Tube, and Multiplexed Detection of RNA Viruses. AB - Reverse-transcription-loop-mediated isothermal amplification (RT-LAMP) has frequently been proposed as an enabling technology for simplified diagnostic tests for RNA viruses. However, common detection techniques used for LAMP and RT LAMP have drawbacks, including poor discrimination capability, inability to multiplex targets, high rates of false positives, and (in some cases) the requirement of opening reaction tubes postamplification. Here, we present a simple technique that allows closed-tube, target-specific detection, based on inclusion of a dye-labeled primer that is incorporated into a target-specific amplicon if the target is present. A short, complementary quencher hybridizes to unincorporated primer upon cooling down at the end of the reaction, thereby quenching fluorescence of any unincorporated primer. Our technique, which we term QUASR (for quenching of unincorporated amplification signal reporters, read "quasar"), does not significantly reduce the amplification efficiency or sensitivity of RT-LAMP. Equipped with a simple LED excitation source and a colored plastic gel filter, the naked eye or a camera can easily discriminate between positive and negative QUASR reactions, which produce a difference in signal of approximately 10:1 without background subtraction. We demonstrate that QUASR detection is compatible with complex sample matrices such as human blood, using a novel LAMP primer set for bacteriophage MS2 (a model RNA virus particle). Furthermore, we demonstrate single-tube duplex detection of West Nile virus (WNV) and chikungunya virus (CHIKV) RNA. PMID- 26980449 TI - A review of selective laser trabeculoplasty in the Hong Kong Chinese population. AB - INTRODUCTION: Selective laser trabeculoplasty was first introduced to Hong Kong in 2004 for intra-ocular pressure lowering in the treatment of primary glaucoma. Since then, it has gained popularity as an alternative to anti-glaucoma medications and as a bridging therapy prior to more invasive glaucoma surgeries because of the high safety profile of the laser. METHODS: An Ovid search was performed using "selective laser trabeculoplasty" as the key word, which identified 190 unique articles; 24 reviews and/or meta-analyses were excluded. All remaining abstracts of original articles were in English. This review particularly focuses on the local population by summarising the findings from peer-reviewed publications that involved a Hong Kong Chinese population. RESULTS AND CONCLUSION: This review addresses some of the clinically relevant questions relating to selective laser trabeculoplasty including laser application, optimal energy, efficacies and success rates among different glaucoma subtypes, predictors of success, adverse effects, and intra-ocular pressure fluctuation after selective laser trabeculoplasty. PMID- 26980450 TI - Mushroom poisoning in Hong Kong: a ten-year review. AB - INTRODUCTION: Mushroom poisoning is a cause of major mortality and morbidity all over the world. Although Hong Kong people consume a lot of mushrooms, there are only a few clinical studies and reviews of local mushroom poisoning. This study aimed to review the clinical characteristics, source, and outcome of mushroom poisoning incidences in Hong Kong. METHODS: This descriptive case series review was conducted by the Hong Kong Poison Information Centre and involved all cases of mushroom poisoning reported to the Centre from 1 July 2005 to 30 June 2015. RESULTS: Overall, 67 cases of mushroom poisoning were reported. Of these, 60 (90%) cases presented with gastrointestinal symptoms of vomiting, diarrhoea, and abdominal pain. Gastrointestinal symptoms were early onset (<6 hours post ingestion) and not severe in 53 patients and all recovered after symptomatic treatment and a short duration of hospital care. Gastrointestinal symptoms, however, were of late onset (>=6 hours post-ingestion) in seven patients; these were life-threatening cases of amatoxin poisoning. In all cases, the poisonous mushroom had been picked from the wild. Three cases were imported from other countries, and four collected and consumed the amatoxin-containing mushrooms in Hong Kong. Of the seven cases of amatoxin poisoning, six were critically ill, of whom one died and two required liver transplantation. There was one confirmed case of hallucinogenic mushroom poisoning caused by Tylopilus nigerrimus after consumption of a commercial mushroom product. A number of poisoning incidences involved the consumption of wild-harvested dried porcini purchased in the market. CONCLUSION: Most cases of mushroom poisoning in Hong Kong presented with gastrointestinal symptoms and followed a benign course. Life-threatening cases of amatoxin poisoning are occasionally seen. Doctors should consider this diagnosis in patients who present with gastrointestinal symptoms that begin 6 hours or more after mushroom consumption. PMID- 26980451 TI - Prevalence of motor problems in children with attention deficit hyperactivity disorder in Hong Kong. AB - INTRODUCTION: Local data on the occurrence of motor problems in children with attention deficit hyperactivity disorder are not available but an understanding of this important issue may enable better planning of medical services. We aimed to determine the prevalence of motor problems in children with attention deficit hyperactivity disorder in a local population. METHODS: In this descriptive cross sectional study, children aged 6 to 9 years diagnosed with attention deficit hyperactivity disorder over a period of 6 months from 1 July to 31 December 2011 were recruited from the Joint Paediatric and Child Psychiatric ADHD Program in New Territories East Cluster in Hong Kong. Movement Assessment Battery for Children and Developmental Coordination Disorder Questionnaire-Chinese version were used to determine the presence of motor problems. RESULTS: Data from 95 participants were included in the final analysis. The number of children who had no, borderline, or definite motor problems was 63, 15, and 17, respectively. It is estimated that up to one third of local children with attention deficit hyperactivity disorder might have developmental coordination disorder. CONCLUSIONS: Motor problems are common in local children with attention deficit hyperactivity disorder and figures are comparable with those from other parts of the world. Despite the various limitations of this study, the magnitude of the problem should not be overlooked. PMID- 26980452 TI - Poor preoperative nutritional status is an important predictor of the retardation of rehabilitation after cardiac surgery in elderly cardiac patients. AB - BACKGROUND: Preoperative nutritional status and physical function are important predictors of mortality and morbidity after cardiac surgery. However, the influence of nutritional status before cardiac surgery on physical function and the progress of postoperative rehabilitation requires clarification. AIMS: To determine the effect of preoperative nutritional status on preoperative physical function and progress of rehabilitation after elective cardiac surgery. METHODS: We enrolled 131 elderly patients with mean age of 73.7 +/- 5.8 years undergoing cardiac surgery. We divided them into two groups by nutritional status as measured by the Geriatric Nutritional Risk Index (GNRI): high GNRI group (GNRI >= 92, n = 106) and low GNRI group (GNRI < 92, n = 25). Physical function was estimated by handgrip strength, knee extensor muscle strength (KEMS), the Short Physical Performance Battery (SPPB), and 6-minute walk test (6MWT). Progress of postoperative rehabilitation was evaluated by the number of days to independent walking after surgery, length of stay in the ICU, and length of hospital stay. RESULTS: After adjusting for potential confounding factors, preoperative handgrip strength (P = 0.034), KEMS (P = 0.009), SPPB (P < 0.0001), and 6MWT (P = 0.012) were all significantly better in the high GNRI group. Multiple regression analysis revealed that a low GNRI was an independent predictor of the retardation of postoperative rehabilitation. CONCLUSIONS: Preoperative nutritional status as assessed by the GNRI could reflect perioperative physical function. Preoperative poor nutritional status may be an independent predictor of the retardation of postoperative rehabilitation in patients undergoing elective cardiac surgery. PMID- 26980453 TI - Predictors of poor cognitive status among older Malaysian adults: baseline findings from the LRGS TUA cohort study. AB - BACKGROUND: Concepts of successful aging (SA), usual aging (UA), and mild cognitive impairment (MCI) have been developed to identify older adults at high risk of Alzheimer's diseases (AD), however, the predictors have rarely been investigated in a single study. Thus, this study aims to explore the risk factors of MCI as compared to UA and SA among older adults, in a large community based cohort study in Malaysia. METHOD: 1993 subjects from four states in Malaysia were recruited. A comprehensive interview-based questionnaire was administered to determine socio-demographic information, followed by assessments to evaluate cognitive function, functional status, dietary intake, lifestyle and psychosocial status. Risk factors of cognitive impairment were assessed using the ordinal logistic regression (OLR). RESULT: The prevalence of SA, UA and MCI in this study was 11, 73 and 16 % respectively. OLR indicated that higher fasting blood sugar, hyperlipidemia, disability, lower education level, not regularly involved in technical based activities, limited use of modern technologies, lower intake of fruits and fresh fruit juices and not practicing calorie restriction were among the risk factors of poor cognitive performance in this study. CONCLUSION: This study will be a stepping stone for future researchers to develop intervention strategies to prevent cognitive decline. PMID- 26980455 TI - Stability analysis of the ODE model representation of amyloidogenic processing in Alzheimer's disease in the presence of SORLA. AB - The proteolytic breakdown of the amyloid precursor protein (APP) by secretases is a complex cellular process that results in the formation of neurotoxic Abeta peptides, causative of neurodegeneration in Alzheimer's disease (AD). Processing involves monomeric and dimeric forms of APP that are transported through distinct cellular compartments where the various secretases reside. Amyloidogenic processing is also influenced by modifiers such as sorting receptor-related protein (SORLA), an inhibitor of APP breakdown and a major AD risk factor. This paper analyzed the temporal behavior of a mathematical model describing APP processing under the influence of SORLA, by performing a stability analysis of the mathematical model. We found one biochemically meaningful equilibrium point xi. By means of linearization, Hartman-Grobman theorem, and Routh-Hurwitz test, it was shown that xi is a locally asymptotically stable equilibrium point. The region of attraction of xi was approximated by using the fluctuation lemma. An immediate consequence of the stability analysis of the reduced system to the temporal behavior of the solutions of the original system was also obtained. The biological implications of these results for the dynamic behavior of the activity of APP and secretases under SORLA's influence were established. PMID- 26980454 TI - Biodistribution and pharmacokinetics of Mad2 siRNA-loaded EGFR-targeted chitosan nanoparticles in cisplatin sensitive and resistant lung cancer models. AB - BACKGROUND: The present study focuses on biodistribution profile and pharmacokinetic parameters of EGFR-targeted chitosan nanoparticles (TG CS nanoparticles) for siRNA/cisplatin combination therapy of lung cancer. MATERIAL & METHODS: Mad2 siRNA was encapsulated in EGFR targeted and nontargeted (NTG) CS nanoparticles by electrostatic interaction. The biodistribution of the nanoparticles was assessed qualitatively and quantitatively in cisplatin (DDP) sensitive and resistant lung cancer xenograft model. RESULTS: TG nanoparticles showed a consistent and preferential tumor targeting ability with rapid clearance from the plasma to infiltrate and sustain within the tumor up to 96 h. They exhibit a sixfold higher tumor targeting efficiency compared with the NTG nanoparticles. CONCLUSION: TG nanoparticles present as an attractive drug delivery platform for RNAi therapeutics against NSCLC. PMID- 26980456 TI - Long-range magnetic coupling across a polar insulating layer. AB - Magnetic interactions in solids are normally mediated by short-range exchange or weak dipole fields. Here we report a magnetic interaction that can propagate over long distances (~10 nm) across a polar insulating oxide spacer. Evidence includes oscillations of magnetization, coercivity and field-cooled loop shift with the thickness of LaAlO3 in La0.67Sr0.33MnO3/LaAlO3/SrTiO3 heterostructures. Similar modifications of the hysteresis loop appear when two coupled films of La0.67Sr0.33MnO3 are separated by LaAlO3, or another polar insulator, but they are absent when the oxide spacer layer is nonpolar. The loop shift is attributed to strong spin-orbit coupling and Dzyaloshinskii-Moriya interaction at the interfaces. There is evidence from inelastic light scattering that the polar spacer mediates long-range transmission of orbital magnetization. This coupling mechanism is expected to apply for any conducting ferromagnetic oxide with mixed valence; in view of electron hopping frequency involved, it raises the prospect of terahertz tunability of magnetic coupling. PMID- 26980457 TI - Multiple cranial neuropathies following zoledronic acid infusion: a relationship? Clinical features and pathogenic discussion concerning a case. AB - The widespread use of bisphosphonates, especially in osteoporosis, has led to a greater number of reports of side effects. We describe for the first time a case of a 75-year-old female patient with a history of indolent sicca syndrome who developed multiple cranial neuropathies after zoledronic acid infusion. In this case, the elimination of the main causes of multiple cranial neuropathies, the chronology with zoledronic acid infusion, the absence of secondary complications of the Sjogren's syndrome, reported cases of similar peripheral nerve injuries with interferon infusions, the spontaneous remission of this multiple cranial neuropathy in parallel with the induced flu-like syndrome, argue for its iatrogenic origin, probably by a great release of inflammatory mediators in this particular background of primary Sjogren's syndrome. PMID- 26980459 TI - Sequential BART for imputation of missing covariates. AB - To conduct comparative effectiveness research using electronic health records (EHR), many covariates are typically needed to adjust for selection and confounding biases. Unfortunately, it is typical to have missingness in these covariates. Just using cases with complete covariates will result in considerable efficiency losses and likely bias. Here, we consider the covariates missing at random with missing data mechanism either depending on the response or not. Standard methods for multiple imputation can either fail to capture nonlinear relationships or suffer from the incompatibility and uncongeniality issues. We explore a flexible Bayesian nonparametric approach to impute the missing covariates, which involves factoring the joint distribution of the covariates with missingness into a set of sequential conditionals and applying Bayesian additive regression trees to model each of these univariate conditionals. Using data augmentation, the posterior for each conditional can be sampled simultaneously. We provide details on the computational algorithm and make comparisons to other methods, including parametric sequential imputation and two versions of multiple imputation by chained equations. We illustrate the proposed approach on EHR data from an affiliated tertiary care institution to examine factors related to hyperglycemia. PMID- 26980460 TI - A double-blind randomized study assessing safety and efficacy following one-year adjunctive treatment with bitopertin, a glycine reuptake inhibitor, in Japanese patients with schizophrenia. AB - BACKGROUND: Bitopertin, a glycine reuptake inhibitor, was investigated as a novel treatment for schizophrenia. We report all the results of a double-blind randomized study assessing safety and efficacy following 52-week adjunctive treatment with bitopertin in Japanese patients with schizophrenia. METHODS: This study enrolled Japanese outpatients with schizophrenia who met criteria for either "negative symptoms", i.e., patients with persistent, predominant negative symptoms of schizophrenia even after long-term treatment with antipsychotics or "sub-optimally controlled symptoms", i.e., patients with insufficiently improved symptoms of schizophrenia even after long-term treatment with antipsychotics, respectively. One hundred sixty-one patients were randomly assigned to receive 52 week treatments with bitopertin doses of 5, 10, or 20 mg/day at ratio of 1:5:5, where existing antipsychotics were concomitantly administered. Efficacy endpoints included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI), and Personal and Social Performance (PSP). The purpose of the present study is primarily to evaluate the safety, and secondarily to investigate the clinical efficacy of bitopertin. RESULTS: One hundred fourteen patients (71 %) completed 52-week treatment with bitopertin. Most of the adverse events were mild or moderate in their severity. The patients in the 20-mg group experienced more adverse events than the patients in the other two groups. Common dose-dependent adverse events were somnolence and insomnia associated with worsening schizophrenia. The blood hemoglobin levels gradually decreased from baseline in a dose-dependent manner, but there were no patients with the decrease below 10 g/dL that would have led to their discontinuation. All the efficacy endpoints gradually improved in all the treatment groups for both of the two symptoms, while there were no clear differences among the three dose groups. CONCLUSIONS: Altogether, bitopertin was found to be generally safe and well-tolerated for the treatment of patients with schizophrenia. All three bitopertin treated groups showed improvements in all the efficacy endpoints for both of the two symptoms, i.e., "negative symptoms" and "sub-optimally controlled symptoms", throughout the duration of the study. TRIAL REGISTRATION: Japan Pharmaceutical Information Center, number JapicCTI-111627 (registered on September 20, 2011). PMID- 26980458 TI - Diabetes and disordered bone metabolism (diabetic osteodystrophy): time for recognition. AB - Diabetes and osteoporosis are rapidly growing diseases. The link between the high fracture incidence in diabetes as compared with the non-diabetic state has recently been recognized. While this review cannot cover every aspect of diabetic osteodystrophy, it attempts to incorporate current information from the First International Symposium on Diabetes and Bone presentations in Rome in 2014. Diabetes and osteoporosis are fast-growing diseases in the western world and are becoming a major problem in the emerging economic nations. Aging of populations worldwide will be responsible for an increased risk in the incidence of osteoporosis and diabetes. Furthermore, the economic burden due to complications of these diseases is enormous and will continue to increase unless public awareness of these diseases, the curbing of obesity, and cost-effective measures are instituted. The link between diabetes and fractures being more common in diabetics than non-diabetics has been widely recognized. At the same time, many questions remain regarding the underlying mechanisms for greater bone fragility in diabetic patients and the best approach to risk assessment and treatment to prevent fractures. Although it cannot cover every aspect of diabetic osteodystrophy, this review will attempt to incorporate current information particularly from the First International Symposium on Diabetes and Bone presentations in Rome in November 2014. PMID- 26980463 TI - [Inappropriate ICD shocks after collision with a pole]. AB - A 60-year-old man experienced inappropriate ICD shocks after collision with a pole. Cine-fluoroscopy demonstrated lead fracture of the proximal lead, which was not so clearly visible on the chest radiograph. He underwent lead extraction and implantation of a new ICD system. PMID- 26980462 TI - Mobile technology habits: patterns of association among device usage, intertemporal preference, impulse control, and reward sensitivity. AB - Mobile electronic devices are playing an increasingly pervasive role in our daily activities. Yet, there has been very little empirical research investigating how mobile technology habits might relate to individual differences in cognition and affect. The research presented in this paper provides evidence that heavier investment in mobile devices is correlated with a relatively weaker tendency to delay gratification (as measured by a delay discounting task) and a greater inclination toward impulsive behavior (i.e., weaker impulse control, assessed behaviorally and through self-report) but is not related to individual differences in sensitivity to reward. Analyses further demonstrated that individual variation in impulse control mediates the relationship between mobile technology usage and delay of gratification. Although based on correlational results, these findings lend some backing to concerns that increased use of portable electronic devices could have negative impacts on impulse control and the ability to appropriately valuate delayed rewards. PMID- 26980464 TI - [Peroneal nerve injury due to heterotopic ossification: rare complication following surgical treatment of an acetabular fracture]. AB - BACKGROUND: Sciatic nerve entrapment due to heterotopic ossification is a rare late complication of the surgical treatment of an acetabular fracture. CASE DESCRIPTION: In this article we present the case of a 34-year-old male, who developed weakness of the dorsiflexors of his right ankle several months after an open reduction of an acetabular fracture. The weakness was caused by isolated ectopic bone formation around the peroneal nerve in the presence of an anatomical variation, namely a high division of the sciatic nerve into the tibial and peroneal nerves. Surgical resection of the heterotopic ossification resulted in nearly complete recovery of dorsiflexion function. CONCLUSION: This case describes a rare late complication secondary to surgical treatment of an acetabular fracture. The anamnesis shows the clinical relevance of knowledge of the anatomical variation in the course of the sciatic nerve. PMID- 26980461 TI - Does insecticide resistance contribute to heterogeneities in malaria transmission in The Gambia? AB - BACKGROUND: Malaria hotspots, areas with consistently higher than average transmission, may become increasingly common as malaria declines. This phenomenon, currently observed in The Gambia, may be caused by several factors, including some related to the local vectors, whose contribution is poorly understood. METHODS: Using WHO susceptibility bioassays, insecticide resistance status was determined in vector populations sampled from six pairs of villages across The Gambia, each pair contained a low and high prevalence village. RESULTS: Three vector species were observed (23.5% Anopheles arabiensis, 31.2% Anopheles gambiae, 43.3% Anopheles coluzzii and 2.0% An. coluzzii * An. gambiae hybrids). Even at a fine scale, significant differences in species composition were detected within village pairs. Resistance to both DDT and deltamethrin was more common in An. gambiae, most markedly in the eastern part of The Gambia and partly attributable to differing frequencies of resistance mutations. The Vgsc 1014F target site mutation was strongly associated with both DDT (OR = 256.7, (95% CI 48.6-6374.3, p < 0.001) and deltamethrin survival (OR = 9.14, (95% CI 4.24-21.4, p < 0.001). A second target site mutation, Vgsc-1575Y, which co-occurs with Vgsc-1014F, and a metabolic marker of resistance, Gste2-114T, conferred additional survival benefits to both insecticides. DDT resistance occurred significantly more frequently in villages with high malaria prevalence (p = 0.025) though this did not apply to deltamethrin resistance. CONCLUSION: Whilst causality of relationships requires further investigation, variation in vector species and insecticide resistance in The Gambia is associated with malaria endemicity; with a notably higher prevalence of infection and insecticide resistance in the east of the country. In areas with heterogeneous malaria transmission, the role of the vector should be investigated to guide malaria control interventions. PMID- 26980465 TI - ['Which breast implant do I have?'; the importance of the Dutch Breast Implant Registry]. AB - About 1 in 300 women in the Netherlands has a breast implant but many patients do not know what type of implant was inserted. The quality of breast implants is currently monitored by the implant manufacturers. Sufficient incidents have occurred to show that an independent registry is required to measure the quality of breast implants and to facilitate a national recall, if necessary. Good national and international collaboration with the government, the manufacturers and other specialist associations is crucial for setting up an implant registry. Since April 2015, data about patients and their implants have been collected, independently and prospectively, in the Dutch Breast Implant Registry to increase patient safety in cases of breast implant surgery in the Netherlands. PMID- 26980466 TI - [A female runner with a painful knee]. AB - A 36-year-old, healthy woman presented with pain in her left knee. The X-ray of this knee showed a lytic tumour. The MRI scan also revealed this lesion, which was highly suspicious for a giant cell tumour of the distal femur. She was treated in a specialised centre. PMID- 26980467 TI - [New medicines at an acceptable cost?]. AB - The Dutch minister of Health, Welfare and Sport recently informed the Dutch Parliament that the current system of access to new medicines has failed because it is becoming too costly. She plans to tackle the pricing-problem within the current system by e.g. putting restrictions on patenting and market-protection of new medicines. In order to reform the system and to achieve rational pharmacotherapy, the government should do more. For example, the government could set up its own biotechnology companies, reject non-inferiority studies, and stop the rapid market access for new medicines when sound clinical evidence is lacking. Patients should be protected because they have the right, including during end-of-life care, to receive medicines that have been thoroughly evaluated. PMID- 26980468 TI - [Tuberculosis among asylum-seekers in the Netherlands: a descriptive study among the two largest groups of asylum-seekers]. AB - OBJECTIVE: To investigate the prevalence and incidence of tuberculosis (TB) among the two largest groups of asylum-seekers in the Netherlands, i.e. Syrians and Eritreans/Ethiopians. DESIGN: Descriptive study. METHOD: We collected data from the screening of Syrian and Eritrean/Ethiopian asylum-seekers for the period January 2013 - September 2015 and linked these to notifications in the Netherlands Tuberculosis Register. RESULTS: Asylum-seekers from Syria and Eritrea/Ethiopia represented 65% and 72% of all asylum applications in 2014 and in the first nine months of 2015 respectively. Fourteen Syrian asylum-seekers applying during the study period were diagnosed with tuberculosis. The prevalence was 22 cases per 100,000 persons screened upon arrival (95% CI: 10-44), while the incidence within the first year after arrival was 19 per 100,000 persons (95% CI: 3-62). Tuberculosis was diagnosed in 133 Eritrean/Ethiopian asylum-seekers applying during the study period. The prevalence was 283 cases per 100,000 persons screened upon arrival (95% CI: 198-393) and the incidence in the first year after arrival was 1394 per 100,000 persons (95% CI: 1095-1751). CONCLUSION: In the last two years, most asylum-seekers have originated from Syria and among them tuberculosis is relatively uncommon. However, among Eritrean/Ethiopian asylum-seekers, prevalence and incidence in the first year in the Netherlands are high. This suggests that many of them have been recently infected, in their country of origin or during the journey. Other interventions are required, such as screening for latent infection, to prevent tuberculosis among high-risk asylum seekers and further reduce the incidence of this disease in the Netherlands. PMID- 26980470 TI - [Surfactant doses: From words to action]. PMID- 26980469 TI - QTL Mapping of Endocochlear Potential Differences between C57BL/6J and BALB/cJ mice. AB - We reported earlier that the endocochlear potential (EP) differs between C57BL/6J (B6) and BALB/cJ (BALB) mice, being lower in BALBs by about 10 mV (Ohlemiller et al. Hear Res 220: 10-26, 2006). This difference corresponds to strain differences with respect to the density of marginal cells in cochlear stria vascularis. After about 1 year of age, BALB mice also tend toward EP reduction that correlates with further marginal cell loss. We therefore suggested that early sub-clinical features of the BALB stria vascularis may predispose these mice to a condition modeling Schuknecht's strial presbycusis. We further reported (Ohlemiller et al. J Assoc Res Otolaryngol 12: 45-58, 2011) that the acute effects of a 2-h 110 dB SPL noise exposure differ between B6 and BALB mice, such that the EP remains unchanged in B6 mice, but is reduced by 40-50 mV in BALBs. In about 25 % of BALBs, the EP does not completely recover, so that permanent EP reduction may contribute to noise-induced permanent threshold shifts in BALBs. To identify genes and alleles that may promote natural EP variation as well as noise-related EP reduction in BALB mice, we have mapped related quantitative trait loci (QTLs) using 12 recombinant inbred (RI) strains formed from B6 and BALB (CxB1-CxB12). EP and strial marginal cell density were measured in B6 mice, BALB mice, their F1 hybrids, and RI mice without noise exposure, and 1-3 h after broadband noise (4 45 kHz, 110 dB SPL, 2 h). For unexposed mice, the strain distribution patterns for EP and marginal cell density were used to generate preliminary QTL maps for both EP and marginal cell density. Six QTL regions were at least statistically suggestive, including a significant QTL for marginal cell density on chromosome 12 that overlapped a weak QTL for EP variation. This region, termed Maced (Marginal cell density QTL) supports the notion of marginal cell density as a genetically influenced contributor to natural EP variation. Candidate genes for Maced notably include Foxg1, Foxa1, Akap6, Nkx2-1, and Pax9. Noise exposure produced significant EP reductions in two RI strains as well as significant EP increases in two RI strains. QTL mapping of the EP in noise-exposed RI mice yielded four suggestive regions. Two of these overlapped with QTL regions we previously identified for noise-related EP reduction in CBA/J mice (Ohlemiller et al. Hear Res 260: 47-53, 2010) on chromosomes 5 and 18 (Nirep). The present map may narrow the Nirep interval to a ~10-Mb region of proximal Chr. 18 that includes Zeb1, Arhgap12, Mpp7, and Gjd4. This study marks the first exploration of natural gene variants that modulate the EP. Their orthologs may underlie some human hearing loss that originates in the lateral wall. PMID- 26980471 TI - The Effect of Necitumumab in Combination with Gemcitabine plus Cisplatin on Tolerability and on Quality of Life: Results from the Phase 3 SQUIRE Trial. AB - INTRODUCTION: Necitumumab, a second-generation, recombinant human immunoglobulin G1 epidermal growth factor receptor antibody in the phase 3 SQUIRE trial (NCT00981058), increased survival benefit for patients randomized to receive necitumumab plus gemcitabine-cisplatin compared with those who received gemcitabine-cisplatin. Here we characterize health-related quality of life (HRQoL) and tolerability results. METHODS: A total of 1093 patients with stage IV squamous non-small cell lung cancer were randomized 1:1 to receive necitumumab (800 mg absolute dose intravenously [IV]) plus gemcitabine-cisplatin (gemcitabine = 1250 mg/m(2) IV on days 1 and 8; cisplatin = 75 mg/m(2) IV on day 1) or gemcitabine-cisplatin alone (every 21 days) for up to six cycles. Patients receiving necitumumab plus gemcitabine-cisplatin without disease progression continued necitumumab until progression. HRQoL was measured by Eastern Cooperative Oncology Group performance status, the Lung Cancer Symptom Scale (LCSS), and the European Quality of Life Five-Dimensions questionnaire. Efficacy and LCSS outcomes were analyzed using the baseline maximum severity score of the LCSS. Tolerability was measured in terms of exposure to the study treatment and adverse events. Hospitalization rates were collected. RESULTS: Most patients in both study arms similarly maintained Eastern Cooperative Oncology Group performance status and comparable LCSS and European Quality of Life Five Dimensions questionnaire assessments. Patients with a higher baseline LCSS had a greater survival benefit on the necitumumab arm. Chemotherapy exposure was similar in both treatment arms; 51% of patients on the necitumumab plus gemcitabine-cisplatin arm continued on single-agent necitumumab. The most frequent grade 4 adverse events were neutropenia (6.1% versus 7.9%) and thrombocytopenia (3.2% versus 4.3%) in the necitumumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin arms, respectively. Hospitalizations were slightly higher with necitumumab plus gemcitabine-cisplatin (36.4%) than with gemcitabine cisplatin (34.0%). CONCLUSIONS: The addition of necitumumab to gemcitabine cisplatin was well tolerated, did not negatively affect HRQoL or toxicity, and particularly benefited patients with more severe baseline symptoms or lower HRQoL. PMID- 26980472 TI - Variations in Receipt of Curative-Intent Surgery for Early-Stage Non-Small Cell Lung Cancer (NSCLC) by State. AB - BACKGROUND: Previous studies reported racial and socioeconomic disparities in receipt of curative-intent surgery for early-stage non-small cell lung cancer (NSCLC) in the United States. We examined variation in receipt of surgery and whether the racial disparity varies by state. METHODS: Patients in whom stage I or II NSCLC was diagnosed from 2007 to 2011 were identified from 38 state and the District of Columbia population-based cancer registries compiled by the North American Association of Central Cancer Registries. Percentage of patients receiving curative-intent surgery was calculated for each registry. Adjusted risk ratios were generated by using modified Poisson regression to control for sociodemographic (e.g., age, sex, race, insurance) and clinical (e.g., grade, stage) factors. Non-Hispanic (NH) whites and Massachusetts were used as references for comparisons because they had the lowest uninsured rates. RESULTS: In all registries combined, 66.4% of patients with early-stage NSCLC (73,475 of 110,711) received curative-intent surgery. Receipt of curative-intent surgery for early-stage NSCLC varied substantially by state, ranging from 52.2% to 56.1% in Wyoming, Louisiana, and New Mexico to 75.2% to 77.2% in Massachusetts, New Jersey, and Utah. In a multivariable analysis, the likelihood of receiving curative-intent surgery was significantly lower in all but nine states/registries compared with Massachusetts, ranging from 7% lower in California to 25% lower in Wyoming. Receipt of curative-intent surgery for early-stage NSCLC was lower for NH blacks than for NH whites in every state, although statistically significant in Florida and Texas. CONCLUSIONS: Receipt of curative-intent surgery for early stage NSCLC varies substantially across states in the United States, with northeastern states generally showing the highest rates. Further, receipt of treatment appeared to be lower in NH blacks than in NH whites in every state, although statistically significant in Florida and Texas. PMID- 26980473 TI - Icotinib in Patients with Pretreated Advanced Esophageal Squamous Cell Carcinoma with EGFR Overexpression or EGFR Gene Amplification: A Single-Arm, Multicenter Phase 2 Study. AB - INTRODUCTION: Epidermal growth factor receptor (EGFR) has been reported to be overexpressed and amplified in a high percentage of patients with esophageal squamous cell carcinoma (ESCC). The activity of icotinib, an EGFR tyrosine kinase inhibitor, was assessed in previously treated ESCC with EGFR overexpression or amplification. METHODS: For this phase 2, single-arm, multicenter trial undertaken at six hospitals in China, we included Chinese patients with previously treated, histologically confirmed advanced ESCC and EGFR overexpression (immunohistochemical staining sore of 3+) or amplification (positive fluorescence in situ hybridization result). These patients received oral icotinib (250 mg, three times daily).The primary end point was the proportion of patients with objective responses as assessed by an independent radiology review committee. RESULTS: Between December 5, 2013, and May 28, 2015, a total of 281 patients were screened. Fifty-four eligible patients were enrolled. Nine responses were observed, including one complete response and eight partial responses, and 16 patients had stable disease, resulting in a 16.7% objective response rate (95% confidence interval [CI]: 6.7-26.6) and 46.3% disease control rate (95% CI: 33.0-59.6). The median progression-free survival and overall survival times were 52 (95% CI: 40-95) days and 153 (95% CI: 139-218) days, respectively. A total of 43 patients experienced at least one adverse event, but most were only grade 1 to 2 in severity. The most frequent was rash (48.1%), followed by diarrhea (22.2%). CONCLUSIONS: Icotinib showed favorable activity in patients with advanced, previously treated ESCC with EGFR overexpression or amplification. These findings suggest further research into EGFR overexpression or amplification for selecting responsive patients. PMID- 26980474 TI - New technique to improve lower facial contour using a three-dimensional, custom made, positional stent. PMID- 26980475 TI - Feasibility of eye-tracking technology to quantify expertise in ultrasound-guided regional anesthesia. AB - Ultrasound-guided regional anesthesia (UGRA) requires an advanced procedural skill set that incorporates both sonographic knowledge of relevant anatomy as well as technical proficiency in needle manipulation in order to achieve a successful outcome. Understanding how to differentiate a novice from an expert in UGRA using a quantifiable tool may be useful for comparing educational interventions that could improve the rate at which one develops expertise. Exploring the gaze pattern of individuals performing a task has been used to evaluate expertise in many different disciplines, including medicine. However, the use of eye-tracking technology has not been previously applied to UGRA. The purpose of this preliminary study is to establish the feasibility of applying such technology as a measurement tool for comparing procedural expertise in UGRA. eye-tracking data were collected from one expert and one novice utilizing Tobii Glasses 2 while performing a simulated ultrasound-guided thoracic paravertebral block in a gel phantom model. Area of interest fixations were recorded and heat maps of gaze fixations were created. Results suggest a potential application of eye-tracking technology in the assessment of UGRA learning and performance. PMID- 26980477 TI - Investigating piconewton forces in cells by FRET-based molecular force microscopy. AB - The ability of cells to sense and respond to mechanical forces is crucial for a wide range of developmental and pathophysiological processes. The molecular mechanisms underlying cellular mechanotransduction, however, are largely unknown because suitable techniques to measure mechanical forces across individual molecules in cells have been missing. In this article, we highlight advances in the development of molecular force sensing techniques and discuss our recently expanded set of FRET-based tension sensors that allows the analysis of mechanical forces with piconewton sensitivity in cells. In addition, we provide a theoretical framework for the design of additional tension sensor modules with adjusted force sensitivity. PMID- 26980476 TI - Autophagy and Apoptosis Play Opposing Roles in Overall Survival of Esophageal Squamous Cell Carcinoma. AB - Esophageal cancer is among the most aggressive gastrointestinal tract malignancies, and squamous cell carcinoma is the most common subtype. Although both autophagy and apoptosis involve programmed cell death, autophagy also maintains cell survival by recycling cellular waste. The relationship between autophagy and apoptosis in esophageal squamous cell carcinoma (ESCC) is unclear. Autophagic and apoptotic markers of ESCC were detected by immunohistochemical staining (IHC) in 43 ESCC patients treated during 2007-2011. Chi-square test and Kaplan-Meier method were used to determine how clinicopathological parameters were related to IHC results for LC3B, Beclin-1 and caspase-3 (CASP-3). Correlations among Beclin-1, LC3B, and CASP-3 were analyzed by Spearman rho. The statistical analyses revealed no clinicopathological parameters that significantly correlated with expressions of Beclin-1, LC3B, and CASP-3. However, low CASP-3 expression and high LC3B expression revealed by IHC were predictors of a poor prognosis. Additionally, LC3B expression had a significant negative correlation with CASP-3 expression. Autophagy is antagonistic to apoptosis and predicts poor overall survival in ESCC. PMID- 26980478 TI - Hoxa5 undergoes dynamic DNA methylation and transcriptional repression in the adipose tissue of mice exposed to high-fat diet. AB - BACKGROUND/OBJECTIVES: The genomic bases of the adipose tissue abnormalities induced by chronic positive calorie excess have been only partially elucidated. We adopted a genome-wide approach to directly test whether long-term high-fat diet (HFD) exposure affects the DNA methylation profile of the mouse adipose tissue and to identify the functional consequences of these changes. SUBJECTS/METHODS: We have used epididymal fat of mice fed either high-fat (HFD) or regular chow (STD) diet for 5 months and performed genome-wide DNA methylation analyses by methylated DNA immunoprecipitation sequencing (MeDIP-seq). Mouse Homeobox (Hox) Gene DNA Methylation PCR, RT-qPCR and bisulphite sequencing analyses were then performed. RESULTS: Mice fed the HFD progressively expanded their adipose mass accompanied by a significant decrease in glucose tolerance (P<0.001) and insulin sensitivity (P<0.05). MeDIP-seq data analysis revealed a uniform distribution of differentially methylated regions (DMR) through the entire adipocyte genome, with a higher number of hypermethylated regions in HFD mice (P<0.005). This different methylation profile was accompanied by increased expression of the Dnmt3a DNA methyltransferase (Dnmt; P<0.05) and the methyl-CpG binding domain protein Mbd3 (P<0.05) genes in HFD mice. Gene ontology analysis revealed that, in the HFD-treated mice, the Hox family of development genes was highly enriched in differentially methylated genes (P=0.008). To validate this finding, Hoxa5, which is implicated in fat tissue differentiation and remodeling, has been selected and analyzed by bisulphite sequencing, confirming hypermethylation in the adipose tissue from the HFD mice. Hoxa5 hypermethylation was associated with downregulation of Hoxa5 mRNA and protein expression. Feeding animals previously exposed to the HFD with a standard chow diet for two further months improved the metabolic phenotype of the animals, accompanied by return of Hoxa5 methylation and expression levels (P<0.05) to values similar to those of the control mice maintained under standard chow. CONCLUSIONS: HFD induces adipose tissue abnormalities accompanied by epigenetic changes at the Hoxa5 adipose tissue remodeling gene. PMID- 26980479 TI - Treatment with TUG891, a free fatty acid receptor 4 agonist, restores adipose tissue metabolic dysfunction following chronic sleep fragmentation in mice. AB - BACKGROUND: Sleep fragmentation (SF), a frequent occurrence in multiple sleep and other diseases leads to increased food intake and insulin resistance via increased macrophage activation and inflammation in visceral white adipose tissue (VWAT). Free fatty acid receptor 4 (FFA4) is reduced in pediatric sleep apnea patients and FFA4 agonists have been proposed in the treatment of obesity and metabolic dysfunction. METHODS: Male mice were subjected to SF exposures for 6 weeks, and treated during the last 2 weeks with either TUG891, a potent and selective FFA4 agonist, or vehicle (Veh). Glucose and insulin tolerance tests and VWAT insulin sensitivity tests were conducted (phosphorylated Akt/total Akt), along with flow cytometric assessments of VWAT macrophage polarity, and T-cell lymphocyte subsets. RESULTS: SF-TUG891 mice showed reduction in food consumption, weight gain and VWAT mass. Furthermore, TUG891 treatment ameliorated glucose tolerance test and insulin tolerance test responses and increased VWAT p-Akt/Akt responses to insulin. Increases in M1/M2 macrophages and decreased Treg counts in VWAT associated with SF were markedly improved by TUG891, and VWAT macrophages from TUG891-treated mice had markedly attenuated insulin resistance effects on naive cultured adipocytes. CONCLUSIONS: Treatment with an FFA4 agonist reverses SF-induced food intake increases and gains in body weight, and significantly attenuates VWAT inflammation and insulin resistance. Thus, interventional dietary or pharmaceutical strategies aimed at increasing FFA4 activity may serve as potentially useful adjunctive therapies for sleep disorders accompanied by metabolic morbidity. PMID- 26980481 TI - Physical activity, dietary vitamin C, and metabolic syndrome in the Korean adults: the Korea National Health and Nutrition Examination Survey 2008 to 2012. AB - OBJECTIVES: Metabolic syndrome is a global public health problem, and regular physical activity is a well-known critical factor in its management. A recent study suggests that the effect of exercise on metabolic syndrome may be enhanced by sufficient plasma vitamin C concentrations. We therefore examined the combined effect of physical activity and dietary vitamin C on the risk of metabolic syndrome in the general Korean population. STUDY DESIGN: Cross-sectional study. METHODS: We analyzed data from 22,671 adults aged 20 years or older from the Korea National Health and Nutrition Examination Survey 2008-2012. Physical activity was computed as the total metabolic equivalent (METs-hr/week) summed from MET scores of walking, moderate activity, and vigorous activity. Vitamin C intake was assessed using a 24-h dietary recall. Participants were classified into four combined groups based on median values of physical activity and vitamin C intake. RESULTS: After adjustment for potential confounders, the odds ratio (OR) for metabolic syndrome in individuals with both high physical activity and vitamin C intake (vs. both low physical activity and vitamin C intake) was 0.79 (95% confidence interval (CI), 0.71-0.87). The estimated combined effect was more than either high physical activity alone (OR, 0.81 (95% CI, 0.73-0.90)) or high vitamin C intake alone (OR, 0.89 (95% CI, 0.80-0.99)), although each of those was beneficial. CONCLUSIONS: Physical activity and dietary intake of vitamin C are both associated with a lower risk of metabolic syndrome. Our findings suggest further that a combination of physical activity and a diet rich in vitamin C may help in preventing metabolic syndrome. PMID- 26980482 TI - Synthesis of Indeno[1',2':4,5]imidazo[1,2-a]pyridin-11-ones and Chromeno[4',3':4,5]imidazo[1,2-a]pyridin-6-ones through Palladium-Catalyzed Cascade Reactions of 2-(2-Bromophenyl)imidazo[1,2-a]pyridines. AB - A novel and efficient synthesis of 11H-indeno[1',2':4,5]imidazo[1,2-a]pyridin-11 one, a hybrid structure of indenone with imidazo[1,2-a]pyridine, from the reaction of 2-(2-bromophenyl)imidazo[1,2-a]pyridine with carbon monoxide through palladium-catalyzed CO insertion and C-H bond activation, has been developed. Intriguingly, under similar conditions but in the presence of Cu(OAc)2, the reaction selectively afforded 6H-chromeno[4',3':4,5]imidazo[1,2-a]pyridin-6-one, a hybrid structure of chromenone with imidazo[1,2-a]pyridine, via a more sophisticated cascade process including acetoxylation, deacetylation, CO insertion, and C-H bond activation. PMID- 26980480 TI - Human papillomavirus type 16 viral load is decreased following a therapeutic vaccination. AB - In the dose-escalation phase of a Phase I clinical trial in which six subjects each were vaccinated with PepCan at the 50, 100, 250, and 500 MUg per peptide dose, the 50 MUg dose showed the best histological regression rate. Ten additional subjects were vaccinated at this dose in the final dose phase. As with the dose-escalation phase, no dose-limiting toxicities were observed. Overall, the histological regression rates were 50% at the 50 MUg dose (7 of 14) and 100 MUg dose (3 of 6), and 45 % overall (14 of 31). Of subjects in whom HPV type 16 (HPV 16) was detected at entry, it became undetectable in three subjects after vaccination, and the viral loads significantly decreased in nine subjects in whom HPV 16 infection was detected at entry and exit (p = 0.008). Immune profiling revealed increased T-helper type 1 cells after vaccinations (p = 0.02 and 0.0004 after 2 and 4 vaccinations, respectively). T-helper type 2 cells initially increased after two vaccinations (p = 0.01), but decreased below the baseline level after four vaccinations although not significantly. Pre-vaccination regulatory T cell levels were significantly lower in histological responders compared to non-responders (p = 0.03). Feasibility of testing plasma for multiplex cytokine/chemokine analysis and of performing proteomic analysis of PBMCs was examined for potentially identifying biomarkers in the future. While these analyses are feasible to perform, attention needs to be given to how soon the blood samples would be processed after phlebotomy. As sufficient safety of PepCan has been demonstrated, enrollment for the Phase II clinical trial has been opened. PMID- 26980483 TI - Complications and Yield of Computed Tomography-Guided Transthoracic Core Needle Biopsy of Lung Nodules at a High-Volume Academic Center in an Endemic Coccidioidomycosis Area. AB - PURPOSE: Previous studies with small sample sizes have shown a wide range of complication rates and no study has investigated the yield of computed tomography guided transthoracic core needle biopsies (CTTCB) for coccidioidomycosis. To better assess the safety, accuracy, and risk factors for complications of CTTCB of pulmonary nodules, we conducted a retrospective study at a high-volume academic center in an endemic coccidioidomycosis area. METHODS: We conducted a retrospective study of 203 patients who underwent CTTCB of pulmonary nodules between December 2010 and May 2013. We collected demographics, clinical, and radiographic data. Each case was reviewed for complications. Diagnostic accuracy was assessed by comparing CTTCB with final diagnoses. RESULTS: The overall complication rate was 25 %. Pneumothorax accounted for 24 % of complications with 7 % of pneumothoraces requiring chest tube. 1.5 % were complicated by hemoptysis but none required blood transfusions. There was an association between complications and age, presence of emphysema on CT, traversed lung length, and lesion depth. The overall sensitivity of the CTTCB for all types of lung cancer was 93 %, and specificity of 100 %. The positive predictive value of CTTCB for lung cancer was 100 %. The sensitivity and specificity of CTTCB for a coccidiomycosis lung nodule was 83 % with a specificity of 100 % with a PPV of 100 %. CONCLUSION: Our study demonstrates that CTTCB is a relatively safe method for evaluating lung nodules and highly accurate in evaluating lung nodules due to coccidioidomycosis in an endemic area. The primary risk factors for complications from CTTCB are the presence of emphysema on CT scan, lesion depth, and traversed lung length. PMID- 26980484 TI - Competing endogenous RNA networks of CYP4Z1 and pseudogene CYP4Z2P confer tamoxifen resistance in breast cancer. AB - Patients with estrogen receptor alpha (ERalpha)-positive breast cancer can be treated with endocrine therapy using anti-estrogens such as tamoxifen; nonetheless, patients often develop resistance limiting the success of breast cancer treatment. The potential mechanisms remain elusive. In detail, many miRNAs have been associated with breast cancer tamoxifen resistance, but no studies have addressed the role of miRNA-mediated competitive endogenous RNAs network (ceRNET) in tamoxifen resistance. The ceRNET between CYP4Z1 and pseudogene CYP4Z2P has been revealed to promote breast cancer angiogenesis. However, its function in tamoxifen resistance remains unclear. Here we report CYP4Z1 and CYP4Z2P were downregulated in MCF-7 cells compared with tamoxifen-resistant MCF-7-TamR cells. Enforced upregulation of CYP4Z1- or CYP4Z2P-3'UTR level renders MCF-7 Cells resistant to tamoxifen. We find that overexpression of CYP4Z1- or CYP4Z2P-3'UTR enhances the transcriptional activity of ERalpha through the activation of ERalpha phosphorylation. Furthermore, we find that CYP4Z1- and CYP4Z2P-3'UTRs increase ERalpha activity dependent on cyclin-dependent kinase 3 (CDK3). Reporter gene and western blot assays revealed that CYP4Z1- and CYP4Z2P-3'UTRs act as CDK3 ceRNAs. More importantly, the blocking of CYP4Z1- and CYP4Z2P-3'UTRs reversed tamoxifen resistance in MCF-7-TamR cells. Our data demonstrates that the ceRNET between CYP4Z1 and pseudogene CYP4Z2P acts as a sub-ceRNET to promote CDK3 expression in ER-positive breast cancer and is a potential therapeutic target for treatment of tamoxifen-resistant breast cancer. PMID- 26980485 TI - Recycling WEEE: Extraction and concentration of silver from waste crystalline silicon photovoltaic modules. AB - Photovoltaic modules (or panels) are important power generators with limited lifespans. The modules contain known pollutants and valuable materials such as silicon, silver, copper, aluminum and glass. Thus, recycling such waste is of great importance. To date, there have been few published studies on recycling silver from silicon photovoltaic panels, even though silicon technology represents the majority of the photovoltaic market. In this study, the extraction of silver from waste modules is justified and evaluated. It is shown that the silver content in crystalline silicon photovoltaic modules reaches 600g/t. Moreover, two methods to concentrate silver from waste modules were studied, and the use of pyrolysis was evaluated. In the first method, the modules were milled, sieved and leached in 64% nitric acid solution with 99% sodium chloride; the silver concentration yield was 94%. In the second method, photovoltaic modules were milled, sieved, subjected to pyrolysis at 500 degrees C and leached in 64% nitric acid solution with 99% sodium chloride; the silver concentration yield was 92%. The first method is preferred as it consumes less energy and presents a higher yield of silver. This study shows that the use of pyrolysis does not assist in the extraction of silver, as the yield was similar for both methods with and without pyrolysis. PMID- 26980486 TI - The multiple sclerosis drug fingolimod (FTY720) stimulates neuronal gene expression, axonal growth and regeneration. AB - Fingolimod (FTY720) is a new generation oral treatment for multiple sclerosis (MS). So far, FTY720 was mainly considered to target trafficking of immune cells but not brain cells such as neurons. Herein, we analyzed FTY720's potential to directly alter neuronal function. In CNS neurons, we identified a FTY720 governed gene expression response. FTY720 upregulated immediate early genes (IEGs) encoding for neuronal activity associated transcription factors such as c-Fos, FosB, Egr1 and Egr2 and induced actin cytoskeleton associated genes (actin isoforms, tropomyosin, calponin). Stimulation of primary neurons with FTY720 enhanced neurite growth and altered growth cone morphology. In accordance, FTY720 enhanced axon regeneration in mice upon facial nerve axotomy. We identified components of a FTY720 engaged signaling cascade including S1P receptors, G12/13G proteins, RhoA-GTPases and the transcription factors SRF/MRTF. In summary, we uncovered a broader cellular and therapeutic operation mode of FTY720, suggesting beneficial FTY720 effects also on CNS neurons during MS therapy and for treatment of other neurodegenerative diseases requiring neuroprotective and neurorestorative processes. PMID- 26980487 TI - MLKL inhibition attenuates hypoxia-ischemia induced neuronal damage in developing brain. AB - Mixed lineage kinase domain-like protein (MLKL) is a critical molecule mediating cell necroptosis. However, its role in brain injury remains obscure. We first investigated the functions and mechanisms of MLKL in mediating neuronal damage in developing brain after hypoxia-ischemia. Neuronal necroptosis was induced by oxygen-glucose deprivation (OGD) plus caspase inhibitor zVAD treatment (OGD/zVAD). We found that two important necroptosis related proteins, receptor interacting protein 1 and 3 (RIP1, RIP3) were upregulated. Furthermore, the interaction of RIP1-RIP3 with MLKL increased. Inhibition of MLKL through siRNA diminished RIP1-RIP3-MLKL interaction and attenuated neuronal death induced by OGD/zVAD. The translocation of oligomerized MLKL to the neuronal membrane leading to the injury of cellular membrane is the possible new mechanism of neuronal necroptosis. Animal experiment with neonatal rats further proved that MLKL inhibition attenuated brain damage induced by hypoxia-ischemia. These findings suggest that MLKL is a target to attenuate brain damage in developing brain. PMID- 26980488 TI - Genetic alteration in phosphofructokinase family promotes growth of muscle invasive bladder cancer. AB - AIMS: Metabolic alterations in cancer, including bladder cancer, have been addressed in recent years. We aimed to study the role of phosphofructokinase (PFK) in muscle-invasive bladder cancer (MIBC). METHOD: By in silico analysis of the bladder cancer data from the Cancer Genome Atlas (TCGA) database using the cBioPortal platform, we studied genetic alteration of genes within the PFK family (PFKL, PFKM, PFKP, PFKFB1, PFKFB2, PFKFB3, and PFKFB4). In vitro studies were carried out using the PFK inhibitor 2,5-anhydro-D-glucitol-6-phosphate. RESULTS: Genetic alterations of PFK family genes were observed in ~44% of MIBC cases in TCGA. The main alterations were amplification and upregulation. Patients with altered PFK gene status were more likely to have a history of noninvasive bladder cancer. Altered PFK status was not associated with survival or disease relapse. Use of the PFK inhibitor significantly decreased the level of glycolysis and inhibited the growth and invasion of bladder cancer cells. CONCLUSIONS: PFKs were critical genes in charge of glycolysis and were upregulated in bladder cancer. Targeting this pathway could inhibit cell growth in bladder cancer. PMID- 26980489 TI - Immunomodulating microRNAs of mycobacterial infections. AB - MicroRNAs are a class of small non-coding RNAs that have emerged as key regulators of gene expression at the post-transcriptional level by sequence specific binding to target mRNAs. Some microRNAs block translation, while others promote mRNA degradation, leading to a reduction in protein availability. A single miRNA can potentially regulate the expression of multiple genes and their encoded proteins. Therefore, miRNAs can influence molecular signalling pathways and regulate many biological processes in health and disease. Upon infection, host cells rapidly change their transcriptional programs, including miRNA expression, as a response against the invading microorganism. Not surprisingly, pathogens can also alter the host miRNA profile to their own benefit, which is of major importance to scientists addressing high morbidity and mortality infectious diseases such as tuberculosis. In this review, we present recent findings on the miRNAs regulation of the host response against mycobacterial infections, providing new insights into host-pathogen interactions. Understanding these findings and its implications could reveal new opportunities for designing better diagnostic tools, therapies and more effective vaccines. PMID- 26980491 TI - Comparison of the socio-demographic and clinical features of pulmonary TB patients infected with sub-lineages within the W-Beijing and non-Beijing Mycobacterium tuberculosis. AB - BACKGROUND: Highly lethal outbreaks of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are increasing. Mycobacterium tuberculosis variant Beijing family and its members is regarded as a successful clone of M. tuberculosis that is associated with drug resistance in China. Understanding the genetic characteristics and molecular mechanism of drug resistant tuberculosis within Beijing family may help to clarify its origin and evolutionary history and the driving forces behind its emergence and current dissemination. METHODS: Totally of 1222 Mycobacterium tuberculosis isolates were recovered from patients in six counties of two provinces in eastern China within 2010/2012. Strain lineage and its major subgroups were studied respectively by using Spoligotyping and MIRU-VNTR. The 1st-line drug susceptibility was analyzed by proportional method and 2nd-line drug susceptibility was determined by the HAINs MTBDRsl test. The genetic characterization of drug resistance was analyzed by sequencing the previously reported genes and loci associated with drug resistance together with the multiple genotyping including MIRU-VNTR, Spoligotyping and LSP genotyping. RESULTS: Of the 1222 Mtb isolates, 298 (24.4%) were resistant to 1st-line drug and 73 (5.9%) were simultaneously resistant to INH and RIF namely MDR-TB. Respectively 23.8% of 1st-line drug resistant TB and 12.0% of the drug susceptible TB contained the mutation associated with 2nd-line drugs by HAINs test. The Spoligotyping of 1222 Mtb isolates revealed the 967 (79.1%) of the isolates belonged to the W-Beijing family. Within W-Beijing family, 78.8% MDR-TB were observed in the isolates with simultaneous deletion of RD105 and RD207, with sub-lineage 181 accounting for 75% of MDR-TB. Analysis of 24 MIRU-VNTR loci revealed that 88.2% (15/17) of MDR and extensively drug resistant (XDR) clustered isolates were sub-lineage 181. CONCLUSIONS: Sublineage 181 might have the capacity to spread throughout the general community in rural China. This is the first report on the extensive association of sub-lineage 181 with MDR TB and possibly pre-XDR TB and XDR TB. It is important to monitor sublineage 181 to verify its heightened transmission and understand its importance in the global MDR-TB and XDR-TB epidemics. PMID- 26980492 TI - Evaluation of a lens-free imager to facilitate tuberculosis diagnostics in MODS. AB - Tuberculosis (TB) control efforts are hampered by a mismatch in diagnostic technology. Lack of adequate early diagnostics and Multi-drug resistant (MDR) detection is a critical problem in control efforts. Alternate and novel diagnostic approaches are required, especially in low-resources settings where they are needed most. The Microscopic Observation Drug Susceptibility (MODS) assay is a cost-effective, highly sensitive, and specific method based on the detection of characteristic cording growth patterns of Mycobacterium tuberculosis (MTB), in microscopic examination of a liquid culture under an inverted microscope. By adding antimicrobials to the wells, MODS also determines antimicrobial susceptibility in both MDR and Extreme Drug Resistant (XDR) tuberculosis. The interpretation of a MODS culture performed in a 24 well plate, requires an extensive inspection over the entire surface to detect TB cords. This process requires significant time and effort from a trained microscopist. We evaluated a lens-free imager system, able to render microscopic images of live specimens, for the proof of principle to be used for MODS culture interpretation. The lens-free imager system is able to digitalize a 24-mm(2) surface with approximately 40X magnification in a single capture. The evaluation of the lens free imager found that it produced microscopic images that were adequate for MODS interpretation by a human expert. Compared to the average time that takes a microscopist to completely examine a MODS culture sample, the lens free imager notably reduced the time of inspection. Therefore, lens-free imager variants may constitute promising systems to aid in the diagnostics of tuberculosis, by simplifying and reducing the time of inspection and permitting automatization of MODS interpretation. PMID- 26980490 TI - Tuberculosis as a three-act play: A new paradigm for the pathogenesis of pulmonary tuberculosis. AB - Lack of access to human tissues with untreated tuberculosis (TB) has forced generations of researchers to use animal models and to adopt a paradigm that granulomas are the characteristic lesion of both primary and post primary TB. An extended search of studies of human lung tissues failed to find any reports that support this paradigm. We found scores of publications from gross pathology in 1804 through high resolution CT scans in 2015 that identify obstructive lobular pneumonia, not granulomas, as the characteristic lesion of developing post primary TB. This paper reviews this literature together with other relevant observations to formulate a new paradigm of TB with three distinct stages: a three-act play. First, primary TB, a war of attrition, begins with infection that spreads via lymphatics and blood stream before inducing systemic immunity that contains and controls the organisms within granulomas. Second, post-primary TB, a sneak attack, develops during latent TB as an asymptomatic obstructive lobular pneumonia in persons with effective systemic immunity. It is a paucibacillary process with no granulomas that spreads via bronchi and accumulates mycobacterial antigens and host lipids for 1-2 years before suddenly undergoing caseous necrosis. Third, the fallout, is responsible for nearly all clinical post primary disease. It begins with caseous necrotic pneumonia that is either retained to become the focus of fibrocaseous disease or is coughed out to leave a cavity. This three-stage paradigm suggests testable hypotheses and plausible answers to long standing questions of immunity to TB. PMID- 26980493 TI - Mutations in lysX as the new and reliable markers for tuberculosis Beijing and modern Beijing strains. AB - Genotyping results and DNA sequencing analysis of 235 Mycobacterium tuberculosis (M. tuberculosis) isolates from China indicated that mutations at codon 995 (Pro CCG to Pro CCA) and 701 (Ile ATT to Thr ACT) in lysX gene (Rv1640c), are specific markers for Beijing and modern Beijing strains, respectively. This observation was also confirmed by 24 genomes of M. tuberculosis strains from other countries. Moreover, a simple and fast multiplex allele-specific PCR (MAS-PCR) method for detecting mutations at codon 995 and 701 in lysX has been established and used to screen 235 DNA samples obtained from M. tuberculosis isolates. In all cases, Beijing and modern Beijing strains were identified correctly. PMID- 26980494 TI - Identification of a novel inhibitor of isocitrate lyase as a potent antitubercular agent against both active and non-replicating Mycobacterium tuberculosis. AB - OBJECTIVE: Screen and identify novel inhibitors of isocitrate lyase (ICL) as potent antitubercular agents against Mycobacterium tuberculosis and determine their inhibitory characteristics, antitubercular activities and mechanisms of action. METHODS: Recombinant ICL of M. tuberculosis was expressed and purified, which was used for high-throughput screening (HTS) and the following experiments. A total of 71,765 compounds were screened to identify ICL inhibitors which were then evaluated for their roles as potent antitubercular agents. To determine the inhibitory characteristics of the agents against latent M. tuberculosis in persistent infections, a macrophage model (mouse J774A.1 cell) infected with Mycobacterium marinum BAA-535 strain was built and assessed. The potent antitubercular agents were identified using the macrophage model. Then, the inhibitory intensity and mode of the agents that exhibit on ICL protein of M. tuberculosis were analyzed, and the interaction mechanisms were preliminarily clarified according to the parameters of enzyme kinetics, circular dichroism experiments, fluorescence quenching assay, and molecular docking. RESULTS: The previously established ICL inhibitor screening model was evaluated to be suitable for HTS assay. Of the 71,765 compounds, 13 of them were identified to inhibit ICL effectively and stably. IMBI-3 demonstrated the most significant inhibitory activity with IC50 of 30.9 MUmol/L. Its minimum inhibitory concentration (MIC) for M. tuberculosis, including extensively drug-resistant tuberculosis (XDR-TB) and multidrug-resistant tuberculosis (MDR-TB), were determined in the range of 0.25-1 MUg/mL. When IMBI-3 is used in combination with isoniazid, the colony forming units (CFU) counting of latent M. tuberculosis in J774A.1 macrophage cells decreased significantly as IMBI-3 concentration increased. The inhibition mode of IMBI-3 on ICL was probably competitive inhibition with an inhibition constant (Ki) of approximate 1.85 MUmol/L. The interaction between IMBI-3 and ICL of M. tuberculosis was also confirmed by circular dichroism experiments and fluorescence quenching assay. And seven possible active amino acids of ICL of M. tuberculosis were identified in the active site through molecular docking. CONCLUSION: IMBI-3, a novel potent antitubercular agent targeting ICL of M. tuberculosis, was identified and evaluated. It inhibited both log-phase M. tuberculosis in vitro and dormant M. tuberculosis in macrophages. It was the first representative compound of this family with the ICL enzyme inhibition and antimycobacterial activities. PMID- 26980496 TI - The endoplasmic reticulum stress response: A link with tuberculosis? AB - Tuberculosis (TB) remains a major cause of mortality and morbidity in the worldwide. The endoplasmic-reticulum stress (ERS) response constitutes a cellular process that is triggered by mycobacterial infection that disturbs the folding of proteins in the endoplasmic reticulum (ER). The unfolded protein response (UPR) is induced to suspend the synthesis of early proteins and reduce the accumulation of unfolded- or misfolded proteins in the ER restoring normal physiological cell function. Prolonged or uncontrolled ERS leads to the activation of three signaling pathways (IRE1, PERK and ATF6) which directs the cell towards apoptosis. The absence of this process facilitates spread of the mycobacteria within the body. We summarize here recent advances in understanding the signaling pathway diversity governing ERS in relation to TB. PMID- 26980495 TI - Association of autophagy-related IRGM polymorphisms with latent versus active tuberculosis infection in a Chinese population. AB - The autophagy-related immunity-related GTPase family M protein, IRGM, plays an important role in the defense against tuberculosis (TB) infection. IRGM polymorphisms are associated with TB infection susceptibility, and recent studies demonstrate host genetic differences between active and latent TB. Here, we investigated the association between IRGM polymorphisms and TB infection type in a Chinese population. We recruited 268 and 321 patients with confirmed or latent TB, respectively, and 475 TB-free healthy controls. Three single nucleotide polymorphisms, rs10065172, rs10051924, and rs13361189 within IRGM were genotyped using TaqMan-based assays. Interferon-gamma release levels were tested by T-SPOT. rs10065172 (P = 0.024, OR 0.67 (95% CI 0.48-0.95)), rs10051924 (P = 0.01, OR 0.64 (95% CI 0.46-0.90)), and rs13361189 (P = 0.055, OR 0.72 (95% CI 0.51-1.01)) were associated with a protective role against latent TB progression. Haplotype analysis showed that TCC was protective for latent TB (P = 0.022, OR 0.74 (95% CI 0.57-0.96)) whereas TTC conferred a higher risk of active TB. Additionally, patients with the rs10065172 TT genotype had a higher response to TB specific antigens. Thus, IRGM polymorphism differences between latent and active TB suggests that genetic differences in autophagy might partly affect host TB infection status. PMID- 26980497 TI - First insight into the molecular epidemiology of Mycobacterium tuberculosis in Santa Catarina, southern Brazil. AB - Molecular epidemiology of Mycobacterium tuberculosis is useful for understanding disease transmission dynamics, and to establish strategic measures for TB control and prevention. The aim of this study was to analyze clinical, epidemiological and molecular characteristics of MTBC clinical isolates from Santa Catarina state, southern Brazil. During one-year period, 406 clinical isolates of MTBC were collected from Central Laboratory of Public Health and typed by spoligotyping. Demographic and clinical data were collected from the Brazilian National Mandatory Disease Reporting System. The majority of cases occurred in highest population densities regions and about 50% had some condition associated with TB. Among all isolates, 5.7% were MDR, which showed association with drug addiction. LAM was the most predominant lineage with 47.5%, followed by the T superfamily with 25.9% and Haarlem with 12.3%. The MST showed two major groups: the first was formed mainly by the LAM lineage and the second was mainly formed by the T and Haarlem lineages. Others lineages were distributed in peripheral positions. This study provides the first insight into the population structure of M. tuberculosis in SC State. Spoligotyping and other genotyping analyses are important to establish strategic measures for TB control and prevention. PMID- 26980498 TI - Morphological changes and differentially expressed efflux pump genes in Mycobacterium tuberculosis exposed to a rifampicin and verapamil combination. AB - The aim of the present study was to (i) evaluate the in vitro action of rifampicin (RIF), ethambutol or isoniazid with efflux pumps inhibitors (EPIs) in Mycobacterium tuberculosis (Mtb) H37Rv and (ii) evaluate the morphological and efflux pumps (EPs) transcriptional changes by the action of rifampicin + verapamil combination (RIF + VP). The minimal inhibitory concentration and synergic effect of drug combinations were determined by Resazurin Microtiter Plate Assay and Resazurin Drugs Combination Microtiter Assay, respectively. VP showed greater capacity of ethidium bromide accumulation and RIF + VP had the lower fractional inhibitory concentration index. The RIF + VP exerted a similar reduction of viable cell counts to RIF by time-kill curve, but decreases in the expression of EPs genes were observed by Real time PCR at 72 h of RIF + VP exposure. Accumulative morphological changes (wrinkled and rounding) caused by each drug were observed by scanning electron microscopy after RIF + VP exposure. The downexpression of EPs related genes exposed to RIF + VP, suggest an effective inhibitory activity of VP in Mtb H37Rv. The role of EPs and the use of EPIs open up a powerful approach and the RIF + VP combination should be studied in Mtb more thoroughly. PMID- 26980499 TI - Canonical pathways, networks and transcriptional factor regulation by clinical strains of Mycobacterium tuberculosis in pulmonary alveolar epithelial cells. AB - Limited knowledge exists on pathways, networks and transcriptional factors regulated within epithelial cells by diverse Mycobacterium tuberculosis genotypes. This study aimed to elucidate these mechanisms induced in A549 epithelial cells by dominant clinical strains in KwaZulu-Natal, South Africa. RNA for sequencing was extracted from epithelial cells at 48 h post-infection with 5 strains at a multiplicity of infection of approximately 10:1. Bioinformatics analysis performed with the RNA-Seq Tuxedo pipeline identified differentially expressed genes. Changes in pathways, networks and transcriptional factors were identified using Ingenuity Pathway Analysis (IPA). The interferon signalling and hepatic fibrosis/hepatic stellate cell activation pathways were among the top 5 canonical pathways in all strains. Hierarchical clustering for enrichment of cholesterol biosynthesis and immune associated pathways revealed similar patterns for Beijing and Unique; F15/LAM4/KZN and F11; and, F28 and H37Rv strains, respectively. However, the induction of top scoring networks varied among the strains. Among the transcriptional factors, only EHL, IRF7, PML, STAT1, STAT2 and VDR were induced by all clinical strains. Activation of the different pathways, networks and transcriptional factors revealed in the current study may be an underlying mechanism that results in the differential host response by clinical strains of M. tuberculosis. PMID- 26980500 TI - Dietary zinc deficiency impairs humoral and cellular immune responses to BCG and ESAT-6/CFP-10 vaccination in offspring and adult rats. AB - BACKGROUND: Besides being the world's most widely used vaccine, BCG is the most controversial vaccine in current use. Estimates of protection impaired by BCG against pulmonary TB vary from nil to 80%. Dietary zinc deficiency has been confirmed to impair the immune function of animals. However, knowledge about effects of mild dietary zinc deficiency and the time of vaccination on BCG vaccine responsiveness in offspring and adult rats is limited. This work investigated the consequences of feeding zinc deficient and normal zinc diets to rats during gestation, infancy or adulthood on the immune responses to BCG vaccination. METHODS: On gestation day 0, sixteen maternal rats were divided into two groups and fed with diets bellow: a control diet ad libitum (30 MUg zinc/g diet, NC), a zinc deficient diet ad libitum (8 MUg zinc/g diet, ZnD). Pup rats were served as experimental subjects. From day 1 of pregnancy upon delivery, maternal rats were given a standard diet (30 mg/kg/day zinc) or zinc deficient diet (8 mg/kg/day zinc) respectively. Adult male 10-week Wistar rats were divided into two dietary groups for 17 weeks of feeding: a control diet ad libitum (30 MUg zinc/g diet, NC), a zinc deficient diet ad libitum (8 MUg zinc/g diet, ZnD). The birth time of newborn pups was recorded as the zero week. For adult male rats, the time of receiving different assigned diet was recorded as the zeroth week. Newborn pups of these maternal rats were immunized with BCG vaccine or MTB antigen ESAT-6/CFP-10 at postnatal 0 and 2 week. The adult male rats were immunized on the 12th and 14th week. Then, blood samples, thymus and spleen from the rats were harvested for detection of humoral and cell-mediated immune responses using ELISA, MTT and QRT-PCR analysis. Decreased INF-gamma and TNF alpha production in plasma, changes of expression level of ZIP2, ZIP8, NF-kappaB and IL-6 mRNA in immune organs, together with reduced T cell proliferation was observed in pups and adult BCG rats suffered from dietary zinc deficiency. Small differences were observed between rats received BCG vaccine and MTB antigen ESAT 6/CFP-10. RESULTS: Our data clearly indicate that dietary zinc deficiency can weaken the plasma cytokine levels and cell-mediated responses to BCG and ESAT 6/CFP-10 vaccine via decreasing T cell proliferation, down-regulating INF-gamma and TNF-alpha production and affecting the expression of ZIP2, ZIP8, NF-kappaB and IL-6 mRNA. In addition, the vaccine immunogenicity of BCG and ESAT-6/CFP-10 was not significantly affected by the time of vaccination. PMID- 26980501 TI - Dynamics of the T cell response to Mycobacterium tuberculosis DosR and Rpf antigens in a Colombian population of household contacts of recently diagnosed pulmonary tuberculosis patients. AB - Immune response to DosR and Rpf antigens from Mycobacterium tuberculosis (Mtb) seems to be important for latency maintenance. Little is known about the dynamics of the immune response to these antigens in an endemic community. Thus, the IFNgamma response and cytokine production in response to PPD, Esat6-Cfp10 (E6 C10), DosR and Rpf antigens in healthy HHC of tuberculosis (TB) patients over a 12 (T12) months period (short-term, stLTBI) was investigated. This response was compared with a group of LTBI, who have remained healthy for 5-7 years (long term, ltLTBI). According to the IFNgamma response, two groups of HHCs were identified in stLTBI in response to E6-C10. At T12, E6-C10(+) HHCs displayed a decrease in the IFNgamma levels and a generalized decrease in cytokines production. The E6-C10(-) HHC showed an increase in the IFNgamma response and cytokine levels. In stLTBI, the responses to E6-C10, DosR, and Rpf may be interpreted as a protective immune response controlling Mtb infection and may be leading to a state of latent infection. Comparing the response of stLTBI and ltLTBI, we observed significant changes in the proportions of CD45RO(+)CD27(+) T cells to specific DosR and Rpf, which may indicate a persistent immune response to Mtb antigens in ltLTBI. PMID- 26980502 TI - Profiling the human immune response to Mycobacterium tuberculosis by human cytokine array. AB - OBJECT: Tuberculosis (TB) continues to be one of the most serious infectious diseases in the world, however, no effective biomarkers can be used for rapid screening of latent tuberculosis infection (LTBI) and active TB. In this study, serum cytokines were screened and tested as potential biomarker for TB diagnosis. METHOD: Cytokine array was used to track the cytokine profile and its dynamic change after TB infection. The different expressions of cytokines were confirmed by ELISA assay. ROC curve analyses were used to evaluate the efficacy of a cytokine or cytokine combination for diagnosis. RESULTS: Eotaxin-2, ICAM-1, MCSF, IL-12p70, and IL-11 were significantly higher in the LTBI individuals. I-309, MIG, Eotaxin-2, IL-8, ICAM-1, IL-6sR, and Eotaxin were significantly higher in active TB patients. ROC curve analyses gave AUCs of 0.843, 0.898, and 0.888 for I 309, MIG, and IL-8, respectively, and 0.894 for the combination panel in active TB diagnosis. IFN-gamma/IL-4 and IL-2/TNF-alpha ratios exhibit dynamic changes in the healthy control and LTBI to different stages of active TB. CONCLUSIONS: Serum cytokines, including I-309 and MIG, IL-8, Extoxin-2, ICAM-1 and combinations of cytokines, including IFN-gamma/IL-4 and IL-2/TNF-alpha, can be used as serum biomarkers for LTBI and active TB screening, thus indicating prospective clinical applications. PMID- 26980503 TI - Comparison of long-term clinical outcomes after the second-generation cobalt chromium sirolimus-eluting stents implantation in diabetic versus non-diabetic patients: a subgroup analysis from the prospective FOCUS registry. AB - BACKGROUND: Diabetes mellitus (DM) was broadly acknowledged as a risk factor for adverse events after coronary stent implantation. However, the role of DM in patients treated with second-generation cobalt-chromium sirolimus-eluting stents (CoCr-SES) was less known. METHODS: A total of 4720 patients available for 3-year follow-up in the prospective FOCUS registry were subdivided into the DM group and the non-DM group to assess the effect of DM on the clinical outcomes after CoCr SES implantation both before and after propensity score matching. RESULTS: The rates of major adverse cardiovascular event was low (<10%) in both DM and non-DM groups but significantly greater in the DM group after matching (9.6% versus 6.1%; p = 0.005). Although the soft endpoints including target vessel revascularization (2.3% versus 2.3%; p = 0.938) and target lesion revascularization (1.2% versus 1.1%; p = 0.828) was not significantly different between two groups, the hard endpoints represented by cardiovascular death or myocardial infarction (7.3% versus 5.3%; p = 0.012) demonstrated a significant increase in the DM group. CONCLUSIONS: This subgroup analysis demonstrated that DM significantly increased the risk of adverse events after implantation of CoCr SES, but the general safety and efficacy performance of CoCr-SES in both diabetic and non-diabetic patients was satisfying and comparable with other types of new generation drug-eluting stents. PMID- 26980504 TI - Celebrating Public Health Lives - Marcus (Marek) Klingberg, 1918-2015. PMID- 26980505 TI - Prevalence and characterization of methicillin-resistant Staphylococcus aureus isolates in food industry workers. AB - BACKGROUND: Methicillin-resistant S. aureus (MRSA) is a pathogen spread not only in the hospital environment but also in the community and amongst livestock (LA MRSA). LA-MRSA can be transmitted to humans that live in close contact with MRSA colonized animals, and human colonization and/or infection has been reported worldwide, particularly among those involved with livestock farming. In this study the authors evaluated the prevalence of S. aureus and MRSA among healthy carriers who worked in the food industry in Apulia, Southern Italy. METHODS: Nasal swabs were taken from pasta and pork industry workers. All swab samples were subjected to tests for the isolation, identification and typing of S. aureus and MRSA strains. The identification of the strains was confirmed by molecular assessment using multiplex-PCR for the amplification of the nuc and mecA genes. The strains identified as MRSA were then subjected to a PCR protocol for the characterization of sequence type ST398. RESULTS: In total 26.3% of examined nasal swabs were positive for S. aureus, 8.2% of them were methicillin resistant strains and 28.5% of MRSA isolates were characterized as ST398. The MRSA prevalence among pork factory workers was 3% , whereas among the pasta operators the prevalence was 11.5. CONCLUSION: The presence of S. aureus and MRSA among food workers represents a public health risk. Further, considering the dissemination of S. aureus and MRSA among non-nosocomial environments, including communities and livestock, careful surveillance and continuous monitoring of the emergence of MRSA is fundamental for safeguarding public health. PMID- 26980506 TI - A surveillance system of Invasive Pneumococcal Disease in North-Eastern Italy. AB - BACKGROUND: From 2007, in the Veneto Region (Italy), a surveillance system for invasive pneumococcal diseases (IPD) was implemented to estimate the regional epidemiology of IPD and to evaluate the impact of 13-valent pneumococcal conjugate vaccine (PCV13) vaccination. METHODS: Data were collected from 2007 to 2014 and the total, annual and age-specific IPD notification rates were calculated. A Poisson regression model was used to identify the possible risk factors for developing IPD. RESULTS: A total of 713 IPD cases were notified and the overall IPD notification rate was equal to 2.0 cases per 100,000 population (95% CI: 1.7-2.1), with an increasing trend between 2007 and 2014. The pneumococcal serotypes were identified in 608 (85.3%) isolates from biological specimens, and the most distributed serotypes were those contained in PCV13. Children <5 year-old and the adults over 65 year-old showed the highest PCV13 vaccine-type IPD notification rate, equal to 2.7/100,000 and 2.8/100,000, respectively. The risk to develop IPD was greater in children aged <5 years (RR = 8.9, 95% CI: 5.1-15.9; p<0.0001) and in adults aged >65 years (RR = 4.3, 95% CI: 2.7-6.9; p<0.0001), especially in males > 65 years of age (RR = 1.7, 95% CI: 1.0 2.8; p = 0.042). The invasive pneumococcal disease was mainly caused by the PCV13 serotypes (RR = 2.9, 95%CI: 2.3-3.9; p<0.0001), principally after the PCV13 introduction (RR = 2.3, 95% CI: 1.4-3.8; p<0.001). In spite of that, a significant reduction of the overall IPD incidence is evident in the period following the PCV13 vaccine introduction (RR = 0.4, 95% CI: 0.3-0.5; p<0.0001), particularly in children aged <5 years (RR = 0.3, 95% CI: 0.2-0.7; p = 0.002), demonstrating the real efficacy of PCV13 immunization for children. CONCLUSIONS: In the Veneto Region, the surveillance system has allowed to describe the detailed epidemiological profile of invasive pneumococcal disease, pointing out that the most circulating pneumococcal serotypes were those contained in the PCV13 vaccine. PMID- 26980507 TI - Gender perspective in occupational medicine and workplace risk assessment: state of the art and research agenda. AB - The aim of this study was to investigate the current situation and the research agenda in the field of gender differences, both generically in the occupational settings and in the specific activity of risk assessment. Gender is a key determinant of health; the evaluation of documents and scientific literature shows increasing attention to a gender oriented approach, as demonstrated by the development of Gender Medicine, actually cross-oriented in all medical specialties, the publication of books dedicated to this topic and the birth of "ad hoc" new scientific societies and journals. Even today, however, the gender differences are not considered as they should in the context of health disciplines, including occupational medicine. In this respect, in fact, the critical issues to be overcome are numerous, such as the phenomena of "segregation", the exposure to risk factors and their effects, related also to non-professional, socio-cultural features that differentiate male and female workers. All these factors can lead to situations of inequality in health. In fact, the European directives on safety at work repeatedly highlight the attention to gender differences in prevention, assessment and management of risks. In this regard, the European Agency for Safety and Health at Work advocates an approach "more sensitive" to gender in all the processes of assessment and risk management, from the research of all potential sources of risk to the decision-making processes, in order to address the prevention of risks in a holistic manner. PMID- 26980508 TI - Work-related stress in healthcare workers. AB - BACKGROUND: In the assessment of work-related stress it is crucial to find the factors that generate and increase it in order to identify categories of individuals at risk, to plan interventions for prevention, elimination or reduction of risk. The aim of the study is to assess the subjective stress in 68 workers of a large Italian company dealing with human health, through the use of a questionnaire-indicating tool, elaborated by the Italian National Institute for insurance against accidents at work (INAIL) and developed by the Health and Safety Executive (HSE). METHODS: We studied a final sample of 68 individuals (34 drivers/rescuers and 34 video display unit (VDU) operators). The questionnaire consists of 35 items (divided into six areas) with five possible answers each, that cover working conditions considered potential causes of stress. RESULTS: The drivers/rescuers had a better performance than the VDU operators, especially in the areas "demand", "relationships" and "role". We compared men and women in the two groups, finding that, in VDU operators, women had a better performance than men in all areas, except "role" and "changes", in which the overall scores were the same in men and women. In the drivers/rescuers women showed more critical scores in the items "relationships" and "change". CONCLUSION: The results show that: the questionnaire-indicating tool is useful, with a demonstrated effectiveness for the occupational physician during the visits and proven validity; additional future efforts should focus on understanding the psycho social, organizational and individual problems related to stress and the consequent implementation of preventive measures. PMID- 26980510 TI - Nurses' Job satisfaction: an Italian study. AB - BACKGROUND: The aim of the work presented was to assess job satisfaction of a number of nurses from different departments working in public hospitals in Italy. The assessment was carried out through the combined use of questionnaires, which measured different aspects of job satisfaction, such as coping abilities, stress level and optimism/pessimism. The literature supports the fact that nurses' job dissatisfaction is closely connected with high levels of stress, burnout and physical and mental exhaustion, together with high workload levels and the complexity of care. The growing interest in measuring the levels of nurses' job satisfaction is attributable to a number of problems that have been raised worldwide, two of which are becoming ever so important: turnover and shortage of nurses. The research question is: Which are the main motivating factors of Italian nurses' job satisfaction/dissatisfaction? METHODS: The study used a convenience (non probability) sample of 1,304 nurses from 15 different wards working in Italian public hospitals from a number of cities in northern, central and southern Italy. The survey instrument was a questionnaire consisting of 205 items which included 5 different questionnaires combined together. RESULTS: The results show a low level of job satisfaction (IWS= 11.5, JSS=126.4). However, the participants were overall happy about their job and considered autonomy and salary important factors for job satisfaction. CONCLUSION: Research has shown that the nurses' level of satisfaction in Italian hospitals is low. The results revealed dissatisfaction with task requirements, organizational policies and advance in career. Nurses interviewed did not feel stressed and showed to be optimistic overall. New research on the subject should be conducted by focusing on ward differences, North and South of Italy and on gender differences. PMID- 26980509 TI - Italy and Argentina compared: an epidemiological study of occupational diseases. AB - BACKGROUND: The research presented in this paper analyses the clinic-pathological manifestations and work-related health risks identified among outpatients treated in the hospitals of Rome and Buenos Aires. MATERIALS AND METHODS: The occupational anamnestic data were collected between 2013 and 2014 through questionnaires with specific items aimed at detecting occupational diseases classified by target organ systems in outpatient clinics of cardiology, dermatology, physical medicine, ophthalmology, orthopedics, endocrinology (thyroid and gonads). An inferential statistical analysis was then carried out to evaluate the relationship between nationality, exposure to occupational risks and the prevalence and incidence of the selected pathologies. An univariate statistical analysis was performed for this purpose and, in the case of statistically significant results, a subsequent multivariate analysis was used to evaluate the incidence of occupational risk factors and nationality on the pathology diagnosed in conjunction with other confounding factors such as smoking habits and gender. The total sample consisted of 1090 subjects of both sexes. Risks were grouped into seven categories and diseases into 12 diagnostic groups. We analyzed the correlation between risks and diseases with respect to hospital outpatients and to the total sample then comparing Argentina and Italy's data. RESULTS: Analysis of data revealed a higher prevalence of hypertension and dysmetabolic disorders for DSE (Display Screen Equipment) workers both in Italy and Argentina; however, multivariate analysis showed that smoking represents a confounding factor for this association. A higher prevalence of allergic contact dermatitis (ACD) was found in the population samples of Rome and there appeared to be a correlation between eye disorders/defects and Argentine data source. CONCLUSIONS: Our study suggests the usefulness of collecting occupational anamnestic data from outpatient departments to highlight possible associations between occupational risks, lifestyles and pathologies, so as to implement the appropriate prevention strategies. PMID- 26980511 TI - History and Medicine: ex voto as a tool for health and epidemiological surveillance. AB - BACKGROUND: Ex voto is a donation for a divinity, a Saint or to Virgin Mary for a received mercy. From the analysis of an ex voto it's possible to obtain lots of information and therefore it can be used as a tool for health and epidemiological surveillance, to study morbidity in the past. The aim of this study was the creation of a database to rebuild epidemiological events and diseases, using ex voto as a source of health surveillance. METHODS: We chose to study votive pictures using three types of sources: photographed alive, on-line archives, books and photographic collections. Ex voto have been saved in an Hard Disk, numbered and inserted in a database, then analyzed using Stata(r). RESULTS: total of 6231 ex voto were collected and catalogued in our database. Ex voto referring to diseases are the most represented (41%), but they have decreased with the time. Road accidents (21.4%) have a constant increase, especially with the appearance of cars and motorcycles. Aggressions (5.45%) decrease constantly; warlike accidents (4.44%) had a peak in the period including both world wars; non professional accidents (10.60%) and accidents at work (3.79%) increase without peaks; maritime accidents (8.88%) have not uniform ups and downs during the time. CONCLUSIONS: The database let us rebuild epidemiological events of the past, which are not deductible from other sources. Our purpose is to expand in the space-time our source data in order to perform an interesting comparison between past and present. PMID- 26980512 TI - ncRNA orthologies in the vertebrate lineage. AB - Annotation of orthologous and paralogous genes is necessary for many aspects of evolutionary analysis. Methods to infer these homology relationships have traditionally focused on protein-coding genes and evolutionary models used by these methods normally assume the positions in the protein evolve independently. However, as our appreciation for the roles of non-coding RNA genes has increased, consistently annotated sets of orthologous and paralogous ncRNA genes are increasingly needed. At the same time, methods such as PHASE or RAxML have implemented substitution models that consider pairs of sites to enable proper modelling of the loops and other features of RNA secondary structure. Here, we present a comprehensive analysis pipeline for the automatic detection of orthologues and paralogues for ncRNA genes. We focus on gene families represented in Rfam and for which a specific covariance model is provided. For each family ncRNA genes found in all Ensembl species are aligned using Infernal, and several trees are built using different substitution models. In parallel, a genomic alignment that includes the ncRNA genes and their flanking sequence regions is built with PRANK. This alignment is used to create two additional phylogenetic trees using the neighbour-joining (NJ) and maximum-likelihood (ML) methods. The trees arising from both the ncRNA and genomic alignments are merged using TreeBeST, which reconciles them with the species tree in order to identify speciation and duplication events. The final tree is used to infer the orthologues and paralogues following Fitch's definition. We also determine gene gain and loss events for each family using CAFE. All data are accessible through the Ensembl Comparative Genomics ('Compara') API, on our FTP site and are fully integrated in the Ensembl genome browser, where they can be accessed in a user friendly manner. Database URL: http://www.ensembl.org. PMID- 26980513 TI - Principles of metadata organization at the ENCODE data coordination center. AB - The Encyclopedia of DNA Elements (ENCODE) Data Coordinating Center (DCC) is responsible for organizing, describing and providing access to the diverse data generated by the ENCODE project. The description of these data, known as metadata, includes the biological sample used as input, the protocols and assays performed on these samples, the data files generated from the results and the computational methods used to analyze the data. Here, we outline the principles and philosophy used to define the ENCODE metadata in order to create a metadata standard that can be applied to diverse assays and multiple genomic projects. In addition, we present how the data are validated and used by the ENCODE DCC in creating the ENCODE Portal (https://www.encodeproject.org/). Database URL: www.encodeproject.org. PMID- 26980514 TI - Effect of database drift on network topology and enrichment analyses: a case study for RegulonDB. AB - RegulonDB is a database storing the biological information behind the transcriptional regulatory network (TRN) of the bacterium Escherichia coli. It is one of the key bioinformatics resources for Systems Biology investigations of bacterial gene regulation. Like most biological databases, the content drifts with time, both due to the accumulation of new information and due to refinements in the underlying biological concepts. Conclusions based on previous database versions may no longer hold. Here, we study the change of some topological properties of the TRN of E. coli, as provided by RegulonDB across 16 versions, as well as a simple index, digital control strength, quantifying the match between gene expression profiles and the transcriptional regulatory networks. While many of network characteristics change dramatically across the different versions, the digital control strength remains rather robust and in tune with previous results for this index. Our study shows that: (i) results derived from network topology should, when possible, be studied across a range of database versions, before detailed biological conclusions are derived, and (ii) resorting to simple indices, when interpreting high-throughput data from a network perspective, may help achieving a robustness of the findings against variation of the underlying biological information. Database URL: www.regulondb.ccg.unam.mx. PMID- 26980515 TI - 2P2Idb v2: update of a structural database dedicated to orthosteric modulation of protein-protein interactions. AB - 2P2Idb is a hand-curated structural database dedicated to protein-protein interactions with known small molecule orthosteric modulators. It compiles the structural information related to orthosteric inhibitors and their target [i.e. related 3D structures available in the RCSB Protein Data Bank (PDB)] and provides links to other useful databases. 2P2Idb includes all interactions for which both the protein-protein and protein-inhibitor complexes have been structurally characterized. Since its first release in 2010, the database has grown constantly and the current version contains 27 protein-protein complexes and 274 protein inhibitor complexes corresponding to 242 unique small molecule inhibitors which represent almost a 5-fold increase compared to the previous version. A number of new data have been added, including new protein-protein complexes, binding affinities, molecular descriptors, precalculated interface parameters and links to other webservers. A new query tool has been implemented to search for inhibitors within the database using standard molecular descriptors. A novel version of the 2P2I-inspector tool has been implemented to calculate a series of physical and chemical parameters of the protein interfaces. Several geometrical parameters including planarity, eccentricity and circularity have been added as well as customizable distance cutoffs. This tool has also been extended to protein-ligand interfaces. The 2P2I database thus represents a wealth of structural source of information for scientists interested in the properties of protein-protein interactions and the design of protein-protein interaction modulators. Database URL: http://2p2idb.cnrs-mrs.fr. PMID- 26980516 TI - DemaDb: an integrated dematiaceous fungal genomes database. AB - Many species of dematiaceous fungi are associated with allergic reactions and potentially fatal diseases in human, especially in tropical climates. Over the past 10 years, we have isolated more than 400 dematiaceous fungi from various clinical samples. In this study, DemaDb, an integrated database was designed to support the integration and analysis of dematiaceous fungal genomes. A total of 92 072 putative genes and 6527 pathways that identified in eight dematiaceous fungi (Bipolaris papendorfii UM 226, Daldinia eschscholtzii UM 1400, D. eschscholtzii UM 1020, Pyrenochaeta unguis-hominis UM 256, Ochroconis mirabilis UM 578, Cladosporium sphaerospermum UM 843, Herpotrichiellaceae sp. UM 238 and Pleosporales sp. UM 1110) were deposited in DemaDb. DemaDb includes functional annotations for all predicted gene models in all genomes, such as Gene Ontology, EuKaryotic Orthologous Groups, Kyoto Encyclopedia of Genes and Genomes (KEGG), Pfam and InterProScan. All predicted protein models were further functionally annotated to Carbohydrate-Active enzymes, peptidases, secondary metabolites and virulence factors. DemaDb Genome Browser enables users to browse and visualize entire genomes with annotation data including gene prediction, structure, orientation and custom feature tracks. The Pathway Browser based on the KEGG pathway database allows users to look into molecular interaction and reaction networks for all KEGG annotated genes. The availability of downloadable files containing assembly, nucleic acid, as well as protein data allows the direct retrieval for further downstream works. DemaDb is a useful resource for fungal research community especially those involved in genome-scale analysis, functional genomics, genetics and disease studies of dematiaceous fungi. Database URL: http://fungaldb.um.edu.my. PMID- 26980517 TI - HerDing: herb recommendation system to treat diseases using genes and chemicals. AB - In recent years, herbs have been researched for new drug candidates because they have a long empirical history of treating diseases and are relatively free from side effects. Studies to scientifically prove the medical efficacy of herbs for target diseases often spend a considerable amount of time and effort in choosing candidate herbs and in performing experiments to measure changes of marker genes when treating herbs. A computational approach to recommend herbs for treating diseases might be helpful to promote efficiency in the early stage of such studies. Although several databases related to traditional Chinese medicine have been already developed, there is no specialized Web tool yet recommending herbs to treat diseases based on disease-related genes. Therefore, we developed a novel search engine, HerDing, focused on retrieving candidate herb-related information with user search terms (a list of genes, a disease name, a chemical name or an herb name). HerDing was built by integrating public databases and by applying a text-mining method. The HerDing website is free and open to all users, and there is no login requirement. Database URL: http://combio.gist.ac.kr/herding. PMID- 26980518 TI - Fish Karyome version 2.1: a chromosome database of fishes and other aquatic organisms. AB - A voluminous information is available on karyological studies of fishes; however, limited efforts were made for compilation and curation of the available karyological data in a digital form. 'Fish Karyome' database was the preliminary attempt to compile and digitize the available karyological information on finfishes belonging to the Indian subcontinent. But the database had limitations since it covered data only on Indian finfishes with limited search options. Perceiving the feedbacks from the users and its utility in fish cytogenetic studies, the Fish Karyome database was upgraded by applying Linux, Apache, MySQL and PHP (pre hypertext processor) (LAMP) technologies. In the present version, the scope of the system was increased by compiling and curating the available chromosomal information over the globe on fishes and other aquatic organisms, such as echinoderms, molluscs and arthropods, especially of aquaculture importance. Thus, Fish Karyome version 2.1 presently covers 866 chromosomal records for 726 species supported with 253 published articles and the information is being updated regularly. The database provides information on chromosome number and morphology, sex chromosomes, chromosome banding, molecular cytogenetic markers, etc. supported by fish and karyotype images through interactive tools. It also enables the users to browse and view chromosomal information based on habitat, family, conservation status and chromosome number. The system also displays chromosome number in model organisms, protocol for chromosome preparation and allied techniques and glossary of cytogenetic terms. A data submission facility has also been provided through data submission panel. The database can serve as a unique and useful resource for cytogenetic characterization, sex determination, chromosomal mapping, cytotaxonomy, karyo evolution and systematics of fishes. Database URL: http://mail.nbfgr.res.in/Fish_Karyome. PMID- 26980519 TI - PhyloPro2.0: a database for the dynamic exploration of phylogenetically conserved proteins and their domain architectures across the Eukarya. AB - PhyloPro is a database and accompanying web-based application for the construction and exploration of phylogenetic profiles across the Eukarya. In this update article, we present six major new developments in PhyloPro: (i) integration of Pfam-A domain predictions for all proteins; (ii) new summary heatmaps and detailed level views of domain conservation; (iii) an interactive, network-based visualization tool for exploration of domain architectures and their conservation; (iv) ability to browse based on protein functional categories (GOSlim); (v) improvements to the web interface to enhance drill down capability from the heatmap view; and (vi) improved coverage including 164 eukaryotes and 12 reference species. In addition, we provide improved support for downloading data and images in a variety of formats. Among the existing tools available for phylogenetic profiles, PhyloPro provides several innovative domain-based features including a novel domain adjacency visualization tool. These are designed to allow the user to identify and compare proteins with similar domain architectures across species and thus develop hypotheses about the evolution of lineage specific trajectories. Database URL: http://www.compsysbio.org/phylopro/. PMID- 26980520 TI - PolyQ 2.0: an improved version of PolyQ, a database of human polyglutamine proteins. AB - Proteins with expanded polyglutamine (polyQ) repeats are involved in human neurodegenerative diseases, via a gain-of-function mechanism of neuronal toxicity involving protein conformational changes that result in the formation and deposition of beta-sheet-rich aggregates. Aggregation is dependent on the context and properties of the host protein, such as domain context and location of the repeat tract. In order to explore this relationship in greater detail, here we describe PolyQ 2.0, an updated database that provides a comprehensive knowledgebase for human polyQ proteins. Compared with the previous PolyQ database, our new database provides a variety of substantial updates including detailed biological annotations and search options. Biological annotations in terms of domain context information, protein structural and functional annotation, single point mutations, predicted disordered regions, protein-protein interaction partners, metabolic/signaling pathways, post-translational modification sites and evolutionary information are made available. Several new database functionalities have also been provided, including search using multiple/combinatory keywords, and submission of new data entries. Also, several third-party plug-ins are employed to enhance data visualization in PolyQ 2.0. In PolyQ 2.0 the proteins are reclassified into 3 new categories and contain 9 reviewed disease-associated polyQ proteins, 105 reviewed non-disease polyQ proteins and 146 un-reviewed polyQ proteins (reviewed by UniProt curators). We envisage that this updated database will be a useful resource for functional and structural investigation of human polyQ proteins. Database URL: http://lightning.med.monash.edu/polyq2/. PMID- 26980521 TI - Impact of secular trends on sex assessment evaluated through femoral dimensions of the Czech population. AB - Human skeletal variability is influenced by several factors, including genetics, environment, and socio-cultural background. Forensic methods being traditionally based on targeted reference groups, it is recognized that they are population specific. Additionally, secular trends highly impact on the skeletal morphology, but the effect of outdated methods on forensic cases is not yet well documented. This paper compares the sexual dimorphism of femoral dimensions in two samples from the Czech population separated by 60 years in time (Pachner and the Prague National Museum Collections). Significant secular trends are present within this short span in both sexes and for most of the seven tested linear variables. The consequence of secular trends on sex determination is tested with logistic regression, and a decrease in reliability is systematically observed when using the older Czech sample on the 20th century sample, whichever the set of variables included. A model based on a recent Croatian sample provides a higher reliability on contemporaneous Czech individuals. These results imply that above population specificity, temporal consistency may be a major criterion to fulfil when applying forensic anthropology identification methods. PMID- 26980522 TI - Biologic relativity: Who is the observer and what is observed? AB - When quantum physics and biological phenomena are analogously explored, it emerges that biologic causation must also be understood independently of its overt appearance. This is similar to the manner in which Bohm characterized the explicate versus the implicate order as overlapping frames of ambiguity. Placed in this context, the variables affecting epigenetic inheritance can be properly assessed as a key mechanistic principle of evolution that significantly alters our understanding of homeostasis, pleiotropy, and heterochrony, and the purposes of sexual reproduction. Each of these become differing manifestations of a new biological relativity in which biologic space-time becomes its own frame. In such relativistic cellular contexts, it is proper to question exactly who has observer status, and who and what are being observed. Consideration within this frame reduces biology to cellular information sharing through cell-cell communication to resolve ambiguities at every scope and scale. In consequence, it becomes implicit that eukaryotic evolution derives from the unicellular state, remaining consistently adherent to it in a continuous evolutionary arc based upon elemental, non-stochastic physiologic first principles. Furthermore, the entire cell including its cytoskeletal apparatus and membranes that participate in the resolution of biological uncertainties must be considered as having equivalent primacy with genomes in evolutionary terms. PMID- 26980523 TI - Disturbances of cardiac wavelength and repolarization precede Torsade de Pointes and ventricular fibrillation in Langendorff perfused rabbit hearts. AB - Drug-induced proarrhythmia is strongly focused on Torsade de Pointes (TdP), and QT prolongation is commonly used as a surrogate for TdP. This surrogate may be of limited value, as it produces false positives and false negatives. Cardiac electrophysiological parameters were obtained from monophasic action potentials recorded from Langendorff perfused female rabbit hearts. In 3939 experiments 179 VFs and 124 TdPs occurred during testing of various chemicals. TdP occurred with prolongation of action potential duration (APD), but also with shortening. Thus, APD/QT prolongation alone cannot predict TdP. Drug-induced abnormalities, associated with TdP or VF, were identified. The 11 most predictive abnormalities were combined in a proarrhythmic score, proportional to the incidence and amplitude of the abnormalities. This score significantly increases starting at concentrations ~100-fold below that at which TdP/VF developed (P < 0.001) and preceded all TdP and ~98% of VF. This derived proarrhythmic score was then tested in 451 additional experiments (not used to develop the score) and it was found to predict all 15 TdPs and 18 of the 19 VFs. In conclusion, the derived proarrhythmic score has fewer false positives and false negative than the widely used surrogate (QT-prolongation). As such, it may help in preclinical development of safer medications (better rejection of false negatives) and allowing development of safe beneficial medications with QT prolongation (less rejection of false positives). Recognition of disturbances of the score in the clinical ECG may yield safer use of some medications in vulnerable patients. PMID- 26980524 TI - P2X7 Receptor Suppression Preserves Blood-Brain Barrier through Inhibiting RhoA Activation after Experimental Intracerebral Hemorrhage in Rats. AB - Blockading P2X7 receptor(P2X7R) provides neuroprotection toward various neurological disorders, including stroke, traumatic brain injury, and subarachnoid hemorrhage. However, whether and how P2X7 receptor suppression protects blood-brain barrier(BBB) after intracerebral hemorrhage(ICH) remains unexplored. In present study, intrastriatal autologous-blood injection was used to mimic ICH in rats. Selective P2X7R inhibitor A438079, P2X7R agonist BzATP, and P2X7R siRNA were administrated to evaluate the effects of P2X7R suppression. Selective RhoA inhibitor C3 transferase was administered to clarify the involvement of RhoA. Post-assessments, including neurological deficits, Fluoro Jade C staining, brain edema, Evans blue extravasation and fluorescence, western blot, RhoA activity assay and immunohistochemistry were performed. Then the key results were verified in collagenase induced ICH model. We found that endogenous P2X7R increased at 3 hrs after ICH with peak at 24 hrs, then returned to normal at 72 hrs after ICH. Enhanced immunoreactivity was observed on the neurovascular structure around hematoma at 24 hrs after ICH, along with perivascular astrocytes and endothelial cells. Both A438079 and P2X7R siRNA alleviated neurological deficits, brain edema, and BBB disruption after ICH, in association with RhoA activation and down-regulated endothelial junction proteins. However, BzATP abolished those effects. In addition, C3 transferase reduced brain injury and increased endothelial junction proteins' expression after ICH. These data indicated P2X7R suppression could preserve BBB integrity after ICH through inhibiting RhoA activation. PMID- 26980525 TI - Survival after severe amitriptyline poisoning with prolonged ventricular tachycardia and cardiac arrest. AB - BACKGROUND: Tricyclic antidepressants (TCA) are becoming one of the most frequently used substances in self poisoning. Significant morbidity and mortality associated with TCA overdose are often related to and refractory hypotension. We report the first case of survival after severe amitriptyline poisoning, leading to prolonged cardiac arrest and ventricular tachycardia (VT), resuscitated with 3 h of uninterrupted cardiac massage and Direct current (DC) shocks. CASE PRESENTATION: A 25 year old girl presented with severe amitriptyline poisoning causing pulseless VT and prolonged cardiac arrest. After 3 h of uninterrupted external cardiac massage, together with nine DC shocks and intra venous bicarbonate injections the rhythm reverted to a nodal tachycardia, initial 2D echocardiogram showed left ventricular dysfunction, which recovered to normal after 2 weeks and the patient had a complete recovery subsequently. CONCLUSION: Our case highlights the importance of continued resuscitation in patients presenting with TCA poisoning and resistant arrhythmia, especially in young and otherwise healthy patients. PMID- 26980527 TI - [Pay attention to study on the appropriate populations and mechanism of bronchial thermoplasty]. PMID- 26980526 TI - Safety classification of herbal medicines used in pregnancy in a multinational study. AB - BACKGROUND: The use of herbal medicines for health prevention and ailments is an increasing trend worldwide. Women in pregnancy are no exception; the reported prevalence of herbal medicine use in pregnancy ranges from 1 to 60 %. Despite a common perception of safety, herbal medicines may have potent pharmacological actions, and historically, have been used for this reason. METHODS: A multinational, cross-sectional study on how women treat disease and pregnancy related health ailments was conducted between October 2011 and February 2012 in Europe, North America, and Australia. This study's primary aim was to evaluate and classify the herbal medicines used according to their safety in pregnancy and, secondly, to investigate risk factors associated with the use of contraindicated herbal medicines during pregnancy. RESULTS: In total, 29.3 % of the women (n = 2673) reported the use of herbal medicines in pregnancy; of which we were able to identify 126 specific herbal medicines used by 2379 women (89.0 %). Twenty seven out of 126 herbal medicines were classified as contraindicated in pregnancy, and were used by 476 women (20.0 %). Twenty-eight were classified as safe for use in pregnancy and used by the largest number of women (n = 1128, 47.4 %). The greatest number was classified as requiring caution in pregnancy; these sixty herbal medicines were used by 751 women (31.6 %). Maternal factors associated with the use of contraindicated herbal medicines in pregnancy were found to be working in the home, having a university education, not using folic acid, and consuming alcohol. Interestingly, the recommendation to take a contraindicated herbal medicine was three times more likely to be from a healthcare practitioner (HCP) than an informal source. CONCLUSION: Based on the current literature the majority of women in this study used an herbal medicine that was classified as safe for use in pregnancy. Women who reported taking a contraindicated herb were more likely to have been recommended it use by an HCP rather than informal source(s), indicating an urgent need for more education among HCPs. The paucity of human studies on herbal medicines safety in pregnancy stands in stark contrast to the widespread use of these products among pregnant women. PMID- 26980528 TI - [Diagnostic problems and experts' consensus on patients with fever and lung infiltrates]. PMID- 26980529 TI - [Standardized management of bronchial thermoplasty]. PMID- 26980530 TI - [Effectiveness and safety of bronchial thermoplasty in patients with severe asthma]. AB - OBJECTIVE: To assess the effectiveness and safety of bronchial thermoplasty (BT) in patients with severe asthma. METHOD: The China-Japan Friendship Hospital recruited 12 patients with severe asthma who were voluntary to take BT treatment from March 2014 to November 2014. The levels of airway inflammation and biological markers (percentage of blood eosinophils, percentage of sputum eosinophils, serum IgE, fractional exhaled nitric oxide) of the patients were examined before the treatment in order to identify the types of airway inflammation. The numbers of severe exacerbations and related hospitalizations within 1 year before and after BT were obtained for each patient. The occurrence of adverse events within 3 weeks after the treatment was collected. And the patient status within 1 year after the BT treatment was compared with that before the treatment, in terms of the number of severe exacerbations, exacerbation rate, the number of related hospitalizations, hospitalization rate and oral corticosteroid dose. RESULTS: For before and 1 year after the treatment, the numbers of subjects suffering severe exacerbations were 11 and 6, the numbers of total severe exacerbation were 76 and 16, the numbers of patients hospitalized due to acute attacks were 10 and 3, and the numbers of total hospitalizations were 56 and 6, respectively. The severe exacerbation rate, hospitalization rate and oral corticosteroid dose were significantly reduced 1 year after the treatment [(1.3+/-0.48 vs. 6.3+/-1.9) events/subject/year, (0.50+/-0.26 vs. 4.67+/-1.90) events/subject/year, (8.5+/-4.6 vs. 22.0+/-2.6) mg/d, P<0.05]. The most common adverse events within 3 weeks after BT treatment were cough (8 events), expectoration (20 events), temporary PEF reduction (7 events), wheezing (4 events), but most of these symptoms were relieved in 1 week. One subject suffered pneumonia after each of the 3 procedures but also recovered soon after an antibiotic therapy. No adverse events occurred because of BT treatment within 3 weeks after the treatment. Computed tomographic scans from baseline to 1 year after the BT treatment showed no structural abnormalities related to BT. CONCLUSIONS: These data demonstrate the benefits of BT with regard to both asthma control (based on reduction in severe exacerbations and hospitalizations due to acute exacerbations) and safety. BT might offer a new approach to treating severe asthma. PMID- 26980531 TI - [Bronchial thermoplasty in the treatment of severe asthma]. AB - OBJECTIVE: To assess the effectiveness and safety of bronchial thermoplasty (BT) in the treatment of severe asthma. METHODS: The safety and effectiveness of BT were studied prospectively in 6 patients with poorly controlled severe asthma on long-term inhaled high-dose glucocorticoids and long-acting beta2-agonists in the First Affiliated Hospital of Guangzhou Medical University. Outcomes assessed after BT included asthma symptoms, frequency of acute exacerbations, pulmonary function, medication adjustment, and postoperative complications at 6 and 12 months after treatment. RESULTS: The mini-AQLQ scores (6.4+/-0.5), the frequency of acute exacerbations [0.4(0.1-1.3) times/month], and the symptom-free days [(21.2+/-7.2) days/month] were significantly improved at 6 months after operation compared to those before operation [5.2+/-0.9, 2.0 (0.9-4.0) times/month, (14.5+/ 3.7) days/month, respectively, P<0.05]. Data collected at the 6(th) month indicated significant improvements in the variation rate of PEF, the dose of inhaled glucocorticoids and oral glucocorticoids [(5.6+/-3.3)% vs. (21.1+/ 7.8)%), (800+/-620) vs. (1 133+/-432) MUg/d), 9.7 (1.3-10.0) vs. 15.0 (10-20) mg/d, P<0.05]. Outcomes mentioned above were improved as well at the 12(th) month. But the ACQ-6 scores, ACT scores, the ratio of PEF and its predicted value (%), the ratio of FVC and its predicted value (%), the ratio of FEV1 and its predicted value (%) were not changed significantly (P>0.05). The PEF values and lung function measurements remained stable throughout the study period. The most common complications were cough (24.1%), wheezing (13.8%), followed by lower respiratory infection and atelectasis during the treatment. Pneumothorax and respiratory failure occurred in 1 patient 12 h after the third procedure. CONCLUSION: Our preliminary study demonstrated promising effect of BT in the treatment of severe asthma, although there are some complications which need further observation. PMID- 26980532 TI - [Effects and significance of methacholine bronchial provocation tests and salbutamol bronchial dilation test on measurements of fractional exhaled nitric oxide in patients with asthma]. AB - OBJECTIVE: To study the effects and significance of methacholine (Mch) bronchial provocation tests and salbutamol bronchial dilation test on measurements of fractional exhaled nitric oxide (FeNO) in patients with asthma. METHODS: This was a prospective study conducted between November 2014 and August 2015. A total of 135 patients with asthma visiting the respiratory clinic of Zhujiang Hospital were enrolled. The patients received either Mch bronchial provocation test or salbutamol bronchial dilation test based on their FEV1/FVC values and cooperative degree. Mch bronchial provocation test was performed by using Astograph Jupiter 21 (Astograh group) or APS-Pro airway reaction testing apparatus (APS group), and salbutamol bronchial dilation test was performed by using Jaeger spirometer (Dilation group). We compared the differences between FeNO values measured before examinations (Pre-FeNO) and 5 min after completion of these examinations (Post FeNO). RESULTS: The geometric mean of Pre-FeNO and Post-FeNO was 28.07 ppb and 24.08 ppb respectively in the Astograh group, with a significant decrease of the FeNO value after the examination (Z=-3.093, P=0.002). A significant difference between Pre-FeNO and Post-FeNO was found in patients who had positive provocation results in the Astograh group (Z=-2.787, P=0.005), but not in the patients with negative results (Z=-1.355, P=0.176). The geometric mean of FeNO in the APS group decreased significantly from 27.95 ppb to 23.15 ppb after the examination was completed (Z=-5.170, P=0.000); both in patients with positive saline or Mch provocation results and in patients with negative provocation results, the differences between Pre-FeNO and Post-FeNO in the APS group being significant (Z= 2.705, -3.709, -2.371, P=0.002, 0.000, 0.018). No difference of FeNO change(DeltaFeNO) was observed between the 2 Mch bronchial provocation test groups (U<918.000, P=0.117). The geometric mean of Pre-FeNO was 36.74 ppb and that of Post-FeNO was 34.79 ppb in the Dilation group; the difference being not significant (Z=-1.281, P=0.200). CONCLUSIONS: Our results confirm that salbutamol bronchial dilation test has minor effect on the measurement of FeNO, but Mch bronchial provocation tests can significantly decrease measured FeNO value in patients with asthma, and therefore Post-FeNO values should be interpreted with caution. PMID- 26980533 TI - [A preliminary study of the distribution and the characteristics of nonspecific pulmonary function]. AB - OBJECTIVE: To investigate the manifestations, pulmonary function test (PFT) characteristics and imaging features of patients with nonspecific pulmonary function (NSPF). METHODS: All the data from the same PFT apparatus in Beijing Hospital were collected from January 2003 to December 2012. NSPF was defined as normal FEV1/FVC and TLC, but decreased FEV1 or FVC or both. Patients with complete clinical data from January 2012 to June 2012 were enrolled into this analysis. The NSPF group was compared with the normal group, the obstructive group, the restrictive group and the mixed group. RESULTS: There were totally 14 771 cases of PFT on this apparatus during 10 year period, and those with NSPF were 2759 (18.68%). From January 2012 to June 2012, 341 patients were enrolled into this study with a sex ratio of 1.37:1, and an average age of 66+/-12 years. Compared with the normal group, the NSPF group had a significantly higher rate of small airway abnormalities and elevated RV/TLC. Multiple logistic regression analysis showed that statistical differences were found in TLC%pred (OR=0.668, P<0.01, 95%CI 0.563-0.791), FEF25-75%pred (OR=0.963, P<0.01, 95%CI 0.939-0.988), RV%pred (OR=1.144, P<0.01, 95%CI 1.075-1.217), and RV/TLC (OR=1.31, P<0.01, 95%CI 1.15-1.492). Compared with the obstructive group, the NSPF group had a significantly lower rate of small airway abnormalities. Multiple logistic regression analysis showed that female gender(OR=15.283, P<0.001, 95%CI 3.526 66.248), TLC%pred (OR=0.961, P=0.02, 95%CI 0.928-0.994), and FEF50%%pred (OR=1.189, P<0.001, 95%CI 1.103-1.281) were significantly different between the 2 groups. Respiratory symptoms were more common in the NSPF group. Airway diseases were diagnosed in more cases of the NSPF group when compared to the normal group, but in fewer cases when compared to the obstructive group. Clinical manifestations and imaging features of the NSPF cases were not specific. CONCLUSIONS: NSPF is a common clinical condition which mainly affects the small airway function with some degree of restrictive dysfunction. NSPF has limited predictive value for diagnosis because the manifestations and imaging features are not specific. PMID- 26980534 TI - [Clinical characteristics of lung cancer complicated with pulmonary embolism]. AB - OBJECTIVE: To investigate the clinical characteristics, risk factors, and survival time of patients with lung cancer (LC) and pulmonary embolism (PE). METHODS: A total of 17 LC patients complicated with PE admitted to this hospital from February 2012 to January 2014 were retrospectively reviewed. There were 13 males and 4 females, with an average age of (65+/-9) years (range, 38-82 years). Twenty LC patients, including 14 males and 6 females with an average age of (63+/ 9) years (range, 34-81 years), and 10 PE patients , including 7 males and 3 females with an average age of (70+/-7) years (range, 42-85 years), were selected respectively as the LC control group and the PE control group. Logistic regression analysis was used to evaluate the risk factors for LC complicated with PE. The survival of these patients was compared with that of the control subjects by Kaplan-Meier analysis. RESULTS: In the 17 patients with LC and PE, the diagnosis of PE was made simultaneously with LC in 2, before the diagnosis of LC in 4, and after the diagnosis of LC in 11 patients. These patients showed a higher incidence of unexplained dyspnea (12 cases) than those with LC only (6 cases) (P<0.05). These patients also had a higher incidence of cough (11 cases) than those with PE only (2 cases) (P<0.05). The patients with both PE and LC had a lower PaO2 (67+/-18) mmHg (1 mmHg=0.133 kPa) than those with LC only (87+/-12) mmHg (P<0.05). They also showed higher WBC count (8.9+/-5.3) g/L and D-Dimer level (850+/-537) MUg/L than those with LC only (4.5+/-3.0) g/L, (306+/-188) MUg/L (P<0.05). Multi-factor analysis showed that Hb<100 g/L, WBC>11*10(9)/L, D Dimer>500 MUg/L, PO2<80 mmHg, adenocarcinoma, and high pathological grade (TNM grade) were the risk factors for LC with PE (odds ratio 1.58, 2.24, 3.06, 3.15, 3.44, 2.09, respectively). On January 31, 2014, the median survival time of patients with LC and PE was 8.7 months, which was significantly lower than that of patients with LC only (P<0.05). CONCLUSIONS: The common clinical manifestations in patients with both LC and PE included unexplained dyspnea, fever and cough. The most common pathological type was adenocarcinoma. The first 5 months after LC diagnosis were the peak time for PE. Patients with LC and PE had a shorter survival time. LC of grade III to IV, lower Hb, higher WBC, higher D-Dimer and hyoxemia were independent risk factors for LC complicated with PE. PMID- 26980535 TI - [Relationship between gene polymorphisms of tumor necrosis factor-alpha-308 and phenotypes of acute exacerbation of chronic obstructive pulmonary diseases]. AB - OBJECTIVE: To observe the relationship between gene polymorphisms of tumor necrosis factor-alpha (TNF-alpha)-308 and phenotypes of acute exacerbation of chronic obstructive pulmonary diseases (AECOPD). METHODS: 198 AECOPD cases in the Minhang Hospital of Shanghai were recruited into the patient group, and 195 healthy people were recruited into the control group. PCR and sequencing method were used to detect the polymorphism of TNF-alpha-308 in all the people. RESULTS: Three genotypes with GG, GA and AA were detected in the 2 groups. The frequencies of GG/GA/AA genotype in AECOPD group were 87.4%, 10.6% and 2.0% respectively, and the control group were 95.4%, 4.6% and 0 respectively. The differences of the genotypes between AECOPD and health control were statistically significant (P<0.05). The frequencies of G and A were 92.7% and 7.3% in the AECOPD group, 97.7% and 2.3% in the control group. The differences were statistically significant (P<0.05). Dyspnea, smoke index and the increased thickness of bronchial wall in lung HRCT were the clinical features in patients with the TNF alpha-308 genotype of GA/AA. CONCLUSION: There is correlation between genetic predisposition of AECOPD and TNF-alpha-308 genotype of GA/ AA. Clinical dyspnea, smoke index and increased thickness of bronchial wall are the chief clinical features in patients with genotype of GA/AA. PMID- 26980536 TI - [Rosiglitazone inhibited the transformation and synthesis of collagen in rats' embryonic lung fibroblasts through the modulation of plasminogen activator inhibitor-1]. AB - OBJECTIVE: To investigate the role of plasminogen activator inhibitor-1 (PAI-1) in the inhibition of rosiglitazone on the transformation and collagen synthesis of rats' embryo lung fibroblasts and to examine the signal pathways in the process. METHODS: Fibroblasts from rats' embryo lung tissues were divided into 3 groups: Control, Rosiglitazone (Rosiglitazone 30 mmol/L) and PAI-1 (Rosiglitazone 30 mmol/L and PAI-1 20 mmol/L) groups. The fibroblasts were collected at 24, 48 and 72 h, and stored at -80 degrees C. RT-PCR was used to determine the expressions of collagen type-1 and type-3 at 24 h. Western blot analysis was used to determine the expressions of PAI-1, a-smooth muscle actin (alpha-SMA), p-AKT and p-ERK at 24, 48 and 72 h. RESULTS: There was a significant decrease in the protein expression of PAI-1 in the Rosiglitazone group (0.732+/-0.015, 0.583+/ 0.005, 0.762+/-0.032) at 24, 48 and 72 h compared with the Control group (1.116+/ 0.046). There was a significant increase in the protein expression in the PAI-1 group (0.923+/-0.042, 1.024+/-0.009, 1.070+/-0.011) compared with the Rosiglitazone group (F=78.609, P<0.01). The alpha-SMA protein expressions were significantly reduced in the Rosiglitazone group (0.209+/-0.012, 0.280+/-0.140, 0.254+/-0.025) compared with the Control group (0.340+/-0.026), while the expressions were significantly increased in the PAI-1 group (0.386+/-0.042, 0.400+/-0.037, 0.385+/-0.026) compared with the Rosiglitazone group (F=35.009, P<0.01). The collagen type-1 (1.065+/-0.004) and type-3 (1.282+/-0.001) mRNA expressions were significantly reduced in the Rosiglitazone group compared with the Control group (1.279+/-0.013, 1.690+/-0.005), while the expressions were significantly increased in the PAI-1 groups (1.390+/-0.029, 1.350+/-0.044) compared with the Rosiglitazone group (type-1: F=12.429, P<0.01; type-3: F=127.456, P<0.01). The expressions of p-AKT showed no differences among the 3 groups, but there were significant differences in the expressions of p-ERK in the Rosiglitazone group (0.288+/-0.010, 0.311+/-0.034, 0.336+/-0.038) compared with the Control group (0.506+/-0.032), and in PAI-1 groups (0.561+/-0.101, 0.448+/ 0.022, 0.406+/-0.003) compared with the Rosiglitazone group (F=153.548, P<0.01). CONCLUSIONS: Rosiglitazone inhibits PAI-1 expression in fibroblasts from rats' embryo lung tissues and activates the fibrinolytic system. The up-regulation of PAI-1 expression alleviates the inhibition effect of rosiglitazone on the transformation and collagen synthesis of fibroblasts. The cross-talk between PAI 1 and ERK signal pathway may play an important role in the regulation of rosiglitazone on fibrosis. PMID- 26980537 TI - [Progressing of bronchial thermoplasty in asthma]. PMID- 26980538 TI - [Ten years of tiotropium in chronic obstructive pulmonary diseases: review and future]. PMID- 26980539 TI - [Interventional treatment of acquired respiratory fistulas]. PMID- 26980540 TI - [Research progress in breath analysis for patients with pulmonary infection and respiratory critical diseases]. PMID- 26980541 TI - Geometry strategy for engineering the recombination possibility of excitons in nanowires. AB - We proposed a geometry strategy to engineer the radiative recombination possibility and thus the lifetime of excitons in nanowires of some photovoltaic semiconductors by using theoretical analysis and first-principles calculations. We demonstrated that the shape can engineer the symmetry of the wave-functions of band-edge states and influence the radiative recombination possibility. The nanowires need to satisfy the following requirements to forbid the radiative recombination possibility of band-edge excitons: (i) wurtzite structure; (ii) pxy characterized wave-function of VBM state and (iii) C3v-symmetry shape. The geometrical symmetry results in the pxy-characterized C3v-symmetry wave-function of VBM state and leads to forbidden radiative recombination of band-edge excitons. The geometry strategy offers a flexible proposal to prolong the exciton lifetime, leaving optical absorption impregnable. PMID- 26980543 TI - Comment on a meta-analysis of re-treatment for intravenous immunoglobulin resistant Kawasaki disease. PMID- 26980542 TI - Coupled metal partitioning dynamics and toxicodynamics at biointerfaces: a theory beyond the biotic ligand model framework. AB - A mechanistic understanding of the processes governing metal toxicity to microorganisms (bacteria, algae) calls for an adequate formulation of metal partitioning at biointerfaces during cell exposure. This includes the account of metal transport dynamics from bulk solution to biomembrane and the kinetics of metal internalisation, both potentially controlling the intracellular and surface metal fractions that originate cell growth inhibition. A theoretical rationale is developed here for such coupled toxicodynamics and interfacial metal partitioning dynamics under non-complexing medium conditions with integration of the defining cell electrostatic properties. The formalism explicitly considers intertwined metal adsorption at the biointerface, intracellular metal excretion, cell growth and metal depletion from bulk solution. The theory is derived under relevant steady-state metal transport conditions on the basis of coupled Nernst-Planck equation and continuous logistic equation modified to include metal-induced cell growth inhibition and cell size changes. Computational examples are discussed to identify limitations of the classical Biotic Ligand Model (BLM) in evaluating metal toxicity over time. In particular, BLM is shown to severely underestimate metal toxicity depending on cell exposure time, metal internalisation kinetics, cell surface electrostatics and initial cell density. Analytical expressions are provided for the interfacial metal concentration profiles in the limit where cell growth is completely inhibited. A rigorous relationship between time-dependent cell density and metal concentrations at the biosurface and in bulk solution is further provided, which unifies previous equations formulated by Best and Duval under constant cell density and cell size conditions. The theory is sufficiently flexible to adapt to toxicity scenarios with involved cell survival-death processes. PMID- 26980544 TI - Invariant two-component structure of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). AB - The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS; Randolph, 1998 , 2012 ) is a brief neurocognitive instrument used to evaluate cognitive functioning in clinical settings. Prior investigations of the factor structure have revealed subtle differences across samples. It was hypothesized that these differences are primarily the result of methodological decisions made by researchers. The present study utilized empirically supported extraction criteria (parallel analysis; minimum average partial procedure) and uniformly investigated 5 samples. RBANS data from 4 previously published studies (Carlozzi, Horner, Yang, & Tilley, 2008 ; Duff, Hobson, Beglinger, & O'Bryant, 2010 ; Duff et al., 2006 ; Wilde, 2006 ) were reanalyzed, and a new clinical sample was obtained from the Gundersen Health System Memory Center. The congruence of factor structures was investigated by conducting orthogonal vector matrix comparisons (Barrett, 2005 ), and a robust 2-factor structure reliably emerged across samples. The invariant RBANS 2-factor structure primarily emphasized memory and visuospatial functioning. This finding offered further support for a 2-factor RBANS structure identified in previous studies and additionally provided empirical documentation of replication across diverse samples. Due to the expansive use of the RBANS, this psychometric knowledge has significant clinical implications. It should facilitate accurate interpretation of test data and allow clinicians to make more informed decisions regarding whether the instrument is appropriate to use in various clinical settings. PMID- 26980545 TI - Aqueous sodium borohydride induced thermally stable porous zirconium oxide for quick removal of lead ions. AB - Aqueous sodium borohydride (NaBH4) is well known for its reducing property and well-established for the development of metal nanoparticles through reduction method. In contrary, this research paper discloses the importance of aqueous NaBH4 as a precipitating agent towards development of porous zirconium oxide. The boron species present in aqueous NaBH4 play an active role during gelation as well as phase separated out in the form of boron complex during precipitation, which helps to form boron free zirconium hydroxide [Zr(OH)4] in the as synthesized condition. Evolved in-situ hydrogen (H2) gas-bubbles also play an important role to develop as-synthesized loose zirconium hydroxide and the presence of intra-particle voids in the loose zirconium hydroxide help to develop porous zirconium oxide during calcination process. Without any surface modification, this porous zirconium oxide quickly adsorbs almost hundred percentages of toxic lead ions from water solution within 15 minutes at normal pH condition. Adsorption kinetic models suggest that the adsorption process was surface reaction controlled chemisorption. Quick adsorption was governed by surface diffusion process and the adsorption kinetic was limited by pore diffusion. Five cycles of adsorption-desorption result suggests that the porous zirconium oxide can be reused efficiently for removal of Pb (II) ions from aqueous solution. PMID- 26980547 TI - Acupuncture for irritable bowel syndrome: 2-year follow-up of a randomised controlled trial. AB - BACKGROUND: A recent randomised controlled trial (RCT) of acupuncture as a treatment for irritable bowel syndrome (IBS) demonstrated sustained benefits over a period of 12 months post-randomisation. AIM: To extend the trial follow-up to evaluate the effects of acupuncture at 24 months post-randomisation. METHODS: Patients in primary care with ongoing IBS were recruited to a two-arm pragmatic RCT of acupuncture for IBS. Participants were randomised to the offer of up to 10 weekly sessions of acupuncture plus usual care (n=116 patients) or to continue with usual care alone (n=117). The primary outcome was the self-reported IBS symptom severity score (IBS SSS) measured at 24 months post-randomisation. Analysis was by intention-to-treat using an unstructured multivariate linear model incorporating all repeated measures. RESULTS: The overall response rate was 61%. The adjusted difference in mean IBS SSS at 24 months was -18.28 (95% CI 40.95 to 4.40) in favour of the acupuncture arm. Differences at earlier time points estimated from the multivariate model were: -27.27 (-47.69 to -6.86) at 3 months; -23.69 (-45.17 to -2.21) at 6 months; -24.09 (-45.59 to -2.59) at 9 months; and -23.06 (-44.52 to -1.59) at 12 months. CONCLUSIONS: There were no statistically significant differences between the acupuncture and usual care groups in IBS SSS at 24 months post-randomisation, and the point estimate for the mean difference was approximately 80% of the size of the statistically significant results seen at 6, 9 and 12 months. TRIAL REGISTRATION NUMBER: ISRCTN08827905. PMID- 26980548 TI - Surface PEGylation of intraocular lens for PCO prevention: An in vivo evaluation. AB - Posterior capsular opacification (PCO) is a common complication in cataract surgery. The development of PCO is attributed to the combination of adhesion, migration, proliferation, and transdifferentiation of the residual lens epithelial cells (LEC) onto the interface of intraocular lens (IOL) material and lens posterior, in which the initial adhesion is the beginning step and plays important roles. In the present study, hydrophilic polyethylene glycol (PEG) was immobilized onto IOL surface via plasma-aided chemical grafting procedure. The attenuated total reflection - Fourier transform infrared (ATR-FTIR) and contact angle (CA) - measurements indicate the successful surface PEGylation, as well as the excellent hydrophilicity of the surfaces. Compared with pristine IOL, the PEGylation does not influent its optical property, whereas the initial adhesion of LEC is greatly inhibited. In vivo ocular implantation results show that the PEGylated IOL presents good in vivo biocompatibility, and can effectively prevent the PCO development. PMID- 26980550 TI - Blood compatibility evaluations of poly(ethylene glycol)-poly(lactic acid) copolymers. AB - Poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) copolymers have been widely used for various biomedical applications. However, their hemocompatibility has not been clarified, which would lag their developments and clinical applications. In this work, we studied the effect of PEG-PLA copolymers on key human blood components in terms of their structure and bio-functions, including morphology and lysis of red blood cells, fibrinogen structure and conformation, and plasma and blood coagulation. To elucidate a structure-activity relationship, we used diblock PEG-PLA copolymers with different molecular weight, PEG(5 kDa)-PLA(25 kDa) and PEG(2 kDa)-PLA(2 kDa), abbreviated as PEG5k-PLA25k and PEG2k-PLA2k, respectively. The results show that the PEG-PLA copolymers at the concentration range studied in this work neither caused morphological alteration and lysis of red blood cells nor affected the oxygen delivery function and fibrinogen conformation. PEG5k-PLA25k from 10 to 100 mg/mL and PEG2k-PLA2k from 1.5 to 5 mg/mL disturbed the local microenvironments of fibrinogen molecules. PEG5k-PLA25k at up to 0.1 mg/mL did not interfere in the coagulation process of plasma or whole blood, while PEG2k-PLA2k from 0.1 mg/mL significantly interfered in the intrinsic plasma coagulation pathway and impaired whole blood coagulation. The results provide important information for the molecular design and clinical applications of PEG-PLA copolymers. PMID- 26980549 TI - Improving PEEK bioactivity for craniofacial reconstruction using a 3D printed scaffold embedded with mesenchymal stem cells. AB - OBJECTIVE: Polyetheretherketone (PEEK) is a bioinert thermoplastic that has been investigated for its potential use in craniofacial reconstruction; however, its use in clinical practice is limited by a poor integration with adjacent bone upon implantation. To improve the bone-implant interface, two strategies have been employed: to modify its surface or to impregnate PEEK with bioactive materials. This study attempts to combine and improve upon the two approaches by modifying the internal structure into a trabecular network and to impregnate PEEK with mesenchymal stem cells. Furthermore, we compare the newly designed PEEK scaffolds' interactions with both bone-derived (BMSC) and adipose (ADSC) stem cells. DESIGN: Customized PEEK scaffolds were designed to incorporate a trabecular microstructure using a computer-aided design program and then printed via selective laser sintering (SLS), a 3D-printing process with exceptional accuracy. The scaffold structure was evaluated using microCT. Scanning electron microscopy (SEM) was used to evaluate scaffold morphology with and without mesenchymal stem cells (MSCs). Adipose and bone marrow mesenchymal cells were isolated from rats and cultured on scaffolds. Cell proliferation and differentiation were assessed using alamarBlue and alkaline phosphatase assays, respectively. Cell morphology after one week of co-culturing cells with PEEK scaffolds was evaluated using SEM. RESULTS: SLS 3D printing fabricated scaffolds with a porosity of 36.38% +/- 6.66 and density of 1.309 g/cm(2). Cell morphology resembled viable fibroblasts attaching to the surface and micropores of the scaffold. PEEK scaffolds maintained the viability of both ADSCs and BMSCs; however, ADSCs demonstrated higher osteodifferentiation than BMSCs (p < 0.05). CONCLUSIONS: This study demonstrates for the first time that SLS 3D printing can be used to fabricate customized porous PEEK scaffolds that maintain the viability of adipose and bone marrow-derived MSCs and induce the osteodifferentiation of the adipose-derived MSCs. The combination of 3D printed PEEK scaffolds with MSCs could overcome some of the limitations using PEEK biopolymers for load-bearing bone regeneration in craniofacial reconstruction. PMID- 26980551 TI - The Ultrastructures and Mechanical Properties of the Descement's Membrane in Fuchs Endothelial Corneal Dystrophy. AB - Fuchs endothelial corneal dystrophy (FECD), is the most common corneal endothelial dystrophy, and contributes up to 50% of all corneal transplantations performed in developed countries. FECD develops in Descemet's membrane (DM) and possibly alters the mechanical properties and internal structures in this basal lamina. In this work, the morphology and mechanical properties of FECD-DMs are studied by transmission electron microscopy (TEM) and quantitative dynamic atomic force microscopy (QD-AFM) at nano scale. Pathological wide-space collagens that are typical of FECD display different mechanical properties in that they are softer than the remaining tissue both for dehydrated- and fully hydrated samples. Additionally, the hydration level has major influence on the mechanical properties. These findings could help to further understand the structural changes in FECD, and possibly be useful for further characterization of the disease, the diagnosis and assessment or even pathologic analysis. PMID- 26980553 TI - First preparation of low band gap fulvene-modified polynorbornene via ring opening metathesis polymerization. AB - New polymers containing intact pendant-fulvene moieties have been successfully prepared from 1,3-phenyl-6-norbornenylfulvene via ring-opening metathesis polymerization (ROMP). The prepared polyfulvenes have unique electrochemical and photophysical properties which make them interesting candidates for light harvesting materials. PMID- 26980554 TI - Chlorambucil for the treatment of patients with chronic lymphocytic leukemia (CLL) - a systematic review and meta-analysis of randomized trials. AB - Randomized clinical trials that compared chlorambucil to different regimens, for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) do not support an overall survival (OS) benefit. To assess the efficacy and safety of chlorambucil as frontline treatment, we conducted a systematic review and meta-analysis of randomized controlled trials. OS was the primary outcome. Meta-analysis of 18 trials that compared purine analogs, alkylators, alemtuzumab and ibrutinib to chlorambucil demonstrated no OS benefit for therapy without chlorambucil over chlorambucil (pooled HR 0.99, 95% CI 0.91-1.08; 4133 patients). PFS was longer with purine analogs compared with chlorambucil with an increased risk of infection. The risk of secondary malignancies was not increased with chlorambucil. In conclusion, our study showed that chlorambucil is an acceptable chemotherapy backbone for unfit patients with CLL. Purine analogs should be preferred in fit younger patients because of longer PFS. Future trials should focus on unfit patients who are underrepresented in clinical trials. PMID- 26980555 TI - Quality of laboratory studies assessing effects of Bt-proteins on non-target organisms: minimal criteria for acceptability. AB - The potential risks that genetically modified plants may pose to non-target organisms and the ecosystem services they contribute to are assessed as part of pre-market risk assessments. This paper reviews the early tier studies testing the hypothesis whether exposure to plant-produced Cry34/35Ab1 proteins as a result of cultivation of maize 59122 is harmful to valued non-target organisms, in particular Arthropoda and Annelida. The available studies were assessed for their scientific quality by considering a set of criteria determining their relevance and reliability. As a case-study, this exercise revealed that when not all quality criteria are met, weighing the robustness of the study and its relevance for risk assessment is not obvious. Applying a worst-case expected environmental concentration of bioactive toxins equivalent to that present in the transgenic crop, confirming exposure of the test species to the test substance, and the use of a negative control were identified as minimum criteria to be met to guarantee sufficiently reliable data. This exercise stresses the importance of conducting studies meeting certain quality standards as this minimises the probability of erroneous or inconclusive results and increases confidence in the results and adds certainty to the conclusions drawn. PMID- 26980556 TI - Angiogenic activity mediates bone repair from human pluripotent stem cell-derived osteogenic cells. AB - Human pluripotent stem cells provide a standardized resource for bone repair. However, criteria to determine which exogenous cells best heal orthopedic injuries remain poorly defined. We evaluated osteogenic progenitor cells derived from both human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs). Phenotypic and genotypic analyses demonstrated that these hESCs/hiPSCs are similar in their osteogenic differentiation efficiency and they generate osteogenic cells comparable to osteogenic cells derived from mesenchymal stromal cells (BM-MSCs). However, expression of angiogenic factors, such as vascular endothelial growth factor and basic fibroblast growth factor in these osteogenic progenitor cells are markedly different, suggesting distinct pro-angiogenic potential of these stem cell derivatives. Studies to repair a femur non-union fracture demonstrate only osteogenic progenitor cells with higher pro-angiogenic potential significantly enhance bone repair in vivo. Together, these studies highlight a key role of pro-angiogenic potential of transplanted osteogenic cells for effective cell-mediated bone repair. PMID- 26980557 TI - Can progress in reducing alcohol-impaired driving fatalities be resumed? Results of a workshop sponsored by the Transportation Research Board, Alcohol, Other Drugs, and Transportation Committee (ANB50). AB - OBJECTIVE: Despite successes in the 1980s and early 1990s, progress in reducing impaired driving fatalities in the United States has stagnated in recent years. Since 1997, the percentage of drivers involved in fatal crashes with illegal blood alcohol concentration (BAC) levels has remained at approximately 20 to 22%. Many experts believe that public complacency, competing social and public health issues, and the lack of political fortitude have all contributed to this stagnation. The number of alcohol-related crashes, injuries, and fatalities is still unacceptable, and most are preventable. The public needs to be aware that the problem presented by drinking drivers has not been solved. Political leaders need guidance on which measures will affect the problem, and stakeholders need to be motivated once again to implement effective strategies. METHODS: The National Academy of Sciences (NAS) Transportation Research Board (TRB), Alcohol, Other Drugs, and Transportation Committee (ANB50) sponsored a workshop held at the NAS facility in Woods Hole, Massachusetts, on August 24-25, 2015, to discuss the lack of progress in reducing impaired driving and to make recommendations for future progress. A total of 26 experts in research and policy related to alcohol impaired driving participated in the workshop. The workshop began by examining the static situation in the rate of alcohol-impaired driving fatal crashes to determine what factors may be inhibiting further progress. The workshop then discussed 8 effective strategies that have not been fully implemented in the United States. Workshop participants (16 of the 26) rated their top 3 strategies. RESULTS: 3 strategies received the most support: 1. Impose administrative sanctions for drivers with BACs = 0.05 to 0.08 g/dL. 2. Require alcohol ignition interlocks for all alcohol-impaired driving offenders. 3. Increase the frequency of sobriety checkpoints, including enacting legislation to allow them in the 11 states that currently prohibit them. 5 other important strategies included the following: (1) increase alcohol taxes to raise the price and reduce alcohol consumption; (2) reengage the public and raise the priority of impaired driving; (3) lower the illegal per se BAC limit to 0.05 for a criminal offense; (4) develop and implement in-vehicle alcohol detection systems; and (5) expand the use of screening and brief interventions in medical facilities. CONCLUSIONS: Each of these strategies is proven to be effective, yet all are substantially underutilized. Each is used in some jurisdictions in the United States or Canada, but none is used extensively. Any one of the 3 strategies implemented on a widespread basis would decrease impaired driving crashes, injuries, and fatalities. Based on the research, all 3 together would have a substantial impact on the problem. PMID- 26980558 TI - The Protective Effects of Caffeic Acid Phenethyl Ester on Acetylsalicylic Acid induced Lung Injury in Rats. AB - AIM: We aimed to investigate the protective effect of caffeic acid phenethyl ester (CAPE) on acetylsalicylic acid (ASA)-induced lung damage in rats in the present study. METHODS: A total of 40 rats were randomly divided into five groups, with eight rats in each group-group 1: control, not receiving any medication; group 2: ASA (50 mg/kg/day); group 3: ASA (50 mg/kg/day) plus CAPE (20 MUg/kg/day); group 4: ASA (100 mg/kg/day); and group 5: ASA (100 mg/kg/day) plus CAPE (20 MUg/kg/day). ASA and CAPE were given via orogastric gavage for 5 days. The total oxidant status (TOS), total antioxidant capacity (TAC), oxidant stress index (OSI), and paraoxonase-1 (PON-1) activity of the blood samples and lung tissues were determined. Histopathological examinations of the lung tissues were performed by using light microscopic methods. RESULTS: CAPE treatment significantly increased antioxidant PON-1 level both in the lung tissue and plasma (p < .05). Plasma antioxidant marker (TAC, PON-1) levels significantly increased and oxidant marker (TOS, OSI) levels significantly decreased in CAPE treated rats (groups 3,5) compared to ASA given no-CAPE groups (group 2,4) (p < .05). Treatment with CAPE improved pulmonary interstitial inflammation and eosinophil accumulation due to ASA histopathologically. CONCLUSION: Eosinophil rich inflammation and oxidative stress play important roles in ASA-induced lung toxicity, and CAPE may protect against ASA-induced lung toxicity by reduction of oxidative damage and inflammation in rats. PMID- 26980560 TI - Reliability of lumbar movement dysfunction tests for chronic low back pain patients. AB - Assessment of lumbar movement dysfunction commonly comprises trunk range of motion (ROM), movement or control impairment (MCI), and reposition error (RE). Those assessments are typically based on visual observation. Consequently it is not possible to reliably quantify back movements for intersubject comparisons, or for monitoring changes before and after an intervention. Inertial measurement unit (IMU)-systems could be used to quantify these movement dysfunctions in clinical settings. The aim of this study was to evaluate the reliability of movement dysfunction tests when measured with a novel IMU-system. The reliability of eleven movement dysfunction tests (four ROM, six MCI and one RE tests) were analysed using generalizability-theory and minimal detectable change, measuring 21 chronic low back pain patients in seven trials on two days. Reliability varied across tests and variables. Four ROM and selected MCI tests and variables were identified as reliable. On average, ROM test were more reliable, compared to MCI and RE tests. An attempt should be made to improve the reliability of MCI and RE measures, for example through better standardizations. Subsequently these measures should be studied further for intersubject comparisons and monitoring changes after an intervention. PMID- 26980561 TI - A Quantitative Polymerase Chain Reaction Assay for the Detection and Quantification of Epizootic Epitheliotropic Disease Virus (EEDV; Salmonid Herpesvirus 3). AB - Epizootic epitheliotropic disease virus (EEDV; salmonid herpesvirus [SalHV3]; family Alloherpesviridae) causes a systemic disease of juvenile and yearling Lake Trout Salvelinus namaycush. No cell lines are currently available for the culture and propagation of EEDV, so primary diagnosis is limited to PCR and electron microscopy. To better understand the pervasiveness of EEDV (carrier or latent state of infection) in domesticated and wild Lake Trout populations, we developed a sensitive TaqMan quantitative PCR (qPCR) assay to detect the presence of the EEDV terminase gene in Lake Trout tissues. This assay was able to detect a linear standard curve over nine logs of plasmid dilution and was sensitive enough to detect single-digit copies of EEDV. The efficiency of the PCR assay was 99.4 +/- 0.06% (mean +/- SD), with a 95% confidence limit of 0.0296 (R(2) = 0.994). Methods were successfully applied to collect preliminary data from a number of species and water bodies in the states of Pennsylvania, New York, and Vermont, indicating that EEDV is more common in wild fish than previously known. In addition, through the development of this qPCR assay, we detected EEDV in a new salmonid species, the Cisco Coregonus artedi. The qPCR assay was unexpectedly able to detect two additional herpesviruses, the Atlantic Salmon papillomatosis virus (ASPV; SalHV4) and the Namaycush herpesvirus (NamHV; SalHV5), which both share high sequence identity with the EEDV terminase gene. With these unexpected findings, we subsequently designed three primer sets to confirm initial TaqMan qPCR assay positives and to differentiate among EEDV, ASPV, and NamHV by detecting the glycoprotein genes via SYBR Green qPCR. Received April 20, 2015; accepted November 10, 2015. PMID- 26980562 TI - Focus Groups--What Is the Same, What Is New, What Is Next? PMID- 26980563 TI - Germline Competent Pluripotent Mouse Stem Cells Generated by Plasmid Vectors. AB - We developed nonintegrated methods to reprogram mouse embryonic fibroblast (MEF) cells into induced pluripotent stem cells (iPSCs) using pig pOct4, pSox2, and pc Myc as well as human hKLF4, hAID, and hTDG that were carried by plasmid vectors. The 4F method employed pOct4, pSox2, pc-Myc, and hKLF4 to derive iPSC clones with naive embryonic stem cell (ESC)-like morphology. These 4F clones expressed endogenous mouse Nanog protein and could generate chimeras. In addition to the four conventional reprogramming factors used in the 4F method, hAID and hTDG were utilized in a 6F method to increase the conversion efficiency of reprogramming by approximately five-fold. One of the 6F plasmid derived iPSC (piPSC) clones was shown to be germline transmission competent. PMID- 26980564 TI - Mold spoilage of bread and its biopreservation: A review of current strategies for bread shelf life extension. AB - Microbial spoilage of bread and the consequent waste problem causes large economic losses for both the bakery industry and the consumer. Furthermore the presence of mycotoxins due to fungal contamination in cereals and cereal products remains a significant issue. The use of conventional chemical preservatives has several drawbacks, necessitating the development of clean-label alternatives. In this review, we describe current research aiming to extend the shelf life of bread through the use of more consumer friendly and ecologically sustainable preservation techniques as alternatives to chemical additives. Studies on the in situ-production/-expression of antifungal compounds are presented, with special attention given to recent developments over the past decade. Sourdough fermented with antifungal strains of lactic acid bacteria (LAB) is an area of increasing focus and serves as a high-potential biological ingredient to produce gluten containing and gluten-free breads with improved nutritional value, quality and safety due to shelf-life extension, and is in-line with consumer's demands for more products containing less additives. Other alternative biopreservation techniques include the utilization of antifungal peptides, ethanol and plant extracts. These can be added to bread formulations or incorporated in antimicrobial films for active packaging (AP) of bread. This review outlines recent progress that has been made in the area of bread biopreservation and future perspectives in this important area. PMID- 26980565 TI - Non-Photoinduced Biological Properties of Verteporfin. AB - BACKGROUND: Verteporfin is a porphyrinic photosensitizer clinically used for the photodynamic treatment of age-related macular degeneration. It has been identified almost simultaneously as a YAP/TEAD and an autophagosome inhibitor. Over the last few years, YAP (TAZ), the downstream effectors of the Hippo pathway, have emerged as promising anticancer targets, as shown by several experimental lines of evidence, showing the overproduction of YAP in several cancers. However, YAP was also found to be closely connected to autophagy, mitochondria and reactive oxygen/nitrogen species. We herein, review the recent studies where VP was used without photoactivation as a YAP/TEAD inhibitor or protein oligomerization promoter, focusing on its effects on the YAP/TEAD gene targets and other biomarkers related to autophagy. RESULTS: Since the identification of VP as YAP/TEAD inhibitor, several in vitro and in vivo studies have revealed the new potential of this molecule in different cancers, where YAP is overexpressed. However, detailed structural information about its interaction with YAP is still lacking. Concomitantly, VP was identified as autophagosome inhibitor by promoting oligomerization of p62. Moreover, VP proves to be tumor selective proteotoxic (by oligomerization of p62, STAT3) in colorectal cancer. Knowledge on the biological properties of the only YAP inhibitor available to date is vital for its pharmacological use on cellular and animal models. CONCLUSION: VP is a multi-target drug interacting with several proteins implicated in major cellular processes. Although this does not impact its clinical use, VP does not seem to be the ideal drug for pharmacological inhibitions of YAP/TEAD. PMID- 26980566 TI - Is Nitric Oxide Assuming a Janus-Face in The Central Nervous System? AB - Nitric Oxide, synthesized from L-arginine by the nitric oxide synthases, has a complex role within the human body. It contributes to almost every physiological system and has been found to be both protective and toxic in disease states. An aging population faces an increasing incidence of neurodegenerative disease and the pathological action of nitric oxide in Alzheimer's and Parkinson's diseases may be important therapeutic targets for the future. Nitric oxide's protective effects are also important to consider, through inhibition of caspase-3, nitrosylation of NMDA and increased activation of protein kinase B and CREB transcription factor. Nitric oxide has been shown to play a part in long term potentiation, revealing its importance in synaptic plasticity. Due to nitric oxide's mixed effects it is an exciting and varied therapeutic target. Currently, the impact of these therapies has been explored and developed in animal studies, but is yet to be fully realized in human trials. This paper outlines both the pathological and protective roles of nitric oxide in the central nervous system and the potential pharmacological therapies and targets these indicate. PMID- 26980567 TI - Chondroitin Sulfate and Glucosamine as Disease Modifying Anti- Osteoarthritis Dru gs (DMOADs). AB - Osteoarthritis is a disabling affliction expected to increase in the coming decades, and disease- modifying osteoarthritis drugs (DMOADs) would be highly desirable adjuncts to symptomatic relief and structure reconstruction as they may delay the disease process. Chondroitin sulfate and glucosamine have been observed to exert beneficial effects on the metabolism of various cells involved in osteoarthritis as well as in animal models and clinical trials. Clinical trials have reported beneficial effects of both these biological agents, alone or in combination, on pain and functions as well as their structure-modifying capacity reported and analyzed in recent meta-analyses. Nonetheless, the effectiveness of these bioactive (macro)molecules as DMOADs reported from randomized trials is mismatched. Current studies with varying levels of evidence suggest that chondroitin sulfate and glucosamine can modify the disease progression but at the same time there are not absolute certainties on their efficacy in modifying the course of the disease. This comprehensive review aims to clarify the role of these compounds in the therapeutic molecules/ drugs useful to patients affected by osteoarthritis. PMID- 26980568 TI - Cinnamic Acid Derivatives as Inhibitors of Oncogenic Protein Kinases--Structure, Mechanisms and Biomedical Effects. AB - Cinnamic acid belongs to phenolic-acid class of polyphenols, one of the most abundant plant secondary metabolites. These substances are widely studied because of plethora of their biological activities. In particular, their inhibition of protein kinases contributes to the pleiotropic effects in the cell. Protein kinases are essential in controlling cell signaling networks. Selective targeting of oncogenic protein kinases increases clinical anticancer efficacy. Cinnamic acid and related compounds have inspired researchers in the design of numerous synthetic and semisynthetic inhibitors of oncogenic protein kinases for the past three decades. Interest in cinnamoyl-scaffold-containing compounds revived in recent years, which was stimulated by modern drug design and discovery methodologies such as in vitro and in silico HTS. This review presents cinnamic acid derivatives and analogs for which direct inhibition of protein kinases was identified. We also summarize significance of the above protein kinase families - validated or promising targets for anticancer therapies. The inhibition mode may vary from ATP-competitive, through bisubstrate-competitive and mixedcompetitive, to non-competitive one. Kinase selectivity is often correlated with subtle chemical modifications, and may also be steered by an additional non-cinnamoyl fragment of the inhibitor. Specific cinnamic acid congeners may synergize their effects in the cell by a wider range of activities, like suppression of additional enzymes, e.g. deubiquitinases, influencing the same signaling pathways (e.g. JAK2/STAT). Cinnamic acid, due to its biological and physicochemical properties, provides nature-inspired ideas leading to novel inhibitors of oncogenic protein kinases and related enzymes, capable to target a variety of cancer cells. PMID- 26980569 TI - New Insight into 2-Methoxyestradiol- a Possible Physiological Link between Neurodegeneration and Cancer Cell Death. AB - The pathways leading to development of neurodegenerative disease and cancer cell death may overlap. Interestingly, the main neurodegeneration-causing factors have been suggested to play a pivotal role in the regulation of tumor growth. Another common component in neurodegenerations and cancer is nitro-oxidative stress. Depending on the environmental conditions, the nitro-oxidative stress may lead to cancerogenesis or cancer cell death. On the other side, it may also result in a variety of neurodegenerative diseases. Based on the literature data, we suggest that 2-methoxyestradiol may be considered as a physiological link between development of neurodegenerations and cancer cell death. 2-methoxyestradiol is a physiological compound, a metabolite of 17beta-estradiol. Interestingly, 2 methoxyestradiol, branded as Panzem, is also considered as a potent anticancer agent, currently investigated in several clinical trials. The review aims on making closer the facts concerning anticancer and plausible neurotoxic activities of 2-methoxyestradiol, which may suggest adverse neurological long-term effects of the drug in cancer patients. PMID- 26980570 TI - Altered RNA editing in 3' UTR perturbs microRNA-mediated regulation of oncogenes and tumor-suppressors. AB - RNA editing is a molecular event that alters specific nucleotides in RNA post transcriptionally. RNA editing has the potential to impact a variety of cellular processes and is implicated in diseases such as cancer. Yet, the precise mechanisms by which RNA editing controls cellular processes are poorly understood. Here, we characterize sequences altered by RNA editing in patient samples from lymphoma, neuroblastoma and head and neck cancers. We show that A-to I RNA editing sites are highly conserved across samples of the same tissue type and that most editing sites identified in tumors are also detectable in normal tissues. Next, we identify the significant changes in editing levels of known sites between tumor and paired "normal" tissues across 14 cancer types (627 pairs) from The Cancer Genome Atlas project and show that the complexity of RNA editing regulation cannot be captured by the activity of ADAR family genes alone. Our pan-cancer analysis confirms previous results on individual tumor types and suggests that changes of RNA editing levels in coding and 3'UTR regions could be a general mechanism to promote tumor growth. We also propose a model explaining how altered RNA editing levels affect microRNA-mediated post-transcriptional regulation of oncogenes and tumor-suppressors. PMID- 26980571 TI - Systolic MOLLI T1 mapping with heart-rate-dependent pulse sequence sampling scheme is feasible in patients with atrial fibrillation. AB - BACKGROUND: T1 mapping enables assessment of myocardial characteristics. As the most common type of arrhythmia, atrial fibrillation (AF) is often accompanied by a variety of cardiac pathologies, whereby the irregular and usually rapid ventricle rate of AF may cause inaccurate T1 estimation due to mis-triggering and inadequate magnetization recovery. We hypothesized that systolic T1 mapping with a heart-rate-dependent (HRD) pulse sequence scheme may overcome this issue. METHODS: 30 patients with AF and 13 healthy volunteers were enrolled and underwent cardiovascular magnetic resonance (CMR) at 3 T. CMR was repeated for 3 patients after electric cardioversion and for 2 volunteers after lowering heart rate (HR). A Modified Look-Locker Inversion Recovery (MOLLI) sequence was acquired before and 15 min after administration of 0.1 mmol/kg gadopentetate dimeglumine. For AF patients, both the fixed 5(3)3/4(1)3(1)2 and the HRD sampling scheme were performed at diastole and systole, respectively. The HRD pulse sequence sampling scheme was 5(n)3/4(n)3(n)2, where n was determined by the heart rate to ensure adequate magnetization recovery. Image quality of T1 maps was assessed. T1 times were measured in myocardium and blood. Extracellular volume fraction (ECV) was calculated. RESULTS: In volunteers with repeated T1 mapping, the myocardial native T1 and ECV generated from the 1st fixed sampling scheme were smaller than from the 1st HRD and 2nd fixed sampling scheme. In healthy volunteers, the overall native T1 times and ECV of the left ventricle (LV) in diastolic T1 maps were greater than in systolic T1 maps (P < 0.01, P < 0.05). In the 3 AF patients that had received electrical cardioversion therapy, the myocardial native T1 times and ECV generated from the fixed sampling scheme were smaller than in the 1st and 2nd HRD sampling scheme (all P < 0.05). In patients with AF (HR: 88 +/- 20 bpm, HR fluctuation: 12 +/- 9 bpm), more T1 maps with artifact were found in diastole than in systole (P < 0.01). The overall native T1 times and ECV of the left ventricle (LV) in diastolic T1 maps were greater than systolic T1 maps, either with fixed or HRD sampling scheme (all P < 0.05). CONCLUSION: Systolic MOLLI T1 mapping with heart-rate-dependent pulse sequence scheme can improve image quality and avoid T1 underestimation. It is feasible and with further validation may extend clinical applicability of T1 mapping to patients with atrial fibrillation. PMID- 26980572 TI - MicroRNA-203 suppresses gastric cancer growth by targeting PIBF1/Akt signaling. AB - BACKGROUND: MicroRNAs (miRNAs) have been proved involved in many tumorigenic behaviors including tumor growth. But, the clinical significance and functions of miRNA-203 in gastric cancer (GC) remain elusive. RESULTS: Decreased expression of miRNA-203 was correlated with tumor size, poor prognosis and recurrence in GC patients. Overexpression of miR-203 or knockdown of its target progesterone immunomodulatory binding factor 1 (PIBF1) inhibited GC growth in vitro and in vivo, while miR-203 knockdown promoted GC proliferation. In addition, PIBF1 overexpression attenuated the inhibitory effects of miR-203 on GC growth and enhanced that effect on p-Akt expression. CONCLUSIONS: MiR-203 as a tumor biomarker suppresses GC growth through targeting the PIBF1/Akt signaling, suggesting that it may have the important therapeutic potential for the treatment of GC. PMID- 26980574 TI - Faster Convergence of Diffusion Anisotropy Detection by Three-Step Relation of Single-Particle Trajectory. AB - We focus on the issue of limited number of samples in the single particle tracking (SPT) when trying to extract the diffusion anisotropy that originates from the particle asymmetry. We propose a novel evaluation technique of SPT making use of the relation of the consecutive three steps. More specifically, the trend of the angle comprised of the three positions and the displacements are plotted on a scatter diagram. The particle anisotropy dependence of the shape of the scatter diagram is examined through the data from the standard numerical model of anisotropic two-dimensional Brownian motion. Comparison with the existing method reveals the faster convergence in the evaluation. In particular, our proposed method realizes the detection of diffusion anisotropy under the conditions of not only less number of data but also larger time steps. This is of practical importance not only when the abundant data is hard to achieve but also when the rotational diffusion is fast compared to the frame rate of the camera equipment, which tends to be more common for smaller particles or molecules of interest. PMID- 26980573 TI - Low total cholesterol level is the independent predictor of poor outcomes in patients with acute ischemic stroke: a hospital-based prospective study. AB - BACKGROUND: Total cholesterol is a well-documented risk factor for coronary disease. Previous studies have shown that high total cholesterol level is associated with better stroke outcomes, but the association of low total cholesterol levels and ischemic stroke outcomes is rare. Therefore, we aimed to assess the association of low total cholesterol levels and stroke outcomes among acute ischemic stroke patients in China. METHODS: This study recruited 6407 atherothrombotic infarction patients from Tianjin, China, between May 2005 and September 2014. All patients were categorized into five groups according to TC level quintiles at admission. Differences in subtypes, severity, risk factors, and outcomes at 3, 12, and 36 months after stroke were compared between these groups. RESULTS: In total, 1256 (19.6%) patients had low cholesterol levels, with a higher prevalence in men than in women (23.7% vs. 11.2%, P < 0.001). Compared with higher cholesterol levels, the lowest cholesterol level quintile (TC, <4.07 mmol/L) was associated with older age (64.7 years, P = 0.033), anterior circulation infarct (22.8%), atrial fibrillation (4.9%), current smoking (41.1%), and alcohol consumption (21.1%) and lower frequencies of hypertension (72.9%), diabetes (30.7%), and obesity (9.9%). Dependency and recurrence rates were significantly higher at 36 months in patients in the lowest TC level quintile than in those with higher cholesterol levels (dependency rates, 51.2% vs 45.2%; P = 0.007 and recurrence rates, 46.3% vs 37.3%, P = 0.001). Moreover, these differences remained after adjustment for age, sex, stroke severity, and Oxfordshire Community Stroke Project classification (odds ratios [ORs] for dependency rate, 1.41; 95% confidence interval [CI], 1.11, 1.79; P = 0.005 and recurrence rate, 1.50; 95% CI, 1.19, 1.89; P = 0.001). However, mortality rates after stroke were not significantly different between the groups. CONCLUSIONS: These findings suggest that statin treatment for patients with atherothrombotic infarction and low cholesterol levels increase long-term dependency and recurrence rates, but do not increase mortality rates. It is crucial to highlight the different impact of statin treatment on patients with atherothrombotic infarction and lower cholesterol levels for secondary stroke prevention in China. PMID- 26980575 TI - A new paradigm of genetic testing for hereditary breast/ovarian cancers. AB - INTRODUCTION: Genetic risk factors and family history play an important role in breast cancer development. This review aimed to summarise the current genetic testing approach to hereditary breast/ovarian cancer. METHODS: A systematic literature review was performed by searching the PubMed database. Publications available online until January 2015 that addressed issues related to hereditary breast/ovarian cancer genetic counselling/testing were selected. The search terms used were "familial breast/ovarian cancer", "susceptibility genes", "genetic counselling", and "genetic testing". The data extracted for this review were analysed by the authors, with a focus on genetic testing for hereditary breast/ovarian cancer. RESULTS: Although a greater proportion of inherited breast/ovarian cancers are due to the BRCA1 and BRCA2 mutations, a number of new genes have emerged as susceptibility candidates, including rare germline mutations in high penetrance genes, such as TP53 and PTEN, and more frequent mutations in moderate/low penetrance genes, such as PALB2, CHEK2 and ATM. Multi gene testing, if used appropriately, is generally a more cost- and time-effective method than single-gene testing, and may increase the number of patients who can be offered personal surveillance, risk-reduction options, and testing of high risk family members. CONCLUSIONS: Recent advances in molecular genetics testing have identified a number of susceptibility genes related to hereditary breast and/or ovarian cancers other than BRCA1 and BRCA2. The introduction of multi-gene testing for hereditary cancer has revolutionised the clinical management of high risk patients and their families. Individuals with hereditary breast/ovarian cancer will benefit from genetic counselling/testing. PMID- 26980576 TI - Response to Intravenous Cyclophosphamide Treatment for Lupus Nephritis Associated with Polymorphisms in the FCGR2B-FCRLA Locus. AB - OBJECTIVE: Cyclophosphamide (CYC) is an immunosuppressant drug widely used to treat various diseases including lupus nephritis, but its efficacy highly varies from individual to individual. This pharmacogenomics association study searched for genetic variations associated with CYC efficacy. METHODS: Genome-wide association scan was performed for 109 Korean patients with systemic lupus erythematosus with lupus nephritis (classes III-V) who received intravenous CYC induction therapy. Genetic differences between responders and nonresponders were examined using Cochran-Armitage trend tests, and genotype imputation was used for defining the association locus. RESULTS: Genetic polymorphisms in the Fcgamma receptor gene (FCGR) cluster at human chromosome 1q23, previously associated with lupus nephritis susceptibility, were associated with the response to CYC treatment for lupus nephritis. Significant response association was found for 3 perfectly correlated (r(2) = 1) single-nucleotide polymorphisms (SNP): rs6697139, rs10917686, and rs10917688, located between the FCGR2B and FCRLA genes (p = 3.4 * 10(-8)). Carriage of the minor alleles in these SNP was found only in nonresponders (31%) and none in responders (0%). CONCLUSION: This first genome wide association approach for CYC response yielded a robust profile of genetic associations including large-effect SNP in the FCGR2B-FCRLA locus, which may provide better insights to CYC metabolism and efficacy. PMID- 26980577 TI - Leflunomide Use and Risk of Lung Disease in Rheumatoid Arthritis: A Systematic Literature Review and Metaanalysis of Randomized Controlled Trials. AB - OBJECTIVE: To evaluate the relative risk (RR) of pulmonary disease among patients with rheumatoid arthritis (RA) treated with leflunomide (LEF). METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials to April 15, 2014. We included double-blind randomized controlled trials (RCT) of LEF versus placebo or active comparator agents in adults with RA. Studies with fewer than 50 subjects or shorter than 12 weeks were excluded. Two investigators independently searched both databases. All authors reviewed selected studies. We compared RR differences using the Mantel-Haenszel random-effects method to assess total respiratory adverse events, infectious respiratory adverse events, noninfectious respiratory adverse events, interstitial lung disease, and death. RESULTS: Our literature search returned 5673 results. A total of 8 studies, 4 with placebo comparators, met our inclusion criteria. There were 708 respiratory adverse events documented in 4579 participants. Six cases of pneumonitis occurred, all in the comparator group. Four pulmonary deaths were reported, none in the LEF group. LEF was not associated with an increased risk of total adverse respiratory events (RR 0.99, 95% CI 0.56-1.78) or infectious respiratory adverse events (RR 1.02, 95% CI 0.58-1.82). LEF was associated with a decreased risk of noninfectious respiratory adverse events (RR 0.64, 95% CI 0.41-0.97). CONCLUSION: Our study found no evidence of increased respiratory adverse events in RCT of LEF treatment. PMID- 26980578 TI - Gout Prophylaxis Evaluated According to the 2012 American College of Rheumatology Guidelines: Analysis from the CORRONA Gout Registry. AB - OBJECTIVE: To analyze prophylaxis using the CORRONA (COnsortium of Rheumatology Researchers Of North America) Gout Registry according to the American College of Rheumatology (ACR) guidelines, and to evaluate whether differences in disease characteristics influenced prophylaxis. METHODS: All patients with gout in the CORRONA Gout Registry between November 1, 2012, and November 26, 2013, were included. They were divided into 2 groups: "receiving prophylaxis" versus "not receiving prophylaxis" at the time of enrollment. Patients having a flare at time of visit were excluded. Descriptive statistics and multivariable logistic regression models were performed to evaluate the factors associated with prophylaxis. RESULTS: There were 1049 patients with gout available for analysis. There were 441 patients (42%) receiving prophylaxis and 608 (58%) not receiving prophylaxis. The most common drugs used for prophylaxis were colchicine (78%) and nonsteroidal antiinflammatory drugs (32%). Prophylaxis drug combination was used by 45 patients (10.2%). Patients in the "receiving prophylaxis" group were more likely to have a gout duration of <= 1 year (n = 68, p < 0.001), >= 1 flare in the year previous to enrollment (p < 0.001), >= 1 healthcare uses in the last year [Emergency Department (p = 0.029); outpatient visit to primary care, rheumatologist, or urgent care clinic (p < 0.001)], have tophi (p < 0.001), report pain > 3 (p = 0.001), and have disease activity > 10 (p < 0.001) compared with patients in the "not receiving prophylaxis" group. CONCLUSION: Forty-two percent of patients with gout in the CORRONA Gout Registry were receiving prophylaxis. Prophylaxis was significantly more common in patients with a higher disease burden and activity, which is in agreement with the ACR guidelines. Our study highlights disease characteristics influencing prophylaxis and furthers our knowledge on current use of flare prophylaxis. PMID- 26980579 TI - Inflammatory Cells in Patients with Endstage Knee Osteoarthritis: A Comparison between the Synovium and the Infrapatellar Fat Pad. AB - OBJECTIVE: To get a better understanding of inflammatory pathways active in the osteoarthritic (OA) joint, we characterized and compared inflammatory cells in the synovium and the infrapatellar fat pad (IFP) of patients with knee OA. METHODS: Infiltrating immune cells were characterized by flow cytometry in 76 patients with knee OA (mean age 63.3, 52% women, median body mass index 28.9) from whom synovial tissue (n = 40) and IFP (n = 68) samples were obtained. Pain was assessed by the visual analog scale (VAS; 0-100 mm). Spearman rank correlations and linear regression analyses adjusted for sex and age were performed. RESULTS: Macrophages and T cells, followed by mast cells, were the most predominant immune cells in the synovium and IFP, and were equally abundant in these tissues. Macrophages and T cells secreted mostly proinflammatory cytokines even without additional stimulation, indicating their activated state. Accordingly, most CD4+ T cells had a memory phenotype and contained a significant population of cells expressing activation markers (CD25+, CD69+). Interestingly, the percent of CD69+ T cells was higher in synovial than IFP CD4+ T cells. Preliminary analyses indicated that the number of synovial CD4+ T cells were associated with VAS pain (beta 0.51, 95% CI 0.09-1.02, p = 0.02). CONCLUSION: Our data suggest that the immune cell composition of the synovium and the IFP is similar, and includes activated cells that could contribute to inflammation through secretion of proinflammatory cytokines. Moreover, preliminary analyses indicate that synovial CD4+ T cells might associate with pain in patients with endstage OA of the knee. PMID- 26980580 TI - Disability in Fibromyalgia Associates with Symptom Severity and Occupation Characteristics. AB - OBJECTIVE: It is intuitive that disability caused by illness should be reflected in illness severity. Because disability rates for fibromyalgia (FM) are high in the developed world, we have examined disease and work characteristics for patients with FM who were working, unemployed, or receiving disability payments for disability as a result of FM. METHODS: Of the 248 participants in a tertiary care cohort study of patients with FM, 90 were employed, 81 were not employed and not receiving disability payments, and 77 were not working and currently receiving disability payments awarded for disability caused by FM. Demographic, occupation, and disease characteristics were compared among the groups. RESULTS: The prevalence of disability caused by FM was 30.8%. There were no demographic differences among the working, unemployed, or disabled patients. With the exception of measures for anxiety and depression, all measurements for disease severity differed significantly among the groups, with greater severity reported for the disabled group, which used more medications and participated less in physical activity. Disabled patients were more likely previously employed in manual professions or the service industry, whereas employed patients were more commonly working in non-manual jobs that included clerical, managerial, or professional occupations (p = 0.005). CONCLUSION: The one-third rate of disability for this Canadian cohort of patients with FM is in line with other reports from the western world. Associations of disability compensation were observed for subjective report of symptom severity, increased use of medications, and previous employment in more physically demanding jobs. PMID- 26980581 TI - Assessment of Response to Treatment, Remission, and Minimal Disease Activity in Axial Psoriatic Arthritis Treated with Tumor Necrosis Factor Inhibitors. AB - OBJECTIVE: To assess the response to treatment, remission, and minimal disease activity (MDA) in a group of patients with predominant axial psoriatic arthritis (axPsA). Predictors of response were also evaluated. METHODS: Patients fulfilling the ClASsification of Psoriatic ARthritis (CASPAR) criteria and treated with anti tumor necrosis factor (anti-TNF) agents adalimumab, etanercept, and golimumab were enrolled and prospectively followed every 4 months for 1 year in a clinical practice setting. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 was assessed as a set of response criteria to treatment; Composite Psoriatic Disease Activity Index (CPDAI) < 4, Disease Activity Index for Psoriatic Arthritis (DAPSA) score <= 3.3, and partial remission (PR) were also evaluated as remission criteria. Patients were considered in MDA when they met at least 5/7 of the criteria previously defined. Patients achieving BASDAI 50, PR, and MDA were compared to identify outcome predictor factors. Concordance between the outcome measures was also performed. RESULTS: Of the 58 patients treated with anti-TNF, at baseline no patients were in PR or MDA. No patients had a CPDAI < 4 or a DAPSA score <= 3.3. After 12 months, BASDAI 50 was achieved in 15/48 patients (31.2%). CPDAI < 4, DAPSA score <= 3.3, PR, and MDA were achieved, respectively, in 17/48 (35.4%), 11/48 (22.9%), 11/48 (22.9%), and 24/48 (50%) patients. No difference was found among the 3 anti-TNF. Predictors for MDA were male sex, young age, low disease duration, low Health Assessment Questionnaire score, and absence of enthesitis. CONCLUSION: This longitudinal observational study, based on a clinical practice setting, showed that remission and MDA are achievable targets in axPsA treated with anti-TNF. Predictors of remission and MDA were also identified. PMID- 26980582 TI - Inactive Disease in Enthesitis-related Arthritis: Association of Increased Body Mass Index. AB - OBJECTIVE: Patients with enthesitis-related arthritis (ERA) were less likely to achieve and sustain inactive disease than children with other subtypes of juvenile idiopathic arthritis. The aim of this study was to evaluate the effect of increased body mass index (BMI) on clinical features of the disease and to investigate whether being overweight or obese limits the possibility of achieving clinically inactive disease in patients with ERA. METHODS: The hospital charts of 72 patients with ERA were reviewed. Demographic and clinical findings were recorded. Patients were divided into 2 groups according to whether they had "healthy weight" (BMI < 85th percentile) or "increased weight" (BMI >= 85th percentile) at baseline. The primary outcome of this study was to achieve inactive disease at 1 year after the initiation of therapy. The inactive disease criterion of Wallace, et al was used to define inactive disease status. RESULTS: Twenty patients had increased BMI. The frequency of tarsitis and ankle involvement was higher in patients with increased weight. Thirty-seven patients were inactive at the end of 1 year. In univariate analyses, male sex, increased BMI, ankle involvement, and tarsitis were found to be associated with failure to achieve inactive disease. Multivariate backward stepwise regression analyses revealed that failure to achieve clinically inactive disease was associated with increased BMI and ankle involvement. CONCLUSION: Being overweight or obese was associated with failure to achieve inactive disease in patients with ERA. Because body weight is a modifiable factor, individualized interventions may have clinical implications for better therapeutic outcome. PMID- 26980583 TI - Longterm Clinical Outcomes in 420 Patients with Psoriatic Arthritis Taking Anti tumor Necrosis Factor Drugs in Real-world Settings. AB - OBJECTIVE: An observational study to evaluate the longterm clinical outcomes of adalimumab (ADA), etanercept (ETN), and infliximab (IFX) in patients with psoriatic arthritis (PsA), in real-world settings. METHODS: From a prospective cohort we studied 420 biologic-naive patients with PsA who had peripheral arthritis and were beginning a treatment with ADA, ETN, or IFX. Drug survival was evaluated by Kaplan-Meier life analysis, and baseline predictors of drug discontinuation were assessed by Cox regression analysis. The frequency of concomitant glucocorticoids and the daily mean dosage were compared by chi-square test and ANOVA repeated measures across 4 years. RESULTS: After 4 years the overall survival of the first anti-tumor necrosis factor-alpha (anti-TNF) was 51.0%, but significantly higher for ETN (58.9%) than ADA (43.9%) or IFX (44.0%; p = 0.003). Patients taking ETN also had the lowest HR of drug discontinuation (HR 0.57, 95% CI 0.34-0.93, p = 0.02). The strongest predictor of drug interruption was female sex (HR 2.02, 95% CI 1.28-3.20, p = 0.002). The disease duration was inversely correlated with drug discontinuation (HR 0.96, 95% CI 0.93-0.99, p = 0.02). The average daily dose of prednisone significantly decreased from baseline: 5.6 +/- 2.5 to 4.7 +/- 1.9 at 1 year (p = 0.01) to 4.0 +/- 1.8 at 4 years (p = 0.001). Additionally, compared to baseline (49.6%), a significant reduction of patients taking glucocorticoids was detected at 2 years (36.5%, p < 0.05), 3 years (29.9%, p < 0.01), and 4 years (22.6%, p < 0.01). CONCLUSION: In real-world settings, TNF inhibitors showed a high rate of drug survival at 4 years. Further, the need for glucocorticoids for controlling active PsA was lowered with time. PMID- 26980584 TI - A Family History of Psoriasis in a First-degree Relative in Children with JIA: to Include or Exclude? AB - OBJECTIVE: To determine the consequences of disregarding first-degree relatives with psoriasis (FRP) as a classification criterion in juvenile idiopathic arthritis (JIA). METHODS: Criteria were examined in children from a prospective cohort with unclassified and psoriatic JIA. RESULTS: FRP was the most common reason children were unclassified (57/85, 67%); all 57 children could be classified if FRP were disregarded as an exclusion criterion. FRP was a necessary inclusion criterion to classify 11/77 (14.3%) children with psoriatic JIA. CONCLUSION: Eliminating FRP as an exclusion criterion, but keeping it as an inclusion criterion in psoriatic JIA simplifies classification, though it is unclear whether the resulting classification would be better. PMID- 26980585 TI - Nanoparticles for brain-specific drug and genetic material delivery, imaging and diagnosis. AB - The poor access of therapeutic drugs and genetic material into the central nervous system due to the presence of the blood-brain barrier often limits the development of effective noninvasive treatments and diagnoses of neurological disorders. Moreover, the delivery of genetic material into neuronal cells remains a challenge because of the intrinsic difficulty in transfecting this cell type. Nanotechnology has arisen as a promising tool to provide solutions for this problem. This review will cover the different approaches that have been developed to deliver drugs and genetic material efficiently to the central nervous system as well as the main nanomaterials used to image the central nervous system and diagnose its disorders. PMID- 26980587 TI - Non-affective psychosis in refugees. PMID- 26980586 TI - Impact of cadmium on the ecdysteroids production in Gammarus fossarum. AB - Gammarus fossarum is an important test organism which is currently used as a bio indicator as well as in ecotoxicological tests. Nevertheless, data on ecdysteroids in endocrine toxicity test are not yet available for these species, despite its crucial role in molting and reproduction. In the present paper, ecdysteroids concentrations were studied during the molt cycle (in females) and embryonic development in G. fossarum (Crustacea, Amphipoda) in order to propose an ecdysteroids toxicity test. Ecdysteroids levels in G. fossarum showed a single peak during premolt at stage Dl-D2. In embryos, ecdysteroids levels progressively increased over stages 3 and 4, with peak levels at stage 4. A Cadmium toxicity test was proposed to examine if the molting and embryogenesis disturbances previously observed after cadmium exposure (Geffard et al. 2010) could be attributed to changes in ecdysteroids titers. Exposure to the different cadmium concentrations (3; 9; 300; 900 ug/l) increased ecdysteroids secretion by Y-organs in vitro, but it had no significant effect on exposed embryos (in vivo). Based on previous findings, we are led to conclude that the molting impairments in cadmium exposed females of G. fossarum is connected to the changes in ecdysteroids concentrations. PMID- 26980588 TI - Coupling of growth to nutritional status: The role of novel periphery-to-brain signaling by the CCHa2 peptide in Drosophila melanogaster. AB - The coupling of growth to nutritional status is an important adaptive response of living organisms to their environment. For this ability, animals have evolved various strategies, including endocrine systems that respond to changing nutritional conditions. In animals, nutritional information is mostly perceived by peripheral organs, such as the digestive tract and adipose tissues, and is subsequently transmitted to other peripheral organs or the brain, which integrates the incoming signals and orchestrates physiological and behavioral responses. In Drosophila melanogaster, adipose tissue, known as the fat body, functions as an endocrine organ that communicates with the brain. This fat body brain axis coordinates growth with nutritional status by regulating the secretion of Drosophila insulin-like peptides (Dilps) from the brain. However, the molecular nature of the fat body-brain axis remains to be elucidated. We recently demonstrated that a small peptide, CCHamide-2 (CCHa2), expressed in the fat body and gut, directly stimulates its receptor (CCHa2-R) in the brain, leading to Dilp production. Notably, the expression of CCHa2 is sensitive to the presence of nutrients, particularly sugars. Our results, together with the results of previous studies, show that signaling between peripheral organs and the brain is a conserved strategy that couples nutritional availability to organismal physiology. PMID- 26980589 TI - Approaches to the Assessment of Children in the Context of Disasters. AB - Children exposed to disasters are a vulnerable population, making the assessment of children post-disaster an important issue. Utilizing a Multiple Gating Stepped Care framework, we highlight recent literature related to post-disaster assessment and intervention for children. In particular, we focus on screening, clinical evaluation, and feedback-informed service delivery. Screening allows large populations of children to be assessed at a relatively low cost. Children identified by screening as being at risk may then be assessed through more in depth clinical evaluations, in order to assess clinical symptoms, strengths, and stressors, and to make determinations about appropriate interventions. Continued assessment during therapy provides important feedback for the delivery of appropriate care. New formats for assessment, as well as issues related to identifying sources for assessment, are discussed. Recommendations for future directions are provided. PMID- 26980590 TI - The inflammatory markers in polycystic ovary syndrome: association with obesity and IVF outcomes. AB - OBJECTIVE: To investigate the inflammatory markers in polycystic ovary syndrome (PCOS) and associations of these markers with obesity and in vitro fertilization (IVF) outcomes. METHODS: A total of 292 women underwent IVF procedure either with PCOS (n = 146) or without PCOS (n = 146, age, and body mass index (BMI) matched controls) were included in the study. All patients were classified according to BMI levels (normal weight: NW, BMI <25 kg/m(2) and obese: OB, BMI >=25 kg/m(2)). The inflammatory markers were leukocyte count, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), mean platelet volume (MPV). RESULTS: BMI of PCOS was positively correlated with leukocyte, neutrophil, lymphocyte and MPV (p < 0.05), but negatively correlated with NLR and PLR (p < 0.05). Both NLR and PLR increased significantly in PCOS (p < 0.001). PLR increased significantly in NW PCOS compared the NW-controls and OB-PCOS. MPV values increased only in OB-PCOS subjects. The logistic regression analyzes showed that MPV was the independent variable in PCOS to effect CPR (p = 0.000; OR 0.1; CI 0.06-0.2). CONCLUSIONS: NLR and PLR were significantly increased in all PCOS subjects compared to the BMI matched controls. Despite PLR being decreased by adiposity, PLR increased in NW PCOS. These results are supporting the hypothesis that PCOS is a chronic inflammatory process independent of obesity. MPV levels were independently associated with CPR in PCOS. Further prospective studies concerning inflammation and IVF outcomes of PCOS are needed. PMID- 26980592 TI - Hermaphroditism in Leonardo da Vinci's Drawing "Angel in the Flesh" (1513-1515). PMID- 26980591 TI - Meta-analysis of radiofrequency ablation for treating the local recurrence of thyroid cancers. AB - OBJECTIVES: Our aim was to evaluate the efficacy of ultrasound-guided radiofrequency ablation (RFA) for localized recurrent thyroid cancers. METHODS: We did a systematic review and meta-analysis of the scientific literature by searching the PubMed, Embase, Web of Science,Scopus and the Cochrane Library up to November 26, 2015. We assessed the pooled standard mean difference (SMD) of nodule volume, largest diameter and serum thyroglobulin (Tg) level by comparing pre-RFA with post-RFA using fixed or random-effects model. The Newcastle-Ottawa Scale was used to evaluate the methodological quality of the included studies, risk of bias in the selective populations, comparability of groups and exposure. RESULTS: We finally identified nine articles including 189 patients (male: 54 and female: 135) with 255 tumor lesions, who underwent ultrasound (US)-guided RFA beyond the mean 6 months of follow-up. The results showed that tumor volume (SWD: 0.77, 95 % CI: 0.57-0.97, I (2) = 25.9 %, p = 0.231), largest diameter (SWD: 1.56, 95 % CI: 0.94-2.17, I (2) = 82.6 %, p < 0.001) and Tg level (SWD: 0.52, 95 % CI: 0.30-0.73, I (2) = 0 %, p = 0.493) were decreased and no significant publication bias was detectable. CONCLUSIONS: The pooled data indicated that the prognosis improved for patients with localized recurrent thyroid cancers and RFA is a promising treatment for these patients with infeasible surgery. PMID- 26980594 TI - Opportunities to use drugs and the transition to drug use among adolescents from Caracas, Venezuela. AB - Few studies have examined exposure to drug use and the lag between exposure and use. This paper estimates prevalence of opportunity to use a substance, for use, and for use given an opportunity to use among a sample of Venezuelan adolescents. Several covariates on the opportunity to use and the transition to use are also examined. Findings show that lifetime prevalence of substance use among Venezuelan adolescents increases dramatically and more closely resembles rates among US and European samples when having had an opportunity to use was taken into account. A majority of youth who transitioned to use did so the same year exposure occurred, and females had a shorter time difference compared to males. Covariates primarily predicted exposure rather than having used after controlling for exposure, and their effects varied by substance. Implications for prevention efforts are discussed. PMID- 26980595 TI - Pseudomonas aeruginosa outcompetes other bacteria in the manifestation and maintenance of a biofilm in polyvinylchloride tubing as used in dental devices. AB - In a PVC tube as a model system for dental devices, Pseudomonas aeruginosa outcompetes Staphylococcus aureus and Klebsiella pneumoniae for the biofilm formation. P. aeruginosa has advantage over the other strains due to higher tolerance for low-nutrient situations or direct killing by the production of soluble factors like pyocyanin. PMID- 26980593 TI - Connecting two proteins using a fusion alpha helix stabilized by a chemical cross linker. AB - Building a sophisticated protein nano-assembly requires a method for linking protein components in a predictable and stable structure. Most of the cross linkers available have flexible spacers. Because of this, the linked hybrids have significant structural flexibility and the relative structure between their two components is largely unpredictable. Here we describe a method of connecting two proteins via a 'fusion alpha helix' formed by joining two pre-existing helices into a single extended helix. Because simple ligation of two helices does not guarantee the formation of a continuous helix, we used EY-CBS, a synthetic cross linker that has been shown to react selectively with cysteines in alpha-helices, to stabilize the connecting helix. Formation and stabilization of the fusion helix was confirmed by determining the crystal structures of the fusion proteins with and without bound EY-CBS. Our method should be widely applicable for linking protein building blocks to generate predictable structures. PMID- 26980596 TI - Is delayed surgery related to worse outcomes in native left-sided endocarditis? PMID- 26980597 TI - Complete carotid and coronary revascularization in brain malperfusion. AB - A 54-year-old man presented with unstable angina and stroke with right hemiplegia and aphasia due to left main coronary plus 3-vessel disease, severe stenosis of bilateral internal carotid, proximal left common carotid, and proximal left subclavian arteries. Simultaneous complete revascularization was undertaken with the use of conventional cardiopulmonary bypass and moderate hypothermia (25C). The left internal mammary artery and two saphenous vein grafts were used for coronary artery bypass, and brain revascularization consisted of a left aorta-to common carotid Dacron graft and bilateral carotid endarterectomy. Recovery was good. PMID- 26980598 TI - Neoantigen Load, Antigen Presentation Machinery, and Immune Signatures Determine Prognosis in Clear Cell Renal Cell Carcinoma. AB - Tumors commonly harbor multiple genetic alterations, some of which initiate tumorigenesis. Among these, some tumor-specific somatic mutations resulting in mutated protein have the potential to induce antitumor immune responses. To examine the relevance of the latter to immune responses in the tumor and to patient outcomes, we used datasets of whole-exome and RNA sequencing from 97 clear cell renal cell carcinoma (ccRCC) patients to identify neoepitopes predicted to be presented by each patient's autologous HLA molecules. We found that the number of nonsilent or missense mutations did not correlate with patient prognosis. However, combining the number of HLA-restricted neoepitopes with the cell surface expression of HLA or beta2-microglobulin(beta2M) revealed that an A neo(hi)/HLA-A(hi) or ABC-neo(hi)/beta2M(hi) phenotype correlated with better clinical outcomes. Higher expression of immune-related genes from CD8 T cells and their effector molecules [CD8A, perforin (PRF1) and granzyme A (GZMA)], however, did not correlate with prognosis. This may have been due to the observed correlation of these genes with the expression of other genes that were associated with immunosuppression in the tumor microenvironment (CTLA-4, PD-1, LAG-3, PD-L1, PD-L2, IDO1, and IL10). This suggested that abundant neoepitopes associated with greater antitumor effector immune responses were counterbalanced by a strongly immunosuppressive microenvironment. Therefore, immunosuppressive molecules should be considered high-priority targets for modulating immune responses in patients with ccRCC. Blockade of these molecular pathways could be combined with immunotherapies targeting neoantigens to achieve synergistic antitumor activity. Cancer Immunol Res; 4(5); 463-71. (c)2016 AACR. PMID- 26980600 TI - Identification of independent risk factors for flap failure: A retrospective analysis of 1530 free flaps for breast, head and neck and extremity reconstruction. AB - Reconstructive microsurgery is a powerful method of treating various complex defects. However, flap loss remains a possibility, leading to additional surgery, hospitalisation and costs. Consequently, it is important to know which factors lead to an increased risk of flap failure, so that measures can be undertaken to reduce this risk. Therefore, we analysed our results over a 20-year period to identify risk factors for flap failure after breast, head and neck and extremity reconstruction. The medical files of all patients treated between 1992 and 2012 were reviewed. Patient characteristics, surgical data and post-operative complications were scored, and independent risk factors for flap loss were identified. Reconstruction with a total of 1530 free flaps was performed in 1247 patients. Partial and total flap loss occurred in 5.5% and 4.4% of all free flaps, respectively. In all flaps, signs of compromised flap circulation were a risk factor for flap failure. More specifically, the risk factors for flap failure in breast reconstruction were previous radiotherapy, venous anastomosis revision, gluteal artery perforator (GAP) flap choice and post-operative bleeding. In head and neck reconstruction, pulmonary co-morbidity and anastomosis to the lingual vein or superficial temporal artery were risk factors, whereas a radial forearm flap reduced the risk. In extremity reconstruction, diabetes, prolonged anaesthesia time and post-operative wound infection were risk factors. Independent pre-, intra- and post-operative risk factors for flap failure after microvascular breast, head and neck and extremity reconstruction were identified. These results may be used to improve patient counselling and to adjust treatment algorithms to further reduce the chance of flap failure. PMID- 26980602 TI - Erratum to: Annual changes in radiographic indices of the spine in cerebral palsy patients. PMID- 26980601 TI - Diversity of arsenite oxidase gene and arsenotrophic bacteria in arsenic affected Bangladesh soils. AB - Arsenic (As) contaminated soils are enriched with arsenotrophic bacteria. The present study analyzes the microbiome and arsenotrophic genes-from As affected soil samples of Bhanga, Charvadrason and Sadarpur of Faridpur district in Bangladesh in summer (SFDSL1, 2, 3) and in winter (WFDSL1, 2, 3). Total As content of the soils was within the range of 3.24-17.8 mg/kg as per atomic absorption spectroscopy. The aioA gene, conferring arsenite [As (III)] oxidation, was retrieved from the soil sample, WFDSL-2, reported with As concentration of 4.9 mg/kg. Phylogenetic analysis revealed that the aioA genes of soil WFDSL-2 were distributed among four major phylogenetic lineages comprised of alpha, beta, gamma Proteobacteria and Archaea with a dominance of beta Proteobacteria (56.67 %). An attempt to enrich As (III) metabolizing bacteria resulted 53 isolates. ARDRA (amplified ribosomal DNA restriction analysis) followed by 16S rRNA gene sequencing of the 53 soil isolates revealed that they belong to six genera; Pseudomonas spp., Bacillus spp., Brevibacillus spp., Delftia spp., Wohlfahrtiimonas spp. and Dietzia spp. From five different genera, isolates Delftia sp. A2i, Pseudomonas sp. A3i, W. chitiniclastica H3f, Dietzia sp. H2f, Bacillus sp. H2k contained arsB gene and showed arsenite tolerance up-to 27 mM. Phenotypic As (III) oxidation potential was also confirmed with the isolates of each genus and isolate Brevibacillus sp. A1a showed significant As (III) transforming potential of 0.2425 mM per hour. The genetic information of bacterial arsenotrophy and arsenite oxidation added scientific information about the possible bioremediation potential of the soil isolates in Bangladesh. PMID- 26980599 TI - Expression of the MHC Class II Pathway in Triple-Negative Breast Cancer Tumor Cells Is Associated with a Good Prognosis and Infiltrating Lymphocytes. AB - Triple-negative breast cancer (TNBC) is a subtype with heterogeneous patient outcomes. Approximately 40% of patients experience rapid relapse, while the remaining patients have long-term disease-free survival. To determine if there are molecular differences between primary tumors that predict prognosis, we performed RNA-seq on 47 macrodissected tumors from newly diagnosed patients with TNBC (n = 47; 22 relapse, 25 no relapse; follow-up median, 8 years; range, 2-11 years). We discovered that expression of the MHC class II (MHC II) antigen presentation pathway in tumor tissue was the most significant pathway associated with progression-free survival (HR, 0.36; log-rank P = 0.0098). The association between MHC II pathway expression and good prognosis was confirmed in a public gene expression database of 199 TNBC cases (HR, 0.28; log-rank P = 4.5 * 10(-8)). Further analysis of immunohistochemistry, laser-capture microdissected tumors, and TNBC cell lines demonstrated that tumor cells, in addition to immune cells, aberrantly express the MHC II pathway. MHC II pathway expression was also associated with B-cell and T-cell infiltration in the tumor. Together, these data support the model that aberrant expression of the MHC II pathway in TNBC tumor cells may trigger an antitumor immune response that reduces the rate of relapse and enhances progression-free survival. Cancer Immunol Res; 4(5); 390-9. (c)2016 AACR. PMID- 26980603 TI - Correlation between severity of adolescent idiopathic scoliosis and pulmonary artery systolic pressure: a study of 338 patients. AB - PURPOSE: Study of patients with adolescent idiopathic scoliosis. OBJECTIVE: To examine the correlation between pulmonary arterial pressure and coronal Cobb angle of idiopathic scoliosis. METHODS: A total of 338 patients (82.8 % female) with idiopathic scoliosis (average age 15.6 years; range 14-20 years) were included. Preoperatively, the coronal Cobb angle of curvature and the apex location and direction were determined from radiographic records. Tricuspid regurgitation velocity (TRV) and inferior vena cava diameter were also measured using Doppler echocardiography. Pulmonary arterial systolic pressure (sPAP) was calculated from the TRV according to the modified Bernoulli equation and correlations between sPAP and the features of scoliosis were identified by statistical analysis. RESULTS: Among the 338 patients, there were 305 thoracic curves, 276 (90.5 %) of which were right curves, and 265 thoracolumbar/lumbar curves. sPAP varied from 5.0 to 37.6 mmHg. Pulmonary hypertension could not be excluded in the case of one patient. A mild correlation (Spearman test, correlation coefficient = 0.187, P = 0.001) between sPAP and coronal Cobb angle of the main thoracic (MT) curves was identified. Correlations between sPAP and the degree of other curves were not significant. Patients with sPAP >20 mmHg also had larger thoracic curve angles (mean MT 42.16 degrees vs. 52.45 degrees ; U test, P = 0.002). There were no differences in sPAP levels between patients with right and left thoracic curves. CONCLUSIONS: A mild positive correlation was identified between sPAP and the coronal Cobb angle of the MT curves. There was no relationship between sPAP and the direction of the curvature. PMID- 26980604 TI - Characterizing the genetic diversity of the monkey malaria parasite Plasmodium cynomolgi. AB - Plasmodium cynomolgi is a malaria parasite that typically infects Asian macaque monkeys, and humans on rare occasions. P. cynomolgi serves as a model system for the human malaria parasite Plasmodium vivax, with which it shares such important biological characteristics as formation of a dormant liver stage and a preference to invade reticulocytes. While genomes of three P. cynomolgi strains have been sequenced, genetic diversity of P. cynomolgi has not been widely investigated. To address this we developed the first panel of P. cynomolgi microsatellite markers to genotype eleven P. cynomolgi laboratory strains and 18 field isolates from Sarawak, Malaysian Borneo. We found diverse genotypes among most of the laboratory strains, though two nominally different strains were found to be genetically identical. We also investigated sequence polymorphism in two erythrocyte invasion gene families, the reticulocyte binding protein and Duffy binding protein genes, in these strains. We also observed copy number variation in rbp genes. PMID- 26980605 TI - Whole genome sequencing reveals genetic heterogeneity of G3P[8] rotaviruses circulating in Italy. AB - After a sporadic detection in 1990s, G3P[8] rotaviruses emerged as a predominant genotype during recent years in many areas worldwide, including parts of Italy. The present study describes the molecular epidemiology and evolution of G3P[8] rotaviruses detected in Italian children with gastroenteritis during two survey periods (2004-2005 and 2008-2013). Whole genome of selected G3P[8] strains was determined and antigenic differences between these strains and rotavirus vaccine strains were analyzed. Among 819 (271 in 2004-2005 and 548 in 2008-2013) rotaviruses genotyped during the survey periods, the number of G3P[8] rotavirus markedly varied over the years (0/83 in 2004, 30/188 in 2005 and 0/96 in 2008, 6/88 in 2009, 4/97 in 2010, 0/83 in 2011, 9/82 in 2012, 56/102 cases in 2013). The genotypes of the 11 gene segments of 15 selected strains were assigned to G3 P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1; thus all strains belonged to the Wa genogroup. Phylogenetic analysis of the Italian G3P[8] strains showed a peculiar picture of segregation with a 2012 lineage for VP1-VP3, NSP1, NSP2, NSP4 and NSP5 genes and a 2013 lineage for VP6, NSP1 and NSP3 genes, with a 1.3-20.2% nucleotide difference from the oldest Italian G3P[8] strains. The genetic variability of the Italian G3P[8] observed in comparison with sequences of rotaviruses available in GenBank suggested a process of selection acting on a global scale, rather than the emergence of local strains, as several lineages were already circulating globally. Compared with the vaccine strains, the Italian G3P[8] rotaviruses segregated in different lineages (5-5.3% and 7.2-11.4% nucleotide differences in the VP7 and VP4, respectively) with some mismatches in the putative neutralizing epitopes of VP7 and VP4 antigens. The accumulation of point mutations and amino acid differences between vaccine strains and currently circulating rotaviruses might generate, over the years, vaccine-resistant variants. PMID- 26980606 TI - Mitochondrial genomes of Heterakis gallinae and Heterakis beramporia support that they belong to the infraorder Ascaridomorpha. AB - Heterakis gallinae and Heterakis beramporia are the most prevalent nematode infecting native chicken breed, causing major economic losses. In the present study, the complete mitochondrial genomes (mt) of H. gallinae and H. beramporia were amplified by long-PCR and then sequenced. The complete mt genomes of H. gallinae and H. beramporia were 13,973bp and 14,012bp in size, respectively. Both mt genomes contain 12 protein-coding genes, 22 transfer RNA genes and 2 ribosomal RNA genes. All genes are transcribed in the same direction and the gene arrangement is identical to Ascaridia spp. Phylogenetic analysis based on the 12 protein-coding genes revealed that the family Heterakidae (represented by H. gallinae and H. beramporia) was more closely related to the infraorder Ascaridomorpha than it was to the infraorder Oxyuridomorpha. The present study determined the complete mt genome sequences for two Heterakis species, providing useful markers for studying the systematics, population genetics, and molecular epidemiology of these Heterakis parasites. PMID- 26980607 TI - Effects of Epoetin Alfa Titration Practices, Implemented After Changes to Product Labeling, on Hemoglobin Levels, Transfusion Use, and Hospitalization Rates. AB - BACKGROUND: Little is known about epoetin alfa (EPO) dosing at dialysis centers after implementation of the US Medicare prospective payment system and revision of the EPO label in 2011. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Approximately 412,000 adult hemodialysis patients with Medicare Parts A and B as primary payer in 2009 to 2012 to describe EPO dosing and hemoglobin patterns; of these, about 70,000 patients clustered in about 1,300 dialysis facilities to evaluate facility-level EPO titration practices and patient-level outcomes in 2012. PREDICTOR: Facility EPO titration practices when hemoglobin levels were <10 and >11g/dL (grouped treatment variable) determined from monthly EPO dosing and hemoglobin level patterns. OUTCOMES: Patient mean hemoglobin levels, red blood cell transfusion rates, and all-cause and cause specific hospitalization rates using a facility-based analysis. MEASUREMENTS: Monthly EPO dose and hemoglobin level, red blood cell transfusion rates, and all cause and cause-specific hospitalization rates. RESULTS: Monthly EPO doses declined across all hemoglobin levels, with the greatest decline in patients with hemoglobin levels < 10g/dL (July-October 2011). In 2012, nine distinct facility titration practices were identified. Across groups, mean hemoglobin levels differed slightly (10.5-10.8g/dL) but within-patient hemoglobin standard deviations were similar (~0.68g/dL). Patients at facilities implementing greater dose reductions and smaller dose escalations had lower hemoglobin levels and higher transfusion rates. In contrast, patients at facilities that implemented greater dose escalations (and large or small dose reductions) had higher hemoglobin levels and lower transfusion rates. There were no clinically meaningful differences in all-cause or cause-specific hospitalization events across groups. LIMITATIONS: Possibly incomplete claims data; excluded small facilities and those without consistent titration patterns; hemoglobin levels reported monthly; inferred facility practice from observed dosing. CONCLUSIONS: Following prospective payment system implementation and labeling revisions, EPO doses declined significantly. Under the new label, facility EPO titration practices were associated with mean hemoglobin levels (but not standard deviations) and transfusion use, but not hospitalization rates. PMID- 26980608 TI - 7-Chlorofolipastatin, an inhibitor of sterol O-acyltransferase, produced by marine-derived Aspergillus ungui NKH-007. AB - A new depsidone, named 7-chlorofolipastatin, and five known structurally related depsidones were isolated from the culture broth of the marine-derived fungus Aspergillus ungui NKM-007 by solvent extraction and HPLC using an octadecylsilyl column. The structure of 7-chlorofolipastatin was elucidated by various spectroscopic data including 1D and 2D NMR spectroscopy. 7-Chlorofolipastatin inhibited sterol O-acyltransferase (SOAT) 1 and 2 isozymes in cell-based and enzyme assays using SOAT1- and SOAT2-expressing Chinese hamster ovary (CHO) cells. PMID- 26980609 TI - Comparative analysis of the small RNA transcriptomes of miiuy croaker revealed microRNA-mediated regulation of TLR signaling pathway response to Vibrio anguillarum infection. AB - MicroRNAs (miRNAs) are an abundant class of endogenous noncoding small RNAs (sRNAs) that are partially complementary to their target messenger RNA (mRNA), which post-transcriptionally regulate various biological processes by repressing mRNA translation or inducing mRNA degradation. MiRNAs have been demonstrated to play crucial roles in the host response to infection by diverse pathogens. As an important bacterial pathogen, Vibrio anguillarum has been caused great economic losses in miiuy croaker aquaculture. To identify immune-related miRNAs of miiuy croaker in response to V. anguillarum infection, we constructed two sRNA libraries with or without bacterial infection. High-throughput deep sequencing and subsequent bioinformatic analysis identified 241 conserved and 137 novel miRNA precursors in miiuy croaker based on its whole genome sequences, encoding 293 and 124 mature miRNAs, respectively. Then we compared the expression patterns of miRNAs in the two libraries. There were significant differences in the expression of 12 miRNAs between the infection group (IG) and control group (CG). Further, the expressions of six miRNAs were validated by real-time quantitative PCR. The target gene prediction and function analysis were conducted for the 12 differential miRNAs. This analysis revealed that these miRNAs participated in the regulation multiple immune-related signaling pathways. Transcription factors in TLR signaling, such as AP-1, IRF5, NF-kappaB and IRF3, were activated by these miRNAs via post-transcriptionally regulating the expression of TLRs and TLR associated signaling proteins, inducing effective host immune response to eradicate infectious pathogens. This is the first study of the identification and characterization of miiuy croaker miRNAs in response to V. anguillarum infection. The comprehensive analysis of the expression of miRNAs and the target gene and function prediction of differently expressed miRNAs may help to understand the regulatory mechanisms of miRNA in fish during the interaction between host and bacterial pathogens. PMID- 26980610 TI - Molecular characterization and expression pattern of tumor suppressor protein p53 in mandarin fish, Siniperca chuatsi following virus challenge. AB - In recent years, the tumor suppressor protein p53, which is crucial for cellular defense against tumor development, has also been implicated in host antiviral defense. In the present study, a 1555 bp full-length cDNA of p53 from mandarin fish (Siniperca chuatsi) (Sc-p53) was cloned and characterized. Quantitative real time PCR assays revealed that Sc-p53 was expressed in all tissues examined, and it was most abundant in the gill and kidney. Recombinant Sc-p53 fused with a His.Tag was expressed in Escherichia coli BL21 (DE3) cells and a rabbit polyclonal antibody was raised against recombinant Sc-p53. In addition, the regulation of Sc-p53 gene expression after experimental viral infection was determined and characterized. The mRNA and protein expression of Sc-p53 were significantly up-regulated in the Chinese perch brain (CPB) cell line and mandarin fish after infection with infectious kidney and spleen necrosis virus (ISKNV). The results showed a biphasic expression pattern of Sc-p53 protein in CPB. However, a different expression pattern of Sc-p53 in response to S. chuatsi rhabdovirus (SCRV) infection was found. The mRNA expression of Sc-p53 was significantly up-regulated in CPB at 6 h and spleen of mandarin fish at 24 h post infection. The protein expression of Sc-p53 was significantly up-regulated in CPB at 1 h, remained elevated at 4 h, and then decreased to control level at 8 h post infection by SCRV. All of these data suggested that Sc-p53 plays a critical role in immune defense and antiviral responses. PMID- 26980611 TI - Identification, expression, and innate immune responses of two insulin-like peptide genes in the razor clam Sinonovacula constricta. AB - Insulin-like peptide (ILP) has emerged as a cell regulatory factor with multiple functions in vertebrates and invertebrates. In the present study, we identified and characterized two ILP genes, ILP1 and ILP2, in the razor clam Sinonovacula constricta. Both ILPs have a signal peptide and a mature domain consisting of six strictly conserved cysteines. The tertiary structure is divided into three main alpha-helices with a C-domain loop that separates helix 1 from helix 2. Both of ILPs were found to be regulated according to tissue type and developmental stage. After challenge with Vibrio anguillarum, Vibrio parahaemolyticus and Micrococcus lysodeikticus, the expression of two ILP genes was significantly up-regulated in the liver, hemocytes and mantle tissues, suggesting that the ILPs may play roles in the innate immunity in the razor clam Sinonovacula constricta. PMID- 26980612 TI - The Influence of Host Plant Volatiles on the Attraction of Longhorn Beetles to Pheromones. AB - Host plant volatiles have been shown to strongly synergize the attraction of some longhorn beetle species (Coleoptera: Cerambycidae) to their pheromones. This synergism is well documented among species that infest conifers, but less so for angiosperm-infesting species. To explore the extent of this phenomenon in the Cerambycidae, we first tested the responses of a cerambycid community to a generic pheromone blend in the presence or absence of chipped material from host plants as a source of host volatiles. In the second phase, blends of oak and conifer volatiles were reconstructed, and tested at low, medium, and high release rates with the pheromone blend. For conifer-infesting species in the subfamilies Spondylidinae and Lamiinae, conifer volatiles released at the high rate synergized attraction of some species to the pheromone blend. When comparing high release rate conifer blend with high-release rate alpha-pinene as a single component, species responses varied, with Asemum nitidum LeConte being most attracted to pheromones plus alpha-pinene, whereas Neospondylis upiformis (Mannerheim) were most attracted to pheromones plus conifer blend and ethanol. For oak-infesting species in the subfamily Cerambycinae, with the exception of Phymatodes grandis Casey, which were most attracted to pheromones plus ethanol, neither synthetic oak blend nor ethanol increased attraction to pheromones. The results indicate that the responses to combinations of pheromones with host plant volatiles varied from synergistic to antagonistic, depending on beetle species. Release rates of host plant volatiles also were important, with some high release rates being antagonistic for oak-infesting species, but acting synergistically for conifer-infesting species. PMID- 26980613 TI - Plasticity-Related Gene 1 Affects Mouse Barrel Cortex Function via Strengthening of Glutamatergic Thalamocortical Transmission. AB - Plasticity-related gene-1 (PRG-1) is a brain-specific protein that modulates glutamatergic synaptic transmission. Here we investigated the functional role of PRG-1 in adolescent and adult mouse barrel cortex both in vitro and in vivo. Compared with wild-type (WT) animals, PRG-1-deficient (KO) mice showed specific behavioral deficits in tests assessing sensorimotor integration and whisker-based sensory discrimination as shown in the beam balance/walking test and sandpaper tactile discrimination test, respectively. At P25-31, spontaneous network activity in the barrel cortex in vivo was higher in KO mice compared with WT littermates, but not at P16-19. At P16-19, sensory evoked cortical responses in vivo elicited by single whisker stimulation were comparable in KO and WT mice. In contrast, at P25-31 evoked responses were smaller in amplitude and longer in duration in WT animals, whereas KO mice revealed no such developmental changes. In thalamocortical slices from KO mice, spontaneous activity was increased already at P16-19, and glutamatergic thalamocortical inputs to Layer 4 spiny stellate neurons were potentiated. We conclude that genetic ablation of PRG-1 modulates already at P16-19 spontaneous and evoked excitability of the barrel cortex, including enhancement of thalamocortical glutamatergic inputs to Layer 4, which distorts sensory processing in adulthood. PMID- 26980616 TI - Time for doctors to practise what they preach and preach what they practise. PMID- 26980615 TI - A Model of Representational Spaces in Human Cortex. AB - Current models of the functional architecture of human cortex emphasize areas that capture coarse-scale features of cortical topography but provide no account for population responses that encode information in fine-scale patterns of activity. Here, we present a linear model of shared representational spaces in human cortex that captures fine-scale distinctions among population responses with response-tuning basis functions that are common across brains and models cortical patterns of neural responses with individual-specific topographic basis functions. We derive a common model space for the whole cortex using a new algorithm, searchlight hyperalignment, and complex, dynamic stimuli that provide a broad sampling of visual, auditory, and social percepts. The model aligns representations across brains in occipital, temporal, parietal, and prefrontal cortices, as shown by between-subject multivariate pattern classification and intersubject correlation of representational geometry, indicating that structural principles for shared neural representations apply across widely divergent domains of information. The model provides a rigorous account for individual variability of well-known coarse-scale topographies, such as retinotopy and category selectivity, and goes further to account for fine-scale patterns that are multiplexed with coarse-scale topographies and carry finer distinctions. PMID- 26980617 TI - Accupedo pedometer: daily walking step counter. PMID- 26980614 TI - Shaping Early Reorganization of Neural Networks Promotes Motor Function after Stroke. AB - Neural plasticity is a major factor driving cortical reorganization after stroke. We here tested whether repetitively enhancing motor cortex plasticity by means of intermittent theta-burst stimulation (iTBS) prior to physiotherapy might promote recovery of function early after stroke. Functional magnetic resonance imaging (fMRI) was used to elucidate underlying neural mechanisms. Twenty-six hospitalized, first-ever stroke patients (time since stroke: 1-16 days) with hand motor deficits were enrolled in a sham-controlled design and pseudo-randomized into 2 groups. iTBS was administered prior to physiotherapy on 5 consecutive days either over ipsilesional primary motor cortex (M1-stimulation group) or parieto occipital vertex (control-stimulation group). Hand motor function, cortical excitability, and resting-state fMRI were assessed 1 day prior to the first stimulation and 1 day after the last stimulation. Recovery of grip strength was significantly stronger in the M1-stimulation compared to the control-stimulation group. Higher levels of motor network connectivity were associated with better motor outcome. Consistently, control-stimulated patients featured a decrease in intra- and interhemispheric connectivity of the motor network, which was absent in the M1-stimulation group. Hence, adding iTBS to prime physiotherapy in recovering stroke patients seems to interfere with motor network degradation, possibly reflecting alleviation of post-stroke diaschisis. PMID- 26980618 TI - Silicone ring tourniquet or pneumatic cuff tourniquet for total knee arthroplasty. AB - PURPOSE: The goal of the present study was to evaluate the potential advantages of a silicon ring tourniquet in comparison to the conventional pneumatic cuff tourniquet. The tested hypothesis was that the calculated blood loss will be decreased after use of the silicone ring tourniquet. METHODS: The study was monocentric and mixed retrospective and prospective evaluation of prospectively collected data. Inclusion criterion was implantation of a total knee arthroplasty. The retrospective control group involved 39 patients operated on with a pneumatic cuff tourniquet. The prospective study group involved 33 patients operated on with a silicone ring tourniquet. All patients were followed for three months. Primary criterion was the calculated blood loss (OSTHEO formula). Secondary criteria were pain on third post-op day, need for allogenic transfusion, haemoglobin drop, delay of discharge, and occurrence of complications. RESULTS: The mean calculated blood loss was 901 ml in the study group and 989 ml in the control group (NS). There was no significant difference in pain evaluation and haemoglobin drop between the two groups. There was a non significant decrease of allogeneic transfusion and length of stay in the study group. There was a significant decrease of complication rate in the study group, and especially for skin complications. CONCLUSIONS: The tested hypothesis was not confirmed: there was no significant change in the calculated blood loss. No bias was identified in complication analysis. The decreased rate of skin complication might be a positive influence of the silicone ring tourniquet. PMID- 26980619 TI - Attractive papers and accurate English. PMID- 26980620 TI - A method of treatment for nonunion after fractures using mesenchymal stromal cells loaded on collagen microspheres and incorporated into platelet-rich plasma clots. AB - PURPOSE: There is evidence showing that mesenchymal stromal cells (MSC) may constitute a potential therapeutic strategy to induce bone regeneration. In this work, we investigate the capacity of autologous bone marrow (BM) MSC loaded on collagen microspheres (CM) and included into autologous platelet-rich plasma (PRP) clots (MSC/CM/PRP) to induce bone formation in patients with nonunion lesions. METHODS: MSC were isolated from BM cells of patients with nonunion lesions. Phenotypical (marker expression) and functional studies (osteogenic differentiation) were performed. MSC were seeded on CM and included into autologous PRP clot (MSC/CM/PRP). The capacity of MSC/CM/PRP to induce bone formation was evaluated in three patients diagnosed with nonunion. RESULTS: MSC loaded on CM/PRP clots maintain their biological functions, in vitro. After three months, post-MSC transplantation, all patients showed evidence of osteogenesis at the site of nonunion. After one year, all patients showed a complete healing of the nonunion. CONCLUSIONS: Our results support the use of autologous MSC transplanted as MSC/CM/PRP for the treatment of nonunion fractures. Future studies incorporating a larger number of patients may confirm the results obtained in this work. PMID- 26980621 TI - Conversion from knee arthrodesis to arthroplasty: systematic review. AB - PURPOSE: Arthrodesis (AD) of the knee reduces pain and provides stability, but has severe functional and social limitations. There has been ample discussion on the value of a conversion of an AD to a total knee arthroplasty (TKA). The aim of this study was to perform a review and meta-analysis of the current literature on conversion of an AD to TKA and assess clinical outcome, complication rate, surgical technique and overall patient-related outcome measures. METHODS: PubMed, Embase, Web of Science, Cochrane, CENTRAL, CINAHL, Academic Search Premier, ScienceDirect and searching by hand for papers on conversion of AD of the knee to TKA. Two reviewers independently reviewed all titles and abstracts, and extracted the available data. Study eligibility criteria were: conversion of knee AD to TKA, five cases or more and non-oncology patients. Data consisted of study characteristics, patient demographics, clinical outcome and complications. Additionally, details on surgical technique were reviewed. RESULTS: Of the 866 unique references identified, six papers were included for further analyses, comprising a total of 123 knees with conversion of AD of the knee to TKA. Mean gain of knee flexion was 80 degrees and the mean HSS score improved with 20 points. A complicated postoperative course was found in 65 % of all cases. The most frequent complication was skin necrosis (25 %), followed by arthrofibrosis (13 %), infection (11 %) and revision (11 %). Major complications such as refusion, amputation and death occurred in less than 5 % of all cases. DISCUSSION: The majority of the papers consisted of small case series of moderate methodological quality, resulting in 123 included knees. Further series are necessary to draw definitive conclusions. CONCLUSIONS: This is the first systematic review and meta-analysis on conversion of a knee arthrodesis to TKA. Good clinical results can be expected after conversion, albeit at a high risk of postoperative complications. PMID- 26980622 TI - Assembly of 3-Sulfenylbenzofurans and 3-Sulfenylindoles by Palladium-Catalyzed Cascade Annulation/Arylthiolation Reaction. AB - A novel and efficient palladium-catalyzed cascade annulation/arylthiolation reaction has been developed to afford functionalized 3-sulfenylbenzofuran and 3 sulfenylindole derivatives in moderate to good yields from readily available 2 alkynylphenols and 2-alkynylamines in ionic liquids. This protocol provides a valuable synthetic tool for the assembly of a wide range of 3-sulfenylbenzofuran and 3-sulfenylindole derivatives with high atom- and step-economy and exceptional functional group tolerance. Moreover, the employment of ionic liquids under mild reaction conditions makes this transformation green and practical. Furthermore, this approach enriched current C-S bond formation chemistry, making a valuable and practical method in synthetic and medicinal chemistry. PMID- 26980624 TI - Contribution of Alcoholic and Nonalcoholic Fatty Liver Disease to the Burden of Liver-Related Morbidity and Mortality. AB - Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. NAFLD is associated with obesity and metabolic syndrome whereas ALD is associated with excessive alcohol consumption. Both diseases can progress to cirrhosis, hepatocellular carcinoma, and liver related death. A higher proportion of patients with NAFLD die from cardiovascular disorders than patients with ALD, whereas a higher proportion of patients with ALD die from liver disease. NAFLD and ALD each are associated with significant morbidity, impairment to health-related quality of life, and economic costs to society. PMID- 26980625 TI - The inflammatory inception of gallbladder cancer. AB - Gallbladder cancer is a lethal disease with notable geographical variations worldwide and a predilection towards women. Its main risk factor is prolonged exposure to gallstones, although bacterial infections and other inflammatory conditions are also associated. The recurrent cycles of gallbladder epithelium damage and repair enable a chronic inflammatory environment that promotes progressive morphological impairment through a metaplasia-dysplasia-carcinoma, along with cumulative genome instability. Inactivation of TP53, which is mutated in over 50% of GBC cases, seems to be the earliest and one of the most important carcinogenic pathways involved. Increased cell turnover and oxidative stress promote early alteration of TP53, cell cycle deregulation, apoptosis and replicative senescence. In this review, we will discuss evidence for the role of inflammation in gallbladder carcinogenesis obtained through epidemiological studies, genome-wide association studies, experimental carcinogenesis, morphogenetic studies and comparative studies with other inflammation-driven malignancies. The evidence strongly supports chronic, unresolved inflammation as the main carcinogenic mechanism of gallbladder cancer, regardless of the initial etiologic trigger. Given this central role of inflammation, evaluation of the potential for GBC prevention removing causes of inflammation or using anti inflammatory drugs in high-risk populations may be warranted. PMID- 26980623 TI - Sestrin2 protects the myocardium against radiation-induced damage. AB - The purpose of this study was to investigate the role of Sestrin2 in response to radiation-induced injury to the heart and on the cardiomyopathy development in the mouse. Mice with genetic deletion of the Sestrin2 (Sestrin2 knockout mice [Sestrin2 KO]) and treatment with irradiation (22 or 15 Gy) were used as independent approaches to determine the role of Sestrin2. Echocardiography (before and after isoproterenol challenge) and left ventricular (LV) catheterization were performed to evaluate changes in LV dimensions and function. Masson's trichrome was used to assess myocardial fibrosis. Immunohistochemistry and Western blot were used to detect the capillary density. After 22 or 15 Gy irradiation, the LV ejection fraction (EF) was impaired in wt mice at 1 week and 4 months after irradiation when compared with sham irradiation. Compared to wt mice, Sestrin2 KO mice had significant reduction in reduced LVEF at 1 week and 4 months after irradiation. A significant increase in LV end-diastolic pressure and myocardial fibrosis and a significant decrease in capillary density were observed in irradiation-wt mice, as well as in irradiation-Sestrin2 KO mice. Sestrin2 involved in the regulation of cardiomyopathy (such as myocardial fibrosis) after irradiation. Overexpression of Sestrin2 might be useful in limiting radiation induced myocardial injury. PMID- 26980626 TI - Biodiesel production from crude Jatropha oil catalyzed by non-commercial immobilized heterologous Rhizopus oryzae and Carica papaya lipases. AB - The aim of this study was to evaluate the feasibility of biodiesel production by transesterification of Jatropha oil with methanol, catalyzed by non-commercial sn 1,3-regioselective lipases. Using these lipases, fatty acid methyl esters (FAME) and monoacylglycerols are produced, avoiding the formation of glycerol as byproduct. Heterologous Rhizopus oryzae lipase (rROL) immobilized on different synthetic resins and Carica papaya lipase (rCPL) immobilized on Lewatit VP OC 1600 were tested. Reactions were performed at 30 degrees C, with seven stepwise methanol additions. For all biocatalysts, 51-65% FAME (theoretical maximum=67%, w/w) was obtained after 4h transesterification. Stability tests were performed in 8 or 10 successive 4h-batches, either with or without rehydration of the biocatalyst between each two consecutive batches. Activity loss was much faster when biocatalysts were rehydrated. For rROL, half-life times varied from 16 to 579h. rROL on Lewatit VPOC 1600 was more stable than for rCPL on the same support. PMID- 26980628 TI - Plastic cannula use in hemodialysis access. AB - INTRODUCTION: Successful cannulation of arteriovenous fistula (AVF) or arteriovenous graft (AVG) is an important concept in hemodialysis. Metal needles have been used for cannulation in dialysis for over 50 years. Plastic cannula for dialysis is currently being introduced into Australia. AIMS: To identify if the implementation of plastic cannula could decrease the amount of miscannulations and adverse events in AVFs at first cannulation. METHODS: Train all staff in the Barwon Health renal department in the new technique of plastic cannula insertion and implement a new protocol for cannulation of AVFs in the first two weeks of dialysis. RESULTS: The training process took 12 months longer than anticipated due to issues with 'expert' to 'novice' reservations from staff, but initial results are positive with the statewide key performance indicator of new patients using AVF at first dialysis rising from 50% in 2013 to 78% in 2015. Staff were significantly more successful cannulating with plastic cannula in patients who had AVF only (67% success) than those who had a CVC alternative (24% success). CONCLUSIONS: Plastic cannulas offer a new and innovative way to cannulate AVFs and with time, expertise and training can be utilized to provide a successful cannulation program for patients starting hemodialysis with AVFs. PMID- 26980627 TI - Wheat straw: An inefficient substrate for rapid natural lignocellulosic composting. AB - Composting is a promising method for the management of agricultural wastes. However, results for wheat straw composts with different carbon-to-nitrogen ratios revealed that wheat straw was only partly degraded after composting for 25days, with hemicellulose and cellulose content decreasing by 14% and 33%, respectively. No significant changes in community structure were found after composting according to 454-pyrosequencing. Bacterial communities were represented by Proteobacteria and Bacteroidetes throughout the composting process, including relatively high abundances of pathogenic microbes such as Pseudomonas and Flexibacter, suggesting that innocent treatment of the composts had not been achieved. Besides, the significant lignocellulose degrader Thermomyces was not the exclusively dominant fungus with relative abundance only accounting for 19% of fungal communities. These results indicated that comparing with maize straw, wheat straw was an inefficient substrate for rapid natural lignocellulose-based composting, which might be due to the recalcitrance of wheat straw. PMID- 26980630 TI - Dynamics of flexible active Brownian dumbbells in the absence and the presence of shear flow. AB - The dynamical properties of a flexible dumbbell composed of active Brownian particles are analytically analyzed. The dumbbell is considered as a simplified description of a linear active polymer. The two beads are independently propelled in directions which change in a diffusive manner. The relaxation behavior of the internal degree of freedom is tightly coupled to the dumbbell activity. The latter dominates the dynamics for strong propulsion. As is shown, limitations in bond stretching strongly influence the relaxation behavior. Similarly, under shear flow, activity determines the relaxation and tumbling behavior at strong propulsion. Moreover, shear leads to a preferred alignment and consequently to shear thinning. Thereby, a different power-law dependence on the shear rate compared to passive dumbbells under flow is found. PMID- 26980629 TI - Self-centering split-tip catheter versus conventional split-tip catheter in prevalent hemodialysis patients. AB - PURPOSE: This study compared the patency of a split-tip self-centering catheter with a predesigned curve (CentrosFLO; Merit, Salt Lake City, Utah) and a standard split-tip catheter with straight distal limbs (Medcomp, Harleysville, Pennsylvania) catheter in patients requiring exchange of a dysfunctional tunneled dialysis catheter (TDC). MATERIALS AND METHODS: A single-center retrospective chart review was performed between January 2013 and July 2014. Patients had an existing dysfunctional TDC that was exchanged over a wire using the same access site for either a split-tip self-centering catheter with a predesigned curve or a standard split-tip catheter with straight distal limbs catheter. The primary endpoint was catheter patency analyzed at 1, 3, and 6 months after initial exchange. RESULTS: A total of 73 patients met inclusion criteria (46 in the self centering catheter group and 27 in the standard split-tipped group). Mean durations of the exchanged catheters were similar between groups. The mean 1-, 3 , and 6-month patency rates for the self-centering and split-tip catheters were 89%, 67.4%, and 23.9% and 81.5%, 40.7%, and 14.8%, respectively. Mean blood flow rates (BFRs) were similar between groups at 1 and 3 months; however, at 6 months, mean rates were 388 mL/min versus 352 mL/min for the self-centering group and split-tipped group, respectively (p<0.01). CONCLUSIONS: These results demonstrate improved patency with the CentrosFLO self-centering catheter versus the split-tip catheter. This may be due to the unique design of the self-centering catheter, allowing for preserved BFRs and patency. These results should be further explored in prospective, randomized multicenter studies. PMID- 26980631 TI - Zika, or the burden of uncertainty. AB - In the first phases of an infectious outbreak, health authorities have to face the challenge of communicating uncertainty. Just when the attention of the public is at the top, information about what is going on is usually still missing. This is the case of Zika crisis in Latin America, where an association with microcephaly in newborns and neurological complications have been described, but not yet confirmed. Despite this, and even if the risk would be mainly limited to pregnant women, Zika threat is perceived by the general public as greater than others, such as those from dengue or flu. Some peculiarities of this outbreak explain such a gap between real and perceived risk. Nevertheless, in such a situation, WHO and other health authorities have the duty to act out of an abundance of caution, aware of the lose-lose game they are going through: if they raise alarm, and this subsided, they could be accused to fuel people's fears because of economic interests, as it happened in 2009 A(H1N1) pandemic; if they underestimate the threat, they could find themselves in front of a global tragedy. PMID- 26980632 TI - Advanced epithelioid pleural mesothelioma, long lasting disease stabilization and long term survival with cisplatin-pemetrexed chemotherapy re-challenge: a case report. AB - In this paper we report the case of a seventy-year old man affected by epithelioid malignant mesothelioma with prolonged disease control after chemotherapy with cisplatin pemetrexed, followed by single drug chemotherapy with pemetrexed. PMID- 26980633 TI - Chest pain due to Pinch-off syndrome: radiological findings and endovascular rescue. AB - Port-a-cath is widely used as a route for administration of drugs in hematology and oncology patients and, recently, has been adapted also for hemodialysis patients. Major complications include infection, thrombosis, arrhythmia, and embolization. The Pinch-off-syndrome (POS) means the clavicle and the first rib compress the long-term central venous catheter. The reported incidence rate ranges from 1.4% to 4.1%. This syndrome can be recognized on chest radiography by observing a thinning of the catheter lumen through the passage between the clavicle and the first rib. Catheter fracture is a rare but potentially life threatening complication that must be recognized and treated promptly. Management of dislodged ports includes percutaneous transcatheter retrieval, open thoracotomy retrieval and oral anticoagulant therapy. Among these techniques, percutaneous transcatheter retrieval is an easy, safe and efficient method. We report the successful percutaneous endovascular retrieval of dislodged intracardiac catheter, separated from its port, in a 58 year-old male patient who presented with chest pain. PMID- 26980634 TI - Incidental diagnosis of large colic submucosal lipomas during colorectal cancer screening: What we have to do? PMID- 26980635 TI - Training exposure and confidence level among medical officers: Does an Emergency Physician make a difference? AB - BACKGROUND AND PURPOSE: The training of emergency medical officers has always been informal. Only recently, the presence of emergency physician may have a positive influence in their training and development. This study aims to determine the effect of Emergency Physician (EP) presence on the training exposure and confidence level of medical officers in their practice. MATERIALS AND METHODS: Questionnaires were mailed to all ED (emergency department) medical officers working in 130 Malaysian Ministry of Health hospitals. They were required to answer the 14-item questionnaire, which includes demographic section, training modalities available and confidence score of listed clinical scenarios related to their work practice. RESULTS: The response rate was 41.3% (n=217). Only 210 questionnaires were complete for analysis. There were more responses gathered from ED medical officers with EP (123 vs 87). ED medical officers working with in-house EP were exposed to more training modalities as compared to their counterparts in ED with absence of EP. All five responses (100%) that stated that there was no training available in their department came from ED without EP. Total confidence score was found to be significantly higher among ED medical officers in ED with EP presence (mean score 132.5 versus 120.45; p<0.001; 95%CI: 6.526-17.58). CONCLUSIONS: Presence of EP in the ED have positive influences on medical officers training exposure and hence confidence level in performing their clinical duties. PMID- 26980636 TI - Upper lip reconstruction and aesthetic aspects in the female patient: our point of view. AB - Brief title: A brief description of our point of view about upper lip reconstruction supporting a quite simple and effective surgical option, which surgeons could consider whenever little neoformations must be removed from the lips, an aesthetically important anatomical region. PMID- 26980637 TI - Economic evaluation of Dental Sealants: A systematic review. PMID- 26980638 TI - Telemedicine in pediatric wound care. AB - BACKGROUND: Telemedical wound care is one of the possible applications of teledermatology. The treatment of pediatric wounds needs frequent and periodic assessments of their local status and adjustment of dressings choice. MATERIALS AND METHODS: We present our experience using telemedicine in the successful assessment and treatment of 19 pediatric patients at the OPBG, Rome . Photographs with a digital camera were taken and sent weekly by mail to a wound care specialist in Rome. This allowed the expert to diagnose and evaluate the wounds periodically. RESULTS: In the shown cases, telemedicine allowed us to have an immediate evaluation and therapy adjustment. The quality of the images was good enough that the physician could regularly evaluate the status of the wound and immediately give his feedback to the parents. Of these 19, 13 patients (68%) experienced a wound resolution during the remote monitoring period. The satisfaction of the parents detected at 3, 6 and 12 months was found to be respectively 57%, 71%, 84%. CONCLUSION: Reducing transportation to the hospital to obtain a specialist advice, wound teleconsultation lowers health care costs and improve the quality of life for pediatric patients and their family, while still maintaining a high quality of pediatric wound care. PMID- 26980639 TI - Chiari type 1 malformation in Neurofibromatosis type 1: experience of a center and review of the literature. AB - OBJECTIVE: To evaluate the possible correlation and the true incidence between Neurofibromatosis type 1 and Arnold-Chiari malformation type I. MATERIALS AND METHODS: We reviewed all clinical charts, neurological consultations and MRI scans of 428 NF1 patients followed by 1994 to 2014 in our Department. NF1 patients in our clinic are seen usually every year by both the dermatologist and the neurologist. All patients also undergo a brain and spinal cord with the same 1.5 Tesla MRI scan. RESULTS: We found a diagnosis of Arnold Chiari malformation type I in 9 of the 428 NF1 cases (2%). CONCLUSION: This frequency is higher than that expected on the basis of a chance association. Therefore we underline the importance of serial MRI studies in patients with NF1 to assess the presence of cranio-cervical anomalies. Future studies should try to better understand what are the pathogenetic mechanisms underlying this close association. PMID- 26980640 TI - Refractory and severe status epilepticus in a patient with ring chromosome 20 syndrome. AB - Ring chromosome 20 [r(20)] syndrome is a rare chromosomal disorder that is characterized by the development of refractory epilepsy during childhood with gradual declines in cognitive performance and behavior. Although the prognoses of seizures and intellectual disability associated with this condition are poor, life-threatening complications have rarely been described. We herein presented a case of a 17-year-old female with [r(20)] syndrome who developed recurrent status epilepticus (SE) at 14years of age that evolved into unremitting SE in spite of vigorous antiepileptic treatments. She was administered thiopental anesthesia for 1year, and was subsequently left in severe neurological sequelae. It is important to note that patients with this syndrome not only have severe epileptic encephalopathy persisting into adulthood, but are also at risk of fatal SE. PMID- 26980641 TI - Commentaries on Viewpoint: Reappraisal of the acute, moderate intensity exercise catecholamines interaction effect on speed of cognition: Role of the vagal/NTS afferent pathway. PMID- 26980642 TI - Last Word on Viewpoint: Reappraisal of the acute, moderate intensity exercise catecholamines interaction effect on speed of cognition: role of the vagal/NTS afferent pathway. PMID- 26980643 TI - Corrigendum. PMID- 26980644 TI - Laparoendoscopic single-site surgery in gynecologic oncology: An update. AB - The preferred surgical approach for many gynecologic oncology procedures is now laparoscopy. Reduced morbidity, shorter hospitalization and a more rapid recovery have been associated with minimally invasive surgical approaches when compared to laparotomy. Incisional morbidity, including vascular and viscous injury, postoperative hernia, infection, and pain remain significant concerns. Use of fewer and smaller incisions during laparoscopy may be expected to further minimize these risks. Laparoendoscopic single-site surgery (LESS), or single incision laparoscopy, describes the use of one small skin incision to complete laparoscopic surgical procedures. Recent advances in instrumentation have allowed increasingly complex procedures in gynecologic cancer patients to be completed. This review will serve as an update in regards to implementation of LESS in gynecologic oncology. Technical challenges encountered during performance of LESS as well as strategies to overcome these challenges will be discussed. PMID- 26980645 TI - Surgical tips of intramedullary nailing in severely bowed femurs in atypical femur fractures: Simulation with 3D printed model. AB - INTRODUCTION: The surgical management of atypical femoral fractures (AFFs) is complex in cases with severe bowing of the femur, being associated with a high rate of failure. Our first aim was to use preoperative templating and 3D printed model characterise the technical difficulties associated with use of current commercially available intramedullary nail (IMN) systems for the management of AFFs with severe bowing. Our second aim was to use outcomes of our 3D printing analysis to define technical criteria to overcome these problems. MATERIAL AND METHODS: The modelled femur with 3D printing had an anterior bowing curvature radius of 772mm and an angle of lateral bowing of 15.4 degrees . Nine commercially available IMN systems were evaluated in terms of position of the nail within the medullary canal, occurrence of perforation of femoral cortex by the distal tip of the nail, and location of the site of perforation relative to the knee joint. The following IMN systems were evaluated: unreamed femoral nail (UFN), cannulated femoral nail (CFN), Sirus nail, right and left expert Asian femoral nail (A2FN), right and left Zimmer Natural Nail (ZNN), proximal femoral nail anti-rotation (PFNA), and Zimmer Cephalomedullary Nail (CMN). RESULTS: Along the sagittal plane, the UFN, CFN and Sirus systems were acceptably contained within the medullary canal, as well as the "opposite side" A2FN and ZNN. Only the Sirus IMN system was contained along the coronal plane. The distal part of the all other IMN systems perforated the anterior cortex of the femur, at distances ranging between 2.8 and 11.7cm above the distal end of the femoral condyles. Using simulated fracture reduction in the 3D printed model, none of the 9 IMN systems provided acceptable anatomical reduction of the fracture. A residual gap in fragment position and translation was provided by the "opposite side" ZNN, followed by the UFN and Sirus systems. CONCLUSION: Commercially available IMN systems showed mismatch with severely bowed femurs. Our simulation supports that fit of these systems can be improved using an IMN system with a small radius of curvature and diameter, and by applying specific operative procedures. PMID- 26980646 TI - Postoperative negative pressure therapy significantly reduces flap complications in distally based peroneus brevis flaps: Experiences from 74 cases. AB - BACKGROUND: The distally based peroneus brevis muscle flap is a valuable therapeutic option for coverage of tissue defects around the ankle and the distal lower leg. However, the rate of postoperative flap complications requiring revisional surgery is high due to an impaired venous drainage and oedema formation. The purpose of this study was to evaluate if postoperative negative pressure therapy is able to reduce flap complications. METHODS: From April 2010 until March 2014, we treated 74 patients with distally based peroneus brevis muscle flaps for defect coverage at the lower leg. In four cases, an osteomuscular composite flap has been used to treat partly stability-relevant bone defects. In 43 cases, negative pressure therapy (75mmHg, continuous) with a circular dressing was initiated after the flap procedure for 7 days. In 31 cases no negative pressure therapy was initiated. We retrospectively analysed those two groups of patients. The primary endpoint was the incidence of flap complications with a need for revision surgery, which were classified in three grades. RESULTS: The group treated with negative pressure therapy had significantly less flap complications when compared to the control group (p<0.0001). Concerning the single grades of complication, the negative pressure therapy-group had a significantly smaller rate of skin graft necrosis (Grade 1; p=0.014) and partial flap loss (Grade 2; p=0.002) compared to the control group. There were no statistically significant differences concerning complete flap loss (Grade 3) between both groups. CONCLUSION: Postoperative negative pressure therapy for 7 days reduces flap complications in distally based peroneus brevis flaps. PMID- 26980647 TI - Knockout of Foxp2 disrupts vocal development in mice. AB - The FOXP2 gene is important for the development of proper speech motor control in humans. However, the role of the gene in general vocal behavior in other mammals, including mice, is unclear. Here, we track the vocal development of Foxp2 heterozygous knockout (Foxp2+/-) mice and their wildtype (WT) littermates from juvenile to adult ages, and observe severe abnormalities in the courtship song of Foxp2+/- mice. In comparison to their WT littermates, Foxp2+/- mice vocalized less, produced shorter syllable sequences, and possessed an abnormal syllable inventory. In addition, Foxp2+/- song also exhibited irregular rhythmic structure, and its development did not follow the consistent trajectories observed in WT vocalizations. These results demonstrate that the Foxp2 gene is critical for normal vocal behavior in juvenile and adult mice, and that Foxp2 mutant mice may provide a tractable model system for the study of the gene's role in general vocal motor control. PMID- 26980648 TI - [Condylar fracture and temporomandibular joint ankylosis]. AB - This article summarized the advances in treatment and research of temporomandibular joint surgery in the last 5 years which was presented in "The 2nd Condyle Fracture and Temporomandibular Joint Ankylosis Symposium". The content includes 5 parts: non-surgical treatment of children condyle fracture and long-term follow-up, the improvement of operative approach for condyle fracture and key techniques, the importance and the method for the simultanesous reduction of disc in condylar fracture treatment, the development of traumatic temporomandibular joint ankylosis similar to hypertrophic non-union and the improved safety and accuracy by applying digital surgery in joint surgery. PMID- 26980649 TI - [Positive lymph node ratio is an important prognostic factor of oral squamous cell carcinoma]. AB - OBJECTIVE: To investigate the cutoff value and significance of lymph node ratio (LNR) in oral squamous cell carcinoma. METHODS: This retrospective study included 286 patients with oral cancer and pathological positive lymph nodes. Used time dependent receiver operating characteristic (ROC) curves to determine which LNR best defines different risk groups of oral squamous cell carcinoma (OSCC) patients. All the variables were subjected to the univariate analysis, then only the variables that had prognostic potential were subjected to multivariate analysis by the COX proportional hazards regression model. RESULTS: The cutoff value of LNR was 0.092. When LNR was greater than 0.092, the overall survival rate was 24.2%, when LNR was less than 0.092, the overall survival rate was 45.8% (P<0.05). CONCLUSIONS: Lymph node ratio is a predictor of outcome in patients with oral squamous cell carcinoma, and the cutoff value is 0.092. PMID- 26980650 TI - [Expression of voltage-gated potassium channel Kv3.4 in oral squamous cell carcinoma]. AB - OBJECTIVE: To evaluate the expression of voltage-gated potassium channel Kv3.4 and to determine its significance in oral squamous cell carcinoma (OSCC) and precancerous lesions. METHODS: Immunohistochemical SP methods were performed to detect the expression of Kv3.4 at tissue level on 57 paraffin-embedded samples collected from Pathology Department of Anhui Province Stomatological Hospital during January 2013 to June 2014. The relationships between the expression of Kv3.4 and precancerous lesion and clinical pathologic factors of oral squamous cell carcinoma, such as pathologic classification, clinical stage and lymph node metastasis, were also analyzed. Totally 6 samples of normal oral mucosa tissue, 23 samples of OSCC and 13 samples of precancerous lesions were collected from the Department of Oral and Maxillofacial Surgery of The First Affiliated Hospital of Anhui Medical University during May 2014 to March 2015. Real-time quantitative PCR and Western blotting were used to detect the expression of Kv3.4 in these 42 samples at molecular and protein levels. RESULTS: Real-time quantitative PCR showed the relative expression quantity of Kv3.4 in normal oral mucosa, precancerous lesions, and OSCC tissues were 0.85+/-0.48, 3.50+/-2.51 and 18.48+/ 7.70, respectively. The relative expression quantity of Kv3.4 in OSCC and precancerous lesions were higher than that in normal group, the differences were both statistically significant (P=0.002, P=0.029). The relative expression quantities of Kv3.4 protein in precancerous and OSCC tissues were 0.87+/-0.14 and 0.35+/-0.03 respectively by Western blotting, and both were higher than that in normal tissues (0.18+/-0.10). The differences were statistically significant (P=0.002). In 57 paraffin-embedded samples, the positive expression rates of Kv3.4 in normal, precancerous and OSCC tissues were 2/6, 13/18 and 95% (37/39), respectively. The differences were statistically significant(P<0.05). However, the expression of Kv3.4 did not show obvious correlation with patients' genders, presence of lymph node metastasis and clinical stages (P>0.05). CONCLUSIONS: The expression of Kv3.4 is positively correlated to OSCC's occurrence and development. Detection of the expression of Kv3.4 may be used for early diagnosis and prognostic judgment of oral squamous cell carcinoma and precancerous lesions. PMID- 26980651 TI - [Adhesive performance of infiltrating resin bonded on dentin in vitro]. AB - OBJECTIVE: To evaluate the adhesive interface and micro-tensile bond strength (MUTBS) of infiltrating resin directly bonded to normal dentin. METHODS: Twenty extracted human molars were collected and ground to expose fresh dentin surface. An infiltrating resin (ICON, DMG, Germany) was served as experimental group and Clearfil SE Bond adhesive (Kuraray, Japan) as control group. Following the application of primer (Kuraray, Japan), the specimens were applied infiltrating resin or adhesive respectively and blocks of composite resin were built up. The adhesive interfaces were observed using scanning electron microscope (SEM) and the MUTBS was measured by micro-tensile test before and after thermal cycling. RESULTS: The infiltrating resin could penetrate into micro-structure of dentin created by SE Bond primer. A layer of about 180 MUm-long and dense resin tags was observed under SEM in infiltrating resin group. The MUTBSs were (35 +/- 10) MPa before and (35 +/- 9) MPa after thermal cycling respectively in infiltrating resin group, and the difference was not statistically significant (P>0.05). The MUTBSs were (38+/-8) MPa before and (24+/-7) MPa after thermal cycling respectively in control group, and the difference was statistically significant (P<0.05). After thermal cycling, the MUTBS of infiltrating resin group was significant higher than that of control group. CONCLUSIONS: The infiltrating resin could penetrate into the micro-structure of dentin created by SE Bond primer. The bond strength and the bonding durability of infiltrating resin were similar to that of SE Bond adhesive. PMID- 26980652 TI - [Biomodifying effect of epigallocatechin-3-gallate on dentine substrate splicing surface]. AB - OBJECTIVE: To investigate the effect of epigallocatechin-3-gallate (EGCG) on biomodification of demineralized dentine substrate, in its permeability, hydrophobicity, and inhibition ability to collagen enzymatic degradation. METHODS: The dentine substrates were treated with simulated pulpal pressure created by mixtures of 0.02%, 0.1% EGCG/bovine serum albumin (BSA) in acidic environment (pH4.4) for 48 h. A fluid-transport model was used to measure the fluid permeability through demineralized dentine substrate. Positive replicas of dentine substrate were fabricated before and after being subjected to acidic environment for scanning electron microscope (SEM) examination. The blank group contained no EGCG and the positive group were treated with Gluma desensitizer. Static contact angle measurements on demineralized dentin and 0.1% EGCG primed dentin were performed by contact angle analyzer. The priming time were 60 s, 120 s, 0.5 h, 1 h. Dentine specimens bonded with Adper single bond 2 were subjected to 100 mg/L collagenase and observed under SEM. Resin-bonded specimens (with 0.02%, 0.1%, 0.5% EGCG priming, or without EGCG priming) were created for micro tensile bond strength evaluation (MTBS). Resin-bonded specimens after thermol cycling were created for MTBS evaluation. RESULTS: The fluid permeability in the blank control group increased ([151.3+/-22.3]%), the fluid permeability in 0.1% EGCG/BSA group decreased ([23.7+/-6.3]%). Compared to the blank control group, the contact angle of 120 s, 0.5 h, 1 h groups increased by 31.0%, 53.5%, 57.8% in deep dentin and 37.4%, 59.3%, 62.4% in shallow dentin. The SEM examination showed that 0.1% and 0.5% EGCG priming for 120 s significantly increased dentin collagen's resistance to collagenase. The immediate MTBS of 0.1% and 0.5% EGCG groups were (29.4+/-4.8) and (19.8+/- 4.9) MPa. After thermol cycling, the MTBS of 0.1% and 0.5% EGCG groups were (19.9+/-5.1) and (15.3+/- 6.3) MPa. CONCLUSIONS: Under acidic environment (pH4.4), the 0.1% EGCG can reduce dentine permeability under acidic environment. The 0.1% EGCG can increase hydrophobicity of dentin substrate, and strengthen dentin substrate's resistance to collagenase hydrolysis, thus increased the resin-dentin bonding durability. PMID- 26980653 TI - [Extracellular signal-regulated kinase signaling pathway regulates the endothelial differentiation of periodontal ligament stem cells]. AB - OBJECTIVE: To investigate the effect of extracellular signal-regulated kinase (ERK) signaling pathway on the endothelial differentiation of periodontal ligament stem cells (PDLSC). METHODS: Human PDLSC was cultured in the medium with vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b FGF) to induce endothelial differentiation. Endothelial inducing cells was incubated with U0126, a specific p-ERK1/2 inhibitor. PDLSC from one person were randomly divided into four groups: control group, endothelial induced group, endothelial induced+DMSO group and endothelial induced+U0126 group. The protein expression of the p-EKR1/2 was analyzed by Western blotting at 0, 1, 3, 6 and 12 hours during endonthelial induction. The mRNA expressions of CD31, VE-cadherin, and VEGF were detected by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) after a 7-day induction. The proportion of CD31(+) to VE cadherin(+) cells was identified by flow cytometry, and the ability of capillary like tubes formation was detected by Matrigel assay after a 14-day induction. The measurement data were statistically analyzed. RESULTS: Phosphorylated ERK1/2 protein level in PDLSC was increased to 1.24+/-0.12 and 1.03+/-0.24 at 1 h and 3 h respectively, during the endothelial induction (P<0.01). The mRNA expressions of CD31 and VEGF in induced+U0126 group were decreased to 0.09+/-0.18 and 0.49+/ 0.17, which were both significantly different with those in induced group (P<0.05). The proportion of CD31(+) to VE-cadherin(+) cells of induced+U0126 group were decreased to 5.22+/-0.85 and 3.56+/-0.87, which were both significantly different with those in induced group (P<0.05). In Matrigel assay, the branching points, tube number and tube length were decreased to 7.0+/-2.7, 33.5+/-6.4, and (15 951.0+/-758.1) pixels, which were all significantly different with those in induced group (P<0.05). CONCLUSIONS: The endothelial differentiation of PDLSC is positively regulated by ERK signaling pathway. Inhibition of ERK1/2 phosphorylation could suppress endothelial differentiation of PDLSC. PMID- 26980655 TI - [Effect of stiffness of polyelectrolyte multilayer on titanium surface on bacterium adhesion]. AB - OBJECTIVE: To provide a theoretical basis for surface modification of titanium implants, the effects of the stiffness of polyelectrolyte multilayer films on titanium surface on bacterium adhesion was explored. METHODS: Via layer-by-layer technique, catechol functionalized polyelectrolyte multilayer film (cPEM) was constructed on titanium surface by using catechol functionalized hyaluronic acid (cHA) and lipopolysaccharide-amine nanopolymersomes (NP). The stiffness of cPEM was controlled by adjusting the catechol substitution degree of cHA (5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%). Titanium samples covered with cPEM were selected as test group, and the cPEM was constructed with the lowest, medium and highest stiffness. The polished titanium was used as a control. The surface topography of titanium before and after film construction was observed by scanning electron microscopy (SEM). At 1 and 24 h after incubation, the adhesion and clonal formation of Streptococcus mutans (S. mutans) on different titanium surfaces were quantified, and their morphology and survival status were observed by SEM and laser scanning confocal microscope (LSCM). RESULTS: When the catechol grafting ratio was 5%, 30% and 70%, the lowest, medium and highest cPEM stiffness were obtained, and the cPEM stiffness were (10.69+/-4.54) GPa(cPEM-L), (20.99+/- 5.81) GPa (cPEM-M) and (32.57+/-6.93) GPa (cPEM-H) respectively, and the stiffness of polished titanium was (107.12+/-8.68) GPa (P<0.05). SEM observation showed that after cPEM coating, the titanium surface became smoother. After incubation for 1 and 24 h, the amount of adhesion and clonal formation of S. mutans on cPEM were higher than those on control titanium, and the difference was statistically significant (P<0.05). SEM images showed that for 1 h incubation, softer surfaces were beneficial for S. mutans adhering and agglomerating, while this difference nearly disappeared at 24 h. Observation under LSCM revealed that most of bacteria were alive on titanium disks at 1 h, and their amount decreased with the increase of stiffness. At 24 h, the living/dead bacterium ratios on cPEM-L and control titanium was higher than that on cPEM-M and cPEM-H, and cPEM-L surface was dominated by living bacteria, while stiffer cPEM-M and cPEM-H had more dead bacteria than living bacteria. CONCLUSIONS: Increasing the stiffness of polyelectrolyte films on titanium limits the adhesion of S. mutans. As an independent factor, stiffness influences the bacterium adhesion. PMID- 26980654 TI - [Effect of aspirin on cell biological activities in murine bone marrow stromal cells]. AB - OBJECTIVE: To determine the effect of aspirin on cell proliferation, alkaline phosphatase (ALP) activity, cell cycle and apoptosis in murine bone marrow stromal cells, so as to explore an appropriate dose range to improve bone regeneration in periodontal treatment. METHODS: ST2 cells were stimulated with aspirin (concentrations of 1, 10, 100 and 1 000 MUmol/L) for 1, 2, 3, 5 and 7 d. Cell proliferation was measured by methyl thiazolyl tetrazolium (MTT) assay. After ST2 cells were treated for 1, 3 and 7 d, ALP activity was measured by ALP kit, cell cycle and apoptosis were measured by flow cytometry (FCM) after treated for 48 h. RESULTS: MTT assays showed that various doses of aspirin have different effects on the cell growth. Briefly, lower concentrations (1, 10 MUmol/L) of aspirin promoted the cell growth, the A value of 0, 1 and 10 MUmol/L aspirin 7 day-treated cells were 0.313+/-0.012, 0.413+/-0.010 and 0.387+/-0.017 respectively (P <0.01 vs control), and so did the ALP level ([4.3+/-0.9], [6.0+/ 0.3] and [7.7+/-0.4] MUmol.min(-1).g(-1), P <0.05 vs control), while higher concentrations, especially 1000 MUmol/L of aspirin might inhibit the cell growth with time going, A value and ALP level were 0.267+/-0.016, (4.3+/-1.3) MUmol.min( 1).g(-1) respectively (P <0.05 vs control). Cell cycle analysis revealed no changes in comparison to control cells after treatment with 1 or 10 MUmol/L aspirin, but it was observed that cell mitosis from S phase to G2/M phase proceeded at higher concentrations of 100 MUmol/L aspirin, and the cell cycle in phase G0/G1 arrested at 1000 MUmol/L. Parallel apoptosis/necrosis studies showed that the percentage of cells in apoptosis decreased dramatically at all doses of aspirin, the apoptosis rates of ST2 cells responded to 0, 1, 10, 100 and 1000 MUmol/L aspirin were (11.50+/-0.90)%, (5.30+/-0.10)%, (5.50+/-0.10)%, (4.90+/ 0.90)% and (7.95+/-0.25)% respectively (P<0.05 vs control). CONCLUSIONS: This study demonstrated that lower dosage of aspirin can promote ST2 cells growth, osteogenic activity and inhibit its apoptosis. Aspirin maybe used for the bone reconstruction with a proper concentration. PMID- 26980656 TI - [Effect of 2-methacryloyloxyethyl phosphorylcholine on the protein-repellent property of dental adhesive]. AB - OBJECTIVE: To evaluate the effect of 2-methacryloyloxyethyl phosphorylcholine (MPC) and nanoparticles of amorphous calcium phosphate (NACP) on the protein repellent property of dental adhesive. METHODS: MPC and NACP were incorporated into SBMP as the test group. Scotchbond Multi-Purpose (SBMP) was used as control group. Human dentin shear bond strengths were measured. Protein adsorption onto samples was determined by micro bicinchoninic acid (BCA) method. A dental plaque microcosm biofilm model with human saliva as inoculum was used to investigate biofilm viability. RESULTS: The dentin bond strength of modified group was (28.7+/-2.2) MPa, which was not significantly different from that of the SBMP control group. The amount of protein adsorption in the modified group and the SBMP control group were (0.21+/-0.02) ug/cm(2) and (4.17+/-0.45) ug/cm(2) respectively. Lactic acid production of biofilms in modified group and SBMP control were (7.71 +/- 1.01) mmol/L and (19.18 +/- 2.34) mmol/L repectively. CONCLUSIONS: MPC-NACP based dental adhesive greatly reduce the protein adsorption and bacterial adhesion, without compromising dentin shear bond strength. This novel bonding agent may have wide application. PMID- 26980658 TI - [The influences of anterior disc displacement on oral mandibular function and morphology and their biological mechanisms]. AB - Anterior disc displacement is a common subtype seen in temporomandibular disorders (TMD) patients. It may cause mandibular movement disorders, such as clicking of joint, intermittent closed lock, limitation of mouth opening, etc. These disorders may affect the life qualities of patients. Anterior disc displacement may also cause mandibular malformations, especially among adolescents, which may affect the growth of condyle, therefore may have a correlation with mandibular retrusion or mandibular deviation when grown up. This paper going to review the influences of anterior disc displacement on oral mandibular function and morphology and their biological mechanisms. PMID- 26980657 TI - [Trigeminal purinergic P2X4 receptor involved in experimental occlusal interference-induced hyperalgesia in rat masseter muscle]. AB - OBJECTIVE: To explore the expression of purinergic p2X4 receptor (P2X4R) in trigeminal ganglion of rats after occlusal interference. Investigation of peripheral receptor mechanism of occlusal interference-induced masticatory muscle pain will aid the development of drug intervention against this condition. METHODS: Experimental occlusal interference was established by application of 0.4 mm metal crown to the upper right first molar of male Sprague-Dawley rats. Real time PCR assay was used to investigate P2X4R mRNA level in trigeminal ganglion in rats with occlusal interference for 3, 7, 10 and 14 days and in control rats without occlusal interference (n=5 in each). Retrograde labelling combining immunofluorescence was performed to evaluate the percentage of P2X4R-positive cells in masseter afferent neurons (n=5 in each group). Graded concentrations of P2XR antagonist TNP-ATP (0.1, 10, 125, 250, 500 MUmol/L) or saline (n=5 in each group) was administrated in right masseter and the mechanical sensitivity of bilateral masseters was measured before occlusal interference application, before the injection, and 30 min as well as 60 min after the injection. RESULTS: Compared with control rats (P2X4R mRNA: right side: 1.00+/-0.26, left side: 0.94+/- 0.21; percentage of P2X4R-positive masseter afferents: right side: [64.3+/-6.3]%, left side: [67.7+/-5.8]%), the level of P2X4R mRNA in bilateral trigeminal ganglia (right side: 5.98+/-3.56; left side: 5.06+/-2.88) of rats with occlusal interference for 7 days up-regulated (P<0.01) and the percentage of P2X4R-positive masseter afferent neurons(right side: [81.7+/-1.5]%; left side: [82.9+/-2.3]%) increased (P<0.05). Local administration of 10, 125, 250, 500 MUmol/L TNP-ATP increased the mechanical withdrawal threshold in masseter 30 min after injection, compared with those before injection (P<0.05). CONCLUSIONS: Increased expression of trigeminal P2X4R involves in the development of occlusal interference-induced masseter hyperalgesia. PMID- 26980659 TI - [Anatomical and radiographical studies of the bifid mandibular canal]. AB - To review the recent progress about the anatomical and radiographical studies of bifid mandibular canal (BMC) in English literature recorded in PubMed from 2006 to 2015 to deepen our understanding of BMC. A BMC is an anatomical variation of the mandibular canal; its occurrence might be a result of the incomplete fusion of mandibular canal during prenatal development. The four types of BMC have been classified according to anatomical location and configuration. Characteristic radiographic features and identifying methods of BMC on panoramic radiography and cone beam computed tomography (CBCT) were described; the visibility of BMC on panoramic radiographs and CBCT images was compared. Clinical value of identifying the location as well as the configuration of BMC for surgical procedures that involve the mandible was discussed. PMID- 26980660 TI - [The application of universal adhesives in dental bonding]. AB - The bonding restoration has become an important clinical technique for the development of dental bonding technology. Because of its easy operation and the maximum preservation of tooth tissues, bonding repair is widely used in dental restoration. The recent multi-mode universal adhesives have brought new progress in dental bonding restoration. In this article the universal adhesives were reviewed according to its definition, development, improvement, application features and possible problems. PMID- 26980661 TI - Validation of the PASAT in Argentina. AB - The Paced Auditory Serial Addition Test (PASAT) is one of the most used neuropsychological tests to assess information processing speed and working memory in brain injured patients. This study was carried out with the purpose of obtaining normative data for the PASAT-3" in a healthy Argentinean population, which would result in a reference control population. The PASAT-3" was administered in a sample of 296 healthy voluntary subjects, born and living in Argentina. The age range went from 20 to 70 years-old. The level of education was 0 to 13 or more years of schooling. The sample obtained a mean of 44.60 (SD = 10.72) in the PASAT-3". It was found that the score obtained in the PASAT-3" was related to the age and the level of instruction of the participants. Their performance diminished as age increased and, conversely, it increased as the level of instruction was higher. Normative data was obtained for a Latin American population from Argentina. Percentile distributions obtained by decades of age and different levels of education should be considered as useful reference values for clinicians and investigators when applying the PASAT-3" to assess cognitive function in different pathologies. PMID- 26980665 TI - Ultrafine potassium titanate nanowires: a new Ti-based anode for sodium ion batteries. AB - K2Ti6O13 with an analogous tunnel structure to Na2Ti6O13 is proposed as a new anode for sodium-ion batteries. By fabricating ultrafine nanowires growing perpendicularly to the Na(+) diffusion direction, the K2Ti6O13 nanowires show a much enhanced capacity (186 mA h g(-1)) as well as good rate capability for sodium storage. PMID- 26980663 TI - Dynamic Balance of Excitation and Inhibition in Human and Monkey Neocortex. AB - Balance of excitation and inhibition is a fundamental feature of in vivo network activity and is important for its computations. However, its presence in the neocortex of higher mammals is not well established. We investigated the dynamics of excitation and inhibition using dense multielectrode recordings in humans and monkeys. We found that in all states of the wake-sleep cycle, excitatory and inhibitory ensembles are well balanced, and co-fluctuate with slight instantaneous deviations from perfect balance, mostly in slow-wave sleep. Remarkably, these correlated fluctuations are seen for many different temporal scales. The similarity of these computational features with a network model of self-generated balanced states suggests that such balanced activity is essentially generated by recurrent activity in the local network and is not due to external inputs. Finally, we find that this balance breaks down during seizures, where the temporal correlation of excitatory and inhibitory populations is disrupted. These results show that balanced activity is a feature of normal brain activity, and break down of the balance could be an important factor to define pathological states. PMID- 26980666 TI - Psychometric Evaluation of the Physical Activity Enjoyment Scale in Adults with Functional Limitations. AB - Enjoyment is an important construct for understanding physical activity participation, and it has not been examined in adults with functional limitations. This secondary analysis reported the reliability and validity of the Physical Activity Enjoyment Scale (PACES) in a convenience sample of 40 adults with functional limitations. The participants completed the PACES, Center for Epidemiological Studies Depression Scale (CES-D), and the Late Life Function and Disability Instrument (LLFDI) prior to beginning a 12-week feasibility dance intervention study. Results indicated reliability as Cronbach's alpha was .95 and mean inter-item correlation was .52. To further support reliability, homogeneity of the instrument was evaluated using item-to-total scale correlations. Homogeneity was supported as all items had corrected item-to-total correlations greater than .30. For validity, the PACES was significantly related to only the Physical Function component of the LLFDI (r = .38, p = .02), but not the CES-D. Exploratory factor analysis revealed a 3-factor structure that accounted for 73.76% of the variance. This feasibility intervention dance study represented the first attempt to examine the psychometric properties of the PACES in adults with functional limitations. The findings demonstrate support for the scale's reliability and validity among adults with functional limitations. Results are informative as further psychometric testing of the PACES is recommended using randomized clinical trials with larger sample sizes. Enjoyment for physical activity is an important construct for understanding physical activity participation in adults with functional limitations. PMID- 26980667 TI - Long-range and high-speed electronic spin-transport at a GaAs/AlGaAs semiconductor interface. AB - Spin-valves or spin-transistors in magnetic memories and logic elements are examples of structures whose functionality depends crucially on the length and time-scales at which spin-information is transferred through the device. In our work we employ spatially resolved optical pump-and-probe technique to investigate these fundamental spin-transport parameters in a model semiconductor system. We demonstrate that in an undoped GaAs/AlGaAs layer, spins are detected at distances reaching more than ten microns at times as short as nanoseconds. We have achieved this unprecedented combination of long-range and high-speed electronic spin transport by simultaneously suppressing mechanisms that limit the spin life-time and the mobility of carriers. By exploring a series of structures we demonstrate that the GaAs/AlGaAs interface can provide superior spin-transport characteristics whether deposited directly on the substrate or embedded in complex semiconductor heterostructures. We confirm our conclusions by complementing the optical experiments with dc and terahertz photo-conductivity measurements. PMID- 26980664 TI - TLR3-/4-Priming Differentially Promotes Ca(2+) Signaling and Cytokine Expression and Ca(2+)-Dependently Augments Cytokine Release in hMSCs. AB - In human mesenchymal stem cells (hMSCs), toll-like receptor 3 (TLR3) and TLR4 act as key players in the tissue repair process by recognizing their ligands and stimulating downstream processes including cytokine release. The mechanisms of TLR3- and TLR4-mediated cytokine releases from hMSCs remain uncertain. Here, we show that exposure to the TLR3 agonist polyinosinic-polycytidylic acid (poly(I:C)) or incubation with the TLR4 agonist lipopolysaccharide (LPS) increased the mRNA expression levels of TLR3, TLR4 and cytokines in hMSCs. Poly(I:C) exposure rather than LPS incubation not only elevated inositol 1,4,5 triphosphate receptor (IP3R) expression and IP3R-mediated Ca(2+) release, but also promoted Orai and STIM expression as well as store-operated Ca(2+) entry into hMSCs. In addition, we also observed that 21 Ca(2+) signaling genes were significantly up-regulated in response to TLR3 priming of hMSCs by RNA sequencing analysis. Both poly(I:C) and LPS exposure enhanced cytokine release from hMSCs. The enhanced cytokine release vanished upon siRNA knockdown and chelation of intracellular Ca(2+). These data demonstrate that TLR3- and TLR4-priming differentially enhance Ca(2+) signaling and cytokine expression, and Ca(2+) dependently potentiates cytokine release in hMSCs. PMID- 26980668 TI - Exposure factors of Victoria's active motorcycle fleet related to serious injury crash risk. AB - OBJECTIVE: The purpose of this study was to describe the nature and extent of current powered 2-wheeler (PTW) risk exposures in order to support future efforts to improve safety for this mode of transport. METHODS: A cross-sectional analysis of the control arm of a population-based case-control study was conducted. The control sample was selected from 204 sites on public roads within 150 km of the city of Melbourne that were locations of recent serious injury motorcycle crashes. Traffic observations and measurements at each site were sampled for a mean of 2 h on the same type of day (weekday, Saturday, or Sunday) and within 1 h of the crash time. Photographs of passing riders during this observation period recorded data relating to characteristics of PTWs, age of riders, travel speed of PTWs and all vehicles, time gaps between vehicles, visibility, and protective clothing use. RESULTS: Motorcycles and scooters represented 0.6% of all traffic (compared with 4% of all vehicle registrations). Riders were significantly more likely to have larger time gaps in front and behind when compared to other vehicles. The average travel speed of motorcycles was not significantly different than the traffic, but a significantly greater proportion were exceeding the speed limit when compared to other vehicles (6 vs. 3%, respectively). The age of registered owners of passing motorcycles was 42 years. Over half of riders were wearing dark clothing with no fluorescent or reflective surfaces. One third of motorcyclists had maximum coverage of motorcycle-specific protective clothing. CONCLUSIONS: A very low prevalence of motorcyclists combined with relatively higher rates of larger time gaps to other vehicles around motorcycles may help explain their overrepresentation in injury crashes where another vehicle fails to give way. An increased risk of injury in the event of a crash exists for a small but greater proportion of motorcyclists (compared to other vehicle types) who were exceeding the speed limit. An apparent shift toward older age of the active rider population may be reducing injury crash risk relative to exposure time. There is significant scope to improve the physical conspicuity of motorcyclists and the frequency of motorcycle specific protective clothing use. These results can be used to inform policy development and monitor progress of current and future road safety initiatives. PMID- 26980669 TI - Quantifying facial skin erythema more precisely by analyzing color channels of The VISIA Red images. AB - BACKGROUND: The VISIA Red images were developed to document and measure facial skin erythema, but diffuse erythema cannot be fully segmented by the VISIA system due to the automatic thresholding segmentation method. Moreover, topical area analysis is not available in the system. MATERIALS AND METHODS: Erythema severity degrees of 20 simulated Red images were designated 1-20 with 1-20 inflammatory lesions for each, respectively. The RGB channel mean values of each simulated image were acquired by ImageJ and relative intensity of red values calculated. RESULTS: The relative intensity of red values positively correlate to erythema severity with a coefficient of 0.999345 (p < 0.001). We also proposed a method for calibration when pustules were present in the erythema area. The method was proved by mathematical reasoning and verified by certified dermatologists. CONCLUSION: We demonstrated a simple and more precise method to quantify and compare facial skin erythema by analyzing the RGB channel values of the VISIA Red images. Our method brings convenience for erythema evaluation in dermatological studies. PMID- 26980670 TI - SiC7 siligraphene: a novel donor material with extraordinary sunlight absorption. AB - The SiC7 siligraphene (g-SiC7) is a novel 2D nanomaterial with a graphene-like structure. Based on theoretical calculations, we have systematically investigated the structure, stability, electronic and optical properties of g-SiC7 siligraphene. The calculated results reveal that g-SiC7 siligraphene is a semiconductor with a direct band gap of 1.13 eV, which can be easily tuned by applying biaxial strain or a perpendicular electric field. Such a g-SiC7 siligraphene shows superior sunlight optical absorbance and is better than g-SiC2 siligraphene and single-layer black phosphorus (phosphorene) in near infrared and visible photon ranges, thus holding great potential for photovoltaics applications as a light donor material. PMID- 26980671 TI - Characteristic amino acid changes of influenza A(H1N1)pdm09 virus PA protein enhance A(H7N9) viral polymerase activity. AB - Human coinfection with a novel H7N9 influenza virus and the 2009 pandemic A(H1N1) influenza virus, H1N1pdm09, has recently been reported in China. Because reassortment can occur during coinfection, it is necessary to clarify the effects of gene reassortment between these two viruses. Among the viral ribonucleoprotein complex (vRNP) genes, only the PA gene of H1N1pdm09 enhances the avian influenza viral polymerase activity. Based on a phylogenetic analysis, we show a special evolutionary feature of the H1N1pdm09 PA gene, which clustered with those of the novel H7N9 virus and related H9N2 viruses, rather than in the outgroup as the H1N1pdm09 genes do on the phylogenetic trees of other vRNP genes. Using a minigenome system of the novel H7N9 virus, we further demonstrate that replacement of its PA gene significantly enhanced its polymerase activity, whereas replacement of the other vRNP genes reduced its polymerase activity. We also show that the residues of PA evolutionarily conserved between H1N1pdm09 and the novel H7N9 virus are associated with attenuated or neutral polymerase activity. The mutations associated with the increased activity of the novel H7N9 polymerase are characteristic of the H1N1pdm09 gene, and are located almost adjacent to the surface of the PA protein. Our results suggest that the novel H7N9 virus has more effective PB1, PB2, and NP genes than H1N1pdm09, and that H1N1pdm09-like PA mutations enhance the novel H7N9 polymerase function. PMID- 26980673 TI - Detection of novel adenoviruses in fecal specimens from rodents and shrews in southern China. AB - The prevalence and phylogenetic characteristics of AdVs in rodents and shrews in China are still unknown. To explore the epidemiological characteristics of rodent and shrew AdVs in southern China, 255 fecal samples derived from four rodent species and 90 from shrews were collected in Xiamen and Guangzhou city of southern China. Amplification of a 314-324-bp fragment from the DNA polymerase gene of AdVs was attempted by using a nested PCR. Twenty-nine (11.4 %) specimens from rodents and one (1.1 %) specimen from shrews were tested positive for AdVs. Phylogenetic analysis revealed that nine samples from Rattus norvegicus in Guangzhou city between 2012 and 2013 might be the genuine AdV of R. norvegicus. The same putative AdV sequences were derived from samples of different host species from different/same places. A novel adenovirus was detected in Suncus murinus Linnaeus (SML/14GDGZ72) for the first time. Our findings provide new data on the prevalence and diversity of AdVs in rodents and shrews. PMID- 26980674 TI - Molecular characterization of a novel reassortant H1N2 influenza virus containing genes from the 2009 pandemic human H1N1 virus in swine from eastern China. AB - Pandemic outbreaks of H1N1 swine influenza virus have been reported since 2009. Reassortant H1N2 viruses that contain genes from the pandemic H1N1 virus have been isolated in Italy and the United States. However, there is limited information regarding the molecular characteristics of reassortant H1N2 swine influenza viruses in eastern China. Active influenza surveillance programs in Zhejiang Province identified a novel H1N2 influenza virus isolated from pigs displaying clinical signs of influenza virus infection. Whole-genome sequencing was performed and this strain was compared with other influenza viruses available in GenBank. Phylogenetic analysis suggested that the novel strain contained genes from the 2009 pandemic human H1N1 and swine H3N2 viruses. BALB/c mice were infected with the isolated virus to assess its virulence in mice. While the novel H1N2 isolate replicated well in mice, it was found to be less virulent. These results provide additional evidence that swine serve as intermediate hosts or 'mixing vessels' for novel influenza viruses. They also emphasize the importance of surveillance in the swine population for use as an early warning system for influenza outbreaks in swine and human populations. PMID- 26980672 TI - Construction of a bivalent DNA vaccine co-expressing S genes of transmissible gastroenteritis virus and porcine epidemic diarrhea virus delivered by attenuated Salmonella typhimurium. AB - Porcine transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV) can cause severe diarrhea in newborn piglets and led to significant economic losses. The S proteins are the main structural proteins of PEDV and TGEV capable of inducing neutralizing antibodies in vivo. In this study, a DNA vaccine SL7207 (pVAXD-PS1-TS) co-expressing S proteins of TGEV and PEDV delivered by attenuated Salmonella typhimurium was constructed and its immunogenicity in piglets was investigated. Twenty-day-old piglets were orally immunized with SL7207 (pVAXD-PS1-TS) at a dosage of 1.6 * 10(11) CFU per piglet and then booster immunized with 2.0 * 10(11) CFU after 2 weeks. Humoral immune responses, as reflected by virus neutralizing antibodies and specific IgG and sIgA, and cellular immune responses, as reflected by IFN-gamma, IL-4, and lymphocyte proliferation, were evaluated. SL7207 (pVAXD-PS1-TS) simultaneously elicited immune responses against TGEV and PEDV after oral immunization. The immune levels started to increase at 2 weeks after immunization and increased to levels statistically significantly different than controls at 4 weeks post-immunization, peaking at 6 weeks and declined at 8 weeks. The humoral, mucosal, and cellular immune responses induced by SL7207 (pAXD-PS1-TS) were significantly higher than those of the PBS and SL7207 (pVAXD) (p < 0.01). In particular, the levels of IFN gamma and IL-4 were higher than those induced by the single-gene vaccine SL7207 (pVAXD-PS1) (p < 0.05). These results demonstrated that SL7207 (pVAXD-PS1-TS) possess the immunological functions of the two S proteins of TGEV and PEDV, indicating that SL7207 (pVAXD-PS1-TS) is a candidate oral vaccine for TGE and PED. PMID- 26980675 TI - The light and the dark sides of Interleukin-10 in immune-mediated diseases and cancer. AB - Interleukin-10 (IL-10) is known to be a tolerogenic cytokine since it inhibits pro-inflammatory cytokine production and T cell stimulatory capacities of myeloid cells, such as macrophages and dendritic cells. In particular, it has a non redundant tolerogenic role in intestinal immune homeostasis, since mice and patients with genetic defects in the IL-10/IL-10R pathway develop spontaneously colitis in the presence of a normal intestinal flora. However, IL-10 is also a growth and differentiation factor for B-cells, can promote autoantibody production and has consequently a pathogenic role in systemic lupus erythematosus. Moreover, IL-10 can promote cytotoxic T-cell (CTL) responses and this immunogenic activity might be relevant in type-1 diabetes and anti-tumor immune responses. This review summarizes these paradoxic effects of IL-10 on different types of immune responses, and proposes that different cellular sources of IL-10, in particular IL-10-secreting helper and regulatory T-cells, have different effects on B-cell and CTL responses. Based on this concept we discuss the rationales for targeting the IL-10 pathway in immune-mediated diseases and cancer. PMID- 26980676 TI - Stimulator of interferon genes (STING): A "new chapter" in virus-associated cancer research. Lessons from wild-derived mouse models of innate immunity. AB - Thanks to the numerous studies that have been carried out recently in the field of cytosolic DNA sensing, STING (Stimulator of Interferon Genes) is now recognized as a key mediator of innate immune signaling. A substantial body of evidence derived from in vivo mouse models demonstrates that STING-regulated pathways underlie the pathogenesis of many diseases including infectious diseases and cancers. It has also become evident from these studies that STING is a promising therapeutic target for the treatment of cancer. However, mouse strains commonly used for modelling innate immune response against infections or tumors do not allow investigators to accurately reproduce certain specific characteristics of immune response observed in human cells. In this review, we will discuss recent data demonstrating that the use of wild-derived genetically distinct inbred mice as a model for investigation into the innate immunity signaling networks may provide valuable insight into the STING-regulated pathways specific for human cells. The maximum complexity of STING-mediated mechanisms can probably be seen in case of DNA virus-induced carcinogenesis in which STING may perform unexpected biological activities. Therefore, in another part of this review we will summarize emerging data on the role of STING in human DNA virus related oncopathologies, with particular attention to HPV-associated cervical cancer, aiming to demonstrate that STING indeed "starts a new chapter" in research on this issue and that wild-derived mouse models of STING-mediated response to infections will probably be helpful in finding out molecular basis for clinical observations. PMID- 26980677 TI - A biochar-based medium in the biofiltration system: Removal efficiency, microorganism propagation, and the medium penetration modeling. AB - Biofiltration is a method of biological treatment belonging to cleaner technologies because it does not produce secondary air pollutants, but helps to integrate natural processes in microorganisms for decomposing volatile air pollutants and solving odor problems. The birch wood biochar has been chosen as a principal material for biofilter bed medium. The experiments were conducted at the temperatures of 24, 28, and 32 degrees C, while the concentration of acetone, xylene, and ammonium reached 300 mg/m(3) and the flow rate was 100 m(3)/hr. Before passing through the stage of the experimental research into the packing material inside biofilters, microorganisms were introduced. Four strains of microorganisms (including micromycetes Aspergillus versicolor BF-4 and Cladosporium herbarum 7KA, as well as yeast Exophiala sp. BF1 and bacterium Bacillus subtilis B20) were selected. At the inlet loading rate of 120 g/m(3)/hr, the highest elimination capacity of xylene in the biochar-based biofilter with the inoculated medium was 103 g/m(3)/hr, whereas that of ammonia was 102 g/m(3)/hr and that of acetone was 97 g/m(3)/hr, respectively. The maximum removal efficiency reached 86%, 85%, and 81%, respectively. The temperature condition (though characterized by some rapid changes) can hardly have a considerable influence on the biological effect (i.e., microbiological activity) of biofiltration; however, it can cause the changes in physical properties (e.g., solubility) of the investigated compounds. IMPLICATIONS: The birch biochar can be successfully used in the biofiltration system for propagation of inoculated microorganisms, biodegrading acetone, xylene, and ammonia. At the inlet loading rate of 120 g/m(3)/hr, the highest elimination capacity of xylene was 103 g/m(3)/hr, that of ammonia was 102 g/m(3)/hr, and that of acetone was 97 g/m(3)/hr, respectively. The morphological structure of biochar can be affected by the aggressive air contaminants, causing the change in the medium specific surface area, which is one of the factors controlling the biofilter performance. Although biological effects in biofiltration are typically considered to be more important than physical effects, the former may be more important for compounds with high Henry's Law coefficient values, and the biofilter design should thus provide conditions for better compound absorption. PMID- 26980678 TI - Aqueous phase hydration and hydrate acidity of perfluoroalkyl and n:2 fluorotelomer aldehydes. AB - The SPARC software program and comparative density functional theory (DFT) calculations were used to investigate the aqueous phase hydration equilibrium constants (Khyd) of perfluoroalkyl aldehydes (PFAlds) and n:2 fluorotelomer aldehydes (FTAlds). Both classes are degradation products of known industrial compounds and environmental contaminants such as fluorotelomer alcohols, iodides, acrylates, phosphate esters, and other derivatives, as well as hydrofluorocarbons and hydrochlorofluorocarbons. Prior studies have generally failed to consider the hydration, and subsequent potential hydrate acidity, of these compounds, resulting in incomplete and erroneous predictions as to their environmental behavior. In the current work, DFT calculations suggest that all PFAlds will be dominantly present as the hydrated form in aqueous solution. Both SPARC and DFT calculations suggest that FTAlds will not likely be substantially hydrated in aquatic systems or in vivo. PFAld hydrates are expected to have pKa values in the range of phenols (ca. 9 to 10), whereas n:2 FTAld hydrates are expected to have pKa values ca. 2 to 3 units higher (ca. 12 to 13). In order to avoid spurious modeling predictions and a fundamental misunderstanding of their fate, the molecular and/or dissociated hydrate forms of PFAlds and FTAlds need to be explicitly considered in environmental, toxicological, and waste treatment investigations. The results of the current study will facilitate a more complete examination of the environmental fate of PFAlds and FTAlds. PMID- 26980679 TI - [Not Available]. PMID- 26980680 TI - [CME: Autosomal dominant polycystic kidney disease]. PMID- 26980682 TI - [Effectiveness of an inpatient multimodal psychiatric-psychotherapeutic program for the treatment of job burnout]. AB - We studied the clinical course and long-term effects of inpatient treatment in 723 patients with job burnout referred with an ICD-10 F diagnosis and Z73.0 code ("overwhelming exhaustion") to a Swiss hospital specialized in the treatment of job stress-related disorders. Patients were characterized in terms of age, gender, socioeconomic status. Self-rated psychological measures related to general and burnout-specific symptoms (i. e., emotional exhaustion, depersonalization, and diminished personal accomplishments) were applied before and after a six-week treatment program, as well as at 15 months after hospital discharge in 232 patients. The results show that the multimodal inpatient psychiatric-psychotherapeutic treatment was successful with a sustainable effect on psychological well-being (>90 %), including improvements regarding emotional exhaustion, depersonalization and personal accomplishments as well as professional reintegration in 71 % of cases. PMID- 26980683 TI - [Problems with Ureteral Stents - a Never-Ending Story]. AB - Temporary drainage of the upper urinary tract by internal ureteral stents is a common procedure to assure renal function and to treat pain caused by ureteral obstruction. Ureteral stents are frequently associated with side effects like urinary symptoms, pain or hematuria resulting in frequent medical consultations. In addition to good patient education, symptomatic drug therapy of stent associated symptoms is often indicated and sufficient. However, complications like stent dysfunction or significant urinary tract infections have to be kept in mind, as they require further diagnostics and treatment. Therefore, especially general practitioners as a primary point of contact for the patients should be familiar with common ureteral stent-associated problems, their treatment and indications for patient referrals. PMID- 26980685 TI - [Serious Headache]. AB - A patient with fever, headache and discrete neurologic symptoms developed a coma followed by severe paralysis. The cause was a tick-borne encephalitis. In the follow-up, the patient required supportive care on the intensive care unit for almost two months and further on, a rehabilitation of almost seven months was needed. The patient has not been vaccinated, even though he fulfilled the criteria for the recommendation of vaccination because he occasionally visited areas at risk. PMID- 26980684 TI - [Gliomas - What I Have to Know in ten Questions]. AB - Gliomas are the most common primary tumors involving the central nervous system. They can manifest with diverse and non-specific general and neurological symptoms. The diagnostic gold standard is cerebral magnetic resonance imaging and subsequent histological confirmation of the diagnosis. Steroids, especially dexamethasone, are used in case of focal symptoms and of symptoms caused by increased intracranial pressure, and antiepileptic drugs are used to manage epileptic seizures. Non-enzyme-inducing antiepileptic drugs are preferable. Glioma patients have an inherently elevated thromboembolic risk, and therapeutic anticoagulation is indicated following a thromboembolic event. Surgery, radiotherapy and systemic therapy are used as tumor-specific therapy modalities in gliomas. Molecular markers play an increasing role in the prognosis and selection of therapy in daily oncological routine. PMID- 26980686 TI - [An Uncommon Cerebral Lesion in Computed Tomography]. AB - We report the case of a 84-year-old man who suffered a hematoma of the septum pellucidum due to a fall. The development of the septum pellucidum and its implications on pathomechanisms in head injury are discussed. In the setting of trauma, a reliable differentiation to other septal lesions can be impossible in computed tomography alone, unless earlier examinations are availabe for comparison. Additional magnetic resonance imaging may be warranted in case of vicinity of the lesion to the interventricular foramina. PMID- 26980687 TI - [Correct and safe treatment of acute, uncomplicated diverticulitis]. PMID- 26980688 TI - [Empagliflozin: an oral antidiabetic with documented positive effect on cardiac mortality]. PMID- 26980694 TI - Are campus food environments healthy? A novel perspective for qualitatively evaluating the nutritional quality of food sold at foodservice facilities at a Brazilian university. AB - AIMS: The purpose of this novel study was to evaluate the food environment at a Brazilian university, encompassing 6 restaurants and 13 snack bars. The investigation uniquely analyses the food environment (barriers, facilitators, type of foods and prices). This was a food-based analysis of the nutritional quality of the products sold on campus. METHODS: A cross-sectional descriptive design was used, applying the classic Nutrition Environment Measures Survey Restaurants (NEMS-R) adapted for Brazil and an original methodology to evaluate and classify qualitatively the nutritional quality and characteristics of the food. A census of all campus food environments was applied. RESULTS: The main results show most food and beverage products were made with processed ingredients and had a lower nutritional quality and price when compared with similar products made on premises, that is, processed iced tea compared with fresh tea ( p < .001), fried refined flour salgados compared with baked wholegrain flour salgados ( p < .001) and refined flour biscuits compared with those made with whole grains ( p = .028). Only 16% of the outlets provided food ingredients or nutritional information of products available. CONCLUSION: The overall options for healthy food choices and good nutritional quality on campus were mostly limited by the availability and higher prices of products. These findings could be used to develop new policy perspectives for the offering of healthy food items and to facilitate better food choices among students in a healthier food environment. PMID- 26980693 TI - Ferritin cage for encapsulation and delivery of bioactive nutrients: From structure, property to applications. AB - Ferritin is a class of naturally occurring iron storage proteins, which is distributed widely in animal, plant, and bacteria. It usually consists of 24 subunits that form a hollow protein shell with high symmetry. One holoferritin molecule can store up to 4500 iron atom within its inner cavity, and it becomes apoferritin upon removal of iron from the cavity. Recently, scientists have subverted these nature functions and used reversibly self-assembled property of apoferritin cage controlled by pH for the encapsulation and delivery of bioactive nutrients or anticancer drug. In all these cases, the ferritin cages shield their cargo from the influence of external conditions and provide a controlled microenvironment. More importantly, upon encapsulation, ferritin shell greatly improved the water solubility, thermal stability, photostability, and cellular uptake activity of these small bioactive compounds. This review aims to highlight recent advances in applications of ferritin cage as a novel vehicle in the field of food science and nutrition. Future outlooks are highlighted with the aim to suggest a research line to follow for further studies. PMID- 26980695 TI - Distinct Biochemical Activities of Eyes absent During Drosophila Eye Development. AB - Eyes absent (Eya) is a highly conserved transcriptional coactivator and protein phosphatase that plays vital roles in multiple developmental processes from Drosophila to humans. Eya proteins contain a PST (Proline-Serine-Threonine)-rich transactivation domain, a threonine phosphatase motif (TPM), and a tyrosine protein phosphatase domain. Using a genomic rescue system, we find that the PST domain is essential for Eya activity and Dac expression, and the TPM is required for full Eya function. We also find that the threonine phosphatase activity plays only a minor role during Drosophila eye development and the primary function of the PST and TPM domains is transactivation that can be largely substituted by the heterologous activation domain VP16. Along with our previous results that the tyrosine phosphatase activity of Eya is dispensable for normal Eya function in eye formation, we demonstrate that a primary function of Eya during Drosophila eye development is as a transcriptional coactivator. Moreover, the PST/TPM and the threonine phosphatase activity are not required for in vitro interaction between retinal determination factors. Finally, this work is the first report of an Eya-Ey physical interaction. These findings are particularly important because they highlight the need for an in vivo approach that accurately dissects protein function. PMID- 26980697 TI - VEGF Promotes Glycolysis in Pancreatic Cancer via HIF1alpha Up-Regulation. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is highly expressed in many types of tumors, including pancreatic cancer. Tumor cellderived VEGF promotes angiogenesis and tumor progression. However, the role of VEGF in glucose metabolism remains unclear. OBJECTIVE: We investigated the role and the underlying mechanism of VEGF in the glucose metabolism of pancreatic cancer cells. METHOD: Pancreatic cancer cells were stimulated with VEGF165 for 1 or 2 h. The oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) were measured using the Seahorse XF96 Extracellular Flux Analyzer. Glycolytic enzymes were detected by quantitative real-time PCR. Neuropilin 1 (NRP1) was silenced by shRNA in order to investigate its role in VEGF-induced glycolysis. Immunohistochemistry (IHC) was performed to identify the correlation among VEGF, NRP1 and hypoxia inducible factor 1alpha (HIF1alpha) in pancreatic cancer tissues. RESULTS: VEGF stimulation led to a metabolic transition from mitochondrial oxidative phosphorylation to glycolysis in pancreatic cancer. HIF1alpha and NRP1 protein levels were both increased after VEGF stimulation. The down-regulation of NRP1 reduced glycolysis in pancreatic cancer cells. NRP1 and VEGF levels both correlated with HIF1alpha expression in pancreatic tumor tissues. CONCLUSION: VEGF enhances glycolysis in pancreatic cancer via HIF1alpha up-regulation. NRP1 plays a key role in VEGF-induced glycolysis. PMID- 26980696 TI - MBD1 is an Epigenetic Regulator of KEAP1 in Pancreatic Cancer. AB - BACKGROUND: MBD1 (Methyl-CpG Binding Domain Protein 1) is highly expressed in pancreatic cancer. Nrf2 (NF-E2 p45-related factor 2) and the 'antioxidant response element' (ARE)-driven genes that NRF2 controls are frequently upregulated in pancreatic cancer and correlate with poor survival. Keap1 (Kelch like ECH-associated protein 1) is a dominant negative regulator of NRF2 and is reported to be epigenetically regulated by promoter methylation. However, the role of MBD1 with antioxidant response and its association with KEAP1 has never been reported before and remains unclear. OBJECTIVE: We investigated the role of MBD1 in antioxidant response and its regulatory function in KEAP1 transcription in pancreatic cancer cells. METHOD: MBD1 was silenced to examine its role in antioxidant response. To explore the underlying mechanism, transcriptional and protein levels of KEAP1 was examined. The correlation between MBD1 and KEAP1 was confirmed in pancreatic cancer tissue samples by using immunohistochemistry (IHC). Dualluciferase reporter assay and Chromatin immunoprecipitation (ChIP) were used to elucidate he mechanism of MBD1 in KEAP1 transcriptional control. Moreover, co-immunoprecipitation (CoIP) assay was performed to uncover the regulatory role of MBD1 in KEAP1 transcription through its association with c myc. RESULTS: MBD1 silencing decreased antioxidant response and the related ARE target genes through epigenetic regulation of KEAP1. MBD1 negatively correlated with KEAP1 in pancreatic cancer tissue samples. Moreover, c-myc was a MBD1 interaction partner in KEAP1 epigenetic regulation. CONCLUSION: MBD1 can induce antioxidant response in pancreatic cancer through down-regulation of KEAP1. c-myc plays a key role in MBD1 mediated epigenetic silencing of KEAP1. PMID- 26980698 TI - Higher Expression of NOD1 and NOD2 is Associated with Vogt-Koyanagi-Harada (VKH) Syndrome But Not Behcet's Disease (BD). AB - NOD1 and NOD2 have been found to play a significant regulatory role in autoimmune disease. To analyze the role of NOD1 and NOD2 in the pathogenesis of Vogt- Koyanagi-Harada (VKH) syndrome and Behcet's disease (BD). We analyzed the expression of NOD1 and NOD2 from PBMCs by RT-PCR and Western Blot. PBMCs and DCs were cultured with NOD receptor ligands iE-DAP (NOD1) or MDP (NOD2) and cells and supernatants were analyzed by flow cytometry (FCM) and enzyme-linked immunosorbent assay (ELISA). DCs and CD4+T cells were co-cultured with or without stimulation and cells and supernatants were analyzed by FCM and ELISA. A higher expression of NOD1 and NOD2 was observed in patients with active VKH syndrome as compared with controls. However, no significant differences were found between BD patients and controls. Activation of NOD1 and NOD2 with iE-DAP or MDP markedly increased the level of IL-6, TNF-alpha and IL-1beta in PBMCs and DCs and induced the expression of CD40, CD80, CD83, CD86 and HLA-DR on DCs. Activation of NOD1 and NOD2 in DCs promoted the differentiation and proliferation of CD4(+)T cells. In conclusion, activation of NOD1 or NOD2 increased the production of pro inflammatory cytokines in PBMCs and promoted the maturation and activation of human DCs in association with stimulation of Th1 and Th17 cells. Our results suggest that over-expression of NOD1 and NOD2 may be involved in the pathogenesis of VKH syndrome. PMID- 26980700 TI - The Impact of CRISPR/Cas9-Based Genomic Engineering on Biomedical Research and Medicine. AB - There has been prolonged and significant interest in manipulating the genome for a wide range of applications in biomedical research and medicine. An existing challenge in realizing this potential has been the inability to precisely edit specific DNA sequences. Past efforts to generate targeted double stranded DNA cleavage have fused DNA-targeting elements such as zinc fingers and DNA-binding proteins to endonucleases. However, these approaches are limited by both design complexity and inefficient, costineffective operation. The discovery of CRISPR/Cas9, a branch of the bacterial adaptive immune system, as a potential genomic editing tool holds the promise of facile targeted cleavage. Its novelty lies in its RNA-guided endonuclease activity, which enhances its efficiency, scalability, and ease of use. The only necessary components are a Cas9 endonuclease protein and an RNA molecule tailored to the gene of interest. This lowbarrier of adoption has facilitated a plethora of advances in just the past three years since its discovery. In this review, we will discuss the impact of CRISPR/Cas9 on biomedical research and its potential implications in medicine. PMID- 26980702 TI - HOX Genes as Potential Markers of Circulating Tumour Cells. AB - Circulating tumour cells (CTCs) have significant diagnostic potential as they can reflect both the presence and recurrence of a wide range of cancers. However, this potential continues to be limited by the lack of robust and accessible isolation technologies. An alternative to isolation might be their direct detection amongst other peripheral blood cells, although this would require markers that allow them to be distinguished from an exceptionally high background signal. This review assesses the potential role of HOX genes, a family of homeodomain containing transcription factors with key roles in both embryonic development and oncogenesis, as unique and possibly disease specific markers of CTCs. PMID- 26980701 TI - Prostacyclin, Atherothrombosis and Diabetes Mellitus: Physiologic and Clinical Considerations. AB - Prostacyclin (PGI2) and other metabolites of arachidonic acid are increasingly recognized for their role in the pathophysiology of human disease. A growing body of evidence from randomized controlled trials, studies of human prostacyclin receptor (hIP) variants, and IP-receptor knockout studies in mice has shown that PGI2 may have a protective effect on atherothrombotic risk. Increased risk of atherosclerosis and thrombotic sequelae may be attributed, in part, to downregulation of the prostacyclin pathway. Clinical studies with nonsteroidal antiinflammatory drugs (NSAIDs) that were selective for the cyclooxygenase-2 (COX 2) isoenzyme, although protective of mucosa in the gastrointestinal tract, first alluded to a potential role of PGI2 in atherothrombotic risk. Outcomes from early clinical trials showed a 2- to 3-fold increase in risk of incurring a thrombotic event (e.g., myocardial infarction or stroke). Further analyses suggested that atherothrombotic risk is a continuous variable with relative NSAID COX-2 selectivity, and that the COX-2 metabolic product, PGI2, appears to play a key role. Effects of reduced PGI2 levels may be felt in particular by patients with diabetes mellitus, a patient population at the high end of the cardiovascular risk spectrum. Therapies that spare PGI2 may provide the greatest level of protection. The mechanism of protection by PGI2 is under intense investigation. PMID- 26980703 TI - Preparation of a Chicken scFv to Analyze Gentamicin Residue in Animal Derived Food Products. AB - Chicken is an ideal model for simplified recombinant antibody library generation. It has been rarely been reported to apply chicken single-chain variable fragments (scFvs) in immunoassays for the detection of antibiotic and chemical contaminants in animal food products. In this study, the scFvs (S-1 and S-5) were isolated from a phage display library derived from a hyperimmunized chicken. The checker board titration revealed that the optimum concentrations of S-1 and S-5 were 0.78 MUg/mL and 0.44 MUg/mL respectively, to obtain OD450 around 1.0 at 5 MUg/mL of Gent-OVA coating concentration. Both S-1 and S-5 exhibited negligible cross reactivity with kanamycin and amikacin. The 50% inhibitory concentration (IC50) of S-1 and S-5 were 12.418 ng/mL and 14.674 ng/mL respectively. In the indirect competitive ELISA (ic-ELISA), the limits of detection for S-1 and S-5 were 0.147 ng/mL and 0.219 ng/mL respectively. The mean recovery for Gent ranged from 60.91% to 118.09% with no more than 10.35% relative standard deviation (RSD) between the intra-assay and the inter-assay. These results indicate the chicken scFv based ic ELISA method is suitable for the detection of Gent residue in animal derived edible tissues and milk. PMID- 26980704 TI - Luteinizing hormone-releasing hormone peptide tethered nanoparticulate system for enhanced antitumoral efficacy of paclitaxel. AB - AIM: Paclitaxel (PTX) is an effective anticancer agent used in the therapy of a wide variety of cancers. However, the drug is difficult to formulate due to its low solubility, and therefore, it is administered under slow infusion with castor oil/ethanol solution as surfactant that causes serious side effects. This investigation investigates leutinizing hormone releasing hormone (LHRH)-tethered nanparticulate system as modality for cancer-specific delivery of PTX and therefore minimizing the adverse effects. MATERIALS & METHODS: LHRH-tethered poly(lactic-co-glycolic acid) copolymer with poly ethylene glycol side chain was synthesized, characterized and employed to formulate PTX-loaded nanoparticulate system. RESULTS & CONCLUSION: The developed nanoparticulate appears to be proficient in carrying as well as targeted delivery of PTX with improved therapeutic efficacy and better safety. PMID- 26980705 TI - Instigation of NLRP3 inflammasome activation and glomerular injury in mice on the high fat diet: role of acid sphingomyelinase gene. AB - Ceramide has been reported to initiate inflammasome formation and activation in obesity and different pathological conditions. The present study was performed to explore the role of acid sphingomyelinase (Asm) in the development of high fat diet (HFD)-induced inflammasome and activation and consequent glomerular injury. Asm knockout (Asm(-/-)) and wild type (Asm(+/+)) mice with or without Asm short hairpin RNA (shRNA) transfection were fed a HFD or normal chow for 12 weeks to produce obesity and associated glomerular injury. HFD significantly enhanced the Asm activity, ceramide production, colocalization of Nlrp3 (Nod-like receptor protein 3) with ASC (apoptosis-associated speck-like protein) or Caspase-1, NADPH dependent superoxide (O2(*-)) production in glomeruli of Asm(+/+) mice than in control diet-fed mice. However, such HFD-induced increases in Asm activity, ceramide production, colocalization of Nlrp3 with ASC or Caspase-1, superoxide (O(2*-)) production was attenuated in Asm(-/-) or Asm shRNA-transfected wild-type mice. In consistency with decreased inflammasome formation, the caspase-1 activity and IL-1beta production was significantly attenuated in Asm(-/-) or Asm shRNA-transfected wild-type mice fed a HFD. Morphological examinations showed that HFD-induced profound injury in glomeruli of Asm(+/+) mice which was markedly attenuated in Asm(-/-) mice. The decreased glomerular damage index in Asm(-/-) mice was accompanied by attenuated proteinuria. Fluorescent immunohistochemical examinations using podocin as a podocyte marker showed that inflammasome formation induced by the HFD were mostly located in podocytes as demonstrated by co-localization of podocin with Nlrp3. In conclusion, these observations disclose a pivotal role of Asm in the HFD-induced inflammasome formation and consequent glomerular inflammation and injury. PMID- 26980706 TI - The Bif-1-Dynamin 2 membrane fission machinery regulates Atg9-containing vesicle generation at the Rab11-positive reservoirs. AB - Atg9 is a multispanning transmembrane protein that is required for autophagosome formation. During autophagy, vesicles containing Atg9 are generated through an unknown mechanism and delivered to the autophagosome formation sites. We have previously reported that Atg9-containing membranes undergo continuous tubulation and fission during nutrient starvation in a manner dependent on the curvature inducing protein Bif-1/Sh3glb1. Here, we identify Dynamin 2 (DNM2) as a Bif-1 interacting protein that mediates the fission of Atg9-containing membranes during autophagy. The interaction of Bif-1 and DNM2 is enhanced upon nutrient starvation, and Bif-1 and DNM2 cooperatively induce the generation of Atg9 containing vesicles. Inhibition of the GTPase activity of DNM2 results in the accumulation of Atg9-positive tubular structures that originate from a Rab11 positive reservoir. Although Atg9 seems to be constitutively trafficked to the reservoir regardless of Bif-1 expression, membrane tubulation from the Atg9 reservoir is dependent on Bif-1 and is strongly induced upon nutrient starvation. These findings suggest that the generation of Atg9 vesicles from a Rab11-positive reservoir is tightly controlled by the Bif-1-DNM2 membrane fission machinery in response to cellular demand for autophagy. PMID- 26980699 TI - The High Mobility Group A1 (HMGA1) Transcriptome in Cancer and Development. AB - BACKGROUND & OBJECTIVES: Chromatin structure is the single most important feature that distinguishes a cancer cell from a normal cell histologically. Chromatin remodeling proteins regulate chromatin structure and high mobility group A (HMGA1) proteins are among the most abundant, nonhistone chromatin remodeling proteins found in cancer cells. These proteins include HMGA1a/HMGA1b isoforms, which result from alternatively spliced mRNA. The HMGA1 gene is overexpressed in cancer and high levels portend a poor prognosis in diverse tumors. HMGA1 is also highly expressed during embryogenesis and postnatally in adult stem cells. Overexpression of HMGA1 drives neoplastic transformation in cultured cells, while inhibiting HMGA1 blocks oncogenic and cancer stem cell properties. Hmga1 transgenic mice succumb to aggressive tumors, demonstrating that dysregulated expression of HMGA1 causes cancer in vivo. HMGA1 is also required for reprogramming somatic cells into induced pluripotent stem cells. HMGA1 proteins function as ancillary transcription factors that bend chromatin and recruit other transcription factors to DNA. They induce oncogenic transformation by activating or repressing specific genes involved in this process and an HMGA1 "transcriptome" is emerging. Although prior studies reveal potent oncogenic properties of HMGA1, we are only beginning to understand the molecular mechanisms through which HMGA1 functions. In this review, we summarize the list of putative downstream transcriptional targets regulated by HMGA1. We also briefly discuss studies linking HMGA1 to Alzheimer's disease and type-2 diabetes. CONCLUSION: Further elucidation of HMGA1 function should lead to novel therapeutic strategies for cancer and possibly for other diseases associated with aberrant HMGA1 expression. PMID- 26980707 TI - Oridonin, a novel lysine acetyltransferases inhibitor, inhibits proliferation and induces apoptosis in gastric cancer cells through p53- and caspase-3-mediated mechanisms. AB - Lysine acetylation has been reported to involve in the pathogenesis of multiple diseases including cancer. In our screening study to identify natural compounds with lysine acetyltransferase inhibitor (KATi) activity, oridonin was found to possess acetyltransferase-inhibitory effects on multiple acetyltransferases including P300, GCN5, Tip60, and pCAF. In gastric cancer cells, oridonin treatment inhibited cell proliferation in a concentration-dependent manner and down-regulated the expression of p53 downstream genes, whereas p53 inhibition by PFT-alpha reversed the antiproliferative effects of oridonin. Moreover, oridonin treatment induced cell apoptosis, increased the levels of activated caspase-3 and caspase-9, and decreased the mitochondrial membrane potential in gastric cancer cells in a concentration-dependent manner. Caspase-3 inhibition by Ac-DEVD-CHO reversed the proapoptosis effect of oridonin. In conclusion, our study identified oridonin as a novel KATi and demonstrated its tumor suppressive effects in gastric cancer cells at least partially through p53-and caspase-3-mediated mechanisms. PMID- 26980708 TI - shRNA-armed conditionally replicative adenoviruses: a promising approach for cancer therapy. AB - The small-interfering RNAs (siRNAs) have been employed to knockdown the expression of cancer-associated genes and shown some promise in cancer therapy. However, synthetic siRNA duplexes or plasmid mediated delivery of siRNAs have several problems, such as short half-life, low transfection efficiency and cytotoxicity associated with transfection. Conditionally replicating adenovirus (CRAds) as the delivery vector for short hairpin RNAs (shRNAs) could overcome these limitations and have shown augmented anti-tumor effects in experimental studies and preclinical trials. In this review, we summarize recent progress in the development of CRAds-shRNA for cancer treatment. Combination of CRAds-shRNA with chemotherapeutics, radiation, dendritic cells, monoclonal antibodies and small-molecule inhibitors will be necessary to eradicate cancer cells and cancer stem cells and achieve superior outcomes. The use of CRAd platform for efficient delivery of shRNAs and foreign genes will open a new avenue for cancer therapy. PMID- 26980709 TI - ERalpha propelled aberrant global DNA hypermethylation by activating the DNMT1 gene to enhance anticancer drug resistance in human breast cancer cells. AB - Drug-induced aberrant DNA methylation is the first identified epigenetic marker involved in chemotherapy resistance. Understanding how the aberrant DNA methylation is acquired would impact cancer treatment in theory and practice. In this study we systematically investigated whether and how ERalpha propelled aberrant global DNA hypermethylation in the context of breast cancer drug resistance. Our data demonstrated that anticancer drug paclitaxel (PTX) augmented ERalpha binding to the DNMT1 and DNMT3b promoters to activate DNMT1 and DNMT3b genes, enhancing the PTX resistance of breast cancer cells. In support of these observations, estrogen enhanced multi-drug resistance of breast cancer cells by up-regulation of DNMT1 and DNMT3b genes. Nevertheless, the aberrant global DNA hypermethylation was dominantly induced by ERalpha-activated-DNMT1, since DNMT1 over-expression significantly increased global DNA methylation and DNMT1 knockdown reversed the ERalpha-induced global DNA methylation. Altering DNMT3b expression had no detectable effect on global DNA methylation. Consistently, the expression level of DNMT1 was positively correlated with ERalpha in 78 breast cancer tissue samples shown by our immunohistochemistry (IHC) analysis and negatively correlated with relapse-free survival (RFS) and distance metastasis free survival (DMFS) of ERalpha-positive breast cancer patients. This study provides a new perspective for understanding the mechanism underlying drug resistance-facilitating aberrant DNA methylation in breast cancer and other estrogen dependent tumors. PMID- 26980711 TI - The effect of resveratrol on beta amyloid-induced memory impairment involves inhibition of phosphodiesterase-4 related signaling. AB - Resveratrol, a natural polyphenol found in red wine, has wide spectrum of pharmacological properties including antioxidative and antiaging activities. Beta amyloid peptides (Abeta) are known to involve cognitive impairment, neuroinflammatory and apoptotic processes in Alzheimer's disease (AD). Activation of cAMP and/or cGMP activities can improve memory performance and decrease the neuroinflammation and apoptosis. However, it remains unknown whether the memory enhancing effect of resveratrol on AD associated cognitive disorders is related to the inhibition of phosphodiesterase 4 (PDE4) subtypes and subsequent increases in intracellular cAMP and/or cGMP activities. This study investigated the effect of resveratrol on Abeta1-42-induced cognitive impairment and the participation of PDE4 subtypes related cAMP or cGMP signaling. Mice microinfused with Abeta1-42 into bilateral CA1 subregions displayed learning and memory impairment, as evidenced by reduced memory acquisition and retrieval in the water maze and retention in the passive avoidance tasks; it was also significant that neuroinflammatory and pro-apoptotic factors were increased in Abeta1-42-treated mice. Abeta1-42-treated mice also increased in PDE4A, 4B and 4D expression, and decreased in PKA level. However, PKA inhibitor H89, but not PKG inhibitor KT5823, prevented resveratrol's effects on these parameters. Resveratrol also reversed Abeta1-42-induced decreases in phosphorylated cAMP response-element binding protein (pCREB), brain derived neurotrophic factor (BDNF) and anti-apoptotic factor BCl-2 expression, which were reversed by H89. These findings suggest that resveratrol reversing Abeta-induced learning and memory disorder may involve the regulation of neuronal inflammation and apoptosis via PDE4 subtypes related cAMP CREB-BDNF signaling. PMID- 26980710 TI - FAK and paxillin, two potential targets in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer in large part due to late diagnosis and a lack of effective screening tests. In spite of recent progress in imaging, surgery and new therapeutic options for pancreatic cancer, the overall five-year survival still remains unacceptably low. Numerous studies have shown that focal adhesion kinase (FAK) is activated in many cancers including PDAC and promotes cancer progression and metastasis. Paxillin, an intracellular adaptor protein that plays a key role in cytoskeletal organization, connects integrins to FAK and plays a key role in assembly and disassembly of focal adhesions. Here, we have reviewed evidence in support of FAK as a potential therapeutic target and summarized related combinatorial therapies. PMID- 26980712 TI - Honoring Indigenous culture-as-intervention: Development and validity of the Native Wellness AssessmentTM. AB - There is a need for Indigenous-centered research to appraise culture's role in wellness. Researchers described the development and validity of the Native Wellness Assessment (NWATM). The NWA has culture-as-intervention at its apex. Wellness, culture, and cultural intervention practices (CIPs) are explored from an Indigenous perspective. Indigenous clients completed matching self-report and observer versions of the NWA at three time points during addictions treatment. Statistically and psychometrically, the NWA content and structure performed well, demonstrating that culture is an effective and fair intervention for Indigenous peoples with addictions. The NWA can inform Indigenous health and community-based programs and policy. PMID- 26980713 TI - A triangular connection between Cyclin G, PP2A and Akt1 in the regulation of growth and metabolism in Drosophila. AB - Size and weight control is a tightly regulated process, involving the highly conserved Insulin receptor/target of rapamycin (InR/TOR) signaling cascade. We recently identified Cyclin G (CycG) as an important modulator of InR/TOR signaling activity in Drosophila. cycG mutant flies are underweight and show a disturbed fat metabolism resembling TOR mutants. In fact, InR/TOR signaling activity is disturbed in cycG mutants at the level of Akt1, the central kinase linking InR and TORC1. Akt1 is negatively regulated by protein phosphatase PP2A. Notably the binding of the PP2A B'-regulatory subunit Widerborst (Wdb) to Akt1 is differentially regulated in cycG mutants, presumably by a direct interaction of CycG and Wdb. Since the metabolic defects of cycG mutant animals are abrogated by a concomitant loss of Wdb, CycG presumably influences Akt1 activity at the PP2A nexus. Here we show that Well rounded (Wrd), another B' subunit of PP2A in Drosophila, binds CycG similar to Wdb, and that its loss ameliorates some, but not all, of the metabolic defects of cycG mutants. We propose a model, whereby the binding of CycG to a particular B'-regulatory subunit influences the tissue specific activity of PP2A, required for the fine tuning of the InR/TOR signaling cascade in Drosophila. PMID- 26980714 TI - A game of two discs: a case of non-contiguous and occult cervical spine injury in a rugby player. AB - The aim of this case report was to highlight the application of magnetic resonance imaging (MRI) in elucidating serious and occult injuries in a single case of hyperflextion injury of a patient cervical spine (C-Spine). A chart and radiology review was performed to establish the sequence of care and how the results of imaging studies influenced the clinical management in this trauma case. Plain radiographs and computed tomography (CT) imaging modalities of the C Spine revealed bilateral C4/C5 facetal subluxation with no obvious fractures; however, the MR imaging of the C-Spine revealed a non-contiguous and occult injury to C6/C7 disc with a posterior annular tear and associated disc extrusion. This altered the operative intervention that was initially planned. MR imaging proved an invaluable diagnostic addition in this particular case of cervical trauma in a rugby player following a hyperflextion injury, by revealing a serious non-contiguous and occult injury of the C-Spine. PMID- 26980716 TI - Antibiotic resistance in children with E coli urinary tract infection. PMID- 26980717 TI - Shedding a Light on Phototherapy Studies with People having Dementia: A Critical Review of the Methodology from a Light Perspective. AB - Light therapy is applied to older people with dementia as a treatment to reset the biological clock, to improve the cognitive functioning, and to reduce behavioral symptoms. Although the methodological quality of light therapy studies is essential, many aspects concerning the description of the lighting applied are missing. This study reviewed light therapy studies concerning the effects on people with dementia as a way to check the methodological quality of the description of light from a light engineering perspective. Twelve studies meeting the inclusion criteria were chosen for further analysis. Each study was scored on a list of aspects relevant to a proper description of lighting aspects. The overview demonstrates that the overall quality of the methodologies is poor. The studies describe the lighting insufficiently and not in the correct metrics. The robustness of light therapy studies can be improved by involving a light engineer or specialist. PMID- 26980718 TI - Hydrogen Proton Magnetic Resonance Spectroscopy in Multidomain Amnestic Mild Cognitive Impairment and Vascular Cognitive Impairment Without Dementia. AB - To investigate the value of hydrogen proton magnet resonance spectroscopy ((1)H MRS) in the differential diagnosis of multiple-domain amnestic mild cognitive impairment (M-aMCI) and vascular cognitive impairment with no dementia (VCIND); (1)H-MRS was performed in patients with M-aMCI and VCIND. The level was determined for N-acetylaspartate (NAA), glutamate (Glu), inositol (mI), choline (Cho), and creatine (Cr). Compared with the normal control group, the NAA-Cr ratio in all regions studied was significantly lower in the M-aMCI and VCIND groups. The Glu-Cr ratio in the posterior cingulate gyrus of the M-aMCI group was significantly lower than in the VCIND. The mI-Cr ratio in the frontal white matter of the VCIND was significantly higher than in the M-aMCI group. In the white matter adjacent to the lateral ventricles, the Cho-Cr ratio was significantly higher in the VCIND than the M-aMCI. Our results suggested (1)H-MRS is an effective method in the differential diagnosis of M-aMCI and VCIND. PMID- 26980715 TI - Cellular forces and matrix assembly coordinate fibrous tissue repair. AB - Planar in vitro models have been invaluable tools to identify the mechanical basis of wound closure. Although these models may recapitulate closure dynamics of epithelial cell sheets, they fail to capture how a wounded fibrous tissue rebuilds its 3D architecture. Here we develop a 3D biomimetic model for soft tissue repair and demonstrate that fibroblasts ensconced in a collagen matrix rapidly close microsurgically induced defects within 24 h. Traction force microscopy and time-lapse imaging reveal that closure of gaps begins with contractility-mediated whole-tissue deformations. Subsequently, tangentially migrating fibroblasts along the wound edge tow and assemble a progressively thickening fibronectin template inside the gap that provide the substrate for cells to complete closure. Unlike previously reported mechanisms based on lamellipodial protrusions and purse-string contraction, our data reveal a mode of stromal closure in which coordination of tissue-scale deformations, matrix assembly and cell migration act together to restore 3D tissue architecture. PMID- 26980719 TI - Dietary metabolism, gut microbiota and acute heart failure. PMID- 26980720 TI - Updated guidance from NICE on implantable defibrillators: does it work in real life? PMID- 26980722 TI - Dynamics of Spontaneous Peptidization of l-, d- and dl-Serine in an Abiotic Solution as Investigated with Use of TLC-Densitometry and the Auxiliary Chromatographic Techniques. AB - From our earlier investigations, it comes out that proteinogenic amino acids can undergo spontaneous oscillatory reactions of chiral inversion and peptidization. l-Serine (l-Ser) is an important proteinogenic amino acid with many vital functions in human and mammalian organisms, e.g., it is responsible for good condition of the nervous cell membranes. It undergoes spontaneous oscillatory processes of chiral inversion and peptidization, and the goal of this study was to compare the dynamics of its peptidization with that of d-Ser and dl-Ser (racemate). The main analytical technique used in our experiment was TLC densitometry, and the auxiliary chromatographic techniques were HPLC-evaporative light scattering detector and LC-MS. The results obtained witness to the differences in peptidization dynamics of the two Ser enantiomers (l and d) and of the racemic mixture thereof (dl). It was shown that dl-Ser characterizes with the higher, and l- and d-Ser with the lower peptidization yields. PMID- 26980721 TI - Recurrent AICD shocks in a 60-year-old man. AB - CLINICAL INTRODUCTION: We present the case of a 60-year-old man with history of non-ischaemic cardiomyopathy with left ventricular ejection fraction of 40%. His baseline surface 12-lead ECG shows sinus rhythm with PR interval of 170 ms, no evidence of pre-excitation and a normal QT interval. He had a single-chamber automated implantable cardiac defibrillator (AICD) inserted for sustained wide complex tachycardia associated with palpitations. Subsequently, he presented with recurrent shocks from the AICD coming on at rest despite treatment with amiodarone. He did not experience any significant cardiovascular symptoms except for mild palpitations. There were no reversible causes found for his arrhythmia. Figure 1 shows the device EGM of the event leading to the shock. QUESTION: What is the tachycardia that caused the AICD shock? (figure 1) Atrial fibrillation (AF) with pre-excitationVentricular fibrillation (VF)Multiform ventricular tachycardia (VT)Atrial tachycardia (AT) with bundle branch blockTorsades de Pointes (TdP). PMID- 26980723 TI - Development and Validation of a Sensitive and Specific LC-MS-MS Method for the Determination of Acotiamide in Rat Plasma. AB - Acotiamide is a new prokinetic drug that is used to treat functional dyspepsia (FD). A sensitive and specific LC-MS-MS method has been developed and validated for the analysis of acotiamide in rat plasma. The assay involved a simple protein precipitation (PPT) step with methanol-acetonitrile (50:50, v/v) and a gradient elution using a mobile phase consisting of water containing 0.1% formic acid and methanol containing 0.1% formic acid. The analytes were chromatographed on a reverse-phase Agilent Zorbax XDB C18 column (2.1 mm * 50 mm, 3.5 MUm) with a flow rate of 0.50 mL/min. The analytes were monitored by tandem-mass spectrometry with positive electrospray ionization. The precursor-product transitions (m/z) in the positive ion mode were 451.4 -> 271.3 and 386.2 -> 122.2 for acotiamide and buspirone (internal standard, IS), respectively. The assay was shown to be linear over the range of 0.10-200 ng/mL, with a lower limit of quantification of 0.10 ng/mL. The method was shown to be reproducible and reliable with the inter- and intra-batch accuracy and precision were within +/-15%. The assay has been successfully used for pharmacokinetic evaluation of acotiamide after intravenous and oral administration of 10 mg/kg acotiamide in rats. The oral absolute bioavailability (F) of acotiamide in rats was estimated to be 38.4 +/- 13.5% with an elimination half-life (t1/2) value of 9.11 +/- 0.40 h. PMID- 26980724 TI - Cu-Catalyzed Multicomponent Reaction of Styrenes, Perfluoroalkyl Halide, Alcohol, and tert-Butyl Hydroperoxide: One-Pot Synthesis of (Z)-beta Alkoxyperfluoroalkenone. AB - An efficient synthesis of Z-perfluoroalkyl-substituted enones by a multicomponent reaction strategy has been described. A variety of elusive perfluoroalkylated enones are furnished under mild reaction conditions in good yields with unique chemo- and stereoselectivity. A sequence of radical-mediated Kornblum-DeLaMare reaction, Michael addition, and HF elimination is proposed for the mechanism. PMID- 26980725 TI - Clock gene expression in human and mouse hepatic models shows similar periodicity but different dynamics of variation. AB - The biological hard-wiring of 24-hour rhythmicity relies on the circadian clock circuitry, made of peripheral oscillators operated by molecular clockworks and synchronized through humoral and neural outputs by central oscillators located in the hypothalamic suprachiasmatic nuclei. Metabolically active tissues, such as the liver, are entrained also by local cues represented by metabolic flux related to feeding. The mechanics of the molecular clockwork have been explored by studies using cell lines and wild type or genetically engineered mouse models. There is a compelling need to reduce the use of animals in experimental settings. The aim of our study was to evaluate the periodicity and dynamics of functioning of the hepatic clock gene machinery in human and mouse hepatic models. We compared the results obtained in human hepatoma cells (HepG2 cells) and in mouse liver, and a significant 24-hour rhythmic component was found for five clock genes in the HepG2 cells (Bmal1, Cry1, Per1, Per2, NR1D1) and for six clock genes in the mouse liver (Bmal1, Clock, Cry1, Per1, Per2, NR1D1). The amplitude of oscillation rendered by the cosine curve and the dynamics of expression rendered by the rate of change (the derivative of gene expression level with respect to time) were greater in the mouse liver than in the HepG2 cells for Bmal1, Per1, Per2 and NR1D1, and the cosine curve phase was different for many of them. In conclusion, the periodicity of expression of the clock genes showed similar patterns when the two experimental models were compared, whereas the dynamics of transcription in human hepatoma cells cultured in vitro were less vigorous and phased in a different way when compared to mouse hepatic tissue. The results support the reliability of the human hepatic in vitro model as an alternative to animal models only to study the periodicity of function of the molecular clockwork, but not to evaluate the dynamics of clock gene expression. PMID- 26980726 TI - Comprehensive mutational profiling of core binding factor acute myeloid leukemia. AB - Acute myeloid leukemia (AML) with t(8;21) or inv(16) have been recognized as unique entities within AML and are usually reported together as core binding factor AML (CBF-AML). However, there is considerable clinical and biological heterogeneity within this group of diseases, and relapse incidence reaches up to 40%. Moreover, translocations involving CBFs are not sufficient to induce AML on its own and the full spectrum of mutations coexisting with CBF translocations has not been elucidated. To address these issues, we performed extensive mutational analysis by high-throughput sequencing in 215 patients with CBF-AML enrolled in the Phase 3 Trial of Systematic Versus Response-adapted Timed-Sequential Induction in Patients With Core Binding Factor Acute Myeloid Leukemia and Treating Patients with Childhood Acute Myeloid Leukemia with Interleukin-2 trials (age, 1-60 years). Mutations in genes activating tyrosine kinase signaling (including KIT, N/KRAS, and FLT3) were frequent in both subtypes of CBF-AML. In contrast, mutations in genes that regulate chromatin conformation or encode members of the cohesin complex were observed with high frequencies in t(8;21) AML (42% and 18%, respectively), whereas they were nearly absent in inv(16) AML. High KIT mutant allele ratios defined a group of t(8;21) AML patients with poor prognosis, whereas high N/KRAS mutant allele ratios were associated with the lack of KIT or FLT3 mutations and a favorable outcome. In addition, mutations in epigenetic modifying or cohesin genes were associated with a poor prognosis in patients with tyrosine kinase pathway mutations, suggesting synergic cooperation between these events. These data suggest that diverse cooperating mutations may influence CBF-AML pathophysiology as well as clinical behavior and point to potential unique pathogenesis of t(8;21) vs inv(16) AML. PMID- 26980727 TI - The 2016 revision of the World Health Organization classification of lymphoid neoplasms. AB - A revision of the nearly 8-year-old World Health Organization classification of the lymphoid neoplasms and the accompanying monograph is being published. It reflects a consensus among hematopathologists, geneticists, and clinicians regarding both updates to current entities as well as the addition of a limited number of new provisional entities. The revision clarifies the diagnosis and management of lesions at the very early stages of lymphomagenesis, refines the diagnostic criteria for some entities, details the expanding genetic/molecular landscape of numerous lymphoid neoplasms and their clinical correlates, and refers to investigations leading to more targeted therapeutic strategies. The major changes are reviewed with an emphasis on the most important advances in our understanding that impact our diagnostic approach, clinical expectations, and therapeutic strategies for the lymphoid neoplasms. PMID- 26980728 TI - Long-term multilineage engraftment of autologous genome-edited hematopoietic stem cells in nonhuman primates. AB - Genome editing in hematopoietic stem and progenitor cells (HSPCs) is a promising novel technology for the treatment of many human diseases. Here, we evaluated whether the disruption of the C-C chemokine receptor 5 (CCR5) locus in pigtailed macaque HSPCs by zinc finger nucleases (ZFNs) was feasible. We show that macaque specific CCR5 ZFNs efficiently induce CCR5 disruption at levels of up to 64% ex vivo, 40% in vivo early posttransplant, and 3% to 5% in long-term repopulating cells over 6 months following HSPC transplant. These genome-edited HSPCs support multilineage engraftment and generate progeny capable of trafficking to secondary tissues including the gut. Using deep sequencing technology, we show that these ZFNs are highly specific for the CCR5 locus in primary cells. Further, we have adapted our clonal tracking methodology to follow individual CCR5 mutant cells over time in vivo, reinforcing that CCR5 gene-edited HSPCs are capable of long term engraftment. Together, these data demonstrate that genome-edited HSPCs engraft, and contribute to multilineage repopulation after autologous transplantation in a clinically relevant large animal model, an important step toward the development of stem cell-based genome-editing therapies for HIV and potentially other diseases as well. PMID- 26980730 TI - Overall Architecture of the Intraflagellar Transport (IFT)-B Complex Containing Cluap1/IFT38 as an Essential Component of the IFT-B Peripheral Subcomplex. AB - Intraflagellar transport (IFT) is essential for assembly and maintenance of cilia and flagella as well as ciliary motility and signaling. IFT is mediated by multisubunit complexes, including IFT-A, IFT-B, and the BBSome, in concert with kinesin and dynein motors. Under high salt conditions, purified IFT-B complex dissociates into a core subcomplex composed of at least nine subunits and at least five peripherally associated proteins. Using the visible immunoprecipitation assay, which we recently developed as a convenient protein protein interaction assay, we determined the overall architecture of the IFT-B complex, which can be divided into core and peripheral subcomplexes composed of 10 and 6 subunits, respectively. In particular, we identified TTC26/IFT56 and Cluap1/IFT38, neither of which was included with certainty in previous models of the IFT-B complex, as integral components of the core and peripheral subcomplexes, respectively. Consistent with this, a ciliogenesis defect of Cluap1 deficient mouse embryonic fibroblasts was rescued by exogenous expression of wild type Cluap1 but not by mutant Cluap1 lacking the binding ability to other IFT-B components. The detailed interaction map as well as comparison of subcellular localization of IFT-B components between wild-type and Cluap1-deficient cells provides insights into the functional relevance of the architecture of the IFT-B complex. PMID- 26980731 TI - The use of medical care and out-of-pocket payments in Russia. AB - BACKGROUND: Despite the constitutional right of all Russian citizens to free medical care, out-of-pocket payment is a widespread phenomenon for all types of medical treatment. The aims of this paper are twofold: To present new evidence on the use of, and payment for, outpatient and inpatient treatment in Russia; and to compare the motivations behind both official and informal payments for outpatient services provided in public medical institutions. METHODS: This study uses data from a quantitative household survey conducted in April 2014. The sample comprised 1602 individuals aged ? 18 years, representing the entire adult population of the Russian Federation. We studied three types of medical care: inpatient treatment, outpatient treatment and medicines. RESULTS: Our study found that 22.2% of patients pay for outpatient services, 37.5% pay for inpatient services and 91.5% pay for outpatient medicinal treatment. The informal payments are almost equally met in both outpatient (13.4%) and inpatient (12.2%) care; while the official payments are more common in inpatient care (25.2%), compared to outpatient care (8.8%). The main reasons for informal payment include: improvements in the quality of care and gratitude for medical staff. The official payments are more frequently motivated by an inability to receive a certain treatment free of charge. CONCLUSIONS THIS STUDY DEMONSTRATES THAT BOTH OFFICIAL AND INFORMAL PAYMENTS FOR MEDICAL TREATMENT ARE WIDESPREAD IN RUSSIA INFORMAL PAYMENTS ARE STRONGLY PREFERRED OVER OFFICIAL PAYMENTS FOR OUTPATIENT CARE, WHILE OFFICIAL PAYMENTS DOMINATE IN INPATIENT CARE. PMID- 26980729 TI - Catalytically Active Guanylyl Cyclase B Requires Endoplasmic Reticulum-mediated Glycosylation, and Mutations That Inhibit This Process Cause Dwarfism. AB - C-type natriuretic peptide activation of guanylyl cyclase B (GC-B), also known as natriuretic peptide receptor B or NPR2, stimulates long bone growth, and missense mutations in GC-B cause dwarfism. Four such mutants (L658F, Y708C, R776W, and G959A) bound (125)I-C-type natriuretic peptide on the surface of cells but failed to synthesize cGMP in membrane GC assays. Immunofluorescence microscopy also indicated that the mutant receptors were on the cell surface. All mutant proteins were dephosphorylated and incompletely glycosylated, but dephosphorylation did not explain the inactivation because the mutations inactivated a "constitutively phosphorylated" enzyme. Tunicamycin inhibition of glycosylation in the endoplasmic reticulum or mutation of the Asn-24 glycosylation site decreased GC activity, but neither inhibition of glycosylation in the Golgi by N acetylglucosaminyltransferase I gene inactivation nor PNGase F deglycosylation of fully processed GC-B reduced GC activity. We conclude that endoplasmic reticulum mediated glycosylation is required for the formation of an active catalytic, but not ligand-binding domain, and that mutations that inhibit this process cause dwarfism. PMID- 26980732 TI - Genomic markers of panitumumab resistance including ERBB2/ HER2 in a phase II study of KRAS wild-type (wt) metastatic colorectal cancer (mCRC). AB - A prospective study was conducted to identify biomarkers associated with resistance to panitumumab monotherapy in patients with metastatic colorectal cancer (mCRC). Patients with previously treated, codon 12/13 KRAS wt, mCRC were prospectively administered panitumumab 6 mg/kg IV q2weeks. Of 34 panitumumab treated patients, 11 (32%) had progressive disease at 8 weeks and were classified as non-responders. A Nanostring nCounter-based assay identified a 5-gene expression signature (ERBB2, MLPH, IRX3, MYRF, and KLK6) associated with panitumumab resistance (P = 0.001). Immunohistochemistry and in situ hybridization determined that the HER2 (ERBB2) protein was overexpressed in 4/11 non-responding and 0/21 responding cases (P = 0.035). Two non-responding tumors had ERBB2 gene amplification only, and one demonstrated both ERBB2 amplification and mutation. A non-codon 12/13 KRAS mutation occurred in one panitumumab resistant patient and was mutually exclusive with ERBB2/HER2 abnormalities. This study identifies a 5-gene signature associated with non-response to single agent panitumumab, including a subgroup of non-responders with evidence of aberrant ERBB2/HER2 signaling. KRAS wt tumors resistant to EGFRi may be identified by gene signature analysis, and the HER2 pathway plays an important role in resistance to therapy. PMID- 26980733 TI - The long non-coding RNA EPB41L4A-AS2 inhibits tumor proliferation and is associated with favorable prognoses in breast cancer and other solid tumors. AB - EPB41L4A-AS2 is a novel long non-coding RNA of unknown function. In this study, we investigated the expression of EPB41L4A-AS2 in breast cancer tissues and evaluated its relationship with the clinicopathological features and prognosis of patients with breast cancer. This entailed conducting a meta-analysis and prognosis validation study using two cohorts from the Gene Expression Omnibus (GEO). In addition, we assessed EPB41L4A-AS2 expression and its relationship with the clinicopathological features of renal and lung cancers using the Cancer Genome Atlas cohort and a GEO dataset. We also clarified the role of EPB41L4A-AS2 expression in mediating cancer cell proliferation in breast, renal, and lung cancer cell lines transfected with an EPB41L4A-AS2 expression vector. We found that high EPB41L4A-AS2 expression is associated with favorable disease outcomes. Gene ontology enrichment analysis revealed that EPB41L4A-AS2 may be involved in processes associated with tumor biology. Finally, overexpression of EPB41L4A-AS2 inhibited tumor cell proliferation in breast, renal, and lung cancer cell lines. Our clinical and in vitro results suggest that EPB41L4A-AS2 inhibits solid tumor formation and that evaluation of this long non-coding RNA may have prognostic value in the clinical management of such malignancies. PMID- 26980734 TI - Prognostic effect of pregnancy on young female patients with nasopharyngeal carcinoma: results from a matched cohort analysis. AB - OBJECTIVES: We aimed to evaluate the prognosis of pregnancy-associated patients with nasopharyngeal carcinoma (NPC) in a young population. METHODS: From June 1999 to December 2010, 51 patients aged <= 35 years who were diagnosed with NPC during pregnancy or within one year after delivery were admitted into the pregnancy-associated group in our institution. An additional 51 patients who were not pregnant at diagnosis were selected from 451 patients based on the matching criteria to match the pregnancy-associated female patients. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS) and distant-metastasis failure-free survival (DMFS) and locoregional failure-free survival (LRFS). RESULTS: The advanced stage was not different between the pregnant and the non-pregnant group before matching (69.8% vs. 70.3%, P = 0.690). No difference in OS at the median follow-up time of 92 months was observed between the pregnancy-associated and the non-pregnant group (85.4% vs. 92.2%, P = 0.478); likewise, no differences were observed regarding PFS and DMFS. However, the pregnancy-associated group had worse LRFS than the non-pregnant group (84.8% vs. 95.9%, P = 0.033). When the pregnancy-associated patients were dichotomized into an early pregnancy group and a late pregnancy group, our data showed that pregnancy interval did not seem to impact the risk of death or relapse. CONCLUSION: Our results show that patients in the pregnant group did not seem to have more advanced stage or inferior survival than that in the non pregnant group. PMID- 26980735 TI - Melatonin inhibits TPA-induced oral cancer cell migration by suppressing matrix metalloproteinase-9 activation through the histone acetylation. AB - Melatonin exerts antimetastatic effects on liver and breast cancer and also inhibits matrix metalloproteinase (MMP) activity. However, the detailed impacts and underlying mechanisms of melatonin on oral cancer cell metastasis are still unclear. This study showed that melatonin attenuated the 12-O tetradecanoylphorbol-13-acetate-induced migration of oral cancer cell lines, HSC 3 and OECM-1. Zymography, quantitative real-time PCR, and Western blotting analyses revealed that melatonin lessened MMP-9 enzyme activity as well as the expression of MMP-9 mRNA and protein. Furthermore, melatonin suppressed the phosphorylation of the ERK1/2 signalling pathway, which dampened MMP-9 gene transcription by affecting the expression of transcriptional coactivators, such as CREB-binding protein (CREBBP) and E1A binding protein p300 (EP300), and decreasing histone acetylation in HSC-3 and OECM-1 cells. Examinations on clinical samples exhibited that MMP-9, CREBBP, and EP300 were significantly increased in oral cancer tissues. Moreover, the relative level of CREBBP was positively correlated with the expression of MMP-9 and EP300. In conclusion, we demonstrated that melatonin inhibits the motility of HSC-3 and OECM-1 cells in vitro through a molecular mechanism that involves attenuation of MMP-9 expression and activity mediated by decreased histone acetylation. PMID- 26980737 TI - Mutation based treatment recommendations from next generation sequencing data: a comparison of web tools. AB - Interpretation of complex cancer genome data, generated by tumor target profiling platforms, is key for the success of personalized cancer therapy. How to draw therapeutic conclusions from tumor profiling results is not standardized and may vary among commercial and academically-affiliated recommendation tools. We performed targeted sequencing of 315 genes from 75 metastatic breast cancer biopsies using the FoundationOne assay. Results were run through 4 different web tools including the Drug-Gene Interaction Database (DGidb), My Cancer Genome (MCG), Personalized Cancer Therapy (PCT), and cBioPortal, for drug and clinical trial recommendations. These recommendations were compared amongst each other and to those provided by FoundationOne. The identification of a gene as targetable varied across the different recommendation sources. Only 33% of cases had 4 or more sources recommend the same drug for at least one of the usually several altered genes found in tumor biopsies. These results indicate further development and standardization of broadly applicable software tools that assist in our therapeutic interpretation of genomic data is needed. Existing algorithms for data acquisition, integration and interpretation will likely need to incorporate artificial intelligence tools to improve both content and real-time status. PMID- 26980739 TI - Abrupt quitting is more likely to work than gradual reduction of cigarettes, study finds. PMID- 26980736 TI - Next-generation sequencing for sensitive detection of BCR-ABL1 mutations relevant to tyrosine kinase inhibitor choice in imatinib-resistant patients. AB - In chronic myeloid leukemia (CML) and Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) patients who fail imatinib treatment, BCR-ABL1 mutation profiling by Sanger sequencing (SS) is recommended before changing therapy since detection of specific mutations influences second-generation tyrosine kinase inhibitor (2GTKI) choice. We aimed to assess i) in how many patients who relapse on second-line 2GTKI therapy next generation sequencing (NGS) may track resistant mutations back to the sample collected at the time of imatinib resistance, before 2GTKI start (switchover sample) and ii) whether low level mutations identified by NGS always undergo clonal expansion. To this purpose, we used NGS to retrospectively analyze 60 imatinib-resistant patients (CML, n = 45; Ph+ ALL,n = 15) who had failed second-line 2GTKI therapy and had acquired BCR-ABL1 mutations (Group 1) and 25 imatinib-resistant patients (CML, n = 21; Ph+ ALL, n = 4) who had responded to second-line 2GTKI therapy, for comparison (Group 2). NGS uncovered that in 26 (43%) patients in Group 1, the 2GTKI-resistant mutations that triggered relapse were already detectable at low levels in the switchover sample (median mutation burden, 5%; range 1.1%-18.4%). Importantly, none of the low level mutations detected by NGS in switchover samples failed to expand whenever the patient received the 2GTKI to whom they were insensitive. In contrast, no low level mutation that was resistant to the 2GTKI the patients subsequently received was detected in the switchover samples from Group 2. NGS at the time of imatinib failure reliably identifies clinically relevant mutations, thus enabling a more effective therapeutic tailoring. PMID- 26980738 TI - Development of a new outcome prediction model for Chinese patients with penile squamous cell carcinoma based on preoperative serum C-reactive protein, body mass index, and standard pathological risk factors: the TNCB score group system. AB - PURPOSE: To determine the predictive value and feasibility of the new outcome prediction model for Chinese patients with penile squamous cell carcinoma. RESULTS: The 3-year disease-specific survival (DSS) survival (DSS) was 92.3% in patients with < 8.70 mg/L CRP and 54.9% in those with elevated CRP (P < 0.001). The 3-year DSS was 86.5% in patients with a BMI < 22.6 Kg/m2 and 69.9% in those with a higher BMI (P = 0.025). In a multivariate analysis, pathological T stage (P < 0.001), pathological N stage (P = 0.002), BMI (P = 0.002), and CRP (P = 0.004) were independent predictors of DSS. A new scoring model was developed, consisting of BMI, CRP, and tumor T and N classification. In our study, we found that the addition of the above-mentioned parameters significantly increased the predictive accuracy of the system of the American Joint Committee on Cancer (AJCC) anatomic stage group. The accuracy of the new prediction category was verified. METHODS: A total of 172 Chinese patients with penile squamous cell cancer were analyzed retrospectively between November 2005 and November 2014. Statistical data analysis was conducted using the nonparametric method. Survival analysis was performed with the log-rank test and the Cox proportional hazard model. Based on regression estimates of significant parameters in multivariate analysis, a new BMI-, CRP- and pathologic factors-based scoring model was developed to predict disease--specific outcomes. The predictive accuracy of the model was evaluated using the internal and external validation. CONCLUSIONS: The present study demonstrated that the TNCB score group system maybe a precise and easy to use tool for predicting outcomes in Chinese penile squamous cell carcinoma patients. PMID- 26980740 TI - Association between TYK2 polymorphisms and susceptibility to autoimmune rheumatic diseases: a meta-analysis. AB - OBJECTIVE: This study aimed to explore whether TYK2 polymorphisms are associated with susceptibility to autoimmune rheumatic diseases. METHODS: We conducted a meta-analysis on the association between TYK2 polymorphisms and autoimmune rheumatic diseases. RESULTS: Twelve studies with a total of 16,335 patients and 30,065 controls were included in the meta-analysis. Meta-analysis revealed an association between rheumatic diseases and the 2 allele of the TYK2 rs2304256 (OR = 0.885, 95% CI = 0.802-0.978, p = 0.016). Furthermore, stratification by ethnicity identified a significant association between this polymorphism and rheumatic diseases in Caucasians (OR = 0.822, 95% CI = 0.706-0.889, p = 9.5 * 10( 7)), but not in Asians (OR = 1.127, 95% CI = 0.835-1.522, p = 0.434). Meta analysis by rheumatic disease type revealed a significant association between the 2 allele of the TYK2 rs2304256 and SLE in Caucasians (OR = 0.737, 95% CI = 0.673 0.808, p < 1.0 * 10(-8)) but not in Asians (OR = 1.211, 95% CI = 0.813-1.804, p = 0.347). Meta-analysis revealed that the rs12720356 polymorphism was associated with susceptibility to rheumatic diseases in Caucasians (OR = 0.812, 95% CI = 0.661-0.997, p = 0.046) but not in Asians. Interestingly, the rs280519 polymorphism was significantly associated with susceptibility to SLE both in Caucasians and Asians. However, no associations were found between the rs12720270, rs280500, rs280523 and rs8108236 polymorphisms and susceptibility to rheumatic diseases. CONCLUSIONS: This meta-analysis demonstrates that the TYK2 rs2304256 and rs12720356 polymorphisms are associated with susceptibility to rheumatic diseases, rs2304256 polymorphism is associated with SLE in Caucasians, and rs280519 polymorphism is associated with SLE in Caucasians and Asians. PMID- 26980741 TI - Factors associated with thrombosis in pediatric patients with systemic lupus erythematosus. AB - OBJECTIVE: The risk of thrombosis is increased in patients with systemic lupus erythematosus (SLE). Few studies have assessed factors associated with thrombosis within the pediatric SLE (pSLE) population. We sought to better characterize these associated factors in pSLE patients using the Childhood Arthritis & Rheumatology Research Alliance (CARRA) registry. METHODS: Within the CARRA registry, patients with a history of thrombosis were compared to those without. Univariate logistic regression was used to calculate odds ratios. A multivariable logistic regression model was conducted that included variables from the univariate analysis that had a p value < 0.10 and other variables identified as clinically significant from published literature. RESULTS: Among the 979 pSLE patients in the CARRA registry, 24 (2.5%) patients had a history of arterial thrombosis and 35 (3.6%) of venous thrombosis. In the univariate analysis, the odds ratio of having a thrombotic event were found to be significantly higher in patients with a history of vasculitis, avascular necrosis (AVN), or antiphospholipid antibody (aPL). Similar results were found for vasculitis, AVN, and aPL in the multivariable analysis. CONCLUSION: Our study of pSLE patients suggests that vasculitis, positive APL, and AVN are associated with thrombotic events in this population. PMID- 26980742 TI - Interval estimation in multi-stage drop-the-losers designs. AB - Drop-the-losers designs have been discussed extensively in the past decades, mostly focusing on two-stage models. The designs with more than two stages have recently received increasing attention due to their improved efficiency over the corresponding two-stage designs. In this paper, we consider the problem of estimating and testing the effect of selected treatment under the setting of three-stage drop-the-losers designs. A conservative interval estimator is proposed, which is proved to have at least the specified coverage probability using a stochastic ordering approach. The proposed interval estimator is also demonstrated numerically to have narrower interval width but higher coverage rate than the bootstrap method proposed by Bowden and Glimm (Biometrical Journal, vol. 56, pp. 332-349) in most cases. It is also a straightforward derivation from the stochastic ordering result that the family-wise error rate is strongly controlled with the maximum achieved at the global null hypothesis. PMID- 26980743 TI - The BMJ should be adventurous and lead the way on qualitative research. PMID- 26980744 TI - The efficacy and toxicity of individualized intensity-modulated radiotherapy based on the tumor extension patterns of nasopharyngeal carcinoma. AB - BACKGROUND: To evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) using individualized clinical target volumes (CTVs) based on the loco-regional extension patterns of nasopharyngeal carcinoma (NPC). METHODS: From December 2009 to February 2012, 220 patients with histologically-proven, non disseminated NPC were prospectively treated with IMRT according to an individualized delineation protocol. CTV1 encompassed the gross tumor volume, entire nasopharyngeal mucosa and structures within the pharyngobasilar fascia with a margin. CTV2 encompassed bilateral high risk anatomic sites and downstream anatomic sites adjacent to primary tumor, bilateral retropharyngeal regions, levels II, III and Va, and prophylactic irradiation was gave to one or two levels beyond clinical lymph nodes involvement. Clinical outcomes and toxicities were evaluated. RESULTS: Median follow-up was 50.8 (range, 1.3-68.0) months, four-year local relapse-free, regional relapse-free, distant metastasis-free, disease-free and overall survival rates were 94.7%, 97.0%, 91.7%, 87.2% and 91.9%, respectively. Acute severe (>= grade 3) mucositis, dermatitis and xerostomia were observed in 27.6%, 3.6% and zero patients, respectively. At 1 year, xerostomia was mild, with frequencies of Grade 0, 1, 2 and 3 xerostomia of 27.9%, 63.3%, 8.3% and 0.5%, respectively. CONCLUSIONS: IMRT using individualized CTVs provided high rates of local and regional control and a favorable toxicity profile in NPC. Individualized CTV delineation strategy is a promising one that may effectively avoid unnecessary or missed irradiation, and deserve optimization to define more precise individualized CTVs. PMID- 26980745 TI - PTBP1-associated microRNA-1 and -133b suppress the Warburg effect in colorectal tumors. AB - It is known that pyruvate kinase in muscle (PKM), which is a rate-limiting glycolytic enzyme, has essential roles in the Warburg effect and that expression of cancer-dominant PKM2 is increased by polypyrimidine tract-binding protein 1 (PTBP1), which is a splicer of the PKM gene. In other words, PKM2 acts as a promoter of the Warburg effect. Previously, we demonstrated that the Warburg effect was partially established by down-regulation of several microRNAs (miRs) that bind to PTBP1 and that ectopic expression of these miRs suppressed the Warburg effect. In this study, we investigated the functions of miR-1 and -133b, which are well known as muscle-specific miRs, from the viewpoint of the Warburg effect in colorectal tumors. The expression levels of miR-1 and -133b were relatively high in colon tissue except muscle and very frequently down-regulated in 75 clinical colorectal tumors samples, even in adenomas, compared with those of the adjacent normal tissue samples. The ectopic expression of these miRs induced growth suppression and autophagic cell death through the switching of PKM isoform expression from PKM2 to PKM1 by silencing PTBP1 expression both in vitro and in vivo. Also, we showed that the resultant increase in the intracellular level of reactive oxygen species (ROS) was involved in this mechanism. Furthermore, PTBP1 was highly expressed in most of the 30 clinical colorectal tumor samples examined, even in adenomas. Our results suggested that PTBP1 and PTBP1-associated miR-1 and -133b are crucial molecules for the maintenance of the Warburg effect in colorectal tumors. PMID- 26980746 TI - Zoledronic acid-encapsulating self-assembling nanoparticles and doxorubicin: a combinatorial approach to overcome simultaneously chemoresistance and immunoresistance in breast tumors. AB - The resistance to chemotherapy and the tumor escape from host immunosurveillance are the main causes of the failure of anthracycline-based regimens in breast cancer, where an effective chemo-immunosensitizing strategy is lacking.The clinically used aminobisphosphonate zoledronic acid (ZA) reverses chemoresistance and immunoresistance in vitro. Previously we developed a nanoparticle-based zoledronic acid-containing formulation (NZ) that allowed a higher intratumor delivery of the drug compared with free ZA in vivo. We tested its efficacy in combination with doxorubicin in breast tumors refractory to chemotherapy and immune system recognition as a new combinatorial approach to produce chemo- and immunosensitization.NZ reduced the IC50 of doxorubicin in human and murine chemoresistant breast cancer cells and restored the doxorubicin efficacy against chemo-immunoresistant tumors implanted in immunocompetent mice. By reducing the metabolic flux through the mevalonate pathway, NZ lowered the activity of Ras/ERK1/2/HIF-1alpha axis and the expression of P-glycoprotein, decreased the glycolysis and the mitochondrial respiratory chain, induced a cytochrome c/caspase 9/caspase 3-dependent apoptosis, thus restoring the direct cytotoxic effects of doxorubicin on tumor cell. Moreover, NZ restored the doxorubicin induced immunogenic cell death and reversed the tumor-induced immunosuppression due to the production of kynurenine, by inhibiting the STAT3/indoleamine 2,3 dioxygenase axis. These events increased the number of dendritic cells and decreased the number of immunosuppressive T-regulatory cells infiltrating the tumors.Our work proposes the use of nanoparticle encapsulating zoledronic acid as an effective tool overcoming at the same time chemoresistance and immunoresistance in breast tumors, thanks to the effects exerted on tumor cell and tumor-infiltrating immune cells. PMID- 26980747 TI - Activation of the IGF1R pathway potentially mediates acquired resistance to mutant-selective 3rd-generation EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer. AB - Mutant-selective, 3rd-generation EGFR-TKIs were recently developed to control lung cancer cells harboring T790M-mediated resistance. However, the development of resistance to these novel drugs seems inevitable. Thus, we investigated the mechanism of acquired resistance to the mutant-selective EGFR-TKI WZ4002. We established five WZ4002-resistant cells, derived from cells harboring both EGFR and T790M mutations by long-term exposure to increasing doses of WZ4002. Compared with the parental cells, all resistant cells showed 10-100-folds higher resistance to WZ4002, as well as cross-resistance to other mutant-selective inhibitors. Among them, three resistant cells (HCC827/WR, PC-9/WR and H1975/WR) showed dependency on EGFR signaling, but two other cells (PC-9/GR/WR and PC 9/ER/WR) were not. Notably, insulin-like growth factor-1 receptor (IGF1R) was aberrantly activated in PC-9/GR/WR cells in phospho-receptor tyrosine kinase array, consistently accompanied by loss of IGF binding protein-3 (IGFBP3). Down regulation of IGF1R by shRNA, as well as inhibition of IGF1R activity either by AG-1024 (a small molecule IGF1R inhibitor) or BI 836845 (a monoclonal anti-IGF1/2 blocking antibody), restored the sensitivity to WZ4002 both in vitro and xenograft. Taken together, these results suggest that activation of the IGF1R pathway associated with IGFBP3 loss can induce an acquired resistance to the mutant-selective EGFR-TKI, WZ4002. Therefore, a combined therapy of IGF1R inhibitors and mutant-selective EGFR-TKIs might be a viable treatment strategy for overcoming acquired resistance. PMID- 26980748 TI - Whole transcriptome profiling of patient-derived xenograft models as a tool to identify both tumor and stromal specific biomarkers. AB - The tumor microenvironment is emerging as a key regulator of cancer growth and progression, however the exact mechanisms of interaction with the tumor are poorly understood. Whilst the majority of genomic profiling efforts thus far have focused on the tumor, here we investigate RNA-Seq as a hypothesis-free tool to generate independent tumor and stromal biomarkers, and explore tumor-stroma interactions by exploiting the human-murine compartment specificity of patient derived xenografts (PDX).Across a pan-cancer cohort of 79 PDX models, we determine that mouse stroma can be separated into distinct clusters, each corresponding to a specific stromal cell type. This implies heterogeneous recruitment of mouse stroma to the xenograft independent of tumor type. We then generate cross-species expression networks to recapitulate a known association between tumor epithelial cells and fibroblast activation, and propose a potentially novel relationship between two hypoxia-associated genes, human MIF and mouse Ddx6. Assessment of disease subtype also reveals MMP12 as a putative stromal marker of triple-negative breast cancer. Finally, we establish that our ability to dissect recruited stroma from trans-differentiated tumor cells is crucial to identifying stem-like poor-prognosis signatures in the tumor compartment.In conclusion, RNA-Seq is a powerful, cost-effective solution to global analysis of human tumor and mouse stroma simultaneously, providing new insights into mouse stromal heterogeneity and compartment-specific disease markers that are otherwise overlooked by alternative technologies. The study represents the first comprehensive analysis of its kind across multiple PDX models, and supports adoption of the approach in pre-clinical drug efficacy studies, and compartment-specific biomarker discovery. PMID- 26980750 TI - Mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia: a report from the Italian AIEOP study group. AB - Juvenile myelomonocytic leukemia (JMML) is a rare aggressive disease of early childhood. Driver mutations in the Ras signaling pathways are a key feature of JMML patients. Mutations in SETBP1 and JAK3 were recently identified in a subset of JMML patients characterized by poor prognosis and progression of disease. In this study, we report the results of a screening for mutations in SETBP1 and JAK3 of a cohort of seventy Italian patients with JMML, identifying 11.4% of them harboring secondary mutations in these two genes and discovering two new mutations in the SKI domain of SETBP1.JMML xenotransplantation and colony assay provide an initial understanding of the secondary nature of these events occurring in early precursor cells and suggest a different propagating capacity of clones harboring particular mutations. PMID- 26980751 TI - The holistic rhizosphere: integrating zones, processes, and semantics in the soil influenced by roots. AB - Despite often being conceptualized as a thin layer of soil around roots, the rhizosphere is actually a dynamic system of interacting processes. Hiltner originally defined the rhizosphere as the soil influenced by plant roots. However, soil physicists, chemists, microbiologists, and plant physiologists have studied the rhizosphere independently, and therefore conceptualized the rhizosphere in different ways and using contrasting terminology. Rather than research-specific conceptions of the rhizosphere, the authors propose a holistic rhizosphere encapsulating the following components: microbial community gradients, macroorganisms, mucigel, volumes of soil structure modification, and depletion or accumulation zones of nutrients, water, root exudates, volatiles, and gases. These rhizosphere components are the result of dynamic processes and understanding the integration of these processes will be necessary for future contributions to rhizosphere science based upon interdisciplinary collaborations. In this review, current knowledge of the rhizosphere is synthesized using this holistic perspective with a focus on integrating traditionally separated rhizosphere studies. The temporal dynamics of rhizosphere activities will also be considered, from annual fine root turnover to diurnal fluctuations of water and nutrient uptake. The latest empirical and computational methods are discussed in the context of rhizosphere integration. Clarification of rhizosphere semantics, a holistic model of the rhizosphere, examples of integration of rhizosphere studies across disciplines, and review of the latest rhizosphere methods will empower rhizosphere scientists from different disciplines to engage in the interdisciplinary collaborations needed to break new ground in truly understanding the rhizosphere and to apply this knowledge for practical guidance. PMID- 26980749 TI - Evaluation and consequences of heterogeneity in the circulating tumor cell compartment. AB - A growing understanding of the molecular biology of cancer and the identification of specific aberrations driving cancer evolution have led to the development of various targeted agents. Therapeutic decisions concerning these drugs are often guided by single biopsies of the primary tumor. Yet, it is well known that tumors can exhibit significant heterogeneity and change over time as a result of selective pressure. Circulating tumor cells (CTCs) are shed from various tumor sites and are thought to represent the molecular landscape of a patient's overall tumor burden. Moreover, a minimal-invasive liquid biopsy facilitates monitoring of clonal evolution during therapy pressure and disease progression in real-time. While more information becomes available regarding heterogeneity among CTCs, comparison between these studies is needed. In this review, we focus on the genomic and transcriptional heterogeneity found in the CTC compartment, and its significance for clinical decision making. PMID- 26980753 TI - Is Tradition Trumping Evidence in the Treatment of Young, Febrile Infants? PMID- 26980752 TI - A Meta-analysis of the Rates of Listeria monocytogenes and Enterococcus in Febrile Infants. AB - CONTEXT: A change in the epidemiology of pathogens causing serious bacterial infection (SBI) has been noted since original recommendations were made for the empirical antibiotic choices for young infants with fever. OBJECTIVE: To assess the prevalence of SBI caused by Listeria monocytogenes and Enterococcus species. DATA SOURCES: A literature search was conducted on keywords related to SBI, L. monocytogenes, and Enterococcus spp. infections. STUDY SELECTION: Eligible studies were those conducted in the United States and published between January 1998 and June 2014 focusing on SBI in infants<=90 days of age. DATA EXTRACTION: The rates of urinary tract infection, bacteremia, and meningitis for each pathogen were recorded for each study. Meta-analysis was performed to calculate the prevalence for each pathogen in a random effects model with 0.5 continuity correction added to studies with zero events. RESULTS: Sixteen studies were included. A total of 20,703 blood cultures were included, with weighted prevalences for L. monocytogenes and Enterococcus spp. bacteremia of 0.03% and 0.09%, respectively. A total of 13,775 cerebrospinal fluid cultures were included with event rates (unweighted prevalences) for L. monocytogenes and Enterococcus spp. meningitis of 0.02% and 0.03%, respectively. A total of 18,283 urine cultures were included, with no cases of L. monocytogenes and a weighted prevalence for Enterococcus spp. urinary tract infection of 0.28%. LIMITATIONS: There may have been reporting bias or incomplete retrieval or inadvertent exclusion of relevant studies. CONCLUSIONS: SBI caused by L. monocytogenes and Enterococcus spp. in febrile infants is rare, and therefore clinicians may consider a change in empirical antibiotic choices. PMID- 26980754 TI - Trends in US Hospital Stays for Listeriosis in Infants. AB - BACKGROUND AND OBJECTIVES: Although listeriosis is rare in infants, it is common for young infants with suspected serious bacterial infection to be treated empirically with agents selected, in part, for their activity against Listeria monocytogenes. Our objectives were to describe the recent epidemiology of hospital discharges for listeriosis among infants in the United States and to precisely estimate the incidence of listeriosis according to infant age and meningitis status. METHODS: We generated national estimates for listeriosis discharges in each of the 6 years for which samples were available in the Kids' Inpatient Database during the period 1997-2012. We used random-effects models to pool descriptive information and population rates across study years. RESULTS: The cumulative number of US hospital discharges for listeriosis in infants was 344 (95% confidence interval [CI]: 290-397) over the 6 study years. The pooled annual incidence rate in infants (per 100,000 births) was 1.41 (95% CI: 1.01 1.80) after accounting for marked fluctuation in annual rates (range: 0.66-1.86; I2=79.3%). Discharges for listeriosis without meningitis were particularly rare after the first week of life. Our models predicted only 2.7 (95% CI: 1.1-4.2) and 1.8 (95% CI: 0.0-3.6) such discharges per year in infants admitted at ages 7 to 28 days and 29 to 364 days, respectively. CONCLUSIONS: From the perspective of providing coverage against listeriosis, the routine practice of including ampicillin in the empirical treatment of febrile infants should be reevaluated for those older than 1 week without clinical evidence of meningitis. PMID- 26980755 TI - Salicylic acid analogues as chemical exchange saturation transfer MRI contrast agents for the assessment of brain perfusion territory and blood-brain barrier opening after intra-arterial infusion. AB - The blood-brain barrier (BBB) is a major obstacle for drug delivery to the brain. Predicted, focal opening of the BBB through intra-arterial infusion of hyperosmolar mannitol is feasible, but there is a need to facilitate imaging techniques (e.g. MRI) to guide interventional procedures and assess the outcomes. Here, we show that salicylic acid analogues (SAA) can depict the brain territory supplied by the catheter and detect the BBB opening, through chemical exchange saturation transfer (CEST) MRI. Hyperosmolar SAA solutions themselves are also capable of opening the BBB, and, when multiple SAA agents were co-injected, their locoregional perfusion could be differentiated. PMID- 26980756 TI - Searching for a truly "iso-metabolic" gas challenge in physiological MRI. AB - Hypercapnia challenge (e.g. inhalation of CO2) has been used in calibrated fMRI as well as in the mapping of vascular reactivity in cerebrovascular diseases. An important assumption underlying these measurements is that CO2 is a pure vascular challenge but does not alter neural activity. However, recent reports have suggested that CO2 inhalation may suppress neural activity and brain metabolic rate. Therefore, the goal of this study is to propose and test a gas challenge that is truly "iso-metabolic," by adding a hypoxic component to the hypercapnic challenge, since hypoxia has been shown to enhance cerebral metabolic rate of oxygen (CMRO2). Measurement of global CMRO2 under various gas challenge conditions revealed that, while hypercapnia (P = 0.002) and hypoxia (P = 0.002) individually altered CMRO2 (by -7.6 +/- 1.7% and 16.7 +/- 4.1%, respectively), inhalation of hypercapnic-hypoxia gas (5% CO2/13% O2) did not change brain metabolism (CMRO2 change: 1.5 +/- 3.9%, P = 0.92). Moreover, cerebral blood flow response to the hypercapnic-hypoxia challenge (in terms of % change per mmHg CO2 change) was even greater than that to hypercapnia alone (P = 0.007). Findings in this study suggest that hypercapnic-hypoxia gas challenge may be a useful maneuver in physiological MRI as it preserves vasodilatory response yet does not alter brain metabolism. PMID- 26980757 TI - Metabolic network expression in parkinsonism: Clinical and dopaminergic correlations. AB - Little is known of the precise relationship between the expression of disease related metabolic patterns and nigrostriatal dopaminergic dysfunction in parkinsonism. We studied 51 subjects with Parkinson's disease (PD) (18 non demented, 24 demented, and 9 dementia with Lewy bodies) and 127 with atypical parkinsonian syndromes (47 multiple system atrophy (MSA), 38 progressive supranuclear palsy (PSP), and 42 corticobasal syndrome (CBS)) with 18F fluorodeoxyglucose PET to quantify the expression of previously validated disease related patterns for PD, MSA, PSP, and CBS and 18F-fluoropropyl-beta-CIT PET to quantify caudate and putamen dopamine transporter (DAT) binding. The patients in each group exhibited significant elevations in the expression of the corresponding disease-related pattern ( p < 0.001), relative to 16 healthy subjects. With the exception of cerebellar MSA (MSA-C), all groups displayed significant reductions in putamen DAT binding relative to healthy subjects ( p < 0.05). Correlations between the dopaminergic and metabolic measures were significant in PD and CBS but not in MSA and PSP. In all patient groups with the exception of MSA-C and CBS, pattern expression values and DAT binding correlated with disease duration and severity measures. The findings suggest that in these parkinsonian disorders, metabolic network expression and DAT binding provide complementary information regarding the underlying disease process. PMID- 26980758 TI - Qualitative research, observational research, and The BMJ. PMID- 26980761 TI - Oncoprotein HBXIP Modulates Abnormal Lipid Metabolism and Growth of Breast Cancer Cells by Activating the LXRs/SREBP-1c/FAS Signaling Cascade. AB - Abnormal lipid metabolism is a hallmark of tumorigenesis. Accumulating evidence demonstrates that fatty acid synthase (FAS, FASN) is a metabolic oncogene that supports the growth and survival of tumor cells and is highly expressed in many cancers. Here, we report that the oncoprotein, hepatitis B X-interacting protein (HBXIP, LAMTOR5) contributes to abnormal lipid metabolism. We show that high expression of HBXIP in 236 breast cancer patients was significantly associated with decreased overall survival and progression-free survival. Interestingly, the expression of HBXIP was positively related to that of FAS in clinical breast cancer tissues, and HBXIP overexpression in breast cancer cells resulted in FAS upregulation. Mechanistically, HBXIP upregulated SREBP-1c (SREBF1), which activates the transcription of FAS, by directly interacting with and coactivating nuclear receptor (NR) liver X receptors (LXR). Physiologically, LXRs are activated via a coactivator containing NR motif in a ligand-dependent manner. However, in breast cancer cells, HBXIP containing the corepressor/nuclear receptor motif with special flanking sequence could coactivate LXRs independent of ligand. Moreover, overexpressed SREBP-1c was able to activate the transcription of HBXIP, forming a positive-feedback loop. Functionally, HBXIP enhanced lipogenesis, resulting in the growth of breast cancer cells in vitro and in vivo Thus, we conclude that the oncoprotein HBXIP contributes to the abnormal lipid metabolism in breast cancer through LXRs/SREBP-1c/FAS signaling, providing new insights into the mechanisms by which cancer cells reprogram lipid metabolism in their favor. Cancer Res; 76(16); 4696-707. (c)2016 AACR. PMID- 26980763 TI - MIF Maintains the Tumorigenic Capacity of Brain Tumor-Initiating Cells by Directly Inhibiting p53. AB - Tumor-initiating cells thought to drive brain cancer are embedded in a complex heterogeneous histology. In this study, we isolated primary cells from 21 human brain tumor specimens to establish cell lines with high tumorigenic potential and to identify the molecules enabling this capability. The morphology, sphere forming ability upon expansion, and differentiation potential of all cell lines were indistinguishable in vitro However, testing for tumorigenicity revealed two distinct cell types, brain tumor-initiating cells (BTIC) and non-BTIC. We found that macrophage migration inhibitory factor (MIF) was highly expressed in BTIC compared with non-BTIC. MIF bound directly to both wild-type and mutant p53 but regulated p53-dependent cell growth by different mechanisms, depending on glioma cell line and p53 status. MIF physically interacted with wild-type p53 in the nucleus and inhibited its transcription-dependent functions. In contrast, MIF bound to mutant p53 in the cytoplasm and abrogated transcription-independent induction of apoptosis. Furthermore, MIF knockdown inhibited BTIC-induced tumor formation in a mouse xenograft model, leading to increased overall survival. Collectively, our findings suggest that MIF regulates BTIC function through direct, intracellular inhibition of p53, shedding light on the molecular mechanisms underlying the tumorigenicity of certain malignant brain cells. Cancer Res; 76(9); 2813-23. (c)2016 AACR. PMID- 26980762 TI - Analysis of Liver Tumor-Prone Mouse Models of the Hippo Kinase Scaffold Proteins RASSF1A and SAV1. AB - The tumor suppressor gene RASSF1A is epigenetically silenced in most human cancers. As a binding partner of the kinases MST1 and MST2, the mammalian orthologs of the Drosophila Hippo kinase, RASSF1A is a potential regulator of the Hippo tumor suppressor pathway. RASSF1A shares these properties with the scaffold protein SAV1. The role of this pathway in human cancer has remained enigmatic inasmuch as Hippo pathway components are rarely mutated in tumors. Here we show that Rassf1a homozygous knockout mice develop liver tumors. However, heterozygous deletion of Sav1 or codeletion of Rassf1a and Sav1 produced liver tumors with much higher efficiency than single deletion of Rassf1a. Analysis of RASSF1A binding partners by mass spectrometry identified the Hippo kinases MST1, MST2, and the oncogenic IkappaB kinase TBK1 as the most enriched RASSF1A-interacting proteins. The transcriptome of Rassf1a(-/-) livers was more deregulated than that of Sav1(+/-) livers, and the transcriptome of Rassf1a(-/-), Sav1(+/-) livers was similar to that of Rassf1a(-/-) mice. We found that the levels of TBK1 protein were substantially upregulated in livers lacking Rassf1a. Furthermore, transcripts of several beta-tubulin isoforms were increased in the Rassf1a deficient livers presumably reflecting a role of RASSF1A as a microtubule stabilizing protein. In human liver cancer, RASSF1A frequently undergoes methylation at the promoter but this was not observed for MST1, MST2, or SAV1. Our results suggest a multifactorial role of RASSF1A in suppression of liver carcinogenesis. Cancer Res; 76(9); 2824-35. (c)2016 AACR. PMID- 26980764 TI - IL15 Agonists Overcome the Immunosuppressive Effects of MEK Inhibitors. AB - Many signal transduction inhibitors are being developed for cancer therapy target pathways that are also important for the proper function of antitumor lymphocytes, possibly weakening their therapeutic effects. Here we show that most inhibitors targeting multiple signaling pathways have especially strong negative effects on T-cell activation at their active doses on cancer cells. In particular, we found that recently approved MEK inhibitors displayed potent suppressive effects on T cells in vitro However, these effects could be attenuated by certain cytokines that can be administered to cancer patients. Among them, clinically available IL15 superagonists, which can activate PI3K selectively in T lymphocytes, synergized with MEK inhibitors in vivo to elicit potent and durable antitumor responses, including by a vaccine-like effect that generated resistance to tumor rechallenge. Our work identifies a clinically actionable approach to overcome the T-cell-suppressive effects of MEK inhibitors and illustrates how to reconcile the deficiencies of signal transduction inhibitors, which impede desired immunologic effects in vivo Cancer Res; 76(9); 2561-72. (c)2016 AACR. PMID- 26980766 TI - CK2alpha' Drives Lung Cancer Metastasis by Targeting BRMS1 Nuclear Export and Degradation. AB - Breast cancer metastasis suppressor 1 (BRMS1) is decreased in non-small cell lung cancer (NSCLC) and other solid tumors, and its loss correlates with increased metastases. We show that BRMS1 is posttranslationally regulated by TNF-induced casein kinase 2 catalytic subunit (CK2alpha') phosphorylation of nuclear BRMS1 on serine 30 (S30), resulting in 14-3-3epsilon-mediated nuclear exportation, increased BRMS1 cytosolic expression, and ubiquitin-proteasome-induced BRMS1 degradation. Using our in vivo orthotopic mouse model of lung cancer metastases, we found that mutation of S30 in BRMS1 or the use of the CK2-specific small molecule inhibitor CX4945 abrogates CK2alpha'-induced cell migration and invasion and decreases NSCLC metastasis by 60-fold. Analysis of 160 human NSCLC specimens confirmed that tumor CK2alpha' and cytoplasmic BRMS1 expression levels are associated with increased tumor recurrence, metastatic foci, and reduced disease free survival. Collectively, we identify a therapeutically exploitable posttranslational mechanism by which CK2alpha-mediated degradation of BRMS1 promotes metastases in lung cancer. Cancer Res; 76(9); 2675-86. (c)2016 AACR. PMID- 26980768 TI - Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance. AB - DNA-damaging anticancer drugs remain a part of metastatic melanoma therapy. Epigenetic reprogramming caused by increased histone deacetylase (HDAC) activity arising during tumor formation may contribute to resistance of melanomas to the alkylating drugs temozolomide, dacarbazine, and fotemustine. Here, we report on the impact of class I HDACs on the response of malignant melanoma cells treated with alkylating agents. The data show that malignant melanomas in situ contain a high level of HDAC1/2 and malignant melanoma cells overexpress HDAC1/2/3 compared with noncancer cells. Furthermore, pharmacologic inhibition of class I HDACs sensitizes malignant melanoma cells to apoptosis following exposure to alkylating agents, while not affecting primary melanocytes. Inhibition of HDAC1/2/3 caused sensitization of melanoma cells to temozolomide in vitro and in melanoma xenografts in vivo HDAC1/2/3 inhibition resulted in suppression of DNA double strand break (DSB) repair by homologous recombination because of downregulation of RAD51 and FANCD2. This sensitized cells to the cytotoxic DNA lesion O(6) methylguanine and caused a synthetic lethal interaction with the PARP-1 inhibitor olaparib. Furthermore, knockdown experiments identified HDAC2 as being responsible for the regulation of RAD51. The influence of class I HDACs on DSB repair by homologous recombination and the possible clinical implication on malignant melanoma therapy with temozolomide and other alkylating drugs suggests a combination approach where class I HDAC inhibitors such as valproic acid or MS 275 (entinostat) appear to counteract HDAC- and RAD51/FANCD2-mediated melanoma cell resistance. Cancer Res; 76(10); 3067-77. (c)2016 AACR. PMID- 26980765 TI - The EGF Receptor Promotes the Malignant Potential of Glioma by Regulating Amino Acid Transport System xc(-). AB - Extracellular free amino acids contribute to the interaction between a tumor and its microenvironment through effects on cellular metabolism and malignant behavior. System xc(-) is composed of xCT and CD98hc subunits and functions as a plasma membrane antiporter for the uptake of extracellular cystine in exchange for intracellular glutamate. Here, we show that the EGFR interacts with xCT and thereby promotes its cell surface expression and function in human glioma cells. EGFR-expressing glioma cells manifested both enhanced antioxidant capacity as a result of increased cystine uptake, as well as increased glutamate, which promotes matrix invasion. Imaging mass spectrometry also revealed that brain tumors formed in mice by human glioma cells stably overexpressing EGFR contained higher levels of reduced glutathione compared with those formed by parental cells. Targeted inhibition of xCT suppressed the EGFR-dependent enhancement of antioxidant capacity in glioma cells, as well as tumor growth and invasiveness. Our findings establish a new functional role for EGFR in promoting the malignant potential of glioma cells through interaction with xCT at the cell surface. Cancer Res; 76(10); 2954-63. (c)2016 AACR. PMID- 26980769 TI - The Prosurvival IKK-Related Kinase IKKepsilon Integrates LPS and IL17A Signaling Cascades to Promote Wnt-Dependent Tumor Development in the Intestine. AB - Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikkepsilon in Wnt-driven tumor development. We found that Ikkepsilon was activated in intestinal tumors forming upon loss of the tumor suppressor Apc Genetic ablation of Ikkepsilon in beta-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkepsilon to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikkepsilon was also required for lipopolysaccharide (LPS) and IL17A induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding pro-inflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikkepsilon-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikkepsilon phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikkepsilon to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. Cancer Res; 76(9); 2587-99. (c)2016 AACR. PMID- 26980767 TI - TGFbeta Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis. AB - In early pancreatic carcinogenesis, TGFbeta acts as a tumor suppressor due to its growth-inhibitory effects in epithelial cells. However, in advanced disease, TGFbeta appears to promote tumor progression. Therefore, to better understand the contributions of TGFbeta signaling to pancreatic carcinogenesis, we generated mouse models of pancreatic cancer with either epithelial or systemic TGFBR deficiency. We found that epithelial suppression of TGFbeta signals facilitated pancreatic tumorigenesis, whereas global loss of TGFbeta signaling protected against tumor development via inhibition of tumor-associated fibrosis, stromal TGFbeta1 production, and the resultant restoration of antitumor immune function. Similarly, TGFBR-deficient T cells resisted TGFbeta-induced inactivation ex vivo, and adoptive transfer of TGFBR-deficient CD8(+) T cells led to enhanced infiltration and granzyme B-mediated destruction of developing tumors. These findings paralleled our observations in human patients, where TGFbeta expression correlated with increased fibrosis and associated negatively with expression of granzyme B. Collectively, our findings suggest that, despite opposing the proliferation of some epithelial cells, TGFbeta may promote pancreatic cancer development by affecting stromal and hematopoietic cell function. Therefore, the use of TGFBR inhibition to target components of the tumor microenvironment warrants consideration as a potential therapy for pancreatic cancer, particularly in patients who have already lost tumor-suppressive TGFbeta signals in the epithelium. Cancer Res; 76(9); 2525-39. (c)2016 AACR. PMID- 26980771 TI - Usefulness of Heart-Type Fatty Acid-Binding Protein and Myocardial Performance Index for Early Detection of 5-Fluorouracil Cardiotoxicity. AB - In the present study, we aimed to evaluate temporal changes in heart-type fatty acid-binding protein (h-FABP) and myocardial performance index (Tei index) following administration of 5-fluorouracil (5-FU), a chemotherapeutic agent associated with myocardial ischemia induced by coronary vasospasm. Thirty-two patients with cancer receiving their first 5-FU-based chemotherapy were included in the study. Prior to chemotherapy and 24 hours after the initiation of chemotherapy, all patients underwent a comprehensive echocardiographic examination. Blood samples were taken for h-FABP and troponin I (TnI) measurements at different time points during the first 24 hours of 5-FU administration. Postinfusion echocardiography revealed worsening in Tei index (0.37 +/- 0.08 vs 0.43 +/- 0.07, P < .001). Clinically overt cardiotoxicity was evident in 4 (12.5%) of our patient population. Heart-type fatty acid binding protein and TnI levels were within normal ranges at all time points. Our results suggest that ischemia coronary vasospasm due to 5-FU cardiotoxicity should be reviewed. Furthermore, Tei index might be a sensitive indicator of occult 5-FU cardiotoxicity. PMID- 26980770 TI - Effectiveness of bilateral tubotubal anastomosis in a large outpatient population. AB - STUDY QUESTION: Is bilateral tubotubal anastomosis a successful treatment in an outpatient patient population? SUMMARY ANSWER: For women wanting children after tubal sterilization, bilateral tubotubal anastomosis is an effective outpatient treatment. WHAT IS KNOWN ALREADY: With the current emphasis in reproductive medicine on high technology procedures, the effectiveness of female surgical sterilization reversal is often overlooked. Previous clinical studies of tubal sterilization reversal have been mostly retrospective analyses of small patient populations. STUDY DESIGN, SIZE, DURATION: A cohort of women who underwent outpatient bilateral tubotubal anastomosis from January 2000 to June 2013 was followed prospectively until December 2014 to determine the proportions of women undergoing the procedure who became pregnant and who had live births. Data were collected at the time of pregnancy. Differences in pregnancy rates and live birth rates associated with age, race and sterilization method were evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 6692 women, aged 20-51 years, underwent outpatient bilateral tubotubal anastomosis. MAIN RESULTS AND THE ROLE OF CHANCE: The crude overall pregnancy rate was 69%. The crude overall birth rate was 35%. Results varied according to age at sterilization reversal and the method of sterilization. Women under 30 years of age at reversal of ring/clip sterilizations had an 88% pregnancy rate and 62% birth rate. Pregnancy and birth rates declined as age increased at sterilization reversal. Coagulation sterilization reversals resulted in the lowest rates of pregnancies and births. Ligation/resection reversals had intermediate success rates. LIMITATIONS, REASONS FOR CAUTION: Limitations of our study include probable underreporting of pregnancies based on patient-initiated reports; possible errors in the reporting of pregnancies or early miscarriages that may have been based solely on home pregnancy tests; and probable over-reporting of the diagnosis of ectopic pregnancies. We identified age and sterilization method as being associated with subsequent pregnancy, however, in order to be considered predictive, the associations would need to be validated in an independent second prospectively studied group of representative patients. Finally, we also included patients in the study population who had additional surgical procedures performed at the time of tubotubal anastomosis (e.g. uterine myomectomy, fimbrioplasty, ovarian cystectomy and adhesiolysis), factors that could result in differences in pregnancy statistics in our study versus other patient populations. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study can help inform patients and clinicians about this low technology alternative to IVF. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A. PMID- 26980772 TI - Plasma Endocan Levels in Patients With Isolated Coronary Artery Ectasia. AB - Endocan is a soluble proteoglycan, secreted by human vascular endothelial cells. Endocan is a marker for vascular pathologies and an important mediator of angiogenesis, strongly associated with inflammation, vascular endothelial dysfunction, and atherosclerosis. The relationship between coronary artery ectasia (CAE) and endocan has not been evaluated. We aimed to investigate this association. Fifty-four patients with isolated CAE without coronary stenosis and 30 controls with normal coronary angiogram were included in this study. Endocan plasma concentrations were measured using an enzyme-linked immunosorbent assay. Patients with isolated CAE had significantly higher levels of endocan compared to the controls (18.9 +/- 7.3 vs 15.6 +/- 3.6 ng/mL; P = .007). There was a significant correlation between endocan levels and severity of isolated CAE according to the Markis classification ( r = -.593, P < .001). Plasma endocan levels may reflect the presence and severity of isolated CAE, suggesting that endocan may be involved in pathogenesis of isolated CAE. PMID- 26980773 TI - Endovascular Therapy for Infrainguinal Artery Disease With Coronary Devices: A Retrospective Observational Study Comparing Drug-Eluting Stents Versus Bioresorbable Vascular Scaffolds. AB - Several devices are available for infrainguinal endovascular therapy, with drug eluting stents (DES) among the most promising. Bioresorbable vascular scaffolds (BVS) may further improve outcomes. We have liberally used in our practice coronary DES and BVS for infrainguinal endovascular therapy and hereby report our preliminary results. We conducted an observational study by retrospectively identifying characteristics of patients undergoing infrainguinal implantation of coronary DES or BVS. We compared the risk of major adverse events (MAE: death, amputation, or target vessel revascularization [TVR]) and components of MAE in the overall sample and after propensity matching. We included a total of 204 patients (207 limbs), 148 (72.5%) treated with DES and 56 (27.5%) with BVS. Bivariate analysis showed that TVR was less common in the DES group (41.9% vs 18.4%, P = .014). However, propensity-matched analysis showed nearly identical risks of MAE, amputation, TVR, or symptom burden with DES and BVS (all P > .05). In conclusion, the present pilot experience with coronary BVS suggests that they could provide acceptable results for infrainguinal endovascular procedures, comparable to those obtained by their metallic counterpart. PMID- 26980775 TI - Efficacy and Safety of Endovascular Therapy for Aortoiliac TASC D Lesions. AB - BACKGROUND: Although there is increasing evidence of the effectiveness of endovascular therapy for complex aortoiliac (AI) occlusive disease, it is not universally applied to TASC D lesions. METHODS: A total of 2096 patients, 2601 limbs with AI occlusive disease, were enrolled. The lesions were categorized as TASC D (395) or TASC A-C (2206), and we compared baseline data, procedure, and follow-up result between the 2 groups. RESULTS: The success rate of the procedure was significantly lower in the TASC D group (91.6% vs 99.3%, P < .01), and more procedure complications occurred in the TASC D group (11.1% vs 5.2%, P < .01). The results of a 5-year follow-up revealed no significant difference in primary patency (77.9% vs 77.1%, P = .17) and major adverse cardiovascular and limb events (MACLE; 30.5% vs 33.4%, P = .42) between the 2 groups. A multivariate analysis revealed complications and critical limb ischemia are independent predictors of MACLE in the TASC D group. CONCLUSION: The success rate of the procedure was lower in the TASC D group. Complications were more frequent in the TASC D group, and they were related to MACLE. PMID- 26980774 TI - Lipoprotein(a) Levels in Patients With Abdominal Aortic Aneurysm. AB - Circulating markers relevant to the development of abdominal aortic aneurysm (AAA) are currently required. Lipoprotein(a), Lp(a), is considered a candidate marker associated with the presence of AAA. The present meta-analysis aimed to evaluate the association between circulating Lp(a) levels and the presence of AAA. The PubMed-based search was conducted up to April 30, 2015, to identify the studies focusing on Lp(a) levels in patients with AAA and controls. Quantitative data synthesis was performed using a random effects model, with standardized mean difference (SMD) and 95% confidence interval (CI) as summary statistics. Overall, 9 studies were identified. After a combined analysis, patients with AAA were found to have a significantly higher level of Lp(a) compared to the controls (SMD: 0.87, 95% CI: 0.41-1.33, P < .001). This result remained robust in the sensitivity analysis, and its significance was not influenced after omitting each of the included studies from the meta-analysis. The present meta-analysis confirmed a higher level of circulating Lp(a) in patients with AAA compared to controls. High Lp(a) levels can be associated with the presence of AAA, and Lp(a) may be a marker in screening for AAA. Further studies are needed to establish the clinical utility of measuring Lp(a) in the prevention and management of AAA. PMID- 26980776 TI - Circulating miR-130a, miR-27b, and miR-210 in Patients With Peripheral Artery Disease and Their Potential Relationship With Oxidative Stress. AB - Some emerging risk factors such as oxidative stress biomarkers and microRNAs (miRs) may add additional value to the established risk factors for peripheral artery disease (PAD). We enrolled 27 patients with PAD and 27 age-matched controls. We examined the levels of a series of miRs (miR-130a, miR-27b, and miR 210) in serum samples. The level of well-established oxidative stress biomarkers, such as lipid hydroperoxides, isoprostanes, hemeoxygenase-1 (HO-1) and reduced glutathione, was also measured in plasma and their relationship with the miRs was determined. Levels of miR-130a, miR-27b, and miR-210 were significantly increased in patients with PAD when compared to the controls. The level of miR-130 was positively correlated with body mass index, whereas miR-210 was inversely associated with pain-free walking distance (PfWD). None of the evaluated miRs was associated with lowered PfWD of patients with PAD (stage IIa > 250 m, IIb < 250 m) or oxidative stress parameters. In conclusion, our findings suggest the need for more research to assess if miRs can serve as useful markers for the early diagnosis and monitoring of PAD. PMID- 26980778 TI - Premature closure? Not so fast. PMID- 26980777 TI - Gonadotropin ratio affects the in vitro growth of rhesus ovarian preantral follicles. AB - In vitro follicle growth (IVFG) strategy is critical in the fertility preservation of cancer survivors; however, its optimal protocol needs to be developed using primate models since the availability of human samples is limited. Only a few previous studies have reported the successful IVFG of rhesus monkey ovaries using low-dose follicle-stimulating hormone (FSH) (0.3 or 3 ng/mL) and long-term culture (up to 5 weeks) and it is still uncertain in regard to the optimal culture duration and effective dose of treated gonadotropins applicable to the IVFG of rhesus preantral follicles. Recently, we have reported that the FSH to luteinizing hormone (LH) ratio affects the in vitro growth of murine ovarian follicles. We aimed to investigate whether gonadotropin ratios affect the efficiency of rhesus follicular growth in vitro Ovaries were collected from six necropsied rhesus macaques (4-9 years) and preantral follicles were retrieved and cultured for 14 days using 200 mIU/mL FSH. The characteristics of follicular growth were compared between the FSH:LH=1:1 (n=24) and FSH:LH=2:1 (n=24) groups. High concentration gonadotropin treatment shortened the duration required for in vitro maturation of rhesus preantral follicles. The FSH:LH=2:1 group showed a faster follicular growth and enabled the acquisition of mature oocytes, although the expression of growth differentiation factor (GDF)-9 and anti-Mullerian hormone (AMH) did not differ significantly between the two groups. Taken together, high dose gonadotropin treatment can shorten the duration of IVFG and the gonadotropin ratio is important in the IVFG of rhesus monkey ovaries. PMID- 26980780 TI - Ambiguity produces attention shifts in category learning. AB - It has been suggested that people and nonhuman animals protect their knowledge from interference by shifting attention toward the context when presented with information that contradicts their previous beliefs. Despite that suggestion, no studies have directly measured changes in attention while participants are exposed to an interference treatment. In the present experiments, we adapted a dot-probe task to track participants' attention to cues and contexts while they were completing a simple category learning task. The results support the hypothesis that interference produces a change in the allocation of attention to cues and contexts. PMID- 26980779 TI - Basal levels of AMPA receptor GluA1 subunit phosphorylation at threonine 840 and serine 845 in hippocampal neurons. AB - Dephosphorylation of AMPA receptor (AMPAR) GluA1 subunits at two sites, serine 845 (S845) and threonine 840 (T840), is thought to be involved in NMDA receptor dependent forms of long-term depression (LTD). Importantly, the notion that dephosphorylation of these sites contributes to LTD assumes that a significant fraction of GluA1 subunits are basally phosphorylated at these sites. To examine this question, we used immunoprecipitation/depletion assays to estimate the proportion of GluA1 subunits basally phosphorylated at S845 and T840. Although dephosphorylation of S845 is thought to have a key role in LTD, our results indicate that few GluA1 subunits in hippocampal neurons are phosphorylated at this site. In contrast, ~50% of GluA1 subunits are basally phosphorylated at T840, suggesting that dephosphorylation of this site can contribute to the down regulation of AMPAR-mediated synaptic transmission in LTD. PMID- 26980781 TI - Counterconditioned fear responses exhibit greater renewal than extinguished fear responses. AB - This series of experiments used rats to compare counterconditioning and extinction of conditioned fear responses (freezing) with respect to the effects of a context shift. In each experiment, a stimulus was paired with shock in context A, extinguished or counterconditioned through pairings with sucrose in context B, and then tested for renewal outside of context B. Counterconditioned fear responses exhibited greater ABA renewal than extinguished fear responses. This result was observed using a between-subjects design (Experiment 1) and a within-subject design in which counterconditioned and extinguished stimuli were equated in all respects other than their signaling of sucrose (Experiment 2). Counterconditioned fear responses also exhibited greater ABC renewal than extinguished fear responses (Experiment 3). This result was observed using a within-subject design in which context C was identical to context B in terms of its associative history, and when counterconditioned and extinguished CSs were tested in compounds matched for their association with both shock and sucrose (Experiment 4). These results are consistent with models which hold that context regulates expression of associations formed in counterconditioning and extinction, and allow the level of regulation to be greater following counterconditioning than extinction, as noted in previous studies. PMID- 26980782 TI - An omission procedure reorganizes the microstructure of sign-tracking while preserving incentive salience. AB - Appetitive sign-tracking, in which reward-paired cues elicit approach that can result in cue interaction, demonstrates how cues acquire motivational value. For example, rats will approach and subsequently interact with a lever insertion cue that signals food delivery upon its retraction. However, lever deflections are rapidly reduced once rats are trained on an omission schedule in which lever interactions cancel food delivery. Here we evaluated the change in sign-tracking response topography in rats exposed to such an omission procedure. Lever deflections dropped precipitously when they canceled reward. However, rats that were on an omission schedule continued to approach, sniff, and contact the lever without pressing it, and did so at comparable rates to rats that were not under an omission schedule. Thus, sign-tracking was maintained, albeit in a different manner, following omission. Such findings show that the motivational attraction to reward cues can be expressed with remarkable persistence and flexibility. PMID- 26980783 TI - Proteolytic cleavage of proBDNF into mature BDNF in the basolateral amygdala is necessary for defeat-induced social avoidance. AB - Brain-derived neurotrophic factor (BDNF) is essential for memory processes. The present study tested whether proteolytic cleavage of proBDNF into mature BDNF (mBDNF) within the basolateral amygdala (BLA) regulates the consolidation of defeat-related memories. We found that acute social defeat increases the expression of mBDNF, but not proBDNF, in the BLA/central amygdala. We also showed that blocking plasmin in the BLA with microinjection of alpha2-antiplasmin immediately following social defeat decreases social avoidance 24 h later. These data suggest the proteolytic cleavage of BDNF in the BLA is necessary for defeat induced social avoidance. PMID- 26980785 TI - Practice makes perfect in memory recall. AB - A large variability in performance is observed when participants recall briefly presented lists of words. The sources of such variability are not known. Our analysis of a large data set of free recall revealed a small fraction of participants that reached an extremely high performance, including many trials with the recall of complete lists. Moreover, some of them developed a number of consistent input-position-dependent recall strategies, in particular recalling words consecutively ("chaining") or in groups of consecutively presented words ("chunking"). The time course of acquisition and particular choice of positional grouping were variable among participants. Our results show that acquiring positional strategies plays a crucial role in improvement of recall performance. PMID- 26980787 TI - Lethal bilateral cerebral infarction caused by Moyamoya disease. PMID- 26980784 TI - Pretrial functional connectivity differentiates behavioral outcomes during trace eyeblink conditioning in the rabbit. AB - Fluctuations in neural activity can produce states that facilitate and accelerate task-related performance. Acquisition of trace eyeblink conditioning (tEBC) in the rabbit is enhanced when trials are contingent on optimal pretrial activity in the hippocampus. Other regions which are essential for whisker-signaled tEBC, such as the cerebellar interpositus nucleus (IPN), somatosensory and prelimbic cortices, may also show optimal connectivity prior to successful performance. Functional magnetic resonance imaging (fMRI) was acquired in nine rabbits during tEBC on the first and tenth days of initial training and once again after a 30-d, training-free hiatus. Data acquired during the intertrial interval was parsed depending on whether or not a conditioned response (CR) occurred on the upcoming trial and seed-based functional connectivity was calculated among the IPN, hippocampus, somatosensory, and prelimbic cortices. Functional connectivity between the left somatosensory cortex and right IPN, regions critical for establishing and producing CRs evoked by right vibrissae vibration and right corneal airpuff, was significantly negative prior to successful, CR trials as compared with unsuccessful, non-CR trials. Differences were not observed for any of the other possible combinations of connectivity. Our results demonstrate that specific pretrial functional connectivity exists within the rabbit brain and differentiates between upcoming behavioral response outcomes. Online analysis of network fluctuations has the potential to be used as the basis for therapeutic interventions to facilitate learning and memory. PMID- 26980788 TI - Abandoned areas in post-disaster Fukushima, Japan. PMID- 26980789 TI - Closing the circle: from organoids back to development. PMID- 26980790 TI - An interview with Melissa Little. AB - Melissa Little is a Senior Principal Research Fellow at the Murdoch Childrens Research Institute in Melbourne, Australia. Her lab has studied kidney development and regeneration for over 20 years, recently making notable advances in the generation of kidney organoids from human iPSCs. We chatted with Melissa about her career, her thoughts on the potential of the organoid and stem cell fields, and what she hopes to achieve during her guest editorship with Development. PMID- 26980786 TI - Phosphorylation of K+ channels at single residues regulates memory formation. AB - Phosphorylation is a ubiquitous post-translational modification of proteins, and a known physiological regulator of K+ channel function. Phosphorylation of K()channels by kinases has long been presumed to regulate neuronal processing and behavior. Although circumstantial evidence has accumulated from behavioral studies of vertebrates and invertebrates, the contribution to memory of single phosphorylation sites on K+ channels has never been reported. We have used gene targeting in mice to inactivate protein kinase A substrate residues in the fast inactivating subunit Kv4.2 (T38A mutants), and in the small-conductance Ca2+ activated subunit SK1 (S105A mutants). Both manipulations perturbed a specific form of memory, leaving others intact. T38A mutants had enhanced spatial memory for at least 4 wk after training, whereas performance in three tests of fear memory was unaffected. S105A mutants were impaired in passive avoidance memory, sparing fear, and spatial memory. Together with recent findings that excitability governs the participation of neurons in a memory circuit, this result suggests that the memory type supported by neurons may depend critically on the phosphorylation of specific K+ channels at single residues. PMID- 26980791 TI - From single genes to entire genomes: the search for a function of nuclear organization. AB - The existence of different domains within the nucleus has been clear from the time, in the late 1920s, that heterochromatin and euchromatin were discovered. The observation that heterochromatin is less transcribed than euchromatin suggested that microscopically identifiable structures might correspond to functionally different domains of the nucleus. Until 15 years ago, studies linking gene expression and subnuclear localization were limited to a few genes. As we discuss in this Review, new genome-wide techniques have now radically changed the way nuclear organization is analyzed. These have provided a much more detailed view of functional nuclear architecture, leading to the emergence of a number of new paradigms of chromatin folding and how this folding evolves during development. PMID- 26980792 TI - Development of the lymphatic system: new questions and paradigms. AB - The lymphatic system is a blind-ended network of vessels that plays important roles in mediating tissue fluid homeostasis, intestinal lipid absorption and the immune response. A profound understanding of the development of lymphatic vessels, as well as of the molecular cues governing their formation and morphogenesis, might prove essential for our ability to treat lymphatic-related diseases. The embryonic origins of lymphatic vessels have been debated for over a century, with a model claiming a venous origin for the lymphatic endothelium being predominant. However, recent studies have provided new insights into the origins of lymphatic vessels. Here, we review the molecular mechanisms controlling lymphatic specification and sprouting, and we discuss exciting findings that shed new light on previously uncharacterized sources of lymphatic endothelial cells. PMID- 26980793 TI - H19 controls reactivation of the imprinted gene network during muscle regeneration. AB - The H19 locus controls fetal growth by regulating expression of several genes from the imprinted gene network (IGN). H19 is fully repressed after birth, except in skeletal muscle. Using loss-of-function H19(Delta3) mice, we investigated the function of H19 in adult muscle. Mutant muscles display hypertrophy and hyperplasia, with increased Igf2 and decreased myostatin (Mstn) expression. Many imprinted genes are expressed in muscle stem cells or satellite cells. Unexpectedly, the number of satellite cells was reduced by 50% in H19(Delta3) muscle fibers. This reduction occurred after postnatal day 21, suggesting a link with their entry into quiescence. We investigated the biological function of these mutant satellite cells in vivo using a regeneration assay induced by multiple injections of cardiotoxin. Surprisingly, despite their reduced number, the self-renewal capacity of these cells is fully retained in the absence of H19. In addition, we observed a better regeneration potential of the mutant muscles, with enhanced expression of several IGN genes and genes from the IGF pathway. PMID- 26980794 TI - Reck enables cerebrovascular development by promoting canonical Wnt signaling. PMID- 26980795 TI - Pdx1 regulates pancreas tubulogenesis and E-cadherin expression. PMID- 26980796 TI - The stroke interventionalist. PMID- 26980798 TI - Ethical foundations of the radiological protection system. AB - The International Commission on Radiological Protection (ICRP) has established Task Group 94 under Committee 4 to develop a report on the ethical foundations of the system of radiological protection. The aim of this report is to consolidate the basis of ICRP recommendations, to improve understanding of the system, and to provide a basis for communication on radiation risk and its perception. Through a series of workshops organised by the Commission in cooperation with the International Radiation Protection Association and its associate societies involving radiological protection professionals and specialists of ethics around the world, Task Group 94 has identified the key ethical and social values underpinning the system of radiological protection. The purpose of eliciting the ethical principles and values of the radiological protection system is not only to clarify the rationale for recommendations made by the Commission, but also to assist in discussions related to its practical implementation. A clear understanding of the ethical principles will help resolve dilemmas caused by potential conflicts in actions that might be considered, or decisions that must be made. PMID- 26980797 TI - Operational quantities and new approach by ICRU. AB - The protection quantities, equivalent dose in a tissue or organ and effective dose, were developed by the International Commission on Radiological Protection (ICRP) to allow quantification of the extent of exposure of the human body to ionising radiation. These quantities are used for the implementation of limitation and optimisation principles. Body-related protection quantities are not measurable in practice. Therefore, the International Commission on Radiation Units and Measurements (ICRU) developed a set of operational dose quantities for use in radiation measurements for external exposure that can assess the protection quantities. The current ICRU operational quantities were defined more than 30 years ago. ICRU Report Committee 26 examined the rationale for the operational quantities, taking account of changes in the definitions of the protection quantities in ICRP's 2007 Recommendations. The considerations included the range of types and energies of particles contributing to exposure of workers and members of the public. ICRU Report Committee 26 investigated a set of alternative definitions for the operational quantities. The major change to the currently favoured set of quantities is redefinition of the operational quantities, from being based on doses at specific points in the ICRU sphere and soft tissue, to being based on particle fluence and conversion coefficients for effective dose and absorbed dose to the lens of the eye and local skin. PMID- 26980800 TI - Use of effective dose. AB - International Commission on Radiological Protection (ICRP) Publication 103 provided a detailed explanation of the purpose and use of effective dose and equivalent dose to individual organs and tissues. Effective dose has proven to be a valuable and robust quantity for use in the implementation of protection principles. However, questions have arisen regarding practical applications, and a Task Group has been set up to consider issues of concern. This paper focusses on two key proposals developed by the Task Group that are under consideration by ICRP: (1) confusion will be avoided if equivalent dose is no longer used as a protection quantity, but regarded as an intermediate step in the calculation of effective dose. It would be more appropriate for limits for the avoidance of deterministic effects to the hands and feet, lens of the eye, and skin, to be set in terms of the quantity, absorbed dose (Gy) rather than equivalent dose (Sv). (2) Effective dose is in widespread use in medical practice as a measure of risk, thereby going beyond its intended purpose. While doses incurred at low levels of exposure may be measured or assessed with reasonable reliability, health effects have not been demonstrated reliably at such levels but are inferred. However, bearing in mind the uncertainties associated with risk projection to low doses or low dose rates, it may be considered reasonable to use effective dose as a rough indicator of possible risk, with the additional consideration of variation in risk with age, sex and population group. PMID- 26980799 TI - Radiological protection in ion beam radiotherapy: practical guidance for clinical use of new technology. AB - Recently introduced technologies in radiotherapy have significantly improved the clinical outcome for patients. Ion beam radiotherapy, involving proton and carbon ion beams, provides excellent dose distributions in targeted tumours, with reduced doses to the surrounding normal tissues. However, careful treatment planning is required in order to maximise the treatment efficiency and minimise the dose to normal tissues. Radiation exposure from secondary neutrons and photons, particle fragments, and photons from activated materials should also be considered for radiological protection of the patient and medical staff. Appropriate maintenance is needed for the equipment and air in the treatment room, which may be activated by the particle beam and its secondary radiation. This new treatment requires complex procedures and careful adjustment of parameters for each patient. Therefore, education and training for the personnel involved in the procedure are essential for both effective treatment and patient protection. The International Commission on Radiological Protection (ICRP) has provided recommendations for radiological protection in ion beam radiotherapy in Publication 127 Medical staff should be aware of the possible risks resulting from inappropriate use and control of the equipment. They should also consider the necessary procedures for patient protection when new technologies are introduced into clinical practice. PMID- 26980803 TI - Correction to "Effects of Phenobarbital on Expression of UDP Glucuronosyltransferase 1a6 and 1a7 in Rat Brain". PMID- 26980804 TI - Correction to: "A Novel Loading Method for Doxycycline Liposomes for Intracellular Drug Delivery: Characterization of In Vitro and In Vivo Release Kinetics and Efficacy in a J774A.1 Cell Line Model of Mycobacterium smegmatis Infection". PMID- 26980801 TI - Stability of Syk protein and mRNA in human peripheral blood basophils. AB - In human basophils, Syk expression is 10-fold lower than most other types of leukocytes. There are indirect studies that suggest that Syk protein is highly unstable (a calculated half-life less than 15 min) in human peripheral blood basophils. Therefore, in these studies, Syk stability was directly examined. Purified basophils were metabolically labeled and a pulse-chase experimental design showed Syk protein to be stable in the time frame of 12 h (95% likelihood that half-life is more than 12 h). However, its synthetic rate was very slow (~10 fold slower) compared with CD34-derived basophils, which have been shown to express levels of Syk consistent with other mature circulating leukocytes. Syk mRNA expression was found to be 5-30-fold lower than other cell types (CD34 derived basophils, peripheral blood eosinophils, and plasmacytoid dendritic cells). Syk protein and mRNA levels, across cell types, were relatively concordant. Syk mRNA in basophils showed a half-life of 3.5 h, which was greater than that of interleukin-4 or Fc epsilon receptor I-alpha mRNA (~2 h), but somewhat shorter than Fc epsilon receptor I-beta mRNA (8 h). A comparison of miR expression between CD34-derived and peripheral blood basophils demonstrated only 1 significant increase, in miR-150 (77-fold). Transfection in human embryonic kidney cells of a stabilized form of miR-150 showed that it modified expression of c-Myb mRNA but not of Syk mRNA or protein. These results suggest that low Syk expression in basophils results, not from protein instability and perhaps not from mRNA stability. Instead, the results point to the transcriptional nature of an important point of regulation. PMID- 26980802 TI - Retinoic acid-primed human dendritic cells inhibit Th9 cells and induce Th1/Th17 cell differentiation. AB - All-trans-retinoic acid plays a central role in mucosal immunity, where it promotes its synthesis by up-regulating CD103 expression on dendritic cells, induces gut tropic (alpha4beta7(+) and CCR9(+)) T cells, and inhibits Th1/Th17 differentiation. Recently, murine studies have highlighted the proinflammatory role of retinoic acid in maintaining inflammation under a variety of pathologic conditions. However, as a result of limited human data, we investigated the effect of retinoic acid on human dendritic cells and CD4(+) T cell responses in the presence of polarizing (Th1/Th9/Th17) and inflammatory (LPS-induced dendritic cells) conditions. We report a novel role of retinoic acid in an inflammatory setup, where retinoic acid-primed dendritic cells (retinoic acid-monocyte-derived dendritic cells) up-regulated CCR9(+)T cells, which were observed to express high levels of IFN-gamma in the presence of Th1/Th17 conditions. Retinoic acid monocyte-derived dendritic cells, under Th17 conditions, also favored the induction of IL-17(+) T cells. Furthermore, in the presence of TGF-beta1 and IL 4, retinoic acid-monocyte-derived dendritic cells inhibited IL-9 and induced IFN gamma expression on T cells. Experiments with naive CD4(+) T cells, activated in the presence of Th1/Th17 conditions and absence of DCs, indicated that retinoic acid inhibited IFN-gamma and IL-17 expression on T cells. These data revealed that in the face of inflammatory conditions, retinoic acid, in contrast from its anti-inflammatory role, could maintain or aggravate the intestinal inflammation. PMID- 26980805 TI - Catalytic behavior of noble metal nanoparticles for the hydrogenation and oxidation of multiwalled carbon nanotubes. AB - The catalytic behavior of various noble metal nanoparticles (NPs) supported directly on multiwalled carbon nanotubes (MWCNTs) was observed using environmental transmission electron microscopy (E-TEM). Gasification of the MWCNTs via catalytic hydrogenation or oxidation progressed at ~450 degrees C in conjunction with certain noble metal NP catalysts at the interface between MWCNTs and the NPs. During such catalytic reactions, the NPs were observed to move rapidly over the MWCNT surfaces. The mobility and wettability of the NPs varied depending on the particular metal NPs employed and the ambient atmosphere. While rhodium NPs exhibited high wettability under both hydrogen and oxygen atmospheres, the wettability of platinum, palladium and iridium NPs on MWCNTs varied with the atmosphere. The metal NPs seemed to have high degrees of crystallinity while their morphologies fluctuated throughout the catalytic reactions. PMID- 26980806 TI - Roles of EDNs in regulating oviductal NO synthesis and smooth muscle motility in cows. AB - Endothelins (EDNs) participate in various physiological events including smooth muscle contraction, nitric oxide (NO) synthesis, and embryonic development. In this study, we investigated the regional roles of EDNs produced by bovine oviductal epithelial cells in NO synthesis and smooth muscle motility. Quantification of mRNA expressions indicated that expression of EDN receptor B (EDNRB) in the ampullary region was higher after ovulation than before ovulation, whereas expression of EDNRA in the isthmic region was higher after ovulation than before ovulation. Immunohistochemistry revealed that the EDN receptors (EDNRA and EDNRB) were expressed in the epithelium, whereas smooth muscle showed positive staining only for EDNRA. The expressionsPlease suggest whether 'NOS2' can be treated as the updated symbol for 'iNOS' as per gene nomenclature. of inducible NO synthase (iNOS) protein and its mRNA (NOS2) in cultured epithelial cells isolated from the ampulla were stimulated by EDN1, but not by EDN2 or EDN3, after 1h of incubation. In isthmic epithelial cells, none of the EDNs affected the expression of NOS2 Isometric contraction tests indicated that spontaneous waves were strong in the isthmic region but weak in the ampullary region. EDN1 modulated smooth muscle motility in both the regions. The overall findings suggest that EDN1 plays region-specific roles in smooth muscle motility and epithelial NO synthesis, providing an optimal oviductal microenvironment for transport of gametes, fertilization, and development/transport of early embryo. PMID- 26980807 TI - N-carbamylglutamate and L-arginine improved maternal and placental development in underfed ewes. AB - The objectives of this study were to determine how dietary supplementation of N carbamylglutamate (NCG) and rumen-protected L-arginine (RP-Arg) in nutrient restricted pregnant Hu sheep would affect (1) maternal endocrine status; (2) maternal, fetal, and placental antioxidation capability; and (3) placental development. From day 35 to day 110 of gestation, 32 Hu ewes carrying twin fetuses were allocated randomly into four groups: 100% of NRC-recommended nutrient requirements, 50% of NRC recommendations, 50% of NRC recommendations supplemented with 20g/day RP-Arg, and 50% of NRC recommendations supplemented with 5g/day NCG product. The results showed that in maternal and fetal plasma and placentomes, the activities of total antioxidant capacity and superoxide dismutase were increased (P<0.05); however, the activity of glutathione peroxidase and the concentration of maleic dialdehyde were decreased (P<0.05) in both NCG- and RP-Arg-treated underfed ewes. The mRNA expression of vascular endothelial growth factor and Fms-like tyrosine kinase 1 was increased (P<0.05) in 50% NRC ewes than in 100% NRC ewes, and had no effect (P>0.05) in both NCG- and RP-Arg-treated underfed ewes. A supplement of RP-Arg and NCG reduced (P<0.05) the concentrations of progesterone, cortisol, and estradiol-17beta; had no effect on T4/T3; and improved (P<0.05) the concentrations of leptin, insulin-like growth factor 1, tri-iodothyronine (T3), and thyroxine (T4) in serum from underfed ewes. These results indicate that dietary supplementation of NCG and RP-Arg in underfed ewes could influence maternal endocrine status, improve the maternal-fetal placental antioxidation capability, and promote fetal and placental development during early-to-late gestation. PMID- 26980808 TI - Meta-analysis of gene expression profiles in granulosa cells during folliculogenesis. AB - Folliculogenesis involves coordinated profound changes in different follicular compartments and significant modifications of their gene expression patterns, particularly in granulosa cells. Huge datasets have accumulated from the analyses of granulosa cell transcriptomic signatures in predefined physiological contexts using different technological platforms. However, no comprehensive overview of folliculogenesis is available. This would require integration of datasets from numerous individual studies. A prerequisite for such integration would be the use of comparable platforms and experimental conditions. The EmbryoGENE program was created to study bovine granulosa cell transcriptomics under different physiological conditions using the same platform. Based on the data thus generated so far, we present here an interactive web interface called GranulosaIMAGE (Integrative Meta-Analysis of Gene Expression), which provides dynamic expression profiles of any gene of interest and all isoforms thereof in granulosa cells at different stages of folliculogenesis. GranulosaIMAGE features two kinds of expression profiles: gene expression kinetics during bovine folliculogenesis from small (6 mm) to pre-ovulatory follicles under different hormonal and physiological conditions and expression profiles of granulosa cells of dominant follicles from post-partum cows in different metabolic states. This article provides selected examples of expression patterns along with suggestions for users to access and generate their own patterns using GranulosaIMAGE. The possibility of analysing gene expression dynamics during the late stages of folliculogenesis in a mono-ovulatory species such as bovine should provide a new and enriched perspective on ovarian physiology. PMID- 26980809 TI - Granulocyte colony-stimulating factor in repeated IVF failure, a randomized trial. AB - Recent studies have revealed key roles for granulocyte colony-stimulating factor (GCSF) in embryo implantation process and maintenance of pregnancy, and some studies showed promising results by using local intrauterine infusion of GCSF in patients undergoing in vitro fertilization (IVF). This multicenter, randomized, controlled trial included 112 infertile women with repeated IVF failure to evaluate the efficacy of systemic single-dose subcutaneous GCSF administration on IVF success in these women. In this study, the Long Protocol of ovarian stimulation was used for all participants. Sealed, numbered envelopes assigned 56 patients to receive subcutaneous 300 ug GCSF before implantation and 56 in the control group. The implantation (number of gestational sacs on the total number of transferred embryos), chemical pregnancy (positive serum beta-HCG), and clinical pregnancy (gestational sac and fetal heart) rates were compared between the two groups. This trial is registered at www.irct.ir (IRCT201503119568N11). The successful implantation (18% vs 7.2%, P=0.007), chemical pregnancy (44.6% vs 19.6%, P=0.005), and clinical pregnancy (37.5% vs 14.3%, P=0.005) rates were significantly higher in the intervention group than in the control group. After adjustment for participants' age, endometrial thickness, good-quality oocyte counts, number of transferred embryos, and anti-Mullerian hormone levels, GCSF treatment remained significantly associated with successful implantation (OR=2.63, 95% CI=1.09-6.96), having chemical pregnancy (OR= 2.74, 95% CI=1.11 7.38) and clinical pregnancy (OR=2.94, 95% CI=1.23-8.33). In conclusion, administration of single-dose systemic subcutaneous GCSF before implantation significantly increases the IVF success, implantation, and pregnancy rates in infertile women with repeated IVF failure. PMID- 26980810 TI - Calcium Supplementation to Prevent Preeclampsia: Translating Guidelines into Practice in Low-Income Countries. AB - The WHO issued a strong recommendation that pregnant women be provided calcium supplements to prevent preeclampsia. This is the first recommended nutritional intervention to prevent this condition, a leading cause of maternal mortality globally. As health systems seek to implement this new intervention, a number of issues require further clarification and guidance, including dosage regimen, supplement formulation, and alignment with other antenatal nutritional interventions. We summarize key evidence on the above points and offer our views on good practices. Most developing countries have low calcium intake, so where habitual calcium intake is unknown, calcium supplements are likely beneficial. In our view, policymakers and program planners should consider adopting doses between 1.0 and 1.5 g elemental calcium/d, depending on the local average and variation in dietary calcium intake, logistical feasibility, and acceptability in the target population. Prudent practice would entail daily administration as calcium carbonate administered in divided doses of not >500 mg elemental calcium per dose. For ease of prescribing and adherence, calcium [as with iron and folic acid (IFA)] should be administered routinely to pregnant women from the earliest contact in pregnancy until delivery. Calcium's acute inhibitory effect on iron absorption translates to minimal effects in clinical studies. Therefore, to simplify the regimen and facilitate adherence, providers should not counsel that calcium and IFA pills must be taken separately. Although further research will shed more light on clinical and programmatic issues, policies can be implemented with ongoing revision as we continue to learn what works to improve maternal and newborn health. PMID- 26980811 TI - Comparison of Formulas Based on Lipid Emulsions of Olive Oil, Soybean Oil, or Several Oils for Parenteral Nutrition: A Systematic Review and Meta-Analysis. AB - Many studies have reported that olive oil-based lipid emulsion (LE) formulas of soybean oil, medium-chain triglycerides, olive oil, and fish oil (SMOF) may be a viable alternative for parenteral nutrition. However, some randomized controlled clinical trials (RCTs) have raised concerns regarding the nutritional benefits and safety of SMOFs. We searched principally the MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Scopus, EMBASE, and Cochrane Central Register of Controlled Trials databases from inception to March 2014 for the relevant literature and conducted a meta-analysis of 15 selected RCTs that 1) compared either olive oil- or SMOF-based LEs with soybean oil-based LEs and 2) reported plasma concentrations of alpha-tocopherol, oleic acid, and omega-6 (n-6) and omega-3 (n-3) long-chain polyunsaturated fatty acids (PUFAs) and liver concentrations of total bilirubin and the enzymes alanine transaminase, aspartate transaminase, alkaline phosphatase, and gamma-glutamyl transferase. The meta analysis suggested that SMOF-based LEs were associated with higher plasma concentrations of plasma alpha-tocopherol, oleic acid, and the omega-3 PUFAs eicosapentaenoic and docosahexaenoic acid. Olive oil- and SMOF-based LEs correlated with lower plasma concentrations of long-chain omega-6 PUFAs and were similar to soybean oil-based LEs with regard to their effects on liver function indicators. In summary, olive oil- and SMOF-based LEs have nutritional advantages over soybean oil-based LEs and are similarly safe. However, their performance in clinical settings requires further investigation. PMID- 26980812 TI - Genetic Variation in Human Vitamin C Transporter Genes in Common Complex Diseases. AB - Adequate plasma, cellular, and tissue vitamin C concentrations are required for maintaining optimal health through suppression of oxidative stress and optimizing functions of certain enzymes that require vitamin C as a cofactor. Polymorphisms in the vitamin C transporter genes, compromising genes encoding sodium-dependent ascorbate transport proteins, and also genes encoding facilitative transporters of dehydroascorbic acid, are associated with plasma and tissue cellular ascorbate status and hence cellular redox balance. This review summarizes our current knowledge of the links between variations in vitamin C transporter genes and common chronic diseases. We conclude that emerging genetic knowledge has a good likelihood of defining future personalized dietary recommendations and interventions; however, further validations through biological studies as well as controlled dietary trials are required to identify predictive and actionable genetic biomarkers. We further advocate the need to consider genetic variation of vitamin C transporters in future clinical and epidemiologic studies on common complex diseases. PMID- 26980813 TI - PUFAs, Bone Mineral Density, and Fragility Fracture: Findings from Human Studies. AB - Osteoporosis is a global health problem that leads to an increased incidence of fragility fracture. Recent dietary patterns of Western populations include higher than recommended intakes of n-6 (omega-6) polyunsaturated fatty acids (PUFAs) relative to n-3 (omega-3) PUFAs that may result in a chronic state of sterile whole body inflammation. Findings from human bone cell culture experiments have revealed both benefits and detriments to bone-related outcomes depending on the quantity and source of PUFAs. Findings from observational and randomized controlled trials suggest that higher fatty fish intake is strongly linked with reduced risk of fragility fracture. Moreover, human studies largely support a greater intake of total PUFAs, total n-6 (omega-6) fatty acid, and total n-3 (omega-3) fatty acid for higher bone mineral density and reduced risk of fragility fracture. Less consistent evidence has been observed when investigating the role of long chain n-3 (omega-3) PUFAs or the ratio of n-6 (omega-6) PUFAs to n-3 (omega-3) PUFAs. Aspects to consider when interpreting the current literature involve participant characteristics, study duration, diet assessment tools, and the primary outcome measure. PMID- 26980814 TI - Systematic Review of the Methodological Quality of Studies Aimed at Creating Gestational Weight Gain Charts. AB - A range of adverse outcomes is associated with insufficient and excessive maternal weight gain in pregnancy, but there is no consensus regarding what constitutes optimal gestational weight gain (GWG). Differences in the methodological quality of GWG studies may explain the varying chart recommendations. The goal of this systematic review was to evaluate the methodological quality of studies that aimed to create GWG charts by scoring them against a set of predefined, independently agreed-upon criteria. These criteria were divided into 3 domains: study design (12 criteria), statistical methods (7 criteria), and reporting methods (4 criteria). The criteria were broken down further into items, and studies were assigned a quality score (QS) based on these criteria. For each item, studies were scored as either high (score = 0) or low (score = 1) risk of bias; a high QS correlated with a low risk of bias. The maximum possible QS was 34. The systematic search identified 12 eligible studies involving 2,268,556 women from 9 countries; their QSs ranged from 9 (26%) to 29 (85%) (median, 18; 53%). The most common sources for bias were found in study designs (i.e., not prospective); assessments of prepregnancy weight and gestational age; descriptions of weighing protocols; sample size calculations; and the multiple measurements taken at each visit. There is wide variation in the methodological quality of GWG studies constructing charts. High-quality studies are needed to guide future clinical recommendations. We recommend the following main requirements for future studies: prospective design, reliable evaluation of prepregnancy weight and gestational age, detailed description of measurement procedures and protocols, description of sample-size calculation, and the creation of smooth centile charts or z scores. PMID- 26980815 TI - Building a Beneficial Microbiome from Birth. AB - The microbiota has recently been recognized as a driver of health that affects the immune, nervous, and metabolic systems. This influence is partially exerted through the metabolites produced, which may be relevant for optimal infant development and health. The gut microbiota begins developing early in life, and this initial colonization is remarkably important because it may influence long term microbiota composition and activity. Considering that the microbiome may play a key role in health and disease, maintaining a protective microbiota could be critical in preventing dysbiosis-related diseases such as allergies, autoimmunity disorders, and metabolic syndrome. Breast milk and milk glycans in particular are thought to play a major role in shaping the early-life microbiota and promoting its development, thus affecting health. This review describes some of the effects the microbiota has on the host and discusses the role microbial metabolites play in shaping newborn health and development. We describe the gut microbiota structure and function during early life and the factors that determine its composition and hypothesize about the effects of human milk oligosaccharides and other prebiotic fibers on the neonatal microbiota. PMID- 26980817 TI - Culinary Spice Plants in Dietary Supplement Products and Tested in Clinical Trials. AB - Dried plant parts used as culinary spices (CSs) in food are permitted as dietary ingredients in dietary supplements (DSs) within certain constraints in the United States. We reviewed the amounts, forms, and nutritional support (structure/function) claims of DSs that contain CS plants listed in the Dietary Supplement Label Database (DSLD) and compared this label information with trial doses and health endpoints for CS plants that were the subject of clinical trials listed in clinicaltrials.gov. According to the DSLD, the CS plants occurring most frequently in DSs were cayenne, cinnamon, garlic, ginger, pepper, rosemary, and turmeric. Identifying the botanical species, categorizing the forms used, and determining the amounts from the information provided on DS labels was challenging. CS plants were typically added as a component of a blend, as the powered biomass, dried extracts, and isolated phytochemicals. The amounts added were declared on about 55% of the labels, rendering it difficult to determine the amount of the CS plant used in many DSs. Clinicaltrials.gov provided little information about the composition of test articles in the intervention studies. When plant names were listed on DS labels and in clinical trials, generally the common name and not the Latin binomial name was given. In order to arrive at exposure estimates and enable researchers to reproduce clinical trials, the Latin binomial name, form, and amount of the CS plant used in DSs and tested in clinical trials must be specified. PMID- 26980816 TI - Endogenous Synthesis of Amino Acids Limits Growth, Lactation, and Reproduction in Animals. AB - Amino acids (AAs) are building blocks of protein. Eight AAs (Ala, Asn, Asp, Glu, Gln, Gly, Pro, and Ser) are formed by all animals, whereas de novo synthesis of Arg occurs in a species-specific manner in most mammals (e.g., humans, pigs, and rats). Synthesizable AAs were traditionally classified as nutritionally nonessential for animals, because they were thought to be formed in sufficient amounts. However, this assumption is not supported by evidence showing that 1) rats grow slowly when their diets do not contain Arg, Glu, or Gln despite adequate provision of all other proteinogenous AAs; 2) pigs cannot achieve maximum growth, lactation, or reproduction performance when fed corn- and soybean meal-based diets meeting National Research Council-recommended requirements of protein and AAs without supplemental Arg, Glu, Gln, Gly, or Pro; 3) chickens exhibit increases in lean tissue gain and feed efficiency when their diets are supplemented with Glu, Gln, Gly, and Pro; 4) lactating cows cannot obtain maximum milk protein production without a postruminal supply of Gln or Pro; 5) fish cannot achieve maximum growth when diets do not contain Gln or Pro; and 6) men fail to sustain spermatogenesis when fed an Arg-deficient diet. Quantitative analysis of nitrogen metabolism showed that AA synthesis in animals is constrained by both precursor availability and enzyme activity. Taken together, these findings support the conclusion that the endogenous synthesis of AAs limits growth, lactation, and reproduction in animals. This new knowledge can guide the optimization of human nutrition for improving health and well-being. PMID- 26980819 TI - Early Child Development and Nutrition: A Review of the Benefits and Challenges of Implementing Integrated Interventions. AB - Poor nutrition (substandard diet quantity and/or quality resulting in under- or overnutrition) and the lack of early learning opportunities contribute to the loss of developmental potential and life-long health and economic disparities among millions of children aged <5 y. Single-sector interventions representing either early child development (ECD) or nutrition have been linked to positive child development and/or nutritional status, and recommendations currently advocate for the development and testing of integrated interventions. We reviewed the theoretical and practical benefits and challenges of implementing integrated nutrition and ECD interventions along with the evidence for best practice and benefit-cost and concluded that the strong theoretical rationale for integration is more nuanced than the questions that the published empirical evidence have addressed. For example, further research is needed to 1) answer questions related to how integrated messaging influences caregiver characteristics such as well being, knowledge, and behavior and how these influence early child nutrition and development outcomes; 2) understand population and nutritional contexts in which integrated interventions are beneficial; and 3) explore how varying implementation processes influence the efficacy, uptake, and cost-benefit of integrated nutrition and ECD interventions. PMID- 26980818 TI - Overview of the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) Project. AB - Anemia remains a widespread public health problem. Although iron deficiency is considered the leading cause of anemia globally, the cause of anemia varies considerably by country. To achieve global targets to reduce anemia, reliable estimates of the contribution of nutritional and non-nutritional causes of anemia are needed to guide interventions. Inflammation is known to affect many biomarkers used to assess micronutrient status and can thus lead to incorrect diagnosis of individuals and to overestimation or underestimation of the prevalence of deficiency in a population. Reliable assessment of iron status is particularly needed in settings with high infectious disease burden, given the call to screen for iron deficiency to mitigate potential adverse effects of iron supplementation. To address these information gaps, in 2012 the CDC, National Institute for Child Health and Human Development, and Global Alliance for Improved Nutrition formed a collaborative research group called Biomarkers Reflecting Inflammation and Nutrition Determinants of Anemia (BRINDA). Data from nationally and regionally representative nutrition surveys conducted in the past 10 y that included preschool children and/or women of childbearing age were pooled. Of 25 data sets considered for inclusion, 17 were included, representing ~30,000 preschool children, 26,000 women of reproductive age, and 21,000 school aged children from all 6 WHO geographic regions. This article provides an overview of the BRINDA project and describes key research questions and programmatic and research implications. Findings from this project will inform global guidelines on the assessment of anemia and micronutrient status and will guide the development of a research agenda for future longitudinal studies. PMID- 26980820 TI - Postprandial Metabolism of Macronutrients and Cardiometabolic Risk: Recent Developments, Emerging Concepts, and Future Directions. AB - Cardiovascular disease (CVD) is the leading cause of death in the United States. Although the role of habitual lifestyle factors such as physical activity and dietary patterns in increasing CVD risk has long been appreciated, less is known about how acute daily activities may cumulatively contribute to long-term disease risk. Here, the term acute refers to metabolic responses occurring in a short period of time after eating, and the goal of this article is to review recently identified stressors that can occur after meals and during the sleep-wake cycle to affect macronutrient metabolism. It is hypothesized that these events, when repeated on a regular basis, contribute to the observed long-term behavioral risks identified in population studies. In this regard, developments in research methods have supported key advancements in 3 fields of macronutrient metabolism. The first of these research areas is the focus on the immediate postmeal metabolism, spanning from early intestinal adsorptive events to the impact of incretin hormones on these events. The second topic is a focus on the importance of meal components on postprandial vasculature function. Finally, some of the most exciting advances are being made in understanding dysregulation in metabolism early in the day, due to insufficient sleep, that may affect subsequent processing of nutrients throughout the day. Key future research questions are highlighted which will lead to a better understanding of the relations between nocturnal, basal (fasting), and early postmeal events, and aid in the development of optimal sleep and targeted dietary patterns to reduce cardiometabolic risk. PMID- 26980822 TI - The Challenge of Reproducibility and Accuracy in Nutrition Research: Resources and Pitfalls. AB - Inconsistent and contradictory results from nutrition studies conducted by different investigators continue to emerge, in part because of the inherent variability of natural products, as well as the unknown and therefore uncontrolled variables in study populations and experimental designs. Given these challenges inherent in nutrition research, it is critical for the progress of the field that researchers strive to minimize variability within studies and enhance comparability between studies by optimizing the characterization, control, and reporting of products, reagents, and model systems used, as well as the rigor and reporting of experimental designs, protocols, and data analysis. Here we describe some recent developments relevant to research on plant-derived products used in nutrition research, highlight some resources for optimizing the characterization and reporting of research using these products, and describe some of the pitfalls that may be avoided by adherence to these recommendations. PMID- 26980821 TI - Importance of Accurate Measurements in Nutrition Research: Dietary Flavonoids as a Case Study. AB - Accurate measurements of the secondary metabolites in natural products and plant foods are critical for establishing relations between diet and health. There are as many as 50,000 secondary metabolites that may influence human health. Their structural and chemical diversity presents a challenge to analytical chemistry. With respect to flavonoids, putative identification is accessible, but positive identification and quantification are limited by the lack of standards. Quantification has been tested with use of both nonspecific and specific methods. Nonspecific methods, which include antioxidant capacity methods, fail to provide information on the measured components, suffer from numerous interferences, are not equatable, and are unsuitable for health research. Specific methods, such as LC with diode array and mass spectrometric detection, require the use of internal standards and relative molar response factors. These methods are relatively expensive and require a high level of expertise and experimental verification; however, they represent the only suitable means of relating health outcomes to specific dietary components. PMID- 26980823 TI - The Importance of Method Selection in Determining Product Integrity for Nutrition Research. AB - The American Herbal Products Association estimates that there as many as 3000 plant species in commerce. The FDA estimates that there are about 85,000 dietary supplement products in the marketplace. The pace of product innovation far exceeds that of analytical methods development and validation, with new ingredients, matrixes, and combinations resulting in an analytical community that has been unable to keep up. This has led to a lack of validated analytical methods for dietary supplements and to inappropriate method selection where methods do exist. Only after rigorous validation procedures to ensure that methods are fit for purpose should they be used in a routine setting to verify product authenticity and quality. By following systematic procedures and establishing performance requirements for analytical methods before method development and validation, methods can be developed that are both valid and fit for purpose. This review summarizes advances in method selection, development, and validation regarding herbal supplement analysis and provides several documented examples of inappropriate method selection and application. PMID- 26980826 TI - Selenium. PMID- 26980825 TI - Does Insulin Explain the Relation between Maternal Obesity and Poor Lactation Outcomes? An Overview of the Literature. AB - It is well established that obese women are at increased risk of delayed lactogenesis and short breastfeeding duration, but the underlying causal contributors remain unclear. This review summarizes the literature examining the role of insulin in lactation outcomes. Maternal obesity is a strong risk factor for insulin resistance and prediabetes, but until recently a direct role for insulin in milk production had not been elucidated. Over the past 6 y, studies in both animal models and humans have shown insulin-sensitive gene expression to be dramatically upregulated specifically during the lactation cycle. Insulin is now considered to play a direct role in lactation, including essential roles in secretory differentiation, secretory activation, and mature milk production. At the same time, emerging clinical research suggests an important association between suboptimal glucose tolerance and lactation difficulty. To develop effective interventions to support lactation success in obese women further research is needed to identify how, when, and for whom maternal insulin secretion and sensitivity affect lactation ability. PMID- 26980827 TI - World Cancer Report 2014. Geneva, Switzerland: World Health Organization, International Agency for Research on Cancer, WHO Press, 2015. PMID- 26980828 TI - Residue, Fiber, and Subjectivity. PMID- 26980824 TI - Circadian Rhythms, Metabolism, and Chrononutrition in Rodents and Humans. AB - Chrononutrition is an emerging discipline that builds on the intimate relation between endogenous circadian (24-h) rhythms and metabolism. Circadian regulation of metabolic function can be observed from the level of intracellular biochemistry to whole-organism physiology and even postprandial responses. Recent work has elucidated the metabolic roles of circadian clocks in key metabolic tissues, including liver, pancreas, white adipose, and skeletal muscle. For example, tissue-specific clock disruption in a single peripheral organ can cause obesity or disruption of whole-organism glucose homeostasis. This review explains mechanistic insights gained from transgenic animal studies and how these data are being translated into the study of human genetics and physiology. The principles of chrononutrition have already been demonstrated to improve human weight loss and are likely to benefit the health of individuals with metabolic disease, as well as of the general population. PMID- 26980829 TI - Nutrition and Autism: Intervention Compared with Identification. PMID- 26980830 TI - Erratum for Drewnowski. The Carbohydrate-Fat Problem: Can We Construct a Healthy Diet Based on Dietary Guidelines? Adv Nutr 2015;6(Suppl):318S-25S. PMID- 26980832 TI - Volatile Compounds Emitted by Pseudomonas aeruginosa Stimulate Growth of the Fungal Pathogen Aspergillus fumigatus. AB - Chronic lung infections with opportunistic bacterial and fungal pathogens are a major cause of morbidity and mortality especially in patients with cystic fibrosis. Pseudomonas aeruginosa is the most frequently colonizing bacterium in these patients, and it is often found in association with the filamentous fungus Aspergillus fumigatus. P. aeruginosa is known to inhibit the growth of A. fumigatus in situations of direct contact, suggesting the existence of interspecies communication that may influence disease outcome. Our study shows that the lung pathogens P. aeruginosa and A. fumigatus can interact at a distance via volatile-mediated communication and expands our understanding of interspecific signaling in microbial communities. IMPORTANCE: Microbiota studies have shown that pathogens cannot be studied individually anymore and that the establishment and progression of a specific disease are due not to a single microbial species but are the result of the activity of many species living together. To date, the interaction between members of the human microbiota has been analyzed in situations of direct contact or liquid-mediated contact between organisms. This study showed unexpectedly that human opportunistic pathogens can interact at a distance after sensing volatiles emitted by another microbial species. This finding will open a new research avenue for the understanding of microbial communities. PMID- 26980831 TI - SuhB Associates with Nus Factors To Facilitate 30S Ribosome Biogenesis in Escherichia coli. AB - A complex of highly conserved proteins consisting of NusB, NusE, NusA, and NusG is required for robust expression of rRNA in Escherichia coli. This complex is proposed to prevent Rho-dependent transcription termination by a process known as "antitermination." The mechanism of this antitermination in rRNA is poorly understood but requires association of NusB and NusE with a specific RNA sequence in rRNA known as BoxA. Here, we identify a novel member of the rRNA antitermination machinery: the inositol monophosphatase SuhB. We show that SuhB associates with elongating RNA polymerase (RNAP) at rRNA in a NusB-dependent manner. Although we show that SuhB is required for BoxA-mediated antitermination in a reporter system, our data indicate that the major function of the NusB/E/A/G/SuhB complex is not to prevent Rho-dependent termination of rRNA but rather to promote correct rRNA maturation. This occurs through formation of a SuhB-mediated loop between NusB/E/BoxA and RNAP/NusA/G. Thus, we have reassigned the function of these proteins at rRNA and identified another key player in this complex. IMPORTANCE: As RNA polymerase transcribes the rRNA operons in E. coli, it complexes with a set of proteins called Nus that confer enhanced rates of transcription elongation, correct folding of rRNA, and rRNA assembly with ribosomal proteins to generate a fully functional ribosome. Four Nus proteins were previously known, NusA, NusB, NusE, and NusG; here, we discover and describe a fifth, SuhB, that is an essential component of this complex. We demonstrate that the main function of this SuhB-containing complex is not to prevent premature transcription termination within the rRNA operon, as had been long claimed, but to enable rRNA maturation and a functional ribosome fully competent for translation. PMID- 26980833 TI - Features of Circulating Parainfluenza Virus Required for Growth in Human Airway. AB - Respiratory paramyxoviruses, including the highly prevalent human parainfluenza viruses, cause the majority of childhood croup, bronchiolitis, and pneumonia, yet there are currently no vaccines or effective treatments. Paramyxovirus research has relied on the study of laboratory-adapted strains of virus in immortalized cultured cell lines. We show that findings made in such systems about the receptor interaction and viral fusion requirements for entry and fitness-mediated by the receptor binding protein and the fusion protein-can be drastically different from the requirements for infection in vivo. Here we carried out whole genome sequencing and genomic analysis of circulating human parainfluenza virus field strains to define functional and structural properties of proteins of circulating strains and to identify the genetic basis for properties that confer fitness in the field. The analysis of clinical strains suggests that the receptor binding-fusion molecule pairs of circulating viruses maintain a balance of properties that result in an inverse correlation between fusion in cultured cells and growth in vivo. Future analysis of entry mechanisms and inhibitory strategies for paramyxoviruses will benefit from considering the properties of viruses that are fit to infect humans, since a focus on viruses that have adapted to laboratory work provides a distinctly different picture of the requirements for the entry step of infection. IMPORTANCE: Mechanistic information about viral infection-information that impacts antiviral and vaccine development-is generally derived from viral strains grown under laboratory conditions in immortalized cells. This study uses whole-genome sequencing of clinical strains of human parainfluenza virus 3-a globally important respiratory paramyxovirus-in cell systems that mimic the natural human host and in animal models. By examining the differences between clinical isolates and laboratory-adapted strains, the sequence differences are correlated to mechanistic differences in viral entry. For this ubiquitous and pathogenic respiratory virus to infect the human lung, modulation of the processes of receptor engagement and fusion activation occur in a manner quite different from that carried out by the entry glycoprotein expressing pair of laboratory strains. These marked contrasts in the viral properties necessary for infection in cultured immortalized cells and in natural host tissues and animals will influence future basic and clinical studies. PMID- 26980834 TI - Novel Trypanosomatid-Bacterium Association: Evolution of Endosymbiosis in Action. AB - We describe a novel symbiotic association between a kinetoplastid protist, Novymonas esmeraldas gen. nov., sp. nov., and an intracytoplasmic bacterium, "Candidatus Pandoraea novymonadis" sp. nov., discovered as a result of a broad scale survey of insect trypanosomatid biodiversity in Ecuador. We characterize this association by describing the morphology of both organisms, as well as their interactions, and by establishing their phylogenetic affinities. Importantly, neither partner is closely related to other known organisms previously implicated in eukaryote-bacterial symbiosis. This symbiotic association seems to be relatively recent, as the host does not exert a stringent control over the number of bacteria harbored in its cytoplasm. We argue that this unique relationship may represent a suitable model for studying the initial stages of establishment of endosymbiosis between a single-cellular eukaryote and a prokaryote. Based on phylogenetic analyses, Novymonas could be considered a proxy for the insect-only ancestor of the dixenous genus Leishmania and shed light on the origin of the two host life cycle within the subfamily Leishmaniinae. IMPORTANCE: The parasitic trypanosomatid protist Novymonas esmeraldas gen. nov., sp. nov. entered into endosymbiosis with the bacterium "Ca. Pandoraea novymonadis" sp. nov. This novel and rather unstable interaction shows several signs of relatively recent establishment, qualifying it as a potentially unique transient stage in the increasingly complex range of eukaryotic-prokaryotic relationships. PMID- 26980838 TI - Pollen--tiny and ephemeral but not forgotten: New ideas on their ecology and evolution. AB - Ecologists and evolutionary biologists have been interested in the functional biology of pollen since the discovery in the 1800s that pollen grains encompass tiny plants (male gametophytes) that develop and produce sperm cells. After the discovery of double fertilization in flowering plants, botanists in the early 1900s were quick to explore the effects of temperature and maternal nutrients on pollen performance, while evolutionary biologists began studying the nature of haploid selection and pollen competition. A series of technical and theoretic developments have subsequently, but usually separately, expanded our knowledge of the nature of pollen performance and how it evolves. Today, there is a tremendous diversity of interests that touch on pollen performance, ranging from the ecological setting on the stigma, structural and physiological aspects of pollen germination and tube growth, the form of pollen competition and its role in sexual selection in plants, virus transmission, mating system evolution, and inbreeding depression. Given the explosion of technical knowledge of pollen cell biology, computer modeling, and new methods to deal with diversity in a phylogenetic context, we are now more than ever poised for a new era of research that includes complex functional traits that limit or enhance the evolution of these deceptively simple organisms. PMID- 26980836 TI - Phylogenetic Diversity of Vibrio cholerae Associated with Endemic Cholera in Mexico from 1991 to 2008. AB - An outbreak of cholera occurred in 1991 in Mexico, where it had not been reported for more than a century and is now endemic. Vibrio cholerae O1 prototype El Tor and classical strains coexist with altered El Tor strains (1991 to 1997). Nontoxigenic (CTX(-)) V. cholerae El Tor dominated toxigenic (CTX(+)) strains (2001 to 2003), but V. cholerae CTX(+) variant El Tor was isolated during 2004 to 2008, outcompeting CTX(-) V. cholerae. Genomes of six Mexican V. cholerae O1 strains isolated during 1991 to 2008 were sequenced and compared with both contemporary and archived strains of V. cholerae. Three were CTX(+) El Tor, two were CTX(-) El Tor, and the remaining strain was a CTX(+) classical isolate. Whole-genome sequence analysis showed the six isolates belonged to five distinct phylogenetic clades. One CTX(-) isolate is ancestral to the 6th and 7th pandemic CTX(+) V. cholerae isolates. The other CTX(-) isolate joined with CTX(-) non O1/O139 isolates from Haiti and seroconverted O1 isolates from Brazil and Amazonia. One CTX(+) isolate was phylogenetically placed with the sixth pandemic classical clade and the V. cholerae O395 classical reference strain. Two CTX(+) El Tor isolates possessing intact Vibrio seventh pandemic island II (VSP-II) are related to hybrid El Tor isolates from Mozambique and Bangladesh. The third CTX(+) El Tor isolate contained West African-South American (WASA) recombination in VSP-II and showed relatedness to isolates from Peru and Brazil. Except for one isolate, all Mexican isolates lack SXT/R391 integrative conjugative elements (ICEs) and sensitivity to selected antibiotics, with one isolate resistant to streptomycin. No isolates were related to contemporary isolates from Asia, Africa, or Haiti, indicating phylogenetic diversity. IMPORTANCE: Sequencing of genomes of V. cholerae is critical if genetic changes occurring over time in the circulating population of an area of endemicity are to be understood. Although cholera outbreaks occurred rarely in Mexico prior to the 1990s, genetically diverse V. cholerae O1 strains were isolated between 1991 and 2008. Despite the lack of strong evidence, the notion that cholera was transmitted from Africa to Latin America has been proposed in the literature. In this study, we have applied whole-genome sequence analysis to a set of 124 V. cholerae strains, including six Mexican isolates, to determine their phylogenetic relationships. Phylogenetic analysis indicated the six V. cholerae O1 isolates belong to five phylogenetic clades: i.e., basal, nontoxigenic, classical, El Tor, and hybrid El Tor. Thus, the results of phylogenetic analysis, coupled with CTXphi array and antibiotic susceptibility, do not support single-source transmission of cholera to Mexico from African countries. The association of indigenous populations of V. cholerae that has been observed in this study suggests it plays a significant role in the dynamics of cholera in Mexico. PMID- 26980835 TI - Molecular and Structural Characterization of a Novel Escherichia coli Interleukin Receptor Mimic Protein. AB - Urinary tract infection (UTI) is a disease of extremely high incidence in both community and nosocomial settings. UTIs cause significant morbidity and mortality, with approximately 150 million cases globally per year. Uropathogenic Escherichia coli (UPEC) is the primary cause of UTI and is generally treated empirically. However, the rapidly increasing incidence of UTIs caused by multidrug-resistant UPEC strains has led to limited available treatment options and highlights the urgent need to develop alternative treatment and prevention strategies. In this study, we performed a comprehensive analysis to define the regulation, structure, function, and immunogenicity of recently identified UPEC vaccine candidate C1275 (here referred to as IrmA). We showed that the irmA gene is highly prevalent in UPEC, is cotranscribed with the biofilm-associated antigen 43 gene, and is regulated by the global oxidative stress response OxyR protein. Localization studies identified IrmA in the UPEC culture supernatant. We determined the structure of IrmA and showed that it adopts a unique domain swapped dimer architecture. The dimeric structure of IrmA displays similarity to those of human cytokine receptors, including the interleukin-2 receptor (IL-2R), interleukin-4 receptor (IL-4R), and interleukin-10 receptor (IL-10R) binding domains, and we showed that purified IrmA can bind to their cognate cytokines. Finally, we showed that plasma from convalescent urosepsis patients contains high IrmA antibody titers, demonstrating the strong immunogenicity of IrmA. Taken together, our results indicate that IrmA may play an important role during UPEC infection. IMPORTANCE: Uropathogenic E. coli (UPEC) is the primary cause of urinary tract infection (UTI), a disease of major significance to human health. Globally, the incidence of UPEC-mediated UTI is strongly associated with increasing antibiotic resistance, making this extremely common infection a major public health concern. In this report, we describe the regulatory, structural, functional, and immunogenic properties of a candidate UPEC vaccine antigen, IrmA. We demonstrate that IrmA is a small UPEC protein that forms a unique domain swapped dimer with structural mimicry to several human cytokine receptors. We also show that IrmA binds to IL-2, IL-4, and IL-10, is strongly immunogenic in urosepsis patients, and is coexpressed with factors associated with biofilm formation. Overall, this work suggests a potential novel contribution for IrmA in UPEC infection. PMID- 26980839 TI - Ulcerative Colitis Is Characterized by a Decrease in Regulatory B Cells. AB - BACKGROUND AND AIMS: Ulcerative colitis (UC) is characterized by Th2-polarized, B cell responses. However, neither size, composition, nor activity of the Breg compartment in active UC has been evaluated. METHODS: Peripheral blood of 25 patients with UC, 5 patients with Crohn's disease (CD) and 15 control subjects was examined for Bregs subsets by flow cytometry. Intestinal tissue of 5 patients with UC, 3 patients with CD and 5 control subjects was also examined for Bregs. The levels of serum interleukin (IL)-10, immunoglobulin (Ig), and C-reactive protein (CRP), and the erythrocyte sedimentation rate (ESR) in individual subjects were measured. Interleukin-10 production in B cells isolated from patients with UC was examined. Potential associations between the values of the different measures were analysed by the Spearman correlation test. RESULTS: Compared with controls, the UC patients had significantly reduced frequencies of CD24(high)CD38(high) and CD5(+) Bregs in peripheral blood as well as in intestinal tissues, accompanied by lower serum IL-10 levels. Interleukin-10 production was significantly decreased in stimulated B cells from patients with UC, whereas patient IL-10(+) B cells were found to be enriched in CD24(high)CD38(high) and CD5(+) B cells. However, increased percentages of CD95(+)-exhausted Bregs were encountered in subsets. Furthermore, Mayo clinic scores, CRP, and ESR in UC patients was negatively correlated with the frequency of Bregs and the IL-10 concentration, whereas these parameters were positively correlated with the frequency of CD95(+)-exhausted Bregs and the IgG levels. CONCLUSIONS: Active UC is characterized by exhaustion of regulatory control in the B cell compartment. PMID- 26980837 TI - Early Interactions of Murine Macrophages with Francisella tularensis Map to Mouse Chromosome 19. AB - Differences among individuals in susceptibility to infectious diseases can be modulated by host genetics. Much of the research in this field has aimed to identify loci within the host genome that are associated with these differences. In mice, A/J (AJ) and C57BL/6J (B6) mice show differential susceptibilities to various pathogens, including the intracellular pathogen Francisella tularensis. Because macrophages are the main initial target during F. tularensis infection, we explored early interactions of macrophages from these two mouse strains with F. tularensis as well as the genetic factors underlying these interactions. Our results indicate that bacterial interactions with bone marrow-derived macrophages (BMDMs) during early stages of infection are different in the AJ and B6 strains. During these early stages, bacteria are more numerous in B6 than in AJ macrophages and display differences in trafficking and early transcriptional response within these macrophages. To determine the genetic basis for these differences, we infected BMDMs isolated from recombinant inbred (RI) mice derived from reciprocal crosses between AJ and B6, and we followed early bacterial counts within these macrophages. Quantitative trait locus (QTL) analysis revealed a locus on chromosome 19 that is associated with early differences in bacterial counts in AJ versus B6 macrophages. QTL analysis of published data that measured the differential susceptibilities of the same RI mice to an in vivo challenge with F. tularensis confirmed the F. tularensis susceptibility QTL on chromosome 19. Overall, our results show that early interactions of macrophages with F. tularensis are dependent on the macrophage genetic background. IMPORTANCE: Francisella tularensis is a highly pathogenic bacterium with a very low infectious dose in humans. Some mechanisms of bacterial virulence have been elucidated, but the host genetic factors that contribute to host resistance or susceptibility are largely unknown. In this work, we have undertaken a genetic approach to assess what these factors are in mice. Analyzing early interactions of macrophages with the bacteria as well as data on overall susceptibility to infection revealed a locus on chromosome 19 that is associated with both phenotypes. In addition, our work revealed differences in the early macrophage response between macrophages with different genetic backgrounds. Overall, this work suggests some intriguing links between in vitro and in vivo infection models and should aid in further elucidating the genetic circuits behind the host response to Francisella tularensis infection. PMID- 26980840 TI - Early Mucosal Healing with Exclusive Enteral Nutrition is Associated with Improved Outcomes in Newly Diagnosed Children with Luminal Crohn's disease. AB - BACKGROUND: Exclusive Enteral Nutrition (EEN) induction in children with luminal Crohn's disease (CD) gives early mucosal healing (MH), but the long-term benefits of EEN-induced MH are just emerging. AIMS & METHODS: We prospectively followed an Australian cohort of newly diagnosed children with predominantly luminal CD who completed at least six weeks EEN and with paired clinical Pediatric Crohn's Disease Activity Index (PCDAI), biochemical (C-reactive protein; CRP) and endoscopic assessment at diagnosis and post EEN. All commenced immunomodulators (IMs) early (<3 months from diagnosis) and had a minimum of 1 year follow-up. Complete MH was a simple endoscopic score for Crohn's disease (SES-CD) of 0, and SES-CD>=1 was ascribed to active endoscopic disease (aED) and further divided into near complete MH (SES 1-3), mild active disease (SES-CD 4-10) and moderate to severe disease (SES-CD>10). The primary outcome was long-term supervised sustained remission (SR) on IMs alone without need for corticosteroids, infliximab (IFX) or surgery. RESULTS: A total of 54 eligible children (33 males) completing EEN induction were analysed. The median duration between pre and post EEN assessments was 60.5 days [interquartile range (IQR), 56-69.5]. Post EEN: clinical remission (PCDAI < 10) was observed in 45/54 (83%), and biochemical remission (PCDAI < 10 and CRP < 5 mg/dl) was observed in 39/54 (72%). Complete MH was observed in 18/54 (33%), near complete in 10/54(19%). SR was superior in those with complete MH vs. aED; 13/18, (72%) vs. 10/36 (28%), p = 0.003 at 1 year, 8/16, (50%) vs. 3/24, (8%), p = 0.008 at 2 years and (8/16, (50%) vs. 1/19, (6%), p = 0.005) at 3 years. Near-complete MH did not lead to superior SR. CONCLUSIONS: Only complete MH post EEN induction predicts more favourable SR for up to 3 years. PMID- 26980841 TI - Response to 'A relational approach to Saviour Siblings?' by Selgelid. AB - In his concise argument, 'A relational approach to saviour siblings?', Selgelid reiterates some of the arguments raised in the author meets critics discussion of my book, Saviour Siblings In this response, I highlight an important misunderstanding in one of the arguments put forward by Selgelid, which forms the basis of a large portion of his analysis. Contrary to what Selgelid contends, I do not use the deafness case in my discussion of the non-identity problem to contend that the case of selecting for deafness is ethically different from the case of saviour siblings. As I state in my reply, I use the case of deafness not as a comparator for saviour siblings but rather to illustrate the different categories of risk that apply in selection cases Given this confusion, I restate my objection to relying on the non-identity problem in evaluating risk of harm associated with the embryo biopsy process for preimplantation genetic diagnosis. Finally, I reiterate that the individual interests of saviour siblings remain important in the decision-making matrix and emphasise that Saviour Siblings offers a more contextualised approach to the welfare of the child in selective reproduction, which includes both individual and collective interests. PMID- 26980842 TI - Colon cancer and Salicylates. PMID- 26980843 TI - Determinants of orthodontic treatment need and demand: a cross-sectional path model study. AB - OBJECTIVES: To put forward a model predicting orthodontic treatment need and demand. Furthermore, to explore how much of the variance in treatment demand could be explained by a set of self-assessed measures, and how these measures relate to professionally assessed treatment need. SUBJECTS AND METHODS: One hundred and fifty adolescents, aged 13 years, completed a questionnaire which included a set of self-assessed measures dealing with self-esteem, such as dental and global self-esteem, various aspects of malocclusion, such as perceived malocclusion and perceived functional limitation, and treatment demand. Treatment need was assessed by Dental Health Component of the Index of Orthodontic Treatment Need grading. Path analysis was used to examine the relations between the measures and if they could predict treatment need and demand. RESULTS: The measures proved to be reliable and inter-correlated. Path analysis revealed that the proposed model had good fit to the data, providing a test of the unique effect of all included measures on treatment need and demand. The model explained 33% of the variance in treatment demand and 22% of the variance in treatment need. LIMITATIONS: The specific age group could affect the generalizability of the findings. Moreover, although showing good fit to data, the final model is based on a combination of theoretical reasoning and semi-explorative approach. CONCLUSIONS: The proposed model displays the unique effect of each included measure on treatment need and demand, explaining a large proportion of the variance in perceived treatment demand and professionally assessed treatment need. The model would hopefully lead to improved and more cost-efficient predictions of treatment need and demand. PMID- 26980844 TI - A Randomized Clinical Trial to Assess the Clinical Effectiveness of a Measured Objective Tensioning Device in Hamstring Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Soft tissue grafts are commonly used in surgical reconstruction of the anterior cruciate ligament (ACL). Applying the appropriate tension to the final graft reconstruction has traditionally been performed by the surgeon and is based on the surgeon's experience and perception of applied tension. Problems with manual application of tension to the ACL reconstruction include under- or overtightening the reconstruction, inconsistent tension application among subjects, and variable load application to each strand. PURPOSE: To assess whether measured tensioning of hamstring ACL grafts during fixation improves clinical outcome or knee laxity postoperatively when compared with conventional tensioning maneuvers. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: This was a prospective randomized controlled trial of consecutive primary ACL patients. The device group included patients in whom a measured tensioning device was used for graft tensioning (80 N), and the physician group did not use a tensioning device. The primary outcome was KT-1000 arthrometer side-to-side laxity differences between knees at 6, 12, and 18 months postoperatively. Secondary outcomes included the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form and Anterior Cruciate Ligament Quality of Life Questionnaire (ACL-QoL) at those intervals. Chi-square and t tests were used for analysis. The study had 90% power to detect a difference of 2 mm between groups. RESULTS: A sample of 127 patients was randomized. Of those, 14 did not have follow-up data and were excluded from this analysis, resulting in a final sample of 113 (55 patients in the device group and 58 in the physician group). No significant differences were found in baseline demographics or comorbidities. There were no significant differences between the groups (physician vs device) at baseline and at 6, 12, and 18 months in side-to-side laxity (4.6 vs 4.7 mm, 1.6 vs 1.3 mm, 1.5 vs 1.3 mm, and 1.1 vs 1.0 mm, respectively), IKDC score (58.2 vs 56.4, 72.0 vs 67.9, 79.9 vs 76.0, and 81.3 vs 78.5, respectively), or ACL-QoL score (998.2 vs 901.2, 1846.4 vs 1647.5, 2150.4 vs 2268.3, and 2436.9 vs 2231.8, respectively). CONCLUSION: Measured tensioning of hamstring ACL grafts during fixation does not improve clinical outcome or knee laxity postoperatively when compared with conventional tensioning maneuvers. PMID- 26980845 TI - Reliability and Associated Risk Factors for Performance on the Vestibular/Ocular Motor Screening (VOMS) Tool in Healthy Collegiate Athletes. AB - BACKGROUND: The Vestibular/Ocular Motor Screening (VOMS) is a newly developed screening tool that evaluates vestibular and ocular motor symptom (eg, headache, dizziness, nausea, fogginess) provocation after a sport-related concussion. Baseline data on the VOMS are needed to extend the application of this measure to broad age groups and to document normal variations in performance. PURPOSE: The primary purpose of this study was to examine the internal consistency of the VOMS in a large sample of healthy, nonconcussed collegiate athletes. The secondary purpose was to investigate the effects of patient sex and history of motion sickness, migraines, and concussions on baseline VOMS scores. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 263 National Collegiate Athletic Association Division I athletes (mean +/- SD age, 19.85 +/- 1.35 years) completed self-reported demographic and medical history at preseason physical examinations and baseline screening. Internal consistency of the VOMS was assessed with Cronbach alpha. A series of univariate nonparametric tests (chi(2) with odds ratios [ORs] and 95% CIs) were used to examine the associations among medical history risk factors and VOMS clinical cutoff scores (score of >=2 for any individual VOMS symptom, near point of convergence [NPC] distance of >=5 cm), with higher scores representing greater symptom provocation. RESULTS: Internal consistency of the VOMS was high (Cronbach alpha = .97), and 89% of athletes scored below cutoff levels (ie, 11% false-positive rate). Female athletes (OR, 2.99 [95% CI, 1.34-6.70]; P = .006) and those with a personal history of motion sickness (OR, 7.73 [95% CI, 1.94-30.75]; P = .009) were more likely to have >=1 VOMS scores above cutoff levels. No risk factors were associated with increased odds of an abnormal NPC distance. CONCLUSION: The VOMS possesses internal consistency and an acceptable false-positive rate among healthy Division I collegiate student-athletes. Female sex and a history of motion sickness were risk factors for VOMS scores above clinical cutoff levels among healthy collegiate student-athletes. Results support a comprehensive baseline evaluation approach that includes an assessment of premorbid vestibular and oculomotor symptoms. PMID- 26980846 TI - The Inverted Discoid Meniscus Segment: Clinical, Radiographic, and Arthroscopic Description of a Hidden Tear Pattern. AB - BACKGROUND: A flipped, or inverted, meniscus segment is easily visualized in the normal meniscus. However, an inverted discoid meniscus segment may be difficult to appreciate because the tear occurs more centrally and leaves more meniscal rim; thus, it may be undertreated if not addressed during arthroscopy. PURPOSE: To describe findings on clinical history, radiographs, MRI, and arthroscopy of a lateral discoid meniscus with an inverted segment and compare them with characteristics of a lateral discoid meniscus without an inverted segment. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Between 2009 and 2012, a retrospective series of 121 consecutive knee arthroscopies for symptomatic lateral discoid meniscus were reviewed for the presence of an inverted fragment. Chart review of clinical presentation, operative reports, radiographic images, and arthroscopic images was performed. Comparative analysis of the clinical presentation between lateral discoid menisci with an inverted segment and noninverted lateral discoid menisci was performed by use of Fisher exact test and Mann-Whitney test. RESULTS: Nineteen patients with an inverted discoid meniscus segment (14 males, 5 females; average age, 15.0 years; range, 9.5-17.0 years) were compared with 102 patients with a noninverted discoid meniscus (53 males, 49 females; average age, 12.3 years; range, 5-17.0 years) (P = .011 for sex and P < .001 for age). All 19 discoid meniscus patients with an inverted segment had activity-related knee pain. Only 4 patients (21.0%) reported mechanical symptoms. Patients with an inverted discoid segment, compared with patients with discoid menisci without inverted segments, were more likely to have instability and effusion (P = .012 and P < .001, respectively). Eighteen discoid meniscus patients with an inverted segment (94.7%) had an injury, while only 41.2% of patients with noninverted symptomatic discoid menisci had an injury (P < .001). On MRI, an inverted discoid segment was seen as a horizontal longitudinal tear, a free fragment, or a double meniscus. During arthroscopy, the inverted discoid segment appeared normal, without a tear; upon probing, however, the inverted segment could be exposed. CONCLUSION: An inverted discoid segment occurs during adolescence, and it is more likely to occur in male patients and more likely to be associated with activity-related pain and injury compared with a noninverted symptomatic discoid meniscus. A discoid meniscus with an inverted segment does not have the standard radiographic and arthroscopic features normally associated with a discoid meniscus. PMID- 26980847 TI - Compliance with the Use of Medical and Cloth Masks Among Healthcare Workers in Vietnam. AB - BACKGROUND: Masks are often worn in healthcare settings to prevent the spread of infection from healthcare workers (HCWs) to patients. Masks are also used to protect the employee from patient-generated infectious organisms but poor compliance can reduce efficacy. The aim of this study was to examine the factors influencing compliance with the use of medical and cloth masks amongst hospital HCWs. METHODS: HCWs compliance with the use of medical and cloth masks was measured over a 4-week period in a randomized controlled trial in Vietnam. HCWs were instructed to record their daily activities in diary cards. Demographic, clinical, and diary card data were used to determine the predictors of compliance and the relationship of compliance with infection outcomes. RESULTS: Compliance rates for both medical and cloth masks decreased during the 4 weeks: medical mask use decreased from 77 to 68% (P < 0.001) and cloth masks from 78 to 69% (P < 0.001). The presence of adverse events (adjusted RR 0.90, 95% CI 0.85-0.95), and performing aerosol-generating procedures (adjusted RR 0.78, 95% CI 0.73-0.82) were negatively associated with compliance, while contact with febrile respiratory illness patients was positively associated (adjusted RR 1.14, 95% CI 1.07-1.20). Being compliant with medical or cloth masks use (average use >=70% of working time) was not associated with clinical respiratory illness, influenza like illness, and laboratory-confirmed viral infection. CONCLUSION: Understanding the factors that affect compliance is important for the occupational health and safety of HCWs. New strategies and tools should be developed to increase compliance of HCWs. The presence of adverse events such as discomfort and breathing problems may be the main reasons for the low compliance with mask use and further studies should be conducted to improve the design/material of masks to improve comfort for the wearer. PMID- 26980848 TI - Simultaneous early-onset immune thrombocytopenia and autoimmune thyroid disease following alemtuzumab treatment in relapsing-remitting multiple sclerosis. AB - OBJECTIVE: We report two cases of patients with relapsing-remitting multiple sclerosis with early-onset thrombocytopenia and autoimmune thyroid disease after the first treatment course with 60-mg alemtuzumab. METHODS: Case series and review of the literature. RESULTS: Both patients showed severe thrombocytopenia with platelet counts of 2 * 10(9) and 11 * 10(9)/L, respectively, as well as increased thyroid antibodies within only a few months after initiating alemtuzumab treatment (11 and 9 months). Both patients responded considerably well to medical therapy including corticosteroids and intravenous immunoglobulins with slow platelet recovery over several weeks. Interestingly, both patients were previously treated with fingolimod and showed a marked lymphocytopenia that led to discontinuation. CONCLUSION: These cases emphasize the necessity of careful clinical surveillance and proper education of patients treated with alemtuzumab as proposed by the safety-monitoring program. Previous severe lymphocytopenia under therapy with other disease-modifying therapies may be a risk factor for the development of immune thrombocytopenia. PMID- 26980849 TI - Care of the Student With Special Healthcare Needs: The Development of the WISHeS Unlicensed Assistive Personnel Training. AB - Care of the Student With Special Healthcare Needs is a free resource that can assist school nurses in ensuring they are providing the most up-to-date, evidence based care to children. Although the training module was developed to improve the care provided to Wisconsin children, the module can be accessed by school nurses and unlicensed assistive personnel (UAP) across the United States and internationally. School nurses in other states would need to review their state's nurse practice act and school district policies to evaluate which procedures they are allowed to delegate. PMID- 26980850 TI - Can Grit Be Nurtured in Undergraduate Nursing Students? AB - Grit, a positive psychological trait, is a character trait of great benefit to the practice of nursing. Nurses who exemplify a combination of excellence, determination, and compassion in their practice are often described as having grit. This article discusses the five major traits of grit and the development and nurturing of these traits in both nursing students and novice nurses. The topic of the development of grit is relevant to school nurses who find themselves in mentor roles with nursing students and with nurses new to school nursing. PMID- 26980851 TI - Managing Use of Over-the-Counter Medications in the School Setting: Keeping Kids in School and Ready to Learn. AB - The use of over-the-counter (OTC) medications in our unique school setting has proven to be a cost-effective and valuable tool in keeping students in the classroom and prepared to learn. Disruptions in educational time due to minor complaints become frustrating for students and teachers. Utilizing the assessment skills of the school nurse and treatment options available through the use of OTC medications decreases those disruptions and protects the educational time. The opportunity to increase student understanding and health literacy regarding the correct use of OTC medications is a valuable way to protect the health of students. Lessons learned in the residential setting may have application to other school settings. PMID- 26980852 TI - The Part 1 MFSRH Examination: the new Single Best Answer paper. PMID- 26980853 TI - Health, Safety, and a Sustainable Environment Require Participatory Democracy and a Commitment to Social Justice and Equality. PMID- 26980854 TI - Predictors of health-related quality of life in community-dwelling stroke survivors: a cohort study. AB - BACKGROUND: Impaired health-related quality of life (HRQoL) post stroke is common, though prevalence estimates vary considerably. Few longitudinal studies explore post-stroke patterns of HRQoL and factors contributing to their change over time. Accurately identifying HRQoL after stroke is essential to understanding the extent of stroke effects. OBJECTIVES: This study aimed to assess change in levels of, and identify independent predictors of, HRQoL over the first 12-months post-stroke. METHODS: Design. A prospective cohort study. SETTING AND PARTICIPANTS: Community-dwelling stroke survivors in metropolitan Newcastle, New South Wales (NSW), Australia. Consecutively recruited stroke patients (n = 134) participated in face-to-face interviews at baseline, 3, 6, 9 and 12 months. OUTCOME MEASURE: HRQoL (measured using the Assessment Quality-of life).Independent measures. Physical and psycho-social functioning, including depression and anxiety (measured via Hospital Anxiety and Depression Scale), disability (Modified Rankin Scale), social support (Multi-dimensional Scale Perceived Social Support) and community participation (Adelaide Activities Profile). ANALYSES: A linear mixed model was used to establish the predictors of, change in HRQoL over time. RESULTS: On multivariable analysis, HRQOL did not change significantly with time post-stroke. Higher HRQoL scores were independently associated with higher baseline HRQoL (P = 0.03), younger age (P = 0.006), lower disability (P = 0.003), greater community participation (P <= 0.001) and no history of depression (P = 0.03). CONCLUSION: These results contribute to an understanding of HRQoL in the first year post-stroke. Community participation and stroke-related disability are potentially modifiable risk factors affecting post-stroke HRQoL. Interventions aimed at addressing participation and disability post-stroke should be developed and tested. PMID- 26980859 TI - Understanding Tobacco Use Behaviors Among African Americans: Progress, Critical Gaps, and Opportunities. AB - INTRODUCTION: Although multiple factors likely influence the differences between African Americans (AAs) and whites in cardiovascular disease and lung cancer mortality rates, historical patterns of tobacco use, particularly cigarette smoking, are the major contributors. This issue of Nicotine & Tobacco Research presents original research, a review, and commentaries that will serve to advance our understanding of several relevant behavioral similarities and differences between AAs and whites. BEHAVIORAL ANALYSIS: Here, we illustrate how the diverging trends in cigarette smoking between AA and white high school seniors observed since the mid-1970s were influenced by patterns of ever use and current use among ever users. During 1977 to 2014, the percentage of current users among ever users was higher, but less variable, among whites than AAs. Among adults, trends in self-reported cigarette smoking among non-Hispanic AAs and non-Hispanic whites are available since 1978. The trends observed were likely due in part to the maturation of the high school senior cohorts from the 1970s and 1980s when AA smoking rates declined sharply relative to whites. Later age of initiation among AAs and less quitting among older AAs, relative to whites, also contribute. CONCLUSIONS: Further research on multiple topics, including the continuation of use among ever users, use of multiple combusted and noncombusted products, provision of cessation support services, influence of discrimination, and validity of self-report would expand the science base. Strategies to reduce the marketing and availability of menthol and other characterizing flavorings and to enrich environments would promote the public's health. PMID- 26980860 TI - The African American Youth Smoking Experience: An Overview. AB - INTRODUCTION: Beginning in the late 1970s, a very sharp decline in cigarette smoking prevalence was observed among African American (AA) high school seniors compared with a more modest decline among whites. This historic decline resulted in a lower prevalence of cigarette smoking among AA youth that has persisted for several decades. METHODS: We synthesized information contained in the research literature and tobacco industry documents to provide an account of past influences on cigarette smoking behavior among AA youth to help understand the reasons for these historically lower rates of cigarette smoking. RESULTS: While a number of protective factors including cigarette price increases, religiosity, parental opposition, sports participation, body image, and negative attitudes towards cigarette smoking may have all played a role in maintaining lower rates of cigarette smoking among AA youth as compared to white youth, the efforts of the tobacco industry seem to have prevented the effectiveness of these factors from carrying over into adulthood. CONCLUSION: Continuing public health efforts that prevent cigarette smoking initiation and maintain lower cigarette smoking rates among AA youth throughout adulthood have the potential to help reduce the negative health consequences of smoking in this population. IMPLICATIONS: While AA youth continue to have a lower prevalence of cigarette smoking than white youth, they are still at risk of increasing their smoking behavior due to aggressive targeted marketing by the tobacco industry. Because AAs suffer disproportionately from tobacco-related disease, and have higher incidence and mortality rates from lung cancer, efforts to prevent smoking initiation and maintain lower cigarette smoking rates among AA youth have the potential to significantly lower lung cancer death rates among AA adults. PMID- 26980861 TI - Comparison of Smoking History Patterns Among African American and White Cohorts in the United States Born 1890 to 1990. AB - INTRODUCTION: Characterizing smoking history patterns summarizes life course exposure for birth cohorts, essential for evaluating the impact of tobacco control on health. Limited attention has been given to patterns among African Americans. METHODS: Life course smoking histories of African Americans and whites were estimated beginning with the 1890 birth cohort. Estimates of smoking initiation and cessation probabilities, and intensity can be used as a baseline for studying smoking intervention strategies that target smoking exposure. US National Health Interview Surveys conducted from 1965 to 2012 yielded cross sectional information on current smoking behavior among African Americans and whites. Additional detail for smokers including age at initiation, age at cessation and smoking intensity were available in some surveys and these were used to construct smoking histories for participants up to the date that they were interviewed. Age-period-cohort models with constrained natural splines provided estimates of current, former and never-smoker prevalence in cohorts beginning in 1890. RESULTS: This approach yielded yearly estimates of initiation, cessation and smoking intensity by age for each birth cohort. Smoking initiation probabilities tend to be lower among African Americans compared to whites, and cessation probabilities also were generally lower. Higher initiation leads to higher smoking prevalence among whites in younger ages, but lower cessation leads to higher prevalence at older ages in blacks, when adverse health effects of smoking become most apparent. CONCLUSIONS: These estimates provide a summary that can be used to better understand the effects of changes in smoking behavior following publication of the Surgeon General's Report in 1964. IMPLICATIONS: A novel method of estimating smoking histories was applied to data from the National Health Interview Surveys, which provided an extensive summary of the smoking history in this population following publication of the Surgeon General's Report in 1964. The results suggest that some of the existing disparities in smoking-related disease may be due to the lower cessation rates in African Americans compared to whites. However, the number of cigarettes smoked is also lower among African Americans. Further work is needed to determine mechanisms by which smoking duration and intensity can account for racial disparities in smoking-related diseases. PMID- 26980863 TI - Does a Race-Gender-Age Crossover Effect Exist in Current Cigarette Smoking Between Non-Hispanic Blacks and Non-Hispanic Whites? United States, 2001-2013. AB - INTRODUCTION: For years, national US surveys have found a lower prevalence of cigarette smoking among non-Hispanic (NH) black adolescents and young adults than their NH white counterparts while finding either similar or higher prevalence in NH blacks among older adults. We present results from four US surveys, including one supplemented by cotinine data, to determine if a race-gender-age crossover effect exists between NH black and NH white current cigarette smokers. METHODS: We present NH black and NH white current cigarette smoking estimates in the National Youth Tobacco Survey (2004-2013), National Survey on Drug Use and Health (2002-2013), National Health Interview Survey (2001-2013), and National Health and Nutrition Examination Survey (2001-2012). RESULTS: All surveys consistently found that NH black females aged 12-25 years had a lower smoking prevalence than NH white females of the same age while NH black males aged 26 years or older had a higher smoking prevalence than NH white males of the same age. Results were inconsistent between surveys for current smoking estimates for males 12-25 years and females aged 26 years or older. CONCLUSION: Our results are inconclusive in consistently detecting the existence of a race-gender-age crossover effect for current cigarette smoking between NH blacks and NH whites. National birth cohort studies are better suited to detect a race-gender-age crossover effect in smoking prevalence between these two racial groups. PMID- 26980862 TI - National Surveys and Tobacco Use Among African Americans: A Review of Critical Factors. AB - INTRODUCTION: Beginning in the 1970s, US national surveys showed African American youth having a lower prevalence of cigarette smoking than white youth. Yet, during adulthood, African Americans have a smoking prevalence comparable to white adults. Data sources chosen can contribute in different ways to understanding tobacco use behaviors among African American youth and adults; this article is a review of national and/or state-based health surveys to examine their methodology, racial and ethnic classifications, and tobacco-use related measures. METHODS: Eleven national and/or state based surveys were selected for review. Eight surveys were multitopic and included questions on tobacco use and three surveys were tobacco specific. Survey methods included telephone (4), household (3), and school (4). Three major characteristics examined for each survey were: (1) survey design and methods, (2) racial and ethnic background classification, and (3) selected tobacco smoking questions. Within these three characteristics, 15 factors considered to be important for examining tobacco use behaviors by African Americans were identified a priori using previously published reviews and studies. RESULTS: Within survey design and methods, the majority of surveys (>=7) oversampled African Americans and did not use proxy respondents for tobacco questions. All surveys used Office of Management and Budget standard classification for race/ethnicity classification. The majority of surveys (>=7) captured five of the seven tobacco-related smoking questions. CONCLUSIONS: Programmatic objectives and/or research questions should guide the selection of data sources for tobacco control programs and researchers examining African American tobacco use behaviors. IMPLICATIONS: This review of 11 national and state tobacco-related surveys shows that these surveys provide much needed estimates of tobacco use behaviors. However, as tobacco programs and researchers seek to examine tobacco use behaviors among African Americans, it is important to consider multiple surveys as each can contribute to informing the tobacco experience in African Americans. Most importantly, programmatic objectives and/or research questions should guide the selection of data sources for tobacco control programs and researchers examining African American tobacco use behaviors. PMID- 26980864 TI - Understanding Tobacco Use Onset Among African Americans. AB - INTRODUCTION: Compared to the majority of non-Hispanic white ("white") cigarette smokers, many African American smokers demonstrate a later age of initiation. The goal of the present study was to examine African American late-onset smoking (ie, regular smoking beginning at age 18 or later) and determine whether late-onset (vs. early-onset) smoking is protective in terms of quit rates and health outcomes. METHODS: We used data from the National Survey of Midlife Development in the United States (MIDUS) because the wide age range of participants (20-75 at baseline) allowed the examination of smoking cessation and mortality incidence across the lifespan. RESULTS: Consistent with previous research, results indicated a later average age of smoking onset among African Americans, compared to whites. Disentangling effects of race from age-of-onset, we found that the cessation rate among late-onset African American smokers was 33%, whereas rates for early-onset African American smokers and early- and late-onset white smokers ranged from 52% to 57%. Finally, results showed that among white, low socioeconomic status (SES) smokers, the hazard rate for mortality was greater among early- versus late-onset smokers; in contrast, among African American smokers (both low- and high-SES) hazard rates for mortality did not significantly differ among early- versus late-onset smokers. CONCLUSIONS: Although late (vs. early) smoking onset may be protective for whites, the present results suggest that late-onset may not be similarly protective for African Americans. Tobacco programs and regulatory policies focused on prevention should expand their perspective to include later ages of initiation, in order to avoid widening tobacco-related health disparities. IMPLICATIONS: This study indicates that late onset smoking is not only the norm among African American adult smokers, but that late- versus early-onset smoking (ie, delaying onset) does not appear to afford any benefits for African Americans in terms of cessation or mortality. These results suggest that prevention and intervention efforts need to consider individual groups (not just overall averages) and that tobacco control efforts need to be targeted beyond the teenage years. Tobacco programs and regulatory policies focused on prevention should expand their perspective to include later ages of initiation, to avoid widening tobacco-related health disparities. PMID- 26980865 TI - Not Just Cigarettes: A More Comprehensive Look at Marijuana and Tobacco Use Among African American and White Youth and Young Adults. AB - INTRODUCTION: Cigarettes, cigars, and marijuana have generally been studied in isolation yet their use does not occur in isolation. Focus on cigarette smoking may overstate the observation that African American youth and young adults are less likely to smoke any combustible product compared with their white counterparts. Assessing cigarette, cigar, and marijuana use trends may help identify the extent of this difference. METHODS: Data from the 2002-2012 National Survey on Drug Use and Health (N = 25 541 to N = 28 232) were used to investigate past 30-day cigarette, cigar, and marijuana use trends among African American and white youth (12-17) and young adults (18-25). Logistic regressions assessed trends in combustible tobacco (cigarettes and cigars) and marijuana use, alone and in combination. RESULTS: From 2002-2012, the absolute difference in cigarette smoking prevalence between African American and white youth (9.6%-4.2%) and young adults (19.0%-10.5%) narrowed. Any combustible tobacco/marijuana use was significantly lower among African Americans than whites but, relative to cigarettes, the absolute difference was much smaller among youth (7.2%-2.2%) and young adults (15.8%-5.6%). Among any combustible tobacco/marijuana users, using two or more substances ranged from 31.4% to 40.3% among youth and 29.1% to 39.8% among young adults. CONCLUSION: Any combustible tobacco/marijuana use trends suggest the smoking prevalence difference between African American and white youth and young adults is real, but less pronounced than when assessing cigarette smoking alone. Policies and programs addressing smoking behaviors may benefit from broadening focus to monitor and address cigar and marijuana use as well. IMPLICATIONS: Trends in any use of cigarettes, cigars, and/or marijuana suggest the difference in smoking prevalence between African American and white youth and young adults is real, but less pronounced than when cigarette smoking is assessed alone. In 2012, more than 10% of African American and white youth, more than a third of African American young adults, and nearly half of white young adults reported past 30-day use of cigarette, cigars, and/or marijuana. Public health programs aimed at reducing these behaviors among youth and young adults could be informed by considering detailed, race-specific information regarding tobacco and marijuana use patterns. PMID- 26980866 TI - Understanding the African American "Smoker". AB - This commentary draws on the articles contained in this special African American youth and adult tobacco use supplement to better understand the apparent paradox of low youth smoking rates and high adult smoking rates. Implications for tobacco use prevention and control are discussed. IMPLICATIONS: This commentary introduces the reader to the topics and questions addressed in the supplement and urges an invigorated public health response to address tobacco-caused disease and death in African Americans. PMID- 26980867 TI - Cigarette Smoking Among Inmates by Race/Ethnicity: Impact of Excluding African American Young Adult Men From National Prevalence Estimates. AB - INTRODUCTION: Cigarette smoking prevalence is more than two times greater among incarcerated adults, a population usually excluded from national health surveys. African American young adult (18-25) men are less likely to smoke cigarettes than their white counterparts. However, they are two and a-half-times more likely to be incarcerated. This study estimated smoking prevalence with noninstitutionalized and incarcerated samples combined to determine if excluding incarcerated adults impacts smoking prevalence for certain populations. METHODS: The Bureau of Justice Statistics last fielded the Survey of Inmates in State and Federal Correction Facilities in 2003-2004. We combined data from Survey of Inmates in State and Federal Correction Facilities (n = 17 910) and the 2003 and 2004 National Health Interview Survey (n = 61 470) to calculate combined cigarette smoking estimates by race/ethnicity, sex, and age. RESULTS: Inmates represented the greatest proportion of smokers among African American men. Among African American young adult men, inmates represented 15.2% of all smokers in the combined population, compared to 2.0% among white young adult men. Cigarette smoking prevalence was 17.6% in the noninstitutionalized population of young adult African American men and 19.7% in the combined population. Among white young adult men, cigarette smoking prevalence was 29.8% in the noninstitutionalized population, and 30.2% in the combined population. There was little difference in estimates among women. CONCLUSIONS: The exclusion of incarcerated African American young adult men may result in a small underestimation of cigarette smoking prevalence in this population. Increasing access to smoking cessation support among inmates may reduce smoking prevalence in disproportionately incarcerated segments of the US population. IMPLICATIONS: The exclusion of incarcerated adults from national survey data should be considered when examining differences in cigarette smoking prevalence estimates between African American and white young adult men. Approximately one in six African American young adult men who smoke were incarcerated. Increasing access to smoking cessation support among inmates may reduce smoking prevalence among disproportionately incarcerated segments of the population. PMID- 26980869 TI - Race and Tobacco Use: A Global Perspective. AB - These findings suggest that there are no "fixed" racial patterns of tobacco use around the globe. Cross-country differences in tobacco use among races could be modified by cultural influences, domestic tobacco control, or socioeconomic factors. There is need for enhanced efforts to monitor tobacco use by race/ethnicity to identify existing and emerging patterns in tobacco use by race, as well as identify opportunities for interventions. Tailored interventions to reduce tobacco use within different settings and countries may help reduce tobacco use among racial/ethnic minorities. Implementation of comprehensive tobacco control measures could be facilitated by community-based efforts, ensuring that disadvantaged populations are engaged as partners to adapt tobacco control policies and interventions to local contexts and health equity issues. PMID- 26980875 TI - Reply to the Letter by J. Hambraeus, 'Ganglion Impar Blocks for More than Coccygodynia'. PMID- 26980868 TI - Differences in Quit Attempts and Cigarette Smoking Abstinence Between Whites and African Americans in the United States: Literature Review and Results From the International Tobacco Control US Survey. AB - INTRODUCTION: While cigarette smoking prevalence is declining among US adults, quit rates may differ between white and African American smokers. Here, we summarize the literature on smoking cessation behaviors in whites and African Americans across four study designs and report the findings of new analyses of International Tobacco Control (ITC) US Survey cohort data. METHODS: We reviewed 32 publications containing 39 relevant analyses that compared quit attempts and abstinence between US whites and African Americans. Two additional longitudinal analyses were conducted on 821 white and 76 African American cigarette smokers from Waves 7 and 8 of the ITC US Survey (mean follow-up = 19 months). RESULTS: Of 17 total analyses of quit attempts, nine (including the ITC US Survey) observed that African American smokers were more likely than whites to attempt to quit during a given year; seven found no differences. Whites were more likely than African Americans to be abstinent in five of six retrospective cohort analyses and in two of five considered community- and population-based cohort studies. Four of these 11 analyses, including one from the ITC US Survey, found no differences. CONCLUSIONS: Of 11 population- or community-based analyses, all seven that found significant differences indicated that whites were more likely to quit than African Americans. These findings, combined with the similar results from population-based birth cohort analyses, support the conclusion that white smokers are more likely to quit than African American smokers. Efforts to encourage and support quitting among all tobacco users remain a priority. IMPLICATIONS: This article provides a review of the literature on smoking cessation among African American and white smokers, and adds new analyses that compare quit attempts and abstinence between US African Americans and whites. Results demonstrate a clear distinction between the findings of cross-sectional and retrospective cohort studies with those of cohort studies. Reasons for these differences merit further study. PMID- 26980870 TI - Why We Must Continue to Investigate Menthol's Role in the African American Smoking Paradox. AB - BACKGROUND: The disproportionate burden of tobacco use among African Americans is largely unexplained. The unexplained disparities, referred to as the African American smoking paradox, includes several phenomena. Despite their social disadvantage, African American youth have lower smoking prevalence rates, initiate smoking at older ages, and during adulthood, smoking rates are comparable to whites. Smoking frequency and intensity among African American youth and adults are lower compared to whites and American Indian and Alaska Natives, but tobacco-caused morbidity and mortality rates are disproportionately higher. Disease prediction models have not explained disease causal pathways in African Americans. It has been hypothesized that menthol cigarette smoking, which is disproportionately high among African Americans, may help to explain several components of the African American smoking paradox. PURPOSE: This article provides an overview of the potential role that menthol plays in the African American smoking paradox. We also discuss the research needed to better understand this unresolved puzzle. METHODS: We examined prior synthesis reports and reviewed the literature in PubMed on the menthol compound and menthol cigarette smoking in African Americans. RESULTS: The pharmacological and physiological effects of menthol and their interaction with biological and genetic factors may indirectly contribute to the disproportionate burden of cigarette use and diseases among African Americans. CONCLUSIONS: Future studies that examine taste sensitivity, the menthol compound, and their effects on smoking and chronic disease would provide valuable information on how to reduce the tobacco burden among African Americans. IMPLICATIONS: Our study highlights four counterintuitive observations related to the smoking risk profiles and chronic disease outcomes among African Americans. The extant literature provides strong evidence of their existence and shows that long-standing paradoxes have been largely unaffected by changes in the social environment. African Americans smoke menthols disproportionately, and menthol's role in the African American smoking paradox has not been thoroughly explored. We propose discrete hypotheses that will help to explain the phenomena and encourage researchers to empirically test menthol's role in smoking initiation, transitions to regular smoking and chronic disease outcomes in African Americans. PMID- 26980876 TI - Reply to Yue. PMID- 26980877 TI - Bacterial Persistent Infection at the Interface Between Host and Microbiota. PMID- 26980878 TI - Using Social Media to Increase HIV Testing Among Gay and Bisexual Men, Other Men Who Have Sex With Men, and Transgender Persons: Outcomes From a Randomized Community Trial. AB - We tested an intervention designed to increase human immunodeficiency virus (HIV) testing among men who have sex with men and transgender persons within existing and commonly used social media. At follow-up, intervention communities had significantly higher past 12-month HIV testing than the comparison communities. Findings suggest that promoting HIV testing via social media can increase testing. PMID- 26980879 TI - Case Report of Spontaneous Resolution of a Congenital Glioblastoma. AB - Glioblastoma multiforme (GBM) is a rare, highly aggressive brain tumor associated with a poor outcome in both children and adults. Treatment usually involves a combination of surgical resection, chemotherapy, and radiotherapy, but ultimately it is incurable. Evidence suggests that congenital GBM may have a better prognosis with improved survival compared with GBM in older children. We describe the first known report of spontaneous resolution of a congenital GBM without any systemic therapy. A limited debulking procedure was performed at diagnosis, and the residual tumor underwent spontaneous resolution over the following 21 months. The patient remains in remission, with no tumor recurrence after 5 years of follow-up. Despite the tumor regressing, the patient has had an adverse neurologic outcome, with severe developmental delay and seizures. This case suggests that congenital GBM may be a separate biological entity much like neuroblastomas in infants, and therefore associated with better outcomes and even spontaneous resolution. PMID- 26980880 TI - Management of Neonates Born to Mothers With Graves' Disease. AB - Neonates born to mothers with Graves' disease are at risk for significant morbidity and mortality and need to be appropriately identified and managed. Because no consensus guidelines regarding the treatment of these newborns exist, we sought to generate a literature-based management algorithm. The suggestions include the following: (1) Base initial risk assessment on maternal thyroid stimulating hormone (TSH) receptor antibodies. If levels are negative, no specific neonatal follow-up is necessary; if unavailable or positive, regard the newborn as "at risk" for the development of hyperthyroidism. (2) Determine levels of TSH-receptor antibodies in cord blood, or as soon as possible thereafter, so that newborns with negative antibodies can be discharged from follow-up. (3) Measurement of cord TSH and fT4 levels is not indicated. (4) Perform fT4 and TSH levels at day 3 to 5 of life, repeat at day 10 to 14 of life and follow clinically until 2 to 3 months of life. (5) Use the same testing schedule in neonates born to mothers with treated or untreated Graves' disease. (6) When warranted, use methimazole (MMI) as the treatment of choice; beta-blockers can be added for sympathetic hyperactivity. In refractory cases, potassium iodide may be used in conjunction with MMI. The need for treatment of asymptomatic infants with biochemical hyperthyroidism is uncertain. (7) Assess the MMI-treated newborn on a weekly basis until stable, then every 1 to 2 weeks, with a decrease of MMI (and other medications) as tolerated. MMI treatment duration is most commonly 1 to 2 months. (8) Be cognizant that central or primary hypothyroidism can occur in these newborns. PMID- 26980881 TI - Urgent Care and Emergency Department Visits in the Pediatric Medicaid Population. AB - BACKGROUND: Urgent care (UC) is one of the fastest growing venues of health care delivery. We compared clinical and cost attributes of pediatric UC and emergency department (ED) visits that did not result in admission. METHODS: Our study examined 5 925 568 ED and UC visits of children under 19 years old in the 2010 through 2012 Marketscan Medicaid Multi-State Database. Basic demographics, diagnoses, severity, and payments were compared. Between ED and UC visits, chi(2) tests were used for proportions and Wilcoxon rank-sum tests were used for continuous variables. RESULTS: The UC and ED had the same most common diagnoses. Over half the UC visits were low severity. The ED had a higher rate of return within 7 days (8.4% vs 6.9%, P < .001) and follow-up with their primary care physician (22% vs 17.2%, P < .001). Few (<1%) were admitted on return visits from the ED or UC. Payments for UC were significantly less (median $76.90 vs $186.20, P < .001). This continued to hold true when comparing payments for selected diagnoses and each severity level. By extrapolating the cost savings, a national Medicaid per-year savings, if all lowest severity level visits were seen in UC, was more than $50 million. CONCLUSIONS: UC and ED Medicaid visits have similar most common diagnoses, rate of return, and admission. Severity level and payments were lower in UC. There is potential significant cost savings if lower acuity cases can be transitioned from the ED to UC. PMID- 26980884 TI - Where Have All the Nursing Theories Gone? PMID- 26980883 TI - Outcomes With Intravascular Ultrasound-Guided Stent Implantation: A Meta-Analysis of Randomized Trials in the Era of Drug-Eluting Stents. AB - BACKGROUND: In the era of drug-eluting stents, it is unknown if intravascular ultrasound (IVUS) guidance for percutaneous coronary intervention should be routinely endorsed. This study aimed to determine if IVUS-guided stent implantation is associated with improved outcomes. METHODS AND RESULTS: Randomized trials that reported clinical outcomes and compared routine IVUS guided stent implantation with an angiography-guided approach in the era of drug eluting stents were included. Summary estimates were constructed primarily using the Peto model. Seven trials with 3192 patients were analyzed. The mean length of the coronary lesions was 32 mm. At a mean of 15 months, routine IVUS-guided percutaneous coronary intervention was associated with a reduction in the risk of major adverse cardiac events (6.5% versus 10.3%; odds ratio, 0.60; 95% confidence interval, 0.46-0.77; P<0.0001), mainly because of reduction in the risk of ischemia-driven target lesion revascularization (4.1% versus 6.6%; odds ratio, 0.60; 95% confidence interval, 0.43-0.84; P=0.003). The risk of cardiovascular mortality (0.5% versus 1.2%; odds ratio, 0.46; 95% confidence interval, 0.21 1.00; P=0.05), and stent thrombosis (0.6% versus 1.3%; odds ratio, 0.49; 95% confidence interval, 0.24-0.99; P=0.04) also appeared to be lower in the IVUS guided group. CONCLUSIONS: In the era of drug-eluting stents for diffuse coronary lesions, IVUS-guided percutaneous coronary intervention is superior to angiography-guided percutaneous coronary intervention in reducing the risk of major adverse cardiac events. This is primarily because of reduction in the risk of ischemia-driven target lesion revascularization. This analysis also suggests that risk of cardiovascular mortality and stent thrombosis might be lower with an IVUS-guided approach. PMID- 26980882 TI - Genetic Risk Scores Predict Recurrence of Acute Coronary Syndrome. AB - BACKGROUND: Several clinical risk estimation tools have established their role in the prediction of recurrence of acute coronary syndrome (ACS), but the value of genetic risk scores (GRSs) remains unclear. We examined how well 2 different GRSs estimate recurrent ACS and whether clinical factors are associated with GRSs. METHODS AND RESULTS: A cohort of 2090 consecutive patients with ACS who underwent coronary angiography between July 2006 and March 2008 in a single tertiary center was genotyped and prospectively followed up for a median of 5.5 years. We formed 2 partially overlapping GRSs: GRS47 of 47 single-nucleotide polymorphisms with previously reported significant association with coronary artery disease and GRS153 of 153 single-nucleotide polymorphisms with significant or suggestive association with coronary artery disease. GRS47 showed association with recurrent ACS independent of clinical factors (P=0.037; hazard ratio, 1.17; 95% confidence interval, 1.01-1.36). GRS153 had no association with either recurrent ACS or composite of recurrent ACS or death. Also, GRS47 was associated inversely with smoking and ST-segment-elevation myocardial infarction (P=0.004; odds ratio, 0.22; 95% confidence interval, 0.08-0.62 and P=0.041; odds ratio, 0.36; 95% confidence interval, 0.13-0.96, respectively). CONCLUSIONS: GRSs combined of 47 known coronary artery disease risk single-nucleotide polymorphisms were associated with recurrent ACS after multivariable adjustments in a heterogenic ACS population for the first time. Smoking and ST-segment-elevation myocardial infarction had an inverse association with the GRSs. The significance of smoking in relation to genetic coronary artery disease predisposition may merit further evaluation in patients with ACS. PMID- 26980885 TI - I Am Community. AB - This column explores the humanbecoming paradigm perspective of community. Community is written about as a vastness of the galaxy; as serene valley, mountain, turbulent sea; and, as nameless stranger, friend, family. Presented are tenets and indicators for living the art of humanbecoming community for health professionals. PMID- 26980886 TI - Evidence-Based Practice: What's New Is Old. AB - The purpose of this column is to demonstrate that evidence -based practice actually grew out of the process of research utilization. To that end, there will be a discussion about research utilization and evidence -based practice to expose the linkage between them. Then the newer ideas of implementation and de implementation science will also be shown to have roots in the process of research utilization. PMID- 26980887 TI - Power with Social Media: A Nursing Perspective. AB - Power is an emanating force typically associated with personal relationships. With the expanding capacities and utilization of social media, power with media is an emerging ethical concern to the discipline of nursing. The author here discusses potential ethical meanings and implications of power with social media while utilizing technology in future nurse practice and education. PMID- 26980888 TI - Community-Centered Service Learning: A Transformative Lens for Teaching-Learning in Nursing. AB - Although service learning has been proposed as a teaching-learning modality in response to an ongoing challenge to transform nursing education, there is a risk to community and student when service learning is poorly conceived. A community centered service learning approach founded on a nursing theoretical perspective and community model is explored as a way to honor the wisdom and perspective of the community in changing while illuminating a new way of being a nurse in community for the nursing student. PMID- 26980889 TI - Sorting It Out: Cultural Competency and Healthcare Literacy in the World Today. AB - Healthcare literacy and cultural competence are necessary components in keeping patients informed. Nurses are the foundation of healthcare and pivotal in creating trusting relationships with patients by sharing information. Respect is key in developing a tailored approach to individuals' healthcare literacy and nurses' cultural competence. In practice, the consequence of understanding healthcare literacy and being culturally competent should not be understated. Whether on a mission trip to another country or working in a clinic in the United States, diverse cultures abound. While a person from a particular culture may have some of the same beliefs of others in a culture, the breadth of expression of culture, personal beliefs, and worldview may be vastly different. Humans express themselves in unique ways even within cultures. Seeking ways to understand one another is vital not only in healthcare but in all aspects of life. PMID- 26980890 TI - Culture: Distinct or an Illusion? PMID- 26980891 TI - Are We Really Measuring Cultural Competence? AB - One of the major goals of culturally competent nursing and healthcare practice is to decrease health and healthcare disparities. All healthcare professionals need similar information for cultural competence. However, to date, most of the tools measure knowledge, skills and abilities but not true competence from a clinical practice setting. Several tools measure and/or evaluate the organization's cultural diversity mission but not the providers of healthcare. PMID- 26980892 TI - Humanbecoming Hermeneutic Sciencing: Reverence, Awe, Betrayal, and Shame in The Lives of Others. AB - The purpose of this article is to report the details of the humanbecoming hermeneutic sciencing of dignity--the universal living experiences of reverence, awe, betrayal, and shame in The Lives of Others. With this report new language for humanbecoming hermeneutic sciencing is introduced. Language both reflects and cocreates meanings. Language is an evolutionary patterning of symbols specifying meanings for the moment; it is fluid and everchanging. All language evolves gradually as generative ideas dawn, shifting the meaning of words and systems of words. The new language here includes: humanbecoming hermeneutic sciencing as coming to know a text or artform in discoursing with penetrating engaging, interpreting with quiescent beholding, and understanding with inspiring envisaging; horizon of inquiry; scholar-text; scholar-artform; contextually construed circumstance; foreknowings; and newknowings--all of which cocreate new meanings. PMID- 26980893 TI - Emotional Eating Mediates the Relationship Between Role Stress and Obesity in Clergy. AB - The purpose of this study was to investigate the relationships between role stress, emotional eating, and obesity in clergy. A random sample of United States Lutheran Church Missouri Synod clergy who met the study criteria (N = 430), response rate 38%, completed the Role Stress and Emotional Eating Behavior Scales, and self-reported height and weight for Body Mass Index (BMI) calculation. Obesity was high (81.4% overweight/obese, 36.7% obese), and emotional eating partially mediated the relationship between role stress and obesity. This study tested relations of the Neuman Systems Model. PMID- 26980894 TI - Building a Middle-Range Theory of Adaptive Spirituality. AB - The purpose of this article is to describe a Roy adaptation model based- research abstraction, the findings of which were synthesized into a middle-range theory (MRT) of adaptive spirituality. The published literature yielded 21 empirical studies that investigated religion/spirituality. Quantitative results supported the influence of spirituality on quality of life, psychosocial adjustment, well being, adaptive coping, and the self-concept mode. Qualitative findings showed the importance of spiritual expressions, values, and beliefs in adapting to chronic illness, bereavement, death, and other life transitions. These findings were abstracted into six theoretical statements, a conceptual definition of adaptive spirituality, and three hypotheses for future testing. PMID- 26980895 TI - Reformulating the Common Sense Model of Self-Regulation: Toward Parent-Child Shared Regulation. AB - Asthma is one of the most common chronic diseases of childhood with nearly 7 million children affected in the United States. Nonadherence to controller medication is a substantial issue that results in higher pediatric asthma disease morbidity. The common sense model of self-regulation is a useful theoretical framework to understand chronic disease self-management in adults, but has not been used in the context of pediatric chronic disease. Using Fawcett's framework, the authors analyze and evaluate the common sense model. To conclude, the authors propose a reformulation of the model that incorporates parent-child shared regulation of pediatric asthma. PMID- 26980896 TI - A Human Science View of Behavioral Health. AB - An exclusively quantitative public health approach to substance use in Mexico is criticized here as being of limited use to nurses working as clinicians with persons, families, and communities struggling with this issue. Three human science-based studies from three different countries are discussed to serve as options for addressing this limitation. PMID- 26980897 TI - Nursing and Substance Use Disorders in Mexico. AB - The authors of this article see substance use disorders as a major public health problem in Mexico in which nursing is taking on an increasingly important role in addressing. The authors discuss some the challenges and opportunities nurse researchers, educators, and clinicians face in the prevention and treatment of substance use disorders in Mexico. PMID- 26980898 TI - Collaborative Partnerships: A Leading-Following Perspective. AB - In the following article, Dr. Linda Everett, a veteran nurse executive, describes the ebb and flow of leading-following within a nursing academic-nursing practice partnership that was grounded in respectful collaboration. PMID- 26980899 TI - Academic-Practice Partnerships: The Interdependence Between Leadership and Followership. AB - In this article, there is a discussion focused on three contemporary nursing topics: leadership, followership, and academic-practice partnerships. These comments are framed within the context of the current healthcare system transformation. There is a focus on why each of these topics is relevant to the nursing profession in leading change and advancing health. Finally, there is a description about the interdependence of leadership and followership and the significance these hold for the interdependence between nursing education and nursing practice. PMID- 26980900 TI - Thoughts About Social Issues: A Neuman Systems Model Perspective. AB - The Neuman systems model includes social issues as a client system of interest. The other client systems of this conceptual model of nursing are individuals, families, other groups, and communities, about which exists a considerable amount of literature. However, social issues as a client system have not yet been defined or described, nor has any application of this client system been published. This essay is a discussion of the meaning of social issues as a client system from the perspective of the Neuman systems model, and offers examples from the literature, from the results of a survey of Neuman systems model trustees, including Betty Neuman, and from dialogue with participants at the 15th Biennial Neuman systems model symposium. This article was adapted from a paper presented at the 15(th) Biennial International Neuman Systems Model Symposium, Philadelphia, PA. June 19, 2015. PMID- 26980903 TI - Correction. PMID- 26980904 TI - Cochlear Implantation in Canal Wall Down Mastoid Cavities. AB - Cochlear implantation in canal wall down mastoid (CWD) cavities is fraught with the issue of how best to manage the mastoid cavity. Decision points include whether the external auditory meatus should be overclosed, whether the implantation should be staged, or even if the eustachian tube should be plugged. Given these options, we sought to describe our experience of cochlear implantation in CWD cavities. Among evaluation of subjects >=18 years of age, 9 had cochlear implants placed in CWD mastoid cavities, 7 of which had the external auditory meatus overclosed, while 2 maintained open cavities following implantation. With an average follow-up of 36.7 months (median, 22.8 months), 2 subjects who had overclosure developed meatal dehiscences requiring further intervention, while no complications were observed in the 2 patients who maintained open cavities. PMID- 26980905 TI - Diode Laser Stapedotomy vs Conventional Stapedotomy in Otosclerosis: A Double Blinded Randomized Clinical Trial. AB - OBJECTIVES: To assess and compare the efficacy of diode laser stapedotomy (DLS) and conventional manual stapedotomy (CMS) in the treatment of otosclerosis. STUDY DESIGN: Randomized clinical trial. SETTING: Tertiary health center. SUBJECTS AND METHODS: We randomly assigned 60 patients with otosclerosis planned for primary stapedotomy to receive either DLS or CMS. Primary outcome measure was hearing gain measured by pure-tone audiometry (PTA) performed preoperatively and postoperatively. Hearing gain was compared within and between the groups. Secondary outcome measures were the incidence of intraoperative (bleeding and fractured footplate) and postoperative (vomiting, vertigo, sensorineural hearing loss, tinnitus, facial nerve paralysis, and hospital stay) morbidities. RESULTS: Sixty primary stapedotomies (30 in the CMS group and 30 in the DLS group) done for 60 patients (male, n = 42; female, n = 18) were included in the analysis. Preoperative mean air-bone (AB) gap in the DLS and CMS groups was 38.51 +/- 8.643 dB and 36.42 +/- 8.678 dB, respectively. Mean AB gap at 6 month was 10.86 +/- 5.383 dB and 11.05 +/- 5.236 dB in the CMS and DLS groups, respectively. Air conduction was improved by 24.98 +/- 5.348 dB in the DLS group and 24.08 +/- 5.911 dB in the CMS group at 6 months. No statistically significant differences were found in hearing gain between the 2 groups at 6 months (P > .05). A decreased rate and severity of intraoperative bleeding, postoperative vertigo, and vomiting were observed with the diode laser (0%, 6.6%, and 10%) compared with the conventional technique (16.7%, 16.7%, and 16.7%), but these differences were not statistically significant (P > .05). CONCLUSION: Hearing outcomes and complications of DLS were similar to CMS. These study findings confirm the efficacy of the diode laser in stapedotomy, but DLS offers no advantages over CMS for otosclerosis surgery. PMID- 26980906 TI - Comparison of Robotic versus Conventional Selective Neck Dissection and Total Thyroidectomy for Papillary Thyroid Carcinoma. AB - OBJECTIVE: To compare the surgical outcomes of robotic selective neck dissection (SND) with total thyroidectomy and conventional transcervical SND with total thyroidectomy. STUDY DESIGN: Case series with chart review. SETTING: University tertiary care facility. SUBJECT AND METHODS: We retrospectively analyzed 66 patients who underwent total thyroidectomy with SND (>=3 levels of II-V) and bilateral central neck dissection for cN1b papillary thyroid carcinoma, of whom 41 underwent conventional SND and 25 of whom underwent robotic SND. Subjective pain, sensory change, and cosmetic satisfaction were evaluated regularly for 3 months with a questionnaire. RESULTS: Compared with the conventional group, patients in the robotic group were younger (mean, 36.7 vs 47.5 years; P = .003) and more female dominant (96.0% vs 73.2%; P = .023). Mean total operative time was longer in the robotic group than the conventional group (298 vs 236 minutes; P < .001). Anterior chest pain was higher in the robotic group at postoperative 1 day (pain score, 1.88 vs 0.62; P = .011), 1 week (1.30 vs 0.43; P = .036), and 1 month (0.90 vs 0.18; P = .029). Postoperative cosmetic satisfaction was significantly superior in the robotic group. CONCLUSION: Compared with conventional transcervical SND with total thyroidectomy, robotic SND with total thyroidectomy yields superior outcomes for cosmetic satisfaction, longer operative time, and higher chest pain in the short term. Further study with a larger number of patients is mandatory. PMID- 26980907 TI - Robotic Thyroidectomy: Comparison of a Postauricular Facelift Approach with a Gasless Unilateral Axillary Approach. AB - OBJECTIVES: Robotic thyroidectomy using remote access approaches has gained popularity with patients seeking to avoid neck scarring and enhanced cosmetic satisfaction. The aim of this study was to compare the efficacy and advantages of a postauricular facelift approach vs a gasless unilateral axillary (GUA) approach in robotic thyroidectomy. STUDY DESIGN: Case series with chart review. SETTING: University tertiary care hospital. SUBJECTS AND METHODS: We retrospectively analyzed the data of 65 patients who underwent robotic thyroidectomy with or without central neck dissection using a GUA approach (45 patients) or a postauricular facelift approach (20 patients) between September 2013 and December 2014. We excluded patients who underwent simultaneous lateral neck dissection or completion thyroidectomy. RESULTS: Robotic procedures were completed without being converted to an open procedure in all patients. There were no significant differences in terms of patient and tumor characteristics, extent of thyroidectomy and central neck dissection, operative time, complications, and postoperative pain between the 2 approaches, except the higher female ratio in the GUA approach group (female ratio, 95.6% vs 75%, P = .042). Cosmetic satisfaction evaluated by a questionnaire was not significantly different between the 2 groups, and most patients of both groups (85.7%) were satisfied with postoperative cosmesis. CONCLUSION: Both GUA and postauricular facelift approaches are feasible, with no significant adverse events in patients, and result in excellent cosmesis. However, a GUA approach seems to be superior when performing total thyroidectomy using a unilateral incision based on the preliminary result. PMID- 26980908 TI - Upper Airway Stimulation for OSA: Early Adherence and Outcome Results of One Center. AB - OBJECTIVE: To review outcome measures and objective adherence data for patients treated with hypoglossal nerve stimulation (HNS) therapy for moderate to severe obstructive sleep apnea (OSA). STUDY DESIGN: Case series with chart review. SETTING: Academic sleep medicine center. SUBJECTS AND METHODS: The first 20 implanted patients to complete postoperative sleep laboratory testing were assessed. All patients had moderate to severe OSA, were unable to adhere to positive pressure therapy, and met previously published inclusion criteria for the commercially available implantable HNS system. Data included demographics, body mass index (BMI), apnea-hypopnea index (AHI), Epworth Sleepiness Score (ESS), nightly hours of device usage, and procedure- and therapy-related complications. RESULTS: Mean age was 64.8 +/- 12.0 years, with 50% female. Mean BMI was unchanged postoperatively (26.5 +/- 4.2 to 26.8 +/- 4.5 kg/m(2); P > .05). Mean AHI (33.3 +/- 13.0 to 5.1 +/- 4.3; P < .0001) and mean ESS (10.3 +/- 5.2 to 6.0 +/- 4.4; P < .01) decreased significantly. Seventy percent (14/20) of patients achieved a treatment AHI <5, 85% (17/20) an AHI <10, and 95% (19/20) an AHI <15. Average stimulation amplitude was 1.89 +/- 0.50 V after titration. Adherence monitoring via device interrogation showed high rates of voluntary device use (mean 7.0 +/- 2.2 h/night). CONCLUSION: For a clinical and anatomical subset of patients with OSA, HNS therapy is associated with good objective adherence, low morbidity, and improved OSA outcome measures. Early results at one institution suggest that HNS therapy can be implemented successfully into routine clinical practice, outside of a trial setting. PMID- 26980909 TI - Clinical Examination of Tissue Eosinophilia in Patients with Chronic Rhinosinusitis and Nasal Polyposis. AB - OBJECTIVE: (1) Describe clinical and histopathologic findings in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). (2) Determine if tissue and serum eosinophilia predicts disease severity in CRSwNP. STUDY DESIGN: Case series with chart review. SETTING: Academic hospital specializing in respiratory and allergic disease. SUBJECTS: Patients with CRSwNP treated from 2008 to 2010. METHODS: Clinical data were collected; sinus computed tomography (CT) scans were scored according to the Lund-Mackay system; and surgical specimens were evaluated for degree of tissue eosinophilia. Statistical analysis was performed to compare eosinophilia with indicators of disease severity. RESULTS: Seventy CRSwNP patients were included, with a mean Lund-Mackay score of 16.7; 62.1% of patients had severe asthma, and 62.9% were aspirin sensitive. Elevated tissue eosinophil level did not correlate with medication usage, olfactory symptoms, or Lund-Mackay scores, nor did it correlate with presence of asthma or aspirin-sensitivity (P = .09). Patients with mild asthma had significantly more tissue eosinophils versus patients with severe asthma, possibly because of the high amount of chronic corticosteroid use in severe asthmatics. There was no correlation between tissue and serum eosinophil counts (P = .97), but there was a significant positive correlation between CT score and peripheral eosinophil level (P < .05). CONCLUSIONS: Higher serum eosinophil levels may indicate more extensive mucosal disease as measured on CT scan. Neither serum nor tissue eosinophilia predicted disease severity in our retrospective analysis of CRSwNP patients, and serum eosinophil level did not serve as a marker of tissue eosinophilia. PMID- 26980910 TI - Impact of Sensory and Motor Defects on Oral Function in an Animal Model. AB - OBJECTIVE: To evaluate the combined functional impact on swallowing of tongue sensory and motor loss using a rat model. STUDY DESIGN: Rats underwent selective neurectomies with transection of the motor (hypoglossal) nerve or motor and sensory (lingual) nerves. Postoperative functional parameters were followed for 2 weeks. SETTING: Translational research. SUBJECTS AND METHODS: Thirty-six adolescent male Wistar rats were divided into 4 groups: anesthetic (n = 6), sham surgery (n = 8), hypoglossal transection (n = 10), and hypoglossal and lingual transection (n = 12). Each morning on postoperative days 1 to 14, the water and food intake were quantified and the animal weighed. Two-way analyses of variance (SigmaPlot; SYSTAT, San Jose, California) were performed with factors of "group" and "postoperative day" (POD) to analyze whether a significant difference existed between water intake, pellet consumption, and weight change. RESULTS: The hypoglossal and lingual group consumed significantly less water during PODs 1 to 2 and significantly less food during PODs 1 to 3 than any other group. This established a significant difference in body weight between the hypoglossal and lingual group and all other groups for the duration of the study. Measured parameters in the hypoglossal group better approximated those of the control anesthetic and sham groups. CONCLUSIONS: The addition of a sensory loss to a motor deficit involving the oral tongue results in a measurably significant difference in weight gain, a marker of function, compared with rats with only a motor deficit. Additional studies are needed to determine if there would be similar findings in a model of sensate vs asensate oral tongue reconstruction. PMID- 26980911 TI - Use of Pericranial Flap Coverage in Cochlear Implantation of the Radical Cavity: Rationale, Technique, and Experience. AB - Cochlear implant (CI) surgery in the setting of an open mastoid cavity is evolving. Two strategies are commonly pursued: a staged approach, clearing the disease, closing the meatus or the external auditory canal (EAC), and reevaluating in 3 to 6 months prior to implantation, or a single-stage procedure with mastoid obliteration without EAC closure. Meatal closure is often employed in the setting of an open mastoid cavity to reduce the risk of electrode extrusion and infection. An open cavity offers the advantages of being a single stage procedure, permitting direct surveillance for recurrent cholesteatoma, and reducing the need for repeat computed tomography scans. We describe an approach to the coverage of a CI within a dry, open mastoid cavity using an anteriorly based postauricular pericranial flap. PMID- 26980912 TI - Effects of Cell-Based Therapy for Treating Tympanic Membrane Perforations in Mice. AB - OBJECTIVE: To investigate the effectiveness of scaffold-embedded mesenchymal stem cells (MSCs) as a topical treatment for healing tympanic membrane perforations (TMPs) in a mouse model. STUDY DESIGN: Prospective animal study. SETTING: Experimental. SUBJECTS AND METHODS: In vitro: under sterile conditions, porcine derived (Gelita-Spon [GS]), hyaluronate-derived (EpiDisc [ED]), and polyvinyl alcohol (PVA) scaffolds were cut into small pieces and cocultured with murine bone marrow-derived MSCs (BM-MSCs) expressing green fluorescent protein (GFP) for 72 hours. The cultures were either analyzed by confocal microscopy or used for subsequent in vivo experiments. In vivo: 26 mice were divided into 3 groups (ie, control [n = 9], GS [n = 8], ED [n = 9]). Under general anesthesia, TMPs of equal sizes were performed bilaterally using a sterile 27-gauge needle under a surgical microscope. The BM-MSCs embedded within GS or ED scaffolds were soaked in phosphate-buffered saline and then topically applied on right TMPs, and scaffolds alone were applied on left TMPs 6 to 8 hours after injury. Control mice did not receive treatment. On day 7, animals were euthanized and bullae were harvested for histological analysis. RESULTS: In vitro: BM-MSCs grew well on both GS (P = .0012) and ED (P = .0001) scaffolds compared with PVA. In vivo: 100% of untreated (control) TMPs remained open after 7 days. Animals treated with MSC-embedded ED scaffolds had a higher percentage of TMP closure (P = .016) and a thicker neotympanum (P = .0033) than control animals. The experimentally applied BM-MSCs engrafted and differentiated into epithelial cells suggested by the colocalized expression of cytokeratin-19 and GFP. CONCLUSIONS: The topical application of bone marrow-derived MSCs enhances the healing of TMPs in this animal model and is a promising alternative to tympanoplasty. PMID- 26980913 TI - Reconstruction of Lateral Skull Base Defects: A Comparison of the Submental Flap to Free and Regional Flaps. AB - OBJECTIVES: To compare reconstructive techniques, operative times, duration of hospitalization, and need for subsequent flap revisions between reconstructive approaches to lateral skull base defects. STUDY DESIGN: Case series with chart review. SETTING: Tertiary academic referral center. SUBJECTS: Patients (n = 31) undergoing reconstruction of composite lateral skull base defects from 2002 to 2014. METHODS: Data were analyzed for demographics, tumor characteristics, reconstructive technique, operative time, duration of hospitalization, complications, and outcomes. RESULTS: Thirty-one patients were identified for inclusion. Lateral temporal bone defects resulted from resection of malignant lesions, including squamous cell carcinoma (n = 25), basal cell carcinoma (n = 2), and other carcinoma (n = 4). Defects were reconstructed with submental flaps (n = 16), pedicled latissimus dorsi flaps (n = 6), and free anterolateral thigh flaps (n = 9). All cases involved neurosurgery, neurotology, and head and neck surgery services. Although time of surgical resection was similar, time saving was noticed with submental reconstruction. Compared with free flaps, submental flap reconstruction was associated with significantly reduced total operative time (mean, 544 vs 683 min; P = .00817) and duration of hospitalization (4.9 vs 9.8 days; P = .02067). Submental flaps were significantly less likely to require revision debulking procedures (mean = 0.6) compared with latissimus dorsi flaps (mean, 1.3; P < .00001) and free flaps (mean, 1.6; P < .00001). There was 100% flap survival. CONCLUSION: The musculocutaneous submental flap provides an excellent option for reconstruction of lateral skull base defects given its proximity, reliability, ease of harvest, and exceptional color match. Submental flap reconstruction was associated with reduced operative time, hospitalization duration, and flap revisions. PMID- 26980914 TI - Contralateral Vocal Fold Reactive Lesions: Nomenclature, Treatment Choice, and Outcome. AB - OBJECTIVE: Contralateral reactive lesions (RLs) represent a distinct entity among benign bilateral vocal fold (VF) lesions. Lack of uniform nomenclature and a myriad of surgical options have hampered attempts to develop treatment guidelines. The objective of this study is to better define RLs and their prognosis, through the development of a standard nomenclature, with an aim to guide treatment and delineate the role of phonosurgery. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care center. SUBJECTS AND METHODS: Analysis was performed on patients with Current Procedural Terminology code 31545. Operative reports with a primary lesion and contralateral RL were included. Outcomes included the Voice Handicap Index-10 (VHI-10) and GRBAS (grade, roughness, breathiness, asthenia, and strain) scale, lesion persistence/recurrence, mucosal wave, and edge character based on blinded videostroboscopy review. RESULTS: A nomenclature was developed based on intraoperative RLs (n = 30), defined by lesion consistency (fibrous or polypoid) and relationship to normal VF edge (gradual or steep). Reactive lesion treatment included no intervention, excision, potassium titanyl phosphate laser, steroid injection, or a combination thereof. Observations included the following: inconsistent treatment modalities were employed, excision of RLs did not yield better outcomes, fibrous RLs were more likely to persist and polypoid lesions more likely to recur, gradual lesions were more likely to remain disease free, and most treatments showed improved mucosal wave, VHI-10, and GRBAS. CONCLUSIONS: Reactive lesions have not been well classified, and treatments are based on subjective intraoperative decision making with unpredictable outcomes. The nomenclature proposed will allow for a better definition of the RL and provide a framework for future research to identify optimal treatment. PMID- 26980917 TI - Obstructive Sleep Apnea: Differences between Normal-Weight, Overweight, Obese, and Morbidly Obese Children. AB - INTRODUCTION: The severity of obstructive sleep apnea in children determines perioperative management and is an indication for postoperative polysomnography. The relationship between increasing weight and sleep apnea severity in children remains unclear. OBJECTIVES: To compare demographic, clinical, and polysomnography parameters in normal-weight, overweight, obese, and morbidly obese children, as well as identify demographic factors that predict sleep apnea severity. STUDY DESIGN: Case series with chart review. SETTING: Academic children's hospital. METHODS: A retrospective chart review of 290 children aged 2 to 18 years who underwent polysomnography at an academic children's hospital was performed. Demographics, clinical findings, and polysomnographic parameters were recorded. Children were categorized as normal weight, overweight, obese, or morbidly obese. Differences were assessed using linear and logistical regression models. Significance was set at P < .05. RESULTS: Morbidly obese were older than normal-weight children (mean, 8.0 +/- 0.5 years vs 5.8 +/- 0.3 years; P < .001) and less likely to have a normal polysomnogram (16% vs 48%; P = .02). There were no differences in sex, ethnicity, birth status (term or preterm), or tonsil size between normal-weight, overweight, obese, and morbidly obese children. Sleep efficiency and percentage of time in rapid eye movement were decreased in morbidly obese compared with other children (P < .05). The apnea-hypopnea index was positively correlated with increasing body mass index z score only as a function of increasing age (P < .001). CONCLUSION: Obstructive sleep apnea severity is correlated with a combination of increasing age and weight but not with either variable independently. This study suggests that obese and morbidly obese older children are most likely to have severe obstructive sleep apnea. PMID- 26980915 TI - Tumor Biomarkers in Spindle Cell Variant Squamous Cell Carcinoma of the Head and Neck. AB - OBJECTIVE: To determine biomarkers of recurrence and survival in patients with spindle cell variant squamous cell carcinoma (SpSCC) of the head and neck. STUDY DESIGN: Retrospective case control study. SETTING: Tertiary academic center. SUBJECTS AND METHODS: Thirty-two SpSCC patients (mean age, 68.8) between 1987 and 2009 were identified and reviewed. A tissue microarray (TMA) was constructed from tumor specimens. Tumor biomarkers under study included p16, epidermal growth factor receptor (EGFR), p53, EZH2, cyclin D1, CD104, HGFa, p21, and cMET. An additional TMA was constructed from patients with non-SpSCC oral cavity squamous cell carcinoma for comparative purposes. The main outcomes were overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS). RESULTS: In the SpSCC cohort, tumors positive for cMet had worse OS (P < .001). Patients positive for cMet (P = .007), cyclin D1 (P = .019), and p16 (P = .004) had worse DSS. Recurrence-free survival was also worse in patients with tumors positive for cMet (P = .037), cyclin D1 (P = .012), and p16 (P < .001). Compared with the oral cavity cohort, there was a significantly larger proportion of patients in the SpSCC group with tumors staining positive for cMet and a lower proportion of tumors positive for cyclin D1. CONCLUSION: cMet, cyclin D1, and p16 are predictive tumor biomarkers for risk of recurrence and worse DSS in patients with SpSCC. PMID- 26980916 TI - Efficacy of Upper Airway Stimulation on Collapse Patterns Observed during Drug Induced Sedation Endoscopy. AB - OBJECTIVE: To describe upper airway collapse patterns observed on drug-induced sedation endoscopy (DISE) during screening for a clinical trial and to evaluate the impact of collapse patterns found on preoperative DISE on response rates to upper airway stimulation (UAS) therapy. STUDY DESIGN: Retrospective review of an ongoing prospective multi-institutional cohort study. SETTING: Twenty-two participating institutions of the STAR trial. SUBJECTS AND METHOD: In total, 222 subjects were screened with DISE to determine eligibility for an implantable UAS device. Supine laryngoscopy was performed during moderate sedation (propofol and/or midazolam). Airway collapse pattern and severity were graded at 4 levels, including velum, oropharynx, tongue base, and epiglottis (VOTE classification). Patients with complete concentric collapse (CCC) at the velum were excluded from implantation. RESULTS: The CCC at the velum was observed in 52 (23%) of screened subjects, and these subjects were subsequently excluded from implantation. Of the 170 subjects without CCC at the velum, 126 (77%) underwent implantation: 121 (96%) had multilevel collapse and 5 (4%) had single-level collapse. When comparing preimplantation DISE findings, UAS responders at 12 months had lower baseline VOTE scores compared with therapy nonresponders. CONCLUSION: Drug induced sedation endoscopy is an efficient and safe method for determining UAS eligibility and has the potential to identify UAS nonresponders. Most patients had multilevel airway collapse, illustrating the limitations of single-level upper airway surgery in treating obstructive sleep apnea. Upper airway stimulation is effective therapy for most patients with multilevel airway collapse; however, patients with complete anterior-posterior or lateral soft palate and/or epiglottic collapse may be at increased risk of therapy failure. PMID- 26980918 TI - Salivary Duct Carcinoma of the Parotid: Outcomes with a Contemporary Multidisciplinary Treatment Approach. AB - OBJECTIVE: Salivary duct carcinoma (SDC) is a rare and aggressive malignancy for which an optimal treatment algorithm is lacking. We endeavored to assess the current treatment outcomes for SDC with a multimodality treatment approach combining surgery with adjuvant radiotherapy +/- concurrent chemotherapy. STUDY DESIGN: Case series with chart review. SETTING: A National Cancer Institute designated comprehensive cancer center. SUBJECTS AND METHODS: The clinical record of 17 patients with salivary duct carcinoma were analyzed to assess locoregional control, recurrence-free survival, and overall survival. RESULTS: All SDC cases (n = 17) were managed with surgical resection, followed by adjuvant radiotherapy (47.1%) or concurrent chemotherapy and radiotherapy (52.9%). Median patient follow up was 37 months. An aggressive disease course was generally observed, with 3-year recurrence-free survival and overall survival of 34.4% and 35.5%, respectively. The majority of recurrences were distant. Intensification with adjuvant concurrent chemotherapy was not associated with improved outcomes on univariate survival analysis. CONCLUSION: For salivary duct carcinoma, a multimodality treatment approach is associated with acceptable locoregional control rates but poor distant control and overall survival. Novel systemic therapies may be needed to optimize clinical outcomes. PMID- 26980919 TI - Oral Flurbiprofen Spray for Posttonsillectomy Pain. AB - OBJECTIVE: Tonsillectomy is still one of the most common surgical procedures, but there exists no standard guideline for pain management after tonsillectomy. Our aim is to determine whether oral spray of flurbiprofen reduces pain and has an influence on other morbid outcomes following tonsillectomy. STUDY DESIGN: Prospective, double-blind, randomized, placebo controlled. SETTING: Patients at Ataturk Training and Research Hospital, Ankara, Turkey. SUBJECTS AND METHODS: This study was performed on 84 patients (45 in flurbiprofen group, 39 in placebo group) who underwent tonsillectomy. The patients were randomly chosen, and each used oral spray of flurbiprofen 3 times daily or placebo solution at the same regimen. Efficacy was assessed by changes in Numeric Pain Rating Scale. Data were collected at postoperative days 1, 3, 5, and 7 for pain, bleeding, and healing. Data for Mallampati scores were also collected. RESULTS: There were no significant difference between groups with respect to the demographic data. The flurbiprofen group had statistically significant lower pain scores at days 1, 3, 5, and 7 (P = .000, P = .002, P = .001, P = .000, respectively). On days 3 and 7, pain scores were significantly different between different Mallampati groups (P = .049, P = .015, respectively). The flurbiprofen group required less analgesic than the placebo group during the study period on days 1, 3, 5, and 7 (P = .001, P = .001, P = .03, P = .001, respectively). Healing and side effects were not significantly different between the groups. CONCLUSION: In this study, topical use of flurbiprofen may reduce posttonsillectomy pain without any evidence of additional complications. PMID- 26980920 TI - Financial and Health Impacts of Multidisciplinary Aerodigestive Care. AB - OBJECTIVES: (1) Analyze upstream and downstream activity before and after enrollment with the Multidisciplinary Pediatric Aerodigestive Care Team (MPACT). (2) Identify potential demand for MPACT services with ICD-9 data. STUDY DESIGN: Retrospective review of financial claims data. SETTING: Tertiary care children's center. SUBJECTS: Pediatric patients (0-18 years old) enrolled with MPACT (pediatric otolaryngology, gastroenterology, pulmonary, speech-language pathology). METHODS: Case mix data from fiscal years (FYs) 2010-2013 were analyzed for primary, secondary, and tertiary ICD-9 codes in 4 aerodigestive diagnostic categories (ADCs): dysphagia, chronic cough, gastroesophageal disease, and chronic pulmonary disease/asthma. Inclusion criteria included patients <18 years old, seen by MPACT, with FY2010-FY2013 case mix data and >=2 ADCs. Unique outpatient and inpatient encounters and associated charges were evaluated to determine upstream and downstream activity trends. RESULTS: Of the 126 patients meeting inclusion criteria, 55 (44%) had >=3 ADCs, and 11 (9%) had 4. These 126 patients received outpatient care during 3068 unique encounters. Outpatient total charges were $282,102 before and $744,542 after MPACT intervention. Eighty-six (68%) patients received inpatient care during 423 unique encounters. Inpatient charges were $4,257,137 before and $2,872,849 after MPACT enrollment. Overall, a net reduction of $921,848 in total charges, $7316 per MPACT patient, was noted. FY2010-FY2014 data identified an additional 1728 pediatric patients with >=2 ADCs not enrolled in MPACT. CONCLUSION: A cohort of children with aerodigestive disease experienced a shift from inpatient to outpatient care with an overall 20% reduction in patient charges when the years before and after MPACT enrollment were compared. Available ICD-9 data suggest potential demand for MPACT services. PMID- 26980921 TI - Impact of Nodal Level Distribution on Survival in Oral Cavity Squamous Cell Carcinoma: A Population-Based Study. AB - OBJECTIVE: Regional lymph node metastasis is an important prognostic factor in squamous cell carcinoma of the head and neck, decreasing survival by up to 50%. Oral cavity squamous cell carcinoma (OC-SCCa) most commonly spreads to levels I, II, and III. STUDY DESIGN: Retrospective analysis of a population-based tumor registry. SETTING: Academic medical center. SUBJECTS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for cases of OC-SCCa from 2004 to 2011 (22,973 cases). Resulting data including patient demographics, clinicopathological features, topographical distribution of nodal metastasis, and survival based on lymph node level involvement were analyzed. RESULTS: In total, 8281 patients were identified with OC-SCCa who underwent neck dissection. Level I, closely followed by levels II and III, represented the most commonly involved nodal basins. The 5-year disease-specific survival (DSS) for patients with only level I, II, or III was 42.0% compared with 30.6% for the level IV group (P < .0001) and 26.4% for the level V group (P < .0001). Surgery with adjuvant radiotherapy improved 5-year DSS for patients with level I to III, level IV, and level V neck disease compared with surgery alone (50.7% vs 48.6%, P = .0109; 39.9% vs 23.2%, P < .0001; and 33.3% vs 9.1%, P = .0005, for levels I III, IV, and V, respectively). CONCLUSION: Oral cavity squamous cell carcinoma most commonly involves nodal levels I, II, and III. Involvement of nodal level IV or V portends a worse prognosis than patients with only level I to III disease, and multimodality therapy should be considered for these patients. PMID- 26980922 TI - An introduced parasitic fly may lead to local extinction of Darwin's finch populations. AB - Introduced pathogens and other parasites are often implicated in host population level declines and extinctions. However, such claims are rarely supported by rigorous real-time data. Indeed, the threat of introduced parasites often goes unnoticed until after host populations have declined severely. The recent introduction of the parasitic nest fly, Philornis downsi, to the Galapagos Islands provides an opportunity to monitor the current impact of an invasive parasite on endemic land bird populations, including Darwin's finches.In this paper we present a population viability model to explore the potential long-term effect of P. downsi on Darwin's finch populations. The goal of our study was to determine whether P. downsi has the potential to drive host populations to extinction and whether management efforts are likely to be effective.Our model is based on data from five years of experimental field work documenting the effect of P. downsi on the reproductive success of medium ground finch Geospiza fortis populations on Santa Cruz Island. Under two of the three scenarios tested, the model predicted medium ground finches are at risk of extinction within the next century.However, sensitivity analyses reveal that even a modest reduction in the prevalence of the parasite could improve the stability of finch populations. We discuss the practicality of several management options aimed at achieving this goal.Synthesis and applications. Our study demonstrates the predicted high risk of local extinction of an abundant host species, the medium ground finch Geospiza fortis due to an introduced parasite, Philornis downsi. However, our study further suggests that careful management practices aimed at reducing parasite prevalence have the potential to significantly lower the risk of host species extinction. PMID- 26980923 TI - Serum Galectin and Renal Dysfunction in ST-Segment Elevation Myocardial Infarction. AB - This study aimed to evaluate the association between serum galectin levels and renal dysfunction in relation to in-hospital prognosis and unfavorable prognosis 1 year after ST-elevated myocardial infarction (STEMI). Patients were assigned to two groups according to the cystatin C-based estimate of GFR on day 12 after STEMI: (1) STEMI patients with normal renal function (GFR based on cystatin C levels = 60 mL/min/1.73 m(2)) and (2) those with renal dysfunction (RD) (GFR based on cystatin C levels <60 mL/min/1.73 m(2)). A decrease in GFR estimated from the CKD-EPI equation on day 12 was more frequently found in patients with a reduced GFR based on cystatin C levels (41.9%) compared with those without RD (21.3%). Galectin levels exceeded the cut-off value (17.8 ng/mL) in 50.6% of cases in the group with GFR <60 mL/min/1.73 m(2) and in 32% of cases in the group with a normal GFR. The presence of RD and elevated galectin levels >17.8 ng/mL on day 12 after MI are independent predictors of an adverse prognosis at 1 year in STEMI patients. Elevated galectin levels are directly correlated with the presence of early postinfarction angina. PMID- 26980925 TI - Seventy Years of the Journal "Medical Archives". AB - This year journal "Medical Archives" celebrates 70th anniversary of its continuing publication. Medical Archives is oldest biomedical journal in Bosnia and Herzegovina and one of the oldest medical journals in Europe, established in the year 1947, as official scientific and professional journal of Association of Physicians of Bosnia and Herzegovina. Until present Medical Archives has published over 5000 articles. Today Medical Archives is internationally recognized medical peer-reviewed indexed journal, visible in more than 30 international on-line databases. PMID- 26980926 TI - Scientometric Analysis of Scientific Validity of Medical Archives Regarding Other Medical Journals in Bosnia and Herzegovina. AB - INTRODUCTION: Medical Archives is the oldest medical journal in Bosnia and Herzegovina (B&H) (founded in 1947.). A total of 104 articles were published in Medical Archives during 2015. Analyzing the type of articles, original articles are present in majority during 2015-80.7% (in last seven years, 561 (76%) were original out of 738). In last seven years, 651 (88.2%) articles were from the field of clinical medicine (preclinical disciplines, in the last three years are more represented than in previous years). Collaboration rate in 2015 was 0,92. Articles written in collaboration of five authors (21.1 %) are found to be predominant. From year to year, most often required time for a decision on acceptance or on the revision prior acceptance is between 50 and 60 days (30% of cases in 2015). During 2015, 47.1% of articles were originally from B&H (eleven countries were represented). H index of Medical Archive for 2014 was 12, and does not vary during the last decade. FINDINGS: In 2015 in B&H about twenty-five journals are issued in the field of biomedical and life sciences in general (six are indexed on Medline/PubMed, one is indexed in the Science Citation Index Expanded (SCIE)/Web of Science base). According to GoogleScholar the biggest h5 index has Bosnian Journal of Basic Medical Sciences (BJBMS) and Medical Archives, while the biggest h5 median has BJBMS i Acta Informatica Medica. The highest H index (13) in B&H has Izet Masic MD, PhD, Enver Zerem MD, PhD and Semir Vranic MD, PhD, while highest g-index (22) has Enver Zerem MD, PhD (analyzed by software package "Publish or Perish"). CONCLUSION: By comparing the state of medical publishing in B&H with neighboring countries (Croatia, Serbia, Montenegro), we have concluded that B&H is behind Croatia and Serbia by following parameters: Total Documents, Total Cites and H index but in front of Montenegro. PMID- 26980927 TI - The Significance of Bronchoalveolar Lavage Fluid Cytology in Diagnosing Lung Infiltrates in Children. AB - AIM: The aim of this research is to show why is it important in diagnosing children with lung infiltrates. METHODS: Our study included 50 children with lung infiltrates during period 2005-2012, and was conducted on Pediatric Clinic of the University Clinical Center Sarajevo. We sent all cytological BAL analyses to the University Clinical Center Sarajevo. Cytology was performed by direct microscopy. BAL cytology was performed by the principle of sending samples for centrifuging, 12000 revolutions during a 10 min Shandon-cyto spin. Then the centrifuged sample is dried in the air during 1-2 hours, and is then dyed under the May-Grunwald Giemsa staining, and analyzed under the Olympus BX41 microscope. RESULTS: Nosocomial pneumonia has occurred in 32% children, acquired pneumonia in 38%, and 30% children had a lung infiltrates. 6 (12%) of children were younger then 1 year old, 23 (46%) children were between 1 to 5 years, 14 (28%) of children were between 5 to 10 ages, and 7 (14%) of children were between 10-15 ages. The most of the changes in observed children took place on the right lung, 34%, while 26% occurred on the left side, 22% were normal and 18% changes have affected both lungs, right and left. Percentage of cells in cytological smear in children with BAL were: cylindrical cells 28%, lung macrophage 26%, lymphocytes 17%, detritus 17% and phlegm 12%. Erythrocyte sedimentation rate (ESR) in children with BAL was up to 10-52%, to 50-30%, while ESR after first hour was above 50-18 %. CONCLUSION: Clinical parameters and local inflammation of the affected lobe are associated with positive bronchoalveolar cytology lavage findings. PMID- 26980928 TI - Renalase Gene rs2576178 Polymorphism in Hemodialysis Patients: Study in Bosnia and Herzegovina. AB - INTRODUCTION: Renalase is a protein secreted in kidneys and considered as a blood pressure modulator. High rates of hypertension and its regulation in patients on hemodialysis demands search for potential cause and treatment. The aim of this study was to determine the genotype and allele frequencies of renalase gene rs2576178 polymorphism in population from Bosnia and Herzegovina. Also, the objective of present study was to find the possible association between renalase gene rs2576178 polymorphism and hypertension in patients on hemodialysis. MATERIAL AND METHODS: The genotype of renalase gene rs2576178 polymorphism was determined in 137 participants (100 patients on hemodialysis and 37 controls), using polymerase chain reaction (PCR) and subsequent cleavage with MspI restriction endonuclease. Genotype and allele frequencies were assessed for Hardy Weinberg equilibrium using a Chi-squared test. The value of P<0.05 was considered as statistically significant. RESULTS: Comparison of genotype distribution and allele frequency in participants on hemodialysis with and without hypertension, and healthy control showed no statistical difference. CONCLUSION: The results of the study suggest that renalase gene rs2576178 polymorphism is not a factor that influences blood pressure in patients on hemodialysis. PMID- 26980924 TI - A Pathophysiologic Approach to Biomarkers in Acute Respiratory Distress Syndrome. AB - Acute respiratory distress syndrome (ARDS) is an acute-onset hypoxic condition with radiographic bilateral lung infiltration. It is characterized by an acute exudative phase combining diffuse alveolar damage and lung edema followed by a later fibroproliferative phase. Despite an improved understanding of ARDS pathobiology, our ability to predict the development of ARDS and risk-stratify patients with the disease remains limited. Biomarkers may help to identify patients at the highest risk of developing ARDS, assess response to therapy, predict outcome, and optimize enrollment in clinical trials. After a short description of ARDS pathobiology, here, we review the scientific evidence that supports the value of various ARDS biomarkers with regard to their major biological roles in ARDS-associated lung injury and/or repair. Ongoing research aims at identifying and characterizing novel biomarkers, in order to highlight relevant mechanistic explorations of lung injury and repair, and to ultimately develop innovative therapeutic approaches for ARDS patients. This review will focus on the pathophysiologic, diagnostic, and therapeutic implications of biomarkers in ARDS and on their utility to ultimately improve patient care. PMID- 26980929 TI - Investigation of Cardiac Complications and their Incidence in Patients with Ankylosing Spondylitis. AB - INTRODUCTION: Ankylosing Spondylitis (AS) is a chronic inflammatory disease with unknown etiology which involves the sacroiliac and axial joints, but can also cause peripheral conflicts. It also comprises non-joint symptoms such as acute anterior uveitis, cardiac conduction defects, upper lobe pulmonary fibrosis, neurological involvement and renal amyloidosis. MATERIAL AND METHODS: This study was a cross-sectional descriptive and analytical survey. In this study, 50 patients with AS were examined according to the New York Criteria in Army 501 Hospital in Tehran. Physical examinations, laboratory testing and HLA-B27, as well as X-ray of the spine and sacroiliac joint were taken from all subjects and involvement grading was identified. The control group consisted of 40 healthy people with no evidence of disease. The people resembled the study group in terms of age, sex, smoking, presence of high blood pressure, history of ischemic heart disease and also diabetes. RESULTS: The mean age of patients in control and study group was 33.97 and 33.65 years, respectively. 37 (92.5%) patients in the control group and 46 in study group (92%) were male. The mean duration of cardiac involvement in patients was 8.6 years with SD=6.26. In AS group, 48 (96%) patients suffered from back pain, 43 from enteritis, 100% from Ankylosing Spondylitis, one from unilateral involvement, 22(44%) from peripheral arthritis and 27 (54%) from HLA-B27. CONCLUSION: In total, Average heart involvement in the control group and AS group was 13.25 with SD=7.64 and 16.2 with SA=8.54, respectively, indicating no significant difference. In sum, based on the results obtained in this study, some types of heart involvements, such as mitral valve regurgitation and Mitral Valve Prolapse in AS patients are more prevalent than in the normal population. PMID- 26980930 TI - The Effects of Total Motile Sperm Count on Spontaneous Pregnancy Rate and Pregnancy After IUI Treatment in Couples with Male Factor and Unexplained Infertility. AB - INTRODUCTION: Male infertility factor is defined if the total number of motile spermatozoa (TMSC) < 20 * 10(6)/ejaculated, and unexplained infertility if spermiogram is normal with normal female factor. THE AIM: of this study was to determine the predictive value of TMSC for spontaneous pregnancy (ST) and pregnancy after treatment with intrauterine insemination (IUI) in couples with male factor and unexplained infertility. WHAT IS KNOWN ALREADY: According to the WHO qualification system abnormal spermiogram can be diagnosed as oligozoospermia (O), asthenozoospermia (A), teratozoospermia (T) or combination (O+A+T) and azoospermia (A). Although this classification indicates the accuracy of findings its relevance for prognosis in infertile couple and the choice of treatment is questionable. MATERIALS AND METHODS: The study included 98 couples with male infertility factor (bad spermiogram) and couples with normospermia and normal female factor (unexplained infertility). Testing group is randomized at: group (A) with TMSC> 3,10(6) / ejaculate and a spontaneous pregnancy, group (B) with TMSCl <3 x 10(6) / ejaculate and pregnancy after IUI, plus couples who have not achieved SP with TMSC> 3 x 10(6) / ejaculate and couples who have not achieved pregnancy. MAIN RESULTS: From a total of 98 pairs of men's and unexplained infertility, 42 of them (42.8%) achieved spontaneous pregnancy, while 56 (57.2%) pairs did not achieve spontaneous pregnancy. TMSC was significantly higher (42.4 +/- 28.4 vs. 26.2 +/- 24, p <0.05) in the group A compared to group B. Couples with TMSC 1-5 * 10(6) ejaculate had significantly lower (9.8% vs. 22.2%, p <0.0001) rate of spontaneous pregnancy in comparison to couples after IUI treatment. Couples with unexplained infertility had significantly higher (56.8% vs. 29.9%, p <0.01) spontaneous pregnancy rate compared to couples after IUI treatment. Infertile couples had significant pregnancy rate with TMSC 5-10 x 10(6) / ejaculate (OR = 1.45, 95% CI:1.26-1.78, <0.01); with TMSC 10-20 x 10(6) / ejaculate (OR = 1.36, 95% CI: 1:12 to 1:46, <0.0001) with TMSC> 20 x 10(6) / ejaculate (RR = 1.7, 95% CI: 1.56-1.82, <0.001) after treatment with IUI compared to spontaneous pregnancy. CONCLUSION / INTERPRETATION: Based on these results we can conclude that couples with the TMSC> 5 x 10(6) / ejaculate are indicated for treatment with IUI. TMSC can be used as the method of choice for diagnosis and treatment of male infertility. PMID- 26980931 TI - Elevated Liver Enzymes in Cases of Preeclampsia and Intrauterine Growth Restriction. AB - AIM: The aim of this study was to evaluate biochemical parameters in serum of women with preeclampsia and IUGR. MATERIAL AND METHODS: A clinical prospective study was conducted and included 120 pregnant women divided in two groups: non IUGR group included healthy pregnant women (n=60) and IUGR group included pregnant women with preeclampsia and IUGR (n=60). Outcome measures were following values of biochemical parameters in serum of mother and fetuses: aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), bilirubin (indirect and direct) and cholesterol. A blood for analysis was drawn from the cubital vein of mothers and the umbilical vein of the fetuses during delivery period. RESULTS: The mean of maternal age was 30.0+/-6.1 years in women with preeclampsia and IUGR and 28.1+/-5.1 years in healthy pregnant women, p > 0.05. The most of women with preeclampsia and IUGR had grade III of placental maturation (48.3%). There is a significant association between the placental maturation and the diagnosis, p < 0.001. There was a statistically significant difference in body mass of newborns between IUGR and non IUGR groups, p < 0.001. There was a significant statistically difference in serum value of AST, ALT, LDH and total cholesterol between women with preeclampsia and IUGR and healthy pregnant women (all p < 0.001). CONCLUSION: Measurement of AST, ALT, LDH, and total cholesterol in serum of pregnant women and newborns with IUGR allows the differentiation and threatening risk of perinatal complications due to hypoxia. PMID- 26980932 TI - Prognostic Significance of Ascites and Serum Sodium in Patients with Low Meld Scores. AB - OBJECTIVE: to determine ascites and serum sodium significance in short term mortality prediction in patients with advanced liver cirrhosis. METHODS: a cohort of 115 cirrhotic patients referred to our Department were followed up for 6 months in non-transplant settings. The c index equivalent to the area under the receiver operating curve (ROC) was calculated and compared to estimate the short term prognostic accuracy of the following parameters: ascites, serum sodium and MELD score. RESULTS: in patients with a MELD score less than 21, ascites and low serum sodium (c index 0,687, p<0 0,001 and 0,748, p<0,001 respectively) showed better prognostic accuracy and were independent predictors of mortality. For MELD scores above 21, only MELD was an independent mortality prognostic factor (c index 0,710, p<0,001). CONCLUSION: in our study, sample ascites and low serum sodium help identify patients with advanced liver disease who are at high risk of mortality despite low MELD scores. These parameters should be considered as additional prognostic parameters that could improve available treatment options and outcomes in this group of patients. PMID- 26980934 TI - Vancomycin-Resistant Pseudomonas Aeroginosa in the Cases of Trauma. AB - BACKGROUND: One of the main problems in the treatment of cases of P. aeruginosa especially in the orthopedic infections is the occurrence of high antibiotic resistance. The present study was carried out in order to investigate the prevalence of vancomycin-resistant P. aeruginosa in the cases of trauma in Iran. METHODS: Two hundred and fifty swab samples were collected from the site of trauma from the patients who referred to the orthopedic wards of the Iranian health centers. Samples were cultured immediately and those that were P. aeruginosa-positive were analyzed by the disk diffusion method. RESULTS: Of 250 swab samples collected, 43 were positive for P. aeruginosa (17.2%). The results of the culture technique were also confirmed by the PCR reaction. Of 43 P. aeruginosa isolates, 32 strains (74.41%) were resistant to vancomycin. Total prevalence of bacteria in Tehran and Mashhad hospitals were 18.46% and 15.83%, respectively. Statistically significant difference was seen for the prevalence of vancomycin-resistant P. aeruginosa between the samples collected from Tehran and Mashhad (P =0.027). More than 55 years old and less than 10 years old patients had the highest prevalence of P. aeruginosa. P. aeruginosa strains of male and more than 55 years old patients harbored the highest levels of resistance against vancomycin. CONCLUSIONS: It is logical to primary identification of type of bacteria causing infection in the site of trauma and then using from the disk diffusion method to choose the best antimicrobial agent. Highest levels of health care should be performed for the patients less than 10 years and more than 55 years old patients. PMID- 26980935 TI - Factors Beyond the Language Barrier in Providing Health Care to Immigrant Patients. AB - BACKGROUND: Due to the enormous migration as the result of war and disasters during the last decades, health systems in Europe are faced with various cultural traditions and both healthcare systems and healthcare professionals are challenged by human rights and values. In order to minimize difficulties in providing healthcare services to patients with different cultural backgrounds, cultural competence healthcare professionals are needed. MATERIAL AND METHODS: Four focus group interviews, were conducted with Kurdish immigrants in Scandinavian countries (N=26). The majority were males (n=18) aged between 33-61 years (M= 51.6 years) and a few were (n=8) females aged 41-63 years (M=50.7 years). The data were analyzed by using qualitative content analysis method. RESULTS: According to the study results participants experienced that diversities both in culture and healthcare routines create a number of difficulties regarding contact with healthcare services. Though culture related aspects influenced the process of all contact with health care services, the obstacles were more obvious in the case of psychological issues. The results of the study showed that cultural diversities were an obvious reason for immigrants' attitudes regarding healthcare services in resettlement countries. CONCLUSION: The results of the study revealed a number of difficulties beyond linguistic problems regarding immigrants' contact with healthcare services in Scandinavian countries. Problems were rooted both in diversities in healthcare services and cultural aspects. Immigrants' views of healthcare systems and healthcare professionals' approach in providing healthcare were some of the problems mentioned. PMID- 26980933 TI - Comparing the Intramedullary Nailing Method Versus Dynamic Hip Screw in Treatment of Unstable Intertrochanteric Fractures. AB - INTRODUCTION: Dynamic Hip Screw fixation is currently considered as a standard treatment for pre-trochanteric fractures; however, due to the long-term hospitalization and some other complications, some researchers have proposed intramedullary nailing as the alternative surgical treatment. The aim of this study was to compare and examine the consequences of the using intramedullary nailing method versus Dynamic Hip Screw. METHODS: In this study 114 patients with unstable Intertrochanteric fracture refer to Rasoul Akram hospital during 2011 to 2013 has been selected. After reduction, fixation surgery with PFN nail (60 patients) and Dynamic Hip Screw (54 patients) has been performed. All patients were screen during surgery and six months after surgery and some parameters like, bleeding, union, as well as complications such as collapse, varus and medialization of the distal fragment were record and patients. RESULTS: About some parameters like cutting length, surgery duration, bleeding there were significant differences between two groups. In six months follow up period 2 patinas from nail and 8 patients from DHS group had non-union. Also from the point of radiologic and clinical parameters, like anterior thigh pain, cut out, medialization of the distal fragment, collapse of the neck, walking recovery and daily activities were significant between two groups. CONCLUSION: Due to the reduced hospital stay in intramedullary nailing method and the necessity of doing repeated surgery and applying intramedullary nailing when the patients are not treated with external fixation, the researchers recommend intramedullary nailing as the first option in treating such patients. PMID- 26980936 TI - Correlation of Osteoporosis and Calcium Urolithiasis in Adult Population. AB - INTRODUCTION: Scientific studies indicate that there is a correlation between decreased bone mineral density and the age of the patient, especially in post menopausal women. GOAL: The aim of our study was to assess the connection between osteoporosis and the age of respondents, based on the DEXA findings in patients with calcium urolithiasis. MATERIAL AND METHODS: The study was prospectively and conducted in University Clinical Center Banja Luka, at the Urology Clinic and Clinic of Internal Medicine. In this study the respondents were divided into two groups: experimental group-subjects with calcium urolithiasis and control group without calcium urolithiasis. The study included 240 patients, in both groups of 120 patients who were divided into three age groups: 20-40 years, 40-60 years and more than 60 years. In both groups of respondents was conducted determination of bone mineral density in L2-L4 vertebra lumbar spine and hip by DEXA method. RESULTS: Observing the whole sample of the experimental group, according to age groups it can be noticed that DEXA results are at 72.5% normal, 27.5% below expected value, more in women within older subgroups, 20% show signs of osteopenia and osteoporosis in 7.5 %. Share of patients with osteoporosis is statistically different (p<0.05) only between sub-groups 20-40 years and over 60 years. Although appears absolute difference in the participation of patients with osteopenia by age groups, the differences are not statistically significant (p>0.05). The share of patients with normal DEXA values was significantly lower in the group over 60 years compared to the other two age groups (p<0.05). At age subgroups of the control group, the youngest group of respondents share with normal DEXA finding is 95% and among the oldest group (over 60 years) this share is much lower and is 60%, which represents a statistically significant difference, and confirms the relationship (p<0.01). Normal DEXA findings decreases with increasing years, the share of those who do not have normal findings is higher in the elderly population. CONCLUSION: Our study has just shown that in adult patients with calcium urolithiasis osteoporosis is more prevalent in older patients and more pronounced in patients with calcium urolithiasis in relation to the population without the same. PMID- 26980937 TI - Spontaneous Splenic Rupture Following Intravenous Thrombolysis with Alteplase Applied as Stroke Therapy - Case Report and Review of Literature. AB - INTRODUCTION: Stroke is a medical emergency in neurology, and is one of the leading causes of death nowadays. At a recent time, a therapeutic method used in adequate conditions is thrombolysis, a treatment of an emerging clot in the brain vascular system by alteplase. The application of alteplase also has a high risk of life threatening conditions. CASE REPORT: This is a brief report of a case with thrombolysis complication which manifested as a spleen rupture. PMID- 26980938 TI - The Uncommon Localization of Herpes Zoster. AB - INTRODUCTION: Herpes zoster is an acute, cutaneous viral infection caused by the reactivation of varicella-zoster virus (VZV) that is the cause of varicella. It is an acute neurological disease which can often lead to serious postherpetic neuralgia (PHN). Different nerves can be included with the skin rash in the area of its enervation especially cranial nerves (CV) and intercostal nerves. CASE REPORT: In this report we present a patient with herpes zoster which involved ulnar nerve with skin rash in the region of ulnar innervations in women with no disease previously diagnosed. The failure of her immune system may be explained by great emotional stress and overwork she had been exposed to with neglecting proper nutrition in that period. CONCLUSION: Herpes zoster may involve any nerve with characteristic skin rash in the area of its innervations, and failure in immune system which leads reactivation of VZV may be caused by other factors besides the underlying illness. PMID- 26980939 TI - Aspergilloma Mimicking Metastasis in a Case with Laryngeal Carcinoma. AB - INTRODUCTION: Aspergilloma is a fungal ball which is composed of hyphal structure fungus, fibrin, mucus and cellular debris and settled in a pre-existing pulmonary cavity or an ectatic bronchial. It may cause colonization in patients with an immunosuppressive and underlying lung disease. Although chest radiography provides valuable information, it can be scanned more effectively by computed tomography (CT). Monitoring fungal ball within the cavity in CT provides establishing the diagnosis. CASE REPORT: However, in this case report, we presented a case with operated laryngeal carcinoma whom we first had considered to have metastasis and who had received a diagnosis of aspergilloma in CT and Positron emission tomography (PET). CONCLUSION: Imaging findings may remain limited in definitive diagnosis of aspergilloma. Therefore, surgical resection will allow for both pathological diagnosis and treatment. PMID- 26980940 TI - A Cause of Mortal Massive Upper Gastrointestinal Bleeding: Aortoesophageal Fistula. AB - INTRODUCTION: Aortoesophageal fistula is an uncommon but mortal cause of massive upper gastrointestinal bleeding. The most common causes are thoracic aortic aneurisym, foreign body reaction, malignancy and postoperative complication. It can be seen in different pattern on upper gastrointestinal endoscopy. There are surgical, endoscopic and interventional radiological treatment options, however, definitive treatment is surgical intervention. Diagnosis and treatment desicion should be made quickly because of rapid and mortal course. CASE REPORT: In this article, a case of aortoesophageal fistula was presented that resulted in mortality as a result of massive bleeding. PMID- 26980941 TI - Erratum: Non-Small-Cell Lung Cancer: Treatment of Late Stage Disease: Chemotherapeutics and New Frontiers. AB - [This corrects the article DOI: 10.1055/s-0033-1342961.]. PMID- 26980942 TI - Predictors for Return to Work in Subjects with Mild Traumatic Brain Injury. AB - Objective. To predict return to work (RTW) at 12 months for patients who either were sick-listed or were at risk to be sick-listed with persistent postconcussion symptoms (PCS) at six to eight weeks after injury. Method. A prospective cohort study of 151 patients with mild traumatic brain injury (MTBI) admitted consecutively to outpatient clinics at two University Hospitals in Norway. The study was conducted as part of a randomised clinical trial. Injury characteristics were obtained from the medical records. Sick leave data from one year before to one year after MTBI were obtained from the Norwegian Labour and Welfare Service. Self-report questionnaires were used to obtain demographic and symptom profiles. Results. We observed a significant negative association between RTW at 12 months and psychological distress, global functioning, and being sick listed at two months after MTBI, as well as having been sick-listed the last year before injury. Conclusion. Psychological distress, global functioning postinjury, and the sick leave trajectory of the subjects were negative predictors for RTW. These findings should be taken into consideration when evaluating future vocational rehabilitation models. PMID- 26980943 TI - Dietary Cocoa Powder Improves Hyperlipidemia and Reduces Atherosclerosis in apoE Deficient Mice through the Inhibition of Hepatic Endoplasmic Reticulum Stress. AB - Cocoa powder is rich in flavonoids, which have many beneficial effects on human health, including antioxidative and anti-inflammatory effects. The aim of our study was to investigate whether the intake of cocoa powder has any influence on hyperlipidemia and atherosclerosis and examine the underlying molecular mechanisms. We fed apoE knockout mice a Western diet supplemented with either 0.2% (low group) or 2% (high group) cocoa powder for 12 weeks. The groups fed dietary cocoa powder showed a significant reduction in both plasma cholesterol levels and aortic atherosclerosis compared to the control group. Analysis of mRNA profiling of aortic atherosclerotic lesions revealed that the expression of several genes related to apoptosis, lipid metabolism, and inflammation was significantly reduced, while the antiapoptotic gene Bcl2 was significantly increased in the cocoa powder group compared to the control. RT-PCR analysis along with Western blotting revealed that a diet containing cocoa powder inhibited the expression of hepatic endoplasmic reticulum stress. These data suggest that cocoa powder intake improves hyperlipidemia and atherosclerosis, and such beneficial effects are possibly mediated through the suppression of hepatic endoplasmic reticulum stress. PMID- 26980945 TI - Altered Autophagy-Associated Genes Expression in T Cells of Oral Lichen Planus Correlated with Clinical Features. AB - Oral lichen planus (OLP) is a T cell-mediated inflammatory autoimmune disease. Autophagy has emerged as a fundamental trafficking event in mediating T cell response, which plays crucial roles in innate and adaptive immunity. The present study mainly investigated the mRNA expression of autophagy-associated genes in peripheral blood T cells of OLP patients and evaluated correlations between their expression and the clinical features of OLP. Five differentially expressed autophagy-associated genes were identified by autophagy array. Quantitative real time RT-PCR results confirmed that IGF1 expression in the peripheral blood T cells of OLP patients was significantly higher than that in controls, especially in female and middle-aged (30-50 years old) OLP patients. In addition, ATG9B mRNA levels were significantly lower in nonerosive OLP patients. However, no significant differences were found in the expression of HGS, ESR1, and SNCA between OLP patients and controls. Taken together, dysregulation of T cell autophagy may be involved in immune response of OLP and may be correlated with clinical patterns. PMID- 26980944 TI - Metabolism Is Central to Tolerogenic Dendritic Cell Function. AB - Immunological tolerance is a fundamental tenant of immune homeostasis and overall health. Self-tolerance is a critical component of the immune system that allows for the recognition of self, resulting in hyporeactivity instead of immunogenicity. Dendritic cells are central to the establishment of dominant immune tolerance through the secretion of immunosuppressive cytokines and regulatory polarization of T cells. Cellular metabolism holds the key to determining DC immunogenic or tolerogenic cell fate. Recent studies have demonstrated that dendritic cell maturation leads to a shift toward a glycolytic metabolic state and preferred use of glucose as a carbon source. In contrast, tolerogenic dendritic cells favor oxidative phosphorylation and fatty acid oxidation. This dichotomous metabolic reprogramming of dendritic cells drives differential cellular function and plays a role in pathologies, such as autoimmune disease. Pharmacological alterations in metabolism have promising therapeutic potential. PMID- 26980949 TI - From the Author's desk. PMID- 26980950 TI - From the Editor's desk. PMID- 26980948 TI - Inhibition of P38 MAPK Downregulates the Expression of IL-1beta to Protect Lung from Acute Injury in Intestinal Ischemia Reperfusion Rats. AB - Acute lung injury (ALI) induced by intestinal ischemia/reperfusion (II/R) has high incidence and mortality, in which IL-1beta was essential for the full development of ALI. However, the detailed regulating mechanism for this phenomenon remains to be unclear. The purpose of this study was to investigate whether inhibition of P38 MAPK could downregulate the expression of IL-1beta to protect lung from acute injury in II/R rats. Here, we found that the level of pulmonary edema at 16 hours after operation (hpo) was obviously enhanced compared to that in 8hpo and sham groups. Immunofluorescent staining demonstrated that IL 1beta and P38 MAPK were detected in lung tissues. And rats with II/R have the highest translation level for IL-1beta and phosphorylation of P38 MAPK in lung tissues at 16hpo compared with 8hpo and sham groups. Moreover, administration of SB239063, an inhibitor of P38 alpha and beta, could effectively downregulate the expressions of IL-1beta and protects lung tissues from injury in II/R rats. Our findings indicate that the inhibition of P38 alpha and beta may downregulate the expression of IL-1beta to protect lung from acute injury in II/R, which could be used as a potential target for reducing ALI induced by II/R in the future clinical trial. PMID- 26980951 TI - Cancer Conundrum. PMID- 26980952 TI - The Azzopardi phenomenon. PMID- 26980947 TI - Cancer Stem Cells and Macrophages: Implications in Tumor Biology and Therapeutic Strategies. AB - Cancer stem cells (CSCs) are a unique subset of cells within tumors with stemlike properties that have been proposed to be key drivers of tumor initiation and progression. CSCs are functionally defined by their unlimited self-renewal capacity and their ability to initiate tumor formation in vivo. Like normal stem cells, CSCs exist in a cellular niche comprised of numerous cell types including tumor-associated macrophages (TAMs) which provides a unique microenvironment to protect and promote CSC functions. TAMs provide pivotal signals to promote CSC survival, self-renewal, maintenance, and migratory ability, and in turn, CSCs deliver tumor-promoting cues to TAMs that further enhance tumorigenesis. Studies in the last decade have aimed to understand the molecular mediators of CSCs and TAMs, and recent advances have begun to elucidate the complex cross talk that occurs between these two cell types. In this review, we discuss the molecular interactions that define CSC-TAM cross talk at each stage of tumor progression and examine the clinical implications of targeting these interactions. PMID- 26980946 TI - Pathogen-Associated Molecular Patterns Induced Crosstalk between Dendritic Cells, T Helper Cells, and Natural Killer Helper Cells Can Improve Dendritic Cell Vaccination. AB - A coordinated cellular interplay is of crucial importance in both host defense against pathogens and malignantly transformed cells. The various interactions of Dendritic Cells (DC), Natural Killer (NK) cells, and T helper (Th) cells can be influenced by a variety of pathogen-associated molecular patterns (PAMPs) and will lead to enhanced CD8(+) effector T cell responses. Specific Pattern Recognition Receptor (PRR) triggering during maturation enables DC to enhance Th1 as well as NK helper cell responses. This effect is correlated with the amount of IL-12p70 released by DC. Activated NK cells are able to amplify the proinflammatory cytokine profile of DC via the release of IFN-gamma. The knowledge on how PAMP recognition can modulate the DC is of importance for the design and definition of appropriate therapeutic cancer vaccines. In this review we will discuss the potential role of specific PAMP-matured DC in optimizing therapeutic DC-based vaccines, as some of these DC are efficiently activating Th1, NK cells, and cytotoxic T cells. Moreover, to optimize these vaccines, also the inhibitory effects of tumor-derived suppressive factors, for example, on the NK-DC crosstalk, should be taken into account. Finally, the suppressive role of the tumor microenvironment in vaccination efficacy and some proposals to overcome this by using combination therapies will be described. PMID- 26980953 TI - Epstein-Barr virus and its association with rheumatoid arthritis and oral lichen planus. AB - CONTEXT: Pathogenesis of autoimmune diseases (AD) is one of a multifactorial milieu. A genetic predisposition, an immune system failure, hormonal imbalance and environmental factors play important roles. Among the many environmental factors, the role of infection is gaining importance in the pathogenesis of various autoimmune disorders; among them, Epstein-Barr virus (EBV) plays a pivotal role. Literature states an association of various AD with EBV namely multiple sclerosis, autoimmune thyroiditis, systemic lupus erythematous, oral lichen planus (OLP), rheumatoid arthritis (RA), autoimmune hepatitis, Sjogren's syndrome and Kawasaki disease; among these, the most commonly occurring are OLP and RA. AIM: Considering the frequency of occurrences, our aim was to perform a qualitative analysis of EBV viral capsid antigen (EBV VCA) IgG in the sera of patients with RA, OLP and establish a comparison with normal. SETTINGS AND DESIGN: In-vitro experiment in a research laboratory. SUBJECTS AND METHODS: Five milliliter blood sample was collected from 25 patients diagnosed with RA and OLP. Serum was separated and EBV VCA IgG antibody titer was detected using NovaTec EBV VCA IgG ELISA kit. STATISTICAL ANALYSIS USED: Chi-square test. RESULTS: Six out of 25 subjects with RA and 4 out of 25 subjects with OLP tested positive for EBV VCA IgG. CONCLUSIONS: Both environmental and genetic factors are important contributory components for autoimmune conditions. Screening for viral etiology would improve the efficacy of conventional treatment and reduce the risk of relapses. PMID- 26980954 TI - Role of tissue eosinophils in oral Leukoplakia: A pilot study. AB - CONTEXT: Tissue eosinophilia in oral squamous cell carcinoma has been well - recognized. Studies have reported both favorable and unfavorable prognoses associated with tissue eosinophils in oral squamous cell carcinoma. However, the role of eosinophils in the development of tumor is still unclear. AIMS: The present study was an attempt to elucidate the potential role of tissue eosinophils in oral leukoplakia, a potentially malignant lesion. SETTINGS AND DESIGN: To count eosinophils in tissues of normal subjects and oral leukoplakia cases. To compare tissue eosinophil count (TEC) between normal and oral leukoplakia cases. To compare TEC between dysplastic and non-dysplastic cases of oral leukoplakia and to correlate with degree of epithelial dysplasia. MATERIALS AND METHODS: A total of 85 cases (59 cases of oral leukoplakia and 26 normal oral tissues) constituted the study material. Tissue eosinophils were counted in 10 different high- power fields. STATISTICAL ANALYSIS USED: Non-parametric tests (Mann-Whitney U-test, Kruskal-Wallis test, Mann-Whitney post hoc analysis and Spearman's correlation statistics). RESULTS: Mean eosinophil count (MEC) in oral leukoplakia cases was significantly more when compared to normal subjects. MEC in dysplastic cases of oral leukoplakia was significantly more when compared to those without epithelial dysplasia (Mann-Whitney U-test). Furthermore, MEC was directly proportional to the degree of epithelial dysplasia (Spearman's correlation statistics). CONCLUSIONS: TEC may be used as an adjunct to predict the malignant transformation of dysplastic cases of oral leukoplakia. Eosinophilic infiltration in oral dysplastic cases should prompt a thorough evaluation for invasiveness, especially when features of invasion are absent or suspected in smaller biopsy specimens. Use of TEC as a prognostic indicator demands larger sample size and mandates long-term follow-up. PMID- 26980955 TI - Immunohistochemical analysis of tenascin expression in different grades of oral submucous fibrosis. AB - AIM: Tenascin, a glycoprotein, is one of the major constituents of extracellular matrix, which may function in organizing the stroma in normal and pathological conditions. The study aimed to correlate the structural organization of tenascin with the pathological progression of disease from early, moderate and advanced changes in oral submucous fibrosis (OSMF). STUDY DESIGN: A retrospective cross sectional immunohistochemical (IHC) analysis of OSMF cases was performed. Total 70 slide samples were prepared for the study from 35 formalin-fixed paraffin embedded tissue blocks with 10 each from histologically proven and graded as early, moderate and advanced OSMF and 5 of normal oral mucosa. The IHC sections were analyzed for the intensity and pattern of tenascin expression at the junction of epithelium and connective tissue (ECJ) and deeper connective tissue (CT), as well as presence or absence of staining around inflammatory cells, fibroblast and endothelial cells using anti-human tenascin. RESULT: Most of the OSMF cases showed retention of antigen at ECJ and in deeper CT. Its expression varied in different grades as well as around inflammatory cells, fibroblast and endothelial cells in same tissue section. Highly significant P values of 0.001 and 0.003 were obtained for tenascin intensity and pattern, respectively, at ECJ in different OSMF grades. In addition, for the expression of tenascin pattern in deeper CT among different OSMF grades, a significant P value of 0.018 was obtained. CONCLUSION: A differential expression of tenascin was observed with the progression of disease. The expression of tenascin as bright and continuous deposition at ECJ in early and moderate stages of OSMF signifies either proliferative organization within the overlying epithelium or an epithelial mesenchymal interaction. However, a weak immunoreactivity of tenascin at ECJ was observed in advanced stage of OSMF. PMID- 26980956 TI - Evaluation of cell proliferation in malignant and potentially malignant oral lesions. AB - AIMS: To evaluate the cell proliferation rate by the expression of proliferating cell nuclear antigen (PCNA) and argyrophilic nucleolar organizing region (AgNOR) counts and to assess its usefulness as a marker for malignant potential in oral epithelial lesions. MATERIALS AND METHODS: The study group included 30 cases of leukoplakia, 15 nondysplastic (NDL), 15 dysplastic (DL), 15 cases of oral squamous cell carcinoma (OSCC) and 5 cases of normal oral mucosa. Formalin fixed paraffin embedded tissues were subjected to immunohistochemical staining for PCNA and AgNOR technique. The PCNA labeling index (LI) and the AgNOR dots were evaluated for the entire sample. STATISTICAL ANALYSIS USED: ANOVA, Tukey honestly significant difference, Pearson's correlation. RESULTS: In this study, the AgNOR count of OSCC was lower than the DL lesions moreover the AgNOR counts were found to be higher in normal mucosa as compared to the DL and the NDL epithelium. The study results also showed that the mean AgNOR count failed to distinguish between DL and NDL lesions. Overall we observed increased PCNA expression from normal epithelium to NDL to DL lesion. CONCLUSIONS: Based on the findings of the present study on oral epithelial precancerous and cancerous lesions we conclude that mean AgNOR count alone cannot be a valuable parameter to distinguish between the normal, NDL, DL epithelium and OSCC but, on the other hand, we found out that PCNA can be a useful biomarker for delineating normal epithelium from DL epithelium and OSCC. PMID- 26980957 TI - A rapid manual processing technique for resource-limited small laboratories. AB - BACKGROUND: Surgical pathology is an integral part of diagnosis and management planning in patient care. In the absence of widespread automation, many small laboratories are unable to provide this service due to lack of time. Currently, the shortest processing schedule for formalin-fixed paraffin-embedded tissues is 16 working hours; most small laboratories cannot complete the rapid schedules within the average 8-9 working hours. Thus, the availability of an 8-9 h processing schedule that provide satisfactory results can help many small laboratories in routinely providing surgical pathology services. OBJECTIVES: To evaluate the effectiveness of a new rapid processing schedule and compare it with two existing rapid processing schedules. MATERIALS AND METHODS: This animal study tested a new rapid processing schedule suggested by authors with overnight preprocessing in 60% isopropyl alcohol followed by an 8 h processing schedule. This was tested and compared with the rapid processing schedules described by Godkar's (11 h) and Bancroft's (2 working days). A routinely used automatic tissue processor long cycle (17 h) was the control. Each schedule was used on 20 tongue specimens. The prepared slides were evaluated for surface area and linear tissue shrinkage, ease of sectioning, quality of hematoxylin and eosin staining, histological appearance and artifacts. RESULTS: No statistical differences were found between schedules. Overall total average performance ranking placed Bancroft's schedule as the best with only 27.9% of the sections processed and stained showing any shortcomings, followed closely by the test schedule suggested by authors (28.7%), Godkar's (31.8%) and the automatic processor schedule/control (33.3%). CONCLUSION: The test results indicated that the schedule devised by authors is an effective rapid processing cycle that produces diagnostic quality histological results when compared with other conventional processing schedules for small tissue blocks (average 6 mm * 8 mm). PMID- 26980958 TI - Comparison of specimen adequacy and smear quality in oral smears prepared by manual liquid-based cytology and conventional methods. AB - BACKGROUND: Liquid-based cytology (LBC), recommended in the mass screening of potentially malignant cervical and oral lesions, suffers from high cost owing to the use of expensive automated devices and materials. Considering the need for cost-effective LBC techniques, we evaluated the efficacy of an inexpensive manual LBC (MLBC) technique against conventional cytological technique in terms of specimen adequacy and smear quality of oral smears. MATERIALS AND METHODS: Cytological samples were collected from 21 patients using a cytobrush device. After preparation of a conventional smear, the brush containing the remaining sample was immersed in the preservative vial. The preserved material was processed by an MLBC technique and subsequently, direct smears were made from the prepared cell button. Both conventional and MLBC smears were stained by routine Papanicolaou technique and evaluated by an independent observer for the thickness of the smear, cellular distribution, resolution/clarity of cells, cellular staining characteristics and the presence of unsatisfactory background/artifacts. Each parameter was graded as satisfactory; or satisfactory, but limited; or unsatisfactory. Chi-square test was used to compare the values obtained (significance set at P <= 0.05). RESULTS: MLBC technique produced a significant number of satisfactory smears with regard to cell distribution, clarity/resolution, staining characteristics and background/artifacts compared to conventional methods. CONCLUSIONS: MLBC is a cost-effective cytological technique that may produce oral smears with excellent cytomorphology and longer storage life. PMID- 26980959 TI - Cytomegalovirus and Mucoepidermoid carcinoma: A possible causal relationship? A pilot study. AB - BACKGROUND: Human cytomegalovirus (CMV) infection has tropism for salivary gland ductal epithelium and establishes a persistent and lifelong infection. Mucoepidermoid carcinoma (MEC) is the most common salivary gland tumor. Recent studies have established that mouse CMV-induced tumorigenesis displays histologic and molecular characteristics similar to human MEC. We wished to explore further down the lane by analyzing the expression of pp65 and the key oncogenic signaling pathway in cases of MEC and their etiological relevance in the Indian scenario as a pilot study. MATERIALS AND METHODS: Histopathologically confirmed cases of MEC (n = 4) and normal salivary gland tissue (n = 4) were subjected to immunohistochemical analysis using the markers pp65 and epidermal growth factor receptor (EGFR). RESULTS: The pp65 antigen expression was found to be negative in all the studied cases and one case of high-grade MEC showed EGFR expression. CONCLUSION: The purpose of the study was to explore the role of CMV in the development of MEC, as it might help to exploit this etiological agent as a therapeutic target. Similar to human papillomavirus (HPV), these might identify a subset of neoplasms with a varied biological behavior and alternative therapies. However, this vision is obscured by contradicting evidence in the literature. As of today, surgery remains the only best possible management for these patients unless proven otherwise. PMID- 26980960 TI - Fibrous architecture of cementodentinal junction in disease: A scanning electron microscopic study. AB - BACKGROUND: The cementodentinal junction (CDJ) forms a biological and structural link between cementum and dentin. This biological link is regarded as a distinct tissue in its own right. Certain important proteins responsible for periodontal regeneration are said to be present in this tissue. Few studies have described the structure and composition of this layer by light and electron microscopy. Scanning electron microscopic studies pertaining to CDJ in health and disease are few and documentation of periodontal pathological changes of CDJ is unclear. In the first phase of our study, the collagenous architecture of CDJ of healthy teeth has been reported. AIM: The objective of this study is to observe and report periodontal pathological changes in the fibrous or collagenous architecture of CDJ of periodontitis-affected teeth and discuss the probable clinical implications of CDJ in disease. MATERIALS AND METHODS: Twenty periodontitis-affected teeth were collected and processed for observing under a scanning electron microscope. RESULTS: The results are as follows: Increased width of interface at CDJ in periodontitis samples (7.1 MU) compared to that of healthy samples; fewer areas of fiber intermingling at CDJ in periodontitis samples as compared to healthy samples; frequent detachment of cementum from dentin during sodium hydroxide maceration of samples. CONCLUSION: It may be inferred from results that there is a possibility of a definite weakening of CDJ in periodontally affected root surfaces and we believe that clinical procedures such as scaling and root planning may have a detrimental effect on the cementodentinal attachment of periodontally involved root surfaces. PMID- 26980961 TI - Reactive hyperplasic lesions of the oral cavity: A survey of 295 cases at a Tertiary Health Institution in Kerala. AB - BACKGROUND: The aim of this study was to review the clinicopathologic features of reactive hyperplastic lesions (RHLs) of the oral cavity at a Tertiary Health Institution in Kerala and compare these data with those of previously reported studies. MATERIALS AND METHODS: The patient case files from the Department of Oral and Maxillofacial Pathology during the period between January 2007 and December 2011 were reviewed for cases of RHLs of the oral cavity. Both clinical and histopathological diagnoses of reactive lesions were selected for the study. Data including the type of the lesion, age, gender and the site involved were collected. RESULTS: From a total of 2753 cases reviewed, 295 histologically diagnosed cases of RHLs were obtained with a prevalence of 10.7%. The data consist of 85 (28.8%) males and 210 (71.2%) females. The most common lesion clinically was traumatic fibroma (69.3%) and histologically fibrous hyperplasia (51.9%). The reactive lesions clinically presented as either sessile (54.9%) or pedunculated (45.1%) lesions. CONCLUSION: The clinical features of reactive hyperplasia among our patients were similar to those reported previously with divergence in some analyzed data. The novelty in our study was the correlation between histopathology and clinical features which were not reported in literature until date. PMID- 26980962 TI - Perineural invasion in oral squamous cell carcinoma: Case series and review of literature. AB - BACKGROUND AND OBJECTIVES: Oral cancer constitutes 3% of all neoplasms and is the eighth most frequent cancer in the world. Oral squamous cell carcinoma (OSCC) corresponds to 95% of all oral cancers. It is associated with severe morbidity, recurrence and reduced survival rates. Its prognosis is affected by several clinicopathologic factors, one of which is perineural invasion (PNI). It is the third most common form of tumor spread exhibited by neurotropic malignancies that correlate with aggressive behavior, disease recurrence and increased morbidity and mortality. In this retrospective study, our aim was to assess the presence of PNI in different grades of both primary and recurrent cases of OSCC correlating it with tumor size and lymph node status. The various patterns of PNI we encountered were also noted. MATERIALS AND METHODS: PNI was assessed in 117 cases of primary and recurrent cases of OSCC. PNI was correlated with tumor thickness, lymph node status and with the different histologic grades. Location of PNI, density of PNI and various patterns of PNI were also assessed. STATISTICAL ANALYSIS: Chi-square test. RESULTS: Our study showed that 47 out of 117 patients (40.5%) showed PNI. Both primary and recurrent tumors showed PNI of 42.50% and 40.50%, respectively. PNI was present in 34 out of 69 cases (49.3%) of clinically positive nodes. Around 79% of the nerves involved by PNI were intratumoral in location, 80% of the cases showed PNI density of 1-3 nerves per section and incomplete and/or "crescent-like" encirclement was the most common pattern of PNI noted in our study. CONCLUSION: Our study showed that the incidence of PNI was as high as 40% in OSCC. PNI was present in both primary and recurrent tumors, irrespective of its histologic grading. Tumor thickness and lymph node status correlated well with PNI. Therefore, the presence of PNI should be checked in every surgical specimen with OSCC as it gives significant prognostic value, influences treatment decisions, recurrence and distant metastasis. The presence of PNI necessitates more aggressive resection, coincident management of neck lymph nodes and the addition of adjuvant therapy. Also, targeted drug therapy for this type of tumor spread can open up new avenues in the treatment of OSCC. PMID- 26980963 TI - Honey as an alternative fixative for oral tissue: An evaluation of processed and unprocessed honey. AB - BACKGROUND: Fixation is the most imperative step in the practice of diagnostic histopathology, which is intimately linked to 10% formalin. As a result of increasing concerns about the potential carcinogenicity of the formaldehyde, attempt to find safer alternatives is necessary. Honey has been shown to possess antimicrobial, antiviral and antimutagenic properties. Many studies have reported that honey possesses dehydrating and preserving effects also. AIMS AND OBJECTIVES: To study the fixative properties of processed and unprocessed honey in oral tissues followed by comparision with formalin. MATERIALS AND METHODS: The study group comprised 12 different tissues. Each tissue was cut into 3 segments and were immediately fixed in bottles containing 10% unprocessed honey, 10% processed honey and 10% formalin, respectively, for 24 h at room temperature. After fixation, tissues were processed using the routine standard processing protocol followed by hematoxylin and eosin staining. Data were statistically analyzed using descriptive statistics such as mean, standard deviation and percentage. Kruskal-Wallis test followed by post hoc Dunn's multiple comparisons test and Chi-square test or Fisher's exact test for small sample size. A P < 0.05 was considered as significant. Data analysis was done by using software Minitab v14.0. RESULTS: When all the stained sections were assessed for the parameters, there was no statistically significant difference between tissues fixed in processed and unprocessed honey compared to formalin (P = 0.004). The tissue morphology and staining adequacy for diagnosis in honey fixed tissue was at par with formalin fixed tissue. Hence, our results suggest that both processed honey and unprocessed honey can be used as a safe alternative for formalin. PMID- 26980964 TI - Are herpes virus associated to aggressive periodontitis? A review of literature. AB - Periodontal Disease includes a wide variety of infectious entities with various clinical manifestations in the oral cavity and responses to treatment. The determinants of clinical manifestations of periodontal disease include the type of infectious agent, the host immune response and environmental factors. Aggressive periodontitis (AP) is defined as a type of inflammation with specific clinical and laboratory features, which distinguish it from other types of periodontitis, with high incidence rates in a sub-group of individuals. Bacteria have been frequently mentioned as the agent inciting gingival inflammation and tissue destruction that underlies the pathogenesis of periodontitis. However, recent studies, with some controversial results, have suggested that the herpes family of viruses, including CMV and EBV-1 as well as papillomaviruses, HIV, Human T-lymphotropic virus type 1, Torquetenovirus and hepatitis B and C occur with high frequency in active periodontal lesions. There is a lack of information about this disease and the role of herpesviruses in its pathophysiology. This review provides a critical analysis of the scientific evidence linking bacteria and viruses with AP and their potential impact on clinical characteristics, prognosis and therapy. PMID- 26980965 TI - Microorganisms in periradicular tissues: Do they exist? A perennial controversy. AB - There is no greater association between the basic science and the practice of endodontics than that of microbiology. One of the strongest factors contributing to the controversies often encountered in the endodontic field is the lack of understanding that the disease processes of the pulp and periradicular tissues generally have a microbiological etiology. The vast majority of diseases of dental pulp and periradicular tissues are associated with microorganisms. After the microbial invasion of these tissues, the host responds with both nonspecific inflammatory responses and with specific immunologic responses to encounter such infections. The aim of this study is to fill the gaps in our knowledge regarding the role of microorganisms in endodontics and to discuss in depth whether their presence in periradicular lesions is a myth or a reality. An electronic search was carried out on PubMed database (custom range of almost 50 years) and Google using specific keywords and phrases. Inclusion and exclusion criteria were specified and around 50 articles were found suitable for inclusion. Full text of all the articles was retrieved and studied. Appropriate data were extracted and pooled and finally synthesized. It is important to understand the close relationship between the presence of microorganisms and endodontic disease process to develop an effective rationale for treatment. PMID- 26980966 TI - Oral lichen planus to oral lichenoid lesions: Evolution or revolution. AB - The diagnosis between different diseases may be impaired by clinical and histopathologic similarities, as observed in the oral lichen planus (OLP) and oral lichenoid lesion (OLL). Inspite of similar clinicopathological features; etiology, diagnosis and prognosis differ which mandates separation of OLL from OLP. Hence, it is essential for the oral physician and oral pathologist to be familiarized with the individual variations among clinicopathological features of OLP and OLL as well as to obtain a thorough history and perform a complete mucocutaneous examination in addition to specific diagnostic testing. The difficulties faced to establish the diagnosis between these two pathologies are widely investigated in the literature with a lack of definite conclusion. This review is an attempt to throw some light on these clinicopathologic entities with the aim to resolve the diagnostic dilemma. PMID- 26980967 TI - Odontogenic ghost cell carcinoma with pulmonary metastasis. AB - Odontogenic ghost cell carcinoma (OGCC) is an exceptionally rare malignant odontogenic epithelial tumor. It is characterized by ameloblastic-like islands of epithelial cells with aberrant keratinization in the form of ghost cells with varying amounts of dysplastic dentin. Malignant histological characteristics include infiltration, cellular pleomorphism, numerous mitosis and necrosis. Its biological behavior varies from slow-growing locally invasive lesions to rapidly growing highly aggressive tumors. OGCC metastasizing to distant sites is extremely rare. Only three cases of metastasis have been reported in literature. We are reporting the case of a 54-year-old male patient who presented with tender swelling in the malar region. Histopathological examination revealed OGCC and he received postoperative radiotherapy. Two years later, he presented with a lung mass. Biopsy from the lung lesion showed the same morphology as that of maxillary tumor with scattered ghost cells. This case points to the aggressive behavior of OGCC and its metastatic potential. It also highlights the need for long-term follow-up of these patients. PMID- 26980969 TI - Follicular lymphoma transforming into anaplastic diffuse large B-cell lymphoma of oral cavity: A case report with review of literature. AB - Follicular lymphoma (FL) is a common form of non-Hodgkin's lymphoma (NHL) with the ability to transform into a more aggressive disease, frequently to B cell lymphoblastic lymphoma. Diffuse large B-cell lymphoma (DLBCL) is a subtype of NHL, which is characterized by diffuse proliferation of large neoplastic B lymphocytes. It accounts for 30% of all NHL and its occurrence in the mandible is very rare. It is often seen in young adults, but in the present case, a 50-year old male patient presented with painless swelling in left lower jaw since 25 days following extraction of left lower molar teeth. There was a history of fever and submandibular lymph nodes were enlarged. On incisional biopsy, features of NHL like lesion were observed and confirmed by immunohistochemistry using CD20, bcl 2, CD10, CD3, CD5, Ki67 markers to be FL (3A) lymphoma transforming into DLBCL. This is a very uncommon presentation. PMID- 26980968 TI - Rhinocerebral mucormycosis in a 5-month heart transplant recipient. AB - Mucormycosis is an opportunistic acute fungal infection with a high mortality rate seen in immunocompromised patients. It is extremely rare in heart transplant recipients. Rhinocerebral mucormycosis (RM) is the most frequently observed presentation. We report a case of RM in a heart transplant recipient 5-month after the procedure, with a fatal outcome. PMID- 26980970 TI - Metastasis of lung adenocarcinoma to the jaw bone. AB - Oral cavity is an uncommon site for metastasis and is usually an evidence of widespread disease. The clinical presentation of the metastatic lesions differs between the various sites in the oral region. Metastatic tumors account for 1-3% of all oral malignancies. The jawbones, particularly the mandibular molar area is more frequently affected than the oral soft tissues (2:1). Here, we report a case of a 60-year-old male patient with metastasis from lung to the mandible, where the metastasis was detected before primary tumor. PMID- 26980971 TI - Bilateral condylar anomaly: A case report and review. AB - A case report of trifid and aplastic condyle in a 26-year-old female has been discussed. A marked oval radiolucency in the head of right condyle and absence of left condyle was observed on a panoramic radiograph. Diagnosis of trifid condyle was established and confirmed using computed tomography. Magnetic resonance images showed degenerative changes of the disc. PMID- 26980972 TI - Cystic lymphangioma: A differential diagnosis. PMID- 26980973 TI - Age estimation using annulations in root cementum of human teeth: A comparison between longitudinal and cross sections. AB - BACKGROUND: Age estimation is an important factor in the identification of an individual in forensic science. Research indicates that cemental annulations may be used more reliably than other morphological or histological traits of human skeleton for age estimation. MATERIALS AND METHODS: Twenty-five teeth were sectioned longitudinally, and twenty-five teeth were cross-sectioned at the mid portion of the root. Sections were ground, mounted and viewed under a bright light microscope. The area selected for counting was photographed under *10 objective, magnified 5 times; cemental lines were counted and added to the eruption age of that patient, to obtain the chronological age. The statistical software SAS 9.2, SPSS 15.0, Stata 10.1, MedCalc 9.0.1, Systat 12.0 and R environment ver.2.11.1 were used for the analysis of the data. RESULTS: The P value comparing actual age and calculated age using longitudinal sections is moderately significant and the P value comparing actual age and calculated age in the age group of <30 years is significant. INTERPRETATION AND CONCLUSION: The middle third of tooth root was most suitable to count annulations. The cross sections are easier to count but longitudinal sections give more appropriate results on age estimation. Though the procedure predicts under assessment of age in the younger age group and over assessment of age in the older age group, it provides a close estimate of the actual age of an individual. It can be correlated with other age estimation methods for better reliability. PMID- 26980974 TI - Sinonasal inverted papilloma: A case report and mini review of histopathological features. AB - Inverted papilloma is a benign epithelial growth in the underlying stroma of the nasal cavity and paranasal sinuses. The pathogenesis of this lesion remains unclear although allergy, chronic sinusitis and viral infections have been suggested as possible causes. The tumor is well known for its invasiveness, tendency to recur and association with malignancy. Recurrence rates of inverted papilloma are unacceptably high, which actually represents residual disease in most cases. In this study, we have presented a case report and reviewed the histological features of sinonasal inverted papilloma. PMID- 26980975 TI - Cemento-ossifying fibroma of mandible: An unusual case report and review of literature. AB - The term ossifying fibroma (OF) has recently been included under fibro-osseous lesions. Cemento-OF (COF) is a benign neoplasm that arises from the periodontal membrane which contains multipotential cells that are capable of forming cementum, lamellar bone and fibrous tissue. These tumors occur in the third and fourth decades of life with a predilection for women. The mandible is more commonly involved than the maxilla. This lesion has caused considerable controversy regarding the use of terminology, origin and diagnostic criteria. This article describes an unusual case of COF presenting as unilocular lytic lesion of mandible in a 38-year-old male patient with review of literature. PMID- 26980976 TI - Primary intraosseous squamous cell carcinoma in odontogenic keratocyst: A rare entity. AB - Squamous cell carcinoma (SCC) arising from the wall of an odontogenic cyst (also known as primary intraosseous carcinoma) is a rare tumor which occurs only in jaw bones. This tumor was first described by Loos in 1913 as a central epidermoid carcinoma of the jaw. Primary intraosseous carcinomas (PIOC) may theoretically arise from the lining of an odontogenic cyst or de novo from presumed odontogenic cell rests. According to the new histological classification of tumors of the World Health Organization, odontogenic keratocyst is nowadays considered a specific odontogenic tumor and the PIOC derived from it is considered as a specific entity which is different from other PIOCs derived from the odontogenic cysts. The following report describes a case of such extremely rare entity that is primary intraosseous SCC of the mandible derived from an OKC in a 60-year-old male patient with brief review of literature. PMID- 26980977 TI - Spindle cell hemangioma: Unusual presentation of an uncommon tumor. AB - Spindle cell hemangioma (SCH) is an uncommon tumor that usually presents as subcutaneous or deep dermal nodule affecting the extremities and is typically <2 cm in size. A few cases have been reported in the head and neck region. To the best of the authors' knowledge, there are no previous reports of SCH occurring in the orbit in the English literature. We, therefore, report the case of a large SCH involving the right orbit of a healthy 9-year-old Nigerian girl. PMID- 26980978 TI - Giant osteochondroma of the mandibular condyle. AB - Osteochondroma or osteocartilaginous exostosis is an exophytic lesion that arises from the cortex of the bone and is cartilage-capped. Osteochondroma of the mandibular condyle is extremely rare. The following is a case report of an osteochondroma of the mandibular condyle removed via extended preauricular approach to the temporomandibular joint. PMID- 26980979 TI - Congenital epulis of the newborn. AB - Congenital epulis, a benign tumor of the oral cavity, is an extremely rare condition in newborn. It may lead to mechanical obstruction, therefore resulting in respiratory distress and difficulty in feeding. Addressing the problem may need a multidisciplinary team approach at the time of birth. Antenatal ultrasonography and perinatal magnetic resonance imaging are an adjunct to treatment planning. Prenatal diagnosis remains difficult as the findings are nonspecific due to the late development of the tumor. Surgical excision is, therefore, the treatment of choice. Our report discusses this condition and the treatment thereafter on a newborn, with an epulis originating from the upper alveolar ridge discovered at birth. Histological examination confirmed the diagnosis of large polygonal granular cells. The mass was excised under general anesthesia, and the outcome was good after surgery allowing regular feeds on the second postoperative day. PMID- 26980980 TI - Hybrid lesions comprising central giant cell granuloma and fibrous dysplasia: A diagnostic challenge for pathologist. AB - Hybrid lesions are the lesions consisting of association of features from different pathologies. We present a rare case of hybrid lesion with features of central giant cell granuloma (CGCG) and fibrous dysplasia (FD) involving mandible in a 33-year-old male. Hybrid lesions consisting of features of both benign fibro osseous lesions and CGCG are very rare. Thus, the purpose of this paper is not only to present a rare case of hybrid lesion with features of CGCG and FD but also to emphasize on the need of careful clinical, radiological and histopathological examination of each and every tissue. There is an important need to report similar and other such cases, which will lead us to understand the interrelationship between these hybrid lesions in a better way and will further clarify their biologic behavior. This will decrease the incidence of misdiagnosis for such cases and will help in preventing recurrences. PMID- 26980981 TI - A rare case of primary orofacial granulomatosis of gingiva during pregnancy. AB - Orofacial granulomatosis (OFG) comprises a group of diseases characterized by noncaseating granulomatous inflammation affecting the soft tissues of the oral and maxillofacial region. It is important to establish the diagnosis accurately because this condition is sometimes a manifestation of many systemic conditions like Crohn's disease or sarcoidosis. The clinical outcome of OFG patients continues to be unpredictable. Current therapies remain unsatisfactory. This article reports a rare case of isolated OFG with langhans type giant cells and inflammatory infiltrate without any systemic involvement, in which the condition was a manifestation of pregnancy. The diagnostic approach to and the treatment of OFG are reviewed. PMID- 26980982 TI - Epidermoid cyst of the soft palate in an infant. AB - Epidermoid cysts are benign malformations that can be encountered anywhere in the body and are rarely observed in the oral cavity accounting for <0.01% of all cysts of the oral cavity. They can be classified as either congenital or acquired without any clinical or histologic differences. Our literature search did not find any report of a congenital epidermoid cyst located in the soft palate associated with a complete palatal cleft in an infant. This is a case report of a 9-month-old female patient who had a cleft palate with an associated soft tissue mass at the junction of soft palate and uvula. PMID- 26980984 TI - Inter and intra-system size variability of reverse shoulder arthroplasty polyethylene inserts. AB - BACKGROUND: As the incidence of reverse shoulder arthroplasty (RSA) increases, so will the revision burden. At times, the revision surgeon may be faced with a well fixed component on one side of the joint and revision implants from a different manufacturer. The ability to use glenoid and humeral implants from different manufacturers could simplify the revision procedure. This study hypothesized that across a range of RSA systems, some implants would demonstrate high size compatibility and others would demonstrate low compatibility. MATERIALS AND METHODS: Six polyethylene inserts each from eight reverse total shoulder arthroplasty systems were examined (48 total inserts). All inserts were scanned using a laboratory micro-computed tomography scanner at 50 MUm isotropic voxel spacing, and their surface geometries were reconstructed. The different implant geometries were co-registered, and the three-dimensional (3D) variability between the articular surfaces of the different implant systems was measured. Intrasystem manufacturing variability was also determined by measuring the 3D variability of inserts from the same system. RESULTS: The intersystem polyethylene articular surface deviations between same-size systems were not significantly different (P = 0.61) and were a mean maximum of 60 +/- 16 MUm (range: 30-80 MUm). Intrasystem manufacturing variability was equivalent between all but two models, averaging 49 +/- 17 MUm (range: 23-99 MUm). DISCUSSION: Differences in articular geometry between same-size inserts from different systems were on the same scale as intrasystem manufacturing variability, suggesting that different implant systems of the same nominal diameter could potentially be used interchangeably in revision or extenuating circumstances. CONCLUSION: The results of this study suggest that surgeons can theoretically interchange same-sized implant components from the different RSA systems tested when conducting revisions. PMID- 26980983 TI - Midterm clinical outcomes following arthroscopic transosseous rotator cuff repair. AB - PURPOSE: Arthroscopic transosseous (TO) rotator cuff repair has recently emerged as a new option for surgical treatment of symptomatic rotator cuff tears. Limited data is available regarding outcomes using this technique. This study evaluated midterm clinical outcomes following a novel arthroscopic TO (anchorless) rotator cuff repair technique. MATERIALS AND METHODS: A consecutive series of 107 patients and 109 shoulders underwent arthroscopic TO (anchorless) rotator cuff repair for a symptomatic full-thickness tear. Pre and postoperative range of motion (ROM) was compared at an average of 11.8 months. Postoperative outcome scores were obtained at an average of 38.0 months. Statistical analysis was performed to compare pre and postoperative ROM data. Univariate analysis was performed using Student's t-test to compare the effect of other clinical characteristics on final outcome. RESULTS: Statistically significant improvements were noted in forward flexion, external rotation and internal rotation (P < 0.0001). Average postoperative subjective shoulder value was 93.7, simple shoulder test 11.6, and American Shoulder and Elbow Surgeons (ASES) score 94.6. According to ASES scores, results for the 109 shoulders available for final follow-up were excellent in 95 (87.1%), good in 8 (7.3%), fair in 3 (2.8%), and poor in 3 (2.8%). There was no difference in ROM or outcome scores in patients who underwent a concomitant biceps procedure (tenodesis or tenotomy) compared with those who did not. Furthermore, there was no significant difference in outcome between patients who underwent either biceps tenodesis or tenotomy. Age, history of injury preceding the onset of pain, tear size, number of TO tunnels required to perform the repair, and presence of fatty infiltration did not correlate with postoperative ROM or subjective outcome measures at final follow up. Two complications and four failures were noted. CONCLUSIONS: Arthroscopic TO rotator cuff repair technique leads to statistically significant midterm improvement in ROM and satisfactory midterm subjective outcome scores with low complication/failure rates in patients with average medium-sized rotator cuff tears with minimal fatty infiltration. Further work is required to evaluate radiographic healing rates with this technique and to compare outcomes following suture anchor repair. LEVEL OF EVIDENCE: Level IV. PMID- 26980985 TI - Biomechanical evaluation of the Nice knot. AB - BACKGROUND: The Nice knot is a bulky double-stranded knot. Biomechanical data supporting its use as well as the number of half hitches required to ensure knot security is lacking. MATERIALS AND METHODS: Nice knots with, one, two, or three half-hitches were compared with the surgeon's and Tennessee slider knots with three half hitches. Each knot was tied 10 times around a fixed diameter using four different sutures: FiberWire (Arthrex, Naples, FL), Ultrabraid (Smith and Nephew, Andover, MA), Hi-Fi (ConMed Linvatec, Largo, FL) and Force Fiber (Teleflex Medical OEM, Gurnee, IL). Cyclic testing was performed for 10 min between 10N and 45N, resulting in approximately 1000 cycles. Displacement from an initial 10N load was recorded. Knots surviving cyclic testing were subjected to a load to failure test at a rate of 60 mm/min. Load at clinical failure: 3 mm slippage or opening of the suture loop was recorded. Bulk, mode of ultimate failure, opening of the loop past clinical failure, was also recorded. RESULTS: During cyclic testing, the Nice knots with one or more half-hitches performed the best, slipping significantly less than the surgeon's and Tennessee Slider (P < 0.002). After one half-hitch, the addition of half-hitches did not significantly improve Nice knot performance during cyclic testing (P > 0.06). The addition of half-hitches improved the strength of the Nice knot during the force to failure test, however after two half-hitches, increase of strength was not significant (P = 0.59). While FiberWire was the most bulky of the sutures tested, it also performed the best, slipping the least. CONCLUSION: The Nice knot, especially using FiberWire, is biomechanically superior to the surgeon's and Tennessee slider knots. Two half hitches are recommended to ensure adequate knot security. PMID- 26980986 TI - Revision of failed humeral head resurfacing arthroplasty. AB - PURPOSE: The purpose of this study is to assess the outcomes of a consecutive series of patients who underwent revision surgery after humeral head resurfacing (HHR). Our joint registry was queried for all patients who underwent revision arthroplasty for failed HHR at our institution from 2005 to 2010. Eleven consecutive patients (average age 54 years; range 38-69 years) that underwent revision of 11 resurfacing arthroplasties were identified. The primary indication for resurfacing had been osteoarthritis in six, glenoid dysplasia in two, a chondral lesion in two, and postinstability arthropathy in one patient. The indication for revision was pain in 10 and infection in one patient. Seven patients had undergone an average of 1.9 surgeries prior to resurfacing (range 1 3). MATERIALS AND METHODS: All patients were revised to stemmed arthroplasties, including one hemiarthroplasty, two reverse, and eight anatomic total shoulder arthroplasties at a mean 33 months after primary resurfacing (range 10-131 months). A deltopectoral approach was used in seven patients; four patients required an anteromedial approach due to severe scarring. Subscapularis attenuation was found in four cases, two of which required reverse total shoulder arthroplasty. Bone grafting was required in one glenoid and three humeri. RESULTS: At a mean follow-up of 3.5 years (range 1.6-6.9 years), modified Neer score was rated as satisfactory in five patients and unsatisfactory in six. Abduction and external rotation improved from 73 degrees to 88 degrees (P = 0.32) and from 23 degrees to 32 degrees (P = 0.28) respectively. Reoperation was required in two patients, including one hematoma and one revision for instability. CONCLUSION: Outcomes of revision of HHR arthroplasty in this cohort did not improve upon those reported for revision of stemmed humeral implants. A comparative study would be required to allow for definitive conclusions to be made. PMID- 26980988 TI - Type IV acromioclavicular joint dislocation associated with a mid-shaft clavicle malunion. AB - This reports presents the case of a combined clavicle fracture malunion and chronic Type IV acromioclavicular (AC) joint dislocation. The patient was seen acutely in the emergency department following a mountain bike accident at which time the clavicle fracture was identified and managed conservatively however the AC dislocation was not diagnosed. The patient presented 25 months following the injury with persistent pain and disability and was treated with clavicle osteotomy and AC stabilization. We document the clinical details, surgical treatment and outcome. PMID- 26980987 TI - Surgical options for the young patient with glenohumeral arthritis. AB - Young patients with glenohumeral arthritis are an ongoing treatment challenge. They typically have high demands of their shoulders, require long-term durability due to their young age, and often have altered local anatomy, through their disease process (instability arthropathy, juvenile rheumatoid arthritis, etc.) or from previous surgery (capsulorraphy arthropathy, chondrolysis, etc.). Workup to evaluate underlying causes of early arthritis, and to exclude infectious causes are necessary. When nonoperative management fails, arthroscopic debridement, hemiarthroplasty (isolated, with glenoid reaming, or with biological interposition), and total shoulder arthroplasty are treatment options available to the treating surgeon. Debridement or hemiarthroplasty can provide pain relief for a subset of patients, but results have not been reproducible across the literature and have not been durable over time. Total shoulder arthroplasty provides the most reliable pain relief, but long-term glenoid loosening and wear continue to lead to high revision rates in this patient population. PMID- 26980990 TI - Fracture of the proximal humerus with disruption of the tendon of the pectoralis major. AB - Combined pectoralis major disruption and proximal humeral fractures are uncommon. A simple radiologic diagnostic tool which consists of the measurement of the displacement from the humeral shaft to the lateral side of the humeral head (lateral to the outer proximal cortex) can help to diagnose this combined lesion. PMID- 26980989 TI - Early asymptomatic intrathoracic migration of a threaded pin after proximal humeral osteosynthesis. AB - Pinning with metallic wires is a suitable therapeutic option for proximal humeral fractures. Loosening and migration of such devices from this site is uncommon. Despite infrequently occurring, however, the literature reports dramatic and potentially lethal complications related to wires dislocation. A 69-year-old woman underwent closed reduction and fixation of a proximal 3-part humeral fracture by mean of two retrograde Kirschner wires and one anterograde threaded pin. One month after surgery, during a routine follow-up control, it was diagnosed the migration of the threaded pin in the left lung parenchyma. In the meantime, the only symptom the patient complained was an episodic intercostal pain of mild intensity, with referred onset 1 week after surgery. The migrated pin was removed through thoracoscopic approach in the emergency setting, without intra- or post-operative complications. Only a few authors reported similar complications after fixation of proximal humeral fractures. Immediate surgical removal of the device is always mandatory. When considering pinning fixation for shoulder girdle's fractures, orthopedic surgeons should take into account the risk for wire dislocation, and take up adequate precautions during surgery and follow-up control visits. PMID- 26980991 TI - Snapping shoulder caused by glenoid labral bone apposition: A case report. PMID- 26980992 TI - A unique bipolar clavicle fracture sustained with minimal trauma. PMID- 26980993 TI - Erratum: Posterior shoulder instability following anatomic total shoulder arthroplasty: A case report and review of management. AB - [This corrects the article on p. 131 in vol. 9, PMID: 26622130.]. PMID- 26980995 TI - Erratum: Long-term functional results and isokinetic strength evaluation after arthroscopic tenotomy of the long head of biceps tendon. AB - [This corrects the article on p. 76 in vol. 8, PMID: 25258498.]. PMID- 26980994 TI - Erratum: The accuracy of "subacromial grind test" in diagnosis of supraspinatus rotator cuff tears. AB - [This corrects the article on p. 43 in vol. 9, PMID: 25937713.]. PMID- 26980996 TI - Role of DNA barcoding in marine biodiversity assessment and conservation: An update. AB - More than two third area of our planet is covered by oceans and assessment of marine biodiversity is a challenging task. With the increasing global population, there is a tendency to exploit marine resources for food, energy and other requirements. This puts pressure on the fragile marine environment and necessitates sustainable conservation efforts. Marine species identification using traditional taxonomical methods is often burdened with taxonomic controversies. Here we discuss the comparatively new concept of DNA barcoding and its significance in marine perspective. This molecular technique can be useful in the assessment of cryptic species which is widespread in marine environment and linking the different life cycle stages to the adult which is difficult to accomplish in the marine ecosystem. Other advantages of DNA barcoding include authentication and safety assessment of seafood, wildlife forensics, conservation genetics and detection of invasive alien species (IAS). Global DNA barcoding efforts in the marine habitat include MarBOL, CeDAMar, CMarZ, SHARK-BOL, etc. An overview on DNA barcoding of different marine groups ranging from the microbes to mammals is revealed. In conjugation with newer and faster techniques like high throughput sequencing, DNA barcoding can serve as an effective modern tool in marine biodiversity assessment and conservation. PMID- 26980997 TI - Batch culture and repeated-batch culture of Cunninghamella bainieri 2A1 for lipid production as a comparative study. AB - This research was performed based on a comparative study on fungal lipid production by a locally isolated strain Cunninghamella bainieri 2A1 in batch culture and repeated-batch culture using a nitrogen-limited medium. Lipid production in the batch culture was conducted to study the effect of different agitation rates on the simultaneous consumption of ammonium tartrate and glucose sources. Lipid production in the repeated-batch culture was studied by considering the effect of harvesting time and harvesting volume of the culture broth on the lipid accumulation. The batch cultivation was carried out in a 500 ml Erlenmeyer flask containing 200 ml of the fresh nitrogen-limited medium. Microbial culture was incubated at 30 degrees C under different agitation rates of 120, 180 and 250 rpm for 120 h. The repeated-batch culture was performed at three harvesting times of 12, 24 and 48 h using four harvesting cultures of 60%, 70%, 80% and 90%. Experimental results revealed that nitrogen source (ammonium tartrate) was fully utilized by C. bainieri 2A1 within 24 h in all agitation rates tested. It was also observed that a high amount of glucose in culture medium was consumed by C. bainieri 2A1 at 250 rpm agitation speed during the batch fermentation. Similar results showed that the highest lipid concentration of 2.96 g/L was obtained at an agitation rate of 250 rpm at 120 h cultivation time with the maximum lipid productivity of 7.0 * 10(-2) mg/ml/h. On the other hand, experimental results showed that the highest lipid concentration produced in the repeated-batch culture was 3.30 g/L at the first cycle of 48 h harvesting time using 70% harvesting volume, while 0.23 g/L gamma-linolenic acid (GLA) was produced at the last cycle of 48 h harvesting time using 80% harvesting volume. PMID- 26980998 TI - Antioxidant, alpha-glucosidase inhibitory and anti-inflammatory effects of aerial parts extract from Korean crowberry (Empetrum nigrum var. japonicum). AB - Crowberry (Empetrum nigrum L.) is a wild berry commonly found in the northern hemisphere. Crowberry fruits have been suggested as good resources for functional applications in the cosmetic and pharmaceutical industries, but the high polyphenolic content in crowberry leaves also indicates crowberry aerial parts as potential dietary health supplements. In this study, therefore, the biological activities of the aerial parts of Korean crowberry (E. nigrum var. japonicum) were investigated. Antioxidant activity was measured by three different assays on DPPH free radical scavenging, reducing power, and total antioxidant capacities. Dose-dependent antioxidant activities were exhibited by crude methanol extract and its fractions, suggesting that the crude methanol extract and EtOAc fraction possessed strong antioxidant activities and capacities. In addition, the crude methanol extract and EtOAc strongly inhibited alpha-glucosidase activity and suppressed the secretion of pro-inflammatory mediator and nitrite oxide from LPS stimulated RAW 264.7 cells. These findings provide valuable evidence for the potential of such parts as good dietary sources of natural antioxidant, alpha glucosidase inhibitory, and anti-inflammatory components, suggesting that using the non-edible parts (e.g., leaves and stems) of crowberry can be a potential natural avenue for improving human health. PMID- 26981000 TI - Comparison of cold resistance physiological and biochemical features of four Herba Rhodiola seedlings under low temperature. AB - To discuss the cold resistance performance of different Herba Rhodiolae and successfully transplant Herba Rhodiolae to the Gansu plateau area for nursing, domestication and planting, this paper systematically studies six physiological and biochemical features of Rhodiola kirilowii, Rhodiola algida, Rhodiola crenulata and Herba Rhodiolae that are closely associated with cold resistance features and concludes with the cold resistance capability of Rhodiola kirilowii. In the selected six main indexes of the Herba Rhodiolae, the POD, SOD and CAT activity and MDA and Pro content in the leaf are the main physiological and biochemical indexes to indicate the cold resistance performance of four Herba Rhodiolae seedlings and can be regarded as the preliminary indexes to assess the winter performance of Herba Rhodiolae. The research work will provide the theoretical basis for the wild variants of Herba Rhodiolae and GAPJ base construction. PMID- 26980999 TI - The recognition of multi-class protein folds by adding average chemical shifts of secondary structure elements. AB - The recognition of protein folds is an important step in the prediction of protein structure and function. Recently, an increasing number of researchers have sought to improve the methods for protein fold recognition. Following the construction of a dataset consisting of 27 protein fold classes by Ding and Dubchak in 2001, prediction algorithms, parameters and the construction of new datasets have improved for the prediction of protein folds. In this study, we reorganized a dataset consisting of 76-fold classes constructed by Liu et al. and used the values of the increment of diversity, average chemical shifts of secondary structure elements and secondary structure motifs as feature parameters in the recognition of multi-class protein folds. With the combined feature vector as the input parameter for the Random Forests algorithm and ensemble classification strategy, we propose a novel method to identify the 76 protein fold classes. The overall accuracy of the test dataset using an independent test was 66.69%; when the training and test sets were combined, with 5-fold cross validation, the overall accuracy was 73.43%. This method was further used to predict the test dataset and the corresponding structural classification of the first 27-protein fold class dataset, resulting in overall accuracies of 79.66% and 93.40%, respectively. Moreover, when the training set and test sets were combined, the accuracy using 5-fold cross-validation was 81.21%. Additionally, this approach resulted in improved prediction results using the 27-protein fold class dataset constructed by Ding and Dubchak. PMID- 26981001 TI - Evaluation of red seaweed Gracilaria arcuata as dietary ingredient in African catfish, Clarias gariepinus. AB - The aim of this study was to evaluate the use of dried marine seaweed, Gracilaria arcuata for the first time as dietary ingredient in partial substitution of fishmeal on the growth performance, feed utilization and body composition of African catfish, Clarias gariepinus. Four experimental diets were formulated: D1 as a control group; D2; D3 and D4 which included 10%, 20% and 30% G. arcuata meal respectively. One hundred and eighty African catfish weighing 9.62 +/- 0.42 g, (mean +/- SE) was divided into four groups corresponding to the different feeding regimes. The final body weight of the fishes showed significant differences (P < 0.05) between the control (D1); D2 and other treated groups D3 and D4, with weights of 66.98, 59.60, 47.34 and 30.73 g recorded for D1, D2, D3 and D4, respectively. Significant differences (P < 0.05) were also evident in weight gain, specific growth rate, and feed utilization between treatment and control groups. However, no significant differences (P > 0.05) were observed between the control group and fishes fed D2 for all previous parameters. Protein productive value, protein efficiency ratio, daily dry feed intake and total feed intake were also significantly lower in fish fed with a diet containing G. arcuata than in the control group and D2 which contains 10% of G. arcuata. Overall, the results of the experiment revealed that African catfish fed a diet with G. arcuata included in 20% and 30% levels showed poorer growth and feed utilization than the control group and D2. However, the study recommended that C. gariepinus can accept this ingredient up to 10% in their diets. More defined experiments therefore seem to be necessary in order to determine the maximum level of this marine seaweed in diets with amino acid supplementation for African catfish. PMID- 26981002 TI - Biodegradation of diesel fuel hydrocarbons by mangrove fungi from Red Sea Coast of Saudi Arabia. AB - Mangrove sediments were collected from major mangrove stands on the Red Sea Coast of Saudi Arabia. Forty five isolates belonging to 12 genera were purified and five isolates as well as their consortium were found to be able to grow in association with petroleum oil as sole carbon source under in vitro conditions. The isolated strains were identified based on internal transcribed spacer (ITS) rDNA sequence analysis. The fungal strains with the greatest potentiality to degrade diesel oil, without developing antagonistic activity, were identified as Alternaria alternata, Aspergillus terreus, Cladosporium sphaerospermum, Eupenicillium hirayamae and Paecilomyces variotii. As compared to the controls, these fungi accumulated significantly higher biomass, produced extracellular enzymes and liberated larger volumes of CO2. These observations with GC-MS data confirm that these isolates displayed rapid diesel oil bioremoval and when used together as a consortium, there was no antagonistic activity. PMID- 26981003 TI - Effects of curcumin on the social behavior, blood composition, reproductive hormones in plasma and brain acetylcholinesterase in cadmium intoxicated mice. AB - Cadmium (Cd) exposure can induce acute lethal health-related threats in humans since it has an exceptional ability to accumulate in living organism tissues and cause toxicological effects. Curcumin (Cur) on the other hand has a wide variety of biological activities and several studies have suggested its potential therapeutic or protective effects against several ailments and infections. To study the effect of Cur on the toxicity of Cd, Swiss-Webster strain male and female mice (sixty each) were divided into 6 groups of ten each at random. Group 1 served as the naive control and received no treatment. Group-2, 3 and 4 were the experimental controls and were administered once a day with a single oral dose of 50% dimethyl sulfoxide (DMSO), Cur (300 mg/kg) or Cd (100 mg/kg) respectively, for 2 weeks. Group-5 and 6 received Cur and Cd in combination once a day orally for 2 weeks except that Cur in a dose of 150 and 300 mg/kg to group 5 and 6 respectively, was administered one hour before Cd administration to both groups. After treatment period, the male animals were subjected to social standard opponent test and females were subjected to the tube restraint tests and thereafter, their blood was collected to measure the blood composition indices and level of reproductive hormones. The animals were sacrificed to collect their brain for the estimation of acetylcholinesterase (AChE). Results indicated that Cd significantly increased nonsocial activities in males and latency to first bite in females, whereas the social activities in males and the number of bites in females were significantly decreased. All measured indices of blood composition and levels of progesterone (female) and testosterone (male) in blood and AChE in their brain tissues were significantly decreased due to Cd treatment. However, administration of Cur along with Cd had an ameliorating effect on all the behavioral and biochemical parameters studied herein and reduced the toxicity of Cd significantly and dose-dependently. Thus, Cur may be beneficial for general health and for protection from Cd intoxication. PMID- 26981004 TI - Assessment of biological activity and UPLC-MS based chromatographic profiling of ethanolic extract of Ochradenus arabicus. AB - Natural products from wild and medicinal plants, either in the form of crude extracts or pure compounds provide unlimited opportunities for new drug leads owing to the unmatched availability of chemical diversity. In the present study, the cytotoxic potential of crude ethanolic extract of Ochradenus arabicus was analyzed by MTT cell viability assay in MCF-7 adenocarcinoma breast cancer cells. We further investigated its effect against oxidative stress induced by anticancer drug doxorubicin. In addition, Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) based chromatographic profiling of crude extract of O. arabicus was performed. The MTT assay data showed that the extract is moderately toxic to the MCF-7 cells. However, its treatment alone does not induce oxidative stress while doxorubicin increases the level of oxidative stress in MCF-7 cells. Whereas, simultaneous treatment of plant extract and doxorubicin significantly (p < 0.05) decreased the level of intracellular reactive oxygen species (ROS) and lipid peroxidation while an increase in the reduced glutathione and superoxide dismutase activity was observed in time and dose dependent manner. Hence, our finding confirmed cytotoxic and antioxidant potential of crude extract of O. arabicus in MCF-7 cells. However, further investigations on O. arabicus as a potential chemotherapeutic agent are needed. The analysis of bioactive compounds present in the plant extracts involving the applications of common phytochemical screening assays such as chromatographic techniques is discussed. PMID- 26981005 TI - Characterization of a Sorghum mosaic virus (SrMV) isolate in China. AB - Sorghum mosaic virus (SrMV), a causal agent of the destructive sugarcane mosaic disease, has a global presence. An isolate of SrMV infecting a commercially-grown sugarcane plant was recovered from the Hainan province of China. The virions were visualized by an electron microscope, and the coat proteins (CPs) were sequenced by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and tandem mass spectrometry. Discrepancies between the CP predicted and actual amino acid sequences were noted, which confounded the phylogenetic assignment of the isolate. The apparent variations may have physiological effects on the pathogenicity and virulence of SrMV. PMID- 26981006 TI - Expression analysis of ClpB/Hsp100 gene in faba bean (Vicia faba L.) plants in response to heat stress. AB - Heat stress adversely affects the growth and yield of faba bean crop. Accumulation of ClpB/Hsp100 class of proteins is a critical parameter in induction of acquired heat stress tolerance in plants. Heat-induced expression of ClpB/Hsp100 genes has been noted in diverse plant species. Using primers complementary to soybean ClpB/Hsp100 gene, we analyzed the transcript expression profile of faba bean ClpB/Hsp100 gene in leaves of seedlings and flowering plants and in pollen grains. ClpB/Hsp100 protein accumulation profile was analyzed in leaves of faba bean seedlings using Arabidopsis thaliana cytoplasmic Hsp101 antibodies. The transcript and protein levels of faba bean ClpB/Hsp100 were significantly induced in response to heat stress. PMID- 26981007 TI - In vitro anti-cancer activities of Job's tears (Coix lachryma-jobi Linn.) extracts on human colon adenocarcinoma. AB - The whole seed (W), endosperm (E) and hull (H) of five cultivars of Job's tears (Coix lachryma-jobi Linn. var. ma-yuen Stapf) including Thai Black Phayao, Thai Black Loei, Laos Black Loei, Laos White Loei and Laos Black Luang Phra Bang were processed before solvent extraction by non-cooking, roasting, boiling and steaming Each part of the Job's tears was extracted by the cold and hot process by refluxing with methanol and hexane. The total of 330 extracts included 150 methanol extracts and 180 hexane extracts were investigated for anti proliferative activity on human colon adenocarcinoma cell line (HT-29) by the sulforhodamine B (SRB) assay. The extracts which gave high anti-proliferative activity were tested for apoptotic activity by acridine orange and ethidium bromide double staining and anti-oxidative activities including free radical scavenging and lipid peroxidation inhibition activities. The extract from the hull of Thai Black Loei roasted before extracting by hot methanol (M-HTBL-R2) showed the highest anti-proliferative activity on HT-29 with the IC50 values of 11.61 +/- 0.95 MUg/ml, while the extract from the non-cooked hull of Thai Black Loei by cold methanol extraction (M-HTBL-N1) gave the highest apoptosis (8.17 +/- 1.18%) with no necrosis. In addition, M-HTBL-R2 and M-HTBL-N1 indicated free radical scavenging activity at the SC50 values of 0.48 +/- 0.12 and 2.47 +/- 1.15 mg/ml, respectively. This study has demonstrated the anti-colorectal cancer potential of the M-HTBL-R2 and M-HTBL-N1 extracts. PMID- 26981008 TI - A review of maturation diets for mud crab genus Scylla broodstock: Present research, problems and future perspective. AB - Study of broodstock maturation diets is important in order to increase the quality of berried females, which indirectly improve the larval quantity in the hatchery production of cultured species. This paper reviewed the studies on the maturation diets for mud crab broodstock, genus Scylla and compared independently to identify their effect on reproductive performance and larval quality. The broodstock is usually caught from the wild and held in the spawning or maturation tank for further use of hatchery seed production. Mud crab broodstock was fed either natural diet, artificial diet or mixed diet. Trash fishes were commonly used as a natural feed for mud crab broodstock; meanwhile artificial diets are from formulated fish meal and various kinds of feed. The results indicated that mud crab broodstock has a high dietary requirement for lipids, fatty acids and protein which are to be used during the maturation and breeding processes. However, the natural diet produce better larval quality compared to the artificial diet. The mixed diet is the better diet which resulted in better reproductive performances such as growth, survival, fecundity and maturation processes. This review also discusses the problems in the previous studies for the potential future research to develop very high quality and cost-effective formulated diet for the enhancement of broodstock and seed production technology. Information from this review can be useful in developing a better quality of crustacean broodstock's diet for commercial hatchery production. PMID- 26981009 TI - Assessment of the bacterial contamination of hand air dryer in washrooms. AB - The present study was carried out, using standard techniques, to identify and count the bacterial contamination of hand air dryers, used in washrooms. Bacteria were isolated from the air flow, outlet nozzle of warm air dryers in fifteen air dryers used in these washrooms. Bacteria were found to be relatively numerous in the air flows. Bacterially contaminated air was found to be emitted whenever a warm air dryer was running, even when not being used for hand drying. Our investigation shows that Staphylococcus haemolyticus, Micrococcus luteus, Pseudomonas alcaligenes, Bacillus cereus and Brevundimonad diminuta/vesicularis were emitted from all of the dryers sampled, with 95% showing evidence of the presence of the potential pathogen S. haemolyticus. It is concluded that hot air dryers can deposit pathogenic bacteria onto the hands and body of users. Bacteria are distributed into the general environment whenever dryers are running and could be inhaled by users and none-users alike. The results provide an evidence base for the development and enhancement of hygienic hand drying practices. PMID- 26981010 TI - Alleviation of cadmium stress in Solanum lycopersicum L. by arbuscular mycorrhizal fungi via induction of acquired systemic tolerance. AB - Experiments were conducted to evaluate cadmium (Cd) stress-induced changes in growth, antioxidants and lipid composition of Solanum lycopersicum with and without arbuscular mycorrhizal fungi (AMF). Cadmium stress (50 MUM) caused significant changes in the growth and physio-biochemical attributes studied. AMF mitigated the deleterious impact of Cd on the parameters studied. Cadmium stress increased malonaldehyde and hydrogen peroxide production but AMF reduced these parameters by mitigating oxidative stress. The activity of antioxidant enzymes enhanced under Cd treatment and AMF inoculation further enhanced their activity, thus strengthening the plant's defense system. Proline and phenol content increased in Cd-treated as well as AMF-inoculated plants providing efficient protection against Cd stress. Cadmium treatment resulted in great alterations in the main lipid classes leading to a marked change in their composition. Cadmium stress caused a significant reduction in polyunsaturated fatty acids resulting in enhanced membrane leakage. The present study supports the use of AMF as a biological means to ameliorate Cd stress-induced changes in tomato. PMID- 26981011 TI - Immunological characterization of diphtheria toxin recovered from Corynebacterium pseudotuberculosis. AB - Diphtheria toxin (DT) is a potent toxin produced by the so-called diphtheria group which includes Corynebacterium diphtheriae (C. diphtheriae), Corynebacterium ulcerans (C. ulcerans), and Corynebacterium pseudotuberculosis (C. pseudotuberculosis). The present investigation is aimed to study in detail the production of DT by C. pseudotuberculosis. Twenty isolates were obtained from sheep diseased with caseous lymphadenitis (CLA) and twenty-six isolates were obtained from 26 buffaloes diseased with oedematous skin disease (OSD). All isolates were identified by standard microbiological and DT production was assayed serologically by modified Elek test and immunoblotting. All sheep isolates were nitrate negative, failed to hydrolyze starch and could not produce DT, while all buffalo isolates (biotype II) revealed positive results and a specific band of 62 kDa, specific to DT, was resulted in all concentrated cell fractions (CF), but was absent from non-toxigenic biotype I isolates. At the same time, another band of 31 kDa specific to the PLD gene was obtained with all isolates of biotype I and II. Moreover, all isolates showed positive synergistic hemolytic activity and antagonistic hemolysis with beta-hemolytic Staphylococci. The obtained results also indicated that C. pseudotuberculosis could be classified into two strains; non-toxigenic biotype I strain, which failed to produce DT as well as being negative to nitrate and starch hydrolysis, and toxigenic biotype II strain, which can reduce nitrate, hydrolyze starch as well as produce DT. PMID- 26981012 TI - Effects of different inoculum densities of Trichoderma harzianum and Trichoderma viride against Meloidogyne javanica on tomato. AB - A greenhouse experiment was conducted to evaluate the effects of different inoculum densities of two Saudi isolates of Trichoderma harzianum and Trichoderma viride against Meloidogyne javanica on tomato. Four densities (10(4), 10(6), 10(8) and 10(10) spores/g of soil) of each fungus were used. The results indicate that all four inoculum densities of the two Trichoderma species suppressed the nematode reproduction and root galling; and increased the growth of tomato plants, compared to controls. Efficacy of both fungi increased as their inoculum densities increased. Generally, efficacy of T. harzianum was better than that of T. viride, especially at the highest used density (10(10) spore/g soil) which resulted in the best control. PMID- 26981013 TI - Prevalence, distribution and intraspecific variation of Heterodera schachtii populations from semiarid environment. AB - A two-year survey study was carried-out to identify and determine the distribution, community characteristics and intraspecific variation of the sugar beet cyst nematode, Heterodera schachtii populations collected from the six major sugar beet-producing governorates in Syria, west Asia. A total of 178 composite rhizosphere soil samples were collected from the six governorates during 2009 and 2010 growing seasons as follows: Aleppo (26), Ar Raqqah (17), Dayr az Zawr (33), Idlib (34), Hamah (41) and Homs (27 samples). The nematode was originally identified on the basis of morphometrics and morphological features of the cyst vulvar cones and second-stage juveniles (J2). The communities of H. schachtii were then analyzed using the criteria of frequency of occurrence (FO%), mean population density (PD) and prominence value (PV). Results showed that H. schachtii was the most frequent and prominent in Homs (FO% = 70.37% and PV = 23472.37) and the least frequent and prominent in Ar Raqqah (FO% = 5.88% and PV = 28.86). The highest nematode population density was also recorded in Homs in 2009 (50,545 J2 + eggs/100 g soil) while the least was recorded in Ar Raqqah in 2010 (119 J2 + eggs/100 g soil). The morphometric data of cyst vulvar cone, second stage juveniles (J2) and eggs were also subjected to a multivariate principal component analysis to analyze the relationships between the studied populations, and to identify the variables that show the highest multiple correlations with these populations. Results showed that at the high order of hierarchical cluster analysis, four populations (Idlib, Hamah, Homs and Aleppo) formed one main cluster, while Dair az Zawr and Ar Raqqah failed to form clusters and separated individually. However, at low distance value, the main cluster further subdivided to separate the Aleppo population from Idlib, Hamah and Homs populations. The morphometric distance values ranged from 0.07 to 0.61. Hamah and Homs were the closest populations while Dair az Zawr showed the most diverse population. This study also revealed the value of J2 body length, egg length and width, fenestral length and width and the number of bullae inside the cyst vulvar cone in determining the intraspecific variations among the Syrian populations of H. schachtii. PMID- 26981014 TI - Attenuation of hepatotoxicity and oxidative stress in diabetes STZ-induced type 1 by biotin in Swiss albino mice. AB - Diabetes mellitus is one of the major health problems. This study was designed to investigate the effect of biotin to regulate blood glucose level, reduced toxicity and oxidative stress in liver of diabetic mice STZ-induced type 1. Male mice were divided into three groups, the first one served as the control group, the second and the third groups received single ip dose of 150 mg/kg of STZ, the second group served as the untreated diabetic group, the third group received daily oral dose of 15 mg/kg of biotin, livers and liver index showed insignificant difference among groups. Blood glucose level showed a significant decrease in treated diabetic mice compared to untreated diabetic mice. Biochemical analysis showed a significant decrease in liver enzymes AST and ALT compared to the control group. Histopathological examination showed severe changes in untreated diabetic liver tissue manifested by dilated portal vein, leukocytic infiltration, fatty degeneration and moderate to severe histopathological score, whereas, treated diabetic mice with biotin showed reduction in hepatotoxicity represented by appearance of relative healthy hepatocytes and normal histopathological score. Immunohistochemistry of acrolein showed intense immunoreactions in liver section of untreated diabetic mice and faint immunoreactions in treated diabetic mice with biotin as evidence to oxidative stress reduction. PMID- 26981015 TI - Reference intervals: current status, recent developments and future considerations. AB - Reliable and accurate reference intervals (RIs) for laboratory analyses are an integral part of the process of correct interpretation of clinical laboratory test results. RIs given in laboratory reports have an important role in aiding the clinician in interpreting test results in reference to values for healthy populations. Since the 1980s, the International Federation of Clinical Chemistry (IFCC) has been proactive in establishing recommendations to clarify the true significance of the term 'RIs, to select the appropriate reference population and statistically analyse the data. The C28-A3 guideline published by the Clinical and Laboratory Standards Institute (CLSI) and IFCC is still the most widely-used source of reference in this area. In recent years, protocols additional to the Guideline have been published by the IFCC, Committee on Reference Intervals and Decision Limits (C-RIDL), including all details of multicenter studies on RIs to meet the requirements in this area. Multicentric RIs studies are the most important development in the area of RIs. Recently, the C-RIDL has performed many multicentric studies to obtain common RIs. Confusion of RIs and clinical decision limits (CDLs) remains an issue and pediatric and geriatric age groups are a significant problem. For future studies of RIs, the genetic effect would seem to be the most challenging area. ?The aim of the review is to present the current theory and practice of RIs, with special emphasis given to multicenter RIs studies, RIs studies for pediatric and geriatric age groups, clinical decision limits and partitioning by genetic effects on RIs. PMID- 26981018 TI - The effect of extremely high glucose concentrations on 21 routine chemistry and thyroid Abbott assays: interference study. AB - INTRODUCTION: Extremely high glucose concentrations have been shown to interfere with creatinine assays especially with Jaffe method in peritoneal dialysate. Because diabetes is the fastest growing chronic disease in the world, laboratories study with varying glucose concentrations. We investigated whether different levels of glucose spiked in serum interfere with 21 routine chemistry and thyroid assays at glucose concentrations between 17-51 mmol/L. MATERIALS AND METHODS: Baseline (group I) serum pool with glucose concentration of 5.55 (5.44 5.61) mmol/L was prepared from patient sera. Spiking with 20% dextrose solution, sample groups were obtained with glucose concentrations: 17.09, 34.52, and 50.95 mmol/L (group II, III, IV, respectively). Total of 21 biochemistry analytes and thyroid tests were studied on Abbott c8000 and i2000sr with commercial reagents. Bias from baseline value was checked statistically and clinically. RESULTS: Creatinine increased significantly by 8.74%, 31.66%, 55.31% at groups II, III, IV, respectively with P values of < 0.001. At the median glucose concentration of 50.95 mmol/L, calcium, albumin, chloride and FT4 biased significantly clinically (-0.85%, 1.63%, 0.65%, 7.4% with P values 0.138, 0.214, 0.004, < 0.001, respectively). Remaining assays were free of interference. CONCLUSION: Among the numerous biochemical parameters studied, only a few parameters are affected by dramatically increased glucose concentration. The creatinine measurements obtained in human sera with the Jaffe alkaline method at high glucose concentrations should be interpreted with caution. Other tests that were affected with extremely high glucose concentrations were calcium, albumin, chloride and FT4, hence results should be taken into consideration in patients with poor diabetic control. PMID- 26981016 TI - Phlebotomy, a bridge between laboratory and patient. AB - The evidence-based paradigm has changed and evolved medical practice. Phlebotomy, which dates back to the age of ancient Greece, has gained experience through the evolution of medicine becoming a fundamental diagnostic tool. Nowadays it connects the patient with the clinical laboratory dimension building up a bridge. However, more often there is a gap between laboratory and phlebotomist that causes misunderstandings and burdens on patient safety. Therefore, the scope of this review is delivering a view of modern phlebotomy to "bridge" patient and laboratory. In this regard the paper describes devices, tools and procedures in the light of the most recent scientific findings, also discussing their impact on both quality of blood testing and patient safety. It also addresses the issues concerning medical aspect of venipuncture, like the practical approach to the superficial veins anatomy, as well as the management of the patient's compliance with the blood draw. Thereby, the clinical, technical and practical issues are treated with the same relevance throughout the entire paper. PMID- 26981017 TI - Laboratory use of hepcidin in renal transplant recipients. AB - Hepcidin is a small peptide with a critical role in cellular iron homeostasis, as it regulates utilization of stored iron and antimicrobial defense in inflammation (bacterial and fungal). Since it was isolated in 2000, and especially in the last decade, numerous studies aimed to evaluate the clinical use of plasma and urine hepcidin as a marker of anemia, especially anemia of chronic disease and post transplant anemia (PTA). Hepcidin regulation is delicately tuned by two inflammatory pathways activated by interleukin-6 (IL-6) and bone morphogenic proteins (BMPs) and iron regulated pathway sensitive to circulating transferin iron (TR-Fe) complex. BMP-mediated pathway and TR-Fe sensitive pathway seem to be connected by hemojuveline, a BMP co-factor that interacts with transferine receptor 2 (TRF2) in cases of high TR-Fe circulatory concentration. In addition to these regulatory mechanisms other regulators and signaling pathways are being extensively researched. ?Hepcidin has been identified as an important contributor to morbidity and mortality in end stage renal disease (ESRD) but no such association has jet been found in case of PTA. However, there is an association between higher doses of erythropoiesis-stimulating agents (ESA) and mortality in the posttransplant period and the assumption that hepcidin might play a role in ESA resistance in PTA. Thus the review's main goal was to summarize papers published on the association of hepcidin with PTA, give up-to-date information on hepcidin regulation and on potential therapeutics that optimize hepcidin regulation. We also compared the performances of tests for hepcidin determination and reviewed research on immunosuppressants' (IS) effect on hepcidin concentration. PMID- 26981019 TI - Failure to review STAT clinical laboratory requests and its economical impact. AB - BACKGROUND: Failure to follow-up laboratory test results has been described as one of the major processes contributing to unsafe patient care. Currently, most of the laboratories do not know with certainty not only their rate of missed (or unreviewed) requests but the economical cost and impact that this issue implies. The aim of our study was to measure that rate and calculate the resulting costs. MATERIAL AND METHODS: In January 2015, we checked in our Laboratory Information Management System (LIMS) for every emergency request from 1(st) July 2011 to 30(th) June 2014, if they had been reviewed by any allowed user or not. 319,064 requests were ordered during that period of time. Results were expressed as "ordered requests", "missed requests" and its percentage. Additionally, total cost of missed requests was calculated in euros (?). "Non-productive days" were theorised (as the days producing requests that were not reviewed) based on these results. RESULTS: 7924 requests (2.5%) were never reviewed by clinicians. This represented a total cost of 203,039 ? and 27 "non-productive" days in three years. Significant differences between inpatients, outpatients and emergency department as well as different emergencies units were found after application of statistical analysis. CONCLUSIONS: In terms of resources, never reviewed or missed requests appear to be a not negligible problem for the clinical laboratory management. Electronic result delivery, with electronic endorsement to indicate follow-up of requests along with better systems of electronic requesting should be investigated as a way of improving patient outcomes and save unnecessary expenses. PMID- 26981020 TI - Effectiveness of citrate buffer-fluoride mixture in Terumo tubes as an inhibitor of in vitro glycolysis. AB - INTRODUCTION: Glycolysis affects glucose determination in vitro. The placement of sample tubes in ice-water slurry with plasma separation within 30 minutes is recommended, or alternatively the use of a glycolysis inhibitor. The aim of our two-steps study was to evaluate which Terumo tube is best for glucose determination in routine clinical setting. MATERIALS AND METHODS: In the first study, blood from 100 volunteers was collected into lithium heparin (LH), NaF/Na heparin (FH) and NaF/citrate buffer/Na2EDTA (FC-Mixture) tubes. LH sample was treated as recommended and considered as reference, while FH and FC-Mixture samples were aliquoted, maintained at room temperature (RT) for 1, 2 and 4 hours; centrifuged and plasma analysed in triplicate. In the second study, samples from 375 volunteers were collected in LH, FH and FC-Mixture tubes and held at RT before centrifugation from 10 to 340 minutes, depending on each laboratory practice. Samples were analysed in one analytical run. RESULTS: In the first study, FH glucose concentrations were 5.15 +/- 0.66 mmol/L, 5.05 +/- 0.65 mmol/L and 5.00 +/- 0.65 mmol/L (P < 0.001) in tubes stored at RT for 1, 2 and 4 hours, respectively. Mean biases in all time points exceeded the analytical goal for desirable bias based on biological variation criteria. FC-Mixture glucose concentrations were 5.48 +/- 0.65 mmol/L, 5.46 +/- 0.6 mmol/L and 5.46 +/- 0.64 mmol/L in tubes stored at RT for 1, 2 and 4 hours, respectively. Mean biases for FC-Mixture glucose in all time points reached optimal analytical goals. In the second study, the biases for LH and FH glucose compared to reference FC-Mixture glucose exceeded the preset analytical goals, regardless of the blood collection to centrifugation time interval. CONCLUSIONS: FC-mixture tubes glucose concentrations were preserved up to 4h storage at RT. We confirmed that NaF alone does not allow immediate glycolysis inhibition in real life pre-centrifugation storage conditions (up to 340 minutes). FC-Mixture should be used exclusively for glucose determination in laboratories unable to implement the recommended blood samples' treatment. PMID- 26981021 TI - Unnecessary repeated total cholesterol tests in biochemistry laboratory. AB - INTRODUCTION: We aimed to determine the number of repeated cholesterol (RC) tests and the ratio of unnecessary-repeated cholesterol (URC) tests among patients admitted to Pamukkale University Hospital (Denizli, Turkey) and provide solutions to avoid URC testing. MATERIALS AND METHODS: Total cholesterol (T-cholesterol) tests (N = 86,817) between June 2014 and May 2015 were evaluated. The tests performed more than once per patient were determined as RC test (N = 28,811). RC test with an interval shorter than 4 weeks were determined as URC test (N = 3968) according to the shortest retest interval stated in ACC/AHA blood cholesterol guideline. RC testing included internal medicine, surgery and paediatric outpatients and inpatients. Reference change value (RCV) of total cholesterol was calculated. RESULTS: The 33.1% of the T-cholesterol tests were RC tests (N = 28,811), 13.7% of them were URC tests (N = 3968). Our RCV value was 25%. The percentage change between consecutive tests was less than RCV in 86.1% (N = 3418) of URC tests. URC tests were performed more frequently in patients with desirable total cholesterol value (P < 0.001). CONCLUSION: There is a significant part of repeated T-cholesterol tests requested in our hospital. URC test requests can be evaluated by laboratories and the obtained data should be shared with clinicians. Laboratories can calculate RCV for the tests they performed and report this value with the test result. To prevent from URC tests, a warning plug-in can be added to hospital information software in accordance with guidelines to prevent from URC test requests. PMID- 26981022 TI - Evaluation of the appropriate time period between sampling and analyzing for automated urinalysis. AB - INTRODUCTION: Preanalytical specifications for urinalysis must be strictly adhered to avoid false interpretations. Aim of the present study is to examine whether the preanalytical factor 'time point of analysis' significantly influences stability of urine samples for urine particle and dipstick analysis. MATERIALS AND METHODS: In 321 pathological spontaneous urine samples, urine dipstick (UrisysTM2400, Combur-10-TestTMstrips, Roche Diagnostics, Mannheim, Germany) and particle analysis (UF-1000 iTM, Sysmex, Norderstedt, Germany) were performed within 90 min, 120 min and 240 min after urine collection. RESULTS: For urine particle analysis, a significant increase in conductivity (120 vs. 90 min: P < 0.001, 240 vs. 90 min: P < 0.001) and a significant decrease in WBC (120 vs. 90 min P < 0.001, 240 vs. 90 min P < 0.001), RBC (120 vs. 90 min P < 0.001, 240 vs. 90 min P < 0.001), casts (120 vs. 90 min P < 0.001, 240 vs. 90 min P < 0.001) and epithelial cells (120 vs. 90 min P = 0.610, 240 vs. 90 min P = 0.041) were found. There were no significant changes for bacteria. Regarding urine dipstick analysis, misclassification rates between measurements were significant for pH (120 vs. 90 min P < 0.001, 240 vs. 90 min P < 0.001), leukocytes (120 vs. 90 min P < 0.001, 240 vs. 90 min P < 0.001), nitrite (120 vs. 90 min P < 0.001, 240 vs. 90 min P < 0.001), protein (120 vs. 90 min P < 0.001, 240 vs. 90 min P<0.001), ketone (120 vs. 90 min P < 0.001, 240 vs. 90 min P < 0.001), blood (120 vs. 90 min P < 0.001, 240 vs. 90 min P < 0.001), specific gravity (120 vs. 90 min P < 0.001, 240 vs. 90 min P < 0.001) and urobilinogen (120 vs. 90 min, P = 0.031). Misclassification rates were not significant for glucose and bilirubin. CONCLUSION: Most parameters critically depend on the time window between sampling and analysis. Our study stresses the importance of adherence to early time points in urinalysis (within 90 min). PMID- 26981023 TI - The knowledge and understanding of preanalytical phase among biomedicine students at the University of Zagreb. AB - INTRODUCTION: The educational program for health care personnel is important for reducing preanalytical errors and improving quality of laboratory test results. The aim of our study was to assess the level of knowledge on preanalytical phase in population of biomedicine students through a cross-sectional survey. MATERIALS AND METHODS: A survey was sent to students on penultimate and final year of Faculty of Pharmacy and Biochemistry--study of medical biochemistry (FPB), Faculty of Veterinary Medicine (FVM) and School of Medicine (SM), University of Zagreb, Croatia, using the web tool SurveyMonkey. Survey was composed of demographics and 14 statements regarding the preanalytical phase of laboratory testing. Comparison of frequencies and proportions of correct answers was done with Fisher's exact test and test of comparison of proportions, respectively. RESULTS: Study included 135 participants, median age 24 (23-40) years. Students from FPB had higher proportion of correct answers (86%) compared to students from other biomedical faculties 62%, P < 0.001. Students from FPB were more conscious of the importance of specimen mixing (P = 0.027), prevalence of preanalytical errors (P = 0.001), impact of hemolysis (P = 0.032) and lipemia interferences (P = 0.010), proper choice of anticoagulants (P = 0.001), transport conditions for ammonia sample (P < 0.001) and order of draw during blood specimen collection (P < 0.001), in comparison with students from SM and FVM. CONCLUSIONS: Students from FPB are more conscious of the importance of preanalytical phase of testing in comparison with their colleagues from other biomedical faculties. No difference in knowledge between penultimate and final year of the same faculty was found. PMID- 26981024 TI - The characterization of four gene expression analysis in circulating tumor cells made by Multiplex-PCR from the AdnaTest kit on the lab-on-a-chip Agilent DNA 1000 platform. AB - INTRODUCTION: Nowadays, on-a-chip capillary electrophoresis is a routine method for the detection of PCR fragments. The Agilent 2100 Bioanalyzer was one of the first commercial devices in this field. Our project was designed to study the characteristics of Agilent DNA 1000 kit in PCR fragment analysis as a part of circulating tumour cell (CTC) detection technique. Despite the common use of this kit a complex analysis of the results from a long-term project is still missing. MATERIALS AND METHODS: A commercially available Agilent DNA 1000 kit was used as a final step in the CTC detection (AdnaTest) for the determination of the presence of PCR fragments generated by Multiplex PCR. Data from 30 prostate cancer patients obtained during two years of research were analyzed to determine the trueness and precision of the PCR fragment size determination. Additional experiments were performed to demonstrate the precision (repeatability, reproducibility) and robustness of PCR fragment concentration determination. RESULTS: The trueness and precision of the size determination was below 3% and 2% respectively. The repeatability of the concentration determination was below 15%. The difference in concentration determination increases when Multiplex PCR/storage step is added between the two measurements of one sample. CONCLUSIONS: The characteristics established in our study are in concordance with the manufacturer's specifications established for a ladder as a sample. However, the concentration determination may vary depending on chip preparation, sample storage and concentration. The 15% variation of concentration determination repeatability was shown to be partly proportional and can be suppressed by proper normalization. PMID- 26981025 TI - Colorectal cancer detection in an asymptomatic population: fecal immunochemical test for hemoglobin vs. fecal M2-type pyruvate kinase. AB - INTRODUCTION: Screening programs for colorectal cancer (CRC) are mainly based on a first-line fecal immunochemical test for hemoglobin (FIT). Fecal M2-type pyruvate kinase (M2-PK) has been evaluated in clinical settings showing promising results for early CRC detection. However, the impact of fecal M2-PK assessment on the performance of first-round CRC screening programs is not known. We investigated whether fecal M2-PK alone or in combination with FIT may improve CRC screening efficacy in the general population. MATERIALS AND METHODS: A total of 1027 asymptomatic subjects (median age 66 [59-74] years; females 504 [49.1%]), identified through the general practitioners' rosters, were invited for the collection of 2 fecal samples for FIT and M2-PK evaluation. Participants with at least positive one fecal test were referred for colonoscopy. Quality indicators for screening performance were calculated and analyzed using Fisher's exact test. RESULTS: Overall, 572 subjects underwent both FIT and M2-PK assessment (participation rate 55.7%): 93 participants showed positive results for at least one test (positivity rate 16.3%). Only 10 patients were positive for both tests. Attendance rate to colonoscopy was 86.0% and a total of 65 adenomas and 7 cancers were detected. Combined use of FIT and fecal M2-PK permitted the identification of 18 more neoplasm (25%) without improving colonoscopy workload, as deduced by the comparable number needed to scope (P = 0.402). CONCLUSION: The addition of M2 PK testing to FIT offers the potential to detect additional neoplasms that either do not bleed or only bleed intermittently without reducing participation rate and without increasing endoscopy workload. PMID- 26981028 TI - LOW BACK PAIN IN SCHOOLCHILDREN: A CROSS-SECTIONAL STUDY IN A WESTERN CITY OF SAO PAULO STATE, BRAZIL. AB - OBJECTIVE: To determine the prevalence of low back pain in children and its relationship with gender, age, exercise practice and sedentary activities (time on TV and on computer and/or video game). METHODS: We conducted a cross-sectional study with a sample of 1,461 students, being 754 males and 707 females enrolled in the 5(th) to 8(th) grades of all five local elementary schools of urban Ourinhos, SP, Brasil, aged 10-14 years old, from whom sociodemographic data, time spent on sedentary activities such as TV and computer and/or video game were collected. We conducted a descriptive, bivariate and multivariate binary logistic regression. RESULTS: The results showed that the prevalence of low back pain in the sample was 18.5%, being 15.5% in boys and 21.6% in girls. Low back pain was associated to the female gender, age range between 12-14 years and the habit of watching TV more than three times a week and over 3 hours per day. CONCLUSION: The students analyzed showed high prevalence of low back pain related to gender, age and habit of watching TV. Appropriate interventions should be implemented to reduce the occurrences of back pain in schoolchildren. Level of Evidence III, Cross Sectioning. PMID- 26981027 TI - Viewpoint in the Visual-Spatial Modality: The Coordination of Spatial Perspective. AB - Sign languages express viewpoint-dependent spatial relations (e.g., left, right) iconically but must conventionalize from whose viewpoint the spatial relation is being described, the signer's or the perceiver's. In Experiment 1, ASL signers and sign-naive gesturers expressed viewpoint-dependent relations egocentrically, but only signers successfully interpreted the descriptions non-egocentrically, suggesting that viewpoint convergence in the visual modality emerges with language conventionalization. In Experiment 2, we observed that the cost of adopting a non-egocentric viewpoint was greater for producers than for perceivers, suggesting that sign languages have converged on the most cognitively efficient means of expressing left-right spatial relations. We suggest that non linguistic cognitive factors such as visual perspective-taking and motor embodiment may constrain viewpoint convergence in the visual-spatial modality. PMID- 26981026 TI - Automatic laboratory-based strategy to improve the diagnosis of type 2 diabetes in primary care. AB - INTRODUCTION: To study the pre-design and success of a strategy based on the addition of hemoglobin A1c (HbA1c) in the blood samples of certain primary care patients to detect new cases of type 2 diabetes. MATERIALS AND METHODS: In a first step, we retrospectively calculated the number of HbA1c that would have been measured in one year if HbA1c would have been processed, according to the guidelines of the American Diabetes Association (ADA). Based on those results we decided to prospectively measure HbA1c in every primary care patient above 45 years, with no HbA1c in the previous 3 years, and glucose concentration between 5.6-6.9 mmol/L, during an 18 months period. We calculated the number of HbA1c that were automatically added by the LIS based on our strategy, we evaluated the medical record of such subjects to confirm whether type 2 diabetes was finally confirmed, and we calculated the cost of our intervention. RESULTS: In a first stage, according to the guidelines, Hb1Ac should have been added to the blood samples of 13,085 patients, resulting in a cost of 14,973?. In the prospective study, the laboratory added Hb1Ac to 2092 patients, leading to an expense of 2393?. 314 patients had an HbA1c value >= 6.5% (48 mmol/mol). 82 were finally diagnosed as type 2 diabetes; 28 thanks to our strategy, with an individual cost of 85.4?; and 54 due to the request of HbA1c by the general practitioners (GPs), with a cost of 47.5?. CONCLUSION: The automatic laboratory-based strategy detected patients with type 2 diabetes in primary care, at a cost of 85.4? per new case. PMID- 26981029 TI - TREATMENT OF INFECTION AFTER TOTAL KNEE ARTHROPLASTY. AB - OBJECTIVES: To identify and compare the rate of success of therapeutic modalities applied in surgeries for the treatment of infections associated with total knee arthroplasty (TKA), and to evaluate the functional outcome and pain in different therapeutic modalities by means of quality of life scores. METHODS: We evaluated all patients who developed periprosthetic infection after TKA for primary or secondary osteoarthritis, in the period from January 1(st), 2008 to December 31(st), 2010. RESULTS: In the study period, 29 patients with TKA had infection, and 12 of these underwent debridement and retention of the prosthesis (D+R), seven received two-stage and six one-stage exchange arthroplasties, and four patients were treated with suppressive antibiotic therapy because they could not undergo another surgical procedure. CONCLUSION: The D+R, one-stage revision and two-stage revision success rates were 75%, 83.3%, and 100%, respectively. The best results of quality of life (QoL) and function occur in patients undergoing D+R. In contrast, the worst QoL and functional results were obtained in patients treated with two-stage revision arthroplasty. Level of Evidence II, Prognostic Studies - Investigating the Effect of a Patient Characteristic on the Outcome of Disease. PMID- 26981031 TI - EXTRACORPOREAL SHOCKWAVE TERAPY TO TREAT CHRONIC MUSCLE INJURY. AB - OBJECTIVE: To evaluate the low energy extracorporeal shock waves therapy (ESWT) associated with physical therapy in the treatment of chronic muscle injuries classified as grades 2 and 3 in the lower limbs of amateur athletes. METHODS: Eight athletes presenting with lower limb muscle injury for more than three weeks were treated with physiotherapy and ESWT. We evaluated the following parameters during treatment: palpable gap, muscle strength, pain, and Tegner score, as well as ultrasound image features and the ability to return to sports practice. RESULTS: The average time of the first evaluation of the injury was 8.75 weeks. All patients presented muscle strength grade V after eight weeks. The pain score evolved from 5.75 to 0.5 points of the visual analogue scale (VAS), at the end of the treatment. The Tegner score after treatment was six points on average. Patients returned to sports practice after 8.14 weeks. CONCLUSION: ESWT associated with physical therapy proved to be effective to treat long-term muscle injury, with good performance and the ability to return to sport practice for all patients. Level of Evidence IV, Case Series, Prospective Study. PMID- 26981030 TI - PROFILE OF PATIENTS ON SICK LEAVE WITH CARPAL TUNNEL SYNDROME. AB - OBJECTIVE: To report clinical and epidemiological characteristics and risk factors of patients with Carpal Tunnel Syndrome (CTS) on sick leave admitted in a University Hospital. METHODS: This is a transversal study conducted with patients admitted sequentially over 18 years of age, without distinction of gender and race in the period between September and November 2014. Patients answered a questionnaire and underwent physical examination carried out by the authors. RESULTS: Twenty-five patients were admitted within three months, all females, the mean age was 50.24 years old (standard deviation 10,39) . Among the professions they performed, general and cleaning services were the most prevalent. Most patients featured obesity, followed by depression and systemic arterial hypertension. Approximately half of them were on sick leave. Sleep disorders were also a frequent complaint. CONCLUSION: CTS is a frequent cause of sick leave and it is related to obesity, dyslipidemia and depression. Level of Evidence IV, Series of Cases. PMID- 26981032 TI - FATTY MUSCLE INFILTRATION IN CUFF TEAR: PRE AND POST OPERATIVE EVALUATION BY MRI. AB - OBJECTIVE: To evaluate the fatty infiltration and atrophy of the supraespinatus in the pre- and postoperative of a rotator cuff lesion (RCL), by MRI. METHODS: Ten patients with full-thickness rotator cuff tears who had undergone surgical arthroscopic rotator cuff repair between September and December 2011 were included. This is a prospective study, with analysis and comparison of fatty infiltration and atrophy of the supraespinatus. The occupation ratio was measured using the magic selection tool in Adobe Photoshop CS3((r)) on T1 oblique sagittal Y-view MRI. Through Photoshop, the proportion occupied by the muscle belly regarding its fossae was calculated. RESULTS: There was a statistically significant increase in the muscle ratio (p=0.013) comparing images pre and postoperative, analyzed by the Wilcoxon T test. CONCLUSION: The proportion of the supraspinal muscle above the pit increases in the immediate postoperative period, probably due to the traction exerted on the tendon at the time of repair. Level of Evidence II, Cohort Study. PMID- 26981033 TI - KIRSCHNER WIRE VERSUS TITANIUM ELASTIC NAILS IN PEDIATRIC FEMORAL SHAFT FRACTURES. AB - OBJECTIVE: To evaluate the effectiveness of intramedullary fixation using the Kirschner-wire (K-wire) compared to the titanium elastic nail (TEN) in pediatric femoral shaft fractures. METHODS: A sample of 42 pediatric patients with a mean age of 6.55+/-2.42 years (range 4-11 years) presenting femoral shaft fractures underwent intramedullary fixation using the K-wire or TEN. RESULTS: There was no significant difference found between groups, of which 16 (38.1%) patients were treated with K-wire and 26 (61.9%) patients were treated with TEN in terms of union duration. Moreover, none of the patients showed nonunion or a delayed union. CONCLUSIONS: The use of adjusted K-wire instead of TEN in the intramedullary fixation of femoral shaft fractures in selected children may be an advantageous surgical option due to the lower cost, easy accessibility and no need for a second surgery for implant removal. Level of Evidence III, Retrospective Study. PMID- 26981034 TI - NERVE ENDINGS AND VASCULAR SUPPLY IN SEMITENDINOSUS TENDON OF CEREBRAL PALSY CHILDREN. AB - OBJECTIVE: To evaluate the distribution of SP (substance P) and S-100 peptide immunoreactivity, as well as the vascular supply of tissues commonly used as grafts for anterior cruciate ligament (ACL) reconstruction. A second aim was to compare the above mentioned distribution in the semitendinosus muscle tendons of cerebral palsy (CP) patients with the semitendinosus muscle tendons and patellar tendons of patients without CP. METHODS: The first group consisted of 14 children with cerebral palsy with a mean age of 11.7 years old. At the time of hamstring lengthening operation, a sample of semitendinosus muscle was taken for analysis. The second group comprised 20 patients treated for isolated ACL rupture of the knee (mean age 32 years old). Group three comprised ten patients in the mean age of 14.3 years old treated for recurrent lateral patellar dislocation, and from whom a sample of patellar tendon was obtained. RESULTS: No statistically significant differences were demonstrated with regard to the amount of immunopositive nerve fibers expressing SP or S-100 in all 3 groups of patients. A significant difference was noted in the number of blood vessels between the adult and child semitendinosus muscles, but not between the semitendinosus muscles and patellar tendon of children. CONCLUSION: The number of nociceptors as well as proprioceptive fibers is similar in patients with CP and patients from a neurologically healthy population. Level of Evidence IV, Cases Series. PMID- 26981035 TI - COMPARATIVE STUDY BETWEEN OSTEOSYNTHESIS IN CONVENTIONAL AND BIOABSORBABLE IMPLANTS IN ANKLE FRACTURES. AB - OBJECTIVE: To compare the functional results of ankle fractures treated with metallic and absorbable plates. Twenty patients were randomized into two groups (metallic and absorbable implant groups) and followed prospectively. In the immediate postoperative period, patients were immobilized with plaster casts for one week, which was replaced by a removable cast for another four weeks. Partial weight-bearing was allowed after three weeks, and full weight-bearing after six weeks. Functional recovery was similar in both groups. At six months, three patients in the metallic group complained of local pain, and had their implants removed. One patient in the absorbable group exhibited early dehiscence of the suture and underwent debridement and suturing with good evolution. The American Orthopaedic Foot and Ankle Society (AOFAS) score was similar between the two groups after six and nine months of follow-up. The absorbable implants showed clinical and functional results that were similar to those of metallic implants. Level of Evidence II, Prospective Comparative Study. PMID- 26981036 TI - BLEEDING OF FEMORAL HEAD DURING TOTAL HIP ARTHROPLASTY FOR OSTEOARTHROSIS. AB - OBJECTIVE: To evaluate the bleeding of the femoral head on hip osteoarthritis in patients who underwent total hip arthroplasty. METHODS: One hundred and three hips affected by primary hip osteoarthritis were evaluated. After surgical dislocation, the femoral head was divided into four quadrants, and micro perforations were made in order to observe and assess the presence of bleeding, as early type (EB), late type (LB) or without bleeding (WB). RESULTS: We observed early bleeding (EB) in the upper quadrant in 16 hips (15.5%), late bleeding in 14 hips (13.6%) and no bleeding (WB) in 73 hips (70.9%). The anterior quadrant showed EB in 24 hips (23.3%), LB in 7 hips (6.8%) and WB in 72 hips (69.9%). The lower quadrant presented EB in 40 hips (38.8%), LB 14 hips (13.6%) and WB in 49 hips (47.6%). The posterior quadrant showed EB in 39 hips (37.9%), LB 19 hips (18.4%) and WB in 45 hips (43.7%). Comparing BMI and gender, we found no association between these parameters (p> 0.05). CONCLUSIONS: The inferior and posterior quadrant had the highest bleeding levels, following the path of the medial circumflex artery. Level of Evidence III, Therapeutic Study. PMID- 26981037 TI - EPIDEMIOLOGICAL PROFILE OF PATIENTS WITH PROXIMAL HUMERUS FRACTURE TREATED AT HOSPITAL SAO PAULO, BRAZIL. AB - OBJECTIVE: To analyze the epidemiological aspects of proximal humerus fractures and describe the profile of patients with proximal humerus fractures hospitalized and treated at Hospital Sao Paulo, between 2008 and 2013. METHODS: Hospital records were retrospectively analyzed for surgically treated patients diagnosed with proximal humerus fracture. Age, gender, injury mechanism, length of hospital stay, performed treatment and associated diseases were considered. RESULTS: From all patients studied, 52 were female at their sixth decade of life. As for the injury mechanism, fall from height was the main cause for women (88.46%) and for man it was motorcycle accidents (31.42%). Fixation with locked plate was the most frequently used treatment. CONCLUSION: Most patients were female in their fifth decade of life, injured mainly by fall from height. Fixation with locked plate was the most frequently used treatment and the patients were admitted for 7 days, on average. Level of Evidence II, Retrospective Study. PMID- 26981038 TI - PROPRIOCEPTION, BODY BALANCE AND FUNCTIONALITY IN INDIVIDUALS WITH ACL RECONSTRUCTION. AB - OBJECTIVE: : To evaluate and compare proprioception, body balance and knee functionality of individuals with or without unilateral anterior cruciate ligament (ACL) reconstruction. METHODS: : Forty individuals were divided in two groups: Experimental group, 20 individuals with ACL reconstruction at six months postoperative, and control group, 20 individuals with no history of lower limb pathologies. In the experimental group, we assessed lower limbs with reconstructed ACL and contralateral limb; in the control group the dominant and the non-dominant lower limbs were assessed. All subjects were submitted to joint position sense test to evaluate proprioception, postural control measure in single-limb, and step up and down (SUD) test for functional assessment. RESULTS: : There were no deficits in proprioception and postural control. In the SUD test, a 5% decrease in lift up force was found in reconstructed ACL lower limbs, however, a statistically not significant difference. The impact and step down force during the course of test were 30% greater in anatomic ACL than in control lower limbs. CONCLUSION: : The individuals with ACL reconstruction at six months postoperative did not show changes in proprioception and postural control, but showed motor control changes, influencing knee functionality. Level of Evidence IV, Prognostic Studies. PMID- 26981039 TI - USE OF SPATIOTEMPORAL GAIT PARAMETERS TO DETERMINE RETURN TO SPORTS AFTER ACL RECONSTRUCTION. AB - OBJECTIVE: : To compare gait spatiotemporal parameters of healthy and ACL reconstructed subjects in order to classify the status of gait normality. METHODS: : Fourteen healthy subjects and eight patients submitted to ACL reconstruction walked along a walkway while the lower limbs movement was captured by an infrared camera system. The frames where the initial contact and toe-off took place were determined and the following dependent variables, which were compared between groups through the Mann-Whitney test (a=0.05) were calculated: percentage of time in initial double stance, percentage of time in single stance, percentage of time in terminal double stance, stride length and gait velocity. Initially, all variables were compared between groups using a Mann-Whitney test. A logistic regression was applied, including all dependent variables, to create a model that could differentiate healthy and ACL reconstructed subjects. RESULTS: : ACL reconstructed group showed no differences in any spatiotemporal parameter of gait (p > 0.05) in relation to the control group, although the angular kinematic differences of the knee remained altered, as evidenced in a study with a similar sample. CONCLUSION: : The regression classified all subjects as healthy, including the ACL reconstructed group, suggesting the spatiotemporal variables should not be used as the sole criterion of return to sports activities at the same level as prior to injury. Level of Evidence III, Case Control Study. PMID- 26981040 TI - CLINICAL AND RADIOGRAPHIC EVALUATION OF ELBOWS FROM SPINAL CORD INJURIED PATIENTS. AB - OBJECTIVES: : To evaluate clinically and radiologically the elbows of spinal cord injured patients and compare them to the control group. METHODS: : Twenty patients (10 paraplegics and 10 tetraplegics) were clinically evaluated through assessment of pain scale, measurement of active and passive range of motion, degree of muscle strength and MEPS score. They were also submitted to bilateral plain radiography of the elbows. Both groups were compared to the control group. RESULTS: : Four paraplegic and three tetraplegic patients referred mild to moderate, sporadic and motion related pain. The control group was asymptomatic. No statistic significant difference was found in passive range of motion among the three groups. The tetraplegic group showed a lower active range of motion as well as lower MEPS score as compared to the control group. Equal number of patients in the spinal cord injured patients had radiological abnormalities, but those were more severe in the tetraplegic group. CONCLUSION: : Spinal cord injured patients presented clinical and radiological elbow abnormalities, which were more evident on tetraplegics. Level of Evidence III, Case Control. PMID- 26981041 TI - EVALUATION OF CHILDREN WITH RADIAL NECK FRACTURES TREATED WITH FLEXIBLE INTRAMEDULLARY NAIL. AB - OBJECTIVE: : To evaluate the results of displaced radial neck fractures in children trated surgically with flexible titanium intramedullary nails. METHOD: : This is a retrospective study of five cases of radial neck fractures with displacement greater than 30 degrees fixed with flexible intramedullary nails. Patients were evaluated regarding functional outcome through range of motion and the Mayo Elbow Performance Score (MEPS), as well as radiographic exams. RESULTS: : Five patients, with a mean age of 8.4 years were assessed, during a mean post operative follow up of 12.2 months. Open reduction was necessary in three cases with major displacement. At the end of the follow up, 80% of the patients had excellent results, 20% good results, and all fractures healed. As complications we observed: heterotopic ossification, superficial infection and radial head necrosis. CONCLUSIONS: : In spite of the small sample, our results with flexible titanium intramedullary nails were similar to the current literature, with good functional outcomes. Level of Evidence III, Retrospective Study. PMID- 26981042 TI - MANAGEMENT OF INFANTILE BLOUNT'S DISEASE WITH MOLDED ORTHOSES: A NEW PERSPECTIVE. AB - OBJECTIVE: : This retrospective study evaluated treatment with individually contoured molded bracing at early stages of the disease. METHODS: : We evaluated the medical records of patients undergoing treatment of Blount's disease with molded orthoses for medial decompression between 2010 and 2014. The deformity angle (Drennan's metaphyseal-diaphyseal angle) and Langenskiold classification were measured before and after treatment by a pediatric orthopedic surgeon with over 5 years of practice, blinded for the study and patients. RESULTS: : The mean age was 2.57 years old. Four patients were female and six male. Half of the total sample had bilateral disease. The average deformity angle showed a statistically significant reduction after treatment (p <0.001). Gender and laterality did not statistically influence the change of the deformity angle after treatment (p> 0.05). CONCLUSION: : The nightly use of molded orthoses for medial decompression was effective in reducing the metaphyseal-diaphyseal angle in Blount's disease in children under 3 years of age, regardless of gender and bilateral disease. Patients over 3 years old did not benefit from bracing. Level of Evidence IV, Case Series. PMID- 26981043 TI - ASSESSMENT OF REPRODUCIBILITY OF SANDERS CLASSIFICATION FOR CALCANEAL FRACTURES. AB - OBJECTIVE: : To assess intra- and interobserver reproducibility of Sanders Classification System of calcaneal fractures among experienced and less experienced observers. METHODS: : Forty-six CT scans of intra-articular calcaneal fractures were reviewed. Four observers, two with ten years of experience in foot and ankle surgery and two third-year residents in Orthopedics and Traumatology classified the fractures on two separate occasions three weeks apart from each other. The intra and inter-observer reliability was analyzed using the Kappa index. RESULTS: : There was good intraobserver reliability for the two experienced observers and one less experienced observer (Kappa values 0.640, 0.632 and 0.629, respectively). The interobserver reliability was fair between the experienced observers (Kappa = 0.289) and moderate among the less experienced observers (Kappa = 0.527). CONCLUSIONS: : The Sanders Classification System showed good intraobserver reliability, but interobserver reproducibility below the ideal level, both among experienced and less experienced observers. Level of Evidence III, Diagnostic Studies. PMID- 26981044 TI - INTRAMUSCULAR MARTIN-GRUBER ANASTOMOSIS. AB - OBJECTIVE: : This paper reports the incidence, origin, course and anatomical relationships of intramuscular Martin-Gruber anastomosis. METHODS: : Anatomical dissection of 100 limbs from 50 adults cadavers was performed. The intramuscular Martin-Gruber anastomosis was found in five forearms, three in the right and two in the left side, one was bilateral. All communication were located between the anterior interosseous nerve and the ulnar nerve. CONCLUSION: : The purpose of intramuscular Martin-Gruber anastomosis, which we found in 5% of dissected limbs, is to supply the flexor digitorum profundus muscle and it is unlikely to have any influence on the innervation of the intrinsic muscles of the hand. Level of Evidence IV, Cases Series. PMID- 26981045 TI - GLYCOSAMINOGLYCANS AND PROTEOGLYCANS IN PALMAR FASCIA OF PATIENTS WITH DUPUYTREN. AB - OBJECTIVE: : To evaluate and compare the behavior of glycosaminoglycans (GAGs) in Dupuytren disease (DD). METHODS: : This is an experimental study with 23 patients diagnosed with DD. Tissue collected through fasciectomy with incision type Brunner or McCash were evaluated by electrophoresis for identification of GAGs. The quantification was carried out by immunofluorescence and dosage of proteins for different types of glycosaminoglycans. The results were expressed in percentage and statistically evaluated. RESULTS: : A significant increase was observed through eletrophoresis in GAGs, as compared to the control (p<0.05). Immunofluorescence of hyaluronic acid was reduced (23 times) when compared to the control (p<0.0001). CONCLUSION: : An increase of sulfated GAGs in Dupuytren's disease, mainly dermatan sulfate, was evident from our results, as well as a pronounced decrease of hyaluronic acid in the palmar aponeurosis from the same patients. Level of Evidence III, Case-Control Study. PMID- 26981046 TI - CADAVERIC STUDY ON THE LEARNING CURVE OF THE TWO-APPROACH GANZ PERIACETABULAR OSTEOTOMY. AB - OBJECTIVE: : The Bernese periacetabular osteotomy (PAO) is a widely used technique for the treatment of non-arthritic, dysplastic, painful hips. It is considered a highly complex procedure with a steep learning curve. In an attempt to minimize complications, a double anterior-posterior approach has been described. We report on our experience while performing this technique on cadaveric hips followed by meticulous dissection to verify possible complications. METHODS: : We operated on 15 fresh cadaveric hips using a combined posterior Kocher-Langenbeck and an anterior Smith-Petersen approach, without fluoroscopic control. The PAO cuts were performed and the acetabular fragment was mobilized. A meticulous dissection was carried out to verify the precision of the cuts. RESULTS: : Complications were observed in seven specimens (46%). They included a posterior column fracture, and posterior and anterior articular fractures. The incidence of complications decreased over time, from 60% in the first five procedures to 20% in the last five procedures. CONCLUSIONS: : We concluded that PAO using a combined anterior-posterior approach is a reproducible technique that allows all cuts to be done under direct visualization. The steep learning curve described in the classic single incision approach was also observed when using two approaches. EVIDENCE LEVEL: IV, Cadaveric Study. PMID- 26981047 TI - PERPENDICULAR DOUBLE-PLATE FIXATION WITH LOCKING SYSTEM FOR ACROMION PEDICLE FRACTURE. AB - OBJECTIVE: : To describe the surgical technique and preliminary clinical outcomes in a series of open reduction internal fixation of basal acromion process fractures applying a double-plating technique. METHODS: : Nine consecutive patients, mean age 33.4 years old (range, 23-61 years old) with unilateral acromion fracture (Type 3 AO/OTA) with more than 1cm displacement who underwent fixation utilizing a locked double-plating technique, were evaluated on average at 7.8 months (range, 3-15 months) for outcomes related to pain, shoulder function, and surgical complications. RESULTS: : Eight patients recovered with complete radiographic union and favorable shoulder function. One case failed to be fully evaluated for more than 3 months follow-up. The overall scores of Constant, Shoulder Pain and Disability Index (SPADI) and DASH for the eight patients reviewed were 91.9+/- 6.31, 3.11+/- 3.79 and 5.2+/- 6.35, respectively. No post-operative infection or surgical hardware irritation was identified at final follow-up of these eight patients. CONCLUSION: : While more evidence is needed to justify its advantages over traditional implants, perpendicular double plate with a locking system may be indicated for acromion pedicle fracture treatment, since it performed well for fracture healing and joint function rehabilitation. Level of Evidence IV, Therapeutic Study. PMID- 26981048 TI - A case control study of the factors associated with occurrence of aerodigestive foreign bodies in children in a regional referral hospital in South Western Uganda. AB - BACKGROUND: Aerodigestive foreign bodies (ADFB) in children are a common emergency in ENT clinics globally. The aim of this study was to determine the prevalence and common types of ADFB's presenting to a referral hospital in South Western Uganda, and to review clinical presentation and factors that influence their occurrence among children under 12 years of age. METHODS: We conducted a case control study comprising 40 cases and 80 unmatched controls. Consecutive and random sampling were used for the cases and controls respectively. A questionnaire was used to collect data. Clinic records were reviewed to calculate prevalence. RESULTS: Prevalence was 6.6 % of all paediatric cases seen in the ENT department that year. The most common symptoms included: history of choking [45 %], sudden cough [72.5 %], stridor [60 %] and failure to swallow [35 %]. The most common location for an airway foreign body was the right main bronchus [40 %] and the upper one third of the oesophagus [32.5 %] for digestive tract foreign bodies. Seeds and coins were most frequently removed. Children from upper level SES had a significantly lower risk of foreign body occurrence [OR = 0.29, p = 0.02] compared to those from a low SES. Also significantly, most cases were referrals from other government health centres [p = <0.01]. The male to female ratio among cases was 2:1. Children of older mothers were less likely to have an ADFB. CONCLUSION: Prevalence of ADFB's is relatively high. The most common symptoms are a history of choking, cough and failure to swallow. Age under 5 years, male sex, younger maternal age and low socioeconomic status increased odds of ADFBs. PMID- 26981049 TI - Knockdown of PSCA induces EMT and decreases metastatic potentials of the human prostate cancer DU145 cells. AB - BACKGROUND: Prostate stem cell antigen (PSCA) expression has been shown to correlate with prostatic carcinogenesis and prostate cancer (PCa) progression. The underlying mechanisms for these processes are currently unknown. Epithelial to mesenchymal transition (EMT) has been associated with the invasiveness and the distant metastasis of PCa. In this study, we investigated the effects of knocking down the PSCA on the cell migration, the invasiveness, and the EMT of the PCa cell line DU145 in vitro and in vivo. METHODS: Four target sequences of the small hairpin RNA for PSCA were designed, and the best effect knockdown sequence shRNA#1 was screened to construct the stable transfected DU145 cell line (DU145 shRNA#1), the scramble sequence was also designed to construct the stable transfected DU145 cell line(DU145 scramble). Cell migration and invasion were studied using Transwell assay. Quantitative RT-PCR, Western blot (WB) were used to quantify PSCA, E-cadherin, beta-catenin, Vimentin, Fibronectin expression in DU145, DU145 scramble, DU145 shRNA#1 in vitro and in vivo. RT-PCR, immunofluorescent staining were used to quantify PSCA, E-cadherin, and Vimentin expression in vitro. EMT-related genes Snail, Slug, and Twist, were quantified by quantitative RT-PCR in vitro. RESULTS: The constructed stable knockdown of the PSCA in the DU145 cell had a silencing effect up to 90.5 %. DU145 shRNA#1 became scattered from the tightly packed colonies. It was associated with decreased cell migration and invasion. There was also an increased Vimentin and Fibronectin expression, an inhibited E-cadherin and beta-catenin expression at both the mRNA and the protein levels when compared to the DU145 and the DU145 scramble in vitro and vivo. Furthermore, with the exception of the Snail, the expression of EMT related Slug and Twist genes were upregulated. CONCLUSIONS: Our data indicated that knockdown of PSCA induced EMT and reduced metastatic potentials of the DU145 cells, suggesting that PSCA played an important role in prostatic carcinogenesis and progression. PMID- 26981051 TI - Lets Address Health and Well-Being in Our Profession. PMID- 26981050 TI - Causes of death in Vanuatu. AB - BACKGROUND: The population of the Pacific Melanesian country of Vanuatu was 234,000 at the 2009 census. Apart from subsistence activities, economic activity includes tourism and agriculture. Current completeness of vital registration is considered too low to be usable for national statistics; mortality and life expectancy (LE) are derived from indirect demographic estimates from censuses/surveys. Some cause of death (CoD) data are available to provide information on major causes of premature death. METHODS: Deaths 2001-2007 were coded for cause (ICDv10) for ages 0-59 years from: hospital separations (HS) (n = 636), hospital medical certificates (MC) of death (n = 1,169), and monthly reports from community health facilities (CHF) (n = 1,212). Ill-defined causes were 3 % for hospital deaths and 20 % from CHF. Proportional mortality was calculated by cause (excluding ill-defined) and age group (0-4, 5-14 years), and also by sex for 15-59 years. From total deaths by broad age group and sex from 1999 and 2009 census analyses, community deaths were estimated by deduction of hospital deaths MC. National proportional mortality by cause was estimated by a weighted average of MC and CHF deaths. RESULTS: National estimates indicate main causes of deaths <5 years were: perinatal disorders (45 %) and malaria, diarrhea, and pneumonia (27 %). For 15-59 years, main causes of male deaths were: circulatory disease 27 %, neoplasms 13 %, injury 13 %, liver disease 10 %, infection 10 %, diabetes 7 %, and chronic respiratory disease 7 %; and for females: neoplasms 29 %, circulatory disease 15 %, diabetes 10 %, infection 9 %, and maternal deaths 8 %. Infection included tuberculosis, malaria, and viral hepatitis. Liver disease (including hepatitis and cancer) accounted for 18 % of deaths in adult males and 9 % in females. Non-communicable disease (NCD), including circulatory disease, diabetes, neoplasm, and chronic respiratory disease, accounted for 52 % of premature deaths in adult males and 60 % in females. Injuries accounted for 13 % in adult males and 6 % in females. Maternal deaths translate into an annual maternal mortality ratio of 130/100,000 for the period. CONCLUSION: Vanuatu manifests a double burden of disease with significant proportional mortality from perinatal disorders and infection/pneumonia <5 years and maternal mortality, coupled with significant proportional mortality in adults (15-59 years) from cardiovascular disease (CVD), neoplasms, and diabetes. PMID- 26981052 TI - The Axillary View Typically Does Not Contribute to Decision Making in Care for Proximal Humeral Fractures. AB - BACKGROUND: Convention dictates that an axillary view be obtained when evaluating proximal humerus fractures (PHF). However, the axillary view is frequently omitted because of pain and technical considerations. Furthermore, its diagnostic utility is unclear in this setting. QUESTIONS/PURPOSES: The purpose of this study was to (1) determine the rate of obtaining an adequate axillary X-ray and complete shoulder series at a level I trauma center, (2) understand the cost of ordering and attempting an axillary radiograph, and (3) determine if axillary radiographs influence the management of PHF. PATIENTS AND METHODS: PHF treated between 2009 and 2011 that were ordered for an AP, scapular Y, and axillary view was identified. The types of radiographs actually obtained were recorded. The cost of obtaining three views and a single view of the shoulder with X-ray was determined. Lastly, three surgeons reviewed 42 PHF, both with and without an axillary view (AV), and treatment recommendations were compared. RESULTS: 30% of PHF in this series had an adequate axillary view, and 14% received a complete trauma series. No factors could be identified that were associated with successfully obtaining an axillary view. Reviewers demonstrated substantial intraobserver reliability (kappa = 0.759-0.808) regarding treatment recommendations for PHF with and without the axillary view. The addition of the AV had minimal influence on treatment recommendations. CONCLUSION: Considering that the axillary view for PHF is painful, labor-intensive, costly, and does not appear to provide additional diagnostic value, orthopedic surgeons can consider foregoing the use of the axillary view when evaluating and treating PHF, particularly if other advanced imaging is utilized. PMID- 26981053 TI - High Rates of Occult Infection After Shoulder Fracture Fixation: Considerations for Conversion Shoulder Arthroplasty. AB - BACKGROUND: Existing hardware may contribute to increased risk of bacterial contamination and subsequent periprosthetic joint infection (PJI) in conversion shoulder arthroplasty performed for failed fracture fixation. QUESTIONS/PURPOSES: This study examined the incidence of positive pre-operative aspiration and inflammatory marker data, along with correlation of pre-operative positive aspiration or inflammatory markers and subsequent infection following conversion shoulder arthroplasty for failed open reduction and internal fixation (ORIF) and the need for re-operation at 4.6-year follow-up. METHODS: Twenty-eight patients who underwent conversion to shoulder arthroplasty for any reason after fracture fixation were retrospectively reviewed in a single center. A pre-operative aspiration was done in 17 patients; all patients had intra-operative tissue sampling. All procedures were single-stage removal of hardware and performance of the arthroplasty. In cases of pre-operative positive bacterial growth, a single stage procedure was performed according to the septic ENDO-Klinik protocol. RESULTS: In 4 of 17 pre-operative joint aspirations, bacterial growth was detected; one pre-operative negative aspiration demonstrated bacterial growth in intra-operative sampling. In three of them, the infection has been validated through intra-operatively results. Pre-operative aspiration showed a sensitivity of 75% and specificity of 92% (p < 0.005) for infection. No post-operative PJIs were observed. Six revisions were performed, most commonly for aseptic loosening (two cases) and conversion of hemiarthroplasty to a reverse design (two cases). CONCLUSIONS: In conclusion, the risk of low-grade shoulder infection after fracture osteosynthesis may be higher than in hip and knee joints, based on limited study data. Adequate pre-operative testing is recommended to rule out occult shoulder infection in this setting. PMID- 26981054 TI - Capitellum Fracture Fragment Excision: a Case Series. AB - BACKGROUND: Fractures of the capitellum are rare injuries, and few studies have reported the results of fragment excision. QUESTIONS/PURPOSES: The purpose of this study was to determine range of motion and short-term clinical outcomes for patients treated with capitellum excision. METHODS: A retrospective review was performed to identify all patients with an isolated capitellum fracture who underwent excision as definitive treatment at our institutions. Mechanism of injury, associated elbow injuries, type of capitellum fracture, complications, and postoperative outcomes including final elbow range of motion (ROM), elbow instability, and Disabilities of the Arm, Shoulder and Hand (DASH) score were recorded. RESULTS: Four patients met the inclusion and exclusion criteria of this study. All patients were female with an average age of 69 years (range 42-85). Based on the Bryan and Morrey classification system, three (75%) fractures were classified as type I and one (25%) fracture as type III. The average clinical follow-up was 11 months. Final examination demonstrated a mean elbow range of motion from 14 degrees (range 0-30) of extension to 143 degrees (range 130-160) of flexion. All patients had full forearm rotation, and there was no clinical evidence of elbow instability. The average DASH score was 18.3 (12.5-24.2) at final follow-up. CONCLUSION: Excision of the capitellum, much like excision of the radial head, results in acceptable short-term outcome scores and elbow range of motion in patients with fractures that are not amenable to open reduction and internal fixation. PMID- 26981055 TI - Older Age and Leg Pain Are Good Predictors of Pain and Disability Outcomes in 2710 Patients Who Receive Lumbar Fusion. AB - BACKGROUND: Identifying appropriate candidates for lumbar spine fusion is a challenging and controversial topic. The purpose of this study was to identify baseline characteristics related to poor/favorable outcomes at 1 year for a patient who received lumbar spine fusion. QUESTIONS/PURPOSES: The aims of this study were to describe baseline characteristics of those who received lumbar surgery and to identify baseline characteristics from a spine repository that were related to poor and favorable pain and disability outcomes for patient who received lumbar fusion (with or without decompression), who were followed up for 1 full year and discriminate predictor variables that were either or in contrast to prognostic variables reported in the literature. METHODS: This study analyzed data from 2710 patients who underwent lumbar spine fusion. All patient data was part of a multicenter, multi-national spine repository. Ten relatively commonly captured data variables were used as predictors for the study. Univariate/multivariate logistic regression analyses were run against outcome variables of pain/disability. RESULTS: Multiple univariate findings were associated with pain/disability outcomes at 1 year including age, previous surgical history, baseline disability, baseline pain, baseline quality of life scores, and leg pain greater than back pain. Notably significant multivariate findings for both pain and disability include older age, previous surgical history, and baseline mental summary scores, disability, and pain. CONCLUSION: Leg pain greater than back pain and older age may yield promising value when predicting positive outcomes. Other significant findings may yield less value since these findings are similar to those that are considered to be prognostic regardless of intervention type. PMID- 26981057 TI - Comorbid Profile Rather than Age Determines Hip Fracture Mortality in a Nonagenarian Population. AB - BACKGROUND: In light of poor outcomes with nonoperative management of hip fractures, orthopedic surgeons are faced with difficult decisions about which patients are too ill or too old for surgical treatment. QUESTIONS/PURPOSES: This study sought to investigate if patients over 90 years had different preoperative laboratory, clinical, and injury characteristics than younger patients with the same injury. We compared our cohort with previously published data. We wished to identify if there were pre-injury risk factors associated with 30-day mortality, which could be modified to enhance postoperative outcomes. METHODS: This is a retrospective review of 198 operatively managed hip fractures in patients 75 years or older. We collected data on demographics, select preoperative laboratory values, injury type, comorbidities, and 30-day mortality. RESULTS: Eleven (5.6%) of the cohort died within 30 days of surgery, 6.3% in the younger group, and 3.7% in the older group; the difference was not statistically significant. For baseline characteristics, there was no difference between the age groups for pre injury comorbidities, hemoglobin, serum albumin, BUN, prevalence of UTI, or fracture type. A total of 67 (35.8%) patients had evidence of UTI on admission. CONCLUSIONS: These findings reveal that in our dichotomized cohort, pre-injury characteristics were similar and age alone was not an independent predictor of mortality. These data may inform decision-making for orthopedic surgeons and the medical providers who consult to optimize these patients for surgery. We identified high rates of UTI in both age groups, a potentially remediable factor to optimize outcomes in hip fracture surgery in elderly patients. PMID- 26981056 TI - Do Current Recommendations for Upper Instrumented Vertebra Predict Shoulder Imbalance? An Attempted Validation of Level Selection for Adolescent Idiopathic Scoliosis. AB - BACKGROUND: Shoulder balance for adolescent idiopathic scoliosis (AIS) patients is associated with patient satisfaction and self-image. However, few validated systems exist for selecting the upper instrumented vertebra (UIV) post-surgical shoulder balance. QUESTIONS/PURPOSES: The purpose is to examine the existing UIV selection criteria and correlate with post-surgical shoulder balance in AIS patients. METHODS: Patients who underwent spinal fusion at age 10-18 years for AIS over a 6-year period were reviewed. All patients with a minimum of 1-year radiographic follow-up were included. Imbalance was determined to be radiographic shoulder height |RSH| >= 15 mm at latest follow-up. Three UIV selection methods were considered: Lenke, Ilharreborde, and Trobisch. A recommended UIV was determined using each method from pre-surgical radiographs. The recommended UIV for each method was compared to the actual UIV instrumented for all three methods; concordance between these levels was defined as "Correct" UIV selection, and discordance was defined as "Incorrect" selection. RESULTS: One hundred seventy-one patients were included with 2.3 +/- 1.1 year follow-up. For all methods, "Correct" UIV selection resulted in more shoulder imbalance than "Incorrect" UIV selection. Overall shoulder imbalance incidence was improved from 31.0% (53/171) to 15.2% (26/171). New shoulder imbalance incidence for patients with previously level shoulders was 8.8%. CONCLUSIONS: We could not identify a set of UIV selection criteria that accurately predicted post-surgical shoulder balance. Further validated measures are needed in this area. The complexity of proximal thoracic curve correction is underscored in a case example, where shoulder imbalance occurred despite "Correct" UIV selection by all methods. PMID- 26981058 TI - Lower-Dose Mepivacaine Plus Fentanyl May Improve Spinal Anesthesia for Knee Arthroscopy. AB - BACKGROUND: Previous work indicates that 30 mg isobaric mepivacaine 1.5% plus 10 MUg fentanyl produces reliable anesthesia for knee arthroscopy with a more rapid recovery profile than 45 mg mepivacaine. QUESTIONS/PURPOSES: This randomized controlled trial compared plain mepivacaine to three reduced doses of mepivacaine with 10 MUg fentanyl for spinal anesthesia. METHODS: Following written informed consent, subjects undergoing outpatient knee arthroscopy were prospectively randomized into one of four groups: mepivacaine 37.5 mg (M37.5); mepivacaine 30 mg plus fentanyl 10 MUg (M30/F10); mepivacaine 27 mg plus fentanyl 10 MUg (M27/F10); and mepivacaine 24 mg plus fentanyl 10 MUg (M24/F10). The spinal was evaluated by the blinded anesthetist and surgeon. In the post-anesthesia care unit, sensory and motor block resolution was assessed. Subjects rated their satisfaction with the overall experience. RESULTS: Group M30/F10 (n = 6) had two "fair" anesthetics, and group M27/F10 (n = 10) had one "fair" and one "inadequate" anesthetic. Both groups were eliminated from further enrollment per study protocol. The recovery profiles showed little difference between groups M37.5 and M30/F10, except for motor block resolution (median (25th percentile, 75th percentile): 171 (135, 195) and 128 (120, 135), respectively). Groups M27/F10 and M24/F10 demonstrated recovery profiles that were faster than group M37.5. Patient satisfaction was 10/10 for all groups. CONCLUSIONS: Adding fentanyl 10 MUg to a lower dose of mepivacaine 1.5% can lead to quicker recovery profiles. However, this advantage of a quicker recovery must be weighed against the likelihood of an incomplete anesthetic. PMID- 26981059 TI - Modified Lapidus Procedure with Joint Compression, Meticulous Surface Preparation, and Shear-Strain-Relieved Bone Graft Yields Low Nonunion Rate. AB - BACKGROUND: The modified Lapidus procedure is widely used to correct hallux valgus but has been reported with high nonunion rates. In this study, we retrospectively reviewed the nonunion rate of the modified Lapidus procedure performed with rigid cross screw fixation, meticulous joint preparation, and shear-strain-relieved calcaneal bone graft. QUESTIONS/PURPOSES: Does the performance of the Lapidus procedure with rigid cross screw fixation, complete joint preparation, and shear-strain-relieved calcaneal bone graft achieve higher union rates than currently reported? If nonunion does occur, what is the clinical course? METHODS: We reviewed both radiographic and clinical results of the modified Lapidus procedure with the above technique in 171 patients (182 feet). Evaluation included age, gender, tobacco use, diabetic status, and radiographic analysis at least 3 months postoperatively. RESULTS: The modified Lapidus procedure described above resulted in a union rate of 97.3% (177 of 182 feet). Three of the five feet with radiographic nonunions were clinically symptomatic. CONCLUSIONS: The union rate of the modified Lapidus procedure is higher than previously reported when performed with rigid cross screw fixation, meticulous joint preparation, and shear-strain-relieved bone graft. Nonunion of the first tarsometatarsal joint should be considered an infrequent occurrence. PMID- 26981061 TI - A Case Report of Familial Mediterranean Fever Diagnosed Following the Total Knee Arthroplasty. PMID- 26981062 TI - Peri-operative DDAVP Use Leading to Severe Hyponatremia after Total Shoulder Replacement in a Patient with von Willebrand's Disease. PMID- 26981060 TI - Low Vitamin D Levels in Children with Fractures: a Comparative Cohort Study. AB - BACKGROUND: The currently accepted ranges for "normal" serum vitamin D have recently been challenged in adults on the basis that healthy bone metabolism requires higher levels of vitamin D than previously thought. PURPOSE: The purpose of this study was to evaluate whether a new "biologically based" classification based on 25(OH)vitamin D levels that invoke an endocrine biomarker response (<20 ng/mL for deficiency and <32 ng/mL for insufficiency) is more appropriate for children with fractures than historical criteria. METHODS: Serum 25(OH)vitamin D levels were collected from 58 children with acute low-energy fractures from an outpatient orthopedic clinic from 2009 to 2012. These vitamin D levels were compared with a cohort of 103 children with chronic kidney disease (CKD) from an adjacent clinic, a condition with acknowledged low levels of vitamin D. Then, the prevalence of vitamin D sufficiency in the fracture cohort was evaluated and compared using both historical guidelines and newer biologically based criteria. RESULTS: 25(OH)vitamin D levels in the fracture cohort did not differ from levels in the CKD cohort (27.5 vs. 24.6 ng/mL) indicating a similar distribution of vitamin D levels. This finding was consistent when controlling for significant covariables using linear regression analyses. In the fracture cohort, there was a discrepancy between historical and biologically based criteria in 64% of children. CONCLUSIONS: The results of the current study suggest that fracture patients are more frequently vitamin D deficient than previously thought. This finding is more readily apparent when newer biologically based criteria for vitamin D sufficiency are used. PMID- 26981063 TI - Stem-Sleeve Junction Failure of a Modular Femoral Hip System: a Retrieval Analysis. PMID- 26981064 TI - Closing Verses Opening Wedge High Tibial Osteotomy: an Evidence-Based Review. PMID- 26981066 TI - Letter from the Editors-in-Chief. PMID- 26981065 TI - 24-Hour Fitness: the Orthopedic Resident On-Call Workout. PMID- 26981067 TI - New era of treatment and evaluation of traumatic brain injury and spinal cord injury. PMID- 26981068 TI - Magnetic resonance imaging and cell-based neurorestorative therapy after brain injury. AB - Restorative cell-based therapies for experimental brain injury, such as stroke and traumatic brain injury, substantially improve functional outcome. We discuss and review state of the art magnetic resonance imaging methodologies and their applications related to cell-based treatment after brain injury. We focus on the potential of magnetic resonance imaging technique and its associated challenges to obtain useful new information related to cell migration, distribution, and quantitation, as well as vascular and neuronal remodeling in response to cell based therapy after brain injury. The noninvasive nature of imaging might more readily help with translation of cell-based therapy from the laboratory to the clinic. PMID- 26981069 TI - A brief report on MRI investigation of experimental traumatic brain injury. AB - Traumatic brain injury is a major cause of death and disability. This is a brief report based on a symposium presentation to the 2014 Chinese Neurotrauma Association Meeting in San Francisco, USA. It covers the work from our laboratory in applying multimodal MRI to study experimental traumatic brain injury in rats with comparisons made to behavioral tests and histology. MRI protocols include structural, perfusion, manganese-enhanced, diffusion-tensor MRI, and MRI of blood brain barrier integrity and cerebrovascular reactivity. PMID- 26981070 TI - The potential of neural transplantation for brain repair and regeneration following traumatic brain injury. AB - Traumatic brain injury is a major health problem worldwide. Currently, there is no effective treatment to improve neural structural repair and functional recovery of patients in the clinic. Cell transplantation is a potential strategy to repair and regenerate the injured brain. This review article summarized recent development in cell transplantation studies for post-traumatic brain injury brain repair with varying types of cell sources. It also discussed the potential of neural transplantation to repair/promote recovery of the injured brain following traumatic brain injury. PMID- 26981071 TI - RhoA/Rho kinase in spinal cord injury. AB - A spinal cord injury refers to an injury to the spinal cord that is caused by a trauma instead of diseases. Spinal cord injury includes a primary mechanical injury and a much more complex secondary injury process involving inflammation, oxidation, excitotoxicity, and cell death. During the secondary injury, many signal pathways are activated and play important roles in mediating the pathogenesis of spinal cord injury. Among them, the RhoA/Rho kinase pathway plays a particular role in mediating spinal degeneration and regeneration. In this review, we will discuss the role and mechanism of RhoA/Rho kinase-mediated spinal cord pathogenesis, as well as the potential of targeting RhoA/Rho kinase as a strategy for promoting both neuroprotection and axonal regeneration. PMID- 26981072 TI - Direct reprogramming of somatic cells into neural stem cells or neurons for neurological disorders. AB - Direct reprogramming of somatic cells into neurons or neural stem cells is one of the most important frontier fields in current neuroscience research. Without undergoing the pluripotency stage, induced neurons or induced neural stem cells are a safer and timelier manner resource in comparison to those derived from induced pluripotent stem cells. In this prospective, we review the recent advances in generation of induced neurons and induced neural stem cells in vitro and in vivo and their potential treatments of neurological disorders. PMID- 26981073 TI - The progress in optic nerve regeneration, where are we? AB - Optic nerve regeneration is an important area of research. It can be used to treat patients suffering from optic neuropathy and provides insights into the treatment of numerous neurodegenerative diseases. There are many hurdles impeding optic regeneration in mammals. The mammalian central nervous system is non permissive to regeneration and intrinsically lacks the capacity for axonal regrowth. Any axonal injury also triggers a vicious cycle of apoptosis. Understanding these hurdles provides us with a rough framework to appreciate the essential steps to bring about optic nerve regeneration: enhancing neuronal survival, axon regeneration, remyelination and establishing functional synapses to the original neuronal targets. In this review article, we will go through current potential treatments for optic nerve regeneration, which includes neurotrophic factor provision, inflammatory stimulation, growth inhibition suppression, intracellular signaling modification and modeling of bridging substrates. PMID- 26981074 TI - Glucocorticoids and nervous system plasticity. AB - Glucocorticoid and glucocorticoid receptor (GC/GR) interactions alter numerous aspects of neuronal function. These consequences (e.g., anti-inflammatory vs. pro inflammatory) can vary depending on the duration of GC exposure or central nervous system (CNS) injury model. In this review we discuss how GC/GR interactions impact neuronal recovery after a central or peripheral nerve injury and discuss how GC exposure duration can produce divergent CNS neuronal growth responses. Finally we consider how new findings on gender specific immune cell responses after a nerve injury could intersect with GC/GR interactions to impact pain processing. PMID- 26981076 TI - Unmasking the responses of the stem cells and progenitors in the subventricular zone after neonatal and pediatric brain injuries. AB - There is great interest in the regenerative potential of the neural stem cells and progenitors that populate the subventricular zone (SVZ). However, a comprehensive understanding of SVZ cell responses to brain injuries has been hindered by the lack of sensitive approaches to study the cellular composition of this niche. Here we review progress being made in deciphering the cells of the SVZ gleaned from the use of a recently designed flow cytometry panel that allows SVZ cells to be parsed into multiple subsets of progenitors as well as putative stem cells. We review how this approach has begun to unmask both the heterogeneity of SVZ cells as well as the dynamic shifts in cell populations with neonatal and pediatric brain injuries. We also discuss how flow cytometric analyses also have begun to reveal how specific cytokines, such as Leukemia inhibitory factor are coordinating SVZ responses to injury. PMID- 26981075 TI - SCYL pseudokinases in neuronal function and survival. AB - The generation of mice lacking SCYL1 or SCYL2 and the identification of Scyl1 as the causative gene in the motor neuron disease mouse model muscle deficient (Scyl1(mdf/mdf) ) demonstrated the importance of the SCY1-like family of protein pseudokinases in neuronal function and survival. Several essential cellular processes such as intracellular trafficking and nuclear tRNA export are thought to be regulated by SCYL proteins. However, whether deregulation of these processes contributes to the neurodegenerative processes associated with the loss of SCYL proteins is still unclear. Here, I briefly review the evidence supporting that SCYL proteins play a role in these processes and discuss their possible involvement in the neuronal functions of SCYL proteins. I also propose ways to determine the importance of these pathways for the functions of SCYL proteins in vivo. PMID- 26981077 TI - Tracking of iron-labeled human neural stem cells by magnetic resonance imaging in cell replacement therapy for Parkinson's disease. AB - Human neural stem cells (hNSCs) derived from the ventral mesencephalon are powerful research tools and candidates for cell therapies in Parkinson's disease. However, their clinical translation has not been fully realized due, in part, to the limited ability to track stem cell regional localization and survival over long periods of time after in vivo transplantation. Magnetic resonance imaging provides an excellent non-invasive method to study the fate of transplanted cells in vivo. For magnetic resonance imaging cell tracking, cells need to be labeled with a contrast agent, such as magnetic nanoparticles, at a concentration high enough to be easily detected by magnetic resonance imaging. Grafting of human neural stem cells labeled with magnetic nanoparticles allows cell tracking by magnetic resonance imaging without impairment of cell survival, proliferation, self-renewal, and multipotency. However, the results reviewed here suggest that in long term grafting, activated microglia and macrophages could contribute to magnetic resonance imaging signal by engulfing dead labeled cells or iron nanoparticles dispersed freely in the brain parenchyma over time. PMID- 26981078 TI - Macrophage polarization in nerve injury: do Schwann cells play a role? AB - In response to peripheral nerve injury, the inflammatory response is almost entirely comprised of infiltrating macrophages. Macrophages are a highly plastic, heterogenic immune cell, playing an indispensable role in peripheral nerve injury, clearing debris and regulating the microenvironment to allow for efficient regeneration. There are several cells within the microenvironment that likely interact with macrophages to support their function - most notably the Schwann cell, the glial cell of the peripheral nervous system. Schwann cells express several ligands that are known to interact with receptors expressed by macrophages, yet the effects of Schwann cells in regulating macrophage phenotype remains largely unexplored. This review discusses macrophages in peripheral nerve injury and how Schwann cells may regulate their behavior. PMID- 26981080 TI - Promoting neuronal regeneration using extracellular vesicles loaded with superparamagnetic iron oxide nanoparticles. PMID- 26981079 TI - Spinal cord concussion: studying the potential risks of repetitive injury. PMID- 26981081 TI - Developmental transcription factors in age-related CNS disease: a phoenix rising from the ashes? PMID- 26981082 TI - The concentration game: differential effects of bioactive signaling in 2D and 3D culture. PMID- 26981083 TI - Skeletal muscle activity and CNS neuro-plasticity. PMID- 26981085 TI - Schwannomas provide insight into the role of p75(NTR) and merlin in Schwann cells following nerve injury and during regeneration. PMID- 26981084 TI - Exploiting kinase polypharmacology for nerve regeneration. PMID- 26981086 TI - Role of neuronal gap junctions in NMDA receptor-mediated excitotoxicity and ischemic neuronal death. PMID- 26981087 TI - Lipid mediators of inflammation in neurological injury: shifting the balance toward resolution. PMID- 26981088 TI - Nootropics with potential to (re)build neuroarchitecture. PMID- 26981089 TI - Polarizing the immune system towards neuroprotection in brain ischemia. PMID- 26981090 TI - Future needs for informed consent in stem cell clinical trials in neurodegenerative diseases. PMID- 26981091 TI - How does resveratrol influence the genesis of some neurodegenerative diseases? PMID- 26981092 TI - Lingo-1: a novel target in therapy for Alzheimer's disease? PMID- 26981093 TI - Mesenchymal stem cells require the peripheral immune system for immunomodulating effects in animal models of multiple sclerosis. PMID- 26981094 TI - Absence of galectin-3 attenuates neuroinflammation improving functional recovery after spinal cord injury. PMID- 26981096 TI - Verbascoside promotes the regeneration of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra. AB - Tyrosine hydroxylase is a key enzyme in dopamine biosynthesis. Change in tyrosine hydroxylase expression in the nigrostriatal system is closely related to the occurrence and development of Parkinson's disease. Verbascoside, an extract from Radix Rehmanniae Praeparata has been shown to be clinically effective in treating Parkinson's disease. However, the underlying mechanisms remain unclear. It is hypothesized that the effects of verbascoside on Parkinson's disease are related to tyrosine hydroxylase expression change in the nigrostriatal system. Rat models of Parkinson's disease were established and verbascoside (60 mg/kg) was administered intraperitoneally once a day. After 6 weeks of verbascoside treatment, rat rotational behavior was alleviated; tyrosine hydroxylase mRNA and protein expression and the number of tyrosine hydroxylase-immunoreactive neurons in the rat right substantia nigra were significantly higher than the Parkinson's model group. These findings suggest that the mechanism by which verbascoside treats Parkinson's disease is related to the regeneration of tyrosine hydroxylase immunoreactive neurons in the substantia nigra. PMID- 26981095 TI - Neuroprotective effect of Shenqi Fuzheng injection pretreatment in aged rats with cerebral ischemia/reperfusion injury. AB - Shenqi Fuzheng injection is extracted from the Chinese herbs Radix Astragali and Radix Codonopsis. The aim of the present study was to investigate the neuroprotective effects of Shenqi Fuzheng injection in cerebral ischemia and reperfusion. Aged rats (20-22 months) were divided into three groups: sham, model, and treatment. Shenqi Fuzheng injection or saline (40 mL/kg) was injected into the tail vein daily for 1 week, after which a cerebral ischemia/reperfusion injury model was established. Compared with model rats that received saline, rats in the treatment group had smaller infarct volumes, lower brain water and malondialdehyde content, lower brain Ca(2+) levels, lower activities of serum lactate dehydrogenase and creatine kinase, and higher superoxide dismutase activity. In addition, the treatment group showed less damage to the brain tissue ultrastructure and better neurological function. Our findings indicate that Shenqi Fuzheng injection exerts neuroprotective effects in aged rats with cerebral ischemia/reperfusion injury, and that the underlying mechanism relies on oxygen free radical scavenging and inhibition of brain Ca(2+) accumulation. PMID- 26981097 TI - Umbilical cord-derived mesenchymal stem cell transplantation combined with hyperbaric oxygen treatment for repair of traumatic brain injury. AB - Transplantation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) for repair of traumatic brain injury has been used in the clinic. Hyperbaric oxygen (HBO) treatment has long been widely used as an adjunctive therapy for treating traumatic brain injury. UC-MSC transplantation combined with HBO treatment is expected to yield better therapeutic effects on traumatic brain injury. In this study, we established rat models of severe traumatic brain injury by pressurized fluid (2.5-3.0 atm impact force). The injured rats were then administered UC-MSC transplantation via the tail vein in combination with HBO treatment. Compared with monotherapy, aquaporin 4 expression decreased in the injured rat brain, but growth-associated protein-43 expression, calaxon-like structures, and CM-Dil positive cell number increased. Following combination therapy, however, rat cognitive and neurological function significantly improved. UC-MSC transplantation combined with HBO therapyfor repair of traumatic brain injury shows better therapeutic effects than monotherapy and significantly promotes recovery of neurological functions. PMID- 26981098 TI - Specific effects of c-Jun NH2-terminal kinase-interacting protein 1 in neuronal axons. AB - c-Jun NH2-terminal kinase (JNK)-interacting protein 3 plays an important role in brain-derived neurotrophic factor/tropomyosin-related kinase B (TrkB) anterograde axonal transport. It remains unclear whether JNK-interacting protein 1 mediates similar effects, or whether JNK-interacting protein 1 affects the regulation of TrkB anterograde axonal transport. In this study, we isolated rat embryonic hippocampus and cultured hippocampal neurons in vitro. Coimmunoprecipitation results demonstrated that JNK-interacting protein 1 formed TrkB complexes in vitro and in vivo. Immunocytochemistry results showed that when JNK-interacting protein 1 was highly expressed, the distribution of TrkB gradually increased in axon terminals. However, the distribution of TrkB reduced in axon terminals after knocking out JNK-interacting protein 1. In addition, there were differences in distribution of TrkB after JNK-interacting protein 1 was knocked out compared with not. However, knockout of JNK-interacting protein 1 did not affect the distribution of TrkB in dendrites. These findings confirm that JNK-interacting protein 1 can interact with TrkB in neuronal cells, and can regulate the transport of TrkB in axons, but not in dendrites. PMID- 26981099 TI - Connectivity differences between adult male and female patients with attention deficit hyperactivity disorder according to resting-state functional MRI. AB - Attention deficit hyperactivity disorder (ADHD) is a pervasive psychiatric disorder that affects both children and adults. Adult male and female patients with ADHD are differentially affected, but few studies have explored the differences. The purpose of this study was to quantify differences between adult male and female patients with ADHD based on neuroimaging and connectivity analysis. Resting-state functional magnetic resonance imaging scans were obtained and preprocessed in 82 patients. Group-wise differences between male and female patients were quantified using degree centrality for different brain regions. The medial-, middle-, and inferior-frontal gyrus, superior parietal lobule, precuneus, supramarginal gyrus, superior- and middle-temporal gyrus, middle occipital gyrus, and cuneus were identified as regions with significant group wise differences. The identified regions were correlated with clinical scores reflecting depression and anxiety and significant correlations were found. Adult ADHD patients exhibit different levels of depression and anxiety depending on sex, and our study provides insight into how changes in brain circuitry might differentially impact male and female ADHD patients. PMID- 26981100 TI - Does hemispheric lateralization influence therapeutic effects of transcranial direct current stimulation? AB - This study investigated the effect of transcranial direct current stimulation (tDCS) polarity depending on lateralized function of task property in normal individuals performing visuomotor and simple repetitive tasks. Thirty healthy participants with no neurological disorders were recruited to participate in this study. Participants were randomly allocated into active or control condition. For the active condition, tDCS intensity was 2 mA with stimulation applied for 15 minutes to the right hemisphere (tDCS condition). For the sham control, electrodes were placed in the same position, but the stimulator was turned off after 30 seconds (sham condition). The tapping and tracking task tests were performed before and after for both conditions. Univariate analysis revealed significant difference only in the tracking task. For direct comparison of both tasks within each group, the tracking task had significantly higher Z score than the tapping task in the tDCS group (P < 0.05). Thus, our study indicates that stimulation of the right hemisphere using tDCS can effectively improve visuomotor (tracking) task over simple repetitive (tapping) task. PMID- 26981101 TI - Traumatic axonal injury of the medial lemniscus pathway in a patient with traumatic brain injury: validation by diffusion tensor tractography. PMID- 26981102 TI - Spatiotemporal expression of Nogo-66 receptor after focal cerebral ischemia. AB - NgR, the receptor for the neurite outgrowth inhibitor Nogo-66, plays a critical role in the plasticity and regeneration of the nervous system after injury such as ischemic stroke. In the present study, we used immunohistochemistry to investigate the regional expression of NgR in rat brain following middle cerebral artery occlusion (MCAO). NgR protein expression was not observed in the center of the lesion, but was elevated in the marginal zone compared with control and sham operated rats. The cerebral cortex and hippocampus (CA1, CA2, and CA3) showed the greatest expression of NgR. Furthermore, NgR expression was higher in the ipsilesional hemisphere than on the control side in the same coronal section. Although time-dependent changes in NgR expression across brain regions had their own characteristics, the overall trend complied with the following rules: NgR expression changes with time showed two peaks and one trough; the first peak in expression appeared between 1 and 3 days after MCAO; expression declined at 5 days; and the second peak occurred at 28 days. PMID- 26981103 TI - Time representation of mitochondrial morphology and function after acute spinal cord injury. AB - Changes in mitochondrial morphology and function play an important role in secondary damage after acute spinal cord injury. We recorded the time representation of mitochondrial morphology and function in rats with acute spinal cord injury. Results showed that mitochondria had an irregular shape, and increased in size. Mitochondrial cristae were disordered and mitochondrial membrane rupture was visible at 2-24 hours after injury. Fusion protein mitofusin 1 expression gradually increased, peaked at 8 hours after injury, and then decreased to its lowest level at 24 hours. Expression of dynamin-related protein 1, amitochondrial fission protein, showed the opposite kinetics. At 2-24 hours after acute spinal cord injury, malondialdehyde content, cytochrome c levels and caspase-3 expression were increased, but glutathione content, adenosine triphosphate content, Na(+)-K(+)-ATPase activity and mitochondrial membrane potential were gradually reduced. Furthermore, mitochondrial morphology altered during the acute stage of spinal cord injury. Fusion was important within the first 8 hours, but fission played a key role at 24 hours. Oxidative stress was inhibited, biological productivity was diminished, and mitochondrial membrane potential and permeability were reduced in the acute stage of injury. In summary, mitochondrial apoptosis is activated when the time of spinal cord injury is prolonged. PMID- 26981104 TI - Treatment with analgesics after mouse sciatic nerve injury does not alter expression of wound healing-associated genes. AB - Animal models of sciatic nerve injury are commonly used to study neuropathic pain as well as axon regeneration. Administration of post-surgical analgesics is an important consideration for animal welfare, but the actions of the analgesic must not interfere with the scientific goals of the experiment. In this study, we show that treatment with either buprenorphine or acetaminophen following a bilateral sciatic nerve crush surgery does not alter the expression in dorsal root ganglion (DRG) sensory neurons of a panel of genes associated with wound healing. These findings indicate that the post-operative use of buprenorphine or acetaminophen at doses commonly suggested by Institutional Animal Care and Use Committees does not change the intrinsic gene expression response of DRG neurons to a sciatic nerve crush injury, for many wound healing-associated genes. Therefore, administration of post-operative analgesics may not confound the results of transcriptomic studies employing this injury model. PMID- 26981106 TI - Cerebrolysin improves sciatic nerve dysfunction in a mouse model of diabetic peripheral neuropathy. AB - To examine the effects of Cerebrolysin on the treatment of diabetic peripheral neuropathy, we first established a mouse model of type 2 diabetes mellitus by administering a high-glucose, high-fat diet and a single intraperitoneal injection of streptozotocin. Mice defined as diabetic in this model were then treated with 1.80, 5.39 or 8.98 mL/kg of Cerebrolysin via intraperitoneal injections for 10 consecutive days. Our results demonstrated that the number, diameter and area of myelinated nerve fibers increased in the sciatic nerves of these mice after administration of Cerebrolysin. The results of several behavioral tests showed that Cerebrolysin dose-dependently increased the slope angle in the inclined plane test (indicating an improved ability to maintain body position), prolonged tail-flick latency and foot-licking time (indicating enhanced sensitivity to thermal and chemical pain, respectively, and reduced pain thresholds), and increased an index of sciatic nerve function in diabetic mice compared with those behavioral results in untreated diabetic mice. Taken together, the anatomical and functional results suggest that Cerebrolysin ameliorated peripheral neuropathy in a mouse model of type 2 diabetes mellitus. PMID- 26981105 TI - A novel bioactive nerve conduit for the repair of peripheral nerve injury. AB - The use of a nerve conduit provides an opportunity to regulate cytokines, growth factors and neurotrophins in peripheral nerve regeneration and avoid autograft defects. We constructed a poly-D-L-lactide (PDLLA)-based nerve conduit that was modified using poly{(lactic acid)-co-[(glycolic acid)-alt-(L-lysine)]} and beta tricalcium phosphate. The effectiveness of this bioactive PDLLA-based nerve conduit was compared to that of PDLLA-only conduit in the nerve regeneration following a 10-mm sciatic nerve injury in rats. We observed the nerve morphology in the early period of regeneration, 35 days post injury, using hematoxylin-eosin and methylene blue staining. Compared with the PDLLA conduit, the nerve fibers in the PDLLA-based bioactive nerve conduit were thicker and more regular in size. Muscle fibers in the soleus muscle had greater diameters in the PDLLA bioactive group than in the PDLLA only group. The PDLLA-based bioactive nerve conduit is a promising strategy for repair after sciatic nerve injury. PMID- 26981107 TI - Dexamethasone prevents vascular damage in early-stage non-freezing cold injury of the sciatic nerve. AB - Non-freezing cold injury is a prevalent cause of peripheral nerve damage, but its pathogenic mechanism is poorly understood, and treatment remains inadequate. Glucocorticoids have anti-inflammatory and lipid peroxidation-inhibiting properties. We therefore examined whether dexamethasone, a synthetic glucocorticoid compound, would alleviate early-stage non-freezing cold injury of the sciatic nerve. We established Wistar rat models of non-freezing cold injury by exposing the left sciatic nerve to cold (3-5 degrees C) for 2 hours, then administered dexamethasone (3 mg/kg intraperitoneally) to half of the models. One day after injury, the concentration of Evans blue tracer in the injured sciatic nerve of rats that received dexamethasone was notably lower than that in the injured sciatic nerve of rats that did not receive dexamethasone; neither Evans blue dye nor capillary stenosis was observed in the endoneurium, but myelinated nerve fibers were markedly degenerated in the injured sciatic nerve of animals that received dexamethasone. After dexamethasone administration, however, endoneurial vasculopathy was markedly improved, although damage to the myelinated nerve fiber was not alleviated. These findings suggest that dexamethasone protects the blood-nerve barrier, but its benefit in non-freezing cold injury is limited to the vascular system. PMID- 26981108 TI - Angiogenesis in tissue-engineered nerves evaluated objectively using MICROFIL perfusion and micro-CT scanning. AB - Angiogenesis is a key process in regenerative medicine generally, as well as in the specific field of nerve regeneration. However, no convenient and objective method for evaluating the angiogenesis of tissue-engineered nerves has been reported. In this study, tissue-engineered nerves were constructed in vitro using Schwann cells differentiated from rat skin-derived precursors as supporting cells and chitosan nerve conduits combined with silk fibroin fibers as scaffolds to bridge 10-mm sciatic nerve defects in rats. Four weeks after surgery, three dimensional blood vessel reconstructions were made through MICROFIL perfusion and micro-CT scanning, and parameter analysis of the tissue-engineered nerves was performed. New blood vessels grew into the tissue-engineered nerves from three main directions: the proximal end, the distal end, and the middle. The parameter analysis of the three-dimensional blood vessel images yielded several parameters, including the number, diameter, connection, and spatial distribution of blood vessels. The new blood vessels were mainly capillaries and microvessels, with diameters ranging from 9 to 301 MUm. The blood vessels with diameters from 27 to 155 MUm accounted for 82.84% of the new vessels. The microvessels in the tissue engineered nerves implanted in vivo were relatively well-identified using the MICROFIL perfusion and micro-CT scanning method, which allows the evaluation and comparison of differences and changes of angiogenesis in tissue-engineered nerves implanted in vivo. PMID- 26981110 TI - Digital Microdroplet Ejection Technology-Based Heterogeneous Objects Prototyping. AB - An integrate fabrication framework is presented to build heterogeneous objects (HEO) using digital microdroplets injecting technology and rapid prototyping. The heterogeneous materials part design and manufacturing method in structure and material was used to change the traditional process. The net node method was used for digital modeling that can configure multimaterials in time. The relationship of material, color, and jetting nozzle was built. The main important contributions are to combine the structure, material, and visualization in one process and give the digital model for manufacture. From the given model, it is concluded that the method is effective for HEO. Using microdroplet rapid prototyping and the model given in the paper HEO could be gotten basically. The model could be used in 3D biomanufacturing. PMID- 26981109 TI - Vascular endothelial growth factor: an attractive target in the treatment of hypoxic/ischemic brain injury. AB - Cerebral hypoxia or ischemia results in cell death and cerebral edema, as well as other cellular reactions such as angiogenesis and the reestablishment of functional microvasculature to promote recovery from brain injury. Vascular endothelial growth factor is expressed in the central nervous system after hypoxic/ischemic brain injury, and is involved in the process of brain repair via the regulation of angiogenesis, neurogenesis, neurite outgrowth, and cerebral edema, which all require vascular endothelial growth factor signaling. In this review, we focus on the role of the vascular endothelial growth factor signaling pathway in the response to hypoxic/ischemic brain injury, and discuss potential therapeutic interventions. PMID- 26981111 TI - Parallel Digital Watermarking Process on Ultrasound Medical Images in Multicores Environment. AB - With the advancement of technology in communication network, it facilitated digital medical images transmitted to healthcare professionals via internal network or public network (e.g., Internet), but it also exposes the transmitted digital medical images to the security threats, such as images tampering or inserting false data in the images, which may cause an inaccurate diagnosis and treatment. Medical image distortion is not to be tolerated for diagnosis purposes; thus a digital watermarking on medical image is introduced. So far most of the watermarking research has been done on single frame medical image which is impractical in the real environment. In this paper, a digital watermarking on multiframes medical images is proposed. In order to speed up multiframes watermarking processing time, a parallel watermarking processing on medical images processing by utilizing multicores technology is introduced. An experiment result has shown that elapsed time on parallel watermarking processing is much shorter than sequential watermarking processing. PMID- 26981112 TI - The Correlation of PPARalpha Activity and Cardiomyocyte Metabolism and Structure in Idiopathic Dilated Cardiomyopathy during Heart Failure Progression. AB - This study aimed to define relationship between PPARalpha expression and metabolic-structural characteristics during HF progression in hearts with DCM phenotype. Tissue endomyocardial biopsy samples divided into three groups according to LVEF ((I) 45-50%, n = 10; (II) 30-40%, n = 15; (III) <30%, n = 15; and control (donor hearts, >60%, n = 6)) were investigated. The PPARalpha mRNA expression in the failing hearts was low in Group (I), high in Group (II), and comparable to that of the control in Group (III). There were analogous changes in the expression of FAT/CD36 and CPT-1 mRNA in contrast to continuous overexpression of GLUT-4 mRNA and significant increase of PDK-4 mRNA in Group (II). In addition, significant structural changes of cardiomyocytes with glycogen accumulation were accompanied by increased expression of PPARalpha. For the entire study population with HF levels of FAT/CD36 mRNA showed a strong tendency of negative correlation with LVEF. In conclusion, PPARalpha elevated levels may be a direct cause of adverse remodeling, both metabolic and structural. Thus, there is limited time window for therapy modulating cardiac metabolism and protecting cardiomyocyte structure in failing heart. PMID- 26981113 TI - Macular Amyloidosis and Epstein-Barr Virus. AB - Background. Amyloidosis is extracellular precipitation of eosinophilic hyaline material of self-origin with special staining features and fibrillar ultrastructure. Macular amyloidosis is limited to the skin, and several factors have been proposed for its pathogenesis. Detection of Epstein-Barr virus (EBV) DNA in this lesion suggests that this virus can play a role in pathogenesis of this disease. Objective. EBV DNA detection was done on 30 skin samples with a diagnosis of macular amyloidosis and 31 healthy skin samples in the margin of removed melanocytic nevi by using PCR. Results. In patients positive for beta globin gene in PCR, BLLF1 gene of EBV virus was positive in 23 patients (8 patients in case and 15 patients in the control group). There was no significant difference in presence of EBV DNA between macular amyloidosis (3.8%) and control (23.8%) groups (P = 0.08). Conclusion. The findings of this study showed that EBV is not involved in pathogenesis of macular amyloidosis. PMID- 26981114 TI - Malignant Biliary Obstruction: Evidence for Best Practice. AB - What should be done next? Is the stricture benign? Is it resectable? Should I place a stent? Which one? These are some of the questions one ponders when dealing with biliary strictures. In resectable cases, ongoing questions remain as to whether the biliary tree should be drained prior to surgery. In palliative cases, the relief of obstruction remains the main goal. Options for palliative therapy include surgical bypass, percutaneous drainage, and stenting or endoscopic stenting (transpapillary or via an endoscopic ultrasound approach). This review gathers scientific foundations behind these interventions. For operable cases, preoperative biliary drainage should not be performed unless there is evidence of cholangitis, there is delay in surgical intervention, or intense jaundice is present. For inoperable cases, transpapillary stenting after sphincterotomy is preferable over percutaneous drainage. The use of plastic stents (PS) has no benefit over Self-Expandable Metallic Stents (SEMS). In case transpapillary drainage is not possible, Endoscopic Ultrasonography- (EUS-) guided drainage is still an option over percutaneous means. There is no significant difference between the types of SEMS and its indication should be individualized. PMID- 26981116 TI - Drug Efflux Transporters Are Overexpressed in Short-Term Tamoxifen-Induced MCF7 Breast Cancer Cells. AB - Tamoxifen is the first line drug used in the treatment of estrogen receptor positive (ER+) breast cancer. The development of multidrug resistance (MDR) to tamoxifen remains a major challenge in the treatment of cancer. One of the mechanisms related to MDR is decrease of drug influx via overexpression of drug efflux transporters such as P-glycoprotein (P-gp/MDR1), multidrug resistance associated protein (MRP), or BCRP (breast cancer resistance protein). We aimed to investigate whether the sensitivity of tamoxifen to the cells is maintained through the short period and whether the expressions of several drug efflux transporters have been upregulated. We exposed MCF7 breast cancer cells with tamoxifen 1 MUM for 10 passages (MCF7 (T)). The result showed that MCF7 began to lose their sensitivity to tamoxifen from the second passage. MCF7 (T) also showed a significant increase in all transporters examined compared with MCF7 parent cells. The result also showed a significant increase of CC50 in MCF7 (T) compared to that in MCF7 (97.54 MUM and 3.04 MUM, resp.). In conclusion, we suggest that the expression of several drug efflux transporters such as P-glycoprotein, MRP2, and BCRP might be used and further studied as a marker in the development of tamoxifen resistance. PMID- 26981118 TI - Cement Dust Exposure and Perturbations in Some Elements and Lung and Liver Functions of Cement Factory Workers. AB - Background. Cement dust inhalation is associated with deleterious health effects. The impact of cement dust exposure on the peak expiratory flow rate (PEFR), liver function, and some serum elements in workers and residents near cement factory were assessed. Methods. Two hundred and ten subjects (50 workers, 60 residents, and 100 controls) aged 18-60 years were studied. PEFR, liver function {aspartate and alanine transaminases (AST and ALT) and total and conjugated bilirubin (TB and CB)}, and serum elements {lead (Pb), copper (Cu), manganese (Mn), iron (Fe), cadmium (Cd), selenium (Se), chromium (Cr), zinc (Zn), and arsenic (As)} were determined using peak flow meter, colorimetry, and atomic absorption spectrometry, respectively. Data were analysed using ANOVA and correlation at p = 0.05. Results. The ALT, TB, CB, Pb, As, Cd, Cr, Se, Mn, and Cu were significantly higher and PEFR, Fe, and Zn lower in workers and residents compared to controls (p < 0.05). Higher levels of ALT, AST, and Fe and lower levels of Pb, Cd, Cr, Se, Mn, and Cu were seen in cement workers compared to residents (p < 0.05). Negative correlation was observed between duration of exposure and PEFR (r = -0.416, p = 0.016) in cement workers. Conclusions. Cement dust inhalation may be associated with alterations in serum elements levels and lung and liver functions while long term exposure lowers peak expiratory flow rate. PMID- 26981115 TI - Local Ablative Strategies for Ductal Pancreatic Cancer (Radiofrequency Ablation, Irreversible Electroporation): A Review. AB - Pancreatic ductal adenocarcinoma (PDAC) has still a dismal prognosis. Locally advanced pancreatic cancer (LAPC) accounts for the 40% of the new diagnoses. Current treatment options are based on chemo- and radiotherapy regimens. Local ablative techniques seem to be the future therapeutic option for stage-III patients with PDAC. Radiofrequency Ablation (RFA) and Irreversible Electroporation (IRE) are actually the most emerging local ablative techniques used on LAPC. Initial clinical studies on the use of these techniques have already demonstrated encouraging results in terms of safety and feasibility. Unfortunately, few studies on their efficacy are currently available. Even though some reports on the overall survival are encouraging, randomized studies are still required to corroborate these findings. This study provides an up-to-date overview and a thematic summary of the current available evidence on the application of RFA and IRE on PDAC, together with a comparison of the two procedures. PMID- 26981117 TI - Inhibition of Mycobacterium-RmlA by Molecular Modeling, Dynamics Simulation, and Docking. AB - The increasing resistance to anti-tb drugs has enforced strategies for finding new drug targets against Mycobacterium tuberculosis (Mtb). In recent years enzymes associated with the rhamnose pathway in Mtb have attracted attention as drug targets. The present work is on alpha-D-glucose-1-phosphate thymidylyltransferase (RmlA), the first enzyme involved in the biosynthesis of L rhamnose, of Mtb cell wall. This study aims to derive a 3D structure of RmlA by using a comparative modeling approach. Structural refinement and energy minimization of the built model have been done with molecular dynamics. The reliability assessment of the built model was carried out with various protein checking tools such as Procheck, Whatif, ProsA, Errat, and Verify 3D. The obtained model investigates the relation between the structure and function. Molecular docking interactions of Mtb-RmlA with modified EMB (ethambutol) ligands and natural substrate have revealed specific key residues Arg13, Lys23, Asn109, and Thr223 which play an important role in ligand binding and selection. Compared to all EMB ligands, EMB-1 has shown better interaction with Mtb-RmlA model. The information thus discussed above will be useful for the rational design of safe and effective inhibitors specific to RmlA enzyme pertaining to the treatment of tuberculosis. PMID- 26981119 TI - Biomonitoring with Micronuclei Test in Buccal Cells of Female Farmers and Children Exposed to Pesticides of Maneadero Agricultural Valley, Baja California, Mexico. AB - Feminization of the agricultural labor is common in Mexico; these women and their families are vulnerable to several health risks including genotoxicity. Previous papers have presented contradictory information with respect to indirect exposure to pesticides and DNA damage. We aimed to evaluate the genotoxic effect in buccal mucosa from female farmers and children, working in the agricultural valley of Maneadero, Baja California. Frequencies of micronucleated cells (MNc) and nuclear abnormalities (NA) in 2000 cells were obtained from the buccal mucosa of the study population (n = 144), divided in four groups: (1) farmers (n = 37), (2) unexposed (n = 35), (3) farmers' children (n = 34), and (4) unexposed children (n = 38). We compared frequencies of MNc and NA and fitted generalized linear models to investigate the interaction between these variables and exposition to pesticides. Differences were found between farmers and unexposed women in MNc (p < 0.0001), CC (p = 0.3376), and PN (p < 0.0001). With respect to exposed children, we found higher significant frequencies in MNc (p < 0.0001), LN (p < 0.0001), CC (p < 0.0001), and PN (p < 0.004) when compared to unexposed children. Therefore working as a farmer is a risk for genotoxic damage; more importantly indirectly exposed children were found to have genotoxic damage, which is of concern, since it could aid in future disturbances of their health. PMID- 26981120 TI - Evaluating the Effects of Tetrachloro-1,4-benzoquinone, an Active Metabolite of Pentachlorophenol, on the Growth of Human Breast Cancer Cells. AB - Tetrachloro-1,4-benzoquinone (TCBQ), an active metabolite of pentachlorophenol (PCP), is genotoxic and potentially carcinogenic. As an electrophilic and oxidative molecule, TCBQ can conjugate with deoxyguanosine in DNA molecules and/or impose oxidative stress in cells. In the current study, we investigated the effects of TCBQ on intracellular ROS production, apoptosis, and cytotoxicity against three different subtypes of human breast cancer cells. Luminal A subtype MCF7 (ER(+), PR(+), HER2(-)) cells maintained the highest intracellular ROS level and were subjected to TCBQ-induced ROS reduction, apoptosis, and cytotoxicity. HER2 subtype Sk-Br-3 (ER(-), PR(-), HER2(+)) cells possessed the lowest intracellular ROS level. TCBQ promoted ROS production, inhibited apoptosis, and elevated cytotoxicity (due to necrosis) against Sk-Br-3 cells. Triple negative/basal-like subtype MDA-MB-231 cells were less sensitive towards TCBQ treatment. Therefore, the effect of prolonged exposure to PCP and its active metabolites on cancer growth is highly cancer-cell-type specific. PMID- 26981121 TI - The Relationship between Alcohol Consumption and Incidence of Glycometabolic Abnormality in Middle-Aged and Elderly Chinese Men. AB - Aim. The relationship between alcohol consumption and glycometabolic abnormality is controversial, especially in different ethnic population. In this study, a cross-sectional survey was carried out to examine the relationship between alcohol consumption and glycometabolic abnormality in middle-aged and elderly Chinese men. Methods. Using cluster random sampling, Chinese men aged more than 40 years from Changchun, China, were given standardized questionnaires. In total, 1996 individuals, for whom complete data was available, were recruited into the study. We calculated the incidence of prediabetes and newly diagnosed diabetes by three levels of alcohol consumption: light, moderate, and heavy. Multivariate logistic regression models adjusted for socioeconomic variables and diabetes related risk factors were used to analyze the association between alcohol consumption and the onset of prediabetes and diabetes. Results. The univariate analysis revealed higher incidence of prediabetes among drinkers (32.8%) compared with nondrinkers (28.6%), particularly in heavy alcohol consumers. The logistic regression analysis showed that alcohol consumption, especially heavy consumption, was an independent risk factor for prediabetes. Conclusions. Alcohol consumption, heavy consumption in particular, is an independent risk factor for the development of prediabetes, but not for diabetes. PMID- 26981122 TI - The Oncogenic Functions of Nicotinic Acetylcholine Receptors. AB - Nicotinic acetylcholine receptors (nAChRs) are ion channels that are expressed in the cell membrane of all mammalian cells, including cancer cells. Recent findings suggest that nAChRs not only mediate nicotine addiction in the brain but also contribute to the development and progression of cancers directly induced by nicotine and its derived carcinogenic nitrosamines whereas deregulation of the nAChRs is observed in many cancers, and genome-wide association studies (GWAS) indicate that SNPs nAChRs associate with risks of lung cancers and nicotine addiction. Emerging evidences suggest nAChRs are posited at the central regulatory loops of numerous cell growth and prosurvival signal pathways and also mediate the synthesis and release of stimulatory and inhibitory neurotransmitters induced by their agonists. Thus nAChRs mediated cell signaling plays an important role in stimulating the growth and angiogenic and neurogenic factors and mediating oncogenic signal transduction during cancer development in a cell type specific manner. In this review, we provide an integrated view of nAChRs signaling in cancer, heightening on the oncogenic properties of nAChRs that may be targeted for cancer treatment. PMID- 26981124 TI - Sol-Gel Derived Mg-Based Ceramic Scaffolds Doped with Zinc or Copper Ions: Preliminary Results on Their Synthesis, Characterization, and Biocompatibility. AB - Glass-ceramic scaffolds containing Mg have shown recently the potential to enhance the proliferation, differentiation, and biomineralization of stem cells in vitro, property that makes them promising candidates for dental tissue regeneration. An additional property of a scaffold aimed at dental tissue regeneration is to protect the regeneration process against oral bacteria penetration. In this respect, novel bioactive scaffolds containing Mg(2+) and Cu(2+) or Zn(2+), ions known for their antimicrobial properties, were synthesized by the foam replica technique and tested regarding their bioactive response in SBF, mechanical properties, degradation, and porosity. Finally their ability to support the attachment and long-term proliferation of Dental Pulp Stem Cells (DPSCs) was also evaluated. The results showed that conversely to their bioactive response in SBF solution, Zn-doped scaffolds proved to respond adequately regarding their mechanical strength and to be efficient regarding their biological response, in comparison to Cu-doped scaffolds, which makes them promising candidates for targeted dental stem cell odontogenic differentiation and calcified dental tissue engineering. PMID- 26981123 TI - Exosomes in Human Immunodeficiency Virus Type I Pathogenesis: Threat or Opportunity? AB - Nanometre-sized vesicles, also known as exosomes, are derived from endosomes of diverse cell types and present in multiple biological fluids. Depending on their cellular origins, the membrane-bound exosomes packed a variety of functional proteins and RNA species. These microvesicles are secreted into the extracellular space to facilitate intercellular communication. Collective findings demonstrated that exosomes from HIV-infected subjects share many commonalities with Human Immunodeficiency Virus Type I (HIV-1) particles in terms of proteomics and lipid profiles. These observations postulated that HIV-resembled exosomes may contribute to HIV pathogenesis. Interestingly, recent reports illustrated that exosomes from body fluids could inhibit HIV infection, which then bring up a new paradigm for HIV/AIDS therapy. Accumulative findings suggested that the cellular origin of exosomes may define their effects towards HIV-1. This review summarizes the two distinctive roles of exosomes in regulating HIV pathogenesis. We also highlighted several additional factors that govern the exosomal functions. Deeper understanding on how exosomes promote or abate HIV infection can significantly contribute to the development of new and potent antiviral therapeutic strategy and vaccine designs. PMID- 26981125 TI - Relative Susceptibilities of ABO Blood Groups to Plasmodium falciparum Malaria in Ghana. AB - The clinical outcome of falciparum malaria in endemic areas is influenced by erythrocyte polymorphisms including the ABO blood groups. Studies have reported association of ABO blood group to resistance, susceptibility, and severity of P. falciparum malaria infection. Individuals with blood group "A" have been found to be highly susceptible to falciparum malaria whereas blood group "O" is said to confer protection against complicated cases. We analyzed samples from 293 young children less than six years old with malaria in the Korle-Bu Teaching Hospital in Accra, Ghana. It was observed that group O was present in about 16.1% of complicated cases weighed against 40.9% of uncomplicated controls. Individuals with complicated malaria were about twice likely to be of blood groups A and B compared to group O (A versus O, OR = 1.90, 95% CI = 1.59-2.26, P < 0.0001; B versus O, OR = 1.82. 95% CI = 1.57-2.23, P < 0.0001). Blood group O participants with complicated diseases had low parasitaemia compared to the other blood groups (P < 0.0001). This may give blood group O individuals a survival advantage over the other groups in complicated malaria as suggested. Participants with complicated falciparum malaria were generally anaemic and younger than those with uncomplicated disease. PMID- 26981126 TI - The EpiNo(r) Device: Efficacy, Tolerability, and Impact on Pelvic Floor Implications for Future Research. AB - Aims. The aim of this review is to provide a comprehensive overview of the available literature on preventing perineal trauma with the EpiNo. Methods. We perfomed a literature research in the MedLine and EMBASE databases for studies referring to EpiNo published between 1990 and 2014, without restrictions for language and study type. Results. Five published studies were identified, regarding the effect of EpiNo on the rate of episiotomy and perineal tears, pelvic floor muscle function, and fetal outcome. The device seems to reduce episiotomy and perineal tears' rate, as well as the risk for levator ani microtrauma and avulsion, though not always statistically significant. It does not seem to have an effect on duration of second stage of labour and fetal outcome. The device is well tolerated and the adverse events are rare and mild. However, design and reporting bias in the reviewed articles do not allow evidence based conclusions. Conclusions. The EpiNo device seems to be promising, with potential positive effects on natural birth, while being uncomplicated to use and without major complications. Well designed, randomized trials are needed in order to understand the effects of EpiNo on pelvic floor and make evidence based recommendations on its use. PMID- 26981127 TI - A Case of Relapsing Polychondritis Initiating with Unexplained Fever. AB - Relapsing polychondritis (RP) is a rare autoimmune disease affecting the multiple organ system. Here, we describe a case of RP initially presenting with high fever. The patient was referred to our hospital for further examination of fever of unknown origin (FUO). On admission, the patient reported dry cough in addition to fever. On physical examination, her red, swollen ears were noted, attributed on histology to inflammation with auricular perichondritis. She was diagnosed with RP and treated with oral prednisone (50 mg/day); her fever and auricular inflammation resolved. The patient no longer reported cough and body temperature returned to normal and the elevated levels of C-reactive protein (CRP) were normalized. In this case, identification of the origin of fever was a challenge because of unspecific symptoms; however, awareness of the systemic manifestations of RP may lead to the prompt diagnosis and therapeutic intervention. PMID- 26981128 TI - Spontaneous Intracranial Hypotension Treated with a Targeted CT-Guided Epidural Blood Patch. AB - Spontaneous intracranial hypotension (SIH) is an important cause of new daily persistent headache. It is thought to be due to spontaneous spinal cerebrospinal fluid (CSF) leaks, which probably have a multifactorial etiology. The classic manifestation of SIH is an orthostatic headache, but other neurological symptoms may be present. An epidural blood patch is thought to be the most effective treatment, but a blind infusion may be ineffective. We describe the case of a young man who developed an acute severe headache, with pain worsening when assuming an upright posture and relief gained with recumbency. No history of previous headache, recent cranial or cervical trauma, or invasive procedures was reported. Magnetic resonance imaging showed pachymeningeal enhancement and other features consistent with SIH and pointed towards a cervical CSF leak site. After failure of conservative treatment, a targeted computer tomography-guided EBP was performed, with complete recovery. PMID- 26981129 TI - Human Adipose-Derived Mesenchymal Stem Cells Cryopreservation and Thawing Decrease alpha4-Integrin Expression. AB - Aim. The effects of cryopreservation on adipose tissue-derived mesenchymal stem cells are not clearly documented, as there is a growing body of evidence about the importance of adipose-derived mesenchymal stem cells for regenerative therapies. The aim of this study was to analyze human adipose tissue-derived mesenchymal stem cells phenotypic expression (CD34, CD45, CD73, CD90, CD105, and CD49d), colony forming unit ability, viability, and differentiation potential before and after cryopreservation. Materials and Methods. 12 samples of the adipose tissue were collected from a healthy donor using the liposuction technique. The cell isolation was performed by enzymatic digestion and then the cells were cultured up to passage 2. Before and after cryopreservation the immunophenotype, cellular viability analysis by flow cytometer, colony forming units ability, differentiation potential into adipocytes and osteoblasts as demonstrated by Oil Red O and Alizarin Red staining, respectively. Results. The immunophenotypic markers expression was largely preserved, and their multipotency was maintained. However, after cryopreservation, the cells decreased alpha4 integrin expression (CD49d), cell viability, and number of colony forming units. Conclusions. These findings suggest that ADMSC transplanted after cryopreservation might compromise the retention of transplanted cells in the host tissue. Therefore, further studies are warranted to standardize protocols related to cryopreservation to attain full benefits of stem cell therapy. PMID- 26981131 TI - Theoretical and Practical Issues That Are Relevant When Scaling Up hMSC Microcarrier Production Processes. AB - The potential of human mesenchymal stem cells (hMSCs) for allogeneic cell therapies has created a large amount of interest. However, this presupposes the availability of efficient scale-up procedures. Promising results have been reported for stirred bioreactors that operate with microcarriers. Recent publications focusing on microcarrier-based stirred bioreactors have demonstrated the successful use of Computational Fluid Dynamics (CFD) and suspension criteria (N S1u , N S1) for rapidly scaling up hMSC expansions from mL- to pilot scale. Nevertheless, one obstacle may be the formation of large microcarrier-cell aggregates, which may result in mass transfer limitations and inhomogeneous distributions of stem cells in the culture broth. The dependence of microcarrier cell-aggregate formation on impeller speed and shear stress levels was investigated for human adipose derived stromal/stem cells (hASCs) at the spinner scale by recording the Sauter mean diameter (d 32) versus time. Cultivation at the suspension criteria provided d 32 values between 0.2 and 0.7 mm, the highest cell densities (1.25 * 10(6) cells mL(-1) hASCs), and the highest expansion factors (117.0 +/- 4.7 on day 7), while maintaining the expression of specific surface markers. Furthermore, suitability of the suspension criterion N S1u was investigated for scaling up microcarrier-based processes in wave-mixed bioreactors for the first time. PMID- 26981130 TI - Advances in Adipose-Derived Stem Cells Isolation, Characterization, and Application in Regenerative Tissue Engineering. AB - Obesity is a complex, multifactorial disease that has been extensively researched in recent times. Obesity is characterized by excess deposition of adipose tissue in response to surplus energy. Despite the negative connotations of adipose tissue (AT), it serves as a critical endocrine organ. Adipose tissue is a source of several adipokines and cytokines which have been deemed important for both normal metabolic function and disease formation. The discoveries of metabolically active brown AT in adult humans and adipose tissue derived stem cells (ADSC) have been key findings in the past decade with potential therapeutic implications. ADSCs represent an enticing pool of multipotent adult stem cells because of their noncontroversial nature, relative abundance, ease of isolation, and expandability. A decade and a half since the discovery of ADSCs, the scientific community is still working to uncover their therapeutic potential in a wide range of diseases. In this review, we provide an overview of the recent developments in the field of ADSCs and examine their potential use in transplantation and cell based therapies for the regeneration of diseased organs and systems. We also hope to provide perspective on how to best utilize this readily available, powerful pool of stem cells in the future. PMID- 26981132 TI - Fate and Effect of Intravenously Infused Mesenchymal Stem Cells in a Mouse Model of Hepatic Ischemia Reperfusion Injury and Resection. AB - Liver ischemia reperfusion injury (IRI) is inevitable during transplantation and resection and is characterized by hepatocellular injury. Therapeutic strategies to reduce IRI and accelerate regeneration could offer major benefits. Mesenchymal stem cells (MSC) are reported to have anti-inflammatory and regeneration promoting properties. We investigated the effect of MSC in a model of combined IRI and partial resection in the mouse. Hepatic IRI was induced by occlusion of 70% of the blood flow during 60 minutes, followed by 30% hepatectomy. 2 * 10(5) MSC or PBS were infused 2 hours before or 1 hour after IRI. Six, 48, and 120 hours postoperatively mice were sacrificed. Liver damage was evaluated by liver enzymes, histology, and inflammatory markers. Regeneration was determined by liver/body weight ratio, proliferating hepatocytes, and TGF-beta levels. Fate of MSC was visualized with 3D cryoimaging. Infusion of 2 * 10(5) MSC 2 hours before or 1 hour after IRI and resection showed no beneficial effects. Tracking revealed that MSC were trapped in the lungs and did not migrate to the site of injury and many cells had already disappeared 2 hours after infusion. Based on these findings we conclude that intravenously infused MSC disappear rapidly and were unable to induce beneficial effects in a clinically relevant model of IRI and resection. PMID- 26981134 TI - Transcatheter Arterial Infusion of Autologous CD133(+) Cells for Diabetic Peripheral Artery Disease. AB - Microvascular lesion in diabetic peripheral arterial disease (PAD) still cannot be resolved by current surgical and interventional technique. Endothelial cells have the therapeutic potential to cure microvascular lesion. To evaluate the efficacy and immune-regulatory impact of intra-arterial infusion of autologous CD133(+) cells, we recruited 53 patients with diabetic PAD (27 of CD133(+) group and 26 of control group). CD133(+) cells enriched from patients' PB-MNCs were reinfused intra-arterially. The ulcer healing followed up till 18 months was 100% (3/3) in CD133(+) group and 60% (3/5) in control group. The amputation rate was 0 (0/27) in CD133(+) group and 11.54% (3/26) in control group. Compared with the control group, TcPO2 and ABI showed obvious improvement at 18 months and significant increasing VEGF and decreasing IL-6 level in the CD133(+) group within 4 weeks. A reducing trend of proangiogenesis and anti-inflammatory regulation function at 4 weeks after the cells infusion was also found. These results indicated that autologous CD133(+) cell treatment can effectively improve the perfusion of morbid limb and exert proangiogenesis and anti-inflammatory immune-regulatory impacts by paracrine on tissue microenvironment. The CD133(+) progenitor cell therapy may be repeated at a fixed interval according to cell life span and immune-regulatory function. PMID- 26981133 TI - Tumor Mesenchymal Stem-Like Cell as a Prognostic Marker in Primary Glioblastoma. AB - The isolation from brain tumors of tumor mesenchymal stem-like cells (tMSLCs) suggests that these cells play a role in creating a microenvironment for tumor initiation and progression. The clinical characteristics of patients with primary glioblastoma (pGBM) positive for tMSLCs have not been determined. This study analyzed samples from 82 patients with pGBM who had undergone tumor removal, pathological diagnosis, and isolation of tMSLC from April 2009 to October 2014. Survival, extent of resection, molecular markers, and tMSLC culture results were statistically evaluated. Median overall survival was 18.6 months, 15.0 months in tMSLC-positive patients and 29.5 months in tMSLC-negative patients (P = 0.014). Multivariate cox regression model showed isolation of tMSLC (OR = 2.5, 95% CI = 1.1~5.6, P = 0.021) showed poor outcome while larger extent of resection (OR = 0.5, 95% CI = 0.2~0.8, P = 0.011) has association with better outcome. The presence of tMSLCs isolated from the specimen of pGBM is associated with the survival of patient. PMID- 26981135 TI - Enhanced Ex Vivo Expansion of Human Hematopoietic Progenitors on Native and Spin Coated Acellular Matrices Prepared from Bone Marrow Stromal Cells. AB - The extracellular microenvironment in bone marrow (BM) is known to regulate the growth and differentiation of hematopoietic stem and progenitor cells (HSPC). We have developed cell-free matrices from a BM stromal cell line (HS-5), which can be used as substrates either in native form or as tissue engineered coatings, for the enhanced ex vivo expansion of umbilical cord blood (UCB) derived HSPC. The physicochemical properties (surface roughness, thickness, and uniformity) of native and spin coated acellular matrices (ACM) were studied using scanning and atomic force microscopy (SEM and AFM). Lineage-specific expansion of HSPC, grown on these substrates, was evaluated by immunophenotypic (flow cytometry) and functional (colony forming) assays. Our results show that the most efficient expansion of lineage-specific HSPC occurred on spin coated ACM. Our method provides an improved protocol for ex vivo HSPC expansion and it offers a system to study the in vivo roles of specific molecules in the hematopoietic niche that influence HSPC expansion. PMID- 26981136 TI - Priming Adipose-Derived Mesenchymal Stem Cells with Hyaluronan Alters Growth Kinetics and Increases Attachment to Articular Cartilage. AB - Background. Biological therapeutics such as adipose-derived mesenchymal stem cell (MSC) therapy are gaining acceptance for knee-osteoarthritis (OA) treatment. Reports of OA-patients show reductions in cartilage defects and regeneration of hyaline-like-cartilage with MSC-therapy. Suspending MSCs in hyaluronan commonly occurs in animals and humans, usually without supporting data. Objective. To elucidate the effects of different concentrations of hyaluronan on MSC growth kinetics. Methods. Using a range of hyaluronan concentrations, we measured MSC adherence and proliferation on culture plastic surfaces and a novel cartilage adhesion assay. We employed time-course and dispersion imaging to assess MSC binding to cartilage. Cytokine profiling was also conducted on the MSC-secretome. Results. Hyaluronan had dose-dependent effects on growth kinetics of MSCs at concentrations of entanglement point (1 mg/mL). At higher concentrations, viscosity effects outweighed benefits of additional hyaluronan. The cartilage adhesion assay highlighted for the first time that hyaluronan-primed MSCs increased cell attachment to cartilage whilst the presence of hyaluronan did not. Our time-course suggested patients undergoing MSC-therapy for OA could benefit from joint-immobilisation for up to 8 hours. Hyaluronan also greatly affected dispersion of MSCs on cartilage. Conclusion. Our results should be considered in future trials with MSC-therapy using hyaluronan as a vehicle, for the treatment of OA. PMID- 26981137 TI - The Dipeptides Ile-Tyr and Ser-Tyr Exert Distinct Effects on Catecholamine Metabolism in the Mouse Brainstem. AB - Catecholamine synthesis and transmission in the brain are influenced by the availability of Tyr in the body. In this study, we compared the effects of oral administration of Tyr-containing dipeptides Ile-Tyr, Ser-Tyr, and Tyr-Pro with Tyr alone on catecholamine metabolism in the mouse brainstem. Among these dipeptides, Ile-Tyr administration led to increases in dopamine, the dopamine metabolites homovanillic acid, and 3,4-dihydroxyphenylacetic acid, compared to administration of Ser-Tyr, Tyr-Pro, or Tyr alone. In comparison, administration of Ser-Tyr induced significantly increasing noradrenaline turnover, while Tyr-Pro administration suppressed dopamine turnover. Therefore, oral administration of Ile-Tyr, Ser-Tyr, and Tyr-Pro differentially affected metabolism of dopamine and noradrenaline. These observations strongly suggest that Tyr-containing dipeptides exert distinct effects on catecholamine metabolism in the brainstem when ingested orally. PMID- 26981138 TI - The Effects of Positive or Neutral Communication during Acupuncture for Relaxing Effects: A Sham-Controlled Randomized Trial. AB - Introduction. The link between patient-clinician communication and its effect on clinical outcomes is an important clinical issue that is yet to be elucidated. Objective. Investigating if communication type (positive or neutral) about the expected treatment outcome affected (i) participants' expectations and (ii) short term relaxation effects in response to genuine or sham acupuncture and investigating if expectations were related to outcome. Methods. Healthy volunteers (n = 243, mean age of 42) were randomized to one treatment with genuine or sham acupuncture. Within groups, participants were randomized to positive or neutral communication, regarding expected treatment effects. Visual Analogue Scales (0-100 millimeters) were used to measure treatment expectations and relaxation, directly before and after treatment. Results. Participants in the positive communication group reported higher treatment expectancy, compared to the neutral communication group (md 12 versus 6 mm, p = 0.002). There was no difference in relaxation effects between acupuncture groups or between communication groups. Participants with high baseline expectancy perceived greater improvement in relaxation, compared to participants with low baseline levels (md 27 versus 15 mm, p = 0.022). Conclusion. Our data highlights the importance of expectations for treatment outcome and demonstrates that expectations can be effectively manipulated using a standardized protocol that in future research may be implemented in clinical trials. PMID- 26981139 TI - Effects of Cymbidium Root Ethanol Extract on Atopic Dermatitis. AB - Cymbidium has known antibacterial and antiedema activity and has been used as an ingredient in cosmetics and fragrances. The effects of Cymbidium ethanol extract (CYM) on allergic response and the underlying mechanisms of action have not been reported. Therefore, the purpose of this study was to determine the effect of CYM on allergic responses. Topical application of CYM was effective against immunoglobulin E (IgE)/dinitrophenyl-conjugated bovine serum albumin- (DNP-BSA-) induced degranulation of RBL-2H3 cells and anaphylaxis in ICR mice. An allergic dermatitis-like mouse model was used to evaluate the therapeutic potential of CYM in vivo. Continuous application of 2,4-dinitrochlorobenzene (DNCB) not only induced dermatitis in ICR mice but also aggravated the skin lesioning. However, the application of CYM decreased skin lesion severity, scratching behavior, and IgE levels. In addition, CYM downregulated the expression of the proinflammatory cytokines interleukin- (IL-) 4, IL-13, and tumor necrosis factor- (TNF-) alpha. Studies of signal transduction pathways showed that CYM suppressed the phosphorylation of spleen tyrosine kinase (Syk), an upstream molecule. It also inhibited the phosphorylation of Akt, phospholipase C- (PLC-) gamma, and mitogen activated protein kinase kinase kinase (MEKK). These results indicate that CYM may be effective in preventing and reducing allergic response and may have therapeutic potential as an antiallergic agent in disorders such as atopic dermatitis. PMID- 26981140 TI - Recent Advances and Perspective of Studies on Phlegm Syndrome in Chinese Medicine. AB - This review paper summarized the current situation of studies on the essence of phlegm syndrome and relation between phlegm syndrome, diseases, and therapeutics based on published English articles. In studies on the essence of phlegm syndrome, omic technologies were used to explore the molecular basis of phlegm syndrome; in studies on relation between phlegm syndrome and diseases, discovery of markers of phlegm syndrome in diseases becomes a hotspot; the distribution of phlegm syndromes in some common chronic diseases was found; in the therapy of phlegm syndrome, two therapeutic models, treatment with CM formula and treatment with a combination of CM formula and Western medicine, were used most frequently. It is certainly that using one omic technology is not able to deal with the complexity of phlegm syndrome and that the use of a combination of multiple omic methods will be a trend in future studies. Meanwhile, for rapidly increasing clinical research quality of phlegm syndrome, a series of agreed criteria, such as syndrome diagnostic criteria and efficacy criteria clinical studies of phlegm syndrome, needed to be established urgently, and there was an urgent need of standardizing syndrome names in English. PMID- 26981141 TI - The Efficacy of Shen Shuaining Capsule on Chronic Kidney Disease: A Systematic Review and Meta-Analysis. AB - Objective. To evaluate the efficacy of Shen shuaining capsule on treating chronic kidney disease (CKD). Methods. All randomized controlled trials (RCTs) of Shen shuaining capsule in treating CKD were collected from CBM, CNKI, VIP, Wanfang, EMBASE, MEDLINE, PubMed, and Cochrane library clinical controlled trials database. Two reviewers independently performed analysis of the included trials according to the inclusion and exclusion criteria. The risk of bias tool was from the Cochrane Handbook version 5.1.0. The Review Manager 5.2 software was employed for data analysis. Funnel plot and Egger's test were applied to evaluate publication bias. Results. 20 studies including 1606 participants met the inclusion criteria, most of which were of low quality. Meta-analysis indicated that Shen shuaining capsule was effective for CKD in terms of SCR, BUN, Hb, and response rate and with less adverse effects, of which SCR and BUN decreased significantly (MD = -84.72, 95% CI: -107.36, -62.07, P < 0.00001) (MD = -4.30, 95% CI: -5.71, -2.89, P < 0.00001); Hb and response rate increased significantly (MD = 9.94, 95% CI: 9.24, 10.64, P < 0.00001) (OR = 4.25, 95% CI (3.32, 5.42), P < 0.00001). Conclusion. Shen shuaining capsule significantly reduced SCR and BUN, increased HB, and improved total efficiency of the symptoms and signs in patients with CKD. Subgroup analysis found that Shen shuaining capsule group was better than control group. Due to low quality of the methodology of included studies, further high-quality researches were needed to study its efficacy and safety. PMID- 26981142 TI - Assessment of Cardiovascular Parameters during Meditation with Mental Targeting in Varsity Swimmers. AB - Introduction. Athletes who develop an immunosuppressed state because of intensive training get upper respiratory infections (URIs) and may respond to meditation. Reflective exercise (RE), a westernized form of Qigong, combines meditation, breathing, and targeted mental attention to an internal pulsatile sensation, previously shown to protect varsity swimmers from URIs during the height of training. We report here the evaluation of cardiovascular parameters measured during meditation combined with targeted imagery (interoception) in a cohort of varsity swimmers taught RE. Methods. Thirteen subjects were enrolled on a prospective protocol that used the CareTaker, a noninvasive cardiovascular monitor before, during, and after RE training. Questionnaires regarding targeted mental imagery focusing on a pulsatile sensation were collected. The cardiovascular parameters include heart rate, blood pressure, and heart rate variability (HRV). Results. Increased variance in the subjects' BP and HRV was observed over the training period of 8 weeks. In nine subjects there was an increased low frequency (LF) HRV that was significantly (p < 0.05) associated with the subject's awareness of the pulsatile sensation that makes up a basic part of the RE practice. Summary. These data support further evaluation of HRV measurements in subjects while meditating with mental imagery. This direction could contribute to better understanding of neurocardiac mechanisms that relate meditation to enhanced immunity. PMID- 26981143 TI - New Claims for Wild Carrot (Daucus carota subsp. carota) Essential Oil. AB - The essential oil of Daucus carota subsp. carota from Portugal, with high amounts of geranyl acetate (29.0%), alpha-pinene (27.2%), and 11alphaH-himachal-4-en 1beta-ol (9.2%), was assessed for its biological potential. The antimicrobial activity was evaluated against several Gram-positive and Gram-negative bacteria, yeasts, dermatophytes, and Aspergillus strains. The minimal inhibitory concentration (MIC) and minimal lethal concentration (MLC) were evaluated showing a significant activity towards Gram-positive bacteria (MIC = 0.32-0.64 MUL/mL), Cryptococcus neoformans (0.16 MUL/mL), and dermatophytes (0.32-0.64 MUL/mL). The inhibition of the germ tube formation and the effect of the oil on Candida albicans biofilms were also unveiled. The oil inhibited more than 50% of filamentation at concentrations as low as 0.04 MUL/mL (MIC/128) and decreased both biofilm mass and cell viability. The antioxidant capacity of the oil, as assessed by two in chemico methods, was not relevant. Still, it seems to exhibit some anti-inflammatory potential by decreasing nitric oxide production around 20% in LPS-stimulated macrophages, without decreasing macrophages viability. Moreover, the oils safety profile was assessed on keratinocytes, alveolar epithelial cells, macrophages, and hepatocytes. Overall, the oil demonstrated a safety profile at concentrations below 0.64 MUL/mL. The present work highlights the bioactive potential of D. carota subsp. carota suggesting its industrial exploitation. PMID- 26981145 TI - Link of dysfunctional attitudes with the negative self-model. AB - BACKGROUND: Beck's cognitive theory postulates that dysfunctional attitudes predisposing to depression are formed by early negative experiences. Meanwhile, Bowlby's attachment theory contends that distorted working models built through insecure attachment relationships lead to various psychopathologies such as depression. The present study examined the correlations of dysfunctional attitudes about achievement, dependency, and self-control with working models of the self and other, and tried to promote understanding of those dysfunctional attitudes from an attachment perspective. METHODS: The subjects were 591 Japanese healthy volunteers. Dysfunctional attitudes about achievement, dependency, and self-control were evaluated by the corresponding subscales of the 24-item Dysfunctional Attitude Scale, and working models of the self and other were assessed by the relationship scales questionnaire. RESULTS: The scores of the achievement (beta = -0.26, P < 0.001), dependency (beta = -0.41, P < 0.001), and self-control (beta = -0.14, P < 0.01) subscales had negative correlations with the self-model score, suggesting the connections of all clusters of dysfunctional attitudes with the negative self-model. The score of the dependency subscale (beta = 0.21, P < 0.001) had a positive correlation with the other-model score, suggesting the connection of this cluster of dysfunctional attitudes with the positive other-model. Meanwhile, the scores of the achievement (beta = -0.17, P < 0.001) and self-control (beta = -0.13, P < 0.01) subscales had negative correlations with the other-model score, suggesting the connections of these clusters of dysfunctional attitudes with the negative other-model. CONCLUSION: The present study suggests that dysfunctional attitudes as a whole are linked with the negative self-model built through negative attachment experiences, while the content specificity of each cluster is related to the differential correlations with the other-model. PMID- 26981144 TI - Fluorescence characterisation and visual ecology of pseudocheilinid wrasses. AB - BACKGROUND: Wrasses represent the second largest family of marine fishes and display a high diversity of complex colours linked to ecological functions. Recently, red autofluorescent body colouration has been reported in some of these fishes. However, little is known about the distribution of such fluorescent body patterns in wrasses or the animals' ability to perceive such colours. RESULTS: Against this background, we (1) investigated long-wavelength emission autofluorescence in thirteen species of pseudocheilinid wrasses and (2) characterised the spectral absorbance of visual pigments in one of the examined species, the fairy wrasse Cirrhilabrus solorensis. Spectrophotometric analysis revealed that fluorescent body colouration is widespread and diverse within this clade, with considerable variation in both fluorescent pattern and maximum emission wavelength between species. Characterisation of visual pigments in retinal photoreceptors showed a single class of rod and three spectrally distinct cone photoreceptors, suggesting possible trichromacy. CONCLUSION: Combining the emission characteristics of fluorescence body colouration and the spectral sensitivity data of retinal cells suggests that the visual system of C. solorensis is sensitive to pseudocheilinid fluorescence. PMID- 26981146 TI - Gesture-Controlled Interface for Contactless Control of Various Computer Programs with a Hooking-Based Keyboard and Mouse-Mapping Technique in the Operating Room. AB - We developed a contactless interface that exploits hand gestures to effectively control medical images in the operating room. We developed an in-house program called GestureHook that exploits message hooking techniques to convert gestures into specific functions. For quantitative evaluation of this program, we used gestures to control images of a dynamic biliary CT study and compared the results with those of a mouse (8.54 +/- 1.77 s to 5.29 +/- 1.00 s; p < 0.001) and measured the recognition rates of specific gestures and the success rates of tasks based on clinical scenarios. For clinical applications, this program was set up in the operating room to browse images for plastic surgery. A surgeon browsed images from three different programs: CT images from a PACS program, volume-rendered images from a 3D PACS program, and surgical planning photographs from a basic image viewing program. All programs could be seamlessly controlled by gestures and motions. This approach can control all operating room programs without source code modification and provide surgeons with a new way to safely browse through images and easily switch applications during surgical procedures. PMID- 26981148 TI - Novel treatments for complications after bariatric surgery. AB - Bariatric surgery has been considered one of best treatments for obesity. As every surgical procedure-and any medical intervention, it is not exempt of complications, among which leaks, strictures, acute hemorrhages and fistulae highlight. Leaks are more common in the gastro-jejunal anastomosis (GJA) in the case of Roux-en-y Gastric Bypass (RYGB), while in Sleeve Gastrectomy (LSG) they locate in the stapler line. Stenosis can be seen in the gastro-jejunostomy in the RYGB and in the gastric tube in case of the LSG. For each of these complications, many innovative solutions have been developed, including new surgical devices. In spite of promising good results, evidence regarding utility and safeness of these technologies is still scarce. Self-expandable endoscopic stents have been used to treat leaks, with an overall success rate of 80-90 % and a migration rate of 15 35 %. The bear trap-like over-the-scope (Ovesco) clips have been used to treat GI hemorrhages, leaks and even fistulae, with a 70-80 % success rate, although more endoscopic sessions may be needed. Overstitch, an endosurgical suture devices, have been used to treat leaks, fistulae and perforations. Overall, technical success achievement approaches to 90 %, while clinical success ranges from 80 to 90 %, except for leaks closure, where a lower success rate has been observed. Despite of all of these advances, early diagnosis and treatment remains the main strategy to achieve success. In summary, novel therapies for complication management can be very useful, though further studies with larger series are still needed in order to confirm their efficacy and safeness. PMID- 26981147 TI - Boolean Modeling of Cellular and Molecular Pathways Involved in Influenza Infection. AB - Systems virology integrates host-directed approaches with molecular profiling to understand viral pathogenesis. Self-contained statistical approaches that combine expression profiles of genes with the available databases defining the genes involved in the pathways (gene-sets) have allowed characterization of predictive gene-signatures associated with outcome of the influenza virus (IV) infection. However, such enrichment techniques do not take into account interactions among pathways that are responsible for the IV infection pathogenesis. We investigate dendritic cell response to seasonal H1N1 influenza A/New Caledonia/20/1999 (NC) infection and infer the Boolean logic rules underlying the interaction network of ligand induced signaling pathways and transcription factors. The model reveals several novel regulatory modes and provides insights into mechanism of cross talk between NFkappaB and IRF mediated signaling. Additionally, the logic rule underlying the regulation of IL2 pathway that was predicted by the Boolean model was experimentally validated. Thus, the model developed in this paper integrates pathway analysis tools with the dynamic modeling approaches to reveal the regulation between signaling pathways and transcription factors using genome-wide transcriptional profiles measured upon influenza infection. PMID- 26981149 TI - Human papillomavirus infection and risk of breast cancer: a meta-analysis of case control studies. AB - BACKGROUND: Although systematic reviews (SR) report that human papillomavirus (HPV) increases the risk of breast cancer, there are still disputes regarding this association. In particular, it has been argued that the risk level differs depending on nationality, type of tissue, subtype of HPV, and publication year. Considering that the searching year of publication for the previous SRs was June 2013, a renewal meta-analysis needs to be conducted. METHODS: Using articles selected in the previous SRs, we compiled a list of references, cited articles, and related articles from the PubMed and Scopus databases. Of these, only publications with data from case-control studies on HPV DNA-positivity in tissues were chosen. Summary odds ratio (SOR) and 95 % confidence interval (CI) were calculated through meta-analysis. Meta-regression analysis was performed for nationality, types of tissue, subtype of HPV, and publication year. RESULTS: Twenty-two case-control studies were selected, and the total number of individuals in the case and control group was 1897 and 948, respectively. According to the meta-analysis about the 22 publications, HPV infection increased the risk of breast cancer (SOR = 4.02, 95 % CI: 2.42-6.68; I-squared = 44.7 %). Statistical significance was not found in meta-regression performed on the four variables of nationality, type of tissue, subtype of HPV, and publication year which some researchers think sources of heterogeneity. CONCLUSIONS: The results of the present study supported the argument that HPV infection increases the risk of breast cancer. Age-matched case-control studies are in need in the future. PMID- 26981151 TI - Mental health needs and services in the West Bank, Palestine. AB - BACKGROUND: Palestine is a low income country with scarce resources, which is seeking independence. This paper discusses the high levels of mental health need found amongst Palestinian people, and examines services, education and research in this area with particular attention paid to the West Bank. METHODS: CINAHL, PubMed, and Science Direct were used to search for materials. RESULTS AND CONCLUSION: Evidence from this review is that there is a necessity to increase the availability and quality of mental health care. Mental health policy and services in Palestine need development in order to better meet the needs of service users and professionals. It is essential to raise awareness of mental health and increase the integration of mental health services with other areas of health care. Civilians need their basic human needs met, including having freedom of movement and seeing an end to the occupation. There is a need to enhance the resilience and capacity of community mental health teams. There is a need to increase resources and offer more support, up-to-date training and supervision to mental health teams. PMID- 26981150 TI - Synthesis and structural properties of 2-((10-alkyl-10H-phenothiazin-3 yl)methylene)malononitrile derivatives; a combined experimental and theoretical insight. AB - BACKGROUND: Donor acceptor moieties connected through pi-conjugated bridges i.e. D-pi-A, in order to facilitate the electron/charge transfer phenomenon, have wide range of applications. Many classes of organic compounds, such as cyanine, coumarin carbazole, indoline, perylene, phenothiazine, triphenylamine, tetrahydroquinoline and pyrrole can act as charge transfer materials. Phenothiazines have been extensively studied as electron donor candidates due to their potential applications as electrochemical, photovoltaic, photo-physical and DSSC materials. RESULTS: Two phenothiazine derivatives, 2-((10-hexyl-10H phenothiazin-3-yl)methylene)malononitrile (3a) and 2-((10-octyl-10H-phenothiazin 3-yl)methylene)malononitrile (3b) have been synthesized in good yields and characterized by various spectroscopic techniques like FT-IR, UV-vis, (1)H-NMR, (13)C-NMR, and finally confirmed by single crystal X-ray diffraction studies. Density functional theory (DFT) calculations have been performed to compare the theoretical results with the experimental and to probe structural properties. In order to investigate the excited state stabilities the absorption studies have been carried out experimentally as well as theoretically. CONCLUSIONS: Compound 3a crystallises as monoclinic, P2 (1)/a and 3b as P-1. The X-ray crystal structures reveal that asymmetric unit contains one independent molecule in 3a, whereas 3b exhibits a very interesting behavior in having a higher Z value of 8 and four independent molecules in its asymmetric unit. The molecular electrostatic potential (MEP) mapped over the entire stabilized geometries of the molecules indicates the potential sites for chemical reactivities. Furthermore, high first hyperpolarizability values entitle these compounds as potential candidates in photonic applications.Graphical abstractPhenothiazines; a comparison of experimental and theoretical analysis. PMID- 26981152 TI - Oral and maxillofacial considerations in Gardner's syndrome: a report of two cases. AB - Gardner's syndrome (GS) is a genetic disorder characterised by intestinal polyps, multiple osteomas, and soft-tissue tumours. Dentists play an important role in the syndrome diagnosis considering that craniomaxillofacial osteomas are a major criteria for Gardner's syndrome diagnosis. This study aimed to describe the main stomatological manifestation of GS and the importance of dentists in its diagnosis. Two patients presenting GS were evaluated. The first one had two osteomas in the mandible and GS was suspected. The colonoscopy confirmed the presence of polyposis and a prophylactic proctocolectomy was performed. The other patient had a late-stage diagnosis of GS and developed a rectum adenocarcinoma. The presence of craniomaxillofacial osteomas are a hallmark of the disease. Early stage GS diagnosis may enable early diagnosis and preventive strategies in carriers. Other dental abnormalities, such as supernumerary teeth, hypercementosis and odontomas, can also be observed. PMID- 26981153 TI - Dabrafenib in metastatic melanoma: a monocentric 'real life' experience. AB - Dabrafenib is a potent BRAF-kinase inhibitor. Its activity was evaluated on 40 consecutive metastatic melanoma patients (pts) harboring the V600BRAF mutations. Dabrafenib was administered orally at the dosage of 150 mg b.i.d. daily. ORR was 82%, with 7% CR, 62% PR, 13% SD and 18% PD. The median PFS and OS were seven and 17 months, respectively (median follow-up: 8.5 months). Increased risk of progression was found in pts with elevated LDH, ECOG PS >1 and more than two metastatic sites. Grade 3-4 adverse events were recorded in 4 pts. In this retrospective analysis, Dabrafenib confirmed its role as the standard clinical option in metastatic melanoma pts. PMID- 26981154 TI - Endoscopic detection of the gastric lesions of peripheral T-cell lymphoma. AB - An 82-year-old Japanese man presented with a gastric involvement of peripheral T cell lymphoma, not otherwise specified. Although gastrointestinal lesions were not detected on computed tomography, oesophagogastroduodenoscopy revealed a slight elevation of the gastric mucosa, with changes in mucosal colour and the presence of abnormal microvessels. This led to the prompt detection of gastric involvement in lymphoma. This case highlights the usefulness of detailed observation of the gastric mucosa for the endoscopic detection of gastric involvement of peripheral T-cell lymphoma. PMID- 26981155 TI - Maize feedstocks with improved digestibility reduce the costs and environmental impacts of biomass pretreatment and saccharification. AB - BACKGROUND: Despite the recognition that feedstock composition influences biomass conversion efficiency, limited information exists as to how bioenergy crops with reduced recalcitrance can improve the economics and sustainability of cellulosic fuel conversion platforms. We have compared the bioenergy potential-estimated as total glucose productivity per hectare (TGP)-of maize cultivars contrasting for cell wall digestibility across processing conditions of increasing thermochemical severity. In addition, exploratory environmental impact and economic modeling were used to assess whether the development of bioenergy feedstocks with improved cell wall digestibility can enhance the environmental performance and reduce the costs of biomass pretreatment and enzymatic conversion. RESULTS: Systematic genetic gains in cell wall degradability can lead to significant advances in the productivity (TGP) of cellulosic fuel biorefineries under low severity processing; only if gains in digestibility are not accompanied by substantial yield penalties. For a hypothetical maize genotype combining the best characteristics available in the evaluated cultivar panel, TGP under mild processing conditions (~3.7 t ha(-1)) matched the highest realizable yields possible at the highest processing severity. Under this scenario, both, the environmental impacts and processing costs for the pretreatment and enzymatic saccharification of maize stover were reduced by 15 %, given lower chemical and heat consumption. CONCLUSIONS: Genetic improvements in cell wall composition leading to superior cell wall digestibility can be advantageous for cellulosic fuel production, especially if "less severe" processing regimes are favored for further development. Exploratory results indicate potential cost and environmental impact reductions for the pretreatment and enzymatic saccharification of maize feedstocks exhibiting higher cell wall degradability. Conceptually, these results demonstrate that the advance of bioenergy cultivars with improved biomass degradability can enhance the performance of currently available biomass-to-ethanol conversion systems. PMID- 26981156 TI - Systematic review of time trends in the prevalence of Helicobacter pylori infection in China and the USA. AB - It has been suggested that the prevalence of Helicobacter pylori infection has stabilized in the USA and is decreasing in China. We conducted a systematic literature analysis to test this hypothesis. PubMed and Embase searches were conducted up to 19 January 2015. Trends in the prevalence of H. pylori infection over time were assessed by regression analysis using Microsoft Excel. Overall, 25 Chinese studies (contributing 28 datasets) and 11 US studies (contributing 11 datasets) were included. There was a significant decrease over time in the H. pylori infection prevalence for the Chinese studies overall (p = 0.00018) and when studies were limited to those that used serum immunoglobulin G (IgG) assays to detect H. pylori infection (p = 0.014; 20 datasets). The weighted mean prevalence of H. pylori infection was 66 % for rural Chinese populations and 47 % for urban Chinese populations. There was a significant trend towards a decreasing prevalence of H. pylori infection for studies that included only urban populations (p = 0.04; 9 datasets). This trend was no longer statistically significant when these studies were further restricted to those that used serum IgG assays to detect H. pylori infection, although this may have been because of low statistical power due to the small number of datasets available for this analysis (p = 0.28; 6 datasets). There were no significant trends in terms of changes in the prevalence of H. pylori infection over time for studies conducted in the USA. In conclusion, the prevalence of H. pylori infection is most likely decreasing in China, due to a combination of increasing urbanization, which we found to be associated with lower H. pylori infection rates, and possibly also decreasing rates of H. pylori infection within urban populations. This will probably result in a gradual decrease in peptic ulcer and gastric cancer rates in China over time. PMID- 26981157 TI - A graph-based approach to construct target-focused libraries for virtual screening. AB - BACKGROUND: Due to exorbitant costs of high-throughput screening, many drug discovery projects commonly employ inexpensive virtual screening to support experimental efforts. However, the vast majority of compounds in widely used screening libraries, such as the ZINC database, will have a very low probability to exhibit the desired bioactivity for a given protein. Although combinatorial chemistry methods can be used to augment existing compound libraries with novel drug-like compounds, the broad chemical space is often too large to be explored. Consequently, the trend in library design has shifted to produce screening collections specifically tailored to modulate the function of a particular target or a protein family. METHODS: Assuming that organic compounds are composed of sets of rigid fragments connected by flexible linkers, a molecule can be decomposed into its building blocks tracking their atomic connectivity. On this account, we developed eSynth, an exhaustive graph-based search algorithm to computationally synthesize new compounds by reconnecting these building blocks following their connectivity patterns. RESULTS: We conducted a series of benchmarking calculations against the Directory of Useful Decoys, Enhanced database. First, in a self-benchmarking test, the correctness of the algorithm is validated with the objective to recover a molecule from its building blocks. Encouragingly, eSynth can efficiently rebuild more than 80 % of active molecules from their fragment components. Next, the capability to discover novel scaffolds is assessed in a cross-benchmarking test, where eSynth successfully reconstructed 40 % of the target molecules using fragments extracted from chemically distinct compounds. Despite an enormous chemical space to be explored, eSynth is computationally efficient; half of the molecules are rebuilt in less than a second, whereas 90 % take only about a minute to be generated. CONCLUSIONS: eSynth can successfully reconstruct chemically feasible molecules from molecular fragments. Furthermore, in a procedure mimicking the real application, where one expects to discover novel compounds based on a small set of already developed bioactives, eSynth is capable of generating diverse collections of molecules with the desired activity profiles. Thus, we are very optimistic that our effort will contribute to targeted drug discovery. eSynth is freely available to the academic community at www.brylinski.org/content/molecular-synthesis.Graphical abstractAssuming that organic compounds are composed of sets of rigid fragments connected by flexible linkers, a molecule can be decomposed into its building blocks tracking their atomic connectivity. Here, we developed eSynth, an automated method to synthesize new compounds by reconnecting these building blocks following the connectivity patterns via an exhaustive graph-based search algorithm. eSynth opens up a possibility to rapidly construct virtual screening libraries for targeted drug discovery. PMID- 26981159 TI - Erratum to: Neural selectivity for communicative auditory signals in Phelan McDermid syndrome. AB - [This corrects the article DOI: 10.1186/s11689-016-9138-9.]. PMID- 26981158 TI - Reduced engagement with social stimuli in 6-month-old infants with later autism spectrum disorder: a longitudinal prospective study of infants at high familial risk. AB - BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1 % of the population and close to 20 % of prospectively studied infants with an older sibling with ASD. Although significant progress has been made in characterizing the emergence of behavioral symptoms of ASD, far less is known about the underlying disruptions to early learning. Recent models suggest that core aspects of the causal path to ASD may only be apparent in early infancy. Here, we investigated social attention in 6- and 12-month-old infants who did and did not meet criteria for ASD at 24 months using both cognitive and electrophysiological methods. We hypothesized that a reduction in attention engagement to faces would be associated with later ASD. METHODS: In a prospective longitudinal design, we used measures of both visual attention (habituation) and brain function (event-related potentials to faces and objects) at 6 and 12 months and investigated the relationship to ASD outcome at 24 months. RESULTS: High-risk infants who met criteria for ASD at 24 months showed shorter epochs of visual attention, faster but less prolonged neural activation to faces, and delayed sensitization responses (increases in looking) to faces at 6 months; these differences were less apparent at 12 months. These findings are consistent with disrupted engagement of sustained attention to social stimuli. CONCLUSIONS: These findings suggest that there may be fundamental early disruptions to attention engagement that may have cascading consequences for later social functioning. PMID- 26981161 TI - Analysis on the Effect of Individualized Aerobic Exercise Intervention for Teenagers with Type 2 Diabetes. AB - OBJECTIVE: To investigate the intervention effect of individualized aerobic exercise on type 2 diabetes in teenagers. METHOD: To select 60 cases of teenager with type 2 diabetes in Zhoukou Hospital of Traditional Medicine in February 2013 to February 2014 as the research object, test all enrolled patients' maximal oxygen and blood glucose fluctuation, and then give individualized aerobic exercise intervention, after 6 months intervention, compare the changes of patients' indexes and evaluate the effect of individualized aerobic exercise intervention. RESULT: After the intervention, the patients' plasma triglyceride and cholesterol content are significantly lower than before (P < 0.05); there's no significant difference between high and low-density lipoprotein (P > 0.05). Moreover, the patients' insulin and C-peptide level are significantly higher than those before intervention (P < 0.05); before intervention, their blood glucose and glycated hemogiobin level are higher than normal, after intervention, they are weakened, but there's no significant difference (P > 0.05). The maximal oxygen uptake and different intensity of metabolic equivalents are higher than before, but there's no significant difference (P > 0.05). CONCLUSION: For teenagers with type 2 diabetes, the implementation of individualized aerobic exercise intervention can effectively improve the patients' lipid metabolism and cardio-pulmonary function, and effectively promote the insulin and C-peptide secretion, to provide scientific basis for effective control of blood glucose. PMID- 26981162 TI - Weightlifter Lumbar Physiology Health Influence Factor Analysis of Sports Medicine. AB - Chinese women's weightlifting project has been in the advanced world level, suggests that the Chinese coaches and athletes have many successful experience in the weight lifting training. Little weight lifting belongs to high-risk sports, however, to the lumbar spine injury, some young good athletes often due to lumbar trauma had to retire, and the national investment and athletes toil is regret things. This article from the perspective of sports medicine, weightlifting athletes training situation analysis and put forward Suggestions, aimed at avoiding lumbar injury, guarantee the health of athletes. In this paper, first of all to 50 professional women's weightlifting athletes doing investigation, found that 82% of the athletes suffer from lumbar disease symptoms, the reason is mainly composed of lumbar strain, intensity is too large, motion error caused by three factors. From the Angle of sports medicine and combined with the characteristics of the structure of human body skeleton athletes lumbar structural mechanics analysis, find out the lumbar force's two biggest technical movement, study, and regulate the action standard, so as to minimize lumbar force, for athletes to contribute to the health of the lumbar spine. PMID- 26981160 TI - Dynamic interplay between locus-specific DNA methylation and hydroxymethylation regulates distinct biological pathways in prostate carcinogenesis. AB - BACKGROUND: Despite the significant global loss of DNA hydroxymethylation marks in prostate cancer tissues, the locus-specific role of hydroxymethylation in prostate tumorigenesis is unknown. We characterized hydroxymethylation and methylation marks by performing whole-genome next-generation sequencing in representative normal and prostate cancer-derived cell lines in order to determine functional pathways and key genes regulated by these epigenomic modifications in cancer. RESULTS: Our cell line model shows disruption of hydroxymethylation distribution in cancer, with global loss and highly specific gain in promoter and CpG island regions. Significantly, we observed locus specific retention of hydroxymethylation marks in specific intronic and intergenic regions which may play a novel role in the regulation of gene expression in critical functional pathways, such as BARD1 signaling and steroid hormone receptor signaling in cancer. We confirm a modest correlation of hydroxymethylation with expression in intragenic regions in prostate cancer, while identifying an original role for intergenic hydroxymethylation in differentially expressed regulatory pathways in cancer. We also demonstrate a successful strategy for the identification and validation of key candidate genes from differentially regulated biological pathways in prostate cancer. CONCLUSIONS: Our results indicate a distinct function for aberrant hydroxymethylation within each genomic feature in cancer, suggesting a specific and complex role for the deregulation of hydroxymethylation in tumorigenesis, similar to methylation. Subsequently, our characterization of key cellular pathways exhibiting dynamic enrichment patterns for methylation and hydroxymethylation marks may allow us to identify differentially epigenetically modified target genes implicated in prostate cancer tumorigenesis. PMID- 26981163 TI - Fuzzy Analytic Hierarchy Process-based Chinese Resident Best Fitness Behavior Method Research. AB - With explosive development in Chinese economy and science and technology, people's pursuit of health becomes more and more intense, therefore Chinese resident sports fitness activities have been rapidly developed. However, different fitness events popularity degrees and effects on body energy consumption are different, so bases on this, the paper researches on fitness behaviors and gets Chinese residents sports fitness behaviors exercise guide, which provides guidance for propelling to national fitness plan's implementation and improving Chinese resident fitness scientization. The paper starts from the perspective of energy consumption, it mainly adopts experience method, determines Chinese resident favorite sports fitness event energy consumption through observing all kinds of fitness behaviors energy consumption, and applies fuzzy analytic hierarchy process to make evaluation on bicycle riding, shadowboxing practicing, swimming, rope skipping, jogging, running, aerobics these seven fitness events. By calculating fuzzy rate model's membership and comparing their sizes, it gets fitness behaviors that are more helpful for resident health, more effective and popular. Finally, it gets conclusions that swimming is a best exercise mode and its membership is the highest. Besides, the memberships of running, rope skipping and shadowboxing practicing are also relative higher. It should go in for bodybuilding by synthesizing above several kinds of fitness events according to different physical conditions; different living conditions so that can better achieve the purpose of fitness exercises. PMID- 26981164 TI - BP Neural Network Model-based Physical Exercises and Dietary Habits Relationships Exploration. AB - With the continuous progress of society, increment of social pressure, people have paid little and little attentions to physical exercises and dietary necessity. Take Beijing, Shanghai, Guangzhou, Shenzhen, Shijiazhuang and Baotou university students as research objects, targeted at physical exercises time and dietary habits, it starts investigation. Make principal component analysis of investigation results, results indicates that cereal intake is principal component in dietary habits; strenuous exercise time and general physical exercise time are the principal components in physical exercise. Utilize BP neural network model, analyze these seven cities' physical exercises and dietary habits conditions, the result indicates that except for Shenzhen, all the other six cities haven't reached the standard. PMID- 26981165 TI - Screening SIRT1 Activators from Medicinal Plants as Bioactive Compounds against Oxidative Damage in Mitochondrial Function. AB - Sirtuin type 1 (SIRT1) belongs to the family of NAD(+) dependent histone deacetylases and plays a critical role in cellular metabolism and response to oxidative stress. Traditional Chinese medicines (TCMs), as an important part of natural products, have been reported to exert protective effect against oxidative stress in mitochondria. In this study, we screened SIRT1 activators from TCMs and investigated their activities against mitochondrial damage. 19 activators were found in total by in vitro SIRT1 activity assay. Among those active compounds, four compounds, ginsenoside Rb2, ginsenoside F1, ginsenoside Rc, and schisandrin A, were further studied to validate the SIRT1-activation effects by liquid chromatography-mass spectrometry and confirm their activities against oxidative damage in H9c2 cardiomyocytes exposed to tert-butyl hydroperoxide (t-BHP). The results showed that those compounds enhanced the deacetylated activity of SIRT1, increased ATP content, and inhibited intracellular ROS formation as well as regulating the activity of Mn-SOD. These SIRT1 activators also showed moderate protective effects on mitochondrial function in t-BHP cells by recovering oxygen consumption and increasing mitochondrial DNA content. Our results suggested that those compounds from TCMs attenuated oxidative stress-induced mitochondrial damage in cardiomyocytes through activation of SIRT1. PMID- 26981166 TI - Polyethylene Glycol Preconditioning: An Effective Strategy to Prevent Liver Ischemia Reperfusion Injury. AB - Hepatic ischemia reperfusion injury (IRI) is an inevitable clinical problem for liver surgery. Polyethylene glycols (PEGs) are water soluble nontoxic polymers that have proven their effectiveness in various in vivo and in vitro models of tissue injury. The present study aims to investigate whether the intravenous administration of a high molecular weight PEG of 35 kDa (PEG 35) could be an effective strategy for rat liver preconditioning against IRI. PEG 35 was intravenously administered at 2 and 10 mg/kg to male Sprague Dawley rats. Then, rats were subjected to one hour of partial ischemia (70%) followed by two hours of reperfusion. The results demonstrated that PEG 35 injected intravenously at 10 mg/kg protected efficiently rat liver against the deleterious effects of IRI. This was evidenced by the significant decrease in transaminases levels and the better preservation of mitochondrial membrane polarization. Also, PEG 35 preserved hepatocyte morphology as reflected by an increased F-actin/G-actin ratio and confocal microscopy findings. In addition, PEG 35 protective mechanisms were correlated with the activation of the prosurvival kinase Akt and the cytoprotective factor AMPK and the inhibition of apoptosis. Thus, PEG may become a suitable agent to attempt pharmacological preconditioning against hepatic IRI. PMID- 26981167 TI - The complete genome sequence of Eubacterium limosum SA11, a metabolically versatile rumen acetogen. AB - Acetogens are a specialized group of anaerobic bacteria able to produce acetate from CO2 and H2 via the Wood-Ljungdahl pathway. In some gut environments acetogens can compete with methanogens for H2, and as a result rumen acetogens are of interest in the development of microbial approaches for methane mitigation. The acetogen Eubacterium limosum SA11 was isolated from the rumen of a New Zealand sheep and its genome has been sequenced to examine its potential application in methane mitigation strategies, particularly in situations where hydrogenotrophic methanogens are inhibited resulting in increased H2 levels in the rumen. The 4.15 Mb chromosome of SA11 has an average G + C content of 47 %, and encodes 3805 protein-coding genes. There is a single prophage inserted in the chromosome, and several other gene clusters appear to have been acquired by horizontal transfer. These include genes for cell wall glycopolymers, a type VII secretion system, cell surface proteins and chemotaxis. SA11 is able to use a variety of organic substrates in addition to H2/CO2, with acetate and butyrate as the principal fermentation end-products, and genes involved in these metabolic pathways have been identified. An unusual feature is the presence of 39 genes encoding trimethylamine methyltransferase family proteins, more than any other bacterial genome. Overall, SA11 is a metabolically versatile organism, but its ability to grow on such a wide range of substrates suggests it may not be a suitable candidate to take the place of hydrogen-utilizing methanogens in the rumen. PMID- 26981168 TI - Insights into kidney stem cell development and regeneration using zebrafish. AB - Kidney disease is an escalating global health problem, for which the formulation of therapeutic approaches using stem cells has received increasing research attention. The complexity of kidney anatomy and function, which includes the diversity of renal cell types, poses formidable challenges in the identification of methods to generate replacement structures. Recent work using the zebrafish has revealed their high capacity to regenerate the integral working units of the kidney, known as nephrons, following acute injury. Here, we discuss these findings and explore the ways that zebrafish can be further utilized to gain a deeper molecular appreciation of renal stem cell biology, which may uncover important clues for regenerative medicine. PMID- 26981170 TI - Use of platelet lysate for bone regeneration - are we ready for clinical translation? AB - Current techniques to improve bone regeneration following trauma or tumour resection involve the use of autograft bone or its substitutes supplemented with osteoinductive growth factors and/or osteogenic cells such as mesenchymal stem cells (MSCs). Although MSCs are most commonly grown in media containing fetal calf serum, human platelet lysate (PL) offers an effective alternative. Bone marrow - derived MSCs grown in PL-containing media display faster proliferation whilst maintaining good osteogenic differentiation capacity. Limited pre-clinical investigations using PL-expanded MSCs seeded onto osteoconductive scaffolds indicate good potential of such constructs to repair bone in vivo. In an alternative approach, nude PL-coated scaffolds without seeded MSCs have been proposed as novel regenerative medicine devices. Even though methods to coat scaffolds with PL vary, in vitro studies suggest that PL allows for MSC adhesion, migration and differentiation inside these scaffolds. Increased new bone formation and vascularisation in comparison to uncoated scaffolds have also been observed in vivo. This review outlines the state-of-the-art research in the field of PL for ex vivo MSC expansion and in vivo bone regeneration. To minimise inconsistency between the studies, further work is required towards standardisation of PL preparation in terms of the starting material, platelet concentration, leukocyte depletion, and the method of platelet lysis. PL quality control procedures and its "potency" assessment are urgently needed, which could include measurements of key growth and attachment factors important for MSC maintenance and differentiation. Furthermore, different PL formulations could be tailor-made for specific bone repair indications. Such measures would undoubtedly speed up clinical translation of PL-based treatments for bone regeneration. PMID- 26981171 TI - Human pluripotent stem cells: Towards therapeutic development for the treatment of lifestyle diseases. AB - There are two types of human pluripotent stem cells: Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), both of which launched themselves on clinical trials after having taken measures to overcome problems: Blocking rejections by immunosuppressants regarding ESCs and minimizing the risk of tumorigenicity by depleting exogenous gene components regarding iPSCs. It is generally assumed that clinical applications of human pluripotent stem cells should be limited to those cases where there are no alternative measures for treatments because of the risk in transplanting those cells to living bodies. Regarding lifestyle diseases, we have already several therapeutic options, and thus, development of human pluripotent stem cell-based therapeutics tends to be avoided. Nevertheless, human pluripotent stem cells can contribute to the development of new therapeutics in this field. As we will show, there is a case where only a short-term presence of human pluripotent stem-derived cells can exert long-term therapeutic effects even after they are rejected. In those cases, immunologically rejections of ESC- or allogenic iPSC-derived cells may produce beneficial outcomes by nullifying the risk of tumorigenesis without deterioration of therapeutic effects. Another utility of human pluripotent stem cells is the provision of an innovative tool for drug discovery that are otherwise unavailable. For example, clinical specimens of human classical brown adipocytes (BAs), which has been attracting a great deal of attention as a new target of drug discovery for the treatment of metabolic disorders, are unobtainable from living individuals due to scarcity, fragility and ethical problems. However, BA can easily be produced from human pluripotent stem cells. In this review, we will contemplate potential contribution of human pluripotent stem cells to therapeutic development for lifestyle diseases. PMID- 26981169 TI - Generation of diverse neural cell types through direct conversion. AB - A characteristic of neurological disorders is the loss of critical populations of cells that the body is unable to replace, thus there has been much interest in identifying methods of generating clinically relevant numbers of cells to replace those that have been damaged or lost. The process of neural direct conversion, in which cells of one lineage are converted into cells of a neural lineage without first inducing pluripotency, shows great potential, with evidence of the generation of a range of functional neural cell types both in vitro and in vivo, through viral and non-viral delivery of exogenous factors, as well as chemical induction methods. Induced neural cells have been proposed as an attractive alternative to neural cells derived from embryonic or induced pluripotent stem cells, with prospective roles in the investigation of neurological disorders, including neurodegenerative disease modelling, drug screening, and cellular replacement for regenerative medicine applications, however further investigations into improving the efficacy and safety of these methods need to be performed before neural direct conversion becomes a clinically viable option. In this review, we describe the generation of diverse neural cell types via direct conversion of somatic cells, with comparison against stem cell-based approaches, as well as discussion of their potential research and clinical applications. PMID- 26981172 TI - Human albumin solution for patients with cirrhosis and acute on chronic liver failure: Beyond simple volume expansion. AB - To provide an overview of the properties of human serum albumin (HSA), and to review the evidence for the use of human albumin solution (HAS) in critical illness, sepsis and cirrhosis. A MEDLINE search was performed using the terms "human albumin", "critical illness", "sepsis" and "cirrhosis". The references of retrieved articles were reviewed manually. Studies published between 1980 and 2014 were selected based on quality criteria. Data extraction was performed by all authors. HSA is the main plasma protein contributing greatly to its oncotic pressure. HSA demonstrates important binding properties for endogenous and exogenous toxins, drugs and drug metabolites that account for its anti-oxidant and anti-inflammatory properties. In disease states, hypoalbuminaemia is secondary to decreased HSA production, increased loss or transcapillary leakage into the interstitial space. HSA function can be also altered in disease with reduced albumin binding capacity and increased production of modified isoforms. HAS has been used as volume expander in critical illness, but received criticism due to cost and concerns regarding safety. More recent studies confirmed the safety of HAS, but failed to show any survival benefit compared to the cheaper crystalloid fluids, therefore limiting its use. On the contrary, in cirrhosis there is robust data to support the efficacy of HAS for the prevention of circulatory dysfunction post-large volume paracentesis and in the context of spontaneous bacterial peritonitis, and for the treatment of hepato-renal syndrome and hypervolaemic hyponatraemia. It is likely that not only the oncotic properties of HAS are beneficial in cirrhosis, but also its functional properties, as HAS replaces the dysfunctional HSA. The role of HAS as the resuscitation fluid of choice in critically ill patients with cirrhosis, beyond the established indications for HAS use, should be addressed in future studies. PMID- 26981174 TI - Non-initiation of hepatitis C virus antiviral therapy in patients with human immunodeficiency virus/hepatitis C virus co-infection. AB - AIM: To assess whether reasons for hepatitis C virus (HCV) therapy non-initiation differentially affect racial and ethnic minorities with human immunodeficiency virus (HIV)/HCV co-infection. METHODS: Analysis included co-infected HCV treatment-naive patients in the University of North Carolina CFAR HIV Clinical Cohort (January 1, 2004 and December 31, 2011). Medical records were abstracted to document non-modifiable medical (e.g., hepatic decompensation, advanced immunosuppression), potentially modifiable medical (e.g., substance abuse, severe depression, psychiatric illness), and non-medical (e.g., personal, social, and economic factors) reasons for non-initiation. Statistical differences in the prevalence of reasons for non-treatment between racial/ethnic groups were assessed using the two-tailed Fisher's exact test. Three separate regression models were fit for each reason category. Odds ratios and their 95%CIs (Wald's) were computed. RESULTS: One hundred and seventy-one patients with HIV/HCV co infection within the cohort met study inclusion. The study sample was racially and ethnically diverse; most patients were African-American (74%), followed by Caucasian (19%), and Hispanic/other (7%). The median age was 46 years (interquartile range = 39-50) and most patients were male (74%). Among the 171 patients, reasons for non-treatment were common among all patients, regardless of race/ethnicity (50% with >= 1 non-modifiable medical reason, 66% with >= 1 potentially modifiable medical reason, and 66% with >= 1 non-medical reason). There were no significant differences by race/ethnicity. Compared to Caucasians, African-Americans did not have increased odds of non-modifiable [adjusted odds ratio (aOR) = 1.47, 95%CI: 0.57-3.80], potentially modifiable (aOR = 0.72, 95%CI: 0.25-2.09) or non-medical (aOR = 0.90, 95%CI: 0.32-2.52) reasons for non initiation. CONCLUSION: Race/ethnicity alone is not predictive of reasons for HCV therapy non-initiation. Targeted interventions are needed to improve access to therapy for all co-infected patients, including minorities. PMID- 26981173 TI - Indocyanine green kinetics to assess liver function: Ready for a clinical dynamic assessment in major liver surgery? AB - Indocyanine green (ICG) kinetics (PDR/R15) used to quantitatively assess hepatic function in the perioperative period of major resective surgery and liver transplantation have been the object of an extensive, updated and critical review. New, non invasive bedside monitors (pulse dye densitometry technology) make this opportunity widely available in clinical practice. After having reviewed basic concepts of hepatic clearance, we analysed the most common indications ICG kinetic parameters have nowadays in clinical practice, focusing in particular on the diagnostic and prognostic role of PDR and R15 in the perioperative period of major liver surgery and liver transplantation. As recently pointed out, even if of extreme interest, ICG clearance parameters have still some limitations, to be considered when using these tests. PMID- 26981175 TI - Significant cohort of non-alcoholic fatty liver disease with portal vein thrombosis in transplant waiting list. AB - AIM: To characterize non-alcoholic fatty liver disease (NAFLD) presentation with esophageal varices. METHODS: We carried out a retrospective cohort study on 258 patients with esophageal varices at a single tertiary referral center. These patients underwent diagnosis of several liver diseases, including: NAFLD associated cirrhosis, hepatitis B, hepatitis C, Wilson disease, autoimune liver diseases, and others. RESULTS: Of the 258 patients, 39% of patients exhibited esophageal varices due to NAFLD-associated cirrhosis. Of the 38 (14.7%) patients developed hepatocellular carcinoma during follow-up, 52% were due to hepatitis B, 26% due to hepatitis C and 13.2% due to NAFLD. Of the 258 patients, 50.0% with NAFLD, 33.3% with hepatitis B, 26.3% with hepatitis C, and 58.3% with other diseases were alive at the end of the 5-year period with a significant difference according to the Kaplan-Meier log Rank test (P = 0.040). Portal vein thrombosis was detected in 47.5% of patients with NAFLD, in 29% of patients with hepatitis B, in 17% of patients with hepatitis C, and in 62% of patients with other related diseases (P < 0.0001). CONCLUSION: Our study showed a proportionally greater elevation in liver transplant candidacy in patients with NAFLD and portal vein thrombosis. Older patients were more prone to developing cirrhosis, hepatocellular carcinoma and a high mortality rate. However, younger patients exhibited more portal vein thrombosis and gastric varices. PMID- 26981178 TI - Efforts to increase image quality during endoscopy: The role of pronase. AB - Clear visualization of the gastrointestinal mucosal surface is essential for thorough endoscopy. An unobstructed assessment can reduce the need for additional time-consuming manipulations such as frequent washing and suction, which tend to prolong total procedure time. However, mucus, foam, and bubbles often hinder clear visibility during endoscopy. Premedication with pronase, a compound of mixed proteolytic enzymes, has been studied in order to improve mucosal visibility during endoscopy. Although its effects differ according to the location in the stomach, premedication with pronase 10 to 20 min before endoscopy significantly improves mucosal visibility without affecting the accuracy of Helicobacter pylori identification. The effects of pronase as premedication also extend to chromoendoscopy, narrow-band imaging, magnifying endoscopy, and endoscopic ultrasonography. In addition, endoscopic flushing with pronase during endoscopy may improve the quantity and the quality of a biopsy to some degree. Although improved mucosal visibility does not necessarily improve clinical outcomes, premedication with pronase may be helpful for increasing the detection rate of early cancers. PMID- 26981177 TI - Endoscopic imaging of Barrett's esophagus. AB - The incidence of esophageal adenocarcinoma (EAC) has dramatically increased in the United States as well as Western European countries. The majority of esophageal adenocarcinomas arise from a backdrop of Barrett's esophagus (BE), a premalignant lesion that can lead to dysplasia and cancer. Because of the increased risk of EAC, GI society guidelines recommend endoscopic surveillance of patients with BE. The emphasis on early detection of dysplasia in BE through surveillance endoscopy has led to the development of advanced endoscopic imaging technologies. These techniques have the potential to both improve mucosal visualization and characterization and to detect small mucosal abnormalities which are difficult to identify with standard endoscopy. This review summarizes the advanced imaging technologies used in evaluation of BE. PMID- 26981176 TI - New era of colorectal cancer screening. AB - Colorectal cancer (CRC) is the 2(nd) most common cancer in women and 3(rd) most common cancer in men worldwide. Most CRCs develop from adenomatous polyps arising from glandular epithelium. Tumor growth is initiated by mutation of the tumor suppressor gene APC and involves other genetic mutations in a stepwise process over years. Both hereditary and environmental factors contribute to the development of CRC. Screening has been proven to reduce the incidence of CRC. Screening has also contributed to the decrease in CRC mortality in the United States. However, CRC incidence and/or mortality remain on the rise in some parts of the world (Eastern Europe, Asia, and South America), likely due to factors including westernized diet, lifestyle, and lack of healthcare infrastructure. Multiple screening options are available, ranging from direct radiologic or endoscopic visualization tests that primarily detect premalignant or malignant lesions such as flexible sigmoidoscopy, optical colonoscopy, colon capsule endoscopy, computed tomographic colonography, and double contrast barium enema - to stool based tests which primarily detect cancers, including fecal DNA, fecal immunochemical test, and fecal occult blood test. The availability of some of these tests is limited to areas with high economic resources. This article will discuss CRC epidemiology, pathogenesis, risk factors, and screening modalities with a particular focus on new technologies. PMID- 26981179 TI - Raman spectroscopy for early real-time endoscopic optical diagnosis based on biochemical changes during the carcinogenesis of Barrett's esophagus. AB - Raman spectroscopy is a spectroscopic technique based on the inelastic scattering of monochromatic light that represents the molecular composition of the interrogated volume to provide a direct molecular fingerprint. Several investigations have revealed that confocal Raman spectroscopy can differentiate non-dysplastic Barrett's esophagus from esophageal high-grade dysplasia and adenocarcinoma with high sensitivity and specificity. An automated on-line Raman spectral diagnostic system has made it possible to use Raman spectroscopy to guide accurate target biopsy instead of multiple random forceps-biopsies, this novel system is expected to improve in vivo precancerous diagnosis and tissue characterization of Barrett's esophagus. PMID- 26981180 TI - Endoscopic mucosal resection of colorectal adenomas > 20 mm: Risk factors for recurrence. AB - AIM: To evaluate risk factors for local recurrence after endoscopic mucosal resection of colorectal adenomas > 20 mm. METHODS: Retrospective data analysis of 216 endoscopic mucosal resections for colorectal adenomas > 20 mm in 179 patients (40.3% female; median age 68 years; range 35-91 years). All patients had at least 1 follow-up endoscopy with a minimum control interval of 2 mo (mean follow-up 6 mo/2.0-43.4 mo). Possible factors associated with local recurrence were analyzed by univariate and multivariate analysis. RESULTS: Median size of the lesions was 30 mm (20-70 mm), 69.0% were localized in the right-sided (cecum, ascending and transverse) colon. Most of the lesions (85.6%) showed a non-pedunculated morphology and the majority of resections was in piecemeal technique (78.7%). Histology showed carcinoma or high-grade intraepithelial neoplasia in 51/216 (23.6%) lesions including 4 low risk carcinomas (pT1a, L0, V0, R0 - G1/G2). Histologically proven recurrence was observed in 33/216 patients (15.3%). Patient age > 65 years, polyp size > 30 mm, non-pedunculated morphology, localization in the right-sided colon, piecemeal resection and tubular-villous histology were found as associated factors in univariate analysis. On multivariate analysis, only localization in the right-sided colon (HR = 6.842/95%CI: 1.540-30.394; P = 0.011), tubular-villous histology (HR = 3.713/95%CI: 1.617-8.528; P = 0.002) and polyp size > 30 mm (HR = 2.563/95%CI: 1.179-5.570; P = 0.017) were significantly associated risk factors for adenoma recurrence. CONCLUSION: Meticulous endoscopic follow-up is warranted after endoscopic mucosal resection of adenomas localized in the right-sided colon larger than > 30 mm, with tubular-villous histology. PMID- 26981181 TI - Use of fibrates in the metabolic syndrome: A review. AB - The use of fibrates in the treatment of dyslipidaemia has changed significantly over recent years. Their role appeared clear at the start of this century. The Helsinki Heart Study and Veterans Affairs High-Density Cholesterol Intervention Trial suggested significant benefit, especially in patients with atherogenic dyslipidaemia. However, this clarity disintegrated following the negative outcomes reported by the Bezafibrate Infarction Prevention, Fenofibrate Intervention and Event Lowering in Diabetes and Action to Control Cardiovascular Risk in Diabetes randomised controlled trials. In this review we discuss these and other relevant trials and consider patient subgroups such as those with the metabolic syndrome and those needing treatment to prevent the microvascular complications associated with diabetes in whom fibrates may be useful. We also discuss observations from our group that may provide some explanation for the varying outcomes reported in large trials. The actions of fibrates in patients who are also on statins are interesting and appear to differ from those in patients not on statins. Understanding this is key as statins are the primary lipid lowering agents and likely to occupy that position for the foreseeable future. We also present other features of fibrate treatment we have observed in our clinical practice; changes in creatinine, liver function tests and the paradoxical high density lipoprotein reduction. Our purpose is to provide enough data for the reader to make objective decisions in their own clinical practice regarding fibrate use. PMID- 26981183 TI - Hyporeninemic hypoaldosteronism and diabetes mellitus: Pathophysiology assumptions, clinical aspects and implications for management. AB - Patients with diabetes mellitus (DM) frequently develop electrolyte disorders, including hyperkalemia. The most important causal factor of chronic hyperkalemia in patients with diabetes is the syndrome of hyporeninemic hypoaldosteronism (HH), but other conditions may also contribute. Moreover, as hyperkalemia is related to the blockage of the renin-angiotensin-aldosterone system (RAAS) and HH is most common among patients with mild to moderate renal insufficiency due to diabetic nephropathy (DN), the proper evaluation and management of these patients is quite complex. Despite its obvious relationship with diabetic nephropathy, HH is also related to other microvascular complications, such as DN, particularly the autonomic type. To confirm the diagnosis, plasma aldosterone concentration and the levels of renin and cortisol are measured when the RAAS is activated. In addition, synthetic mineralocorticoid and/or diuretics are used for the treatment of this syndrome. However, few studies on the implications of HH in the treatment of patients with DM have been conducted in recent years, and therefore little, if any, progress has been made. This comprehensive review highlights the findings regarding the epidemiology, diagnosis, and management recommendations for HH in patients with DM to clarify the diagnosis of this clinical condition, which is often neglected, and to assist in the improvement of patient care. PMID- 26981182 TI - Role of vitamin D in diabetes mellitus and chronic kidney disease. AB - Approximately 30%-50% of people are recognized to have low levels of vitamin D, and insufficiency and deficiency of vitamin D are recognized as global health problems worldwide. Although the presence of hypovitamin D increases the risk of rickets and fractures, low vitamin D levels are also associated with hypertension, cancer, and cardiovascular disease. In addition, diabetes mellitus (DM) and chronic kidney disease (CKD) are also related to vitamin D levels. Vitamin D deficiency has been linked to onset and progression of DM. Although in patients with DM the relationship between vitamin D and insulin secretion, insulin resistance, and beta-cell dysfunction are pointed out, evidence regarding vitamin D levels and DM is contradictory, and well controlled studies are needed. In addition, vitamin D influences the renin-angiotensin system, inflammation, and mineral bone disease, which may be associated with the cause and progression CKD. There is increasing evidence that vitamin D deficiency may be a risk factor for DM and CKD; however, it remains uncertain whether vitamin D deficiency also predisposes to death from DM and CKD. Although at this time, supplementation with vitamin D has not been shown to improve glycemic control or prevent incident DM, clinical trials with sufficient sample size, study periods, and optimal doses of vitamin D supplementation are still needed. This review focuses on the mechanism of vitamin D insufficiency and deficiency in DM or CKD, and discusses the current evidence regarding supplementation with vitamin D in patients with these diseases. PMID- 26981184 TI - Laparoscopic complete mesocolic excision with central vascular ligation in right colon cancer: A comprehensive review. AB - Aim of the study is to comprehensively review the latest trends in laparoscopic complete mesocolic excision (CME) with central vascular ligation (CVL) for the multimodal management of right colon cancer. Historical and up-to-date anatomo embryological concepts are analyzed in detail, focusing on the latest studies of the mesenteric organ, its dissection by mesofascial and retrofascial cleavage planes, and questioning the need for a new terminology in colonic resections. The rationale behind Laparoscopic CME with CVL is thoroughly investigated and explained. Attention is paid to the current surgical techniques and the quality of the surgical specimen, yielded through mesocolic, intramesocolic and muscularis propria plane of surgery. We evaluate the impact on long term oncologic outcome in terms of local recurrence, overall and disease-free survival, according to the plane of resection achieved. Conclusions are drawn on the basis of the available evidence, which suggests a pivotal role of laparoscopic CME with CVL in the multimodal management of right sided colonic cancer: performed in the right mesocolic plane of resection, laparoscopic CME with CVL demonstrates better oncologic results when compared to standard non mesocolic planes of surgery, with all the advantages of laparoscopic techniques, both in faster recovery and better immunological response. The importance of minimally invasive meso-resectional surgery is thus stressed and highlighted as the new frontier for a modern laparoscopic total right mesocolectomy. PMID- 26981186 TI - Associating liver partition and portal vein ligation for staged hepatectomy: From technical evolution to oncological benefit. AB - Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a novel approach in liver surgery that allows for extensive resection of liver parenchyma by inducing a rapid hypertrophy of the future remnant liver. However, recent reports indicate that not all patients eligible for ALPPS will benefit from this procedure. Therefore, careful patient selection will be necessary to fully exploit possible benefits of ALPPS. Here, we provide a comprehensive overview of the technical evolution of ALPPS with a special emphasis on safety and oncologic efficacy. Furthermore, we review the contemporary literature regarding indication and benefits, but also limitations of ALPPS. PMID- 26981185 TI - Intestinal inflammation and the diet: Is food friend or foe? AB - Inflammatory bowel disease (IBD) is a chronic intestinal illness of autoimmune origin affecting millions across the globe. The most common subtypes include ulcerative colitis (UC) and Crohn's disease. While many medical treatments for IBD exist, none come without the risk of significant immunosuppression and in general do not have benign side effect profiles. Surgical intervention exists only as radical resection for medically refractory UC. There exists a dire need for novel treatments that target the inherent pathophysiologic disturbances of IBD, rather than global immune suppression. One avenue of investigation that could provide such an agent is the interaction between certain dietary elements and the aryl hydrocarbon receptor (AHR). The AHR is a cytosolic transcription factor with a rich history in environmental toxicant handling, however, recently a role has emerged for the AHR as a modulator of the gastrointestinal immune system. Studies have come to elucidate these effects to include the enhancement of Th cell subset differentiation, interactions between enteric flora and the luminal wall, and modulation of inflammatory interleukin and cytokine signaling. This review highlights advancements in our understanding of AHR activity in the digestive tract and how this stimulation may be wrought by certain dietary "micronutriceuticals", namely indole-3-carbinol (I3C) and its derivatives. Greater clarity surrounding these dynamics could lead to a novel diet-derived agonist of the AHR which is not only non-toxic, but also efficacious in the amelioration of clinical IBD. PMID- 26981187 TI - Laparoscopic treatment of complicated colonic diverticular disease: A review. AB - Up to 10% of acute colonic diverticulitis may necessitate a surgical intervention. Although associated with high morbidity and mortality rates, Hartmann's procedure (HP) has been considered for many years to be the gold standard for the treatment of generalized peritonitis. To reduce the burden of surgery in these situations and as driven by the accumulated experience in colorectal and minimally-invasive surgery, laparoscopy has been increasingly adopted in the management of abdominal emergencies. Multiple case series and retrospective comparative studies confirmed that with experienced hands, the laparoscopic approach provided better outcomes than the open surgery. This technique applies to all interventions related to complicated diverticular disease, such as HP, sigmoid resection with primary anastomosis (RPA) and reversal of HP. The laparoscopic approach also provided new therapeutic possibilities with the emergence of the laparoscopic lavage drainage (LLD), particularly interesting in the context of purulent peritonitis of diverticular origin. At this stage, however, most of our knowledge in these fields relies on studies of low-level evidence. More than ever, well-built large randomized controlled trials are necessary to answer present interrogations such as the exact place of LLD or the most appropriate sigmoid resection procedure (laparoscopic HP or RPA), as well as to confirm the advantages of laparoscopy in chronic complications of diverticulitis or HP reversal. PMID- 26981188 TI - Overview of robotic colorectal surgery: Current and future practical developments. AB - Minimal access surgery has revolutionised colorectal surgery by offering reduced morbidity and mortality over open surgery, while maintaining oncological and functional outcomes with the disadvantage of additional practical challenges. Robotic surgery aids the surgeon in overcoming these challenges. Uptake of robotic assistance has been relatively slow, mainly because of the high initial and ongoing costs of equipment but also because of limited evidence of improved patient outcomes. Advances in robotic colorectal surgery will aim to widen the scope of minimal access surgery to allow larger and more complex surgery through smaller access and natural orifices and also to make the technology more economical, allowing wider dispersal and uptake of robotic technology. Advances in robotic endoscopy will yield self-advancing endoscopes and a widening role for capsule endoscopy including the development of motile and steerable capsules able to deliver localised drug therapy and insufflation as well as being recharged from an extracorporeal power source to allow great longevity. Ultimately robotic technology may advance to the point where many conventional surgical interventions are no longer required. With respect to nanotechnology, surgery may eventually become obsolete. PMID- 26981190 TI - Does autologous blood transfusion during liver transplantation for hepatocellular carcinoma increase risk of recurrence? AB - AIM: To analyze outcomes in patients who underwent liver transplantation (LT) for hepatocellular carcinoma (HCC) and received autologous intraoperative blood salvage (IBS). METHODS: Consecutive HCC patients who underwent LT were studied retrospectively and analyzed according to the use of IBS or not. Demographic and surgical data were collected from a departmental prospective maintained database. Statistical analyses were performed using the Fisher's exact test and the Wilcoxon rank sum test to examine covariate differences between patients who underwent IBS and those who did not. Univariate and multivariate Cox regression models were developed to evaluate recurrence and death, and survival probabilities were estimated using the Kaplan-Meier method and compared by the log-rank test. RESULTS: Between 2002 and 2012, 158 consecutive patients who underwent LT in the same medical center and by the same surgical team were identified. Among these patients, 122 (77.2%) were in the IBS group and 36 (22.8%) in the non-IBS group. The overall survival (OS) and recurrence free survival (RFS) at 5 years were 59.7% and 83.3%, respectively. No differences in OS (P = 0.51) or RFS (P = 0.953) were detected between the IBS and non-IBS groups. On multivariate analysis for OS, degree of tumor differentiation remained as the only independent predictor. Regarding patients who received IBS, no differences were detected in OS or RFS (P = 0.055 and P = 0.512, respectively) according to the volume infused, even when outcomes at 90 d or longer were analyzed separately (P = 0.518 for both outcomes). CONCLUSION: No differences in RFS or OS were detected according to IBS use. Trials addressing this question are justified and should be designed to detect small differences in long-term outcomes. PMID- 26981189 TI - Chronic radiation proctopathy: A practical review of endoscopic treatment. AB - Chronic radiation proctopathy (CRP) is a troublesome complication of pelvic radiotherapy. The most common presentation is rectal bleeding. CRP symptoms interfere with daily activities and decrease quality of life. Rectal bleeding management in patients with CRP represents a conundrum for practitioners. Medical therapy is ineffective in general and surgical approach has a high morbid mortality. Endoscopy has a role in the diagnosis, staging and treatment of this disease. Currently available endoscopic modalities are formalin, potassium titanyl phosphate laser, neodymium:yttrium-aluminum-garnet laser, argon laser, bipolar electrocoagulation (BiCAP), heater probe, band ligation, cryotherapy, radiofrequency ablation and argon plasma coagulation (APC). Among these options, APC is the most promising. PMID- 26981191 TI - Laparoscopic surgery for small-bowel obstruction caused by Meckel's diverticulum. AB - A 26-year-old woman was referred to our hospital because of abdominal distention and vomiting. Contrast-enhanced computed tomography showed a blind loop of the bowel extending to near the uterus and a fibrotic band connecting the mesentery to the top of the bowel, suggestive of Meckel's diverticulum (MD) and a mesodiverticular band (MDB). After intestinal decompression, elective laparoscopic surgery was carried out. Using three 5-mm ports, MD was dissected from the surrounding adhesion and MDB was divided intracorporeally. And subsequent Meckel's diverticulectomy was performed. The presence of heterotopic gastric mucosa was confirmed histologically. The patient had an uneventful postoperative course and was discharged 5 d after the operation. She has remained healthy and symptom-free during 4 years of follow-up. This was considered to be an unusual case of preoperatively diagnosed and laparoscopically treated small bowel obstruction due to MD in a young adult woman. PMID- 26981192 TI - Pneumatosis intestinalis with obstructing intussusception: A case report and literature review. AB - Pneumatosis intestinalis (PI) often represents a benign condition that should not be considered as an argument for surgery. We report a patient with PI and obstructing intussusception who underwent urgent colectomy and review the literatures regarding PI with intussusception. A 20-year-old man presented at our hospital with a 3-d intermittent lower abdominal pain history. He underwent steroid therapy for membranoproliferative glomerulonephritis for 4 years. Computed tomography revealed ascending colon intussusception with air within the wall. Intraoperative colonoscopy revealed numerous soft polypoid masses with normal overlying mucosa and right hemicolectomy was performed. Histological examination of colonic wall sections revealed large cysts in the submucosal layer. The pathological diagnosis was PI. Nine cases of intussusception associated with primary PI have been reported. Although primary PI often represents a benign condition that should not be considered as an argument for surgery, if the case involves intussusception and obstruction, emergent laparotomy should be considered. PMID- 26981193 TI - Yersinia type III effectors perturb host innate immune responses. AB - The innate immune system is the first line of defense against invading pathogens. Innate immune cells recognize molecular patterns from the pathogen and mount a response to resolve the infection. The production of proinflammatory cytokines and reactive oxygen species, phagocytosis, and induced programmed cell death are processes initiated by innate immune cells in order to combat invading pathogens. However, pathogens have evolved various virulence mechanisms to subvert these responses. One strategy utilized by Gram-negative bacterial pathogens is the deployment of a complex machine termed the type III secretion system (T3SS). The T3SS is composed of a syringe-like needle structure and the effector proteins that are injected directly into a target host cell to disrupt a cellular response. The three human pathogenic Yersinia spp. (Y. pestis, Y. enterocolitica, and Y. pseudotuberculosis) are Gram-negative bacteria that share in common a 70 kb virulence plasmid which encodes the T3SS. Translocation of the Yersinia effector proteins (YopE, YopH, YopT, YopM, YpkA/YopO, and YopP/J) into the target host cell results in disruption of the actin cytoskeleton to inhibit phagocytosis, downregulation of proinflammatory cytokine/chemokine production, and induction of cellular apoptosis of the target cell. Over the past 25 years, studies on the Yersinia effector proteins have unveiled tremendous knowledge of how the effectors enhance Yersinia virulence. Recently, the long awaited crystal structure of YpkA has been solved providing further insights into the activation of the YpkA kinase domain. Multisite autophosphorylation by YpkA to activate its kinase domain was also shown and postulated to serve as a mechanism to bypass regulation by host phosphatases. In addition, novel Yersinia effector protein targets, such as caspase-1, and signaling pathways including activation of the inflammasome were identified. In this review, we summarize the recent discoveries made on Yersinia effector proteins and their contribution to Yersinia pathogenesis. PMID- 26981194 TI - Complexity of vitamin E metabolism. AB - Bioavailability of vitamin E is influenced by several factors, most are highlighted in this review. While gender, age and genetic constitution influence vitamin E bioavailability but cannot be modified, life-style and intake of vitamin E can be. Numerous factors must be taken into account however, i.e., when vitamin E is orally administrated, the food matrix may contain competing nutrients. The complex metabolic processes comprise intestinal absorption, vascular transport, hepatic sorting by intracellular binding proteins, such as the significant alpha-tocopherol-transfer protein, and hepatic metabolism. The coordinated changes involved in the hepatic metabolism of vitamin E provide an effective physiological pathway to protect tissues against the excessive accumulation of, in particular, non-alpha-tocopherol forms. Metabolism of vitamin E begins with one cycle of CYP4F2/CYP3A4-dependent omega-hydroxylation followed by five cycles of subsequent beta-oxidation, and forms the water-soluble end product carboxyethylhydroxychroman. All known hepatic metabolites can be conjugated and are excreted, depending on the length of their side-chain, either via urine or feces. The physiological handling of vitamin E underlies kinetics which vary between the different vitamin E forms. Here, saturation of the side chain and also substitution of the chromanol ring system are important. Most of the metabolic reactions and processes that are involved with vitamin E are also shared by other fat soluble vitamins. Influencing interactions with other nutrients such as vitamin K or pharmaceuticals are also covered by this review. All these processes modulate the formation of vitamin E metabolites and their concentrations in tissues and body fluids. Differences in metabolism might be responsible for the discrepancies that have been observed in studies performed in vivo and in vitro using vitamin E as a supplement or nutrient. To evaluate individual vitamin E status, the analytical procedures used for detecting and quantifying vitamin E and its metabolites are crucial. The latest methods in analytics are presented. PMID- 26981196 TI - Dynamic interplay between adhesion surfaces in carcinomas: Cell-cell and cell matrix crosstalk. AB - Cell-cell and cell-matrix signaling and communication between adhesion sites involve mechanisms which are required for cellular functions during normal development and homeostasis; however these cellular functions and mechanisms are often deregulated in cancer. Aberrant signaling at cell-cell and cell-matrix adhesion sites often involves downstream mediators including Rho GTPases and tyrosine kinases. This review discusses these molecules as putative mediators of cellular crosstalk between cell-cell and cell-matrix adhesion sites, in addition to their attractiveness as therapeutic targets in cancer. Interestingly, inter junctional crosstalk mechanisms are frequently typified by the way in which bacterial and viral pathogens opportunistically infect or intoxicate mammalian cells. This review therefore also discusses the concept of learning from pathogen host interaction studies to better understand coordinated communication between cell-cell and cell-matrix adhesion sites, in addition to highlighting the potential therapeutic usefulness of exploiting pathogens or their products to tap into inter-junctional crosstalk. Taken together, we feel that increased knowledge around mechanisms of cell-cell and cell-matrix adhesion site crosstalk and consequently a greater understanding of their therapeutic targeting offers a unique opportunity to contribute to the emerging molecular revolution in cancer biology. PMID- 26981197 TI - RNA-binding proteins related to stress response and differentiation in protozoa. AB - RNA-binding proteins (RBPs) are key regulators of gene expression. There are several distinct families of RBPs and they are involved in the cellular response to environmental changes, cell differentiation and cell death. The RBPs can differentially combine with RNA molecules and form ribonucleoprotein (RNP) complexes, defining the function and fate of RNA molecules in the cell. RBPs display diverse domains that allow them to be categorized into distinct families. They play important roles in the cellular response to physiological stress, in cell differentiation, and, it is believed, in the cellular localization of certain mRNAs. In several protozoa, a physiological stress (nutritional, temperature or pH) triggers differentiation to a distinct developmental stage. Most of the RBPs characterized in protozoa arise from trypanosomatids. In these protozoa gene expression regulation is mostly post-transcriptional, which suggests that some RBPs might display regulatory functions distinct from those described for other eukaryotes. mRNA stability can be altered as a response to stress. Transcripts are sequestered to RNA granules that ultimately modulate their availability to the translation machinery, storage or degradation, depending on the associated proteins. These aggregates of mRNPs containing mRNAs that are not being translated colocalize in cytoplasmic foci, and their numbers and size vary according to cell conditions such as oxidative stress, nutritional status and treatment with drugs that inhibit translation. PMID- 26981195 TI - New insights into sodium transport regulation in the distal nephron: Role of G protein coupled receptors. AB - The renal handling of Na(+) balance is a major determinant of the blood pressure (BP) level. The inability of the kidney to excrete the daily load of Na(+) represents the primary cause of chronic hypertension. Among the different segments that constitute the nephron, those present in the distal part (i.e., the cortical thick ascending limb, the distal convoluted tubule, the connecting and collecting tubules) play a central role in the fine-tuning of renal Na(+) excretion and are the target of many different regulatory processes that modulate Na(+) retention more or less efficiently. G-protein coupled receptors (GPCRs) are crucially involved in this regulation and could represent efficient pharmacological targets to control BP levels. In this review, we describe both classical and novel GPCR-dependent regulatory systems that have been shown to modulate renal Na(+) absorption in the distal nephron. In addition to the multiplicity of the GPCR that regulate Na(+) excretion, this review also highlights the complexity of these different pathways, and the connections between them. PMID- 26981199 TI - Recent advances in production, purification and applications of phycobiliproteins. AB - An obligatory sunlight requirement for photosynthesis has exposed cyanobacteria to different quantity and quality of light. Cyanobacteria can exhibit efficient photosynthesis over broad region (450 to 650 nm) of solar spectrum with the help of brilliantly coloured pigment proteins called phycobiliproteins (PBPs). Besides light-harvesting, PBPs are found to involve in several life sustaining phenomena including photoprotection in cyanobacteria. The unique spectral features (like strong absorbance and fluorescence), proteineous nature and, some imperative properties like hepato-protective, anti-oxidants, anti-inflammatory and anti aging activity of PBPs enable their use in food, cosmetics, pharmaceutical and biomedical industries. PBPs have been also noted to show beneficial effect in therapeutics of some disease like Alzheimer and cancer. Such large range of applications increases the demand of PBPs in commodity market. Therefore, the large-scale and coast effective production of PBPs is the real need of time. To fulfil this need, many researchers have been working to find the potential producer of PBPs for the production and purification of PBPs. Results of these efforts have caused the inventions of some novel techniques like mixotrophic and heterotrophic strategies for production and aqueous two phase separation for purification purpose. Overall, the present review summarises the recent findings and identifies gaps in the field of production, purification and applications of this biological and economically important proteins. PMID- 26981198 TI - Understanding the molecular mechanisms of cancer prevention by dietary phytochemicals: From experimental models to clinical trials. AB - Chemoprevention is one of the cancer prevention approaches wherein natural/synthetic agent(s) are prescribed with the aim to delay or disrupt multiple pathways and processes involved at multiple steps, i.e., initiation, promotion, and progression of cancer. Amongst environmental chemopreventive compounds, diet/beverage-derived components are under evaluation, because of their long history of exposure to humans, high tolerability, low toxicity, and reported biological activities. This compilation briefly covers and compares the available evidence on chemopreventive efficacy and probable mechanism of chemoprevention by selected dietary phytochemicals (capsaicin, curcumin, diallyl sulphide, genistein, green/black tea polyphenols, indoles, lycopene, phenethyl isocyanate, resveratrol, retinoids and tocopherols) in experimental systems and clinical trials. All the dietary phytochemicals covered in this review have demonstrated chemopreventive efficacy against spontaneous or carcinogen-induced experimental tumors and/or associated biomarkers and processes in rodents at several organ sites. The observed anti-initiating, anti-promoting and anti progression activity of dietary phytochemicals in carcinogen-induced experimental models involve phytochemical-mediated redox changes, modulation of enzymes and signaling kinases resulting to effects on multiple genes and cell signaling pathways. Results from clinical trials using these compounds have not shown them to be chemopreventive. This may be due to our: (1) inability to reproduce the exposure conditions, i.e., levels, complexity, other host and lifestyle factors; and (2) lack of understanding about the mechanisms of action and agent-mediated toxicity in several organs and physiological processes in the host. Current research efforts in addressing the issues of exposure conditions, bioavailability, toxicity and the mode of action of dietary phytochemicals may help address the reason for observed mismatch that may ultimately lead to identification of new chemopreventive agents for protection against broad spectrum of exposures. PMID- 26981201 TI - API2-MALT1 oncoprotein promotes lymphomagenesis via unique program of substrate ubiquitination and proteolysis. AB - Lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is the most common extranodal B cell tumor and accounts for 8% of non-Hodgkin's lymphomas. Gastric MALT lymphoma is the best-studied example and is a prototypical neoplasm that occurs in the setting of chronic inflammation brought on by persistent infection or autoimmune disease. Cytogenetic abnormalities are commonly acquired during the course of disease and the most common is chromosomal translocation t(11;18)(q21;q21), which creates the API2-MALT1 fusion oncoprotein. t(11;18) positive lymphomas can be clinically aggressive and have a higher rate of dissemination than t(11;18)-negative tumors. Many cancers, including MALT lymphomas, characteristically exhibit deregulated over-activation of cellular survival pathways, such as the nuclear factor-kappaB (NF-kappaB) pathway. Molecular characterization of API2-MALT1 has revealed it to be a potent activator of NF-kappaB, which is required for API2-MALT1-induced cellular transformation, however the mechanisms by which API2-MALT1 exerts these effects are only recently becoming apparent. The API2 moiety of the fusion binds tumor necrosis factor (TNF) receptor associated factor (TRAF) 2 and receptor interacting protein 1 (RIP1), two proteins essential for TNF receptor-induced NF-kappaB activation. By effectively mimicking ligand-bound TNF receptor, API2-MALT1 promotes TRAF2 dependent ubiquitination of RIP1, which then acts as a scaffold for nucleating and activating the canonical NF-kappaB machinery. Activation occurs, in part, through MALT1 moiety-dependent recruitment of TRAF6, which can directly modify NF kappaB essential modulator, the principal downstream regulator of NF-kappaB. While the intrinsic MALT1 protease catalytic activity is dispensable for this canonical NF-kappaB signaling, it is critical for non-canonical NF-kappaB activation. In this regard, API2-MALT1 recognizes NF-kappaB inducing kinase (NIK), the essential upstream regulator of non-canonical NF-kappaB, and cleaves it to generate a stable, constitutively active fragment. Thus, API2-MALT1 harnesses multiple unique pathways to achieve deregulated NF-kappaB activation. Emerging data from our group and others have also detailed additional gain-of function activities of API2-MALT1 that extend beyond NF-kappaB activation. Specifically, API2-MALT1 recruits and subverts multiple other signaling factors, including LIM domain and actin-binding protein 1 (LIMA1) and Smac/DIABLO. Like NIK, LIMA1 represents a unique substrate for API2-MALT1 protease activity, but unlike NIK, its cleavage sets in motion a major NF-kappaB-independent pathway for promoting oncogenesis. In this review, we highlight the most recent results characterizing these unique and diverse gain-of-function activities of API2-MALT1 and how they contribute to lymphomagenesis. PMID- 26981200 TI - Longevity of animals under reactive oxygen species stress and disease susceptibility due to global warming. AB - The world is projected to experience an approximate doubling of atmospheric CO2 concentration in the next decades. Rise in atmospheric CO2 level as one of the most important reasons is expected to contribute to raise the mean global temperature 1.4 degrees C-5.8 degrees C by that time. A survey from 128 countries speculates that global warming is primarily due to increase in atmospheric CO2 level that is produced mainly by anthropogenic activities. Exposure of animals to high environmental temperatures is mostly accompanied by unwanted acceleration of certain biochemical pathways in their cells. One of such examples is augmentation in generation of reactive oxygen species (ROS) and subsequent increase in oxidation of lipids, proteins and nucleic acids by ROS. Increase in oxidation of biomolecules leads to a state called as oxidative stress (OS). Finally, the increase in OS condition induces abnormality in physiology of animals under elevated temperature. Exposure of animals to rise in habitat temperature is found to boost the metabolism of animals and a very strong and positive correlation exists between metabolism and levels of ROS and OS. Continuous induction of OS is negatively correlated with survivability and longevity and positively correlated with ageing in animals. Thus, it can be predicted that continuous exposure of animals to acute or gradual rise in habitat temperature due to global warming may induce OS, reduced survivability and longevity in animals in general and poikilotherms in particular. A positive correlation between metabolism and temperature in general and altered O2 consumption at elevated temperature in particular could also increase the risk of experiencing OS in homeotherms. Effects of global warming on longevity of animals through increased risk of protein misfolding and disease susceptibility due to OS as the cause or effects or both also cannot be ignored. Therefore, understanding the physiological impacts of global warming in relation to longevity of animals will become very crucial challenge to biologists of the present millennium. PMID- 26981202 TI - Development of regional specificity of spinal and medullary dorsal horn neurons. AB - Extensive studies have focused on the development and regionalization of neurons in the central nervous system (CNS). Many genes, which play crucial roles in the development of CNS neurons, have been identified. By using the technique "direct reprogramming", neurons can be produced from multiple cell sources such as fibroblasts. However, understanding the region-specific regulation of neurons in the CNS is still one of the biggest challenges in the research field of neuroscience. Neurons located in the trigeminal subnucleus caudalis (Vc) and in the spinal dorsal horn (SDH) play crucial roles in pain and sensorimotor functions in the orofacial and other somatic body regions, respectively. Anatomically, Vc represents the most caudal component of the trigeminal system, and is contiguous with SDH. This review is focused on recent data dealing with the regional specificity involved in the development of neurons in Vc and SDH. PMID- 26981204 TI - Engineered magnetic core shell nanoprobes: Synthesis and applications to cancer imaging and therapeutics. AB - Magnetic core shell nanoparticles are composed of a highly magnetic core material surrounded by a thin shell of desired drug, polymer or metal oxide. These magnetic core shell nanoparticles have a wide range of applications in biomedical research, more specifically in tissue imaging, drug delivery and therapeutics. The present review discusses the up-to-date knowledge on the various procedures for synthesis of magnetic core shell nanoparticles along with their applications in cancer imaging, drug delivery and hyperthermia or cancer therapeutics. Literature in this area shows that magnetic core shell nanoparticle-based imaging, drug targeting and therapy through hyperthermia can potentially be a powerful tool for the advanced diagnosis and treatment of various cancers. PMID- 26981203 TI - Regulation of RNA binding proteins in trypanosomatid protozoan parasites. AB - Posttranscriptional mechanisms have a critical role in the overall outcome of gene expression. These mechanisms are especially relevant in protozoa from the genus Trypanosoma, which is composed by death threatening parasites affecting people in Sub-saharan Africa or in the Americas. In these parasites the classic view of regulation of transcription initiation to modulate the products of a given gene cannot be applied. This is due to the presence of transcription start sites that give rise to long polycistronic units that need to be processed costranscriptionally by trans-splicing and polyadenylation to give mature monocistronic mRNAs. Posttranscriptional mechanisms such as mRNA degradation and translational repression are responsible for the final synthesis of the required protein products. In this context, RNA-binding proteins (RBPs) in trypanosomes have a relevant role as modulators of mRNA abundance and translational repression by associating to the 3' untranslated regions in mRNA. Many different RBPs have been proposed to modulate cohorts of mRNAs in trypanosomes. However, the current understanding of their functions lacks a dynamic view on the different steps at which these RBPs are regulated. Here, we discuss different evidences to propose regulatory events for different RBPs in these parasites. These events vary from regulated developmental expression, to biogenesis of cytoplasmic ribonucleoprotein complexes in the nucleus, and condensation of RBPs and mRNA into large cytoplasmic granules. Finally, we discuss how newly identified posttranslational modifications of RBPs and mRNA metabolism-related proteins could have an enormous impact on the modulation of mRNA abundance. To understand these modifications is especially relevant in these parasites due to the fact that the enzymes involved could be interesting targets for drug therapy. PMID- 26981205 TI - Arctic ground squirrel neuronal progenitor cells resist oxygen and glucose deprivation-induced death. AB - AIM: To investigate the influence of ischemia/reperfusion on arctic ground squirrel (AGS) neuronal progenitor cells (NPCs), we subjected these cultured cells to oxygen and glucose deprivation. METHODS: AGS NPCs were expanded and differentiated into NPCs and as an ischemia vulnerable control, commercially available human NPCs (hNPCs) were seeded from thawed NPCs. NPCs, identified by expression of TUJ1 were seen at 14-21 d in vitro (DIV). Cultures were exposed to control conditions, hypoxia, oxygen and glucose deprivation or glucose deprivation alone or following return to normal conditions to model reperfusion. Cell viability and death were assessed from loss of ATP as well as from measures of alamarBlue((r)) and lactate dehydrogenase in the media and from counts of TUJ1 positive cells using immunocytochemistry. Dividing cells were identified by expression of Ki67 and phenotyped by double labeling with GFAP, MAP2ab or TUJ1. RESULTS: We report that when cultured in NeuraLifeTM, AGS cells remain viable out to 21 DIV, continue to express TUJ1 and begin to express MAP2ab. Viability of hNPCs assessed by fluorescence alamarBlue (arbitrary units) depends on both glucose and oxygen availability [viability of hNPCs after 24 h oxygen glucose deprivation (OGD) with return of oxygen and glucose decreased from 48151 +/- 4551 in control cultures to 43481 +/- 2413 after OGD, P < 0.05]. By contrast, when AGS NPCs are exposed to the same OGD with reperfusion at 14 DIV, cell viability assessed by alamarBlue increased from 165305 +/- 11719 in control cultures to 196054 +/- 13977 after OGD. Likewise AGS NPCs recovered ATP (92766 +/- 6089 in control and 92907 +/- 4290 after modeled reperfusion; arbitrary luminescence units), and doubled in the ratio of TUJ1 expressing neurons to total dividing cells (0.11 +/- 0.04 in control cultures vs 0.22 +/- 0.2 after modeled reperfusion, P < 0.05). Maintaining AGS NPCs for a longer time in culture lowered resistance to injury, however, did not impair proliferation of NPCs relative to other cell lineages after oxygen deprivation followed by re-oxygenation. CONCLUSION: Ischemic-like insults decrease viability and increase cell death in cultures of human NPCs. Similar conditions have less affect on cell death and promote proliferation in AGS NPCs. PMID- 26981206 TI - High levels of homocysteine downregulate apolipoprotein E expression via nuclear factor kappa B. AB - AIM: To investigate the effect of high homocysteine (Hcy) levels on apolipoprotein E (apoE) expression and the signaling pathways involved in this gene regulation. METHODS: Reverse transcriptase polymerase chain reaction (RT PCR) and Western blot were used to assess apoE expression in cells treated with various concentrations (50-500 MUmol/L) of Hcy. Calcium phosphate-transient transfections were performed in HEK-293 and RAW 264.7 cells to evaluate the effect of Hcy on apoE regulatory elements [promoter and distal multienhancer 2 (ME2)]. To this aim, plasmids containing the proximal apoE promoter [( 500/+73)apoE construct] alone or in the presence of ME2 [ME2/(-500/+73)apoE construct] to drive the expression of the reporter luciferase gene were used. Co transfection experiments were carried out to investigate the downstream effectors of Hcy-mediated regulation of apoE promoter by using specific inhibitors or a dominant negative form of IKbeta. In other co-transfections, the luciferase reporter was under the control of synthetic promoters containing multiple specific binding sites for nuclear factor kappa B (NF-kappaB), activator protein 1 (AP-1) or nuclear factor of activated T cells (NFAT). Chromatin immunoprecipitation (ChIP) assay was accomplished to detect the binding of NF kappaB p65 subunit to the apoE promoter in HEK-293 treated with 500 MUmol/L Hcy. As control, cells were incubated with similar concentration of cysteine. NF kappaB p65 proteins bound to DNA were immunoprecipitated with anti-p65 antibodies and DNA was identified by PCR using primers amplifying the region -100/+4 of the apoE gene. RESULTS: RT-PCR revealed that high levels of Hcy (250-750 MUmol/L) induced a 2-3 fold decrease in apoE mRNA levels in HEK-293 cells, while apoE gene expression was not significantly affected by treatment with lower concentrations of Hcy (100 MUmol/L). Immunoblotting data provided additional evidence for the negative role of Hcy in apoE expression. Hcy decreased apoE promoter activity, in the presence or absence of ME2, in a dose dependent manner, in both RAW 264.7 and HEK-293 cells, as revealed by transient transfection experiments. The downstream effectors of the signaling pathways of Hcy were also investigated. The inhibitory effect of Hcy on the apoE promoter activity was counteracted by MAPK/ERK kinase 1/2 (MEK1/2) inhibitor U0126, suggesting that MEK1/2 is involved in the downregulation of apoE promoter activity by Hcy. Our data demonstrated that Hcy induced inhibition of apoE took place through activation of NF-kappaB. Moreover, we demonstrated that Hcy activated a synthetic promoter containing three NF kappaB binding sites, but did not affect promoters containing AP-1 or NFAT binding sites. ChIP experiments revealed that NF-kappaB p65 subunit is recruited to the apoE promoter following Hcy treatment of cells. CONCLUSION: Hcy-induced stress negatively modulates apoE expression via MEK1/2 and NF-kappaB activation. The decreased apoE expression in peripheral tissues may aggravate atherosclerosis, neurodegenerative diseases and renal dysfunctions. PMID- 26981207 TI - Epigenetic alteration to activate Bmp2-Smad signaling in Raf-induced senescence. AB - AIM: To investigate epigenomic and gene expression alterations during cellular senescence induced by oncogenic Raf. METHODS: Cellular senescence was induced into mouse embryonic fibroblasts (MEFs) by infecting retrovirus to express oncogenic Raf (RafV600E). RNA was collected from RafV600E cells as well as MEFs without infection and MEFs with mock infection, and a genome-wide gene expression analysis was performed using microarray. The epigenomic status for active H3K4me3 and repressive H3K27me3 histone marks was analyzed by chromatin immunoprecipitation-sequencing for RafV600E cells on day 7 and for MEFs without infection. These data for Raf-induced senescence were compared with data for Ras induced senescence that were obtained in our previous study. Gene knockdown and overexpression were done by retrovirus infection. RESULTS: Although the expression of some genes including secreted factors was specifically altered in either Ras- or Raf-induced senescence, many genes showed similar alteration pattern in Raf- and Ras-induced senescence. A total of 841 commonly upregulated 841 genes and 573 commonly downregulated genes showed a significant enrichment of genes related to signal and secreted proteins, suggesting the importance of alterations in secreted factors. Bmp2, a secreted protein to activate Bmp2-Smad signaling, was highly upregulated with gain of H3K4me3 and loss of H3K27me3 during Raf-induced senescence, as previously detected in Ras-induced senescence, and the knockdown of Bmp2 by shRNA lead to escape from Raf-induced senescence. Bmp2-Smad inhibitor Smad6 was strongly repressed with H3K4me3 loss in Raf-induced senescence, as detected in Ras-induced senescence, and senescence was also bypassed by Smad6 induction in Raf-activated cells. Different from Ras-induced senescence, however, gain of H3K27me3 did not occur in the Smad6 promoter region during Raf-induced senescence. When comparing genome-wide alteration between Ras- and Raf-induced senescence, genes showing loss of H3K27me3 during senescence significantly overlapped; genes showing H3K4me3 gain, or those showing H3K4me3 loss, also well-overlapped between Ras- and Raf-induced senescence. However, genes with gain of H3K27me3 overlapped significantly rarely, compared with those with H3K27me3 loss, with H3K4me3 gain, or with H3K4me3 loss. CONCLUSION: Although epigenetic alterations are partly different, Bmp2 upregulation and Smad6 repression occur and contribute to Raf-induced senescence, as detected in Ras induced senescence. PMID- 26981208 TI - Omega 3 and atrial fibrillation: Where are we? AB - Anti-arrhythmic properties of n-3 polyunsaturated fatty acids, at least in part mediated by anti-oxidant, anti-inflammatory and anti-fibrotic power, have been widely proved. Effect of fish oil on atrial fibrillation, both in primary and in secondary prevention and after cardiac surgery, are controversial, mostly due to lack of homogeneity between studies but also due to individual variability in response to fatty acids administration. Inclusion of measurement of incorporation of fish oil into cell membranes, appears to be essential in future studies, to assess their antiarrhythmic effect. PMID- 26981210 TI - Impact of cardiac magnetic resonance imaging in non-ischemic cardiomyopathies. AB - Non-ischemic cardiomyopathies include a wide spectrum of disease states afflicting the heart, whether a primary process or secondary to a systemic condition. Cardiac magnetic resonance imaging (CMR) has established itself as an important imaging modality in the evaluation of non-ischemic cardiomyopathies. CMR is useful in the diagnosis of cardiomyopathy, quantification of ventricular function, establishing etiology, determining prognosis and risk stratification. Technical advances and extensive research over the last decade have resulted in the accumulation of a tremendous amount of data with regards to the utility of CMR in these cardiomyopathies. In this article, we review CMR findings of various non-ischemic cardiomyopathies and focus on current literature investigating the clinical impact of CMR on risk stratification, treatment, and prognosis. PMID- 26981209 TI - Psoriasis, non-alcoholic fatty liver disease, and cardiovascular disease: Three different diseases on a unique background. AB - Psoriasis is a chronic inflammatory immune-mediated skin disease, frequently associated with systemic comorbidities. According to recent data, patients with psoriasis show a greater prevalence of metabolic syndrome, which confers a higher cardiovascular risk. The link between these pathological conditions appears to be a chronic low-grade inflammatory status. The aim of this review is to focus on the multiple epidemiological and physio-pathogenetic aspects linking non alcoholic fatty liver disease, psoriasis, and cardiovascular disease. PMID- 26981211 TI - Mechanical dyssynchrony and deformation imaging in patients with functional mitral regurgitation. AB - Chronic functional mitral regurgitation (FMR) is a frequent finding of ischemic heart disease and dilated cardiomyopathy (DCM), associated with unfavourable prognosis. Several pathophysiologic mechanisms are involved in FMR, such as annular dilatation and dysfunction, left ventricle (LV) remodeling, dysfunction and dyssynchrony, papillary muscles displacement and dyssynchrony. The best therapeutic choice for FMR is still debated. When optimal medical treatment has already been set, a further option for cardiac resynchronization therapy (CRT) and/or surgical correction should be considered. CRT is able to contrast most of the pathophysiologic determinants of FMR by minimizing LV dyssynchrony through different mechanisms: Increasing closing forces, reducing tethering forces, reshaping annular geometry and function, correcting diastolic MR. Deformation imaging in terms of two-dimensional speckle tracking has been validated for LV dyssynchrony assessment. Radial speckle tracking and three-dimensional strain analysis appear to be the best methods to quantify intraventricular delay and to predict CRT-responders. Speckle-tracking echocardiography in patients with mitral valve regurgitation has been usually proposed for the assessment of LV and left atrial function. However it has also revealed a fundamental role of intraventricular dyssynchrony in determining FMR especially in DCM, rather than in ischemic cardiomyopathy in which MR severity seems to be more related to mitral valve deformation indexes. Furthermore speckle tracking allows the assessment of papillary muscle dyssynchrony. Therefore this technique can help to identify optimal candidates to CRT that will probably demonstrate a reduction in FMR degree and thus will experience a better outcome. PMID- 26981214 TI - Diagnosis and management of patients with asymptomatic severe aortic stenosis. AB - Aortic stenosis (AS) is a disease that progresses slowly for years without symptoms, so patients need to be carefully managed with appropriate follow up and referred for aortic valve replacement in a timely manner. Development of symptoms is a clear indication for aortic valve intervention in patients with severe AS. The decision for early surgery in patients with asymptomatic severe AS is more complex. In this review, we discuss how to identify high-risk patients with asymptomatic severe AS who may benefit from early surgery. PMID- 26981212 TI - Micromanaging cardiac regeneration: Targeted delivery of microRNAs for cardiac repair and regeneration. AB - The loss of cardiomyocytes during injury and disease can result in heart failure and sudden death, while the adult heart has a limited capacity for endogenous regeneration and repair. Current stem cell-based regenerative medicine approaches modestly improve cardiomyocyte survival, but offer neglectable cardiomyogenesis. This has prompted the need for methodological developments that crease de novo cardiomyocytes. Current insights in cardiac development on the processes and regulatory mechanisms in embryonic cardiomyocyte differentiation provide a basis to therapeutically induce these pathways to generate new cardiomyocytes. Here, we discuss the current knowledge on embryonic cardiomyocyte differentiation and the implementation of this knowledge in state-of-the-art protocols to the direct reprogramming of cardiac fibroblasts into de novo cardiomyocytes in vitro and in vivo with an emphasis on microRNA-mediated reprogramming. Additionally, we discuss current advances on state-of-the-art targeted drug delivery systems that can be employed to deliver these microRNAs to the damaged cardiac tissue. Together, the advances in our understanding of cardiac development, recent advances in microRNA-based therapeutics, and innovative drug delivery systems, highlight exciting opportunities for effective therapies for myocardial infarction and heart failure. PMID- 26981213 TI - Genetic testing in congenital heart disease: A clinical approach. AB - Congenital heart disease (CHD) is the most common type of birth defect. Traditionally, a polygenic model defined by the interaction of multiple genes and environmental factors was hypothesized to account for different forms of CHD. It is now understood that the contribution of genetics to CHD extends beyond a single unified paradigm. For example, monogenic models and chromosomal abnormalities have been associated with various syndromic and non-syndromic forms of CHD. In such instances, genetic investigation and testing may potentially play an important role in clinical care. A family tree with a detailed phenotypic description serves as the initial screening tool to identify potentially inherited defects and to guide further genetic investigation. The selection of a genetic test is contingent upon the particular diagnostic hypothesis generated by clinical examination. Genetic investigation in CHD may carry the potential to improve prognosis by yielding valuable information with regards to personalized medical care, confidence in the clinical diagnosis, and/or targeted patient follow-up. Moreover, genetic assessment may serve as a tool to predict recurrence risk, define the pattern of inheritance within a family, and evaluate the need for further family screening. In some circumstances, prenatal or preimplantation genetic screening could identify fetuses or embryos at high risk for CHD. Although genetics may appear to constitute a highly specialized sector of cardiology, basic knowledge regarding inheritance patterns, recurrence risks, and available screening and diagnostic tools, including their strengths and limitations, could assist the treating physician in providing sound counsel. PMID- 26981215 TI - Dyslipidemia management in primary prevention of cardiovascular disease: Current guidelines and strategies. AB - Cardiovascular disease is the leading cause of death in the United States. In 2010, the Centers for Disease Control and Prevention estimated that $444 billion was spent on cardiovascular diseases alone, about $1 of every $6 spent on health care. As life expectancy continues to increase, this annual cost will also increase, making cost-effective primary prevention of cardiovascular disease highly desirable. Because of its role in development of atherosclerosis and clinical events, dyslipidemia management is a high priority in cardiovascular prevention. Multiple major dyslipidemia guidelines have been published around the world recently, four of them by independent organizations in the United States alone. They share the goal of providing clinical guidance on optimal dyslipidemia management, but guidelines differ in their emphasis on pharmacotherapy, stratification of groups, emphasis on lifestyle modification, and use of a fixed target or percentage reduction in low density lipoprotein cholesterol. This review summarizes eight major guidelines for dyslipidemia management and considers the basis for their recommendations. Our primary aim is to enhance understanding of dyslipidemia management guidelines in patient care for primary prevention of future cardiovascular risk. PMID- 26981217 TI - Red cell distribution width in anemic patients undergoing transcatheter aortic valve implantation. AB - AIM: To determine the impact of red blood cell distribution width on outcome in anemic patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: In a retrospective single center cohort study we determined the impact of baseline red cell distribution width (RDW) and anemia on outcome in 376 patients with aortic stenosis undergoing TAVI. All patients were discussed in the institutional heart team and declined for surgical aortic valve replacement due to high operative risk. Collected data included patient characteristics, imaging findings, periprocedural in hospital data, laboratory results and follow up data. Blood samples for hematology and biochemistry analysis were taken from every patient before and at fixed intervals up to 72 h after TAVI including blood count and creatinine. Descriptive statistics were used for patient's characteristics. Kaplan-Meier survival curves were used for time to event outcomes. A recursive partitioning regression and classification was used to investigate the association between potential risk factors and outcome variables. RESULTS: Mean age in our study population was 81 +/- 6.1 years. Anemia was prevalent in 63.6% (n = 239) of our patients. Age and creatinine were identified as risk factors for anemia. In our study population, anemia per se did influence 30-d mortality but did not predict longterm mortality. In contrast, a RDW > 14% showed to be highly predictable for a reduced short- and longterm survival in patients with aortic valve disease after TAVI procedure. CONCLUSION: Age and kidney function determine the degree of anemia. The anisocytosis of red blood cells in anemic patients supplements prognostic information in addition to that derived from the WHO-based definition of anemia. PMID- 26981216 TI - Novel epigenetic-based therapies useful in cardiovascular medicine. AB - Epigenetic modifications include DNA methylation, histone modifications, and microRNA. Gene alterations have been found to be associated with cardiovascular diseases, and epigenetic mechanisms are continuously being studied to find new useful strategies for the clinical management of afflicted patients. Numerous cardiovascular disorders are characterized by the abnormal methylation of CpG islands and so specific drugs that could inhibit DNA methyltransferase directly or by reducing its gene expression (e.g., hydralazine and procainamide) are currently under investigation. The anti-proliferative and anti-inflammatory properties of histone deacetylase inhibitors and their cardio-protective effects have been confirmed in preclinical studies. Furthermore, the regulation of the expression of microRNA targets through pharmacological tools is still under development. Indeed, large controlled trials are required to establish whether current possible candidate antisense microRNAs could offer better therapeutic benefits in clinical practice. Here, we updated therapeutic properties, side effects, and feasibility of emerging epigenetic-based strategies in cardiovascular diseases by highlighting specific problematic issues that still affect the development of large scale novel therapeutic protocols. PMID- 26981218 TI - Association of arterial stiffness with coronary flow reserve in revascularized coronary artery disease patients. AB - AIM: To investigate the association of arterial wave reflection with coronary flow reserve (CFR) in coronary artery disease (CAD) patients after successful revascularization. METHODS: We assessed 70 patients with angiographically documented CAD who had undergone recent successful revascularization. We measured (1) reactive hyperemia index (RHI) using fingertip peripheral arterial tonometry (RH-PAT Endo-PAT); (2) carotid to femoral pulse wave velocity (PWVc-Complior); (3) augmentation index (AIx), the diastolic area (DAI%) and diastolic reflection area (DRA) of the central aortic pulse wave (Arteriograph); (4) CFR using Doppler echocardiography; and (5) blood levels of lipoprotein-phospholipase A2 (Lp-PLA2). RESULTS: After adjustment for age, sex, blood pressure parameter, lipidemic, diabetic and smoking status, we found that coronary flow reserve was independently related to AIx (b = -0.38, r = 0.009), DAI (b = 0.36, P = 0.014), DRA (b = 0.39, P = 0.005) and RT (b = -0.29, P = 0.026). Additionally, patients with CFR < 2.5 had higher PWVc (11.6 +/- 2.3 vs 10.2 +/- 1.4 m/s, P = 0.019), SBPc (139.1 +/- 17.8 vs 125.2 +/- 19.1 mmHg, P = 0.026), AIx (38.2% +/- 14.8% vs 29.4% +/- 15.1%, P = 0.011) and lower RHI (1.26 +/- 0.28 vs 1.50 +/- 0.46, P = 0.012), DAI (44.3% +/- 7.9% vs 53.9% +/- 6.7%, P = 0.008), DRA (42.2 +/- 9.6 vs 51.6 +/- 11.4, P = 0.012) and LpPLA2 (268.1 +/- 91.9 vs 199.5 +/- 78.4 ng/mL, P = 0.002) compared with those with CFR >= 2.5. Elevated LpPLA2 was related with reduced CFR (r = -0.33, P = 0.001), RHI (r = -0.37, P < 0.001) and DRA (r = 0.35, P = 0.001) as well as increased PWVc (r = 0.34, P = 0.012) and AIx (r = 0.34, P = 0.001). CONCLUSION: Abnormal arterial wave reflections are related with impaired coronary flow reserve despite successful revascularization in CAD patients. There is a common inflammatory link between impaired aortic wall properties, endothelial dysfunction and coronary flow impairment in CAD. PMID- 26981219 TI - Biodegradable polymer stents vs second generation drug eluting stents: A meta analysis and systematic review of randomized controlled trials. AB - AIM: To evaluate the premise, that biodegradable polymer drug eluting stents (BD DES) could improve clinical outcomes compared to second generation permanent polymer drug eluting stents (PP-DES), we pooled the data from all the available randomized control trials (RCT) comparing the clinical performance of both these stents. METHODS: A systematic literature search of PubMed, Cochrane, Google scholar databases, EMBASE, MEDLINE and SCOPUS was performed during time period of January 2001 to April 2015 for RCT and comparing safety and efficacy of BD-DES vs second generation PP-DES. The primary outcomes of interest were definite stent thrombosis, target lesion revascularization, myocardial infarction, cardiac deaths and total deaths during the study period. RESULTS: A total of 11 RCT's with a total of 12644 patients were included in the meta-analysis, with 6598 patients in BD-DES vs 6046 patients in second generation PP-DES. The mean follow up period was 16 mo. Pooled analysis showed non-inferiority of BD-DES, comparing events of stent thrombosis (OR = 1.42, 95%CI: 0.79-2.52, P = 0.24), target lesion revascularization (OR = 0.99, 95%CI: 0.84-1.17, P = 0.92), myocardial infarction (OR = 1.06, 95%CI: 0.86-1.29, P = 0.92), cardiac deaths (OR = 1.07, 95%CI 0.82 1.41, P = 0.94) and total deaths (OR = 0.96, 95%CI: 0.80-1.17, P = 0.71). CONCLUSION: BD-DES, when compared to second generation PP-DES, showed no significant advantage and the outcomes were comparable between both the groups. PMID- 26981220 TI - Brainstem tegmental lesions in neonates with hypoxic-ischemic encephalopathy: Magnetic resonance diagnosis and clinical outcome. AB - Lesions of the brainstem have been reported in the clinical scenarios of hypoxic ischemic encephalopathy (HIE), although the prevalence of these lesions is probably underestimated. Neuropathologic studies have demonstrated brainstem involvement in severely asphyxiated infants as an indicator of poor outcome. Among survivors to HIE, the most frequent clinical complaints that may be predicted by brainstem lesions include feeding problems, speech, language and communication problems and visual impairments. Clinical series, including vascular and metabolic etiologies, have found selective involvement of the brainstem with the demonstration of symmetric bilateral columnar lesions of the tegmentum. The role of brainstem lesions in HIE is currently a matter of debate, especially when tegmental lesions are present in the absence of supra-tentorial lesions. Differential diagnosis of tegmental lesions in neonates and infants include congenital metabolic syndromes and drug-related processes. Brainstem injury with the presence of supratentorial lesions is a predictor of poor outcome and high rates of mortality and morbidity. Further investigation will be conducted to identify specific sites of the brainstem that are vulnerable to hypoxic-ischemic and toxic-metabolic insults. PMID- 26981221 TI - Role of imaging in the evaluation of inflammatory bowel disease: How much is too much? AB - Inflammatory bowel disease (IBD) is a lifelong condition with waxing and waning disease course that requires reassessment of disease status as well as screening for complications throughout a patient's lifetime. Laboratory testing, endoscopic assessment, and fecal biomarkers are often used in the initial diagnosis and ongoing monitoring of a patient with IBD. Imaging plays an integral role in the diagnosis and evaluation of IBD. Different imaging modalities can be used over the course of a patient's lifetime, from the initial screening and diagnosis of IBD, to determining the extent of intestinal involvement, monitoring for disease activity, and evaluating for complications of uncontrolled IBD. The various imaging modalities available to the provider each have a unique set of risks and benefits when considering cost, radiation exposure, need for anesthesia, and image quality. In this article we review the imaging techniques available for the evaluation of IBD including fluoroscopic small bowel follow-through, computed tomography enterography, magnetic resonance enterography, and transabdominal ultrasound with particular focus on the judicious use of imaging and the risks and benefits of each option. We also review the risks of ionizing radiation, strategies to reduce exposure to ionizing radiation, and current imaging guidelines among pediatric and adult patient with IBD. PMID- 26981222 TI - Multi-modality imaging review of congenital abnormalities of kidney and upper urinary tract. AB - Congenital abnormalities of the kidney and urinary tract (CAKUT) include a wide range of abnormalities ranging from asymptomatic ectopic kidneys to life threatening renal agenesis (bilateral). Many of them are detected in the antenatal or immediate postnatal with a significant proportion identified in the adult population with varying degree of severity. CAKUT can be classified on embryological basis in to abnormalities in the renal parenchymal development, aberrant embryonic migration and abnormalities of the collecting system. Renal parenchymal abnormalities include multi cystic dysplastic kidneys, renal hypoplasia, number (agenesis or supernumerary), shape and cystic renal diseases. Aberrant embryonic migration encompasses abnormal location and fusion anomalies. Collecting system abnormalities include duplex kidneys and Pelvi ureteric junction obstruction. Ultrasonography (US) is typically the first imaging performed as it is easily available, non-invasive and radiation free used both antenatally and postnatally. Computed tomography (CT) and magnetic resonance imaging (MRI) are useful to confirm the ultrasound detected abnormality, detection of complex malformations, demonstration of collecting system and vascular anatomy and more importantly for early detection of complications like renal calculi, infection and malignancies. As CAKUT are one of the leading causes of end stage renal disease, it is important for the radiologists to be familiar with the varying imaging appearances of CAKUT on US, CT and MRI, thereby helping in prompt diagnosis and optimal management. PMID- 26981223 TI - Importance of establishing radiation protection culture in Radiology Department. AB - The increased use of ionization radiation for diagnostic and therapeutic purposes, the rapid advances in computed tomography as well as the high radiation doses delivered by interventional procedures have raised serious safety and health concerns for both patients and medical staff and have necessitated the establishment of a radiation protection culture (RPC) in every Radiology Department. RPC is a newly introduced concept. The term culture describes the combination of attitudes, beliefs, practices and rules among the professionals, staff and patients regarding to radiation protection. Most of the time, the challenge is to improve rather than to build a RPC. The establishment of a RPC requires continuing education of the staff and professional, effective communication among stakeholders of all levels and implementation of quality assurance programs. The RPC creation is being driven from the highest level. Leadership, professionals and associate societies are recognized to play a vital role in the embedding and promotion of RPC in a Medical Unit. The establishment of a RPC enables the reduction of the radiation dose, enhances radiation risk awareness, minimizes unsafe practices, and improves the quality of a radiation protection program. The purpose of this review paper is to describe the role and highlight the importance of establishing a strong RPC in Radiology Departments with an emphasis on promoting RPC in the Interventional Radiology environment. PMID- 26981224 TI - Advances in determining abdominal aortic aneurysm size and growth. AB - Abdominal aortic aneurysm is a common pathology in the aging population of the developed world which carries a significant mortality in excess of 80% in case of rupture. Aneurysmal disease probably represents the only surgical condition in which size is such a critical determinant of the need for intervention and therefore the ability to accurately and reproducibly record aneurysm size and growth over time is of outmost importance. In the same time that imaging techniques may be limited by intra- and inter-observer variability and there may be inconsistencies due to different modalities [ultrasound, computed tomography (CT)], rapid technologic advancement have taken aortic imaging to the next level. Digital imaging, multi-detector scanners, thin slice CT and most- importantly the ability to perform 3-dimensional reconstruction and image post-processing have currently become widely available rendering most of the imaging modalities used in the past out of date. The aim of the current article is to report on various imaging methods and current state of the art techniques used to record aneurysm size and growth. Moreover we aim to emphasize on the future research directions and report on techniques which probably will be widely used and incorporated in clinical practice in the near future. PMID- 26981225 TI - Blunt pancreatic trauma: A persistent diagnostic conundrum? AB - Blunt pancreatic trauma is an uncommon injury but has high morbidity and mortality. In modern era of trauma care, pancreatic trauma remains a persistent challenge to radiologists and surgeons alike. Early detection of pancreatic trauma is essential to prevent subsequent complications. However early pancreatic injury is often subtle on computed tomography (CT) and can be missed unless specifically looked for. Signs of pancreatic injury on CT include laceration, transection, bulky pancreas, heterogeneous enhancement, peripancreatic fluid and signs of pancreatitis. Pan-creatic ductal injury is a vital decision-making parameter as ductal injury is an indication for laparotomy. While lacerations involving more than half of pancreatic parenchyma are suggestive of ductal injury on CT, ductal injuries can be directly assessed on magnetic resonance imaging (MRI) or encoscopic retrograde cholangio-pancreatography. Pancreatic trauma also shows temporal evolution with increase in extent of injury with time. Hence early CT scans may underestimate the extent of injures and sequential imaging with CT or MRI is important in pancreatic trauma. Sequential imaging is also needed for successful non-operative management of pancreatic injury. Accurate early detection on initial CT and adopting a multimodality and sequential imaging strategy can improve outcome in pancreatic trauma. PMID- 26981226 TI - Benign neck masses showing restricted diffusion: Is there a histological basis for discordant behavior? AB - Diffusion weighted imaging (DWI) evolved as a complementary tool to morphologic imaging by offering additional functional information about lesions. Although the technique utilizes movement of water molecules to characterize biological tissues in terms of their cellularity, there are other factors related to the histological constitution of lesions which can have a significant bearing on DWI. Benign lesions with atypical histology including presence of lymphoid stroma, inherently increased cellularity or abundant extracellular collagen can impede movement of water molecules similar to malignant tissues and thereby, show restricted diffusion. Knowledge of these atypical entities while interpreting DWI in clinical practice can avoid potential misdiagnosis. This review aims to present an imaging spectrum of such benign neck masses which, owing to their distinct histology, can show discordant behavior on DWI. PMID- 26981227 TI - Xanthogranulomatous cholecystitis: What every radiologist should know. AB - Xanthogranulomatous cholecystitis (XGC) is an uncommon variant of chronic cholecystitis characterized by xanthogranulomatous inflammation of the gallbladder. Intramural accumulation of lipid-laden macrophages and acute and chronic inflammatory cells is the hallmark of the disease. The xanthogranulomatous inflammation of the gallbladder can be very severe and can spill over to the neighbouring structures like liver, bowel and stomach resulting in dense adhesions, perforation, abscess formation, fistulous communication with adjacent bowel. Striking gallbladder wall thickening and dense local adhesions can be easily mistaken for carcinoma of the gallbladder, both intraoperatively as well as on preoperative imaging. Besides, cases of concomitant gallbladder carcinoma complicating XGC have also been reported in literature. So, we have done a review of the imaging features of XGC in order to better understand the entity as well as to increase the diagnostic yield of the disease summarizing the characteristic imaging findings and associations of XGC. Among other findings, presence of intramural hypodense nodules is considered diagnostic of this entity. However, in some cases, an imaging diagnosis of XGC is virtually impossible. Fine needle aspiration cytology might be handy in such patients. A preoperative counselling should include possibility of differential diagnosis of gallbladder cancer in not so characteristic cases. PMID- 26981228 TI - Impaired swallowing mechanics of post radiation therapy head and neck cancer patients: A retrospective videofluoroscopic study. AB - AIM: To determine swallowing outcomes and hyolaryngeal mechanics associated with post radiation therapy head and neck cancer (rtHNC) patients using videofluoroscopic swallow studies. METHODS: In this retrospective cohort study, videofluoroscopic images of rtHNC patients (n = 21) were compared with age and gender matched controls (n = 21). Penetration-aspiration of the bolus and bolus residue were measured as swallowing outcome variables. Timing and displacement measurements of the anterior and posterior muscular slings elevating the hyolaryngeal complex were acquired. Coordinate data of anatomical landmarks mapping the action of the anterior muscles (suprahyoid muscles) and posterior muscles (long pharyngeal muscles) were used to calculate the distance measurements, and slice numbers were used to calculate time intervals. Canonical variate analysis with post-hoc discriminant function analysis was performed on coordinate data to determine multivariate mechanics of swallowing associated with treatment. Pharyngeal constriction ratio (PCR) was also measured to determine if weak pharyngeal constriction is associated with post radiation therapy. RESULTS: The rtHNC group was characterized by poor swallowing outcomes compared to the control group in regards to: Penetration-aspiration scale (P < 0.0001), normalized residue ratio scale (NRRS) for the valleculae (P = 0.002) and NRRS for the piriform sinuses (P = 0.003). Timing and distance measurements of the anterior muscular sling were not significantly different in the two groups, whereas for the PMS time of displacement was abbreviated (P = 0.002) and distance of excursion was reduced (P = 0.02) in the rtHNC group. A canonical variate analysis shows a significant reduction in pharyngeal mechanics in the rtHNC group (P < 0.0001). The PCR was significantly higher in the test group than the control group (P = 0.0001) indicating reduced efficiency in pharyngeal clearance. CONCLUSION: Using videofluoroscopy, this study shows rtHNC patients have worse swallowing outcomes associated with reduced hyolaryngeal mechanics and pharyngeal constriction compared with controls. PMID- 26981229 TI - Comparisons between glucose analogue 2-deoxy-2-((18)F)fluoro-D-glucose and (18)F sodium fluoride positron emission tomography/computed tomography in breast cancer patients with bone lesions. AB - AIM: To compare 2-deoxy-2-((18)F)fluoro-D-glucose((18)F-FDG) and (18)F-sodium ((18)F-NaF) positron emission tomography/computed tomography (PET/CT) accuracy in breast cancer patients with clinically/radiologically suspected or known bone metastases. METHODS: A total of 45 consecutive patients with breast cancer and the presence or clinical/biochemical or radiological suspicion of bone metastatic disease underwent (18)F-FDG and (18)F-fluoride PET/CT. Imaging results were compared with histopathology when available, or clinical and radiological follow up of at least 1 year. For each technique we calculated: Sensitivity (Se), specificity (Sp), overall accuracy, positive and negative predictive values, error rate, and Youden's index. McNemar's chi(2) test was used to test the difference in sensitivity and specificity between the two diagnostic methods. All analyses were computed on a patient basis, and then on a lesion basis, with consideration ofthe density of independent lesions on the co-registered CT (sclerotic, lytic, mixed, no-lesions) and the divergent site of disease (skull, spine, ribs, extremities, pelvis). The impact of adding (18)F-NaF PET/CT to the work-up of patients was also measured in terms of change in their management due to (18)F-NaF PET/CT findings. RESULTS: The two imaging methods of (18)F-FDG and (18)F-fluoride PET/CT were significantly different at the patient-based analysis: Accuracy was 86.7% and 84.4%, respectively (McNemar's chi(2) = 6.23, df = 1, P = 0.01). Overall, 244 bone lesions were detected in our analysis. The overall accuracy of the two methods was significantly different at lesion-based analysis (McNemar's chi(2) = 93.4, df = 1, P < 0.0001). In the lesion density-based and site-based analysis, (18)F-FDG PET/CT provided more accurate results in the detection of CT-negative metastasis (P < 0.002) and vertebral localizations (P < 0.002); (18)F-NaF PET/CT was more accurate in detecting sclerotic (P < 0.005) and rib lesions (P < 0.04). (18)F-NaF PET/CT led to a change of management in 3 of the 45 patients (6.6%) by revealing findings that were not detected at (18)F-FDG PET/CT. CONCLUSION: (18)F-FDG PET/CT is a reliable imaging tool in the detection of bone metastasis in most cases, with a diagnostic accuracy that is slightly, but significantly, superior to that of (18)F-NaF PET/CT in the general population of breast cancer patients. However, the extremely high sensitivity of (18)F fluoride PET/CT can exploit its diagnostic potential in specific clinical settings (i.e., small CT-evident sclerotic lesions, high clinical suspicious of relapse, and negative (18)F-FDG PET and conventional imaging). PMID- 26981233 TI - Should Israel be concerned by the high proportion of medical care paid for privately: comments from a U.S. perspective. AB - As a frequent visitor to Israel, I am keenly aware of the concerns of many Israelis that limits in government funding is forcing a high proportion of the country's medical care to be paid by private sources. Frequently used statistics suggested that close to 40 % of health care is paid for by private funds and that this generates inequalities in terms of access to needed services. The results of a recent IJHPR paper by Engelcin-Nissan and Shmueli cast some doubts on these concerns although they do suggest some degree of inequality in access to needed care. The authors suggest that a better measure of the proportion of private uses of care is not 39 % but about 15 %. And that for some essential medical services it is much lower; in particular, it is less than 10 % for primary care. On the other hand, the study indicates that, in 2009, 15 % of hospitalizations had some private funding. Moreover, a related study has indicated that in 2014 60 % of surgeries were supported by private funds. The authors raise additional concerns that sicker individuals and those with higher income are more likely to use private financing. Whether this level of private spending and its concentration on sicker and higher income individuals violates the commitment of equity and fairness is up to the citizens of Israel. For those of us in the U.S. we only wish our level of inequality was so low. In making the decision on what Israel should do about its inequality it would be helpful to understand why individuals use private funding for services that are covered by the national health insurance system. And, most importantly does using a different source of funds (private versus public) impact on the health outcomes of the care involved. This issue is particularly relevant with respect to the very high use of private financing for surgeries. PMID- 26981230 TI - Functional magnetic resonance imaging of internet addiction in young adults. AB - AIM: To report the results of functional magnetic resonance imaging (fMRI) studies pertaining internet addiction disorder (IAD) in young adults. METHODS: We conducted a systematic review on PubMed, focusing our attention on fMRI studies involving adult IAD patients, free from any comorbid psychiatric condition. The following search words were used, both alone and in combination: fMRI, internet addiction, internet dependence, functional neuroimaging. The search was conducted on April 20(th), 2015 and yielded 58 records. Inclusion criteria were the following: Articles written in English, patients' age >= 18 years, patients affected by IAD, studies providing fMRI results during resting state or cognitive/emotional paradigms. Structural MRI studies, functional imaging techniques other than fMRI, studies involving adolescents, patients with comorbid psychiatric, neurological or medical conditions were excluded. By reading titles and abstracts, we excluded 30 records. By reading the full texts of the 28 remaining articles, we identified 18 papers meeting our inclusion criteria and therefore included in the qualitative synthesis. RESULTS: We found 18 studies fulfilling our inclusion criteria, 17 of them conducted in Asia, and including a total number of 666 tested subjects. The included studies reported data acquired during resting state or different paradigms, such as cue-reactivity, guessing or cognitive control tasks. The enrolled patients were usually males (95.4%) and very young (21-25 years). The most represented IAD subtype, reported in more than 85% of patients, was the internet gaming disorder, or videogame addiction. In the resting state studies, the more relevant abnormalities were localized in the superior temporal gyrus, limbic, medial frontal and parietal regions. When analyzing the task related fmri studies, we found that less than half of the papers reported behavioral differences between patients and normal controls, but all of them found significant differences in cortical and subcortical brain regions involved in cognitive control and reward processing: Orbitofrontal cortex, insula, anterior and posterior cingulate cortex, temporal and parietal regions, brain stem and caudate nucleus. CONCLUSION: IAD may seriously affect young adults' brain functions. It needs to be studied more in depth to provide a clear diagnosis and an adequate treatment. PMID- 26981232 TI - Cold temperature blocks thyroid hormone-induced changes in lipid and energy metabolism in the liver of Lithobates catesbeianus tadpoles. AB - BACKGROUND: Exposure of the American bullfrog Lithobates catesbeianus tadpoles to low temperature affects many biological processes including lipid metabolism and the thyroid hormone (TH) signaling pathway, resulting in arrest of TH-induced metamorphosis. To clarify what molecular events occur in this phenomenon, we investigated the glycerophospholipid and fatty acid (FA) compositions, the activities of mitochondrial enzymes and the transcript levels of related genes in the liver of control (26 degrees C) and cold-treated (4 degrees C) tadpoles with or without 5 nM 3,3',5-triiodothyronine (T3). RESULTS: Exposure to T3 decreased the tail height and polyunsaturation of FAs in the glycerophospholipids, and increased plasma glucose levels and transcript levels of primary TH-response genes including TH receptor, and some energy metabolic (cox4, srebp1 and fas) and FA chain elongase genes (elovl3 and elovl5). However, these T3-induced responses were abolished at 4 degrees C. Exposure to cold temperature enhanced plasma glucose, triglyceride and free FA levels, monounsaturation of FAs, mitochondrial enzymes activities (cytochrome c oxidase and carnitine palmitoyltransferase; U/g liver), with the upregulation of the genes involved in glycogenolysis (pygl), gluconeogenesis (pck1 and g6pc2), FA beta-oxidation (acadl), and cholesterol uptake and synthesis (hmgcr, srebp2 and ldlr1), glycerophospholipids synthesis (pcyt1, pcyt2, pemt, and pparg), and FA monounsaturation (scd1) and chain elongation (elovl1 and elovl2). T3 had little effect on the cold-induced changes. CONCLUSIONS: Our study demonstrated that exposures to T3 and cold temperature exert different effects on lipid metabolism, resulting in changes in the FA composition in glycerophospholipids, and suggests that a cold-induced signal may block TH-signaling pathway around primary TH response genes. PMID- 26981231 TI - Chromatin-wide and transcriptome profiling integration uncovers p38alpha MAPK as a global regulator of skeletal muscle differentiation. AB - BACKGROUND: Extracellular stimuli induce gene expression responses through intracellular signaling mediators. The p38 signaling pathway is a paradigm of the mitogen-activated protein kinase (MAPK) family that, although originally identified as stress-response mediator, contributes to establishing stem cell differentiation fates. p38alpha is central for induction of the differentiation fate of the skeletal muscle stem cells (satellite cells) through not fully characterized mechanisms. METHODS: To investigate the global gene transcription program regulated by p38alpha during satellite cell differentiation (myogenesis), and to specifically address whether this regulation occurs through direct action of p38alpha on gene promoters, we performed a combination of microarray gene expression and genome-wide binding analyses. For experimental robustness, two myogenic cellular systems with genetic and chemical loss of p38alpha function were used: (1) satellite cells derived from mice with muscle-specific deletion of p38alpha, and (2) the C2C12 murine myoblast cell line cultured in the absence or presence of the p38alpha/beta inhibitor SB203580. Analyses were performed at cell proliferation and early differentiation stages. RESULTS: We show that p38alpha binds to a large set of active promoters during the transition of myoblasts from proliferation to differentiation stages. p38alpha-bound promoters are enriched with binding motifs for several transcription factors, with Sp1, Tcf3/E47, Lef1, FoxO4, MyoD, and NFATc standing out in all experimental conditions. p38alpha association with chromatin correlates very well with high levels of transcription, in agreement with its classical function as an activator of myogenic differentiation. Interestingly, p38alpha also associates with genes repressed at the onset of differentiation, thus highlighting the relevance of p38 dependent chromatin regulation for transcriptional activation and repression during myogenesis. CONCLUSIONS: These results uncover p38alpha association and function on chromatin at novel classes of target genes during skeletal muscle cell differentiation. This is consistent with this MAPK isoform being a transcriptional regulator. PMID- 26981234 TI - Basophil activation test: food challenge in a test tube or specialist research tool? AB - Oral food challenge (OFC) is the gold-standard to diagnose food allergy; however, it is a labour and resource-intensive procedure with the risk of causing an acute allergic reaction, which is potentially severe. Therefore, OFC are reserved for cases where the clinical history and the results of skin prick test and/or specific IgE do not confirm or exclude the diagnosis of food allergy. This is a significant proportion of patients seen in Allergy clinics and results in a high demand for OFC. The basophil activation test (BAT) has emerged as a new diagnostic test for food allergy. With high diagnostic accuracy, it can be particularly helpful in the cases where skin prick test and specific IgE are equivocal and may allow reducing the need for OFC. BAT has high specificity, which confers a high degree of certainty in confirming the diagnosis of food allergy and allows deferring the performance of OFC in patients with a positive BAT. The diagnostic utility of BAT is allergen-specific and needs to be validated for different allergens and in specific patient populations. Standardisation of the laboratory methodology and of the data analyses would help to enable a wider clinical application of BAT. PMID- 26981236 TI - miRNA expression profiles in cerebrospinal fluid and blood of patients with Alzheimer's disease and other types of dementia - an exploratory study. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules that function as posttranscriptional regulators of gene expression. Measurements of miRNAs in cerebrospinal fluid (CSF) and blood have just started gaining attention as a novel diagnostic tool for various neurological conditions. The purpose of this exploratory investigation was to analyze the expression of miRNAs in CSF and blood of patients with Alzheimer's disease (AD) and other neurodegenerative disorders in order to identify potential miRNA biomarker candidates able to separate AD from other types of dementia. METHODS: CSF was collected by lumbar puncture performed on 10 patients diagnosed with AD and 10 patients diagnosed with either vascular dementia, frontotemporal dementia or dementia with Lewy bodies. Blood samples were taken immediately after. Total RNA was extracted from cell free fractions of CSF and plasma, and a screening for 372 known miRNA sequences was carried out by real time quantitative polymerase chain reactions (miRCURY LNATM Universal RT miRNA PCR, Polyadenylation and cDNA synthesis kit, Exiqon). RESULTS: Fifty-two miRNAs were detected in CSF in at least nine out of ten patients in both groups. Among these, two miRNAs (let-7i-5p and miR-15a-5p) were found significantly up-regulated and one miRNA (miR-29c-3p) was found significantly down-regulated in patients with AD compared to controls. One hundred and sixty-eight miRNAs were frequently detected in the blood, among which miR-590-5p and miR-142-5p were significantly up-regulated and miR-194-5p was significantly down-regulated in AD patients compared to controls. CONCLUSIONS: Detection of miRNA expression profiles in blood and in particular CSF of patients diagnosed with different types of dementia is feasible and it seems that several expressional differences between AD and other dementia types do exist when measured in a clinically relevant setup. In this explorative pilot study, the deregulated miRNAs in CSF of AD patients may be associated with relevant target genes related to AD pathology, including APP and BACE1, which suggests that miRNAs are interesting candidates for AD biomarkers in the future. PMID- 26981235 TI - Human basal body basics. AB - In human cells, the basal body (BB) core comprises a ninefold microtubule-triplet cylindrical structure. Distal and subdistal appendages are located at the distal end of BB, where they play indispensable roles in cilium formation and function. Most cells that arrest in the G0 stage of the cell cycle initiate BB docking at the plasma membrane followed by BB-mediated growth of a solitary primary cilium, a structure required for sensing the extracellular environment and cell signaling. In addition to the primary cilium, motile cilia are present in specialized cells, such as sperm and airway epithelium. Mutations that affect BB function result in cilia dysfunction. This can generate syndromic disorders, collectively called ciliopathies, for which there are no effective treatments. In this review, we focus on the features and functions of BBs and centrosomes in Homo sapiens. PMID- 26981237 TI - Chronic rhino-orbito-cerebral mucormycosis: A case report and review of the literature. AB - Mucormycosis is a life-threatening disease, were rhinocerebral infection is most commonly seen in the clinical setting. Chronic mucormycosis is a rare presentation that exhibits a challenging diagnosis. We describe the case of a 47 year old diabetic man with complains of left zygomatic arch swelling of 3 months evolution. He had received previous antibiotic treatment without improvement. Biopsy of maxillary sinus revealed the presence of non-septated, 90 degrees angle branched hyphae compatible with zygomicetes. The patient was treated with surgical debridement and amphotericin B until there was no evidence of fungi in the tissue by biopsy. We reviewed chronic rhino-orbito-cerebral mucormycosis from 1964-2014 and 22 cases were found, being this the second case of chronic mucormycosis reported in Mexico. A quarter of the cases were seen in immunocompetent hosts. As only 20% of the causal agent can be isolated by culture, the diagnosis is mainly made by biopsy. Besides treatment with amphotericin B, posaconazole as alternative, and control of the underlying comorbidities, surgical debridement represents the corner stone therapy. We recommend at least 36 month follow-up, due to the 13% risk of recurrence. A chronic presentation has a general survival rate of approximately 83%. PMID- 26981238 TI - Whole clavicle sequestration from chronic osteomyelitis in a 10 year old boy: A case report and review of the literature. AB - Chronic osteomyelitis is a childhood disease and so it is not uncommon to diagnose it in a 10 year old boy who is suffering from pains and discharging sinuses from the left shoulder girdle. What is not common is the involvement of the clavicle in this infective process and even more uncommon is for the whole length of the clavicle to sequester. This case report describes a rare case of chronic osteomyelitis of the left clavicle in which the entire length was removed as a sequestrum during surgery. And despite the removal of an entire length of the clavicle in the patient, there was no functional deficit and there was also no shoulder asymmetry. PMID- 26981239 TI - Clinical audit of ankle fracture management in the elderly. AB - INTRODUCTION: Ankle fractures in the osteoporotic patient are challenging injuries to manage, due to a combination of poor soft tissue, peripheral vascular disease and increased bone fragility, often resulting in more complex fracture patterns. I aim to audit current practice and introduce change by producing recommendations to help improve longer-term functional outcomes. PATIENTS AND METHODS: A retrospective 3-week audit was conducted reviewing results of ankle fracture management in 50 patients aged between 50 and 80 years. Patients admitted for either manipulation under anaesthesia (MUA)/application of cast or open-reduction and internal fixation (ORIF) were considered. Medical notes, including discharge summaries, were used for data extraction. RESULTS: From the 50 patients included within the cohort, forty-two patients (84%) underwent surgical intervention, with eight patients (16%) managed non-operatively. Malunion (63%) and failed fracture fixation (25%) were more commonly reported in patients managed non-operatively. Surgery performed by trainee surgeons was unlikely to prolong theatre time with no statistical significance observed with the consultant led cohort (p = 0.380). However, incidence of fracture malunion and failed fixation were significantly higher following surgery without consultant supervision in the junior trainee group (p = 0.043). CONCLUSIONS: Poor bone quality and associated co-morbidity can present technical difficulties when managing patients surgically. However, our results have shown considerably improved anatomical reduction rates following internal fixation in eligible patients, irrespective of age or gender. PMID- 26981240 TI - Editorial: globalisation and the journal of eating disorders. PMID- 26981241 TI - DCE-MRI and IVIM-MRI of rabbit Vx2 tumors treated with MR-HIFU-induced mild hyperthermia. AB - BACKGROUND: The purpose of this study is to investigate whether changes could be detected in dynamic contrast-enhanced (DCE) and intra-voxel incoherent motion (IVIM) MR parameters upon MR-guided high-intensity focused ultrasound (MR-HIFU) induced hyperthermia in a rabbit Vx2 tumor model. METHODS: Five Vx2 tumor-bearing New Zealand white rabbits were treated with hyperthermia using a clinical MR-HIFU system. Data were acquired before and after hyperthermia. For the DCE analysis, the extended Tofts model was used. For the IVIM analysis, a Bayesian approach was used. Maps were reconstructed of the DCE parameters (K (trans), k ep, and v p ) and IVIM parameters (D t , f p , and D p ). Individual parameter histograms and two-dimensional cross-correlation histograms were constructed to analyze changes in the parameters after hyperthermia. Changes in median values were tested for statistical significance with the Mann-Whitney U test. RESULTS: The MR temperature measurements confirmed that mild hyperthermia (40 to 42 degrees C) was successfully achieved in all rabbits. One rabbit died during treatment and was excluded from the analysis. In the remaining four rabbits, an increase in D t was observed. In three rabbits, an increase in K (trans) was observed, while in the other rabbits, all three DCE parameter values decreased. Mixed changes were seen for v p and f p . CONCLUSIONS: Changes in DCE and IVIM parameters were detected after hyperthermia and were variable between the rabbits. DCE- and IVIM MRI may be promising tools to assess tumor responses to hyperthermia. Further research in a larger number of subjects is necessary in order to assess their value for treatment response monitoring. PMID- 26981242 TI - Systemic versus local responses in melanoma patients treated with talimogene laherparepvec from a multi-institutional phase II study. AB - BACKGROUND: We previously reported that talimogene laherparepvec, an oncolytic herpes virus encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), resulted in an objective response rate of 26 % in patients with advanced melanoma in a phase II clinical trial. The response of individual lesions, however, was not reported. Since talimogene laherparepvec is thought to mediate anti-tumor activity through both direct tumor cytolysis and induction of systemic tumor specific immunity, we sought to determine the independent response rate in virus injected and non-injected lesions. METHODS: Fifty patients with stage IIIC or IV melanoma were treated with talimogene laherparepvec in a multi-institutional single-arm open-label phase II clinical trial. In this study patients were treated until a complete response was achieved, all accessible tumors disappeared, clinically significant disease progression, or unacceptable toxicity. This report is a post hoc analysis of the systemic effects of talimogene laherparepvec in injected lesions and two types of uninjected lesions non-visceral lesions and visceral lesions. RESULTS: Eleven of 23 patients (47.8 %) had a >= 30 % reduction in the total burden of uninjected non-visceral lesions, and 2 of 12 patients (16.7 %) had a >= 30 % reduction in the total burden of visceral lesions. Among 128 evaluable lesions directly injected with talimogene laherparepvec, 86 (67.2 %) decreased in size by >= 30 % and 59 (46.1 %) completely resolved. Of 146 uninjected non-visceral lesions, 60 (41.1 %) decreased in size by >= 30 %, the majority of which (44 [30.1 %]) completely resolved. Of 32 visceral lesions, 4 (12.5 %) decreased in size by >= 30 %, and 3 (9.4 %) completely resolved. The median time to lesion response was shortest for lesions that were directly injected (18.4 weeks), followed by uninjected non visceral lesions (23.1 weeks) and visceral lesions (51.3 weeks), consistent with initiation of a delayed regional and systemic anti-tumor immune response to talimogene laherparepvec. CONCLUSIONS: These results support a regional and systemic effect of talimogene laherparepvec immunotherapy in patients with advanced melanoma. PMID- 26981243 TI - Systemic inflammation in a melanoma patient treated with immune checkpoint inhibitors-an autopsy study. AB - BACKGROUND: Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have been recently approved for treatment of patients with metastatic melanoma and non small cell lung cancer (NSCLC). Despite important clinical benefits, these therapies are associated with a diverse spectrum of immune-related adverse events (irAEs) that are typically transient, but occasionally severe or even fatal. CASE PRESENTATION: This autopsy case illustrates that clinically overt irAEs may represent only a fraction of the total spectrum of immune-related organ pathology in patients treated with immune checkpoint inhibitors. We report a comprehensive analysis of systemic irAE pathology based on the autopsy of a 35-year-old female patient with metastatic melanoma treated first with ipilimumab and then nivolumab. The clinical course was characterized by a mixed tumor response with regression of skin and lung metastases and fatal progression of metastatic disease in the small bowel, peritoneum and brain. During therapy with ipilimumab, radiographic features of immune-related pneumonitis were noted. The autopsy examination established a sarcoid-like granulomatous reaction of the lung, pulmonary fibrosis and diffuse alveolar damage. Importantly, a clinically unapparent but histologically striking systemic inflammation involving the heart, central nervous system, liver and bone marrow was identified. Severe immune related end-organ damage due to lymphocytic myocarditis was found. CONCLUSIONS: Autopsy studies are an important measure of quality control and may identify clinically unapparent irAEs in patients treated with immunotherapy. Pathologists and clinicians need to be aware of the broad spectrum of irAEs for timely management of treatment-related morbidity. PMID- 26981244 TI - From bench to bedside a comprehensive review of pancreatic cancer immunotherapy. AB - The incidence of pancreatic cancer has been increasing while its 5-year survival rate has not changed in decades. In the era of personalized medicine, immunotherapy has emerged as a promising treatment modality in a variety of malignancies, including pancreatic cancer. This review will discuss the unique pancreatic tumor microenvironment, including the cells and receptors that transform the pancreas from its normal architecture into a complex mix of suppressor immune cells and dense extracellular matrix that allows for the unrestricted growth of cancer cells. Next, we will highlight the recently completed immunotherapy clinical trials in pancreatic cancer. Finally, we will explore the on-going immunotherapy clinical trials and future directions of this engaging and changing field. PMID- 26981246 TI - A role for pre-mNK cells in tumor progression. AB - The innate and adaptive immune systems have evolved together to fight infection and cancerous tissues. The innate immune system emerges first with the adaptive immune system following, both ostensibly being bridged by dendritic cells (DC). Recently cells have emerged that possess characteristics of both innate and adaptive immune cell qualities, termed interferon-producing killer dendritic cells (IKDCs). These cells have an indistinct origin that is not well understood. They appear to have more NK cell attributes than DC but purportedly can regulate the immune system similar to immunoregulatory NK cells. Because of this, they have been renamed pre-mNK cells (pre-mature NK cells). We argue in this commentary that pre-mNK cells may contribute to cancer recurrence. PMID- 26981248 TI - Immune monitoring technology primer: immunoprofiling of antigen-stimulated blood. PMID- 26981245 TI - Immunodynamics: a cancer immunotherapy trials network review of immune monitoring in immuno-oncology clinical trials. AB - The efficacy of PD-1/PD-L1 targeted therapies in addition to anti-CTLA-4 solidifies immunotherapy as a modality to add to the anticancer arsenal. Despite raising the bar of clinical efficacy, immunologically targeted agents raise new challenges to conventional drug development paradigms by highlighting the limited relevance of assessing standard pharmacokinetics (PK) and pharmacodynamics (PD). Specifically, systemic and intratumoral immune effects have not consistently correlated with standard relationships between systemic dose, toxicity, and efficacy for cytotoxic therapies. Hence, PK and PD paradigms remain inadequate to guide the selection of doses and schedules, both starting and recommended Phase 2 for immunotherapies. The promise of harnessing the immune response against cancer must also be considered in light of unique and potentially serious toxicities. Refining immune endpoints to better inform clinical trial design represents a high priority challenge. The Cancer Immunotherapy Trials Network investigators review the immunodynamic effects of specific classes of immunotherapeutic agents to focus immune assessment modalities and sites, both systemic and importantly intratumoral, which are critical to the success of the rapidly growing field of immuno-oncology. PMID- 26981249 TI - Metapopulation viability of an endangered shorebird depends on dispersal and human-created habitats: piping plovers (Charadrius melodus) and prairie rivers. AB - BACKGROUND: Many species are distributed as metapopulations in dynamic landscapes, where habitats change through space and time. Individuals locate habitat through dispersal, and the relationship between a species and landscape characteristics can have profound effects on population persistence. Despite the importance of connectivity in dynamic environments, few empirical studies have examined temporal variability in dispersal or its effect on metapopulation dynamics. In response to this knowledge gap, we studied the dispersal, demography, and viability of a metapopulation of an endangered, disturbance dependent shorebird. We examined three subpopulations of piping plovers (Charadrius melodus) on the lower Platte and Missouri rivers from 2008-2013. High flow events from an upstream dam on the Missouri River in 2010 and 2011 allowed us to assess the effect of total habitat loss and the subsequent creation of new habitat associated with a large disturbance at one 'natural' study location. The other two sites within the metapopulation, which were maintained by anthropogenic activities (e.g., mining, development, habitat restoration), were largely unaffected by this disturbance, resulting in a controlled natural experiment. RESULTS: High flow events were associated with increased emigration, decreased immigration, and decreased survival in the subpopulation that experienced high flows. Following the high flow event, immigration into that subpopulation increased. Dispersal rates among subpopulations were negatively correlated with distance. The metapopulation had a low probability of extinction over 100 years (0 %) under the current disturbance interval and associated dispersal and survival rates. However, persistence depended on relatively stable, human-created habitats, not the dynamic, natural habitat (47.7 % extinction probability for this subpopulation). CONCLUSIONS: We found that functional connectivity, as measured by the rate of dispersal among subpopulations, increased as a result of the high flow event in our study metapopulation. Plovers also increased reproductive output following this event. Although the study metapopulation had a low overall probability of extinction, metapopulation persistence depended on anthropogenically created habitats that provided a small but stable source of nesting habitat and dispersers through time. However, all subpopulations remained small, even if persistent, making them individually vulnerable to extinction through stochastic events. Given the highly dynamic nature of habitat availability in this system, maintaining several subpopulations within the metapopulation and stable sources of habitat will be critical, and this species will likely remain conservation-reliant. PMID- 26981250 TI - Are white storks addicted to junk food? Impacts of landfill use on the movement and behaviour of resident white storks (Ciconia ciconia) from a partially migratory population. AB - BACKGROUND: The migratory patterns of animals are changing in response to global environmental change with many species forming resident populations in areas where they were once migratory. The white stork (Ciconia ciconia) was wholly migratory in Europe but recently guaranteed, year-round food from landfill sites has facilitated the establishment of resident populations in Iberia. In this study 17 resident white storks were fitted with GPS/GSM data loggers (including accelerometer) and tracked for 9.1 +/- 3.7 months to quantify the extent and consistency of landfill attendance by individuals during the non-breeding and breeding seasons and to assess the influence of landfill use on daily distances travelled, percentage of GPS fixes spent foraging and non-landfill foraging ranges. RESULTS: Resident white storks used landfill more during non-breeding (20.1 % +/- 2.3 of foraging GPS fixes) than during breeding (14.9 % +/- 2.2). Landfill attendance declined with increasing distance between nest and landfill in both seasons. During non-breeding a large percentage of GPS fixes occurred on the nest throughout the day (27 % +/- 3.0 of fixes) in the majority of tagged storks. This study provides first confirmation of year-round nest use by resident white storks. The percentage of GPS fixes on the nest was not influenced by the distance between nest and the landfill site. Storks travelled up to 48.2 km to visit landfills during non-breeding and a maximum of 28.1 km during breeding, notably further than previous estimates. Storks nesting close to landfill sites used landfill more and had smaller foraging ranges in non-landfill habitat indicating higher reliance on landfill. The majority of non-landfill foraging occurred around the nest and long distance trips were made specifically to visit landfill. CONCLUSIONS: The continuous availability of food resources on landfill has facilitated year-round nest use in white storks and is influencing their home ranges and movement behaviour. White storks rely on landfill sites for foraging especially during the non-breeding season when other food resources are scarcer and this artificial food supplementation probably facilitated the establishment of resident populations. The closure of landfills, as required by EU Landfill Directives, will likely cause dramatic impacts on white stork populations. PMID- 26981247 TI - Phase I study with ONCOS-102 for the treatment of solid tumors - an evaluation of clinical response and exploratory analyses of immune markers. AB - BACKGROUND: We conducted a phase I study with a granulocyte macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, ONCOS-102, in patients with solid tumors refractory to available treatments. The objectives of the study were to determine the optimal dose for further use and to assess the safety, tolerability and adverse event (AE) profile of ONCOS-102. Further, the response rate and overall survival were evaluated as well as preliminary evidence of disease control. As an exploratory endpoint, the effect of ONCOS 102 on biological correlates was examined. METHODS: The study was conducted using a classic 3 + 3 dose escalation study design involving 12 patients. Patients were repeatedly treated intratumorally with ONCOS-102 plus daily low-dose oral cyclophosphamide (CPO). Tumor response was evaluated with diagnostic positron emission tomography (PET) and computed tomography (CT). Tumor biopsies were collected at baseline and after treatment initiation for analysis of immunological correlates. Peripheral blood mononuclear cells (PBMCs) were collected at baseline and during the study to assess antigen specificity of CD8+ T cells by interferon gamma (IFNgamma) enzyme linked immunospot assay (ELISPOT). RESULTS: No dose limiting toxicity (DLT) or maximum tolerated dose (MTD) was identified for ONCOS-102. Four out of ten (40 %) evaluable patients had disease control based on PET/CT scan at 3 months and median overall survival was 9.3 months. A short-term increase in systemic pro-inflammatory cytokines and a prominent infiltration of TILs to tumors was seen post-treatment in 11 out of 12 patients. Two patients showed marked infiltration of CD8+ T cells to tumors and concomitant systemic induction of tumor-specific CD8+ T cells. Interestingly, high expression levels of genes associated with activated TH1 cells and TH1 type immune profile were observed in the post-treatment biopsies of these two patients. CONCLUSIONS: ONCOS-102 is safe and well tolerated at the tested doses. All three examined doses may be used in further development. There was evidence of antitumor immunity and signals of clinical efficacy. Importantly, treatment resulted in infiltration of CD8+ T cells to tumors and up-regulation of PD-L1, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors. TRIAL REGISTRATION: NCT01598129. Registered 19/04/2012. PMID- 26981251 TI - Navigating through the maze of pricing and affordability of branded pharmaceuticals in the midst of the financial crisis: a comparative study among five European recession countries, from a Cyprus perspective. AB - BACKGROUND: Financial recession mandated the introduction of harsh austerity measures. Health, and particularly pharmaceuticals, constitute a significant part of public expenditure and as such they have been subject to significant budget reduction and stringent policies. As a consequence of these measures, an increasing percentage of patients resort to private sector for acquisition of their prescribed pharmaceuticals, due to exclusion of public health care beneficiary status, reduction of breadth of national formularies, delays in reimbursement and excessive waiting times. Affordability for pharmaceuticals in the private sector is of paramount importance since household disposable income plummets and more people are prone to impoverishment. This is critical for branded products, whose active substance and trademark are under patent protection, since no alternative options exist while their monopoly status imply that their prices are high. The impact on affordability regarding access of patient to necessary pharmaceutical care has not been documented in developed countries. METHODS: A laspeyer index was constructed to compare prices of branded pharmaceuticals and assess affordability, by adjusting price index with Gross Domestic Product Purchase Power Parity per capita. Laspeyer index compares prices based on weights, which in our study are the corresponding sales of products in Cyprus. Moreover, we define the percentage of population that will face catastrophic pharmaceutical expenditure after acquisition of one product from eight major and common therapeutic categories. We used data from five European recession countries: Italy, Portugal, Spain, Greece and Cyprus, for 48 products which were selected based on sales. RESULTS: Cyprus displays the highest prices for pharmaceuticals. By adjusting for Gross Domestic Product Purchase Power Parity per capita, affordability is worst for Cyprus and Portugal. CONCLUSIONS: As more patients have to resort to private sector for provision of adequate and timely healthcare, health agencies must reassess affordability of medicines and minimise catastrophic expenditure impact. Health agencies should primarily try to enhance efficiency of the system and reduce waste, instead of resorting to blunt budget reduction, which can demonstrate unpredictable consequences in public health. PMID- 26981252 TI - Pharmaceutical policies in a crisis? Challenges and solutions identified at the PPRI Conference. AB - In October 2015, the third international Pharmaceutical Pricing and Reimbursement Information (PPRI) Conference was held in Vienna to foster discussion on challenges in pricing and reimbursement policies for medicines. The research presented highlighted that commonly used pharmaceutical pricing and reimbursement policies are not sufficiently effective to address current challenges. Conference participants called for fundamental reforms to ensure access to medicines, particularly to new and potentially more effective and/or safe medicines, while safeguarding the financial sustainability of health systems and working towards universal health coverage. PMID- 26981253 TI - An apple rootstock overexpressing a peach CBF gene alters growth and flowering in the scion but does not impact cold hardiness or dormancy. AB - The C-repeat binding factor (CBF) transcription factor is involved in responses to low temperature and water deficit in many plant species. Overexpression of CBF genes leads to enhanced freezing tolerance and growth inhibition in many species. The overexpression of a peach CBF (PpCBF1) gene in a transgenic line of own rooted apple (Malus*domestica) M.26 rootstock (T166) trees was previously reported to have additional effects on the onset of dormancy and time of spring budbreak. In the current study, the commercial apple cultivar 'Royal Gala' (RG) was grafted onto either non-transgenic M.26 rootstocks (RG/M.26) or transgenic M.26 (T166) rootstocks (RG/T166) and field grown for 3 years. No PpCBF1 transcript was detected in the phloem or cambium of RG scions grafted on T166 rootstocks indicating that no graft transmission of transgene mRNA had occurred. In contrast to own-rooted T166 trees, no impact of PpCBF1 overexpression in T166 rootstocks was observed on the onset of dormancy, budbreak or non-acclimated leaf cold hardiness in RG/T166 trees. Growth, however, as measured by stem caliper, current-year shoot extension and overall height, was reduced in RG/T166 trees compared with RG/M.26 trees. Although flowering was evident in both RG/T166 and RG/M.26 trees in the second season, the number of trees in flower, the number of shoots bearing flowers, and the number of flower clusters per shoot was significantly higher in RG/M.26 trees than RG/T166 trees in both the second and third year after planting. Elevated levels of RGL (DELLA) gene expression were observed in RG/T166 trees and T166 trees, which may play a role in the reduced growth observed in these tree types. A model is presented indicating how CBF overexpression in a rootstock might influence juvenility and flower abundance in a grafted scion. PMID- 26981254 TI - The impact of poor glycaemic control on the prevalence of erectile dysfunction in men with type 2 diabetes mellitus: a systematic review. AB - OBJECTIVE: To determine the impact of poor glycaemic control on the prevalence of erectile dysfunction among men with type 2 Diabetics aged 27 to 85 years. DESIGN: The databases Embase classic+Embase, Global health, Ovid Medline and PsychINFO, were searched for relevant studies in June 2014 using the keywords: (Diabetes Mellitus OR diabetes mellitus type2 OR DM2 OR T2DM OR insulin resistance) AND (erectile dysfunction OR sexual dysfunction OR impotence) AND glycaemic control. SETTING: All study settings were considered (primary care, secondary care and tertiary care setting). PARTICIPANTS: Type 2 Diabetic Patients with erectile dysfunction. MAIN OUTCOME MEASURES: Included studies must include one of the following outcomes: (1) HBA1c for assess the level of glycaemic control; (2) Erectile dysfunction (any stage: IIEF-5 = 21 or less). RESULTS: Five cross sectional studies involving 3299 patients were included. The findings pointed to a positive association between erectile dysfunction and glycaemic control. Three studies showed a significant positive association, while one study showed only a weak correlation and one study showed borderline significance. Patients' age, diabetes mellitus duration, peripheral neuropathy and body mass index had positive association with erectile dysfunction. However, smoking and hypertension were not associated with erectile dysfunction in most included studies. Physical activity had a protective effect against erectile dysfunction. CONCLUSION: We may conclude that the risk of erectile dysfunction is higher in type 2 diabetic men with poor glycaemic control than those with good control. PMID- 26981255 TI - Problem-based learning case writing by students based on early years clinical attachments: a focus group evaluation. AB - OBJECTIVES: To evaluate the perception of medical students of the new approach to problem-based learning which involves students writing their own problem-based learning cases based on their recent clinical attachment, and team assessment. DESIGN: Focus group interviews with students using purposive sampling. Transcripts of the audio recordings were analysed using thematic analysis. SETTING: Imperial College School of Medicine, London. PARTICIPANTS: Medical students in the second year of the MBBS course, who attended the problem-based learning case writing session. MAIN OUTCOME MEASURES: To elicit the students' views about problem-based learning case writing and team assessment. RESULTS: The following broad themes emerged: effect of group dynamics on the process; importance of defining the tutor's role; role of summative assessment; feedback as a learning tool and the skills developed during the process. CONCLUSIONS: Overall the students found the new approach, writing problem-based learning cases based on patients seen during their clinical attachments, useful in helping them to gain a better understanding about the problem-based learning process, promoting creativity and reinforcing the importance of team work and peer assessment which are vital professional skills. Further tutor development and guidance for students about the new approach was found to be important in ensuring it is a good learning experience. We hope this evaluation will be of use to other institutions considering introducing students' case writing to problem based learning. PMID- 26981257 TI - The impact of the European Working Time Directive 10 years on: views of the UK medical graduates of 2002 surveyed in 2013-2014. AB - OBJECTIVES: To report doctors' views about the European Working Time Directive ('the Directive'). DESIGN: Survey of the medical graduates of 2002 (surveyed in 2013-2014). PARTICIPANTS: Medical graduates. SETTING: UK. MAIN OUTCOME MEASURES: Questions on views about the Directive. RESULTS: The response rate was 64% (2056/3196). Twelve per cent of respondents agreed that the Directive had benefited senior doctors, 39% that it benefited junior doctors, and 17% that it had benefited the NHS. More women (41%) than men (35%) agreed that the Directive had benefited junior doctors. Surgeons (6%) and adult medical specialists (8%) were least likely to agree that the Directive had benefited senior doctors. Surgeons (20%) were less likely than others to agree that the Directive had benefited junior doctors, whilst specialists in emergency medicine (57%) and psychiatry (52%) were more likely to agree. Surgeons (7%) were least likely to agree that the Directive had benefited the NHS. Most respondents (62%) reported a positive effect upon work-life balance. With regard to quality of patient care, 45% reported a neutral effect, 40% reported a negative effect, and 15% a positive effect. Most respondents (71%) reported a negative effect of the Directive on continuity of patient care, and 71% felt that the Directive had a negative effect upon junior doctors' training opportunities. Fifty-two per cent reported a negative effect on efficiency in managing patient care. CONCLUSIONS: Senior doctors agreed that the Directive benefited doctors' work-life balance. In other respects, they were more negative about it. Surgeons were the least positive about aspects of the Directive. PMID- 26981256 TI - Why do parents use the emergency department for minor injury and illness? A cross sectional questionnaire. AB - OBJECTIVE: To understand decision-making when bringing a child to an emergency department. DESIGN: A cross-sectional survey of parents attending with children allocated a minor triage category. SETTING: Emergency department in South West England, serving 450,000 people per annum. PARTICIPANTS: All English-speaking parents/caregivers whose children attended the emergency department and were triaged as minor injury/illness. MAIN OUTCOME MEASURES: Parental and child characteristics, injury/illness characteristics, advice seeking behaviour, views regarding emergency department service improvement, GP access and determinants of emergency department use. RESULTS: In sum, 373 responses were analysed. The majority of attendances were for minor injury, although illness was more common in <4 year olds. Most presentations were within 4 h of injury/illness and parents typically sought advice before attending. Younger parents reported feeling more stressed. Parents of younger children perceived the injury/illness to be more serious, reporting greater levels of worry, stress, helplessness and upset and less confidence. Parents educated to a higher level were more likely to administer first-aid/medication. Around 40% did not seek advice prior to attending and typically these were parents aged <24 and parents of <1 year olds. The main determinants of use were: advised by someone other than a GP; perceived urgency; perceived appropriateness. The need for reassurance also featured. CONCLUSIONS: The findings suggest that it is difficult for parents to determine whether their child's symptoms reflect minor conditions. Efforts should focus on building parental confidence and self-help and be directed at parents of younger children and younger parents. This is in addition to appropriate minor injury/illness assessment and treatment services. PMID- 26981258 TI - Effects of dietary supplementation with rice bran oil on the growth performance, blood parameters, and immune response of broiler chickens. AB - BACKGROUND: The objective of this experiment was to investigate the effects of dietary supplementation of rice bran oil (RBO) on growth performance, blood parameter, and immune response in broiler chickens. METHODS: A total of 240 1-d old ROSS 308 male broilers were randomly allotted to 4 dietary treatments with six replicated pens consisting of ten chicks. The basal diet was formulated to be adequate in energy and nutrients. Three additional diets were prepared by adding 5, 10 or 20 g/kg of RBO to the basal diet. The experimental diets were fed on an ad libitum basis to the birds during 35 d. RESULTS: Results indicated that increasing inclusion level of RBO in diets improved BW gain (linear and quadratic, P < 0.01), improve feed conversion ratio (linear, P < 0.05) of birds during 0 to 35 d. There was no effect of inclusion level of RBO in diets on feed intake of birds. There was no effect of inclusion level of RBO in diets on erythrocytes of birds. However, heterophil, lymphocyte, and monocytes increased (linear and quadratic, P < 0.01) with inclusion level of RBO in diets increased. Feeding the diets containing increasing amount of RBO to birds increased (linear, P < 0.01) the concentrations of total cholesterol. Increasing inclusion level of RBO in diets increased concentrations of IgG (linear, P < 0.01). There was no effect of inclusion level of RBO in diets on concentrations of IgM. CONCLUSIONS: These results suggest that dietary RBO may be used functional ingredient to improve growth performance, total cholesterol in serum, and immune response of birds. PMID- 26981260 TI - Surgery of the airway. PMID- 26981259 TI - Effects of poly(L-lactide-epsilon-caprolactone) and magnesium hydroxide additives on physico-mechanical properties and degradation of poly(L-lactic acid). AB - BACKGROUND: Biodegradable poly(L-lactic acid) (PLLA) is one of the most widely used polymer in biomedical devices, but it still has limitations such as inherent brittleness and acidic degradation products. In this work, PLLA blends with poly(L-lactide-epsilon-caprolactone) (PLCL) and Mg(OH)2 were prepared by the thermal processing to improve their physico-mechanical and thermal properties. In addition, the neutralizing effect of Mg(OH)2 was evaluated by degradation study. RESULTS: The elongation of PLLA remarkably increased from 3 to 164.4 % and the glass transition temperature (Tg) of PLLA was slightly reduced from 61 to 52 degrees C by adding PLCL additive. Mg(OH)2 in polymeric matrix not only improved the molecular weight reduction and mechanical strength of PLLA, but also neutralized the acidic byproducts generated during polyester degradation. CONCLUSIONS: Therefore, the results demonstrated that the presence of PLCL and Mg(OH)2 additives in PLLA matrix could prevent the thermal decomposition and control degradation behavior of polyester. PMID- 26981261 TI - Surgery of the airway: historic notes. AB - Prior to the 20(th) century, the need for surgical procedures on the airway was infrequent and consisted mainly of tracheostomy to relieve airway obstruction or repair of tracheal injuries such as lacerations. Even the ability of tracheal suture lines to heal primarily was viewed with concern due to the rigidity of the tracheal wall, its precarious blood supply and uncertainty as to whether the cartilage components could heal without complications. In the 20(th) century the evolution of tracheal procedures on major airways evolved to meet the challenges provided by the expanding fields of thoracic surgery and advent of mechanical respiratory support with its associated complications. In the first half of the century lobar and lung resections done for tuberculosis and lung cancer required methods for safe closure of the resulting bronchial stumps and end-to-end bronchial anastomosis in the case of sleeve resections of the lung. Beginning in mid-century the advent of respiratory care units for the treatment of polio and for the expanding fields of thoracic and cardiac surgery resulted in a significant number of post-intubation tracheal stenosis requiring resection and primary repair. In the last 20 years of the century the development of lung transplantation with its requirement for successful bronchial anastomoses between the donor and recipient bronchi, created unique challenges including ischemia of the donor bronchus the adverse effects of immunosuppression, donor lung preservation and diagnosis and management of post-transplant infection and rejection. PMID- 26981262 TI - Surgical anatomy of the tracheobronchial tree. AB - Airway surgery is often indicated in the management of benign or malignant pathological processes of the tracheobronchial tree. The surgeon undertaking this type of work has, however, the responsibility of understanding the particular anatomy applicable to these structures and procedures as well as be able to correlate imaging, intraoperative findings and anatomy. These are important considerations if one wants to reduce operative morbidity and improve potential for better long-term results. This paper reviews the most important anatomic features of the tracheobronchial tree putting emphasis on those features that are important to surgeons performing surgical procedures on those organs. PMID- 26981264 TI - Subglottic tracheal stenosis. AB - Benign subglottic stenosis represents a major therapeutic challenge. Interventional bronchoscopic treatment has a limited role in this setting due to anatomical and technical reasons. The benefit with these techniques is generally temporary, due to frequent recurrences, need for repeated procedures and risk of extending the area of damage. Laryngotracheal resection is at present the curative treatment of choice. Literature data show that surgical treatment may allow very high success rates at long term with low perioperative morbidity and mortality. Technical aspects and results are reported and discussed. PMID- 26981263 TI - Operative endoscopy of the airway. AB - Airway endoscopy has long been an important and useful tool in the management of thoracic diseases. As thoracic specialists have gained experience with both flexible and rigid bronchoscopic techniques, the technology has continued to evolve so that bronchoscopy is currently the foundation for diagnosis and treatment of many thoracic ailments. Airway endoscopy plays a significant role in the biopsy of tumors within the airways, mediastinum, and lung parenchyma. Endoscopic methods have been developed to treat benign and malignant airway stenoses and tracheomalacia. And more recently, techniques have been conceived to treat end-stage emphysema and prolonged air leaks in select patients. This review describes the abundant uses of airway endoscopy, as well as technical considerations and limitations of the current technologies. PMID- 26981265 TI - Tracheal resection and reconstruction for malignant disease. AB - Malignant tracheal neoplasms are rare diseases, mostly represented by squamous cell carcinoma (SCC) and adenoid cystic carcinoma (ACC). Symptoms presentation is often misleading and diagnosis may be delayed for months or years, so clinical suspicion plays a fundamental role. Corner stones in the diagnostic pathway are represented by rigid endoscopy and computed tomography (CT) scan, necessary to correctly stage the patients and identify the optimal surgical candidate. When appropriate, surgical resection and reconstruction is still the best opportunity to achieve a long-term survival with a good quality of life, but this kind of surgery is always a very challenging procedure and a wide experience with an in depth knowledge of every technical detail, from selection of patient, to choice of surgical approach to reconstruction techniques, are needed and recommended. PMID- 26981266 TI - Reresection for recurrent stenosis after primary tracheal repair. AB - Failure of the anastomosis after primary tracheal reconstruction for benign disease is uncommon. Here we review the available evidence on tracheal restenosis and the results of second reconstructions. Factors associated with failed primary anastomosis are examined. Temporizing immediate and alternative long-term management with T-tube or tracheostomy is described, emphasizing the role of tracheal stenting in abating the urgency for reoperation. From available evidence, elective reoperative treatment of failed tracheal reconstruction should be considered in selected patients after careful review and reversal of patient- and operation-specific factors that initiated failure. Referral to a high-volume center with a deep bench of nursing, anesthesiologic and surgical expertise is recommended for reoperation. PMID- 26981267 TI - Complications after tracheal resection and reconstruction: prevention and treatment. AB - Tracheal resection and reconstruction (TRR) and laryngotracheal resection and reconstruction (LTRR) is commonly performed for post-intubation tracheal stenosis, tracheal tumor, idiopathic laryngotracheal stenosis (ILTS), and tracheoesophageal fistula (TEF). Ninety-five percent of patients have a good result from surgery. Complications occur in ~20% of patients, of which half are anastomotic complications. Complications include granulation tissue formation, restenosis of the trachea, anastomotic separation, TEF and tracheoinnominate fistula (TIF), wound infection, laryngeal edema, and glottic dysfunction. Risk factors for anastomotic complication include diabetes, reoperation, previous tracheal appliance, and long-segment tracheal resection. Bronchoscopy should be part of the diagnostic workup when a complication is suspected. Anastomotic separation-the most feared complication of tracheal surgery-may present subtly with stridor and wound infection, or with respiratory distress and extremis. Prompt management is required to prevent devastating consequences. The airway should be secured, bronchoscopy should be performed to address the degree of separation, and the anastomosis should be revised if needed, usually with the addition of t-tube or tracheostomy. Anastomotic complications that are managed aggressively typically yield good results. More than half of such patients will eventually have a satisfactory airway. However, an anastomotic complication is associated with a thirteen-fold increase in the risk of death following tracheal resection. PMID- 26981268 TI - Reconstruction of the bronchus and pulmonary artery. AB - Bronchovascular reconstructive procedures employed in order to avoid pneumonectomy (PN) in patients functionally unsuitable have provided, over time, excellent results, similar or even better than those obtained by PN. In recent years, new successful techniques have been developed that pertain in particular the prevention of major complications and the reconstruction of the pulmonary artery (PA). Encouraging data from increasing number of published experiences support the choice of parenchymal sparing procedures for lung cancer also in patients with good functional reserve. This is even more true if considering trials published in the last 10 years, thus indicating that improved outcome can be achieved with increased experience in reconstructive techniques and perioperative management. This article discusses the main technical aspects and results of literature. PMID- 26981269 TI - Techniques of protection and revascularization of the bronchial anastomosis. AB - Airway anastomosis has been traditionally considered at risk for the onset of complications, particularly dehiscence with consequent infection and erosion in the adjacent vessels. Although the modifications and improvements of the surgical technique has contributed to reduce the incidence of complications, the protection and revascularization of the anastomotic site is still considered mandatory at many centers Many techniques have been proposed for encircling the bronchial anastomosis. PMID- 26981270 TI - Tracheal replacement. AB - Non-malignant and malignant obstruction of the tracheal airway causes significant morbidity and mortality. With increased use of artificial airways, benign and iatrogenic complications are increasing. A tracheal stenosis that is less than 5 cm in length can be resected with end-to-end anastomosis. Longer tracheal lesions can be treated in a palliative way by placement of a stent to secure airway lumen patency. The management of tracheal defects is an evolving field. Tracheal transplantation and tracheal regeneration may bring major treatment advances to cases with long-segment tracheal involvement. This review examines the current possibilities and future prospects in the area of tracheal transplantation and regeneration. PMID- 26981271 TI - Airway anastomosis for lung transplantation. AB - Lung transplantation (LT) is the only viable option for a selected group of patients with end stage pulmonary diseases. During the recent years satisfactory results in terms of long-term survival and quality of life have been achieved with improvements in surgical technique, immunosuppression and perioperative management. Since the beginning, the airway anastomosis has been considered crucial and significant efforts have been made to understand the healing process. A number of experimental studies allowed improving the surgical technique by modifying the technique of suturing, the anastomotic protection and type and dose of immunosuppression, reducing the risk of airway complications. Furthermore, a huge progress has been made in the management of such complications. Early diagnosis of bronchial complications and their prompt and correct management are crucial to achieve long-term survival. PMID- 26981272 TI - Idiopathic laryngotracheal stenosis. AB - Idiopathic laryngotracheal stenosis (ILTS) is a rare inflammatory disease of unknown etiology. Infectious, traumatic and immunologic processes must first be excluded. The majority of patients affected are female who present with progressive symptoms of upper airway obstruction, which can extend over a number of years. ILTS is characterized by short segment, circumferential stenotic lesions, located particularly at the level of the cricoid. Bronchoscopic evaluation is essential for establishing the diagnosis and operative planning. Various temporizing interventions have historically been utilized, including dilation and laser ablation, for symptomatic management. However these interventions have demonstrated diminishing returns and poor long-term outcomes. Patients with ILTS should be considered early for definitive surgical intervention to minimize complications and optimize outcomes. Laryngotracheal resection and reconstruction is a viable intervention, which has demonstrated good long-term results and low recurrence rates for this patient population. PMID- 26981274 TI - Robotic sleeve lobectomy: technical details and early results. PMID- 26981273 TI - Uniportal video-assisted thoracoscopic bronchoplastic and carinal sleeve procedures. AB - Despite of the recent advanced with the video-assisted thoracoscopic surgery (VATS), the most common approach for bronchial and carinal resection is still the open surgery. The technical difficulties, the steep learning curve and the concerns about performing an oncologic and safe reconstruction in advanced cases, are the main reasons for the low adoption of VATS for sleeve resections. Most of the authors use 3-4 incisions for thoracoscopic sleeve procedures. However these surgical techniques can be performed by a single incision approach by skilled uniportal VATS surgeons. The improvements of the surgical instruments, high definition cameras and recent 3D systems have greatly contributed to facilitate the adoption of uniportal VATS techniques for sleeve procedures. In this article we describe the technique of thoracoscopic bronchial sleeve, bronchovascular and carinal resections through a single incision approach. PMID- 26981276 TI - The Cost of Blindness in the Republic of Ireland 2010-2020. AB - Aims. To estimate the prevalence of blindness in the Republic of Ireland and the associated financial and total economic cost between 2010 and 2020. Methods. Estimates for the prevalence of blindness in the Republic of Ireland were based on blindness registration data from the National Council for the Blind of Ireland. Estimates for the financial and total economic cost of blindness were based on the sum of direct and indirect healthcare and nonhealthcare costs. Results. We estimate that there were 12,995 blind individuals in Ireland in 2010 and in 2020 there will be 17,997. We estimate that the financial and total economic costs of blindness in the Republic of Ireland in 2010 were ?276.6 million and ?809 million, respectively, and will increase in 2020 to ?367 million and ?1.1 billion, respectively. Conclusions. Here, ninety-eight percent of the cost of blindness is borne by the Departments of Social Protection and Finance and not by the Department of Health as might initially be expected. Cost of illness studies should play a role in public policy making as they help to quantify the indirect or "hidden" costs of disability and so help to reveal the true cost of illness. PMID- 26981275 TI - Feeding Patterns and Xenomonitoring of Trypanosomes among Tsetse Flies around the Gashaka-Gumti National Park in Nigeria. AB - In order to understand the epidemiology of trypanosomoses in Gashaka-Gumti National Park, Nigeria, we determined the density, infection rates, and feeding patterns of tsetse flies using biconical traps, ITS, and mitochondrial cytochrome b PCRs. A total of 631 tsetse flies were captured, of which 531 (84.2%) and 100 (15.8%) were analyzed for trypanosomes and blood meals, respectively. Tsetse distribution varied significantly (p < 0.05) across study sites with average trap and daily catches of 4.39 and 26.34, respectively. Overall tsetse infection rate was 5.08% and ranged between 3.03% and 6.84% across study sites. We identified 10 T. brucei, 3 T. congolense savannah, 2 T. congolense forest, and 2 mixed infections among the 13 pools made from the 27 flies positive for trypanosomes with light microscopy. The distribution of vertebrate blood meals in tsetse flies varied significantly (p < 0.05) and ranged between 6.0% and 45% across hosts. We also observed dual feeding patterns involving at least 2 hosts in 24% and multiple feeding involving at least 3 hosts in 17% of the flies. We observed predominance of G. palpalis which also recorded higher infection rate. T. brucei was more prevalent among tsetse flies. Tsetse flies fed predominantly on cattle and less frequently on humans and also showed mixed feeding habits. PMID- 26981277 TI - Growth Hormone Influence on the Morphology and Size of the Mouse Meibomian Gland. AB - Purpose. We hypothesize that growth hormone (GH) plays a significant role in the regulation of the meibomian gland. To test our hypothesis, we examined the influence of GH on mouse meibomian gland structure. Methods. We studied four groups of mice, including (1) bovine (b) GH transgenic mice with excess GH; (2) GH receptor (R) antagonist (A) transgenic mice with decreased GH; (3) GHR knockout (-/-) mice with no GH activity; and (4) wild type (WT) control mice. After mouse sacrifice, eyelids were processed for morphological and image analyses. Results. Our results show striking structural changes in the GH deficient animals. Many of the GHR-/- and GHA meibomian glands featured hyperkeratinized and thickened ducts, acini inserting into duct walls, and poorly differentiated acini. In contrast, the morphology of WT and bGH meibomian glands appeared similar. The sizes of meibomian glands of bGH mice were significantly larger and those of GHA and GHR-/- mice were significantly smaller than glands of WT mice. Conclusions. Our findings support our hypothesis that the GH/IGF-1 axis plays a significant role in the control of the meibomian gland. In addition, our data show that GH modulates the morphology and size of this tissue. PMID- 26981278 TI - Symptom Endorsement and Sociodemographic Correlates of Postnatal Distress in Three Low Income Countries. AB - Background. Maternal mental illness has been implicated in adverse child development outcomes. Factors such as context and culture may influence experiences of maternal distress and explain differences in outcomes across settings. Methods. We analyzed baseline data from 5,647 mothers in Ethiopia, India (Andhra Pradesh), and Vietnam participating in an ongoing cohort study (Young Lives) to compare symptom endorsement and sociodemographic correlates of distress. Maternal distress was assessed using the Self-Reporting Questionnaire 20 Items (cutoff: >=8). Logistic regressions were stratified by sample to identify correlates of distress. Results. Symptom endorsement was similar among distressed women, particularly with regard to feeling unhappy (76%, 80%, and 79%). Notable differences were observed in three items assessing Depressive Thoughts, which were most highly endorsed in Ethiopia (49%-56%). Having a child experiencing a life-threatening event was correlated with distress in all three samples. A variety of correlates were unique to only one sample. Conclusions. There were multiple similarities but also notable differences across sites in the expression and correlates of maternal distress. Feeling unhappy appears to be a hallmark feature of distress. Correlates highlight the relationship between distress and indicators of poverty, child wellbeing, and economic shocks. Differences demonstrate the value of further exploration of cross-cultural differences. PMID- 26981279 TI - Factor Structure, Internal Consistency, and Screening Sensitivity of the GARS-2 in a Developmental Disabilities Sample. AB - The Gilliam Autism Rating Scale-Second Edition (GARS-2) is a widely used screening instrument that assists in the identification and diagnosis of autism. The purpose of this study was to examine the factor structure, internal consistency, and screening sensitivity of the GARS-2 using ratings from special education teaching staff for a sample of 240 individuals with autism or other significant developmental disabilities. Exploratory factor analysis yielded a correlated three-factor solution similar to that found in 2005 by Lecavalier for the original GARS. Though the three factors appeared to be reasonably consistent with the intended constructs of the three GARS-2 subscales, the analysis indicated that more than a third of the GARS-2 items were assigned to the wrong subscale. Internal consistency estimates met or exceeded standards for screening and were generally higher than those in previous studies. Screening sensitivity was .65 and specificity was .81 for the Autism Index using a cut score of 85. Based on these findings, recommendations are made for instrument revision. PMID- 26981280 TI - Synthesis and Evaluation of Mannitol-Based Inhibitors for Lipopolysaccharide Biosynthesis. AB - Antibiotic resistance is a serious threat against humankind and the need for new therapeutics is crucial. Without working antibiotics, diseases that we thought were extinct will come back. In this paper two new mannitol bisphosphate analogs, 1,6-dideoxy-1,6-diphosphoramidate mannitol and 1,6-dideoxy-1,6 dimethansulfonamide mannitol, have been synthesized and evaluated as potential inhibitors of the enzyme GmhB in the biosynthesis of lipopolysaccharides. 1,6 Dideoxy-1,6-diphosphoramidate mannitol showed promising result in computational docking experiments, but neither phosphate analog showed activity in the Kirby Bauer antibiotic susceptibility test. PMID- 26981281 TI - Syntheses and Antibiotic Evaluation of 2-{[(2R,4R)-4-Carboxy-2-hydroxypyrrolidin 1-yl]carbonyl}benzene-1,5-dicarboxylic Acids and 2-Carbamoylbenzene-1,5 dicarboxylic Acid Analogues. AB - Our search for new antibiotics led to the syntheses and biological evaluation of new classes of dicarboxylic acid analogues. The syntheses involve nucleophilic addition of different substituted benzylamine, aniline, alkylamine, and 4 hydroxyl-L-proline with carbamoylbenzoic acid. The results of the antimicrobial activity as indicated by the zone of inhibition (ZOI) showed that Z 10 is the most active against Pseudomonas aeruginosa (32 mm) and least active against Candida stellatoidea (27 mm) and Vancomycin Resistant Enterococci (VRE) (27 mm), while Z 7 shows the least zone of inhibition (22 mm) against Methicillin Resistant Staphylococcus aureus (MRSA). The minimum inhibition concentration (MIC) determination reveals that Z 10 inhibits the growth of tested microbes at a low concentration of 6.25 MUg/mL, while Z 9 and Z 12 inhibits the growth of most microbes at a concentration of 12.5 MUg/mL, recording the least MIC. The Minimum Bactericidal/Fungicidal Concentration (MBC/MFC) results revealed that Z 10 has the highest bactericidal/fungicidal effect on the test microbes, at a concentration of 12.5 MUg/mL, with the exception of Candida stellatoidea and Vancomycin Resistant Enterococci (VRE) with MBC/MFC of 25 MUg/mL. The result of this investigation reveals the potential of the target compounds (Z 1-3,5,7-12 ) in the search for new antimicrobial agents. PMID- 26981282 TI - Routine Head Computed Tomography for Patients in the Emergency Room with Trauma Requires Both Thick- and Thin-Slice Images. AB - Background. Images of head CT for the supratentorial compartment are sometimes recommended to be reconstructed with a thickness of 8-10 mm to achieve lesion conspicuity. However, additional images of a thin slice may not be routinely provided for patients with trauma in the emergency room (ER). We investigated the diagnostic sensitivity of a head CT, where axial images were 10 mm thick slices, in cases of linear skull fractures. Methods. Two trauma surgeons retrospectively reviewed head CT with 10 mm slices and skull X-rays of patients admitted to the ER that were diagnosed with a linear skull fracture. All patients had undergone both head CT and skull X-rays (n = 410). Result. The diagnostic sensitivity of head CT with a thickness of sequential 10 mm was 89% for all linear skull fractures but only 56% for horizontal fractures. This CT technique with 10 mm slices missed 6% of patients with linear skull fractures. False-negative diagnoses were significantly more frequent for older (>=55 years) than for young (<15 years) individuals (p = 0.048). Conclusions. A routine head CT of the supratentorial region for patients in the ER with head injuries requires both thick-slice images to visualize cerebral hemispheres and thin-slice images to detect skull fractures of the cranial vault. PMID- 26981283 TI - The Use of Computer-Assisted Home Exercises to Preserve Physical Function after a Vestibular Rehabilitation Program: A Randomized Controlled Study. AB - Objective. The purpose of this study was to evaluate whether elderly patients with vestibular dysfunction are able to preserve physical functional level, reduction in dizziness, and the patient's quality of life when assistive computer technology is used in comparison with printed instructions. Materials and Methods. Single-blind, randomized, controlled follow-up study. Fifty-seven elderly patients with chronic dizziness were randomly assigned to a computer assisted home exercise program or to home exercises as described in printed instructions and followed for tree month after discharge from an outpatient clinic. Results. Both groups had maintained their high functional levels three months after finishing the outpatient rehabilitation. No statistically significant difference was found in outcome scores between the two groups. In spite of moderate compliance levels, the patients maintained their high functional level indicating that the elderly should not necessarily exercise for the first three months after termination of the training in the outpatient clinic. Conclusion. Elderly vestibular dysfunction patients exercising at home seem to maintain their functional level, level of dizziness, and quality of life three months following discharge from hospital. In this specific setup, no greater effect was found by introducing a computer-assisted training program, when compared to standard home training guided by printed instructions. This trial is registered with NCT01344408. PMID- 26981284 TI - Genotyping of Cryptosporidium Species and Their Clinical Manifestations in Patients with Renal Transplantation and Human Immunodeficiency Virus Infection. AB - In the present study we aimed to determine (i) frequency of Cryptosporidium species among patients with renal transplantation (RT) and human immunodeficiency virus (HIV) infection and (ii) relationship of the nature, severity, and duration of symptoms with different species and load of Cryptosporidium. Stool samples from 70 (42 RT and 28 HIV) and 140 immunocompromised patients with and without cryptosporidiosis by modified Kinyoun's staining were subjected to qPCR-melting curve analysis for identification of parasite species. qPCR detected one microscopically negative sample to be positive for cryptosporidiosis. C. hominis, C. parvum, and mixed infection were detected in 50/71 (70.4%), 19/71 (26.8%), and 2/71 (2.8%) patients, respectively. Patients with cryptosporidiosis had higher stool frequency (median, IQR: 4, 3-6/d versus 3, 2-4/d; P = 0.017) and watery stool (52/71 [73%] versus 64/139 [46%]; P = 0.003). Parasite load (median, IQR: Log10 6.37 (5.65-7.12), Log10 5.81 (4.26-6.65); P = 0.046) and nausea/vomiting (29/50 [58%] versus 5/19 [26%]; P = 0.032) were more frequent with C. hominis than with C. parvum infection. Thus, Cryptosporidium spp. (mainly C. hominis) is a common cause of diarrhoea in RT and HIV patients. PMID- 26981285 TI - Flexible Stabilisation of the Degenerative Lumbar Spine Using PEEK Rods. AB - Posterior lumbar interbody fusion using cages, titanium rods, and pedicle screws is considered today as the gold standard of surgical treatment of lumbar degenerative disease and has produced satisfying long-term fusion rates. However this rigid material could change the physiological distribution of load at the instrumental and adjacent segments, a main cause of implant failure and adjacent segment disease, responsible for a high rate of further surgery in the following years. More recently, semirigid instrumentation systems using rods made of polyetheretherketone (PEEK) have been introduced. This clinical study of 21 patients focuses on the clinical and radiological outcomes of patients with lumbar degenerative disease treated with Initial VEOS PEEK((r))-Optima system (Innov'Spine, France) composed of rods made from PEEK-OPTIMA((r)) polymer (Invibio Biomaterial Solutions, UK) without arthrodesis. With an average follow up of 2 years and half, the chances of reoperation were significantly reduced (4.8%), quality of life was improved (ODI = 16%), and the adjacent disc was preserved in more than 70% of cases. Based on these results, combined with the biomechanical and clinical data already published, PEEK rods systems can be considered as a safe and effective alternative solution to rigid ones. PMID- 26981286 TI - Prismatic Adaptation Induces Plastic Changes onto Spatial and Temporal Domains in Near and Far Space. AB - A large literature has documented interactions between space and time suggesting that the two experiential domains may share a common format in a generalized magnitude system (ATOM theory). To further explore this hypothesis, here we measured the extent to which time and space are sensitive to the same sensorimotor plasticity processes, as induced by classical prismatic adaptation procedures (PA). We also exanimated whether spatial-attention shifts on time and space processing, produced through PA, extend to stimuli presented beyond the immediate near space. Results indicated that PA affected both temporal and spatial representations not only in the near space (i.e., the region within which the adaptation occurred), but also in the far space. In addition, both rightward and leftward PA directions caused opposite and symmetrical modulations on time processing, whereas only leftward PA biased space processing rightward. We discuss these findings within the ATOM framework and models that account for PA effects on space and time processing. We propose that the differential and asymmetrical effects following PA may suggest that temporal and spatial representations are not perfectly aligned. PMID- 26981288 TI - Is It Possible to Maintain Consciousness and Spontaneous Ventilation with Chest Compression in the Early Phase of Cardiac Arrest? AB - Chest compression is important in cardiopulmonary resuscitation. However, life support algorithms do not specify when chest compression should be initiated in patients with persistent spontaneous normal breathing in the early phase after cardiac arrest. Here we describe the case of a 69-year-old man who underwent femoral bypass surgery and was extubated at the end of the procedure. After extubation, the patient's breathing pattern and respiratory rate were normal. The patient subsequently developed ventricular fibrillation, evident on two monitors. Because defibrillation was ineffective, chest compression was initiated even though the patient had spontaneous normal breathing and defensive motor reflexes, which were continued throughout resuscitation. He regained consciousness and underwent tracheal extubation without neurological sequelae on postoperative day 1. This case highlights the necessity of chest compression in the early phase of cardiac arrest. PMID- 26981290 TI - Tender Endothelium Syndrome: Combination of Hypotension, Bradycardia, Contrast Induced Chest Pain, and Microvascular Angina. AB - Hypotension, bradycardia, and contrast induced chest pain are potential complications of cardiac catheterization and coronary angiography. Catheter induced coronary spasm has been occasionally demonstrated, but its relationship to spontaneous coronary spasm is unclear. We describe a 64-year-old female who underwent coronary artery bypass surgery in 1998 on the basis of an angiographic diagnosis of severe left main disease, who recently presented with increasingly frequent typical angina. Repeat coronary angiography was immediately complicated by severe chest pain, hypotension, and bradycardia but demonstrated only mild disease of the left main artery and entire coronary tree with complete occlusion of her prior grafts. This reaction was almost identical to that observed during her original coronary angiogram. We now believe her original angiogram was complicated by severe catheter-induced left main spasm, with the accompanying contrast reaction attributed to left main disease, and the occlusion of coronary grafts explained by the absence of significant left main disease. The combination of these symptoms has not been documented in the literature. In this instance, these manifestations erroneously led to coronary bypass surgery. It is unknown whether routine, systematic injection of intracoronary nitroglycerin prior to angiography might blunt the severity of such reactions. PMID- 26981289 TI - Physiologic Functional Evaluation of Left Internal Mammary Artery Graft to Left Anterior Descending Coronary Artery Steal due to Unligated First Thoracic Branch in a Case of Refractory Angina. AB - Unligated side branches of the left internal mammary artery (LIMA) have been described in the literature as a cause of coronary steal resulting in angina. Despite a number of studies reporting successful side branch embolization to relieve symptoms, this phenomenon remains controversial. Hemodynamic evidence of coronary steal using angiographic and intravascular Doppler techniques has been supported by some and rejected by others. In this case study using an intracoronary Doppler wire with adenosine, we demonstrate that a trial occlusion of the LIMA thoracic side branch with selective balloon inflation can confirm physiologic significant steal and whether coil embolization of the side branch is indicated. PMID- 26981291 TI - A Practical Method for No-Reflow Treatment. AB - No-reflow is an undesirable result of percutaneous coronary interventions. Vasoactive drug administration at the distal part of the coronary artery is suggested as a therapeutic option for no-reflow treatment. Here, we represent two cases of successful no-reflow management with previously used monorail balloon at the same procedure as a hand-made distal infusion catheter. PMID- 26981287 TI - Recent Advance in the Relationship between Excitatory Amino Acid Transporters and Parkinson's Disease. AB - Parkinson's disease (PD) is the most common movement disorder disease in the elderly and is characterized by degeneration of dopamine neurons and formation of Lewy bodies. Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS). If glutamate is not removed promptly in the synaptic cleft, it will excessively stimulate the glutamate receptors and induce excitotoxic effects on the CNS. With lack of extracellular enzyme to decompose glutamate, glutamate uptake in the synaptic cleft is mainly achieved by the excitatory amino acid transporters (EAATs, also known as high-affinity glutamate transporters). Current studies have confirmed that decreased expression and function of EAATs appear in PD animal models. Moreover, single unilateral administration of EAATs inhibitor in the substantia nigra mimics several PD features and this is a solid evidence supporting that decreased EAATs contribute to the process of PD. Drugs or treatments promoting the expression and function of EAATs are shown to attenuate dopamine neurons death in the substantia nigra and striatum, ameliorate the behavior disorder, and improve cognitive abilities in PD animal models. EAATs are potential effective drug targets in treatment of PD and thus study of relationship between EAATs and PD has predominant medical significance currently. PMID- 26981292 TI - Spurious Hyperchloremia and Negative Anion Gap in a Child with Refractory Epilepsy. AB - We report a case with spurious hyperchloremia with negative anion gap in a child who was taking potassium bromide for refractory epilepsy. Blood chemistry showed a high chloride level (171 mEq/L) and a negative anion gap (-52 mEq/L). Plasma chloride concentration is measured by an ion-selective electrode method; however the presence of other anions like bromide and iodides can interfere with chloride level and largely overestimates the chloride concentration. Thus hyperchloremia with a negative anion gap is a clue to the diagnosis of halides like bromide and iodide ingestion. PMID- 26981293 TI - Peripheral Developing Odontoma or Peripheral Ameloblastic Fibroodontoma: A Rare Challenging Case. AB - Peripheral odontogenic lesions are considered to be rare within the classification of odontogenic tumors. They share the same microscopic characteristics of their central counterparts. Here, we report an ulcerated mass of the maxillary gingiva that on histopathological examination was diagnosed as peripheral developing odontoma or peripheral ameloblastic fibroodontoma. The diagnosis of this tumor is challenging and may lead to unnecessary treatment. PMID- 26981295 TI - Neuroendoscopic Removal of Acute Subdural Hematoma with Contusion: Advantages for Elderly Patients. AB - Background. Large craniotomy for acute subdural hematoma is sometimes too invasive. We report good outcomes for two cases of neuroendoscopic evacuation of hematoma and contusion by 1 burr hole surgery. Case Presentation. Both patients arrived by ambulance at our hospital with disturbed consciousness after falling. Case 1 was an 81-year-old man who took antiplatelet drugs for brain infarction. Case 2 was a 73-year-old alcoholic woman. CT scanning showed acute subdural hematoma and frontal contusion in both cases. In the acute stage, glycerol was administered to reduce edema; CTs after 48 and 72 hours showed an increase of subdural hematoma and massive contusion of the frontal lobe. Disturbed consciousness steadily deteriorated. The subdural hematoma and contusion were removed as soon as possible by neuroendoscopy under local anesthesia, because neither patient was a good candidate for large craniotomy considering age and past history. 40%~70% of the hematoma was removed, and the consciousness level improved. Conclusion. Neuroendoscopic removal of acute subdural hematoma and contusion has advantages and disadvantages. For patients with underlying medical issues or other risk factors, it is likely to be effective. PMID- 26981294 TI - Acute Kidney Injury Associated with Linagliptin. AB - Linagliptin is a dipeptidyl peptidase-IV (DPP-IV) inhibitor that is approved for the treatment of type 2 diabetes mellitus. About 5% of linagliptin is eliminated by the kidneys and no dose adjustment is recommended in kidney impairment. We report a first case of linagliptin-associated acute kidney injury (AKI) in a patient with preexisting chronic kidney disease (CKD). We hypothesize that AKI was due to renal hypoperfusion from linagliptin-induced natriuresis and intravascular volume contraction in the setting of concomitant lisinopril use, which is known to impair autoregulation and potentiate hypotension-induced AKI. It may be prudent to exert caution and closely monitor kidney function when initiating linagliptin in combination with ACE-inhibitors in CKD patients. PMID- 26981296 TI - Metastasis of Pregnancy-Associated Breast Cancer (Suspected to Be Hereditary Breast and Ovarian Cancer) to the Brain, Diagnosed at 18 Weeks' Gestation: A Case Report and Review of the Literature. AB - We report a case of pregnancy-associated breast cancer with metastasis to the brain, likely resulting from hereditary breast and ovarian cancer (HBOC). A 35 year-old woman (gravida 2, para 0-1-0-1) underwent a right mastectomy and right axillary dissection after a cesarean section at 30 years of age; her mother died at 47 years of age due to breast cancer. Histopathological examination indicated an invasive ductal carcinoma with triple-negative cancer (cancer stage 2B [pT3N0M0]). The patient refused adjuvant therapy because of the risk of infertility. After 4 years, she became pregnant naturally. At 18 weeks' gestation, she experienced aphasia and dyslexia due to brain metastasis. The pregnancy was terminated at 21 weeks' gestation after thorough counseling. Her family history, young-onset disease, and histopathological findings suggested HBOC. She declined genetic testing for BRCA1/2, though genetic counseling was provided. In cases of pregnancy-related breast cancer, consideration must be given to whether the pregnancy should be continued and to posttreatment fertility. HBOC should also be considered. Genetic counseling should be provided and the patient should be checked for the BRCA mutation, as it is meaningful for the future of any potential children. Genetic counseling should be provided even if the cancer is advanced or recurrent. PMID- 26981297 TI - Acute Coronary Syndrome Manifesting as an Adverse Effect of All-trans-Retinoic Acid in Acute Promyelocytic Leukemia: A Case Report with Review of the Literature and a Spotlight on Management. AB - Background. Acute promyelocytic leukemia is characterized by t(15;17). This leads to the formation of PML/RARalpha which blocks the differentiation of blasts at the stage of promyelocytes. This is reversed by all-trans-retinoic acid (ATRA), a vitamin A derivative. Acute myocardial ischemia is a rare side effect of ATRA. Case Report. We report a case of acute coronary syndrome manifesting as an adverse effect of ATRA in a lady with APL who had no other risk factors for cardiovascular disease. Conclusions. We emphasize the need for high index of suspicion for the diagnosis of this entity. In the light of this case, the rare instances of ATRA associated acute myocardial ischemia recorded in the literature and the options available for treatment of acute promyelocytic leukemia sans ATRA have been reviewed. PMID- 26981298 TI - A Woman with Rheumatoid Arthritis and a Bilateral Fracture of the Proximal Tibia. AB - A 52-year-old woman presented herself with pain on the medial sides of the proximal tibia after a minimal trauma. Conventional X-rays did not show any pathology. However, the MRI showed a bilateral fracture of the proximal tibia. Since the patient was treated with methotrexate due to rheumatoid arthritis, methotrexate osteopathy was considered. Long term treatment with low doses of methotrexate proved to inhibit osteoblast proliferation and may eventually lead to decreased bone formation and osteopenia. On the other hand, immobilization, joint deformities, and steroid treatment are associated with rheumatoid arthritis and are also known risk factors for fractures. The clinical relevance of methotrexate osteopathy still has to be established. However, if a patient treated with methotrexate localizes pain in the tibia, methotrexate osteopathy should be considered. Withdrawal of the drug may improve symptoms. PMID- 26981299 TI - Group B Streptococcal Septic Arthritis of the Shoulder and Potential Association with Pelvic Examination and PAP Smear. AB - Group B streptococcal (GBS) infection of a native joint in a nonpregnant adult is uncommon. While many women are colonized with this flora, it rarely becomes pathogenic in its adult host. GBS associated joint infections have been reported, most of which have been related to hematogenous seeding from unknown sources. To our knowledge, there are no published case reports of a GBS joint infection in association with a pelvic exam and Papanicolaou (PAP) smear. In this case report, we present a case of GBS sepsis of a native shoulder, possibly resulting from a routine pelvic exam and PAP smear. PMID- 26981300 TI - Severe Hyperacusis, Photophobia, and Skin Hypersensitivity. AB - We report a case of a patient with severe hyperacusis, photophobia, and skin hypersensitivity. The patient was initially treated with sound therapy and medical therapy for 4 months and successfully with a selective serotonin reuptake inhibitor (SSRI) and cognitive behavioral therapy which improved her mood and the tolerance for sounds and light. PMID- 26981301 TI - Use of Aripiprazole Long Acting Injection in Negative Symptoms of Schizophrenia. AB - Background. Evidence for the efficacious use of second-generation antipsychotics for the treatment of negative symptoms in schizophrenia is scant. Case Presentation. We report the case of a 34-year-old female of Afro-Caribbean origin, who presented with prominent negative symptoms of schizophrenia and was successfully treated with aripiprazole long acting injection. Within a period of six to nine months, the patient returned to her premorbid level of functioning. Conclusion. Aripiprazole long acting injection promises benefits in the treatment of negative symptoms of schizophrenia. Further research needs to be conducted on the use of this drug. PMID- 26981302 TI - Giant Cell Tumor within the Proximal Tibia after ACL Reconstruction. AB - 26-year-old female with prior anterior cruciate ligament reconstruction developed an enlarging lytic bone lesion around the tibial screw with sequential imaging over the course of one year demonstrating progression of this finding, which was confirmed histologically to be a giant cell tumor of bone. The lesion originated around the postoperative bed, making the diagnosis challenging during the early course of the presentation. The case demonstrates giant cell tumor which originated in the metaphysis and subsequently grew to involve the epiphysis; therefore, early course of the disease not involving the epiphysis should not exclude this diagnosis. PMID- 26981303 TI - Segmental Testicular Infarction, an Underdiagnosed Entity: Case Report with Histopathologic Correlation and Review of the Diagnostic Features. AB - A 30-year-old male presented with a 1-day history of left scrotal pain and a tender left testicle and epididymis on physical exam. Scrotal ultrasound showed an avascular, heterogeneous, hypoechoic lesion in the superior left testis suggestive of infarction or neoplasm. The patient was managed conservatively; however, his pain continued and follow-up ultrasound 6 days later showed interval increase in the size of the mass. Left radical orchiectomy was done and pathology result showed segmental infarction of the left testis. PMID- 26981304 TI - Atypical Cutaneous Manifestations in Adult Onset Still's Disease. AB - Adult Onset Still's Disease (AOSD), an adult variant of systemic onset juvenile idiopathic arthritis, is a rare systemic inflammatory disorder of unknown aetiology. The rarity of this disease is associated with low index of suspicion and delayed diagnosis in patients suffering from it and in the presence of atypical features the diagnosis can be further challenging. This is a case report on a 24-year-old woman, who was a diagnostic dilemma for 2 years due to the nonspecific symptoms of recurrent fever, generalized maculopapular persistent pruritic and tender rash, and polyarthralgia. She was initially diagnosed as leukocytoclastic vasculitis on a skin biopsy and was managed by a dermatologist with various medications including NSAIDs, hydroxychloroquine, dapsone, colchicine, cyclosporine, and high doses of oral steroids with minimal response. Subsequently, she has had multiple admissions with similar symptoms with raised inflammatory markers and negative septic workup. On one occasion, her iron study revealed hyperferritinaemia which led to the suspicion of AOSD. Once the rheumatic fever and infectious, malignant, autoimmune, and lymphoproliferative disorders were excluded, she was diagnosed as probable AOSD and managed successfully with IL-1 (interleukin-1) receptor antagonist, Anakinra, with remarkable and lasting response both clinically and biochemically. PMID- 26981305 TI - An Unusual Case of Systemic Lupus Erythematosus and Hemophagocytic Syndrome. AB - Hemophagocytic syndrome (HS) or hemophagocytic lymphohistiocytosis (HLH) is an immune mediated phenomenon that can occur in the setting of an autoimmune disease, chronic immunosuppression, malignancy, or infection. It has been more commonly described in the pediatric population and less commonly in adults. We describe a case of a 52-year-old male who presented with a rash. He simultaneously met the Systemic Lupus International Collaborating Clinics (SLICC) criteria for the diagnosis of systemic lupus erythematosus (SLE) and the diagnostic criteria of HS as described in the hemophagocytic lymphohistiocytosis (HLH) 2004 trial. The bone marrow on autopsy showed the presence of abundant hemosiderophages with focal hemophagocytosis. SLE-associated HS might be underdiagnosed due to the overlap in clinical findings. This case represents the importance of prompt diagnosis and treatment of such a potentially fatal clinical syndrome. PMID- 26981306 TI - Glucagonoma and Glucagonoma Syndrome: A Case Report with Review of Recent Advances in Management. AB - The rarity of glucagonoma imposes a challenge with most patients being diagnosed after a long period of treatment for their skin rash (months-years). Awareness of physicians and dermatologists of the characteristic necrolytic migratory erythema often leads to early diagnosis. Early diagnosis of glucagonoma even in the presence of resectable liver metastases may allow curative resection. Herein, we present a typical case of glucagonoma treated at our center and review the literature pertinent to its management. PMID- 26981307 TI - Coexisting Situs Inversus Totalis and Immune Thrombocytopenic Purpura. AB - Situs inversus totalis is a rare congenital abnormality with mirror symmetry of mediastinal and abdominal organs. Immune thrombocytopenic purpura is an autoimmune disease with destruction of thrombocytes. This paper is presentation of surgical approach to a case with coexistence of these two conditions. PMID- 26981308 TI - Mechanisms and Clinical Management of Ventricular Arrhythmias following Blunt Chest Trauma. AB - Nonpenetrating, blunt chest trauma is a serious medical condition with varied clinical presentations and implications. This can be the result of a dense projectile during competitive and recreational sports but may also include other etiologies such as motor vehicle accidents or traumatic falls. In this setting, the manifestation of ventricular arrhythmias has been observed both acutely and chronically. This is based on two entirely separate mechanisms and etiologies requiring different treatments. Ventricular fibrillation can occur immediately after chest wall injury (commotio cordis) and requires rapid defibrillation. Monomorphic ventricular tachycardia can develop in the chronic stage due to underlying structural heart disease long after blunt chest injury. The associated arrhythmogenic tissue may be complex and provides the necessary substrate to form a reentrant VT circuit. Ventricular tachycardia in the absence of overt structural heart disease appears to be focal in nature with rapid termination during ablation. Regardless of the VT mechanism, patients with recurrent episodes, despite antiarrhythmic medication in the chronic stage following blunt chest injury, are likely to require ablation to achieve VT control. This review article will describe the mechanisms, pathophysiology, and treatment of ventricular arrhythmias that occur in both the acute and chronic stages following blunt chest trauma. PMID- 26981309 TI - The Role of Adenosine in Pulmonary Vein Isolation: A Critical Review. AB - The cornerstone of atrial fibrillation (AF) ablation is pulmonary vein isolation (PVI), which can be achieved in more than 95% of patients at the end of the procedure. However, AF recurrence rates remain high and are related to recovery of PV conduction. Adenosine testing is used to unmask dormant pulmonary vein conduction (DC). The aim of this study is to review the available literature addressing the role of adenosine testing and determine the impact of ablation at sites of PV reconnection on freedom from AF. Adenosine infusion, by restoring the excitability threshold, unmasks reversible injury that could lead to recovery of PV conduction. The studies included in this review suggest that adenosine is useful to unmask nontransmural lesions at risk of reconnection and that further ablation at sites of DC is associated with improvement in freedom from AF. Nevertheless it has been demonstrated that adenosine is not able to predict all veins at risk of later reconnection, which means that veins without DC are not necessarily at low risk. The role of the waiting period in the setting of adenosine testing has also been analyzed, suggesting that in the acute phase adenosine use should be accompanied by enough waiting time. PMID- 26981311 TI - Association of Alanine Aminotransferase and Periodontitis: A Cross-Sectional Analysis-NHANES 2009-2012. AB - Objective. Alanine Aminotransferase is an enzyme associated with not only liver diseases, liver conditions, and metabolic syndrome, but also inflammation. Periodontitis is associated with increased cytokines and other markers of inflammation. The purpose of this study is to determine if an independent association between Alanine Aminotransferase and periodontitis exists. Methods. Data from the 2009-2010 and 2011-2012 National Health and Nutrition Surveys (NHANES) were combined. Data concerning periodontitis and Alanine Aminotransferase were extracted and analyzed with Rao Scott Chi-square and logistic regressions. Serum Alanine Aminotransferase was dichotomized at 40 units/liter, and periodontitis was dichotomized to the presence or absence of periodontitis. Results. In bivariate Chi-square analyses, periodontitis and Alanine Aminotransferase were associated (p = 0.0360) and remained significant in unadjusted logistic regression (OR = 1.30 [95% CI: 1.02, 1.65]). However, when other known risk factors of periodontitis were included in the analyses, the relationship attenuated and failed to reach significance (adjusted OR = 1.17 [95% CI: 0.85, 1.60]). Conclusion. Our study adds to the literature a positive but attenuated association of serum Alanine Aminotransferase with periodontitis which failed to reach significance when other known, strong risk factors of periodontitis were included in the analysis. PMID- 26981312 TI - Rotigotine Objectively Improves Sleep in Parkinson's Disease: An Open-Label Pilot Study with Actigraphic Recording. AB - Sleep disturbances represent important predictors of poor quality of life (QoL) in Parkinson's disease (PD). This open-label pilot study aimed to objectively assess, by means of actigraphic recording, effect of rotigotine on sleep in PD patients with self-reported sleep complaints. 15 PD patients underwent one-week actigraphic recording before (T0) and during (T1) rotigotine treatment, which was titrated to the dose subjectively improving motor symptoms (4-8 mg/24 h). Sleep disturbances, daytime sleepiness, cognitive performance, QoL, and depression were also evaluated with questionnaires. Actigraphic recordings showed a significant reduction in nocturnal motor activity and mean duration of wake episodes after sleep onset during rotigotine treatment compared to baseline. In 10 patients presenting objective evidence of poor sleep quality at T0 (sleep efficiency <= 85%), rotigotine also significantly improved other sleep parameters and further reduced nocturnal motor activity and mean duration of wake episodes. A significant decrease in number and duration of daytime sleep episodes was also observed at T1. Finally we confirmed that rotigotine significantly improves perceived sleep quality and QoL. Our study showed for the first time that rotigotine is associated with an objective improvement of nocturnal and diurnal sleep disturbances in PD patients with self-reported sleep complaints. This study is registered with AIFA-observational study registry number 12021. PMID- 26981310 TI - Cellular and Molecular Mechanisms of Arrhythmia by Oxidative Stress. AB - Current therapies for arrhythmia using ion channel blockade, catheter ablation, or an implantable cardioverter defibrillator have limitations, and it is important to search for new antiarrhythmic therapeutic targets. Both atrial fibrillation and heart failure, a condition with increased arrhythmic risk, are associated with excess amount of reactive oxygen species (ROS). There are several possible ways for ROS to induce arrhythmia. ROS can cause focal activity and reentry. ROS alter multiple cardiac ionic currents. ROS promote cardiac fibrosis and impair gap junction function, resulting in reduced myocyte coupling and facilitation of reentry. In order to design effective antioxidant drugs for treatment of arrhythmia, it is essential to explore the molecular mechanisms by which ROS exert these arrhythmic effects. Activation of Ca(2+)/CaM-dependent kinase II, c-Src tyrosine kinase, protein kinase C, and abnormal splicing of cardiac sodium channels are among the recently discovered molecular mechanisms of ROS-induced arrhythmia. PMID- 26981314 TI - Light and Electron Microscopic Studies on Prenatal Differentiation of Exocrine Pancreas in Buffalo. AB - The study was conducted on pancreas of 24 buffalo fetuses collected from abattoir and Veterinary clinics, GADVASU, Ludhiana. The buffalo fetuses were divided into three groups after measuring their CVRL, namely, group I (CVRL between 0 and 20 cm), group II (CVRL above 20 cm and up to 40 cm), and group III (CVRL above 40 cm) and their approximate age was calculated. The tissues were processed for light and ultrastructural studies. In group I, at 1.2 cm CVRL (34 days), the pancreas comprised tubules and solid nest of undifferentiated epithelial cells. At 7.5 cm CVRL (63 days) acinar cells with zymogen granules were observed. These acinar cells varied in shape from columnar to pyramidal. At 12.8 cm CVRL (86 days), parenchyma began to organize into lobes and lobules. The centroacinar cells were observed at 12.8 cm CVRL (86 days). In group II, at 28.3 cm CVRL (137 days), there was extensive branching of tubules that resulted in highly branched ductal tree connecting exocrine secretary units to the duct system. The interlobular and intralobular ducts were well observed at this age yet the intercalated ducts were not completely developed. In group III, exocrine pancreas showed a massive growth at 48 cm CVRL (182 days) with distinct pancreatic lobes and lobules. At 54 cm CVRL (195 days), well developed pancreatic architecture was seen with the presence of extensive development of exocrine part organized in lobes and lobules with interlobular and intralobular ducts whereas the intercalated ducts were observed in 80 cm CVRL (254 days). PMID- 26981313 TI - Comparative mRNA Expression of eEF1A Isoforms and a PI3K/Akt/mTOR Pathway in a Cellular Model of Parkinson's Disease. AB - The PI3K/Akt/mTOR pathway is one of dysregulated pathways in Parkinson's disease (PD). Previous studies in nonneuronal cells showed that Akt regulation can be increased by eukaryotic protein elongation factor 1 alpha 2 (eEF1A2). eEF1A2 is proposed to contribute protection against apoptotic death, likely through activation of the PI3K/Akt pathway. Whether eEF1A2 plays a role in the prevention of cell death in PD has not been investigated. Recently, gene profiling on dopaminergic neurons from postmortem PD patients showed both upregulation and downregulation of some PI3K and mTOR genes. In this paper, the expression of all gene members of the PI3K/Akt/mTOR pathway in relation to those of the eEF1A isoforms in a cellular model of PD was investigated at the mRNA level. The results showed a similar trend of upregulation of genes of the eEF1A isoforms (eEF1A1 and eEF1A2) and of the PI3K (classes I-III)/Akt (Akt1, Akt2, and Akt3)/mTOR (mTORC1 and mTORC2) pathway in both nondifferentiated and differentiated SH-SY5Y dopaminergic cells treated with 1-methyl-4 phenylpyridinium (MPP(+)). Upregulation of eEF1A2, Akt1, and mTORC1 was consistent with the relative increase of eEF1A2, Akt, phospho-Akt, and mTORC1 proteins. The possible role of eEF1A isoforms in the regulation of the PI3K/Akt/mTOR pathway in PD is discussed. PMID- 26981315 TI - Prevalence of Neoplastic Diseases in Pet Birds Referred for Surgical Procedures. AB - Neoplastic disease is common in pet birds, particularly in psittacines, and treatment should be primarily aimed at tumor eradication. Nineteen cases of pet birds submitted to diagnostic and/or therapeutic surgical procedures due to neoplastic disease characterized by the presence of visible masses were retrospectively analyzed; affected species, types of neoplasms and respective locations, and outcomes of surgical procedures were determined. All birds undergoing surgery belonged to the order Psittaciformes; the Blue-fronted parrot (Amazona aestiva) was the prevalent species. Lipoma was the most frequent neoplasm in the sample studied. Most neoplasms affected the integumentary system, particularly the pericloacal area. Tumor resection was the most common surgical procedure performed, with high resolution and low recurrence rates. PMID- 26981316 TI - A Homemade Snare: An Alternative Method for Mechanical Removal of Dirofilaria immitis in Dogs. AB - Canine dirofilariosis is a life-threatening parasitic disease that is increasingly reported worldwide. Once diagnosed the main treatment goals are to improve the animal's clinical condition and to eliminate all life stages of the parasite with minimal posttreatment side effects. This can be achieved through mechanical, surgical, or chemotherapeutical approaches. Currently, manual extraction is the preferred method to remove adult heartworms due to its diminished invasiveness, reduced damage to the vascular endothelium, and shortened anaesthesia duration. However, it remains an expensive technique that can be highly traumatic. To address this issue, a nontraumatic homemade catheter guided snare was developed for heartworm removal by adapting and folding a 0.014 inch coronary wire (BMW, Abbott Vascular). Transvenous heartworm extraction was performed on a dog severely infected with adult heartworms by inserting the modified snare into a 6-F Judkins right coronary guiding catheter BMW (Cordis) and advancing it into the right ventricle under fluoroscopic guidance. Fifteen adult specimens of Dirofilaria immitis were successfully extracted from the pulmonary artery and right ventricle without complications. To assure the death of both larvae and adults, postoperative treatment was successfully managed using ivermectin, doxycycline, and melarsomine, with no recurrence after surgery. PMID- 26981317 TI - The New TLC Method for Separation and Determination of Multicomponent Mixtures of Plant Extracts. AB - The new mode of two-dimensional gradient thin layer chromatography (MGD-2D TLC) has been presented. Short distance development of sample in the first dimension leads to formation of the preconcentrated narrow zones. They are consecutively separated in the second dimension with the mobile phase gradient in several steps of development until the eluent reaches the further end of the chromatographic plate. The use of the above-mentioned technique allows isolating and then identifying the compounds of various polarity from the multicomponent mixture. The practical application of two-dimensional gradient thin layer chromatography has been performed for isolation of the two plant (Juniperus and Thymus) oils components as the examples of test mixtures. The experiments have been carried out with the use of silica gel plates as well as a normal phase condition. The results of solute separation with isocratic one-dimensional thin layer chromatography system have been compared with those of two-dimensional gradient system. It has been observed that application of the latter mode leads to almost triplicated number of zones in comparison with the former one. It is purposeful to apply the proposed mode to control the purity of the dominant component or components of the mixture. PMID- 26981318 TI - Pharmacy Students' Knowledge Assessment of Naegleria fowleri Infection. AB - A cross-sectional study was conducted from April to August 2015 to assess the knowledge of pharmacy students towards Naegleria fowleri infection. A questionnaire was distributed to senior pharmacy students in different private and public sector universities of Karachi. Descriptive statistics were used to demonstrate students' demographic information and their responses to the questionnaire. Pearson chi-square test was adopted to assess the relationship between independent variables and responses of students. The study revealed that pharmacy students were having adequate awareness of Naegleria fowleri infection and considered it as a serious health issue that necessitates instantaneous steps by the government to prevent the general public from the fatal neurological infection. The students recommended that appropriate methods should be projected in the community from time to time that increases public awareness about the associated risk factors. PMID- 26981319 TI - Cellulose Acetate 398-10 Asymmetric Membrane Capsules for Osmotically Regulated Delivery of Acyclovir. AB - The study was aimed at developing cellulose acetate asymmetric membrane capsules (AMCs) of acyclovir for its controlled delivery at the absorption site. The AMCs were prepared by phase inversion technique using wet process. A 2(3) full factorial design assessed the effect of independent variables (level(s) of polymer, pore former, and osmogen) on the cumulative drug release from AMCs. The buoyant optimized formulation F7 (low level of cellulose acetate; high levels of both glycerol and sodium lauryl sulphate) displayed maximum drug release of 97.88 +/- 0.77% in 8 h that was independent of variation in agitational intensity and intentional defect on the cellulose acetate AMC. The in vitro data best fitted zero-order kinetics (r (2) = 0.9898). SEM micrograph of the transverse section confirmed the asymmetric nature of the cellulose acetate capsular membrane. Statistical analysis by Design Expert software indicated no interaction between the independent variables confirming the efficiency of the design in estimating the effects of variables on drug release. The optimized formulation F7 (desirability = 0.871) displayed sustenance of drug release over the drug packed in AMC in pure state proving the superiority of osmotically active formulation. Conclusively the AMCs have potential for controlled release of acyclovir at its absorption site. PMID- 26981321 TI - Frontal lobe signs after posterior fossa surgery: Is hypoperfusion ignored? PMID- 26981322 TI - A rare intracranial tumor consisting of malignant anaplastic and papillary meningioma subtypes. AB - BACKGROUND: Intracranial tumors with heterogeneous histopathology are a well described pathologic entity. Pathologically, distinct tumors in direct contact with one another, also known as collision tumors are exceptionally rare, and collision between meningioma subtypes has not been previously described in the literature. CASE DESCRIPTION: A 79-year-old female with a history of breast carcinoma presenting with visual and motor deficits and imaging/intraoperative findings consistent with separate, distinct lesions. Histopathologic findings provided evidence for a collision between World Health Organization Grade III anaplastic and papillary meningioma. CONCLUSION: We report a possible collision tumor between two separate meningioma subtypes based on the unique radiologic, intraoperative, and histopathologic findings. Submission of multiple pathologic specimens during surgical resection is key for accurate histopathologic diagnosis. PMID- 26981320 TI - According to which factors in severe traumatic brain injury craniectomy could be beneficial. AB - BACKGROUND: To investigate the clinical outcome at 101 patients undergoing decompressive craniectomy (DC) after severe traumatic brain injury (TBI). METHODS: Age, Glasgow Coma Scale (GCS) at the time of intubation, and the intraoperative intracranial pressure (ICP) were recorded. Formal DC was performed in all cases and the square surface of bone flap was calculated in cm(2) based on the length and the width from computed tomography scan. RESULTS: The difference of good neurological recovery (Glasgow outcome score 4-5), between patients with ICP <=20 mmHg, GCS >=5, age <=60 years, and bone flap >=130 cm(2) and those with ICP >20 mmHg, GCS <5, age >60 years, and bone flap <130 cm(2), was statistically significant. CONCLUSION: Although the application of DC in severe TBI is controversial and the population in this study is small, our study demonstrates the threshold of the specific factors (patient age, ICP and GCS on the day of the surgery and the size of the bone flap) which may help in the decision of performing DC. Furthermore, this study proves that the different combinations and mainly at the same time involvement of all prognostic parameters (age <60, GCS <5, bone flap >=130 cm(2), and ICP <=20 at time of DC surgery) allow a better outcome. PMID- 26981323 TI - The new era of anticoagulation. PMID- 26981324 TI - Role of computed tomography scores and findings to predict early death in patients with traumatic brain injury: A reappraisal in a major tertiary care hospital in Nepal. AB - BACKGROUND: Glasgow Coma Scale has been a long sought model to classify patients with head injury. However, the major limitation of the score is its assessment in the patients who are either sedated or under the influence of drugs or intubated for airway protection. The rational approach for prognostication of such patients is the utility of scoring system based on the morphological criteria based on radiological imaging. Among the current armamentarium, a scoring system based on computed tomography (CT) imaging holds the greatest promise in conquering our conquest for the same. METHODS: We included a total of 634 consecutive neurosurgical trauma patients in this series, who presented with mild-to-severe traumatic brain injury (TBI) from January 2013 to April 2014 at a tertiary care center in rural Nepal. All pertinent medical records (including all available imaging studies) were reviewed by the neurosurgical consultant and the radiologist on call. Patients' worst CT image scores and their outcome at 30 days were assessed and recorded. We then assessed their independent performance in predicting the mortality and also tried to seek the individual variables that had significant interplay for determining the same. RESULTS: Both imaging score (Marshall) and clinical score (Rotterdam) can be used to reliably predict mortality in patients with acute TBI with high prognostic accuracy. Other specific CT characteristics that can be used to predict early mortality are traumatic subarachnoid hemorrhage, midline shift, and status of the peri mesencephalic cisterns. CONCLUSION: We demonstrated in this cohort that though the Marshall score has the high predictive power to determine the mortality, better discrimination could be sought through the application of the Rotterdam score that encompasses various individual CT parameters. We thereby recommend the use of such comprehensive prognostic model so as to augment our predictive power for properly dichotomizing the prognosis of the patients with TBI. In the future, it will therefore be important to develop prognostic models that are applicable for the majority of patients in the world they live in, and not just a privileged few who can use resources not necessarily representative of their societal environment. PMID- 26981325 TI - Characteristics of an Effective International Humanitarian Assistance: A Systematic Review. AB - INTRODUCTION: The objective of this study is to identify the effectiveness characteristics, review the definition of them, and develop a conceptual mapping of existing domains in the field of International Humanitarian Assistance (IHA). METHODS: We conducted a systematic review and searched the major databases (Science Direct, Scopus, Springer and Pubmed) and grey literature, including references of potentially eligible articles and conference proceedings through March 2015. Articles were included if they focused on IHA effectiveness. Reviewers independently identified the eligible studies and extracted data. RESULTS: 10 studies were included and 48 characteristics were identified. There is a lack of scientific studies and agreement on the characteristics of IHA effectiveness. CONCLUSION: This study could be the step toward an understanding of IHA effectiveness characteristics and its definitions with the findings making a base line for more research in this area. PMID- 26981326 TI - Assessing Households Preparedness for Earthquakes: An Exploratory Study in the Development of a Valid and Reliable Persian-version Tool. AB - INTRODUCTION: Iran is placed among countries suffering from the highest number of earthquake casualties. Household preparedness, as one component of risk reduction efforts, is often supported in quake-prone areas. In Iran, lack of a valid and reliable household preparedness tool was reported by previous disaster studies. This study is aimed to fill this gap by developing a valid and reliable tool for assessing household preparedness in the event of an earthquake. METHODS: This survey was conducted through three phases including literature review and focus group discussions with the participation of eight key informants, validity measurements and reliability measurements. Field investigation was completed with the participation of 450 households within three provinces of Iran. Content validity, construct validity, the use of factor analysis; internal consistency using Cronbach's alpha coefficient, and test-retest reliability were carried out to develop the tool. RESULTS: Based on the CVIs, ranging from 0.80 to 0.100, and exploratory factor analysis with factor loading of more than 0.5, all items were valid. The amount of Cronbach's alpha (0.7) and test-retest examination by Spearman correlations indicated that the scale was also reliable. The final instrument consisted of six categories and 18 questions including actions at the time of earthquakes, nonstructural safety, structural safety, hazard map, communications, drill, and safety skills. CONCLUSION: Using a Persian-version tool that is adjusted to the socio-cultural determinants and native language may result in more trustful information on earthquake preparedness. It is suggested that disaster managers and researchers apply this tool in their future household preparedness projects. Further research is needed to make effective policies and plans for transforming preparedness knowledge into behavior. PMID- 26981327 TI - Rapid and Near Real-Time Assessments of Population Displacement Using Mobile Phone Data Following Disasters: The 2015 Nepal Earthquake. AB - INTRODUCTION: Sudden impact disasters often result in the displacement of large numbers of people. These movements can occur prior to events, due to early warning messages, or take place post-event due to damages to shelters and livelihoods as well as a result of long-term reconstruction efforts. Displaced populations are especially vulnerable and often in need of support. However, timely and accurate data on the numbers and destinations of displaced populations are extremely challenging to collect across temporal and spatial scales, especially in the aftermath of disasters. Mobile phone call detail records were shown to be a valid data source for estimates of population movements after the 2010 Haiti earthquake, but their potential to provide near real-time ongoing measurements of population displacements immediately after a natural disaster has not been demonstrated. METHODS: A computational architecture and analytical capacity were rapidly deployed within nine days of the Nepal earthquake of 25th April 2015, to provide spatiotemporally detailed estimates of population displacements from call detail records based on movements of 12 million de identified mobile phones users. RESULTS: Analysis shows the evolution of population mobility patterns after the earthquake and the patterns of return to affected areas, at a high level of detail. Particularly notable is the movement of an estimated 390,000 people above normal from the Kathmandu valley after the earthquake, with most people moving to surrounding areas and the highly-populated areas in the central southern area of Nepal. DISCUSSION: This analysis provides an unprecedented level of information about human movement after a natural disaster, provided within a very short timeframe after the earthquake occurred. The patterns revealed using this method are almost impossible to find through other methods, and are of great interest to humanitarian agencies. PMID- 26981328 TI - Correlating Photoreceptor Mosaic Structure to Clinical Findings in Stargardt Disease. AB - PURPOSE: To demonstrate a method for correlating photoreceptor mosaic structure with optical coherence tomography (OCT) and microperimetry findings in patients with Stargardt disease. METHODS: A total of 14 patients with clinically diagnosed Stargardt disease were imaged using confocal and split-detection adaptive optics scanning light ophthalmoscopy. Cone photoreceptors were identified manually in a band along the temporal meridian. Resulting values were compared to a normative database (n = 9) to generate cone density deviation (CDD) maps. Manual measurement of outer nuclear layer plus Henle fiber layer (ONL+HFL) thickness was performed, in addition to determination of the presence of ellipsoid zone (EZ) and interdigitation zone (IZ) bands on OCT. These results, along with microperimetry data, were overlaid with the CDD maps. RESULTS: Wide variation in foveal structure and CDD maps was seen within this small group. Disruption of ONL+HFL and/or IZ band was seen in all patients, with EZ band preservation in regions with low cone density in 38% of locations analyzed. Normality of retinal lamellar structure on OCT corresponded with cone density and visual function at 50/78 locations analyzed. Outer retinal tubulations containing photoreceptor-like structures were observed in 3 patients. CONCLUSIONS: The use of CDD color-coded maps enables direct comparison of cone mosaic local density with other measures of retinal structure and function. Larger normative datasets and improved tools for automation of image alignment are needed. TRANSLATIONAL RELEVANCE: The approach described facilitates comparison of complex multimodal data sets from patients with inherited retinal degeneration, and can be expanded to incorporate other structural imaging or functional testing. PMID- 26981329 TI - Incorporating Spatial Models in Visual Field Test Procedures. AB - PURPOSE: To introduce a perimetric algorithm (Spatially Weighted Likelihoods in Zippy Estimation by Sequential Testing [ZEST] [SWeLZ]) that uses spatial information on every presentation to alter visual field (VF) estimates, to reduce test times without affecting output precision and accuracy. METHODS: SWeLZ is a maximum likelihood Bayesian procedure, which updates probability mass functions at VF locations using a spatial model. Spatial models were created from empirical data, computational models, nearest neighbor, random relationships, and interconnecting all locations. SWeLZ was compared to an implementation of the ZEST algorithm for perimetry using computer simulations on 163 glaucomatous and 233 normal VFs (Humphrey Field Analyzer 24-2). Output measures included number of presentations and visual sensitivity estimates. RESULTS: There was no significant difference in accuracy or precision of SWeLZ for the different spatial models relative to ZEST, either when collated across whole fields or when split by input sensitivity. Inspection of VF maps showed that SWeLZ was able to detect localized VF loss. SWeLZ was faster than ZEST for normal VFs: median number of presentations reduced by 20% to 38%. The number of presentations was equivalent for SWeLZ and ZEST when simulated on glaucomatous VFs. CONCLUSIONS: SWeLZ has the potential to reduce VF test times in people with normal VFs, without detriment to output precision and accuracy in glaucomatous VFs. TRANSLATIONAL RELEVANCE: SWeLZ is a novel perimetric algorithm. Simulations show that SWeLZ can reduce the number of test presentations for people with normal VFs. Since many patients have normal fields, this has the potential for significant time savings in clinical settings. PMID- 26981330 TI - Objective Evaluation of Vergence Disorders and a Research-Based Novel Method for Vergence Rehabilitation. AB - PURPOSE: We performed video-oculography to evaluate vergence eye movement abnormalities in students diagnosed clinically with vergence disorders. We tested the efficiency of a novel rehabilitation method and evaluated its benefits with video-oculography cross-correlated with clinical tests and symptomatology. METHODS: A total of 19 students (20-27 years old) underwent ophthalmologic, orthoptic examination, and a vergence test coupled with video-oculography. Eight patients were diagnosed with vergence disorders with a high symptomatology score (CISS) and performed a 5-week session of vergence rehabilitation. Vergence and rehabilitation tasks were performed with a trapezoid surface of light emitting diodes (LEDs) and adjacent buzzers (US 8851669). We used a novel Vergence double step (Vd-s) protocol: the target stepped to a second position before the vergence movement completion. Afterward the vergence test was repeated 1 week and 1 month later. RESULTS: Abnormally increased intertrial variability was observed for many vergence parameters (gain, duration, and speed) for the subjects with vergence disorders. High CISS scores were correlated with variability and increased latency. After the Vd-s, variability of all parameters dropped to normal or better levels. Moreover, the convergence and divergence latency diminished significantly to levels better than normal; benefits were maintained 1 month after completion of Vd-s. CISS scores dropped to normal level, which was maintained up to 1 year. CONCLUSIONS AND TRANSLATIONAL RELEVANCE: Intertrial variability is the major marker of vergence disorders. The Vd-s research-based method leads to normalization of vergence properties and lasting removal of symptoms. The efficiency of the method is due to the spatiotemporal parameters of repetitive trials that stimulate neural plasticity. PMID- 26981331 TI - VEGF: From Discovery to Therapy: The Champalimaud Award Lecture. AB - PURPOSE: Intraocular vascular diseases are leading causes of adult vision loss, and in the mid-1900s, I. C. Michaelson postulated that the retina releases a soluble, diffusible factor that causes abnormal vascular growth and leakage. What became known as "Factor X" eluded investigators for decades. METHODS: The field of cancer research, where Judah Folkman pioneered the concept of angiogenesis, provided the inspiration for the work honored by the 2014 Champalimaud Vision Award. Recognizing that tumors recruit their own blood supply to achieve critical mass, Dr Folkman proposed that angiogenic factors could be therapeutic targets in cancer. Napoleone Ferrara identified vascular endothelial growth factor (VEGF) as such an angiogenic agent: stimulated by hypoxic tumor tissue, secreted, and able to induce neovascularization. VEGF also was a candidate for Factor X, and the 2014 Champalimaud Laureates and colleagues worked individually and collaboratively to identify the role of VEGF in ocular disease. RESULTS: The Champalimaud Laureates correlated VEGF with ocular neovascularization in animal models and in patients. Moreover, they showed that VEGF not only was sufficient, but it also was required to induce neovascularization in normal animal eyes, as VEGF inhibition abolished ocular neovascularization in key animal models. CONCLUSIONS: The identification of VEGF as Factor X altered the therapeutic paradigms for age-related macular degeneration (AMD), diabetic retinopathy, retinal vein occlusion, and other retinal disorders. TRANSLATIONAL RELEVANCE: The translation of VEGF from discovery to therapy resulted in the most successful applications of antiangiogenic therapy to date. Annually, over one million patients with eye disease are treated with anti-VEGF agents. PMID- 26981332 TI - VEGF and Intraocular Neovascularization: From Discovery to Therapy. AB - I am honored and humbled to be one of the awardees of the 2014 A. Champalimaud Vision Award. I offer my heartfelt thanks to the Champalimaud Foundation President, Leonor Beleza, and to the Award Committee Members for this wonderful recognition. I feel especially fortunate to have had the opportunity to witness my scientific discoveries move from the bench to the clinic. Scientific discovery is hugely exciting, but the ability to translate that work into potentially helping someone lead a better life is even more fulfilling. This Award is dedicated to the patients. PMID- 26981333 TI - A Drug Delivery System for Administration of Anti-TNF-alpha Antibody. AB - PURPOSE: To describe the fabrication, evaluation, and preliminary in vivo safety of a new drug delivery system (DDS) for topical anti-TNF-alpha antibody administration. METHODS: A DDS was fabricated using inverse template fabrication of a hydrophobic three-dimensional porous scaffold (100-300 MUm in diameter porosity) loaded with 10% polyvinyl alcohol hydrogel carrying 5 mg/ml (weight/volume) of anti-TNF-alpha antibody. Drug-loaded DDS was sterilized with 25 kGy of gamma irradiation. Long-term in vitro antibody affinity and release was evaluated at room temperature or 37 degrees C using enzyme-linked immunosorbent assay (ELISA) and protein fluorescence. In vivo clinical and histolopathological assessment was performed by subcutaneous implantation in BALB/c mice for 3 months. RESULTS: Gamma irradiation, repeated dry/wet cycles, and storage at room temperature for 1 year or 37 degrees C for 1 month had no deleterious effects on antibody affinity. Anti-TNF-alpha release was high during the first minutes of aqueous exposure, followed by stabilization and gradual, low-dose, antibody release over the next 30 days. Histopathologic evaluation of explanted DDS showed a fibrous pseudocapsule and a myxoid acute/chronic inflammation without granuloma formation surrounding the implants. CONCLUSIONS: Sustained local delivery of anti TNF-alpha antibody is feasible using the described DDS, which provides stability of the enclosed antibody for up to 1 year of storage. Preliminary results show good in vivo tolerance following subcutaneous placement for 3 months. The proposed fabrication and sterilization process opens new possibilities for the delivery of biologic agents to the anterior surface of the eye. TRANSLATIONAL RELEVANCE: The described DDS will facilitate the treatment of ocular surface diseases amenable to biologic therapy. PMID- 26981334 TI - Hepatoma-Targeted Radionuclide Immune Albumin Nanospheres: (131)I-antiAFPMcAb-GCV BSA-NPs. AB - An effective strategy has been developed for synthesis of radionuclide immune albumin nanospheres ((131)I-antiAFPMcAb-GCV-BSA-NPs). In vitro as well as in vivo targeting of (131)I-antiAFPMcAb-GCV-BSA-NPs to AFP-positive hepatoma was examined. In cultured HepG2 cells, the uptake and retention rates of (131)I antiAFPMcAb-GCV-BSA-NPs were remarkably higher than those of (131)I alone. As well, the uptake rate and retention ratios of (131)I-antiAFPMcAb-GCV-BSA-NPs in AFP-positive HepG2 cells were also significantly higher than those in AFP negative HEK293 cells. Compared to (131)I alone, (131)I-antiAFPMcAb-GCV-BSA-NPs were much more easily taken in and retained by hepatoma tissue, with a much higher T/NT. Due to good drug-loading, high encapsulation ratio, and highly selective affinity for AFP-positive tumors, the (131)I-antiAFPMcAb-GCV-BSA-NPs are promising for further effective radiation-gene therapy of hepatoma. PMID- 26981335 TI - A Disease Around the Corner. PMID- 26981336 TI - Mediating and Moderating Effects in Ageism and Depression among the Korean Elderly: The Roles of Emotional Reactions and Coping Reponses. AB - OBJECTIVES: This study evaluated the relationship between ageism and depression, exploring the stress-mediating and stress-moderating roles of emotional reactions and coping behaviors. METHODS: Data were from the 2013 Ageism and Health Study (n = 816), a cross-sectional survey of urban and rural community-dwelling seniors aged 60-89 years in South Korea. Participants with at least one experience of ageism reported on their emotional reactions and coping responses. The measure yielded two types of coping: problem-focused (taking formal action, confrontation, seeking social support) and emotion-focused (passive acceptance, emotional discharge). RESULTS: Although ageism was significantly associated with depressive symptoms (B = 0.27, p < 0.0001), the association was entirely mediated by emotional reactions such as anger, sadness, and powerlessness. Problem-focused coping, especially confrontation and social support, seemingly reduced the impact of emotional reactions on depression, whereas emotion-focused coping exacerbated the adverse effects. CONCLUSION: These findings support the cultural characterization explanation of ageism and related coping processes among Korean elderly and suggest that regulating emotional reactions may determine the efficacy of coping with ageism. PMID- 26981337 TI - Effects of Electromagnetic Radiation from Smartphones on Learning Ability and Hippocampal Progenitor Cell Proliferation in Mice. AB - OBJECTIVES: Nonionizing radiation is emitted from electronic devices, such as smartphones. In this study, we intended to elucidate the effect of electromagnetic radiation from smartphones on spatial working memory and progenitor cell proliferation in the hippocampus. METHODS: Both male and female mice were randomly separated into two groups (radiated and control) and the radiated group was exposed to electromagnetic radiation for 9 weeks and 11 weeks for male and female mice, respectively. Spatial working memory was examined with a Y maze, and proliferation of hippocampal progenitor cells were examined by 5 bromo-2'-deoxyuridine administration and immunohistochemical detection. RESULTS: When spatial working memory on a Y maze was examined in the 9(th) week, there was no significant difference in the spontaneous alternation score on the Y maze between the two groups. In addition, there was no significant difference in hippocampal progenitor cell proliferation. However, immunoreactivity to glial fibrillary acidic protein was increased in exposed animals. Next, to test the effect of recovery following chronic radiation exposure, the remaining female mice were further exposed to electromagnetic radiation for 2 more weeks (total 11 weeks), and spontaneous alternation was tested 4 weeks later. In this experiment, although there was no significant difference in the spontaneous alternation scores, the number of arm entry was significantly increased. CONCLUSION: These data indicate that although chronic electromagnetic radiation does not affect spatial working memory and hippocampal progenitor cell proliferation it can mediate astrocyte activation in the hippocampus and delayed hyperactivity-like behavior. PMID- 26981338 TI - Factors associated with health services utilization between the years 2010 and 2012 in Korea: using Andersen's Behavioral model. AB - OBJECTIVES: This study aimed to examine the factors associated with health services utilization using Andersen's behavioral model. METHODS: We collected Korea Health Panel data between the years 2010 and 2012 from the consortium of the National Health Insurance Service and the Korea Institute for Health and Social Affairs, and analyzed the data to determine the outpatients and inpatients of health services utilization. RESULTS: Health services utilization was more significantly explained by predisposing and need factors than enabling factors. The outpatients were examined more specifically; sex, age, and marital status as predisposing factors, and chronic illness as a need factor were the variables that had significant effects on health-services-utilization experience. The inpatients were examined more specifically: sex, age, and marital status in predisposing factors; education level, economic activities, and insurance type in enabling factors; and chronic illness and disability status in need factors were the significant variables having greater effects on health-services-utilization experience. CONCLUSION: This study suggests the practical implications for providing health services for outpatients and inpatients. Moreover, verifying the general characteristics of outpatients and inpatients by focusing on their health services utilization provides the baseline data for establishing health service policies and programs with regard to the recently increasing interest in health services. PMID- 26981339 TI - Are Free Maternity Services Completely Free of Costs? AB - OBJECTIVES: The Government of Nepal revised free maternity health services, "Aama Surakshya Karyakram", beginning at the start of Fiscal Year 2012/13, which specifies the services to be funded, the tariffs for reimbursement, and the system for claiming and reporting on free deliveries each month. This study was designed to investigate the amount of monetary expenditure incurred by families using apparently free maternity services. METHODS: Between August 2014 and December 2014, a hospital-based cross-sectional study was conducted at Manipal Teaching Hospital and Western Regional Hospital. Nepalese women were not involved with family finances and had very little knowledge of income or expenditures. Therefore, face-to-face interviews with 384 postpartum mothers with their husbands or the head of the family household were conducted at the time of discharge by using a pre-tested semi-structural questionnaire. RESULTS: The average monthly family income was 19,272.4 NRs (189.01 US$), the median duration of hospital stay was 4 days (range, 2-19 days), and the median patient expenditure was equivalent to 13% of annual family income. The average total visible cost was 3,887.07 NRs (38.1 US$). When the average total hidden cost of 27,288.5 NRs (267.6 US$) was added, then the average total maternity care expenditure was 31,175.6 NRs (305.76 US$), with an average cost per day of 7,167.5 NRs (70.29 US$). The mean patient expenditure on food and drink, clothes, transport, and medicine was equivalent to 53.07%, 9.8%. 7.3%, and 5.6% of the mean total maternity care expenditure, respectively. The earnings lost by respondent women, husbands, and heads of household were 5,963.7 NRs (58.4 US$), 7,429.3 NRs (72.9 US$), and 6,175.9 NRs (60.6 US$), respectively. CONCLUSION: The free maternity service in Nepal has high out-of-pocket expenditures, and did not represent a system completely free of costs. Therefore, arrangements should be made by hospitals free of cost to provide medicine that is not included as essential during the hospital stay and at discharge time. Similarly, arrangements for liquid, food, and hot water, as well as clothes for mothers and newborns, should be made by the hospital in order to enhance hospital attendance. PMID- 26981340 TI - Drug Resistance Pattern of Mycobacterium tuberculosis Isolates From Patients Referred to TB Reference Laboratory in Ahvaz. AB - OBJECTIVES: Tuberculosis remains one of the top three infectious disease killers. The prevalence of multidrug-resistant tuberculosis (MDR-TB) has increased substantially in the past 20 years. When drug resistance is not detected, MDR-TB patients cannot access life-saving treatment; this puts their communities at risk of ongoing MDR-TB transmission. We aimed to determine the patterns of resistance to antituberculosis drugs among Mycobacterium tuberculosis isolates from Khuzestan province in Iran. METHODS: A total of 850 clinical specimens from patients suspected of active TB were cultured in 2015. Drug susceptibility testing to the first line antiTB drugs for culture positive MTB was performed on Lowenstein-Jensen medium using the proportion method. RESULTS: Of 850 cultured specimens, 272 (32%) were culture positive for mycobacteria. Of 64 MTB isolates that were analyzed by the proportion method, 62 (96.8%) were pan-susceptible and two (3.1%) were MDR. CONCLUSION: An important way to prevent the emergence of MDR and XDR TB, and the principles of full implementation of the strategy is directly observed treatment, short-course (DOTS). The efficient diagnosis and timely treatment of MDR-TB patients can prevent disease transmission, reduce the risk of drug resistance developing, and avoid further lung damage. PMID- 26981341 TI - Impact of Community-Based Approach as Policy Tool: World Health Organization Designated Safe Communities of Korea and Health Action Zones of the United Kingdom. AB - OBJECTIVES: The aim of this study is to ascertain and identify the effectiveness of area-based initiatives as a policy tool mediated by societal and individual factors in the five World Health Organization (WHO)-designated Safe Communities of Korea and the Health Action Zones of the United Kingdom (UK). METHODS: The Korean National Hospital discharge in-depth injury survey from the Korea Centers for Disease Control and Prevention and causes of death statistics by the Statistics Korea were used for all analyses. The trend and changes in injury rate and mortality by external causes were compared among the five WHO-designated Safe Communities in Korea. RESULTS: The injury incident rates decreased at a greater level in the Safe Communities compared with the national average. Similar results were shown for the changes in unintentional injury incident rates. In comparison of changes in mortality rate by external causes between 2005 and 2011, the rate increase in Safe Communities was higher than the national average except for Jeju, where the mortality rate by external causes decreased. CONCLUSION: When the Healthy Action Zones of the UK and the WHO Safe Communities of Korea were examined, the outcomes were interpreted differently among the compared index, regions, and time periods. Therefore, qualitative outcomes, such as bringing the residents' attention to the safety of the communities and promoting participation and coordination of stakeholders, should also be considered as important impacts of the community-based initiatives. PMID- 26981342 TI - Modeling the Spread of Ebola. AB - OBJECTIVES: This study aims to create a mathematical model to better understand the spread of Ebola, the mathematical dynamics of the disease, and preventative behaviors. METHODS: An epidemiological model is created with a system of nonlinear differential equations, and the model examines the disease transmission dynamics with isolation through stability analysis. All parameters are approximated, and results are also exploited by simulations. Sensitivity analysis is used to discuss the effect of intervention strategies. RESULTS: The system has only one equilibrium point, which is the disease-free state (S,L,I,R,D) = (N,0,0,0,0). If traditional burials of Ebola victims are allowed, the possible end state is never stable. Provided that safe burial practices with no traditional rituals are followed, the endemic-free state is stable if the basic reproductive number, R 0, is less than 1. Model behaviors correspond to empirical facts. The model simulation agrees with the data of the Nigeria outbreak in 2004: 12 recoveries, eight deaths, Ebola free in about 3 months, and an R 0 value of about 2.6 initially, which signifies swift spread of the infection. The best way to reduce R 0 is achieving the speedy net effect of intervention strategies. One day's delay in full compliance with building rings around the virus with isolation, close observation, and clear education may double the number of infected cases. CONCLUSION: The model can predict the total number of infected cases, number of deaths, and duration of outbreaks among others. The model can be used to better understand the spread of Ebola, educate about prophylactic behaviors, and develop strategies that alter environment to achieve a disease free state. A future work is to incorporate vaccination in the model when the vaccines are developed and the effects of vaccines are known better. PMID- 26981343 TI - The Characteristics of Middle Eastern Respiratory Syndrome Coronavirus Transmission Dynamics in South Korea. AB - OBJECTIVES: The outbreak of Middle Eastern respiratory syndrome coronavirus (MERS CoV) was one of the major events in South Korea in 2015. In particular, this study pays attention to formulating a mathematical model for MERS transmission dynamics and estimating transmission rates. METHODS: Incidence data of MERS-CoV from the government authority was analyzed for the first aim and a mathematical model was built and analyzed for the second aim of the study. A mathematical model for MERS-CoV transmission dynamics is used to estimate the transmission rates in two periods due to the implementation of intensive interventions. RESULTS: Using the estimates of the transmission rates, the basic reproduction number was estimated in two periods. Due to the superspreader, the basic reproduction number was very large in the first period; however, the basic reproduction number of the second period has reduced significantly after intensive interventions. CONCLUSION: It turned out to be the intensive isolation and quarantine interventions that were the most critical factors that prevented the spread of the MERS outbreak. The results are expected to be useful to devise more efficient intervention strategies in the future. PMID- 26981344 TI - Nurse-Perceived Patient Adverse Events depend on Nursing Workload. AB - OBJECTIVES: The purpose of this study was to investigate the correlation between nursing workload and nurse-perceived patient adverse events. METHODS: A total of 1,816 nurses working in general inpatient units of 23 tertiary general hospitals in South Korea were surveyed, and collected data were analyzed through multilevel logistic regression analysis. RESULTS: Among variables related to nursing workload, the non-nursing task experience had an influence on all four types of patient adverse events. Nurses with non-nursing tasks experienced patient adverse events-falls [odds ratio (OR) = 1.31], nosocomial infections (OR = 1.23), pressure sores (OR = 1.16), and medication errors (OR = 1.23)-more often than occasionally. In addition, when the bed to nurse ratio was higher, nurses experienced cases of pressure sores more often (OR = 1.35). By contrast, nurses who said the nursing workforce is sufficient were less likely than others to experience cases of pressure sores (OR = 0.78). Hospitals with a relatively high proportion of nurses who perceived the nursing workforce to be sufficient showed a low rate of medication error (OR = 0.28). CONCLUSION: The study suggested that the high level of nursing workload in South Korea increases the possibility of patient adverse events. PMID- 26981345 TI - Factors Affecting Korean Registered Nurses' Intention to Implement Smoking Cessation Intervention. AB - OBJECTIVES: Nurses have been identified as an instrumental partner in tobacco reduction. This study aimed to examine factors affecting Korean nurses' intention to implement smoking cessation intervention in Busan, Korea. METHODS: The participants were a total of 215 Korean registered nurses. A self-administered questionnaire evaluated predisposing factors, motivational factors (attitude, social influence, and self-efficacy) and intention to implement smoking cessation intervention. Data were analyzed by t tests, Pearson's correlation, and hierarchical multiple regression. RESULTS: The mean age of the participants was 28.12 +/- 5.72 years. The majority of the participants were staff nurses (85.6%), and 64.2% of the sample had < 5 years of work experience. Significant predictors of intention to implement smoking cessation intervention included perceived barrier of smoking cessation intervention (beta = -0.128, p = 0.023), willingness to receive smoking cessation training (beta = 0.123, p = 0.034), more positive attitude (beta = 0.203, p = 0.002), higher social influence (beta = 0.292, p < 0.001), and higher self-efficacy toward smoking cessation intervention (beta = 0.151, p = 0.021), which explained 45% of the total variance of intention to implement smoking cessation intervention. CONCLUSION: Attitude, social influence, and self-efficacy towards smoking cessation intervention had a significant positive influence in determining the intention to implement smoking cessation intervention. These findings can be used to develop evidence-based smoking cessation training programs for nurses in Korea. The programs should aim for positive attitude, higher social influence, and higher self-efficacy in hospital settings. PMID- 26981346 TI - Comparison of the Epidemiological Aspects of Imported Dengue Cases between Korea and Japan, 2006-2010. AB - To compare the epidemiological characteristics of dengue cases imported by travelers or immigration in both Korea and Japan, we determined dengue incidence and related risk factors. During 2006-2010, 367 and 589 imported dengue cases were reported in Korea and Japan, respectively. In Korea, the presumptive origins for the dengue infections were Southeast Asia (82.6%), Southern Asia (13.9%), Eastern Asia (1.1%), South America (0.3%), Central America (0.3%), Africa (0.3%), and other countries (1.6%). In Japan, the origins of the infections were Southeast Asia (69.8%), Southern Asia (20.0%), Eastern Asia (1.7%), South America (2.5%), Central America (1.2%), Africa (1.2%), Oceania (2.4%), and other countries (1.2%). In both countries, more dengue cases were reported for men than for women (p < 0.01), and those aged 20-30 years accounted for > 60% of the total cases. The frequency of imported cases in summer and autumn (~70% of total cases) was similar in both countries. This study demonstrates that there is a similar pattern of imported dengue cases in Korea and Japan. Therefore, there is a risk of an autochthonous dengue outbreak in Korea, as indicated by the recent outbreak in Japan in 2014. PMID- 26981347 TI - The Escherichia coli transcriptome linked to growth fitness. AB - A series of Escherichia coli strains with varied genomic sequences were subjected to high-density microarray analyses to elucidate the fitness-correlated transcriptomes. Fitness, which is commonly evaluated by the growth rate during the exponential phase, is not only determined by the genome but is also linked to growth conditions, e.g., temperature. We previously reported genetic and environmental contributions to E. coli transcriptomes and evolutionary transcriptome changes in thermal adaptation. Here, we describe experimental details on how to prepare microarray samples that truly represent the growth fitness of the E. coli cells. A step-by-step record of sample preparation procedures that correspond to growing cells and transcriptome data sets that are deposited at the GEO database (GSE33212, GSE52770, GSE61739) are also provided for reference. PMID- 26981348 TI - Transcriptomic analysis of monocytes and macrophages derived from CLL patients which display differing abilities to respond to therapeutic antibody immune complexes. AB - Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. While therapeutic antibodies show clinical activity in CLL patients, resistance inevitably develops resulting in treatment failure. Identifying mechanisms of antibody resistance and methods to reduce resistance would be valuable in managing CLL. Monocyte derived cells (MDCs), also known as nurse like cells (NLCs) in CLL [1], [2], are known to be crucial components of the CLL microenvironment network and following "maturation" in in vitro culture systems are able to provide support for the survival of the malignant B cells from CLL patients. In addition to their protective role, MDCs are key effector cells in mediating responses to therapeutic antibody therapies [3]. We have determined that macrophages from patients with early stable CLL are able to elicit superior cytotoxic response to therapeutic antibodies than macrophages derived from patients with progressive CLL. We have exploited this unique finding to gain insight into antibody resistance. Thus, we have profiled monocytes on day 0 and MDCs on day 7 from antibody sensitive and antibody resistant CLL patients (GEO accession number GEO: GSE71409). We show that there are no significant differences in transcriptomes from the monocytes or MDCs derived from sensitive or resistant patient samples. However, we show that MDCs acquire an M2-like macrophage transcriptomic signature following 7 days culture regardless of whether they were derived from sensitive or resistant patient samples. PMID- 26981349 TI - Transcriptomic analyses of primary astrocytes under TNFalpha treatment. AB - Astrocytes, the most abundant glial cell population in the central nervous system, have important functional roles in the brain as blood brain barrier maintenance, synaptic transmission or intercellular communications [1], [2]. Numerous studies suggested that astrocytes exhibit a functional and morphological high degree of plasticity. For example, following any brain injury, astrocytes become reactive and hypertrophic. This phenomenon, also called reactive gliosis, is characterized by a set of progressive gene expression and cellular changes [3]. Interestingly, in this context, astrocytes can re-acquire neurogenic properties. It has been shown that astrocytes can undergo dedifferentiation upon injury and inflammation, and may re-acquire the potentiality of neural progenitors [4], [5], [6], [7]. To assess the effect of inflammation on astrocytes, primary mouse astrocytes were treated with tumor necrosis factor alpha (TNFalpha), one of the main pro-inflammatory cytokines. The strength of this study is that pure primary astrocytes were used. As microglia are highly reactive immune cells, we used a magnetic cell sorting separation (MACS) method to further obtain highly pure astrocyte cultures devoid of microglia. Here, we provide details of the microarray data, which have been deposited in the Gene Expression Omnibus (GEO) under the series accession number GSE73022. The analysis and interpretation of these data are included in Gabel et al. (2015). Analysis of gene expression indicated that the NFkappaB pathway-associated genes were induced after a TNFalpha treatment. We have shown that primary astrocytes devoid of microglia can respond to a TNFalpha treatment with the re-expression of genes implicated in the glial cell development. PMID- 26981350 TI - RNA-seq analysis for secondary metabolite pathway gene discovery in Polygonum minus. AB - Polygonum minus plant is rich in secondary metabolites, especially terpenoids and flavonoids. Present study generates transcriptome resource for P. minus to decipher its secondary metabolite biosynthesis pathways. Raw reads and the transcriptome assembly project have been deposited at GenBank under the accessions SRX313492 (root) and SRX669305 (leaf) respectively. PMID- 26981351 TI - Autoimmune disease-associated gene expression is reduced by BET-inhibition. AB - For many autoimmune diseases, the underlying mechanism is still unknown. In order to get more insight into the etiology of autoimmune diseases, we recently published a study were we performed epigenetic profiling and RNA sequencing on CD4(+)CD45RO(+) T cells derived from the site of inflammation of Juvenile Idiopathic Arthritis (JIA) patients and compared this with healthy controls [1]. In this "Data in Brief", we focus on the analysis of our RNA sequencing data reported in this study, of which the raw and processed files can be found in GEO under GSE71595. We provide a detailed description of the downstream analysis, quality controls, and different analysis methods or techniques that validate the results obtained with RNA-sequencing. PMID- 26981352 TI - RNA-seq analysis for plant carnivory gene discovery in Nepenthes * ventrata. AB - Carnivorous plants have the ability to capture and digest insects for nutrients, which allows them to survive in land deprived of nitrogenous nutrients. Nepenthes spp. are one of the carnivorous plants, which uniquely produce pitcher from the tip of an elongated leaf. This study provides the first transcriptome resource from pitcher of a Nepenthes ventricosa * Nepenthes alata hybrid, Nepenthes * ventrata to understand carnivory mechanism in Nepenthes spp., as well as in other carnivorous species. Raw reads and the transcriptome assembly project have been deposited to SRA database with the accession numbers SRX1389337 (day 0 control), SRX1389392 (day 3 longevity), and SRX1389395 (day 3 chitin-treated). PMID- 26981353 TI - Transcriptomic comparisons between cultured human adipose tissue-derived pericytes and mesenchymal stromal cells. AB - Mesenchymal stromal cells (MSCs), sometimes called mesenchymal stem cells, are cultured cells able to give rise to mature mesenchymal cells such as adipocytes, osteoblasts, and chondrocytes, and to secrete a wide range of trophic and immunomodulatory molecules. Evidence indicates that pericytes, cells that surround and maintain physical connections with endothelial cells in blood vessels, can give rise to MSCs (da Silva Meirelles et al., 2008 [1]; Caplan and Correa, 2011 [2]). We have compared the transcriptomes of highly purified, human adipose tissue pericytes subjected to culture-expansion in pericyte medium or MSC medium, with that of human adipose tissue MSCs isolated with traditional methods to test the hypothesis that their transcriptomes are similar (da Silva Meirelles et al., 2015 [3]). Here, we provide further information and analyses of microarray data from three pericyte populations cultured in pericyte medium, three pericyte populations cultured in MSC medium, and three adipose tissue MSC populations deposited in the Gene Expression Omnibus under accession number GSE67747. PMID- 26981354 TI - Endometrial transcriptional profiling of a bovine fertility model by Next Generation Sequencing. AB - Studying the multitude of molecular networks and pathways that are potentially involved in a complex trait such as fertility requires an equally complex and broad strategy. Here, we used Next-Generation Sequencing for the characterization of the transcriptional signature of the bovine endometrial tissue. Periovulatory endocrine environments were manipulated to generate two distinctly different fertility phenotypes. Cycling, non-lactating, multiparous Nelore cows were manipulated to ovulate larger (> 13 mm; LF group; high fertility phenotype) or smaller (< 12 mm; SF group) follicles. As a result, greater proestrus estrogen concentrations, corpora lutea and early diestrus progesterone concentrations were also observed in LF group in comparison to SF group. Endometrial cell proliferation was estimated by the protein marker MKI67 on tissues collected 4 (D4) and 7 (D7) days after induction of ovulation. Total RNA extracts from D7 were sequenced and compared according to the transcriptional profile of each experimental group (LF versus SF). Functional enrichment analysis revealed that LF and SF endometria were asynchronous in regards to their phenotype manifestation. Major findings indicated an LF endometrium that was switching phenotypes earlier than the SF one. More specifically, a proliferating SF endometrium was observed on D7, whereas the LF tissue, which expressed a proliferative phenotype earlier at D4, seemed to have already shifted towards a biosynthetically and metabolically active endometrium on D7. Data on MKI67 support the transcriptomic results. RNA-Seq-derived transcriptional profile of the endometrial tissue indicated a temporal effect of the periovulatory endocrine environment, suggesting that the moment of the endometrial exposure to the ovarian steroids, E2 and P4, regulates the timing of phenotype manifestation. Gene expression profiling revealed molecules that may be targeted to elucidate ovarian steroid-dependent mechanisms that regulate endometrial tissue receptivity. Data was deposited in the SRA database from NCBI (SRA Experiment SRP051330) and are associated with the Bio-Project (PRJNA270391). An overview of the gene expression data has been deposited in NCBI's Gene Expression Omnibus (GEO) and is accessible through GEO Series accession number GSE65450. Further assessment of the data in combination with other data sets exploring the transcriptional profile of the endometrial tissue during early diestrus may potentially identify novel molecular mechanisms and/or markers of the uterine receptivity. PMID- 26981355 TI - p53 transcriptional programs in B cells upon exposure to genotoxic stress in vivo: Computational analysis of next-generation sequencing data. AB - The transcriptional programs activated by p53 in B cells in vivo following exposure to ionizing radiation were studied through the integrated analysis of various types of next-generation sequencing data: genome-wide profiling of p53 binding sites, mapping of histone marks and open chromatin regions and quantification of gene expression. Moreover, the binding of p53 was associated to a series of specific motifs on the DNA, which were directly inferred from the data. Here, we describe in detail the computational analysis of the datasets associated with our study (Tonelli et al., Oncotarget 6 (2015), 24611-26), deposited in the GEO archive (accession code GSE71180), and we provide the R scripts needed to generated the figures of the paper. PMID- 26981356 TI - DNA microarray-based experimental strategy for trustworthy expression profiling of the hippocampal genes by astaxanthin supplementation in adult mouse. AB - Naturally occurring astaxantin (ASX) is one of the noticeable carotenoid and dietary supplement, which has strong antioxidant and anti-inflammatory properties, and neuroprotective effects in the brain through crossing the blood brain barrier. Specially, we are interested in the role of ASX as a brain food. Although ASX has been suggested to have potential benefit to the brain function, the underlying molecular mechanisms and events mediating such effect remain unknown. Here we examined molecular factors in the hippocampus of adult mouse fed ASX diets (0.1% and 0.5% doses) using DNA microarray (Agilent 4 * 44 K whole mouse genome chip) analysis. In this study, we described in detail our experimental workflow and protocol, and validated quality controls with the housekeeping gene expression (Gapdh and Beta-actin) on the dye-swap based approach to advocate our microarray data, which have been uploaded to Gene Expression Omnibus (accession number GSE62197) as a gene resource for the scientific community. This data will also form an important basis for further detailed experiments and bioinformatics analysis with an aim to unravel the potential molecular pathways or mechanisms underlying the positive effects of ASX supplementation on the brain, in particular the hippocampus. PMID- 26981357 TI - Genomic variation in recently collected maize landraces from Mexico. AB - The present dataset comprises 36,931 SNPs genotyped in 46 maize landraces native to Mexico as well as the teosinte subspecies Zea maiz ssp. parviglumis and ssp. mexicana. These landraces were collected directly from farmers mostly between 2006 and 2010. We accompany these data with a short description of the variation within each landrace, as well as maps, principal component analyses and neighbor joining trees showing the distribution of the genetic diversity relative to landrace, geographical features and maize biogeography. High levels of genetic variation were detected for the maize landraces (H E = 0.234 to 0.318 (mean 0.311), while slightly lower levels were detected in Zea m. mexicana and Zea m. parviglumis (H E = 0.262 and 0.234, respectively). The distribution of genetic variation was better explained by environmental variables given by the interaction of altitude and latitude than by landrace identity. This dataset is a follow up product of the Global Native Maize Project, an initiative to update the data on Mexican maize landraces and their wild relatives, and to generate information that is necessary for implementing the Mexican Biosafety Law. PMID- 26981359 TI - Genome sequences of six Phytophthora species associated with forests in New Zealand. AB - In New Zealand there has been a long association of Phytophthora diseases in forests, nurseries, remnant plantings and horticultural crops. However, new Phytophthora diseases of trees have recently emerged. Genome sequencing has been performed for 12 Phytophthora isolates, from six species: Phytophthora pluvialis, Phytophthora kernoviae, Phytophthora cinnamomi, Phytophthora agathidicida, Phytophthora multivora and Phytophthora taxon Totara. These sequences will enable comparative analyses to identify potential virulence strategies and ultimately facilitate better control strategies. This Whole Genome Shotgun data have been deposited in DDBJ/ENA/GenBank under the accession numbers LGTT00000000, LGTU00000000, JPWV00000000, JPWU00000000, LGSK00000000, LGSJ00000000, LGTR00000000, LGTS00000000, LGSM00000000, LGSL00000000, LGSO00000000, and LGSN00000000. PMID- 26981358 TI - In silico genome wide mining of conserved and novel miRNAs in the brain and pineal gland of Danio rerio using small RNA sequencing data. AB - MicroRNAs (miRNAs) are small, non-coding RNA molecules that bind to the mRNA of the target genes and regulate the expression of the gene at the post transcriptional level. Zebrafish is an economically important freshwater fish species globally considered as a good predictive model for studying human diseases and development. The present study focused on uncovering known as well as novel miRNAs, target prediction of the novel miRNAs and the differential expression of the known miRNA using the small RNA sequencing data of the brain and pineal gland (dark and light treatments) obtained from NCBI SRA. A total of 165, 151 and 145 known zebrafish miRNAs were found in the brain, pineal gland (dark treatment) and pineal gland (light treatment), respectively. Chromosomes 4 and 5 of zebrafish reference assembly GRCz10 were found to contain maximum number of miR genes. The miR-181a and miR-182 were found to be highly expressed in terms of number of reads in the brain and pineal gland, respectively. Other ncRNAs, such as tRNA, rRNA and snoRNA, were curated against Rfam. Using GRCz10 as reference, the subsequent bioinformatic analyses identified 25, 19 and 9 novel miRNAs from the brain, pineal gland (dark treatment) and pineal gland (light treatment), respectively. Targets of the novel miRNAs were identified, based on sequence complementarity between miRNAs and mRNA, by searching for antisense hits in the 3'-UTR of reference RNA sequences of the zebrafish. The discovery of novel miRNAs and their targets in the zebrafish genome can be a valuable scientific resource for further functional studies not only in zebrafish but also in other economically important fishes. PMID- 26981360 TI - Transcriptome sequencing of hematopoietic stem cells and chronic myelgenous leukemia stem cells. AB - Dipeptide species are accumulated in the chronic myelogenous leukemia (CML) stem cells [1]. To investigate the molecular mechanisms of the accumulation of dipeptide species in CML stem cells, we performed transcriptome sequencing of long-term stem cells, short-term stem cells, progenitor cells from healthy control and CML-affected mice (GSE70031). The transcriptome data revealed that the expression of a dipeptide transporter (solute carrier family 15, member 2 (SLC15A2)) was elevated only in the CML stem cells. This result indicates that dipeptide species accumulates in CML stem cells through a dipeptide transporter SLC15A2. PMID- 26981361 TI - Whole genome sequence of the emerging oomycete pathogen Pythium insidiosum strain CDC-B5653 isolated from an infected human in the USA. AB - Pythium insidiosum ATCC 200269 strain CDC-B5653, an isolate from necrotizing lesions on the mouth and eye of a 2-year-old boy in Memphis, Tennessee, USA, was sequenced using a combination of Illumina MiSeq (300 bp paired-end, 14 millions reads) and PacBio (10 Kb fragment library, 356,001 reads). The sequencing data were assembled using SPAdes version 3.1.0, yielding a total genome size of 45.6 Mb contained in 8992 contigs, N50 of 13 Kb, 57% G + C content, and 17,867 putative protein-coding genes. This Whole Genome Shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession JRHR00000000. PMID- 26981362 TI - DNA-seq analysis of Garcinia mangostana. AB - Mangosteen (Garcinia mangostana Linn.) is a tropical tree mainly found in South East Asia and considered as "the queen of fruits". The asexually produced fruit is dark purple or reddish in color, with white flesh which is slightly acidic with sweet flavor and a pleasant aroma. The purple pericarp tissue is rich in xanthones which are useful for medical purposes. We performed the first genome sequencing of this commercially important fruit tree to study its genome composition and attempted draft genome assembly. Raw reads of the DNA sequencing project have been deposited to SRA database with the accession number SRX1426419. PMID- 26981363 TI - Transcriptional profiling of dendritic cells matured in different osmolarities. AB - Tissue-specific microenvironments shape the fate of mononuclear phagocytes [1-3]. Interstitial osmolarity is a tissue biophysical parameter which considerably modulates the phenotype and function of dendritic cells [4]. In the present report we provide a detailed description of our experimental workflow and bioinformatic analysis applied to our gene expression dataset (GSE72174), aiming to investigate the influence of different osmolarity conditions on the gene expression signature of bone marrow-derived dendritic cells. We established a cell culture system involving murine bone marrow cells, cultured under different NaCl-induced osmolarity conditions in the presence of the dendritic cell growth factor GM-CSF. Gene expression analysis was applied to mature dendritic cells (day 7) developed in different osmolarities, with and without prior stimulation with the TLR2/4 ligand LPS. PMID- 26981364 TI - Lists of HumanMethylation450 BeadChip probes with nucleotide-variant information obtained from the Phase 3 data of the 1000 Genomes Project. AB - The Illumina's Infinium HumanMethylation450 (HM450) BeadChip array provides a simultaneous examination of DNA methylation status of more than 480,000 CpG sites in the human genome. Its relatively simple protocol is achieved by employing a hybridization methodology followed by single-base extension reactions. However, nucleotide variations among individuals in the hybridization probe sequences can affect the results, i.e. estimates of methylation levels. To investigate possible effects of maternal nutritional conditions on the extent of epigenetic alterations in utero, we examined genome-wide DNA methylation profiles of 33 chorionic villi samples collected in Japan (GEO accession number GSE62733), and revealed using Smirnov-Grubbs' outlier test that epigenetic alterations accumulate in placentas under adverse in utero environments. In that study, we compiled a list of HM450 probes overlapping with the reported nucleotide variants in the Phase 3 dataset (release 20130502) of the 1000 Genomes Project. We excluded the probes whose sequences overlapped with variants with minor allele frequency (MAF) higher than 1% in the Japanese population from identified methylation outliers, to diminish the number of outliers that could have been spuriously identified due to variants at/near the target CpG sites. We herein compiled lists of HM450 probes with MAF information of the African, European, American, South Asian and East Asian populations, in addition to the Japanese population. The provided lists are useful for methylome analyses for human populations using the HM450 BeadChip arrays. PMID- 26981365 TI - Genome sequence of carboxylesterase, carboxylase and xylose isomerase producing alkaliphilic haloarchaeon Haloterrigena turkmenica WANU15. AB - We report draft genome sequence of Haloterrigena turkmenica strain WANU15, isolated from Soda Lake. The draft genome size is 2,950,899 bp with a G + C content of 64% and contains 49 RNA sequence. The genome sequence can be accessed at DDBJ/EMBL/GenBank under the accession no. LKCV00000000. PMID- 26981366 TI - RNA sequencing analysis to demonstrate Erk dependent and independent functions of Mek. AB - Mek inhibition and Erk knockout (KO) have quite distinct effects on pluripotency maintenance in mouse embryonic stem cells (ESCs). To test whether there is an Erk independent function of Mek, RNA-sequencing (RNA-seq) is carried out on six samples, WT KH2 ESCs treated with or without PD0325901 (PD) for 48 h (KH2_PD and KH2, respectively), iErk1; Erk KO ESCs cultured in the presence of Dox (P0), 48 and 96 h after Dox withdrawal (P1 and P2, respectively), and iErk1; Erk KO ESCs cultured without Dox for 96 h, and treated with PD in the last 48 h (P2_PD). These RNA-seq data demonstrate that Mek inhibition has quite different effect on the transcriptional profile of mouse ESCs, compared to Erk KO. Moreover, a significant fraction of genes is regulated by Mek inhibition, regardless of the presence or absence of Erk, indicating an Erk-independent function of Mek. RNA seq data are deposited in Gene Expression Omnibus (GEO) datasets under accession number GSE70304. PMID- 26981368 TI - Plasmodium falciparum epigenome: A distinct dynamic epigenetic regulation of gene expression. AB - Histone modification profiles are predictive of gene expression and most of the knowledge gained is acquired through studies done in higher eukaryotes. However, genome-wide studies involving Plasmodium falciparum, the causative agent of malaria, have been rather few, at lower resolution (mostly using ChIP-on-chip), and covering limited number of histone modifications. In our recent study [1], we have performed extensive genome-wide analyses of multiple histone modifications including the active (H3K4me2, H3K4me3, H3K9ac, H3K14ac, H3K27ac and H4ac), inactive (H3K9me3 and H3K27me3), elongation (H3K79me3) and regulatory element (H3K4me1) in a stage-specific manner. Furthermore, we used a ligation-based method suitable for sequencing homopolymeric stretches as seen in P. falciparum for next-generation sequencing library amplification [2], enabling highly quantitative analysis of the extremely AT-rich P. falciparum genome. Our recently published study suggests that transcription regulation by virtue of poised chromatin and differential histone modifications is unique to P. falciparum [1]. Here we describe the experiments, quality controls and chromatin immunoprecipitation-sequencing data analysis of our associated study published in Epigenetics and Chromatin [1]. Stage-specific ChIP-sequencing data for histone modifications is submitted to Gene Expression Omnibus (GEO) database under the accession number GSE63369. PMID- 26981367 TI - Bacterial diversity assessment of pristine mangrove microbial community from Dhulibhashani, Sundarbans using 16S rRNA gene tag sequencing. AB - The global knowledge of microbial diversity and function in Sundarbans ecosystem is still scarce, despite global advancement in understanding the microbial diversity. In the present study, we have analyzed the diversity and distribution of bacteria in the tropical mangrove sediments of Sundarbans using 16S rRNA gene amplicon sequencing. Metagenome is comprised of 1,53,926 sequences with 108.8 Mbp data and with 55 +/- 2% G + C content. Metagenome sequence data are available at NCBI under the Bioproject database with accession no. PRJNA245459. Bacterial community metagenome sequences were analyzed by MG-RAST software representing the presence of 56,547 species belonging to 44 different phyla. The taxonomic analysis revealed the dominance of phyla Proteobacteria within our dataset. Further taxonomic analysis revealed abundance of Bacteroidetes, Acidobactreia, Firmicutes, Actinobacteria, Nitrospirae, Cyanobacteria, Planctomycetes and Fusobacteria group as the predominant bacterial assemblages in this largely pristine mangrove habitat. The distribution of different community datasets obtained from four sediment samples originated from one sampling station at two different depths providing better understanding of the sediment bacterial diversity and its relationship to the ecosystem dynamics of this pristine mangrove sediment of Dhulibhashani in, Sundarbans. PMID- 26981370 TI - Microarray analysis of microRNA expression in bone marrow-derived progenitor cells from mice with type 2 diabetes. AB - Bone-marrow derived vascular precursors are an important endogenous repair reservoir for vascular repair and neovascularization [1]. Therapies of stem/progenitor cells targeting on angiogenesis are considered hopeful solutions for tissue repair and regeneration. However, the dysfunction of patient-derived progenitor cells has been implicated in diabetes [2], which limited the efficacy of autologous cell therapies in the clinic [3,4]. MicroRNAs are important gene regulators whose functions remain largely unknown. In this project we reported the different microRNA expression profiles in bone marrow-derived progenitor cells from type 2 diabetic mice and their normal controls using microRNA array analysis. All microarray data are available at the Gene Expression Omnibus (GEO) at NCBI (http://www.ncbi.nlm.nih.gov/geo), under accession number GSE72616. PMID- 26981369 TI - Transcriptional profile of immediate response to ionizing radiation exposure. AB - Astronauts participating in long duration space missions are likely to be exposed to ionizing radiation associated with highly energetic and charged heavy particles. Previously proposed gene biomarkers for radiation exposure include phosphorylated H2A Histone Family, Member X (gammaH2AX), Tumor Protein 53 (TP53), and Cyclin-Dependent Kinase Inhibitor 1A (CDKN1A). However, transcripts of these genes may not be the most suitable biomarkers for radiation exposure due to a lack of sensitivity or specificity. As part of a larger effort to develop lab-on a-chip methods for detecting radiation exposure events using blood samples, we designed a dose-course microarray study in order to determine coding and non coding RNA transcripts undergoing differential expression immediately following radiation exposure. The main goal was to elicit a small set of sensitive and specific radiation exposure biomarkers at low, medium, and high levels of ionizing radiation exposure. Four separate levels of radiation were considered: 0 Gray (Gy) control; 0.3 Gy; 1.5 Gy; and 3.0 Gy with four replicates at each radiation level. This report includes raw gene expression data files from the resulting microarray experiments from all three radiation levels ranging from a lower, typical exposure than an astronaut might see (0.3 Gy) to high, potentially lethal, levels of radiation (3.0 Gy). The data described here is available in NCBI's Gene Expression Omnibus (GEO), accession GSE64375. PMID- 26981371 TI - mRNA and microRNA transcriptomics analyses in a murine model of dystrophin loss and therapeutic restoration. AB - Duchenne muscular dystrophy (DMD) is a pediatric, X-linked, progressive muscle wasting disorder caused by loss of function mutations affecting the gene encoding the dystrophin protein. While the primary genetic insult in DMD is well described, many details of the molecular and cellular pathologies that follow dystrophin loss are incompletely understood. To investigate gene expression in dystrophic muscle we have applied mRNA and microRNA (miRNA) microarray technology to the mdx mouse model of DMD. This study was designed to generate a complete description of gene expression changes associated with dystrophic pathology and the response to an experimental therapy which restores dystrophin protein function. These datasets have enabled (1) the determination of gene expression changes associated with dystrophic pathology, (2) identification of differentially expressed genes that are restored towards wild-type levels after therapeutic dystrophin rescue, (3) investigation of the correlation between mRNA and protein expression (determined by parallel mass spectrometry proteomics analysis), and (4) prediction of pathology associated miRNA-target interactions. Here we describe in detail how the data were generated including the basic analysis as contained in the manuscript published in Human Molecular Genetics with PMID 26385637. The data have been deposited in the Gene Expression Omnibus (GEO) with the accession number GSE64420. PMID- 26981372 TI - Microarray expression analysis of genes involved in innate immune memory in peritoneal macrophages. AB - Immunological memory has been believed to be a feature of the adaptive immune system for long period, but recent reports suggest that the innate immune system also exhibits memory-like reaction. Although evidence of innate immune memory is accumulating, no in vivo experimental data has clearly implicated a molecular mechanism, or even a cell-type, for this phenomenon. In this study of data deposited into Gene Expression Omnibus (GEO) under GSE71111, we analyzed the expression profile of peritoneal macrophages isolated from mice pre-administrated with toll-like receptor (TLR) ligands, mimicking pathogen infection. In these macrophages, increased expression of a group of innate immunity-related genes was sustained over a long period of time, and these genes overlapped with ATF7 regulated genes. We conclude that ATF7 plays an important role in innate immune memory in macrophages. PMID- 26981373 TI - Identification of genes responsible for RelA-dependent proliferation arrest in human mammary epithelial cells conditionally expressing RelA. AB - The molecular mechanisms responsible for opposing oncogenic and tumor-suppressor activities of NF-kB are obscure. Semi-quantitative immunohistochemistry of primary breast tumors using antibodies to RelA, the pleiotropic NF-kB factor, and Ki67 revealed a negative correlation between RelA levels and Ki67-index among ER +/HER2 - tumors [1]. Similarly, expression of AURKA, a marker for proliferation, negatively correlates with expression of NFKBIA, a surrogate for RelA expression and activity, in ER +/HER2 - tumors analyzed by The Cancer Genome Atlas [2], [3], [4]. Furthermore, conditional expression of RelA using a Tetracycline-inducible system in Human Mammary Epithelial Cells (HRA cells) caused proliferation arrest while withdrawal of Doxycycline (Dox) and suppression of RelA expression in arrested cells restored cell cycle progression [1]. To identify genes responsible for the negative relationship between RelA levels and proliferation, we performed genome-wide gene expression analysis of HRA cells under the following conditions: RelA un-induced, No Dox (ND); Dox induced for 24 h; Dox induced for 72 h; Dox induced for 24 h then Dox withdrawn for 48 h. The expression data was submitted to Gene Expression Ominibus (GEO) and the accession number is GSE65040. Analysis of the data identified cross-talk between basal RelA activity and the Interferon pathway mediated by IRF1, a target of RelA [5]. Activation of the Interferon pathway lead to down-regulation of CDK4 expression resulting in RB1 hypo phosphorylation and suppression of cell cycle progression. The tumor-suppressor activity of NF-kB, specifically RelA, may stem from cross-talk with the Interferon pathway. PMID- 26981374 TI - Metagenomic exploration of the bacterial community structure at Paradip Port, Odisha, India. AB - This is a pioneering report on the metagenomic exploration of the bacterial diversity from a busy sea port in Paradip, Odisha, India. In our study, high throughput sequencing of community 16S rRNA gene amplicon was performed using 454 GS Junior platform. Metagenome contain 34,121 sequences with 16,677,333 bp and 56.3% G + C content. Metagenome sequences data are now available at NCBI under the Sequence Read Archive (SRA) database with accession no. SRX897055. Community metagenome sequence revealed the presence of 11,705 species belonging to 40 different phyla. Bacteroidetes (23%), Firmicutes (19%), Proteobacteria (17%), Spirochaetes (10%), Nitrospirae (8%), Actinobacteria (7%) and Acidobacteria (3%) are the predominant bacterial phyla in this port soil. Analysis of metagenomic sequences unfolded the interesting distribution of several phyla which pointed to the significant anthropogenic intervention influencing the bacterial community character of this port. PMID- 26981375 TI - Analysis of copy number variations in Mexican Holstein cattle using axiom genome wide Bos 1 array. AB - Recently, for copy number variation (CNV) analysis, bovine researchers have focused mainly on the use of genome-wide SNP genotyping arrays. One of the highest densities commercially available SNPchips for cattle is the Affymetrix axiom genome-wide Bos 1, which assays 648,315 informative SNPs across the whole bovine genome. Here, we describe the microarray data, quality controls and validation implemented in a study published in Genetics and Molecular Research Journal in 2015 [1]. The microarray raw data has been deposited into Gene Expression Omnibus under accession #GSE54813. PMID- 26981376 TI - Structural insights of microbial community of Deulajhari (India) hot spring using 16s-rRNA based metagenomic sequencing. AB - Insights about the distribution of the microbial community prove to be the major goal of understanding microbial ecology which remains to be fully deciphered. Hot springs being hub for the thermophilic microbiota attract the attention of the microbiologists. Deulajhari hot spring cluster is located in the Angul district of Odisha. Covered within a wooded area, Deulajhari hot spring is also fed by the plant litter resulting in a relatively high amount of total organic content (TOC). For the first time, Illumina sequencing based biodiversity analysis of microbial composition is studied through amplicon metagenome sequencing of 16s rRNA targeting V3-V4 region using metagenomic DNA from the hot spring sediment. Over 28 phyla were detected through the amplicon metagenome sequencing of which the most dominating phyla at the existing physiochemical parameters like; temperature 69 degrees C, pH 8.09, electroconductivity 0.025 dSm(- 1) and total organic carbon 0.356%, were Proteobacteria (88.12%), Bacteriodetes (10.76%), Firmicutes (0.35%), Spirochetes (0.18%) and chloroflexi (0.11%). Approximately 713 species were observed at the above physiochemical parameters. The analysis of the metagenome provides the quantitative insights into microbial populations based on the sequence data in Deulajhari hot spring. Metagenome sequence is deposited to SRA database which is available at NCBI with accession no. SRX1459736. PMID- 26981377 TI - Gene expression profiling of Ctr9-regulated transcriptome in ERalpha-positive breast cancer. AB - Ctr9, the key scaffold subunit in human RNA polymerase II associated factor complex (PAFc), has diverse functions in cells and has been implicated in human diseases. Recently, our study found that loss of Ctr9 led to apparent morphological change, decrease of proliferation, and reduced colony formation in ERalpha(+) breast cancer cells. Moreover, Ctr9 and ERalpha show positive correlation at protein levels and the high levels of Ctr9 are associated with poor survival among all women with ERalpha(+) breast cancers, and specifically among those treated with tamoxifen. To gain a molecular understanding of the role of Ctr9 in promoting ERalpha(+) breast cancer, we performed a microarray gene expression profiling of Ctr9-regulated transcriptome. Here we provide the experimental details and analysis of the microarray data, which have been deposited into Gene Expression Omnibus (GEO): GSE73388. PMID- 26981378 TI - Whole genome analysis of Klebsiella pneumoniae T2-1-1 from human oral cavity. AB - Klebsiella pneumoniae T2-1-1 was isolated from the human tongue debris and subjected to whole genome sequencing on HiSeq platform and annotated on RAST. The nucleotide sequence of this genome was deposited into DDBJ/EMBL/GenBank under the accession JAQL00000000. PMID- 26981379 TI - Gene expression profiling of human calcific aortic valve disease. AB - Calcific aortic valve disease is a slowly progressive disorder that ranges from mild valve thickening (i.e. aortic sclerosis) to severe calcification of valves (i.e. aortic stenosis). Gene expression profiling analysis of non-calcified controls, sclerotic, and calcified aortic valves was performed to better understand the progression of calcific aortic valve disease. The complementary information related to processing and statistical analysis of the DNA microarray data is provided in this article. Interpretation of this data can be found in a research article entitled "MicroRNA-125b and chemokine CCL4 expression are associated with calcific aortic valve disease" [1]. The microarray data complies with MIAME guidelines and is deposited in the Gene Expression Omnibus (GEO) database under accession number GSE51472. PMID- 26981380 TI - Transcriptome profiling of Musculus longissimus dorsi in two cattle breeds with different intramuscular fat deposition. AB - Intramuscular fat (IMF) deposition is a physiological process in cattle and is highly variable among breeds suggesting a large influence of genetic factors besides environmental factors. In order to elucidate molecular pathways underlying the genetic variation in this trait we compared transcriptomes of Musculus longissimus dorsi (MLD) in steers of Japanese Black and Holstein Friesian cattle breeds fed a high energy diet typically applied in Japan to achieve maximum IMF content. We identified a total of 569 differentially expressed genes (DEGs) with the majority (433) up-regulated in Japanese Black cattle. This breed is characterized by an extreme capacity for IMF deposition. Subsequent Ingenuity Pathway Analysis (IPA) revealed a gene network linking parameters of cell morphology and maintenance with lipid metabolism. The data from this study were deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE75348. We provide here a dataset which is of potential value to dissect molecular pathways influencing differences in fat deposition under high-energy nutrition. PMID- 26981382 TI - LmSmdB: an integrated database for metabolic and gene regulatory network in Leishmania major and Schistosoma mansoni. AB - A database that integrates all the information required for biological processing is essential to be stored in one platform. We have attempted to create one such integrated database that can be a one stop shop for the essential features required to fetch valuable result. LmSmdB (L. major and S. mansoni database) is an integrated database that accounts for the biological networks and regulatory pathways computationally determined by integrating the knowledge of the genome sequences of the mentioned organisms. It is the first database of its kind that has together with the network designing showed the simulation pattern of the product. This database intends to create a comprehensive canopy for the regulation of lipid metabolism reaction in the parasite by integrating the transcription factors, regulatory genes and the protein products controlled by the transcription factors and hence operating the metabolism at genetic level. PMID- 26981381 TI - Transcriptome profiling of Lactococcus lactis subsp. cremoris CECT 8666 in response to agmatine. AB - The dairy strain Lactococcus lactis subsp. cremoris CECT 8666 (formerly GE2-14) synthesizes the biogenic amine putrescine from agmatine via the agmatine deiminase (AGDI) pathway [1]. The AGDI cluster of L. lactis is composed by five genes aguR, aguB, aguD, aguA and aguC. The last four genes are co-transcribed as a single policistronic mRNA forming the catabolic operon aguBDAC, which encodes the proteins necessary for agmatine uptake and its conversion into putrescine [1], [2]. The first gene of the cluster, aguR, encodes a transmembrane protein that functions as a one-component signal transduction system that senses the agmatine concentration of the medium and accordingly regulates the transcription of aguBDAC[2]. The catabolic operon aguBDAC is transcriptionally activated by agmatine [2] and transcriptionally regulated by carbon catabolite repression (CCR) via glucose, but not by other sugars such as lactose or galactose [1], [3]. On the contrary, the transcription of the aguR regulatory gene is not subject to CCR regulation [1], [3] nor is regulated by agmatine [2]. In this study we report the transcriptional profiling of L. lactis subsp. cremoris CECT 8666 grown in M17 medium with galactose (GalM17) as carbon source and supplemented with agmatine, compared to that of the strain grown in the same culture medium without agmatine. The transcriptional profiling data of agmatine-regulated genes were deposited in the Gene Expression Omnibus (GEO) database under Accession no. GSE74808. PMID- 26981383 TI - Genome Sequencing and Annotation of Mycobacterium tuberculosis PR08 strain. AB - Mycobacterium tuberculosis is an acid fast bacterial species in the family Mycobacteriaceae and is the causative agent of most cases of tuberculosis. Here, we report the genomic features of Mycobacterium tuberculosis isolated from the cerebrospinal fluid (CSF) of a patient diagnosed with both pulmonary and extrapulmonary tuberculosis (TB). The isolated strain was identified as Mycobacterium tuberculosis PR08 (MTB PR08). Genomic DNA of the MTB PR08 strain was extracted and subjected to whole genome sequencing using MiSeq (Illumina, CA,USA). The draft genome size of MTB PR08 strain is 4,292,364 bp with a G + C content of 65.2%. This strain was annotated to have 4723 genes and 48 RNAs. This whole genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession number CP010895. PMID- 26981385 TI - Androgen receptor DNA binding and chromatin accessibility profiling in prostate cancer. AB - Prostate cancer (PCa) is the second most common cancer in men. The Androgen Receptor (AR) is the major driver of PCa and the main target of therapy in the advanced setting. AR is a nuclear receptor that binds the chromatin and regulates transcription of genes involved in cancer cell proliferation and survival. In a study by Stelloo et al. (1) we explored prostate cancer on the level of transcriptional regulation by means of Formaldehyde-Assisted Isolation of Regulatory Elements and Chromatin Immunoprecipitation coupled with massive parallel sequencing (FAIRE-seq and ChIP-seq, respectively). We employed these data for the assessment of differences in transcriptional regulation at distinct stages of PCa progression and to construct a prognostic gene expression classifier. Genomics data includes FAIRE-seq data from normal prostate tissue as well as primary, hormone therapy resistant and metastatic PCa. Furthermore, ChIP seq data from primary and resistant PCa were generated, along with multiple input controls. The data are publicly available through NCBI GEO database with accession number GSE65478. Here we describe the genomics and clinical data in detail and provide comparative analysis of FAIRE-seq and ChIP-seq data. PMID- 26981384 TI - Draft genome sequence of Kocuria sp. SM24M-10 isolated from coral mucus. AB - Here, we describe the genomic features of the Actinobacteria Kocuria sp. SM24M-10 isolated from mucus of the Brazilian endemic coral Mussismilia hispida. The sequences are available under accession number LDNX01000000 (http://www.ncbi.nlm.nih.gov/nuccore/LDNX00000000). The genomic analysis revealed interesting information about the adaptation of bacteria to the marine environment (such as genes involved in osmotic and oxidative stress) and to the nutrient-rich environment provided by the coral mucus. PMID- 26981386 TI - Cultivation-independent comprehensive investigations on bacterial communities in serofluid dish, a traditional Chinese fermented food. AB - Serofluid dish (or Jiangshui, in Chinese), a traditional food in the Chinese culture, is made from vegetables by fermentation. In this study, bacterial community of the fermented serofluid dish was assessed by Illumina amplicon sequencing. The metagenome comprised of 49,589 average raw reads with an average 11,497,917 bp and G + C content is 52.46%. This is the first report on V4 hyper variable region of the 16S rRNA metagenome sequence employing Illumina platform to profile the microbial community of this little known fermented food from Gansu Province, China. The metagenome sequence can be accessed at NCBI, SRA database accession no. SRP065370. PMID- 26981387 TI - Mapping transcriptome profiles of in vitro iPSC-derived cardiac differentiation to in utero heart development. AB - The dataset includes microarray data (Affymetrix Mouse Genome 430 2.0 Array) from WT and Nos3(-/-) mouse embryonic heart ventricular tissues at 14.5 days post coitum (E14.5), induced pluripotent stem cells (iPSCs) derived from WT and Nos3( /-) mouse tail tip fibroblasts, iPSC-differentiated cardiomyocytes at Day 11, and mouse embryonic stem cells (mESCs) and differentiated cardiomyocytes as positive controls for mouse iPSC differentiation. Both in utero (using embryonic heart tissues) and in vitro (using iPSCs and differentiated cells) microarray datasets were deposited to the NCBI Gene Expression Omnibus (GEO) database. The deposited data in GEO include raw microarray data, metadata for sample source information, experimental design, sample and data processing, and gene expression matrix. The data are available under GEO Access Number GSE69317 (GSE69315 for tissue sample microarray data, GSE69316 for iPSCs microarray data, http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc= GSE69317). PMID- 26981388 TI - Gene expression profile of Musculus longissimus dorsi in bulls of a Charolais * Holstein F2-cross with divergent intramuscular fat content. AB - Transcriptomes of Musculus longissimus dorsi (MLD) were compared between bulls from a F2-cross derived from Charolais and Holstein Friesian. Two groups of 10 bulls were selected which differed significantly in intramuscular fat (IMF) deposition despite standardized husbandry and feeding conditions and identical sires in both groups. Consequently, genetic factors underlying the different capability of IMF deposition should be identified. A total of 32 differentially expressed genes (DEGs) were found of which 11 were up-regulated and 21 were down regulated in the high IMF group. Ingenuity Pathway Analysis (IPA) identified a gene network comprising DEGs with functions in carbohydrate metabolism, lipid metabolism and molecular transport. The data from this study were deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE75347. We provide here a dataset which is of potential value to dissect molecular pathways influencing differences in IMF deposition in crossbred cattle with standardized genetic background. PMID- 26981389 TI - Metagenomic data of fungal internal transcribed spacer from serofluid dish, a traditional Chinese fermented food. AB - Serofluid dish (or Jiangshui, in Chinese), a traditional food in the Chinese culture for thousands of years, is made from vegetables by fermentation. In this work, microorganism community of the fermented serofluid dish was investigated by the culture-independent method. The metagenomic data in this article contains the sequences of fungal internal transcribed spacer (ITS) regions of rRNA genes from 12 different serofluid dish samples. The metagenome comprised of 50,865 average raw reads with an average of 8,958,220 bp and G + C content is 45.62%. This is the first report on metagenomic data of fungal ITS from serofluid dish employing Illumina platform to profile the fungal communities of this little known fermented food from Gansu Province, China. The Metagenomic data of fungal internal transcribed spacer can be accessed at NCBI, SRA database accession no. SRP067411. PMID- 26981390 TI - Genome wide expression after different doses of irradiation of a three dimensional (3D) model of oral mucosal. AB - We evaluated a three-dimensional (3D) human oral cell culture that consisted of two types of cells, oral keratinocytes and fibroblasts as a model of oral mucositis which is a debilitating adverse effect of chemotherapy and radiation treatment. The 3D cell culture model was irradiated with 12 or 2 Gy, and total RNA was collected 6 h after irradiation to compare global gene expression profiles via microarray analysis. Here we provide detailed methods and analysis on these microarray data, which have been deposited in Gene Expression Omnibus (GEO): GSE62395. PMID- 26981391 TI - Complete metagenome sequencing based bacterial diversity and functional insights from basaltic hot spring of Unkeshwar, Maharashtra, India. AB - Unkeshwar hot springs are located at geographical South East Deccan Continental basalt of India. Here, we report the microbial community analysis of this hot spring using whole metagenome shotgun sequencing approach. The analysis revealed a total of 848,096 reads with 212.87 Mbps with 50.87% G + C content. Metagenomic sequences were deposited in SRA database with accession number (SUB1242219). Community analysis revealed 99.98% sequences belonging to bacteria and 0.01% to archaea and 0.01% to Viruses. The data obtained revealed 41 phyla including bacteria and Archaea and including 719 different species. In taxonomic analysis, the dominant phyla were found as, Actinobacteria (56%), Verrucomicrobia (24%), Bacteriodes (13%), Deinococcus-Thermus (3%) and firmicutes (2%) and Viruses (2%). Furthermore, functional annotation using pathway information revealed dynamic potential of hot spring community in terms of metabolism, environmental information processing, cellular processes and other important aspects. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of each contig sequence by assigning KEGG Orthology (KO) numbers revealed contig sequences that were assigned to metabolism, organismal system, Environmental Information Processing, cellular processes and human diseases with some unclassified sequences. The Unkeshwar hot springs offer rich phylogenetic diversity and metabolic potential for biotechnological applications. PMID- 26981392 TI - Transcriptional profiling of the epigenetic regulator Smchd1. AB - Smchd1 is an epigenetic repressor with important functions in healthy cellular processes and disease. To elucidate its role in transcriptional regulation, we performed two independent genome-wide RNA-sequencing studies comparing wild-type and Smchd1 null samples in neural stem cells and lymphoma cell lines. Using an R based analysis pipeline that accommodates observational and sample-specific weights in the linear modeling, we identify key genes dysregulated by Smchd1 deletion such as clustered protocadherins in the neural stem cells and imprinted genes in both experiments. Here we provide a detailed description of this analysis, from quality control to read mapping and differential expression analysis. These data sets are publicly available from the Gene Expression Omnibus database (accession numbers GSE64099 and GSE65747). PMID- 26981393 TI - Transcriptomic analysis of mouse EL4 T cells upon T cell activation and in response to protein synthesis inhibition via cycloheximide treatment. AB - T cell activation involves the recognition of a foreign antigen complexed to the major histocompatibility complex on the antigen presenting T cell to the T cell receptor. This leads to activation of signaling pathways, which ultimately leads to induction of key cytokine genes responsible for eradication of foreign antigens. We used the mouse EL4 T cell as a model system to study genes that are induced as a result of T cell activation using phorbol myristate acetate (PMA) and calcium ionomycin (I) as stimuli. We were also interested to examine the importance of new protein synthesis in regulating the expression of genes involved in T cell activation. Thus we have pre-treated mouse EL4 T cells with cycloheximide, a protein synthesis inhibitor, and left the cells unstimulated or stimulated with PMA/I for 4 h. We performed microarray expression profiling of these cells to correlate the gene expression with chromatin state of T cells upon T cell activation [1]. Here, we detail further information and analysis of the microarray data, which shows that T cell activation leads to differential expression of genes and inducible genes can be further classified as primary and secondary response genes based on their protein synthesis dependency. The data is available in the Gene Expression Omnibus under accession number GSE13278. PMID- 26981394 TI - Transcriptome response to copper heavy metal stress in hard-shelled mussel (Mytilus coruscus). AB - The hard-shelled mussel (Mytilus coruscus) has considerably one of the most economically important marine shellfish worldwide and considered as a good invertebrate model for ecotoxicity study for a long time. In the present study, we used Illumina sequencing technology (HiSeq2000) to sequence, assemble and annotate the transcriptome of the hard-shelled mussel which challenged with copper pollution. A total of 21,723,913 paired-end clean reads (NCBI SRA database SRX1411195) were generated from HiSeq2000 sequencer and 96,403 contigs (with N50 = 1118 bp) were obtained after de novo assembling with Trinity software. Digital gene expression analysis reveals 1156 unigenes are upregulated and 1681 unigenes are downregulated when challenged with copper. By KEGG pathway enrichment analysis, we found that unigenes in four KEGG pathways (aminoacyl-tRNA biosynthesis, apoptosis, DNA replication and mismatch repair) show significant differential expressed between control and copper treated groups. We hope that the gill transcriptome in copper treated hard-shelled mussel can give useful information to understand how mussel handles with heavy metal stress at molecular level. PMID- 26981395 TI - De novo assembly and comparison of the ovarian transcriptomes of the common Chinese cuttlefish (Sepiella japonica) with different gonadal development. AB - The common Chinese cuttlefish (Sepiella japonica) has been considered one of the most economically important marine Cephalopod species in East Asia and seed breeding technology has been established for massive aquaculture and stock enhancement. In the present study, we used Illumina HiSeq2000 to sequence, assemble and annotate the transcriptome of the ovary tissues of S. japonica for the first time. A total of 53,116,650 and 53,446,640 reads were obtained from the immature and matured ovaries, respectively (NCBI SRA database SRX1409472 and SRX1409473), and 70,039 contigs (N50 = 1443 bp) were obtained after de novo assembling with Trinity software. Digital gene expression analysis reveals 47,288 contigs show differential expression profile and 793 contigs are highly expressed in the immature ovary, while 38 contigs are highly expressed in the mature ovary with FPKM > 100. We hope that the ovarian transcriptome and those stage-enriched transcripts of S. japonica can provide some insight into the understanding of genome-wide transcriptome profile of cuttlefish gonad tissue and give useful information in cuttlefish gonad development. PMID- 26981396 TI - Microarray studies on the effect of silencing tynA in Escherichia coli K-12. AB - To study the biological role of the tynA gene product of Escherichia coli, a primary amine oxidase (ECAO, E.C. 1.4.3.21), the tynA gene was genetically silenced by conjugation with a kanamycin resistance cassette. We used a microarray method to compare the mRNA expression in the modified strain (DeltatynA) to that in the wild type (wt) strain at the time of induction of ECAO expression (0 h) as well as 1 h and 4 h after the induction. These data in brief describe the different experimental conditions, sample preparation, data collection and analysis of the conducted microarray experiment. The differential expression of genes in the studied strains 1 h after the induction of ECAO expression is described. The microarray data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE65385. PMID- 26981397 TI - Genome-wide localization of Rrm3 and Pif1 DNA helicases at stalled active and inactive DNA replication forks of Saccharomyces cerevisiae. AB - The genome of the budding yeast Saccharomyces cerevisiae is sequenced and the location and dynamic of activation of DNA replication origins are known. G1 synchronized yeast cells can be released into S-phase in the presence of hydroxyurea (HU) (1), which slows down DNA replication and retains replication forks in proximity of DNA replication origins. In this condition, the Chromatin Immuno-Precipitation on chip (ChIP on chip) (2-4) of replisome components allows the precise localization of all active DNA replication forks. This analysis can be coupled with the ssDNA-BromodeoxyUridine (ssDNA-BrdU) Immuno-Precipitation on chip (ssDNA-BrdU IP on chip) technique (5-7), which detects the location of newly synthesized DNA. Comparison of binding and BrdU incorporation profiles allows to locate a factor of interest at DNA replication forks genome wide. We present datasets deposited in the gene expression omnibus (GEO) database under accession number GSE68214, which show how the DNA helicases Rrm3 and Pif1 (8) associate to active and inactive DNA replication forks. PMID- 26981398 TI - Type I and type II interferon responses in two human liver cell lines (Huh-7 and HuH6). AB - Most studies investigating the biology of Hepatitis C virus (HCV) have used the human hepatoma cell line Huh-7 or subclones thereof, as these are the most permissive cell lines for HCV infection and replication. Other cell lines also support replication of HCV, most notably the human hepatoblastoma cell line HuH6. HCV replication in cell culture is generally highly sensitive to interferons (IFNs) and differences in the IFN-mediated inhibition of virus replication may reflect alterations in the IFN-induced antiviral response inherent to different host cells. For example, HCV replication is highly sensitive to IFN-gamma treatment in Huh-7, but not in HuH6 cells. In this study, we used microarray based gene expression profiling to compare the response of Huh-7 and HuH6 cells to stimulation with IFN-alpha and IFN-gamma. Furthermore, we determined whether the resistance of HCV replication in HuH6 cells can be linked to differences in the expression profile of IFN-regulated genes. Although both cells lines responded to IFNs with rapid changes in gene expression, thereby demonstrating functional type I and type II signaling pathways, differences were observed for a number of genes. Raw and normalized expression data have been deposited in GEO under accession number GSE68927. PMID- 26981399 TI - Genome-wide identification and analysis of mRNA expression in fibroblasts, ES cells, and iPS cells. AB - Genome-wide expression patterns of mRNA were compared between mouse embryonic fibroblasts (MEFs), embryonic stem cells (ESCs), and various types of induced pluripotent stem cells (iPSCs). iPSCs were established and maintained using modified Oct4 with or without exogenous leukemia inhibitory factor (LIF) and used to identify mRNAs that were potentially involved in the LIF-independence. The data have been deposited in the NCBI's Gene Expression Omnibus (GEO) database with the accession number GSE65563. PMID- 26981400 TI - Nucleosomal chromatin in the mature sperm of Drosophila melanogaster. AB - During spermiogenesis in mammals and many other vertebrate classes, histone containing nucleosomes are replaced by protamine toroids, which can repackage chromatin at a 10 to 20-fold higher density than in a typical somatic nucleus. However, recent evidence suggests that sperm of many species, including human and mouse retain a small compartment of nucleosomal chromatin, particularly near genes important for embryogenesis. As in mammals, spermiogenesis in the fruit fly, Drosophila melanogaster has also been shown to undergo a programmed substitution of nucleosomes with protamine-like proteins. Using chromatin immunoprecipitation (ChIP) and whole-genome tiling array hybridization (ChIP chip), supported by immunocytochemical evidence, we show that in a manner analogous to nucleosomal chromatin retention in mammalian spermatozoa, distinct domains packaged by the canonical histones H2A, H2B, H3 and H4 are present in the fly sperm nucleus. We also find evidence for the retention of nucleosomes with specific histone H3 trimethylation marks characteristic of chromatin repression (H3K9me3, H3K27me3) and active transcription (H3K36me3). Raw and processed data from the experiments are available at GEO, accession GSE52165. PMID- 26981401 TI - IL-22 regulation of functional gene expression in salivary gland cells. AB - TH17 cells and their associated signature cytokines, IL-17 and IL-22, are highly elevated in primary Sjogren's syndrome (pSjS). The levels of IL-22 present in sera showed significant correlations with many disease parameters, specifically hyposalivation, anti-SSB, anti-SSA/SSB, hypergammaglobulinemia and rheumatoid factor. The present study aims to examine the biological function of IL-22 on human salivary glands. To accomplish the goal, microarray analysis using the HumanHT-12 v4 Expression BeadChip was utilized to determine the biological function of IL-22. Differential expression analyses were conducted using the LIMMA package from the Bioconductor project. MTT assay, flow cytometry and Western blotting were used to identify the function of IL-22 on human salivary gland cells. Results indicate an extensive effect of IL-22 on many major molecular functions including activation of antimicrobial genes and downregulation of immune-associated pathways. Functional studies performed in vitro using human salivary gland cells treated with IL-22 indicated a direct effect of IL-22 on cell cycling, specifically reducing cellular proliferation at the G2-M phase by activation of STAT3. These results suggest the important role of IL-22 in the salivary gland function. The present study suggests that IL-22 might be involved in regulating inflammation and controlling the cell proliferation in SjS. PMID- 26981402 TI - Draft genome sequence of a multidrug-resistant Chryseobacterium indologenes isolate from Malaysia. AB - Chryseobacterium indologenes is an emerging pathogen which poses a threat in clinical healthcare setting due to its multidrug-resistant phenotype and its common association with nosocomial infections. Here, we report the draft genome of a multidrug-resistant C. indologenes CI_885 isolated in 2014 from Malaysia. The 908,704-kb genome harbors a repertoire of putative antibiotic resistance determinants which may elucidate the molecular basis and underlying mechanisms of its resistant to various classes of antibiotics. The genome sequence has been deposited in DDBJ/EMBL/GenBank under the accession number LJOD00000000. PMID- 26981404 TI - High-quality ChIP-seq analysis of MBD3 in human breast cancer cells. AB - Chromatin accessibility is tightly regulated by multiple factors/mechanisms to establish different cell type-specific gene expression programs from a single genome. Dysregulation of this process can lead to diseases including cancer. The Mi-2/nucleosome remodeling and deacetylase (NuRD) complex is thought to orchestrate chromatin structure using its intrinsic nucleosome remodeling and histone deacetylase activities. However, the detailed mechanisms by which the NuRD complex regulates chromatin structure in vivo are not yet known. To explore the regulatory mechanisms of the NuRD complex, we mapped genome-wide localization of MBD3, a structural component of NuRD, in a human breast cancer cell line (MDA MB-231) using a modified ChIP-seq protocol. Our data showed high quality localization information (i.e., high mapping efficiency and low PCR duplication rate) and excellent consistency between biological replicates. The data are deposited in the Gene Expression Omnibus (GSE76116). PMID- 26981403 TI - Complete genome sequence of Acinetobacter baumannii XH386 (ST208), a multi-drug resistant bacteria isolated from pediatric hospital in China. AB - Acinetobacter baumannii is an important bacterium that emerged as a significant nosocomial pathogen worldwide. The rise of A. baumannii was due to its multi-drug resistance (MDR), while it was difficult to treat multi-drug resistant A. baumannii with antibiotics, especially in pediatric patients for the therapeutic options with antibiotics were quite limited in pediatric patients. A. baumannii ST208 was identified as predominant sequence type of carbapenem resistant A. baumannii in the United States and China. As we knew, there was no complete genome sequence reproted for A. baumannii ST208, although several whole genome shotgun sequences had been reported. Here, we sequenced the 4087-kilobase (kb) chromosome and 112-kb plasmid of A. baumannii XH386 (ST208), which was isolated from a pediatric hospital in China. The genome of A. baumannii XH386 contained 3968 protein-coding genes and 94 RNA-only encoding genes. Genomic analysis and Minimum inhibitory concentration assay showed that A. baumannii XH386 was multi drug resistant strain, which showed resistance to most of antibiotics, except for tigecycline. The data may be accessed via the GenBank accession number CP010779 and CP010780. PMID- 26981405 TI - Profiling of microbial community of Odisha hot spring based on metagenomic sequencing. AB - Deulajhari hot spring has diverse temperature and pH range varying from 43 degrees C to 65 degrees C and 7.83 to 8.10 respectively. Dense foliage around Deulajhari hot spring contributes to the high total organic carbon content (TOC). In our experiment we took sediment samples from the two Deulajhari hot springs (S1 and S2) out of the cluster having temperature of 43 degrees C and 55 degrees C and pH of 7.83 and 7.14 respectively. Sediment samples were analysed using 16S rRNA of V3-V4 region by amplicon metagenome sequencing. Over 34 phyla were detected in cluster S1 and 32 phyla in cluster S2 at the existing physiochemical parameters temperature 43 degrees C, pH 7.83, electroconductivity 0.019 dSm(- 1), and total organic carbon (TOC) 3.80% for S1 and temperature 55 degrees C, pH 7.14, electroconductivity 0.019 dSm(- 1), and total organic carbon (TOC) 0.97% for S2. Existence of a vast number of unresolved sequences 179 out of 292 in S1 and 186 out of 314 in S2 at the genus level emphasizes the significance of our study. Metagenome sequence information for the both clusters S1 and S2 of Deulajhari is available at NCBI, SRA database with accession number SRX1459732 and SRX1459733 respectively. Direct link to the deposited data: www.ncbi.nlm.nih.gov/sra/SRX1459732 www.ncbi.nlm.nih.gov/sra/SRX1459733. PMID- 26981406 TI - Mutation-based structural modification and dynamics study of amyloid beta peptide (1-42): An in-silico-based analysis to cognize the mechanism of aggregation. AB - Alzheimer's disease is the prevalent cause of premature senility, a progressive mental disorder due to degeneration in brain and deposition of amyloid beta peptide (1-42, a misfolded protein) in the form of aggregation that prevails for a prolonged time and obstructs every aspect of life. One of the primary hallmarks of the neuropathological disease is the accretion of amyloid beta peptide in the brain that leads to Alzheimer's disease, but the mechanism is still a mystery. Several investigations have shown that mutations at specific positions have a significant impact in stability of the peptide as predicted from aggregation profiles. Here in our study, we have analyzed the mutations by substituting residues at position A22G, E22G, E22K, E22Q, D23N, L34V and molecular dynamics have been performed to check the deviation in stability and conformation of the peptide. The results validated that the mutations at specific positions lead to instability and the proline substitution at E22P and L34P stalled the aggregation of the peptide. PMID- 26981407 TI - Genome sequence of Enterobacter sp. ST3, a quorum sensing bacterium associated with marine dinoflagellate. AB - Phycosphere environment is a typical marine niche, harbor diverse populations of microorganisms, which are thought to play a critical role in algae host and influence mutualistic and competitive interactions. Understanding quorum sensing based acyl-homoserine lactone (AHL) language may shed light on the interaction between algal-associated microbial communities in the native environment. In this work, we isolated an epidermal bacterium (was tentatively named Enterobacter sp. ST3, and deposited in SOA China, the number is MCCC1K02277-ST3) from the marine dinoflagellate Scrippsiella trochoidea, and found it has the ability to produce short-chain AHL signal. In order to better understand its communication information at molecular level, the genomic map was investigated. The genome size was determined to be 4.81 Mb with a G + C content of 55.59%, comprising 6 scaffolds of 75 contigs containing 4647 protein-coding genes. The functional proteins were predicted, and 3534 proteins were assigned to COG functional categories. An AHL-relating gene, LuxR, was found in upstream position at contig 1. This genome data may provide clues to increase understanding of the chemical characterization and ecological behavior of strain ST3 in the phycosphere microenvironment. PMID- 26981408 TI - De novo transcriptome assembly of two contrasting pumpkin cultivars. AB - Cucurbita pepo (squash, pumpkin, gourd), a worldwide-cultivated vegetable of American origin, is extremely variable in fruit characteristics. However, the information associated with genes and genetic markers for pumpkin is very limited. In order to identify new genes and to develop genetic markers, we performed a transcriptome analysis (RNA-Seq) of two contrasting pumpkin cultivars. Leaves and female flowers of cultivars, 'Big Moose' with large round fruits and 'Munchkin' with small round fruits, were harvested for total RNA extraction. We obtained a total of 6 GB (Big Moose; http://www.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3056882) and 5 GB (Munchkin; http://www.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3056883) sequence data (NCBI SRA database SRX1502732 and SRX1502735, respectively), which correspond to 18,055,786 and 14,824,292 150-base reads. After quality assessment, the clean sequences where 17,995,932 and 14,774,486 respectively. The numbers of total transcripts for 'Big Moose' and 'Munchkin' were 84,727 and 68,051, respectively. TransDecoder identified possible coding regions in assembled transcripts. This study provides transcriptome data for two contrasting pumpkin cultivars, which might be useful for genetic marker development and comparative transcriptome analyses. PMID- 26981409 TI - Similarity analysis between chromosomes of Homo sapiens and monkeys with correlation coefficient, rank correlation coefficient and cosine similarity measures. AB - In this paper, we consider correlation coefficient, rank correlation coefficient and cosine similarity measures for evaluating similarity between Homo sapiens and monkeys. We used DNA chromosomes of genome wide genes to determine the correlation between the chromosomal content and evolutionary relationship. The similarity among the H. sapiens and monkeys is measured for a total of 210 chromosomes related to 10 species. The similarity measures of these different species show the relationship between the H. sapiens and monkey. This similarity will be helpful at theft identification, maternity identification, disease identification, etc. PMID- 26981410 TI - The testis and ovary transcriptomes of the rock bream (Oplegnathus fasciatus): A bony fish with a unique neo Y chromosome. AB - The rock bream (Oplegnathus fasciatus) is considerably one of the most economically important marine fish in East Asia and has a unique neo-Y chromosome system that is a good model to study the sex determination and differentiation in fish. In the present study, we used Illumina sequencing technology (HiSeq2000) to sequence, assemble and annotate the transcriptome of the testis and ovary tissues of rock bream. A total of 40,004,378 (NCBI SRA database SRX1406649) and 53,108,992 (NCBI SRA database SRX1406648) high quality reads were obtained from testis and ovary RNA sequencing, respectively, and 60,421 contigs (with average length of 1301 bp) were obtained after de novo assembling with Trinity software. Digital gene expression analysis reveals 14,036 contigs that show gender-enriched expressional profile with either testis-enriched (237 contigs) or ovary-enriched (581 contigs) with RPKM > 100. There are 237 male- and 582 female-abundant expressed genes that show sex dimorphic expression. We hope that the gonad transcriptome and those gender-enriched transcripts of rock bream can provide some insight into the understanding of genome-wide transcriptome profile of teleost gonad tissue and give useful information in fish gonad development. PMID- 26981411 TI - Computational gene expression profiling under salt stress reveals patterns of co expression. AB - Plants respond differently to environmental conditions. Among various abiotic stresses, salt stress is a condition where excess salt in soil causes inhibition of plant growth. To understand the response of plants to the stress conditions, identification of the responsible genes is required. Clustering is a data mining technique used to group the genes with similar expression. The genes of a cluster show similar expression and function. We applied clustering algorithms on gene expression data of Solanum tuberosum showing differential expression in Capsicum annuum under salt stress. The clusters, which were common in multiple algorithms were taken further for analysis. Principal component analysis (PCA) further validated the findings of other cluster algorithms by visualizing their clusters in three-dimensional space. Functional annotation results revealed that most of the genes were involved in stress related responses. Our findings suggest that these algorithms may be helpful in the prediction of the function of co-expressed genes. PMID- 26981412 TI - Investigation of the microbial community in the Odisha hot spring cluster based on the cultivation independent approach. AB - Deulajhari hot spring is located in the Angul district of Odisha. The significance of this hot spring is the presence of the hot spring cluster adjacent to the cold spring which attracts the attention of microbiologists to understand the role of physio-chemical factors of these springs on bacterial community structure. Next-generation sequencing technology helps us to depict the pioneering microflora of any ecological niche based on metagenomic approach. Our study represents the first Illumina based metagenomic study of Deulajhari hot spring DH1, and DH2 of the cluster with temperature 65 degrees C to 55 degrees C respectively establishing a difference of 10 degrees C. Comprehensive study of microbiota of these two hot springs was done using the metagenomic sequencing of 16S rRNA of V3-V4 region extracting metagenomic DNA from the two hot spring sediments. Sequencing community DNA reported about 28 phyla in spring DH1 of which the majority were Chloroflexi (22.98%), Proteobacteria (15.51%), Acidobacteria (14.51%), Chlorobi (9.52%), Nitrospirae (8.54%), and Armatimonadetes (7.07%), at the existing physiochemical conditions like; temperature 65 degrees C, pH 8.06, electro conductivity 0.020 dSm(- 1), and total organic carbon (TOC) 3.76%. About 40 phyla were detected in cluster DH2 at the existing physiochemical parameters like temperature 55 degrees C, pH 8.10, electro conductivity 0.019 dSm(- 1), and total organic carbon (TOC) 0.58% predominated with Chloroflexi (41.98%), Proteobacteria (10.74%), Nitrospirae (10.01%), Chlorobi (8.73%), Acidobacteria (6.73%) and Planctomycetes (3.73%). Approximately 68 class, 107 order, 171 genus and 184 species were reported in cluster DH1 but 102 class, 180 order, 375 genus and 411 species in cluster DH2. The comparative metagenomics study of the Deulajhari hot spring clusters DH1, and DH2 depicts the differential profile of the microbiota. Metagenome sequences of these two hot spring clusters are deposited to the SRA database and are available in NCBI with accession no. SRX1459734 for DH1 and SRX1459735 for DH2. PMID- 26981413 TI - Analyses of MYMIV-induced transcriptome in Vigna mungo as revealed by next generation sequencing. AB - Mungbean Yellow Mosaic Virus (MYMIV) is the viral pathogen that causes yellow mosaic disease to a number of legumes including Vigna mungo. VM84 is a recombinant inbred line resistant to MYMIV, developed in our laboratory through introgression of resistance trait from V. mungo line VM-1. Here we present the quality control passed transcriptome data of mock inoculated (control) and MYMIV infected VM84, those have already been submitted in Sequence Read Archive (SRX1032950, SRX1082731) of NCBI. QC reports of FASTQ files generated by 'SeqQC V2.2' bioinformatics tool. PMID- 26981414 TI - Gene expression profiling of the tumor microenvironment in human intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) is the second most common type of malignant primary tumors in the liver. ICC is an aggressive cancer with a poor survival and limited therapeutic options. At the histological level, ICC is characterized by an abundant stroma (i.e. the tumor microenvironment that notably includes components of the extracellular matrix, stromal cells and soluble factors). Tumor microenvironment is known to play a key role in tumor onset and progression but it is poorly characterized at the molecular level. Thus, this study was specifically designed to identify genes that are significantly deregulated in the tumor microenvironment of human ICC. Here we provide a detailed description of the experimental design and methods used to acquire the genomic data deposited into Gene Expression Omnibus (GEO) under the accession number GSE45001. Our genomic dataset provides insights on the molecular pathways altered in the microenvironment of ICC and allows the identification of novel ICC biomarkers, as exemplified previously in Hepatology (PMID: 23775819). PMID- 26981415 TI - Draft genome of Leisingera aquaemixtae CECT 8399(T), a member of the Roseobacter clade isolated from a junction of fresh and ocean water in Jeju Island, South Korea. AB - We report the draft genome sequence and annotation of Leisingera aquaemixtae CECT 8399(T) (DDBJ/EMBL/GenBank accession number CYSR00000000) which comprises 4,614,060 bp, 4313 protein coding genes, 54 tRNA coding genes and 7 rRNA coding genes. General findings of the annotated genome, such as pigment indigoidine operon, phenylacetate oxidation genes or predictable number of replicons, are commented in comparison to other Leisingera species. Average Nucleotide Identity between available genomes of type strains of species of Leisingera and Phaeobacter genera has been calculated to evaluate its current classification. PMID- 26981416 TI - Draft genome sequence of Thalassobius mediterraneus CECT 5383(T), a poly-beta hydroxybutyrate producer. AB - Thalassobius mediterraneus is the type species of the genus Thalassobius and a member of the Roseobacter clade, an abundant representative of marine bacteria. T. mediterraneus XSM19(T) (= CECT 5383(T)) was isolated from the Western Mediterranean coast near Valencia (Spain) in 1989. We present here the draft genome sequence and annotation of this strain (ENA/DDBJ/NCBI accession number CYSF00000000), which is comprised of 3,431,658 bp distributed in 19 contigs and encodes 10 rRNA genes, 51 tRNA genes and 3276 protein coding genes. Relevant findings are commented, including the complete set of genes required for poly beta-hydroxybutyrate (PHB) synthesis and genes related to degradation of aromatic compounds. PMID- 26981417 TI - MIF inhibition reverts the gene expression profile of human melanoma cell line induced MDSCs to normal monocytes. AB - Myeloid-derived suppressor cells (MDSCs) are potently immunosuppressive innate immune cells that accumulate in advanced cancer patients and actively inhibit anti-tumor T lymphocyte responses [1]. Increased numbers of circulating MDSCs directly correlate with melanoma patient morbidity and reduced anti-tumor immune responses [2], [3]. Previous studies have revealed that monocyte-derived macrophage migration inhibitory factor (MIF) is necessary for the immune suppressive function of MDSCs in mouse models of melanoma [4], [5]. To investigate whether MIF participates in human melanoma-induced MDSC differentiation and/or suppressive function, we have established an in vitro MDSC induction model using primary, normal human monocytes co-cultured with human melanoma cell lines in the presence or absence of the MIF antagonist-4-IPP [4], [6], [7], [8], [9]. To identify potential mechanistic effectors, we have performed transcriptome analyses on cultured monocytes and on melanoma-induced MDSCs obtained from either untreated or 4-IPP-treated A375:monocyte co-cultures. Here, we present a detailed protocol, which can facilitate easy reproduction of the microarray results (NCBI GEO accession number GSE73333) published by Yaddanapudi et al. (2015) in Cancer Immunology Research [10]. PMID- 26981418 TI - Draft genome sequence of strain MC1A, a UV-resistant bacterium isolated from dry soil in Puerto Rico. AB - We report here the draft genome sequence of a novel UV-resistant bacterium isolated from dry soil on the south coast of Puerto Rico. Based on polyphasic taxonomy, strain MC1A represents a new species and the name Solirubrum puertoriconensis is proposed. Assembly was performed using NGEN Assembler into eight contigs (N50 = 1,292,788), the largest of which included 1,549,887 bp. The draft genome consists of 4,810,875 bp and has a GC content of 58.7%. Several genes related to DNA repair and UV resistance were found. The Whole Genome Shotgun project is available at DDBJ/EMBL/GenBank under the accession LNAL00000000. PMID- 26981419 TI - Genome sequencing and annotation of multidrug resistant Mycobacterium tuberculosis (MDR-TB) PR10 strain. AB - Here, we report the draft genome sequence and annotation of a multidrug resistant Mycobacterium tuberculosis strain PR10 (MDR-TB PR10) isolated from a patient diagnosed with tuberculosis. The size of the draft genome MDR-TB PR10 is 4.34 Mbp with 65.6% of G + C content and consists of 4637 predicted genes. The determinants were categorized by RAST into 400 subsystems with 4286 coding sequences and 50 RNAs. The whole genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession number CP010968. PMID- 26981420 TI - Genome-wide RNA-seq and ChIP-seq reveal Linc-YY1 function in regulating YY1/PRC2 activity during skeletal myogenesis. AB - Little is known how lincRNAs are involved in skeletal myogenesis. Here we describe the discovery and functional annotation of Linc-YY1, a novel lincRNA originating from the promoter of the transcription factor (TF) Yin Yang 1 (YY1). Starting from whole transcriptome shotgun sequencing (a.k.a. RNA-seq) data from muscle C2C12 cells, a series of bioinformatics analysis was applied towards the identification of hundreds of high-confidence novel lincRNAs. Genome-wide approaches were then employed to demonstrate that Linc-YY1 functions to promote myogenesis through associating with YY1 and regulating YY1/PRC2 transcriptional activity in trans. Here we describe the details of the ChIP-seq, RNA-seq experiments, and data analysis procedures associated with the study published by Zhou and colleagues in the Nature Communications Journal in 2015 Zhou et al. (2015) [1]. The data was deposited on NCBI's Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) with accession number GSE74049. PMID- 26981421 TI - Genome-wide analysis of KAP1, the 7SK snRNP complex, and RNA polymerase II. AB - The transition of RNA polymerase II (Pol II) from transcription initiation into productive elongation in eukaryotic cells is regulated by the P-TEFb kinase, which phosphorylates the C-terminal domain of paused Pol II at promoter-proximal regions. Our recent study found that P-TEFb (in an inhibited state bound to the 7SK snRNP complex) interacts with the KAP1/TRIM28 transcriptional regulator, and that KAP1 and the 7SK snRNP co-occupy most gene promoters containing paused Pol II. Here we provide a detailed experimental description and analysis of the ChIP seq datasets that have been deposited into Gene Expression Omnibus (GEO): GS72622, so that independent groups can replicate and expand upon these findings. We propose these datasets would provide valuable information for researchers studying mechanisms of transcriptional regulation including Pol II pausing and pause release. PMID- 26981422 TI - Transcriptomic profiling of Arabidopsis gene expression in response to varying micronutrient zinc supply. AB - Deficiency of the micronutrient zinc is a widespread condition in agricultural soils, causing a negative impact on crop quality and yield. Nevertheless, there is an insufficient knowledge on the regulatory and molecular mechanisms underlying the plant response to inadequate zinc nutrition [1]. This information should contribute to the development of plant-based solutions with improved nutrient-use-efficiency traits in crops. Previously, the transcription factors bZIP19 and bZIP23 were identified as essential regulators of the response to zinc deficiency in Arabidopsis thaliana [2]. A microarray experiment comparing gene expression between roots of wild-type and the mutant bzip19 bzip23, exposed to zinc deficiency, led to the identification of differentially expressed genes related with zinc homeostasis, namely its transport and plant internal translocation [2]. Here, we provide the detailed methodology, bioinformatics analysis and quality controls related to the microarray gene expression profiling published by Assuncao and co-workers [2]. Most significantly, the present dataset comprises new experimental variables, including analysis of shoot tissue, and zinc sufficiency and excess supply. Thus, it expands from 8 to 42 microarrays hybridizations, which have been deposited at the Gene Expression Omnibus (GEO) under the accession number GSE77286. Overall, it provides a resource for research on the molecular basis and regulatory events of the plant response to zinc supply, emphasizing the importance of Arabidopsis bZIP19 and bZIP23 transcription factors. PMID- 26981423 TI - Draft genome sequence of Diaporthe aspalathi isolate MS-SSC91, a fungus causing stem canker in soybean. AB - Diaporthe aspalathi (Syn. Diaporthe phaseolorum var. meridionalis) is the causal agent of the southern stem canker (SSC) disease in soybean. This disease can kill plants from the middle to the end of the growing season resulting in severe yield loss. The mechanisms of SSC disease development and pathogen invasion of soybean are not fully understood. The genome sequence of D. aspalathi has not been described. In this article, we report the successful assembly of the draft genome sequence of a D. aspalathi isolate, designated MS-SSC91, that was isolated from the stem of a field-grown soybean plant in Mississippi, USA in 2006. This study represents the first reported genome sequence of D. aspalathi in the Diaporthe Phomopsis complex. The whole genome shotgun sequence of the MS-SSC91 isolate has been deposited at DDBJ/EMBL/GenBank under the accession LJJS00000000 and the sequences could be found at the site http://www.ncbi.nlm.nih.gov/assembly/GCA_001447215.1/. The MS-SSC91 genome sequences will provide information on the genetic basis of fungal infection of the soybean stem. It is valuable for studying soybean-fungal interactions and developing new control strategies for this pathogen. PMID- 26981424 TI - Identification of Tox chromatin binding properties and downstream targets by DamID-Seq. AB - In recent years, DNA adenine methyltransferase identification (DamID) has emerged as a powerful tool to profile protein-DNA interaction on a genome-wide scale. While DamID has been primarily combined with microarray analyses, which limits the spatial resolution and full potential of this technique, our group was the first to combine DamID with sequencing (DamID-Seq) for characterizing the binding loci and properties of a transcription factor (Tox) (sequencing data available at NCBI's Gene Expression Omnibus under the accession number GSE64240). Our approach was based on the combination and optimization of several bioinformatics tools that are here described in detail. Analysis of Tox proximity to transcriptional start sites, profiling on enhancers and binding motif has allowed us to identify this transcription factor as an important new regulator of neural stem cells differentiation and newborn neurons maturation during mouse cortical development. Here we provide a valuable resource to study the role of Tox as a novel key determinant of mammalian somatic stem cells during development of the nervous and lymphatic system, in which this factor is known to be active, and describe a useful pipeline to perform DamID-Seq analyses for any other transcription factor. PMID- 26981425 TI - Analysis of telomerase target gene expression effects from murine models in patient cohorts by homology translation and random survival forest modeling. AB - Acute myeloid leukemia (AML) is an aggressive and rapidly fatal blood cancer that affects patients of any age group. Despite an initial response to standard chemotherapy, most patients relapse and this relapse is mediated by leukemia stem cell (LSC) populations. We identified a functional requirement for telomerase in sustaining LSC populations in murine models of AML and validated this requirement using an inhibitor of telomerase in human AML. Here, we describe in detail the contents, quality control and methods of the gene expression analysis used in the published study (Gene Expression Omnibus GSE63242). Additionally, we provide annotated gene lists of telomerase regulated genes in AML and R code snippets to access and analyze the data used in the original manuscript. PMID- 26981426 TI - Microarray analysis of kiwifruit (Actinidia chinensis) bark following challenge by the sucking insect Hemiberlesia lataniae (Hemiptera: Diaspididae). AB - Both commercial and experimental genotypes of kiwifruit (Actinidia spp.) exhibit large differences in response to insect pests. An understanding of the vine's physiological response to insect feeding and its genetic basis will be important in assisting the development of varieties with acceptable levels of pest resistance. This experiment describes transcriptome changes observed in the bark of kiwifruit 2 and 7 days after the commencement of feeding by the armored scale insect pest, Hemiberlesia lataniae. Using a cDNA microarray consisting of 17,512 unigenes, we measured transcriptome changes and analyzed these into functional ontology categories using MapMan. Results are available in the GEO database GSE73922 and are described fully in Ref. Hill et al. (2015) [1]. After 7 days, transcripts associated with photosynthesis were down-regulated and secondary metabolism was up-regulated. Differential expression of transcripts associated with stress response was consistent with a defense response involving both effector and herbivore-triggered immunities, with predominant involvement of the salicylic acid phytohormonal pathway. This hypothesis was supported by the results of two laboratory experiments. The methods described here could be further adapted and applied to the study of plant responses to a wide range of sessile sucking pests. PMID- 26981427 TI - Draft genome sequence of Halorubrum tropicale strain V5, a novel halophilic archaeon isolated from the solar salterns of Cabo Rojo, Puerto Rico. AB - The genus Halorubrum is a member of the family Halobacteriaceae which currently has the highest number of described species (31) of all the haloarchaea. Here we report the draft genome sequence of strain V5, a new species within this genus that was isolated from the solar salterns of Cabo Rojo, Puerto Rico. Assembly was performed and rendered the genome into 17 contigs (N50 = 515,834 bp), the largest of which contains 1,031,026 bp. The genome consists of 3.57 MB in length with G + C content of 67.6%. In general, the genome includes 4 rRNAs, 52 tRNAs, and 3246 protein-coding sequences. The NCBI accession number for this genome is LIST00000000 and the strain deposit number is CECT9000. PMID- 26981428 TI - Draft genome of Haloarcula rubripromontorii strain SL3, a novel halophilic archaeon isolated from the solar salterns of Cabo Rojo, Puerto Rico. AB - The genus Haloarcula belongs to the family Halobacteriaceae which currently has 10 valid species. Here we report the draft genome sequence of strain SL3, a new species within this genus, isolated from the Solar Salterns of Cabo Rojo, Puerto Rico. Genome assembly performed using NGEN Assembler resulted in 18 contigs (N50 = 601,911 bp), the largest of which contains 1,023,775 bp. The genome consists of 3.97 MB and has a GC content of 61.97%. Like all species of Haloarcula, the genome encodes heterogeneous copies of the small subunit ribosomal RNA. In addition, the genome includes 6 rRNAs, 48 tRNAs, and 3797 protein coding sequences. Several carbohydrate-active enzymes genes were found, as well as enzymes involved in the dihydroxyacetone processing pathway which are not found in other Haloarcula species. The NCBI accession number for this genome is LIUF00000000 and the strain deposit number is CECT9001. PMID- 26981429 TI - Transcriptional analysis of antiviral small molecule therapeutics as agonists of the RLR pathway. AB - The recognition of pathogen associated molecular patterns (PAMPs) by pattern recognition receptors (PRR) during viral infection initiates the induction of antiviral signaling pathways, including activation of the Interferon Regulator Factor 3 (IRF3). We identified small molecule compounds that activate IRF3 through MAVS, thereby inhibiting infection by viruses of the families Flaviviridae (West Nile virus, dengue virus and hepatitis C virus), Filoviridae (Ebola virus), Orthomyxoviridae (influenza A virus), Arenaviridae (Lassa virus) and Paramyxoviridae (respiratory syncytial virus, Nipah virus) (1). In this study, we tested a lead compound along with medicinal chemistry-derived analogs to compare the gene transcriptional profiles induced by these molecules to that of other known MAVS-dependent IRF3 agonists. Transcriptional analysis of these small molecules revealed the induction of specific antiviral genes and identified a novel module of host driven immune regulated genes that suppress infection of a range of RNA viruses. Microarray data can be found in Gene Expression Omnibus (GSE74047). PMID- 26981430 TI - Differential RNA-seq analysis comparing APC-defective and APC-restored SW480 colorectal cancer cells. AB - The adenomatous polyposis coli (APC) tumour suppressor gene is mutated in about 80% of colorectal cancers (CRC) Brannon et al. (2014) [1]. APC is a large multifunctional protein that regulates many biological functions including Wnt signalling (through the regulation of beta-catenin stability) Reya and Clevers (2005) [2], cell migration Kroboth et al. (2007), Sansom et al. (2004) [3], [4], mitosis Kaplan et al. (2001) [5], cell adhesion Faux et al. (2004), Carothers et al. (2001) [6], [7] and differentiation Sansom et al. (2004) [4]. Although the role of APC in CRC is often described as the deregulation of Wnt signalling, its other biological functions suggest that there are other factors at play that contribute to the onset of adenomas and the progression of CRC upon the truncation of APC. To identify genes and pathways that are dysregulated as a consequence of loss of function of APC, we compared the gene expression profiles of the APC mutated human CRC cell line SW480 following reintroduction of wild type APC (SW480 + APC) or empty control vector (SW480 + vector control) Faux et al. (2004) . Here we describe the RNA-seq data derived for three biological replicates of parental SW480, SW480 + vector control and SW480 + APC cells, and present the bioinformatics pipeline used to test for differential gene expression and pathway enrichment analysis. A total of 1735 genes showed significant differential expression when APC was restored and were enriched for genes associated with cell polarity, Wnt signalling and the epithelial to mesenchymal transition. There was additional enrichment for genes involved in cell-cell adhesion, cell-matrix junctions, angiogenesis, axon morphogenesis and cell movement. The raw and analysed RNA-seq data have been deposited in the Gene Expression Omnibus (GEO) database under accession number GSE76307. This dataset is useful for further investigations of the impact of APC mutation on the properties of colorectal cancer cells. PMID- 26981432 TI - Whole-genome sequence of Clostridium lituseburense L74, isolated from the larval gut of the rhinoceros beetle, Trypoxylus dichotomus. AB - Clostridium lituseburense L74 was isolated from the larval gut of the rhinoceros beetle, Trypoxylus dichotomus collected in Yeong-dong, Chuncheongbuk-do, South Korea and subjected to whole genome sequencing on HiSeq platform and annotated on RAST. The nucleotide sequence of this genome was deposited into DDBJ/EMBL/GenBank under the accession NZ_LITJ00000000. PMID- 26981431 TI - Genome-wide analysis of TIAR RNA ligands in mouse macrophages before and after LPS stimulation. AB - TIA-1 related protein (TIAR) is a RNA-binding protein involved in several steps of gene expression such as RNA splicing Aznarez et al. (2008) [1] and translation Piecyk et al. (2000) [2]. TIAR contains three RNA recognition motifs (RRMs) allowing its interaction with specific sequences localized in the untranslated regions (UTRs) of several mRNAs. In myeloid cells, TIAR has been shown to bind and regulate the translation and stability of various mRNA-encoding proteins important for the inflammatory response, such as TNFalpha Piecyk et al. (2000), Gueydan et al. (1999) [2], [3], Cox-2 Cok et al. (2003) [4] or IL-8 Suswam et al. (2005) [5]. Here, we generated two macrophage-like RAW 264.7 cell lines expressing either a tagged full-length TIAR protein or a RRM2-truncated mutant unable to bind RNA with high affinity Dember et al. (1996), Kim et al. (2013) . By a combination of RNA-IP and microarray analysis (RIP-chip), we identified mRNAs specifically bound by the full-length protein both in basal conditions and in response to LPS (GSE77577). PMID- 26981433 TI - Optimization of gene expression microarray protocol for formalin-fixed paraffin embedded tissues. AB - Formalin-fixed paraffin-embedded (FFPE) tissue is a widely available clinical specimen for retrospective studies. The possibility of long-term clinical follow up of FFPE samples makes them a valuable source to evaluate links between molecular and clinical information. Working with FFPE samples in the molecular research area, especially using high-throughput molecular techniques such as microarray gene expression profiling, has come into prominence. Because of the harmful effects of formalin fixation process such as degradation of nucleic acids, cross-linking with proteins, and chemical modifications on DNA and RNA, there are some limitations in gene expression profiling studies using FFPE samples. To date many studies have been conducted to evaluate gene expression profiling using microarrays (Thomas et al., Thomas et al. (2013) [1]; Scicchitano et al., Scicchitano et al. (2006) [2]; Frank et al., Frank et al. (2007) [3]; Fedorowicz et al., Fedorowicz et al. (2009) [4]). However, there is still no generally accepted, efficient and standardized procedure for microarray analysis of FFPE samples. This paper describes the microarray data presented in our recently accepted to be published article showing a standard protocol from deparaffinization of FFPE tissue sections and RNA extraction to microarray gene expression analysis. Here we represent our data in detail, deposited in the gene expression omnibus (GEO) database with the accession number GSE73883. Four combinations of two different cRNA/cDNA preparation and labeling protocols with two different array platforms (Affymetrix Human Genome U133 Plus 2.0 and U133_X3P) were evaluated to determine which combination gives the best percentage of present call. The study presents a dataset for comparative analysis which has a potential in terms of providing a robust protocol for gene expression profiling with FFPE tissue samples. PMID- 26981434 TI - Next generation sequencing (NGS) database for tandem repeats with multiple pattern 2 degrees -shaft multicore string matching. AB - Next generation sequencing (NGS) technologies have been rapidly applied in biomedical and biological research in recent years. To provide the comprehensive NGS resource for the research, in this paper , we have considered 10 loci/codi/repeats TAGA, TCAT, GAAT, AGAT, AGAA, GATA, TATC, CTTT, TCTG and TCTA. Then we developed the NGS Tandem Repeat Database (TandemRepeatDB) for all the chromosomes of Homo sapiens, Callithrix jacchus, Chlorocebus sabaeus, Gorilla gorilla, Macaca fascicularis, Macaca mulatta, Nomascus leucogenys, Pan troglodytes, Papio anubis and Pongo abelii genome data sets for all those locis. We find the successive occurence frequency for all the above 10 SSR (simple sequence repeats) in the above genome data sets on a chromosome-by-chromosome basis with multiple pattern 2 degrees shaft multicore string matching. PMID- 26981435 TI - Invert emulsion: Method of preparation and application as proper formulation of entomopathogenic fungi. AB - The present article describes the technique used for preparing the invert emulsion (water-in-oil type) then, selecting the most proper formulation of invert emulsion for being used as a carrier formulation of entomopathogenic fungi. It also describes the method used for testing the efficacy of the formulated fungi as biocontrol agents of targeted insects. Detailed examples demonstrating the efficacy of formulated strains of entomopathogenic fungi against certain species of insect pests were included in the present article. The techniques and methods described in this article are reproducible and helpful in enhancing the effectiveness of formulated fungi against wide range of targeted insects in comparison with the unformulated form of these fungi. Also, these techniques and methods can be used effectively in crop protection and in the integrated pest management programs. Finally, it is important to indicate that the ingredients used for preparation of the invert emulsion have no environmental side-effects or health risks since these ingredients are safe to use and can be used in manufacturing of cosmetics or as food additives.*Description of method used for preparation of invert emulsion (water-in-oil type) and selecting the most stable and non-viscous emulsion.*Description of technique used for introducing the entomopathogenic fungi into the selected stable and non-viscous invert emulsion.*Description of method for testing the efficacy of introduced entomopathogenic fungus into the selected invert emulsion against targeted insects with detailed examples on the efficacy testing. PMID- 26981437 TI - Major comorbid disease processes associated with increased incidence of acute kidney injury. AB - Acute kidney injury (AKI) is commonly seen amongst critically ill and hospitalized patients. Individuals with certain co-morbid diseases have an increased risk of developing AKI. Thus, recognizing the co-morbidities that predispose patients to AKI is important in AKI prevention and treatment. Some of the most common co-morbid disease processes that increase the risk of AKI are diabetes, cancer, cardiac surgery and human immunodeficiency virus (HIV) acquired immune deficiency syndrome (AIDS). This review article identifies the increased risk of acquiring AKI with given co-morbid diseases. Furthermore, the pathophysiological mechanisms underlying AKI in relation to co-morbid diseases are discussed to understand how the risk of acquiring AKI is increased. This paper reviews the effects of various co-morbid diseases including: Diabetes, cancer, cardiovascular disease and HIV AIDS, which all exhibit a significant increased risk of developing AKI. Amongst these co-morbid diseases, inflammation, the use of nephrotoxic agents, and hypoperfusion to the kidneys have been shown to be major pathological processes that predisposes individuals to AKI. The pathogenesis of kidney injury is complex, however, effective treatment of the co morbid disease processes may reduce its risk. Therefore, improved management of co-morbid diseases may prevent some of the underlying pathology that contributes to the increased risk of developing AKI. PMID- 26981438 TI - Health literacy in kidney disease: Review of the literature and implications for clinical practice. AB - Health literacy is the capacity of an individual to understand information related to a disease in order to make an informed decision. In patients with kidney diseases, studies have reported increasing impact of limited health literacy on health outcomes. Our paper discusses current literature on health literacy in kidney diseases. PMID- 26981439 TI - Proton-pump inhibitor-induced hypomagnesemia: Current research and proposed mechanisms. AB - Since the early reports nearly a decade ago, proton-pump inhibitor-induced hypomagnesemia (PPIH) has become a well-recognized phenomenon. While many observational studies in the inpatient and outpatient populations have confirmed the association of PPI exposure and serum magnesium concentrations, there are no prospective, controlled studies to support causation. Molecular mechanisms of magnesium transporters, including the pH-dependent regulation of transient receptor potential melastatin-6 transporters in the colonic enterocyte, have been proposed to explain the effect of PPIs on magnesium reabsorption, but may be a small part of a more complicated interplay of molecular biology, pharmacology, and genetic predisposition. This review explores the current state of research in the field of PPIH and the proposed mechanisms of this effect. PMID- 26981436 TI - Extracellular vesicles as mediators of vascular inflammation in kidney disease. AB - Vascular inflammation is a common cause of renal impairment and a major cause of morbidity and mortality of patients with kidney disease. Current studies consistently show an increase of extracellular vesicles (EVs) in acute vasculitis and in patients with atherosclerosis. Recent research has elucidated mechanisms that mediate vascular wall leukocyte accumulation and differentiation. This review addresses the role of EVs in this process. Part one of this review addresses functional roles of EVs in renal vasculitis. Most published data address anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis and indicate that the number of EVs, mostly of platelet origin, is increased in active disease. EVs generated from neutrophils by activation by ANCA can contribute to vessel damage. While EVs are also elevated in other types of autoimmune vasculitis with renal involvement such as systemic lupus erythematodes, functional consequences beyond intravascular thrombosis remain to be established. In typical hemolytic uremic syndrome secondary to infection with shiga toxin producing Escherichia coli, EV numbers are elevated and contribute to toxin distribution into the vascular wall. Part two addresses mechanisms how EVs modulate vascular inflammation in atherosclerosis, a process that is aggravated in uremia. Elevated numbers of circulating endothelial EVs were associated with atherosclerotic complications in a number of studies in patients with and without kidney disease. Uremic endothelial EVs are defective in induction of vascular relaxation. Neutrophil adhesion and transmigration and intravascular thrombus formation are critically modulated by EVs, a process that is amenable to therapeutic interventions. EVs can enhance monocyte adhesion to the endothelium and modulate macrophage differentiation and cytokine production with major influence on the local inflammatory milieu in the plaque. They significantly influence lipid phagocytosis and antigen presentation by mononuclear phagocytes. Finally, platelet, erythrocyte and monocyte EVs cooperate in shaping adaptive T cell immunity. Future research is needed to define changes in uremic EVs and their differential effects on inflammatory leukocytes in the vessel wall. PMID- 26981440 TI - Upper tract urothelial carcinoma: Paradigm shift towards nephron sparing management. AB - Upper tract urothelial carcinoma (UTUC) is relatively rare compared to urothelial carcinoma of the lower tract, comprising only 5%-10% of all urothelial cancers. Although both entities share histologic properties, UTUC tends to be more invasive at diagnosis and portend a worse prognosis, with a 5 year overall mortality of 23%. To date, the gold standard management of UTUC has been radical nephroureterectomy (RNU), with nephron sparing techniques reserved for solitary kidneys or cases where the patient could not tolerate radical surgery. Limited data from these series, as well as select series where nephron-sparing endoscopic management has been offered to a broader patient base, suggest that minimally invasive, nephron sparing techniques can offer comparable oncologic and survival outcomes to RNU in appropriately selected patients. We review the current literature on the topic and discuss long term outcomes and sequelae of the gold standard treatment, RNU. We also discuss the oncologic outcomes of minimally invasive, endoscopic management of UTUC. Our goal is to provide the reader a comprehensive overview of the current state of the field in order to inform and guide their treatment decisions. PMID- 26981441 TI - Cooling dialysate during in-center hemodialysis: Beneficial and deleterious effects. AB - The use of cooled dialysate temperatures first came about in the early 1980s as a way to curb the incidence of intradialytic hypotension (IDH). IDH was then, and it remains today, the most common complication affecting chronic hemodialysis patients. It decreases quality of life on dialysis and is an independent risk factor for mortality. Cooling dialysate was first employed as a technique to incite peripheral vasoconstriction on dialysis and in turn reduce the incidence of intradialytic hypotension. Although it has become a common practice amongst in center hemodialysis units, cooled dialysate results in up to 70% of patients feeling cold while on dialysis and some even experience shivering. Over the years, various studies have been performed to evaluate the safety and efficacy of cooled dialysate in comparison to a standard, more thermoneutral dialysate temperature of 37 degrees C. Although these studies are limited by small sample size, they are promising in many aspects. They demonstrated that cooled dialysis is safe and equally efficacious as thermoneutral dialysis. Although patients report feeling cold on dialysis, they also report increased energy and an improvement in their overall health following cooled dialysis. They established that cooling dialysate temperatures improves hemodynamic tolerability during and after hemodialysis, even in patients prone to IDH, and does so without adversely affecting dialysis adequacy. Cooled dialysis also reduces the incidence of IDH and has a protective effect over major organs including the heart and brain. Finally, it is an inexpensive measure that decreases economic burden by reducing necessary nursing intervention for issues that arise on hemodialysis such as IDH. Before cooled dialysate becomes standard of care for patients on chronic hemodialysis, larger studies with longer follow-up periods will need to take place to confirm the encouraging outcomes mentioned here. PMID- 26981443 TI - Sentinel lymph node biopsy in renal malignancy: The past, present and future. AB - Sentinel lymph node biopsy (SLNB) is now an established technique in penile and pelvic cancers, resulting in a lower mortality and morbidity when compared with the traditional lymph node dissection. In renal cancer however, despite some early successes for the SLNB technique, paucity of data remains a problem, thus lymph node dissection and extended lymph node dissection remain the management of choice in clinically node positive patients, with surveillance of lymph nodes in those who are clinically node negative. SLNB is a rapidly evolving technique and the introduction of new techniques such as near infra-red fluorescence optical imaging agents and positron emission tomography/computed tomography scans, may improve sensitivity. Evidence in support of this has already been recorded in bladder and prostate cancer. Although the lack of large multi-centre studies and issues around false negativity currently prevent its widespread use, with evolving techniques improving accuracy and the support of large-scale studies, SLNB does have the potential to become an integral part of staging in renal malignancy. PMID- 26981442 TI - Use of percutaneous nephrostomy and ureteral stenting in management of ureteral obstruction. AB - The management options for ureteral obstruction are diverse, including retrograde ureteral stent insertion or antegrade nephrostomy placement, with or without eventual antegrade stent insertion. There is currently no consensus on the ideal treatment or treatment pathway for ureteral obstruction owing, in part, to the varied etiologies of obstruction and diversity of institutional practices. Additionally, different clinicians such as internists, urologists, oncologists and radiologists are often involved in the care of patients with ureteral obstruction and may have differing opinions concerning the best management strategy. The purpose of this manuscript was to review available literature that compares percutaneous nephrostomy placement vs ureteral stenting in the management of ureteral obstruction from both benign and malignant etiologies. PMID- 26981444 TI - Experimental models of renal calcium stones in rodents. AB - In human nephrolithiasis, most stones are containing calcium and are located within urinary cavities; they may contain monohydrate calcium oxalate, dihydrate calcium oxalate and/or calcium phosphates in various proportion. Nephrolithiasis may also be associated with nephrocalcinosis, i.e., crystal depositions in tubular lumen and/or interstitium, an entity which suggests specific pathological processes. Several rodents models have been developed in order to study the pathophysiology of intrarenal crystal formation. We review here calcium rodent models classified upon the presence of nephrolithiasis and/or nephrocalcinosis. As rodents are not prone to nephrolithiasis, models require the induction of a long standing hypercalciuria or hyperoxaluria (thus explaining the very few studies reported), conversely to nephrocalcinosis which may occur within hours or days. Whereas a nephrotoxicity leading to tubular injury and regeneration appears as a critical event for crystal retention in nephrocalcinosis models, surprisingly very little is known about the physiopathology of crystal attachment to urothelium in nephrolithiasis. Creating new models of nephrolithiasis especially in different genetic mice strains appears an important challenge in order to unravel the early mechanisms of urinary stone formation in papilla and fornices. PMID- 26981445 TI - How botulinum toxin in neurogenic detrusor overactivity can reduce upper urinary tract damage? AB - Intradetrusor injections of botulinum toxin are the cornerstone of medical treatment of neurogenic detrusor overactivity. The primary aim of this treatment is to ensure a low pressure regimen in the urinary bladder, but the mechanisms leading to long-term protection of the urinary tract remain poorly understood. In this paper, we highlight the potential benefits of intradetrusor injections of botulinum toxin regarding local effects on the bladder structures, urinary tract infections, stone disease, vesico ureteral reflux, hydronephrosis, renal function based on a comprehensive literature review. PMID- 26981446 TI - Matrix metalloproteinase-2 as a superior biomarker for peritoneal deterioration in peritoneal dialysis. AB - AIM: To investigate the efficacy of effluent biomarkers for peritoneal deterioration with functional decline in peritoneal dialysis (PD). METHODS: From January 2005 to March 2013, the subjects included 218 PD patients with end-stage renal disease at 18 centers. Matrix metalloproteinase-2 (MMP-2), interleukin-6 (IL-6), hyaluronan, and cancer antigen 125 (CA125) in peritoneal effluent were quantified with enzyme-linked immunosorbent assay. Peritoneal solute transport rate was assessed by peritoneal equilibration test (PET) to estimate peritoneal deterioration. RESULTS: The ratio of the effluent level of creatinine (Cr) obtained 4 h after injection (D) to that of plasma was correlated with the effluent levels of MMP-2 (rho = 0.74, P < 0.001), IL-6 (rho = 0.46, P < 0.001), and hyaluronan (rho = 0.27, P < 0.001), but not CA125 (rho = 0.13, P = 0.051). The area under receiver operating characteristic curve for the effluent levels of MMP-2, IL-6, and hyaluronan against high PET category were 0.90, 0.78, 0.62, and 0.51, respectively. No patient developed new-onset encapsulating peritoneal sclerosis for at least 1.5 years after peritoneal effluent sampling. CONCLUSION: The effluent MMP-2 level most closely reflected peritoneal solute transport rate. MMP-2 can be a reliable indicator of peritoneal deterioration with functional decline. PMID- 26981447 TI - Chronic kidney disease in children and adolescents in Brunei Darussalam. AB - AIM: To determine epidemiology of Bruneian paediatric chronic kidney disease (CKD) patients and factors that affect growth and progression of disease. METHODS: A cross-sectional study conducted on all children below 18 years old who were diagnosed with CKD over a ten year period (2004 to 2013). The reference population was all children (< 18 years old) suffering from CKD and attending the tertiary paediatric nephrology clinic in Brunei Darussalam. Demographic (current age, age of diagnosis, gender, ethnicity), anthropometric (weight and height), diagnosis, laboratory data (serum creatinine and haemoglobin, urinalysis) and blood pressure were extracted from the patients' clinical case notes and recorded using a data collection form. RESULTS: The study revealed a high national prevalence [736 per million child population (pmcp)] and incidence (91 pcmp) of CKD. If CKD was defined at Stage 1, 2, 3, 4 or 5, the associated prevalence figures were 736, 132, 83, 50 and 33 pmcp. Glomerulonephritis accounted for 69% of all prevalent cases, followed by congenital abnormalities of kidney and urinary tract (20%) and tubulointerstitial diseases (8%). Minimal change disease being the most common histological diagnosis. The median age of diagnosis was 4.5 years, with congenital disease patients experiencing an earlier onset of diagnosis. A large proportion of patients were below the 5% percentile for height and weight. Non-glomerular diseases, adolescent and female patients were significantly associated with poor growth, but not glomerular filtration rate, age of diagnosis or steroid usage. CONCLUSION: Brunei has a high prevalence of chronic kidney disease in the paediatric population with glomerulonephritis being the most common disease. PMID- 26981448 TI - Comamonas testosteroni-associated peritonitis in a pediatric peritoneal dialysis patient. AB - Comamonas testosteroni (C. testosteroni) has been rarely observed as an infectious agent in clinical practice. Few reports described its potential pathogenicity in bloodstream and abdominal infections. Here, we report our experience in the treatment of a C. testosteroni-associated peritonitis in a four year-old girl receiving chronic peritoneal dialysis (PD). The organism was shown to be highly susceptible to appropriate antibiotic therapy. Infection responded promptly and the patient was managed conservatively without withdrawal from PD. PMID- 26981449 TI - Comparison of dual energy subtraction chest radiography and traditional chest X rays in the detection of pulmonary nodules. AB - BACKGROUND: Dual energy subtraction (DES) radiography is a powerful but underutilized technique which aims to improve the diagnostic value of an X-ray by separating soft tissue from bones, producing two different images. Compared to traditional chest X-rays, DES requires exposure to higher doses of radiation but may achieve higher accuracy. The objective of this study was to assess the clinical benefits of DES radiography by comparing the speed and accuracy of diagnosis of pulmonary nodules with DES versus traditional chest X-rays. METHODS: Five radiologists and five radiology residents read the DES and traditional chest X-rays of 51 patients, 34 with pulmonary nodules and 17 without. Their accuracy and speed in the detection of nodules were measured using specialized image display software. RESULTS: DES radiography reduced reading time from 13 to 10 sec (P<0.0001) in staff and from 21 to 15 sec in residents (P<0.0001). There was also a small increase in sensitivity 0.58 to 0.67 overall (P<0.10) with no change in specificity (0.85 overall). CONCLUSIONS: By eliminating rib shadows in soft tissue images, DES improved the speed and accuracy of radiologists in the diagnosis of pulmonary nodules. PMID- 26981450 TI - Role of quantitative computed tomography texture analysis in the differentiation of primary lung cancer and granulomatous nodules. AB - BACKGROUND: Texture analysis is a computer tool that enables quantification of gray-level patterns, pixel interrelationships, and spectral properties of an image. It can enhance visual methods of image analysis. Primary lung cancer and granulomatous nodules have identical CT imaging features. The purpose of this study was to assess the sensitivity and specificity of CT texture analysis in differentiating lung cancer and granulomas. METHODS: This retrospective study evaluated 55 patients with primary lung cancer and granulomatous nodules who had contrast-enhanced (CE) and/or non-contrast-enhanced (NCE) CT within 3 months of biopsy. Textural features were extracted from 61 nodules. Mann-Whitney U tests were used to compare values for nodules. Receiver operating characteristic (ROC) curves were constructed and the area under the curve (AUC) calculated with histopathology as outcome. Combinations of features were entered as predictors in logistic regression models and optimal threshold criteria were used to estimate sensitivity and specificity. RESULTS: The model generated by sum of squares, sum difference, and sum entropy features for NCE CT yielded 88% sensitivity and 92% specificity (AUC =0.90+/-0.06, P<0.0001). For nodules with fluorodeoxyglucose positron emission tomography (FDG-PET)/CT, sensitivity for detection of lung cancer was 79.2% (CI: 57.8-92.9%), specificity was 38.5% (CI: 13.9-68.4%) and accuracy was 64.8%. CONCLUSIONS: Quantitative CT texture analysis has the potential to differentiate primary lung cancer and granulomatous lesions. PMID- 26981451 TI - Lung nodule segmentation in chest computed tomography using a novel background estimation method. AB - BACKGROUND: Lung cancer results in the highest number of cancer deaths worldwide. The segmentation of lung nodules is an important task in computer systems to help physicians differentiate malignant lesions from benign lesions. However, it has already been observed that this may be a difficult task, especially when nodules are connected to an anatomical structure. METHODS: This paper proposes a method to estimate the background of the nodule area and how this estimation is used to facilitate the segmentation task. RESULTS: Our experiments indicate more than 99% of accuracy with less than 1% of false positive rate (FPR). CONCLUSIONS: The proposed methods achieved better results than a state-of-the-art approach, indicating potential to be used in medical image processing systems. PMID- 26981452 TI - Arterial input function placement effect on computed tomography lung perfusion maps. AB - BACKGROUND: A critical source of variability in dynamic perfusion computed tomography (DPCT) is the arterial input function (AIF). However, the impact of the AIF location in lung DPCT has not been investigated yet. The purpose of this study is to determine whether the location of the AIF within the central pulmonary arteries influences the accuracy of lung DPCT maps. METHODS: A total of 54 lung DPCT scans were performed in three pigs using different rates and volumes of iodinated contrast media. Pulmonary blood flow (PBF) perfusion maps were generated using first-pass kinetics in three different AIF locations: the main pulmonary trunk (PT), the right main (RM) and the left main (LM) pulmonary arteries. A total of 162 time density curves (TDCs) and corresponding PBF perfusion maps were generated. Linear regression and Spearman's rank correlation coefficient were used to compare the TDCs. PBF perfusion maps were compared quantitatively by taking twenty six regions of interest throughout the lung parenchyma. Analysis of variance (ANOVA) was used to compare the mean PBF values among the three AIF locations. Two chest radiologists performed qualitative assessment of the perfusion maps using a 3-point scale to determine regions of perfusion mismatch. RESULTS: The linear regression of the TDCs from the RM and LM compared to the PT had a median (range) of 1.01 (0.98-1.03). The Spearman rank correlation between the TDCs was 0.88 (P<0.05). ANOVA analysis of the perfusion maps demonstrated no statistical difference (P>0.05). Qualitative comparison of the perfusion maps resulted in scores of 1 and 2, demonstrating either identical or comparable maps with no significant difference in perfusion defects between the different AIF locations. CONCLUSIONS: Accurate PBF perfusion maps can be generated with the AIF located either at the PT, RM or LM pulmonary arteries. PMID- 26981453 TI - The use of isodose levels to interpret radiation induced lung injury: a quantitative analysis of computed tomography changes. AB - BACKGROUND: Patients treated with stereotactic body radiation therapy (SBRT) for lung cancer are often found to have radiation-induced lung injury (RILI) surrounding the treated tumor. We investigated whether treatment isodose levels could predict RILI. METHODS: Thirty-seven lung lesions in 32 patients were treated with SBRT and received post-treatment follow up (FU) computed tomography (CT). Each CT was fused with the original simulation CT and treatment isodose levels were overlaid. The RILI surrounding the treated lesion was contoured. The RILI extension index [fibrosis extension index (FEI)] was defined as the volume of RILI extending outside a given isodose level relative to the total volume of RILI and was expressed as a percentage. RESULTS: Univariate analysis revealed that the planning target volume (PTV) was positively correlated with RILI volume at FU: correlation coefficient (CC) =0.628 and P<0.0001 at 1(st) FU; CE =0.401 and P=0.021 at 2(nd) FU; CE =0.265 and P=0.306 at 3(rd) FU. FEI -40 Gy at 1(st) FU was significantly positively correlated with FEI -40 Gy at subsequent FU's (CC =0.689 and P=6.5*10(-5) comparing 1(st) and 2(nd) FU; 0.901 and P=0.020 comparing 2(nd) and 3(rd) FU. Ninety-six percent of the RILI was found within the 20 Gy isodose line. Sixty-five percent of patients were found to have a decrease in RILI on the second 2(nd) CT. CONCLUSIONS: We have shown that RILI evolves over time and 1(st) CT correlates well with subsequent CTs. Ninety-six percent of the RILI can be found to occur within the 20 Gy isodose lines, which may prove beneficial to radiologists attempting to distinguish recurrence vs. RILI. PMID- 26981454 TI - T1 characteristics of interstitial pulmonary fibrosis on 3T MRI-a predictor of early interstitial change? AB - BACKGROUND: Computed tomography (CT) is routinely used for diagnosis and characterisation of idiopathic pulmonary fibrosis (IPF). The technique however has limited sensitivity in detection and monitoring of early fibrotic changes. The aim of this study was to evaluate T1 characteristics in the radiologically diseased lung parenchyma in IPF patient compared to apparently normal parenchyma in both interstitial lung disease (ILD) patients and healthy volunteers and to investigate the feasibility of the technique in prediction of early fibrotic lung changes that may not be visible on CT. METHODS: Ten patients with IPF underwent high resolution computed tomography (HRCT) and magnetic resonance imaging (MRI) on the same day of attendance. 3T MRI was repeated in seven patients with IPF to test the reproducibility of results. The control group included healthy volunteers (n=10). A modified look-locker inversion-recovery (MOLLI) sequence (124*192 acquisition matrix; 8 mm slice) was performed during a 15-20 s breathhold in a single slice. The position of MR slice was pre-selected where there was CT evidence of normal and fibrotic lung. MOLLI imaging was performed prior to the contrast administration, and at 15, 25, 30 and 35 min post Gadolinium. The imaging data were then processed with a curve-fitting technique to estimate T1 values. T1 values of the apparent fibrotic and normal lung in IPF patients and normal lung were compared. RESULTS: Fibrotic lung had a higher pre contrast T1 than either morphologically normal lung in ILD patients or control lung (P=0.02) in healthy volunteers (1309+/-123, 1069+/-71, and 1011+/-172 ms, respectively). Morphologically normal lung T1 and control lung T1 were not significantly different pre-contrast, however, at 10 min after administration of Gadolinium, control lung had a significantly shorter T1 than either fibrotic or morphologically normal lung (494+/-34, 670+/-63, and 619+/-41 ms, respectively; P=0.001). T1 for fibrotic lung continued to decrease until 20 min after contrast agent administration (P<=0.0001), whereas morphologically normal lung T1 did not significantly change after 10 min (P>0.3). This indicates delayed uptake of contrast agent in the fibrotic lung compared with morphologically normal lung. CONCLUSIONS: T1 mapping of patients with IPF at 3T is feasible and demonstrates a significant difference between fibrotic lung tissue and morphologically normal lung tissue both before Gadolinium administration and at 10 min delayed post contrast images. The technique is able to evaluate early fibrosis in patients with apparently morphologically normal lung. PMID- 26981455 TI - Quantitative volumetric assessment of pulmonary involvement in patients with systemic sclerosis. AB - BACKGROUND: Computed tomography (CT) is the gold standard for assessing interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). In this study, we performed a quantitative calculation of ILD severity by examining the lung volume of SSc patients. METHODS: The present study was performed retrospectively on 38 patients with SSc who were referred to our clinic. Patients were divided into two groups based on high-resolution computed tomography (HRCT): patients with ILD and patients without ILD.The percentage of lower lobe volume (PLLV) was calculated using HRCT. In addition, we evaluated the PLLV in all patients according to age, diffusing capacity of the lung for carbon monoxide (DLCO) and spirometric findings, and assessed the relationships among these factors. RESULTS: PLLV of the right lung in patients with ILD was reduced when compared with patients without ILD (P=0.041). The PLLV of the right lung in patients with ILD was negatively correlated with age and forced vital capacity (FVC; P=0.01 and P=0.012, respectively). CONCLUSIONS: The PLLV of the right lung may decrease in SSc patients with ILD. In these patients, the PLLV may be a quantitative parameter indicating damage in the lung. PMID- 26981456 TI - Differentiating inflamed and normal lungs by the apparent reaction rate constants of lactate dehydrogenase probed by hyperpolarized (13)C labeled pyruvate. AB - BACKGROUND: Clinically translatable hyperpolarized (HP) (13)C-NMR can probe in vivo enzymatic reactions, e.g., lactate dehydrogenase (LDH)-catalyzed reaction by injecting HP (13)C-pyruvate into the subject, which is converted to (13)C labeled lactate by the enzyme. Parameters such as (13)C-lactate signals and lactate-to pyruvate signal ratio are commonly used for analyzing the HP (13)C-NMR data. However, the biochemical/biological meaning of these parameters remains either unclear or dependent on experimental settings. It is preferable to quantify the reaction rate constants with a clearer physical meaning. Here we report the extraction of the kinetic parameters of the LDH reaction from HP (13)C-NMR data and investigate if they can be potential predictors of lung inflammation. METHODS: Male Sprague-Dawley rats (12 controls, 14 treated) were used. One dose of bleomycin (2.5 U/kg) was administered intratracheally to the treatment group. The lungs were removed, perfused, and observed by the HP-NMR technique, where a HyperSense dynamic nuclear polarization system was used to generate the HP (13)C pyruvate for injecting into the lungs. A 20 mm (1)H/(13)C dual-tuned coil in a 9.4-T Varian vertical bore NMR spectrometer was employed to acquire the (13)C spectral data every 1 s over a time period of 300 s using a non-selective, 15 degree radiofrequency pulse. The apparent rate constants of the LDH reaction and their ratio were quantified by applying ratiometric fitting analysis to the time series data of (13)C labeled pyruvate and lactate. RESULTS: The apparent forward rate constant kp =(3.67+/-3.31)*10(-4) s(-1), reverse rate constant kl =(4.95+/ 2.90)*10(-2) s(-1), rate constant ratio kp /kl =(7.53+/-5.75)*10(-3) for the control lungs; kp =(11.71+/-4.35)*10(-4) s(-1), kl =(9.89+/-3.89)*10(-2) s(-1), and kp /kl =(12.39+/-4.18)*10(-3) for the inflamed lungs at the 7(th) day post treatment. Wilcoxon rank-sum test showed that the medians of these kinetic parameters of the 7-day cohort were significantly larger than those of the control cohort (P<0.001, P=0.001, and P=0.019, respectively). The rate constants of individual lungs correlated significantly with the histology scores of neutrophils and organizing pneumonia foci but not macrophages. Both kp and kp /kl positively correlated with lactate labeling signals. No correlation was found between kl and lactate labeling signals. CONCLUSIONS: The results indicate bleomycin-induced lung inflammation significantly increased both the forward and reverse reaction rate constants of LDH and their ratio at day-7 after bleomycin treatment. PMID- 26981457 TI - (1)H-MR imaging of the lungs at 3.0 T. AB - BACKGROUND: One disadvantage of magnetic resonance imaging (MRI) is the inability to adequately image the lungs. Recent advances in hyperpolarized gas technology [e.g., helium-3 ((3)He) and xenon-129 ((129)Xe)] have changed this. However, the required technology is expensive and often needing extra physics or engineering staff. Hence there is considerable interest in developing (1)H (proton)-based MRI approaches that can be readily implemented on standard clinical systems. Thus, the purpose of this work was to compare a newly developed free breathing proton based MR lung imaging method to that of a standard gadolinium (Gd) based perfusion approach. METHODS: Healthy volunteers [10] were scanned using a 3-T MRI with 8 parallel receivers, and a cardiac gated fast spin echo (FSE) sequence. Acquisition was cardiac triggered, with different time delays incremented to cover the entire cardiac cycle. Image k-space was filled rectilinearly. But to reduce motion artefacts k-space was retrospectively sorted using the minimal variance algorithm (MVA), based on physiologic data recorded from both the respiratory bellows and electrocardiogram (ECG). Resorted and reconstructed FSE images were compared to contrast enhanced lung images, obtained following intravenous injection of Gd-DTPA-BMA. RESULTS: Biphasic variation in FSE lung signal intensity was observed across the cardiac cycle with a maximal signal change following rapid cardiac ejection (between S and T waves), and following rapid isovolumetric relaxation. A difference image between systolic and diastolic states in the cardiac cycle resulted in images with improved lung contrast to noise ratio (CNR). FSE image intensity was uniform over lung parenchyma while Gd based enhancement of spoiled gradient recalled echo (SPGR) images showed gravitational dependence. CONCLUSIONS: Here we show how 1H-MR images of lung can be obtained during free breathing. The image contrast obtained during this approach is likely the result of flow and oxygen modulation during the cardiac cycle. This free breathing method provides lung images comparable to those obtained using Gd-enhancement. Besides having the advantage of free breathing, this approach doesn't require any Gd-contrast or suffer from methodological problems associated with perfusion (e.g., poor bolus timing). However, as gravitational differences typically observed in lung perfusion are not visible with this method it is not providing exclusive microvascular perfusion information. PMID- 26981458 TI - Quantitative computed tomography imaging of airway remodeling in severe asthma. AB - Asthma is a heterogeneous condition and approximately 5-10% of asthmatic subjects have severe disease associated with structure changes of the airways (airway remodeling) that may develop over time or shortly after onset of disease. Quantitative computed tomography (QCT) imaging of the tracheobronchial tree and lung parenchyma has improved during the last 10 years, and has enabled investigators to study the large airway architecture in detail and assess indirectly the small airway structure. In severe asthmatics, morphologic changes in large airways, quantitatively assessed using 2D-3D airway registration and recent algorithms, are characterized by airway wall thickening, luminal narrowing and bronchial stenoses. Extent of expiratory gas trapping, quantitatively assessed using lung densitometry, may be used to assess indirectly small airway remodeling. Investigators have used these quantitative imaging techniques in order to attempt severity grading of asthma, and to identify clusters of asthmatic patients that differ in morphologic and functional characteristics. Although standardization of image analysis procedures needs to be improved, the identification of remodeling pattern in various phenotypes of severe asthma and the ability to relate airway structures to important clinical outcomes should help target treatment more effectively. PMID- 26981460 TI - Complications of facial rejuvenation surgery. PMID- 26981459 TI - AME survey-003 A2: on the attractiveness of an medicine career in current China with a survey of 7,508 medical professionals and 443 non-medical professionals. AB - This is a part of the study of AME survey-003, aiming to understand the motivation and attractiveness of a career in medicine in China. The surveys were conducted on DXY platform with 3,564 medical professionals during October 26 to November 20; on Sojump platform with 1,587 medical professionals during October 28 to December 14, and 443 non-medical professionals during November 15 to December, all in 2015. Similar to our previous result, the not regretted participants vs. regretted participants (N/Y) ratio was 1.1 (P<0.01), and there was no significant difference in N/Y ratio between male and female medical professionals. Medical professionals working in class-IIIA hospitals, small township hospitals, or primary care clinics had a relatively higher job satisfaction than those in hospitals of other classes, while lecturer-level attending doctors (zhuzhi yishi) had a relatively lower job satisfaction than doctors of other grades. A large portion of respondents who replied they regretted entered medical profession said they would still like to be in this profession if they could be in their preferred hospital class and specialty. Public health and basic science research staff, anesthesiologists, oncologists had a relatively higher job satisfaction, while accident and emergency physicians, nurses, and pediatricians had a relatively lower job satisfaction. Medical professionals in Yunnan and Gansu ranked consistently high in job satisfaction than other provinces; despite they were not in the economically advanced regions in China. Similar to our previous result, the majority of the participants favored China to open up medical market to qualified foreign medical organizations to take part in fair competition, as well as favor the government to support regulated private hospitals. Pooled data of 7,508 medical professionals with data from AME survey-003 A1 included showed medicine was the top career choice among medical professionals' children (104/508, 20.5%), followed by finance and economics (74/508, 14.4%), and then electronic engineering or computer science (67/508, 13.2%). Among the 443 non-medical professionals, 122 have children who are attending university or have graduated, 12 (9.8%, 12/122) of them are pursuing a career in medicine. For the 100 non medical professional parents whose children did not study medicine and if a choice could be given to them to start again, 60 parents (54.5%) replied they would support their children to study medicine. Our results consistently show medicine remained an attractive profession in China. PMID- 26981461 TI - The use of distraction osteogenesis in oral and maxillofacial surgery. PMID- 26981462 TI - Perpendicular serial maxillary distraction osteogenesis in cleft lip and palate patients. AB - BACKGROUND: Cleft lip and palate patients often have a retruded maxilla with a severely narrowed deficient maxillary arch. This report aims to describe the management of severe maxillary retrusion and constriction in cleft lip and palate patients using distraction osteogenesis applied in serial sequence in two directions perpendicular to each other. MATERIALS AND METHODS: Two adult male cleft lip and palate patients were treated with maxillary distraction osteogenesis in two stages. In the first stage, surgically assisted rapid palatal expansion with a tooth-borne device was performed to significantly expand the maxillary arch in the transverse dimension. After the teeth were orthodontically aligned, the horizontal distraction of the maxilla was made by two internal maxillary distraction devices. RESULTS: In the first patient, the maxilla was initially widened by 11 mm and then distracted forward by 20 mm. Despite the breakage of the shaft of one of the two distractors at the end of distraction, a satisfactory occlusion was found at the time of distractor device removal. The maxillary position has remained stable through 8 years of follow-up. In the second patient, the palate was widened by 14 mm and the maxilla was distracted forward by 22 mm. The maxillary position has remained stable through 3 years of follow-up. CONCLUSION: Sequential serial distraction of maxilla in two planes perpendicular to each other is a safe and stable approach for the treatment of cleft lip and palate patients with severe transverse and anteroposterior discrepancies. PMID- 26981463 TI - Arthroscopic lysis and lavage for internal derangement of the temporomandibular joint. AB - INTRODUCTION: Arthroscopy of the temporomandibular joint (TMJ) is a valuable diagnostic and therapeutic tool for various intra-articular disorders, especially internal derangement (ID) of the TMJ. OBJECTIVES: To evaluate the efficacy and safety of a standardized arthroscopic procedure for the treatment of two stages of ID; early/intermediate stage and intermediate/late stage. MATERIALS AND METHODS: Retrospective analysis of medical records of 78 patients (99 joints) treated by arthroscopic lysis and lavage in the authors' department during a 5 year period. Patients were diagnosed preoperatively as suffering from ID of the TMJ. The results were stratified according to the stage of ID. Three outcome variables were used to assess efficacy of treatment: Maximal interincisal opening (MIO), level of pain on a visual analog scale (VAS), and frequency of intermittent locking episodes. In addition, complications were reported. RESULTS: Mean MIO of the group of patients with intermediate/late stage ID increased from 27 +/- 4.7 mm preoperatively to 38 +/- 5.4 mm postoperatively (P < 0.0001). For the group of patients with early/intermediate stage ID, mean MIO did not change significantly after arthroscopy (39.1 +/- 6.2 mm compared to 41.4 +/- 5 mm, P = 0.06), however, subjective evaluation of pain on a VAS decreased from 7.2 +/- 1.2 preoperatively to 3.4 +/- 2.2 postoperatively (P < 0.0001), and 80% of the patients (25 of 31) denied experiencing intermittent locking episodes after treatment (P < 0.0001). CONCLUSION: Arthroscopic lysis and lavage is a safe and effective therapeutic modality for the treatment of both mild and advanced stages of ID. PMID- 26981464 TI - Two stage ear/microtia reconstruction using costal cartilage. AB - BACKGROUND: Reconstruction of Grade III microtia is a challenging entity in maxillofacial esthetic rehabilitation. Several advocacies and philosophies exist in this field. The aim of the manuscript is to present a single South Indian Experience with Ear reconstruction among South Indian Population. MATERIALS AND METHODS: Retrospective analysis of unilateral Grade III microtia reconstruction was performed. Using a set of predefined inclusion and exclusion criteria, the population was selected. Outcome measures in terms of the ear size, auriculocephalic angle, and the conchal depth were measured in the reconstructed and normal side. Descriptive statistics is presented. RESULTS: Twenty-four patients formed the study group and had undergone the classical two-stage reconstruction in a similar fashion. The mean ear size in normal side was 65.8 +/ 2.8 mm whereas on the reconstructed side, it was 61.3 +/- 5.8 mm. The center's technique achieved above 75% similarity as that of the other normal ear. The mean auriculocephalic angle was 44.6 +/- 5.2 degrees whereas for the surgically reconstructed ear, it was 41.9 +/- 2.6 degrees . Overall, in these patients, we achieved a 79.94% similarity of auriculocephalic angle in the reconstructed ear as compared to the normal auricle. The conchal depth was 19.2 +/- 2.1 mm and 16.6 +/- 1.9 mm for normal and reconstructed ear, respectively. In terms of conchal depth, the present study group showed an achievement of 82.88% of accuracy even after a prolonged follow-up. DISCUSSION AND CONCLUSION: The center employs a classic two stage reconstruction with a customized prosthesis that helps to avoid the loss of projection geometry and minimizes adhesion, infection, and early loss of structural stability. PMID- 26981465 TI - Retrospective analysis of etiology and comorbid diseases associated with Ludwig's Angina. AB - INTRODUCTION: Ludwig's angina (LA) still presents regularly at our tertiary academic hospital. Various etiologies and comorbid diseases are documented worldwide, but the South African population has not been studied. AIM: To establish whether LA cases presenting to the department are different from international reports regarding etiology and comorbidities. SETTINGS AND DESIGN: Retrospective analysis of patients presenting with LA to a tertiary hospital. MATERIALS AND METHODS: 93 patients were included over a 5-year period. Archived files were analyzed for data including age, gender, comorbid diseases, etiology, airway management, and season on admission. STATISTICAL ANALYSIS: Descriptive statistics with the inclusion of frequency distributions. RESULTS: 93 patients were included; 65 (69.9%) male and 28 (30.1%) female; age - minimum 20 years, maximum 75 years, mean 40.366. ETIOLOGY: 68 (73.1%) odontogenic, 13 (14%) nonodontogenic, and 12 (12.9%) unknown cause. Comorbid diseases: 21 (22.6%) diabetes mellitus (DM), 19 (20.4%) hypertension, and 18 (19.4%) human immunodeficiency virus (HIV). Airway management: 61 (65.6%) tracheostomy and 32 (34.4%) nonsurgical. COMPLICATIONS: 11 (11.8%) deaths, 8 (8.60%) descending mediastinitis, and 7 (7.53%) necrotizing fasciitis. Seasonal occurrence: 30 (32.3%) spring, 24 (25.8%) winter, 22 (23.7%) summer, and 17 (18.3%) autumn. CONCLUSION: A 2.32:1 ratio male: female presentation mirrors previous statistics. DM patients had increased risks of complications, which resulted in multiple deaths. HIV patients showed increased risks for complications with more intense, longer hospital stays, but lower percentages of deaths compared to patients with DM and complications who died. There was no statistically significant finding regarding seasonal tendency. PMID- 26981466 TI - Posteriorly based lateral tongue flap for reconstruction of large palatal alveolar fistulas in cleft patients. AB - BACKGROUND: Large palatal fistula in cleft patients is a difficult situation, especially with previous multiple surgeries, which have led to severe scars in the palatal mucosa. Tongue flaps are useful aids in such situations. MATERIALS AND METHODS: Seven cleft patients who were reconstructed by posteriorly based lateral tongue flap between 2005 and 2012 were studied. Variables such as flap ability to close the fistula, remaining tongue shape at least 1 year after operation, and speech improvement (patients' self-assessment) were evaluated. RESULTS: Age range of the patients was 14-45 years. The male-to-female ratio was 2/7. Posteriorly based lateral tongue flap effectively closed the large fistula in 6/7 of patients. The largest dimensions of fistula closed by this flap was 5 cm * 1.5 cm. Follow-up of 2-7 years showed that the tongue never returned to the original size and remained asymmetrical. In addition, the nasal speech did not improve dramatically after the closure of large palatal/alveolar fistulas in this age group. CONCLUSION: Posteriorly based lateral tongue flap is an effective method to solve the problem of large palatal fistulas in adult cleft patients. The most useful indication for this flap is a large longitudinal palatal fistula, extending to the alveolar process. Asymmetrical tongue shape after surgery is the rule and speech improvement depends on patient's age and location of fistula. PMID- 26981467 TI - The use of Buccal fat pad free graft in regenerative treatment of peri implantitis: A new and predictable technique. AB - INTRODUCTION: Peri-implantitis is a common condition, but no particular treatment protocol has shown to be definitively effective. Fat tissue in the oral cavity is widely available and easily accessed. The aim of the current study is to present a novel technique in the treatment of peri-implant lesions, utilizing a free fat tissue graft from the buccal fat pad (BFP). PATIENTS AND METHODS: Free fat graft (FFG) was harvested from the BFP in eight patients and used with bone substitutes to regenerate 22 peri-implant lesions. Mechanical debridement of the implants surface and the granulation tissue were made with curettes or with Er: YAG laser. Clinical parameters such as plaque index, bleeding on probing, pocket depth, gingival recession, and the clinical attachment level were recorded as a baseline during the follow-up period. In addition, radiological evaluation was made preoperative during the follow-up period. RESULTS: The donor site of the free fat graft was healed without cosmetic defect in all patients. Twenty-two peri-implant lesions were followed up for 12 months. Bleeding on probing and the pocket depth were significantly improved, and the clinical attachment level was achieved and maintained during the follow-up period due to the fibrous healing of the free fat graft. Satisfactory esthetic and functional outcomes of the treated implants were achieved and maintained. CONCLUSIONS: Free buccal fat graft heals by fibrosis. The fibrotic tissue adheres strongly to the implant surface and with stand the recurrence of the peri-implant lesion and provides stable and predictable outcome. PMID- 26981468 TI - Perspectives of patients about bioabsorbable internal fixation for maxillofacial fractures. AB - PURPOSE: Resorbable/bioabsorbable internal fixation provides effective treatment for maxillofacial fractures and avoids the need for metal hardware removal. We evaluated the initial knowledge, attitudes, subjective demand, and treatment satisfaction of patients concerning bioabsorbable osteofixation for maxillofacial trauma. MATERIALS AND METHODS: From May 2007 to October 2009, there were 71 patients (63 males and 8 females; mean age: 35 +/- 15 years) included in this prospective study. The patients completed preoperative and postoperative (4-6 weeks and 1 year) questionnaires. RESULTS: After receiving information, 70 patients (99%) preferred resorbable/bioabsorbable bone fixation, usually because they preferred to avoid a second operation to remove metal hardware (67 patients [94%]). The higher cost of resorbable/bioabsorbable bone fixation was believed and justified by 41 patients (58%) and not justified by 30 patients (42%). No adverse events were reported by 27 of 34 patients (79%) at 4-6 weeks and by 14 of 21 patients (67%) at 1 year after surgery. Most patients were very satisfied with the outcome of surgery. CONCLUSION: Patients who have maxillofacial trauma have a high frequency of preference and high satisfaction with resorbable/bioabsorbable than metal osteofixation. Literature review showed increased activity in research and publication worldwide about resorbable bone fixation, suggesting that there may be increased patient demand for resorbable bone fixation in the future. PMID- 26981469 TI - Reconstruction in oral malignancy: Factors affecting morbidity of various procedures. AB - AIMS AND OBJECTIVE: (1) To study the age and sex distribution of patient with oral malignancies. (2) To analyze various types of surgery performed. (3) Evaluation of reconstruction and factors affecting complications and its relation to the type of reconstruction. MATERIALS AND METHODS: Cases of oral malignancies, undergoing surgery for the same in Sri Aurobindo Medical College and PG Institute, Indore from the period from October 1, 2012, to March 31, 2015. RESULTS: Out of analysis of 111 cases of oral malignancy, 31 (27.9%) cases were in the fifth decade of life with male to female ratio 1.9:1. The commonest site of cancer was buccal mucosa. Forty-seven cases (43.2%) were in stage IVa. Diabetes was the most common co-morbidity reported, accounting for 53.9% of cases with reported morbidity. Tobacco chewing was the common entity in personal habits. All the cases underwent neck dissection along with resection of the primary. Hemimandibulectomy was the most preferred form of primary resection accounting for 53.15% (59 cases), followed by wide resection of primary 27% (30 cases). Pectoralis major myocutaneous (PMMC) flap only was the most common reconstruction across the study population. PMMC alone accounted for 38.7% (43 cases). The infection rate was 16.21%. PMMC alone accounted for 5 out of 18 (27.8%) of total infection rate, and 4.5% of the total study population. PMMC + deltopectoral accounted for 5 out of 18 (27.8%) of total infection rate, and 4.5% of the total study population. CONCLUSION: PMMC is a major workhorse for reconstruction with better functional outcome and acceptance among operated patients. PMID- 26981470 TI - Evaluation of inorganic bovine bone graft in periodontal defects after third molar surgery. AB - AIM: This study evaluated the e cacy of inorganic bovine bone graft (IBB) in periodontal defect after mandibular third molar (3M) surgery. METHODS: The authors conducted a split-mouth, prospective, randomized, blinded, placebo controlled clinical trial involving 20 participants with a mean age of 21.60 +/- 6.5 years who had symmetrical bilateral lower 3M randomly assigned to receive IBB or left empty (blooding clot). The clinical variables studied were probing depth and clinical attachment level (CAL) at preoperative and postoperative periods of 10, 30, and 60 days. Radiographic measures included the distance from the alveolar bone crest to the cementoenamel junction and the bone density at 30 and 60 days postsurgical procedure. For statistical analysis, we used the paired t test at a level of signi cance of 5%. RESULTS: It was observed a reduction in pocket depth and CAL in both groups, but IBB did not provide better results than blooding clot (P > 0.05). On the other hand, IBB group showed an increased in the bone density, and a decrease in the periodontal defect on the distal surface of second molar (2M) after 30 and 60 days of surgery compared to the control group (P < 0.05). CONCLUSION: The use of inorganic bone graft (GenOx) did not enhance the probing depth after 3M removal. Although the radiographic ndings have showed an increase in bone density and a decrease in the periodontal defect on the distal surface of the 2M, we cannot recommend the use of IBB as a treatment for periodontal defect prevention after 3M removal. PMID- 26981472 TI - Two-dimensional morphometric analysis of young Asian females to determine attractiveness. AB - INTRODUCTION: Attractive people do not seem to consistently possess such ideal characteristics or share common features. There is no general consensus about the linear and angular characteristics that discriminate between attractive and normal persons. AIM: This study determines how young Asian women considered to be attractive differ in their twodimensional facial characteristics from normal women of the same age and race. MATERIALS AND METHODS: Frontal and lateral photographs of 70 young Asian females were taken under standardized setting and were given to 15 judges who did not know the subjects in the study, to rate the attractiveness of each photograph. All 70 photographs were arranged in descending order of their total score by all the judges and were classified into three groups. Three angular, 8 linear measurements, and 3 ratios were compared between these groups. RESULTS: This study showed that most attractive group had least convex face, larger forehead, and wider faces. Conversely, the middle facial height was larger in the least attractive group. The ratio of middle third to total face of the most attractive group is higher than the average attractive ones. The ratio of lower third to total face of the most attractive group is lower than the average attractive ones. PMID- 26981471 TI - Facial nerve reconstruction following radical parotidectomy and subtotal petrosectomy for advanced malignant parotid neoplasms. AB - INTRODUCTION: To describe the oncological management and functional outcome of patients with advanced parotid malignant tumors undergoing facial nerve reconstruction after radical parotidectomy and subtotal petrosectomy. MATERIALS AND METHODS: A combined approach was used to treat advanced stage parotid malignancies with intrapetrous involvement of the facial nerve main trunk or abutment on the stylomastoid foramen. Patients underwent facial nerve rehabilitation with cable graft reconstruction or with static techniques. RESULTS: Six patients were included. All patients had Stage IV disease and underwent surgical treatment using a combined approach. Three patients underwent facial-nerve cable graft technique and three patients underwent static techniques to rehabilitate facial nerve function. Five patients received adjuvant treatment with radiotherapy and/or chemotherapy. The mean follow-up was 27.5 months, with a minimum of 7 months and a maximum of 8 years. Four patients remain disease-free, with an overall survival rate of 66%. Among the patients undergoing dynamic reconstruction, first signs of recovery were established at 6 months of follow up. All patients achieved a House-Brackmann score of III-IV within the first two postoperative years. CONCLUSIONS: When possible, facial nerve grafting is the preferred method of facial nerve rehabilitation in an advanced stage parotid tumors. A multidisciplinary approach allows better functional and oncological outcomes. PMID- 26981474 TI - Lemierre's syndrome from odontogenic infection: Review of the literature and case description. AB - Lemierre's syndrome (LS) is a rare potentially fatal sequel of head and neck infection, classically described as thrombophlebitis of the internal jugular vein (IJV) with cervical space infection extending into the thorax. Our objective was to answer the clinical question: "Does Lemierre syndrome (LS) from odontogenic infection differ from nonodontogenic LS in regard to clinical sequence, treatment, and survival." We reviewed the literature on the management of LS over the last two decades, with a focus on LS from odontogenic infection. Such a case is presented in order to portray the clinical sequence. Only 10 cases met the inclusion criteria (including the case presented). The recorded data were analyzed in comparison to large case series reviewing LS. Our data reflect the moderate differences in regard to IJV thrombosis and bacteriogram. There is an overall rise in published LS cases in the last 20 years. Odontogenic infection leading to LS is scarce, yet with survival rates similar to nonodontogenic LS. Repeated surgical interventions and aggressive wide spectrum antibiotic therapy remain the treatment of choice. PMID- 26981473 TI - Comparison of platelet rich plasma and synthetic graft material for bone regeneration after third molar extraction. AB - AIMS: To compare the efficacy of Platelet rich plasma and synthetic graft material for bone regeneration after bilateral third molar extraction. MATERIAL AND METHODS: This study was conducted in 10 patients visiting the outpatient department of Oral & Maxillofacial Surgery, Yenepoya Dental College & Hospital. Patients requiring extraction of bilateral mandibular third molars were taken for the study. Following extraction, PRP (Platelet Rich Plasma) was placed in one extraction socket and synthetic graft material in form granules [combination of Hydroxyapatite (HA) and Bioactive glass (BG)] in another extraction socket. The patients were assessed for postoperative pain and soft tissue healing. Radiological assessment of the extraction site was done at 8, 12 and 16 weeks interval to compare the change in bone density in both the sockets. RESULTS: Pain was less on PRP site when compared to HA site. Soft tissue evaluation done using gingival healing index given by Landry et al showed better healing on PRP site when compared to HA site. The evaluation of bone density by radiological assessment showed the grey level values calculated at 4 months at the PRP site were comparatively higher than HA site. CONCLUSION: The study showed that the platelet rich plasma is a better graft material than synthetic graft material in terms of soft tissue and bone healing. However a more elaborate study with a larger number of clinical cases is very much essential to be more conclusive regarding the efficacy of both the materials. PMID- 26981475 TI - Palatopharyngeus the missing palatal muscles: Anatomical and physiological review. AB - The first true anatomical descriptions of the normal anatomy of the palate and pharynx were published by Von Luschka in 1868, and then in 1935 anatomist James Whillis described pharyngeal sphincter. Later, in 1941 Michael Oldfield noted that the muscular elements of the soft palate have a sling-like function. Although there have been conflicting descriptions of the role of the palatopharyngeus, multiple function such as speech, swallowing, and respiration, it could role in all this function. Although, the palatopharyngeus muscle has many important functions, but it remains the missing muscle that we need to know more about it. PMID- 26981476 TI - The tensor stitch for soft palate closure revisited. AB - The tensor veli palatini muscle is involved in opening of the Eustachian tube during chewing and swallowing, allowing for equilibration of pressure between the middle ear and external environment. In patients with cleft palate, abnormal musculature in the region of the cleft results in Eustachian tube dysfunction. A palatoplasty with muscle repositioning is advocated to reduce the incidence of otitis media, which is a result of this. A special suture is described which can be incorporated into a palatoplasty procedure to further reduce the incidence of otitis media. This suture is inserted around the tendon of the tensor veli palatini muscle bilaterally, and when activated under tension in the midline, it results in opening of the Eustachian tube with improved middle ear ventilation. This novel suture results in a reduction in the incidence of otitis media due to improved middle ear ventilation and reduces tension across the suture margins. PMID- 26981477 TI - Use of templates and self-tapping metal screws for temporary fixation of a resorbable plate system. AB - Resorbable plate systems combine the benefits of rigid internal fixation with the convenience of biodegradation; thus, precluding the need for removal and reducing their interference with craniofacial growth. However, in surgeries involving maxillofacial bone, when reduction or repositioning of the bone segment is inaccurate, refixation and rebending of the plate may be necessary. Here, we report using a temporary plate with self-tapping metal screws to avoid repeated rebending of the resorbable plate and using additional screws following inaccurate fixation in maxillofacial surgeries. PMID- 26981478 TI - Reconstruction of anterior maxillary defect with buccal pad fat after excision of melanotic neuroectodermal tumor of infancy. AB - This paper highlights a rare case of melanotic neuroectodermal tumor of infancy involving the anterior maxilla in a 3-month-old infant. The tumor was excised completely, and the defect was reconstructed with a bilateral buccal pad of fat. The patient has been followed for 2 years without any evidence of recurrence. We propose that for similar anterior maxillary defects in infants and children, a buccal pad of fat can be utilized as an appropriate pedicled flap for coverage after tumor resection. PMID- 26981479 TI - A common tumor in an uncommon location: Lipoma of the palate. AB - Lipomas are benign mesenchymal neoplasms that originate in mature adipose cells. Although rare in the oral cavity, they are mostly seen in the buccal mucosa, tongue, and gingiva; those arising from the palate are very rare. We report a case of a 42-year-old male patient with a large intraoral swelling that on excision was reported as a lipoma. Oral lipomas are rare and those occurring on the hard palate are even rarer. Radiological evaluation is warranted for larger lesions to know exact extent. Lipoma should be considered in the differential diagnosis of a palatal swelling. PMID- 26981480 TI - Carcinosarcoma of parotid gland (malignant mixed tumor). AB - Salivary gland carcinosarcoma is a rare neoplasm; with a poor prognosis. The most common epithelial components are adenocarcinoma or squamous cell carcinoma, whereas the most common mesenchymal components are chondrosarcoma. It should not be confused with the most common carcinoma ex-pleomorphic adenoma, in which the epithelial component alone is malignant. This condition might exhibit with a wide variety of presentation and symptoms along with associated conditions. We present a case of an old patient who presented with a very unusual type clinically with confusing presentation which was eventually diagnosed as carsinosarcoma. In addition, the literature is reviewed, and the possible clinical signs and management of malignant mixed tumor of the salivary gland are briefly discussed. PMID- 26981481 TI - Chondromyxoid fibroma of zygoma in an elderly patient: A rare presentation. AB - Chondromyxoid fibroma (CF) is a benign bone tumor of cartilaginous origin and is considered the least common of cartilage-derived neoplasms. The lesion's most frequent location is in long bones, while involvement of craniofacial skeleton is extremely unusual. It generally appears in the second and third decade of life and most frequent in men. We present the case of a 68-year-old female with a CF of the zygomatic region. The resection of the tumor and reconstruction of the defect is described. PMID- 26981482 TI - Application of virtual three-dimensional surgery planning in management of open bite with idiopathic condylar resorption. AB - This case report describes the successful treatment of an adult patient with idiopathic condylar resorption and Class II skeletal open bite malocclusion and temporomandibular joint disorder. A segmental Le Fort I bilateral osteotomy, ramus increasing length inverted L-osteotomy, and genioplasty combined with orthodontic treatment were performed. The treatment plan and surgery was aided by three-dimensional medical modeling, and we managed to resolve functional, esthetic, and pain concerns to a satisfactory level. PMID- 26981483 TI - Early magnetic resonance imaging control after temporomandibular joint arthrocentesis. AB - Temporomandibular joint (TMJ) lysis and lavage arthrocentesis with viscosupplementation are an effective treatment for acute disc displacement (DD) without reduction. Clinical success seems to be related to multiple factors despite the lack of understanding of its mechanisms. The authors present a case report of 17-year-old women with acute open mouth limitation (12 mm), right TMJ pain-8/10 visual analog scale, right deviation when opening her mouth. The clinical and magnetic resonance imaging (MRI) diagnosis was acute DD without reduction of right TMJ. Right TMJ arthrocentesis was purposed to the patient with lysis, lavage, and viscosupplementation of the upper joint space. After 5 days, a new MRI was performed to confirm upper joint space distension and disc position. Clinical improvement was obtained 5 days and 1 month after arthrocentesis. Upper joint space increased 6 mm and the disc remained displaced. We report the first early TMJ MRI image postoperative, with measurable upper joint space. PMID- 26981484 TI - A case of isolated abducens nerve paralysis in maxillofacial trauma. AB - Nervus abducens is a pure motor nerve located in the pons. It retracts the eyeball laterally by stimulating rectus lateralis muscle. In case of their paralysis, diplopia and restriction in the eye movements while looking sideways, are seen. Since the same signs are seen due to the muscle entrapment in blowout fractures, its differential diagnosis has importance in terms of the treatment protocol and avoiding unnecessary operations. In this article, we present a 22 year-old male patient who was referred to our department due to the prediagnosis of blowout fracture following maxillofacial trauma. However, he was diagnosed with abducens nerve paralysis after the consultations and analysis and his restriction of movement was resolved via systemic steroid treatment instead of unnecessary operation. PMID- 26981485 TI - Blowout fracture-orbital floor reconstruction using costochondral cartilage causing pain, warping, and diplopia. AB - Orbital floor reconstruction is the most challenging component in the midfacial trauma management. Most often owing to the complexity of the fractures, the floor reconstruction requires grafts or other substitutes. Literature reveals several sources of autogenous sources of such grafts. Though most of the grafts are well taken and gives an ideal result, at certain instances, owing to the complex nature of the graft, its biochemical nature, reaction to the grafting, biochemical response, a reactionary change may result at late stages. The aim of this manuscript is to present a rare instance of warping of a costochondral graft that was used as a part of the orbital floor reconstruction giving rise to an ophthalmic emergency. The situation was immediately diagnosed and successfully managed. The situation, structural, and biochemical mechanisms behind such a phenomenon are discussed. PMID- 26981486 TI - Treatment outcome with guiding flange prosthesis in hemimandibulectomy patients: Case series of three patients. AB - There are various indications that may necessitate partial or complete resection of the mandible, from trauma to congenital deformities. However, the most prevalent indication that requires surgical resection of the mandible along with the involved adjacent oral structures is the presence of a locally aggressive neoplastic growth. The resultant continuity defect leads to an alteration in the range and direction of mandibular movement, impedes clear articulation of syllables and cosmetic disfigurement. The role of a prosthodontist is paramount in bringing about the restoration of the esthetic and functional dysfunction. This article discusses a series of hemimandibulectomy cases wherein mandibular deviation was successfully corrected using guide-flange prosthesis. PMID- 26981487 TI - The closure of postpalatoplasty fistula with local turn-down flap. AB - INTRODUCTION: The three common complications after cleft palate repair are velopharyngeal incompetence, delayed maxillary growth, and fistula formation. Fistula formation rates are reported 0-76% in the literature. Wider palatal defects are more challenging to avoid excess tension, and recent reports suggest defects >15 mm have a significantly higher risk of fistula formation. By localization, the fistulas are divided into seven groups with Pittsburgh fistula classification system (PFCS). The timing of treatment of fistula can vary considerably, and a recurrence rate after surgical correction ranges 10-37%. MATERIALS AND METHODS: Three patients with fistula in the hard palate (PFCS-4) in size 7-12 mm, between 2010 and 2012, who underwent fistula repair with local turn down flap. In two cases, surgery was the first fistula repair and was the second repair in one case. The incisions in the frontal and bilateral edges were made around the fistula, in the distal side of fistula incision was made 3-5 mm longer than fistula size in the oral mucosa, and separate oral and nasal mucosa was rendered by organizing flap. This flap was turn-down and closed nasal side of fistula. The oral side of fistula was closed with the two-flap procedure by Bardach technique. RESULTS: The postoperative wound was covered initially in all cases. CONCLUSION: We believe this two layer method for correction big palatal fistula is simpler than tongue, and buccal flap and patients need only intervention in this case. In addition, this method involves more effective usage of mucosal tissues bilaterally for closure on the oral side of the defect. PMID- 26981488 TI - A case of laryngeal leiomyosarcoma and review of the literature. AB - Leiomyosarcoma (LMS) of the larynx is a very rare malignancy that originates from blood vessel, smooth muscle or from the heterotopic mesenchymal tissue in the larynx. The histological diagnosis of LMS depends on the immunohistochemical investigation. The case is here presented of an 82-year-old man with shortness of breath and hoarseness. Indirect laryngoscopy showed a pedunculated large glottic lesion causing airway obstruction. Direct laryngoscopy was performed and biopsies were taken. From the pathological examination, the diagnosis of LMS was made. This case is presented of laryngeal LMS with the clinical, radiological, and histological findings. PMID- 26981489 TI - Multiple keratocystic odontogenic tumors in nevoid basal cell carcinoma syndrome. AB - Keratocystic odontogenic tumor (KCOT) is of particular interest because its recurrence rate is high and its behavior is aggressive. Nevoid basal cell carcinoma syndrome (NBCCS), which is also known as Gorlin syndrome, is a hereditary condition characterized by a wide range of developmental abnormalities and with a predisposition to neoplasms. These multiple KCOTs have warranted an aggressive treatment at the earliest because of the damage and possible complications. Recurrence of these lesions is a characteristic feature that has to be considered while explaining the prognosis to the patient. Here, we report a case of a 14-year-old boy with clinical features of basal cell nevus syndrome and multiple KCOTs. In addition to the other common features, congenitally missing third molars in all the four quadrants is a feature which has not been previously reported in association with NBCCS in Indian patients. PMID- 26981490 TI - Killian's polyp mimicking malignant tumor. AB - Killian polyp is predominantly found in children and any sinonasal tumor in elderly presenting with epistaxis and pain usually indicates malignant growth until proved otherwise. We present an unusual case of Killian polyp in an elderly patient that behaved as a malignant tumor. This case report reminded us that paranasal sinuses are still dark hollow mysterious cavities, and we should take utmost clinical acumen in managing such cases. PMID- 26981491 TI - Variant anatomy of internal jugular vein branching. AB - The knowledge of both normal and abnormal anatomy of the veins of the neck is important for clinicians performing catheterization and surgeons operating in the region of the neck. The presence of such anomalous communications may also be important for radiologists performing angiographic and sonographic studies. This study presents three cases of variant anatomy in posterior branching and abnormal branching of internal jugular vein found during our routine neck dissection. PMID- 26981492 TI - Keutel syndrome: Augmentation of the nose with serial fat grafting. PMID- 26981493 TI - Erratum: Developing a visual rating chart for the esthetic outcome of unilateral cleft lip and palate repair. AB - [This corrects the article on p. 55 in vol. 5, PMID: 26389035.]. PMID- 26981494 TI - Insomnia and Restless Leg Syndrome in Patients Undergoing Chronic Hemodialysis in Rafsanjan Ali Ibn Abitaleb Hospital. AB - BACKGROUND: Sleep is one of the most fundamental human needs; without any doubt sleep is even more essential for sick patients, especially for patients with chronic illnesses. Sleep disturbance may lead to anxiety and reduced quality of life. Restless leg syndrome (RLS) is a sensory-motor disorder accompanied by a strong desire to move the legs or other parts of the body, which can cause sleep disturbance. Its etiology is unknown, but increased urea and creatinine levels before dialysis, iron deficiency due to kidney failure and end-stage renal disease (ESRD) are mentioned as causes. OBJECTIVES: This study is designed to examine the prevalence of insomnia and restless leg syndrome in patients undergoing chronic hemodialysis in Rafsanjan Ali Ibn Abitaleb Hospital. PATIENTS AND METHODS: In this study we used two questionnaires to evaluate the presence of RLS and insomnia in ESRD patients who were undergoing hemodialysis treatment as kidney replacement therapy. RESULTS: According to our results, 54.5% of patients were diagnosed with RLS, and of those 65.2% and 42.9% were women and men, respectively. RLS is seen more often among patients with blood group type A, but this result was not statistically significant. There was a statistically significant correlation between RLS and a positive family history of RLS, between RLS and the number of hemodialysis treatments per week and also between RLS and the Insomnia Severity Index. Unlike previous studies, in this study we did not find any statistically significant correlation between RLS and biochemical factors such as serum iron, TIBC, BUN, creatinine, potassium, calcium and phosphorous levels. CONCLUSIONS: The frequency of RLS among our patients was remarkable and we conclude that all patients who are undergoing hemodialysis should be screened for RLS, which can assist in providing proper attention and treatment. PMID- 26981495 TI - Improving Compliance With a Single Post-Operative Dose of Intravesical Chemotherapy After Transurethral Resection of Bladder Tumour. AB - BACKGROUND: Post-operative single dose intravesical chemotherapy (PSDIVC) in patients with non-muscle invasive bladder cancer has been shown to reduce recurrence rates by up to 39%. However, some studies have suggested poor compliance with PSDIVC stating logistical issues and reluctance to give chemotherapy prior to histological confirmation as some of the reasons. OBJECTIVES: This study aims to analyse appropriate administration of PSDIVC practice in St. Mary's Hospital against European Association of Urology guidelines and implement an intervention bundle to improve practice. PATIENTS AND METHODS: All patients that underwent transurethral resection of bladder tumour (TURBT) between March 2012 and February 2013 were analysed retrospectively to review indication for post-operative chemotherapy, instillation rates and limiting factors preventing appropriate instillation. An intervention bundle including pre-operative delivery of mitomycin C (MMC) to the theatre suite, proforma placed in the operative notes and designated roles for PSDIVC induction was introduced to improve instillation and documentation rates. Prospective re audit data was collected over six months between July 2013 and December 2013 following intervention. RESULTS: Sixty-four patients in group A underwent TURBT prior to introduction of the intervention bundle. Fifty-four patients had non muscle invasive bladder cancer (NMIBC), which would have been eligible for PSDIVC. Fifteen (28% of NMIBC) were administered PSDIVC. Twenty-three (36% of all patients) were either given PSDIVC or had a documented contraindication. Thirty one patients in group B underwent TURBT following induction of intervention bundle. Twelve (50% of NMIBC) patients were given PSDIVC. Twenty-eight (90% of all patients) were either given PSDIVC or had a documented contraindication. CONCLUSIONS: The intervention bundle prompted increased administration of PSDIVC and documentation. Similar centres may benefit from an intervention to improve compliance. PMID- 26981496 TI - Serum Klotho Levels in Trained Athletes. AB - BACKGROUND: Klotho is an anti-aging protein that is predominantly secreted by the kidneys. OBJECTIVES: The aim of the study was to measure and compare the circulating Klotho levels in the serum of trained athletes and in healthy, non athlete controls. MATERIALS AND METHODS: Thirty trained football players were enrolled and their serum Klotho levels were measured the morning after their last evening exercise training. RESULTS: The plasma free Klotho concentration was significantly higher in the athlete group (3.375 +/- 1.48 ng/mL) compared to the non-athletes (1.39 +/- 0.43 ng/mL) (P < 0.05). Serum levels of cholesterol, triglycerides, calcium, and phosphorus were not significantly different between the two groups. CONCLUSIONS: Regular aerobic exercise could increase plasma Klotho levels, and this could be an explanation for exercise-related anti-aging effects. PMID- 26981497 TI - Comparison Between Tadalafil Plus Paroxetine and Paroxetine Alone in the Treatment of Premature Ejaculation. AB - BACKGROUND: Several recent studies have investigated the therapeutic role of phosphodiesterase type 5 (PDE5) inhibitors in premature ejaculation (PE) used in the treatment of erectile dysfunction. OBJECTIVES: In the present research, the efficacy of paroxetine alone and paroxetine plus tadalafil was compared in patients referred because of premature ejaculation. PATIENTS AND METHODS: This quasi-experimental study was performed on 100 consecutive 17 to 49-year-old potent men with premature ejaculation and without any clear organic disease. All patients had lifelong PE with an intravaginal ejaculation latency time (IELT) shorter than 1.5 minutes. Informed consent was obtained from all patients who were randomly divided into two groups using a computer-generated random tabulation list. In group A, patients received 10 mg paroxetine daily, in addition to four hours before planned sexual activity. In group B, 10 mg paroxetine was taken daily, plus 10 mg tadalafil one hour before planned sexual activity. The duration of the intervention was six months and patients were evaluated for IELT three and six months after the beginning of therapy. RESULTS: The mean age of patients in groups A and B were 33 +/- 9.6 and 31.2 +/- 9.3 years, respectively (P = 0.368). The mean number of intercourses were 1.08 +/- 0.6 and 1.12 +/- 0.6 per week in groups A and B, respectively (P = 0.791). Mean IELT at the 3-month follow up in groups A and B was 4.5 +/- 1.5 and 5 +/- 2.4 minutes, respectively (P = 0.285) and at the 6-month follow up was 4.8 +/- 1 and 5.3 +/- 2 minutes, respectively (P = 0.278). CONCLUSIONS: The results of the study show that tadalafil can increase the mean IELT and can be used for treatment of premature ejaculation in combination with paroxetine. PMID- 26981498 TI - Antiproliferative and Antioxidant Effects of Withania coagulans Extract on Benign Prostatic Hyperplasia in Rats. AB - BACKGROUND: Benign prostate hyperplasia (BPH) is a common urological disorder in elderly men. Phytotherapy is frequently used to alleviate the symptoms of this condition. OBJECTIVES: The present study investigated the effect of Withania coagulans extract (WCE), which is known to have antioxidant, anti-inflammatory, antihyperglycemic, and anti-cancer properties, on testosterone-induced BPH in rats. MATERIALS AND METHODS: Forty Wistar rats were divided into five groups (each n = 8): the control group, the untreated BPH group, and three WCE-treated groups (WCE250, 500, and 1000). BPH was induced with 3 mg/kg subcutaneous injections of testosterone propionate for four weeks. WCE was concomitantly administrated by oral gavage. At the end of the induction schedule, the animals were sacrificed and their prostate glands were dissected, weighed, and fixed for histological examination (H&E and proliferating cell nuclear antigen [PCNA] staining). Half of each sample was prepared for measurement of malondialdehyde (MDA) and total antioxidant capacity (TAC) levels in the prostate. RESULTS: The present study revealed that BPH caused elevation of MDA levels, suppression of TAC levels, and increased PCNA expression in the prostate gland. Interestingly, in a dose-dependent manner, WCE caused decreased MDA levels and increased TAC levels in the prostate gland, compared to the untreated BPH group. Histopathological examinations showed a reduction in PCNA expression in the prostate epithelium of the WCE animals. CONCLUSIONS: W. coagulans inhibits the development of BPH can be useful for the treatment of this condition. PMID- 26981499 TI - A Comparison of the Progression and Recurrence Risk Index in Non-Muscle-Invasive Bladder Tumors Detected by Narrow-Band Imaging Versus White Light Cystoscopy, Based on the EORTC Scoring System. AB - BACKGROUND: Transitional cell carcinoma of the bladder, the second most common urologic malignancy, is amenable to early diagnosis. This study presents the potential prognostic benefit for a less invasive modification to the standard endoscopic approach. OBJECTIVES: To evaluate the risk index for the progression and recurrence of additional tumors detected with narrow-band imaging (NBI) cystoscopy compared to standard white light imaging (WLI) cystoscopy in non muscle-invasive bladder cancer (NMIBC), based on the European organization for research and treatment of cancer (EORTC) scoring system. PATIENTS AND METHODS: Patients with NMIBC, who were scheduled for resection between May 2012 and May 2013, were studied and mapped under NBI and WLI cystoscopy by independent surgeons prior to resection. Detection rates and tumor characteristics, including EORTC progression and the recurrence risk index, were compared. RESULTS: Fifty patients, aged 63.86 +/- 10.05 years, were enrolled. The overall detection rate was 98.9% for NBI vs. 89.4% for WLI (P = 0.001), and the false-positive rates were 9.6% and 5.8%, respectively (P = 0.051). Ten tumors were detected by NBI alone, including four grade I tumors, four grade III tumors, and two carcinomas in situ. The tumor progression index was not significantly reduced with NBI compared to WLI (P > 0.05); however, the recurrence index was significantly lower in the NBI group (P < 0.05). CONCLUSIONS: NBI cystoscopy improved the detection rate. Although false positives were more common with NBI, this was not statistically significant. NBI found additional aggressive tumors, which underscores the impact of detection in EORTC recurrence risk scoring. PMID- 26981500 TI - Could Urinary Tract Infection Cause Female Stress Urinary Incontinence? A Clinical Study. AB - BACKGROUND: Stress urinary incontinence (SUI), the most common type of urinary incontinence (UI), is usually defined as leakage of urine during movement or activity which puts pressure on the bladder, such as coughing, sneezing, running or heavy lifting. It is reported in most countries that 15% to 40% of women struggle with SUI and its severe implications for daily life, including social interactions, sexuality, and psychological wellbeing. OBJECTIVES: The aim of our study was to assess the relationship between urinary tract infection and the severity of stress urinary incontinence (SUI). PATIENTS AND METHODS: This research was a cross-sectional study conducted in a public urology clinic in Tehran. The study population was all females with complaints of SUI who visited the clinic during 2014. We compared Valsalva leak point pressure (VLPP) in two groups of patients, with and without history of urinary tract infection (UTI). RESULTS: According to the findings of our study, the mean VLPP was 83.10 cm H2O in the group with UTI history, and 81.29 cm H2O in those without history of UTI. The difference in VLPP between the two groups was not significant (P < 0.05), even after controlling for confounding variables including age, body mass index, history of hysterectomy and number of deliveries. CONCLUSIONS: Our study did not confirm a significant relationship between UTI and severity of SUI as measured by VLPP. A decisive opinion would require extensive future studies by prospective methods. PMID- 26981501 TI - Obsessive Compulsive Inventory-Child Version (OCV-CI) to Evaluate Obsessive Compulsive Disorder in Children With Early Stages of Chronic Kidney Disease: A Case Control Study. AB - BACKGROUND: Chronic kidney disease (CKD) is a common medical condition among children and obsessive-compulsive disorder (OCD) is a frequent, chronic, costly, and disabling disorder among them. OBJECTIVES: The aim of this study was to investigate obsessive-compulsive disorder (OCD) in children with early stages of CKD, and to compare it with the occurrence of OCD in healthy children. PATIENTS AND METHODS: In this case-control study, we evaluated 160 children aged 7 to 17 years old who were visited in the pediatric clinics of Amir-Kabir hospital, Arak, Iran. The control group consisted of 80 healthy children and the case group included 80 children with Stage 1 to 3 CKD. The ages and sex of the children in the two groups were matched. OCD in children was evaluated using the obsessive compulsive inventory-child version (OCI-CV). RESULTS: The mean scores of doubting/checking (case: 3.52 +/- 2.54, control: 2.5 +/- 2.32, P = 0.007) and ordering (case: 2.59 +/- 1.81, control: 1.5 +/- 2.56, P = 0.005) in the children with CKD was significantly higher than in the healthy ones. Moreover, the mean total scores for the OCI-CV of the children with CKD at 15.32 +/- 7.69 was significantly higher than the scores of the healthy ones at 11.12 +/- 2.54 (P = 0.021). There was a significant correlation between the CKD duration and doubting/checking (P = 0.004, correlation coefficient (CC): 0.4), obsessing (P = 0.06, CC: 0.02), washing (P = 0.031, CC: 0.8), ordering (P = 0.001, CC: 0.2), and the total scores of the OCI-CV questionnaire (P = 0.04, CC: 0.4). CONCLUSIONS: The risk of OCD in children with CKD is significantly higher than that in healthy children. Although the results seem to suggest that psychiatric intervention can be helpful in treating OCD in children with CKD, further investigation into the medical condition is required so as to obtain more definitive conclusions. PMID- 26981502 TI - Hyperbaric Oxygen Therapy Suppresses Apoptosis and Promotes Renal Tubular Regeneration After Renal Ischemia/Reperfusion Injury in Rats. AB - BACKGROUND: Renal ischemia/reperfusion (I/R) injury remains a major cause of acute kidney injury (AKI), in addition to I/R injury-induced tissue inflammation, necrosis and apoptosis. Hyperbaric oxygen therapy (HBO) is defined as a treatment in which a patient is intermittently exposed to 100% oxygen pressurized to a pressure above sea level (> 2.0 atmospheres absolute (ATA), 1.0 ATA = 760 mmHg). It has been used in a number of medical conditions with a proven efficacy in a limited number of disorders. However, the effects of HBO therapy on apoptosis and proliferative activity after I/R injury have not been fully understood. OBJECTIVES: We studied the possible beneficial effects of HBO therapy on apoptosis and tubular cell regeneration after renal I/R injury in rats. MATERIALS AND METHODS: Sprague-Dawley (SD) rats were randomized into three groups: Sham (Sham-operated rats); I/R (animals submitted to I/R); and I/R + HBO (I/R rats exposed to HBO). Tubular cell apoptosis was confirmed by DNA laddering and the terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL) assay. Cellular proliferation activity was determined using the anti-Ki-67 antibody. RESULTS: A significant decrease in apoptotic cells and increase in proliferative reaction were observed in the I/R + HBO group compared to the I/R group. CONCLUSIONS: We demonstrated that HBO suppressed apoptosis, which caused inflammation after renal I/R, and promoted tubular cell regeneration. HBO has protective effects against AKI caused by renal I/R through the inhibition of apoptosis. PMID- 26981503 TI - Development of an Accident Reproduction Simulator System Using a Hemodialysis Extracorporeal Circulation System. AB - BACKGROUND: Accidents that occur during dialysis treatment are notified to the medical staff via alarms raised by the dialysis apparatus. Similar to such real accidents, apparatus activation or accidents can be reproduced by simulating a treatment situation. An alarm that corresponds to such accidents can be utilized in the simulation model. OBJECTIVES: The aim of this study was to create an extracorporeal circulation system (hereinafter, the circulation system) for dialysis machines so that it sets off five types of alarms for: 1) decreased arterial pressure, 2) increased arterial pressure, 3) decreased venous pressure, 4) increased venous pressure, and 5) blood leakage, according to the five types of accidents chosen based on their frequency of occurrence and the degree of severity. MATERIALS AND METHODS: In order to verify the alarm from the dialysis apparatus connected to the circulation system and the accident corresponding to it, an evaluation of the alarm for its reproducibility of an accident was performed under normal treatment circumstances. The method involved testing whether the dialysis apparatus raised the desired alarm from the moment of control of the circulation system, and measuring the time it took until the desired alarm was activated. This was tested on five main models from four dialyzer manufacturers that are currently used in Japan. RESULTS: The results of the tests demonstrated successful activation of the alarms by the dialysis apparatus, which were appropriate for each of the five types of accidents. The time between the control of the circulatory system to the alarm signal was as follows, 1) venous pressure lower limit alarm: 7 seconds; 2) venous pressure lower limit: 8 seconds; 3) venous pressure upper limit: 7 seconds; 4) venous pressure lower limit alarm: 2 seconds; and 5) blood leakage alarm: 19 seconds. All alarms were set off in under 20 seconds. CONCLUSIONS: Thus, we can conclude that a simulator system using an extracorporeal circulation system can be set to different models of dialyzers, and that the reproduced treatment scenarios can be used for simulation training. PMID- 26981504 TI - Correlation between cyclin D1 expression and standard clinicopathological variables in invasive breast cancer in Eastern India. AB - INTRODUCTION: Breast cancer is the leading oncogenic threat in South-East Asian women showing an inexplicable biological aggressiveness. High expression of cyclin D1, a key molecule in breast cancer pathogenesis, has been shown by previous studies in the Western world to be associated with favorable tumoral characteristics. Apart from determining the correlation between cyclin D1 expression and standard clinicopathological variables in invasive breast cancer in Eastern India, questions that we aimed to answer through this study included: Is there a significant regional difference in expression patterns of this protein? And if yes, can it possibly account for the epidemiological differences in breast cancer occurrence and biological behavior? Finally, is testing for overexpression of this protein in regions with limited resources beneficial? MATERIALS AND METHODS: The present study was carried out on 110 previously untreated, female patients with primary breast carcinoma. Cyclin D1 expression was determined by immunohistochemistry using specific anti-cyclin D1 monoclonal antibodies. RESULTS: Overexpression of cyclin Dl was found in 78 of 110 cases (70.9%). High expression of cyclin D1 showed a significant negative correlation with tumor size (P = 0.023) and tumor grade (P = 0.045). Estrogen receptor and progesterone receptor positive cases showed a significantly positive correlation with cyclin D1 overexpression (P = 0.026 and 0.046, respectively). Interestingly, cyclin D1 positivity showed a strong correlation with the type of surgical procedure performed (P = 0.002). CONCLUSION: Cyclin D1 overexpression in breast cancer is associated with less aggressive tumoral characteristics. Furthermore, its potential epidemiological role and utility as a prognostic marker have been discussed. PMID- 26981505 TI - Radiobiological case study of volumetric modulated arc therapy planning techniques for treatment of low-risk prostate cancer in patients with bilateral hip prostheses. PMID- 26981506 TI - Molecular classification and prognostication of 300 node-negative breast cancer cases: A tertiary care experience. AB - BACKGROUND: The proportion of node-negative breast cancer patients has been increasing with improvement of diagnostic modalities and early detection. However, there is a 20-30% recurrence in node-negative breast cancers. Determining who should receive adjuvant therapy is challenging, as the majority are cured by surgery alone. Hence, it requires further stratification using additional prognostic and predictive factors. SUBJECTS AND METHODS: Ours is a single institution retrospective study, on 300 node-negative breast cancer cases, who underwent primary surgery over a period of 7 years (2005-2011). We excluded all cases who took NACT. Prognostic factors of age, size, lymphovascular emboli, estrogen receptor (ER), progesterone receptor (PR), HER2neu Ki-67, grade and molecular classification were analyzed with respect to those with and without early events (recurrence, metastases or second malignancy, death) using-Pearson Chi-square method and logistic regression method for statistical analysis. RESULTS: Majority belonged to the age group of 50-70 years. On univariate analysis, size >5 cm (P = 0.03) and ER negativity had significant association (P = 0.05) for early failures; PR negativity and lymphovascular emboli (LVE) had borderline significance (P = 0.07). Multivariate analysis showed size >5 cm to be significant (P = 0.04) and LVE positivity showed borderline significant association (P = 0.07) with early failures. About 62% belonged to luminal category followed by basal-like (25%) in molecular classification. CONCLUSIONS: ER negativity, PR negativity, LVE/lymphovascular invasion positivity and size >5 cm (T3 and T4) are associated with poor prognosis in node-negative breast cancers. PMID- 26981508 TI - Outcomes of adult medulloblastoma treated with a multimodality approach: A tertiary cancer center experience. AB - OBJECTIVES: Adult medulloblastoma (AMB) is a rare central nervous system tumor. We aimed to analyze the treatment outcomes of AMB treated at our institute with surgery followed by craniospinal irradiation (CSI) and adjuvant chemotherapy. METHODS: We retrospectively evaluated the treatment charts of 31 patients of AMB treated from 2003-2011. The patient demography, treatment details and survival data were collected in a predesigned proforma. Kaplan Meier method was used to analyze disease free survival (DFS) and the impact of prognostic factors was determined by univariate analysis (log rank test). RESULTS: Male: Female ratio was 21:10. Cerebrospinal fluid dissemination was noted in 16% cases. CSI (36 Gray at 1.8 Gray/fraction to entire neuraxis and 20 Gray at 2 Gray/fraction boost to posterior fossa) was used in all cases. 26 patients received adjuvant chemotherapy (carboplatin plus etoposide). Median follows up was 26.85 months (9.47-119.73 months). The estimated 3 and 5 years DFS was found to be 84.9% and 50.7% respectively. On univariate analysis, tumor located laterally had a trend towards better DFS (HR 3.04; 95%CI 0.722 to 12.812; P = 0.07) compared to midline tumors. Other factors like adjuvant chemotherapy, age, gender, surgical extent had no statistically significant impact on survival. CONCLUSION: The results of our study (largest series from India) show that the regimen of surgery, adjuvant CSI and chemotherapy is feasible and confers descent survival. AMB patients should be treated with a multimodality approach in a tertiary care centre. PMID- 26981509 TI - A relationship between quality-of-life and head and neck cancer: A systemic review. AB - AIM: The aim was to identify the literature and to assess the association between quality-of-life (QoL) and head and neck cancer (HNC) related outcomes systemically. MATERIALS AND METHODS: The full articles published in English language bio-medical journals between 1992 and December 2014 were searched using Medline database. The keywords used for searching the articles include the combination of "health-related of QoL," "QoL," "HNC." The search limited only to the observational studies using questionnaires European Organization for Research and Treatment of Cancer (EORTC) QLQ C 30 and EORTC QLQ H and N 35. Purely psychological studies were excluded. RESULTS: A total of 5055 articles were retrieved, and 16 articles were selected for this review. Of 16 observational studies, 13 (81.25%) were prospective cohort studies while remaining 3 (18.75%) were cross-sectional studies. The main findings of the studies revealed that the treatment of HNC had a statistically significant influence on QoL. Others associated factors like age, female sex, duration of treatment, advance tumor, and site of the tumor has also the impact on QoL on patients suffering from HNC. CONCLUSION: This review provides evidence for a positive relationship between cancer-related outcomes and QoL. Assessment of QoL in relation to HNC with proper methodology and validated instruments is lacking hence there is a need for further evidence to support the relation between cancer and QoL. PMID- 26981507 TI - Recurrent Glioblastoma: Where we stand. AB - Current first-line treatment regimens combine surgical resection and chemoradiation for Glioblastoma that provides a slight increase in overall survival. Age on its own should not be used as an exclusion criterion of glioblastoma multiforme (GBM) treatment, but performance should be factored heavily into the decision-making process for treatment planning. Despite aggressive initial treatment, most patients develop recurrent diseases which can be treated with re-resection, systemic treatment with targeted agents or cytotoxic chemotherapy, reirradiation, or radiosurgery. Research into novel therapies is investigating alternative temozolomide regimens, convection-enhanced delivery, immunotherapy, gene therapy, antiangiogenic agents, poly ADP ribose polymerase inhibitors, or cancer stem cell signaling pathways. Given the aggressive and resilient nature of GBM, continued efforts to better understand GBM pathophysiology are required to discover novel targets for future therapy. PMID- 26981510 TI - Late effects of cancer treatment in breast cancer survivors. PMID- 26981511 TI - To evaluate disparity between clinical and pathological tumor-node-metastasis staging in oral cavity squamous cell carcinoma patients and its impact on overall survival: An institutional study. AB - BACKGROUND: Accurate clinical staging is important for patient counseling, treatment planning, prognostication, and rational design of clinical trials. In head and neck squamous cell carcinoma, discrepancy between clinical and pathological staging has been reported. OBJECTIVE: To evaluate any disparity between clinical and pathological tumor-node-metastasis (TNM) staging in oral cavity squamous cell carcinoma (OCSCC) patients and any impact of the same on survival. MATERIALS AND METHODS: Retrospective chart review from year 2007 to 2013, at a tertiary care center. STATISTICAL ANALYSIS: All survival analyses were performed using SPSS for Windows version 15 (Chicago, IL, USA). Disease-free survival curves were generated using Kaplan-Meier algorithm. RESULTS: One hundred and twenty-seven patients with OCSCC were analyzed. Seventy-nine (62.2%) were males and 48 (37.8%) females with a mean age at presentation 43.6 years (29-79 years). The highest congruence between clinical and pathological T-staging seen for clinical stage T1 and T4 at 76.9% and 73.4% with pathological T-stage. Similarly, the highest congruence between clinical and pathological N-stage seen for clinical N0 and N3 at 86.4% and 91.7% with pathological N-stage. Of clinically early stage patients, 67.5% remained early stage, and 32.5% were upstaged to advanced stage following pathological analysis. Of the clinically advanced stage patients, 75% remained advanced, and 25% were pathologically downstaged. This staging discrepancy did not significantly alter the survival. CONCLUSION: Some disparity exists in clinical and pathological TNM staging of OCSCC, which could affect treatment planning and survival of patients. Hence, more unified and even system of staging for the disease is required for proper decision-making. PMID- 26981513 TI - Palliative low dose fortnightly methotrexate in oral cancer. PMID- 26981512 TI - Role of iron chelation in improving survival: An integral part of current therapy for myelodysplastic syndromes. AB - This review article highlights the current role of iron chelation in MDS to optimize survival and quality of life. Its role in specific subtypes of MDS is also discussed. PMID- 26981514 TI - The Association between Urine Albumin to Creatinine Ratio and Osteoporosis in Postmenopausal Women with Type 2 Diabetes. AB - BACKGROUND: Osteoporosis is a progressive bone disease that is characterized by a decrease in bone mass density and destruction of microstructure, which can lead to an increased risk of fracture. Although many studies have been published about the relationship between end-stage renal disease and osteoporosis, research on the relationship between proteinuria and the prevalence of osteoporosis is still lacking. METHODS: We assessed 91 postmenopausal women with type 2 diabetes who visited our hospital from January 2009 to January 2012. RESULTS: Among 91 patients, the prevalence of osteoporosis and osteopenia was 35.2% (32 cases) and 32.9% (30 cases) according to bone mineral density. The patients with microalbuminuria and macroalbuminuria (urine albumin-to-creatinine ratio [UACR] >= 30) had a significantly higher incidence of osteoporosis compared to subjects with normoalbuminuria (P<0.05). CONCLUSIONS: This study indicates that UACR may be a useful biomarker for increased risk of osteoporosis in postmenopausal women with type 2 diabetes who have been linked to higher UACR levels. PMID- 26981515 TI - Deficiency of Lipocalin-2 Promotes Proliferation and Differentiation of Osteoclast Precursors via Regulation of c-Fms Expression and Nuclear Factor-kappa B Activation. AB - BACKGROUND: Lipocalin-2 (LCN2), a small glycoprotein, has a pivotal role in diverse biological processes such as cellular proliferation and differentiation. We previously reported that LCN2 is implicated in osteoclast formation induced by receptor activator of nuclear factor-kappa B ligand (RANKL) and macrophage colony stimulating factor (M-CSF). In the present study, we used a knockout mouse model to further investigate the role of LCN2 in osteoclast development. METHODS: Osteoclastogenesis was assessed using primary bone marrow-derived macrophages. RANKL and M-CSF signaling was determined by immunoblotting, cell proliferation by bromodeoxyuridine (BrdU) enzyme-linked immunosorbent assay (ELISA), and apoptosis by cell death detection ELISA. Bone morphometric parameters were determined using a micro-computed tomography system. RESULTS: Our results showed that LCN2 deficiency increases tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclast formation in vitro, a finding that reflects enhanced proliferation and differentiation of osteoclast lineage cells. LCN2 deficiency promotes M-CSF-induced proliferation of bone marrow macrophages (BMMs), osteoclast precursors, without altering their survival. The accelerated proliferation of LCN2-deficient precursors is associated with enhanced expression and activation of the M-CSF receptor, c-Fms. Furthermore, LCN2 deficiency stimulates the induction of c-Fos and nuclear factor of activated T cells c1 (NFATc1), key transcription factors for osteoclastogenesis, and promotes RANKL induced inhibitor of kappa B (IkappaBalpha) phosphorylation. Interestingly, LCN2 deficiency does not affect basal osteoclast formation in vivo, suggesting that LCN2 might play a role in the enhanced osteoclast development that occurs under some pathological conditions. CONCLUSIONS: Our study establishes LCN2 as a negative modulator of osteoclast formation, results that are in accordance with our previous findings. PMID- 26981516 TI - Serum Sclerostin Levels in Patients with Human Immunodeficiency Virus Infection and Their Association with Bone Turnover Markers and Bone Mineral Densitometry. AB - BACKGROUND: The aim of the study was to compare serum sclerostin levels in human im-munodeficiency virus (HIV)-infected patients and healthy controls, and to evaluate their relationship with bone turnover markers (BTM) and bone mineral density (BMD). METHODS: We prospectively studied 33 HIV treatment-naive patients and 63 healthy individuals; matched for age and sex. Serum sclerostin levels, BTM, BMD were measured. Viral load and cluster of differentiation 4 (CD4) levels were also assessed in HIV-infected patients. RESULTS: The mean+/-standard deviation (SD) age of sample was 37.6+/-10.3 years (range, 19 to 59 years). Of the 96 subjects, 58 (60.4%) were male and 38 (39.6%) were female. Infection with HIV is associated with significant reduction in serum sclerostin levels (HIV infected: 39.4+/-28.3 vs. non HIV: 76.6+/-15.7 pmol/L; P<0.001) and a decrease in BMD at femoral neck and lumbar spine compared to healthy controls. Sclerostin however was not correlated with BMD and was not related to age, generally a strong correlation. There were no significant correlations between sclerostin and BTM (P>0.05). CONCLUSIONS: These findings suggest that untreated HIV and the resulting immune deficiency and/or systemic inflammation could be an important regulator of serum sclerostin in this population. PMID- 26981517 TI - Prevalence of Sarcopenia in the Korean Woman Based on the Korean National Health and Nutritional Examination Surveys. AB - BACKGROUND: The criteria for defining sarcopenia vary among studies and confusion has arisen when defining the cutoff value. As a result, the prevalence of sarcopenia differs markedly depending on the definition. This study used the Asian Working Group for Sarcopenia (AWGS) definition to determine the prevalence of sarcopenia among Korean women. METHODS: This study was based on data obtained from the 2008 to 2011 Korean National Health and Nutrition Examination Surveys IV and V. We used the AWGS recommended cutoff value of 5.4 kg/m(2) to determine the prevalence of sarcopenia in Korean women. RESULTS: The prevalence rates of sarcopenia using a cutoff value of 5.4 kg/m(2) were 385 (19.5%) in women in their 50s, 286 (16.6%) in women in their 60s, 293 (23.7%) in women in their 70s, and 91 (30.8%) in women >=80 years. The prevalence rates of sarcopenia were 307 (19.0%) in women 65 to 74 years, 194 (27.4%) in women 75 to 84 years, and 32 (40.5%) in women >=85 years. The overall prevalence among women >50 years was 20.2%. The prevalence of sarcopenia in women >65 years was 22.1%. CONCLUSIONS: The prevalence of sarcopenia among Korean women was within the range of values of previous research about sarcopenia. Furthermore, using 5.4 kg/m(2) as the cutoff value was useful to compare various studies about sarcopenia in Koreans. PMID- 26981518 TI - Relationship between Serum Inflammatory Marker and Bone Mineral Density in Healthy Adults. AB - BACKGROUND: Inflammatory markers have been shown to play an important role in bone remodeling. The purpose of this study was to investigate the relationship among serum C-reactive protein (CRP), adiponectin, tumor necrosis factor-alpha (TNF-alpha) and bone health in healthy adults. METHODS: We measured serum levels of CRP, adiponectin, TNF-alpha as well as lumbar spine and femoral neck bone mineral density (BMD) in 76 adults. Anthropometric measurements and nutrient intake survey of participants were carried out. The participants were divided into two groups (normal BMD group=40; 52.6%, decreased BMD group=36; 47.4%). RESULTS: The CRP concentration was significantly higher in the decreased BMD group. The adiponectin concentration was lower in the decreased BMD group but the difference was not significant. The TNF-alpha concentration was higher in the decreased BMD group, the difference was not significant. The participants in the decreased BMD group were found to have lower calcium intakes. The sodium intake of the decreased BMD group was significantly higher. The BMD in the decreased BMD group showed inverse correlations with CRP and dietary sodium intake. CONCLUSIONS: Serum CRP and dietary sodium intake is associated with BMD. Further research is needed to confirm the potential role of inflammatory marker to modulate the effects on bone. PMID- 26981520 TI - Multiple Fractures in Patient with Graves' Disease Accompanied by Isolated Hypogonadotropic Hypogonadism. AB - Isolated hypogonadotropic hypogonadism (IHH) is known to decrease bone mineral density due to deficiency of sex steroid hormone. Graves' disease is also an important cause of secondary osteoporosis. However, IHH does not preclude the development of primary hyperthyroidism caused by Graves' disease, leading to more severe osteoporosis rapidly. Here, we describe the first case of 35-year-old Asian female patient with IHH accompanied by Graves' disease and osteoporosis induced multiple fractures. Endocrine laboratory findings revealed preserved anterior pituitary functions except for secretion of gonadotropins and showed primary hyperthyroidism with positive autoantibodies. Sella magnetic resonance imaging showed slightly small sized pituitary gland without mass lesion. Dual energy X-ray absorptiometry revealed severe osteoporosis in lumbar spine and femur neck of the patient. Plain film radiography of the pelvis and shoulder revealed a displaced and nondisplaced fracture, respectively. After surgical fixation with screws for the femoral fracture, the patient was treated with antithyroid medication, calcium, and vitamin D until now and has been recovering fairly well. We report a patient of IHH with Graves' disease and multiple fractures that is a first case in Korea. PMID- 26981519 TI - Osteoporotic Fracture Risk Assessment Using Bone Mineral Density in Korean: A Community-based Cohort Study. AB - BACKGROUND: Fracture-risk assessment tool (FRAX) using just clinical risk factors of osteoporosis has been developed to estimate individual risk of osteoporotic fractures. We developed prediction model of fracture risk using bone mineral density (BMD) as well as clinical risk factors in Korean, and assessed the validity of the final model. METHODS: To develop and validate an osteoporotic FRAX, a total of 768 Korean men and women aged 50 to 90 years were followed for 7 years in a community-based cohort study. BMD as well as clinical risk factors for osteoporotic fracture including age, sex, body mass index, history of fragility fracture, family history of fracture, smoking status, alcohol intake, use of oral glucocorticoid, rheumatoid arthritis, and other causes of secondary osteoporosis were assessed biannually. RESULTS: During the follow-up period, 86 osteoporotic fractures identified (36 in men and 50 in women). The developed prediction models showed high discriminatory power and had goodness of fit. CONCLUSIONS: The developed a Korean specific prediction model for osteoporotic fractures can be easily used as a screening tool to identify individual with high risk of osteoporotic fracture. Further studies for validation are required to confirm the clinical feasibility in general Korean population. PMID- 26981521 TI - Calcaneal Insufficiency Fracture after Ipsilateral Total Knee Arthroplasty. AB - Insufficiency fracture of the calcaneus is a rare entity. In the absence of trauma, evaluating a painful ankle in an elderly patient can be difficult and also it might be overlook the insufficiency fracture. We experienced a case of insufficiency calcaneus fracture that occurred after ipsilateral total knee arthroplasty. Here, we report our case with a review of literatures. PMID- 26981522 TI - Erratum to: Vitamin D Deficiency Is Highly Concomitant but Not Strong Risk Factor for Mortality in Patients Aged 50 Year and Older with Hip Fracture. AB - [This corrects the article on p. 205 in vol. 22, PMID: 26713312.]. PMID- 26981523 TI - The Content and Bioavailability of Mineral Nutrients of Selected Wild and Traditional Edible Plants as Affected by Household Preparation Methods Practiced by Local Community in Benishangul Gumuz Regional State, Ethiopia. AB - Edible parts of some wild and traditional vegetables used by the Gumuz community, namely, Portulaca quadrifida, Dioscorea abyssinica, Abelmoschus esculentus, and Oxytenanthera abyssinica, were evaluated for their minerals composition and bioavailability. Mineral elements, namely, Ca, Fe, Zn, and Cu, were analyzed using Shimadzu atomic absorption spectrophotometer. Effects of household processing practices on the levels of mineral elements were evaluated and the bioavailability was predicted using antinutrient-mineral molar ratios. Fe, Zn, Ca, Cu, P, Na, and K level in raw edible portions ranged in (0.64 +/- 0.02-27.0 +/- 6.24), (0.46 +/- 0.02-0.85 +/- 0.02), (24.49 +/- 1.2-131.7 +/- 8.3), (0.11 +/ 0.01-0.46 +/- 0.04), (39.13 +/- 0.34-57.27 +/- 0.94), (7.34 +/- 0.42-20.42 +/- 1.31), and (184.4 +/- 1.31-816.3 +/- 11.731) mg/100 g FW, respectively. Although statistically significant losses in minerals as a result of household preparation practices were observed, the amount of nutrients retained could be valuable especially in communities that have limited alternative sources of these micronutrients. The predicted minerals' bioavailability shows adequacy in terms of calcium and zinc but not iron. PMID- 26981524 TI - Plant Responses to High Frequency Electromagnetic Fields. AB - High frequency nonionizing electromagnetic fields (HF-EMF) that are increasingly present in the environment constitute a genuine environmental stimulus able to evoke specific responses in plants that share many similarities with those observed after a stressful treatment. Plants constitute an outstanding model to study such interactions since their architecture (high surface area to volume ratio) optimizes their interaction with the environment. In the present review, after identifying the main exposure devices (transverse and gigahertz electromagnetic cells, wave guide, and mode stirred reverberating chamber) and general physics laws that govern EMF interactions with plants, we illustrate some of the observed responses after exposure to HF-EMF at the cellular, molecular, and whole plant scale. Indeed, numerous metabolic activities (reactive oxygen species metabolism, alpha- and beta-amylase, Krebs cycle, pentose phosphate pathway, chlorophyll content, terpene emission, etc.) are modified, gene expression altered (calmodulin, calcium-dependent protein kinase, and proteinase inhibitor), and growth reduced (stem elongation and dry weight) after low power (i.e., nonthermal) HF-EMF exposure. These changes occur not only in the tissues directly exposed but also systemically in distant tissues. While the long-term impact of these metabolic changes remains largely unknown, we propose to consider nonionizing HF-EMF radiation as a noninjurious, genuine environmental factor that readily evokes changes in plant metabolism. PMID- 26981526 TI - Menoprogen, a TCM Herbal Formula for Menopause, Increases Endogenous E2 in an Aged Rat Model of Menopause by Reducing Ovarian Granulosa Cell Apoptosis. AB - The effect of Menoprogen (MPG) on ovarian granulosa cell (GC) apoptosis was investigated in vitro and in vivo in an aged rat model of menopause. Intragastric administration of Menoprogen or estradiol valerate to 14-month-old senile female rats for eight weeks increased plasma E2 levels, as well as the weight of both ovarian and uterine tissues. Flow cytometric (FCM) analysis of isolated GCs from MPG-treated aged rats showed reductions in the G0/G1 ratio and apoptotic peaks. Isolated GCs also exhibited an increase in cell size and the number of cytoplastic organelles and intracellular gap junctions, the reappearance of secretory granules, and a lack of apoptotic bodies as determined by TEM. Results from a TdT-mediated dUTP nick end-labeling (TUNEL) assay revealed a reduction in TUNEL-positive GCs after MPG treatment. Immunohistochemical analysis showed a downregulation of proapoptotic Bax proteins and an upregulation of antiapoptotic Bcl-2 proteins. The addition of MPG-medicated serum to the media of cultured GCs also reduced cadmium chloride-induced apoptosis and downregulated caspase-3 protein expression. This work demonstrates that Menoprogen inhibits GC apoptosis in aged female rats and thereby increases E2 production. This represents a novel mechanism of action for this herbal medicine in the treatment of menopausal symptoms. PMID- 26981527 TI - Assessment of Structural and Functional Abnormalities of the Myocardium and the Ascending Aorta in Fetus with Hypoplastic Left Heart Syndrome. AB - Aims. To detect anatomical and intrinsic histopathological features of the ascending aorta and left ventricular (LV) myocardium and evaluate right ventricular (RV) function in fetuses with hypoplastic left heart syndrome (HLHS). Methods. Twenty-five fetuses diagnosed with HLHS were followed up in the antenatal and postpartum periods. 12 necropsy heart specimens were analyzed for morphological and histological changes. Results. Prenatal echocardiography and pathologic anatomy displayed the typical characteristics of HLHS as a severe underdevelopment of the LV in the form of mitral stenosis or atresia or as aortic atresia or stenosis, with a decreased ratio of aortic diameter to pulmonary artery diameter (median of 0.49 with a range of 0.24 to 0.69, p <= 0.001) and a higher ratio of RV diameter to LV diameter (median of 2.44 with a range of 1.33 to 6.25, p <= 0.001). The RV volume, stroke volume, and cardiac output in HLHS fetuses were increased compared with the gestational age-matched normal controls (p < 0.01). Histological changes in the 12 HLHS specimens included LV myocardial fibrosis, aortic elastic fragmentation, and fibrosis. Conclusions. In addition to severe anatomical deformity, distinct histological abnormalities in the LV myocardium and aortic wall were identified in the fetuses with HLHS. RV function damage may be potentially exists. PMID- 26981525 TI - Substance P Receptor Signaling Mediates Doxorubicin-Induced Cardiomyocyte Apoptosis and Triple-Negative Breast Cancer Chemoresistance. AB - Doxorubicin (DOX), an anthracycline, is broadly considered the most active single agent available for treating breast cancer but has been known to induce cardiotoxicity. Although DOX is highly effective in treating triple-negative breast cancer (TNBC), DOX can have poor outcomes owing to induction of chemoresistance. There is an urgent need to develop new therapies for TNBC aimed at improving DOX outcome and DOX-induced cardiotoxicity. Substance P (SP), a neuropeptide involved in pain transmission is known to stimulate production of reactive oxygen species (ROS). Elevated cardiac ROS is linked with heart injury and failure. We investigated the role of SP in chemotherapy-associated death of cardiomyocytes and chemoresistance. We showed that pretreating a cardiomyocyte cell line (H9C2) and a TNBC cell line (MDA-MB 231) with aprepitant, a SP receptor antagonist that is routinely used to treat chemotherapy-associated associated nausea, decreased DOX-induced reduction of cell viability, apoptotic cell death, and ROS production in cardiomyocytes and increased DOX-induced reduction of cell viability, apoptotic cell death, and ROS production in TNBC cells compared with cells treated with DOX alone. Our findings demonstrate the ability of aprepitant to decrease DOX-induced killing of cardiomyocytes and to increase cancer cell sensitivity to DOX, which has tremendous clinical significance. PMID- 26981528 TI - Could In-Home Sensors Surpass Human Observation of People with Parkinson's at High Risk of Falling? An Ethnographic Study. AB - Self-report underpins our understanding of falls among people with Parkinson's (PwP) as they largely happen unwitnessed at home. In this qualitative study, we used an ethnographic approach to investigate which in-home sensors, in which locations, could gather useful data about fall risk. Over six weeks, we observed five independently mobile PwP at high risk of falling, at home. We made field notes about falls (prior events and concerns) and recorded movement with video, Kinect, and wearable sensors. The three women and two men (aged 71 to 79 years) having moderate or severe Parkinson's were dependent on others and highly sedentary. We most commonly noted balance protection, loss, and restoration during chair transfers, walks across open spaces and through gaps, turns, steps up and down, and tasks in standing (all evident walking between chair and stairs, e.g.). Our unobtrusive sensors were acceptable to participants: they could detect instability during everyday activity at home and potentially guide intervention. Monitoring the route between chair and stairs is likely to give information without invading the privacy of people at high risk of falling, with very limited mobility, who spend most of the day in their sitting rooms. PMID- 26981529 TI - The Role of (18)F-FDG PET/CT and MRI in Assessing Pathological Complete Response to Neoadjuvant Chemotherapy in Patients with Breast Cancer: A Systematic Review and Meta-Analysis. AB - PURPOSE: We performed this meta-analysis to determine the utilities of (18)F-FDG PET/CT and MRI in assessing the pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in the same cohort of patients with breast cancer. METHODS: Two reviewers systematically searched on PubMed, Scopus, and Springer (from the beginning of 1992 to Aug. 1, 2015) for the eligible articles. Heterogeneity, pooled sensitivity and specificity, positive likelihood ratio, negative likelihood ratio, and the summary receiver operating characteristic (SROC) curve were calculated to estimate the diagnostic efficacy of (18)F-FDG PET/CT and MRI. RESULTS: A total of 6 studies including 382 pathologically confirmed patients were eligible. The pooled sensitivity and specificity of (18)F FDG PET/CT were 0.86 (95% CI: 0.76-0.93) and 0.72 (95% CI: 0.49-0.87), respectively. Pooled sensitivity and specificity of MRI were 0.65 (95% CI: 0.45 0.80) and 0.88 (95% CI: 0.75-0.95), respectively. The area under the SROC curve of (18)F-FDG PET/CT and MRI was 0.88 and 0.84, respectively. CONCLUSION: Study indicated that (18)F-FDG PET/CT had a higher sensitivity and MRI had a higher specificity in assessing pCR in breast cancer patients. Therefore, the combined use of these two imaging modalities may have great potential to improve the diagnostic performance in assessing pCR after NAC. PMID- 26981530 TI - Cancer Related Fatigue and Quality of Life in Patients with Advanced Prostate Cancer Undergoing Chemotherapy. AB - Cancer related fatigue (CRF) is a common and debilitating symptom that can influence quality of life (QoL) in cancer patients. The increase in survival times stresses for a better understanding of how CRF affects patients' QoL. This was a cross-sectional descriptive study with 148 randomly recruited prostate cancer patients aiming to explore CRF and its impact on QoL. Assessments included the Cancer Fatigue Scale, EORTC QLQ-C30, and EORTC QLQ-PR25. Additionally, 15 in depth structured interviews were performed. Quantitative data were analyzed with simple and multiple regression analysis and independent samples t-test. Qualitative data were analyzed with the use of thematic content analysis. The 66.9% of the patients experienced CRF with higher levels being recorded for the affective subscale. Statistically significant differences were found between the patients reporting CRF and lower levels of QoL (mean = 49.1) and those that did not report fatigue and had higher levels of QoL (mean = 72.1). The interviews emphasized CRF's profound impact on the patients' lives that was reflected on the following themes: "dependency on others," "loss of power over decision making," and "daily living disruption." Cancer related fatigue is a significant problem for patients with advanced prostate cancer and one that affects their QoL in various ways. PMID- 26981532 TI - TOT 8/4: A Way to Standardize the Surgical Procedure of a Transobturator Tape. AB - Suburethral tapes are placed "tension-free" below the urethra. Several studies reported considerable differences of the distance between urethra and tape. These distances ranged from 1 to 10 mm amongst different patients. This either caused urethral obstruction or had no effect on urinary incontinence. Therefore, we decided to standardize the procedure by placing a Hegar dilator of 8-millimeter diameter in the urethra and another Hegar dilator of 4-millimeter diameter between the urethra and the tape during transobturator tape placement. Using that simple technique, which we named "TOT 8/4," we observed that 83% of the tapes were placed in the desired distance between 3 and 5 millimeters below the urethra. PMID- 26981531 TI - Formation and Biopharmaceutical Characterization of Electrospun PVP Mats with Propolis and Silver Nanoparticles for Fast Releasing Wound Dressing. AB - Antibacterial, antiviral, antifungal, antioxidant, anti-inflammatory, and anticancer activities of propolis and its ability to stimulate the immune system and promote wound healing make it a proper component for wound dressing materials. Silver nanoparticles are recognized to demonstrate strong antiseptic and antimicrobial activity; thus, it also could be considered in the development of products for wound healing. Combining propolis and silver nanoparticles can result in improved characteristics of products designed for wound healing and care. The aim of this study was to formulate electrospun fast dissolving mats for wound dressing containing propolis ethanolic extract and silver nanoparticles. Produced electrospun nano/microfiber mats were evaluated studying their structure, dissolution rate, release of propolis phenolic compounds and silver nanoparticles, and antimicrobial activity. Biopharmaceutical characterization of electrospun mats demonstrated fast release of propolis phenolic compounds and silver nanoparticles. Evaluation of antimicrobial activity on Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Bacillus subtilis, Bacillus cereus, and Candida albicans strains confirmed the ability of electrospun mats to inhibit the growth of the tested microorganisms. PMID- 26981534 TI - Optimized Biotransformation of Icariin into Icariside II by beta-Glucosidase from Trichoderma viride Using Central Composite Design Method. AB - A crude beta-glucosidase has been produced from Trichoderma viride and used to explore a simple method to prepare icariside II from icariin. The crude enzyme has been studied by zymography method and used for hydrolysis of ICA. To achieve a high conversion rate of ICA, various factors have been studied including pH, reaction time, temperature, initial concentration of enzyme, and initial concentration of ICA through central composite design experiments. In the condition of the optimum hydrolysis parameters with pH 4.0, 41 degrees C, 1.0 mg/mL ICA, and 9.8 U/mL crude beta-glucosidase, the conversion rate of ICA reached 95.03% at 1 h. Moreover, the cytotoxicity test showed that ICA II performed inhibition effects on proliferation of A549 cell, while ICA has no cytotoxicity. It indicated that the hydrolysis transformation study of ICA is valuable for exploration of active new drugs. PMID- 26981535 TI - Molecular Typing Characteristic and Drug Susceptibility Analysis of Mycobacterium tuberculosis Isolates from Zigong, China. AB - China is one of the 22 countries with high TB burden worldwide, and Sichuan contained the second-largest number of TB cases among all of the Chinese provinces. But the characteristics of Mycobacterium tuberculosis circulated in Zigong, Sichuan, were still unknown. To investigate the character and drug resistance profile, 265 clinical isolates were cultured from tuberculosis patient's sputum samples in the year of 2010, of which the genetic profile was determined by using Spoligotyping and MIRU-VNTR typing methods, and the drug sensibility testing to the four first-line and four second-line antituberculosis (anti-TB) drugs was performed by using proportion method on Lowenstein-Jensen (L J) media. The major Spoligotype was Beijing family (143/265, 53.96%), followed by T (80/265, 30.19%) and H (9/265, 3.40%) genotypes; the total Hunter-Gaston discrimination index (HGDI) of the 24 loci MIRU-VNTR was 0.9995. About 27.17% (72/265) of the isolates were resistant to at least one of the eight tested anti TB drugs, and for Beijing and non-Beijing family isolates the proportion of drug resistance was 28.47% (41/144) and 25.62% (31/121), respectively. That is, the most prevalent genotype here was Beijing family, and the 24 loci VNTR analysis could supply a high resolution for genotyping, and Beijing and non-Beijing isolates had no difference (p > 0.05) for drug resistance. PMID- 26981533 TI - Antibacterial Action of a Condensed Tannin Extracted from Astringent Persimmon as a Component of Food Addictive Pancil PS-M on Oral Polymicrobial Biofilms. AB - The purpose of this study was to evaluate the antibacterial activity against polymicrobial (PM) biofilms of a condensed tannin extracted from astringent persimmon (PS-M), which is contained in refreshing beverages commercially available in Japan. Salivary PM biofilms were formed anaerobically on glass coverslips for 24 and 72 h and were treated for 5 min with sterilized deionized water (DW), 0.05 and 0.2 wt% chlorhexidine digluconate (CHX), and 0.5-4.0 wt% PS M solution. The colony forming units (CFU/mL) were determined and morphological changes of the biofilms were observed by scanning electron microscopy (SEM). The CFUs were lower in all PS-M and CHX groups compared to the DW group. PS-M exerted a dose-dependent effect. PS-M (1.53 * 10(7)) at a dose of 4.0 wt% had the same effect as 0.2 wt% CHX (2.03 * 10(7)), regardless of the culture period. SEM revealed the biofilm structures were considerably destroyed in the 4.0 wt% PS-M and 0.2 wt% CHX. These findings indicate that the antibacterial effects of PS-M, a naturally derived substance, are comparable to those of CHX. PS-M may keep the oral cavity clean and prevent dental caries and periodontal disease related to dental plaque, as well as systemic disease such as aspiration pneumonitis. PMID- 26981536 TI - Determining the Independent Risk Factors and Mortality Rate of Nosocomial Infections in Pediatric Patients. AB - The objective of this study was to determine the rate, independent risk factors, and outcomes of healthcare-associated infections in pediatric patients. This study was performed between 2011 and 2014 in pediatric clinic and intensive care unit. 86 patients and 86 control subjects were included in the study. Of 86 patients with nosocomial infections (NIs), there were 100 NIs episodes and 90 culture growths. The median age was 32.0 months. The median duration of hospital stay of the patients was 30.0 days. The most frequent pathogens were Coagulase negative Staphylococcus, Acinetobacter spp., Klebsiella spp., and Candida spp. Unconsciousness, prolonged hospitalization, transfusion, mechanical ventilation, use of central venous catheter, enteral feeding via a nasogastric tube, urinary catheter, and receiving carbapenems and glycopeptides were found to be significantly higher in NIs patients. Multivariate logistic regression analysis showed prolonged hospitalization, neutropenia, and use of central venous catheter and carbapenems as the independent risk factors for NIs. In the univariate analysis, unconsciousness, mechanical ventilation, enteral feeding, use of enteral feeding via a nasogastric tube, H2 receptor blockers, and port and urinary catheter were significantly associated with mortality. In the multiple logistic regression analysis, only mechanical ventilation was found as an independent predictor of mortality in patients with NIs. PMID- 26981537 TI - Epidemic Profile of Maternal Syphilis in China in 2013. AB - OBJECTIVE: The aim of this study was to investigate the epidemiological characteristics and adverse pregnancy outcomes of pregnant women with syphilis infection in China. METHODS: Data were from China's Information System of Prevention of Mother-to-Child Transmission of Syphilis Management. Women who were registered in the system and delivered in 2013 were included in the analysis. RESULTS: A total of 15884 pregnant women with syphilis infection delivered in China in 2013. 79.1% of infected women attended antenatal care at or before 37 gestational weeks; however, 55.4% received no treatment or initiated the treatment after 37 gestational weeks. 14.0% of women suffered serious adverse pregnancy outcomes including stillbirth/neonatal death, preterm delivery/low birth weight, or congenital syphilis in newborns. High maternal titer (>=1 : 64) and late treatment (>37 gestational weeks)/nontreatment were significantly associated with increased risk of congenital syphilis and the adjusted ORs were 1.88 (95% CI 1.27 to 2.80) and 3.70 (95% CI 2.36 to 5.80), respectively. CONCLUSION: Syphilis affects a great number of pregnant women in China. Large proportions of women are not detected and treated at an early pregnancy stage. Burden of adverse pregnancy outcomes is high among infected women. Comprehensive interventions still need to be strengthened to improve uptake of screening and treatment for maternal syphilis. PMID- 26981538 TI - Nanosilica and Polyacrylate/Nanosilica: A Comparative Study of Acute Toxicity. AB - We compared the acute toxicity of nanosilica and polyacrylate/nanosilica instillation in Wistar rats (n = 60). Exposure to nanosilica and polyacrylate/nanosilica showed a 30% mortality rate. When compared with saline treated rats, animals in both exposure groups exhibited a significant reduction of PO2 (P < 0.05) at both 24 and 72 hr. after exposure. Both exposure groups exhibited a significant reduction of neutrophils in arterial blood compared to saline controls (P < 0.05) 24 hr. after exposure. The levels of blood ALT and LDH in exposed groups were found to be significantly increased (P < 0.05) 24 hr. following exposure. The exposed groups exhibited various degrees of pleural effusion and pericardial effusion. Our findings indicated respiratory exposure to polyacrylate/nanosilica and nanosilica is likely to cause multiple organ toxicity. PMID- 26981539 TI - Intercellular Adhesion Molecule and Endogenous NOS Inhibitor: Asymmetric Dimethylarginine in Pregnant Women with Gestational Diabetes Mellitus. AB - OBJECTIVE: The aim of the study was to evaluate the concentrations of soluble intercellular adhesion molecule-1 (s-ICAM-1) and endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA), as markers of endothelium dysfunction in patients with gestational diabetes mellitus (GDM). PATIENTS AND METHODS: The levels of s-ICAM-1 and ADMA were analysed in the group of 56 patients with GDM and compared to 25 healthy pregnant women. The concentrations of s-ICAM-1 and ADMA were measured in serum using ELISA tests. RESULTS: The groups did not differ by baseline descriptors: age (30.75 +/- 6.32 versus 28.50 +/- 4.95 years, NS) and gestational age (28.96 +/- 2.85 versus 29.12 +/- 2.96 hbd, NS). The patients with GDM were more obese (BMI 27.93 +/- 7.02 versus 22.34 +/- 4.21 kg/m(2), p = 0.032) and had higher concentration of C-reactive protein (6.46 +/- 6.03 versus 3.18 +/- 3.83 mg/L, p = 0.029). In the GDM group the level of ADMA was lower (0.38 +/- 0.17 versus 0.60 +/- 0.28 MUmol/L, p = 0.001) and the level of s-ICAM-1 was significantly higher (289.95 +/- 118.12 versus 232.56 +/- 43.31 ng/mL, p = 0.036) compared to controls. CONCLUSIONS: The pregnant women with GDM are characterized by higher concentration of s-ICAM-1 that reflects the activation and dysfunction of the endothelial cells. The decreased ADMA level in GDM patients seems to be preventive in the limitation of NO synthesis caused by the impaired insulin action and the endothelial dysfunction. PMID- 26981540 TI - Epigenetic Studies Point to DNA Replication/Repair Genes as a Basis for the Heritable Nature of Long Term Complications in Diabetes. AB - Metabolic memory (MM) is defined as the persistence of diabetic (DM) complications even after glycemic control is pharmacologically achieved. Using a zebrafish diabetic model that induces a MM state, we previously reported that, in this model, tissue dysfunction was of a heritable nature based on cell proliferation studies in limb tissue and this correlated with epigenetic DNA methylation changes that paralleled alterations in gene expression. In the current study, control, DM, and MM excised fin tissues were further analyzed by MeDIP sequencing and microarray techniques. Bioinformatics analysis of the data found that genes of the DNA replication/DNA metabolism process group (with upregulation of the apex1, mcm2, mcm4, orc3, lig1, and dnmt1 genes) were altered in the DM state and these molecular changes continued into MM. Interestingly, DNA methylation changes could be found as far as 6-13 kb upstream of the transcription start site for these genes suggesting potential higher levels of epigenetic control. In conclusion, DNA methylation changes in members of the DNA replication/repair process group best explain the heritable nature of cell proliferation impairment found in the zebrafish DM/MM model. These results are consistent with human diabetic epigenetic studies and provide one explanation for the persistence of long term tissue complications as seen in diabetes. PMID- 26981541 TI - The Predictive Effects of Early Pregnancy Lipid Profiles and Fasting Glucose on the Risk of Gestational Diabetes Mellitus Stratified by Body Mass Index. AB - This study aimed at evaluating the predictive effects of early pregnancy lipid profiles and fasting glucose on the risk of gestational diabetes mellitus (GDM) in patients stratified by prepregnancy body mass index (p-BMI) and to determine the optimal cut-off values of each indicator for different p-BMI ranges. A retrospective system cluster sampling survey was conducted in Beijing during 2013 and a total of 5,265 singleton pregnancies without prepregnancy diabetes were included. The information for each participant was collected individually using questionnaires and medical records. Logistic regression analysis and receiver operator characteristics analysis were used in the analysis. Outcomes showed that potential markers for the prediction of GDM include early pregnancy lipid profiles (cholesterol, triacylglycerols, low-density lipoprotein cholesterol/high density lipoprotein cholesterol ratios [LDL-C/HDL-C], and triglyceride to high density lipoprotein cholesterol ratios [TG/HDL-C]) and fasting glucose, of which fasting glucose level was the most accurate indicator. Furthermore, the predictive effects and cut-off values for these factors varied according to p BMI. Thus, p-BMI should be a consideration for the risk assessment of pregnant patients for GDM development. PMID- 26981542 TI - Identification of HNF4A Mutation p.T130I and HNF1A Mutations p.I27L and p.S487N in a Han Chinese Family with Early-Onset Maternally Inherited Type 2 Diabetes. AB - Maturity-onset diabetes of the young (MODY) is characterized by the onset of diabetes before the age of 25 years, positive family history, high genetic predisposition, monogenic mutations, and an autosomal dominant mode of inheritance. Here, we aimed to investigate the mutations and to characterize the phenotypes of a Han Chinese family with early-onset maternally inherited type 2 diabetes. Detailed clinical assessments and genetic screening for mutations in the HNF4alpha, GCK, HNF-1alpha, IPF-1, HNF1beta, and NEUROD1 genes were carried out in this family. One HNF4A mutation (p.T130I) and two HNF1A polymorphisms (p.I27L and p.S487N) were identified. Mutation p.T130I was associated with both early-onset and late-onset diabetes and caused downregulated HNF4A expression, whereas HNF1A polymorphisms p.I27L and p.S487N were associated with the age of diagnosis of diabetes. We demonstrated that mutation p.T130I in HNF4A was pathogenic as were the predicted polymorphisms p.I27L and p.S487N in HNF1A by genetic and functional analysis. Our results show that mutations in HNF4A and HNF1A genes might account for this early-onset inherited type 2 diabetes. PMID- 26981543 TI - Neck Circumference May Be a Better Alternative to Standard Anthropometric Measures. AB - This paper evaluates neck circumference as a metabolic risk marker. Overweight/obese, nondiabetic Hispanics, 40-65 years old, who are free of major cardiovascular diseases, were recruited for the San Juan Overweight Adults Longitudinal Study (SOALS). Baseline exams were completed by 1,206 participants. Partial correlation coefficients (r) and logistic models adjusted for age, gender, smoking status, and physical activity were computed. Neck circumference was significantly correlated with waist circumference (r = 0.64), BMI (r = 0.66), and body fat % (r = 0.45). Neck circumference, highest (compared to lowest) tertile, had higher association with prediabetes: multivariable OR = 2.30 (95% CI: 1.71-3.06) compared to waist circumference OR = 1.97 (95% CI: 1.48-2.66) and other anthropometric measures. Neck circumference showed higher associations with HOMA, low HDL-C, and triglycerides, multivariable OR = 8.42 (95% CI: 5.43-13.06), 2.41 (95% CI: 1.80-3.21), and 1.52 (95% CI: 1.14-2.03), but weaker associations with hs-CRP and hypertension, OR = 3.61 (95% CI: 2.66-4.90) and OR = 2.58 (95% CI: 1.90-3.49), compared to waist circumference. AIC for model fit was generally similar for neck or waist circumference. Neck circumference showed similar or better associations with metabolic factors and is more practicable than waist circumference. Hence, neck circumference may be a better alternative to waist circumference. PMID- 26981544 TI - Sulfatide Preserves Insulin Crystals Not by Being Integrated in the Lattice but by Stabilizing Their Surface. AB - BACKGROUND: Sulfatide is known to chaperone insulin crystallization within the pancreatic beta cell, but it is not known if this results from sulfatide being integrated inside the crystal structure or by binding the surface of the crystal. With this study, we aimed to characterize the molecular mechanisms underlying the integral role for sulfatide in stabilizing insulin crystals prior to exocytosis. METHODS: We cocrystallized human insulin in the presence of sulfatide and solved the structure by molecular replacement. RESULTS: The crystal structure of insulin crystallized in the presence of sulfatide does not reveal ordered occupancy representing sulfatide in the crystal lattice, suggesting that sulfatide does not permeate the crystal lattice but exerts its stabilizing effect by alternative interactions such as on the external surface of insulin crystals. CONCLUSIONS: Sulfatide is known to stabilize insulin crystals, and we demonstrate here that in beta cells sulfatide is likely coating insulin crystals. However, there is no evidence for sulfatide to be built into the crystal lattice. PMID- 26981545 TI - Immunological Aspects of Fulminant Type 1 Diabetes in Chinese. AB - Background. Fulminant type 1 diabetes (FT1D) is a novel subtype of type 1 diabetes characterized by extremely rapid onset and complete deficiency of insulin due to the destruction of pancreatic beta cells. However, the precise mechanisms underlying the etiology of this disease remain unclear. Methods. A total of 22 patients with FT1D and 10 healthy subjects were recruited. Serum antibodies to GAD, IA2, and ZnT8 in patients were tested. And peripheral T cell responses to GAD65, insulin B9-23 peptide, or C peptide were determined in 10 FT1D patients and 10 healthy controls. The mRNA levels of several related cytokines and molecules, such as IFN-gamma, IL-4, RORC, and IL-17 in PBMCs from FT1D patients were analyzed by qRT-PCR. Result. We found that a certain proportion of Chinese FT1D patients actually have developed islet-related autoantibodies after onset of the disease. The GAD, insulin, or C peptide reactive T cells were found in some FT1D patients. We also detected a significant increase for IFN-gamma expression in FT1D PBMCs as compared with that of healthy controls. Conclusion. Autoimmune responses might be involved in the pathogenesis of Chinese FT1D. PMID- 26981549 TI - 2-D DIGE proteomic profiles of three strains of Fusarium graminearum grown in agmatine or glutamic acid medium. AB - 2D DIGE proteomics data obtained from three strains belonging to Fusarium graminearum s.s. species growing in a glutamic acid or agmatine containing medium are provided. A total of 381 protein species have been identified which do differ for abundance among the two treatments and among the strains (ANOVA<0.05 and abundance ratio>+/-1.3). Data on the diversity of protein species profiles between the two media for each strain are made available. Shared profiles among strains are discussed in Pasquali et al. [1]. Here proteins that with diverse profile can be used to differentiate strains are highlighted. The full dataset allow to obtaining single strain proteomic profiles. PMID- 26981548 TI - The use of intracorneal ring segments in keratoconus. AB - Keratoconus is a corneal degeneration that usually appears during puberty and may seriously deteriorate the quality of life of the patients. This corneal disease is today the first indication of corneal transplantation in young patients. Until the last decade of the XX century, keratoplasty procedures were the only alternative to treat this pathological condition. In the beginning of the XXI century, intracorneal ring segments implantation was proposed as a therapeutic choice for treating keratoconus patients. Since then, several published articles have reported the benefits of this surgical procedure in treating this type of corneal ectatic disorder. The purpose of the present investigative work is to summarize the characteristic of the intracorneal ring segments and also to review the different features published in the literature in relation to this surgical technique for the treatment of keratoconus patients. PMID- 26981546 TI - Molecular Mechanisms of Induction of Tolerant and Tolerogenic Intestinal Dendritic Cells in Mice. AB - How does the host manage to tolerate its own intestinal microbiota? A simple question leading to complicated answers. In order to maintain balanced immune responses in the intestine, the host immune system must tolerate commensal bacteria in the gut while it has to simultaneously keep the ability to fight pathogens and to clear infections. If this tender equilibrium is disturbed, severe chronic inflammatory reactions can result. Tolerogenic intestinal dendritic cells fulfil a crucial role in balancing immune responses and therefore creating homeostatic conditions and preventing from uncontrolled inflammation. Although several dendritic cell subsets have already been characterized to play a pivotal role in this process, less is known about definite molecular mechanisms of how intestinal dendritic cells are converted into tolerogenic ones. Here we review how gut commensal bacteria interact with intestinal dendritic cells and why this bacteria-host cell interaction is crucial for induction of dendritic cell tolerance in the intestine. Hereby, different commensal bacteria can have distinct effects on the phenotype of intestinal dendritic cells and these effects are mainly mediated by impacting toll-like receptor signalling in dendritic cells. PMID- 26981550 TI - Data on synthesis of oligomeric and polymeric poly(butylene adipate-co-butylene terephthalate) model substrates for the investigation of enzymatic hydrolysis. AB - The aliphatic-aromatic copolyester poly(butylene adipate-co-butylene terephthalate) (PBAT), also known as ecoflex, contains adipic acid, 1,4 butanediol and terephthalic acid and is proven to be compostable [1], [2], [3]). We describe here data for the synthesis and analysis of poly(butylene adipate-co butylene terephthalate variants with different adipic acid:terephatalic acid ratios and 6 oligomeric PBAT model substrates. Data for the synthesis of the following oligomeric model substrates are described: mono(4-hydroxybutyl) terephthalate (BTa), bis(4-(hexanoyloxy)butyl) terephthalate (HaBTaBHa), bis(4 (decanoyloxy)butyl) terephthalate (DaBTaBDa), bis(4-(tetradecanoyloxy)butyl) terephthalate (TdaBTaBTda), bis(4-hydroxyhexyl) terephthalate (HTaH) and bis(4 (benzoyloxy)butyl) terephthalate (BaBTaBBa). Polymeric PBAT variants were synthesized with adipic acid:terephatalic acid ratios of 100:0, 90:10, 80:20, 70:30, 60:40 and 50:50. These polymeric and oligomeric substances were used as ecoflex model substrates in enzymatic hydrolysis experiments in the article "Substrate specificities of cutinases on aliphatic-aromatic polyesters and on their model substrates" [4]. PMID- 26981547 TI - The Role of gammadelta T Cells in Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by the overproduction of autoantibodies against an array of nuclear and cytoplasmic antigens and affects multiple organs, such as the skin, joints, kidneys, and neuronal tissues. T cells have been recognized as important players in the development of SLE due to their functions in cytokine secretion, antigen presentation, and supporting B cells for antibody production. gammadelta T cells are a minor population of T cells that play important roles in infection and tumor-associated disease. In recent years, the role of gammadelta T cells in autoimmune diseases has been investigated. In this review, we discussed the role of gammadelta T cells in the pathogenesis of SLE. PMID- 26981552 TI - Clinical and immunological data of nine patients with chronic mucocutaneous candidiasis disease. AB - This paper describes the heterogeneous clinical phenotype of a cohort of nine patients diagnosed with heterozygous mutations in STAT1. We report data of extended immunophenotyping over time and we show lung damage in four patients. The increased phosphorylation of STAT1 in response to IFNgamma and IFNalpha stimulation proves the gain-of-function nature of the defects. The data are supplemental to our original article concurrently published "Clinical heterogeneity of dominant chronic mucocutaneous candidiasis disease: presenting as treatment-resistant candidiasis and chronic lung disease" [1], where additional results and interpretation of our research can be found. PMID- 26981551 TI - Active site specificity profiling datasets of matrix metalloproteinases (MMPs) 1, 2, 3, 7, 8, 9, 12, 13 and 14. AB - The data described provide a comprehensive resource for the family-wide active site specificity portrayal of the human matrix metalloproteinase family. We used the high-throughput proteomic technique PICS (Proteomic Identification of protease Cleavage Sites) to comprehensively assay 9 different MMPs. We identified more than 4300 peptide cleavage sites, spanning both the prime and non-prime sides of the scissile peptide bond allowing detailed subsite cooperativity analysis. The proteomic cleavage data were expanded by kinetic analysis using a set of 6 quenched-fluorescent peptide substrates designed using these results. These datasets represent one of the largest specificity profiling efforts with subsequent structural follow up for any protease family and put the spotlight on the specificity similarities and differences of the MMP family. A detailed analysis of this data may be found in Eckhard et al. (2015) [1]. The raw mass spectrometry data and the corresponding metadata have been deposited in PRIDE/ProteomeXchange with the accession number PXD002265. PMID- 26981553 TI - A Clinical Indications Prediction Scale Based on TWIST1 for Human Mesenchymal Stem Cells. AB - In addition to their stem/progenitor properties, mesenchymal stem cells (MSCs) also exhibit potent effector (angiogenic, antiinflammatory, immuno-modulatory) functions that are largely paracrine in nature. It is widely believed that effector functions underlie most of the therapeutic potential of MSCs and are independent of their stem/progenitor properties. Here we demonstrate that stem/progenitor and effector functions are coordinately regulated at the cellular level by the transcription factor Twist1 and specified within populations according to a hierarchical model. We further show that manipulation of Twist1 levels by genetic approaches or by exposure to widely used culture supplements including fibroblast growth factor 2 (Ffg2) and interferon gamma (IFN-gamma) alters MSC efficacy in cell-based and in vivo assays in a predictable manner. Thus, by mechanistically linking stem/progenitor and effector functions our studies provide a unifying framework in the form of an MSC hierarchy that models the functional complexity of populations. Using this framework, we developed a CLinical Indications Prediction (CLIP) scale that predicts how donor-to-donor heterogeneity and culture conditions impact the therapeutic efficacy of MSC populations for different disease indications. PMID- 26981554 TI - Circulating Cell Free DNA in the Diagnosis of Trophoblastic Tumors. AB - Gestational trophoblastic neoplasia (GTN) represents a group of diseases characterized by production of human chorionic gonadotropin (hCG). Since non gestational tumors may occasionally secrete hCG, histopathological diagnosis is important for appropriate clinical management. However, a histopathological diagnosis is not always available. We therefore investigated the feasibility of extracting cell free DNA (cfDNA) from the plasma of women with GTN for use as a "liquid biopsy" in patients without histopathological diagnosis. cfDNA was prepared from the plasma of 20 women with a diagnosis of GTN and five with hCG secreting tumors of unknown origin. Genotyping of cfDNA from the patient, genomic DNA from her and her partner and DNA from the tumor tissue identified circulating tumor DNA (ctDNA) (from 9% to 53% of total cfDNA) in 12 of 20 patients with GTN. In one case without a tissue diagnosis, ctDNA enabled a diagnosis of GTN originating in a non-molar conception and in another a diagnosis of non gestational tumor, based on the high degree of allelic instability and loss of heterozygosity in the ctDNA. In summary ctDNA can be detected in the plasma of women with GTN and can facilitate the diagnosis of both gestational and non gestational trophoblastic tumors in cases without histopathological diagnosis. PMID- 26981555 TI - Rapid Diagnosis of 83 Patients with Niemann Pick Type C Disease and Related Cholesterol Transport Disorders by Cholestantriol Screening. AB - Niemann Pick type C (NP-C) is a rare neurodegenerative disorder caused by an impairment of intracellular lipid transport. Due to the heterogeneous clinical phenotype and the lack of a reliable blood test, diagnosis and therapy are often delayed for years. In the cell, accumulating cholesterol leads to increased formation of oxysterols that can be used as a powerful screening parameter for NP C. In a large scale study, we evaluated the oxysterol cholestane 3beta,5alpha,6beta-triol (c-triol) as potential biomarker for a rapid diagnosis of NP-C. Using GC/MS, c-triol has been analyzed in 1902 plasma samples of patients with the suspicion for NP-C. Diagnosis in patients with elevated oxysterols was confirmed by genetic analysis. 71 new NP-C patients (69 NP-C1 and two NP-C2) and 12 Niemann Pick type A/B patients were identified. 24 new mutations in NPC1, one new mutation in NPC2 and three new mutations in the SMPD1 gene were found. Cholestane-3beta,5alpha,6beta-triol was elevated in Niemann Pick type C1, type C2, type A/B and in CESD disease. No other study has ever identified so many NP-C patients, proving that c-triol is a rapid and reliable biomarker to detect patients with NP-C disease and related cholesterol transport disorders. It should replace the filipin test as the first-line diagnostic assay. PMID- 26981557 TI - Disease, iPSCs and a Quest for the Perfect Model. PMID- 26981556 TI - The Impact of Alzheimer's Disease on the Chinese Economy. AB - BACKGROUND: Recent increases in life expectancy may greatly expand future Alzheimer's Disease (AD) burdens. China's demographic profile, aging workforce and predicted increasing burden of AD-related care make its economy vulnerable to AD impacts. Previous economic estimates of AD predominantly focus on health system burdens and omit wider whole-economy effects, potentially underestimating the full economic benefit of effective treatment. METHODS: AD-related prevalence, morbidity and mortality for 2011-2050 were simulated and were, together with associated caregiver time and costs, imposed on a dynamic Computable General Equilibrium model of the Chinese economy. Both economic and non-economic outcomes were analyzed. FINDINGS: Simulated Chinese AD prevalence quadrupled during 2011 50 from 6-28 million. The cumulative discounted value of eliminating AD equates to China's 2012 GDP (US$8 trillion), and the annual predicted real value approaches US AD cost-of-illness (COI) estimates, exceeding US$1 trillion by 2050 (2011-prices). Lost labor contributes 62% of macroeconomic impacts. Only 10% derives from informal care, challenging previous COI-estimates of 56%. INTERPRETATION: Health and macroeconomic models predict an unfolding 2011-2050 Chinese AD epidemic with serious macroeconomic consequences. Significant investment in research and development (medical and non-medical) is warranted and international researchers and national authorities should therefore target development of effective AD treatment and prevention strategies. PMID- 26981558 TI - T memory stem cell formation: Caveat mTOR. PMID- 26981559 TI - Endothelial Progenitors and Blood Microparticles: Are They Relevant to Heart Failure With Preserved Ejection Fraction? PMID- 26981560 TI - Phosphodiesterase inhibitors as adjunctive therapies for tuberculosis. PMID- 26981561 TI - Biomarkers for Identifying Risk of Immune Reconstitution Inflammatory Syndrome. PMID- 26981563 TI - Gene by Environment Interaction Linking the Chromosome 15q25 Locus with Cigarette Consumption and Lung Cancer Susceptibility--Are African American Affected Differently?--Authors' Reply. PMID- 26981562 TI - Circulating Tumor DNA: A Potential Novel Diagnostic Approach in Gestational Trophoblastic Neoplasia. PMID- 26981564 TI - Matrix Gla-Protein (MGP) Not Only Inhibits Calcification in Large Arteries But Also May Be Renoprotective: Connecting the Dots. PMID- 26981565 TI - Towards a New Diagnostic Standard for Niemann-Pick C Disease. PMID- 26981566 TI - The Puzzle of Structural Brain Connectivity Following Traumatic Incidents. PMID- 26981567 TI - The Impact of Alzheimer's Disease in China. PMID- 26981568 TI - Precision Medicine: The new era in medicine. PMID- 26981569 TI - Emerging Tools for Stroke Prevention in Atrial Fibrillation. AB - Ischaemic strokes resulting from atrial fibrillation (AF) constitute a devastating condition for patients and their carers with huge burden on health care systems. Prophylactic treatment against systemic embolization and ischaemic strokes is the cornerstone for the management of AF. Effective stroke prevention requires the use of the vitamin K antagonists or non-vitamin K oral anticoagulants (NOACs). This article summarises the latest developments in the field of stroke prevention in AF and aims to assist physicians with the choice of oral anticoagulant for patients with non-valvular AF with different risk factor profile. PMID- 26981570 TI - Reversing Gut Damage in HIV Infection: Using Non-Human Primate Models to Instruct Clinical Research. AB - Antiretroviral therapy (ART) has led to dramatic improvements in the lives of HIV infected persons. However, residual immune activation, which persists despite ART, is associated with increased risk of non-AIDS morbidities. Accumulating evidence shows that disruption of the gut mucosal epithelium during SIV/HIV infections allows translocation of microbial products into the circulation, triggering immune activation. This disruption is due to immune, structural and microbial alterations. In this review, we highlighted the key findings of gut mucosa studies of SIV-infected macaques and HIV-infected humans that have revealed virus-induced changes of intestinal CD4, CD8 T cells, innate lymphoid cells, myeloid cells, and of the local cytokine/chemokine network in addition to epithelial injuries. We review the interplay between the host immune response and the intestinal microbiota, which also impacts disease progression. Collectively, these studies have instructed clinical research on early ART initiation, modifiers of microbiota composition, and recombinant cytokines for restoring gut barrier integrity. PMID- 26981571 TI - Modulation of mTOR Signalling Triggers the Formation of Stem Cell-like Memory T Cells. AB - Robust, long-lasting immune responses are elicited by memory T cells that possess properties of stem cells, enabling them to persist long-term and to permanently replenish the effector pools. Thus, stem cell-like memory T (TSCM) cells are of key therapeutic value and efforts are underway to characterize TSCM cells and to identify means for their targeted induction. Here, we show that inhibition of mechanistic/mammalian Target of Rapamycin (mTOR) complex 1 (mTORC1) by rapamycin or the Wnt-beta-catenin signalling activator TWS119 in activated human naive T cells leads to the induction of TSCM cells. We show that these compounds switch T cell metabolism to fatty acid oxidation as favoured metabolic programme for TSCM cell generation. Of note, pharmacologically induced TSCM cells possess superior functional features as a long-term repopulation capacity after adoptive transfer. Furthermore, we provide insights into the transcriptome of TSCM cells. Our data identify a mechanism of pharmacological mTORC1 inhibitors, allowing us to confer stemness to human naive T cells which may be significantly relevant for the design of innovative T cell-based cancer immunotherapies. PMID- 26981572 TI - Mapping Human Pluripotent-to-Cardiomyocyte Differentiation: Methylomes, Transcriptomes, and Exon DNA Methylation "Memories". AB - The directed differentiation of human cardiomyocytes (CMs) from pluripotent cells provides an invaluable model for understanding mechanisms of cell fate determination and offers considerable promise in cardiac regenerative medicine. Here, we utilize a human embryonic stem cell suspension bank, produced according to a good manufacturing practice, to generate CMs using a fully defined and small molecule-based differentiation strategy. Primitive and cardiac mesoderm purification was used to remove non-committing and multi-lineage populations and this significantly aided the identification of key transcription factors, lncRNAs, and essential signaling pathways that define cardiomyogenesis. Global methylation profiles reflect CM development and we report on CM exon DNA methylation "memories" persisting beyond transcription repression and marking the expression history of numerous developmentally regulated genes, especially transcription factors. PMID- 26981574 TI - Bacterial Cytological Profiling (BCP) as a Rapid and Accurate Antimicrobial Susceptibility Testing Method for Staphylococcus aureus. AB - Successful treatment of bacterial infections requires the timely administration of appropriate antimicrobial therapy. The failure to initiate the correct therapy in a timely fashion results in poor clinical outcomes, longer hospital stays, and higher medical costs. Current approaches to antibiotic susceptibility testing of cultured pathogens have key limitations ranging from long run times to dependence on prior knowledge of genetic mechanisms of resistance. We have developed a rapid antimicrobial susceptibility assay for Staphylococcus aureus based on bacterial cytological profiling (BCP), which uses quantitative fluorescence microscopy to measure antibiotic induced changes in cellular architecture. BCP discriminated between methicillin-susceptible (MSSA) and -resistant (MRSA) clinical isolates of S. aureus (n = 71) within 1-2 h with 100% accuracy. Similarly, BCP correctly distinguished daptomycin susceptible (DS) from daptomycin non-susceptible (DNS) S. aureus strains (n = 20) within 30 min. Among MRSA isolates, BCP further identified two classes of strains that differ in their susceptibility to specific combinations of beta-lactam antibiotics. BCP provides a rapid and flexible alternative to gene-based susceptibility testing methods for S. aureus, and should be readily adaptable to different antibiotics and bacterial species as new mechanisms of resistance or multidrug-resistant pathogens evolve and appear in mainstream clinical practice. PMID- 26981573 TI - Pattern of endothelial progenitor cells and apoptotic endothelial cell-derived microparticles in chronic heart failure patients with preserved and reduced left ventricular ejection fraction. AB - BACKGROUND: Chronic heart failure (HF) remains a leading cause of cardiovascular (CV) mortality and morbidity worldwide. The aim of the study was to investigate whether the pattern of angiogenic endothelial progenitor cells (EPCs) and apoptotic endothelial cell-derived microparticles (EMPs) would be able to differentiate HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction. METHODS: One hundred sixty four chronic HF subjects met inclusion criteria. Patients with global left ventricular ejection fraction >= 50% were categorized as the HFpEF group (n = 79) and those with <= 45% as the HFrEF group (n = 85). Therefore, to compare the circulating levels of biological markers 35 control subjects without HF were included in the study. All control individuals were age- and sex-matched chronic HF patients. The serum level of biomarkers was measured at baseline. The flow cytometric technique was used for predictably distinguishing circulating cell subsets depending on expression of CD45, CD34, CD14, Tie-2, and CD309 antigens and determining endothelial cell-derived microparticles. CD31(+)/annexin V(+) was defined as apoptotic endothelial cell derived MPs, MPs labeled for CD105(+) or CD62E(+) were determined as MPs produced due to activation of endothelial cells. RESULTS: In multivariate logistic regression model T2DM (R(2) = 0.26; P = 0.001), obesity (R(2) = 0.22; P = 0.001), previous MI (R(2) = 0.17; P = 0.012), galectin-3 (R(2) = 0.67; P = 0.012), CD31(+)/annexin V(+) EMPs (R(2) = 0.11; P = 0.001), NT-proBNP (R(2) = 0.11; P = 0.046), CD14(+) CD309(+) cells (R(2) = 0.058; P = 0.001), and CD14(+) SD309(+) Tie-2(+) cells (R(2) = 0.044; P = 0.028) were found as independent predictors of HFpEF. Using multivariate Cox-regression analysis adjusted etiology (previous myocardial infarction), cardiovascular risk factors (obesity, type 2 diabetes mellitus) we found that NT-proBNP (OR 1.08; 95% CI = 1.03-1.12; P = 0.001) and CD31(+)/annexin V(+) EMPs to CD14(+) CD309(+) cell ratio (OR 1.06; 95% CI = 1.02 1.11; P = 0.02) were independent predictors for HFpEF. CONCLUSION: We found that CD31(+)/annexin V(+) EMPs to CD14(+) CD309(+) cell ratio added to NT-proBNP, clinical data, and cardiovascular risk factors has exhibited the best discriminate value and higher reliability to predict HFpEF compared with NT proBNP and clinical data/cardiovascular risk factors alone. PMID- 26981575 TI - Adjunctive Phosphodiesterase-4 Inhibitor Therapy Improves Antibiotic Response to Pulmonary Tuberculosis in a Rabbit Model. AB - OBJECTIVES: Adjunctive host-directed therapy is emerging as a new potential approach to improve the outcome of conventional antimicrobial treatment for tuberculosis (TB). We tested the ability of a phosphodiesterase-4 inhibitor (PDE4i) CC-11050, co-administered with the first-line anti-TB drug isoniazid (INH), to accelerate bacillary killing and reduce chronic inflammation in the lungs of rabbits with experimental Mycobacterium tuberculosis (Mtb) infection. METHODS: A rabbit model of pulmonary TB that recapitulates the pathologic manifestations seen in humans was used. Rabbits were infected with virulent Mtb by aerosol exposure and treated for eight weeks with INH with or without CC 11050, starting at four weeks post infection. The effect of CC-11050 treatment on disease severity, pathology, bacillary load, T cell proliferation and global lung transcriptome profiles were analyzed. RESULTS: Significant improvement in bacillary clearance and reduced lung pathology and fibrosis were noted in the rabbits treated for eight weeks with INH + CC-11050, compared to those treated with INH or CC-11050 only. In addition, expression of host genes associated with tissue remodeling, tumor necrosis factor alpha (TNF-alpha) regulation, macrophage activation and lung inflammation networks was dampened in CC-11050-treated, compared to the untreated rabbits. CONCLUSIONS: Adjunctive CC-11050 therapy significantly improves the response of rabbits with experimental pulmonary TB to INH treatment. We propose that CC-11050 may be a promising candidate for host directed therapy of patients with pulmonary TB, reducing the duration and improving clinical outcome of antibiotic treatment. PMID- 26981576 TI - Vitamin D, D-dimer, Interferon gamma, and sCD14 Levels are Independently Associated with Immune Reconstitution Inflammatory Syndrome: A Prospective, International Study. AB - To determine the immunological profile most important for IRIS prediction, we evaluated 20 baseline plasma biomarkers in Acquired Immunodeficiency Syndrome (AIDS) patients initiating antiretroviral therapy (ART). Patients were enrolled in a randomized, placebo-controlled ART initiation trial in South Africa and Mexico to test whether maraviroc could prevent IRIS. Participants were classified prospectively as having IRIS within 6 months of ART initiation. Twenty plasma biomarkers were measured at study enrollment for 267 participants. Biomarkers were tested for predicting IRIS with adjustment for covariates chosen through forward stepwise selection. Sixty-two participants developed IRIS and of these 19 were tuberculosis (TB)-IRIS. Baseline levels of vitamin D and higher d-dimer, interferon gamma (IFNgamma), and sCD14 were independently associated with risk of IRIS in multivariate analyses. TB-IRIS cases exhibited a distinct biosignature from IRIS related to other pathogens, with increased levels of C-reactive protein (CRP), sCD14, IFNgamma, and lower levels of Hb that could be captured by a composite risk score. Elevated markers of Type 1 T helper (Th1) response, monocyte activation, coagulation and low vitamin D were independently associated with IRIS risk. Interventions that decrease immune activation and increase vitamin D levels warrant further study. PMID- 26981577 TI - Oral Phage Therapy of Acute Bacterial Diarrhea With Two Coliphage Preparations: A Randomized Trial in Children From Bangladesh. AB - BACKGROUND: Antibiotic resistance is rising in important bacterial pathogens. Phage therapy (PT), the use of bacterial viruses infecting the pathogen in a species-specific way, is a potential alternative. METHOD: T4-like coliphages or a commercial Russian coliphage product or placebo was orally given over 4 days to Bangladeshi children hospitalized with acute bacterial diarrhea. Safety of oral phage was assessed clinically and by functional tests; coliphage and Escherichia coli titers and enteropathogens were determined in stool and quantitative diarrhea parameters (stool output, stool frequency) were measured. Stool microbiota was studied by 16S rRNA gene sequencing; the genomes of four fecal Streptococcus isolates were sequenced. FINDINGS: No adverse events attributable to oral phage application were observed (primary safety outcome). Fecal coliphage was increased in treated over control children, but the titers did not show substantial intestinal phage replication (secondary microbiology outcome). 60% of the children suffered from a microbiologically proven E. coli diarrhea; the most frequent diagnosis was ETEC infections. Bacterial co-pathogens were also detected. Half of the patients contained phage-susceptible E. coli colonies in the stool. E. coli represented less than 5% of fecal bacteria. Stool ETEC titers showed only a short-lived peak and were otherwise close to the replication threshold determined for T4 phage in vitro. An interim analysis after the enrollment of 120 patients showed no amelioration in quantitative diarrhea parameter by PT over standard care (tertiary clinical outcome). Stool microbiota was characterized by an overgrowth with Streptococcus belonging to the Streptococcus gallolyticus and Streptococcus salivarius species groups, their abundance correlated with quantitative diarrhea outcome, but genome sequencing did not identify virulence genes. INTERPRETATION: Oral coliphages showed a safe gut transit in children, but failed to achieve intestinal amplification and to improve diarrhea outcome, possibly due to insufficient phage coverage and too low E. coli pathogen titers requiring higher oral phage doses. More knowledge is needed on in vivo phage-bacterium interaction and the role of E. coli in childhood diarrhea for successful PT. FUNDING: The study was supported by a grant from Nestle Nutrition and Nestle Health Science. The trial was registered with Identifier NCT00937274 at ClinicalTrials.gov. PMID- 26981578 TI - Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma. AB - Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44(high)EpCAM(low/-) CD24(+) cell surface marker profile. Treatment with TGFbeta and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs. PMID- 26981582 TI - Enabling Precision Medicine With Digital Case Classification at the Point-of Care. AB - Infectious and inflammatory diseases of the central nervous system are difficult to identify early. Case definitions for aseptic meningitis, encephalitis, myelitis, and acute disseminated encephalomyelitis (ADEM) are available, but rarely put to use. The VACC-Tool (Vienna Vaccine Safety Initiative Automated Case Classification-Tool) is a mobile application enabling immediate case ascertainment based on consensus criteria at the point-of-care. The VACC-Tool was validated in a quality management program in collaboration with the Robert-Koch Institute. Results were compared to ICD-10 coding and retrospective analysis of electronic health records using the same case criteria. Of 68,921 patients attending the emergency room in 10/2010-06/2013, 11,575 were hospitalized, with 521 eligible patients (mean age: 7.6 years) entering the quality management program. Using the VACC-Tool at the point-of-care, 180/521 cases were classified successfully and 194/521 ruled out with certainty. Of the 180 confirmed cases, 116 had been missed by ICD-10 coding, 38 misclassified. By retrospective application of the same case criteria, 33 cases were missed. Encephalitis and ADEM cases were most likely missed or misclassified. The VACC-Tool enables physicians to ask the right questions at the right time, thereby classifying cases consistently and accurately, facilitating translational research. Future applications will alert physicians when additional diagnostic procedures are required. PMID- 26981584 TI - An Elliptic Curve Based Schnorr Cloud Security Model in Distributed Environment. AB - Cloud computing requires the security upgrade in data transmission approaches. In general, key-based encryption/decryption (symmetric and asymmetric) mechanisms ensure the secure data transfer between the devices. The symmetric key mechanisms (pseudorandom function) provide minimum protection level compared to asymmetric key (RSA, AES, and ECC) schemes. The presence of expired content and the irrelevant resources cause unauthorized data access adversely. This paper investigates how the integrity and secure data transfer are improved based on the Elliptic Curve based Schnorr scheme. This paper proposes a virtual machine based cloud model with Hybrid Cloud Security Algorithm (HCSA) to remove the expired content. The HCSA-based auditing improves the malicious activity prediction during the data transfer. The duplication in the cloud server degrades the performance of EC-Schnorr based encryption schemes. This paper utilizes the blooming filter concept to avoid the cloud server duplication. The combination of EC-Schnorr and blooming filter efficiently improves the security performance. The comparative analysis between proposed HCSA and the existing Distributed Hash Table (DHT) regarding execution time, computational overhead, and auditing time with auditing requests and servers confirms the effectiveness of HCSA in the cloud security model creation. PMID- 26981580 TI - Vitamin K Dependent Protection of Renal Function in Multi-ethnic Population Studies. AB - BACKGROUND: Following activation by vitamin K (VK), matrix Gla protein (MGP) inhibits arterial calcification, but its role in preserving renal function remains unknown. METHODS: In 1166 white Flemish (mean age, 38.2 years) and 714 South Africans (49.2% black; 40.6 years), we correlated estimated glomerular filtration (eGFR [CKD-EPI formula]) and stage of chronic kidney disease (CKD [KDOQI stages 2-3]) with inactive desphospho-uncarboxylated MGP (dp-ucMGP), using multivariable linear and logistic regression. RESULTS: Among Flemish and white and black Africans, between-group differences in eGFR (90, 100 and 122 mL/min/1.73 m(2)), dp-ucMGP (3.7, 6.5 and 3.2 MUg/L), and CKD prevalence (53.5, 28.7 and 10.5%) were significant, but associations of eGFR with dp-ucMGP did not differ among ethnicities (P >= 0.075). For a doubling of dp-ucMGP, eGFR decreased by 1.5 (P = 0.023), 1.0 (P = 0.56), 2.8 (P = 0.0012) and 2.1 (P < 0.0001) mL/min/1.73 m(2) in Flemish, white Africans, black Africans and all participants combined; the odds ratios for moving up one CKD stage were 1.17 (P = 0.033), 1.03 (P = 0.87), 1.29 (P = 0.12) and 1.17 (P = 0.011), respectively. INTERPRETATION: In the general population, eGFR decreases and CKD risk increases with higher dp ucMGP, a marker of VK deficiency. These findings highlight the possibility that VK supplementation might promote renal health. PMID- 26981583 TI - Say "GDNT": Frequency of Adolescent Texting at Night. AB - OBJECTIVE: Electronic media use is pervasive among adolescents. However, prior studies of media use have not specifically focused on texting behavior, and current estimates of teen texting -- a primary form of communication among adolescents - are based on teens' self-reported use. Evaluating the frequency of nighttime texting is crucial, given evidence that such behaviors may contribute to epidemic levels of insufficient sleep among adolescents. METHODS: Descriptive analysis of objectively recorded outgoing text message data in a sample of adolescents (N=43; M=16.06, SD 1.29 years of age; 63% females). RESULTS: The current study found that texting behavior was ubiquitous in the pre-bedtime period with 98% of adolescents sending at least one text after 8:00 pm. Texting was also very prevalent at night: 70% of participating teens sent at least one text between10:00 pm and 5:59 am. CONCLUSIONS: These findings add to a growing body of literature highlighting the potential role of mobile electronic devices in adolescent sleep disturbances. PMID- 26981581 TI - White Matter Abnormalities in Post-traumatic Stress Disorder Following a Specific Traumatic Event. AB - Studies of posttraumatic stress disorder (PTSD) are complicated by wide variability in the intensity and duration of prior stressors in patient participants, secondary effects of chronic psychiatric illness, and a variable history of treatment with psychiatric medications. In magnetic resonance imaging (MRI) studies, patient samples have often been small, and they were not often compared to similarly stressed patients without PTSD in order to control for general stress effects. Findings from these studies have been inconsistent. The present study investigated whole-brain microstructural alterations of white matter in a large drug-naive population who survived a specific, severe traumatic event (a major 8.0-magnitude earthquake). Using diffusion tensor imaging (DTI), we explored group differences between 88 PTSD patients and 91 matched traumatized non-PTSD controls in fractional anisotropy (FA), as well as its component elements axial diffusivity (AD) and radial diffusivity (RD), and examined these findings in relation to findings from deterministic DTI tractography. Relations between white matter alterations and psychiatric symptom severity were examined. PTSD patients, relative to similarly stressed controls, showed an FA increase as well as AD and RD changes in the white matter beneath left dorsolateral prefrontal cortex and forceps major. The observation of increased FA in the PTSD group suggests that the pathophysiology of PTSD after a specific acute traumatic event is distinct from what has been reported in patients with several years duration of illness. Alterations in dorsolateral prefrontal cortex may be an important aspect of illness pathophysiology, possibly via the region's established role in fear extinction circuitry. Use-dependent myelination or other secondary compensatory changes in response to heightened demands for threat appraisal and emotion regulation may be involved. PMID- 26981579 TI - Gene by Environment Investigation of Incident Lung Cancer Risk in African Americans. AB - BACKGROUND: Genome-wide association studies have identified polymorphisms linked to both smoking exposure and risk of lung cancer. The degree to which lung cancer risk is driven by increased smoking, genetics, or gene-environment interactions is not well understood. METHODS: We analyzed associations between 28 single nucleotide polymorphisms (SNPs) previously associated with smoking quantity and lung cancer in 7156 African-American females in the Women's Health Initiative (WHI), then analyzed main effects of top nominally significant SNPs and interactions between SNPs, cigarettes per day (CPD) and pack-years for lung cancer in an independent, multi-center case-control study of African-American females and males (1078 lung cancer cases and 822 controls). FINDINGS: Nine nominally significant SNPs for CPD in WHI were associated with incident lung cancer (corrected p-values from 0.027 to 6.09 * 10(-5)). CPD was found to be a nominally significant effect modifier between SNP and lung cancer for six SNPs, including CHRNA5 rs2036527[A](betaSNP*CPD = - 0.017, p = 0.0061, corrected p = 0.054), which was associated with CPD in a previous genome-wide meta-analysis of African-Americans. INTERPRETATION: These results suggest that chromosome 15q25.1 variants are robustly associated with CPD and lung cancer in African-Americans and that the allelic dose effect of these polymorphisms on lung cancer risk is most pronounced in lighter smokers. PMID- 26981585 TI - Front and Back Movement Analysis of a Triangle-Structured Three-Wheeled Omnidirectional Mobile Robot by Varying the Angles between Two Selected Wheels. AB - Omnidirectional robots can move in all directions without steering their wheels and it can rotate clockwise and counterclockwise with reference to their axis. In this paper, we focused only on front and back movement, to analyse the square- and triangle-structured omnidirectional robot movements. An omnidirectional mobile robot shows different performances with the different number of wheels and the omnidirectional mobile robot's chassis design. Research is going on in this field to improve the accurate movement capability of omnidirectional mobile robots. This paper presents a design of a unique device of Angle Variable Chassis (AVC) for linear movement analysis of a three-wheeled omnidirectional mobile robot (TWOMR), at various angles (theta) between the wheels. Basic mobility algorithm is developed by varying the angles between the two selected omnidirectional wheels in TWOMR. The experiment is carried out by varying the angles (theta = 30 degrees , 45 degrees , 60 degrees , 90 degrees , and 120 degrees ) between the two selected omniwheels and analysing the movement of TWOMR in forward direction and reverse direction on a smooth cement surface. Respectively, it is compared to itself for various angles (theta), to get its advantages and weaknesses. The conclusion of the paper provides effective movement of TWOMR at a particular angle (theta) and also the application of TWOMR in different situations. PMID- 26981586 TI - Native Nephrectomy in Renal Transplant Recipients with Autosomal Dominant Polycystic Kidney Disease. AB - BACKGROUND: Native nephrectomy (NNx) is often done in patients with autosomal dominant polycystic kidney disease (ADPKD). Controversy exists concerning the need and timing of nephrectomy in transplant candidates. We hypothesize that post transplant NNx does not negatively impact patient and graft survival. METHODS: Among 470 ADPKD transplant recipients included in the study, 114 (24.3%) underwent pre- (30.7%) or post-transplant (69.3%) NNx. Clinical data was retrieved from electronic records. Follow up was until death, graft loss or June 2014. Perioperative complications were compared between the surgical techniques (open or laparoscopic) and between the pre- and post-transplant nephrectomy groups. The effect of nephrectomy on graft survival was analyzed as a time dependent covariate when performed post-transplant. RESULTS: Mean age at transplant was 52.4 years, 53.8% were male, 93% white, 70% were from living donors and 56.8% were pre-emptive. Nephrectomy was done laparoscopically in 31% and 86% in the pre- and post- transplant nephrectomy groups, respectively. Complications were less common in those who underwent nephrectomy post-transplant (26.6% vs. 48%, p=0.03) but were similar regardless of surgical technique (open, 33.3% vs. laparoscopic 33%, p=0.66). Patient and graft survival were similar between those who underwent pre-transplant nephrectomy and the rest of the recipients. In the post-transplant nephrectomy group, nephrectomy did not affect patient (HR 0.77, CI 0.38-1.54, p=0.45) or graft survival (HR 1.0, CI 0.57-1.76, p=0.1). CONCLUSIONS: Nephrectomy does not adversely affect patient or graft survival. Post-transplant nephrectomy is feasible when indicated without compromising long term graft outcome and has fewer complications than pre transplant nephrectomy. PMID- 26981587 TI - Biomarkers for bladder cancer: The search continues! PMID- 26981588 TI - Past, present and future of urological robotic surgery. AB - The first urologic robotic program in the world was built at the Vattikuti Urology Institute, Henry Ford Hospital Detroit, Michigan, in 2000 under the vision of surgical innovator, Dr. Mani Menon for the radical prostatectomy. The robot-assisted radical prostatectomy continues being modified with techniques to improve perioperative and surgical outcomes. The application of robotic surgical technique has since been expanded to the bladder and upper urinary tract surgery. The evolution of surgical technique and its expansion of application will continue to improve quality, outcome parameters and experience for the patients. PMID- 26981589 TI - Persistence and compliance with medication management in the treatment of overactive bladder. AB - Overactive bladder (OAB) is a common and chronic condition that impacts patients' daily activities and quality of life. Pharmaco-therapy for OAB is a mainstay of treatment. Antimuscarinics and beta3-adrenoceptor agonists are the two major classes of oral pharmacotherapy and have similar efficacy for treating the symptoms of OAB. Owing to the chronic nature of OAB, long-term use of medication is essential for OAB symptom control and positive health outcomes. However, many patients elect to stop their medications during the treatment period. Unmet expectations of treatment and side effects seem to be the major factors for discontinuing OAB pharmacotherapy. Furthermore, the short- and long-term persistence and compliance with medication management are markedly worse in OAB than in other chronic medical conditions. Improvement in persistence and compliance with OAB pharmacotherapy is a hot topic in OAB treatment and should be an important goal in the treatment of OAB. Effective strategies should be identified to improve persistence and compliance. In this review, we outline what is known about persistence and compliance and the factors affecting persistence with pharmacotherapy in patients with OAB. PMID- 26981590 TI - Prevention of sepsis prior to prostate biopsy. AB - PURPOSE: Urosepsis is the most feared complication of transrectal prostate biopsy. The incidence may be increasing from <1% to 2%-3% in contemporary series. Historically, fluoroquinolones have been effective antibiotic prophylaxis to prevent infective complications but antibiotic resistance is increasing. The increase in antibiotic resistance may contribute to reported increases in urosepsis and hospitalization after transrectal biopsy. This article will review other methods clinicians may employ to reduce the incidence of infective complications after prostate biopsy. MATERIALS AND METHODS: A systematic review of the literature was conducted using literature databases PubMed and Ovid MEDLINE in August 2015 in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) criteria. RESULTS: Effective strategies to reduce infective complications after transrectal prostate biopsy include augmented prophylaxis with other antibiotics, rectal swab culture directed antibiotic prophylaxis or a transperineal biopsy approach. Needle disinfection, minimizing the number of biopsy needles and rectal disinfectants may also be of use. These methods may be of particular utility in patients with risk factors for developing urosepsis such as recent antibiotic use and overseas travel. CONCLUSIONS: The scientific literature describes various techniques designed to reduce infective complications caused by prostate biopsy. Clinicians should consider incorporating these novel techniques into their contemporary practice. PMID- 26981591 TI - The role of Bosniak classification in malignant tumor diagnosis: A single institution experience. AB - PURPOSE: To evaluate the clinical reliability of the Bosniak classification in Korea, and to identify independent predictors of malignancy in complicated renal cysts. MATERIALS AND METHODS: We reviewed the records of 368 patients with renal cysts between January 2001 and December 2014; 14 patients were excluded, due to interobserver variability in Bosniak classification between the radiologist and urologist. Clinical characteristics and radiologic findings of malignant cystic masses were analyzed, retrospectively. RESULTS: In 324 surgically excised lesions from patients (n=312) with renal cysts, the percentages of malignancy in the different Bosniak classifications were as follows: category I, 1.0% (1 of 103); II, 3.8% (2 of 53); IIF, 17.1% (7 of 41); III, 38.0% (27 of 71); and IV, 82.1% (46 of 56). Mean age and lesion size were 59.88+/-11.9 years (180 men, 144 women) and 5.47+/-3.51 cm, respectively. Univariate analysis identified hypertension (p=0.011), a history of smoking (p=0.038), and obesity (p=0.015) as the strongest risk factors of malignancy. In a study of Bosniak category III patients, hypertension (p=0.018), lesion size (p<0.001), and difference of Hounsfield Unit (HU) (p=0.027) were the strongest risk factors of malignancy. Multivariate analysis identified lesion size as the strongest potential predictor of malignancy, followed by hypertension and difference of HU. CONCLUSIONS: Risk factors of malignancy in complicated renal cyst patients were not different from those published previously. In Bosniak category III lesions, hypertension and lesion size were the strongest predictors of malignancy. Characteristically, the lesion size was smaller than in benign complicated renal cysts, in contrast with other categories. PMID- 26981592 TI - Value of urinary topoisomerase-IIA cell-free DNA for diagnosis of bladder cancer. AB - PURPOSE: Topoisomerase-II alpha (TopoIIA ), a DNA gyrase isoform that plays an important role in the cell cycle, is present in normal tissues and various human cancers, and can show altered expression in both. The aim of the current study was to examine the value of urinary TopoIIA cell-free DNA as a noninvasive diagnosis of bladder cancer (BC). MATERIALS AND METHODS: Two patient cohorts were examined. Cohort 1 (73 BC patients and seven controls) provided bladder tissue samples, whereas cohort 2 (83 BC patients, 54 nonmalignant hematuric patients, and 61 normal controls) provided urine samples. Real-time quantitative polymerase chain reaction was used to measure expression of TopoIIA mRNA in tissues and TopoIIA cell-free DNA in urine samples. RESULTS: The results showed that expression of TopoIIA mRNA in BC tissues was significantly higher than that in noncancer control tissues (p<0.001). The expression of urinary TopoIIA cell-free DNA in BC patients was also significantly higher than that in noncancer patient controls and hematuria patients (p < 0.001 and p < 0.001, respectively). High expression of urinary TopoIIA cell-free DNA was also detected in muscle invasive bladder cancer (MIBC) when compared with nonmuscle invasive bladder cancer (NMIBC) (p=0.002). Receiver operating characteristics (ROC) curve analysis was performed to examine the sensitivity/specificity of urinary TopoIIA cell-free DNA for diagnosing BC, NMIBC, and MIBC. The areas under the ROC curve for BC, NMIBC, and MIBC were 0.741, 0.701, and 0.838, respectively. CONCLUSIONS: In summary, the results of this study provide evidence that cell-free TopoIIA DNA may be a potential biomarker for BC. PMID- 26981593 TI - Radiation dosing in the investigation and follow-up of urolithiasis: Comparison between historical and contemporary practices. AB - PURPOSE: Computed tomography (CT) is the gold standard imaging modality for the diagnosis and follow-up of urolithiasis. Before the use of CT, intravenous urography (IVU) was the imaging modality of choice. CT remains contentious because of the cancer risk related to radiation exposure above a threshold level. We aimed to compare the radiation exposure dose to the average patient with urolithiasis in the era of CT with that of IVU. MATERIALS AND METHODS: Our hospital medical records database was searched for patients who presented to the Emergency Department over a 1-month period in 1990 with a diagnosis of renal colic. Patients with the same presentation, from the same month, in 2013 were also identified. A total of 14 patients from each year fulfilled the inclusion criteria. The estimated effective radiation exposure dose for each patient was calculated by using data from population-based studies. RESULTS: The median effective radiation dose per patient in the 1990 group, for initial diagnosis and subsequent follow-up, was 4.05 mSv (interquartile range [IQR], 3.7-4.4 mSv). The corresponding median dose in the 2013 group was 4.2 mSv (IQR, 4.2-4.9 mSv), and there was no evidence of a statistical difference between the groups (p=0.8). CONCLUSIONS: Despite the contentiousness related to the use of serial CT scanning, our study demonstrated that for radiological investigation and follow up of urolithiasis, the estimated effective radiation exposure dose to each patient is only marginally higher than in the era of IVU, with improvements in length of hospital stay and time to definitive diagnosis. PMID- 26981594 TI - The mathematical formula of the intravaginal ejaculation latency time (IELT) distribution of lifelong premature ejaculation differs from the IELT distribution formula of men in the general male population. AB - PURPOSE: To find the most accurate mathematical description of the intravaginal ejaculation latency time (IELT) distribution in the general male population. MATERIALS AND METHODS: We compared the fitness of various well-known mathematical distributions with the IELT distribution of two previously published stopwatch studies of the Caucasian general male population and a stopwatch study of Dutch Caucasian men with lifelong premature ejaculation (PE). The accuracy of fitness is expressed by the Goodness of Fit (GOF). The smaller the GOF, the more accurate is the fitness. RESULTS: The 3 IELT distributions are gamma distributions, but the IELT distribution of lifelong PE is another gamma distribution than the IELT distribution of men in the general male population. The Lognormal distribution of the gamma distributions most accurately fits the IELT distribution of 965 men in the general population, with a GOF of 0.057. The Gumbel Max distribution most accurately fits the IELT distribution of 110 men with lifelong PE with a GOF of 0.179. There are more men with lifelong PE ejaculating within 30 and 60 seconds than can be extrapolated from the probability density curve of the Lognormal IELT distribution of men in the general population. CONCLUSIONS: Men with lifelong PE have a distinct IELT distribution, e.g., a Gumbel Max IELT distribution, that can only be retrieved from the general male population Lognormal IELT distribution when thousands of men would participate in a IELT stopwatch study. The mathematical formula of the Lognormal IELT distribution is useful for epidemiological research of the IELT. PMID- 26981595 TI - Vancomycin resistant enterococci in urine cultures: Antibiotic susceptibility trends over a decade at a tertiary hospital in the United Kingdom. AB - PURPOSE: Enterococci are a common cause of urinary tract infection and vancomycin resistant strains are more difficult to treat. The purpose of this surveillance program was to assess the prevalence of and determine the risk factors for vancomycin resistance in adults among urinary isolates of Enterococcus sp. and to detail the antibiotic susceptibility profile, which can be used to guide empirical treatment. MATERIALS AND METHODS: From 2005 to 2014 we retrospectively reviewed 5,528 positive Enterococcus sp. urine cultures recorded in a computerized laboratory results database at a tertiary teaching hospital in Cambridge, United Kingdom. RESULTS: Of these cultures, 542 (9.8%) were vancomycin resistant. No longitudinal trend was observed in the proportion of vancomycin resistant strains over the course of the study. We observed emerging resistance to nitrofurantoin with rates climbing from near zero to 40%. Ampicillin resistance fluctuated between 50% and 90%. Low resistance was observed for linezolid and quinupristin/dalfopristin. Female sex and inpatient status were identified as risk factors for vancomycin resistance. CONCLUSIONS: The incidence of vancomycin resistance among urinary isolates was stable over the last decade. Although resistance to nitrofurantoin has increased, it still serves as an appropriate first choice in uncomplicated urinary tract infection caused by vancomycin-resistant Enterococcus sp. PMID- 26981596 TI - Penile inversion through a penoscrotal incision for the treatment of penile urethral strictures. AB - PURPOSE: This article describes a novel technique for the repair of penile urethral strictures and establishes the safety, feasibility, and efficacy of this innovative surgical approach. MATERIALS AND METHODS: Patients with urethral strictures underwent a one-sided anterior dorsal oral mucosal graft urethroplasty through a penoscrotal inversion technique. The clinical outcome was considered a failure when any instrumentation was needed postoperatively, including dilatation. RESULTS: Five patients underwent the novel procedure. The patients' mean age was 58 years. The cause of stricture was instrumentation in 2 cases (40%), lichen sclerosis in 1 case (20%), and failed hypospadias repair in 2 cases (40%). The mean stricture length was 3 cm. The overall mean (range) follow-up was 6 months (range, 3-9 months). Of the 5 patients, 4 (80%) had a successful outcome and 1 (20%) had a failed outcome. The failure was successfully treated by use of a meatotomy. CONCLUSIONS: The penile inversion technique through a penoscrotal incision is a viable option for the management of penile urethral strictures with several advantages to other techniques: namely, no penile skin incision, a single stage operation, and supine positioning. PMID- 26981597 TI - Robot-assisted "Santosh-Post Graduate Institute tubularized flap pyelovesicostomy" in a solitary functioning kidney with giant hydronephrosis: A minimally invasive salvage procedure. AB - We describe a case of a solitary functioning kidney with giant hydronephrosis secondary to ureteropelvic junction obstruction in a young girl who underwent successful robot-assisted tubularized flap pyelovesicostomy. The aim of this report was to highlight the feasibility and efficacy of this technique in salvaging such renal moieties and to present a brief review of the surgical options available for the management of giant hydronephrosis. PMID- 26981598 TI - Simultaneous Retzius-sparing robot-assisted radical prostatectomy and partial nephrectomy. AB - We present a 61-year-old man who was diagnosed with synchronous prostate cancer and suspicious renal cell carcinoma of the right kidney, treated with combined Retzius-sparing robot-assisted radical prostatectomy (RS-RARP) and robot-assisted partial nephrectomy (RAPN). The combined approach using RS-RARP and RAPN is technically feasible and safe surgical option for treatment of concomitant prostate cancer and suspicious renal cell carcinoma. PMID- 26981599 TI - Letter to the editor: Comment on "Simultaneous treatment of anterior vaginal wall prolapse and stress urinary incontinence by using transobturator four arms polypropylene mesh". PMID- 26981600 TI - The authors reply: Simultaneous treatment of anterior vaginal wall prolapse and stress urinary incontinence by using transobturator four arms polypropylene mesh. PMID- 26981601 TI - Time flies and the new year of 2016 has finally arrived. Introduction. PMID- 26981602 TI - Human Papilloma Virus and Oropharyngeal Carcinoma - Lessons from History. AB - The human papilloma virus (HPV) is a common virus that infects epithelium in 10% of the world's population. While most sexually active people become infected, the majority with a healthy natural immunity control their infection. When the infection becomes persistent in cervical mucosa for instance, it is associated with nearly all cervical cancers. Fortunately cervical cancer screening is both sensitive and specific and when accessed has led to significant reductions of this disease. Despite this, cervical cancer still remains one of the leading causes of death from cancer. Oropharyngeal mucosa is becoming persistently infected with HPV in an increasing number of people leading to a potential epidemic of oropharyngeal carcinoma. While only 10% of new oropharyngeal infections persist, those in elderly men who smoke are more likely to do so. Some centres report more than 70% of oropharyngeal cancers are associated with HPV infection, which is different to cancers caused by alcohol and tobacco. Other centres report only a 20% association. Education against high-risk sexual behaviour has been met with limited success. Screening for oropharyngeal HPV infection has been disappointing with a pickup rate of only 40%. Some hope lies in detecting viral DNA in both the saliva and plasma. A HPV vaccine has been available since 2006 but is not yet routinely given to both sexes in many countries. Its effect on the incidence of HPV-positive oropharyngeal carcinomas is currently unknown. Vigilance by dental and medical colleagues in the meantime is essential. PMID- 26981603 TI - Human Papilloma Virus in Oral Squamous Cell Carcinoma - The Enigma Unravelled. AB - Squamous cell carcinoma of the head and neck (HNSCC) has long been regarded as a disease entity having a remarkable incidence worldwide and a fairly onerous prognosis; thus encouraging further research on factors that might modify disease outcome. Squamous cell carcinomas encompass at least 90% of all oral malignancies. Several factors like tobacco and tobacco-related products, alcohol, genetic predisposition and hormonal factors are suspected as possible causative factors. Human papilloma virus (HPV), the causal agent of cervical cancer also appears to be involved in the aetiology of oral and oropharyngeal cancer. HPVpositive squamous cell carcinoma (SCC) seems to differ from HPV-negative SCC. Many questions about the natural history of oral HPV infection remain under investigation. The aim of this review is to highlight the current understanding of HPV-associated oral cancer with an emphasis on its prognosis, detection and management. PMID- 26981604 TI - Molecular Mechanisms of Chemoresistance in Oral Cancer. AB - Oral cancer is an aggressive disease with the propensity for local recurrence and distal metastasis in the head and neck region. Currently, cisplatin-based chemotherapy or concurrent radiochemotherapy is still the first choice to treat the advanced stage cancers, in particular, the unresectable tumours. Unfortunately, innate and acquired resistance to chemotherapy agent greatly limited its effectiveness and often led to treatment failure in these patients. Hence, it is urgent to clarify the mechanisms underlying the development of chemoresistance in patients with oral cancer. In this article, the current understandings on molecular mechanisms of chemoresistance in oral cancer were reviewed, including drug efflux, apoptosis, DNA damage and repair, epithelial mesenchymal transition, autophagy and miRNA. PMID- 26981605 TI - Non-steroidal Anti-inflammatory Drugs Attenuate Hyperalgesia and Block Upregulation of Trigeminal Ganglionic Sodium Channel 1.7 after Induction of Temporomandibular Joint Inflammation in Rats. AB - OBJECTIVE: To investigate the association between the analgesic effect of non steroidal antiinflammatory drugs (NSAIDs) and sodium channel 1.7 (Nav1.7) expression in the trigeminal ganglion (TG). METHODS: Temporomandibular joint (TMJ) inflammation was induced by complete Freund's adjuvant (CFA) in female rats. Ibuprofen, diclofenac sodium and meloxicam were given intragastrically before induction of TMJ inflammation. Histopathological evaluation and scoring of TMJ inflammation was used to evaluate the level of inflammation. The head withdrawal threshold and food intake were measured to evaluate TMJ nociceptive responses. The mRNA and protein expression of trigeminal ganglionic Nav1.7 was examined using real-time polymerase chain reaction and western blot. RESULTS: Twenty-four hours after the injection of CFA into the TMJs, NSAIDs attenuated hyperalgesia of inflamed TMJ and simultaneously blocked inflammation-induced upregulation of Nav1.7 mRNA and protein expression in the TG. However, ibuprofen and diclofenac sodium slightly attenuated TMJ inflammation and meloxicam did not affect TMJ inflammation. CONCLUSION: Attenuation of hyperalgesia of inflamed TMJ by NSAIDs might be associated with their role in blocking upregulation of trigeminal ganglionic Nav1.7. PMID- 26981606 TI - Mechanical Properties of Orthodontic Thermoplastics PETG/ PC2858 after Blending. AB - OBJECTIVE: To characterise and compare the tensile characteristics after multi proportional blending, to determine the proper blending ratio for new thermoplastic material and to compare its mechanical performance with commercial thermoplastics. METHODS: PETG and PC2858 aggregates were blended in five different ratios. Standard specimens of each ratio were molded and tested to determine their mechanical performance. Then the new material with the proper blending ratio was chosen and compared against commercial thermoplastics. RESULTS: With the increase of PC2858 content, the tensile and impact strength increased but elongation at break decreased. When blending ratio (wt %) was 70/30, the PETG/PC2858 exhibited optimal mechanical properties, with a tensile strength of 63.42 +/- 1.67 MPa, and a stress relaxation rate of 0.0080 +/- 0.0005 N/s, which exceeded those of Erkodur and Biolon. CONCLUSION: By blending PETG and PC2858 at the weight ratio 70/30, we obtained new thermoplastic material which outperformed commercial products. PMID- 26981607 TI - Preliminary Evaluation of Platelet Rich Fibrin-Mediated Tissue Repair in Immature Canine Pulpless Teeth. AB - OBJECTIVE: To evaluate the use of platelet-rich fibrin (PRF) in the regenerative therapy of immature canine permanent teeth. METHODS: Eight immature premolars of beagle dogs were pulp extracted and cleaned with irrigation, then divided into two groups of empty root canals and those filled with a PRF clot. All of the eight premolars were sealed with mineral trioxide aggregate and glass ionomer cement. Two premolars were left naturally grown as a positive control. The root development was assessed radiographically and histologically after 12 weeks. RESULTS: The radiological findings showed greater increases in the thickness of lateral dentinal wall in the PRF group than in the vacant group. Histologically, dental-associated mineral tissue, connective tissue, and bone-like mineral tissue grew into the root canals independent of PRF clot use. The PRF was able to increase the thickness of dental-associated mineral tissue. However, the vital tissue differed from the pulp dentin complex. CONCLUSION: Our study demonstrated the feasibility of using PRF-mediated regenerative therapy in pulpless immature teeth for improving tissue repair. PMID- 26981608 TI - Comprehensive Oral Health Care to Reduce the Incidence of Severe Early Childhood Caries (s-ECC) in Urban China. AB - OBJECTIVE: To explore the effectiveness of comprehensive oral health care to reduce the caries incidence for children with severe early childhood caries (s ECC) in an urban area in China. METHODS: A total of 357 children aged 3 to 4 years old and diagnosed with s-ECC were recruited in this randomised controlled, single-blinded clinical trial for 1 year. Children of two different kindergarten classes were enrolled in this study and randomly divided into a test group (205 children) and a control group (152 children). The test group received comprehensive oral health care, which included: oral health examination, oral health education, topical fluoride application and dental treatment, and the children in the control group only received the oral health examination. The evaluation of the oral health questionnaire for parents was also performed. An evaluation was carried out at the time of recruitment and 1 year later to explore the effectiveness of the comprehensive oral health care model. RESULTS: The differences in decayed teeth (dt), decayed tooth surfaces (ds), filled teeth (ft), filled tooth surfaces (fs) and the ratio of ft /(dt + ft) between the two groups were statistically significant (P < 0.001) at 1 year. The incidence of caries in the control group was higher than that of the test group (P = 0.02). The rate of awareness of oral health knowledge (P = 0.01) and the practice of good diet habits (P = 0.02) by parents in the test group were significantly higher than those in the control group. CONCLUSION: The present study demonstrated that the comprehensive oral health care program reduces and prevents caries amongst children with s-ECC. PMID- 26981610 TI - Sensitive and selective colorimetric detection of Hg(2+) by a Hg(2+) induced dual signal amplification strategy based on cascade-type catalytic reactions. AB - A simple and fast colorimetric method is developed for the sensitive and selective detection of Hg(2+) based on a dual signal amplification strategy: in situ Hg(2+) induced catalytic synthesis of oxidase-like AuHg nanoparticles and subsequent catalytic oxidation of TMB by AuHg nanoparticles. PMID- 26981609 TI - Development and comparative investigation of Ag-sensitive layer based SAW and QCM sensors for mercury sensing applications. AB - Piezoelectric acoustic wave devices integrated with noble metal surfaces provide exciting prospects for the direct measurement of toxic gas species such as mercury (Hg) in the atmosphere. Even though gold (Au) based acoustic wave sensors have been utilized extensively for detecting Hg, the potential of using other metal surfaces such as silver (Ag) is yet to be thoroughly studied. Here, we developed Ag sensitive layer-based surface acoustic wave (SAW) and quartz crystal microbalance (QCM) sensors and focused on their comparative analysis for Hg sensing applications with parameters such as the sensor sensitivity, selectivity, adsorption/desorption isotherm and Hg diffusion into the surface thoroughly studied. The SAW sensor was fabricated with nickel (Ni) interdigitated transducer (IDT) electrodes and a Ag thin film on the delay line of the device. In the case of the QCM sensor, the electrodes were constructed of Ag thin film and simultaneously employed as a sensitive layer. Mercury sensing experiments were conducted for a range of concentrations between 24-365 ppbv without/with the presence of some common industrial interfering gas species (i.e. ammonia, acetaldehyde, ethyl mercaptan, dimethyl disulphide, methyl ethyl ketone and humidity) at various operating temperatures in the range of 35-95 degrees C. The SAW sensor was found to possess up to 70 times higher response magnitudes than its QCM counterpart at 35 degrees C while up to 30 and 23 times higher response magnitudes were observed for the SAW sensor at elevated temperatures of 75 and 95 degrees C, respectively. Furthermore, the SAW sensor showed good selectivity (>89%) toward Hg(0) vapor in the presence of all the interferents tested at an operating temperature of 75 degrees C while the QCM sensor exhibited significant cross-sensitivity when ethyl mercaptan was introduced along with Hg(0) vapor. Overall, it is indicative that Ag-based acoustic wave sensors do have great potential for Hg sensing applications, given that right operating conditions are applied. PMID- 26981611 TI - In vitro and in cell analysis of chemically synthesized histone H2A with multiple modifications. AB - The chemical synthetic route to histone H2A is described. An H2A-H2B dimer, histone octamer, and nucleosome were reconstituted with the synthetic H2A. Fluorescein-labeled H2A and multiply modified H2A, which has three different posttranslational modifications, were also synthesized, and applied to live-cell imaging and in vitro nucleosome stability assays, respectively. PMID- 26981613 TI - Flexible Near-Field Nanopatterning with Ultrathin, Conformal Phase Masks on Nonplanar Substrates for Biomimetic Hierarchical Photonic Structures. AB - Multilevel hierarchical platforms that combine nano- and microstructures have been intensively explored to mimic superior properties found in nature. However, unless directly replicated from biological samples, desirable multiscale structures have been challenging to efficiently produce to date. Departing from conventional wafer-based technology, new and efficient techniques suitable for fabricating bioinspired structures are highly desired to produce three dimensional architectures even on nonplanar substrates. Here, we report a facile approach to realize functional nanostructures on uneven microstructured platforms via scalable optical fabrication techniques. The ultrathin form (~3 MUm) of a phase grating composed of poly(vinyl alcohol) makes the material physically flexible and enables full-conformal contact with rough surfaces. The near-field optical effect can be identically generated on highly curved surfaces as a result of superior conformality. Densely packed nanodots with submicron periodicity are uniformly formed on microlens arrays with a radius of curvature that is as low as ~28 MUm. Increasing the size of the gratings causes the production area to be successfully expanded by up to 16 in(2). The "nano-on-micro" structures mimicking real compound eyes are transferred to flexible and stretchable substrates by sequential imprinting, facilitating multifunctional optical films applicable to antireflective diffusers for large-area sheet-illumination displays. PMID- 26981614 TI - Identification of cytokines for early prediction of malignant middle cerebral artery infarction. AB - PURPOSE: We aimed to profile cytokines in patients with malignant middle cerebral artery infarction (MMI) and non-acute cerebral infarction (NACI), and identify potential cytokines for early prediction of MMI. MATERIALS AND METHODS: A total of 16 subjects were recruited, including 8 patients with MMI and 8 patients with NACI. Cytokine profiles and levels in serums were analyzed by Quantibody(r) Human Cytokine Antibody Array700. The two-tailed Student t-test and Fisher's Exact Test were respectively conducted for continuous variables and categorical variables to evaluate their differences between patients with MMI and those with NACI. Binary logistic regression was further conducted to verify the association of differentially expressed cytokines with MMI. RESULTS: The concentrations of 320 unique inflammatory cytokines in serums were measured. Ten cytokines were discovered to be differentially expressed between patients with MMI and patients with NACI, including transforming growth factor beta-1 (TGFB1), matrix metallopeptidase 10 (MMP10), neural cell adhesion molecule 1 (NCAM1), interleukin 27 (IL27), epidermal growth factor (EGF), insulin-like growth factor-binding protein 6 (IGFBP6), platelet-derived growth factor subunit A (PDGFA), C-C motif chemokine 2 (C-C CCL2), neutrophil gelatinase-associated lipocalin (Lipocalin 2) and lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE1). Among these cytokines, the concentrations of NCAM1, IGFBP6, Lipocalin2 and LYVE1 were significantly higher while the concentrations of the other six cytokines were significantly lower in patients with MMI compared with those in patients with NACI. Multivariate logistic regression analysis verified the association of these 10 cytokines with MMI except for IL-27 (p = 0.5422). CONCLUSIONS: Nine cytokines, including NCAM1, IGFBP6, Lipocalin2, LYVE1, TGFB1, MMP10, EGF, PDGFA and CCL2, might act as potential markers for early prediction of MMI and involve in the progression from NACI to MMI. Further studies with a better control group are still needed. PMID- 26981615 TI - Cannonballs in Pap Smears: Double Whammy of Bacterial Vaginosis and Associated Infections. AB - INTRODUCTION: Cannonballs are structures consisting of neutrophils adherent to epithelial cells, often seen in vaginal Pap smears of patients with trichomoniasis and chlamydiasis. We frequently observed these cannonballs in inflammatory Pap smears showing evidence of bacterial vaginosis. OBJECTIVE: To study the association between cannonballs and bacterial vaginosis with associated infections in inflammatory Pap smears. STUDY DESIGN: This was a retrospective study performed over a period of 6 months between April 2014 and September 2014. Three hundred consecutive Pap smears assessed during the study period were retrieved from the archives and studied. RESULTS: A total of 280 smears were studied. Neutrophilic infiltrates were seen in 83.6%, cannonballs in 82.3%, and bacterial vaginosis in 70.7% of the smears. Cannonballs were found in 84.4% of the smears showing evidence of bacterial vaginosis with associated inflammatory infiltrates. There was a significant association between cannonballs and bacterial vaginosis (p = 0.0001). The odds ratio was 13.8 (95% CI: 7.2-26.2). CONCLUSION: The present study shows a significant association between cannonballs and bacterial vaginosis and associated vaginal infections. PMID- 26981616 TI - Prevalence, Patterns, and Predictors of T'ai Chi and Qigong Use in the United States: Results of a Nationally Representative Survey. AB - OBJECTIVE: This study examined the prevalence, patterns, and predictors of t'ai chi and qigong use in the U.S. general population. DESIGN: Cross-sectional survey. METHODS: Data from the 2012 National Health Interview Survey (n = 34,525). Weighted frequencies were used to analyze lifetime and 12-month prevalence and patterns of use. Independent predictors of practice were analyzed by using logistic regression models. Analyzes were conducted in 2015. RESULTS: The lifetime and 12-month prevalence of t'ai chi/qigong practice were 3.1% and 1.2%, respectively. The 12-month prevalence was associated with age older than 30 years; being African American, Asian, or other ethnic origin; living in the West; being college educated and single; and being a light to heavy alcohol consumer. Almost 39% of users attended formal classes. T'ai chi/qigong was practiced for wellness/disease prevention and to improve energy, immune function, athletic performance, or memory/concentration. Stress, arthritis, and joint problems were the most frequent specific health problems for practice. CONCLUSIONS: Despite an only marginal increase of t'ai chi/qigong practice in the United States over the past 10 years, the proportion of minorities among practitioners has increased significantly. Gaps between clinical application and research are discussed. PMID- 26981618 TI - Considerations for the Characterization and Interpretation of Results Related to Alternative Complement Activation in Monkeys Associated with Oligonucleotide Based Therapeutics. AB - This article provides an overview of the discussions held by the Immunomodulatory Subcommittee of the Oligonucleotide Safety Working Group on complement activation induced by oligonucleotides, most notably the phosphorothioate-containing oligonucleotides. Alternative complement pathway activation in monkeys is a common effect of single-stranded phosphorothioate backbone oligonucleotides in toxicology studies. This article discusses the mechanism for activation, general investigational strategy, and the impact of various chemical modifications. The goal is to provide the best practice approach to characterizing this effect, understanding the implication of the species specificity, and the interpretation of clinical relevance. PMID- 26981617 TI - Antitumor and Antimetastatic Effect of Small Immunostimulatory RNA against B16 Melanoma in Mice. AB - Small interfering RNAs, depending on their structure, delivery system and sequence, can stimulate innate and adaptive immunity. The aim of this study was to investigate the antitumor and antimetastatic effects of immunostimulatory 19 bp dsRNA with 3'- trinucleotide overhangs (isRNA) on melanoma B16 in C57Bl/6 mice. Recently developed novel cationic liposomes 2X3-DOPE were used for the in vivo delivery of isRNA. Administration of isRNA/2X3-DOPE complexes significantly inhibits melanoma tumor growth and metastasis. Histopathological analysis of spleen cross sections showed hyperplasia of the lymphoid white pulp and formation of large germinal centers after isRNA/2X3-DOPE administration, indicating activation of the immune system. The treatment of melanoma-bearing mice with isRNA/2X3-DOPE decreases the destructive changes in the liver parenchyma. Thus, the developed isRNA displays pronounced immunostimulatory, antitumor and antimetastatic properties against melanoma B16 and may be considered a potential agent in the immunotherapy of melanoma. PMID- 26981612 TI - Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment. AB - INTRODUCTION: Despite remarkable advances in tumor treatment, many patients still die from common tumors (breast, prostate, lung, CNS, colon, and pancreas), and thus, new approaches are needed. Many of these tumors synthesize bombesin (Bn) related peptides and over-express their receptors (BnRs), hence functioning as autocrine-growth-factors. Recent studies support the conclusion that Bn peptides/BnRs are well-positioned for numerous novel antitumor treatments, including interrupting autocrine-growth and the use of over-expressed receptors for imaging and targeting cytotoxic-compounds, either by direct-coupling or combined with nanoparticle-technology. AREAS COVERED: The unique ability of common neoplasms to synthesize, secrete, and show a growth/proliferative/differentiating response due to BnR over-expression, is reviewed, both in general and with regard to the most frequently investigated neoplasms (breast, prostate, lung, and CNS). Particular attention is paid to advances in the recent years. Also considered are the possible therapeutic approaches to the growth/differentiation effect of Bn-peptides, as well as the therapeutic implication of the frequent BnR over-expression for tumor-imaging and/or targeted-delivery. EXPERT OPINION: Given that Bn-related-peptides/BnRs are so frequently ectopically-expressed by common tumors, which are often malignant and become refractory to conventional treatments, therapeutic interventions using novel approaches to Bn-peptides and receptors are being explored. Of particular interest is the potential of reproducing with BnRs in common tumors the recent success of utilizing overexpression of somatostatin-receptors by neuroendocrine tumors to provide the most sensitive imaging methods and targeted delivery of cytotoxic-compounds. PMID- 26981619 TI - Endoscopic treatment of food intolerance after a banded gastric bypass: inducing band erosion for removal using a plastic stent. AB - BACKGROUND AND STUDY AIMS: Ring complications after a banded Roux-en-Y gastric bypass (RYGB) are usually managed surgically. The aim of this study was to analyze the safety and effectiveness of endoscopic removal of noneroded rings after banded-RYGB, by inducing intragastric erosion of the ring using a self expandable plastic stent (SEPS). PATIENTS AND METHODS: A total of 41 patients with banded RYGB who had noneroded rings and food intolerance were prospectively enrolled. Patients were treated with endoscopic SEPS placement and ring removal. Data from time of stenting, resolution of symptoms, need for endoscopic dilation, and complications were recorded. RESULTS: Successful ring removal was possible in all patients. In 21 cases, the SEPS induced complete erosion, and in 17 cases the ring was removed a month later because of incomplete erosion at the time of SEPS removal. Nine patients (22.0 %) needed endoscopic dilation after stent removal in order to treat fibrotic strictures. Food tolerance was observed in 32 patients (78.0 %) after the procedure. No patient needed surgery and there were no deaths. CONCLUSIONS: Endoscopic removal of the ring using SEPS appeared to be safe and effective after a banded RYGB. PMID- 26981621 TI - Septic acute kidney injury in critically ill patients - a single-center study on its incidence, clinical characteristics, and outcome predictors. AB - Purpose The objective of this study is to examine the incidence, clinical characteristics, and outcome (90-day mortality) of critically ill Chinese patients with septic AKI. Methods Patients admitted to the ICU of a regional hospital from 1 January 2011 to 31 December 2013 were included, excluding those on chronic renal replacement therapy. AKI was defined using KDIGO criteria. Patients were followed till 90 days from ICU admission or death, whichever occurred earlier. Demographics, diagnosis, clinical characteristics, and outcome were analyzed. Results In total, 3687 patients were included and 54.7% patients developed AKI. Sepsis was the most common cause of AKI (49.2%). Compared to those without AKI, AKI patients had higher disease severity, more physiological and biochemical disturbance, and carried significant co-morbidities. Ninety-day mortality increased with severity of AKI (16.7, 27.5, and 48.3% for KDIGO stage 1, 2, and 3 AKI, p < 0.001). Full renal recovery was achieved in 71.6% of AKI patients. Compared with non-septic AKI, septic AKI was associated with higher disease severity and required more aggressive support. Non-recovery of renal function occurred in 2.5% of patients with septic AKI, compared with 6.4% in non septic AKI (p < 0.001). Cox regression analysis showed that age, emergency ICU admission, post-operative cases, admission diagnosis, etiology of AKI, disease severity score, mechanical ventilation, vasopressor support, and blood parameters (like albumin, potassium and pH) independently predicted 90-day mortality. Conclusions AKI, especially septic AKI is common in critically ill Chinese patients and is associated with poor patient outcome. Etiology of AKI has a significant impact on 90-day mortality and may affect renal outcome. PMID- 26981620 TI - MamO Is a Repurposed Serine Protease that Promotes Magnetite Biomineralization through Direct Transition Metal Binding in Magnetotactic Bacteria. AB - Many living organisms transform inorganic atoms into highly ordered crystalline materials. An elegant example of such biomineralization processes is the production of nano-scale magnetic crystals in magnetotactic bacteria. Previous studies implicated the involvement of two putative serine proteases, MamE and MamO, during the early stages of magnetite formation in Magnetospirillum magneticum AMB-1. Here, using genetic analysis and X-ray crystallography, we show that MamO has a degenerate active site, rendering it incapable of protease activity. Instead, MamO promotes magnetosome formation through two genetically distinct, noncatalytic activities: activation of MamE-dependent proteolysis of biomineralization factors and direct binding to transition metal ions. By solving the structure of the protease domain bound to a metal ion, we identify a surface exposed di-histidine motif in MamO that contributes to metal binding and show that it is required to initiate biomineralization in vivo. Finally, we find that pseudoproteases are widespread in magnetotactic bacteria and that they have evolved independently in three separate taxa. Our results highlight the versatility of protein scaffolds in accommodating new biochemical activities and provide unprecedented insight into the earliest stages of biomineralization. PMID- 26981622 TI - Oral Nitrate Administration Ameliorates Cardiogenic Shock due to Eclipsed Mitral Regurgitation. AB - Eclipsed mitral regurgitation (MR) has been reported as transient massive functional MR caused by a sudden coaptation defect in the absence of left ventricular remodeling or epicardial coronary artery stenosis. Coronary spasm or microvascular dysfunction has been suggested to be associated with the pathogenesis. Here, we present a 68-year-old woman with eclipsed MR with cardiogenic shock ameliorated by nitrate. She was admitted for transient shock with massive functional MR. Transient MR was associated with a complete absence of mitral leaflet coaptation owing to tethering of the lateral posterior mitral leaflet. The leaflet tethering was triggered by transient myocardial ischemia around the anterolateral papillary muscle, which could have been caused by coronary spasm and/or microvascular dysfunction. During admission, she experienced similar repeated episodes, which were ameliorated by oral nitrate administration. This is the first described case of eclipsed MR with shock ameliorated by nitrate. Although eclipsed MR, a cause of life-threatening shock, is uncommon, we need to keep in mind that nitrate administration could be a treatment option even in patients with cardiogenic shock. PMID- 26981623 TI - Characteristics of Patients at First Visit to a Polio Clinic in Sweden. AB - AIM: Describe polio patients visiting a polio clinic in Sweden, a country where vaccination was introduced in 1957. DESIGN: A consecutive cohort study. PATIENTS: Prior polio patients. METHODS: All patients (n = 865) visiting the polio clinic at Sahlgrenska University Hospital, Gothenburg Sweden, between 1994 and 2012 were included in this study. Data at first visit regarding patient characteristics, polio classification, data of electromyography, origin, assistive devices and gait speed as well as muscle strength were collected for these patients. Twenty three patients were excluded because no polio diagnosis could be established. A total of 842 patients with confirmed polio remained in the study. RESULTS: More than twenty percent of the patients were from countries outside the Nordic region and considerably younger than those from the Nordic region. The majority of the emigrants were from Asia and Africa followed by Europe (outside the Nordic region). Of all patients included ninety-seven percent (n = 817) had polio in the lower extremity and almost 53% (n = 444) had polio in the upper extremity while 28% (n = 238) had polio in the trunk, according to clinical classification of polio. Compared with a sample of the normal population, the polio patients walked 61-71% slower, and were 53-77% weaker in muscle strength of the knee and foot as well as grip strength. CONCLUSION: The younger patients with polio emigrating from countries with different cultures may lead to a challenge for the multi professional teams working with post-polio rehabilitation and are of importance when planning for the care of polio patients the coming years. PMID- 26981624 TI - Terpenoid Oligomers of Dammar Resin. AB - Dammar is a triterpenoid resin containing a volatile fraction, a monomeric fraction, and a high-molecular weight fraction. Although the low-molecular-weight components comprising sesquiterpenoids and triterpenoids have been extensively studied, the nature of the macromolecular components is still not fully understood, and different and sometimes contradictory theories have been proposed. The aim of this paper is to clarify the nature of the macromolecular components of dammar resin. A multianalytical approach was adopted based on thermoanalytical-thermogravimetric analysis (TGA), and thermogravimetric analysis coupled with Fourier transform infrared spectroscopy (TGA/FTIR)--and mass spectrometric techniques-direct exposure mass spectrometry (DE/MS), pyrolysis coupled to gas chromatography and mass spectrometry (Py/GC/MS), flow injection analysis electrospray ionization mass spectrometry (FIA/ESI/MS), and gas chromatography/mass spectrometry (GC/MS). The data indicate that the oligomeric fraction comprises triterpenoids bound through ester bonds, and that these triterpenoids are the same as those found in the free terpenoid fraction. The oligomeric fraction also includes triterpenoids containing carbonyl moieties, such as formyl groups, thus suggesting that these are involved in the esters in their corresponding enolic form. PMID- 26981626 TI - Cross-Cultural Register Differences in Infant-Directed Speech: An Initial Study. AB - Infant-directed speech (IDS) provides an environment that appears to play a significant role in the origins of language in the human infant. Differences have been reported in the use of IDS across cultures, suggesting different styles of infant language-learning. Importantly, both cross-cultural and intra-cultural research suggest there may be a positive relationship between the use of IDS and rates of language development, underscoring the need to investigate cultural differences more deeply. The majority of studies, however, have conceptualized IDS monolithically, granting little attention to a potentially key distinction in how IDS manifests across cultures during the first two years. This study examines and quantifies for the first time differences within IDS in the use of baby register (IDS/BR), an acoustically identifiable type of IDS that includes features such as high pitch, long duration, and smooth intonation (the register that is usually assumed to occur in IDS), and adult register (IDS/AR), the type of IDS that does not include such features and thus sounds as if it could have been addressed to an adult. We studied IDS across 19 American and 19 Lebanese mother-infant dyads, with particular focus on the differential use of registers within IDS as mothers interacted with their infants ages 0-24 months. Our results showed considerable usage of IDS/AR (>30% of utterances) and a tendency for Lebanese mothers to use more IDS than American mothers. Implications for future research on IDS and its role in elucidating how language evolves across cultures are explored. PMID- 26981627 TI - HIV post-test practices: an online survey examining perceived delivery of HIV test results, post-test discussion and referral in healthcare settings across the WHO European Region. AB - Background The aim of this study was to assess perceptions of health professionals involved in HIV testing policy and practice in national settings across the WHO European Region regarding the delivery of HIV test results, post test discussion and referral to specialist HIV services as recommended in authoritative guidelines. METHODS: An online self-report survey was completed by a convenience sample of 338 respondents (response rate 34.1%) from 55 countries. Respondents worked with non-government organisations (49.4%), health services (32.8%), non-health service government agencies (6.2%) or other organisations (11.5%; e.g. prisons, education and research, international development). RESULTS: Experts' perceptions indicate that delivery of HIV-positive test results and related post-test discussion in their country generally corresponded to recommendations. However, results pointed to a significant gap perceived by experts between recommendations and the practice of delivering HIV-negative test results. Fewer respondents thought that suitable time is taken to deliver a negative HIV-test result (54.1%) than a positive result (73.1%). Also, fewer respondents thought there was a procedure for referral to specialist treatment, care and support services for people receiving a HIV-negative test result (34.9%) than for people receiving an HIV-positive test result (86.2%). Experts also reported low perceived use of communication technologies (i.e. telephone, email, text messaging, a secure website) for delivering HIV test results. CONCLUSIONS: This expert survey offers new insight into perceived HIV post-test practices in almost all national settings across the WHO European Region. The findings provide valuable guidance for future HIV testing guidelines for the WHO European Region. PMID- 26981625 TI - Higher Dimensional Meta-State Analysis Reveals Reduced Resting fMRI Connectivity Dynamism in Schizophrenia Patients. AB - Resting-state functional brain imaging studies of network connectivity have long assumed that functional connections are stationary on the timescale of a typical scan. Interest in moving beyond this simplifying assumption has emerged only recently. The great hope is that training the right lens on time-varying properties of whole-brain network connectivity will shed additional light on previously concealed brain activation patterns characteristic of serious neurological or psychiatric disorders. We present evidence that multiple explicitly dynamical properties of time-varying whole-brain network connectivity are strongly associated with schizophrenia, a complex mental illness whose symptomatic presentation can vary enormously across subjects. As with so much brain-imaging research, a central challenge for dynamic network connectivity lies in determining transformations of the data that both reduce its dimensionality and expose features that are strongly predictive of important population characteristics. Our paper introduces an elegant, simple method of reducing and organizing data around which a large constellation of mutually informative and intuitive dynamical analyses can be performed. This framework combines a discrete multidimensional data-driven representation of connectivity space with four core dynamism measures computed from large-scale properties of each subject's trajectory, ie., properties not identifiable with any specific moment in time and therefore reasonable to employ in settings lacking inter-subject time-alignment, such as resting-state functional imaging studies. Our analysis exposes pronounced differences between schizophrenia patients (Nsz = 151) and healthy controls (Nhc = 163). Time-varying whole-brain network connectivity patterns are found to be markedly less dynamically active in schizophrenia patients, an effect that is even more pronounced in patients with high levels of hallucinatory behavior. To the best of our knowledge this is the first demonstration that high-level dynamic properties of whole-brain connectivity, generic enough to be commensurable under many decompositions of time-varying connectivity data, exhibit robust and systematic differences between schizophrenia patients and healthy controls. PMID- 26981628 TI - Effectiveness of a Mobile Short-Message-Service-Based Disease Outbreak Alert System in Kenya. AB - We conducted a randomized, controlled trial to test the effectiveness of a text messaging system used for notification of disease outbreaks in Kenya. Health facilities that used the system had more timely notifications than those that did not (19.2% vs. 2.6%), indicating that technology can enhance disease surveillance in resource-limited settings. PMID- 26981630 TI - Methotrexate for Inflammatory Bowel Diseases - New Developments. AB - Methotrexate (MTX) is an established therapy for patients with steroid-dependent Crohn's disease (CD). MTX is also frequently used in combination with anti-TNF agents to suppress anti-drug antibody formation. It has been suggested in the past that MTX lacks any clinical effectiveness in patients with ulcerative colitis (UC); however, newer data at least partially contradict this assumption. The following review will discuss recent data for the use of MTX in CD, UC and in combination with anti-TNF agents. PMID- 26981632 TI - Smoking and Diet: Impact on Disease Course? AB - BACKGROUND: The impact of current smoking on inflammatory bowel disease (IBD) course has been studied extensively; smoking is deleterious in Crohn's disease (CD), and beneficial in ulcerative colitis (UC). Except for enteral nutrition, there are only limited data regarding the impact of diet on disease course. KEY MESSAGES: Current smoking worsens the course of CD, increasing the incidence of flares, the need for steroids, immunosuppressants and re-operations. Conversely, smoking cessation has a rapid beneficial effect on disease course, decreasing the risk of flares and of post-operative recurrences. From 3 months after the quit date, quitters have a disease course similar to that of never smokers. Achieving smoking cessation in CD is thus an important goal of therapy. On the contrary, smoking improves the course of UC and in particular, is associated with a decreased need for colectomy. Smoking cessation increases the risk of flare and the need for steroids or immunosuppressants. However, patients with UC should not be discouraged to quit, because the beneficial effect of smoking for their disease is counterbalanced by the deleterious systemic effects of tobacco. Among dietary interventions, only exclusive enteral nutrition was shown to induce remission and achieve mucosal healing in some patients with CD. The beneficial effect of liquid-defined diet is observed whatever be the type of administration (orally or by tube), the type of diet regarding protein and fat content and resulting alterations in the gut microbiota. In UC, enteral nutrition has no effect. Finally, popularized restrictive diets in IBD as the specific carbohydrate diet and the gluten-free diet have not been rigorously tested. In a small trial, a semi-vegetarian diet was shown to be effective in maintaining remission over 2 years in CD. CONCLUSIONS: Patients with IBD should not smoke and avoid passive smoking. Aside from the defined liquid diets, there is no rationale for advising particular diets. PMID- 26981631 TI - High Resolution Ultrasonography for Assessment of Renal Cysts in the PCK Rat Model of Autosomal Recessive Polycystic Kidney Disease. AB - BACKGROUND/AIMS: The PCK rat model of polycystic kidney disease is characterized by the progressive development of renal medullary cysts. Here, we evaluated the suitability of high resolution ultrasonography (HRU) to assess the kidney and cyst volume in PCK rats, testing three different ultrasound image analysis methods, and correlating them with kidneys weights and histological examinations. METHODS: After inducing anesthesia, PCK rats (n=18) were subjected to HRU to visualize the kidneys, to perform numeric and volumetric measurements of the kidney and any cysts observed, and to generate 3-dimensional images of the cysts within the kidney parenchyma. RESULTS: HRU provided superior information in comparison to microscopic analysis of stained kidney sections. HRU-based kidney volumes correlated strongly with kidney weights (R2=0.809; P<0.0001). CONCLUSION: HRU represents a useful diagnostic tool for kidney and cyst volume measurements in PCK rats. Sequential HRU examinations may be useful to study the effect of drugs on cyst growth without the need to euthanize experimental animals. PMID- 26981633 TI - REG4 Is Highly Expressed in Mucinous Ovarian Cancer: A Potential Novel Serum Biomarker. AB - Preoperative diagnostics of ovarian neoplasms rely on ultrasound imaging and the serum biomarkers CA125 and HE4. However, these markers may be elevated in non neoplastic conditions and may fail to identify most non-serous epithelial cancer subtypes. The objective of this study was to identify histotype-specific serum biomarkers for mucinous ovarian cancer. The candidate genes with mucinous histotype specific expression profile were identified from publicly available gene-expression databases and further in silico data mining was performed utilizing the MediSapiens database. Candidate biomarker validation was done using qRT-PCR, western blotting and immunohistochemical staining of tumor tissue microarrays. The expression level of the candidate gene in serum was compared to the serum CA125 and HE4 levels in a patient cohort of prospectively collected advanced ovarian cancer. Database searches identified REG4 as a potential biomarker with specificity for the mucinous ovarian cancer subtype. The specific expression within epithelial ovarian tumors was further confirmed by mRNA analysis. Immunohistochemical staining of ovarian tumor tissue arrays showed distinctive cytoplasmic expression pattern only in mucinous carcinomas and suggested differential expression between benign and malignant mucinous neoplasms. Finally, an ELISA based serum biomarker assay demonstrated increased expression only in patients with mucinous ovarian cancer. This study identifies REG4 as a potential serum biomarker for histotype-specific detection of mucinous ovarian cancer and suggests serum REG4 measurement as a non-invasive diagnostic tool for postoperative follow-up of patients with mucinous ovarian cancer. PMID- 26981634 TI - The Association between VEGFR Gene Polymorphisms and Stroke: A Meta-Analysis. AB - Several published articles investigated the relationship between VEGF receptor gene polymorphisms and stroke, but they failed to reach the same conclusion. This meta-analysis was performed to identify the relationships between VEGF receptor gene and the risk of stroke. The PubMed, Embase, China National Knowledge Infrastructure (CNKI) database, Wanfang Chinese database, and VIP Chinese database were systemically searched. Data was extracted by two independent reviewers. The pooled odds ratio (OR) with 95% confidence interval (CI) were calculated. 5 case-control studies with a total of 2904 patients with stroke and 2824 control subjects were included, including 2904 cases and 2824 controls for 604T>C, 2733 cases and 2663 controls for +1192C>T, and 2733 cases and 2663 controls for +1719A>T. Under the dominant and recessive models, respectively, the overall ORs and 95% CIs of -604 C were 0.749, 0.493-1.138 (P = 0.176) and 0.819, 0.544-1.234 (P = 0.340); the overall ORs and 95% CIs of +1192 T were 1.148, 0.876 1.504 (P = 0.318) and 1.611, 1.004-2.586 (P = 0.048); the overall ORs and 95% CIs of +1719 T were 1.227, 0.932-1.615 (P = 0.146) and 1.139, 1.015-1.279 (P = 0.027). Our finding indicates that +1192C>T and +1719A>T may be associated with the risk of stroke, but not -604T>C. PMID- 26981635 TI - Sialyltransferase and Neuraminidase Levels/Ratios and Sialic Acid Levels in Peripheral Blood B Cells Correlate with Measures of Disease Activity in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis: A Pilot Study. AB - OBJECTIVE: We attempted to determine whether the level of enzymes sialyltransferase (ST) and neuraminidase (Neu) and sialic acid (SIA) in patients with systemic lupus erythematosus (SLE) correlates with the SLE Disease Activity Index (SLEDAI) and in patients with rheumatoid arthritis (RA) correlates with the Disease Activity Score28 (DAS28). METHODS: We examined cell-surface levels of ST6Gal-1, Neu1, ST3Gal-1, Neu3, alpha-2,6-SIA, and alpha-2,3-SIA by using fluorescent anti-enzyme antibodies, fluorescent-conjugated Sambucus nigra lectin, and fluorescent-conjugated Maackia amurensis lectin on blood cells in SLE and RA patients and assessed correlations of these levels with SLEDAI and with DAS28. Areas under the curve (AUC) were calculated for different variables against SLEDAI. RESULTS: The B-cell ST3Gal-1/Neu3 ratio positively correlated with SLEDAI scores (rho = 0.409 and P = 0.002, statistically significant after Bonferroni' correction for multiple analyses.). It was supported by the inverse correlation of B-cell Neu3 levels with SLEDAI scores (rho = -0.264, P = 0.048). The B-cell ST3Gal-1/Neu3 ratio against SLEDAI yielded an AUC of 0.689, which was comparable to that of anti-dsDNA levels at 0.635. In contrast, both ST3Gal-1 and Neu3 levels of RA B cells (r = 0.376, P = 0.013; r = 0.425, P = 0.005, respectively) correlated positively with high disease-activity DAS28 scores. CONCLUSION: B-cell ST3Gal-1/Neu3 ratios in SLE and B-cell ST3Gal-1 and Neu3 levels in RA with high disease-activity DAS28 scores correlated with disease activity measures and may be useful in monitoring disease activities. PMID- 26981637 TI - Driving Forces of Dynamic Changes in Soil Erosion in the Dahei Mountain Ecological Restoration Area of Northern China Based on GIS and RS. AB - Dynamic change in soil erosion is an important focus of regional ecological restoration research. Here, the dynamic changes of soil erosion and its driving forces in the Dahei Mountain ecological restoration area of northern China were analyzed by LANDSAT TM remote sensing captured via geographic information system (GIS) technologies during three typical periods in 2004, 2008 and 2013. The results showed the following: (1) a decrease in intensive erosion and moderate erosion areas, as well as an increase in light erosion areas, was observed during two periods: one from 2004 to 2008 and the other from 2008 to 2013. (2) Between 2004 and 2008, the variation in the range of slight erosion was the largest (24.28%), followed by light erosion and intensive erosion; between 2008 and 2013, the variation in the range of intensive erosion area was the largest (9.89%), followed by slight erosion and moderate erosion. (3) Socioeconomic impact, accompanied by natural environmental factors, was the main driving force underlying the change in soil erosion within the ecological restoration area. In particular, the socioeconomic factors of per capita forest area and land reclamation rate, as well as the natural environmental factor of terrain slope, significantly influenced soil erosion changes within the ecological restoration area. PMID- 26981636 TI - Stigma against People Living with HIV/AIDS in China: Does the Route of Infection Matter? AB - In the current study, we tested the hypothesis that people who contracted HIV from "blameless" routes (e.g., blood transfusion, sex with stable partners) are less stigmatized compared to people who contracted HIV from "blamable" routes (e.g., injection drug use, sex with sex workers). A cross-sectional study was conducted among 2,987 participants in Guangxi province, China, between 2012 and 2013. We employed both explanatory and predictive modeling strategy by using multivariate linear regression models. In the explanatory models, we assessed the association between routes of infection and three types of stigma (perceived, internalized, and enacted). From identified routes of infection that significantly contributed to higher stigma, we employed predictive modeling to explore predictors for the specific type of stigma. Multiple-imputation was employed for sensitivity analyses. Of the total sample, 63% were male and the average age was 42.9 years (ranged between 18 and 88). Multivariate regression models revealed that contraction from commercial sex increased the perceived (beta = 0.46, 95%CI = 0.02, 0.90) and internalized stigma (beta = 0.60, 95%CI = 0.09, 1.10), while injecting drug use increased the perceived (beta = 0.65, 95%CI = 0.07, 1.22) and enacted stigma (beta = 0.09, 95%CI = 0.02, 0.16) after controlling for confounders. Among PLWHA who were infected via commercial sex partners, social support was negatively associated with perceived (beta = -0.47, 95%CI = -0.79, -0.14) and internalized stigma (beta = -0.80, 95%CI = -1.24, 0.35). Among PLWHA who were infected via injecting drugs, no adherence to antiretroviral treatment (beta = 0.41, 95%CI = 0.01, 0.82) was positively associated with perceived stigma, and disclosure of serostatus to others was negatively associated with enacted stigma (beta = -0.20, 95%CI = -0.34, -0.05). Knowledge of the association between routes of infection and stigma can guide health professionals and policy makers to develop tailored intervention strategies to mitigate the effects of stigma and enhance HIV care utilization among PLWHA in China. PMID- 26981638 TI - Modification of the hTERT promoter by heat shock elements enhances the efficiency and specificity of cancer targeted gene therapy. AB - PURPOSE: One of the current challenges facing cancer gene therapy is the tumour specific targeting of therapeutic genes. Effective targeting in gene therapy requires accurate spatial and temporal control of gene expression. To develop a sufficient and accurate tumour-targeting method for cancer gene therapy, we have investigated the use of hyperthermia to control the expression of a transgene under the control of the human telomerase reverse transcriptase (hTERT) promoter and eight heat shock elements (8HSEs). MATERIALS AND METHODS: Luciferase reporters were constructed by inserting eight HSEs and the hTERT promoter (8HSEs hTERTp) upstream of the pGL4.20 vector luciferase gene. The luciferase activity of the hTERT promoter and 8HSEs-hTERT promoter were then compared in the presence and absence of heat. The differences in luciferase activity were analysed using dual luciferase assays in SW480 (high hTERT expression), MKN28 and MRC-5 cells (low hTERT expression). The luciferase activity of the Hsp70B promoter was also compared to the 8HSEs-hTERT promoter in the above listed cell lines. Lentiviral vector and heat-induced expression of EGFP expression under the control of the 8HSEs-hTERT promoter in cultured cells and mouse tumour xenografts was measured by reverse transcription polymerase (RT-PCR), Western blot and immunofluorescence assays. RESULTS: hTERT promoter activity was higher in SW480 cells than in MKN28 or MRC-5 cells. At 43 degrees C, the luciferase activity of the 8HSEs-hTERT promoter was significantly increased in SW480 cells, but not in MKN28 or MRC-5 cells. Importantly, the differences in luciferase activity were much more obvious in both high (SW480) and low (MKN28 and MRC-5) hTERT expressing cells when the activity of the 8HSEs-hTERT promoter was compared to the Hsp70B promoter. Moreover, under the control of 8HSEs-hTERT promoter in vitro and in vivo, EGFP expression was obviously increased by heat treatment in SW480 cells but not in MKN28 or MRC-5 cells, nor was expression increased under normal temperature conditions. CONCLUSIONS: The hTERT promoter is a potentially powerful tumour specific promoter and gene therapy tool for cancer treatment. Incorporating heat inducible therapeutic elements (8HSEs) into the hTERT promoter may enhance the efficiency and specificity of cancer targeting gene therapy under hyperthermic clinical conditions. PMID- 26981639 TI - A Comparison of Frontal Theta Activity During Shooting among Biathletes and Cross Country Skiers before and after Vigorous Exercise. AB - BACKGROUND: Previous studies using electroencephalography (EEG) to monitor brain activity have linked higher frontal theta activity to more focused attention and superior performance in goal-directed precision tasks. In biathlon, shooting performance requires focused attention after high-intensity cross-country skiing. PURPOSE: To compare biathletes (serving as experts) and cross-country skiers (novices) and examine the effect of vigorous exercise on frontal theta activity during shooting. METHODS: EEG frontal theta (4-7 Hz) activity was compared between nine biathletes and eight cross-country skiers at comparable skiing performance levels who fired 100 shots on a 5-m indoor shooting range in quiescent condition followed by 20 shots after each of five 6-min high-intensity roller skiing sessions in the skating technique on a treadmill. RESULTS: Biathletes hit 80+/-14% and 81+/-10% before and after the roller skiing sessions, respectively. For the cross-country skiers these values were significantly lower than for the biathletes and amounted to 39+/-13% and 44+/-11% (p<0.01). Biathletes had on average 6% higher frontal theta activity during shooting as compared to cross-country skiers (F1,15 = 4.82, p = 0.044), but no significant effect of vigorous exercise on frontal theta activity in either of the two groups were found (F1,15 = 0.14, p = 0.72). CONCLUSIONS: Biathletes had significantly higher frontal theta activity than cross-country skiers during shooting, indicating higher focused attention in biathletes. Vigorous exercise did not decrease shooting performance or frontal theta activity during shooting in biathletes and cross-country skiers. PMID- 26981641 TI - Using Variable Ionization Energy Time-of-Flight Mass Spectrometry with Comprehensive GC*GC To Identify Isomeric Species. AB - Although GC*GC-ToF-MS allows the separation of thousands of peaks, many of these peaks are not positively identified owing to the lack of mass spectral library data and/or standard materials, leading to a substantial amount of information being inaccessible. The fragmentation patterns of molecules in mass spectrometers using electron impact ionization at 70 eV can be useful for molecule identification, provided a match is available in a published EI MS library, but are indistinguishable for many isomeric organic compounds (for example, linear and branched alkanes). Lower ionization energies have been exploited leading to organic compounds being ionized with lower excess internal energy and less fragmentation, retaining the molecular ion and maximizing its relative signal. This has enabled the identification of a large number of isomeric organic compounds, both aliphatic and aromatic, between C12-C36, in the previously unresolved complex mixture (UCM) of two motor oil samples. This technique also demonstrates problems associated with separation of coeluting isomers, particularly for the n-alkanes, which are routinely measured by 1D GC/MS and may be overestimated, due to coelution. As a consequence retention times in 2 dimensions and mass spectra at variable ionization energies are shown to give unparalleled power to identify specific isomers. PMID- 26981640 TI - Evaluation of Tigecycline Efficacy and Post-Discharge Outcomes in a Clinical Practice Population with Complicated Intra-Abdominal Infection: A Propensity Score-Matched Analysis. AB - BACKGROUND: The utility of tigecycline as compared with other antibiotic therapies in the treatment of patients with complicated intra-abdominal infection (cIAI) and the short- and long-term outcomes of a large cohort of severely ill patients were examined. We provide the first published data on post-discharge events for these patients. METHODS: Retrospective data for the cIAI cohort were obtained from a large clinical database. Patients aged >=18 y were selected for inclusion based on hospitalization with a relevant diagnosis code and procedure code, and guideline-compliant antimicrobial therapy. Propensity scoring was used to reduce treatment-selection bias introduced by the use of observational data. Tigecycline patients were placed into quintiles based on propensity score and were matched 1:3. RESULTS: The final model based on propensity score matching included 2,424 patients: Tigecycline (n = 606) and other antibiotic therapy (n = 1,818). Treatment was successful in 426 (70.3%) tigecycline-treated patients and in 1,294 (71.2%) patients receiving other antibiotics. Similar treatment success occurred across all infection sites. Among survivors, treatment failure was associated with a greater need for all-cause re-hospitalization at 30 d and 180 d. No differences in cIAI-related re-hospitalization and discharge status were observed. CONCLUSIONS: Using propensity scores to match populations, similar outcomes were demonstrated between treatment with tigecycline and other antibiotics as expressed by treatment success, the need for re-admission, similar 30-d discharge status, and the need for re-admission at 180 d. PMID- 26981642 TI - Ritual Slaughter as Overlooked Risk Factor for Brucellosis. PMID- 26981643 TI - Iontophoresis for drug delivery into the nail apparatus: exploring hyponychium as the site of delivery. AB - In present studies, a hyponychium pathway (from ventral side of the nail plate) was investigated as a potential route of drug delivery into the nail apparatus using iontophoresis as an active physical method. In vitro transport studies were performed across the human nail plate using sodium fluorescein as a marker substrate for 24 h. After transport studies, the amount of sodium fluorescein extracted from an active diffusion area of the nail plate in case of iontophoresis was found to be ~54-folds more to that of passive. The amount of sodium fluorescein retained in the peripheral area of the nail plate after application of iontophoresis was found to be ~30-folds more relative to passive. Ex vivo transport studies were performed on excised human cadaver toe using terbinafine hydrochloride as a model drug for three days (8 h/day). The amount of terbinafine retained in the nail plate after application of iontophoresis (3.43 +/- 1.34 ug/mg) was ~20-folds more when compared with passive (0.17 +/- 0.10 ug/mg). The amount of drug extracted from the nail bed and nail matrix was 1.73 +/- 0.12 ug/mg and 0.55 +/- 0.22 ug/mg, respectively. On the other hand, there was no detectable amount of terbinafine found in the nail bed and nail matrix in case of control (passive delivery). These studies show that the iontophoretic drug delivery through hyponychium region to other parts of the nail apparatus could be a potential way of onychomycosis treatment. PMID- 26981644 TI - Multimodal Applications of Transcranial Magnetic Stimulation for Circuit-Based Psychiatry. PMID- 26981645 TI - Targeted training planned in older people's care. AB - The government plans to develop nurses' skills in caring for older people through targeted pre and post-registration training. PMID- 26981646 TI - Extra funding for HCAs who want to become nurses. AB - The boards that assumed responsibility for commissioning nurse education and training this week will each be given L1 million in 2013/14 to explore ways to encourage healthcare assistants (HCAs) to train as nurses. PMID- 26981647 TI - Managers should do more to support long-serving nurses under stress. AB - Employers have been urged to address burnout among experienced nurses by providing special supervision to help them manage stress at work. PMID- 26981649 TI - Annual appraisals will focus on staff values. AB - NHS staff appraisals should focus on individuals' behaviour and attitudes, the government said in its response to the Francis report last week. PMID- 26981648 TI - Hunt rejects calls for statutory HCA regulation. AB - Regulation of healthcare assistants will not be introduced by the government because it would create a 'bureaucratic quagmire', says health secretary Jeremy Hunt. PMID- 26981650 TI - Statutory duty of candour rejected. AB - The government is holding off from agreeing to criminal sanctions for NHS staff who fail to be open and transparent about poor care. PMID- 26981653 TI - Patient records are 'too defensive'. AB - Ward nurses need extra support to help them identify deteriorating patients, says the author of an analysis of patient records. PMID- 26981652 TI - Notice period extended for NHS Direct nurses. AB - Some NHS Direct staff have been asked to continue working for the service until June to provide clinical advice to patients where new NHS 111 providers are not yet in place. PMID- 26981654 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 26981655 TI - Children prefer the flavour of ibuprofen over other analgesics. AB - Ibuprofen is the most palatable analgesic medicine for children, suggests a UK study of young people's opinions on the taste of commonly used medicines in liquid form. PMID- 26981656 TI - Association between aspirin use and lower melanoma risk warrants further investigation. AB - Long-term use of aspirin may reduce the risk of melanoma in postmenopausal women, an analysis of findings from a large study of women in the United States suggests. PMID- 26981657 TI - Techniques for training memory boost nutrition in people with dementia. AB - Nurse researchers in Taiwan have developed an intervention that helps people with dementia remember to eat. People who have dementia are known to be at risk of poor nutrition, and decreased food intake has been associated with depression. PMID- 26981658 TI - Information about resuming sex postpartum may allay anxiety in new parents. AB - Most first-time mothers wait more than six weeks after their baby's birth to resume vaginal sex, reveals an Australian study. PMID- 26981659 TI - Mental disorders are strongly associated with risk of death by homicide. AB - People with mental health disorders have a significantly increased risk of becoming a victim of homicide compared to the general population, according to a nationwide study in Sweden. PMID- 26981660 TI - Nurses in every setting can help improve dementia care. AB - The Department of Health launched a new nursing vision and strategy for dementia care last month. PMID- 26981662 TI - Passing fad. AB - Never underestimate a woman, it is said, but I would add my own adage - never underestimate constipation. PMID- 26981661 TI - Just like you and me. AB - At the top of a hill in the pretty German town of Hadamar, a memorial garden sits in the grounds of a hospital. PMID- 26981663 TI - Teletubby health. AB - According to a recent article in the British Medical Journal, the supposed benefits of telehealth could be a myth. Telehealth? Sorry, but what on earth is telehealth? PMID- 26981664 TI - Clinicians need national guidance on physical restraint. AB - The brutal treatment handed out to residents at Winterbourne View hospital in Bristol - shown on the BBC's Panorama programme in 2011 - shocked and appalled the nation. PMID- 26981665 TI - Readers panel - The burden of entitlement. AB - Our experts consider a hot topic of the day. PMID- 26981666 TI - Starting out - I must confront my own health problems if I am to care for others. AB - I was two months into my nursing training when I was diagnosed with type 2 diabetes at just 24 years of age. PMID- 26981667 TI - Transcribing of medicines should only be undertaken in exceptional circumstances. AB - Is it legal for nurses to transcribe controlled drugs? PMID- 26981668 TI - James Buchan explains why some trusts are upping expenditure on temporary staff. AB - Reports that some NHS trusts' spending on temporary nurses may be on the rise flies in the face of fiscal logic, especially given that other organisations are reported to be reducing agency use as a cost-cutting measure. PMID- 26981669 TI - The Practice of Nursing Research: Appraisal, Synthesis, and Generation of Evidence - Seventh edition Grove Susan K The Practice of Nursing Research: Appraisal, Synthesis, and Generation of Evidence - Seventh edition 752pp Elsevier 9781455707362 1455707368 [Formula: see text]. AB - This classic research text has been updated for nursing students and those in nursing practice. Though a substantial book, it is easy to dip in and out of, covering a wide range of topics from the research process and analysing data to sampling and seeking funding. PMID- 26981670 TI - Social Media for Nurses - Educating Practitioners and Patients in a Networked World Nelson Ramona Social Media for Nurses - Educating Practitioners and Patients in a Networked World 284pp Springer Publishing Company 9780826195883 0826195881 [Formula: see text]. AB - This book's three American authors describe how social media is changing the way nurses and patients interact. They argue that not only do healthcare professionals need to establish their telepresence, they also have a responsibility to educate patients to use Health 2.0 tools in managing their health and health care. PMID- 26981671 TI - Parkinson's Disease - A Personal Account in Pictures Rummins Terry Parkinson's Disease - A Personal Account in Pictures 37pp Matador 9781780885520 1780885520 [Formula: see text]. AB - Terry Rummins was diagnosed with Parkinson's disease at the age of 58. She was working full time, married and with a family. Illustrated by her husband Jack, her book is dedicated to everyone living with the condition. In an A4, 'comic magazine' format, she describes ten years of living with Parkinson's, the trauma of diagnosis, changing realities and building a new understanding of herself. She discusses relaxation techniques, drug regimens, movement, slowing down, exercise, sleeping, lifestyle changes and her speech. Terry looks at her present self and the need to take all possible action to help her future, less capable self. She considers 'deep brain stimulation' to lessen her tremors and her concern of how to prepare for the time when the drugs become less effective. Her book ends with 'PS. I decided against the brain op. PPS. Thanks to all the people who have given up their seats to me on London's buses and underground trains over the past ten years.' This is an excellent guide for all those affected by Parkinson's and their health and social care practitioners. PMID- 26981672 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 26981673 TI - Why does the government assume there are problems with all nurses? AB - Commenting on the government's proposal that nurses spend a year working as healthcare assistants, Dean Fathers, director of the centre for health enterprise at Cass Business School in London, says: 'The need for care and compassion in the health system is essential. PMID- 26981674 TI - Nurse managers risk losing sight of quality patient care. AB - I am most grateful to Michael Owen (letters March 27) for his kind words about me winning the nurse of the year award. PMID- 26981675 TI - Commercial probiotic yogurts have few, if any, health benefits. AB - Mary Hickson's article examining the evidence for the use of probiotics in clinical practice (art&science March 20) is most informative. PMID- 26981676 TI - Can anyone help me disseminate my body of nursing research? AB - More than 40 years ago, I researched the nurse-patient relationship in The Unpopular Patient. My research, particularly on unmet social needs, has led me to investigate the key issue of maternal-infant bonding. PMID- 26981677 TI - Trans people report significant prejudice within health services. AB - We welcome Yvonne Coghill's comment (reflections March 27) that prejudice against trans people is totally at odds with the ethos of the NHS. PMID- 26981678 TI - Royal london hospital set P28 plans 30th anniversary reunion. AB - Members of Set P28 at the Royal London Hospital who began their training in February 1980 are planning a reunion on July 27 in London. The venue will be announced later. Email fran-joy@hotmail.com for details. PMID- 26981679 TI - Correction. AB - Heather Hasthorpe, rheumatology specialist nurse at Norfolk and Norwich University Hospitals NHS Foundation Trust, and winner of the Innovations in Your Specialty award at the Nurse Awards 2013, was misquoted in our nurse awards supplement (March 13). Talking about her work with patients with rheumatoid arthritis, she was quoted as saying: 'My responsibility is to patients, to prevent the disability, pain and deformity associated with this degenerative disease.' Rather than describing the disease as 'degenerative', Ms Hasthorpe used the word 'destructive'. Nursing Standard apologises for the error. PMID- 26981682 TI - Taxing matters. AB - Nurses who earn income that is not taxed at source are required to complete a tax return form after April 6. PMID- 26981681 TI - Notice board. AB - Courses, events, grants, and awards to progress your career. PMID- 26981685 TI - Serum and Plasma Cholinesterase Activity in the Cape Griffon Vulture (Gyps coprotheres). AB - Vulture (Accipitridae) poisonings are a concern in South Africa, with hundreds of birds dying annually. Although some of these poisonings are accidental, there has been an increase in the number of intentional baiting of poached rhinoceros (Rhinocerotidae) and elephant (Elephantidae) carcasses to kill vultures that alert officials to poaching sites by circling overhead. The primary chemicals implicated are the organophosphorous and carbamate compounds. Although most poisoning events can be identified by dead vultures surrounding the scavenged carcass, weak birds are occasionally found and brought to rehabilitation centers for treatment. The treating veterinarian needs to make an informed decision on the cause of illness or poisoning prior to treatment. We established the reference interval for serum and plasma cholinesterase activity in the Cape Griffon Vulture ( Gyps coprotheres ) as 591.58-1,528.26 U/L, providing a clinical assay for determining potential exposure to cholinesterase-depressing pesticides. Both manual and automated samplers were used with the butyrylthiocholine method. Species reference intervals for both serum and plasma cholinesterase showed good correlation and manual and automated measurements yielded similar results. PMID- 26981683 TI - Mast Cell Inhibition Attenuates Cardiac Remodeling and Diastolic Dysfunction in Middle-aged, Ovariectomized Fischer 344 * Brown Norway Rats. AB - The incidence of left ventricular diastolic dysfunction (LVDD) increases in women after menopause, yet the mechanisms are unclear. Because mast cells participate in the pathological processes of various cardiac diseases, we hypothesized that mast cell inhibition would protect against estrogen loss-induced LVDD. The mast cell stabilizer, cromolyn sodium (30 mg.kg.d), or vehicle was administered subcutaneously by osmotic minipump to ovariectomized (OVX) female Fischer 344 * Brown Norway (F344BN) rats starting at 4 weeks after surgery. Eight weeks after OVX, systolic blood pressure increased by 20% in OVX versus sham rats, and this effect was attenuated after 4 weeks of cromolyn treatment. Also, cromolyn mitigated the adverse reductions in myocardial relaxation (e') and increases in left ventricle (LV) filling pressures (E/e'), LV mass, wall thicknesses, and interstitial fibrosis from OVX. Although cardiac mast cell number was increased after OVX, cardiac chymase activity was not overtly altered by estrogen status and tended to decrease by cromolyn. Contrariwise, Ang II content was greater in hearts of OVX versus sham rats, and cromolyn attenuated this effect. Taken together, mast cell inhibition with cromolyn attenuates LV remodeling and LVDD in OVX-Fischer 344 * Brown Norway rats possibly through actions on the heart level and/or through vasodilatory effects at the vascular level. PMID- 26981684 TI - Cell-Specific Polymorphism and Hormonal Regulation of DNA Methylation in Scavenger Receptor Class B, Type I. AB - The scavenger receptor class B, type I (SR-BI), is a cell-surface glycoprotein that mediates selective uptake of high density lipoprotein (HDL)-derived cholesteryl ester. SR-BI plays an important role in cellular delivery of cholesterol. Both human and rodent SR-BI are expressed most abundantly in the liver parenchymal cells and steroidogenic cells of the adrenal gland and gonads, where the selective pathway exhibits its highest activity. In steroidogenic cells, the expression of SR-BI is regulated by trophic hormones (adrenocorticotropic hormone or gonadotropins luteinizing hormone or follicle stimulating hormone) in concert with the regulation of steroid hormone production. DNA methylation has been implicated in a large number of biological processes mainly by regulating gene expression. The SR-BI promoter contains one CpG island (CGI) in its promoter and seven CGIs in its intronic regions. Here, we studied the DNA methylation status of SR-BI gene and provide evidence that the DNA methylation is cell specific in this gene promoter as well as in intronic regions. The DNA methylation in the SR-BI promoter is subject to N(6), 2'-O dibutyryladenosine3':5'-cyclic monophosphate regulation in mouse adrenal Y1 cells and mouse Leydig tumor cells (MLTCs). The seven intron CGIs are methylated differentially in Y1 cells, MLTCs, ovarian granulosa cells, and mouse liver hepa 1-6 cells. Our experiments raised the possibility that DNA methylation participates in hormonal regulation of SR-BI expression in a tissue-specific manner. We further suggest that the cell-specific DNA methylation in SR-BI intronic regions may be associated with specific biological function(s) of these regions, including regulation of gene expression. PMID- 26981686 TI - ALTERNATE FOOD-CHAIN TRANSFER OF THE TOXIN LINKED TO AVIAN VACUOLAR MYELINOPATHY AND IMPLICATIONS FOR THE ENDANGERED FLORIDA SNAIL KITE (ROSTRHAMUS SOCIABILIS). AB - Avian vacuolar myelinopathy (AVM) is a neurologic disease causing recurrent mortality of Bald Eagles ( Haliaeetus leucocephalus ) and American Coots ( Fulica americana ) at reservoirs and small impoundments in the southern US. Since 1994, AVM is considered the cause of death for over 170 Bald Eagles and thousands of American Coots and other species of wild birds. Previous studies link the disease to an uncharacterized toxin produced by a recently described cyanobacterium, Aetokthonos hydrillicola gen. et sp. nov. that grows epiphytically on submerged aquatic vegetation (SAV). The toxin accumulates, likely in the gastrointestinal tract of waterbirds that consume SAV, and birds of prey are exposed when feeding on the moribund waterbirds. Aetokthonos hydrillicola has been identified in all reservoirs where AVM deaths have occurred and was identified growing abundantly on an exotic SAV hydrilla ( Hydrilla verticillata ) in Lake Tohopekaliga (Toho) in central Florida. Toho supports a breeding population of a federally endangered raptor, the Florida Snail Kite ( Rostrhamus sociabilis ) and a dense infestation of an exotic herbivorous aquatic snail, the island applesnail ( Pomacea maculata ), a primary source of food for resident Snail Kites. We investigated the potential for transmission in a new food chain and, in laboratory feeding trials, confirmed that the AVM toxin was present in the hydrilla/A. hydrillicola matrix collected from Toho. Additionally, laboratory birds that were fed apple snails feeding on hydrilla/A. hydrillicola material from a confirmed AVM site displayed clinical signs (3/5), and all five developed brain lesions unique to AVM. This documentation of AVM toxin in central Florida and the demonstration of AVM toxin transfer through invertebrates indicate a significant risk to the already diminished population of endangered Snail Kites. PMID- 26981687 TI - Demodicosis in Chamois ( Rupicapra rupicapra subsp. rupicapra) in the Italian Alps, 2013-14. AB - We report demodicosis in five alpine chamois ( Rupicapra rupicapra subsp. rupicapra) from the Italian Alps that showed moderate crusts on the head and dorsal aspect of the trunk. We detected intramural folliculitis, moderate dermatitis, and T-lymphocytes and macrophages associated with Demodex spp. in follicles and sebaceous glands. PMID- 26981688 TI - Occurrence of Prosthenorchis elegans in Free-living Primates from the Atlantic Forest of Southern Bahia, Brazil. AB - Parasite prevalence and abundance are important factors affecting species' conservation. During necropsies on a free-living golden-headed lion tamarin ( Leontopithecus chrysomelas ) and two Wied's marmosets ( Callithrix kuhlii ) in the Atlantic Forest of southern Bahia, Brazil, we collected a large number of adult intestinal parasites that we identified as Prosthenorchis elegans. This parasite is pathogenic for neotropical primates. Prosthenorchis spp. infestation is influenced by diet with increased risk of exposure from ingesting invertebrate intermediate hosts. The biological similarities and sympatric nature of these two nonhuman primates support that they may harbor similar infectious and parasitic agents. PMID- 26981689 TI - Osseous Metaplasia in a Free-living Snake (Patagonian Green Racer; Philodryas patagoniensis) in Brazil, 2012. AB - We describe an osseous metaplasia in a wild Patagonian green racer (Philodryas patagoniensis). The 5.5*1.5-cm lesion of irregular contour on the right dorsolateral surface proximal to the snake's cloaca was raised, hard, ulcerated centrally, and radiopaque and interfered with mobility. Microscopy revealed osseous metaplasia on skin and muscle. PMID- 26981690 TI - Chlamydia pecorum Infection in Free-ranging Koalas ( Phascolarctos cinereus ) on French Island, Victoria, Australia. AB - We detected Chlamydia pecorum in two koalas ( Phascolarctos cinereus ) from a closed island population in Victoria, Australia, previously free of Chlamydia infection. The ompA and multilocus sequence type were most closely related to published isolates of livestock rather than koala origin, suggesting potential cross-species transmission of C. pecorum . PMID- 26981691 TI - Toxoplasmosis May Lead to Road Kills of Persian Leopards ( Panthera pardus saxicolor) in Golestan National Park, Iran. AB - Three Persian leopards ( Panthera pardus saxicolor) that died from car accidents in Golestan National Park, Iran, were tested for Toxoplasma gondii and rabies virus infection. Acute T. gondii infection was diagnosed in two Persian leopards; no rabies virus was detected. Acute toxoplasmosis may be a factor in Persian leopard road kills. PMID- 26981692 TI - SUSCEPTIBILITY AND ANTIBODY RESPONSE OF VESPER SPARROWS (POOECETES GRAMINEUS) TO WEST NILE VIRUS: A POTENTIAL AMPLIFICATION HOST IN SAGEBRUSH-GRASSLAND HABITAT. AB - West Nile virus (WNV) spread to the US western plains states in 2003, when a significant mortality event attributed to WNV occurred in Greater Sage-grouse ( Centrocercus urophasianus ). The role of avian species inhabiting sagebrush in the amplification of WNV in arid and semiarid regions of the North America is unknown. We conducted an experimental WNV challenge study in Vesper Sparrows ( Pooecetes gramineus ), a species common to sagebrush and grassland habitats found throughout much of North America. We found Vesper Sparrows to be moderately susceptible to WNV, developing viremia considered sufficient to transmit WNV to feeding mosquitoes, but the majority of birds were capable of surviving infection and developing a humoral immune response to the WNV nonstructural 1 and envelope proteins. Despite clearance of viremia, after 6 mo, WNV was detected molecularly in three birds and cultured from one bird. Surviving Vesper Sparrows were resistant to reinfection 6 mo after the initial challenge. Vesper sparrows could play a role in the amplification of WNV in sagebrush habitat and other areas of their range, but rapid clearance of WNV may limit their importance as competent amplification hosts of WNV. PMID- 26981693 TI - SURVEY FOR WEST NILE VIRUS ANTIBODIES IN WILD DUCKS, 2004-06, USA. AB - Detection of West Nile virus (WNV) in ducks has been reported in North America in isolated cases of mortality in wild waterbirds and following outbreaks in farmed ducks. Although the virus has been noted as an apparent incidental finding in several species of ducks, little is known about the prevalence of exposure or the outcome of infection with WNV in wild ducks in North America. From 2004-06, we collected sera from 1,406 wild-caught American Wigeon ( Anas americana ), Mallard ( Anas platyrhynchos ), and Northern Pintail ( Anas acuta ) ducks at national wildlife refuges (NWRs) in North Dakota and Wood Ducks ( Aix sponsa ) at NWRs in South Carolina and Tennessee. We measured the prevalence of previous exposure to WNV in these ducks by measuring WNV antibodies and evaluated variation in exposure among species, age, and year. Additionally, we evaluated the performance of a commercial antibody to wild bird immunoglobulin in duck species that varied in their phylogenetic relatedness to the bird species the antibody was directed against. As determined by a screening immunoassay and a confirmatory plaque reduction neutralization assay, the prevalence of WNV antibody was 10%. In light of experimental studies that show ducks to be relatively resistant to mortality caused by WNV, the antibody prevalence we detected suggests that wild ducks may be less-frequently exposed to WNV than expected for birds inhabiting wetlands where they may acquire infection from mosquitoes. PMID- 26981696 TI - Editor's message. PMID- 26981697 TI - The multisystem adverse effects of NSAID therapy. AB - The clinical utility of nonsteroidal anti-inflammatory drugs (NSAlDs) to manage pain and inflammation is limited by adverse side effects. Although effective analgesic and anti-inflammatory agents, NSAlDs are associated with side effects that are a consequence of nonspecific inhibition of both cyclooxygenase-1 (COX-1) and 1 cyclooxygenase-2 (COX-2).The primary adverse events associated with NSAID therapy are upper gastrointestinal (GI) ulceration, perforation, or bleeding, all of which involve mucosal damage of varying severity and can be asymptomatic and I occur with little warning. Clinicians who prescribe NSAIDs should be able to identify patients who are at risk of an NSAID-induced GI adverse event and to detect and manage the event should one occur. The use of COX-2-specific inhibitors to manage pain and inflammation may minimize the risks of NSAID associated toxicities. PMID- 26981695 TI - Genomic Organization Under Different Environmental Conditions: Hoplosternum Littorale as a Model. AB - The Amazon has abundant rivers, streams, and floodplains in both polluted and nonpolluted environments, which show great adaptability. Thus, the goal of this study was to map repetitive DNA sequences in both mitotic chromosomes and erythrocyte micronuclei of tamoatas from polluted and nonpolluted environments and to assess the possible genotoxic effects of these environments. Individuals were collected in Manaus, Amazonas (AM), and submitted to classical and molecular cytogenetic techniques, as well as to a blood micronucleus test. Diploid number equal to 60 chromosomes are present in all individuals, with 18S ribosomal DNA sites present in one chromosome pair and no interstitial telomeric sites on chromosomes. The micronucleus test showed no significant differences in pairwise comparisons between environments or collection sites, but the Rex3 retroelement was dispersed on the chromosomes of individuals from unpolluted environments and compartmentalized in individuals from polluted environments. Divergent numbers of 5S rDNA sites are present in individuals from unpolluted and polluted environments. The mapping of repetitive sequences revealed that micronuclei have different compositions both intra- and interindividually that suggests different regions are lost in the formation of micronuclei, and no single fragile region undergoes breaks, although repetitive DNA elements are involved in this process. PMID- 26981698 TI - Celecoxib for the treatment of pain and inflammation: the preclinical and clinical results. AB - Inflammation and pain, the principal signs and symptoms of arthritis along with swelling and stiffness, are routinely controlled by treatment with a nonsteroidal antiinflammatory drug (NSAID). Celecoxib, an anti-inflammatory and analgesic agent indicated for the treatment of osteoarthritis and rheumatoid arthritis, is the first cyclooxygenase (COX) inhibitor with well-defined cyclooxygenase-2 (COX 2) specificity. Preclinical studies of celecoxib in vitro and in vivo support the COX-2 hypothesis that the therapeutic effects of NSAIDs are due to the inhibition of COX-2, and the adverse events associated with NSAID therapy are due to the inhibition of cyclooxygenase-I (COX-I), the constitutively expressed isoform of COX. Clinical trials in patients with osteoarthritis or rheumatoid arthritis found that the efficacy of celecoxib is superior to that of placebo and comparable to that of naproxen, a conventional NSAID. Clinical studies also found celecoxib to be safe and well tolerated, with no evidence of alteration in platelet aggregation or gastrointestinal ulceration. PMID- 26981699 TI - COX-2--specific inhibition: Implications for clinical practice. AB - Although conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have long been a major therapeutic choice for the management of arthritic conditions, the potential adverse effects of these agents sometimes compromise their clinical utility. New modes of therapy have recently been introduced, and data on the cyclooxygenase-2 (COX-2)-specific inhibitors celecoxib and rofecoxib suggest that these agents will meet the need for safe and effective therapeutic alternatives to conventional NSAIDs. PMID- 26981700 TI - CME QUIZ. PMID- 26981701 TI - COX-1 and COX-2 in health and disease. AB - Nearly 30 years ago, cyclooxygenase (COX) was identified as an enzyme that initiates the biotransformation of arachidonic acid to prostanoids. It is now known that COX exists as two distinct but similar isozymes, COX-l and COX-2. Prostaglandins (PGs) formed by the enzymatic activity of COX-l are primarily involved in the regulation of homeostatic functions throughout the body, whereas PGs formed by COX-2 primarily mediate pain and inflammation. Based on structural differences in the active sites of COX-l and COX-2, a new class of drugs has been developed that specifically inhibits COX-2 but not COX-l activity. By preserving the synthesis of homeostatic PGs, these specific inhibitors of COX-2 provide the clinical benefits of nonsteroidal anti-inflammatory drugs and minimize the consequences of nonspecific inhibition of PG synthesis. PMID- 26981703 TI - Pathology and diagnosis of necrotic enteritis: is it clear-cut? AB - The ability to correctly recognize the disease necrotic enteritis (NE) is important not only to those involved in control and treatment of the disease at farm level, but it is also critically important to the search for virulence factors, since a fundamental part of that process is the correct assignation of strains of Clostridium perfringens with respect to virulence. Thus, diagnosticians and investigators need to be able to correctly recognize the lesions of NE. To do this, they must be able to distinguish NE lesions from (1) other enteric diseases such as coccidiosis or viral enteritis, (2) normal features of the intestine, such as the small raised, sometimes red, foci that represent gut-associated lymphoid tissue, (3) autolytic change which may be mistaken for lesions, especially at the microscopical level, by the inexperienced. Errors in diagnosis of NE due to C. perfringens or failure to culture affected areas in which the bacteria of interest with respect to NE are definitively found, might explain some of the early apparently conflicting results with respect to the role of netB in NE. This paper describes at the gross, microscopical and bacteriological level, important features of the intestine of normal poultry and those with NE due to C. perfringens, as well as the common interpretative pitfalls that can lead both to underdiagnosis and overdiagnosis of NE, and to incorrect determination of the virulence of individual C. perfringens strains. PMID- 26981702 TI - Metacognitive Confidence Increases with, but Does Not Determine, Visual Perceptual Learning. AB - While perceptual learning increases objective sensitivity, the effects on the constant interaction of the process of perception and its metacognitive evaluation have been rarely investigated. Visual perception has been described as a process of probabilistic inference featuring metacognitive evaluations of choice certainty. For visual motion perception in healthy, naive human subjects here we show that perceptual sensitivity and confidence in it increased with training. The metacognitive sensitivity-estimated from certainty ratings by a bias-free signal detection theoretic approach-in contrast, did not. Concomitant 3Hz transcranial alternating current stimulation (tACS) was applied in compliance with previous findings on effective high-low cross-frequency coupling subserving signal detection. While perceptual accuracy and confidence in it improved with training, there were no statistically significant tACS effects. Neither metacognitive sensitivity in distinguishing between their own correct and incorrect stimulus classifications, nor decision confidence itself determined the subjects' visual perceptual learning. Improvements of objective performance and the metacognitive confidence in it were rather determined by the perceptual sensitivity at the outset of the experiment. Post-decision certainty in visual perceptual learning was neither independent of objective performance, nor requisite for changes in sensitivity, but rather covaried with objective performance. The exact functional role of metacognitive confidence in human visual perception has yet to be determined. PMID- 26981704 TI - A comparison between surgical risk scores for predicting outcome in patients undergoing transcatheter aortic valve implantation. AB - BACKGROUND: Surgical risk scoring systems are of modest value in predicting outcome following transcatheter aortic valve implantation (TAVI). There is no consensus as to which scoring system is the most useful. We examined the efficacy of all four currently available global scorings systems (Additive EuroScore [aES], Logistic EuroScore [LES], EuroScore II [ES II], Society of Thoracic Surgeons [STS] Score) in predicting outcome, both in the short (30 day) and longer term, in patients undergoing TAVI. METHODS: Additive EuroScore (aES), Logistic EuroScore (LES), EuroScore II (ES II), and Society of Thoracic Surgeons (STS) score were assessed in 312 consecutive TAVI patients. Mortality tracking was obtained from the Office of National Statistics as of May 2014. RESULTS: Mean age was 81.2+/-7.0 years; 53.2% were male. Mean aES, LES, ESII and STS were 9.7+/ 1.9, 17.4+/-9.4, 6.1+/-4.3 and 4.6+/-2.8, respectively. Thirty-day mortality was 4.8%; long-term mortality (maximum 5.8 years, mean 2.2+/-1.5 years) was 25.3%. Using both univariate and multivariate modelling all four scoring systems failed to predict outcomes in the short term. In the longer term, univariable analysis demonstrated that higher aES and LES scores were associated with higher mortality (aES P=0.0048, LES P=0.054, respectively). After multivariable analysis, only higher aES remained significant. CONCLUSIONS: Surgical risk scores are poor at predicting outcomes in patients undergoing TAVI, particularly in the short term. PMID- 26981706 TI - The perceived impact of stuttering on personality as measured by the NEO-FFI-3. AB - The NEO-FFI has been widely used to demonstrate personality differences between people who stutter (PWS) and those who do not. These differences can be interpreted as indicators of internal sources of disability that contribute to handicaps associated with stuttering. The aim of the current study was to use this same tool to determine the perceived impact of stuttering on personality in order to provide a similar indicator of how external factors may contribute to the stuttering disability. A total of 49 non-stuttering young adults were given the NEO-FFI-3 after watching a video of someone stuttering (moderately to severely) and after watching a video of someone speaking fluently. Participants were asked to answer test items while imagining that they had spoken like the persons in the videos for their entire lives. When asked to assume the stuttering perspective, participants reported themselves to be significantly more neurotic (P < 0.01) and less extraverted (P < 0.01) than when they assumed the perspective of the fluent speaker. The large differences (~10 points; greater than one standard deviation) in these domains between the fluent and stuttered perspectives are consistent with existing stereotypes about PWS. These differences are greater than and only partially consistent with differences in personality found between PWS and non-stuttering individuals. The findings support the notion that external factors (e.g. listener reactions and stereotypes about PWS) contribute strongly to the manner in which stuttering restricts function and results in handicaps. PMID- 26981707 TI - Whole Genome Sequence Analysis of Pig Respiratory Bacterial Pathogens with Elevated Minimum Inhibitory Concentrations for Macrolides. AB - Macrolides are often used to treat and control bacterial pathogens causing respiratory disease in pigs. This study analyzed the whole genome sequences of one clinical isolate of Actinobacillus pleuropneumoniae, Haemophilus parasuis, Pasteurella multocida, and Bordetella bronchiseptica, all isolated from Australian pigs to identify the mechanism underlying the elevated minimum inhibitory concentrations (MICs) for erythromycin, tilmicosin, or tulathromycin. The H. parasuis assembled genome had a nucleotide transition at position 2059 (A to G) in the six copies of the 23S rRNA gene. This mutation has previously been associated with macrolide resistance but this is the first reported mechanism associated with elevated macrolide MICs in H. parasuis. There was no known macrolide resistance mechanism identified in the other three bacterial genomes. However, strA and sul2, aminoglycoside and sulfonamide resistance genes, respectively, were detected in one contiguous sequence (contig 1) of A. pleuropneumoniae assembled genome. This contig was identical to plasmids previously identified in Pasteurellaceae. This study has provided one possible explanation of elevated MICs to macrolides in H. parasuis. Further studies are necessary to clarify the mechanism causing the unexplained macrolide resistance in other Australian pig respiratory pathogens including the role of efflux systems, which were detected in all analyzed genomes. PMID- 26981708 TI - Transmission of Middle East Respiratory Syndrome Coronavirus Infections in Healthcare Settings, Abu Dhabi. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) infections sharply increased in the Arabian Peninsula during spring 2014. In Abu Dhabi, United Arab Emirates, these infections occurred primarily among healthcare workers and patients. To identify and describe epidemiologic and clinical characteristics of persons with healthcare-associated infection, we reviewed laboratory-confirmed MERS-CoV cases reported to the Health Authority of Abu Dhabi during January 1, 2013-May 9, 2014. Of 65 case-patients identified with MERS-CoV infection, 27 (42%) had healthcare-associated cases. Epidemiologic and genetic sequencing findings suggest that 3 healthcare clusters of MERS-CoV infection occurred, including 1 that resulted in 20 infected persons in 1 hospital. MERS-CoV in healthcare settings spread predominantly before MERS-CoV infection was diagnosed, underscoring the importance of increasing awareness and infection control measures at first points of entry to healthcare facilities. PMID- 26981709 TI - Utilizing the Experience of Consumers in Consultation to Develop the Australasian Oncofertility Consortium Charter. AB - PURPOSE: In Australia and New Zealand, there has not been a national systematic development of oncofertility services for cancer patients of reproductive age although many cancer and fertility centers have independently developed services. A number of barriers exist to the development of these services, including a lack of clear referral pathways, a lack of communication between clinicians and patients about fertility preservation, differences in the knowledge base of clinicians about the risk of cancer treatment causing infertility and fertility preservation options, a lack of national health insurance funding covering all aspects of fertility preservation, and storage costs and cultural, religious, and ethical barriers. The development of strategies to overcome these barriers is a high priority for oncofertility care to ensure that equitable access to the best standard of care is available for all patients. METHOD: The FUTuRE Fertility Research Group led a collaborative consultation process with the Australasian Oncofertility Consumer group and oncofertility specialists to explore consumers' experiences of oncofertility care. Consumers participated in qualitative focus group meetings to define and develop a model of consumer driven or informed "gold standard oncofertility care" with the aim of putting together a Charter that specifically described this. CONCLUSIONS: The finalized Australasian Oncofertility Consortium Charter documents eight key elements of gold standard oncofertility care that will be used to monitor the implementation of oncofertility services nationally, to ensure that these key elements are incorporated into standard practice over time. PMID- 26981710 TI - The impact of spatial arrangements on epidemic disease dynamics and intervention strategies. AB - The role of spatial arrangements on the spread and management strategies of a cholera epidemic is investigated. We consider the effect of human and pathogen movement on optimal vaccination strategies. A metapopulation model is used, incorporating a susceptible-infected-recovered system of differential equations coupled with an equation modelling the concentration of Vibrio cholerae in an aquatic reservoir. The model compared spatial arrangements and varying scenarios to draw conclusions on how to effectively manage outbreaks. The work is motivated by the 2010 cholera outbreak in Haiti. Results give guidance for vaccination strategies in response to an outbreak. PMID- 26981712 TI - L-Tetrahydropalmatine alleviates mechanical hyperalgesia in models of chronic inflammatory and neuropathic pain in mice. AB - Chronic pain is categorized as inflammatory and neuropathic, and there are common mechanisms underlying the generation of each pain state. Such pain is difficult to treat and the treatment at present is inadequate. Corydalis yanhusuo is a traditional Chinese medicine with demonstrated analgesic efficacy in humans. The potential antihyperalgesic effect of its active component is L tetrahydropalmatine (L-THP). L-THP has been used for the treatment of headache and other mild pain. However, little is known about its analgesic effect on chronic pain and its mechanism. Here, we report that L-THP exerts remarkable antihyperalgesic effects on neuropathic and inflammatory pain in animal models. Neuropathic hypersensitivity was induced by segmental spinal nerve ligation and inflammatory hypersensitivity was induced by an intraplantar injection of complete Freund's adjuvant. To determine the receptor mechanism underlying the antihyperalgesic actions of L-THP, we used SCH23390, an antagonist of a dopamine D1 receptor, in an attempt to block the antihyperalgesic effects of L-THP. We found that L-THP (1-4 mg/kg, i.p.) produced a dose-dependent antihyperalgesic effect in spinal nerve ligation and complete Freund's adjuvant models. The antihyperalgesic effects of L-THP were abolished by a dopamine D1 receptor antagonist SCH23390 (0.02 mg/kg). Furthermore, L-THP (4 mg/kg, i.p.) did not influence motor function. These findings suggest that L-THP may ameliorate mechanical hyperalgesia by enhancing dopamine D1 receptor-mediated dopaminergic transmission. PMID- 26981711 TI - Comparative outcomes of active and passive hearing devices by transcutaneous bone conduction. AB - Conclusion Bonebridge (BB) and Sophono (SP) devices improved hearing; with the BB implant showing a better performance at medium and high frequencies. Furthermore, the BB, as an active implant, showed higher functional gain and increased time of use, when compared to the SP, a passive system. Objectives This study aims to compare surgical and audiological outcomes of SP and BB devices in order to assess and further differentiate the indication criteria. Methods Fourteen patients with conductive and mixed hearing loss were evaluated pre- and post operatively (BB or SP) (period 2013-2014). Age, gender, surgical history, cause and type of hearing loss, implant use per day, levels of bone and air conduction, and functional gain were recorded. Data was analysed by Wilcoxon singed-rank and Wilcoxon rank-sum tests. Results Fourteen patients (BB; n = 10 and SP; n = 4) with an average age = 25.42 years (CI95 = 12.41-38.43) were evaluated. The gender relation was equal (1:1), with pre-implantation osseous thresholds of 20.42 dB (CI95 = 11.15-29.69), and pre-implantation aerial thresholds of 70.83 dB (CI95 = 62.52-79.14). The SP wearing time was significantly lower than that of the BB (SP = 7-10 h/day, BB = 8-12 h/day; p = 0.0323). The functional gain did not differ significantly between the two devices (BB = 40.00 +/- 13.19 dB, SP = 34.06 +/- 15.63 dB; p = 0.3434), but a significant improvement from pre- to post implantation was observed (p < 0.05). BB and SP decreased auditory thresholds at 1 and 2 kHz (< 0.01), respectively. The BB even significantly decreased thresholds at 0.5 kHz (p = 0.0140) and 4 kHz (p < 0.0001). No relevant surgical complications were found. PMID- 26981713 TI - Proton magnetic resonance spectroscopy as a diagnostic biomarker in mild cognitive impairment following stroke in acute phase. AB - To investigate proton magnetic resonance spectroscopy (HMRS) as a diagnostic biomarker to identify mild cognitive impairment (MCI) following stroke in the acute phase. A total of 72 stroke patients were recruited in the acute phase of stroke from the Department of Neurology, including 36 stroke patients with MCI and 36 stroke patients without MCI. All patients underwent brain MRI/MRS examination on a 3.0 T scanner and a neuropsychological test in the acute phase of stroke. Single-voxel HMRS was performed to obtain hippocampal metabolism intensities and brain infarcts were assessed on MRI. Group difference in metabolite ratios was analyzed using a T-test. Spearman rank correlation was used to study the correlation between metabolite ratios and Montreal Cognitive Assessment scores. The hippocampal n-acetylaspartate/creatine (NAA/Cr) ratio was found to be significantly lower in stroke patients with MCI compared with stroke patients without MCI (P<0.02). However, we found no differences in the metabolite ratios between hippocampus ipsilateral to infarctions and the contralateral side (P>0.05) in stroke patients with MCI. Furthermore, a correlation was found between hippocampal NAA/Cr ratios and Montreal Cognitive Assessment scores in stroke patients with MCI (P<0.01). HMRS could be a biomarker to identify MCI following stroke in the acute phase by capturing neurodegenerative changes. PMID- 26981715 TI - Structural and Energetic Characterization of Prebiotic Molecules: The Case Study of Formamide and Its Dimer. AB - State-of-the-art quantum-chemical computations have been employed to determine the accurate equilibrium structure of formamide and its symmetric dimer as well as the interaction energy of the latter, thus extending available reference data for the peptide (also denoted as amide) bond and the hydrogen-bond interaction that characterizes peptides and proteins. Equilibrium geometries and electronic energies have been evaluated by means of a composite scheme based on coupled cluster calculations, including up to triple excitations, which also accounts for extrapolation to the complete basis set limit and core-correlation effects. This approach provides molecular structures with an accuracy of 0.001-0.002 A and 0.05 0.1 degrees for bond lengths and angles, respectively, and relative energies with an accuracy of about 1-2 kJ/mol. PMID- 26981714 TI - Evidence of altered corticomotor excitability following targeted activation of gluteus maximus training in healthy individuals. AB - It has been proposed that strengthening and skill training of gluteus maximus (GM) may be beneficial in treating various knee injuries. Given the redundancy of the hip musculature and the small representational area of GM in the primary motor cortex (M1), learning to activate this muscle before prescribing strength exercises and modifying movement strategy would appear to be important. This study aimed to determine whether a short-term activation training program targeting the GM results in neuroplastic changes in M1. Using transcranial magnetic stimulation, motor evoked potentials (MEPs) were obtained in 12 healthy individuals at different stimulation intensities while they performed a double leg bridge. Participants then completed a home exercise program for ~1 h/day for 6 days that consisted of a single exercise designed to selectively target the GM. Baseline and post-training input-output curves (IOCs) were generated by graphing average MEP amplitudes and cortical silent period durations against corresponding stimulation intensities. Following the GM activation training, the linear slope of both the MEP IOC and cortical silent period IOC increased significantly. Short term GM activation training resulted in a significant increase in corticomotor excitability as well as changes in inhibitory processes of the GM. We propose that the observed corticomotor plasticity will enable better utilization of the GM in the more advanced stages of a rehabilitation/training program. PMID- 26981716 TI - Turnover of hydrogen isotopes in lake sturgeon blood: implications for tracking movements of wild populations. AB - Naturally occurring deuterium ((2)H) in biota can be used to trace movement, migration and geographic origin of a range of organisms. However, to evaluate movements of animals using delta(2)H measurements of tissues, it is necessary to establish the turnover time of (2)H in the tissues and the extent of isotopic discrimination from different environmental (2)H sources to those tissues. We investigated the turnover of (2)H in lake sturgeon (Acipenser fulvescens) blood by manipulating both environmental water delta(2)H and diet delta(2)H over a four month period. The half-life of deuterium in lake sturgeon blood was 37.9 days after an increase in the environmental water delta(2)H of +714 0/00. However, no clear turnover in blood (2)H occurred over the same period in a separate trial following a change of -63.8 0/00 or +94.2 0/00 in diet. These findings suggest that environmental water (2)H exchanges much faster with blood than diets and that blood delta(2)H values can be used to trace movements of sturgeon and other fish moving among isotopically distinct waters. PMID- 26981718 TI - Prevention of Thyroidectomy Scars in Asian Adults With Low-Level Light Therapy. AB - BACKGROUND: Abnormal wound-healing after thyroidectomy with a resulting scar is a common dermatologic consultation. Despite many medical and surgical approaches, prevention of postoperative scars is challenging. OBJECTIVE: This study validated the efficacy and safety of low-level light therapy (LLLT) using an 830/590 nm light-emitting diode (LED)-based device for prevention of thyroidectomy scars. METHODS AND MATERIALS: Thirty-five patients with linear surgical suture lines after thyroidectomy were treated with 830/590 nm LED-LLLT. Daily application of 60 J/cm (11 minutes) for 1 week starting on postoperative day 1 was followed by treatment 3 times per week for 3 additional weeks. The control group (n = 15) remained untreated. Scar-prevention effects were evaluated 1 and 3 months after thyroidectomy with colorimetric evaluation using a tristimulus-color analyzer. The Vancouver Scar Scale (VSS) score, global assessment, and a subjective satisfaction score (range: 1-4) were also determined. RESULTS: Lightness (L*) and chrome values (a*) decreased significantly at the 3-month follow-up visit in the treatment group compared with those of controls. The average VSS and GAS scores were lower in the treatment group, whereas the subjective score was not significantly different. CONCLUSION: Light-emitting diode based LLLT treatment suppressed the formation of scars after thyroidectomy and could be safely used without noticeable adverse effects. PMID- 26981719 TI - Treating Filler Related Visual Loss. PMID- 26981720 TI - Changes in Saphenous Vein Stump and Low Incidence of Endovenous Heat-Induced Thrombosis After Radiofrequency Ablation of Great Saphenous Vein Incompetence. AB - BACKGROUND: Relationship between the distance of the catheter tip from the saphenous femoral junction and the length of residual stump after radiofrequency ablation (RFA) has not been sufficiently examined. OBJECTIVE: The purpose of this study was to investigate the change of great saphenous vein (GSV) stump with clinical outcomes after RFA. MATERIAL AND METHODS: From January 2014 to September 2014, 67 patients (91 limbs) underwent GSV RFA and the collected data were analyzed prospectively. Change of GSV stump length and clinical symptoms was evaluated at 1-, 3-, and 6-month intervals. Ablations were performed between 2 to 2.5 cm distal to the saphenofemoral junction. RESULTS: The residual GSV stump decreased in length to 1.465 +/- 0.504 cm at the first month follow-up. This length persisted throughout the 1-, 3-, and 6-month follow-ups. There were no statistically significant differences during the follow-up period. Both the Venous Clinical Severity Score and the Aberdeen Varicose Vein Symptom Severity Score was significantly improved at 1 month and improved even further at 3 months. One patient (1.1%) developed endovenous heat-induced thrombosis (EHIT) Class 3 at 1-month follow-up and was treated with anticoagulation. CONCLUSION: This study has shown that the adequate positioning of RFA catheter tip (2.0-2.5 cm) is recommended to decrease the incidence of EHIT. PMID- 26981721 TI - Absence of Koebnerization Following Ablative and Nonablative Laser Therapy in Patients With Plaque Psoriasis. AB - BACKGROUND: The adverse effects of laser procedures performed in patients with psoriasis have not been reported to date. OBJECTIVE: The authors report the incidence of koebnerization in patients with psoriasis who underwent laser treatment with different devices over the past 12 years. MATERIALS AND METHODS: The medical records of 38 patients with psoriasis treated with laser therapy were reviewed. Patient characteristics, including duration and severity of psoriasis, baseline psoriasis treatment, laser modality and settings, facial areas treated, and number of sessions, were collected. The primary outcome of interest was incidence of koebnerization. RESULTS: None of the 38 patients with psoriasis treated with laser therapy experienced subsequent koebnerization. Seven patients were on oral systemic medications, 14 were on biologic agents, and 3 were on combination therapy. None of the patients experienced skin infections, delayed healing, or scarring, irrespective of their psoriasis therapy. CONCLUSION: Koebnerization did not occur on the face, neck, or scalp of patients with psoriasis who underwent laser therapy, irrespective of psoriasis severity or types of psoriasis medications they were receiving. Although these results are encouraging, the risk of koebnerization should be discussed with patients with psoriasis who wish to undergo laser procedures. PMID- 26981722 TI - Vitiligo Involving the Nipple and Areola: A Good Indication for Epidermal Grafting. PMID- 26981723 TI - A Rethink on Hyaluronidase Injection, Intraarterial Injection, and Blindness: Is There Another Option for Treatment of Retinal Artery Embolism Caused by Intraarterial Injection of Hyaluronic Acid? PMID- 26981725 TI - Urban health and well-being. PMID- 26981726 TI - The rise of the urbanite. PMID- 26981727 TI - Mobility: The urban downshift. PMID- 26981728 TI - Flooding: Water potential. PMID- 26981724 TI - Micelle Mixtures for Coadministration of Gemcitabine and GDC-0449 To Treat Pancreatic Cancer. AB - Hedgehog (Hh) signaling plays an important role in the development and metastasis of pancreatic ductal adenocarcinoma (PDAC). Although gemcitabine (GEM) has been used as a first-line therapy for PDAC, its rapid metabolism and short plasma half life restrict its use as a single chemotherapy. Combination therapy with more than one drug is a promising approach for treating cancer. Herein, we report the use of methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate)-graft-dodecanol (mPEG-b-PCC-g-DC) copolymer for conjugating GEM and encapsulating a Hh inhibitor, vismodegib (GDC-0449), into its hydrophobic core for treating PDAC. Our objective was to determine whether the micelle mixtures of these two drugs could show better response in inhibiting Hh signaling pathway and restraining the proliferation and metastasis of pancreatic cancer. The in vivo stability of GEM significantly increased after conjugation, which resulted in its increased antitumor efficacy. Almost 80% of encapsulated GDC-0449 and 19% conjugated GEM were released in vitro at pH 5.5 in 48 h in a sustained manner. The invasion, migration, and colony forming features of MIA PaCa-2 cells were significantly inhibited by micelle mixture carrying GEM and GDC-0449. Remarkable increase in PARP cleavage and Bax proved increased apoptosis by this combination formulation compared to individual micelles. This combination therapy efficiently inhibited tumor growth, increased apoptosis, reduced Hh ligands PTCH-1 and Gli-1, and lowered EMT-activator ZEB-1 when injected to athymic nude mice bearing subcutaneous tumor generated using MIA PaCa-2 cells compared to monotherapy as observed from immunohistochemical analysis. In conclusion, micelle mixtures carrying GEM and GDC-0449 have the potential to treat pancreatic cancer. PMID- 26981729 TI - Green space: A natural high. PMID- 26981730 TI - Stress: The privilege of health. PMID- 26981731 TI - Perspective: City farming needs monitoring. PMID- 26981732 TI - Disease: Poverty and pathogens. PMID- 26981733 TI - Policy: Urban physics. PMID- 26981735 TI - Distinctive Pattern of Adipophilin Expression in Necrobiotic Xanthogranuloma. PMID- 26981734 TI - Nonmelanoma Skin Cancer With Aggressive Subclinical Extension in Immunosuppressed Patients. AB - IMPORTANCE: Immunosuppression (IS), such as in solid-organ transplant recipients (SOTRs) and patients with human immunodeficiency virus (HIV) or hematologic malignant neoplasms, increases the risk of developing nonmelanoma skin cancers (NMSCs). However, it is unknown whether IS patients are at increased risk of developing NMSCs with aggressive subclinical extensions (NMSC-ASE), which may extend aggressively far beyond conventional surgical margins. OBJECTIVE: To study clinical characteristics of NMSC-ASE among immunocompetent (IC) and various subgroups of IS patients and to suggest a predictive model for NMSC-ASE lesions. DESIGN, SETTING, AND PARTICIPANTS: A 6-year retrospective review of 2998 NMSC cases between February 26, 2007, and February 17, 2012, at the Dermatologic and Mohs Micrographic Surgery Unit of the University of California, San Diego, Medical Center. Nonmelanoma skin cancers that required at least 3 Mohs micrographic surgery stages with final surgical margins of at least 10 mm were defined as ASE lesions. All cases were categorized into 1 of 2 groups, IS or IC. Immunosuppressed cases were further subcategorized into 3 subgroups: SOTRs and patients with HIV or hematologic malignant neoplasm. The data were analyzed in December 2012. MAIN OUTCOMES AND MEASURES: We evaluated the odds ratio of having NMSC-ASE lesions in IS patients (SOTRs, HIV, hematologic malignant neoplasm) compared with IC patients. Other clinical characteristics and preoperative risks were analyzed and compared. RESULTS: Of all 2998 cases, we identified 805 NMSC ASE cases: 137 IS and 668 IC. Immunosuppressed patients had an odds ratio of 1.94 of having ASE lesions compared with IC patients (95% CI, 1.54-2.44; P < .001). Additionally, the SOTR subgroup was associated with a 2.74 odds of having NSMC ASE compared with non-SOTRs (95% CI, 2.00-3.76; P < .001), and the presence of hematologic malignant neoplasm was associated with 1.74 times the odds compared with IC patients (95% CI, 1.04-2.90; P = .04). Multivariate analysis found older age (P < .001), lesion locations such as zone 1 (OR, 1.39 [95% CI, 1.04-1.85]; P = .02) or zone 2 (OR, 1.45 [95% CI, 1.08-1.94]; P = .01), and IS status (OR, 1.94 [95% CI, 1.54-2.44]; P < .001) to be significant predictors of ASE. CONCLUSIONS AND RELEVANCE: The findings of this study suggest an increased risk for NMSC-ASE lesions in IS patients, especially in SOTRs and those with hematologic malignant neoplasm, but not patients with HIV. Statistically significant predictors of NMSC ASE lesions such as age, location, and IS status can help physicians choose the most appropriate treatment modalities and optimize surgical planning. PMID- 26981736 TI - Gunshot Entry Wound of the Skin. PMID- 26981737 TI - Actinic Prurigo Cheilitis: A Clinicopathologic Review of 75 Cases. AB - Actinic prurigo (AP) is a chronic idiopathic photodermatosis that primarily affects American Indians in the United States and Mestizos in Latin American countries. Clinically, the onset of the disease is usually in the first decade of life but may appear initially in adult life, and it is characterized by symmetric involvement of sun-exposed areas of the skin, particularly areas of the face, resulting in polymorphic erythematous papules, macules, and plaques in different stages of evolution. Lower lip involvement includes swelling, scaling, fissures, hyperpigmentation, and ulcerations of the vermilion border. and in some cases could represent the only manifestation of the disease. The histopathologic features of AP have been studied; however, there is a controversy regarding whether AP cheilitis has distinct histopathologic features that could allow accurate separation from other specific and nonspecific forms of cheilitis. The diagnosis can be challenging, mainly when lip lesions are the only manifestation of the disease. In this study, the authors investigate the clinicopathologic features of 75 cases of AP cheilitis to provide further criteria for its diagnosis and classification. All 75 patients presented with lip lesions. Thirty three cases were diagnosed as AP cheilitis with cutaneous lesions and 42 cases were diagnosed as AP cheilitis without cutaneous lesions (only lip lesions). Histologically, of the 33 cases with AP cheilitis with cutaneous lesions, 17 (52%) cases showed follicular cheilitis, and of the 42 cases that had only lip lesions, 18 (43%) cases showed follicular cheilitis. Histologically, AP cheilitis can present as follicular cheilitis; thus, supporting the diagnosis. Also, our findings confirm that lip lesions can present as the only manifestation of the disease, showing typical histological and clinical features. This form of cheilitis has not being well described in the dermatologic and dermatopathologic literature. PMID- 26981738 TI - A Primary Cutaneous CD30-Positive T-Cell Lymphoproliferative Disorder Arising in a Patient With Multiple Myeloma and Cutaneous Amyloidosis. AB - CD30-positive cutaneous lymphoproliferative disorders, a group of T-cell neoplasms, including lymphomatoid papulosis (LyP) and cutaneous anaplastic large cell lymphoma, require careful clinicopathologic correlation for diagnosis. An association between LyP and the development of a second hematolymphoid malignancy has been established in the literature. LyP has also been reported with systemic amyloidosis, but no such reports have documented coexisting cutaneous amyloid deposition with LyP to our knowledge. A 66-year-old woman with cutaneous amyloidosis, secondary to multiple myeloma, in remission, presented with erythematous and dark-brown papules involving the right arm, scalp, and torso. Punch biopsy of the arm showed a dermal infiltrate of intermediate-sized lymphocytes, some of which displayed a plasmacytoid morphology and prominent nodular subepidermal amyloid deposition. Punch biopsy of the scalp similarly showed a nonepidermotropic dense dermal infiltrate of intermediate-sized plasmacytoid lymphocytes and multifocal amyloid deposition. Both infiltrates were immunophenotypically CD30-positive, anaplastic lymphoma kinase-negative T-cell lymphoproliferative processes. Subsequent studies showed no systemic involvement, and clinical correlation suggested a final diagnosis of LyP. We present this case of LyP, which histologically mimics a B-cell proliferation with a plasmacytoid morphology arising in association with cutaneous amyloidosis to highlight the importance of clinicopathologic correlation, a thorough battery of immunohistochemical studies, and consideration for a second hematologic malignancy arising in the setting of LyP. PMID- 26981739 TI - Cutaneous Adenomyoepithelioma: Report of a Case and Review of the Literature. AB - Adenomyoepithelioma (AME) is a biphasic neoplasm of epithelial and myoepithelial cells. It is most commonly found in the breast, although rare cases have been reported from the lung, salivary glands, and skin. There are 5 well-documented cases of cutaneous AME in the literature. We report a new case of cutaneous AME. Our case was commingled with apocrine hidrocystoma. This is the first report of cutaneous AME in a male patient and the first to describe SOX10 immunostaining in cutaneous AME. We review the literature on cutaneous AME and note the greater than chance colocalization with other adnexal tumors. We speculate that AME may represent localized overgrowth of myoepithelial cells within a pre-existent sweat gland tumor. Histopathologists should be aware of the potential of SOX10-positive myoepithelial neoplasms to mimic nodular melanocytic proliferations. PMID- 26981740 TI - An Unusual Association of Adult T-Cell Leukemia/Lymphoma With Hyalohyphomycosis. AB - Infection by human T-cell lymphotropic virus (HTLV-1) causes deregulation of the immune system, which makes the infected individuals more susceptible to infectious diseases. Immune deregulation is even more pronounced in HTLV-1 carriers with adult T-cell leukemia/lymphoma (ATLL), which results in frequent opportunistic infections. Hyalohyphomycosis is a rare subcutaneous mycosis which is more commonly associated with immunocompromised patients. We report a case of a HTLV-1-infected man with skin tumors, inguinal lymphadenomegaly, and lymphocytosis. Histopathological examination of skin biopsies revealed a T-cell lymphoma intermingled with a granulomatous process with abscesses and hyaline septated hyphae. The lymph node showed only a T-cell lymphoma. The patient was diagnosed with acute ATLL and hyalohyphomycosis. He was treated with itraconazole for the subcutaneous mycosis and with chemotherapy for ATLL. A few months later, despite the treatment, he died because of progression of ATLL. PMID- 26981741 TI - "Secretory" Carcinoma of the Skin Mimicking Secretory Carcinoma of the Breast: Case Report and Literature Review. AB - Secretory carcinoma is a unique kind of adenocarcinoma. It has distinct histological features and a special genetic change, that is, t (12; 15) (p13; q25) translocation which leads to the expression of the ETV6-NTRK3 fusion gene. Secretory carcinoma has been found to occur both in the breast and salivary gland. Here the authors present a case of 22-year-old woman with a unique cutaneous neoplasm located at the axilla. The tumor was characterized histologically with the formation of round to ovoid microcysts and papillary structure, which was similar to the secretory carcinoma of the breast and salivary gland. Furthermore, the gene sequence analysis of reverse-transcription polymerase chain reaction products demonstrated the expression of the ETV6-NTRK3 fusion gene. To the authors' knowledge, this is the first case of secretory carcinoma from the skin which has the same genetic change as those from the breast and salivary gland. Local excision was performed on this patient. She had been followed up for nearly 1 year. No recurrence or metastasis was found yet. PMID- 26981742 TI - Symplastic Pilar Leiomyoma: Description of a Rare Entity. PMID- 26981743 TI - Direct Immunofluorescence Findings in Discoid Lupus Erythematosus and Bullous Pemphigoid. PMID- 26981745 TI - Ultrasonographic characteristics of volar-lateral ligament constrains after proximal interphalangeal joint injuries. AB - Objective To characterise posttraumatic constrains of the volar-lateral ligaments by analysing volar plate (VP) dynamics after proximal interphalangeal (PIP) joint injuries using ultrasonography. Materials and methods From the anatomical and biomechanical perspectives of the VP and its surrounding structures, posttraumatic constrains of the volar-lateral ligament were evaluated by analysing the changes of VP motion. Using ultrasound, VP motion during active flexion of 0-60 degrees was recorded in the central sagittal plane at 12 weeks after injury. VP trajectories visualised by 5-point tracing on the VP were analysed qualitatively to detect differential patterns of the ligament constrains. Quantitatively, correlation between averaged constrain index determined by measuring volar locational values of the 5 points on the VP and limitation in extension at the final follow-up was assessed. Results Eleven patients with PIP joint injuries involving five VP avulsions, three volar intra articular fractures, or three dorsal fracture-dislocations were included. All patients with VP avulsion revealed a totally-constrained pattern, whereas patients with intra-articular or fracture-dislocation injuries showed distally constrained pattern or normal. Averaged constrain index was negatively correlated with limitation in extension, indicating positive contribution of volar-lateral ligament constrains to residual flexion contracture. Conclusion Ultrasonographic visualisation of VP motion characterised posttraumatic constrained conditions of the volar-lateral ligaments. Knowledge of the manner of ligament damages might be useful to set treatment strategies for PIP joint injuries. PMID- 26981744 TI - Novel conformation-specific monoclonal antibodies against amyloidogenic forms of transthyretin. AB - INTRODUCTION: Transthyretin amyloidosis (ATTR amyloidosis) is caused by the misfolding and deposition of the transthyretin (TTR) protein and results in progressive multi-organ dysfunction. TTR epitopes exposed by dissociation and misfolding are targets for immunotherapeutic antibodies. We developed and characterized antibodies that selectively bound to misfolded, non-native conformations of TTR. METHODS: Antibody clones were generated by immunizing mice with an antigenic peptide comprising a cryptotope within the TTR sequence and screened for specific binding to non-native TTR conformations, suppression of in vitro TTR fibrillogenesis, promotion of antibody-dependent phagocytic uptake of mis-folded TTR and specific immunolabeling of ATTR amyloidosis patient-derived tissue. RESULTS: Four identified monoclonal antibodies were characterized. These antibodies selectively bound the target epitope on monomeric and non-native misfolded forms of TTR and strongly suppressed TTR fibril formation in vitro. These antibodies bound fluorescently tagged aggregated TTR, targeting it for phagocytic uptake by macrophage THP-1 cells, and amyloid-positive TTR deposits in heart tissue from patients with ATTR amyloidosis, but did not bind to other types of amyloid deposits or normal tissue. CONCLUSIONS: Conformation-specific anti-TTR antibodies selectively bind amyloidogenic but not native TTR. These novel antibodies may be therapeutically useful in preventing deposition and promoting clearance of TTR amyloid and in diagnosing TTR amyloidosis. PMID- 26981747 TI - Many-Electron Integrals over Gaussian Basis Functions. I. Recurrence Relations for Three-Electron Integrals. AB - Explicitly correlated F12 methods are becoming the first choice for high-accuracy molecular orbital calculations and can often achieve chemical accuracy with relatively small Gaussian basis sets. In most calculations, the many three- and four-electron integrals that formally appear in the theory are avoided through judicious use of resolutions of the identity (RI). However, for the intrinsic accuracy of the F12 wave function to not be jeopardized, the associated RI auxiliary basis set must be large. Here, inspired by the Head-Gordon-Pople and PRISM algorithms for two-electron integrals, we present an algorithm to directly compute three-electron integrals over Gaussian basis functions and a very general class of three-electron operators without invoking RI approximations. A general methodology to derive vertical, transfer, and horizontal recurrence relations is also presented. PMID- 26981746 TI - 1,3-Dipolar Cycloadditions of Diazo Compounds in the Presence of Azides. AB - The diazo group has untapped utility in chemical biology. The tolerance of stabilized diazo groups to cellular metabolism is comparable to that of azido groups. However, chemoselectivity has been elusive, as both groups undergo 1,3 dipolar cycloadditions with strained alkynes. Removing strain and tuning dipolarophile electronics yields diazo group selective 1,3-dipolar cycloadditions that can be performed in the presence of an azido group. For example, diazoacetamide but not its azido congener react with dehydroalanine residues, as in the natural product nisin. PMID- 26981748 TI - Is advising food allergic patients to avoid food with precautionary allergen labelling out of date? AB - PURPOSE OF REVIEW: Precautionary allergen labelling (PAL) continues to be used by the food manufacturing industry to alert the food allergic consumer that cross contact may have occurred during the supply chain for ingredients or the manufacturing process. This review will summarize recent evidence regarding use and interpretation of precautionary labels by industry, healthcare professionals, and food allergic consumers. Consumers find precautionary labels difficult to interpret and often distrust them as disclaimers of product liability. It is unclear from a clinician's perspective how healthcare professionals should advise their patients regarding these statements. RECENT FINDINGS: Recent studies suggest that consumers do not always read food labels and that these labels are difficult to interpret and are often distrusted by consumers as disclaimers of liability. There is evidence to suggest that this behaviour occurs in all countries assessed that use PAL. The healthcare professional remains confused about the interpretation and value of the current PAL system as it is unclear whether foods that contain no advisory labels are safe to consume. There is a need for improvement in the value and use of precautionary labelling for allergen risk assessment for allergic consumers. SUMMARY: New studies have shown the confusion that currently exists in regard to PAL for the healthcare professional and the consumer alike. The studies have also highlighted certain gaps in the literature that, once addressed, will improve the uniformity of PAL and provide the healthcare professional with appropriate advice which they can in turn relay to the allergic consumer. Because of the global supply of food products there is a need for an international approach in improving PAL. PMID- 26981749 TI - Parental influence on children's answers to an oral-health-related quality of life questionnaire. AB - The aim of the study was to evaluate parental influence on children's answers to an oral health-related quality of life (OHRQoL) questionnaire. A cross-sectional study was conducted with a non-probabilistic sample of 84 pairs of 5-year-olds and parents/guardians. The participants were selected from a primary family healthcare center in Campina Grande, Brazil. First, the children and parents answered respective versions of the Scale of Oral Health Outcomes for Five-Year Old Children (SOHO-5). Seven days later, the children answered their version of the SOHO-5, without the presence of their parents/guardians, and underwent a clinical exam of dental caries, traumatic dental injury and malocclusion, by a previously calibrated researcher. Statistical analysis involved a comparison of mean scores and the calculation of the intraclass correlation coefficient (ICC). Poisson regression models were used to associate the variables (alpha = 5%). No significant differences were found between the mean SOHO-5 scores of the children when alone or accompanied by parents/guardians (p > 0.05). The ICC between the answers of the children alone or accompanied was 0.84. White spot (PR = 6.32; 95%CI: 1.36 - 29.40) and cavitated lesions (PR = 9.81; 95%CI: 3.22 - 29.85) had an impact on OHRQoL, according to the children's self-report, whereas cavitated lesions (PR = 90.52; 95%CI: 13.26 - 617.74) and anterior open bite (PR = 1.95; 95%IC: 1.07 - 3.53) remained on the final model, according to the parents' version of the SOHO-5. In conclusion, parents did not influence the children's responses, and dental caries are the oral health problem exerting the greatest impact on the children's OHRQoL. PMID- 26981750 TI - Micro-CT evaluation of the radioprotective effect of resveratrol on the mandibular incisors of irradiated rats. AB - The purpose of this study was to perform a microcomputed tomographic evaluation of the radioprotective effect of resveratrol on the volume of mandibular incisors of irradiated rats. A second aim was to make a quantitative assessment of the effect of x-ray exposure on these dental tissues. Twenty adult male rats were divided into four groups: control, irradiated control, resveratrol, and irradiated resveratrol. The resveratrol groups received 100 mg/kg of resveratrol, whereas the irradiated groups were exposed to 15 Gy of irradiation. The animals were sacrificed 30 days after the irradiation procedure, and their mandibles were removed and scanned in a microcomputed tomography unit. The images were loaded into Mimics software to allow segmentation of the mandibular incisor and assessment of its volume. The results were compared by One-way ANOVA and Tukey's post hoc test, considering a 5% significance level. The irradiated groups showed significantly diminished volumes of the evaluated teeth, as compared with the control group (p < 0.05). The resveratrol group presented higher values than those of the irradiated groups, and volumes similar to those of the control group. High radiation doses significantly affected tooth formation, resulting in alterations in the dental structure, and thus lower volumes. Moreover, resveratrol showed no effective radioprotective impact on dental tissues. Future studies are needed to evaluate different concentrations of this substance, in an endeavor to verify its potential as a radioprotector for these dental tissues. PMID- 26981751 TI - Tomographic evaluation of the temporomandibular joint in malocclusion subjects: condylar morphology and position. AB - The aim of this study was to investigate condyle concentricity and morphology, and their association with Class I and II malocclusions (Angle). The sample consisted of 49 individuals of both genders, between 11 and 35 years old, divided into two groups, G1: 26 patients with Class I malocclusion, and G2: 23 patients with Class II malocclusion, selected for orthodontic treatment. Evaluation of the condyle morphology and position was performed by the same previously calibrated examiner using cone-beam computed tomography (CBCT) images of the subjects. The CBCT scans were analyzed by means of a 3D program (Dolphin 11.5, Dolphin Imaging & Management Solutions, Chatsworth, CA, USA), with a 25% level of sensitivity. The images obtained from the coronal slices were employed for the condyle morphology analysis, which classified the condyle form as rounded, as flat or convex, and as triangular or angled. The sagittal slices were used to classify further the condyles as concentric and displaced anteriorly or posteriorly. A clinical examination was also performed, including TMJ and muscle palpation. The kappa test was used to evaluate investigator calibration; the Chi-square and paired t-tests were used for analysis. The convex and anteriorly positioned condyles were found most frequently, regardless of the type of malocclusion. No association was observed between the groups regarding condylar characteristics. PMID- 26981752 TI - LPS levels in root canals after the use of ozone gas and high frequency electrical pulses. AB - The present study aims to verify the effect of ozone gas (OZY(r) System) and high frequency electric pulse (Endox(r) System) systems on human root canals previously contaminated with Escherichia colilipopolysaccharide (LPS). Fifty single-rooted teeth had their dental crowns removed and root lengths standardized to 16 mm. The root canals were prepared up to #60 hand K-files and sterilized using gamma radiation with cobalt 60. The specimens were divided into the following five groups (n = 10) based on the disinfection protocol used: OZY(r) System, one 120-second-pulse (OZY 1p); OZY(r) System, four 24-second-pulses (OZY 4p); and Endox(r) System (ENDOX). Contaminated and non-contaminated canals were exposed only to apyrogenic water and used as positive (C+) and negative (C-) controls, respectively. LPS (O55:B55) was administered in all root canals except those belonging to group C-. After performing disinfection, LPS samples were collected from the canals using apyrogenic paper tips. Limulus Amoebocyte Lysate (LAL) was used to quantify the LPS levels, and the data obtained was analyzed using one-way ANOVA. The disinfection protocols used were unable to reduce the LPS levels significantly (p = 0.019). The use of ozone gas and high frequency electric pulses was not effective in eliminating LPS from the root canals. PMID- 26981754 TI - Mixed biofilms formed by C. albicans and non-albicans species: a study of microbial interactions. AB - Most Candida infections are related to microbial biofilms often formed by the association of different species. The objective of this study was to evaluate the interactions between Candida albicans and non-albicans species in biofilms formed in vitro. The non-albicans species studied were:Candida tropicalis, Candida glabrata and Candida krusei. Single and mixed biofilms (formed by clinical isolates of C. albicans and non-albicans species) were developed from standardized suspensions of each strain (10(7) cells/mL), on flat-bottom 96-well microtiter plates for 48 hour. These biofilms were analyzed by counting colony forming units (CFU/mL) in Candida HiChrome agar and by determining cell viability, using the XTT 2,3-bis (2-methoxy-4-nitro-5-sulphophenyl)-5 [(phenylamino) carbonyl]-2H-tetrazolium hydroxide colorimetric assay. The results for both the CFU/mL count and the XTT colorimetric assay showed that all the species studied were capable of forming high levels of in vitro biofilm. The number of CFU/mL and the metabolic activity of C. albicans were reduced in mixed biofilms with non-albicans species, as compared with a single C. albicans biofilm. Among the species tested, C. krusei exerted the highest inhibitory action against C. albicans. In conclusion, C. albicans established antagonistic interactions with non-albicans Candida species in mixed biofilms. PMID- 26981753 TI - Medium modification with bone morphogenetic protein 2 addition for odontogenic differentiation. AB - The aim of this study was to evaluate whether medium modification improves the odontogenic differentiation of human dental pulp stem cells (DPSC) in vitro and in vivo. DPSC isolated from human impacted third molar teeth were analysed for clusters of differentiation with flow cytometry. Odontogenic differentiation was stimulated by medium modification with the addition of bone morphogenetic protein 2 (BMP2). The expression of dentin sialophosphoprotein, dentin matrix protein 1, enamelysin/matrix metalloproteinase 20 and the phosphate-regulating gene with homologies to endopeptidases on the X chromosome of the cells were analysed with RT-PCR at 7, 14 and 21 days. Then, DPSC were transplanted on the back of immunocompromised mice via a hydroxyapatite tricalcium phosphate scaffold, and the structure of the formed tissue was investigated. The cells were identified as mesenchymal stem cells with a 98.3% CD73 and CD90 double-positive cell rate. The increase in mineralization capacity and expression of human enamel-dentin specific transcripts proportional to the culture period were determined after differentiation. Six weeks after transplantation, an osteo-dentin matrix was formed in the group in which odontogenic differentiation was stimulated, and the odontogenic characteristics of the matrix were confirmed by histological examination and RT-PCR analysis. Odontogenic differentiation of the isolated and characterized human DPSC was improved with medium modification by the addition of BMP2 in vitro and in vivo. The defined medium and applied technique have a potential use for forming reparative dentin in the future, but the effects of the method should be investigated in long-term studies. PMID- 26981755 TI - Cytotoxic effects of new MTA-based cement formulations on fibroblast-like MDPL-20 cells. AB - The present study aimed at evaluating the cytotoxic effects of a novel cement called CER on periodontal fibroblast-like cells of mice (MDPL-20), in comparison with different formulations of Mineral Trioxide Aggregate (MTA), by means of the cell viability test (MTT) and cell morphology analysis. Thirty-two round-shaped samples were fabricated with the following cements: white MTA, white and gray CER and experimental white MTA. The samples were immersed in serum-free culture medium for 24 hours or 7 days (n = 16). The extracts (culture medium + components released from the cements) were applied for 24 hours to previously cultured cells (40.000 cells/cm2) in the wells of 24-well plates. Cells seeded in complete culture medium were used as a negative control. Cell viability was assessed using the MTT assay. Two samples of each cement were used for cell morphology analysis by Scanning Electron Microscopy (SEM). The extracts obtained at the 7-day period presented higher cytotoxicity compared with the 24-hour period (p < 0.05). The gray CER obtained at 24 hours presented the highest cytotoxic effect, whereas the experimental white MTA presented the lowest, similar to the control (p > 0.05). However, at the 7-day period, the experimental white MTA presented no significant difference in comparison with the other cements (p > 0.05). At the 7-day period, CER cement presented cytotoxic effects on fibroblast-like cells, similar to different MTA formulations. However, the immersion period in the culture medium influenced the cytotoxicity of the cements, which was greater for CER cement at 24 hours. PMID- 26981756 TI - Antiseptics and microcosm biofilm formation on titanium surfaces. AB - Oral rehabilitation with osseointegrated implants is a way to restore esthetics and masticatory function in edentulous patients, but bacterial colonization around the implants may lead to mucositis or peri-implantitis and consequent implant loss. Peri-implantitis is the main complication of oral rehabilitation with dental implants and, therefore, it is necessary to take into account the potential effects of antiseptics such as chlorhexidine (CHX), chloramine T (CHT), triclosan (TRI), and essential oils (EO) on bacterial adhesion and on biofilm formation. To assess the action of these substances, we used the microcosm technique, in which the oral environment and periodontal conditions are simulated in vitro on titanium discs with different surface treatments (smooth surface - SS, acid-etched smooth surface - AESS, sand-blasted surface - SBS, and sand blasted and acid-etched surface - SBAES). Roughness measurements yielded the following results: SS: 0.47 um, AESS: 0.43 um, SB: 0.79 um, and SBAES: 0.72 um. There was statistical difference only between SBS and AESS. There was no statistical difference among antiseptic treatments. However, EO and CHT showed lower bacterial counts compared with the saline solution treatment (control group). Thus, the current gold standard (CHX) did not outperform CHT and EO, which were efficient in reducing the biofilm biomass compared with saline solution. PMID- 26981758 TI - Combined effect of end-rounded versus tapered bristles and a dentifrice on plaque removal and gingival abrasion. AB - Two previous clinical studies evaluated the effect of end-rounded versus tapered bristles of soft manual brushes on the removal of plaque and gingival abrasion. However, the combined effect of an abrasive dentifrice on these outcomes has yet to be understood. The purpose of the present study was to compare the incidence of gingival abrasion and the degree of plaque removal obtained after the use of toothbrushes with tapered or end-rounded bristles in the presence or absence of an abrasive dentifrice. The study involved a randomized, single-blind, crossover model (n = 39) with a split-mouth design. Subjects were instructed to refrain from performing oral hygiene procedures for 72 hours. Quadrants were randomized and subjects brushed with both types of toothbrushes using a dentifrice (relative dentin abrasion = +/- 160). Plaque and gingival abrasion were assessed before and after brushing. After 7 days, the experiment was repeated without the dentifrice. The average reduction in plaque scores and the average increase in the number of abrasion sites were assessed by repeated-measures ANOVA and Bonferroni's post-hoc tests. End-rounded bristles removed significantly more plaque than tapered bristles, regardless of the use of a dentifrice. The dentifrice did not improve plaque removal. In the marginal area (cervical free gingiva), no difference in the incidence of gingival abrasion was detected between toothbrush types when used with a dentifrice (p >= 0.05). However, the dentifrice increased the incidence of abrasion (p < 0.001), irrespective of the toothbrush type tested. End-rounded bristles therefore removed plaque more effectively without causing a higher incidence of gingival abrasion when compared with tapered bristles. An abrasive dentifrice can increase the incidence of abrasion, and should be used with caution by individuals who are at risk of developing gingival recession. PMID- 26981757 TI - Does a toothpaste containing blue covarine have any effect on bleached teeth? An in vitro, randomized and blinded study. AB - The objective of this study was to analyze the effect of bleaching toothpastes, both conventional and those containing the new whitening agent Blue Covarine, on teeth previously bleached by conventional techniques (in-office and at-home). Squared bovine enamel/dentin blocks (6.0 x 6.0 x 2.0 mm) were randomly distributed in 6 groups (n = 15), according to the technique used to bleach them (in-office: HP35%; at-home: PC10%) and the type of bleaching toothpaste (none: control; Blue Covarine containing: BC; and without Blue Covarine: NBC). Experimental groups denominated HP35%, HP35%BC and HP35%NBC received in-office tooth bleaching before toothbrushing, and groups PC10%, PC10%BC and PC10%NBC were subjected to at-home tooth bleaching prior to toothbrushing. After bleaching treatment, groups HP35%BC, PC10%BC, HP35%NBC and PC10%NBC underwent daily tooth brushing in a brushing machine for 3 minutes (150 strokes/min, with a load of 375 g). Tooth color alteration was measured by reflectance spectroscopy (Vita EasyShade, Vident, Brea, CA, USA) at: T0 (baseline) - after in-office or at-home bleaching treatment; T1 - immediately after tooth brushing; T2 - 7 days and T3 - 14 days after tooth brushing. Data was analyzed by repeated measures mixed ANOVA and the Bonferroni post hoc test, with a significance level of 5%. Statistically significant differences were found between different experimental groups, evaluation times and for the interaction between them (p < 0.001). Tooth brushing using either bleaching toothpaste (conventional or with Blue Covarine) showed no color alteration on teeth previously bleached by in-office and at-home tooth bleaching. The use of bleaching toothpastes on previously bleached teeth did not produce a color alteration. PMID- 26981760 TI - Effects of different torque levels on the implant-abutment interface in a conical internal connection. AB - The fit of the implant-abutment interface was assessed by the metallographic technique and by scanning electron microscopy (SEM), using solid abutment types at different torque levels. Forty Morse taper connections and forty solid abutments were used at different torque levels (repeated after 10 minutes) in the following groups (n = 10): 25 Ncm (group g1), 30 Ncm (group g2), 35 Ncm (group g3), and 40 Ncm (group g4). The samples were embedded in a metallographic resin, sectioned lengthwise, and polished. SEM images were used to measure the linear contacts and the fits between abutments and the internal walls of the implant. The overall mean gap and standard deviation were as follows: 9.0 +/- 1.36 um for group g1, 7.9 +/- 2.81 um for group g2, 2.0 +/- 0.76 um for group g3, and 0.3 +/- 0.40 um for group g4. A significant difference was observed in the average fit values between the groups (p < 0.05). The linear area of contact between the abutment and the implant increased as torque augmented. This study demonstrated that higher insertion torque values in a conical internal connection increase the fit (contact) of the implant-abutment interface. PMID- 26981759 TI - Antimicrobial action of calcium hydroxide-based endodontic sealers after setting, against E. faecalis biofilm. AB - Enterococcus faecalis are gram positive bacteria that can mostly resist endodontic therapy, inducing persistent infection in the root canal system. Endodontic sealers with antimicrobial activity may help eliminate residual microorganisms that survive endodontic treatment. The present study aimed at comparing the antimicrobial activity of Acroseal, Sealapex and AH Plus endodontic sealers in an in vitro biofilm model. Bovine dentin specimens (144) were prepared, and twelve blocks for each sealer and each experimental time point (2, 7 and 14 days) were placed and left in contact with plates containing inoculum of E. faecalis (ATCC 51299), to induce biofilm formation. After 14 days, the samples were transferred to another plate with test sealers and kept at 37 degrees C and 5% CO2 for 2, 7 and 14 days. The specimens without sealers were used as a control for each period. The samples were agitated in a sonicator after each experiment. The suspensions were agitated in a vortex mixer, serially diluted in saline, and triple plated onto m-Enterococcus agar. Colonyforming units were counted, and the data were statistically analyzed using ANOVA, Shapiro-Wilk and Kruskal-Wallis one way tests (p < 0.05) to determine antimicrobial potential. Sealapex showed significant differences at all the experimental time points, in comparison with all the other groups. AH Plus and Acroseal showed antimicrobial activity only on the 14th experimental day. Neither of the sealers tested were able to completely eliminate the biofilm. Sealapex showed the highest antimicrobial activity in all the experimental periods. The antimicrobial activity of all the sealers analyzed increased over time. PMID- 26981761 TI - Zika virus infection spread through saliva--a truth or myth? AB - In this Point-of-view article we highlighted some features related to saliva and virus infection, in special for zika virus. In addition, we pointed out the potential oral problems caused by a microcephaly originated by a zika virus infection. In the end the, we demonstrated the importance of a more comprehensive exploration of saliva and their components as a fluid for diagnostic and therapeutic approaches on oral and systemic diseases. PMID- 26981763 TI - Domain-specific interference between storage and processing in complex span is driven by cognitive and motor operations. AB - The role of domain-specific interference in the complex-span paradigm is still controversial. Here we distinguish two operations within the processing task of this paradigm-a cognitive operation to solve the task and a motor operation to give the answer. Their domain-specific interference with maintenance was investigated within the complex-span paradigm. Presentation of the memoranda-six words or four spatially distributed dots-was interleaved with the presentation of letter pairs to be processed. Cognitive operation domain was manipulated by asking participants to make either a rhyme judgment or a symmetry judgment for each letter pair. Motor operation domain was varied by requiring a response by either speaking or pointing. Cognitive load was held constant. Cognitive and motor operation showed separate domain-specific effects on memory: Visuospatial memory was impaired more by visuospatial than verbal cognitive operations and more by manual-spatial than oral motor operations. In contrast, verbal memory performance was worse when verbal cognitive operations and oral motor operations were executed. The results are discussed in relation to the multicomponent model, the time-based resource-sharing (TBRS) model, and the Serial Order in a Box Complex-Span (SOB-CS) model. They imply that models of working memory must incorporate mechanisms that allow for domain-specific interference in the verbal and the visuospatial domain. PMID- 26981762 TI - Novel Infection Site and Ecology of Cryptic Didymocystis sp. (Trematoda) in the Fish Scomberomorus maculatus. AB - An undescribed, cryptic species of Didymocystis, as determined from sequences of 2 ribosomal genes and superficially similar to Didymocystis scomberomori ( MacCallum and MacCallum, 1916 ), infected the skin of the Spanish mackerel, Scomberomorus maculatus , in the north-central Gulf of Mexico (GOM). An analysis of 558 fish from 2011 to 2013 from Louisiana, Mississippi, Alabama, and the Florida panhandle showed the prevalence of the trematode varied both spatially and temporally but not with sex of the fish host. Month, year, and geographic location were identified by a negative binomial generalized linear model as indicators of the abundance and intensity of infection. Prevalence, abundance, and intensity of infection were greatest in spring and fall months off the Florida panhandle. Furthermore, the abundance and intensity of infection correlated negatively with fork length, weight, and gonad weight of mature fish but positively with longitude. Therefore, smaller adult fish tended to be more infected than larger adults, and prevalence and intensity increased from west to east (Louisiana to Florida). Spatial and temporal trends seemed to result from physical factors (e.g., water temperature, salinity, bottom type), but they also coincided with the annual migration of S. maculatus as fish moved northward along the GOM coastline from the southern tip of Florida in the spring months and returned in the fall, being present in the north-central GOM from late spring through fall. This pattern suggests the possibility that acquisition of infections occurred from a molluscan host in waters off the Florida panhandle. PMID- 26981764 TI - Ratio of cystatin C and creatinine-based estimates of the glomerular filtration rate predicts mortality in healthy seniors independent of kidney function. PMID- 26981765 TI - Temporal changes in extracellular polymeric substances on hydrophobic and hydrophilic membrane surfaces in a submerged membrane bioreactor. AB - Membrane surface hydrophilic modification has always been considered to mitigating biofouling in membrane bioreactors (MBRs). Four hollow-fiber ultrafiltration membranes (pore sizes ~0.1 MUm) differing only in hydrophobic or hydrophilic surface characteristics were operated at a permeate flux of 10 L/m(2) h in the same lab-scale MBR fed with synthetic wastewater. In addition, identical membrane modules without permeate production (0 L/m(2) h) were operated in the same lab-scale MBR. Membrane modules were autopsied after 1, 10, 20 and 30 days of MBR operation, and total extracellular polymeric substances (EPS) accumulated on the membranes were extracted and characterized in detail using several analytical tools, including conventional colorimetric tests (Lowry and Dubois), liquid chromatography with organic carbon detection (LC-OCD), fluorescence excitation - emission matrices (FEEM), fourier transform infrared (FTIR) and confocal laser scanning microscope (CLSM). The transmembrane pressure (TMP) quickly stabilized with higher values for the hydrophobic membranes than hydrophilic ones. The sulfonated polysulfone (SPSU) membrane had the highest negatively charged membrane surface, accumulated the least amount of foulants and displayed the lowest TMP. The same type of organic foulants developed with time on the four membranes and the composition of biopolymers shifted from protein dominance at early stages of filtration (day 1) towards polysaccharides dominance during later stages of MBR filtration. Nonmetric multidimensional scaling of LC OCD data showed that biofilm samples clustered according to the sampling event (time) regardless of the membrane surface chemistry (hydrophobic or hydrophilic) or operating mode (with or without permeate flux). These results suggest that EPS composition may not be the dominant parameter for evaluating membrane performance and possibly other parameters such as biofilm thickness, porosity, compactness and structure should be considered in future studies for evaluating the development and impact of biofouling on membrane performance. PMID- 26981766 TI - Enabling and Probing Oxidative Addition and Reductive Elimination at a Group 14 Metal Center: Cleavage and Functionalization of E-H Bonds by a Bis(boryl)stannylene. AB - By employing strongly sigma-donating boryl ancillary ligands, the oxidative addition of H2 to a single site Sn(II) system has been achieved for the first time, generating (boryl)2SnH2. Similar chemistry can also be achieved for protic and hydridic E-H bonds (N-H/O-H, Si-H/B-H, respectively). In the case of ammonia (and water, albeit more slowly), E-H oxidative addition can be shown to be followed by reductive elimination to give an N- (or O-)borylated product. Thus, in stoichiometric fashion, redox-based bond cleavage/formation is demonstrated for a single main group metal center at room temperature. From a mechanistic viewpoint, a two-step coordination/proton transfer process for N-H activation is shown to be viable through the isolation of species of the types Sn(boryl)2.NH3 and [Sn(boryl)2(NH2)](-) and their onward conversion to the formal oxidative addition product Sn(boryl)2(H)(NH2). PMID- 26981767 TI - Prenatal and Postnatal Clinical Course of an Urachus Identified as an Allantoic Cyst in the Umbilical Cord. AB - PURPOSE: The aim of this study was to clarify the prenatal and postnatal clinical courses of an urachus identified as an allantoic cyst in the umbilical cord. METHODS: Allantoic cysts in the umbilical cord were identified in five fetuses over the past 12 years at our hospital. The prenatal and postnatal clinical courses of these patients were retrospectively reviewed. RESULTS: The presence of allantoic cysts in the umbilical cord was first detected at 15 to 27 weeks of gestation. The cysts subsequently became enlarged, reaching a maximum diameter of 34 to 61 mm at 17 to 32 weeks of gestation. The cysts then suddenly disappeared due to spontaneous rupture at 26 to 35 weeks of gestation. After being born at 38 (35-39) weeks of gestation, four patients were diagnosed with a patent urachus requiring surgery in the infantile period and one was diagnosed with an urachal cyst, which is currently being observed without surgery. CONCLUSION: The presence of an urachus identified as an allantoic cyst in the umbilical cord is frequently associated with spontaneous rupture during the prenatal period, resulting in a patent urachus after birth that requires surgical intervention. PMID- 26981769 TI - Sequestration of host metabolism by an intracellular pathogen. AB - For intracellular pathogens, residence in a vacuole provides a shelter against cytosolic host defense to the cost of limited access to nutrients. The human pathogen Chlamydia trachomatis grows in a glycogen-rich vacuole. How this large polymer accumulates there is unknown. We reveal that host glycogen stores shift to the vacuole through two pathways: bulk uptake from the cytoplasmic pool, and de novo synthesis. We provide evidence that bacterial glycogen metabolism enzymes are secreted into the vacuole lumen through type 3 secretion. Our data bring strong support to the following scenario: bacteria co-opt the host transporter SLC35D2 to import UDP-glucose into the vacuole, where it serves as substrate for de novo glycogen synthesis, through a remarkable adaptation of the bacterial glycogen synthase. Based on these findings we propose that parasitophorous vacuoles not only offer protection but also provide a microorganism-controlled metabolically active compartment essential for redirecting host resources to the pathogens. PMID- 26981768 TI - The human SKA complex drives the metaphase-anaphase cell cycle transition by recruiting protein phosphatase 1 to kinetochores. AB - The spindle- and kinetochore-associated (Ska) complex is essential for normal anaphase onset in mitosis. The C-terminal domain (CTD) of Ska1 binds microtubules and was proposed to facilitate kinetochore movement on depolymerizing spindle microtubules. Here, we show that Ska complex recruits protein phosphatase 1 (PP1) to kinetochores. This recruitment requires the Ska1 CTD, which binds PP1 in vitro and in human HeLa cells. Ska1 lacking its CTD fused to a PP1-binding peptide or fused directly to PP1 rescues mitotic defects caused by Ska1 depletion. Ska1 fusion to catalytically dead PP1 mutant does not rescue and shows dominant negative effects. Thus, the Ska complex, specifically the Ska1 CTD, recruits PP1 to kinetochores to oppose spindle checkpoint signaling kinases and promote anaphase onset. Microtubule binding by Ska, rather than acting in force production for chromosome movement, may instead serve to promote PP1 recruitment to kinetochores fully attached to spindle microtubules at metaphase. PMID- 26981771 TI - Two new compounds from the fruits of Arctium lappa. AB - Phytochemical investigation of the extract of Arctii Fructus led to the isolation and characterization of two new compounds, named arctiisesquineolignan B (1) and arctiiphenolglycoside A (2). Their structures were elucidated by means of spectroscopic methods (UV, IR, HR-ESI-MS, 1D and 2D NMR) and chemical evidence, as well as by comparison with known analogs in the literature. Compound 2 exhibited stronger antioxidant activity than the positive control ascorbic acid at a concentration of 10 MUM. PMID- 26981772 TI - Follow-up of Ebola Patient, 2014-2015. PMID- 26981770 TI - Deletion Variants of Middle East Respiratory Syndrome Coronavirus from Humans, Jordan, 2015. AB - We characterized Middle East respiratory syndrome coronaviruses from a hospital outbreak in Jordan in 2015. The viruses from Jordan were highly similar to isolates from Riyadh, Saudi Arabia, except for deletions in open reading frames 4a and 3. Transmissibility and pathogenicity of this strain remains to be determined. PMID- 26981773 TI - Dual-targeting triplebody 33-3-19 mediates selective lysis of biphenotypic CD19+ CD33+ leukemia cells. AB - Simultaneous targeting of multiple tumor-associated antigens (TAAs) in cancer immunotherapy is presumed to enhance tumor cell selectivity and to reduce immune escape.The combination of B lymphoid marker CD19 and myeloid marker CD33 is exclusively present on biphenotypic B/myeloid leukemia cells. Triplebody 33-3-19 binds specifically to both of these TAAs and activates T cells as immune effectors. Thereby it induces specific lysis of established myeloid (MOLM13, THP 1) and B-lymphoid cell lines (BV173, SEM, Raji, ARH77) as well as of primary patient cells. EC50 values range from 3 pM to 2.4 nM. In accordance with our hypothesis, 33-3-19 is able to induce preferential lysis of double- rather than single-positive leukemia cells in a target cell mixture: CD19/CD33 double positive BV173 cells were eliminated to a significantly greater extent than CD19 single-positive SEM cells (36.6% vs. 20.9% in 3 hours, p = 0.0048) in the presence of both cell lines. In contrast, equivalent elimination efficiencies were observed for both cell lines, when control triplebody 19-3-19 or a mixture of the bispecific single chain variable fragments 19-3 and 33-3 were used. This result highlights the potential of dual-targeting agents for efficient and selective immune-intervention in leukemia patients. PMID- 26981774 TI - Identification of extracellular vesicle-borne periostin as a feature of muscle invasive bladder cancer. AB - Muscle-invasive bladder cancer (MIBC) is an aggressive malignancy with high mortality, and heterogeneity in MIBC results in variable clinical outcomes, posing challenges for clinical management. Extracellular vesicles (EVs) derived from MIBC have been shown to promote cancer progression. EVs derived from bladder cell lines were subjected to proteomic analysis, and periostin was chosen for further characterization due to its stage-specific gene expression profile. Knockdown of periostin by RNA interference reduces invasiveness in vitro and produces a rounder morphology. Importantly, treating low grade BC cells with periostin-rich EVs promotes cell aggressiveness and activates ERK oncogenic signals, and periostin suppression reverses these effects. These data suggest that MIBC might transfer periostin in an EV-mediated paracrine manner to promote the disease. To determine the potential of periostin as a bladder cancer indicator, patient urinary EVs were examined and found to have markedly higher levels of periostin than controls. In addition, immunohistochemical staining of a bladder cancer tissue microarray revealed that the presence of periostin in MIBC cells is correlated with worse prognosis. In conclusion, periostin is a component of bladder cancer cells associated with poor clinical outcome, and EVs can transfer oncogenic molecules such as periostin to affect the tumor environment and promote cancer progression. PMID- 26981775 TI - Near infrared photoimmunotherapy with an anti-mesothelin antibody. AB - Near Infrared-Photoimmunotherapy (NIR-PIT) is a new, highly selective tumor treatment that employs an antibody-photon absorber conjugate (APC). When the APC attaches to its target cell and is exposed to NIR light, highly selective cell killing is observed. NIR-PIT has been demonstrated with a limited number of antibodies. Mesothelin is overexpressed in several malignancies and is emerging as a therapeutic target. A recently humanized antibody (hYP218) has been generated against mesothelin that demonstrates high affinity binding. Here, we describe the efficacy of NIR-PIT, using hYP218 as the antibody within the APC to target a mesothelin expressing A431/H9 cell. The hYP218 antibody was conjugated to a photo-absorber, IR700 and incubated with the cells. The hYP218-IR700 showed specific binding to cells and cell-specific killing was observed in vitro. After implanting A431/H9 cells in an athymic nude mouse, tumor-bearing mice were treated with the following regimen of NIR-PIT; 100 MUg of hYP218-IR700 i.v., NIR light was administered at 50 J/cm2 on day 1 after injection and 100 J/cm2 of light on day 2 after injection. The hYP218-IR700 showed high tumor accumulation and a high tumor-background ratio (TBR). Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other control groups (p < 0.001), and significantly prolonged survival (p < 0.0001 vs other groups). Thus, the new anti mesothelin antibody, hYP218, is suitable as an antibody-drug conjugate for NIR PIT. Furthermore, NIR-PIT with hYP218-IR700 is a promising candidate for the treatment of mesothelin-expressing tumors that could be readily translated to humans. PMID- 26981776 TI - Regulation of limited N-terminal proteolysis of APE1 in tumor via acetylation and its role in cell proliferation. AB - Mammalian apurinic/apyrimidinic (AP) endonuclease 1 (APE1), a ubiquitous and multifunctional protein, plays an essential role in the repair of both endogenous and drug-induced DNA damages in the genome. Unlike its E.coli counterpart Xth, mammalian APE1 has a unique N-terminal domain and possesses both DNA damage repair and transcriptional regulatory functions. Although the overexpression of APE1 in diverse cancer types and the association of APE1 expression with chemotherapy resistance and poor prognosis are well documented, the cellular and molecular mechanisms that alter APE1 functions during tumorigenesis are largely unknown. Here, we show the presence of full-length APE1 and N-terminal truncated isoforms of APE1 in tumor tissue samples of various cancer types. However, primary tumor tissue has higher levels of acetylated APE1 (AcAPE1) as well as full-length APE1 compared to adjacent non-tumor tissue. We found that APE1 is proteolytically cleaved by an unknown serine protease at its N-terminus following residue lysine (Lys) Lys6 and/or Lys7 and after Lys27 and Lys31 or Lys32. Acetylation of these Lys residues in APE1 prevents this proteolysis. The N terminal domain of APE1 and its acetylation are required for modulation of the expression of hundreds of genes. Importantly, we found that AcAPE1 is essential for sustained cell proliferation. Together, our study demonstrates that increased acetylation levels of APE1 in tumor cells inhibit the limited N-terminal proteolysis of APE1 and thereby maintain the functions of APE1 to promote tumor cells' sustained proliferation and survival. PMID- 26981777 TI - Therapy of solid tumors using probiotic Symbioflor-2: restraints and potential. AB - To date, virulent bacteria remain the basis of most bacteria mediated cancer therapies. For clinical application attenuation is required. However, this might result in a drastically lowered therapeutic capacity. Herein we argue that the E. coli probiotic Symbioflor-2, with a history of safe application may constitute a viable tumor therapeutic candidate. We demonstrate that Symbioflor-2 displays a highly specific tumor targeting ability as determined in murine CT26 and RenCa tumor models. The excellent specificity was ascribed to reduced levels of adverse colonization. A high safety standard was demonstrated in WT and Rag1-/- mice. Thus, Symbioflor-2 may represent an ideal tumor targeting delivery system for therapeutic molecules. Moreover, Symbioflor-2 was capable of inducing CT26 tumor clearance as result of an adjuvant effect on tumor specific CD8+ T cells analogous to the Salmonella variant SL7207. However, lower therapeutic efficacy against RenCa tumors suggested a generally reduced therapeutic potency for probiotics. Interestingly, concurrent depletion of Gr-1+ or Ly6G+ cells installed therapeutic efficacy equal to SL7207, thus highlighting the role of innate effector cells in restraining the anti-tumor effects of Symbioflor-2. Collectively, our findings argue for a strategy of safe strain application and a more sustainable use of bacteria as a delivery system for therapeutic molecules. PMID- 26981778 TI - ABCG1 maintains high-grade glioma survival in vitro and in vivo. AB - The overall survival for adults with malignant glioma (glioblastoma) remains poor despite advances in radiation and chemotherapy. One of the mechanisms by which cancer cells develop relative resistance to treatment is through de-regulation of endoplasmic reticulum (ER) homeostasis. We have recently shown that ABCG1, an ATP binding cassette transporter, maintains ER homeostasis and suppresses ER stress induced apoptosis in low-grade glioma. Herein, we demonstrate that ABCG1 expression is increased in human adult glioblastoma, where it correlates with poor survival in individuals with the mesenchymal subtype. Leveraging a mouse model of mesenchymal glioblastoma (NPcis), shRNA-mediated Abcg1 knockdown (KD) increased CHOP ER stress protein expression and resulted in greater NPcis glioma cell death in vitro. Moreover, Abcg1 KD reduced NPcis glioma growth and increased mouse survival in vivo. Collectively, these results demonstrate that ABCG1 is critical for malignant glioma cell survival, and might serve as a future therapeutic target for these deadly brain cancers. PMID- 26981781 TI - Metal-metal chalcogenide molecular precursors to binary, ternary, and quaternary metal chalcogenide thin films for electronic devices. AB - Bulk metals and metal chalcogenides are found to dissolve in primary amine dithiol solvent mixtures at ambient conditions. Thin-films of CuS, SnS, ZnS, Cu2Sn(S(x),Se(1-x))3, and Cu2ZnSn(S(x)Se(1-x))4 (0 <= x <= 1) were deposited using the as-dissolved solutions. Cu2ZnSn(S(x)Se(1-x))4 solar cells with efficiencies of 6.84% and 7.02% under AM1.5 illumination were fabricated from two example solution precursors, respectively. PMID- 26981782 TI - Synthesis and Structure-Activity Relationships of N-Dihydrocoptisine-8-ylidene Aromatic Amines and N-Dihydrocoptisine-8-ylidene Aliphatic Amides as Antiulcerative Colitis Agents Targeting XBP1. AB - In this study, natural quaternary coptisine was used as a lead compound to design and synthesize structurally stable and actively potent coptisine analogues. Of the synthesized library, 13 N-dihydrocoptisine-8-ylidene amines/amides were found not only to be noncytotoxic toward intestinal epithelial cells (IECs), but they were also able to activate the transcription of X-box-binding protein 1 (XBP1) targets to varying extents in vitro. Antiulcerative colitis (UC) activity levels were assessed at the in vitro molecular level as well as in vivo in animals using multiple biomarkers as indices. In an in vitro XBP1 transcriptional activity assay, four compounds demonstrated good dose-effect relationships with EC50 values of 0.0708-0.0132 MUM. Moreover, two compounds were confirmed to be more potent in vivo than a positive control, demonstrating a curative effect for UC in experimental animals. Thus, the findings of this study suggest that these coptisine analogues are promising candidates for the development of anti-UC drugs. PMID- 26981783 TI - Don't be afraid of anesthesia mumps. PMID- 26981780 TI - Ruxolitinib synergizes with DMF to kill via BIM+BAD-induced mitochondrial dysfunction and via reduced SOD2/TRX expression and ROS. AB - We determined whether the myelofibrosis drug ruxolitinib, an inhibitor of Janus kinases 1/2 (JAK1 and JAK2), could interact with the multiple sclerosis drug dimethyl-fumarate (DMF) to kill tumor cells; studies used the in vivo active form of the drug, mono-methyl fumarate (MMF). Ruxolitinib interacted with MMF to kill brain, breast, lung and ovarian cancer cells, and enhanced the lethality of standard of care therapies such as paclitaxel and temozolomide. MMF also interacted with other FDA approved drugs to kill tumor cells including Celebrex(r) and Gilenya(r). The combination of [ruxolitinib + MMF] inactivated ERK1/2, AKT, STAT3 and STAT5; reduced expression of MCL-1, BCL-XL, SOD2 and TRX; increased BIM expression; decreased BAD S112 S136 phosphorylation; and enhanced pro-caspase 3 cleavage. Expression of activated forms of STAT3, MEK1 or AKT each significantly reduced drug combination lethality; prevented BAD S112 S136 dephosphorylation and decreased BIM expression; and preserved TRX, SOD2, MCL-1 and BCL-XL expression. The drug combination increased the levels of reactive oxygen species in cells, and over-expression of TRX or SOD2 prevented drug combination tumor cell killing. Over-expression of BCL-XL or knock down of BAX, BIM, BAD or apoptosis inducing factor (AIF) protected tumor cells. The drug combination increased AIF : HSP70 co-localization in the cytosol but this event did not prevent AIF : eIF3A association in the nucleus. PMID- 26981779 TI - Genomic portfolio of Merkel cell carcinoma as determined by comprehensive genomic profiling: implications for targeted therapeutics. AB - Merkel cell carcinoma is an ultra-rare cutaneous neuroendocrine cancer for which approved treatment options are lacking. To better understand potential actionability, the genomic landscape of Merkel cell cancers was assessed. The molecular aberrations in 17 patients with Merkel cell carcinoma were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine, Cambridge, MA) using next-generation sequencing (182 or 236 genes) and analyzed by N-of-One, Inc. (Lexington, MA). There were 30 genes harboring aberrations and 60 distinct molecular alterations identified in this patient population. The most common abnormalities involved the TP53 gene (12/17 [71% of patients]) and the cell cycle pathway (CDKN2A/B, CDKN2C or RB1) (12/17 [71%]). Abnormalities also were observed in the PI3K/AKT/mTOR pathway (AKT2, FBXW7, NF1, PIK3CA, PIK3R1, PTEN or RICTOR) (9/17 [53%]) and DNA repair genes (ATM, BAP1, BRCA1/2, CHEK2, FANCA or MLH1) (5/17 [29%]). Possible cognate targeted therapies, including FDA-approved drugs, could be identified in most of the patients (16/17 [94%]). In summary, Merkel cell carcinomas were characterized by multiple distinct aberrations that were unique in the majority of analyzed cases. Most patients had theoretically actionable alterations. These results provide a framework for investigating tailored combinations of matched therapies in Merkel cell carcinoma patients. PMID- 26981784 TI - Modeling Method for Increased Precision and Scope of Directly Measurable Fluxes at a Genome-Scale. AB - Metabolic flux analysis (MFA) is considered to be the gold standard for determining the intracellular flux distribution of biological systems. The majority of work using MFA has been limited to core models of metabolism due to challenges in implementing genome-scale MFA and the undesirable trade-off between increased scope and decreased precision in flux estimations. This work presents a tunable workflow for expanding the scope of MFA to the genome-scale without trade offs in flux precision. The genome-scale MFA model presented here, iDM2014, accounts for 537 net reactions, which includes the core pathways of traditional MFA models and also covers the additional pathways of purine, pyrimidine, isoprenoid, methionine, riboflavin, coenzyme A, and folate, as well as other biosynthetic pathways. When evaluating the iDM2014 using a set of measured intracellular intermediate and cofactor mass isotopomer distributions (MIDs),1 it was found that a total of 232 net fluxes of central and peripheral metabolism could be resolved in the E. coli network. The increase in scope was shown to cover the full biosynthetic route to an expanded set of bioproduction pathways, which should facilitate applications such as the design of more complex bioprocessing strains and aid in identifying new antimicrobials. Importantly, it was found that there was no loss in precision of core fluxes when compared to a traditional core model, and additionally there was an overall increase in precision when considering all observable reactions. PMID- 26981787 TI - Everyday memory in individuals with Down syndrome: Validation of the Observer Memory Questionnaire - Parent Form. AB - The memory profile of individuals with Down syndrome (DS) has mainly been examined through traditional laboratory tasks, often revealing substantial deficits in episodic and declarative memory. Little is known about the relation between memory abilities as measured in the laboratory versus naturalistic settings in this population, and no questionnaire assessments of everyday memory have been formally validated for this group. The current study's aims were twofold: 1) to describe the psychometric characteristics of a parent-reported everyday memory measure (the Observer Memory Questionnaire - Parent Form, OMQ-PF) in this population with known hippocampal and memory impairment (i.e., DS, ages 7 35 years), and 2) to determine if the measure has the sensitivity to detect impairments, thus providing some of the first data to document parent reports of everyday memory in individuals with DS. The results indicate that this scale is a reliable instrument for detecting and tracking memory deficits over time in this population. We found a correlation between parent reports of everyday memory difficulties and well-replicated deficits in a laboratory-based memory task (i.e., place-object paired associates learning). Our results suggest that the OMQ PF has the potential to be used as a tool to help to track the status of memory function in this group both for use in descriptive studies and in studies of behavior and pharmacological intervention. PMID- 26981788 TI - Role of PALB2 Polymorphisms with Regard to Susceptibility to Female Breast Cancer Risk in the Chinese Population. AB - AIMS: PALB2 (partner and localizer of BRCA2) is a nuclear partner of BRCA2 and promotes its localization and stability in the nucleus, allowing it to function in DNA repair and at the S-phase checkpoint. It has been hypothesized that polymorphisms in the PALB2 gene may be associated with tumorigenesis, particularly with respect to susceptibility to breast cancer. METHODS: To assess the association of polymorphisms in the PALB2 gene with breast cancer risk in a Chinese female population a total of 351 female breast cancer patients and 360 age-, gender-matched tumor-free individuals were enrolled in this case-control study. The genotypes of five PALB2 gene polymorphic sites (rs120963, rs16940342, rs249954, rs447529, and rs249935) were characterized by using the Sequenom MassARRAY platform. RESULTS: The data showed that the genotypes rs249954 CT (adjusted odds ratio [OR] = 1.52; 95% confidence interval [95% CI], 1.10-2.09), TT (adjusted OR = 2.36; 95% CI, 1.39-4.02), and CT/TT (adjusted OR = 1.65; 95% CI, 1.22-2.24) were associated with increased risk of breast cancer, respectively, relative to the CC genotype. Similarly, the rs120963 TC (adjusted OR = 1.89; 95% CI, 1.38-2.59), CC (adjusted OR = 3.88; 95% CI, 1.75-8.60), and TC/CC (adjusted OR = 2.05; 95% CI, 1.51-2.78) genotypes were associated with increased risk of breast cancer, respectively, relative to the TT genotype. Additionally, a weakly significant association was observed between G allele (AG/GG genotype) carriers of the rs249935 SNP in the sub-group of T1-2 (Adjusted OR = 1.43; 95% CI, 1.03-10.84) and negative lymphatic involvement (Adjusted OR = 3.23; 95% CI, 0.97-10.84) and risk of breast cancer. CONCLUSIONS: This case control study provided evidence that rs120963 and rs249954 of the PALB2 gene are associated with increased breast cancer risk, and that the association of rs249935 with breast cancer risk may be modified by the tumor pathological characteristics. PMID- 26981786 TI - Lassa Virus Seroprevalence in Sibirilia Commune, Bougouni District, Southern Mali. AB - Lassa virus (LASV) is endemic to several nations in West Africa. In Mali, LASV was unknown until an exported case of Lassa fever was reported in 2009. Since that time, rodent surveys have found evidence of LASV-infected Mastomys natalensis rats in several communities in southern Mali, near the border with Cote d'Ivoire. Despite increased awareness, to date only a single case of Lassa fever has been confirmed in Mali. We conducted a survey to determine the prevalence of LASV exposure among persons in 3 villages in southern Mali where the presence of infected rodents has been documented. LASV IgG seroprevalence ranged from 14.5% to 44% per village. No sex bias was noted; however, seropositivity rates increased with participant age. These findings confirm human LASV exposure in Mali and suggest that LASV infection/Lassa fever is a potential public health concern in southern Mali. PMID- 26981789 TI - The protective role of G protein-coupled estrogen receptor 1 (GPER-1) on methotrexate-induced nephrotoxicity in human renal epithelium cells. AB - Nephrotoxicity is an important problem during methotrexate (MTX) treatment, which has been widely used for the treatment of several cancer types. Females are less susceptible to kidney diseases; however, the reason for this condition has not to be fully clarified. But sex hormones such as estrogen may have a protective effect on the kidney. We aimed to evaluate the possible protective role of estrogen on the MTX-induced renal epithelial cell death. Primary renal proximal tubular epithelial cells (RPTEC) were incubated with MTX (1, 10 and 100 MUM), either alone or in combination with the 17beta-estradiol, G protein-coupled estrogen receptor 1 (GPER1) agonist G-1, estrogen receptor alpha agonist propyl pyrazole triol (PPT), estrogen receptor beta agonist diarylpropionitrile (DPN). Cell viability was determined by MTT assays. Interleukin (IL)-1beta, IL-6, superoxide dismutase (SOD) and malondialdehyde (MDA) levels were determined in RPTEC. Approximately half of the cell death was observed with 10 MUM MTX incubation for 48 h. The cell death was prevented by co-incubating with17beta estradiol, PPT and G-1. MTX was significantly induced IL-1beta and IL-6.17beta estradiol, PPT and G-1 significantly decreased effects of MTX. SOD activity was significantly decreased treatment with MTX compared to control group. SOD activity was increased with co-incubation with 17beta-estradioland G-1 compared to treatment with MTX. MDA levels significantly increased in treatment with MTX compared with the control group. Increased MDA levels by MTX-induced was decreased significantly by the treatment with 17beta-estradiol and G-1. These data indicate that especially 17beta-estradiol and G-1 may be useful in preventing undesirable effects of MTX in renal failure. PMID- 26981790 TI - Prevalence of the C-terminal truncations of NS1 in avian influenza A viruses and effect on virulence and replication of a highly pathogenic H7N1 virus in chickens. AB - Highly pathogenic (HP) avian influenza viruses (AIV) evolve from low pathogenic (LP) precursors after circulation in poultry by reassortment and/or single mutations in different gene segments including that encoding NS1. The carboxyl terminal end (CTE) of NS1 exhibits deletions between amino acid 202 and 230 with still unknown impact on virulence of AIV in chickens. In this study, NS1 protein sequences of all AIV subtypes in birds from 1902 to 2015 were analyzed to study the prevalence and distribution of CTE truncation (DeltaCTE). Thirteen different DeltaCTE forms were observed in NS1 proteins from 11 HA and 8 NA subtypes with high prevalences in H9, H7, H6 and H10 and N9, N2, N6 and N1 subtypes particularly in chickens and minor poultry species. With 88% NS217 lacking amino acids 218-230 was the most common DeltaCTE form followed by NS224 (3.6%). NS217 was found in 10 and 8 different HA and NA subtypes, respectively, whereas NS224 was detected exclusively in the Italian HPAIV H7N1 suggesting relevance for virulence. To test this assumption, 3 recombinant HPAIV H7N1 were constructed carrying wild-type HP NS1 (Hp-NS224), NS1 with extended CTE (Hp-NS230) or NS1 from LPAIV H7N1 (Hp-NSLp), and tested in-vitro and in-vivo. Extension of CTE in Hp NS1 significantly decreased virus replication in chicken embryo kidney cells. Truncation in the NS1 decreased the tropism of Hp-NS224 to the endothelium, central nervous system and respiratory tract epithelium without significant difference in virulence in chickens. This study described the variable forms of DeltaCTE in NS1 and indicated that CTE is not an essential virulence determinant particularly for the Italian HPAIV H7N1 but may be a host-adaptation marker required for efficient virus replication. PMID- 26981791 TI - Chikusetsusaponin V attenuates lipopolysaccharide-induced liver injury in mice. AB - Chikusetsusaponin V (CsV), a saponin from Panax japonicus, has been reported to inhibit inflammatory responses in lipopolysaccharide (LPS)-induced macrophage cells. However, whether CsV could alleviate LPS-induced liver injury in vivo and the potential mechanisms involved remain unclear. In the present study, we investigated the anti-inflammatory effects of CsV on LPS-induced acute liver injury in mice and further explored the potential mechanisms involved. Our results showed that CsV significantly attenuated elevation of alanine transaminase (ALT) and aspartate aminotransferase (AST) levels and improved liver histopathological changes in LPS-induced mice. In addition, CsV decreased serum tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels and inhibited mRNA expressions of inducible nitric oxide synthase (iNOS), TNF alpha and IL-1beta in LPS challenged mice. Furthermore, CsV inhibited nuclear factor kappa B (NF-kappaB) activation by downregulating phosphorylated NF-kappaB, IkappaB-alpha, ERK, c-Jun N-terminal kinase (JNK) and p38 levels in the liver tissue, which ultimately decreased nucleus NF-kappaB protein level. In conclusion, our data suggested that CsV could be a promising drug for preventing LPS challenged liver injury since it attenuated LPS-induced inflammatory responses, partly via inhibiting NF-kappaB and MAPK signaling pathways. PMID- 26981794 TI - Continence charity appoints specialist. AB - A children's charity has recruited a nurse dedicated to help young people with continence problems. PMID- 26981793 TI - MPs say nurse's dismissal was heavy-handed. AB - Two MPs have criticised a trust for sacking a nurse who stole soft drinks from a faulty vending machine at work. PMID- 26981792 TI - Glove Perforation Rate in Surgery: A Randomized, Controlled Study To Evaluate the Efficacy of Double Gloving. AB - BACKGROUND: The risk of exposure of either the patient or the surgeon to communicable disease when the surgical glove is perforated is important. Both patients and the surgical team need to be protected from this risk. Therefore, we intended to determine the efficacy of double gloving in our center. METHODS: This was a prospective cohort study, involving (randomly selected) surgeons, who wore single or double latex surgical gloves during procedures. Gloves were collected and evaluated for perforations (using air insufflation and water leak methods). RESULTS: A total of 1,536 gloves were collected (512 single gloves and 1,024 double gloves), with 78 of 512 gloves perforated, giving a rate of 15.2%. Perforation rate was 15.2% in single gloves, 14.4% in double gloves, 15.5% in emergency operations, and 14.3% in elective surgery. It was highest (30.8%) among registrars in training, particularly when doing any deep (16.0%) surgery. Glove perforation rate was highest (17.4%) among general surgery procedures as opposed to pediatric surgery (14.6%), urology (13.9%), neurosurgery (11.7%), and plastic surgery (10.6%), with (42.1%) index finger injury. In unused (control group) gloves, the rate of perforation was (0.8%). There was a substantial difference in the overall perforation rate between single and double glove sets (15.2% versus 14.4%) (X(2) = 1748, p < 0.0001). However, among the double set, total gloves [outer and inner set] analysis revealed a perforation rate of 27.5% (141 of 512). Of this set, the number of inner gloves that perforated as a result of a through and through puncture from outer to the inner gloves gave a rate of 1.17% (six of 512). Thus, the protection offered by double gloves was 98.83% (X(2) = 280.9, p < 0.0001) even if the outer gloves were perforated. CONCLUSION: The use of double gloves has more than 90% protection to patient and the surgeon. Therefore, wearing double gloves should be encouraged in surgery. PMID- 26981795 TI - Staff need to 'listen more to patient concerns'. AB - The Labour MP heading up a major review of the way the NHS in England deals with complaints has urged staff to 'listen more' to patient concerns. PMID- 26981796 TI - NHS Direct personnel asked to stay on to help new NHS 111 service cope. AB - NHS Direct nurses are working 'flat out' as teething problems with the new NHS 111 service continue. PMID- 26981797 TI - Nursing cuts could put vaccination programme at risk. AB - The national immunisation programme to protect people against flu, shingles and diarrhoea could be hampered by a lack of nursing staff to administer the vaccines, the union Unite has warned. PMID- 26981798 TI - Support for return to civvie street. AB - A former army sergeant who retrained as a nurse has helped develop a government programme to support forces veterans experiencing mental health problems. PMID- 26981799 TI - NHS announces biggest ever staff development scheme. AB - Thousands of healthcare professionals are to receive leadership and communication training over the next three years through the largest ever NHS development initiative. PMID- 26981802 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 26981801 TI - Children's sticker books are a passport to reassurance. AB - A game to help young patients combat their fears of being in hospital has been so successful it is being introduced in all children's hospitals in Scotland. PMID- 26981803 TI - Private hospital vows to meet key standards. AB - Nursing staff at a private hospital that failed to meet eight out of nine basic standards were working without policies on how to manage pain in children or guidelines for analgesia. PMID- 26981805 TI - 'So listen to us, hear us goddamn roar'. AB - Second-year nursing student Molly Case penned her poem Nursing the Nation after she and fellow students became demoralised by the barrage of media criticism about the profession. PMID- 26981804 TI - Home closures trigger concerns. AB - Plans to close government-funded residential care homes in Northern Ireland will place extra pressure on community nurses at a time when numbers are dwindling, the RCN warns. PMID- 26981806 TI - Home visits help ease stresses and worries in pregnant couples. AB - A nursing intervention for distressed pregnant women that also involves their partners has proved effective in reducing symptoms of depression. PMID- 26981807 TI - Women who have undergone endometriosis surgery have a reduced risk of ovarian cancer. AB - Surgical treatment for endometriosis reduces the risk of ovarian cancer significantly, suggests a study of women in Sweden. PMID- 26981808 TI - Optimal potassium intake improves blood pressure in adults with hypertension. AB - The health benefits of potassium are greatest when at least 90mmol a day is consumed, according to a new systematic literature review and meta-analysis. PMID- 26981810 TI - Consuming moderately less salt in the long-term can lower blood pressure significantly. AB - A modest reduction in salt intake for four or more weeks causes significant falls in blood pressure. PMID- 26981809 TI - Likelihood of being obese or overweight increases with each subsequent generation. AB - Young adults today are less healthy than their counterparts in previous generations, suggests a large cohort study in the Netherlands. PMID- 26981811 TI - Ten APPS approved by the NHS. AB - At the NHS Innovation Expo conference in March, ten new NHS-approved apps were unveiled by the then NHS Commissioning Board (now NHS England). Most are available to all, often free of charge, but others require links to clinical systems. All have received the NHS 'stamp of approval'. PMID- 26981812 TI - Voices - A fully inclusive workforce is good for patient care, writes Yvonne Coghill. AB - At last month's RCN congress I was invited to give a presentation at a Nursing Standard fringe event on how equality and diversity will be managed in the new NHS. PMID- 26981813 TI - Another side to the story. AB - I came into nursing to nurse people. My mother and my aunt were nurses, and most of my best friends are nurses. PMID- 26981814 TI - None too clever. AB - I am sure many of you are fans of the BBC TV programme 'Call the Midwife'. As a Londoner, I remember that world from my childhood, when I was taught by nuns as kind and gentle as those in Nonnatus House. PMID- 26981816 TI - Readers panel - When protection is unwanted. AB - Our experts consider a hot topic of the day. PMID- 26981815 TI - Blurred vision. AB - I have just discovered beer goggles. Not as in: 'He had drunk at least six pints so he must have been wearing beer goggles if he fancied her!' But 'visual impairment glasses', which are optically designed 'to simulate the effects of intoxication'. PMID- 26981817 TI - On a high. AB - I always find it reassuring how RCN congress treads the same path every year: the opening night and the president's rousing speech, followed by the awards ceremony celebrating the amazing diversity of nursing achievement. PMID- 26981818 TI - Starting out - Patient's appreciative words taught me to look for the good in others. AB - I remember clearly my placement in a hospice as a first-year nursing student. My thoughts when I started the placement were that it would involve death and a lot of sadness, but this was not what I found. PMID- 26981819 TI - yecco.com. AB - Keeping patients in the comfortable and familiar surroundings of their homes for as long as possible is a key part of today's care pathways. PMID- 26981820 TI - My Journey - Reflections on Life from a Cancer Survivor Shirley Shirley My Journey - Reflections on Life from a Cancer Survivor 128pp $11.95/L7.83 WestBow Press 978 1 4497 4822 7 1449748228 [Formula: see text]. AB - The journey that follows a cancer diagnosis should not be undertaken alone, but involve caring and compassion from many people who provide help, guidance and support. PMID- 26981821 TI - A Nurse's Survival Guide to the Ward - Third edition Richards Ann Edwards Sharon A Nurse's Survival Guide to the Ward - Third edition 500pp L19.99 Elsevier 978 0 7020 4603 2 0702046035 [Formula: see text]. AB - This guide is a useful 'friend and companion' to keep close at hand. It is an essential reference for nurses, not only on the ward but in every field of practice where patient care is given. In fact, it makes an accessible guide for all healthcare practitioners. PMID- 26981822 TI - A Place in History - Britain's Headline News Stories Remembered Philpott Colin A Place in History - Britain's Headline News Stories Remembered 248pp L14.99 Ammonite Press 978 1 9077 0869 5 1907708693 [Formula: see text]. AB - There is an endless fascination to be found in browsing photographs of historic places associated with key events in history, whether they serve to jog our own memory or give insight into a time before we were born. PMID- 26981824 TI - In uncertain times, it is vital nurses keep communication channels open. AB - Last month's RCN congress could not have happened at a more turbulent time (news May 1). Nursing is having such a bad press and much of what is fundamental to our profession is being attacked. PMID- 26981823 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 26981825 TI - Great response to my chernobyl vigil, despite the pie thieves. AB - On April 26, I held my 27th annual solitary vigil in Glasgow's George Square on the anniversary of the Chernobyl nuclear accident in Ukraine (letters April 24). PMID- 26981826 TI - Although nurses' fund is closed, financial help is still available. AB - Reviewing the book Football and Management - Comparisons Between Sport and Enterprise, Nicola Evans points out that football is big business, much like health care (reviews April 17). PMID- 26981827 TI - Sponsor my run in aid of a good friend who died of mesothelioma. AB - My last sponsored run was a marathon in the 1980s to raise funds for the miners. Now I will be running a half-marathon on Sunday May 12 in honour of my friend Simon Pickvance. PMID- 26981828 TI - RCN should resist temptation to quit international nursing body. AB - The RCN is on the cusp of a decision that could have profound effects on nursing worldwide. RCN council faces a momentous choice about whether and when to exercise its new power to withdraw the college from membership of the International Council of Nurses (ICN) (letters April 10, analysis and letters April 17, news and letters May 1). PMID- 26981829 TI - Exorbitant ICN fees could be better spent elsewhere. AB - Delegates at RCN congress recently voted overwhelmingly in favour of giving RCN council the option to decide if the college will quit the International Council of Nurses (ICN), the global nursing body (news and letters May 1). PMID- 26981830 TI - Leave the nurse station where it is and address staffing levels. AB - Ann Clwyd MP wants nurses' stations to be replaced by desks dotted around wards (news April 10). She claims that staff just gather and chat constantly, rather than spending time at the bedside. PMID- 26981832 TI - Shop locally for food to help reduce your carbon footprint. AB - Writing about the role of the nurse in addressing the health effects of climate change (learning zone May 1), Benny Goodman says nurses should be viewed as global citizens for health. PMID- 26981833 TI - Charities such as GMFA need to be supported and encouraged. AB - It is a tough time for charities and particularly difficult for organisations such as GMFA, the health promotion charity campaigning to improve gay men's health (letters April 24). PMID- 26981834 TI - Fond memories of Susan Pembrey, the best line manager i ever had. AB - Thank you for the obituaries of nursing research pioneer Susan Pembrey - a short obituary on the letters pages (April 24) and a longer version on the Nursing Standard website ( www.nursing-standard.co.uk ). PMID- 26981835 TI - Jillian MacGuire 1936-2013 Emeritus professor of nursing, University of Wales, Cardiff. AB - Jill's varied career began with a sociology degree from the London School of Economics, from where she graduated in 1958. A keen interest in nursing followed and she qualified as an RGN in 1984. PMID- 26981836 TI - Notice board. AB - Courses, events, grants, and awards to progress your career. PMID- 26981837 TI - 'I used the technique to summon help for a critically ill patient'. AB - Communication is critical when a patient is deteriorating rapidly. Lisa Johnson describes an experience as a second-year student. PMID- 26981838 TI - Long Noncoding RNA Highly Upregulated in Liver Cancer Regulates the Tumor Necrosis Factor-alpha-Induced Apoptosis in Human Vascular Endothelial Cells. AB - Atherosclerosis is the major cause of myocardial infarction and stroke, which is a leading cause of morbidity and mortality in developed countries. During the pathological process of atherosclerosis, inflammation participates in all stages of atherosclerosis. Tumor necrosis factor-alpha (TNF-alpha), one of the most important inflammatory factor, induces apoptosis of endothelial cells, which play a central role in endothelial dysfunction. However, the underlying mechanism involved in long noncoding RNA (lncRNA) remains unclear. In the present study, we demonstrated the role of lncRNA highly upregulated in liver cancer (HULC) in TNF alpha-induced apoptosis. HULC expression was decreased with TNF-alpha treatment. Restoring HULC expression rescued the apoptosis induced by TNF-alpha. HULC regulated TNF-alpha-induced apoptosis through regulation of miR-9 expression. Furthermore, RNA immunoprecipitation and RNA pull-down assays showed that HULC modulated miR-9 expression through association with DNA methyltransferases and suppression of miR-9 expression. HULC-miR-9 pathway may be a potential target for treating atherosclerosis. PMID- 26981839 TI - Deformability properties of timolol-loaded transfersomes based on the extrusion mechanism. Statistical optimization of the process. AB - The purpose of this work was to analyze the deformability properties of different timolol maleate (TM)-loaded transfersomes by extrusion. This was performed because elastic liposomes may contribute to the elevation of amount and rate of drug permeation through the corneal membrane. This paper describes the optimization of a transfersome formulation by use of Taguchi orthogonal experimental design and two different statistical analysis approaches were utilized. The amount of cholesterol (F1), the amount of edge-activator (F2), the distribution of the drug into the vesicle (F3), the addition of stearylamine (F4) and the type of edge-activator (F5) were selected as causal factors. The deformability index, the phosphorous recovery, the vesicle size, the polydispersity index, the zeta potential and percentage of drug entrapped were fixed as the dependent variables and these responses were evaluated for each formulation. Two different statistical analysis approaches were applied. The better statistical approach was determined by comparing their prediction errors, where regression analysis provided better optimized responses than marginal means. From the study, an optimized formulation of TM-loaded transfersomes was prepared and obtained for the proposed ophthalmic delivery for the treatment of open angle glaucoma. It was found that the lipid to surfactant ratio and type of surfactant are the main key factors for determining the flexibility of the bilayer of transfersomes. From in vitro permeation studies, we can conclude that TM-loaded transfersomes may enhance the corneal transmittance and improve the bioavailability of conventional TM delivery. PMID- 26981841 TI - Efficacy of avilamycin for the prevention of necrotic enteritis caused by a pathogenic strain of Clostridium perfringens in broiler chickens. AB - The efficacy of avilamycin for the prevention of necrotic enteritis (NE) was investigated in a 35-day floor pen study of 2200 broiler cockerels using a Clostridium perfringens (Cp) feed inoculum challenge model. Treatments consisted of (1) nonmedicated, nonchallenged; (2) nonmedicated, challenged; (3) avilamycin at 15 ppm, challenged; (4) avilamycin at 30 ppm, challenged. Avilamycin was administered in the feed from day 7 to day 30 of the study. Challenge inoculum was administered on day 14 and delivered approximately 10(9) CFU Cp/bird. NE mortality rates from day 14-35 were significantly (P < 0.0001) lower in birds treated with avilamycin at 15 and 30 ppm when compared to nonmedicated, challenged birds. Treatment with avilamycin also resulted in a significant reduction in ileal Cp count on day 21 (P < 0.0001) and NE lesion scores on day 17 (P < 0.006) when compared to nonmedicated, challenged birds. The performance of birds treated with avilamycin was also improved when compared to nonmedicated, challenged birds. Cockerels that received either 15 or 30 ppm avilamycin had a significantly (P < 0.0001) increased body weight on day 35 and average daily gain from days 0-35 than nonmedicated, challenged birds. Furthermore, birds treated with avilamycin had an improved feed conversion rate from days 0-35 compared to both nonmedicated, nonchallenged birds and nonmedicated, challenged birds. This study confirms that avilamycin is effective at controlling mortality related to NE in growing broiler chickens. PMID- 26981840 TI - Analysis of cognitive variables and sexual risk behaviors among infected and HIV uninfected people from Spain. AB - The wider availability of anti-retroviral treatment has brought about an improvement in the immunological situation of human immunodeficiency virus (HIV) positive individuals, which in turn has led to significant reductions in AIDS related morbidity and mortality and better quality of life for patients. However, the rate of diagnosis of new cases of HIV among the adult population is on the increase due to high-risk sexual behavior practices, particularly not using condoms, sexual relations with a large number of partners and starting sexual relations at a younger age, with unplanned pregnancies and sexually transmitted infections (STIs), including HIV. For this reason, public health managers have invested considerable effort in recent years in creating STI and HIV prevention programs. Yet, in spite of the implementation of measures for reducing the rates of infection, few studies have been published in Spain comparing individuals living with HIV with the general population about cognitive variables and the link between these variables and high-risk sexual behavior. The objective was to compare a group of individuals living with HIV with another group from the general population in terms of cognitive variables (knowledge about STIs and HIV, concern about STI/HIV and pregnancy, self-efficacy to refuse sexual relations and resilience) and sexual behavior. The sample consisted of 318 adults, 159 were from the general population and 159 were individuals living with HIV. Individuals living with HIV had higher scores for concern about HIV/AIDS, STIs, pregnancy and knowledge of STI/HIV compared with the general population. We concluded that uninfected people who had low and high level of concern about HIV/AIDS began having anal sex at a younger age than those with a medium level of concern. Overall, results indicate that the concern about HIV/AIDS should be addressed in preventive health interventions to minimize the risks of sexual behavior. PMID- 26981842 TI - The Importance of Antenatal Partner Support. PMID- 26981843 TI - Introduction of cationic virosome derived from vesicular stomatitis virus as a novel gene delivery system for sf9 cells. AB - Insect-derived cell lines are used extensively to produce recombinant proteins because they are capable of performing a range of post-translational modifications. Due to their significance in biotechnological applications, various methods have been developed to transfect them. In this study, we introduce a virosome constructed from vesicular stomatitis virus (VSV) as a new delivery system for sf9 cells. We labeled these VSV virosomes by fluorescent probe Rhodamine B chloride (R18). By fluorescence microscope observation and conducting a fusion assay, we confirmed the uptake of VSV virosomes via endocytosis by sf9 cells and their fusion with the endosomal membrane. Moreover, we incubated cationic VSV virosomes with a GFP-expressing bacmid and transfected sf9 cells, after 24 h some cells expressed GFP indicating the ability of VSV virosomes to deliver heterologous DNA to these cells. This is the first report of a virosome-based delivery system introduced for an insect cell line. PMID- 26981844 TI - Facility Design and Health Management Program at the Sinnhuber Aquatic Research Laboratory. AB - The number of researchers and institutions moving to the utilization of zebrafish for biomedical research continues to increase because of the recognized advantages of this model. Numerous factors should be considered before building a new or retooling an existing facility. Design decisions will directly impact the management and maintenance costs. We and others have advocated for more rigorous approaches to zebrafish health management to support and protect an increasingly diverse portfolio of important research. The Sinnhuber Aquatic Research Laboratory (SARL) is located ~3 miles from the main Oregon State University campus in Corvallis, Oregon. This facility supports several research programs that depend heavily on the use of adult, larval, and embryonic zebrafish. The new zebrafish facility of the SARL began operation in 2007 with a commitment to build and manage an efficient facility that diligently protects human and fish health. An important goal was to ensure that the facility was free of Pseudoloma neurophilia (Microsporidia), which is very common in zebrafish research facilities. We recognize that there are certain limitations in space, resources, and financial support that are institution dependent, but in this article, we describe the steps taken to build and manage an efficient specific pathogen-free facility. PMID- 26981845 TI - Overcoming challenges of treating inflammatory bowel disease in pregnancy. AB - Inflammatory bowel disease (IBD) is frequently diagnosed before or during the peak reproductive years. Overall management of inflammatory bowel disease is becoming more complex given the nuances involved with multiple mechanisms of action of the current treatment and need for therapeutic monitoring for safety and efficacy; another layer of complexity is added in the setting of a pregnancy. In this review, we have identified several key challenges that health care providers face when caring for patients with IBD during pregnancy. The goal of this review is to provide the most up-to-date evidence and provide our expert recommendations so that providers can more comfortably address patients' questions about pregnancy in IBD and the associated risks as well as optimize their care to ensure the best outcomes possible. PMID- 26981846 TI - Lactoferrin, a Pleiotropic Protein in Health and Disease. AB - SIGNIFICANCE: Lactoferrin (Lf) is a nonheme iron-binding glycoprotein strongly expressed in human and bovine milk and it plays many functions during infancy such as iron homeostasis and defense against microorganisms. In humans, Lf is mainly expressed in mucosal epithelial and immune cells. Growing evidence suggests multiple physiological roles for Lf after weaning. RECENT ADVANCES: The aim of this review is to highlight the recent advances concerning multifunctional Lf activities. CRITICAL ISSUES: First, we will provide an overview of the mechanisms related to Lf intrinsic synthesis or intestinal absorption as well as its interaction with a wide spectrum of mammalian receptors and distribution in organs and cell types. Second, we will discuss the large variety of its physiological functions such as iron homeostasis, transportation, immune regulation, oxidative stress, inflammation, and apoptosis while specifying the mechanisms of action. Third, we will focus on its recent physiopathology implication in metabolic disorders, including obesity, type 2 diabetes, and cardiovascular diseases. Additional efforts are necessary before suggesting the potential use of Lf as a diagnostic marker or as a therapeutic tool. FUTURE DIRECTIONS: The main sources of Lf in human cardiometabolic disorders should be clarified to identify new perspectives for future research and develop new strategies using Lf in therapeutics. Antioxid. Redox Signal. 24, 813-836. PMID- 26981847 TI - Molecular and Phenotypic Characterization of Multidrug-Resistant Clones of Staphylococcus epidermidis in Iranian Hospitals: Clonal Relatedness to Healthcare Associated Methicillin-Resistant Isolates in Northern Europe. AB - The aim of the study was to investigate the molecular epidemiology of Staphylococcus epidermidis in Iranian hospitals and to compare the genotypes with a previously characterized collection of >1,300 S. epidermidis isolates of nosocomial and community origin from Northern Europe, Australia, and USA. In total, 82 clinical S. epidermidis isolates from three Iranian hospitals were examined by multilocus sequence typing, pulsed-field gel electrophoresis (PFGE) and staphylococcal cassette chromosome mec (SCCmec) typing. In addition, antimicrobial susceptibility, the presence of the ica operon, and the predilection to biofilm formation were assessed. Three predominant PFGE clones were found. The PFGE patterns of the most common sequence type (PFGE type 040 ST2) showed 80% similarity to multidrug-resistant S. epidermidis (MDRSE) clinical isolates from eight hospitals in Northern Europe. The second most common (PFGE 024-ST22) showed an unique PFGE pattern, whereas the third most predominant genotype (PFGE 011-ST5) proved indistinguishable to the PFGE Co-ST5 identified in five hospitals in Northern Europe. In conclusion, the study documented the dissemination of three MDRSE clones within and between hospitals in Iran and revealed an intercontinental spread of two clonal multidrug-resistant lineages (ST2 and ST5) in the hospital environment. Isolates of the predominant clones were significantly more frequently associated with multidrug-resistance and biofilm formation compared to nonclonal isolates. Further studies are needed to explore and characterize the genetic traits that enable these successful MDRSE clones to persist and disseminate worldwide in the healthcare settings. PMID- 26981849 TI - Lanthanum Nitrate As Electrolyte Additive To Stabilize the Surface Morphology of Lithium Anode for Lithium-Sulfur Battery. AB - Lithium-sulfur (Li-S) battery is regarded as one of the most promising candidates beyond conventional lithium ion batteries. However, the instability of the metallic lithium anode during lithium electrochemical dissolution/deposition is still a major barrier for the practical application of Li-S battery. In this work, lanthanum nitrate, as electrolyte additive, is introduced into Li-S battery to stabilize the surface of lithium anode. By introducing lanthanum nitrate into electrolyte, a composite passivation film of lanthanum/lithium sulfides can be formed on metallic lithium anode, which is beneficial to decrease the reducibility of metallic lithium and slow down the electrochemical dissolution/deposition reaction on lithium anode for stabilizing the surface morphology of metallic Li anode in lithium-sulfur battery. Meanwhile, the cycle stability of the fabricated Li-S cell is improved by introducing lanthanum nitrate into electrolyte. Apparently, lanthanum nitrate is an effective additive for the protection of lithium anode and the cycling stability of Li-S battery. PMID- 26981850 TI - Erratum. PMID- 26981848 TI - A Study Protocol for the Australasian Oncofertility Registry: Monitoring Referral Patterns and the Uptake, Quality, and Complications of Fertility Preservation Strategies in Australia and New Zealand. AB - Improvements in cancer diagnosis and treatment in patients of a reproductive age have led to significant improvements in survival rates; however, a patient's fertility can be affected by both cancer and its treatment. As survival rates improve, there is an expectation by clinicians and patients that patient's reproductive potential should be considered and protected as much as possible. However, there is a lack of data about current fertility preservation (FP) uptake as well as accurate data on the acute or permanent reproductive risks of cancer treatment, complications of FP in cancer patients, and the use and success of assisted reproductive technology by cancer survivors. FP remains a major gap in acute cancer management with lifelong implications for cancer survivors. The FUTuRE Fertility research team has established the first binational multisite Australasian Oncofertility Registry, which is collecting a complete oncofertility data set from cancer and fertility centers in Australia and New Zealand. Outcomes from the research study will monitor referral, uptake, and complications of FP, document patient's reproductive potential after treatment, and collect data on the use of assisted reproductive technology following cancer treatment. The data will be linked to other routine health and administrative data sets to allow for other research projects to be carried out. The changes in oncofertility care will be benchmarked against the Australasian Oncofertility Charter. The data will be used to develop evidence-based guidelines and resources, including development of accurate risk projections for patients' risk of infertility, allowing clinicians to make recommendations for FP or assisted reproductive technology. Australian New Zealand Clinical Trials Number-12615000221550. PMID- 26981851 TI - The auditory characteristics of children with inner auditory canal stenosis. AB - Conclusions This study shows that the prevalence of auditory neuropathy spectrum disorder (ANSD) in the children with inner auditory canal (IAC) stenosis is much higher than those without IAC stenosis, regardless of whether they have other inner ear anomalies. In addition, the auditory characteristics of ANSD with IAC stenosis are significantly different from those of ANSD without any middle and inner ear malformations. Objectives To describe the auditory characteristics in children with IAC stenosis as well as to examine whether the narrow inner auditory canal is associated with ANSD. Method A total of 21 children, with inner auditory canal stenosis, participated in this study. A series of auditory tests were measured. Meanwhile, a comparative study was conducted on the auditory characteristics of ANSD, based on whether the children were associated with isolated IAC stenosis. Results Wave V in the ABR was not observed in all the patients, while cochlear microphonic (CM) response was detected in 81.1% ears with stenotic IAC. Sixteen of 19 (84.2%) ears with isolated IAC stenosis had CM response present on auditory brainstem responses (ABR) waveforms. There was no significant difference in ANSD characteristics between the children with and without isolated IAC stenosis. PMID- 26981852 TI - Development, Technical, and User Evaluation of a Web Mobile Application for Self Control of Diabetes. AB - OBJECTIVE: The main objective of this research was to develop and evaluate a Web based mobile application (app) known as "Diario Diabetes" on both a technical and user level, by means of which individuals with diabetes may monitor their illness easily at any time and in any place using any device that has Internet access. METHODS: The technologies used to develop the app were HTML, CSS, JavaScript, PHP, and MySQL, all of which are an open source. Once the app was developed, it was evaluated on a technical level (by measuring loading times) and on a user level, through a survey. RESULTS: Different loading times for the application were measured, with it being noted that under no circumstances does this exceed 2 s. Usability was evaluated by 150 users who initially used the application. A majority (71%) of users used a PC to access the app, 83% considered the app's design to be attractive, 67% considered the tasks to be very useful, and 67% found it very easy to use. CONCLUSIONS: Although applications exist for controlling diabetes both at mobile virtual shops or on a research level, our app may help to improve the administration of these types of patients and they are the ones who will ultimately opt for one or the other. According to the results obtained, we can state that all users would recommend the app's use to other users. PMID- 26981853 TI - The Susceptibility to Dental Erosion Differs among Individuals. AB - Studies of wine tasters and patients with self-induced vomiting have revealed that 30-50% of individuals at high risk do not develop erosive lesions. The aim was to investigate this apparent individual susceptibility to enamel erosion. Two enamel specimens were made from each of 3 premolars from 8 persons (donors). Six acrylic mouth appliances were worn by 6 volunteers (carriers). One specimen from each donor was mounted on each appliance. The carriers wore the appliances for 9 days. The appliances were immersed in 0.01 M HCl for 3 min twice per day to imitate a vomiting/reflux situation. The enamel specimens were analysed by a white-light interferometer to measure enamel loss (in micrometres). The enamel loss varied significantly both between the donor teeth (p = 0.009) and the carriers (p = 0.004). The lesion in the specimen with the largest amount of enamel loss was 4 times as deep as in the specimen with the lowest. In 1 carrier, all specimens displayed enamel loss above the mean, including the specimen from the donor with the most resistant enamel. The variation in susceptibility to erosion among individuals appears to be influenced both by the sustainability of the enamel and by factors in the oral environment. This could explain the variation in prevalence and severity of dental erosions among patients exposed to similar acidic challenges. The results suggest that for certain individuals, only minimal acidic challenges may be sufficient to cause damage to the teeth, while others may never develop dental erosions despite extensive exposure to acid. PMID- 26981854 TI - Preface. PMID- 26981855 TI - 'Treat to Target' - Lessons Learnt. AB - BACKGROUND: Therapeutic management in inflammatory bowel diseases (IBD) has significantly changed in the last decades with the advent of biological therapy resulting in new treatment targets other than clinical symptoms. KEY MESSAGES: Patient stratification in the early stage of the disease is an important step to identify patients with poor prognosis, who might benefit from early aggressive treatment to avoid complications in the later disease course. Recent randomized and hypothesis driven (e.g., Randomized Evaluation of an Algorithm for Crohn's Treatment, Post-Operative Crohn's Endoscopic Recurrence) clinical trials conducted in the biological era underscore the need of objective disease monitoring including assessment of biomarkers (e.g., C-reactive protein and calprotectin), mucosal healing and, for biologically treated patients, therapeutic drug monitoring beside clinical symptom assessment in both Crohn's disease and ulcerative colitis. CONCLUSIONS: Assessing the treatment efficacy objectively has become an important element of patient monitoring besides clinical symptom assessment. Further clinical studies are needed to assess whether implementation of new therapeutic algorithms based on these targets and tight monitoring in clinical practice have the potential to further improve long term disease outcomes in IBD. PMID- 26981856 TI - A Novel Scoring System Based on Fibrinogen and the Neutrophil-Lymphocyte Ratio as a Predictor of Chemotherapy Response and Prognosis in Patients with Advanced Gastric Cancer. AB - OBJECTIVE: We assessed the clinical applicability of the F-NLR score, which is based on fibrinogen (F) and the neutrophil-lymphocyte ratio (NLR), and the Glasgow Prognostic Score (GPS) to predict the therapeutic effects of chemotherapy or chemoradiotherapy on advanced gastric cancer and the prognoses of patients. METHODS: Sixty-eight patients with advanced gastric cancer treated with first line chemotherapy or chemoradiotherapy were classified into two groups based on tumor response. Furthermore, we categorized patients according to cutoff F-NLR scores of 2 [hyperfibrinogenemia (>400 mg/dl) and high NLR (>3.0)], 1 [one of these hematological abnormalities], and 0 [neither hyperfibrinogenemia nor high NLR]. RESULTS: A total of 27 patients had progressive disease (PD) and 41 did not. The F-NLR scores were significantly higher in the PD than in the non-PD group (p = 0.003). Survival was significantly shorter for patients with high F NLR scores and GPS (p = 0.0071 and p = 0.0065, respectively). Multivariate analysis selected the F-NLR score as an independent prognostic factor (p = 0.017). CONCLUSION: A novel grading system based on F-NLR scores, as well as the GPS, appears to have value as a clinical predictor of the therapeutic response of advanced gastric cancer to chemotherapy or chemoradiotherapy and the prognoses of patients. PMID- 26981857 TI - Analysis of Road Network Pattern Considering Population Distribution and Central Business District. AB - This paper proposes a road network growing model with the consideration of population distribution and central business district (CBD) attraction. In the model, the relative neighborhood graph (RNG) is introduced as the connection mechanism to capture the characteristics of road network topology. The simulation experiment is set up to illustrate the effects of population distribution and CBD attraction on the characteristics of road network. Moreover, several topological attributes of road network is evaluated by using coverage, circuitness, treeness and total length in the experiment. Finally, the suggested model is verified in the simulation of China and Beijing Highway networks. PMID- 26981858 TI - Nodular Fasciitis: Definitive Diagnosis by Fine Needle Aspiration. AB - OBJECTIVES: Nodular fasciitis (NF) is a self-limited, mass-forming, fibrous proliferation that can occur in the head and neck and may mimic malignancy. Fine needle aspiration biopsy (FNAB) is a minimally invasive, rapid, accurate method of obtaining diagnostic material from head and neck masses. In this study, we verify the usefulness of FNAB in obtaining a definitive diagnosis of NF. METHODS: Cases were identified from our laboratory information system. Cytology slides were reviewed to note morphologic features and confirm diagnoses. Clinical history was obtained to document the case presentations and outcomes. RESULTS: All 9 cases were found to have clinical presentations and common distinguishing morphologic features consistent with NF. Two cases were excised surgically, and the remainder regressed spontaneously. There were no recurrences. CONCLUSIONS: FNAB can produce a definitive diagnosis of NF, providing an opportunity to avoid surgical excision in patients with a typical clinical presentation. PMID- 26981859 TI - Incidence and Predictive Factors of Central Nervous System Dysfunction in Patients Consulting for Dengue Fever in Cayenne Hospital, French Guiana. AB - INTRODUCTION: The frequency, the clinical characteristics, and the prognosis of dengue is highly variable. Dengue fever is associated with a range of neurological manifestations. The objective of the present study was to determine the incidence of neurological signs and their predictive factors using data from cases of dengue seen and followed in Cayenne Hospital during the Dengue 2 epidemic in 2013. METHODS: In 2013, a longitudinal study using data from all cases of dengue seen in Cayenne hospital was collected. Medical records used a standardized form to collect demographic information, clinical signs and biological results and the date at which they were present. The analysis used Cox proportional modeling to obtain adjusted Hazard ratios. RESULTS: A total of 1574 patients were included 221 of whom developed central nervous system signs. These signs were spontaneously resolutive. There were 9298person days of follow-up and the overall incidence rate for central nervous system signs was 2.37 per 100 person-days. The variables independently associated with central nervous system anomalies were headache, Adjusted Hazard ratio (AHR) = 1.9(95%CI = 1.4-2.6), bleeding AHR = 2 ((95%CI = 1.3-3.1), P = 0.001, abdominal pain AHR = 1.9 ((95%CI = 1.4-2.6), P<0.001, aches AHR = 2.1 ((95%CI = 1.5-2.9), P<0.001, and fatigue AHR = 1.5 ((95%CI = 1.3-1.7), P<0.001. DISCUSSION: Overall, the present study suggests that neurological signs of dengue are not exceptional even in patients without the most severe features of dengue. These manifestations were spontaneously resolutive. Here it was not possible to distinguish between encephalitis or encephalopathy. Further studies would require more in depth exploration of the patients. PMID- 26981860 TI - Developing Repair Materials for Stress Urinary Incontinence to Withstand Dynamic Distension. AB - BACKGROUND: Polypropylene mesh used as a mid-urethral sling is associated with severe clinical complications in a significant minority of patients. Current in vitro mechanical testing shows that polypropylene responds inadequately to mechanical distension and is also poor at supporting cell proliferation. AIMS AND OBJECTIVES: Our objective therefore is to produce materials with more appropriate mechanical properties for use as a sling material but which can also support cell integration. METHODS: Scaffolds of two polyurethanes (PU), poly-L-lactic acid (PLA) and co-polymers of the two were produced by electrospinning. Mechanical properties of materials were assessed and compared to polypropylene. The interaction of adipose derived stem cells (ADSC) with the scaffolds was also assessed. Uniaxial tensiometry of scaffolds was performed before and after seven days of cyclical distension. Cell penetration (using DAPI and a fluorescent red cell tracker dye), viability (AlamarBlue assay) and total collagen production (Sirius red assay) were measured for ADSC cultured on scaffolds. RESULTS: Polypropylene was stronger than polyurethanes and PLA. However, polypropylene mesh deformed plastically after 7 days of sustained cyclical distention, while polyurethanes maintained their elasticity. Scaffolds of PU containing PLA were weaker and stiffer than PU or polypropylene but were significantly better than PU scaffolds alone at supporting ADSC. CONCLUSIONS: Therefore, prolonged mechanical distension in vitro causes polypropylene to fail. Materials with more appropriate mechanical properties for use as sling materials can be produced using PU. Combining PLA with PU greatly improves interaction of cells with this material. PMID- 26981861 TI - Self-Generated Chemoattractant Gradients: Attractant Depletion Extends the Range and Robustness of Chemotaxis. AB - Chemotaxis is fundamentally important, but the sources of gradients in vivo are rarely well understood. Here, we analyse self-generated chemotaxis, in which cells respond to gradients they have made themselves by breaking down globally available attractants, using both computational simulations and experiments. We show that chemoattractant degradation creates steep local gradients. This leads to surprising results, in particular the existence of a leading population of cells that moves highly directionally, while cells behind this group are undirected. This leading cell population is denser than those following, especially at high attractant concentrations. The local gradient moves with the leading cells as they interact with their surroundings, giving directed movement that is unusually robust and can operate over long distances. Even when gradients are applied from external sources, attractant breakdown greatly changes cells' responses and increases robustness. We also consider alternative mechanisms for directional decision-making and show that they do not predict the features of population migration we observe experimentally. Our findings provide useful diagnostics to allow identification of self-generated gradients and suggest that self-generated chemotaxis is unexpectedly universal in biology and medicine. PMID- 26981863 TI - Modulation of the Cutaneous Silent Period in the Upper-Limb with Whole-Body Instability. AB - The silent period induced by cutaneous electrical stimulation of the digits has been shown to be task-dependent, at least in the grasping muscles of the hand. However, it is unknown if the cutaneous silent period is adaptable throughout muscles of the entire upper limb, in particular when the task requirements are substantially altered. The purpose of the present study was to examine the characteristics of the cutaneous silent period in several upper limb muscles when introducing increased whole-body instability. The cutaneous silent period was evoked in 10 healthy individuals with electrical stimulation of digit II of the right hand when the subjects were seated, standing, or standing on a wobble board while maintaining a background elbow extension contraction with the triceps brachii of ~5% of maximal voluntary contraction (MVC) strength. The first excitatory response (E1), first inhibitory response (CSP), and second excitatory response (E2) were quantified as the percent change from baseline and by their individual durations. The results showed that the level of CSP suppression was lessened (47.7 +/- 7.7% to 33.8 +/- 13.2% of baseline, p = 0.019) and the duration of the CSP inhibition decreased (p = 0.021) in the triceps brachii when comparing the seated and wobble board tasks. For the wobble board task the amount of cutaneous afferent inhibition of EMG activity in the triceps brachii decreased; which is proposed to be due to differential weighting of cutaneous feedback relative to the corticospinal drive, most likely due to presynaptic inhibition, to meet the demands of the unstable task. PMID- 26981864 TI - High Altitude Journeys, Flights and Hypoxia: Any Role for Disease Flares in IBD Patients? AB - The importance of environmental factors in the pathogenesis including their disease-modifying potential are increasingly recognized in inflammatory bowel disease (IBD) patients, largely driven by the perception that the prevalence and incidence of IBD are on the rise within the last few years, especially in non western countries. One of those factors is believed to be hypoxia. The role of hypoxia as a modifying or even causative factor in the genesis and maintenance of inflammation has been increasingly elucidated in recent years. Hypoxia is believed to be a main inducing factor of inflammation. This has been studied in different animal experiments as well as in humans exposed to hypoxia. In several studies - mainly in mice - animals exposed to short-term hypoxia accumulated inflammatory cells in multiple organs and showed elevated cytokines in the blood. Comparable studies were performed in humans, mainly in healthy mountaineers. Recently, we reported on the association between IBD flare-up episodes and antecedent journeys to high-altitude region and aircraft travels. According to these findings, we concluded that flights and stays at high altitudes of >2,000 mg are a risk factor for increased disease activity in IBD. To evaluate the potential influence of hypoxia on the course of IBD on a biomolecular level and to test the effects of hypoxia under standardized conditions, we initiated a prospective and controlled investigation in both healthy controls and IBD patients in stable remission. The study participants underwent a 3-hour exposure to hypoxic conditions simulating an altitude of 4,000 m above sea level in a hyperbaric pressure chamber and clinical parameters as well as blood and stool samples were collected at several time points. The first results of this study are expected in the near future. PMID- 26981862 TI - CYP1B1 Enhances Cell Proliferation and Metastasis through Induction of EMT and Activation of Wnt/beta-Catenin Signaling via Sp1 Upregulation. AB - Cytochrome P450 1B1 (CYP1B1) is a major E2 hydroxylase involved in the metabolism of potential carcinogens. CYP1B1 expression has been reported to be higher in tumors compared to normal tissues, especially in hormone-related cancers including breast, ovary, and prostate tumors. To explore the role of CYP1B1 in cancer progression, we investigated the action of CYP1B1 in cells with increased CYP1B1 via the inducer 7,12-dimethylbenz[alpha]anthracene (DMBA) or an overexpression vector, in addition to decreased CYP1B1 via the inhibitor tetramethoxystilbene (TMS) or siRNA knockdown. We observed that CYP1B1 promoted cell proliferation, migration, and invasion in MCF-7 and MCF-10A cells. To understand its molecular mechanism, we measured key oncogenic proteins including beta-catenin, c-Myc, ZEB2, and matrix metalloproteinases following CYP1B1 modulation. CYP1B1 induced epithelial-mesenchymal transition (EMT) and activated Wnt/beta-catenin signaling via upregulation of CTNNB1, ZEB2, SNAI1, and TWIST1. Sp1, a transcription factor involved in cell growth and metastasis, was positively regulated by CYP1B1, and suppression of Sp1 expression by siRNA or DNA binding activity using mithramycin A blocked oncogenic transformation by CYP1B1. Therefore, we suggest that Sp1 acts as a key mediator for CYP1B1 action. Treatment with 4-hydroxyestradiol (4-OHE2), a major metabolite generated by CYP1B1, showed similar effects as CYP1B1 overexpression, indicating that CYP1B1 activity mediated various oncogenic events in cells. In conclusion, our data suggests that CYP1B1 promotes cell proliferation and metastasis by inducing EMT and Wnt/beta-catenin signaling via Sp1 induction. PMID- 26981865 TI - Safe Oral Triiodo-L-Thyronine Therapy Protects from Post-Infarct Cardiac Dysfunction and Arrhythmias without Cardiovascular Adverse Effects. AB - BACKGROUND: A large body of evidence suggests that thyroid hormones (THs) are beneficial for the treatment of cardiovascular disorders. We have shown that 3 days of triiodo-L-thyronine (T3) treatment in myocardial infarction (MI) rats increased left ventricular (LV) contractility and decreased myocyte apoptosis. However, no clinically translatable protocol is established for T3 treatment of ischemic heart disease. We hypothesized that low-dose oral T3 will offer safe therapeutic benefits in MI. METHODS AND RESULTS: Adult female rats underwent left coronary artery ligation or sham surgeries. T3 (~6 MUg/kg/day) was available in drinking water ad libitum immediately following MI and continuing for 2 month(s) (mo). Compared to vehicle-treated MI, the oral T3-treated MI group at 2 mo had markedly improved anesthetized Magnetic Resonance Imaging-based LV ejection fraction and volumes without significant negative changes in heart rate, serum TH levels or heart weight, indicating safe therapy. Remarkably, T3 decreased the incidence of inducible atrial tachyarrhythmias by 88% and improved remodeling. These were accompanied by restoration of gene expression involving several key pathways including thyroid, ion channels, fibrosis, sympathetic, mitochondria and autophagy. CONCLUSIONS: Low-dose oral T3 dramatically improved post-MI cardiac performance, decreased atrial arrhythmias and cardiac remodeling, and reversed many adverse changes in gene expression with no observable negative effects. This study also provides a safe and effective treatment/monitoring protocol that should readily translate to humans. PMID- 26981866 TI - Documenting Penicillin Allergy: The Impact of Inconsistency. AB - BACKGROUND: Allergy documentation is frequently inconsistent and incomplete. The impact of this variability on subsequent treatment is not well described. OBJECTIVE: To determine how allergy documentation affects subsequent antibiotic choice. DESIGN: Retrospective, cohort study. PARTICIPANTS: 232,616 adult patients seen by 199 primary care providers (PCPs) between January 1, 2009 and January 1, 2014 at an academic medical system. MAIN MEASURES: Inter-physician variation in beta-lactam allergy documentation; antibiotic treatment following beta-lactam allergy documentation. KEY RESULTS: 15.6% of patients had a reported beta-lactam allergy. Of those patients, 39.8% had a specific allergen identified and 22.7% had allergic reaction characteristics documented. Variation between PCPs was greater than would be expected by chance (all p<0.001) in the percentage of their patients with a documented beta-lactam allergy (7.9% to 24.8%), identification of a specific allergen (e.g. amoxicillin as opposed to "penicillins") (24.0% to 58.2%) and documentation of the reaction characteristics (5.4% to 51.9%). After beta-lactam allergy documentation, patients were less likely to receive penicillins (Relative Risk [RR] 0.16 [95% Confidence Interval: 0.15-0.17]) and cephalosporins (RR 0.28 [95% CI 0.27-0.30]) and more likely to receive fluoroquinolones (RR 1.5 [95% CI 1.5-1.6]), clindamycin (RR 3.8 [95% CI 3.6-4.0]) and vancomycin (RR 5.0 [95% CI 4.3-5.8]). Among patients with beta-lactam allergy, rechallenge was more likely when a specific allergen was identified (RR 1.6 [95% CI 1.5-1.8]) and when reaction characteristics were documented (RR 2.0 [95% CI 1.8-2.2]). CONCLUSIONS: Provider documentation of beta-lactam allergy is highly variable, and details of the allergy are infrequently documented. Classification of a patient as beta-lactam allergic and incomplete documentation regarding the details of the allergy lead to beta-lactam avoidance and use of other antimicrobial agents, behaviors that may adversely impact care quality and cost. PMID- 26981867 TI - Demonstrating Functional Equivalence of Pilot and Production Scale Freeze-Drying of BCG. AB - Process analytical technology (PAT)-tools were used to monitor freeze-drying of Bacille Calmette-Guerin (BCG) at pilot and production scale. Among the evaluated PAT-tools, there is the novel use of the vacuum valve open/close frequency for determining the endpoint of primary drying at production scale. The duration of primary drying, the BCG survival rate, and the residual moisture content (RMC) were evaluated using two different freeze-drying protocols and were found to be independent of the freeze-dryer scale evidencing functional equivalence. The absence of an effect of the freeze-dryer scale on the process underlines the feasibility of the pilot scale freeze-dryer for further BCG freeze-drying process optimization which may be carried out using a medium without BCG. PMID- 26981868 TI - Challenges for the management of health work in the public sector. PMID- 26981869 TI - [Educational inequality in the occurrence of abdominal obesity according to gender and color/race: the Pro-Health Study, 1999-2001 and 2011-2012]. AB - Cross-sectional data from the Pro-Health Study in 1999-2001 and 2011-2012 revealed important gender and color/race differences in the size and variation across time in educational inequalities related to abdominal obesity. Probability of obesity increased steadily in women (independently of color/race) and men (brown/black) with less schooling. These gradients were quantified according to the relative index of inequality (RII). Over the course of the decade, there was a reduction in inequality in brown/black women (DeltaRII: 0.5; 95%CI: 0.2-1.1), underlying a relatively higher increase in the prevalence of abdominal obesity in women with more schooling. RII was stable in white women and brown/black men, indicating a similar increase in the prevalence of abdominal obesity in educational subgroups. The association between schooling and abdominal obesity was affected by the multiple interaction of socio-demographic factors. Our results recommend joint stratification by gender and color/race in the study of socioeconomic inequalities related to abdominal obesity. PMID- 26981870 TI - Lobbying by Big Pharma, bottlenecks for clinical research, and loosening of ethical standards in Brazil. PMID- 26981871 TI - The tragedy of mining and development in Brazil: public health challenges. PMID- 26981872 TI - Synthesis of Vinyl Isocyanides and Development of a Convertible Isonitrile. AB - The reaction of isocyanomethylenetriphenylphosphorane, generated in situ from the corresponding phosphonium salt, with a diverse set of aldehydes afforded vinyl isocyanides in good to high yields. Excellent E-selectivity was observed for aliphatic aldehydes and 2,6-disubstituted aromatic aldehydes, whereas Z-olefins were formed predominantly with ortho-substituted aryl aldehydes. (Z)-1-Bromo-2-(2 isocyanovinyl)benzene (5l) was found to be a truly universal isonitrile since, after Ugi reaction, the resulting secondary amide unit (RNHCO-) is convertible under both acidic and basic conditions. The application of 5l in the synthesis of polyheterocycles is also illustrated. PMID- 26981873 TI - Mycobacterium tuberculosis Peptidyl-Prolyl Isomerases Also Exhibit Chaperone like Activity In-Vitro and In-Vivo. AB - Peptidyl-prolyl cis-trans isomerases (Ppiases), also known as cyclophilins, are ubiquitously expressed enzymes that assist in protein folding by isomerization of peptide bonds preceding prolyl residues. Mycobacterium tuberculosis (M.tb) is known to possess two Ppiases, PpiA and PpiB. However, our understanding about the biological significance of mycobacterial Ppiases with respect to their pleiotropic roles in responding to stress conditions inside the macrophages is restricted. This study describes chaperone-like activity of mycobacterial Ppiases. We show that recombinant rPpiA and rPpiB can bind to non-native proteins in vitro and can prevent their aggregation. Purified rPpiA and rPpiB exist in oligomeric form as evident from gel filtration chromatography.E. coli cells overexpressing PpiA and PpiB of M.tb could survive thermal stress as compared to plasmid vector control. HEK293T cells transiently expressing M.tb PpiA and PpiB proteins show increased survival as compared to control cells in response to oxidative stress and hypoxic conditions generated after treatment with H2O2 and CoCl2 thereby pointing to their likely role in adaption under host generated oxidative stress and conditions of hypoxia. The chaperone-like function of these M.tuberculosis cyclophilins may possibly function as a stress responder and consequently contribute to virulence. PMID- 26981875 TI - Sustained Elevated Cytokine Levels during Recovery Phase of Mayaro Virus Infection. PMID- 26981874 TI - Isolation of Bartonella henselae and Two New Bartonella Subspecies, Bartonellakoehlerae Subspecies boulouisii subsp. nov. and Bartonella koehlerae Subspecies bothieri subsp. nov. from Free-Ranging Californian Mountain Lions and Bobcats. AB - Domestic cats are the natural reservoir of Bartonella henselae, B. clarridgeiae and B. koehlerae. To determine the role of wild felids in the epidemiology of Bartonella infections, blood was collected from 14 free-ranging California mountain lions (Puma concolor) and 19 bobcats (Lynx rufus). Bartonella spp. were isolated from four (29%) mountain lions and seven (37%) bobcats. These isolates were characterized using growth characteristics, biochemical reactions, molecular techniques, including PCR-RFLP of selected genes or interspacer region, pulsed field gel electrophoresis (PFGE), partial sequencing of several genes, and DNA DNA hybridization. Two isolates were identical to B. henselae genotype II. All other isolates were distinguished from B. henselae and B. koehlerae by PCR-RFLP of the gltA gene using endonucleases HhaI, TaqI and AciI, with the latter two discriminating between the mountain lion and the bobcat isolates. These two novel isolates displayed specific PFGE profiles distinct from B. henselae, B. koehlerae and B. clarridgeiae. Sequences of amplified gene fragments from the three mountain lion and six bobcat isolates were closely related to, but distinct from, B. henselae and B. koehlerae. Finally, DNA-DNA hybridization studies demonstrated that the mountain lion and bobcat strains are most closely related to B. koehlerae. We propose naming the mountain lion isolates B. koehlerae subsp. boulouisii subsp. nov. (type strain: L-42-94), and the bobcat isolates B. koehlerae subsp. bothieri subsp. nov. (type strain: L-17-96), and to emend B. koehlerae as B. koehlerae subsp. koehlerae. The mode of transmission and the zoonotic potential of these new Bartonella subspecies remain to be determined. PMID- 26981876 TI - Stabilization of the Amorphous Ezetimibe Drug by Confining Its Dimension. AB - The purpose of this paper is to investigate the influence of nanoconfinement on the molecular mobility, as well as on the physical stability, of amorphous ezetimibe drug. Two guest/host systems, ezetimibe-Aeroperl 300 and ezetimibe Neusilin US2, were prepared and studied using various experimental techniques, such as X-ray diffraction (XRD), differential scanning calorimetry (DSC), and broadband dielectric spectroscopy (BDS). Our investigation has shown that the molecular mobility of the examined anticholesterol agent incorporated into nanopore matrices strongly depends on the pore size of the host system. Moreover, it was found that the amorphous ezetimibe confined in 30 nm pores of Aeroperl 300 has a tendency to recrystallize, while the drug incorporated into the smaller--5 nm--pores of Neusilin US2 is not able to crystallize. It has been shown that this significant stabilization of ezetimibe drug can be achieved by an interplay of three factors: changes in molecular dynamics of the confined amorphous drug, the immobilization effect of pore walls on a part of ezetimibe molecules, and the use of host materials with pores that are smaller than the critical size of the drug crystal nuclei. PMID- 26981877 TI - Low-Cost National Media-Based Surveillance System for Public Health Events, Bangladesh. AB - We assessed a media-based public health surveillance system in Bangladesh during 2010-2011. The system is a highly effective, low-cost, locally appropriate, and sustainable outbreak detection tool that could be used in other low-income, resource-poor settings to meet the capacity for surveillance outlined in the International Health Regulations 2005. PMID- 26981878 TI - Two new phenolic compounds from the tuber of Sparganium stoloniferum. AB - Two new phenolic compounds, 2-(2-hydroxyphenyl)-4-methoxycarbonyl-5 hydroxybenzofuran (1) and 1-methoxycarbonyl-2, 3-dihydroxydibenzo[b, f]oxepine (2), were isolated from the tuber of Sparganium stoloniferum. The structures of both new compounds were determined on basis of spectroscopic means including HR ESI-MS, 1D and 2D NMR experiments. PMID- 26981879 TI - Pathway analysis of whole exome sequence data provides further support for the involvement of histone modification in the aetiology of schizophrenia. AB - Weighted burden pathway analysis was applied to whole exome sequence data for 2045 schizophrenic patients and 2045 controls. Overall, there was a statistically significant excess of pathways with more rare, functional variants in cases than in controls. Among the highest ranked were pathways relating to histone modification, as well as neuron differentiation and membrane and vesicle function. This bolsters the evidence from previous studies that histone modification pathways may be important in the aetiology of schizophrenia. PMID- 26981880 TI - Associations between APOE polymorphisms and seven diseases with cognitive impairment including Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies in southeast China. AB - OBJECTIVE: To explore the effect of APOE polymorphisms on patients with cognitive impairments in The Chinese Han population. MATERIALS AND METHODS: A total of 1027 cases with Alzheimer's disease (AD), 40 cases with vascular dementia (VaD), 28 cases with behavioral variant frontotemporal dementia (bvFTD), 54 cases with semantic dementia (SD), 44 cases with dementia with Lewy bodies (DLB), 583 cases with mild cognitive impairment (MCI), and 32 cases with vascular cognitive impairment no dementia (VCIND) were recruited consecutively from memory disorders clinics in Huashan Hospital between January 2010 and December 2014. The 1149 cognitively normal controls were recruited from the community epidemiologic investigations. The APOE genotypes were determined using the TaqMan assay. RESULTS: The distribution of genotype and allele frequencies of APOE differed significantly between control and AD or MCI, with epsilon4 increasing the risk of AD and MCI in a dose-dependent pattern and epsilon2 decreasing the risk of AD, but not the risk of MCI. As for VaD, significant differences in the APOE genotype distribution were found compared with the controls. E4/4 increased the risk of VaD and epsilon4 increased the risk of VCIND in women. The allele distribution differed between bvFTD and controls, but genotype and allele frequencies of APOE did not affect the risk of bvFTD, SD, and DLB. CONCLUSION: In The Chinese Han population, APOE epsilon4 increased the risk of AD and MCI in a dose-dependent manner and epsilon2 decreased the risk of AD as reported previously. APOE epsilon4 might increase risk in VaD and female patients with VCIND, but no effects of APOE on bvFTD, DLB, and SD were found. PMID- 26981881 TI - Propofol, but not ketamine or midazolam, exerts neuroprotection after ischaemic injury by inhibition of Toll-like receptor 4 and nuclear factor kappa-light-chain enhancer of activated B-cell signalling: A combined in vitro and animal study. AB - BACKGROUND: Propofol, midazolam and ketamine are widely used in today's anaesthesia practice. Both neuroprotective and neurotoxic effects have been attributed to all three agents. OBJECTIVE: To establish whether propofol, midazolam and ketamine in the same neuronal injury model exert neuroprotective effects on injured neurones in vitro and in vivo by modulation of the Toll-like receptor 4-nuclear factor kappa-light-chain-enhancer of activated B cells (TLR-4 NF-kappaB) pathway. DESIGN AND SETTING: Cell-based laboratory (n = 6 repetitions per experiment) and animal (n = 6 per group) studies using a neuronal cell line (SH-SY5Y cells) and adult Sprague-Dawley rats. INTERVENTIONS: Cells were exposed to oxygen-glucose deprivation before or after treatment using escalating, clinically relevant doses of propofol, midazolam and ketamine. In animals, retinal ischaemia (60 min) was induced followed by reperfusion and randomised treatment with saline or propofol. MAIN OUTCOME MEASURES: Neuronal cell death was determined using flow-cytometry (mitochondrial membrane potential) and lactate dehydrogenase (LDH) release. Nuclear factor NF-kappaB and hypoxia-inducible factor 1 alpha-activity were analysed by DNA-binding ELISA, expression of NF kappaB-dependent genes and TLR-4 by luciferase-assay and flow-cytometry, respectively. In animals, retinal ganglion cell density, caspase-3 activation and gene expression (TLR-4, NF-kappaB) were used to determine in vivo effects of propofol. Results were compared using ANOVA (Analysis of Variance) and t test. A P value less than 0.05 was considered statistically significant. RESULTS: Post treatment with clinically relevant concentrations of propofol (1 to 10 MUg ml) preserved the mitochondrial membrane potential in oxygen-glucose deprivation injured cells by 54% and reduced LDH release by 21%. Propofol diminished TLR-4 surface expression and preserved the DNA-binding activity of the protective hypoxia-inducible factor 1 alpha transcription factor. DNA-binding and transcriptional NF-kappaB-activity were inhibited by propofol. Neuronal protection and inhibition of TLR-4-NF-kappaB signalling were not consistently seen with midazolam or ketamine. In vivo, propofol treatment preserved rat retinal ganglion cell densities (cells mm, saline 1504 +/- 251 vs propofol 2088 +/- 144, P = 0.0001), which was accompanied by reduced neuronal caspase-3, TLR-4 and NF-kappaB expression. CONCLUSION: Propofol, but neither midazolam nor ketamine, provides neuroprotection to injured neuronal cells via inhibition of TLR-4-NF-kappaB-dependent signalling. PMID- 26981882 TI - Gas Chromatography/Mass Spectrometry-Based Metabolomic Profiling Reveals Alterations in Mouse Plasma and Liver in Response to Fava Beans. AB - Favism is a life-threatening hemolytic anemia resulting from the intake of fava beans by susceptible individuals with low erythrocytic glucose 6-phosphate dehydrogenase (G6PD) activity. However, little is known about the metabolomic changes in plasma and liver after the intake of fava beans in G6PD normal and deficient states. In this study, gas chromatography/mass spectrometry was used to analyze the plasma and liver metabolic alterations underlying the effects of fava beans in C3H- and G6PD-deficient (G6PDx) mice, and to find potential biomarkers and metabolic changes associated with favism. Our results showed that fava beans induced oxidative stress in both C3H and G6PDx mice. Significantly, metabolomic differences were observed in plasma and liver between the control and fava bean treated groups of both C3H and G6PDx mice. The levels of 7 and 21 metabolites in plasma showed significant differences between C3H-control (C3H-C)- and C3H fava beans-treated (C3H-FB) mice, and G6PDx-control (G6PDx-C)- and G6PDx fava beans treated (G6PDx-FB) mice, respectively. Similarly, the levels of 7 and 25 metabolites in the liver showed significant differences between C3H and C3H-FB, and G6PDx and G6PDx-FB, respectively. The levels of oleic acid, linoleic acid, and creatinine were significantly increased in the plasma of both C3H-FB and G6PDx-FB mice. In the liver, more metabolic alterations were observed in G6PDx-FB mice than in C3H-FB mice, and were involved in a sugar, fatty acids, amino acids, cholesterol biosynthesis, the urea cycle, and the nucleotide metabolic pathway. These findings suggest that oleic acid, linoleic acid, and creatinine may be potential biomarkers of the response to fava beans in C3H and G6PDx mice and therefore that oleic acid and linoleic acid may be involved in oxidative stress induced by fava beans. This study demonstrates that G6PD activity in mice can affect their metabolic pathways in response to fava beans. PMID- 26981883 TI - (99m)Tc-DPD scintigraphy as a novel imaging modality for identification of skeletal muscle amyloid deposition in light-chain amyloidosis. PMID- 26981885 TI - X-ray absorption study of ceria nanorods promoting the disproportionation of hydrogen peroxide. AB - A quasi in situ X-ray absorption study demonstrated that the disproportionation of hydrogen peroxide (H2O2) promoted by ceria nanorods was associated with a reversible Ce(3+)/Ce(4+) reaction and structural transformations in ceria. The direction of this reversible reaction was postulated to depend on the H2O2 concentration and the fraction of Ce(3+) species in ceria nanorods. PMID- 26981886 TI - Conduction and Reactivity in Heterogeneous-Molecular Catalysis: New Insights in Water Oxidation Catalysis by Phosphate Cobalt Oxide Films. AB - Cyclic voltammetry of phosphate cobalt oxide (CoPi) films catalyzing O2-evolution from water oxidation as a function of scan rate, phosphate concentration and film thickness allowed for new insights into the coupling between charge transport and catalysis. At pH = 7 and low buffer concentrations, the film is insulating below 0.8 (V vs SHE) but becomes conductive above 0.9 (V vs SHE). Between 1.0 to 1.3 (V vs SHE), the mesoporous structure of the film gives rise to a large thickness dependent capacitance. At higher buffer concentrations, two reversible proton coupled redox couples appear over the capacitive response with 0.94 and 1.19 (V vs SHE) pH = 7 standard potentials. The latter is, at most, very weakly catalytic and not responsible for the large catalytic current observed at higher potentials. CV-response analysis showed that the amount of redox-active cobalt species in the film is small, less than 10% of total. The catalytic process involves a further proton-coupled-electron-transfer and is so fast that it is controlled by diffusion of phosphate, the catalyst cofactor. CV-analysis with newly derived relationships led to a combination of the catalyst standard potential with the catalytic rate constant and a lower-limit estimation of these parameters. The large currents resulting from the fast catalytic reaction result in significant potential losses related to charge transport through the film. CoPi films appear to combine molecular catalysis with semiconductor-type charge transport. This mode of heterogeneous molecular catalysis is likely to occur in many other catalytic films. PMID- 26981888 TI - The uranium isotopes in the characterisation of groundwater in the Thermi Vasilika region, northern Greece. AB - The activity concentrations of (238)U and (234)U have been determined in groundwater samples in the Thermi-Vasilika region, northern Greece. The analysis was performed by alpha spectrometry after pre-concentration and separation of uranium by cation exchange and finally its electrodeposition on stainless steel discs. The obtained isotopic ratio (234)U/(238)U varies between 0.95 and 3.50 and is correlated with the different aquifer types and water flow paths in the study area. Lower values (up to 1.10) are located in the shallow porous aquifer indicating younger waters. Moderate values of the activity ratio characterise the deeper porous aquifer as well as the fissured rock aquifer (1.5-2.05). The geothermal spring illustrates the highest activity ratio (3.5) due to older water. PMID- 26981889 TI - Indicators for Remission of Suicidal Ideation Following Magnetic Seizure Therapy in Patients With Treatment-Resistant Depression. AB - IMPORTANCE: Magnetic seizure therapy (MST) is a novel therapeutic option for treatment-resistant depression (TRD). Suicidal ideation is often associated with TRD and contributes to the increased mortality and morbidity of the disorder. OBJECTIVE: To identify a biomarker that may serve as an indicator of remission of suicidal ideation following a course of MST by using cortical inhibition measures from interleaved transcranial magnetic stimulation and electroencephalography (TMS-EEG). DESIGN, SETTING, AND PARTICIPANTS: Thirty-three patients with TRD were part of an open-label clinical trial of MST treatment. Data from 27 patients (82%) were available for analysis in this study. Baseline TMS-EEG measures were assessed within 1 week before the initiation of MST treatment using the TMS-EEG measures of cortical inhibition (ie, N100 and long-interval cortical inhibition [LICI]) from the left dorsolateral prefrontal cortex and the left motor cortex, with the latter acting as a control site. INTERVENTIONS: The MST treatments were administered under general anesthesia, and a stimulator coil consisting of 2 individual cone-shaped coils was used. MAIN OUTCOMES AND MEASURES: Suicidal ideation was evaluated before initiation and after completion of MST using the Scale for Suicide Ideation (SSI). Measures of cortical inhibition (ie, N100 and LICI) from the left dorsolateral prefrontal cortex were selected. N100 was quantified as the amplitude of the negative peak around 100 milliseconds in the TMS-evoked potential (TEP) after a single TMS pulse. LICI was quantified as the amount of suppression in the double-pulse TEP relative to the single-pulse TEP. RESULTS: Of the 27 patients included in the analyses, 15 (56%) were women; mean (SD) age of the sample was 46.0 (15.3) years. At baseline, patients had a mean SSI score of 9.0 (6.8), with 8 of 27 patients (30%) having a score of 0. After completion of MST, patients had a mean SSI score of 4.2 (6.3) (pre-post treatment mean difference, 4.8 [6.7]; paired t26 = 3.72; P = .001), and 18 of 27 individuals (67%) had a score of 0 for a remission rate of 53%. The N100 and LICI in the frontal cortex-but not in the motor cortex-were indicators of remission of suicidal ideation with 89% accuracy, 90% sensitivity, and 89% specificity (area under the curve, 0.90; P = .003). CONCLUSIONS AND RELEVANCE: These results suggest that cortical inhibition may be used to identify patients with TRD who are most likely to experience remission of suicidal ideation following a course of MST. Stronger inhibitory neurotransmission at baseline may reflect the integrity of transsynaptic networks that are targeted by MST for optimal therapeutic response. PMID- 26981887 TI - Hepatocellular carcinoma cases with high levels of c-Raf-1 expression may benefit from postoperative adjuvant sorafenib after hepatic resection even with high risk of recurrence. AB - BACKGROUND AND AIMS: Liver resection combined with postoperative sorafenib to prevent recurrence remains a controversial approach for cases of hepatocellular carcinoma (HCC), especially cases with a high risk of recurrence. This study aimed to investigate the efficacy and safety of liver resection combined with sorafenib for HCC with a high risk of recurrence. RESULTS: Most of the cases of HCC were caused by hepatitis B virus (HBV) infection (23 cases, 92%). Most of these tumors (21 cases, 84%) were stage III according to the TNM staging system (12 cases with IIIa, 9 cases with IIIb). In the months after hepatic resection, 19 of the 25 cases (76%) were diagnosed with HCC recurrence or metastasis. Based on the tumor histological biomarker grading system, the group with higher expression levels of c-Raf-1 showed significantly longer overall survival than the group with lower expression of c-Raf-1 (P = 0.012). However, the long-term tumor-free survival advantage disappeared (P = 0.061). Univariate and multivariate analyses indicated that higher expression of c-Raf-1 was significantly associated with better overall survival (hazard ratio [HR]: 1.842; 95% confidence interval [CI]: 1.211-2.542; P = 0.031) and tumor-free survival (HR: 1.319; 95% CI: 1.017-1.543; P = 0.046) in HCC patients who underwent radical hepatic resection. PATIENTS AND METHODS: We retrospectively collected 25 HCC cases with a high risk of recurrence who underwent radical liver resection and who took sorafenib postoperatively from Jan 2010 to Dec 2012. Factors that might contribute to tumor recurrence and treatment failure such as clinical factors, tumor features, and molecular biomarkers were included in our analysis. CONCLUSIONS: HCC patients with a high risk of post-hepatic resection recurrence may benefit from postoperative sorafenib administered as an adjuvant therapy, especially in cases with high levels of c-Raf-1 expression on histological examination. PMID- 26981890 TI - Usefulness of mycophenolic acid monitoring with PETINIA for prediction of adverse events in kidney transplant recipients. AB - Background Therapeutic drug monitoring of mycophenolic acid (MPA) is required to optimize the immunosuppressive effect and minimize toxicity. We validated a new particle-enhanced turbidimetric inhibition immunoassay (PETINIA) for the determination of MPA levels and evaluated the relationship of MPA trough level with drug-related adverse events. Methods PETENIA and liquid chromatography-mass spectrometry (LC-MS) were used to determine MPA concentrations from 54 kidney transplant recipients (KTRs). Agreement between PETINIA and LC-MS results was assessed by Passing-Bablok regression and the Bland-Altman plot method. The association of adverse events with MPA trough level obtained by PETINIA was analyzed. Results PETINIA revealed a good agreement with the LC-MS; Regression analysis gave an equation of y = 1.27x - 0.12 (r(2) = 0.975, p < 0.001). PETINIA showed a systemic positive bias with a mean difference of 0.66 mg/L compared to LC-MS. However, the magnitude of the positive bias decreased to 0.44 mg/L within the therapeutic range of MPA. Multiple logistic regression showed that MPA trough level determined by PETINIA was an independent risk factor for adverse events (odds ratio 2.28, 95% CI 1.25-4.16, p = 0.007). MPA trough level predicted adverse events with a sensitivity of 77.8% and a specificity of 86.7% using a cut off level of 5.25 mg/L. Conclusions Good correlation between the two methods indicates that PETINIA is an acceptable method for the monitoring of MPA therapeutic levels. Furthermore, MPA trough level obtained by PETINIA is a useful monitoring tool to minimize toxicity in KTRs. PMID- 26981893 TI - From the FDA: Abbott aggrees to correct manufacturing deficiencies. PMID- 26981895 TI - CME QUIZ. PMID- 26981892 TI - Engineering of a Nepetalactol-Producing Platform Strain of Saccharomyces cerevisiae for the Production of Plant Seco-Iridoids. AB - The monoterpene indole alkaloids (MIAs) are a valuable family of chemicals that include the anticancer drugs vinblastine and vincristine. These compounds are of global significance-appearing on the World Health Organization's list of model essential medicines-but remain exorbitantly priced due to low in planta levels. Chemical synthesis and genetic manipulation of MIA producing plants such as Catharanthus roseus have so far failed to find a solution to this problem. Synthetic biology holds a potential answer, by building the pathway into more tractable organisms such as Saccharomyces cerevisiae. Recent work has taken the first steps in this direction by producing small amounts of the intermediate strictosidine in yeast. In order to help improve on these titers, we aimed to optimize the early biosynthetic steps of the MIA pathway to the metabolite nepetalactol. We combined a number of strategies to create a base strain producing 11.4 mg/L of the precursor geraniol. We also show production of the critical intermediate 10-hydroxygeraniol and demonstrate nepetalactol production in vitro. Lastly we demonstrate that activity of the iridoid synthase toward the intermediates geraniol and 10-hydroxygeraniol results in the synthesis of the nonproductive intermediates citronellol and 10-hydroxycitronellol. This discovery has serious implications for the reconstruction of the MIA in heterologous organisms. PMID- 26981894 TI - Editorial comments. PMID- 26981896 TI - Medi-notes: OMT versus standard care for patients with low back pain. PMID- 26981891 TI - Strategies for improving the intratumoral distribution of liposomal drugs in cancer therapy. AB - INTRODUCTION: A major limitation of current liposomal cancer therapies is the inability of liposome therapeutics to penetrate throughout the entire tumor mass. This inhomogeneous distribution of liposome therapeutics within the tumor has been linked to treatment failure and drug resistance. Both liposome particle transport properties and tumor microenvironment characteristics contribute to this challenge in cancer therapy. This limitation is relevant to both intravenously and intratumorally administered liposome therapeutics. AREAS COVERED: Strategies to improve the intratumoral distribution of liposome therapeutics are described. Combination therapies of intravenous liposome therapeutics with pharmacologic agents modulating abnormal tumor vasculature, interstitial fluid pressure, extracellular matrix components, and tumor associated macrophages are discussed. Combination therapies using external stimuli (hyperthermia, radiofrequency ablation, magnetic field, radiation, and ultrasound) with intravenous liposome therapeutics are discussed. Intratumoral convection-enhanced delivery (CED) of liposomal therapeutics is reviewed. EXPERT OPINION: Optimization of the combination therapies and drug delivery protocols are necessary. Further research should be conducted in appropriate cancer types with consideration of physiochemical features of liposomes and their timing sequence. More investigation of the role of tumor associated macrophages in intratumoral distribution is warranted. Intratumoral infusion of liposomes using CED is a promising approach to improve their distribution within the tumor mass. PMID- 26981897 TI - New England Journal of Medicine article may be misleading about OMT. PMID- 26981898 TI - Obesity article ignores surgery as possible option. PMID- 26981899 TI - Response: Obesity article ignores surgery as possible option. PMID- 26981900 TI - The dichotomy of overdosing or underdosing for pain. PMID- 26981901 TI - The importance of referencing osteopathic medical literature. PMID- 26981902 TI - From the FDA: FDA approves Tamiflu for influenza. PMID- 26981903 TI - From the FDA: Abbott aggrees to correct manufacturing deficiencies. PMID- 26981904 TI - From the FDA: FDA allows soy health claim on food labels. PMID- 26981905 TI - From the CDC: Flu, pneumonia shots urged. PMID- 26981906 TI - From the CDC: Obesity increases dramatically in the United States. PMID- 26981907 TI - From the CDC: Rotavirus vaccine withdrawn from market. PMID- 26981908 TI - From the CDC: Guidelines modified for meningitis vaccination. PMID- 26981909 TI - From the NICHHD: Day care has impact on mother-child bond. PMID- 26981910 TI - Heliobacter pylori in gastric carcinoma. PMID- 26981911 TI - Prevalence of sensitization to methylisothiazolinone in an Italian Skin Allergy Unit. AB - BACKGROUND: An alarming increase in the prevalence of sensitization to the preservative methylisothiazolinone (MI), alone or in combination with methylchloroisothiazolinone (MCI), has recently been reported, mainly in Northern Europe. Prevalence data from Southern Europe are scanty. METHODS: We evaluated the prevalence of contact allergy to MI and MCI/MI among 1392 patients consecutively patch tested in 2012-2013 at the Clinica Dermatologica of San Martino Hospital, Genoa, Italy. The patients were patch tested with 2000 ppm MI aq. in addition to the Italian baseline series. The MOAHLFA Index (Male, Occupation, Atopic Dermatitis, Hand, Legs, Face, Age above 40 years) was registered for all patients. Relevant exposures to MI and/or MI/MCI were determined and the patients' clinical outcome after isothiazolinones avoidance was evaluated. RESULTS: The prevalence of sensitization to MI showed a steep increase of prevalence from 2.3% in 2012 to 6.9% in 2013 while sensitization to MI/MCI rose from 6.76% in 2012 to 9.04% in 2013. Hand and face dermatitis were significantly prevalent in MI allergic patients. Cosmetics, followed by household products, were the most common sources of relevant exposure to both MI and MI/MCI. Clinical improvement after avoidance of isothiazolinones containing products was reported by 85.3% of followed up patients. CONCLUSIONS: In Italy the prevalence of MI and MI/MCI contact allergy is alarmingly high and it is increasing. PMID- 26981912 TI - Extemporaneous transposition flap for closing two contiguous surgical excision. AB - The authors present a surgical procedure to remove two contiguous cutaneous lesions using a single transposition flap and suture line without an evident scar. This method is useful when rhomboid surgical exeresis could not represent the best choice to obtain an optimum aesthetic result. PMID- 26981913 TI - Comparison of the Radiation Dose from Cone Beam Computed Tomography and Multidetector Computed Tomography in Examinations of the Hand. AB - PURPOSE: Comparison of radiation dose of cone beam computed tomography (CBCT) and multidetector computed tomography (MDCT) in examinations of the hand. MATERIALS AND METHODS: Dose calculations were carried out by means of Monte Carlo simulations in MDCT and CBCT. A corpse hand was examined in a 320-row MDCT scanner and a dedicated extremities CBCT scanner with standard protocols and multiple low-dose protocols. The image quality of the examinations was evaluated by 5 investigators using a Likert scale from 1 (very good) to 5 (very poor) regarding depiction of cortical bone, cancellous bone, joint surfaces, soft tissues and artifacts. For a sum of ratings of all structures < 50 a good overall image quality was expected. The studies with at least good overall image quality were compared with respect to the dose. RESULTS: The dose of the standard examination was 13.21 (12.96 to 13.46 CI) mGy in MDCT and 7.15 (6.99 to 7.30 CI) mGy in CBCT. The lowest dose in a study with good overall image quality was 4.54 (4.43 to 4.64 CI) mGy in MDCT and 5.72 (5.59 to 5.85 CI) mGy in CBCT. CONCLUSION: Although the dose of the standard protocols in the CBCT is lower than in the MDCT, the MDCT can realize a good overall image quality at a lower dose than the CBCT. Dose optimization of CT examination protocols for the hand is useful in both modalities, the MDCT has an even greater potential for optimization. KEY POINTS: * Low dose examinations of the hand are feasible in CBCT and MDCT.* In default settings CBCT has a lower dose than MDCT.* MDCT enables a good image quality at a lower dose than CBCT. Citation Format: * Neubauer J, Neubauer C, Gerstmair A et al. Comparison of the Radiation Dose from Cone Beam Computed Tomography and Multidetector Computed Tomography in Examinations of the Hand. Fortschr Rontgenstr 2016; 188: 488 - 493. PMID- 26981914 TI - Fast Abdominal Magnetic Resonance Imaging. AB - Abdominal imaging is the driving force that necessitates the development of numerous techniques for accelerated image acquisition in magnetic resonance imaging (MRI). Today, numerous techniques are available that enable rapid, high spatial resolution acquisition for both T1 and T2 weighted images. These techniques open new opportunities in the detection and classification of numerous pathologies in the abdomen. However, there is still ongoing progress in the development of fast and ultrafast sequences and promising techniques are currently close to clinical application. With these 4D-technologies, MRI is becoming the central imaging modality for dynamic, motion-compensated imaging of the parenchymal abdominal organs such as liver, pancreas and kidney. KEY POINTS: * Fast imaging techniques are especially valuable in the upper abdomen, as this region is particularly affected by respiratory motion.* Parallel imaging and k space-based acceleration techniques are the basic components of fast 3 D sequences.* By further accelerating 3 D imaging with high spatial resolution, 4 D techniques become available. Citation Format: * Budjan J., Schoenberg S. O., Riffel P. Fast Abdominal Magnetic Resonance Imaging. Fortschr Rontgenstr 2016; 188: 551 - 558. PMID- 26981915 TI - Thermoablation of Bone Tumors. AB - The aim of this article is to review the significance of percutaneous thermal ablation in the treatment of bone tumors. We describe available ablation techniques as well as advantages and disadvantages in specific settings. In detail, radiofrequency ablation (RFA), microwave ablation (MWA), laser ablation, high intensity focused ultrasound (HIFU) and cryoablation are presented. In the second part of this review curative and palliative indications for the treatment of benign and malignant bone tumors are discussed. This includes especially RFA, laser or cryoablation for the treatment of osteoid osteoma, as well as the palliative treatment of painful bone metastases, for example, by means of MWA or MR-guided HIFU. KEY POINTS: * The various thermoablative techniques demonstrate specific advantages and disadvantages.* Radiofrequency ablation is the evidence based method of choice for treating osteoid osteoma.* Laser ablation is primarily suited for the treatment of small lesions of the hands and feet.* The intrinsically analgesic effect of cryoablation is advantageous when treating painful lesions.* Palliative treatment of painful bone metastases can for example be performed using MWA or MR-guided HIFU, by itself or combined with cementoplasty. Citation Format: * Ringe KI, Panzica M, von Falck C. Thermoablation of Bone Tumors. Fortschr Rontgenstr 2016; 188: 539 - 550. PMID- 26981916 TI - [In Process Citation]. PMID- 26981917 TI - [In Process Citation]. PMID- 26981918 TI - [In Process Citation]. PMID- 26981920 TI - A SrTiO3 photoanode prepared by the particle transfer method for oxygen evolution from water with high quantum efficiencies. AB - A photoanode prepared from flux-synthesized Al-doped SrTiO3 by the particle transfer method with a Ta contact layer exhibited a high IPCE of 69% at 320 nm. The photocatalytic activity of SrTiO3 particles was very sensitive to the synthesis method used to make the SrTiO3 particles, while its photoelectrochemical performance was not. PMID- 26981921 TI - Dual Sensing by Simple Heteroditopic Salt Receptors Containing an Anthraquinone Unit. AB - We synthesized simple ion pair receptors consisting of a crown ether cation binding site and an anthraquinone-supported thiourea anion binding domain and studied their anion-, cation-, and salt-binding properties using spectroscopic, spectrophotometric, and electrochemical measurements in acetonitrile solution. Apart from carboxylate anions, which cause deprotonation, all the anions tested were found to associate with receptor 1 more strongly in the presence of sodium cations, whereas in the presence of potassium or ammonium cation the anion binding strength was greatly diminished. A homotopic anion receptor 3, lacking a crown ether unit, was unable to bind sodium salt more strongly than tetrabutylammonium salts. Solution and solid-state X-ray measurements revealed that strong sodium coordination with the cation-binding domain is responsible for the salt-binding enhancement. Electrochemical measurements showed that the addition of anions to the receptor 1 pretreated with sodium cations resulted in greater changes in reduction potentials compared to the addition of anions to receptor 1 in the absence of Na(+). PMID- 26981919 TI - [In Process Citation]. PMID- 26981923 TI - Intravenous Heroin Abuse and Acute Myocardial Infarction: Forensic Study. AB - OBJECTIVE: The purpose of this study was to investigate chronic intravenous heroin abuse and its potential to induce acute myocardial infarction (AMI). It also aims to examine the causative factors and the incidence of heroin-induced myocardial infarction. MATERIAL AND METHODS: The hearts of 113 intravenous heroin abusers were studied for a duration exceeding 3 years. The parameters studied included sex, age, time of intravenous heroin abuse, medical history, and body and heart weight. Macroscopic histological studies of the heart were also performed. RESULTS: The histological examination revealed only 1 case of AMI. The victim was an intravenous heroin abuser for the last 7 years. The age and the medical history of the victim do not act as dissuading factors for the potential of an AMI. CONCLUSIONS: The incidence of heroin-induced myocardial infarction is rare, and the actual mechanism remains unclear. The increased heart weight in relation to the increased thickness of the heart walls may be an aggravating factor, and thus, it is a fact that should be investigated. PMID- 26981922 TI - Secretion and Reversible Assembly of Extracellular-like Matrix by Enzyme-Active Colloidosome-Based Protocells. AB - The secretion and reversible assembly of an extracellular-like matrix by enzyme active inorganic protocells (colloidosomes) is described. Addition of N-fluorenyl methoxycarbonyl-tyrosine-(O)-phosphate to an aqueous suspension of alkaline phosphatase-containing colloidosomes results in molecular uptake and dephosphorylation to produce a time-dependent sequence of supramolecular hydrogel motifs (outer membrane wall, cytoskeletal-like interior and extra-protocellular matrix) that are integrated and remodelled within the microcapsule architecture and surrounding environment. Heat-induced disassembly of the extra-protocellular matrix followed by cooling produces colloidosomes with a densely packed hydrogel interior. These procedures are exploited for the fabrication of nested colloidosomes with spatially delineated regions of hydrogelation. PMID- 26981924 TI - Rapid Clozapine Titration in an Acutely Agitated Patient With Schizoaffective Disorder: A Case Report. PMID- 26981925 TI - The US Food and Drug Administration's Proposed Rule to Increase Regulation of Indoor Tanning Devices. PMID- 26981927 TI - Screening for Fabry's disease in young patients with ischemic stroke in a Chinese population. AB - PURPOSE: Fabry disease is an X-linked lysosomal storage disorder frequently associated with cerebrovascular disease. Data regarding Fabry disease and ischemic stroke has been lacking in China. In this study, we investigated the prevalence of Fabry disease and the distribution of the alpha-galactosidase A (alpha-GalA) gene - GLA mutations in young stroke patients in the Chinese population and its association with stroke subtypes. METHODS: A total of 357 ischemic stroke patients admitted to Xuanwu Hospital of Capital Medical University, aged 18-55 years old, including 293 patients with cerebral infarction and 64 patients with transient ischemic attack, were enrolled in this study. Mutations in the GLA gene were screened by Sanger sequencing. Enzyme levels were measured to further confirm the disease in patients with the gene mutation. The mutation frequency was compared among different stroke subtypes and further compared with the control group individually. RESULTS: No pathogenic mutations in the coding regions of the GLA gene were identified in this group of patients and thus no Fabry disease was found in our study. However, the frequency of an intronic polymorphism c.-10C>T was significantly different among different Trial of Org 10172 in Acute Stroke Treatment subtypes (p < 0.01). The frequency of the c.-10C>T polymorphism in patients with stroke due to other causes and undetermined causes was much higher than that in the control group (OR = 3.18, 95% CI: 1.29-7.83, p < 0.01). CONCLUSIONS: Fabry disease is a rare disease, and it will not benefit to screen all stroke patients. In addition, our results suggested that the c.-10C>T polymorphism may be a risk factor for ischemic stroke of other and undetermined causes. Further study is required to confirm our findings. PMID- 26981929 TI - Cu,Zn-SOD deficiency induces the accumulation of hepatic collagen. AB - Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic diseases, and results in the development of fibrosis. Oxidative stress is thought to be one of the underlying causes of NAFLD. Copper/zinc superoxide dismutase (SOD1) is a primary antioxidative enzyme that scavenges superoxide anion radicals. Although SOD1 knockout (KO) mice have been reported to develop fatty livers, it is not known whether this lack of SOD1 leads to the development of fibrosis. Since the accumulation of collagen typically precedes liver fibrosis, we assessed the balance between the synthesis and degradation of collagen in liver tissue from SOD1 KO mice. We found a higher accumulation of collagen in the livers of SOD1 KO mice compared to wild type mice. The level of expression of HSP47, a chaperone of collagen, and a tissue inhibitor (TIMP1) of matrix metalloproteinases (a collagen degradating enzyme) was also increased in SOD1 KO mice livers. These results indicate that collagen synthesis is increased but that its degradation is inhibited in SOD1 KO mice livers. Moreover, SOD1 KO mice liver sections were extensively modified by advanced glycation end products (AGEs), which suggest that collagen in SOD1 KO mice liver might be also modified with AGEs and then would be more resistant to the action of collagen degrading enzymes. These findings clearly show that oxidative stress plays an important role in the progression of liver fibrosis. PMID- 26981930 TI - Scandal as a Sentinel Event--Recognizing Hidden Cost-Quality Trade-offs. PMID- 26981928 TI - Nipah Virus Transmission from Bats to Humans Associated with Drinking Traditional Liquor Made from Date Palm Sap, Bangladesh, 2011-2014. AB - Nipah virus (NiV) is a paramyxovirus, and Pteropus spp. bats are the natural reservoir. From December 2010 through March 2014, hospital-based encephalitis surveillance in Bangladesh identified 18 clusters of NiV infection. The source of infection for case-patients in 3 clusters in 2 districts was unknown. A team of epidemiologists and anthropologists investigated these 3 clusters comprising 14 case-patients, 8 of whom died. Among the 14 case-patients, 8 drank fermented date palm sap (tari) regularly before their illness, and 6 provided care to a person infected with NiV. The process of preparing date palm trees for tari production was similar to the process of collecting date palm sap for fresh consumption. Bat excreta was reportedly found inside pots used to make tari. These findings suggest that drinking tari is a potential pathway of NiV transmission. Interventions that prevent bat access to date palm sap might prevent tari associated NiV infection. PMID- 26981931 TI - Beyond the VA Crisis--Becoming a High-Performance Network. PMID- 26981932 TI - Health Care Tax Inversions--Robbing Both Peter and Paul. PMID- 26981934 TI - A Randomized Trial of a Cervical Pessary to Prevent Preterm Singleton Birth. AB - BACKGROUND: Preterm birth is the leading cause of neonatal and infant death and of disability among survivors. It is unclear whether a pessary inserted around the cervix reduces the risk of preterm singleton birth. METHODS: We conducted a multicenter, randomized, controlled trial comparing pessary placement with expectant management (control) in girls and women who were pregnant with singletons (singleton pregnancies) and who had a cervical length of 25 mm or less at 20 weeks 0 days to 24 weeks 6 days of gestation. Participants in either group who had a cervical length of 15 mm or less, at randomization or at subsequent visits, received treatment with vaginal progesterone. The primary outcome was spontaneous delivery before 34 weeks of gestation. RESULTS: In an intention-to treat analysis, there was no significant difference between the pessary group (465 participants) and the control group (467 participants) in the rate of spontaneous delivery before 34 weeks (12.0% and 10.8%, respectively; odds ratio in the pessary group, 1.12; 95% confidence interval, 0.75 to 1.69; P=0.57). There were no significant differences in the rates of perinatal death (3.2% in the pessary group and 2.4% in the control group, P=0.42), adverse neonatal outcome (6.7% and 5.7%, respectively; P=0.55), or neonatal special care (11.6% and 12.9%, respectively; P=0.59). The incidence of new or increased vaginal discharge was significantly higher in the pessary group than in the control group. CONCLUSIONS: Among girls and women with singleton pregnancies who had a short cervix, a cervical pessary did not result in a lower rate of spontaneous early preterm delivery than the rate with expectant management. (Funded by the Fetal Medicine Foundation; Current Controlled Trials number, ISRCTN01096902.). PMID- 26981935 TI - Safer Prescribing--A Trial of Education, Informatics, and Financial Incentives. AB - BACKGROUND: High-risk prescribing and preventable drug-related complications are common in primary care. We evaluated whether the rates of high-risk prescribing by primary care clinicians and the related clinical outcomes would be reduced by a complex intervention. METHODS: In this cluster-randomized, stepped-wedge trial conducted in Tayside, Scotland, we randomly assigned participating primary care practices to various start dates for a 48-week intervention comprising professional education, informatics to facilitate review, and financial incentives for practices to review patients' charts to assess appropriateness. The primary outcome was patient-level exposure to any of nine measures of high risk prescribing of nonsteroidal antiinflammatory drugs (NSAIDs) or selected antiplatelet agents (e.g., NSAID prescription in a patient with chronic kidney disease or coprescription of an NSAID and an oral anticoagulant without gastroprotection). Prespecified secondary outcomes included the incidence of related hospital admissions. Analyses were performed according to the intention to-treat principle, with the use of mixed-effect models to account for clustering in the data. RESULTS: A total of 34 practices underwent randomization, 33 of which completed the study. Data were analyzed for 33,334 patients at risk at one or more points in the preintervention period and for 33,060 at risk at one or more points in the intervention period. Targeted high-risk prescribing was significantly reduced, from a rate of 3.7% (1102 of 29,537 patients at risk) immediately before the intervention to 2.2% (674 of 30,187) at the end of the intervention (adjusted odds ratio, 0.63; 95% confidence interval [CI], 0.57 to 0.68; P<0.001). The rate of hospital admissions for gastrointestinal ulcer or bleeding was significantly reduced from the preintervention period to the intervention period (from 55.7 to 37.0 admissions per 10,000 person-years; rate ratio, 0.66; 95% CI, 0.51 to 0.86; P=0.002), as was the rate of admissions for heart failure (from 707.7 to 513.5 admissions per 10,000 person-years; rate ratio, 0.73; 95% CI, 0.56 to 0.95; P=0.02), but admissions for acute kidney injury were not (101.9 and 86.0 admissions per 10,000 person-years, respectively; rate ratio, 0.84; 95% CI, 0.68 to 1.09; P=0.19). CONCLUSIONS: A complex intervention combining professional education, informatics, and financial incentives reduced the rate of high-risk prescribing of antiplatelet medications and NSAIDs and may have improved clinical outcomes. (Funded by the Scottish Government Chief Scientist Office; ClinicalTrials.gov number, NCT01425502.). PMID- 26981936 TI - Colorectal Adenomas. PMID- 26981933 TI - Loss of B Cells in Patients with Heterozygous Mutations in IKAROS. AB - BACKGROUND: Common variable immunodeficiency (CVID) is characterized by late onset hypogammaglobulinemia in the absence of predisposing factors. The genetic cause is unknown in the majority of cases, and less than 10% of patients have a family history of the disease. Most patients have normal numbers of B cells but lack plasma cells. METHODS: We used whole-exome sequencing and array-based comparative genomic hybridization to evaluate a subset of patients with CVID and low B-cell numbers. Mutant proteins were analyzed for DNA binding with the use of an electrophoretic mobility-shift assay (EMSA) and confocal microscopy. Flow cytometry was used to analyze peripheral-blood lymphocytes and bone marrow aspirates. RESULTS: Six different heterozygous mutations in IKZF1, the gene encoding the transcription factor IKAROS, were identified in 29 persons from six families. In two families, the mutation was a de novo event in the proband. All the mutations, four amino acid substitutions, an intragenic deletion, and a 4.7 Mb multigene deletion involved the DNA-binding domain of IKAROS. The proteins bearing missense mutations failed to bind target DNA sequences on EMSA and confocal microscopy; however, they did not inhibit the binding of wild-type IKAROS. Studies in family members showed progressive loss of B cells and serum immunoglobulins. Bone marrow aspirates in two patients had markedly decreased early B-cell precursors, but plasma cells were present. Acute lymphoblastic leukemia developed in 2 of the 29 patients. CONCLUSIONS: Heterozygous mutations in the transcription factor IKAROS caused an autosomal dominant form of CVID that is associated with a striking decrease in B-cell numbers. (Funded by the National Institutes of Health and others.). PMID- 26981937 TI - IMAGES IN CLINICAL MEDICINE. Froin's Syndrome. PMID- 26981938 TI - CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 8-2016. A 71-Year-Old Man with Recurrent Fevers, Hypoxemia, and Lung Infiltrates. PMID- 26981939 TI - A CRISPR Way to Block PERVs--Engineering Organs for Transplantation. PMID- 26981940 TI - Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. PMID- 26981941 TI - Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. PMID- 26981942 TI - Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. PMID- 26981943 TI - Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. PMID- 26981944 TI - Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. PMID- 26981945 TI - Lixisenatide in Type 2 Diabetes and Acute Coronary Syndrome. PMID- 26981946 TI - Lixisenatide in Type 2 Diabetes and Acute Coronary Syndrome. PMID- 26981948 TI - Immunotherapy-Associated Hemolytic Anemia with Pure Red-Cell Aplasia. PMID- 26981947 TI - Lixisenatide in Type 2 Diabetes and Acute Coronary Syndrome. PMID- 26981949 TI - Osteochemonecrosis after Mandible Reconstruction. PMID- 26981950 TI - VIDEOS IN CLINICAL MEDICINE. Transfusion of Red Cells. PMID- 26981951 TI - IMAGES IN CLINICAL MEDICINE. Scabies. PMID- 26981952 TI - Investor Outlook: After the Biotech Bubble Popped. AB - After a few torrid years of value appreciation, the biotech "bubble" has precipitously popped over the past few months. In this report, we take a look at some of the factors that drove the run-up in valuations, the triggers that led to their substantial pullback, and where the industry may be headed from here. Gene therapy/editing companies have been particularly affected by these dynamics, raising a new set of questions and challenges for the group. PMID- 26981953 TI - Protective effect of propolis on methotrexate-induced kidney injury in the rat. AB - Objectives Propolis is a potent antioxidant and a free radical scavenger. Pharmacological induction of heat shock proteins (HSPs) has been investigated for restoring normal cellular function following an injury. In this study, effect of propolis on HSP-70 expression in methotrexate-induced nephrotoxicity and direct preventive effect of propolis in this toxicity were investigated. Material and methods A total of 40 male Wistar albino rats were divided into four groups: Group 1 was the untreated control. On the eighth day of the experiment, groups 2 and 3 received single intraperitoneal injections of methotrexate (MTX) at 20 mg/kg. Groups 3 and 4 received 100 mg/kg/day propolis (by oral gavage) for 15 d by the first day of the experimental protocol. Then the rats were decapitated under ketamine esthesia and their kidney tissues were removed. HSP-70 expression, apoptosis, and histopathological damage scores were then compared. Results MTX caused epithelial desquamation into the lumen of the tubules, dilatation, and congestion of the peritubular vessels and renal corpuscles with obscure Bowman's space. The number of apoptotic cells (p = 0.000) and HSP-70 (p = 0.002) expression were increased in group 2. Propolis prevented the rise in number of apoptotic cells (p = 0.017), HSP-70 (p = 0.000) expression, and improved kidney morphology. Conclusions It was found that methotrexate gives rise to serious damage in the kidney and propolis is a potent antioxidant agent in preventing kidney injury. PMID- 26981954 TI - Laparoscopic-Assisted Anorectal Pull-Through for High Imperforate Anus: 14 Years Experience in a Single Center. AB - PURPOSE: To report our 14 years experience with the laparoscopic-assisted anorectal pull-through (LAARP) for the treatment of male neonates with high imperforate anus. MATERIALS AND METHODS: We reviewed all medical charts of patients who underwent LAARP from January 2001 to January 2015 collecting information regarding demographic data, associated anomalies, type of fistula, pelvic floor muscles tropism, surgery (operative time, conversion to open technique, and complications), and follow-up. Follow-up data were obtained through the use of validated questionnaires that aim to assess the intestinal function in terms of constipation and continence. RESULTS: At the Department of Pediatric Surgery of the University of Bologna, 13 male patients were operated in the study period (our protocol consisted of colostomy at birth followed by delayed LAARP). Mean age at operation was 4.75 months (range 1-14). There was one conversion to open technique due to a strong tension from the colostomy (this patient was excluded). Functional results were acceptable at a minimum 2-year long follow-up. CONCLUSIONS: LAARP is a good choice for the correction of the high imperforate anus. Short-term outcomes are similar to those after posterior sagittal anorectoplasty (PSARP). Long-term outcomes should be better assessed. PMID- 26981957 TI - Academy of Surgical Research 28th Annual Meeting Charlotte, North Carolina October 2-6, 2012, Part 2. PMID- 26981958 TI - Erratum. PMID- 26981956 TI - Overexpression of ADAM9 Promotes Colon Cancer Cells Invasion. AB - INTRODUCTION: ADAM9 is a membrane-anchored metalloprotease that is markedly upregulated in several human carcinomas. We previously showed that ADAM9 staining was increased in colon cancer tissues. In the present work, we investigated the expression pattern of ADAM9 in colon cell lines, and the effects of overexpression ADAM9 on colon cancer proliferation and invasion. MATERIALS AND METHODS: ADAM9 mRNA expression was determined in colon cancer tissues by RT-PCR assay, meanwhile, ADAM9 DNA and protein levels were measured in colon cancer cell lines by PCR and western blot, respectively. ADAM9 transfection was carried out in HT-29 colon cancer cells, and cell growth was measured by MTT assay, cell invasion ability was assessed by Matrigel assay. RESULTS: ADAM9 mRNA was upregulated in colon cancer tissues, ADAM9 DNA and protein was overexpressed in Lovo cell lines, while the ADAM9 expression levels in HT-29, HCT-8, and Ls174t cells were below the levels of detection. Enhanced ADAM9 expression by ADAM9 transfection in HT-29 cells promoted cell invasion without increasing cell proliferation. CONCLUSIONS: These results suggest that ADAM9 contributes to cell invasion and progression in colon cancer. PMID- 26981955 TI - Efficient production of polyhydroxyalkanoates (PHAs) from Pseudomonas mendocina PSU using a biodiesel liquid waste (BLW) as the sole carbon source. AB - Conditions for the optimal production of polyhydroxyalkanoate (PHA) by Pseudomonas mendocina PSU using a biodiesel liquid waste (BLW) were determined by response surface methodology. These were an initial carbon to nitrogen ratio (C/N) of 40 (mole/mole), an initial pH of 7.0, and a temperature of 35 degrees C. A biomass and PHA concentration of 3.65 g/L and about 2.6 g/L (77% DCW), respectively, were achieved in a growth associated process using 20 g/L glycerol in the BLW after 36 h of exponential growth. The PHA monomer compositions were 3HB (3-hydroxybutyrate), a short-chain-length-PHA, and the medium-chain-length PHA e.g. 3-hydroxyoctanoate and 3-hydroxydecanoate. Both the phbC and phaC genes were characterized. The phbC enzyme had not been previously detected in a Pseudomonas mendocina species. A 2.15 g/L of an exopolysaccharide, alginate, was also produced with a similar composition to that of other Pseudomonas species. PMID- 26981959 TI - Oriental Medicine Woohwangchungsimwon Attenuates Kainic Acid-Induced Seizures and Neuronal Cell Death in the Hippocampus. AB - Woohwangchungsimwon (WCW) is an oriental medicine that has been extensively prescribed in Asia to patients with apoplexy, high blood pressure, acute/chronic convulsion, and so on. However, the potential therapeutic value of WCW in treating the pathologic brain has not yet been fully investigated. In the present study, we evaluated whether WCW has beneficial effects on kainic acid (KA) induced excitotoxicity. An intraperitoneal injection of KA (40 mg/kg) and an intracerebroventricular injection of KA (0.2 MUg) produced typical seizure behavior and neuronal cell death in the CA1 and CA3 pyramidal layers of the hippocampus, respectively. However, the systemic administration of WCW significantly attenuated the seizure behavior and neuronal cell death. WCW was found to exert the best protective effect when it was administrated 2 hours before a KA injection. Moreover, this WCW-induced neuroprotection was accompanied by a reduction in microglia activation and tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, inducible nitric oxide synthase, and cyclooxyganase 2 in the hippocampus. These results suggest that WCW has therapeutic potential to suppress KA-induced pathogenesis in the brain by inhibiting inflammation. PMID- 26981961 TI - Carter reassures over new neglect crime. AB - RCN general secretary Peter Carter urged nurses not to be unduly concerned about a new law that will mean healthcare professionals can be jailed for up to five years if they wilfully neglect patients. PMID- 26981960 TI - Focus on safe staffing levels as ministers respond to Francis report. AB - Senior nurses running a safe staffing campaign have welcomed the government's commitment to ensuring wards are staffed appropriately. PMID- 26981962 TI - Whitehall to turn down uniform call. AB - The government is expected to reject the call by Robert Francis for standard uniforms for each professional group to be introduced across the NHS as a way of avoiding confusion about roles. PMID- 26981964 TI - New GP contracts will end some annual checks. AB - Practice nurses' workloads will involve less paperwork when GPs' terms and conditions change, the British Medical Association says. PMID- 26981963 TI - NHS direct nurses are disillusioned by 111 recruitment policies, says college. AB - Nurses at risk of redundancy following the demise of NHS Direct will be frustrated at proposals to boost the numbers of clinical staff working for its beleaguered replacement, according to the RCN. PMID- 26981967 TI - Degree-only entry to profession 'thwarts skilled and caring HCAs'. AB - Making entry to nursing degree-only was 'probably a mistake' because it has prevented many healthcare assistants from pursuing a nursing career, a government adviser says. PMID- 26981966 TI - Michael helps with typhoon aid effort. AB - Members of the Philippine Nurses Association of UK say they have been overwhelmed by the response to an appeal to help victims of the typhoon. PMID- 26981965 TI - Unions make case for pay award in face-to-face talks. AB - The RCN represented health unions at the NHS Pay Review Body (RB) last week, when it pushed for a minimum 1 per cent pay increase from next April. PMID- 26981968 TI - Laptops could help prevent care scandal. AB - An online programme that logs nurses' complaints could be used as an early warning system to prevent a scandal on the scale of Mid Staffs happening again. PMID- 26981969 TI - Learning empathy from social science. AB - A two-year series of seminars will explore how social sciences can contribute to nurse education. PMID- 26981970 TI - Wireless patient monitor detects deterioration earlier. AB - Nurses are preparing to test a wireless device the size of a sticking plaster that is placed on a patient's chest and provides almost constant monitoring of vital signs. PMID- 26981973 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 26981972 TI - Career progression needed to relieve pressure and increase job satisfaction. AB - Providing nurses with greater opportunities for career progression and access to continuing professional development is vital for improving retention and reducing burnout, a conference heard last week. PMID- 26981974 TI - Calendar reveals professional heritage and recipes for patients. AB - A bygone era of district nursing is being celebrated in a new calendar produced by the Queen's Nursing Institute (QNI). PMID- 26981975 TI - Political notebook. AB - The NHS has made 'good progress' towards achieving its goal of being one of the best health services in Europe for helping people with long-term conditions, an NHS England senior official has told MPs. PMID- 26981976 TI - Cannabis triggers impulsive behaviour among all users. AB - Regular cannabis users have increased levels of impulsive behaviour, leaving them vulnerable to developing addictions, according to a study. PMID- 26981977 TI - Analysis of obesity treatments shows the potential benefits of surgical intervention. AB - Bariatric surgery is more effective than non-surgical obesity treatments at inducing weight loss, remission of type 2 diabetes and metabolic syndrome, according to the most comprehensive review of the evidence yet conducted. PMID- 26981978 TI - Study dismisses the link between headaches and autoimmune disorder lupus. AB - Headache is common in patients with lupus, but a study suggests it is not a direct consequence of the disease or its treatment. PMID- 26981979 TI - New analysis of existing data finds that flu vaccine is of benefit to older people. AB - The case for vaccinating older people against influenza appeared to be weakened in 2010 when a Cochrane review confirmed the vaccine's safety, but found no evidence of its effectiveness in this group. PMID- 26981980 TI - Topical eczema treatments are less effective when children resist their application. AB - Poor adherence to application of topical treatments is the main cause of treatment failure in childhood eczema. PMID- 26981981 TI - A time to speak. PMID- 26981982 TI - Voices - Jane Cummings reflects on what has been achieved in a busy 2013. AB - December marks one year since Compassion in Practice (CiP) was launched, in which we aimed to get to the essence of great care. Through the 6Cs, I am confident we have done this. PMID- 26981983 TI - The closest of bonds. AB - I first became aware of the Kangaroo Mother Care (KMC) programme when I travelled to Colombia before studying to be a children's nurse. PMID- 26981984 TI - In the dark. AB - 'For the patients in ED' I heard someone say while I was attending some statutory training. ED? What's that? ED phone home? No, that was ET. PMID- 26981985 TI - Older but wiser. AB - I told him so. I tried to warn him. I said: 'Listen son, you could do yourself an injury.' But was he bothered? Teenagers are never bothered. PMID- 26981986 TI - Starting out - Being the only non-native speaker changed my view of communication. AB - A two-week observational placement in Spain during my final year of training provided a valuable learning opportunity about effective communication. PMID- 26981987 TI - Readers panel - Losing the connection. AB - Our experts consider a hot topic of the day. PMID- 26981988 TI - Take courage. AB - I have never been scared to speak up when something is wrong, but I have come to realise that advocating for patients can be hard, especially when balanced against other constraints. PMID- 26981989 TI - Brain Facts. AB - The Brain Facts website is a treasure trove of information about neuroscience and the brain. It covers a range of diseases and disorders, as well as the science of ageing, and is relevant to practitioners and students in all branches of nursing and midwifery. PMID- 26981990 TI - Granddaughter of the Windrush Nnaemeka Barbara Maria Granddaughter of the Windrush 129pp L10.99 Book Guild Publishing 978 1 8462 4841 2 1846248418 [Formula: see text]. AB - This memoir will take older nurses down nostalgia lane, particularly those who travelled from the Caribbean in the post-war years to start a new life in the UK. It will also appeal to students and younger nurses interested in what life in England has been like for a nurse during the past 50 years. PMID- 26981991 TI - Disraeli or The Two Lives Hurd Douglas and Young Edward Disraeli or The Two Lives 320pp L20 Weidenfeld & Nicolson 978 0 2978 6097 6 0297860976 [Formula: see text]. AB - As prime minister during some of the most important years of Britain's imperial power, the Conservative politician Benjamin Disraeli was surprisingly forward thinking. PMID- 26981992 TI - MRSA eGuideline app MRSA eGuideline app L2.49 [Formula: see text]. AB - This Guidelines Pocketcard app on MRSA from the International Guidelines Center is now available in an updated and debugged version 1.1 at a competitive price. PMID- 26981993 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 26981994 TI - Fighting the good fight from Lambeth to Cambridgeshire. AB - Please join us for the next meeting of Lambeth Keep Our NHS Public on Thursday November 21, from 7pm at the Duke of Cambridge, 74 Lansdowne Way, London SW8 2DR. For further details, email lambethkonp@gmail.com. PMID- 26981996 TI - Notice board. AB - Courses, events, grants, and awards to progress your career. PMID- 26981998 TI - Is there a hero in your team? AB - Do you know an outstanding healthcare assistant, brilliant assistant practitioner or inspirational support worker? If so, then now is the time to nominate them for a Nursing Standard award. PMID- 26981997 TI - The management challenge. AB - The RCN executive nurse network celebrates its first anniversary this year, at a time when all nurse managers face many challenges. PMID- 26981999 TI - Courses & resources. AB - Courses, events, grants, and awards to progress your career. PMID- 26982000 TI - News update. AB - A roundup of the latest nursing news. PMID- 26982001 TI - SPRY4 Intronic Transcript 1 Promotes Epithelial-Mesenchymal Transition Through Association with Snail1 in Osteosarcoma. AB - Osteosarcoma is an aggressive tumor and the most common malignancy of the skeleton. Due to pulmonary metastasis, the 5-year survival rate is still unsatisfactory. It has been reported that SPRY4 intronic transcript 1 (SPRY4-IT1) promotes cell growth, invasion, and inhibits apoptosis in several cancers. However, the role of SPRY4-IT1 in osteosarcoma remains unclear. In the present study, we investigated the role of SPRY4-IT1 in osteosarcoma cells. Loss- and gain-of-function assays demonstrated that SPRY4-IT1 promoted cell proliferation, migration, and invasion in osteosarcoma. Moreover, SPRY4-IT1 induced epithelial mesenchymal transition phenotype in osteosarcoma cells. Subsequent investigations revealed that SPRY4-IT1 promoted migration and invasion through association with Snail1 and regulating its stability. Based on these findings, the SPRY4 IT1/Snail1/E-cadherin pathway may play a crucial role in promoting osteosarcoma metastasis. Thus, SPRY4-IT1 may be a potential target for new therapies of osteosarcoma. PMID- 26982002 TI - Longitudinal associations between perceived age discrimination and subjective well-being: variations by age and subjective life expectancy. AB - OBJECTIVES: Perceived age discrimination can have negative effects on one's subjective well-being (SWB). The response to age discrimination might differ based on age, and based on perceived longevity, or subjective life expectancy (SLE). These differential effects have not yet been prospectively examined within adult life span samples. METHOD: We examined the association between perceived age discrimination at baseline (T1) and SWB at follow-up (T2), and the moderation effect of SLE. We compared differences in these effects between middle-aged and older adults. Analyses were based on participants who took part in the 2008 (T1) and 2011 (T2) assessments of the German Ageing Survey (DEAS; listwise N = 1534), a population-based representative sample of the German adult population. Participants were categorized as middle-aged (ages 40-64; n = 919) or older adults (ages 65-93; n = 615). RESULTS: Regression analyses indicated that T1 perceived age discrimination significantly predicts lower T2 SWB among middle aged, but not among older adults, after adjusting for covariates and T1 SWB. There is a significant interaction between age discrimination and SLE for predicting SWB, only among middle-aged participants, suggesting that age discrimination predicts decreases in SWB for those reporting higher, but not lower levels of SLE. CONCLUSION: People in the transition from midlife to old age, who hold higher SLE, appear to be more vulnerable to age discrimination. This may be due to the experience of age discrimination as an 'off-time', or unexpected event for those in midlife who have a higher expectation to live longer. PMID- 26982003 TI - Increasing persistency in lay and stabilising egg quality in longer laying cycles. What are the challenges? AB - In the past 50 years, selection starting initially at the breed level and then using quantitative genetics coupled with a sophisticated breeding pyramid, has resulted in a very productive hybrid for a variety of traits associated with egg production. One major trait currently being developed further is persistency of lay and the concept of the "long life" layer. Persistency in lay however cannot be achieved without due consideration of how to sustain egg quality and the health and welfare of the birds in longer laying cycles. These multiple goals require knowledge and consideration of the bird's physiology, nutritional requirements, which vary depending on age and management system, reproductive status and choice of the selection criteria applied. The recent advent of molecular genetics offers considerable hope that these multiple elements can be balanced for the good of all in the industry including the hens. The "long life" layer, which will be capable of producing 500 eggs in a laying cycle of 100 weeks, is therefore on the horizon, bringing with it the benefits of a more efficient utilisation of diminishing resources, including land, water, raw materials for feed as well as a reduction in waste, and an overall reduced carbon footprint. PMID- 26982004 TI - Controlling Endemic Pathogens-Challenges and Opportunities. AB - By most measures, the University of Utah Centralized Zebrafish Animal Resource is a successful zebrafish core facility: we house ~4000-5000 tanks for over 16 research groups; provide services and equipment for ~150 users; are currently undergoing an expansion by 3000 tanks; and have been praised by institutional and national regulatory agencies for the cleanliness and efficiency of our facility. In recent years, we have implemented new programs to improve the overall health of our colony and believe we have seen a reduction in apparently sick fish. However, there are still deficiencies in our monitoring and pathogen control programs. Our histopathology sample sizes have been insufficient to estimate prevalence, but our sentinel tank program reveals the presence of Pseudoloma neurophilia and myxozoan, presumably Myxidium streisinger, in our facility. As we develop protocols to further reduce the burden of disease, we are focused on defining our baseline, establishing goals, and implementing methods to monitor our progress. The data generated by this approach will allow us to evaluate and implement the most cost-effective protocols to improve fish health. PMID- 26982005 TI - Pentraxin 3: an immune modulator of infection and useful marker for disease severity assessment in sepsis. AB - The acute phase protein pentraxin 3 (PTX3) is a pattern recognition receptor involved in regulation of the host immune response. This relatively newly discovered member of the pentraxin superfamily elicits both immunostimulatory and immunoregulatory functions preventing autoimmune pathology and orchestrated clearance of pathogens through opsonization of damage- and pathogen-associated molecular patterns (DAMP/PAMP). Thus, PTX3 has been described as a possible evolutionary precursor to immunoglobulins. While shown to provide protection against specific bacterial and fungal pathogens, persistent elevation of PTX3 levels following initial onset of infection appear to predict poor patient outcome and may contribute to disease sequelae such as tissue damage and coagulopathy. Measurement of PTX3 following onset of sepsis may improve patient risk assessment and thus be useful in guiding subsequent therapeutic interventions including steroidal anti-inflammatory and altered antibiotic therapies. In this review, we summarize the role of PTX3 in inflammatory syndromes and its utility as a marker of sepsis disease severity. PMID- 26982006 TI - A niosomal bilayer of sorbitan monostearate in complex with flavones: a molecular dynamics simulation study. AB - Bilayers prepared from sorbitan fatty acid esters (Span) have been frequently used for delivery of drugs including flavonoids. We applied molecular dynamics simulation to characterize the structure of a sorbitan monostearate (Span 60) bilayer in complex with three representative flavones, a subclass of flavonoids. At a low concentration, unsubstituted flavone, the most hydrophobic member, was able to flip over and cross the bilayer with a large diffusion coefficient. At a high concentration, it was accumulated at the bilayer center resulting in a phase separation. The leaflets of the bilayer were pushed in the opposite directions increasing the membrane thickness. Order parameter of the stearate chain of Span 60 was not affected significantly by unsubstituted flavone. In contrast, chrysin with hydroxylated ring A was lined up with the acyl chains of Span 60 with its hydroxyl group facing the membrane surface. Neither flipping nor transbilayer movement were allowed. Diffusion coefficient was only 15-25% of that of unsubstituted flavone and order parameter decreased with the concentration of chrysin. Luteolin, the most hydroxylated member, interacted mainly with the headgroup of Span 60 and assumed many different orientations without crossing the bilayer. Unlike chrysin and unsubstituted flavone the bilayer integrity was disrupted at 50 mol% luteolin. These behaviors and structures of flavones in a Span 60 bilayer can be accounted for by their hydrophobicity and sites of hydroxylation. PMID- 26982007 TI - Narratives of Participants in National Career Development Programs for Women in Academic Medicine: Identifying the Opportunities for Strategic Investment. AB - BACKGROUND: Academic medicine has initiated changes in policy, practice, and programs over the past several decades to address persistent gender disparity and other issues pertinent to its sociocultural context. Three career development programs were implemented to prepare women faculty to succeed in academic medicine: two sponsored by the Association of American Medical Colleges, which began a professional development program for early career women faculty in 1988. By 1995, it had evolved into two programs one for early career women and another for mid-career women. By 2012, more than 4000 women faculty from medical schools across the U.S and Canada had participated in these intensive 3-day programs. The third national program, the Hedwig van Ameringen Executive Leadership in Academic Medicine((r)) (ELAM) program for women, was developed in 1995 at the Drexel University College of Medicine. METHODS: Narratives from telephone interviews representing reflections on 78 career development seminars between 1988 and 2010 describe the dynamic relationships between individual, institutional, and sociocultural influences on participants' career advancement. RESULTS: The narratives illuminate the pathway from participating in a career development program to self-defined success in academic medicine in revealing a host of influences that promoted and/or hindered program attendance and participants' ability to benefit after the program in both individual and institutional systems. The context for understanding the importance of these career development programs to women's advancement is nestled in the sociocultural environment, which includes both the gender-related influences and the current status of institutional practices that support women faculty. CONCLUSIONS: The findings contribute to the growing evidence that career development programs, concurrent with strategic, intentional support of institutional leaders, are necessary to achieve gender equity and diversity inclusion. PMID- 26982008 TI - Diabetes Incidence and Glucose Tolerance after Termination of Pioglitazone Therapy: Results from ACT NOW. AB - CONTEXT: Thiazolidinediones have proven efficacy in preventing diabetes in high risk individuals. However, the effect of thiazolidinediones on glucose tolerance after cessation of therapy is unclear. OBJECTIVE: To examine the effect of pioglitazone (PIO) on incidence of diabetes after discontinuing therapy in ACT NOW. Design, Settings and Patients: Two-hundred ninety-three subjects (placebo [PLAC], n = 138; PIO, n = 152) completed a median followup of 11.7 mo after study medication was stopped. RESULTS: Diabetes developed in 138 (12.3%) of PLAC vs 17 of 152 PIO patients (11.2%; P = not significant, PIO vs PLAC). However, the cumulative incidence of diabetes from start of study medication to end of washout period remained significantly lower in PIO vs PLAC (10.7 vs 22.3%; P < .005). After therapy was discontinued, 23.0% (35/152) of PIO-treated patients remained normal-glucose tolerant (NGT) vs 13.8% (19/138) of PLAC-treated patients (P = .04). Insulin secretion/insulin resistance index (I0-120/G0-120 * Matsuda index) was markedly lower in subjects with impaired glucose tolerance (IGT) who converted to diabetes during followup vs those who remained IGT or NGT. The decline in-cell function (insulin secretion/insulin resistance index) was similar in subjects with IGT who developed diabetes, irrespective of whether they were treated with PIO or PLAC. CONCLUSIONS: 1) The protective effect of PIO on incidence of diabetes attenuates after discontinuation of therapy, 2) cumulative incidence of diabetes in individuals exposed to PIO remained significantly (56%) lower than PLAC and a greater number of PIO-treated individuals maintained NGT after median followup of 11.4 mo, and 3) low insulin secretion/insulin resistance index is a strong predictor of future diabetes following PIO discontinuation. PMID- 26982009 TI - Somatic GPR101 Duplication Causing X-Linked Acrogigantism (XLAG)-Diagnosis and Management. AB - CONTEXT: Recent reports have proposed that sporadic or familial germline Xq26.3 microduplications involving the GPR101 gene are associated with early-onset X linked acrogigantism (XLAG) with a female preponderance. CASE DESCRIPTION: A 4 year-old boy presented with rapid growth over the previous 2 years. He complained of sporadic headaches and had coarse facial features. His height Z-score was +4.89, and weight Z-score was +5.57. Laboratory testing revealed elevated serum prolactin (185 MUg/L; normal, <18 MUg/L), IGF-1 (745 MUg/L; normal, 64-369 MUg/L), and fasting GH > 35.0 MUg/L. Magnetic resonance imaging demonstrated a homogenous bulky pituitary gland (18 * 15 * 13 mm) without obvious adenoma. A pituitary biopsy showed hyperplastic pituitary tissue with enlarged cords of GH and prolactin cells. Germline PRKAR1A, MEN1, AIP, DICER1, CDKN1B, and somatic GNAS mutations were negative. Medical management was challenging until institution of continuous sc infusion of short-acting octreotide combined with sc pegvisomant and oral cabergoline. The patient remains well controlled with minimal side effects 7 years after presentation. His phenotype suggested XLAG, but his peripheral leukocyte-, saliva-, and buccal cell-derived DNA tested negative for microduplication in Xq26.3 or GPR101. However, DNA isolated from the pituitary tissue and forearm skin showed duplicated dosage of GPR101, suggesting that he is mosaic for this genetic abnormality. CONCLUSIONS: Our patient is the first to be described with somatic microduplication leading to typical XLAG phenotype. This patient demonstrates that a negative test for Xq26.3 microduplication or GPR101 duplication on peripheral blood DNA does not exclude the diagnosis of XLAG because it can result from a mosaic mutation affecting the pituitary. PMID- 26982011 TI - Novel Management of Insulin Autoimmune Syndrome with Rituximab and Continuous Glucose Monitoring. AB - CONTEXT: Insulin autoimmune syndrome (IAS), or Hirata's disease, is a rare hypoglycemic disorder characterized by spontaneous hypoglycemia without evidence of exogenous insulin administration, a high serum concentration of total immunoreactive insulin, and the presence of insulin autoantibodies in high titer. The majority of cases occur in the Asian population, and treatment is generally successful with watchful waiting or steroids. CASE DESCRIPTION: We report the case of a 71-year-old Caucasian man with severe hypoglycemia due to IAS that was refractory to a prolonged course of high-dose steroids. Type 1 diabetes prevention trials using rituximab have shown selective suppression of insulin autoantibodies, which are the pathogenic antibodies in IAS, and therefore we provided this therapy. Treatment with two doses of rituximab and daily use of a continuous glucose monitor resulted in disease remission. CONCLUSION: We present the first case where potentially life-threatening hypoglycemia due to IAS was successfully managed with rituximab and a continuous glucose monitor. We conclude that these treatment modalities are effective for the management of severe, refractory IAS. PMID- 26982010 TI - C1q/TNF-Related Protein-9 (CTRP9) Levels Are Associated With Obesity and Decrease Following Weight Loss Surgery. AB - CONTEXT: C1q/TNF-related protein-9 (CTRP9) is a novel adipokine that has beneficial metabolic and cardiovascular effects in various animal models. Alterations in circulating CTRP9 have also been observed in patients with cardiovascular disease and diabetes, but little is known about the impact of obesity and bariatric surgery on CTRP9 concentrations. OBJECTIVE: The aim of this study was to compare CTRP9 levels in obese and lean subjects and to determine whether circulating CTRP9 levels in morbidly obese patients are altered by bariatric surgery. DESIGN, SETTING, AND PARTICIPANTS: Fifty-nine obese bariatric surgical patients and 62 lean controls were recruited to participate in a cross sectional study at an academic medical center. The obese patients were further invited to participate in a cohort study, and 21 returned for analysis at 3 and 6 months postsurgery. INTERVENTION: Bariatric surgery (Roux-en-Y gastric bypass and vertical sleeve gastrectomy) was the intervention for this study. MAIN OUTCOME MEASURES: Fasting serum was obtained from all subjects on entry to the study and was analyzed in the core laboratory for hemoglobin A1c, glucose, aspartate aminotransferase, alanine aminotransferase, total cholesterol, high- and low density lipoprotein cholesterol, and triglycerides; CTRP9, insulin, adiponectin, and leptin were measured by ELISA. Serum from the patients in the cohort study was also analyzed at 3 and 6 months. RESULTS: Serum CTRP9 was significantly higher in the obese group compared to the lean group. CTRP9 was associated with obesity, even after controlling for age, gender, and ethnicity. Following bariatric surgery, there was a significant decrease in weight at 3 and 6 months postprocedure, accompanied by decreases in CTRP9, hemoglobin A1c and leptin, and an increase in serum adiponectin. CONCLUSIONS: CTRP9 levels are elevated in obesity and significantly decrease following weight loss surgery. Our data suggest that CTRP9 may play a compensatory role in obesity, similar to that of insulin, and is down-regulated following weight loss surgery. PMID- 26982012 TI - Anti-Integrins in Ulcerative Colitis and Crohn's Disease: What Is Their Place? AB - BACKGROUND: Inflammatory bowel diseases (IBD) are a group of heterogeneous conditions, characterized by immune-mediated inflammation of the gastrointestinal tract. Traditionally, medical management of these disorders has been based on use of systemic immunosuppressives. The development of new drugs that selectively inhibit leukocyte trafficking to the gut has the potential to reduce inflammation and minimize systemic toxicities. KEY MESSAGES: In this article, we review the immunology of the gut and the mechanism of action these emerging therapies for IBD. Natalizumab, a monoclonal antibody to the alpha4 integrin, was approved for the treatment of multiple sclerosis and showed promise in Crohn's disease (CD), however it is encumbered by the risk of progressive multifocal leukoencephalopathy. Vedolizumab inhibits the alpha4beta7 integrin to induce clinical remission in patients with both ulcerative colitis and CD. Long-term safety data on this agent is not yet available. We also review agents in the pipeline. Finally, we discuss the positioning of therapies and potential alterations to therapeutic algorithms as new medications emerge. CONCLUSIONS: New therapies are emerging for IBD; however, long-term data are pending. The positioning of these agents in algorithms will evolve. PMID- 26982013 TI - Three-Dimensional Imaging Using Contrast-Enhanced and Three-Dimensional Ultrasound Techniques in the Ablative Zone Treated with a Multipolar Radiofrequency Ablation System for Hepatocellular Carcinoma. AB - OBJECTIVES: The aim of this study was to generate three-dimensional (3D) images of the ablative zone in patients with hepatocellular carcinoma (HCC) treated with multipolar radiofrequency ablation (RFA) using contrast-enhanced ultrasound (CEUS) and 3DUS and to investigate the shape of the ablative zone among several patterns after insertion of two or three electrodes. METHODS: This study included 16 patients and 20 HCCs treated with a multipolar RFA system. All patients underwent CEUS within 14 days after multipolar RFA therapy. The 3D scanning functionality of the LOGIQ E9 US imaging system (GE Healthcare, Milwaukee, Wis., USA), which acquires volume data using a manually controlled sweep on perfusion defects of CEUS, was used in this study to acquire CEUS/3DUS data. The ablative area shapes resulting from three insertion patterns were investigated, using two electrodes (T20-T20 and T30-T30) or three electrodes (T30-T30-T30). RESULTS: The resulting shapes using two electrodes were globule-like (T20-T20) or elliptical (T30-T30). The shape using three electrodes (T30-T30-T30) was almost ellipse-like but slightly irregular. CONCLUSIONS: Generating 3D images using CEUS/3DUS techniques is simple and useful for evaluating the shape of the ablative area, and these images provide informational or educational tools for patients and medical staff associated with multipolar RFA procedures. PMID- 26982014 TI - Generalized Arterial Calcification in a Recipient Twin: Discordant Fetal Hemodynamics Result in Differing Phenotypes in Monozygotic Twins with an ABCC6 Mutation. AB - Recipients of the twin-twin transfusion syndrome (TTTS) often develop cardiac manifestations, but arterial calcification has rarely been reported. Generalized arterial calcification of infancy (GACI) is a genetic disorder with high infantile mortality. We report the case of a TTTS recipient with moderate cardiomyopathy at diagnosis who developed progressive calcification of the pulmonary arteries and aorta after successful in utero laser therapy. Postnatally, both twins were diagnosed with a heterozygous ABCC6 gene mutation associated with GACI. The recipient had progressive supravalvular pulmonary and aortic stenosis, was treated with bisphosphonate therapy, and successfully underwent cardiac surgery at 4 months of age. The donor twin with the same mutation remained phenotypically normal at 15 months of age. This case illustrates monozygotic fetuses with discordant in utero hemodynamics, with subsequent development of phenotypic differences. TTTS recipients with arterial calcifications should undergo genetic testing for GACI. PMID- 26982015 TI - Thermally Stable Siloxane Hybrid Matrix with Low Dielectric Loss for Copper-Clad Laminates for High-Frequency Applications. AB - We report vinyl-phenyl siloxane hybrid material (VPH) that can be used as a matrix for copper-clad laminates (CCLs) for high-frequency applications. The CCLs, with a VPH matrix fabricated via radical polymerization of resin blend consisting of sol-gel-derived linear vinyl oligosiloxane and bulky siloxane monomer, phenyltris(trimethylsiloxy)silane, achieve low dielectric constant (Dk) and dissipation factor (Df). The CCLs with the VPH matrix exhibit excellent dielectric performance (Dk = 2.75, Df = 0.0015 at 1 GHz) with stability in wide frequency range (1 MHz to 10 GHz) and at high temperature (up to 275 degrees C). Also, the VPH shows good flame resistance without any additives. These results suggest the potential of the VPH for use in high-speed IC boards. PMID- 26982017 TI - Exploring the Challenges and Opportunities of Health Mobile Apps for Individuals with Type 2 Diabetes Living in Rural Communities. AB - BACKGROUND: Many adults with type 2 diabetes (T2D), living in rural communities, are not optimally managing the disease through their diet and physical activities. Mobile apps have the potential to facilitate self-management activities, such as providing educational content, assisting with problem solving, and self-regulation. The goal of this study was to understand the perceived barriers, benefits, and facilitators among rural adults with T2D regarding the use of free mobile apps available in Apple App store or Google Play store for diabetes management or behavior monitoring. MATERIALS AND METHODS: Four focus groups were conducted with 18 participants with T2D who owned a smartphone (age: M = 54.4, SD = 12.7; 27.8% male). The participants were asked about their general app and health-specific app usage. They were then shown features of four apps related to diabetes self-management (Glucose Buddy, mySugr, MyFitnessPal, and MapMyWalk) and prompted to provide feedback. The focus groups were audio recorded, transcribed verbatim, and coded using inductive thematic analysis. RESULTS: Four themes were identified as follows: (1) perceived barriers to use or continuous use, (2) perceived benefits of desired features of diabetes self management, (3) facilitators to motivate use, and (4) information sharing with family, friends, and health professionals. CONCLUSIONS: The findings provide initial user perceptions regarding the feasibility and acceptability of mobile apps for T2D self-management. These findings regarding perceived barriers, benefits, and facilitators can guide the development and design of apps for individuals with T2D and help researchers determine best practices when developing apps for other chronic conditions. PMID- 26982016 TI - Enterococcus faecium ST17 from Coastal Marine Sediment Carrying Transferable Multidrug Resistance Plasmids. AB - The multidrug-resistant Enterococcus faecium 17i48, sequence type 17, from marine sediment, carrying erm(B), tet(M), and tet(L) genes, was analyzed for the presence of antibiotic resistance plasmids and for the ability to transfer resistance genes. The strain was found to harbor the replicon type (repA) of pRE25, pRUM, pHTbeta, and the axe-txe toxin-antitoxin (TA) system. In mating experiments, tet(M) and tet(L) were cotransferred with the repApRE25, whereas erm(B) was consistently cotransferred with the axe-txe and repApRUM, suggesting that tetracycline and erythromycin resistance genes were carried on different elements both transferable by conjugation, likely via pHTbeta-mediated mobilization. Hybridization and PCR mapping demonstrated that tet(M) and tet(L) were located in tandem on a pDO1-like plasmid that also carried the repApRE25, whereas erm(B) was carried by a pRUM-like plasmid. Sequencing of the latter plasmid showed a high nucleotide identity with pRUM and the presence of cat, aadE, sat4, and a complete aphA resistance genes. These findings show that the genetic features of E. faecium 17i48 are consistent with a hospital-adapted clone and suggest that antibiotic resistance may spread in the environment, also in the absence of antibiotic pressure, due to TA system plasmid maintenance. PMID- 26982018 TI - The expression and prognostic relevance of indoleamine 2,3-dioxygenase in tongue squamous cell carcinoma. AB - Conclusion IDO might be useful for predicting progression of primary tumor stage T2 and T3 in tongue squamous cell carcinoma (TSCC), but does not seem like a specific biomarker for diagnosing TSCC and predicting patient survival. Objectives Indoleamine 2,3-dioxygenase (IDO) is expressed in many cells and it catabolises the essential amino acid tryptophan to kynurenine. IDO acts as an immune modulator through suppression of T-cell immunity and other pathways. In cancer cells, IDO has been proposed to promote tumor progression by enabling malignant cells to escape from the immune system. The aim of this study was to evaluate the association and prognostic relevance of IDO expression in TSCC. Method One hundred and eight retrospective tongue and lymph node specimens were stained immunohistochemically with monoclonal antibody anti-indoleamine 2,3 dioxygenase. The relative abundance of IDO positive epithelial cells, IDO staining intensity, and inflammation were assessed semi-quantitatively with light microscopy. Results IDO was expressed stronger in tongue hyperplasia than in TSCC. However, IDO expression associated with poor survival in the sub-groups with primary tumor stage T2-T4 and in the sub-group with strong inflammation in tumors' invasive front. PMID- 26982020 TI - Flagging fortunes invite reform. PMID- 26982019 TI - A network of knowledge. PMID- 26982021 TI - Eye on the prize, but grasp loosens. PMID- 26982022 TI - Swimming against the tide. PMID- 26982023 TI - Top teams to be reckoned with. PMID- 26982024 TI - A guide to the Nature Index. PMID- 26982025 TI - Nature Index 2016 Japan. PMID- 26982026 TI - Intramolecular Functionalization of Benzylic Methylene Adjacent to the Ring Nitrogen Atom in N-Aryltetrahydroisoquinoline Derivatives. AB - Functionalization at the benzylic methylene group that is adjacent to the ring nitrogen atom in a series of N-aryltetrahydroisoquinoline compounds has been realized through intramolecular cross-dehydrogenative coupling reactions. The presented transformation provided straightforward access to the formation of C(sp(3))-Y (Y = C, N or O) bond via I(III) reagent. PMID- 26982027 TI - Risk Genes of Inflammatory Bowel Disease in Asia: What Are the Most Important Pathways Affected? AB - Genetic factors play an important role in the pathogenesis of inflammatory bowel disease (IBD), and IBD is now recognized as a complex disease that results from interplay between genetic and environment factors. To date, over 160 IBD susceptible loci have been identified using genome-wide association studies (GWAS). The risk genes identified in these studies are involved in various pathways in innate and adaptive immune response such as innate bacterial sensing, autophagy and interleukin-23 receptor/T-helper cell 17 pathway. It was initially believed that the genetic backgrounds of Asian IBD patients differ from that of other populations. Recent GWAS and meta-analysis found that there is pervasive sharing of risk loci between the East and West. Overlapping risk genes between populations of different ancestries indicate that pathways underlying the etiology of IBD may be common between Asia and other areas. However, the importance of individual pathways may be different in Asia from the Western countries. Identifying the most important pathways affected in Asian IBD patients may provide a better understanding of pathogenesis of IBD in Asia and improve the clinical management of the patients. PMID- 26982028 TI - Spatio-Temporal Analysis of Micro Economic Activities in Rome Reveals Patterns of Mixed-Use Urban Evolution. AB - Understanding urban growth is one with understanding how society evolves to satisfy the needs of its individuals in sharing a common space and adapting to the territory. We propose here a quantitative analysis of the historical development of a large urban area by investigating the spatial distribution and the age of commercial activities in the whole city of Rome. We find that the age of activities of various categories presents a very interesting double exponential trend, with a transition possibly related to the long-term economical effects determined by the oil crisis of the Seventies. The diversification of commercial categories, studied through various measures of entropy, shows, among other interesting features, a saturating behaviour with the density of activities. Moreover, different couples of commercial categories exhibit over the years a tendency to attract in space. Our results demonstrate that the spatio temporal distribution of commercial activities can provide important insights on the urbanisation processes at work, revealing specific and non trivial socio economical dynamics, as the presence of crisis periods and expansion trends, and contributing to the characterisation of the maturity of urban areas. PMID- 26982029 TI - Thyroid Ultrasound-Guided Fine-Needle Aspiration: The Positive Influence of On Site Adequacy Assessment and Number of Needle Passes on Diagnostic Cytology Rate. AB - OBJECTIVE: Nondiagnostic cytology is the most important limitation of thyroid ultrasound-guided fine-needle aspiration (US-FNA). This study aimed to identify factors associated with the adequacy rate of thyroid US-FNA. STUDY DESIGN: Consecutive thyroid US-FNAs (2006-2013) were retrospectively included. Attending radiologists, radiology fellows and radiology residents performed US-FNA, usually involving 2-3 needle passes. In more recent years, rapid on-site adequacy assessment (ROSAA) was performed to ensure specimen adequacy. US characteristics, procedural variations and cytology results were extracted from US and pathology reports and statistically evaluated. RESULTS: Diagnostic cytology was obtained in 64.6% of 1,381 thyroid US-FNAs. Factors associated with nondiagnostic cytology were ROSAA (74.6% diagnostic cytology, OR 0.55, 95% CI 0.42-0.71), >=3 clinic visits for US-FNA of the same thyroid nodule (54.7%, OR 1.56, 95% CI 1.16-2.10) and increased intranodular vascularization (51.8%, OR 1.73, 95% CI 1.17-2.57). With ROSAA, an increasing number of needle passes demonstrated improving adequacy rates. The adequacy rate was not operator-dependent. CONCLUSION: This study demonstrates that ROSAA improves the adequacy rate of thyroid US-FNA. Without ROSAA, we recommend performing at least 3 needle passes. Less diagnostic cytology is obtained from nodules with increased intranodular vascularization or from those undergoing US-FNA >=3 times. PMID- 26982030 TI - Monitoring Flower Visitation Networks and Interactions between Pairs of Bumble Bees in a Large Outdoor Flight Cage. AB - Pollinators, such as bees, often develop multi-location routes (traplines) to exploit subsets of flower patches within larger plant populations. How individuals establish such foraging areas in the presence of other foragers is poorly explored. Here we investigated the foraging patterns of pairs of bumble bees (Bombus terrestris) released sequentially into an 880m2 outdoor flight cage containing 10 feeding stations (artificial flowers). Using motion-sensitive video cameras mounted on flowers, we mapped the flower visitation networks of both foragers, quantified their interactions and compared their foraging success over an entire day. Overall, bees that were released first (residents) travelled 37% faster and collected 77% more nectar, thereby reaching a net energy intake rate 64% higher than bees released second (newcomers). However, this prior-experience advantage decreased as newcomers became familiar with the spatial configuration of the flower array. When both bees visited the same flower simultaneously, the most frequent outcome was for the resident to evict the newcomer. On the rare occasions when newcomers evicted residents, the two bees increased their frequency of return visits to that flower. These competitive interactions led to a significant (if only partial) spatial overlap between the foraging patterns of pairs of bees. While newcomers may initially use social cues (such as olfactory footprints) to exploit flowers used by residents, either because such cues indicate higher rewards and/or safety from predation, residents may attempt to preserve their monopoly over familiar resources through exploitation and interference. We discuss how these interactions may favour spatial partitioning, thereby maximising the foraging efficiency of individuals and colonies. PMID- 26982031 TI - Analysis of Gene Expression in 3D Spheroids Highlights a Survival Role for ASS1 in Mesothelioma. AB - To investigate the underlying causes of chemoresistance in malignant pleural mesothelioma, we have studied mesothelioma cell lines as 3D spheroids, which acquire increased chemoresistance compared to 2D monolayers. We asked whether the gene expression of 3D spheroids would reveal mechanisms of resistance. To address this, we measured gene expression of three mesothelioma cell lines, M28, REN and VAMT, grown as 2D monolayers and 3D spheroids. A total of 209 genes were differentially expressed in common by the three cell lines in 3D (138 upregulated and 71 downregulated), although a clear resistance pathway was not apparent. We then compared the list of 3D genes with two publicly available datasets of gene expression of 56 pleural mesotheliomas compared to normal tissues. Interestingly, only three genes were increased in both 3D spheroids and human tumors: argininosuccinate synthase 1 (ASS1), annexin A4 (ANXA4) and major vault protein (MVP); of these, ASS1 was the only consistently upregulated of the three genes by qRT-PCR. To measure ASS1 protein expression, we stained 2 sets of tissue microarrays (TMA): one with 88 pleural mesothelioma samples and the other with additional 88 pleural mesotheliomas paired with matched normal tissues. Of the 176 tumors represented on the two TMAs, ASS1 was expressed in 87 (50%; staining greater than 1 up to 3+). For the paired samples, ASS1 expression in mesothelioma was significantly greater than in the normal tissues. Reduction of ASS1 expression by siRNA significantly sensitized mesothelioma spheroids to the pro apoptotic effects of bortezomib and of cisplatin plus pemetrexed. Although mesothelioma is considered by many to be an ASS1-deficient tumor, our results show that ASS1 is elevated at the mRNA and protein levels in mesothelioma 3D spheroids and in human pleural mesotheliomas. We also have uncovered a survival role for ASS1, which may be amenable to targeting to undermine mesothelioma multicellular resistance. PMID- 26982033 TI - 2016 - a second step. PMID- 26982034 TI - Ischemia/reperfusion-induced lung injury prevention: many options, no choices. PMID- 26982032 TI - MKS5 and CEP290 Dependent Assembly Pathway of the Ciliary Transition Zone. AB - Cilia have a unique diffusion barrier ("gate") within their proximal region, termed transition zone (TZ), that compartmentalises signalling proteins within the organelle. The TZ is known to harbour two functional modules/complexes (Meckel syndrome [MKS] and Nephronophthisis [NPHP]) defined by genetic interaction, interdependent protein localisation (hierarchy), and proteomic studies. However, the composition and molecular organisation of these modules and their links to human ciliary disease are not completely understood. Here, we reveal Caenorhabditis elegans CEP-290 (mammalian Cep290/Mks4/Nphp6 orthologue) as a central assembly factor that is specific for established MKS module components and depends on the coiled coil region of MKS-5 (Rpgrip1L/Rpgrip1) for TZ localisation. Consistent with a critical role in ciliary gate function, CEP-290 prevents inappropriate entry of membrane-associated proteins into cilia and keeps ARL-13 (Arl13b) from leaking out of cilia via the TZ. We identify a novel MKS module component, TMEM-218 (Tmem218), that requires CEP-290 and other MKS module components for TZ localisation and functions together with the NPHP module to facilitate ciliogenesis. We show that TZ localisation of TMEM-138 (Tmem138) and CDKL-1 (Cdkl1/Cdkl2/Cdkl3/Cdlk4 related), not previously linked to a specific TZ module, similarly depends on CEP-290; surprisingly, neither TMEM-138 or CDKL-1 exhibit interdependent localisation or genetic interactions with core MKS or NPHP module components, suggesting they are part of a distinct, CEP-290-associated module. Lastly, we show that families presenting with Oral-Facial-Digital syndrome type 6 (OFD6) have likely pathogenic mutations in CEP-290-dependent TZ proteins, namely Tmem17, Tmem138, and Tmem231. Notably, patient fibroblasts harbouring mutated Tmem17, a protein not yet ciliopathy-associated, display ciliogenesis defects. Together, our findings expand the repertoire of MKS module associated proteins--including the previously uncharacterised mammalian Tmem80- and suggest an MKS-5 and CEP-290-dependent assembly pathway for building a functional TZ. PMID- 26982036 TI - The Manchester Respiratory Activities of Daily Living questionnaire for use in COPD patients: translation into Portuguese and cross-cultural adaptation for use in Brazil. AB - OBJECTIVE: To translate The Manchester Respiratory Activities of Daily Living (MRADL) questionnaire into Portuguese and to create a version of the MRADL that is cross-culturally adapted for use in Brazil. METHODS: The English-language version of the MRADL was translated into Portuguese by two health care researchers who were fluent in English. A consensus version was obtained by other two researchers and a pulmonologist. That version was back-translated into English by another translator who was a native speaker of English and fluent in Portuguese. The cognitive debriefing process consisted in having 10 COPD patients complete the translated questionnaire in order to test its understandability, clarity, and acceptability in the target population. On the basis of the results, the final Portuguese-language version of the MRADL was produced and approved by the committee and one of the authors of the original questionnaire. RESULTS: The author of the MRADL questioned only a few items in the translated version, and some changes were made to the mobility and personal hygiene domains. Cultural differences regarding the domestic activities domain were found, in particular regarding the item "Do you have the ability to do a full clothes wash and hang them out to dry?", due to socioeconomic and climatic issues. The item "Do you take care of your garden?" was questioned by the participants who lived in apartments, being modified to "Do you take care of your garden or plants in your apartment?" CONCLUSIONS: The final Portuguese-language version of the MRADL adapted for use in Brazil was found to be easy to understand and easily applied. PMID- 26982035 TI - Effects of N-acetylcysteine and pentoxifylline on remote lung injury in a rat model of hind-limb ischemia/reperfusion injury. AB - OBJECTIVE: To investigate the effects of N-acetylcysteine (NAC) and pentoxifylline in a model of remote organ injury after hind-limb ischemia/reperfusion (I/R) in rats, the lungs being the remote organ system. METHODS: Thirty-five male Wistar rats were assigned to one of five conditions (n = 7/group), as follows: sham operation (control group); hind-limb ischemia, induced by clamping the left femoral artery, for 2 h, followed by 24 h of reperfusion (I/R group); and hind-limb ischemia, as above, followed by intraperitoneal injection (prior to reperfusion) of 150 mg/kg of NAC (I/R+NAC group), 40 mg/kg of pentoxifylline (I/R+PTX group), or both (I/R+NAC+PTX group). At the end of the trial, lung tissues were removed for histological analysis and assessment of oxidative stress. RESULTS: In comparison with the rats in the other groups, those in the I/R group showed lower superoxide dismutase activity and glutathione levels, together with higher malondialdehyde levels and lung injury scores (p < 0.05 for all). Interstitial inflammatory cell infiltration of the lungs was also markedly greater in the I/R group than in the other groups. In addition, I/R group rats showed various signs of interstitial edema and hemorrhage. In the I/R+NAC, I/R+PTX, and I/R+NAC+PTX groups, superoxide dismutase activity, glutathione levels, malondialdehyde levels, and lung injury scores were preserved (p < 0.05 for all). The differences between the administration of NAC or pentoxifylline alone and the administration of the two together were not significant for any of those parameters (p > 0.05 for all). CONCLUSIONS: Our results suggest that NAC and pentoxifylline both protect lung tissue from the effects of skeletal muscle I/R. However, their combined use does not appear to increase the level of that protection. PMID- 26982037 TI - Restrictive pattern on spirometry: association with cardiovascular risk and level of physical activity in asymptomatic adults. AB - OBJECTIVE: To determine whether a restrictive pattern on spirometry is associated with the level of physical activity in daily life (PADL), as well as with cardiovascular disease (CVD) risk factors, in asymptomatic adults. METHODS: A total of 374 participants (mean age, 41 +/- 14 years) underwent spirometry, which included the determination of FVC and FEV1. A restrictive pattern on spirometry was defined as an FEV1/FVC ratio > 0.7 and an FVC < 80% of the predicted value. After conducting demographic, anthropometric, and CVD risk assessments, we evaluated body composition, muscle function, and postural balance, as well as performing cardiopulmonary exercise testing and administering the six-minute walk test. The PADL was quantified with a triaxial accelerometer. RESULTS: A restrictive pattern on spirometry was found in 10% of the subjects. After multivariate logistic regression, adjusted for confounders (PADL and cardiorespiratory fitness), the following variables retained significance (OR; 95% CI) as predictors of a restrictive pattern: systemic arterial hypertension (17.5; 1.65-184.8), smoking (11.6; 1.56-87.5), physical inactivity (8.1; 1.43 46.4), larger center-of-pressure area while standing on a force platform (1.34; 1.05-1.71); and dyslipidemia (1.89; 1.12-1.98). CONCLUSIONS: A restrictive pattern on spirometry appears to be common in asymptomatic adults. We found that CVD risk factors, especially systemic arterial hypertension, smoking, and physical inactivity, were directly associated with a restrictive pattern, even when the analysis was adjusted for PADL and cardiorespiratory fitness. Longitudinal studies are needed in order to improve understanding of the etiology of a restrictive pattern as well as to aid in the design of preventive strategies. PMID- 26982038 TI - Respiratory therapy: a problem among children and adolescents with cystic fibrosis. AB - OBJECTIVE: To evaluate the level of self-reported adherence to physical therapy recommendations in pediatric patients (6-17 years) with cystic fibrosis (CF) and to ascertain whether the different levels of adherence correlate with pulmonary function, clinical aspects, and quality of life. METHODS: This was a cross sectional study. The patients and their legal guardians completed a questionnaire regarding adherence to physical therapy recommendations and a CF quality of life questionnaire. We collected demographic, spirometric, and bacteriological data, as well as recording the frequency of hospitalizations and Shwachman-Kulczycki (S K) clinical scores. RESULTS: We included 66 patients in the study. Mean age, FEV1 (% of predicted), and BMI were 12.2 +/- 3.2 years, 90 +/- 24%, and 18.3 +/- 2.5 kg/m2, respectively. The patients were divided into two groups: high-adherence (n = 39) and moderate/poor-adherence (n = 27). No statistically significant differences were found between the groups regarding age, gender, family income, and total S-K clinical scores. There were statistically significant differences between the high-adherence group and the moderate/poor-adherence group, the latter showing lower scores for the "radiological findings" domain of the S-K clinical score (p = 0.030), a greater number of hospitalizations (p = 0.004), and more days of hospitalization in the last year (p = 0.012), as well as lower scores for the quality of life questionnaire domains emotion (p = 0.002), physical (p = 0.019), treatment burden (p < 0.001), health perceptions (p = 0.036), social (p = 0.039), and respiratory (p = 0.048). CONCLUSIONS: Low self reported adherence to physical therapy recommendations was associated with worse radiological findings, a greater number of hospitalizations, and decreased quality of life in pediatric CF patients. PMID- 26982039 TI - Alternative diagnoses based on CT angiography of the chest in patients with suspected pulmonary thromboembolism. AB - OBJECTIVE: To determine the prevalence of alternative diagnoses based on chest CT angiography (CTA) in patients with suspected pulmonary thromboembolism (PTE) who tested negative for PTE, as well as whether those alternative diagnoses had been considered prior to the CTA. METHODS: This was a cross-sectional, retrospective study involving 191 adult patients undergoing CTA for suspected PTE between September of 2009 and May of 2012. Chest X-rays and CTAs were reviewed to determine whether the findings suggested an alternative diagnosis in the cases not diagnosed as PTE. Data on symptoms, risk factors, comorbidities, length of hospital stay, and mortality were collected. RESULTS: On the basis of the CTA findings, PTE was diagnosed in 47 cases (24.6%). Among the 144 patients not diagnosed with PTE via CTA, the findings were abnormal in 120 (83.3%). Such findings were consistent with an alternative diagnosis that explained the symptoms in 75 patients (39.3%). Among those 75 cases, there were only 39 (20.4%) in which the same alterations had not been previously detected on chest X-rays. The most common alternative diagnosis, made solely on the basis of the CTA findings, was pneumonia (identified in 20 cases). Symptoms, risk factors, comorbidities, and the in-hospital mortality rate did not differ significantly between the patients with and without PTE. However, the median hospital stay was significantly longer in the patients with PTE than in those without (18.0 and 9.5 days, respectively; p = 0.001). CONCLUSIONS: Our results indicate that chest CTA is useful in cases of suspected PTE, because it can confirm the diagnosis and reveal findings consistent with an alternative diagnosis in a significant number of patients. PMID- 26982040 TI - The Program for the Prevention of Childhood Asthma: a specialized care program for children with wheezing or asthma in Brazil. AB - OBJECTIVE: To present the Programa Infantil de Prevencao de Asma (PIPA, Program for the Prevention of Childhood Asthma) and the characteristics of the patients followed in this program. METHODS: Implemented in the city of Uruguaiana, Brazil, PIPA has as its target population children and adolescents (< 18 years of age) with asthma or suspected asthma. Patients either enroll in PIPA spontaneously or are referred by pediatricians or primary care physicians. In this retrospective study, we use a standardized protocol to assess PIPA patients. RESULTS: By the end of the study period, 646 patients were being followed. Of those, 298 (46.1%) were <= 3 years of age. In this group of patients, recurrent wheezing was identified in 60.7%, and the first episode of wheezing occurred in the first six months of life in 86.0%. Severe wheezing was identified in 29.5% and 45.4% in the children <= 3 and > 3 years of age, respectively. Physician-diagnosed asthma was reported in 26.5% and 82.2%, respectively. In the sample as a whole, the prevalence of passive smoking was high (> 36%), occurring during pregnancy in > 15%; > 40% of the patients had been born by cesarean section; and 30% had a mother who had had < 8 years of schooling. CONCLUSIONS: A prevention program for children with asthma is an effective strategy for controlling the disease. Knowledge of local epidemiological and environmental characteristics is essential to reducing the prevalence of the severe forms of asthma, to improving the use of health resources, and to preventing pulmonary changes that could lead to COPD in adulthood. PMID- 26982041 TI - Obstructive sleep apnea related to rapid-eye-movement or non-rapid-eye-movement sleep: comparison of demographic, anthropometric, and polysomnographic features. AB - OBJECTIVE: To determine whether there are significant differences between rapid eye-movement (REM)-related obstructive sleep apnea (OSA) and non-REM (NREM) related OSA, in terms of the demographic, anthropometric, and polysomnographic characteristics of the subjects. METHODS: This was a retrospective study of 110 patients (75 males) with either REM-related OSA (n = 58) or NREM-related OSA (n = 52). To define REM-related and NREM-related OSA, we used a previously established criterion, based on the apnea-hypopnea index (AHI): AHI-REM/AHI-NREM ratio > 2 and <= 2, respectively. RESULTS: The mean age of the patients with REM-related OSA was 49.5 +/- 11.9 years, whereas that of the patients with NREM-related OSA was 49.2 +/- 12.6 years. The overall mean AHI (all sleep stages combined) was significantly higher in the NREM-related OSA group than in the REM-related OSA group (38.6 +/- 28.2 vs. 14.8 +/- 9.2; p < 0.05). The mean AHI in the supine position (s-AHI) was also significantly higher in the NREM-related OSA group than in the REM-related OSA group (49.0 +/- 34.3 vs. 18.8 +/- 14.9; p < 0.0001). In the NREM-related OSA group, the s-AHI was higher among the men. In both groups, oxygen desaturation was more severe among the women. We found that REM-related OSA was more common among the patients with mild-to-moderate OSA, whereas NREM related OSA was more common among those with severe OSA. CONCLUSIONS: We found that the severity of NREM-related OSA was associated mainly with s-AHI. Our findings suggest that the s-AHI has a more significant effect on the severity of OSA than does the AHI-REM. When interpreting OSA severity and choosing among treatment modalities, physicians should take into consideration the sleep stage and the sleep posture. PMID- 26982042 TI - Cervical computed tomography in patients with obstructive sleep apnea: influence of head elevation on the assessment of upper airway volume. AB - OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) has a high prevalence and carries significant cardiovascular risks. It is important to study new therapeutic approaches to this disease. Positional therapy might be beneficial in reducing the apnea-hypopnea index (AHI). Imaging methods have been employed in order to facilitate the evaluation of the airways of OSAS patients and can be used in order to determine the effectiveness of certain treatments. This study was aimed at determining the influence that upper airway volume, as measured by cervical CT, has in patients diagnosed with OSAS. METHODS: This was a quantitative, observational, cross-sectional study. We evaluated 10 patients who had been diagnosed with OSAS by polysomnography and on the basis of the clinical evaluation. All of the patients underwent conventional cervical CT in the supine position. Scans were obtained with the head of the patient in two positions (neutral and at a 44 degrees upward inclination), and the upper airway volume was compared between the two. RESULTS: The mean age, BMI, and neck circumference were 48.9 +/- 14.4 years, 30.5 +/- 3.5 kg/m2, and 40.3 +/- 3.4 cm, respectively. The mean AHI was 13.7 +/- 10.6 events/h (range, 6.0-41.6 events/h). The OSAS was classified as mild, moderate, and severe in 70%, 20%, and 10% of the patients, respectively. The mean upper airway volume was 7.9 cm3 greater when the head was at a 44 degrees upward inclination than when it was in the neutral position, and that difference (17.5 +/- 11.0%) was statistically significant (p = 0.002). CONCLUSIONS: Elevating the head appears to result in a significant increase in the caliber of the upper airways in OSAS patients. PMID- 26982044 TI - Angiosarcoma of the lung. AB - Angiosarcoma is a rare malignant vascular tumor. Pulmonary involvement is usually attributable to metastasis from other primary sites, primary pulmonary angiosarcoma therefore being quite uncommon. We report a case of angiosarcoma with pulmonary involvement, probably primary to the lung, which had gone untreated for more than two years. We describe this rare neoplasm and its growth, as well as the extensive local invasion and hematogenous metastasis at presentation. We also discuss its poor prognosis. PMID- 26982045 TI - Tumor seeding along the needle track after percutaneous lung biopsy. PMID- 26982043 TI - Psychological distress related to smoking cessation in patients with acute myocardial infarction. AB - Among all causes of preventable deaths, smoking is responsible for the greatest number of deaths worldwide and predisposes to fatal, noncommunicable diseases, especially cardiovascular diseases. Lifestyle changes are effective in the treatment of patients with smoking-related diseases and assist in the prevention of premature mortality. Our objective was to investigate the available scientific evidence regarding the psychological distress related to smoking cessation in patients who have had acute myocardial infarction. To that end, we conducted an integrative review of the literature in order to summarize relevant studies on this topic. The selected databases were Scopus, PubMed Central, Institute for Scientific Information Web of Science (Core Collection), ScienceDirect, EMBASE, SciELO, LILACS e PsycINFO. On the basis of the inclusion and exclusion criteria adopted for this study, 14 articles were selected for analysis. Those studies showed that the prevalence of psychological distress is higher among smokers than among nonsmokers, and distress-related symptoms are much more common in smokers with acute myocardial infarction than in those without. Smoking cessation depends on the active participation of the smoker, whose major motivation is the underlying disease. Most studies have shown that there is a need to create treatment subgroups as a means of improving the treatment provided. This review article expands the knowledge regarding smoking cessation and shows the need to invest in future research that investigates subgroups of smokers diagnosed with the major smoking-related comorbidities, such as acute myocardial infarction, in order to develop specific interventions and psychological support strategies. PMID- 26982046 TI - Tracheal lobular capillary hemangioma treated with laser photocoagulation. PMID- 26982047 TI - Idiopathic pulmonary fibrosis can be a transient diagnosis. PMID- 26982049 TI - What is survival analysis, and when should I use it? PMID- 26982050 TI - ERRATUM. PMID- 26982051 TI - ERRATUM. PMID- 26982048 TI - Crazy-paving pattern. PMID- 26982052 TI - ERRATUM. PMID- 26982053 TI - IBD and Environment: Are There Differences between East and West. AB - BACKGROUND: The inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis (UC) occur worldwide with differences in epidemiology, etiology and phenotype between regions. Breakthroughs have occurred in IBD genetics, although the genes that predispose to IBD differ between racial groups. What do we know about the 'envirotype' of those who develop IBD, and are there differences between the East and the West? KEY MESSAGES: The strongest IBD risk factor identified to date is a family history of IBD. Whilst likely representing an underlying genetic predisposition, it may also reflect shared environmental factors amongst family members. Cigarette smoking increases the risk of developing CD, whilst smoking is less common in those who develop UC. Having ceased smoking increases the risk of developing UC subsequently. Unlike the West, cigarette smoking appears to play a lesser role in the East. Other environmental risk factors are inconsistent. Studies of migrant populations moving from regions of low to high IBD incidence point to early life as a key time for environmental triggers. In these populations, it is the second generation (those born in the high incidence region) with higher IBD incidence rates than their parents. Early life environmental exposures have been studied exhaustively but, except for having been breastfed, few putative early childhood environmental risk factors have been shown consistently to alter the risk of developing IBD. CONCLUSIONS: The identification of IBD environmental risk factors remains elusive in both the East and West. In the West, case-control studies are unlikely to move the field forward without multi-level (phenotype, genotype, diet history, 'envirotype' and microbiome) data, ideally collected prospectively. Cohort studies (such as the Genes, Environment, Microbiome project) may address some of these issues. However, in the East where IBD incidence is still increasing, well-designed comprehensive case-control studies may identify differences that give an insight into the 'envirotype' driving IBD incidence. PMID- 26982054 TI - Compatible Models of Carbon Content of Individual Trees on a Cunninghamia lanceolata Plantation in Fujian Province, China. AB - We tried to establish compatible carbon content models of individual trees for a Chinese fir (Cunninghamia lanceolata (Lamb.) Hook.) plantation from Fujian province in southeast China. In general, compatibility requires that the sum of components equal the whole tree, meaning that the sum of percentages calculated from component equations should equal 100%. Thus, we used multiple approaches to simulate carbon content in boles, branches, foliage leaves, roots and the whole individual trees. The approaches included (i) single optimal fitting (SOF), (ii) nonlinear adjustment in proportion (NAP) and (iii) nonlinear seemingly unrelated regression (NSUR). These approaches were used in combination with variables relating diameter at breast height (D) and tree height (H), such as D, D2H, DH and D&H (where D&H means two separate variables in bivariate model). Power, exponential and polynomial functions were tested as well as a new general function model was proposed by this study. Weighted least squares regression models were employed to eliminate heteroscedasticity. Model performances were evaluated by using mean residuals, residual variance, mean square error and the determination coefficient. The results indicated that models with two dimensional variables (DH, D2H and D&H) were always superior to those with a single variable (D). The D&H variable combination was found to be the most useful predictor. Of all the approaches, SOF could establish a single optimal model separately, but there were deviations in estimating results due to existing incompatibilities, while NAP and NSUR could ensure predictions compatibility. Simultaneously, we found that the new general model had better accuracy than others. In conclusion, we recommend that the new general model be used to estimate carbon content for Chinese fir and considered for other vegetation types as well. PMID- 26982055 TI - Facile Preparation of Nanostructured, Superhydrophobic Filter Paper for Efficient Water/Oil Separation. AB - In this paper, we present a facile and cost-effective method to obtain superhydrophobic filter paper and demonstrate its application for efficient water/oil separation. By coupling structurally distinct organosilane precursors (e.g., octadecyltrichlorosilane and methyltrichlorosilane) to paper fibers under controlled reaction conditions, we have formulated a simple, inexpensive, and efficient protocol to achieve a desirable superhydrophobic and superoleophilic surface on conventional filter paper. The silanized superhydrophobic filter paper showed nanostructured morphology and demonstrated great separation efficiency (up to 99.4%) for water/oil mixtures. The modified filter paper is stable in both aqueous solutions and organic solvents, and can be reused multiple times. The present study shows that our newly developed binary silanization is a promising method of modifying cellulose-based materials for practical applications, in particular the treatment of industrial waste water and ecosystem recovery. PMID- 26982056 TI - The Ecology of Defensive Medicine and Malpractice Litigation. AB - Using an evolutionary game, we show that patients and physicians can interact with predator-prey relationships. Litigious patients who seek compensation are the 'predators' and physicians are their 'prey'. Physicians can adapt to the risk of being sued by performing defensive medicine. We find that improvements in clinical safety can increase the share of litigious patients and leave unchanged the share of physicians who perform defensive medicine. This paradoxical result is consistent with increasing trends in malpractice claims in spite of safety improvements, observed for example in empirical studies on anesthesiologists. Perfect cooperation with neither defensive nor litigious behaviors can be the Pareto-optimal solution when it is not a Nash equilibrium, so maximizing social welfare may require government intervention. PMID- 26982057 TI - [Results of gestational trophoblastic neoplasia treatment in the Slovak Republic in the years from 1993 to 2012]. AB - OBJECTIVE: Analysis and epidemiology of gestational trophoblastic neoplasia treatment in the Slovak Republic in the years 1993-2012. DESIGN: Retrospective epidemiological national study. SETTING: Centre for gestational trophoblastic disease Ministry of Health the Slovak Republic, Bratislava. METHODS: Retrospective analysis results of gestational trophoblastic neoplasia treatment according to prognostic scoring and staging system FIGO/WHO in Centre for gestational trophoblastic disease Ministry of Health the Slovak Republic Bratislava in the years 1993-2012. RESULTS: The treatment of gestational trophoblastic neoplasia (GTN) in the Czech and Slovak Republics started in 1955 and lasted till 1993. After the split of the former Czechoslovakia the Centre for gestational trophoblastic disease was created in Slovakia. 75 patients were treated in this Centre in the years 1993-2012. According to prognostic scoring and staging system FIGO/WHO 56 (75%) patients had low-risk gestational trophoblastic neoplasia and 19 (25%) of patients had high-risk gestational trophoblastic neoplasia. There were 41 patients (55%), 2 (3%), 24 (32%) and 8 (11%) in stage I., II., III. and IV. respectively. Total curability rate was 94.7% and mortality rate was 5.3%. Curability rate 100% was achieved in stage I & II and all placental site trophoblastic tumours (PSTT), 98.3% in stage III and 50% stage IV. In the years 1993-2012 the incidence of choriocarcinoma was one in 76 273 pregnancies and one in 53 203 deliveries. The incidence of other gestational trophoblastic neoplasia in the same years was for PSTT one in 533 753 pregnancies and one in 372 422 deliveries, invasive mole one in 145 611 pregnancies and one in 101 569 deliveries, and persistent GTN one in 40 043 pregnancies and one in 27 932 deliveries. 225-241 patients were treated in the same period of time in the Czech Republic with curability rate 98.2-98. 3%. CONCLUSION: Early detection and treatment in the centre for trophoblastic disease are crucial points in the manage-ment of gestational trophoblastic neoplasia, because the effective therapy of gestational trophoblastic neoplasia with high curability rate is available. PMID- 26982058 TI - [Post-traumatic stress disorder after childbirth]. AB - The aim of this paper is to introduce the issue of post-traumatic stress disorder after childbirth to health care professionals. The text focuses on the diagnostic definition of post-traumatic stress disorder after childbirth, symptoms, physiological background, prevalence, course, risk factors and consequences of post-traumatic stress disorder after childbirth for a woman, her child and her partner. Options for interventions and therapy are outlined as well. PMID- 26982059 TI - [Hematocervix as a complication after thermal balloon ablation]. AB - OBJECTIVE: Case report of the hematocervix following thermal balloon ablation. DESIGN: Case report. SETTINGS: Department of Gynecology and Obstetric, Royal United Hospital in Bath, UK. METHODOLOGY: Case report of the 46-year-old patient who has been treated in our department due to the hematocervix following thermal balloon ablation. We discuss the etiopathogenesis in the discussion section. CONCLUSION: A cyclical bleeding from the area of the cervix or hematocervix is a rare complication of subtotal hysterectomy. Our case report describes the first reported case following thermal balloon ablation. PMID- 26982060 TI - [Level of AMH as a predictor of the result of ovarian stimulation]. AB - AMH levels are commonly measured in fertility clinics to assess ovarian reserve and give an indication of female fertility potential. AMH levels are useful in deciding on stimulation protocols for IVF cycles. High AMH levels are useful to confirm a diagnosis of polycystic ovaries. AMH is useful to predict ovarian response to stimulation. Currently AMH levels can not be used to predict a couples ability to conceive naturally. PMID- 26982061 TI - [Intracranial haemorrhage due to decompensationof hypertension in severe preeclampsia with the needof a hysterectomy - case report]. AB - OBJECTIVE: To present a case of intracranial haemorrhage due to decompensated hypertension in case of severe preeclampsia which resulted in acute caesarean section followed by hysterectomy. DESIGN: Case report. SETTING: Department of Obstetrics and Gynaecology, Hospital Kladno. CASE REPORT: We report the case of a 36-year old multiparous woman in the 35th week of pregnancy with no prenatal care. According to her medical history, she had a caesarean section three years earlier and six previous spontaneous deliveries without complications (including spontaneously delivered twins). She underwent three abortions and one spontaneous miscarriage. This patient arrived to our department in serious condition with critical values of blood pressure, strong headache, impaired vision, dysarthria and right hemiparesis. In cooperationwith a neurologist we performed an acute native brain CT which revealed an acute intracranial haemorrhage. According to the neurosurgeon, this finding was not suitable for neurosurgical intervention. The patient was indicated for acute caesarean section. Due to heavy bleeding during the caesarean section, a hysterectomy was performed. CONCLUSION: In presenting this serious case of preeclampsia, the authors want to emphasize the need for early diagnosis, interdisciplinary cooperation, sufficient treatment and knowledge of surgical interventions such as abdominal hysterectomy, as a final solution for a life-threatening perinatal haemorrhage. PMID- 26982062 TI - [Functional morphology of recently discovered telocytes inside the female reproductive system]. AB - Discovery of telocytes has become an important and key challenge in past few years. These cells are interstitial cells extending very long cytoplasmic processes named telopodes, by which they create functional networks in the interstitium of different organs. Telocytes are considered to be connective tissue elements that create contacts among each other, but they also function as intercellular structures, functionally connected with cells of the immune system, neurons and smooth muscle cells. Telocytes can be found also in the different parts of female reproductive system with functions and purpose, which is summarized in our overview. Telocytes regulate for example peristaltic movements in fallopian tubes. The decrease of their number (due to inflammatory disease or endometriosis) causes impairment in transport through fallopian tubes which may result in sterility or tubal gravidity. In uterus they regulate contraction of myometrial smooth muscle (blood expulsion in menstrual phase, childbirth) as well as they contribute in immunological care during embryo implantation. Telocytes probably control also the involution of uterus after delivery. Their function in vagina has not been yet clearly defined; they probably take part in slow muscle contraction movement during sexual intercourse. In mammary glands some scientists suppose their function in control of cell proliferation and apoptosis, that is why, they may play a role in carcinogenesis. In placenta they probably monitor and regulate flow of blood in vessels of chorionic villi and they may be responsible also for etiopathogenesis of pre-eclampsy. All these mentioned functions of telocytes are only in the level of hypothesis and have been published recently. New research and studies will try to answer the questions whether telocytes play a key role in these processes. Our review we completed with some original microphotographs of telocytes in different organs of female reproductive system. PMID- 26982063 TI - [Electrical cardioversion in pregnancy - case report]. AB - OBJECT: Describing the course of pregnancy and perinatal outcomes in a patient with supraventricular tachycardia treated by electrical cardioversion. DESIGN: Case report. SETTING: Department of Obstetrics and Gynaecology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital. CASE REPORT: We report a case of electrical cardioversion performed during pregnancy. Young patient with a history of surgical correction of congenital heart defect (double outlet right ventricle, aortic arch hypoplasia and coarctation) with implanted pacemaker for dysfunction of both SA and AV node was diagnosed with persistent atrial flutter leading to incipient heart failure during pregnancy. At 30 weeks of pregnancy, the electrical cardioversion was performed under continuous fetal monitoring. Rest of the pregnancy was uneventful, delivery via caesarean section with obstetric indication (breech presentation, premature rupture of membranes at 37+3/7 weeks) without any complications. PMID- 26982064 TI - [The experiences, attitudes and knowledge of medical personnel towards women with intellectual disabilities being mothers]. AB - AIM: The aim of the study was to analyse experiences, attitudes and knowledge of Czech medical personnel towards women with intellectual disabilities being pregnant and/or mothers. TYPE OF STUDY: Survey research. SETTING: Charles University, Faculty of Education, Department of Special Education, Prague. RESEARCH METHODOLOGY: There were 175 medical personnel who completed a survey. The statistical analysis was conducted in a statistical program SPSS21. The data was analysed using the factor analysis approach. FINDINGS: The majority of respondents were medical personnel with decades of practice in their fields, however with minimal experiences with women with intellectual disabilities who are pregnant and/or mothers. The respondents had a relatively low level of knowledge about services available to these women. The participating medical personnel identified the diverse needs of women with intellectual disabilities during antenatal period, childbirth and in a postnatal period, however they also believed that these needs are not addressed accordingly. The majority of participants believed that women with intellectual disabilities can be successful mothers and should be allowed to have children in their custody. However more than half of the medical personnel admitted the possibility of abortion, and two thirds of the participants would not allow women with intellectual disabilities to make a decision about how many children they wish to have. CONCLUSION: Information and development of practical competencies in providing complex and individually oriented support to women with intellectual disabilities needs to be included in systemic education of medical personnel. PMID- 26982065 TI - [Leiomyomas of the uterine body: Molecular-genetical aspects of formation and development]. AB - OBJECTIVE: An overview of the molecular-genetical aspects of formation and development of leiomyomas of the uterine body. DESIGN: A review article. SETTING: Department of Gynecology and Obstetrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovak Republic. METHODS: An analysis of the literature using database search engines PubMed, Blast, Science direct and Web of Knowledge focused on tumorigenesis of leiomyoma. RESULTS: Benign uterine leiomyomas, also known as myoma, fibroids or fibromyomas are the most common tumours located in the pelvic area of women. The prevalence of this disease reaches, on the global scale, values higher than 50%, depending on the ethnicity even up to 80% of women of reproductive age. Despite such a high value, the origin of leiomyomas is still unknown. The main reason is the heterogeneity of the disease, and a number of factors that influence their development. In the case of leiomyomata occurrence, it has so far been observed several genome rearrangements and a number of aberrantly expressed genes. There are several reasons for overexpression or underexpression of a particular gene, from a point mutation in the exon region of the gene, promoter or other regulatory sequences to epigenetic modifications, most commonly the nature of methylation, or more precisely inadequate regulation short molecule miRNA. Many of these genes belong to the group of tumour-suppressor genes, or more precisely to genes, which can affect the cell cycle in a different way and thus can affect even the cell division. The aim of this work is to describe the various factors influencing the formation of leiomyomas and their impact on tumorigenesis. PMID- 26982067 TI - [Laparoscopic abdominal cerclage in a patient with recurrent miscarriages abortions - case report]. AB - OBJECTIVE: The use of laparoscopic abdominal cerclage in a patient with habitual miscarriage. DESIGN: Case report and literature review. SETTING: Department of Obstetrics and Gynecology, University Hospital Olomouc, Faculty of Medicine, Palacky University Olomouc, Department of Neonatology, University Hospital Olomouc, Faculty of Medicine, Palacky University Olomouc, Institute of Medical Genetics, University Hospital Olomouc, Faculty of Medicine, Palacky University Olomouc. CASE REPORT: The patient is a 37 years old woman with a history of recurrent miscarriages. She had one labor at term and six pregnancies that were lost in the second trimester despite McDonald cerclages. Abdominal cerclages are necessary when the standard transvaginal cerclages fail or anatomical abnormalities preclude the vaginal placement. The disadvantage of the transabdominal approach is that it requires at least 2 laparotomies with significant morbidity and hospital stays. We discuss a case of abdominal cerclage performed laparoscopically. A 5 mm Mersilene tape was placed laparoscopically at the level of the internal os as an interval procedure. We feel it offers less morbidity and in the proper hands eliminates or significantly shortens hospital stays. Subsequent pregnancy was terminated at 28 weeks by caesarean section after premature rupture of membranes. CONCLUSION: Laparoscopic abdominal cerclage seems to be relatively effective option for the prevention of habitual abortion patients, which fail conventional surgical procedures in dealing with cervical incompetence. The success of subsequent full term pregnancy is given as 70%. PMID- 26982066 TI - Comparative analysis of perinatal outcomes among different typesof deliveries in term pregnancies in a reference maternity of Southeast Brazil. AB - OBJECTIVE: To compare the perinatal outcomes of women undergoing an elective cesarean section (CS) with those who had an emergency CS during the labor. DESIGN: Retrospective cohort study. SETTING: Hospital Estadual Azevedo Lima (HEAL), Niteroi, Brazil. METHODS: We analysed elective CS, emergent CS and vaginal delivery as dependent variables and neonatal data (admission in intensive care unit) as independent variables. Using the Statement of Live Birth during a three-month period, all patients who had their children after 38 complete weeks of pregnancy were selected. chi2 test and Student t-tests were applied to compare the groups. RESULTS: When patients who had vaginal delivery were compared with those who had an elective CS, we observed 219 normal deliveries with 1.8% of hospitalizations in neonatal intensive care units (NICU), and 88 patients of elective CS with 2.3% of admissions in closed units (p = 0.401). We had a sample of 108 newborns delivered by CS during the labor with 8.3% rate of hospitalization in NICU versus 1.8% of 219 newborns delivered vaginally (p = 0.005). CONCLUSION: The worst perinatal outcomes occurred when emergency CS were performed. PMID- 26982068 TI - [Ectopic pregnancy in the ultrasound. Case reports. Retrospektive analysis]. AB - OBJECTIVE: To evaluate the ultrasound findings of ectopic pregnancy in the group of women examined in our department transvaginal ultrasound. Analysis of ectopic pregnancy cases covers the period from 1. 8. 2012. to 31. 9. 2015. We introduced several case studies. DESIGN: Retrospective analysis. SETTING: Department of Gynecology and Obstetrics, Hospital Jindrichuv Hradec. METHODS: The methodology is based on a retrospective evaluation of the history, laboratory and ultrasound findings in a group of 30 patients with ectopic pregnancy. RESULTS: At the first visit were diagnosed by transvaginal ultrasound 82% ectopic pregnancy. A patological adnexal mass was visualised in 84% cases. A negative ultrasound finding was observed in 16% cases. The results of our group of patients are more or less comparable with other studies. We recorded the same risk factors for ectopic pregnancy. CONCLUSION: Most ectopic pregnancies can be diagnosed at the first examination before starting treatment and treated at an early stage. Transvaginal ultrasound is the "gold standard" diagnostic tool of choice in the diagnosis of ectopic pregnancy in combination with the dynamics of serum levels beta-hCG.. PMID- 26982069 TI - [Giant uterine fibroid - case report]. AB - OBJECTIVE: The aim of this article is to present a patient with a giant uterine fibroid who underwent surgery in our department. Uniqueness of this case is the extent of uterine fibroid. DESIGN: Case report. SETTING: Department of Obstetrics and Gynaecology, Masaryk Municipal Hospital Jilemnice. CASE REPORT: We report a case of 42 years old female patient with a giant myoma who underwent surgery in our department. Fibroid weihgt was more than 15 kg. CONCLUSION: Fibroids gigantic proportions are extreme and rare benign tumor variant of normal uterine muscle. Their formation is possible inertia or disimulation patients and their treatment is mostly surgical. PMID- 26982070 TI - [Transdermal estrogen spray in therapy of postmenopausal syndrome]. AB - OBJECTIVE: To show possibilities of new application method of estrogen replacement therapy - mettered-dose transdermal spray. DESIGN: Review articleResults: Transdermal spray contains 1.53 mg estradiol in one dose. It gives possibility of individual aproach in estradiol application 1, 2 or 3 doses daily. About 85% of patients showed the significant reduction of hot flushes. Perfect safety profile is predicted especially in cardiovascular point. PMID- 26982071 TI - "Pandemic Public Health Paradox": Time Series Analysis of the 2009/10 Influenza A / H1N1 Epidemiology, Media Attention, Risk Perception and Public Reactions in 5 European Countries. AB - In 2009, influenza A H1N1 caused the first pandemic of the 21st century. Although a vaccine against this influenza subtype was offered before or at the onset of the second epidemic wave that caused most of the fatal cases in Europe, vaccination rates for that season were lower than expected. We propose that the contradiction between high risk of infection and low use of available prevention measures represents a pandemic public health paradox. This research aims for a better understanding of this paradox by exploring the time-dependent interplay among changing influenza epidemiology, media attention, pandemic control measures, risk perception and public health behavior among five European countries (Czech Republic, Denmark, Germany, Spain and the UK). Findings suggest that asynchronicity between media curves and epidemiological curves may potentially explain the pandemic public health paradox; media attention for influenza A H1N1 in Europe declined long before the epidemic reached its peak, and public risk perceptions and behaviors may have followed media logic, rather than epidemiological logic. PMID- 26982072 TI - Enterovirus A71 Genogroups C and E in Children with Acute Flaccid Paralysis, West Africa. PMID- 26982073 TI - The Angiotensin Converting Enzyme Insertion/Deletion Polymorphism Modifies Exercise-Induced Muscle Metabolism. AB - OBJECTIVE: A silencer region (I-allele) within intron 16 of the gene for the regulator of vascular perfusion, angiotensin-converting enzyme (ACE), is implicated in phenotypic variation of aerobic fitness and the development of type II diabetes. We hypothesised that the reportedly lower aerobic performance in non carriers compared to carriers of the ACE I-allele, i.e. ACE-DD vs. ACE-ID/ACE-II genotype, is associated with alterations in activity-induced glucose metabolism and capillarisation in exercise muscle. METHODS: Fifty-three, not-specifically trained Caucasian men carried out a one-legged bout of cycling exercise to exhaustion and/or participated in a marathon, the aim being to identify and validate genotype effects on exercise metabolism. Respiratory exchange ratio (RER), serum glucose and lipid concentration, glycogen, and metabolite content in vastus lateralis muscle based on ultra-performance lipid chromatography-mass spectrometry (UPLC-MS), were assessed before and after the cycling exercise in thirty-three participants. Serum metabolites were measured in forty subjects that completed the marathon. Genotype effects were assessed post-hoc. RESULTS: Cycling exercise reduced muscle glycogen concentration and this tended to be affected by the ACE I-allele (p = 0.09). The ACE-DD genotype showed a lower maximal RER and a selective increase in serum glucose concentration after exercise compared to ACE ID and ACE-II genotypes (+24% vs. +2% and -3%, respectively). Major metabolites of mitochondrial metabolism (i.e. phosphoenol pyruvate, nicotinamide adenine dinucleotide phosphate, L-Aspartic acid, glutathione) were selectively affected in vastus lateralis muscle by exercise in the ACE-DD genotype. Capillary-to-fibre ratio was 24%-lower in the ACE-DD genotype. Individuals with the ACE-DD genotype demonstrated an abnormal increase in serum glucose to 7.7 mM after the marathon. CONCLUSION: The observations imply a genetically modulated role for ACE in control of glucose import and oxidation in working skeletal muscle. ACE-DD genotypes thereby transit into a pre-diabetic state with exhaustive exercise, which relates to a lowered muscle capillarisation, and deregulation of mitochondria-associated metabolism. PMID- 26982074 TI - Nontyphoidal Salmonella Infection, Guangdong Province, China, 2012. AB - We used active and passive surveillance to estimate nontyphoidal Salmonella (NTS) infection during 2012 in Guangdong Province, China. Under passive surveillance, for every reported NTS infection, an estimated 414.8 cases occurred annually. Under active surveillance, an estimated 35.8 cases occurred. Active surveillance provides remarkable advantages in incidence estimate. PMID- 26982075 TI - Two natural compounds - a benzofuran and a phenylpropane - from Artemisia dracunculus. AB - The structure elucidation of three metabolites herniarin (7-methoxy-2H-chromen-2 one, 1), phytoalexin (5-acetyl-6-hydroxy-2-(1-hydroxy-1-methylethyl)benzofuran, 2), and prestragol (3-(4'-methoxyphenyl)-prop-1,2-diol, 3) isolated from Artemisia dracunculus was determined on the basis of 1D, 2D NMR methods and by an X-ray crystallographic determination. PMID- 26982076 TI - The Blurred Line between Form and Process: A Comparison of Stream Channel Classification Frameworks. AB - Stream classification provides a means to understand the diversity and distribution of channels and floodplains that occur across a landscape while identifying links between geomorphic form and process. Accordingly, stream classification is frequently employed as a watershed planning, management, and restoration tool. At the same time, there has been intense debate and criticism of particular frameworks, on the grounds that these frameworks classify stream reaches based largely on their physical form, rather than direct measurements of their component hydrogeomorphic processes. Despite this debate surrounding stream classifications, and their ongoing use in watershed management, direct comparisons of channel classification frameworks are rare. Here we implement four stream classification frameworks and explore the degree to which each make inferences about hydrogeomorphic process from channel form within the Middle Fork John Day Basin, a watershed of high conservation interest within the Columbia River Basin, U.S.A. We compare the results of the River Styles Framework, Natural Channel Classification, Rosgen Classification System, and a channel form-based statistical classification at 33 field-monitored sites. We found that the four frameworks consistently classified reach types into similar groups based on each reach or segment's dominant hydrogeomorphic elements. Where classified channel types diverged, differences could be attributed to the (a) spatial scale of input data used, (b) the requisite metrics and their order in completing a framework's decision tree and/or, (c) whether the framework attempts to classify current or historic channel form. Divergence in framework agreement was also observed at reaches where channel planform was decoupled from valley setting. Overall, the relative agreement between frameworks indicates that criticism of individual classifications for their use of form in grouping stream channels may be overstated. These form-based criticisms may also ignore the geomorphic tenet that channel form reflects formative hydrogeomorphic processes across a given landscape. PMID- 26982077 TI - The normal tissue effects of microbeam radiotherapy: What do we know, and what do we need to know to plan a human clinical trial? AB - Purpose Microbeam Radiotherapy (MRT) is a promising pre-clinical cancer therapy which represents a radical departure from the radiobiological principles of conventional radiotherapy (CRT). In order to translate MRT to human clinical trials, robust normal tissue toxicity data are required. This review summarizes the normal tissue effects reported by pre-clinical MRT animal studies and compares these data to clinical recommendations in CRT. Conclusion Few pre clinical studies are specifically designed to evaluate the dose-response of normal tissue to MRT. However, it remains clear that a range of normal tissues can tolerate peak MRT doses at least an order of magnitude higher than CRT. Furthermore, the dose deposited in the valley regions, predominantly determined by microbeam spacing, has a greater influence on the normal tissue response to MRT compared to the peak regions. The development of a new normal tissue complication probability model for MRT, in conjunction with a treatment planning system, will be pivotal in the collection of robust normal tissue toxicity data and the translation of MRT to clinical use. PMID- 26982078 TI - Impact of Type of Needle on Incidence of Intravascular Injection During Diagnostic Lumbar Medial Branch Block. AB - BACKGROUND AND OBJECTIVES: Intravascular (IV) injection of local anesthetics is a potential cause of false-negative results after lumbar medial branch nerve blockade (L-MBB) performed to diagnose facetogenic back pain. The aim of the present study was to identify the relationship between the needle type and the incidence of IV injection in patients undergoing L-MBB using fluoroscopy with digital subtraction imaging (DSI). METHODS: In this prospective randomized study, we compared the incidence of IV uptake of contrast medium using the Quincke needle and Whitacre needle under real-time DSI during L-MBB. Clinical and demographic factors associated with the occurrence of IV uptake were also investigated. RESULTS: In total, 126 patients were randomized into the Quincke needle group (n = 62) and Whitacre needle group (n = 64). Intravascular uptake of contrast medium was observed in 66 (9.8%) of 671 L-MBB procedures under DSI. The incidence of IV uptake was 13.9% (47/338) using the Quincke needle and 5.7% (19/333) using the Whitacre needle. In the multivariate generalized estimating equations analysis, use of a Quincke needle was related to positive IV injection at a 1.898-fold higher rate than was use of a Whitacre needle (95% confidence interval, 1.025-3.516) and a positive aspiration test predicted IV injection at a 21.735-fold higher rate (95% confidence interval, 11.996-52.258). CONCLUSIONS: Lumbar medial branch nerve blockade using the Quincke needle was associated with a 1.9-fold higher rate of IV injection than was L-MBB using the Whitacre needle under DSI. Although further study is needed to confirm the clinical efficacy, Whitacre needles can be considered to reduce the risk of IV injection during L MBB. PMID- 26982079 TI - Lumbar Epidural Hematoma Following Interlaminar Fluoroscopically Guided Epidural Steroid Injection. AB - OBJECTIVE: Spinal epidural steroid injections are generally considered a safe, effective treatment for radicular pain in a variety of spinal conditions. Complications secondary to these injections, although rare, can result in devastating neurologic symptoms. Patients with preexisting moderate-to-severe spinal stenosis and recent use of chronic anticoagulation pose a challenging dilemma when making treatment decisions, as a history of both can increase the risk of complications. CASE REPORT: The following case study provides a description of a patient with spinal stenosis who discontinued anticoagulation therapy according to the recommended guidelines but who experienced a subsequent acute epidural hematoma and significant neurologic injury. CONCLUSIONS: This case report describes the potential risk factors present in this patient. Presence of spinal stenosis and the interlaminar approach seem to be significant risk factors in this case. Presence of an intrinsic coagulopathy was not determined. PMID- 26982080 TI - Preparation and investigation of a novel levobupivacaine in situ implant gel for prolonged local anesthetics. AB - In this study, levobupivacaine (LBP) was successfully incorporated into implant application based on the concept of in situ gel (PECE). The physicochemical characterization (preparation, phase transition temperature, in vitro release) were investigated. The results of viscosity measurement showed that the preparations behaved like a fluid but formed a rigid gel when exposed to increasing temperature (37 degrees C). In vitro release, LBP was graduated released from the gels as time lapsed, suggesting that LBP was well entrapped in PECE in situ gels. As is shown in pharmacokinetic parameters, the half-life of LBP injection (2.7 h) was shorter than that of LBP in situ gels (23.9 h), suggesting that LBP injection was taken up by other tissues more rapidly than gels. The area under the curve of LBP in situ gels was 2.18 times the size of that of LBP injection (P< 0.05). In pharmacodynamic test, even after nine hours of injection, gel group could still maintain rather good anesthesia effect and rats' stinging reaction maintained at a relatively low level, which had obvious statistical differences compared to injection group. PMID- 26982081 TI - Oxidative Stress, Cytotoxicity and Genotoxicity in Earthworm Eisenia fetida at Different Di-n-Butyl Phthalate Exposure Levels. AB - Recognized as ubiquitous contaminants in soil, the environmental risk of phthalic acid esters (PAEs) is of great concern recently. Effects of di-n-butyl phthalate (DnBP), an extensively used PAE compound to Eisenia fetida have been investigated in spiked natural brown yellow soil (Alfisol) for soil contact test. The toxicity of DnBP to E. fetida on the activity of superoxide dismutase (SOD) activity, peroxidase (POD), reactive oxygen species (ROS) content, and the apoptosis of coelomocytes and DNA damage at the 7th, 14th, 21st and 28th day of the incubation have been paid close attention to. In general, SOD activity and ROS content were significantly induced, opposite to total protein content and POD activity, during the toxicity test of 28 days especially under concentrations higher than 2.5 mg kg-1. The reduction in neutral red retention (NRR) time along with the increase of dead coelomocytes as the increasing of DnBP concentrations, indicating severe damage to cell viability under varying pollutant stress during cultivation, which could also be proved by comet assay results for exerting evident DNA damage in coelomocytes. DnBP in spiked natural soil could indeed cause damage to tissues, coelomocytes and the nucleus of E. fetida. The key point of the apparent change in different indices presented around 2.5 mg DnBP kg-1 soil, which could be recommended as the threshold of DnBP soil contamination, so that further investigation on threshold values to other soil animals or microorganisms could be discussed. PMID- 26982082 TI - Internal Activation of Peptidyl Prolyl Thioesters in Native Chemical Ligation. AB - Prolyl thioesters have shown significantly lower reactivities in native chemical ligation (NCL) in comparison to that of the alanyl thioester. This report describes a mild and efficient internal activation protocol of peptidyl prolyl thioesters in NCL without using any thiol-based additives, where the introduction of a 4-mercaptan substituent on the C-terminal proline significantly improves the reactivity of prolyl thioesters via the formation of a bicyclic thiolactone intermediate. The kinetic data indicate that the reaction rate is comparable to that of the reported data of alanyl thioesters, and the mechanistic studies suggest that the ligation of two peptide segments proceeds through an NCL-like pathway instead of a direct aminolysis, which ensures the chemoselectivity and compatibility of various amino acid side chains. This 4-mercaptoprolyl thioester based protocol also allows an efficient one-pot ligation-desulfurization procedure. The utility of this method has been further demonstrated in the synthesis of a proline-rich region of Wilms tumor protein 1. PMID- 26982083 TI - TNFSF10/TRAIL regulates human T4 effector memory lymphocyte radiosensitivity and predicts radiation-induced acute and subacute dermatitis. AB - Sensitivity of T4 effector-memory (T4EM) lymphocytes to radiation-induced apoptosis shows heritability compatible with a Mendelian mode of transmission. Using gene expression studies and flow cytometry, we show a higher TNF-Related Apoptosis Inducing Ligand (TRAIL/TNFSF10)mRNA level and a higher level of membrane bound TRAIL (mTRAIL) on radiosensitive compared to radioresistant T4EM lymphocytes. Functionally, we show that mTRAIL mediates a pro-apoptotic autocrine signaling after irradiation of T4EM lymphocytes linking mTRAIL expression to T4EM radiosensitivity. Using single marker and multimarker Family-Based Association Testing, we identified 3 SNPs in the TRAIL gene that are significantly associated with T4EM lymphocytes radiosensitivity. Among these 3 SNPs, two are also associated with acute and subacute dermatitis after radiotherapy in breast cancer indicating that T4EM lymphocytes radiosensitivity may be used to predict response to radiotherapy. Altogether, these results show that mTRAIL level regulates the response of T4EM lymphocytes to ionizing radiation and suggest that TRAIL/TNFSF10 genetic variants hold promise as markers of individual radiosensitivity. PMID- 26982084 TI - Intraspecific variability of carbon isotope discrimination and its correlation with grain yield in safflower: prospects for selection in a Mediterranean climate. AB - The goals of the present study were to obtain a first estimate of intraspecific variability of carbon isotope discrimination (Delta) in safflower, a thistle-like herbaceous plant, and to determine the statistical relationship between Delta and grain yield as well as its components in a collection of 45 accessions of different origins. Grain yield and aboveground biomass, harvest index, average grain weight, and Delta (measured on the bulk leaf organic matter) were investigated in experimental field conditions. A large variability was noted for all traits but a principal component analysis (PCA) allowed to identify several homogeneous groups of accessions. Average grain yield per plant varied between 1 and 39 g. Delta varied between 21.3 and 25.2 0/00, i.e. a large variation of 3.9 0/00. In our experiment, the variation of Delta was not significantly related to that of grain yield in the whole accession sample. However, we found contrasting trends for this relation within accession groups. These initial results motivate further experiments to assess more in depth correlation between Delta and yield in safflower and are encouraging regarding the possibility of using Delta as an effective selection index in safflower to obtain genotypes that efficiently consume water. This study also highlighted one accession that combines the two characters required in the Mediterranean regions, i.e. high yield performance and high water-use efficiency. PMID- 26982087 TI - CHRNA4 was associated with prepulse inhibition of schizophrenia in Chinese: a pilot study. AB - INTRODUCTION: Prepulse inhibition (PPI) of the auditory startle reflex, as an operational measurement used to evaluate the function of brain sensorimotor gating, appears to be a sensitive potential endophenotype for schizophrenia. CHRNA4 is highly expressed in the central nervous system and has been demonstrated to be significantly associated with schizophrenia by previous studies. The purpose of the current study was to evaluate the effect of CHRNA4 on PPI and acoustic startle parameters in schizophrenia. METHODS: 77 patients with schizophrenia and 62 controls were administered the test PPI, and 3 single nucleotide polymorphisms (SNPs) (rs3746372, rs1044396, and rs3787140) of CHRNA4 were genotyped in these subjects. RESULTS: Patients with schizophrenia showed significantly lower levels of PPI at the 120 ms prepulse intervals and longer peak latency than controls, and the GG genotype of rs3746372 and the TT genotype of rs1044396 were associated with decreased PPI levels in schizophrenia but not in controls. CONCLUSION: PPI may be influenced by the polymorphisms of the CHRNA4 in schizophrenia and it may be a potential endophenotype of schizophrenia. An independent replication would greatly increase the value of this study. PMID- 26982088 TI - The history of Brugada syndrome -- Continuum with arrhythmogenic cardiomyopathy or lone disease? PMID- 26982086 TI - Individual Case Analysis of Postmortem Interval Time on Brain Tissue Preservation. AB - At autopsy, the time that has elapsed since the time of death is routinely documented and noted as the postmortem interval (PMI). The PMI of human tissue samples is a parameter often reported in research studies and comparable PMI is preferred when comparing different populations, i.e., disease versus control patients. In theory, a short PMI may alleviate non-experimental protein denaturation, enzyme activity, and other chemical changes such as the pH, which could affect protein and nucleic acid integrity. Previous studies have compared PMI en masse by looking at many different individual cases each with one unique PMI, which may be affected by individual variance. To overcome this obstacle, in this study human hippocampal segments from the same individuals were sampled at different time points after autopsy creating a series of PMIs for each case. Frozen and fixed tissue was then examined by Western blot, RT-PCR, and immunohistochemistry to evaluate the effect of extended PMI on proteins, nucleic acids, and tissue morphology. In our results, immunostaining profiles for most proteins remained unchanged even after PMI of over 50 h, yet by Western blot distinctive degradation patterns were observed in different protein species. Finally, RNA integrity was lower after extended PMI; however, RNA preservation was variable among cases suggesting antemortem factors may play a larger role than PMI in protein and nucleic acid integrity. PMID- 26982089 TI - Visual and acoustic information supporting a happily expressed speech-in-noise advantage. AB - There was an advantage found for recognizing happily expressed audio and audio visual speech-in-noise relative to speech spoken with neutral or sad expressions. The advantage of happily expressed speech was explored in a set of visual and acoustic manipulations designed to isolate the potential contributions from each signal. For this research, a replication of previous research with the happily expressed speech advantage was completed with a novel inclusion of a learning paradigm. Additional experiments directly investigated the role of the fundamental frequency of the voice for affect, and the affective facial components with the eyes and mouth. We found that the happily expressed speech advantage persisted despite constraints to the amount of frequency modulation and with distortions to the talker's face. These findings seem largely attributable to the influences of affect on low-level acoustical and articulatory information, with only a very subtle role of approach/withdrawal motivation. PMID- 26982085 TI - Structural Brain Abnormalities in Youth With Psychosis Spectrum Symptoms. AB - IMPORTANCE: Structural brain abnormalities are prominent in psychotic disorders, including schizophrenia. However, it is unclear when aberrations emerge in the disease process and if such deficits are present in association with less severe psychosis spectrum (PS) symptoms in youth. OBJECTIVE: To investigate the presence of structural brain abnormalities in youth with PS symptoms. DESIGN, SETTING, AND PARTICIPANTS: The Philadelphia Neurodevelopmental Cohort is a prospectively accrued, community-based sample of 9498 youth who received a structured psychiatric evaluation. A subsample of 1601 individuals underwent neuroimaging, including structural magnetic resonance imaging, at an academic and children's hospital health care network between November 1, 2009, and November 30, 2011. MAIN OUTCOMES AND MEASURES: Measures of brain volume derived from T1-weighted structural neuroimaging at 3 T. Analyses were conducted at global, regional, and voxelwise levels. Regional volumes were estimated with an advanced multiatlas regional segmentation procedure, and voxelwise volumetric analyses were conducted as well. Nonlinear developmental patterns were examined using penalized splines within a general additive model. Psychosis spectrum (PS) symptom severity was summarized using factor analysis and evaluated dimensionally. RESULTS: Following exclusions due to comorbidity and image quality assurance, the final sample included 791 participants aged youth 8 to 22 years. Fifty percent (n = 393) were female. After structured interviews, 391 participants were identified as having PS features (PS group) and 400 participants were identified as typically developing comparison individuals without significant psychopathology (TD group). Compared with the TD group, the PS group had diminished whole-brain gray matter volume (P = 1.8 * 10-10) and expanded white matter volume (P = 2.8 * 10-11). Voxelwise analyses revealed significantly lower gray matter volume in the medial temporal lobe (maximum z score = 5.2 and cluster size of 1225 for the right and maximum z score = 4.5 and cluster size of 310 for the left) as well as in frontal, temporal, and parietal cortex. Volumetric reduction in the medial temporal lobe was correlated with PS symptom severity. CONCLUSIONS AND RELEVANCE: Structural brain abnormalities that have been commonly reported in adults with psychosis are present early in life in youth with PS symptoms and are not due to medication effects. Future longitudinal studies could use the presence of such abnormalities in conjunction with clinical presentation, cognitive profile, and genomics to predict risk and aid in stratification to guide early interventions. PMID- 26982090 TI - S100B and the influence of seasonal variation. AB - Background A blood test for S100B can be used to rule out intracranial complications after minor head injury and thereby reduce the need for computed tomography (CT) examinations. The aim of this study was to investigate the clinical importance of a possible influence of seasonal variation on S100B. Methods The individual seasonal variation of S100B in 69 healthy volunteers living at latitudes with extremely variable seasonal exposure to sunlight was investigated. Results The mean serum concentration of S100B was 13% higher in August than in February, but however, not statistically significant (p = 0.068). A good agreement between summer and winter S100B values was confirmed by Bland Altman analysis and a significant correlation (r = 0.317, p = 0.008) was shown between summer and winter S100B values. Conclusion This study did not show any clinical importance of seasonal variation of S100B that may influence the decision of CT scanning patients with head injuries. PMID- 26982092 TI - Editor's message. PMID- 26982093 TI - Procedures and lifestyle changes that can enhance the lives of diabetic patients. AB - This article emphasizes to primary care physicians the importance of maintaining a diabetic patient's blood sugar level within the normal range. Additionally, it aims to impress on those who care for diabetic patients some of the adverse consequences of surgical and dental procedures that can be avoided by proper precautionary measures taken before the procedures. PMID- 26982094 TI - Complications of type 2 diabetes mellitus: a brief overview. AB - The recent findings of the United Kingdom Prospective Diabetes Study (UKPDS) have focused attention on the need to prevent complications in type 2 diabetes mellitus. Understanding the pathogenesis and physiologic mechanisms that lead to complications in the patients with type 2 diabetes mellitus is imperative to prevent their progression and improve treatment. This article discusses the more common complications and their possible etiologies, progression, and contribution to the morbidity of the diabetic population. It also reviews treatment of these complications and recent advances. In addition, some of the less common complications will be identified so that primary care physicians and specialists will be aware and not overlook these in patients who can be treated early and aggressively. PMID- 26982091 TI - The RNA binding protein IMP3 facilitates tumor immune escape by downregulating the stress-induced ligands ULPB2 and MICB. AB - Expression of the stress-induced ligands MICA, MICB and ULBP 1-6 are up-regulated as a cellular response to DNA damage, excessive proliferation or viral infection; thereby, they enable recognition and annihilation by immune cells that express the powerful activating receptor NKG2D. This receptor is present not exclusively, but primarily on NK cells. Knowledge about the regulatory mechanisms controlling ULBP expression is still vague. In this study, we report a direct interaction of the oncogenic RNA binding protein (RBP) IMP3 with ULBP2 mRNA, leading to ULBP2 transcript destabilization and reduced ULBP2 surface expression in several human cell lines. We also discovered that IMP3 indirectly targets MICB with a mechanism functionally distinct from that of ULBP2. Importantly, IMP3-mediated regulation of stress-ligands leads to impaired NK cell recognition of transformed cells. Our findings shed new light on the regulation of NKG2D ligands and on the mechanism of action of a powerful oncogenic RBP, IMP3. PMID- 26982096 TI - CME QUIZ. PMID- 26982095 TI - Pharmacologic management of diabetes mellitus. AB - Recently, the number of agents to treat type 2 diabetes has increased markedly. In the past, the only agents practitioners had available to treat patients with type 2 diabetes mellitus were insulin and sulfonylureas. Today, three additional classes of agents with a total of six new drugs are available: acarbose, migital, repaglinide, metformin hydrochloride, troglitazone, and rosiglitazone. In the not too-distant future, several other agents will be available for treating patients with diabetes. These new agents will allow physicians to control their diabetic patients' blood sugar levels without the need for insulin injections. This article reviews the new agents and provides practical suggestions regarding their use as monotherapy or in combination therapy. PMID- 26982097 TI - Herbal products and supplemental nutrients used in the management of diabetes. AB - As companies, including large pharmaceutical houses, try to market supplemental nutrients and herbal products to ever-increasing numbers of consumers, diabetics will start to approach their physicians about these alternative remedies. A whole new industry know as "neutraceuticals" has evolved. This new industry is a combination of the vitamin supplement and herbal industries trying to work with regulatory agents to develop good manufacturing processes to ensure that consumers obtain good products. In fact, some diabetics may be taking herbal or nutritional supplements without their physician's knowledge. Therefore, it is important to query diabetic patients at least once a year as to whether they are using any herbal or nutritional products. Once it is determined that a patient is using these products, physicians must decide if they or someone else should address the issue of taking these products. Physicians who have a good comfort level with herbal products by all means should recommend them to their patients. If such a comfort level is lacking or low, patients can be referred for a consultation on the use of supplements or told that information will be forwarded to them after contact is made with someone who has knowledge of diabetes and use of appropriate supplements. This article reviews nine nutrient and herbal remedies commonly used for diabetes to facilitate such patient education. PMID- 26982098 TI - Vitamin D status, body composition and glycemic control in Polish adolescents with type 1 diabetes. AB - BACKGROUND: High prevalence of vitamin D deficiency in adolescents with type 1 diabetes (T1DM) has been recorded but data focused on the relationship between vitamin D, glycemic control and body composition is limited in T1DM patients. The study was aimed to investigate vitamin D status in T1DM patients and its association with body composition (fat and lean body mass) and clinical data. METHODS: The study group comprised of 100 adolescents (15.3+/-1.9 yrs; 54 girls), including 60 T1DM patients (15.1+/-1.9 yrs; 32 girls) and 40 controls (15.6+/-1.8 yrs; 20 girls) from Warsaw, Poland. Serum total 25-hydroxyvitamin D (25(OH)D) levels and iPTH were measured by an ECLIA (Roche Diagnostics). Glycosylated hemoglobin (% HbA1c), serum calcium and inorganic phosphorous, and the use of dietary supplements were also assessed. DXA (GE Prodigy) was used to assess lean body mass (LBM; g), fat mass (FM; g), FM/LBM ratio, and respective Z-scores. RESULTS: Mean 25(OH)D level of 15.3+/-7.0 ng/mL (range 4.2-37.7 ng/mL) in T1DM was not different from that observed in controls (17.9+/-9.3 ng/mL; range 6.3 40.4 ng/mL). Eighty-two percent of T1DM patients and 67% controls had 25(OH)D levels <20 ng/mL, among them 25% T1DM and 12.5% controls revealed values <10 ng/mL. 5% T1DM and 15% controls had 25(OH)D>30 ng/mL. 25% from T1DM and 22% from control groups declared to use vitamin D supplementation and had significantly higher 25(OH)D levels compared to non-users (22.6+/-7.6 vs. 12.8+/-4.8 ng/mL in the T1DM; 26.9+/-11.5 vs. 15.3+/-6.8 ng/mL in controls, respectively). In the T1DM, low 25(OH)D levels negatively correlated with HbA1c (r=-0.320, P=0.013) and with iPTH (r=-0.434, P=0.001). 25(OH)D levels correlated negatively with Z-scores for FM/LBM ratio (r=-0.324; P=0.012) and Z-scores for FM (r=-0.229; P=0.079) and positively with LBM Z-scores (r=0.300; P=0.020). Serum Ca, serum iPTH did not differ T1DM and control groups but serum P level was significantly higher in T1DM patients compared to controls (1.39+/-0.19 mmol/L vs. 1.18+/-0.18 mmol/L; P=0.001, respectively). CONCLUSIONS: In T1DM adolescents vitamin D deficiency coincided with poor glycemic control and disturbed body composition. 25(OH)D levels were positively related to muscle stores and negatively with fat stores. Therefore, to limit a risk of disease related clinical complications both disturbed body composition and vitamin D deficiency should be corrected by implementation of regular vitamin D supplementation and increased intake of vitamin D-rich foods, as well as increased outdoors activities. PMID- 26982099 TI - [In Process Citation]. PMID- 26982100 TI - A Case of Vivid Hallucinations Secondary to Ropinirole. PMID- 26982101 TI - Probing binding mechanism of interleukin-6 and olokizumab: in silico design of potential lead antibodies for autoimmune and inflammatory diseases. AB - Computer-aided antibody engineering has been successful in the design of new biologics for disease diagnosis and therapeutic interventions. Interleukin-6 (IL 6), a well-recognized drug target for various autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and psoriasis, was investigated in silico to design potential lead antibodies. Here, crystal structure of IL-6 along with monoclonal antibody olokizumab was explored to predict antigen-antibody (Ag - Ab)-interacting residues using DiscoTope, Paratome, and PyMOL. Tyr56, Tyr103 in heavy chain and Gly30, Ile31 in light chain of olokizumab were mutated with residues Ser, Thr, Tyr, Trp, and Phe. A set of 899 mutant macromolecules were designed, and binding affinity of these macromolecules to IL-6 was evaluated through Ag - Ab docking (ZDOCK, ClusPro, and Rosetta server), binding free-energy calculations using Molecular Mechanics/Poisson Boltzman Surface Area (MM/PBSA) method, and interaction energy estimation. In comparison to olokizumab, eight newly designed theoretical antibodies demonstrated better result in all assessments. Therefore, these newly designed macromolecules were proposed as potential lead antibodies to serve as a therapeutics option for IL-6-mediated diseases. PMID- 26982102 TI - Exploiting the equilibrium dynamics in the self-assembly of inorganic macrocycles based upon polyoxothiometalate building blocks. AB - We report the preparation and characterization of two new polyoxothiometalate species, {Mo16} = {(Mo2O2S2)8(OH)16(C4O4)2}(4-) (compound 1) and {Mo12} = {(Mo2O2S2)6(OH)12(CH3COO)2}(2-) (compound 2). Control of synthesis is achieved by the addition of the organic-template and further re-arrangement is controlled simply by the addition of potassium to a precursor compound yielding compound 2. The structures of the compounds are discussed and we also show that ion-mobility mass spectrometry can be used to resolve the species and their building blocks in solution. PMID- 26982103 TI - Tigecycline: Alone or in combination? AB - Background The broad spectrum antibiotic tigecyline has promising efficacy against many multidrug-resistant (MDR) pathogens. However, when used clinically, many reports about treatment failures of tigecycline monotherapy indicate that it might not be sufficient to control severe infections. Combination therapy has become an option to treat infection with MDR bacteria because of the distinct advantage in terms of broad coverage, synergistic effect and prevention of drug resistance development. Methods Search terms 'tigecycline', 'GAR-936' and 'glycylcycline' combined with the term 'combination' were applied to retrieve the available in vitro and in vivo studies on tigecycline combination therapy from PubMed database (January 1993-August 2015). Results Colistin-tigecycline was the most studied combination and showed promising efficacy. Other combination regimens, such as tigecycline plus sulbactam, carbapenem or rifampicin, also showed synergistic effects against different bacteria. However, most of the data was from in vitro and animal studies. Only some case reports indicated that tigecycline containing combination therapy had favourable outcomes. Conclusions Although this study could not conclude that combination therapy with tigecycline was superior to monotherapy, when severe infection leaves no other choice, selection of combination drugs according to infection status and in vitro susceptibility testing is recommended. There is a great need for well-designed studies to evaluate the effectiveness and safety of combination therapy compared to tigecyline monotherapy. PMID- 26982104 TI - Determinants and Drivers of Infectious Disease Threat Events in Europe. AB - Infectious disease threat events (IDTEs) are increasing in frequency worldwide. We analyzed underlying drivers of 116 IDTEs detected in Europe during 2008-2013 by epidemic intelligence at the European Centre of Disease Prevention and Control. Seventeen drivers were identified and categorized into 3 groups: globalization and environment, sociodemographic, and public health systems. A combination of >2 drivers was responsible for most IDTEs. The driver category globalization and environment contributed to 61% of individual IDTEs, and the top 5 individual drivers of all IDTEs were travel and tourism, food and water quality, natural environment, global trade, and climate. Hierarchical cluster analysis of all drivers identified travel and tourism as a distinctly separate driver. Monitoring and modeling such disease drivers can help anticipate future IDTEs and strengthen control measures. More important, intervening directly on these underlying drivers can diminish the likelihood of the occurrence of an IDTE and reduce the associated human and economic costs. PMID- 26982106 TI - A Simple Technique to Avoid Restenosis for Dacryocystorhinostomy. AB - The most common reason for failure in dacryocystorhinostomy has been proven to be the granuloma or membranous obstruction of scar tissue formation on lacrimal opening in the nasal cavity during the healing process. In this article, the authors suggest an easy maneuver to avoid the risk of scarring and collapsing of the knot in bony window by using a piece of an aspiration catheter. Using this easy maneuver, the authors can manage to reduce the risk of scarring and stenosis, and when the authors take out the tubes after 2 months, removing the silicone tube was easier with our technique. Moreover with the present technique the authors observed there was no embedding of the knot in the scar. PMID- 26982105 TI - Comparing Publicly Reported Surgical Outcomes With Quality Measures From a Statewide Improvement Collaborative. PMID- 26982107 TI - Endoscopic Intradural Subtemporal Keyhole Kawase Approach to the Petroclival and Ventrolateral Brainstem Regions. AB - OBJECTIVE: To study the endoscope anatomy of the petroclival and ventrolateral brainstem regions via the intradural subtemporal keyhole Kawase approach and discuss the feasibility and indications of this approach to the regions. MATERIALS AND METHODS: Craniotomy procedures performed via the intradural subtemporal keyhole Kawase approach were simulated on 16 sides of 8 adult cadaveric heads fixed by formalin, and the related anatomical structures were observed through the 0-degree endoscope or alternatively 30-degree one. Measurements of the shortest distances from the highest point of arcuate eminence to the 4 anatomic marks and the lengths of the Kawase rhombus were recorded, and the 2 kinds of milled ranges of petrous apex were compared. RESULT: Most of the related anatomical structures could be clearly observed under the endoscope. The shortest distances from the highest point of arcuate eminence to the foramen spinosum, the greater superficial petrosal nerve hiatus, the intersection of the greater superficial petrosal nerve and mandibular nerve, and the outside edge of the trigeminal impression are 22.90 +/- 2.34, 14.05 +/- 2.09, 24.94 +/- 1.98, 23.49 +/- 2.38 mm. The area of routine milled Kawase rhombus is 3.04 +/- 0.47 cm, which would increase 0.66 cm on average after the maximum drilling of the petrous apex. CONCLUSIONS: The intradural subtemporal keyhole Kawase approach can provide an ideal exposure to the petroclival and ventrolateral brainstem regions via the endoscope with less damaging of the normal structures. It can be used to treat the lesions located in those areas through the natural gap combined with the drilling of petrous apex bone. PMID- 26982108 TI - Aberrant Internal Carotid Artery: A Rare Cause of Dysphagia. PMID- 26982109 TI - Clinical Features and Treatment of Distal Intracranial Aneurysms. AB - To analyze the clinical characteristics, therapies, and outcomes of distal intracranial aneurysms, the authors retrospectively studied the clinical and imaging data of 18 patients with distal intracranial aneurysms. There were 10 males and 8 females, aged from 11 months to 59 years (mean, 40.4 +/- 11.4 years). All patients were diagnosed by digital subtract angiography. Aneurysm locations were as follows: distal anterior cerebral artery (n = 5), distal middle cerebral artery (n = 2), distal posterior cerebral artery (n = 6), distal posterior inferior cerebellar artery (n = 3), distal anterior inferior cerebellar artery (n = 1), and distal superior cerebellar artery (n = 1). Endovascular embolization was performed on 16 patients, including coil embolization on 10 patients and embolization using Glubran 2 surgical glue on 6 patients, and 7 of the 16 patients also underwent parent artery occlusion. Aneurysms were all completely embolized at the first phase for these 16 patients. The other 2 patients underwent craniotomy with hematoma evacuation and complete aneurysm clipping. Postoperatively, 14 patients showed a good recovery, 2 patients had neurological deficits, 1 patient had seizures and was managed with drugs, 1 patient developed hydrocephalus, and a ventriculo-peritoneal shunt was performed. Follow-up angiographies showed no aneurysm recurrence. Clinical manifestations of distal intracranial aneurysms are varied. Their treatment should follow the principle of individual choice. Endovascular embolization is an effective way to treat distal intracranial aneurysms; and for those with intracranial hematoma, craniotomy with hematoma evacuation and aneurysm clipping may be a feasible treatment. PMID- 26982110 TI - Changes in Corneal Curvature After Upper Eyelid Surgery Measured by Corneal Topography. AB - PURPOSE: To analyze corneal curvature changes (eg, central corneal power and corneal astigmatism) after upper eyelid surgery, and to compare the effects of different upper eyelid procedures on corneal curvature. METHODS: Fifty eyes of 34 patients with various degrees of dermatochalasis or ptosis underwent corneal topography before surgery, and at 6 weeks after blepharoplasty or levator resection. Patients were divided into groups according to the method of surgery. Preoperative and postoperative changes in corneal curvature of each operated eye were compared within each group. RESULTS: At 6 weeks after levator resection, 50% of the eyes showed an increase in corneal power, 34.6% showed a decrease, and 15.4% showed no change. The corneal astigmatism in 50% of eyes with levator resection decreased, increased in 19.2% of eyes, and showed no change in 30.8% of eyes. At 6 weeks after blepharoplasty, 12.5% of the eyes showed an increase in corneal power, 37.5% showed a decrease, and 66.7% showed no change. Regarding corneal astigmatism in patients who underwent blepharoplasty, 16.7% of the eyes decreased, 16.7% increased, and 66.6% showed no change. Comparing eyes treated with the 2 surgical techniques, there was a statistical difference in the percentage eye which showed corneal diopter and astigmatism change using these 2 techniques (P < 0.05). CONCLUSION: Repositioning of the upper eyelid after levator resection showed greater changes of corneal curvature (eg, central corneal power and corneal astigmatism) than blepharoplasty. The advanced aponeurosis technique may have a greater effect on the lid/cornea interface, by lifting the eyelids pressing against the eyeball to affect corneal curvature. PMID- 26982111 TI - Meta-analysis of the Incidence of Lingual Nerve Deficits After Mandibular Bilateral Sagittal Split Osteotomy. AB - INTRODUCTION: Bilateral sagittal split osteotomy is a relatively common maxillofacial surgical procedure. The most commonly reported complication is neurosensory disturbances (NSD). The inferior alveolar nerve is by far the most commonly affected but sporadic reports of NSD of the lingual nerve also exist. The aim of this meta-analysis is to estimate the incidence of lingual nerve NSD following bilateral sagittal split osteotomy. MATERIALS AND METHODS: A systematic search of the English literature was conducted in February 2015 including several databases and using numerous MeSH terms. Article selection was based on preset criteria. Then pertinent data were collected and the incidence of the complications was calculated. RESULTS: Three articles were included in the meta analysis. Incidence rates ranged between 0.3% and 18% with a pooled incidence of 0.7%. DISCUSSION: Lingual nerve NSD is an infrequent complication of bilateral sagittal split osteotomy. Fortunately, the complication usually resolves within 1 year of the procedure. PMID- 26982112 TI - Repair of Critical Calvarias Defects With Systemic Epimedium sagittatum Extract. AB - It is well established in reconstructive surgery the repair of great bone defects is a difficult goal to be achieved. The aim of this study was to evaluate the influence of an extract rich in icariin on bone neoformation in critically sized defects in rat calvaria. Under continual saline irrigation, a circular bone defect was created in 40 rat calvarias with an 8-mm diameter trephine drill. Animals were randomly divided into a test group that received an Epimedium sagittatum extract (containing 5.8 mg/mL of icariin) and a control group that received an equal volume of saline solution. Substances were administered daily through a feeding tube until euthanasia. After 7, 14, 21, and 42 days, 5 animals from each group were euthanized. Calvaria defect samples were fixed in 10% formalin for 48 hours, X-rayed, and histologically processed. In the test group, there was a significant reduction in the bone defect area on X-ray images and an increase in new bone area in all of the experimental periods in the test group. At 42 days, the bone in the test group also exhibited a significant reduction in osteocyte (P = 0.002) and osteoclast density (P = 0.041). The authors conclude that administration of systemic Epimedium extracts containing high concentrations of icariin can induce bone neoformation and reduce osteocyte and osteoclast densities, thereby altering the normal deposition and remodeling patterns that are present in critically sized bone defects. PMID- 26982113 TI - Upper Triangular Flap in Unilateral Cleft Lip Repair. AB - In this article, the authors describe their use of the upper triangular flap method to repair unilateral cleft lips in 250 patients with cosmetically appealing and predictable results. This method produces a straight philtral column scar that is parallel to the noncleft side and hides the surgical scars on the medial aspect of the nostril and in the lip-columellar crease. The first step is to assign the reference points along the vermilion border and the nostril sills. It is important to identify the nostril sill on the cleft nose, which could be particularly attenuated in wide clefts. Next, the upper triangular flap is designed on the upper part of the cleft side, having made allowance for the sillo-columellar distance. The dissections are performed along the drawn line joining functional points. The repair begins from the floor of the nostril, where the "neo-sill" is sutured directly opposite to the noncleft sill. The sillo columellar distance (s-c) must be reestablished and the small triangular flap is not dissected into 3 layers to avoid devitalizing the skin. The muscle layers are identified, approximated, and held on stay sutures, which are tied in sequence. In this work, the authors identify the apparent lip length and the real lip length. It must be noted that the correction for shortening of the cleft philtral column is done on the real lip length by all other methods used for unilateral cleft lip repair, including our upper triangular flap method. On the basis of its simplicity and their postoperative results, the authors believe this approach offers further insight into cleft lip repair. PMID- 26982114 TI - Urinary markers of nucleic acid oxidation in Danish overweight/obese children and youths. AB - Urinary excretion of the RNA and DNA oxidation markers, 8-oxo-7,8 dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in newly diagnosed adult type 2 diabetics are reported to be long-term predictors of mortality independent of conventional risk factors. In the current study, we investigated the relationships between urinary markers of nucleic acid oxidation concentrations and the degree of obesity and glucose metabolism in overweight compared to lean children. Forty-two (24 girls) overweight and 35 lean (19 girls) children and adolescents were recruited from the Registry of the Danish Childhood Obesity Biobank. Anthropometric measurements were collected at baseline and glucose metabolism was assessed by an oral glucose tolerance test. A urine sample was obtained during the test. Linear regression did not demonstrate any associations between the urinary markers and the degree of obesity or glucose metabolism in lean and obese children. However, sub-analyses adjusted for age, sex, and the degree of obesity showed positive associations between the 2 h glucose and the urinary markers, 8-oxoGuo (p = 0.02, r(2)= 0.63) and 8-oxodG (p = 0.046, r(2)= 0.48), and between the insulinogenic index and 8-oxoGuo (p = 0.03, r(2 )=( )0.60) in the 12 obese children exhibiting impaired glucose tolerance. Excretion of the urinary markers of nucleic acid oxidation and the degree of obesity or the glucose metabolism were not associated in this study. Nevertheless, obese children with impaired glucose tolerance seem to exhibiting an increased oxidative stress level, but due to the small sample size in this study, further investigations are required to elucidate this correlation. PMID- 26982116 TI - The obese patient undergoing nonbariatric surgery. AB - PURPOSE OF REVIEW: This article provides the reader with recent findings on the pathophysiology of comorbidities in the obese, as well as evidence-based treatment options to deal with perioperative respiratory challenges. RECENT FINDINGS: Our understanding of obesity-associated asthma, obstructive sleep apnea, and obesity hypoventilation syndrome is still expanding. Routine screening for obstructive sleep apnea using the STOP-Bang score might identify high-risk patients that benefit from perioperative continuous positive airway pressure and close postoperative monitoring. Measures to most effectively support respiratory function during induction of and emergence from anesthesia include optimal patient positioning and use of noninvasive positive pressure ventilation. Appropriate mechanical ventilation settings are under investigation, so that only the use of protective low tidal volumes could be currently recommended. A multimodal approach consisting of adjuvants, as well as regional anesthesia/analgesia techniques reduces the need for systemic opioids and related respiratory complications. SUMMARY: Anesthesia of obese patients for nonbariatric surgical procedures requires knowledge of typical comorbidities and their respective treatment options. Apart from cardiovascular diseases associated with the metabolic syndrome, awareness of any pulmonary dysfunction is of paramount. A multimodal analgesia approach may be useful to reduce postoperative pulmonary complications. PMID- 26982115 TI - Parental and Volunteer Perception of Pyloromyotomy Scars: Comparing Laparoscopic, Open, and Nonsurgical Volunteers. AB - INTRODUCTION: Despite evidence from prospective trials and meta-analyses supporting laparoscopic pyloromyotomy (LP) over open pyloromyotomy (OP), the open technique is still utilized by some surgeons on the premise that there is minimal clinical benefit to LP over OP. Although the potential cosmetic benefit of LP over OP is often cited in reports, it has never been objectively evaluated. METHODS: After internal review board approval, the parents of patients from a previous prospective trial who had undergone LP (n = 9) and OP (n = 10) were contacted. After consent was obtained, the parents and patients were asked to complete a validated scar scoring questionnaire that was compared between groups. Standardized photos were taken of study subjects and controls with no abdominal procedures. Blinded volunteers were recruited to view the photos, identify if scars were present, and complete questions if a scar(s) was seen. Volunteers were also asked about the degree of satisfaction if their child had similar scars on a four-point scale from happy to unacceptable. RESULTS: Mean age was 7 years in both groups. Parental scar assessment scores were superior in the LP group in every category. Blinded volunteers detected abdominal scars significantly more often in the OP group (98%) vs. the LP group (28%; P < .001). The volunteers detected a scar in 16% of the controls, comparable to the 28% detected in the LP group (P = .17). The degree of satisfaction estimate by volunteers was 1.78 for OP and 1.02 for LP and controls, generating a Cohen's d effect size of 5.1 standard deviation units comparing OP to either LP or controls (very large >=1.3). CONCLUSIONS: Parents of children scored LP scars superior to OP scars. Surgical scars are almost always identifiable with OP while the surgical scars associated with LP approach invisibility to the observer, appearing similar to patients with no prior abdominal operation. PMID- 26982118 TI - Lead-Free Halide Double Perovskites via Heterovalent Substitution of Noble Metals. AB - Lead-based halide perovskites are emerging as the most promising class of materials for next-generation optoelectronics; however, despite the enormous success of lead-halide perovskite solar cells, the issues of stability and toxicity are yet to be resolved. Here we report on the computational design and the experimental synthesis of a new family of Pb-free inorganic halide double perovskites based on bismuth or antimony and noble metals. Using first-principles calculations we show that this hitherto unknown family of perovskites exhibits very promising optoelectronic properties, such as tunable band gaps in the visible range and low carrier effective masses. Furthermore, we successfully synthesize the double perovskite Cs2BiAgCl6, perform structural refinement using single-crystal X-ray diffraction, and characterize its optical properties via optical absorption and photoluminescence measurements. This new perovskite belongs to the Fm3m space group and consists of BiCl6 and AgCl6 octahedra alternating in a rock-salt face-centered cubic structure. From UV-vis and photoluminescence measurements we obtain an indirect gap of 2.2 eV. PMID- 26982120 TI - Protestors give voice to staffing concerns. AB - Members of safe staffing pressure group 4:1 protested last week against the government's decision not to introduce minimum staffing levels. PMID- 26982117 TI - Evaluation of Viremia Frequencies of a Novel Human Pegivirus by Using Bioinformatic Screening and PCR. AB - Next-generation sequencing has critical applications in virus discovery, diagnostics, and environmental surveillance. We used metagenomic sequence libraries for retrospective screening of plasma samples for the recently discovered human hepegivirus 1 (HHpgV-1). From a cohort of 150 hepatitis C virus (HCV)-positive case-patients, we identified 2 persons with HHpgV-1 viremia and a high frequency of human pegivirus (HPgV) viremia (14%). Detection of HHpgV-1 and HPgV was concordant with parallel PCR-based screening using conserved primers matching groups 1 (HPgV) and 2 (HHPgV-1) nonstructural 3 region sequences. PCR identified 1 HHPgV-1-positive person with viremia from a group of 195 persons with hemophilia who had been exposed to nonvirally inactivated factor VII/IX; 18 (9%) were HPgV-positive. Relative to HCV and HPgV, active infections with HHpgV-1 were infrequently detected in blood, even in groups that had substantial parenteral exposure. Our findings are consistent with lower transmissibility or higher rates of virus clearance for HHpgV-1 than for other bloodborne human flaviviruses. PMID- 26982119 TI - Structural transition of kidney cystatin in dimethylnitrosamine-induced renal cancer in rats: identification as a novel biomarker for kidney cancer and prognosis. AB - In our study, renal cancer is induced in rats making use of dimethylnitrosamine (DMN). G1 - Group 1 were control rats and G2 - Group 2 rats were given a single intra-peritoneal injection of DMN of 50 mg/kg body weight resulting in 100% incidences of renal tumors after 12 months. SEM and histopathology confirmed the presence of renal cancer in the DMN-treated rats. Making use of ammonium sulfate precipitation and gel filtration chromatography on Sephacryl S-100HR column, a thiol protease inhibitor was isolated from kidney of control rats known as Rat kidney Cystatin (RKC) as well as from kidney of cancerous rat called as Cancerous Rat Kidney Cystatin (CRKC). Both these inhibitors were characterized, and interestingly, it was found that CRKC showed greater anti-papain activity and also it was stable in a broad pH and temperature range thus implying that CRKC is more stable as compared to RKC. UV and fluorescence spectroscopy point out in structural difference between RKC and CRKC which was further confirmed by Circular dichroism (CD) and FTIR spectroscopy. Our study clearly showed that kidney cystatin is structurally modified in the case of renal cancer and performs its role in a more efficacious manner. PMID- 26982121 TI - Chief nurse and minister launch guide to identifying malnutrition risk. AB - Nurses should care for patients in the same way they would a member of their own family, Northern Ireland's chief nurse has said. PMID- 26982122 TI - Hunt focuses on patient safety and defining success. AB - Patient safety must be transformed within the NHS, health secretary Jeremy Hunt told hundreds of senior nurses last week. PMID- 26982124 TI - Revalidation fears for those appraised by chief execs. AB - Directors of nursing are concerned that they may struggle to meet proposed revalidation requirements drawn up by the Nursing and Midwifery Council if they are appraised by their trust chief executive. PMID- 26982125 TI - Sister honoured for ward plan. AB - A ward sister who improved older people's care by changing the ward culture has become RCN Wales's nurse of the year. PMID- 26982123 TI - Boards need to share responsibility for safe staffing levels. AB - Nursing directors should not shoulder sole responsibility for ensuring safe staffing on every shift, because trust boards are also accountable. PMID- 26982127 TI - Lack of specialist lung cancer care. AB - Three quarters of UK lung cancer patients do not have regular access to 'vital' clinical nurse specialists, a new report reveals. PMID- 26982126 TI - Trust-wide smoking ban reduces violence and promotes cessation. AB - A mental health trust's pilot scheme to make some of its hospital grounds smoke free has reduced the incidence of violence among patients, according to the nurse who led the project. PMID- 26982128 TI - NICE gives green light to wound treatment technique. AB - A procedure to treat open abdominal wounds has been approved as safe by the National Institute for Health and Care Excellence. PMID- 26982130 TI - Scotland could break away on pay if the 'yes' campaign wins. AB - Health unions warned last week that any proposals to change nurses' pay, terms and conditions under an independent Scotland would require staff-side negotiations. PMID- 26982131 TI - Political notebook. AB - Labour MSP Jayne Baxter tabled a motion last week in support of RCN Scotland's Health Visitors for Scotland campaign during a parliamentary debate on the Children and Young People Bill. The campaign calls for the bill to specify that the named person caring for under fives is always a health visitor. PMID- 26982132 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 26982134 TI - Late shifts aim to deliver better winter care. AB - Matrons at Epsom and St Helier University Hospitals NHS Trust in Surrey have had their working hours extended to oversee care this winter. PMID- 26982133 TI - Police launch investigation into claims of falsified cancer lists. AB - Police have launched a criminal investigation into claims that cancer waiting lists were altered at Colchester Hospital University NHS Foundation Trust. PMID- 26982135 TI - Hospitalisation of pregnant women raises risk of blood clots. AB - Women admitted to hospital during pregnancy for reasons other than delivery have an increased risk of blood clots, according to a UK study. PMID- 26982136 TI - Bisphosphonates may help to reduce bone loss caused by antiepileptic drugs. AB - Many patients with epilepsy control their seizures by taking antiepileptic drugs (AEDs) that may accelerate bone loss and increase the risk of osteoporotic fractures. PMID- 26982137 TI - Testosterone therapy increases risk of death or serious conditions. AB - Rates of testosterone therapy have increased markedly in the United States over the past decade, with annual prescriptions reaching 5.3 million in 2011. PMID- 26982138 TI - Academics might have increased public anxiety and demand for flu drugs. AB - Analysis of UK media reporting of the 2009/10 A/H1N1 influenza pandemic has found that public health academics with links to pharmaceutical companies were more likely than other academics to assess the risk to the public as higher than official predictions. PMID- 26982139 TI - Support needed to address surgeons' emotional wellbeing following complications. AB - Surgeons who are involved in major surgical complications often feel guilt and other emotions that can negatively effect their practice. PMID- 26982140 TI - Voices - Black and minority ethnic nurses lack recognition, writes Yvonne Coghill. AB - November was the NHS awards season, hot on the heels of October's Black History Month, which celebrated the achievements and contribution to society of people of African origin. PMID- 26982141 TI - Open to inspection. AB - The nursing profession has never been more under the microscope. Inspections by the Care Quality Commission and foundation trust regulator Monitor are on the increase, not to mention the local checks, mystery shoppers and talk of CCTV cameras in care homes. PMID- 26982142 TI - Give me a break. AB - What is it about me and Friday afternoons? I am not superstitious, but it feels as though the most eagerly-awaited time of the working week for most of the population has become my nemesis. PMID- 26982144 TI - Readers panel - Providing food for thought. AB - Our experts consider a hot topic of the day. PMID- 26982143 TI - Aisle be there. AB - I like grocery shopping. Does that make me weird? Then I might as well tell the whole truth - I actually enjoy pushing a trolley round a supermarket, even on a Saturday morning. Phew. I feel better for getting that off my chest. PMID- 26982145 TI - Numbers game. AB - In last month's long-awaited response to the Francis report, the government committed to introducing mandatory reporting of ward staff numbers. PMID- 26982146 TI - Starting out - It was a surprise and an inspiration to meet someone unafraid of dying. AB - During the final week of my community placement, I accompanied my mentor to see an elderly lady who was reaching the end of her life. I will call her Ann. PMID- 26982147 TI - Medicines management. AB - I am moving from a hospital-based role to primary care where my patients will have a much broader range of conditions. What prescribing advice can you give me? PMID- 26982148 TI - Sign of the times. AB - The news that one in three NHS trusts in England has recruited nurses from abroad says as much about the state of Europe as it does about the NHS. PMID- 26982149 TI - College of Health Care Chaplains. AB - The London-based College of Health Care Chaplains is a multi-faith, interdenominational organisation open to paid and voluntary healthcare chaplaincy staff and those with an interest in this area. It is a professional section of Unite, the UK's largest trades union. PMID- 26982150 TI - Caring in Nursing Classics - An Essential Resource Smith Marlaine C et al Caring in Nursing Classics - An Essential Resource 532pp $75/L63.50 Springer Publishing Company 978 0 8261 7111 5 0826171117 [Formula: see text]. AB - While most nurses would agree that warm, empathetic human interactions should form the core of their professional practice, defining this largely intangible phenomenon remains challenging. PMID- 26982151 TI - On a Wing and a Prayer - Flight to Redemption Wing Peter On a Wing and a Prayer - Flight to Redemption 304pp L7.99 Troubador 978 1 7808 8137 9 1780881371 [Formula: see text]. AB - Peter Wing reflects on his interesting and somewhat dysfunctional life working as cabin crew, nurse and charity worker, inviting us on a journey through the highs and lows of his professional and personal life. PMID- 26982152 TI - Nursing Central app Nursing Central app One-year subscription $169.95/L104 [Formula: see text]. AB - Nursing Central is a comprehensive mobile and web-aligned American app providing detailed information on diseases, tests, procedures, medicines and access to a range of evidence-based nursing journals and resources. PMID- 26982155 TI - On the move. AB - Promotions / new appointments. PMID- 26982153 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 26982156 TI - Notice board. AB - Courses, events, grants, and awards to progress your career. PMID- 26982157 TI - Neonatal Fc Receptor-Mediated IgG Transport Across Porcine Intestinal Epithelial Cells: Potentially Provide the Mucosal Protection. AB - It has been well characterized that piglets can absorb colostrum IgG across the intestine to neonatal bloodstream and a certain level of IgG has been found in the mucosal secretions of the porcine intestinal tract. However, little is known about how the maternal IgG transport across the intestinal barrier and how IgG enter the lumen of intestinal tract. In this study, we demonstrated that the porcine neonatal Fc receptor (pFcRn) was expressed in a model of normal porcine intestinal epithelial cells (IPEC-J2) as well as in kidney cells (PK-15), and pFcRn was mainly distributed in the apical side of the polarized IPEC-J2 cells. Analyzing the phylogenetic relatedness of this gene we found that swine and human neonatal Fc receptor (FcRn) amino acid sequence are closer than rodents. We also showed that pFcRn mediated bidirectional IgG transport across polarized IPEC-J2 cells and bound to IgG in a pH-dependent manner. Furthermore, pFcRn-transcytosed viral-specific IgG reduced the transmissible gastroenteritis virus (TGEV) yield from the luminal direction by a 50% tissue culture infective dose (TCID50) assay. Our results indicate that pFcRn-dependent bidirectional IgG transport across the intestinal epithelium plays critical role in the acquisition of humoral immunity in early life and in host defense at mucosal surfaces. PMID- 26982158 TI - A natural lipopeptide of surfactin for oral delivery of insulin. AB - Surfactin, a natural lipopeptide produced by Bacillus, is gaining attention for potentially biomedical and pharmaceutical applications. Here, surfactin was assayed for oral delivery of insulin (INS) by its ability to bind to and promote protein to penetrate through the cell membrane. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, surfactin was found to form co precipitates with INS to protect it from acidic and enzymatic attack in the gastrointestinal tract. Further analysis by non-reductive electrophoresis showed surfactin could bind to INS forming heteropolymers. Analysis with circular dichroism, we found this binding significantly influenced the INS structure with decreased rigid alpha-helix and beta-turn, but with increased flexible beta-sheet and random coil. The change with more flexible structure was favorable for INS to penetrate through the cell membrane. Fluorescence spectra analysis also showed surfactin could lead Phe and Tyr in the inner of INS exposed outside, further promoting INS permeabilization by improving the hydrophobic-lipophilic interactions between INS and cell membrane. As a result, the effective permeability (Peff) of INS plus surfactin was 4.3 times of that of INS alone. In vivo assay showed oral INS with surfactin displayed excellent hypoglycemic effects with a relative bioavailability of 12.48% and 5.97% in diabetic mice and non-diabetic dogs, respectively. Summary, surfactin is potential for oral delivery of INS by its role as an effective protease inhibitor and permeability enhancer. PMID- 26982159 TI - 'I shouldn't have had to push and fight': health care experiences of persons with dementia and their caregivers in primary care. AB - OBJECTIVES: Most persons with dementia (PWD) receive the majority of their care from primary care providers (PCPs). A number of challenges have been identified with providing quality dementia care in primary care from the perspective of PCP. However, less is known of the primary care health care experience (HCE) of PWD and their caregivers. We examined the primary care HCE of PWD and their caregivers in Ontario, Canada. METHODS: Participants were recruited through local Alzheimer Society chapter support groups. A semi-structured interview guide was developed. Focus groups were audio recorded, transcribed verbatim, anonymized, and then reviewed and coded for themes independently by two study authors. Thematic analysis was conducted to identify major themes and a model proposing the common components of a perceived positive HCE was created. RESULTS: Five focus groups were conducted across urban and rural settings. Each focus group included both PWD and their caregivers and a total of eight PWD and 21 caregivers participated. Four main themes emerged from the analysis: communication, caregiver as manager, system navigation, ease of access. The model for positive HCE included: an informed patient/caregiver; supported patient/caregiver; strong PCP-patient/caregiver relationship; an accessible provider; a knowledgeable provider; and strong communication by the provider. CONCLUSION: The HCE of PWD and their caregivers is complex and a number of factors which are potentially modifiable by PCP may improve the HCE for the growing number of PWD in primary care. Understanding these experiences may help to identify strategies to improve care and patient and provider experiences. PMID- 26982160 TI - Methyl-CpG-Binding Protein 2 Improves the Development of Mouse Somatic Cell Nuclear Transfer Embryos. AB - Methyl-CpG-binding domain proteins (MBPs) connect DNA methylation and histone modification, which are the key changes of somatic cell reprogramming. Methyl-CpG binding protein 2 (MeCP2) was the first discovered MBP that has been extensively studied in the neurodevelopmental disorder Rett syndrome. However, a role for MeCP2 during cellular reprogramming associated with somatic cell nuclear transfer (SCNT) has not been examined. In this study, we discovered that MeCP2 expression was significantly lower in embryos generated by SCNT compared with those generated by intracytoplasmic sperm injection (ICSI). We genetically modified mouse embryonic fibroblasts (MEFs) to overexpress MeCP2 and serve as donor cells for nuclear transfer (NT) to investigate the effects of MeCP2 on preimplantation development of SCNT embryos. The blastocyst rate (35.71%) of MeCP2 overexpressed embryos (NT(+)) was significantly greater than in nontransgenic embryos (NT(-), 24.29%). Furthermore, immunofluorescence experiments revealed that 5 methylcytosine (5mC) was transferred to 5-hydroxymethylcytosine (5hmC) to a greater extent in NT(+) embryos than in NT(-) embryos. Real-time PCR evaluation of gene expression also showed that embryonic development-associated genes, such as Oct4 and Nanog, were significantly higher in the NT(+) group compared to the NT(-) group. Collectively, these results suggested that MeCP2 facilitated Tet3 activity, enhanced expression of pluripotency-related genes, and eventually improved the development of NT embryos. Finally, we performed chromatin immunoprecipitation to identify direct targets of MeCP2 and constructed a protein interaction network to elucidate several putative MeCP2 targets. PMID- 26982162 TI - Education Platform at ZDM8. AB - Interest among the zebrafish community in education and science accessibility for all ages has increased. At the 8th Annual Zebrafish Disease Models Conference (ZDM8), a specifically designed session enabled professional scientists, educators, and students to have a venue to present their science, discuss ideas in education, and partner to navigate a scientific meeting as an educational experience. This meeting report describes the format of the Platform Session as well as challenges and future plans to leverage impact of conferences on the local communities. PMID- 26982163 TI - Risk-adapted treatment and follow-up management in childhood-onset craniopharyngioma. AB - Craniopharyngiomas are rare embryonic malformations of the sellar/parasellar region with low histological grade. Here, we review findings on the diagnosis, treatment, clinical course, follow-up, and prognosis of craniopharyngioma patients. Clinical manifestations develop from increased intracranial pressure, anterior visual pathway damage, and hypothalamic/pituitary deficiencies. If the tumor is favorably localized (no anatomical involvement with the hypothalamic and optical structures) therapy of choice is complete resection, meticulously performed to preserve hypothalamic and optic functions. In patients with unfavorable tumor involvement, optimal therapy is limited hypothalamus-sparing surgical strategy, followed by judicious irradiation dosage to minimize recurrences and progression. Surgical lesions and/or anatomical involvement of posterior hypothalamic areas result in serious sequelae, mainly hypothalamic syndrome. Craniopharyngioma is a chronic disease and must be managed as such, providing ongoing care of pediatric and adult patients by experienced multidisciplinary teams in the context of multicenter trials. PMID- 26982164 TI - Tumor delivery of liposomal doxorubicin prepared with poly-L-glutamic acid as a drug-trapping agent. AB - CONTEXT: Poly-l-glutamic acid (PGA) is an anionic polymer with a large number of carboxyl groups that can interact electrostatically with cationic drugs such as doxorubicin (DOX). OBJECTIVE: For stable encapsulation of DOX into liposomes, we prepared triethylamine (TEA)-PGA-liposomes using PGA as an internal trapping agent. METHODS: We prepared TEA-PGA-liposomes by remote loading of DOX with a TEA gradient into preformed liposomes prepared with 1, 2, or 4 mg/mL PGA (molecular weights 4800, 9800, and 20 500), and evaluated their biodistribution and antitumor effects on Lewis lung carcinoma (LLC) tumor-bearing mice. RESULTS: TEA PGA-liposomes using the higher the molecular weight or concentration of PGA showed a slower release of DOX from the liposomes. TEA-PGA-liposomes prepared with a high concentration of PGA could enhance DOX accumulation in tumors and prolonged DOX circulation in the serum, indicating that DOX may be retained stably in the liposomal interior by interaction with PGA. Furthermore, injection of TEA-PGA-liposomes prepared with 4 mg/mL of PGA9800 or 2 mg/mL PGA20500 strongly inhibited tumor growth in LLC tumor-bearing mice. CONCLUSIONS: PGA may be a potential trapping agent for liposomal DOX for tumor drug delivery. PMID- 26982161 TI - Hearing Assessment in Zebrafish During the First Week Postfertilization. AB - The zebrafish (Danio rerio) is a valuable vertebrate model for human hearing disorders because of many advantages in genetics, embryology, and in vivo visualization. In this study, we investigated auditory function of zebrafish during the first week postfertilization using microphonic potential recording. Extracellular microphonic potentials were recorded from hair cells in the inner ear of wild-type AB and transgenic Et(krt4:GFP)(sqet4) zebrafish at 3, 5, and 7 days postfertilization in response to 20, 50, 100, 200, 300, and 400-Hz acoustic stimulation. We found that microphonic threshold significantly decreased with age in zebrafish. However, there was no significant difference of microphonic responses between wild-type and transgenic zebrafish, indicating that the transgenic zebrafish have normal hearing like wild-type zebrafish. In addition, we observed that microphonic threshold did not change with the recording electrode location. Furthermore, microphonic threshold increased significantly at all tested stimulus frequencies after displacement of the saccular otolith but only increased at low frequencies after displacement of the utricular otolith, showing that the saccule rather than the utricle plays the major role in larval zebrafish hearing. These results enhance our knowledge of early development of auditory function in zebrafish and the factors affecting hearing assessment with microphonic potential recording. PMID- 26982166 TI - High-Mobility Group Box-1 Protein Disrupts Alveolar Elastogenesis of Hyperoxia Injured Newborn Lungs. AB - Although high-mobility group box-1 (HMGB1) levels in tracheal aspirates are associated with the pathological features of bronchopulmonary dysplasia (BPD), the role of HMGB1 in the terminal stage of abnormal alveologenesis has not yet been understood. In this study, we addressed the role of HMGB1 in the elastogenesis disruption in the lungs of newborn mice with BPD. We found that elevations of whole lung HMGB1 level were associated with impaired alveolar development and aberrant elastin production in 85% O2-exposed lungs. HMGB1 neutralizing antibody attenuated the structural disintegration developed in hyperoxia-damaged lungs. Furthermore, HMGB1 inhibition rescued the neutrophil influx in hyperoxia-injured lung and partially abolished the mRNA level of the proinflammatory mediators, interleukin (IL)-1beta and transforming growth factor (TGF)-beta1. These data suggested that pulmonary HMGB1 plays an important role in the disruption of elastogenesis in the terminal stage of lung development through reduced pulmonary inflammatory response. PMID- 26982165 TI - Hepatitis C Viral Kinetic Changes in a Retrospective Cohort Study of Chronic Hepatitis C Virus Egyptian Patients on Pegylated Interferon and Ribavirin Therapy. AB - The aim of this study was to determine the relative importance of the kinetics of antiviral response compared to baseline host and virological factors for predicting treatment outcome. A retrospective analysis of 285 chronic hepatitis C virus (HCV) patients, encompassing genotypes 4 treated with peginterferon alpha 2a and ribavirin, was performed. Baseline characteristics were compared across HCV genotypes and pretreatment factors associated with rapid virological response (RVR) were identified. The relative significance of RVR compared to other baseline factors for predicting sustained virological response was analyzed by multiple logistic regression analysis. Ninety-seven percent of the patients harbored HCV genotype 4a patients. The positive predictive value (PPV) of RVR for end-of-treatment response (ETR) was 88% and of early virological response (EVR) was 85%, which means that achievement of both RVR and EVR is a good positive predictive factor of response. The negative predictive value (NPV) of RVR for ETR was low and equals 26.77%, which means that approximately two-thirds of patients were able to achieve ETR despite not experiencing RVR, which means RVR is a bad negative predictive factor of response. The NPV of EVR for ETR was high and equals 90%, which means that only 10% of patients were able to achieve an ETR despite not experiencing EVR, which explains that EVR is a very good negative predictive factor of response. In univariate logistic regression analysis, which included the following: female gender, alanine aminotransferase, aspartate transaminase, alpha-fetoprotein, baseline HCV-RNA levels, grade of activity, stage of fibrosis, and positive HCV-RNA, by polymerase chain reaction at week 4, none of the previous factors was a significant independent factor of failure of response to treatment. The current study demonstrated that a viremia at week 4 has a good PPV, but it has a very low NPV. The NPV of EVR was more robust for ETR (90%). EVR is regarded as a robust indicator of treatment outcome, and a 12-week stopping rule for patients is strongly evident. PMID- 26982168 TI - Rabies in Costa Rica: Documentation of the Surveillance Program and the Endemic Situation from 1985 to 2014. AB - This is the first comprehensive epidemiological analysis of rabies in Costa Rica. We characterized the occurrence of the disease and demonstrated its endemic nature in this country. In Costa Rica, as in other countries in Latin America, hematophagous vampire bats are the primary wildlife vectors transmitting the rabies virus to cattle herds. Between 1985 and 2014, a total of 78 outbreaks of bovine rabies was reported in Costa Rica, with documented cases of 723 dead cattle. Of cattle outbreaks, 82% occurred between 0 and 500 meters above sea level, and seasonality could be demonstrated on the Pacific side of the country, with significantly more outbreaks occurring during the wet season. A total of 1588 animal samples, or an average of 55 samples per year, was received by the veterinary authority (SENASA) for rabies diagnostic testing at this time. Of all samples tested, 9% (143/1588) were positive. Of these, 85.6% (125/1588) were from cattle; four dogs (0.3% [4/1588]) were diagnosed with rabies in this 30-year period. Simultaneously, an extremely low number (n = 3) of autochthonous rabies cases were reported among human patients, all of which were fatal. However, given the virus' zoonotic characteristics and predominantly fatal outcome among both cattle and humans, it is extremely important for healthcare practitioners and veterinarians to be aware of the importance of adequate wound hygiene and postexpositional rabies prophylaxis when dealing with both wild and domestic animal bites. PMID- 26982169 TI - Small-Colony Variants in Persistent and Recurrent Staphylococcus aureus Bacteremia. AB - The small-colony variant (SCV) phenotype of Staphylococcus aureus is associated with intracellular persistence and reduced antimicrobial susceptibility, which can lead to therapeutic failure. Since SCVs grow slowly and have a confusing morphology, the identification of infections due to SCV is difficult. We have identified SCVs in two patients who presented with persistent methicillin resistant Staphylococcus aureus (MRSA) bacteremia complicated by surgical site infections after cardiothoracic surgery. Nine blood isolates were collected from the two patients for species identification, antimicrobial susceptibility testing, and phenotypic and genotypic characterization. Colonies on Columbia blood agar were pinpoint, nonpigmented, nonhemolytic, and reverted to normal colonies after 48 hr of incubation on Schaedler agar. Auxotrophy assays revealed hemin dependence. Susceptibility to vancomycin (minimal inhibitory concentrations 1.0 MUg/mL) was confirmed by E-test and broth microdilution test. All the isolates were identified as MRSA by multiplex polymerase chain reaction specific for the mecA, femA, and 16S rRNA genes, and all had the same genotype: Multilocus sequence typing ST5, SCCmec type II, agr type II, and spa type t2460. Moreover pulsed-field gel electrophoresis typing revealed that all nine isolates belonged to the same clone. Mutations in the relA gene were not found, and none of the isolates was identified as hVISA by population analysis profiling-AUC ratio. A high level of suspicion is required to detect SCVs, and although it is not common, the possibility of the SCV phenotype has to be considered in persistent S. aureus bacteremia. PMID- 26982170 TI - Mucosal Healing - How Deep Is Enough? AB - Mucosal healing has emerged as an important outcome measure of treatment in inflammatory bowel disease (IBD). It is increasingly incorporated in the outcome measures of clinical trials along with patient reported outcomes and used in clinical practice as a therapeutic target or goal. The exact definition of mucosal healing continues to evolve and several scoring systems have been developed, some of which require further validation. Considerable inter-observer variation may also exist in interpretation of mucosal appearance in IBD. Novel endoscopic techniques demonstrate that even in patients who have achieved mucosal healing by conventional criteria, subtle inflammation may continue to persist. Whether mucosal healing needs to incorporate or reflect histological healing is a topic of intense debate and further studies. In addition, surrogate markers of mucosal healing, such as fecal calprotectin, may serve as a therapeutic target, but there is debate about whether normalization of fecal calprotectin always reflects mucosal healing. Patients with mucosal healing may also continue to have clinical symptoms reflecting visceral hypersensitivity. PMID- 26982167 TI - Microfluidic Droplet-Facilitated Hierarchical Assembly for Dual Cargo Loading and Synergistic Delivery. AB - Bottom-up hierarchical assembly has emerged as an elaborate and energy-efficient strategy for the fabrication of smart materials. Herein, we present a hierarchical assembly process, whereby linear amphiphilic block copolymers are self-assembled into micelles, which in turn are accommodated at the interface of microfluidic droplets via cucurbit[8]uril-mediated host-guest chemistry to form supramolecular microcapsules. The monodisperse microcapsules can be used for simultaneous carriage of both organic (Nile Red) and aqueous-soluble (fluorescein isothiocyanate-dextran) cargo. Furthermore, the well-defined compartmentalized structure benefits from the dynamic nature of the supramolecular interaction and offers synergistic delivery of cargos with triggered release or through photocontrolled porosity. This demonstration of premeditated hierarchical assembly, where interactions from the molecular to microscale are designed, illustrates the power of this route toward accessing the next generation of functional materials and encapsulation strategies. PMID- 26982171 TI - Validation of the Balance Board for Clinical Evaluation of Balance During Serious Gaming Rehabilitation Exercises. AB - BACKGROUND: Balance and posture can be affected in various conditions or become decreased with aging. A diminution of balance control induces an increase of fall's risk. INTRODUCTION: The Nintendo Wii Balance BoardTM (WBB) is used in rehabilitation to perform balance exercises (using commercial video games). The WBB has also been validated to assess balance and posture in static conditions. However, there is currently no study investigating the use of WBB to assess balance during the realization of balance exercises using this device. The aim of this study was to validate the use of WBB, coupled with specially developed serious games, to assess dynamic balance during rehabilitation exercises. MATERIALS AND METHODS: Thirty five subjects participated in this study. Subjects were asked to play two specially developed serious games. Center of pressure (CP) displacements were simultaneously recorded with a WBB and a gold standard force plate (FP). Nine parameters were derived from CP displacement. Bland and Altman plots, paired-sample t tests, intraclass correlation coefficient's, and Pearson's coefficient correlations were computed. RESULTS: Excellent correlation between both devices was found for each parameter for the two games (R = 0.95 and 0.96). DISCUSSION: Unlike previous work on the WBB, these excellent results were obtained without using any calibration procedure. Despite this, results were highly correlated between the WBB and the FP. CONCLUSIONS: The WBB could be used in clinics to assess balance during rehabilitation exercises and, thus, allows a more regular patient follow-up. PMID- 26982172 TI - Superparamagnetic nanoparticles as vectors for inner ear treatments: driving and toxicity evaluation. AB - Conclusion Super paramagnetic nanoparticles (MNP) are a promising vector to achieve controlled drug delivery into the cochlea. Objective The goal of the study was to evaluate the toxicological risk of MNP upon the inner ear. Methods Fe3O4-MNP displacement was studied in various catheter materials, shape, and solvent with a local magnetic field. EC5V cells (derived from the inner ear) were cultured with MNP (100 and 500 nm) at various concentrations or without MNP. Cell survival was assessed with a flow cytometry analysis. Localization of MNP within the cells was studied with confocal microscopy. In vivo, a single intra-cochlear administration of 200 nm MNP (3 * 10(10)MNP/mL, n = 8; 1.5 * 10(12) MNP/mL, n = 6) or saline (n = 14) was performed in guinea pigs. Hearing thresholds were assessed with auditory brainstem responses at Day 7. Results MNP could be concentrated at different locations of the catheter with sequential activation of solenoids. MNP were internalized in the cytoplasm, but not in the nuclei nor in endosomes at 48 h. After 48 h of incubation, no difference for cell survival between the groups was observed, whatever the MNP concentration. A size effect was observed with less survival in the 100 nm group. In guinea pigs at day 7, hearing threshold shift was not different in the three groups. PMID- 26982173 TI - De Novo Asymmetric Synthesis of a 6-O-Methyl-D-glycero-L-gluco-heptopyranose Derived Thioglycoside for the Preparation of Campylobacter jejuni NCTC11168 Capsular Polysaccharide Fragments. AB - An enantioselective de novo synthesis of a thioglycoside derivative of the 6-O methyl-D-glycero-L-gluco-heptopyranose residue found in the Campylobacter jejuni NCTC11168 (HS:2) capsular polysaccharide is reported. The compound is obtained from a furfural-derived chiral diol in 11 steps. Notably, compared to the only previous synthesis of this molecule, this approach significantly reduces the number of purification steps required to obtain the target. PMID- 26982174 TI - The p.Gly61Glu Mutation in CYP1B1 Affects the Extracellular Matrix in Glaucoma Patients. AB - PURPOSE: The aim of this work was to assess the possible effects of CYP1B1 mutations on the extracellular matrix (ECM) in glaucoma patients. CYP1B1 mutations are the cause of disease in a notable fraction of primary congenital glaucoma (PCG) patients and in a smaller fraction of primary open angle glaucoma (POAG) patients. METHODS: The study was performed on a glaucoma family with the common homozygous p.Gly61Glu CYP1B1 mutation. The father was affected with POAG and three siblings had PCG. Microscopy was performed on the skin of the father and one son, as well as controls. Immunohistochemical studies were done using anti-CYP1B1 and anti-fibrillin-1 antibodies. Fibrillin-1 served as a marker for the ECM, and electron microscopy was also performed. RESULTS: CYP1B1 expression patterns were the same in the patients and controls. However, microfibrils that are associated with fibrillin-1 were less abundant and more fragmented in both patients. Electron microscopy showed disturbed collagen fibers only in the PCG patient. CONCLUSIONS: The p.Gly61Glu mutation in CYP1B1 affects the ECM structure. This implies that the ECM of the trabecular meshwork may also be disrupted in a manner that affects aqueous humor flow resulting in increased intraocular pressure and contributing to the glaucoma phenotype. PMID- 26982175 TI - Genotype and Phenotype Characteristics in 22 Patients with Vitamin D-Dependent Rickets Type I. AB - BACKGROUND AND AIMS: Vitamin D-dependent rickets type I (VDDR1) is an autosomal recessive disorder caused by mutations in the 25-hydroxyvitamin D 1-alpha hydroxylase gene (CYP27B1). Mutations in CYP27B1 disrupt or lead to a total loss of the 1-alpha-hydroxylase activity and require treatment with physiological doses of calcitriol. PATIENTS AND METHODS: A genetic analysis of the CYP27B1 gene was conducted in 22 Turkish patients with VDDR1 from 13 families. Presenting characteristics, biochemical features, treatment, and results from the genetic analysis are described. RESULTS: A splice donor site mutation c.195 + 2T>G was found in 10 patients. The novel missense p.192K>E (c.574A>G) mutation was detected in 5 patients, and a novel missense p.197G>D (c.590G>A) mutation was found in 4 patients. A previously reported 7-bp duplication 1319-1325dupCCCACCC (Phe443Profs*24) in exon 8 was detected in 1 patient, and 1 patient was a compound heterozygote for the novel p.192K>E and the previously described 1319 1325dupCCCACCC mutations. A novel single base pair deletion, c.171_171delG, leading to a frameshift, was found in 1 patient. CONCLUSIONS: We identified 3 novel and 2 previously described mutations in the CYP27B1 gene. A marked phenotypical diversity was observed between families that carried identical mutations, suggesting phenotypical heterogeneity. PMID- 26982176 TI - CCR2 and CCR5 genes polymorphisms in women with cervical lesions from Pernambuco, Northeast Region of Brazil: a case-control study. AB - Polymorphisms in chemokine receptors play an important role in the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer (CC). Our study examined the association of CCR2-64I (rs1799864) andCCR5-Delta32 (rs333) polymorphisms with susceptibility to develop cervical lesion (CIN and CC) in a Brazilian population. The genotyping of 139 women with cervical lesions and 151 women without cervical lesions for the CCR2-64I and CCR5-Delta32 polymorphisms were performed using polymerase chain reaction-restriction fragment length polymorphism. The individuals carrying heterozygous or homozygous genotypes (GA+AA) for CCR2-64I polymorphisms seem to be at lower risk for cervical lesion [odds ratio (OR) = 0.37, p = 0.0008)]. The same was observed for the A allele (OR = 0.39, p = 0.0002), while no association was detected (p > 0.05) with CCR5 Delta32 polymorphism. Regarding the human papillomavirus (HPV) type, patients carrying the CCR2-64Ipolymorphism were protected against infection by HPV type 16 (OR = 0.35, p = 0.0184). In summary, our study showed a protective effect ofCCR2 64I rs1799864 polymorphism against the development of cervical lesions (CIN and CC) and in the susceptibility of HPV 16 infection. PMID- 26982177 TI - Novel point mutations in the ERG11 gene in clinical isolates of azole resistant Candida species. AB - The azoles are the class of medications most commonly used to fight infections caused by Candida sp. Typically, resistance can be attributed to mutations in ERG11 gene (CYP51) which encodes the cytochrome P450 14alpha-demethylase, the primary target for the activity of azoles. The objective of this study was to identify mutations in the coding region of theERG11 gene in clinical isolates of Candida species known to be resistant to azoles. We identified three new synonymous mutations in the ERG11 gene in the isolates of Candida glabrata (C108G, C423T and A1581G) and two new nonsynonymous mutations in the isolates of Candida krusei--A497C (Y166S) and G1570A (G524R). The functional consequence of these nonsynonymous mutations was predicted using evolutionary conservation scores. The G524R mutation did not have effect on 14alpha-demethylase functionality, while the Y166S mutation was found to affect the enzyme. This observation suggests a possible link between the mutation and dose-dependent sensitivity to voriconazole in the clinical isolate of C. krusei. Although the presence of the Y166S in phenotype of reduced azole sensitivity observed in isolate C. krusei demands investigation, it might contribute to the search of new therapeutic agents against resistant Candida isolates. PMID- 26982178 TI - New host, geographic records, and histopathologic studies of Angiostrongylus spp (Nematoda: Angiostrongylidae) in rodents from Argentina with updated summary of records from rodent hosts and host specificity assessment. AB - To date, 21 species of the genus Angiostrongylus (Nematoda: Angiostrongylidae) have been reported around the world, 15 of which are parasites of rodents. In this study, new host, geographic records, and histopathologic studies of Angiostrongylus spp in sigmodontine rodents from Argentina, with an updated summary of records from rodent hosts and host specificity assessment, are provided. Records of Angiostrongylus costaricensis from Akodon montensis and Angiostrongylus morerai from six new hosts and geographical localities in Argentina are reported. The gross and histopathologic changes in the lungs of the host species due to angiostrongylosis are described. Published records of the genus Angiostrongylus from rodents and patterns of host specificity are presented. Individual Angiostrongylus species parasitise between one-19 different host species. The most frequent values of the specificity index (STD) were between 1-5.97. The elevated number of host species (n = 7) of A. morerai with a STD = 1.86 is a reflection of multiple systematic studies of parasites from sigmodontine rodents in the area of Cuenca del Plata, Argentina, showing that an increase in sampling effort can result in new findings. The combination of low host specificity and a wide geographic distribution of Angiostrongylus spp indicates a troubling epidemiological scenario although, as yet, no human cases have been reported. PMID- 26982180 TI - Phytoplankton across Tropical and Subtropical Regions of the Atlantic, Indian and Pacific Oceans. AB - We examine the large-scale distribution patterns of the nano- and microphytoplankton collected from 145 oceanic stations, at 3 m depth, the 20% light level and the depth of the subsurface chlorophyll maximum, during the Malaspina-2010 Expedition (December 2010-July 2011), which covered 15 biogeographical provinces across the Atlantic, Indian and Pacific oceans, between 35 degrees N and 40 degrees S. In general, the water column was stratified, the surface layers were nutrient-poor and the nano- and microplankton (hereafter phytoplankton, for simplicity, although it included also heterotrophic protists) community was dominated by dinoflagellates, other flagellates and coccolithophores, while the contribution of diatoms was only important in zones with shallow nutriclines such as the equatorial upwelling regions. We applied a principal component analysis to the correlation matrix among the abundances (after logarithmic transform) of the 76 most frequent taxa to synthesize the information contained in the phytoplankton data set. The main trends of variability identified consisted of: 1) A contrast between the community composition of the upper and the lower parts of the euphotic zone, expressed respectively by positive or negative scores of the first principal component, which was positively correlated with taxa such as the dinoflagellates Oxytoxum minutum and Scrippsiella spp., and the coccolithophores Discosphaera tubifera and Syracosphaera pulchra (HOL and HET), and negatively correlated with taxa like Ophiaster hydroideus (coccolithophore) and several diatoms, 2) a general abundance gradient between phytoplankton-rich regions with high abundances of dinoflagellate, coccolithophore and ciliate taxa, and phytoplankton-poor regions (second principal component), 3) differences in dominant phytoplankton and ciliate taxa among the Atlantic, the Indian and the Pacific oceans (third principal component) and 4) the occurrence of a diatom-dominated assemblage (the fourth principal component assemblage), including several pennate taxa, Planktoniella sol, Hemiaulus hauckii and Pseudo-nitzschia spp., in the divergence regions. Our findings indicate that consistent assemblages of co-occurring phytoplankton taxa can be identified and that their distribution is best explained by a combination in different degrees of both environmental and historical influences. PMID- 26982179 TI - Pharmacokinetic and pharmacodynamic responses in adult patients with Chagas disease treated with a new formulation of benznidazole. AB - Pharmacological treatment of Chagas disease with benznidazole (BNZ) is effective in children in all stages, but it is controversial in chronically infected adults. We report the pharmacokinetics and pharmacodynamics in six adult patients with Chagas disease treated with the new BNZ formulation (ABARAX(r)) in doses between 2.5-5.5 mg/Kg/day. All but one patient had plasmatic BNZ concentrations within the expected range. All patients finalised treatment with nondetectable Trypanosoma cruzi quantitative polymerase chain reaction, which remained nondetectable at the six month follow-up. Our data suggests parasitological responses with the new BNZ and supports the hypothesis that treatment protocols with lower BNZ doses may be effective. PMID- 26982181 TI - The Promise of Epigenetics. Has It Delivered New Insights? AB - Enrichment of GWAS signals within cell-specific enhancers defines cellular subsets most associated to IBD and highlights the critical role of epigenetics in IBD. We review the central role of the interleukin 23 (IL-23) pathway in cellular plasticity, mechanisms which are significantly mediated by epigenetic regulation of master transcription factors of various CD4+ T-cell subsets. Present studies need to be complemented by a deeper understanding of intestine-specific gene expression and epigenetics, especially in mononuclear phagocytes, given their enormous plasticity, and tissue-dependent function. A deeper understanding and application of epigenetics may impact and guide early treatment and ultimately, disease prevention in IBD. PMID- 26982182 TI - Periostin Contributes to Cisplatin Resistance in Human Non-Small Cell Lung Cancer A549 Cells via Activation of Stat3 and Akt and Upregulation of Survivin. AB - BACKGROUND/AIMS: Periostin is upregulated in non-small cell lung cancer (NSCLC). This study was done to explore the function of periostin in the development of cisplatin (CDDP) resistance in NSCLC. METHODS: The effects of overexpression or knockdown of periostin on CDDP sensitivity was examined in A549 cells. The involvement of signal transducer and activator of transcription 3 (Stat3) and Akt signaling in the action of periostin was checked. The in vivo effect of periostin silencing on CDDP susceptibility was determined in a mouse xenograft model. RESULTS: Periostin was significantly upregulated in CDDP-resistant A549 cells, compared to parental controls. Overexpression of periostin rendered A549 cells more resistant to CDDP-induced apoptosis and enhanced Stat3 and Akt phosphorylation and survivin expression. Periostin-mediated protection against CDDP-induced apoptosis was compromised by downregulation of survivin. Furthermore, knockdown of periostin re-sensitized CDDP-resistant A549 cells to CDDP. After CDDP treatment, greater volume reduction was observed in periostin silenced xenograft tumors than in control tumors, which was accompanied by reduced levels of phosphorylated Stat3 and survivin in periostin-depleted tumors. CONCLUSION: In conclusion, periostin promotes CDDP resistance in NSCLC cells largely through activation of Stat3 and Akt and upregulation of survivin and thus represents a promising target for overcoming CDDP resistance. PMID- 26982183 TI - Production of 15N-Labelled Liquid Organic Fertilisers Based on Manure and Crop Residue for Use in Fertigation Studies. AB - Large quantities of crop residue and animal manure from agricultural and livestock activities are annually produced worldwide. With proper management, these residues are potentially valuable sources of plant nutrients, mainly N. Recycling such subproducts in sustainably-based agricultural systems can minimise the use of mineral fertilisers, and hence reduce the potential risk of surface and groundwater pollution. Therefore, the purpose of this study was to obtain (small scale) two liquid labelled-organic fertilisers, an animal- and a vegetal based organic (AO and VO, respectively) fertiliser, to be used as organic N sources in subsequent fertigation studies. Forage maize (Zea mays L.) grown under 15N-labelled fertiliser supply was used as raw material for VO fertiliser production, and also as 15N-labelled sheep feed to obtain 15N-labelled manure. The labelled faeces fraction was used as raw material for the AO fertiliser. The VO fertiliser was obtained after an acidic and an enzyme-driven hydrolysis. The AO fertiliser was obtained after acidic hydrolysis. The VO liquid fertiliser presented an N concentration of 330 mg.L-1, 85% of total N was organic, while ammonium and nitrate N accounted for 55% and 45% of the mineral nitrogen fraction, respectively. This fertiliser also exhibited high K, Ca and S concentrations and notable values for the remaining macro- and micronutrients. The AO liquid fertiliser had a similar total N concentration (496 mg.L-1, 82% of total N in an organic form) to that of VO, but its mineral N fraction significantly differed, which came in a predominantly (95%) ammonia form. It also had a high content of N, P, K and other macronutrients, and sufficient Fe, Zn, Mn, Cu and B levels, which suggests its suitability as a potential fertiliser. The percentage of 15N enrichment in both VO and AO liquid fertilisers exceeded 2% 15N atom excess, which enabled their use in subsequent assays run to assess nitrogen uptake efficiency. PMID- 26982186 TI - [Existing laparoscopic simulators and their benefit for the surgeon]. AB - INTRODUCTION: Nowadays, laparoscopic operations are a common part of surgical practice. However, they have their own characteristics and require a specific method of preparation. Recently, simulation techniques have been increasingly used for the training of skills. The aim of this review is to provide a summary of available literature on the topic of laparoscopic simulators, to assess their contribution to the training of surgeons, and to identify the most effective type of simulation. METHODS: PubMed database, Web of Science and Cochrane Library were used to search for relevant publications. The keywords "laparoscopy, simulator, surgery, assessment" were used in the search. The search was limited to prospective studies published in the last 5 years in the English language. RESULTS: From a total of 354 studies found, we included in the survey 26 that matched our criteria. Nine studies compared individual simulators to one another. Five studies evaluated "high and low fidelity" (a virtual box simulator) as equally effective (EBM 2a). In three cases the "low fidelity" box simulator was found to be more efficient (EBM 2a3b). Only one study preferred the virtual simulator (VR) (EBM2b).Thirteen studies evaluated the benefits of simulators for practice. Twelve found training on a simulator to be an effective method of preparation (EBM 1b3b). In contrast, one study did not find any difference between the training simulator and traditional preparation (EBM 3b). Nine studies evaluated directly one of the methods of evaluating laparoscopic skills. Three studies evaluated VR simulator as a useful assessment tool. Other studies evaluated as successful the scoring system GOALS-GH. The hand motion analysis model was successful in one case. Most studies were observational (EBM 3b) and only 2 studies were of higher quality (EBM 2b). CONCLUSION: Simulators are an effective tool for practicing laparoscopic techniques (EBM: 1b). It cannot be determined based on available data which of the simulators is most effective. The virtual simulator, however, still remains the most self-sufficient unit suitable for teaching as well as evaluation of laparoscopic techniques (EBM 2b3b). Further studies are needed to find an effective system and parameters for an objective evaluation of skills. KEY WORDS: laparoscopy - simulator - surgery assessment. PMID- 26982185 TI - Estimation of Directed Effective Connectivity from fMRI Functional Connectivity Hints at Asymmetries of Cortical Connectome. AB - The brain exhibits complex spatio-temporal patterns of activity. This phenomenon is governed by an interplay between the internal neural dynamics of cortical areas and their connectivity. Uncovering this complex relationship has raised much interest, both for theory and the interpretation of experimental data (e.g., fMRI recordings) using dynamical models. Here we focus on the so-called inverse problem: the inference of network parameters in a cortical model to reproduce empirically observed activity. Although it has received a lot of interest, recovering directed connectivity for large networks has been rather unsuccessful so far. The present study specifically addresses this point for a noise-diffusion network model. We develop a Lyapunov optimization that iteratively tunes the network connectivity in order to reproduce second-order moments of the node activity, or functional connectivity. We show theoretically and numerically that the use of covariances with both zero and non-zero time shifts is the key to infer directed connectivity. The first main theoretical finding is that an accurate estimation of the underlying network connectivity requires that the time shift for covariances is matched with the time constant of the dynamical system. In addition to the network connectivity, we also adjust the intrinsic noise received by each network node. The framework is applied to experimental fMRI data recorded for subjects at rest. Diffusion-weighted MRI data provide an estimate of anatomical connections, which is incorporated to constrain the cortical model. The empirical covariance structure is reproduced faithfully, especially its temporal component (i.e., time-shifted covariances) in addition to the spatial component that is usually the focus of studies. We find that the cortical interactions, referred to as effective connectivity, in the tuned model are not reciprocal. In particular, hubs are either receptors or feeders: they do not exhibit both strong incoming and outgoing connections. Our results sets a quantitative ground to explore the propagation of activity in the cortex. PMID- 26982187 TI - [Colorectal cancer in the elderly]. AB - INTRODUCTION: High incidence of colorectal cancer in the Czech Republic is an actual and demographically significant health issue. Half of all of the patients is older than 70 years. Both surgical and non-surgical treatment options in this group of patients depend on factors that are difficult to measure only by current oncological and anesthesiological classifications (cTcNcM, ASA). The objective of this paper is to measure the impact of age on the use of various treatment modalities within the protocol and their results, and also to suggest alternative options for therapy tolerance assessment. METHODS: Analysis of data over a five year period from the NOR database prepared by the Institute of Biostatistics and Analyses, Masaryk University. RESULTS: In all parameters a difference was demonstrated between patients below the age of 70 and those above the age of 70 years. Older patients were disadvantaged. Only 11.2% of patients younger than 70 years were not treated, whereas 25.2% over the age of 70 years were not treated. CONCLUSION: A complex geriatric examination could improve the indication process in various treatment modalities, including surgery. KEY WORDS: colorectal cancer elderly - treatment - geriatric assesment. PMID- 26982184 TI - Ideal Binocular Disparity Detectors Learned Using Independent Subspace Analysis on Binocular Natural Image Pairs. AB - An influential theory of mammalian vision, known as the efficient coding hypothesis, holds that early stages in the visual cortex attempts to form an efficient coding of ecologically valid stimuli. Although numerous authors have successfully modelled some aspects of early vision mathematically, closer inspection has found substantial discrepancies between the predictions of some of these models and observations of neurons in the visual cortex. In particular analysis of linear-non-linear models of simple-cells using Independent Component Analysis has found a strong bias towards features on the horoptor. In order to investigate the link between the information content of binocular images, mathematical models of complex cells and physiological recordings, we applied Independent Subspace Analysis to binocular image patches in order to learn a set of complex-cell-like models. We found that these complex-cell-like models exhibited a wide range of binocular disparity-discriminability, although only a minority exhibited high binocular discrimination scores. However, in common with the linear-non-linear model case we found that feature detection was limited to the horoptor suggesting that current mathematical models are limited in their ability to explain the functionality of the visual cortex. PMID- 26982188 TI - [Development of tracheal resection technique - our experience]. AB - INTRODUCTION: Tracheal resections are very frequent interventions on the trachea in general. In borderline cases where the tracheal resection length is too high, the situation can be resolved by inserting a stent or Montgomerys T cannula. Tracheal stenoses are of benign origin in 94%, and malignant in 6% of cases. We present a summary of tracheal resection interventions for the last 21 years. METHOD: 235 tracheal resections were performed at the authors institution in 1993 2013. In total 221 benign stenosis cases (85 % developed after tracheostomy, 15% developed after intubation) and 14 malignant cases were treated. The patients were divided into two groups: A resection in years 19932002 and B - resection in years 20032013. The comparison of these two time periods is presented with focus on surgical procedures development and recommendations based on experienced complications. RESULTS: Restenosis (early or late) is the most common complication during the process of tracheal resection treatment. Tiny fistulas in the suture can be diagnosed easily by minor air leaking and are treated conservatively without intervention. Fortunately, suture insufficiency is relatively rare. In some cases the restenoses can be resected or treated by stent application or by Montgomerys T-cannula application. Complications were observed in 2% of the treated patients, which is a number presented also by international studies. CONCLUSION: Tracheal resection is definitely an optimal solution for patients suffering from tracheal stenosis. As presented in our study, in the hands of experienced thoracic surgeons tracheal resections is a safe and final solution of tracheal stenosis. KEY WORDS: trachea - stenosis resection. PMID- 26982189 TI - [Short-term results of minimally invasive pectus excavatum repair in adult patients]. AB - INTRODUCTION: Pectus excavatum is the most common congenital chest wall deformity. Aproximatelly 1 out of 400 to 1000 newborns are affected by this diagnosis. Surgical correction is indicated in patients that fulfil the indication criteria. The highly modified Ravitch correction (HMRR) and minimally invasive pectus excavatum repair (MIRPE) are by far the most popular methods of correction. MIRPE has been established as the method of choice amongst children. Feasibility of the minimally invasive approach in the funnel chest correction in adult population still remains controversial. METHODS: The authors present a retrospective analysis of adult patients treated by MIRPE in their institution. Sixty adult patients with pectus excavatum underwent MIRPE from October 2010 to March 2015. Various parameters were evaluated retrospectively. The effectiveness and safety of both techniques were evaluated with the use of statistical software SPSS(r) version 21.0 (IBM, USA). Data were evaluated using Student's t-test or Mann-Whitney U-test for normally and non-normally distributed data, respectively. The comparison of categorical variables between the groups was evaluated by Pearson's chi-square test. A p value of less than 0.05 was considered statistically significant. RESULTS: 45 men and 15 women underwent MIRPE during the period. Median age in the group was 23 years without any statistically significant difference between males and females (p=0.386). Median Haller index was 3.93 and was slightly higher in women (p= 0.285). Asymmetric deformities were present in 20 patients (33.3%) without any statistically significant difference between the sexes (p=0.206). Median duration of the surgical correction was 73 minutes and was longer in males (p=0.312). Two bars were implanted in 27 patients with no significant difference between the sexes (p=0.454). Complication rate was 25% (15/60) without any significant difference based on the number of implanted bars (p=0.178), sex (p=0.863) or the presence of an asymmetric deformity (p=0.527). Wound seromas with 10% (6/60) were the most common complication. Median postoperative length of stay was 5 days without any significant difference between males and females (p=0.653) and patients with different number of bars implanted (p=0.600). The need for rehospitalisation and reoperation was indicated in 5 patients (8.3%). Allergy to chromium led to bar extraction in 1 patient and 4 patients were treated by V.A.C.(r) therapy (KCI, USA) because of wound abscess (1) and seroma (3). CONCLUSION: Minimally invasive pectus excavatum repair is an effective surgical technique for the treatment of pectus excavatum in adult patients. This technique can be learned and performed safely even without any former experience with this correction in children. KEY WORDS: adult patients - MIRPE pectus excavatum. PMID- 26982191 TI - [Granulomatous inflammation in differential diagnosis of hepatobiliary malignancy]. AB - The authors present two case reports to demonstrate wide differential diagnosis of granulomatous disorders of the hepatobiliary tract. Isolated granulomatous disorders are very rare in this area. Differantial diagnosis includes infectious and systemic diseases or chemical irritation. Granulomas often immitate malignant tumors and the surgeon could be first to diagnose this disease during liver resection or cholecystectomy. KEY WORDS: granulomatous inflammation hepatic granuloma non-specific inflammation liver resection cholecystectomy. PMID- 26982190 TI - [Transanal endoscopic microsurgery (TEM) our experience]. AB - INTRODUCTION: The purpose of this paper is to present our experience with transanal endoscopic microsurgery (TEM) as an operative approach in a selected group of patients with rectal tumours. METHODS: We present a retrospective study of 80 patients operated for rectal tumour using TEM. Specific preoperative and postoperative indicators were gathered and statistically evaluated. We assessed histological examination before the surgery and definitive histology of the resected tumour, resection depth and basic demographic data of our patients. RESULTS: Our experience suggests that there is no significant difference between the age of patients according to sex, even if malignant and benign tumours are assessed separately. The majority of our operated patients were male patients, mean age of 64 years who were primarily referred to our department because of bleeding low-grade adenomas of the rectum. In 17 patients a malignant tumour was diagnosed based on final histopathologic examination. None of them had signs of malignancy before the surgery. CONCLUSION: In the hands of an experienced surgeon, TEM is a feasible option of radical removal of rectal, locally not advanced malignancies if within reach of TEM rectoscope. TEM is a safe procedure that does not result in any alteration of rectal sphincter functions. Possible false negative preoperative benign diagnosis leads us to approach radical removal of the tumour with full wall thickness resection. Although the posterior aspect of the rectum is an optimal location for the rectoscope, anterior tumours were found in almost one half of our patients. Considering technical feasibility of the rectal wall suture, the base of the tumour should not extend beyond one half of the rectal circumference. Low non-stenotising noninvasive tumours of the rectum are suitable for TEM. Our good results are particularly due to strict patient selection criteria, mastering the operating technique and long-time experience. KEY WORDS: transanal endoscopic microsurgery (TEM) benign rectal tumours rectal cancer. PMID- 26982192 TI - [Extragenital malignant Mullerian carcinosarcoma with invasion of inferior vena cava - a case report]. AB - The authors present the case of a 57-year-old woman with a very rare extragenital malignant retroperitoneal Mullerian carcinosarcoma invading the inferior vena cava. Tumor resection with partial resection of the vena cava wall and resection of metastases in the pelvic area is described. The authors further discuss diagnostic options of metastases of this tumour and the recommended adjuvant chemotherapy. KEY WORDS: extragenital Mullerian carcinosarcoma malignant mixed Mullerian tumour - diagnosis therapy. PMID- 26982193 TI - ASCA, ANCA, ALCA and Many More: Are They Useful in the Diagnosis of Inflammatory Bowel Disease? AB - BACKGROUND: Inflammatory bowel disease (IBD) is characterized by excessive immune responses to altered intestinal microbiota in genetically susceptible individuals. The diagnosis of IBD depends on clinical, endoscopic, histological, radiological and biochemical criteria, which may be invasive, time consuming and usually not accepted by patients with IBD. KEY MESSAGES: Serological biomarkers have been demonstrated to be a series of rapid, non-invasive approaches for assessments of early diagnosis, disease activity and prognosis for IBD. Importantly, serum antibodies against microbial antigens or auto-antigens have been used as biomarkers in predicting disease course, complications and responses to medications and surgery. Moreover, they have been demonstrated to be useful in distinguishing patients with Crohn's disease (CD) from those with ulcerative colitis (UC). Recently, a great number of new serum biomarkers (e.g., anti glycoprotein 2, anti-granulocyte macrophage colony-stimulating factor, anti neutrophil cytoplasmic antibody, anti-Saccharomyces cerevisiae antibody, anti laminaribioside carbohydrate IgG antibody, anti-mannobioside carbohydrate IgG antibody, antibody to the outer membrane protein of Escherichia coli, anti-CBir1) have been found to be present in patients with IBD and are potentially used in the diagnosis and prediction. The presence of these antibodies in the sera is due to the disruption of intestinal mucosa barrier and they may reflect a possibly genetic loss of immunological tolerance toward microbiota-derived antigens. Due to their non-invasive, easily accessible, repetitive and economical characteristics, these biomarkers have been found to serve as precious supplementary means in the diagnosis and disease evaluation of IBD. CONCLUSIONS: Currently, the most important utility of serological biomarkers is to evaluate the aggressive risks of disease phenotype, complications or surgery requirement, predict prognosis of the disease and distinguish CD from UC. However, they have limited values in making initially definite diagnosis for IBD. Therefore, more effective biomarkers with high sensitivity and specificity need to be further explored in the future. PMID- 26982194 TI - Co-Culture of S. epidermidis and Human Osteoblasts on Implant Surfaces: An Advanced In Vitro Model for Implant-Associated Infections. AB - OBJECTIVES: Total joint arthroplasty is one of the most frequent and effective surgeries today. However, despite improved surgical techniques, a significant number of implant-associated infections still occur. Suitable in vitro models are needed to test potential approaches to prevent infection. In the present study, we aimed to establish an in vitro co-culture setup of human primary osteoblasts and S. epidermidis to model the onset of implant-associated infections, and to analyze antimicrobial implant surfaces and coatings. MATERIALS AND METHODS: For initial surface adhesion, human primary osteoblasts (hOB) were grown for 24 hours on test sample discs made of polystyrene, titanium alloy Ti6Al4V, bone cement PALACOS R(r), and PALACOS R(r) loaded with antibiotics. Co-cultures were performed as a single-species infection on the osteoblasts with S. epidermidis (multiplicity of infection of 0.04), and were incubated for 2 and 7 days under aerobic conditions. Planktonic S. epidermidis was quantified by centrifugation and determination of colony-forming units (CFU). The quantification of biofilm bound S. epidermidis on the test samples was performed by sonication and CFU counting. Quantification of adherent and vital primary osteoblasts on the test samples was performed by trypan-blue staining and counting. Scanning electron microscopy was used for evaluation of topography and composition of the species on the sample surfaces. RESULTS: After 2 days, we observed approximately 104 CFU/ml biofilm-bound S. epidermidis (103 CFU/ml initial population) on the antibiotics-loaded bone cement samples in the presence of hOB, while no bacteria were detected without hOB. No biofilm-bound bacteria were detectable after 7 days in either case. Similar levels of planktonic bacteria were observed on day 2 with and without hOB. After 7 days, about 105 CFU/ml planktonic bacteria were present, but only in the absence of hOB. Further, no bacteria were observed within the biofilm, while the number of hOB was decreased to 10% of its initial value compared to 150% in the mono-culture of hOB. CONCLUSION: We developed a co culture setup that serves as a more comprehensive in vitro model for the onset of implant-associated infections and provides a test method for antimicrobial implant materials and coatings. We demonstrate that observations can be made that are unavailable from mono-culture experiments. PMID- 26982195 TI - Hepatitis E Virus Prevalence among Blood Donors, Ouagadougou, Burkina Faso. PMID- 26982197 TI - Mortality Salience, System Justification, and Candidate Evaluations in the 2012 U.S. Presidential Election. AB - Experiments conducted during the 2004 and 2008 U.S. presidential elections suggested that mortality salience primes increased support for President George W. Bush and Senator John McCain, respectively. Some interpreted these results as reflecting "conservative shift" following exposure to threat, whereas others emphasized preferences for "charismatic" leadership following exposure to death primes. To assess both hypotheses in the context of a new election cycle featuring a liberal incumbent who was considered to be charismatic, we conducted four experiments shortly before the 2012 election involving President Barack Obama and Governor Mitt Romney. Contrary to earlier studies, there was little evidence that mortality salience, either by itself or in interaction with political orientation, affected overall candidate ratings or voting intentions. However, a significant interaction between mortality salience and system justification in some studies indicated a more circumscribed effect. The failure to "replicate" previous results in the context of this election may be attributable to disagreement among participants as to which of the candidates better represented the societal status quo. PMID- 26982198 TI - Computer Simulation Studies of the Mechanism of Hydrotrope-Assisted Solubilization of a Sparingly Soluble Drug Molecule. AB - The effect of hydrotrope sodium cumene sulfonate (SCS) on the solubility of a sparingly water-soluble drug, griseofulvin, is studied by employing classical molecular dynamics simulation technique. We mainly focus on the underlying mechanism by which SCS enhances the solubility of a sparingly soluble or insoluble solute in water. The main observations are the following: (a) The self aggregation of SCS molecules (through its hydrophobic tail) above the minimum hydrotrope concentration (MHC) causes the formation of micellar-like frameworks. Interestingly, though the drug griseofulvin possesses both polar and nonpolar groups, it prefers to get encapsulated inside the hydrophobic core of SCS aggregates. The decomposition of total SCS-drug interaction energy into van der Waals and electrostatic components suggests that the former plays a major role in this interaction. (b) The calculated Flory-Huggins interaction parameter values give a strong indication of the mixing ability of hydrotrope SCS and griseofulvin drug molecules. (c) As expected, we do not observe any strong effect of SCS aggregates on SCS-water and water-water average hydrogen-bond number, but it affects water-drug griseofulvin average hydrogen-bond number. With the help of these observations we try to elucidate the hydrotropic action of hydrotrope SCS on the solubility of drug griseofulvin. PMID- 26982196 TI - Timed Rise from Floor as a Predictor of Disease Progression in Duchenne Muscular Dystrophy: An Observational Study. AB - BACKGROUND: The role of timed items, and more specifically, of the time to rise from the floor, has been reported as an early prognostic factor for disease progression and loss of ambulation. The aim of our study was to investigate the possible effect of the time to rise from the floor test on the changes observed on the 6MWT over 12 months in a cohort of ambulant Duchenne boys. SUBJECTS AND METHODS: A total of 487 12-month data points were collected from 215 ambulant Duchenne boys. The age ranged between 5.0 and 20.0 years (mean 8.48 +/-2.48 DS). RESULTS: The results of the time to rise from the floor at baseline ranged from 1.2 to 29.4 seconds in the boys who could perform the test. 49 patients were unable to perform the test at baseline and 87 at 12 month The 6MWT values ranged from 82 to 567 meters at baseline. 3 patients lost the ability to perform the 6mwt at 12 months. The correlation between time to rise from the floor and 6MWT at baseline was high (r = 0.6, p<0.01). CONCLUSIONS: Both time to rise from the floor and baseline 6MWT were relevant for predicting 6MWT changes in the group above the age of 7 years, with no interaction between the two measures, as the impact of time to rise from the floor on 6MWT change was similar in the patients below and above 350 m. Our results suggest that, time to rise from the floor can be considered an additional important prognostic factor of 12 month changes on the 6MWT and, more generally, of disease progression. PMID- 26982199 TI - Severe Infections with Human Adenovirus 7d in 2 Adults in Family, Illinois, USA, 2014. AB - Human adenovirus 7d, a genomic variant with no reported circulation in the United States, was isolated from 2 adults with severe respiratory infections in Illinois. Molecular typing identified a close relationship with strains of the same genome type isolated from cases of respiratory disease in several provinces of China since 2009. PMID- 26982201 TI - Two new prenylated phloroglucinol derivatives from Hypericum scabrum. AB - Two new prenylated phloroglucinol derivatives (1-2), and a known compound furohyperforim isomer 2 (3), were isolated from the aerial parts of Hypericum scabrum. Their structures were elucidated by various spectroscopic methods, including MS, IR, UV, and NMR. PMID- 26982200 TI - HIV-1 Protease in the Fission Yeast Schizosaccharomyces pombe. AB - BACKGROUND: HIV-1 protease (PR) is an essential viral enzyme. Its primary function is to proteolyze the viral Gag-Pol polyprotein for production of viral enzymes and structural proteins and for maturation of infectious viral particles. Increasing evidence suggests that PR cleaves host cellular proteins. However, the nature of PR-host cellular protein interactions is elusive. This study aimed to develop a fission yeast (Schizosaccharomyces pombe) model system and to examine the possible interaction of HIV-1 PR with cellular proteins and its potential impact on cell proliferation and viability. RESULTS: A fission yeast strain RE294 was created that carried a single integrated copy of the PR gene in its chromosome. The PR gene was expressed using an inducible nmt1 promoter so that PR specific effects could be measured. HIV-1 PR from this system cleaved the same indigenous viral p6/MA protein substrate as it does in natural HIV-1 infections. HIV-1 PR expression in fission yeast cells prevented cell proliferation and induced cellular oxidative stress and changes in mitochondrial morphology that led to cell death. Both these PR activities can be prevented by a PR-specific enzymatic inhibitor, indinavir, suggesting that PR-mediated proteolytic activities and cytotoxic effects resulted from enzymatic activities of HIV-1 PR. Through genome-wide screening, a serine/threonine kinase, Hhp2, was identified that suppresses HIV-1 PR-induced protease cleavage and cell death in fission yeast and in mammalian cells, where it prevented PR-induced apoptosis and cleavage of caspase-3 and caspase-8. CONCLUSIONS: This is the first report to show that HIV-1 protease is functional as an enzyme in fission yeast, and that it behaves in a similar manner as it does in HIV-1 infection. HIV-1 PR-induced cell death in fission yeast could potentially be used as an endpoint for mechanistic studies, and this system could be used for developing a high-throughput system for drug screenings. PMID- 26982202 TI - Transcriptome Analysis for Abnormal Spike Development of the Wheat Mutant dms. AB - BACKGROUND: Wheat (Triticum aestivum L.) spike development is the foundation for grain yield. We obtained a novel wheat mutant, dms, characterized as dwarf, multi pistil and sterility. Although the genetic changes are not clear, the heredity of traits suggests that a recessive gene locus controls the two traits of multi pistil and sterility in self-pollinating populations of the medium plants (M), such that the dwarf genotype (D) and tall genotype (T) in the progeny of the mutant are ideal lines for studies regarding wheat spike development. The objective of this study was to explore the molecular basis for spike abnormalities of dwarf genotype. RESULTS: Four unigene libraries were assembled by sequencing the mRNAs of the super-bulked differentiating spikes and stem tips of the D and T plants. Using integrative analysis, we identified 419 genes highly expressed in spikes, including nine typical homeotic genes of the MADS-box family and the genes TaAP2, TaFL and TaDL. We also identified 143 genes that were significantly different between young spikes of T and D, and 26 genes that were putatively involved in spike differentiation. The result showed that the expression levels of TaAP1-2, TaAP2, and other genes involved in the majority of biological processes such as transcription, translation, cell division, photosynthesis, carbohydrate transport and metabolism, and energy production and conversion were significantly lower in D than in T. CONCLUSIONS: We identified a set of genes related to wheat floral organ differentiation, including typical homeotic genes. Our results showed that the major causal factors resulting in the spike abnormalities of dms were the lower expression homeotic genes, hormonal imbalance, repressed biological processes, and deficiency of construction materials and energy. We performed a series of studies on the homeotic genes, however the other three causal factors for spike abnormal phenotype of dms need further study. PMID- 26982203 TI - Inflammation in arthritis induces expression of BMP3, an inhibitor of bone formation. AB - OBJECTIVES: Inflammation in diseases such as rheumatoid arthritis (RA) stimulates osteoclast-mediated articular bone erosion and inhibits osteoblast-mediated bone formation, leading to a net loss of bone. Pro-inflammatory cytokines and antagonists of the Wnt signalling pathway have been implicated in the inhibition of osteoblast differentiation and activity in RA, contributing to the erosive process and impairing erosion healing. Importantly, osteoblast differentiation and function are also regulated by the osteogenic bone morphogenetic protein (BMP) signalling pathway, which is antagonized by BMP3. We therefore examined the potential role of BMP3 in inflammatory arthritis. METHOD: Two murine models of RA, K/BxN serum transfer arthritis (STA) and antigen-induced arthritis (AIA), were used to establish the temporal expression of BMP3 and the cellular sources of BMP3 mRNA and protein in inflammatory arthritis. To determine the effects of inflammation on the expression of BMP3 in osteoblasts, murine calvarial osteoblasts were treated with pro-inflammatory cytokines and BMP3 expression was assessed. RESULTS: In both murine models of RA, BMP3 mRNA and protein are highly expressed by osteoblasts lining inflammation-bone interfaces late in the course of arthritis. Synovial tissues are not a significant source of BMP3. BMP3 expression is induced in osteocalcin-expressing osteoblasts in vitro following stimulation by tumour necrosis factor (TNF). CONCLUSIONS: These data implicate BMP3 as a novel factor that may act locally to contribute to the erosive process and inhibit the repair of articular bone in RA through inhibition of osteoblast differentiation and function. PMID- 26982204 TI - Large arterial occlusive strokes as a medical emergency: need to accurately predict clot location. AB - BACKGROUND: Endovascular treatment for acute ischemic stroke with a large intracranial occlusion was recently shown to be effective. Timely knowledge of the presence, site, and extent of arterial occlusions in the ischemic territory has the potential to influence patient selection for endovascular treatment. We aimed to find predictors of large vessel occlusive strokes, on the basis of available demographic, clinical, radiological, and laboratory data in the emergency setting. METHODS: Patients enrolled in ASTRAL registry with acute ischemic stroke and computed tomography (CT)-angiography within 12 h of stroke onset were selected and categorized according to occlusion site. Easily accessible variables were used in a multivariate analysis. RESULTS: Of 1645 patients enrolled, a significant proportion (46.2%) had a large vessel occlusion in the ischemic territory. The main clinical predictors of any arterial occlusion were in-hospital stroke [odd ratios (OR) 2.1, 95% confidence interval 1.4-3.1], higher initial National Institute of Health Stroke Scale (OR 1.1, 1.1-1.2), presence of visual field defects (OR 1.9, 1.3-2.6), dysarthria (OR 1.4, 1.0-1.9), or hemineglect (OR 2.0, 1.4-2.8) at admission and atrial fibrillation (OR 1.7, 1.2-2.3). Further, the following radiological predictors were identified: time-to imaging (OR 0.9, 0.9-1.0), early ischemic changes (OR 2.3, 1.7-3.2), and silent lesions on CT (OR 0.7, 0.5-1.0). The area under curve for this analysis was 0.85. Looking at different occlusion sites, National Institute of Health Stroke Scale and early ischemic changes on CT were independent predictors in all subgroups. CONCLUSION: Neurological deficits, stroke risk factors, and CT findings accurately identify acute ischemic stroke patients at risk of symptomatic vessel occlusion. Predicting the presence of these occlusions may impact emergency stroke care in regions with limited access to noninvasive vascular imaging. PMID- 26982205 TI - Intranasal fentanyl for the prehospital management of acute pain in children. AB - INTRODUCTION: Acute pain is the most common symptom in the emergency setting and its optimal management continues to challenge prehospital emergency care practitioners, particularly in the paediatric population. Difficulty in establishing vascular access and fear of opiate administration to small children are recognized reasons for oligoanalgesia. Intranasal fentanyl (INF) has been shown to be as safe and effective as intravenous morphine in the treatment of severe pain in children in the Emergency Department setting. AIM: This study aimed to describe the clinical efficacy and safety of INF when administered by advanced paramedics in the prehospital treatment of acute severe pain in children. METHODS: A 1-year prospective cross-sectional study was carried out of children (>1 year, <16 years) who received INF as part of the prehospital treatment of acute pain by the statutory national emergency medical services in Ireland. RESULTS: Ninety-four children were included in the final analysis [median age 11 years (interquartile range 7-13)]; 53% were males and trauma was implicated in 86% of cases. A clinically effective reduction in the pain score was found in 78 children [83% (95% confidence interval: 74-89%)]. The median initial pain rating score was 10. Pain assessment at 10 min after INF administration indicated a median pain rating of 5 (interquartile range 2-7). No patient developed an adverse event as a result of INF. DISCUSSION: INF at a dose of 1.5 ug/kg appears to be a safe and effective analgesic in the prehospital management of acute severe pain in children and may be an attractive alternative to both oral and intravenous opiates. PMID- 26982206 TI - Examination of the Impact of Copper(II) alpha-(N)-Heterocyclic Thiosemicarbazone Complexes on DNA Topoisomerase IIalpha. AB - Type II DNA topoisomerases resolve topological knots and tangles in DNA that result from routine cellular processes and are effective targets for anticancer therapeutics. To this end, thiosemicarbazones have been identified as having the ability to kill cancer cells from several cell lines. Literature evidence suggests that at least some thiosemicarbazones have an impact on topoisomerase II activity. However, the mechanism is not as clearly defined. Therefore, we set out to analyze the activity of four alpha-(N)-heterocyclic thiosemicarbazone compounds against topoisomerase IIalpha. The ligands, acetylpyridine ethylthiosemicarbazone (APY-ETSC) and acetylpyrazine-methylthiosemicarbazone (APZ MTSC), and their copper(II) [Cu(II)] complexes [Cu(APY-ETSC)Cl] and [Cu(APZ MTSC)Cl] were examined for the ability to impact the catalytic cycle of human topoisomerase IIalpha. Both [Cu(APY-ETSC)Cl] and [Cu(APZ-MTSC)Cl] were more effective at inhibiting DNA relaxation compared with the ligands alone. Further, both [Cu(APY-ETSC)Cl] and [Cu(APZ-MTSC)Cl] increased double-stranded DNA cleavage levels without inhibiting topoisomerase IIalpha-mediated DNA ligation. The Cu(II) complexes inactivate enzyme activity over time suggesting a critical interaction with the enzyme. Additionally, we found that the Cu(II)-thiosemicarbazone complexes do not significantly impact DNA cleavage by the catalytic core of the enzyme. This evidence is supported by the fact that both [Cu(APY-ETSC)Cl] and [Cu(APZ-MTSC)Cl], and to a lesser extent the ligands, inhibit topoisomerase IIalpha-mediated ATP hydrolysis. Based upon kinetic analysis, the Cu(II) complexes appear to be noncompetitive inhibitors of the ATPase domain of topoisomerase IIalpha. Taken together, our results provide evidence that Cu(II) complexes of alpha-(N)-heterocyclic thiosemicarbazones catalytically inhibit the enzyme through the ATPase domain but also promote double-stranded DNA cleavage by the enzyme. PMID- 26982207 TI - Windows Instant Messaging App Forensics: Facebook and Skype as Case Studies. AB - Instant messaging (IM) has changed the way people communicate with each other. However, the interactive and instant nature of these applications (apps) made them an attractive choice for malicious cyber activities such as phishing. The forensic examination of IM apps for modern Windows 8.1 (or later) has been largely unexplored, as the platform is relatively new. In this paper, we seek to determine the data remnants from the use of two popular Windows Store application software for instant messaging, namely Facebook and Skype on a Windows 8.1 client machine. This research contributes to an in-depth understanding of the types of terrestrial artefacts that are likely to remain after the use of instant messaging services and application software on a contemporary Windows operating system. Potential artefacts detected during the research include data relating to the installation or uninstallation of the instant messaging application software, log-in and log-off information, contact lists, conversations, and transferred files. PMID- 26982208 TI - A NEW TECHNIQUE WITH AUTOLOGOUS FIBRIN FOR THE TREATMENT OF PERSISTENT OPTIC PIT MACULOPATHY. AB - PURPOSE: To report the use of autologous fibrin for the treatment of persistent optic pit maculopathy. METHODS: The authors report two patients with an optic pit related serous macular detachment, which persisted after vitrectomy and internal limiting membrane peeling. Autologous fibrin was prepared from the patients' whole blood and injected over the optic disk pit area to seal the pit/coloboma area followed by fluid-air-gas exchange. RESULTS: Retina stayed attached starting from the first postoperative visit till the last visit at 27 (Case 1) and 14 (Case 2) months after surgery. CONCLUSION: The use of autologous fibrin for the treatment of optic disk pit-related serous macular detachment seems a worthy contribution to the treatment of persistent cases. PMID- 26982209 TI - INTRAVITREAL DEXAMETHASONE IMPLANTATION FOR BIRDSHOT CHORIORETINOPATHY. AB - PURPOSE: Birdshot chorioretinopathy is a rare form of posterior uveitis. This article reports a case series of patients with HLA-A29+ birdshot chorioretinopathy managed with intravitreal dexamethasone implants. METHODS: Retrospective case report. RESULTS: Three patients with birdshot chorioretinopathy (6 eyes) were seen from 2013 to 2015 and managed with dexamethasone intravitreal implant; there was an average of 6 months between implants. All 3 experienced control of ocular inflammation and macular edema with intravitreal dexamethasone and achieved best-corrected visual acuity of at least 20/25 during the course of treatment. Two patients tolerated serial dexamethasone implants for over a year without glaucoma or cataract surgery. Dexamethasone implantation was not repeated in one patient with preexisting uveitic glaucoma because of persistently elevated intraocular pressure. In this series, all patients had improvement in visual acuity, macular edema, intraocular inflammation, and quality of life, and no patients developed visually significant cataracts. Only one eye with preexisting uveitic glaucoma exhibited an increased intraocular pressure requiring discontinuation of therapy. CONCLUSION: Intravitreal dexamethasone implant can be an effective alternative in the management of birdshot chorioretinopathy. PMID- 26982212 TI - Strong pyro-catalysis of pyroelectric BiFeO3 nanoparticles under a room temperature cold-hot alternation. AB - A strong pyro-catalytic dye degradation with an ultrahigh degradation efficiency (>99%) in hydrothermally synthesized pyroelectric BiFeO3 nanoparticles was achieved under a room-temperature cold-hot alternating excitation (between 27 degrees C to 38 degrees C). The pyro-catalysis originated from a combination of the pyroelectric effect and the electrochemical oxidation-reduction reaction. The intermediate products (hydroxyl radicals and superoxide radicals) of pyro-electro catalysis were observed. Pyro-catalysis provides a highly efficient and reusable dye wastewater decomposition technology through utilizing environmental day-night temperature variation. PMID- 26982210 TI - Important differences in the durability of glycaemic response among second-line treatment options when added to metformin in type 2 diabetes: a retrospective cohort study. AB - IMPORTANCE: There is limited information about the durability of glycaemic control when different oral glucose-lowering therapies (GLTs) are used as add-on treatments to metformin (MET) in patients with type 2 diabetes mellitus (T2DM). OBJECTIVE: To compare time to treatment failure between different classes of oral GLT when used as second line (add-on) treatments to MET monotherapy at HbA1c >= 7.5%. DESIGN, SETTING AND PARTICIPANTS: A retrospective cohort study on 20,070 patients who were newly treated with a sulphonylurea (SU), dipeptidyl-peptidase-4 (DPP-4) inhibitor or thiazolidinedione (TZD) following MET therapy failure (2007 2014). Patients' data was sourced from UK General Practices via The Health Improvement Network (THIN) database. The risk of dual therapy failure was compared between three treatment groups: MET + SU (reference group, n = 15,508), MET + DPP-4 inhibitor (n = 3,080) and MET + TZD (n = 1,482). Follow-up was until treatment substitution or intensification with a 3rd GLT, or for up to 5 years (totalling 46,430 person-years). Propensity score weighting and Cox proportional hazard regression analyses were employed. MAIN OUTCOMES AND MEASURES: Risk of dual therapy failure was compared between treatment groups while adjusting for baseline covariates. RESULTS: Unadjusted survival analysis showed the incidence of dual therapy failure at 1 year was 15% with SU, 23% with DPP-4 inhibitor and 8% with TZD. Corresponding failure rates at 2 years were 26, 38 and 12%, respectively. Adjusted multivariate models showed that, compared to the SU group, adding a DPP-4 inhibitor was associated with an increased risk of treatment failure (adjusted hazard ratio, aHR, 1.58; 95% CI: 1.48-1.68), while adding a TZD was associated with a reduced hazard (aHR, 0.45; 95% CI: 0.41-0.50). Baseline parameters associated with an increased hazard of intensification included HbA1c, diabetes duration, gender, smoking status and the use of statins. CONCLUSIONS AND RELEVANCE: In routine clinical practice, adding a DPP-4 inhibitor to MET is associated with an increased, earlier requirement for treatment intensification compared to adding an SU or TZD. Adding a TZD to MET resulted in the most durable glycaemic response. Key messages The Agency for Healthcare Research and Quality has suggested that the durability of glycaemic response after treatment intensification is best investigated using well-designed long-term observational studies. In routine clinical practice, among patients with T2DM receiving a second line glucose lowering treatment as add-on to MET, the addition of a Thiazolidinediones is associated with the most durable glycaemic response, followed by a Sulfonylurea and then a DPP-4 inhibitor. Factors associated with earlier dual therapy failure included concomitant use of statin therapy, being female, a smoker, those with longer diabetes duration and higher baseline HbA1c levels. The addition of a Thiazolidinediones was associated with significant weight gain (1.8 kg, p < 0.001), while add-on DPP-4 inhibitor produced a significant weight reduction (-1.8 kg, p < 0.001). A very small reduction in body weight was observed with the SU (-0.2 kg, p < 0.001). PMID- 26982211 TI - Establishment of a standard reference material (SRM) herbal DNA barcode library of Vitex negundo L. (lagundi) for quality control measures. AB - The majority of the population in the Philippines relies on herbal products as their primary source for their healthcare needs. After the recognition of Vitex negundo L. (lagundi) as an important and effective alternative medicine for cough, sore throat, asthma and fever by the Philippine Department of Health (DOH), there was an increase in the production of lagundi-based herbal products in the form of teas, capsules and syrups. The efficiency of these products is greatly reliant on the use of authentic plant material, and to this day no standard protocol has been established to authenticate plant materials. DNA barcoding offers a quick and reliable species authentication tool, but its application to plant material has been less successful due to (1) lack of a standard DNA barcoding loci in plants and (2) poor DNA yield from powderised plant products. This study reports the successful application of DNA barcoding in the authentication of five V. negundo herbal products sold in the Philippines. Also, the first standard reference material (SRM) herbal library for the recognition of authentic V. negundo samples was established using 42 gene accessions of ITS, psbA-trnH and matK barcoding loci. Authentication of the herbal products utilised the SRM following the BLASTn and maximum-likelihood (ML) tree construction criterion. Barcode sequences were retrieved for ITS and psbA trnH of all products tested and the results of the study revealed that only one out of five herbal products satisfied both BLASTn and ML criterion and was considered to contain authentic V. negundo. The results prompt the urgent need to utilise DNA barcoding in authenticating herbal products available in the Philippine market. Authentication of these products will secure consumer health by preventing the negative effects of adulteration, substitution and contamination. PMID- 26982214 TI - Confinement properties of 2D porous molecular networks on metal surfaces. AB - Quantum effects that arise from confinement of electronic states have been extensively studied for the surface states of noble metals. Utilizing small artificial structures for confinement allows tailoring of the surface properties and offers unique opportunities for applications. So far, examples of surface state confinement include thin films, artificial nanoscale structures, vacancy and adatom islands, self-assembled 1D chains, vicinal surfaces, quantum dots and quantum corrals. In this review we summarize recent achievements in changing the electronic structure of surfaces by adsorption of nanoporous networks whose design principles are based on the concepts of supramolecular chemistry. Already in 1993, it was shown that quantum corrals made from Fe atoms on a Cu(1 1 1) surface using single atom manipulation with a scanning tunnelling microscope confine the Shockley surface state. However, since the atom manipulation technique for the construction of corral structures is a relatively time consuming process, the fabrication of periodic two-dimensional (2D) corral structures is practically impossible. On the other side, by using molecular self assembly extended 2D porous structures can be achieved in a parallel process, i.e. all pores are formed at the same time. The molecular building blocks are usually held together by non-covalent interactions like hydrogen bonding, metal coordination or dipolar coupling. Due to the reversibility of the bond formation defect-free and long-range ordered networks can be achieved. However, recently also examples of porous networks formed by covalent coupling on the surface have been reported. By the choice of the molecular building blocks, the dimensions of the network (pore size and pore to pore distance) can be controlled. In this way, the confinement properties of the individual pores can be tuned. In addition, the effect of the confined state on the hosting properties of the pores will be discussed in this review article. PMID- 26982213 TI - Light-Emitting Superstructures with Anion Effect: Coordination-Driven Self Assembly of Pure Tetraphenylethylene Metallacycles and Metallacages. AB - Herein, we describe the synthesis of tetraphenylethylene (TPE)-based di-Pt(II) acceptors as shown by X-ray analysis, which are subsequently used to construct pure TPE-based 2D hexagonal metallacycles and 3D drumlike metallacages with three different counteranions via coordination-driven self-assembly. The metallacycles possess alternating TPE donor and acceptor units that arrange 12 pendant phenyl rings along the outer perimeter that provide the basis for the observed aggregation-induced emission (AIE) behavior. The metallacages are similarly constructed from TPE-based building blocks, specifically two donors and four acceptors, resulting in eight freely rotating phenyl rings decorating the prismatic core. The fluorescence of these cages in dilute solution is intensified when hexane is added to CH2Cl2 solutions, indicative of aggregation-induced enhanced emission (AIEE). The influence of the counteranions on the photophysics of the assemblies was investigated. The molar absorption coefficients (epsilon), fluorescence emission intensities, and quantum yield (PhiF) values of the SCCs with different counteranions in CH2Cl2 follow the order PF6(-) > OTf(-) > NO3(-). The same trend also applies to the AIE characteristics of the SCCs in the aggregated state. The metal-organic materials developed here not only enrich a newly emerging library of self-assembly AIE metallacycles and cages that are promising candidates for turn-on fluorescent sensors and advanced optical devices but also provide an understanding of how structural factors affect the photophysics of AIE-active SCCs. PMID- 26982215 TI - Correlations of Electrophysiological Measurements with Identification Levels of Ancient Chinese Characters. AB - Studies of event-related potential (ERP) in the human brain have shown that the N170 component can reliably distinguish among different object categories. However, it is unclear whether this is true for different identifiable levels within a single category. In the present study, we used ERP recording to examine the neural response to different identification levels and orientations (upright vs. inverted) of Chinese characters. The results showed that P1, N170, and P250 were modulated by different identification levels of Chinese characters. Moreover, time frequency analysis showed similar results, indicating that identification levels were associated with object recognition, particularly during processing of a single categorical stimulus. PMID- 26982216 TI - Bactericidal Efficacy of Photodynamic Therapy Against Periodontal Pathogens in Periodontal Disease: A Systematic Review. AB - OBJECTIVE: The aim of this study was to assess the bactericidal efficacy of antimicrobial photodynamic dynamic therapy (aPDT) as an adjunct to scaling and root planing (SRP) against periodontal pathogens. BACKGROUND DATA: SRP followed by laser therapy has better clinical outcomes than conventional SRP alone. MATERIALS AND METHODS: The question addressed was "Does aPDT as an adjunct to SRP exhibit better bactericidal effect against periodontal pathogens than the use of SRP alone in periodontal disease?" MEDLINE((r))/PubMed, Embase, Scopus, Web of Science, and Google Scholar databases were searched from 1977 to December 2015, using different combinations of key words. Review articles, in vitro and experimental studies, and articles in languages other than English were excluded. RESULTS: Seventeen clinical studies were included. Laser wavelengths and duration of irradiation ranged between 470 and 810 nm and 60 and 300 sec, respectively. All studies showed that aPDT application was effective in reducing the counts of periodontal microbes at follow-up. Four studies showed significantly reduced bacterial counts for aPDT as an adjunct to SRP compared with SRP alone. Thirteen studies showed comparable reduction in the counts of periodontal bacteria when aPDT alone or as an adjunct to SRP was compared with SRP alone. CONCLUSIONS: The bactericidal efficacy of aPDT as an adjunct to SRP against periodontal pathogens in periodontal disease remains debatable. PMID- 26982217 TI - Trajectories of Depressive Symptoms in Older Adults and Risk of Dementia. AB - IMPORTANCE: Depression has been identified as a risk factor for dementia. However, most studies have measured depressive symptoms at only one time point, and older adults may show different patterns of depressive symptoms over time. OBJECTIVE: To investigate the association between trajectories of depressive symptoms and risk of dementia in older adults. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort investigation of black and white community-dwelling older adults in the Health, Aging, and Body Composition study. Participants were enrolled between May 1997 and June 1998 and followed up through 2001-2002. The dates of this analysis were September 2014 to December 2015. The setting was community research centers in Memphis, Tennessee, and Pittsburgh, Pennsylvania. Trajectories of depressive symptoms were assessed from baseline to year 5. Symptoms were measured with the Center for Epidemiologic Studies Depression Scale Short Form, and trajectories were calculated using latent class growth curve analysis. MAIN OUTCOMES AND MEASURES: Incident dementia through year 11, determined by dementia medication use, hospital records, or significant cognitive decline (>=1.5 SD race-specific decline on the Modified Mini-Mental State Examination). We examined the association between depressive symptom trajectories and dementia incidence using Cox proportional hazards regression models adjusted for demographics, health factors that differed between groups, and cognition during the depressive symptom assessment period (baseline to year 5). RESULTS: The analytic cohort included 2488 black and white older adults with repeated depressive symptom assessments from baseline to year 5 who were free of dementia throughout that period. Their mean (SD) age at baseline was 74.0 (2.8) years, and 53.1% (n = 1322) were female. The following 3 depressive symptom trajectories were identified: consistently minimal symptoms (62.0% [n = 1542] of participants), moderate and increasing symptoms (32.2% [n = 801] of participants), and high and increasing symptoms (5.8% [n = 145] of participants). Compared with the consistently minimal trajectory, having a high and increasing depressive symptom trajectory was associated with significantly increased risk of dementia (fully adjusted hazard ratio, 1.94; 95% CI, 1.30-2.90), while the moderate and increasing trajectory was not associated with risk of dementia after full adjustment. Sensitivity analyses indicated that the high and increasing trajectory was associated with dementia incidence, while depressive symptoms at individual time points were not. CONCLUSIONS AND RELEVANCE: Older adults with a longitudinal pattern of high and increasing depressive symptoms are at high risk for dementia. Individuals' trajectory of depressive symptoms may inform dementia risk more accurately than one-time assessment of depressive symptoms. PMID- 26982220 TI - Correction: Nanobodies: site-specific labeling for super-resolution imaging, rapid epitope-mapping and native protein complex isolation. PMID- 26982221 TI - Editorial comments. PMID- 26982222 TI - From the FDA: Asthma inhalers recalled. PMID- 26982218 TI - "Stockpile" of Slight Transcriptomic Changes Determines the Indirect Genotoxicity of Low-Dose BPA in Thyroid Cells. AB - Epidemiological and experimental data highlighted the thyroid-disrupting activity of bisphenol A (BPA). Although pivotal to identify the mechanisms of toxicity, direct low-dose BPA effects on thyrocytes have not been assessed. Here, we report the results of microarray experiments revealing that the transcriptome reacts dynamically to low-dose BPA exposure, adapting the changes in gene expression to the exposure duration. The response involves many genes, enriching specific pathways and biological functions mainly cell death/proliferation or DNA repair. Their expression is only slightly altered but, since they enrich specific pathways, this results in major effects as shown here for transcripts involved in the DNA repair pathway. Indeed, even though no phenotypic changes are induced by the treatment, we show that the exposure to BPA impairs the cell response to further stressors. We experimentally verify that prolonged exposure to low doses of BPA results in a delayed response to UV-C-induced DNA damage, due to impairment of p21-Tp53 axis, with the BPA-treated cells more prone to cell death and DNA damage accumulation. The present findings shed light on a possible mechanism by which BPA, not able to directly cause genetic damage at environmental dose, may exert an indirect genotoxic activity. PMID- 26982223 TI - From the FDA: New drug approved to reduce stroke. PMID- 26982224 TI - From the CDC: Influenza is hitting 37 states. PMID- 26982225 TI - Exercise and Circulation in Health and Disease. PMID- 26982219 TI - Stereotyped spatial patterns of functional synaptic connectivity in the cerebellar cortex. AB - Motor coordination is supported by an array of highly organized heterogeneous modules in the cerebellum. How incoming sensorimotor information is channeled and communicated between these anatomical modules is still poorly understood. In this study, we used transgenic mice expressing GFP in specific subsets of Purkinje cells that allowed us to target a given set of cerebellar modules. Combining in vitro recordings and photostimulation, we identified stereotyped patterns of functional synaptic organization between the granule cell layer and its main targets, the Purkinje cells, Golgi cells and molecular layer interneurons. Each type of connection displayed position-specific patterns of granule cell synaptic inputs that do not strictly match with anatomical boundaries but connect distant cortical modules. Although these patterns can be adjusted by activity-dependent processes, they were found to be consistent and predictable between animals. Our results highlight the operational rules underlying communication between modules in the cerebellar cortex. PMID- 26982226 TI - CME QUIZ. PMID- 26982227 TI - Take the time to teach to ensure the legacy and future of our profession. PMID- 26982228 TI - From the FDA: FDA approves Keppra. PMID- 26982229 TI - From the FDA: Breast scanning system receives second FDA regulatory approval. PMID- 26982230 TI - From the FDA: First drug device combined treatment for certain precancerous skin lesions approved. PMID- 26982231 TI - From the CDC: CDC urges caution to reduce workplace needlestick injuries. PMID- 26982232 TI - From the CDC: Pet reptiles pose health hazard. PMID- 26982233 TI - Geriatrics at Your Fingertips. PMID- 26982234 TI - 5-((3-Amidobenzyl)oxy)nicotinamides as Sirtuin 2 Inhibitors. AB - Derived from our previously reported human sirtuin 2 (SIRT2) inhibitors that were based on a 5-aminonaphthalen-1-yloxy nicotinamide core structure, 5-((3 amidobenzyl)oxy)nicotinamides offered excellent activity against SIRT2 and high isozyme selectivity over SIRT1 and SIRT3. Selected compounds also exhibited generally favorable in vitro absorption, distribution, metabolism, and excretion properties. Kinetic studies revealed that a representative SIRT2 inhibitor acted competitively against both NAD(+) and the peptide substrate, an inhibitory modality that was supported by our computational study. More importantly, two selected compounds exhibited significant protection against alpha-synuclein aggregation-induced cytotoxicity in SH-SY5Y cells. Therefore, 5-((3 amidobenzyl)oxy)nicotinamides represent a new class of SIRT2 inhibitors that are attractive candidates for further lead optimization in our continued effort to explore selective inhibition of SIRT2 as a potential therapy for Parkinson's disease. PMID- 26982235 TI - Recurrent implantation failure: a comprehensive review. AB - Successful pregnancy involves a synchronized, coordinated cross-talk between an embryo capable of implanting, and an endometrium enabling implantation. Recurrent implantation failure (RIF) refers to unsuccessful implantation after repeated transfers of morphologically good quality embryos into a normal uterus. The etiology for RIF can be attributed to the embryo itself, the mother or, in some cases, both. Despite extensive research on underlying causes for RIF, our understanding of this condition is still limited. With the evolving molecular technologies, efforts are focused on studying the implantation process itself, including the molecular aspects of endometrial-embryonic interactions, normal human embryonic development, and preimplantation genetic evaluation. This knowledge will pave the way toward new diagnostic and therapeutic strategies for RIF. In this article, we present a comprehensive review of our current knowledge on this topic. PMID- 26982236 TI - Forward thinking: where next for delirium prevention research? PMID- 26982237 TI - Nab-paclitaxel-induced cystoid macular edema in a patient with pre-existing optic neuropathy. AB - Paclitaxel is a widely used chemotherapy agent that has rarely been associated with ophthalmic toxicities. Cystoid macular edema is one such rare side effect of paclitaxel therapy. Its pathophysiology remains poorly understood. Here, we report on a 69-year-old woman who developed cystoid macular edema associated with the albumin-bound formulation of paclitaxel after several months of therapy for breast cancer. After 2 months of drug withdrawal, her vision improved and there was a significant improvement in the macular edema by imaging with spectral domain optical coherence tomography. Oncologists using taxane agents should be aware of this rare adverse outcome for timely patient referral to an ophthalmologist and appropriate treatment to preserve a patient's visual acuity. PMID- 26982238 TI - Schedule-dependent interaction between temsirolimus and cetuximab in head and neck cancer: a preclinical study. AB - Aberrant epidermal growth factor receptor (EGFR) signaling is associated with tumor growth in head and neck squamous cell carcinoma (HNSCC) and is a major focus of targeted therapy. The phosphatidylinositol-3-kinase/AKT/mammalian target of the rapamycin (PI3K/AKT/mTOR) signaling pathway is frequently mutated in HNSCC and is involved in disease progression and resistance to EGFR inhibitors. The aim of this study was to assess the antiproliferative effects of mTOR inhibition (temsirolimus) combined with the anti-EGFR monoclonal antibody cetuximab, administered according to different combination schedules. Antiproliferative effects of the combination of temsirolimus and cetuximab were determined on the representative HNSCC CAL33 cell line (PI3KCA H1047R mutated and K-RAS wild-type). In addition, key proteins related to the EGFR pathway (pEGFR/EGFR, pAKT/AKT) and the mTOR pathway (p-p70S6K1, p4E-BP1) were determined to explain the cytotoxic effects. Temsirolimus and cetuximab showed a synergistic effect when administered in combination. Supra-additive effect was lost when the two drugs were administered sequentially, irrespective of which drug was administered first. Synergistic effect of the combination was corroborated by a marked downregulation of pEGFR, significant downregulation of pAKT expression, and a marked diminution of p70S6K1 and p4E-BP1 expression. Our study demonstrated a synergistic effect of temsirolimus and cetuximab administered in combination, well illustrated by a simultaneous blockade of intracellular signaling pathways regulating cell proliferation and survival. These results establish the notion of a schedule dependency for the combined treatment, which can be of importance at the clinical level. PMID- 26982239 TI - A successful approach to overcome imatinib-induced skin toxicity in a GIST patient. AB - Since the introduction of tyrosine kinase inhibitors in gastrointestinal stromal tumor patients, the median survival of patients has increased from less than 1 to more than 5 years. The chronic use of a tyrosine kinase inhibitor has an impact on quality of life because of its toxicity. Adequate supportive therapy is therefore important. We describe a female patient with a metastatic gastrointestinal stromal tumor. During treatment with the c-KIT inhibitor imatinib, she developed severe therapy-limiting skin toxicity. After several different supportive attempts, the combination of doxycycline and clemastine proved to be the solution, enabling successful chronic treatment with imatinib. Chronic use of doxycycline and clemastine is useful in the management of skin toxicity caused by c-KIT inhibitors, enabling the needed long-term use of these kind of anticancer drugs without hampering the quality of life. PMID- 26982241 TI - Coordination complexes of niobium and tantalum pentahalides with a bulky NHC ligand. AB - The 1 : 1 molar reactions of niobium and tantalum pentahalides with the monodentate NHC ligand 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (Ipr), in toluene (or benzene) at ca. 80 degrees C, afforded the complexes NbX5(Ipr) (X = F, ; Br, ) and TaX5(Ipr) (X = F, ; Cl, ; Br, ), in generally good yields. Complexes represent uncommon cases of stable NHC adducts of metal halides with the metal in an oxidation state higher than +4, and also rare examples of Nb-NHC and Ta-NHC bonding systems. In particular, the X-ray molecular structure determined for provides the unprecedented crystallographic characterization of a tantalum compound with a monodentate NHC ligand. DFT results indicate that the metal-carbon bond in is a purely sigma one. According to NMR studies ((1)H, (13)C, (93)Nb), the formation of , , , as well as the previously communicated NbCl5(Ipr), , proceeded with the intermediacy of [MX6](-) salts, presumably due to steric reasons. On the other hand, the intermediate formation of MF6(-) in the pathways to and was not observed, according to (19)F (and (93)Nb in the case of ) NMR. DFT calculations were carried out in order to shed light on structural and mechanistic aspects, and allowed to trace possible reaction routes. PMID- 26982240 TI - Hearing, reactive metabolite formation, and oxidative stress in cochleae after a single acute overdose of acetaminophen: an in vivo study. AB - CONTEXT: Although the liver is the primary target organ in acetaminophen (APAP) toxicity, other organs are affected. Previous data suggested that chronic APAP abuse can be ototoxic and the mechanism involves APAP-induced oxidative stress and reactive metabolite (N-acetyl-p-benzoquinone imine, NAPQI)-induced endoplasmic reticulum stress. However, the effect of a single acute overdose on hearing has not been tested. OBJECTIVES: To determine if a single acute APAP overdose causes hearing damage, and to explore possible mechanisms of APAP ototoxicity. MATERIALS AND METHODS: Male C57BL/6 J mice were treated with a single human-relevant overdose of APAP (300 mg APAP per kg bodyweight). Blood, liver and cochleae were harvested at 0, 2, 6 and 24 h post-APAP. In some mice, auditory brainstem responses (ABRs) to a range of frequencies were measured at 24 h. The furosemide plus kanamycin (FS/K) model of drug ototoxicity was used as a positive control for hearing loss. NAPQI formation after APAP was assessed by measuring glutathione depletion and covalent protein binding, and oxidative stress was assessed by measuring glutathione disulfide. RESULTS: There was no evidence of reactive metabolite formation or hearing loss after a single overdose of APAP at a clinically relevant dose. However, there was a transient increase in oxidative stress. DISCUSSION: Although a single acute overdose was not ototoxic, there was evidence of oxidative stress which may support a role for oxidative stress in hearing loss due to chronic APAP abuse. CONCLUSION: A single human relevant acute overdose of APAP causes transient oxidative stress in cochleae but not hearing loss. PMID- 26982242 TI - Asymptomatic faecal carriage of ESBL producing enterobacteriaceae in Hungarian healthy individuals and in long-term care applicants: A shift towards CTX-M producers in the community. AB - Background Faecal carriage of extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae in healthy individuals was examined and compared to previous results obtained in such individuals a few years earlier. Methods Faecal samples from 779 individuals screened for employment purposes and from 225 applicants to long-term care (LTC) were screened between November 2013 and May 2014. Results The overall rate of faecal carriage was 3.0% (30/1004). The carriage rate was significantly higher in applicants for LTC (5.3% vs 2.3%; p = 0.019). All isolates carried CTX-M ESBLs, with an overwhelming dominance of blaCTX-M-15 (84.4%) in both groups and in both E. coli and Klebsiella pneumoniae. Conclusions The prevalences were comparable to those in the earlier study, but a marked decrease of the diversity of ESBL genes in E. coli from the employment screening group was found, suggesting that the ESBL-producing isolates originating from diverse sources are being replaced by highly successful blaCTX-M-15 producing strains. PMID- 26982245 TI - Differential Outcomes of Sleep Problems in Children with and Without Special Health Care Needs: Australian Population Study. AB - OBJECTIVE: In a nationally representative sample of Australian children at ages 4 to 5, 6 to 7, 8 to 9, 10 to 11, and 12 to 13 years, we aim to examine the (1) prevalence of sleep problems in children with and without special health care needs (SHCN); (2) association of sleep problems with child behavior, health related quality of life, learning and parent mental health outcomes; and (3) whether associations between sleep problems and outcomes among children with SHCN are larger in magnitude than among children without SHCN. METHOD: Biennial data from 5 waves of the Growing Up in Australia Study. EXPOSURES: Child SHCN as defined by the Children Special Health Care Needs Screener and parent report of child sleep problem. OUTCOMES: Child: parent-reported health-related quality of life; parent-reported and teacher-reported behavior; nonverbal and verbal cognition and teacher-reported learning. Parent: self-report mental health. ANALYSIS: Logistic and linear regression, adjusted for family socioeconomic position. RESULTS: Children with SHCN were more likely to have sleep problems, odds ranging from 2.0 (95% confidence interval [CI], 1.6-2.5) at 4 to 5 years to 3.9 (95% CI, 3.0-5.2) at 8 to 9 years. Compared with children who had neither condition, those with either sleep problems or SHCN had similarly poor child and maternal outcomes. Children with both SHCN and sleep problems had the poorest outcomes at every age (all p < .001). Tests of interaction found sleep problems are more strongly associated with poorer behavior and health-related quality of life among children with SHCN than those without during the preschool and early school years. CONCLUSION: Sleep problems in children with SHCN are common and are associated with poorer child and maternal outcomes. These associations are stronger for poorer behavior and health-related quality of life among children with SHCN than those without during the preschool and early school years. PMID- 26982243 TI - Shiga Toxin-Producing Escherichia coli O157, England and Wales, 1983-2012. AB - We evaluated clinical Shiga toxin-producing Escherichia coli O157 infections in England and Wales during 1983-2012 to describe changes in microbiological and surveillance methods. A strain replacement event was captured; phage type (PT) 2 decreased to account for just 3% of cases by 2012, whereas PT8 and PT21/28 strains concurrently emerged, constituting almost two thirds of cases by 2012. Despite interventions to control and reduce transmission, incidence remained constant. However, sources of infection changed over time; outbreaks caused by contaminated meat and milk declined, suggesting that interventions aimed at reducing meat cross-contamination were effective. Petting farm and school and nursery outbreaks increased, suggesting the emergence of other modes of transmission and potentially contributing to the sustained incidence over time. Studies assessing interventions and consideration of policies and guidance should be undertaken to reduce Shiga toxin-producing E. coli O157 infections in England and Wales in line with the latest epidemiologic findings. PMID- 26982244 TI - Bundled Payments for Surgical Colectomy Among Medicare Enrollees: Potential Savings vs the Need for Further Reform. AB - IMPORTANCE: The Bundled Payments for Care Improvement Initiative was proposed by the Centers for Medicare and Medicaid Services to obtain and reward a greater value of care. Still in its infancy, little is known regarding the potential effects of the Bundled Payments for Care Improvement Initiative on hospital payments and net margins. OBJECTIVE: To investigate the potential effects of the Bundled Payments for Care Improvement Initiative on net margins among Medicare patients undergoing colectomy at a tertiary care hospital. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional retrospective analysis conducted in October 2015. Medicare enrollees undergoing an elective colectomy at a large tertiary care hospital between January 1, 2009, and December 31, 2013, were identified using diagnosis-related group and International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. MAIN OUTCOMES AND MEASURES: Multivariable linear regression analysis was performed to calculate risk adjusted, diagnosis-related group-specific hospital costs and payments for each patient. Net margins were calculated as the difference between total hospital costs and total payments received. RESULTS: A total of 821 Medicare enrollees underwent an elective colectomy and met inclusion criteria. The median age of patients was 69 years (interquartile range [IQR], 65-74 years), with 51.3% being female. Postoperative complications were observed among 27.5% of patients (n = 226) and the median length of stay was 8 days (IQR, 5-14 days). The median risk adjusted cost among all patients was $24 951 (IQR, $16 197-$38 922). Risk adjusted costs were higher among patients who developed a postoperative complication ($42 537 [IQR, $28 918-$72 316] vs $22 829 [IQR, $14 820-$26 150]; P < .001) and among patients with an observed to expected length of stay greater than 1 ($36 826 [IQR, $24 951-$65 016] vs $16 197 [IQR, $14 182-$23 998]; P < .001). The median payment under the fee-for-service structure was $29 603 (IQR, $17 742-$44 819), resulting in an overall net margin of $3177 (IQR, -$1692 to $10 773), with 33.7% of patients (n = 277) contributing to an overall negative margin. In contrast, under the bundled payment paradigm, the net margin per patient was $3442 (IQR, -$9311 to $8203), with 41.7% of patients (n = 342) contributing to a net negative margin. CONCLUSIONS AND RELEVANCE: Postoperative complications, length of stay, and total hospital costs were strongly associated with hospital costs. Payments under the bundled payments system were lower and the proportion of patients contributing to a net negative margin increased. Further study is warranted to define the effect of bundled payments on quality of care and hospital finances. PMID- 26982247 TI - Sleep and Self-Regulation from Birth to 7 Years: A Retrospective Study of Children with and Without Attention-Deficit Hyperactivity Disorder at 8 to 9 Years. AB - OBJECTIVE: To examine mean level differences and longitudinal and reciprocal relations among behavioral sleep problems, emotional dysregulation, and attentional regulation across early childhood for children with and without attention-deficit hyperactivity disorder (ADHD) at 8 to 9 years. METHOD: This study used data from Growing Up in Australia: The Longitudinal Study of Australian Children (LSAC)-Infant Cohort (n = 4,109 analyzed). Children with and without ADHD were identified at age 8 to 9 years via parent report of ADHD diagnosis and the 5-item Inattention-Hyperactivity subscale from the Strengths and Difficulties Questionnaire. Maternal report of child sleep problems and self regulation was collected at 0 to 1, 2 to 3, 4 to 5, and 6 to 7 years of age. Analysis of variance was used to compare mean level differences in sleep problems and emotional and attentional regulation by ADHD group. Longitudinal structural equation modeling examined the relations among sleep and self-regulation across time in children with and without ADHD. RESULTS: Children with ADHD had persistently elevated levels of sleep problems (from infancy) and emotional and attentional dysregulation compared to controls (from 2 to 3 years of age). Sleep problems, emotional dysregulation, and attentional regulation were stable over time for both groups. Sleep problems were associated with greater emotional dysregulation 2 years later from 2 to 3 years of age for both groups, which in turn was associated with poorer attentional regulation. There was no direct relationship between sleep problems and later attentional regulation. CONCLUSION: Sleep problems in children with and without ADHD are associated with emotional dysregulation, which in turn contributes to poorer attentional functioning. This study highlights the importance of assessing and managing sleep problems in young children. PMID- 26982246 TI - Prevalence of Diagnosed Sleep Disorders and Related Diagnostic and Surgical Procedures in Children with Autism Spectrum Disorders. AB - OBJECTIVE: Sleep disorders are common and important comorbid conditions in children with autism spectrum disorder (ASD) and can contribute to cognitive and behavioral problems. Sleep-disordered breathing (SDB) is a diagnosable and treatable cause of behavioral problems in children. We aimed to quantify the relative risk for children with ASD versus controls of being diagnosed with sleep disorders including SDB and undergoing related diagnostic and surgical procedures. METHOD: This retrospective case-cohort study included 48,762 children with ASD aged 2 to 18 years enrolled in the military health system (MHS) from 2000 to 2013. Children with ASD were matched 1:5 by birthdate, sex, and enrollment time to children without an ASD diagnosis. The MHS database was queried for International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for sleep disorders or ICD-9-CM and Current Procedural Terminology codes for diagnostic and surgical procedures. Relative risks (RR) and 95% confidence intervals (CI) were determined with binary Poisson regression conditional on the match and adjusting for confounders. RESULTS: Children with ASD were at higher risk of receiving any sleep disorder diagnosis (RR: 1.97 [95% CI, 1.91-2.02]) including SDB (RR: 1.96 [95% CI, 1.88-2.05]). Children with ASD also were at increased risk of undergoing polysomnography (RR: 3.74 [95% CI, 3.56-3.93]) and sleep disorder-related surgery (RR: 1.50 [95% CI, 1.46-1.54]). CONCLUSION: Children with ASD are more likely to be given a sleep disorder diagnosis including SDB and are more likely to undergo related diagnostic and surgical procedures compared with controls without ASD. PMID- 26982248 TI - Hydrogen sulfide attenuates ferric chloride-induced arterial thrombosis in rats. AB - Hydrogen sulfide (H2S) is a novel gaseous transmitter, regulating a multitude of biological processes in the cardiovascular and other systems. However, it remains unclear whether it exerts any effect on arterial thrombosis. In this study, we examined the effect of H2S on ferric chloride (FeCl3)-induced thrombosis in the rat common carotid artery (CCA). The results revealed a decrease of the H2S producing enzyme cystathionine gamma-lyase (CSE) expression and H2S production that persisted until 48 h after FeCl3 application. Intriguingly, administration with NaHS at appropriate regimen reduced the thrombus formation and enhanced the blood flow, accompanied with the alleviation of CSE and CD31 downregulation, and endothelial cell apoptosis in the rat CCA following FeCl3 application. Moreover, the antithrombotic effect of H2S was also observed in Rose Bengal photochemical model in which the development of thrombosis is contributed by oxidative injury to the endothelium. The in vitro study demonstrated that the mRNA and protein expression of CSE, as well as H2S production, was decreased in hydrogen peroxide (H2O2)-treated endothelial cells. Exogenous supplement of NaHS and CSE overexpression consistently alleviated the increase of cleaved caspase-3 and endothelial cell damage caused by H2O2. Taken together, our findings suggest that endogenous H2S generation in the endothelium may be impaired during arterial thrombosis and that modulation of H2S, either exogenous supplement or boost of endogenous production, may become a potential venue for arterial thrombosis therapy. PMID- 26982249 TI - An Analysis of Complications, Quality of Life, and Nutritional Index After Laparoscopic Distal Pancreatectomy with Regard to Spleen Preservation. AB - BACKGROUND: Whether splenectomy is adverse or spleen preservation offers significant advantages in distal pancreatic resection is unclear. The aim was to compare the early/late clinical results and the functional outcomes in terms of quality of life (QoL) and nutrition between conventional laparoscopic distal pancreatectomy (LDP) and laparoscopic spleen-preserving distal pancreatectomy (LSPDP). STUDY DESIGN: Clinical data and computed tomography findings of 111 laparoscopic distal resections (79 LDPs and 32 LSPDPs) between 1999 and 2012 were retrospectively reviewed. QoL was assessed by the EORTC QLQ-C30. Body mass index and biochemical tests were examined as nutritional indices. Comparative analysis was done. RESULTS: The mean follow-up was 25 months. The operation time was shorter in LSPDP (127.9 minutes vs. 158.0 minutes, P < .001). The lesion size was larger in LDP (36.8 mm vs. 27.2 mm, P < .01). Mucinous cystic neoplasm (MCN) was the most common diagnosis in LDP and intraductal papillary mucinous neoplasm (IPMN) in LSPDP. Early results showed similar hospital days and infection episodes. Nonvascular complications were more frequent in LDP owing to more fluid collections (43.0% vs. 21.9%, P = .04). The ISGPF grade B/C pancreatic fistula rates were similar (27.8% in LDP vs. 25.0% in LSPDP, P = .760). Vascular complications were more frequent in LSPDP (64.5% vs. 26.0%, P < .01). Excluding some fluid collections, none required a specific treatment. Late results demonstrated no differences in nonvascular results. Vascular complications were more frequent in LSPDP (65.6% vs. 4.2%, P < .01). The vascular complications did not require any specific treatment or have any serious sequelae. There was no overwhelming postsplenectomy infection. QoL and nutritional indices showed no difference. QoL decreased at discharge and recovered from 3 months thereafter. Nutritional indices showed a similar pattern. CONCLUSION: LDP is associated with more fluid collections and LSPDP with more vascular complications, all with a minimal clinical impact. Both methods had similar functional outcomes. Either LDP or LSPDP could be performed depending on the indication and surgeon's experiences considering the comparable results. PMID- 26982251 TI - Fetal Implications of Diagnostic Radiation Exposure During Pregnancy: Evidence based Recommendations. AB - The purpose of this article is to review the fetal and long-term implications of diagnostic radiation exposure during pregnancy. Evidence-based recommendations for radiologic imaging modalities utilizing exposure of diagnostic radiation during pregnancy, including conventional screen-film mammography, digital mammography, tomosynthesis, and contrast-enhanced mammography are described. PMID- 26982252 TI - Magnetic Resonance Imaging of the Breast. AB - Magnetic resonance imaging (MRI) is an imaging modality that is complementary to mammography and ultrasound in the evaluation of breast disease. It has demonstrated utility in many clinical scenarios, and shows promise in others. In this chapter, we discuss the indications and contraindications to MRI. We include information that is essential for the clinician to understand when considering a breast MRI for his patient. PMID- 26982250 TI - Tobacco Mosaic Virus Delivery of Phenanthriplatin for Cancer therapy. AB - Phenanthriplatin, cis-[Pt(NH3)2Cl(phenanthridine)](NO3), is a cationic monofunctional DNA-binding platinum(II) anticancer drug candidate with unusual potency and cellular response profiles. Its in vivo efficacy has not yet been demonstrated, highlighting the need for a delivery system. Here we report tobacco mosaic virus (TMV) as a delivery system for phenanthriplatin. TMV forms hollow nanotubes with a polyanionic interior surface; capitalizing on this native structure, we developed a one-step phenanthriplatin loading protocol. Phenanthriplatin release from the carrier is induced in acidic environments. This delivery system, designated PhenPt-TMV, exhibits matched efficacy in a cancer cell panel compared to free phenanthriplatin. In vivo tumor delivery and efficacy were confirmed by using a mouse model of triple negative breast cancer. Tumors treated with PhenPt-TMV were 4* smaller than tumors treated with free phenanthriplatin or cisplatin, owing to increased accumulation of phenanthriplatin within the tumor tissue. The biology-derived TMV delivery system may facilitate translation of phenanthriplatin into the clinic. PMID- 26982253 TI - Preface. PMID- 26982254 TI - Molecular Imaging and Its Role in the Management of Breast Cancer. AB - Molecular imaging plays an important role in the management of breast cancer. An understanding of all the available technologies and their appropriate use are important to navigate patient care in this evolving specialty. The information gained from molecular imaging will impact patient care and may become a springboard for molecular therapy. PMID- 26982256 TI - Ultrafast Structural Evolution and Chromophore Inhomogeneity inside a Green Fluorescent-Protein-Based Ca(2+) Biosensor. AB - Understanding excited-state structural dynamics of fluorescent-protein-based biosensors for Ca(2+) imaging is crucial for developing new in vivo Ca(2+) indicators and advancing bioimaging. We implemented wavelength-tunable femtosecond stimulated Raman spectroscopy (FSRS) with a 530 nm Raman pump to uncover the working mechanism of an intensiometric fluorescent-protein biosensor, G-GECO1.1, highlighting the deprotonation process of its embedded chromophore. Besides confirming the dynamic difference of excited-state proton transfer (ESPT) in the Ca(2+)-free/bound protein, we revealed a chromophore two-ring twisting process with time constants of 36/60 ps that competes with ESPT. In contrast with FSRS data collected using the 800 nm Raman pump, the bluer Raman pump enables us to access a subset of reactant population with partially deprotonated character that exhibits an additional ESPT component on the ~5 ps time scale. These findings provide deep mechanistic insights into the inhomogeneity and subpopulation-specific conformational dynamics of biosensor chromophores, which will guide the rational design of improved biosensors for metal ion imaging. PMID- 26982255 TI - Shiga Toxin 1-Producing Shigella sonnei Infections, California, United States, 2014-2015. AB - Shiga toxins (Stx) are primarily associated with Shiga toxin-producing Escherichia coli and Shigella dysenteriae serotype 1. Stx production by other shigellae is uncommon, but in 2014, Stx1-producing S. sonnei infections were detected in California. Surveillance was enhanced to test S. sonnei isolates for the presence and expression of stx genes, perform DNA subtyping, describe clinical and epidemiologic characteristics of case-patients, and investigate for sources of infection. During June 2014-April 2015, we identified 56 cases of Stx1 producing S. sonnei, in 2 clusters. All isolates encoded stx1 and produced active Stx1. Multiple pulsed-field gel electrophoresis patterns were identified. Bloody diarrhea was reported by 71% of case-patients; none had hemolytic uremic syndrome. Some initial cases were epidemiologically linked to travel to Mexico, but subsequent infections were transmitted domestically. Continued surveillance of Stx1-producing S. sonnei in California is necessary to characterize its features and plan for reduction of its spread in the United States. PMID- 26982257 TI - Chiral Asymmetric Structures in Aspartic Acid and Valine Crystals Assessed by Atomic Force Microscopy. AB - Structures of crystallized deposits formed by the molecular self-assembly of aspartic acid and valine on silicon substrates were imaged by atomic force microscopy. Images of d- and l-aspartic acid crystal surfaces showing extended molecularly flat sheets or regions separated by single molecule thick steps are presented. Distinct orientation surfaces were imaged, which, combined with the single molecule step size, defines the geometry of the crystal. However, single molecule step growth also reveals the crystal chirality, i.e., growth orientations. The imaged ordered lattice of aspartic acid (asp) and valine (val) mostly revealed periodicities corresponding to bulk terminations, but a previously unreported molecular hexagonal lattice configuration was observed for both l-asp and l-val but not for d-asp or d-val. Atomic force microscopy can then be used to identify the different chiral forms of aspartic acid and valine crystals. PMID- 26982258 TI - Left ventricular free wall rupture complicating acute STEMI. PMID- 26982259 TI - Muscle co-activation and its influence on running performance and risk of injury in elite Kenyan runners. AB - The relationship between muscle co-activation and energy cost of transport and risk of injury (initial loading rate and joint stiffness) has not been jointly studied. Fourteen elite Kenyan male runners were tested at two speeds (12 and 20 km . h-1), where oxygen consumption, kinematic, kinetic and electromyography were recorded. Electromyography of seven lower limb muscles was recorded. Pre activation and ground contact of agonist:antagonist co-activation was determined. All muscles displayed higher activity during pre-activation except rectus femoris (RF). Conversely, no differences were found during ground contact except for higher biceps femoris (BF) at 20 km . h-1. Knee stiffness was correlated to RF-BF co-activation during both pre-activation and ground contact at both running speeds. However, energy cost of transport was only positively correlated to the above-mentioned muscle pairs at 20 km . h-1 (r = 0620, P = 0.032; r = 0.682, P = 0.015, respectively). These findings emphasise the influence of neuromuscular control and performance and its support to musculoskeletal system to optimise function and modulate risk of injury. Further, neuromuscular activity during terminal swing is also important and necessary to execute and maintain performance. PMID- 26982260 TI - Predicting Outcomes after Severe and Moderate Traumatic Brain Injury: An External Validation of Impact and Crash Prognostic Models in a Large Spanish Cohort. AB - Prognostic models that were developed by the International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) study group and the Corticosteroid Randomization After Signification Head injury (CRASH) collaborators are the most commonly used prognostic models for outcome after traumatic brain injury (TBI). Although they have been considered to be useful tools in clinical practice, a continuous process of external validation in recent cohorts of different populations is necessary. The objective of this study was to determine the external validity and compare the IMPACT and CRASH-refitted models for prediction of outcomes after moderate or severe TBI in a non-selected 1301 patient Spanish cohort. We studied discrimination, calibration, and overall fit as external validation measures. Excellent discrimination was indicated (area under the curve [AUC] 0.78-0.87) by the higher values in the validation than in the development sample for both models and outcomes. Calibration revealed that IMPACT models, in general, predict lower probabilities of both outcomes (mortality and disability). In contrast, CRASH-refitted models provided higher predicted probabilities than those observed. We can conclude that both models demonstrate an adequate performance in our representative traumatic brain Mediterranean population. Therefore, these models can be sensibly applied in our clinical practice so long as their limitations are observed during individual outcome prediction. PMID- 26982261 TI - Deciphering the mechanism behind the varied binding activities of COXIBs through Molecular Dynamic Simulations, MM-PBSA binding energy calculations and per residue energy decomposition studies. AB - COX-2 is a well-known drug target in inflammatory disorders. COX-1/COX-2 selectivity of NSAIDs is crucial in assessing the gastrointestinal side effects associated with COX-1 inhibition. Celecoxib, rofecoxib, and valdecoxib are well known specific COX-2 inhibiting drugs. Recently, polmacoxib, a COX-2/CA-II dual inhibitor has been approved by the Korean FDA. These COXIBs have similar structure with diverse activity range. Present study focuses on unraveling the mechanism behind the 10-fold difference in the activities of these sulfonamide containing COXIBs. In order to obtain insights into their binding with COX-2 at molecular level, molecular dynamics simulations studies, and MM-PBSA approaches were employed. Further, per-residue decomposition of these energies led to the identification of crucial amino acids and interactions contributing to the differential binding of COXIBs. The results clearly indicated that Leu338, Ser339, Arg499, Ile503, Phe504, Val509, and Ser516 (Leu352, Ser353, Arg513, Ile517, Phe518, Val523, and Ser530 in PGHS-1 numbering) were imperative in determining the activity of these COXIBs. The binding energies and energy contribution of various residues were similar in all the three simulations. The results suggest that hydrogen bond interaction between the hydroxyl group of Ser516 and five-membered ring of diarylheterocycles augments the affinity in COXIBs. The SAR of the inhibitors studied and the per-residue energy decomposition values suggested the importance of Ser516. Additionally, the positive binding energy obtained with Arg106 explains the binding of COXIBs in hydrophobic channel deep in the COX-2 active site. The findings of the present work would aid in the development of potent COX-2 inhibitors. PMID- 26982262 TI - Do normal-weight women pregnant with twins are at the lowest risk of developing preeclampsia? AB - OBJECTIVE: To determine the relation between preeclampsia (PE) and pregravid body mass index (BMI) in twin pregnancy. METHODS: Retrospective cohort study of 542 women pregnant with twins. RESULTS: Forty-nine patients developed PE (9%). Underweight, overweight and obese women were at a higher risk of PE than normal weight mothers. There was no linear (p = 0.7) but significant U-shaped relation between BMI and PE (p < 0.006). The lowest risk of PE development was related to BMI of about 23 kg/m2. CONCLUSIONS: Nonlinear relation between PE occurrence and BMI suggests that using homogeneous PE risks of BMI groups may be incorrect. PMID- 26982265 TI - GPs succumb to patient pressure as antibiotic prescribing surges by 40 per cent. AB - The proportion of patients being given antibiotics for coughs and colds has soared by 40 per cent since the millennium, amid warnings the public is developing a worrying reliance on the drugs. PMID- 26982263 TI - Can gaze-contingent mirror-feedback from unfamiliar faces alter self-recognition? AB - This study focuses on learning of the self, by examining how human observers update internal representations of their own face. For this purpose, we present a novel gaze-contingent paradigm, in which an onscreen face mimics observers' own eye-gaze behaviour (in the congruent condition), moves its eyes in different directions to that of the observers (incongruent condition), or remains static and unresponsive (neutral condition). Across three experiments, the mimicry of the onscreen face did not affect observers' perceptual self-representations. However, this paradigm influenced observers' reports of their own face. This effect was such that observers felt the onscreen face to be their own and that, if the onscreen gaze had moved on its own accord, observers expected their own eyes to move too. The theoretical implications of these findings are discussed. PMID- 26982264 TI - Claudin 1 Expression Levels Affect miRNA Dynamics in Human Basal-Like Breast Cancer Cells. AB - Deemed a putative tumor suppressor in breast cancer, the tight junction protein claudin 1 has now been shown to be highly expressed in the basal-like molecular subtype. Moreover, recent in vitro studies show that claudin 1 can regulate breast cancer cell motility and proliferation. Herein, we investigated whether microRNA (miRNA) dysregulation is associated with alterations in the level of claudin 1. Using next-generation sequencing (NGS), we identified seven miRNAs (miR-9-5p, miR-9-3p, let-7c, miR-127-3p, miR-99a-5p, miR-129-5p, and miR-146a-5p) that were deregulated as a consequence of claudin 1 overexpression in the MDA MB231 human breast cancer (HBC) cell line. Most of these miRNAs have been associated with tumor suppression in a variety of cancers, including breast cancer. Moreover, through gene expression profiling analysis, we identified epithelial-mesenchymal transition-related genes, including platelet-derived growth factor receptor-beta (PDGFRB) and cadherin 1 (CDH1, E cadherin), whose downregulation correlated with claudin 1 overexpression. Collectively, we show for the first time that in HBC, claudin 1 can alter the dynamics of a number of miRNAs involved in tumor progression. Our data suggest that the dysregulated expression of these miRNAs, in conjunction with the high claudin 1 levels, could serve as a useful biomarker that identifies a subset of tumors within the poorly characterized basal-like subtype of breast cancer. Further studies are warranted to determine the role of these miRNAs in facilitating the function of claudin 1 in breast cancer. PMID- 26982266 TI - US study shows nurses benefit from naturally lit wards. AB - Nurses perform more effectively when they have access to windows and natural daylight, a US study has found. PMID- 26982267 TI - News digest August 05 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26982268 TI - Nurses applauded for work with anxiety disorder patients. AB - Two general nurses have been recognised for their outstanding achievement in treating more than 70 patients with the anxiety disorder cyberchondria. PMID- 26982269 TI - Researchers to explore possible benefits of exercise for people with leg ulcers. AB - Scientists are examining whether exercise can help improve outcomes for patients with leg ulcers caused by chronic venous insufficiency. PMID- 26982270 TI - News digest August 04 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26982271 TI - Health Education England invites nurses to share their views on education and training. AB - Health Education England (HEE) said it wants to hear nurses' views on how their education and training might be improved. PMID- 26982272 TI - Nurses in Northern Ireland feel blamed for A&E problems, says RCN. AB - Emergency nurses in Northern Ireland believe they are being scapegoated for delays in A&E departments when these are the result of broader failings in the health and social care system, the RCN has warned. PMID- 26982274 TI - Spectre of industrial action shows extent of pay-freeze anger among NHS nurses and midwives. AB - Nursing and health unions plan to ballot members on industrial action over pay during August and September. PMID- 26982273 TI - News digest August 01 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26982275 TI - Lib Dems move closer to making minimum nurse-patient staffing ratios law in Wales. AB - Draft legislation that paves the way for Wales to become the first country in the UK to set mandatory nurse-patient staffing ratios has been published. PMID- 26982276 TI - News digest July 31 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26982277 TI - Global mental health: anthropological perspectives, edited by Brandon A. Kohrt and Emily Mendenhall. PMID- 26982278 TI - Does the Bovine Pre-Ovulatory Follicle Harbor Progenitor Stem Cells? AB - Recent studies have revealed the presence of a mesenchymal stem cell (MSC) population in human and in gilt granulosa cells (GCs), thus increasing the interest in identifying the same population in the bovine species. We first isolated GCs by scraping from bovine preovulatory follicles and then tested several different media to define the ideal conditions to select granulosa derived stem cells. Although expressing MSC-associated markers, none of the media tested proven to be efficient in selecting MSC-like cells that were able to differentiate into mesodermic or ectodermic lineages. We performed another experimental approach exposing cells to a chemical stress, such as lowering of pH, as a system to select a more plastic population. Following the treatment, granulosa-specific granulose markers [follicle-stimulating hormone receptor (FSHR), follistatin (FST), and leukemia inhibitory factor receptor (LIFR)] were lost in bovine GCs, whereas an increase in multi- (CD29, CD44, CD73) and pluripotent (Oct-4 and c-Myc) genes was noticed. The stress allowed up-regulation of tumor necrosis factor-alpha and interleukin-1beta expression and the dedifferentiation of GCs, which was demonstrated by differentiation studies. Indeed, pH-treated cells were able to differentiate into the mesodermic and ectodermic lineages, thus suggesting that the chemical stress allows for the selection of cells that are more prone to adjust and respond to the environmental changes. PMID- 26982279 TI - Interest in Use of Technology for Healthcare Among Veterans Receiving Treatment for Mental Health. AB - INTRODUCTION: There is great interest in leveraging technology, including cell phones and computers, to improve healthcare. A range of e-health applications pertaining to mental health such as messaging for prescription refill or mobile device videoconferencing are becoming more available, but little is known about the mental health patient's interest in using these newer applications. METHODS: We mailed a survey to 300 patients seen in the general mental health clinic of a local Veterans Affairs Medical Center. Survey questions focused on interest in use of cell phones, tablets, and other computers in patients' interactions with the healthcare system. RESULTS: A total of 74 patients, primarily treated for depression, post-traumatic stress disorder, or anxiety disorders, returned completed surveys. Nearly all reported having a cell phone (72/74, 97%), but fewer than half reported having a smartphone (35/74, 47%). Overall, a substantial majority (64/74, 86%) had access to an Internet-capable device (smartphone or computer, including tablets). Respondents appeared to prefer computers to cell phones for some health-related communications, but did not express differential interest for other tasks (such as receiving appointment reminders). Interest in use was higher among younger veterans. DISCUSSION: Most veterans with a mental health diagnosis have access to technology (including cell phones and computers) and are interested in using that technology for some types of healthcare-related communications. CONCLUSIONS: While there is capacity to utilize information technology for healthcare purposes in this population, interests vary widely, and a substantial minority does not have access to relevant devices. Although interest in using computers for health-related communication was higher than interest in using cell phones, single-platform technology-based interventions may nonetheless exclude crucial segments of the population. PMID- 26982280 TI - Effects of milk flow on the physiological and behavioural responses to feeding in an infant with hypoplastic left heart syndrome. AB - Infants with hypoplastic left heart syndrome often experience difficulty with oral feeding, which contributes to growth failure, morbidity, and mortality. In response to feeding difficulty, clinicians often change the bottle nipple, and thus milk flow rate. Slow-flow nipples have been found to reduce the stress of feeding in other fragile infants, but no research has evaluated the responses of infants with hypoplastic left heart syndrome to alterations in milk flow. The purpose of this study was to evaluate the physiological and behavioural responses of an infant with hypoplastic left heart syndrome to bottle feeding with either a slow-flow (Dr. Brown's Preemie) or a standard-flow (Dr. Brown's Level 2) nipple. A single infant was studied for three feedings: two slow-flow and one standard flow. Oral feeding, whether with a slow-flow or a standard-flow nipple, was distressing for this infant. During slow-flow feeding, she experienced more coughing events, whereas during standard-flow she experienced more gagging. Disengagement and compelling disorganisation were most common during feeding 3, that is slow-flow, which occurred 2 days after surgical placement of a gastrostomy tube. Clinically significant changes in heart rate, oxygen saturation, and respiratory rate were seen during all feedings. Heart rate was higher during standard-flow and respiratory rate was higher during slow-flow. Further research is needed to examine the responses of infants with hypoplastic left heart syndrome to oral feeding and to identify strategies that will support these fragile infants as they learn to feed. Future research should evaluate an even slower-flow nipple along with additional supportive feeding strategies. PMID- 26982281 TI - Molecular Characterization of Methicillin-Resistant Staphylococcus aureus Bloodstream Isolates in a Turkish University Hospital Between 2002 and 2012. AB - AIMS: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most important pathogens in the hospital environment. Monitoring of this pathogen by molecular characterization and phenotypic methods is important for the development of suitable infection control measures and proper therapy design. In this study, our aim was to investigate the molecular epidemiological characteristics of MRSA bloodstream isolates obtained from patients hospitalized at Ankara University Ibn-i Sina Hospital in a 10-year period (2002-2012) and monitor the possible changes. A total of 134 isolates were characterized according to their antimicrobial susceptibility profiles, biofilm formation capabilities, accessory gene regulator (agr) locus types, presence of genes encoding Panton-Valentine leukocidin (PVL), staphylococcal enterotoxins A-J (SEs A-J), toxic shock syndrome toxin, sasX, and genes associated with biofilm formation (icaD, icaA, IS256) by polymerase chain reaction. The staphylococcal cassette chromosome mec (SCCmec) types of isolates were also defined and their clonal relationships were investigated by pulsed-field gel electrophoresis (PFGE) analysis and multilocus sequence typing was performed for representative isolates obtained by PFGE. RESULTS: The majority of the isolates were resistant to rifampin (100%), ciprofloxacin (97%), tetracycline (97.7%), and gentamicin (94.7%); 100% carried type-III SCCmec and 89.5% were agr type-1. All the isolates were negative for PVL, and sasX genes while all of them carried the icaD, icaA, and IS256 genes. The most common SE was enterotoxin A (97%). Four major PFGE patterns with the dominance of one pattern and seven unique patterns were obtained. All the representative PFGE isolates (n = 11) belonged to sequence type 239. CONCLUSION: We have documented the characteristics of the dominant MRSA clone in our hospital, which was a PVL (-), sasX (-) ST239 clone carrying sea (+) with type-III SCCmec, and type-1 agr locus. PMID- 26982282 TI - Premature Infants 750-1,250 g Birth Weight Supplemented with a Novel Human Milk Derived Cream Are Discharged Sooner. AB - OBJECTIVE: Infants may benefit from early nutritional intervention to decrease hospital stay. To evaluate the effects of adding a human milk (HM)-derived cream (Cream) product to a standard feeding regimen in preterm infants. MATERIALS AND METHODS: In a prospective multicenter randomized study, infants with birth weights 750-1,250 g were assigned to a Control or Cream group. The Control group received a standard feeding regimen consisting of mother's own milk or donor HM with donor HM-derived fortifier. The Cream group received the standard feeding regimen along with an additional HM-derived cream supplement when the HM they received was <20 kcal/oz. Primary outcomes of this secondary analysis included comorbidities, length of stay (LOS), and postmenstrual age (PMA) at discharge. RESULTS: We enrolled 75 infants (Control n = 37, Cream n = 38) with gestational age 27.7 +/- 1.8 weeks and birth weight 973 +/- 145 g (mean +/- SD). After adjusting for gestational age, birth weight, and presence of bronchopulmonary dysplasia (BPD), the Cream group had a decreased PMA at discharge (39.9 +/- 4.8 versus 38.2 +/- 2.7 weeks, p = 0.03) and LOS (86 +/- 39 versus 74 +/- 22 days, p = 0.05). For 21 infants with BPD, these values trended toward significance for PMA at discharge (44.2 +/- 6.1 versus 41.3 +/- 2.7 weeks, p = 0.08) and LOS (121 +/- 49 versus 104 +/- 23 days, p = 0.08). CONCLUSIONS: Very preterm infants who received an HM-derived cream supplement were discharged earlier. Infants with BPD may have benefited the most. PMID- 26982283 TI - Effect of Bilberry Extract on Development of Form-Deprivation Myopia in the Guinea Pig. AB - PURPOSE: To investigate the effects of bilberry extract, Difrarel, on form deprivation myopia in guinea pigs. METHOD: Thirty healthy pigmented guinea pigs, at the age of 3 weeks, were randomly assigned to 3 groups: 2 groups receiving daily orally administered Difrarel (300 mg/kg) either from the outset for 4 or 2 weeks after form deprivation and a control group. Form deprivation was induced with translucent eye patches on the right eye and lasted for 4 weeks. Another 12 guinea pigs without the form deprivation were assigned into 2 groups for oral administration of Difrarel and saline for 4 weeks. The refractive errors and axial length were measured in both eyes, and the posterior sclera was removed and assayed to evaluate the expressions of matrix metalloproteinase 2 (MMP2) and collagen I by a quantitative polymerase chain reaction and Western blot. RESULTS: Oral administration of Difrarel for 4 weeks was found to inhibit the axial elongation and decrease the myopic shift of refractive errors in the form deprived eye. Upregulation of MMP2 and degradation of collagen I in the sclera of form-deprived eye were observed, and these were prevented by orally administered Difrarel. Moreover, oral administration of Difrarel had no effects on axial length, refractive errors, and the expression of MMP2 in the normal eye. CONCLUSION: This work demonstrates that orally administered Difrarel has an effect against form-deprivation myopia and raises the possibility that bilberry extracts or specific components might represent a useful treatment for preventing the progression of myopia in clinical practice. PMID- 26982285 TI - Alkyne [2 + 2 + 2]-Cyclotrimerization Approach for Synthesis of 6,7 Cyclopropylallocolchicinoids. AB - Employing a cobalt-catalyzed [2 + 2 + 2] alkyne cyclotrimerization as the final step, the short and efficient synthesis of cyclopropylallocolchicinoid and its analogues having functional group variations at C9 and/or C10 and C11 of ring C has been accomplished. PMID- 26982286 TI - Personalizing IBD Therapy: The Asian Perspective. AB - BACKGROUND: All patients with inflammatory bowel disease (IBD) share common therapeutic goals, such as complete mucosal healing and improved long-term outcomes (e.g., reduction in hospitalization, surgery and mortality). However, because IBD patients have diverse features in terms of severity, phenotypes, clinical courses and responses to therapy, therapeutic options for achieving these goals differ among patients, from no therapy to early introduction of combination therapy with anti-TNF and immunosuppressive agents. KEY MESSAGES: By personalizing IBD therapy, we may be able to maximize management efficacy, minimize the risk of adverse events and ultimately decrease costs. The initial steps of personalized therapy involve the selection of the right patients by predicting the clinical course of IBD and the subsequent selection of the right therapy by predicting the response to therapy. The next step of personalized therapy involves the adjustment of therapy through therapeutic response evaluation and therapeutic drug monitoring. Notably, current recommendations on personalized IBD therapy are mainly based on results derived from Western populations. However, Asian patients with IBD are different from Western patients in many respects, including clinical characteristics, therapeutic response and prognosis, probably due to differences in environmental and genetic backgrounds. In addition, the healthcare systems and sociocultural backgrounds of Asian countries are not the same as those of Western countries. Therefore, personalized IBD therapy for Asians may differ from that for Westerners in some aspects. CONCLUSIONS: This review discusses the current progress of personalized IBD therapy and its application from the Asian perspective. PMID- 26982287 TI - The Brazilian Journal of Epidemiology at the dawn of its 19 th year of existence. PMID- 26982288 TI - Tribute to Mr. Mervyn Susser and Mr. Ruy Laurenti. PMID- 26982289 TI - Mervyn Susser. PMID- 26982290 TI - ...the timeline... PMID- 26982291 TI - Sickness absence due to mental disorders and psychosocial stressors at work. AB - INTRODUCTION: Mental disorders are the third leading cause of social security benefit due to sickness in Brazil. Occupational exposure to psychosocial stressors can affect the workers' mental health. The social security medical experts are responsible for characterizing if those sicknesses are work-related. OBJECTIVE: To evaluate the factors associated with sick leave due to mental disorders, in particular, the perception of workers on psychosocial factors at work. METHODS: This is an analytical study carried out in Sao Paulo, Brazil, with 131 applicants for sickness benefit due to mental disorders. Questionnaires were applied to assess the sociodemographic data, habits/lifestyle information, and perceived psychosocial factors at work. RESULTS: The most common diagnosis was depressive disorders (40.4%). The medical experts considered 23.7% of all applications as work-related. Most of the participants were female (68.7%), up to 40 years of age (73.3%), married/common-law marriage (51.1%), with educational level greater than or equal to 11 years (80.2%), nonsmokers (80.9%), not alcohol consumers (84%), and practice of physical activities (77.9%). Regarding psychosocial factors, most of the participants informed a high job strain (56.5%), low social support (52.7%), effort-reward imbalance (55.7%), and high overcommitment (87.0%). There was no statistical association between the work related mental disorders sickness benefits and independent variables. CONCLUSION: The concession of social security sickness benefits is not associated with sociodemographic data, habits/lifestyle, or psychosocial factors at work. Occupational exposure to unfavorable psychosocial factors was reported by most workers on sick leave due to mental disorders. However, several cases were not recognized by the social security medical experts as work-related, which may have influenced the results of the associations. PMID- 26982292 TI - Assessing vaccine data recording in Brazil. AB - OBJECTIVES: Vaccines represent an important advancement for improving the general health of a population. The effective recording of vaccine data is a factor for the definition of its supply chain. This study investigated vaccine data recording relatively to data collected from vaccination rooms and data obtained from a government-developed Internet platform. METHODS: The monthly recorded total number of diphtheria and tetanus toxoids and pertussis vaccine (alone or in combination with the Haemophilus influenzae type b conjugate vaccine) doses administered in a medium-sized city of the Southeast region of Brazil was collected for the period January/2006 through December/2010 from two sources: City level (directly from vaccination rooms, the study "gold standard"), and Federal level (from an Internet platform developed by the country government). Data from these sources were compared using descriptive statistics and the Percentage error. RESULTS: The data values made available by the Internet platform differed from those obtained from the vaccination rooms, with a Percentage error relatively to the actual values in the range [-0.48; 0.39]. Concordant values were observed only in one among the sixty analyzed months (1.66%). CONCLUSIONS: A frequent and large difference between the number of diphtheria and tetanus toxoids and pertussis vaccine doses administered in the two levels was detected. PMID- 26982293 TI - The independent effect of chronic diseases, sociodemographic and behavioral factors related to disability in older people living in Ribeirao Preto, SP, 2007 The EPIDCV Project. AB - OBJECTIVES: To investigate the prevalence and correlates of functional disability in elderly people living in Ribeirao Preto, SP. METHODS: This is a cross sectional population-based epidemiological study with multistage sampling. Design effect was corrected using a weighted sample composed by 536 elderly people. Disability based on daily living activities dependence (outcome) was assessed by using a validated questionnaire for population-based epidemiological studies. Points and 95% confidence intervals estimated crude and stratified prevalence rates of the outcome according to sociodemographic, behavioral, health-related, and self-reported morbidity variables. To identify the correlates, the crude and adjusted prevalence ratios were estimated using Poisson regression. RESULTS: The crude prevalence of disability was 50.31%. In the multivariate models, after simultaneous intra-group adjustment (final models), the following variables remained independently associated with the outcome: sociodemographic (age, education, and contribution to familiar income); behavioral (daily mean of sitting time); health-related factors (hypertension, ischemic heart disease, medicines taken, and low cognitive performance); and self-reported morbidity (number of diseases and low hearing performance). CONCLUSIONS: The high prevalence of disability among elderly people in Ribeirao Preto and the presence of modifiable variables impose the need for specific health promotion and prevention measures, aiming a better quality of life for this population group, which is already well represented in the city's most recent population pyramids. PMID- 26982294 TI - Characterization of hospitalizations due to external causes in the public health system, Brazil, 2011. AB - The aim of this work is to describe the characteristics of hospital admissions owing to external causes in the public health system in Brazil in 2011. Data from the Hospital Information System of the Unified Health System (SIH/SUS) were analyzed to obtain the frequency, coefficient of hospitalization, and hospital morbidity indicators. Of the 973,015 admissions, falls (38.4%) predominated, followed by traffic accidents (15.8%). The estimated coefficient of hospitalization owing to external causes increased with the age, and it was higher in male patients and in the midwest region of the country. The average stay was higher in hospitalizations for traffic accidents (6.1 days) and assaults (6.0 days), while the hospital mortality rate reached higher values in hospitalizations for assaults (4.7%) and self-harms (4.0%). It is evident from the knowledge of the characteristics described the usefulness of hospital morbidity data for planning care actions and prevention of the external causes. PMID- 26982295 TI - Factors that contribute to the body image concern of female college students. AB - OBJECTIVE: To estimate the contribution of sociodemographic and labor variables and body mass index to body image concern. METHODS: In order to estimate body image concern, the Body Shape Questionnaire (BSQ) and the Weight Concerns Scale (WCS) were applied. A confirmatory factor analysis of scales was carried out. The reason chi2 by degree of freedom ratio (chi2/df ), Comparative Fit Index (CFI), Normed Fit Index (NFI), and root mean square error of approximation (RMSEA) were used. Convergent validity was assessed through the average variance extracted and composed reliability and the internal consistency through standardized Cronbach's alpha coefficient (alpha). A structural model was developed, and the body image concern was the second-order main construct. The model appropriation was evaluated based on the goodness-of-fit indices. The z test was used to estimate the significance of trajectories (beta) using a 5% significance level. RESULTS: Totally, 595 female college students participated in the study, with a mean age of 20.42 +/- 2.44 years. The entire model, with the inclusion of all independent variables, showed unsatisfactory adjustment and was refined. The final model presented a satisfactory adjustment (chi2/df = 5.75; CFI = 0.87; NFI = 0.85; RMSEA = 0.09) with inclusion of medication use because of studies (beta = 0.08; p = 0.04), academic performance (beta = 0.09; p = 0.02), economic class (beta = 0.08; p = 0.03), and body mass index (beta = 0.44; p < 0.001). This model explained 22% of body image concern. CONCLUSION: Medication use due to studies, academic performance, economic class and body mass index significantly contribute to body image concern. PMID- 26982296 TI - Dietary intake of adolescents compared with the Brazilian Food Guide and their differences according to anthropometric data and physical activity. AB - OBJECTIVE: To assess the dietary intake of adolescents compared with the Brazilian Food Guide and to explore their differences according to anthropometric data and physical activity. METHODS: A total of 476 adolescents from public schools of Piracicaba, SP, Brazil participated in this study. A semi-quantitative food frequency questionnaire was used to estimate food group intake of adolescents. Height, weight and waist circumference of all participants were measured. Physical activity pattern was determined by questioning about participation in regular sport activities. RESULTS: The prevalence of overweight was 36.1% and 60% were not physically active. 7.8, 7.1, 6.3, and 0.2% of adolescents consumed vegetables, fruits, milk and derivatives, and cereals, respectively, according to recommendations. About 55 and 79% of adolescents consumed excessively oils/fats and sugar/sweets, respectively. Physically active adolescents consumed more cereals, fruits, vegetables, milk and derivatives, and meats and eggs. CONCLUSION: Most adolescents did not follow the food group recommendations and those who were physically active have healthier food habits. PMID- 26982297 TI - Delays in tuberculosis suspicion and diagnosis and related factors. AB - OBJECTIVE: To measure the delays in tuberculosis (TB) suspicion and diagnosis and to identify factors related. METHODS: We defined the delay in TB suspicion as the time between the perception of the symptoms by the patient and the search for health-care service and the diagnosis, as the time between the first visit to the health-care service and the diagnosis. We interviewed 100 patients treated at the health services in Sao Jose do Rio Preto that were diagnosed and reported/notified in 2008 and 2009, and the delays were quantified. We obtained the possible explanatory variables from interviews and secondary information available in the surveillance system. The addresses of TB patients and health care services were geocoded. Variables were assessed by multiple linear regression analysis and, when spatial dependency was detected, by spatial regression. RESULTS: The median values for the delays in TB suspicion and diagnosis were both 15 days. The first was modeled by linear regression and a positive relationship was found with the distances covered by the patients in order to get primary health-care service. The last was modeled by spatial regression and a positive relationship was found with the age and the frequency with the patients sought health-care services and a negative relationship with the pulmonary clinical form. CONCLUSION: The study revealed the existence of gaps in TB control activities related to the patients and the organization of the health-care services and showed the importance of taking into account the spatial dependence of the phenomena analyzed. PMID- 26982299 TI - Dietary patterns: a literature review of the methodological characteristics of the main step of the multivariate analyzes. AB - OBJECTIVE: To describe the solutions adopted in the multiple steps of the use of multivariate techniques to obtain a dietary pattern (DP) concerning: the objective of the studies, the selection of the method for measuring food intake, the criteria for grouping the foods, the number of food groups used, the number of DP obtained, and the nomenclature criteria. METHODS: The articles were selected from MEDLINE and Lilacs scientific databases using the following keywords: "dietary patterns" versus "factor analysis"; "principal components analysis"; "cluster analysis" and "reduced regression rank." The initial search resulted in 1,752 articles. After inclusion and exclusion criteria, 189 publications were selected. RESULTS: The following aspects were relevant among the studies: the prevalence of the principal component analysis (PCA); the prevalence of the use of 4 to 5 DPs in the studies of association with health outcomes; the use of 30 or more food groups from the food frequency questionnaire (FFQ); the prevalence of studies that associated DPs with health outcomes and socioeconomic factors; and the heterogeneity of criteria used throughout the analytical stages of the multivariate techniques. CONCLUSION: The heterogeneity between the publications concentrates on the criteria for food grouping, the nomenclature, and the number of dietary patterns calculated, which varied depending on the number of food groups present in these analyses. To understand, apply, and explore in full, the multivariate techniques has become necessary in order to improve the reliability of the results and, consequently, to improve the relationships with health outcomes and socioeconomic factors. PMID- 26982298 TI - Vitamin A supplementation in Brazilian pregnant and postpartum women: a systematic review. AB - OBJECTIVE: To assess the impact of vitamin A supplementation on adult pregnant and puerperal women in Brazil regarding the content of vitamin A and secretory immunoglobulin A on colostrum and breast milk, in child's health conditions, and in mother-child binomial vitamin A status. METHODS: A research was conducted in Medline, Scopus, Web of Science, and Lilacs electronic databases for the studies published between January 2000 and January 2014. The methodological quality of the studies was assessed according to Jadad scale. The study search was conducted in January 2014, independently by two authors. RESULTS: Seven studies were found concerning the effects of vitamin A supplementation in the puerperal period on breast milk and infant morbidity. No study regarding pregnant women supplementation was found. The supplementation in the puerperal period raised the retinol content on breast milk, thus increasing the offer of vitamin A for the child and the concentration of secretory immunoglobulin A on colostrum. There was no description of effects on infant morbidity. CONCLUSION: It seems that the advantages of postpartum supplementation were not established in the Brazilian program, although the supplementation contributes to a better nutritional status of vitamin A for both the child and the puerperal woman and increases the offer of vitamin A for the newborn through the breast milk. PMID- 26982300 TI - Prevalence and factors associated with excessive weight gain in pregnancy in health units in the southwest of Bahia. AB - OBJECTIVE: To determine the prevalence of excessive gestational weekly weight gain and to identify its association with demographic, socioeconomic, obstetric, anthropometric, and behavioral characteristics. METHODS: This cross-sectional study included 328 pregnant women attending all health units in the urban area of Vitoria da Conquista, Bahia. The data were collected from May 2010 to June 2011. The weekly weight gain was evaluated according to the current recommendations of the Institute of Medicine. The association among the studied factors and the excessive weekly weight gain was observed in pregnant women in the second and third trimesters, using the Poisson regression with robust variance. RESULTS: The prevalence rate of excessive weekly weight gain in pregnant women in the second and third trimesters was found to be 42.5%. The determinants of excessive weekly weight gain were family income < 1 minimum wage (PR: 2.65; 95%CI 1.18 - 4.83) and pregestational weight status overweight/obesity (PR: 1.33; 95%CI 1.01 - 1.75). CONCLUSION: The results emphasize the importance of monitoring the weight gain during pregnancy. The evaluation of the weekly weight gain enables early interventions with the goal of preventing the excessive total weight gain and its consequences for both the mother and the child. PMID- 26982301 TI - Analysis of vaccination status of preschool children in Teresina (PI), Brazil. AB - INTRODUCTION: Immunization is a priority action of the Ministry of Health for contributing to reducing child mortality; however, studies show increased vaccination delays and non-vaccination. OBJECTIVE: This study aims to analyze the immunization status of preschool children in Teresina - PI. METHODS: Cross sectional study involving 542 children, aged 2-6 years, enrolled in local public schools in four Municipal Childhood Education Centers selected at random, following the proportional division by regions of the city. Data were collected through a pre-coded and pre-tested form, in addition to scanning the children's vaccination card. For univariate descriptive statistical analysis, Pearson's chi2 Test and Fisher's Exact Test were used, and for multivariate analysis, multiple logistic regression was conducted using SPSS version 17.0. The study complied with the ethical aspects in accordance with current legislation. RESULTS: The frequency of delayed vaccination/non-vaccination was 24.9%. The average of non administered vaccines was 1.7 (SD +/- 1.2) and of delayed vaccines was 3.3 (SD +/ 1.6). The binomial logistic regression model showed a significant association (p < 0.05) between young caregivers (under 24 years) and low frequency in childcare consultations with delayed vaccination/non-vaccination. There was no association with the variables related to the experience of children in the vaccination room and with the implementation of the Family Health Strategy. CONCLUSION: Ensuring and strengthening primary healthcare actions are essential tools to reduce non vaccination and vaccine delays. Professionals who care for children in vaccination rooms need to sensitize themselves to guide and encourage parents/caregivers to meet the vaccination schedules without delays or errors. PMID- 26982302 TI - Automatic coding and selection of causes of death: an adaptation of Iris software for using in Brazil. AB - OBJECTIVE: To prepare a dictionary in Portuguese for using in Iris and to evaluate its completeness for coding causes of death. METHODS: Iniatially, a dictionary with all illness and injuries was created based on the International Classification of Diseases - tenth revision (ICD-10) codes. This dictionary was based on two sources: the electronic file of ICD-10 volume 1 and the data from Thesaurus of the International Classification of Primary Care (ICPC-2). Then, a death certificate sample from the Program of Improvement of Mortality Information in Sao Paulo (PRO-AIM) was coded manually and by Iris version V4.0.34, and the causes of death were compared. Whenever Iris was not able to code the causes of death, adjustments were made in the dictionary. RESULTS: Iris was able to code all causes of death in 94.4% death certificates, but only 50.6% were directly coded, without adjustments. Among death certificates that the software was unable to fully code, 89.2% had a diagnosis of external causes (chapter XX of ICD-10). This group of causes of death showed less agreement when comparing the coding by Iris to the manual one. CONCLUSION: The software performed well, but it needs adjustments and improvement in its dictionary. In the upcoming versions of the software, its developers are trying to solve the external causes of death problem. PMID- 26982303 TI - Associated factors with oral cancer: a study of case control in a population of the Brazil's Northeast. AB - OBJECTIVE: This study aimed at assessing the association between factors such as age, sex, skin color, occupation, educational level, marital status, place of residence, and tobacco and alcohol consumptions and oral cancer in individuals in a city in the northeast of Brazil between 2002 and 2012. METHODS: This is a case control study. The case group consisted of 127 people attended at the Oral Injury Reference Center with histopathological diagnosis of oral squamous cell carcinoma. The control group consisted of 254 individuals treated at the same center. The study considered two controls for each case. The cases and controls were adjusted according to sex and age. Univariate and bivariate analyses were performed (Pearson chi2-test) to verify the correlation between the dependent variable (oral cancer) and the independent variables; odds ratio (OR) and the confidence interval of 95% (95%CI) were calculated. Finally, in the multivariate analysis, it was used as the hierarchical model with logistic regression to explain the interrelationships between the independent variables and oral cancer. RESULTS: Consumption of more than 20 cigarettes per day [OR = 6.64; 95%CI 2.07 - 21.32; p <= 0.001], an excessive alcohol consumption [OR = 3.25; 95%CI 1.03 - 10.22; p <= 0.044], and the synergistic consumption of tobacco and alcohol [OR = 9.65; 95%CI 1.57 - 59.08; p <= 0.014] are the most important risk factors for oral cancer. CONCLUSION: It was concluded that tobacco and alcohol consumptions are the most important factors for the development of oral cancer. Sociodemographic factors were not associated with this neoplasm after adjusting for smoking and drinking. PMID- 26982305 TI - Psychiatric hospitalizations in the Rio Grande do Sul State (Brazil) from 2000 to 2011. AB - OBJECTIVE: To examine the variation in the rates of psychiatric hospitalization and the mean hospital stay time in the public health system in the state of Rio Grande do Sul, in the south of Brazil, from 2000 to 2011. METHODS: This was an ecological study. Data were collected from DATASUS. The rates were obtained from diagnosis of admissions due to psychoactive substance use and to other causes, stratified by the gender of the patients. The data were analyzed using Poisson regression and Spearman correlation coefficient. RESULTS: Increasing hospitalization rates were observed for women with disorders due to substance use (p < 0.001) and other causes (p < 0.001), and among men with disorders due to the use of alcohol or other drugs (p < 0.001). This elevation of the rates remained statistically significant and inversely correlated to the length of hospital stay (p < 0.001). DISCUSSION: In a period of expansion of the local care networks for mental health, an increase in the occupancy of psychiatric beds in the state was noticed, with shorter length of stay and greater diversity of gender and causes of hospitalization. PMID- 26982304 TI - Food and nutrition security in families with children under five years old in the city of Campina Grande, Paraiba. AB - OBJECTIVE: To estimate the prevalence and identify the socioeconomic risk factors for food insecurity in households with children under five years in the city of Campina Grande, Paraiba. METHODS: This cross-sectional study involved 793 families with children assisted in municipal day care centers in Campina Grande, Paraiba, Brazil. Household socioeconomic variables were analyzed as the possible predictors of mild food insecurity and moderate/severe food insecurity. For the evaluation of food and nutrition security of households, the Brazilian Food Insecurity Scale was used. RESULTS: Mild food insecurity was characterized in 37.6% of families, and moderate/severe food insecurity affected 31.6% of households. Regarding the household socioeconomic variables, none was associated with mild food insecurity. Meanwhile, the highest prevalence of moderate/severe food insecurity, when compared with reference categories, was present in households without water treatment for drinking purposes, with toilets that are not flushable and individual, with larger families, and without a refrigerator. Being a beneficiary, or not, of the social welfare program "Bolsa Familia" did not represent a factor associated with food insecurity. CONCLUSIONS: The results show high rates of food insecurity with the most severe degrees being related to factors dependent on the family purchasing power, indicating a major challenge for them. PMID- 26982306 TI - Fatty acid intake and metabolic syndrome among overweight and obese women. AB - OBJECTIVE: To examine relations between fatty acids intake and metabolic syndrome (MetS) status among overweight and obese women (n = 223). METHODS: This was a cross-sectional study. The physical and laboratory tests included anthropometry, body composition evaluation and measurements of blood pressure, fasting blood glucose, insulinemia and lipid profiles. A three-day food diary was used to evaluate fatty acids consumption. Statistical analysis included chi2 test and odds ratio measurements. RESULTS: The women had 35.2 (6.9) years old and 15.2% presented MetS. Women with MetS presented higher serum levels of very low-density lipoprotein cholesterol, triglycerides, glucose and insulin in addition to higher diastolic blood pressure in comparison to women without MetS. Overweight women with MetS consumed higher amounts of monounsaturated fatty acids - 24.3 g (24.7 - 36.4) versus overweight women without MetS - 23.9 g (23.8 - 26.8), polyunsaturated fatty acids - 16.7 g (14.6 - 21.1) versus overweight women without MetS - 13.6 g (13.8 - 15.8) and linoleic fatty acids - 15.9 g (6.5) versus overweight women without MetS - 13.1 g (5.1). Among obese women with MetS, higher intake of linoleic fatty acids was also noted - 17.6 g (6.1) versus obese women without MetS - 14.3 g (6.6) in addition to higher consumption of trans fatty acids - 4.7 g (4.8 - 6.3) versus obese women without MetS - 3.9 g (2.9 - 4.6). Increased quartiles of monounsaturated, polyunsaturated, linoleic and trans fatty acid intake were significantly associated with a greater occurrence of MetS. CONCLUSION: Lipid intake may be related to MetS, although other factors also need to be considered, such as lifestyle, genetics and metabolism. PMID- 26982307 TI - Development of the Brazilian brief version of the Diabetes Quality of Life Measure (DQOL-Brazil-8). AB - OBJECTIVE: To provide for Brazil, through the selection of items of the Brazilian version of the Diabetes Quality of Life Measure (DQOL-Brazil), a concise instrument. METHODS: This is a cross-sectional study in which the DQOL-Brazil was administered to 150 type 1 diabetic patients and 146 type 2 diabetic patients. The items of the instrument were selected according to the analysis of the principal components and Spearman's correlations with treatment satisfaction, glycated hemoglobin level, and Nottingham Health Profile. RESULTS: From a total of 44 items, only 8 were selected to compose the summary instrument (DQOL-Brazil 8). The DQOL-Brazil-8 presented Spearman's correlation of 0.873 with the DQOL Brazil and a Cronbach's alpha coefficient of 0.702. CONCLUSION: The Brazilian health professionals now have a brief tool for a fast application that preserves the best features of the full DQOL-Brazil. PMID- 26982309 TI - Perinatal outcomes and changes in the oral cavity: Brazilian cohorts of Ribeirao Preto and Sao Luis. AB - Studies have shown a possible association of oral diseases during pregnancy with preterm birth (PTB) and low birth weight (LBW). These perinatal outcomes appear to be associated with enamel defects in the primary dentition, which, in turn, seem to predispose to future development of caries in children. Therefore it is relevant to include oral health variables of the mother/child dyad in cohort studies to understand how these factors are associated. The objectives of this study are: 1) check if there is an association between diseases of the oral cavity of pregnant women and PTB, 2) test the hypothesis of association between perinatal outcomes and enamel defects/dental caries in children, 3) examine whether there are associations between perinatal outcomes and disorders of tooth eruption in children; 4) build theoretical models to study social inequities as a common factor between oral conditions and perinatal outcomes. We used an integrated, collaborative approach between two Brazilian cities with contrasting socioeconomic conditions: Sao Luis , MA, and Ribeirao Preto, SP - British Birth Cohort Studies study (BRISA Ribeirao Preto, Sao Luis). Two cohorts were evaluated: one initiated at birth, representative of the population of live births, and another, initiated prenatally. Participants were reassessed from the beginning of the second year of life. It is expected that these cohorts will contribute to foster the development and consolidation of population-based follow up studies in Brazil. PMID- 26982308 TI - Prevalence and associated factors of diabetes in the elderly population in Vicosa, Minas Gerais, Brazil. AB - OBJECTIVES: To assess the prevalence and factors associated with diabetes in the elderly population and verify the correlation between the use of medications for diabetes and information about the disease. METHODS: This epidemiological cross sectional study was conducted in Vicosa, Minas Gerais, Brazil, with 621 elderly people aged 60 years or older selected by simple random sampling. A semi structured questionnaire was used as a research tool and included questions about socioeconomic conditions, lifestyle, health conditions, and nutritional status. The weight, height, and waist circumference were measured. The dependent variable was the self-reported diabetes. In the association analysis between explanatory variables and self-reported diabetes, the Poisson regression analysis with robust variance was used. In the bivariate analysis, a p value < 0.25 was used to include the variables for the multivariate modeling, and in the final model, the variables with p value < 0.10 association were included. RESULTS: The prevalence of diabetes was 22.4%. The multivariate hierarchical analysis showed the following factors independently and positively associated with diabetes: gender, self-reported health, history of hypertension/dyslipidemia, polypharmacy, and waist circumference. The elderly schooling was negatively associated with diabetes. CONCLUSION: The results showed the need for implementation of educational public policies to promote behavior changes of the population to prevent and control diabetes and its complications. PMID- 26982310 TI - The Critical Epidemiology of the 21 st century and cyberspace. PMID- 26982311 TI - Epidemiology of the 21 st century and cyberspace: rethinking power and the social determination of health. AB - The study of epidemiologic processes as a form of socially determined movement requires a renewed understanding of the social order, and thus, an updated understanding of the social relations that move society. Recently, the dominance of big corporations on cyberspace has become visible as a new historical process that conditions the social order and extends the technological subordination of daily life, therefore expanding community massive submission to standard conducts. The new digital technological revolution, about which some frightening prognoses are made for the next decades, could easily imply the advent of an era of radical subsumption of life processes. This will negatively affect not only our general way of living, thinking and planning, but also our deepest daily intimacy. This movement implies radical effects on health which we call cybernetic determination and subsumption. This novel process raises new questions on public health and prevention; but also requires a new reading of reality, a rethinking of human life and health, of its social determination, which implies the need for new new categories and analysis and renewed challenges for critical epidemiology. PMID- 26982312 TI - Health and empowerment in the 21 st Century: reification and vulnerability in the context of cybertechnologies. PMID- 26982313 TI - Capitalism, cyberspace and society: avoiding extremism. PMID- 26982315 TI - Answers to commentaries: implications and challenges in the frontier of epidemiology. PMID- 26982314 TI - The challenges of critical epidemiology and responses of capitalism to their reproductive difficulties: the cybersphere case. PMID- 26982316 TI - Labor in early life, vulnerability for health in Brazilian schoolchildren: National Adolescent School-based Health Survey (PeNSE 2012). PMID- 26982317 TI - Sexual initiation among adolescents (10 to 14 years old) and health behaviors. PMID- 26982318 TI - Mineralocorticoid Antagonists in the Treatment of Central Serous Chorioretinopathy: A Comparative Analysis. AB - BACKGROUND AND OBJECTIVE: Overaction of mineralocorticoid receptor (MR) pathways has been implicated in the pathophysiology of central serous chorioretinopathy (CSCR). The purpose of this study was to evaluate MR antagonists in the treatment of CSCR. STUDY DESIGN AND METHODS: A retrospective chart review was conducted of all CSCR patients at one center treated with spironolactone or eplerenone (50 mg p.o. b.i.d.) or observation. Patients were followed at monthly intervals with examination and optical coherence tomography. RESULTS: 32 patients (12 eplerenone, 12 spironolactone, 8 observation) were enrolled in the study. Both MR antagonists demonstrated statistically significant visual acuity improvement and subretinal fluid reduction at 1, 2, and 3 months compared to baseline (p < 0.05). 58.3% of patients had complete resolution of subretinal fluid at 2 months on MR antagonists, compared to 12.5% under observation (p < 0.05). Photodynamic therapy was used to treat refractory subretinal fluid past 6 months in 1/24 (4.2%) on MR antagonists and 2/8 (25%) patients under observation. There was no difference in efficacy between eplerenone and spironolactone. Spironolactone exhibited increased side effects (8/12, 75%) compared to eplerenone (3/12, 25%; p < 0.05). CONCLUSIONS: This data supports the use of MR antagonists in CSCR and suggests an accelerated improvement compared to observation. Prospective randomized trials are needed to better elucidate the precise role of MR antagonists in the management of CSCR. PMID- 26982319 TI - Influence of Antenatal Glucocorticosteroid Exposure on Osteoprotegerin and Receptor Activator of Nuclear Factor x03BA;B Ligand Levels in Newborn Infants. AB - BACKGROUND/AIMS: The physiologic relevance of osteoprotegerin (OPG) and the receptor activator of nuclear factor x03BA;B ligand (RANKL) in the preterm neonate is unknown. The aim of this study was to examine the effects of prematurity on OPG and RANKL concentrations at birth and to investigate in particular whether antenatal corticosteroid (ACS) exposure affects serum OPG and RANKL levels in premature neonates. METHODS: Quantitative determination (enzyme immunoassay) of serum OPG and RANKL at 24 postnatal hours was performed in 47 healthy term neonates, 43 preterm newborns not exposed to ACS, and 55 preterm infants exposed to ACS. RESULTS: OPG in the ACS-exposed preterm group (median 5.13 pmol/l, range 1.62-15.12) was significantly higher compared to preterm neonates not exposed to ACS (median 4.52 pmol/l, range 0.86-8.98, p < 0.05) and to unexposed term neonates (median 4.47 pmol/l, range 2.70-10.72, p < 0.05). Conversely, there was no difference in RANKL levels between the study groups. OPG and RANKL values were also similar between term and preterm neonates not exposed to ACS. CONCLUSIONS: Preterm neonates exposed to ACS have higher serum levels of OPG, while premature neonates not exposed to ACS have serum OPG and RANKL levels similar to those measured in healthy term neonates. PMID- 26982320 TI - Preformulation Studies on Piperlongumine. AB - Piperlongumine is a natural alkaloid extracted from piper plants which has been used traditionally for the treatment of certain diseases. This compound shows interesting in vitro pharmacological activity such as selective anticancer activity and higher cytotoxicity than methotrexate, cyclophosphamide and adriamycin on breast, colon, and osteosarcoma cancers, respectively. However, the physicochemical properties for this compound have not been well characterized. In this research, preformulation studies for piperlongumine have been performed to determine factors which influence solubility and stability which, in turn, can be used to assist future formulation development. The solubility of piperlongumine in water was found to be approximately 26 MUg/ml. Using 10% polysorbate 80 as a surfactant resulted in a 27 fold increase in solubility. Cosolvents and cyclodextrins afforded concentrations of 1 mg/ml and higher. The pH degradation rate profile for piperlongumine at various temperatures shows significant instability of the drug at pH values >= 7 and 3, and maximum stability around pH 4. It was estimated that it would take approximately 17 weeks for piperlongumine to degrade by 10% at 25 degrees C, pH 4. Additionally, piperlongumine showed marked photo-degradation upon exposure to an ultraviolet light source, especially in aqueous media. PMID- 26982321 TI - Environment and Genes: What Is the Interaction? AB - Inflammatory bowel disease (IBD) results from a continuum of complex interactions between a quartet of host-derived and external elements that involve various aspects of the intestinal microbiota, the immune system that is centered around the intestinal epithelial cell barrier, the genetic composition of the host and specific environmental factors. Recent studies into the complexity of these arrangements increasingly support the syndromic nature of this disorder and involve a wide range of interacting biologic pathways that affect innate immunity, adaptive immunity, endoplasmic reticulum stress and autophagy as well as metabolic pathways associated with cellular homeostasis. It is further likely that all of the aforementioned host factors including the microbiota, which is as much a part of ourselves as is any organ system, are under the influence of yet to-be-understood environmental factors that predispose to and precipitate IBD. Notwithstanding the importance of genetic predisposition, these environmental influences are no doubt central to disease pathogenesis in light of the rapid emergence of IBD throughout the world and assumption of disease in migrating populations from low to high risk environments. It can thus be anticipated that environmental factors that modify the risk for development of IBD have the common attribute of affecting the relationship between the commensal microbiota and the immune system in a manner that intersects with the functionally relevant immuno genetic pathways, and potentially modifies them through epigenetic effects, in a manner that are uniquely operative within a particular syndromic context of IBD and occur sequentially and in a reiterative fashion, perhaps beginning in early life. PMID- 26982323 TI - Life Satisfaction and the Pursuit of Happiness on Twitter. AB - Life satisfaction refers to a somewhat stable cognitive assessment of one's own life. Life satisfaction is an important component of subjective well being, the scientific term for happiness. The other component is affect: the balance between the presence of positive and negative emotions in daily life. While affect has been studied using social media datasets (particularly from Twitter), life satisfaction has received little to no attention. Here, we examine trends in posts about life satisfaction from a two-year sample of Twitter data. We apply a surveillance methodology to extract expressions of both satisfaction and dissatisfaction with life. A noteworthy result is that consistent with their definitions trends in life satisfaction posts are immune to external events (political, seasonal etc.) unlike affect trends reported by previous researchers. Comparing users we find differences between satisfied and dissatisfied users in several linguistic, psychosocial and other features. For example the latter post more tweets expressing anger, anxiety, depression, sadness and on death. We also study users who change their status over time from satisfied with life to dissatisfied or vice versa. Noteworthy is that the psychosocial tweet features of users who change from satisfied to dissatisfied are quite different from those who stay satisfied over time. Overall, the observations we make are consistent with intuition and consistent with observations in the social science research. This research contributes to the study of the subjective well being of individuals through social media. PMID- 26982322 TI - Regulation of Oral Squamous Cell Carcinoma Proliferation Through Crosstalk Between SMAD7 and CYLD. AB - BACKGROUND/AIMS: SMAD7 is a key inhibitor of transforming growth factor beta (TGFbeta) receptor signaling, which regulates the alteration of cancer cell invasiveness through epithelial-mesenchymal cell conversion. Dysfunction of protein ubiquitination plays a critical role in carcinogenesis, whereas the involvement a deubiquitinating enzyme, cylindromatosis gene (CYLD), in the tumor invasion of oral squamous cell carcinoma (OSCC) is unknown. METHODS: Here, we studied the role of CYLD in regulation of OSCC cell invasion, using clinic specimens and cell lines. We modified SMAD7 levels in OSCC cells, and examined its effects on CYLD mRNA and protein levels by RT-qPCR and by Western blot, respectively. We also modified CYLD levels in OSCC cells, and examined its effects on SMAD7 mRNA and protein levels by RT-qPCR and by Western blot, respectively. Then, we examined the cell invasiveness in CYLD and/or SMAD7 modified OSCC cells in a transwell cell invasion assay. RESULTS: We found that the levels of CYLD and SMAD7 were significantly decreased in OSCC specimens, compared to the paired normal tissue. Metastatic OSCC appeared to contained lower levels of CYLD and SMAD7. Moreover, CYLD and SMAD7 levels strongly correlated in OSCC specimens. Low CYLD levels were associated with poor patients' survival. Moreover, SMAD did not regulate CYLD, but CYLD regulated the levels of SMAD7 in OSCC cells. Furthermore, CYLD overexpression inhibited SMAD7-mediated cell invasion, while CYLD depletion increased SMAD7-mediated cell invasion in OSCC cells. CONCLUSION: Suppression of CYLD in OSCC cells may promote SMAD7-mediated cancer invasion. Thus, CYLD appears to be an intriguing therapeutic target to prevent OSCC metastases. PMID- 26982325 TI - Observing Oxygen Vacancy Driven Electroforming in Pt-TiO2-Pt Device via Strong Metal Support Interaction. AB - Oxygen vacancy formation, migration, and subsequent agglomeration into conductive filaments in transition metal oxides under applied electric field is widely believed to be responsible for electroforming in resistive memory devices, although direct evidence of such a pathway is lacking. Here, by utilizing strong metal-support interaction (SMSI) between Pt and TiO2, we observe via transmission electron microscopy the electroforming event in lateral Pt/TiO2/Pt devices where the atomic Pt from the electrode itself acts as a tracer for the propagating oxygen vacancy front. SMSI, which originates from the d-orbital overlap between Pt atom and the reduced cation of the insulating oxide in the vicinity of oxygen vacancies, was optimized by fabricating nanoscale devices causing Pt atom migration tracking the moving oxygen vacancy front from the anode to cathode during electroforming. Experiments performed in different oxidizing and reducing conditions, which tune SMSI in the Pt-TiO2 system, further confirmed the role of oxygen vacancies during electroforming. These observations also demonstrate that the noble metal electrode may not be as inert as previously assumed. PMID- 26982324 TI - Porcine Deltacoronavirus, Thailand, 2015. PMID- 26982326 TI - Music and Video Gaming during Breaks: Influence on Habitual versus Goal-Directed Decision Making. AB - Different systems for habitual versus goal-directed control are thought to underlie human decision-making. Working memory is known to shape these decision making systems and their interplay, and is known to support goal-directed decision making even under stress. Here, we investigated if and how decision systems are differentially influenced by breaks filled with diverse everyday life activities known to modulate working memory performance. We used a within-subject design where young adults listened to music and played a video game during breaks interleaved with trials of a sequential two-step Markov decision task, designed to assess habitual as well as goal-directed decision making. Based on a neurocomputational model of task performance, we observed that for individuals with a rather limited working memory capacity video gaming as compared to music reduced reliance on the goal-directed decision-making system, while a rather large working memory capacity prevented such a decline. Our findings suggest differential effects of everyday activities on key decision-making processes. PMID- 26982328 TI - Swift Heavy Ion Irradiation as a Tool for Homogeneous Dispersion of Nanographite Platelets within the Polymer Matrices: Toward Tailoring the Properties of PEDOT:PSS/Nanographite Nanocomposites. AB - Performance of the polymer nanocomposites is dependent to a great extent on efficient and homogeneous dispersion of nanoparticles in polymeric matrices. The dispersion of nanographite platelets (NGPs) in polymer matrix is a great challenge because of the inherent inert nature of the NGPs, poor wettability toward polymer matrices, and easy agglomeration due to van der Waals interactions. In the present study, attempts have been made to use a new approach involving the irradiation of polymer nanocomposites through swift heavy ion (SHI) to homogeneously disperse the NGPs within the polymer matrices. Poly(3,4 ethylenedioxythiophene) poly(styrenesulfonate) ( PEDOT: PSS)/nanographite nanocomposite (NC) films prepared by the solution blending method were irradiated with SHI (Ni ion beam, 80 MeV) at a fluence range of 1 * 10(10) to 1 * 10(12) ions/cm(2). XRD studies revealed that ion irradiation results in delamination and better dispersion of NGPs in the irradiated nanocomposite films compared to unirradiated films, which is also depicted through SEM, AFM, TEM, and Raman studies. In the irradiated polymer nanocomposite films, the conformation of PEDOT chains changes from coiled to extended coiled structure, which, along with homogeneously dispersed NGPs in irradiated NCs, shows an excellent synergistic effect facilitating charge transport. The remarkable improvement in conductivity from 1.9 * 10(-2) in unirradiated NCs to 0.45 S/cm in irradiated NCs is observed with marked improvement in sensing the response toward nitroaromatic vapors at room temperature. The temperature induced conductivity studies have been carried out for PEDOT: PSS/nanographite NCs to comprehend the charge transport mechanism in NC films using the 3D Mott variable range hopping model also. The study reveals SHI as a novel method, addressing the challenge associated with the dispersion of NGPs within the polymer matrix for their enhanced performance toward various applications. PMID- 26982329 TI - Calprotectin or Lactoferrin: Do They Help. AB - BACKGROUND: The diagnosis and monitoring of inflammatory bowel disease (IBD) has traditionally relied on clinical assessment, serum markers of inflammation and endoscopic examination. Fecal biomarkers such as calprotectin (FC) and lactoferrin (FL) are predominantly derived from neutrophils, are easily detectable in the feces and are now established as valuable markers of intestinal inflammation. In recent years, a 'treat to target' concept has emerged for the management of IBD. Adequate control of inflammation in IBD at a biochemical level is quickly becoming an important target in IBD management. KEY MESSAGES: Fecal biomarkers have been shown to be significantly and consistently increased in both adult and pediatric patients with IBD versus those without IBD. Fecal biomarkers are therefore useful in determining those patients with gastrointestinal symptoms who are likely to benefit from colonoscopy versus those in whom colonoscopy is likely to be normal. Fecal biomarkers correlate significantly with endoscopic disease in both Crohn's disease and ulcerative colitis. Suggested cutoffs for FC for endoscopically active disease in IBD range from 50 to 280 MUg/g. Fecal biomarkers reflect the success of treatment intensification and can help predict clinical relapse. Both FC and FL are accurate in the detection of postoperative endoscopic recurrence of Crohn's disease, and FC may be clinically useful in predicting those patients with acute severe ulcerative colitis who may progress to colectomy. There are limitations to these fecal tests including a false positive rate and intra-individual variability. CONCLUSIONS: This review focuses on the role of fecal biomarkers in the diagnosis, monitoring and management of IBD and how best to interpret results. We will discuss the emerging role of these biomarkers in the IBD management landscape including FC-guided drug dosing and the development of home-based testing and e-health applications. Fecal biomarker results must always be interpreted in a clinical context. Endoscopic assessment remains the gold standard for diagnosis and monitoring of IBD. PMID- 26982327 TI - Hybrid Dysgenesis in Drosophila simulans Associated with a Rapid Invasion of the P-Element. AB - In a classic example of the invasion of a species by a selfish genetic element, the P-element was horizontally transferred from a distantly related species into Drosophila melanogaster. Despite causing 'hybrid dysgenesis', a syndrome of abnormal phenotypes that include sterility, the P-element spread globally in the course of a few decades in D. melanogaster. Until recently, its sister species, including D. simulans, remained P-element free. Here, we find a hybrid dysgenesis like phenotype in the offspring of crosses between D. simulans strains collected in different years; a survey of 181 strains shows that around 20% of strains induce hybrid dysgenesis. Using genomic and transcriptomic data, we show that this dysgenesis-inducing phenotype is associated with the invasion of the P element. To characterize this invasion temporally and geographically, we survey 631 D. simulans strains collected on three continents and over 27 years for the presence of the P-element. We find that the D. simulans P-element invasion occurred rapidly and nearly simultaneously in the regions surveyed, with strains containing P-elements being rare in 2006 and common by 2014. Importantly, as evidenced by their resistance to the hybrid dysgenesis phenotype, strains collected from the latter phase of this invasion have adapted to suppress the worst effects of the P-element. PMID- 26982330 TI - Hypervirulent emm59 Clone in Invasive Group A Streptococcus Outbreak, Southwestern United States. AB - The hyper-virulent emm59 genotype of invasive group A Streptococcus was identified in northern Arizona in 2015. Eighteen isolates belonging to a genomic cluster grouped most closely with recently identified isolates in New Mexico. The continued transmission of emm59 in the southwestern United States poses a public health concern. PMID- 26982331 TI - Influence of In Vitro IL-2 or IL-15 Alone or in Combination with Hsp 70 Derived 14-Mer Peptide (TKD) on the Expression of NK Cell Activatory and Inhibitory Receptors on Peripheral Blood T Cells, B Cells and NKT Cells. AB - Previous studies from Multhoff and colleagues reported that plasma membrane Hsp70 acts as a tumour-specific recognition structure for activated NK cells, and that the incubation of NK cells with Hsp70 and/or a 14-mer peptide derived from the N terminal sequence of Hsp70 (TKDNNLLGRFELSG, TKD, aa 450-463) plus a low dose of IL-2 triggers NK cell proliferation and migration, and their capacity to kill cancer cells expressing membrane Hsp70. Herein, we have used flow cytometry to determine the influence of in vitro stimulation of peripheral blood mononuclear cells from healthy individuals with IL-2 or IL-15, either alone or in combination with TKD peptide on the cell surface expression of CD94, NK cell activatory receptors (CD16, NK2D, NKG2C, NKp30, NKp44, NKp46, NKp80, KIR2DL4, DNAM-1 and LAMP1) and NK cell inhibitory receptors (NKG2A, KIR2DL2/L3, LIR1/ILT-2 and NKR P1A) by CD3+CD56+ (NKT), CD3+CD4+, CD3+CD8+ and CD19+ populations. NKG2D, DNAM-1, LAMP1 and NKR-P1A expression was upregulated after the stimulation with IL-2 or IL-15 alone or in combination with TKD in NKT, CD8+ T cells and B cells. CD94 was upregulated in NKT and CD8+ T cells. Concurrently, an increase in a number of CD8+ T cells expressing LIR1/ILT-2 and CD4+ T cells positive for NKR-P1A was observed. The proportion of CD8+ T cells that expressed NKG2D was higher after IL 2/TKD treatment, when compared with IL-2 treatment alone. In comparison with IL 15 alone, IL-15/TKD treatment increased the proportion of NKT cells that were positive for CD94, LAMP1 and NKRP-1A. The more potent effect of IL-15/TKD on cell surface expression of NKG2D, LIR1/ILT-2 and NKRP-1A was observed in B cells compared with IL-15 alone. However, this increase was not of statistical significance. IL-2/TKD induced significant upregulation of LAMP1 in CD8+ T cells compared with IL-2 alone. Besides NK cells, other immunocompetent cells present within the fraction of peripheral blood mononuclear cells were influenced by the treatment with low-dose interleukins themselves or in combination with hsp70 derived (TKD) peptide. PMID- 26982333 TI - Two new 28-nor-oleanane-type triterpene saponins from roots of Camellia oleifera and their cytotoxic activity. AB - Two new 28-nor-oleanane-type triterpene saponins, oleiferoside U (1), and oleiferoside V (2) were isolated from the 50% EtOH extract of the roots of Camellia oleifera C. Abel. Their structures were elucidated as camellenodiol 3beta-O-beta-d-galactopyranosyl-(1->2)-beta-d-xylopyranosyl-(1->2)-[beta-d galactopyranosyl-(1->3)]-beta-d-glucuronopyranoside and camellenodiol 3beta-O beta-d-galactopyranosyl-(1->3)-beta-d-xylopyranosyl-(1->2)-[beta-d galactopyranosyl-(1->3)]-beta-d-glucuronopyranoside. Their chemical structures were established mainly on the basis of integrated spectroscopic techniques. In vitro, cytotoxic activities of the two new triterpene saponins were evaluated against three human tumor cell lines (A549, SMMC-7721, and MCF-7) using the MTT assay. Both of them showed a certain cytotoxic activities toward the tested cell lines and gave IC50 values in the range of 45.04-63.22 MUM. PMID- 26982332 TI - Estradiol and Estrogen Receptor Agonists Oppose Oncogenic Actions of Leptin in HepG2 Cells. AB - Obesity is a significant risk factor for certain cancers, including hepatocellular carcinoma (HCC). Leptin, a hormone secreted by white adipose tissue, precipitates HCC development. Epidemiology data show that men have a much higher incidence of HCC than women, suggesting that estrogens and its receptors may inhibit HCC development and progression. Whether estrogens antagonize oncogenic action of leptin is uncertain. To investigate potential inhibitory effects of estrogens on leptin-induced HCC development, HCC cell line HepG2 cells were treated with leptin in combination with 17 beta-estradiol (E2), estrogen receptor-alpha (ER-alpha) selective agonist PPT, ER-beta selective agonist DPN, or G protein-coupled ER (GPER) selective agonist G-1. Cell number, proliferation, and apoptosis were determined, and leptin- and estrogen-related intracellular signaling pathways were analyzed. HepG2 cells expressed a low level of ER-beta mRNA, and leptin treatment increased ER-beta expression. E2 suppressed leptin induced HepG2 cell proliferation and promoted cell apoptosis in a dose-dependent manner. Additionally E2 reversed leptin-induced STAT3 and leptin-suppressed SOCS3, which was mainly achieved by activation of ER-beta. E2 also enhanced ERK via activating ER-alpha and GPER and activated p38/MAPK via activating ER-beta. To conclude, E2 and its receptors antagonize the oncogenic actions of leptin in HepG2 cells by inhibiting cell proliferation and stimulating cell apoptosis, which was associated with reversing leptin-induced changes in SOCS3/STAT3 and increasing p38/MAPK by activating ER-beta, and increasing ERK by activating ER alpha and GPER. Identifying roles of different estrogen receptors would provide comprehensive understanding of estrogenic mechanisms in HCC development and shed light on potential treatment for HCC patients. PMID- 26982334 TI - Genetic Diversity and Local Connectivity in the Mediterranean Red Gorgonian Coral after Mass Mortality Events. AB - Estimating the patterns of connectivity in marine taxa with planktonic dispersive stages is a challenging but crucial task because of its conservation implications. The red gorgonian Paramuricea clavata is a habitat forming species, characterized by short larval dispersal and high reproductive output, but low recruitment. In the recent past, the species was impacted by mass mortality events caused by increased water temperatures in summer. In the present study, we used 9 microsatellites to investigate the genetic structure and connectivity in the highly threatened populations from the Ligurian Sea (NW Mediterranean). No evidence for a recent bottleneck neither decreased genetic diversity in sites impacted by mass mortality events were found. Significant IBD pattern and high global FST confirmed low larval dispersal capability in the red gorgonian. The maximum dispersal distance was estimated at 20-60 km. Larval exchange between sites separated by hundreds of meters and between different depths was detected at each site, supporting the hypothesis that deeper subpopulations unaffected by surface warming peaks may provide larvae for shallower ones, enabling recovery after climatically induced mortality events. PMID- 26982335 TI - Effective treatment with azathioprine for renal amyloidosis secondary to familial Mediterranean fever. PMID- 26982337 TI - Insulin resistance is associated with esophageal varices in alcoholic liver disease patients. AB - BACKGROUND AND AIM: Insulin resistance plays an important role in chronic liver disease, where it has been associated with the progression of fibrosis and correlated with portal hypertension in cirrhotic patients with mixed etiology. However, the impact of insulin resistance in alcoholic liver disease remains mostly unknown. The aim of this study was to evaluate the association between insulin resistance, portal hypertension, severity of liver disease, and mortality in patients with alcoholic cirrhosis. PATIENTS AND METHODS: A total of 106 consecutive alcoholic cirrhotic patients undergoing hepatic venous pressure gradient measurement at Erasme Hospital were included. Insulin resistance was estimated using the homeostatic model assessment-2 index. RESULTS: The median model for end-stage liver disease (MELD) score was 15 (9-21) and the mean hepatic venous pressure gradient was16.3+/-6 mmHg. Twenty-six percent of the patients had compensated cirrhosis. Insulin resistance was significantly associated with portal hypertension in compensated cirrhotic patients and with the presence of esophageal varices, but was not associated with the MELD score and mortality. MELD score was the only independent covariate associated with mortality at 6 (P<0.001) and 12 months (P<0.001). CONCLUSION: Insulin resistance is associated with the presence of esophageal varices, suggesting that the presence of insulin resistance could be harmful to alcoholic liver disease patients. PMID- 26982338 TI - Comparative analysis of online patient education material pertaining to hepatitis and its complications. AB - BACKGROUND AND AIMS: Approximately 50% of patients leave the doctor's office with a poor understanding of their diagnosis. Online patient education websites are becoming a major source of information for many of the patients. Here, we determine the reading grade level of online patient education materials on hepatitis B, hepatitis C, cirrhosis, and hepatocellular cancer and compare it with the National Institutes of Health-recommended reading grade level of sixth to seventh grade or under. METHODS: A Google search was performed to retrieve patient reading materials. Text was modified to remove medical terms that were defined within the article. Documents were then divided into categories of introduction, risk factors, symptoms, diagnosis, treatment, and prevention. Each document was then analyzed using six validated readability tests to determine the grade level and complexity on the basis of the number of words, syllables, or number of uncommon words. RESULTS: Modified documents had a mean readability score of 10.23, although the recommended score is less than 7.0. Cirrhosis had the highest reading grade level, with a median of 11.3, whereas hepatitis B and hepatocellular carcinoma had the easiest readability, with a median of 9.5. Furthermore, treatment subsection was the most difficult, with a median score of 10.8. CONCLUSION: Patient reading materials reviewed in this study were written well above the recommended reading grade level. These findings suggest review of patient education materials in an effort to close the gap between the average reading level and the reading materials. PMID- 26982336 TI - An Approach to Function Annotation for Proteins of Unknown Function (PUFs) in the Transcriptome of Indian Mulberry. AB - The modern sequencing technologies are generating large volumes of information at the transcriptome and genome level. Translation of this information into a biological meaning is far behind the race due to which a significant portion of proteins discovered remain as proteins of unknown function (PUFs). Attempts to uncover the functional significance of PUFs are limited due to lack of easy and high throughput functional annotation tools. Here, we report an approach to assign putative functions to PUFs, identified in the transcriptome of mulberry, a perennial tree commonly cultivated as host of silkworm. We utilized the mulberry PUFs generated from leaf tissues exposed to drought stress at whole plant level. A sequence and structure based computational analysis predicted the probable function of the PUFs. For rapid and easy annotation of PUFs, we developed an automated pipeline by integrating diverse bioinformatics tools, designated as PUFs Annotation Server (PUFAS), which also provides a web service API (Application Programming Interface) for a large-scale analysis up to a genome. The expression analysis of three selected PUFs annotated by the pipeline revealed abiotic stress responsiveness of the genes, and hence their potential role in stress acclimation pathways. The automated pipeline developed here could be extended to assign functions to PUFs from any organism in general. PUFAS web server is available at http://caps.ncbs.res.in/pufas/ and the web service is accessible at http://capservices.ncbs.res.in/help/pufas. PMID- 26982339 TI - Gastro-oesophageal reflux disease and dental erosions in adults: influence of acidified food intake and impact on quality of life. AB - BACKGROUND AND AIM: Gastro-oesophageal reflux disease (GORD) and dental erosions (DE) have an established association. We assessed whether GORD is associated with DE controlling for acidified food intake and their relationships with quality of life (QOL). METHODS: In this cross-sectional study, 419 adult patients who sought dentistry consultation were considered eligible. Patients responded to questionnaires for GORD symptoms, acidified food ingestion and World Health Organization quality of life (WHOQOL Bref), followed by an oral examination, in which DE were characterized according to the Smith & Knight criteria. RESULTS: A total of 417 patients were included (43.8+/-13.7 years; 68.8% women). There were 143 patients with GORD (34.3%) and 274 controls without GORD. The prevalence of DE was higher in GORD patients compared with the controls (25.9 vs. 17.2%; P=0.041). GORD was associated with DE after adjusting for acidified food intake (P=0.035), with a prevalence ratio of 1.52 (0.95 confidence interval 1.03-2.22). The WHOQOL Bref score was significantly lower in the presence of GORD [median 17.2 (GORD-DE-) vs. 15.4 (GORD+DE+); P<0.01], irrespective of DE. CONCLUSION: In adults examined in a referential dentistry centre in South America, DE were prevalent and significantly associated with GORD. This association was independent of the intake of acidified food in our study. Impairment in QOL was observed in GORD patients irrespective of the presence of DE. PMID- 26982340 TI - OUTCOMES AFTER PARS PLANA VITRECTOMY FOR EPIRETINAL MEMBRANES ASSOCIATED WITH TOXOPLASMOSIS. AB - PURPOSE: To evaluate outcomes and complications of pars plana vitrectomy in patients with epiretinal membrane secondary to toxoplasmic retinochoroiditis. METHODS: Retrospective evaluation of the records of 14 patients who underwent pars plana vitrectomy for epiretinal membrane secondary to toxoplasmic retinochoroiditis. The best-corrected visual acuity, intraoperative and postoperative complications, and macular optical coherence tomography were analysed. All patients received postoperative prophylactic treatment with trimethoprim/sulfamethoxazole. RESULTS: Fourteen patients, 5 men and 9 women, were included. Mean follow-up period after surgery was 6.07 +/- 2.64 months. Preoperative mean best-corrected visual acuity was 20/200, and postoperative mean best-corrected visual acuity was 20/60. There were no intraoperative complications. Three patients developed posterior capsule opacification, and one patient developed cataract. CONCLUSION: Pars plana vitrectomy is a safe and effective procedure in patients with epiretinal membrane secondary to toxoplasmic retinochoroiditis, improving both visual acuity and anatomical result on macular optical coherence tomography. The most frequent postoperative complications were posterior capsule opacification and cataract. No recurrences of the disease were recorded. PMID- 26982341 TI - Automatic Multiple-Needle Surgical Planning of Robotic-Assisted Microwave Coagulation in Large Liver Tumor Therapy. AB - The "robotic-assisted liver tumor coagulation therapy" (RALTCT) system is a promising candidate for large liver tumor treatment in terms of accuracy and speed. A prerequisite for effective therapy is accurate surgical planning. However, it is difficult for the surgeon to perform surgical planning manually due to the difficulties associated with robot-assisted large liver tumor therapy. These main difficulties include the following aspects: (1) multiple needles are needed to destroy the entire tumor, (2) the insertion trajectories of the needles should avoid the ribs, blood vessels, and other tissues and organs in the abdominal cavity, (3) the placement of multiple needles should avoid interference with each other, (4) an inserted needle will cause some deformation of liver, which will result in changes in subsequently inserted needles' operating environment, and (5) the multiple needle-insertion trajectories should be consistent with the needle-driven robot's movement characteristics. Thus, an effective multiple-needle surgical planning procedure is needed. To overcome these problems, we present an automatic multiple-needle surgical planning of optimal insertion trajectories to the targets, based on a mathematical description of all relevant structure surfaces. The method determines the analytical expression of boundaries of every needle "collision-free reachable workspace" (CFRW), which are the feasible insertion zones based on several constraints. Then, the optimal needle insertion trajectory within the optimization criteria will be chosen in the needle CFRW automatically. Also, the results can be visualized with our navigation system. In the simulation experiment, three needle-insertion trajectories were obtained successfully. In the in vitro experiment, the robot successfully achieved insertion of multiple needles. The proposed automatic multiple-needle surgical planning can improve the efficiency and safety of robot-assisted large liver tumor therapy, significantly reduce the surgeon's workload, and is especially helpful for an inexperienced surgeon. The methodology should be easy to adapt in other body parts. PMID- 26982342 TI - Intractable Central Hyperthermia in the Setting of Brainstem Hemorrhage. AB - Hyperthermia from a central cause is associated with increased morbidity and mortality. Dysfunction of brainstem thermoregulatory pathways may explain the intractable rise in temperature. Antipyretics, dantrolene, bromocriptine, and surface and intravascular cooling devices have been attempted for temperature control. We report the case of a 54-year-old woman with history of hypertension who presented with pontine hemorrhage with extension into the midbrain and medulla. On days 8-9 of her hospital admission, she developed intractable fever and expired the same day despite aggressive treatment of hypothermia, including antipyretics, ice lavage, cold fluid boluses, surface cooling, dantrolene, and bromocriptine. Hyperthermia from brainstem hemorrhage can be difficult to manage with current treatment options. Early recognition of those patients who may develop hyperthermia could lead to early intervention and possibly better outcomes. More evidence from prospective randomized controlled trials will elucidate the risk-benefit profile of achieving normothermia with aggressive fever control in these patients. PMID- 26982343 TI - Loss of BAP1 Expression Is Very Rare in Pancreatic Ductal Adenocarcinoma. AB - BACKGROUND: Pancreatic cancer is both common and highly lethal and therefore new biomarkers or potential targets for treatment are needed. Loss of BRCA associated protein-1 (BAP1) expression has been found in up to a quarter of intrahepatic cholangiocarcinomas. Given the close anatomical relationship between intrahepatic cholangiocarcinoma and pancreatic ductal adenocarcinoma, we therefore sought to investigate the frequency of loss of BAP1 expression in pancreatic ductal adenocarcinoma. METHODS: The records of the department of Anatomical Pathology Royal North Shore Hospital, Sydney, Australia, were searched for cases of pancreatic ductal adenocarcinoma diagnosed between 1992 and 2014 with material available in archived formalin fixed paraffin embedded tissue blocks. Immunohistochemistry for BAP1 was performed on tissue microarray sections and if staining was equivocal or negative it was confirmed on whole sections. Negative staining for BAP1 was defined as loss of expression in all neoplastic nuclei, with preserved expression in non-neoplastic cells which acted as an internal positive control. RESULTS: Loss of BAP1 expression was found in only 1 of 306 (0.33%) pancreatic ductal adenocarcinomas. This case was confirmed to demonstrate diffuse loss of expression throughout all neoplastic cells in multiple blocks, consistent with BAP1 loss being an early clonal event. All other cases demonstrated positive expression of BAP1. CONCLUSION: We conclude that, in contrast to intrahepatic cholangiocarcinoma, loss of expression of BAP1 occurs very rarely in pancreatic ductal adenocarcinoma. Therefore BAP1 inactivation is unlikely to be a frequent driver abnormality in pancreatic adenocarcinoma. PMID- 26982345 TI - Pancreas Transplantation of US and Non-US Cases from 2005 to 2014 as Reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR). AB - This report is an update of pancreas and kidney transplant activities in the US and non-US region in two periods, 2005-2009 and 2010-2014. The aim of the report was to analyze transplant progress and success in the US compared to non-US countries, and to compare trends between the two periods. Between 2005-2009 and 2010-2014, the number of US pancreas transplants declined by over 20%, while the overall number of pancreas transplants performed outside the US has increased. The decline in US numbers is predominantly due to the decline in primary and secondary pancreas after kidney transplants (PAK). During the time period studied, the number of PAK transplants dropped by 50%. In contrast, the number of simultaneous pancreas/kidney transplants (SPK) declined by only 10%, and the number of pancreas transplants alone (PTA) by 20%. Over 90% of pancreas transplants worldwide were performed, with a simultaneous kidney transplant and excellent results. Transplant outcomes in SPK improved significantly because of a decrease in the rates of technical and immunologic graft loss. In 2010-2014 vs. 2005-2009, US SPK transplant patient survival at 1 year post-transplant increased from 95.7% to 97.4%, pancreas graft function from 88.3% to 91.3%, and kidney function from 93.6% to 95.5%. A significant improvement was also noted in PAK transplants. One-year patient survival increased from 96.4% to 97.9% and pancreas graft function from 81.0% to 86.0%. PTA 1-year patient survival remained constant at 97%, and pancreas 1-year graft survival improved from 81.0% to 85.7%. With the decline in the number of transplants, a change towards better pancreas donor selection was observed. In solitary transplants, the donors were primarily young trauma victims, and the pancreas preservation time was relatively short. A general tendency towards transplanting older recipients was noted. In 2010-2014 vs. 2005-2009, PTA recipients 50 years of age or older accounted for 32% vs. 22%, PAK for 28% vs. 22%, and SPK for 22% vs. 20%. This may be due to a relatively lower immunologic graft loss rate, especially in solitary transplants, which historically has been high in young recipients. The number of pancreas transplants in patients with type 2 diabetes and end-stage renal disease has increased, and accounted for 9% of all SPK recipients in 2010-2014. PMID- 26982346 TI - Pediatric liver transplantation: a North American perspective. AB - Liver transplantation (LT) is an important component in the therapeutic armamentarium of managing end-stage liver disease. In North American children, biliary atresia remains the most common indication for LT compared to hepatitis C in adults, while hepatoblastoma is the most common liver tumor requiring LT, versus Hepatocellular carcinoma in adults. Rejection, lymphoproliferative disease, renal insufficiency, metabolic syndrome, recurrent disease, 'de novo' autoimmune hepatitis and malignancy require careful surveillance and prompt action in adults and children after LT. In children, specific attention to EBV viremia, growth, development, adherence and transition to the adult services is also required. Antibody mediated rejection and screening for donor specific antibodies is becoming important in managing liver graft dysfunction. Biomarkers to identify and predict tolerance are being developed. Machine perfusion and stem cells (iPS) to synthesize organs are generating interest and are a focus for research. PMID- 26982347 TI - Effects of CO2 Lasers on Dental Pulp Biology in Rats. AB - OBJECTIVE: The purpose of this study was to investigate the effects of CO2 lasers on the proliferation and differentiation of dental pulp cells, and their latent self-recovery in connection with their stemness using reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. MATERIALS AND METHODS: The first molars from male Sprague-Dawley rats, each weighing ~150-200 g, were used for this study. The upper first molars were irradiated with a 10,600 nm wavelength CO2 laser under identical parameters (2 W CO2 laser, energy 4J, energy density 203.84 J/cm(2) for 8.8 sec) through the dentin of the occlusal surface. The molars were extracted immediately, or at 1, 3 or 5 days after the laser irradiation. RT-PCR analysis using primers specific for heat shock protein 70 (Hsp70), adenosine triphosphate (ATP)-binding cassette transporter G2 (ABCG2), dentin sialophosphoprotein (DSPP), and dentin matrix protein 1 (DMP1), and immunohistochemistry using antibodies specific for proliferating cell nuclear antigen (PCNA), ABCG2, CD34, and CD44 were performed. RESULTS: RT-PCR analysis revealed that Hsp70 mRNA expression in the immediate group and ABCG2 mRNA expression at day 1 were the highest. DSPP and DMP1 mRNA expression in the laser irradiated groups increased gradually, reaching its peak on the 5th day of the experiment, although no significant difference found among groups with regard to DMP1 expression. Immunohistochemically, PCNA-positive cells were observed at all times after the laser irradiation; however, they were most evident on day 3. CD44 positive cells were observed strongly on day 1 and day 3, while ABCG2-positive cells were the most evident on day 3. CONCLUSIONS: These results demonstrate that CO2 laser irradiation induces degeneration in the pulp tissue, which is then repaired by newly formed odontoblast-like cells. PMID- 26982348 TI - Changing the Direction of Suicide Prevention Research: A Necessity for True Population Impact. PMID- 26982349 TI - Pertuzumab for the treatment of breast cancer: a safety review. AB - INTRODUCTION: Approximately twenty to thirty percent of newly diagnosed breast cancers are human epidermal growth factor receptor 2 (HER2) positive. The use of trastuzumab, and more recently pertuzumab, has significantly improved the progression free survival (PFS) and overall survival (OS) in this patient population. However, pertuzumab has side effects that can impact treatment tolerability and quality of life. AREAS COVERED: This review describes the safety and tolerability of pertuzumab, a monoclonal antibody targeted at HER2 approved by the United States Food and Drug Administration (FDA) for use in the neoadjuvant and first line metastatic settings. EXPERT OPINION: The combination of trastuzumab, pertuzumab, and chemotherapy is approved in the neoadjuvant and first line metastatic settings and should be strongly considered by providers. Further studies are needed to look at side effect prevention, novel pertuzumab containing regimens, and re-treating patients with pertuzumab. PMID- 26982350 TI - Interaction between the Rev1 C-Terminal Domain and the PolD3 Subunit of Polzeta Suggests a Mechanism of Polymerase Exchange upon Rev1/Polzeta-Dependent Translesion Synthesis. AB - Translesion synthesis (TLS) is a mutagenic branch of cellular DNA damage tolerance that enables bypass replication over DNA lesions carried out by specialized low-fidelity DNA polymerases. The replicative bypass of most types of DNA damage is performed in a two-step process of Rev1/Polzeta-dependent TLS. In the first step, a Y-family TLS enzyme, typically Poleta, Poliota, or Polkappa, inserts a nucleotide across a DNA lesion. In the second step, a four-subunit B family DNA polymerase Polzeta (Rev3/Rev7/PolD2/PolD3 complex) extends the distorted DNA primer-template. The coordinated action of error-prone TLS enzymes is regulated through their interactions with the two scaffold proteins, the sliding clamp PCNA and the TLS polymerase Rev1. Rev1 interactions with all other TLS enzymes are mediated by its C-terminal domain (Rev1-CT), which can simultaneously bind the Rev7 subunit of Polzeta and Rev1-interacting regions (RIRs) from Poleta, Poliota, or Polkappa. In this work, we identified a previously unknown RIR motif in the C-terminal part of PolD3 subunit of Polzeta whose interaction with the Rev1-CT is among the tightest mediated by RIR motifs. Three-dimensional structure of the Rev1-CT/PolD3-RIR complex determined by NMR spectroscopy revealed a structural basis for the relatively high affinity of this interaction. The unexpected discovery of PolD3-RIR motif suggests a mechanism of "inserter" to "extender" DNA polymerase switch upon Rev1/Polzeta-dependent TLS, in which the PolD3-RIR binding to the Rev1-CT (i) helps displace the "inserter" Poleta, Poliota, or Polkappa from its complex with Rev1, and (ii) facilitates assembly of the four-subunit "extender" Polzeta through simultaneous interaction of Rev1-CT with Rev7 and PolD3 subunits. PMID- 26982352 TI - Tissue-Resident Macrophage Ontogeny and Homeostasis. AB - Defining the origins and developmental pathways of tissue-resident macrophages should help refine our understanding of the role of these cells in various disease settings and enable the design of novel macrophage-targeted therapies. In recent years the long-held belief that macrophage populations in the adult are continuously replenished by monocytes from the bone marrow (BM) has been overturned with the advent of new techniques to dissect cellular ontogeny. The new paradigm suggests that several tissue-resident macrophage populations are seeded during waves of embryonic hematopoiesis and self-maintain independently of BM contribution during adulthood. However, the exact nature of the embryonic progenitors that give rise to adult tissue-resident macrophages is still debated, and the mechanisms enabling macrophage population maintenance in the adult are undefined. Here, we review the emergence of these concepts and discuss current controversies and future directions in macrophage biology. PMID- 26982351 TI - The Impact of Myeloperoxidase and Activated Macrophages on Metaphase II Mouse Oocyte Quality. AB - Myeloperoxidase (MPO), an abundant heme-containing enzyme present in neutrophils, monocytes, and macrophages, is produced in high levels during inflammation, and associated with poor reproductive outcomes. MPO is known to generate hypochlorous acid (HOCl), a damaging reactive oxygen species (ROS) utilizing hydrogen peroxide (H2O2) and chloride (Cl-). Here we investigate the effect of activated immune cells and MPO on oocyte quality. Mouse metaphase II oocytes were divided into the following groups: 1) Incubation with a catalytic amount of MPO (40 nM) for different incubation periods in the presence of 100 mM Cl- with and without H2O2 and with and without melatonin (100 MUM), at 37 degrees C (n = 648/648 total number of oocytes in each group for oocytes with and without cumulus cells); 2) Co-cultured with activated mouse peritoneal macrophage and neutrophils cells (1.0 x 106 cells/ml) in the absence and presence of melatonin (200 MUM), an MPO inhibitor/ROS scavenger, for different incubation periods in HTF media, at 37 degrees C (n = 200/200); 3) Untreated oocytes incubated for 4 hrs as controls (n = 73/64). Oocytes were then fixed, stained and scored based on the microtubule morphology and chromosomal alignment. All treatments were found to negatively affect oocyte quality in a time dependent fashion as compared to controls. In all cases the presence of cumulus cells offered no protection; however significant protection was offered by melatonin. Similar results were obtained with oocytes treated with neutrophils. This work provides a direct link between MPO and decreased oocyte quality. Therefore, strategies to decrease MPO mediated inflammation may influence reproductive outcomes. PMID- 26982354 TI - Phagocytosis: An Immunobiologic Process. AB - It has been a century since the death of Elie Metchnikoff, who championed the role of phagocytosis in cellular immunity. Whereas others had observed the uptake of particles by cells from simple to complex organisms, he grasped its significance in the host response to injury and infection and established a firm basis for our understanding of inflammation and tissue homeostasis. The past century has brought improved tools of cellular and molecular biology to the study of phagocytosis and its contribution to physiological and pathological processes, including receptor function in innate and acquired immunity. In this review, I assess our present knowledge and consider opportunities for future research and therapeutic targeting. PMID- 26982355 TI - Molecular Determinants in Phagocyte-Bacteria Interactions. AB - Phagocytes are crucial for host defense against bacterial pathogens. As first demonstrated by Metchnikoff, neutrophils and mononuclear phagocytes share the capacity to engulf, kill, and digest microbial invaders. Generally, neutrophils focus on extracellular, and mononuclear phagocytes on intracellular, pathogens. Reciprocally, extracellular pathogens often capitalize on hindering phagocytosis and killing of phagocytes, whereas intracellular bacteria frequently allow their engulfment and then block intracellular killing. As foreseen by Metchnikoff, phagocytes become highly versatile by acquiring diverse phenotypes, but still retaining some plasticity. Further, phagocytes engage in active crosstalk with parenchymal and immune cells to promote adjunctive reactions, including inflammation, tissue healing, and remodeling. This dynamic network allows the host to cope with different types of microbial invaders. Here we present an update of molecular and cellular mechanisms underlying phagocyte functions in antibacterial defense. We focus on four exemplary bacteria ranging from an opportunistic extracellular to a persistent intracellular pathogen. PMID- 26982357 TI - Microglial Physiology and Pathophysiology: Insights from Genome-wide Transcriptional Profiling. AB - Microglia originate from erythromyeloid progenitors (EMPs) in the yolk sac and develop in the forming CNS. Microglia are fundamental for the development and function of a healthy brain. By contrast, their role in immune host defense of the CNS remains speculative, given the immune privilege of this organ. Alterations in microglia functionality are involved in brain aging, as well as in neurodegenerative disease severity and progression. The combination of their ontogeny with the influence of the complex environment of the CNS makes microglia a unique cell population. Recent observations about microglia ontogeny combined with extensive gene expression profiling allow us to better capture the variety of nuances that microglia can manifest. Here, we provide a contemporary appraisal of microglial uniqueness based on their origin, functions, and expression profiles. Furthermore, we give an overview of the impact of aging and neurodegenerative diseases on microglia transcriptomes. PMID- 26982358 TI - A Pioneer's Tail. AB - In this issue of Immunity, Boller et al. (2016) show that a C-terminal domain of EBF1 is required for chromatin binding and induction of DNase I hypersensitive sites. These properties mark EBF1 as a pioneer factor in B cell development and demonstrate a role for non-DNA binding domains in this process. PMID- 26982353 TI - Macrophages in Tissue Repair, Regeneration, and Fibrosis. AB - Inflammatory monocytes and tissue-resident macrophages are key regulators of tissue repair, regeneration, and fibrosis. After tissue injury, monocytes and macrophages undergo marked phenotypic and functional changes to play critical roles during the initiation, maintenance, and resolution phases of tissue repair. Disturbances in macrophage function can lead to aberrant repair, such that uncontrolled production of inflammatory mediators and growth factors, deficient generation of anti-inflammatory macrophages, or failed communication between macrophages and epithelial cells, endothelial cells, fibroblasts, and stem or tissue progenitor cells all contribute to a state of persistent injury, and this could lead to the development of pathological fibrosis. In this review, we discuss the mechanisms that instruct macrophages to adopt pro-inflammatory, pro wound-healing, pro-fibrotic, anti-inflammatory, anti-fibrotic, pro-resolving, and tissue-regenerating phenotypes after injury, and we highlight how some of these mechanisms and macrophage activation states could be exploited therapeutically. PMID- 26982359 TI - Taking the Broad View on B Cell Affinity Maturation. AB - Germinal center (GC) responses are required for the generation of high-affinity antigen-specific B cells. Kuraoka et al. (2016) explore the importance of inter clonal competition in GC affinity maturation through the use of complex immunizing antigens and discover an unexpected increase in clonal diversity over the course of the response. PMID- 26982360 TI - Silence of the ROS. AB - Reactive oxygen species (ROS) are generated during T cell activation and serve a signaling function but can also be damaging. In this issue of Immunity, Zhang et al. (2016) show that miR-23a prevents ROS-elicited necrosis by suppressing cyclophilin D (PPIF), a regulator of ROS escape from mitochondria. PMID- 26982356 TI - Macrophages and Iron Metabolism. AB - Iron is a transition metal that due to its inherent ability to exchange electrons with a variety of molecules is essential to support life. In mammals, iron exists mostly in the form of heme, enclosed within an organic protoporphyrin ring and functioning primarily as a prosthetic group in proteins. Paradoxically, free iron also has the potential to become cytotoxic when electron exchange with oxygen is unrestricted and catalyzes the production of reactive oxygen species. These biological properties demand that iron metabolism is tightly regulated such that iron is available for core biological functions while preventing its cytotoxic effects. Macrophages play a central role in establishing this delicate balance. Here, we review the impact of macrophages on heme-iron metabolism and, reciprocally, how heme-iron modulates macrophage function. PMID- 26982361 TI - Chitosan: An Adjuvant with an Unanticipated STING. AB - Adjuvants promote adaptive immunity through the triggering of innate signals that are largely poorly understood. In this issue of Immunity, Lavelle and colleagues describe an unexpected role for the DNA sensing cGAS-STING pathway in the mechanism of action of the Th1 cell-promoting polysaccharide adjuvant chitosan. PMID- 26982362 TI - Cancer Immunosurveillance Caught in the Act. AB - The role of the immune system in the control of cancer formation and progression has been a matter of considerable debate over many years. In this issue of Immunity, Mlecnik et al. (2016) show the importance of immunosurveillance in controlling tumors in a series of microsatellite-instable human colon carcinomas. PMID- 26982363 TI - Pioneering Activity of the C-Terminal Domain of EBF1 Shapes the Chromatin Landscape for B Cell Programming. AB - Lymphopoiesis requires the activation of lineage-specific genes embedded in naive, inaccessible chromatin or in primed, accessible chromatin. The mechanisms responsible for de novo gain of chromatin accessibility, known as "pioneer" function, remain poorly defined. Here, we showed that the EBF1 C-terminal domain (CTD) is required for the regulation of a specific gene set involved in B cell fate decision and differentiation, independently of activation and repression functions. Using genome-wide analysis of DNaseI hypersensitivity and DNA methylation in multipotent Ebf1(-/-) progenitors and derivative EBF1wt- or EBF1DeltaC-expressing cells, we found that the CTD promoted chromatin accessibility and DNA demethylation in previously naive chromatin. The CTD allowed EBF1 to bind at inaccessible genomic regions that offer limited co occupancy by other transcription factors, whereas the CTD was dispensable for EBF1 binding at regions that are occupied by multiple transcription factors. Thus, the CTD enables EBF1 to confer permissive lineage-specific changes in progenitor chromatin landscape. PMID- 26982364 TI - NEMO Prevents RIP Kinase 1-Mediated Epithelial Cell Death and Chronic Intestinal Inflammation by NF-kappaB-Dependent and -Independent Functions. AB - Intestinal epithelial cells (IECs) regulate gut immune homeostasis, and impaired epithelial responses are implicated in the pathogenesis of inflammatory bowel diseases (IBD). IEC-specific ablation of nuclear factor kappaB (NF-kappaB) essential modulator (NEMO) caused Paneth cell apoptosis and impaired antimicrobial factor expression in the ileum, as well as colonocyte apoptosis and microbiota-driven chronic inflammation in the colon. Combined RelA, c-Rel, and RelB deficiency in IECs caused Paneth cell apoptosis but not colitis, suggesting that NEMO prevents colon inflammation by NF-kappaB-independent functions. Inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity or combined deficiency of Fas-associated via death domain protein (FADD) and RIPK3 prevented epithelial cell death, Paneth cell loss, and colitis development in mice with epithelial NEMO deficiency. Therefore, NEMO prevents intestinal inflammation by inhibiting RIPK1 kinase activity-mediated IEC death, suggesting that RIPK1 inhibitors could be effective in the treatment of colitis in patients with NEMO mutations and possibly in IBD. PMID- 26982365 TI - Lymphoid-Tissue-Resident Commensal Bacteria Promote Members of the IL-10 Cytokine Family to Establish Mutualism. AB - Physical separation between the mammalian immune system and commensal bacteria is necessary to limit chronic inflammation. However, selective species of commensal bacteria can reside within intestinal lymphoid tissues of healthy mammals. Here, we demonstrate that lymphoid-tissue-resident commensal bacteria (LRC) colonized murine dendritic cells and modulated their cytokine production. In germ-free and antibiotic-treated mice, LRCs colonized intestinal lymphoid tissues and induced multiple members of the IL-10 cytokine family, including dendritic-cell-derived IL-10 and group 3 innate lymphoid cell (ILC3)-derived IL-22. Notably, IL-10 limited the development of pro-inflammatory Th17 cell responses, and IL-22 production enhanced LRC colonization in the steady state. Furthermore, LRC colonization protected mice from lethal intestinal damage in an IL-10-IL-10R dependent manner. Collectively, our data reveal a unique host-commensal-bacteria dialog whereby selective subsets of commensal bacteria interact with dendritic cells to facilitate tissue-specific responses that are mutually beneficial for both the host and the microbe. PMID- 26982368 TI - Self-learning kinetic Monte Carlo simulations of Al diffusion in Mg. AB - Vacancy-mediated diffusion of an Al atom in the pure Mg matrix is studied using the atomistic, on-lattice self-learning kinetic Monte Carlo (SLKMC) method. Activation barriers for vacancy-Mg and vacancy-Al atom exchange processes are calculated on the fly using the climbing image nudged-elastic-band method and binary Mg-Al modified embedded-atom method interatomic potential. Diffusivities of an Al atom obtained from SLKMC simulations show the same behavior as observed in experimental and theoretical studies available in the literature; that is, an Al atom diffuses faster within the basal plane than along the c-axis. Although the effective activation barriers for an Al atom diffusion from SLKMC simulations are close to experimental and theoretical values, the effective prefactors are lower than those obtained from experiments. We present all the possible vacancy Mg and vacancy-Al atom exchange processes and their activation barriers identified in SLKMC simulations. A simple mapping scheme to map an HCP lattice onto a simple cubic lattice is described, which enables simulation of the HCP lattice using the on-lattice framework. We also present the pattern recognition scheme which is used in SLKMC simulations to identify the local Al atom configuration around a vacancy. PMID- 26982366 TI - Intestinal Interleukin-17 Receptor Signaling Mediates Reciprocal Control of the Gut Microbiota and Autoimmune Inflammation. AB - Interleukin-17 (IL-17) and IL-17 receptor (IL-17R) signaling are essential for regulating mucosal host defense against many invading pathogens. Commensal bacteria, especially segmented filamentous bacteria (SFB), are a crucial factor that drives T helper 17 (Th17) cell development in the gastrointestinal tract. In this study, we demonstrate that Th17 cells controlled SFB burden. Disruption of IL-17R signaling in the enteric epithelium resulted in SFB dysbiosis due to reduced expression of alpha-defensins, Pigr, and Nox1. When subjected to experimental autoimmune encephalomyelitis, IL-17R-signaling-deficient mice demonstrated earlier disease onset and worsened severity that was associated with increased intestinal Csf2 expression and elevated systemic GM-CSF cytokine concentrations. Conditional deletion of IL-17R in the enteric epithelium demonstrated that there was a reciprocal relationship between the gut microbiota and enteric IL-17R signaling that controlled dysbiosis, constrained Th17 cell development, and regulated the susceptibility to autoimmune inflammation. PMID- 26982369 TI - Four types of ensemble coding in data visualizations. AB - Ensemble coding supports rapid extraction of visual statistics about distributed visual information. Researchers typically study this ability with the goal of drawing conclusions about how such coding extracts information from natural scenes. Here we argue that a second domain can serve as another strong inspiration for understanding ensemble coding: graphs, maps, and other visual presentations of data. Data visualizations allow observers to leverage their ability to perform visual ensemble statistics on distributions of spatial or featural visual information to estimate actual statistics on data. We survey the types of visual statistical tasks that occur within data visualizations across everyday examples, such as scatterplots, and more specialized images, such as weather maps or depictions of patterns in text. We divide these tasks into four categories: identification of sets of values, summarization across those values, segmentation of collections, and estimation of structure. We point to unanswered questions for each category and give examples of such cross-pollination in the current literature. Increased collaboration between the data visualization and perceptual psychology research communities can inspire new solutions to challenges in visualization while simultaneously exposing unsolved problems in perception research. PMID- 26982367 TI - Integrative Analyses of Colorectal Cancer Show Immunoscore Is a Stronger Predictor of Patient Survival Than Microsatellite Instability. AB - Microsatellite instability in colorectal cancer predicts favorable outcomes. However, the mechanistic relationship between microsatellite instability, tumor infiltrating immune cells, Immunoscore, and their impact on patient survival remains to be elucidated. We found significant differences in mutational patterns, chromosomal instability, and gene expression that correlated with patient microsatellite instability status. A prominent immune gene expression was observed in microsatellite-instable (MSI) tumors, as well as in a subgroup of microsatellite-stable (MSS) tumors. MSI tumors had increased frameshift mutations, showed genetic evidence of immunoediting, had higher densities of Th1, effector-memory T cells, in situ proliferating T cells, and inhibitory PD1-PDL1 cells, had high Immunoscores, and were infiltrated with mutation-specific cytotoxic T cells. Multivariate analysis revealed that Immunoscore was superior to microsatellite instability in predicting patients' disease-specific recurrence and survival. These findings indicate that assessment of the immune status via Immunoscore provides a potent indicator of tumor recurrence beyond microsatellite instability staging that could be an important guide for immunotherapy strategies. PMID- 26982370 TI - Binocular contrast discrimination needs monocular multiplicative noise. AB - The effects of signal and noise on contrast discrimination are difficult to separate because of a singularity in the signal-detection-theory model of two alternative forced-choice contrast discrimination (Katkov, Tsodyks, & Sagi, 2006). In this article, we show that it is possible to eliminate the singularity by combining that model with a binocular combination model to fit monocular, dichoptic, and binocular contrast discrimination. We performed three experiments using identical stimuli to measure the perceived phase, perceived contrast, and contrast discrimination of a cyclopean sine wave. In the absence of a fixation point, we found a binocular advantage in contrast discrimination both at low contrasts (<4%), consistent with previous studies, and at high contrasts (>=34%), which has not been previously reported. However, control experiments showed no binocular advantage at high contrasts in the presence of a fixation point or for observers without accommodation. We evaluated two putative contrast discrimination mechanisms: a nonlinear contrast transducer and multiplicative noise (MN). A binocular combination model (the DSKL model; Ding, Klein, & Levi, 2013b) was first fitted to both the perceived-phase and the perceived-contrast data sets, then combined with either the nonlinear contrast transducer or the MN mechanism to fit the contrast-discrimination data. We found that the best model combined the DSKL model with early MN. Model simulations showed that, after going through interocular suppression, the uncorrelated noise in the two eyes became anticorrelated, resulting in less binocular noise and therefore a binocular advantage in the discrimination task. Combining a nonlinear contrast transducer or MN with a binocular combination model (DSKL) provides a powerful method for evaluating the two putative contrast-discrimination mechanisms. PMID- 26982371 TI - Flexible timing of eye movements when catching a ball. AB - In ball games, one cannot direct ones gaze at the ball all the time because one must also judge other aspects of the game, such as other players' positions. We wanted to know whether there are times at which obtaining information about the ball is particularly beneficial for catching it. We recently found that people could catch successfully if they saw any part of the ball's flight except the very end, when sensory-motor delays make it impossible to use new information. Nevertheless, there may be a preferred time to see the ball. We examined when six catchers would choose to look at the ball if they had to both catch the ball and find out what to do with it while the ball was approaching. A catcher and a thrower continuously threw a ball back and forth. We recorded their hand movements, the catcher's eye movements, and the ball's path. While the ball was approaching the catcher, information was provided on a screen about how the catcher should throw the ball back to the thrower (its peak height). This information disappeared just before the catcher caught the ball. Initially there was a slight tendency to look at the ball before looking at the screen but, later, most catchers tended to look at the screen before looking at the ball. Rather than being particularly eager to see the ball at a certain time, people appear to adjust their eye movements to the combined requirements of the task. PMID- 26982372 TI - Bcl-2/MDM2 Dual Inhibitors Based on Universal Pyramid-Like alpha-Helical Mimetics. AB - No alpha-helical mimetic that exhibits Bcl-2/MDM2 dual inhibition has been rationally designed due to the different helicities of the alpha-helixes at their binding interfaces. Herein, we extracted a one-turn alpha-helix-mimicking ortho triarene unit from o-phenylene foldamers. Linking benzamide substrates with a rotatable C-N bond, we constructed a novel semirigid pyramid-like scaffold that could support its two-turn alpha-helix mimicry without aromatic stacking interactions and could adopt the different dihedral angles of the key residues of p53 and BH3-only peptides. On the basis of this universal scaffold, a series of substituent groups were installed to capture the key residues of both p53TAD and BimBH3 and balance the differences of the bulks between them. Identified by FP, ITC, and NMR spectroscopy, a compound 6e (zq-1) that directly binds to Mcl-1, Bcl 2, and MDM2 with balanced submicromolar affinities was obtained. Cell-based experiments demonstrated its antitumor ability through Bcl-2/MDM2 dual inhibition simultaneously. PMID- 26982374 TI - The treatment of Ta-T1 bladder cancer in the era of worldwide BCG shortage. PMID- 26982375 TI - The case for salvage cystectomy after pelvic radiation. AB - Radical cystectomy is considered the standard of care for muscle invasive bladder cancer (MIBC), as well as some high-grade or recurrent non-muscle invasive bladder cancers. There are a number of reasons that urologic surgeons may find themselves considering a salvage cystectomy (SC) for a patient. Understanding the risks associated with performing SC is important for patient counseling when considering primary management of MIBC. Awareness of the unique complications that can occur can alter surgical technique and approach and can equip clinical staff with knowledge to properly monitor the patient during post-operative surveillance to identify and treat these situations. In this review, we characterize the outcomes of patients who underwent SC, elucidate the special considerations that must be made when performing this surgery, and discuss these outcomes in comparison to primary surgery in the absence of radiation. PMID- 26982373 TI - Dexmedetomidine Protects against Transient Global Cerebral Ischemia/Reperfusion Induced Oxidative Stress and Inflammation in Diabetic Rats. AB - BACKGROUND: Transient global cerebral ischemia/reperfusion (I/R) is a major perioperative complication, and diabetes increases the response of oxidative stress and inflammation induced by I/R. The objective of this study was to determine the protective effect of dexmedetomidine against transient global cerebral ischemia/reperfusion induced oxidative stress and inflammation in diabetic rats. METHODS: Sixty-four rats were assigned into four experimental groups: normoglycemia, normoglycemia + dexmedetomidine, hyperglycemia, and hyperglycemia + dexmedetomidine and all subsequent neurological examinations were evaluated by a blinded observer. Damage to the brain was histologically assessed using the TUNEL staining method while western blotting was used to investigate changes in the expression levels of apoptosis-related proteins as well as the microglia marker, ionized calcium-binding adapter molecule 1 (Iba1). Water content in the brain was also analyzed. In addition, hippocampal concentrations of malondialdehyde (MDA) and Nox2 (a member of the Nox family of NADPH oxidases), and the activity of superoxide dismutase and catalase were analyzed. Finally, changes in serum concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 were detected. RESULTS: Results showed that diabetes increased brain water content, the number of apoptotic neurons, early neurological deficit scores, oxidative stress (MDA and Nox2) and inflammation (pro-inflammatory cytokines including TNF-alpha and IL-6) levels following transient global I/R injury, but that these symptoms were attenuated following administration of dexmedetomidine. CONCLUSIONS: These findings suggest that dexmedetomidine can significantly alleviate damage resulting from I/R, and this mechanism may be related to a reduction in both oxidative stress and inflammation which is normally associated with I/R. PMID- 26982376 TI - Catheter impregnation, coating or bonding for reducing central venous catheter related infections in adults. AB - BACKGROUND: The central venous catheter (CVC) is essential in managing acutely ill patients in hospitals. Bloodstream infection is a major complication in patients with a CVC. Several infection control measures have been developed to reduce bloodstream infections, one of which is impregnation of CVCs with various forms of antimicrobials (either with an antiseptic or with antibiotics). This review was originally published in June 2013 and updated in 2016. OBJECTIVES: Our main objective was to assess the effectiveness of antimicrobial impregnation, coating or bonding on CVCs in reducing clinically-diagnosed sepsis, catheter related blood stream infection (CRBSI), all-cause mortality, catheter colonization and other catheter-related infections in adult participants who required central venous catheterization, along with their safety and cost effectiveness where data were available. We undertook the following comparisons: 1) catheters with antimicrobial modifications in the form of antimicrobial impregnation, coating or bonding, against catheters without antimicrobial modifications and 2) catheters with one type of antimicrobial impregnation against catheters with another type of antimicrobial impregnation. We planned to analyse the comparison of catheters with any type of antimicrobial impregnation against catheters with other antimicrobial modifications, e.g. antiseptic dressings, hubs, tunnelling, needleless connectors or antiseptic lock solutions, but did not find any relevant studies. Additionally, we planned to conduct subgroup analyses based on the length of catheter use, settings or levels of care (e.g. intensive care unit, standard ward and oncology unit), baseline risks, definition of sepsis, presence or absence of co-interventions and cost effectiveness in different currencies. SEARCH METHODS: We used the standard search strategy of the Cochrane Anaesthesia, Critical and Emergency Care Review Group (ACE). In the updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 3), MEDLINE (OVID SP; 1950 to March 2015), EMBASE (1980 to March 2015), CINAHL (1982 to March 2015), and other Internet resources using a combination of keywords and MeSH headings. The original search was run in March 2012. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that assessed any type of impregnated catheter against either non-impregnated catheters or catheters with another type of impregnation in adult patients cared for in the hospital setting who required CVCs. We planned to include quasi-RCT and cluster-RCTs, but we identified none. We excluded cross over studies. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methodological procedures expected by Cochrane. Two authors independently assessed the relevance and risk of bias of the retrieved records. We expressed our results using risk ratio (RR), absolute risk reduction (ARR) and number need to treat to benefit (NNTB) for categorical data and mean difference (MD) for continuous data, where appropriate, with their 95% confidence intervals (CIs). MAIN RESULTS: We included one new study (338 participants/catheters) in this update, which brought the total included to 57 studies with 16,784 catheters and 11 types of impregnations. The total number of participants enrolled was unclear, as some studies did not provide this information. Most studies enrolled participants from the age of 18, including patients in intensive care units (ICU), oncology units and patients receiving long-term total parenteral nutrition. There were low or unclear risks of bias in the included studies, except for blinding, which was impossible in most studies due to the catheters that were being assessed having different appearances. Overall, catheter impregnation significantly reduced catheter-related blood stream infection (CRBSI), with an ARR of 2% (95% CI 3% to 1%), RR of 0.62 (95% CI 0.52 to 0.74) and NNTB of 50 (high-quality evidence). Catheter impregnation also reduced catheter colonization, with an ARR of 9% (95% CI 12% to 7%), RR of 0.67 (95% CI 0.59 to 0.76) and NNTB of 11 (moderate-quality evidence, downgraded due to substantial heterogeneity). However, catheter impregnation made no significant difference to the rates of clinically diagnosed sepsis (RR 1.0, 95% CI 0.88 to 1.13; moderate-quality evidence, downgraded due to a suspicion of publication bias), all-cause mortality (RR 0.92, 95% CI 0.80 to 1.07; high-quality evidence) and catheter-related local infections (RR 0.84, 95% CI 0.66 to 1.07; 2688 catheters, moderate quality evidence, downgraded due to wide 95% CI).In our subgroup analyses, we found that the magnitudes of benefits for impregnated CVCs varied between studies that enrolled different types of participants. For the outcome of catheter colonization, catheter impregnation conferred significant benefit in studies conducted in ICUs (RR 0.70;95% CI 0.61 to 0.80) but not in studies conducted in haematological and oncological units (RR 0.75; 95% CI 0.51 to 1.11) or studies that assessed predominantly patients who required CVCs for long-term total parenteral nutrition (RR 0.99; 95% CI 0.74 to 1.34). However, there was no such variation for the outcome of CRBSI. The magnitude of the effects was also not affected by the participants' baseline risks.There were no significant differences between the impregnated and non-impregnated groups in the rates of adverse effects, including thrombosis/thrombophlebitis, bleeding, erythema and/or tenderness at the insertion site. AUTHORS' CONCLUSIONS: This review confirms the effectiveness of antimicrobial CVCs in reducing rates of CRBSI and catheter colonization. However, the magnitude of benefits regarding catheter colonization varied according to setting, with significant benefits only in studies conducted in ICUs. A comparatively smaller body of evidence suggests that antimicrobial CVCs do not appear to reduce clinically diagnosed sepsis or mortality significantly. Our findings call for caution in routinely recommending the use of antimicrobial-impregnated CVCs across all settings. Further randomized controlled trials assessing antimicrobial CVCs should include important clinical outcomes like the overall rates of sepsis and mortality. PMID- 26982377 TI - Cryopreservation of human blood for alkaline and Fpg-modified comet assay. AB - The Comet assay is a reproducible and sensitive assay for the detection of DNA damage in eukaryotic cells and tissues. Incorporation of lesion specific, oxidative DNA damage repair enzymes (for example, Fpg, OGG1 and EndoIII) in the standard alkaline Comet assay procedure allows for the detection and measurement of oxidative DNA damage. The Comet assay using white blood cells (WBC) has proven useful in monitoring DNA damage from environmental agents in humans. However, it is often impractical to performance Comet assay immediately after blood sampling. Thus, storage of blood sample is required. In this study, we developed and tested a simple storage method for very small amount of whole blood for standard and Fpg modified modified Comet assay. Whole blood was stored in RPMI 1640 media containing 10% FBS, 10% DMSO and 1 mM deferoxamine at a sample to media ratio of 1:50. Samples were stored at -20 degrees C and -80 degrees C for 1, 7, 14 and 28 days. Isolated lymphocytes from the same subjects were also stored under the same conditions for comparison. Direct DNA strand breakage and oxidative DNA damage in WBC and lymphocytes were analyzed using standard and Fpg-modified alkaline Comet assay and compared with freshly analyzed samples. No significant changes in either direct DNA strand breakage or oxidative DNA damage was seen in WBC and lymphocytes stored at -20 degrees C for 1 and 7 days compared to fresh samples. However, significant increases in both direct and oxidative DNA damage were seen in samples stored at -20 degrees C for 14 and 28 days. No changes in direct and oxidative DNA damage were observed in WBC and lymphocytes stored at 80 degrees C for up to 28 days. These results identified the proper storage conditions for storing whole blood or isolated lymphocytes to evaluate direct and oxidative DNA damage using standard and Fpg-modified alkaline Comet assay. PMID- 26982378 TI - Strangulated lesser omentum hiatus hernia: a rare case report and a literature review. AB - Intestinal obstruction caused by primary intraperitoneal hernia is infrequent and difficult to diagnose. Incorrect diagnosis and delayed surgical treatment will lead to serious consequences. We report a rare case of a 62-year-old Chinese woman with strangulated lesser omentum hiatus hernia. Contrast-enhanced abdominal computed tomography(CT) scan is recommended for early revealing direct and indirect signs. We propose three diagnostic points of primary intraperitoneal hernia: 1. "Three-no" pathography: with no history of abdominal operation, abdominal trauma and abdominal infection. 2. It begins with mechanical intestinal obstruction, then turns into strangulated intestinal obstruction easily. 3. Exclude intestinal wall lesions and intestinal blockage. We also summarize surgical procedure into four steps. We hope this case can provide a reference for the diagnosis and treatment of similar situations. PMID- 26982380 TI - Setting a National Agenda for Surgical Disparities Research: Recommendations From the National Institutes of Health and American College of Surgeons Summit. AB - Health care disparities (differential access, care, and outcomes owing to factors such as race/ethnicity) are widely established. Compared with other groups, African American individuals have an increased mortality risk across multiple surgical procedures. Gender, sexual orientation, age, and geographic disparities are also well documented. Further research is needed to mitigate these inequities. To do so, the American College of Surgeons and the National Institutes of Health-National Institute of Minority Health and Disparities convened a research summit to develop a national surgical disparities research agenda and funding priorities. Sixty leading researchers and clinicians gathered in May 2015 for a 2-day summit. First, literature on surgical disparities was presented within 5 themes: (1) clinician, (2) patient, (3) systemic/access, (4) clinical quality, and (5) postoperative care and rehabilitation-related factors. These themes were identified via an exhaustive preconference literature review and guided the summit and its interactive consensus-building exercises. After individual thematic presentations, attendees contributed research priorities for each theme. Suggestions were collated, refined, and prioritized during the latter half of the summit. Breakout sessions yielded 3 to 5 top research priorities by theme. Overall priorities, regardless of theme, included improving patient clinician communication, fostering engagement and community outreach by using technology, improving care at facilities with a higher proportion of minority patients, evaluating the longer-term effect of acute intervention and rehabilitation support, and improving patient centeredness by identifying expectations for recovery. The National Institutes of Health and American College of Surgeons Summit on Surgical Disparities Research succeeded in identifying a comprehensive research agenda. Future research and funding priorities should prioritize patients' care perspectives, workforce diversification and training, and systematic evaluation of health technologies to reduce surgical disparities. PMID- 26982379 TI - Nosocomial Co-Transmission of Avian Influenza A(H7N9) and A(H1N1)pdm09 Viruses between 2 Patients with Hematologic Disorders. AB - A nosocomial cluster induced by co-infections with avian influenza A(H7N9) and A(H1N1)pdm09 (pH1N1) viruses occurred in 2 patients at a hospital in Zhejiang Province, China, in January 2014. The index case-patient was a 57-year-old man with chronic lymphocytic leukemia who had been occupationally exposed to poultry. He had co-infection with H7N9 and pH1N1 viruses. A 71-year-old man with polycythemia vera who was in the same ward as the index case-patient for 6 days acquired infection with H7N9 and pH1N1 viruses. The incubation period for the second case-patient was estimated to be <4 days. Both case-patients died of multiple organ failure. Virus genetic sequences from the 2 case-patients were identical. Of 103 close contacts, none had acute respiratory symptoms; all were negative for H7N9 virus. Serum samples from both case-patients demonstrated strong proinflammatory cytokine secretion but incompetent protective immune responses. These findings strongly suggest limited nosocomial co-transmission of H7N9 and pH1N1 viruses from 1 immunocompromised patient to another. PMID- 26982381 TI - Effects of diuretics on sodium-dependent glucose cotransporter 2 inhibitor induced changes in blood pressure in obese rats suffering from the metabolic syndrome. AB - OBJECTIVE: Experiments were carried out to investigate whether diuretics (hydrochlorothiazide + furosemide) impact on the effects of a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor on glucose metabolism and blood pressure (BP) in metabolic syndrome SHR/NDmcr-cp(+/+) rats (SHRcp). METHODS: Male 13-week-old SHRcp were treated with: vehicle; the SGLT2-inhibitor luseogliflozin (10 mg/kg per day); diuretics (hydrochlorothiazide; 10 mg/kg/day + furosemide; 5 mg/kg per day); or luseogliflozin + diuretics (n = 5-8 for each group) daily by oral gavage for 5 weeks. BP and glucose metabolism were evaluated by a telemetry system and oral glucose tolerance test, respectively. RESULTS: Vehicle-treated SHRcp developed nondipper type hypertension (dark vs. light-period mean arterial pressure: 148.6 +/- 0.7 and 148.0 +/- 0.7 mmHg, respectively, P = 0.2) and insulin resistance. Compared with vehicle-treated animals, luseogliflozin-treated rats showed an approximately 4000-fold increase in urinary excretion of glucose and improved glucose metabolism. Luseogliflozin also significantly decreased BP and turned the circadian rhythm of BP from a nondipper to dipper pattern (dark vs. light-period mean arterial pressure: 138.0 +/- 1.6 and 132.0 +/- 1.3 mmHg, respectively, P < 0.01), which were associated with a significant increase in urinary excretion of sodium. Addition of diuretics did not influence luseogliflozin-induced improvement of glucose metabolism and circadian rhythm of BP in SHRcp. CONCLUSION: These data suggest that a SGLT2 inhibitor elicits its beneficial effects on glucose metabolism and hypertension in study participants with metabolic syndrome undergoing treatment with diuretics. PMID- 26982382 TI - Management of the hypertensive patient with elevated heart rate: Statement of the Second Consensus Conference endorsed by the European Society of Hypertension. AB - In June 2015, a panel of experts gathered in a consensus conference to plan updating recommendations on the management of the hypertensive patient with elevated heart rate (HR), previously released in 2006. The issues examined during that meeting and further discussed by the participants during the following months involved the assessment of HR, the relevance of HR as a cardiovascular risk factor, the definition of tachycardia and the treatment of the hypertensive patient with high HR. For the measurement of resting HR the panel experts recommended that scientific investigations focusing on HR should report information on length of resting period before measurement, information about temperature and environment, method of measurement, duration of measurement, number of readings, time interval between measurements, body position and type of observer. According to the panellists there is convincing evidence that HR is an important risk factor for cardiovascular disease and they suggest to routinely include HR measurement in the assessment of the hypertensive patient. Regarding the definition of tachycardia, the panellists acknowledged that in the absence of convincing data any threshold used to define tachycardia is arbitrary. Similarly, as there are no outcome studies of HR lowering in tachycardia hypertension, the panellists could not make practical therapeutic suggestions for the management of such patients. However, the experts remarked that absence of evidence does not mean evidence against the importance of tachycardia as a risk factor for cardiovascular disease and that long-term exposure to a potentially important risk factor may impair the patient's prognosis. The main aims of the present document are to alert researchers and physicians about the importance of measuring HR in hypertensive patients, and to stimulate research to clarify unresolved issues. PMID- 26982383 TI - Prognostic, diagnostic, and therapeutic advances in hypertension. PMID- 26982384 TI - Effectiveness of estrogen treatment before transcervical resection of adhesions on moderate and severe uterine adhesion patients. AB - Intrauterine adhesion (IUA), also known as Asherman's syndrome, is a common disease for among women. The extent of adhesion and pre-surgery hormone therapy greatly affects the function of uterine cavity. This current study investigates the association of different doses of estrogen before transcervical resection of adhesions (TCRA) surgery and clinical outcome in serious IUA. About 120 newly diagnostic serious IUA patients who underwent TCRA were randomly divided into three study groups: Estradiol valerate (progynova) 3 or 9 mg per diet before surgery and the control group. Follow-up hysteroscopy checkups were taken in 1- and 3-month post-operation. The effective power of 9 mg group was significantly higher than other groups. The 9 mg group achieved the best menstrual recovery rate in all study groups compared with the other two groups in 6 months post operatively (p < 0.05). Our results confirmed estradiol valerateas an alternative effective drug for the prevention of IUAs before and after hysteroscopic surgery. PMID- 26982385 TI - Supine Colonoscopy: An Advantage over Left Lateral in Synchronous Proctological Surgery. AB - BACKGROUND: Repositioning sedated or anesthetized patients between colonoscopy and further surgical procedures is potentially unsafe and time consuming. We aim to show that colonoscopy performed in the modified lithotomy position offers surgical, anesthetic, and patient advantage. METHODS: Patients presenting for colonoscopy and a synchronous surgical procedure between May 2013 and August 2014 were prospectively included. Colonoscopy duration, cecal intubation rate (CIR), terminal ileum intubation rate, and patient characteristics were recorded. RESULTS: Sixty-eight patients were included in this study. Of them, 24 (35%) were women and mean age was 42.3 years. Mean colonoscopy duration was 7 minutes (2-24 minutes). CIR was 100%. Terminal ileum intubation rate was 92%. Utilization of ancillary colonoscopic maneuvers was easier for the operator/assistant. Overall theatre time was reduced and there was no increase in length of stay. CONCLUSION: The modified lithotomy position offers multiple surgical, anesthetic, theatre, and patient advantage in those undergoing a colonoscopy followed by a further proctological or surgical procedure. PMID- 26982387 TI - Continued advances for hepatology in 2015. PMID- 26982386 TI - Protein-Assisted Assembly of Modular 3D Plasmonic Raspberry-like Core/Satellite Nanoclusters: Correlation of Structure and Optical Properties. AB - We present a bottom-up assembly route for a large-scale organization of plasmonic nanoparticles (NPs) into three-dimensional (3D) modular assemblies with core/satellite structure. The protein-assisted assembly of small spherical gold or silver NPs with a hydrophilic protein shell (as satellites) onto larger metal NPs (as cores) offers high modularity in sizes and composition at high satellite coverage (close to the jamming limit). The resulting dispersions of metal/metal nanoclusters exhibit high colloidal stability and therefore allow for high concentrations and a precise characterization of the nanocluster architecture in dispersion by small-angle X-ray scattering (SAXS). Strong near-field coupling between the building blocks results in distinct regimes of dominant satellite-to satellite and core-to-satellite coupling. High robustness against satellite disorder was proved by UV/vis diffuse reflectance (integrating sphere) measurements. Generalized multiparticle Mie theory (GMMT) simulations were employed to describe the electromagnetic coupling within the nanoclusters. The close correlation of structure and optical property allows for the rational design of core/satellite nanoclusters with tailored plasmonics and well-defined near-field enhancement, with perspectives for applications such as surface enhanced spectroscopies. PMID- 26982388 TI - Arenavirus Diversity and Phylogeography of Mastomys natalensis Rodents, Nigeria. AB - Mastomys natalensis rodents are natural hosts for Lassa virus (LASV). Detection of LASV in 2 mitochondrial phylogroups of the rodent near the Niger and Benue Rivers in Nigeria underlines the potential for LASV emergence in fresh phylogroups of this rodent. A Mobala-like sequence was also detected in eastern Nigeria. PMID- 26982389 TI - Trial of Portable Continuous Positive Airway Pressure for the Management of Tracheobronchomalacia. PMID- 26982390 TI - Far-Infrared Signatures of Hydrogen Bonding in Phenol Derivatives. AB - One of the most direct ways to study the intrinsic properties of the hydrogen bond interaction is by gas-phase far-infrared (far-IR) spectroscopy because the modes involving hydrogen-bond deformation are excited in this spectral region; however, the far-IR regime is often ignored in molecular structure identification due to the absence of strong far-IR light sources and difficulty in assigning the observed modes by quantum chemical calculations. Far-IR/UV ion-dip spectroscopy using the free electron laser FELIX was applied to directly probe the intramolecular hydrogen-bond interaction in a family of phenol derivatives. Three vibrational modes have been identified, which are expected to be diagnostic for the hydrogen-bond strength: hydrogen-bond stretching and hydrogen-bond-donating and -accepting OH torsion vibrations. Their position is evaluated with respect to the hydrogen bond strength, that is, the length of the hydrogen-bonded OH length. This shows that the hydrogen bond stretching frequency is diagnostic for the size of the ring that is closed by the hydrogen bond, while the strength of the hydrogen bond can be determined from the hydrogen-bond-donating OH torsion frequency. The combination of these two normal modes allows the direct probing of intramolecular hydrogen-bond characteristics using conformation-selective far-IR vibrational spectroscopy. PMID- 26982392 TI - The effects of localised fatigue on upper extremity jump shot kinematics and kinetics in team handball. AB - Team handball is a popular sport worldwide that requires numerous throws to be made throughout the course of a game. Because of the upper extremity demands of repetitive throwing, it is possible that fatigue can alter the mechanics of a shot. The purpose of this study was to determine the influence of localised fatigue on jump shot kinematics and kinetics. Eleven male team handball players (23.1 +/- 3.1 years; 185.1 +/- 8.3 cm; 89.7 +/- 12.2 kg) volunteered. An electromagnetic tracking system was used to examine the jump shot prior to and following localised fatigue. The fatiguing protocol consisted of throwing a 2.2 kg medicine ball into a rebounder until volitional fatigue. No significant kinematic or kinetic differences were observed following fatigue. Shoulder external rotation was -74.8 +/- 14.9 degrees prior to and -79.0 +/- 14.7 degrees following fatigue at MER. Scapula, external rotation at ball release (BR) prior to fatigue was -2.2 +/- 7.0 degrees and -3.2 +/- 11.1 degrees following fatigue. Scapular internal rotation, at maximum shoulder internal rotation (MIR), changed from 18.4 +/- 11.2 degrees to 20.4 +/- 11.8 degrees . Ball velocity decreased from19.8 m . s-1 to 18.8 m . s-1 (P = 0.12). Accuracy percentage in the pre-fatigue trials was 60.8 +/- 14.1% and 52.8 +/- 12.7% following fatigue (P = 0.20). While no significant changes were observed, it is possible that other fatiguing protocols that more closely represent the aerobic and throwing demands of the sport may have a greater effect on the kinematics and kinetics of the jump shot. PMID- 26982391 TI - Transposition of great arteries with natural partial Senning: A rare case report. AB - The association of transposition of the great arteries (TGA) and anomalous pulmonary venous connection is extremely rare. Children with transposition of the great arteries improved dramatically with the advent of the atrial repair. In this report, we describe a 40-day old male infant with TGA and associated anomalous pulmonary venous connection who presented with the history of cyanosis and hurried breathing. This patient underwent successful balloon atrial septostomy and discharged with uneventful recovery. PMID- 26982393 TI - QSAR models on H4 receptor antagonists associated with inflammation and anaphylaxis. AB - Histamine, an endogenous amine is implicated in hypersensitivity (allergic) responses, gastric acid secretion, neurotransmission, immuno-modulation, cell differentiation, and embryonic development. It exerts its effects via four histamine receptor subtypes, termed H1 to H4 receptors (H1R-H4R) belonging to the superfamily of G-protein coupled receptors. The latest discovered histamine receptor, H4R, is implicated in the chemotaxis of several cell types and strongly associated with immune and inflammatory responses. Thus, we found interesting to analyze in terms of 2D-QSAR a number of H4 antagonists in order to highlight the most important physicochemical properties implicated in their mechanism of action and in continuation to suggest structural modifications. The C-QSAR platform of Biobyte has been used in this study. The study reveals that lipophilicity, clog P (linear or bilinear model) as well as steric factors such as the overall molar refractivity (CMR), molar volume or the substitutents molar refractivity (linear) or the sterimol parameters B1 and B5 are important. Electronic effects appear only in one model. The study shows that log P as calculated from the C-QSAR program of Biobyte is suitable for this form of QSAR study. PMID- 26982395 TI - Prince does the honours for leading nurses. AB - A community nurse consultant spoke of her pride at collecting an OBE from Prince William at Buckingham Palace. PMID- 26982396 TI - Outsourcing is compromising quality, says Peter Carter. AB - Too many NHS contracts are being outsourced to private sector companies based on cost and at the expense of quality, RCN general secretary Peter Carter told the annual general meeting. PMID- 26982398 TI - Membership fee set to increase by 1% as vote is passed to set rate for five years. AB - The RCN's annual membership fee may rise by 16p a month from next year, after members voted to allow the college's council to set the rate for the next five years. PMID- 26982394 TI - Menstrual cyclicity post OC withdrawal in PCOS: Use of non-hormonal options. AB - There is no data on menstrual cyclicity post oral contraceptive (OC) withdrawal with nonhormonal options in PCOS patients. OC could affect obesity, insulin and gonadotropins factors integral to pathogenesis of PCOS, thereby adversely affecting the HPG axis. Menstrual cycles of PCOS patients were retrospectively studied post OCP. Patients developing regular versus irregular cycles post OC were compared. Forty-eight PCOS patients were followed for an average of 1.9 years post OC. Thirty-six (75%) achieved regular cycles over a period of one year with other nonhormonal options like spironolactone and metformin. Seven patients required no treatment. Patients who continued to have irregular cycles had a longer pre OC cycle length (p < 0.01) and a greater duration of menstrual irregularity (p < 0.02), though age, BMI and hormones were similar in the two groups. In conclusion, spironolactone and metformin are effective nonhormonal options for regular periods post OC. Around 15% PCOS may not require any treatment post OC. PMID- 26982397 TI - Revalidation is a 'nightmare' for some nurses. AB - Proposals on revalidation drawn up by the Nursing and Midwifery Council that would require nurses to ask for patient feedback could prove to be a 'nightmare' for independent nurses, it has been claimed. PMID- 26982400 TI - NMC report reveals fall in FtP referrals. AB - The number of new referrals to the Nursing and Midwifery Council fell between 2011 and 2013. PMID- 26982399 TI - Brown is ready to tackle the big issues. AB - Safe staffing is the RCN's priority, the incoming chair of the college's council told Nursing Standard last week. PMID- 26982401 TI - Pension rights retained for transferred NHS workers. AB - Nurses who are transferred compulsorily from the NHS into a private company delivering NHS-funded services will remain in the public sector pension scheme. PMID- 26982403 TI - Nurse's hep C test yields speedy results. AB - A successful nurse-led screening programme to tackle hepatitis C prevalence in south Asian and Somali communities is to be expanded. PMID- 26982404 TI - Institute strives to increase the number of BME Queen's nurses. AB - The Queen's Nursing Institute (QNI) has launched a drive to recruit more nurses from minority communities for its nurse programme. PMID- 26982406 TI - World in brief. AB - What's happening in nursing across the globe. PMID- 26982405 TI - Political notebook. AB - Urgent action is needed to solve a health crisis in Wales, Plaid Cymru leader Leanne Wood claims. PMID- 26982407 TI - Appeal for return of stolen badge. AB - A nurse's daughter has appealed for help in tracing her late mother's prized pre war nursing badge after it was taken by burglars. PMID- 26982409 TI - Men at greater risk of almost all post-operative complications than women. AB - Older black and Hispanic patients have a higher risk than white patients of developing complications following surgery, a study undertaken in the United States suggests. PMID- 26982408 TI - Exercise is an effective treatment for lower limb osteoarthritis. AB - Osteoarthritis is the most common form of arthritis and one of the leading causes of pain and disability worldwide. The economic burden of treatment costs and lost productivity is substantial, with the total cost to the UK estimated at 1 per cent of gross national product. PMID- 26982410 TI - Adalimumab keeps bowel disease in remission aft er up to four years of treatment. AB - Long-term treatment with adalimumab can help patients with Crohn's disease maintain remission for up to four years, with no increased risk of adverse effects, according to an analysis of data from two clinical trials. PMID- 26982411 TI - Benefits of bisphosphonates outweigh risks, despite links to atypical femural fractures. AB - A review of recent evidence linking bisphosphonate (BP) drugs used to treat osteoporosis with atypical femural fractures (AFFs) has found that long-term use of the drugs increases the risk of these rare fractures. PMID- 26982413 TI - Global outreach service. PMID- 26982412 TI - Unemployment levels after the global financial crisis linked to increase in suicides. AB - The 2008 global economic crisis appears to have triggered an increase in suicides, particularly among men in Europe and America. To investigate the impact of the economic crisis on international trends in suicide, researchers conducted an analysis comparing the number of suicides in 2009 with the number that would have been expected based on trends before the crisis (2000-2007). The analysis included data from 54 countries. PMID- 26982415 TI - The enemy within. AB - An interesting article recently appeared on The Guardian website. Written by June Girvin, nurse and pro-vice chancellor at Oxford Brookes University, and Mark Hayter, professor in the faculty of health and social care at the University of Hull, it argued why nursing needs to be a graduate profession. PMID- 26982414 TI - Voices - Going 'back to the floor' reinforced Yvonne Coghill's pride in her profession. AB - Earlier this month I went 'back to the floor' to work alongside nursing colleagues at Wrightington, Wigan and Leigh NHS Foundation Trust in north west England. PMID- 26982416 TI - On deaf ears. AB - 'I am sure it is the eye clinic, nurse,' the woman pushing the wheelchair said indignantly. I took her to be the patient's daughter. PMID- 26982418 TI - Readers panel- Intervention at an early age. AB - Our experts consider a hot topic of the day. PMID- 26982417 TI - Trial and error. AB - I have never taken part in a drug trial, but I can see the appeal. 'That new doctor said they were trialling these tablets. Of course I agreed to help out. Who knows? They might do the trick.' PMID- 26982419 TI - Reason for rage. AB - Following health secretary Jeremy Hunt's announcement about NHS wages, it is time for nurses to bombard their MPs with letters and emails to express their indignation at being targeted yet again. PMID- 26982420 TI - Starting out - Inpatients with dementia showed me how much we need to improve care. AB - I was on a gastroenterology ward placement during my first year of training when I read a poem by an unknown author with dementia. PMID- 26982421 TI - National Numeracy. AB - The National Numeracy charity provides information and resources to ensure 'numeracy for everyone, for life'. Its website is a fantastic resource for those involved in recruitment or teaching numeracy. PMID- 26982422 TI - Understanding and Interpreting Educational Research Martella Ronald C et al Understanding and Interpreting Educational Research 704pp $80/L46.99 The Guildford Press 978 1 4625 0962 1462509622 [Formula: see text]. AB - This American text is a comprehensive and substantial tool for research design. PMID- 26982423 TI - Nursing Ethics in Everyday Practice Ulrich Connie M Nursing Ethics in Everyday Practice 256pp $39.95/L25.61 Sigma Theta Tau International Honor Society of Nursing 978 1 9354 7650 4 1935476505 [Formula: see text]. AB - This is a useful and informative book for nurses, nursing students, managers and lecturers. It is, however, an American text that has not been adapted for readers outside the United States in terms of the role of nurses, or the way that health care is delivered. PMID- 26982425 TI - The best of the week's health-related TV and radio. AB - Our roundup of what's on. PMID- 26982424 TI - NHS Symptom Checker app NHS Symptom Checker app Free [Formula: see text]. AB - What started out as an app that was prone to crashing is now available in a much improved version 2.0.3. Developed by NHS Direct, it is targeted at users in England. PMID- 26982426 TI - Help me research Edith Cavell, who saved a relative of mine. AB - I was moved by Terri Arthur's account of nurse Edith Cavell, her arrest for treason and execution in 1915 (Reflections October 16). Almost a century after her death, Miss Cavell's professionalism and courage continue to inspire us. PMID- 26982428 TI - Notice board. AB - Courses, events, grants, and awards to progress your career. PMID- 26982429 TI - Employment tribunals in action. AB - Most people will never need to become familiar with the Employment Tribunals (Constitution and Rules of Procedure) Regulations 2013, which came into force in July. But for some nurses, whose grievance against an employer cannot be resolved locally, the changes are significant. PMID- 26982430 TI - Student life - Inspired improvements. AB - Through its 1,000 Lives Plus campaign, NHS Wales is committed to saving lives and delivering the best quality and safest health care for people in Wales. PMID- 26982431 TI - Involvement of Cyclin-Dependent Kinase 1 during Postovulatory Aging-Mediated Abortive Spontaneous Egg Activation in Rat Eggs Cultured In Vitro. AB - Freshly ovulated rat eggs do not remain arrested at metaphase II (MII) and undergo exit from MII arrest with initiation of extrusion of the second polar body (PBII), a characteristic feature of abortive spontaneous egg activation (SEA). The biochemical and molecular changes during postovulatory aging-mediated abortive SEA remain poorly understood. We investigated the morphological, cellular, and molecular changes during postovulatory aging-mediated abortive SEA in eggs cultured in vitro. Our results suggest that postovulatory egg aging in vitro induced initiation of PBII extrusion in a time-dependent manner. Postovulatory aging increased Wee1 kinase and Thr-14/Tyr-15 phosphorylated cyclin dependent kinase 1 (Cdk1) levels, whereas Thr-161 phosphorylated Cdk1 and cyclin B1 levels were significantly decreased in eggs cultured in vitro. The early mitotic inhibitor 2 (Emi2) level was significantly reduced, but anaphase promoting complex/cyclosome (APC/C) and mitotic arrest deficient protein (MAD2) levels were increased initially and then reduced during a later period of in vitro culture. These results suggest that an increased Wee1 kinase level modulated the specific phosphorylation status of Cdk1, increased Cdk1 activity, and decreased the cyclin B1 level. Furthermore, the decreased Emi2 level was associated with an increased level of APC/C and decreased level of cyclin B1, which resulted in maturation promoting factor (MPF) destabilization and finally led to postovulatory aging-mediated abortive SEA in rat eggs cultured in vitro. PMID- 26982432 TI - Rethinking the social history in the era of biolegitimacy: global health and medical education in the care of Palestinian and Syrian refugees in Beirut, Lebanon. AB - The critiques leveled towards medical humanitarianism by the social sciences have yet to be felt in medical education. The elevation of biological suffering, at the detriment of sociopolitical contextualization, has been shown to clearly impact both acute and long-term care of individuals and communities. With many medical students spending a portion of their educational time in global learning experiences, exposure to humanitarianism and its consequences becomes a unique component of biomedical education. How does the medical field reconcile global health education with the critiques of humanitarianism? This paper argues that the medical response to humanitarian reason should begin at the level of a social history. Using experiential data culled from fieldwork with Palestinian and Syrian refugees in Lebanon, the authors argue that an expanded social history, combined with knowledge derived from the social sciences, can have significant clinical implications. The ability to contextualize an individual's disease and life within a complex sociopolitical framework means that students must draw on disciplines as varied as anthropology, sociology, and political history to further their knowledge base. Moreover, situating these educational goals within the framework of physician advocacy can build a strong base in medical education from both a biomedical and activist perspective. PMID- 26982433 TI - 'The body remembers': narrating embodied reconciliations of eating disorder and recovery. AB - After severe illness, there are stories: narrative strands to suture discontinuities of identities, practices, and lives. But within these narratives of illness and recovery, the body's discontinuities stand apart, striking in the materiality of change, in the tangible multiplicity of bodies - healthy, ill, recovering, recovered - that a person can call one's own. Based on longitudinal research interviews with Israeli women who identified as recovered from long-term eating disorders (fieldwork conducted in 2005-2006 and in 2011), this paper explores how these bodily discontinuities are expressed, drawing particular attention to the narrative role of embodied memory in linking past and present tense bodies and selves. Embodied memory, as narrated by the participants, is deeply, sometimes surprisingly, embedded in lived experience, imbuing recovered bodies with moments of sensory continuity, the past coming into presence through forms of sensation and perception learned at the height of disorder. Examining narrative moments of sensory remembrance, this paper analyses how participants narrate embodied memory as a mode of reflection, self-protection, and dynamic integration, wherein the experience of disorder informs practices of recovery, and the body becomes a site for the reconciliation of past and present. PMID- 26982434 TI - Pneumococcal conjugate vaccine introduction in Latin America and the Caribbean: progress and lessons learned. AB - In Latin America and the Caribbean, pneumococcus has been estimated to cause 12,000-28,000 deaths, 182,000 hospitalizations, and 1.4 million clinic visits annually. Countries in the Americas have been among the first developing nations to introduce pneumococcal conjugate vaccines into their Expanded Programs on Immunization, with 34 countries and territories having introduced these vaccines as of September 2015. Lessons learned for successful vaccine introduction include the importance of coordination between political and technical decision makers, adjustments to the cold chain prior to vaccine introduction, and the need for detailed plans addressing the financial and technical sustainability of introduction. Though many questions on the Pneumococcal Conjugate Vaccine remain unanswered, the experience of the Americas suggests that the vaccines can be introduced quickly and effectively. PMID- 26982436 TI - Structure and Evolution of Insect Sperm: New Interpretations in the Age of Phylogenomics. AB - This comprehensive review of the structure of sperm in all orders of insects evaluates phylogenetic implications, with the background of a phylogeny based on transcriptomes. Sperm characters strongly support several major branches of the phylogeny of insects-for instance, Cercophora, Dicondylia, and Psocodea-and also different infraordinal groups. Some closely related taxa, such as Trichoptera and Lepidoptera (Amphiesmenoptera), differ greatly in sperm structure. Sperm characters are very conservative in some groups (Heteroptera, Odonata) but highly variable in others, including Zoraptera, a small and morphologically uniform group with a tremendously accelerated rate of sperm evolution. Unusual patterns such as sperm dimorphism, the formation of bundles, or aflagellate and immotile sperm have evolved independently in several groups. PMID- 26982435 TI - Co-encapsulation of Nigella sativa oil and plasmid DNA for enhanced gene therapy of Alzheimer's disease. AB - Alzheimer disease involves genetic and non-genetic factors and hence it is rational to be treated with genetic and non-genetic therapeutic agents. Nigella sativa has multiple therapeutic properties including neuroregeneration. Nigella sativa oil (NSO) was encapsulated in PLGA nanoparticles and pDNA was loaded either by adsorption on chitosan-modified particles or encapsulation within PLGA nanoparticles. The particle size and zeta potential of NSO-pDNA-chitosan-PLGA nanoparticles were highly dependent on the medium and exhibited high burst release. Meanwhile, NSO-pDNA-PLGA nanoparticles were more consistent with lower burst release. The fabricated nanoparticles revealed the expected outcomes of both pDNA and NSO. The pDNA transfected N2a cell while the encapsulated NSO promoted neurite outgrowth that is crucial for neuroregeneration. Results from this study suggest that NSO could be added to the gene delivery carrier to enhance treatment benefits for Alzheimer disease. PMID- 26982438 TI - Remote Sensing and Reflectance Profiling in Entomology. AB - Remote sensing describes the characterization of the status of objects and/or the classification of their identity based on a combination of spectral features extracted from reflectance or transmission profiles of radiometric energy. Remote sensing can be benchtop based, and therefore acquired at a high spatial resolution, or airborne at lower spatial resolution to cover large areas. Despite important challenges, airborne remote sensing technologies will undoubtedly be of major importance in optimized management of agricultural systems in the twenty first century. Benchtop remote sensing applications are becoming important in insect systematics and in phenomics studies of insect behavior and physiology. This review highlights how remote sensing influences entomological research by enabling scientists to nondestructively monitor how individual insects respond to treatments and ambient conditions. Furthermore, novel remote sensing technologies are creating intriguing interdisciplinary bridges between entomology and disciplines such as informatics and electrical engineering. PMID- 26982437 TI - Antarctic Entomology. AB - The Antarctic region comprises the continent, the Maritime Antarctic, the sub Antarctic islands, and the southern cold temperate islands. Continental Antarctica is devoid of insects, but elsewhere diversity varies from 2 to more than 200 species, of which flies and beetles constitute the majority. Much is known about the drivers of this diversity at local and regional scales; current climate and glacial history play important roles. Investigations of responses to low temperatures, dry conditions, and varying salinity have spanned the ecological to the genomic, revealing new insights into how insects respond to stressful conditions. Biological invasions are common across much of the region and are expected to increase as climates become warmer. The drivers of invasion are reasonably well understood, although less is known about the impacts of invasion. Antarctic entomology has advanced considerably over the past 50 years, but key areas, such as interspecific interactions, remain underexplored. PMID- 26982439 TI - Biosynthesis, Turnover, and Functions of Chitin in Insects. AB - Chitin is a major component of the exoskeleton and the peritrophic matrix of insects. It forms complex structures in association with different assortments of cuticle and peritrophic matrix proteins to yield biocomposites with a wide range of physicochemical and mechanical properties. The growth and development of insects are intimately coupled with the biosynthesis, turnover, and modification of chitin. The genes encoding numerous enzymes of chitin metabolism and proteins that associate with and organize chitin have been uncovered by bioinformatics analyses. Many of these proteins are encoded by sets of large gene families. There is specialization among members within each family, which function in particular tissues or developmental stages. Chitin-containing matrices are dynamically modified at every developmental stage and are under developmental and/or physiological control. A thorough understanding of the diverse processes associated with the assembly and turnover of these chitinous matrices offers many strategies to achieve selective pest control. PMID- 26982441 TI - Plasticity in Insect Olfaction: To Smell or Not to Smell? AB - In insects, olfaction plays a crucial role in many behavioral contexts, such as locating food, sexual partners, and oviposition sites. To successfully perform such behaviors, insects must respond to chemical stimuli at the right moment. Insects modulate their olfactory system according to their physiological state upon interaction with their environment. Here, we review the plasticity of behavioral responses to different odor types according to age, feeding state, circadian rhythm, and mating status. We also summarize what is known about the underlying neural and endocrinological mechanisms, from peripheral detection to central nervous integration, and cover neuromodulation from the molecular to the behavioral level. We describe forms of olfactory plasticity that have contributed to the evolutionary success of insects and have provided them with remarkable tools to adapt to their ever-changing environment. PMID- 26982440 TI - Chemical Ecology of Neuroptera. AB - With 6,000 species, Neuroptera (lacewings, antlions, dustywings, and allies) is a relatively small order; however, most larval neuropterans are predacious, often in agricultural systems, lending added importance to this group. Advances in neuropteran phylogeny, most recently through genomic studies, stabilized the nomenclature of this ancestral order of Holometabola, facilitating basic and applied research on these important and interesting insects. The first pheromones for green lacewings (Chrysopidae) have been identified; this, and other research on antlions (Myrmeleontidae), suggests that male-produced long-range pheromones are the norm for the order. Characterizations of the myriad neuropteran exocrine gland systems, including prothoracic, metathoracic, abdominal, dermal, and anal glands, are revealing unforeseen trophic relationships with biological control implications. For examples, males of Chrysopa and other lacewing genera evidently must sequester specific chemical precursors from prey or plants to produce their attractant pheromones, and larval antlion venoms are potentially important genetic leads for insecticidal peptides. PMID- 26982442 TI - Studying the Complex Communities of Ants and Their Symbionts Using Ecological Network Analysis. AB - Ant colonies provide well-protected and resource-rich environments for a plethora of symbionts. Historically, most studies of ants and their symbionts have had a narrow taxonomic scope, often focusing on a single ant or symbiont species. Here we discuss the prospects of studying these assemblies in a community ecology context using the framework of ecological network analysis. We introduce three basic network metrics that we consider particularly relevant for improving our knowledge of ant-symbiont communities: interaction specificity, network modularity, and phylogenetic signal. We then discuss army ant symbionts as examples of large and primarily parasitic communities, and symbiotic sternorrhynchans as examples of generally smaller and primarily mutualistic communities in the context of these network analyses. We argue that this approach will provide new and complementary insights into the evolutionary and ecological dynamics between ants and their many associates, and will facilitate comparisons across different ant-symbiont assemblages as well as across different types of ecological networks. PMID- 26982443 TI - Rift Valley Fever: An Emerging Mosquito-Borne Disease. AB - Rift Valley fever (RVF), an emerging mosquito-borne zoonotic infectious viral disease caused by the RVF virus (RVFV) (Bunyaviridae: Phlebovirus), presents significant threats to global public health and agriculture in Africa and the Middle East. RVFV is listed as a select agent with significant potential for international spread and use in bioterrorism. RVFV has caused large, devastating periodic epizootics and epidemics in Africa over the past ~60 years, with severe economic and nutritional impacts on humans from illness and livestock loss. In the past 15 years alone, RVFV caused tens of thousands of human cases, hundreds of human deaths, and more than 100,000 domestic animal deaths. Cattle, sheep, goats, and camels are particularly susceptible to RVF and serve as amplifying hosts for the virus. This review highlights recent research on RVF, focusing on vectors and their ecology, transmission dynamics, and use of environmental and climate data to predict disease outbreaks. Important directions for future research are also discussed. PMID- 26982444 TI - The Molecular Evolution of Xenobiotic Metabolism and Resistance in Chelicerate Mites. AB - Chelicerate mites diverged from other arthropod lineages more than 400 million years ago and subsequently developed specific and remarkable xenobiotic adaptations. The study of the two-spotted spider mite, Tetranychus urticae, for which a high-quality Sanger-sequenced genome was first available, revealed expansions and radiations in all major detoxification gene families, including P450 monooxygenases, carboxyl/cholinesterases, glutathione-S-transferases, and ATP-binding cassette transporters. Novel gene families that are not well studied in other arthropods, such as major facilitator family transporters and lipocalins, also reflect the evolution of xenobiotic adaptation. The acquisition of genes by horizontal gene transfer provided new routes to handle toxins, for example, the beta-cyanoalanine synthase enzyme that metabolizes cyanide. The availability of genomic resources for other mite species has allowed researchers to study the lineage specificity of these gene family expansions and the distinct evolution of genes involved in xenobiotic metabolism in mites. Genome-based tools have been crucial in supporting the idiosyncrasies of mite detoxification and will further support the expanding field of mite-plant interactions. PMID- 26982445 TI - Foreword. PMID- 26982446 TI - Adult Cancer Patient Recruitment and Enrollment into Cell Phone Text Message Trials. AB - INTRODUCTION: Text messaging (TMs) on cell phones is emerging as an effective means of delivering behavioral interventions. However, little is known about TM use in adult cancer patients. The present study aimed to extend knowledge on acceptability of a TM intervention in adult cancer patients; examine factors of those screened and enrolled; and compare recruitment at a large national specialty pharmacy versus community-based cancer clinics. MATERIALS AND METHODS: Screening, enrollment, and baseline data collected in two randomized controlled trials examining the efficacy of TMs on medication adherence or symptom severity in adults prescribed oral anticancer agents were linked. Chi-square, Fisher's exact, t-tests, and generalized linear modeling were used to examine sociodemographics, cancer type and stage, depressive symptoms, self-efficacy, social support, and symptoms. RESULTS: The cancer clinics screened 293 patients, 43% were eligible, and 56% consented. The specialty pharmacy screened 169 patients, 72% were eligible, and 74% consented. Mean age was 58 years and did not differ by recruitment setting. Later stage disease (p = 0.01) and higher number of symptoms (p < 0.01), and symptom severity (p = 0.02) and interference (p = 0.01) were observed among patients recruited at the specialty pharmacy. No group differences were found for depression, physical function, cognition, self efficacy, or social support. DISCUSSION: Adult cancer patients were likely to participate in a TM intervention trial. Recruiting through the specialty pharmacy reached a population with higher cell phone ownership and TM usage; with greater interest in a TM intervention compared to the cancer clinics. PMID- 26982447 TI - Eye-Directed Overpressure Airwave-Induced Trauma Causes Lasting Damage to the Anterior and Posterior Globe: A Model for Testing Cell-Based Therapies. AB - PURPOSE: Characterization of the response of the Balb/c mouse to an eye-directed overpressure airwave, with the hypothesis that this mouse strain and model is useful for testing potential therapeutics for the treatment of traumatic eye injury. METHODS: The left eyes of adult Balb/c mice were exposed to an eye directed overpressure airwave. Intraocular pressure (IOP) was measured and eyes were inspected for gross pathology changes. Optical coherence tomography and histology were used to examine the structural integrity of the retina and optic nerve. Immunohistochemistry, in vivo molecular fluorophores, and a multiplex enzyme-linked immunosorbent assay were utilized to identify changes in cell death, neuroinflammation, and oxidative stress. RESULTS: This model induced a transient increase in IOP, corneal injuries, infrequent large retinal detachments, retinal pigment epithelium (RPE) vacuolization, glial reactivity, and retinal cell death. Both the corneal damage and RPE vacuolization persisted with time. Optic nerve degeneration occurred as early as 7 days postinjury and persisted out to 60 days. Retinal cell death, increased levels of reactive oxygen species, and neuroinflammation were detected at 7 days postinjury. CONCLUSIONS: The injury profile of the Balb/c mouse is consistent with commonly observed pathologies in blast-exposed patients. The damage is throughout the eye and persistent, making this mouse model useful for testing cell-based therapies. PMID- 26982449 TI - An Update from the Academy of Breastfeeding Medicine's Ethics Committee: Key Policy Revised. PMID- 26982448 TI - Fatty Acid Content of Plasma Triglycerides May Contribute to the Heterogeneity in the Relationship Between Abdominal Obesity and the Metabolic Syndrome. AB - BACKGROUND: About one-third of the people with abdominal obesity do not exhibit the metabolic syndrome (MetS). Fatty acids in plasma triglycerides (TGs) may help to explain part of this heterogeneity. This study compared TG fatty acid profile of adults with and without abdominal obesity and examined the associations of these fatty acids with MetS components. METHODS: Fifty-four abdominally obese subjects were matched by age and sex with 54 adults without abdominal obesity. People were classified with MetS according to the harmonizing criteria for MetS. Fatty acids in plasma TGs were analyzed by gas chromatography. RESULTS: There were no differences in fatty acids of plasma TGs between people with and without abdominal obesity. However, there were differences between abdominally obese people with and without MetS. The abdominally obese group with MetS had higher palmitic (+2.9%; P = 0.012) and oleic (+4.0%; P = 0.001) acids and lower linoleic (-6.4%; P = 0.018) and arachidonic (-1.2%; P = 0.004) acids. After adjustment for abdominal obesity, age, and sex, a stepwise regression analysis showed that palmitic acid positively contributed to the variance in insulin (beta = +1.08 +/- 1.01; P = 0.000) and homeostasis model assessment of insulin resistance (HOMA-IR) index (beta = +1.09 +/- 1.01; P = 0.000) and myristic acid positively contributed to the variance in systolic blood pressure (beta = +1.09 +/- 1.03; P = 0.006). In contrast, linoleic acid negatively contributed to the variance in glucose (beta = -0.321 +/- 0.09; P = 0.001) and high-sensitivity C-reactive protein (hsCRP; beta = -1.05 +/- 1.01; P = 0.000). CONCLUSIONS: There were no differences in the plasma TG fatty acid profile between people with and without abdominal obesity. Likewise, fatty acids in plasma TGs associated with many of the MetS variables independently of abdominal obesity. These results suggest that the plasma TG fatty acid profile may help to explain part of the heterogeneity between abdominal obesity and the MetS. PMID- 26982450 TI - Mechanisms of modulation of cytokine release by human cord blood monocytes exposed to high concentrations of caffeine. AB - BACKGROUND: Serum caffeine concentrations >20 MUg/ml (100 MUmol/l) in infants treated for apnea of prematurity increases TNF-alpha and decreases IL-10, changes that perhaps are linked to comorbidities. We hypothesize that this proinflammatory cytokine profile may be linked to differential binding of caffeine to adenosine receptor subtypes (AR), inhibition of phosphodiesterases (PDEs), and modulation of toll-like receptors (TLR). METHODS: Lipopolysaccharide activated cord blood monocytes (CBM) from 19 infants were exposed to caffeine (0 200 MUmol/l) with or without previous exposure to A1R, A3R, or PDE IV antagonists to determine changes in dose-response curves. Cytokines levels (enzyme-linked immunosorbent assay (ELISA)), intracellular cyclic adenosine monophosphate (cAMP) accumulation (enzyme immunoassay (EIA)), and TLR gene expression (real time qRT PCR) were measured. RESULTS: Caffeine at <=100 MUmol/l decreased TNF-alpha levels (~25%, P = 0.01) and cAMP. All caffeine concentrations decreased IL-10 levels (17 35%, P < 0.01). A1R, A3R, and PDE blockades decreased TNF-alpha (31, 21, and 88%, P <= 0.01), but not IL-10. Caffeine further decreased TNF-alpha following A3R and PDE blockades. Caffeine concentrations directly correlated to TLR4 gene expression (r = 0.84; P < 0.001). CONCLUSION: Neither A3R, nor PDE blockades are involved in caffeine's modulation of cytokine release by CBM at any concentration. Besides A1R blockade, caffeine's upregulation of TLR4 may promote inflammation at high concentrations. PMID- 26982451 TI - Fecal microbiota transplantation in children: a brief review. AB - There has been a growing interest in fecal microbiota transplantation (FMT) over recent years, in part due to the increasing prevalence of Clostridium difficile infection (CDI) and expanding association of intestinal dysbiosis with a wide range of human diseases. Many adult studies have shown that FMT is an effective treatment for recurrent CDI and may possibly have applications in other illnesses such as inflammatory bowel disease (IBD); however, there is a paucity of data available in children who may differ from adults for many reasons including having a dynamic developing microbiome compared to adults who have a relatively stable microbiome. Here, we review published studies looking at FMT in children, for CDI and IBD, and discuss special considerations needed when conducting FMT in children. PMID- 26982452 TI - Assessment of the measurement properties of the post stroke motor function instruments available in Brazil: a systematic review. AB - BACKGROUND: While there are several instruments in Brazil that measure motor function in patients after stroke, it is unknown whether the measurement properties of these instruments are appropriate. OBJECTIVE: To identify the motor function instruments available in Brazil for patients after stroke. To assess the methodological quality of the studies and the results related to the measurement properties of these instruments. METHOD: Two independent reviewers conducted searches on PubMed, LILACS, CINAHL, Web of Science, and Scopus. Studies that aimed to cross-culturally adapt an existing instrument or create a Brazilian instrument and test at least one measurement property related to motor function in patients after stroke were included. The methodological quality of these studies was checked by the COSMIN checklist with 4-point rating scale and the results of the measurement properties were analyzed by the criteria developed by Terwee et al. RESULTS: A total of 11 instruments were considered eligible, none of which were created in Brazil. The process of cross-cultural adaptation was inadequate in 10 out of 11 instruments due to the lack of back-translation or due to inappropriate target population. All of the instruments presented flaws in the measurement properties, especially reliability, internal consistency, and construct validity. CONCLUSION: The flaws observed in both cross-cultural adaptation process and testing measurement properties make the results inconclusive on the validity of the available instruments. Adequate procedures of cross-cultural adaptation and measurement properties of these instruments are strongly needed. PMID- 26982453 TI - Effects of chest wall compression on expiratory flow rates in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Manual chest wall compression (CWC) during expiration is a technique for removing airway secretions in patients with respiratory disorders. However, there have been no reports about the physiological effects of CWC in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVE: To compare the effects of CWC on expiratory flow rates in patients with COPD and asymptomatic controls. METHOD: Fourteen subjects were recruited from among patients with COPD who were receiving pulmonary rehabilitation at the University Hospital (COPD group). Fourteen age-matched healthy subjects were also consecutively recruited from the local community (Healthy control group). Airflow and lung volume changes were measured continuously with the subjects lying in supine position during 1 minute of quiet breathing (QB) and during 1 minute of CWC by a physical therapist. RESULTS: During CWC, both the COPD group and the healthy control group showed significantly higher peak expiratory flow rates (PEFRs) than during QB (mean difference for COPD group 0.14 L/sec, 95% confidence interval (CI) 0.04 to 0.24, p<0.01, mean difference for healthy control group 0.39 L/sec, 95% CI 0.25 to 0.57, p<0.01). In the between-group comparisons, PEFR was significantly higher in the healthy control group than in the COPD group (-0.25 L/sec, 95% CI -0.43 to -0.07, p<0.01). However, the expiratory flow rates at the lung volume at the PEFR during QB and at 50% and 25% of tidal volume during QB increased in the healthy control group (mean difference for healthy control group 0.31 L/sec, 95% CI 0.15 to 0.47, p<0.01: 0.31 L/sec, 95% CI 0.15 to 0.47, p<0.01: 0.27 L/sec, 95% CI 0.13 to 0.41, p<0.01, respectively) but not in the COPD group (0.05 L/sec, 95% CI 0.01 to 0.12: -0.01 L/sec, 95% CI -0.11 to 0.08: 0.02 L/sec, 95% CI -0.05 to 0.90) with the application of CWC. CONCLUSION: The effects of chest wall compression on expiratory flow rates was different between COPD patients and asymptomatic controls. PMID- 26982454 TI - Inductive plethysmography potential as a surrogate for ventilatory measurements during rest and moderate physical exercise. AB - BACKGROUND: Portable respiratory inductive plethysmography (RIP) systems have been validated for ventilatory assessment during resting conditions and during incremental treadmill exercise. However, in clinical settings and during field based exercise, intensity is usually constant and submaximal. A demonstration of the ability of RIP to detect respiratory measurements accurately during constant intensity conditions would promote and validate the routine use of portable RIP devices as an alternative to ergospirometry (ES), the current gold standard technique for ventilatory measures. OBJECTIVE: To investigate the agreement between respiratory variables recorded by a portable RIP device and by ES during rest and constant intensity exercise. METHOD: Tidal volume (VT), respiratory rate (RR) and minute ventilation (VE) were concurrently acquired by portable RIP and ES in seven healthy male volunteers during standing rest position and constant intensity treadmill exercise. RESULTS: Significant agreement was found between RIP and ES acquisitions during the standing rest position and constant intensity treadmill exercise for RR and during the standing rest position for VE. CONCLUSION: Our results suggest that portable RIP devices might represent a suitable alternative to ES during rest and during constant submaximal exercise. PMID- 26982455 TI - Reliability of measuring pectoralis minor muscle resting length in subjects with and without signs of shoulder impingement. AB - BACKGROUND: Pectoralis minor adaptive shortening may change scapula resting position and scapular kinematics during arm elevation. A reliable and clinically feasible method for measuring pectoralis minor length will be useful for clinical decision making when evaluating and treating individuals with shoulder pain and dysfunction. OBJECTIVES: To evaluate intrarater, interrater, and between-day reliability of a pectoralis minor (PM) muscle length measurement in subjects with and without signs of shoulder impingement. METHOD: A convenience sample of 100 individuals (50 asymptomatic and 50 symptomatic) participated in this study. Intra- and interrater reliability of the measurement was estimated in 50 individuals (25 asymptomatic and 25 symptomatic), and between-day reliability of the measurement repeated over an interval of 7 days was estimated in an independent sample of 50 additional participants. Pectoralis minor length was measured using a flexible tape measure with subjects standing. RESULTS: Intraclass correlation coefficients (ICC3,k) for intrarater and interrater reliability ranged from 0.86-0.97 and 0.95 for between-day reliability in both groups. Standard error of measurements (SEM) ranged from 0.30-0.42 cm, 0.70-0.84 cm, and 0.40-0.41 cm for intrarater, interrater, and between-day reliability, respectively, across the sample. The minimal detectable change (MDC) for between day measurements ranged from 1.13-1.14 cm for both groups. CONCLUSIONS: In asymptomatic individuals and in those with signs of shoulder impingement, a single rater or pair of raters can measure pectoralis minor muscle length using a tape measure with very good reliability. This measurement can also be reliably used by the same rater over a seven day interval. PMID- 26982457 TI - The Future of IBD Therapy: Where Are We and Where Should We Go Next? AB - BACKGROUND: The advent of biologic agents opens up a new era for the treatment of inflammatory bowel disease (IBD). In this era, the treatment goal has evolved from the traditional goal of clinical remission to a combination of clinical remission, laboratory normalization and mucosal healing, designated as 'complete deep remission'. Such complete deep remission comprises a more ambitious disease control strategy that is believed to probably modify the natural course of IBD. KEY MESSAGES: To achieve this goal, optimization of current strategy and introduction of novel therapies have gained significant interest. In this concise review, we aim to provide an overview of the current status and future direction of IBD treatment. Specifically, we will describe the application of personalized therapy, development of new biologics, intestinal microbiome manipulation and out of-the-box agents for IBD. CONCLUSIONS: More evidence is still desirable to better optimize the current treatment and apply novel biologics. Personalized medicine has the potential to optimize efficacy, decrease the risk of adverse events and minimize costs and should be proposed as a standard of care for the management of IBD. PMID- 26982458 TI - Decreasing the Effective Thermal Conductivity in Glass Supported Thermoelectric Layers. AB - As thermoelectric devices begin to make their way into commercial applications, the emphasis is put on decreasing the thermal conductivity. In this purely theoretical study, finite element analysis is used to determine the effect of a supporting material on the thermal conductivity of a thermoelectric module. The simulations illustrate the heat transfer along a sample, consisting from Cu, Cu2O and PbTe thermoelectric layers on a 1 mm thick Pyrex glass substrate. The influence of two different types of heating, at a constant temperature and at a constant heat flux, is also investigated. It is revealed that the presence of a supporting material plays an important role on lowering the effective thermal conductivity of the layer-substrate ensemble. By using thinner thermoelectric layers the effective thermal conductivity is further reduced, almost down to the value of the glass substrate. As a result, the temperature gradient becomes steeper for a fixed heating temperature, which allows the production of devices with improved performance under certain conditions. Based on the simulation results, we also propose a model for a robust thin film thermoelectric device. With this suggestion, we invite the thermoelectric community to prove the applicability of the presented concept for practical purposes. PMID- 26982460 TI - Weakened Flexural Strength of Nanocrystalline Nanoporous Gold by Grain Refinement. AB - High density of grain boundaries in solid materials generally leads to high strength because grain boundaries act as strong obstacles to dislocation activity. We find that the flexural strength of nanoporous gold of grain size 206 nm is 33.6% lower than that of grain size 238 MUm. We prepared three gold-silver precursor alloys, well-annealed, prestrained, and high-energy ball-milled, from which nanoporous gold samples were obtained by the same free-corrosion dealloying process. Ligaments of the same size are formed regardless of precursor alloys, and microstructural aspects of precursor alloys such as crystallographic orientation and grain size is preserved in the dealloying process. While the nanoindentation hardness of three nanoporous golds is independent of microstructural variation, flexural strength of nanocrystalline nanoporous gold is significantly lower than that of nanoporous golds with much larger grain size. We investigate weakening mechanisms of grain boundaries in nanocrystalline nanoporous gold, leading to weakening of flexural strength. PMID- 26982461 TI - Ebola Virus in Breast Milk in an Ebola Virus-Positive Mother with Twin Babies, Guinea, 2015. PMID- 26982459 TI - Examining the effects of emotion regulation on the ERP response to highly negative social stigmas. AB - In order to determine if highly negative stigma is a more salient cue than other negative emotional, non-stigmatized cues, participants underwent electroencephalography while passively viewing or actively regulating their emotional response to images of highly negative stigmatized (e.g., homeless individuals, substance abusers) or highly negative non-stigmatized (e.g., a man holding a gun, an injured person) individuals. Event-related potential (ERP) analyses focused on the N2 (associated with detecting novelty), the early positive potential (associated with processing emotion), and a sustained late positive potential (associated with modulating regulatory goals). A salience effect for highly negative stigma was revealed in the early positive potential, with higher magnitude ERP responses to images of highly negative stigmatized as compared to highly negative non-stigmatized individuals 355 ms poststimulus onset. Moreover, the amplitude of this effect was predicted by individual differences in implicit bias. Our results also demonstrated that the late positivity response was not modulated by regulatory goals (passively view versus to reappraise) for images of highly negative stigmatized individuals, but was for images of highly negative, non-stigmatized individuals (replicating previous findings). Our findings suggest that the neural response to highly negative stigma is salient and rigid. PMID- 26982462 TI - Dengue vaccine: an update on recombinant subunit strategies. AB - Dengue is an increasing public health problem worldwide, with the four serotypes of the virus infecting over 390 million people annually. There is no specific treatment or antiviral drug for dengue, and prevention is largely limited to controlling the mosquito vectors or disrupting the human-vector contact. Despite the considerable progress made in recent years, an effective vaccine against the virus is not yet available. The development of a dengue vaccine has been hampered by many unique challenges, including the need to ensure the absence of vaccine induced enhanced severity of disease. Recombinant protein subunit vaccines offer a safer alternative to other vaccine approaches. Several subunit vaccine candidates are presently under development, based on different structural and non structural proteins of the virus. Novel adjuvants or immunopotentiating strategies are also being tested to improve their immunogenicity. This review summarizes the current status and development trends of subunit dengue vaccines. PMID- 26982463 TI - Lymphocytic choriomeningitis virus: ways to establish and maintain non-cytolytic persistent infection. AB - Lymphocytic choriomeningitis virus (LCMV) is a prototype virus of the Arenaviridae family that is attracting considerable attention both as an important experimental model system to study acute and persistent viral infections, and as a neglected human pathogen of clinical significance. Notably, LCMV is capable of persisting in an infected host, and escaping the immune system. Here we describe the strategies used by the virus to establish and maintain long-term infection in vitro and/or persistent infection in vivo. We discuss how the viral components (RNA, nucleoprotein, glycoprotein, Z protein) manipulate the host cell machinery to facilitate survival and spread of the virus without disturbing the basal cellular processes. Deep understanding of these strategies is inevitable for the development of approaches towards restricting the virus spread and/or preventing its harmful reactivation. This review summarizes the current status in this area and presents ideas emerging from existing data. PMID- 26982464 TI - Modifications in the glycerophospholipid composition between the Coxiella burnetii phase I and phase II cells suggest an association with phase variation of the bacterium. AB - Glycerophospholipids (GP) extracted from the Coxiella burnetii strain Nine Mile in virulent phase I (NM I) and low virulent phase II (NM II) were analyzed by Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry (MS) that gave a superior mass resolution and mass accuracy allowing unambiguous peak recognition and precise assignment of ions. We showed that GP present in the pathogen's outer membrane underwent considerable modifications during the phase variation that might be related to impact of various environmental factors. It was found that GP from phase I cells were much more complex than those from phase II cells. While glycerophosphoethanolamines (PE), glycerophosphocholines (PC) and glycerophosphoglycerols (PG) were present in both phases of C. burnetii, major differences were observed in the presence of glycerophosphates (PA) and glycerophosphoserines (PS). Thus, PA but no PS were detected in NM I variant in contrast with NM II cells where PS but no PA were identified. It is suggested that enzymes for PA head group modifications to form PS, PE, and PG become active during the phase variation of the bacterium. PMID- 26982465 TI - Genotypic characterization of Indian isolates of infectious bursal disease virus strains by reverse transcription-polymerase chain reaction combined with restriction fragment length polymorphism analysis. AB - The reverse transcription PCR (RT-PCR) combined with restriction fragment length polymorphism (RFLP) is used for the differentiation of classical virulent (cv), virulent (v) and very virulent (vv) strains of infectious bursal disease virus (IBDV) isolates from chicken bursal tissues in southern states of India. In the present study, six different isolates (MB11, HY12, PY12, BGE14, VCN14 and NKL14) of IBDV strains were subjected for genotyping along with vaccine virus (Georgia, intermediate strain) using RT-PCR for amplification of a 743 bp sequence in the hypervariable region of VP2 gene followed by restriction enzyme digestion with 5 different restriction enzymes (BspMI, SacI, HhaI, StuI and SspI). The RT-PCR products obtained from vvIBDV strains were digested by SspI enzyme except PY12, BGE14 and MB11 isolates. The SacI digested the isolate MB11, PY12 and the vaccine strain, but it did not cleave the very virulent isolates of IBDV. HhaI cleaved all the isolates with different restriction profile patterns. StuI digested all the vvIBDV isolates and BspMI was not able to differentiate field isolates from vaccine strain. Though RT-PCR combined with RFLP is a genotypic method, further confirmation of serotypes to distinguish the vvIBDV from cvIBDV has to be carried out using pathogenicity studies. PMID- 26982467 TI - Genome sequence of a divergent Colombian isolate of potato virus V (PVV) infecting Solanum phureja. AB - Deep sequencing analysis of the transcriptome of a Solanum phureja cv. Criolla Colombia plant with symptoms typical of a virus disease revealed an infection with potato virus V (PVV). The PVV-phureja genome comprises 9904 nt, exhibits 83% nucleotide identity with currently fully sequenced PVV isolates and contains one large ORF that codes for a polyprotein of 3065 residues flanked by 5' and 3' UTR of 217 and 448 nt, respectively. Phylogenetic analysis of the PVV-phureja polyprotein indicates that it is divergent with respect to most PVV isolates. This is the first complete PVV genome of an isolate infecting a host different to S. tuberosum and, to this date, the only one from the South American Andes. PMID- 26982466 TI - Accumulation of a soluble form of human nectin-2 is required for exerting the resistance against herpes simplex virus type 2 infection in transfected cells. AB - Cell entry of herpes simplex virus type 2 (HSV-2) requires the interaction of viral glycoprotein D (gD) with the receptor nectin-1 and herpesvirus entry mediator (HVEM). In addition, it is known that nectin-2 is also functional as a receptor for HSV-2, although the binding to the gD is weak. To examine an antiviral potential of a soluble form of human nectin-2 (hNectin-2Ig), transfected Vero cells expressing the entire ectodomain of nectin-2 fused to the Fc portion of human IgG were established. Specific binding of hNectin-2Ig to HSV 2 gD was confirmed by ELISA. Competitive ELISA demonstrated that accumulation of hNectin-2Ig in transfected cells increased significantly in a cell culture time dependent manner. Viral growth of several HSV-2 strains was significantly inhibited in the transfected cells that were cultured for 72 hr compared with control Vero cells, but not in cells that were cultured for 24 hr. These results indicate that accumulation of a soluble form of nectin-2 is required for exerting the resistance against HSV-2 infection. PMID- 26982468 TI - The rate of co-infection for piglet diarrhea viruses in China and the genetic characterization of porcine epidemic diarrhea virus and porcine kobuvirus. AB - Piglet diarrhea epidemics result in major economic losses for the swine industry. Four viruses are closely linked to porcine diarrhea: porcine kobuvirus (PKV), porcine epidemic diarrhea virus (PEDV), porcine transmissible gastroenteritis virus (TGEV), and porcine rotavirus (PRoV). We have conducted an epidemiology study to determine the frequency of infection and co-infection with these viruses in China, and characterized the genetic variation of the isolated PEDV and PKV strains. Stool and intestinal samples (n = 314) were collected from piglets with diarrhea in China from years 2012 to 2014. RT-PCR was used to detect PKV, PEDV, TGEV, and PRoV. Phylogenetic relationships between reference strains and the isolated PEDV and PKV strains were determined based on the M and 3D gene sequence. The rates of infection with PKV, PEDV, TGEV and PRoV were 29.9%, 24.2%, 1.91%, and 0.31%, respectively. Co-infections with PKV and the other three viruses were very common. Co-infection of PKV and PEDV was detected in 15.0% (47/314) of the samples. Phylogenetic analysis of the PKV 3D gene indicated that there were some phylogenetic differences in the PKV strains across regions within China. However, according to the PEDV M gene, strains clustered into three groups and the primary group was distinct from the vaccine strain CV777. This study provides insights in to the prevalence of diarrhea viruses and their prevention and control in China. PMID- 26982470 TI - Kinetic analysis of RNA editing of Newcastle disease virus P gene in the early period of infection. AB - As a paramyxovirus, Newcastle disease virus (NDV) has the ability to edit its P (phosphoprotein) gene to synthesize three kinds of viral protein (P, V and W). It is technically very difficult to differentiate P, V and W mRNAs, and little was known about NDV regulation of RNA-editing frequency. To investigate the rules of NDV RNA editing, the ratio of the P gene-derived transcripts (P, V and W) was determined by sequencing at different time points post-infection. The results showed unstable ratio of V and W mRNA at different time points, and the frequency of NDV editing was significantly increased at the early period of infection (P KEYWORDS: Newcastle disease virus; phosphoprotein; RNA editing; G insertion. PMID- 26982471 TI - Establishment of indirect immunofluorescence assay for rotavirus. AB - Rotavirus infection is the most frequent cause of infantile gastroenteritis worldwide and a significant cause of death in infants and young children, following severe diarrhea and dehydration. Rotavirus vaccines are considered the most effective way to prevent rotavirus infections. In the process of developing rotavirus vaccines, it is crucial to establish a reliable and standardized method to determine vaccine titer. In this study, we developed an indirect immunofluorescence assay (IFA) to determine the infectious titer of Lanzhou lamb rotavirus (LLR) vaccine grown in MA104 cells. The activating concentration of trypsin was 1 ug/ml for healthy monolayers of MA104 cells at 100% confluence. After incubation for 18 hr, a rabbit anti-SA11 polyclonal antibody, diluted at 1:800 in PBS, was added to all wells, followed by an Alexa-488-conjugated secondary antibody diluted at 1:500 in PBS. Cells were examined with a fluorescence microscope. Our results show that IFA was more reproducible, more sensitive, simpler, and more rapid than the log 50% cell culture infectious dose ELISA (lgCCID50-ELISA) in measuring the rotavirus vaccines. IFA provided a reliable basis for the qualitative and quantitative analysis of rotavirus, and the certification of rotavirus vaccine production. PMID- 26982469 TI - The split Renilla luciferase complementation assay is useful for identifying the interaction of Epstein-Barr virus protein kinase BGLF4 and a heat shock protein Hsp90. AB - Protein-protein interactions can regulate different cellular processes, such as transcription, translation, and oncogenic transformation. The split Renilla luciferase complementation assay (SRLCA) is one of the techniques that detect protein-protein interactions. The SRLCA is based on the complementation of the LN and LC non-functional halves of Renilla luciferase fused to possibly interacting proteins which after interaction form a functional enzyme and emit luminescence. The BGLF4 of Epstein-Barr virus (EBV) is a viral protein kinase that is expressed during the early and late stages of lytic cycles, which can regulate multiple cellular and viral substrates to optimize the DNA replication environment. The heat shock protein Hsp90 is a molecular chaperone that maintains the integrity of structure and function of various interacting proteins, which can form a complex with BGLF4 and stabilize its expression in cells. The interaction between BGLF4 and Hsp90 could be specifically detected through the SRLCA. The region of aa 250 295 of BGLF4 is essential for the BGLF4/Hsp90 interaction and the mutation of Phe 254, Leu-266, and Leu-267 can disrupt this interaction. These results suggest that the SRLCA can specifically detect the BGLF4/Hsp90 interaction and provide a reference to develop inhibitors that disrupt the BGLF4/Hsp90 interaction. PMID- 26982472 TI - Bovine Mx1 enables resistance against foot-and-mouth disease virus in naturally susceptible cells by inhibiting the replication of viral RNA. AB - Innate immunity, especially the anti-viral genes, exerts an important barrier function in preventing viral infections. Myxovirus-resistant (Mx) gene take an anti-viral role, whereas its effects on foot-and-mouth disease virus (FMDV) in naturally susceptible cells are still unclear. The bovine primary fetal tracheal epithelial cell line BPTE-siMx1, in which bovine Mx1 gene was silenced, was established and treated with IFN alpha for 6 hr before FMDV infection. The copy numbers of the negative and positive strand viral RNA were determined by strand specific real-time fluorescence quantitative RT-PCR. The TCID50 of BPTE-siMx1 cells increased at least 17-fold as compared to control cells BPTE-LacZ at 8 hr post infection, thus silencing of bovine Mx1 could promote the replication of FMDV. The amount of both the negative and positive strand viral RNA in BPTE-siMx1 cells significantly increased as compared to BPTE-LacZ cells, indicating that the replication levels of viral RNA were promoted by silencing bovine Mx1. The bovine Mx1 gene could provide resistance against FMDV in the bovine primary fetal tracheal epithelial cells via suppressing the replication of viral RNA. PMID- 26982473 TI - Mapping of the regions involved in self-interaction of rice stripe virus P3 protein. AB - Rice stripe virus (RSV) protein P3 is a suppressor of RNA silencing in plants. P3 has been shown by biomolecular fluorescence complementation assay to self interact in planta but the regions responsible for homotypic interaction have not been determined. Here we analyzed the domains for the self-interaction of P3 by using yeast two-hybrid, co-immunoprecipitation and fluorescence experiments. The results showed that P3 was also able to interact with itself in yeast and insect cells. The domain responsible for P3-P3 interaction was mapped to amino acids 15 30 at the N-terminal region of P3. Furthermore, subcellular localization suggested that the homo-oligomerization was the prerequisite for P3 to form larger protein aggregates in the nucleus of insect cell. PMID- 26982474 TI - Sequence variation of block III segment identifies three distinct lineages within Eggplant mottled dwarf virus isolates from Italy, Spain and Greece. AB - Partial polymerase (L) gene sequences of 919 nts, including the conserved segments pre-motif A and motif A of block III, of 20 Eggplant mottled dwarf virus (EMDV) isolates were generated, and trimmed sequences of 889 nts, based on the length of available sequences of other isolates, were used to determine phylogenetic relationships. Phylogenetic reconstructions revealed two divergent lineages, designated as genetic group A (Italian isolates) and group B, with the latter further divided into subgroups BI (Greek isolates) and BII (Spanish isolates). No evidence of recombination signals among sequences was detected, whereas analysis of the nonsynonymous/synonymous ratio indicated strong purifying selection, with codons under negative selection uniformly distributed along the sequences. An RT-PCR-RFLP method able to discriminate EMDV isolates of the two main genetic groups was proposed. PMID- 26982475 TI - Phylogenetic analysis of VP2 gene of canine parvovirus and comparison with Indian and world isolates. AB - Canine parvovirus (CPV) causes hemorrhagic enteritis, especially in young dogs, leading to high morbidity and mortality. It has four main antigenic types CPV-2, CPV-2a, CPV-2b and CPV-2c. Virus protein 2 (VP2) is the main capsid protein and mutations affecting VP2 gene are responsible for the evolution of various antigenic types of CPV. Full length VP2 gene from field isolates was amplified and cloned for sequence analysis. The sequences were submitted to the GenBank and were assigned Acc. Nos., viz. KP406928.1 for P12, KP406927.1 for P15, KP406930.1 for P32, KP406926.1 for Megavac-6 and KP406929.1 for NobivacDHPPi. Phylogenetic analysis indicated that the samples were forming a separate clad with vaccine strains. When the samples were compared with the world and Indian isolates, it was observed that samples formed a separate node indicating regional genetic variation in CPV. PMID- 26982476 TI - Sequence variability among murine herpesvirus isolates shows possible effect of long-term in vitro passaging on their genome. AB - No abstract Keywords: murine herpesvirus 68; virus isolates; sequence analysis; restriction fragment length polymorphism. PMID- 26982477 TI - Genetic diversity of 2006-2009 Chikungunya virus outbreaks in Andhra Pradesh, India, reveals complete absence of E1:A226V mutation. PMID- 26982480 TI - Ultrasonic Relaxation Study of 1-Alkyl-3-methylimidazolium-Based Room-Temperature Ionic Liquids: Probing the Role of Alkyl Chain Length in the Cation. AB - Ultrasound absorption spectra of four 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imides were determined as a function of the alkyl chain length on the cation from 1-propyl to 1-hexyl from 293.15 to 323.15 K at ambient pressure. Herein, the ultrasound absorption measurements were carried out using a standard pulse technique within a frequency range from 10 to 300 MHz. Additionally, the speed of sound, density, and viscosity have been measured. The presence of strong dissipative processes during the ultrasound wave propagation was found experimentally, i.e., relaxation processes in the megahertz range were observed for all compounds over the whole temperature range. The relaxation spectra (both relaxation amplitude and relaxation frequency) were shown to be dependent on the alkyl side chain length of the 1-alkyl-3-methylimidazolium ring. In most cases, a single-Debye model described the absorption spectra very well. However, a comparison of the determined spectra with the spectra of a few other imidazolium-based ionic liquids reported in the literature (in part recalculated in this work) shows that the complexity of the spectra increases rapidly with the elongation of the alkyl chain length on the cation. This complexity indicates that both the volume viscosity and the shear viscosity are involved in relaxation processes even in relatively low frequency ranges. As a consequence, the sound velocity dispersion is present at relatively low megahertz frequencies. PMID- 26982481 TI - Haptic Guidance Needs to Be Intuitive Not Just Informative to Improve Human Motor Accuracy. AB - Humans make both random and systematic errors when reproducing learned movements. Intuitive haptic guidance that assists one to make the movements reduces such errors. Our study examined whether any additional haptic information about the location of the target reduces errors in a position reproduction task, or whether the haptic guidance needs to be assistive to do so. Holding a haptic device, subjects made reaches to visible targets without time constraints. They did so in a no-guidance condition, and in guidance conditions in which the direction of the force with respect to the target differed, but the force scaled with the distance to the target in the same way. We examined whether guidance forces directed towards the target would reduce subjects' errors in reproducing a prior position to the same extent as do forces rotated by 90 degrees or 180 degrees, as it might because the forces provide the same information in all three cases. Without vision of the arm, both the accuracy and precision were significantly better with guidance directed towards the target than in all other conditions. The errors with rotated guidance did not differ from those without guidance. Not surprisingly, the movements tended to be faster when guidance forces directed the reaches to the target. This study shows that haptic guidance significantly improved motor performance when using it was intuitive, while non-intuitively presented information did not lead to any improvements and seemed to be ignored even in our simple paradigm with static targets and no time constraints. PMID- 26982478 TI - Links of Autophagy Dysfunction to Inflammatory Bowel Disease Onset. AB - INTRODUCTION: Autophagy is a cellular stress response that plays key roles in physiological processes, such as adaptation to starvation, degradation of aberrant proteins or organelles, anti-microbial defense, protein secretion, and innate and adaptive immunity. Dysfunctional autophagy is recognized as a contributing factor in many chronic inflammatory diseases, including inflammatory bowel disease (IBD). Genetic studies have identified multiple IBD-associated risk loci that include genes required for autophagy, and several lines of evidence demonstrate that autophagy is impaired in IBD patients. How dysfunctional autophagy contributes to IBD onset is currently under investigation by researchers. KEY MESSAGES: Dysfunctional autophagy has been identified to play a role in IBD pathogenesis by altering processes that include (1) intracellular bacterial killing, (2) anti-microbial peptide secretion by Paneth cells, (3) pro inflammatory cytokine production by macrophages, (4) antigen presentation by dendritic cells, (5) goblet cell function, and (6) the endoplasmic reticulum stress response in enterocytes. The overall effect of dysregulation of these processes varies by cell type, stimulus, as well as cellular context. Manipulation of the autophagic pathway may provide a new avenue in the search for effective therapies for IBD. CONCLUSION: Autophagy plays multiple roles in IBD pathogenesis. A better understanding of the role of autophagy in IBD patients may provide better subclassification of IBD phenotypes and novel approaches to disease management. PMID- 26982479 TI - Adding Glucagon-Stimulated GH Testing to the Diagnostic Fast Increases the Detection of GH-Sufficient Children. AB - BACKGROUND/AIMS: The evaluation of children with unexplained hypoglycemia may include a diagnostic fast. However, low growth hormone (GH) concentration during hypoglycemia is not specific to GH deficiency (GHD). The aim of this study was to determine if serial GH measurement following glucagon administration, in the setting of a diagnostic fast, would increase the number of children identified as not having GHD. METHODS: We conducted a retrospective chart review of children who had serial GH measurements performed after glucagon administration at the end of a diagnostic fast. Glucagon was administered at the end of the fasting study, and GH was measured every 30 min for 210 min. RESULTS: Of the 29 children in this series, only 3 (10%) had GH concentrations >7 ng/ml at the end of the fast, which increased by 16 (55%) after serial GH testing. The percentages of samples with GH concentrations >7 ng/ml were: 10% at baseline, and 25, 39, 41, 41, 33, 43, and 0% every 30 min thereafter. CONCLUSION: Additional GH measurements after glucagon administration following a diagnostic fast can improve the identification of children without GHD and thereby save them unnecessary GH stimulation testing and potential GH treatment. PMID- 26982482 TI - Leishmania infantum Infection in Blood Donors, Northeastern Brazil. PMID- 26982483 TI - Chemical constituents from Piper hainanense and their cytotoxicities. AB - Two new compounds, (Z,R)-1-phenylethylcinnamate (1) and (1R,2R,3R,6S)-pipoxide (2) were isolated from the aerial part of Piper hainanense, along with 12 known compounds, including nine benzene derivatives (4-11), one isobutylamide (12), and two polyoxygenated cyclohexene derivatives (13-14). Their structures were elucidated on the basis of the HRESIMS, 1D and 2D NMR spectroscopic analyses, and ECD in cases of 2 and 3. The absolute configuration of ellipeiopsol B (3) was determined for the first time. All these compounds 1-14 were reported from the titled plant for the first time. Most of the isolates were tested for their cytotoxicities against five human cancer cell lines. Four of which, 2, 3, 9, 14 showed moderate bioactivities. Among them, the new compound 2 showed potential cytotoxicity against SMMC-7721, MCF-7, and SW-480 with IC50 values of 9.7, 15.0, and 13.2 MUM, respectively. PMID- 26982484 TI - Simulating the Oceanic Migration of Silver Japanese Eels. AB - The oceanic migration of silver Japanese eels starts from their continental growth habitats in East Asia and ends at the spawning area near the West Mariana Ridge seamount chain. However, the actual migration routes remain unknown. In this study, we examined the possible oceanic migration routes and strategies of silver Japanese eels using a particle tracking method in which virtual eels (v eels) were programmed to move vertically and horizontally in an ocean circulation model (Japan Coastal Ocean Predictability Experiment 2, JCOPE2). Four horizontal swimming strategies were tested: random heading, true navigation (readjusted heading), orientation toward the spawning area (fixed heading), and swimming against the Kuroshio. We found that all strategies, except random swimming, allowed v-eels swimming at 0.65 m s-1 to reach the spawning area within eight months after their departure from the south coast of Japan (end of the spawning season). The estimated minimum swimming speed required to reach the area spawning within eight months was 0.1 m s-1 for true navigation, 0.12 m s-1 for constant compass heading, and 0.35 m s-1 for swimming against the Kuroshio. The lowest swimming speed estimated from tracked Japanese eels at sea was 0.03 m.s-1, which would not allow them to reach the spawning area within eight months, through any of the tested orientation strategies. Our numerical experiments also showed that ocean circulation significantly affected the migration of Japanese v-eels. A strong Kuroshio could advect v-eels further eastward. In addition, western Pacific ocean currents accelerated the migration of navigating v-eels. The migration duration was shortened in years with a stronger southward flow, contributed by a stronger recirculation south of Japan, an enhanced subtropical gyre, or a higher southward Kuroshio velocity. PMID- 26982485 TI - The discriminative value of inflammatory back pain in patients with persistent low back pain. AB - OBJECTIVES: To estimate the prevalence of inflammatory back pain (IBP) characteristics and analyse the discriminative value of IBP relative to axial spondyloarthritis (SpA) according to the Assessment of SpondyloArthritis international Society (ASAS) criteria. METHOD: Patients who had low back pain for > 3 months were selected from a cohort of secondary care patients aged 18-40 years. Data included information on SpA features, human leucocyte antigen (HLA) B27 typing, C-reactive protein (CRP) level, magnetic resonance imaging (MRI) of the sacroiliac joints, and self-reported IBP questions covering the pain characteristics included in the Calin, Berlin, and ASAS IBP definitions. RESULTS: Of the 759 included patients, 99% [95% confidence interval (CI) 98-100] had at least one IBP characteristic. The prevalence of the single IBP characteristics ranged from 10% (95% CI 7-12) for 'pain worst in the morning' to 79% (95% CI 76 82) for 'morning stiffness'. Two-thirds of the patients (67%, 95% CI 63-70), met at least one of the three IBP definitions. In all, 86 (11%) were classified as 'SpA according to ASAS'. All three IBP definitions were significantly associated with 'SpA according to ASAS'; however, the discriminative value was low, with sensitivity, specificity, and balanced accuracy values of 64, 50, and 57% for Calin, 59, 60, and 60% for Berlin, and 35, 79, and 57% for ASAS IBP definitions, respectively. CONCLUSIONS: In this study population, IBP characteristics were in general common and the discriminative value was low, as IBP could not differentiate patients with SpA according to ASAS criteria from patients with other causes of back pain. PMID- 26982487 TI - Contribution of indigenous foods towards nutrient intakes and nutritional status of women in the Santhal tribal community of Jharkhand, India. AB - OBJECTIVE: The indigenous food environment, dietary intake and nutritional status of women in the Santhal tribal community of Jharkhand were assessed. Contribution of indigenous foods to nutritional status and nutrient intakes was explored. DESIGN: Exploratory cross-sectional study with a longitudinal dietary intake assessment component. Household and dietary surveys were conducted to elicit information on socio-economic and demographic profile and food consumption patterns at household level. A 24 h dietary recall for two consecutive days (repeat surveys in two more seasons) and anthropometric assessments were carried out on one woman per household. SETTING: Households (n 151) with at least one woman of reproductive age in four villages of Godda district of Jharkhand, India. SUBJECTS: Women aged 15-49 years. RESULTS: Almost all households owned agricultural land and grew fruits and vegetables in backyards for household consumption. A wide variety of indigenous foods were reported but dietary recalls revealed low intake. Women consumed adequate energy and protein but micronutrient intake was inadequate (less than 66 % of recommended) in the majority (more than 50 %) for Ca, Fe, vitamin B2, folate and vitamin B12. Women consuming indigenous foods in the past 2 d had significantly higher intakes of Ca (P=0.008) and Fe (P=0.010) than those who did not. Varying degrees of underweight were observed in 50 % of women with no significant association between underweight and consumption of indigenous foods. CONCLUSIONS: Promotion of preferential cultivation of nutrient-dense indigenous food sources and effective nutrition education on their importance may facilitate better micronutrient intakes among women in Santhal community of Jharkhand. PMID- 26982488 TI - Iron Deficiency, Zinc, Magnesium, Vitamin Deficiencies in Crohn's Disease: Substitute or Not? AB - Inflammatory bowel disease (IBD) is characterized by inflammatory reactions, complications, extraintestinal manifestations and a loss of intestinal functions, for example, failures of absorption and secretion. According to intestinal dysfunction, a wide array of pathogenetic pathways is existing leading to iron deficiency and numerous vitamins as well as trace element deficiencies. Complications, symptoms and signs of those deficiencies are common in IBD with varying degrees of clinical significance. This review focuses on selected micronutrients including iron, zinc, magnesium and some vitamins. Epidemiology with respect to IBD, pathophysiology, diagnosis and clinical aspects are addressed. Finally, some suggestions for treatment of deficient situations are discussed. In conclusion, some micronutrients have significant impact on complications and quality of life in IBD. Deficiencies may even influence the course of the disease. Those deficiencies should be thoroughly supplemented. PMID- 26982486 TI - Evolution of KaiC-Dependent Timekeepers: A Proto-circadian Timing Mechanism Confers Adaptive Fitness in the Purple Bacterium Rhodopseudomonas palustris. AB - Circadian (daily) rhythms are a fundamental and ubiquitous property of eukaryotic organisms. However, cyanobacteria are the only prokaryotic group for which bona fide circadian properties have been persuasively documented, even though homologs of the cyanobacterial kaiABC central clock genes are distributed widely among Eubacteria and Archaea. We report the purple non-sulfur bacterium Rhodopseudomonas palustris (that harbors homologs of kaiB and kaiC) only poorly sustains rhythmicity in constant conditions-a defining characteristic of circadian rhythms. Moreover, the biochemical characteristics of the Rhodopseudomonas homolog of the KaiC protein in vivo and in vitro are different from those of cyanobacterial KaiC. Nevertheless, R. palustris cells exhibit adaptive kaiC-dependent growth enhancement in 24-h cyclic environments, but not under non-natural constant conditions. Therefore, our data indicate that Rhodopseudomonas does not have a classical circadian rhythm, but a novel timekeeping mechanism that does not sustain itself in constant conditions. These results question the adaptive value of self-sustained oscillatory capability for daily timekeepers and establish new criteria for circadian-like systems that are based on adaptive properties (i.e., fitness enhancement in rhythmic environments), rather than upon observations of persisting rhythms in constant conditions. We propose that the Rhodopseudomonas system is a "proto" circadian timekeeper, as in an ancestral system that is based on KaiC and KaiB proteins and includes some, but not necessarily all, of the canonical properties of circadian clocks. These data indicate reasonable intermediate steps by which bona fide circadian systems evolved in simple organisms. PMID- 26982490 TI - Geography of community health information organization activity in the United States: Implications for the effectiveness of health information exchange. AB - BACKGROUND: The United States has invested nearly a billion dollars in creating community health information organizations (HIOs) to foster health information exchange. Community HIOs provide exchange services to health care organizations within a distinct geographic area. While geography is a key organizing principle for community HIOs, it is unclear if geography is an effective method for organization or what challenges are created by a geography-based approach to health information exchange. PURPOSE: This study describes the extent of reported community HIO coverage in the United States and explores the practical and policy implications of overlaps and gaps in HIO service areas. Furthermore, because self reported service areas may not accurately reflect the true extent of HIOs activities, this study maps the actual markets for health services included in each HIO. METHODOLOGY: An inventory of operational community HIOs that included self-reported geographic markets and participating organizations was face validated using a crowd-sourcing approach. Aggregation of the participating hospitals' individual health care markets provided the total geographic market served by each community HIO. Mapping and overlay analyses using geographic information system methods described the extent of community HIO activity in the United States. FINDINGS: Evidence suggests that community HIOs may be inefficiently distributed. Parts of the United States have multiple, overlapping HIOs, while others do not have any providing health information exchange services. In markets served by multiple community HIOs, 45% of hospitals were participants of only one HIO. PRACTICE IMPLICATIONS: The current geography of community HIO activity does not provide comprehensive patient information to providers, nor community-wide information for public health agencies. The discord between the self-reported and market geography of community HIOs raises concerns about the potential effectiveness of health information exchange, illustrates the limitations of geography as an organizing principle, and indicates operational challenges facing those leading and working with community HIOs. PMID- 26982489 TI - Effects of Multi-Generational Stress Exposure and Offspring Environment on the Expression and Persistence of Transgenerational Effects in Arabidopsis thaliana. AB - Plant phenotypes can be affected by environments experienced by their parents. Parental environmental effects are reported for the first offspring generation and some studies showed persisting environmental effects in second and further offspring generations. However, the expression of these transgenerational effects proved context-dependent and their reproducibility can be low. Here we study the context-dependency of transgenerational effects by evaluating parental and transgenerational effects under a range of parental induction and offspring evaluation conditions. We systematically evaluated two factors that can influence the expression of transgenerational effects: single- versus multiple-generation exposure and offspring environment. For this purpose, we exposed a single homozygous Arabidopsis thaliana Col-0 line to salt stress for up to three generations and evaluated offspring performance under control and salt conditions in a climate chamber and in a natural environment. Parental as well as transgenerational effects were observed in almost all traits and all environments and traced back as far as great-grandparental environments. The length of exposure exerted strong effects; multiple-generation exposure often reduced the expression of the parental effect compared to single-generation exposure. Furthermore, the expression of transgenerational effects strongly depended on offspring environment for rosette diameter and flowering time, with opposite effects observed in field and greenhouse evaluation environments. Our results provide important new insights into the occurrence of transgenerational effects and contribute to a better understanding of the context-dependency of these effects. PMID- 26982491 TI - Rehabilitation Utilization following a Work-Related Traumatic Brain Injury: A Sex Based Examination of Workers' Compensation Claims in Victoria, Australia. AB - OBJECTIVES: To report on and examine differences in the use of four types of rehabilitation services (occupational therapy, physiotherapy, psychology, and speech therapy) by men and women following a work-related traumatic brain injury in Victoria, Australia; and to examine the importance of demographic, need, work related and geographic factors in explaining these differences. METHODS: A retrospective cohort design was used to analyze 1786 work-related traumatic brain injury workers' compensation claims lodged between 2004 and 2012 in Victoria, Australia. ZINB regressions were conducted for each type of rehabilitation service to examine the relationship between sex and rehabilitation use. Covariates included demographic, need-related, work-related, and geographic factors. RESULTS: Out of all claims (63% male, 37% female), 13% used occupational therapy, 23% used physiotherapy, 9% used psychology, and 2% used speech therapy at least once during the first year of service utilization. After controlling for demographic, need-related, work-related, and geographic factors, women were more likely to use physiotherapy compared to men. Men and women were equally likely to use occupational therapy and psychology services. The number of visits in the first year for each type of service did not differ between male and female users. CONCLUSIONS: Our findings support a sex-based approach to studying rehabilitation utilization in work-related populations. Future research is needed to examine other factors associated with rehabilitation utilization and to determine the implications of different rehabilitation utilization patterns on health and return-to-work outcomes. PMID- 26982492 TI - Therapeutic Drug Monitoring of Everolimus: A Consensus Report. AB - In 2014, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology called a meeting of international experts to provide recommendations to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice. EVR is a potent inhibitor of the mammalian target of rapamycin, approved for the prevention of organ transplant rejection and for the treatment of various types of cancer and tuberous sclerosis complex. EVR fulfills the prerequisites for TDM, having a narrow therapeutic range, high interindividual pharmacokinetic variability, and established drug exposure-response relationships. EVR trough concentrations (C0) demonstrate a good relationship with overall exposure, providing a simple and reliable index for TDM. Whole-blood samples should be used for measurement of EVR C0, and sampling times should be standardized to occur within 1 hour before the next dose, which should be taken at the same time everyday and preferably without food. In transplantation settings, EVR should be generally targeted to a C0 of 3-8 ng/mL when used in combination with other immunosuppressive drugs (calcineurin inhibitors and glucocorticoids); in calcineurin inhibitor-free regimens, the EVR target C0 range should be 6-10 ng/mL. Further studies are required to determine the clinical utility of TDM in nontransplantation settings. The choice of analytical method and differences between methods should be carefully considered when determining EVR concentrations, and when comparing and interpreting clinical trial outcomes. At present, a fully validated liquid chromatography tandem mass spectrometry assay is the preferred method for determination of EVR C0, with a lower limit of quantification close to 1 ng/mL. Use of certified commercially available whole blood calibrators to avoid calibration bias and participation in external proficiency-testing programs to allow continuous cross-validation and proof of analytical quality are highly recommended. Development of alternative assays to facilitate on-site measurement of EVR C0 is encouraged. PMID- 26982493 TI - Assuring the Proper Analytical Performance of Measurement Procedures for Immunosuppressive Drug Concentrations in Clinical Practice: Recommendations of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology Immunosuppressive Drug Scientific Committee. AB - Monitoring immunosuppressive drugs (ISDs) in blood or plasma is still a key therapeutic drug monitoring (TDM) application in clinical settings. Narrow target ranges and severe side effects at drug underexposure or overexposure make accurate and precise measurements a must. This overview prepared by the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology is intended to serve as a summary and guidance document describing the current state-of-the-art in the TDM of ISDs. PMID- 26982494 TI - Health Risks in Same-Sex Attracted Ugandan University Students: Evidence from Two Cross-Sectional Studies. AB - Widespread discrimination across much of sub-Saharan Africa against persons with same-sex sexuality, including recent attempts in Uganda to extend criminal sanctions against same-sex behavior, are likely to have profound effects on this group's health, health care access, and well-being. Yet knowledge of the prevalence of same-sex sexuality in this region is scarce. This study aimed to systematically examine prevalence of same-sex sexuality and related health risks in young Ugandan adults. We conducted two cross-sectional survey studies in south western Uganda targeting student samples (n = 980, n = 1954) representing 80% and 72% of the entire undergraduate classes attending a university in 2005 and 2010, respectively. A questionnaire assessed items concerning same-sex sexuality (same sex attraction/fantasies, same-sex sexual relations), mental health, substance use, experience of violence, risky sexual behavior, and sexual health counseling needs. Our findings showed that same-sex sexual attraction/fantasies and behavior were common among male and female students, with 10-25% reporting having sexual attraction/fantasies regarding persons of the same-sex, and 6-16% reporting same sex sexual relations. Experiences of same-sex sexuality were associated with health risks, e.g. poor mental health (2010, AOR = 1.5; 95% CI: 1.0-2.3), sexual coercion (2010, AOR 2.9; CI: 1.9-4.6), and unmet sexual health counseling needs (2010, AOR 2.2; CI: 1.4-3.3). This first study of young adults in Uganda with same-sex sexuality found high levels of health needs but poor access to health care. Effective response is likely to require major shifts in current policy, efforts to reduce stigmatization, and reorientation of health services to better meet the needs of this vulnerable group of young people. PMID- 26982496 TI - Methods for Measuring Lung Volumes: Is There a Better One? AB - BACKGROUND: Accurate measurement of lung volumes is of paramount importance to establish the presence of ventilatory defects and give insights for diagnostic and/or therapeutic purposes. OBJECTIVES: It was the aim of this study to measure lung volumes in subjects with respiratory disorders and in normal controls by 3 different techniques (plethysmographic, dilutional and radiographic methods), in an attempt to clarify the role of each of them in performing such a task, without any presumptive 'a priori' superiority of one method above others. Patients andMethods: In different groups of subjects with obstructive and restrictive ventilatory defects and in a normal control group, total lung capacity, functional residual capacity (FRC) and residual volume were measured by body plethysmography, multi-breath helium (He) dilution and radiographic CT scan method with spirometric gating. RESULTS: The 3 methods gave comparable results in normal subjects and in patients with a restrictive defect. In patients with an obstructive defect, CT scan and plethysmography showed similar lung volumes, while on average significantly lower lung volumes were obtained with the He dilution technique. Taking into account that the He dilution technique does primarily measure FRC during tidal breathing, our data suggest that in some patients with an obstructive defect, a number of small airways can be functionally closed at end-expiratory lung volume, preventing He to reach the lung regions subserved by these airways. CONCLUSION: In all circumstances, both CT scan with spirometric gating and plethysmographic methods provide similar values of lung volumes. In contrast, the He dilution method can measure lower lung volumes in some patients with chronic airflow obstruction. PMID- 26982495 TI - Long-Term Toxicity of 213Bi-Labelled BSA in Mice. AB - BACKGROUND: Short-term toxicological evaluations of alpha-radioimmunotherapy have been reported in preclinical assays, particularly using bismuth-213 (213Bi). Toxicity is greatly influenced not only by the pharmacokinetics and binding specificity of the vector but also by non-specific irradiation due to the circulating radiopharmaceutical in the blood. To assess this, an acute and chronic toxicity study was carried out in mice injected with 213Bi-labelled Bovine Serum Albumin (213Bi-BSA) as an example of a long-term circulating vector. METHOD: Biodistribution of 213Bi-BSA and 125I-BSA were compared in order to evaluate 213Bi uptake by healthy organs. The doses to organs for injected 213Bi BSA were calculated. Groups of nude mice were injected with 3.7, 7.4 and 11.1 MBq of 213Bi-BSA and monitored for 385 days. Plasma parameters, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and creatinine, were measured and blood cell counts (white blood cells, platelets and red blood cells) were performed. Mouse organs were examined histologically at different time points. RESULTS: Haematological toxicity was transient and non-limiting for all evaluated injected activities. At the highest injected activity (11.1 MBq), mice died from liver and kidney failure (median survival of 189 days). This liver toxicity was identified by an increase in both ALT and AST and by histological examination. Mice injected with 7.4 MBq of 213Bi BSA (median survival of 324 days) had an increase in plasma BUN and creatinine due to impaired kidney function, confirmed by histological examination. Injection of 3.7 MBq of 213Bi-BSA was safe, with no plasma enzyme modifications or histological abnormalities. CONCLUSION: Haematological toxicity was not limiting in this study. Liver failure was observed at the highest injected activity (11.1 MBq), consistent with liver damage observed in human clinical trials. Intermediate injected activity (7.4 MBq) should be used with caution because of the risk of long-term toxicity to kidneys. PMID- 26982498 TI - Leptin as a Potential Regulator of FGF21. AB - BACKGROUND/AIMS: Fibroblast growth factor 21 (FGF21), a potent metabolic regulator, has been shown to improve insulin sensitivity in animal models of insulin resistance. Several studies have focused on identifying mediators of FGF21 effects. However, the identification of factors involved in FGF21 regulation is far from complete. As leptin is a potent metabolic modulator as well, we aimed at characterizing whether leptin may regulate FGF21. METHODS: We investigated a potential regulation of FGF21 by leptin in vivo in Wistar rats and in vitro using human derived hepatocarcinoma HepG2 cells. This model was chosen as the liver is considered the main FGF21 expression site. RESULTS: We found that leptin injections increased plasma FGF21 levels in adult Wistar rats. This was confirmed in vitro, as leptin increased FGF21 expression in HepG2 cells. We also showed that the leptin effect on FGF21 expression was mediated by STAT3 activation in HepG2 cells. CONCLUSION: New findings regarding a leptin-STAT3 FGF21 axis were provided in this study, although investigating the exact mechanisms linking leptin and FGF21 are still needed. These results are of great interest in the context of identifying potential new clinical approaches to treat metabolic diseases associated with insulin resistance, such as obesity and type 2 diabetes. PMID- 26982497 TI - An Unusual Inverted Saline Microbial Mat Community in an Interdune Sabkha in the Rub' al Khali (the Empty Quarter), United Arab Emirates. AB - Salt flats (sabkha) are a recognized habitat for microbial life in desert environments and as analogs of habitats for possible life on Mars. Here we report on the physical setting and microbiology of interdune sabkhas among the large dunes in the Rub' al Khali (the Empty Quarter) in Liwa Oasis, United Arab Emirates. The salt flats, composed of gypsum and halite, are moistened by relatively fresh ground water. The result is a salinity gradient that is inverted compared to most salt flat communities with the hypersaline layer at the top and freshwater layers below. We describe and characterize a rich photosynthetically based microbial ecosystem that is protected from the arid outside environment by a translucent salt crust. Gases collected from sediments under shallow ponds in the sabkha contain methane in concentrations as high as 3400 ppm. The salt crust could preserve biomarkers and other evidence for life in the salt after it dries out. Chloride-filled depressions have been identified on Mars and although surface flow of water is unlikely on Mars today, ground water is possible. Such a near surface system with modern groundwater flowing under ancient salt deposits could be present on Mars and could be accessed by surface rovers. PMID- 26982499 TI - Advances in the treatment of portal hypertension in cirrhosis. AB - Non-selective beta-blockers and handling of esophageal varices has been key elements in the treatment of portal hypertension in recent decades. Liver vein catheterization has been essential in diagnosis and monitoring of portal hypertension, but ongoing needs for noninvasive tools has led to research in areas of both biomarkers, and transient elastography, which displays promising results in discerning clinically significant portal hypertension. Novel research into the areas of hepatic stellate cell function and the dynamic components of portal hypertension has revealed promising areas of treatment modalities, targeting intestinal decontamination, angiogenesis, inflammation and oxidative stress. Future studies may reveal if these initiatives lead to developments of new drugs for treatment of portal hypertension. PMID- 26982500 TI - Set Configuration in Resistance Exercise: Muscle Fatigue and Cardiovascular Effects. AB - PURPOSE: Cardiovascular responses of traditional resistance (TS) training have been extensively explored. However, the fatigue mechanisms associated with an intra-set rest configuration (ISR) have not been investigated. This study compares two modalities of set configurations for resistance exercise that equates work to rest ratios and measures the central and peripheral fatigue in combination with cortical, hemodynamic and cardiovascular measures. METHODS: 11 subjects performed two isometric knee extension training sessions using TS and ISR configurations. Voluntary activation (VA), single twitch amplitude, low frequency fatigue (LFF), Mwave, motor evoked potential (MEP), short intracortical inhibition (SICI), intracortical facilitation (ICF) and heart rate variability were evaluated before and after each training session. During each session beat to beat heart rate, blood pressure and rate pressure product (RPP) were also evaluated. RESULTS: After exercise VA decreased significantly for TS but not for ISR (P < 0.001), single twitch amplitude and LFF values were lower for TS than ISR (P < 0.004), and SICI was reduced only for the TS configuration (P = 0.049). During exercise RPP values were significantly higher for the TS than for ISR (P = 0.001). RPP correlated with VA for TS (r = -.85 P < 0.001) suggesting a relationship between central fatigue and cardiovascular stress. CONCLUSIONS: We conclude that ISR induced lower central and peripheral fatigue as well as lower cardiovascular stress in comparison with TS configuration. Our study suggests that set configuration is a key factor in the regulation of the neuromuscular and cardiovascular responses of resistance training. PMID- 26982501 TI - CD117+ Dendritic and Mast Cells Are Dependent on RasGRP4 to Function as Accessory Cells for Optimal Natural Killer Cell-Mediated Responses to Lipopolysaccharide. AB - Ras guanine nucleotide-releasing protein-4 (RasGRP4) is an evolutionarily conserved calcium-regulated, guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor. While an important intracellular signaling protein for CD117+ mast cells (MCs), its roles in other immune cells is less clear. In this study, we identified a subset of in vivo-differentiated splenic CD117+ dendritic cells (DCs) in wild-type (WT) C57BL/6 mice that unexpectedly contained RasGRP4 mRNA and protein. In regard to the biologic significance of these data to innate immunity, LPS-treated splenic CD117+ DCs from WT mice induced natural killer (NK) cells to produce much more interferon-gamma (IFN gamma) than comparable DCs from RasGRP4-null mice. The ability of LPS-responsive MCs to cause NK cells to increase their expression of IFN-gamma was also dependent on this intracellular signaling protein. The discovery that RasGRP4 is required for CD117+ MCs and DCs to optimally induce acute NK cell-dependent immune responses to LPS helps explain why this signaling protein has been conserved in evolution. PMID- 26982503 TI - Sunlight mediated synthesis of silver nanoparticles by a novel actinobacterium (Sinomonas mesophila MPKL 26) and its antimicrobial activity against multi drug resistant Staphylococcus aureus. AB - Synthesis of silver nanoparticles using microorganism are many, but there are only scanty reports using actinobacteria. In the present study, the actinobacterium of the genus Sinomonas was reported to synthesis silver nanoparticles for the first time. A photo-irradiation based method was developed for the synthesis of silver nanoparticles, which includes two day old cultural supernatant of novel species Sinomonas mesophila MPKL 26 and silver nitrate solution, exposed to sunlight. The preliminary synthesis of silver nanoparticles was noted by the color change of the solution from colorless to brown; the synthesis was further confirmed using UV-visible spectroscopy which shows a peak between 400 and 450nm. Spherical shape silver nanoparticles of size range 4-50nm were synthesized, which were characterized using transmission electron microscopy. The Fourier transform infrared spectroscopy result indicates that, the metabolite produced by the novel species S. mesophila MPKL 26 was the probable reducing/capping agent involved in the synthesis of silver nanoparticles. The synthesized silver nanoparticles maintained consistent shape with respect to different time periods. The synthesized silver nanoparticles were evaluated for the antimicrobial activity against multi drug resistant Staphylococcus aureus which show good antimicrobial activity. The method developed for synthesis is easy, requires less time (20min) and produces spherical shape nanoparticles of size as small as 4nm, having good antimicrobial activity. Hence, our study enlarges the scope of actinobacteria for the rapid biosynthesis of silver nanoparticles and can be used in formulating remedies for multi drug resistant S. aureus. PMID- 26982505 TI - The Ethics of Introducing New Surgical Technology Into Clinical Practice: The Importance of the Patient-Surgeon Relationship. PMID- 26982506 TI - Laparoscopic Colorectal Resection in Patients with Sarcopenia: A Retrospective Case-Control Study. AB - BACKGROUND AND OBJECTIVES: Previous study has reported that sarcopenia increases the risk of postoperative complications following open colorectal resection. The aim of this retrospective case-control study was to evaluate the feasibility of laparoscopic colorectal resection in patients with sarcopenia. METHODS: We retrospectively analyzed 60 patients who underwent laparoscopic colorectal resection for primary colorectal cancer between April 2012 and March 2015 at our institution. The patients were divided into two groups: sarcopenia group (normalized total psoas muscle area in males, <538 mm/m(2); in females, <346 mm/m(2); n = 20) and nonsarcopenia group (n = 40). RESULTS: No significant differences in the overall rate of postoperative complications (20% vs. 20%) or major postoperative complications of Clavien-Dindo Grade III or more (5% vs. 5%) were observed between the patients in the sarcopenia and nonsarcopenia groups. Sarcopenia was not found to be a predictor of postoperative complications by univariate analysis. CONCLUSION: Laparoscopic colorectal resection was feasible in patients with sarcopenia. PMID- 26982502 TI - Coumarin Derivatives as Substrate Probes of Mammalian Cytochromes P450 2B4 and 2B6: Assessing the Importance of 7-Alkoxy Chain Length, Halogen Substitution, and Non-Active Site Mutations. AB - Using a combined structural and biochemical approach, the functional importance of a recently described peripheral pocket bounded by the E-, F-, G-, and I helices in CYP2B4 and 2B6 was probed. Three series of 4-substituted-7 alkoxycoumarin derivatives with -H, -CH3, or -CF3 at the 4 position of the coumarin core were used initially to monitor functional differences between CYP2B4 and 2B6. 7-Ethoxy-4-(trifluoromethyl)coumarin (7-EFC) displayed the highest catalytic efficiency among these substrates. Mutants were made to alter side-chain polarity (V/E194Q) or bulk (F/Y244W) to alter access to the peripheral pocket. Modest increases in catalytic efficiency of 7-EFC O-deethylation by the mutants were magnified considerably by chlorination or bromination of the substrate ethoxy chain. A structure of CYP2B6 Y244W in complex with (+)-alpha pinene was solved at 2.2 A and showed no CYMAL-5 in the peripheral pocket. A ligand free structure of CYP2B4 F244W was solved at 3.0 A with CYMAL-5 in the peripheral pocket. In both instances, comparison of the respective wild-type and mutant CYP2B enzymes revealed that CYMAL-5 occupancy of the peripheral pocket had little effect on the topology of active site residue side-chains, despite the fact that the peripheral pocket and active site are located on opposite sides of the I-helix. Analysis of available CYP2B structures suggest that the effect of the amino acid substitutions within the peripheral pocket derive from altered interactions between the F and G helices. PMID- 26982504 TI - Quantifying Transmission of Clostridium difficile within and outside Healthcare Settings. AB - To quantify the effect of hospital and community-based transmission and control measures on Clostridium difficile infection (CDI), we constructed a transmission model within and between hospital, community, and long-term care-facility settings. By parameterizing the model from national databases and calibrating it to C. difficile prevalence and CDI incidence, we found that hospitalized patients with CDI transmit C. difficile at a rate 15 (95% CI 7.2-32) times that of asymptomatic patients. Long-term care facility residents transmit at a rate of 27% (95% CI 13%-51%) that of hospitalized patients, and persons in the community at a rate of 0.1% (95% CI 0.062%-0.2%) that of hospitalized patients. Despite lower transmission rates for asymptomatic carriers and community sources, these transmission routes have a substantial effect on hospital-onset CDI because of the larger reservoir of hospitalized carriers and persons in the community. Asymptomatic carriers and community sources should be accounted for when designing and evaluating control interventions. PMID- 26982507 TI - Photodynamic Therapy in Patients with Advanced Hilar Cholangiocarcinoma: Percutaneous Cholangioscopic Versus Peroral Transpapillary Approach. AB - OBJECTIVE: This study aimed to compare the clinical outcomes of patients with advanced hilar cholangiocarcinoma (CC) who underwent photodynamic therapy (PDT) with either percutaneous transhepatic cholangioscopy (PTCS) or endoscopic retrograde cholangiopancreatography (ERCP). BACKGROUND DATA: PDT has been proposed as a promising therapy for treatment of unresectable hilar CC that is resistant to conventional standard treatment. However, few studies have compared the delivery methods of PDT in unresectable hilar CC patients. METHODS: Thirty seven adult patients with advanced hilar CC were included in this study. Twenty four patients treated with PTCS-directed PDT and 13 patients treated with ERCP directed PDT were analyzed retrospectively. RESULTS: The PTCS- and ERCP-directed PDT groups were comparable with respect to age, gender, health status, pretreatment bilirubin levels, Bismuth type, and hilar CC stage. The length of hospital stay differed significantly (p < 0.001) between the two groups, with a median hospital stay of 37 days (range, 13-77 days) in the ERCP-directed PDT group versus 63 days (range, 23-125 days) in the PTCS-directed group. PTCS directed PDT patients demonstrated an overall survival similar to that of ERCP directed PDT patients, with a median survival of 11.6 versus 9.5 months, respectively (p = 0.96). Only lower pre-PDT bilirubin levels (p = 0.002) were a significant predictor of improved survival in all patients who underwent PDT, as determined by multivariate analysis. Median metal stent patency was similar between the groups [PTCS-directed PDT group (n = 8), 6.2 months; ERCP-directed PDT group (n = 7), 7.2 months; p = 0.642]. Survival after PTCS- or ERCP-directed PDT was not statistically different in patients with advanced hilar CC. CONCLUSIONS: Lower pre-PDT bilirubin levels were associated with longer survival in all patients. PMID- 26982508 TI - Neural Control of Inflammation: Implications for Perioperative and Critical Care. AB - Inflammation and immunity are regulated by neural reflexes. Recent basic science research has demonstrated that a neural reflex, termed the inflammatory reflex, modulates systemic and regional inflammation in a multiplicity of clinical conditions encountered in perioperative medicine and critical care. In this review, the authors describe the anatomic and physiologic basis of the inflammatory reflex and review the evidence implicating this pathway in the modulation of sepsis, ventilator-induced lung injury, postoperative cognitive dysfunction, myocardial ischemia-reperfusion injury, and traumatic hemorrhage. The authors conclude with a discussion of how these new insights might spawn novel therapeutic strategies for the treatment of inflammatory diseases in the context of perioperative and critical care medicine. PMID- 26982509 TI - No Silver Medal for Nobel Prize Contenders: Why Anesthesia Pioneers Were Nominated for but Denied the Award. AB - Taking the examples of the pioneers Carl Ludwig Schleich, Carl Koller, and Heinrich Braun, this article provides a first exploratory account of the history of anesthesiology and the Nobel Prize for physiology or medicine. Besides the files collected at the Nobel Archive in Sweden, which are presented here for the first time, this article is based on medical literature of the early 20th century. Using Nobel Prize nominations and Nobel committee reports as points of departure, the authors discuss why no anesthesia pioneer has received this coveted trophy. These documents offer a new perspective to explore and to better understand aspects of the history of anesthesiology in the first half of the 20th century. PMID- 26982510 TI - The safety of monoclonal antibodies for treatment of colorectal cancer. AB - INTRODUCTION: Monoclonal antibodies such as bevacizumab, ramucirumab, cetuximab and panitumumab play an important role in the treatment of metastatic colorectal cancer (mCRC). With the introduction of these drugs considerable improvements in both progression-free survival (PFS) and overall survival (OS) were achieved. However these antibodies are associated with a unique side effect profile. AREAS COVERED: This review provides an overview about drug efficacy of bevacizumab, cetuximab, panitumumab and ramucirumab in the treatment algorithm of mCRC. Additionally, we discuss the most common toxicites of these monoclonal antibodies. EXPERT OPINION: The most common toxicities associated with the VEGF-A directed antibody bevacizumab are hypertension, proteinuria, thromboembolism, bleeding, gastrointestinal perforation and prolonged wound healing. Similarly, the rate of hypertension and proteinuria is increased during treatment with the VEGFR2 antibody ramucirumab. On the other hand the most frequent side effects of EGFR targeted antibodies are skin rash, hypersensitivity reactions and hypomagnesemia. Due to the murine portions of cetuximab the incidence of infusion reactions is more frequent compared to panitumumab which is a pure human monoclonal antibody. PMID- 26982511 TI - Hair and Nail Changes During Long-term Therapy With Ibrutinib for Chronic Lymphocytic Leukemia. AB - IMPORTANCE: Ibrutinib, a Bruton tyrosine kinase inhibitor, is a new targeted agent approved by the US Food and Drug Administration for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and Waldenstrom macroglobulinemia. Ibrutinib is overall well tolerated but long-term treatment is required until disease progression or intolerable toxic effects occur. Little is known regarding its cutaneous adverse effects. OBJECTIVE: To describe the hair and nail manifestations associated with the long-term use of ibrutinib for the treatment of CLL. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 66 patients with CLL enrolled in a single-arm phase 2 clinical trial of ibrutinib for CLL between March 2014 and October 2015 at the National Institutes of Health. MAIN OUTCOMES AND MEASURES: The primary outcome, nail and hair changes associated with ibrutinib therapy, was assessed by an 11-question survey. In addition, the severity of nail changes was determined from a 0 to 3 rating scale for both onychoschizia and onychorrhexis. RESULTS: Among 66 patients (43 men and 23 women with ages ranging from 55 to 85 years), 44 (67%) reported brittle fingernails at a median of 6.5 (95% CI, 6-12) months after starting ibrutinib therapy. Fifteen patients (23%) developed brittle toenails after a median of 9 (95% CI, 6-15) months of ibrutinib therapy. Textural hair changes were reported in 17 patients (26%), at a median of 9 (95% CI, 6-12) months of ibrutinib treatment. CONCLUSIONS AND RELEVANCE: Hair and nail abnormalities are commonly associated with ibrutinib and appear several months after initiating therapy. Ibrutinib inhibits Bruton tyrosine kinase by covalently binding to cysteine 481. Whether ibrutinib affects the hair and nails by binding and altering cysteine-rich proteins of hair and nails or by means of another mechanism remains unknown. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01500733. PMID- 26982512 TI - On the structural origin of the single-ion magnetic anisotropy in LuFeO3. AB - The electronic structure for the conduction bands of both hexagonal and orthorhombic LuFeO3 thin films have been measured using x-ray absorption spectroscopy at oxygen K (O K) edge. Dramatic differences in both the spectral features and the linear dichroism are observed. These differences in the spectra can be explained using the differences in crystal field splitting of the metal (Fe and Lu) electronic states and the differences in O 2p-Fe 3d and O 2p-Lu 5d hybridizations. While the oxidation states have not changed, the spectra are sensitive to the changes in the local environments of the Fe(3+) and Lu(3+) sites in the hexagonal and orthorhombic structures. Using the crystal-field splitting and the hybridizations that are extracted from the measured electronic structures and the structural distortion information, we derived the occupancies of the spin minority states in Fe(3+), which are non-zero and uneven. The single ion anisotropy on Fe(3+) sites is found to originate from these uneven occupancies of the spin minority states via spin-orbit coupling in LuFeO3. PMID- 26982514 TI - Keratinocytes as modulators of sensory afferent firing. PMID- 26982513 TI - Plumbagin Protects Mice from Lethal Sepsis by Modulating Immunometabolism Upstream of PKM2. AB - Sepsis is characterized by dysregulated systemic inflammation with release of early (for example, interleukin (IL)-1beta) and late (for example, HMGB1) proinflammatory mediators from macrophages. Plumbagin, a medicinal plant-derived naphthoquinone, has been reported to exhibit antiinflammatory activity, but the underling mechanisms remain unclear. Here, we have demonstrated that plumbagin inhibits the inflammatory response through interfering with the immunometabolism pathway in activated macrophages. Remarkably, plumbagin inhibited lipopolysaccharide (LPS)-induced aerobic glycolysis by downregulating the expression of pyruvate kinase M2 (PKM2), a protein kinase responsible for the final and rate-limiting reaction step of the glycolytic pathway. Moreover, the NADPH oxidase 4 (NOX4)-mediated oxidative stress was required for LPS-induced PKM2 expression, because pharmacologic or genetic inhibition of NOX4 by plumbagin or RNA interference limited LPS-induced PKM2 expression, lactate production and subsequent proinflammatory cytokine (IL-1beta and HMGB1) release in macrophages. Finally, plumbagin protected mice from lethal endotoxemia and polymicrobial sepsis induced by cecal ligation and puncture. These findings identify a new approach for inhibiting the NOX4/PKM2-dependent immunometabolism pathway in the treatment of sepsis and inflammatory diseases. PMID- 26982515 TI - Unexplained resolution of diagnosed hypogonadism. PMID- 26982516 TI - Reply. PMID- 26982518 TI - Erratum. PMID- 26982517 TI - Erratum. PMID- 26982519 TI - Supplemental oxygen for caesarean section during regional anaesthesia. AB - BACKGROUND: Supplementary oxygen is routinely administered to low-risk pregnant women during an elective caesarean section under regional anaesthesia; however, maternal and foetal outcomes have not been well established. This is an update of a review first published in 2013. OBJECTIVES: The primary objective was to determine whether supplementary oxygen given to low-risk term pregnant women undergoing elective caesarean section under regional anaesthesia can prevent maternal and neonatal desaturation. The secondary objective was to compare the mean values of maternal and neonatal blood gas levels between mothers who received supplementary oxygen and those who did not (control group). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, issue 11), MEDLINE (1948 to November 2014) and EMBASE (1980 to November 2014). The original search was first performed in February 2012. We reran the search in CENTRAL, MEDLINE, EMBASE in February 2016. One potential new study of interest was added to the list of 'Studies awaiting Classification' and will be incorporated into the formal review findings during the next review update. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of low-risk pregnant women undergoing an elective caesarean section under regional anaesthesia and compared outcomes with, and without, oxygen supplementation. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, assessed methodological quality and performed subgroup and sensitivity analyses. MAIN RESULTS: We found one new included study in this updated version. In total, our updated review includes 11 trials (with 753 participants). The low quality of evidence showed no significant differences in average Apgar scores at one minute (N = six trials, 519 participants; 95% confidence (CI) -0.16 to 0.31, P = 0.53) and at five minutes (N = six trials, 519 participants; 95% CI -0.06 to 0.06, P = 0.98). None of the 11 trials reported maternal desaturation. The very low quality of evidence showed that in comparison to room air, women in labour receiving supplementary oxygen had higher maternal oxygen saturation (N = three trials, 209 participants), maternal PaO2 (oxygen pressure in the blood; N = six trials, 241 participants), UaPO2 (foetal umbilical arterial blood; N = eight trials, 504 participants; 95% CI 1.8 to 4.9, P < 0.0001) and UvPO2 (foetal umbilical venous blood; N = 10 trials, 683 participants). There was high heterogeneity among these outcomes. A subgroup analysis showed no significant difference in UaPO2 between the two intervention groups in low-risk studies, whereas the high-risk studies showed a benefit for the neonatal oxygen group. AUTHORS' CONCLUSIONS: Overall, we found no convincing evidence that giving supplementary oxygen to healthy term pregnant women during elective caesarean section under regional anaesthesia is either beneficial or harmful for either the mother or the foetus' short-term clinical outcome as assessed by Apgar scores. Although, there were significant higher maternal and neonatal blood gas values and markers of free radicals when extra oxygen was given, the results should be interpreted with caution due to the low grade quality of the evidence. PMID- 26982520 TI - The why's and wherefore's of this vascular biology section of Current Opinion in Hematology. PMID- 26982521 TI - Is therapeutic judgement influenced by the patient's socio-economic status? A factorial vignette survey. AB - Background In Denmark patients are entitled to rehabilitation regardless of socio economic status (SES). During this process therapists have to balance cost effectiveness with providing equal treatment. Aim To investigate whether occupational therapists and physiotherapists were influenced by the patient's SES. Material and method An experimental factorial vignette survey was used. Four different vignettes describing fictitious patient cases with different SES variables were randomly allocated to therapists working in somatic hospitals. Thereafter, the therapists judged specific clinical situations and general attitudes in relation to the patient's SES. Chi-square was used to test the statistical association between the variables. Results No statistically significant associations were found between the specific clinical situations and the patient's SES. A statistical significant association was found between general attitudes and the patient's SES. Subgroup analysis revealed a statistically significant association between the therapist's gender, age, and the therapeutic judgement in relation to SES. Conclusion In the specific clinical situations, Danish therapists seem to maintain their professional ethical principles, although they might face ethical dilemmas during their clinical decision-making. In order to prevent and resolve these dilemmas, they have to be made explicit. However, further research on how SES influences the health care professional's judgement is warranted. PMID- 26982524 TI - Multicolor detection of every chromosome as a means of detecting mosaicism and nuclear organization in human embryonic nuclei. AB - Fluorescence in-situ hybridization (FISH) revolutionized cytogenetics using fluorescently labelled probes with high affinity with target (nuclear) DNA. By the early 1990s FISH was adopted as a means of preimplantation genetic diagnosis (PGD) sexing for couples at risk of transmitting X-linked disorders and later for detection of unbalanced translocations. Following a rise in popularity of PGD by FISH for sexing and the availability of multicolor probes (5-8 colors), the use of FISH was expanded to the detection of aneuploidy and selective implantation of embryos more likely to be euploid, the rationale being to increase pregnancy rates (referral categories were typically advanced maternal age, repeated IVF failure, repeated miscarriage or severe male factor infertility). Despite initial reports of an increase in implantation rates, reduction in trisomic offspring and spontaneous abortions criticism centered around experimental design (including lack of randomization), inadequate control groups and lack of report on live births. Eleven randomized control trials (RCTs) (2004-2010) showed that preimplantation genetic screening (PGS) with FISH did not increase delivery rates with some demonstrating adverse outcomes. These RCTs, parallel improvements in culturing and cryopreservation and a shift to blastocyst biopsy essentially outdated FISH as a tool for PGS and it has now been replaced by newer technologies (array CGH, SNP arrays, qRT-PCR and NGS). Cell-by-cell follow up analysis of individual blastomeres in non-transferred embryos is however usually prohibitively expensive by these new approaches and thus FISH remains an invaluable resource for the study of mosaicism and nuclear organization. We thus developed the approach described herein for the FISH detection of chromosome copy number of all 24 human chromosomes. This approach involves 4 sequential layers of hybridization, each with 6 spectrally distinct fluorochromes and a bespoke capturing system. Here we report previously published studies and hitherto unreported data indicating that 24 chromosome FISH is a useful tool for studying chromosome mosaicism, one of the most hotly debated topics currently in preimplantation genetics. Our results suggest that mosaic embryo aneuploidy is not highly significantly correlated to maternal age, probably due, in part, to the large preponderance of post-zygotic (mitotic) errors. Chromosome loss (anaphase lag) appears to be the most common mechanism, followed by chromosome gain (endoreduplication), however 3:1 mitotic non-disjunction of chromosomes appears to be rare. Nuclear organization (i.e. the spatial and temporal topology of chromosomes or sub-chromosomal compartments) studies indicate that human morula or blastocyst embryos (days 4-5) appear to adopt a "chromocentric" pattern (i.e. almost all centromeric signals reside in the innermost regions of the nuclear volume). By the blastocyst stage however, a more ordered organization with spatial and temporal cues important for embryo development appears. We have however found no association between aneuploidy and nuclear organization using this approach despite our earlier studies. In conclusion, while FISH is mostly "dead and buried" for mainstream PGS, it still has a place for basic biology studies; the development of a 24 chromosome protocol extends the power of this analysis. PMID- 26982522 TI - Synergistic Inhibitory Effect of Peptide-Organic Coassemblies on Amyloid Aggregation. AB - Inhibition of amyloid aggregation is important for developing potential therapeutic strategies of amyloid-related diseases. Herein, we report that the inhibition effect of a pristine peptide motif (KLVFF) can be significantly improved by introducing a terminal regulatory moiety (terpyridine). The molecular level observations by using scanning tunneling microscopy reveal stoichiometry dependent polymorphism of the coassembly structures, which originates from the terminal interactions of peptide with organic modulator moieties and can be attributed to the secondary structures of peptides and conformations of the organic molecules. Furthermore, the polymorphism of the peptide-organic coassemblies is shown to be correlated to distinctively different inhibition effects on amyloid-beta 42 (Abeta42) aggregations and cytotoxicity. PMID- 26982523 TI - Design, Synthesis, and Biological Evaluation of Imidazo[1,5-a]quinoline as Highly Potent Ligands of Central Benzodiazepine Receptors. AB - A series of imidazo[1,5-a]quinoline derivatives was designed and synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high CBR affinity with Ki values within the submicromolar and subnanomolar ranges with interesting modulations in their structure-affinity relationships. In particular, fluoroderivative 7w (Ki = 0.44 nM) resulted in the most potent ligand among the imidazo[1,5-a]quinoline derivatives described so far. Overall, these observations confirmed the assumption concerning the presence of a large though apparently saturable lipophilic pocket in the CBR binding site region interacting with positions 4 and 5 of the imidazo[1,5-a]quinoline nucleus. The in vivo biological characterization revealed that compounds 7a,c,d,l,m,q,r,w show anxiolytic and antiamnestic activities without the unpleasant myorelaxant side effects of the classical 1,4-BDZ. Furthermore, the effect of 7l,q,r, and 8i in lowering lactate dehydrogenase (LDH) release induced by ischemia-like conditions in rat brain slices suggested neuroprotective properties for these imidazo[1,5-a]quinoline derivatives. PMID- 26982525 TI - Telehealth for patients with Parkinson's disease: delivering efficient and sustainable long-term care. AB - OBJECTIVES: We set out to demonstrate the benefits of providing long-term care via telehealth for patients with Parkinson's disease living in continuous care facilities. METHODS: A cohort of 16 patients with Parkinson's disease residing at one of 2 locations of a multi-facility continuous care retirement organization were seen virtually in follow-up over a 3-year period by Telehealth Services at a large, academic, tertiary care hospital in southeastern Pennsylvania. The data collected during that period, studied retrospectively, included demographic information, number of telehealth visits, and UPDRS scores obtained at each visit. Satisfaction and potential cost savings were also reviewed. RESULTS: UPDRS scores declined over the period of observation, from a range of 18-60 at study start to 28-72 at study end. Actual cost savings are difficult to define; however, the cost per telehealth visit at $117.30 was often lower than the facility's average cost for transporting patients to a visit in the neurologist's office. Patients, families, subspecialists, and the nursing staff expressed uniformly high satisfaction with telehealth. CONCLUSION: This model for providing care proved to be sustainable and efficient, and promoted collaboration among the providers at the long-term care facility and those at the remote site. These benefits may be applicable to patients with degenerative disorders in similar settings. PMID- 26982526 TI - Elevated Toxoplasma gondii Infection Rates for Retinas from Eye Banks, Southern Brazil. AB - We found significantly higher incidence of Toxoplasma gondii DNA in eye bank specimens from Joinville in southern Brazil (13/15, 87%) than in Sao Paulo (3/42, 7%; p = 2.1 * 10E-8). PCR DNA sequence analysis was more sensitive at locus NTS2 than at locus B1; a high frequency of mixed co-infections was detected. PMID- 26982527 TI - The color lexicon of the Somali language. AB - This empirical study had three goals: (a) to describe Somali color naming and its motifs, (b) to relate color naming by Somali informants to their color vision, and (c) to search for historical and demographic clues about the diversity of Somali color naming. Somali-speaking informants from Columbus, Ohio provided monolexemic color terms for 83 or 145 World Color Survey (WCS) color samples. Proximity analysis reduced the 103 color terms to the eight chromatic color meanings from the WCS plus black, white, and gray. Informants' data sets were grouped by spectral clustering analysis into four WCS color naming motifs named after the terms for the cool colors: (a) Green-Blue, (b) Grue (a single term meaning "green or blue"), (c) Gray, and (d) Dark. The results show that, first, the Somali language has about four motifs among its speakers. Second, individuals' color vision test results and their motifs were not correlated, suggesting that multiple motifs do not arise from individual variation in color vision. Last, the Somali color lexicon has changed over the past century. New color terms often came from the names of familiar colored objects, and informants' motifs were closely related to their ages and genders, suggesting that the diversity of color naming across speakers of Somali probably results from ongoing language change. PMID- 26982528 TI - Geometric figure-ground cues override standard depth from accretion-deletion. AB - Accretion-deletion is widely considered a decisive cue to surface depth ordering, with the accreting or deleting surface interpreted as behind an adjoining surface. However, Froyen, Feldman, and Singh (2013) have shown that when accretion-deletion occurs on both sides of a contour, accreting-deleting regions can also be perceived as in front and as self-occluding due to rotation in three dimensions. In this study we ask whether geometric figure-ground cues can override the traditional "depth from accretion-deletion" interpretation even when accretion-deletion takes place only on one side of a contour. We used two tasks: a relative-depth task (front/back), and a motion-classification task (translation/rotation). We conducted two experiments, in which texture in only one set of alternating regions was moving; the other set was static. Contrary to the traditional interpretation of accretion-deletion, the moving convex and symmetric regions were perceived as figural and rotating in three dimensions in roughly half of the trials. In the second experiment, giving different motion directions to the moving regions (thereby weakening motion-based grouping) further weakened the traditional accretion-deletion interpretation. Our results show that the standard "depth from accretion-deletion" interpretation is overridden by static geometric cues to figure-ground. Overall, the results demonstrate a rich interaction between accretion-deletion, figure-ground, and structure from motion that is not captured by existing models of depth from motion. PMID- 26982529 TI - Characterization of Intersubunit Communication in the Virginiamycin trans-Acyl Transferase Polyketide Synthase. AB - Modular polyketide synthases (PKSs) direct the biosynthesis of clinically valuable secondary metabolites in bacteria. The fidelity of chain growth depends on specific recognition between successive subunits in each assembly line: interactions mediated by C- and N-terminal "docking domains" (DDs). We have identified a new family of DDs in trans-acyl transferase PKSs, exemplified by a matched pair from the virginiamycin (Vir) system. In the absence of C-terminal partner (VirA (C)DD) or a downstream catalytic domain, the N-terminal DD (VirFG (N)DD) exhibits multiple characteristics of an intrinsically disordered protein. Fusion of the two docking domains results in a stable fold for VirFG (N)DD and an overall protein-protein complex of unique topology whose structure we support by site-directed mutagenesis. Furthermore, using small-angle X-ray scattering (SAXS), the positions of the flanking acyl carrier protein and ketosynthase domains have been identified, allowing modeling of the complete intersubunit interface. PMID- 26982530 TI - Effect of aliskiren and carvedilol on expression of Ca(2+)/calmodulin-dependent protein kinase II delta-subunit isoforms in cardiac hypertrophy rat model. AB - CONTEXT: The critical role of CaMKIIdelta isoforms in cardiac hypertrophy is well documented. OBJECTIVE: This study was aimed to investigate the possible inhibitory effects of aliskiren (ALS) and/or carvedilol (CAV) on CaMKIIdelta isoforms expression in experimental cardiac hypertrophy. MATERIALS AND METHODS: Male Wistar albino rats were subcutaneously injected with isoproterenol (ISO) (5 mg/kg/day) for 4 weeks to induce cardiac hypertrophy. Hypertrophied rats were daily treated with either ALS (10 mg/kg) and/or CAV (10 mg/kg). At the end of the treatment, rats were killed; blood and hearts were collected for assessing different biochemical parameters. RESULTS: ISO treatment significantly increased heart weight to body weight (HW/BW) ratio, serum creatine kinase MB (CK-MB) and troponin T (Tn-T) levels, and plasma renin activity (PRA) as compared to control rats. Additionally, ISO treatment produced a significant increase in the expression of myocardial CaMKIIdelta2 and CaMKIIdelta3 that were associated with significant elevation in myocardial caspase-3 protein expression. Histopathological examination of rats exposed to ISO treatment showed severe myocardial cell degeneration. ALS and/or CAV treatment significantly reduced the altered HW/BW ratio, serum CK-MB and Tn-T levels, PRA, and caspase-3 protein expression in hypertrophied rats, with maximal improvement in the combination group. These biochemical findings were supported by the histopathological examination of the heart tissue. Additionally, treatment with ALS and CAV significantly inhibited ISO-induced increase in CaMKIIdelta2 and CaMKIIdelta3 expression levels. DISCUSSION AND CONCLUSION: The present study indicated that ALS and CAV treatment ameliorated ISO-induced hypertrophy via inhibiting the expression and the activity of CaMKIIdelta isoforms and the associated myocardial apoptosis. PMID- 26982531 TI - Mechanistic insights into transient severe mitral regurgitation. AB - Acute mitral regurgitation (AMR), a known complication of acute coronary syndromes, is usually associated with posterior papillary muscle dysfunction/rupture. In severe cases, management of AMR requires surgical intervention. Reversible severe AMR in patients in the absence of left ventricular systolic dysfunction and coronary artery stenosis may result from processes which cause transient subendocardial ischemia, such as intermittent episodes of hypotension or coronary artery vasospasm. We present two cases of reversible transient AMR due to subendocardial and/or endocardial ischemia, both of which offer insight into the mechanism of transient severe AMR. PMID- 26982532 TI - Revisiting Street Intersections Using Slot-Based Systems. AB - Since their appearance at the end of the 19th century, traffic lights have been the primary mode of granting access to road intersections. Today, this centuries old technology is challenged by advances in intelligent transportation, which are opening the way to new solutions built upon slot-based systems similar to those commonly used in aerial traffic: what we call Slot-based Intersections (SIs). Despite simulation-based evidence of the potential benefits of SIs, a comprehensive, analytical framework to compare their relative performance with traffic lights is still lacking. Here, we develop such a framework. We approach the problem in a novel way, by generalizing classical queuing theory. Having defined safety conditions, we characterize capacity and delay of SIs. In the 2 road crossing configuration, we provide a capacity-optimal SI management system. For arbitrary intersection configurations, near-optimal solutions are developed. Results theoretically show that transitioning from a traffic light system to SI has the potential of doubling capacity and significantly reducing delays. This suggests a reduction of non-linear dynamics induced by intersection bottlenecks, with positive impact on the road network. Such findings can provide transportation engineers and planners with crucial insights as they prepare to manage the transition towards a more intelligent transportation infrastructure in cities. PMID- 26982533 TI - The effect of dimple error on the horizontal launch angle and side spin of the golf ball during putting. AB - This study aimed to examine the effect of the impact point on the golf ball on the horizontal launch angle and side spin during putting with a mechanical putting arm and human participants. Putts of 3.2 m were completed with a mechanical putting arm (four putter-ball combinations, total of 160 trials) and human participants (two putter-ball combinations, total of 337 trials). The centre of the dimple pattern (centroid) was located and the following variables were measured: distance and angle of the impact point from the centroid and surface area of the impact zone. Multiple regression analysis was conducted to identify whether impact variables had significant associations with ball roll variables, horizontal launch angle and side spin. Significant associations were identified between impact variables and horizontal launch angle with the mechanical putting arm but this was not replicated with human participants. The variability caused by "dimple error" was minimal with the mechanical putting arm and not evident with human participants. Differences between the mechanical putting arm and human participants may be due to the way impulse is imparted on the ball. Therefore it is concluded that variability of impact point on the golf ball has a minimal effect on putting performance. PMID- 26982534 TI - Chemico-biological interaction of Etravirine and its beta-Cyclodextrin complex with macromolecular targets. AB - The interaction of etravirine with beta-cyclodextrin is analyzed by UV-visible absorption, infrared, fluorescence, nuclear magnetic resonance, two-dimensional rotational frame nuclear Overhauser effect spectroscopy, and molecular modeling studies. The 4-hydroxy-3, 5-dimethylbenzonitrile moiety is found to take part in the binding. The stoichiometry of the inclusion complex of ET with beta-CD is 1:1 with the binding constant of 2.03 * 103 mol-1 dm3. The binding of ET with calf thymus DNA (ctDNA) and bovine serum albumin (BSA) protein is investigated in the presence and the absence of beta-CD. Fluorescence enhancement is observed during the binding of ET with ctDNA in the absence of beta-CD, whereas in the presence of beta-CD, fluorescence quenching is observed. The binding constants of the binding of ET and ET-beta-CD to ctDNA are 7.84 * 104 and 4.38 * 104 mol-1 dm3, respectively. The binding constant of the binding of ET and ET-beta-CD to BSA are 3.14 * 104 and 1.6396 * 104 mol-1 dm3, respectively. The apparent binding constants between ET-beta-CD complex and ctDNA or BSA protein decreases significantly. The numbers of binding sites of interaction of ET with BSA protein and the binding distance between BSA protein and ET the absence and the presence of beta-CD differ. beta-CD modulates the binding of ET with the macromolecular targets. PMID- 26982535 TI - An unusual case of Meckel-Gruber syndrome (MKS) associated with visceroatrial heterotaxy and facial anomalies. PMID- 26982536 TI - Group-based delivery of interventions in traumatic brain injury rehabilitation: a scoping review. AB - PURPOSE: Whilst there are potential advantages of group-based interventions in rehabilitation, facilitation of groups for patients following traumatic brain injury (TBI) has challenges due to the complexity of impairments experienced. This paper aims to review the literature concerning therapy groups within TBI rehabilitation. METHOD: A scoping review with systematic searching of relevant databases and review of reference lists of included studies was conducted. Key search terms included brain injury, group and rehabilitation OR therapy OR intervention. Studies were included if at least some participants had a TBI diagnosis and they investigated rehabilitation interventions conducted in a group setting. Articles were collated, summarised and key findings are presented. RESULTS: The total number of included articles was 99. The results indicated group interventions are widely practised in TBI rehabilitation. Existing research consists mostly of pre-post intervention studies addressing cognitive impairments with outpatient participants. Most studies have identified significant positive changes on some targeted outcome measures suggesting group interventions are effective. CONCLUSIONS: Studies of the effectiveness of interventions targeting 'real-world' activities and participation-based goals are under-represented in the TBI rehabilitation literature. Further research investigating the effectiveness of group processes and the perceptions of patients and clinicians is warranted to guide clinical practice. Implications for Rehabilitation Group based interventions are common in TBI rehabilitation, usually targeting cognitive skills and impairments. The majority of studies demonstrated positive changes pre post group interventions on some outcome measures. Few studies directly compare the outcome of an intervention delivered in a group setting to the same intervention delivered in an individual setting. Patients perceive group interventions to be beneficial for sharing experiences and reducing isolation, receiving help and feedback and, assisting with adjustment and adaptation to life after TBI, however, this research is limited. Greater emphasis on group-delivered interventions that target 'real world' activities, or participation may be beneficial with this population. Further research regarding consumer experiences and processes that facilitate effective group interventions in TBI rehabilitation is recommended. PMID- 26982537 TI - Report into clostridium difficile deaths at Vale of Leven reveals poor care and lack of leadership. AB - An inquiry into the deaths of patients from clostridium difficile at the Vale of Leven Hospital in Scotland has criticised nurses for providing substandard care. PMID- 26982538 TI - 1 per cent pay rise would be cheaper than paying midwives for their overtime. AB - If midwives claimed for every hour of overtime they worked in a year it would cost the government significantly more than if they awarded them the recommended 1 per cent pay rise, the Royal College of Midwives (RCM) has said. PMID- 26982539 TI - News digest November 25 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26982541 TI - Don't demonise overweight nurses, says obesity expert. AB - Nurses can be healthy role models for their patients, but it would be wrong to 'demonise' those who are overweight, an obesity expert has said. PMID- 26982540 TI - Nurses and midwives stage second pay strike. AB - Thousands of nurses and midwives in England are on strike today (November 24) for the second time in six weeks. PMID- 26982542 TI - News digest November 24 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26982543 TI - Nurses in Wales to receive 1 per cent pay rise in 2015. AB - Nurses in Wales will get a 1 per cent pay rise next year after health unions agreed a new pay deal with the Welsh Government and NHS Wales. PMID- 26982545 TI - News digest November 20 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26982544 TI - News digest November 21 2014. AB - A round-up of nursing and health stories from today's papers. PMID- 26982546 TI - Influence of Age, Gender, and Living Circumstances on Patterns of Attention Deficit/Hyperactivity Disorder Medication Use in Children and Adolescents With or Without Intellectual Disabilities. AB - AIMS AND OBJECTIVES: The aim of the study was to determine whether there are differences in psychopharmacological practice for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents dependent on the presence or absence of associated intellectual disability; and if there are, whether the differences are influenced by factors such as age, gender, and living circumstances. METHODOLOGY: A case-control cross-sectional design was used. Each arm of the study had a total of 107 children and adolescents aged 5-18 years. Case participants had diagnoses of having intellectual disability and ADHD; comparison participants had diagnoses of having ADHD, but no intellectual disability. Outcome measurements were (1) concurrent use of medications-single medication event as against concurrent multiple medication events-and (2) type of medication used-stimulants versus nonstimulants. Demographic factors considered were gender, age, and living circumstances. RESULTS: Male-to-female ratio in each group was 90:17. Mean age in the case group was 10.93 years (standard deviation [SD]: 3.39 years) and in the comparison group, 12.34 years (SD: 3.22 years). Seventy percent of the case group lived with their biological families, while 84% of the comparison group did so. In the case group, 7.5% were in residential school placements compared with only 0.9% of the comparison group. There were no statistically significant differences in broad measurements of outcomes between the case and comparison groups. Age appeared to be an important moderating factor for type of medication prescribed. Younger children with intellectual disabilities and ADHD were more likely to be established on nonstimulant medications than those with ADHD and no intellectual disabilities (p = 0.024, odds ratio: 1.8; 95% CI: 1.2-2.7). CONCLUSIONS: Being between the ages of 5 and 12 years and having intellectual disability and ADHD are associated with raised likelihood of being prescribed nonstimulant medications for ADHD. This difference is maintained irrespective of gender and living circumstances. Reasons for these differences in prescribing practice require further exploration. PMID- 26982547 TI - Serological Prevalence of Enteropathogenic Yersinia spp. in Pigs and Wild Boars from Different Production Systems in the Moravian Region, Czech Republic. AB - Human yersiniosis caused by pathogenic Yersinia spp. is one of the most common reported zoonoses in the European Union and pigs are considered as the major reservoir of these bacteria. Serological testing represents a suitable method to obtain information about the prevalence of enteropathogenic Yersinia spp. in food animals. The prevalence of antibodies against enteropathogenic Yersinia spp. was studied in 319 slaughtered pigs and 135 wild boars from different production systems in the Moravian region (Czech Republic) using a commercially available ELISA test (an apparent prevalence). The seroprevalence was significantly associated with the type of breeding system, with the lowest seroprevalence being observed in household-raised pigs (13/29, 44.8%). No significant difference between the prevalence of anti-Yersinia antibodies in conventional (146/180, 81.1%) and organic pigs (92/110, 83.6%) was found. Antibodies were found in 65.9% (89/135) of wild boars without a significant difference between adult (23/41, 56.1%) and young (66/94, 70.2%) animals. Seropositivity was significantly higher in domestic (251/319, 78.7% in total) compared to feral pigs. A Bayesian approach taking into account the sensitivity and specificity of the ELISA test was used to estimate the true prevalence of anti-Yersinia antibodies in pigs and wild boars. According to our results, domestic pigs and wild boars proved to be an important reservoir of enteropathogenic Yersinia in the Czech Republic. Attention should be paid to good hygienic practice during slaughtering and handling of meat to prevent meat contamination and subsequently human infection. PMID- 26982548 TI - Telehealth Measures Screening for Developmental Language Disorders in Spanish Speaking Toddlers. AB - BACKGROUND: This is the second of two studies that described the use of telehealth language screening measures for use with young Spanish-speaking children. INTRODUCTION: The purpose of this study was to describe the classification accuracy of individual telehealth language screening measures as well as the accuracy of combinations of measures used with Spanish-speaking toddler-age children from rural and underserved areas of the country. MATERIALS AND METHODS: This study applied an asynchronous hybrid telehealth approach that implemented parent-structured play activities with a standard set of stimuli, and interaction with a My First Words e-book. These interactions were recorded with a mini camcorder. In addition, a traditional pen and paper parent questionnaire measure was collected. Sixty-two mostly Spanish-speaking preschool-age children and their parents participated. Twenty-two children had developmental language disorders (DLDs) and 40 had typical language development. RESULTS: Although several of the individual measures were significantly and strongly associated with standardized language scores, only reported vocabulary had classification accuracy values that were desirable for screening for DLDs. An improvement was observed when reported vocabulary was combined with a number of different words children produced during interactions with parents. CONCLUSIONS: This research provides additional evidence showing the effectiveness of a hybrid telehealth model in screening the language development of Spanish-speaking children. More specifically, reported vocabulary combined with number of different words produced by a child can provide informative and accurate diagnostic information when screening Spanish-speaking toddler-age children for DLDs. These findings replicate the first study in showing that hybrid telehealth approaches that combine the use of video technology and traditional pen and paper surveys yield strong results, and may be a viable screening alternative when face-to-face access to a bilingual provider is not possible. PMID- 26982549 TI - The Value of Mouse Models for Glaucoma Drug Discovery. PMID- 26982550 TI - Differences in false recollection according to the cognitive reserve of healthy older people. AB - We present an associative recognition experiment comparing three samples of healthy people (young people, older people with high cognitive reserve [HCR], and older people with low cognitive reserve [LCR], with each sample consisting of 40 people), manipulating stimuli repetition during the study phase. The results show significant differences among the three samples in their overall performance. However, these differences are not due to a different use of familiarity, but rather due to a different way of using recollection: although there are no differences in the hit rates between the HRC and LRC samples, the LCR group makes significantly more recollective false alarms than the HCR group. Moreover, repetition provokes an increase in the recollective false alarms in the LCR group, but this does not occur in the group of young people or in the HCR group. These findings are explained in terms of recollection-based monitoring errors and seem to provide support for the cognitive reserve hypothesis. PMID- 26982551 TI - An Alternative Strategy to Solve the Problem of the Discontinuity of Breastfeeding Care. PMID- 26982552 TI - Targeting Tumor Cells by Natural Anti-Carbohydrate Antibodies Using Rhamnose Functionalized Liposomes. AB - Recruitment of antibodies in human immune systems for targeted destruction of tumor cells has emerged as an exciting area of research due to its low occurrence of side effects, high efficacy, and high specificity. The presence of large amounts of anticarbohydrate natural antibodies in human sera has prompted research efforts to utilize carbohydrate epitopes for immune recruitment. Here, we have developed a general strategy for specific targeted destruction of tumor cells based on rhamnose-functionalized liposomes. Tumor cells artificially decorated with rhamnose epitopes were subjected to complement-mediated cytotoxicity in vitro and showed delayed tumor growth in vivo. This study highlights the therapeutic potential for activation of endogenous immune response through cell-surface glycan engineering. PMID- 26982554 TI - Sodium-glucose cotransporter-2 inhibitors and genital and urinary tract infections in type 2 diabetes. AB - Coincident with the high and increasing worldwide prevalence of type 2 diabetes (T2D), a growing armamentarium of antidiabetes medications has been introduced to target different organ systems that play a role in the pathophysiology of T2D. Among these, the sodium-glucose cotransporter-2 (SGLT-2) inhibitors were introduced in the United States in 2013 as a new treatment option to address the hyperglycemia associated with T2D. SGLT-2 inhibitors decrease renal glucose reabsorption, resulting in glucosuria, alleviation of hyperglycemia, and modest weight loss and are associated with a low risk of hypoglycemia. The SGLT-2 inhibitors have been linked to an increased incidence of genital mycotic infections and, to a lesser extent, urinary tract infections, which may limit their utility in some patients. This review examines the prevalence, recurrence rates, treatment options, and responses to treatment of genital and urinary tract infections in patients with T2D receiving SGLT-2 inhibitors, with the aim of guiding clinicians in the most effective use of these agents for the treatment of hyperglycemia. PMID- 26982556 TI - Correlation study and histopathological description of intestinal alterations in dogs infected with Leishmania infantum. AB - The aim of this work was a correlation study and histopathological description of alterations associated with the presence of Leishmania infantumamastigote in the intestinal wall of dogs infected with canine visceral leishmaniasis (CVL). Three groups were used: G1 (n = 8), comprising naturally infected dogs with CVL with amastigotes of L. infantum in the small and large intestines; G2 (n = 9), infected dogs with CVL, without intestinal amastigotes; and G3 (n = 3), uninfected dogs. Histochemistry and immunohistochemistry methods were used for histopathology and amastigotes identification. 47.1% (8/17) of dogs from G1 group had amastigotes in the mucosa, submucosa and muscle layers of the small and large intestines and it was observed a prominent inflammatory reaction characterized by chronic infiltration of mononuclear cells: macrophages, lymphocytes and plasma cells. Comparison between the groups showed only a significant difference in relation to mucosal microscopic structural alterations in dogs from G1 in relation to G2 and G3. Parasite burden showed significant correlations with the microscopic alterations and clinical status of dogs in G1. By the conclusion, the inflammatory reactions caused by the parasites in the intestines might have contributed towards alterations in digestive processes, worsening the dogs' clinical status of CVL. PMID- 26982555 TI - Risk factors associated with seropositivity for Leishmania spp. and Trypanosoma cruzi in dogs in the state of Paraiba, Brazil. AB - The aim of this survey was to determine the seropositivity and risk factors for Leishmania spp. and Trypanosoma cruzi in dogs in the State of Paraiba, Northeastern Brazil. A total of 1,043 dogs were tested, and the serological diagnoses of Chagas disease (CD) and canine visceral leishmaniasis (CVL) was performed by the indirect fluorescent antibody test (IFAT). Animals that tested seropositive for both diseases (by IFAT) were further subjected to ELISA. Of the 1,043 dogs 81 (7.8%; 95% CI = 6.1-9.4%) tested seropositive for Leishmania spp., while 83 were seropositive for T. cruzi (7.9%; 95% CI = 6.3-9.6%). Simultaneous serological reactions were detected in 49 animals (4.6%; 95% CI= 3.6-6.2%). Semi domiciled housing (OR = 2.044), free housing (OR = 4.151), and soil (OR = 3.425) and soil/cement (OR = 3.065) environmental conditions were identified as risk factors for CVL seropositivity. The risk factors identified for CD seropositivity were semi-domiciled (OR = 2.353) or free housing (OR = 3.454), and contact with bovine (OR = 2.015). This study revealed the presence of dogs in the Paraiba State seropositive for CVL and CD, suggesting the need for revisiting and intensification of disease control measures through constant monitoring of the canine population. PMID- 26982553 TI - Development of new fusion proteins for visualizing amyloid-beta oligomers in vivo. AB - The intracellular accumulation of amyloid-beta (Abeta) oligomers critically contributes to disease progression in Alzheimer's disease (AD) and can be the potential target of AD therapy. Direct observation of molecular dynamics of Abeta oligomers in vivo is key for drug discovery research, however, it has been challenging because Abeta aggregation inhibits the fluorescence from fusion proteins. Here, we developed Abeta1-42-GFP fusion proteins that are oligomerized and visualize their dynamics inside cells even when aggregated. We examined the aggregation states of Abeta-GFP fusion proteins using several methods and confirmed that they did not assemble into fibrils, but instead formed oligomers in vitro and in live cells. By arranging the length of the liker between Abeta and GFP, we generated two fusion proteins with "a long-linker" and "a short linker", and revealed that the aggregation property of fusion proteins can be evaluated by measuring fluorescence intensities using rat primary culture neurons transfected with Abeta-GFP plasmids and Abeta-GFP transgenic C. elegans. We found that Abeta-GFP fusion proteins induced cell death in COS7 cells. These results suggested that novel Abeta-GFP fusion proteins could be utilized for studying the physiological functions of Abeta oligomers in living cells and animals, and for drug screening by analyzing Abeta toxicity. PMID- 26982557 TI - Prevalence of antibodies against Neospora spp. and Sarcocystis neurona in donkeys from northeastern Brazil. AB - Sarcocystis neurona and Neospora hughesi are coccidian protozoa that can cause neurological illness in horses in America. In this study we report seroprevalence of Neospora spp. andS. neurona in sera of 333 donkeys from the northeastern region of Brazil. Antibodies to Neospora spp. were detected in 2% (7 donkeys) of 333 sera tested by the indirect fluorescent antibody test (IFAT) with a cut-off dilution of 1:40. Antibodies to S. neurona were found in 3% (10 donkeys) of the samples tested by IFAT (cut-off >=50) and 21% (69 donkeys) by the direct agglutination test (SAT >=50). The SAT and IFAT results for S. neurona showed a poor concordance (value of Kappa=0.051). This is the first report of Neospora spp. antibodies in Brazilian donkeys and the first detection of antibodies against S. neurona in this animal species. PMID- 26982558 TI - New records of mites (Acari: Spinturnicidae) associated with bats (Mammalia, Chiroptera) in two Brazilian biomes: Pantanal and Caatinga. AB - A first survey of mite species that ectoparasitize bats in the states of Ceara and Mato Grosso was conducted. The specimens of bats and their mites were collected in areas of the Caatinga and Pantanal biomes. A total of 450 spinturnicids representing two genera and ten species was collected from 15 bat species in the Private Reserve of the Natural Patrimony Serra das Almas, Ceara State, Northeast Brazil and 138 spinturnicids represented by two genera and four species were found in seven bats species collected in Private Reserve of the Natural Patrimony Sesc Pantanal, Mato Grosso State, Central-Western Brazil. The occurrence of Cameronieta genus and the species Mesoperiglischrus natali as well as four new associations (Periglischrus iheringi - Chiroderma vizottoi; P. micronycteridis - Micronycteris sanborni; P. paracutisternus - Trachops cirrhosus; Spinturnix americanus - Myotis riparius) are registered for the first time in Brazil. PMID- 26982560 TI - Overview of anthelmintic resistance of gastrointestinal nematodes of small ruminants in Brazil. AB - Frequent and inappropriate use of all classes of antiparasitic drugs in small ruminants has led to failures in their effectiveness, culminating in a global problem of anthelmintic resistance. Brazil stands out as one of the world's leaders in publications about anthelmintic resistance, and for having the most numerous reports of this resistance in small ruminants in the Americas. These studies have involved mainly the fecal egg count reduction test (FECRT) and its correlation with field management practices. In vivoeffectiveness testing is conducted in areas where livestock is of greater economic significance, e.g., in the South (sheep) and Northeast (goats), or is important for research and economic centers, such as the Southeast (sheep). The most widely studied species is sheep, for which the widest range of drugs is also evaluated. Despite significant advances achieved in molecular research, laboratory analyses should include knowledge about the reality in the field so that they can become feasible for the producer. Moreover, molecular studies can be underpinned by the analysis of field studies, such as the maintenance of antiparasitic effectiveness over time and the mechanisms involved in this process. PMID- 26982561 TI - First record of Paratanaisia bragai (Digenea: Eucotylidae) in blue and gold macaw (Ara ararauna). AB - The aim of this study was to provide the first report on a new host for the digenean Paratanaisia bragai in the caninde macaw Ara ararauna along with the pathological aspects of the infection in the new host. The microscopic findings revealed the presence of granulomatous interstitial nephritis. This study contributes towards knowledge of parasitism by P. bragai in A. ararauna, and emphasizes the need to use best practices in wildlife conservation parks. PMID- 26982562 TI - Anti-Toxoplasma gondii and anti-Neospora caninum antibodies in capybaras (Hydrochoerus hydrochaeris) from Itu Municipality, Sao Paulo. AB - Capybaras (Hydrochoerus hydrochaeris) are the largest rodents found in South America. The aim of the present study was to investigate the occurrence of anti Toxoplasma gondii and anti-Neospora caninum antibodies in 170 free-living capybaras in a residential park area in Itu Municipality, Sao Paulo State, Brazil. Serum samples were tested by indirect fluorescent antibody test (IFAT) for T. gondii (IFAT >= 1:16) and N. caninum (IFAT >= 1:50). Among the 170 samples analyzed, 10% (17/170) and 0% (0/170) were seropositive for T. gondii and N. caninum, respectively. This study confirms the widespread presence of T. gondii and reinforces the role of capybaras in the life cycle of this parasite. Capybaras may not be important as intermediate hosts of N. caninum in the studied environment. PMID- 26982563 TI - Alterations in the oxidative metabolism of Rhipicephalus (Boophilus) microplus ticks in response to exposure to the insect growth regulator fluazuron. AB - Aiming to characterize the potential off-target effects of fluazuron on ticks, biochemical analyses were conducted to evaluate changes in the carbohydrate metabolism of Rhipicephalus (Boophilus) microplus ticks after exposure to fluazuron. Hemolymph and fat body were collected from female ticks before and after (4, 8 and 15 days) exposure to fluazuron. Spectrophotometric analyses were done to quantify glucose concentration and lactate dehydrogenase (LDH) activity in the hemolymph and the concentration of glycogen in the tick's fat body. High Performance Liquid Chromatography (HPLC) was employed to determine the concentration of carboxylic acids in the hemolymph and to evaluate changes in intermediary metabolic processes requiring oxygen consumption. Increases in the levels of LDH activity and lactic acid concentration indicated that fluazuron enhanced fermentative metabolism in ticks. Exposure to fluazuron was also found to increase glucose concentrations in the hemolymph over time, although no significant differences were noted daily. In addition to expanding the body of knowledge about the mode of action of fluazuron, investigations into these mechanisms may also be useful in discovering new and as yet unexplored secondary effects. PMID- 26982564 TI - Early Liver Failure after Transjugular Intrahepatic Portosystemic Shunt in Patients with Cirrhosis with Model for End-Stage Liver Disease Score of 12 or Less: Incidence, Outcome, and Prognostic Factors. AB - Purpose To evaluate the incidence, outcomes, and prognostic factors of early liver failure (ELF) after transjugular intrahepatic portosystemic shunt (TIPS) creation in patients with cirrhosis with Model for End-Stage Liver Disease (MELD) score of 12 or less. Materials and Methods Institutional review board approved this retrospective study, with waiver of written informed consent. Two-hundred sixteen consecutive patients with cirrhosis (140 men, 76 women; mean age, 55.9 years; virus-related cirrhosis, 67.6% [146 of 216 patients]) with baseline MELD score of 12 or less who underwent TIPS placement between September 1999 and July 2012 were followed until last clinical evaluation, liver transplantation, or death. The Kaplan-Meier method, log-rank test, area under the receiver operating characteristic curve, and univariate and multivariate analyses were used, as appropriate. Results Twenty of 216 patients (9.2%) developed ELF within 3 months of TIPS (10 patients died, one required liver transplantation, and nine increased the MELD score to >18). ELF was associated with lower survival, 37% versus 95% at 6 months, and 24% versus 86% at 12 months (P < .001) compared with patients without ELF. ELF occurred in 16 of 95 (16.8%) patients with refractory ascites and in four of 121 (3.3%) patients with other indications for TIPS. Multivariate analysis confirmed MELD scores of 11 or 12 (odds ratio, 3.96 [95% confidence interval: 1.07, 14.67]; P = .040), decreased hemoglobin level (odds ratio, 0.68 [95% confidence interval: 0.49, 0.95]; P = .022), and decreased platelet count (odds ratio, 0.99 [95% confidence interval: 0.99, 0.99]; P = .024) as predictors for ELF in patients with refractory ascites. Conclusion ELF is not uncommon in cirrhotic patients with a MELD score of 12 or less who undergo TIPS placement for refractory ascites (especially in patients with MELD of 11 or 12) and decreased hemoglobin level and platelet count. ((c)) RSNA, 2016. PMID- 26982565 TI - Current-Induced Spin Polarization in Topological Insulator-Graphene Heterostructures. AB - Further development of the field of all-electric spintronics requires the successful integration of spin transport channels with spin injector/generator elements. While with the advent of graphene and related 2D materials high performance spin channel materials are available, the use of nanostructured spin generators remains a major challenge. Especially promising for the latter purpose are 3D topological insulators, whose 2D surface states host massless Dirac Fermions with spin-momentum locking. Here, we demonstrate injection of spin polarized current from a topological insulator into graphene, enabled by its intimate coupling to an ultrathin Bi2Te2Se nanoplatelet within a van der Waals epitaxial heterostructure. The spin switching signal, whose magnitude scales inversely with temperature, is detectable up to ~15 K. Our findings establish topological insulators as prospective future components of spintronic devices wherein spin manipulation is achieved by purely electrical means. PMID- 26982566 TI - Chronic Infection of Domestic Cats with Feline Morbillivirus, United States. PMID- 26982567 TI - Changes in Gait Balance and Brain Connectivity in Response to Equine-Assisted Activity and Training in Children with Attention Deficit Hyperactivity Disorder. AB - OBJECTIVES: Equine-assisted activity and training (EAAT) is thought to improve body balance and clinical symptoms in children with attention deficit hyperactivity disorder (ADHD). The study hypostheses were that EAAT would improve the clinical symptoms and gait balance in children with ADHD and that these improvements would be associated with increased brain connectivity within the balance circuit. METHODS: A total of 12 children with ADHD and 12 age- and sex matched healthy control children were recruited. EAAT consisted of three training sessions, each 70 minutes long, once a week for 4 weeks. Brain functional connectivity was assessed by using functional magnetic resonance imaging. RESULTS: After 4 weeks of EAAT, children with ADHD showed improved scores on the Korean ADHD scale (K-ARS), while the K-ARS scores of healthy children did not change. During the 4 weeks, the plantar pressure difference between the left foot and right foot decreased in both the healthy control group and the ADHD group. After 4 weeks of EAAT, healthy controls showed increased brain connectivity from the cerebellum to the left occipital lingual gyrus, fusiform gyrus, right and left thalami, right caudate, right precentral gyrus, and right superior frontal gyrus. However, children with ADHD showed increased brain connectivity from the cerebellum to the right insular cortex, right middle temporal gyrus, left superior temporal gyrus, and right precentral gyrus. In contrast, children with ADHD exhibited decreased brain connectivity from the cerebellum to the left inferior frontal gyrus. CONCLUSION: EAAT may improve clinical symptoms, gait balance, and brain connectivity, the last of which controls gait balance, in children with ADHD. However, children with ADHD who have deficits in the fronto cerebellar tract did not exhibit changes in brain connectivity as extensive as those in healthy children in response to EAAT. PMID- 26982568 TI - An (Anti)-Inflammatory Microbiota: Defining the Role in Inflammatory Bowel Disease? AB - While it is now accepted that the gut microbiota contribute to the genotype environment-lifestyle interactions triggering inflammatory bowel disease (IBD) episodes, efforts to identify the pathogen(s) that cause these diseases have met with limited success. The advent of culture-independent techniques for characterizing the structure and/or function of microbial communities (hereafter referred to as metagenomics) has provided new insights into the events associated with the onset, remission and recurrence of IBD. A large number of observational and/or case-control studies of IBD patients have confirmed substantive changes in gut bacterial profiles (dysbiosis) associated with disease. These types of studies have been augmented by new profiling approaches that support the identification of more 'colitogenic' bacteria from numerically predominant taxa. Evidence of alterations in lesser abundant taxa such as the methanogenic archaea, to favor types that are more immunogenic, has also been forthcoming. Several recent longitudinal studies of patients with Crohn's disease have produced additional insights, including evidence for the role of 'anti-inflammatory' microbiota in providing a protective effect and/or promoting remission. In summation, the implications of dysbiosis and restoration of a 'healthy microbiota' in IBD patients requires definition beyond a taxonomic assessment of the changes in the gut microbiota during disease course. The available evidence does suggest that specific members of the gut microbiota can contribute either pro- or anti-inflammatory effects, and their ecological fitness in the large bowel affects the onset and recurrence of IBD. While metagenomics and related approaches offer the potential to provide novel and important insights into these microbiota and thereby the pathophysiology of IBD, we also need to better understand factors affecting the ecological fitness of these microbes, if new treatment of IBD patients are to be delivered. PMID- 26982570 TI - PFC and Triglyme for Li-Air Batteries: A Molecular Dynamics Study. AB - In this work, we present an all-atom molecular dynamics (MD) study of triglyme and perfluorinated carbons (PFCs) using classical atomistic force fields. Triglyme is a typical solvent used in nonaqueous Li-air battery cells. PFCs were recently reported to increase oxygen availability in such cells. We show that O2 diffusion in two specific PFC molecules (C6F14 and C8F18) is significantly faster than in triglyme. Furthermore, by starting with two very different initial configurations for our MD simulation, we demonstrate that C8F18 and triglyme do not mix. The mutual solubility of these molecules is evaluated both theoretically and experimentally, and a qualitative agreement is found. Finally, we show that the solubility of O2 in C8F18 is considerably higher than in triglyme. The significance of these results to Li-air batteries is discussed. PMID- 26982569 TI - Smelling the Diagnosis: The Electronic Nose as Diagnostic Tool in Inflammatory Arthritis. A Case-Reference Study. AB - OBJECTIVE: To investigate whether exhaled breath analysis using an electronic nose can identify differences between inflammatory joint diseases and healthy controls. METHODS: In a cross-sectional study, the exhaled breath of 21 rheumatoid arthritis (RA) and 18 psoriatic arthritis (PsA) patients with active disease was compared to 21 healthy controls using an electronic nose (Cyranose 320; Smiths Detection, Pasadena, CA, USA). Breathprints were analyzed with principal component analysis, discriminant analysis, and area under curve (AUC) of receiver operating characteristics (ROC) curves. Volatile organic compounds (VOCs) were identified by gas chromatography and mass spectrometry (GC-MS), and relationships between breathprints and markers of disease activity were explored. RESULTS: Breathprints of RA patients could be distinguished from controls with an accuracy of 71% (AUC 0.75, 95% CI 0.60-0.90, sensitivity 76%, specificity 67%). Breathprints from PsA patients were separated from controls with 69% accuracy (AUC 0.77, 95% CI 0.61-0.92, sensitivity 72%, specificity 71%). Distinction between exhaled breath of RA and PsA patients exhibited an accuracy of 69% (AUC 0.72, 95% CI 0.55-0.89, sensitivity 71%, specificity 72%). There was a positive correlation in RA patients of exhaled breathprints with disease activity score (DAS28) and number of painful joints. GC-MS identified seven key VOCs that significantly differed between the groups. CONCLUSIONS: Exhaled breath analysis by an electronic nose may play a role in differential diagnosis of inflammatory joint diseases. Data from this study warrant external validation. PMID- 26982572 TI - Antimicrobial and antifouling efficacy of urinary catheters impregnated with a combination of macrolide and fluoroquinolone antibiotics against Pseudomonas aeruginosa. AB - The incidence of catheter associated urinary tract infections (CAUTIs) is increasing worldwide. This study was designed to modify a biomaterial by impregnating a silicone urinary catheter with combination of a macrolide, azithromycin (AZM) and a fluoroquinolone, ciprofloxacin (CIP). Drug release profiles showed slow yet continuous release of antibiotics from catheters for one month. In vitro efficacy testing showed that group B catheters [3% (w v(-1)) CIP + 6% (w v(-1)) AZM] outperformed group A catheters [2% (w v(-1)) CIP + 5% (w v( 1)) AZM] by (1) showing larger zones of inhibition (>31 mm) compared to group A (<28 mm) for up to 30 days against Pseudomonas aeruginosa PAO1; (2) killing adhered bacteria in 24 h compared to 24-48 h in group A; (3) showing longer antimicrobial durability for four weeks; and (4) exhibiting a stable real-time shelf life of one year, suggesting that these catheters can be explored in clinical settings, especially in long-term CAUTI. PMID- 26982571 TI - Morbillivirus and Pilot Whale Deaths, Canary Islands, Spain, 2015. PMID- 26982573 TI - Hygiene Hypothesis: Is the Evidence the Same All Over the World? AB - BACKGROUND: The hygiene hypothesis refers to where modern living conditions are responsible for the increasing incidences of immune-related diseases including the development of inflammatory bowel diseases (IBD). Improved hygiene may result in decreased enteric microbiota diversity and dysbiosis, which may be responsible for the development of IBD. KEY MESSAGES: The rising incidence of IBD is well documented in developing regions of the world, in accordance with the hygiene hypothesis. What is unknown, however, is whether the hygiene hypothesis is applicable all over the world. Hygiene cannot be easily measured and proxy markers need to be used. These include regional data such as a country's gross domestic product or an individual's affluence or exposure to infection risk factors. A comparative case-control study of Caucasian Australian IBD subjects versus migrants from the Middle East to Australia identified that environmental risk factors are different in the 2 populations. Among Australian Caucasians, hygiene-related environmental risk factors are no longer relevant in the development of IBD. Given the country's high affluence, there has been high hygienic standard for several generations. However, migrants from less affluent countries exposed to hygiene-related environmental factors are at increased risks of developing IBD, especially in the second generation migrants born in the affluent country. Divergent risk factors include the use of antibiotics in childhood increasing the risk of IBD in developed societies but being a risk factor for developing IBD in migrants. In India, risk factors associated with infections were found to be positively associated with the development of ulcerative colitis, rather than protective. CONCLUSIONS: The hygiene hypothesis is not applicable to all populations worldwide, being most relevant in societies undergoing increasing affluence or following migration from less to more affluent countries. This review examines data from around the world that link the hygiene hypothesis with the development of IBD and in particular the divergent results arising from data from affluent countries versus less-affluent countries. PMID- 26982574 TI - Hind limb perconditioning renoprotection by modulation of inflammatory cytokines after renal ischemia/reperfusion. AB - Purpose Renal ischemia/reperfusion (I/R) injury is a common clinical problem associated with significant mortality and morbidity. One newly described strategy to reduce this damage is remote perconditioning (RPEC), in which short-time ischemia of a limb during renal ischemia reduces the I/R-induced kidney injury. This study aimed to assess whether RPEC confer protection through changes in pro inflammatory mediators. Methods Rats were subjected to right nephrectomy and randomized into: sham (no intervention), I/R (subjected to 45-min left renal ischemia) and RPEC group (subjected to four cycles of 5-min I/R of the femoral artery administered during renal ischemia). After 24-h, blood, urine, and kidney samples were collected. Biochemical indicators of renal dysfunction were measured in the cases of Neutrophil gelatinase-associated lipocalin (NGAL), and N-acetyl-B diglucosaminidase (NAG) activity. Inflammatory cytokines [interleukin (IL)-6 and tumor necrosis factor-alpha, TNF-alpha] expression in the renal tissues as well as Periodic acid-Schiff stained histological sections were evaluated. Results I/R resulted in renal dysfunction, as evidenced by higher renal NGAL expression and urinary NAG activities. This was accompanied by increased TNF-alpha and IL-6 expressions as well as histological changes in this group. However, RPEC improved renal histology and function compared with the I/R group. Furthermore, the RPEC group showed decreases in TNF-alpha and IL-6 expression. Conclusions These results suggest that RPEC reduces the dysfunction and injury associated with I/R of the kidney. This technique reduced the pro-inflammatory cytokine in the kidney. RPEC could be a promising strategy against I/R-induced acute kidney injury partly by down-regulation of inflammatory mediators. PMID- 26982575 TI - Practice of the Treatment of Milk Allergy in the UK: A National Audit. AB - BACKGROUND: The management of cow's milk allergy (CMA) includes initial dairy exclusion with suitable dietary substitution, diagnostic challenges where indicated, and supervised re-introduction as the condition resolves. Information on clinician practice is limited. We audited the current practice of clinicians in the UK to evaluate adherence to international guidelines. METHODS: An online questionnaire was sent to all clinicians whose practice included children identified on the national allergy society website. One hundred and sixty questionnaires were sent and 116 (73%) responded. RESULTS: Skin prick tests were more commonly used than serum-specific IgE as diagnostic tests. Respective proportions selecting amino acid formulas (AAF) or extensively hydrolysed formulas (EHF) in severe versus mild/moderate presentations were 78 and 40% versus 20 and 88%; soya formula was the first choice in 8.6 and 24%. The criteria for selection of AAF as the first choice were predominantly severe IgE-mediated and non-IgE-mediated reactions, failure to thrive and if infants refused EHF. Oral challenges might be used to diagnose CMA in 69%, whereas nearly 90% performed challenges to assess tolerance. Most of these were open challenges, more commonly with fresh milk (90%) than baked milk (60%). Home baked milk challenges were frequently considered (70%), although only after consideration of the clinical scenario. Practice did not vary with experience. CONCLUSIONS: Current practice amongst UK clinicians of the management of CMA is broadly in line with current guidance, particularly the positioning of hypoallergenic milks as substitute milk choices. A notable deviation was the use of home baked milk challenges or re-introduction. PMID- 26982576 TI - Cloning and Expression of Multiple Cytochrome P450 Genes: Induction by Fipronil in Workers of the Red Imported Fire Ant (Solenopsis invicta Buren). AB - Both exogenous and endogenous compounds can induce the expression of cytochrome P450 genes. The insect cytochrome P450 genes related to insecticide resistance are likely to be expressed as the "first line of defense" when challenged with insecticides. In this study, four cytochrome P450 genes, SinvCYP6B1, SinvCYP6A1, SinvCYP4C1, and SinvCYP4G15, were firstly isolated from workers of the red imported fire ant (Solenopsis invicta) through rapid amplification of cDNA ends (RACE) and sequenced. The fipronil induction profiles of the four cytochrome P450 genes and the two previously isolated CYP4AB1 and CYP4AB2 were characterized in workers. The results revealed that the expression of SinvCYP6B1, SinvCYP6A1, CYP4AB2, and SinvCYP4G15, increased 1.4-fold and 1.3-fold more than those of acetone control, respectively, after 24 h exposure to fipronil at concentrations of 0.25 MUg mL-1 (median lethal dose) and 0.56 MUg mL-1 (90% lethal dose), while no significant induction of the expression of CYP4AB1 and SinvCYP4C1 was detected. Among these genes, SinvCYP6B1 was the most significantly induced, and its maximum expression was 3.6-fold higher than that in acetone control. These results might suggest that multiple cytochrome P450 genes are co-up-regulated in workers of the fire ant through induction mechanism when challenged with fipronil. These findings indicated that cytochrome P450 genes play an important role in the detoxification of insecticides and provide a theoretical basis for the mechanisms of insecticide metabolism in the fire ant. PMID- 26982577 TI - Heparan Sulfate in the Developing, Healthy, and Injured Lung. AB - Remarkable progress has been achieved in understanding the regulation of gene expression and protein translation, and how aberrancies in these template-driven processes contribute to disease pathogenesis. However, much of cellular physiology is controlled by non-DNA, nonprotein mediators, such as glycans. The focus of this Translational Review is to highlight the importance of a specific glycan polymer-the glycosaminoglycan heparan sulfate (HS)-on lung health and disease. We demonstrate how HS contributes to lung physiology and pathophysiology via its actions as both a structural constituent of the lung parenchyma as well as a regulator of cellular signaling. By highlighting current uncertainties in HS biology, we identify opportunities for future high-impact pulmonary and critical care translational investigations. PMID- 26982578 TI - Multiple Paternity in a Reintroduced Population of the Orinoco Crocodile (Crocodylus intermedius) at the El Frio Biological Station, Venezuela. AB - The success of a reintroduction program is determined by the ability of individuals to reproduce and thrive. Hence, an understanding of the mating system and breeding strategies of reintroduced species can be critical to the success, evaluation and effective management of reintroduction programs. As one of the most threatened crocodile species in the world, the Orinoco crocodile (Crocodylus intermedius) has been reduced to only a few wild populations in the Llanos of Venezuela and Colombia. One of these populations was founded by reintroduction at Cano Macanillal and La Ramera lagoon within the El Frio Biological Station, Venezuela. Twenty egg clutches of C. intermedius were collected at the El Frio Biological Station for incubation in the lab and release of juveniles after one year. Analyzing 17 polymorphic microsatellite loci from 335 hatchlings we found multiple paternity in C. intermedius, with half of the 20 clutches fathered by two or three males. Sixteen mothers and 14 fathers were inferred by reconstruction of multilocus parental genotypes. Our findings showed skewed paternal contributions to multiple-sired clutches in four of the clutches (40%), leading to an overall unequal contribution of offspring among fathers with six of the 14 inferred males fathering 90% of the total offspring, and three of those six males fathering more than 70% of the total offspring. Our results provide the first evidence of multiple paternity occurring in the Orinoco crocodile and confirm the success of reintroduction efforts of this critically endangered species in the El Frio Biological Station, Venezuela. PMID- 26982579 TI - Ineffectiveness of nicotinic acetylcholine receptor antagonists for treatment resistant depression: a meta-analysis. AB - Emerging preclinical and clinical evidences suggest a potential role of nicotinic acetylcholine receptors in the pathophysiology of depression. Several clinical trials have investigated the efficacy of nicotinic acetylcholine receptor antagonists in treatment-resistant depression. We carried out this meta-analysis to investigate whether nicotinic acetylcholine receptor antagonists significantly improve symptoms in patients with major depressive disorder who have an inadequate response to standard antidepressant therapy. A comprehensive literature search identified six randomized-controlled trials. These six trials, which included 2067 participants, were pooled for this meta-analysis using a random-effects model. Nicotinic acetylcholine receptor antagonists failed to show superior efficacy compared with placebo in terms of the mean change in the Montgomery-Asberg Depression Rating Scale score [mean difference=-0.12 (95% confidence interval (CI)=-0.96 to 0.71]; response rate [risk ratio=0.92 (95% CI=0.83-1.02)]; and remission rate [risk ratio=1.01 (95% CI=0.83-1.23)]. This meta-analysis failed to confirm preliminary positive evidence for the efficacy of nicotinic acetylcholine receptor antagonists in treatment-resistant depression. Further studies investigating the efficacy of various alternative treatment strategies for treatment-resistant depression will help clinicians to better understand and choose better treatment options for these populations. PMID- 26982582 TI - Buried Alive: The Behavioural Response of the Mussels, Modiolus modiolus and Mytilus edulis to Sudden Burial by Sediment. AB - Sedimentation in the sea occurs through natural processes, such as wave and tidal action, which can be exacerbated during storms and floods. Changes in terrestrial land use, marine aggregate extraction, dredging, drilling and mining are known to result in substantial sediment deposition. Research suggests that deposition will also occur due to the modern development of marine renewable energy. The response to individual burial under three depths of sediment, three sediment fractions and five burial durations was investigated in two mussel species, Modiolus modiolus and Mytilus edulis in specialist mesocosms. Both mussel species showed substantial mortality, which increased with duration of burial and burial by finer sediment fractions. M. modiolus was better able to survive short periods of burial than M. edulis, but at longer durations mortality was more pronounced. No mortality was observed in M. modiolus in burial durations of eight days or less but by 16 days of burial, over 50% cumulative mortality occurred. Under variable temperature regimes, M. edulis mortality increased from 20% at 8 degrees C to over 60% at 14.5 and 20 degrees C. Only M. edulis was able to emerge from burial, facilitated by increased byssus production, laid mostly on vertical surfaces but also on sediment particles. Emergence was higher from coarse sediment and shallow burials. Byssus production in M. edulis was not related to the condition index of the mussels. Results suggest that even marginal burial would result in mortality and be more pronounced in warm summer periods. Our results suggest that in the event of burial, adult M. modiolus would not be able to emerge from burial unless local hydrodynamics assist, whereas a small proportion of M. edulis may regain contact with the sediment water interface. The physiological stress resulting in mortality, contribution of local hydrodynamics to survival and other ecological pressures such as mussels existing in aggregations, are discussed. PMID- 26982581 TI - Detection of Mycobacterium ulcerans DNA in the Environment, Ivory Coast. AB - BACKGROUND: Ivory Coast is a West African country with the highest reported cases of Buruli ulcer, a disabling subcutaneous infection due to Mycobacterium ulcerans. However, the prevalence of environmental M. ulcerans is poorly known in this country. METHODS: We collected 496 environmental specimens consisting of soil (n = 100), stagnant water (n = 200), plants (n = 100) and animal feces (n = 96) in Ivory Coast over five months in the dry and wet seasons in regions which are free of Buruli ulcer (control group A; 250 specimens) and in regions where the Buruli ulcer is endemic (group B; 246 specimens). After appropriate total DNA extraction incorporating an internal control, the M. ulcerans IS2404 and KR-B gene were amplified by real-time PCR in samples. In parallel, a calibration curve was done for M. ulcerans Agy99 IS2404 and KR-B gene. RESULTS: Of 460 samples free of PCR inhibition, a positive real-time PCR detection of insertion sequence IS2404 and KR-B gene was observed in 1/230 specimens in control group A versus 9/230 specimens in group B (P = 0.02; Fisher exact test). Positive specimens comprised seven stagnant water specimens, two feces specimens confirmed to be of Thryonomys swinderianus (agouti) origin by real-time PCR of the cytb gene; and one soil specimen. Extrapolation from the calibration curves indicated low inoculums ranging from 1 to 102 mycobacteria/mL. CONCLUSION: This study confirms the presence of M. ulcerans in the watery environment surrounding patients with Buruli ulcer in Ivory Coast. It suggests that the agouti, which is in close contacts with populations, could play a role in the environmental cycle of M. ulcerans, as previously suggested for the closely related possums in Australia. PMID- 26982583 TI - Is a Heated Breathing Tube the Emergent Factor for Continuous Positive Airway Pressure Therapy in Obstructive Sleep Apnea? PMID- 26982585 TI - Infectious clones of the crinivirus cucurbit chlorotic yellows virus are competent for plant systemic infection and vector transmission. AB - Cucurbit chlorotic yellows virus (CCYV), a recently identified bipartite crinivirus, causes economic losses in cucurbit plants. CCYV is naturally transmitted only by whitefly Bemisia tabaci. Here we constructed full-length cDNA clones of CCYV (RNA1 and RNA2) fused to the T7 RNA polymerase promoter and the cauliflower mosaic virus 35S promoter. CCYV replicated and accumulated efficiently in Cucumis sativus protoplasts transfected with in vitro transcripts. Without RNA2, RNA1 replicated efficiently in C. sativus protoplasts. Agroinoculation with the infectious cDNA clones of CCYV resulted in systemic infection in the host plants of C. sativus and Nicotiana benthamiana. Virus derived from the infectious clones could be transmitted between cucumber plants by vector whiteflies. This system will greatly enhance the reverse genetic studies of CCYV gene functions. PMID- 26982580 TI - Regulation of Budding Yeast CENP-A levels Prevents Misincorporation at Promoter Nucleosomes and Transcriptional Defects. AB - The exclusive localization of the histone H3 variant CENP-A to centromeres is essential for accurate chromosome segregation. Ubiquitin-mediated proteolysis helps to ensure that CENP-A does not mislocalize to euchromatin, which can lead to genomic instability. Consistent with this, overexpression of the budding yeast CENP-A(Cse4) is lethal in cells lacking Psh1, the E3 ubiquitin ligase that targets CENP-A(Cse4) for degradation. To identify additional mechanisms that prevent CENP-A(Cse4) misincorporation and lethality, we analyzed the genome-wide mislocalization pattern of overexpressed CENP-A(Cse4) in the presence and absence of Psh1 by chromatin immunoprecipitation followed by high throughput sequencing. We found that ectopic CENP-A(Cse4) is enriched at promoters that contain histone H2A.Z(Htz1) nucleosomes, but that H2A.Z(Htz1) is not required for CENP-A(Cse4) mislocalization. Instead, the INO80 complex, which removes H2A.Z(Htz1) from nucleosomes, promotes the ectopic deposition of CENP-A(Cse4). Transcriptional profiling revealed gene expression changes in the psh1Delta cells overexpressing CENP-A(Cse4). The down-regulated genes are enriched for CENP-A(Cse4) mislocalization to promoters, while the up-regulated genes correlate with those that are also transcriptionally up-regulated in an htz1Delta strain. Together, these data show that regulating centromeric nucleosome localization is not only critical for maintaining centromere function, but also for ensuring accurate promoter function and transcriptional regulation. PMID- 26982584 TI - Decreasing Fires in Mediterranean Europe. AB - Forest fires are a serious environmental hazard in southern Europe. Quantitative assessment of recent trends in fire statistics is important for assessing the possible shifts induced by climate and other environmental/socioeconomic changes in this area. Here we analyse recent fire trends in Portugal, Spain, southern France, Italy and Greece, building on a homogenized fire database integrating official fire statistics provided by several national/EU agencies. During the period 1985-2011, the total annual burned area (BA) displayed a general decreasing trend, with the exception of Portugal, where a heterogeneous signal was found. Considering all countries globally, we found that BA decreased by about 3020 km2 over the 27-year-long study period (i.e. about -66% of the mean historical value). These results are consistent with those obtained on longer time scales when data were available, also yielding predominantly negative trends in Spain and France (1974-2011) and a mixed trend in Portugal (1980-2011). Similar overall results were found for the annual number of fires (NF), which globally decreased by about 12600 in the study period (about -59%), except for Spain where, excluding the provinces along the Mediterranean coast, an upward trend was found for the longer period. We argue that the negative trends can be explained, at least in part, by an increased effort in fire management and prevention after the big fires of the 1980's, while positive trends may be related to recent socioeconomic transformations leading to more hazardous landscape configurations, as well as to the observed warming of recent decades. We stress the importance of fire data homogenization prior to analysis, in order to alleviate spurious effects associated with non-stationarities in the data due to temporal variations in fire detection efforts. PMID- 26982586 TI - Practical Considerations and the Intestinal Microbiome in Disease: Antibiotics for IBD Therapy. AB - The inflammatory bowel diseases, Crohn's and ulcerative colitis, have been treated with a range of antibiotics for inducing and maintaining remission, as well as the prevention of post-operative symptoms. To date, many studies have been performed assessing the efficacy of antibiotics when used alone, in combination with other antibiotics, or as an adjunctive therapy to other pharmaceutical treatments. Literature evidence supporting the use of antibiotics in IBD can be ambiguous, especially when considering the potential role of dysbiosis in the gastrointestinal tract. The review considers the systemic effect of antibiotics and the evidence base for their efficacy in the treatment of IBD. PMID- 26982587 TI - Rice Grain Quality and Consumer Preferences: A Case Study of Two Rural Towns in the Philippines. AB - Hedonic pricing analysis is conducted to determine the implicit values of various attributes in the market value of a good. In this study, hedonic pricing analysis was applied to measure the contribution of grain quality search and experience attributes to the price of rice in two rural towns in the Philippines. Rice samples from respondents underwent quantitative routine assessments of grain quality. In particular, gelatinization temperature and chalkiness, two parameters that are normally assessed through visual scores, were evaluated by purely quantitative means (differential scanning calorimetry and by digital image analysis). Results indicate that rice consumed by respondents had mainly similar physical and chemical grain quality attributes. The respondents' revealed preferences were typical of what has been previously reported for Filipino rice consumers. Hedonic regression analyses showed that grain quality characteristics that affected price varied by income class. Some of the traits or socioeconomic factors that affected price were percent broken grains, gel consistency, and household per capita rice consumption. There is an income effect on rice price and the characteristics that affect price vary between income classes. PMID- 26982588 TI - D, L-Sulforaphane Loaded Fe3O4@ Gold Core Shell Nanoparticles: A Potential Sulforaphane Delivery System. AB - A novel design of gold-coated iron oxide nanoparticles was fabricated as a potential delivery system to improve the efficiency and stability of d, l sulforaphane as an anticancer drug. To this purpose, the surface of gold-coated iron oxide nanoparticles was modified for sulforaphane delivery via furnishing its surface with thiolated polyethylene glycol-folic acid and thiolated polyethylene glycol-FITC. The synthesized nanoparticles were characterized by different techniques such as FTIR, energy dispersive X-ray spectroscopy, UV visible spectroscopy, scanning and transmission electron microscopy. The average diameters of the synthesized nanoparticles before and after sulforaphane loading were obtained ~ 33 nm and ~ 38 nm, respectively, when ~ 2.8 mmol/g of sulforaphane was loaded. The result of cell viability assay which was confirmed by apoptosis assay on the human breast cancer cells (MCF-7 line) as a model of in vitro-cancerous cells, proved that the bare nanoparticles showed little inherent cytotoxicity, whereas the sulforaphane-loaded nanoparticles were cytotoxic. The expression rate of the anti-apoptotic genes (bcl-2 and bcl-xL), and the pro apoptotic genes (bax and bak) were quantified, and it was found that the expression rate of bcl-2 and bcl-xL genes significantly were decreased when MCF-7 cells were incubated by sulforaphane-loaded nanoparticles. The sulforaphane loaded into the designed gold-coated iron oxide nanoparticles, acceptably induced apoptosis in MCF-7 cells. PMID- 26982591 TI - Pterostilbene Inhibits the Growth of Human Esophageal Cancer Cells by Regulating Endoplasmic Reticulum Stress. AB - BACKGROUND/AIMS: Pterostilbene (PTE), a natural dimethylated resveratrol analog from blueberries, is known to have diverse pharmacological activities, including anticancer properties. In this study, we investigated the anticancer activity of PTE against human esophageal cancer cells both in vitro and in vivo and explored the role of endoplasmic reticulum (ER) stress (ERS) signaling in this process. METHODS: Cell viability, the apoptotic index, Caspase 3 activity, adhesion, migration, reactive oxygen species (ROS) levels, and glutathione (GSH) levels were detected to explore the effect of PTE on human EC109 esophageal cancer cells. Furthermore, siRNA transfection and a chemical inhibitor were employed to confirm the role of ERS. RESULTS: PTE treatment dose- and time-dependently decreased the viability of human esophageal cancer EC109 cells. PTE also decreased tumor cell adhesion, migration and intracellular GSH levels while increasing the apoptotic index, Caspase 3 activity and ROS levels, which suggest the strong anticancer activity of PTE. Furthermore, PTE treatment increased the expression of ERS-related molecules (GRP78, ATF6, p-PERK, p-eIF2alpha and CHOP), upregulated the pro-apoptosis-related protein PUMA and downregulated the anti apoptosis-related protein Bcl-2 while promoting the translocation of cytochrome c from mitochondria to cytosol and the activation of Caspase 9 and Caspase 12. The downregulation of ERS signaling by CHOP siRNA desensitized esophageal cancer cells to PTE treatment, whereas upregulation of ERS signaling by thapsigargin (THA) had the opposite effect. N-Acetylcysteine (NAC), a ROS scavenger, also desensitized esophageal cancer cells to PTE treatment. CONCLUSIONS: Overall, the results indicate that PTE is a potent anti-cancer pharmaceutical against human esophageal cancer, and the possible mechanism involves the activation of ERS signaling pathways. PMID- 26982589 TI - Stopped-Flow Studies of the Reduction of the Copper Centers Suggest a Bifurcated Electron Transfer Pathway in Peptidylglycine Monooxygenase. AB - Peptidylglycine monooxygenase (PHM) is a dicopper enzyme that plays a vital role in the amidation of glycine-extended pro-peptides. One of the crucial aspects of its chemistry is the transfer of two electrons from an electron-storing and transferring site (CuH) to the oxygen binding site and catalytic center (CuM) over a distance of 11 A during one catalytic turnover event. Here we present our studies of the first electron transfer (ET) step (reductive phase) in wild-type (WT) PHM as well as its variants. Stopped flow was used to record the reduction kinetic traces using the chromophoric agent N,N-dimethyl-p-phenylenediamine dihydrochloride (DMPD) as the reductant. The reduction was found to be biphasic in the WT PHM with an initial fast phase (17.2 s(-1)) followed by a much slower phase (0.46 s(-1)). We were able to ascribe the fast and slow phase to the CuH and CuM sites, respectively, by making use of the H242A and H107AH108A mutants that contain only the CuH site and CuM site, respectively. In the absence of substrate, the redox potentials determined by cyclic voltammetry were 270 mV (CuH site) and -15 mV (CuM site), but binding of substrate (Ac-YVG) was found to alter both potentials so that they converged to a common value of 83 mV. Substrate binding also accelerated the slow reductive phase by ~10-fold, an effect that could be explained at least partially by the equalization of the reduction potential of the copper centers. Studies of H108A showed that the ET to the CuM site is blocked, highlighting the role of the H108 ligand as a component of the reductive ET pathway. Strikingly, the rate of reduction of the H172A variant was unaffected despite the rate of catalysis being 3 orders of magnitude slower than that of the WT PHM. These studies strongly indicate that the reductive phase and catalytic phase ET pathways are different and suggest a bifurcated ET pathway in PHM. We propose that H172 and Y79 form part of an alternate pathway for the catalytic phase ET while the H108 ligand along with the water molecules and substrate form the reductive phase ET pathway. PMID- 26982590 TI - Shedding Light on the Nature of Seminal Round Cells. AB - INTRODUCTION: In this investigation we assess the incidence of round cells (RCs) in semen samples in our infertile patient population and their significance on intracytoplasmic sperm injection (ICSI) cycle outcomes. We also evaluate the usefulness of RCs as indicators of bacterial infection and highlight the origin of this cell-type, as well as its role in the human ejaculate. PATIENTS AND METHODS: In a prospective fashion, a total of 4,810 ejaculated samples were included in the study during a period of 24 months. RCs were characterized for white blood cell (WBC) components versus exfoliated germ cells by testing for multiple markers of ploidy as well as protamine assays. Cases displaying >= 2 x 106/ml RCs were screened for bacteria. Raw specimens containing RC were processed by peroxidase and other leukocyte assays, specific stains for protamines were used to identify spermiogenic stage, aneuploidy (FISH) assessment was carried out, and the presence of various Sertoli-cell cytoplasmic remnants was analyzed to identify and characterize immature germ cells. The effect of RC on clinical outcome was assessed in specimens used for ICSI. RESULTS: The average age of the men involved was 39.2 +/- 7 years. Semen samples had a mean concentration of 40.7 +/- 31 x 106/ml, motility of 42.6 +/- 35%, and morphology of 2.3 +/- 2%. RCs were identified in 261 specimens, representing a proportion of 5.4%. Men with RCs had comparable age but lower sperm concentration and morphology than the control group (P<0.001). The aneuploidy rate of 4.3% in RCs group was remarkably higher than the control group (2.3%; P<0.001). Sperm aneuploidy rate positively correlated with the number of RCs (P<0.001). Of 44 men, 17 of them in 18 cycles had up to 1.9 x 106/ml RCs without affecting fertilization and clinical pregnancy rates when compared to controls (n = 365 cycles). In 27 men undergoing 33 ICSI cycles with >= 2 x 106/ml RCs, the fertilization rate trended lower and the miscarriage rate was significantly increased (P = 0.05). There was lack of correlation between RC and bacteriological growth. Specific markers indicated that seminal RCs are mostly immature germ cells encased in the remnants of Sertoli cell cytoplasm. Moreover, their modest protamine content and their haploid status confirm that they are post-meiotic. Sequential observation in the same man showed that RC episodes were followed by an amelioration of semen parameters, and interestingly, the episodic occurrence of RCs often coincides with flu season peaks. CONCLUSIONS: Seminal RCs are not a marker of infectiousness but rather a transient indicator of spermatogenic insult that possibly occurs in most men following a mild and transient ailment such as the flu. PMID- 26982592 TI - Collagen-Hydroxyapatite Scaffolds Induce Human Adipose Derived Stem Cells Osteogenic Differentiation In Vitro. AB - Mesenchymal stem cells (MSCs) play a crucial role in regulating normal skeletal homeostasis and, in case of injury, in bone healing and reestablishment of skeletal integrity. Recent scientific literature is focused on the development of bone regeneration models where MSCs are combined with biomimetic three dimensional scaffolds able to direct MSC osteogenesis. In this work the osteogenic potential of human MSCs isolated from adipose tissue (hADSCs) has been evaluated in vitro in combination with collagen/Mg doped hydroxyapatite scaffolds. Results demonstrate the high osteogenic potential of hADSCs when cultured in specific differentiation induction medium, as revealed by the Alizarin Red S staining and gene expression profile analysis. In combination with collagen/hydroxyapatite scaffold, hADSCs differentiate into mature osteoblasts even in the absence of specific inducing factors; nevertheless, the supplement of the factors markedly accelerates the osteogenic process, as confirmed by the expression of specific markers of pre-osteoblast and mature osteoblast stages, such as osterix, osteopontin (also known as bone sialoprotein I), osteocalcin and specific markers of extracellular matrix maturation and mineralization stages, such as ALPL and osteonectin. Hence, the present work demonstrates that the scaffold per se is able to induce hADSCs differentiation, while the addition of osteo-inductive factors produces a significant acceleration of the osteogenic process. This observation makes the use of our model potentially interesting in the field of regenerative medicine for the treatment of bone defects. PMID- 26982594 TI - Microevolution of Monophasic Salmonella Typhimurium during Epidemic, United Kingdom, 2005-2010. AB - Microevolution associated with emergence and expansion of new epidemic clones of bacterial pathogens holds the key to epidemiologic success. To determine microevolution associated with monophasic Salmonella Typhimurium during an epidemic, we performed comparative whole-genome sequencing and phylogenomic analysis of isolates from the United Kingdom and Italy during 2005-2012. These isolates formed a single clade distinct from recent monophasic epidemic clones previously described from North America and Spain. The UK monophasic epidemic clones showed a novel genomic island encoding resistance to heavy metals and a composite transposon encoding antimicrobial drug resistance genes not present in other Salmonella Typhimurium isolates, which may have contributed to epidemiologic success. A remarkable amount of genotypic variation accumulated during clonal expansion that occurred during the epidemic, including multiple independent acquisitions of a novel prophage carrying the sopE gene and multiple deletion events affecting the phase II flagellin locus. This high level of microevolution may affect antigenicity, pathogenicity, and transmission. PMID- 26982595 TI - IL-27 suppresses type 2 immune responses in vivo via direct effects on group 2 innate lymphoid cells. AB - Group 2 innate lymphoid cells (ILC2) were recently characterized by their ability to produce significant amounts of type-2 signature cytokines and drive central beneficial and pathological features of type-2 immune responses. Although factors such as IL-33 and IL-25 were shown to have ILC2 activating capacity, it is not well understood, how ILC2 responses are regulated in vivo. Here we provide compelling evidence that IL-27-signalling directly inhibits ILC2 responses and reveal a novel mechanism for negative regulation of the innate arm of type-2 immunity. We demonstrate that IL-27-deficiency is linked to increased mucosal presence of ILC2 in a model of inflammatory lung disease. Moreover, IL-27 treatment inhibited ILC2 proliferation and cytokine production and significantly reduced their accumulation in vivo. During helminth infection, regulation of ILC2 by IL-27 directly impacted anti-parasitic immunity. Thus, therapeutic modulation of the IL-27/IL-27R axis may be relevant in a number of inflammatory conditions associated with dysregulated type-2 responses. PMID- 26982600 TI - Potential Barriers to the Diffusion of Surgical Innovation. PMID- 26982598 TI - Suboptimal HIV Testing Uptake Among Men Who Engage in Commercial Sex Work with Men in Asia. AB - PURPOSE: Men who have sex with men and are sex workers (MSMSW) are disproportionately affected by the growing and emerging HIV epidemic. As sex work and same-sex behavior are heavily stigmatized and often illegal in most Asian countries, HIV research focusing on MSMSW has been limited. The goal of this analysis is to examine HIV testing practices and identify correlates of HIV testing among MSMSW in Asia. METHODS: The Asia Internet MSM Sex Survey, an online cross-sectional survey of 10,861 men who have sex with men (MSM), was conducted in 2010. Data on sociodemographic characteristics, HIV testing behaviors, and sexual behaviors were collected. Five hundred and seventy-four HIV negative/unknown respondents reported receiving payment for sex with men at least once in the past 6 months and were included in this analysis. Multivariable logistic regression was conducted to identify independent correlates of HIV testing in the past year. RESULTS: About half (48.6%) of the participants had been tested for HIV at least once within the past year, and 30.5% had never been tested. We also found that MSMSW participants who engaged in risky behaviors were less likely to be tested. CONCLUSION: While one might expect a high HIV testing rate among MSMSW due to the risks associated with engaging in sex work, we found that HIV testing uptake is suboptimal among MSMSW in Asia. These results suggest that targeted HIV prevention and testing promotion among MSMSW are needed. PMID- 26982596 TI - Transient receptor potential melastatin 8 ion channel in macrophages modulates colitis through a balance-shift in TNF-alpha and interleukin-10 production. AB - The transient receptor potential (TRP) ion channel family is well characterized in sensory neurons; however, little is known about its role in the immune system. Here we show that the cold-sensing TRPM8 has an unexpected role in innate immunity. TRPM8 expression and function in macrophages were demonstrated in vitro using molecular techniques and calcium imaging. In addition, adoptive macrophage transfer and systemic interleukin (IL)-10 overexpression were performed in experimental colitis. TRPM8 activation induced calcium-transients in murine peritoneal macrophages (PM) and bone marrow-derived macrophages of wild-type (WT) but not TRPM8-deficient mice. TRPM8-deficient PM exhibited defective phagocytosis and increased motility compared with those in WT, whereas the opposite effects of TRPM8 activation were induced in WT PM. TRPM8 activation or blockage/genetic deletion induced a anti- or pro-inflammatory macrophage cytokine profile, respectively. WT mice treated with repeated menthol (TRPM8 agonist) enemas were consistently protected from experimental colitis, whereas TRPM8-deficient mice showed increased colitis susceptibility. Adoptive transfer of TRPM8-deficient macrophages aggravated colitis, whereas systemic IL-10 overexpression rescued this phenotype. TRPM8 activation in peptidergic sensory neurons did not affect neuropeptide release from the inflamed colon. TRPM8 in macrophages determines pro or anti-inflammatory actions by regulating tumor necrosis factor-alpha and interleukin-10 production. These findings suggest novel TRPM8-based options for immunomodulatory intervention. PMID- 26982599 TI - When helping hurts: the effect of surgical interventions on ovarian reserve. AB - This commentary reviews some of the major papers that have been published on the effect of ovarian reserve after surgical interventions. At the end, the authors outline a summary on the effect of these interventions, in terms of future fertility and menopause. PMID- 26982601 TI - Linear Vesicles in Newborn Resolving With Hyperpigmented Macules. PMID- 26982602 TI - Combination of pregabalin with duloxetine for fibromyalgia: a randomized controlled trial. AB - Fibromyalgia is a syndrome characterized by chronic widespread pain and associated with sleep disturbance, depression, fatigue, and cognitive dysfunction. Polypharmacy is commonly used, but supportive evidence is limited. Most fibromyalgia trials focus primarily on pain reduction with monotherapy. This trial compares a pregabalin-duloxetine combination to each monotherapy. Using a randomized, double-blind, 4-period crossover design, participants received maximally tolerated doses of placebo, pregabalin, duloxetine, and pregabalin duloxetine combination-for 6 weeks. Primary outcome was daily pain (0-10); secondary outcomes included global pain relief, Fibromyalgia Impact Questionnaire, SF-36 survey, Medical Outcomes Study Sleep Scale, Beck Depression Inventory (BDI-II), adverse events, and other measures. Of 41 participants randomized, 39 completed >=2 treatments. Daily pain during placebo, pregabalin, duloxetine, and combination was 5.1, 5.0, 4.1, and 3.7, respectively (P < 0.05 only for combination vs placebo, and pregabalin). Participants (%) reporting >=moderate global pain relief were 18%, 39%, 42%, and 68%, respectively (P < 0.05 for combination vs placebo, pregabalin, and duloxetine). Fibromyalgia Impact Questionnaire scores were 42.9, 37.4, 36.0, and 29.8, respectively (P < 0.05 for combination vs placebo, pregabalin, and duloxetine). SF-36 scores were 50.2, 55.7, 56.0, and 61.2, respectively (P < 0.05 for combination vs placebo, pregabalin, and duloxetine). Medical Outcomes Study Sleep Scale scores were 48.9, 35.2, 46.1, and 32.1, respectively (P < 0.05 only for combination vs placebo, and duloxetine). BDI-II scores were 11.9, 9.9, 10.7, and 8.9, respectively (P < 0.05 only for combination vs placebo). Moderate-severe drowsiness was more frequent during combination vs placebo. Combining pregabalin and duloxetine for fibromyalgia improves multiple clinical outcomes vs monotherapy. Continued research should compare this and other combinations to monotherapy for fibromyalgia. PMID- 26982603 TI - Experimental study on the detection of rabbit intracranial hemorrhage using four coil structures based on magnetic induction phase shift. AB - Intracranial hemorrhage (ICH) is the bleeding induced by parenchyma vascular rupture. In this paper, four novel coils (a contralateral hemisphere cancellation coil, a coaxial coil, a double-end exciting coil, and a Helmholtz coil) were developed to detect the volume change of ICH with the magnetic induction phase shift (MIPS) technique. Both numerical studies on an ICH model and animal experiments on rabbits' hemorrhage model were performed with four coils. Twenty rabbits were measured for each coil. The animal results were consistent with the simulation and the theoretical analysis for each coil. The MIPS first declined and then increased with increasing injection volume, indicating the existence of a turning point. The MRI images showed that the average CSF decreased in the heads of five rabbits after blood injection was approximately equal to the average injection volume corresponding to the turning point of all animals. Thus, we concluded that when the MIPS turning point occurs, the CSF is already exhausted and the compensatory stage has ended. The results show that the MIPS technique has the potential to detect ICH growth and MIPS changes with increasing blood in a regular way. The turning point is expected to provide an early warning for ICH growth. PMID- 26982604 TI - Association of dioxins, furans and dioxin-like PCBs in human blood with nephropathy among US teens and young adults. AB - We assessed the association of three chlorinated dibenzo-p-dioxins, a chlorinated dibenzofuran, and four dioxin-like polychlorinated biphenyls (PCBs) in human blood with nephropathy (microalbuminuria or macroalbuminuria) among teens and young adults (12-30 years old) having normal glycohemoglobin (A1c <5.7%). The data were derived from the 1999-2004 National Health and Nutrition Examination Survey (unweighted n=1504, population estimate=38,806,338). In this paper, nephropathy refers to normal A1c with nephropathy. In an all-adult sample (Everett CJ, Thompson OM. Dioxins, furans and dioxin-like PCBs in human blood: causes or consequences of diabetic nephropathy? Environ Res 2014;132:126-31), the cut-offs for these chemicals being considered elevated, were defined as the 75th percentile. Using these same cut-offs again, the proportion of those with one or more of the eight dioxin-like compounds elevated was 9.9%. The four chemicals associated with nephropathy were 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin, PCB 126, PCB 169, and PCB 156. The proportion with one or more of these four dioxin-like chemicals elevated was 3.9% (unweighted n=46) and the odds ratio (OR) for nephropathy was 7.1 [95% confidence interval (CI) 1.8-28.1]. The association was strong among females (OR 17.4, 95% CI 3.4-88.6), but among males there were no cases of nephropathy when one or more of the four dioxin-like chemicals were elevated, and therefore no association. In a separate analysis, elevated toxic equivalency, defined using the eight dioxin-like chemicals (TEQ8), was associated with nephropathy. TEQ8 >=50.12 fg/g included 2.6% of the sample (unweighted n=28) and had an OR of 5.8 (95% 1.3-25.9) for nephropathy. As found in the analysis of one or more of four dioxin-like chemicals elevated, TEQ8 >=50.12 fg/g was associated with nephropathy among females (OR 11.9, 95% CI 1.6-87.2), but not males. Trends for least-squares means also differed by gender, but there were no significant differences in mean TEQ8 between normal subjects and those having nephropathy in either males or females. We also evaluated pre-diabetes (A1c 5.7 6.4%) without nephropathy and found no associations when one or more of four dioxin-like compounds were elevated, or when TEQ8 was >=50.12 fg/g. In this study, associations of dioxin-like chemicals with nephropathy were found among females at an early age. Prospective studies are needed to determine if dioxin like compounds cause nephropathy, or if these relationships are cases of reverse causation. PMID- 26982605 TI - Traditional and emerging environmental hazards in South-East Asia: double-trouble in the 21st century. PMID- 26982597 TI - Altered gut microbiota profile in common variable immunodeficiency associates with levels of lipopolysaccharide and markers of systemic immune activation. AB - Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by low immunoglobulin (Ig)G and IgA, and/or IgM. In addition to bacterial infections, a large subgroup has noninfectious inflammatory and autoimmune complications. We performed 16S ribosomal RNA-based profiling of stool samples in 44 CVID patients, 45 patients with inflammatory bowel disease (disease controls), and 263 healthy controls. We measured plasma lipopolysaccharide (LPS) and markers of immune cell activation (i.e., soluble (s) CD14 and sCD25) in an expanded cohort of 104 patients with CVID and in 30 healthy controls. We found a large shift in the microbiota of CVID patients characterized by a reduced within-individual bacterial diversity (alpha diversity, P<0.001) without obvious associations to antibiotics use. Plasma levels of both LPS (P=0.001) and sCD25 (P<0.0001) were elevated in CVID, correlating negatively with alpha diversity and positively with a dysbiosis index calculated from the taxonomic profile. Low alpha diversity and high dysbiosis index, LPS, and immune markers were most pronounced in the subgroup with inflammatory and autoimmune complications. Low level of IgA was associated with decreased alpha diversity, but not independently from sCD25 and LPS. Our findings suggest a link between immunodeficiency, systemic immune activation, LPS, and altered gut microbiota. PMID- 26982606 TI - Novel industrial wastewater treatment integrated with recovery of water and salt under a zero liquid discharge concept. AB - Conventional industrial effluent treatment systems are designed to reduce biochemical oxygen demand (BOD), chemical oxygen demand (COD) but not total dissolved solids (TDS), mainly contributed by chlorides. In addition to the removal of TDS, it is necessary to recover water for reuse to meet the challenges of shortage of quality water. To recover water, the wastewater needs to be further treated by adopting treatment systems including microfilters, low pressure membrane units such as ultrafiltration (UF), membrane bioreactors (MBR), etc., for the application of reverse osmosis (RO) systems. By adopting the RO system, 75%-80% of quality water with <500 mg/L of TDS is recovered from treated effluent. The management of 20%-25% of the saline water rejected from the RO system with high TDS concentration is being addressed by methods such as forced evaporation systems. The recovery of water from domestic and industrial waste for reuse has become a reality. The membrane system has been used for different applications. It has become mandatory to achieve zero liquid discharge (ZLD) in many states in India and other countries such as Spain, China, etc., and resulted in development of new treatment technologies to suit the local conditions. PMID- 26982607 TI - Environmental exposures due to natural disasters. AB - The environmental mobilization of contaminants by "natural disasters" is a subject of much interest, however, little has been done to address these concerns, especially in the developing world. Frequencies and predictability of events, both globally and regionally as well as the intensity, vary widely. It is clear that there are greater probabilities for mobilization of modern contaminants in sediments. Over the past 100 years of industrialization many chemicals are buried in riverine, estuarine and coastal sediments. There are a few studies, which have investigated this potential risk especially to human health. Studies that focus on extreme events need to determine the pre-existing baseline, determine the medium to long term fate and transport of contaminants and investigate aquatic and terrestrial pathways. Comprehensive studies are required to investigate the disease pathways and susceptibility for human health concerns. PMID- 26982608 TI - Children's environmental health indicators in Australia: are we collecting the right information? AB - In order to assess progress in improving children's health objectively standardized measurements are required. The World Health Organization (WHO) undertook a pilot project to develop and implement a series of children's environmental health indicators (CEHI) to facilitate this process. No countries in Oceania were included in this pilot. This project was undertaken to determine whether data collected and publicly available in Australia were sufficient to address the CEHI. Government documents and websites were searched to obtain publicly available data. These data adequately reflected outcome indicators but data addressing many exposure indicators were either missing or not available in a child-specific format. Australia does collect data on child health and well being but not in a form compatible with the WHO CEHI. PMID- 26982609 TI - Correlation of intrapartum translabial ultrasound parameters with computed tomographic 3D reconstruction of the female pelvis. AB - AIMS: Intrapartum translabial ultrasound [ITU] can be an objective, reproducible and more reliable method than digital vaginal examination when evaluating fetal head position and station in prolonged second stage of labor. However, two dimensional (2D) ultrasound is not sufficient to demonstrate the ischial spines and other important "landmarks" of the female pelvis. Therefore, the purpose of this study was to evaluate the distance of the interspinous plane as a parallel line to the infrapubic line in 2D ITU with the help of 3D computed tomography and digital reconstruction. RESULTS: Mean distance between the infrapubic plane and the tip of the ischiadic spine was 32.35 (+/-4.46) mm. The mean height was 166 (+/-7) cm; the mean weight was 67.5 (+/-18.4) kg. Body height and the measured distance were significantly correlated (P=0.025; correlation coefficient of 0.5), whereas body weight was not (P=0.37; correlation coefficient of -0.214). CONCLUSIONS: With the present results, clinicians were enabled to transfer the reproducible measurements of the "head station" by ITU to the widespread but observer-depending vaginal examination. Furthermore, ITU can be verified as an objective method in comparison to subjective palpation with the ability to optimize the evaluation of the head station according to bony structures as landmarks in a standardized application. PMID- 26982610 TI - Risk and protective profile of tobacco and alcohol use among Iranian adolescents: a population- based study. AB - BACKGROUND: Identification of risk and protective factors is of great importance in designing preventive and interventional programs. The aim of the present study has been to investigate peer/individual, family, school, and community risk and protective factors as predictors of tobacco and alcohol use among Iranian adolescents. METHODS: In a cross-sectional population-based study, 870 Iranian adolescents aged 15-18 years old, filled out the adopted form of "Communities That Care Youth Survey". Thirty-two risk and protective factors were entered in adjusted logistic regression analyses to predict the lifetime cigarette and alcohol use. RESULTS: Sixteen risk and seven protective factors predicted both lifetime cigarette and alcohol use in the bivariate logistic regression analysis. In the multivariate logistic regression analysis 12 risk factors including friends' use of drugs, interaction with antisocial peers, sensation seeking, intention to use, perceived risks of drug use, family history of drug use, poor family management, parental attitudes favorable toward drug use, family conflict, academic failure, school low commitment, perceived availability of drugs predicted both lifetime cigarette and alcohol use as well as four protective factors including religiosity, self-esteem, family rewards for prosocial involvement, and school rewards for prosocial involvement. The highest OR were related to the risk factor of "Rewards for antisocial involvement" [3.9(1.5-10)], and protective factor of "Religiosity" [0.1(0.1-0.3)]. CONCLUSION: The present study has produced evidences about risk and protective factors related to adolescents substance use and can help designing and implementing of preventive interventions for maintaining and promoting adolescents health. PMID- 26982611 TI - Laboratory screening in overweight/obese adolescents: do the results change the management? AB - Due to the growth of the epidemic of obesity and the association of obesity with both short-term and long-term medical complications, many professional organizations have recommended performing laboratory testing as part of the initial evaluation of overweight and obese children and adolescents. We report on the results of laboratory testing performed on 110 patients (mean age 14.0 years, range 8-20 years) referred to our weight management program between 2011 and 2013. Our results showed mild abnormalities in levels of cholesterol, glucose, liver enzymes, and thyroid stimulating hormone (TSH) in fewer than 5% of patients for each test and no changes in management based on these results for any of the patients. We call for re-consideration of the recommendations for laboratory testing in children and adolescents being evaluated and treated for overweight and obesity. PMID- 26982612 TI - Cross-sectional analysis of food choice frequency, sleep confounding beverages, and psychological distress predictors of sleep quality. AB - BACKGROUND: Poor sleep quality is a significant public health problem. The role of nutrition in predicting sleep quality is a relatively unexplored area of inquiry. The purpose of this study was to evaluate the capacity of 10 food choice categories, sleep confounding beverages, and psychological distress to predict the sleep quality of college students. METHODS: A logistic regression model comprising 10 food choice variables (healthy proteins, unhealthy proteins, healthy dairy, unhealthy dairy, healthy grains, unhealthy grains, healthy fruits and vegetables, unhealthy empty calories, healthy beverages, unhealthy beverages), sleep confounding beverages (caffeinated/alcoholic beverages), as well as psychological distress (low, moderate, serious distress) was computed to determine the capacity of the variables to predict sleep quality (good/poor). RESULTS: The odds of poor sleep quality were 32.4% lower for each unit of increased frequency of healthy proteins consumed (p<0.001; OR=0.676), 14.1% lower for each unit of increased frequency of healthy dairy food choices consumed (p=0.024; OR=0.859), 13.1% higher for each unit of increased frequency of empty calorie food choices consumed (p=0.003; OR=1.131), and 107.3% higher for those classified in the moderate psychological distress (p=0.016; OR=2.073). CONCLUSION: Collectively, healthy proteins, healthy dairy, unhealthy empty calories, and moderate psychological distress were moderately predictive of sleep quality in the sample (Nagelkerke R2=23.8%). Results of the study suggested higher frequency of consumption of healthy protein and healthy dairy food choices reduced the odds of poor sleep quality, while higher consumption of empty calories and moderate psychological distress increased the odds of poor sleep quality. PMID- 26982613 TI - Urate crystals deposition in the feet of overweight juveniles and those with symptomatic hyperuricemia: a dual-energy CT study. AB - BACKGROUND: The present study evaluated the clinical value of dual-energy computed tomography (DECT) for detecting urate crystals in juveniles with symptomatic hyperuricemia. METHODS: We recruited 24 juveniles (15 male and 9 female) who presented with symptomatic hyperuricemia. The mean body mass index (BMI) was 26.4 kg/m2 (standard deviation, SD 11.3 kg/m2). Fifteen juveniles (71.4%) were overweight. DECT scans of the feet were performed. For post processing, a color-coding gout software protocol was used. RESULTS: Urate crystals deposition was observed in 21/24 (87.5%) juveniles with symptomatic hyperuricemia. Urate crystals were detected in or around the anatomic site included the first metatarsophalangeal (MTP) joints (5/24, 20.8%); the calcaneus (5/24, 20.8%); any other toe joints (3/24, 12.5%); the astragalus (3/24, 12.5%); the ankle joints (3/24, 12.5%); the metatarsals (2/24, 8.3%); the cuboid (1/24, 4.2%); and other parts of the feet (2/24, 8.3%). Importantly, urate crystals deposition weas located in the soft tissue (tendon/tendon insertion sites/entheses) around the above-mentioned sites in a majority of these patients. CONCLUSIONS: Urate crystals deposition can be detected by dual-energy CT in the feet of symptomatic hyperuricemia juveniles. DECT can be a valuable diagnostic tool for helping diagnose in juvenile gout. PMID- 26982614 TI - Interrelations between cognitive dysfunction and motor symptoms of Parkinson's disease: behavioral and neural studies. AB - Parkinson's disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (tremor, bradykinesia/akinesia, and rigidity), PD patients also show other motor deficits, including gait disturbance, speech deficits, and impaired handwriting. However, along with these key motor symptoms, PD patients also experience cognitive deficits in attention, executive function, working memory, and learning. Recent evidence suggests that these motor and cognitive deficits of PD are not completely dissociable, as aspects of cognitive dysfunction can impact motor performance in PD. In this article, we provide a review of behavioral and neural studies on the associations between motor symptoms and cognitive deficits in PD, specifically akinesia/bradykinesia, tremor, gait, handwriting, precision grip, and speech production. This review paves the way for providing a framework for understanding how treatment of cognitive dysfunction, for example cognitive rehabilitation programs, may in turn influence the motor symptoms of PD. PMID- 26982615 TI - Nephroprotective effect of beta-sitosterol on N-diethylnitrosamine initiated and ferric nitrilotriacetate promoted acute nephrotoxicity in Wistar rats. AB - BACKGROUND: The most abundant plant sterol beta-sitosterol is widely used for treating heart diseases and chronic inflammatory conditions. The objective of the current study was to evaluate the nephroprotective effect of beta-sitosterol against nephrotoxicants which were studied using renal function markers, antioxidant and lipid peroxidation status, and inflammatory markers. METHODS: Male albino Wistar rats were randomly grouped into four: group 1 was vehicle control rats (0.1% carboxymethyl cellulose [CMC]); group 2 was rats treated with N-diethylnitrosamine (DEN) (200 mg/kg body weight [bw] i.p. on the 15th day) and ferric nitrilotriacetate (Fe-NTA) (9 mg/kg bw i.p. on 30th and 32nd days); group 3 was rats that received beta-sitosterol (20 mg/kg bw in 0.1% CMC, p.o. for 32 days) 2 weeks prior to the exposure to the nephrotoxicant; and group 4 was rats that received beta-sitosterol alone. The experiment was terminated after the 24 h of last dosage of Fe-NTA, and all the animals were sacrificed. The blood, liver and kidney from each group were analyzed for biochemical, molecular and histological changes. RESULTS: All the parameters showed significant changes in DEN and Fe-NTA treated animals, whereas beta-sitosterol pretreated animals' altered biochemical parameters were restored to near normal. Histopathological and immunoexpression studies on tissues also corroborate the biochemical endpoints. CONCLUSIONS: Administration of beta-sitosterol to nephrotoxicity induced rats showed significant positive changes in biochemical parameters, histopathological and immunohistochemical observations, and up-regulation of Nrf2 gene expression. From this, it was clear that beta-sitosterol showed renal protective function. PMID- 26982616 TI - Lessons from mammalian hibernators: molecular insights into striated muscle plasticity and remodeling. AB - Striated muscle shows an amazing ability to adapt its structural apparatus based on contractile activity, loading conditions, fuel supply, or environmental factors. Studies with mammalian hibernators have identified a variety of molecular pathways which are strategically regulated and allow animals to endure multiple stresses associated with the hibernating season. Of particular interest is the observation that hibernators show little skeletal muscle atrophy despite the profound metabolic rate depression and mechanical unloading that they experience during long weeks of torpor. Additionally, the cardiac muscle of hibernators must adjust to low temperature and reduced perfusion, while the strength of contraction increases in order to pump cold, viscous blood. Consequently, hibernators hold a wealth of knowledge as it pertains to understanding the natural capacity of myocytes to alter structural, contractile and metabolic properties in response to environmental stimuli. The present review outlines the molecular and biochemical mechanisms which play a role in muscular atrophy, hypertrophy, and remodeling. In this capacity, four main networks are highlighted: (1) antioxidant defenses, (2) the regulation of structural, contractile and metabolic proteins, (3) ubiquitin proteosomal machinery, and (4) macroautophagy pathways. Subsequently, we discuss the role of transcription factors nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Myocyte enhancer factor 2 (MEF2), and Forkhead box (FOXO) and their associated posttranslational modifications as it pertains to regulating each of these networks. Finally, we propose that comparing and contrasting these concepts to data collected from model organisms able to withstand dramatic changes in muscular function without injury will allow researchers to delineate physiological versus pathological responses. PMID- 26982617 TI - Differential methylation tests of regulatory regions. AB - Differential methylation of regulatory elements is critical in epigenetic researches and can be statistically tested. We developed a new statistical test, the generalized integrated functional test (GIFT), that tests for regional differences in methylation based on the methylation percent at each CpG site within a genomic region. The GIFT uses estimated subject-specific profiles with smoothing methods, specifically wavelet smoothing, and calculates an ANOVA-like test to compare the average profile of groups. In this way, possibly correlated CpG sites within the regulatory region are compared all together. Simulations and analyses of data obtained from patients with chronic lymphocytic leukemia indicate that GIFT has good statistical properties and is able to identify promising genomic regions. Further, GIFT is likely to work with multiple different types of experiments since different smoothing methods can be used to estimate the profiles of data without noise. Matlab code for GIFT and sample data are available at http://www.augusta.edu/mcg/biostatepi/people/software/gift.html. PMID- 26982618 TI - Evaluation of the effects of roselle (Hibiscus sabdariffa L.) on oxidative stress and serum levels of lipids, insulin and hs-CRP in adult patients with metabolic syndrome: a double-blind placebo-controlled clinical trial. AB - BACKGROUND: Roselle (Hibiscus sabdariffa L.) is a plant with antihyperlipidemic and antihypertensive effects. This study aimed to evaluate the effects of roselle calyces on the serum levels of lipids and insulin, inflammation, and oxidative stress in patients with metabolic syndrome (MetS). METHODS: Forty adult patients with MetS were randomly assigned to receive either 500 mg of H. sabdariffa calyx powder or placebo once daily for 4 weeks. Systolic and diastolic blood pressures (SBP and DBP) and BMI (body mass index) as well as fasting serum levels of glucose (FPG; fasting plasma glucose), insulin, lipoproteins, triglycerides (TG), high-sensitivity C-reactive protein (hs-CRP), and malondialdehyde (MDA) were determined pre- and post-intervention and compared. RESULTS: H. sabdariffa significantly reduced serum TG (p=0.044) and SBP (p=0.049) compared to placebo. All other variables were not significantly affected by the interventions. CONCLUSIONS: Daily consumption of 500 mg of H. sabdariffa L. calyx powder can decrease SBP and serum TG in MetS patients. PMID- 26982619 TI - Comparative Proteome Analysis of the Tuberous Roots of Six Cassava (Manihot esculenta) Varieties Reveals Proteins Related to Phenotypic Traits. AB - Cassava (Manihot esculenta Crantz) is a staple food and an important source of starch, and the attributes of its tuberous root largely depend on the variety. The proteome of cassava has been investigated; however, to date, no study has focused on varieties that reveal the molecular basis of phenotypical characteristics. Therefore, we aimed to compare the proteome of the tuberous roots of six cassava varieties that differed in carbohydrates, carotenoids, and resistance to diseases, among other attributes. Two-dimensional gels showed 146 differential spots between the varieties, and the functional roles of some differential proteins were correlated to phenotypic characteristics of the varieties, such as the amount of carbohydrates or carotenoids and the resistance to biotic or abiotic stresses. The results obtained here highlight elements that might help to direct the improvement of new cultivars of cassava, which is an economically and socially relevant crop worldwide. PMID- 26982621 TI - Trichomes and chemical composition of the volatile oil of Trichogonia cinerea (Gardner) R. M. King & H. Rob. (Eupatorieae, Asteraceae). AB - Trichogonia cinerea is endemic to Brazil and occurs in areas of cerrado and campo rupestre. In this study, we characterized the glandular and non-glandular trichomes on the aerial parts of this species, determined the principal events in the development of the former, and identified the main constituents of the volatile oil produced in its aerial organs. Fully expanded leaves, internodes, florets, involucral bracts, and stem apices were used for the characterization of trichomes. Leaves, internodes, florets, and involucral bracts were examined by light microscopy and scanning electron microscopy, whereas stem apices were examined only by light microscopy. Branches in the reproductive phase were used for the extraction and determination of the composition of the volatile oil. The species has three types of glandular trichomes, biseriate vesicular, biseriate pedunculate, and multicellular uniseriate, which secrete volatile oils and phenolic compounds. The major components identified in the volatile oil were 3,5 muuroladiene (39.56%) and butylated hydroxytoluene (13.07%). PMID- 26982620 TI - Post-encoding emotional arousal enhances consolidation of item memory, but not reality-monitoring source memory. AB - The current study examined whether the effect of post-encoding emotional arousal on item memory extends to reality-monitoring source memory and, if so, whether the effect depends on emotionality of learning stimuli and testing format. In Experiment 1, participants encoded neutral words and imagined or viewed their corresponding object pictures. Then they watched a neutral, positive, or negative video. The 24-hour delayed test showed that emotional arousal had little effect on both item memory and reality-monitoring source memory. Experiment 2 was similar except that participants encoded neutral, positive, and negative words and imagined or viewed their corresponding object pictures. The results showed that positive and negative emotional arousal induced after encoding enhanced consolidation of item memory, but not reality-monitoring source memory, regardless of emotionality of learning stimuli. Experiment 3, identical to Experiment 2 except that participants were tested only on source memory for all the encoded items, still showed that post-encoding emotional arousal had little effect on consolidation of reality-monitoring source memory. Taken together, regardless of emotionality of learning stimuli and regardless of testing format of source memory (conjunction test vs. independent test), the facilitatory effect of post-encoding emotional arousal on item memory does not generalize to reality monitoring source memory. PMID- 26982622 TI - Current concepts: diagnosis and management of food allergy in children. AB - PURPOSE OF REVIEW: Advances in the prevention and treatment of food allergy have been published in the last few years and are placed in context using a review format. RECENT FINDINGS: Preventing food allergy has been studied for years with questions of whether avoidance or exposure was a better strategy. Recent research has suggested that peanut allergy can be substantially reduced in high-risk infants through intentional oral exposure. For children with food allergy, the primary treatment remains avoidance, but controlled trials have shown some success with oral immunotherapy and sublingual immunotherapy. SUMMARY: Providers who see children with food allergies should be aware of the newer recommendations of preventing peanut allergy and the emerging therapies for children with immunoglobulin E-mediated food allergy. PMID- 26982625 TI - Hot Carrier Extraction with Plasmonic Broadband Absorbers. AB - Hot charge carrier extraction from metallic nanostructures is a very promising approach for applications in photocatalysis, photovoltaics, and photodetection. One limitation is that many metallic nanostructures support a single plasmon resonance thus restricting the light-to-charge-carrier activity to a spectral band. Here we demonstrate that a monolayer of plasmonic nanoparticles can be assembled on a multistack layered configuration to achieve broadband, near-unit light absorption, which is spatially localized on the nanoparticle layer. We show that this enhanced light absorbance leads to ~40-fold increases in the photon-to electron conversion efficiency by the plasmonic nanostructures. We developed a model that successfully captures the essential physics of the plasmonic hot electron charge generation and separation in these structures. This model also allowed us to establish that efficient hot carrier extraction is limited to spectral regions where (i) the photons have energies higher than the Schottky junctions and (ii) the absorption of light is localized on the metal nanoparticles. PMID- 26982624 TI - A Feasibility Study Evaluating Extraoral Photobiomodulation Therapy for Prevention of Mucositis in Pediatric Hematopoietic Cell Transplantation. AB - OBJECTIVE: The objective of this study was to determine the feasibility, safety, and tolerability of providing extraoral photobiomodulation therapy (PBT) for prevention of oral mucositis (OM) in pediatric hematopoietic cell transplantation (HCT). BACKGROUND DATA: OM is a frequent complication in pediatric HCT. METHODS: Patients 4-21 years of age scheduled for myeloablative HCT were eligible to participate. PBT was delivered using a THOR Model LX2M with a 69 Diode LED Cluster Probe (34 * 660 nm 10 mW, 35 * 850 nm 30 mW; 1390 mW total power output) at an irradiance of 50 mW/cm(2). Daily treatment exposed six sites (right, left, and midline face and neck) for 60 sec each, for a total dose of 3.0 J/cm(2). Treatment was initiated on the 1st day of conditioning, through day +20. OM assessments were completed at baseline then daily, from day -1 through day +20. Feasibility assessment included both qualitative and quantitative measures and outcomes from patients and providers. RESULTS: Thirteen patients with a median age of 15 years (range, 4.8-21.6) were consented and enrolled, and completed the protocol. The incidence of severe OM [World Health Organization (WHO) Grade >=3] was 77%, with a median duration of 4 days (range, 1-14). Of 355 attempted PBT administrations, there were six refusals, and the mean proportion of days with data submitted was 96.2% [95% confidence interval (CI): 78.5-97.2%]. The 10 trained nurses all reported that the device was accessible, maneuverable, and lightweight, and that training was effective. There was no reported toxicity attributed to the PBT. CONCLUSIONS: Daily delivery of external PBT and completion of OM evaluations is feasible in children undergoing HCT. PMID- 26982623 TI - Discovery of a 9-mer Cationic Peptide (LTX-315) as a Potential First in Class Oncolytic Peptide. AB - Oncolytic immunotherapies represent a new promising strategy in the treatment of cancer. In our efforts to develop oncolytic peptides, we identified a series of chemically modified 9-mer cationic peptides that were highly effective against both drug-resistant and drug-sensitive cancer cells and with lower toxicity toward normal cells. Among these peptides, LTX-315 displayed superior anticancer activity and was selected as a lead candidate. This peptide showed relative high plasma protein binding abilities and a human plasma half-life of 160 min, resulting in formation of nontoxic metabolites. In addition, the lead candidate demonstrated relatively low ability to inhibit CYP450 enzymes. Collectively these data indicated that this peptide has potential to be developed as a new anticancer agent for intratumoral administration and is currently being evaluated in a phase I/IIa study. PMID- 26982627 TI - The effect of occupational therapy in patients with chronic obstructive pulmonary disease: A randomized controlled trial. AB - Aim The main aim of this study was to evaluate the effect of individualized occupational therapy in patients with chronic obstructive pulmonary disease (COPD). Additionally, the authors wanted to explore the occupational problems experienced in daily life by individuals with COPD. Methods A total of 52 patients were randomly assigned to the intervention group (occupational therapy) or control group (treatment as usual). The primary outcome was assessed using the Canadian Occupational Performance Measure (COPM), and participants were assessed at baseline and after four and 12 months. Results There were no treatment effects on occupational performance or satisfaction with performance, as measured by the COPM. However, we found a significant effect in favour of the intervention group at exertion when performing an individually chosen activity, and in the activity dimension of St George's Respiratory Questionnaire. A total of 595 occupational problems were reported, most frequently within mobility, active recreation, and household management. Conclusions The results show that, compared with the usual care, individualized occupational therapy did not improve occupational performance or satisfaction with performance. Small but significant changes in activity performance in favour of the intervention group were found in some of the secondary outcomes. PMID- 26982626 TI - A no-gold-standard technique for objective assessment of quantitative nuclear medicine imaging methods. AB - The objective optimization and evaluation of nuclear-medicine quantitative imaging methods using patient data is highly desirable but often hindered by the lack of a gold standard. Previously, a regression-without-truth (RWT) approach has been proposed for evaluating quantitative imaging methods in the absence of a gold standard, but this approach implicitly assumes that bounds on the distribution of true values are known. Several quantitative imaging methods in nuclear-medicine imaging measure parameters where these bounds are not known, such as the activity concentration in an organ or the volume of a tumor. We extended upon the RWT approach to develop a no-gold-standard (NGS) technique for objectively evaluating such quantitative nuclear-medicine imaging methods with patient data in the absence of any ground truth. Using the parameters estimated with the NGS technique, a figure of merit, the noise-to-slope ratio (NSR), can be computed, which can rank the methods on the basis of precision. An issue with NGS evaluation techniques is the requirement of a large number of patient studies. To reduce this requirement, the proposed method explored the use of multiple quantitative measurements from the same patient, such as the activity concentration values from different organs in the same patient. The proposed technique was evaluated using rigorous numerical experiments and using data from realistic simulation studies. The numerical experiments demonstrated that the NSR was estimated accurately using the proposed NGS technique when the bounds on the distribution of true values were not precisely known, thus serving as a very reliable metric for ranking the methods on the basis of precision. In the realistic simulation study, the NGS technique was used to rank reconstruction methods for quantitative single-photon emission computed tomography (SPECT) based on their performance on the task of estimating the mean activity concentration within a known volume of interest. Results showed that the proposed technique provided accurate ranking of the reconstruction methods for 97.5% of the 50 noise realizations. Further, the technique was robust to the choice of evaluated reconstruction methods. The simulation study pointed to possible violations of the assumptions made in the NGS technique under clinical scenarios. However, numerical experiments indicated that the NGS technique was robust in ranking methods even when there was some degree of such violation. PMID- 26982629 TI - Mechanical Characterization of Ultralow Interfacial Tension Oil-in-Water Droplets by Thermal Capillary Wave Analysis in a Microfluidic Device. AB - Measurements of the ultralow interfacial tension and surfactant film bending rigidity for micron-sized heptane droplets in bis(2-ethylhexyl) sodium sulfosuccinate-NaCl aqueous solutions were performed in a microfluidic device through the analysis of thermally driven droplet interface fluctuations. The Fourier spectrum of the stochastic droplet interface displacement was measured through bright-field video microscopy and a contour analysis technique. The droplet interfacial tension, together with the surfactant film bending rigidity, was obtained by fitting the experimental results to the prediction of a capillary wave model. Compared to existing methods for ultralow interfacial tension measurements, this contactless, nondestructive, all-optical approach has several advantages, such as fast measurement, easy implementation, cost-effectiveness, reduced amount of liquids, and integration into lab-on-a-chip devices. PMID- 26982628 TI - Neisseria meningitidis Serogroup X in Sub-Saharan Africa. AB - The epidemiology of meningococcal disease varies by geography and time. Whole genome sequencing of Neisseria meningitidis serogroup X isolates from sub-Saharan Africa and Europe showed that serogroup X emergence in sub-Saharan Africa resulted from expansion of particular variants within clonal complex 181. Virulence of these isolates in experimental mouse models was high. PMID- 26982630 TI - Practical implications of novel serum ELISA-assay for matrix metalloproteinase-8 in acute cardiac diagnostics. AB - Matrix metalloproteinases (MMPs) play a major role in inflammatory processes as they degrade extracellular proteins and modify immune responses. Inflammation is the driving factor in atherogenesis and MMPs, particularly MMP-8, has been linked to atherosclerotic plaque progression. MMP-8 is shown to be strongly associated with cardiovascular diseases (CVDs) and its complications thus providing a potential marker to identify patients at risk. Previously, laborious and expensive immunofluorometric assay (IFMA) was needed to reliably detect MMP-8 levels in serum. In this study, we compared a novel in-house ELISA-assay, dentoELISA, to the standard IFMA in determination of serum MMP-8 concentrations. As a cheaper and non-laborious assay, ELISA proved to be diagnostically as sensitive and specific as the IFMA. ROC statistics showed highly similar areas under the curve for both assays (0.779 versus 0.781). Furthermore, the concentrations measured by ELISA correlated significantly with concentrations determined with IFMA (r = 0.881, P < 0.001). In our study population, MMP-8 levels were significantly higher in the acute coronary syndrome patients (n = 2071) in comparison to reference population without significant coronary artery disease (n = 653). With this background, MMP-8-ELISA could provide interesting new approaches to novel CVD diagnostics. PMID- 26982631 TI - Outcome Analysis of The B.E. S.T.R.O.N.G. Childhood Obesity Treatment Program: Effectiveness of an Eight-Week Family-Based Childhood Obesity Program Using an Internet-Based Health Tracker. AB - BACKGROUND: We describe the development, testing, and analysis of the B.E. S.T.R.O.N.G. program, a comprehensive family-based multidisciplinary child obesity treatment program. The program uses an innovative Internet-based health tracker that was developed by the Children's Wellness Institute (CWI) for data collection, analysis, and storage. METHODS: Data were obtained on 112 subjects who enrolled in the B.E. S.T.R.O.N.G. program in several healthcare institutions during the 2013-2014 academic year. There were 74 females and 38 males. The mean age was 9.75 +/- 2.21 years. There were 89 white, 14 African American, 3 Hispanic, and 6 listed as other. Height and weight data were collected during the first, fourth, and seventh week. Diet and exercise data were collected in a HIPAA compliant manner each week for seven weeks, using the health tracker, and transmitted electronically for statistical analysis and storage. RESULTS: Subjects involved in the program demonstrated significant weight loss, averaging 3.8% reduction in BMI from their starting point. Weight loss in these subjects was associated with significant and measurable changes in diet, physical activity, and screen time. Participants in the B.E. S.T.R.O.N.G. program increased fruit and vegetable consumption to more than five daily servings and also demonstrated significant increases in the consumption of grains and protein foods. Furthermore, they maintained screen time at less than one hour per day, and increased all forms of physical activity to exceed one hour daily. CONCLUSIONS: The Internet-based health tracker demonstrated the effectiveness of the B.E. S.T.R.O.N.G. program, delivered by several healthcare institutions, in treating childhood obesity. PMID- 26982633 TI - Identification of abelson tyrosine kinase inhibitors as potential therapeutics for Alzheimer's disease using multiple e-pharmacophore modeling and molecular dynamics. AB - Efforts to combat Alzheimer's disease are focused predominantly on inhibiting the activity of the enzyme(s) that have been identified to be responsible for the production of the amyloid-forming peptide. However, the inherent complexity associated with the network of pathways leading to the disease may involve additional targets for designing effective therapies. Recent experimental findings have identified abelson tyrosine kinase, a non-receptor kinase as a new target for Alzheimer's. In this work, we employed energy optimized multiple pharmacophore modeling strategy from multiple c-Abl structures bound with ligands in the inactive ATP binding conformation (DFG-out). Virtual screening followed by docking of molecules from ChemBridge resulted in the identification of 10 best scoring molecules. MD simulations of the top three complexes revealed that Compound A, C are the most stable complexes with the most persistent protein ligand interactions consistent with the calculated binding affinities for the top three compounds. Given the implied role of c-Abl not only in AD but in Parkinson's disease, the identified compounds may serve as leads for effective neurotherapeutics. PMID- 26982635 TI - HoxA13 Stimulates Myometrial Cells to Secrete IL-1beta and Enhance the Expression of Contraction-Associated Proteins. AB - Bipedalism in humans requires regionalization of myometrial function with a contracted lower uterine segment and a relaxed fundus during pregnancy to prevent fetal pressure on the cervix and reversal of this phenotype during labor. The HoxA13 gene is highly expressed in the lower uterine segment before term labor and regulates the regionalization of myometrium contractility. However, how HoxA13 regulates signal pathways to exert its functions remains unclear. Using a gene microarray technique, we profiled HoxA13 transcriptome in myometrial cells containing immune response genes (eg, IL-1beta, IL-6, and IL-8) and contraction associated proteins (CAPs) such as cyclooxygenase-2 (Cox-2) and connexin-43. IL 1beta is responsible for mediating HoxA13 actions in up-regulating IL-6, IL-8, Cox-2, and connexin-43 expression. Blocking IL-1beta with its inhibitor abolishes these HoxA13 actions. HoxA13-induced IL-1beta stimulates the recruitment of activated THP-1 monocytes to myometrial cells, which in turn amplify the secretion of IL-1beta, IL-6, and IL-8 through a mutual feed-forward loop between these cell types. As a result, Cox-2 expression is dramatically enhanced. These findings lead us to conclude that HoxA13 increases myometrial cell contractility by enhancing the secretion of IL-1beta, resulting in an up-regulation of CAP and other proinflammatory cytokine expression. HoxA13-induced IL-1beta in myometrial cells also prompts leukocyte recruitment and further amplifies CAP expression. PMID- 26982632 TI - Stimulant Treatment of Young People in the United States. AB - OBJECTIVE: To describe national stimulant treatment patterns among young people focusing on patient age and prescribing specialty. METHODS: Stimulant prescriptions to patients aged 3-24 were analyzed from the 2008 IMS LifeLink LRx Longitudinal Prescription database (n = 3,147,352), which includes 60% of all U.S. retail pharmacies. A subset of young people from 2009 with service claims (n = 197,654) were also analyzed. Denominators were adjusted to generalize estimates to the U.S. POPULATION: Population percentages filling >=1 stimulant prescription during the study year by sex and age group (younger children, 3-5 years; older children, 6-12 years; adolescents, 13-18 years; and young adults, 19-24 years) were determined. Percentages prescribed stimulants by psychiatrists, child and adolescent psychiatrists, pediatricians, and other physicians were also determined along with percentages that were treated for a long or short duration; coprescribed other psychotropic medications; used psychosocial services; and received clinical psychiatric diagnoses. RESULTS: Population percentages with any stimulant use varied across younger children (0.4%), older children (4.5%), adolescents (4.0%), and young adults (1.7%). Among children and adolescents, males were over twice as likely as females to receive stimulants. Percentages of stimulant-treated young people with >=1 stimulant prescription from a child and adolescent psychiatrist varied from younger children (19.1%), older children (17.1%), and adolescents (18.2%) to young adults (10.1%), and these percentages increased among those who were also prescribed other psychotropic medications: young children (31.0%), older children (37.9%), adolescents (35.1%), and young adults (15.8%). Antipsychotics were the most commonly coprescribed class to stimulant-treated younger (15.0%) and older children (11.8%), while antidepressants were most commonly coprescribed to adolescents (17.5%) and young adults (23.9%). CONCLUSIONS: Stimulant treatment peaks during middle childhood, especially for boys. For young people treated with stimulants, including younger children, low rates of treatment by child and adolescent psychiatrists highlight difficulties with access to specialty mental health services. PMID- 26982634 TI - A Functional Coupling Between Carbon Monoxide and Nitric Oxide Contributes to Increased Vasopressin Neuronal Activity in Heart Failure rats. AB - Despite the pathophysiological importance of neurohumoral activation in patients with heart failure (HF), the precise underlying mechanisms contributing to elevated vasopressin (VP) activation in HF remains unknown. Carbon monoxide (CO) is a gaseous neurotransmitter in the central nervous system that stimulates VP neuronal firing activity. Recently, we showed that the excitatory effect of CO on VP neurons in the hypothalamic paraventricular nucleus (PVN) was mediated by inhibition of nitric oxide (NO). Given that previous studies showed that VP neuronal activity is enhanced, whereas NO inhibitory signaling is blunted in HF rats, we tested whether an enhanced endogenous CO availability within the PVN contributes to elevated VP neuronal activity and blunted NO signaling in HF rats. We found that both haeme-oxygenase 1 (the CO-synthesizing enzyme) protein and mRNA expression levels were enhanced in the PVN of HF compared with sham rats (~18% and ~38%, respectively). We report that in sham rats, bath application of a CO donor (tricarbonyldichlororuthenium dimer) increased the firing activity of identified PVN VP neurons (P < .05), whereas inhibition of endogenous CO production (Tin-protoporphyrin IX [SnPP]) failed to affect neuronal activity. In HF rats, however, SnPP decreased VP activity (P < .05), an effect that was occluded by previous NO synathase blockade NG-nitro-larginine methyl ester. Finally, we found that SnPP increased the mean frequency of gamma-aminobutyric acid inhibitory postsynaptic currents in VP neurons in HF (P < .05) but not sham rats. Our results support an enhanced endogenous CO excitatory signaling in VP neurons, which likely contributes to blunted NO and gamma-aminobutyric acid inhibitory function in HF rats. PMID- 26982637 TI - Targeted Foxe1 Overexpression in Mouse Thyroid Causes the Development of Multinodular Goiter But Does Not Promote Carcinogenesis. AB - Recent genome-wide association studies have identified several single nucleotide polymorphisms in the forkhead box E1 gene (FOXE1) locus, which are strongly associated with the risk for thyroid cancer. In addition, our recent work has demonstrated FOXE1 overexpression in papillary thyroid carcinomas. To assess possible contribution of Foxe1 to thyroid carcinogenesis, transgenic mice overexpressing Foxe1 in their thyroids under thyroglobulin promoter (Tg-Foxe1) were generated. Additionally, Tg-Foxe1 mice were exposed to x-rays at the age of 5 weeks or crossed with Pten(+/-) mice to examine the combined effect of Foxe1 overexpression with radiation or activated phosphatidylinositol-3-kinase/Akt pathway, respectively. In 5- to 8-week-old Tg-Foxe1 mice, severe hypothyroidism was observed, and mouse thyroids exhibited hypoplasia of the parenchyma. Adult 48 week-old mice were almost recovered from hypothyroidism, their thyroids were enlarged, and featured colloid microcysts and multiple benign nodules of macrofollicular-papilloid growth pattern, but no malignancy was found. Exposure of transgenic mice to 1 or 8 Gy of x-rays and Pten haploinsufficiency promoted hyperplastic nodule formation also without carcinogenic effect. These results indicate that Foxe1 overexpression is not directly involved in the development of thyroid cancer and that proper Foxe1 dosage is essential for achieving normal structure and function of the thyroid. PMID- 26982639 TI - eLearning or technology enhanced learning in medical education-Hope, not hype. AB - This Personal View elaborates on my strong conviction that the excitement and positive feelings that many of us have for eLearning or Technology enhanced learning (TeL) is well founded, and will argue why our hopes are justified, and not misplaced. In a nutshell, I believe that eLearning or TeL is a significant advance from previous generations of educational innovation, and offers benefits for students, educators and administrators; by synergistically combining the capabilities of digital content, the Internet, and mobile technology, supported by software and applications or "Apps". PMID- 26982638 TI - Possible relationship between amino acids, aggression and psychopathy. AB - OBJECTIVE: Aggressive behaviour is associated with reduced serotonin metabolism in the brain, but there is not enough knowledge on potential changes of the serotonin precursor levels among violent offenders. In this study, we aimed to evaluate the relationships among the tendency of psychopathy, anger and the basic amino acids. METHODS: Fifty-two young adult male patients with antisocial personality disorder (APD) and 30 healthy men included the study. Serum amino acid levels were measured by HPLC method. Aggression questionnaire and Hare Psychopathology Scale were used for all participants. RESULTS: Blood levels of phosphoserine, aspartic acid, glutamic acid, aminoadipic acid and 1 methylhistidine in group of patients with APD were significantly higher than the control group. Blood levels of TRP, asparagine, citrulline, cystine, isoleucine, tyrosine, histidine, hydroxylysine, lysine, ethanolamine and arginine in the group of patients were found lower than the control group. A significant positive correlation between anger scores and histidine, methionine and GABA was found. GABA and methionine showed a significant correlation with the indirect aggression score. CONCLUSION: Our study showed a relationship between serum amino acid levels and the scores of aggression and psychopathy. We think that this is a productive research area for understanding the relationship among biochemical factors, aggression and psychopathy. PMID- 26982636 TI - A Human Variant of Glucose-Regulated Protein 94 That Inefficiently Supports IGF Production. AB - IGFs are critical for normal intrauterine and childhood growth and sustaining health throughout life. We showed previously that the production of IGF-1 and IGF 2 requires interaction with the chaperone glucose-regulated protein 94 (GRP94) and that the amount of secreted IGFs is proportional to the GRP94 activity. Therefore, we tested the hypothesis that functional polymorphisms of human GRP94 affect IGF production and thereby human health. We describe a hypomorphic variant of human GRP94, P300L, whose heterozygous carriers have 9% lower circulating IGF 1 concentration. P300L was found first in a child with primary IGF deficiency and was later shown to be a noncommon single-nucleotide polymorphism with frequencies of 1%-4% in various populations. When tested in the grp94(-/-) cell-based complementation assay, P300L supported only approximately 58% of IGF secretion relative to wild-type GRP94. Furthermore, recombinant P300L showed impaired nucleotide binding activity. These in vitro data strongly support a causal relationship between the GRP94 variant and the decreased concentration of circulating IGF-1, as observed in human carriers of P300L. Thus, mutations in GRP94 that affect its IGF chaperone activity represent a novel causal genetic mechanism that limits IGF biosynthesis, quite a distinct mechanism from the known genes in the GH/IGF signaling network. PMID- 26982641 TI - [Not Available]. PMID- 26982640 TI - The role of Aflibercept in the management of age-related macular degeneration. AB - INTRODUCTION: During the past decade, significant advances have occurred in the management of neovascular age-related macular degeneration (NV-AMD). The advent of anti-vascular endothelial growth factor (anti-VEGF) therapy has shifted the treatment goal of NV-AMD from merely salvaging vision to improving visual acuity and maintaining a good quality of life. Aflibercept (AFL) is a significant addition to the arsenal of anti-VEGF therapies against the NV-AMD. In the index review, pharmacology and efficacy of AFL has been reviewed. AREAS COVERED: An extensive literature search was performed to identify preclinical and clinical studies performed to illustrate the role of AFL in NV-AMD. Randomized clinical trials evaluating other anti-VEGF agents were also included for comparison. Additionally, studies where AFL was employed to treat anti-VEGF-resistant cases agents have been reviewed. EXPERT OPINION: AFL is an effective agent in the management of NV-AMD and its efficacy has been found to be comparable to ranibizumab (RBZ). Additionally, AFL is a good alternative agent in patients with NV-AMD resistant to RBZ and bevacizumab (BVZ), and can potentially lessen the treatment burden. As more research is conducted, the role of AFL in varying dosing regimens, as monotherapy and in combination with other agents, will become further defined. PMID- 26982642 TI - [Developments in modern cataract surgery - a critical overview]. AB - Cataract surgery has tremendously evolved in recent years. Innovations include micro-incision cataract surgery through incisions smaller than 2mm, high-fluidics phacoaspiration and laser phacoemulsification to minimize or replace the use of ultrasound, the advent of femtolasers for high-precision incisions in the cornea, the lens capsule and the cataractous lens, aspheric intraocular lenses (IOLs) to enhance the quality and contrast of the image, multifocal and enhanced-depth-of focus IOLs to correct presbyopia, advancements in biometry and IOL power calculation, prevention of secondary capsule opacification by improvements in the design and material of the IOLs and surgical techniques like capsule polishing and posterior capsulorhexis, and pharmacological prophylaxis and possible future treatment of the cataract itself. Finally, cost-effectiveness and future potential of same-session bilateral cataract surgery are discussed. PMID- 26982644 TI - [Early detection and treatment of strabismus]. AB - An early diagnosis of strabismus is important in order to rule out treatable organic causes and in children, if indicated, to start as early as possible with an amblyopia treatment. Early detection will also decrease the risk for accidents secondary to diplopia, to the loss of binocular vision and to the restriction of the binocular visual field in case of esodeviations. The following therapeutic options exist: in some cases the prescription of the correct refraction will be sufficient, for small deviations a prismatic correction may allow a longstanding treatment, for larger or incomitant deviations strabismus surgery will be necessary, which nowadays can be performed using minimal-invasive technique on an outpatient base. PMID- 26982643 TI - [Anesthesia for ophthalmic surgery]. AB - The majority of ophthalmic interventions can be done today under locoregional anesthesia using "Monitored Anesthesia Care" (MAC). General anesthesia techniques are mostly reserved for the pediatric segment and for patients with specific comorbidity and/or lengthy procedure. Cataract surgery in predominantly geriatric patients belongs to the field of the so-called "high volume-surgery": Given the low perioperative risk in this patient group, adapted and optimized processes are indicated. A focused premedication and informing these patients ensures good perioperative compliance. Preoperative tests are be conducted in this patient population only as a function of relevant comorbidity. Premedication usually takes place as a classical anesthesia consultation, but new methods such as an internet-based premedication for healthy patients offers a new option. The intraoperative anesthesia method depends on the needs of the surgeon and the expectations and possibilities of cooperation of the patient. PMID- 26982646 TI - [Age-related macular degeneration - a challenge for public health care]. AB - Age-related macular degeneration (AMD) is the predominant cause of legal blindness in the population over 50 years of age. The disorder shows exponentially increasing prevalence with age, and the late forms with their vision threatening evolution are found in approximately one third of cases. The late AMD may be purely atrophic and so far untreatable. Or it may be neovascular and exudative, for which medical treatment is available, consisting of repetitive intravitreous injections of Anti-VEGF molecules. The treatment is highly effective in blocking the growth of the pathological vessels and allowing resolution of the accompanying edema. Visual improvement is variable but often very meaningful for the patients. However, the final visual level depends mostly on early intervention. Thus, screening for the first signs of neovascular AMD is crucial for the endresult. However, the repetitive intraocular injections are an important burden for the patients. Due to the high patient numbers, the chronic care management with steadily adding new patients is a major challenge for treating institutions. Limited resources may put patients at risk of undertreatment with resulting visual loss. Various strategies have been developed to cope with the burden. In addition, the financial cost is high for the health care system. On the other hand, timely and ongoing treatment is the best investment to achieve meaningful visual improvement, which is extremely important for the quality of life and autonomy of the patients. Side effects of the treatment are limited and mostly procedure related. Systemic side effects are possible but despite the large studies not conclusive. However, care must be taken in cases of high cardiovascular risk, as thromboembolic risk increase may rarely happen. So far unsolved problems include the long term visual results, the degree of reversibility of neovascularization, and the missing treatment options of atrophic AMD. Basic and clinical research on various treatment options for AMD is ongoing, and some additional molecules are expected for the near future, hopefully not only for neovascular AMD but including atrophic AMD as well. PMID- 26982647 TI - [Retinal vein occlusion: an interdisciplinary approach]. AB - Retinal vein occlusion provide a common cause of significant visual reduction but also late ocular complications. The medical care of these patients pursue two goals: On the one hand vision threatening complications need to be identified and treated, and on the other hand treatable risk factors are need to be identified and treated. This paper summarizes the common ophthalmological therapeutic approaches as well as recommended medical evaluations carried out by the general practitioner. This supports the interdisciplinary approach in evaluating and treating retinal vein occlusions by ophthalmologists and the general practitioners/specialist in internal medicine. PMID- 26982645 TI - [Visual training in children]. AB - The visual system has a pivotal role in most human activities. Many health disorders and psychomotor deficits involve the visual system at some level. From this some therapists infer a causal relation and apply a variety of visual therapies and trainings to cure a variety of deficits. The most prominent example is dyslexia, a disorder not caused by a defect in the primary visual system. Worldwide various non-evidence based therapies are used to treat dyslexia. The great number of exercises and visual trainings is contrasted by scientific evidence, which shows that exercises are useful in only few and selected disorders. The human visual system seems to be optimized such that no improvement can be achieved with training. PMID- 26982649 TI - [Early recognition and management of the disease]. AB - Glaucoma is a progressive disease of the optic nerve potentially leading to a destruction of the nerve and therefore to blindness. It is a multifactorial disease and patients of all age groups can be affected. Different risk factors influence the course of the disease. The quality of life of the patients is already reduced when the patients show moderate changes of their visual field. The patients experience more falls and may be forced to stop driving. With an early and adequate treatment the progression of the disease can be slowed down. The early recognition of the disease is important and belongs into the hands of ophthalmologists. The treatment for glaucoma is a difficult task and needs an intense collaboration of the ophthalmologist with the patient and the treating primary care physician. PMID- 26982650 TI - [Dry Eye - not always easy to detect]. AB - Dry Eye Disease (DED) is in its milder forms often fairly easy to diagnose and to fairly easy treat in a way satisfactory for the patient. In moderate to severe DED or in patients who show no solid signs of dry eye despite suffereing from severe symptoms, diagnosis and treatment is often much more difficult. A systematic approach is required, but both the patient and the doctor need patience, too. Patient education and training is one focus in the therapy. In addition, this multifactorial disease often needs further evaluation, if clinically plausible, in the fields of dermatology, gastroenterology, rheumatology and endocrinology. PMID- 26982648 TI - [Fitness to drive under traffic ophthalmological aspects in elderly drivers]. AB - The Federal Roads Office (FEDRO), Switzerlands federal authority carries responsibility for the action program "Via Sicura" in order to reduce drastically the number of road traffic fatalities and serious injuries on Swiss roads. The revision of the VZV (Verkehrszulassungsverordnung) included in this program will come in to force on 1.July 2016. On that account the legal medical requirements for driver will be renewed. In particular, the requirements for vision (visual acuity, visual field) will be adjusted to international standards. Due to demographic changes the number of elderly drivers with old age (85 - 90+) with eye associated diseases increases. Therefore, questions concerning traffic ophthalmological problems have to be increasingly considered within traffic medical assessments. The driver's vision in traffic's safety must enable him to perceive relevant information, process information quickly and perform an adequate reaction in time, even if visibility is limited (e. g. due to rain, night, darkness) or in the presence of physical or psychical constraints. PMID- 26982651 TI - Triterpenoids from the stems of Schisandra grandiflora and their biological activity. AB - One new ursane-type triterpenoid (1), named granditriol, along with 14 known compounds (2-15), was isolated from the organic extracts of Schisandra grandiflora stems. The structure of the new compound was elucidated by extensive spectroscopic methods as 28-norursa-12,17,19,21-tetraen-2alpha,3alpha,23-triol. These isolates were evaluated for anti-phytopathogenic fungi activity and cytotoxicity against human cancer cell line (HepG2). Asiatic acid (8) and 2alpha,3alpha,19alpha-trihydroxyurs-12-en-28-oic acid (9) inhibited the growth of two plant pathogens, Alternaria alternata and Alternaria solani. In addition, compounds 12, 15, and 11 displayed notable anti-proliferative activity against HepG2 cells. Compound 1 is the first report of 28-nortriterpenoid from the Schisandraceae family. All these were obtained from this plant for the first time. PMID- 26982652 TI - CD40 Ligand and GMCSF Coexpression Enhance the Immune Responses and Protective Efficacy of PCV2 Adenovirus Vaccine. AB - Porcine circovirus 2 (PCV2) capsid protein (Cap) is the major structural protein that is responsible for neutralizing antibodies development and protective immunity, thus it is usually used to develop vaccines against porcine circovirus associated disease (PCVAD). Porcine CD40 ligand (CD40L) and granulocyte macrophage colony-stimulating factor (GMCSF) have positive immunostimulatory effects on immunocytes and have been applied in vaccine efficacy improvement as attractive adjuvant cytokines, respectively. However, whether these two cytokines can produce synergistic effect in vaccines still need to be further studied. In this study, porcine CD40L and GMCSF were inserted into recombinant adenoviruses to test the immunogenicity of PCV2 adenovirus vaccine in mice. Western blot and indirect immunofluorescence assay showed that Ad-Cap, Ad-CD40L-Cap, Ad-Cap-GMCSF, and Ad-CD40L-Cap-GMCSF were successfully constructed. Indirect ELISA and virus neutralizing assay showed that CD40L and GMCSF could enhance humoral immune responses, and PCV2 Cap-specific antibody titer and neutralizing activities were significantly higher in Ad-CD40L-Cap-GMCSF group than that in the other groups that just inserted either porcine CD40L or GMCSF in recombinant adenoviruses. Moreover, lymphocyte proliferation assay and cytokine release assay showed that CD40L and GMCSF enhanced the cellular immune responses of Ad-Cap, and had synergistic effects in lymphocyte proliferative activities and Th1-type cytokine production. Following PCV2 challenge, the viral loads in lungs of Ad-CD40L-Cap GMCSF group were significantly lower compared with Ad-Cap, Ad-CD40L-Cap, and Ad Cap-GMCSF group. Taken together, the results of this study demonstrated that CD40L and GMCSF could synergistically enhance the protective immune responses of PCV2 adenovirus vaccine, which would be used as a potent vaccine for the prevention and control of PCVAD. PMID- 26982653 TI - Successful Implementation of a Program for Increasing Donor Eyes for Research: The Duke-Miracles In Sight Program. AB - PURPOSE: Although essential for development of ocular therapeutics, the quality and quantity of human donor eyes for research have been on the decline. To streamline procurement protocols, provide better medical documentation of tissue, and improve freshness and number of eyes, a pilot cooperative program was undertaken between the Duke University Eye Center and Miracles In Sight Eye Bank. METHODS: For research eye donors who expire at Duke University Hospital, age restrictions to procurement were lifted, access to donors' electronic medical records was granted to researchers, and eye tissue was delivered directly to scientists. The number of eye pairs received per month and the time from death to arrival in the laboratory were documented, and independent-samples t-tests were used to compare the number of paired eyes and the death-to-laboratory time before and after implementation of the program. A cost analysis of the program was also conducted. RESULTS: Implementation of the program decreased the time from death to arrival in the laboratory from an average of 22.1 +/- 1.5 h (n = 22) to 11.6 +/- 0.8 h (n = 75) for a pair of eyes (P < 0.0001). Moreover, the number of whole eye pairs increased from 1.57 +/- 0.32 to 3.26 +/- 0.27 donors per month (P = 0.0019). Cost analysis indicates that our program is financially viable and sustainable for the eye bank. CONCLUSIONS: The Duke-Miracles In Sight Program implemented a number of operational changes that resulted in improved quantity and quality of ocular tissue to researchers. Such a model appears feasible for adoption between other eye centers and eye banks. PMID- 26982654 TI - The protective role of long-term meditation on the decline of the executive component of attention in aging: a preliminary cross-sectional study. AB - Life expectancy is constantly increasing. However, a longer life not always corresponds to a healthier life. Indeed, even normal aging is associated with a decline in different cognitive functions. It has been proposed that a central mechanism that could contribute to this widespread cognitive decline is an ineffective inhibitory attentional control. Meditation, to the other hand, has been associated, in young adults, to enhancement of several attentional processes. Nevertheless, attention is not a unitary construct. An influent model proposed the distinction of three subsystems: the alerting (the ability to reach and maintain a vigilance state), the orienting (the capacity of focusing attention on a subset of stimuli), and the conflict resolution or executive component (the ability to resolve conflict or allocate limited resources between competing stimuli). Here, we investigated, employing the Attentional Network Task (ANT), the specific impact of age on these three subcomponents, and the protective role of long-term meditation testing a group of older adults naive to meditation, a group of age-matched adults with long-term practice of meditation, and a group of young adults with no previous meditation experience. We reported a specific decline of the efficiency of the executive component in elderly that was not observed in age-matched meditators. Our results are encouraging for the investigation of the potential beneficial impact of meditation on other cognitive processes that decline in aging such as memory. Moreover, they could inform geriatric healthcare prevention and intervention strategies, proposing a new approach for cognitive remediation in elderly populations. PMID- 26982656 TI - Breastmilk-Derived Mesenchymal Stem Cells In Vitro Are Likely to Be Mediated Through Epithelial-Mesenchymal Transition. PMID- 26982655 TI - Structural Abnormalities in the Hair of a Patient with a Novel Ribosomopathy. AB - We report the biophysical characterization of hair from a patient with a de novo ribosomopathy. The patient was diagnosed with a mutation on gene RPS23, which codes for a protein which comprises part of the 40S subunit of the ribosome. The patient presents with a number of phenotypes, including hypotonia, autism, extra teeth, elastic skin, and thin/brittle hair. We combined optical microscopy, tensile tests, and X-ray diffraction experiments on hair samples obtained from the scalp of the patient to a multi-scale characterization of the hair from macroscopic to molecular length scales and observe distinct differences in the biophysical properties in the patient's hair when compared to hair from other family members. While no differences were observed in the coiled-coil structure of the keratin proteins or the structure of the intermediate filaments, the patient's hair was 22% thinner, while the Young's modulus remained roughly constant. The X-ray diffraction results give evidence that the amount of lipids in the cell membrane complex is reduced by 20%, which well accounts for the other observations. The pathologies characterized by these techniques may be used to inform the diagnosis of similar de novo mutations in the future. PMID- 26982658 TI - Prevalence of Occlusal Traits in the Deciduous Dentition of Children of Kaski District, Nepal. AB - INTRODUCTION: The prevalence of occlusal traits varies among various populations. Ethnic, genetic and environmental factors are the major contributors, with a role in the specific cause of malocclusion. The aim of this epidemiological study was to assess the prevalence of occlusal traits in the deciduous dentition of children of Kaski District,Nepal. METHODS: A total of 506 children (251 girls, 255 boys), aged 3-5 years, were assessed. The occlusion examination was carried out by three examiners, in the school camps,community dental care centre and general health camps, utilizing a mouih mirror and probe. Intra investigator error was calculated using kappa statistics. The data were analyzed by the statistical program SPSS version 17 using the Chi-square test. RESULTS: The present study studied occlusal traits of 506 children (251 girls, 255 boys), aged 3-5 years. The study result showed that bilateral mesial step seen in 40.3%,bilateral flush terminal plane in 33.5%, bilateral distal steps in 8.5%,mesial step one side and flush terminal other side in 12.7%,mesial step one side and distal step other side in 2.6%,flush terminal one side and distal step other side in 2.4%,anterior crossbite in 3%,posterior crossbite in 0.4% and non spaced dentition in 20% children. CONCLUSIONS: Mesial step was the most prevalent followed by straight terminal plane and the distal terminal plane showed least prevalence. There were diverse traits for malocclusion. There was no significant difference(p>0.05) in occlusal traits between male and female children. PMID- 26982657 TI - Predicting Structures of Ru-Centered Dyes: A Computational Screening Tool. AB - Dye-sensitized solar cells (DSCs) represent a means for harvesting solar energy to produce electrical power. Though a number of light harvesting dyes are in use, the search continues for more efficient and effective compounds to make commercially viable DSCs a reality. Computational methods have been increasingly applied to understand the dyes currently in use and to aid in the search for improved light harvesting compounds. Semiempirical quantum chemistry methods have a well-deserved reputation for giving good quality results in a very short amount of computer time. The most recent semiempirical models such as PM6 and PM7 are parametrized for a wide variety of molecule types, including organometallic complexes similar to DSC chromophores. In this article, the performance of PM6 is tested against a set of 20 molecules whose geometries were optimized using a density functional theory (DFT) method. It is found that PM6 gives geometries that are in good agreement with the optimized DFT structures. In order to reduce the differences between geometries optimized using PM6 and geometries optimized using DFT, the PM6 basis set parameters have been optimized for a subset of the molecules. It is found that it is sufficient to optimize the basis set for Ru alone to improve the agreement between the PM6 results and the DFT results. When this optimized Ru basis set is used, the mean unsigned error in Ru-ligand bond lengths is reduced from 0.043 to 0.017 A in the set of 20 test molecules. Though the magnitude of these differences is small, the effect on the calculated UV/vis spectra is significant. These results clearly demonstrate the value of using PM6 to screen DSC chromophores as well as the value of optimizing PM6 basis set parameters for a specific set of molecules. PMID- 26982659 TI - Effect of Gender and Body Weight on Postprandial Glucose and Lipid Metabolism in Adults with Type 2 Diabetes. AB - INTRODUCTION: The magnitude of the healthcare problem of type-2-diabetes increases according to its association with several risk factors for cardiovascular diseases such as obesity and dyslipidemia. METHODS: This study took place in the north-western region of Algeria. We aimed to assess the effect of body weight and gender on postprandial lipid and glucose in type-2-diabetes patients. 93 diabetic patients (age 55.65+/-13.81 years) were studied. Anthropometric parameters and body mass index (BMI) were measured. Fasting and postprandial (PP) glucose and lipid (total cholesterol, HDLcholesterol, LDL cholesterol, triglycerides, apo A-I and apo B) profiles were evaluated. RESULTS: There were a positive correlation between postprandial glucose and BMI in women (r2 = 0.041). Negative correlation with BMI was noticed for PP TG in both males (r2 = 0.011) and females (r2 = 0.021). A significant difference (p= 0.019) was observed for PP HDL-c in women (0.39 +/- 0.10 g/L vs. men 0.33 +/- 0.12 g/L) and also for PP apo A-I (women: 1.33 +/- 0.27 g/L vs. men: 1.09 +/- 0.34 g/L; p= 0.0003). According to gender and weight groups, our results indicated that female gender and overweight are associated with elevated PP HDL-c and PP apo A-I levels. However, obesity in women is related to high concentration of PP TG. CONCLUSIONS: The present study suggests that gender difference and weight classes are important factors that contribute to determining the postprandial responses, both for glucose and lipids, in type 2 diabetic patients. PMID- 26982660 TI - Emergency Department Overcrowding in Turkey: Reasons, Facts and Solutions. AB - INTRODUCTION: The purpose of this study was to determine the factors affecting the long waiting times of the patients in a university hospital. METHODS: This study included 3000 of the adults above 18 years and pediatric trauma patients under 18 years who applied to emergency department between February 2009 and April 2009. The examination period of the physician, length of stay, length of hospitalization, waiting times for hospitalization and follow up times in the emergency department were recorded. Moreover, the patients were divided into four groups according to the reasons for waiting. RESULTS: In our study, the time period between 4 pm-12 pm was determined as the busiest time for the applications. Average length of stay in the emergency department for 3000 patients was 146.7+/-160.2 minutes. The length of stay for the patients consulted was longer than the length of stay for the ones who were not consulted. Because of the fact that our hospital did not have appropriate bed capacity, 41.1% of the patients waited less than two hours, 13. 4% of the patients waited more than 8 hours. It was also found that the waiting times of the Group two patients (206,7+/-145,2 minutes) was longer than Group one (95,5+/-73,9 minutes) patients and the waiting times of Group three patients (470,7+/-364,7 minutes) was longer than Group one patients. CONCLUSIONS: In conclusion, cooperation of the managers, relevant departments and a multidisciplinary approach are necessary to achieve the goals to reduce overcrowding in the emergency departments. PMID- 26982661 TI - Clinico-microbiological Profile and Visual outcome in Traumatic Endophthalmitis following Pars Plana Vitrectomy at a Tertiary Eye Care Centre of Nepal. AB - INTRODUCTION: Endophthalmitis is a potentially devastating ocular complication of perforating eye injury (PEI) where prompt intervention can save some vision. This study aims to explore the clinico-microbiologic profile and visual outcome following pars plana vitrectomy (PPV) in traumatic endophthalmitis. METHODS: This is a retrospective interventional case series study conducted at a tertiary eye care centre of Nepal. A total of 49 consecutive cases (49 eyes) of endophthalmitis following PEI, who underwent PPV from January 2007 to June 2010 were included in the study. RESULTS: Mean age was 14.7 years (S.D. 14.27). Twenty seven patients (55%) were of age group below 10 years. Male to female ratio was 2.75:1. Mean duration of presentation was 8.9 days. Nineteen eyes (36.73%) had injuries with wooden sticks, followed by injury with metallic objects in 16 patients (32.56%). PEI involving zone I was found in 31 eyes (63.25%). The retained intraocular foreign body was found in seven patients (14.2%). The post operative vision improved in almost 24 cases (49%) with visual recovery of 20/200 and better in six cases (12.24%). The vitreous culture was positive in five cases (12.8%) with predominant streptococcus pneumonia in four cases (10.25%). CONCLUSIONS: Children were the mostly affected group with males outnumbering females. Wooden sticks and metallic objects were the commonest insulting agents. Despite the late presentation and predominant zone I injury, eye could be salvaged in majority with visual recovery of 20/200 and better in six cases (12.24%). PMID- 26982662 TI - Effect of Physical Exercise on some Hematological Parameters in Female Athletes in Bangladesh. AB - INTRODUCTION: Long term physical training has been considered to adversely affect the performance of athletes especially the females. It may be due to the iron depletion caused by hemolysis or hemodilution results from plasma volume expansion. This study aims to assess the effect of heavy exercise on hemoglobin concentration and some other hematological parameters in female athletes. METHODS: This cross sectional study was carried out in the Department of physiology, Dhaka Medical College, Dhaka, from July 2010-June 2011. A total number of 105 females (70 athletes and 35 non athletes) between 15-25 years of age were recruited. The 35 apparently healthy female non athletes were taken as control (Group-A) and 70 female athletes comprise the study group (Group-B). According to sporting category, Group-B was further subdivided as B1:Runners and B2:Cyclists. Hemoglobin percentages (Hb %), red blood cell (RBC) concentration, packed cell volume (PCV), serum iron, serum ferritin and total iron binding capacity (TIBC) were measured in fasting state after two months training. Statistical analysis was done by using SPSS/ win.15.0 for comparison between the groups, using student's unpaired "t" test. RESULTS: Mean Hb%, RBC, PCV, iron and ferritin level were significantly (P<0.001) lower in athletes than those of control group. Within the study groups, runner's serum iron and ferritin level were lower than cyclists. TIBC significantly (P<0.001) rose in Group-B2 in comparison to Group-A. CONCLUSIONS: The current study showed that intense physical exercise leads to early stages of Hb%, RBC, PCV, iron and ferritin depletion which might compromise the health and performance of athletes. PMID- 26982663 TI - Frontalis Sling Operation using Silicone Rod Compared with Autogenous Fascia Lata for Simple Congenital Ptosis. AB - INTRODUCTION: To evaluate the cosmetic results and recurrence of unilateral frontalis sling surgery using a silicone rod compared with autogenous fascia lata in cases of simple congenital ptosis. METHODS: This is a retrospective comparative study of 59 patients who underwent a frontalis sling operation for congenital ptosis. Patients were divided into two groups according to the sling material used; an autogeneous fascia lata (fl) group (n = 24) and a silicone rod group (sl) (n = 35). Cosmetic results and recurrence rates were compared between these 2 groups. The cosmetic results of the frontalis sling operation were assessed as good, fair, or poor based on the difference between the Margin Reflex Distance (MRD) of both eyelids and graded as good if the difference in two eyes was <=1mm and poor if it was 2mm or more. Recurrence was defined as the conversion of the cosmetic result from good or fair to poor category. RESULTS: At postoperative day seven and 30, MRD of both the groups were good but on three months follow-up MRD of silicon rod group dropped, however it was not statistically significant .Lid contour was good in both the groups, however, lid symmetry was poor in two cases of fascia lata at three months follow-up. Repeat surgery for poor outcome was done in 8.6% of cases in silicon rod and 8.3% of fascia lata group. CONCLUSIONS: The frontalis sling operation using either a silicone rod or autogenous fascia lata showed equally good cosmetic results and lower recurrence rate at three months follow up. PMID- 26982664 TI - Screening for Oral Cavity Cancer: A 1-year Experience of a Regional Hospital in Taiwan. AB - INTRODUCTION: The purpose of this study was to analyze the risk factors affecting precancerous lesions, and cancer of oral cavity, and to assess efficacy of visual screening for oral mucosal lesions. METHODS: The medical records of patients older than 30 years of age with history of habitual cigarette smoking or betel quid chewing that received screening for oral mucosal lesions between January 2012 and December 2012 were retrospectively reviewed. The patients' age, gender, risk factors, screening findings, and histopathology results of biopsy were included for further analysis. RESULTS: A total of 1341 patients were enrolled in this study. There were 1080 males and 261 females ranging from 30 to 96 years of age, with a mean age of 53.9+/-13.6 years. After screening, 226 (16.9%) were found to be positive of oral lesions. Among these 226 patients, 69 (30.5%) underwent biopsy under local anesthesia, and the histopathology showed malignancy in 13 (5.8%). All of the confirmed malignant cases were squamous cell carcinoma. Among them, 12 received further staging examination and one was lost to follow-up resulting in unknown stage. The early stage oral cavity cancer (stage I and II) accounted for 84.6% (11/13). CONCLUSIONS: The detection rate of early stage oral cavity cancer in our study was reasonable. Therefore, visual screening for oral cavity cancer is recommended for patients with habitual cigarette smoking or betel quid chewing. PMID- 26982665 TI - Clinical Profile, Dyslipidemia and ACS - a Correlation. AB - INTRODUCTION: To analyze lipid profile in patients with ACS, and to study the pattern of the involvement and complication in ACS. METHODS: Hundred and eight consecutive cases of ACS, attending the CCU of Tribhuvan University Teaching Hospital fulfilling the criteria, were taken for the present study. Patient from age 30 and older were studied. All cases were scrutinized to detail serial 12 lead EKG, serial cardiac biochemical markers, laboratory test, echocardiographic study. Design of the study was carried out in prospective, cross sectional study. RESULTS: Hyperlipidemia was present in 61% of the patients. Only 27% of them were on statins. Most of them had high cholesterol level 68%, high Tgl level 75%, Ldl 50%, where as <40 Hdl (93%) patient were found to be low. 40% was found to have UAP. In addition patient with hypertension (76%) diabetes (65%) also had comorbidity for obesity 35%, and lipid abnormalities 75% for triglycerides, 66% for TC, 50% for LDL-C, 93% for low HDL-C, and a family history of CAD in 57%. CONCLUSIONS: The outcome of this study showed that the majority are male, relatively younger as compared to Western population. USA and STEMI were the dominant types of ACS. Strong correlations between TC, LDL-C, and low HDL-C in patient with ACS were noted. Majority of patients had hypertension, IHD in their families and Hyperlipidemia diabetes, smoking as the major risk factors. Better control of risk factors and the awareness of preventive strategies are needed. PMID- 26982666 TI - Prevalence of Conventional Risk Factors in ST Segment Elevation Myocardial Infarction Patients in Shahid Gangalal National Heart Centre, Nepal. AB - INTRODUCTION: Smoking, diabetes mellitus, hypertension, and dyslipidemia are labelled as conventional risk factors for coronary artery disease. Prevalence of these risk factors varies across populations. This study aimed to assess the prevalence of these conventional risk factors in patients, who were discharged from our hospital, with the diagnosis of ST elevation myocardial infarction. METHODS: Medical records of 495 ST elevation myocardial infarction patients discharged from our centre in between January 2012 to December 2012 were retrospectively reviewed to evaluate the prevalence of conventional risk factors. RESULTS: Clear dominance (75%) of male patients was seen. Inferior wall myocardial infarction (29.9%) was the most common diagnosis followed by anterior wall myocardial infarction (25.1%). Hypertension (65%), smoking (57.8%) and dyslipidemia (45.5%) were the most common risk factors. Diabetes (31.1%) was the least common. Prevalence of hypertension, dyslipidemia was similar among male and female. Smoking was statistically common in male (76.8%vs 49.5%),though diabetes was common in female (36.5%vs.29.3%) not statistically significant. CONCLUSIONS: Conventional risk factors are common among ST elevation myocardial infarction patients. Early detection and treatment of these risk factors play a vital role for the prevention of coronary artery disease. Much more focus should be stressed on preventive programs throughout the country. PMID- 26982667 TI - Effect of Dexamethasone and Pheniramine Maleate in Patients Undergoing Elective Laparoscopic Cholecystectomy. AB - INTRODUCTION: Laparoscopic cholecystectomy (LC) is elective surgical procedure for uncomplicated gallstone disease and gallbladder polyp. The objective of this study was to assess the efficacy of Dexamethasone and Pheniramine hydrogen maleate on reducing stress response and pain after surgery in patients undergoing laparoscopic cholecystectomy. METHODS: After obtaining approval from the institutional ethics committee and written informed consent, 120 patients undergoing elective laparoscopic cholecystectomy were enrolled in the study from Sep 2103 to Aug 2014 at Department of Surgery, Manipal College of Medical Sciences, Pokhara, Nepal. Patients were randomized to receive either 8mg/2ml of Dexamethasone + 45.5/2ml Pheniramine hydrogen maleate (treatment group, n= 60) or 5 ml of normal saline (control group, n=60) 90 minutes before skin incision. RESULTS: There was a reduction of total bilirubin, C-reactive protein (CRP) value and Visual Analogue Score (VAS) in treatment group as compared to control group (p <0.05). CONCLUSIONS: Use of Dexamethasone and Pheniramine hydrogen maleate prior to surgical skin incision helps to reduce both postoperative pain and acute physiological stress. PMID- 26982668 TI - Construction and Validation of a Women's Autonomy Measurement Scale with Reference to Utilization of Maternal Health Care Services in Nepal. AB - INTRODUCTION: Women's autonomy is one of the predictors of maternal health care service utilization. This study aimed to construct and validate a scale for measuring women's autonomy with relevance to developing countries. METHODS: We conducted a study for construction and validation of a scale in Rupandehi and further validated in Kapilvastu districts of Nepal. Initially, we administered a 24-item preliminary scale and finalized a 23-item scale using psychometric tests. After defining the construct of women's autonomy, we pooled 194 items and selected 24 items to develop a preliminary scale. The scale development process followed different steps i.e. definition of construct, generation of items pool, pretesting, analysis of psychometric test and further validation. RESULTS: The new scale was strongly supported by Cronbach's Alpha value (0.84), test-retest Pearson correlation (0.87), average content validity ratio (0.8) and overall agreement- Kappa value of the items (0.83) whereas all values were found satisfactory. From factor analysis, we selected 23 items for the final scale which show good convergent and discriminant validity. From preliminary draft, we removed one item; the remaining 23 items were loaded in five factors. All five factors had single loading items by suppressing absolute coefficient value less than 0.45 and average coefficient was more than 0.60 of each factor. Similarly, the factors and loaded items had good convergent and discriminant validity which further showed strong measurement capacity of the scale. CONCLUSIONS: The new scale is a reliable tool for assessing women's autonomy in developing countries. We recommend for further use and validation of the scale for ensuring the measurement capacity. PMID- 26982670 TI - A Giant Urethral Calculus. AB - Urethral calculi are rare forms of urolithiasis. Majority of the calculi are migratory from urinary bladder or upper urinary tract. Primary urethral calculi usually occur in presence of urethral stricture or diverticulum. In this article we report a case of a giant posterior urethral calculus measuring 7x3x2 cm in a 47 years old male. Patient presented with acute retention of urine which was preceded by burning micturition and dribbling of urine for one week. The calculus was pushed in to the bladder through the cystoscope and was removed by suprapubic cystolithotomy. PMID- 26982671 TI - Crossed Testicular Ectopia. AB - Crossed testicular ectopia also known as transverse testicular ectopia is a rare anomaly of the testis which is ectopically located in contralateral hemiscrotum with absent testis in the ipsilateral hemiscrotum. Most case are incidentally discovered intraopeartively during operation of inguinal hernia and few case reports are available which have reported preoperative diagnosis of crossed testicular ectopia. We report a case of crossed testicular ectopia in 12 year old boy who presented with right undescended testis diagnosed preoperative on Ultrasound and Magnetic Resonance Imaging as crossed testicular ectopia. PMID- 26982669 TI - Status of Vitamin D and its Association with Stroke Risk Factors in Patients with Acute Ischemic Stroke in a Tertiary Care Hospital. AB - INTRODUCTION: Vitamin D deficiency has been associated with many neurological illnesses. The status of Vitamin D in Nepalese ischemic stroke patients is still unknown. This study aims to assess the status of vitamin D and its association with stroke risk factors in patients with acute ischemic stroke from Central Nepal. METHODS: A total of 60 patients with ischemic stroke were included in the study. Their clinical profile and Vitamin D status were assessed. Frequency distribution, Pearson chi2test and Kruskal-Wallis test were performed for statistical analysis using SPSS-IBM 20. RESULTS: The median (IQR) age of the patient was 65 (53.25, 70.75) years, ranging from 18-87 years. Thirty-four (56.7%) were males. Fourty-eight (80%) patients had hypertension and 34 (56.7%) were smoker. Previous stroke was present in six (10%) cases. Thirty-seven (61.6%) patients had low levels of Vitamin D out of which 26 (43.3%) had vitamin D insufficiency and 11 (18.3%) had vitamin D deficiency. Vitamin D level was significantly associated with previous history of stroke (P=0.043). CONCLUSIONS: Vitamin D deficiency occurs in patients with ischemic stroke. Previous episodes of stroke with low vitamin D levels could be a cause of recurrent strokes. Further studies are necessary to establish the role of vitamin D in acute ischemic stroke in Nepalese population. PMID- 26982672 TI - Uncommon course of the ulnar artery through the pronator teres muscle. AB - In this paper, we describe a very rare variant in the course of the ulnar artery that we encountered in dissecting the right upper limb of a 74-year-old man. The ulnar artery arose standardly from the brachial artery in the cubital fossa. However, its ensuing course differed from the norm. The artery entered together with the ulnar vein and median nerve into the pronator canal (between the humeral and ulnar heads of the pronator teres). Further, the ulnar artery descended classically to the ulnar side of the forearm between the flexor carpi ulnaris and flexor digitorum superficialis. Knowledge of this variation in the course of the ulnar artery may have significance in clinical practice because accumulation of anatomical structures in the pronator canal could be a predisposing factor for the compression of nerve or blood vessels. PMID- 26982673 TI - Unusual Presentation of Lacrimal Gland Pleomorphic Adenoma. AB - The pleomorphic adenoma of lacrimal gland presents as a painless, progressive, slowly growing supero-temporal swelling with variable proptosis. This tumor is usually found in adults and extremely rare in teenage. We report a case of a 15 year-old boy with pleomorphic adenoma of lacrimal gland which mimicked pseudotumor of orbit due to its presentation as an orbital inflammatory disease and the age distribution. Neuroimaging also suggested pseudotumor and oral steroid was started. But, there was no improvement on steroids and ultrasound guided Fine Needle Aspiration Cytology (FNAC) was performed which suggested Pleomorphic adenoma of the lacrimal gland. En-bloc excision of the mass through antero-lateral orbitotomy was done with satisfactory final outcome The histopathological evaluation was consistent with pleomorphic adenoma of the lacrimal gland. PMID- 26982674 TI - Radiation induced myxoma of superior vena cava origin presenting as a right atrial mass. AB - Myxomas are the most common benign cardiac tumors. Myxomas are more common in the left heart chamber than the right side chamber. An extracardiac origin presenting as a right atrial mass is very rare. Right-sided tumors are considerably less common than left-sided tumors, and however myxoma of great vessels origin presenting as right atrial masses are rare but radiation induced villous myxoma in superior vena cava (SVC) is exceedingly rare tumor. A case of radiation induced myxoma originating in a previously undescribed location and presenting as a right atrial mass is reported. PMID- 26982675 TI - A Rare Case of Multiorgan Involvement of Rosai Dorfman Disease in an Elderly Female. AB - Sinus histiocytosis with massive lymphadenopathy (SHML), Rosai-Dorfman Disease, is a rare histiocytic syndrome first described by Rosai and Dorfman, most frequently seen in children and young adults.The disease is more common in males and in individuals of African descent but rare in Asians. It is mainly characterized by painless bilateral cervical lymph node enlargement and is often associated with fever and leucocytosis. This case is being reported for its rarity in presentation in an elderly female with both generalized nodal as well as extranodal manifestations. Without the awareness about RDD, the diagnosis of RDD is unexpected especially in South East Asian Countries where certain lymphadenopathies such as tuberculosis, metastatic malignancies and lymphomas are common. PMID- 26982676 TI - Restoration of finger and thumb movement using one-stage free muscle transplantation. AB - OBJECTIVE: Functional reconstruction following severe traumatic muscle loss may cause problems for reconstructive surgeons. In such situations, functioning free muscle transplantation (FFMT) represents an important alternative treatment option. METHODS: The clinico-demographic characteristics of 11 patients receiving modified FFMT between 2005-2013 were retrospectively reviewed. The muscle strength, range of joint motion (ROM), total active motion (TAM) of the fingers, and Disability of Arm Shoulder and Hand (DASH) score were adopted to assess the functional results. RESULTS: All FFMTs were performed in the secondary stage. The authors found that the mean ROM, TAM, ratio of TAM compared with the contralateral side, and DASH score were 112 degrees, 150 degrees, 62%, and 22.8, respectively; and eight and nine patients achieved greatly improved grip function and M4 muscle strength, respectively. CONCLUSION: Using one-stage free muscle transplantation to restore finger and thumb movement simultaneously is an effective method for functional restoration following traumatic multi-muscle loss. PMID- 26982678 TI - Three-dimensional MR Cholangiopancreatography in a Breath Hold with Sparsity based Reconstruction of Highly Undersampled Data. AB - Purpose To develop a three-dimensional breath-hold (BH) magnetic resonance (MR) cholangiopancreatographic protocol with sampling perfection with application optimized contrast using different flip-angle evolutions (SPACE) acquisition and sparsity-based iterative reconstruction (SPARSE) of prospectively sampled 5% k space data and to compare the results with conventional respiratory-triggered (RT) acquisition. Materials and Methods This HIPAA-compliant prospective study was institutional review board approved. Twenty-nine patients underwent conventional RT SPACE and BH-accelerated SPACE acquisition with 5% k-space sampling at 3 T. Spatial resolution and other parameters were matched when possible. BH SPACE images were reconstructed by enforcing joint multicoil sparsity in the wavelet domain (SPARSE-SPACE). Two board-certified radiologists independently evaluated BH SPARSE-SPACE and RT SPACE images for image quality parameters in the pancreatic duct and common bile duct by using a five-point scale. The Wilcoxon signed-rank test was used to compare BH SPARSE-SPACE and RT SPACE images. Results Acquisition time for BH SPARSE-SPACE was 20 seconds, which was significantly (P < .001) shorter than that for RT SPACE (mean +/- standard deviation, 338.8 sec +/- 69.1). Overall image quality scores were higher for BH SPARSE-SPACE than for RT SPACE images for both readers for the proximal, middle, and distal pancreatic duct, but the difference was not statistically significant (P > .05). For reader 1, distal common bile duct scores were significantly higher with BH SPARSE-SPACE acquisition (P = .036). More patients had acceptable or better overall image quality (scores >= 3) with BH SPARSE-SPACE than with RT SPACE acquisition, respectively, for the proximal (23 of 29 [79%] vs 22 of 29 [76%]), middle (22 of 29 [76%] vs 18 of 29 [62%]), and distal (20 of 29 [69%] vs 13 of 29 [45%]) pancreatic duct and the proximal (25 of 28 [89%] vs 22 of 28 [79%]) and distal (25 of 28 [89%] vs 24 of 28 [86%]) common bile duct. Conclusion BH SPARSE-SPACE showed similar or superior image quality for the pancreatic and common duct compared with that of RT SPACE despite 17-fold shorter acquisition time. ((c)) RSNA, 2016. PMID- 26982679 TI - Health problems among nursing workers in a haemodialysis service. AB - Objective The aim was to measure work-related health problems among nursing workers at a haemodialysis unit in southern Brazil and associate these issues with the socio-occupational characteristics of the workers. Method This is a qualitative study conducted with 46 nursing workers. Data were collected using a general health questionnaire with socio-occupational information and a work related health assessment scale. The data were subjected to descriptive, correlational, bivariate analysis with significance levels of 5% using Epi info(r) and Predictive Analytics Software. Results Physical, psychological, and social problems were considered bearable, and job satisfaction was associated with current income and work absenteeism for health treatment (p< 0.05). Back pain (3.74 +/- 2.04) and leg pain (3.48 +/- 2.10) were considered severe. There was a direct correlation between the health issues (r> 0.31, p <0.05). Conclusion In spite of the positive results of the work-related health assessment among the studied population, the results confirm the need to promote the health of nursing workers. PMID- 26982677 TI - Three-dimensional Radiologic Assessment of Chemotherapy Response in Ewing Sarcoma Can Be Used to Predict Clinical Outcome. AB - Purpose To compare the agreement of three-dimensional (3D) tumor measurements for therapeutic response assessment of Ewing sarcoma according to the Children's Oncology Group (COG) criteria, one-dimensional (1D) Response Evaluation Criteria in Solid Tumors (RECIST), and two-dimensional (2D) measurements defined by the World Health Organization (WHO) with tumor volume measurements as the standard of reference and to determine which method correlates best with clinical outcomes. Materials and Methods This retrospective study was approved by the institutional review board of three institutions. Seventy-four patients (mean age +/- standard deviation, 14.5 years +/- 6.5) with newly diagnosed Ewing sarcoma treated at three medical centers were evaluated. Primary tumor size was assessed on pre- and posttreatment magnetic resonance images according to 1D RECIST, 2D WHO, and 3D COG measurements. Tumor responses were compared with the standard of reference (tumor volume) on the basis of RECIST, COG, and WHO therapeutic response thresholds. Agreement between the percentage reduction measurements of the methods was assessed with concordance correlation, Bland-Altman analysis, and Spearman rank correlation. Agreement between therapeutic responses was assessed with Kendall tau and unweighted kappa statistics. Tumor responses were compared with patient survival by using the log-rank test, Kaplan-Meier plots, and Cox regression. Results Agreement with the reference standard was significantly better for 3D measurement than for 1D and 2D measurements on the basis of RECIST and COG therapeutic response thresholds (concordance correlation of 0.41, 0.72, and 0.84 for 1D, 2D, and 3D measurements, respectively; P < .0001). Comparison of overall survival of responders and nonresponders demonstrated P values of .4133, .0112, .0032, and .0027 for 1D, 2D, 3D, and volume measurements, respectively, indicating that higher dimensional measurements were significantly better predictors of overall survival. Conclusion The 3D tumor measurements according to COG are better predictors of therapeutic response of Ewing sarcoma than 1D RECIST or 2D WHO measurements and show a significantly higher correlation with clinical outcomes. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 26982680 TI - Socioeconomic and regional inequalities of pap smear coverage. AB - Objectives To identify socioeconomic and regional inequalities of pap smear coverage in the state of Rio Grande do Sul. Methods An ecological study based on data of the 2011-2012 national health information system to estimate the annual coverage of pap smears for the overall female population of the state and for women without private health insurance. We estimated annual pap smear coverage according to the Municipal Social Vulnerability Index and health macro-regions and regions of the state. Results The percentage of women without private health insurance ranged from 38.1% to 94.2% in the health regions. Pap smear coverage was 17.3% for the overall female population and 23.8% for women without private health insurance. Pap smear coverage was higher in more socially vulnerable municipalities and regions with a higher percentage of women with private health insurance. Conclusions The prevalence of private health insurance should be considered in studies that address the coverage of the Brazilian Unified Health System (SUS). PMID- 26982681 TI - Children and adolescents living with diabetes and celiac disease. AB - Objective To understand the experience of children and adolescents living with type 1 diabetes and celiac disease. Method This is a qualitative exploratory descriptive study. The participants were 3 children and 2 adolescents. The data were collected by means of semi-structured interviews between January and September 2012 at the participant's residence or at the diabetic outpatient clinic of the Hospital das Clinicas, Faculty of Medicine, University of Sao Paulo in Sao Paulo, Brazil. The content analysis technique was used to process the data. Results The key aspect of the illness experience of the patients was their diet, but with different meanings. The children had difficulty following the diet, while the adolescents reported that they had greater difficulty coping with the social and affective aspects of their diet. Conclusion The results reinforce the importance of nurses who seek strategies, together with the patients and their families, that help minimize the difficulties of these patients, especially with regard to managing the diet imposed by both diseases. PMID- 26982682 TI - Terms used by nurses in the documentation of patient progress. AB - Objective Describe the terms used in written records of patients' progress by nurses. Methods Descriptive research with a quantitative method that used a software to extract terms related to 148,200 nursing documentations of patient's progress, from 2010 to 2012, in a university hospital in Curitiba - Parana. The terms were normalized, if appropriate, in spelling, gender, number and tense; then corpus of 2.638 terms was classified for analysis. Results There were problems related to the identification of the records; the use of trade names for designating artifacts used in the nursing practice; unconventional acronyms and abbreviations; and colloquial terms. Records of terms contained in standardized language of nursing diagnoses were found. Conclusion The language used by nurses is heterogeneous. There is a tendency to use terms of specialized language, even when there is no formal terminology standardization in the institution. PMID- 26982683 TI - Information needs of family caregivers regarding liver transplant candidates. AB - Objective To assess the information needs of family caregivers of candidates on the waiting list for a liver transplant. Methods It is a cross-sectional study conducted in a transplant center in Sao Paulo State in the period between April and October of 2012. For the assessment of information needed, an instrument submitted to face and content value was used. The caregivers put 10 subjects in order according to their importance and the amount of interest they had in learning about each, prior to the transplant their family member would be subjected to. Sociodemographic characteristics were also recorded. For data analysis, descriptive statistics were used. Results 42 families participated in the study. The information need about liver disease complications, complications after transplantation and care needed after surgery had higher averages. Conclusions Knowing the information needs of caregivers is important to plan teaching-learning strategies aimed at improving assistance to patients and families in transplant programs. PMID- 26982684 TI - Morphological Expression of the Coherence and Relative Phase of Optical Inputs to the Photoelectrodeposition of Nanopatterned Se-Te Films. AB - Highly anisotropic and ordered nanoscale lamellar morphologies can be spontaneously generated over macroscopic areas, without the use of a photomask or any templating agents, via the photoelectrodeposition of Se-Te alloy films. To form such structures, the light source can be a single, linearly polarized light source that need not necessarily be highly coherent. In this work, the variation in the morphologies produced by this deposition process was evaluated in response to differences in the coherence and relative phase between multiple simultaneous linearly polarized illumination inputs. Specifically, the morphologies of photoelectrodeposits were evaluated when two tandem same-wavelength sources with discrete linear polarizations, both either mutually incoherent or mutually coherent (with defined phase differences), were used. Additionally, morphologies were simulated via computer modeling of the interfacial light scattering and absorption during the photoelectrochemical growth process. The morphologies that were generated using two coherent, in-phase sources were equivalent to those generated using only a single source. In contrast, the use of two coherent, out of-phase sources produced a range of morphological patterns. For small out-of phase addition of orthogonal polarization components, lamellar-type patterns were observed. When fully out-of-phase orthogonal sources (circular polarization) were used, an isotropic, mesh-type pattern was instead generated, similar to that observed when unpolarized illumination was utilized. In intermediate cases, anisotropic lamellar-type patterns were superimposed on the isotropic mesh-type patterns, and the relative height between the two structures scaled with the amount of out-of-phase addition of the orthogonal polarization components. Similar results were obtained when two incoherent sources were utilized. In every case, the long axis of the lamellar-type morphology component aligned parallel to the intensity-weighted average polarization orientation. The observations consistently agreed with computer simulations, indicating that the observed morphologies were fully determined by the nature of the illumination utilized during the growth process. The collective data thus indicated that the photoelectrodeposition process exhibits sensitivity toward the coherency, relative phase, and polarization orientations of all optical inputs and that this sensitivity is physically expressed in the morphology of the deposit. PMID- 26982685 TI - Difficulties in Schistosomiasis Assessment, Corsica, France. PMID- 26982691 TI - Percutaneous Microwave Ablation Liver Partition and Portal Vein Embolization for Rapid Liver Regeneration: A Minimally Invasive First Step of ALPPS for Hepatocellular Carcinoma. PMID- 26982686 TI - Does Acupuncture Treatment Affect Utilization of Other Hospital Services at an Urban Safety-Net Hospital? AB - BACKGROUND: Little is known regarding the interaction between acupuncture and biomedical healthcare among vulnerable patient populations. In particular, the association between acupuncture and total cost of healthcare has not been characterized. METHODS: Total hospital system visits and associated charges were retrospectively reviewed among patients who received acupuncture at a large safety-net hospital system from 2007 to 2014. Inclusion criteria were Medicare or Medicaid insurance coverage, older than age 18 years, and one or more on-site acupuncture appointments. Patients were stratified into five groups based on the number of acupuncture visits: 1-3, 4-6, 7-9, 10-12, or 13-15 treatments. The total number of biomedical hospital visits and total associated charges were compared 6 months before and 6 months after initiation of acupuncture. RESULTS: A total of 329 patients met our inclusion criteria. Although not statistically significant, there appeared to be an association between acupuncture treatment and a decrease in total hospital charges. The group receiving 1-3 acupuncture treatments showed a per-patient average increase in total charges in the 6-month period after acupuncture ($1771.34; p = 0.38). The patients who received 7-9 treatments showed the largest average decrease in total charges ($8967.24; p = 0.17). CONCLUSION: This study shows a previously unreported aggregate relationship between number of treatments and total healthcare charges in a single urban safety-net hospital. Given the sample size available and the heterogeneity of the patient population, no statistically significant associations could be established between initiation of acupuncture treatment and charges. However, some suggestive patterns were observed. Further prospective studies with a matched-group control are warranted to further explore this relationship. Additional study across wider locations is warranted to best guide practitioners and hospitals in designing efficacious, high-value integrative medicine programs. PMID- 26982693 TI - Serogroup-specific Seasonality of Verotoxigenic Escherichia coli, Ireland. PMID- 26982694 TI - Amikacin induced renal damage and the role of the antioxidants on neonatal rats. AB - Amikacin (AK) is frequently used on the treatment of Gram-negative infections on neonates, but its usage is restricted because of nephrotoxicity. In this study, on neonatal rats, we aimed to investigate the effects of erythropoietin and vitamin E on AK induced nephrotoxicity. A total of 35 newborn Wistar Albino rats were divided into four groups: (1) injected with saline (serum physiological was administered to placebo controls), (2) injected with AK (1200 mg/kg), (3) injected with AK + vitamin E (150 mg/kg), (4) injected with AK + erythropoietin (EPO) (300 IU/kg/day). In renal tissue, AK levels were significantly high in all groups except the control. Tissue malondialdehyde (MDA) and nitric oxide (NO) levels were statistically higher in AK -treated group than the control. MDA and NO levels were significantly decreased with the administration of vitamin E and EPO. Glutathione peroxidase (GPX) levels were statistically low in AK group compared with the controls. The levels of GPX, in vitamin E group, were increased significantly. However, superoxide dismutase and catalase levels were not significantly different in none of the groups. Insulin-like growth factor-1 values in AK, EPO and vitamin E groups were significantly higher than the control group. Histomorphological changes such as tubular epithelial necrosis were seen in AK treated group. Histopathological improvements observed with EPO and vitamin E administration. AK nephrotoxicity is related to oxidative stress and is supported with biochemical and histopathological findings. Vitamin E and EPO, as antioxidants, can be useful renoprotective agents for ameliorating AK induced nephrotoxicity in neonates. PMID- 26982695 TI - Natural and anthropogenic variations in the Po river waters (northern Italy): insights from a multi-isotope approach. AB - Po is the main Italian river and the delta(18)O and delta(2)H of its water reveal a similarity between the current meteoric fingerprint and that of the past represented by groundwater. As concerns the hydrochemisty, the Ca-HCO3 facies remained constant over the last 50 year, and only nitrate significantly increased from less than 1 mg/L to more than 10 mg/L in the 1980s, and then attenuated to a value of 9 mg/L. Coherently, delta(13)CDIC and delta(34)SSO4 are compatible with the weathering of the lithologies outcropping in the basin, while extremely variable delta(15)NNO3 indicates contribution from pollutants released by urban, agricultural and zootechnical activities. This suggests that although the origin of the main constituents of the Po river water is geogenic, anthropogenic contributions are locally significant. Noteworthy, the associated aquifers have the same nitrogen isotopic signature of the Po river, but are characterized by significantly higher NO(-) 3 concentration. This implies that aquifers' pollution is not ascribed to inflow of current river water, and that the attenuation of the nitrogen load recorded in the river is not occurring in the aquifers, due to their longer water residence time and delayed recovery from anthropogenic contamination. PMID- 26982698 TI - Awareness, Interest, and HIV Pre-Exposure Prophylaxis Candidacy Among Young Transwomen. PMID- 26982700 TI - Endothelial Cell-Immune Cell Interaction in IBD. AB - The proper delivery of immune cells throughout the host's various tissues and organs is essential to health, and abnormalities in the type and quantity of leukocyte distribution is usually associated with disease. Because of its size and presence of a very large amount of immunocytes in the mucosa and mesenteric lymph nodes, the gut is the recipient of a constant influx of leukocytes, a process tightly regulated by multiple factors. These include cell adhesion molecules on the leukocytes and their counter-receptors on the microvascular endothelial cells in the bowel wall, a number of chemokines and cytokines that help attracting immune cells, platelets, bacterial products, danger signals, the size of the vascular and lymphatic beds and the process of leukocyte exit and circulation in the blood and lymphatic fluid. The disruption of any of the above regulatory mechanism can lead to inflammation, as is the case for inflammatory bowel disease. Learning how leukocyte and endothelial cells mutually function in health and what goes wrong in inflammation offers the opportunity to intervene therapeutically and re-establish the normal crosstalk between leukocytes and endothelial cells. PMID- 26982701 TI - The Hartford Consensus revisited: Notes from the field. PMID- 26982697 TI - Cluster Randomised Trials in Cochrane Reviews: Evaluation of Methodological and Reporting Practice. AB - OBJECTIVE: Systematic reviews can include cluster-randomised controlled trials (C RCTs), which require different analysis compared with standard individual randomised controlled trials. However, it is not known whether review authors follow the methodological and reporting guidance when including these trials. The aim of this study was to assess the methodological and reporting practice of Cochrane reviews that included C-RCTs against criteria developed from existing guidance. METHODS: Criteria were developed, based on methodological literature and personal experience supervising review production and quality. Criteria were grouped into four themes: identifying, reporting, assessing risk of bias, and analysing C-RCTs. The Cochrane Database of Systematic Reviews was searched (2nd December 2013), and the 50 most recent reviews that included C-RCTs were retrieved. Each review was then assessed using the criteria. RESULTS: The 50 reviews we identified were published by 26 Cochrane Review Groups between June 2013 and November 2013. For identifying C-RCTs, only 56% identified that C-RCTs were eligible for inclusion in the review in the eligibility criteria. For reporting C-RCTs, only eight (24%) of the 33 reviews reported the method of cluster adjustment for their included C-RCTs. For assessing risk of bias, only one review assessed all five C-RCT-specific risk-of-bias criteria. For analysing C-RCTs, of the 27 reviews that presented unadjusted data, only nine (33%) provided a warning that confidence intervals may be artificially narrow. Of the 34 reviews that reported data from unadjusted C-RCTs, only 13 (38%) excluded the unadjusted results from the meta-analyses. CONCLUSIONS: The methodological and reporting practices in Cochrane reviews incorporating C-RCTs could be greatly improved, particularly with regard to analyses. Criteria developed as part of the current study could be used by review authors or editors to identify errors and improve the quality of published systematic reviews incorporating C-RCTs. PMID- 26982702 TI - Firearm injury prevention: A consensus approach to reducing preventable deaths. PMID- 26982699 TI - Magnetic Resonance Elastography of the Liver: Qualitative and Quantitative Comparison of Gradient Echo and Spin Echo Echoplanar Imaging Sequences. AB - OBJECTIVE: The aim of this study was to compare 2-dimensional (2D) gradient recalled echo (GRE) and 2D spin echo echoplanar imaging (SE-EPI) magnetic resonance elastography (MRE) sequences of the liver in terms of image quality and quantitative liver stiffness (LS) measurement. MATERIALS AND METHODS: This prospective study involved 50 consecutive subjects (male/female, 33/17; mean age, 58 years) who underwent liver magnetic resonance imaging at 3.0 T including 2 MRE sequences, 2D GRE, and 2D SE-EPI (acquisition time 56 vs 16 seconds, respectively). Image quality scores were assessed by 2 independent observers based on wave propagation and organ coverage on the confidence map (range, 0-15). A third observer measured LS on stiffness maps (in kilopascal). Mean LS values, regions of interest size (based on confidence map), and image quality scores between SE-EPI and GRE-MRE were compared using paired nonparametric Wilcoxon test. Reproducibility of LS values between the 2 sequences was assessed using intraclass coefficient correlation, coefficient of variation, and Bland-Altman limits of agreement. T2* effect on image quality was assessed using partial Spearman correlation. RESULTS: There were 4 cases of failure with GRE-MRE and none with SE-EPI-MRE. Image quality scores and region of interest size were significantly higher using SE-EPI-MRE versus GRE-MRE (P < 0.0001 for both measurements and observers). Liver stiffness measurements were not significantly different between the 2 sequences (3.75 +/- 1.87 kPa vs 3.55 +/- 1.51 kPa, P = 0.062), were significantly correlated (intraclass coefficient correlation, 0.909), and had excellent reproducibility (coefficient of variation, 10.2%; bias, 0.023; Bland-Altman limits of agreement, -1.19; 1.66 kPa). Image quality scores using GRE-MRE were significantly correlated with T2* while there was no correlation for SE-EPI-MRE. CONCLUSIONS: Our data suggest that SE-EPI-MRE may be a better alternative to GRE-MRE. The diagnostic performance of SE-EPI-MRE for detection of liver fibrosis needs to be assessed in a future study. PMID- 26982703 TI - Gunshot wounds: A review of ballistics, bullets, weapons, and myths. PMID- 26982704 TI - Sociable Weavers Increase Cooperative Nest Construction after Suffering Aggression. AB - The major transitions in evolution rely on the formation of stable groups that are composed of previously independent units, and the stability of these groups requires both cooperation and reduced conflict. Conflict over group resources may be common, as suggested by work in both cichlids and humans that has investigated how societies resolve conflict regarding investment in group resources, i.e. public goods. We investigated whether sociable weavers (Philetairus socius) use aggressive behaviors to modulate the cooperative behavior of group mates. We find that the individuals that build the communal thatch of the nest, i.e. the individuals most at risk of exploitation, are the most aggressive individuals. We show that individuals that invest in interior chamber maintenance, possibly a more selfish behavior, suffer relatively more aggression. After suffering aggression individuals significantly increase cooperative construction of the communal nest thatch. We show that cooperative individuals target aggression towards selfish individuals, and the individuals suffering aggression perform cooperative behaviors subsequent to suffering aggression. In addition to other evolutionary mechanisms, these results suggest that aggression, possibly via the pay-to-stay mechanism, is possibly being used to maintain a public good. PMID- 26982705 TI - Bullying in the American Graduate Medical Education System: A National Cross Sectional Survey. AB - OBJECTIVES: To deliver an estimate of bullying among residents and fellows in the United States graduate medical education system and to explore its prevalence within unique subgroups. DESIGN/SETTING/PARTICIPANTS: A national cross-sectional survey from a sample of residents and fellows who completed an online bullying survey conducted in June 2015. The survey was distributed using a chain sampling method that relied on electronic referrals from 4,055 training programs, with 1,791 residents and fellows completing the survey in its entirety. Survey respondents completed basic demographic and programmatic information plus four general bullying and 20 specific bullying behavior questions. Between-group differences were compared for demographic and programmatic stratifications. MAIN OUTCOMES/MEASURES: Self-reported subjected to workplace bullying from peers, attendings, nurses, ancillary staff, or patients in the past 12 months. RESULTS: Almost half of the respondents (48%) reported being subjected to bullying although both those subjected and not subjected reported experiencing >= 1 bullying behaviors (95% and 39% respectively). Attendings (29%) and nurses (27%) were the most frequently identified source of bullying, followed by patients, peers, consultants and staff. Attempts to belittle and undermine work and unjustified criticism and monitoring of work were the most frequently reported bullying behaviors (44% each), followed by destructive innuendo and sarcasm (37%) and attempts to humiliate (32%). Specific bullying behaviors were more frequently reported by female, non-white, shorter than < 5'8 and BMI >= 25 individuals. CONCLUSIONS/RELEVANCE: Many trainees report experiencing bullying in the United States graduate medical education programs. Including specific questions on bullying in the Accreditation Council for Graduate Medical Education annual resident/fellow survey, implementation of anti-bullying policies, and a multidisciplinary approach engaging all stakeholders may be of great value to eliminate these pervasive behaviors in the field of healthcare. PMID- 26982706 TI - Immune Response to Dengue Virus Infection in Pediatric Patients in New Delhi, India--Association of Viremia, Inflammatory Mediators and Monocytes with Disease Severity. AB - Dengue virus, a mosquito-borne flavivirus, is a causative agent for dengue infection, which manifests with symptoms ranging from mild fever to fatal dengue shock syndrome. The presence of four serotypes, against which immune cross protection is short-lived and serotype cross-reactive antibodies that might enhance infection, pose a challenge to further investigate the role of virus and immune response in pathogenesis. We evaluated the viral and immunological factors that correlate with severe dengue disease in a cohort of pediatric dengue patients in New Delhi. Severe dengue disease was observed in both primary and secondary infections. Viral load had no association with disease severity but high viral load correlated with prolonged thrombocytopenia and delayed recovery. Severe dengue cases had low Th1 cytokines and a concurrent increase in the inflammatory mediators such as IL-6, IL-8 and IL-10. A transient increase in CD14+CD16+ intermediate monocytes was observed early in infection. Sorting of monocytes from dengue patient peripheral blood mononuclear cells revealed that it is the CD14+ cells, but not the CD16+ or the T or B cells, that were infected with dengue virus and were major producers of IL-10. Using the Boruta algorithm, reduced interferon-alpha levels and enhanced aforementioned pro-inflammatory cytokines were identified as some of the distinctive markers of severe dengue. Furthermore, the reduction in the levels of IL-8 and IL-10 were identified as the most significant markers of recovery from severe disease. Our results provide further insights into the immune response of children to primary and secondary dengue infection and help us to understand the complex interplay between the intrinsic factors in dengue pathogenesis. PMID- 26982709 TI - Oral or Topical 5-ASA in Ulcerative Colitis. AB - Aminosalicylates (5-ASAs) are foundational therapies for patients with mild moderate active ulcerative colitis (UC) and to maintain remissions. A variety of oral and topical formulations have been evaluated in both active and quiescent disease in both extensive and distal UC. This review summarizes data on pharmacokinetics and applications of oral and topical 5-ASA therapies in active and quiescent, extensive colitis and distal disease, both as monotherapies and in combination and reviews dosing and dosing intervals for oral 5-ASA in both active disease and to maintain remissions. PMID- 26982708 TI - The Intestinal Eukaryotic Virome in Healthy and Diarrhoeic Neonatal Piglets. AB - Neonatal porcine diarrhoea of uncertain aetiology has been reported from a number of European countries. The aim of the present study was to use viral metagenomics to examine a potential viral involvement in this diarrhoea and to describe the intestinal virome with focus on eukaryotic viruses. Samples from the distal jejunum of 50 diarrhoeic and 19 healthy piglets from 10 affected herds were analysed. The viral fraction of the samples was isolated and nucleic acids (RNA and DNA fractions) were subjected to sequence independent amplification. Samples from diarrhoeic piglets from the same herds were pooled whereas samples from healthy piglets were analysed individually. In total, 29 clinical samples, plus two negative controls and one positive control consisting of a mock metagenome were sequenced using the Ion Torrent platform. The resulting sequence data was subjected to taxonomic classification using Kraken, Diamond and HMMER. In the healthy specimens, eight different mammalian virus families were detected (Adenoviridae, Anelloviridae, Astroviridae, Caliciviridae, Circoviridae, Parvoviridae, Picornaviridae, and Reoviridae) compared to four in the pooled diarrhoeic samples (Anelloviridae, Circoviridae, Picornaviridae, and Reoviridae). It was not possible to associate a particular virus family with the investigated diarrhoea. In conclusion, this study does not support the hypothesis that the investigated diarrhoea was caused by known mammalian viruses. The results do, however, indicate that known mammalian viruses were present in the intestine as early as 24-48 hours after birth, indicating immediate infection post-partum or possibly transplacental infection. PMID- 26982707 TI - Microglia-Derived Cytokines/Chemokines Are Involved in the Enhancement of LPS Induced Loss of Nigrostriatal Dopaminergic Neurons in DJ-1 Knockout Mice. AB - Mutation of DJ-1 (PARK7) has been linked to the development of early-onset Parkinson's disease (PD). However, the underlying molecular mechanism is still unclear. This study is aimed to compare the sensitivity of nigrostriatal dopaminergic neurons to lipopolysaccharide (LPS) challenge between DJ-1 knockout (KO) and wild-type (WT) mice, and explore the underlying cellular and molecular mechanisms. Our results found that the basal levels of interferon (IFN)-gamma (the hub cytokine) and interferon-inducible T-cell alpha chemoattractant (I-TAC) (a downstream mediator) were elevated in the substantia nigra of DJ-1 KO mice and in microglia cells with DJ-1 deficiency, and the release of cytokine/chemokine was greatly enhanced following LPS administration in the DJ-1 deficient conditions. In addition, direct intranigral LPS challenge caused a greater loss of nigrostriatal dopaminergic neurons and striatal dopamine content in DJ-1 KO mice than in WT mice. Furthermore, the sensitization of microglia cells to LPS challenge to release IFN-gamma and I-TAC was via the enhancement of NF-kappaB signaling, which was antagonized by NF-kappaB inhibitors. LPS-induced increase in neuronal death in the neuron-glia co-culture was enhanced by DJ-1 deficiency in microglia, which was antagonized by the neutralizing antibodies against IFN-gamma or I-TAC. These results indicate that DJ-1 deficiency sensitizes microglia cells to release IFN-gamma and I-TAC and causes inflammatory damage to dopaminergic neurons. The interaction between the genetic defect (i.e. DJ-1) and inflammatory factors (e.g. LPS) may contribute to the development of PD. PMID- 26982710 TI - Ultrasonography in the Evaluation of Breast Cancer-Related Lymphedema. PMID- 26982711 TI - Dermal Structure in Lymphedema Patients with History of Acute Dermatolymphangioadenitis Evaluated by Histogram Analysis of Ultrasonography Findings: A Case-Control Study. AB - BACKGROUND: Acute dermatolymphangioadenitis (ADLA) is a risk factor for increasing of edema and worsening severity. Reducing ADLA frequency is an important objective of lymphedema management because ADLA episodes are strongly associated with poor quality of life. Lymphedema changes dermal and subcutaneous structure, favoring ADLA; ADLA recurrence may be caused by structural change of the dermis. However, the structure of the skin following ADLA episodes has not been studied in depth. The aim of this study was to examine changes in the skin after episodes of ADLA in breast cancer-related lymphedema (BCRL) using histogram analysis of ultrasonography findings. METHODS AND RESULTS: This was a case control study with matching for the duration of lymphedema. We compared 10 limbs (5 BCRL patients, Cases) with a history of ADLA and 14 limbs (7 BCRL patients, Controls) without. Ultrasonography was performed using a 20-MHz probe, and measurements were made at a site 10 cm proximal to the ulnar styloid process. We compared "skewness" of the images in the dermis from the histogram analysis. This study was approved by the Ethics Committee of Kanazawa University. Skewness was significantly different between the affected and unaffected limbs (p = 0.02). Cases showed a positive value (median 0.74, range -0.18 to 1.26), whereas Controls showed a negative value (median -0.21, range -0.45 to 0.31). CONCLUSIONS: Episodes of ADLA changed the distribution of echogenicity on imaging, which indicates a change in the collagen fibers in the dermis. These findings might contribute to improving the management of lymphedema and prevention of recurrent ADLA. PMID- 26982714 TI - Molecular Typing and Epidemiology of Human Listeriosis Cases, Denmark, 2002-2012. AB - Denmark has a high incidence of invasive listeriosis (0.9 cases/100,000 population in 2012). We analyzed patient data, clinical outcome, and trends in pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) of Listeria monocytogenes strains isolated in Denmark during 2002-2012. We performed 2-enzyme PFGE and serotyping on 559 isolates and MLST on 92 isolates and identified some correlation between molecular type and clinical outcome and patient characteristics. We found 178 different PFGE types, but isolates from 122 cases belonged to just 2 closely related PFGE types, clonal complex 8 and sequence type 8. These 2 types were the main cause of a peak in incidence of invasive listeriosis during 2005-2009, possibly representing an outbreak or the presence of a highly prevalent clone. However, current typing methods could not fully confirm these possibilities, highlighting the need for more refined discriminatory typing methods to identify outbreaks within frequently occurring L. monocytogenes PFGE types. PMID- 26982715 TI - Clonal expansion of Escherichia coli ST38 carrying a chromosomally integrated OXA 48 carbapenemase gene. AB - Many isolates of Escherichia coli carrying blaOXA-48 referred to Public Health England's national reference laboratory during 2014 and 2015 shared similar pulsed-field gel electrophoresis (PFGE) profiles, despite coming from patients in multiple different hospitals and regions. Whole genome sequencing on an Illumina platform revealed that these belonged to sequence type (ST) 38. The OXA-48 gene is usually carried on a 62 kb IncL/M plasmid (pOXA48a), but those belonging to this ST appeared either to lack plasmid elements or to have only a partial complement. Two isolates, one belonging to a main cluster sharing identical PFGE profiles and the other having a distinct profile, were further sequenced on a minION. The long reads provided by the nanopore sequencing technology facilitated assembly of a much larger contig around the blaOXA-48 region, showing that both isolates shared a similar arrangement, with a plasmid fragment containing blaOXA 48 flanked by IS1R elements integrated into the chromosome, although the length of the plasmid fragment and the insertion site differed between the two isolates. That belonging to the main cluster contained a 21.9 kb Tn6237 insert, as previously described in E. coli EC-15 from Lebanon, but in a different insertion site. PCR mapping indicated that a further 14/31 representatives of this cluster also contained this insert in the same insertion site, with most of the remainder differing only by having additional E. coli sequence on one side of the insertion. This sub-cluster of ST38 was found from 25 different hospital laboratories, suggesting widespread distribution of a successful type. PMID- 26982717 TI - Brain-Computer Interface Controlled Cyborg: Establishing a Functional Information Transfer Pathway from Human Brain to Cockroach Brain. AB - An all-chain-wireless brain-to-brain system (BTBS), which enabled motion control of a cyborg cockroach via human brain, was developed in this work. Steady-state visual evoked potential (SSVEP) based brain-computer interface (BCI) was used in this system for recognizing human motion intention and an optimization algorithm was proposed in SSVEP to improve online performance of the BCI. The cyborg cockroach was developed by surgically integrating a portable microstimulator that could generate invasive electrical nerve stimulation. Through Bluetooth communication, specific electrical pulse trains could be triggered from the microstimulator by BCI commands and were sent through the antenna nerve to stimulate the brain of cockroach. Serial experiments were designed and conducted to test overall performance of the BTBS with six human subjects and three cockroaches. The experimental results showed that the online classification accuracy of three-mode BCI increased from 72.86% to 78.56% by 5.70% using the optimization algorithm and the mean response accuracy of the cyborgs using this system reached 89.5%. Moreover, the results also showed that the cyborg could be navigated by the human brain to complete walking along an S-shape track with the success rate of about 20%, suggesting the proposed BTBS established a feasible functional information transfer pathway from the human brain to the cockroach brain. PMID- 26982718 TI - Drug monitoring and individual dose optimization of antimicrobial drugs: oxazolidinones. AB - INTRODUCTION: Oxazolidinones are synthetic antibiotics with bacteriostatic activity against Gram-positive pathogens. Linezolid, the first marketed oxazolidinone, has shown also activity against Mycobaterium tuberculosis, including multidrug-resistant and extensively drug-resistant strains. Recently, a second agent of this class (tedizolid) has been approved for the treatment of acute bacterial skin and skin structure infections, and other oxazolidinones are under active investigation in clinical trials. AREAS COVERED: In the present review, we consider factors that affect oxazolidinones pharmacokinetics and their role in reducing the effectiveness of these drugs and increasing the risk of drug related adverse events. Furthermore, we review the potential role of strategies aimed at individualizing drug doses. A MEDLINE PubMed search for articles published from January 1990 to November 2015 was completed matching the terms oxazolidinones, linezolid, or tedizolid with pharmacokinetics, therapeutic drug monitoring, pharmacology or clinical trials. Moreover, additional studies were identified from the reference list of retrieved papers. EXPERT OPINION: Consistent evidence is now available showing that therapeutic drug monitoring and guided individual dose optimization of linezolid is justified and feasible in clinical practice to improve tolerability and possibly response to therapy. The role of individualized drug dosing regimens for other oxazolidinones remains to be proven. PMID- 26982720 TI - Erratum: Epithelial tricellular junctions act as interphase cell shape sensors to orient mitosis. PMID- 26982719 TI - PGC1alpha drives NAD biosynthesis linking oxidative metabolism to renal protection. AB - The energetic burden of continuously concentrating solutes against gradients along the tubule may render the kidney especially vulnerable to ischaemia. Acute kidney injury (AKI) affects 3% of all hospitalized patients. Here we show that the mitochondrial biogenesis regulator, PGC1alpha, is a pivotal determinant of renal recovery from injury by regulating nicotinamide adenine dinucleotide (NAD) biosynthesis. Following renal ischaemia, Pgc1alpha(-/-) (also known as Ppargc1a( /-)) mice develop local deficiency of the NAD precursor niacinamide (NAM, also known as nicotinamide), marked fat accumulation, and failure to re-establish normal function. Notably, exogenous NAM improves local NAD levels, fat accumulation, and renal function in post-ischaemic Pgc1alpha(-/-) mice. Inducible tubular transgenic mice (iNephPGC1alpha) recapitulate the effects of NAM supplementation, including more local NAD and less fat accumulation with better renal function after ischaemia. PGC1alpha coordinately upregulates the enzymes that synthesize NAD de novo from amino acids whereas PGC1alpha deficiency or AKI attenuates the de novo pathway. NAM enhances NAD via the enzyme NAMPT and augments production of the fat breakdown product beta-hydroxybutyrate, leading to increased production of prostaglandin PGE2 (ref. 5), a secreted autacoid that maintains renal function. NAM treatment reverses established ischaemic AKI and also prevented AKI in an unrelated toxic model. Inhibition of beta hydroxybutyrate signalling or prostaglandin production similarly abolishes PGC1alpha-dependent renoprotection. Given the importance of mitochondrial health in ageing and the function of metabolically active organs, the results implicate NAM and NAD as key effectors for achieving PGC1alpha-dependent stress resistance. PMID- 26982721 TI - The 'Tully monster' is a vertebrate. AB - Problematic fossils, extinct taxa of enigmatic morphology that cannot be assigned to a known major group, were once a major issue in palaeontology. A long-favoured solution to the 'problem of the problematica', particularly the 'weird wonders' of the Cambrian Burgess Shale, was to consider them representatives of extinct phyla. A combination of new evidence and modern approaches to phylogenetic analysis has now resolved the affinities of most of these forms. Perhaps the most notable exception is Tullimonstrum gregarium, popularly known as the Tully monster, a large soft-bodied organism from the late Carboniferous Mazon Creek biota (approximately 309-307 million years ago) of Illinois, USA, which was designated the official state fossil of Illinois in 1989. Its phylogenetic position has remained uncertain and it has been compared with nemerteans, polychaetes, gastropods, conodonts, and the stem arthropod Opabinia. Here we review the morphology of Tullimonstrum based on an analysis of more than 1,200 specimens. We find that the anterior proboscis ends in a buccal apparatus containing teeth, the eyes project laterally on a long rigid bar, and the elongate segmented body bears a caudal fin with dorsal and ventral lobes. We describe new evidence for a notochord, cartilaginous arcualia, gill pouches, articulations within the proboscis, and multiple tooth rows adjacent to the mouth. This combination of characters, supported by phylogenetic analysis, identifies Tullimonstrum as a vertebrate, and places it on the stem lineage to lampreys (Petromyzontida). In addition to increasing the known morphological disparity of extinct lampreys, a chordate affinity for T. gregarium resolves the nature of a soft-bodied fossil which has been debated for more than 50 years. PMID- 26982722 TI - The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation. AB - The integrated stress response (ISR) is a homeostatic mechanism by which eukaryotic cells sense and respond to stress-inducing signals, such as amino acid starvation. General controlled non-repressed (GCN2) kinase is a key orchestrator of the ISR, and modulates protein synthesis in response to amino acid starvation. Here we demonstrate in mice that GCN2 controls intestinal inflammation by suppressing inflammasome activation. Enhanced activation of ISR was observed in intestinal antigen presenting cells (APCs) and epithelial cells during amino acid starvation, or intestinal inflammation. Genetic deletion of Gcn2 (also known as Eif2ka4) in CD11c(+) APCs or intestinal epithelial cells resulted in enhanced intestinal inflammation and T helper 17 cell (TH17) responses, owing to enhanced inflammasome activation and interleukin (IL)-1beta production. This was caused by reduced autophagy in Gcn2(-/-) intestinal APCs and epithelial cells, leading to increased reactive oxygen species (ROS), a potent activator of inflammasomes. Thus, conditional ablation of Atg5 or Atg7 in intestinal APCs resulted in enhanced ROS and TH17 responses. Furthermore, in vivo blockade of ROS and IL 1beta resulted in inhibition of TH17 responses and reduced inflammation in Gcn2( /-) mice. Importantly, acute amino acid starvation suppressed intestinal inflammation via a mechanism dependent on GCN2. These results reveal a mechanism that couples amino acid sensing with control of intestinal inflammation via GCN2. PMID- 26982723 TI - Derivation and differentiation of haploid human embryonic stem cells. AB - Diploidy is a fundamental genetic feature in mammals, in which haploid cells normally arise only as post-meiotic germ cells that serve to ensure a diploid genome upon fertilization. Gamete manipulation has yielded haploid embryonic stem (ES) cells from several mammalian species, but haploid human ES cells have yet to be reported. Here we generated and analysed a collection of human parthenogenetic ES cell lines originating from haploid oocytes, leading to the successful isolation and maintenance of human ES cell lines with a normal haploid karyotype. Haploid human ES cells exhibited typical pluripotent stem cell characteristics, such as self-renewal capacity and a pluripotency-specific molecular signature. Moreover, we demonstrated the utility of these cells as a platform for loss-of function genetic screening. Although haploid human ES cells resembled their diploid counterparts, they also displayed distinct properties including differential regulation of X chromosome inactivation and of genes involved in oxidative phosphorylation, alongside reduction in absolute gene expression levels and cell size. Surprisingly, we found that a haploid human genome is compatible not only with the undifferentiated pluripotent state, but also with differentiated somatic fates representing all three embryonic germ layers both in vitro and in vivo, despite a persistent dosage imbalance between the autosomes and X chromosome. We expect that haploid human ES cells will provide novel means for studying human functional genomics and development. PMID- 26982724 TI - Corrigendum: CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. PMID- 26982727 TI - Cancer immunotherapy: Killers on sterols. PMID- 26982726 TI - Deletions linked to TP53 loss drive cancer through p53-independent mechanisms. AB - Mutations disabling the TP53 tumour suppressor gene represent the most frequent events in human cancer and typically occur through a two-hit mechanism involving a missense mutation in one allele and a 'loss of heterozygosity' deletion encompassing the other. While TP53 missense mutations can also contribute gain-of function activities that impact tumour progression, it remains unclear whether the deletion event, which frequently includes many genes, impacts tumorigenesis beyond TP53 loss alone. Here we show that somatic heterozygous deletion of mouse chromosome 11B3, a 4-megabase region syntenic to human 17p13.1, produces a greater effect on lymphoma and leukaemia development than Trp53 deletion. Mechanistically, the effect of 11B3 loss on tumorigenesis involves co-deleted genes such as Eif5a and Alox15b (also known as Alox8), the suppression of which cooperates with Trp53 loss to produce more aggressive disease. Our results imply that the selective advantage produced by human chromosome 17p deletion reflects the combined impact of TP53 loss and the reduced dosage of linked tumour suppressor genes. PMID- 26982728 TI - Memory retrieval by activating engram cells in mouse models of early Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role. However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD. PMID- 26982725 TI - Acceleration of petaelectronvolt protons in the Galactic Centre. AB - Galactic cosmic rays reach energies of at least a few petaelectronvolts (of the order of 10(15) electronvolts). This implies that our Galaxy contains petaelectronvolt accelerators ('PeVatrons'), but all proposed models of Galactic cosmic-ray accelerators encounter difficulties at exactly these energies. Dozens of Galactic accelerators capable of accelerating particles to energies of tens of teraelectronvolts (of the order of 10(13) electronvolts) were inferred from recent gamma-ray observations. However, none of the currently known accelerators- not even the handful of shell-type supernova remnants commonly believed to supply most Galactic cosmic rays--has shown the characteristic tracers of petaelectronvolt particles, namely, power-law spectra of gamma-rays extending without a cut-off or a spectral break to tens of teraelectronvolts. Here we report deep gamma-ray observations with arcminute angular resolution of the region surrounding the Galactic Centre, which show the expected tracer of the presence of petaelectronvolt protons within the central 10 parsecs of the Galaxy. We propose that the supermassive black hole Sagittarius A* is linked to this PeVatron. Sagittarius A* went through active phases in the past, as demonstrated by X-ray outburstsand an outflow from the Galactic Centre. Although its current rate of particle acceleration is not sufficient to provide a substantial contribution to Galactic cosmic rays, Sagittarius A* could have plausibly been more active over the last 10(6)-10(7) years, and therefore should be considered as a viable alternative to supernova remnants as a source of petaelectronvolt Galactic cosmic rays. PMID- 26982730 TI - Boreal and temperate trees show strong acclimation of respiration to warming. AB - Plant respiration results in an annual flux of carbon dioxide (CO2) to the atmosphere that is six times as large as that due to the emissions from fossil fuel burning, so changes in either will impact future climate. As plant respiration responds positively to temperature, a warming world may result in additional respiratory CO2 release, and hence further atmospheric warming. Plant respiration can acclimate to altered temperatures, however, weakening the positive feedback of plant respiration to rising global air temperature, but a lack of evidence on long-term (weeks to years) acclimation to climate warming in field settings currently hinders realistic predictions of respiratory release of CO2 under future climatic conditions. Here we demonstrate strong acclimation of leaf respiration to both experimental warming and seasonal temperature variation for juveniles of ten North American tree species growing for several years in forest conditions. Plants grown and measured at 3.4 degrees C above ambient temperature increased leaf respiration by an average of 5% compared to plants grown and measured at ambient temperature; without acclimation, these increases would have been 23%. Thus, acclimation eliminated 80% of the expected increase in leaf respiration of non-acclimated plants. Acclimation of leaf respiration per degree temperature change was similar for experimental warming and seasonal temperature variation. Moreover, the observed increase in leaf respiration per degree increase in temperature was less than half as large as the average reported for previous studies, which were conducted largely over shorter time scales in laboratory settings. If such dampening effects of leaf thermal acclimation occur generally, the increase in respiration rates of terrestrial plants in response to climate warming may be less than predicted, and thus may not raise atmospheric CO2 concentrations as much as anticipated. PMID- 26982731 TI - Alzheimer's disease: Lost memories found. PMID- 26982732 TI - Microbial oceanography: Viral strategies at sea. PMID- 26982729 TI - Lytic to temperate switching of viral communities. AB - Microbial viruses can control host abundances via density-dependent lytic predator-prey dynamics. Less clear is how temperate viruses, which coexist and replicate with their host, influence microbial communities. Here we show that virus-like particles are relatively less abundant at high host densities. This suggests suppressed lysis where established models predict lytic dynamics are favoured. Meta-analysis of published viral and microbial densities showed that this trend was widespread in diverse ecosystems ranging from soil to freshwater to human lungs. Experimental manipulations showed viral densities more consistent with temperate than lytic life cycles at increasing microbial abundance. An analysis of 24 coral reef viromes showed a relative increase in the abundance of hallmark genes encoded by temperate viruses with increased microbial abundance. Based on these four lines of evidence, we propose the Piggyback-the-Winner model wherein temperate dynamics become increasingly important in ecosystems with high microbial densities; thus 'more microbes, fewer viruses'. PMID- 26982733 TI - Visualization of immediate immune responses to pioneer metastatic cells in the lung. AB - Lung metastasis is the lethal determinant in many cancers and a number of lines of evidence point to monocytes and macrophages having key roles in its development. Yet little is known about the immediate fate of incoming tumour cells as they colonize this tissue, and even less known about how they make first contact with the immune system. Primary tumours liberate circulating tumour cells (CTCs) into the blood and we have developed a stable intravital two-photon lung imaging model in mice for direct observation of the arrival of CTCs and subsequent host interaction. Here we show dynamic generation of tumour microparticles in shear flow in the capillaries within minutes of CTC entry. Rather than dispersing under flow, many of these microparticles remain attached to the lung vasculature or independently migrate along the inner walls of vessels. Using fluorescent lineage reporters and flow cytometry, we observed 'waves' of distinct myeloid cell subsets that load differentially and sequentially with this CTC-derived material. Many of these tumour-ingesting myeloid cells collectively accumulated in the lung interstitium along with the successful metastatic cells and, as previously understood, promote the development of successful metastases from surviving tumour cells. Although the numbers of these cells rise globally in the lung with metastatic exposure and ingesting myeloid cells undergo phenotypic changes associated with microparticle ingestion, a consistently sparse population of resident conventional dendritic cells, among the last cells to interact with CTCs, confer anti-metastatic protection. This work reveals that CTC fragmentation generates immune-interacting intermediates, and defines a competitive relationship between phagocyte populations for tumour loading during metastatic cell seeding. PMID- 26982735 TI - Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy for the treatment of primary peritoneal serous carcinoma: Results of a Chinese retrospective study. AB - Purpose Primary peritoneal serous carcinoma (PPSC) is a rare condition with a poor survival rate, even after treatment with debulking surgery followed by systemic chemotherapy. This study evaluated the efficacy and safety of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of PPSC. Patients and methods This retrospective study included 22 female patients with primary advanced PPSC (group A, n = 12) or recurrent PPSC (group B, n = 10) treated with 25 CRS + HIPEC procedures. The primary end point was overall survival (OS), and the secondary end points were safety profiles. Results A total of 25 CRS + HIPEC procedures were performed in these 22 patients. The median OS was 31.0 months (95% confidence interval (CI) 22.3-39.7), and the 1-, 3-, and 5-year survival rates were 100%, 45.5%, and 27.3%, respectively. Subgroup analyses revealed that the median OS was 31.0 months (95% CI 19.8-42.2) for group A vs. 38.5 months (95% CI 9.6-67.4) for group B (P = 0.832, log rank test); 51.5 months (95% CI 34.9-68.1) for peritoneal cancer index (PCI) <= 15 vs. 20.3 months (95% CI 12.6-28.0) for PCI > 15 (P = 0.000, log rank test); and 38.5 months (95% CI 22.5-54.5) for completeness of cytoreduction (CC) of 0-1 vs. 23.5 months (95% CI 15.3-31.7) for CC of 2-3 (P = 0.178, log rank test). There were no perioperative deaths. Serious adverse events (SAEs) occurred in two patients (9.1%). A univariate analysis identified PCI <= 15 as the only prognostic predicator (hazard ratio (HR) 13.1, 95% CI 2.7-63.4, P = 0.001). Conclusions CRS + HIPEC could contribute to favourable outcomes for select PPSC patients with acceptable safety profiles. PMID- 26982736 TI - Hereditary haemorrhagic telangiectasia manifesting as subdural empyema. AB - Hereditary haemorrhagic telangiectasia (HHT) also known as Osler-Weber-Rendu disease is a rare autosomal dominant condition causing vascular dysplasia. Cerebral abscess formation, secondary to paradoxical septic emboli via HHT derived pulmonary arteriovenous malformations (pAVMs) in this context is well documented. Herein, we present the first case of subdural empyema with this aetiology. PMID- 26982734 TI - Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. AB - CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8(+) T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8(+) T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8(+) but not CD4(+) T cells. This is due to the increase in the plasma membrane cholesterol level of CD8(+) T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8(+) T cells were better than wild-type CD8(+) T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy. PMID- 26982738 TI - US Hospitals Prepare for Penis Transplants. PMID- 26982737 TI - Genomic Instability Associated with p53 Knockdown in the Generation of Huntington's Disease Human Induced Pluripotent Stem Cells. AB - Alterations in DNA damage response and repair have been observed in Huntington's disease (HD). We generated induced pluripotent stem cells (iPSC) from primary dermal fibroblasts of 5 patients with HD and 5 control subjects. A significant fraction of the HD iPSC lines had genomic abnormalities as assessed by karyotype analysis, while none of our control lines had detectable genomic abnormalities. We demonstrate a statistically significant increase in genomic instability in HD cells during reprogramming. We also report a significant association with repeat length and severity of this instability. Our karyotypically normal HD iPSCs also have elevated ATM-p53 signaling as shown by elevated levels of phosphorylated p53 and H2AX, indicating either elevated DNA damage or hypersensitive DNA damage signaling in HD iPSCs. Thus, increased DNA damage responses in the HD genotype is coincidental with the observed chromosomal aberrations. We conclude that the disease causing mutation in HD increases the propensity of chromosomal instability relative to control fibroblasts specifically during reprogramming to a pluripotent state by a commonly used episomal-based method that includes p53 knockdown. PMID- 26982740 TI - Association of CYP2C19 *17/*17 Genotype With the Risk of Voriconazole-Associated Squamous Cell Carcinoma. PMID- 26982739 TI - Upper Urinary Tract Urothelial Carcinoma Tumor Seeding along Percutaneous Nephrostomy Track: Case Report and Review of the Literature. AB - Upper urinary tract urothelial carcinomas (UTUC) account for 5-10% of all transitional cells neoplasms. Kidney-sparing treatment should be considered for low grade (LG) UTUC and for imperative conditions. Percutaneous approach may have a role in LG tumors not manageable endoscopically. Tumor seeding along nephrostomy track is a rare report. We describe the case of a 73-year-old male, with a history of high-grade UC of the left renal pelvis. A CT scan showed the thickening of left renal pelvic wall, and percutaneous biopsy was performed. The patient underwent laparoscopic left nephroureterectomy. Seven months later, he was admitted for left flank pain due to a mass along the percutaneous track site. Mass en-bloc resection was performed, and histopathology finding demonstrated undifferentiated carcinoma, compatible with UTUC metastasis. The percutaneous approach should be considered to be the possible cause of tumor seeding. Multimodal therapy seems mandatory, as highlighted in our outcomes, with 5 years of recurrence free survival. PMID- 26982742 TI - Corrigendum. PMID- 26982741 TI - Single Nucleotide Variant rs2232710 in the Protein Z-Dependent Protease Inhibitor (ZPI, SERPINA10) Gene Is Not Associated with Deep Vein Thrombosis. AB - Rare mutations in PROC, PROS1 or SERPINC1 as well as common variants in F5, F2, F11 and SERPINC1 have been identified as risk factors for deep vein thrombosis (DVT). To identify novel genetic risk factors for DVT, we have developed and applied next-generation DNA sequencing (NGS) of the coding area of hemostatic and proinflammatory genes. Using this strategy, we previously identified a single nucleotide variant (SNV) rs6050 in the FGA gene and novel, rare SNVs in the ADAMTS13 gene associated with DVT. To identify novel coding variants in the genetic predisposition to DVT, we applied NGS analysis of the coding area of 186 hemostatic and proinflammatory genes in 94 DVT cases and 98 controls and we identified 18 variants with putative role in DVT. A group of 585 Italian idiopathic DVT patients and 550 healthy controls was used to genotype all the 18 risk-associated variants identified by NGS. Replication study in the Italian population identified the rs2232710 variant in the protein Z-dependent protease inhibitor (ZPI) gene to be associated with an increased risk of DVT (OR 2.74; 95% CI 1.33-5.65; P = 0.0045; Bonferroni P = 0.081). However, the rs2232710 SNV showed no association with DVT in two Dutch replication cohorts the LETS study (454 patients and 451 controls) and the MEGA study (3799 patients and 4399 controls), indicating that the rs2232710 variant is not a risk factor for DVT. PMID- 26982743 TI - TheBDKRB2 +9/-9 Polymorphisms Influence Pro-Inflammatory Cytokine Levels in Knee Osteoarthritis by Altering TLR-2 Expression: Clinical and in Vitro Studies. AB - BACKGROUND/AIMS: The bradykinin B2 receptor (BDKRB2) +9/-9 gene polymorphisms have been shown to be associated with the susceptibility and severity of osteoarthritis (OA); however, the underlying mechanisms are unclear. In this study, we investigated the correlation between the BDKRB2 +9/-9 polymorphisms and pro-inflammatory cytokine levels in OA and the molecular mechanisms involved. METHODS: A total of 156 patients with primary knee OA and 121 healthy controls were enrolled. The BDKRB2 +9/-9 polymorphisms were genotyped. The tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-8 levels were determined using Enzyme-linked immunosorbent assay (ELISA). The toll-like receptor (TLR)-2 and TLR-4 mRNA levels were determined by quantitative real-time PCR. The basal and bradykinin-stimulated pro-inflammatory cytokine secretion in human OA synoviocytes and the involvement of TLR-2 and mitogen-activated protein kinases (MAPKs) were investigated. RESULTS: The presence of -9 bp genotype is associated with higher TNF-alpha, IL-6, and IL-8 levels and higher TLR-2 expression in OA patients. The basal and bradykinin-induced TLR-2 expressions in human OA synoviocytes were significantly reduced by specific inhibitors of p38, JNK1/2, and ERK1/2. Both the B2 receptor antagonist MEN16132 and TLR-2 silencing inhibited IL-6 and IL-8 secretion in human OA synoviocytes. CONCLUSION: The data suggested that the BDKRB2 +9/-9 polymorphisms influence pro-inflammatory cytokine levels in knee osteoarthritis by altering TLR-2 expression. PMID- 26982745 TI - Gut Microbiota Differences in Children From Distinct Socioeconomic Levels Living in the Same Urban Area in Brazil. AB - OBJECTIVE: To compare gut microbiota in impoverished children versus children of high socioeconomic status living in the same urban area in Brazil. METHODS: A cross-sectional study was conducted to evaluate 100 children living in a slum and 30 children from a private school, ages between 5 and 11 years old, in Sao Paulo State, Brazil. To characterize the groups, data based on socioeconomic status, sanitation, and housing conditions were collected. Anthropometric measurements and neonatal data were obtained from both groups. Gut microbiota were quantified in fecal samples by real-time polymerase chain reaction. RESULTS: The children in the private school group had higher rates of cesarean delivery and premature birth than the children in the slum group. Staphylococcus aureus (90% vs 48.0%) and Clostridium difficile (100% vs 43.0%) were more commonly found in the children from the private school than in the impoverished children (P < 0.0001). C perfringens was most frequently identified in the group of children from the slum (92.0% vs 80%; P = 0.064). Higher counts of total eubacteria, Firmicutes and Bacteroidetes phyla organisms, Escherichia coli, Lactobacillus spp., and Methanobrevibacter smithii were found in the children living in poverty, whereas higher counts of Salmonella spp., C difficile, and C perfringens were observed in the children living in satisfactory housing conditions (P < 0.05). CONCLUSIONS: Important differences were observed between the gut microbiota of children living under distinct socioeconomic and environmental conditions within the same city. Our findings suggest that children of high socioeconomic status have less favorable gut microbiota than do children who live in poverty. PMID- 26982744 TI - Diaryl Disulfides as Novel Stabilizers of Tumor Suppressor Pdcd4. AB - The translation inhibitor and tumor suppressor Pdcd4 was reported to be lost in various tumors and put forward as prognostic marker in tumorigenesis. Decreased Pdcd4 protein stability due to PI3K-mTOR-p70S6K1 dependent phosphorylation of Pdcd4 followed by beta-TrCP1-mediated ubiquitination, and proteasomal destruction of the protein was characterized as a major mechanism contributing to the loss of Pdcd4 expression in tumors. In an attempt to identify stabilizers of Pdcd4, we used a luciferase-based high-throughput compatible cellular assay to monitor phosphorylation-dependent proteasomal degradation of Pdcd4 in response to mitogen stimulation. Following a screen of approximately 2000 compounds, we identified 1,2-bis(4-chlorophenyl)disulfide as a novel Pdcd4 stabilizer. To determine an initial structure-activity relationship, we used 3 additional compounds, synthesized according to previous reports, and 2 commercially available compounds for further testing, in which either the linker between the aryls was modified (compounds 2-4) or the chlorine residues were replaced by groups with different electronic properties (compounds 5 and 6). We observed that those compounds with alterations in the sulfide linker completely lost the Pdcd4 stabilizing potential. In contrast, modifications in the chlorine residues showed only minor effects on the Pdcd4 stabilizing activity. A reporter with a mutated phospho degron verified the specificity of the compounds for stabilizing the Pdcd4 reporter. Interestingly, the active diaryl disulfides inhibited proliferation and viability at concentrations where they stabilized Pdcd4, suggesting that Pdcd4 stabilization might contribute to the anti-proliferative properties. Finally, computational modelling indicated that the flexibility of the disulfide linker might be necessary to exert the biological functions of the compounds, as the inactive compound appeared to be energetically more restricted. PMID- 26982746 TI - Investigation of an Immunoassay with Broad Specificity to Quinolone Drugs by Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Data Sets and Advanced Quantitative Structure-Activity Relationship Analysis. AB - A polyclonal antibody against the quinolone drug pazufloxacin (PAZ) but with surprisingly broad specificity was raised to simultaneously detect 24 quinolones (QNs). The developed competitive indirect enzyme-linked immunosorbent assay (ciELISA) exhibited limits of detection (LODs) for the 24 QNs ranging from 0.45 to 15.16 ng/mL, below the maximum residue levels (MRLs). To better understand the obtained broad specificity, a genetic algorithm with linear assignment of hypermolecular alignment of data sets (GALAHAD) was used to generate the desired pharmacophore model and superimpose the QNs, and then advanced comparative molecular field analysis (CoMFA) and advanced comparative molecular similarity indices analysis (CoMSIA) models were employed to study the three-dimensional quantitative structure-activity relationship (3D QSAR) between QNs and the antibody. It was found that the QNs could interact with the antibody with different binding poses, and cross-reactivity was mainly positively correlated with the bulky substructure containing electronegative atom at the 7-position, while it was negatively associated with the large bulky substructure at the 1 position of QNs. PMID- 26982747 TI - Dwarfism in art. AB - Throughout the history of mankind the birth of a child with congenital malformation raised anxiety and torment, along with attempts to explain its origins. It is possible to find relics of such events in prehistoric rock drawings and primitive sculptures, in numerous art pieces produced through the centuries up to modern sculptures, paintings and drawings. The aim of the present article is to show how dwarfs were portrayed in a variety of art forms at different moments in the history of our world. PMID- 26982748 TI - Imaging in the diagnosis of rare diseases. AB - A disease is considered rare if it affects no more than 5 in 10,000 people. More than six thousand rare diseases have been detected so far and they affect 6-8% of the population which equals 2.3-3 million people in Poland. Some of the rare diseases are already diagnosed in utero, e.g. skeletal dysplasias on ultrasonography or central nervous system diseases on magnetic resonance imaging (MRI). Many cases are finally diagnosed after radiologist's suggestion in a radiological report. Although diagnostic imaging cannot be considered as a basis for diagnosis of most of rare diseases, these studies represent an important element in the diagnostic chain. The complicated and long process of diagnosis may be significantly shortened by suggestions of the radiologist, based on the observation of these elements of radiological appearance of the lesions that are characteristic for a particular group of diseases, or even for a particular disease entity. However, the absolute condition for success is the close clinical radiological cooperation, with clinicians providing the radiologists with their knowledge of patient's history, clinical manifestations, and the results of other investigations. PMID- 26982749 TI - Genetic analysis in inherited metabolic disorders--from diagnosis to treatment. Own experience, current state of knowledge and perspectives. AB - Inherited metabolic disorders, also referred to as inborn errors of metabolism (IEM), are a group of congenital disorders caused by mutation in genomic or mitochondrial DNA. IEM are mostly rare disorders with incidence ranging from 1/50,000-1/150,000), however in total IEM may affect even 1/1000 people. A particular mutation affects specific protein or enzyme that improper function leads to alterations in specific metabolic pathway. Inborn errors of metabolism are monogenic disorders that can be inherited in autosomal recessive manner or, less frequently, in autosomal dominant or X-linked patterns. Some exceptions to Mendelian rules of inheritance have also been described. Vast majority of mutations responsible for IEM are small DNA changes affecting single or several nucleotides, although larger rearrangements were also identified. Therefore, the methods used for the identification of pathogenic mutations are mainly based on molecular techniques, preferably on Sanger sequencing. Moreover, the next generation sequencing technique seems to be another prospective method that can be successfully implemented for the diagnosis of inborn errors of metabolism. The identification of the genetic defect underlying the disease is not only indispensable for genetic counseling, but also might be necessary to apply appropriate treatment to the patient. Therapeutic strategies for IEM are continuously elaborated and tested (eg. enzyme replacement therapy, specific cells or organ transplantation or gene therapy, both in vivo and ex vivo) and have already been implemented for several disorders. In this article we present current knowledge about various aspects of IEM on the basis of our own experience and literature review. PMID- 26982750 TI - Novel cytogenetic and molecular techniques in the diagnosis of congenital anomalies in newborns. AB - Knowledge of what causes developmental disorders, including congenital structural defects/anomalies, in the newborn population, facilitates the choice of further investigations, therapy and rehabilitation, allows the use of appropriate prophylaxis against comorbidities, makes it possible to specify prognosis, as well as provide reliable family counselling (both pre- and postnatal). Attempting to formulate a clinical diagnosis of a specific congenital anomaly syndrome, with or without dysmorphic features, based on history and detailed physical examination, remains crucial for the selection of the right genetic testing. Modern methods of molecular cytogenetics and molecular biology are targeted in nature (microdeletion MLPA, single gene sequencing) or are capable of analyzing the genome as a whole (array CGH, newgeneration sequencing). Especially the latter techniques are now causing a rapid increase of diagnostic efficacy across different age groups, including newborns. PMID- 26982751 TI - Clinical manifestation of mitochondrial diseases. AB - Mitochondrial disorders (MD) represent a clinically, biochemically and genetically heterogeneous group of diseases associated with dysfunction of the oxidative phosphorylation system and pyruvate dehydrogenase complex. Our aim was to illustrate the most common clinical presentation of MD on the example of selected diseases and syndromes. The minimal prevalence of MD is estimated as 1 to 5,000. MD may manifest at any age since birth until late-adulthood with acute manifestation or as a chronic progressive disease. Virtually any organ may be impaired, but the organs with the highest energetic demands are most frequently involved, including brain, muscle, heart and liver. Some MD may manifest as a characteristic cluster of clinical features (e.g. MELAS syndrome, Kearns-Sayre syndrome). Diagnostics includes detailed history, the comprehensive clinical examination, results of specialized examinations (especially cardiology, visual fundus examination, brain imaging, EMG), laboratory testing of body fluids (lactate, aminoacids, organic acids), and analysis of bioptic samples of muscle, skin, and liver, eventually. Normal lactate level in blood does not exclude the possibility of MD. Although the aimed molecular genetic analyses may be indicated in some of mitochondrial diseases, the methods of next generation sequencing come into focus. Examples of treatment are arginine supplementation in MELAS syndrome, ketogenic diet in pyruvate oxidation disorders or quinone analogs in patients with LHON. Conclusion: The clinical suspicion of a mitochondrial disorder is often delayed, or the disease remains undiagnosed. The correct diagnosis and adequate treatment can improve prognosis of the patient. Access to genetic counseling is also of great importance. PMID- 26982752 TI - Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency--diagnostic difficulties and own experience in multidisciplinary management. AB - A 19-year old female patient presented with a two-year history of muscle pain and weakness before she was admitted to an acute medical ward with rhabdomyolysis (creatine kinase of 83,344 IU/L) and normal renal function tests. Following admission she was under the care of the rheumatology and neurology teams, which investigated her thoroughly. As part of the belt-and-braces approach, both teams contacted the specialist Adult Inherited Metabolic Disorders team for advice, instigating definitive diagnostic investigations. An accurate diagnosis was required, as an inherited metabolic disorders can present in adult patients as a milder form of the disease. Very-long-chain Acyl-CoA dehydrogenase (VLCAD) deficiency should always be considered as a differential diagnosis of myopathy related symptoms. Hence, the liaison between neurologists, rheumatologists and metabolic physicians is essential in early diagnosis and the management of patients with conditions causing myopathy. PMID- 26982753 TI - Glucose transporter type 1 deficiency due to SLC2A1 gene mutations--a rare but treatable cause of metabolic epilepsy and extrapyramidal movement disorder; own experience and literature review. AB - THE AIM: To present the molecular and clinical characteristics of three children with glucose deficiency syndrome, an inborn rare metabolic disease, caused by mutations in the SLC2A1 gene. MATERIAL AND METHODS: The investigation was carried out in three children: two girls and one boy showing symptoms of GLUT1 deficiency syndrome (GLUT1-DS). They were referred for SLC2A1 gene analysis. RESULTS: The presence of mutations in all of them was confirmed. Only point mutations were identified, two missenses p.Gly132Ser, p.Arg212Cys and amino acid insertion p.Ser_Val227insValProPro. In two cases the mutations arose de novo, one was heritable of paternal origin. CONCLUSIONS: GLUT1-DS shows high clinical variability. It should be suspected in children of any age presenting with single features or a combination of any form of intractable epilepsy with seizures of various types, movement disorders and paroxysmal events, especially triggered by exercise, exertion, or fasting, and any unexplainable neurological deterioration. The basic diagnostic hallmarks of GLUT1-DS are CSF hypoglycorrhachia and lowered CSF/Blood serum glucose ratio. This is why lumbar punction should be considered more frequently than it is in practice being performed nowadays. Antiepileptic drug treatment may be ineffective or even potentially detrimental. Early identification and molecular confirmation of GLUT1-DS is important, because this is a metabolic disorder and patients should as soon as possible primarily be treated with a ketogenic diet. PMID- 26982754 TI - A multidisciplinary treatment of patients with craniofacial disorders. Own experience. AB - Oral rehabilitation of patients with craniofacial disorders is a great challenge and needs a multidisciplinary approach. This is due to the diverse etiology of the disease and severity of changes in tissues and organs. Congenital absence of tooth germs manifested in the form of oligodontia or anodontia, the presence of persistent deciduous teeth in ectodermal dysplasia (ED), cleft lip and hard palate or cancer-induced changes in the tissues of the stomatognathic system are the most common causes of these disorders. The observed abnormalities are responsible for functional disorders of musculo-articular system, speech and chewing. In addition, noticeable adverse changes in the appearance have a huge psychological impact on patients and their well-being. Therefore, the treatment of these medical conditions should begin in childhood and comprise interdisciplinary rehabilitation, involving prosthetics and orthodontics supported by surgery, as well as speech or laryngological therapy. In this paper the interdisciplinary treatment of patients with oral hard and soft tissues disorders during ectodermal dysplasia is discussed. Early oral rehabilitation can restore lost or abnormally shaped tissues and proper functions of the masticatory system. It can also have a positive impact on further physical and psychological development of patients. PMID- 26982755 TI - Occluso-facial manifestations in a child with the Rasmussen syndrome and intercurrent Lyme disease--a case report. AB - The Rasmussen Syndrome (RS) is a rare neurological disease, usually diagnosed in the 1st decade of life, leading to damage of the central nervous system. It is characterised by sudden seizures in previously healthy children. In this paper we present a case of a 14-year-old female patient with malocclusion who reported to the orthodontic clinic to start orthodontic treatment. The first symptoms of nervous system disorders manifested when the patient was 8 years old. Until then, the patient had been developing correctly. The interview revealed that at the age of 9 the patient was diagnosed with Lyme disease and a long-term antibiotics therapy was started. At the age of 10, the Rasmussen syndrome was diagnosed (the antibiotics therapy was discontinued) and confirmed by magnetic resonance imaging (MRI) and histopathological examination after brain biopsy. The study focuses in particular on the changes in the craniofacial skeleton and oral cavity, taking into account dynamically developing and increasing occlusion defects. The ethical aspect of the treatment has also been considered. PMID- 26982757 TI - Advances in treatment of Rett syndrome. PMID- 26982756 TI - Dental issues in Rett syndrome. AB - The advancements in science and technology allowed saving the lives of children, who had no chance of survival before. Hence the problem of so called rare diseases, usually genetically determined. It is a new challenge for both the physicians and the health services. These children require a coordinated multi specialist oriented health care, which includes also dentists. This situation is reflected by the case of an 18 years old girl with Rett Syndrome, described by us. In this patient despite numerous visits to various dental practices, no decision of a radical surgical extraction of the tooth has been conducted. In our Department the extraction of teeth 22, 16 and 14 has been performed, as a part of 1 day surgery procedures, thus eliminating the dental infections and pain. Conclusion: Elaboration and introduction into praxis principles of dental care in children and young adults with rare diseases are needed. PMID- 26982758 TI - Compound odontoma in the mandible--case study and literature review. AB - INTRODUCTION: Odontomas constitute a developmental defect of hard dental tissues and are classified as benign odontogenic tumours. They are composed of all dental structures and tissues: enamel, dentin, cementum and pulp. As regards histomorphological features, two types of odontomas have been differentiated: complex and compound. Odontomas represent from 4.7% to 76% of odontogenic tumours. Their aetiology has not been fully understood, yet injury, infection and genetic factors are often named among the causes. Odontomas are usually detected by chance in radiographic images taken in relation to disrupted eruption or mislocation of teeth. AIM OF STUDY: To present the case study of an erupting compound odontoma on the right side of the mandible in an 11-year-old girl. MATERIAL, METHODS AND RESULTS: The analysis covered medical documentation of the patient, diagnostic casts, orthopantomographs and cone beam computed tomography scans. The case study has been complemented with the review of up-to-date literature. A lesion composed of 30 odontoids was removed during one-day surgery without subsequent augmentation with bone substitute material. There were no post surgery complications. A follow-up orthopantomograph taken 3 months later showed that the wound had been healing correctly, which made it possible to plan subsequent orthodontic treatment with a fixed appliance. CONCLUSIONS: 1. Odontomas are benign lesions which can be removed during one-day surgery without the absolute need of augmentation with xenogenic or allogenic material. 2. The pressure exerted by the plate of a removable appliance is very likely to initiate the eruption of the odontoma. PMID- 26982760 TI - Dental problems in a patient with the classic type of Ehlers-Danlos syndrome--a case report. AB - The huge progress in diagnostic and therapeutic procedures in developmental medicine allowed not only to save lives of many children and adolescents, but also enforced the necessity of close cooperation between many specialists. Unfortunately dental treatment is still not an integral part of taking care of disabled children and youth with chronic diseases. The situation worsens, when we come across the so-called rare diseases. Lack of access to dental services, when it comes to disabled patients, results from financial situation, healthcare system, as well as parents' ignorance of necessity of more frequent prophylactic and treatment visits. Whereas the reluctance of dentists towards the care of disabled patients is caused by difficulties with enforcing the recommendations and lack of procedures for taking care of patients with rare diseases, which was repeatedly signalled by us. Such situation is ideally pictured by yet another described case of the 17 year old patient with Ehlers-Danlos syndrome. Despite many dental visits, no vital treatment decisions have been made. In our Department, in the procedures of 1-day surgery, tooth 48, being the cause of pain, has been extracted. Basing on all of the above, it can be deduced that preserving the continuation and consequence in spreading the knowledge of rare diseases among patients, as well as physicians and dentists, is a responsibility of everyone who even once came across this problem. PMID- 26982759 TI - Malocclusions and craniofacial anomalies in a child with velo-cardio-facial syndrome. AB - Velo-Cardio-Facial syndrome (VCFS), also called 22q11.2 microdeletion syndrome, is a rare pathology. The syndrome is caused by 22q11.2 deletion, recognized as one of the most frequent pathogenic human microdeletions. The scope and severity of the phenotypic expression of 22q11.2 microdeletion is characterised by high variability, although cleft palate and congenital conotruncal malformations are among the clinical features often associated with that syndrome. In the presented case of a boy patient with submucous cleft palate and congenital cardiac defect, 22q11.2 microdeletion was identified at the age of 13 months. In the presented paper particular emphasis was placed on the issue of dental and orthodontic care in patients with changes in the oral cavity and the craniofacial area, as well as on the possibilities of treatment and prophylaxis. The necessity to perform a thorough examination of the oral cavity in infants was also underlined as a vital element of clinical assessment, in particular in the case of co-occurring structural defects of internal organs. PMID- 26982761 TI - Multiple, supernumerary retained teeth in the course of cleido-cranial dysplasia. A case report. AB - Cleido-cranial dysplasia, often referred to as Scheuthauer-Marie-Sainton syndrome, is an autosomal dominant disorder of the musculo-skeletal system. Patients with cleido-cranial dysplasia are characterized by short stature, frequent varus or valgus hip, kyphoscoliosis, underdevelopment of the scapulas and the sternum, incorrect number of ribs. The most characteristic feature is unilateral or bilateral, partial or total underdevelopment of clavicles. Mental development is not affected in this syndrome. Malocclusion, occlusal irregularities, multiple supernumerary teeth, impacted teeth, and persistent milk teeth are found in the stomatognathic system. Teeth often have abnormal anatomy. Gothic palate, cleft hard and soft palate are diagnosed. The aim of this paper is to present a case of a 12-year-old boy diagnosed with irregularities in the masticatory system involving an additional number of retained teeth. The boy was referred by an orthodontist for surgical and orthodontic team therapy. The case presented confirms the observations of other authors that only the multi specialty collaboration of a pediatrician, a geneticist, an orthopedist, an orthodontist, a maxillofacial surgeon, an implant prosthetic surgeon and a physiotherapist can provide proper diagnosis and treatment. PMID- 26982762 TI - Alkaptonuria--first inborn error of metabolism known for a century and new treatment option--preliminary report. AB - Alkaptonuria is a rare inborn error of metabolism, identified over a century ago. But its basic pathomechanism (i.e. ochronosis) is still not completely explained. Though clinical onset of osteoarthropathy and complications from other organs (including: heart and blood vessels, skin, eyes, kidneys) occurs at adult age, the symptoms are progressive, cause severe pains and significantly limit everyday life of the patients. Until now no effective therapeutic methods have been known in alkaptonuria. Recently, thanks to an initiative of the international patient organization for alkaptonuria, a hope for a potential treatment availability, appears. So, alkaptonuria is an example of a role of multidysciplinary care, cooperation and ongoing progress in the area of rare diseases. PMID- 26982763 TI - Challenges of caring for a patient with a rare disease--as demonstrated by Cornelia de Lange Syndrome. AB - There are over 12,500 diseases defined by European researchers as rare disorders occurring in less than 1:2000 live births. The majority of these manifest in childhood. The clinical picture of a rare disorder is dominated by intellectual disability of various severity and organ defects. Targeted therapy is not available for the majority of rare disorders, therefore multidisciplinary patient care is the only means of improving the quality and duration of the patient's life. In this paper, the authors share their experience organizing a system of care for patients with Cornelia de Lange Syndrome. Over the last 13 years, multidisciplinary diagnostics and consultations were provided to 92 patients and their families, including rehabilitation and psychological support. The model suggested here demonstrates a shorter diagnostic process, continuous contact with the patient, his/her family and pediatrician. Guidelines and recommendations regarding the particular rare disease should be published. PMID- 26982764 TI - Pediatric rehabilitation in children with rare diseases--preliminary report. AB - As consultants in rehabilitation medicine and pediatrics sometimes we realize that most of our patients and their families are left unsupported and alone in terms of rehabilitation therapy during the treatment of their primary disease. Probably we forget that rehabilitation should be an integral part of every treatment process. In the case of rare diseases, their basic treatment should be carried out in speciality facilities (speciality hospitals) where personel and equipment are able to run the most effective treatment. Rehabilitation medicine offers full range of cheap, non-invasive diagnostic tools. Well-chosen equipment can help with physical therapy and allow the independence of the child and full social integration. In an era of rapid change in civilization and progress of science, professionals use new technologies more often. This also refers to the field of rehabilitation medicine. Exoskeletons and lokomats created nowadays allow the use of new technologies in rehabilitation treatment processes. For specific disorders effective treatment may include even virtual reality (VR). Early initiation of the rehabilitation process can improve the therapeutic effects and the overall outcome of the treatment, identifying the needs and realizing the available goals of rehabilitation that could build the sense of safety in the family and enhance their trust in the therapeutic team. PMID- 26982765 TI - Procreation in families with inborn error of metabolism--new challenges for medical care. AB - Several years ago genetic counseling with the estimation of the risk of the disease in the next pregnancies of the same parents was the only offer for the family with a child with an inborn error of metabolism (IEM). Nowadays diagnostics and treatment of IEM improve. So there are more and more adult patients thinking about having their own offspring. Each woman with IEM who wants to have own child needs special medical care from preconception time up to postpartum period. Depending on the type of disease, such elements as the mother's diet and medicines used for her treatment may influence the foetus and child health and development. In the opposite the growing foetus may have an influence on mother's metabolic status and on her health complications. Therefore interdisciplinary team of specialists should be involved in the health care of women with inborn errors of metabolism. PMID- 26982766 TI - The principles of the transition process from paediatric to adult services in inborn errors of metabolism--own experience. AB - The transition from the paediatric to the adult service is a complex process that requires early planning to prepare young adults and their families for the transfer to the adult hospital. The article outlines the main principles of the successful transition period. Importantly, a young adult becomes an independent individual, interacts with medical professionals independently, and makes the appropriate choices. Both healthcare professionals and parents should facilitate the process of building new relationships between the adolescent and the adult metabolic teams. PMID- 26982767 TI - Economic aspects of rare diseases. AB - Economic problems related to the prevention, diagnosis and treatment of rare diseases are presented paying particular attention to the costs of financing treatment, including the issue of its refund, which is a fundamental and difficult to solve economic problem of the health care system. Rare diseases, despite the low frequency of occurrence, together cover a large group of diseases being a serious medical, social and economic problem. The adoption of Polish National Plan for Rare Diseases resulting from the recommendations of the Council of the European Union, the extension of institutional activities related to the area of public health and social initiatives seeking innovative solutions to create a model of social support for patients and their families, with very high complexity of the issues regarding rare diseases, results in the need for a coherent, comprehensive, system operations and adoption of comprehensive solutions. PMID- 26982768 TI - Ethical issues in rare diseases. AB - Scientific, technical and medical advances continue to raise consequential ethical questions and dilemmas also in the field of rare diseases. Difficult and complex issues of medical ethics in rare diseases are presented and several different ethical problems, like those regarding inborn errors of metabolism, are discussed. PMID- 26982769 TI - Polish activity within Orphanet Europe--state of art of database and services. AB - Orphanet is an international project aiming to help in improvement the diagnostic process, care and treatment of patients with rare diseases, and to provide information on development in research and new therapy. Orphanet is currently represented in 38 countries. The infrastructure and coordination activities are jointly funded by Inserm, the French Directorate General for Health, and the European Commission. Moreover, certain services are specially funded by other partners. Orphanet's activities in each country of the network are partially financed by national institutions and(or) specific contracts. In this paper we present the Orphanet portal as well as the Polish national activity within this project. PMID- 26982770 TI - A flexible fast spin echo triple-echo Dixon technique. AB - PURPOSE: To develop a flexible fast spin echo (FSE) triple-echo Dixon (FTED) technique. METHODS: An FSE pulse sequence was modified by replacing each readout gradient with three fast-switching bipolar readout gradients with minimal interecho dead time. The corresponding three echoes were used to generate three raw images with relative phase shifts of -theta, 0, and theta between water and fat signals. A region growing-based two-point Dixon phase correction algorithm was used to joint process two separate pairs of the three raw images, yielding a final set of water-only and fat-only images. The flexible FTED technique was implemented on 1.5T and 3.0T scanners and evaluated in five subjects for fat suppressed T2-weighted imaging and in one subject for post-contrast fat suppressed T1-weighted imaging. RESULTS: The flexible FTED technique achieved a high data acquisition efficiency, comparable to that of FSE, and was flexible in scan protocols. The joint two-point Dixon phase correction algorithm helped to ensure consistency in the processing of the two separate pairs of raw images. Reliable and uniform separation of water and fat was achieved in all of the test cases. CONCLUSION: The flexible FTED technique incorporates the benefits of both FSE and Dixon imaging and provided more flexibility than the original FTED in applications such as fat-suppressed T2-weighted and T1-weighted imaging. Magn Reson Med 77:1049-1057, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 26982771 TI - New Year. PMID- 26982773 TI - Evaluation of treatment with carboxymethylcellulose on chronic venous ulcers. AB - BACKGROUND: Among the chronic leg ulcers, venous ulcers are the most common and constitute a major burden to public health. Despite all technology available, some patients do not respond to established treatments. In our study, carboxymethylcellulose was tested in the treatment of refractory chronic venous ulcers. OBJECTIVE: To evaluate the efficacy of carboxymethylcellulose 20% on the healing of chronic venous ulcers refractory to conventional treatments. METHODS: This is an analytical, pre-experimental study. Thirty patients were included with refractory venous ulcers, and applied dressings with carboxymethylcellulose 20% for 20 weeks. The analysis was based on measurement of the area of ulcers, performed at the first visit and after the end of the treatment. RESULTS: There was a reduction of 3.9 cm2 of lesion area (p=0.0001), corresponding to 38.8% (p=0.0001). There was no interruption of treatment and no increase in lesion area in any patient. CONCLUSIONS: Carboxymethylcellulose 20% represents a low cost and effective therapeutic alternative for the treatment of refractory chronic venous ulcers. However, controlled studies are necessary to prove its efficacy. PMID- 26982774 TI - Correlation of serum IgE levels and clinical manifestations in patients with actinic prurigo. AB - BACKGROUND: Actinic prurigo is an idiopathic photodermatosis, the pathophysiology of which has been hypothesized to involve subtype IV type b (Th2) hypersensitive response, whereby IL4, IL5, and IL13 are secreted and mediate the production of B cells, IgE, and IgG4. OBJECTIVES: To examine the association of serum IgE levels and the clinical severity of injuries. METHODS: This case-control study comprised patients with a clinical and histopathological diagnosis of actinic prurigo, as well as clinically healthy subjects, from whom 3cc of peripheral blood was taken for immunoassay. Cases were classified by lesion severity as mild, moderate, and severe. Descriptive statistics were analyzed, and chi-square test was performed. RESULTS: We included 21 actinic prurigo patients and 21 subjects without disease; 11 patients with actinic prurigo had elevated serum IgE levels, and 10 had low serum levels. Six actinic prurigo (AP) patients with elevated serum levels of IgE had moderate injuries, 4 had severe injuries, and 1 had minor injuries. Eight out of 10 patients with normal IgE levels presented with minor injuries in the clinical evaluation. The 21 controls did not have increased serum IgE levels. CONCLUSIONS: Elevated IgE levels are associated with moderate to severe clinical lesions, suggesting that actinic prurigo entails a type IV subtype b hypersensitivity response in which Th2 cells predominate. PMID- 26982772 TI - Psoriasis: new comorbidities. AB - Psoriasis is a chronic inflammatory disease associated with several comorbidities. A few decades ago, it was considered an exclusive skin disease but today it is considered a multisystem disease. It is believed that 73% of psoriasis patients have at least one comorbidity. Studies have demonstrated the association of psoriasis with inflammatory bowel disease, uveitis, psychiatric disorders, metabolic syndrome and its components and cardiovascular diseases. The systemic inflammatory state seems to be the common denominator for all these comorbidities. This work aims at presenting a review of the current literature on some new comorbidities that are associated with psoriasis as osteoporosis, obstructive sleep apnea and chronic obstructive pulmonary disease. While there is still controversy, many studies already point to a possible bone involvement in patients with psoriasis, especially in the male group, generally less affected by osteoporosis. Psoriasis and chronic obstructive pulmonary disease present some risk factors in common as obesity, smoking and physical inactivity. Besides, both diseases are associated with the metabolic syndrome. These factors could be potential confounders in the association of the two diseases. Further prospective studies with control of those potential confounders should be developed in an attempt to establish causality. Existing data in the literature suggest that there is an association between obstructive sleep apnea and psoriasis, but studies performed until now have involved few patients and had a short follow-up period. It is, therefore, premature to assert that there is indeed a correlation between these two diseases. PMID- 26982775 TI - Leprosy incidence, characterization of cases and correlation with household and cases variables of the Brazilian states in 2010. AB - BACKGROUND: Leprosy is millenary disease and still persists in several countries. OBJECTIVES: To estimate the incidence of leprosy in the Brazilian states and for the country in the year 2010; to describe the cases reported according to the studied variables; to verify the correlation between the overall incidence and the studied variables. METHODS: Ecological descriptive study, with population data from the 27 states, 2010. Information about reported cases were collected: gender, race, percentage of patients younger than 15 years old and living conditions. The analysis was performed using percentages, means, incidence rates and the Spearman correlation test. RESULTS: The states of Mato Grosso and Tocantins recorded the highest incidence rates; Rio Grande do Sul and Santa Catarina, the lowest; there was a higher incidence of leprosy among men; the incidence of leprosy increases proportionally with the nonwhites among the inhabitants; patients younger than 15 years; the average number of residents per household; and a decrease in coverage of water supply and presence of bathrooms. CONCLUSION: The incidence of leprosy is related to factors as gender, race and house conditions (p<0,05 for all). PMID- 26982776 TI - Ultraviolet index: a light in atopic dermatitis and vitamin D research? AB - BACKGROUND: The role played by vitamin D in atopic dermatitis is controversial and has been the focus of many studies. The ultraviolet index has not been considered in this type of research. OBJECTIVES: The objectives of the study were to assess 25-hydroxy vitamin D [25(OH)D] serum level in atopic dermatitis patients and control group, to investigate the association between atopic dermatitis clinical severity (using the SCORing Atopic Dermatitis index - SCORAD) and 25(OH)D serum levels, and to evaluate the independent predictors, including Ultraviolet index, SCORAD and 25(OH)D. METHODS: We conducted a cross-sectional study of 106 atopic dermatitis patients. A control group was matched with a subsample of 54 participants with atopic dermatitis. SCORAD index, laboratory tests, and local Ultraviolet index were assessed. RESULTS: The atopic dermatitis patients had serum 25(OH)D levels and mean UVI significantly higher than the control group. Immunoglobulin E and Ultraviolet index were associated with the SCORAD index. Skin type, age and Ultraviolet index were independent predictors of 25(OH)D. CONCLUSIONS: Although statistically significant, the different levels of 25(OH)D between the paired groups may be attributed to the higher mean Ultraviolet index in atopic dermatitis patients. Since Ultraviolet index is an independent predictor of SCORAD index and of 25(OH)D level, it may work as a confounding factor in studies involving atopic dermatitis and 25(OH)D and must be considered in this kind of research. PMID- 26982777 TI - Melanoma patterns of distant relapse: a study of 108 cases from a South Brazilian center. AB - BACKGROUND: The incidence of cutaneous melanoma has increased over the last decades. Recurrences occur most frequently within the first 2-3 years after diagnosis but patients carry a lifelong risk of relapse. Nevertheless, there is no consensus in the literature on what screening tests patients should undergo. OBJECTIVES: To evaluate the most common melanoma metastasis sites among a South Brazilian population from a city with one of the highest melanoma rates, and establish the best screening method for these patients. METHODS: A cross sectional retrospective study of 108 consecutive melanoma patients followed up at a center from 2009 to 2013. Data were collected on demographic and tumoral characteristics, as well as the site of the first diagnosed metastasis. RESULTS: Patients were divided into 3 groups for analytical purposes: Non-visceral metastases (48% of patients), visceral metastasis (39%) and brain metastasis (13%). We tried to correlate age, gender, mean Breslow thickness, mitosis and death rates with the aforementioned groups but none showed any statistically significant association. CONCLUSION: Melanoma patients must be monitored to detect early relapse and subsequent effective treatment but the best follow-up strategy remains to be established. PMID- 26982778 TI - Variants of CARD14 gene and psoriasis vulgaris in southern Chinese cohort. AB - BACKGROUND: Recent mutation analysis identified several missense mutations in CARD14 in psoriasis. OBJECTIVES: We performed the genomic sequence analysis on CARD14 in southern Chinese Han Cantonese with Psoriasis Vulgaris (PsV) to reveal more causative missense mutations. METHODS: A total of 131 patients with PsV and 207 matched controls were included. We conducted sequence analysis of all the exon and exon-intron boundaries of CARD14 in the group of PsV patients and subsequent case control analysis of potential sequence variants of significance. RESULTS: We found five rare mutations and four of them are annotated or reported. Only the variant (c.1291C>G) has not been reported and annotated, but the variant was also found in controls. No significant difference was detected among all rare variant allele frequencies of patients and controls. CONCLUSION: None of the new definite variants were pathogenic. The other pathogenic mutations for PsV are still elusive in our cohort. PMID- 26982780 TI - Skin barrier in rosacea. AB - Recent studies about the cutaneous barrier demonstrated consistent evidence that the stratum corneum is a metabolically active structure and also has adaptive functions, may play a regulatory role in the inflammatory response with activation of keratinocytes, angiogenesis and fibroplasia, whose intensity depends primarily on the intensity the stimulus. There are few studies investigating the abnormalities of the skin barrier in rosacea, but the existing data already show that there are changes resulting from inflammation, which can generate a vicious circle caused a prolongation of flare-ups and worsening of symptoms. This article aims to gather the most relevant literature data about the characteristics and effects of the state of the skin barrier in rosacea. PMID- 26982779 TI - Brazilian guidelines for diagnosis, treatment and follow-up of primary cutaneous melanoma - Part II. AB - The last Brazilian guidelines on melanoma were published in 2002. Development in diagnosis and treatment made updating necessary. The coordinators elaborated ten clinical questions, based on PICO system. A Medline search, according to specific MeSH terms for each of the 10 questions was performed and articles selected were classified from A to D according to level of scientific evidence. Based on the results, recommendations were defined and classified according to scientific strength. The present Guidelines were divided in two parts for editorial and publication reasons. In this second part, the following clinical questions were answered: 1) which patients with primary cutaneous melanoma benefit from sentinel lymph node biopsy? 2) Follow-up with body mapping is indicated for which patients? 3) Is preventive excision of acral nevi beneficious to patients? 4) Is preventive excision of giant congenital nevi beneficious to patients? 5) How should stages 0 and I primary cutaneous melanoma patients be followed? PMID- 26982781 TI - Patch-test results in children and adolescents: systematic review of a 15-year period. AB - The number of studies on patch-test results in children and adolescents has gradually increased in recent years, thus stimulating reviews. This paper is a systematic review of a 15-year period devoted to studying the issue. Variations pertaining to the number and age groups of tested children and/or adolescents, the number of subjects with atopy/atopic dermatitis history, the quantity, type and concentrations of the tested substances, the test technique and type of data regarding clinical relevance, must all be considered in evaluating these studies, as they make it harder to formulate conclusions. The most common allergens in children were nickel, thimerosal, cobalt, fragrance, lanolin and neomycin. In adolescents, they were nickel, thimerosal, cobalt, fragrance, potassium dichromate, and Myroxylon pereirae. Knowledge of this matter aids health professionals in planning preventive programs aimed at improving children's quality of life and ensuring that their future prospects are not undermined. PMID- 26982782 TI - Cutaneous invasion from sarcomatoid urothelial carcinoma: clinical and dermatopathologic features. AB - In Brazil, without considering the non-melanoma skin tumors, bladder cancer in men is the eighth most common, and the urothelial carcinoma or transitional cell carcinoma is the most common among these. Cutaneous metastases from urothelial neoplasms appear as single or multiple erythematous, infiltrated nodules or plaques, and like other cases of distant disease, it is indicative of poor prognosis. The invasive urothelial carcinoma is recognized for its ability to present divergent differentiation and morphological variants. The sarcomatoid urothelial carcinoma is a rare cancer that consists of two different components: one composed of epithelial tissue and the other with sarcomatoid features of mesenchymal origin. The authors describe a case of cutaneous metastasis of sarcomatoid urothelial carcinoma in a 63-year-old male patient. PMID- 26982783 TI - Cutaneous involvement by cytomegalovirus in a renal transplant recipient as an indicator of severe systemic infection. AB - Cytomegalovirus is an opportunistic virus that commonly affects immunosuppressed patients. Cutaneous involvement by this virus is rare and occurs in significantly immunocompromised hosts, with a poor prognosis. Skin ulcers may represent the first sign of systemic infection by cytomegalovirus in these patients. Herein, a case of a systemic infection by Cytomegalovirus presenting as genital and oral ulcers in a kidney-transplant recipient is reported. PMID- 26982784 TI - Erosive lichen planus: a therapeutic challenge. AB - Erosive lichen planus is an uncommon variant of lichen planus. Chronic erosions of the soles, accompanied by intense and disabling pain, are some of its most characteristic manifestations. We present the case of a woman who developed oral and plantar erosive lichen planus associated with lichen planus pigmentosus and ungueal lichen planus that were diagnosed after several years. The patient failed to respond to multiple therapies requiring longstanding medication but remained refractory. Knowledge of the treatment options for erosive lichen planus is insufficient. Further research is required to clarify their effectiveness, ideally adopting an evidence-based methodology. PMID- 26982785 TI - Infantile generalized hypertrichosis caused by topical minoxidil. AB - Rare cases of hypertrichosis have been associated with topically applied minoxidil. We present the first reported case in the Brazilian literature of generalized hypertrichosis affecting a 5-year-old child, following use of minoxidil 5%, 20 drops a day, for hair loss. The laboratory investigation excluded hyperandrogenism and thyroid dysfunction. Topical minoxidil should be used with caution in children. PMID- 26982786 TI - Phaeohyphomycosis in renal transplantation: report of two cases. AB - Phaeohyphomycosis is an infection caused by a filamentous fungus that contains pigment melanin in its cell wall. We report two cases caused by Exophiala sp. emphasizing the clinical variability of the disease, as well as diagnostic and therapeutic difficulties of this opportunistic infection in immunosuppressed patients (kidney transplant). PMID- 26982787 TI - Sweet's syndrome associated with cellulitis - a challenging diagnosis. AB - Sweet's syndrome is a neutrophilic dermatosis with worldwide distribution that has been associated with inflammatory autoimmune diseases, infections, malignancies, drugs, and pregnancy. The disease is idiopathic in up to 50% of patients. A 64-year-old woman, diagnosed with right limb cellulitis (4 days of evolution), was seen at our department, due to persistent cellulitis and progressive appearance of painful nodules and plaques in both shins and the right forearm (2 days of evolution). Taken together, clinical, laboratory and pathological data suggested the diagnosis of Sweet's syndrome, probably secondary to cellulitis of the right inferior limb. We suggest that cellulitis may be associated with Sweet's syndrome, a rare association in the literature. PMID- 26982788 TI - Myxofibrosarcoma - Case report. AB - Myxofibrosarcoma is recognized as a malignant neoplasm of fibroblastic origin with increased prevalence in the elderly, presenting as nodules or tumors that may extend to the dermis and skeletal muscle, preferably in the lower limbs. Histologically it is characterized by a proliferation of spindle cells in a myxoid stroma. Myxofibrosarcoma has a high potential for local recurrence and metastasis, mainly when it presents a high or intermediate histological grade. We report the case of an eighty-four year old patient with a difficult diagnosis of a highly aggressive tumor. PMID- 26982789 TI - Pretibial mucinosis in an euthyroid patient. AB - A case of exuberant pretibial mucinosis in a patient with normal thyroid function is reported. A review of literature on possible etiologies other than thyroid disease for the accumulation of mucin in the pretibial area is presented. In the patient described, it is possible that vascular insufficiency is involved. However, this is not the only factor responsible for the accumulation of mucin, since there are still unidentified causes and many patients with vascular diseases do not develop similar injuries. PMID- 26982790 TI - Surgical management for large chest keloids with internal mammary artery perforator flap. AB - Therapy for large symptomatic keloids is often plagued with complicated reconstruction manner and recurrence. This article reports a rare treatment combination for a chest keloid with internal mammary artery perforator flap reconstruction and radiation therapy. We excised the keloid and covered the defect with an internal mammary artery perforator flap. Immediate electron-beam irradiation therapy was applied on the second postoperative day. There was no sign of recurrence over the follow-up period of 18 months. The combination of internal mammary artery perforator flap and immediate radiation therapy is useful when faced with chest keloids of similar magnitude and intractability. PMID- 26982791 TI - Pitted keratolysis. AB - Pitted keratolysis is a skin disorder that affects the stratum corneum of the plantar surface and is caused by Gram-positive bacteria. A 30-year-old male presented with small punched-out lesions on the plantar surface. A superficial shaving was carried out for scanning electron microscopy. Hypokeratosis was noted on the plantar skin and in the acrosyringium, where the normal elimination of corneocytes was not seen. At higher magnification (x 3,500) bacteria were easily found on the surface and the described transversal bacterial septation was observed. PMID- 26982792 TI - Cutaneous ectopic schistosomiasis: diagnostic challenge. AB - Cutaneous schistosomiasis is a rare clinical manifestation of schistosomiasis, an infectious and parasitic disease, caused in Brazil by the trematode Schistosoma mansoni. The lesions are due to the deposition of eggs or, rarely, adult worms, usually involving the genital and groin areas. Extra-genital lesions occur mainly on the torso as papules of zosteriform appearance. The case of a patient with ectopic cutaneous schistosomiasis is reported in this article, due to the rarity of its occurrence and its difficult clinical diagnosis. PMID- 26982793 TI - Syndrome in question. AB - Ross syndrome is a rare disease characterized by peripheral nervous system dysautonomia with selective degeneration of cholinergic fibers. It is composed by the triad of unilateral or bilateral segmental anhidrosis, deep hyporeflexia and Holmes-Adie's tonic pupil. The presence of compensatory sweating is frequent, usually the symptom that most afflicts patients. The aspects of the syndrome are put to discussion due to the case of a male patient, caucasian, 47 years old, with clinical onset of 25 years. PMID- 26982795 TI - Effect of Electron-Hole Overlap and Exchange Interaction on Exciton Radiative Lifetimes of CdTe/CdSe Heteronanocrystals. AB - Wave function engineering has become a powerful tool to tailor the optical properties of semiconductor colloidal nanocrystals. Core-shell systems allow to design the spatial extent of the electron (e) and hole (h) wave functions in the conduction- and valence bands, respectively. However, tuning the overlap between the e- and h-wave functions not only affects the oscillator strength of the coupled e-h pairs (excitons) that are responsible for the light emission, but also modifies the e-h exchange interaction, leading to an altered excitonic energy spectrum. Here, we present exciton lifetime measurements in a strong magnetic field to determine the strength of the e-h exchange interaction, independently of the e-h overlap that is deduced from lifetime measurements at room temperature. We use a set of CdTe/CdSe core/shell heteronanocrystals in which the electron-hole separation is systematically varied. We are able to unravel the separate effects of e-h overlap and e-h exchange on the exciton lifetimes, and we present a simple model that fully describes the recombination lifetimes of heteronanostructures (HNCs) as a function of core volume, shell volume, temperature, and magnetic fields. PMID- 26982794 TI - Use of clobetasol in lacquer for plaque psoriasis treatment. AB - Clobetasol benefits to control psoriasis lesions are well defined, but there were not studies about its action when used in lacquer vehicle to control skin lesions. A double-blind study was conducted with 40 patients that utilized clobetasol 0.05% in one hemibody and just the vehicle in the other hemibody. Twenty of them used petrolatum as vehicle and the others used lacquer. An assessment was conducted using the clinical index PASI and a quality of life questionnaire (Dermatological Life Quality Index). There was no statistical difference between groups. There was a trend of favorable response particularly in the hemibody treated with clobetasol. PMID- 26982796 TI - A new cytotoxic diterpenoid glycoside from the leaves of Blumea lacera and its effects on apoptosis and cell cycle. AB - A new diterpenoid glycoside, 6E,10E,14Z-(3S)-17-hydroxygeranyllinalool-17-O-beta d-glucopyranosyl-(1 -> 2)-[alpha-l-rhamnopyranosyl-(1 -> 6)]-beta-d glucopyranoside (1) together with the known diterpenoid glycoside (2) and two known flavonoid glycosides (3, 4) were isolated from the methanol extract of Blumea lacera leaves. The structures were determined by the interpretation of their spectroscopic data and comparison with the literature. All compounds were isolated for the first time from B. lacera and evaluated for their cytotoxic activity. Only the new compound (1) showed strong cytotoxic activity with the lowest IC50 value (8.3 MUM) being displayed against MCF-7 breast cancer cells. In apoptosis and cell cycle analysis, 1 revealed strong apoptotic activity against MCF-7 cells (45.5% AV+/PI-) after 24 h, but showed no arresting of any of the cell cycle phases in MCF-7. PMID- 26982797 TI - The "Gatekeeper" Residue Influences the Mode of Binding of Acetyl Indoles to Bromodomains. AB - Small-molecule hits for the bromodomains of CREBBP and BAZ2B have been identified by scaffold hopping followed by docking of a set of ~200 compounds containing the acetyl indole scaffold. Chemical synthesis of nearly 30 derivatives has resulted in ligands of representatives of three subfamilies of human bromodomains with favorable ligand efficiency. The X-ray crystal structures of three different bromodomains (CREBBP, BAZ2B, and BRPF1b) in complex with acetyl indole derivatives reveal the influence of the gatekeeper residue on the orientation of small-molecule ligands in the acetyl lysine binding site. PMID- 26982798 TI - Measurement of intrinsic rise times for various L(Y)SO and LuAG scintillators with a general study of prompt photons to achieve 10 ps in TOF-PET. AB - The coincidence time resolution (CTR) of scintillator based detectors commonly used in positron emission tomography is well known to be dependent on the scintillation decay time (taud) and the number of photons detected (n'), i.e. CTR proportional variant ?taud/n'. However, it is still an open question to what extent the scintillation rise time (taur) and other fast or prompt photons, e.g. Cherenkov photons, at the beginning of the scintillation process influence the CTR. This paper presents measurements of the scintillation emission rate for different LSO type crystals, i.e. LSO:Ce, LYSO:Ce, LSO:Ce codoped Ca and LGSO:Ce. For the various LSO-type samples measured we find an average value of 70 ps for the scintillation rise time, although some crystals like LSO:Ce codoped Ca seem to have a much faster rise time in the order of 20 ps. Additional measurements for LuAG:Ce and LuAG:Pr show a rise time of 535 ps and 251 ps, respectively. For these crystals, prompt photons (Cherenkov) can be observed at the beginning of the scintillation event. Furthermore a significantly lower rise time value is observed when codoping with calcium. To quantitatively investigate the influence of the rise time to the time resolution we measured the CTR with the same L(Y)SO samples and compared the values to Monte Carlo simulations. Using the measured relative light yields, rise- and decay times of the scintillators we are able to quantitatively understand the measured CTRs in our simulations. Although the rise time is important to fully explain the CTR variation for the different samples tested we determined its influence on the CTR to be in the order of a few percent only. This result is surprising because, if only photonstatistics of the scintillation process is considered, the CTR would be proportional to the square root of the rise time. The unexpected small rise time influence on the CTR can be explained by the convolution of the scintillation rate with the single photon time resolution (SPTR) of the photodetector and the photon travel spread (PTS) in the crystal. The timing benefits of prompt photons at the beginning of the scintillation process (Cherenkov etc) are further studied, which leads to the conclusion that the scintillation rise time, SPTR and PTS have to be lowered simultaneously to fully profit from these fast photons in order to improve the CTR significantly. PMID- 26982799 TI - The rate of joint replacement in osteoarthritis depends on the patient's socioeconomic status. AB - Background and purpose - Assessment of potential disparities in access to care is a vital part of achieving equity in health and healthcare. We have therefore studied the effect of socioeconomic status (SES) on the rates of knee and hip replacement due to osteoarthritis. Methods - This was a cohort study in Skane, Sweden. We included all residents aged >= 35 years with consultations between 2004 and 2013 for hip or knee osteoarthritis. We retrieved individual information on income, education, and occupation and evaluated the rates of knee and hip replacement according to SES, with adjustment for age and sex. Professionals, legislators, senior officials, and managers, and individuals with the longest education, served as the reference group. Results - We followed 50,498 knee osteoarthritis patients (59% women) and 20,882 hip osteoarthritis patients (58% women). The mutually adjusted rate of knee replacement was lower in those with an elementary occupation (hazard ratio (HR) = 0.81, 95% CI: 0.72-0.92), in craft workers and those with related trades (HR = 0.88, CI: 0.79-0.98), and in skilled agricultural/fishery workers (HR = 0.83, CI: 0.72-0.96), but higher in the 2 least educated groups (HR = 1.2 in both). The rate of hip replacement was lower in those with an elementary occupation (HR = 0.77, 95% CI: 0.68-0.87), in plant and machine operators/assemblers (HR = 0.83, CI: 0.75-0.93), and service workers/shop assistants (HR = 0.88, CI: 0.80-0.96). The rate of hip replacement was higher in the highest income group (HR = 1.1, 95% CI: 1.0-1.2). Interpretation - There was a lower rate of joint replacement in osteoarthritis patients working in professions often associated with lower socioeconomic status, suggesting inequity in access to care. However, the results are not unanimous, as the rate of knee replacement was higher in the least educated groups. PMID- 26982800 TI - Cross-Neutralization between Human and African Bat Mumps Viruses. AB - Recently, a new paramyxovirus closely related to human mumps virus (MuV) was detected in bats. We generated recombinant MuVs carrying either or both of the fusion and hemagglutinin-neuraminidase bat virus glycoproteins. These viruses showed replication kinetics similar to human MuV in cultured cells and were neutralized efficiently by serum from healthy humans. PMID- 26982804 TI - Beyond Attributable Burden: Estimating the Avoidable Burden of Disease Associated with Household Air Pollution. AB - BACKGROUND: The Global Burden of Disease (GBD) studies have transformed global understanding of health risks by producing comprehensive estimates of attributable disease burden, or the current disease that would be eliminated if a risk factor did not exist. Yet many have noted the greater policy significance of avoidable burden, or the future disease that could actually be eliminated if a risk factor were eliminated today. Avoidable risk may be considerably lower than attributable risk if baseline levels of exposure or disease are declining, or if a risk factor carries lagged effects on disease. As global efforts to deliver clean cookstoves accelerate, a temporal estimation of avoidable risk due to household air pollution (HAP) becomes increasingly important, particularly in light of the rapid uptake of modern stoves and ongoing epidemiologic transitions in regions like South and Southeast Asia. METHODS AND FINDINGS: We estimate the avoidable burden associated with HAP using International Futures (IFs), an integrated forecasting system that has been used to model future global disease burdens and risk factors. Building on GBD and other estimates, we integrated a detailed HAP exposure estimation and exposure-response model into IFs. We then conducted a counterfactual experiment in which HAP exposure is reduced to theoretical minimum levels in 2015. We evaluated avoidable mortality and DALY reductions for the years 2015 to 2024 relative to a Base Case scenario in which only endogenous changes occurred. We present results by cause and region, looking at impacts on acute lower respiratory infection (ALRI) and four noncommunicable diseases (NCDs). We found that just 2.6% of global DALYs would be averted between 2015 and 2024, compared to 4.5% of global DALYs attributed to HAP in the 2010 GBD study, due in large part to the endogenous tendency towards declining traditional stove usage in the IFs base case forecast. The extent of diminished impact was comparable for ALRI and affected NCDs, though for different reasons. ALRI impacts diminish due to the declining burden of ALRI in the base case forecast, particularly apparent in South Asia and Southeast Asia. Although NCD burdens are rising in regions affected by HAP, the avoidable risk of NCD nonetheless diminishes due to lagged effects. Because the stove transition and the decline of ALRI are proceeding more slowly in Sub-Saharan Africa, avoidable impacts would also be more persistent (3.9% of total DALY due to HAP) compared to South Asia (3.6%) or Southeast Asia (2.5%). CONCLUSIONS: Our results illustrate how a temporal dynamic calculation of avoidable risk may yield different estimates, compared to a static attributable risk estimate, of the global and regional burden of disease. Our results suggest a window of rising and falling opportunity for HAP interventions that may have already closed in Southeast Asia and may be closing quickly in South Asia, but may remain open longer in Sub-Saharan Africa. A proper accounting of global health priorities should apply an avoidable risk framework that considers the role of ongoing social, economic and health transitions in constantly altering the disease and risk factor landscape. PMID- 26982801 TI - Traditional Banana Diversity in Oceania: An Endangered Heritage. AB - This study aims to understand the genetic diversity of traditional Oceanian starchy bananas in order to propose an efficient conservation strategy for these endangered varieties. SSR and DArT molecular markers are used to characterize a large sample of Pacific accessions, from New Guinea to Tahiti and Hawaii. All Pacific starchy bananas are shown of New Guinea origin, by interspecific hybridization between Musa acuminata (AA genome), more precisely its local subspecies M. acuminata ssp. banksii, and M. balbisiana (BB genome) generating triploid AAB Pacific starchy bananas. These AAB genotypes do not form a subgroup sensu stricto and genetic markers differentiate two subgroups across the three morphotypes usually identified: Iholena versus Popoulu and Maoli. The Popoulu/Maoli accessions, even if morphologically diverse throughout the Pacific, cluster in the same genetic subgroup. However, the subgroup is not strictly monophyletic and several close, but different genotypes are linked to the dominant genotype. One of the related genotypes is specific to New Caledonia (NC), with morphotypes close to Maoli, but with some primitive characters. It is concluded that the diffusion of Pacific starchy AAB bananas results from a series of introductions of triploids originating in New Guinea area from several sexual recombination events implying different genotypes of M. acuminata ssp. banksii. This scheme of multiple waves from the New Guinea zone is consistent with the archaeological data for peopling of the Pacific. The present geographic distribution suggests that a greater diversity must have existed in the past. Its erosion finds parallels with the erosion of cultural traditions, inexorably declining in most of the Polynesian or Melanesian Islands. Symmetrically, diversity hot spots appear linked to the local persistence of traditions: Maoli in New Caledonian Kanak traditions or Iholena in a few Polynesian islands. These results will contribute to optimizing the conservation strategy for the ex-situ Pacific Banana Collection supported collectively by the Pacific countries. PMID- 26982806 TI - Dendritic Cell-T-Cell Circuitry in Health and Changes in Inflammatory Bowel Disease and Its Treatment. AB - BACKGROUND: Dendritic, antigen-presenting cells (DCs) determine not only whether lymphocytes produce different types of immune response but also tissue-homing profiles of lymphocytes they stimulate. For example, in health, mucosal DC stimulate T cells focused to home to the mucosa; DC/T-cell circuitry thus targets immune responses to specific tissue locations. Therapies being introduced for inflammatory bowel disease (IBD) include antibodies to gut-homing molecules such as alpha4beta7 (Vedolizumab) used ostensibly to block gut-homing lymphocytes. However, such lymphocytes are dependent on the tissue specificity of DC that stimulated them. KEY MESSAGES: In health, blood DCs have the potential to home to multiple tissues including gut (alpha4beta7+) and skin (CLA+). DCs have become gut-specific within the intestinal microenvironment stimulated partially by local retinoid to express alpha4beta7 (mucosal homing marker) and/or CCR9 (ileal homing marker) in the absence of skin-specific indicators. They spread veiled extensions, sample their environment, acquire/process antigens, produce cytokines and initiate innate immunity. Myeloid DC also traffic to draining lymph nodes where compartmentalization of adaptive immune responses is determined by DCs from the site of antigen exposure which dictate the homing profiles of lymphocytes they stimulate. In IBD, site and activity of disease are reflected in changes in homing/activation of gut DCs and T-cells they stimulate and also, in greater gut specificity and activation of blood DC. Homing potential of DC can be modulated toward mucosa or skin by vitamins A and D, respectively. Infliximab or interleukin-6 can divert homing profiles toward skin, perhaps predisposing to skin involvement in IBD. Probiotic bacteria or their products can also change homing profiles of gut DC toward skin homing and away from gut. CONCLUSIONS: In conclusion, development of gut focused inflammation and its treatment relies on changes in DC tissue specificity; therefore, removal or diversion of gut-homing DC as well as T-cells is likely to be critical in prevention of gut-focused inflammation in IBD. PMID- 26982805 TI - Antigen-Specific Antibody Glycosylation Is Regulated via Vaccination. AB - Antibody effector functions, such as antibody-dependent cellular cytotoxicity, complement deposition, and antibody-dependent phagocytosis, play a critical role in immunity against multiple pathogens, particularly in the absence of neutralizing activity. Two modifications to the IgG constant domain (Fc domain) regulate antibody functionality: changes in antibody subclass and changes in a single N-linked glycan located in the CH2 domain of the IgG Fc. Together, these modifications provide a specific set of instructions to the innate immune system to direct the elimination of antibody-bound antigens. While it is clear that subclass selection is actively regulated during the course of natural infection, it is unclear whether antibody glycosylation can be tuned, in a signal-specific or pathogen-specific manner. Here, we show that antibody glycosylation is determined in an antigen- and pathogen-specific manner during HIV infection. Moreover, while dramatic differences exist in bulk IgG glycosylation among individuals in distinct geographical locations, immunization is able to overcome these differences and elicit antigen-specific antibodies with similar antibody glycosylation patterns. Additionally, distinct vaccine regimens induced different antigen-specific IgG glycosylation profiles, suggesting that antibody glycosylation is not only programmable but can be manipulated via the delivery of distinct inflammatory signals during B cell priming. These data strongly suggest that the immune system naturally drives antibody glycosylation in an antigen specific manner and highlights a promising means by which next-generation therapeutics and vaccines can harness the antiviral activity of the innate immune system via directed alterations in antibody glycosylation in vivo. . PMID- 26982808 TI - Coupling Demographic and Genetic Variability from Archived Collections of European Anchovy (Engraulis encrasicolus). AB - It is well known that temporal fluctuations in small populations deeply influence evolutionary potential. Less well known is whether fluctuations can influence the evolutionary potentials of species with large census sizes. Here, we estimated genetic population parameters from as survey of polymorphic microsatellite DNA loci in archived otoliths from Adriatic European anchovy (Engraulis encrasicolus), a fish with large census sizes that supports numerous local fisheries. Stocks have fluctuated greatly over the past few decades, and the Adriatic fishery collapsed in 1987. Our results show a significant reduction of mean genetic parameters as a consequence of the population collapse. In addition, estimates of effective population size (Ne) are much smaller than those expected in a fishes with large population census sizes (Nc). Estimates of Ne indicate low effective population sizes, even before the population collapse. The ratio Ne/Ne ranged between 10-6 and 10-8, indicating a large discrepancy between the anchovy gene pool and population census size. Therefore, anchovy populations may be more vulnerable to fishery effort and environmental change than previously thought. PMID- 26982809 TI - When to Start Immunomodulators in Inflammatory Bowel Disease? AB - BACKGROUND: Immunomodulators (IMMs), including thiopurines (TPs) and methotrexate (MTX), are commonly used in the treatment of inflammatory bowel disease (IBD). KEY MESSAGES: In ulcerative colitis (UC), TPs have modest steroid-sparing effects and established efficacy in maintenance of remission. The role of MTX in UC is unclear but current evidence suggests no benefit over placebo. In Crohn's disease (CD), MTX is not effective for induction but has a modest steroid-sparing effect and is superior to placebo in maintenance of remission in responders. The addition of MTX to infliximab reduces immunogenicity and boosts infliximab levels but does not improve outcomes in active CD. TPs are not effective for induction of remission in CD but have proven steroid-sparing effects and modest efficacy in maintenance of remission and prevention of postoperative recurrence. Although effective in pediatric CD, recent evidence has questioned the benefit of early TPs in newly diagnosed adult CD. The addition of TPs to infliximab reduces immunogenicity and inflammatory markers, leads to higher infliximab levels and improves outcomes in patients with early disease. However, the benefit of continued TP therapy in this setting is unclear and should be weighed against possible side effects including an increased risk of opportunistic infections, lymphoma and non-melanoma skin cancer. CONCLUSIONS: IMMs are an important therapeutic option in IBD particularly in non-severe steroid-dependent disease and for maintenance of remission. Combination with anti-TNF agents is an important emerging option as part of a treat-to-target strategy but further research regarding patient selection, long-term use and de-escalation options is needed. PMID- 26982807 TI - Evaluation of a Mixing versus a Cycling Strategy of Antibiotic Use in Critically Ill Medical Patients: Impact on Acquisition of Resistant Microorganisms and Clinical Outcomes. AB - OBJECTIVE: To compare the effect of two strategies of antibiotic use (mixing vs. cycling) on the acquisition of resistant microorganisms, infections and other clinical outcomes. METHODS: Prospective cohort study in an 8-bed intensive care unit during 35- months in which a mixing-cycling policy of antipseudomonal beta lactams (meropenem, ceftazidime/piperacillin-tazobactam) and fluoroquinolones was operative. Nasopharyngeal and rectal swabs and respiratory secretions were obtained within 48h of admission and thrice weekly thereafter. Target microorganisms included methicillin-resistant S. aureus, vancomycin-resistant enterococci, third-generation cephalosporin-resistant Enterobacteriaceae and non fermenters. RESULTS: A total of 409 (42%) patients were included in mixing and 560 (58%) in cycling. Exposure to ceftazidime/piperacillin-tazobactam and fluoroquinolones was significantly higher in mixing while exposure to meropenem was higher in cycling, although overall use of antipseudomonals was not significantly different (37.5/100 patient-days vs. 38.1/100 patient-days). There was a barely higher acquisition rate of microorganisms during mixing, but this difference lost its significance when the cases due to an exogenous Burkholderia cepacia outbreak were excluded (19.3% vs. 15.4%, OR 0.8, CI 0.5-1.1). Acquisition of Pseudomonas aeruginosa resistant to the intervention antibiotics or with multiple-drug resistance was similar. There were no significant differences between mixing and cycling in the proportion of patients acquiring any infection (16.6% vs. 14.5%, OR 0.9, CI 0.6-1.2), any infection due to target microorganisms (5.9% vs. 5.2%, OR 0.9, CI 0.5-1.5), length of stay (median 5 d for both groups) or mortality (13.9 vs. 14.3%, OR 1.03, CI 0.7-1.3). CONCLUSIONS: A cycling strategy of antibiotic use with a 6-week cycle duration is similar to mixing in terms of acquisition of resistant microorganisms, infections, length of stay and mortality. PMID- 26982810 TI - Occupational exposure limit for silver nanoparticles: considerations on the derivation of a general health-based value. AB - With the increased production and widespread commercial use of silver nanoparticles (AgNPs), human and environmental exposures to silver nanoparticles are inevitably increasing. In particular, persons manufacturing and handling silver nanoparticles and silver nanoparticle containing products are at risk of exposure, potentially resulting in health hazards. While silver dusts, consisting of micro-sized particles and soluble compounds have established occupational exposure limits (OELs), silver nanoparticles exhibit different physicochemical properties from bulk materials. Therefore, we assessed silver nanoparticle exposure and related health hazards in order to determine whether an additional OEL may be needed. Dosimetric evaluations in our study identified the liver as the most sensitive target organ following inhalation exposure, and as such serves as the critical target organ for setting an occupational exposure standard for airborne silver nanoparticles. This study proposes an OEL of 0.19 MUg/m(3) for silver nanoparticles derived from benchmark concentrations (BMCs) from subchronic rat inhalation toxicity assessments and the human equivalent concentration (HEC) with kinetic considerations and additional uncertainty factors. It is anticipated that this level will protect workers from potential health hazards, including lung, liver, and skin damage. PMID- 26982811 TI - Expression Profiling of Developing Zebrafish Retinal Cells. AB - During retinal development, a variety of different types of neurons are produced. Understanding how each of these types of retinal nerve cells is generated is important from a developmental biology perspective. It is equally important if one is interested in how to regenerate cells after an injury or a disease. To gain more insight into how retinal neurons develop in the zebrafish, we performed single-cell mRNA profiling and in situ hybridizations (ISHs) on retinal sections and whole-mount zebrafish. Through the series of ISHs, designed and performed solely by undergraduate students in the laboratory, we were able to retrospectively identify our single-cell mRNA profiles as most likely coming from developing amacrine cells. Further analysis of these profiles will reveal genes that can be mutated using genome editing techniques. Together these studies increase our knowledge of the genes driving development of different cell types in the zebrafish retina. PMID- 26982813 TI - Secukinumab (AIN457) in the treatment of ankylosing spondylitis. AB - INTRODUCTION: Ankylosing spondylitis (AS) is a chronic immune-mediated disease characterised by inflammation and new bone formation in the axial skeleton. Current therapeutic strategies include non-steroidal anti-inflammatory drugs, local glucocorticoids and tumour necrosis factor inhibitors. However, an unmet need exists for more treatment options particularly for patients who become unresponsive to and/or cannot tolerate these medications. Interleukin (IL)-17A, a proinflammatory cytokine that plays a crucial role in the pathogenesis of AS, has emerged as a promising target in the search for new therapies. Recently, the IL 17A inhibitor secukinumab has demonstrated significant efficacy in reducing the signs and symptoms of AS. AREAS COVERED: Inhibition of IL-17A by secukinumab represents a novel therapeutic approach in the management of AS. Secukinumab selectively targets IL-17A and inhibits its interaction with the IL-17 receptor, thus inhibiting the release of proinflammatory cytokines, chemokines and mediators of tissue damage. Here we provide an overview of the pharmacology, clinical efficacy and safety of secukinumab in the treatment of AS. EXPERT OPINION: Secukinumab has shown strong efficacy and a good safety profile in several immune-mediated diseases including psoriasis, psoriatic arthritis and AS. Secukinumab recently received Food and Drug Administration (FDA) and European Union (EU) approval for the treatment of adult patients with active AS and can be expected to become an established therapy for AS over the next 5 years. PMID- 26982814 TI - Enhanced Flexibility of the O2 + N2 Interaction and Its Effect on Collisional Vibrational Energy Exchange. AB - Prompted by a comparison of measured and computed rate coefficients of Vibration to-Vibration and Vibration-to-Translation energy transfer in O2 + N2 non-reactive collisions, extended semiclassical calculations of the related cross sections were performed to rationalize the role played by attractive and repulsive components of the interaction on two different potential energy surfaces. By exploiting the distributed concurrent scheme of the Grid Empowered Molecular Simulator we extended the computational work to quasiclassical techniques, investigated in this way more in detail the underlying microscopic mechanisms, singled out the interaction components facilitating the energy transfer, improved the formulation of the potential, and performed additional calculations that confirmed the effectiveness of the improvement introduced. PMID- 26982812 TI - Association between SCAP and SREBF1 gene polymorphisms and metabolic syndrome in schizophrenia patients treated with atypical antipsychotics. AB - OBJECTIVES: The use of atypical antipsychotics (AAPs) in the treatment of schizophrenia has been relevant because of the high prevalence of metabolic syndrome (MetS). The sterol-regulatory element-binding protein (SREBP) pathway may contribute to the underlying pathophysiology of AAP-induced metabolic adverse effects. We explored the association between the variants of the sterol regulatory element-binding transcription factor-1 (SREBF1) gene and the SREBP cleavage-activation protein (SCAP) gene with AAP-induced MetS in a genetic case control study. METHODS: Eleven single nucleotide polymorphisms (SNPs) of SREBF1 and five of SCAP were genotyped in a Han Chinese population in Beijing, China: a sample of 722 schizophrenia patients on monotherapy with AAPs (clozapine, olanzapine or risperidone). Metabolic parameters were collected and evaluated for MetS criteria. RESULTS: The rs11654081 T-allele of the SREBF1 gene was significantly associated with an increased risk for MetS after correction (P = 0.019, odds ratio, OR =2.56, 95% confidence interval, CI: 1.4 4-4.54). The rs11654081-TT genotype appeared more frequently in MetS than in non-MetS after correction (P = 0.026, OR =2.37, 95% CI: 1.3 6-4.12). SCAP polymorphisms with drug-induced MetS were negative in this study. CONCLUSIONS: The genetic polymorphisms of SREBF1 could play a role in the mechanism for interindividual variation of AAP-induced MetS. PMID- 26982815 TI - A randomized, placebo-controlled, double-blind phase IIb trial evaluating the safety and efficacy of tirasemtiv in patients with amyotrophic lateral sclerosis. AB - Our objectives were to evaluate the safety and tolerability of tirasemtiv over 12 weeks and its effect on the revised ALS Functional Rating Scale (ALSFRS-R) and other secondary functional measures. This randomized, double-blind, placebo controlled trial enrolled adults with ALS and slow vital capacity (SVC) > 50% from 73 centers in eight countries. Patients who tolerated open-label tirasemtiv 125 mg b.i.d. for one week were randomized to double-blind treatment either to placebo or tirasemtiv, escalating to a maximum tolerated dose up to 250 mg b.i.d. The primary endpoint was the change from baseline in ALSFRS-R; secondary endpoints included SVC, maximum voluntary ventilation, sniff nasal inspiratory pressure, isometric muscle strength, and sub-maximum handgrip fatigue. Of 711 patients enrolled, 596 were randomized and received at least one dose of double blind treatment. The primary endpoint showed no treatment effect (tirasemtiv: 2.98 +/- 0.28, placebo: -2.40 +/- 0.25, p = 0.114); however, SVC and muscle strength declined significantly more slowly on tirasemtiv (95% CI p = 0.0006, p = 0.0158, respectively). Dropouts and serious adverse events occurred more frequently in the tirasemtiv group. In conclusion, this was a negative study with respect to the primary endpoint; however, the effects on SVC and muscle strength suggest a potentially important effect of tirasemtiv warranting further evaluation over a longer period in ALS. PMID- 26982816 TI - Pt-Doped NiFe2O4 Spinel as a Highly Efficient Catalyst for H2 Selective Catalytic Reduction of NO at Room Temperature. AB - H2 selective catalytic reduction (H2-SCR) has been proposed as a promising technology for controlling NOx emission because hydrogen is clean and does not emit greenhouse gases. We demonstrate that Pt doped into a nickel ferrite spinel structure can afford a high catalytic activity of H2-SCR. A superior NO conversion of 96% can be achieved by employing a novel NiFe1.95Pt0.05O4 spinel type catalyst at 60 degrees C. This novel catalyst is different from traditional H2-SCR catalysts, which focus on the role of metallic Pt species and neglect the effect of oxidized Pt states in the reduction of NO. The obtained Raman and XPS spectra indicate that Pt in the spinel lattice has different valence states with Pt(2+) occupying the tetrahedral sites and Pt(4+) residing in the octahedral ones. These oxidation states of Pt enhance the back-donation process, and the lack of filling electrons of the 5d band causes Pt to more readily hybridize with the 5sigma orbital of the NO molecule, especially for octahedral Pt(4+), which enhances the NO chemisorption on the Pt sites. We also performed DFT calculations to confirm the enhancement of adsorption of NO onto Pt sites when doped into the Ni-Fe spinel structure. The prepared Pt/Ni-Fe catalysts indicate that increasing the dispersity of Pt on the surfaces of the individual Ni-Fe spinel-type catalysts can efficiently promote the H2-SCR activity. Our demonstration provides new insight into designing advanced catalysts for H2-SCR. PMID- 26982818 TI - ENTPRISE: An Algorithm for Predicting Human Disease-Associated Amino Acid Substitutions from Sequence Entropy and Predicted Protein Structures. AB - The advance of next-generation sequencing technologies has made exome sequencing rapid and relatively inexpensive. A major application of exome sequencing is the identification of genetic variations likely to cause Mendelian diseases. This requires processing large amounts of sequence information and therefore computational approaches that can accurately and efficiently identify the subset of disease-associated variations are needed. The accuracy and high false positive rates of existing computational tools leave much room for improvement. Here, we develop a boosted tree regression machine-learning approach to predict human disease-associated amino acid variations by utilizing a comprehensive combination of protein sequence and structure features. On comparing our method, ENTPRISE, to the state-of-the-art methods SIFT, PolyPhen-2, MUTATIONASSESSOR, MUTATIONTASTER, FATHMM, ENTPRISE exhibits significant improvement. In particular, on a testing dataset consisting of only proteins with balanced disease-associated and neutral variations defined as having the ratio of neutral/disease-associated variations between 0.3 and 3, the Mathews Correlation Coefficient by ENTPRISE is 0.493 as compared to 0.432 by PPH2-HumVar, 0.406 by SIFT, 0.403 by MUTATIONASSESSOR, 0.402 by PPH2-HumDiv, 0.305 by MUTATIONTASTER, and 0.181 by FATHMM. ENTPRISE is then applied to nucleic acid binding proteins in the human proteome. Disease associated predictions are shown to be highly correlated with the number of protein-protein interactions. Both these predictions and the ENTPRISE server are freely available for academic users as a web service at http://cssb.biology.gatech.edu/entprise/. PMID- 26982820 TI - Mechanism of Action of Thymol on Cell Membranes Investigated through Lipid Langmuir Monolayers at the Air-Water Interface and Molecular Simulation. AB - A major challenge in the design of biocidal drugs is to identify compounds with potential action on microorganisms and to understand at the molecular level their mechanism of action. In this study, thymol, a monoterpenoid found in the oil of leaves of Lippia sidoides with possible action in biological surfaces, was incorporated in lipid monolayers at the air-water interface that represented cell membrane models. The interaction of thymol with dipalmitoylphosphatidylcholine (DPPC) at the air-water interface was investigated by means of surface pressure area isotherms, Brewster angle microscopy (BAM), polarization-modulation reflection-absorption spectroscopy (PM-IRRAS), and molecular dynamics simulation. Thymol expands DPPC monolayers, decreases their surface elasticity, and changes the morphology of the lipid monolayer, which evidence the incorporation of this compound in the lipid Langmuir film. Such incorporation could be corroborated by PM-IRRAS since some specific bands for DPPC were changed upon thymol incorporation. Furthermore, potential of mean force obtained by molecular dynamics simulations indicates that the most stable position of the drug along the lipid film is near the hydrophobic regions of DPPC. These results may be useful to understand the interaction between thymol and cell membranes during biochemical phenomena, which may be associated with its pharmaceutical properties at the molecular level. PMID- 26982819 TI - FKBP5 is associated with amygdala volume in the human brain and mood state: A voxel-based morphometry (VBM) study. AB - The present study was to investigate the effects of 6 FK506 binding protein 51 (FKBP5) single nucleotide polymorphisms (SNPs) on brain structure using voxel based morphometry (VBM) and the psychological tests to psychological stress. We genotyped 112 healthy controls with respect to 6 SNPs (rs) of FKBP5. We examined the Beck Depression Inventory and the State (STAI-S) and Trait (STAI-T) versions of the Spielberger Anxiety Inventory and the Profile of Mood States (POMS) to evaluate mood. The right amygdala was larger in subjects with the minor allele (C) of rs3800373 and rs992105 and the minor allele (T) of rs1360780. The right middle orbitofrontal region in those with the minor allele (C) of rs3800373 and the right inferior orbitofrontal region in those with the minor allele (T) of rs9470080 was larger. Both the amygdala volumes were associated significantly with FKBP5 SNPs. We found significant relationships between factors in POMS and the right and left amygdala and left insula. Our results suggest that FKBP5 SNPs are associated with the alternations of volumes in right amygdala and the right middle and inferior orbitofrontal region. Genetic variants of FKBP5 may be associated with depressive and anxiety state via differential effects on amygdala and orbitofrontal region. PMID- 26982821 TI - Generation and Validation of Monoclonal Antibodies Against the Maltose Binding Protein. AB - The maltose binding protein (MBP) is a commonly used protein tag. Two monoclonal antibodies (mAbs) were generated against the MBP by immunizing mice with purified 6xHis-tagged MBP (6xHis-MBP). A nontoxic adjuvant cocktail of poly(I:C) and anti CD40 mAb was used. The two mAbs, 3D7 and 2A1, are demonstrated to be effective in immunoprecipitation, immunoblotting, western blot hybridization, and the ELISA assay. These two mAbs are available individually or in combination at cost through the Developmental Studies Hybridoma Bank, a nonprofit National Resource created by the National Institutes of Health. PMID- 26982822 TI - Paltry pay award is an immoral affront. PMID- 26982824 TI - Admit failures early or face tough FtP penalties, legal expert warns. PMID- 26982823 TI - Bryony shows she's a fighter and a winner. PMID- 26982826 TI - Protected time needed for safety training. PMID- 26982825 TI - Changes in workplace culture key to tackling nurses' work-related stress. PMID- 26982827 TI - Mental health staff bear brunt of police shortage. PMID- 26982829 TI - Cardiac clinic brings care closer. PMID- 26982828 TI - NHS 1% pay rise falls far short of what nurses deserve, says Unison. PMID- 26982830 TI - Taking the pressure off. PMID- 26982832 TI - NICE consultation on learning disabilities and mental health. PMID- 26982831 TI - Care home staff 'ill equipped' to improve end of life dementia care. PMID- 26982833 TI - Online hydration course for nurses. PMID- 26982835 TI - NHS adopts the carrot approach to staff wellbeing--but will it pay off? PMID- 26982841 TI - Irritable bowel syndrome. PMID- 26982842 TI - Practice nursing: the pitfalls and the potential. AB - A survey by the Queen's Nursing Institute has confirmed that practice nursing is facing major pressures, with one third of practice nurses due to retire by 2020, patchy access to training and widespread discrepancies in pay. But there is also cause for optimism, as new initiatives aim to ensure practice nurses are better supported and rewarded. PMID- 26982843 TI - 'A patient hurt me and got away with it'. AB - A mental health nurse who was assaulted by a patient says she has been let down by managers, who promised to support her but instead undermined her case by advising the police that the patient lacked capacity, which she disputes. She argues that a double standard exists, where mental health patients are only considered to have capacity for decisions that benefit them, but are exempt if they do harm. PMID- 26982856 TI - Sleep Cycle alarm clock app. PMID- 26982857 TI - How are you? Quiz is a tick-box exercise and misses key points. PMID- 26982844 TI - The changing face of modern nursing. PMID- 26982858 TI - Jeremy Hunt's rhetoric on patient safety must be reflected in reality. PMID- 26982859 TI - We should take lessons from France in how we run the NHS. PMID- 26982860 TI - Spare beds for patients but no staff to run mothballed wards. PMID- 26982863 TI - Join our London run in support of meningitis research. PMID- 26982864 TI - A mountain of paperwork is turning nursing into a desk job. PMID- 26982866 TI - How to manage an arterial catheter. PMID- 26982867 TI - Creating an environment for learning. AB - This article, the third in a series of 11, provides guidance to new and existing mentors and practice teachers to enable them to progress in their role and develop a portfolio of evidence that meets the Nursing and Midwifery Council's Standards to Support Learning and Assessment in Practice (SSLAP). The importance of developing a high quality practice placement is discussed in relation to the fifth domain of the SSLAP, 'creating an environment for learning'. The article provides learning activities and suggests ways in which mentors and practice teachers can undertake various self-assessments, enabling them to gather relevant evidence to demonstrate how they can meet and maintain the requirements of this domain. PMID- 26982869 TI - IM injection. PMID- 26982868 TI - An integrated practice approach to mobility care for older people. AB - Mobility is important to older people in nursing homes and residential facilities since it contributes to their health and quality of life. Many residents in such facilities require some form of assistance to move and accomplish activities of daily living. Therefore, nurses and healthcare assistants should have the knowledge and skills to provide effective mobility care. This article discusses three important aspects of mobility care: safety, mobility optimisation and person-centred approaches to care. Safety is important as residents and staff are at risk of injury during mobility care. Mobility optimisation is essential to ensure residents maintain their independence. Person-centred approaches to care are central to providing an integrated approach to mobility care. PMID- 26982870 TI - Secure that ideal job. PMID- 26982871 TI - Local role that's hard to ignore. PMID- 26982873 TI - Up against the clock. PMID- 26982874 TI - Intranasal administration of oxytocin modulates behavioral and amygdala responses to infant crying in females with insecure attachment representations. AB - The current study examined the effects of oxytocin administration on the response to infant crying in individuals with secure or insecure attachment representations as assessed with the Adult Attachment Interview. We measured feelings of irritation and the use of excessive force as indicated by grip strength using a handgrip dynamometer during exposure to infant crying in 42 women without children who were administered intranasal oxytocin or a placebo. In addition, amygdala responses to infant crying and control sounds were measured with functional magnetic resonance imaging (fMRI). The effects of oxytocin on reactivity to crying were moderated by attachment security. Oxytocin decreased the use of excessive handgrip force and amygdala reactivity in response to crying in individuals with insecure attachment representations. Our findings indicate that insecure individuals, who show emotional, behavioral, and neural hyperreactivity to crying, benefit the most from intranasal oxytocin. PMID- 26982875 TI - Prior participation in the strange situation and overstress jointly facilitate disorganized behaviours: implications for theory, research and practice. AB - We seek to understand why a relatively high percentage (39%; vs the meta-analytic average, 15-18%) of disorganized/disoriented (D) classifications has accrued in the low-risk Uppsala Longitudinal Study (ULS) study, using experienced D coders. Prior research indicates that D behaviours do not always indicate attachment disorganization stemming from a history of frightening caregiving. We examined the role of two other presumed factors: participation in a previous strange situation and overstress. Our findings indicate that both factors were highly prevalent in the ULS sample and that they jointly predicted higher rates of D. First, participation in a previous strange situation was associated with significantly higher distress displays during the second visit than occurred among previously untested children, suggesting that prior participation in the strange situation had a sensitizing effect on child distress during the second visit. Second, unless separations were cut short in lieu of high distress during the second visit, re-tested children were disproportionately likely (ca 60%) to be classified D. We argue that these findings have important implications for theory, research, and practice. In particular, we conclude that practitioners must refrain from misattributing the appearance of any D behaviors observed to a history of maltreatment. PMID- 26982876 TI - Parental PTSD, adverse parenting and child attachment in a refugee sample. AB - In contrast with traumatic experiences, there is a dearth of studies on the link between trauma symptoms, disconnected (frightened, threatening and dissociative) parenting behavior, extremely insensitive parenting behavior and child attachment. This study extends previous work on the impact of posttraumatic stress disorder (PTSD) on families by studying the unique contribution of disconnected and extremely insensitive parenting behavior on child attachment in a highly traumatized sample of 68 asylum seekers and refugees and their children (18-42 months). The results show that parental symptoms of PTSD are directly related to children's insecure attachment and disorganized attachment. The greatest proportion of the risk could be attributed to factors related to the dyad and not the family. A mediation effect of adverse parenting behavior was not confirmed. On the one hand the results indicate the need for an effective treatment of PTSD symptomatology while on the other hand the results indicate the need for clinical attention to insecure attachment relationships. PMID- 26982877 TI - Ghosts of Cultivation Past - Native American Dispersal Legacy Persists in Tree Distribution. AB - A long-term assumption in ecology is that species distributions correspond with their niche requirements, but evidence that species can persist in unsuitable habitat for centuries undermines the link between species and habitat. Moreover, species may be more dependent on mutualist partners than specific habitats. Most evidence connecting indigenous cultures with plant dispersal is anecdotal, but historical records suggest that Native Americans transported and cultivated many species, including Gleditsia triacanthos ("Honey locust"). Gleditsia triacanthos was an important medicinal/culinary (e.g., sugar), cultural (e.g., game sticks) and spiritual tree for the Cherokee (southeastern U.S. Native Americans). This study tests the hypothesis that a Cherokee cultivation legacy drives current regional G. triacanthos distribution patterns. Gleditsia triacanthos occurs in rocky uplands and xeric fields, but inexplicably also occurs in mesic riverine corridors and floodplains where Cherokee once settled and farmed. I combined field experiments and surveys in the Southern Appalachian Mountain region (U.S.) to investigate G. triacanthos recruitment requirements and distribution patterns to determine whether there is a quantifiable G. triacanthos association with former Cherokee settlements. Moreover, I also investigated alternate dispersal mechanisms, such as stream transport and domestic cattle. The results indicate that a centuries-old legacy of Native American cultivation remains intact as G. triacanthos' current southern Appalachian distribution appears better explained Cherokee settlement patterns than habitat. The data indicate that the tree is severely dispersal limited in the region, only moving appreciable distances from former Cherokee settlements where cattle grazing is prevalent. Human land use legacy may play a long-term role in shaping species distributions, and pre European settlement activity appears underrated as a factor influencing modern tree species distributions. PMID- 26982878 TI - Repetition blindness and homophone blindness in young and older adults. AB - We tested age effects on repetition blindness (RB), defined as the reduced probability of reporting a target word following presentation of the same word in a rapidly presented list. We also tested age effects on homophone blindness (HB), in which the first word is a homophone of the target word rather than a repeated word. Thirty young and 28 older adults viewed rapidly presented lists of words containing repeated, homophone, or unrepeated word pairs and reported all of the words immediately after each list. Older adults exhibited a greater degree of RB and HB than young adults using a conditional scoring method that provides certainty that blindness has occurred. The existence of RB and HB for both age groups, and increased blindness for older compared to young adults, supports predictions of a binding theory that has successfully accounted for a wide range of phenomena in cognitive aging. PMID- 26982880 TI - Computational Performance Assessment of k-mer Counting Algorithms. AB - This article is about the assessment of several tools for k-mer counting, with the purpose to create a reference framework for bioinformatics researchers to identify computational requirements, parallelizing, advantages, disadvantages, and bottlenecks of each of the algorithms proposed in the tools. The k-mer counters evaluated in this article were BFCounter, DSK, Jellyfish, KAnalyze, KHMer, KMC2, MSPKmerCounter, Tallymer, and Turtle. Measured parameters were the following: RAM occupied space, processing time, parallelization, and read and write disk access. A dataset consisting of 36,504,800 reads was used corresponding to the 14th human chromosome. The assessment was performed for two k-mer lengths: 31 and 55. Obtained results were the following: pure Bloom filter based tools and disk-partitioning techniques showed a lesser RAM use. The tools that took less execution time were the ones that used disk-partitioning techniques. The techniques that made the major parallelization were the ones that used disk partitioning, hash tables with lock-free approach, or multiple hash tables. PMID- 26982879 TI - Complete Reversible Refolding of a G-Protein Coupled Receptor on a Solid Support. AB - The factors defining the correct folding and stability of integral membrane proteins are poorly understood. Folding of only a few select membrane proteins has been scrutinised, leaving considerable deficiencies in knowledge for large protein families, such as G protein coupled receptors (GPCRs). Complete reversible folding, which is problematic for any membrane protein, has eluded this dominant receptor family. Moreover, attempts to recover receptors from denatured states are inefficient, yielding at best 40-70% functional protein. We present a method for the reversible unfolding of an archetypal family member, the beta1-adrenergic receptor, and attain 100% recovery of the folded, functional state, in terms of ligand binding, compared to receptor which has not been subject to any unfolding and retains its original, folded structure. We exploit refolding on a solid support, which could avoid unwanted interactions and aggregation that occur in bulk solution. We determine the changes in structure and function upon unfolding and refolding. Additionally, we employ a method that is relatively new to membrane protein folding; pulse proteolysis. Complete refolding of beta1-adrenergic receptor occurs in n-decyl-beta-D-maltoside (DM) micelles from a urea-denatured state, as shown by regain of its original helical structure, ligand binding and protein fluorescence. The successful refolding strategy on a solid support offers a defined method for the controlled refolding and recovery of functional GPCRs and other membrane proteins that suffer from instability and irreversible denaturation once isolated from their native membranes. PMID- 26982881 TI - Prawn biomonitors of nutrient and trace metal pollution along Asia-Pacific coastlines. AB - To assess coastal ecosystem status and pollution baselines, prawns were collected from the commercial catches of eight Asia-Pacific countries (Australia, Bangladesh, Indonesia, Myanmar, Philippines, Pakistan, Sri Lanka and Thailand). Samples collected from 21 sites along regional coastlines were analysed for trace metal and stable isotopic compositions of H, C, N, O and S. A combination of simple averaging and multivariate analyses was used to evaluate the data. Sites could be assigned to easily recognise polluted and unpolluted groups based on the prawn results. Some filter-feeding clams were also collected and analysed together with the benthic-feeding prawns, and the prawns generally had lower trace metal burdens. Climate change effects were not strongly evident at this time, but altered ocean circulation and watershed run-off patterns accompanying future climate change are expected to change chemical patterns recorded by prawns along these and other coastlines. Stable isotopes, especially (15)N, can help to distinguish between relatively polluted and unpolluted sites. PMID- 26982882 TI - Synergy in Science and Resources. PMID- 26982884 TI - Monoclonal Antibodies. PMID- 26982885 TI - Impact of metallurgical activities on the content of trace elements in the spatial soil and plant parts of Rubus fruticosus L. AB - The concentrations of the trace elements (TEs), Cu, Zn, Pb, As, Cd, Ni, were determined in parts of Rubus fruticosus L. and in topsoil, collected from eight different locations around the copper smelter in Bor, Serbia. Extremely high concentrations of Cu were determined in the soil and in R. fruticosus L., and for arsenic at some locations. The enrichment factors for TEs in soil showed enrichment with Cu, Zn, Pb, and As among which extremely high values were determined for Cu (EFsoil = 8.5-126.1) and As (EFsoil = 6.6-44.4). The enrichment factors for the parts of R. fruticosus L. showed enrichment with all TEs, except for nickel. The most extreme enrichment was found to occur in roots and stems for Cu (EFplant = 56.2 and 51.1) and leaves for Pb (EFplant = 45.68). The mean values of the three ratios of concentrations between plant parts for all TEs indicated pollution via the atmosphere while leaves appeared to be the best indicators for this kind of pollution. Numerous and very strong Pearson's correlations between TEs in the R. fruticosus L. parts confirmed these results. Principal Component Analysis showed that the major pollution source is the copper smelter that contaminates vegetation through soil and air. PMID- 26982883 TI - Genetics of Coronary Artery Disease in Taiwan: A Cardiometabochip Study by the Taichi Consortium. AB - By means of a combination of genome-wide and follow-up studies, recent large scale association studies of populations of European descent have now identified over 46 loci associated with coronary artery disease (CAD). As part of the TAICHI Consortium, we have collected and genotyped 8556 subjects from Taiwan, comprising 5423 controls and 3133 cases with coronary artery disease, for 9087 CAD SNPs using the CardioMetaboChip. We applied penalized logistic regression to ascertain the top SNPs that contribute together to CAD susceptibility in Taiwan. We observed that the 9p21 locus contributes to CAD at the level of genome-wide significance (rs1537372, with the presence of C, the major allele, the effect estimate is -0.216, standard error 0.033, p value 5.8x10-10). In contrast to a previous report, we propose that the 9p21 locus is a single genetic contribution to CAD in Taiwan because: 1) the penalized logistic regression and the follow-up conditional analysis suggested that rs1537372 accounts for all of the CAD association in 9p21, and 2) the high linkage disequilibrium observed for all associated SNPs in 9p21. We also observed evidence for the following loci at a false discovery rate >5%: SH2B3, ADAMTS7, PHACTR1, GGCX, HTRA1, COL4A1, and LARP6 LRRC49. We also took advantage of the fact that penalized methods are an efficient approach to search for gene-by-gene interactions, and observed that two way interactions between the PHACTR1 and ADAMTS7 loci and between the SH2B3 and COL4A1 loci contribute to CAD risk. Both the similarities and differences between the significance of these loci when compared with significance of loci in studies of populations of European descent underscore the fact that further genetic association of studies in additional populations will provide clues to identify the genetic architecture of CAD across all populations worldwide. PMID- 26982886 TI - Telemental Health in Schools. AB - OBJECTIVE: The purpose of this study was to describe the potential and limits of school telemental health (TMH) to support a full continuum from mental health promotion to intervention, particularly for students less likely to access community care. METHODS: A review of school TMH literature and model programs, and of data from focus groups with child psychiatry fellows, was undertaken to inform best practices and future directions for TMH in schools. RESULTS: Existing data suggest that TMH with children and adolescents is promising and well received. Child and adolescent psychiatrists use various models for conducting school-based TMH, which differ in the level of direct care and types of services provided. Literature review and focus group data suggest that advantages of school TMH include greater efficiency, the capacity for higher volume, and increased access to care for many students who would be unlikely to reach traditional community mental healthcare because of barriers such as transportation and healthcare coverage. Disadvantages of school TMH service provision include patient concerns about their own privacy as well as concerns related to the psychiatrist's ability to effectively engage families in care without being present in person. Fellows also noted that the training experience of physically being in the school building and experiencing the school expectations and culture helps them move toward greater appreciation and understanding of the structures, policies, and opportunities and challenges for schools and school-based professionals. Most agreed that a "hybrid" model of care, with some in-person and some TMH care may be most beneficial to all parties, promoting both engagement and efficiency simultaneously. CONCLUSIONS: School TMH should be considered as part of a comprehensive service delivery system for students, in order to address shortages and gaps in specialty child and adolescent mental healthcare, and to maximize efficiency and productivity. PMID- 26982887 TI - Evaluation of serum cysteine-rich protein 61 and cystatin C levels for assessment of acute kidney injury after cardiac surgery. AB - Objective The occurrence of acute kidney injury (AKI) after cardiopulmonary bypass (CPB) can lead to morbidity and mortality. We hypothesized that cysteine rich protein 61 (CYR61) and cystatin C (CysC) may be potential novel biomarkers of AKI after cardiopulmonary bypass. Methods Patients were classified into AKI and non-AKI group depending on serum creatinine. Levels of creatinine, CysC, and CYR61 were measured at five time-points before and within 48 h after the surgery. Results Fifty patients were included in the study. Serum creatinine pre-operative values were 74.0 +/- 43.3 MUmol/L in AKI group vs. 64.8 +/- 17.9 MUmol/L in non AKI group. During 48 h, the values increased to 124.6 +/- 67.2 MUmol/L in AKI group (p < 0.001) but in non-AKI group they did not change significantly. Serum CysC values were significantly increased already 2 h after CBP in AKI group (949 +/- 557 MUg/L, p < 0.05) compared to non-AKI group (700 +/- 170 MUg/L). Pre operative serum CYR61 tended to be lower in AKI group (12.4 MUg/L) than in non AKI group (20.3 MUg/L), but 24 h after the surgery, the levels in AKI group tended to be higher than non-AKI group. Conclusion Serum CYR61 does not seem to be an early predictor of AKI in patients after cardiac surgery with CPB, but it might possibly identify patients at risk of developing more severe kidney injury. Serum CysC could be a promising biomarker of AKI, differentiating patients at risk of developing AKI after cardiac surgery as early as 2 h after surgery. PMID- 26982888 TI - Using a community of practice to evaluate falls prevention activity in a residential aged care organisation: a clinical audit. AB - Objective This study evaluates whether a community of practice (CoP) could conduct a falls prevention clinical audit and identify gaps in falls prevention practice requiring action. Methods Cross-sectional falls prevention clinical audits were conducted in 13 residential aged care (RAC) sites of a not-for-profit organisation providing care to a total of 779 residents. The audits were led by an operationalised CoP assisted by site clinical staff. A CoP is a group of people with a shared interest who get together to innovate for change. The CoP was made up of self-nominated staff representing all RAC sites and comprised of staff from various disciplines with a shared interest in falls prevention. Results All 13 (100%) sites completed the audit. CoP conduct of the audit met identified criteria for an effective clinical audit. The priorities for improvement were identified as increasing the proportion of residents receiving vitamin D supplementation (mean 41.5%, s.d. 23.7) and development of mandatory falls prevention education for staff and a falls prevention policy, as neither was in place at any site. CoP actions undertaken included a letter to visiting GPs requesting support for vitamin D prescription, surveys of care staff and residents to inform falls education development, defining falls and writing a falls prevention policy. Conclusion A CoP was able to effectively conduct an evidence-based falls prevention activity audit and identify gaps in practice. CoP members were well positioned, as site staff, to overcome barriers and facilitate action in falls prevention practice. What is known about the topic? Audit and feedback is an effective way of measuring clinical quality and safety. CoPs have been established in healthcare using workplace staff to address clinical problems but little is known about their ability to audit and influence practice change. What does this paper add? This study contributes to the body of knowledge on CoPs in healthcare by evaluating the performance of one in the domain of falls prevention audit action. What are the implications for practitioners? A CoP is an effective model to engage staff in the clinical audit process. Clinical audits can raise staff awareness of gaps in practice and motivate staff to plan and action change as recommended in best practice guidelines. PMID- 26982889 TI - Hyperthermia treatment planning for cervical cancer patients based on electrical conductivity tissue properties acquired in vivo with EPT at 3 T MRI. AB - Introduction The reliability of hyperthermia treatment planning (HTP) is strongly dependent on the accuracy of the electric properties of each tissue. The values currently used are mostly based on ex vivo measurements. In this study, in vivo conductivity of human muscle, bladder content and cervical tumours, acquired with magnetic resonance-based electric properties tomography (MR-EPT), are exploited to investigate the effect on HTP for cervical cancer patients. Methods Temperature-based optimisation of five different patients was performed using literature-based conductivity values yielding certain antenna settings, which are then used to compute the temperature distribution of the patient models with EPT based conductivity values. Furthermore, the effects of altered bladder and muscle conductivity were studied separately. Finally, the temperature-based optimisation was performed with patient models based on EPT conductivity values. Results The tumour temperatures for all EPT-based dielectric patient models were lower compared to the optimal tumour temperatures based on literature values. The largest deviation was observed for patient 1 with DeltaT90 = -1.37 degrees C. A negative impact was also observed when the treatment was optimised based on the EPT values. For four patients DeltaT90 was less than 0.6 degrees C; for one patient it was 1.5 degrees C. Conclusions Electric conductivity values acquired by EPT are higher than commonly used from literature. This difference has a substantial impact on cervical tumour temperatures achieved during hyperthermia. A higher conductivity in the bladder and in the muscle tissue surrounding the tumour leads to higher power dissipation in the bladder and muscle, and therefore to lower tumour temperatures. PMID- 26982891 TI - Effectiveness of degradable and non-degradable implants to close large septal perforations in an experimental model. AB - Background Reparation of large nasal septum perforations continues to be challenging. Bipedicled mucoperichondrial and inter-positional grafts currently show the most promising results. New implants have emerged to be used as a support membrane to carry on the mucosal cells, taking advantage of the innate proliferative properties of the mucosal tissue. Objective To compare the effectiveness of two kinds of material; non-absorbable dimethylsiloxane (silicone elastomers) and absorbable porcine small intestinal submucosa (Surgisis), both used as an inter-positional graft without neighbouring flaps to close nasal septal perforations in an experimental model. Methods Fifteen dogs were divided into three groups. One group received Surgisis, the other sheets of dimethylsiloxane and the last group a sham group. The dogs were followed for 6 weeks. Results The initial perforation of the nasal septum showed complete mucosal closure in the dimethylsiloxane group. The Surgisis group, on the other hand, had a smaller reduction than that at the beginning (final mean area = 23.0 +/- 5.4 mm(2) (p < 0.05); however, complete closure was not achieved. Sham animals showed an inconstant and slight reduction in dimension from 100 mm(2) to 70 +/- 16 mm(2) of mucosa and cartilage, but closure was not achieved. A significantly higher number of capillaries were observed in the Surgisis group compared to the dimethylsiloxane group (p < 0.05) without differences in inflammation, fibrosis, or necrosis. Conclusions The non-absorbable implant; dimethylsiloxane facilitates a better closure of the nasal septum. PMID- 26982890 TI - Limited Dissemination of Extended-Spectrum beta-Lactamase- and Plasmid-Encoded AmpC-Producing Escherichia coli from Food and Farm Animals, Sweden. AB - Extended-spectrum beta-lactamase (ESBL)- and plasmid-encoded ampC (pAmpC) producing Enterobacteriaceae might spread from farm animals to humans through food. However, most studies have been limited in number of isolates tested and areas studied. We examined genetic relatedness of 716 isolates from 4,854 samples collected from humans, farm animals, and foods in Sweden to determine whether foods and farm animals might act as reservoirs and dissemination routes for ESBL/pAmpC-producing Escherichia coli. Results showed that clonal spread to humans appears unlikely. However, we found limited dissemination of genes encoding ESBL/pAmpC and plasmids carrying these genes from foods and farm animals to healthy humans and patients. Poultry and chicken meat might be a reservoir and dissemination route to humans. Although we found no evidence of clonal spread of ESBL/pAmpC-producing E. coli from farm animals or foods to humans, ESBL/pAmpC producing E. coli with identical genes and plasmids were present in farm animals, foods, and humans. PMID- 26982892 TI - Effect of Vacuum on Venous Drainage: an Experimental Evaluation on Pediatric Venous Cannulas and Tubing Systems. AB - INTRODUCTION: To observe how vacuum assisted venous drainage (VAVD) may influence the flow in a cardiopulmonary bypass circuit with different size of venous lines and cannulas. METHODS: The experimental circuit was assembled to represent the cardiopulmonary bypass circuit routinely used during cardiac surgery. Wall suction was applied directly, modulated and measured into the venous reservoir. The blood flow was measured with a flow-meter positioned on the venous line. The circuit prime volume was replaced with group O date expired re-suspended red cells and Plasmalyte 148 to a hematocrit of 28% to 30%. RESULTS: In an open circuit with gravity siphon venous drain, angled cannulae drain more than straight ones regardless the amount of suction applied to the venous line (16 Fr straight cannula (S) drains 90 ml/min less than a 16 Fr angled (A) with a siphon gravity). The same flow can be obtained with lower cannula size and higher suction (i.e. 12 A with and -30 mmHg). Tables have been created to list how the flow varies according to the size of the cannulas, the size of the venous tubes, and the amount of suction applied to the system. CONCLUSIONS: Vacuum assisted venous drainage allows the use of smaller cannulae and venous lines to maintain a good venous return, which is very useful during minimally invasive approaches. The present study should be considered as a preliminary attempt to create a scientific-based starting point for a uniform the use of VAVD. PMID- 26982894 TI - Clinico-epidemiological Study on Pesticide Poisoning in a Tertiary Care Hospital in Eastern Nepal. AB - INTRODUCTION: Pesticide poisoning is a major health problem worldwide. In Nepal the most common cause is suicidal and pesticides account for more than fifty percent of cases. The objective of the study was to look in detail regarding the pesticide poisoning cases admitted at BPKIHS; their epidemiological profile, presentation, treatment and their outcome during the hospital stay. METHODS: It was a retrospective study which included 2621 patients with poisoning of which 1661 cases were related to pesticides. RESULTS: The mean duration of hospital stay was 6.7 days. The majority of patients 81.16% showed improvement whereas 6.6% of patients died within 24 hours of admission and 3.54% after 48 hours of admission. Among all the patients 0.5% patients were given ICU care and all others were managed in the different units of medicine ward. The total amount of atropine administered varied considerably. Most of the cases were under the influence of alcohol. All the patients had a psychiatry evaluation before discharge. CONCLUSIONS: Pesticide poisoning is increasing in incidence and it is one of the preventable public health problems and includes mainly the patients' age group 20-30 years. Due to easy availability of pesticides it is the most preferred method of suicide and the main reasons being impulsive act and increased indebtedness in the society. PMID- 26982893 TI - Intradialytic Muscle Cramp and its Association with Peripheral Arterial Disease in End Stage Renal Disease Patients on Hemodialysis. AB - INTRODUCTION: Muscle cramp is a common intradialytic complication observed in hemodialysis patients. Similarly Peripheral arterial disease is a common condition in the hemodialysis population. METHODS: Fifty patients with a diagnosis of End Stage Renal Disease who were on hemodialysis were studied over a period of one year. Muscle cramp was defined clinically as contractions of a large muscle group and Peripheral arterial disease was diagnosed on the basis of the ankle -brachial index (ABI). RESULTS: A total of 50 End Stage Renal Disease patients were analyzed. The major causes of End Stage Renal Disease in the study population was Chronic Glomerulonephritis 40 % (n=20). Muscle cramps were present in 26% (n=13) cases. Peripheral arterial disease was present in 30% (n=15) of patients. However there was no statistically significant association between the presence of Intradialytic Muscle cramps and peripheral arterial disease (p value =0.18) CONCLUSIONS: Intradialytic Muscle cramps and peripheral arterial disease were common occurrence in end stage renal disease patients on hemodialysis patients, however there was no association between the presence of intradialytic Muscle cramps and peripheral arterial disease. PMID- 26982895 TI - Growing Resistance to Vancomycin among Methicillin Resistant Staphylococcus Aureus Isolates from Different Clinical Samples. AB - INTRODUCTION: Methicillin resistant Staphylococcus aureus (MRSA), majorly associated with nosocomial and community infections worldwide, are emerging as resistant strains to many antibiotics narrowing down the efficacy of antimicrobial therapy. In order to investigate the changing resistant pattern of MRSA to empirical drugs, the study was carried out at KIST Medical College and Hospital, Nepal. It also aims to determine the minimum inhibitory concentration (MIC) of vancomycin among MRSA. METHODS: Altogether 3500 clinical samples including 1303 blood, 1489 urine and 708 body fluids were collected and processed. Isolated S. aureus were further screened for methicillin resistance by Kirby-Bauer disk diffusion technique using cefoxitin (30ug) disk. All MRSA were subjected to in vitro determination of MIC of vancomycin by agar dilution method as recommended by CLSI guidelines. RESULTS: Total 287 S. aureus were isolated from the different clinical samples. Altogether 248 (86.41%) were found to be multidrug resistance (MDR) while 42 (14.63%) of the isolates were methicillin resistance with the highest prevalence in the age group of 16-30. All 42 (100%) MRSA isolates were resistant to ampicillin and penicillin followed by 41 (97.62%), 32 (76.19%), 31(73.81%), 29 (69.05%), 9 (21.43%) and seven (16.67%) to cefotaxime, gentamycin, cotrimoxazole, erythromycin, tetracycline and ciprofloxacin respectively. Although all MRSA strains were sensitive to vancomycin on disc diffusion, four isolates were intermediates in vitro determination of MIC of vancomycin. The break point for vancomycin was found to be 15mm. CONCLUSIONS: The increment in vancomycin MIC among MRSA is alarming. Strict control measures to prevent MRSA spread and a routine surveillance for VRSA must be incorporated in hospitals. PMID- 26982896 TI - Routine Measurement of Serum Amylase in Acute Abdomen. AB - BACKGROUND: Acute abdominal pain is a common condition presenting to both the emergency department (ED) and surgical admission unit. Increase in serum amylase levels are found in much gastrointestinal pathology. Serum amylase level is consistently high in acute pancreatitis though high values are not pathognomonic of pancreatitis .The aim of this study to assess the level of serum amylase in various diseases presenting with acute abdominal pain and to evaluate the role of routine measurement of serum amylase in the screening of patient with acute abdominal pain for the diagnosis of acute pancreatitis in a prospective series. METHODS: A prospective observational study was performed from 15th May 2014 - 15th Nov 2014 (6 months) at Department of Surgery of Kathmandu medical College Teaching Hospital; Kathmandu. All consecutive patients presented at emergency department and required admissions in surgical ward were included. A multivariate analysis was performed to assess the level of serum amylase in various diseases presenting with acute abdominal pain including acute pancreatitis. RESULTS: Overall, 318 patients were included during a period of 6 months among them 48 patients were excluded. 34 cases (12.6 %) were diagnosed of acute pancreatitis. three cases (1.1%) of non pancreatic pathology with raised serum amylase level (> 1000 U?L). CONCLUSIONS: Routine assessment of serum amylase is helpful in excluding differential diagnosis of patient presenting with acute abdomen and this study identified serum amylase as a good screening tool if done in cases with clinical suspicion. PMID- 26982897 TI - Diversity of Hepatitis B genotypes in Nepal and updated Phylogenetic Tree: a Pilot Survey in 2012. AB - INTRODUCTION: Hepatitis B virus (HBV) is a current global health problem. HBV genotypes influence the treatment and long term outcome of HBV infected patients. Moreover, HBV genotypes differ in various region of the world. Such data was reported haphazardly but yet to be comprehensive for Nepal. This study attempted to find out the diverse hepatitis B genotypes in Nepal. METHODS: A convenient serum sample of 58 HBsAg positive patients from different parts of the country mainly from Nepalgunj, Palpa and Kathmandu were screened for hepatitis B genotype. Sequencing was done and Phylogenetic tree was created. RESULTS: Among 58 samples, 23 were genotype D, 17were genotype A and B wereC/D recombinant. Phylogenetic trees were created by distance-matrix and neighbor-joining analyses after bootstrapping to 1000 replicates. DISCUSSION: HBV genotypes A and D are the most common genotype in Nepal. Horizontal transmission is common in these genotypes. C/D recombinant genotype may be transmitted from Tibetan people living in Kathmandu. Prophylactic major controlling, horizontal and cross border transmission could be effective. CONCLUSIONS: Three major genotypes of HBV in Nepal were found to be A, C and D. Despite being a low prevalence area, Nepal has a diversity of hepatitis B genotypes Keywords: genotypes; HBV; phylogenetic. PMID- 26982898 TI - Surgical Results of Non-small Cell Lung Cancer in Nepal. AB - INTRODUCTION: Surgery remains the only curative modality for early stage of Non small cell lung caner (NSCLC). We reviewed overall scenario of lung cancer and surgical results in Nepal. METHODS: 1000 patients with the pathological diagnosis of lung cancer were analyzed to summarize the overall scenario of lung cancer. 157 NSCLC patients underwent pulmonary resection. cIA, IB, IIA, IIB, IIIA (N1) underwent surgery as initial modality of treatment. cIIIA (N2) patients were taken for surgery after neoadjuvant chemo/ chemoradiation. RESULTS: Analysis of 1000 patients showed squamous cell carcinoma in 41.3%, incurable stage (IIIB/ IV) in 66.8% and rate of curative resection in 6.7% cases. Surgery as a single modality of treatment was used in 38%. Neoadjuvant Chemo/ chemoradiation/ radiation followed by surgery and surgery followed by chemo/ chemoradiation/ radiation was done in 12% and 50%, respectively. In-hospital mortality was 2% (post pneumonectomy: 5.5%; post lobectomy: 1.5%; post sublobar resection: 0%). R0 resction was achieved in 91% cases. Median survival and 5-year overall survival were 36 months and 18%, respectively. Better survival was achieved in pI-II vs pIII/ IV, pN0-1 vs pN2 and pR0 vs pR+ (p <0.05). CONCLUSIONS: Earlier stage (pI II), R0 resection and pathological pNo-1 has the best five year overall survival in Nepalese patients with NSCLC as well. PMID- 26982899 TI - Community Based Survey on Psychiatric Morbidity in Eastern Nepal. AB - INTRODUCTION: Mental health problem is common and ubiquitous. Mental illness cuts across all sections of society, irrespective of socio-economic status. Recent international survey showed a varying prevalence rates ranged (4.7%- 12.0%). The Community study in Nepal yielded prevalence rate of mental illness at 14.0%. METHODS: This is a descriptive, epidemiologic study with systematic randomization sampling. RESULTS: Of 911 respondents majority was married (76.1%), of age group 20-59 yrs. Overall, 113 (12.4%) respondents had at least one psychiatric disorder and the commonest were: Depression, Anxiety disorders, Alcohol use disorders with 1.9% had seizure/epilepsy. CONCLUSIONS: Community prevalence rate of some common psychiatric disorders is high which calls for special attention to address depressive and alcohol related disorder from all quarters of society particularly from government. PMID- 26982900 TI - Clinical Profile of Neonates with Perinatal Asphyxia in a Tertiary Care Hospital of Central Nepal. AB - INTRODUCTION: Birth asphyxia is a serious clinical problem worldwide. It claims approximately 9 million deaths each year. It can lead to serious neurological sequaele, such as cerebral palsy, mental retardation, and epilepsy. METHODS: All babies admitted in College of Medical Sciences Teaching Hospital, Chiwan, Nepal, NICU from January 2013 to December 2013 with a diagnosis of birth asphyxia (5 min Apgar<7 or those with no spontaneous respirations after birth) were included in the study (n=125). This was a descriptive observational study. Clinical information was collected (gravida, hour at presentation, mode of delivery, sex of baby, gestational age of the baby, requirement of resuscitation). Neonates were admitted to NICU, observed for complications and managed as per hospital protocol. RESULTS: Among the 722 neonates admitted to NICU, 125 had perinatal asphyxia (17.3%). Babies with Hypoxic ischemic encephalopathy(HIE) Grade I had a very good outcome but HIE III was associated with a poor outcome. Outborn neonates had higher grades of perinatal asphyxia as compared to inborns (p=0.018). Term gestation, Males and Multigravida were associated with a higher rate of birth asphyxia. 22.4% neonates were delivered via caesarean section and 74.4% required bag and mask ventilation at birth. CONCLUSIONS: Birth asphyxia was one of the commonest causes of admission NICU. Babies with HIE Grade III had a very poor prognosis. Outborn neonates with birth asphyxia had a higher mortality. Males were frequently affected than females. PMID- 26982901 TI - Comparison of Phacotrabeculectomy and Phacotrabeculectomy with Subconjunctival 5 Fluorouracil. AB - INTRODUCTION: Glaucoma is the second leading cause of blindness worldwide. Phacotrabeculectomy is a technique in which glaucoma and cataract surgery performed. METHODS: Prospective study was carried out in the department of glaucoma at Lumbini Eye Institute, Bhairahawa.100 patients who underwent phacotrabeculectomy within a period of two years. Patients were divided into two groups those who received 5FU (n=47) and no antifibrotic agent (n= 53) RESULTS: The age range was from 38 to 80 years; mean age of 62.97+/-9.14 SD. 55% were male and 45% were female.The postoperative IOP reduction in last follow- up group A was mean=13.08+/-1.57SD and mean=13.23+/-1.73SD in group B. This was statically significant with P <0.001. Bleb survival was almost similar in two groups 3.17(78.31%) in group A and 3.20 (78.93%) in group B. 85% visual acuity was improved in both groups. CONCLUSIONS: Phacotrabeculectomy and phacotrabeculectomy with inj. 5FU, both were equally effective surgical techniques in terms of visual acuity, IOP control and bleb survival.There was no significant statistical difference vis-a-vis the success of Phacotrabeculectomy using of either these two techniques. PMID- 26982902 TI - Cytodiagnosis of Sacral Chordoma. AB - We report the cytological findings of a sacro-coccygeal chordoma in a 53 year male diagnosed preoperatively by guided fine needle aspiration cytology. The smears shows characteristic Physalliphorous cells in a metachromatic background of myxoid material entrapping cords of cuboidal cells. Differential diagnosis in cytology include conventional and myxoid chondrosarcoma, myxoid liposarcoma, myxoid malignant fibrous histiocytoma(MFH), metastatic mucinous carcinoma and myxo-papillary ependymoma. The distinguishing features between these neoplasms are discussed. Preoperative diagnosis of chordoma permits optimum planned surgery. PMID- 26982903 TI - Splenic Infarct: A Rare Presentation in a Pediatric Patient. AB - A previously healthy 16-year-old male presented with a two day history of persistent epigastric pain. His physical examination was significant for tenderness in the left hypochondriac region with a palpable spleen 2cm below the left sub-costal margin. A CT scan of the abdomen showed a splenic infarct. Heterophile and EBV VCA IgM antibody test were positive. This is a rare case of infectious mononucleosis presenting with splenic infarct in an adolescent male without co-morbidities. PMID- 26982905 TI - Visual Axis Opacification in Children Following Paediatric Cataract Surgery. AB - Visual axis opacification (VAO) occurs in up to 40% of pediatric patients after cataract surgery withintraocular lens implantation(IOL) even with a primary posterior capsulotomy (PPC). In both children and adult group, opacification does obscure the visual axis. However, in children after PPC, there is no capsule. Hence, the terminology VAO is used in children rather than posterior capsular opacification. This opacification is caused by a proliferation of epithelial cells on the posterior capsule or anterior vitreous face and can hinder the optical image quality needed for normal visual development. The rate of epithelial mitotic activity is higher in children compared to adult. It can be managed by Yag laser or surgical membranectomy, the latter is preferable. International and national published articles were systematically reviewed on aetio-pathogenesis, surgical techniques and equipment, type and material of IOL, and management of VAO in children operated for cataract. Author's experience was also included to write manuscript. VAO is frequent complication following cataract surgery in pediatric patients. Age of cataract patients, surgical technique and type and materials of IOL are most common influencing factor for VAO. Immediate management with advance equipment of VAO reduces the incidence for development of irreversible stimulation deprivation amblyopia. PMID- 26982904 TI - Allergic BronchoPulmonary Aspergillosis in Nepal. AB - Allergic BronchoPulmonary Aspergillosis (ABPA) is clinically under recognized and often misdiagnosed in Nepal. A total of 15 cases of ABPA were enrolled in this case series. Cases were followed up after the 3 months of start of treatment and clinical responses were assessed. The mean age of the patients was 33.06 +/- 9.2 yrs. 80% were male. 26.6% patients were empirically on anti-tubercular treatment at the time of presentation. 40% patients were misdiagnosed and already treated as pulmonary Tuberculosis. 10 patients were previously treated as cases of refractory asthma. Majority of patients had significant eosinophillia and raised total serum IgE. All patients required treatment with bronchodilator and systemic steroid. 80% patients underwent remission with the treatment. Pulmonary Tuberculosis and refractory bronchial asthma are common condition that leads to the misdiagnosis of this disease. PMID- 26982906 TI - Evaluating the Psychometric Properties of the Evidence-Based Practice Attitude and Utilization Survey. AB - OBJECTIVE: Most health professions recognize the value of evidence-based practice (EBP), yet the uptake of EBP across most health disciplines has been suboptimal. To improve EBP uptake, it is important to first understand the many dimensions that affect EBP use. The Evidence-Based practice Attitude and utilization SurvEy (EBASE) was designed to measure the attitudes, skills, and use of EBP among practitioners of complementary and alternative medicine (CAM); however, the dimensionality of the instrument is not well understood. The aim of the current research was to examine the psychometric properties of the attitudes, skills, and use subscales of EBASE. DESIGN: This was a secondary analysis of data obtained from the administration of EBASE. Data were examined using principal components analyses and confirmatory methods. Internal consistency reliabilities of resultant subscales were also computed. PARTICIPANTS: 1314 U.S. chiropractors and 554 Canadian chiropractors. RESULTS: A unidimensional structure best fit the attitudes and use subscales. Skills subscale items were best represented by subscales with a multidimensional structure. Specifically, the skills construct was best modeled with three dimensions (identification of the research question, locating research, and application of EBP). All subscales had acceptable internal consistency reliability estimates. CONCLUSIONS: The findings support the modification of the scoring guidelines for the original EBASE. These changes are likely to result in a more accurate measure of EBP attitudes, skills, and use among chiropractors, and possibly CAM providers more generally. PMID- 26982907 TI - A new benzofuran derivative from Nicotiana tabacum. AB - A new benzofuran derivative, methyl 3-acetyl-7-hydroxy-6-methoxy-2 methylbenzofuran-4-carboxylate (1), and a known compound pyrrolezanthine (2), were isolated from leaves of Nicotiana tabacum. Compound 1 was elucidated by means of spectroscopic methods, as well as X-ray diffraction. Both compounds 1 and 2 exhibited moderate inhibitory activities on human cancer cell lines. PMID- 26982908 TI - Comparison of HIV Testing Uptake in an Urban Academic Emergency Department Using Different Testing Assays and Support Systems. AB - Despite 2006 recommendations by the Centers for Disease Control and Prevention for opt-out HIV testing in all healthcare settings, Emergency Department (ED) testing has been limited. We conducted an observational cohort study to assess the impact of two workflow interventions on the proportion of HIV tests ordered in an urban academic ED. First, a 4(th)-generation HIV antigen/antibody combination test replaced the existing assay, and ED staff continued to notify patients of their reactive tests. Six months later, the HIV Rapid Diagnosis Team, composed of an Infectious Diseases (ID) physician and the HIV Advanced Practice Nurse, immediately assisted with disclosure of positive results to the patients and facilitated linkage to outpatient care. The new assay did not change the proportion of HIV tests ordered (0.14-0.11%, chi2, p = 0.2). However, ID support was associated with a statistically significant increase in the proportion of HIV tests ordered (0.14-0.43%, chi2, p < 0.00010) and a nonstatistically significant increase in the proportion of new HIV diagnoses (1.6-6.8%, Fisher exact test = 0.113). Male gender and lack of insurance were associated with a reactive HIV test. Reduction of barriers to linkage to outpatient HIV care through a collaborative relationship between the ED and ID team increased HIV testing and diagnosis. The role of this model as a component of a universal HIV screening program will need to be further assessed. PMID- 26982909 TI - Determining Consistency of Surrogate Decisions and End-of-Life Care Received with Patient Goals-of-Care Preferences. AB - BACKGROUND: Care consistent with preferences is the goal of advance care planning (ACP). However, comparing written preferences to actual end-of-life care may not capture consistency of care with preferences. OBJECTIVE: We evaluated four additional types of consistency, using prospective data on written preferences and active clinical decision making by patients and their surrogates. METHODS: Secondary analysis of data was done from a trial of an ACP intervention for patient-surrogate dyads. Forty-five patients died during the trial and comprised the sample for the analysis. Sources of data included patients' preferences in a written goals-of-care tool, medical record reviews, and two-week postbereavement interviews with surrogates to complement medical record reviews. RESULTS: Twenty four patients (53.3%) received care consistent with written preferences and 11 (24.4%) inconsistent with written preferences. The remaining 10 patients (22.2%) died suddenly with no opportunity for treatment decision making. Eleven (24.4%) were able to participate in decision making with their surrogates; of those, 9 (81.8%) received care consistent with their expressed preferences. Twenty-two patients were incapacitated and thus the surrogate made treatment decisions alone; of those, 18 (81.8%) made decisions consistent with the patient's written preference. CONCLUSIONS: Simply comparing documented preferences for end-of-life care and medical records of care delivered does not adequately reflect the process of ACP and treatment decision making at the end of life. To understand consistency between preferences and end-of-life care, investigators need data on written and real-time expressed preferences. PMID- 26982910 TI - The Unbearable Whiteness of Bioethics: Exhorting Bioethicists to Address Racism. PMID- 26982912 TI - Racism and Bioethics: Experiences and Reflections. PMID- 26982911 TI - Bioethicists Can and Should Contribute to Addressing Racism. AB - The problems of racism and racially motivated violence in predominantly African American communities in the United States are complex, multifactorial, and historically rooted. While these problems are also deeply morally troubling, bioethicists have not contributed substantially to addressing them. Concern for justice has been one of the core commitments of bioethics. For this and other reasons, bioethicists should contribute to addressing these problems. We consider how bioethicists can offer meaningful contributions to the public discourse, research, teaching, training, policy development, and academic scholarship in response to the alarming and persistent patterns of racism and implicit biases associated with it. To make any useful contribution, bioethicists will require preparation and should expect to play a significant role through collaborative action with others. PMID- 26982913 TI - Race and Bioethics: Bioethical Engagement With a Four-Letter Subject. PMID- 26982914 TI - Bioethics Skill Sets Can Work, But It Would Take Moral Courage to Apply Them and Get Desired Results. PMID- 26982915 TI - The Really New Jim Crow: Why Bioethicists Must Ally With Undocumented Immigrants. PMID- 26982916 TI - Racism and Bioethics: Are We Part of the Problem? PMID- 26982917 TI - Keeping an Eye on Power in Maintaining Racial Oppression and Race-Based Violence. PMID- 26982918 TI - My Bioethics Will Be Intersectional or It Will Be [Bleep]. PMID- 26982919 TI - Policy, Advocacy, and Activism: On Bioethicists' Role in Combating Racism. PMID- 26982920 TI - Bioethicist or Philosopher King? PMID- 26982921 TI - The Role of Historically Black Medical Schools in Expanding the Purview of Bioethics. PMID- 26982923 TI - NIDA's Pharmacologic Calvinism. PMID- 26982924 TI - Research on Controlled Drug Use: A Paradigm for Public Health Research in Sustainable Health. PMID- 26982925 TI - Justice and Research on Controlled Substances With HIV+ Persons. PMID- 26982922 TI - An Ethical Exploration of Barriers to Research on Controlled Drugs. AB - We examine the ethical, social, and regulatory barriers that may hinder research on therapeutic potential of certain controversial controlled substances like marijuana, heroin, or ketamine. Hazards for individuals and society and potential adverse effects on communities may be good reasons for limiting access and justify careful monitoring of these substances. Overly strict regulations, fear of legal consequences, stigma associated with abuse and populations using illicit drugs, and lack of funding may, however, limit research on their considerable therapeutic potential. We review the surprisingly sparse literature and address the particular ethical concerns pertinent to research with illicit and addictive substances, such as undue inducement, informed consent, therapeutic misconception, and risk to participants, researchers, and institutions. We consider the perspectives of key research stakeholders and explore whether they may be infected with bias. We conclude by proposing an empirical research agenda to provide an evidentiary basis for ethical reasoning. PMID- 26982926 TI - Barriers To Research Using Controlled Drugs Are Not Created Equal. PMID- 26982927 TI - Supervised Controlled Substance Use. PMID- 26982928 TI - Changes Need To Be Made To Make Research More Feasible on Scheduled Drugs for Recreational Purposes as Well. PMID- 26982930 TI - Obligations to Act on Patient Reported Outcomes in Electronic Health Records. PMID- 26982929 TI - Research Moratoria and Off-Label Use of Ketamine. PMID- 26982931 TI - Informed Consent for PROs in EHR Research: Are Additional Requirements Necessary? PMID- 26982932 TI - Patient Reported Outcomes at the Crossroads of Clinical Research and Informatics. PMID- 26982933 TI - PROs in the Balance: Ethical Implications of Collecting Patient Reported Outcome Measures in the Electronic Health Record. PMID- 26982934 TI - Selecting Children for an Autism Spectrum Disorder Study: Justice and Geography. PMID- 26982935 TI - Fair Participant Selection: A Negative Obligation Not to Exclude. PMID- 26982936 TI - Unequal Individual Risk and Potential Benefit Balanced by Benefits to the Population at Large in Autism Clinical Trials? PMID- 26982937 TI - Justice in Selecting Participants for a Study in Phelan-McDermid Syndrome. PMID- 26982943 TI - The Porosity of Autonomy: (Some) Replies to Open Peer Commentaries on "The Porosity of Autonomy: Social and Biological Constitution of the Patient in Biomedicine". PMID- 26982938 TI - Research With Controlled Drugs: Why and Why Not? Response to Open Peer Commentaries on "An Ethical Exploration of Barriers to Research on Controlled Drugs". PMID- 26982944 TI - Art Caplan's Missed Opportunity to Engage Across Difference on Abortion. PMID- 26982945 TI - A Panglossian Analysis of the Abortion Controversy. PMID- 26982946 TI - Comments on Progressive Thinning of Regional Macular Thickness After Epiretinal Membrane Surgery. PMID- 26982947 TI - Author Response: Progressive Thinning of Regional Macular Thickness After Epiretinal Membrane Surgery. PMID- 26982949 TI - Editorial: Issue 30.1. PMID- 26982950 TI - The impact of epilepsy on the quality of life of patients with meningioma: A systematic review. AB - Quality of life (QoL) is regarded as an important outcome measure in meningioma, and studies have investigated the role of various clinical and demographic factors. Epilepsy is known to impair quality of life but the impact of epilepsy on quality of life in a meningioma population is not well defined. The aim of this systematic review is to identify and summarise the current literature on meningioma, epilepsy and quality of life. A PubMed search was performed that identified 162 articles. Only 4 articles relevant to meningioma, epilepsy and QoL were found and each were analysed in terms of design, data, findings and conclusions. Each article was different in terms of study population, aims and outcome measure, but all suggest that epilepsy has an impact on quality of life. Anti-epileptic drugs, uncontrolled seizures and cognitive dysfunction may be particularly significant. The identified articles were weakened by small sample size, short follow-up, a lack of recorded epilepsy variables and the use of quality of life measures that are either too specific or not validated. Future studies are warranted to improve understanding in this topic, aid clinical decisions and improve QoL in these patients. PMID- 26982951 TI - Cervical epidural extra-osseous Ewing sarcoma mimicking an epidural abscess. AB - We report a case of a 21-year-old woman presenting with quadriplegia which was initially diagnosed with an epidural abscess in view of her MR scan and raised inflammatory marker levels. Histology revealed an epidural extra-osseous Ewing's sarcoma (EES). Epidural location of EES is a very rare condition which can be very challenging to diagnose. Early diagnosis and surgical excision followed by chemotherapy represent the main stem of management. PMID- 26982953 TI - A Paired Kidney Analysis of Multiorgan Transplantation: Implications for Allograft Survival. AB - BACKGROUND: United Network for Organ Sharing multiorgan transplantation allocation policy allows sequestration of a kidney by another solid organ regardless of the priority of the candidate for the kidney allograft. The implications of this policy for kidney allograft survival are not well understood. METHODS: We conducted a retrospective cohort analysis of pairs of deceased donor kidney transplants where 1 kidney was allocated to a simultaneous liver-kidney (SLK) or simultaneous heart-kidney (SHK) recipient and the contralateral kidney to a kidney transplant alone (KTA) recipient (cohort from February 2002 to December 2010). Graft and patient survivals were assessed with Cox regression models. RESULTS: There were 1998 SLK and 276 SHK transplants with matching KTA transplants. Five-year kidney graft (64% [SLK] vs 75% [KTA], P < 0.001) and patient survivals (66% [SLK] vs 81% [KTA], P < 0.001) were significantly lower in SLK versus KTA recipients of the contralateral kidney. Among the entire cohort of SLK in this analysis, the cumulative difference in graft survival 1 year after transplant was 115 years, and by 5 years, the difference increased to 1062 years. Among the SHK arm of our study, 5-year graft survival (72% [SHK] vs 73% [KTA], P = 0.71) did not significantly differ, although patient survival (75% [SHK] vs 84% [KTA], P = 0.02) was higher in KTA recipients. CONCLUSIONS: Kidney graft survival is inferior among SLK relative to KTA, but not SHK. Multiorgan transplantation allocation may not be congruent with the intention of new kidney allocation policies that attempt to maximize survival after kidney transplantation. PMID- 26982952 TI - Assessment of Immune Isolation of Allogeneic Mouse Pancreatic Progenitor Cells by a Macroencapsulation Device. AB - BACKGROUND: Embryonic stem cell (ESC)-derived beta cells hold the promise of providing a renewable source of tissue for the treatment of insulin-dependent diabetes. Encapsulation may allow ESC-derived beta cells to be transplanted without immunosuppression, thus enabling wider application of this therapy. METHODS: In this study, we investigated the immunogenicity of mouse pancreatic progenitor cells and efficacy of a new macroencapsulation device in protecting these cells against alloimmune and autoimmune responses in mouse models. RESULTS: Mouse pancreatic progenitor cells activated the indirect but not the direct pathway of alloimmune response and were promptly rejected in immune competent hosts. The new macroencapsulation device abolished T cell activation induced by allogeneic splenocytes and protected allogeneic MIN6 beta cells and pancreatic progenitors from rejection even in presensitized recipients. In addition, the device was effective in protecting MIN6 cells in spontaneously diabetic nonobese diabetic recipients against both alloimmune and recurring autoimmune responses. CONCLUSIONS: Our results demonstrate that macroencapsulation can effectively prevent immune sensing and rejection of allogeneic pancreatic progenitor cells in fully sensitized and autoimmune hosts. PMID- 26982954 TI - Does Donation After Cardiac Death Utilization Adversely Affect Hepatocellular Cancer Survival? AB - BACKGROUND: Hepatocellular cancer (HCC) is an established indication for liver transplantation. This group is often allocated a donor after cardiac death (DCD) liver as a solution for waiting times. There are concerns that this approach may oncologically disadvantage HCC recipients. The aim of this study was to determine whether DCD transplantation was associated with poorer cancer-related survival in HCC. METHODS: Study population was from a single institute (2001-2014) with an HCC listing diagnosis. Variables related to recipient, tumor, and graft were analyzed to determine association with HCC death. RESULTS: There were 347 recipients listed for HCC of which 91 received a DCD. Donor after cardiac death and donor after brain stem death (DBD) had equivalent 1-, 3-, and 5-year overall (P = 0.115) and cancer-specific survival (P = 0.7). On univariate analysis recipient age, sex, model for end stage liver disease, viral etiology had no bearing on the risk of HCC death. Neither did the graft variables of type (DCD vs DBD), donor age, steatosis, cold ischemic time, peak aspartate transaminase, day 5 bilirubin or international normalized ratio after transplant. Only tumor variables of alpha-fetoprotein, number, total diameter, microvascular invasion, and differentiation were predictors of HCC death. On multivariate analysis, predictors of HCC death remained tumor number (P = 0.002), total diameter of tumor(s) (P < 0.001), microvascular invasion (P = 0.025), and poor differentiation (P = 0.021). CONCLUSIONS: Donor liver quality in terms of graft type (DCD) has no influence on cancer related survival in transplant for HCC (hazards ratio, 1.143; 95% confidence interval, 0.528-2.423; P = 0.752). PMID- 26982955 TI - Cardiac Screening for Kidney Transplantation: The Clinical Conundrum Continues. PMID- 26982956 TI - Coronary Artery Disease Assessment and Intervention in Renal Transplant Patients: Analysis from the KiHeart Cohort. AB - BACKGROUND: The value of coronary artery disease (CAD) assessment and coronary intervention in the prognosis of patients who undergo renal transplantation is controversial. We investigated whether pretransplant identification of patients with CAD is helpful for defining prognosis and whether preemptive coronary intervention reduces the incidence of cardiovascular events and death after engraftment. METHODS: We analyzed the impact of coronary assessment by clinical stratification and coronary angiography and of coronary intervention on prognosis in 535 chronic kidney disease patients on the transplantation waiting list who underwent renal transplantation. RESULTS: Patients with 70% or greater narrowing experienced more coronary events than patients with less significant lesions (P = 0.01) and subjects at low risk (P = 0.001). Coronary assessment did not discriminate between the risk of death in patients with or without significant CAD, and the independent predictors of death were age (hazards ratio, 1.04; 95% confidence interval, 1.01-1.06, P = 0.001) and diabetes (hazards ratio, 1.63; 95% confidence interval, 1.11-2.39, P = 0.01). No difference occurred in events and mortality between patients treated medically or by intervention, but the severity of CAD was higher in the latter. CONCLUSIONS: Coronary assessment identified patients at increased risk of posttransplant coronary events and was also useful to define a low-risk population that may be safely transplanted without in-depth cardiovascular evaluation. However, it did not differentiate between the risk of death in patients with and those without significant CAD. Survival was similar in patients undergoing either medical or interventional treatment for CAD. PMID- 26982957 TI - Fifty years of the Revista de Saude Publica. PMID- 26982958 TI - Validation of an instrument to evaluate health promotion at schools. AB - OBJECTIVE: To validate an instrument designed to assess health promotion in the school environment. METHODS: A questionnaire, based on guidelines from the World Health Organization and in line with the Brazilian school health context, was developed to validate the research instrument. There were 60 items in the instrument that included 40 questions for the school manager and 20 items with direct observations made by the interviewer. The items' content validation was performed using the Delphi technique, with the instrument being applied in 53 schools from two medium-sized cities in the South region of Brazil. Reliability (Cronbach's alpha and split-half) and validity (principal component analysis) analyses were performed. RESULTS: The final instrument remained composed of 28 items, distributed into three dimensions: pedagogical, structural and relational. The resulting components showed good factorial loads (> 0.4) and acceptable reliability (> 0.6) for most items. The pedagogical dimension identifies educational activities regarding drugs and sexuality, violence and prejudice, auto care and peace and quality of life. The structural dimension is comprised of access, sanitary structure, and conservation and equipment. The relational dimension includes relationships within the school and with the community. CONCLUSIONS: The proposed instrument presents satisfactory validity and reliability values, which include aspects relevant to promote health in schools. Its use allows the description of the health promotion conditions to which students from each educational institution are exposed. Because this instrument includes items directly observed by the investigator, it should only be used during periods when there are full and regular activities at the school in question. PMID- 26982959 TI - Finding Aedes aegypti in a natural breeding site in an urban zone, Sao Paulo, Southeastern Brazil. AB - This is the description of how nine Aedes aegypti larvae were found in a natural breeding site in the Pinheiros neighborhood, city of Sao Paulo, SP, Southeastern Brazil. The record was conducted in December 2014, during an entomological surveillance program of dengue virus vectors, with an active search of potential breeding sites, either artificial or natural. FindingAe. aegypti larvae in a tree hole shows this species' ability to use both artificial and natural environments as breeding sites and habitats, which points towards the importance of maintaining continuous surveillance on this mosquito in all kinds of water holding containers. PMID- 26982960 TI - Air pollution and its impacts on health in Vitoria, Espirito Santo, Brazil. AB - OBJECTIVE: To analyze the impact of air pollution on respiratory and cardiovascular morbidity of children and adults in the city of Vitoria, state of Espirito Santo. METHODS: A study was carried out using time-series models via Poisson regression from hospitalization and pollutant data in Vitoria, ES, Southeastern Brazil, from 2001 to 2006. Fine particulate matter (PM10), sulfur dioxide (SO2), and ozone (O3) were tested as independent variables in simple and cumulative lags of up to five days. Temperature, humidity and variables indicating weekdays and city holidays were added as control variables in the models. RESULTS: For each increment of 10 ug/m3 of the pollutants PM10, SO2, and O3, the percentage of relative risk (%RR) for hospitalizations due to total respiratory diseases increased 9.67 (95%CI 11.84-7.54), 6.98 (95%CI 9.98-4.17) and 1.93 (95%CI 2.95-0.93), respectively. We found %RR = 6.60 (95%CI 9.53-3.75), %RR = 5.19 (95%CI 9.01-1.5), and %RR = 3.68 (95%CI 5.07-2.31) for respiratory diseases in children under the age of five years for PM10, SO2, and O3, respectively. Cardiovascular diseases showed a significant relationship with O3, with %RR = 2.11 (95%CI 3.18-1.06). CONCLUSIONS: Respiratory diseases presented a stronger and more consistent relationship with the pollutants researched in Vitoria. A better dose-response relationship was observed when using cumulative lags in polynomial distributed lag models. PMID- 26982961 TI - Increase in cases of malaria in Mozambique, 2014: epidemic or new endemic pattern? AB - OBJECTIVE: To describe the increase in cases of malaria in Mozambique. METHODS: Cross-sectional study conducted in 2014, in Mozambique with national weekly epidemiological bulletin data. I analyzed the number of recorded cases in the 2009-2013 period, which led to the creation of an endemic channel using the quartile and C-Sum methods. Monthly incidence rates were calculated for the first half of 2014, making it possible to determine the pattern of endemicity. Months in which the incidence rates exceeded the third quartile or line C-sum were declared as epidemic months. RESULTS: The provinces of Nampula, Zambezia, Sofala, and Inhambane accounted for 52.7% of all cases in the first half of 2014. Also during this period, the provinces of Nampula, Sofala and Tete were responsible for 54.9% of the deaths from malaria. The incidence rates of malaria in children, and in all ages, have showed patterns in the epidemic zone. For all ages, the incidence rate has peaked in April (2,573 cases/100,000 inhabitants). CONCLUSIONS: The results suggest the occurrence of an epidemic pattern of malaria in the first half of 2014 in Mozambique. It is strategic to have a more accurate surveillance at all levels (central, provincial and district) to target prevention and control interventions in a timely manner. PMID- 26982962 TI - Pharmacodynamics, pharmacokinetics and clinical efficacy of apixaban in the treatment of thrombosis. AB - INTRODUCTION: Venous thromboembolism (VTE) is a common disorder. Heparin and vitamin K antagonists have been the standard treatment for VTE for over 50 years. The development of apixaban and other direct oral anticoagulants has greatly increased the range of anticoagulants available for the treatment of VTE. AREA COVERED: Studies on the chemistry, pharmacodynamics and pharmacokinetics of apixaban are reviewed. Its clinical efficacy and safety are discussed, with an emphasis on randomized controlled Phase III clinical trials on treatment of thrombosis. EXPERT OPINION: Apixaban is a safe and effective anticoagulant for VTE treatment. It has several attractive features: its oral activity, rapid action, limited drug- interaction profile and limited need for laboratory monitoring. An antidote may become available in the near future. Further studies of certain patient populations such as patients with cancers, elderly (aged 75 years and older) and those with severe renal and liver disease, are required as these patients have not yet been studied in sufficient numbers. As clinical trials included only selected patients, data from these studies may not reflect the 'real-life' patients in clinical practice. There is therefore an unmet need for large post-registration studies of unselected 'real-life' patients, such as registry studies, to validate the clinical trial findings. PMID- 26982963 TI - Treatment of Skin Ulcers Secondary to Sneddon Syndrome With Alprostadil (Prostaglandin E1). PMID- 26982964 TI - Role of Structural H2O in Intercalation Electrodes: The Case of Mg in Nanocrystalline Xerogel-V2O5. AB - Cointercalation is a potential approach to influence the voltage and mobility with which cations insert in electrodes for energy storage devices. Combining a robust thermodynamic model with first-principles calculations, we present a detailed investigation revealing the important role of H2O during ion intercalation in nanomaterials. We examine the scenario of Mg(2+) and H2O cointercalation in nanocrystalline Xerogel-V2O5, a potential cathode material to achieve energy density greater than Li-ion batteries. Water cointercalation in cathode materials could broadly impact an electrochemical system by influencing its voltages or causing passivation at the anode. The analysis of the stable phases of Mg-Xerogel V2O5 and voltages at different electrolytic conditions reveals a range of concentrations for Mg in the Xerogel and H2O in the electrolyte where there is no thermodynamic driving force for H2O to shuttle with Mg during electrochemical cycling. Also, we demonstrate that H2O shuttling with the Mg(2+) ions in wet electrolytes yields higher voltages than in dry electrolytes. The thermodynamic framework used to study water and Mg(2+) cointercalation in this work opens the door for studying the general phenomenon of solvent cointercalation observed in other complex solvent-electrode pairs used in the Li- and Na-ion chemical spaces. PMID- 26982965 TI - Proximal Junctional Kyphosis. AB - Proximal junctional kyphosis (PJK) is a common complication following adult spinal deformity surgery. It is defined by two criteria: a proximal junctional sagittal Cobb angle (1) >= 10 degrees and (2) at least 10 degrees greater than the preoperative measurement. PJK is multifactorial in origin and likely stems from surgical, radiographic, and patient-related risk factors. The diagnosis of PJK represents a broad spectrum of disease ranging from asymptomatic patients with recurrence of deformity to those presenting with increased pain, functional deficit, and, in the most severe cases, neurologic deficits. Recent studies have demonstrated increased pain levels in select patients with PJK. In keeping with the broad spectrum of the disease, classification schemes are needed to better describe and stratify the severity of PJK. The most severe form is proximal junctional failure. A consensus on a uniform definition of proximal junctional failure is needed to allow for more systematic study of this phenomenon. PMID- 26982966 TI - Twisting in the excited state of an N-methylpyridinium fluorescent dye modulated by nano-heterogeneous micellar systems. AB - A push-pull N-methylpyridinium fluorescent dye with a pyrenyl group as the electron-donor portion was investigated within the nano-heterogeneous media provided by some micellar systems. The molecule was studied by stationary and time-resolved spectroscopic techniques in spherical micellar solutions and viscoelastic hydrogels, in order to throw light on the role played by twisting in its excited state deactivation. As proven by femtosecond fluorescence up conversion and transient absorption experiments, the excited state dynamics of the molecule is ruled by charge transfer and twisting processes, which, from the locally excited (LE) state initially populated upon excitation, progressively lead to twisted (TICT) and planar (PICT) intramolecular charge transfer states. The inclusion within micellar aggregates was found to slow down and/or limit the rotation of the molecule with respect to what had previously been observed in water, while its confinement within the hydrophobic domains of the gel matrixes prevents any molecular torsion. The increasing viscosity of the medium, when passing from water to micellar systems, implies that the detected steady-state fluorescence comes from an excited state which is not fully relaxed, as is the case with the TICT state in micelles or the LE state in hydrogels, where the detected emission changes its usual orange colour to yellow. PMID- 26982967 TI - Six-Minute Walk Test in Renal Failure Patients: Representative Results, Performance Analysis and Perceived Dyspnea Predictors. AB - OBJECTIVES: Six-minute walk test in dialysis population hasn't been consistently evaluated for the isolated impact of renal failure and other predictive factors. We measured six-minute walk distance in patients representative for low level of comorbidity and searched for potentially modifiable predictive factors of performance and dyspnea. METHODS: This was a cross-sectional study with hemodialysis patients (N = 90) and control subjects (N = 140). MAIN OUTCOME MEASURES: six-minute walk test distance and dyspnea severity using the 10-item Borg scale. RESULTS: Median distance decreased from 600m below the 6th decade to 420m in the 8th decade of age. Dialysis dependence predicted 101.5m shorter distance in the adjusted model that explained 70% of variability in results. Adjusted for significant covariates of age, height and spontaneous gait speed, fat mass (but not lean body mass) and serum total iron binding capacity were significantly associated with distance (95% CI for B coefficients -4.6 to -1.4 m/kg and 0.1 to 5 m/MUmol/l, respectively). Serum total iron binding capacity as an explanatory variable was superior to C-reactive protein and albumin. Dialysis dependence, odds ratio (OR) 2.97 (1.11-7.94), spontaneous gait speed, OR 0.08 (0.02-0.41), rate-pressure product, OR 1.15 (1.08-1.23) and hemoglobin, OR 0.95 (0.92-0.98) predicted dyspnea in the adjusted model. CONCLUSIONS: Renal failure without the confounding effect of comorbidity is a significant negative predictor of performance at six-minute walk test and perceived level of dyspnea. Body fat mass and serum total iron binding capacity are the main potentially modifiable predictors of performance, total iron binding capacity being superior to C reactive protein and albumin. Although hemoglobin is not associated with test performance, it negatively predicts perceived shortness of breath. PMID- 26982969 TI - Preseason Functional Movement Screen Component Tests Predict Severe Contact Injuries in Professional Rugby Union Players. AB - Tee, JC, Klingbiel, JFG, Collins, R, Lambert, MI, and Coopoo, Y. Preseason Functional Movement Screen component tests predict severe contact injuries in professional rugby union players. J Strength Cond Res 30(11): 3194-3203, 2016 Rugby union is a collision sport with a relatively high risk of injury. The ability of the Functional Movement Screen (FMS) or its component tests to predict the occurrence of severe (>=28 days) injuries in professional players was assessed. Ninety FMS test observations from 62 players across 4 different time periods were compared with severe injuries sustained during 6 months after FMS testing. Mean composite FMS scores were significantly lower in players who sustained severe injury (injured 13.2 +/- 1.5 vs. noninjured 14.5 +/- 1.4, Effect Size = 0.83, large) because of differences in in-line lunge (ILL) and active straight leg raise scores (ASLR). Receiver-operated characteristic curves and 2 * 2 contingency tables were used to determine that ASLR (cut-off 2/3) was the injury predictor with the greatest sensitivity (0.96, 95% confidence interval [CI] = 0.79-1.0). Adding the ILL in combination with ASLR (ILL + ASLR) improved the specificity of the injury prediction model (ASLR specificity = 0.29, 95% CI = 0.18-0.43 vs. ASLR + ILL specificity = 0.53, 95% CI = 0.39-0.66, p <= 0.05). Further analysis was performed to determine whether FMS tests could predict contact and noncontact injuries. The FMS composite score and various combinations of component tests (deep squat [DS] + ILL, ILL + ASLR, and DS + ILL + ASLR) were all significant predictors of contact injury. The FMS composite score also predicted noncontact injury, but no component test or combination thereof produced a similar result. These findings indicate that low scores on various FMS component tests are risk factors for injury in professional rugby players. PMID- 26982968 TI - Pyelonephritis Caused by Salmonella Anatum: An Unusual Case. AB - Salmonella species are a very rare cause of urinary tract infection in healthy children. This species is associated with a high incidence of genitourinary abnormalities and immune deficiencies. We report the first pediatric case of a healthy 9-year-old girl with pyelonephritis due to Salmonella Anatum. PMID- 26982970 TI - Physical and Physiological Responses of Amateur Football Players on Third Generation Artificial Turf Systems During Simulated Game Situations. AB - Sanchez-Sanchez, J, Garcia-Unanue, J, Felipe, JL, Jimenez-Reyes, P, Viejo-Romero, D, Gomez-Lopez, M, Hernando, E, Burillo, P, and Gallardo, L. Physical and physiological responses of amateur football players on third generation artificial turf systems during simulated game situations. J Strength Cond Res 30(11): 3165-3177, 2016-The aim of this study is to evaluate the physical and physiological load imposed on amateur football players in a simulated game situation on different artificial turf systems. For that purpose, 20 football players (21.65 +/- 3.10 year old) were monitored with Global Positioning Systems and heart rate bands during 45-minutes games on 4 selected artificial turf systems. The results show more covered distance in high-intensity ranges on the system with lower levels of damping and higher rates of rotational traction (p <= 0.05). Likewise, this system of artificial turf demonstrated a high number of sprints (12.65 +/- 5.67) and more elevated maximum speed peaks during the last part of the game (28.16 +/- 2.90 km.h) in contrast to the systems with better damping capacity (p <= 0.05). On the other hand, the physiological load was similar across the 4 artificial turf systems (p > 0.05). Finally, the regression analysis demonstrated a significant influence of the mechanical properties of the surface on global distance (15.4%), number (12.6%), and maximum speed (16.6%) of the sprints. To conclude, the mechanical variability of the artificial turf systems resulted in differences in the activity profiles and the players' perceptions during simulated football games. PMID- 26982971 TI - Yo-Yo Intermittent Recovery Test Performance in Subelite Gaelic Football Players From Under Thirteen to Senior Age Groups. AB - Roe, M and Malone, S. Yo-Yo intermittent recovery test performance in subelite Gaelic football players from under thirteen to senior age groups. J Strength Cond Res 30 (11): 3187-3193, 2016-Gaelic football is indigenous to Ireland and has similar locomotion profiles to soccer and Australian Football. Given the increasing attention on long-term player development, investigations on age related variation in Yo-Yo intermittent recovery test level 1 (Yo-YoIR1) performance may provide useful information in talent identification, program design, and player monitoring. Therefore, the aim of this study was to evaluate Yo-YoIR1 performance across Gaelic football age groups. Male participants (n = 355) were recruited from division one, Gaelic football teams. Participants were allocated to one of the 7 groups according to respective age groups from under 13 (U13), under 14, under 15 (U15), under 16 (U16), minor, under 21 (U21), to senior age groups. Total Yo-YoIR1 distance (m) increased progressively from U13 (885 +/- 347 m) to U16 (1,595 +/- 380 m) equating to a rate of change of 180.2%. In comparison to U13, total distance at minor (1,206 +/- 327 m) increased by 136.4%. Subsequent increases were observed in U21 (1,585 +/- 445 m) and senior players (2,365 +/- 489). Minimum (800-880 m) and maximum (2,240-2,280 m) total distances were comparable for U15, U16, and U21 players. Differences in total distance (m) for all age groups were statistically significant when compared to U13 players (p < 0.002). In comparison to U13 players, the magnitude of differences between age groups for total distance was deemed to be large (effect size > 0.8). Similar trends were observed for maximum velocity and estimated V[Combining Dot Above]O2max. The evolution of Yo-YoIR1 performance in Gaelic football players from adolescents to adulthood highlights how maturation may influence sport related running ability. Changes in Yo-YoIR1 performance should be closely monitored to optimize interventions for individuals transitioning across age groups. PMID- 26982972 TI - Change of Direction Deficit: A More Isolated Measure of Change of Direction Performance Than Total 505 Time. AB - Nimphius, S, Callaghan, SJ, Spiteri, T, and Lockie, RG. Change of direction deficit: A more isolated measure of change of direction performance than total 505 time. J Strength Cond Res 30 (11): 3024-3032, 2016-Most change of direction (COD) tests use total time to evaluate COD performance. This makes it difficult to identify COD ability because the majority of time is a function of linear running. The COD deficit has been proposed as a practical measure to isolate COD ability independent of sprint speed. This study evaluated relationships between sprint time, 505 time, and COD deficit, and whether the COD deficit identified a different and more isolated measure of COD ability compared with 505 time. Seventeen cricketers performed the 505 for both left and right sides and 30-m sprint tests (with 10-m split time). The COD deficit for both sides was calculated as the difference between average 505 and 10-m time. Correlations were calculated between all variables (p <= 0.05). To compare 505 time and COD deficit, z-scores were calculated; the difference in these scores was evaluated for each subject. The COD deficit correlated to 505 (r = 0.74-0.81) but not sprint time (r = -0.11 to 0.10). In contrast, 505 time did correlate with sprint time (r = 0.52-0.70). Five of 17 subjects were classified differently for COD ability when comparing standardized scores for 505 time vs. COD deficit. Most subjects (88-94%) had a meaningful difference between 505 time and COD deficit. Using 505 time to determine COD ability may result in a large amount of replication to linear speed assessments. The COD deficit may be a practical tool to better isolate and identify an athlete's ability to change direction. PMID- 26982973 TI - An Analysis of the Pacing Strategies Adopted by Elite Cross-Country Skiers. AB - Losnegard, T, Kjeldsen, K, and Skattebo, O. An analysis of the pacing strategies adopted by elite cross-country skiers. J Strength Cond Res 30(11): 3256-3260, 2016-Understanding the pacing strategies used by the most successful skiers may provide insight into the most desirable pacing approach in cross-country (XC) skiing. This study examined the pacing strategies adopted by male and female XC skiers of different performance standards during 10 and 15 km races in World Cup, World Championships, and Olympic events. Analyses were performed on races involving 5 km laps in the men's 15 km (number of races = 22) and the women's 10 km (n = 14) individual start races (classic and freestyle) from season 2002/2003 to season 2013/2014. Final rank and lap times for the 40 top finishers in each race were analyzed. Both sexes demonstrated a positive pacing pattern shown by a decline in velocity from the first to the last lap (men: 6.76 +/- 0.43 m.s vs. 6.47 +/- 0.46 m.s; p < 0.001; women: 6.0 +/- 0.47 m.s vs. 5.87 +/- 0.53 m.s; p < 0.001). For the men, slower skiers (final ranking 21st-30th and 31st-40th) were characterized by a quick start relative to their average velocity, with a greater decrease during the race compared with the fastest skiers (1st-10th) (p = 0.007 and p < 0.001, respectively). For the women, no group differences in pacing strategy were found. In conclusion, this study shows that the pacing strategy indicates the standard of elite male XC skiers. Examining the pacing strategies of the best male performers suggests that lower-performing male skiers should consider a more even pacing strategy to improve their performance. PMID- 26982974 TI - The Association Between Visual Assessment of Quality of Movement and Three Dimensional Analysis of Pelvis, Hip, and Knee Kinematics During a Lateral Step Down Test. AB - Rabin, A, Portnoy, S, and Kozol, Z. The association between visual assessment of quality of movement and three-dimensional analysis of pelvis, hip, and knee kinematics during a lateral step down test. J Strength Cond Res 30(11): 3204 3211, 2016-Altered movement patterns including contralateral pelvic drop, increased hip adduction, knee abduction, and external rotation have been previously implicated in several lower extremity pathologies. Although various methods exist for assessing movement patterns, real-time visual observation is the most readily available method. The purpose of this study was to determine whether differing visual ratings of trunk, pelvis, and knee alignment, as well as overall quality of movement, are associated with differences in 3-dimensional trunk, pelvis, hip, or knee kinematics during a lateral step down test. Trunk, pelvis, and knee alignment of 30 healthy participants performing the lateral step down were visually rated as "good" or "faulty" based on previously established criteria. An additional categorization of overall quality of movement as either good or moderate was performed based on the aggregate score of each individual rating criterion. Three-dimensional motion analysis of trunk, pelvis, hip, and knee kinematics was simultaneously performed. A faulty pelvis alignment displayed a greater peak contralateral pelvic drop (effect size [ES], 1.65; p < 0.01) and a greater peak hip adduction (ES: 1.04, p = 0.01) compared with participants with a good pelvis alignment. Participants with a faulty knee alignment displayed greater peak knee external rotation compared with participants with a good knee alignment (ES, 0.78; p = 0.02). Participants with an overall moderate quality of movement displayed increased peak contralateral pelvic drop (ES, 1.07; p = 0.01) and peak knee external rotation (ES, 0.72; p = 0.04) compared with those with an overall good quality of movement. Visual rating of quality of movement during a lateral step down test, as performed by an experienced physical therapist, is associated with differences in several kinematics previously implicated in various pathologies. PMID- 26982975 TI - Core Muscle Activation During Unstable Bicep Curl Using a Water-Filled Instability Training Tube. AB - Glass, SC, Blanchette, TW, Karwan, LA, Pearson, SS, O'Neil, AP, and Karlik, DA. Core muscle activation during unstable bicep curl using a water-filled instability training tube. J Strength Cond Res 30(11): 3212-3219, 2016-The purpose of this study was to assess compensatory muscle activation created during a bicep curl using a water-filled, unstable lifting tube. Ten men (age = 21 +/- 1.6 years, height = 180.0 +/- 3.3 cm, mass = 87.4 +/- 15.0 kg) and 10 women (age = 19.6 +/- 1.3 years, height = 161.4 +/- 12.0 cm, mass = 61.2 +/- 7.4 kg) completed bicep curls using an 11.4-kg tube partially filled with water during a 50% open-valve, 100% open, and control setting. Subjects completed 8 repetitions within each condition with integrated electromyographic signal (converted to percent maximal voluntary contraction) of the bicep, deltoid, rectus abdominus, and paraspinal muscles measured. Compensatory activation was determined using the natural log of coefficient of variation across concentric (CON) and eccentric (ECC) contractions. There were no differences between gender for any condition. Significant variability was seen across treatments for paraspinal muscles for CON and ECC at 50% (CON LnCV = 3.13 +/- 0.56%, ECC LnCV = 3.34 +/- 0.58%) and 100% (CON = 3.24 +/- 0.34%, ECC = 3.46 +/- 0.35%) compared with control (CON = 2.59 +/ 0.47%, ECC = 2.80 +/- 0.61%). Deltoid variability was greater at the 100% open setting (CON = 3.51 +/- 0.53%, ECC = 3.56 +/- 0.36%) compared with control (CON = 2.98 +/- 0.35%, ECC = 2.97 +/- 0.45%). The abdominal CON 100% showed variability (3.02 +/- 0.47%) compared with control (2.65 +/- 0.43%). Bicep activation remained unvaried. Compensatory activation of postural muscles contribute to postural stability. This device may be a useful tool for neuromuscular training leading to improved stability and control. PMID- 26982976 TI - Influences of Fascicle Length During Isometric Training on Improvement of Muscle Strength. AB - Tanaka, H, Ikezoe, T, Umehara, J, Nakamura, M, Umegaki, H, Kobayashi, T, Nishishita, S, Fujita, K, Araki, K, and Ichihashi, N. Influences of fascicle length during isometric training on improvement of muscle strength. J Strength Cond Res 30(11): 3249-3255, 2016-This study investigated whether low-intensity isometric training would elicit a greater improvement in maximum voluntary contraction (MVC) at the same fascicle length, rather than the joint angle, adopted during training. Sixteen healthy women (21.8 +/- 1.5 years) were randomly divided into an intervention group and a control group. Before (Pre) and after (Post) training, isometric plantarflexion MVCs were measured every 10 degrees through the range of ankle joint position from 20 degrees dorsiflexion to 30 degrees plantarflexion (i.e., 6 ankle angles). Medial gastrocnemius fascicle length was also measured at each position, using B-mode ultrasound under 3 conditions of muscle activation: at rest, 30%MVC at respective angles, and MVC. Plantarflexion resistance training at an angle of 20 degrees plantarflexion was performed 3 days a week for 4 weeks at 30%MVC using 3 sets of twenty 3-second isometric contractions. Maximum voluntary contraction in the intervention group increased at 0 and 10 degrees plantarflexion (0 degrees ; Pre: 81.2 +/- 26.5 N.m, Post: 105.0 +/- 21.6 N.m, 10 degrees ; Pre: 63.0 +/- 23.6 N.m, Post: 81.3 +/ 20.3 N.m), which was not the angle used in training (20 degrees ). However, the fascicle length adopted in training at 20 degrees plantarflexion and 30%MVC was similar to the value at 0 or 10 degrees plantarflexion at MVC. Low-intensity isometric training at a shortened muscle length may be effective for improving MVC at a lengthened muscle length because of specificity of the fascicle length than the joint angle. PMID- 26982977 TI - Isometric Mid-Thigh Pull Correlates With Strength, Sprint, and Agility Performance in Collegiate Rugby Union Players. AB - Wang, R, Hoffman, JR, Tanigawa, S, Miramonti, AA, La Monica, MB, Beyer, KS, Church, DD, Fukuda, DH, and Stout, JR. Isometric mid-thigh pull correlates with strength, sprint, and agility performance in collegiate rugby union players. J Strength Cond Res 30(11): 3051-3056, 2016-The purpose of this investigation was to examine the relationships between isometric mid-thigh pull (IMTP) force and strength, sprint, and agility performance in collegiate rugby union players. Fifteen members of a champion-level university's club rugby union team (mean +/- SD: 20.67 +/- 1.23 years, 1.78 +/- 0.06 m, and 86.51 +/- 14.18 kg) participated in this investigation. One repetition maximum (1RM) squat, IMTP, speed (40 m sprint), and agility (proagility test and T-test) were performed during 3 separate testing sessions. Rate of force development (RFD) and force output at 30, 50, 90, 100, 150, 200, and 250 milliseconds of IMTP, as well as the peak value were determined. Pearson product-moment correlation analysis was used to examine the relationships between these measures. Performance in the 1RM squat was significantly correlated to the RFD between 90 and 250 milliseconds from the start of contraction (r's ranging from 0.595 to 0.748), and peak force (r = 0.866, p <= 0.05). One repetition maximum squat was also correlated to force outputs between 90 and 250 milliseconds (r's ranging from 0.757 to 0.816, p <= 0.05). Sprint time over the first 5 m in the 40 m sprint was significantly (p <= 0.05) correlated with peak RFD (r = -0.539) and RFD between 30 and 50 milliseconds (r's = -0.570 and -0.527, respectively). Time for the proagility test was correlated with peak RFD (r = -0.523, p <= 0.05) and RFD between 30 and 100 milliseconds (r's ranging from -0.518 to -0.528, p's < 0.05). Results of this investigation indicate that IMTP variables are significantly associated with strength, agility, and sprint performance. Future studies should examine IMTP as a potential tool to monitor athletic performance during the daily training of rugby union players. PMID- 26982979 TI - Elevated B Cell Activation is Associated with Type 2 Diabetes Development in Obese Subjects. AB - BACKGROUND/AIMS: Despite strong association between obesity and the pathogenesis of type 2 diabetes (T2D), only a subset of obese individuals eventually develops T2D. We sought to determine the immunological factors behind this heterogeneity. METHODS: Peripheral blood of obese non-diabetic subjects and obese diabetic subjects were collected and the B cell responses in these subjects were analyzed. RESULTS: We found that the B cells from obese diabetic subjects had similar B cell subtype composition and secreted similar levels of low-grade pro inflammatory cytokines to obese non-diabetic subjects, characteristic to the background chronic immune activation frequently observed in obese subjects. When examining adaptive B cell antibody responses, however, obese diabetic subjects presented much higher levels of polyclonal activation and antibody secretion, with impaired ability to response to new antigens such as seasonal influenza vaccination. CONCLUSIONS: These data demonstrated that in obese diabetic subjects, B cell adaptive response is impaired and potentially contribute to overall higher inflammation. PMID- 26982978 TI - FTH1P3, a Novel H-Ferritin Pseudogene Transcriptionally Active, Is Ubiquitously Expressed and Regulated during Cell Differentiation. AB - Ferritin, the major iron storage protein, performs its essential functions in the cytoplasm, nucleus and mitochondria. The variable assembly of 24 subunits of the Heavy (H) and Light (L) type composes the cytoplasmic molecule. In humans, two distinct genes code these subunits, both belonging to complex multigene families. Until now, one H gene has been identified with the coding sequence interrupted by three introns and more than 20 intronless copies widely dispersed on different chromosomes. Two of the intronless genes are actively transcribed in a tissue specific manner. Herein, we report that FTH1P3, another intronless pseudogene, is transcribed. FTH1P3 transcript was detected in several cell lines and tissues, suggesting that its transcription is ubiquitary, as it happens for the parental ferritin H gene. Moreover, FTH1P3 expression is positively regulated during the cell differentiation process. PMID- 26982981 TI - Masked form priming is moderated by the size of the letter-order-free orthographic neighbourhood. AB - University students made lexical decisions to targets preceded by masked primes. In Experiment 1, transposed-letter primes were used also in the sandwich priming paradigm, in which the target is briefly pre-presented prior to the prime. The priming effects in the masked paradigm, but not in the sandwich paradigm, were moderated by the density of the letter-order-free neighbourhood of the target. In Experiment 2, letter-order-free neighbour prime words produced a priming cost in masked priming. These results are consistent with the idea that sandwich priming attenuates letter-order-free neighbour competition in target identification. Unexpectedly, no priming cost was produced by conventional (letter-position preserving) word neighbour primes. Order-free neighbours may produce facilitation of target processing less, and more variably, than conventional neighbours. PMID- 26982980 TI - Prostate Stem Cell Antigen Expression in Radical Prostatectomy Specimens Predicts Early Biochemical Recurrence in Patients with High Risk Prostate Cancer Receiving Neoadjuvant Hormonal Therapy. AB - We aimed to identify tissue biomarkers that predict early biochemical recurrence (BCR) in patients with high-risk prostate cancer (PC), toward the goal of increasing the benefits of neoadjuvant hormonal therapy (NHT). In 2005-2012, prostatectomy specimens were collected from 134 PC patients who had received NHT and radical prostatectomy. The expression of 13 tissue biomarkers was assessed in the specimens via immunohistochemistry. Time to BCR and factors predictive of BCR were determined by using the Cox proportional hazards model. During the follow-up period (median, 57.5 months), 67 (50.0%) patients experienced BCR. Four (3.0%) patients were tumor-free in the final pathology assessment, and 101 (75.4%) had negative resection margins. Prostate stem cell antigen (PSCA) was the only significant prognostic tissue biomarker of BCR [hazard ratio (HR), 2.58; 95% confidence interval (CI), 1.06-6.27; p = 0.037] in a multivariable analysis adjusted by the clinicopathological variables that also significantly predicted BCR; these were seminal vesicle invasion (HR, 2.39; 95% CI, 1.32-4.34), initial prostate serum antigen level (HR 1.01; 95% CI, 1.001-1.020), prostate size (HR, 0.93; 95% CI, 0.90-0.97), and the Gleason score of preoperative biopsies (HR, 1.34; 95% CI, 1.01-1.79). We suggest that PSCA is a useful tissue marker for predicting BCR in patients with high risk PC receiving NHT and radical prostatectomy. PMID- 26982982 TI - Phosphorus magnetic resonance spectroscopy in the investigation of temporal lobe epilepsy: 'reading between the lines' of metabolic abnormalities. PMID- 26982983 TI - The broad clinical spectrum of hereditary neuropathy with liability to pressure palsy (HNPP). PMID- 26982984 TI - Extratemporal abnormalities in phosphorus magnetic resonance spectroscopy of patients with mesial temporal sclerosis. AB - OBJECTIVE: We evaluated extratemporal metabolic changes with phosphorus magnetic resonance spectroscopy (31P-MRS) in patients with unilateral mesial temporal sclerosis (MTS). METHOD: 31P-MRS of 33 patients with unilateral MTS was compared with 31 controls. The voxels were selected in the anterior, posterior insula basal ganglia (AIBG, PIBG) and frontal lobes (FL). Relative values of phosphodiesters- PDE, phosphomonoesters-PME, inorganic phosphate - Pi, phosphocreatine- PCr, total adenosine triphosphate [ATPt = gamma- + a- + b-ATP] and the ratios PCr/ATPt, PCr/gamma-ATP, PCr/Pi and PME/PDE were obtained. RESULTS: We found energetic abnormalities in the MTS patients compared to the controls with Pi reduction bilaterally in the AIBG and ipsilaterally in the PIBG and the contralateral FL; there was also decreased PCr/gamma-ATP in the ipsilateral AIBG and PIBG. Increased ATPT in the contralateral AIBG and increased gamma-ATP in the ipsilateral PIBG were detected. CONCLUSION: Widespread energy dysfunction was detected in patients with unilateral MTS. PMID- 26982985 TI - Clinical and neurophysiological features of the hereditary neuropathy with liability to pressure palsy due to the 17p11.2 deletion. AB - The hereditary neuropathy with liability to pressure palsies (HNPP) is an autossomal dominant disorder manifesting recurrent mononeuropathies. Objective Evaluate its clinical and nerve conduction studies (NCS) characteristics, searching for diagnostic particularities. Method We reviewed the neurological manifestations of 39 and the NCS of 33 patients. Results Family history was absent in 16/39 (41%). The onset complaints were weakness in 24, pain in 6, sensory deficit in 5 and paresthesias in 4. Pain was seen in 3 other patients. The following neuropathy patterns were found: multiple mononeuropathy (26), mononeuropathy (7), chronic sensorimotor polyneuropathy (4), chronic sensory polyneuropathy (1) and unilateral brachial plexopathy (1). NCS showed a sensorimotor neuropathy with focal conduction slowing in 31, two had mononeuropathy and another brachial plexopathy. Conclusion HNPP presentation is variable and may include pain. The most frequent pattern is of an asymmetrical sensory and motor neuropathy with focal slowing at specific topographies on NCS. PMID- 26982986 TI - A disturbed processing of graviceptive pathways may be involved in the pathophysiology of balance disorders in patients with multiple sclerosis. AB - The purpose of this study was to determine the relationship between perception of verticality and balance disorders in multiple sclerosis patients. We evaluated patients and healthy controls. Patients were divided into two groups according to their risk of fall, with or without risk of fall, measured by a Dynamic Gait Index scale. Graviceptive perception was assessed using the subjective visual vertical test. Patients with risk of fall showed worse perception than those without risk of fall, p < 0.001. Misperception of verticality was correlated with the dynamic gait index scores (p < 0.001), suggesting that the larger the error for verticality judgment, the greater risk for falling. Considering that the perception of verticality is essential for postural control, our results suggested that the disturbed processing of graviceptive pathways may be involved in the pathophysiology of balance disorders in these patients. PMID- 26982988 TI - Speech disorders did not correlate with age at onset of Parkinson's disease. AB - Speech disorders are common manifestations of Parkinson's disease. Objective To compare speech articulation in patients according to age at onset of the disease. Methods Fifty patients was divided into two groups: Group I consisted of 30 patients with age at onset between 40 and 55 years; Group II consisted of 20 patients with age at onset after 65 years. All patients were evaluated based on the Unified Parkinson's Disease Rating Scale scores, Hoehn and Yahr scale and speech evaluation by perceptual and acoustical analysis. Results There was no statistically significant difference between the two groups regarding neurological involvement and speech characteristics. Correlation analysis indicated differences in speech articulation in relation to staging and axial scores of rigidity and bradykinesia for middle and late-onset. Conclusions Impairment of speech articulation did not correlate with age at onset of disease, but was positively related with disease duration and higher scores in both groups. PMID- 26982987 TI - Main determinants of physical activity levels in individuals with Parkinson's disease. AB - This study analyzed the relationship between patient characteristics, factors associated with Parkinson's disease (PD), and physical activity level of individuals affected by the disease. Forty-six volunteers with mild-to-moderate idiopathic PD were assessed using sections II/III of the Unified Parkinson's Disease Rating Scale and their motor functions were classified according to the modified Hoehn and Yahr (HY) scale. Data such as age, disease duration, the Human Activity Profile (HAP), the Fatigue Severity Scale were collected. Lower limb bradykinesia and clinical subtypes of PD were defined. Two models that explained 76% of the variance of the HAP were used. The first comprised age, ability to perform activities of daily living (ADL), and the HY scale; the second comprised age, ability to perform ADL, and lower limb bradykinesia. Possible modifiable factors such as the ability to perform ADL and lower limb bradykinesia were identified as predictors of physical activity level of individuals with PD. PMID- 26982989 TI - Patients with essential tremor can have manual dexterity and attention deficits with no impairments in other cognitive functions. AB - Essential tremor (ET) was long believed to be a monosymptomatic disorder. However, studies have evidenced structural changes and attention is now being focused on non-motor symptoms. The objective of the study is to describe and compare ET patients with control groups according to their cognitive functions, and secondarily, to compare their sociodemographic characteristics and other clinical features. All participants were assessed using the Fahn-Tolosa-Marin Tremor Rating Scale for the severity of tremor; a neuropsychological assessment battery and a screening questionnaire for mood and anxiety symptoms. There were no significant age and gender differences between all groups. As for neuropsychological assessment results, a significant difference was found only in the Pegboard test. We also found a significant negative correlation between a poorer cognitive test results and disease severity and a significant differences regarding depression or anxiety symptoms in patients with ET. The study results suggest that patients with ET have impaired manual dexterity and attention. PMID- 26982990 TI - Cerebrospinal fluid examination may be useful in diagnosing neurosyphilis in asymptomatic HIV+ patients with syphilis. AB - Lumbar puncture in neurologically asymptomatic HIV+ patients is still under debate. There are different criteria for detecting neurosyphilis through cerebrospinal fluid (CSF), especially in cases that are negative through the Venereal Disease Research Laboratory (VDRL), regarding cellularity and protein content. However, a diagnosis of neurosyphilis can still exist despite negative VDRL. Treponema pallidum hemagglutination assay (TPHA) titers and application of the TPHA index in albumin and IgG improve the sensitivity, with a high degree of specificity. Thirty-two patients were selected for this study. VDRL was positive in five of them. The number of diagnoses reached 14 when the other techniques were added. It was not determined whether cellularity and increased protein levels were auxiliary tools in the diagnosis. According to our investigation, CSF analysis using the abovementioned techniques may be useful in diagnosing neurosyphilis in these patients. PMID- 26982991 TI - Performance of four ischemic stroke prognostic scores in a Brazilian population. AB - OBJECTIVE: Ischemic stroke (IS) prognostic scales may help clinicians in their clinical decisions. This study aimed to assess the performance of four IS prognostic scales in a Brazilian population. METHOD: We evaluated data of IS patients admitted at Hospital Paulistano, a Joint Commission International certified primary stroke center. In-hospital mortality and modified Rankin score at discharge were defined as the outcome measures. The performance of National Institutes of Health Stroke Scale (NIHSS), Stroke Prognostication Using Age and NIHSS (SPAN-100), Acute Stroke Registry and Analysis of Lausanne (ASTRAL), and Totaled Health Risks in Vascular Events (THRIVE) were compared. RESULTS: Two hundred six patients with a mean +/- SD age of 67.58 +/- 15.5 years, being 55.3% male, were included. The four scales were significantly and independently associated functional outcome. Only THRIVE was associated with in-hospital mortality. With area under the curve THRIVE and NIHSS were the scales with better performance for functional outcome and THRIVE had the best performance for mortality. CONCLUSION: THRIVE showed the best performance among the four scales, being the only associated with in-hospital mortality. PMID- 26982992 TI - The minimal caloric test asymmetric response in vertigo-free migraine patients. AB - Vertigo symptoms and subclinical vestibular dysfunctions may occur in migraine. The Minimal Caloric Test (MCT), an easy-to-perform, convenient and yet informative procedure was used to test the vestibular function in 30 vertigo-free migraine patients outside attacks and 30 paired controls. Although not statistically significant, a right-to-left nystagmus duration asymmetry greater than 25% was present in both groups. This difference was greater in the patients group, suggesting the presence of subclinical vestibular imbalance in migraine. PMID- 26982993 TI - Educational program on fatigue for brain tumor patients: possibility strategy? AB - OBJECTIVE: To evaluate the effectiveness of an educational program on improvement of fatigue and quality of life of patients with high-grade glioma during radiotherapy and chemotherapy treatment. METHOD: This is a longitudinal, experimental study. Twenty-three patients with high-grade glioma were randomly assigned to one of two groups. Both groups completed the Functional Assessment of Cancer Therapy: Fatigue questionnaire and the Beck Depression Inventory, and one of the groups received the educational intervention. RESULTS AND CONCLUSIONS: The groups did not show any change in quality of life and fatigue in this study, for this reason, the educational program did not present any significant difference. However, there was a significant difference in depressive symptoms during the educational program showing positive evidence for its applicability. PMID- 26982995 TI - Erratum. PMID- 26982994 TI - Clinical and epidemiological profiles of non-traumatic myelopathies. AB - Non-traumatic myelopathies represent a heterogeneous group of neurological conditions. Few studies report clinical and epidemiological profiles regarding the experience of referral services. Objective To describe clinical characteristics of a non-traumatic myelopathy cohort. Method Epidemiological, clinical, and radiological variables from 166 charts of patients assisted between 2001 and 2012 were compiled. Results The most prevalent diagnosis was subacute combined degeneration (11.4%), followed by cervical spondylotic myelopathy (9.6%), demyelinating disease (9%), tropical spastic paraparesis (8.4%) and hereditary spastic paraparesis (8.4%). Up to 20% of the patients presented non traumatic myelopathy of undetermined etiology, despite the broad clinical, neuroimaging and laboratorial investigations. Conclusion Regardless an extensive evaluation, many patients with non-traumatic myelopathy of uncertain etiology. Compressive causes and nutritional deficiencies are important etiologies of non traumatic myelopathies in our population. PMID- 26982997 TI - Atomic-Scale Sliding Friction on Graphene in Water. AB - The sliding of a sharp nanotip on graphene completely immersed in water is investigated by molecular dynamics (MD) and atomic force microscopy. MD simulations predict that the atomic-scale stick-slip is almost identical to that found in ultrahigh vacuum. Furthermore, they show that water plays a purely stochastic role in sliding (solid-to-solid) friction. These observations are substantiated by friction measurements on graphene grown on Cu and Ni, where, oppositely of the operation in air, lattice resolution is readily achieved. Our results promote friction force microscopy in water as a robust alternative to ultra-high-vacuum measurements. PMID- 26982996 TI - A cognitive assessment of highly superior autobiographical memory. AB - Highly Superior Autobiographical Memory (HSAM) is characterised as the ability to accurately recall an exceptional number of experiences and their associated dates from events occurring throughout much of one's lifetime. The source of this ability has only begun to be explored. The present study explores whether other enhanced cognitive processes may be critical influences underlying HSAM abilities. We investigated whether enhanced abilities in the domains of verbal fluency, attention/inhibition, executive functioning, mnemonic discrimination, perception, visual working memory, or the processing of and memory for emotional details might contribute critically to HSAM. The results suggest that superior cognitive functioning is an unlikely basis of HSAM, as only modest advantages were found in only a few tests. In addition, we examined HSAM subjects' memory of the testing episodes. Interestingly, HSAM participants recalled details of their own experiences far better than those experiences that the experimenter shared with them. These findings provide additional evidence that HSAM involves, relatively selectively, recollection of personal, autobiographical material. PMID- 26982999 TI - Bioactive Octahydroxylated C21 Steroids from the Root Bark of Lycium chinense. AB - Lyciumsterols A-K (1-11), 11 new octahydroxylated C21 steroids, were isolated from the root bark of Lycium chinense, along with 15 known compounds. Characterization of these C21 steroids showed the presence of eight hydroxy groups on the C21 steroid skeleton with a (2E,4E)-5-phenyl-2,4-pentadienoate group at C-12 or C-20 and various 2,6-deoxy sugar residues at C-3. The structures of these compounds were elucidated using spectroscopic data interpretation. Compounds 2, 3, and 7 exhibited dose-dependent protective effects on pancreatic islet cells and may help to improve cell viability. In addition, it was found that compounds 7, 8, 9, and 11 exhibited autophagy activation. PMID- 26982998 TI - The relation of illness perceptions to stress, depression, and fatigue in patients with chronic lymphocytic leukaemia. AB - OBJECTIVE: Chronic lymphocytic leukaemia (CLL) is the most prevalent adult leukaemia and is incurable. The course and treatment of CLL is unique and characterised by repeated cycles of treatment, stable disease and relapse. Utilising a Self-Regulatory Model framework, we examined the relationship between patients' illness perceptions and cancer-specific stress, depressive symptoms and fatigue. Our aim was to test illness perceptions as predictors of these outcomes when variance due to disease and treatment variables was controlled. DESIGN: Data were collected on 147 patients with relapsed/refractory CLL as they entered a phase II clinical trial of an investigational medication at a university affiliated, National Cancer Institute designated comprehensive cancer center. MAIN OUTCOME MEASURES: Cancer-specific stress, depressive symptoms and fatigue interference. RESULT: . Hierarchical multiple regression was used. Consequences and emotional representation were related to all outcomes (ps < .01). Illness concern was related to cancer-specific stress (p < .01), and identity was related to fatigue interference (p < .01). All relationships were observed while controlling for number of previous CLL therapies received. CONCLUSION: Illness perceptions are related to cancer-specific stress, depressive symptoms and fatigue interference in relapsed/refractory CLL. Interventions targeted at restructuring maladaptive illness perceptions may have clinical benefit in this population. PMID- 26983000 TI - Pediatric sepsis. AB - PURPOSE OF REVIEW: Sepsis is the leading cause of pediatric death worldwide. In the United States alone, there are 72 000 children hospitalized for sepsis annually with a reported mortality rate of 25% and an economic cost estimated to be $4.8 billion. However, it is only recently that the definition and management of pediatric sepsis has been recognized as being distinct from adult sepsis. RECENT FINDINGS: The definition of pediatric sepsis is currently in a state of evolution, and there is a large disconnect between the clinical and research definitions of sepsis which impacts the application of research findings into clinical practice. Despite this, it is the speed of diagnosis and the timely implementation of current treatment guidelines that has been shown to improve outcomes. However, adherence to treatment guidelines is currently low and it is only through the implementation of protocols that improved care and outcomes have been demonstrated. SUMMARY: The current management of pediatric sepsis is largely based on adaptations from adult sepsis treatment; however, distinct physiology demands more prospective pediatric trials to tailor management to the pediatric population. Adherence to current and emerging practice guidelines will require that protocolized care pathways become a commonplace. PMID- 26983001 TI - New Delhi Metallo-beta-Lactamase-1-Producing Klebsiella pneumoniae, Florida, USA(1). PMID- 26983002 TI - Stanniocalcin-2 overexpression reduces atherosclerosis in hypercholesterolemic mice. AB - BACKGROUND AND AIM: The metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) has been suggested as a proatherogenic molecule by its ability to locally increase insulin-like growth factor signaling. Stanniocalcin-2 (STC2) was recently discovered to be a potent inhibitor of PAPP-A activity, but has not previously been implicated in vascular disease. The aim of this study was to substantiate the interaction between PAPP-A and STC2 as a potential local regulatory mechanism in the artery wall. METHODS AND RESULTS: We found that PAPP A is secreted from cultured primary smooth muscle cells obtained from human aortas as a covalent complex with STC2, devoid of proteolytic activity. Extracts of human carotid atherosclerotic plaques contain both complexed and uncomplexed PAPP-A, and we show by immunohistochemistry that PAPP-A and STC2 are present in the tissue throughout early human lesion development. We then used adeno associated virus-mediated expression of STC2 to increase the fraction of PAPP-A present in the inhibited state and found that it decreased the development of atherosclerosis by 47% (P = 0.0005) in apolipoprotein E-deficient mice challenged with a Western type diet compared to controls. CONCLUSIONS: This study is the first to suggest the involvement of STC2 in regulating PAPP-A activity during the development of atherosclerosis. Furthermore, we demonstrate that lesion development can be inhibited in an experimental model by driving the balance towards inhibited PAPP-A. PMID- 26983003 TI - Outcome of total hip arthroplasty, but not of total knee arthroplasty, is related to the preoperative radiographic severity of osteoarthritis (Acta Orthop 2016; 87(1): 67-71.). PMID- 26983004 TI - Definitive Hosts of Versteria Tapeworms (Cestoda: Taeniidae) Causing Fatal Infection in North America. AB - We previously reported fatal infection of a captive Bornean orangutan with metacestodes of a novel taeniid tapeworm, Versteria sp. New data implicate mustelids as definitive hosts of these tapeworms in North America. At least 2 parasite genetic lineages circulate in North America, representing separate introductions from Eurasia. PMID- 26983007 TI - Child abuse and physical health in adulthood. AB - BACKGROUND: A large literature exists on the association between child abuse and mental health, but less is known about associations with physical health. The study objective was to determine if several types of child abuse were related to an increased likelihood of negative physical health outcomes in a nationally representative sample of Canadian adults. DATA AND METHODS: Data are from the 2012 Canadian Community Health Survey-Mental Health (n = 23,395). The study sample was representative of the Canadian population aged 18 or older. Child physical abuse, sexual abuse, and exposure to intimate partner violence were assessed in relation to self-perceived general health and 13 self-reported, physician-diagnosed physical conditions. RESULTS: All child abuse types were associated with having a physical condition (odds ratios = 1.4 to 2.0) and increased odds of obesity (odds ratios = 1.2 to 1.4). Abuse in childhood was associated with arthritis, back problems, high blood pressure, migraine headaches, chronic bronchitis/emphysema/COPD, cancer, stroke, bowel disease, and chronic fatigue syndrome in adulthood, even when sociodemographic characteristics, smoking, and obesity were taken into account (odds ratios = 1.1 to 2.6). Child abuse remained significantly associated with back problems, migraine headaches, and bowel disease when further adjusting for mental conditions and other physical conditions (odds ratios = 1.2 to 1.5). Sex was a significant moderator between child abuse and back problems, chronic bronchitis/emphysema/COPD, cancer, and chronic fatigue syndrome, with slightly stronger effects for women than men. INTERPRETATION: Abuse in childhood was associated with increased odds of having 9 of the 13 physical conditions assessed in this study and reduced self-perceived general health in adulthood. Awareness of associations between child abuse and physical conditions is important in the provision of health care. PMID- 26983006 TI - Development and implementation of microsimulation models of neurological conditions. AB - BACKGROUND: As part of a program of the first National Population Health Study of Neurological Conditions launched in 2009, a series of microsimulation models of neurological conditions (called POHEM-Neurological meta-model) was developed to project health and economic impacts of seven neurological conditions (NCs) Alzheimer's disease and other dementias, cerebral palsy, epilepsy, multiple sclerosis, Parkinson's disease, traumatic brain injury, and traumatic spinal cord injury-over a 20-year horizon. DATA AND METHODS: The common framework of the seven models allows for dynamic, continuous-time, discrete-event simulation of synthetic large populations in which persons are subject to the risk of developing the NC under study and are assigned a value of functional health and a probability of receiving a caregiver and of entering long-term care. Calculations for transitions are done every year over the life course, and costs are accumulated throughout the life of the synthetic person. The need to reconcile empirical estimates of incidence and mortality with prevalence required implementation of "cure" parameters for two of the NCs. RESULTS: The POHEM Neurological meta-model integrates the latest Canadian microdata on neurological conditions and satisfies most criteria for validation of microsimulation models, including conceptualization, computer implementation, assessment of output plausibility, and comparison with external data. Limitations include an absence of risk factors and the lack of uncertainty measures. INTERPRETATION: The POHEM Neurological meta-model has been useful for projections of health and economic impacts of NCs on persons affected and their caregivers, and allows for comparison of specific scenarios to the base case. PMID- 26983009 TI - Psychological Stress and Depression: Risk Factors for IBD? AB - While it is widely accepted that chronic diseases such as inflammatory bowel disease (IBD) may trigger negative psychological emotions such as distress and even depression, it is unknown if this response to a chronic illness like IBD is solely a psychological response to an adverse situation or whether it also represents a biological response, that is, the active inflammatory state of IBD intersecting with the pathobiology of what mediates mood and anxiety disorders. There is a bi-directionality between psychological comorbidity and IBD with each influencing the course of the other when they coexist. Furthermore, there is much to learn in terms of the underlying pathobiology of depression and anxiety and how this may impact on the pathobiology of IBD. Several important questions in regards to psychological comorbidity and IBD will be reviewed in this chapter. PMID- 26983005 TI - Comparative Genomic Analysis of Sulfurospirillum cavolei MES Reconstructed from the Metagenome of an Electrosynthetic Microbiome. AB - Sulfurospirillum spp. play an important role in sulfur and nitrogen cycling, and contain metabolic versatility that enables reduction of a wide range of electron acceptors, including thiosulfate, tetrathionate, polysulfide, nitrate, and nitrite. Here we describe the assembly of a Sulfurospirillum genome obtained from the metagenome of an electrosynthetic microbiome. The ubiquity and persistence of this organism in microbial electrosynthesis systems suggest it plays an important role in reactor stability and performance. Understanding why this organism is present and elucidating its genetic repertoire provide a genomic and ecological foundation for future studies where Sulfurospirillum are found, especially in electrode-associated communities. Metabolic comparisons and in-depth analysis of unique genes revealed potential ecological niche-specific capabilities within the Sulfurospirillum genus. The functional similarities common to all genomes, i.e., core genome, and unique gene clusters found only in a single genome were identified. Based upon 16S rRNA gene phylogenetic analysis and average nucleotide identity, the Sulfurospirillum draft genome was found to be most closely related to Sulfurospirillum cavolei. Characterization of the draft genome described herein provides pathway-specific details of the metabolic significance of the newly described Sulfurospirillum cavolei MES and, importantly, yields insight to the ecology of the genus as a whole. Comparison of eleven sequenced Sulfurospirillum genomes revealed a total of 6246 gene clusters in the pan genome. Of the total gene clusters, 18.5% were shared among all eleven genomes and 50% were unique to a single genome. While most Sulfurospirillum spp. reduce nitrate to ammonium, five of the eleven Sulfurospirillum strains encode for a nitrous oxide reductase (nos) cluster with an atypical nitrous-oxide reductase, suggesting a utility for this genus in reduction of the nitrous oxide, and as a potential sink for this potent greenhouse gas. PMID- 26983008 TI - The Effect of Disease-Modifying Drugs on Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: A Meta-Analysis. AB - BACKGROUND: The quantification of brain atrophy in relapsing-remitting multiple sclerosis (RRMS) may serve as a marker of disease progression and treatment response. We compared the association between first-line (FL) or second-line (SL) disease-modifying drugs (DMDs) and brain volume changes over time in RRMS. MATERIALS AND METHODS: We reviewed clinical trials in RRMS between January 1, 1995 and June 1, 2014 that assessed the effect of DMDs and reported data on brain atrophy in Medline, Embase, the Cochrane database and meeting abstracts. First, we designed a meta-analysis to directly compare the percentage brain volume change (PBVC) between FLDMDs and SLDMDs at 24 months. Second, we conducted an observational and longitudinal linear regression analysis of a 48-month follow-up period. Sensitivity analyses considering PBVC between 12 and 48 months were also performed. RESULTS: Among the 272 studies identified, 117 were analyzed and 35 (18,140 patients) were included in the analysis. Based on the meta-analysis, atrophy was greater for the use of an FLDMD than that of an SLDMD at 24 months (primary endpoint mean difference, -0.86; 95% confidence interval: -1.57--0.15; P = 0.02). Based on the linear regression analysis, the annual PBVC significantly differed between SLDMDs and placebo (-0.27%/y and -0.50%/y, respectively, P = 0.046) but not between FLDMDs (-0.33%/y) and placebo (P = 0.11) or between FLDMDs and SLDMDs (P = 0.49). Based on sensitivity analysis, the annual PBVC was reduced for SLDMDs compared with placebo (-0.14%/y and -0.56%/y, respectively, P<0.001) and FLDMDs (-0.46%/y, P<0.005), but no difference was detected between FLDMDs and placebo (P = 0.12). CONCLUSIONS: SLDMDs were associated with reduced PBVC slope over time in RRMS, regardless of the period considered. These results provide new insights into the mechanisms underlying atrophy progression in RRMS. PMID- 26983013 TI - Probing Ionic Complexes of Ethylene and Acetylene with Vacuum-Ultraviolet Radiation. AB - Mixed complexes of acetylene-ethylene are studied using vacuum-ultraviolet (VUV) photoionization mass spectrometry and theoretical calculations. These complexes are produced and ionized at different distances from the exit of a continuous nozzle followed by reflectron time-of-flight mass spectrometry detection. Acetylene, with a higher ionization energy (11.4 eV) than ethylene (10.6 eV), allows for tuning the VUV energy and initializing reactions either from a C2H2(+) or a C2H4(+) cation. Pure acetylene and ethylene expansions are separately carried out to compare, contrast, and hence identify products from the mixed expansion: these are C3H3(+) (m/z = 39), C4H5(+) (m/z = 53), and C5H5(+) (m/z = 65). Intensity distributions of C2H2, C2H4, their dimers and reactions products are plotted as a function of ionization distance. These distributions suggest that association mechanisms play a crucial role in product formation closer to the nozzle. Photoionization efficiency (PIE) curves of the mixed complexes demonstrate rising edges closer to both ethylene and acetylene ionization energies. We use density functional theory (omegaB97X-V/aug-cc-pVTZ) to study the structures of the neutral and ionized dimers, calculate their adiabatic and vertical ionization energies, as well as the energetics of different isomers on the potential energy surface (PES). Upon ionization, vibrationally excited clusters can use the extra energy to access different isomers on the PES. At farther ionization distances from the nozzle, where the number densities are lower, unimolecular decay is expected to be the dominant mechanism. We discuss the possible decay pathways from the different isomers on the PES and examine the ones that are energetically accessible. PMID- 26983010 TI - Integrated Cytogenetic and Mitochondrial DNA Analyses Indicate That Two Different Phenotypes of Hypancistrus (L066 and L333) Belong to the Same Species. AB - The diversity of Hypancistrus species in the Xingu River is remarkable and the variation in color morphs represents a real challenge to taxonomists to delimit species boundaries. One of the most recognizable Hypancistrus complexes is the worm-lined species, known in the aquarium trade as King Tiger Plec in English, Hypancistrus "pao" in Portuguese or under the L-numbers L066 and L333 that represent two melanic pigment pattern phenotypes. To assess the identity of these two phenotypes, we described their karyotypes and sequenced part of the mitochondrial cytochrome oxidase I gene (DNA barcode). These fishes have 52 chromosomes (40 meta-submetacentric and 12 subtelo-acrocentric) and a strong heteromorphism in chromosome pair 21 was observed, which does not correlate with the two phenotypes or sex. DNA barcodes separated the samples analyzed from Hypancistrus zebra and other publicly available sequences of Loricariidae showing no divergence between the two phenotypes. The data set indicates that worm-lined Hypancistrus from the Xingu form a single species with clear chromosomal and melanic pigment pattern polymorphisms. PMID- 26983011 TI - Salivary alpha-amylase, secretory IgA and free cortisol as neurobiological components of the stress response in the acute phase of anorexia nervosa. AB - Objectives One novel hypothesis of the pathogenesis of anorexia nervosa (AN) is the possible role of mental stress in hyperactivity of the autonomic nervous system (ANS) and of the hypothalamic-pituitary-adrenal (HPA) axis. Two components of stress response - salivary alpha-amylase (sAA) and free cortisol - have been proposed. They can be determined in saliva, which closely reflects their concentrations in plasma. The purpose of this study was to measure salivary free cortisol, sAA and their correlation to secretory IgA (sIgA) of patients with AN in comparison to the average population. Methods A controlled clinical trial was designed for a matched group of 47 AN patients and 54 healthy individuals. After clinical examination, unstimulated salivary samples were taken during the acute stage of AN (BMI < 15 kg/m(2)) in the first week of hospitalisation. An enzyme linked immunosorbent assay (ELISA) suitable for measuring sAA, sIgA and free cortisol were used. Results Anorexic patients exhibited disturbances in sAA secretion, and significantly increased cortisol and sIgA levels with a distinct correlation between these two parameters. Conclusions The behaviour of cortisol, sAA and sIgA levels can be assessed as an effect of stress reaction among AN patients with hyperactivity of the HPA axis and ANS dysregulation. The effect of stress response can be assessed reliably in saliva. PMID- 26983012 TI - Attack and Success of Native and Exotic Parasitoids on Eggs of Halyomorpha halys in Three Maryland Habitats. AB - Egg parasitoids of the exotic invasive brown marmorated stink bug, Halyomorpha halys (Stal), were investigated using lab-reared fresh (live) and frozen (killed) lab-reared sentinel egg masses deployed for 72h on foliage in three habitats woods, orchard, and soybean field-in Maryland, USA, in summer 2014. Four native hymenopteran species, Telenomus podisi Ashmead (Scelionidae), Trissolcus euschisti (Ashmead) and Tr. brochymenae Ashmead (Scelionidae), and Anastatus reduvii (Howard) (Eupelmidae), developed and emerged from H. halys eggs. One exotic parasitoid, Trissolcus japonicus (Ashmead), emerged, providing the first known occurrence of this species in North America. Native parasitoids emerged from frozen eggs significantly more often than from fresh eggs (89.3% of egg masses and 98.1% of individual eggs), whereas the exotic Tr. japonicus did not show a similar difference, strongly suggesting adaptation to H. halys as a host by Tr. japonicus but not by the native species. Parasitoids were habitat specific: all three Trissolcus species were significantly more likely to occur in the woods habitat, whereas Te. podisi was found exclusively in the soybean field. Further investigations are required to elucidate evolving host-parasitoid relationships, habitat specificity, and non-target effects of Tr. japonicus over the expanded range of H. halys in North America. PMID- 26983015 TI - Anti-TNFs: Originators and Biosimilars. AB - In the last 20 years, the advent of anti-tumor necrosis factor alpha (TNFalpha) biologics has revolutionized the treatment of patients with inflammatory bowel disease (IBD) but the cost of biologic therapy now constitutes a large proportion of all healthcare expenditures. Patent expiration has sparked the healthcare industry's interest in the production of biosimilar (BS) versions of first generation biologics (originators [ORGs]) for market sharing. Having no access to the production line of the ORG, the sponsor of a BS needs to develop his own manufacturing process to produce a highly similar version of the reference product. Similarity in structure, physicochemical properties, biologic activity, efficacy and safety must be demonstrated by a comprehensive comparability exercise that includes the most sensitive in vitro tests, models and clinical condition with pre-defined equivalence margins. Extrapolation of indications, inter-changeability and automatic substitution between BS and ORG depend on a legal framework that varies between different agencies. It is not, therefore, unexpected that marketing authorization by the European Medicines Agency and other regulatory agencies (but not Health Canada) of CT-P13 (Remsima/Inflectra) as infliximab (Remicade) BSs for IBD by indication extrapolation has led to stormy discussions in the IBD community and beyond regarding the scientific adequacy of this decision. However, as we now have to live with BSs, we hope that the impeding automatic substitution in association with post-marketing pharmacovigilance, full traceability, registries and new studies will settle the controversy and will increase the confidence of physicians and patients. A universally adopted legal framework should be implemented because, as expected, the non-anti-TNFalpha BSs will be soon on the stage. PMID- 26983016 TI - Human biology of poverty. PMID- 26983014 TI - Is MTHFR 677 C>T Polymorphism Clinically Important in Polycystic Ovarian Syndrome (PCOS)? A Case-Control Study, Meta-Analysis and Trial Sequential Analysis. AB - BACKGROUND: Optimum efficiency of the folate pathway is considered essential for adequate ovarian function. 677 C>T substitution in the 5, 10-methylene tertrahydrofolatereductase (MTHFR) gene compromises activity of the MTHFR enzyme by about 50%. The significance of correlation between 677C>T substitution and PCOS remains dubious due to the low power of published studies. METHODS AND RESULTS: We analyzed MTHFR 677 C>T site in ethnically two different PCOS case control groups (total 261 cases and 256 controls) from India. The data analysis revealed a lack of association between this polymorphism and PCOS [OR = 1.11 (95%CI = 0.71-1.72), P = 0.66]. Group-wise analysis on the basis of ethnicity also revealed no association in any of the ethnic groups [Indo-Europeans, P = 1; Dravidians, P = 0.70]. Homocysteine levels did not differ significantly between cases (15.51 MUmol/L, SD = 2.89) and controls (15.89 MUmol/L, SD = 2.23). We also undertook a meta-analysis on 960 cases and 1028 controls, which suggested a significant association of the substitution with PCOS in the dominant model of analysis (OR = 1.47 (95%CI = 1.04-2.09), P = 0.032]. Trial sequential analysis corroborated findings of the traditional meta-analysis. However, we found that the conclusions of meta-analysis were strongly influenced by studies that deviated from the Hardy Weinberg equilibrium. A careful investigation of each study and a trial sequential analysis suggested that 677 C>T substitution holds no clinical significance in PCOS in most of the populations. CONCLUSION: In conclusion, MTHFR 677 C>T polymorphism does not affect PCOS risk in India. The association seen in the meta-analysis is due to an outlier study and studies showing deviation from the Hardy Weinberg equilibrium. PMID- 26983019 TI - Silencing PRDX3 Inhibits Growth and Promotes Invasion and Extracellular Matrix Degradation in Hepatocellular Carcinoma Cells. AB - PRDX3 is a mitochondrial peroxide reductase that regulates cellular redox state. It has been reported that PRDX3 is overexpressed in liver cancer, but how PRDX3 is involved in hepatocellular carcinoma (HCC) tumorigenesis and progression has not been well-characterized. In the present study, we established two stable cell lines by overexpressing or knocking down PRDX3 in HepG2 cells. We found that PRDX3 silencing decreased the growth rate of HepG2 cells and increased mtDNA oxidation. Quantitative proteomics identified 475 differentially expressed proteins between the PRDX3 knockdown and the control cells. These proteins were involved in antioxidant activity, angiogenesis, cell adhesion, cell growth, ATP synthesis, nucleic acid binding, redox, and chaperones. PRDX3 knockdown led to the down-regulation of ATP synthases and the decreased cellular ATP level, contributing to the slow-down of cell growth. Furthermore, silencing PRDX3 enhanced invasive properties of HepG2 cells via TIMP-1 down-regulation and the increased ECM degradation. Taken together, our results indicate that PRDX3 promotes HCC growth and mediates cell migration and invasiveness and is a potential therapeutic target for HCC treatment. PMID- 26983020 TI - Eating during treatment can be a cost-effective way to improve outcomes: a letter to the editor. PMID- 26983018 TI - Cost-Effectiveness of Capsaicin 8% Patch Compared with Pregabalin for the Treatment of Patients with Peripheral Neuropathic Pain in Scotland. AB - We evaluated the cost-effectiveness of capsaicin 8% patch (QUTENZATM) versus pregabalin in patients with PNP from the perspective of the National Health Service (NHS) and Personal and Social Services in Scotland, UK. A decision-tree cost-effectiveness model was developed for non-diabetic patients with peripheral neuropathic pain (PNP) who were pregabalin-naive and had not achieved adequate pain relief or tolerated conventional first- or second-line treatments. Patients entering the model received either a single application of capsaicin 8% patch or titrated daily dosing with pregabalin; after 8 weeks patients were classified as responders, non-responders, or were assumed to discontinue treatment due to intolerable adverse events. Responders continued to receive baseline treatment at intervals observed in clinical practice. Non-responders and those who discontinued treatment were assumed to receive last-line therapy (duloxetine). The base-case time horizon was 2 years. Model inputs for effectiveness, discontinuations and health-state utilities were taken from a head-to-head non inferiority study (ELEVATE, NCT01713426). Other inputs were obtained from published sources or clinical expert opinion. Costs were expressed in GBP 2013/14. Results were presented as incremental cost-effectiveness ratios (ICER), i.e. cost per quality-adjusted life-year (QALY) gained. Model assumptions were tested with scenario analyses. Parameter uncertainty was tested using one-way and probabilistic sensitivity analyses. Compared with dose-optimized pregabalin, capsaicin 8% patch was the dominant treatment strategy (total cost difference, L11; total QALY gain, 0.049). Capsaicin 8% patch was also the dominant treatment strategy versus pregabalin in 6 out of 7 scenario analyses. The model was most sensitive to variation in time to capsaicin 8% patch retreatment (maximum ICER, L7,951/QALY at lower-bound 95% confidence interval). At a willingness-to-pay threshold of L20,000/QALY, the probability of capsaicin 8% patch being cost effective versus pregabalin was 97%. Capsaicin 8% patch is a cost-effective treatment option compared with dose-optimized pregabalin in patients with PNP who have failed one or more previous systemic treatments. PMID- 26983021 TI - GeneAnalytics: An Integrative Gene Set Analysis Tool for Next Generation Sequencing, RNAseq and Microarray Data. AB - Postgenomics data are produced in large volumes by life sciences and clinical applications of novel omics diagnostics and therapeutics for precision medicine. To move from "data-to-knowledge-to-innovation," a crucial missing step in the current era is, however, our limited understanding of biological and clinical contexts associated with data. Prominent among the emerging remedies to this challenge are the gene set enrichment tools. This study reports on GeneAnalyticsTM ( geneanalytics.genecards.org ), a comprehensive and easy-to apply gene set analysis tool for rapid contextualization of expression patterns and functional signatures embedded in the postgenomics Big Data domains, such as Next Generation Sequencing (NGS), RNAseq, and microarray experiments. GeneAnalytics' differentiating features include in-depth evidence-based scoring algorithms, an intuitive user interface and proprietary unified data. GeneAnalytics employs the LifeMap Science's GeneCards suite, including the GeneCards(r)--the human gene database; the MalaCards-the human diseases database; and the PathCards--the biological pathways database. Expression-based analysis in GeneAnalytics relies on the LifeMap Discovery(r)--the embryonic development and stem cells database, which includes manually curated expression data for normal and diseased tissues, enabling advanced matching algorithm for gene-tissue association. This assists in evaluating differentiation protocols and discovering biomarkers for tissues and cells. Results are directly linked to gene, disease, or cell "cards" in the GeneCards suite. Future developments aim to enhance the GeneAnalytics algorithm as well as visualizations, employing varied graphical display items. Such attributes make GeneAnalytics a broadly applicable postgenomics data analyses and interpretation tool for translation of data to knowledge-based innovation in various Big Data fields such as precision medicine, ecogenomics, nutrigenomics, pharmacogenomics, vaccinomics, and others yet to emerge on the postgenomics horizon. PMID- 26983022 TI - Hyperlipidemia, Disease Associations, and Top 10 Potential Drug Targets: A Network View. AB - The prevalence of acquired hyperlipidemia has increased due to sedentary life style and lipid-rich diet. In this work, a lipid-protein-protein interaction network (LPPIN) for acquired hyperlipidemia was prepared by incorporating differentially expressed genes in obese fatty liver as seed nodes, protein interactions from PathwayLinker, and lipid interactions from STITCH4.0. Cholesterol, diacylglycreol, phosphatidylinositol-bis-phosphate, and inositol triphosphate were identified as core lipids that influence the signaling pathways in the LPPIN. RACalpha serine/threonine-protein kinase (AKT1) was a highly essential central protein. The gastrin-CREB pathway was greatly enriched; all enriched pathways in the LPPIN showed crosstalk with the phosphatidylinositol-3 kinase-Akt pathway, correlating with the central role of AKT1 in the network. The disease clusters identified in the LPPIN were cardiovascular disease, cancer, Alzheimer's disease, and Type II diabetes. In this context, we note that the commercially approved drug targets for hyperlipidemia in each disease cluster may potentially be repurposed for treatment of the specific disease. We report here top 10 potential drug targets that may mediate progression from hyperlipidemia to the respective disease state. ToppGene Suite was employed to identify candidates followed by a) discarding high closeness centrality nodes, and b) selecting nodes with high bridging centrality. Three potential targets could be mapped to specific disease clusters in the LPPIN. Lipids associated with acquired hyperlipidemia and each disease cluster identified may be useful as prognostic fingerprints. These findings provide an integrative view of lipid-protein interactions leading to acquired hyperlipidemia and the associated diseases, and might prove useful in future translational pharmaceutical research. PMID- 26983023 TI - A Systems Biology Interpretation of Array Comparative Genomic Hybridization (aCGH) Data through Phylogenetics. AB - Array Comparative Genomic Hybridization (aCGH) is a rapid screening technique to detect gene deletions and duplications, providing an overview of chromosomal aberrations throughout the entire genome of a tumor, without the need for cell culturing. However, the heterogeneity of aCGH data obfuscates existing methods of data analysis. Analysis of aCGH data from a systems biology perspective or in the context of total aberrations is largely absent in the published literature. We present here a novel alternative to the functional analysis of aCGH data using the phylogenetic paradigm that is well-suited to high dimensional datasets of heterogeneous nature, but has not been widely adapted to aCGH data. Maximum parsimony phylogenetic analysis sorts out genetic data through the simplest presentation of the data on a cladogram, a graphical evolutionary tree, thus providing a powerful and efficient method for aCGH data analysis. For example, the cladogram models the multiphasic changes in the cancer genome and identifies shared early mutations in the disease progression, providing a simple yet powerful means of aCGH data interpretation. As such, applying maximum parsimony phylogenetic analysis to aCGH results allows for the differentiation between drivers and passenger genes aberrations in cancer specimens. In addition to offering a novel methodology to analyze aCGH results, we present here a crucial software suite that we wrote to carry out the analysis. In a broader context, we wish to underscore that phylogenetic analysis of aCGH data is a non-parametric method that circumvents the pitfalls and frustrations of standard analytical techniques that rely on parametric statistics. Organizing the data in a cladogram as explained in this research article provides insights into the disease common aberrations, as well as the disease subtypes and their shared aberrations (the synapomorphies) of each subtype. Hence, we report the method and make the software suite publicly and freely available at http://software.phylomcs.com so that researchers can test alternative and innovative approaches to the analysis of aCGH data. PMID- 26983024 TI - Metformin Revisited. PMID- 26983025 TI - Limitations of Continuous Glucose Monitor Usage. AB - Much progress has been made in diabetes treatments since the first dose of insulin was administered in 1921. However, a truly transformational moment in diabetes care occurred when urine testing gave way to capillary blood home glucose monitoring. As improvements were made to these devices, continuous glucose monitoring (CGM) was introduced. The advantages of experiential learnings gleaned from seeing continuous real-time data have been borne out in numerous peer-reviewed journals. Limitations to use of CGM include patient's level of numeracy and literacy, development of alarm fatigue, interfering substances leading to erroneous readings, high rates of discontinuation, and poor reimbursement. PMID- 26983028 TI - Governing Global Health - Challenge, Response, Innovation Schrecker Ted Kirton John J Cooper Andrew F Governing Global Health - Challenge, Response, Innovation 320 Ashgate 9780754648734 0754648737. AB - This excellent book provides a comprehensive and analytical overview of the socio political and economic factors that contribute to an understanding of global health governance. The opening chapter outlines compelling arguments for why such an understanding should be everyone's business. PMID- 26983026 TI - Comparative Renal Toxicopathology of Antisense Oligonucleotides. AB - This review summarizes the current understanding of nephrotoxicity related to the administration of therapeutic oligonucleotides, particularly those with 2' methoxy-ethyl (2'-MOE) modifications. To best understand the effects of antisense oligonucleotides (ASOs) on the kidney, the reader should have a general understanding of renal microanatomy, physiology, and general mechanisms related to toxicity, so a short review is presented. Preclinical-clinical correlates are also discussed. Collectively, the data for PS ODN and 2'-MOE-modified ASOs have shown the laboratory animal species utilized in toxicology studies generally overpredict renal effects of these agents. As such, 2'-MOE ASOs do not appear to pose as much of a risk to patients as the preclinical data would suggest. This observation has been confirmed so far in clinical investigations. PMID- 26983030 TI - Vital Notes for Nurses - Promoting Health Wills Jane Vital Notes for Nurses - Promoting Health 196 Blackwell 9781405139991 1405139994. AB - Although presented in scholarly form, the authors ground each chapter in practice through reference to the key issues that most nurses will recognise. PMID- 26983027 TI - Spatial distribution and temporal variability of stable water isotopes in a large and shallow lake. AB - Stable isotopic compositions of lake water provide additional information on hydrological, meteorological and paleoclimate processes. In this study, lake water isotopic compositions were measured for more than three years in Lake Taihu, a large and shallow lake in southern China, to investigate the isotopic spatial and seasonal variations. The results indicated that (1) the whole-lake mean delta(2)H and delta(18)O values of the lake water varied seasonally from 48.4 +/- 5.8 to -25.1 +/- 3.2 0/00 and from -6.5 +/- 0.9 to -3.5 +/- 0.8 0/00, respectively, (2) the spatial pattern of the lake water isotopic compositions was controlled by the direction of water flow and not by local evaporation rate, and (3) using a one-site isotopic measurement to represent the whole-lake mean may result in unreasonable estimates of the isotopic composition of lake evaporation and the lake water residence time in poorly mixed lakes. The original data, documented here as an online supplement, provides a good reference for testing sensitivity of lake water budget to various isotopic sampling strategies. We propose that detailed spatial measurement of lake water isotopic compositions provides a good proxy for water movement and pollutant and alga transports, especially over big lakes. PMID- 26983032 TI - Detection of Panton-Valentine Leukocidin-Positive Methicillin-Resistant Staphylococcus aureus Nasal Carriage among Egyptian Health Care Workers. AB - BACKGROUND: Transmission of methicillin-resistant Staphylococcus aureus (MRSA) among patients is linked mainly to health care personnel. The Panton-Valentine leukocidin (PVL) is a cytotoxin that causes leukocyte lysis. Virulence of pvl positive-MRSA has been attributed to its ability to express PVL toxin. METHODS: Swabs for detection of nasal carriage of pvl-positive MRSA among health care personnel at Fayoum University Hospital, Fayoum, Egypt, were collected from 223 health care personnel including 70 doctors (31.4%), 95 nurses (42.6%), 21 laboratory technicians (9.4%), and 37 housekeeping staff (16.6%). Detection of MRSA was done using conventional screening methods and confirmed by multiplex polymerase chain reaction (PCR) for mecA, or its homologue mecC, and pvl genes amplification. Re-swabbing after decolonization therapy was done to evaluate the efficacy of decolonization therapy. RESULTS: Fifty-one of 223 participants (22.9%) were colonized with S. aureus. This included 13.5% (30/223) colonized with MRSA and 2.2% (5/223) colonized with PVL-positive MRSA. Moreover, all MRSA isolates were negative for mecC genes. Decolonization therapy was successful in 80% of MRSA carriers including all pvl-positive MRSA carriers. CONCLUSIONS: This is the first report on nasal carriage of pvl-positive MRSA among Egyptian health care personnel. High carriage rate of MRSA among health care personnel has been attributed mainly to poor hand hygiene compliance and non-judicious use of antibiotics. Improving compliance, reducing antibiotic overuse, screening for carriers, and decolonization are recommended strategies for reducing the spread of MRSA. Multiplex PCR could be used for confirmation of results obtained by conventional phenotypic methods. PMID- 26983031 TI - A Proof of Concept, Phase II Randomized European Trial, on the Efficacy of ALF 5755, a Novel Extracellular Matrix-Targeted Antioxidant in Patients with Acute Liver Diseases. AB - OBJECTIVE: No efficient medical treatment is available for severe acute hepatitis (SAH) except N-acetylcysteine for acetaminophen-induced acute liver failure. The human C-type lectin Reg3alpha, referred to as ALF-5755, improved survival in an animal model of acute liver failure and was well tolerated in a phase 1 trial in humans. We performed a phase 2a trial of ALF5755 in non-acetaminophen induced SAH. DESIGN: double-blind, randomized, placebo-controlled study. The primary end point was the improvement in the coagulation protein synthesis assessed by the change of Prothrombin (PR) during the 72 hours following treatment initiation calculated as PRH0 minus PRH72 divided by 72 (PR slope H0H72). Intention to treat (ITT) and per-protocol (PP) analysis of the entire group and the Hepatitis B virus (HBV)/AIH (auto-immune hepatitis) sub-group were done separately. RESULTS: 57 patients were included. Twenty-eight received ALF-5755, 29 the placebo. Etiologies were: Hepatitis A (n = 10), HBV (n = 13), AIH (n = 9), drug-induced (n = 8), other (n = 17). On the whole group, nor the PR slope H0H72 (0.18+/-0.31 vs 0.25+/-0.32), nor the transplant-free survival rate at day 21 (75 vs 86%) differed between groups. Conversely, in the HBV-AIH subgroup, in which ALF was more severe, PR slope H0-H72 was higher in the ALF-5755 arm, the difference being significant in PP analysis (0.048+/-0.066 vs -0.040+/-0.099, p = 0.04); the median length of hospitalization was lower in the ALF-5755 group (8 vs 14 days, p = 0.02). CONCLUSION: ALF-5755 was not efficient in a ITT analysis performed on the whole sample; however it led to a significant, although moderate, clinical benefit in a PP analysis of the sub-group of patients with HBV or AIH related SAH. As HBV is the major cause of SAH in Asia and Africa and AIH a growing cause, this study emphasizes the need to pursuit the evaluation of this novel medical treatment of SAH. TRIAL REGISTRATION: ClinicalTrials.gov NCT01318525. PMID- 26983034 TI - Quality of Oocytes Derived from Vitrified Ovarian Follicles Cultured in Two- and Three-Dimensional Culture System in the Presence and Absence of Kit Ligand. AB - The aim of this study was to evaluate the effects of Kit Ligand (KL) on the growth of vitrified follicle, oocyte quality, and embryo development in two- and three-dimensional culture systems. Vitrified and nonvitrified mouse whole ovaries were cultured for 1 week, then their isolated preantral follicles were cultured for 12 days in two- or three-dimensional culture systems in the presence and absence of KL. The growth and diameter of follicles, maturation of oocytes, and hormonal level were assessed. Finally, embryo developmental rate and oocytes reactive oxygen species (ROS) levels, adenosine triphosphate (ATP) content, and distribution of mitochondria were examined. The results showed the maturation and survival rates and steroidogenesis of follicles were significantly higher not only in the three-dimensional culture system but also in the presence of KL (p < 0.001). The embryo development, ATP content, and ROS level of collected oocytes were not significantly different in all groups. Mitochondrial distribution within the oocyte was similar in all groups of the study. Our results demonstrated that KL supplementation during follicular culture in two- and three-dimensional culture systems appeared to significantly increase follicular function and development. The ovarian vitrification had no harmful effect on the steroidogenesis, growth, and maturation of follicles. PMID- 26983033 TI - High Dose Atorvastatin Associated with Increased Risk of Significant Hepatotoxicity in Comparison to Simvastatin in UK GPRD Cohort. AB - BACKGROUND & AIMS: Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment. METHODS: The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions. RESULTS: Moderate to severe hepatotoxicity [bilirubin >60MUmol/L, AST or ALT >200U/L or alkaline phosphatase >1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4 2.6]. High dose was classified as 40-80mg daily and low dose 10-20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2-12.7] for HDA, 1.4 [0.9-2.0] for LDA and 1.5 [1.0 2.2] for HDS. CONCLUSIONS: The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small. PMID- 26983036 TI - Association of interleukin 18-607A/C and -137C/G polymorphisms with oxidative stress in renal transplant recipients. AB - Objectives IL-18 mediates various inflammatory and oxidative responses including renal injury, fibrosis, and graft rejection. It has been reported that the promoter -607 and -137 polymorphisms of IL-18 influence the level of IL-18. This prospective observational study investigated the association between oxidative stress with IL-18-607 and -137 polymorphisms in renal transplant recipients. Patients and methods This study included 75 renal transplant recipients (28 female, 47 male) from living-related donors. Blood samples were collected immediately before and after transplantation at day 7 and month 1. Serum IL-18, creatinine, cystatin C, CRP, and oxidative stress markers (TOS, TAC) were measured. The Oxidative Stress Index (OSI) was calculated. Polymorphisms of the promoter region of the IL-18 gene, IL18-607A/C, and -137C/G were determined by analysis of a "real-time PCR/Melting curve". Results Serum creatinine, cystatin C, CRP, IL-18, TOS, and OSI levels significantly decreased after transplantation. Post-transplant levels of serum TAC and estimated GFR demonstrated consistent significant increases. Serum IL-18 levels were significantly higher in patients with IL-18-137 GG and IL-18-607 CC genotypes before transplantation. Conclusion Our results indicate that the IL-18-137 GG and -607 CC genotypes contribute to higher IL-18 levels; however, the influence of these polymorphisms on oxidative stress has not been observed. PMID- 26983035 TI - Clinical Malaria Transmission Trends and Its Association with Climatic Variables in Tubu Village, Botswana: A Retrospective Analysis. AB - Good knowledge on the interactions between climatic variables and malaria can be very useful for predicting outbreaks and preparedness interventions. We investigated clinical malaria transmission patterns and its temporal relationship with climatic variables in Tubu village, Botswana. A 5-year retrospective time series data analysis was conducted to determine the transmission patterns of clinical malaria cases at Tubu Health Post and its relationship with rainfall, flood discharge, flood extent, mean minimum, maximum and average temperatures. Data was obtained from clinical records and respective institutions for the period July 2005 to June 2010, presented graphically and analysed using the Univariate ANOVA and Pearson cross-correlation coefficient tests. Peak malaria season occurred between October and May with the highest cumulative incidence of clinical malaria cases being recorded in February. Most of the cases were individuals aged >5 years. Associations between the incidence of clinical malaria cases and several factors were strong at lag periods of 1 month; rainfall (r = 0.417), mean minimum temperature (r = 0.537), mean average temperature (r = 0.493); and at lag period of 6 months for flood extent (r = 0.467) and zero month for flood discharge (r = 0.497). The effect of mean maximum temperature was strongest at 2-month lag period (r = 0.328). Although malaria transmission patterns varied from year to year the trends were similar to those observed in sub-Saharan Africa. Age group >5 years experienced the greatest burden of clinical malaria probably due to the effects of the national malaria elimination programme. Rainfall, flood discharge and extent, mean minimum and mean average temperatures showed some correlation with the incidence of clinical malaria cases. PMID- 26983038 TI - Pedicle versus free flap reconstruction in patients receiving intraoperative brachytherapy. AB - Introduction This study compared complication rates between pedicle flaps and free flaps used for resurfacing of intraoperative brachytherapy (IOBT) implants placed following head and neck tumour extirpation to help clarify the ideal reconstructive procedure for this scenario. Patients and methods A retrospective review of reconstructions with IOBT at our institution was conducted. Patient and treatment details were recorded, as were the number and type of flap complications, including re-operations. Logistic regressions compared complications between flap groups. Results Fifty free flaps and 55 pedicle flaps were included. On multivariate analysis, free flap reconstruction with IOBT was significantly associated with both an increased risk of having any flap complication (OR = 2.9, p = 0.037) and with need for operative revision (OR = 3.5, p = 0.048) compared to pedicle flap reconstruction. Conclusions In the setting of IOBT, free flaps are associated with an increased risk of having complications and requiring operative revisions. PMID- 26983037 TI - Post-Ebola Syndrome, Sierra Leone. AB - Thousands of persons have survived Ebola virus disease. Almost all survivors describe symptoms that persist or develop after hospital discharge. A cross sectional survey of the symptoms of all survivors from the Ebola treatment unit (ETU) at 34th Regimental Military Hospital, Freetown, Sierra Leone (MH34), was conducted after discharge at their initial follow-up appointment within 3 weeks after their second negative PCR result. From its opening on December 1, 2014, through March 31, 2015, the MH34 ETU treated 84 persons (8-70 years of age) with PCR-confirmed Ebola virus disease, of whom 44 survived. Survivors reported musculoskeletal pain (70%), headache (48%), and ocular problems (14%). Those who reported headache had had lower admission cycle threshold Ebola PCR than did those who did not (p<0.03). This complete survivor cohort from 1 ETU enables analysis of the proportion of symptoms of post-Ebola syndrome. The Ebola epidemic is waning, but the effects of the disease will remain. PMID- 26983039 TI - Finasteride and Tamsulosin Combination in Benign Prostatic Enlargement in a Tertiary Hospital. AB - INTRODUCTION: Due to aging of the general population, prevalence of Benign Prostatic Enlargement is increasing. Symptoms of BPE may vary between the patients. Aim of the study was to analyze and compare the usefulness of combination drugs therapy and monotherapy after a trial period of six months. METHODS: Out of 100 male patients aged 45 years and above diagnosed with BPE, 92 were included in the study. Patients were randomized using computer generated random number table. Of which, 47 patients received combination therapy with Tamsulosin plus Finasteride and 45 patients received monotherapy with Tamsulosin once daily at bed time. RESULTS: The baseline demographic variables were comparable in both groups. The decrease in the total American Urological Association symptom score was statistically significant in the combination group (p<0.0001) as compared to monotherapy (p=0.0715) respectively. There was a statistically significant reduction in the residual urine volume with combination therapy (p<0.0001) than in patients with monotherapy (p= 0.1271). CONCLUSIONS: The combination therapy is effective in decreasing the irritative and obstructive symptoms in patients with BPE than monotherapy. PMID- 26983040 TI - Efficacy of Combined Antithrombotic, Statins and Anti-Hypertensive Drugs in Acute Ischemic Stroke. AB - INTRODUCTION: Anti-thrombotic, statins and antihypertensive drugs are commonly used for the management of acute ischemic stroke in Nepal but there is no evidence regarding their efficacy in our context. This study aims to explore the efficacy of these combined medications (anti-thrombotic, statins and antihypertensive drugs) in acute ischemic stroke patients for the first time and to assess the risk factors present in those patients. METHODS: The study was conducted on 37 acute ischemic stroke patients admitted and treated at the Neurology Department of College of Medical Sciences-Teaching Hospital, Chitwan, Nepal and they were followed at three months (90+/-10 days). The initial stroke severity and functional disability were evaluated at admission and at 3 months using National Institute of Health Stroke Scale (NIHSS) and Modified Rankin Scale (mRS) respectively. The outcome parameters were functional independence (mRS<=2) and mortality at three months (mRS=6). Frequency distribution, Mann-Whitney U test and chi2 test were performed for statistical analysis. RESULTS: Out of 37 patients, 27 (73%) were Smoker, 22 (59.5%) had hypertension and 19 (51.4%) were alcohol consumer. The stroke severity on admission was statistically significant with functional independence (P=0.003) and mortality (P=0.015) at three month. Similarly, Rankin grade on admission was statistically significant with functional independence (P=0.001) and mortality (P=0.048) at three month. At three months, 20 (69%) survived patients were independent while mortality was seen in eight (21.6%) patients. CONCLUSIONS: The management of acute ischemic stroke with combined anti-thrombotic, statins and antihypertensive drugs seems promising and efficacious in mild to moderately severe ischemic stroke. PMID- 26983041 TI - Role of Eosinophils in Acute Appendicitis. AB - INTRODUCTION: High negative appendectomy rate still prevails on conventional histologic examination. Increased mural eosinophilic infiltrate had been observed in acute appendicitis. Present study aimed to evaluate the role of mural eosinophils in clinically suspected acute appendicitis but histological normal appendix, as an indicator of acute inflammation, alone or in association with edema and to estimate the cut off value for high eosinophil count for the diagnosis of acute appendicitis. METHODS: A prospective cross sectional study was conducted on appendectomy specimens which were categorized into three groups of classical acute appendicitis, negative appendectomy and control. HandE and Giemsa stained section were studied for the presence of mural eosinophilic infiltrate, mast cells and edema. RESULTS: Of total 170 cases, group 1 comprised of 68 cases, group 2 consisted of 78 cases and group 3 consisted of 24 cases. Mean eosinophil and mast cell counts in the muscularis propria were significantly higher in CAA and NA categories when compared to control group. Positive association was found between high eosinophil count and edema in CAA and NA categories. Cut off value of >=6/ mm2 for mural eosinophil count was not significantly different in between NA and control categories. CONCLUSIONS: Increased mural eosinophils were significantly present in acute appendicitis and clinically suspected acute appendicitis but histological normal appendix when compared with control group. Sole presence of increased mural eosinophils might represent acute inflammation. However, cut off value for high eosinophil count could not be established to suggest acute appendicitis. PMID- 26983043 TI - Implementation and Effectiveness of Early Chest Tube Removal during an Enhanced Recovery Programme after Oesophago-gastrectomy. AB - INTRODUCTION: Oesophageal resection were notoriously complicated and produces a cohort of patients prone to postoperative complications and here we would like to focus on the implementation and effectiveness of early chest tube removal in ERAS after oesophago-gastrectomy considering the various aspect like pleural effusion and reducing the length of hospital stay which ultimately lead to reducing the economic burden on patient. METHODS: An ERAS programme was devised and implemented with the support of a dedicated in-hospital task-force. The patients underwent esophago-gastrectomy were randomly divided into two groups: the ERAS group and the control group (non-ERAS). The ERAS group was treated with early removal of the chest tube after surgery, and the control group was treated with traditional way and outcomes were compared between them. RESULTS: The length of hospital stay and the cost of hospitalization in the ERAS group were significantly lower than those in the control group(p<0.05. However, there was no statistical significant difference in the incidences of pleural effusion between the two groups(p>0.05). CONCLUSIONS: The introduction of early chest tube removal as an ERAS programme after oesophago-gastrectomy would not increase the risk of pleural effusion and would not increase the total length of stay and cost of hospitalisation without jeopardising patient safety or clinical outcomes. PMID- 26983044 TI - Cytological Diagnosis of Primary Thyroid Tuberculosis. AB - Primary thyroid tuberculosis is an extremely rare disease, even in countries where other forms of tuberculosis are abundant. TT has no age bar but usually affects women in fourth and fifth decade. Hereby, we report a case of 16-years old girl presented with complaint of progressively increasing, painful thyroid swelling. Diagnosis of TT was made on cytology and there was no evidence of involvement of any other organ by tuberculosis. Despite of its rarity, TT is usually misdiagnosed. So, a clinician should always consider this entity in the differential diagnosis of thyroid swelling. Fine needle aspiration cytology is the best diagnostic method and can result in the avoidance of unnecessary thyroid surgeries. PMID- 26983042 TI - Patterns of Lesions in Hysterectomy Specimens in a Tertiary Care Hospital. AB - INTRODUCTION: Hysterectomy is one of the most common gynaecological procedures performed all over the world. The most frequent indications for hysterectomy are fibroids, abnormal uterine bleeding uterovaginal prolapse and endometriosis. The objective of this study was to present the histopathological patterns of various uterine and adnexal pathologies in the hysterectomy specimens and also to correlate its pre-operative clinical diagnosis with histopathology. METHODS: This is a two-year descriptive study of hysterectomy specimens carried out in the Department of Pathology, Patan Academy of Health Sciences (PAHS), Lalitpur, Nepal. Data of all the hysterectomy specimens collected during this period was analyzed. RESULTS: Out of the 533 cases, fibroid was the most common indication for hysterectomy that was seen in 229 (42.94%) cases followed by uterovaginal prolapse in 101 (18.93%) cases. Leiomyoma was the most common pathology reported in 250 (46.90%) hysterectomy specimens, followed by ovarian tumours in 95 (17.82%) cases. In 17.82% (95/533) cases, no pathology was seen. Overall, the pre operative indications in 533 cases of hysterectomy were histopathologically verifiable in 487 (91.37%) cases. CONCLUSIONS: Though the histopathological examination correlates well with the pre-operative clinical diagnosis, a number of lesions were also encountered as pure incidental findings. Hence, it is mandatory that every hysterectomy specimen should be subjected to histopathological examination so as to ensure better post-operative management. PMID- 26983045 TI - Diagnosis Delayed but not Denied - Sheehan's syndrome. AB - Sheehan's syndrome is a rare complication of postpartum hemorrhage. With advancement in obstetric care, Sheehan's syndrome has become uncommon except in developing countries. Here, we report a patient with Sheehan's syndrome who escaped diagnosis for 22 years and presented with life threatening complications. This patient also had certain unusual features of Sheehan's syndrome like pancytopenia and renal failure. A high index of suspicion is necessary in diagnosing such patients. PMID- 26983046 TI - Ruptured Gall Bladder containing Stones following Blunt Trauma Abdomen: A Rare Presentation of Hemodynamic Instability. AB - Gall bladder injuries are seen in 2% of patients undergoing laparotomy for blunt trauma abdomen. Isolated gall bladder injury is a rare event with associated presence of stones is even rarer. The associated visceral injuries lead to intraoperative identification in most cases. Here we present a case of 30 years old male with isolated gall bladder laceration following blunt abdominal trauma. The diagnosis of gallbladder perforation after blunt injury may be suspected in patients with signs of an acute abdomen and hypotension that is not explained by blood loss. Early suspicion and prompt exploration is imperative. Cholecystectomy is an adequate treatment for the condition. PMID- 26983047 TI - Unilateral Pulmonary Hypoplasia in a Child. AB - Pulmonary hypoplasia is an uncommon congenital anomaly. A case reported in a six year old male child from Bangladesh who presented with chronic dry cough, episodic fever and occasional haemoptysis causing confusion with tuberculosis. X ray suggested lung collapse. Final diagnosis reached by combined bronchoscopy, computed tomogram scan of chest and pulmonary angiogram. In a child with complete radiological lung collapse possibility of pulmonary hypoplasia should be kept in mind. PMID- 26983048 TI - Facilitation of free residential training inside the country - The fundamental health service responsibility of the Government and its regulatory body. AB - For optimum Peripheral Health Service and implementation of various Vertical Public Health Programme Services, network of public Rural and Urban Health Centers with trained Specialists in General Practice (GP) is essential. Later such Specialist GPs will thus fulfill both comprehensive training and experience required for Health Management and Planning Service in the centre. About 40%-50% of all Residential Trainings and Specialists are required in GP. There are further up to 100 to 150 possible specialties in which remaining doctors can be trained for Specialty Health Services. Though free Residential Training has numerous advantages, its shortage inside country is the bottleneck to provide above mentioned Health Services. Planning for health service delivery by at least trainee residents under supervision or appropriately trained specialists guides Residential Training's regulations. Fulfillment of objective training criteria as its core focus is the concept now with the major role of Faculty as supervising residents to provide required service in the specialty and simultaneously updating themselves and their team for Evidence-Based Medicine practice. Similarly the need of Ambulatory Health Service and joint management of in patients by specialists in hospitals has changed unit and bed divisions and requirements for Residential Training. Residents, already the licensed doctors, are thus providing required hospital service as indispensable part of its functional hierarchy for which they need to be paid. With such changing concepts and trends, there are some essential points in existing situation to facilitate free Residential Training inside country. For Government doctors, relevant amendment in their regulation is accordingly required. PMID- 26983049 TI - Interprofessional Care and Role of Team Leaders. AB - Interprofessional care is an essential part of the health service delivery system. It helps to achieve improved care and to deliver the optimal and desired health outcomes by working together, sharing and learning skills. Health care organisation is a collective sum of many leaders and followers. Successful delivery of interprofessional care relies on the contribution of interprofessional care team leaders and health care professionals from all groups. The role of the interprofessional care team leader is vital to ensuring continuity and consistency of care and to mobilise and motivate health care professionals for the effective delivery of health services. Medical professionals usually lead interprofessional care teams. Interprofessional care leaders require various skills and competencies for the successful delivery of interprofessional care. PMID- 26983051 TI - A Comparison of the Haider Tube-Guard(r) Endotracheal Tube Holder Versus Adhesive Tape to Determine if This Novel Device Can Reduce Endotracheal Tube Movement and Prevent Unplanned Extubation. AB - BACKGROUND: Endotracheal tube security is a critical safety issue. We compared the mobility of an in situ endotracheal tube secured with adhesive tape to the one secured with a new commercially available purpose-designed endotracheal tube holder device (Haider Tube-Guard). We also observed for the incidence of oropharyngeal or facial trauma associated with the 2 tube fixation methods. METHODS: Thirty adult patients undergoing general anesthesia with neuromuscular blockade were prospectively enrolled. Immediately after intubation, a single study author positioned the endotracheal tube tip in the distal trachea using a bronchoscope. Anesthesiologists caring for patients secured the tube in their normal fashion (always with adhesive tape). A force transducer was used to apply linear force, increasing to 15 N or until the principal investigator deemed that the force be aborted for safety reasons. The displacement of the endotracheal tube was measured with the bronchoscope. Any tape was then removed and the endotracheal tube secured with the Haider Tube-Guard device. The linear force was reapplied and the displacement of the endotracheal tube measured. The Haider Tube Guard device was left in place for the duration of the case. The patient's face and oropharynx were examined for any evidence of trauma during surgery and in the recovery room. On discharge from the postanesthesia care unit, the patient answered a brief survey assessing for any subjective evidence of minor facial or oropharyngeal trauma. RESULTS: Under standardized tension, the endotracheal tube withdrew a mean distance of 3.4 cm when secured with adhesive tape versus 0.3 cm when secured with the Haider Tube-Guard (P <0.001). Ninety-seven percent of patients (29/30) experienced clinically significant endotracheal tube movement (>1 cm) when adhesive tape was used to secure the tube versus 3% (1/30) when the Haider Tube-Guard was used (P <0.001). Thirty percent of patients (9/30) were potentially deemed a high extubation risk (endotracheal tube movement >4 cm) when the endotracheal tube was secured with tape versus 0% (0/30) when secured with the Haider Tube-Guard (P = 0.004). Six patients with taped endotracheal tubes required the traction to be aborted before 15 N of force was achieved to prevent potential extubation as the tape either separated from the face or stretched to allow excessive endotracheal tube movement. None of the patients appeared to sustain any injury from the Haider Tube-Guard device. CONCLUSIONS: The Haider Tube-Guard significantly reduced the mobility of the endotracheal tube when compared with adhesive tape and was well tolerated in our observations. PMID- 26983052 TI - Anesthetic Care in Mozambique. AB - BACKGROUND: The World Bank and Lancet Commission in 2015 have prioritized surgery in Low-Income Countries (LIC) and Lower-Middle Income Countries (LMICs). This is consistent with the shift in the global burden of disease from communicable to noncommunicable diseases over the past 20 years. Essential surgery must be performed safely, with adequate anesthesia monitoring and intervention. Unfortunately, a huge barrier to providing safe surgery includes the paucity of an anesthesia workforce. In this study, we qualitatively evaluated the anesthesia capacity of Mozambique, a LIC in Africa with limited access to anesthesia and safe surgical care. Country-based solutions are suggested that can expand to other LIC and LMICs. METHODS: A comprehensive review of the Mozambique anesthesia system was conducted through interviews with personnel in the Ministry of Health (MOH), a school of medicine, a public central referral hospital, a general first referral hospital, a private care hospital, and leaders in the physician anesthesia community. Personnel databases were acquired from the MOH and Maputo Central Hospital. RESULTS: Quantitative results reveal minimal anesthesia capacity (290 anesthesia providers for a population of >25 million or 0.01:10,000). The majority of physician anesthesiologists practice in urban settings, and many work in the private sector. There is minimal capacity for growth given only 1 Mozambique anesthesia residency with inadequate resources. The most commonly perceived barriers to safe anesthesia in this critical shortage are lack of teachers, lack of medical student interest in and exposure to anesthesia, need for more schools, low allocation to anesthesia from the list of available specialist prospects by MOH, and low public payments to anesthesiologists. Qualitative results show assets of a good health system design, a supportive environment for learning in the residency, improvement in anesthetic care in past decades, and a desire for more educational opportunities and teachers. CONCLUSIONS: Mozambique has a strong health system design but few resources for surgery and safe anesthesia. At present, similar to other LICs, human resources, access to essential medicines, and safety monitoring limit safe anesthesia in Mozambique. PMID- 26983053 TI - Three new cembranoids from the Bornean soft coral Nephthea sp. AB - Three new cembranoid diterpenes, 10-hydroxy-nephthenol acetate (1), 7,8-epoxy-10 hydroxy-nephthenol acetate (2), and 6-acetoxy-7,8-epoxy-10-hydroxy-nephthenol acetate (3), along with a known compound, 6-acetoxy-7,8-epoxy-nephthenol acetate (4), were isolated from the Bornean soft coral Nephthea sp. Antibacterial and anticancer activities were exhibited by compounds 1 and 2 against Staphylococcus aureus (ATCC 6538)/Escherichia coli (ATCC 13311) and Hela/MCF-7, respectively. PMID- 26983050 TI - Prothrombin Complex Concentrates for Bleeding in the Perioperative Setting. AB - Prothrombin complex concentrates (PCCs) contain vitamin K-dependent clotting factors (II, VII, IX, and X) and are marketed as 3 or 4 factor-PCC formulations depending on the concentrations of factor VII. PCCs rapidly restore deficient coagulation factor concentrations to achieve hemostasis, but like with all procoagulants, the effect is balanced against thromboembolic risk. The latter is dependent on both the dose of PCCs and the individual patient prothrombotic predisposition. PCCs are approved by the US Food and Drug Administration for the reversal of vitamin K antagonists in the setting of coagulopathy or bleeding and, therefore, can be administered when urgent surgery is required in patients taking warfarin. However, there is growing experience with the off-label use of PCCs to treat patients with surgical coagulopathic bleeding. Despite their increasing use, there are limited prospective data related to the safety, efficacy, and dosing of PCCs for this indication. PCC administration in the perioperative setting may be tailored to the individual patient based on the laboratory and clinical variables, including point-of-care coagulation testing, to balance hemostatic benefits while minimizing the prothrombotic risk. Importantly, in patients with perioperative bleeding, other considerations should include treating additional sources of coagulopathy such as hypofibrinogenemia, thrombocytopenia, and platelet disorders or surgical sources of bleeding. Thromboembolic risk from excessive PCC dosing may be present well into the postoperative period after hemostasis is achieved owing to the relatively long half-life of prothrombin (factor II, 60-72 hours). The integration of PCCs into comprehensive perioperative coagulation treatment algorithms for refractory bleeding is increasingly reported, but further studies are needed to better evaluate the safe and effective administration of these factor concentrates. PMID- 26983054 TI - Supporting Veterinary Preceptors in a Distributed Model of Education: A Faculty Development Needs Assessment. AB - Effective faculty development for veterinary preceptors requires knowledge about their learning needs and delivery preferences. Veterinary preceptors at community practice locations in Alberta, Canada, were surveyed to determine their confidence in teaching ability and interest in nine faculty development topics. The study included 101 veterinarians (48.5% female). Of these, 43 (42.6%) practiced veterinary medicine in a rural location and 54 (53.5%) worked in mixed animal or food-animal practice. Participants reported they were more likely to attend an in-person faculty development event than to participate in an online presentation. The likelihood of attending an in-person event differed with the demographics of the respondent. Teaching clinical reasoning, assessing student performance, engaging and motivating students, and providing constructive feedback were topics in which preceptors had great interest and high confidence. Preceptors were least confident in the areas of student learning styles, balancing clinical workload with teaching, and resolving conflict involving the student. Disparities between preceptors' interest and confidence in faculty development topics exist, in that topics with the lowest confidence scores were not rated as those of greatest interest. While the content and format of clinical teaching faculty development events should be informed by the interests of preceptors, consideration of preceptors' confidence in teaching ability may be warranted when developing a faculty development curriculum. PMID- 26983055 TI - Traditional Thermal Therapy with Indirect Moxibustion Decreases Renal Arterial Resistive Index in Patients with Chronic Kidney Disease. AB - OBJECTIVE: To evaluate the immediate effects of traditional local thermal therapy with indirect moxibustion on renal hemodynamics in patients with chronic kidney disease (CKD) by using Doppler ultrasonography (US). DESIGN: Examiner-blinded crossover study. PARTICIPANTS: Forty-three participants with CKD (mean age +/- standard deviation [SD], 44 +/- 15 years; estimated glomerular filtration rate, 69.5 +/- 25.5 mL/min per 1.73 m(2); 20 men and 23 women). INTERVENTION: Participants received three successive treatment sessions of indirect moxibustion bilaterally at BL 23, a crucial acupuncture point, in the session. In the control session, the examiner was blinded by using smoke and aroma produced by moxibustion performed in an ashtray placed near the patient's body. OUTCOME MEASURES: The main outcome measure was resistive index (RI) in the renal segmental arteries. Blood flow parameters, including RI, were measured for six renal segmental arteries by using Doppler US at rest (baseline), immediately after completion of moxibustion (post 1), and 10 minutes later (post 2). Adverse events were monitored during intervention. RESULTS: In the control session, RI at post 1 (median [first, third quartile]: 0.587 [0.562, 0.626]) and post 2 (0.583 [0.567, 0.629]) did not change significantly compared with baseline (0.592 [0.563, 0.636]), while in the treatment session, RI at post 1 (0.565 [0.530, 0.618]) and post 2 (0.561 [0.533, 0.614]) decreased significantly compared with baseline (0.590 [0.550, 0.652]) (p < 0.001 and p < 0.001, respectively). The reduction in RI from baseline to post 2 in treatment session was significantly greater than in control session (mean +/- SD, -0.026 +/- 0.028 versus -0.003 +/- 0.028; mean difference, -0.023 [95% confidence interval, -0.036 to -0.010]; p = 0.001]. No adverse events, such as burns, were observed during the study period. CONCLUSION: Renal vascular resistance was decreased after indirect moxibustion therapy in patients with CKD. PMID- 26983057 TI - Erratum. PMID- 26983058 TI - Editor's message. PMID- 26983059 TI - Chronic fatigue syndrome. AB - The chronic fatigue syndrome is an illness of unknown etiology characterized by severe fatigue, myalgias, lymphadenopathy, arthralgias, chills, fevers, and postexertional malaise. Recognizing chronic fatigue syndrome is primarily a method of exclusion with no definitive diagnostic test or physical findings. As research continues to delve into the many possible etiologic agents for chronic fatigue syndrome-infectious, immunologic, neurologic, or psychiatric alone or in combination- the answer remains elusive. What is known is that chronic fatigue syndrome is a heterogeneous disorder very possibly involving an interaction of biological systems. Therefore, chronic fatigue syndrome may describe a large subset of patients, each exhibiting unique symptoms and serologic profiles dependent on the nature of the onset of illness and the genetic profile of individual patients. PMID- 26983060 TI - Medications frequently used for asthma and rhinitis. AB - Multiple medications are available to treat asthma and other allergic diseases, making it difficult to determine which medications to use. The decision should be based on efficacy, cost, and other advantages and disadvantages. Comparative tables can help for rapid selection and can be used as a tool for enhancing prescribing practices. This article organizes this information into a tabular format, allowing for rapid review. PMID- 26983061 TI - CME QUIZ. PMID- 26983056 TI - The Impact of Youth-Friendly Structures of Care on Retention Among HIV-Infected Youth. AB - Limited data exist on how structures of care impact retention among youth living with HIV (YLHIV). We describe the availability of youth-friendly structures of care within HIV Research Network (HIVRN) clinics and examine their association with retention in HIV care. Data from 680 15- to 24-year-old YLHIV receiving care at 7 adult and 5 pediatric clinics in 2011 were included in the analysis. The primary outcome was retention in care, defined as completing >=2 primary HIV care visits >=90 days apart in a 12-month period. Sites were surveyed to assess the availability of clinic structures defined a priori as 'youth-friendly'. Univariate and multivariable logistic regression models assessed structures associated with retention in care. Among 680 YLHIV, 85% were retained. Nearly half (48%) of the 680 YLHIV attended clinics with youth-friendly waiting areas, 36% attended clinics with evening hours, 73% attended clinics with adolescent health-trained providers, 87% could email or text message providers, and 73% could schedule a routine appointment within 2 weeks. Adjusting for demographic and clinical factors, YLHIV were more likely to be retained in care at clinics with a youth-friendly waiting area (AOR 2.47, 95% CI [1.11-5.52]), evening clinic hours (AOR 1.94; 95% CI [1.13-3.33]), and providers with adolescent health training (AOR 1.98; 95% CI [1.01-3.86]). Youth-friendly structures of care impact retention in care among YLHIV. Further investigations are needed to determine how to effectively implement youth-friendly strategies across clinical settings where YLHIV receive care. PMID- 26983062 TI - Chronic sinusitis in patients with cystic fibrosis. AB - Cystic fibrosis is a lethal genetic disorder whose victims currently have a median life span of approximately 30 years. With this increased life span, new aspects of the disease are identified in patients with cystic fibrosis, including chronic sinusitis. Sinusitis severely affects the quality of life of patients with sinusitis. This article discusses several aspects of sinusitis in patients with cystic fibrosis, including clinical presentation, radiologic findings, and treatment options. By recognizing and treating sinusitis in patients with cystic fibrosis, physicians may improve the quality of life of these patients. PMID- 26983063 TI - Asthma and gastroesophageal reflux. AB - Gastroesophageal reflux and asthma are common diseases in the developed world, and they often coexist in patients. Animal experiments, epidemiologic data, and clinical studies suggest that gastroesophageal reflux may contribute to the pathogenesis of asthma. In addition to classic reflux symptoms, such patients may notice nightly exacerbations of asthma or postprandial worsening of their pulmonary symptoms. Empiric treatment with an acid-suppressive regimen is the most cost-effective approach for asthmatic patients with classic gastroesophageal reflux symptoms, especially if the asthma remains poorly controlled despite conventional treatment. If patients have persistent problems after an adequate duration of acid-suppressive therapy or if they report symptoms indicating complicated reflux disease, such as dysphagia, additional diagnostic studies should be initiated. In most cases, medical therapy should be chosen for the long term treatment of patients with asthma and gastroesophageal reflux. With the availability of less-invasive laparoscopic surgery, fundoplication may be an alternative in selected, mostly young individuals who have documented reflux and symptoms responsive to appropriate acid-suppressive regimens. PMID- 26983064 TI - A cross-sectional survey of cadmium biomarkers and cigarette smoking. AB - Cadmium contamination of tobacco may contribute to the health hazards of cigarette smoking. The 2005-2012 United States National Health and Nutrition Examination Survey data provided a unique opportunity to conduct a cross sectional survey of cadmium biomarkers and cigarette smoking. Among a sample of 6761 participants, we evaluated mean differences and correlations between cadmium biomarkers in the blood and urine and characteristics of never, former and current smokers. We found statistically significant differences in mean cadmium biomarker levels between never and former smokers as well as between never and current smokers. In current smokers, duration in years had a higher correlation coefficient with urinary than blood cadmium levels. In contrast, number of cigarettes smoked per day had a higher correlation coefficient with blood than urinary cadmium levels. These data suggest that blood and urine cadmium biomarker levels differ by duration and dose. These findings should be considered in evaluating any association between cadmium and smoking related diseases, especially cardiovascular disease. PMID- 26983065 TI - Stage-structured wild and sterile mosquito population models and their dynamics. AB - To study the impact of the sterile insect technique and effects of the mosquitoes' metamorphic stage structure on the transmission dynamics of mosquito borne diseases, we formulate stage-structured continuous-time mathematical models, based on systems of differential equations, for the interactive dynamics of the wild and sterile mosquitoes. We incorporate different strategies for the releases of sterile mosquitoes in the models and investigate the model dynamics, including the existence of positive equilibria and their stability. Numerical examples are provided to demonstrate the dynamical features of the models. PMID- 26983066 TI - Risk Factors Associated With Pressure Ulcer Formation in Critically Ill Cardiac Surgery Patients: A Systematic Review. AB - BACKGROUND: Cardiac surgery patients are among those most at risk for developing pressure ulcers (PUs), with a reported incidence as high as 29.5%. Although numerous studies documenting PU risk factors and prevention strategies exist, the availability of literature examining risk factors specific to the cardiac surgery population is limited. AIM: A systematic review was completed that aimed to identify the risk factors associated with PU development in critically ill, adult, cardiac surgery patients. METHODS: The MEDLINE, CINAHL, and Cochrane databases were searched. Studies that focused on PU risk factors in critical care, surgical intensive care, or cardiac surgery populations and used PU occurrences as an outcome variable were included in the review. FINDINGS: Twelve high-quality studies were retrieved and included in the review; they revealed 30 potential PU risk factors. Current evidence is limited in 2 important ways. First, the impact of intraoperative factors, such as cardiopulmonary bypass time or body temperature, appears to be underexplored. Second, a substantive discussion of the risk factors associated specifically with deep tissue injuries, a unique PU category, is absent. CONCLUSION: The relatively high PU incidence among cardiac surgery patients suggests that typical PU prevention methods are insufficient for this population. Targeted prevention measures must be developed and implemented. Completion of this task required identification of risk factors unique to this population. Specific risk factors likely to increase risk among cardiac surgery patients include prolonged exposure to pressure during long surgical procedures, vascular disease, and/or vasopressor use postoperatively. Additional research concerning risk factors specific to this population is urgently needed. PMID- 26983068 TI - Premature Mortality and Schizophrenia-The Need to Heal Right From the Start. PMID- 26983067 TI - Thinking About Electroconvulsive Therapy: The Opinions of Parents of Adolescents with Schizophrenia Spectrum Disorders. AB - OBJECTIVE: To assess the experience with, knowledge of, and attitudes toward electroconvulsive therapy (ECT) among parents of adolescents with schizophrenia spectrum disorders (SSD) who have received ECT. METHODS: A self-administered questionnaire was used to assess the experience with, knowledge of, and attitudes toward ECT in a sample of parents of adolescents diagnosed with SSD. Parents of adolescents treated with ECT before the age of 18 years (ECT group; n = 19) were compared with a randomly selected group of parents of adolescents treated only with antipsychotics (No ECT group; n = 20). RESULTS: Most parents in the ECT group claimed that they had received adequate information about the ECT procedure (94.7%), most of them thought it had been helpful for their children (73.7%) and none thought that it had made things worse. The large majority of parents in the ECT group (80%) thought that the illness had been worse than ECT or medication, and none thought that ECT was the worst. Parents in the ECT group generally had better knowledge of what ECT is and its indications. All the parents in the ECT group (100%) and almost all of those in the No ECT group (94.7%) would agree to the treatment for their children if recommended in the future by a doctor, there being no differences between the groups in this respect (p = 0.447). Most parents in the ECT group (88.9%) thought it was a legitimate treatment when used appropriately, an opinion that was held by a much smaller proportion of parents in the No ECT group (52.6%), although the remaining parents in that group were unsure about it (47.4%). CONCLUSIONS: Most parents of adolescents with SSD treated with ECT had positive views about the treatment. Parents of adolescents treated only with antipsychotics tended either to have positive views about ECT or claimed to have no knowledge about it, with negative views being uncommon. PMID- 26983069 TI - Discovery of Strecker-type alpha-aminonitriles as a new class of human carbonic anhydrase inhibitors using differential scanning fluorimetry. AB - A new type of carbonic anhydrase inhibitors was identified via differential scanning fluorimetry (DSF) screening. The compounds displayed interesting inhibition profile against human carbonic anhydrase isoforms I, II, IX and XII with an obvious selectivity displayed by one compound toward carbonic anhydrase (CA) IX, an established anti-cancer target. A hypothetical mechanism of inhibitory action by the Strecker-type alpha-aminonitriles has been proposed. PMID- 26983070 TI - Anagen Effluvium Caused by Thallium Poisoning. PMID- 26983071 TI - Correction to Total Synthesis of (+/-)-Gracilioether F. PMID- 26983072 TI - A Cross-Sectional Voxel-Based Morphometric Study of Age- and Sex-Related Changes in Gray Matter Volume in the Normal Aging Brain. AB - OBJECTIVE: The aim of the study was to carry out a cross-sectional study of 124 cognitively normal Chinese adults using the voxel-based morphometry approach to delineate age-related changes in the gray matter volume of regions of interest (ROI) in the brain and further analyze their correlation with age. METHODS: One hundred twenty-four cognitively normal adults were divided into the young age group, the middle age group, and the old age group. Conventional magnetic resonance imaging was performed with the Achieva 3.0 T system. Structural images were processed using VBM8 and SPM8. Regions of interest were obtained by WFU PickAtlas and all realigned images were spatially normalized. RESULTS: Females showed significantly greater total gray matter volume than males (t = 4.81, P = 0.0000, false discovery rate corrected). Compared with young subjects, old-aged subjects showed extensive reduction in gray matter volumes in all ROIs examined except the occipital lobe. In young- and middle-aged subjects, female and male subjects showed significant difference in the right middle temporal gyrus, right superior temporal gyrus, left angular gyrus, right middle occipital lobe, left middle cingulate gyrus, and the pars triangularis of the right inferior frontal gyrus, suggesting an interaction between age and sex (P < 0.001, uncorrected). Logistic regression analysis revealed linear negative correlation between the total gray matter volume and age (R = 0.529, P < 0.001). CONCLUSIONS: Significant age-related differences are present in gray matter volume across multiple brain regions during aging. The VPM approach may provide an emerging paradigm in the normal aging brain that may help differentiate underlying normal neurobiological aging changes of specific brain regions from neurodegenerative impairments. PMID- 26983074 TI - Recognizing Patients' Emotions: Teaching Health Care Providers to Interpret Facial Expressions. AB - PURPOSE: Facial expressions are an important clue to a patient's emotions. The authors developed a 90-minute workshop in May 2011 to teach physicians and physicians-in-training to interpret facial expressions and to use that skill in the context of patient care. METHOD: The workshop included a didactic presentation in which facial expression features were taught using progressively more difficult examples, followed by three interactive exercises. The authors presented the workshop at six separate venues in the United States in 2011 and 2012. To test the effectiveness of this workshop, the authors designed a comprehensive pre- and postworkshop evaluation which assessed participants' skill, knowledge, attitude (toward importance), and confidence. RESULTS: A total of 156 health care providers participated in the workshop and completed pre- and postworkshop evaluations. Participants showed substantial improvement in skill and knowledge (fact- and case-based) scores, as well as modest improvement in importance and confidence ratings. Faculty and medical students demonstrated similar baseline measures of skill, knowledge, and importance, though faculty reported a slightly higher confidence in their skills. No correlation was found between baseline ratings of confidence in abilities and any baseline measure of performance. CONCLUSIONS: Given the similar baseline performance of faculty and medical students, the ability to interpret facial expressions does not appear to be learned through routine clinical practice, highlighting the need for dedicated facial expression training. The authors were able to demonstrate that physicians and physicians-in-training could effectively learn to recognize emotion by interpreting facial expressions through a short workshop. PMID- 26983073 TI - A Chronic Disease Management Student-Faculty Collaborative Practice: Educating Students on Innovation in Health Care Delivery. AB - PROBLEM: In the current transformative health care landscape, it is imperative that clinician educators inspire future clinicians to practice primary care in a dynamic environment. A focus on patient-centered, goal-oriented care for patients with chronic conditions is critical. APPROACH: In 2009, Harvard Medical School founded the Crimson Care Collaborative, a student-faculty collaborative practice (SFCP) network. With the aim of expanding clinical and educational opportunities for medical students and improving patient control of chronic disease (i.e., hypertension, obesity, and diabetes) in an innovative learning environment, in 2012, the authors developed a novel SFCP at their hospital-based academic primary care practice. In this SFCP, students learn to explore patient priorities, provide focused counseling and education, and assist patients with self management goals during clinical visits. OUTCOMES: From 2012 to 2014, 250 student volunteers participated in the SFCP as clinicians, innovators, educators, and leaders, with between 80 and 95 medical students engaging each semester. Between January 2012 and March 2014, there were 476 urgent care or chronic disease management visits. Patients with chronic diseases were seen at least twice on average, and by 2014, chronic disease management visits accounted for approximately 74% of visits. NEXT STEPS: Work is under way to create assessment tools to evaluate the practice's educa tional impact and student understanding of the current health care system, develop interdisciplinary care teams, expand efforts in registry management and broaden the patient recruitment scope, further emphasize patient engage ment and retention, and evaluate chronic disease management and patient satisfaction effectiveness. PMID- 26983076 TI - How Residents Develop Trust in Interns: A Multi-Institutional Mixed-Methods Study. AB - PURPOSE: Although residents trust interns to provide patient care, little is known about how trust forms. METHOD: Using a multi-institutional mixed-methods study design, the authors interviewed (March-September 2014) internal medicine (IM) residents in their second or third postgraduate year at a single institution to address how they develop trust in interns. Transcript analysis using grounded theory yielded a model for resident trust. Authors tested (January-March 2015) the model with residents from five IM programs using a two-section quantitative survey (38 items; 31 rated 0 = not at all to 100 = very much; 7 rated 0 = strongly disagree to 100 = strongly agree) to identify influences on how residents form trust. RESULTS: Qualitative analysis of 29 interviews yielded 14 themes within five previously identified factors of trust (resident, intern, relationship, task, and context). Of 478 residents, 376 (78.7%) completed the survey. Factor analysis yielded 11 factors that influence trust. Respondents rated interns' characteristics (reliability, competence, and propensity to make errors) highest when indicating importance to trust (respective means 86.3 [standard deviation = 9.7], 76.4 [12.9], and 75.8 [20.0]). They also rated contextual factors highly as influencing trust (access to an electronic medical record, duty hours, and patient characteristics; respective means 79.8 [15.3], 73.1 [14.4], and 71.9 [20.0]). CONCLUSIONS: Residents form trust based on primarily intern- and context-specific factors. Residents appear to consider trust in a way that prioritizes interns' execution of essential patient care tasks safely within the complexities and constraints of the hospital environment. PMID- 26983075 TI - Leveraging a Redesigned Morbidity and Mortality Conference That Incorporates the Clinical and Educational Missions of Improving Quality and Patient Safety. AB - PROBLEM: The morbidity and mortality (M&M) conference is a vital event that can affect medical education, quality improvement, and peer review in academic departments. Historically, M&M conferences have emphasized cases that highlight diagnostic uncertainty or complex management conundrums. In this report, the authors describe the development, pilot, and refinement of a systems-based M&M conference model that combines the educational and clinical missions of improving quality and patient safety in the University of Colorado Department of Medicine. APPROACH: In 2011, a focused taskforce completed a literature review that informed the development of a framework for the redesigned systems-based M&M conference. The new model included a restructured monthly conference, longitudinal curriculum for residents, and formal channels for interaction with clinical effectiveness departments. Each conference features an in-depth discussion of an adverse event using specific quality improvement tools. Areas for improvement and suggested action items are identified during the conference and delegated to the relevant clinical departments. OUTCOMES: The new process has enabled the review of 27 adverse events over two years. Sixty-three action items were identified, and 33 were pursued. An average of 50 to 60 individuals participate in each conference, including interprofessional and interdisciplinary colleagues. Resident and faculty feedback regarding the new format has been positive, and other departments are starting to adopt this model. NEXT STEPS: A more robust process for identifying and selecting cases to discuss is needed, as is a stable, sufficient mechanism to manage the improvement initiatives that come out of each conference. PMID- 26983078 TI - New-onset toxicity with programmed death-1 inhibitor rechallenge. AB - Immunotherapy has become a mainstay in the treatment of metastatic melanoma. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors and programmed death-1 (PD-1) inhibitors, which have been added more recently, represent two of the main classes of immunomodulating agents. PD-1 inhibitors are well tolerated and are known to have a decreased rate of occurrence of adverse effects compared with CTLA-4 inhibitors. However, the risk remains for serious immune-mediated adverse reactions. Given their long half and extended efficacy, treatment with a CTLA-4 inhibitor before use of a PD-1 inhibitor may increase the risk of adverse effects. In addition, caution should be exercised when rechallenging grade 3 or 4 adverse effects with the same agent or a different agent of the same class. The re-emergence of a previous toxicity may occur or, as found in this case, a new severe effect may arise. This article will present a case of fatal immune-related hepatoxicity in a patient treated with a CTLA-4 inhibitor, followed by treatment with a PD-1 inhibitor. The mechanisms of action and safety profiles for both classes of drugs will also be reviewed. PMID- 26983079 TI - Patient-derived tumor xenograft strategies for informed management of patients with metastatic melanoma. AB - Metastatic melanoma has benefited from immunotherapy and targeted therapy advances. Faced with the inescapable onset of treatment resistance, the choice of a second-line treatment can be guided by a patient-derived tumor xenograft (PDTX). This new approach requires an excellent multidisciplinary collaboration where the surgeon has a key role to play. Each patient included (stage IIIC or IV) presented with subcutaneous melanoma metastasis that could be surgically resected. The surgeon performed orthotopic PDTX on CB17-SCID mice. To validate the model, tumor material was amplified over three successive generations of animals to obtain cohorts compatible with carrying out a study to compare treatment response by targeted therapy (vemurafenib versus controls). Tumors were characterized (histologically and genetically) at all stages of the generations' amplification. Functional imaging by fluorine-18 fluorodeoxyglucose PET scan was performed for the third generation PDTX. Seventeen patients with a mutated BRAF V600E subcutaneous metastasis were included, yielding 257 PDTX. Clinical, histological, and genetic characteristics of the grafted tumors were stable over the three mice generations. The treatment response to vemurafenib was observed for all PDTX. The fluorine-18 fluorodeoxyglucose PET scan evidenced a decreased in glucose uptake in the treated tumors. PDTX models are being widely used in fundamental research and are more compatible with clinical issues. If PDTX are simple and easily reproducible in metastatic melanoma, an organized multidisciplinary platform is essential to implement them. In our experience, surgeons have a key role to play in the cohesion of this new therapeutic approach. PMID- 26983080 TI - Lap Shear and Impact Testing of Ochre and Beeswax in Experimental Middle Stone Age Compound Adhesives. AB - The production of compound adhesives using disparate ingredients is seen as some of the best evidence of advanced cognition outside of the use of symbolism. Previous field and laboratory testing of adhesives has shown the complexities involved in creating an effective Middle Stone Age glue using Acacia gum. However, it is currently unclear how efficient different adhesive recipes are, how much specific ingredients influence their performance, and how difficult it may have been for those ingredients to be combined to maximum effect. We conducted a series of laboratory-based lap shear and impact tests, following modern adhesion testing standards, to determine the efficacy of compound adhesives, with particular regard to the ingredient ratios. We tested rosin (colophony) and gum adhesives, containing additives of beeswax and ochre in varying ratios. During both lap shear and impact tests compound rosin adhesives performed better than single component rosin adhesives, and pure acacia gum was the strongest. The large difference in performance between each base adhesive and the significant changes in performance that occur due to relatively small changes in ingredient ratios lend further support to the notion that high levels of skill and knowledge were required to consistently produce the most effective adhesives. PMID- 26983082 TI - Mechano-Pharmacological Characterization of Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells. AB - BACKGROUND/AIMS: Common systems for the quantification of cellular contraction rely on animal-based models, complex experimental setups or indirect approaches. The herein presented CellDrum technology for testing mechanical tension of cellular monolayers and thin tissue constructs has the potential to scale-up mechanical testing towards medium-throughput analyses. Using hiPS-Cardiac Myocytes (hiPS-CMs) it represents a new perspective of drug testing and brings us closer to personalized drug medication. METHODS: In the present study, monolayers of self-beating hiPS-CMs were grown on ultra-thin circular silicone membranes and deflect under the weight of the culture medium. Rhythmic contractions of the hiPS CMs induced variations of the membrane deflection. The recorded contraction relaxation-cycles were analyzed with respect to their amplitudes, durations, time integrals and frequencies. Besides unstimulated force and tensile stress, we investigated the effects of agonists and antagonists acting on Ca2+ channels (S Bay K8644/verapamil) and Na+ channels (veratridine/lidocaine). RESULTS: The measured data and simulations for pharmacologically unstimulated contraction resembled findings in native human heart tissue, while the pharmacological dose response curves were highly accurate and consistent with reference data. CONCLUSION: We conclude that the combination of the CellDrum with hiPS-CMs offers a fast, facile and precise system for pharmacological, toxicological studies and offers new preclinical basic research potential. PMID- 26983083 TI - Foxn1 Is Dynamically Regulated in Thymic Epithelial Cells during Embryogenesis and at the Onset of Thymic Involution. AB - Thymus function requires extensive cross-talk between developing T-cells and the thymic epithelium, which consists of cortical and medullary TEC. The transcription factor FOXN1 is the master regulator of TEC differentiation and function, and declining Foxn1 expression with age results in stereotypical thymic involution. Understanding of the dynamics of Foxn1 expression is, however, limited by a lack of single cell resolution data. We have generated a novel reporter of Foxn1 expression, Foxn1G, to monitor changes in Foxn1 expression during embryogenesis and involution. Our data reveal that early differentiation and maturation of cortical and medullary TEC coincides with precise sub-lineage specific regulation of Foxn1 expression levels. We further show that initiation of thymic involution is associated with reduced cTEC functionality, and proportional expansion of FOXN1-negative TEC in both cortical and medullary sub lineages. Cortex-specific down-regulation of Foxn1 between 1 and 3 months of age may therefore be a key driver of the early stages of age-related thymic involution. PMID- 26983081 TI - Killer Cell Immunoglobulin-Like Receptor Alleles Alter HIV Disease in Children. AB - BACKGROUND: HLA class I molecules are ligands for killer cell immunoglobin like receptors (KIR) that control the antiviral response of natural killer (NK) cells. However, the effects of KIR and HLA (KIR/HLA) alleles on HIV disease of children have not been studied. METHODS: 993 antiretroviral naive children with symptomatic HIV infection from PACTG protocols P152 and P300 were genotyped for KIR and HLA alleles using the Luminex platform. Linear regression was used to test the association between genotypes and baseline pre-ART HIV RNA, CD4+ lymphocyte count, and cognitive score, adjusting for age, race/ethnicity and study. The interaction between genetic markers and age was investigated. To account for multiple testing the false discovery rate (FDR) was controlled at 0.05. RESULTS: Children with the KIR2DS4*ALL FULL LENGTH (KIR2DS4*AFL) allele had higher CD4+ lymphocyte counts. Among children <=2 years of age, the KIR2DS4*AFL was associated with lower plasma HIV RNA and higher cognitive index scores. KIR Cent2DS3/5_1 had lower CD4+ lymphocyte counts in children <=2 years of age, while the presence of Tel1, Tel2DS4_2, Tel2DS4_4, Tel8, Tel2DS4_6 had higher CD4+ lymphocyte counts in all children. Presence of Cent2, Cent4 and Cent8 was associated with increased HIV RNA load in children <=2 years. Presence of KIR3DL1+Bw4 was associated with higher CD4+ lymphocyte counts in all children. Among children >2 years old, KIR3DS1+Bw4-80I was associated with higher plasma HIV RNA, and Bw6/Bw6 was associated with lower plasma HIV RNA compared to children with KIR3DS1+Bw4-80I. CONCLUSIONS: Presented data show for the first time that specific KIR alleles independently or combined with HLA ligands are associated with HIV RNA and CD4+ lymphocyte counts in infected, antiretroviral naive children; and many of these effect estimates appear to be age dependent. These data support a role for specific KIR alleles in HIV pathogenesis in children. PMID- 26983084 TI - Continuity effects on rotifers and microcrustaceans caused by the construction of a downstream reservoir in a cascade series (Iguacu River, Brazil). AB - This study evaluated changes in the community of rotifers and microcrustaceans associated with the construction of a large and dendritic reservoir in Iguacu River (Brazil), as the last reservoir of a sequence of five cascading systems. Differences were clear between pre-filling and post-filling phases for organisms and some of environmental variables. In the pre-filling phase, the community was more homogeneous along the downstream river gradient, and spatial compartmentalization in the new reservoir was common during the post-filling phase. From 140 identified taxa, 10 species occurred exclusively in the pre filling phase and 32 in the post-filling phase. After completion of the fifth reservoir filling-up, opportunistic, pioneer and fast-developing species quickly dominated, and downstream of the fourth reservoir the pre-filling decreasing gradient of richness, diversity and evenness disappeared. Richness of rotifers and cladocerans, cladocerans diversity, and evenness of rotifers, cladocerans and copepods were generally higher in the post-filling phase. A non-metric multidimensional analysis based on a presence/absence matrix depicted a homogeneous and dense group of species associated to the pre-filling phase and a second, dispersed group related to the post-filling phase. Spearman correlations pointed out significant positive effects of transparency on rotifer species richness in the post-filling phase, and negative effects on the microcrustacean richness in the pre-filling phase. Dam construction caused disruption of the downstream lotic gradient along the series of dams, leading to the development of distinct species in lentic spatial compartments. PMID- 26983086 TI - Effect of temperature on immatures of Stiretrus decastigmus (Hemiptera: Pentatomidae). AB - Stiretrus decastigmus (Herrich-Schaeffer) (Hemiptera: Pentatomidae) is an important predator of the insect pest Microtheca ochroloma Stal (Coleoptera: Chrysomelidae). The present study investigated the pre-imaginal development of S. decastigmus at different temperatures. The temperatures were: 20, 25, and 30 degrees C, with a relative humidity of 70 +/- 10% and a photofase of 12 h, and the nymphs were fed larvae of M. ochroloma. We evaluated the duration and viability of the egg and nymphal stages, the duration of each instar, and the predation potential. The incubation time decreased with increasing temperature, and the viability was highest at 25 degrees C. The duration of the nymphal stage was inversely proportional to the temperature, ranging from 18 days at 30 degrees C to 40.6 days at 20 degrees C. The highest S. decastigmus predation rates were found at 20 degrees C (90.4 larvae) and 30 degrees C (72.5 larvae). S. decastigmus showed the highest viability and lowest consumption of larvae of M. ochroloma at 25 degrees C. PMID- 26983085 TI - Antioxidant and antifungal activities of Camellia sinensis (L.) Kuntze leaves obtained by different forms of production. AB - The antioxidant and anticandidal activities of leaves obtained from Camellia sinensis by non-fermentation (green and white teas), semi-fermentation (red tea) and fermentation method (black tea) were investigated. It was evaluated the total phenolic content by Folin-Ciocalteau assay; antioxidant capacities were evaluated in vitro using DPPH and ABTS radicals, hypochlorous acid and superoxide anion scavenger assays, induced hemolysis, lipid peroxidation by conjugated diene formation and myeloperoxidase activity. Anticandidal activity was performed on three strains of Candida spp. The results showed that non-fermented teas have a higher concentration of phenolic compounds, and then presented the best inhibitory activity of AAPH-induced hemolysis, the best inhibition of conjugated diene formation and more pronounced antioxidant activity in all tests. The highest anticandidal activity was obtained from fermented tea, followed by non fermented tea. These results indicate that the antioxidant activity demonstrated has no direct relation with the anticandidal activity. PMID- 26983087 TI - Synthesis of Peramine, an Anti-insect Defensive Alkaloid Produced by Endophytic Fungi of Cool Season Grasses. AB - A seven-step synthesis of peramine, which required three chromatographic separations, is described. Key to the synthesis is an enolate alkylation of a pyrrole-fused diketopiperazine, reduction of the acyl pyrrole, and dehydration of the intermediate pyrrolyl carbinol to establish the pyrrolopyrazine core of peramine. PMID- 26983090 TI - Part II: General Aspects. AB - In this second article on contact allergy to and chemical composition of essential oils, some general aspects of essential oils are kprovided, including what they are, their applications, their mode of production, factors influencing their chemical composition, analysis of essential oil, and quality aspects. PMID- 26983089 TI - Essential Oils, Part I: Introduction. AB - Essential oils are widely used in the flavor, food, fragrance, and cosmetic industries in many applications. Contact allergy to them is well known and has been described for 80 essential oils. The relevance of positive patch test reactions often remains unknown. Knowledge of the chemical composition of essential oils among dermatologists is suspected to be limited, as such data are published in journals not read by the dermatological community. Therefore, the authors have fully reviewed and published the literature on contact allergy to and chemical composition of essential oils. Selected topics from this publication will be presented in abbreviated form in Dermatitis starting with this issue, including I. Introduction; II. General aspects; III. Chemistry; IV. General aspects of contact allergy; V. Peppermint oil, lavender oil and lemongrass oil; VI: Sandalwood oil, ylang-ylang oil, and jasmine absolute. PMID- 26983091 TI - Burden of Sleep and Fatigue in US Adults With Atopic Dermatitis. AB - BACKGROUND: Intense itch associated with atopic dermatitis (AD) can negatively impact sleep. However, the nature of sleep disturbance and fatigue in AD has not been fully elucidated. OBJECTIVES: The aim of this study was to determine the burden of sleep disturbance and fatigue in US adults with AD. METHODS: This study used a cross-sectional, questionnaire-based survey using a nationally representative sample of 5563 adults from the 2005 to 2006 National Health and Nutrition Examination Survey. Respondents were asked about history of AD, sleep disturbance, and fatigue-related instrumental activity of daily living (IADL) impairment. RESULTS: There was no significant association between having AD and having a diagnosed sleep disorder (10.44% vs 7.27%; odds ratio [OR] [95% confidence interval (CI)], 1.49 [0.84-2.64]; P = 0.23); however, respondents were more likely to report sleep disturbances to clinicians (33.38% vs 23.67%; OR [95% CI], 1.62 [1.10-2.38]; P = 0.04). In multivariate regression models controlling for sociodemographic and lifestyle factors, adults with AD had higher odds of sleep disturbances, including shorter sleep duration (adjusted OR [95% CI], 1.61 [1.16-2.25]), trouble falling asleep (adjusted OR [95% CI], 1.57 [1.10-2.24]), and early morning awakenings (adjusted OR [95% CI], 1.86 [1.24-22.78]). Those with AD also had significantly higher odds of feeling unrested and feeling too tired to perform IADLs. CONCLUSIONS: United States adults with AD have significantly impaired sleep and fatigue affecting IADLs, and sleep disturbances may be underdiagnosed in this population. PMID- 26983093 TI - Lidocaine Allergy: Do Positive Patch Results Restrict Future Use? AB - BACKGROUND: Adverse reactions from lidocaine are commonly reported. When allergy is suspected, patients may be referred for specific skin testing to confirm the association of their clinical findings. OBJECTIVE: We aimed to investigate 13 cases of suspected lidocaine allergy to analyze if positive patch results restricted future use as an injectable local anesthetic. METHODS: A prospective study was conducted from March 2013 to September 2014 at 2 academic hospital based patch test clinics in Toronto. Patients were tested to the North American Contact Dermatitis Group standard series (Smart Practice, Phoenix, AZ) and, if suspicion for lidocaine allergy was high, a local anesthetic series (Chemotechnique Diagnostics, Malmo, Sweden) was added. Intradermal skin testing to local anesthetics below irritant concentrations was subsequently conducted in lidocaine-positive patients. If negative, a subcutaneous challenge with 1% lidocaine was done. RESULTS: Thirteen of 756 patients patch tested were positive to lidocaine. Seven patients had relevant reactions to over-the-counter products containing lidocaine, 2 reacted to subcutaneous lidocaine, and 4 had incidental findings. There were no patients with positive results to intradermal testing. Three patients had delayed reactions to the subcutaneous challenge. CONCLUSIONS: Patients with positive patch tests to lidocaine and negative results to intradermal testing and subcutaneous challenge may be safe to use lidocaine as an injectable local anesthetic in the future. PMID- 26983092 TI - Lack of Association Between Dust Mite Sensitivity and Atopic Dermatitis. AB - BACKGROUND: Dust mites (DMs) play a role in type I respiratory allergy. Studies relating to DM irritant versus immune reactions are somewhat conflicting in atopic dermatitis (AD). OBJECTIVE: The aim of this study was to assess the diagnostic use of patch testing to DM in patients with AD and other dermatitides. METHODS: We performed a prospective study of 323 adults recruited in a patch testing clinic. Patch testing antigens were DM extract (0.01%, 0.1%, 1%, 10%, and 20% in petrolatum; Chemotechnique) and/or 200 index of reactivity in petrolatum (Stallergenes). Patches were placed and read at 48 hours with delayed readings after 72 to 168 hours. RESULTS: There was no association of DM positivity with AD, asthma, hay fever, or demographic factors. There was no association of DM positivity with the clinical diagnosis or phenotype. The number of positive (+, ++, and +++) and doubtful reactions to Chemotechnique DM extract increased with higher concentrations. Positive reactions to DM had a morphological appearance characterized by numerous discrete erythematous papules and, rarely, papulovesicles. Positive reactions to Stallergenes DM 200 IR were infrequent and all weak reactions, similar to DM 0.01%. CONCLUSIONS: Patch testing to DM does not seem to have clinical use for determining the etiology of dermatitis. PMID- 26983094 TI - When Marking Nut Traveled to Washington, DC. PMID- 26983095 TI - Sea Anemone: A Rare Case of Contact Dermatitis in Italy. PMID- 26983096 TI - Severe Allergic Contact Dermatitis to Dermabond Prineo, a Topical Skin Adhesive of 2-Octyl Cyanoacrylate Increasingly Used in Surgeries to Close Wounds. PMID- 26983097 TI - Everolimus-Induced Symmetrical Drug-Related Intertriginous and Flexural Exanthema (SDRIFE). PMID- 26983098 TI - Visual feature binding in younger and older adults: encoding and suffix interference effects. AB - Three experiments investigated younger (18-25 yrs) and older (70-88 yrs) adults' temporary memory for colour-shape combinations (binding). We focused upon estimating the magnitude of the binding cost for each age group across encoding time (Experiment 1; 900/1500 ms), presentation format (Experiment 2; simultaneous/sequential), and interference (Experiment 3; control/suffix) conditions. In Experiment 1, encoding time did not differentially influence binding in the two age groups. In Experiment 2, younger adults exhibited poorer binding performance with sequential relative to simultaneous presentation, and serial position analyses highlighted a particular age-related difficulty remembering the middle item of a series (for all memory conditions). Experiments 1-3 demonstrated small to medium binding effect sizes in older adults across all encoding conditions, with binding less accurate than shape memory. However, younger adults also displayed negative effects of binding (small to large) in two of the experiments. Even when older adults exhibited a greater suffix interference effect in Experiment 3, this was for all memory types, not just binding. We therefore conclude that there is no consistent evidence for a visual binding deficit in healthy older adults. This relative preservation contrasts with the specific and substantial deficits in visual feature binding found in several recent studies of Alzheimer's disease. PMID- 26983100 TI - [Consider the quality of evidence]. PMID- 26983101 TI - [Consider the quality of evidence - in reply]. PMID- 26983102 TI - [Higher cradiovascular risc with hypomagnesemia]. PMID- 26983099 TI - The Impact of Short-Term Video Games on Performance among Children with Developmental Delays: A Randomized Controlled Trial. AB - This prospective, randomized controlled study investigated the effects of short term interactive video game playing among children with developmental delays participating in traditional rehabilitation treatment at a rehabilitation clinic. One hundred and one boys and 46 girls with a mean age of 5.8 years (range: 3 to 12 years) were enrolled in this study. All patients were confirmed to suffer from developmental delays, and were participating in traditional rehabilitation treatment. Children participated in two periods of 4 weeks each, group A being offered intervention of eight 30-minute sessions of interactive video games in the first period, and group B in the second, in addition to the traditional rehabilitation treatment. The physical, psychosocial, and total health of the children was periodically assessed using the parent-reported Pediatric Quality of Life Inventory-Generic Core Scales (PedsQL); and the children's upper extremity and physical function, transfer and basic mobility, sports and physical functioning, and global functioning were assessed using the Pediatric Outcomes Data Collection Instrument. Parental impact was evaluated using the PedsQL-Family Impact Module for family function, PedsQL-Health Satisfaction questionnaire for parents' satisfaction with their children's care and World Health Organization Quality of Life-Brief Version for quality of life. Compared with the baseline, significant improvements of physical function were observed in both groups (5.6 +/- 19.5, p = 0.013; 4.7 +/- 13.8, p = 0.009) during the intervention periods. No significant improvement of psychosocial health, functional performance, or family impact was observed in children with developmental delays. Short-term interactive video game play in conjunction with traditional rehabilitation treatment improved the physical health of children with developmental delays. TRIAL REGISTRATION: ClinicalTrials.gov NCT02184715. PMID- 26983103 TI - [One pill for all HCV-genotypes?]. PMID- 26983104 TI - [Critically ill patients with high serum lactate have poor prognosis]. PMID- 26983105 TI - [Old and new anticoagulants are similarly effective]. PMID- 26983107 TI - [Palliative and terminal care: doctors have to face the discussion]. PMID- 26983108 TI - [Legal basics in palliative care]. AB - The German legal framework concerning end of life decisions is based on two pillars: the medical standards and the patient's autonomy. Every medical treatment, including life-saving and palliative measures, requires medical indication and, crucially, the patient's consent. Without the patient's consent even medically indicated treatment is prohibited.In other cases, complying with the patient's wishes, doctors have to treat symptoms the best they can. This includes palliative sedation accepting that the indicated medication may shorten life.It is prohibited to actively kill a patient to shorten his suffering. Assisting a suicide is only permitted if the suicide decision is made freely and on the patient's own responsibility. Businesslike suicide assistance is prohibited. PMID- 26983106 TI - [43-year old woman with dizziness and dyspnea]. PMID- 26983110 TI - [Personal and dignified death. The role of pastoral care in palliative medicine]. AB - Palliative pastoral care is not about "adding days to life, but about "adding life to days". It does not matter whether the dying process is short or long. What matters is to ensure the best possible quality of life until the very end through mindful companionship. Palliative pastoral care is a path towards a personal dying, dying where the person is taken seriously as an individual until the last moment. Palliative care includes medical assistance, careful care, psychosocial support, and counselling that addresses the spiritual needs of the dying. This palliative care includes inpatient and outpatient hospice work and accompanies not only the patients but also their relatives. It must become the standard procedure in end of life care. The palliative pastoral care also take the needs of medical staff into account: Time-consuming care for the dying exceeds the staff's time budget. A sudden death can be perceived as traumatic. In this case palliative pastoral care must perform the tasks of crisis management, crisis intervention and de-escalation. The debriefing of involved staff can prevent the development of burn-out syndrome. In the view of holistic healthcare, health insurance funds should co-finance pastoral care. Society and humanity benefit from addressing the needs of the dying. In an economically dominated environment it is a social responsibility to make dying humane. PMID- 26983109 TI - [Advance Care Planning and Decisions to limit treatment at the end of life - the view from medical ethics and psychooncology]. AB - Decisions to limit treatment are important in order to avoid overtreatment at the end of life. They proceed more than half of expected deaths in Europe and the US, but are not always communicated with the patient in advance. One reason for non involvement is that conversations that prepare patients for end-of-life decisions and work out their preferences do not take place on a regular basis. At the same time there is growing evidence that such communication improves patients' quality of life, reduces anxiety and depression and allows patients to develop a realistic understanding of their situation - which in turn is a prerequisite for shared decision making about limiting treatment. In this paper we define "treatment limitation" and explain the medical ethics perspective. The main focus, however, is on the causes that hinder advanced care planning and conversations about limiting treatment in the care of patients with advanced disease. Finally the evidence for approaches to improve the situation is presented with concrete suggestions for solutions. PMID- 26983111 TI - [The role of palliative care]. AB - The aim of palliative care is the improvement of quality of life of patients with life limiting disease and their relatives through symptom control, psychosocial and spiritual care. Thorough assessment, treatment of reversible causes and drug therapy supported by other therapeutic measures are essential for symptom relief. Honest, respectful and empathic communication is crucial for the care of patients. In the terminal phase, symptom control, reduction of unnecessary diagnostic and therapeutic measures, as well as care for the relatives are most important. Palliative care should be provided to all patients with advanced disease irrespective of diagnosis and prognosis. Most patients can be seen in generalist palliative care. Specialist palliative care should be offered to patients with complex symptoms and needs through specialist palliative home care, on palliative care units and hospital support teams. PMID- 26983112 TI - [How to do: Bone marrow biopsy]. AB - Bone marrow examination plays an important role in the diagnosis of hematological and oncological diseases. Confirmation of a leukemia, clarification of cytopenias and risk stratification of a disease are possible indications for a bone marrow puncture.Here we describe, step by step, the workflow, possible pitfalls and complications of this procedere. PMID- 26983113 TI - [A rare cause of severe gastrointestinal bleeding]. AB - Upper gastrointestinal hemorrhage represents a common symptom in the internal medical practice. This Case Report depicts a severe gastrointestinal bleeding from an angiosarcoma that required multiple blood transfusion. As shown in this case, the actual cause may initially remain unclear. Repeated tissue sampling is mandatory to confirm a diagnosis and provide adequate treatment. Primary gastrointestinal angiosarcomas are extremely rare and highly aggressive malignant tumors that tend to grow multifocally and metastasise early. The only curative treatment option is radical surgery, thus an early stage diagnosis is crucial. Palliative care for metastatic angiosarkoma is currently a topic for clinical studies. PMID- 26983114 TI - [Acute rheumatic fever]. AB - We report on a young women with acute rheumatic fever. Acute rheumatic fever has become a rare disease in Germany, especially in adults. This carries the risk that it can be missed in the differential diagnostic considerations of acute rheumatic disorders and febrile status. If rheumatic fever is not diagnosed and treated correctly, there is a considerable risk for rheumatic valvular heart disease. In this article diagnosis, differential diagnosis and therapy of rheumatic fever are discussed extensively. PMID- 26983115 TI - [Nosocomial infections and infections with multidrug-resistant pathogens - frequency and mortality]. AB - There is no agreement about the frequency of nosocomial infections and infections caused by multidrug resistant organisms (MDRO) in Germany. The aim of this review is to generate updated estimates of the national burden of these infections and to discuss them in an international context. The most important sources of this analysis are the data of the national prevalence studies conducted in various European countries and in the U.S. It can be assumed that there are between 400,000 and 600,000 patients with nosocomial infections each year in Germany. The mortality attributable to them is between 6000 and 15,000 patients. About 30,000 to 35,000 patients develop nosocomial infections caused by MDRO. Currently there are no robust data how many patients die each year because of MDRO infections. According to the best available estimate, the annual number may be between 1000 and 4000 cases. The problems of nosocomial infections and the increase of antimicrobial resistance are highly relevant and should not be belittled. However, an overestimation of this dangerous trend may lead to inappropriate use of limited resources. PMID- 26983116 TI - [Is the time ripe for cytosorb]. AB - Hemofiltration with Cytosorb can reduce cytokines in sepsis. Since cytokines are involved in the development of vasodilatatory shock in sepsis, their reduction might improve the chance of survival in this condition. In spite of the CE approval of Cytosorb clinical efficacy has not been proved so far. Other techniques reducing cytokines by direct or indirect manners failed to prove an influence on sepsis mortality. Moreover, the nonspecific elimination of pro- and anti-inflammatory cytokines may result in different clinical effects. Benefits and risks of nonspecific cytokine elimination may be determined by the interaction of pro- and anti-inflammatory cytokines. Therefore, the usefulness of cytokine elimination using Cytosorb cannot be estimated without clinical data. The application of cytosorb in life threatening septic shock should be accompanied by a critical discussion of the limits of these curing trials. PMID- 26983117 TI - [Not Available]. PMID- 26983118 TI - [First Results of the German consulting center for infection control outbreak registry]. AB - BACKGROUND: Outbreaks of infectious diseases and / or colonization pose an increasing burden on hospitals and the health system in general and can be a threat to patient safety. METHODS: At the end of 2013 we implemented a quality assurance registry of outbreak investigations performed by the Deutsches Beratungszentrum fur Hygiene (German Consulting Center for Infection Control and prevention) in Freiburg. Now we analyzed the registered outbreaks until January 2015. RESULTS: Norovirus was the leading causative organism and gram negative bacteria dominated the group of bacterial outbreaks. Outbreaks lasted between 6 and 185 days. 24 % of outbreaks were related to colonization only. Within 29 outbreaks we had 187 infected patients, 50 colonized patients und 92 infected health care workers (64 x norovirus, 20 x influenza, 8 x scabies). No deaths were recorded. Several risk factors and improvement potentials for future outbreaks could be identified. CONCLUSION: Lack of staff compliance with vaccination or prophylactic therapy, misuse of personal protective equipment and lapses in absence from work for the required time can play an important role for prolonged outbreak situations esp. with viral outbreaks and scabies. A structured and goal directed outbreak management especially in the initial phase of an outbreak seems to be important for an efficient and fast termination of an outbreak. PMID- 26983119 TI - [Treatment of coronary three-vessel disease in patients above 75 years]. AB - BACKGROUND: Chronic ischemic heart disease take the first place in cause of death in Germany. The proportion of patients aged 75 years or older amounts more than 80 %. Due to their growing part of population the medical care of older patients becomes increasingly important. In this investigation patients aged >= 75 years with coronary three-vessel disease were characterized and various treatment strategies were compared. PATIENTS AND METHODS: This analysis was retrospective. The data of patients aged 75 years or older with three-vessel disease diagnosed by coronary angiography at the Klinikum Lippe Detmold between 2005 and 2007 were collected. Depending on the received therapy they were parted in three groups: optimal drug therapy (OMT), interventional - (PCI) and surgical revascularization (CABG). Patient characteristics as well as survival- and MACCE-rates during follow up were ascertained. Subgroup analyzes were performed for acute coronary syndrom (ACS) and stable coronary artery disease( CAD). RESULTS: The data of 434 patients with an average age of 79 years were documented. 139 (32.0 %) were assigned to the OMT- 189 (43.6 %) to the PCI- and 106 (24.4 %) to the CABG-group. Overall there was no significant difference between the three groups regarding mortality. In the subgroup of patients wit ACS (n = 180) mortality significantly increased in the OMT-group compared to the two invasive therapies (PCI (p = 0.029), CABG (p = 0.045)). The subgroup of patients with stable CAD showed no significant differences in mortality between the three types of therapy. CONCLUSIONS: Older patients benefit from an interventional or surgical revascularization in the context of ACS. In contrast, in elderly with stable CAD optimal medical therapy provides a reasonable alternative to invasive therapy without increase in mortality. PMID- 26983121 TI - Take, eat! PMID- 26983122 TI - Co-publication of systematic reviews. PMID- 26983120 TI - Murciano-Granadina Goat Performance and Methane Emission after Replacing Barley Grain with Fibrous By-Products. AB - The aim of this experiment was to study the effects of substituting dietary barley grain with orange pulp or soybean hulls on energy, nitrogen and carbon balance, methane emission and milk performance in dairy goats. Twelve Murciano Granadina dairy goats in midlactation were selected and divided into three groups based on similar body weight (42.1 +/- 1.2 kg) and milk yield (2.16 +/- 0.060 kg/goat/day). The experiment was conducted in an incomplete crossover design where one group of four goats was fed a mixed ration of barley grain (BRL), another group of four goats replaced barley grain with orange pulp (OP) and the last group of four goats with soybean hulls (SH). After adaptation to diets, the goats were allocated to individual metabolism cages and intake, faeces, urine and milk were recorded and analysed. Then, gas exchange measurements were recorded by a mobile open-circuit indirect calorimetry system using a head box. Dry matter intake was similar for all three groups (2.03 kg/d, on average). No influence of the diet was observed for energy balance and the efficiency of use of metabolizable energy for milk production was 0.61. The OP and SH diets showed greater (P < 0.05) fat mobilization (-42.8 kJ/kg of BW0.75, on average) than BRL (19.2 kJ/kg of BW0.75). Pentadecanoic acid (15:0) and heptadecanoic acid (17:0) were potential biomarkers of rumen function because the higher contents found in the milk of OP and SH goats than BRL suggest a negative impact of these diets on rumen bacterial metabolism; probably linked to the lower nitrogen supply of diet OP to synthesize microbial protein and greater content of fat in diet SH. Replacement of cereal grain with fibrous by-products did not increased enteric methane emissions (54.7 L/goat per day, on average). Therefore, lactating goats could utilize dry orange pulp and soybean hulls diets with no detrimental effect on milk performance. PMID- 26983123 TI - [Time to change track]. PMID- 26983124 TI - [Not Available]. PMID- 26983125 TI - [Not Available]. PMID- 26983126 TI - [Re: A man in his 60s with acute back pain and kidney failure]. PMID- 26983127 TI - [S. Konradsen and colleagues reply]. PMID- 26983128 TI - [Re: An illogical and unfortunate side effect concept]. PMID- 26983129 TI - [Re: An illogical and unfortunate side effect concept]. PMID- 26983130 TI - [Re: Basic course--only for advanced students?]. PMID- 26983131 TI - [Not Available]. PMID- 26983132 TI - [For a better emergency medical service in Norway]. PMID- 26983133 TI - Same-day discharge after percutaneous coronary intervention. PMID- 26983134 TI - [Clinical withdrawal assessment scale for benzodiazepines now in Norwegian]. PMID- 26983135 TI - [The child on the immigration policy altar?]. PMID- 26983136 TI - [Towards national tests in medical school]. PMID- 26983137 TI - [The future is bright!]. PMID- 26983138 TI - Chronic fatigue syndrome and experience with the Lightning Process. PMID- 26983139 TI - [Prednisolone against myalgic encephalomyelitis/chronic fatigue syndrome?]. PMID- 26983141 TI - [Celiac disease in children--new guidelines]. PMID- 26983140 TI - Serum concentration measurements of addictive drugs. PMID- 26983142 TI - [Proper food is the proper prescription!]. PMID- 26983143 TI - [When the patient has a rare diagnosis]. PMID- 26983144 TI - [Not Available]. PMID- 26983145 TI - Use of forms for follow-up of diabetes in general practice. AB - BACKGROUND: The majority of patients with type 2 diabetes are followed up in general practice. We have investigated whether the use of forms by GPs for recording clinical data contributes to lower mortality and morbidity for this patient group. MATERIAL AND METHOD: This systematic review is based on literature searches in MEDLINE, EMBASE, ISI Web of Science, Cochrane CENTRAL and PubMed. We included studies that 1) dealt with adults over 18 years of age with diabetes who were followed up in the primary health service and 2) compared mortality and morbidity with and without the use of forms. We summarised the results qualitatively and using meta-analyses. RESULTS: Seven studies were included. One study (1262 participants) investigated the effect of the form on hard endpoints, without finding clear effects on mortality (HR 0.91; 95% CI 0.72-1.14), retinopathy (OR 0.90; 95% CI 0.53-1.52), peripheral nerve injury (OR 0.86; 95% CI 0.57-1.29), myocardial infarction (OR 0.65; 95% CI 0.31-1.35) or stroke (OR 0.89; 95% CI 0.39-2.01). Use of forms appears to have little or no effect on body weight (3 studies), and a small, positive effect on blood pressure (5 studies) and total cholesterol (2 studies). INTERPRETATION: Published data at present provide no clear answers, but shows that use of forms in the follow-up of patients with diabetes in general practice may tend to contribute to lower mortality and morbidity. PMID- 26983147 TI - [Avalanche accidents and treatment of avalanche victims]. AB - Avalanches may be provoked spontaneously or as a result of human activity, and they trigger the need for considerable rescue resources. Avalanche search and rescue operations are complex and characterised by physical and mental stress. The guidelines for resuscitation of avalanche victims may be perceived as complex and abstruse, which can lead to suboptimal treatment and an increased strain on rescue teams. The purpose of this article is to summarise the principles for medical treatment of avalanche victims. PMID- 26983146 TI - Risk adjustment in measurements of predicted mortality after myocardial infarction. AB - BACKGROUND: In 2014, the government introduced elements of quality-based funding (pay-for-performance) for the hospital sector. Survival is included as a quality indicator. If such quality indicators are to be used for funding purposes, it must be established that the observed variations are caused by conditions that the hospital trusts are able to influence, and not by any underlying variables. The objective of this study was to investigate how the predicted mortality after myocardial infarction was influenced by various forms of risk adjustment. MATERIAL AND METHOD: Data from the Norwegian Patient Register on 10,717 patients who had been discharged with the diagnosis of myocardial infarction in 2009 were linked to data on socioeconomic status, comorbidity, travel distances and mortality. The predicted 30-day mortality after myocardial infarction was analysed at the hospital-trust level, using three different models for risk adjustment. RESULTS: Unadjusted 30-day mortality was highest in the catchment area of Forde Hospital Trust (12.5%) and lowest in Asker og Baerum (5.2%). Risk adjustment changed the estimates of mortality for many of the hospital trusts. In the model involving the most comprehensive risk adjustment, mortality was highest in the catchment area of Akershus University Hospital (10.9%) and lowest in the catchment areas of Sunnmore Hospital Trust (5.2%) and Nordmore og Romsdal Hospital Trust (5.2%). INTERPRETATION: The variation in treatment quality between the hospital trusts, as measured by predicted mortality after myocardial infarction, is influenced by the methods used for risk adjustment. If the quality based funding scheme is to continue, well-documented models for risk adjustment of the quality indicators need to be established. PMID- 26983148 TI - [Genetically determined variation in bioactivation of tamoxifen and clopidogrel]. PMID- 26983149 TI - ["A most strange instance of illness in several siblings"--first description of a rare neurological disease in 1830?]. AB - Was district medical officer Jensen the first doctor to describe patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN) in Volda in 1830? A case series of four siblings with the same disease written by district medical officer Peter Jensen (1799-1832) in Aalesund in 1830, was published in the Norwegian medical journal Eyr in 1832. The children, who were healthy almost up to school age, developed dystonic involuntary movements and deformities in all extremities, lost their ability to speak and were emaciated before they died at around the age of nine years. Further information about the family and a fifth affected child has been found in the parish records. The clinical picture is consistent with Pantothenate Kinase-Associated Neurodegeneration (PKAN), a rare condition with basal ganglia iron deposition, described in 1922 by the German neuropathologists Julius Hallervorden (1882-1965) and Hugo Spatz (1888-1969). The disease was formerly called Hallervorden-Spatz syndrome, but because of the medical activities undertaken by these two researchers before and during the Second World War, this eponym is no longer recommended. PMID- 26983151 TI - [Trust gained, lost and renewed]. PMID- 26983150 TI - Finn Boe--war, medicine, music. AB - In January 1944 the Norwegian Resistance Movement placed a radio transmitter in the attic of the Department of Obstetrics and Gynaecology, the National Hospital (Rikshospitalet), Oslo. Knut Haugland (1917-2009) used this to send messages to the Norwegian government-in-exile in London. The transmitter was discovered by the Gestapo, and German troops surrounded the building on 1 April 1944. Haugland survived a dramatic escape. While the transmitter was in operation, Haugland lived with senior registrar Finn Boe (1906-70) and his family in a hospital apartment. Boe risked his own life and that of his family to assist during a dramatic phase of the resistance struggle. Boe had completed a focused and purposeful clinical and academic training when he was appointed senior registrar at the Department of Obstetrics and Gynaecology, the National Hospital, in 1943. He was professionally ambitious. His thesis from 1938 was disqualified, but four years later he submitted a new, experimental thesis which he successfully defended in 1945. In 1955, Boe became the first senior consultant at the Department of Obstetrics and Gynaecology at Aker hospital. Under his leadership, it became the largest in the Oslo area, and one of the most active in Norway with regard to science. Several of Boe's own academic works on placental morphology and blood circulation have become classics. Outside of medicine, his great interest was music, and not only as a piano player. He also wrote a book about his fellow townsman Edvard Grieg. PMID- 26983153 TI - [Use of drugs beyond approved indications]. PMID- 26983152 TI - Children in Norway who have no right to medical treatment--do they exist? PMID- 26983154 TI - [Not Available]. PMID- 26983155 TI - [Not Available]. PMID- 26983157 TI - [Not Available]. PMID- 26983158 TI - [Working hours and health is connected]. PMID- 26983160 TI - [Not Available]. PMID- 26983159 TI - First-class training in health care leadership. PMID- 26983161 TI - [Not Available]. PMID- 26983162 TI - [Not Available]. PMID- 26983163 TI - [Not Available]. PMID- 26983165 TI - Photoluminescence of Sinthetic Scapolite Na4Ca4Al6Si9O24 Phosphors Activated with Ce3+ and Tb3+ and Energy Transfer from Ce3+ to Tb3+. AB - Natural scapolite including the S2- impurity is a typical silicate luminescent mineral. According to the formation conditions and chemical composition of natural scapolite, we synthesized Na4 Ca4 Al6 Si9O24 (scapolite) by the high temperature solid-phase reaction, and prepared the synthetic scapolite phosphors activated with Ce3+ and Tb3+. The photoluminescence (PL) properties of the obtained phosphors were studied. The results indicated that the PL intensity of green (545 nm) emission corresponding to the 5D4-->7F5 transition within Tb3+ in the Ce3+, Tb3+-codoped samples was much higher than that of the Tb3+-doped samples. The PL properties of the samples activated with various Ce3+ concentrations were measured, and their fluorescence lifetime and energy transfer mechanism were analyzed. We proved that there was energy transfer from Ce3+ to Tb3+, and the energy transfer efficiency was at its maximum when the Ce3+ to Tb3+ mass ratio was 0.02: 0.03. Upon measurement by chromaticity coordinates, we found that the luminescence of the samples could be adjusted in the green area with varying Ce3+ concentrations. We thus deem that scapolite phosphors Na4Ca4 Al6 Si9 O24:Ce3+, Tb3+ are promising to become the new white LED phosphors. PMID- 26983164 TI - Analgesia in Neurocritical Care: An International Survey and Practice Audit. AB - OBJECTIVE: To characterize analgesic administration in neurocritical care. DESIGN: ICU pharmacy database analgesic delivery audits from five countries. A 31 question analgesic agent survey was constructed, validated, and e-distributed in four countries. SETTING: International multicenter neuro-ICU database audit and electronic survey. PATIENTS: Six ICUs provided individual, anonymized analgesic delivery data in primary neurological diagnosis patients. Prescriber surveys were disseminated by neurocritical care societies. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Analgesic delivery data from 173 patients in French, Canadian, American, and Australian and New Zealand ICUs suggest that acetaminophen/paracetamol is the most common first-line analgesic (49.1% of patients); opiates are the "second line" in 31.5% of patients; however, 33% patients received no second agent. In the 2.3% with demyelinating disease, gabapentin was the most likely second analgesic (50.0%). Third-line analgesics were scarce across sites and neuropathologies. Few national or regional differences were found. The analgesic preference rankings noted by the 95 international physicians who completed the survey matched the audits. However, self-reported analgesic prescription rates were much higher than pharmacy records indicate, with self-reported prescribing of both acetaminophen/paracetamol and opiates in 97% of patients and gabapentin in 45% of patients. Third-line analgesic variability appeared to be driven by neuropathology; ibuprofen was preferred for traumatic brain injury, postcraniotomy, and thromboembolic stroke patients, whereas gabapentin/pregabalin were favored in subarachnoid hemorrhage, intracranial hemorrhage, spine, demyelinating disease, and epileptic patients. CONCLUSIONS: Opiates and acetaminophen are preferred analgesic agents, and gabapentin is a contextual third choice, in neurocritically ill patients. Other agents are rarely prescribed. The discordance in physician self-reports and objective audits suggest that pain management optimization studies are warranted. PMID- 26983169 TI - New venues in STS. PMID- 26983168 TI - Effects of passages through a suitable host of the fungus, Metarhizium anisopliae, on the virulence of acaricide-susceptible and resistant strains of the tick, Rhipicephalus microplus. AB - The aim of this work was to assess the virulence of strain M379 of the fungus, Metarhizium anisopliae (Metchnikoff) Sorokin (Hypocreales: Clavicipitaceae) after different passages through a suitable host and at different concentrations for the control of both acaricide-susceptible and resistant strains of the tick, Rhipicephalus (formerly Boophilus) microplus Canestrini (Ixodida:Ixodidae) in vitro. The highest value of LC50 for the susceptible strain corresponded to zero passage with 7.68 * 107 conidia/ml followed by the fourth passage with 2.68 * 107, which reduced 2.87-fold the lethal concentration. When comparing LC50 values of the fourth vs. the seventh passage (2.59 * 105 conidia/ml), the lethal concentration was reduced 103.47-fold by the seventh passage. In addition, in the resistant strain the LC50 highest value corresponded to zero passage with 4.95 * 107 conidia/ml followed by the fourth passage with 7.86 * 106, which reduced 6.30 fold the lethal concentration. When comparing LC50 values of the fourth vs. the seventh passage (1.04 * 105 conidia/ml) in the resistant strain, the lethal concentration was reduced 75.58-fold by the seventh passage. These results suggest that the number of passages on M. anisopliae through a suitable host increased its virulence on both R. microplus strains. When comparing LC50 of the zero passage through a suitable host of both acaricide-susceptible and resistant strains, the highest LC50 values corresponded to the susceptible strain with 7.68 * 107 conidia/ml followed by the resistant one with 4.95 * 107, showing that on the resistant strain the lethal concentration is reduced by 1.55-fold. When comparing the fourth passage, the highest values of LC50 corresponded to the susceptible strain with 2.68 x 107 conidia/ml followed by the resistant one with 7.86 * 106 conidia/ml, showing for the resistant strain a 3.41-fold reduced lethal concentration. Moreover, when comparing the seventh passages, the highest values of LC50 corresponded to the susceptible strain with 2.59 * 105 followed by the resistant with 1.04 * 105 conidia/ml, revealing for the resistant strain a 2.49-fold reduced lethal concentration. These results suggest that the resistant strain needs a lower concentration of conidia than the susceptible strain. In this case, the acaricide-resistant strain is more susceptible to M. anisopliae of zero- and seven-passage strains. PMID- 26983170 TI - Constructing failure in big biology: The socio-technical anatomy of Japan's Protein 3000 Project. AB - This study focuses on the 5-year Protein 3000 Project launched in 2002, the largest biological project in Japan. The project aimed to overcome Japan's alleged failure to contribute fully to the Human Genome Project, by determining 3000 protein structures, 30 percent of the global target. Despite its achievement of this goal, the project was fiercely criticized in various sectors of society and was often branded an awkward failure. This article tries to solve the mystery of why such failure discourse was prevalent. Three explanatory factors are offered: first, because some goals were excluded during project development, there was a dynamic of failed expectations; second, structural genomics, while promoting collaboration with the international community, became an 'anti boundary object', only the absence of which bound heterogeneous domestic actors; third, there developed an urgent sense of international competition in order to obtain patents on such structural information. PMID- 26983171 TI - The anxious production of beauty: Unruly bodies, surgical anxiety and invisible care. AB - This study is based on ethnographic fieldwork at a plastic surgery clinic in Seoul, South Korea. Examining the three phases of plastic--consultation, operation and recovery--I show how surgeons work to shape not only patients' bodies but also expectations and satisfaction. Surgeons do so in part to assuage their own anxieties, which arise from the possibility of misaligned beauty standards and unforeseen anatomies, as well as the possible dissatisfaction of the patient. I offer the concept of 'surgical anxiety', which occurs in relation to inherently unruly patient bodies in which worries, fear, frustration, self pity, cynicism, anger and even loneliness are symptomatic. The unpredictability and uncontrollability of patients' bodies, which generates anxiety for both patients and surgeons, work to constrain the power of plastic surgery and making it inherently vulnerable. This study also pays attention to the invisible work of taking care of surgical anxiety, as practised by female staff members, and surgeons' dependence on these workers. My focus on anxiety is a kind of remedy for the predominant concern with 'ambivalence' in constructivist science and technology studies; rather than continue to highlight the power differentials between experts/practitioners and lay people/patients, this study illuminates surgical anxiety as their shared vulnerability. Thus, this study proposes a new politics of care in technoscience and medicine, which begins with anxiety. PMID- 26983172 TI - Controlled human malaria infection trials: How tandems of trust and control construct scientific knowledge. AB - Controlled human malaria infections are clinical trials in which healthy volunteers are deliberately infected with malaria under controlled conditions. Controlled human malaria infections are complex clinical trials: many different groups and institutions are involved, and several complex technologies are required to function together. This functioning together of technologies, people, and institutions is under special pressure because of potential risks to the volunteers. In this article, the authors use controlled human malaria infections as a strategic research site to study the use of control, the role of trust, and the interactions between trust and control in the construction of scientific knowledge. The authors argue that tandems of trust and control play a central role in the successful execution of clinical trials and the construction of scientific knowledge. More specifically, two aspects of tandems of trust and control will be highlighted: tandems are sites where trust and control coproduce each other, and tandems link the personal, the technical, and the institutional domains. Understanding tandems of trust and control results in setting some agendas for both clinical trial research and science and technology studies. PMID- 26983173 TI - Trust, regulatory processes and NICE decision-making: Appraising cost effectiveness models through appraising people and systems. AB - This article presents an ethnographic study of regulatory decision-making regarding the cost-effectiveness of expensive medicines at the National Institute for Health and Care Excellence (NICE) in England. We explored trust as one important mechanism by which problems of complexity and uncertainty were resolved. Existing studies note the salience of trust for regulatory decisions, by which the appraisal of people becomes a proxy for appraising technologies themselves. Although such (dis)trust in manufacturers was one important influence, we describe a more intricate web of (dis)trust relations also involving various expert advisors, fellow committee members and committee Chairs. Within these complex chains of relations, we found examples of both more blind acquiescent and more critical-Investigative forms of trust as well as, at times, pronounced distrust. Difficulties in overcoming uncertainty through other means obliged trust in some contexts, although not in others. (Dis)trust was constructed through inferences involving abstract systems alongside actors' oral and written presentations-of-self. Systemic features and 'forced options' to trust indicate potential insidious processes of regulatory capture. PMID- 26983176 TI - Quotas for alternative modalities? Maybe. PMID- 26983174 TI - The pluralization of the international: Resistance and alter-standardization in regenerative stem cell medicine. AB - The article explores the formation of an international politics of resistance and 'alterstandardization' in regenerative stem cell medicine. The absence of internationally harmonized regulatory frameworks in the clinical stem cell field and the presence of lucrative business opportunities have resulted in the formation of transnational networks adopting alternative research standards and practices. These oppose, as a universal global standard, strict evidence-based medicine clinical research protocols as defined by scientists and regulatory agencies in highly developed countries. The emergence of transnational spaces of alter-standardization is closely linked to scientific advances in rapidly developing countries such as China and India, but calls for more flexible regulatory frameworks, and the legitimization of experimental for-profit applications outside of evidence-based medical care, are emerging increasingly also within more stringently regulated countries, such as the United States and countries in the European Union. We can observe, then, a trend toward the pluralization of the standards, practices, and concepts in the stem cell field. PMID- 26983175 TI - The symbolic economy of drugs. AB - This essay reviews four recent studies representing a new direction in the history of pharmaceuticals and pharmaceutical science. To this end, it introduces the notion of a symbolic economy of drugs, defined as the production, circulation, and reception of signs that convey information about drugs and establish trust in them. Each of the studies under review focuses on one key signifier in this symbolic economy, namely the brand, the patent, the clinical trial, and the drug itself. Drawing on Pierre Bourdieu's theory of the economy of symbolic goods, I conceptualize these signifiers as symbolic assets, that is, as instruments of communication and credit, delivering knowledge, carrying value, and producing authority. The notion of a symbolic economy is offered with a threefold intention. First, I introduce it in order to highlight the implications of historical and anthropological work for a broader theory of the economy of drugs, thus suggesting a language for interdisciplinary conversations in the study of pharmaceuticals. Second, I deploy it in an attempt to emphasize the contributions of the recent scholarship on drugs to a critical understanding of our own contemporary ways of organizing access to drugs and information about drugs. Finally, I suggest ways in which it might be of use to scholars of other commodities and technologies. PMID- 26983177 TI - Clinicians, payers at odds on CKD identification, management, and prevention. PMID- 26983178 TI - Progress in kidney transplantation: Three recommendations. PMID- 26983179 TI - Using a transitional start dialysis unit to improve modality selection. PMID- 26983180 TI - Answer all the questions when bringing dialysis home. PMID- 26983181 TI - Technology for new home dialysis machines emphasizing simplicity, connectivity. PMID- 26983182 TI - Improving kidney care for residents in nursing facilities: a national model. AB - The RRC Staff Assisted Home Hemodialysis Program started in September 2013 with the target of improving care for the frail elderly residents in skilled facilities by offering hemodialysis in their home setting. Residents all receive short time, frequent dialysis. The residents no longer need to be transported to a local dialysis center three times per week in all types of weather and subject to long waits by the transport company. In addition, Medicare/Medicaid save significant dollars on transportation expenses. Residents needing rehabilitation services can receive their therapy while their dialysis schedule is adjusted around the resident's therapy. Residents no longer miss meals and medications or family visits. Collaboration between RRC and the skilled facility is patient centric whereby the care of each patient is consistent and individualized. The most meaningful measure of the success of this program is the residents themselves. They have self-reported how much better they feel with more energy. The residents can increase their socialization activities within the skilled facility. The dietitians report that the residents are eating better because there are fewer restrictions on foods and fluids. PMID- 26983183 TI - NKF finalizes update for adequacy guidelines. PMID- 26983184 TI - [Epidemiology, morbidity, mortality, cost to society and the individual, and main causes for falls]. AB - Falls are the leading cause of accidental death among the elderly, accounting for about 12 000 deaths per year. The risk of falls increases with age: one-third of subjects over 65 years old living in the community and half of those over 85 fall at least once a year. Despite their frequency, falls should not be trivialized, as they are associated with significant morbidity and care expenditure: 10% of falls have severe traumatic consequences, and30 % of hospital admissions for traumatic injury among elderly individuals are due to falls. Even when they have no physical repercussions, falls can have psychological effects (anxiety while walking, fear of falling), and can be complicated by a psychomotor disadaptation syndrome with voluntary restriction of activities of daily living in 30% of cases. Risk factors for falls are numerous, and falls are rarely due a single, precise reason. Recurrent falls are associated with balance and gait impairment and decreased muscle strength, sometimes due to a latent pathological condition. Factors that may favor falls in the home must be taken into account through targeted prevention actions. Among institutionalized populations, the risk of falls increases with the severity of dementia, the use of certain drugs (particularly psycho tropics) and the existence of wasting, which leads to a decline in quadriceps strength. About 1.5% of all health expenditure is related to falls. The majority of these costs are due to hospitalization, fractures of the proximal femur being the most costly complication. In recent years, thanks to the prevention of both osteoporosis and falls, the annual number of hip fractures has been stable at about 79,500 cases per year, standardized hospitalization rates have declined, and the average length of stay has decreased. With the increasing number of elderly people, one priority to reduce healthcare costs is to identify and correct factors of frailty in midlife, using a preventive approach. PMID- 26983185 TI - [Neurologic examination of the patient who has fallen and of the patient who has not yet fallen but is aging]. PMID- 26983186 TI - [Can falls be prevented?]. AB - Most recommendations and measures intended to prevent falls focus on the elderly (see HAS guideline of April 2009) but, in our opinion, this isfar too late: prevention must begin much earlier, not only by identifying persons at risk, but also by providing personalized lifestyle advice adapted to each individual's biomechanical, somatic, neurological and biological characteristics. The first preventive measure is to identify a possible deterioration of balance, starting with a physical examination at the age of 45 and repeated regularly throughout life. Extrinsic preventive measures focusing on the domestic and external environments are clearly necessary. But what is most important is to detect and, if necessary, correct any degradation of intrinsic (intracorporeal or somatic) factors starting at the age of 45 years; these include vision, vestibular function and balance, proprioception, and psychological and neurological status. Chronic illnesses and their treatments must also be taken into account: treatment must be limited to indispensable drugs; sedative psychotropics must be avoided if possible; and polymedication must be tightly controlled, as it is a major risk factor for falls. Prevention also requires a diet sufficiently rich in protein, calcium and vitamin D3 (to prevent osteoporosis), and regular daily exercise adapted to the individual, if possible associated with a simultaneous cognitive task. The last key point is the absolute need for thorough functional rehabilitation after any accidental or medical trauma, regardless of age, with the aim of restoring functional status to that existing prior to the accident. PMID- 26983187 TI - [Hereditary porphyrias and heme related disorders]. AB - Hereditary porphyrias comprise a group of eight metabolic disorders of the haem biosynthesis pathway, characterised by acute neurovisceral symptoms and/or skin lesions. Each porphyria is caused by abnormal functioning of a particular enzymatic step, resulting in specific accumulation of heme precursors. Seven porphyrias are due to a partial enzyme deficiency, while a gain-of-function mechanism has recently been identify in a novel porphyria. Acute porphyrias present with severe abdominal pain, nausea, constipation and confusion, and are sometimes complicated by seizures and severe neurological disorders, which may be life-threatening. Cutaneous porphyrias can also be present, with either acute painful photosensitivity or skin fragility and blisters. Rare recessive porphyrias usually manifest in early childhood with either severe chronic neurological symptoms or chronic haemolysis and severe cutaneous photosensitivity. Porphyrias are still under-diagnosed, but recent advances in the pathogenesis and genetics of human porphyrias are leading to better care of these patients and their families. PMID- 26983188 TI - [The eyes of the labyrinth]. AB - Reliable knowledge of one's space is a prerequisite for effective action, and only sensory experience, although not alone sufficient, can provide access to knowledge of reality. All the diferent sensory modalities help to make sense of this mental construct, but visual information, when available, is predominant. This requires stable images and constant updating of one's awareness of gaze direction and position in space at the moment of acquisition. The vestibular system is sensitive to angular and linear accelerations and thus acts as a reference for stability--an inertial base which stabilizes and characterizes the gaze direction and encodes the subject's movement tracking. In clinical practice, loss of these capacities induces eye drift, nystagmus, oscillopsia, vertical eye misalignment and a shift in the representation of mental space, leading to dizziness, translational illusions, integration path error, and "senseless" perceptions of the self in space. The reaction time of the eye and of mental image stabilization is of the order of afew tens of milliseconds. Recent tools for vestibular exploration allow us to measure this reactivity, which is a determining factor for quality of life. The video head impulse test, dynamic visual acuity, and cervical vestibular evoked myogenic potentials explore the structures involved in gaze and image stabilization, while subjective visual vertical and ocular vestibular evoked myogenic potentials provide an approach to the utricular contribution. This clinical and instrumental semiology sometimes proves more sensitive than the most advanced and accurate medical imaging methods, but rational listening and multidisciplinary skills on the part of the physician remain necessary to identify "self in space perceptual alterations. PMID- 26983189 TI - [Olfaction: from nose to cortex]. AB - Olfactory physiology involves four main steps: nasal airflow perireceptor events, transduction, and central olfaction. Complex and diverse physiological processes are involved at each step and may be undermined by numerous pathological processes. Nasal airflow physiology involves fluid mechanics and specifc physicochemical properties of odorants; its main pathology is nasal polyposis. Perireceptor events involve transport molecules and enzymes which eliminate xenobiotics; its main pathology is chronic rhinitis. Transduction is the role of primary olfactory neurons, which detect and discriminate various chemical molecules across a wide range of concentrations. To fulfill this task, these cells use a large family of G protein-coupled receptors (odorant receptors). The main pathology is acute viral rhinitis affecting the olfactory organ. Finally, after olfactory signals are generated, the information is processed and coded in the olfactory bulb before being disseminated to several areas of the brain; its pathology is dominated by neurodegenerative disorders. PMID- 26983190 TI - [Non elective cesarean section: use of a color code to optimize management of obstetric emergencies]. AB - The medical team of the Croix Rousse teaching hospital maternity unit has developed, over the last ten years, a set of procedures designed to respond to various emergency situations necessitating Caesarean section. Using the Lucas classification, we have defined as precisely as possible the degree of urgency of Caesarian sections. We have established specific protocols for the implementation of urgent and very urgent Caesarean section and have chosen a simple means to convey the degree of urgency to all team members, namely a color code system (red, orange and green). We have set time goals from decision to delivery: 15 minutes for the red code and 30 minutes for the orange code. The results seem very positive: The frequency of urgent and very urgent Caesareans has fallen over time, from 6.1 % to 1.6% in 2013. The average time from decision to delivery is 11 minutes for code red Caesareans and 21 minutes for code orange Caesareans. These time goals are now achieved in 95% of cases. Organizational and anesthetic difficulties are the main causes of delays. The indications for red and orange code Caesarians are appropriate more than two times out of three. Perinatal outcomes are generally favorable, code red Caesarians being life-saving in 15% of cases. No increase in maternal complications has been observed. In sum: Each obstetric department should have its own protocols for handling urgent and very urgent Caesarean sections. Continuous monitoring of their implementation, relevance and results should be conducted Management of extreme urgency must be integrated into the management of patients with identified risks (scarred uterus and twin pregnancies for example), and also in structures without medical facilities (birthing centers). Obstetric teams must keep in mind that implementation of these protocols in no way dispenses with close monitoring of labour. PMID- 26983191 TI - [Vitamin B12 and related genetic disorders]. AB - Vitamin B12 (B12, cobalamin (Cbl)) is a water-soluble vitamin that requires complex mechanisms for its assimilation, blood transport and intracellular metabolism. Three proteins, intrinsic factor (IF), haptocorrin (HC), and transcobalamin (TC), and their specific receptors are involved in B12 absorption and transport. Acquired and inherited deficiencies can result in megaloblastic anemia and neurological manifestations. Several genetic diseases are linked to these two steps, namely inherited deficits in FI and TC, and Imerslund-Grasbeck disease. In mammalian cells, only two enzymes depend on vitamin B12: L methylmalonyl-CoA mutase (EC 5.4.99.2) in mitochondria, and methionine synthase (EC 2.1.1.13) in cytoplasm. Direct metabolic consequences of impaired B12 absorption and metabolism are the accumulation of methylmalonic acid (MMA) and of homocysteine (HCy), respectively. More than a dozen genes are involved in the intracellular metabolism of B12, and their defects result in several diseases designated cblA through cblJ This article reviews the steps involved in vitamin B12 absorption, transport and intracellular metabolism, and the main related genetic defects. PMID- 26983192 TI - [Application of cytometric bead array in rapid high-throughput detection of small molecules]. AB - Cytometric bead array (CBA) is a new analytical technique, which can achieve real time and rapid detection of targeted components in a small amount of sample. With many advantages of high throughput screening, high specificity and sensitivity, low cost, easy operation and good repeatability, this CBA technique has been widely used for the detection of various components in foods, agricultural products and environmental samples. Recently, it has got significant development in rapid detection of small molecules. This review briefly introduced the theory of CBA technique, summarized the application in the analysis of small molecules, such as mycotoxins, pesticide residues, shellfish toxins, and then prospected the application of trace small molecules detection in the complex matrices of traditional Chinese medicine and the development trend of it. PMID- 26983193 TI - [Interaction between CYP450 enzymes and metabolism of traditional Chinese medicine as well as enzyme activity assay]. AB - Drugs are exogenous compounds for human bodies, and will be metabolized by many enzymes after administration. CYP450 enzyme, as a major metabolic enzyme, is an important phase I drug metabolizing enzyme. In human bodies, about 75% of drug metabolism is conducted by CYP450 enzymes, and CYP450 enzymes is the key factor for drug interactions between traditional Chinese medicine( TCM) -TCM, TCM medicine and other drug combination. In order to make clear the interaction between metabolic enzymes and TCM metabolism, we generally chose the enzymatic activity as an evaluation index. That is to say, the enhancement or reduction of CYP450 enzyme activity was used to infer the inducing or inhibitory effect of active ingredients and extracts of traditional Chinese medicine on enzymes. At present, the common method for measuring metabolic enzyme activity is Cocktail probe drugs, and it is the key to select the suitable probe substrates. This is of great significance for study drug's absorption, distribution, metabolism and excretion (ADME) process in organisms. The study focuses on the interaction between TCMs, active ingredients, herbal extracts, cocktail probe substrates as well as CYP450 enzymes, in order to guide future studies. PMID- 26983194 TI - [Advances in research of pharmacological effects and formulation studies of linalool]. AB - Linalool, as a major volatile compound, is widely distributed in natural plant essential oil. In addition, it can also be artificially synthesized. Linalool is used frequently as an important ingredient of perfumes and household detergents. It is still employed in food flavor and industries. Besides, linalool has some positive effect on healthcare. Many studies have showed that linalool exhibited a variety of pharmacological activities, including analgesic, anxiolytic, sedative, anti-inflammatory, anti-tumor and anti-bacterial effects. Therefore, linalool will be a promising agent for clinical application. This article reviews the pharmacological effects and formulation studies of linalool so as to provide a theoretical basis for its further development and utilization. PMID- 26983195 TI - [Research status on regulation of Chinese herbal compound on intestinal microecology]. AB - The ralationship between traditional Chinese medicine (TCM) and intestinal microecology is increasingly being given more and more attention. Combined with the devolopment of intestinal microecology disciplines, effects of TCM on regulation of intestinal microecology have been gradually explained. Both clinical studies and animal experiments have confirmed that TCM can maintain the balance of intestinal microecology and regulate the intestinal flora. The author arrangemented the documents related to Chinese herbal compound adjusting intestinal flora in the recent ten years, summarized that the Chinese herbal compound which can strength spleen and replenish Qi, relax bowels and regulate Qi, dissipate dampness and check diarrhea, clear away heat and toxic materials, promote digestion and relieve stasis had certain regulation effects on intestinal microecology, providing basis for revealing the TCM essence of intestinal microecology. PMID- 26983196 TI - [Study on standard of safe application of thiamethoxam on GAP of Lonicera japonica]. AB - The paper is aimed to establish a method of residue analysis for thiamethoxam and to study its degradation dynamic and final residue and its standard of safe application of thiamethoxam on Lonicera japonica. Samples extracted with methanol by ultrasonication were purified with dichloromethane by liquid-liquid extraction and SPE column and analysed by HPLC-UV. The results showed that average rate was 84.91%-94.44% and RSD 1.74%-4.96% with addition of thiamethoxam in respectively diverse concentration, which meets inspection requirement of pesticide residue. Two kinds of dosages of thiamethoxam were treated- varying from recommended dosage (90 g x hm(-2)) to high dosage (135 g x hm(-2)), Results of two years test showed that thiamethoxam was degraded more than 90% seven days after application and the half - life period of thiamethoxam was 1.54-1.66 d. The digestion rate of thiamethoxam was fast in the L. japonica. The recommended MRL of thiamethoxam in the L. japonica is 0.1 mg x kg(-1), the dosage of 25% thiamethoxam WDG from 90 135 g x hm(-2) is sprayed less than three times a year on L. japonica and 14 days is proposed for the safety interval of the last pesticide application's and harvest's date. PMID- 26983197 TI - [Effects of P and K fertilizer on content of coumarin and yield of Glehnia littoralis]. AB - By a orthogonal experiment, the influence of different ratio of phosphorus and potassium fertilizers on imperatorin, isoimperatorin and psoralen contents and yield of Glehnia littoralis were studied. The results showed that root dry weight and the yield of G. littoralis increased when reasonably applied phosphorus fertilizer combined with potassium fertilizer within a certain range. And the influence of phosphorus fertilizer was greater than that of potassium fertilizer. The optimal value of root dry weight and yield achieved at both P2O5 360 kg x hm( 2), K2O 270 kg x hm(-2) and P2O5 360 kg x hm(-2), K2O 180 kg x hm(-2). The effects of different phosphorus and potassium treatments on the content of imperatorin, isoimperatorin and psoralen in G. littoralis were determined, which shows that the content increased with the moderate increase of phosphorus and potassium. And the effects of phosphorus fertilizer were more significantly. The isoimperatorin content achieved the largest value at P2O5 360 kg x hm(-2), K2O 270 kg x hm(-2), also a larger content of imperatorin and psoralen. The imperatorin content is the largest when applied P2O5 360 kg x hm(-2), K2O 180 kg x hm(-2), and the isoimperatorin content was higher as well. So that the treatment of P2O5 360 kg x hm(-2), K2O 180 kg x hm(-2) are suitable for promote to the agricultural production, which could improve the quality and yield of G. littoralis. PMID- 26983198 TI - [Study on suitable harvest time of Dendrobium officinale in Yunnan province]. AB - In order to determine the suitable harvest time of Dendrobium officinale from different regions in Yunnan province, the drying rate, mannose and glucose peak area ratio, extract, contents of polysaccharide and mannose of D. officinale samples collected from six producing areas in Ynnnan province were determined. The results indicate that drying rate and the contents of polysaccharide and mannose arrived the peak from January to April, extract reached a higher content from September to December, and mannose and glucose peak area ratio from October to February of the coming met the requirment of the Chinese Pharmacopoeia. Hence, the suitable harvesting time of D. officinale in Yunnan province is from December to February of the coming year,according to the experimental results and the request of the Chinese Pharmacopoeia. PMID- 26983199 TI - [Effect of salicylic acid on photosynthesis, physio-biochemistry and quality of Panax ginseng under full sun shine in spring]. AB - In order to search for a new pathway to improve the yield of ginseng through growing at the full sun shine accompanied by salicylic acid (SA), the net photosynthetic rate (P(n)), superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), malondialdehyde (MDA) in Panax ginseng leaves, and the content of ginsenosides in roots were compared under various concentrations of SA and full sun shine with the traditional shade shed. Under the full sun shine, 0.05, 0.2 mmol x L(-1) SA increased net photosynthetic rate to a great extent. Under the cloudy day, the average net photosynthetic rate increased by 127.8% and 155.0% over the traditional shade shed, 13.9% and 27.5% over the treatment without SA respectively; under the clear day, 23.5% and 30.4% over the traditional shade shed, 8.6% and 14.6% over the treatment without SA, particularly obvious in the morning and late afternoon. With such concentration, SA increased activities of SOD, CAT, POD, and decreased the contents of the MDA. This difference resulted from different light intensity, rise of light saturation point, and fall of compensation point. Full sun shine decreased ginsenosides contents, but with SA, the ginsenosides regained, the content of Rg1 and Re, Rb1, total six types of ginsenosides in SA 0.2 mmol x L(-1) group were higher than those in the control group (P < 0.05) and other groups. The application of 0.2 mmol x L(-1) SA under full sun shine during a short time has little threat to the P. ginseng in spring, and could enhance the resistance to the adversity, which would improve the yield of ginseng heavily. PMID- 26983200 TI - [Study on identification of traditional Chinese medicine Yangqishi and Yinqishi by X-ray diffraction]. AB - The aim of this paper is to clarify the mineral origin of traditional Chinese medicine (TCM) Yangqishi and Yinqishi and guide identification of the both, by X ray diffraction (XRD) Fourier patterns. Morphological identification and conventional physical and chemical analysis wee used to identify 22 batches of Yangqishi and Yinqishi. It used XRD Fourier patterns which has been collected from sample powders to analyze phase composition. It has been found experimentally that the mineral origin of Yinqishi is Talc schist and the mineral origin of Yangqishi is tremolite and actinolite. The results also showed that the method using XRD can get not only an accurate but also rapid identification of Yangqishi and Yinqishi. There are many differences in medicinal properties, efficacy, indications and composition of Yangqishi and Yinqishi, so be careful not to mix them up. PMID- 26983201 TI - [Study on exogenous hormones inducing parthenocarpy fruit growth and development and quality of Siraitia grosvenorii]. AB - To explore the growth and development and analyze the quality of the parthenocarpy fruit induced by exogenous hormones of Siraitia grosvenorii. the horizontal and vertical diameter, volume of the fruit were respectively measured by morphological and the content of endogenous hormones were determined by ELISA. The size and seed and content of mogrosides of mature fruit were determined. The results showed that the fruit of parthenocarpy was seedless and its growth and development is similar to the diploid fruit by hand pollination and triploid fruit by hand pollination or hormones. But the absolute value of horizontal and vertical diameter, volume of parthenocarpy fruit was less than those of fruit by hand pollination, while triploid was opposite. The content of IAA, ABA and ratio of ABA/GA was obviously wavy. At 0-30 d the content of IAA and ABA of parthenocarpy fruit first reduced then increased, content of IAA and GA parthenocarpy fruit was higher than that of fruit by hand pollination. Mogrosides of parthenocarpy fruit was close to pollination fruit. Hormones can induce S. grosvenorii parthenocarpy to get seedless fruit and the fruit shape and size and quality is close to normal diploid fruit by hand pollination and better than triploid fruit by hormone or hand pollination. PMID- 26983203 TI - [Preparation and stability of beta-carotene loaded using mesoporous silica nanoparticles as carriers system]. AB - 1,3,5-Trimethylbenzene (1,3,5-TMB) was used as the pore-enlarging modifier to expand the pore size of MCM-41 (mobil company of matter) mesoporous silica nanoparticles. The solvent impregnation method was adopted to assemble non-water soluble beta-carotene into the pore channel of MCM-41. The MCM-41 and drug assemblies were characterized by TEM, FT-IR, elemental analysis and N2 adsorption desorption. The results showed that MCM-41 has good sphericity and regular pore structure. The research also investigated the optimal loading time, the drug loading and the vitro stability of the beta-carotene. As a drug carrier, the modified MCM-41 showing a shorter drug loading time, the drug loading as high as 85.58% and the stability of beta-carotene in drug assemblies has improved. The study of this new formulation provides a new way for beta-carotene application. PMID- 26983202 TI - [Identification of Bletillae Rhizoma and its adulterants by SNPs in ITS2]. AB - To establish a molecular identification method for Bletillae Rhizoma, this paper extracted genome DNA from Bletillae Rhizoma and its adulterants. The sequences of rDNA ITS2 were sequenced after amplifying. Then multiple alignments of ITS2 were constructed phylogenetic tree with Neighbor Joining by MEGA 5. 1 and found out SNPs loci. The result showed that rDNA ITS2 region could identify Bletillae Rhizoma and its adulterants. There existed the SNPs loci, which could identify Bletilla striata and B. ochracea. Furthermore, we designed specific primers against the SNPs loci of B. striata and B. ochracea, then screened primers and optimized the PCR amplification conditions. Finally, the DNA of B. striata and B. ochracea were specifically amplified by BJ59-412F, BJ59-412R and HHBJ-225R. The length of amplification products were respectively about 350 bp and 520 bp that were effectively identified of B. striata and B. ochracea. While, the adulterants of Bletillae Rhizoma were no-reaction occurring. To sum up, the amplification conditions of the primers can identify B. striata, B. ochracea and their adulterants successfully at the same time. This method was easy, time-saving, and reliable, which can be used as a rapid method for molecular identification of Bletillae Rhizoma. PMID- 26983204 TI - [Optimization of spraying dry technology of Biqiu ranules ethanol extract by Box Behnken response surface method]. AB - With inlet temperature, specific gravity, feeding speed as independent variables, the comprehensive evaluating indexes of content of schisandrin and arctiin as dependent variable, the experimental data were fitted to a second order polynomial equation. Based on establishing the mathematical relationship between the comprehensive evaluating indexes and respective variables, Box-Benhnken central composite test and response surface analysis method was employed to optimize the spray drying technology of Biqiu granules ethanol extract. The optimal drying parameter was as follows: the inlet temperature was 175 degrees C, the specific gravity was 1.10, feeding speed was 32 r x min(-1). Under these conditions, the comprehensive evaluating indexes of spraying dry processes was 92.68, which was close to the model prediction. The spraying dry technology of Biqiu granules ethanol extract optimized by response surface methodology was accurate and feasible, which provided theoretical experiment basis for the industrialization production. PMID- 26983205 TI - [Optimization of extraction technology for salidroside, tyrosol, crenulatin and gallic acid in Rhodiolae Crenulatae Radix et Rhizoma with orthogonal test]. AB - The extracting technology of salidroside, tyrosol, crenulatin and gallic acid from Rhodiolae Crenulatae Radix et Rhizoma was optimized. With extraction rate of salidroside, tyrosol, crenulatin and gallic acid as indexes, orthogonal test was used to evaluate effect of 4 factors on extracting technology, including concentration of solvent, the dosage of solvent, duration of extraction, and frequency of extraction. The results showed that, the best extracting technology was to extract in 70% alcohol with 8 times the weight of herbal medicine for 2 times, with 3 hours once. High extraction rate of salidroside, tyrosol, crenulatin and gallic acid were obtained with the present technology. The extracting technology was stable and feasible with high extraction rate of four compounds from Rhodiolae Crenulatae Radix et Rhizoma, it was suitable for industrial production. PMID- 26983207 TI - [Chemical constituents from Cinnamomum cassia]. AB - Various column chromatography, such as silica gel, Sephadex LH-20, ODS, and semi preparative HPLC was used to isolate and purify the chemical constituents from Cinnamomum cassia. The structures were determined on the basis of NMR and MS spectral data analysis, together with the comparison with literature data. Fifteen compounds were isolated from the 85% aqueous ethanol extract of C. cassia, and their structures were identified as (2R, 3R)-5,7,3',4' tetramethoxyflavan-3-ol( 1), (2R, 3R)-5,7-dimethoxy-3',4'-methylenedioxyflavan-3 ol (2), coumarin (3), cinnamic acid (4), (E)-2-hydroxy-phenylpropionic acid cinnamoyl ester (5), 3, 3', 4, 4'-tetrahydroxy biphenyl (6), methylstictic acid (7), epi-boscialin (8), (1R,2S,3S,4S)-2,3-epoxy-1, 4-dihydroxy-5-methyl-5 cyelohexene (9), 4,5-dihydroxy-3-methyl cyclohex-2-enone (10), cis-4 hydroxymellein (11), and 2-hydroxy-4-methoxyl-cinnamaldehyde (12). Compounds 5-11 were obtained from this genus plants for the first time. PMID- 26983206 TI - [Studies on coumarins from fruit of Cnidium monnieri and their cytotoxic activities]. AB - This study is to study is to investigate the coumarins from Fruit of Cnidium monnieri and their cytotoxic activities. The constituents were separated by column chromatography, and their structures were elucidated by spectroscopic data analyses. The isolated compounds were evaluated for their cytoxic activities by MTT method. Eleven compounds were isolated and identified as osthole (1), bergaptan (2), xanthotoxol (3), xanthotoxin (4), imperatorin (5), isopimpinellin (6), osthenol (7), psoralen (8), 5,7-dimethoxycoumarin (9), oxypeucedaninhydrate (10), and swietenocoumarin F (11). Compounds 7, 9-11 were isolated from the Cnidium genus for the first time. Compounds 1,5,10 and 11 showed significant cytotoxic activities against L1210 cell lines at a concentration of 1 x 10(-5) mol x L(-1) with inhibitory rates of were 70.13, 63.10, 55.77, and 75.08% respectively. PMID- 26983208 TI - [Chemical constituents of Swertia angustifolia]. AB - This present work is to study the chemical constituents of Swertia angustifolia. The whole plants of air-dried Swertia angustifolia was extracted with 90% EtOH. The water extract was suspended in H2O and extracted with petroleum ether, EtOAc and nBuOH, successively. The compounds were isolated and purified by column chromatography from the EtOAc fraction, and identified based on spectral analyses (MS, 1H-NMR, 13C-NMR). Fourteen compounds were isolated and characterized as 1, 8 dihydroxy-3, 7-dimethoxyxanthone (1), 1, 8-dihydroxy-3, 5, 7-trimethoxyxanthone (2), 7-hydroxy-3, 8-dimethoxyxanthone-1-O-beta-D-glucopyranoside (3), 8-0-[beta-D xylopyranosyl-(1-6) -beta-D-glucopyranosyl] -1, 7-dihydroxy-3-methoxyxanthone (4), (+) -syringaresinol (5), ferulic acid (6), trans-coniferyl aldehyde (7), sinapaldehyde (8), trans-coniferyl alcohol (9), 3, 4-dihydroxybenzoic acid (10), 2-hydroxybenzoic acid (11), isophthalic acid (12), 2-furoic acid (13), and 2 methyl-4(3H)-quinazolinone(14). Compounds 2-14 were obtained from this plant for the first time. PMID- 26983209 TI - [Quantitative models of Raman spectroscopy for five kinds of traditional Chinese medicine containing CaCO3 based on an improved siPLS]. AB - The aim of this paper is to apply Raman spectroscopy technique to develop rapid quantitative models for five kinds of Traditional Chinese Medicine containing CaCO3. In the experiment, Raman spectras of 67 batch of sample including Otolithum Sciaenae, Galaxeae Os, Ophicalcitum, Calcite, Stalactite and their mixture which had different content of CaCO3 were collected, and the quantitative models were established by using an improved siPLS to optimize the characteristic spectral bands and using the CaCO3 contents which were measured by EDTA titration method as references. Compared with the results by EDTA titration, the established quantitative model for CaCO, content showed a prediction result that the average relative deviation of the prediction results is 2. 71% and the average recovery rate was 100.46%, when the content is between 0.465 4-0.999 7, and when the characteristic spectral bands of 1 290-1 280, 730-714, 700-690, 660 650, 465-460, 455-445, 405-385 cm(-1) had been optimized. The result also showed that the model using Raman spectroscopy and based on an improved siPLS can get a rapid determination for contents of 5 kinds of Traditional Chinese Medicine containing CaCO3. PMID- 26983210 TI - [Preliminary study on substitution of Antelope Horn in Danqi Piantan capsule with artificial bezoar]. AB - To study the protective effect of Danqi Piantan capsule ( DPC) and its antelope horn substitution (DPCAS) on the cerebral ischemia, in order to preliminary study the possibility of replacing antelope horn with artificial bezoar. In this study, the left middle cerebral artery occlusion (MCAO) was adopted. Totally 150 SD rats were randomly divided into 5 groups: the sham operation group, the model group, the Danqi Piantan capsule (DPC) group (0.246 g x kg(-1) x d(-1)), the Danqi Piantan capsule without antelope horn (DPCRA) group (0.246 g x kg(-1) x d(-1)), the Danqi Piantan capsule without antelope horn and with double artificial bezoar (DPCDB) group (0.246 g x kg(-1) x d(-1)). The MCAO model was prepared 1 h later after the administration on the 5th day. At 24 h after the operation, the inner canthus blood was collected to determine the serum superoxide dismutase (SOD) activity and the endothelin (ET) content. At 72 h after the operation, the cerebral infarct size and the cerebral index were determined by TTC-staining. The fluorescent quantitative PCR method was used to detect brain Bcl-2, Caspase-3, IL 1beta, P-selectin, E-selectin, ICAM-1 mRNA expressions. The mmunohistochemical method was used to detect ICAM-1, IL-1beta, TNF-alpha, IL-6 expressions in ischemic penumbra. According to the results, compared with the model group, DPCDB and DPC groups showed almost consistent results, indicating both of the two group can significantly improved cerebral infarction index and cerebral index (P < 0.05), increase the serum SOD activity (P < 0.05), decrease the serum ET level and Caspase-3 expression, IL-1beta, P-selectin, E-selectin, ICAM-1 mRNA expressions in brain tissues (P < 0.05) and expressions of ICAM-1, IL-1,6, TNF alpha, IL-6 positive cells in ischemic penumbra (P < 0.05) and increase the Bcl-2 expression (P < 0.05). The DPCRA group showed much lower impacts on indexes than DPCDB and DPC groups. This suggests that DPCDB and DPC reveal similar efficacies and antelope horn in Danqi Piantan capsule can be substitutes by artificial bezoar. PMID- 26983211 TI - [Study on hemolytic mechanism of polyphyllin II]. AB - To study the hemolytic effect of polyphyllin II (PP II) mediated by anion channel protein and glucose transporter 1 (GLUT1), in order to initially reveal its hemolytic mechanism in vitro. In the experiment, the spectrophotometric method was adopted to detect the hemolysis of PP II in vitro and the effect of anion channel-related solution and blocker, glucose channel-related inhibitor and multi target drugs dehydroepiandrosterone (DHEA) and diazepam on the hemolysis of PP II. The scanning electron microscope and transmission electron microscope were used to observe the effect of PP II on erythrocyte (RBC) morphology. The results showed that PP II -processed blood cells were severely deformed into spherocytes, acanthocyturia and vesicae. According to the results of the PP II hemolysis experiment in vitro, the anion hypertonic solution LiCl, NaHCO3, Na2SO4 and PBS significantly inhibited the hemolysis induced by PP II (P < 0.05), while blockers NPPB and DIDS remarkably promoted it (P < 0.01). Hyperosmotic sodium chloride, fructose and glucose at specific concentrations notably antagonized the hemolysis induced by PP II (P < 0.05). The glucose channel inhibitor Cytochalasin B and verapamil remarkably antagonized the hemolysis induced by PP II (P < 0.01). The hemolysis induced by PP II could also be antagonized by 1 gmol x L(1) diazepam and 100 MUmol x L(-1) DHEA pretreated for 1 min (P < 0.01). In conclusion, the hemolytic mechanism of PP II in vitro may be related to the increase in intracellular osmotic pressure and rupture of erythrocytes by changing the anion channel transport activity, with GLUT1 as the major competitive interaction site. PMID- 26983212 TI - [Antagonistic effect of gingerols against TNF-alpha release, ROS overproduction and RIP3 expression increase induced by lectin from Pinellia ternata]. AB - To explore the antagonistic effect of gingerols against the inflammation induced by lectin from Pinellia ternata. In this study, ELISA method was used to determine the effect of different extracts from gingerols on the release of inflammatory factor TNF-alpha from macrophages induced by lectin from P. ternata. The fluorescence probe was used to determine the effect of gingerols on the changes in ROS of macrophages induced by lectin from P. ternata. The western-blot method was applied to study the effect of gingerols on the increase in expression of cell receptor interacting protein RIP3 in macrophages induced by lectin from P. ternata. The scanning electron microscope (SEM) was used to study the effect of gingerols on morphological changes in macrophages induced by lectin from P. ternata. According to the results, gingerols can significantly inhibit the release of inflammatory factor from macrophages induced by lectin from P. ternata, ROS overproduction and increase in RIP3 expression. SEM results showed that gingerols can inhibit the cytomorphosis and necrocytosis induced by lectin from P. ternata. Fresh ginger's detoxication may be related to gingerols' effects in inhibiing release of inflammatory factor, ROS overproduction and increase in RIP3 expression caused by macrophages induced by lectin from P. ternata, which are mainly inflammatory development. PMID- 26983213 TI - [Mechanism of tanshinone II A in inhibiting transformation of aortic valvular myofibroblast to osteoblast-like phenotype]. AB - Aortic valve calcification (AVC) is a pathological process correlated with multiple disease causes and actively regulated by cardiac valve cells. In this study, porcine aortic valve myofibroblasts cultured in vitro were treated with 50 MUg z L(-1) of pathological factor tumor necrosis factor alpha (TNF-alpha). Tanshinone II A (TSN) with the concentration of 50 mg x L(-1) and TNF-alpha were combined in incubating cells for 72 h (3 d) and 120 h (5 d). The Western blotting and Real-time PCR were adopted to detect the changes in smooth muscle alpha actin (alpha-SMA), bone morphogenetic protein 2 ( BMP2), alkaline phosphatase (ALP) in cells, and expressions of key effect proteins GSK-3beta and beta-catenin on Wnt/beta-catenin signal pathway. According to the findings, TNF-alpha can significantly increase the expression of myofibroblasts alpha-SMA and add the transformation activity to them, with nearly no expression of BMP2, ALP and mRNA in the control group and the TSN group but significant increase in their expressions in the TNF-alpha group (P < 0.01), which showed osteoblast-like phenotype. Moreover, TNF-alpha down-regulated the expression of up-streaming regulator GSK-3beta and mRNA expression (P < 0. 01) , notably increased the expression of key effect protein beta-catenin, but with no significant difference in mRNA with the control group and the TSN group. The result demonstrated that TSN showed a certain inhibitory effect on TNF-alpha's pathological impact (P < 0.05) in a time-dependent manner. Inflammatory factor TNF-alpha may promote the transformation of aortic valvular myofibroblasts to osteoblast-like phenotype by activating Wnt/beta-catenin signal pathway in aortic valvular myofibroblasts, so as to cause AVC. Tanshinone II A can have a preventive effect in AVC by activating GSK-3beta proteins and regulating signal transduction of Wnt/beta catenin signal pathway. PMID- 26983214 TI - [Establishment of animal model with gastric hot syndrome]. AB - This study is to establish the gastric hot model of rats. After gastric feeding with ethanol solution for 3 weeks and feeding with extra capsaicin and ethanol solution for another 2 weeks, model group show distinct physical sign of gastric hot syndrome. The pathology of gastrics reveals gastricism of model group, while treatment group (treat with Zuojin Wan) shows mild lesion. Elisa detection of model group show that the solution of interleukin-2 (IL-2) is higher than the blank group. The obvious difference among model group, treatment group and blank group reveals the success of the establishment of gastric hot model. PMID- 26983215 TI - [Discovering L-type calcium channels inhibitors of antihypertensive drugs based on drug repositioning]. AB - This study was amid to construct the pharmacophore model of L-type calcium channel antagonist in the application of screening Drugbank and TCMD. This paper repositions the approved drugs resulting from virtual screening and discusses the relocation-based drug discovery methods, screening antihypertensive drugs with L type calcium channel function from TCMD. Qualitative hypotheses wre generated by HipHop separately on the basis of 12 compounds with antagonistic action on L-type calcium channel expressed in rabbit cardiac muscle. Datebase searching method was used to evaluate the generated hypotheses. The optimum hypothesis was used to search Drugbank and TCMD. This paper repositions the approved drugs and evaluates the antihypertensive effect of the chemical constituent of traditional Chinese medicine resulting from virtual screening by the matching score and literature. The results showed that optimum qualitative hypothesis is with six features, which were two hydrogen-bond acceptors, four hydrophobic groups, and the CAI value of 2.78. Screening Drugbank achieves 93 approved drugs. Screening TCMD achieves 285 chemical constituents of traditional Chinese medicine. It was concluded that the hypothesis is reliable and can be used to screen datebase. The approved drugs resulting from virtual screening, such as pravastatin, are potentially L-type calcium channels inhibitors. The chemical constituents of traditional Chinese medicine, such as Arctigenin III and Arctigenin are potentially antihypertensive drugs. It indicates that Drug Repositioning based on hypothesis is possible. PMID- 26983217 TI - [Design method of constitution regulating and healthcare foods based on medicinal property combination mode]. AB - Currently, the herbal prescription therapy for corresponding constitutional diseases is a common constitution regulating method. This method has an obvious effect in treating and regulating constitution-related diseases. However, for people who do not have disease, they prefer to regulate constitution with dietary therapy. In this paper, the researchers came up with a design method of constitution regulating and healthcare foods based on medicinal property combination mode of clinical empirical formulas. With "Yupinfeng San", a common formula for Qi-insufficiency constitution and specific endowment constitution, as the example for constitution regulating and healthcare foods, the researchers proved the effectiveness and rationality of healthcare food schemes in terms of the efficacy of single herb and the modern pharmacological study. PMID- 26983216 TI - [Filtration of active fractions with function of expelling water retention with drastic purgative from Kansui Radix stir-baked with vinegar]. AB - To study the function of expelling water retention with drastic purgative of different polarities of Kansui Radix stir-baked with vinegar on the cancerous ascites model rats, the furosemide was taken as positive control drug, and the cancerous ascites model rats were respectively orally administered with different polarities of Kansui Radix stir-baked with vinegar for 7 d. The amount of urine and ascites, the level of urinary sodium, potassium, chloride ion and pH, and the content of PRL1, AII, ALD in serum were investigated. Compared with model groups, ethyl acetate extract group showed a decreasing trend in ascites; the amount of urine of showed a significant increase (P < 0.05); the level of urinary sodium, potassium, chloride ion (P < 0.05, P < 0.01), pH (P < 0.05), and the content of PRL1, AII, ALD in serum all showed a significant decrease (P < 0.01). The effects of petroleum ether extract and n-butanol extract were weaker than that of ethyl acetate extract. The water exact was the weakest. The results showed that ethyl acetate extract is the active part of Kansui Radix stir-baked with vinegar on the function of expelling water retention with drastic purgative on the cancerous ascites model rats, alleviating the water-electrolyte disorder and body fluid acid-base imbalance, regulating the renin angiotensin aldosterone system. PMID- 26983218 TI - [Food matching based on herbal properties of formulas in "Treatise on Febrile Diseases"]. AB - Based on databases for herbal properties of formulas and foods recorded in "Treatise on Febrile Diseases", a case study was conducted for the food matching method according to herbal properties of formulas in "Treatise on Febrile Diseases". The result show that the method was technically feasible once the herbal properties of foods were determined. Moreover, according to herbal properties of target formulas, the compositions of foods were effectively defined. In this study, researchers determined the similarity between the food matching scheme and the target formulas in function and efficacy, provided a quantitative method for food formulation and promote the development of application technology of the herbal property theory and the compatibility theory. PMID- 26983219 TI - [In vitro microdialysis recoveries of nine active ingredients in Mahuang decoction]. AB - To detect the in vitro probe microdialysis recoveries based on an HPLC-DAD method for simultaneous quantification of nine active ingredients (ephedrine, pseudoephedrine, methylephedrine, amygdalin, liquiritin, cinnamyl alcohol, cinnamic acid, cinnamaldehyde and glycyrrhizic acid) in Mahuang decoction, which provides reference for in vivo pharmacokinetic study. The concentrations of nine active ingredients in dialysate were detected by HPLC-DAD, to investigate the effect of flow rates (incremental method and subtraction method) and intraday stability of the probe recoveries and medium concentrations on the recoveries. Nine active ingredients could be well separated in 52 min. At the perfusion rate of 1.0 MUL x min(-1), the relative recoveries of ephedrine, pseudoephedrine, methylephedrine, amygdalin, liquiritin, cinnamyl alcohol, cinnamic acid, cinnamaldehyde and glycyrrhizic acid were (50.95 +/- 0.82)%, (52.74 +/- 1.13)%, (51.29 +/- 0.51)%, (32.56 +/- 0.84)%, (45.36 +/- 0.83)%, (70.94 +/- 0.99)%, (69.98 +/- 2.30)%, (71.68 +/- 0.63)%, and (22.14 +/- 0.48)%, respectively. And the probe kept steady in 7 hours. At the same medium concentration, the probe recoveries decreased exponentially with the increase in flow rates. The recoveries of seven ingredients detected by these two methods were similar at certain flow rates, except for amygdalin and cinnamaldehyde. At the same flow rate, the relative recoveries of cinnamyl alcohol, cinnamic acid and cinnamaldehyde changed greatly (9.55%-16.2%) and the others six ingredients had less change (3.27%-5.71%) with the changes in medium concentrations. Microdialysis method could be used to detect the in vitro recoveries of nine ingredients in Mahuang decoction. Reverse dialysis method could be used for the in vivo probe recovery calibration of ephedrine, pseudoephedrine, methylephedrine, liquiritin, cinnamyl alcohol and cinnamic acid at the flow rate of 2.0 MUL x min(-1). PMID- 26983220 TI - [Network meta-analysis on selecting Chinese medical injections in radiotherapy for esophageal cancer]. AB - To assess the clinical effect and safety of Chinese traditional medicine injection combined with radiotherapy for esophageal cancer. The relative randomized controlled trials (RCTs) of Chinese medical injections (CMI) combined with radiotherapy as well as simple radiotherapy for esophageal cancer were searched from PubMed, Cochrane Library, EMBASE, Chinese Biomedical Literature Database(CBM), China National Knowledge Infrastructure (CNKI), Wanfang Database and VIP Database as at September 2014. Two researchers completed the data extraction and quality evaluation independently. The data were analyzed by GeMTC 0.14.3 and Stata 12. 0 software. Finally, 43 RCTs involving 3 289 patients were finally included. The star network was constructed by different comparison groups. The results of network meta-analysis showed that the seven CMIs combined with radiotherapy was superior to simple radiotherapy in the treatment of esophageal cancer in efficacy, quality of life, and reduction in the incidence of nausea and leucopenia, but with no significant difference among the seven CMIs. Probability ranking result showed a great possibility for Shenqi Fuzheng and astragalus polysaccharide injections in improving the overall response rate and quality of life, which were followed by cinobufagin and kangai injections. However, only one study was included for Shenqi Fuzheng and astragalus polysaccharide injections. Therefore, cinobufagin or kangai injections were preferred in improving the overall response rate and quality of life. Aidi or compound sophora injections were better than other CMIs in reducing? the incidences of nausea (III-IV) and leukopenia. More RCTs of Shenqi Fuzheng and astragalus polysaccharide injections combined with radiotherapy for patients with esophageal cancer were expected in the future to confirm our results. Moreover, study findings will be reported, particularly for the adverse events in radiotherapy for esophageal cancer. PMID- 26983221 TI - [Research on distribution of patents' holders for Chinese herbal compounds in treating cardiovascular and cerebrovascular based on cluster analysis]. AB - To discuss the distribution of patents' holders for Chinese herbal compounds in treating cardiovascular and cerebrovascular, the patents' holders for Chinese herbal compounds in treating cardiovascular and cerebrovascular were cluster analyzed by means of simple statistics and cluster analysis. Clustering variables were composed of patent applications, patent maintained number, related papers' quantity, etc. Chinese herbal compound patents' holders were divided into four categories according to their different scientific research and patent strength. It is the magic weapon for Chinese herbal compound patents' holders that have scientific research patents' transforming and make coordination of patent protection and scientific innovation. PMID- 26983222 TI - [Effect of Yunnan herb Laggera pterodonta against influenza A (H1N1) virus in vitro]. AB - Laggera pterodonta is commonly used for treating influenza in Southwest China, especially in Yunnnan province. The main clinical effects of L. pterodonta include anti-influenza, anti-microbial, anti-inflammatory. To investigate the anti-influenza A (H1N1) virus effect of L. pterodonta, neutralization inhibition and proliferation inhibition tests were performed. MDCK culture method was used to observe the cytopathic effect (CPE) of extracts from L. pterodonta in inhibiting influenza A (H1N1) virus and haemagglutination titre of H1N1 virus in vitro. The culture medium were collected at 24 h, 48 h, 72 h, 96 h, and detected by Real time RT-PCR, in order to compare the effect of different extracts from L. pterodonta on in vitro proliferation of H1N1, virus. The result of neutralization inhibition test showed that hemagglutination titer of ethyl acetate extract were 8 times lower at 72 h; in proliferation inhibition test, hemagglutination titer of ethyl acetate extracts reduced by 2 and 4 times. According to the results of Real time RT-PCR test, the H1N1 inhibition ratio of ethyl acetate extract was 72.5%, while the proliferation inhibition ratio of ethyl acetate extract was 25.3%; as for petroleum ether extracts, the H1N1 inhibition ratio was 60.2%, while the proliferation inhibition ratio was 81.4%. In conclusion, both ethyl acetate extract and petroleum ether extract of L. pterodonta have significant neutralization and direct proliferation inhibition effects on influenza A virus. PMID- 26983223 TI - [Establish research model of post-marketing clinical safety evaluation for Chinese patent medicine]. AB - The safety of Chinese patent medicine has become a focus of social. It is necessary to carry out work on post-marketing clinical safety evaluation for Chinese patent medicine. However, there have no criterions to guide the related research, it is urgent to set up a model and method to guide the practice for related research. According to a series of clinical research, we put forward some views, which contained clear and definite the objective and content of clinical safety evaluation, the work flow should be determined, make a list of items for safety evaluation project, and put forward the three level classification of risk control. We set up a model of post-marketing clinical safety evaluation for Chinese patent medicine. Based this model, the list of items can be used for ranking medicine risks, and then take steps for different risks, aims to lower the app:ds:risksrisk level. At last, the medicine can be managed by five steps in sequence. The five steps are, collect risk signal, risk recognition, risk assessment, risk management, and aftereffect assessment. We hope to provide new ideas for the future research. PMID- 26983224 TI - [Correlation Analysis Between Physicochemical Properties of Rhizosphere Soil and Appearance Characters of Codonopsis pilosula Root in Jiuzhaigou County]. AB - OBJECTIVE: To study the physicochemical properties of rhizosphere soil and their influence on appearance characters of semi-natural cultivated Codonopsis pilosula root. METHODS: The comprehensive methods by combining outdoor investigating with indoor analyzing were applied. Rhizosphere soil samples and plant materials were collected from 35 collection points, the physicochemical properties of soil and the appearance characters of plant materials were investigated. RESULTS: The physical property of rhizosphere soil under semi-natural cultivated condition was good, the soil texture was coarse powder of loam, slightly alkaline. The cultivated layer contained abundant nutrient components, the average organic matter content of 35 soil samples was 60.66 g/kg,and 2.99 g/kg for total nitrogen, 115.46 mg/g for available nitrogen, 0.8 g/kg for total phosphorus, 6.43 mg/kg for available phosphorus, 23.69 g/kg for total potassium and 124.48 mg/kg for available potassium, respectively. The result of correlation analysis indicated that the physicochemical properties of rhizosphere soil had significant influence on the appearance characters of Codonopsis pilosula root. CONCLUSION: The semi-natural cultivated model can maintain the structure of soil and hold nutrient components, it is conducive to the growth of Codonopsis pilosula and the standardized production base establishment. To increase the yield of Codonopsis pilosula root, it is recommended to increase the application of nitrogen and phosphorus fertilizer. PMID- 26983225 TI - [Isolation of Actinomycete DF02 from Composting and Its Application in Biological Control of Botrytis cinerea]. AB - OBJECTIVE: To isolate and identify the biocontrol actinomycete from composting, and to investigate its potted control effect against Botrytis cinerea. METHODS: Actinomycetes were isolated from composting by pour plate method. Inhibitory activities of acti- nomycetes were determined by dilution plate method and cylinder plate method. Strain with high activities was identified based on mor- phology and biochemical characterization and 16S rDNA gene sequence analysis. And its potted control effect was also investigated. RESULTS: 31 strains of actinomycetes were isolated, three of them had inhibitory effects on the test strains. Of which, the strain DF02 showed antagonistic to five plant pathogenic fungi of all the tested strains, and its inhibitory effect on Botrytis cinerea was the strongest. The results of potted control effect test showed that the protective and therapeutic efficacy of the fermentation suspension to Botrytis cinerea was 58.47% and 53.83%, respectively. According to taxonomic identification, the strain DF02 was identified as Strepto- myces neopeptinius. CONCLUSION: Strain DF02 is a biocontrol actinomycete with broad development potential, and these results provide ex- perimental basis for the biocontrol of Botrytis cinerea. PMID- 26983226 TI - [Study on Embryonic Development of Four Species of Gentiana (Gentianaceae)]. AB - OBJECTIVE: To study the embryonic development of Gentiana straminea, G. robusta, G. crassicaulis and G. tibetica. METHODS: The seed germination rates, length and width of embryos, starch grains and chloroplasts were observed and analyzed by statistic software. RESULTS: The seed germination rates of the four species were all high. The increase of the length of embryo depended mainly on the increase of the length of hypocotyl. Starch grains were stored in cells and chloroplasts appeared in cotyledons. The process of germination was divided into eight periods. CONCLUSION: The embryo growth characteristics of the four species are recognized, and the results can be used to study the in situ conservation, genetic breeding and cultivation of Sect. Cruciata. PMID- 26983227 TI - [Correlation Analysis Between Common Peaks of Angelica sinensis HPLC Fingerprint and Mineral Elements in Its Growing Soil]. AB - OBJECTIVE: To investigate the correlation between common peaks of Angelica sinensis HPLC fingerprint and mineral elements in its growing soil. METHODS: The fingerprints of 120 batches of Angelica sinensis from 12 habitats were determined by HPLC. The contents of Pb, As, Cr, Sb, Hg, Cu, Cd, Ni, Zn, Mg, Mn, Ca, Fe, Na and K in corresponding soil were determined by ICP-MS and AAS. Bivariate and multiple linear regression were used to analyze the correlation. RESULTS: There were significant ( P < 0. 01 or P < 0.05) positive and negative correlation between many common peaks in HPLC fingerprint of Angelica sinensis and mineral elements in its growing soil. The contribution of mineral elements in soil on peak 1 were Zn > K > Sb > Fe > Na; on peak 6 (3-butylphthalide) were Mn > Mg > Ca; on peak 7 were Cr > Zn; on peak 8 were Mn > Na; on peak 11 were As > K > Fe > Cd; on peak 12 were Zn > Mn > K; on peak 13 (Z-butylidenephthalide) were Mn > Zn > Cd; on peak 15 were Zn > K; on peak 16 were Fe > Ni; on peak 17 were Zn > Mn > Ni > Fe > K; on peak 18 were Zn > Na; peaks 2,3 (ferulic acid), 4 and 14 (Z ligustilide) was mainly affected by As, Zn, Sb and Cu, respectively. CONCLUSION: The relationship between HPLC fingerprint peak of Angelica sinensis and mineral elements in its growing soil shows complexity, multiplicity and interactivity, which should be selectively examined during manuring micronutrient fertilizer and Angelica sinensis cultivation. PMID- 26983228 TI - [Analysis on Genetic Diversity of Phenotypic Traits in Cultivated Pseudostellaria heterophylla]. AB - OBJECTIVE: To study the phenotypic genetic diversity of cultivated Pseudostellaria heterophylla, in order to provide theoretical basis for creative utilization and breeding of Pseudostellaria heterophylla germplasm resources. METHODS: The phenotypic genetic diversity of 80 germplasm of Pseudostellaria heterophylla from two superior provenance was analyzed, and the phenotypic characteristics among germplasm and within population were researched by correlation analysis, principal component analysis and cluster analysis. RESULTS: There were abundant phenotypic genetic diversity of Pseudostellaria heterophylla in two cultivated provenance. The genetic diversity index ranged from 1.2446 to 2.0560 and variation coefficient ranged from 13.22% to 59.24%. The leaf dry weight and leaf number had significant correlation (P < 0.05 or P < 0.01) with traits among root tuber. Six main principal components reflected most information of 23 phenotypic traits, and the accumulative contribution rate was 76.47%. The result of the cluster analysis was that 80 germplasm of Pseudostellaria heterophylla could be divided into four groups based on phenotypic difference, the first group can be parents of progenies with high yield potential, the second group could be optimal parents of progenies with high yield, the third group can be parents of first class goods. CONCLUSION: The germplasm resources of cultivated Pseudostellaria heterophylla from Guizhou is useful for breeding of new varieties with abundant diversity. The second group and the third group of Pseudostellaria heterophylla have better germplasm,which can be provide parents for cross breeding of Pseudostellaria heterophylla. PMID- 26983229 TI - [Study on Monosaccharide Compositions of Polysaccharide in Dendrobium Stems of Different Resources by PMP-HPCE]. AB - OBJECTIVE: To establish a PMP-HPCE method for comparing the monosaccharides of polysaccharide in tissue-cultured and wild Dedrobium huoshanese and Dedrobium moniliforme as well as wild Dedrobium henanese, in order to investigate the similarities of their bioactive components. METHODS: The PMP-monosaccharides of polysaccharide from the five investigated Dedrobium samples were separated by HPCE on a fused silica capillary column(100 cm x 50 um) at 25 degrees C with 350 mmol/L BAS (adjusted to pH 10 with 1.0 mol/L NaOH) as running buffer for 34 min. The applied voltage was 20 kV and the detection wavelength was set at 250 nm. RESULTS: Total six monosaccharides including xylose, glucose, mannose, galactose, galacturonic acid and ribose were detected in the five Dendrobiurms samples and the similarity coefficients between the ten batches of the same Dendrobium species were all above 0. 98,while remarkable dissimilarity were exhibited among species and different resources. CONCLUSION: PMP-HPCE technique combined with chemometrics is simple, convenient, precise, reproducible and proved to be an effective strategy for identifying the species and origins, especially in the quality assessment of Dendrobium stems. PMID- 26983230 TI - [Evaluation for Merchandise Character and Quality of Bupleurum chinense Root from Different Habitats]. AB - OBJECTIVE: To evaluate the merchandise character and quality of Bupleurum chinense root from different habitats. METHODS: The spectrophotometer method was used to determine the content of total saponins and total flavonoids in Bupleurum chinense root. The content of alcohol-soluble extract and total ash were determined according to the method in the Chinese Pharmacopoeia. RESULTS: The quality of Bupleuri Radix from different habitats varied greatly. There were also differences (P < 0.05) between the merchandise packaged with selection and the merchandise packaged without selection of Bupleurum chinense root from the same habitats. The merchandise packaged without selection had the better quality, whose root length, root diameter, weight, total length proportional share of residual stems, total saponins, total flavonoids, total alcohol-soluble extract and total ash was 14.50 cm/plant, 0.59 cm/plant, 5.14 g/plant, 36.85%, 0.721%, 0.615%, 12.993% and 4.890%, respectively. CONCLUSION: Bupleurum chinense root from Tong'an, Jiangsu has the best quality in the test samples from different habitats. PMID- 26983231 TI - [Simultaneous Determination of Ten Kinds of Saponins in Raw and Steamed Panax notoginseng Root and Rhizome by HPLC]. AB - OBJECTIVE: To develop an HPLC method for simultaneous determination of notoginsenoside R1 and ginsenosides Rg1 Re, Rh1, Rb1, Rd, Rk3, Rh4, 20(S)-Rg3 and 20(R)-Rg3 in raw and steamed Panax notoginseng root and rhizome. METHODS: Vision HT C18 column (250 mm x 4.6 mm, 5 um) was used with the mobile phase consisted of acetonitrile-H2O in a gradient elution mode at the flow rate of 1.2 ml/min. The column temperature was maintained at 20 degrees C and the detection wavelength was set at 203 nm. RESULTS: The methodological study showed a good linear relationship ( r > 0. 9995 ) . The average recoveries of the ten saponins were 95.93%-102.54%. CONCLUSION: The method is accurate and reproducible, which can be used for simultaneous determination of saponins in raw and steamed Panax notoginseng root and rhizome, and can provide reference for the relationship between material basis and pharmacological effects. PMID- 26983232 TI - [Effect of Different Processed Products and Extracts of Morinda officinalis Root on Adjuvant-Induced Arthritis in Rats]. AB - OBJECTIVE: To study the therapeutic effects of different processed products and extracts of Morinda officinalis root in rat adjuvant-induced arthritis (AA) model, and to explore the possible mechanism. METHODS: AA model in SD rats was established, then the arthritic rats were randomly divided into seven groups such as model, Tripterygium Glycosides Tablet (TGT), morinda with xylem, morinda, salt steamed morinda, licorice-processed morinda, morinda EtOAc extract, morinda n BuOH extract, H2O residue, total polysaccharides and control groups. The paw edema and arthritis indexes were observed, and the contents of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, IL-2 and INF-gamma in AA rats serum were detected by ELISA. RESULTS: Morinda processed by salt and n BuOH extract could reduce paw swelling and levels of TNF-alpha, IL-1beta, IL-6 and INF-gamma in AA rats serum, which followed by morinda EtOAc extract. The differences were significant compared with the model group (P < 0.05 or P < 0.01). CONCLUSION: Salt-steamed morinda and morinda n-BuOH extract have the best curative effect, followed by morinda EtOAc extract. Reducing TNF-alpha, IL-1beta, IL-6 and INF-gamma contents in serum may be the mechanism of drug treatment of rheumatoid arthritis. PMID- 26983233 TI - [Study on UPLC Fingerprint of Corydalis bungeana]. AB - OBJECTIVE: To establish an Ultra Performance Liquid Chromatography fingerprint of Corydalis bungeana from different habitats. METHODS: UPLC-PDA was adopted to analysis ten batches of Corydalis bungeana from different habitats with Phenomenex Luna C18 column (250 mm x 4.6 mm, 5 um) eluted with the mobile phase of acetonitrile and 0. 02% triethylamine in a gradient mode. The flow rate was 0.3 mL/min and the column temperature was 30 degrees C. The detection wavelength was set at 289 nm. RESULTS: The fingerprints of ten batches of Corydalis bungeana from different habitats had 13 common peaks, three of them were identified. The similarities were larger than 0.80. Ten batches of samples were divided into three categories by cluster analysis. Three principal components were ob- served via principal component analysis and the value of three principal components accounted for 89. 607% of the total variance. Two major chemical components of Corydalis bungeana were confirmed. CONCLUSION: The high-performance and rapid method is successfully used for fingerprint analysis and can be used to evaluate the quality of Corydalis bungeana. PMID- 26983234 TI - [Application of Rapid PCR Technology on Authentication of Species in Panax Genus]. AB - OBJECTIVE: To establish an accurate, rapid and efficient method for authentication of Panax species by using PCR amplification of specific alleles. METHODS: The samples of Panax species were collected for extracting the total DNA. matK sequence from the Panax species was amplified by PCR and sequenced directionally, and then aligned by using Clustal W. Specific primers were designed and amplified by two-steps PCR amplification method. RESULTS: By optimizing the denatured and annealing temperature and time, cycle numbers, the rapid PCR methods for authentication of Panax species were established respectively. When SYBR Green I was added in the PCR product, strong green fluorescence was visualized under 365 nm UV lamp whereas adulterants were not. CONCLUSION: The rapid PCR method can identify the Panax species rapidly. This study provides the technical support for authentication of Chinese medicinal materials. PMID- 26983235 TI - [Genetic Diversity and Genetic Relationship of Different Forms of Trichosanthes kirilowii from Shandong Province]. AB - OBJECTIVE: To investigate the genetic diversity and genetic relationship of different forms of Trichosanthes kirilowii from Shandong Province. METHODS: Different forms of Trichosanthes kirilowii from the same planting base were detected by random amplified polymorphic DNA( RAPD) with eight random primers. The amplified bands were detected and the fingerprint was drawn by Biosens Gel Imaging System software. The Jaccard coefficient was worked out by using NTSYS-pc software, and a cluster dendrogram of different samples was established based on unweighted pair-group method with arithmetic means (UPGMA). RESULTS: The eight primers produced 56 bands, among which, 32 bands were polymorphic. The cluster dendrogram displayed there was some differences of genetic relationship of different samples. CONCLUSION: There is similar genetic material basis of Trichosanthes kirilowii from the same planting base, but also there is apparent individual differences. PMID- 26983236 TI - [Study on Chemical Constituents in Seeds of Datura metel from Xinjiang]. AB - OBJECTIVE: To study the chemical constituents in the seeds of Datura metel from Xinjiang Province. METHODS: The constituents were isolated and purified by silica gel, ODS and Sephadex LH-20 column chromatographic methods. Their chemical structures were analyzed and identified on the basis of physical and chemical properties and spectral data. RESULTS: Ten compounds were isolated and identified as Isofraxidin (1), Scopatone (2), Daturadiol (3),1,4-Benzenediol (4), Arenarine D (5), Vanillin (6), N-trans-Feruloyl-tyramine (7), Scopoletin (8), G-Sitosterol (9) and Hyoscyamilactol (10). CONCLUSION: Compounds 1 and 2 are firstly isolated from the plants in Solanaceae, compounds 3-8 are firstly isolated from this plant. PMID- 26983237 TI - [Chemical Constituents from Ethyl Acetate Extract of Psidium guajava Leaves (II)]. AB - OBJECTIVE: To study the chemical constituents from ethyl acetate extract of Psidium guajava leaves. METHODS: The constituents were separated and purified by silica gel and Sephadex LH-20 column chromatography and their structures were identified on the basis of physicochemical properties and spectral data. RESULTS: Eleven compounds were isolated and identified as 6,10,14-trimethyl-2 pentadecanone (1), phytyl-acetate (2), cubenol (3), eucalyptin (4), n-docosanoic acid-p-hydroxy-phenethylol ester (5),8-methyl-5,7- dihydroxy-flavonone (6), 6 methyl-5,7-dihydroxy-flavonone (7), betulinic acid (8), carnosol (9), quercetin (10), and 2,4,6-tirhydroxy- 3,5-dimethyl-diphenylketone-4-O-(6'"-O-galloyl)-beta D-glucoside (11). CONCLUSION: Compounds 1-9 are isolated from this plant for the first time. PMID- 26983239 TI - [Chemical Constituents from Angelica keiskei]. AB - OBJECTIVE: To investigate the chemical constituents from Angelica keiskei. METHODS: The constituents were isolated and purified by silica gel, Sephadex LH 20 column chromatography, and preparative TLC. Their structures were identified on the basis of spectral data and physiochemical characteristics. RESULTS: 14 compounds were isolated from 70% ethanol extracts and identified as falcarindiol (1), selinidin (2), isobavachalcone (3), pteryxin (4), kaempferol-5-O-(6"-O acetyl)-beta-D-glucopyranoside (5), beta-amyrin ace- tate (6), beta-sitosteryl glucoside-6'-O-heptadecoicate (7), 2,5-dimethyl-6,8-dihydroxyl-chromone (8), quercetin-3,3'-di-O-alpha-L-rhamno- side (9), 2-hydroxynaringenin-4'-O glucopyranoside (10), 3-O-alpha-L-rhamnosyl (1-->3)-beta-D-glucopyranosyl (1-->3) alpha-L-rhamnosyl (1--> 2)-alpha-L-arabinopyranosyl hederagenin-28-O-beta-D glucopyranosyl (1-->6)-beta-D-glucopyranosyl ester (11), chrysoeriol (12), orientin (13) and 1beta,6alpha-dihydroxyeudesm-4 (15)-ene (14). CONCLUSION: All compounds are isolated from this plant for the first time. PMID- 26983238 TI - [Triterpenoids from Leaves of Ilex latifolia]. AB - OBJECTIVE: To investigate the chemical constituents from the leaves of Ilex latifolia. METHODS: The constituents were iso- lated and purified by various chromatographic techniques. Their structures were identified by UV, IR, MS and NMR spectroscopic analy- sis. RESULTS: Ten compounds were isolated from the leaves of flex latifolia. Their structures were respectively identified as 3beta,13beta-Di- hydroxy-urs-11-en-28-oic acid-13-lactone (1), beta-sitosterol (2) 3-hydroxy-11-oxours-12-ene (3), (20S,24S)-epoxydammarane-3beta,25- diol (4), 25-deuteriostigmasterol (5), alpha-amyrin (6), foliasalacin A4 (7), 23 hydroxyursolic acid (8), p-coumaric acid (9) and beta-dau- costerol (10). CONCLUSION: Compounds 1,3-5,7 and 9 are isolated from this plant for the first time. PMID- 26983240 TI - [Study on Chemical Constituents from Ethyl Acetate Extraction of Sanicula lamelligera]. AB - OBJECTIVE: To study the chemical constituents from ethyl acetate extraction of Sanicula lamelligera. METHODS: Compounds were isolated and purified by silica gel and Sephadex LH-20 column chromatographic method, and their structures were identified by using spectroscopic analysis. RESULTS: Nine compounds were isolated and identified as angelicin (I), isoferulaldehyde (II), 12- hydroxybakuchiol (III), 22-angeloyl-R1-barrigenol (IV), 5,6,7,8,4'-pentamethoxyflavone (V),3,5,6,7,8,3',4'-heptamethoxyflavone (VI), isobavachin (VII), isoliquiritigenin (VIII) and furano (2",3",7,6) 4'-hydroxyflavanone (IX). CONCLUSION: All compounds are isolated from this plant for the first time. PMID- 26983241 TI - [Chemical Constituents from Rhizome of Valeriana jatamansi]. AB - OBJECTIVE: To study the chemical constituents from the rhizome of Valeriana jatamansi. METHODS: The chemical constituents were separated and purified by silica gel, medium pressure column chromatography, and preparative HPLC. Their structures were determined by physicochemical properties and spectral data. RESULTS: Six compounds were isolated from the dibromochloromethane extract in the rhizome of Valeriana jatamansi, and identified as decursidin (1), decursitin B (2), decursitin A (3), 3'(S)-acetoxy-4'(R)-angeloyloxy-3',4'-dihydroxanthyletin (4), 8-acetoxyl-pathchouli alcohol (5) and dibutyl phthalate (6). CONCLUSION: Compounds 1-4 are coumarins which are isolated from this genus for the first time,and compound 6 is isolated from this genus for the first time. PMID- 26983242 TI - [Study on Chemical Constituents of Panzeria alaschanica]. AB - OBJECTIVE: To study the chemical constituents of the ethyl acetate extract from Panzeria alaschanica. METHODS: The chemical constituents of ethyl acetate extract from Panzeria alaschanica were isolated and purified by silica gel. Their structures were i- dentified by means of spectra. RESULTS: Nine compounds were obtained and identified as 7-Methoxy coumarin (1), Isorhamnetin (2), Caf- feic acid (3), 5-Hydroxy-7,3',4'-trimethoxyflavone (4), 5-Hydroxy-7,4' dimethoxyflavone (5),Kaempferol (6), Isorhamnetin-3-O-beta-D- glucoside (7) Kaempferol-3-O-beta-D-glucoside (8), and Isorhamnetin-7-O-beta-D-glucuronyl-(1- >6)-O-alpha-L-rhamnoside (9). CONCLUSION: Compounds 1-4,6,7 and 9 are isolated from this plant for the first time. PMID- 26983243 TI - [Chemical Constituents from Macaranga denticulata Root]. AB - OBJECTIVE: To study the chemical constituents from Macaranga denticulata Root. METHODS: The chemical constituents were isolated and purified by silica-gel column chromatography and recrystallization, and their structures were identified by physicochemical properties and spectral data. RESULTS: Nine compounds were isolated and identified as: gheddic acid (1), aleuritolic acid-3-acetate (2), beta-sitosterol (3), stigmast-4-en-6beta-ol-3 -one (4), 2alpha-hydroxyaleuritolic acid 3-p-hydroxybenzoate (5), scopoletin (6), daucosterol (7), 2, 6-dimethoxy-1,4 benzoquinone (8) and maslinic acid(9). CONCLUSION: Compounds 1-9 are obtained from this plant for the first time. PMID- 26983245 TI - [Effect of Esculentoside A on Expression of AQP2 and AQP4 Protein of Kidney in Water-Loaded Rats]. AB - OBJECTIVE: To observe the regulatory effect of Esculentoside A (EsA) on urination and the expression of AQP2 and AQP4 protein of kidney in water-loaded rats, and to discuss its mechanism of diuresis. METHODS: 50 male SD rats were randomly divided into five groups, including blank control group, hydrochlorothiazide group (0.4 mg/kg) and EsA high, middle and low dose groups (5.2, 2.6 and 1.3 mg/kg, respectively). After intraperitoneally injecting of different concentrations of EsA, urinary amount of model rats in continuous six hours was measured. Then the expression of AQP2 and AQP4 protein and mRNA of kidney were detected by immunohistochemistry method and Real-Time quantitative PCR. RESULTS: Compared with blank control group, the expression of AQP2 and AQP4 protein and mRNA of kidney were significantly reduced as well as the urinary amount was significantly increased in EsA high dose group (P < 0.05), while the expression of AQP2, AQP4 protein and mRNA of kidney as well as urinary amount had no obvious difference in EsA middle and low dose groups. CONCLUSION: 5.2 mg/kg of EsA can reduce the expression of AQP2 and AQP4 protein and mRNA of kidney and the reabsorption of water, which results in diuresis. PMID- 26983244 TI - [Effects of Ethanol Extracts of Phellinus lonicerinus on Hepatic Stellate Cells of Fibrosis Liver in Rats]. AB - OBJECTIVE: To study the effects of ethanol extracts of Phellinus lonicerinus on hepatic stellate cells of fibrosis liver in rats. METHODS: The model rats of hepatic fibrosis were established by intraperitoneally injection of CCl4 olive oil solution at the dose of 2 mL/kg. And then the model rats were administered orally ethanol extract of Phellinus lonicerinus with 1 g/(kg . d) and 0.5 g/( kg . d) for consecutive eight weeks. Serum transforming growth factor-beta1, (TGF beta1), liver total antioxidant capacity (T-AOC), total superoxide dismutase( T SOD) activity and the content of malondialdehyde ( MDA) were determined. The alpha-smooth muscle actin (alpha-SMA), matrix metalloproteinases-1 (MMP-1) and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) were determined by immunohistochemical. RESULTS: Compared to the model group, the ethanol extracts of Phellinus lonicerinus decreased the content of serum TGF-beta1 and MDA in liver tissue, as well as increased the activity of T-SOD and the level of T-AOC. Immunohistochemical showed that the ethanol extracts of Phellinus lonicerinus downregulated the expression of alpha-SMA in liver tissue and the expression of TIMP-1, as well as upregulated the expression of MMP-1. CONCLUSION: The ethanol extracts of Phellinus lonicerinus has good antioxidative activity with application prospects in prevention of hepatic fibrosis. The mechanism may be related to inhibiting the activation of hepatic stellate cells induced by oxidative stress,reducing the TGF-beta1, and cytokines activating the hepatic stellate cells,and upregulating the expression of MMP-1 promoting the collagen degradation. PMID- 26983246 TI - [Protective Effects of Total Saponins from Panax japonicus on H2O2Induced Injury via Mitochondia Pathway in SH-SY5Y Cells]. AB - OBJECTIVE: To investigate the protective mechanism of total saponins from Panax japonicus (SPJ) on H2O2 induced injury in SH-SY5Y cells. METHODS: SH-SY5Y cells were divided into three groups: blank control group, model group (600 umol/L H2O2) and drug treatment groups. Different concentrations of SPJ (0.1, 1, 5 and 20 ug/mL) were incubated with SH-SY5Y cells for 12 hours prior to exposing to 600 umol/L H2O2 for another 12 h. Mitochondrial membrane potential (MMP) was detected by JC-1 method. Protein expressions of Sirt1 , PGC-1alpha, Foxo3a, LC3-II and Beclin1 were detected by Western blotting. RESULTS: Compared to the H2O2 model group, SPJ pretreatment significantly increased MMP level and enhanced the protein expressions of Sirt1, PGC-1alpha, Foxo3a, LC3-II and Beclin1. CONCLUSION: SPJ exerts protective effect on H2O2 induced SH-SY5Y cell injury through mitochondria pathway. PMID- 26983247 TI - [Protective Effects of Ginkgolide N Against Glutamate-Induced Injury in PC12 Cells]. AB - OBJECTIVE: To study the protective effects of ginkgolide N against glutamte induced injury in PC12 cells and its mechanisms. METHODS: The injury model was established by treating PC12 cells with glutamate, and PC12 cells were treated with different concentrations of ginkgolide N with ginkgolide B as control. The cells activity was analyzed by MTT assay. The apoptosis of PC12 cells were examined by acridine orange( AO) staining, the reactive oxygen species and mitochondrial membrane potential of PC12 cells were examined by flow cytometry. Western blot method was used to examine the expression of Cleaved Caspase-3 protein. RESULTS: Ginkgolides N of 2-8 ugmol/L inhibited PC12 cells apoptosis and ROS accumulation induced by glutamate,stabilized membrane potential of damaged PC12, and reduced the expression of Cleaved Caspase-3 protein. CONCLUSION: Ginkgolide N has a protective effect on PC12 cells injury induced by glutamate, and the mechanism may be associated with reducing ROS generation, stabilizing membrane potential and inhibiting the expression of Cleaved Caspase-3 protein. PMID- 26983248 TI - [Optimization of Ethanol Extraction and Water Extraction Technologies of Zuogui Pills by Orthogonal Test]. AB - OBJECTIVE: To optimize the ethanol extraction and water extraction technologies of Luogui Pills. METHODS: An orthogonal test was used to study the influence of ethanol concentration, amount of ethanol and reflux time on hyperoside in Cuscutae Semen, ursolic acid in Corni Fructus and the yield of dry paste. Also, The effect of soaking time, amount of water and extraction time on acteoside in Rehmanniae Radix Praeparata and the yield of dry paste were investigated. All these factors were adopted as the indices for choosing the best ethanol extraction and water extraction technologies. RESULTS: The best ethanol extraction technology for Cuscutae Semen, Corni Fructus and Achyranthis Bidentatae Radix was reflux extracting for 1 h each time for two times with eight times of 70% ethanol. The best water extraction technology for the residue and the rest herbs after the ethanol extraction was soaking for 0. 5 h and then decocting for 0. 5 h each time for two times with twelve times of water. CONCLUSION: The optimal extraction technologies are stable and feasible, the extraction rate of the alcohol soluble and water soluble effective components is high, and it provides the reference basis for the secondary development of Zuogui Pills. PMID- 26983249 TI - [Study on Effects of Incompatible Herbal Medicine on Intestinal Bacterial Metabolism of Wu-Tou-Tang by ESI-MS]. AB - OBJECTIVE: Electrospray ionization-mass spectrometry (ESI-MS) was used to detect samples of Wu-Tou-Tang as well as the co-decoction of it with Pinelliae Rhizoma, Fritillariae Thunbergii Bulbus and Fritillariae Cirrhosae Bulbus before and after intestinal bacterial metabolism. METHODS: Semi-quantitative method of mass spectrometry was established for analyzing the biotransformation of major chemical constituents in Chinese medicine formula. Based on the changes of relative abundance ratio of alkaloids to internal standard for each decoction before and after intestinal bacterial metabolism, effects of incompatible herbal medicine on the intestinal bacterial metabolism of aconite alkaloids from Wu-Tou Tang were analyzed. RESULTS: Pinelliae Rhizoma, Fritillariae Thunbergii and Fritillariae Cirrhosae Bulbus inhibited the intestinal bacterial biotransformation of diester-alkaloids, which could be considered that the above three Chinese herbal medicines increased the toxicity of Wu-Tou-Tang. CONCLUSION: This study illustrates the scientific connotation of traditional Chinese medicine "eighteen incompatible medicaments" theory from the point of intestinal bacterial metabolism. PMID- 26983250 TI - [Study and Evaluation on Preparation of Monolithic Osmotic Pump Tablet of Resveratrol]. AB - OBJECTIVE: To prepare monolithic osmotic pump tablet of resveratrol. METHODS: Inclusion technology was adopted to enhance its solubility. The optimal formulation of resveratrol inclusion complex osmotic pump tablets was selected by the single-factor method and orthogonal design. The release in vitro of the optimized formulation was also fitted to different models. RESULTS: The tablets with optimized formulation achieved the desired zero-order release profile in 12 h (r = 0.9963) with the cumulative release over 90%. CONCLUSION: Resveratrol can be prepared into monolithic osmotic pump tablets based on the intermediate of inclusion technology, which have obvious characteristic of zero release. PMID- 26983251 TI - [Alexander Alexandrovich Kiter (1813-1879)]. PMID- 26983252 TI - [ULTRASONIC ASSESSMENT OF DIAPHRAGM CONDITION OF THE PATIENTS, WHO PASSED THE SELECTION FOR LUNG VOLUME REDUCTION SURGERY]. AB - The article showed the results of ultrasonic assessment of topographic and functional diaphragm indices in patients with severe diffuse emphysema. They passed the selection for lung volume reduction surgery. The comparison of diaphragm indices was presented in patients with diffuse emphysema and control group of healthy volunteers. Dynamics of diaphragm condition was studied after surgical treatment. There wasn't noted any statistical difference of diaphragm topographic indices as compared with the control group. There wasn't shown a correlation between respiratory function indices and functional diaphragm indices, but it was noted a positive tendency in characteristics during quiet breathing. PMID- 26983253 TI - [CONTROL OF APPLICATION EFFICACY OF THE ASCENDING GAS--FLUID STREAM METHOD IN TREATMENT OF DIFFUSE PERITONITIS]. AB - The ascending gas and fluid stream method was applied in 12 patients with repeated purulent diffuse peritonitis. The number of leukocytes was determined in lavage fluid in order to estimate the efficacy of the method. Dynamics of general laboratory and clinical indices was compared with dynamics of leukocytes quan- tity. The research showed the adequacy of investigation results of lavage fluid to the course of inflammatory process in the abdominal cavity. The study presented an application possibility of given test for regulation usage correction of the ascending gas- fluid stream method. PMID- 26983254 TI - [SUBSTANTIATION OF SURGICAL APPROACH IN IATROGENIC INJURIES OF THE BILE-EXCRETING DUCTS]. AB - The results of examination and treatment were analyzed in 51 patients with iatrogenic injuries of the bile-excreting ducts. Patients were divided into 5 groups according to international classification (EAES, 2013). It depended on the time of detection, the nature and scale of damage of the bile ducts, mechanism of injury, development of infectious and septic complications. Injuries of the main bile duct were detected intraoperatively (n = 14). The complete intersection was in 10 patients (the first group) and the edge intersection--in 4 cases (the second group). Iatrogenic injuries of the bile-excreting ducts were revealed in 37 patients in postoperative period. There were the complete intersections in 28 cases (the third group) and the edge intersections--in 7 cases (the fifth group). Injuries of additional bile ducts were determined in 2 patients (the fifth group). An analysis of the main qualifying features of iatrogenic injuries of the bile-excreting ducts allowed defining indications to reconstructive-restorative surgery in 60.8% patients, restorative operations--in 29.4%, an external drainage -in 5.8% and reclipping of additional bile ducts in relaparoscopy--in 3.9%. The rational surgical approach allowed obtaining perfect results in 65.8% and good, satisfactory results in immediate and long-term period with low postoperative lethality of 1.95%. The study of diagnostics results and treatment of the patients with iatrogenic injuries of the bile- excreting ducts indicated about reasonability of assessment of main factors, which are based on iatrogenic injuries according to the EAES classification. An individual program of examination and more rational variant of surgery could be chosen due to this approach, which provides minimization of negative results and good quality of life. PMID- 26983255 TI - [LONG-TERM RESULTS OF SURGICAL TREATMENT OF PATIENTS WITH FOLLICULAR TUMORS OF THE THYROID]. AB - The article analyzed an experience of treatment of 51 patients with follicular tumors. It was proved, that there weren't any complications and recurrences in case of typically performed operation and adequate replacement therapy in postoperative period. It was noted a good quality of life from 2 to 5 years. PMID- 26983256 TI - [SURGICAL TECHNIQUE OF BLOCKING INTRAMEDULLARY OSTEOSYNTHESIS OF FOREARM FRACTURES]. AB - An introduction of blocking osteosynthesis was recently included into practice of treatment of forearm fractures. The forearm has a very difficult biomechanics and extremely important functional value. There are really high requirements to accuracy of reposition and stability of forearm fracture fixation. The blocking osteosynthesis successfully combines fixation stability with functionality, although its performance technique isn't so simple, that forces experts to use other methods of fixation. It is possible successfully use advantages of the method by studying and keeping variety of operation nuances of blocking osteosynthesis on forearm in order to restore anatomy, biomechanics and obtain the stable fixation. The period of rehabilitation could be combined with period of union of bones in this case without postoperative complications such as nonunion of bones, construction fractures and instability of osteosynthesis. The method would be optimal provided that a surgeon masters the technique of construction implantation. There are maximum advantages in treatment of complicated fractures (nonunion of bones, false joint and defects) due to functionality of the method. PMID- 26983258 TI - [METHOD OF OSTEOSYNTHESIS OF SUPRACONDULAR FRACTURES OF THE HUMERUS]. AB - A treatment of fractures of distal metadiaphysis of the humeral bone remains an actual problem of modern traumatology at present time. This is associated with immediate proximity of the radial nerve and risk of iatrogenic injury in external fixation, presence of short distal fragment, comminuted nature of fracture, complexity of treatment method selection, need of extensible approach. Biomechanical features of different fixators were analyzed in consideration of presence of short distal fragment, traumatic of. external fixation and risk of iatrogenic injury of the nerve. The authors suggested the method of osteosynthesis of the humerus by using blocking osteosynthesis with preliminary extension of intra-medullary canal of distal fragment for obtaining stable osteosynthesis (priority No 2014105323 from 14.02.2014). The proposed method allowed avoiding the iatrogenic neuropathy of the radial nerve, providing the stability of fixation higher, than in case of external fixation. It excludes the need of external immobilization and combines the period of bony union with the period of rehabilitation and socially integrates the patient in minimal terms. PMID- 26983257 TI - [PROGNOSIS OF DEEP INFECTIOUS COMPLICATIONS IN HIP ARTHROPLASTY]. AB - The retrospective research analyzed the data of 893 patients undergoing total hip arthroplasty. There were used the data about patients undergoing hip arthroplasty without complications (the first group--808 cases) and patients with developed deep surgical site infection following total joint arthroplasty after 12 months (the second group--85 patients). It was applied as the training matrix in creation of mathematical prognosis and algorithm of prophylaxis of deep infection in patients undergoing the primary total hip arthroplasty. There were revealed 21 prognostic significant criteria of deep infection development in surgical site. The program was tested in prospective investigation (293 clinical cases) with follow-up term of 12 months after operation. The rate of development of postoperative deep infection in surgical wound reduced as compared with the rate in group of retrospective research from 1.7% to 0.7%. The efficacy of proposed program was 80%. PMID- 26983259 TI - [ASSESSMENT OF EFFICACY OF TEMPORARY EPICARDIAL BIVENTRICULAR RESYNCHRONIZATION PACING AFTER CARDIAC SURGERY]. AB - The temporary pacing is provided as a key principle of maintenance and correction of hemodynamics after weaning the patient from cardiopulmonary bypass. There are conventional algorithms of temporary pacing, but the substantiation of electrode fixation areas is variable. The authors experimentally investigated the efficacy of temporary epicardial pacing in DDD and DDDBV using 18 laboratory animals after cardiac surgery with application of cardiopulmonary bypass. The hemodynamic parameters were compared in given groups. It was noted that in case of temporary epicardial pacing in DDDBV conditions was the best hemodynamic effect. The authors recommended more optimal areas for electrode fixation in temporary pacing: bachmans bunble (closest to the artrial septum), proximal part of the crista terminalis for the right atrium electrodes; the front-side free wall of the right ventricle at the distance of 3-4 cm from the apex of the heart, diaphragmatic surface of the right ventricle proximal to artioventricular groove for the right ventricle electrodes; obtuse margin (side wall of the left ventricle), diaphragmatic surface of the left ventricle proximal to artioventricular groove for the left ventricle electrodes. PMID- 26983260 TI - [TRANSPLANTATION OF TRACHEAL-LUNG COMPLEX IN EXPERIMENT]. AB - The article described the developed and patented method of removal of trancheal lung complex from dead body and its transplantation to the recipient-corps. PMID- 26983261 TI - [RESULTS OF APPLICATION OF THE METHOD OF STERNAL INFECTION ELIMINATION IN CARDIOSURGICAL PATIENTS]. AB - A retrospective analysis of cases of sternal infection development was made in 388 cardiovascular patients from 2006 to 2012. The standard preventive measures of wound infection development were applied in the first period from 2006 to 2009. The method of "elimination of sternal infection" was used in the second period from 2009 to 2012. The application of the method of "elimination of sternal infection" allowed reducing the rate of sternal infection from 7.7 to 0.5% (odds ratio 0.099, 95% CI: 0.013-0.747; p = 0.025). According to results of statistical analysis the most significant factors were: body mass index (p = 0.002), resternotomy in early postoperative period (p < 0.001), risk according EuroSCORE Logistics (p < 0.001) and usage of the method of "elimination of sternal infection" (p = 0.006). The prevention of postoperative infectious complications shorthens the terms of hospital stay no less than 3 weeks, improves the quality of life for the patients and decreases treatment costs on 2.5 times. PMID- 26983262 TI - [SYNDROME OF DIABETIC FOOT: MODERN APPROACHES OF COMPLEX TREATMENT]. AB - The article presents the results of treatment of 201 patients with neuroischemic form of diabetic foot syndrome. The research included 158 women and 43 men of the middle age of 62.5 +/- 11.2 years. The complex approach was applied in treatment including medicamentous treatment, revasculization of extremity, an application of modern combined collagenous coating and foot relieving using silicone insoles and orthopedic footwear. The endovascular and open reconstructive operations were performed in order to obtain the revasculization of extremity. Given complex approach allowed reducing the terms of hospital stay, the rate of ulcerous defects recurrences and relapses of ischemia of lower extremities during one year after endovascular interventions. PMID- 26983263 TI - [REGIONAL LASER THERAPY IN TREATMENT OF PATIENTS WITH STRANGULATED VENTRAL HERNIA]. AB - An analysis of treatment was made of 265 patients with strangulated hernia of the anterior abdominal wall. The patients were divided into main group (n = 138) and control group n = 127). Nonstrain and conventional methods of hernioplasty and low-intensive laser radiation (LILR) were used for the patients of the first group. LILR wasn't applied in the control group. The studied groups were statistically comparable on the basis of main disease, sex and age. Computed thermography was used in addition to standard methods of diagnostics in order to dentify the wound complications in postoperative period. The application of low intensive laser radiation for patients of main group allowed reducing the rate of development of local infectious complications in the area of plasty as compared with control group from 15.7 and 53.4% to 8.9 and 32.8% (p < 0.05); terms of drainage of postoperative wound decreasing from 8.1 +/- 1.0 to 4.2 +/- 1.0 days and hospital stay shortening from 11.6 +/- 1.0 to 6.2 +/- 1.0 days (p < 0.05). The intensity of pain syndrome and rate of complications declined from 38.1 to 17% in control group. There wasn't any recurrence in the main group. Prosthetic methods of plasty and application of LILR significantly improve the immediate and long-term results in case of strangulated hernia of anterior abdominal wall. This rate would approach the results of treatment in planned surgery. Computed thermography allowed well-timed revealing of wound complications and forecasting the course of postoperative period. PMID- 26983264 TI - [ASSESSMENT OF EFFICACY OF MELATONIN IN SURGICAL TREATMENT OF COLON TUMORS]. AB - Melatonin is neurohormone, which is involved in regulation of many functions of an organism, including the digestive system. Therefore the authors offered to include this hormone as a preconditioner factor in surgical treatment of colon tumors using laparotomy and laparoscopy. Preoperative application of melatonin allowed shortening the terms of postoperative period and hospital stay. PMID- 26983265 TI - [COMPARATIVE EVALUATION OF CURRENT METHODS OF ANESTHESIA IN PERFORMANCE OF TRANSRECTAL PROSTATE BIOPSY]. AB - Prostate biopsy guided by transrectal ultrasonography (TRUS) is largely used in prostate cancer diagnostics. This procedure is usually quite painful and fear of pain could scare patients from this important research. The aim of the study was to compare methods of anesthesia for prostate biopsy. The patients were divided into 4 groups (40 patients in each group). TRUS-guided periprostatic anesthesia with 1% solution of lidocaine (10 ml) was carried out in the first group. An intrarectal introduction of 5 g EMLA cream (lidocaine 2,5% and prilocaine 2,5%) was applied in the second group. The intrarectal introduction of 10% lidocaine spray (3 doses) was used in the third group. Placebo as ultrasonic gel was utilized for the fourth group. The authors used the 100-score linear visual analog scale (LVS 1-100) and 5-score numeric visual scale (NVS-4). Minimal scores of pain were obtained in patients using TRUS-guided periprostatic anesthesia with 1% solution of lidocaine (10 ml). This type of anesthesia didn't lead to increase of the number of complications. PMID- 26983266 TI - [Combined therapy of pleomorphic xanthoastrocytoma with sympathetic temporal epilepsy diagnosed in the first trimester of pregnancy]. PMID- 26983267 TI - [Rare case of undiagnosed foreign body in bronchus]. PMID- 26983268 TI - [CLASSIFICATION OF ACUTE PANCREATITIS: CURRENT STATE OF THE ISSUE]. AB - The article analyzed disadvantages of "Atlanta-92" classification of acute pancreatitis and its two modifications: APCWG-2012 and IAP-2011. The school of Saint-Petersburg pancreatologists suggested the classification AP of Russian Surgical Society (2014), which represented the concept of disease staging. PMID- 26983269 TI - [ORGANIZATIONAL AND TACTICAL FEATURES OF EMERGENCY SURGERY PERFORMANCE FOR PREGNANT WOMEN AND PUERPERAS]. AB - The results of treatment of acute surgical diseases are worse in pregnant women, than in ordinary people, because of changes in patient's organism. However, these patients would be treated the same way as ordinary patient according to conventional standards. The authors launched the special centre for treatment of acute surgical diseases of abdominal cavity for pregnant women and puerperas in order to provide the adequacy of treatment to the changes of patient's organism. There was suggested a new standard of diagnostics, based on limited term (4-5 hours) with the following diagnostic laparoscopy or laparotomy in obscure cases. The experience of treatment of 171 patients with acute pancreatitis proved the high efficacy of the new strategy and developed standard of diagnostics. The main part of the patients were operated at the first 2-4 hours (105 patients--61.4%) after hospitalization and 43 (25.1%) patients--within 4-6 hours. The cattaral form (92 patients--53.8%) and phlegmonous (74 patients--43.3%) form of the appendix changes were revealed in majority of patients. The gangrenous appendicitis was detected in 5 cases (2%). All the patients recovered. There wasn't maternal or perinatal mortality. PMID- 26983271 TI - [Surgeon Anna Ivanovna Morozova and her contribution in development of Russian surgery]. PMID- 26983272 TI - [Minimally invasive esophagectomy in surgical treatment of esophageal carcinoma]. PMID- 26983270 TI - [POSTOPERATIVE INTRAABDOMINAL COMPLICATIONS IN COLON CANCER SURGERY COMPLICATED BY BOWEL OBSTRUCTION AND PERFORATION OF THE TUMOR]. AB - The article presents a retrospective analysis of the results of surgical treatment of postoperative intraabdominal complications in 42 patients with colon cancer complicated by bowel obstruction and perforation of the tumor. The pyoinflammatory processes such as peritonitis and abscesses of abdominal cavity took a leading place in the structure of postoperative complications according to the authors. Method of "closed" decompression and intraluminal irrigation of the large intestine without wide opening of organ lumen was developed and applied into practice as perioperative prophylaxis of pyoinflammatory processes. These measures allowed reducing the rate of postoperative intraabdominal complications from 19.2 to 7.7%. PMID- 26983273 TI - [Professor Peter Nikolaevich Zubarev (to his 70th birthday)]. PMID- 26983274 TI - [BEHAVIOURAL AND FUNCTIONAL VESTIBULAR DISTURBANCES AFTER SPACE FLIGHT. 1. MAMMALS]. AB - The review contains data on functional changes in mammals caused by changes in the operation of vestibular system after space flight. These data show that the vestibular system of mammals responds to weightlessness challenge differently at various ontogenetic stages. Orbital space flight conditions have a weak effect on the developing vestibular system during embryonic period. The weightlessness conditions have rather beneficial effect on development of the fetuses. During the early postnatal period, when optimal sensory-motor tactics are created, the prolonged stay under conditions of space flight leads to development of novel, "extraterrestrial" sensory-motor programs that can be fixed in CNS, apparently, for the whole life. In adult individuals after landing essential vestibular changes and disturbances may occur that depend on the spaceflight duration. The adult organism must simultaneously solve two contradicting problems--it should adapt to weightlessness conditions, and should not adapt to them to pass the process of readaptation after returning easier. Thus, individuals must protect themselves against weightlessness influence to keep the intact initial state of health. The protection methods against weightlessness ought to be adjusted according to the duration of space flight. It should be mentioned that not all functional changes registered in adult individuals after landing can be adequately explained. Some of these changes may have chronic or even pathological character. The question of necessity to examine the influence of weightlessness on an aging (senile) organism and on its vestibular system is raised for the first time in this review. In our opinion the development of space gerontology, as a special branch of space biology and medicine, is of undoubted interest, and in the future it may be of practical importance especially taking into account the steadily growing age of cosmonauts (astronauts). PMID- 26983276 TI - [COMPARATIVE SENSITIVITY OF CHOLINESTERASES IN VERTEBRATES AND INVERTEBRATES TO HIGHLY SPECIFIC ORGANOPHOSPHORUS INHIBITORS DIISOPROPYL FLUOROPHOSPHATE (DFP) AND (2-ETHOXYMETHYL PHOSPHORYL THIOETHYL) ETHYL (METHYL) SULPHONIUM SULPHOMETHYLAT (GD-42)]. AB - The review presents data on comparative reactivity of 68 cholinesterase preparation from various organs and tissues in a number of vertebrates and invertebrates based on sensitivity to two highly specific and most studied organophosphorus inhibitors--diisopropyl fluorophosphates (DFP) and (2 ethoxymethyl phosphoryl thioethyl) ethyl (methyl) sulphonium sulphomethylat (GD 42). Analysis of these data suggests a great diversity in enzymologic characteristics of cholinesterase preparation in representatives of vertebrates and invertebrates, this variety observed even for closely related enzymes in animals of almost the same level of development. PMID- 26983275 TI - [AMYGDALA: NEUROANATOMY AND NEUROPHYSIOLOGY OF FEAR]. AB - This work describes neuroanatomical and neurophysiological mechanisms of Pavlovian fear conditioning, focusing on contributions of the amygdala, a subcortical nuclear group, to control of conditioned fear responses. The mechanisms of synaptic plasticity at projections to the amygdala and within amygdala were shown to mediate the formation and retention of fear memory. This work reviews current data on anatomical organization of the amygdala, as well as its afferent and efferent projections, in respect to the role of the amygdala in auditory fear conditioning during which acoustic signals serve as the conditioned stimulus. PMID- 26983277 TI - [ROLE OF CASPASE-3 IN REGULATION OF THE CONTENT OF THE AMYLOID-DEGRADING NEUROPEPTIDASE NEPRILYSIN IN THE CORTEX OF RATS AFTER HYPOXIA]. AB - Analysis of the effect of a caspase-3 inhibitor on the content of the amyloid degrading neuropeptidase neprilysin (NEP) in the cortex of rats subjected to prenatal hypoxia (7% O2, 3 h) on the 14-th day of the embryonic development (E14) was performed. It was found that rats subjected to prenatal hypoxia on days 20-30 after birth have an increased content and activity of caspase-3 with reduced levels of NEP and of the C-terminal fragment of the amyloid precursor protein (AICD) regulating NEP expression. In hypoxic animals 3 days after a single injection of a caspase inhibitor (i. v., Ac-DEVD-CHO, P20) the content of AICD and NEP was found to be increased up to the levels observed in control rats. The data obtained suggest that the increase of caspase-3 enzyme activity could affect NEP expression via proteolytic degradation of its transcription factor AICD. These data for the first time demonstrate the role of caspases in AICD-dependent regulation of NEP production in the brain of mammals under hypoxic conditions. PMID- 26983278 TI - [THE INFLUENCE OF LONG-TERM THYROXINE TREATMENT ON THE ACTIVITY OF NO-SYNTHASES IN TISSUES OF RATS WITH OBESITY INDUCED BY HIGH-FAT DIET]. AB - Under obesity, a component of metabolic syndrome (MS), macro- and microcirculation are attenuated, which is associated with abnormalities of NO dependent cascades and leads to pathology of the cardiovascular system. Among the activators of NO-synthases (NOS), the enzymes catalyzing NO synthesis, are thyroid hormones. Since obesity and MS are characterized by reduced functions, of the thyroid gland, the replacement therapy with thyroid hormones, possessing the properties of vasodilators, is one of approached to restore functioning of the cardiovascular system. However, data on influence of thyroid hormones on NOS activity in obesity are not currently available. The aim of this work was to study the effect of four-week treatment of rats with obesity induced by high-fat diet with L-thyroxine (at a daily dose of 20 mg-kg) on functional activity of total NOS, as well as one endothelial (eNOS) and neuronal (nNOS) isoforms of the enzyme in the brain, myocardium and skeletal muscles of animals. In obese rats the decrease of thyroid hormones level, impaired glucose toleranse, and dyslipidemia were detected. In the myocardium and skeletal muscles of obese rats the activity of total NOS and eNOS was strongly decreased, whereas in the brain the activity of these enzymes was not significantly changed. Long-term treatment of obese rats with thyroxine led to a significant increase in activity of total NOS and eNOS in the myocardium and skeletal muscles and to an increase in activity of total NOS and nNOS in the brain, with the enzyme activity exceeding that in control. In healthy animals treated with thyroxine a significant increase in activity of total NOS and eNOS in the myocardium and skeletal muscles and in activity of total NOS in the brain was also eNOS in the myocardium and skeletal muscles and in activity of total NOS in the brain was also found. A significant contribution to the increasing activity of total NOS in obese rats and healthy animals treated with thyroxine belonged to the inducible isoform of the enzyme whose activity was found by calculation. Thus, the four-week thyroxine treatment of obese rats with deficiency of thyroid hormones led to a complete restoration of activity of total NOS and eNOS, reduced in obesity, in the myocardium and skeletal muscles which indicated the prospects of thyroxine therapy for treatment of vascular pathology in obesity and MS. PMID- 26983279 TI - [THE REGULATING EFFECT OF DIPEPTIDES ON CELL PROLIFERATION IN NERVE TISSUE CULTURE IN MAMMALS AND ON ASSOCIATIVE LEARNING IN INSECTS]. AB - The effect of dipeptides AspPro and AspSer and of their composing amino acids (asparagine acid--Asp, proline--Pro, serin--Ser) on the proliferative activity in the explants of cortex and subcortical structures of the rat brain and on the functional activity of CNS of the honeybee was studied. The square index defined as a proportion of the whole explant square to the square of its central zone was determined. The number of bees responded with the conditional reaction (proboscis extension in the direction to aromatized solution) after 1 min (short-term memory) and 180 min (long-term memory) was detected after single learning procedure. Both dipeptides, as well as the asparagine acid, stimulated an increase of the growth zone of the subcortical structure explants in rats and of the number of honeybees with retention of conditional reaction in the short term/long-term memory independently of the effect of the second member of the dipeptide. The unidirectionality of the effect suggests the existence of common mechanisms of reception and signal transduction established during evolution that require the further study. PMID- 26983280 TI - [INFLUENCE OF OLEAMIDE OF WATER AND ION TRANSPORT IN THE OSMOREGULATORY ORGANS]. AB - Application of oleamide (final concentration of 10 MUM) at the skin basal surface of the frog, Rana temporaria L., augmented the short-circuit current (SCC) from 59.8 +/- 2.5 to 78.2 +/- 1.4 MUA/cm2. Oleamide added to the serous membrane of the frog urinary bladder at a final dose of 1 MUM induced more than 30-fold increase of osmotic permeability. The addition of arginine-vasotocin on the background of oleamide action further increased SCC across the isolated frog skin and osmotic permeability of the frog urinary bladder. Intraperitoneal injection of oleamide at a dose of 0.1 mM/100 g BW to water-loaded non-anesthetized Wistar rats decreased diuresis by 22%, enhanced solute-free water reabsorption and urinary sodium excretion by 31% and 55% respectively, but did not affect the renal potassium excretion. The results obtained provide evidence of similarity of oleamide and neurohypophyseal hormones effects on water and ion transport in epithelial cells of osmoregulatory organs in vertebrates. PMID- 26983281 TI - [NEURONS IN VISUAL THALAMIC CENTERS OF TURTLES, PROJECTING UPON THE TELENCEPHALON, EXPRESS DIFFERENT TYPES OF CALCIUM-BINDING PROTEINS: COMBINED IMMUNOHISTOCHEMICAL AND TRACER STUDY]. AB - In turtles (Testudo horsfieldi, Emys orbicularis) the immunoreactivity for calbindin (CB), parvalbumin (PV), calretinin (CR), and colocalization of PV and CB in neurons of visual thalamic nuclei (Rot, GLD) projecting to the telencephalon were studied using combined immunohistochemical and tracer method. The predominance of CB-ir neurons in Rot, CB-ir and CR-ir neurons in GLD and a lower amount of PV-ir neurons in both nuclei were shown. With double labeling fluoroimmunohistochemistry technique the colocalization of PV with CB was revealed in the majority of PV-ir neurons and in a fewer number of CB-ir neurons within both nuclei. After delivery of horseradish peroxidase into the telencephalic projection fields of Rot and GLD, retrograde labeling was found in the corresponding thalamic projection neurons immunoreactive for every protein investigated. After fluorescent tracer (Fluoro Gold) injection into the same telencephalic regions retrograde labeling was observed in Rot and GLD neurons, immunoreactive only for PV or CB, as well in neurons with colocalization of the both proteins. These data support predominance of CB-ir component in the rotundo telencephalic pathway and CB/CR components in the geniculo-telencephalic pathway in turtles. The role of functional specialization in segregation of neurons expressing different types of calcium-binding proteins is postulated. PMID- 26983282 TI - [NEUROGLOBIN DISTRIBUTION IN THE RAT CEREBELLAR PURKINJE CELLS]. PMID- 26983283 TI - [EFFECT OF COCKROACH PHEROMONE ON CHARACTERISTICS OF CALLING SOUND EMISSION IN THE CRICKET GRYLLUS BIMACULATUS]. PMID- 26983284 TI - Just Breathe. PMID- 26983285 TI - This Is My Truth. PMID- 26983286 TI - Lights, Camera ... PREDIABETES? PMID- 26983287 TI - The Perfect Storm. PMID- 26983288 TI - Are We There Yet? PMID- 26983289 TI - THYROID WOES. PMID- 26983290 TI - The Sweet Stuff. PMID- 26983291 TI - Food. PMID- 26983292 TI - The Kids Aren't All Right. PMID- 26983293 TI - Understanding the CDC's updated HIV test protocol. PMID- 26983295 TI - Biomarkers and personalized cancer medicine. PMID- 26983294 TI - A20 modulation: a potential biological threat that can be mitigated by immunohistochemistry. PMID- 26983296 TI - Management of diabetes: the future is now. PMID- 26983297 TI - Paving the way for prediabetes diagnostics: biomarkers that reflect impaired glucose tolerance. PMID- 26983298 TI - Train the trainer: taking control of your lab's software education. PMID- 26983300 TI - Improving the molecular diagnosis and treatment of epilepsy with complex genetic testing. PMID- 26983299 TI - The laboratory's contribution to advanced medical analytics. PMID- 26983301 TI - First validated clinical test selects best embryos for IVF and viable pregnancies. PMID- 26983303 TI - Industry leader weighs in on glucose monitor regulation controversy. PMID- 26983302 TI - Soaring demand for genetic testing highlights need for streamlined data interpretation. PMID- 26983305 TI - [How to cope in this world marked by uncertainty and concern?]. PMID- 26983306 TI - [Image of the month. A coronary-left ventricular fistula]. PMID- 26983307 TI - [How I TREAT AN ASYMPTOMATIC AORTIC STENOSIS?]. AB - Aortic stenosis (AS) is the most common valvular heart disease in adults. The most frequent aetiology is now degenerative AS. There is general agreement that, in the absence of serious co-morbidity, surgery must be recommended for patients with symptomatic disease. The management of asymptomatic patients with severe aortic disease remains controversial for several reasons: sudden death in asymptomatic patients has been reported with an incidence < 1 % per year. In addition, operative mortality is significantly higher in symptomatic, when compared with asymptomatic, patients. Patients should be carefully educated about the importance of follow-up and reporting symptoms as soon as they develop. Echocardiography confirms the diagnosis and the severity of aortic stenosis. Exercise testing may be helpful when the patient is asymptomatic. If the patient develops symptoms during test, he should be referred for surgery. The management of patients with AS in everyday practice is based on the guidelines developed by ESC in October 2012. PMID- 26983308 TI - [A RARE CAUSE OF THORACIC MYELOPATHY: THE OSSIFICATION OF THE LIGAMENTUM FLAVUM]. AB - Ossification of the ligamentum flavum (OLF) is a rare cause of thoracic myelopathy. Mostly described in Japan and East Asia, a number of cases have recently been reported in western subjects. We present the case of a patient, an asymptomatic carrier of lumbar canal stenosis, presenting with a slowly progressive posterior cord compression and a T12 sensitive level. The diagnosis of thoracic OLF was retrospectively made thanks to medical imaging. We reviewed the literature and focused on the epidemiology, physiopathology, presentation, treatment and prognosis of the thoracic OLJ with or without lumbar spinal stenosis. PMID- 26983309 TI - [VENOUS THROMBOSIS OF THE LEFT OVARIAN AND EXTENSION TO THE RENAL VEIN]. AB - Ovarian vein thrombosis is a rare, but potentially serious postpartum complication. In 80% of the cases, it occurs on the right side and in less than 6% on the left side; it is bilateral in 14% of cases. The usual clinical features include abdominal pain, fever and leucocytosis. However, the diagnosis is often complicated by other non specific signs and symptoms. Ovarian vein thrombosis may cause sepsis, pulmonary thromboembolism, and thrombosis of the inferior vena cava and the renal vein. The diagnosis can be established by CT scan or nuclear magnetic resonance imaging, which has a high sensitivity and specificity. Treatment for the ovarian vein thrombosis includes antibiotics and anticoagulation. The complications can sometimes be surgically managed. Prompt diagnosis and treatment can decrease the morbidity and the mortality. Nowadays, the fatal issue is rare as the appropriate treatment is quickly instaured. PMID- 26983310 TI - [CARDIOVASCULAR INVOLVEMENTS IN BEHCET'S DISEASE: "ANGIO-BEHCET"]. AB - Behcet's disease is a relapsing, immune-mediated systemic vasculitis that may affect blood vessels of all types and sizes. Nowadays, the etiology remains unclear. In the absence of a biological marker or pathognomonic radiology, the diagnosis is mainly based on clinical manifestations. The cardiovascular involvement, known as "angio-Behcet", is relatively common and affects up to 40% of patients. It typi- cally occurs in a young male, usually during the onset of the disease. In general, immunosuppressive and anticoagulant therapies initiated early are likely to induce a remarkable cli- nical improvement. Nevertheless, prompt recognition of the polymorphous cardiovascular manifestations of the disease is challenging and may be responsible for some considerable delay prior to initiation of adequate therapy. The aim of this article is to describe the spectrum of cardiovascular involve- ments of Behcet's disease in order to optimize detection and therapeutic management. PMID- 26983311 TI - [FIRST CONSULTATION IN TEENAGERS FOR CONTRACEPTION PRESCRIPTION]. AB - Adequate contraception prescription is mandatory for teenagers to avoid any unwanted pregnancy. Counselling and description of side effect improve compliance. Use of condom is important to avoid sexually transmitted infections. Combined estroprogestin contraception has multiple non-contraceptive benefits, e.g. dysmenorrhea improvement. Familial and personal history is needed before contraception prescription. Further consultation 3 months later has to be planned to evaluate compliance, side effects and to adapt contraception if needed. PMID- 26983312 TI - [PROGNOSTIC FACTORS IN NON SMALL CELL LUNG CANCER]. AB - Non small cell lung cancer is the most frequent type of lung cancer and its prognosis is still very poor. Relapse is frequent and can be observed even in early stages of the disease, in spite of a surgical management with curative intent. This paper gives an overview of the main prognostic factors, the two most important of which remain the staging and tumor histology. These also determine the therapeutic strategy. Other factors of poor prognosis might also be useful for clinicians, particularly in their decision to refer patients for adjuvant therapies. PMID- 26983313 TI - [THE MALADAPTIVE BELIEFS OF PATIENTS WITH LOW BACK PAIN. A NARRATIVE REVIEW]. AB - OBJECTIVE: to summarize the knowledge regarding the maladaptive beliefs of patients with non-specific low back pain. METHODS: a narrative literature review on these beliefs was conducted by an international and multidisciplinary team of experts in the field. RESULTS: these beliefs, which can result in negative consequences on functioning and on patient prognosis, have various origins: family and friends, media, previous experience and/or health care professionals' messages. The latter, who have a considerable and enduring influence, have the potential to change and correct the patients' misbeliefs; however, they can also reinforce them in case of inappropriate messages and attitudes. Informing and educating the patient (by means of reassurance, explanations of the non systematic association pain-injury, encouragement to get and stay physically active) are the basis of treatment. Taking into account the consequences of some words which may be misinterpreted, the results of imaging should be wisely discussed with the patient. Pain neurophysiology education and cognitive behavioral therapy (i.a., in vivo graded exposure techniques) are effective additional treatments. CONCLUSIONS: Misbeliefs are frequent in patient with low back pain. They do need to be looked for and corrected. PMID- 26983314 TI - [FIXED COMBINATION ATORVASTATIN-EZETIMIBE (ATOZET(r))]. AB - Cardiovascular prevention in subjects at high or very high risk requires a drastic reduction in LDL cholesterol according to the concept "the lower, the better". The combination of an inhibitor of cholesterol synthesis and a selective inhibitor of intestinal absorption results in a complementary and synergistic LDL lowering activity. Besides a first fixed combination ezetimibe-simvastatin (Inegy(r)), a new fixed combination is presented, Atozet(r) that combines atorvastatin and ezetimibe. Because atorvastatin is more potent than simvastatin, this novel fixed combination should facilitate reaching therapeutic goals in terms of LDL cholesterol amongst patients with severe hypercholesterolaemia and/or at high or very high cardiovascular risk. PMID- 26983315 TI - [HOW I EXPLORE... SKIN COMPLEXION BY ANALYTICAL APPROACH]. AB - Skin colour is important for interindividual relationships considerations, as well as for the assessment of some physiopathological aspects. Its subjective assessments varies among observers and according to light. By contrast, an objective approach, both qualitative and quantitative by analytical measurements, has been available for some years. Its application in routine clinical settings is possible. The aspects are dependent on the incident light wavelengths. Accordingly, a series of skin diseases, but also ictera, uremia, anemia and hemochromatosis are possibly assessed in the field of internal medecine according to variations of skin colors. PMID- 26983316 TI - Starting Over on Nuclear Waste Storage. PMID- 26983318 TI - New First Aid and CPR Guidelines: Step In to Save a Life. PMID- 26983317 TI - Common Questions Safety Managers Ask About Using ESLIs for Organic Vapors. PMID- 26983319 TI - New California AED Laws: Bull Rush From the Bear State?. PMID- 26983320 TI - Utilizing Technology in Manual Material Handling and Safe Lifting. AB - There is great potential to decrease injuries with the use of these new technologies, especially musculoskeletal disorders and repetitive task-related injuries. Initial costs can be considerable for some of these units, but they are much cheaper than a back surgery. As with all technology, the first designs cost a small fortune, but as we are seeing even now, the pricing is decreasing and the quality is increasing for these devices. In 30 years, we might all have flying cars like "Back to the Future II" predicted we would in 2015 or be able to figure out a tricorder like on "Star Trek"! For more information on exoskeletons, exoskeletonreport.com is a great resource. PMID- 26983321 TI - Keys to Preventing Eye Injuries. PMID- 26983322 TI - Infrared Sensors Shine a New Light on LEL Combustible Gas Measurement. PMID- 26983323 TI - Whole Air Sampling: No Pump, No Problem. PMID- 26983324 TI - Trends in Marijuana Legalization: A Wake-Up Call for Employers. PMID- 26983325 TI - Marijuana Use and Its Impact on Workplace Safety and Productivity. PMID- 26983326 TI - Get Acquainted With EU Safety Glove Standards. AB - As with many of the standards developed as a result of the EU Directive on PPE, the classification of a glove in a particular test is usually defined as one of a series of performance levels (usually between 1 and 4 or 5). It is then left to the user, following a suitable risk assessment exercise, to select a glove with a suitable profile of performance levels in relevant tests. PMID- 26983327 TI - Help Protect Hard-Working Hands from Occupational Skin Disorders. PMID- 26983328 TI - Solving a Tough Guarding Challenge. PMID- 26983330 TI - Forward Pressure for Courageous Leadership. PMID- 26983329 TI - Contractor Safety Management: Aligning Strategy and Culture. PMID- 26983331 TI - [Diabetes: regression instead progress?]. PMID- 26983332 TI - [New targets in pharmacotherapy of type 2 diabetes]. AB - The number of people with diabetes is expected to increase worldwide to 360 million within the next 15 years of which 90% will have type 2 diabetes (non insulin-dependent diabetes mellitus). Established therapies mainly focus on the following principles: increase in plasma insulin, improving insulin sensitivity of tissues, reducing the rate of carbohydrate absorption and gluconeogenesis. The demand on compounds with new mechanisms of action is obvious. This articles summarizes new targets and compounds under development for pharmacotherapy of typ 2 diabetes; at present approx. 180 compounds are going to be developed worldwide. PMID- 26983333 TI - [Drug treatment of diabetes mellitus type 2]. PMID- 26983334 TI - [Comment by Prof. Dr. med Dirk Muller-Wieland. The therapeutic goal for blood sugar lowering in diabetes treatment]. PMID- 26983335 TI - [Risk and benefit of sulfonylureas--their role in view of new treatment options for type 2 diabetes]. AB - Currently, the therapy with oral antidiabetic drugs undergoes major changes. The use of sulfonylureas is in marked decline. The major argument in favor of newer oral antidiabetic drugs is the lower risk of hypoglycemia. At the present time however, it is unclear whether DDP4 inhibitors or SGLT2 inhibitors lead to better outcomes with respect to cardiovascular events and overall mortality. Most evidence on the therapeutic use of sulfonylureas has been gained with glibenclamide and to some degree sulfonylureas and glibenclamide have become synonymous. Since sulfonylureas vary considerably in their affinity for the K(ATP) channel subtypes and in their pharmacokinetic properties, the epidemiological evidence that outcomes tend to be less favorable with glibenclamide than with glimepiride or gliclazide has gained some attention. Beyond debate is the efficacy of metformin to diminish cardiovascular events in type 2 diabetes, probably due to effects beyond the lowering of blood glucose. PMID- 26983336 TI - [Metformin for the treatment of polycystic ovary syndrome]. AB - For several years there is an evidence for a relationship between the polycystic ovary syndrome (PCOS) and of insulin resistance; therefore metformin, an insulin sensitizer, is used for the treatment for more than 10 years. However, the evidence for metformin is assessed controversially. This review will give an overview about the data published on this topic. PMID- 26983337 TI - [Is vaccination with the meningococcal vaccine Bexsero recommended for asplenia?]. PMID- 26983338 TI - [Larazotide as an option in case of failure of a gluten-free diet]. PMID- 26983339 TI - Big Steps in the Right Direction. PMID- 26983341 TI - Start With Yes. PMID- 26983340 TI - Standards, Practices, and How the ADA Has Our Backs. PMID- 26983343 TI - Disaster Preparedness Meets Dentistry. PMID- 26983342 TI - Principle and Practice in Ethics and Morality--Part One. PMID- 26983344 TI - Smoking, Smokeless Tobacco, and Alcohol Consumption as Contributing Factors to Periodontal Disease. PMID- 26983345 TI - The Healing Power of Forgiveness. PMID- 26983346 TI - Expression, localization and possible functions of aquaporins 3 and 8 in rat digestive system. AB - Although aquaporins (AQPs) play important roles in transcellular water movement, their precise quantification and localization remains controversial. We investigated expression levels and localizations of AQP3 and AQP8 and their possible functions in the rat digestive system using real-time polymerase chain reactions, western blot analysis and immunohistochemistry. We investigated the expression levels and localizations of AQP3 and AQP8 in esophagus, forestomach, glandular stomach, duodenum, jejunum, ileum, proximal and distal colon, and liver. AQP3 was expressed in the basolateral membranes of stratified epithelia (esophagus and forestomach) and simple columnar epithelia (glandular stomach, ileum, and proximal and distal colon). Expression was particularly abundant in the esophagus, and proximal and distal colon. AQP8 was found in the subapical compartment of columnar epithelial cells of the jejunum, ileum, proximal colon and liver; the most intense staining occurred in the jejunum. Our results suggest that AQP3 and AQP8 play significant roles in intestinal function and/or fluid homeostasis and may be an important subject for future investigation of disorders that involve disruption of intestinal fluid homeostasis, such as inflammatory bowel disease and irritable bowel syndrome. PMID- 26983347 TI - Screening and kinetic studies of catharanthine and ajmalicine accumulation and their correlation with growth biomass in Catharanthus roseus hairy roots. AB - Context Catharanthus roseus (L.) G. Don (Apocynaceae) is still one of the most important sources of terpene indole alkaloids including anticancer and hypertensive drugs as vincristine and vinblastine. These final compounds have complex pathway and many enzymes are involved in their biosynthesis. Indeed, ajmalicine and catharanthine are important precursors their increase can lead to enhance levels of molecules of interest. Objective This study aims at selecting the highest yield of hairy root line(s) and at identifying best times for further treatments. We study kinetics growth and alkaloids (ajmalicine and catharanthine) accumulation of three selected hairy root lines during the culture cycle in order to determine the relationship between biomass production and alkaloids accumulation. Materials and methods Comparative analysis has been carried out on three selected lines of Catharanthus roseus hairy roots (LP10, LP21 and L54) for their kinetics of growth and the accumulation of ajamalicine and catharanthine, throughout a 35-day culture cycle. The methanolic extract for each line in different times during culture cycle is analyzed using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Results Maximum accumulation of the alkaloids is recorded for LP10 line in which the peak of ajmalicine and catharanthine accumulation reached to 3.8 and 4.3 mg/g dry weight (DW), respectively. This increase coincides with an exponential growth phase. Discussion and conclusion Our results suggest that the evolution of accumulation of ajmalicine and catharanthine are positively correlated with the development of the biomass growth. Significantly, for LP10 line the most promising line to continue optimizing the production of TIAs. Additionally, the end of exponential phase remains the best period for elicitor stimuli. PMID- 26983348 TI - Co3V2O8 Sponge Network Morphology Derived from Metal-Organic Framework as an Excellent Lithium Storage Anode Material. AB - Metal-organic framework (MOF)-based synthesis of battery electrodes has presntly become a topic of significant research interest. Considering the complications to prepare Co3V2O8 due to the criticality of its stoichiometric composition, we report on a simple MOF-based solvothermal synthesis of Co3V2O8 for use as potential anodes for lithium battery applications. Characterizations by X-ray diffraction, X-ray photoelectron spectroscopy, high resolution electron microscopy, and porous studies revealed that the phase pure Co3V2O8 nanoparticles are interconnected to form a sponge-like morphology with porous properties. Electrochemical measurements exposed the excellent lithium storage (~1000 mAh g( 1) at 200 mA g(-1)) and retention properties (501 mAh g(-1) at 1000 mA g(-1) after 700 cycles) of the prepared Co3V2O8 electrode. A notable rate performance of 430 mAh g(-1) at 3200 mA g(-1) was also observed, and ex situ investigations confirmed the morphological and structural stability of this material. These results validate that the unique nanostructured morphology arising from the use of the ordered array of MOF networks is favorable for improving the cyclability and rate capability in battery electrodes. The synthetic strategy presented herein may provide solutions to develop phase pure mixed metal oxides for high performance electrodes for useful energy storage applications. PMID- 26983350 TI - Medical innovations and discoveries: the mind of a scientist is the most important research instrument. PMID- 26983349 TI - The Relationship Between 24-Hour Symptoms and COPD Exacerbations and Healthcare Resource Use: Results from an Observational Study (ASSESS). AB - This observational study assessed the relationship between nighttime, early morning and daytime chronic obstructive pulmonary disease (COPD) symptoms and exacerbations and healthcare resource use. COPD symptoms were assessed at baseline in patients with stable COPD using a standardised questionnaire during routine clinical visits. Information was recorded on exacerbations and healthcare resource use during the year before baseline and during a 6-month follow-up period. The main objective of the analysis was to determine the predictive nature of current symptoms for future exacerbations and healthcare resource use. 727 patients were eligible (65.8% male, mean age: 67.2 years, % predicted forced expiratory volume in 1 second: 52.8%); 698 patients (96.0%) provided information after 6 months. Symptoms in any part of the day were associated with a prior history of exacerbations (all p < 0.05) and nighttime and early-morning symptoms were associated with the frequency of primary care visits in the year before baseline (both p < 0.01). During follow-up, patients with baseline symptoms during any part of the 24-hour day had more exacerbations than patients with no symptoms in each period (all p < 0.05); there was also an association between 24 hour symptoms and the frequency of primary care visits (all p <= 0.01). Although there was a significant association between early-morning and daytime symptoms and exacerbations during follow-up (both p < 0.01), significance was not maintained when adjusted for potential confounders. Prior exacerbations were most strongly associated with future risk of exacerbation. The results suggest 24-hour COPD symptoms do not independently predict future exacerbation risk. PMID- 26983351 TI - Peduncular hallucinosis due to brain metastases from cervix cancer: a case report. AB - BACKGROUND: Brain metastases from cervical carcinoma are rare. Accompanying symptoms depend on the location of the metastatic lesions. Penduncular hallucinosis is a vivid form of hallucination with clinical findings indicating a lesion of the upper midbrain. We hereby report a probable first case of peduncular hallucinosis associated with brain metastases from cervical cancer. CASE: A 42-year-old woman had been diagnosed with adenocarcinoma of cervix. On admission for her increasing pelvic pain, she had complex visual hallucinations comprising cartoon children, figurative people and a foggy room. Magnetic resonance imaging of the head revealed a lesion in the left mesencephalothalamic area. CONCLUSION: Peduncular hallucinosis is well known for its vivid and life like characteristics associated with a mesencephalic area lesion, and recognition of this may be useful of its diagnosis and differential diagnosis from confusion and other hallucinations. PMID- 26983352 TI - Identification of candidate genes for schizophrenia based on natural resistance to infectious diseases. AB - BACKGROUND: Identification of candidate genes for schizophrenia may be more successful than genome screens as the latter have not found consistent linkages. OBJECTIVE: To assist in the gene search, a model of schizophrenia based on resistance to infectious diseases, rather than susceptibility, is proposed. The theory blends the geography of schizophrenia with the assumption that genes that cause schizophrenia likely evolved and persist from selection pressure. The theory includes the notion that schizophrenia enhances biological survival at the cost of psychological and social functioning. METHOD: To demonstrate the utility of using this model, the Medline literature was searched for resistance genes, mostly identified in mice. RESULTS: Based on homologous locations in the human genome, these resistance genes are shown to be located in human chromosome regions linked significantly, in at least one genome screen, with schizophrenia or some physiologically related function or condition associated with schizophrenia. CONCLUSIONS: The infectious disease resistance theory of schizophrenia is offered as a viable model for understanding the origins of schizophrenia. The theory also allows for the inclusion of persistent infections, seasonal variability and translational pathophysiology to contribute to the etiology of schizophrenia. PMID- 26983353 TI - Hypothalamic digoxin-mediated model for epileptogenesis. AB - BACKGROUND/AIMS: This study assessed the changes in the isoprenoid pathway and its metabolites in seizure disorder (ILAE classification - I generalized - idiopathic generalized epilepsy with age-related onset - epilepsy with generalized tonic clonic seizures on awakening) and the metabolic cascade produced by isoprenoid pathway dysregulation. METHODS: The following parameters were assessed in seizure disorder: isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugates metabolism and red blood cell (RBC) membrane composition. RESULTS: There was elevation in plasma HMG-CoA reductase activity, serum digoxin and dolichol and a reduction in RBC membrane Na-K+ ATPase activity, serum magnesium and ubiquinone levels. Serum tryptophan, serotonin, strychnine, nicotine and quinolinic acid were elevated while tyrosine, dopamine, morphine and norepinephrine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions (except dermatan sulfate), the activity of glycosaminoglycans (GAG) degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins and serum glycolipids were elevated. Total serum cholesterol, LDL cholesterol and free fatty acids were increased while HDL cholesterol and triglycerides were unaltered. The concentration of membrane hexose, fucose, cholesterol and phospholipids in the RBC membrane decreased significantly but the total RBC membrane GAG was unaltered. CONCLUSIONS: Epileptogenesis could be due to a dysfunctional isoprenoidal pathway and paroxysmal hypothalamic digoxin hypersecretion. PMID- 26983354 TI - Influence of whole body cryotherapy on depressive symptoms - preliminary report. AB - BACKGROUND: Cryotherapy has a long tradition in somatic medicine. Yet we know very little about its impact on psyche and mood disturbances in particular. Therefore there is a real need for scientific investigations into this problem. OBJECTIVE: The study reported here was an initial approach to whole-body cryotherapy (WBCT) as a potential treatment modality for depression and was expected to provide rough data helping to design a future project with extended methodology, larger sample groups and longer follow-up. METHODS: Twenty-three patients aged 37-70 years gave informed consent to participate in the study. Ten WBCT procedures (160 s, -150 degrees C) were applied within 2 weeks. Participants were recruited from depressed day hospital patients. Antidepressive medication was not ceased. Symptoms were rated at the beginning and end of this intervention using the 21-item Hamilton Depression Rating Scale (HDRS). Changes in scores were analyzed in the group of patients for every item separately as well as for the sum of all items for each patient. RESULTS: Almost for each individual HDRS item, the overall score for all patients together was significantly lower after WBCT. This means that all symptoms, except for day-night mood fluctuations, were presumably positively influenced by cryotherapy. The HDRS sum-score for each patient after WBCT was lower than that of the baseline and reached statistical significance in a paired samples t-test. Every patient was therefore considerably relieved after WBCT. CONCLUSIONS: It appears that WBCT helps in alleviating depression symptoms. Should this be confirmed in the extended study we are currently implementing, WBCT may become an auxiliary treatment in depression. PMID- 26983355 TI - The serotonin-2A receptor polymorphism and clinical symptoms in mood disorders, schizophrenia and alcohol dependence in Japan. AB - In the past, there have been many epidemiological and genetic studies of mood disorders, schizophrenia, and alcohol dependence, and in this study, the human serotonin 2A receptor (5-HTR2A) polymorphism was examined in 80 patients with mood disorders, 50 patients with schizophrenia and 41 patients with alcohol dependence. 5-HTR is related to affectivity, regulation, and pharmacologic effects of antidepressant, anti-anxiety and antipsychotic medications. The polymorphism in 5-HTR2A (102T/C, -1438 A/G) was identified by the polymerase chain reaction (PCR), followed by restriction fragment length polymorphism (RFLP). The results suggest that 5-HTR2A (102T/C, -1438G/A) polymorphism might not be associated with susceptibility to schizophrenia or mood disorders, and it might not be a risk factor contributing to alcohol dependency. We found that the 102T/C polymorphism was in linkage disequilibrium with the -1438G/A polymorphism in psychosis (mood disorder, schizophrenia, and alcohol dependence) and in health controls. Further studies are needed to determine whether or not the novel serotonin receptor (5-HTR) polymorphism reflects the pathogenesis of schizophrenia, mood disorders, and alcohol dependence. PMID- 26983356 TI - Quetiapine in relapsing schizophrenia: clinical efficacy and effect on monoaminergic parameters. AB - METHODS: Tolerability, safety and effectiveness of quetiapine in an in-patient group with a relapse of schizophrenia and the possible role of plasma amino acid concentrations, 5-HT parameters and HVA in the prediction of response to treatment were investigated in an open-label baseline-controlled trial of 14 weeks in 21 hospitalized schizophrenic patients. Responders were defined as those patients who exhibit at least a 40% reduction of BPRS total scores. Secondary efficacy measures were the PANSS, the Clinical Global Impression (CGI)-severity scale and the MADRS. Extrapyramidal side-effects were evaluated with the AIMS. Other side-effects were monitored at regular intervals. Amino acids and the derived tryptophan and tyrosine ratios, as well as monoaminergic parameters, were assessed in plasma at baseline and at weeks 3, 6 and 14. RESULTS: Treatment with quetiapine resulted in the predefined treatment effect in 10 out of the 17 patients who completed at least 4 weeks of treatment. Effect in responders was observed on all efficacy parameters, including lower MADRS scores. No extrapyramidal side-effects emerged. Clinical and biochemical parameters did not predict response to treatment. CONCLUSIONS: This study demonstrates the moderate antipsychotic efficacy of quetiapine on preferentially positive symptoms in a group of relatively young schizophrenics. Some observed changes in biochemical parameters are discussed. PMID- 26983357 TI - Magnetic resonance imaging studies on autism and childhood-onset schizophrenia in children and adolescents - a review. AB - OBJECTIVE: To find out whether the neurodevelopmental disorders autism and childhood-onset schizophrenia have a common developmental pathway and whether the abnormalities detected are 'disorder-specific', by reviewing magnetic resonance imaging (MRI) studies. METHODS: As a result of a Medline search, we were able to access 28 studies on autism and 12 studies on childhood-onset schizophrenia, which focused on children and adolescents. RESULTS: Larger lateral ventricles were found to be a common abnormality in both disorders. 'Disorder-specific' abnormalities in patients with autism were larger brains, a larger thalamic area, and a smaller right cingulate gyrus. Subjects with childhood-onset schizophrenia were found to have smaller brains, a smaller amygdalum and thalamus, and a larger nucleus caudatus. In subjects with childhood-onset schizophrenia, abnormalities appeared to progress over a limited period of time. CONCLUSIONS: Because the study designs varied so much, the results should be interpreted cautiously. Before abnormalities found in the disorders can be designated as equal or 'disorder-specific', it will be essential to perform large longitudinal and cross sectional follow-up studies. PMID- 26983358 TI - The role of the cytokine network in psychological stress. AB - Although a considerable amount of evidence has shown that psychological stress alters peripheral and brain cytokines, the physiological significance of cytokine alteration in psychological stress remains to be elucidated. The aims of this review are to analyze the influence of acute and chronic psychological stresses on the cytokine network in animals and in humans, and to explore the pathophysiological implication of the cytokine changes in psychological stress. Acute psychological stress may increase proinflammatory cytokines both in animals and in humans, and increase T-helper-1 cell cytokines in humans. Investigations into the effect of chronic psychological stress on cytokine production in animals gives mixed results. However, in humans, academic exam stress or care-giver's stress appears to induce a shift in the Th1/Th2 cytokine balance toward a Th2 response and increase proinflammatory cytokines. Psychological stress-induced cytokines stimulate the activity of indoleamine 2,3 dioxygenase (IDO) and could induce serotonin depletion-related disorders such as depression in susceptible individuals. Psychological stress-induced production of cytokines may increase the risk for human diseases, such as cardiovascular disease and exacerbation of autoimmune diseases. Proinflammatory cytokines may also play a regulatory role in glucocorticoid resistance and may be involved in wound healing and skin barrier function alterations. Finally, psychological stress-induced production of cytokines may play a role in neurodegenerative changes in the brain. PMID- 26983360 TI - A novel curcuminoid exhibits enhanced antitumor activity in nasopharyngeal carcinoma. AB - Curcumin shows growth-inhibition against tumor cells through multi-target mechanisms. Nevertheless, the poor stability and pharmacokinetics considerably limit its clinical functions. Increased effort has been put into the chemical alteration of curcumin to find potential analogues with improved bioavailability and antitumor activities. In this study, the antitumor activity of a novel curcuminoid (B63) in nasopharyngeal carcinoma (NPC) was examined. The MTT and colony formation assays were used to detect NPC cell viability and proliferation. Flow cytometry was used to detect cell cycle distribution. The Annexin V/PI staining assay and cleavage PARP and cleavage caspase-3 expression were used to examine apoptosis. Western blotting was used to examine the protein expression of endoplasmic reticulum (ER) stress pathway markers, XBP-1, ATF-4 and CHOP. The suppressive effect of B63 on tumor growth was examined in vivo by subcutaneously inoculated NPC in a tumor model using nude mice. Treatment with B63 potentially caused growth inhibition and apoptosis in NPC cells in a dose- and time responsive manner. Its antitumor effect was associated with the ER stress activation. Nevertheless, the same dose of curcumin did not activate ER stress. In addition, knockdown of Chop attenuated B63-induced cell viability inhibition, suggesting that the apoptotic pathway is ER stress-dependent. The tumor volume and weight were significantly reduced by pretreating the NPC cells with B63 before implantation in the in vivo mouse model. B63 exhibited a more potent antitumor action than curcumin in NPC. These observations on the novel compound B63 indicate a novel candidate for NPC therapy. PMID- 26983359 TI - Targeted Delivery of C/EBPalpha -saRNA by Pancreatic Ductal Adenocarcinoma specific RNA Aptamers Inhibits Tumor Growth In Vivo. AB - The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) remains dismal despite current chemotherapeutic agents and inhibitors of molecular targets. As the incidence of PDAC constantly increases, more effective multidrug approaches must be made. Here, we report a novel method of delivering antitumorigenic therapy in PDAC by upregulating the transcriptional factor CCAAT/enhancer-binding protein-alpha (C/EBPalpha), recognized for its antiproliferative effects. Small activating RNA (saRNA) duplexes designed to increase C/EBPalpha expression were linked onto PDAC-specific 2'-Fluropyrimidine RNA aptamers (2'F-RNA) - P19 and P1 for construction of a cell type-specific delivery vehicle. Both P19- and P1-C/EBPalpha-saRNA conjugates increased expression of C/EBPalpha and significantly suppressed cell proliferation. Tail vein injection of the saRNA/aptamer conjugates in PANC-1 and in gemcitabine resistant AsPC-1 mouse-xenografts led to reduced tumor size with no observed toxicity. To exploit the specificity of the P19/P1 aptamers for PDAC cells, we also assessed if conjugation with Cy3 would allow it to be used as a diagnostic tool on archival human pancreatic duodenectomy tissue sections. Scoring pattern from 72 patients suggested a positive correlation between high fluorescent signal in the high mortality patient groups. We propose a novel aptamer-based strategy for delivery of targeted molecular therapy in advanced PDAC where current modalities fail. PMID- 26983362 TI - An unexpected transmetalation intermediate: isolation and structural characterization of a solely CH3 bridged di-copper(i) complex. AB - Structural characterization of unsupported, two metal centres bridging methyl groups is rare. They have been proposed as transmetalation intermediates in cuprate chemistry, but as yet no structural evidence has been presented. We have isolated a di-copper(i) complex with solely a methyl ligand bridging two Cu(i) atoms, representing a new bonding mode of CH3. PMID- 26983361 TI - Three chromosomal rearrangements promote genomic divergence between migratory and stationary ecotypes of Atlantic cod. AB - Identification of genome-wide patterns of divergence provides insight on how genomes are influenced by selection and can reveal the potential for local adaptation in spatially structured populations. In Atlantic cod - historically a major marine resource - Northeast-Arctic- and Norwegian coastal cod are recognized by fundamental differences in migratory and non-migratory behavior, respectively. However, the genomic architecture underlying such behavioral ecotypes is unclear. Here, we have analyzed more than 8.000 polymorphic SNPs distributed throughout all 23 linkage groups and show that loci putatively under selection are localized within three distinct genomic regions, each of several megabases long, covering approximately 4% of the Atlantic cod genome. These regions likely represent genomic inversions. The frequency of these distinct regions differ markedly between the ecotypes, spawning in the vicinity of each other, which contrasts with the low level of divergence in the rest of the genome. The observed patterns strongly suggest that these chromosomal rearrangements are instrumental in local adaptation and separation of Atlantic cod populations, leaving footprints of large genomic regions under selection. Our findings demonstrate the power of using genomic information in further understanding the population dynamics and defining management units in one of the world's most economically important marine resources. PMID- 26983363 TI - PAHs and PM2.5 emissions and female breast cancer incidence in metro Atlanta and rural Georgia. AB - Environmental chemical exposure could be an important etiologic factor for geographic differences in breast cancer incidence. In this study, we examined emissions of polycyclic aromatic hydrocarbons (PAHs) and PM2.5 in relation to breast cancer incidence in metro Atlanta and rural Georgia by analyzing data from the Surveillance, Epidemiology, and End Results Program and the Environmental Protection Agency. The results showed that metro Atlanta had a significantly higher age-adjusted annual incidence rate of female breast cancer than rural Georgia (132.6 vs. 113.7 per 100,000) for 1992-2011. Emissions of both PAHs [adjusted beta = 0.568 (95 % CI: 0.209, 0.927); p = 0.004] and PM2.5 [adjusted beta = 2.964 (95 % CI: 0.468, 5.459); p = 0.023] were significantly associated with breast cancer incidence in metro Atlanta area. This study suggests that ambient air pollution, especially PAHs and PM2.5, could have a significant impact on the increased incidence of female breast cancer in urban areas. PMID- 26983364 TI - Reviewing Mindfulness-Based Interventions for Suicidal Behavior. AB - This article describes the rationale for using mindfulness-based interventions (MBIs) to prevent suicidal behavior in high suicide-risk individuals. A narrative review of studies testing the feasibility of MBIs with individuals at risk for suicidal behavior and the effectiveness of MBIs for reducing suicidality was conducted. Studies testing the effectiveness of MBIs for reducing deficits specific to suicide attempters among depressed individuals were also reviewed as were studies examining moderators of MBI treatment adherence and effectiveness to the extent that these might suggest possible limitations to using MBIs with high suicide-risk individuals. Findings from the handful of available studies support targeting suicidal ideation with MBI. Additional studies show deficits associated with suicide attempt, namely attentional dyscontrol, problem solving deficits, and abnormal stress response, are improved by MBI and thus strengthen the rationale for using MBIs with high suicide-risk individuals. PMID- 26983365 TI - Sobriety checkpoint and open container laws in the United States: Associations with reported drinking-driving. AB - OBJECTIVE: The objective of this study was to assess how 2 types of drinking driving laws-permitting sobriety checkpoints and prohibiting open containers of alcohol in motor vehicles-are associated with drinking-driving and how enforcement efforts may affect these associations. METHODS: We obtained 2010 data on state-level drinking-driving laws and individual-level self-reported drinking driving from archival sources (Alcohol Policy Information System, NHTSA, and Behavioral Risk Factor Surveillance System). We measured enforcement of the laws via a 2009 survey of state patrol agencies. We computed multilevel regression models (separate models for each type of law) that first examined how having the state law predicted drinking-driving, controlling for various state- and individual-level covariates; we then added the corresponding enforcement measure as another potential predictor. RESULTS: We found that states with a sobriety checkpoint law, compared with those without a law, had 18.2% lower drinking driving; states that conducted sobriety checks at least monthly (vs. not conducting checks) had 40.6% lower drinking-driving (the state law variable was not significant when enforcement was added). We found no significant association between having an open container law and drinking-driving, but states that conducted open container enforcement, regardless of having a law, had 17.6% less drinking-driving. CONCLUSION: Our results suggest that having a sobriety checkpoint law and conducting checkpoints as well as enforcement of open containers laws may be effective strategies for addressing drinking-driving. PMID- 26983366 TI - Cu(I)-Catalyzed Synthesis of Furan-Substituted Allenes by Use of Conjugated Ene yne Ketones as Carbene Precursors. AB - The synthesis of furan-substituted allenes using conjugated ene-yne ketones as carbene source has been developed. For this reaction, bases play vital roles in controlling the reaction pathways, allowing for access to two types of allene products through trapping of different electrophiles. Mechanistically, the catalytic procedure generated a Cu(I) (2-furyl)carbene intermediate, which is subsequently followed by a migratory insertion process to afford nucleophilic organocopper species. The organocopper species thus generated can be trapped by proton or allyl halide, affording tri- or tetrasubstituted allenes, respectively. The reaction, which is characterized by its mild reaction conditions and the utilization of cheap copper(I) iodide as catalyst, allows for synthesis of a variety of furan-substituted allenes with a wide range of functional groups tolerance. PMID- 26983367 TI - Immunological identification of a cAMP-dependent protein kinase regulatory subunit-like protein from the Trypanosoma equiperdum TeAp-N/D1 isolate. AB - Polyclonal immunoglobulin Y (IgY) antibodies were produced in chicken eggs against the purified R(II)-subunit of the cAMP-dependent protein kinase (PKA) from pig heart, which corresponds to the Sus scrofa R(II)alpha isoform. In order to evaluate whether Trypanosoma equiperdum possessed PKA R-like proteins, parasites from the Venezuelan TeAp-N/D1 strain were examined using the generated anti-R(II) IgY antibodies. Western blot experiments revealed a 57-kDa polypeptide band that was distinctively recognized by these antibodies. Likewise, polyclonal antibodies raised in mice ascites against the recombinant T. equiperdum PKA R like protein recognized the PKA R(II)-subunit purified from porcine heart and the recombinant human PKA R(I)beta-subunit by immunoblotting. However, a partially purified fraction of the parasite PKA R-like protein was not capable of binding cAMP, implying that this protein is not a direct downstream cAMP effector in T. equiperdum. Although the function of the S. scrofa PKA R(II)alpha and the T. equiperdum PKA R-like protein appear to be different, their cross-reactivity together with results obtained by bioinformatics techniques corroborated the high level of homology exhibited by both proteins. Moreover, its presence in other trypanosomatids suggests an important cellular role of PKA R-like proteins in parasite physiology. PMID- 26983368 TI - Correction to: Refining the Openness-Performance Relationship: Construct Specificity, Contextualization, Social Skill, and the Combination of Trait Self- and Other-Ratings. PMID- 26983370 TI - Origin of the step structure of molecular exchange-correlation potentials. AB - The exact exchange-correlation potential of a stretched heteronuclear diatomic molecule exhibits a localized upshift in the region around the more electronegative atom; by this device the Kohn-Sham scheme ensures that the molecule dissociates into neutral atoms. Baerends and co-workers showed earlier that the upshift originates in the response part of the exchange-correlation potential. We describe a reliable numerical method for constructing the response potential of a given many-electron system and report accurate plots of this quantity. We also demonstrate that the step feature itself can be obtained directly from the interacting wavefunction of the system by computing the so called average local electron energy. These findings illustrate in previously unavailable detail the mechanism of the formation of the upshift and the role played by static correlation in this process. PMID- 26983371 TI - Field enhancement factors and self-focus functions manifesting in field emission resonances in scanning tunneling microscopy. AB - Field emission (FE) resonance (or Gundlach oscillation) in scanning tunneling microscopy (STM) is a phenomenon in which the FE electrons emitted from the microscope tip couple into the quantized standing-wave states within the STM tunneling gap. Although the occurrence of FE resonance peaks can be semi quantitatively described using the triangular potential well model, it cannot explain the experimental observation that the number of resonance peaks may change under the same emission current. This study demonstrates that the aforementioned variation can be adequately explained by introducing a field enhancement factor that is related to the local electric field at the tip apex. The peak number of FE resonances increases with the field enhancement factor. The peak intensity of the FE resonance on the reconstructed Au(111) surface varies in the face-center cubic, hexagonal-close-packed, and ridge regions, thus providing the contrast in the mapping through FE resonances. The mapping contrast is demonstrated to be nearly independent of the tip-sample distance, implying that the FE electron beam is not divergent because of a self-focus function intrinsically involved in the STM configuration. PMID- 26983374 TI - Catalytic test reactions for the evaluation of hierarchical zeolites. AB - Hierarchical zeolites have received increasing attention in the last decade due to their outstanding catalytic performance. Several types of hierarchical zeolites can be prepared by a large number of different techniques. Hierarchical zeolites combine the intrinsic catalytic properties of conventional zeolites and the facilitated access and transport in the additional meso- or macropore system. In this tutorial review, we discuss several test reactions that have been explored to show the benefit of the hierarchical pore system with respect to their suitability to prove the positive effects of hierarchical porous zeolites. It is important to note that positive effects on activity, stability and less frequently selectivity observed for hierarchically structured catalysts not necessarily are only a consequence of the additional meso- or macropores but also the number, strength and location of active sites as well as defects and impurities. With regard to these aspects, the test reaction has to be chosen carefully and potential changes in the chemistry of the catalyst have to be considered as well. In addition to the determination of conversion, yield and selectivity, we will show that the calculation of the activation energy and the determination of the Thiele modulus and the effectiveness factor are good indicators of the presence or absence of diffusion limitations in hierarchical zeolites compared to their parent materials. PMID- 26983369 TI - The canonical Wingless signaling pathway is required but not sufficient for inflow tract formation in the Drosophila melanogaster heart. AB - The inflow tracts of the embryonic Drosophila cardiac tube, termed ostia, arise in its posterior three segments from cardiac cells that co-express the homeotic transcription factor Abdominal-A (abdA), the orphan nuclear receptor Seven-up (Svp), and the signaling molecule Wingless (Wg). To define the roles of these factors in inflow tract development, we assessed their function in inflow tract formation. We demonstrate, using several criteria, that abdA, svp, and wg are each critical for normal inflow tract formation. We further show that Wg acts in an autocrine manner to impact ostia fate, and that it mediates this effect at least partially through the canonical Wg signaling pathway. By contrast, neither wg expression nor Wg signaling are sufficient for inflow tract formation when expressed in anterior Svp cells that do not normally form inflow tracts in the embryo. Instead, ectopic abd-A expression throughout the cardiac tube is required for the formation of ectopic inflow tracts, indicating that autocrine Wg signaling must be supplemented by additional Hox-dependent factors to effect inflow tract formation. Taken together, these studies define important cellular and molecular events that contribute to cardiac inflow tract development in Drosophila. Given the broad conservation of the cardiac regulatory network through evolution, our studies provide insight into mechanisms of cardiac development in higher animals. PMID- 26983372 TI - Acute Kidney Injury Classification for Critically Ill Cirrhotic Patients: A Comparison of the KDIGO, AKIN, and RIFLE Classifications. AB - Critically ill cirrhotic patients have high mortality rates, particularly when they present with acute kidney injury (AKI) on admission. The Kidney Disease: Improving Global Outcomes (KDIGO) group aimed to standardize the definition of AKI and recently published a new AKI classification. However, the efficacy of the KDIGO classification for predicting outcomes of critically ill cirrhotic patients is unclear. We prospectively enrolled 242 cirrhotic patients from a 10-bed specialized hepatogastroenterology intensive care unit (ICU) in a 2000-bed tertiary-care referral hospital. Demographic parameters and clinical variables on day 1 of admission were prospectively recorded. The overall in-hospital mortality rate was 62.8%. Liver diseases were usually attributed to hepatitis B viral infection (26.9%). The major cause of ICU admission was upper gastrointestinal bleeding (38.0%). Our result showed that the KDIGO classification had better discriminatory power than RIFLE and AKIN criteria in predicting in-hospital mortality. Cumulative survival rates at the 6-month after hospital discharge differed significantly between patients with and without AKI on ICU admission day. In summary, we identified that the outcome prediction performance of KDIGO classification is superior to that of AKIN or RIFLE classification in critically ill cirrhotic patients. PMID- 26983375 TI - Is There an Additional Value of Inpatient Treatment for Patients with Atopic Dermatitis? AB - An inpatient treatment and education programme has been developed for patients with difficult to control atopic dermatitis (AD), with the aim of achieving adequate self-management and long-term disease control. This observational study included adult patients diagnosed with difficult to control AD, admitted for a structured inpatient treatment and education programme. The primary outcome was the Six Area, Six Sign Atopic Dermatitis (SASSAD) score. In total, 79 patients (mean +/- SD age 38.8 +/- 17.1 years) were included. The median duration of hospitalization was 11 days (interquartile range 8-14). The mean percentage decrease in SASSAD score between admission and discharge was 60.7%, of which 64 (81.0%) patients achieved SASSAD50. The mean percentage decrease in SASSAD score was 69.0% during follow-up, of which 63 (79.7%) patients still had a SASSAD50. In the majority of these patients with difficult to control AD the admission resulted in sustained disease control. This could be achieved by optimization of treatment with topical corticosteroids. PMID- 26983376 TI - Instabilities, defects, and defect ordering in an overdamped active nematic. AB - We consider a phenomenological continuum theory for an extensile, overdamped active nematic liquid crystal, applicable in the dense regime. Constructed from general principles, the theory is universal, with parameters independent of any particular microscopic realization. We show that it exhibits two distinct instabilities, one of which arises due to shear forces, and the other due to active torques. Both lead to the proliferation of defects. We focus on the active torque bend instability and find three distinct nonequilibrium steady states including a defect-ordered nematic in which +1/2 disclinations develop polar ordering. We characterize the phenomenology of these phases and identify the relationship of this theoretical description to experimental realizations and other theoretical models of active nematics. PMID- 26983377 TI - Access to Healthcare among People with Physical Disabilities in Rural Louisiana. AB - The aim was to explore the perceptions about factors that impede and facilitate access to healthcare among rural residents in Louisiana with physical disabilities. The participants were recruited through local churches and word of mouth. Nine in-depth interviews were conducted. The interviews were analyzed using content analysis. Seven categories containing barriers and facilitators were found. The interviewees described lack of transportation, lack of specialized care locally, limits in insurance coverage, lack of financial resources, and lack of knowledge about health care to be the main barriers. The main facilitators were social support, mainly from family and friends, transportation assistance, continuity of care, trust in doctors, and insurance coverage. People with disabilities in rural areas face several barriers when accessing health care but also multiple facilitators. A group that was identified as particularly vulnerable were low-income households that were not eligible for Medicare/Medicaid but still had high expenditures on health care due to disabilities. PMID- 26983373 TI - Clinically Evaluated Cancer Drugs Inhibiting Redox Signaling. AB - SIGNIFICANCE: There are a number of redox-active anticancer agents currently in development based on the premise that altered redox homeostasis is necessary for cancer cell's survival. Recent Advances: This review focuses on the relatively few agents that target cellular redox homeostasis to have entered clinical trial as anticancer drugs. CRITICAL ISSUES: The success rate of redox anticancer drugs has been disappointing compared to other classes of anticancer agents. This is due, in part, to our incomplete understanding of the functions of the redox targets in normal and cancer tissues, leading to off-target toxicities and low therapeutic indexes of the drugs. The field also lags behind in the use biomarkers and other means to select patients who are most likely to respond to redox-targeted therapy. FUTURE DIRECTIONS: If we wish to derive clinical benefit from agents that attack redox targets, then the future will require a more sophisticated understanding of the role of redox targets in cancer and the increased application of personalized medicine principles for their use. Antioxid. Redox Signal. 26, 262-273. PMID- 26983378 TI - Child and teacher acceptability of school-based echocardiographic screening for rheumatic heart disease in Uganda. AB - : Introduction Rheumatic heart disease causes substantial morbidity in children in low-income countries. School-based echocardiographic screening has been suggested as a means to identify children with latent disease; however, little is known about the experience of children and teachers participating in screenings. The aim of our study was to assess students' and teachers' experience of school based echocardiographic screening and identify areas for improvement. Materials and methods A school-based echocardiographic screening programme was conducted in five schools in Northern Uganda in 2013. After 8 months, an age- and gender stratified population that included 5% of the participating students and teachers completed a questionnaire via an in-person interview. Responses were reviewed by question and coded to identify key themes. RESULTS: A total of 255 students (mean 10.7 years; 48% male) and 35 teachers participated in our study. In total, 95% of the students and 100% of the teachers were happy to have participated in the screening; however, students reported feeling scared (35%) and nervous (48%) during the screening process. Programmatic strengths included the following: knowing one's health status, opportunity to receive treatment, and staff interactions. Although 43% of the patients did not suggest a change with open ended questioning, concerns regarding privacy, fear of the screening process, and a desire to include others in the community were noted. Discussion School-based echocardiographic rheumatic heart disease screening was well received by students and teachers. Future programmes would likely benefit from improved pre-screening education regarding the screening process and diagnosis of rheumatic heart disease. Furthermore, education of teachers and students could improve screening perception and establish realistic expectations regarding the scope of screening. PMID- 26983381 TI - [Being of one heart and one mind, with you in the future]. PMID- 26983379 TI - Semiconductor-inspired design principles for superconducting quantum computing. AB - Superconducting circuits offer tremendous design flexibility in the quantum regime culminating most recently in the demonstration of few qubit systems supposedly approaching the threshold for fault-tolerant quantum information processing. Competition in the solid-state comes from semiconductor qubits, where nature has bestowed some very useful properties which can be utilized for spin qubit-based quantum computing. Here we begin to explore how selective design principles deduced from spin-based systems could be used to advance superconducting qubit science. We take an initial step along this path proposing an encoded qubit approach realizable with state-of-the-art tunable Josephson junction qubits. Our results show that this design philosophy holds promise, enables microwave-free control, and offers a pathway to future qubit designs with new capabilities such as with higher fidelity or, perhaps, operation at higher temperature. The approach is also especially suited to qubits on the basis of variable super-semi junctions. PMID- 26983382 TI - [Working together to promote the development of hepatology in China]. PMID- 26983380 TI - The measurement of psychological constructs in people with osteoarthritis of the knee: a psychometric evaluation. AB - Purpose To examine the measurement properties of measures of psychological constructs in people with knee osteoarthritis. Method Participants with osteoarthritis of the knee completed the beck depression inventory (BDI-II), state-trait anxiety inventory (STAI), arthritis helplessness index (AHI), fatigue severity scale (FSS), coping strategies questionnaire (CSQ), beliefs about pain control questionnaire (BPCQ), illness perceptions questionnaire-revised (IPQ-R), pain self-efficacy questionnaire (PSEQ) at home as part of a set of measures covering different aspects of osteoarthritis pain. The questionnaires were returned by pre-paid envelope. Rasch analysis was used to check the psychometric properties of the scales in people with osteoarthritis. Results The STAI-SF was an acceptable measure of anxiety and the revised FSS an acceptable measure of fatigue, with removal of items 1 and 2. The BDI subscales were acceptable for measuring negative thoughts and behaviours related to depressive symptomatology with some modifications to the scale. The helplessness scale of the AHI was acceptable as a measure of helplessness. The PSEQ was an acceptable measure of self-efficacy and the CSQ as a measure of cognitive coping strategies. The BPCQ and IPQ-R did not fit the Rasch model. Conclusions These findings indicate that questionnaires need to be checked for their ability to measure psychological constructs in the clinical groups to which they will be applied. Implications for Rehabilitation For people with osteoarthritis, the STAI-SF is an acceptable measure of anxiety and the revised FSS an acceptable measure of fatigue with removal of items 1 and 2. The BDI subscales, but not the total score, are acceptable for measuring depressive symptomatology with some modifications to the scoring of the scale. And helplessness can be measured using the Helplessness subscale of the AHI. The PSEQ was an acceptable measure of self-efficacy and cognitive coping strategies can be measured with the CSQ. Rasch analysis highlighted lack of unidimensionality, disordered response thresholds and poor targeting in some measures commonly used for people with osteoarthritis. PMID- 26983383 TI - [The management of autoimmune liver diseases: from the consensus to the guideline]. AB - Autoimmune liver disease is an aberrant autoimmunity-mediated liver injury, its early diagnosis and management can significantly improve the prognosis of patients and their quality of life. Most recently, the 3 societies of Hepatology, Gastroenterology and Infectious Diseases of the Chinese Medical Association jointly released 4 consensuses about the diagnosis and management of autoimmune liver diseases. This academic milestone in the Chinese hepatology field should have major impact on the standardization and improvement of autoimmune liver disease management in China. We urgently need to carry out the joint clinical studies, in particular, multicenter randomized control prospective trials, to clarify the clinical and pathological features of Chinese patients with autoimmune liver diseases. We hope more and more original findings in China may promote the transition from the consensuses to guidelines in the near future. PMID- 26983384 TI - [Consensus on the diagnosis and management of primary biliary cirrhosis (cholangitis)]. PMID- 26983385 TI - [Consensus on the diagnosis and management of primary sclerosing cholangitis (2015 version)]. PMID- 26983386 TI - [Chinese consensus on the diagnosis and management of autoimmune hepatitis (2015)]. PMID- 26983387 TI - [Drug-resistant mutations in hepatitis B virus found in chronic HBV carriers using PCR sequencing technology]. AB - OBJECTIVE: To investigate drug-resistant mutations in and genotypes of hepatitis B virus (HBV) in chronic HBV carriers using PCR sequencing technology. METHODS: Chronic HBV carriers were recruited from Tianjin Second People's Hospital between June 2013 and May 2014 and 317 were enrolled in the study according to receipt of nucleos(t)ide analogues (NAs) for at least three months prior. Drug-resistant mutations were detected by PCR followed by sequencing. SPSS21.0 was used for statistical analysis. RESULTS: Drug-resistant mutations were detected in 119 of the 317 patients, including 20 of 46 patients who received lamivudine (LAM), 16 of 34 patients who received adefovir (ADV), 13 of 80 patients who received entecavir (ETV), 5 of 23 patients who received telbivudine (LdT), and 65 of 124 patients who received various sequential/combined NA therapies. Each of the NAs had dominant drug-resistant mutational profiles, with rtM204I+rtL180M+/-rtL80I (30.9%) for LAM, rtA181T/N (21.3%), rtS213T/N (21.3%) and rtV214A (21.3%) for ADV, rtl180M (48%) for ETV, rtM204I for LdT, and rtA194T for tenofovir disoproxil fumarate (TDF). A total of 308 HBV genotypes were detected, including type B in 27 cases (8.8%), type C in 279 cases (90.6%), and type D in 2 cases (0.6%). The different HBV genotypes had no statistically significant difference in drug resistance mutations, though (chi(2) = 1.11, P > 0.05). Two TDF drug-resistant mutations rtA194T were detected. CONCLUSION: The results provide new information on NA drug-resistant mutations and HBV genotype profiles in chronic HBV carriers and may have important clinical implication for HBV drug resistance management. In addition, the data confirmed the preexisting TDF mutation rtA194T. PMID- 26983388 TI - [Oxymatrine inhibits target cell infection in the HCVcc system]. AB - OBJECTIVE: To validate the antiviral effect of oxymatrine against hepatitis C virus (HCV) in the construction of the cell culture-based infectious virus system HCVcc. METHODS: An HCVcc system was established by infecting Huh7.5.1 cells with the J6 adapted virus (J6cc). Cells of the HCVcc system were then treated with different concentrations of oxymatrine for 24 h, 48 h and 72 h, or left untreated (controls). MTT assay was used to detect effects on proliferation. Real-time quantitative PCR was used to detect effects on HCV mRNA expression level, and immunofluorescence was used to detect effects on HCV protein expression. Data were expressed as mean+/-standard deviation, and statistically assessed using one way ANOVA and one-sample t-test. RESULTS: Treatment with 2, 4, 8 and 12 mg/mL of oxymatrine for 24 h inhibited proliferation of the J6cc-infected cells by 8.4%, 15.2%, 29.6% and 48.6% respectively, 48 h treatment inhibited by 14.3%, 25.7%, 46.1% and 66.4% respectively, and 72 h treatment inhibited by 36.5%, 46.6%, 70.6% and 85.4% respectively. Thus, the effects of oxymatrine were time- and dose dependent (P < 0.05). The mRNA expression level in the oxymatrine-treated cells of the HCVcc system was 0.59 +/- 0.12, which was significantly lower than that in the control cells (P < 0.05). Moreover, as the oxymatrine concentration increased from 2 mg/mL to 12 mg/mL, the expression levels of HCV proteins also showed a decreasing trend. CONCLUSION: We successfully constructed a J6cc infection HCVcc system and verified the antiviral effect of oxymatrine against HCV. PMID- 26983389 TI - [Hepatitis B virus X protein-regulated expression of Plk1]. AB - OBJECTIVE: To investigate the ability and underlying mechanism of hepatitis B virus X protein (HBx) regulation of Polo-like kinase 1 (Plk1) expression. METHODS: The human HCC cell line HepG2 was transfected (transiently and stably) with an HBx plasmid expression vector (pCMV-HA-HBx) or empty plasmid vector (control), with and without expression plasmids with the Plk1 promoter. Effects on Plk1 expression were assessed by western blotting. Functional effects on the Plk1 promoter were assessed by luciferase reporter assay. Effects on the mRNA level of Plk1 in S phase HepG2 cells were assessed by quantitative real-time reverse transcriptase polymerase chain reaction. After blocking protein synthesis by treatment with cycloheximide (CHX), the turnover rate of Plk1 was assessed by western blotting. Lastly, the effect of HBx on cell cycle was assessed by flow cytometry. RESULTS: HBx did not increase the protein expression of Plk1 in non synchronized HepG2 cells, but did significantly up-regulate the Plk1 protein level in the synchronized S phase cells (P = 0.026 and P = 0.003, respectively). Ectopic expression of HBx did not increase the mRNA level of Plk1 in HepG2 cells, but did inhibit the degradation of Plk1, as evidenced by an increased half-life of Plk1 protein (from 30 to 90 minutes). The HBx-expressing HepG2 cells showed more frequent entry into the S or G(2)/M phase than the control cells (31.65% vs. 24.56% or 9.43% vs. 4.47%, respectively) and less in the G(0)/G(1) phase (decrease from 70.97% to 58.92% for the HBx-expressing HepG2 cells). CONCLUSION: HBx is able to up-regulate the expression of Plk1 in HepG2 cells by a mechanism involving stabilization of the Plk1 protein primarily in the S phase of the cell cycl. PMID- 26983390 TI - [Safety and efficacy of human umbilical cord derived-mesenchymal stem cell transplantation for treating patients with HBV-related decompensated cirrhosis]. AB - OBJECTIVE: To retrospectively investigate the efficacy of human umbilical cord derived mesenchymal stem cells (UC-MSC) as clinical treatment for HBV-related decompensated liver cirrhosis (HBV-DLC)*D. METHODS: Sixty patients with HBV-DLC were given standard medical treatment combined with a 3-month regimen of UC-MSC at a dose of 0.5-1.0*10(6) cells/kg/month. Another group of patients with HBV-DLC (n=120; control group) that was matched (2:1) to the case group by age, sex, diagnosis, and follow-up period was given the standard medical treatment only. We reviewed all patients' data of biochemical tests, imaging examinations, Child Pugh scores, and adverse reactions. Comparisons of continuous data between the two groups were made by independent-sample t-test, and comparisons of categorical data were made by chi-square test. RESULTS: Compared with the control group, the group that received the combination UC-MSC treatment showed a significant rise in cholinesterase, globulin and alkaline phosphatase, and reduced Child-Pugh scores during the follow-up period. However, there was no significant difference between the groups of patients for levels of alanine transaminase, total bilirubin, albumin, total cholesterol, or prothrombin activity. CONCLUSIONS: Addition of the UC-MSC treatment to the standard therapy could help to improve liver function in patients with HBV-DLC. PMID- 26983391 TI - [Combination measurement of liver and spleen stiffness with portal vein width to evaluate risk of bleeding in esophageal and gastric varices patients]. AB - OBJECTIVE: To evaluate the utility of combined liver stiffness measurement (LSM) and spleen stiffness measurement (SSM), by transient elastography, along with measurement of portal vein width (PVW) for evaluating risk of bleeding in patients with esophageal and gastric varices (EV). METHODS: A total of 73 patients with cirrhosis who were treated in the Department of Gastroenterology of the Second Affiliated Hospital of Xi'an Jiaotong University between April 2014 and March 2015 were included in the study. Child-Pugh classifications were obtained, portal vein widths were measured by ultrasound, liver and spleen stiffness were measured by transient elastography using FibroTouch(r). Patients were examined by electronic endoscopy, upper abdominal computed tomography and standard serum testing. The serum indexes of fibrosis (aspartate aminotransferase (AST) to platelet ratio index (APRI), and AST to alanine aminotransferase ratio (AAR)) were calculated. Patients were grouped according to the results of gastroscopy, with severe (EV) and high risk of bleeding comprising group A and no or mild-to-moderate EV and low risk of bleeding comprising group B. Statistical analysis was carried out with t-test for continuous variables and chi(2) test for categorical variables to first screen out variables different between groups then the correlation with severe EV was assessed by generating receiver operating characteristic (ROC) curves. Lastly, binary logistic regression was used to evaluate the performance of combined variables for diagnosing severe EV and their predictive value for risk of bleeding. RESULTS: Group A and B showed significant differences for LSM, SSM and PVW (all P < 0.05). The cutoff values for diagnosing severe EV were 23.4 kPa for LSM, 40.3 kPa for SSM and 11.5 mm for PVW, with areas under the ROC curve (AUROC) as 0.655, 0.788 and 0.709 respectively. For combined measurements, the AUROC was 0.773 for LSM plus PVW and 0.840 for LSM plus PVW (with highest diagnostic performance). CONCLUSIONS: Combination of SSM plus PVW measurement shows high diagnostic performance for evaluating severe EV, and better performance than LSM plus SSM plus PVW and LSM plus PVW, with good predictive value for risk of EV bleeding. PMID- 26983392 TI - [Meta-analysis of anti-GP210 antibody and anti-SP100 antibody detection for diagnosis of primary biliary cirrhosis]. AB - OBJECTIVE: To conduct a systematic review of studies assessing the association of anti-GP210 antibody and anti-SP100 antibody with diagnosis of primary biliary cirrhosis (PBC) using meta-analysis. METHODS: Five research literature databases, including the Cochrane Library, MEDLINE, VIP, CNKI and WanFang, were searched for studies of anti-GP210 antibody and anti-SP100 antibody in diagnosis of PBC. Meta disc statistical software was used for analysis. RESULTS: The meta-analysis included a total of 25 studies on anti-GP210 antibody and 21 studies on anti SP100 antibody. The diagnostic odds ratio, sensitivity, and specificity of anti GP210 antibody for diagnosis of PBC were 24.854 (11.957-51.660), 0.272 (0.257 0.288), and 0.985 (0.982-0.988), respectively, and for anti-SP100 antibody they were 9.133 (4.739-17.600), 0.231 (0.213-0.249), and 0.977 (0.973-0.981), respectively. CONCLUSIONS: Both anti-GP210 antibody and anti-SP100 antibody show high specificity but low sensitivity in diagnosis of PBC. PMID- 26983393 TI - [Efficiency and influencing factors of ultrasound-guided radiofrequency ablation as treatment in hepatic malignant tumors]. AB - OBJECTIVE: To evaluate the efficiency and influencing factors of ultrasound guided percutaneous radiofrequency ablation (RFA) as treatment of hepatic malignant tumors. METHODS: Clinical data and follow-up radiographic images of patients with hepatic malignant tumors who had undergone treatment with ultrasound-guided percutaneous RFA at our hospital between March 2012 and March 2014 were reviewed. Rates of incomplete ablation, recurrence, and tumor progression were calculated, and the factors affecting each were analyzed. RESULTS: Four hundred and twelve lesions were ablated in a total of 392 ultrasound-guided percutaneous RFA procedures applied to 360 patients. The average tumor size was 2.51+/-1.10 cm. During at least 3 months of follow-up, the complete ablation rate was 86.11% (310/360), the recurrence rate was 7.78% (28/360), and the progression rate was 6.1% (22/360). Tumors with vessel-proximal location, size of >= 3 cm and >= 3 month presence had significantly higher rates of residual lesions after ablation (chi(2) = 4.431, 10.889 and 8.000, respectively; p<0.05). Tumors with >= 3 month presence had significantly higher rates of recurrence and progression (chi(2) = 29.032 and 22.092, P < 0.05). CONCLUSION: Ultrasound-guided percutaneous RFA can effectively control local progression of hepatic malignant tumors. Tumor size, length of presence, and vessel-proximal location are influencing factors of complete ablation rate, while length of presence is also an influencing factor for the recurrence and progression rates. PMID- 26983394 TI - [The First CSH-AASLD Dialogue: meeting highlights and minutes]. PMID- 26983395 TI - [Progressive familial intrahepatic cholestasis related to mutation of the TJP2 gene: recent advances]. AB - Progressive familial intrahepatic cholestasis is a common cause for jaundice and hepatic dysfunction in infancy. Recent studies have provided novel insights into the etiology and pathogenesis of this childhood disease. Japanese scholars have proposed that mutation in the gene encoding the tight junction protein 2 (TJP2) may result in progressive familial intrahepatic cholestasis type 4. Gaining a detailed understanding of the pathogenesis of this disease form, and of its molecular underpinnings, will promote the development of new and more effective diagnostic tools for infantile progressive familial intrahepatic cholestasis. PMID- 26983396 TI - Flaxseed supplementation in non-alcoholic fatty liver disease: a pilot randomized, open labeled, controlled study. AB - A two-arm randomized open labeled controlled clinical trial was conducted on 50 patients with non-alcoholic fatty liver disease (NAFLD). Participants were assigned to take either a lifestyle modification (LM), or LM +30 g/day brown milled flaxseed for 12 weeks. At the end of the study, body weight, liver enzymes, insulin resistance and hepatic fibrosis and steatosis decreased significantly in both groups (p< 0.05); however, this reduction was significantly greater in those who took flaxseed supplementation (p < 0.05). The significant mean differences were reached in hepatic markers between flaxseed and control group, respectively: ALT [-11.12 compared with -3.7 U/L; P< 0.001], AST [-8.29 compared with -4 U/L; p < 0.001], GGT [-15.7 compared with -2.62 U/L; p < 0.001], fibrosis score [-1.26 compared with -0.77 kPa; p = 0.013] and steatosis score [ 47 compared with -15.45 dB/m; p = 0.022]. In conclusion, flaxseed supplementation plus lifestyle modification is more effective than lifestyle modification alone for NAFLD management. PMID- 26983397 TI - TRIM-directed selective autophagy regulates immune activation. AB - Selectivity of autophagy is achieved by target recognition; however, the number of autophagy receptors identified so far is limited. In this study we demonstrate that a subset of tripartite motif (TRIM) proteins mediate selective autophagy of key regulators of inflammatory signaling. MEFV/TRIM20, and TRIM21 act as autophagic receptors recognizing their cognate targets and delivering them for autophagic degradation. MEFV recognizes the inflammasome components NLRP3, CASP1 and NLRP1, whereas TRIM21 specifically recognizes the activated, dimeric from of IRF3 inducing type I interferon gene expression. MEFV and TRIM21 have a second activity, whereby they act not only as receptors but also recruit and organize key components of autophagic machinery consisting of ULK1, BECN1, ATG16L1, and mammalian homologs of Atg8, with a preference for GABARAP. MEFV capacity to organize the autophagy apparatus is affected by common mutations causing familial Mediterranean fever. These findings reveal a general mode of action of TRIMs as autophagic receptor-regulators performing a highly-selective type of autophagy (precision autophagy), with MEFV specializing in the suppression of inflammasome and CASP1 activation engendering IL1B/interleukin-1beta production and implicated in the form of cell death termed pyroptosis, whereas TRIM21 dampens type I interferon responses. PMID- 26983398 TI - Improved Production of Active Streptomyces griseus Trypsin with a Novel Auto Catalyzed Strategy. AB - N-terminal sequences play crucial roles in regulating expression, translation, activation and enzymatic properties of proteins. To reduce cell toxicity of intracellular trypsin and increase secretory expression, we developed a novel auto-catalyzed strategy to produce recombinant trypsin by engineering the N terminus of mature Streptomyces griseus trypsin (SGT). The engineered N-terminal peptide of SGT was composed of the thioredoxin, glycine-serine linker, His6-tag and the partial bovine trypsinogen pro-peptide (DDDDK). Furthermore, we constructed a variant TLEI with insertion of the artificial peptide at N-terminus and site-directed mutagenesis of the autolysis residue R145. In fed-batch fermentation, the production of extracellular trypsin activity was significantly improved to 47.4 +/- 1.2 U.ml(-1) (amidase activity, 8532 +/- 142.2 U.ml(-1) BAEE activity) with a productivity of 0.49 U.ml(-1).h(-1), which was 329% greater than that of parent strain Pichia pastoris GS115-SGT. This work has significant potential to be scaled-up for microbial production of SGT. In addition, the N terminal peptide engineering strategy can be extended to improve heterologous expression of other toxic enzymes. PMID- 26983399 TI - Population aging in local areas and subjective well-being of older adults: Findings from two studies in Japan. AB - Subjective well-being (SWB) of older adults could be affected by both individual and community characteristics. However, the effect of community characteristics, such as population aging in local areas, remains unclear. This study examined the cross-sectional and longitudinal associations between the area-level population aging and SWB of older individuals from two distinct surveys. Those analyzed were 572 respondents aged 75 years and older for a cross-sectional survey in a metropolitan area in Tokyo, Japan (Study 1) and 1,257 and 859 respondents for a cross-sectional and longitudinal analysis, respectively, for a 2-year longitudinal survey project in urban and rural areas of Fukui Prefecture (Study 2). Area-level population aging was assessed by the number of people aged 65 years or older per 100 residents. SWB was assessed with the Life Satisfaction Index-A (LSIA). Multilevel analysis was performed to examine unconditional and conditional associations between the area-level number of older adults per 100 residents and the individual-level LSIA scores. The area-level number of older adults per 100 residents was significantly and positively associated with the LSIA scores in Study 1 (p = 0.042), even after controlling for the area- and individual-level covariates. In Study 2, we also found a significant effect of the area-level number of older adults per 100 residents on LSIA scores in the longitudinal multivariate analysis (p = 0.049). Findings from two survey projects suggested cross-validity in the positive effect of area-level population aging on older adults' SWB. Policymakers should consider older citizens' SWB in the recent urban-to-rural migration governmental policy as well as in urban renovation planning. PMID- 26983400 TI - SIK2 regulates fasting-induced PPARalpha activity and ketogenesis through p300. AB - Fatty acid oxidation and subsequent ketogenesis is one of the major mechanisms to maintain hepatic lipid homeostasis under fasting conditions. Fasting hormone glucagon has been shown to stimulate ketone body production through activation of PPARalpha; however, the signal pathway linking glucagon to PPARalpha is largely undiscovered. Here we report that a SIK2-p300-PPARalpha cascade mediates glucagon's effect on ketogenesis. p300 interacts with PPARalpha through a conserved LXXLL motif and enhances its transcriptional activity. SIK2 disrupts p300-PPARalpha interaction by direct phosphorylation of p300 at Ser89, which in turn decreases PPARalpha-mediated ketogenic gene expression. Moreover, SIK2 phosphorylation defective p300 (p300 S89A) shows increased interaction with PPARalpha and abolishes suppression of SIK2 on PPARalpha-mediated ketogenic gene expression in liver. Taken together, our results unveil the signal pathway that mediates fasting induced ketogenesis to maintain hepatic lipid homeostasis. PMID- 26983402 TI - A word of caution on renal risks of prothrombin complex concentrate use in cardiac surgery. PMID- 26983401 TI - miR-148a downregulates the expression of transforming growth factor-beta2 and SMAD2 in gastric cancer. AB - The effects of miR-148a in regulating the expression of TGFbeta2 and SMAD2 in MNNG-initiated gastric cancer rats and the mechanism of action in GC cells were determined. Effects of miR-148a on the proliferation, migration, and invasion of GC cell lines were demonstrated. We used Wistar rats, Balb/c nude mice, and GC cell lines. Rats were treated with MNNG to establish a GC rat model. Levels of miR-148a, TGFalpha, TGFbeta2, SMAD2, SMAD3, and SMAD4 were tested in gastric tissues from different groups. In GC cell lines, we constructed and transfected a primary miR-148a plasmid to determine the expression patterns of TGFbeta2, SMAD2, and SMAD4. A luciferase activity assay was used to monitor the effects of miR 148a on the TGFbeta2- and SMAD2-3'UTRs. We identified nude mouse models bearing BGC-823-miR-148a or BGC-823-vector cells. Tumor volumes were detected, and TGFbeta2, SMAD2 expression levels were determined in tumor tissues. The in vivo study demonstrated an increase in the mRNA and protein levels of TGFbeta2, SMAD2, and SMAD4 in the MNNG-treated group compared with the control group. However, there were no differences in the mRNA and protein levels in either TGFalpha or SMAD3. The in vitro study demonstrated that overexpression of miR-148a reduced TGFbeta2 and SMAD2 significantly in GC cells. The results of the luciferase activity assay showed that miR-148a could bind to the 3'UTRs of TGFbeta2 and SMAD2 and inhibited their activity. Overexpression of miR-148a inhibited proliferation, migration, and invasion significantly in GC cell lines. In vivo, tumor volume of BGC-823-miR-148a was smaller than that of BGC-823-vector. Overall, miR-148a inhibited the proliferation, migration, invasion, and expression of TGFbeta2 and SMAD2 in GC cells. It was concluded that miR-148a might play an important role in gastric cancer, and is a potential candidate for GC treatment. PMID- 26983403 TI - Shifts in taxonomic and functional microbial diversity with agriculture: How fragile is the Brazilian Cerrado? AB - BACKGROUND: The Cerrado--an edaphic type of savannah--comprises the second largest biome of the Brazilian territory and is the main area for grain production in the country, but information about the impact of land conversion to agriculture on microbial diversity is still scarce. We used a shotgun metagenomic approach to compare undisturbed (native) soil and soils cropped for 23 years with soybean/maize under conservation tillage--"no-till" (NT)--and conventional tillage (CT) systems in the Cerrado biome. RESULTS: Soil management and fertilizer inputs with the introduction of agriculture improved chemical properties, but decreased soil macroporosity and microbial biomass of carbon and nitrogen. Principal coordinates analyses confirmed different taxonomic and functional profiles for each treatment. There was predominance of the Bacteria domain, especially the phylum Proteobacteria, with higher numbers of sequences in the NT and CT treatments; Archaea and Viruses also had lower numbers of sequences in the undisturbed soil. Within the Alphaproteobacteria, there was dominance of Rhizobiales and of the genus Bradyrhizobium in the NT and CT systems, attributed to massive inoculation of soybean, and also of Burkholderiales. In contrast, Rhizobium, Azospirillum, Xanthomonas, Pseudomonas and Acidobacterium predominated in the native Cerrado. More Eukaryota, especially of the phylum Ascomycota were detected in the NT. The functional analysis revealed lower numbers of sequences in the five dominant categories for the CT system, whereas the undisturbed Cerrado presented higher abundance. CONCLUSION: High impact of agriculture in taxonomic and functional microbial diversity in the biome Cerrado was confirmed. Functional diversity was not necessarily associated with taxonomic diversity, as the less conservationist treatment (CT) presented increased taxonomic sequences and reduced functional profiles, indicating a strategy to try to maintain soil functioning by favoring taxa that are probably not the most efficient for some functions. Our results highlight that underneath the rustic appearance of the Cerrado vegetation there is a fragile soil microbial community. PMID- 26983406 TI - Meeting report on the first Sino-Dutch symposium on oncology. AB - On October 31, 2015, the first Sino-Dutch symposium on oncology was organized in Guangzhou (China). The symposium revealed similarities between Chinese and Dutch efforts to improve the care of tumor patients and to create enhanced insight into the nature of cancers. In particular, it became evident for some types of cancer that immunotherapy should focus on counteracting interleukin-17-associated immunity and targeting cancer stroma. Targeting specific cancer microenvironment and stroma also opens new therapeutic options, including the use of radio-active theranostics and live tumor imaging-guided surgeries. PMID- 26983404 TI - Gender differences in white matter pathology and mitochondrial dysfunction in Alzheimer's disease with cerebrovascular disease. AB - BACKGROUND: Dementia risk in women is higher than in men, but the molecular neuropathology of this gender difference remains poorly defined. In this study, we used unbiased, discovery-driven quantitative proteomics to assess the molecular basis of gender influences on risk of Alzheimer's disease with cerebrovascular disease (AD + CVD). RESULTS: We detected modulation of several redox proteins in the temporal lobe of AD + CVD subjects, and we observed sex specific alterations in the white matter (WM) and mitochondria proteomes of female patients. Functional proteomic analysis of AD + CVD brain tissues revealed increased citrullination of arginine and deamidation of glutamine residues of myelin basic protein (MBP) in female which impaired degradation of degenerated MBP and resulted in accumulation of non-functional MBP in WM. Female patients also displayed down-regulation of ATP sub-units and cytochromes, suggesting increased severity of mitochondria impairment in women. CONCLUSIONS: Our study demonstrates that gender-linked modulation of white matter and mitochondria proteomes influences neuropathology of the temporal lobe in AD + CVD. PMID- 26983407 TI - www.kanjidatabase.com: a new interactive online database for psychological and linguistic research on Japanese kanji and their compound words. AB - Most experimental research making use of the Japanese language has involved the 1945 officially standardized kanji (Japanese logographic characters) in the Joyo kanji list (originally announced by the Japanese government in 1981). However, this list was extensively modified in 2010: five kanji were removed and 196 kanji were added; the latest revision of the list now has a total of 2136 kanji. Using an up-to-date corpus consisting of 11 years' worth of articles printed in the Mainichi Newspaper (2000-2010), we have constructed two novel databases that can be used in psychological research using the Japanese language: (1) a database containing a wide variety of properties on the latest 2136 Joyo kanji, and (2) a novel database containing 27,950 two-kanji compound words (or jukugo). Based on these two databases, we have created an interactive website ( www.kanjidatabase.com ) to retrieve and store linguistic information to be used in psychological and linguistic experiments. The present paper reports the most important characteristics for the new databases, as well as their value for experimental psychological and linguistic research. PMID- 26983405 TI - Enhancing evidence informed policymaking in complex health systems: lessons from multi-site collaborative approaches. AB - BACKGROUND: There is an increasing interest worldwide to ensure evidence-informed health policymaking as a means to improve health systems performance. There is a need to engage policymakers in collaborative approaches to generate and use knowledge in real world settings. To address this gap, we implemented two interventions based on iterative exchanges between researchers and policymakers/implementers. This article aims to reflect on the implementation and impact of these multi-site evidence-to-policy approaches implemented in low resource settings. METHODS: The first approach was implemented in Mexico and Nicaragua and focused on implementation research facilitated by communities of practice (CoP) among maternal health stakeholders. We conducted a process evaluation of the CoPs and assessed the professionals' abilities to acquire, analyse, adapt and apply research. The second approach, called the Policy BUilding Demand for evidence in Decision making through Interaction and Enhancing Skills (Policy BUDDIES), was implemented in South Africa and Cameroon. The intervention put forth a 'buddying' process to enhance demand and use of systematic reviews by sub-national policymakers. The Policy BUDDIES initiative was assessed using a mixed-methods realist evaluation design. RESULTS: In Mexico, the implementation research supported by CoPs triggered monitoring by local health organizations of the quality of maternal healthcare programs. Health programme personnel involved in CoPs in Mexico and Nicaragua reported improved capacities to identify and use evidence in solving implementation problems. In South Africa, Policy BUDDIES informed a policy framework for medication adherence for chronic diseases, including both HIV and non-communicable diseases. Policymakers engaged in the buddying process reported an enhanced recognition of the value of research, and greater demand for policy-relevant knowledge. CONCLUSIONS: The collaborative evidence-to-policy approaches underline the importance of iterations and continuity in the engagement of researchers and policymakers/programme managers, in order to account for swift evolutions in health policy planning and implementation. In developing and supporting evidence to-policy interventions, due consideration should be given to fit-for-purpose approaches, as different needs in policymaking cycles require adapted processes and knowledge. Greater consideration should be provided to approaches embedding the use of research in real-world policymaking, better suited to the complex adaptive nature of health systems. PMID- 26983408 TI - Safety of vemurafenib in patients with BRAF V600 mutated metastatic melanoma: the Spanish experience. AB - OBJECTIVES: Vemurafenib tolerability was assessed in a large, open-label, multicentre study in patients with BRAF V600 mutated advanced melanoma. We investigated safety, tolerability and efficacy of vemurafenib in Spanish patients participating in that study. METHODS: Patients with previously treated or treatment-naive, unresectable stage IIIC or stage IV, BRAF V600 mutation-positive melanoma received vemurafenib 960 mg twice daily until disease progression, unacceptable toxicity, withdrawal of consent or death. The primary endpoint was safety; secondary endpoints included overall response rate (ORR), progression free survival (PFS) and overall survival (OS). RESULTS: 301 Spanish patients were included, 70 % with M1c disease, 22 % with brain metastases and 51 % with prior systemic therapy for metastatic disease. Most frequent adverse events included fatigue (48 %), arthralgia (45 %), rash (41 %), photosensitivity (34 %) and skin neoplasms (21 %). Grade 3/4 adverse events occurred in 156 patients (52 %), including cutaneous squamous cell carcinoma (including keratoacanthoma; 16 %), fatigue (6 %) and arthralgia (5 %). The ORR was 28 % (95 % CI 23-34 %). Responses occurred in patients with brain metastases (18 %), elevated baseline lactate dehydrogenase (19 %) and poor performance status (15 %), and elderly patients (22 %). Median PFS was 5.8 (95 % CI 5.0-6.4) months; median OS was 10.5 (95 % CI 9.5 13.5) months. CONCLUSION: Our results for Spanish patients in the vemurafenib safety study indicate similar efficacy and a comparable safety profile in Spanish patients with no new safety signals compared with the overall population. Clinical benefit was demonstrated in poor-prognosis patients and in those with favourable baseline characteristics, suggesting that poor-prognosis patients may also benefit from vemurafenib treatment. PMID- 26983409 TI - Prediction of posterior ligamentous complex injury in thoracolumbar fractures using non-MRI imaging techniques. AB - PURPOSE: We aimed to formulate a radiological index based on plain radiographs and computer tomography (CT) to reliably detect posterior ligamentous complex (PLC) injury without need for MRI. METHODS: Sixty out of 148 consecutive thoracolumbar fractures with doubtful PLC were assessed with MRI, CT and radiographs. PLC injury was assessed with the following radiological parameters: superior-inferior end plate angle (SIEA), vertebral body height (BH), local kyphosis (LK), inter-spinous distance (ISD) and inter-pedicular distance (IPD) and correlated with MRI findings of PLC injury. Statistical analysis was performed to identify the predictive values for the parameters to identify PLC damage. RESULTS: MRI identified PLC injury in 25/60 cases. The ISD and LK were found to be significant predictors of PLC injury. On radiographs the mean LK with PLC damage was 25.86 degrees compared to 21.02 degrees with an intact PLC (p = 0.006). The ISD difference was 6.70 mm in cases with PLC damage compared to 2.86 mm with an intact PLC (p = 0.011). In CT images, the mean LK with PLC damage was 22.96 degrees compared to 18.44 degrees with an intact PLC ( p = 0.019). The ISD difference was 3.10 mm with PLC damage compared to 1.62 mm without PLC damage (p = 0.005). CONCLUSIONS: On plain radiographs the presence of LK greater than 20 degrees (CI 64-95) and ISD difference greater than 2 mm (CI 70-97) can predict PLC injury. These guidelines may be utilised in the emergency room especially when the associated cost, availability and time delay in performing MRI are a concern. PMID- 26983410 TI - One-stage posterior focus debridement, interbody graft using titanium mesh cages, posterior instrumentation and fusion in the surgical treatment of lumbo-sacral spinal tuberculosis in the aged. AB - PURPOSE: Aged patients represent a high risk group for acquiring spinal tuberculosis, and it still remains a leading cause of kyphosis and paraplegia in developing nations. Aged patients often combined with cardiovascular and respiratory disease and single lung ventilation via anterior approach surgery could result in more post-operative complications. We aimed to analyze the efficacy and feasibility of surgical management of aged patients with lumbo sacral spine tuberculosis using one-stage posterior focus debridement, interbody graft using titanium mesh cages, posterior instrumentation, and fusion. METHODS: From March 2009 and July 2012, 17 aged patients with lumbo-sacral spinal tuberculosis were treated with one-stage posterior focus debridement, interbody graft using titanium mesh cages, posterior instrumentation, and fusion. There were eight male and nine female with a mean age of 63.3 years (range: 60-71 years). The mean follow-up was 46.5 months (range 38-70 months). Patients were evaluated before and after surgery in terms of ESR, neurological status, visual analog scale (VAS), and lumbosacral angle. RESULTS: Spinal tuberculosis was completely cured and the grafted bones were fused in all 17 patients. There were no recurrent tuberculous infections. ESR became normal within three months in all patients. The ASIA neurological classification and VAS scores improved in all cases. The average preoperative lumbosacral angle was 20.6 degrees (range 18.1 degrees -22.5 degrees ) and became 29.4 degrees (range 27.1 degrees -32.5 degrees ) at final follow-up. CONCLUSIONS: Our results showed that one-stage posterior focus debridement, interbody graft using titanium mesh cages, posterior instrumentation, and fusion was an effective treatment for aged patients with lumbo-sacral spinal tuberculosis. It is characterized with minimum surgical trauma, good pain relief, good neurological recovery, and good reconstruction of the spinal stability. PMID- 26983411 TI - Effect of the percutaneous pedicle screw fixation at the fractured vertebra on the treatment of thoracolumbar fractures. AB - PURPOSE: The purpose of this study was to evaluate the efficacy and safety of percutaneous pedicle screw fixation at the fractured vertebra in the treatment of thoracolumbar fractures. METHODS: Thirty-two consecutive patients were enrolled in the study. All patients received percutaneous pedicle screw fixation, and they were randomly divided into two groups to undergo either the placement of pedicle screws into the fractured vertebra (fractured group) or not (control group). The operation time and intra-operative blood loss were recorded. Oswestry disability index (ODI) questionnaire and visual analogue scale (VAS) as clinical assessments were quantified. Radiographic follow-up was defined by the vertebral body index (VBI), anterior vertebral body height (AVBH), and Cobb angle (CA). RESULTS: No significant difference was observed in the operation time and intra-operative blood loss between the two groups. Clinical results (VAS and ODI scores) showed no significant difference during all the follow-up periods. In the fractured group, there were better correction and less loss of AVBH and VBI compared with the control group. However, post-operative correction of the CA immediately after surgery and the correction loss at the final follow-up showed no significant difference between the two groups. CONCLUSION: Percutaneous screw fixation combined with intermediate screws at the fractured vertebra could more effectively restore and maintain fractured vertebral height, and is an acceptable, minimally invasive surgical choice for patients with type A thoracolumbar fractures. PMID- 26983412 TI - A dual approach for improving homogeneity of a human-type N-glycan structure in Saccharomyces cerevisiae. AB - N-glycosylation is an important feature of therapeutic and other industrially relevant proteins, and engineering of the N-glycosylation pathway provides opportunities for developing alternative, non-mammalian glycoprotein expression systems. Among yeasts, Saccharomyces cerevisiae is the most established host organism used in therapeutic protein production and therefore an interesting host for glycoengineering. In this work, we present further improvements in the humanization of the N-glycans in a recently developed S. cerevisiae strain. In this strain, a tailored trimannosyl lipid-linked oligosaccharide is formed and transferred to the protein, followed by complex-type glycan formation by Golgi apparatus-targeted human N-acetylglucosamine transferases. We improved the glycan pattern of the glycoengineered strain both in terms of glycoform homogeneity and the efficiency of complex-type glycosylation. Most of the interfering structures present in the glycoengineered strain were eliminated by deletion of the MNN1 gene. The relative abundance of the complex-type target glycan was increased by the expression of a UDP-N-acetylglucosamine transporter from Kluyveromyces lactis, indicating that the import of UDP-N-acetylglucosamine into the Golgi apparatus is a limiting factor for efficient complex-type N-glycosylation in S. cerevisiae. By a combination of the MNN1 deletion and the expression of a UDP-N acetylglucosamine transporter, a strain forming complex-type glycans with a significantly improved homogeneity was obtained. Our results represent a further step towards obtaining humanized glycoproteins with a high homogeneity in S. cerevisiae. PMID- 26983413 TI - Smells like inhibition: The effects of olfactory and visual alcohol cues on inhibitory control. AB - RATIONALE: How the smell of alcohol impacts alcohol-related thoughts and behaviours is unclear, though it is well-documented that alcohol-related stimuli and environments may trigger these. OBJECTIVES: The current study, therefore, aimed to investigate the priming effects of both visual and olfactory alcohol cues on inhibitory control. METHOD: Forty individuals (M age = 23.65, SD = 6.52) completed a go/no-go association task (GNAT) which measured reaction times, response accuracy and false alarm rates whilst being exposed to alcohol-related (or neutral) olfactory and visual cues. RESULTS: Alcohol-related visual cues elicited lower false alarm rates, slower reaction times and higher accuracy rates relative to neutral pictorial cues. False alarm rates were significantly higher for those exposed to alcohol as opposed to neutral olfactory cues. CONCLUSIONS: By highlighting that exposure to alcohol-related olfactory cues may impede response inhibition, the results indicate that exposure to such stimuli may contribute to the activation of cognitive responses which may drive consumption. PMID- 26983415 TI - Tobacco use is associated with reduced amplitude and intensity dependence of the cortical auditory evoked N1-P2 component. AB - RATIONALE: Tobacco use is linked to cerebral atrophy and reduced cognitive performance in later life. However, smoking-related long-term effects on brain function remain largely uncertain. Previous studies suggest that nicotine affects serotonergic signaling, and the intensity dependence (alias loudness dependence) of the auditory evoked N1-P2 potential has been proposed as a marker of serotonergic neurotransmission. OBJECTIVE: In the present study, we assesed the effects of chronic smoking on amplitude and intensity dependence of the auditory evoked N1-P2 potential. METHODS: Subjects underwent a 15-min intensity dependence of auditory evoked potentials (IAEP) paradigm. From N = 1739 eligible subjects (40-79 years), we systematically matched current smokers, ex-smokers, and never smokers by sex, age, alcohol and caffeine consumption, and socioeconomic status. Between-group differences and potential dose-dependencies were evaluated. RESULTS: Analyses revealed higher N1-P2 amplitudes and intensity dependencies in never-smokers relative to ex- and current smokers, with ex-smokers exhibiting intermediate intensity dependencies. Moreover, we observed pack years and number of cigarettes consumed per day to be inversely correlated with amplitudes in current smokers. CONCLUSIONS: According to the IAEP serotonin hypothesis, our results suggest serotonin activity to be highest in current smokers, intermediate in ex-smokers, and lowest in never-smokers. To our knowledge, the present study is the first providing evidence for a dose-dependent reduction in N1-P2 amplitudes. Further, we extend prior research by showing reduced amplitudes and intensity dependencies in ex-smokers even 25 years, on average, after cessation. While we can rule out several smoking-related confounders to bias observed associations, causal inferences remain to be established by future longitudinal studies. PMID- 26983418 TI - Becoming an Academic Researcher in Psychiatry: A View From the Trenches. PMID- 26983416 TI - Global Mental Health: Five Areas for Value-Driven Training Innovation. AB - OBJECTIVE: In the field of global mental health, there is a need for identifying core values and competencies to guide training programs in professional practice as well as in academia. This paper presents the results of interdisciplinary discussions fostered during an annual meeting of the Society for the Study of Psychiatry and Culture to develop recommendations for value-driven innovation in global mental health training. METHODS: Participants (n = 48), who registered for a dedicated workshop on global mental health training advertised in conference proceedings, included both established faculty and current students engaged in learning, practice, and research. They proffered recommendations in five areas of training curriculum: values, competencies, training experiences, resources, and evaluation. RESULTS: Priority values included humility, ethical awareness of power differentials, collaborative action, and "deep accountability" when working in low-resource settings in low- and middle-income countries and high-income countries. Competencies included flexibility and tolerating ambiguity when working across diverse settings, the ability to systematically evaluate personal biases, historical and linguistic proficiency, and evaluation skills across a range of stakeholders. Training experiences included didactics, language training, self-awareness, and supervision in immersive activities related to professional or academic work. Resources included connections with diverse faculty such as social scientists and mentors in addition to medical practitioners, institutional commitment through protected time and funding, and sustainable collaborations with partners in low resource settings. Finally, evaluation skills built upon community-based participatory methods, 360-degree feedback from partners in low-resource settings, and observed structured clinical evaluations (OSCEs) with people of different cultural backgrounds. CONCLUSIONS: Global mental health training, as envisioned in this workshop, exemplifies an ethos of working through power differentials across clinical, professional, and social contexts in order to form longstanding collaborations. If incorporated into the ACGME/ABPN Psychiatry Milestone Project, such recommendations will improve training gained through international experiences as well as the everyday training of mental health professionals, global health practitioners, and social scientists. PMID- 26983420 TI - [Heart valve diseases]. PMID- 26983419 TI - Psychiatry Enrichment Initiatives: A Review of Current Programs, Summer Schools, and Institutes. PMID- 26983414 TI - A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment. AB - RATIONALE: A microdeletion at locus 15q13.3 is associated with high incidence rates of psychopathology, including schizophrenia. A mouse model of the 15q13.3 microdeletion syndrome has been generated (Df[h15q13]/+) with translational utility for modelling schizophrenia-like pathology. Among other deficits, schizophrenia is characterised by dysfunctions in prefrontal cortical (PFC) inhibitory circuitry and attention. OBJECTIVES: The objective of this study is to assess PFC-dependent functioning in the Df(h15q13)/+ mouse using electrophysiological, pharmacological, and behavioural assays. METHOD: Experiments 1-2 investigated baseline firing and auditory-evoked responses of PFC interneurons and pyramidal neurons. Experiment 3 measured pyramidal firing in response to intra-PFC GABAA receptor antagonism. Experiments 4-6 assessed PFC dependent attentional functioning through the touchscreen 5-choice serial reaction time task (5-CSRTT). Experiments 7-12 assessed reversal learning, paired associate learning, extinction learning, progressive ratio, trial-unique non match to sample, and object recognition. RESULTS: In experiments 1-3, the Df(h15q13)/+ mouse showed reduced baseline firing rate of fast-spiking interneurons and in the ability of the GABAA receptor antagonist gabazine to increase the firing rate of pyramidal neurons. In assays of auditory-evoked responses, PFC interneurons in the Df(h15q13)/+ mouse had reduced detection amplitudes and increased detection latencies, while pyramidal neurons showed increased detection latencies. In experiments 4-6, the Df(h15q13)/+ mouse showed a stimulus duration-dependent decrease in percent accuracy in the 5-CSRTT. The impairment was insensitive to treatment with the partial alpha7nAChR agonist EVP 6124. The Df(h15q13)/+ mouse showed no cognitive impairments in experiments 7-12. CONCLUSION: The Df(h15q13)/+ mouse has multiple dysfunctions converging on disrupted PFC processing as measured by several independent assays of inhibitory transmission and attentional function. PMID- 26983422 TI - Testing mediation effects in cross-classified multilevel data. AB - In this article, we propose an approach to test mediation effects in cross classified multilevel data in which the initial cause is associated with one crossed factor, the mediator is associated with the other crossed factor, and the outcome is associated with Level-1 units (i.e., the 2(A)?2(B)?1 design). Multiple membership models and cross-classified random effects models are used to estimate the indirect effects. The method is illustrated using real data from the Early Childhood Longitudinal Study-Kindergarten Cohort (1998). The results from the simulation study show that the proposed method can produce a consistent estimate of the indirect effect and reliable statistical inferences, given an adequate sample size. PMID- 26983421 TI - The association between familial ASD diagnosis, autism symptomatology and developmental functioning in young children. AB - Few studies have directly compared individuals with and without a relative diagnosed with ASD on various domains. The present study aimed to examine the relationship between familial ASD diagnosis and the exhibition of ASD symptoms in young children with and without ASD diagnoses. Participants included 8353 children aged 17-37 months old and their families. They were divided into four groups based on individual and family diagnosis, then compared on autism symptomatology and developmental domains. No differences were found between ASD groups on overall scores and each of the factor domains, indicating no association between family ASD diagnosis and ASD symptomatology or developmental functioning. Disparate results were found for atypically developing groups with and without relatives diagnosed with ASD. Implications of these results are discussed. PMID- 26983423 TI - The intraoperative portable CT scanner-based spinal navigation: a viable option for instrumentation in the region of cervico-thoracic junction. AB - PURPOSE: Innovative intraoperative imaging modalities open new horizons to more precise image acquisition and possibly to better results of spinal navigation. Planning of screw entry points and trajectories in this prospective study had been based on intraoperative imaging obtained by a portable 32-slice CT scanner. The authors evaluated accuracy and safety of this novel approach in the initial series of 18 instrumented surgeries in anatomically complex segment of cervico thoracic junction. METHODS: We report on the single-institution results of assessment of anatomical accuracy of C5-T3 pedicle screw insertion as well as its clinical safety. The evaluation of total radiation dose and of time demands was secondary endpoint of the study. RESULTS: Out of 129 pedicle screws inserted in the segment of C5-T3, only 5 screws (3.9 %) did not meet the criteria for correct implant positioning. These screw misplacements had not been complicated by neural, vascular or visceral injury and surgeon was not forced to change the position intraoperatively or during the postoperative period. Quality of intraoperative CT imaging sufficient for navigation was obtained at all spinal segments regardless of patient's habitus, positioning or comorbidity. A higher radiation exposition of the patient and 27 min longer operative time are consequences of this technique. CONCLUSIONS: The intraoperative portable CT scanner-based spinal navigation is a reliable and safe method of pedicle screw insertion in cervico-thoracic junction. PMID- 26983424 TI - Comparison of the safety outcomes between two surgical approaches for anterior lumbar fusion surgery: anterior lumbar interbody fusion (ALIF) and extreme lateral interbody fusion (ELIF). AB - PURPOSE: To review the evidence on safety of anterior lumbar interbody fusion (ALIF) and extreme lateral transpsoas interbody fusion (ELIF) in the treatment of degenerative spinal disorders with an emphasis on the association between neuromonitoring and complications. METHODS: We performed a systematic literature search in the Cochrane (CENTRAL), MEDLINE, EMBASE and the FDA Medical Devices databases. We abstracted information on study design, sample size, population, procedure, number and location of involved levels, follow-up time and complications, as well as information on conflict of interest and source of funding. In addition, for ELIF we collected information on the use of neuromonitoring during the procedure. RESULTS: 34 publications were included in the review: 24 ELIF (all case series), 9 ALIF (8 randomized controlled trials and 1 case series) and one retrospective cohort that directly compared ELIF with ALIF. 18 out of 24 ELIF studies reported using neuromonitoring. The overall complication rate for ELIF was lower compared to ALIF without FDA reports (16.61 vs. 26.47 %, respectively). However, the rate of neurologic complications in ELIF was almost twice as high compared to ALIF without FDA reports (8.92 and 4.96 %, respectively). The rate of overall complications in ELIF studies that were reported using neuromonitoring was lower compared to the studies that did not report using neuromonitoring (16.34 vs. 21.74 %, respectively). CONCLUSION: Although the overall complications rate for ELIF was lower compared to ALIF, ELIF is associated with a greater risk of neurological complications compared to ALIF even when used with neuromonitoring. PMID- 26983425 TI - Treatment options and prognosis for repeatedly recurrent giant cell tumor of the spine. AB - BACKGROUND: Giant cell tumor of the spine has high rate of postoperative recurrence. There are not much published studies on repeatedly recurrent GCTS (RRGCTS). Also, there are controversies as to the prognostic factors and treatment options for RRGCTS. METHODS AND MATERIALS: A retrospective survival analysis between 2000 and September 2014 was performed on the 74 times of in hospital treatment of the 21 patients. Recurrence-free survival was defined as the time between the date of surgery and the date of recurrence. Factors with P values <0.05 in univariate analysis were subjected to multivariate analysis by means of proportional hazard analysis. RESULT: A total of 21 patients comprising ten males and 11 females with a mean age of 29.7 years (range 15-49) were included, with a total of 74 times of surgery performed. Eighteen patients had no evidence of disease. Univariate and multivariate analysis suggested that total spondylectomy and bisphosphonate therapy were independent prognostic factors for better RFS in RRGCTS patients. CONCLUSION: Patients of RRGCTS are suitable for further surgical treatment with relatively good healing process and restoration of nervous function. Early diagnosis of recurrence may be associated with better prognosis. Total spondylectomy in combination with bisphosphonate therapy could reduce postoperative recurrence rate. PMID- 26983426 TI - Editorial Comment: Current Issues in Orthopaedic Trauma: Tribute to Clifford H. Turen. PMID- 26983427 TI - CORR Insights((r)): Antibiotic-tolerant Staphylococcus aureus Biofilm Persists on Arthroplasty Materials. PMID- 26983428 TI - CORR Insights((r)): Validation of the HOOS, JR: A Short-form Hip Replacement Survey. PMID- 26983430 TI - Bioprobes Based on Aptamer and Silica Fluorescent Nanoparticles for Bacteria Salmonella typhimurium Detection. AB - In this study, we have developed an efficient method based on single-stranded DNA (ssDNA) aptamers along with silica fluorescence nanoparticles for bacteria Salmonella typhimurium detection. Carboxyl-modified Tris(2,2' bipyridyl)dichlororuthenium(II) hexahydrate (RuBPY)-doped silica nanoparticles (COOH-FSiNPs) were prepared using reverse microemulsion method, and the streptavidin was conjugated to the surface of the prepared COOH-FSiNPs. The bacteria S. typhimurium was incubated with a specific ssDNA biotin-labeled aptamer, and then the aptamer-bacteria conjugates were treated with the synthetic streptavidin-conjugated silica fluorescence nanoprobes (SA-FSiNPs). The results under fluorescence microscopy show that SA-FSiNPs can be applied effectively for the labeling of bacteria S. typhimurium with great photostable property. To further verify the specificity of SA-FSiNPs out of multiple bacterial conditions, variant concentrations of bacteria mixtures composed of bacteria S. typhimurium, Escherichia coli, and Bacillus subtilis were treated with SA-FSiNPs.In addition, the feasibility of SA-FSiNPs for bacteria S. typhimurium detection in chicken samples was assessed. All the results display that the established aptamer-based nanoprobes exhibit the superiority for bacteria S. typhimurium detection, which is referentially significant for wider application prospects in pathogen detection. PMID- 26983431 TI - Modelling of Three-Dimensional Nanographene. AB - Monte Carlo simulations and tight-binding calculations shed light on the properties of three-dimensional nanographene, a material composed of interlinked, covalently-bonded nanoplatelet graphene units. By constructing realistic model networks of nanographene, we study its structure, mechanical stability, and optoelectronic properties. We find that the material is nanoporous with high specific surface area, in agreement with experimental reports. Its structure is characterized by randomly oriented and curved nanoplatelet units which retain a high degree of graphene order. The material exhibits good mechanical stability with a formation energy of only ~0.3 eV/atom compared to two-dimensional graphene. It has high electrical conductivity and optical absorption, with values approaching those of graphene. PMID- 26983429 TI - Volume measurements of individual muscles in human quadriceps femoris using atlas based segmentation approaches. AB - OBJECTIVES: Atlas-based segmentation is a powerful method for automatic structural segmentation of several sub-structures in many organs. However, such an approach has been very scarcely used in the context of muscle segmentation, and so far no study has assessed such a method for the automatic delineation of individual muscles of the quadriceps femoris (QF). In the present study, we have evaluated a fully automated multi-atlas method and a semi-automated single-atlas method for the segmentation and volume quantification of the four muscles of the QF and for the QF as a whole. SUBJECTS AND METHODS: The study was conducted in 32 young healthy males, using high-resolution magnetic resonance images (MRI) of the thigh. The multi-atlas-based segmentation method was conducted in 25 subjects. Different non-linear registration approaches based on free-form deformable (FFD) and symmetric diffeomorphic normalization algorithms (SyN) were assessed. Optimal parameters of two fusion methods, i.e., STAPLE and STEPS, were determined on the basis of the highest Dice similarity index (DSI) considering manual segmentation (MSeg) as the ground truth. Validation and reproducibility of this pipeline were determined using another MRI dataset recorded in seven healthy male subjects on the basis of additional metrics such as the muscle volume similarity values, intraclass coefficient, and coefficient of variation. Both non-linear registration methods (FFD and SyN) were also evaluated as part of a single-atlas strategy in order to assess longitudinal muscle volume measurements. The multi- and the single-atlas approaches were compared for the segmentation and the volume quantification of the four muscles of the QF and for the QF as a whole. RESULTS: Considering each muscle of the QF, the DSI of the multi-atlas-based approach was high 0.87 +/- 0.11 and the best results were obtained with the combination of two deformation fields resulting from the SyN registration method and the STEPS fusion algorithm. The optimal variables for FFD and SyN registration methods were four templates and a kernel standard deviation ranging between 5 and 8. The segmentation process using a single-atlas-based method was more robust with DSI values higher than 0.9. From the vantage of muscle volume measurements, the multi atlas-based strategy provided acceptable results regarding the QF muscle as a whole but highly variable results regarding individual muscle. On the contrary, the performance of the single-atlas-based pipeline for individual muscles was highly comparable to the MSeg, thereby indicating that this method would be adequate for longitudinal tracking of muscle volume changes in healthy subjects. CONCLUSION: In the present study, we demonstrated that both multi-atlas and single-atlas approaches were relevant for the segmentation of individual muscles of the QF in healthy subjects. Considering muscle volume measurements, the single atlas method provided promising perspectives regarding longitudinal quantification of individual muscle volumes. PMID- 26983432 TI - The effect of intermittent intraabdominal pressure elevations and low cardiac output on the femoral to carotid arterial blood pressure difference in piglets. AB - BACKGROUND: Our previous work in a laparoscopic setting in piglets revealed that the systolic femoral artery pressure was approximately 5 % higher than its carotid counterpart, whereas the mean and diastolic values showed no significant difference. This remained idem when the intraabdominal pressure (IAP) was gradually increased. In this study, we aimed to investigate the effect of (1) intermittent IAP elevations and (2) a low cardiac output (CO) on the blood pressure (BP) difference cranially (carotid artery) and caudally (femoral artery) of a capnoperitoneum (DeltaP = P a fem-P a carot). METHODS: A total of twenty-two piglets (mean body weight 11.0 kg; range 8.9-13.3 kg) were studied. Of these, 14 underwent intermittent IAP elevations at 8 and 16 mmHg, and DeltaP was measured. In another 8 piglets, a model of reduced CO was created by introducing an air embolism (2 ml/kg over 30 s) in the inferior caval vein (VCI) at 12 mmHg IAP to further assess the influence of this variable on DeltaP. RESULTS: Systolic DeltaP remained at a mean of 5.6 mmHg and was not significantly affected by insufflation or exsufflation up to an IAP of 16 mmHg. Diastolic and mean values showed no differences between P a carot and P a fem. P a fem, systol remained higher than its carotid counterpart as long as the cardiac index (CI) was above 1.5 l/min/m2, but fell significantly below P a carot, systol at a low CI. There was no CO dependent effect on diastolic and mean DeltaP. Repeated IAP elevations do not significantly influence DeltaP. CONCLUSIONS: Intermittent IAP elevations do not significantly influence DeltaP. Despite of a CO-dependent inversion of systolic DeltaP, mean BP measurements at the leg during laparoscopy remain representative even at low CO values. PMID- 26983433 TI - Insulation failure in electrosurgery instrumentation: a prospective evaluation. AB - BACKGROUND: The use of electrosurgery has expanded to a wide variety of surgical specialities, but it has also been accompanied by its share of complications, including thermal injuries to nontargeted tissues, caused by a break or defect in the insulation of the instrument's coat. The purpose of this study was to determine the prevalence and the location of insulation failures (IFs) in electrosurgical instruments, then to assess the necessity of routine IF testing. METHODS: Electrosurgical instruments were visually inspected and checked for IF using a high-voltage detector. Two different detectors were used during two testing sessions: DTU-6 (Petel company) and DIATEG (Morgate company). Laparoscopic and non-laparoscopic instruments were determined to have IF if current crossed the instrument's insulation, signaled by an alarm sound. RESULTS: A total of 489 instruments were tested. The overall prevalence of IFs was 24.1 % with only visual inspection and 37.2 % with the IF detector. Among the 489 instruments, 13.1 % were visually intact, but had an electric test failure. DTU-6 and DIATEG detectors showed comparable efficiency in detection of overall IFs and for laparoscopic and non-laparoscopic instruments. The median location of IFs was more pronounced for laparoscopic instruments (50.4 %) and the distal location for non-laparoscopic instruments (40.4 %). CONCLUSION: Accidental burns are a hidden problem and can lead to patient complications. In Central Sterilization Service Department, prevention currently includes only visual control of electrosurgery instrumentation, but testing campaigns are now necessary in order to identify maximum instruments' defects. PMID- 26983434 TI - Single-port laparoscopic surgery in acute appendicitis: retrospective comparative analysis for 618 patients. AB - BACKGROUND: Transumbilical single-port laparoscopic appendectomy (SPLA) is a promising procedure that features less pain, faster recovery of postoperative bowel function and superior cosmetic results. We performed a retrospective comparative analysis of SPLA versus conventional laparoscopic surgery (CLA) to evaluate the safety and efficacy in acute appendicitis. METHODS: From December 2008 to November 2013, laparoscopic surgery was performed on 636 patients with acute appendicitis at the Department of Surgery, Chuncheon Sacred Heart Hospital. Under approval of Institutional Review Board, data concerning baseline characteristics, operative outcomes, postoperative complications and postoperative functional recovery were compared between both procedures. RESULTS: After exclusion of 18 patients, 618 patients treated for acute appendicitis were included. SPLA was performed in 375 patients and CLA in 243 patients. Complicated appendicitis was more prevalent in the CLA group (26.3 %) than in the SPLA group (17.1 %) (p = 0.005). There was no difference between groups in operation time (p = 0.235), postoperative duration of hospital stay (p = 0.672) and readmission rate (p = 0.688). The rate of postoperative complications was similar in both groups (10.7 % in SPLA vs. 11.1 % in CLA, p = 0.862). In subgroup analysis of complicated appendicitis, more patients needed conversion to open surgery in the SPLA group (15.6 vs. 1.6 %, p = 0.005). CONCLUSION: In uncomplicated appendicitis, SPLA can be performed safely and efficiently. However, more selective indication for SPLA should be applied in cases of complicated appendicitis because of the greater risk of open conversion. PMID- 26983435 TI - A comparative cost analysis of robotic-assisted surgery versus laparoscopic surgery and open surgery: the necessity of investing knowledgeably. AB - BACKGROUND: Robotic surgery has been proposed as a minimally invasive surgical technique with advantages for both surgeons and patients, but is associated with high costs (installation, use and maintenance). The Health Technology Assessment Unit of the Bambino Gesu Children's Hospital sought to investigate the economic sustainability of robotic surgery, having foreseen its impact on the hospital budget METHODS: Break-even and cost-minimization analyses were performed. A deterministic approach for sensitivity analysis was applied by varying the values of parameters between pre-defined ranges in different scenarios to see how the outcomes might differ. RESULTS: The break-even analysis indicated that at least 349 annual interventions would need to be carried out to reach the break-even point. The cost-minimization analysis showed that robotic surgery was the most expensive procedure among the considered alternatives (in terms of the contribution margin). CONCLUSIONS: Robotic surgery is a good clinical alternative to laparoscopic and open surgery (for many pediatric operations). However, the costs of robotic procedures are higher than the equivalent laparoscopic and open surgical interventions. Therefore, in the short run, these findings do not seem to support the decision to introduce a robotic system in our hospital. PMID- 26983437 TI - Use of the Ambu(r) aScope 2TM in laparoscopic common bile duct exploration. AB - BACKGROUND: We have recently begun to use a sterile disposable endoscope to perform laparoscopic common bile duct exploration. We evaluated our practice in a large district general hospital and reported the early feasibility of this equipment in performing bile duct exploration. METHODS: We began to use the Ambu(r) aScope 2TM from June 2015 in our institution. Any case eligible for a laparoscopic common bile duct exploration was included. Our study period is from June 2015 to November 2015. Data were collected and analysed retrospectively. RESULTS: Thirteen patients were included. Nine were female and five were male. The mean age was 59 years old (range 28 to 82 years). Seven were performed as an emergency and six were performed for elective cases. All patients had common bile duct stones with no history of previous cholecystectomy. The Ambu(r) aScope 2TM was used in 11 cases, and a standard choledocoscope was used in two cases due to lack of availability of the Ambu(r) aScope 2TM. There was one conversion due to an impacted bile duct stone and technical difficulty intra-operatively. Five cases were performed as a transcystic exploration with 1 case being converted to a choledocotomy due to inability to pass the cystic duct using the Ambu(r) aScope 2TM. The mean operating time was 158 min (range 85-255 min). The mean operative time using the reusable endoscope was 130 min. The mean postoperative stay was 3 days (range 0-8 days). CONCLUSIONS: The use of the Ambu(r) aScope 2TM is safe and feasible in laparoscopic common bile duct exploration. It confers significant financial benefits and offers an economical alternative to expensive reusable endoscopes. PMID- 26983436 TI - Effectivity of laparoscopic inguinal hernia repair (TAPP) in daily clinical practice: early and long-term result. AB - INTRODUCTION: The aim of the study was to investigate the effectiveness of laparoscopic inguinal hernia repair in daily clinical practice. PATIENTS AND METHODS: All patients admitted to the hospital for surgery of an inguinal hernia during a 1-year period were prospectively documented and included in a follow-up study. The follow-up was performed at least 5 years after surgery and consisted of a clinical examination, ultrasound investigation and a questionnaire. RESULTS: From January 2000 to January 2001 a total of 1208 inguinal hernias in 952 patients were consecutively operated by a total of 11 general surgeons in daily clinical routine. Of the patients, 98.02 % were operated on laparoscopically with the transabdominal preperitoneal patch plasty technique (TAPP) and 1.98 % had an open repair. The frequency of intraoperative and early postoperative complications was 2.8 %. The complication rate in the patients presenting a complex hernia was not higher than in patients with uncomplicated unilateral hernias. Life-threatening complications were seen in four patients (bowel lesion 0.4 %), but all four patients presented extensive adhesions in the abdominal cavity after previous abdominal surgery. The follow-up rate after 5 years was 85.3 %. After 5 years the recurrence rate was 0.4 % and the rate of severe chronic pain 0.59 %. None of the patients took analgesics or had to change his occupation. CONCLUSION: Laparoscopic repair can be applied to all types of inguinal hernia as a daily routine procedure with low rates of recurrences and chronic pain. Limiting factor may be extensive adhesions after previous major surgery in the lower abdomen. PMID- 26983438 TI - The low incidence of bacteremia after esophageal endoscopic submucosal dissection (ESD) obviates the need for prophylactic antibiotics in esophageal ESD. AB - BACKGROUND: Although a high incidence of bacteremia after esophageal endoscopic procedures has been reported, the incidence of bacteremia associated with esophageal endoscopic submucosal dissection (ESD) remains unknown. Therefore, we investigated the incidence of bacteremia associated with esophageal ESD. METHODS: From April 2013 to March 2014, patients who underwent esophageal ESD were enrolled prospectively. Two sets of blood cultures were collected from patients at the following time points: (1) immediately after ESD; (2) the next morning; and (3) when fever >=38 degrees C was present after ESD. RESULTS: A total of 424 blood culture sets were collected from 101 patients. Six patients had positive blood cultures immediately after ESD (4 %, 7/202 sets). Another patient had a positive blood culture the next morning (0.5 %, 1/202 sets). Ten patients (10 %) developed a post-ESD fever >=38 degrees C, and blood cultures from these patients were all negative (0/20 sets). The seven patients with positive blood cultures had no post-ESD fever or infectious symptoms. Growth of Bacteroides thetaiotaomicron was only observed in one patient (1 %) with positive blood cultures immediately after ESD, and this patient was diagnosed with transient bacteremia. The other six patients were considered to have contaminants in their blood cultures. Thus, the incidence of bacteremia after esophageal ESD was 1 % [95 % confidence interval (CI) 0-5 %]. No patient had infectious symptoms, and none required antibiotics after ESD. CONCLUSIONS: The incidence of bacteremia after esophageal ESD was low and post-ESD fever was not associated with bacteremia. We conclude that use of routine prophylactic antibiotics to patients undergoing esophageal ESD is unnecessary. CLINICAL TRIAL REGISTRY NUMBER: UMIN000012908. PMID- 26983439 TI - Clinical outcomes of and management strategy for perforations associated with endoscopic submucosal dissection of an upper gastrointestinal epithelial neoplasm. AB - INTRODUCTION: Perforation is one of the major complications of endoscopic submucosal dissection (ESD). In the present study, we investigated the clinical outcomes of and management strategies for ESD-related perforations. METHODS: Between February 2010 and April 2014, a total of 3821 patients who underwent ESD for an upper gastrointestinal epithelial neoplasm were analyzed using the Yonsei University Severance Hospital database. Clinical outcomes of and management strategies for perforations in 90 patients (2.4 %) were analyzed. The risk factors for the development of perforation were also investigated. RESULTS: The mean age of our subjects was 64.7 +/- 12.2 years (male to female ratio, 3.2:1), and the mean size of the resected specimens was 39.4 +/- 12.5 mm. Endoscopically visible perforations (visible perforation group) were noted in 74 of the 90 patients (82.2 %), and clinically suspected perforations (suspected perforation group) were noted in 16 patients (17.8 %). Immediate closure with endoclips was attempted in cases with a visible perforation and was successful in 72 (97.3 %) cases. Two patients in whom endoscopic closure failed underwent surgery. Conservative care, including fasting and intravenous antibiotic administration, was attempted in the suspected perforation group, and all the patients were treated successfully without surgery. The mean durations of fasting, antibiotic treatment, and hospital stay were 3.8 +/- 3.1, 6.8 +/- 4.2, and 8.7 +/- 5.3 days, respectively. Subgroup analysis of perforation type (visible perforation vs. suspected perforation) revealed no significant difference in the clinical course. Tumor location at the upper or middle third of the stomach was significantly associated with perforation. CONCLUSION: Most of the ESD-related perforations in upper gastrointestinal epithelial neoplasm could be managed successfully in a non surgical manner under strict monitoring. PMID- 26983440 TI - Gaze entropy reflects surgical task load. AB - BACKGROUND: Task (over-)load imposed on surgeons is a main contributing factor to surgical errors. Recent research has shown that gaze metrics represent a valid and objective index to asses operator task load in non-surgical scenarios. Thus, gaze metrics have the potential to improve workplace safety by providing accurate measurements of task load variations. However, the direct relationship between gaze metrics and surgical task load has not been investigated yet. We studied the effects of surgical task complexity on the gaze metrics of surgical trainees. METHODS: We recorded the eye movements of 18 surgical residents, using a mobile eye tracker system, during the performance of three high-fidelity virtual simulations of laparoscopic exercises of increasing complexity level: Clip Applying exercise, Cutting Big exercise, and Translocation of Objects exercise. We also measured performance accuracy and subjective rating of complexity. RESULTS: Gaze entropy and velocity linearly increased with increased task complexity: Visual exploration pattern became less stereotyped (i.e., more random) and faster during the more complex exercises. Residents performed better the Clip Applying exercise and the Cutting Big exercise than the Translocation of Objects exercise and their perceived task complexity differed accordingly. CONCLUSIONS: Our data show that gaze metrics are a valid and reliable surgical task load index. These findings have potential impacts to improve patient safety by providing accurate measurements of surgeon task (over-)load and might provide future indices to assess residents' learning curves, independently of expensive virtual simulators or time-consuming expert evaluation. PMID- 26983442 TI - Vulvar intraepithelial neoplasia grade 3 associated with Behcet's disease. AB - BACKGROUND: Little information is available regarding the association between vulvar intraepithelial neoplasia grade 3 (VIN3) and Behcet's disease (BD). We report here concomitant VIN3 and genital ulcers in a patient with BD. CASE: A 44 year-old Caucasian woman with a history of BD, which had been evolving for 6 years, presented with ulcerated and papillomatous lesions on the vulva. Biopsies revealed a multifocal VIN3 positive for high-risk human papillomavirus (HPV) 33. Multiple biopsies were performed to exclude invasive cancer and VIN3 was treated with laser vaporization. CONCLUSION: We report clinical and anatomopathological features of a rare case of multifocal, high-risk, HPV-related VIN3. We also discuss the possible pathogenesis in the context of BD, featuring chronic ulceration and intrinsic or treatment-induced immunosuppression. PMID- 26983441 TI - Temperature-Dependent Persistence of Human Norovirus Within Oysters (Crassostrea virginica). AB - This study characterizes the persistence of human norovirus in Eastern oysters (Crassostrea virginica) held at different seawater temperatures. Oysters were contaminated with human norovirus GI.1 (Norwalk strain 8FIIa) by exposing them to virus-contaminated water at 15 degrees C, and subsequently holding them at 7, 15, and 25 degrees C for up to 6 weeks. Viral RNA was extracted from oyster tissue and hemocytes and quantitated by RT-qPCR. Norovirus was detected in hemocytes and oysters held at 7 and 15 degrees C for 6 weeks and in hemocytes and oysters held at 25 degrees C for up to 2 and 4 weeks, respectively. Results confirm that NoV is quite persistent within oysters and demonstrate that cooler water temperatures extend norovirus clearance times. This study suggests a need for substantial relay times to remove norovirus from contaminated shellfish and suggests that regulatory authorities should consider the effects of water temperature after a suspected episodic norovirus-contamination event. PMID- 26983443 TI - Radical nephrectomy and regional lymph node dissection for locally advanced type 2 papillary renal cell carcinoma in an at-risk individual from a family with hereditary leiomyomatosis and renal cell cancer: a case report. AB - BACKGROUND: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant tumor susceptibility syndrome, and the disease-related gene has been identified as fumarate hydratase (fumarase, FH). HLRCC-associated kidney cancer is an aggressive tumor characterized by early metastasis to regional lymph nodes and distant organs. Since early diagnosis and provision of definitive therapy is thought to be the best way to reduce the tumor burden, it is widely accepted that germline testing and active surveillance for an at-risk individual from a family with HLRCC is very important. However, it still remains controversial how we should treat HLRCC-associated kidney cancer. We successfully treated the patient with locally advanced HLRCC-associated kidney cancer, who has received active surveillance because of at-risk individual, by radical nephrectomy and extended retroperitoneal lymph node dissection, and examined surgically resected samples from a molecular point of view. CASE PRESENTATION: We recommended that 13 at-risk individuals from a family with HLRCC should receive active surveillance for early detection of renal cancer. A 48-year-old woman with a left renal tumor and involvement of multiple regional lymph nodes with high accumulation of fluorine-18-deoxyglucose on positron emission tomography was treated with axitinib as a neoadjuvant therapy. Preoperative axitinib induced the shrinkage of the tumor with decreased fluorine-18-deoxyglucose accumulation. Resected samples showed two thirds tumor tissue necrosis as well as high expression of serine/threonine kinase Akt and low expression of nuclear factor E2 related factor 2 (Nrf2) which activates anti-oxidant response and protects against oxidative stress in viable cancer cells. Targeted next-generation sequencing revealed that FH mutation and loss of the second allele were completely identical between blood and tumor samples, suggesting that FH mutation plays a direct role in FH-deficient RCC. She has remained well after radical operation for over 33 months. CONCLUSIONS: FH mutation plays a role in tumorigenic feature, a metabolic shift to aerobic glycolysis, and increased an anti-oxidant response phenotype in HLRCC-associated kidney cancer. PMID- 26983445 TI - Tribunal was "unduly lenient" over psychiatrist's deception, says High Court. PMID- 26983444 TI - Ethno-Specific Risk Factors for Adverse Pregnancy Outcomes: Findings from the Born in Bradford Cohort Study. AB - Objectives Preterm birth (PTB) and small for gestational age (SGA) are major causes of perinatal mortality and morbidity. Previous studies indicated a range of risk factors associated with these poor outcomes, including maternal psychosocial and economic wellbeing. This paper will explore a range of psycho social and economic factors in an ethnically diverse population. Methods The UK's Born in Bradford cohort study recruited pregnant women attending a routine antenatal appointment at 26-28 weeks' gestation at the Bradford Royal Infirmary (2007-2010). This analysis includes 9680 women with singleton live births who completed the baseline questionnaire. Data regarding maternal socio-demographic and mental health were recorded. Outcome data were collected prospectively, and analysed using multivariate regression models. The primary outcomes measured were: PTB (<37 weeks' gestation) and SGA (<10th customised centile). Results After adjustment for socio-demographic and medical factors, financial strain was associated with a 45 % increase in PTB (OR 1.45: 95 % CI 1.06-1.98). Contrary to expectation, maternal distress in Pakistani women was negatively associated with SGA (OR 0.65: CI 0.48-0.88). Obesity in White British women was protective for PTB (OR 0.67: CI 0.45-0.98). Previously recognized risk factors, such as smoking in pregnancy and hypertension, were confirmed. Conclusions This study confirms known risk factors for PTB and SGA, along with a new variable of interest, financial strain. It also reveals a difference in the risk factors between ethnicities. In order to develop appropriate targeted preventative strategies to improve perinatal outcome in disadvantaged groups, a greater understanding of ethno-specific risk factors is required. PMID- 26983447 TI - Ephedrae herba stimulates hepatocyte growth factor-induced MET endocytosis and downregulation via early/late endocytic pathways in gefitinib-resistant human lung cancer cells. AB - The MET tyrosine kinase receptor and its ligand, hepatocyte growth factor (HGF), are known to be overexpressed in a variety of malignant tumor cells, and are implicated in the development of gefitinib-resistance in human non-small cell lung cancer (NSCLC) cells. Ephedrae herba was previously reported to prevent HGF induced cancer cell motility by directly suppressing HGF/MET signaling through the inhibition of MET tyrosine kinase, and treatment with its extract also considerably reduced MET protein levels. To further investigate the mechanism underlying the Ephedrae herba-induced inhibition of MET phosphorylation as well as its degradation and subsequent disappearance, we examined the effect of Ephedrae herba on HGF-stimulated MET endocytosis and downregulation via early/late endocytic pathways in an NSCLC cell line. Using immunofluorescence microscopy, we found that pretreatment of cells with Ephedrae herba extract dramatically changed the intracellular distribution of plasma membrane-associated MET, and that the resultant MET staining was distributed throughout the cytoplasm. Pretreatment of the cells with Ephedrae herba extract also led to the rapid loss of MET and phosphorylated (p)-MET in HGF-stimulated cells. In contrast, inefficient endocytic delivery of MET and p-MET from early to late endosomes was observed in the absence of Ephedrae herba extract, since considerable amounts of the internalized MET accumulated in the early endosomes and were not delivered to lysosomes up to 1 h after HGF-stimulation. Furthermore, large amounts of MET and p-MET that had accumulated in late endosomes of Ephedrae herba-pretreated cells after HGF stimulation were observed along with bafilomycin A1. Therefore, we inferred that degradation of MET occurred in the late endosome/lysosome pathway. Moreover, western blot analysis revealed the accelerated degradation of MET and p-MET proceeds in cells pretreated with Ephedrae herba extract. Collectively, our results suggest that some components of Ephedrae herba have a novel role in promoting HGF-stimulated MET and p-MET endocytosis followed by its downregulation, likely mediated by the early/late endocytic pathways. PMID- 26983446 TI - The impact of oophorectomy on survival after breast cancer in BRCA1-positive breast cancer patients. AB - The aim of the study is to identify treatments which predict survival for women with a BRCA1 mutation, including oophorectomy and chemotherapy. 476 women with stage I to stage III breast cancer who carried a BRCA1 mutation were followed from diagnosis until April 2015. Information on treatment was obtained from chart review and patient questionnaires. Dates of death were obtained from the Poland vital statistics registry. Survival curves were compared for different subgroups according to treatment received. Predictors of overall survival were determined using the Cox proportional hazards model. The ten-year overall survival was 78.3 % (95 % CI 74.2-82.6 %) and the ten-year breast cancer-specific survival was 84.2 % (95 % CI 80.5-88.0 %). Sixty-two patients died of breast cancer, 14 patients died of ovarian cancer, and 2 patients died of peritoneal cancer. Oophorectomy was associated with a significant reduction in all-cause mortality in the entire cohort (adjusted HR = 0.41; 95 % CI 0.24-0.69; p = 0.0008) and in breast cancer specific mortality among ER-negative breast cancer patients (HR = 0.44; 95 % CI 0.22-0.89; p = 0.02). Among women with breast cancer and a BRCA1 mutation, survival is greatly improved by oophorectomy due to the prevention of deaths from both breast and ovarian cancer. PMID- 26983448 TI - Improvement in Functioning and Psychological Distress in Adolescents With Postural Orthostatic Tachycardia Syndrome Following Interdisciplinary Treatment. AB - Significant functional impairment and psychological distress have been observed in adolescent patients with postural orthostatic tachycardia syndrome (POTS). Interdisciplinary rehabilitation programs have been shown to be beneficial in the treatment of chronic pain in adults and adolescents. Only preliminary data have examined interdisciplinary rehabilitation efforts in patients with POTS. This study evaluated the impact of an interdisciplinary rehabilitation program on the functional impairment and psychological distress in 33 adolescents diagnosed with POTS. Patients included in the study were adolescents ages 11 to 18 diagnosed with POTS. Measures completed at admission and discharge from the program included the Functional Disability Index, Center for Epidemiological Studies Depression-Child scale, and the Pain Catastrophizing Scale for Children. After participation in the 3-week program, adolescents with POTS demonstrated a significant increase in overall functional ability and significant reductions in depression and catastrophizing. PMID- 26983449 TI - Observational study of trastuzumab-related cardiotoxicity in early and metastatic breast cancer. AB - Introduction Trastuzumab-related cardiotoxicity has been a major concern in clinical practice, since observational studies have shown higher incidences than that reported in clinical trials. We aim to measure the incidence of trastuzumab related cardiotoxicity in patients with early and metastatic breast cancer in the south of Brazil. Methods Multicenter prospective observational study, which included 109 patients with early or metastatic HER-2+ breast cancer undergoing any trastuzumab-based regimen. Cardiac events were measured by transthoracic echocardiography assessments and by signs and symptoms of heart failure. Results Trastuzumab-related cardiotoxicity was observed in 58 patients (53.2%). Emergency and hospitalization admissions were necessary in seven and three patients, respectively, due to symptoms of heart failure. One patient died in consequence of trastuzumab-related cardiotoxicity. In total, trastuzumab was discontinued in 31.2% of patients, of which almost a third could not return to treatment. In this study, no risk factors were significantly associated with the development of cardiotoxicity. Discussion The incidence of TRC and trastuzumab's early discontinuation observed was significantly higher in comparison with other studies. These findings endorse the fact that trastuzumab-related cardiotoxicity is a relevant adverse reaction, and therefore, cardiac dysfunction's monitoring must be highlighted in order to allow a safe use of trastuzumab in this population. PMID- 26983450 TI - Drug Survival and Predictors of Drug Survival for Methotrexate Treatment in a Retrospective Cohort of Adult Patients with Localized Scleroderma. AB - Data regarding the efficacy and safety of methotrexate (MTX) in adults with localized scleroderma (LoS) is scarce. This study gathered data from a retrospective cohort of adult patients with LoS (n?=?107), treated with MTX (1993 2015). MTX drug survival and predictors thereof were analysed. After 1 and 2 years, 26% and 63% of patients stopped MTX due to disease remission, respectively. Patients with younger age at MTX initiation (hazard ratio (HR) 1.159 (95% confidence interval (CI) 1.052-1.277)) and those with no other autoimmune diseases (HR 3.268 (95% CI 1.334-8.009)) more often stopped MTX due to disease remission. In addition, 24% of patients stopped MTX due to treatment failure within one year. Patients with circumscribed superficial LoS (HR 0.221 (95% CI 0.081-0.601)) experienced treatment failure less often than those with other LoS subtypes. Finally, adding folic acid (HR 0.184 (95% CI 0.079-0.425)) and reducing treatment delay (HR 1.056 (95% CI 1.004-1.112)) could be the most important factors in minimizing MTX treatment failure in LoS in clinical practice. PMID- 26983451 TI - Use of non-steroidal anti-inflammatory drugs correlates with the risk of venous thromboembolism in knee osteoarthritis patients: a UK population-based case control study. AB - OBJECTIVE: We aimed to examine whether the current users of specific NSAIDs have an increased risk of venous thromboembolism (VTE) among knee OA patients. METHODS: We conducted a population-based case-control study using The Health Improvement Network, a database of patient records from general practices in the UK. For every VTE case, we identified five controls matched on age, sex and calendar year of study enrolment. We used conditional logistic regression to assess the association between current use of specific NSAIDs and risk of VTE relative to remote NSAID users. RESULTS: Among knee OA patients with at least one NSAID prescription, we identified 4020 incident cases of VTE and 20 059 matched controls. Adjusted odd ratios (ORs) relative to the remote users were 1.38 (95% CI: 1.32, 1.44) for recent users and 1.43 (95% CI: 1.36, 1.49) for current users. Among the current NSAID users, the risk of VTE was increased with diclofenac [OR 1.63 (95% CI: 1.53, 1.74)], ibuprofen [OR = 1.49 (95% CI: 1.38, 1.62)], meloxicam [OR = 1.29 (95% CI: 1.11, 1.50)] and coxibs [celecoxib, OR = 1.30 (95% CI: 1.11, 1.51); rofecoxib, OR = 1.44 (95% CI: 1.18, 1.76)]; naproxen did not increase VTE risk [OR = 1.00 (95% CI: 0.89, 1.12)]. CONCLUSION: Compared with the remote users of NSAIDs, the risk of VTE increased for current users of diclofenac, ibuprofen, meloxicam, and coxibs, but not for naproxen, in the knee OA population. Clinicians should consider the risk profile for specific NSAIDs when recommending their use. PMID- 26983452 TI - Ultrasound Doppler but not temporal summation of pain predicts DAS28 response in rheumatoid arthritis: a prospective cohort study. AB - OBJECTIVE: Previous studies have suggested a link between inflammation and central sensitization of pain in patients with RA. We conducted a prospective cohort study to determine whether US Doppler (USD), temporal summation (TS) of pain-assessed at baseline-and the potential interaction between them could predict the treatment response in RA. METHODS: Patients were recruited from Departments of Rheumatology in the Copenhagen area and from private clinics. RA patients, who were scheduled to initiate therapy with either a conventional synthetic DMARD (csDMARD; including DMARD-naive patients) or a biologic DMARD (bDMARD) agent (including bDMARD switch), were included and examined before the start of treatment and after 4 months. During the 4 months, patients received routine care from their treating rheumatologist. RESULTS: Multiple regression analysis was conducted, with change in DAS28 as the dependent variable. In unadjusted models, baseline USD score was significantly associated with DAS28 (beta = 0.06; 95% CI: 0.02, 0.09; P < 0.001), whereas TS and their interaction were not. After adjusting for age, sex, disease duration, baseline DAS28 and whether patients initiated a csDMARD or a bDMARD, the USD score was still significantly associated with change in DAS28 (beta = 0.032; 95% CI: 0.001, 0.064; P = 0.046), whereas TS remained insignificant. CONCLUSION: USD assessed at baseline is valuable as a prognostic factor for change in disease activity in 'real-life' RA patients. We did not find evidence to suggest that TS or the interaction between USD and TS was prognostically important for this group of patients. PMID- 26983453 TI - A genome-wide association study identifies SLC8A3 as a susceptibility locus for ACPA-positive rheumatoid arthritis. AB - OBJECTIVE: RA patients with serum ACPA have a strong and specific genetic background. The objective of the study was to identify new susceptibility genes for ACPA-positive RA using a genome-wide association approach. METHODS: A total of 924 ACPA-positive RA patients with joint damage in hands and/or feet, and 1524 healthy controls were genotyped in 582 591 single-nucleotide polymorphisms (SNPs) in the discovery phase. In the validation phase, the most significant SNPs in the genome-wide association study representing new candidate loci for RA were tested in an independent cohort of 863 ACPA-positive patients with joint damage and 1152 healthy controls. All individuals from the discovery and validation cohorts were Caucasian and of Southern European ancestry. RESULTS: In the discovery phase, 60 loci not previously associated with RA risk showed evidence for association at P < 5*10(-4) and were tested for replication in the validation cohort. A total of 12 loci were replicated at the nominal level (P < 0.05, same direction of effect as in the discovery phase). When combining the discovery and validation cohorts, an intronic SNP in the Solute Carrier family 8 gene (SLC8A3) was found to be associated with ACPA-positive RA at a genome-wide level of significance RA [odds ratio (95% CI): 1.42 (1.25, 1.6), Pcombined = 3.19*10(-8)]. CONCLUSIONS: SLC8A3 was identified as a new risk locus for ACPA-positive RA. This study demonstrates the advantage of analysing relevant subsets of RA patients to identify new genetic risk variants. PMID- 26983454 TI - Computer aided morphometric analysis of oral leukoplakia and oral squamous cell carcinoma. AB - We compared the changes in the cells in the basal layer of normal mucosa, oral leukoplakia with dysplasia and different grades of oral squamous cell carcinoma (OSCC) using computer aided image analysis of tissue sections. We investigated three morphometric parameters: nuclear area (NA), cell area (CA) and their ratio (NA:CA). NA and NA:CA ratio showed a statistically significant increase from dysplasia to increasing grades of OSCC. Nuclear size was useful for differentiating normal tissue, potentially malignant leukoplakia and OSCC. PMID- 26983455 TI - Absorption mechanism of oxymatrine in cultured Madin-Darby canine kidney cell monolayers. AB - Context Oxymatrine (OMT) is beneficial to human health by exerting various biological effects. Objective To investigate the absorption mechanism of OMT and discover absorption enhancers using Madin-Darby canine kidney (MDCK) cell monolayers. Materials and methods Concentration effects on the transport of OMT were measured in the range of 1.0 * 10(-5)-1.0 * 10(-3) M in 2 h. Then, the effect of time, direction, temperature and pH on the transport of OMT at 10(-4) M was studied. Moreover, Papp of OMT was determined in the absence/presence of cyclosporine and surfactants at 100 MUM to further confirm the relative transport mechanism. Results The Papp AP->BL ranged from (3.040 +/- 0.23) * 10(-6) to (3.697 +/- 0.19) * 10(-6 )cm/s as the concentration varied from 10(-5) to 10(-3) M. OMT showed similar Papp at 4 and 37 degrees C (p > 0.05). Increasing the apical pH 7.4 and 8.0 resulted in Papp versus pH 5.0 (p < 0.01). Furthermore, in the presence of cyclosporine and surfactants including sodium citrate, sodium dodecyl sulphate (SDS) and deoxysodium cholate, Papp was (0.318 +/- 0.033) * 10( 5), (0.464 +/- 0.048) * 10(-5), (0.897 +/- 0.115) * 10(-5) and (1.341 +/- 0.122) * 10(-5 )cm/s, respectively. In the presence of surfactants, Papp significantly increased up to 1.5-4.3-fold (p < 0.05). Discussion and conclusion OMT transport across MDCK cell monolayers was by passive diffusion. Sodium citrate, SDS and deoxysodium cholate serve as excellent absorption enhancers which are useful for the related research improving the oral bioavailability of OMT. PMID- 26983456 TI - Frequency of Exposure to and Engagement in Nonsuicidal Self-Injury Among Inpatient Adolescents. AB - This study examined the relationship between frequency of exposure to non suicidal self-injury (NSSI) and engagement in NSSI among adolescents. Ninety inpatient adolescents with a history of NSSI, ages 12 to 17, completed a structured interview. The majority of participants had learned about NSSI prior to initiating the behavior themselves. More frequent exposure to specific methods of NSSI was associated with greater frequency of using those same methods. Greater exposure to NSSI in the media and seeking out NSSI content were related to greater frequency of engagement in NSSI. Clinicians may help those who self injure to become more knowledgeable and educated consumers of media to prevent NSSI behavior and contagion. PMID- 26983457 TI - Modification of Knee Flexion Angle Has Patient-Specific Effects on Anterior Cruciate Ligament Injury Risk Factors During Jump Landing. AB - BACKGROUND: The incidence of anterior cruciate ligament (ACL) injuries may be decreased through the use of intervention programs that focus on increasing the knee flexion angle during jump landing, which decreases strain on the ACL. PURPOSE: To investigate whether intervention training designed to change the knee flexion angle during landing causes secondary changes in other known measures associated with the risk of ACL injuries and to examine the time points when these secondary measures change. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 39 healthy recreational athletes performed a volleyball block jump task in an instrumented gait laboratory. The participants first completed the jumps without any modification to their normal landing technique. They were then given oral instruction to land softly and to increase their knee flexion angle during landing. Lower body kinematics and kinetics were measured before and after the modification using an optoelectronic motion capture system. RESULTS: The knee flexion angle after the modification significantly increased from 11.2 degrees to 15.2 degrees at initial contact and from 67.8 degrees to 100.7 degrees at maximum flexion, and the time between initial contact and maximum flexion increased from 177.4 to 399.4 milliseconds. The flexion modification produced a substantial reduction in vertical ground-reaction force (243.1 to 187.8 %BW) with a concomitant reduction in the maximum flexion moment. Interestingly, the flexion modification only affected the abduction angle and abduction moment for the group of participants that landed in an initial adducted position before the modification and had no significant effect on the group that landed in an abducted position. CONCLUSION: Increasing the knee flexion angle during jump landing may be an effective intervention to improve knee biomechanical risk factors associated with an ACL injury. However, the fact that the flexion modification only influenced critical risk factors (the abduction angle and abduction moment) in participants who initially landed in an adducted position suggests that the selection of interventions to prevent ACL injuries should account for patient-specific characteristics. CLINICAL RELEVANCE: The study helps elucidate how increasing the knee flexion angle affects lower body biomechanics and provided evidence for the need to introduce patient-specific strategies for preventing ACL injuries. PMID- 26983458 TI - Trends in the Presentation, Management, and Outcomes of Little League Shoulder. AB - BACKGROUND: With rising participation in youth sports such as baseball, proximal humeral epiphysiolysis, or Little League shoulder (LLS), is being seen with increasing frequency. However, there remains a paucity of literature regarding the causes, natural history, or treatment outcomes of LLS. PURPOSE: To analyze the demographic, clinical, and diagnostic features of a population of LLS patients, with an emphasis on identifying underlying risk factors for the development and recurrence of LLS after nonoperative treatment. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A departmental database at a high volume regional children's hospital was queried to identify cases of LLS between 1999 and 2013. Medical records were reviewed to allow for analysis of age, sex, athletic information, physical examination and radiologic findings, treatment details, clinical course, and rates of recurrence. RESULTS: Ninety-five patients (93 males, 2 females; mean age, 13.1 years; range, 8-16 years) were diagnosed with LLS. The number of diagnosed cases increased annually over the study period. All patients had shoulder pain with overhead athletics; secondary symptoms included elbow pain in 13%, shoulder fatigue or weakness in 10%, and mechanical symptoms in 8%. While the majority of patients (97%) were baseball players (86% pitchers, 8% catchers, 7% other positions), a small subset (3%) were tennis players. On physical examination, 30% were reported to have glenohumeral internal rotation deficit (GIRD), defined as a decreased arc of rotational range of motion of the shoulder. Treatment recommendations included rest in 99% of cases, physical therapy in 79% (including 100% of patients with GIRD), and position change upon return to play in 26%. Average time to full resolution of symptoms was 2.6 months, while average time to return to competition was 4.2 months. Recurrent symptoms were reported in 7% of the overall cohort at a mean of 7.6 months after initial diagnosis. The odds of recurrence in the group with diagnosed GIRD (14%) were 3.6 times greater than those without GIRD (5%; 95% CI: 0.7-17.1), but this difference was not statistically significant (P = .11). CONCLUSION: Little League shoulder is being diagnosed with increasing frequency. While most common in male baseball pitchers, the condition can occur in females, youth catchers, other baseball positions players, and tennis players. Concomitant elbow pain may be seen in up to 13%. After rest and physical therapy, recurrent symptoms may occur in a small subset of patients (7%), generally 3 to 6 months after return to sports. Almost one-third of LLS patients had GIRD, and this group had approximately three times higher probability of recurrence compared with those without GIRD. PMID- 26983459 TI - Fastball Pitch Velocity Helps Predict Ulnar Collateral Ligament Reconstruction in Major League Baseball Pitchers. AB - BACKGROUND: Ulnar collateral ligament injury and its subsequent surgical reconstruction are some of the most common issues among Major League Baseball (MLB) players. PURPOSE/HYPOTHESIS: The purpose of this study was to determine factors predictive of ulnar collateral ligament reconstruction (UCLR) among MLB pitchers. The hypothesis was that pitchers who underwent UCLR would have higher preinjury peak fastball pitch velocity. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Data on pitch velocity, number, and type (fastball, curveball, etc) for every pitcher and game within MLB from April 2, 2007 to April 14, 2015 were gathered from the publically available PitchFx database. Pitcher demographic information was also recorded. Data from after 2012 were excluded to avoid lead-time bias. Using publically available information, the names and approximate dates of surgery for every MLB pitcher who ever underwent UCLR, including those before 2007 and after 2012, were collected. Each pitcher-game was then classified as "control," "preinjury," or "postoperative." Control and preinjury pitchers were then compared to determine risk factors for UCLR. RESULTS: Overall, 1327 pitchers were included, of whom 309 (26.8%) had undergone UCLR. Of these, 145 had preinjury velocity data. Peak pitch velocity was significantly higher among preinjury pitchers than control pitchers (mean [95% CI], 93.3 mph [92.8-93.8] vs 92.1 mph [91.9-92.3]; P < .001), as was mean pitch velocity (87.8 mph [87.3-88.3] vs 86.9 mph [86.7-87.1]; P = .001). Both demonstrated a dose-response relationship. Although height did not differ (P = .934), weight was significantly higher for preinjury pitchers than controls (P = .005). Pitch counts per year were significantly lower for preinjury pitchers compared with control pitchers, although preinjury pitchers threw more breaking pitches (P = .003). On multivariate regression, peak pitch velocity was the primary independent predictor of whether a pitcher underwent UCLR (P < .001), with mean velocity (P = .013), body mass index (P = .010), and age (P = .006) being secondary predictors. However, a model constructed with these variables only explained 7% of the variance in UCLR rates. Pitch counts were not significant predictors. CONCLUSION: Higher pitch velocity is the most predictive factor of UCLR in MLB pitchers, with higher weight and younger age being secondary predictors, although these factors only explained 7% of the variance in UCLR rates. PMID- 26983460 TI - Implicit attitudes towards people with visible difference: findings from an Implicit Association Test. AB - Research on implicit and explicit attitudes towards those with a visible difference has provided contradictory findings. While studies suggest explicit attitudes towards those with a visible difference are positive, implicit attitudes are likely to be negative. An Implicit Association Test measured attitudes towards visible differences in 129 adults finding no evidence of negative implicit attitudes. This contrasts with previous findings and accounts of those with a visible difference who report perceiving negative behaviours by the general public. Results are discussed in terms of what is known about perceiving faces that are different, as well as socio-cultural changes. These findings provide preliminary evidence that implicit attitudes towards visible difference are not negative, and that behaviour may be a result of uncertainty regarding how to behave. PMID- 26983462 TI - Current Opinion and Use of Transcranial Doppler Ultrasonography in Traumatic Brain Injury in the Pediatric Intensive Care Unit. AB - The purpose of this study was to identify and review clinical studies using transcranial Doppler (TCD) ultrasonography in children with severe traumatic brain injury (TBI) in the pediatric intensive care unit (PICU). We identified 16 articles from January 2005 to July 2015 that met inclusion (TBI, five or more cases in case series, subjects <18 years old, TCD performed in PICU) and exclusion criteria (age not stated, data from subjects <18 years not separated from adult data, <85% study population <18 years in mixed population with adults). TCD parameters were used to assess autoregulation, intracranial pressure, and vasospasm, and to predict neurological outcome. Incidence of impaired autoregulation varied in severe TBI from 25% to 80%. Altered TCD flows and pulsatility index variably predicted intracranial hypertension across studies. Sonographic vasospasm in the middle cerebral artery occurred in 34% of 69 children with severe TBI. Outcomes seem to be related to altered TCD-derived flow velocities while in the ICU. TCD may be a useful tool to assess autoregulation, intracranial pressure, and vasospasm following TBI in the PICU. Further research is needed to establish gold standards and validate the findings in children. TCD may then impact day-to-day management in the PICU, and potentially improve outcomes in children with severe TBI. PMID- 26983461 TI - Epigenetic Regulation of Monocyte and Macrophage Function. AB - SIGNIFICANCE: Monocytes and macrophages are key players in tissue homeostasis and immune responses. Epigenetic processes tightly regulate cellular functioning in health and disease. Recent Advances: Recent technical developments have allowed detailed characterizations of the transcriptional circuitry underlying monocyte and macrophage regulation. Upon differentiation and activation, enhancers are selected by lineage-determining and signal-dependent transcription factors. Enhancers are shown to be very dynamic and activation of these enhancers underlies the differences in gene transcription between monocytes and macrophages and their subtypes. CRITICAL ISSUES: It has been shown that epigenetic enzymes regulate the functioning of these cells and targeting of epigenetic enzymes has been proven to be a valuable tool to dampen inflammatory responses. We give a comprehensive overview of recent developments and understanding of the epigenetic pathways that control monocyte and macrophage function and of the epigenetic enzymes involved in monocyte and macrophage differentiation and activation. FUTURE DIRECTIONS: The key challenges in the upcoming years will be to study epigenetic changes in human disease and to better understand how epigenetic pathways control the inflammatory repertoire in disease. Antioxid. Redox Signal. 25, 758-774. PMID- 26983463 TI - FBW7 (F-box and WD Repeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer. AB - PURPOSE: FBW7 functions as a tumor suppressor by targeting oncoproteins for destruction. We previously reported that the oncogenic mutation of KRAS inhibits the tumor suppressor FBW7 via the Ras-Raf-MEK-ERK pathway, which facilitates the proliferation and survival of pancreatic cancer cells. However, the underlying mechanism by which FBW7 suppresses pancreatic cancer remains unexplored. Here, we sought to elucidate the function of FBW7 in pancreatic cancer glucose metabolism and malignancy. EXPERIMENTAL DESIGN: Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and FBW7 expression in pancreatic cancer tissues. The impact of FBW7 on glucose metabolism was further validated in vitro and in vivo Finally, gene expression profiling was performed to identify core signaling pathways. RESULTS: The expression level of FBW7 was negatively associated with SUVmax in pancreatic cancer patients. FBW7 significantly suppressed glucose metabolism in pancreatic cancer cells in vitro Using a xenograft model, MicroPET/CT imaging results indicated that FBW7 substantially decreased 18F-fluorodeoxyglucose ((18)F-FDG) uptake in xenograft tumors. Gene expression profiling data revealed that TXNIP, a negative regulator of metabolic transformation, was a downstream target of FBW7. Mechanistically, we demonstrated that TXNIP was a c-Myc target gene and that FBW7 regulated TXNIP expression in a c-Myc-dependent manner. CONCLUSIONS: Our results thus reveal that FBW7 serves as a negative regulator of glucose metabolism through regulation of the c-Myc/TXNIP axis in pancreatic cancer. Clin Cancer Res; 22(15); 3950-60. (c)2016 AACR. PMID- 26983464 TI - Neddylation Inhibition Activates the Extrinsic Apoptosis Pathway through ATF4 CHOP-DR5 Axis in Human Esophageal Cancer Cells. AB - PURPOSE: Targeting the protein neddylation pathway has become an attractive anticancer strategy; however, the role of death receptor-mediated extrinsic apoptosis during treatment remained to be determined. EXPERIMENTAL DESIGN: The activation of extrinsic apoptosis and its role in MLN4924 treatment of human esophageal squamous cell carcinoma (ESCC) were evaluated both in vitro and in vivo The expression of the components of extrinsic apoptotic pathway was determined by immunoblotting analysis and downregulated by siRNA silencing for mechanistic studies. RESULTS: Pharmaceutical or genetic inactivation of neddylation pathway induced death receptor 5 (DR5)-mediated apoptosis and led to the suppression of ESCC in murine models. Mechanistically, neddylation inhibition stabilized activating transcription factor 4 (ATF4), a Cullin-Ring E3 ubiquitin ligases (CRL) substrate. Transcription factor CHOP was subsequently transactivated by ATF4 and further induced the expression of DR5 to activate caspase-8 and induce extrinsic apoptosis. Moreover, the entire neddylation pathway was hyperactivated in ESCC and was negatively associated with patient overall survival. CONCLUSIONS: Our findings highlight a critical role of ATF4 CHOP-DR5 axis-mediated extrinsic apoptosis in neddylation-targeted cancer therapy and support the clinical investigation of neddylation inhibitors (e.g., MLN4924) for the treatment of ESCC, a currently treatment-resistant disease with neddylation hyperactivation. Clin Cancer Res; 22(16); 4145-57. (c)2016 AACR. PMID- 26983465 TI - The Abbreviated Character Strengths Test (ACST): A Preliminary Assessment of Test Validity. AB - The 24-item Abbreviated Character Strengths Test (ACST) was developed to efficiently measure character strengths (Peterson, Park, & Castro, 2011 ). However, its validity for this purpose has not yet been sufficiently established. Using confirmatory factor analysis to test a series of structural models, only a modified bifactor model showed reasonably acceptable fit. Further analyses of this model failed to demonstrate measurement invariance between male and female respondents. Relationships between ACST dimension and Big Five personality trait scores were generally weak-to-moderate, and support for hypotheses regarding each ACST virtue's expected correspondence with specific Big Five dimensions was mixed. Finally, scores on ACST dimensions accounted for a combined 12% of the variance in satisfaction with life scores, after controlling for socially desirability. Although an abbreviated measure of character strengths represents a practical need, considerable improvements to the ACST are needed for it to adequately meet this purpose. PMID- 26983468 TI - Cognitive and Behavioral Outcomes of Intrauterine Growth Restriction School-Age Children. AB - CONTEXT: Children who experienced intrauterine growth restriction (IUGR) may be at increased risk for adverse neurologic developmental outcomes during the school age years of life. OBJECTIVE: To estimate the effect of IUGR on cognition and behavior in school-aged children. DATA SOURCES: Medline, Embase, and PsycINFO were searched for English-language articles published after 1980. DATA SELECTION: We included case-control studies reporting cognitive and/or behavioral data of children who had IUGR and were evaluated afterfifth birthday. DATA EXTRACTION: Cognitive data from 15 studies and behavioral data from 6 studies were selected with a total of 1559 cases and 1630 controls. The cognitive scores and behavioral outcomes were extracted. RESULTS: The controls had significantly higher cognitive scores than the children with IUGR (standardized mean difference [SMD] -0.38, 95% confidence interval [CI] -0.51 to -0.25, P < .00001). The IQ scores of the IUGR group were not significantly correlated with mean birth weight and gestational age (P > .05). Five trials were included in the behavioral outcomes trial, the behavior scores were significantly different between the groups with and without IUGR (SMD 0.31, 95% CI 0.13 to 0.48, P = .001). The incidence of attention deficit/hyperactivity disorder (ADHD) was not significantly different between 2 groups (P = .11). LIMITATIONS: The number of studies that assessed behavioral and ADHD outcome is small. CONCLUSIONS: The findings demonstrate that IUGR is associated with lower cognitive scores in school-age children. However, further large-scale trials are needed to assess the effects of IUGR on the outcome of behavioral disorder and ADHD. PMID- 26983466 TI - A role for ABCG2 beyond drug transport: Regulation of autophagy. AB - The ABC drug transporters, including ABCG2, are well known for their ability to efflux a wide spectrum of chemotherapeutic agents, thereby conferring a multidrug resistant phenotype. However, studies over the past several years suggest that the ABC transporters may play additional role(s) in cell survival in the face of stress inducers that are not ABCG2 substrates (i.e., nutrient deprivation, ionizing radiation, rapamycin). The mechanism by which this occurs is largely unknown. In the present study, using several cancer cell lines and their ABCG2 overexpressing sublines, we show that cells overexpressing ABCG2 were more resistant to these stressors. This resistance was associated with an elevated level of autophagy flux, as measured by a higher rate of SQSTM1/p62 degradation and greater accumulation of LC3-II when compared to parental cells. Knockdown of ABCG2 reduced autophagic activity in resistant cells to a level similar to that observed in parental cells, confirming that the enhanced autophagy was ABCG2 dependent. Moreover, using cell viability, apoptosis, and clonogenic assays, we demonstrated that the ABCG2-expressing cells were more resistant to amino acid starvation and radiation-induced cell death. Importantly, knockdown of the critical autophagy factors ATG5 and ATG7 greatly reduced cell survival, verifying that enhanced autophagy was critical for this effect. Taken together, these data indicate that autophagy induced by various stressors is enhanced/accelerated in the presence of ABCG2, resulting in delayed cell death and enhanced cell survival. This defines a new role for this transporter, one with potential clinical significance. PMID- 26983467 TI - Efficacy of phytosterols and fish-oil supplemented high-oleic-sunflower oil rich diets in hypercholesterolemic growing rats. AB - Phytosterols (P) and fish-oil (F) efficacy on high-oleic-sunflower oil (HOSO) diets were assessed in hypercholesterolemic growing rats. Controls (C) received a standard diet for 8 weeks; experimental rats were fed an atherogenic diet (AT) for 3 weeks, thereafter were divided into four groups fed for 5 weeks a monounsaturated fatty acid diet (MUFA) containing either: extra virgin olive oil (OO), HOSO or HOSO supplemented with P or F. The diets did not alter body weight or growth. HOSO-P and HOSO-F rats showed reduced total cholesterol (T-chol), non high-density lipoprotein-cholesterol (non-HDL-chol) and triglycerides and increased HDL-chol levels, comparably to the OO rats. Total body fat (%) was similar among all rats; but HOSO-F showed the lowest intestinal, epididymal and perirenal fat. However, bone mineral content and density, and bone yield stress and modulus of elasticity were unchanged. Growing hypercholesterolemic rats fed HOSO with P or F improved serum lipids and fat distribution, but did not influence material bone quality. PMID- 26983469 TI - Local Pharmacy Partnership to Prevent Pediatric Asthma Reutilization in a Satellite Hospital. AB - OBJECTIVES: In our previous work, providing medications in-hand at discharge was a key strategy to reduce asthma reutilization (readmissions and emergency revisits) among children in a large, urban county. We sought to spread this work to our satellite hospital in an adjacent county. A key initial barrier was the lack of an outpatient pharmacy on site, so we sought to determine if a partnership with community pharmacies could improve the percentage of patients with medications in-hand at discharge, thus decreasing reutilization. METHODS: A multidisciplinary team partnered with community pharmacies. Using rapid-cycle improvement methods, the team aimed to reduce asthma reutilization by providing medications in-hand at discharge. Run charts were used to display the proportion of patients with asthma discharged with medications in-hand and to track 90-day reutilization rates. RESULTS: During the intervention period, the median percentage of patients with asthma who received medications in-hand increased from 0% to 82%. A key intervention was the expansion of the medication in-hand program to all patients. Additional changes included expanding team to evening stakeholders, narrowing the number of community partners, and building electronic tools to support key processes. The mean percentage of patients with asthma discharged from the satellite who had a readmission or emergency department revisit within 90 days of their index admission decreased from 18% to 11%. CONCLUSIONS: Impacting population-level asthma outcomes requires partnerships between community resources and health providers. When hospital resources are limited, community pharmacies are a potential partner, and providing access to medications in-hand at hospital discharge can reduce asthma reutilization. PMID- 26983471 TI - [Advances in diagnosis and treatment of nonalcoholic fatty liver disease]. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease seen in patients with obesity, diabetes, and metabolic syndrome. Metabolic syndrome is an important predictor of the severe form of NAFLD, nonalcoholic steatohepatitis (NASH), and NASH patients with diabetes have an increased risk of liver cirrhosis and hepatocellular carcinoma. With the prevalence of obesity and diabetes around the world, NAFLD has become a global public health problem. NAFLD is not only one of the most important causes of liver-related disability and mortality, but also associated with the increasing incidence of diabetes and cardiovascular disease. The effective prevention and treatment of NAFLD is expected to reduce the burden of liver disease and cardiovascular disease. Therefore, this article overviews the advances in the diagnosis, prevention, and treatment of NAFLD. PMID- 26983472 TI - [New advances in diagnosis of nonalcoholic fatty liver disease]. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and the spectrum of this disease includes simple liver steatosis, nonalcoholic steatohepatitis, liver fibrosis, and liver cirrhosis. At present, liver biopsy is still the gold standard for the diagnosis of NAFLD and can determine the degree of steatosis, inflammation grade, and fibrosis stage, but its clinical application is limited by its invasiveness and static nature. New diagnostic markers and noninvasive diagnostic methods have been reportedly recently, and the constant development of magnetic resonance imaging, transient elastography, and controlled attenuation parameter provides new methods for the noninvasive diagnosis of NAFLD. PMID- 26983473 TI - [Studies on association between nonalcoholic fatty liver disease and hyperuricemia: current status and future prospects]. AB - Uric acid is the end-product of purine metabolism. It has been widely accepted that the increase in the level of uric acid significantly raises the risks of gout, cardiovascular disease, and type 2 diabetes. The studies in recent years have shown that hyperuricemia is closed related to nonalcoholic fatty liver disease (NAFLD). This review summarizes the research advances in the association between hyperuricemia and NAFLD and related mechanisms based on the author's recent research findings. PMID- 26983470 TI - Determinants of Social Outcomes in Adults With Childhood-onset Epilepsy. AB - BACKGROUND: Adults with childhood-onset epilepsy experience poorer adult social outcomes than their peers. The relative roles of seizures over time versus learning and psychiatric problems are unclear. METHODS: We examined independent influences of psychiatric and learning disorders and of seizure course in 241 young adults (22-35 years old) with uncomplicated epilepsy in a longitudinal community-based cohort study. Social outcomes were ascertained throughout the study. A history of psychiatric and learning problems was ascertained ~9 years after study entry. Seizure course was: "Excellent," no seizures after the first year, in complete remission at last contact (N = 95, 39%); "Good," seizures occurred 1 to 5 years after diagnosis, in complete remission at last contact (N = 56, 23%); "Fluctuating," more complicated trajectories, but never pharmacoresistant (N = 70, 29%); "Pharmacoresistant," long-term pharmacoresistant (N = 20, 8%). Multiple logistic regression was used to identify contributors to each social outcome. RESULTS: Better seizure course predicted college completion, being either employed or pursuing a degree, and driving, but was not substantially associated with other social outcomes. Poorer seizure course was associated with a greater likelihood of having offspring, particularly in women without partners. Learning problems, psychiatric disorders, or both negatively influenced all but 2 of the social outcomes. CONCLUSIONS: In young adults with uncomplicated epilepsy, the course of seizures contributed primarily to education, employment, and driving. A history of learning problems and psychiatric disorders adversely influenced most adult outcomes. These findings identify potential reasons for vocational and social difficulties encountered by young adults with childhood epilepsy and areas to target for counseling and transition planning. PMID- 26983474 TI - [Nonalcoholic fatty liver disease in the elderly]. AB - Along with the aging process, the spectrum of liver disease changes greatly. Nonalcoholic fatty liver disease (NAFLD) in elderly people lead to low liver function and is also the major cause of extrahepatic diseases, such as cardiovascular disease and malignant tumor. This review provides an overview of the morphological structure and function of the liver in aged people, and discusses the characteristics of weakness, malnutrition and limited movement in the elderly, as well as the current status of multiple diseases and multiple drug use. Finally, this article puts forward some appropriate regimens for the diagnosis and treatment of NAFLD in elderly people to provide a reference for clinical practice. PMID- 26983475 TI - [Value of serum osteoprotegerin in noninvasive diagnosis of nonalcoholic steatohepatitis]. AB - OBJECTIVE: To investigate the correlation of serum osteoprotegerin (OPG) with the progression of nonalcoholic fatty liver disease (NAFLD) and the noninvasive prediction and diagnosis of nonalcoholic steatohepatitis (NASH). METHODS: A total of 136 patients with NAFLD were enrolled, and their tissue samples for liver biopsy and serum samples obtained at 1 week after liver biopsy were collected; 83 healthy subjects without the symptoms of fatty liver disease proved by ultrasound examination were enrolled as controls. The physiological indicators including height, body weight, and waist circumference were measured, and body mass index was calculated. The biochemical parameters including alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT, alkaline phosphatase, gamma glutamyl transferase, total cholesterol, triglyceride (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were measured. Double-antibody sandwich enzyme-linked immunosorbent assay was used to determine the serum level of OPG. The rank sum test, chi-square test, t-test, one-way analysis of variance, Spearman correlation analysis, least significant difference test, and receiver operating characteristic (ROC) curve were applied for statistical analysis of various data. RESULTS: Serum OPG level was correlated with AST and TG (P < 0.05), and was highly correlated with hepatocyte fatty degeneration, ballooning degeneration, intralobular inflammation, portal inflammation, and fibrosis degree (P < 0.01). With the increasing NAFLD activity score (NAS), serum OPG level decreased, and there was a highly negative correlation between them (r = -0.928, P < 0.01). Serum OPG level was significantly lower in NASH patients than non-NASH patients. The area under the ROC curve of serum OPG level was 0.963, and according to the Youden index, its optimal sensitivity and specificity were 96.1% and 97.4%, respectively, at an optimal cut-off value of 242.96 ng/L, which suggested a high diagnostic power. CONCLUSION: In NASH patients, serum OPG level decreases significantly. Serum OPG level can be used as an independent predictive factor to evaluate NASH and its severity, as well as a noninvasive diagnostic index for NASH. PMID- 26983476 TI - [Role and mechanism of action of fibroblast growth factor-21 in reducing triglyceride in nonalcoholic fatty liver disease]. AB - OBJECTIVE: To investigate the role and mechanism of action of fibroblast growth factor-21 (FGF-21) in reducing triglyceride (TG) in the in vitro and in vivo models of nonalcoholic fatty liver disease (NAFLD). METHODS: (1) A mixture of free fatty acids was used to establish a model of steatosis in L02 cells, and the cells were treated with various concentrations of FGF-21 or fenofibrate. Twenty four hours later, oil red O staining was performed to observe the degree of steatosis, and intracellular TG content was determined. RT-PCR and Western blot were applied to measure the mRNA and protein expression of sterol regulatory element-binding protein-1c (SREBP-1c). (2) High-fat diet was used to establish a mouse model of steatosis, and these mice were intraperitoneally injected with FGF 21 or fenofibrate. Eight weeks later, whole blood and liver samples were collected, and HE staining was performed to observe steatosis. Meanwhile, the serum levels of TG, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured, and TG content in the liver was also measured. One-way analysis of variance was used for comparison of data between multiple groups, and the least significant difference t-test was used for comparison between any two groups. RESULTS: (1) Compared with the control group, the model group showed significant steatosis, with significant increases in intracellular lipid droplets and TG content (t = -20.57, P < 0.01), while FGF-21 reduced the number of intracellular lipid droplets and TG content (F = 98.16, P < 0.01) in a dose-dependent manner. In addition, the model group had significantly increased mRNA and protein expression of SREBP-1c compared with the control group (t = -10.73 and -0.1006, both P < 0.01), while FGF-21 down-regulated the mRNA and protein expression of SREBP-1c (F = 161.35 and 36.72, both P < 0.01). (2) Compared with the mice in the control group, those in the model group showed significant steatosis and had significant increases in serum TG level and TG content in the liver (t = -18.84 and 15.71, both P < 0.01). FGF-21 relieved hepatic steatosis and reduced the serum TG level and TG content in the liver (t = 18.11 and 9.46, both P < 0.01). Moreover, FGF-21 reduced the serum levels of ALT and AST in NAFLD mice (t = 25.93 and 12.50, both P < 0.01). CONCLUSION: FGF-21 can inhibit the synthesis of TG through suppressing the expression of SREBP-1c, which further confirms the potential therapeutic effect of FGF-21 in the treatment of NAFLD. This may provide new ideas for the treatment of NAFLD. PMID- 26983477 TI - [Value of controlled attenuation parameter in diagnosis of fatty liver using FibroScan]. AB - OBJECTIVE: To investigate the value of controlled attenuation parameter (CAP) in the diagnosis of fatty liver using FibroScan in patients with chronic liver disease (CLD). METHODS: A prospective cohort study was performed for the patients with chronic hepatitis B (CHB), chronic hepatitis C (CHC), and non-alcoholic fatty liver disease (NAFLD) who underwent liver pathological examination followed by CAP measurement within 1 week in The Second People's Hospital of Tianjin from February 2013 to May 2014. According to related guidelines, hepatocyte steatosis was classified as S0: <5%, S1: 5%-33%, S2: 34%-66%, or S3: >=67%. The receiver operating characteristic (ROC) curves were plotted with positive results as the diagnostic criteria, and the optimal cut-off values were determined at the maximum Youden index. Single linear regression and multiple stepwise regression were applied to analyze the influencing factors for CAP. RESULTS: A total of 427 patients were enrolled, consisting of 19 patients (4.4%) with NAFLD, 383 (89.7%) with CHB, and 25 (5.9%) with CHC. The optimal cut-off values for CAP in the diagnosis of steatosis >=5%, >=34%, and >=67% were 230 dB/m, 252 dB/m, and 283 dB/m, respectively, and the areas under the ROC curve were 0.803, 0.942, and 0.938, respectively (Z = 14.194, 28.385, and 16.486, respectively, all P < 0.01). CAP differentiated S0 from S1, S1 from S2, S0 from S2, S0 from S3, and S1 from S3 (Z = 10.109, 10.224, 47.81, 29.917, and 10.999, all P < 0.01), but was not able to differentiate S2 from S3 (Z = 0.656, P = 0.5116). The single linear regression and multiple stepwise regression analyses showed that only body mass index (BMI; B = 4.001, P < 0.01) and hepatic steatosis (B = 33.015, P = 0.000) were correlated with CAP. The coincidence rates between CAP and liver pathological diagnosis were 77.4%, 81.0%, and 96.2% for S0, S3, and >=S2, respectively. CONCLUSION: CAP has a good value in the diagnosis of fatty liver in CLD patients, and can well differentiate between all stages of fatty liver except S2 and S3. CAP is influenced by BMI, but is not found to be associated with liver fibrosis, inflammation, liver stiffness measurement, and etiology. PMID- 26983478 TI - [Association between protective effect of Liuwei Wuling tablets against acute liver injury and its inhibitory effect on cytoplasmic translocation of high mobility group box-1 in hepatocytes in mice]. AB - OBJECTIVE: To investigate the effect of Liuwei Wuling tablets on the cytoplasmic translocation and release of high-mobility group box-1 (HMGB1) in hepatocytes in mice with acute live injury induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS). METHODS: A Balb/c mouse model of acute liver injury was established by intraperitoneal injection of D-GalN (400 mg/kg) and LPS (5 ug/kg). A total of 24 healthy mice were randomly and equally divided into acute liver injury control group and Liuwei Wuling tablet treatment group. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured in both groups at each time point within one week. Liver tissues were collected at 36 hours to perform pathological examination. The serum levels of HMGB1, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), complement 3a (C3a), and complement 5a (C5a) were measured. Immunohistochemistry was used to determine the expression and cytoplasmic translocation of HMGB1 in hepatocytes. RESULTS: At 6, 12, and 24 hours, the Liuwei Wuling tablet treatment group had significantly lower serum levels of ALT than the control group (225.33+/-181.64 U/L vs 471.17+/-174.72 U/L, t = 3.38, P < 0.01; 1509.53+/-182.51 U/L vs 7149.52+/-734.25 U/L, t = 25.82, P < 0.01; 162.89+/ 86.51 U/L vs 1318.16+/-557.71 U/L, t = 7.09, P < 0.01), as well as significantly lower serum levels of AST than the control group (179.22+/-94.57 U/L vs 561.91+/ 209.6 U/L, t = 5.76, P < 0.01; 590.92+/-190.92 U/L vs 2266.48+/-705.64 U/L, t = 7.94, P < 0.01; 231.24+/-87.7 U/L vs 444.32+/-117.01 U/L, t = 5.05, P < 0.01). The treatment group had significantly lower levels of HMGB1 than the control group at 6 and 12 hours (54.21+/-11.89 ng/ml vs 72.07+/-13.65 ng/ml, t = 3.41, P < 0.01; 49.23+/-5.97 ng/ml vs 68.71+/-13.07 ng/ml, t = 4.70, P < 0.01). The treatment group had significantly lower levels of TNF-alpha, IL-1beta, and IL-6 than the control group at 12 hours (163.62+/-9.12 pg/ml vs 237.09+/-51.47 pg/ml, t = 4.86, P < 0.01; 15.66+/-13.13 pg/ml vs 37.43+/-18.68 pg/ml, t = 3.30, P < 0.01; 7.10+/-3.06 pg/ml vs 21.42+/-8.23 pg/ml, t = 5.65, P < 0.01). The treatment group had significantly lower levels of C3a and C5a than the control group at 12 hours (2.52+/-1.27 pg/ml vs 9.83+/-2.96 ng/ml, t = 7.86, P < 0.01; 2.16+/-1.03 ng/ml vs 7.23+/-1.55 ng/ml, t = 9.67, P < 0.01). Compared with the control group, the treatment group had significantly reduced liver inflammation and necrosis, and a significantly lower cytoplasmic translocation rate of HMGB1 in hepatocytes (38.76%+/-7.37% vs 8.15%+/-2.11%, P < 0.01). CONCLUSION: Liuwei Wuling tablets can reduce the cytoplasmic translocation of HMGB1 in hepatocytes and relieve liver inflammation in mice with acute liver injury. PMID- 26983479 TI - [Correlation between red blood cell count and liver function status]. AB - OBJECTIVE: To investigate the changes in red blood cell count in patients with different liver diseases and the correlation between red blood cell count and degree of liver damage. METHODS: The clinical data of 1427 patients with primary liver cancer, 172 patients with liver cirrhosis, and 185 patients with hepatitis were collected, and the Child-Pugh class was determined for all patients. The differences in red blood cell count between patients with different liver diseases were retrospectively analyzed, and the correlation between red blood cell count and liver function status was investigated. The Mann-Whitney U test, Kruskal-Wallis H test, rank sum test, Spearman rank sum correlation test, and chi square test were performed for different types of data. RESULTS: Red blood cell count showed significant differences between patients with chronic hepatitis, liver cancer, and liver cirrhosis and was highest in patients with chronic hepatitis and lowest in patients with liver cirrhosis (P < 0.05). In the patients with liver cirrhosis, red blood cell count tended to decrease in patients with a higher Child-Pugh class (P < 0.05). CONCLUSION: For patients with liver cirrhosis, red blood cell count can reflect the degree of liver damage, which may contribute to an improved liver function prediction model for these patients. PMID- 26983481 TI - [Ephedra protects rats against acute liver failure induced by D-galactosamine and lipopolysaccharide]. PMID- 26983480 TI - [Clinical value of acoustic radiation force impulse elastography in differential diagnosis of focal liver lesions]. AB - OBJECTIVE: To investigate the clinical value of acoustic radiation force impulse (ARFI) elastography in the differential diagnosis of focal liver lesions. METHODS: ARFI elastography was performed for 169 lesions from 163 patients with focal liver lesions and 15 healthy volunteers, and the virtual touch tissue imaging (VTI) findings and measured value of shear wave velocity (SWV) of liver lesions were obtained and compared between groups. The t-test was applied for comparison of means between two groups; the one-way analysis of variance was applied for comparison of means between multiple groups, and the Student-Newman Keuls test was applied for further comparison between any two groups. RESULTS: Benign focal liver lesions were stiffer or softer than or had the same stiffness as the surrounding liver parenchyma. These lesions had a uniform texture, and the ratio between their diameters on elastographic images and two-dimensional images was close to 1. The typical VTI finding of hemangioma lesions was"honeycomb"pattern. Most malignant focal liver lesions were stiffer than the surrounding liver parenchyma, and the ratio between their diameters on elastographic images and two-dimensional images was greater than 1. The typical VTI finding of metastatic lesions was"bull's eye"sign. With a measured SWV of 2.08 m/s as the diagnostic threshold for malignant liver lesions, its sensitivity, specificity, and accuracy were 90.3%, 76.9%, and 84.2%, respectively. Poorly differentiated hepatocellular carcinoma (HCC) showed a significant increase in stiffness compared with moderately differentiated HCC (t = 5.319, P = 0.025) and well-differentiated HCC (t = 6.372, P = 0.011). CONCLUSION: ARFI elastography can reflect changes in the stiffness of focal liver lesions accurately, and is useful for the differential diagnosis of benign and malignant focal liver lesions. PMID- 26983482 TI - [Value of red blood cell distribution width in assessing the severity of hepatitis C virus-related liver diseases]. PMID- 26983483 TI - [Clinical effect of TACE combined with radiofrequency ablation in treatment of malignant tumor at the second porta hepatis]. PMID- 26983484 TI - [Value of ANI in differentiating between alcoholic liver disease and nonalcoholic fatty liver disease]. PMID- 26983485 TI - [One case of Budd-Chiari syndrome secondary to antiphospholipid syndrome]. PMID- 26983486 TI - [Nucleos(t)ide antiviral agents for preventing mother-to-child transmission of hepatitis B virus: an interpretation of relevant international guidelines]. AB - A high maternal viral load is the most important factor affecting immunoprophylaxis against mother-infant transmission of HBV. The application of antiviral drugs in pregnant women with a high serum HBV DNA level (>10(6)~10(7) IU/ml) during the second and third trimesters can reduce the prenatal serum HBV DNA level and significantly increase the success rate of blocking mother-infant transmission in neonates. This article interprets the contents related to antiviral therapy for pregnant women carrying HBV with the purpose of blocking mother-infant transmission of HBV in the guidelines published by Asian Pacific Association for the Study of the Liver, European Association for the Study of the Liver, National Institute for Health and Care Excellence, Korean Association for the Study of the Liver, and World Health Organization. PMID- 26983487 TI - [De novo autoimmune hepatitis after liver transplantation]. AB - Patients who transplanted for non-autoimmune indication may developed de novo autoimmune hepatitis after liver transplantation. It happens about 1.7%-6.6% in liver transplanted population. Most patients with de novo AIH had transplanted for HCV infection, biliary atresia and Cholestatic liver disease. The interval between transplantation and de novo AIH onset is from 3 month to 16 years, mostly more than 1 year. The disease can be seen at any age. More female patients are present in children, while there is no significant difference between male and female in adults. Clinical manifestations of de novo AIH are similar to those of AIH, namely characterized by elevated transaminase with or without bilirubin, as well as elevated serum gammaglobulin (IgG) and positive autoantibodies, while the histological features of an infiltrate rich in plasma cells with interface hepatitis and necro-inflammation and fibrosis. Treatment with corticosteroids and Azathioprine brings good outcomes, but it tends to fluctuate. PMID- 26983488 TI - [Pathogenesis of hepatitis B virus-related hepatocellular carcinoma]. AB - Hepatocellular carcinoma (HCC) is one of the most common cancer worldwide. Most of the HCC occur in developing countries. Chronic hepatitis B virus (HBV) infection is an important risk factor for HCC development. HBV induces immune mediated chronic hepatitis, liver injury, regeneration and scar forming responses, leading to an inflammatory, fibrotic and immune deficient microenvironment. HBV may integrate into host genome, inducing genetic abnormality and altering the expression of HCC-related genes. HBV also expresses active proteins such as X (HBx) and S proteins, which may trans-activate HCC related proteins expression, interact with intracellular specific proteins, activate a variety of signaling pathways, and induce aberrant epigenetic modifications. HBV mutation also has impact on HBV related HCC development. PMID- 26983489 TI - [Occult hepatitis B virus infection: a new challenge for hepatitis B vaccine to block mother-to-child transmission]. AB - Occult hepatitis B virus infection (OBI) could occur in infants born to HBsAg positive mothers after active and passive immunization, even though their serological patterns suggested successful protection from HBV mother-to-infant transmission according to the current criteria of being HBsAg-negative and anti HBs positive. We should take into account its potential clinical impact and reconsider the effectiveness of the present immunoprophylaxis against HBV in this population. This review will focus on topics including the prevalence, serological features and probable risk factors underlying the phenomenon of OBI in infants with HBsAg carrier mothers after immunization. PMID- 26983490 TI - Survey of Information Sharing Related to the Occupational Considerations of Working Cancer Patients Between Occupational Physicians and Treating Physicians. AB - OBJECTIVE: Although a vital element in providing career support to workers with medical ailments is coordination between the worker, the treating physician, and the company (the occupational health staff), little is known about factors that promote or impede coordination between these parties. This study aims to demonstrate what kinds of actions by treating physicians promote or impede the occupational considerations made by occupational physicians. METHODS: A total of 43 occupational physicians who had completed the postgraduate training course (4 years) at the University of Occupational and Environmental Health Japan and were current or former instructors at the Occupational Health Training Center were surveyed using a self-reported questionnaire form. The questionnaire asked about individual attributes (age, years of experience as an occupational physician, etc.) and actions taken by treating physicians that were useful in making occupational considerations in the workplace (good practice cases) or that impeded such considerations (trouble cases). Responses about cases were obtained as freely written descriptions. Case content was analyzed qualitatively according to the KJ method. RESULTS: During the survey period from December 17, 2013 to January 18, 2014, responses were received from 33 occupational physicians (valid response rate, 76.7%; mean age, 37.4+/-6.1 years). Of these, 60.6% exclusively specialized in occupational medicine. Respondents provided 32 good practice cases and 16 trouble cases. The timing of coordination was the period of rehabilitation in 35 of the 48 cases (72.9%). Actions by the treating physicians that influenced occupational considerations were divided into seven major categories: "providing treatment information," "providing physical information," "appropriateness of rehabilitation or occupational considerations," "consistency of information provided," "issuing documentation," "communication that was cognizant of the occupational physician's presence," and "providing information unknown to the worker." CONCLUSIONS: This study clarified the kind of actions by the treating physicians that were relevant to occupational support provided by occupational physicians. Additionally, this study clarified the need for information sharing with occupational physician and treating physician. The good practice cases and trouble cases presented by the respondents were inextricably linked, and actions by the treating physicians that are based on good practices are highly likely to lead to smooth information sharing and occupational considerations. PMID- 26983491 TI - Development of a check sheet for collecting information necessary for occupational safety and health activities and building relevant systems in overseas business places. AB - OBJECTIVES: This study aimed to develop an information gathering check sheet to efficiently collect information necessary for Japanese companies to build global occupational safety and health management systems in overseas business places. METHODS: The study group consisted of 2 researchers with occupational physician careers in a foreign-affiliated company in Japan and 3 supervising occupational physicians who were engaged in occupational safety and health activities in overseas business places. After investigating information and sources of information necessary for implementing occupational safety and health activities and building relevant systems, we conducted information acquisition using an information gathering check sheet in the field, by visiting 10 regions in 5 countries (first phase). The accuracy of the information acquired and the appropriateness of the information sources were then verified in study group meetings to improve the information gathering check sheet. Next, the improved information gathering check sheet was used in another setting (3 regions in 1 country) to confirm its efficacy (second phase), and the information gathering check sheet was thereby completed. RESULTS: The information gathering check sheet was composed of 9 major items (basic information on the local business place, safety and health overview, safety and health systems, safety and health staff, planning/implementation/evaluation/improvement, safety and health activities, laws and administrative organs, local medical care systems and public health, and medical support for resident personnel) and 61 medium items. We relied on the following eight information sources: the internet, company (local business place and head office in Japan), embassy/consulate, ISO certification body, university or other educational institutions, and medical institutions (aimed at Japanese people or at local workers). CONCLUSIONS: Through multiple study group meetings and a two-phased field survey (13 regions in 6 countries), an information gathering check sheet was completed. We confirmed the possibility that this check sheet would enable the user to obtain necessary information when expanding safety and health activities in a country or region that is new to the user. It is necessary in the future to evaluate safety and health systems and activities using this information gathering check sheet in a local business place in any country in which a Japanese business will be established, and to verify the efficacy of the check sheet by conducting model programs to test specific approaches. PMID- 26983492 TI - A case of a young employee with new type of depression who could return to work as a result of an effective therapeutic alliance and daily life guidance based on salutogenesis. PMID- 26983493 TI - Challenges and solutions in immigrant occupational health in the United States: a literature review and comparative analysis. AB - OBJECTIVES: Because of the declining birthrate in Japan, an increasing number of companies are hiring immigrants to fill the labor shortage. Although research on migrant occupational health has progressed in the United States, this topic has received little attention in Japan. The aim of this study was to elucidate the current situation, challenges, and solutions surrounding the occupational health of immigrant workers in the United States. METHODS: Data and selected studies were reviewed and analyzed. The results are discussed, and a few anecdotal experiences in the United States are introduced and compared. RESULTS: Possible causes of disparities in immigrant occupational health fell into the following seven categories. (Keywords for each category are shown in parentheses.) (1) Occupation (hazardous job, injury, missed workday, blue-collar worker, low birth weight); (2) Education (academic record, health literacy, training); (3) Culture (culture-specific, community-based); (4) Environment (poor hygiene, regional disparities, environmental change); (5) Access (language, statistics, workers' compensation, health insurance, voluntary restraint); (6) Infection (tuberculosis, human immunodeficiency virus/AIDS, follow-up); and (7) Discrimination (race, assault, harassment). Lack of data on immigrant workers was found to be a common problem. Some businesses and community groups achieved positive results by simultaneously dealing with multiple aforementioned categories. DISCUSSION: In the United States, the occupational health of immigrant workers has been studied mainly in terms of health disparities. Possible causes of disparities in immigrant occupational health fell into seven categories. Solutions centered on the keywords in each category were inferred. Some businesses and community groups achieved positive results by simultaneously dealing with multiple aforementioned categories. Occupational health professionals have to take each of seven categories into account to improve immigrant occupational health. Even the United States-a developed country facing many migrant occupational health problems-needs further research and better data. To address this issue in Japan, we too need more data and further research on immigrants, along with efforts by businesses and community groups. PMID- 26983494 TI - Chemical management and occupational cholangiocarcinoma among workers in printing industry. PMID- 26983495 TI - Survivin selective inhibitor YM155 promotes cisplatin-induced apoptosis in embryonal rhabdomyosarcoma. AB - Survivin, a member of the inhibitor of apoptosis protein family, functions as a key regulator of programmed cell death. YM155 is a small molecule that selectively inhibits survivin. We investigated the effect of YM155 on survivin suppression in the human rhabdomyosarcoma (RMS) cell line RD. The efficacy of YM155 in combination with cisplatin was also determined in a xenograft model. The effect of YM155 on survivin expression in the RD cell line was examined at both mRNA and protein levels using real-time PCR and western blot analysis. RD cells were cultured with various concentrations of YM155, then cisplatin was added to the medium and the anti-proliferation response was determined. Cell growth was evaluated by WST-8 assay. Finally, the efficacy of YM155 combined with cisplatin was examined in an established xenograft model. Survivin mRNA levels in the RD cell line were decreased to 72 and 24% at 24 and 48 h, respectively, after 10 nM of YM155 was added. YM155 also decreased the levels of survivin protein. YM155 treatment (10 nM) inhibited cell proliferation of RD in a dose-dependent manner in vitro, with 58% of cells viable at 48 h. When cultured with 10 nM of YM155 and 10 uM cisplatin, RD cells demonstrated only 25% of the growth observed when cultured with cisplatin alone. YM155 in combination with cisplatin significantly inhibited tumor growth by 13% compared with control (P<0.0001) in RD xenograft tumors. YM155 increased the sensitivity of cisplatin by suppressing survivin in the embryonal RMS cell line RD. Further studies should investigate the use of YM155 as an apoptosis inducer, either alone or in combination with cisplatin, for the treatment of malignant RMS. PMID- 26983496 TI - Observation of a shape resonance of the positronium negative ion. AB - When an electron binds to its anti-matter counterpart, the positron, it forms the exotic atom positronium (Ps). Ps can further bind to another electron to form the positronium negative ion, Ps(-) (e(-)e(+)e(-)). Since its constituents are solely point-like particles with the same mass, this system provides an excellent testing ground for the three-body problem in quantum mechanics. While theoretical works on its energy level and dynamics have been performed extensively, experimental investigations of its characteristics have been hampered by the weak ion yield and short annihilation lifetime. Here we report on the laser spectroscopy study of Ps(-), using a source of efficiently produced ions, generated from the bombardment of slow positrons onto a Na-coated W surface. A strong shape resonance of (1)P(o) symmetry has been observed near the Ps (n=2) formation threshold. The resonance energy and width measured are in good agreement with the result of three-body calculations. PMID- 26983497 TI - To Be a Flower or Fruiting Branch: Insights Revealed by mRNA and Small RNA Transcriptomes from Different Cotton Developmental Stages. AB - The architecture of the cotton plant, including fruit branch formation and flowering pattern, is the most important characteristic that directly influences light exploitation, yield and cost of planting. Nulliplex branch is a useful phenotype to study cotton architecture. We used RNA sequencing to obtain mRNA and miRNA profiles from nulliplex- and normal-branch cotton at three developmental stages. The differentially expressed genes (DEGs) and miRNAs were identified that preferentially/specifically expressed in the pre-squaring stage, which is a key stage controlling the transition from vegetative to reproductive growth. The DEGs identified were primarily enriched in RNA, protein, and signalling categories in Gossypium barbadense and Gossypium hirsutum. Interestingly, during the pre squaring stage, the DEGs were predominantly enriched in transcription factors in both G. barbadense and G. hirsutum, and these transcription factors were mainly involved in branching and flowering. Related miRNAs were also identified. The results showed that fruit branching in cotton is controlled by molecular pathways similar to those in Arabidopsis and that multiple regulated pathways may affect the development of floral buds. Our study showed that the development of fruit branches is closely related to flowering induction and provides insight into the molecular mechanisms of branch and flower development in cotton. PMID- 26983498 TI - Hypoxia-induced sensitisation of TRPA1 in painful dysesthesia evoked by transient hindlimb ischemia/reperfusion in mice. AB - Dysesthesia is an unpleasant abnormal sensation, which is often accompanied by peripheral neuropathy or vascular impairment. Here, we examined the roles of transient receptor potential ankyrin 1 (TRPA1) in dysesthesia-like behaviours elicited by transient hindlimb ischemia (15-60 min) by tightly compressing the hindlimb, and reperfusion by releasing the ligature. The paw-withdrawal responses to tactile stimulation were reduced during ischemia and lasted for a while after reperfusion. Hindlimb ischemia/reperfusion elicited spontaneous licking of the ischemic hindpaw that peaked within 10 min. The licking was inhibited by reactive oxygen species (ROS) scavengers, a TRPA1 antagonist, or TRPA1 deficiency, but not by TRPV1 deficiency. In human TRPA1-expressing cells as well as cultured mouse dorsal root ganglion neurons, the H2O2-evoked TRPA1 response was significantly increased by pretreatment with hypoxia (80 mmHg) for 30 min. This hypoxia-induced TRPA1 sensitisation to H2O2 was inhibited by overexpressing a catalytically inactive mutant of prolyl hydroxylase (PHD) 2 or in a TRPA1 proline mutant resistant to PHDs. Consistent with these results, a PHD inhibitor increased H2O2 evoked nocifensive behaviours through TRPA1 activation. Our results suggest that transient hindlimb ischemia/reperfusion-evoked spontaneous licking, i.e. painful dysesthesia, is caused by ROS-evoked activation of TRPA1 sensitised by hypoxia through inhibiting PHD-mediated hydroxylation of a proline residue in TRPA1. PMID- 26983500 TI - Study of flux pinning mechanism under hydrostatic pressure in optimally doped (Ba,K)Fe2As2 single crystals. AB - Strong pinning depends on the pinning force strength and number density of effective defects. Using the hydrostatic pressure method, we demonstrate here that hydrostatic pressure of 1.2 GPa can significantly enhance flux pinning or the critical current density (Jc) of optimally doped Ba0.6K0.4Fe2As2 crystals by a factor of up to 5 in both low and high fields, which is generally rare with other Jc enhancement techniques. At 4.1 K, high pressure can significantly enhance Jc from 5 * 10(5 )A/cm(2) to nearly 10(6 )A/cm(2) at 2 T, and from 2 * 10(5 )A/cm(2) to nearly 5.5 * 10(5 )A/cm(2) at 12 T. Our systematic analysis of the flux pinning mechanism indicates that both the pinning centre number density and the pinning force are greatly increased by the pressure and enhance the pinning. This study also shows that superconducting performance in terms of flux pinning or Jc for optimally doped superconducting materials can be further improved by using pressure. PMID- 26983499 TI - Looking at the carcinogenicity of human insulin analogues via the intrinsic disorder prism. AB - Therapeutic insulin, in its native and biosynthetic forms as well as several currently available insulin analogues, continues to be the protein of most interest to researchers. From the time of its discovery to the development of modern insulin analogues, this important therapeutic protein has passed through several stages and product generations. Beside the well-known link between diabetes and cancer risk, the currently used therapeutic insulin analogues raised serious concerns due to their potential roles in cancer initiation and/or progression. It is possible that structural variations in some of the insulin analogues are responsible for the appearance of new oncogenic species with high binding affinity to the insulin-like growth factor 1 (IGF1) receptor. The question we are trying to answer in this work is: are there any specific features of the distribution of intrinsic disorder propensity within the amino acid sequences of insulin analogues that may provide an explanation for the carcinogenicity of the altered insulin protein? PMID- 26983502 TI - Metropolis now. PMID- 26983501 TI - Tunable Lattice Coupling of Multipole Plasmon Modes and Near-Field Enhancement in Closely Spaced Gold Nanorod Arrays. AB - Considering the nanogap and lattice effects, there is an attractive structure in plasmonics: closely spaced metallic nanoarrays. In this work, we demonstrate experimentally and theoretically the lattice coupling of multipole plasmon modes for closely spaced gold nanorod arrays, offering a new insight into the higher order cavity modes coupled with each other in the lattice. The resonances can be greatly tuned by changes in inter-rod gaps and nanorod heights while the influence of the nanorod diameter is relatively insignificant. Experimentally, pronounced suppressions of the reflectance are observed. Meanwhile, the near field enhancement can be further enhanced, as demonstrated through surface enhanced Raman scattering (SERS). We then confirm the correlation between the near-field and far-field plasmonic responses, which is significantly important for maximizing the near-field enhancement at a specific excitation wavelength. This lattice coupling of multipole plasmon modes is of broad interest not only for SERS but also for other plasmonic applications, such as subwavelength imaging or metamaterials. PMID- 26983503 TI - Africa's elite. PMID- 26983504 TI - Practical DNA. PMID- 26983505 TI - The elephant in the room we can't ignore. PMID- 26983517 TI - What Google's winning Go algorithm will do next. PMID- 26983516 TI - 'Brain doping' may improve athletes' performance. PMID- 26983518 TI - Fermat's last theorem earns Andrew Wiles the Abel Prize. PMID- 26983519 TI - Mars launch to test collaboration between Europe and Russia. PMID- 26983520 TI - NASA Mars woes could delay other planetary missions. PMID- 26983521 TI - On the hunt for a mystery planet. PMID- 26983523 TI - Oldest ancient-human DNA details dawn of Neanderthals. PMID- 26983522 TI - The red-hot debate about transmissible Alzheimer's. PMID- 26983524 TI - Reproducibility: Team up with industry. PMID- 26983528 TI - IPBES: Biodiversity central to food security. PMID- 26983529 TI - Junior researchers: Hasty publication compromises rigour. PMID- 26983530 TI - Environment: China draws lines to green future. PMID- 26983531 TI - Australia: Short-sighted to cut environment posts. PMID- 26983532 TI - Advisory network: Six principles for EU peer review. PMID- 26983533 TI - Materials science: How crystals get an edge. PMID- 26983534 TI - Global warming: China's contribution to climate change. PMID- 26983536 TI - Microrobotics: Swimmers by design. PMID- 26983537 TI - Virology: The X-Files of hepatitis B. PMID- 26983538 TI - Interface dynamics and crystal phase switching in GaAs nanowires. AB - Controlled formation of non-equilibrium crystal structures is one of the most important challenges in crystal growth. Catalytically grown nanowires are ideal systems for studying the fundamental physics of phase selection, and could lead to new electronic applications based on the engineering of crystal phases. Here we image gallium arsenide (GaAs) nanowires during growth as they switch between phases as a result of varying growth conditions. We find clear differences between the growth dynamics of the phases, including differences in interface morphology, step flow and catalyst geometry. We explain these differences, and the phase selection, using a model that relates the catalyst volume, the contact angle at the trijunction (the point at which solid, liquid and vapour meet) and the nucleation site of each new layer of GaAs. This model allows us to predict the conditions under which each phase should be observed, and use these predictions to design GaAs heterostructures. These results could apply to phase selection in other nanowire systems. PMID- 26983539 TI - Enhancing coherence in molecular spin qubits via atomic clock transitions. AB - Quantum computing is an emerging area within the information sciences revolving around the concept of quantum bits (qubits). A major obstacle is the extreme fragility of these qubits due to interactions with their environment that destroy their quantumness. This phenomenon, known as decoherence, is of fundamental interest. There are many competing candidates for qubits, including superconducting circuits, quantum optical cavities, ultracold atoms and spin qubits, and each has its strengths and weaknesses. When dealing with spin qubits, the strongest source of decoherence is the magnetic dipolar interaction. To minimize it, spins are typically diluted in a diamagnetic matrix. For example, this dilution can be taken to the extreme of a single phosphorus atom in silicon, whereas in molecular matrices a typical ratio is one magnetic molecule per 10,000 matrix molecules. However, there is a fundamental contradiction between reducing decoherence by dilution and allowing quantum operations via the interaction between spin qubits. To resolve this contradiction, the design and engineering of quantum hardware can benefit from a 'bottom-up' approach whereby the electronic structure of magnetic molecules is chemically tailored to give the desired physical behaviour. Here we present a way of enhancing coherence in solid-state molecular spin qubits without resorting to extreme dilution. It is based on the design of molecular structures with crystal field ground states possessing large tunnelling gaps that give rise to optimal operating points, or atomic clock transitions, at which the quantum spin dynamics become protected against dipolar decoherence. This approach is illustrated with a holmium molecular nanomagnet in which long coherence times (up to 8.4 microseconds at 5 kelvin) are obtained at unusually high concentrations. This finding opens new avenues for quantum computing based on molecular spin qubits. PMID- 26983540 TI - The contribution of China's emissions to global climate forcing. AB - Knowledge of the contribution that individual countries have made to global radiative forcing is important to the implementation of the agreement on "common but differentiated responsibilities" reached by the United Nations Framework Convention on Climate Change. Over the past three decades, China has experienced rapid economic development, accompanied by increased emission of greenhouse gases, ozone precursors and aerosols, but the magnitude of the associated radiative forcing has remained unclear. Here we use a global coupled biogeochemistry-climate model and a chemistry and transport model to quantify China's present-day contribution to global radiative forcing due to well-mixed greenhouse gases, short-lived atmospheric climate forcers and land-use-induced regional surface albedo changes. We find that China contributes 10% +/- 4% of the current global radiative forcing. China's relative contribution to the positive (warming) component of global radiative forcing, mainly induced by well-mixed greenhouse gases and black carbon aerosols, is 12% +/- 2%. Its relative contribution to the negative (cooling) component is 15% +/- 6%, dominated by the effect of sulfate and nitrate aerosols. China's strongest contributions are 0.16 +/- 0.02 watts per square metre for CO2 from fossil fuel burning, 0.13 +/- 0.05 watts per square metre for CH4, -0.11 +/- 0.05 watts per square metre for sulfate aerosols, and 0.09 +/- 0.06 watts per square metre for black carbon aerosols. China's eventual goal of improving air quality will result in changes in radiative forcing in the coming years: a reduction of sulfur dioxide emissions would drive a faster future warming, unless offset by larger reductions of radiative forcing from well-mixed greenhouse gases and black carbon. PMID- 26983542 TI - Living factories of the future. PMID- 26983541 TI - Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor. AB - Chronic hepatitis B virus infection is a leading cause of cirrhosis and liver cancer. Hepatitis B virus encodes the regulatory HBx protein whose primary role is to promote transcription of the viral genome, which persists as an extrachromosomal DNA circle in infected cells. HBx accomplishes this task by an unusual mechanism, enhancing transcription only from extrachromosomal DNA templates. Here we show that HBx achieves this by hijacking the cellular DDB1 containing E3 ubiquitin ligase to target the 'structural maintenance of chromosomes' (Smc) complex Smc5/6 for degradation. Blocking this event inhibits the stimulatory effect of HBx both on extrachromosomal reporter genes and on hepatitis B virus transcription. Conversely, silencing the Smc5/6 complex enhances extrachromosomal reporter gene transcription in the absence of HBx, restores replication of an HBx-deficient hepatitis B virus, and rescues wild-type hepatitis B virus in a DDB1-knockdown background. The Smc5/6 complex associates with extrachromosomal reporters and the hepatitis B virus genome, suggesting a direct mechanism of transcriptional inhibition. These results uncover a novel role for the Smc5/6 complex as a restriction factor selectively blocking extrachromosomal DNA transcription. By destroying this complex, HBx relieves the inhibition to allow productive hepatitis B virus gene expression. PMID- 26983544 TI - Dry-season greening of Amazon forests. PMID- 26983545 TI - Morton et al. reply. PMID- 26983546 TI - The favorable role of homozygosity for killer immunoglobulin-like receptor (KIR) A haplotype in patients with advanced-stage classic Hodgkin lymphoma. AB - BACKGROUND: Interim positron emission tomography after 2 cycles of ABVD (iPET-2) is a good predictor of outcome in advanced-stage classic Hodgkin lymphoma. So far, there are no other prognostic biomarkers capable of identifying chemotherapy refractory patients with comparable accuracy. Despite the considerable amount of evidence suggesting that antitumor immune surveillance is downregulated in classic Hodgkin lymphoma (cHL), few data exist on the impairment of natural killer cell function and the role of their killer immunoglobulin-like receptors (KIRs). METHODS: We investigated KIR gene frequencies, KIR haplotypes, and KIR ligand combinations in a cohort of 135 patients with advanced-stage classic Hodgkin lymphoma and 221 healthy controls. We furthermore evaluated the correlation of KIR genes and KIR haplotypes with the achievement of negative iPET 2. RESULTS: In the cohort of patients, the 5-year overall survival and progression-free survival were 93.6 and 79%, respectively. Homozygosity for KIR A haplotype and the HLA-C1 KIR ligand (KIR-AA/C1C1) was significantly higher in healthy controls (15.7 vs. 4.8%, p = 0.001). The KIR-AA genotype resulted to have a significant predictive power for achieving iPET-2 negativity (p = 0.039). CONCLUSIONS: Homozygosity for KIR A haplotype offers protection against classic Hodgkin lymphoma. The association found for the KIR-AA genotype and achievement of negative iPET-2 suggests that KIR-AA could be used in clinical practice to enhance the chemosensitivity predictive power of iPET-2. Our results point to the possibility of adapting treatment strategies based on the combination of KIR biomarkers and PET scan. PMID- 26983547 TI - Integration of genetic, genomic and transcriptomic information identifies putative regulators of adventitious root formation in Populus. AB - BACKGROUND: Adventitious roots (AR) develop from tissues other than the primary root, in a process physiologically regulated by phytohormones. Adventitious roots provide structural support and contribute to water and nutrient absorption, and are critical for commercial vegetative propagation of several crops. Here we quantified the number of AR, root architectural traits and root biomass in cuttings from a pseudo-backcross population of Populus deltoides and Populus trichocarpa. Quantitative trait loci (QTL) mapping and whole-transcriptome analysis of individuals with alternative QTL alleles for AR number were used to identify putative regulators of AR development. RESULTS: Parental individuals and progeny showed extensive segregation for AR developmental traits. Quantitative trait loci for number of AR mapped consistently in the same interval of linkage group (LG) II and LG XIV, explaining 7-10 % of the phenotypic variation. A time series transcriptome analysis identified 26,121 genes differentially expressed during AR development, particularly during the first 24 h after cuttings were harvested. Of those, 1929 genes were differentially regulated between individuals carrying alternative alleles for the two QTL for number of AR, in one or more time point. Eighty-one of these genes were physically located within the QTL intervals for number of AR, including putative homologs of the Arabidopsis genes SUPERROOT2 (SUR2) and TRYPTOPHAN SYNTHASE ALPHA CHAIN (TSA1), both of which are involved in the auxin indole-3-acetic acid (IAA) biosynthesis pathway. CONCLUSIONS: This study suggests the involvement of two genes of the tryptophan dependent auxin biosynthesis pathway, SUR2 and TSA1, in the regulation of a critical trait for the clonal propagation of woody species. A possible model for this regulation is that poplar individuals that have poor AR formation synthesize auxin indole-3-acetic acid (IAA) primarily through the tryptophan (Trp) pathway. Much of the Trp pathway flux appears to be directed to the synthesis of indole glucosinolates (IG), as suggested by the over-expression of SUR2. Individuals that are efficient in AR formation may utilize alternative (non-Trp) pathways to synthesize IAA, based on the observation that they down-regulate the expression of TSA1, one of the critical steps in the synthesis of tryptophan. PMID- 26983549 TI - Endoscopic Submucosal Dissection for Superficial Esophageal Neoplasm: A Growing Body of Evidence. PMID- 26983551 TI - Financing and collaboration on research and development for nodding syndrome. AB - BACKGROUND: Nodding syndrome is a neurological disease with no known cure or treatment, impacting children aged 3-18 years old, mainly in East Africa. Children progressively develop varying degrees of cognitive impairment which may lead to severe wasting, a vegetative state and, eventually, death. Despite its 50 year existence, little is known about its cause, risk factors and prognosis. It is a disease where markets will not provide solutions because the patients are both too few and too poor, making it especially neglected. Open source innovation has been recommended as an approach to neglected disease research in order to maximize available funding through greater collaboration and openness to results. Nodding syndrome is a useful case to examine the relevance of open source innovation. METHODS: We assessed the magnitude of research related to nodding syndrome, its availability, financing and the amount of collaboration. We surveyed researchers regarding their motivations, attitudes toward open source innovation concepts and barriers to greater collaboration. RESULTS: Little research is occurring for nodding syndrome, but it is openly available and researchers are highly collaborative. The disease is largely unknown, which is partly attributed to WHO not classifying nodding syndrome as a neglected tropical disease and not including it in any formal programme. Impacted countries, particularly Uganda, demonstrate a strong degree of ownership through both authorship and research financing. Nodding syndrome researchers have been allocated a total of ?5 million from 2013 to 2019 in grant funding. Annual financing, due to three new grants, doubled from 2014 to 2015. CONCLUSIONS: Nodding syndrome, a disease previously ignored by the international community, is starting to receive greater attention, although financing remains modest. If infectious, a larger epidemic could take the world by surprise. Open source innovation can likely help by sharing research protocols (to avoid duplication) and early research results (to adjust to the findings of others). The existing scientists have already endorsed open source innovation, but increased financing is needed. The support of just a few high-income countries could reap a large impact. PMID- 26983548 TI - Glutamatergic medication in the treatment of obsessive compulsive disorder (OCD) and autism spectrum disorder (ASD) - study protocol for a randomised controlled trial. AB - BACKGROUND: Compulsivity is a cross-disorder trait underlying phenotypically distinct psychiatric disorders that emerge in childhood or adolescence. Despite the effectiveness of serotonergic compounds in the treatment of obsessive compulsive disorder, treatment-resistant symptoms remaining in 40 to 60 % of patients present a pressing clinical problem. There are currently no medications that effectively treat the core impairments of autism spectrum disorder. There is an urgent need for the development of conceptually novel pharmacological strategies. Agents targeting glutamate neurotransmission, such as memantine, represent promising candidates. This proof-of-concept clinical study will allow pilot-testing of memantine for both clinical effectiveness and tolerability/safety. Memantine is an N-methyl-D-aspartate receptor antagonist, approved for the treatment of Alzheimer's dementia in a number of countries. METHODS/DESIGN: This 12-week study has an add-on, randomised, double-blind, placebo-controlled design of treatment with memantine, including an up-titration phase (forced flexible dose design, 5-15 mg/day), in patients aged 6-17 years and 9 months with obsessive-compulsive disorder or autism spectrum disorder. It is planned to include patients with obsessive-compulsive disorder (N = 50) or autism spectrum disorder (N = 50) across four centres in three European countries. Patients will be randomly assigned to memantine or placebo in a 1:1 ratio. Primary objectives are the investigation of the effectiveness of memantine in paediatric patients for improving symptoms of compulsivity (primary outcome measure: total score on the Children's Yale-Brown Obsessive-Compulsive Scale) and to explore its tolerability and safety. Secondary objectives are to explore the effects of memantine at the level of structure, function and biochemistry of the fronto-striatal circuits, and to collect blood for genetic analyses and biomarkers. Tertiary objectives are to explore the role of new candidate genes and pathways for compulsivity by linking genes to clinical phenotypes, response to treatment, neurocognitive test performance, and key structural and functional neuroimaging measures of the fronto-striatal circuits and to explore biomarkers/proteomics for compulsivity traits. DISCUSSION: This study is part of the large, translational project TACTICS ( http://www.tactics-project.eu/ ) that is funded by the European Union and investigates the neural, genetic and molecular factors involved in the pathogenesis of compulsivity. Its results will provide clinically relevant solid information on potential new mechanisms and medication treatment in obsessive-compulsive and autism spectrum disorders. TRIAL REGISTRATION: EudraCT Number: 2014-003080-38 , date of registration: 14 July 2014. PMID- 26983553 TI - Structure and Abundance of Nitrous Oxide Complexes in Earth's Atmosphere. AB - We have investigated the lowest energy structures and binding energies of a series of atmospherically relevant nitrous oxide (N2O) complexes using explicitly correlated coupled cluster theory. Specifically, we have considered complexes with nitrogen (N2-N2O), oxygen (O2-N2O), argon (Ar-N2O), and water (H2O-N2O). We have calculated rotational constants and harmonic vibrational frequencies for the complexes and the constituent monomers. Statistical mechanics was used to determine the thermodynamic parameters for complex formation as a function of temperature and pressure. These results, in combination with relevant atmospheric data, were used to estimate the abundance of N2O complexes in Earth's atmosphere as a function of altitude. We find that the abundance of N2O complexes in Earth's atmosphere is small but non-negligible, and we suggest that N2O complexes may contribute to absorption of terrestrial radiation and be relevant for understanding the atmospheric fate of N2O. PMID- 26983552 TI - Akt Specific Activator SC79 Protects against Early Brain Injury following Subarachnoid Hemorrhage. AB - A growing body of evidence demonstrates that Akt may serve as a therapeutic target for treatment of early brain injury following subarachnoid hemorrhage (SAH). The purpose of the current study was to evaluate the neuroprotective effect of Akt specific activator SC79 in an experimental rat model of SAH. SAH was induced by injecting 300 MUL of blood into the prechiasmatic cistern. Intracerebroventricular (ICV) injection of SC79 (30 min post-SAH) induced the p Akt (Ser473) expression in a dose-dependent manner. A single ICV dose treatment of SC79 (100 MUg/rat) significantly increased the expression of Bcl-2 and p-GSK 3beta (Ser9), decreased the protein levels of Bax, cytoplasm cytochrome c, and cleaved caspase-3, indicating the antiapoptotic effect of SC79. As a result, the number of apoptotic cells was reduced 24 h post SAH. Moreover, SC79 treatment alleviated SAH-induced oxidative stress, restored mitochondrial morphology, and improved neurological deficits. Strikingly, treatment of SC79 provided a beneficial outcome against neurologic deficit with a therapeutic window of at least 4 h post SAH by ICV injection and 30 min post SAH by intraperitoneal injection. Collectively, SC79 exerts its neuroprotective effect likely through the dual activities of antioxidation and antiapoptosis. These data provide a basic platform to consider SC79 as a novel therapeutic agent for treatment of SAH. PMID- 26983550 TI - A glimpse of the ERM proteins. AB - In all eukaryotes, the plasma membrane is critically important as it maintains the architectural integrity of the cell. Proper anchorage and interaction between the plasma membrane and the cytoskeleton is critical for normal cellular processes. The ERM (ezrin-radixin-moesin) proteins are a class of highly homologous proteins involved in linking the plasma membrane to the cortical actin cytoskeleton. This review takes a succinct look at the biology of the ERM proteins including their structure and function. Current reports on their regulation that leads to activation and deactivation was examined before taking a look at the different interacting partners. Finally, emerging roles of each of the ERM family members in cancer was highlighted. PMID- 26983556 TI - PREFACE: "The Lower the Better" Association between White-coat Effect-excluded Blood Pressure and Cardiovascular Events in High-risk Hypertension: Insights from SPRINT. PMID- 26983554 TI - Variation in Linked Selection and Recombination Drive Genomic Divergence during Allopatric Speciation of European and American Aspens. AB - Despite the global economic and ecological importance of forest trees, the genomic basis of differential adaptation and speciation in tree species is still poorly understood. Populus tremula and Populus tremuloides are two of the most widespread tree species in the Northern Hemisphere. Using whole-genome re sequencing data of 24 P. tremula and 22 P. tremuloides individuals, we find that the two species diverged ~2.2-3.1 million years ago, coinciding with the severing of the Bering land bridge and the onset of dramatic climatic oscillations during the Pleistocene. Both species have experienced substantial population expansions following long-term declines after species divergence. We detect widespread and heterogeneous genomic differentiation between species, and in accordance with the expectation of allopatric speciation, coalescent simulations suggest that neutral evolutionary processes can account for most of the observed patterns of genetic differentiation. However, there is an excess of regions exhibiting extreme differentiation relative to those expected under demographic simulations, which is indicative of the action of natural selection. Overall genetic differentiation is negatively associated with recombination rate in both species, providing strong support for a role of linked selection in generating the heterogeneous genomic landscape of differentiation between species. Finally, we identify a number of candidate regions and genes that may have been subject to positive and/or balancing selection during the speciation process. PMID- 26983557 TI - Leak-tight vertical membrane microvalves. AB - Pneumatic microvalves are fundamental control components in a large range of microfluidic applications. Their key performance parameters are small size, i.e. occupying a minimum of microfluidic real estate, low flow resistance in the open state, and leak-tight closing at limited control pressures. In this work we present the successful design, realization and evaluation of the first leak tight, vertical membrane, pneumatic microvalves. The realization of the vertical membrane microvalves is enabled by a novel dual-sided molding method for microstructuring monolithic 3D microfluidic networks in PDMS in a single step, eliminating the need for layer-to-layer alignment during bonding. We demonstrate minimum lateral device features down to 20-30 MUm in size, and vertical via density of ~30 000 per cm(2), which provides significant gains in chip real estate compared to previously reported PDMS manufacturing methods. In contrast to horizontal membrane microvalves, there are no manufacturing restrictions on the cross-sectional geometry of the flow channel of the vertical membrane microvalves. This allows tuning the design towards lower closing pressure or lower open state flow resistance compared to those of horizontal membrane microvalves. PMID- 26983555 TI - Optimization of Conformational Dynamics in an Epistatic Evolutionary Trajectory. AB - The understanding of protein evolution depends on the ability to relate the impact of mutations on molecular traits to organismal fitness. Biological activity and robustness have been regarded as important features in shaping protein evolutionary landscapes. Conformational dynamics, which is essential for protein function, has received little attention in the context of evolutionary analyses. Here we employ NMR spectroscopy, the chief experimental tool to describe protein dynamics at atomic level in solution at room temperature, to study the intrinsic dynamic features of a metallo- Beta: -lactamase enzyme and three variants identified during a directed evolution experiment that led to an expanded substrate profile. We show that conformational dynamics in the catalytically relevant microsecond to millisecond timescale is optimized along the favored evolutionary trajectory. In addition, we observe that the effects of mutations on dynamics are epistatic. Mutation Gly262Ser introduces slow dynamics on several residues that surround the active site when introduced in the wild type enzyme. Mutation Asn70Ser removes the slow dynamics observed for few residues of the wild-type enzyme, but increases the number of residues that undergo slow dynamics when introduced in the Gly262Ser mutant. These effects on dynamics correlate with the epistatic interaction between these two mutations on the bacterial phenotype. These findings indicate that conformational dynamics is an evolvable trait, and that proteins endowed with more dynamic active sites also display a larger potential for promoting evolution. PMID- 26983558 TI - Free energy contributions and structural characterization of stacking disordered ices. AB - Crystallization of ice from deeply supercooled water and amorphous ices - a process of fundamental importance in the atmosphere, interstellar space, and cryobiology - results in stacking disordered ices with a wide range of metastabilities with respect to hexagonal ice. The structural origin of this high variability, however, has not yet been elucidated. Here we use molecular dynamics simulations with the mW water model to characterize the structure of ice freshly grown from supercooled water at temperatures from 210 to 270 K, the thermodynamics of stacking faults, line defects, and interfaces, and to elucidate the interplay between kinetics and thermodynamics in determining the structure of ice. In agreement with experiments, the ice grown in the simulations is stacking disordered with a random distribution of cubic and hexagonal layers, and a cubicity that decreases with growth temperature. The former implies that the cubicity of ice is determined by processes at the ice/liquid interface, without memory of the structure of buried ice layers. The latter indicates that the probability of building a cubic layer at the interface decreases upon approaching the melting point of ice, which we attribute to a more efficient structural equilibration of ice at the liquid interface as the driving force for growth wanes. The free energy cost for creating a pair of cubic layers in ice is 8.0 J mol(-1) in experiments, and 9.7 +/- 1.9 J mol(-1) for the mW water model. This not only validates the simulations, but also indicates that dispersion in cubicity is not sufficient to explain the large energetic variability of stacking disordered ices. We compute the free energy cost of stacking disorder, line defects, and interfaces in ice and conclude that a characterization of the density of these defects is required to predict the degree of metastability and vapor pressure of atmospheric ices. PMID- 26983559 TI - Shear-driven aggregation of binary colloids for randomly distributing nanoparticles in a matrix. AB - We propose a methodology for preparing composite materials where A nanoparticles (NPs) are uniformly and randomly distributed inside a matrix of B NPs. It is based on intense shear-driven aggregation of binary colloids composed of A and B NPs, without using any additives. Its feasibility has been demonstrated using stable binary colloids composed of poly-methyl methacrylate (PMMA) particles and polystyrene (PS) particles. The PS particles alone undergo shear-driven aggregation (shear-active), while the PMMA particles alone do not exhibit any aggregation under the same conditions (shear-inactive). It is found that the shear-driven aggregation of the binary colloids does occur, and the formed clusters are composed of both the "shear-active" PS and "shear-inactive" PMMA particles. The SEM pictures demonstrate that the PMMA particles are uniformly and randomly distributed among the PS particles in the clusters, thus confirming the feasibility of the proposed methodology. The mechanism leading to the aggregation of the binary colloids has been discussed based on the experimental observations. PMID- 26983560 TI - Molybdenum carbide as an efficient catalyst for low-temperature hydrogenation of dimethyl oxalate. AB - Silica-supported molybdenum carbide (Mo2C/SiO2) is found to be a highly active, selective and stable catalyst for the hydrogenation of dimethyl oxalate to ethanol at low temperatures (473 K). Moreover, the formation of ethanol over the Mo2C catalyst performs via the novel intermediate methyl acetate instead of ethylene glycol forming over the Cu catalyst. PMID- 26983561 TI - Prenatal diagnosis of tetralogy of Fallot with a double aortic arch. AB - In this study, we present a case of prenatally diagnosed tetralogy of Fallot with a double aortic arch, correlating images from fetal echocardiography, transthoracic echocardiography, and cardiac MRI. PMID- 26983562 TI - The body in the brain: towards a representational neurobiology of somatoform disorders. PMID- 26983563 TI - Somatoform disorders revisited. PMID- 26983564 TI - Assessment of somatoform disorders: a review of strategies and instruments. AB - We provide an overview of methods and instruments developed for the assessment of somatoform disorders. Four diagnostic purposes have been identified: (i) classification according to a diagnostic system; (ii) screening for probable cases; (iii) dimensional measurement of syndrome severity; and (iv) assessment of associated clinical features. Existing instruments designed for each of these strategies are described, including specifications of their psychometric properties, particular features, advantages and disadvantages. A conclusion of this review is that the currently existing 'family of assessment instruments' in the field of somatoform disorders should be used to improve the comparability of scientific findings in different cultures and settings. PMID- 26983565 TI - Negative priming for threatening vs. non-threatening information in body dysmorphic disorder. AB - BACKGROUND: Individuals with body dysmorphic disorder (BDD) suffer from unpleasant, repetitive thoughts about imagined defects in appearance which are difficult to control. OBJECTIVE: The purpose of this study was to test for deficits in cognitive inhibition in BDD. METHODS: To test for deficits in cognitive inhibition in BDD, we applied a negative priming paradigm. Specifically, we explored whether BDD patients exhibit greater deficits in cognitive inhibition when lexical targets are threatening than when they are non threatening. RESULTS: Surprisingly, BDD patients exhibited deficits in cognitive inhibition only for non-threatening but not for threatening information. CONCLUSIONS: Although BDD patients often describe their negative thoughts about their appearance as distressing, they may experience them as valid and thus may not try to control them. PMID- 26983566 TI - Enhanced glucocorticoid sensitivity in patients with chronic fatigue syndrome. AB - OBJECTIVE: Alterations of the immune-neuroendocrine interplay have been described in chronic fatigue syndrome (CFS). Employing a recently developed method, the study set out to investigate whether patients with CFS have an altered sensitivity to glucocorticoids (GCs) when under stress. METHODS: A total of 21 CFS patients and 20 healthy age- and gender-matched controls underwent a standardized psychosocial stress test (Trier Social Stress Test, TSST). Salivary and plasma cortisol levels were measured repeatedly following exposure to the stressor. GC sensitivity was assessed in vitro by dexamethasone inhibition of lipopolysaccharide-stimulated production of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNC-alpha). RESULTS: Cortisol responses following the TSST did not differ significantly between CFS patients and healthy controls. GC sensitivity differed significantly between CFS patients and healthy controls, with CFS patients showing a greater sensitivity towards GCs (TNF-alpha: F 1/39 = 7.32, P = 0.01; IL-6: F 1/39 = 9.73, P = 0.004). CONCLUSION: Consistent with recent evidence, CFS patients are characterized by an enhanced sensitivity to glucocorticoids. The implications for secondary processes, such as the regulatory influence of glucocorticoids on immune processes, are discussed. PMID- 26983567 TI - Somatoform disorders in patients with musculoskeletal and cardiovascular diseases in comparison to the general population. AB - OBJECTIVE: The present epidemiological study investigates sex- and age-adjusted 4 week, 12-month, and lifetime prevalence rates of somatoform disorders in in patients with musculoskeletal and cardiovascular diseases in comparison with prevalence rates of these disorders in the general population in Germany. METHODS: Prevalence rates were calculated from two samples, one from rehabilitation in-patients with musculoskeletal (n = 187) or cardiovascular (n = 116) diseases, and one from a large sample of the German National Health Interview and Examination Survey - Mental Health Supplement (GHS-MHS; n = 3889). The prevalence rates were based on the M-CIDI, an interview for the assessment of mental disorders. RESULTS: The adjusted prevalence rates of any mental disorder in both clinical samples are higher compared with rates of the general population (e.g. lifetime musculoskeletal, 59.3%; cardiovascular, 56.2%; general population, 47.9%). Prevalence rates of patients with cardiovascular (e.g. 12.2%) and musculoskeletal (21.5%) diseases do not indicate an increased prevalence of somatoform disorders compared with the general population (18.2%). CONCLUSIONS: The results confirm that patients with chronic somatic diseases have increased prevalence rates of mental disorders. However, these increased prevalence rates go primarily back to affective and anxiety disorders and not to somatoform disorders. The diagnostic criteria for somatoform disorders and the question algorithm of the M-CIDI are probably responsible for potential underestimation of somatoform disorders in patients with chronic somatic diseases. PMID- 26983568 TI - The role of negative and positive affectivity on perceived stress-subjective health relationships. AB - This article reviews the arguments that support the approach regarding the 'inflationary' influence of the negative affectivity (NA) trait, or neuroticism, on relationships between perceived stress (e.g. different means of self-report of psychosocial stress such as major life events or daily stress) and subjective physical health (e.g. somatic symptomatology, health complaints). It has been explained that the said inflationary effect could distort the interpretation of the results that are found if it is done in terms of stress-objective health relationships (known in terms of health behavior, biological markers, morbidity and mortality) and that, in this sense, the NA would be a contaminant. This is why it has been suggested that in these cases, the effect of NA on predictor and criterion relationships should be controlled. The present critical review doesn't support these conclusions. Also, this paper deals with the empirical analysis of some matters that refer to one of the arguments mentioned, namely that NA is a general and penetrating factor that impregnates perceived stress (we will focus on daily stress or hassles) and subjective health measures (we will focus on somatic symptoms), as well as its relationships. We also analyze the role of positive affectivity (PA). The empirical analysis carried out uses a combination of within and interindividual methods. Contrary to the hypothesis regarding the moderating effects (specifically, inflationary) of NA on relationships between daily stress and somatic symptomatology, NA has only presented direct significant effects on both variables (between subjects), while its moderating effects are modest and non-significant. However, PA appears not to have any direct significant effects, but it does have moderating effects (specifically, buffering effects). Finally, we discuss the implications of these findings and we make some suggestions for future research. PMID- 26983569 TI - Psychopharmacotherapy of somatoform disorders: effects of opipramol on symptoms of somatization, anxiety, and depression. AB - BACKGROUND: The psychopharmacotherapy of somatoform disorders (SD; ICD-10: F45) has been less frequently investigated and is not as well established as in other (neurotic) disorders of ICD-10 section F4, i.e. generalized anxiety disorder (GAD; ICD-10: F41.1). The atypical compound opipramol is very often used to treat SD and GAD in clinical practice in Germany. However, state-of-the-art controlled clinical trials have not yet been performed. OBJECTIVES: Two clinical trials were performed with the aim of confirming the efficacy and tolerability of opipramol in SD and GAD. METHODS: Both trials were performed as randomized, double-blind, placebo-controlled, multicenter studies. While the GAD trial was a three-arm study with opipramol (200 mg/day) vs. placebo and alprazolam (2 mg/day) for 28 days, the SD trial was a placebo-controlled two-arm study with a treatment duration of 42 days. Each group consisted of about 100 patients. RESULTS: Significant differences (alpha = 0.05) were found for the primary efficacy criteria (HAMA total score in GAD, HAMA somatic subscore in SD) and most of the secondary criteria in favor of the active drug therapies. Considerable differences between the psychopathology of SD and GAD were detected. CONCLUSION: The well-tolerated anxiolytic opipramol is the first psychotropic drug with proven efficacy in somatoform disorders with effects on symptoms of somatization, anxiety, and depression. The compound is also effective and safe in GAD. PMID- 26983570 TI - Atypical depression spectrum disorder - neurobiology and treatment. AB - Depressive syndromes are a group of heterogeneous disorders. Atypical depression (AD) with reversed vegetative signs, such as hyperphagia or hypersomnia, is traditionally neglected, demonstrated by the fact that in the most widely used depression scales, such as the Hamilton Depression Scale (HAMD), melancholic symptoms have a specific weight, while, by contrast, reversed vegetative signs are not included. However, epidemiologically and phenomenologically related disorders to AD do exist, such as somatoform disorders, neurasthenia (chronic fatigue syndrome) and fibromyalgia (FM). In this spectrum, here called the AD spectrum, instead a decrease in hypothalamus-pituitary-adrenocortical (HPA) axis activity seems to exist. This has similarities to Cushing's disease, where a suppression of central HPA system activity is accompanied by features of AD and somatization in a considerable number of patients. Opposite vegetative features might therefore be related to the opposite dysregulation of the HPA system. The psychopharmacological intervention in the AD spectrum should therefore differ from that used in typical major depression. MAO inhibitors, low-dose tricyclic antidepressants and 5-HT3 antagonists demonstrated therapeutic efficacy, but the existing studies focused on different aspects. Hypericum extracts might be an alternative pharmacological intervention, which demonstrated therapeutic efficacy in the symptom range of the spectrum. PMID- 26983571 TI - Cognitive behavior therapy for functional gastrointestinal disorders: is group treatment effective? AB - OBJECTIVE: The intention of this study was to evaluate therapy outcome of a cognitive-behavioral group treatment program for functional gastrointestinal disorders. As a particular characteristic, gastrointestinal symptoms were investigated independently from diagnostic categories on a dimensional basis, considering the persistence of symptoms as well as the aspect of severity. METHODS: A total of 64 subjects participated in the 10-week treatment program, and 49 completed the study. Subjects underwent four assessments (baseline, pre-, post-treatment, 12-month follow-up), each comprising several self-rated questionnaires on gastrointestinal, somatoform, depressive, hypochondriacal and anxious symptoms, and health locus of control, as well as a diagnostic interview of functional gastrointestinal and mental disorders at the baseline assessment. Treatment effects were controlled by subjects' waiting list period before treatment. RESULTS: Gastrointestinal symptoms, as well as comorbid psychopathology scores, decreased significantly during treatment and remained unchanged during the follow-up period, whereas no relevant changes were found in health locus of control. Largest effect sizes were found for gastrointestinal symptoms, which decreased by 30-50% of their initial number. CONCLUSIONS: The group treatment investigated was effective and particularly successful with respect to functional gastrointestinal symptoms. However, the mechanisms of treatment outcome remain indistinct. Further studies comparing different setting conditions directly are required to clarify the question of whether group treatment is significantly superior or inferior to individual therapy. PMID- 26983572 TI - Biofeedback-based interventions in somatoform disorders: a randomized controlled trial. AB - BACKGROUND AND AIM: The aim of the controlled therapy study was to evaluate the effect of a 6 session biofeedback intervention program on cognitive aspects of patients with somatoform disorders. The treatment consisted of psycho physiological demonstrations how mental processes can influence biological functions. We expected this treatment to be of high credibility, to change maladaptive cognitions, to enhance acceptance of psychosocial causal attribution and to improve coping. METHODS: Patients were assessed using a structured interview to diagnose somatization syndrome (SSI-8) and comorbidity according to DSM-IV criteria. Fifty patients were recruited and randomly assigned to biofeedback treatment or control relaxation group. Participants completed a questionnaire battery assessing cognitive characteristics, causal attributions and controllability before and after intervention as well as evaluation protocols for each session. RESULTS: The results suggest that biofeedback modified the patients' cognitive schemata: Patients with somatization syndrome of the biofeedback group showed a greater reduction of catastrophizing of somatic sensations and higher acceptance of psychosocial causal attributions than the control group. Both groups improved significantly in the conviction of self efficacy. PMID- 26983573 TI - Osseous choristoma of the tongue: two case reports. AB - BACKGROUND: Osseous choristoma is a very rare, benign lesion in the maxillofacial region. It appears as a benign mass of normally matured bony tissue covered by the normal epithelium of the tongue. It is usually seen in front of the foramen cecum of the tongue. Surgical excision is the treatment of choice with an excellent prognosis and there have been very few cases of recurrence. CASE PRESENTATION: Here we present two cases of osseous choristoma on the dorsum of the tongue. Case 1 was a 15-year-old Japanese girl who presented with a painless but gradually growing swelling on the dorsum of her tongue approximately 1 year before her admission. Case 2 was a 21-year-old Japanese woman with a complaint of pain in the lower left, posterior side of her mouth. Histological findings showed that both lesions were composed of well-organized, mature, compact bone beneath the oral mucosal membrane. Subsequent to simple surgical excision, no recurrence of the lesions was observed after the follow-up period. Previous literatures have proposed both malformation and trauma hypotheses as the etiopathologies of osseous choristoma. However, the histopathological findings of the two cases in the present study do not support the trauma hypothesis. CONCLUSIONS: Although osseous choristoma is clinically a benign condition, the underlying histopathological processes are important. The outcome of aberrant formation of calcified tissue in the vicinity of vital structures such as nerves and blood vessels may be of clinical significance. PMID- 26983574 TI - Epigenetic silencing of miR-181c by DNA methylation in glioblastoma cell lines. AB - BACKGROUND: Post-transcriptional regulation by microRNAs is recognized as one of the major pathways for the control of cellular homeostasis. Less well understood is the transcriptional and epigenetic regulation of genes encoding microRNAs. In the present study we addressed the epigenetic regulation of the miR-181c in normal and malignant brain cells. METHODS: To explore the epigenetic regulation of the miR-181c we evaluated its expression using RT-qPCR and the in vivo binding of the CCCTC-binding factor (CTCF) to its regulatory region in different glioblastoma cell lines. DNA methylation survey, chromatin immunoprecipitation and RNA interference assays were used to assess the role of CTCF in the miR-181c epigenetic silencing. RESULTS: We found that miR-181c is downregulated in glioblastoma cell lines, as compared to normal brain tissues. Loss of expression correlated with a notorious gain of DNA methylation at the miR-181c promoter region and the dissociation of the multifunctional nuclear factor CTCF. Taking advantage of the genomic distribution of CTCF in different cell types we propose that CTCF has a local and cell type specific regulatory role over the miR-181c and not an architectural one through chromatin loop formation. This is supported by the depletion of CTCF in glioblastoma cells affecting the expression levels of NOTCH2 as a target of miR-181c. CONCLUSION: Together, our results point to the epigenetic role of CTCF in the regulation of microRNAs implicated in tumorigenesis. PMID- 26983576 TI - Tetrandrine reverses epithelial-mesenchymal transition in bladder cancer by downregulating Gli-1. AB - Hedgehog (Hh) signaling pathway is considered to play a crucial role in vertebrate development and carcinogenesis. Additionally, epithelial-mesenchymal transition (EMT) is a cellular process during which epithelial cells become mesenchymal-appearing cells, facilitating cancer metastasis and invasion. Accumulating evidence has indicated that the Hh signaling pathway could potentiate the epithelial-mesenchymal transition (EMT). In the present study, we demonstrated that tetrandrine, a bisbenzylisoquinoline alkaloid isolated from Stephaniae, exerts its anti-metastatic ability in bladder cancer cells by regulating GLI family zinc finger 1 (Gli-1), a key factor of Hedgehog signaling pathway. In our study, we confirmed that tetrandrine could impede migration and invasion in bladder cancer 5637 and T24 cells. Additionally, tetrandrine reverses EMT by increasing the expression of E-cadherin and reducing the N-cadherin, vimentin and Slug expression in a dose-dependent manner. Interestingly, tetrandrine also decreases mobility and reduces the expression of Gli-1 in bladder cancer cells. Moreover, we verified that tetrandrine inhibits metastasis and induces mesenchymal-epithelial transition (MET) of bladder cancer through downregulation of Gli-1, which could be partially reversed by Gli-1 overexpression. In conclusion, our findings show that tetrandrine inhibits migration and invasion, and reverses EMT of bladder cancer cells through negatively regulating Gli-1. It indicates that Gli-1 may be a potential therapeutic target of tetrandrine against bladder cancer. PMID- 26983575 TI - The antitumor effects of geraniol: Modulation of cancer hallmark pathways (Review). AB - Geraniol is a dietary monoterpene alcohol that is found in the essential oils of aromatic plants. To date, experimental evidence supports the therapeutic or preventive effects of geraniol on different types of cancer, such as breast, lung, colon, prostate, pancreatic, and hepatic cancer, and has revealed the mechanistic basis for its pharmacological actions. In addition, geraniol sensitizes tumor cells to commonly used chemotherapy agents. Geraniol controls a variety of signaling molecules and pathways that represent tumor hallmarks; these actions of geraniol constrain the ability of tumor cells to acquire adaptive resistance against anticancer drugs. In the present review, we emphasize that geraniol is a promising compound or chemical moiety for the development of a safe and effective multi-targeted anticancer agent. We summarize the current knowledge of the effects of geraniol on target molecules and pathways in cancer cells. Our review provides novel insight into the challenges and perspectives with regard to geraniol research and to its application in future clinical investigation. PMID- 26983577 TI - Modulation of R-gene expression across environments. AB - Some environments are more conducive to pathogen growth than others, and, as a consequence, plants might be expected to invest more in resistance when pathogen growth is favored. Resistance (R-) genes in Arabidopsis thaliana have unusually extensive variation in basal expression when comparing the same R-gene among accessions collected from different environments. R-gene expression variation was characterized to explore whether R-gene expression is up-regulated in environments favoring pathogen proliferation and down-regulated when risks of infection are low; down-regulation would follow if costs of R-gene expression negatively impact plant fitness in the absence of disease. Quantitative reverse transcription-PCR was used to quantify the expression of 13 R-gene loci in plants grown in eight environmental conditions for each of 12 A. thaliana accessions, and large effects of the environment on R-gene expression were found. Surprisingly, almost every change in the environment--be it a change in biotic or abiotic conditions--led to an increase in R-gene expression, a response that was distinct from the average transcriptome response and from that of other stress response genes. These changes in expression are functional in that environmental change prior to infection affected levels of specific disease resistance to isolates of Pseudomonas syringae. In addition, there are strong latitudinal clines in basal R-gene expression and clines in R-gene expression plasticity correlated with drought and high temperatures. These results suggest that variation in R-gene expression across environments may be shaped by natural selection to reduce fitness costs of R-gene expression in permissive or predictable environments. PMID- 26983578 TI - Efficacy and acceptability of a home-based, family-inclusive intervention for veterans with TBI: A randomized controlled trial. AB - OBJECTIVE: Traumatic brain injury (TBI) often undermines community re integration, impairs functioning and produces other symptoms. This study tested an innovative programme for veterans with TBI, the Veterans' In-home Programme (VIP), delivered in veterans' homes, involving a family member and targeting the environment (social and physical) to promote community re-integration, mitigate difficulty with the most troubling TBI symptoms and facilitate daily functioning. SETTING: Interviews and intervention sessions were conducted in homes or by telephone. PARTICIPANTS: Eighty-one veterans with TBI at a VA polytrauma programme and a key family member. DESIGN: This was a 2-group randomized controlled trial. Control-group participants received usual-care enhanced by two attention-control telephone calls. Follow-up interviews occurred up to 4 months after baseline interview. MAIN MEASURES: VIP's efficacy was evaluated using measures of community re-integration, target outcomes reflecting veterans' self identified problems and self-rated functional competence. RESULTS: At follow-up, VIP participants had significantly higher community re-integration scores and less difficulty managing targeted outcomes, compared to controls. Self-rated functional competence did not differ between groups. In addition, VIP's acceptability was high. CONCLUSION: A home-based, family-inclusive service for veterans with TBI shows promise for improving meaningful outcomes and warrants further research and clinical application. PMID- 26983581 TI - Prisconnatanones A, a cytotoxic naphthoquinone from Prismatomeris connata, suppresses the proliferation of human laryngocarcinoma HEp-2 cells in vitro. AB - Prisconnatanones A (Priscon-A) is a rare tetrahydroanthraquinone isolated from herbal Prismatomeris connate. In this study, we examine its anti-tumour activity on human laryngocarcinoma HEp-2 cells in vitro. The CCK-8 assay was performed to evaluate its cytotoxicity. Cell cycle and apoptosis were analysed using flow cytometric analysis. Here, we showed Priscon-A inhibited the proliferation of HEp 2 cells in a dose-dependent manner, and at 5 MUM it almost completely inhibited cell growth. Its cytotoxicity was associated with the cell cycle arrest at G2/M phase. The Annexin V-FITC/PI binding assay showed that the cell death induced by Priscon-A was associated with apoptosis. And, western blot analysis revealed that the levels of the apoptosis protein, cleaved caspase-3, PARP, p21 and Bax protein increased, while the level of anti-apoptosis protein Bcl-2 decreased.. These data demonstrated that Priscon-A significantly inhibited HEp-2 cell growth, induced the cell cycle arrest at the G2/M phase and efficiently induced cell apoptosis. PMID- 26983580 TI - Differences in the Effectiveness of Psychosocial Interventions for Suicidal Ideation and Behaviour in Women and Men: A Systematic Review of Randomised Controlled Trials. AB - The objective of this study was to explore outcomes of preventive programs and psychosocial treatments for suicidal ideation and behaviour in gender sub-groups in mixed gender studies and in studies limited to one gender. The method used was a systematic review of randomized controlled trials (RCTs) which included women or men only, or reported and/or examined outcomes of psychosocial interventions in mixed gender samples. A total of 27 (18%) of RCTs reported or examined differences in intervention outcomes. Of the mixed gender RCTs, 5 (33%) reported greater effectiveness for females than males. The review identified promising interventions in female-only samples. None of the trials reported greater effectiveness of the intervention in men. The majority of reviewed studies looking at treatment outcomes in gender sub-groups showed no differences between women and men or indicated that some psychosocial interventions are effective for women. There is a need for studies which look at gender effects and development of interventions more effective and appealing for men at risk of suicide. PMID- 26983579 TI - Trypanocidal and leishmanicidal activities of flavonoids isolated from Stevia satureiifolia var. satureiifolia. AB - Context Chagas' disease and leishmaniasis produce significant disability and mortality with great social and economic impact. The genus Stevia (Asteraceae) is a potential source of antiprotozoal compounds. Objective Aerial parts of four Stevia species were screened on Trypanosoma cruzi. Stevia satureiifolia (Lam.) Sch. Bip. var. satureiifolia (Asteraceae) dichloromethane extract was selected for a bioassay-guided fractionation in order to isolate its active compounds. Additionally, the antileishmanial activity and the cytotoxicity of these compounds on mammalian cells were assessed. Materials and methods The dichloromethane extract was fractionated by column chromatography. The isolated compounds were evaluated using concentrations of 0-100 MUg/mL on T. cruzi epimastigotes and on Leishmania braziliensis promastigotes for 72 h, on trypomastigotes and amastigotes of T. cruzi for 24 h and 120 h, respectively. The compounds' cytotoxicity (12.5-500 MUg/mL) was assessed on Vero cells by the MTT assay. The structure elucidation of each compound was performed by spectroscopic methods and HPLC analysis. Results The dichloromethane extracts of Stevia species showed significant activity on T. cruzi epimastigotes. The flavonoids eupatorin (1.3%), cirsimaritin (1.9%) and 5-desmethylsinensetin (1.5%) were isolated from S. satureiifolia var. satureiifolia extract. Eupatorin and 5-desmethylsinensetin showed IC50 values of 0.2 and 0.4 MUg/mL on T. cruzi epimastigotes and 61.8 and 75.1 MUg/mL on trypomastigotes, respectively. The flavonoid 5-desmethylsinensetin showed moderate activity against T. cruzi amastigotes (IC50 value = 78.7 MUg/mL) and was the most active compound on L. braziliensis promastigotes (IC50 value = 37.0 MUg/mL). Neither of the flavonoids showed cytotoxicity on Vero cells, up to a concentration of 500 MUg/mL. PMID- 26983582 TI - ' ... They should understand why ... ' The knowledge, attitudes and impact of the HIV criminalisation law on a sample of HIV+ women living in Ontario. AB - Over 60 countries criminalise 'the "willful" transmission of HIV'. Such a law has the potential to hinder public health interventions. There is limited literature discussing the perceptions of this law and the impact, it has had on HIV-positive women. This paper describes the knowledge of and attitudes of this law by HIV positive women living in Ontario; and their experiences with its application. Three group discussions (n = 10) and 17 in-depth interviews with HIV-positive women age: 21-56 years. Data were analysed using a modified thematic approach. Most of the respondents knew about the law with regard to adult HIV transmission. However, very few knew about any laws related to mother to child HIV transmission, although some reported having had their children taken away because of breastfeeding. Respondents felt that the law could be fair and protective if there were means of providing a priori support to those women who have been disadvantaged social-culturally and structurally. Without this support, the law could potentially lead HIV-positive women into hiding and not accessing services that could help them. There is need for the law implementers to consider these findings if they are to support the public health efforts to control HIV. PMID- 26983583 TI - Various simultaneous nail changes due to valproic acid use. AB - There are only a few case reports about nail changes due to valproic acid in the literature despite its widespread use. We present a 50-year-old man who had onycholysis, roughness of the nail surface and brownish-yellow discoloration of both fingernails and toenails, which remarkably ameliorated upon cessation of valproic acid. PMID- 26983584 TI - The effect of personal and group discrimination on the subjective well-being of people with mental illness: the role of internalized stigma and collective action intention. AB - The goal of this study is to test a model in which personal discrimination predicts internalized stigma, while group discrimination predicts a greater willingness to engage in collective action. Internalized stigma and collective action, in turn, are associated to positive and negative affect. A cross sectional study with 213 people with mental illness was conducted. The model was tested using path analysis. Although the data supported the model, its fit was not sufficiently good. A respecified model, in which a direct path from collective action to internalized stigma was added, showed a good fit. Personal and group discrimination appear to impact subjective well-being through two different paths: the internalization of stigma and collective action intentions, respectively. These two paths, however, are not completely independent, as collective action predicts a lower internalization of stigma. Thus, collective action appears as an important tool to reduce internalized stigma and improve subjective well-being. Future interventions to reduce the impact of stigma should fight the internalization of stigma and promote collective action are suggested. PMID- 26983585 TI - Lesbians and Gay Men's Vacation Motivations, Perceptions, and Constraints: A Study of Cruise Vacation Choice. AB - This study explores the push-pull vacation motivations of gay male and lesbian consumers and examines how these underpin their perceptions and purchase constraints of a mainstream and LGBT(1) cruise. Findings highlight a complex vacation market. Although lesbians and gay men share many of the same travel motivations as their heterosexual counterparts, the study reveals sexuality is a significant variable in their perception of cruise vacations, which further influences purchase constraints and destination choice. Gay men have more favorable perceptions than lesbians of both mainstream and LGBT cruises. The article recommends further inquiry into the multifaceted nature of motivations, perception, and constraints within the LGBT market in relation to cruise vacations. PMID- 26983587 TI - In focus: Fe3O4 nanoparticles and human mesenteric artery interaction in vitro. AB - AIM: The growing implementation of iron oxide nanoparticles in medicine requires a thorough investigation of their physiological influence. Therefore, effects of Fe3O4 nanoparticles on isometric contractions of healthy human mesenteric artery in vitro were investigated. MATERIALS & METHODS: The effect of increasing concentrations (0.023, 0.069, 0.23, 0.69 and 2.31 MUg/MUl) of Fe3O4 nanoparticles (50-100 nm) on the contractility of mesenteric artery ring preparations was studied using wire myography technique. RESULTS & CONCLUSION: A lack of effects of Fe3O4 nanoparticles (50-100 nm) on isometric contractions of human mesenteric artery segments both in conditions of basal tension and precontraction was found. The observed unresponsiveness of human mesenteric arteries in vitro to Fe3O4 nanoparticles could be attributed to their safe mode of use in biomedicine. PMID- 26983586 TI - Obesity and Diabetic Kidney Disease: Role of Oxidant Stress and Redox Balance. AB - SIGNIFICANCE: Reactive oxygen species (ROS) reactive nitrogen species (RNS) and redox processes are of key importance in obesity- and diabetes-related kidney disease; however, there remains significant controversy in the field. RECENT ADVANCES: New data from imaging and in vivo models of obesity and diabetic kidney disease have shed new insights into this field. In the setting of obesity- and diabetes-related kidney injury, there is a growing recognition that the major moieties of ROS and RNS are hydrogen peroxide and peroxynitrite with the enzymatic sources being NADPH oxidases and nitric oxide synthase, respectively. However, the role of mitochondrial superoxide as a driver of renal complications remains unclear. CRITICAL ISSUES: Several key issues that are often not discussed are the specific ROS and RNS molecules, the source of generation, the location of production, and downstream targets. FUTURE DIRECTIONS: Further understanding of the role of ROS/RNS/redox and their relationship with key signaling and metabolic pathways such as AMP-activated protein kinase (AMPK) and hypoxia-inducible factor 1-alpha (HIF1alpha) will be critical to a new understanding of kidney complications of caloric challenges and new therapeutic approaches. Antioxid. Redox Signal. 25, 208-216. PMID- 26983588 TI - Sexual Harassment, Psychological Distress, and Problematic Drinking Behavior Among College Students: An Examination of Reciprocal Causal Relations. AB - Sexual harassment on college campuses is a frequent occurrence and serious public health concern. Victims of sexual harassment are at risk for many possible negative health consequences. In addition, certain psychological distress symptoms and/or alcohol use may put individuals at increased risk of being victims of sexual harassment. Data from more than 2,000 college students in the Midwestern United States were used to examine reciprocal causal effects of the relations between (a) experiencing sexual harassment and alcohol use and (b) experiencing sexual harassment and psychological distress symptoms, specifically depression and anger/hostility. Analyses were conducted separately for sexual harassment which occurs at school and which occurs in college students' workplaces, and also separately for men and women. Results of cross-lagged panel models showed that there were reciprocal causal effects between sexual harassment and alcohol problems, depression, and anger. Discussion focuses on the overall patterns of results as well as the nuances within these findings. PMID- 26983590 TI - Unusual chest wall pain caused by thoracic disc herniation in a professional baseball pitcher. AB - Symptomatic thoracic disc herniation is clinically rare. There are few cases of disc herniation of the thoracic spine in top athletes described in the literature. We herein present a rare case of chest wall pain due to thoracic disc herniation in a professional baseball pitcher. A 30-year-old, left-handed pitcher complained of left-sided chest wall pain in the region of his lower ribs during a game. Neurological examination revealed hypoesthesia of the left side of the chest at the level of the lower thoracic spine. Magnetic resonance imaging (MRI) of the thoracic spine showed a left-sided paramedian disc herniation at the T9 T10 level. The player was initially prescribed rest, administration of pregabalin (150 mg twice a day), and subsequent physical rehabilitation. He was able to resume full training and pitching without medication 6 months after the onset. A follow-up MRI of the thoracic spine showed a reduction in the size of the herniated disc compared to the initial findings. Though relatively rare, thoracic disc herniation should be considered in cases of chest wall pain in athletes. PMID- 26983591 TI - Curcumin and dexmedetomidine prevents oxidative stress and renal injury in hind limb ischemia/reperfusion injury in a rat model. AB - Curcumin and dexmedetomidine have been shown to have protective effects in ischemia-reperfusion injury on various organs. However, their protective effects on kidney tissue against ischemia-reperfusion injury remain unclear. We aimed to determine whether curcumin or dexmedetomidine prevents renal tissue from injury that was induced by hind limb ischemia-reperfusion in rats. Fifty rats were divided into five groups: sham, control, curcumin (CUR) group (200 mg/kg curcumin, n = 10), dexmedetomidine (DEX) group (25 MUg/kg dexmedetomidine, n = 10), and curcumin-dexmedetomidine (CUR-DEX) group (200 mg/kg curcumin and 25 MUg/kg dexmedetomidine). Curcumin and dexmedetomidine were administered intraperitoneally immediately after the end of 4 h ischemia, just 5 min before reperfusion. The extremity re-perfused for 2 h and then blood samples were taken and total antioxidant capacity (TAC), total oxidative status (TOS) levels, and oxidative stress index (OSI) were measured, and renal tissue samples were histopathologically examined. The TAC activity levels in blood samples were significantly lower in the control than the other groups (p < 0.01 for all comparisons). The TOS activity levels in blood samples were significantly higher in Control group and than the other groups (p < 0.01 for all comparison). The OSI were found to be significantly increased in the control group compared to others groups (p < 0.001 for all comparisons). Histopathological examination revealed less severe lesions in the sham, CUR, DEX, and CUR-DEX groups, compared with the control group (p < 0.01). Rat hind limb ischemia-reperfusion causes histopathological changes in the kidneys. Curcumin and dexmedetomidine administered intraperitoneally was effective in reducing oxidative stress and renal histopathologic injury in an acute hind limb I/R rat model. PMID- 26983592 TI - Polarized three-photon-pumped laser in a single MOF microcrystal. AB - Higher order multiphoton-pumped polarized lasers have fundamental technological importance. Although they can be used to in vivo imaging, their application has yet to be realized. Here we show the first polarized three-photon-pumped (3PP) microcavity laser in a single host-guest composite metal-organic framework (MOF) crystal, via a controllable in situ self-assembly strategy. The highly oriented assembly of dye molecules within the MOF provides an opportunity to achieve 3PP lasing with a low lasing threshold and a very high-quality factor on excitation. Furthermore, the 3PP lasing generated from composite MOF is perfectly polarized. These findings may eventually open up a new route to the exploitation of multiphoton-pumped solid-state laser in single MOF microcrystal (or nanocrystal) for future optoelectronic and biomedical applications. PMID- 26983589 TI - Protection from lethal herpes simplex virus type 1 infection by vaccination with a UL41-deficient recombinant strain. AB - The UL41 gene of herpes simplex virus type 1 (HSV-1) encodes a virion host shut off protein which is involved in immune evasion. The growth and virulence of HSV 1 is markedly reduced by the deletion of UL41. In this report, the UL41-deleted recombinant HSV-1 strain VR?41 was evaluated as a prophylactic live attenuated vaccine against lethal HSV-1 infection in a mouse model. Intraperitoneal (i.p.) inoculation with the VR?41 strain clearly inhibited lethal wild-type HSV-1 (VR-3 strain) infection after both i.p. and intracerebral (i.c.) inoculations. Vaccination with the VR?41 strain was safer than VR-3 vaccination and was able to protect against a wild-type challenge to the same degree as VR-3 vaccination. In contrast, i.p. inoculation with ultraviolet-irradiated VR-3 induced resistance against i.p. infection, but not against i.c. INFECTION: Although replication of the VR?41 strain in mice was greatly reduced compared to that of the VR-3 strain, VR?41 strain maintained the ability to spread to the central nervous system (CNS) from a peripheral inoculation site. These results indicated that the VR?41 strain evoked a potent immune reaction through viral protein expression within CNS without the induction of lethal encephalitis. The entry of antigens into the CNS was essential for the establishment of protective immunity against the lethal HSV encephalitis. We concluded that only a live attenuated vaccine is able to afford a prophylactic effect against CNS infection with HSV. In order to fulfill this requirement, UL41-deleted viruses provide a strong candidate for use as a recombinant live vaccine. PMID- 26983593 TI - Superconducting H5S2 phase in sulfur-hydrogen system under high-pressure. AB - Recently, hydrogen sulfide was experimentally found to show the high superconducting critical temperature (Tc) under high-pressure. The superconducting Tc shows 30-70 K in pressure range of 100-170 GPa (low-Tc phase) and increases to 203 K, which sets a record for the highest Tc in all materials, for the samples annealed by heating it to room temperature at pressures above 150 GPa (high-Tc phase). Here we present a solid H5S2 phase predicted as the low-Tc phase by the application of the genetic algorithm technique for crystal structure searching and first-principles calculations to sulfur-hydrogen system under high pressure. The H5S2 phase is thermodynamically stabilized at 110 GPa, in which asymmetric hydrogen bonds are formed between H2S and H3S molecules. Calculated Tc values show 50-70 K in pressure range of 100-150 GPa within the harmonic approximation, which can reproduce the experimentally observed low-Tc phase. These findings give a new aspect of the excellent superconductivity in compressed sulfur-hydrogen system. PMID- 26983594 TI - Generation and transplantation of reprogrammed human neurons in the brain using 3D microtopographic scaffolds. AB - Cell replacement therapy with human pluripotent stem cell-derived neurons has the potential to ameliorate neurodegenerative dysfunction and central nervous system injuries, but reprogrammed neurons are dissociated and spatially disorganized during transplantation, rendering poor cell survival, functionality and engraftment in vivo. Here, we present the design of three-dimensional (3D) microtopographic scaffolds, using tunable electrospun microfibrous polymeric substrates that promote in situ stem cell neuronal reprogramming, neural network establishment and support neuronal engraftment into the brain. Scaffold supported, reprogrammed neuronal networks were successfully grafted into organotypic hippocampal brain slices, showing an ~ 3.5-fold improvement in neurite outgrowth and increased action potential firing relative to injected isolated cells. Transplantation of scaffold-supported neuronal networks into mouse brain striatum improved survival ~ 38-fold at the injection site relative to injected isolated cells, and allowed delivery of multiple neuronal subtypes. Thus, 3D microscale biomaterials represent a promising platform for the transplantation of therapeutic human neurons with broad neuro-regenerative relevance. PMID- 26983595 TI - Human rhabdomyosarcoma cells express functional pituitary and gonadal sex hormone receptors: Therapeutic implications. AB - Evidence has accumulated that sex hormones play an important role in several types of cancer. Because they are also involved in skeletal muscle development and regeneration, we were therefore interested in their potential involvement in the pathogenesis of human rhabdomyosarcoma (RMS), a skeletal muscle tumor. In the present study, we employed eight RMS cell lines (three fusion positive and five fusion negative RMS cell lines) and mRNA samples obtained from RMS patients. The expression of sex hormone receptors was evaluated by RT-PCR and their functionality by chemotaxis, adhesion and direct cell proliferation assays. We report here for the first time that follicle-stimulating hormone (FSH) and luteinizing hormone (LH) receptors are expressed in established human RMS cell lines as well as in primary tumor samples isolated from RMS patients. We also report that human RMS cell lines responded both to pituitary and gonadal sex hormone stimulation by enhanced proliferation, chemotaxis, cell adhesion and phosphorylation of MAPKp42/44 and AKT. In summary, our results indicate that sex hormones are involved in the pathogenesis and progression of RMS, and therefore, their therapeutic application should be avoided in patients that have been diagnosed with RMS. PMID- 26983596 TI - Abrupt suspension of probiotics administration may increase host pathogen susceptibility by inducing gut dysbiosis. AB - In this study, we investigated the risk associated with suspension of probiotics administration in tilapia, an animal model that may mimic immune-compromised conditions in humans. Tilapias were fed for 14 days using a probiotics supplemented diet, followed by a three-day suspension of probiotics treatment and a subsequent challenge by Aeromonas hydrophila. Unexpectedly, the suspension of a probiotic strain Lactobacillus plantarum JCM1149 significantly triggered susceptibility of the host to A. hydrophila. We further observed that suspension of JCM1149 resulted in host gut microbiota dysbiosis and the subsequent disorder in the intestinal metabolites (bile acids, amino acids, and glucose) and damage in the intestinal epithelium, giving rise to a condition similar to antibiotics induced gut dysbiosis, which collectively impaired tilapia's gut health and resistance to pathogenic challenges. Additionally, we determined that JCM1149 adhered relatively poorly to tilapia intestinal mucosa and was rapidly released from the gastrointestinal tract (GIT) after suspension, with the rapid loss of probiotic strain probably being the direct cause of gut dysbiosis. Finally, three other probiotic Lactobacillus strains with low intestinal mucosa binding activity showed similar rapid loss phenotype following administration suspension, and induced higher host susceptibility to infection, indicating that the risk is a generic phenomenon in Lactobacillus. PMID- 26983597 TI - Identification of E-cadherin signature motifs functioning as cleavage sites for Helicobacter pylori HtrA. AB - The cell adhesion protein and tumour suppressor E-cadherin exhibits important functions in the prevention of gastric cancer. As a class-I carcinogen, Helicobacter pylori (H. pylori) has developed a unique strategy to interfere with E-cadherin functions. In previous studies, we have demonstrated that H. pylori secretes the protease high temperature requirement A (HtrA) which cleaves off the E-cadherin ectodomain (NTF) on epithelial cells. This opens cell-to-cell junctions, allowing bacterial transmigration across the polarised epithelium. Here, we investigated the molecular mechanism of the HtrA-E-cadherin interaction and identified E-cadherin cleavage sites for HtrA. Mass-spectrometry-based proteomics and Edman degradation revealed three signature motifs containing the [VITA]-[VITA]-x-x-D-[DN] sequence pattern, which were preferentially cleaved by HtrA. Based on these sites, we developed a substrate-derived peptide inhibitor that selectively bound and inhibited HtrA, thereby blocking transmigration of H. pylori. The discovery of HtrA-targeted signature sites might further explain why we detected a stable 90 kDa NTF fragment during H. pylori infection, but also additional E-cadherin fragments ranging from 105 kDa to 48 kDa in in vitro cleavage experiments. In conclusion, HtrA targets E-cadherin signature sites that are accessible in in vitro reactions, but might be partially masked on epithelial cells through functional homophilic E-cadherin interactions. PMID- 26983600 TI - Risk factors for occurrence and recurrence of diabetic foot ulcers among Iraqi diabetic patients. AB - There are a few studies that discuss the medical causes for diabetic foot (DF) ulcerations in Iraq, one of them in Wasit province. The aim of our study was to analyze the medical, therapeutic, and patient risk factors for developing DF ulcerations among diabetic patients in Baghdad, Iraq. PMID- 26983598 TI - Comparative Proteomics Analysis Reveals L-Arginine Activates Ethanol Degradation Pathways in HepG2 Cells. AB - L-Arginine (Arg) is a versatile amino acid that plays crucial roles in a wide range of physiological and pathological processes. In this study, to investigate the alteration induced by Arg supplementation in proteome scale, isobaric tags for relative and absolute quantification (iTRAQ) based proteomic approach was employed to comparatively characterize the differentially expressed proteins between Arg deprivation (Ctrl) and Arg supplementation (+Arg) treated human liver hepatocellular carcinoma (HepG2) cells. A total of 21 proteins were identified as differentially expressed proteins and these 21 proteins were all up-regulated by Arg supplementation. Six amino acid metabolism-related proteins, mostly metabolic enzymes, showed differential expressions. Intriguingly, Ingenuity Pathway Analysis (IPA) based pathway analysis suggested that the three ethanol degradation pathways were significantly altered between Ctrl and +Arg. Western blotting and enzymatic activity assays validated that the key enzymes ADH1C, ALDH1A1, and ALDH2, which are mainly involved in ethanol degradation pathways, were highly differentially expressed, and activated between Ctrl and +Arg in HepG2 cells. Furthermore, 10 mM Arg significantly attenuated the cytotoxicity induced by 100 mM ethanol treatment (P < 0.0001). This study is the first time to reveal that Arg activates ethanol degradation pathways in HepG2 cells. PMID- 26983601 TI - Editorial. PMID- 26983599 TI - Metabolic role of dipeptidyl peptidase 4 (DPP4) in primary human (pre)adipocytes. AB - Dipeptidyl peptidase 4 (DPP4) is the target of the gliptins, a recent class of oral antidiabetics. DPP4 (also called CD26) was previously characterized in immune cells but also has important metabolic functions which are not yet fully understood. Thus, we investigated the function of DPP4 in human white preadipocytes and adipocytes. We found that both cell types express DPP4 in high amounts; DPP4 release markedly increased during differentiation. In preadipocytes, lentiviral DPP4 knockdown caused significant changes in gene expression as determined by whole-genome DNA-array analysis. Metabolic genes were increased, e.g. PDK4 18-fold and PPARgammaC1alpha (=PGC1alpha) 6-fold, and proliferation-related genes were decreased (e.g. FGF7 5-fold). These effects, contributing to differentiation, were not inhibited by the PPARgamma antagonist T0070907. Vice versa, the PPARgamma agonist pioglitazone induced a different set of genes (mainly FABP4). DPP4 knockdown also affected growth factor signaling and, accordingly, retarded preadipocyte proliferation. In particular, basal and insulin-induced ERK activation (but not Akt activation) was markedly diminished (by around 60%). This indicates that DPP4 knockdown contributes to adipocyte maturation by mimicking growth factor withdrawal, an early step in fat cell differentiation. In mature adipocytes, DPP4 becomes liberated so that adipose tissue may constitute a relevant source of circulating DPP4. PMID- 26983602 TI - Adenosine kinase facilitated astrogliosis-induced cortical neuronal death in traumatic brain injury. AB - Adenosine kinase (ADK) plays a pivotal role in regulating brain function by regulating adenosine level, and ADK inhibition protects against neuronal damage in cerebral ischemia and epilepsy; however, the effects of ADK in traumatic brain injury (TBI) have not been investigated. For exploring its effects, we generated a blade-induced rat focal brain injury model. Western blot analysis, immunohistochemistry and immunofluorescent staining suggested that ADK was up regulated after TBI, and it was temporally and spatially associated with astrogliosis. Terminal deoxynucleotidyl transferase-mediated biotinylated-dUTP nick-end labeling showed that neuronal apoptosis was paralleled with TBI-induced ADK up-regulation and astrogliosis. For further investigating the role of ADK in astrogliosis-induced neuronal death, primary cultured astrocytes and neurons were utilized, lipopolysaccharide (LPS) was employed to mediate astrogliosis, and condition medium (CM) of reactive astrocytes was used to treat neurons. The results showed that astrocytes increased iNOS expression and secreted pro inflammatory cytokines after LPS treatment, and CM of reactive astrocytes resulted neuronal death. Additionally, ADK knock-down didn't ameliorate LPS induced astrocyte proliferation, but it protected against neuronal death by reducing iNOS expression, tumor necrosis factor alpha and interleukin 1beta secretion of reactive astrocytes. Taken together, ADK was associated with astrogliosis after TBI, its inhibition in reactive astrocytes ameliorated astrogliosis-induced neuronal death. Our findings extended the current knowledge on the role of ADK in astrogliosis, and also provided new evidence for the TBI treatment. PMID- 26983603 TI - The Cost of Intramedullary Nailing for Femoral Shaft Fractures in Dar es Salaam, Tanzania. AB - BACKGROUND: Femoral shaft fractures are one of the most common injuries seen by surgeons in low- and middle-income countries (LMICs). Surgical repair in LMICs is often dismissed as not being cost-effective or unsafe, though little evidence exists to support this notion. Therefore, the goal of this study is to determine the cost of intramedullary nailing of femoral shaft fractures in Tanzania. METHODS: We used micro-costing methods to estimate the fixed and variable costs of intramedullary nailing of femoral shaft fractures. Variable costs assessed included medical personnel costs, ward personnel costs, implants, medications, and single-use supplies. Fixed costs included costs for surgical instruments and administrative and ancillary staff. RESULTS: 46 adult femoral shaft fracture patients admitted to Muhimbili Orthopaedic Institute between June and September 2014 were enrolled and treated with intramedullary fixation. The total cost per patient was $530.87 (SD $129.99). The mean variable cost per patient was $419.87 (SD $129.99), the largest portion coming from ward personnel $144.47 (SD $123.30), followed by implant $134.10 (SD $15.00) medical personnel $106.86 (SD $28.18), and medications/supplies $30.05 (SD $12.28). The mean fixed cost per patient was $111.00, consisting of support staff, $103.50, and surgical instruments, $7.50. CONCLUSIONS: Our study provides empirical information on the variable and fixed costs of intramedullary nailing of femoral shaft fractures in LMICs. Importantly, the lack of surgical capacity was the primary driver of the largest cost for this procedure, preoperative ward personnel time. Our results provide the cost data for a formal cost-effectiveness analysis on this intervention. PMID- 26983604 TI - Evaluation of virus resistance and agronomic performance of rice cultivar ASD 16 after transfer of transgene against Rice tungro bacilliform virus by backcross breeding. AB - Severe losses of rice yield in south and southeast Asia are caused by Rice tungro disease (RTD) induced by mixed infection of Rice tungro bacilliform virus (RTBV) and Rice tungro spherical virus (RTSV). In order to develop transgene-based resistance against RTBV, one of its genes, ORF IV, was used to generate transgenic resistance based on RNA-interference in the easily transformed rice variety Pusa Basmati-1, and the transgene was subsequently introgressed to rice variety ASD 16, a variety popular in southern India, using transgene marker assisted selection. Here, we report the evaluation of BC3F4 and BC3F5 generation rice plants for resistance to RTBV as well as for agronomic traits under glasshouse conditions. The BC3F4 and BC3F5 generation rice plants tested showed variable levels of resistance, which was manifested by an average of twofold amelioration in height reduction, 1.5-fold decrease in the reduction in chlorophyll content, and 100- to 10,000-fold reduction in the titers of RTBV, but no reduction of RTSV titers, in three backcrossed lines when compared with the ASD 16 parent. Agronomic traits of some of the backcrossed lines recorded substantial improvements when compared with the ASD 16 parental line after inoculation by RTBV and RTSV. This work represents an important step in transferring RTD resistance to a susceptible popular rice variety, hence enhancing its yield in areas threatened by the disease. PMID- 26983605 TI - Rapid and Sensitive Detection of sFAT-1 Transgenic Pigs by Visual Loop-Mediated Isothermal Amplification. AB - Genetically modified (GM) livestock have the potential to contribute to improving the environment and human health, with consumption of fewer resources and reduced waste production. However, the transgene process also poses risks. The safety assessment and control of transgenic animal products have drawn wide attention, and the relevant regulations and technology are being developed. Quick testing technology plays a significant role in on-site and customs sampling. Nowadays, loop-mediated isothermal amplification (LAMP) was widely applied in nucleic acid analysis because of its simplicity, rapidity, high efficiency and specificity. In this study, a specific, sensitive detection system for detecting sFAT-1 transgenic pigs was designed. A set of six primers including two loop primers was designed for the target sequence. The DNA samples were amplified in less than 1 h at the optimized temperature and detecting by both Nephelometer LA-320c and unaided eyes directly adding calcein. The detection limit of sFAT-1 LAMP was as low as 1.26 ng/MUL. Furthermore, blind tests of transgenic and non-transgenic DNA samples were all correctly detected. Hence, the results in this study demonstrated that LAMP is a very useful tool for transgenic detection. PMID- 26983607 TI - Combination of low-contact cerclage wiring and osteosynthesis in the treatment of femoral fractures. AB - BACKGROUND AND PURPOSE: Objectives were (1) to evaluate results after cerclage wiring technique for femoral primary and periprosthetic fracture (PPF); (2) to report the incidence of complications and their treatment; (3) to analyze possible prognostic factors. PATIENTS AND METHODS: We analyzed 54 patients treated with different techniques associated with low-contact cerclage wires for femoral fracture. Fractures were stratified according to AO, Vancouver or Rorabeck classification. Cerclage was used as an exclusive implant in four PPFs or combined with internal devices in 50 cases. Comorbidities were assessed using Charlson Comorbidity Index. The Glasgow Outcome Scale was used to compare activities of daily living pre/postoperatively. RESULTS: Cerclage wires with three or four spacers were used in 22 and 32 cases, respectively. Nine patients died within 6 months. Mean follow-up of the remaining 42 patients was 10.5 months. Fracture healing was achieved in 38/42 patients (71 %), with a mean time to callus formation of 57 days and to radiographic union of 3 months (1.5-9 months). Four patients had nonunion. Survival to major complications was 92 and 70 % at 1 and 2 years, respectively, significantly better in cerclage wires with three spacers than those with four spacers (p = 0.0188). No other statistical correlations were found. CONCLUSION: Cerclage wiring in difficult femoral fractures offers minimally invasive reduction and fixation technique, low cost and early holding. We reinforce the concept of "reduce with cerclage cables first, then nail" for displaced long subtrochanteric fractures and support the use of cerclage wiring for challenge PPF using low-contact wires. LEVEL OF EVIDENCE: Therapeutic study, Level IV. PMID- 26983606 TI - Angiotensin AT2-receptor stimulation improves survival and neurological outcome after experimental stroke in mice. AB - This study investigated the effect of post-stroke, direct AT2-receptor (AT2R) stimulation with the non-peptide AT2R-agonist compound 21 (C21) on infarct size, survival and neurological outcome after middle cerebral artery occlusion (MCAO) in mice and looked for potential underlying mechanisms. C57/BL6J or AT2R-knockout mice (AT2-KO) underwent MCAO for 30 min followed by reperfusion. Starting 45 min after MCAO, mice were treated once daily for 4 days with either vehicle or C21 (0.03 mg/kg ip). Neurological deficits were scored daily. Infarct volumes were measured 96 h post-stroke by MRI. C21 significantly improved survival after MCAO when compared to vehicle-treated mice. C21 treatment had no impact on infarct size, but significantly attenuated neurological deficits. Expression of brain derived neurotrophic factor (BDNF), tyrosine kinase receptor B (TrkB) (receptor for BDNF) and growth-associated protein 43 (GAP-43) were significantly increased in the peri-infarct cortex of C21-treated mice when compared to vehicle-treated mice. Furthermore, the number of apoptotic neurons was significantly decreased in the peri-infarct cortex in mice treated with C21 compared to controls. There were no effects of C21 on neurological outcome, infarct size and expression of BDNF or GAP-43 in AT2-KO mice. From these data, it can be concluded that AT2R stimulation attenuates early mortality and neurological deficits after experimental stroke through neuroprotective mechanisms in an AT2R-specific way. Key message * AT2R stimulation after MCAO in mice reduces mortality and neurological deficits.* AT2R stimulation increases BDNF synthesis and protects neurons from apoptosis.* The AT2R-agonist C21 acts protectively when applied post-stroke and peripherally. PMID- 26983608 TI - Nutrient reference value: non-communicable disease endpoints--a conference report. AB - Nutrition is complex-and seemingly getting more complicated. Most consumers are familiar with "essential nutrients," e.g., vitamins and minerals, and more recently protein and important amino acids. These essential nutrients have nutrient reference values, referred to as dietary reference intakes (DRIs) developed by consensus committees of scientific experts convened by the Institute of Medicine of the National Academy of Sciences, Engineering, and Medicine and carried out by the Food and Nutrition Board. The DRIs comprise a set of four nutrient-based reverence values, the estimated average requirements, the recommended dietary allowances (RDAs), the adequate intakes and the tolerable upper intake levels for micronutrient intakes and an acceptable macronutrient distribution range for macronutrient intakes. From the RDA, the US Food and Drug Administration (FDA) derives a labeling value called the daily value (DV), which appears on the nutrition label of all foods for sale in the US. The DRI reports do not make recommendations about whether the DV labeling values can be set only for what have been defined to date as "essential nutrients." For example, the FDA set a labeling value for "dietary fiber" without having the DV. Nutrient reference values-requirements are set by Codex Alimentarius for essential nutrients, and regulatory bodies in many countries use these Codex values in setting national policy for recommended dietary intakes. However, the focus of this conference is not on essential nutrients, but on the "nonessential nutrients," also termed dietary bioactive components. They can be defined as "Constituents in foods or dietary supplements, other than those needed to meet basic human nutritional needs, which are responsible for changes in health status (Office of Disease Prevention and Health Promotion, Office of Public Health and Science, Department of Health and Human Services in Fed Regist 69:55821-55822, 2004)." Substantial and often persuasive scientific evidence does exist to confirm a relationship between the intake of a specific bioactive constituent and enhanced health conditions or reduced risk of a chronic disease. Further, research on the putative mechanisms of action of various classes of bioactives is supported by national and pan-national government agencies, and academic institutions, as well as functional food and dietary supplement manufacturers. Consumers are becoming educated and are seeking to purchase products containing bioactives, yet there is no evaluative process in place to let the public know how strong the science is behind the benefits or the quantitative amounts needed to achieve these beneficial health effects or to avoid exceeding the upper level (UL). When one lacks an essential nutrient, overt deficiency with concomitant physiological determents and eventually death are expected. The absence of bioactive substances from the diet results in suboptimal health, e.g., poor cellular and/or physiological function, which is relative and not absolute. Regrettably at this time, there is no DRI process to evaluate bioactives, although a recent workshop convened by the National Institutes of Health (Options for Consideration of Chronic Disease Endpoints for Dietary Reference Intakes (DRIs); March 10-11, 2015; http://health.gov/dietaryguidelines/dri/ ) did explore the process to develop DVs for nutrients, the lack of which result in increased risk of chronic disease (non-communicable disease) endpoints. A final report is expected soon. This conference (CRN-International Scientific Symposium; "Nutrient Reference Value-Non-Communicable Disease (NRV-NCD) Endpoints," 20 November in Kronberg, Germany; http://www.crn-i.ch/2015symposium/ ) explores concepts related to the Codex NRV process, the public health opportunities in setting NRVs for bioactive constituents, and further research and details on the specific class of bioactives, n-3 long-chain polyunsaturated fatty acids (also termed omega-3 fatty acids) and their constituents, specifically docosahexaenoic acid and eicosapentaenoic acid. PMID- 26983609 TI - Dietary fatty acids specifically modulate phospholipid pattern in colon cells with distinct differentiation capacities. AB - PURPOSE: Although beneficial effects of the dietary n-3 docosahexaenoic acid (DHA) or butyrate in colon carcinogenesis have been implicated, the mechanisms of their action are not fully clear. Here, we investigated modulations of composition of individual phospholipid (PL) classes, with a particular emphasis on cardiolipins (CLs), in colon cells treated with DHA, sodium butyrate (NaBt), or their combination (DHA/NaBt), and we evaluated possible associations between lipid changes and cell fate after fatty acid treatment. METHODS: In two distinct human colon cell models, foetal colon (FHC) and adenocarcinoma (HCT-116) cells, we compared patterns and composition of individual PL classes following the fatty acid treatment by HPLC-MS/MS. In parallel, we measured the parameters reflecting cell proliferation, differentiation and death. RESULTS: In FHC cells, NaBt induced primarily differentiation, while co-treatment with DHA shifted their response towards cell death. In contrast, NaBt induced apoptosis in HCT-116 cells, which was not further affected by DHA. DHA was incorporated in all main PL types, increasing their unsaturation, while NaBt did not additionally modulate these effects in either cell model. Nevertheless, we identified an unusually wide range of CL species to be highly increased by NaBt and particularly by DHA/NaBt, and these effects were more pronounced in HCT-116 cells. DHA and DHA/NaBt enhanced levels of high molecular weight and more unsaturated CL species, containing DHA, which was specific for either differentiation or apoptotic responses. CONCLUSIONS: We identified a wide range of CL species in the colon cells which composition was significantly modified after DHA and NaBt treatment. These specific CL modulations might contribute to distinct cellular differentiation or apoptotic responses. PMID- 26983610 TI - Theoretical insights into thermal cyclophanediene to dihydropyrene electrocyclic reactions; a comparative study of Woodward Hoffmann allowed and forbidden reactions. AB - The thermally allowed electrocyclic reaction syn-cyclophanediene (CPD) to dihydropyrene (DHP) was compared with the disallowed thermal electrocyclic reaction in anti CPD through density functional theory (DFT) calculations at the B3LYP/6-31 + G(d) level. Moreover, the results were also compared with the electrocyclization of 1,3,5 hexatriene to 1,3-cyclohexadiene . The Woodward Hoffmann (W-H) allowed thermal reaction in syn CPD 11 has a calculated activation barrier of 6.23 kcal mol(-1), compared with 29 kcal mol(-1) for the electrocyclization of 1,3,5 hexatriene to 1,3-cyclohexadiene. The enhanced acceleration of electrocyclization is believed to arise from geometrically enforced spatially aligned termini of the hexatriene. Substituents at the electrocyclic terminus of cyclophanediene significantly affected (up to three fold) the activation barriers. Mono-substitution of CPD has substituent dependent acceleration or deceleration whereas di-substitution always increased the activation barrier. The activation barrier for electrocyclization in 33 is 4.44 kcal mol(-1), which is the lowest activation barrier for any thermal electrocyclic reaction. Cyclophanedienes (CPDs) substituted with electron-rich substituents cyclized with high activation barriers and vice versa, a phenomenon significantly different from electrocyclic reaction of 1,3,5-hexatriene where no such trend is traceable. Comparison of W-H allowed and forbidden electrocyclization in syn and anti CPDs, respectively, revealed quite similar electronic demand, although the transition states are different in nature. The transition state for a W-H forbidden reaction is biradicaloid, with most of the spin density at the electrocyclic termini; however, the transition state for a W H allowed reaction has no such contribution. We also believe that this is the first study of its type, where W-H allowed and forbidden reactions are compared on a similar set of molecules, and compared for electronic effect through substituents. PMID- 26983611 TI - Molecular dynamics simulations of trihalomethanes removal from water using boron nitride nanosheets. AB - Molecular dynamics simulations were performed to investigate the separation of trihalomethanes (THMs) from water using boron nitride nanosheets (BNNSs). The studied systems included THM molecules and a functionalized BNNS membrane immersed in an aqueous solution. An external pressure was applied to the z axis of the systems. Two functionalized BNNSs with large fluorinated-hydrogenated pore (F-H-pores) and small hydrogen-hydroxyl pore (H-OH-pores) were used. The pores of the BNNS membrane were obtained by passivating each nitrogen and boron atoms at the pore edges with fluorine and hydrogen atoms in the large pore or with hydroxyl and hydrogen atoms in the small pore. The results show that the BNNS with a small functionalized pore was impermeable to THM molecules, in contrast to the BNNS with a large functionalized pore. Using these membranes, water contaminants can be removed at lower cost. PMID- 26983612 TI - Theoretical study of the effect of N-oxides on the performances of energetic compounds. AB - In order to study the effects of N-oxide on structure and performance, six categories of energetic compounds were systemically investigated. The results indicated that the C-C bonds in the rings were shortened, and the C-N bonds close to the N -> O bond were elongated when N atoms was oxidized to form N -> O bonds. N -> O bonds can increase the densities of most categories of compounds, and the increment will increase with the number of N -> O bonds. As to their detonation performances, almost all categories of compounds had an increased trend, except for some NO2-, NHNO2- and ONO2-substituted compounds. The contribution of 1,2,3,4 tetrazine and 1,2,4,5-tetrazine to performances was better than that of pyrazine and [1,2,5] oxadiazolo [3,4-b] pyrazine on the whole, and the groups, especially energetic groups, made a huge contribution to performance. When R was a NH2 or ONO2 group, all compounds had lower impact sensitivities, and thus represent candidates for novel energetic compounds. However, other than the sixth category of compounds, all compounds had higher impact sensitivities when R was a NO2 or NHNO2 group, and have little significance in application. PMID- 26983614 TI - Use and Evaluation of Newly Synthesized Fluorescence Probes to Detect Generated OH* Radicals in Fibroblast Cells. AB - Reactive oxygen species (ROS) are pro-oxidant molecules synthesized in body with various functions and are essential for life. Increasing in reactive oxygen species or decreasing in antioxidants level cause oxidative stress which is very harmful. OH* radical is one of ROS's, with tendency to bind to lipids, DNA and proteins which cause irreversible damage in cells. The most devastating consequences related to excess OH* radicals occur via direct binding to nucleic acids and proteins. Quantification of this high reactive radical with short life time is difficult. Electron Spin Resonance, Fluorescence, and Luminescence Spectroscopy are commonly used to determine the level of ROS. Fluorescence Probes have higher specificity and sensitivity with their excellent sensors to detect ROS's compare to the other methods. Also, there are different probes specifically designed for each radical. The purpose of this study was to identify the probe better suiting for detection of OH* radical levels. The two most recommended fluorescence probes, 2-[6-(4 V-Hydroxy) phenoxy-3H-xanthen-3-on-9-yl]benzoic acid (HPF) and coumarin-3-carboxylic acid (3-CCA) to determine OH* radical levels were compared. Following the formation of OH* radical with Fenton reaction, HPF and 3 CCA probes were added to cells and spectrofluorometric measurements were performed in their respective wavelengths. The mean amplitude of fluorescence for HPF was 32.72 +/- 2.37 F.I (n = 40) and for 3-CCA was 52.11 +/- 0.5 F.I (n = 40). This difference was statistically significant. 3-CCA also demonstrated more stable measurements at different days compered to HPF. PMID- 26983617 TI - Erratum to: Nebulized Magnesium Sulfate in Acute Bronchiolitis: A Randomized Controlled Trial. AB - In the original article, the authors failed to cite the study by Kose M et al. entitled "The efficacy of nebulized salbutamol, magnesium sulfate and salbutamol/magnesium sulfate combination in moderate bronchiolitis. Eur J Pediatr 2014;173: 1157-1160" as the first in literature to assess the efficacy of magnesium sulfate in the treatment of acute bronchiolitis. The authors apologize for this unintentional omission. PMID- 26983613 TI - S-adenosylmethionine Administration Attenuates Low Brain-Derived Neurotrophic Factor Expression Induced by Chronic Cerebrovascular Hypoperfusion or Beta Amyloid Treatment. AB - Chronic cerebrovascular hypoperfusion is a high-risk factor for Alzheimer's disease (AD) as it is conducive to beta amyloid (Abeta) over-production. Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family widely expressed in the central nervous system. The structure of the rat BDNF gene is complex, consisting of eight non-coding exons (I-VIII) and one coding exon (IX). The BDNF gene is transcribed from multiple promoters located upstream of different 5' non-coding exons to produce a heterogeneous population of BDNF mRNAs. S-adenosylmethionine (SAM) produced in the methionine cycle is the primary methyl donor and the precursor of glutathione. In this study, a cerebrovascular hypoperfusion rat model and an Abeta intrahippocampal injection rat model were used to explore the expression profiles of all BDNF transcripts in the hippocampus with chronic cerebrovascular hypoperfusion or Abeta injection as well as with SAM treatment. We found that the BDNF mRNAs and protein were down regulated in the hippocampus undergoing chronic cerebrovascular hypoperfusion as well as Abeta treatment, and BDNF exons IV and VI played key roles. SAM improved the low BDNF expression following these insults mainly through exons IV and VI. These results suggest that SAM plays a neuroprotective role by increasing the expression of endogenous BDNF and could be a potential target for AD therapy. PMID- 26983616 TI - The role of public policies in reducing smoking prevalence: results from the Michigan SimSmoke tobacco policy simulation model. AB - INTRODUCTION: Michigan has implemented several of the tobacco control policies recommended by the World Health Organization MPOWER goals. We consider the effect of those policies and additional policies consistent with MPOWER goals on smoking prevalence and smoking-attributable deaths (SADs). METHODS: The SimSmoke tobacco control policy simulation model is used to examine the effect of past policies and a set of additional policies to meet the MPOWER goals. The model is adapted to Michigan using state population, smoking, and policy data starting in 1993. SADs are estimated using standard attribution methods. Upon validating the model, SimSmoke is used to distinguish the effect of policies implemented since 1993 against a counterfactual with policies kept at their 1993 levels. The model is then used to project the effect of implementing stronger policies beginning in 2014. RESULTS: SimSmoke predicts smoking prevalence accurately between 1993 and 2010. Since 1993, a relative reduction in smoking rates of 22 % by 2013 and of 30 % by 2054 can be attributed to tobacco control policies. Of the 22 % reduction, 44 % is due to taxes, 28 % to smoke-free air laws, 26 % to cessation treatment policies, and 2 % to youth access. Moreover, 234,000 SADs are projected to be averted by 2054. With additional policies consistent with MPOWER goals, the model projects that, by 2054, smoking prevalence can be further reduced by 17 % with 80,000 deaths averted relative to the absence of those policies. CONCLUSIONS: Michigan SimSmoke shows that tobacco control policies, including cigarette taxes, smoke-free air laws, and cessation treatment policies, have substantially reduced smoking and SADs. Higher taxes, strong mass media campaigns, and cessation treatment policies would further reduce smoking prevalence and SADs. PMID- 26983619 TI - Approach to Pediatric Chest Radiograph. AB - Chest radiograph remains the first line imaging modality even today, especially in ICU settings. Hence proper interpretation of chest radiographs is crucial, which can be achieved by adopting a systematic approach and proper description and identification of abnormalities. In this review, the authors describe a short and comprehensive way of interpreting the pediatric chest radiograph. PMID- 26983615 TI - Residential cancer cluster investigation nearby a Superfund Study Area with trichloroethylene contamination. AB - PURPOSE: Trichloroethylene (TCE) is an industrial solvent associated with liver cancer, kidney cancer, and non-Hodgkin's lymphoma (NHL). It is unclear whether an excess of TCE-associated cancers have occurred surrounding the Middlefield-Ellis Whisman Superfund site in Mountain View, California. We conducted a population based cancer cluster investigation comparing the incidence of NHL, liver, and kidney cancers in the neighborhood of interest to the incidence among residents in the surrounding four-county region. METHODS: Case counts and address information were obtained using routinely collected data from the Greater Bay Area Cancer Registry, part of the Surveillance, Epidemiology, and End Results program. Population denominators were obtained from the 1990, 2000, and 2010 US censuses. Standardized incidence ratios (SIRs) with two-sided 99 % confidence intervals (CIs) were calculated for time intervals surrounding the US Censuses. RESULTS: There were no statistically significant differences between the neighborhood of interest and the larger region for cancers of the liver or kidney. A statistically significant elevation was observed for NHL during one of the three time periods evaluated (1996-2005: SIR = 1.8, 99 % CI 1.1-2.8). No statistically significant NHL elevation existed in the earlier 1988-1995 (SIR = 1.3, 99 % CI 0.5-2.6) or later 2006-2011 (SIR = 1.3, 99 % CI 0.6-2.4) periods. CONCLUSION: There is no evidence of an increased incidence of liver or kidney cancer, and there is a lack of evidence of a consistent, sustained, or more recent elevation in NHL occurrence in this neighborhood. This evaluation included existing cancer registry data, which cannot speak to specific exposures incurred by past or current residents of this neighborhood. PMID- 26983621 TI - [Pulmonary embolism and direct oral anticoagulants]. AB - A new European guideline for the diagnostics and therapy of venous thromboembolism has been published in 2014. As previously, high-risk and low-risk pulmonary embolism is distinguished, however, in the new guideline there is also a definition of intermediate risk PE. The risk finally decides about the diagnostic and therapeutic procedure.Previously, nearly only heparinoids were available for therapy of acute venous thromboembolism and after some days they were switched to a vitamin K antagonist. The direct oral anticoagulants (DOAC) represent a group of drugs that start working as rapidly as heparinoids and can be applied as long-term oral medication. In contrast to vitamin K antagonists, repeated coagulation tests are not necessary. Dosing is easy, although in quite a few cases dose adaptations compared to the standard dose may be necessary. The following article tries to give a rapid orientation. PMID- 26983620 TI - Strategy of arm movement control is determined by minimization of neural effort for joint coordination. AB - Optimality criteria underlying organization of arm movements are often validated by testing their ability to adequately predict hand trajectories. However, kinematic redundancy of the arm allows production of the same hand trajectory through different joint coordination patterns. We therefore consider movement optimality at the level of joint coordination patterns. A review of studies of multi-joint movement control suggests that a 'trailing' pattern of joint control is consistently observed during which a single ('leading') joint is rotated actively and interaction torque produced by this joint is the primary contributor to the motion of the other ('trailing') joints. A tendency to use the trailing pattern whenever the kinematic redundancy is sufficient and increased utilization of this pattern during skillful movements suggests optimality of the trailing pattern. The goal of this study is to determine the cost function minimization of which predicts the trailing pattern. We show that extensive experimental testing of many known cost functions cannot successfully explain optimality of the trailing pattern. We therefore propose a novel cost function that represents neural effort for joint coordination. That effort is quantified as the cost of neural information processing required for joint coordination. We show that a tendency to reduce this 'neurocomputational' cost predicts the trailing pattern and that the theoretically developed predictions fully agree with the experimental findings on control of multi-joint movements. Implications for future research of the suggested interpretation of the trailing joint control pattern and the theory of joint coordination underlying it are discussed. PMID- 26983624 TI - Management of Pregnant Women with Type 2 Diabetes Mellitus and the Consequences of Fetal Programming in Their Offspring. AB - The obesity epidemic has fueled an epidemic of prediabetes and type 2 diabetes mellitus in women of childbearing age. This paper examines the state of the science on preconception and pregnancy management of women with type 2 diabetes to optimize outcomes for the women and their infants. In addition, the consequence of fetal programming as a result of suboptimal maternal glycemic control is discussed. The paper focuses on type 2 diabetes, not type 1 diabetes or gestational diabetes. Management of women with type 2 diabetes includes preconception counseling, preconception weight management and weight loss, proper weight gain during pregnancy, self-monitoring of blood glucose levels, medication, medical nutrition therapy, and exercise. PMID- 26983622 TI - An Evaluation of Psychosocial and Religious Belief Differences in a Diverse Racial and Socioeconomic Urban Cancer Population. AB - Despite years of research aimed at decreasing the cancer mortality rates, the disparity between African-Americans and whites continues to grow. The fundamental psychosocial and belief differences that may mediate these disparities are poorly studied and rarely disentangle race versus specific socioeconomic status (SES) effects. In this study, breast, colon, and lung cancer patients presenting for their first oncology appointment completed a self-administered survey utilizing previously validated instruments regarding psychosocial and belief factors. Results were analyzed by self-identified race, income, and education. In total, 161 African-American (37 %) and 269 white (63 %) new oncology patients with breast (47 %), colon (16 %), or lung (37 %) cancer enrolled. African-Americans were more likely to be in the US$<20,000 income group (45 vs. 9 %) but 21 % had incomes US$>60,000. Apparent racial differences in health literacy and cancer knowledge were primarily mediated by income and education. Significant racial differences in God's perceived role in their cancer remained after adjustments for income and education with African-Americans more likely to feel that God was in control of their cancer (67 vs. 30 %). These findings suggest the need for a more nuanced understanding of how race and socioeconomic status exert both independent and interrelated effects in the health care setting. Only then can effective interventions that reduce disparities in survival be designed. This study adds further substantive evidence to the crucial importance of God's perceived role in the cancer experience for African-Americans. An important area for future research is to examine whether these racial differences in religious belief are also associated with differences in health-related behavior and medical decision-making. PMID- 26983625 TI - Genetic Epidemiology of Type 1 Diabetes in the 22 Arab Countries. AB - Type 1 diabetes (T1D) is a complex autoimmune disorder that results from the T cell-mediated destruction of the pancreatic beta cells and is due to interactions between environmental and genetic factors. Although Arabs have one of the highest global incidence and prevalence rates of T1D, unfortunately, there is a dearth of information regarding the genetic epidemiology of T1D in the Arab world. Arabs share several HLA haplotypes with other ethnic groups, which confer either susceptibility or protection to T1D, but they have specific haplotypes that are distinctive from other ethnicities. Among different Arab countries, several non HLA genes were reported to be associated with susceptibility to T1D, including CTLA4, CD28, PTPN22, TCRbeta, CD3z, IL15, BANK1, and ZAP70. In Arab countries, consanguinity, endogamy, and first-cousin marriage rates are some of the highest reported worldwide and are responsible for the creation of several inbreeding communities within the Arab world that have led to an increase in homozygosity of both the HLA haplotypes and non-HLA genes associated with either protection or susceptibility to T1D among Arabs. Homozygosity reduces the HLA complexity and is expected to facilitate our understanding of the mode of inheritance of HLA haplotypes and provide valuable insight into the intricate genotype-phenotype correlations in T1D patients. In this review, based on literature studies, I will discuss the current epidemiological profile and molecular genetic risks of Arabs with T1D. PMID- 26983623 TI - Racial Disparities in Fertility Care: an Analysis of 4537 Intrauterine Insemination Cycles. AB - BACKGROUND: Studies suggest that race may affect access to fertility treatments and their outcomes. We examined whether race affects the following: duration of infertility prior to seeking evaluation, diagnosis, treatment cycle characteristics, and outcomes. MATERIALS AND METHODS: Design: Retrospective cohort. SETTINGS: Academic fertility center. PATIENTS: 4537 intrauterine insemination +/- ovulation induction (IUI +/- OI) cycles/1495 patients. INTERVENTIONS: IUI following: (i) OI with either clomiphene citrate or gonadotropins and (ii) ultrasound-monitored natural cycles. OUTCOME MEASURES: Duration of infertility prior to seeking treatment, SART diagnosis, treatment cycle characteristics and outcomes (spontaneous abortion (SABR), clinical (CPR) and multiple pregnancy rates (MPR)). RESULTS: Asians and Hispanics compared to Caucasians waited significantly longer prior to seeking fertility evaluation (p < 0.01). The mean age of patients seeking infertility evaluation did not differ between groups nor did the type of treatment initially chosen by the patients. Idiopathic infertility was more common among Caucasians (p < 0.05, compared to all others) while PCOS and tubal factor infertility were more frequent among Hispanics (p < 0.05, compared to Caucasian, Asian, and mixed ancestry women) and decreased ovarian reserve was more common among African-Americans (p < 0.01, compared to Caucasians, Asians, and Hispanics). Gonadotropin cycle characteristics including dosing and duration of treatment, follicular recruitment, peak estradiol levels, and endometrial lining thickness differed between certain groups. However, no difference was found in CPR, MPR, and SABR between groups. CONCLUSION: Race affects timely access to infertility care, diagnosis, and treatment cycle characteristics but not outcomes. Considering the nation's growing multiracial population, understanding the effect of race on fertility care becomes increasingly important. PMID- 26983626 TI - New Insights into Diabetes Cell Therapy. AB - Since insulin discovery, islet transplantation was the first protocol to show the possibility to cure patients with type 1 diabetes using low-risk procedures. The scarcity of pancreas donors triggered a burst of studies focused on the production of new beta cells in vitro. These were rapidly dominated by pluripotent stem cells (PSCs) demonstrating diabetes-reversal potential in diabetic mice. Subsequent enthusiasm fostered a clinical trial with immunoisolated embryonic-derived pancreatic progenitors. Yet safety is the Achilles' heel of PSCs, and a whole branch of beta cell engineering medicine focuses on transdifferentiation of adult pancreatic cells. New data showed the possibility to chemically stimulate acinar or alpha cells to undergo beta cell neogenesis and provide opportunities to intervene in situ without the need for a transplant, at least after weighing benefits against systemic adverse effects. The current studies suggested the pancreas as a reservoir of facultative progenitors (e.g., in the duct lining) could be exploited ex vivo for expansion and beta cell differentiation in timely fashion and without the hurdles of PSC use. Diabetes cell therapy is thus a growing field not only with great potential but also with many pitfalls to overcome for becoming fully envisioned as a competitor to the current treatment standards. PMID- 26983627 TI - Diagnosis and Management of IUGR in Pregnancy Complicated by Type 1 Diabetes Mellitus. AB - This review discusses available literature on the diagnosis and management of intrauterine growth restriction (IUGR) in women with type 1 diabetes. IUGR is diagnosed when ultrasound-estimated fetal weight is below the 10th percentile for gestational age. IUGR diagnosis implies a pathologic process behind low fetal weight. IUGR in pregnancy complicated by type 1 diabetes is usually caused by placental dysfunction related to maternal vasculopathy. Prevention of IUGR should ideally start before pregnancy. Strict glycemic control and intensive treatment of nephropathy and hypertension are essential. Low-dose aspirin initiated before 16 gestational weeks can also reduce IUGR risk in women with vasculopathy. Umbilical and uterine artery Doppler studies can guide diagnosis and surveillance of fetuses with IUGR. Decisions regarding the timing of delivery should be based on assessment of umbilical artery Doppler. The risk of prematurity and impaired fetal lung maturation should always be considered, especially in fetuses younger than 32 weeks. PMID- 26983630 TI - Diuretics in the treatment of hypertension. AB - Diuretics have long been used for the treatment of hypertension. Thiazide diuretics are the most commonly prescribed diuretics for hypertension, but other classes of diuretics may be useful in alternative circumstances. Although diuretics are no longer considered the preferred agent for treatment of hypertension in adults and children, they remain acceptable first-line options. Diuretics effectively decrease blood pressure in hypertensive patients, and in adults with hypertension reduce the risk of adverse cardiovascular outcomes. Because of varied pharmacokinetic and pharmacodynamic differences, chlorthalidone may be the preferred thiazide diuretic in the treatment of primary hypertension. Other types of diuretics (e.g., loop, potassium sparing) may be useful for the treatment of hypertension related to chronic kidney disease (CKD) and other varied conditions. Common side effects of thiazides are mostly dose-related and involve electrolyte and metabolic abnormalities. PMID- 26983629 TI - Interleukin-22 promotes lung cancer cell proliferation and migration via the IL 22R1/STAT3 and IL-22R1/AKT signaling pathways. AB - Lung cancer continues to be an enormous burden on current health care systems throughout the world, with more than a million deaths every year. Previous studies have shown that interleukin-22 (IL-22) promotes survival and resistance to chemotherapy in human lung cancer cells. However, the association of IL-22 expression with recurrence of lung cancer is still unclear. In this study, we found that expression of IL-22 was upregulated in tumor tissues and serum from patients with recurrent non-small cell lung cancer (NSCLC) as compared to primary NSCLC samples. Treatment with IL-22 promoted cell proliferation and enhanced migration and invasion in A549 and H125 cell lines. Furthermore, we revealed that phosphorylation of STAT3 and AKT was highly induced by treatment with IL-22 via IL-22R1. IL-22R1 was also consistently overexpressed in recurrent NSCLC tissues. Finally, we found that siRNA-mediated depletion of IL-22R1 completely abrogated the effects of IL-22 treatment on cell proliferation and migration activity in NSCLC cell lines. Our findings indicate that IL-22 and IL-22R1 may be novel therapeutic targets for treatment of advanced NSCLC. PMID- 26983628 TI - Targeting Homeostatic T Cell Proliferation to Control Beta-Cell Autoimmunity. AB - Immunomodulation of the autoreactive T cell response is considered a major strategy to control beta-cell autoimmunity, both in the natural history of type 1 diabetes and in islet transplantation, which can be affected by autoimmunity recurrence. So far, these strategies have had modest results, prompting efforts to define novel cellular and molecular targets to control autoreactive T cell expansion and activation. Novel findings highlighted the important role of the homeostatic cytokine interleukin-7 in inducing proliferation and differentiation of autoreactive T cell clones that causes beta-cell autoimmunity. In this review, we discuss recent evidences and novel findings on the role of IL-7 mediated homeostatic T cell proliferation in the process of beta-cell destruction and evidences of how targeting IL-7 and its receptor could be an innovative and effective strategy to control beta-cell autoimmunity. PMID- 26983631 TI - Laparoscopic Sleeve Gastrectomy and Gastric Bypass for The Aging Population. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are the two most common bariatric surgeries for treating morbid obesity. The purpose of this study is to determine differences in outcomes from RYGB or SG between patients ages >= 60 years and < 60 years. METHODS: A retrospective review of patients who underwent RYGB and SG at our institution from 01/2008 to 05/2012 was conducted. Forty patients from each group (>=60 years and < 60 years) were matched based on gender, body mass index (BMI), co-morbidities, and type of bariatric surgery performed, and their charts were reviewed up to 1 year post operatively. Primary end points measured were mean length of stay, operative time, incidence of complications, and readmissions in the first post-operative year. A secondary end point measured was percent total weight loss (%TWL) and excess weight loss (%EWL). RESULTS: There were no significant differences between group < 60 and group >= 60 in operative time (210 vs. 229 min; p = 0.177), in hospital post-operative complication rates (2.5 vs. 5 %; p = 1.0), long-term complication rates (2.5 vs. 10 %; p = 0.359), and 30-day readmission rates (2.5 vs. 12.5 %; p = 0.2). Patients in group < 60 had shorter lengths of stay (2.2 vs. 2.7 days; p = 0.031), but this difference is not clinically significant. Both groups achieved similar %TWL (21.4 vs. 20.5 %; p = 0.711) and %EWL (50.6 vs. 50.7 %; p = 0.986). CONCLUSIONS: Advanced age (>=60 years) is not a significant predictor of a worse outcome for SG and RYGB. PMID- 26983634 TI - Successful treatment of very late drug-eluting stent thrombosis using bare-metal stent evaluated using intravascular ultrasound and optical frequency domain imaging. AB - A 65-year-old man who underwent percutaneous coronary intervention with sirolimus eluting stents (SESs) 2 years ago was admitted with recurrent acute chest pain. Coronary angiography showed thrombotic occlusion within the SESs. After aspiration thrombectomy, multi-focal peri-stent contrast staining (PSS) was observed. Optical frequency domain imaging (OFDI) showed intracoronary thrombus, incomplete stent apposition (ISA), and multiple inter-strut hollows. Intravascular ultrasound (IVUS) images showed positive vessel remodeling. We deployed bare-metal stents in the SESs. Follow-up angiography showed no in-stent restenosis or PSS. OFDI showed well-covered stent surface with homogeneous neointima, without ISA. Additionally, IVUS images showed that the vessel remodeling had not worsened. PMID- 26983632 TI - Sex Effect on Obesity Indices and Metabolic Outcomes in Patients with Obese Obstructive Sleep Apnea and Type 2 Diabetes After Laparoscopic Roux-en-Y Gastric Bypass Surgery: a Preliminary Study. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is an effective therapy for obstructive sleep apnea (OSA). However, little attention has been paid to the treatment goals systematically stratified by sex. The objective of this study was to assess how sex differences affect obesity indices and metabolic outcomes after RYGB surgery. METHODS: A sleep questionnaire was conducted and medical histories were taken. Full-night polysomnography (PSG), anthropometric variables, and blood samples were collected. RESULTS: Thirty-five consecutive patients with OSA who underwent laparoscopic RYGB surgery were prospectively examined for at least 6 months were included in the study. Significant improvements (p < 0.01) in sleep parameters (except for micro-arousal), obesity indices, and metabolic outcomes [except low-density lipoprotein in men and high-density lipoprotein (HDL) in women] were obtained in men and women with OSA. Men had higher baseline triglyceride (TG) (p < 0.01) and lower HDL levels (p < 0.01) but a larger neck circumference (NC) (p = 0.03) at follow-up than did women. However, only TG in men improved more than in women (p = 0.02). CONCLUSIONS: Sleep parameters, obesity indices, and metabolic outcomes after RYGB surgery were of similar magnitude in women and men with OSA. Alleviating sleep and obesity problems was correlated with metabolic outcomes in men and women. PMID- 26983633 TI - Doctor, How Much Weight Will I Lose?-a New Individualized Predictive Model for Weight Loss. AB - Bariatric surgery is an effective treatment for weight loss, but the patient's ability to reach a sustained weight loss depends upon several technical and individual factors. Creating an easy model that adapts bariatric surgery's weight loss goals for each patient is very important for pre-surgery and follow-up evaluations. PMID- 26983635 TI - Angiotensin II increases gene expression after selective intra-arterial adenovirus delivery in a rabbit model assessed using in vivo SSTR2-based reporter imaging. AB - BACKGROUND: Gene therapy has been hampered by low expression upon in vivo delivery. Using a somatostatin receptor type 2 (SSTR2)-based reporter, we assessed whether angiotensin II (AII) can improve gene expression by adenovirus upon intra-arterial (IA) delivery in a large animal model. METHODS: A SSTR2-based reporter that can be imaged by a clinically approved radiopharmaceutical was used to assess gene expression. Eight rabbits bearing VX2 tumors in each thigh were randomly injected IA with adenovirus containing a human SSTR2 (Ad-CMV-HA-SSTR2) gene chimera +/- AII or control adenovirus containing green fluorescent protein (Ad-CMV-GFP). Three days later, (111)In-octreotide was given IV after computed tomography (CT) imaging using a clinical CT scanner and intravenous contrast. Tumor uptake of (111)In-octreotide was evaluated the next day using a clinical gamma camera. Gene expression was normalized to tumor weight and morphology from CT to obtain in vivo biodistribution. RESULTS: SSTR2-based expression was readily visualized. VX2 tumors infected with Ad-CMV-HA-SSTR2 upon intra-arterial delivery with AII had greater in vivo biodistribution, thus greater gene expression, than those without AII (p < 0.01, n = 6). VX2 tumors infected with Ad-CMV-HA-SSTR2 upon IA delivery had greater biodistribution, thus greater gene expression, than those with the negative control Ad-CMV-GFP (p < 0.02). Similarly, VX2 tumors infected with Ad-CMV-HA-SSTR2 upon IA delivery with AII had greater biodistribution, thus greater gene expression, than those with the negative control Ad-CMV-GFP (p < 0.01). CONCLUSIONS: Angiotensin II improves in vivo gene expression by adenovirus upon intra-arterial delivery and thus may improve gene therapy efficacy. In vivo SSTR2-based reporter imaging can be used to compare methodologies for improving gene expression. PMID- 26983636 TI - Engineering anti-Lewis-Y hu3S193 antibodies with improved therapeutic ratio for radioimmunotherapy of epithelial cancers. AB - BACKGROUND: The aim of the study was to explore Fc mutations of a humanised anti Lewis-Y antibody (IgG1) hu3S193 as a strategy to improve therapeutic ratios for therapeutic payload delivery. METHODS: Four hu3S193 variants (I253A, H310A, H435A and I253A/H310A) were generated via site-directed mutagenesis and radiolabelled with diagnostic isotopes iodine-125 or indium-111. Biodistribution studies in Lewis-Y-positive tumour-bearing mice were used to calculate the dose in tumours and organs for therapeutic isotopes (iodine-131, yttrium-90 and lutetium-177). RESULTS: (111)In-labelled I253A and H435A showed similar slow kinetics (t 1/2beta, 63.2 and 62.2 h, respectively) and a maximum tumour uptake of 33.11 +/- 4.05 and 33.69 +/- 3.77 percentage injected dose per gramme (%ID/g), respectively. (111)In-labelled I253A/H310A cleared fastest (t 1/2beta, 9.1 h) with the lowest maximum tumour uptake (23.72 +/- 0.85 %ID/g). The highest increase in tumour-to-blood area under the curve (AUC) ratio was observed with the metal-labelled mutants ((90)Y and (177)Lu). (177)Lu-CHX-A" DTPA-hu3S193 I253A/H310A (6:1) showed the highest tumour-to-blood AUC ratio compared to wild type (3:1) and other variants and doubling of calculated dose to tumour based on red marrow dose constraints. CONCLUSIONS: These results suggest that hu3S193 Fc can be engineered with improved therapeutic ratios for (90)Y- and (177)Lu-based therapy, with the best candidate being hu3S193 I253A/H310A for (177)Lu-based therapy. PMID- 26983637 TI - Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2. AB - BACKGROUND: Prostate cancer ranks as the second most lethal malignancy in the Western world. Previous targeting of prostate-specific antigen and human kallikrein-related peptidase 2, two related enzymes abundantly expressed in prostatic malignancies, with radioimmunoconjugates intended for diagnostic purposes, have proven successful in rodent prostate cancer (PCa) models. In this study, we investigated the uptake and therapeutic efficacy of (177)Lu-m11B6, a human kallikrein-related peptidase 2 (hK2)-targeting radioimmunoconjugate in a pre-clinical setting. METHODS: The murine 11B6 antibody, m11B6, with high affinity for hK2, was labeled with (177)Lu. Therapy planning was done from a biokinetic study in LNCaP xenografts, and therapeutic activities of (177)Lu-m11B6 were administered to groups of mice. Body weight and general conditions of the mice were followed over a period of 120 days. RESULTS: The tumor uptake in LNCaP xenografts was 30 +/- 8.2 % injected activity per gram 1 week post-injection. In vivo targeting was hK2-specific as verified by a 2.5-fold decrease in tumor uptake in pre-dosed xenografts or by a fourfold lower tumor accumulation in hK2 negative DU 145 xenografts. Therapy showed a dose-dependent efficacy in LNCaP xenografts treated with (177)Lu-m11B6. No therapeutic effect was seen in the control groups. The median survival for the lowest given activity of (177)Lu m11B6 was 88 days compared to that of 38 days in mice given labeled non-specific IgG. For the higher administrated activities, total tumor regression was seen with minimal normal organ toxicity. CONCLUSIONS: We have proven the possibility of radioimmunotherapy targeting hK2 in subcutaneous prostate cancer xenografts. (177)Lu-m11B6 exhibited high therapeutic efficacy, with low observed toxicity. Additionally, an evaluation of the concept of pre-therapy planning using a dosimetry model was included in this radioimmunotherapy study. PMID- 26983638 TI - Dynamic-Electromembrane Extraction: A Technical Development for the Extraction of Neuropeptides. AB - In this work, a dynamic-electromembrane extraction (d-EME) device was developed for the extraction of neuropeptides. On the basis of a thin polypropylene hollow fiber (50 MUm of wall-thickness and 280 MUm i.d.), this setup allowed for a continual renewal of the acceptor compartment. Because of the reduced size of the device, high preconcentration factors were obtained (up to 50-fold). The extraction remained constant regardless of the extraction time (from 15 to 45 min); accordingly, this new setup minimized the effect of electrolysis on extraction performance while enabling high extraction yield (up to 72%) for most lipophilic neuropeptides. PMID- 26983640 TI - Comparing survival curves based on medians. AB - BACKGROUND: Although some nonparametric methods have been proposed in the literature to test for the equality of median survival times for censored data in medical research, in general they have inflated type I error rates, which make their use limited in practice, especially when the sample sizes are small. METHODS: In this paper, we propose a new nonparametric test with a simple test statistic to compare median survival times. RESULTS: The results from our comprehensive simulation study show the new test controls type I error rate very well under all situations considered, even for small sample sizes. In addition, it has comparable detecting power compared to existing methods. Another advantage of the proposed test is its relatively simple formula that requires less computation. CONCLUSIONS: We propose a new statistical method for comparing survival curves based on their medians. The new method can be easily implemented and applied to censored event time data. PMID- 26983639 TI - Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34(+) cells of juvenile myelomonocytic leukemia. AB - BACKGROUND: Juvenile myelomonocytic leukemia (JMML) is a fatal, myelodysplastic/myeloproliferative neoplasm of early childhood. Patients with JMML have mutually exclusive genetic abnormalities in granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (GMR, CD116) signaling pathway. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option for JMML; however, disease recurrence is a major cause of treatment failure. We investigated adoptive immunotherapy using GMR-targeted chimeric antigen receptor (CAR) for JMML. METHODS: We constructed a novel CAR capable of binding to GMR via its ligand, GM-CSF, and generated piggyBac transposon-based GMR CAR-modified T cells from three healthy donors and two patients with JMML. We further evaluated the anti-proliferative potential of GMR CAR T cells on leukemic CD34(+) cells from six patients with JMML (two NRAS mutations, three PTPN11 mutations, and one monosomy 7), and normal CD34(+) cells. RESULTS: GMR CAR T cells from healthy donors suppressed the cytokine-dependent growth of MO7e cells, but not the growth of K562 and Daudi cells. Co-culture of healthy GMR CAR T cells with CD34(+) cells of five patients with JMML at effector to target ratios of 1:1 and 1:4 for 2 days significantly decreased total colony growth, regardless of genetic abnormality. Furthermore, GMR CAR T cells from a non-transplanted patient and a transplanted patient inhibited the proliferation of respective JMML CD34(+) cells at onset to a degree comparable to healthy GMR CAR T cells. Seven-day co-culture of GMR CAR T cells resulted in a marked suppression of JMML CD34(+) cell proliferation, particularly CD34(+)CD38(-) cell proliferation stimulated with stem cell factor and thrombopoietin on AGM-S3 cells. Meanwhile, GMR CAR T cells exerted no effects on normal CD34(+) cell colony growth. CONCLUSIONS: Ligand-based GMR CAR T cells may have anti proliferative effects on stem and progenitor cells in JMML. PMID- 26983641 TI - Subarachnoid haemorrhage (spontaneous aneurysmal). AB - INTRODUCTION: Subarachnoid haemorrhage (SAH) may arise spontaneously or as a result of trauma. Spontaneous SAH accounts for about 5% of all strokes. Ruptured aneurysms are the cause of 85% of spontaneous SAH. The most characteristic clinical feature is sudden-onset severe headache. Other features include vomiting, photophobia, and focal neurological deficit or seizures, or both. As the headache may have insidious onset in some cases, or may even be absent, a high degree of suspicion is required to diagnose SAH with less typical presentations. METHODS AND OUTCOMES: We conducted a systematic review, aiming to answer the following clinical question: What are the effects of surgical treatments for people with confirmed aSAH? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). RESULTS: At this update, searching of electronic databases retrieved 82 studies. After deduplication and removal of conference abstracts, 47 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 33 studies and the further review of 14 full publications. Of the 14 full articles evaluated, one systematic review, one RCT, and four further reports were added at this update. We performed a GRADE evaluation for six PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for one comparison based on information about the effectiveness and safety of endovascular coiling versus surgical clipping. PMID- 26983642 TI - Oral PSORI-CM01, a Chinese herbal formula, plus topical sequential therapy for moderate-to-severe psoriasis vulgaris: pilot study for a double-blind, randomized, placebo-controlled trial. AB - BACKGROUND: To provide evidence that the Chinese herbal medicine (CHM) PSORI-CM01 combined with Western medicine reduces the relapse rate of psoriasis vulgaris (PV), we plan to conduct a large-scale randomized control trial (RCT). In order to improve and perfect the RCT, this pilot study was designed to determine the feasibility and the potential of a modified protocol for the full-scale RCT. METHODS: Eligible patients with psoriasis vulgaris (PV) were enrolled into a randomized comparison in which all subjects received topical sequential therapy and PSORI-CM01 or placebo for 12 weeks. The primary outcome measure was the relapse rate. Treatment response was computed from Psoriasis Area and Severity Index (PASI), body surface area (BSA), and Dermatology Life Quality Index (DLQI). The secondary outcome measures included time to relapse, time to onset, rebound rate, PASI score, pruritus scores on the Visual Analog Scale (VAS), BSA, DLQI and SF-36 (short form health survey), and incidence of serious adverse events (SAEs). RESULTS: Six of 7 (86 %) subjects reached the PASI-50 in the CHM group compared with nine of 10 (90 %) in the placebo group during the treatment period. Among the subjects who reached PASI-50, one out of six subjects (17 %) relapsed in the CHM group during the treatment period compared with six out of nine patients in the placebo group (67 %). No subjects met the rebound criteria. Changes to baseline in the PASI scores were not significantly different between the two groups (t = 1.764, P = 0.098). CONCLUSION: Oral PSORI-CM01 combined with topical sequential treatment showed a smaller recurrence rate (P = 0.118) than placebo combined with the same topical therapy for moderate-to-severe PV in this pilot study. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( http://www.chictr.org.cn/searchproj.aspx ) ChiCTR-TRC-13003233 ; date of registration: 15 April 2013. PMID- 26983643 TI - Automation of cellular therapy product manufacturing: results of a split validation comparing CD34 selection of peripheral blood stem cell apheresis product with a semi-manual vs. an automatic procedure. AB - BACKGROUND: Automation of cell therapy manufacturing promises higher productivity of cell factories, more economical use of highly-trained (and costly) manufacturing staff, facilitation of processes requiring manufacturing steps at inconvenient hours, improved consistency of processing steps and other benefits. One of the most broadly disseminated engineered cell therapy products is immunomagnetically selected CD34+ hematopoietic "stem" cells (HSCs). METHODS: As the clinical GMP-compliant automat CliniMACS Prodigy is being programmed to perform ever more complex sequential manufacturing steps, we developed a CD34+ selection module for comparison with the standard semi-automatic CD34 "normal scale" selection process on CliniMACS Plus, applicable for 600 * 10(6) target cells out of 60 * 10(9) total cells. Three split-validation processings with healthy donor G-CSF-mobilized apheresis products were performed; feasibility, time consumption and product quality were assessed. RESULTS: All processes proceeded uneventfully. Prodigy runs took about 1 h longer than CliniMACS Plus runs, albeit with markedly less hands-on operator time and therefore also suitable for less experienced operators. Recovery of target cells was the same for both technologies. Although impurities, specifically T- and B-cells, were 5 +/- 1.6-fold and 4 +/- 0.4-fold higher in the Prodigy products (p = ns and p = 0.013 for T and B cell depletion, respectively), T cell contents per kg of a virtual recipient receiving 4 * 10(6) CD34+ cells/kg was below 10 * 10(3)/kg even in the worst Prodigy product and thus more than fivefold below the specification of CD34+ selected mismatched-donor stem cell products. The products' theoretical clinical usability is thus confirmed. CONCLUSIONS: This split validation exercise of a relatively short and simple process exemplifies the potential of automatic cell manufacturing. Automation will further gain in attractiveness when applied to more complex processes, requiring frequent interventions or handling at unfavourable working hours, such as re-targeting of T-cells. PMID- 26983645 TI - Anti-diabetic effect of 3-hydroxy-2-naphthoic acid, an endoplasmic reticulum stress-reducing chemical chaperone. AB - Lots of experimental and clinical evidences indicate that chronic exposure to saturated fatty acids and high level of glucose is implicated in insulin resistance, beta cell failure and ultimately type 2 diabetes. In this study, we set up cell-based experimental conditions to induce endoplasmic reticulum (ER) stress and insulin resistance using high concentration of palmitate (PA). Hydroxynaphthoic acids (HNAs) were formerly identified as novel chemical chaperones to resolve ER stress induced by tunicamycin. In this study, we found the compounds have the same suppressive effect on PA-induced ER stress in HepG2 cells. The representing compound, 3-HNA reduced PA-induced phosphorylation of JNK, IKKbeta and IRS1 (S307) and restored insulin signaling cascade which involves insulin receptor beta, IRS1 and Akt. The insulin sensitizing effect of 3 HNA was confirmed in 3T3-L1 adipocytes, where the compound augmented insulin signaling and glucose transporter 4 (GLUT4) membrane translocation. 3-HNA also protected the pancreatic beta cells from PA-induced apoptosis by reducing ER stress. Upon 3-HNA treatment to ob/ob mice at 150mg/kg/day dosage, the diabetic parameters including glucose tolerance and systemic insulin sensitivity were significantly improved. Postmortem examination showed that 3-HNA markedly reduced ER stress and insulin resistance in the liver tissues and it sensitized insulin signaling in the liver and the skeletal muscle. Our results demonstrated that 3 HNA can sensitize insulin signaling by coping with lipotoxicity-induced ER stress as a chemical chaperone and suggested it holds therapeutic potential for insulin resistance and type 2 diabetes. PMID- 26983644 TI - Association of glucose homeostasis measures with heart rate variability among Hispanic/Latino adults without diabetes: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). AB - BACKGROUND: Reduced heart rate variability (HRV), a measure of cardiac autonomic function, is associated with an increased risk of cardiovascular disease (CVD) and mortality. Glucose homeostasis measures are associated with reduced cardiac autonomic function among those with diabetes, but inconsistent associations have been reported among those without diabetes. This study aimed to examine the association of glucose homeostasis measures with cardiac autonomic function among diverse Hispanic/Latino adults without diabetes. METHODS: The Hispanic community Health Study/Study of Latinos (HCHS/SOL; 2008-2011) used two-stage area probability sampling of households to enroll 16,415 self-identified Hispanics/Latinos aged 18-74 years from four USA communities. Resting, standard 12-lead electrocardiogram recordings were used to estimate the following ultrashort-term measures of HRV: RR interval (RR), standard deviation of all normal to normal RR (SDNN) and root mean square of successive differences in RR intervals (RMSSD). Multivariable regression analysis was used to estimate associations between glucose homeostasis measures with HRV using data from 11,994 adults without diabetes (mean age 39 years; 52 % women). RESULTS: Higher fasting glucose was associated with lower RR, SDNN, and RMSSD. Fasting insulin and the homeostasis model assessment of insulin resistance was negatively associated with RR, SDNN, and RMSSD, and the association was stronger among men compared with women. RMSSD was, on average, 26 % lower in men with higher fasting insulin and 29 % lower in men with lower insulin resistance; for women, the corresponding estimates were smaller at 4 and 9 %, respectively. Higher glycated hemoglobin was associated with lower RR, SDNN, and RMSSD in those with abdominal adiposity, defined by sex-specific cut-points for waist circumference, after adjusting for demographics and medication use. There were no associations between glycated hemoglobin and HRV measures among those without abdominal adiposity. CONCLUSIONS: Impairment in glucose homeostasis was associated with lower HRV in Hispanic/Latino adults without diabetes, most prominently in men and individuals with abdominal adiposity. These results suggest that reduced cardiac autonomic function is associated with metabolic impairments before onset of overt diabetes in certain subgroups, offering clues for the pathophysiologic processes involved as well as opportunity for identification of those at high risk before autonomic control is manifestly impaired. PMID- 26983646 TI - Analyses of methyltransferases across the pathogenicity spectrum of different mycobacterial species point to an extremophile connection. AB - Tuberculosis is a devastating disease, taking one human life every 20 seconds globally. We hypothesize that professional pathogens such as M.tb have acquired specific features that might assist in causing infection, persistence and transmissible pathology in their host. We have identified 121 methyltransferases (MTases) in the M.tb proteome, which use a variety of substrates - DNA, RNA, protein, intermediates of mycolic acid biosynthesis and other fatty acids - that are involved in cellular maintenance within the host. A comparative analysis of the proteome of the virulent strain H37Rv and the avirulent strain H37Ra identified 3 MTases, which displayed significant variations in terms of N terminal extension/deletion and point mutations, possibly impacting various physicochemical properties. The cross-proteomic comparison of MTases of M.tb H37Rv with 15 different Mycobacterium species revealed the acquisition of novel MTases in a MTB complex as a function of evolution. Phylogenetic analysis revealed that these newly acquired MTases showed common roots with certain extremophiles such as halophilic and acidophilic organisms. Our results establish an evolutionary relationship of M.tb with halotolerant organisms and also the role of MTases of M.tb in withstanding the host osmotic stress, thereby pointing to their likely role in pathogenesis, virulence and niche adaptation. PMID- 26983648 TI - Paramagnetic dioxovanadium(IV) molecules inside the channels of zeolite BEA--EPR screening of VO2 reactivity toward small gas-phase molecules. AB - Interaction of small gas-phase molecules (NO, N2O, O2, CO) with VO2 radicals inside the channels of a dealuminated SiBEA zeolite was investigated by means of electron paramagnetic resonance (EPR), infrared (IR), and mass (QMS) spectroscopies to provide direct insights into the chemistry of a unique paramagnetic state of vanadium - VO2 molecules. A facile way of forming VO2 inside the channels of SiBEA via thermal reduction of VO2(+) precursor cations was shown. Dioxovanadium(IV) was identified based on its unusual EPR signal which, as compared with the typical monooxovanadium(IV) (VO(2+) cation), is featured by rhombic symmetry and a positive Aiso value leading to a hyperfine splitting as large as 32 mT. VO2 molecules exhibit reducing properties transforming N2O and O2 into vanadium intrachannel cage adducts comprising of reactive oxygen species (O(-) and O2(-), respectively). Interaction with CO led to its oxidation to CO2, while paramagnetic NO acted as a scavenger for VO2 radicals producing diamagnetic adducts. The observed reactivity was rationalized in terms of spin-pairing, electron transfer, and oxygen transfer processes. As a result new chemical pathways of vanadium reactivity were demonstrated which were not observed so far either in the homogeneous molecular systems or supported vanadium materials. PMID- 26983647 TI - Safety of Intra-arterial Catheter Directed Thrombolysis: Does Level of Care Matter? AB - OBJECTIVES: The aim was to assess whether the level of care influenced the safety related outcomes of catheter directed thrombolysis (CDT) for patients presenting with limb ischaemia and dialysis access thrombosis. METHODS: This was a retrospective cohort study. All consecutive patients at two tertiary referral centres for vascular surgery undergoing CDT for limb ischaemia and dialysis access thrombosis (N = 252) between 2012 and 2014 were included. Patients at Centre 1 were cared for on a general vascular ward and patients at Centre 2 were kept on a post-operative recovery unit with an increased level of care including invasive haemodynamic monitoring. Patient medical records were retrospectively scrutinised and data collected on comorbidities, anti-thrombotic medication, indications for CDT, technical success of CDT, bleeding and non-bleeding related complications, and transfer to a higher level of care. RESULTS: There were no differences in the frequency of non-bleeding related complications between Centre 1 and Centre 2. Patients on the vascular ward had a higher frequency of minor bleeding (p = .002) but there was no difference in major bleeding (p = .12). Eleven patients on the ward required an increased level of care for medical reasons and six were moved for a lack of resources. The presence of cardiac disease was an independent risk factor for patient transfer (OR 3.2; 95% CI 1.04 9.8, p = .04). CONCLUSIONS: CDT may be undertaken outside of a high dependency setting without a significantly increased risk of complications. Pre-existing cardiac disease was an independent risk factor for transfer to a higher level of care. These findings could have an implication for the clinical cost effectiveness of CDT. PMID- 26983649 TI - Long-term follow-up of patients with prior polio over a 17-year period. AB - OBJECTIVE: Follow-up of the health of patients with prior polio over a 17-year period. DESIGN: Follow-up study. PATIENTS: Patients with prior polio. METHODS: The study questionnaire was answered in 1995 by 270 patients. In 2012 the questionnaire was sent again to the surviving patients. RESULTS: Of the patients who answered the questionnaire in 1995, 116 (40%) were still alive in 2012. The group of patients who had died was older, and had a mean age of 70 years in 1995. A total of 60 patients participated in the study by answering the questionnaire in both 1995 and 2012. Most of these patients (84%) reported that they felt progressively worse, with poor mobility and increased muscle weakness in 2012 compared with 1995, and more than half reported a lower quality of life in 2012. The number of wheelchair users had increased significantly. Furthermore, the patients experienced increasing problems with activities of daily living (ADL) function. CONCLUSION: More than half of the patients with prior polio had died between 1995 and 2012. These patients were, on average, older than patients surviving in 2012. When interviewed in 2012 most of the patients felt progressively worse, with poor mobility and increased muscle weakness. PMID- 26983650 TI - Application of anatomically accurate, patient-specific 3D printed models from MRI data in urological oncology. PMID- 26983651 TI - Virtual Special Issue Radiation dose reduction in CT: dose optimisation gains both increasing importance and complexity! PMID- 26983652 TI - Prenatal maternal mental health and fetal growth restriction: a systematic review. AB - Maternal mental disorders during pregnancy are associated with a range of adverse health outcomes for offspring. This systematic review examines studies reporting on the relationship between maternal depression, anxiety or stress during pregnancy and fetal growth measured during pregnancy using ultrasound biometry. A systematic search of PsycINFO, Medline, Scopus, Web of Science and Embase was conducted and 1575 records were identified, with nine studies meeting inclusion criteria gathering data from over 7000 participants. All studies measured depression, six examined anxiety and depression, and five examined all three exposures. The majority measured symptoms rather than clinically diagnosable disorder. Studies consistently reported significant associations between maternal mental health, particularly anxiety symptoms, and reduced fetal head growth. Other fetal growth parameters showed inconsistent findings. A number of studies suggest that cortisol dysregulation associated with maternal mental health may play a role in fetal growth restriction. However, heterogeneity in the timing of growth measurement, assessment measures used for mental health and inconsistencies in adjustment for confounders, limits the synthesis and interpretation of findings. Future studies should consider differences in the timing, intensity and duration of mental health symptoms over pregnancy and should employ diagnostic assessment of mental disorders. Fetal growth should be repeatedly measured and further work is needed to establish the biological mechanisms involved. PMID- 26983653 TI - Association between -174 G/C polymorphism of interleukin-6 gene and alcoholism. AB - OBJECTIVES: IL-6 plays the role as a physiological neuromodulator involved in dopaminergic, serotonergic and other neurotransmissions. The aim of the present association study was to examine the effect of the G/C -174 polymorphism of the IL-6 gene on disposition to alcoholism. METHODS: We investigated the relationship between the G/C -174 polymorphism of the IL-6 gene and alcohol dependence in 281 alcoholics and 242 control subjects. RESULTS: The significant difference in G allele frequency between alcoholic group (0.52) and control group (0.59) was found (P < 0.03). CONCLUSION: To our knowledge, this is the first finding providing evidence for an association between alcoholism and the polymorphism of the IL-6 gene. The background of the relationship between the IL-6 gene and alcoholism is discussed. PMID- 26983654 TI - Borna disease virus and deficit schizophrenia. AB - BACKGROUND: It is controversial whether Borna disease virus (BDV) infects humans and causes psychiatric disorders. OBJECTIVES: The relationship between BDV infection and schizophrenia with deficit syndrome was investigated. STUDY DESIGN: Using the Schedule for the Deficit Syndrome, 62 schizophrenic in-patients were selected from three psychiatric hospitals. RNA was extracted from peripheral blood mononuclear cells and analyzed using nested reverse transcriptase polymerase chain reaction with primers to detect BDV p24 and p40. RESULTS AND CONCLUSIONS: BDV transcripts were not detected in samples from any of the 62 schizophrenic patients. These data do not support an etiologic association between BDV infection and the deficit form of schizophrenia. PMID- 26983655 TI - Isoprenoid pathway dysfunction in chronic fatigue syndrome. AB - BACKGROUND AND AIMS: The isoprenoid pathway was assessed in 15 patients with chronic fatigue syndrome (CFS). The pathway was also assessed in individuals with differing hemispheric dominance to assess whether hemispheric dominance has any correlation with these disease states. METHODS: The isoprenoid metabolites - digoxin, dolichol and ubiquinone - RBC membrane Na+-K+ ATPase activity, serum magnesium and tyrosine/tryptophan catabolic patterns were assessed. The free radical metabolism, glycoconjugate metabolism and RBC membrane composition were also assessed. RESULTS: Membrane Na+-K+ ATPase activity and serum magnesium levels were decreased while HMG-CoA reductase activity and serum digoxin levels were increased in CFS. There were increased levels of tryptophan catabolites - nicotine, strychnine, quinolinic acid and serotonin - and decreased levels of tyrosine catabolites -dopamine, norepinephrine and morphine - in CFS. There was an increase in dolichol levels, carbohydrate residues of glycoproteins, glycolipids, total/individual glycosaminoglycans (GAG) fractions and lysosomal enzymes in CFS. Reduced levels of ubiquinone, reduced glutathione and free radical scavenging enzymes as well as increased lipid peroxidation products and nitric oxide were noticed in CFS. The biochemical patterns in CFS correlated with those obtained in right hemispheric dominance. CONCLUSIONS: The role of hypothalamic digoxin and neurotransmitter-induced immune activation, altered glycoconjugate metabolism and resultant defective viral antigen presentation, NMDA excitotoxicity and cognitive and mitochondrial dysfunction in the pathogenesis of CFS is stressed. CFS occurs in individuals with right hemispheric dominance. PMID- 26983656 TI - The spectrum of subjective effects of antipsychotic medication. AB - BACKGROUND: This study examined the spectrum of subjective experiences which patients attribute to the use of antipsychotic medication. METHODS: We collected interview data and answers to structured questions based on a comprehensive checklist in 77 patients using various types of classical or atypical antipsychotic drugs. RESULTS: The responses of the patients could be categorized into psychological and somatic domains. The psychological domain could be subdivided into emotional, cognitive and sociability domains. The somatic set could be subdivided into activation and physiological domains. CONCLUSIONS: Our data reveal that the same effects may be experienced in either a positive or a negative way by different patients. We conclude that existing scales for measuring subjective effects of antipsychotic medication are incomplete. PMID- 26983657 TI - Disturbed cognitive functioning and clinical symptoms: two independent problem areas in schizophrenia. AB - BACKGROUND: Research findings on the relationship between cognitive functioning and psychiatric symptoms in schizophrenia have yielded inconsistent results. Although several models were postulated linking cognition and symptoms, the most recent studies point in the direction of cognition and symptoms being relatively independent disease processes. OBJECTIVE: The hypothesis that cognitive decline and psychiatric symptoms are independent disease processes was tested. METHODS: The relationship between cognitive functioning and clinical symptoms was examined in a large sample of 100 schizophrenia patients. RESULTS: The hypothesis was largely confirmed. CONCLUSION: No convincing evidence was found that symptoms and cognition were related. PMID- 26983658 TI - An investigation of criteria used to indicate cranial CT in males with schizophrenia. AB - BACKGROUND: With the increased accessibility of the CT scanner, psychiatrists managing schizophrenia and first-episode psychosis have incorporated this imaging technique into their diagnostic work-up. This practice has been reinforced by published criteria for CT scanning in psychiatric patients suggesting that cranial CT should be used as a screening tool to exclude intracranial pathology in all patients with a first presentation of schizophrenia or first psychotic episode. OBJECTIVES: This study reviews the performance of these criteria. METHOD: This consisted of a 3-year retrospective case-note audit, using published criteria, of all male in-patients with an established diagnosis of schizophrenia who had a cranial CT during the review period. RESULTS: The efficacy of the published criteria is not supported. In addition, non-specific abnormalities on cranial CT are related to duration of illness and not age in this sample. CONCLUSIONS: There is a need to establish new and clinically meaningful approaches for the use of cranial CT and similar technologies in clinical psychiatry. Cranial CT performs poorly as a universal screening tool in this population. The decision to use such imaging techniques should be made on a case by-case basis using all available clinical evidence. PMID- 26983659 TI - The prevalence of Capgras syndrome in a university hospital setting. AB - BACKGROUND: Capgras syndrome (CS), the most common type of delusional misidentification syndrome, is the delusional belief that significant people in the patient's life have been replaced by identical doubles. Capgras syndrome is thought to be a rare syndrome which commonly occurs in a psychotic context. OBJECTIVE: The objective of this study was to estimate the 5-year prevalence rate of CS in a university hospital in-patient setting and determine associated etiological and sociodemographic factors. METHODS: All patient files and medical records were reviewed in detail for the presence of Capgras syndrome. The sociodemographic variables, clinical manifestations, and psychiatric and medical diagnoses of patients who fulfilled clinical criteria for Capgras syndrome were recorded for statistical evaluation. RESULTS: The retrospective evaluation of patient files in 920 cases admitted to our psychiatric in-patient unit over 5 years revealed that 12 patients fulfilled the criteria for Capgras syndrome. The crude prevalence of Capgras syndrome in this population during 5-year period was 1.3% (1.8% for females, 0.9% for males). Schizophrenia (50%) was the most common psychiatric diagnosis in these patients. Only two patients presented with an organic etiology underlying Capgras syndrome. CONCLUSIONS: The results of this study indicate that Capgras syndrome is not a rare syndrome, and commonly occurs during the course of either functional or organic psychotic illness. Age seems to be an important predicting factor for the etiology of psychosis underlying Capgras syndrome. PMID- 26983660 TI - Recognition memory abnormalities in asymptomatic biological parents of a patient with schizophrenia. AB - BACKGROUND: Recognition memory dysfunction has been frequently reported in schizophrenic populations, and has been linked with the development of delusions and thought disorder. A range of neuropsychological abnormalities have also been documented in the biological asymptomatic relatives of patients with schizophrenia; however, recognition memory has not been one of them. AIM: This study was carried out in order to investigate: (i) verbal and facial recognition memory in terms of accuracy and false alarm rates; and (ii) contributions from the episodic and semantic memory systems to recognition memory, in the biological asymptomatic parents of a reported schizophrenic patient and a set of male and female psychotic controls. RESULTS: Gender differences failed to emerge between the psychotic controls on any of the recognition measures (discrimination accuracy, response bias, hit and false alarm rates, 'remember' and 'know' recognition memory decisions). However, there was evidence of recognition dysfunction in the female relative, and to a lesser extent, in the male. Both parent's recognition memory performance profiles were marked by a pathologically elevated false alarm rate, and an increased dependence 'remember' judgements, i.e. input from the episodic memory system, to drive recognition memory decisions. CONCLUSIONS: These findings are discussed in the context of models of episodic and semantic memory impairment in schizophrenia. PMID- 26983661 TI - Association of schizophrenia and Carpenter syndrome. PMID- 26983663 TI - CXCR1 promotes malignant behavior of gastric cancer cells in vitro and in vivo in AKT and ERK1/2 phosphorylation. AB - CXCR1 is a member of the chemokine receptor family, which was reported to play an important role in several cancers. The present study investigated the influence of CXCR1 stable knockdown or overexpression on the malignant behavior of gastric cancer cells in vitro and in vivo and the potential mechanisms. MKN45 and BGC823 cells were stably transfected with plasmid pYr-1.1-CXCR1-shRNA (knockdown) and pIRES2-ZsGreen1-CXCR1 (overexpression), respectively. Malignant behavior was evaluated in vitro for changes in proliferation by MTT and colony forming assays; cell cycle and apoptosis by flow cytometry; and migration and invasion using transwell and wound-healing assays. Proliferation, cell cycle, apoptosis, migration and invasion-related signaling molecule expression were measured by real-time RT-PCR and western blot analysis. CXCR1 knockdown and overexpressing xenografts were monitored for in vivo tumor growth. Stable knockdown of CXCR1 inhibited MKN45 cell proliferation, migration and invasion, but were reversed in BGC823 cells stably overexpressing CXCR1. In addition, MKN45 cells stably transfected with CXCR1 shRNA inhibited AKT and ERK1/2 phosphorylation, protein expression of cyclin D1, EGFR, VEGF, MMP-9, MMP-2 and Bcl-2, and increased protein expression of Bax and E-cadherin (all P<0.05). In vivo CXCR1-shRNA-MKN45 cells transplanted into nude mice formed smaller tumors than non-transfected or scrambled-shRNA cells (both P<0.05). In contrast BGC823 cells overexpressing CXCR1 formed larger tumors in mice than cells carrying an empty expression plasmid or non-transfected cells (both P<0.05). CXCR1 promoted gastric cancer cell proliferation, migration and invasion. The present study provides preclinical data to support CXCR1 as a novel therapeutic target for gastric cancer. PMID- 26983664 TI - Factors Affecting Long-Term Results of Above-Knee Femoropopliteal Bypass: A Single-Center Contemporary Study. AB - INTRODUCTION: The aim of this study was to assess whether individual patients' or bypass characteristics may influence long-term results of prosthetic above-knee femoropopliteal bypasses in patients with claudication in today's endovascular era. METHODS: Seventy-one consecutivee Expanded Polytetrafluoroethylene (e-PTFE) bypasses were considered. All patients presented a debilitating claudication. Patency of grafts was achieved by Kaplan-Meier method. The association between individual patients' or graft characteristics and primary patency (PP) or secondary patency (SP) was assessed via Cox regression models. RESULTS: An immediate technical success was achieved in all cases. No patient was lost during follow-up (8-90 months, median = 34 months). The median PP was 48 months. Occlusion occurred in 32 bypasses (45%). Eight (25%) of these were treated conservatively. Fifty-two bypasses (73%) were still patent at the end of follow up, and 13 (25%) of these had been submitted to one or more surgical revisions. There were 2 graft infections. Of 17 (25%) patients with occluded graft at the end of follow-up, 2 (2.8%) had significant aggravation followed by limb loss. The PP was directly influenced by undetected minor distal anastomosis technical defects (hazard ratio [HR] = 5.89, P value = .000002), popliteal artery size (HR = 0.62, P value = 0.007), and distal anastomosis angle >=40 degrees (HR = 5.55, P value = .003). The SP was associated strictly to technical defects (HR = 11.08, P value = .000007). Multivariable analyses confirmed the influence of technical defects (HR = 6.42, P value = .000003) and anastomosis angle (HR = 1.05, P value = .009) on PP and that of technical defects on SP (HR = 10.84, P value = .00003). A significantly shorter SP was also observed after a previous failed endovascular treatment on the superficial femoral artery (HR = 3.73, P value = .02). CONCLUSION: An adequate arterial size, an ideal anastomotic angle, and the absence of minor, technical defects have a major role in prosthetic above-knee femoropopliteal bypass long-term outcome. A previous, failed endovascular procedure on the superficial femoral artery could markedly alter the natural history of patients with claudication because this approach seems to have a detrimental effect on long-term outcome of grafts needing surgical revisions. PMID- 26983665 TI - Retrievable Stent-Assisted Coiling Technique Using a Solitaire Stent: Treatment of Pancreaticoduodenal Artery Aneurysm Associated With Celiac Artery Occlusion. AB - True aneurysm of pancreaticoduodenal arcade (PDA) is usually accompanied by stenosis or occlusion of celiac trunk (CeT). The up-to-date and first choice treatment modality of PDA aneurysm is the endovascular approach in nearly all cases except few selected ones necessitating surgery. The main approach in endovascular treatment is embolization of the aneurysm by preserving the parent artery. A case with concomitant CeT occlusion and PDA aneurysm was treated with coil embolization by preserving inferior pancreaticoduodenal artery with retrievable Solitaire((r)) stent. In our knowledge, this is the first case with PDA aneurysm treated with this technique. PMID- 26983666 TI - Superior Mesenteric Artery Aneurysm Caused by Aortic Valve Endocarditis: The Case Report and Review of the Literature. AB - Infectious aneurysms of the superior mesenteric artery are a rare but life threatening condition due to the risk of visceral ischemia, sepsis, or hemorrhage. In this study, we report the case of a superior mesenteric artery aneurysm (SMAA) secondary to a bioprosthetic valve endocarditis, successfully managed with aneurysm resection and saphenous vein interposition graft. We performed an extensive PubMed-based rewiew of the literature of the last 10 years on SMAA, which include the detection of 38 articles quoting 41 SMAAs. The case histories were divided in 2 groups: 18 cases belonged to nonmycotic group A and 23 cases were included in mycotic group B. In group A, 44.4% of patients were treated surgically, whereas in group B, 90.5%. The 2 study groups significantly differed (P = .01) in terms of surgical treatment. The surgical approach still remains the first choice of treatment in mycotic aneurysm. PMID- 26983668 TI - Dyslipidemia Part 2: Review of Dyslipidemia Treatment in Patients With Noncoronary Vascular Disease. AB - Dyslipidemia is one of the major modifiable risk factors associated with atherosclerotic cardiovascular disease. Appropriate modification of lipid profiles reduces the progression of atherosclerosis in vessel walls across all vascular beds. The management of dyslipidemia has evolved over the last several decades, especially since the discovery of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, also known as statins. Statin use in atherosclerotic heart disease is well described in observational and prospective placebo-controlled studies, citing both lipid-lowering and pleiotropic effects. However, the effect of statins and other lipid-lowering agents on noncoronary arterial beds (the aorta, arteries to the extremities, renal, and carotid arteries) is less understood. This article is part 2 of a 2-part review, with part 1 having focused on lipid metabolism and the downstream effects of lipids on the development of atherosclerosis. The current review (part 2) will discuss trials, retrospective reviews, and observational cohort studies regarding the use of statins and/or other lipid-lowering drugs for primary and secondary prevention of peripheral noncoronary atherosclerotic disease. PMID- 26983667 TI - Dyslipidemia Part 1--Review of Lipid Metabolism and Vascular Cell Physiology. AB - Dyslipidemia, more specifically, high-serum low-density lipoproteins and low serum high-density lipoproteins, are known risk factors for cardiovascular disease. The current clinical treatment of dyslipidemia represents the outcome of a large body of fundamental basic science research on lipids, lipid metabolism, and the effects of different lipids on cellular components of the artery, inflammatory cells, and platelets. In general, lower density lipids activate intracellular pathways to increase local and systemic inflammation, monocyte adhesion, endothelial cell dysfunction and apoptosis, and smooth muscle cell proliferation, resulting in foam cell formation and genesis of atherosclerotic plaque. In contrast, higher density lipids prevent or attenuate atherosclerosis. This article is part 1 of a 2-part review, with part 1 focusing on lipid metabolism and the downstream effects of lipids on the development of atherosclerosis, and part 2 on the clinical treatment of dyslipidemia and the role of these drugs for patients with arterial disease exclusive of the coronary arteries. PMID- 26983669 TI - Sinomenine prevents metastasis of human osteosarcoma cells via S phase arrest and suppression of tumor-related neovascularization and osteolysis through the CXCR4 STAT3 pathway. AB - Osteosarcoma is the most common primary malignant tumor of the bone. The long term survivals continue to be unsatisfactory for patients with metastatic and recurrent disease. Metastasis is still a severe challenge in osteosarcoma treatment. Sinomenine, an alkaloid from traditional Chinese medicine, has been proved to possess potent antitumor and anti-invasion effect on various cancers. However, the effect of sinomenine on human osteosarcoma and the underlying mechanisms remains unknown. We report here that sinomenine inhibited proliferation by inducing S phase arrest and suppressing the clone formation. Significant inhibitory effects were found in invasion and metastasis in osteosarcoma, but little cytotoxicity was observed in tested concentrations. Exposure to sinomenine resulted in suppression of invasion and migration in osteosarcoma cells as well as tube formation ability in the human umbilical vein endothelial cells (HUVEC) and U2OS cells. Furthermore, it demonstrated that CXCR4 played a key role contributing to invasion in osteosarcoma which is considered to be a core target site in sinomenine treatment. Sinomenine inhibited invasion by suppressing CXCR4 and STAT3 phosphorylation then downregulating the expression of MMP-2, MMP-9, RANKL, VEGF downstream. In addition, then RANKL-mediated bone destruction stimulated by osteoclastogenesis and VEGF-related neovascularization were restrained. Importantly, in vivo, sinomenine suppressed proliferation, osteoclastogenesis and bone destruction. Through these various comprehensive means, sinomenine inhibits metastasis in osteosarcoma. Taken together, our results revealed that sinomenine caused S phase arrest, inhibited invasion and metastasis via suppressing the CXCR4-STAT3 pathway and then osteoclastogenesis mediated bone destruction and neovascularization in osteosarcoma. Sinomenine is therefore a promising adjuvant agent for metastasis control in osteosarcoma. PMID- 26983671 TI - A New Era of Pulmonary Delivery of Nano-antimicrobial Therapeutics to Treat Chronic Pulmonary Infections. AB - Pulmonary infections may be fatal especially in immunocompromised patients and patients with underlying pulmonary dysfunction, such as those with cystic fibrosis, chronic obstructive pulmonary disorder, etc. According to the WHO, lower respiratory tract infections ranked first amongst the leading causes of death in 2012, and tuberculosis was included in the top 10 causes of death in low income countries, placing a considerable strain on their economies and healthcare systems. Eradication of lower respiratory infections is arduous, leading to high healthcare costs and requiring higher doses of antibiotics to reach optimal concentrations at the site of pulmonary infection for protracted periods. Hence direct inhalation to the respiratory epithelium has been investigated extensively in the past decade, and seems to be an attractive approach to eradicate and hence overcome this widespread problem. Moreover, engineering inhalation formulations wherein the antibiotics are encapsulated within nanoscale carriers could serve to overcome many of the limitations faced by conventional antibiotics, like difficulty in treating intracellular pathogens such as mycobacteria spp. and salmonella spp., biofilmassociated pathogens like Pseudomonas aeruginosa and Staphylococcus aureus, passage through the sputum associated with disorders like cystic fibrosis and chronic obstructive pulmonary disorder, systemic side effects following oral/parenteral delivery and inadequate concentrations of antibiotic at the site of infection leading to resistance. Encapsulation of antibiotics in nanocarriers may help in providing a protective environment to combat antibiotic degradation, confer controlled-release properties, hence reducing dosing frequency, and may increase uptake via specific and non-specific targeting modalities. Hence nanotechnology combined with direct administration to the airways using commercially available delivery devices, is a highly attractive formulation strategy to eradicate microorganisms from the lower respiratory tract, which might otherwise present opportunities for multi-drug resistance. PMID- 26983670 TI - Effects of CC-chemokine receptor 5 on ROCK2 and P-MLC2 expression after focal cerebral ischaemia-reperfusion injury in rats. AB - OBJECTIVE: CC-chemokine receptor 5 (CCR5) plays a pivotal role in reperfusion after stroke. This study assessed and confirmed the effects of CCR5 in experimental stroke via regulation of ROCK/P-MLC pathway. METHODS: Male Sprague Dawley (SD) rats were randomly divided into sham group, ischaemia-reperfusion group (I/R group) and DAPTA group (I/R + CCR5 antagonist group). The rats of the I/R group were subjected to transient middle cerebral artery occlusion (tMCAO) for 2 hours, followed by 24 hours of reperfusion. Animals were measured for neurologic deficit, cerebral infarct volume, TUNEL and hematoxylin-eosin (HE) staining. The protein expressions of ROCK2 and P-MLC2(Ser19) were determined by western blot. RESULTS: Pre-treatment with DAPTA displayed significantly improved neurological functional outcome and reduced cerebral lesion compared with the I/R group animals (p < 0.05); HE staining showed that the I/R group had severe neuronal damage in the ischaemia core and penumbral; Compared with the I/R group, ROCK2 and P-MLC2(Ser19) protein expression in the DAPTA group was reduced (p < 0.05). CONCLUSIONS: The data demonstrate that CCR5 is correlated with up regulation of the expression of ROCK2 and P-MLC2(Ser19) in the ischaemia cortex. Treated with CCR5 antagonist protects the brain against focal cerebral ischaemia reperfusion injury in rats. PMID- 26983672 TI - Biochemical markers of bone turnover in patients with spinal metastases after resistance training under radiotherapy--a randomized trial. AB - BACKGROUND: To compare the effects of resistance training versus passive physical therapy on bone turnover markers (BTM) in the metastatic bone during radiation therapy (RT) in patients with spinal bone metastases. Secondly, to evaluate an association of BTM to local response, skeletal-related events (SRE), and number of metastases. METHODS: In this randomized trial, 60 patients were allocated from September 2011 to March 2013 into one of the two arms: resistance training (Arm A) or passive physical therapy (Arm B) with thirty patients in each arm during RT. Biochemical markers such as pyridinoline (PYD), desoxy-pyridinoline (DPD), bone alkaline phosphatase (BAP), total amino-terminal propeptide of type I collagen (PINP), beta-isomer of carboxy-terminal telopeptide of type I collagen (CTX-I), and cross-linked N-telopeptide of type I collagen (NTX) were analyzed at baseline, and three months after RT. RESULTS: Mean change values of PYD and CTX-I were significantly lower at 3 months after RT (p = 0.035 and p = 0.043) in Arm A. Importantly, all markers decreased in both arms, except of PYD and CTX-I in arm B, although significance was not reached for some biomarkers. In arm A, the local response was significantly higher (p = 0.003) and PINP could be identified as a predictor for survivors (OR 0.968, 95%CI 0.938-0.999, p = 0.043). BAP (OR 0.974, 95%CI 0.950-0.998, p = 0.034) and PINP (OR 1.025, 95%CI 1.001-1.049, p = 0.044) were related with an avoidance of SRE. CONCLUSIONS: In this group of patients with spinal bone metastases, we were able to show that patients with guided resistance training of the paravertebral muscles can influence BTM. PYD and CTX-I decreased significantly in arm A. PINP can be considered as a complementary tool for prediction of local response, and PINP as well as BAP for avoidance of SRE. TRIAL REGISTRATION: Clinical trial identifier NCT 01409720. August 2, 2011. PMID- 26983673 TI - Monomelic amyotrophy with proximal upper limb involvement: a case report. AB - BACKGROUND: Monomelic amyotrophy is an uncommon, benign, unilateral disorder of the lower motor neurons, affecting predominantly the hand and forearm muscles. Proximal involvement of the arm and shoulder muscles is an unusual presentation that has been rarely reported in the literature. CASE PRESENTATION: A 28-year-old white man presented with insidious-onset, slowly progressive, unilateral weakness and atrophy of his left shoulder girdle and deltoid muscles. A neurological examination revealed weakness and atrophy in his left deltoid, infraspinatus and supraspinatus muscles. Electromyography demonstrated an active and chronic neurogenic pattern affecting his left C5 and C6 myotomes; magnetic resonance imaging of his cervical spine was normal. He did well with conservative treatment. CONCLUSIONS: Upper limb proximal form of monomelic amyotrophy is a rare clinical entity with a wide differential diagnosis. Physicians, especially neurologists, should be familiar with this benign condition to avoid inappropriately labeling patients as having amyotrophic lateral sclerosis and other disorders with less favorable outcomes. PMID- 26983675 TI - Chemical composition and biological activities of Eruca vesicaria subsp. longirostris essential oils. AB - Context To date, there are no reports to validate the Tunisian traditional and folklore claims of Eruca vesicaria (L) Cav. subsp. longirostris (Brassicaceae) for the treatment of disease. Objective Investigation of the chemical composition antimicrobial and antioxidant activity of essential oils from Eruca longirostris leaves, stems, roots and fruits. Materials and methods The essential oils of E. longirostris from leaves, stems, roots and fruits were obtained after 4 h of hydrodistillation. Chemical compositions were determined using a combination of GC/FID and GC/MS. The in vitro antimicrobial activity of the volatile constituents of E. longirostris was performed in sterile 96-well microplates against three Gram-positive, four Gram-negative bacteria and one strain as yeast. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration values were reported. Furthermore, the antioxidant activity was evaluated by DPPH and ABTS assays. Results The main compound for fruits, stems and roots was the erucin (96.6%, 85.3% and 83.7%, respectively), while beta-elemene (35.7%), hexahydrofarnesylacetone (23.9%), (E)-beta-damascone (15.4%), erucin (10.6%) and alpha-longipinene (9.6%) constituted the major compounds in the essential oil of the leaves. The experimental results showed that in all tests, essential oil of fruits showed the better antioxidant activity than the others. On the other hand, the oils of stems, fruits and roots showed significant antimicrobial activity with MIC values ranging from 0.125 to 0.31 mg/mL against Candida species, Gram positive and Gram-negative bacteria, mainly Salmonella enterica. Conclusions The present results indicate that essential oils of E. longirostris can be used as a source of erucin. PMID- 26983676 TI - Comparison of Subjective Well-Being and Personality Assessments in the Clouded Leopard (Neofelis nebulosa), Snow Leopard (Panthera uncia), and African Lion (Panthera leo). AB - The study of subjective well-being in nonhuman animals is growing in the field of psychology, but there are still only a few published studies and the focus is on primates. To consider whether the construct of subjective well-being could be found in another mammal, this study aimed to assess subjective well-being in felids and to examine its association with personality. Personality is one of the strongest and most consistent predictors of well-being in humans. This relationship could have important implications for other species, because personality has also been shown to affect health outcomes including stress, morbidity, and mortality. As in previous studies in nonhuman animals, the study results revealed that subjective well-being was related to agreeableness/openness and neuroticism in clouded leopards, neuroticism in snow leopards, and impulsiveness and neuroticism in African lions. The implications of these results for health outcomes and the welfare of animals in captivity are discussed. More research on any direct links among personality, subjective well-being, and these outcomes is important to advancing this field and adding another tool for improving captive animals' lives. PMID- 26983674 TI - Health Information Seeking, Source Trust, and Culture: A Comparative Analysis of Health Information Trends and Needs Between Guam and the United States. AB - The Guam population offers a unique glimpse into Americans of Pacific Island ancestry and their communication and information-seeking behaviors, experiences, and needs relevant to cancer. National surveys do not typically include the U.S. territories, so there are limited data on the health and cancer information seeking behaviors of these populations, in which health disparities persist. To fill this information gap, we conducted a survey on health communication in Guam using a modified version of the Health Information National Trends Survey instrument supplemented with items measuring specific cultural factors and communication practices. The results of the survey (N = 511) revealed some differences in health and cancer information-seeking patterns in Guam and the mainland United States. Sociodemographic variables, including sex, age, education, income, and employment, were significantly associated with health and cancer information seeking and Internet use. Levels of trust in various information sources were differentiated in the Guam and mainland U.S. SAMPLES: Logistic regression models revealed differences in factors predicting health and cancer information seeking and Internet use. The results suggest that these health information-seeking patterns and factors should be taken into account when developing communication strategies for more effective prevention and control programs. PMID- 26983677 TI - Antiviral effects of black raspberry (Rubus coreanus) seed extract and its polyphenolic compounds on norovirus surrogates. AB - Black raspberry seeds, a byproduct of wine and juice production, contain large quantities of polyphenolic compounds. The antiviral effects of black raspberry seed extract (RCS) and its fraction with molecular weight less than 1 kDa (RCS F1) were examined against food-borne viral surrogates, murine norovirus-1 (MNV-1) and feline calicivirus-F9 (FCV-F9). The maximal antiviral effect was achieved when RCS or RCS-F1 was added simultaneously to cells with MNV-1 or FCV-F9, reaching complete inhibition at 0.1-1 mg/mL. Transmission electron microscopy (TEM) images showed enlarged viral capsids or disruption (from 35 nm to up to 100 nm) by RCS-F1. Our results thus suggest that RCS-F1 can interfere with the attachment of viral surface protein to host cells. Further, two polyphenolic compounds derived from RCS-F1, cyanidin-3-glucoside (C3G) and gallic acid, identified by liquid chromatography-tandem mass spectrometry, showed inhibitory effects against the viruses. C3G was suggested to bind to MNV-1 RNA polymerase and to enlarge viral capsids using differential scanning fluorimetry and TEM, respectively. PMID- 26983678 TI - Successful Outcomes in Robot-Assisted Laparoscopic Pyeloplasty Using a Unidirectional Barbed Suture. AB - INTRODUCTION: Intracorporeal suturing is considered to be the most challenging aspect of laparoscopic and robotic surgery. To overcome this problem, barbed self retaining sutures have been effectively employed in various minimally invasive endourologic surgeries. However, the use of this suture has been recently cautioned for pyeloplasty due to a high failure rate. Our objective was to report our experience using barbed suture during robotic pyeloplasty. METHODS: We retrospectively identified 13 consecutive patients who underwent robotic pyeloplasty with a barbed monofilament (4-0 V-LocTM) suture for the ureteropelvic anastomosis from 2011 to 2014. We compared these patients to 12 consecutive patients who underwent robotic pyeloplasty with a 4-0 nonbarbed suture from 2007 to 2011. We evaluated patient demographics, operative times, preoperative and postoperative symptoms, renal function, and diuretic renograms (DRG). Successful repair was defined as resolution of preoperative symptoms and/or T1/2 improvement on DRG to less than 20 minutes. RESULTS: The median age was 26 (interquartile range [IQR] 20.7-38) years and 35 (IQR 18.3-44) years for the barbed and nonbarbed suture groups, respectively. In the barbed suture group, preoperative DRG revealed ureteropelvic junction obstruction (UPJO) in 11 patients, equivocal UPJO (T1/2 10-20 minutes) in one patient, and no obstruction in one patient. In the nonbarbed group, preoperative DRG revealed UPJO in 10 patients, equivocal UPJO in one patient, and no obstruction in one patient. In the barbed suture group, postoperative DRG was obtained in 11 patients, which showed no obstruction in 10/11 patients with 92% of patients experiencing symptom resolution. Similarly, postoperative DRG was obtained in 11 patients in the nonbarbed group, which showed no obstruction in 10/11 patients with 100% postoperative symptom resolution. CONCLUSIONS: In the largest series reporting use of V-Loc suture for robotic pyeloplasty, the V-Loc suture was safely and effectively used for robotic pyeloplasty repair. PMID- 26983680 TI - Cancer patient experience measures: An evidence review. AB - OBJECTIVES: This research investigates the instruments currently available to measure the cancer patient experience of health care. An investigation of the number of instruments, the domains covered by the instruments, and the structure and psychometric performance of instruments is undertaken. METHODS: A narrative synthesis approach is used to gather evidence from multiple studies and explain the findings. Purposely broad search terms and strategies are used to capture studies with cancer patients at all stages of disease and across a range of cancer types and health care settings. RESULTS: The majority of identified instruments were originally designed for the oncology field. Twelve of the studies developed new cancer patient measures; eight studies adapted existing or utilized items from existing instruments, and seven studies assessed the psychometric properties of existing instruments or assessed validated tools under different conditions (e.g., cross-cultural adaptation). The number of instruments assessing cancer patient experience that have sound psychometric properties across items was found to be low. The properties least tested are test-retest reliability, construct, convergent and discriminant validity, scale variability (floor/ceiling effects), and interpretability. CONCLUSION: This review examined 10 years of research on the development of instruments to measure the cancer patient experience of health care. It found that research in this area is still in early stages of development. Further inquiry based on development and validation of cancer patient experience measures is required to support improvements in cancer care based on the perspective of cancer patients. PMID- 26983681 TI - Tripod USPIONs with high aspect ratio show enhanced T2 relaxation and cytocompatibility. AB - AIM: We synthesized ultra-small iron oxide nanoparticles (USPIONs) with tripod morphology and studied the effect of the aspect ratio (AR) of the tripod arms on mass magnetization, T2 relaxation and cytocompatibility in human cell lines. MATERIALS & METHODS: Tripods were prepared by controlling the temperature during the thermal decomposition of Fe(CO)5, and their magnetic properties were characterized by superconducting quantum interference device, and NMR. Citric acid stabilized USPIONs were used to assess cytocompatibility. RESULTS: T2 relaxivity of tripods showed dependency on AR of the tripod arm. Liver enzyme levels in presence of tripods were comparable to spherical USPIONs, and surprisingly tripods induced lower levels of reactive oxygen species. CONCLUSION: Tripod USPIONs with high AR arms possess excellent magnetic properties and cytocompatibility for further exploration as MRI contrast agents. PMID- 26983683 TI - Development and evaluation of an interferon-gamma release assay in Asian elephants (Elephas maximus). AB - We developed an interferon-gamma release assay (IGRA) specific for Asian elephants (Elephas maximus). Whole blood collected from forty captive Asian elephants was stimulated with three different mitogens i.e., phytohemagglutinin (PHA), pokweed mitogen (PWM) and phorbol myristate aceteate/ionomycin (PMA/I). A sandwich ELISA that was able to recognize the recombinant elephant interferon gamma (rEIFN-gamma) as well as native interferon-gamma from the Asian elephants was performed using anti-elephant IFN-gamma rabbit polyclonal antibodies as capture antibodies and biotinylated anti-elephant IFN-gamma rabbit polyclonal antibodies as detection antibodies. PMA/I was the best mitogen to use as a positive control for an Asian elephant IGRA. The development of an Asian elephant specific IGRA that detects native IFN-gamma in elephant whole blood provides promising results for its application as a potential diagnostic tool for diseases, such as tuberculosis (TB) in Asian elephants. PMID- 26983682 TI - How Condom Discontinuation Occurs: Interviews With Emerging Adult Women. AB - We have almost no data on how and when couples stop using condoms. This qualitative study investigated the process of condom discontinuation. From November 2013 to April 2014, a total of 25 women living in a college town in the Midwest, ages 18 to 25, participated in semistructured interviews centered around three domains: partner interactions, contraceptive use, and sexually transmitted infection (STI) prevention. Analysis followed a critical qualitative research orientation. Participants described actively seeking the best options to prevent pregnancy, perceiving condom discontinuation in favor of hormonal methods as a smart decision, and reported wanting to discontinue using condoms due to physical discomfort. Oftentimes, nonverbal communication around contextual instances of condom unavailability paved the way for discontinuation. Participants indicated the decision to stop using condoms was neither deliberate nor planned. Condom discontinuation rarely occurred at one point in time; instead, it was preceded by a period of occasional use. Even after participants described themselves as not using condoms, sporadic condom use was normal (typically related to fertility cycles). This study provides a more detailed understanding of how and why emerging adults negotiate condom discontinuation, thereby enhancing our ability to design effective condom continuation messages. Attention should be paid to helping emerging adults think more concretely about condom discontinuation. PMID- 26983679 TI - Regulation of sGC via hsp90, Cellular Heme, sGC Agonists, and NO: New Pathways and Clinical Perspectives. AB - SIGNIFICANCE: Soluble guanylate cyclase (sGC) is an intracellular enzyme that plays a primary role in sensing nitric oxide (NO) and transducing its multiple signaling effects in mammals. Recent Advances: The chaperone heat shock protein 90 (hsp90) associates with signaling proteins in cells, including sGC, where it helps to drive heme insertion into the sGC-beta1 subunit. This allows sGC-beta1 to associate with a partner sGC-alpha1 subunit and mature into an NO-responsive active form. CRITICAL ISSUES: In this article, we review evidence to date regarding the mechanisms that modulate sGC activity by a pathway where binding of hsp90 or sGC agonist to heme-free sGC dictates the assembly and fate of an active sGC heterodimer, both by NO and heme-dependent or heme-independent pathways. FUTURE DIRECTIONS: We discuss some therapeutic implications of the NO-sGC-hsp90 nexus and its potential as a marker of inflammatory disease. Antioxid. Redox Signal. 26, 182-190. PMID- 26983684 TI - Sexual dimorphism of the Eurasian otter (Lutra lutra) in South Korea: Craniodental geometric morphometry. AB - Sexual dimorphism of the craniodental morphology of the Eurasian otter in South Korea was studied with geometric morphometrics. 29 adult skulls (15 males and 14 females) were used. Images of the dorsal and ventral view of the cranium and right lateral view of the mandible were taken and then digitized, and measurements were taken on the right side. Results showed that size difference between males and females was significant. Correlations between the size and shape variations have not been observed in this study. The bivariate plots with centroid size showed size dimorphism between males and females with some overlapping. Most relative warp (RW) scores were not significantly different between males and females. We observed only RW2 for dorsal and ventral view of the skull, and only RW1 for mandible was significantly different between the sexes. Shape dimorphisms were revealed at the postorbital constriction, temporal mandibular joint, coronoid process, mandibular condyle and angular process of the skull. Based on our study, sexual dimorphism exists in Eurasian otter from the South Korean population in terms of both the size and shape. Furthermore, the degree of size dimorphism is greater than shape dimorphism. PMID- 26983685 TI - Infant Parenteral Nutrition Remains a Significant Source for Aluminum Toxicity. AB - BACKGROUND: Aluminum toxicity is associated with anemia, impaired bone metabolism, neurologic defects, and parenteral nutrition (PN)-associated liver disease. This element is a ubiquitous contaminant of PN components, especially in infant formulations. We assessed the current levels of aluminum contamination in infant PN at a level III neonatal intensive care unit. MATERIALS AND METHODS: Thirty samples of PN prepared in the same hospital for infants aged <30 days (mean [SD] weight, 1.54 [0.71] kg) were collected from discarded solution. Each sample was analyzed for aluminum content via inductively coupled plasma mass spectrometry. The components of PN (from label) and measured aluminum content were then compared using linear regression and 1-way analysis of variance. RESULTS: The mean (SD) aluminum contamination of infant PN was 14.02 (6.51) mcg/kg/d. Only 3 samples were <5 mcg/kg/d. Aluminum levels and infant weight were not associated. Linear regression revealed a significant correlation between aluminum and both calcium gluconate ( P < .0001) and phosphate ( P = .05), with a trend between aluminum and potassium ( P = .07). CONCLUSIONS: Aluminum contamination in infant PN remains almost 3 times higher than the advised maximum exposure (<5 mcg/kg/d, Food and Drug Administration 2004). Unexpectedly, an association between infant weight and aluminum exposure was not apparent, likely due to the homogeneity of our population. Isolating the source of aluminum contamination is difficult, as multiple components appear to be involved. Calcium gluconate is likely still a major contributor, but further investigations into individual components are warranted to promote the reduction of aluminum in infant PN. PMID- 26983686 TI - Reporting and use of the OECD Health Care Quality Indicators at national and regional level in 15 countries. AB - QUALITY PROBLEM OR ISSUE: OECD member states are involved since 2003 in a project coordinated by the OECD on Health Care Quality Indicators (HCQI). All OECD countries are biennially requested by the OECD to deliver national data on the quality indicators for international benchmarking purposes. INITIAL ASSESSMENT: Currently, there is no knowledge whether the OECD HCQI information is used by the countries themselves for healthcare system accountability and improvement purposes. CHOICE OF SOLUTION: The objective of the study is to explore the reporting and use of OECD HCQI in OECD member-states. IMPLEMENTATION: Data were collected through a questionnaire sent to all OECD member-states containing factual questions on the reporting on all OECD HCQ-indicators. Responses were received between June and December 2014. In this timeframe, two reminders were sent to the participants. The work progress was presented during HCQI Meetings in November 2014 and May 2015. EVALUATION: Fifteen countries reported to have a total of 163 reports in which one or more HCQIs were reported. One hundred and sixteen were national and 47 were regional reports. Forty-nine reports had a general system focus, 80 were disease specific, 10 referred to a specific type of care setting, 22 were thematic and 2 were a combination of two (disease specific for a particular type of care and thematic for a specific type of care). Most reports were from Canada: 49. All 15 countries use one or more OECD indicators. LESSONS LEARNED: The OECD quality indicators have acquired a clear place in national and regional monitoring activities. Some indicators are reported more often than others. These differences partly reflect differences between healthcare systems. Whereas some indicators have become very common, such as cancer care indicators, others, such as mental healthcare and patient experience indicators are relatively new and require some more time to be adopted more widely. PMID- 26983687 TI - Almost three million hospital bed days have been lost through social care cuts, charity warns. PMID- 26983690 TI - Safety and efficacy of mizoribine treatment in nephrotic syndrome complicated with hepatitis B virus infection: a clinical study. AB - Objective The objective of this study is to explore the efficacy and safety of mizoribine (MZR) in treating nephrotic syndrome patients afflicted with hepatitis B virus (HBV). Methods The present study included 36 nephrotic syndrome patients accompanied with HBV infection. A draft of MZR (150-200 mg/d), methylprednisolone (0.6-0.8 mg/kg.d), and entecavir (0.5 mg/d) was administered to study patients over 24 weeks. The serum albumin (AlB), 24-h urine protein (24-U-TP), liver and renal functions, and HBV-DNA were quantified before and at 2, 4, 8, 12, 16, 20, and 24 weeks after the treatment. The adverse responses were recorded. Results The AlB levels of patients increased gradually after comprehensive treatment, while the 24-U-TP, serum cholesterol, and triglyceride (TG) levels declined gradually. The changes at 24 weeks post-treatment were statistically significant. Compared with the levels before treatment, the HBV-DNA, transaminase, and renal functions of the patients were not significantly altered after the treatment. No evident adverse response was found. Conclusion Treatment using MZR in combination with methylprednisolone and entecavir in HBV-positive nephrotic syndrome patients displays significant efficacy with a low incidence of adverse reactions. PMID- 26983691 TI - Cardiomyopathies: The happy heart syndrome. PMID- 26983689 TI - Kinase-Dependent and -Independent Roles for PTK6 in Colon Cancer. AB - Disruption of the gene encoding Protein Tyrosine Kinase 6 (Ptk6) delayed differentiation and increased growth in the mouse intestine. However, Ptk6-null mice were also resistant to azoxymethane-induced colon tumorigenesis. To further explore functions of PTK6 in colon cancer, expression of epithelial and mesenchymal markers, as well as proliferation, migration, and xenograft tumor growth, was examined in human colon tumor cell lines with knockdown or overexpression of PTK6. PTK6 protein, transcript, and activation were also examined in a human colon tumor tissue array, using immunohistochemistry and qRT PCR. Knockdown of PTK6 led to the epithelial-mesenchymal transition (EMT) in SW480 and HCT116 cells, whereas overexpression of PTK6 in SW620 cells restored an epithelial phenotype in a kinase-independent manner. PTK6 knockdown also increased xenograft tumor growth of SW480 cells, suggesting tumor suppressor functions. In clinical specimens, PTK6 expression was highest in normal differentiated epithelial cells and reduced in tumors. In contrast, overexpression of constitutively active PTK6 promoted STAT3 and ERK5 activation in colon cancer cells, and endogenous PTK6 promoted cell survival and oncogenic signaling in response to DNA-damaging treatments. These data indicate that PTK6 has complex, context-specific functions in colon cancer; PTK6 promotes the epithelial phenotype to antagonize the EMT in a kinase-independent manner, whereas activation of PTK6 promotes oncogenic signaling. IMPLICATIONS: Understanding context-specific functions of PTK6 is important, because although it promotes cell survival and oncogenic signaling after DNA damage, expression of PTK6 in established tumors may maintain the epithelial phenotype, preventing tumor progression. Mol Cancer Res; 14(6); 563-73. (c)2016 AACR. PMID- 26983692 TI - Cardiac resuscitation: Optimal duration of prehospital resuscitation after OHCA. PMID- 26983693 TI - MTDH genetic variants in colorectal cancer patients. AB - The colorectal carcinogenesis is a complex process encompassing genetic alterations. The oncoprotein AEG-1, encoded by the MTDH gene, was shown previously to be involved in colorectal cancer (CRC). The aim of this study was to determine the frequency and the spectrum of MTDH variants in tumor tissue, and their relationship to clinicopathological variables in CRC patients. The study included tumors from 356 unselected CRC patients. Mutation analysis of the MTDH gene, including coding region and adjacent intronic sequences, was performed by direct DNA sequencing. The corresponding normal colorectal tissue was analyzed in the carriers of exonic variant to confirm germline or somatic origin. We detected 42 intronic variants, where 25 were novel. Furthermore, we found 8 exonic variants of which four, one missense (c.977C > G-germline) and three frameshift mutations (c.533delA-somatic, c.1340dupA-unknown origin, c.1731delA-unknown origin), were novel. In silico prediction analyses suggested four deleterious variants (c.232G > T, c.533delA, c.1340dupA, and c.1731delA). There were no correlations between the MTDH variants and tumor stage, differentiation or patient survival. We described several novel exonic and intronic variants of the MTDH gene. The detection of likely pathogenic truncating mutations and alterations in functional protein domains indicate their clinical significance, although none of the variants had prognostic potential. PMID- 26983694 TI - Regulation of the collagen cross-linking enzymes LOXL2 and PLOD2 by tumor suppressive microRNA-26a/b in renal cell carcinoma. AB - Our recent studies of microRNA (miRNA) expression signatures in human cancers revealed that microRNA-26a (miRNA-26a) and microRNA-26b (miRNA-26b) were significantly reduced in cancer tissues. To date, few reports have provided functional analyses of miR-26a or miR-26b in renal cell carcinoma (RCC). The aim of the present study was to investigate the functional significance of miR-26a and miR-26b in RCC and to identify novel miR-26a/b-mediated cancer pathways and target genes involved in RCC oncogenesis and metastasis. Downregulation of miR 26a or miR-26b was confirmed in RCC clinical specimens. Restoration of miR-26a or miR-26b in RCC cell lines (786-O and A498) revealed that these miRNAs significantly inhibited cancer cell migration and invasion. Our in silico analysis and luciferase reporter assays showed that lysyl oxidase-like 2 (LOXL2) and procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) were directly regulated by these miRNAs. Moreover, downregulating the PLOD2 gene significantly inhibited cell migration and invasion in RCC cells. Thus, our data showed that two genes promoting metastasis, LOXL2 and PLOD2, were epigenetically regulated by tumor-suppressive microRNAs, miR-26a and miR-26b, providing important insights into the molecular mechanisms of RCC metastasis. PMID- 26983688 TI - New Era of Lipid-Lowering Drugs. AB - There are several established lipid-modifying agents, including statins, fibrates, niacin, and ezetimibe, that have been shown in randomized clinical outcome trials to reduce the risk of having an atherosclerotic cardiovascular event. However, in many people, the risk of having an event remains unacceptably high despite treatment with these established agents. This has stimulated the search for new therapies designed to reduce residual cardiovascular risk. New approaches that target atherogenic lipoproteins include: 1) inhibition of proprotein convertase subtilisin/kexin type 9 to increase removal of atherogenic lipoproteins from plasma; 2) inhibition of the synthesis of apolipoprotein (apo) B, the main protein component of atherogenic lipoproteins; 3) inhibition of microsomal triglyceride transfer protein to block the formation of atherogenic lipoproteins; 4) inhibition of adenosine triphosphate citrate lyase to inhibit the synthesis of cholesterol; 5) inhibition of the synthesis of lipoprotein(a), a factor known to cause atherosclerosis; 6) inhibition of apoC-III to reduce triglyceride-rich lipoproteins and to enhance high-density lipoprotein (HDL) functionality; and 7) inhibition of cholesteryl ester transfer protein, which not only reduces the concentration of atherogenic lipoproteins but also increases the level and function of the potentially antiatherogenic HDL fraction. Other new therapies that specifically target HDLs include infusions of reconstituted HDLs, HDL delipidation, and infusions of apoA-I mimetic peptides that mimic some of the functions of HDLs. This review describes the scientific basis and rationale for developing these new therapies and provides a brief summary of established therapies. PMID- 26983695 TI - Efficient monitoring of the blood-stage infection in a malaria rodent model by the rotating-crystal magneto-optical method. AB - Intense research efforts have been focused on the improvement of the efficiency and sensitivity of malaria diagnostics, especially in resource-limited settings for the detection of asymptomatic infections. Our recently developed magneto optical (MO) method allows the accurate quantification of malaria pigment crystals (hemozoin) in blood by their magnetically induced rotation. First evaluations of the method using beta-hematin crystals and in vitro P. falciparum cultures implied its potential for high-sensitivity malaria diagnosis. To further investigate this potential, here we study the performance of the method in monitoring the in vivo onset and progression of the blood-stage infection in a rodent malaria model. Our results show that the MO method can detect the first generation of intraerythrocytic P. berghei parasites 66-76 hours after sporozoite injection, demonstrating similar sensitivity to Giesma-stained light microscopy and exceeding that of flow cytometric techniques. Magneto-optical measurements performed during and after the treatment of P. berghei infections revealed that both the follow up under treatment and the detection of later reinfections are feasible with this new technique. The present study demonstrates that the MO method - besides being label and reagent-free, automated and rapid - has a high in vivo sensitivity and is ready for in-field evaluation. PMID- 26983696 TI - Intra-articular injection of synovial mesenchymal stem cells improves cartilage repair in a mouse injury model. AB - Controversy remains whether articular cartilage has an endogenous stem/progenitor cell population, since its poor healing capacity after injury can lead to diseases such as osteoarthritis. In the joint environment there are mesenchymal stem/progenitor cells (MSCs) in the synovial membrane and synovial fluid that can differentiate into cartilage, but it is still under debate if these cells contribute to cartilage repair in vivo. In this study, we isolated a Sca-1 positive, chondrogenesis capable population of mouse synovial MSCs from C57BL6 and MRL/MpJ "super-healer" strains. Intra-articular injection of Sca-1 + GFP + synovial cells from C57BL6 or MRL/MpJ into C57BL6 mice following cartilage injury led to increased cartilage repair by 4 weeks after injury. GFP expression was detected in the injury site at 2 weeks, but not 4 weeks after injury. These results suggest that synovial stem/progenitor cells, regardless of strain background, have beneficial effects when injected into an injured joint. MSCs derived from MRL/MpJ mice did not promote an increased repair capacity compared to MSCs derived from non-healing C57BL6 controls; however, MRL/MpJ MSCs were observed within the defect area at the time points examined, while C57BL6 MSCs were not. PMID- 26983697 TI - Complex responses of spring vegetation growth to climate in a moisture-limited alpine meadow. AB - Since 2000, the phenology has advanced in some years and at some locations on the Qinghai-Tibetan Plateau, whereas it has been delayed in others. To understand the variations in spring vegetation growth in response to climate, we conducted both regional and experimental studies on the central Qinghai-Tibetan Plateau. We used the normalized difference vegetation index to identify correlations between climate and phenological greening, and found that greening correlated negatively with winter-spring time precipitation, but not with temperature. We used open top chambers to induce warming in an alpine meadow ecosystem from 2012 to 2014. Our results showed that in the early growing season, plant growth (represented by the net ecosystem CO2 exchange, NEE) was lower in the warmed plots than in the control plots. Late-season plant growth increased with warming relative to that under control conditions. These data suggest that the response of plant growth to warming is complex and non-intuitive in this system. Our results are consistent with the hypothesis that moisture limitation increases in early spring as temperature increases. The effects of moisture limitation on plant growth with increasing temperatures will have important ramifications for grazers in this system. PMID- 26983698 TI - Joint effects of diabetic-related genomic loci on the therapeutic efficacy of oral anti-diabetic drugs in Chinese type 2 diabetes patients. AB - Previous pharmacogenomic studies of oral anti-diabetic drugs have primarily focused on the effect of a single site. This study aimed to examine the joint effects of multiple loci on repaglinide or rosiglitazone efficacy in newly diagnosed type 2 diabetes mellitus (T2DM) patients. A total of 209 newly diagnosed T2DM patients were randomly assigned to treatment with repaglinide or rosiglitazone for 48 weeks. The reductions in fasting glucose (DeltaFPG), 2h glucose (Delta2hPG) and glycated hemoglobin (DeltaHbA1c) levels were significantly associated with genetic score that was constructed using the sum of the effect alleles both in the repaglinide (P = 0.0011, 0.0002 and 0.0067, respectively) and rosiglitazone cohorts (P = 0.0002, 0.0014 and 0.0164, respectively) after adjusting for age, gender, body mass index and dosage. Survival analyses showed a trend towards a greater attainment rate of target HbA1c level in individuals with a high genetic score in the repaglinide cohort and rosiglitazone cohort (Plog-rank = 0.0815 and 0.0867, respectively) when the attainment of treatment targets were defined as more than 20% decrease of FPG, 2hPG, and HbA1c levels after treatment. In conclusion, we identified the joint effects of several T2DM-related loci on the efficacy of oral anti-diabetic drugs; moreover, we built a model to predict the drug efficacy. PMID- 26983699 TI - Production of unstable proteins through the formation of stable core complexes. AB - Purification of proteins that participate in large transient complexes is impeded by low amounts, heterogeneity, instability and poor solubility. To circumvent these difficulties we set up a methodology that enables the production of stable complexes for structural and functional studies. This procedure is benchmarked and applied to two challenging protein families: the human steroid nuclear receptors (SNR) and the HIV-1 pre-integration complex. In the context of transcriptional regulation studies, we produce and characterize the ligand binding domains of the glucocorticoid nuclear receptor and the oestrogen receptor beta in complex with a TIF2 (transcriptional intermediary factor 2) domain containing the three SNR-binding motifs. In the context of retroviral integration, we demonstrate the stabilization of the HIV-1 integrase by formation of complexes with partner proteins and DNA. This procedure provides a powerful research tool for structural and functional studies of proteins participating in non-covalent macromolecular complexes. PMID- 26983701 TI - The co-occurrence of an ovarian Sertoli-Leydig cell tumor with a thyroid carcinoma is highly suggestive of a DICER1 syndrome. AB - The DICER1 gene encodes an endoribonuclease involved in the production of mature microRNAs which regulates gene expression through several mechanisms. Carriers of germline DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 syndrome. Pleuropulmonary blastoma is the most frequent lesion seen in this syndrome. Thyroid abnormalities are also a common finding, essentially concerning multinodular goiter. However, differentiated thyroid carcinoma is infrequently seen in such pedigrees. In addition to germline DICER1 mutations, specific somatic mutations have been identified in the DICER1 RNase IIIb catalytic domain in several tumor types, including ovarian Sertoli-Leydig cell tumors. We report two cases of differentiated thyroid carcinoma associated with ovarian Sertoli Leydig cell tumor and with a heterozygous DICER1 gene mutation, occurring in two unrelated young girls without pleuropulmonary blastoma. Both thyroid carcinomas showed an E1813 mutation in exon 25 while the ovarian tumors harboured a somatic mutation in E1705 in exon 24 and a D1709 mutation in exon 25. Our observations confirm that the occurrence of an ovarian Sertoli-Leydig cell tumor with a thyroid carcinoma is highly suggestive of a DICER1 syndrome. We contend that the possibility of a relationship between sporadic thyroid carcinoma in young patients and somatic DICER1 gene mutation needs further investigation. PMID- 26983702 TI - Association of coexisting morphological umbilical cord abnormality and clinical cord compromise with hypoxic and thrombotic placental histology. AB - To assess the usefulness and limitations of placental histology when morphological umbilical cord (UC) abnormality coexists with clinical UC compromise, 5634 consecutive placentas were divided into four groups and statistically compared: group 1-182 placentas from pregnancies with clinical features of UC compromise (variable decelerations, UC entanglement, prolapse, or true knot at delivery); group 2-1355 placentas with abnormal UC morphology or insertion; group 3-152 placentas with at least one phenotype from group 1 and one from group 2; group 4-3945 placentas with no clinical or morphological UC-related phenotypes (control group).Differences were analyzed by ANOVA or chi (2). Of 68 phenotypes studied, 13 clinical and 18 placental phenotypes were statistically significant. In group 1, 2 phenotypes were most common (oligohydramnios and abnormal fetal heart rate tracing). In group 2, 6 phenotypes were most common, including 4 clinical (abnormal umbilical artery Dopplers, nonmacerated stillbirth, multiple pregnancy, and fetal growth restriction) and 2 placental. In group 3, 23 phenotypes were most common, including 7 clinical (gestational hypertension, polyhydramnios, induction of labor, cesarean section, macerated stillbirth, congenital malformations, and abnormal 3rd stage of labor) and 16 placental. The existence of clinical signs of UC compromise alone was associated with the absence of pathomorphological placental abnormalities. However, the coexistence of clinical and abnormal morphological UC phenotypes was statistically significantly associated with placental histological signs of decreased fetal blood flow, hypoxia (acute and chronic post uterine), shallow placental implantation, and/or amnion nodosum. Thus, confirmation of clinical UC compromise should not be expected on placental examination if no morphological UC abnormality or abnormal UC insertion has been found. PMID- 26983700 TI - Total peroxiredoxin expression is associated with survival in patients with follicular lymphoma. AB - Redox state-regulating enzymes may have roles in chemoresistance and also in lymphomagenesis, but there have been only a limited number of studies on this topic in lymphomas. Our aim was to assess expression of the redox state regulating enzymes peroxiredoxins (Prxs) I-VI and thioredoxin (Trx) and the oxidative stress marker nitrotyrosine in follicular lymphomas (FLs). We immunohistochemically assessed Prxs I-VI, Trx and nitrotyrosine in a cohort of 76 histologically confirmed, untreated FLs. We also studied the localisation of Prxs I, II, III, V and VI by means of immunoelectron microscopy (IEM). Immunohistochemistry results were correlated with disease-specific survival (DSS), progression-free survival (PFS), overall survival (OS) and clinical prognostic factors. When all Prx expression intensities were grouped as a single variable, we discovered that high total Prx intensity correlated with favourable DSS (p = 0.024) and OS (p = 0.035) but not with PFS. No deaths due to lymphoma were recorded amongst patients with high total Prx expression during the median follow-up period of 7.6 years. IEM results were in line with earlier ones demonstrating wide subcellular localisation of Prx isoenzymes. In conclusion, our results demonstrate an association between high total Prx expression and prolonged survival and suggest that Prxs may have a protective role in FL that cannot be compensated by other antioxidant mechanisms. PMID- 26983704 TI - The Role of Time-Resolved MRA for Post-treatment Assessment of Pulmonary Arteriovenous Malformations: A Pictorial Essay. PMID- 26983703 TI - Convenient Preparation of [(68)Ga]DKFZ-PSMA-11 Using a Robust Single-Vial Kit and Demonstration of Its Clinical Efficacy. AB - PURPOSE: [(68)Ga]DKFZ-PSMA-11 has proved to be an important diagnostic radiotracer for targeting prostate-specific membrane antigen (PSMA) overexpression in both recurrent prostate cancer (PC) and relevant metastatic sites. However, the widespread, routine clinical use of such a potential radiopharmaceutical demands availability of a ready-to-use kit formulation to enable convenient radiopharmaceutical preparation. Herein, we report the development of a freeze-dried kit vial for the formulation of [(68)Ga]DKFZ-PSMA 11 and its clinical use in patients using a "shake-bake-inject" methodology. PROCEDURES: The freeze-dried kit vial was developed after optimization of ligand content (PSMA-11) and pH conditions. The kit was formulated using (68)Ga from two different commercially available generators. Positron emission tomography/X-ray computed tomography (PET/CT) images of PC patients were obtained using the kit formulated radiotracer. RESULTS: [(68)Ga]DKFZ-PSMA-11 was prepared in >98 % radiochemical yield and purity using the freeze-dried kit vials. Kits were optimized for the preparation of four patient doses. The clinical utility was evaluated in patients with histologically confirmed prostate cancer, and the images were of good quality as well as conforming to tumor marker and clinical expectations. CONCLUSION: The development of a simple and ready-to-use freeze dried DKFZ-PSMA-11 kit for the preparation of Ga-68-based radiotracers constitutes a major step towards the expedition of the widespread and economical screening of PC patients. PMID- 26983706 TI - Fabrication of Janus droplets by evaporation driven liquid-liquid phase separation. AB - We present a universal and scalable method to fabricate Janus droplets based on evaporation driven liquid-liquid phase separation. In this work, the morphologies and chemical properties of separate parts of the Janus droplets can be flexibly regulated, and more complex Janus droplets (such as core-shell Janus droplets, ternary Janus droplets, and multiple Janus droplets) can be constructed easily. PMID- 26983705 TI - Mechanisms of the Macrolide-Induced Inhibition of Superoxide Generation by Neutrophils. AB - The effect of macrolides on the superoxide (O2 (-)) production by neutrophils was studied. Resting neutrophils become primed by lipopolysaccharide (LPS) or N formyl-methionyl-leucyl-phenylalanine (fMLP), and primed neutrophils generate O2 (-) in response to fMLP or adhesion, respectively. Both LPS-primed fMLP stimulated O2 (-) generation by macrolide-treated neutrophils and adhesion stimulated O2 (-) generation by macrolide-treated fMLP-primed neutrophils were inhibited. Macrolide inhibition of O2 (-) generation was dependent on serum or pH. Serum could be substituted by NaHCO3. The intensity of inhibition was azithromycin = roxithromycin > clarithromycin > erythromycin, in that order. Non antimicrobial derivatives of erythromycin, that is, EM703 and EM900, inhibited O2 (-) generation at pH 7.4. NH4Cl abolished the activity of azithromycin (AZ) only when added to neutrophils with AZ but not after incubation with AZ, suggesting that NH4Cl prevented the influx of AZ. AZ did not affect the expression of alkaline phosphatase, CD11b, and cytochrome b558 in both resting and LPS-primed neutrophils. These results suggested that macrolides did not affect granule mobilization but inhibited O2 (-) generation selectively. PMID- 26983707 TI - Clinical-Morphological Features and Outcomes of Lupus Podocytopathy. AB - BACKGROUND AND OBJECTIVES: Lupus podocytopathy, which is characterized by diffuse foot process effacement without peripheral capillary wall immune deposits and glomerular proliferation, has been described in SLE patients with nephrotic syndrome in case reports and small series. This study aimed to better characterize the incidence, clinical-morphologic features, and outcomes of such patients from a large Chinese cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Lupus podocytopathy was identified from 3750 biopsies of SLE patients obtained from 2000 to 2013 that showed mild glomerular histology in patients with a clinical sign of nephrotic syndrome. The biopsy results were divided into three groups: glomerular minimal change, mesangial proliferation, and FSGS. RESULTS: Fifty (1.33%) cases were identified as lupus podocytopathy and included minimal change in 13 cases, mesangial proliferation in 28 cases, and FSGS in nine cases. Extensive foot process effacement appeared in all the biopsies and mesangial electron-dense deposits were present in 47 biopsies. All patients demonstrated nephrotic syndrome, and the median proteinuria was 5.72 g/24 h (interquartile range [IQR], 3.82, 6.92). Seventeen (34%) cases presented with AKI. Forty-seven (94%) patients achieved remission after immunosuppressive therapy for a median time of 4 weeks (IQR, 2, 8). Compared with the patients with minimal change and mesangial proliferation, patients with FSGS showed significantly higher incidence of AKI and severe tubule-interstitial injury and a much lower complete remission rate. During follow-up of a median of 62 (IQR, 36, 84) months, renal relapses occurred in 28 (59.6%) patients. No patient died or developed ESRD. CONCLUSIONS: The findings from this cohort study suggest that lupus podocytopathy may represent a special entity of lupus nephritis with distinct clinical-morphologic features. The differences in AKI incidence, tubular injury severity, and response to treatment between the patients with minimal change/mesangial proliferation and those with FSGS patterns indicate two different subtypes of lupus podocytopathy. PMID- 26983708 TI - Lupus Podocytopathy: A Distinct Entity. PMID- 26983709 TI - New Famennian colonial coral (Rugosa) from the Holy Cross Mountains (Poland): an example of local evolution after Frasnian-Famennian extinction. AB - Colonial rugose corals are extremely rare in the fossil record after the Late Devonian (Frasnian-Famennian) extinction event. Here, we report a new genus and species, Famastraea catenata, from the late Famennian of the western part of the Holy Cross Mountains (Kowala) in Poland. Although this taxon is colonial, it displays many morphological characters very close to the typically late Famennian solitary species Palaeosmilia aquisgranensis (Frech, 1885), described earlier from the same locality. Hence, we postulate that F. catenata is derived from P. aquisgranensis. In contrast to other Famennian colonial rugose corals, the new taxon represents an example of local evolution within the group of so-called 'Strunian' corals. Consequently, we postulate that the new taxon represents a new colonial rugose fauna, which, however, did not survive the subsequent Late Devonian crisis (i.e. Hangenberg event). F. catenata most probably inhabited deeper water settings, possibly near the boundary between the euphotic and dysphotic zones, as inferred from many other benthic taxa described from this locality. PMID- 26983711 TI - Malignancies after living-donor and cadaveric lung transplantations in Japanese patients. AB - PURPOSE: Lung transplant recipients are known to be at risk of a postoperative malignancy. In Western countries, skin cancer and post-transplant lymphoproliferative disorder (PTLD) are the most common malignancies in this cohort. We conducted this study to evaluate the characteristics of postoperative malignancies in Japanese patients following living-donor lobar lung transplantation (LDLLT) or cadaveric lung transplantation (CLT). METHODS: We reviewed the medical records of 120 Japanese patients who underwent either LDLLT (n = 62) or CLT (n = 58) between April 2002 and July 2015. RESULTS: Postoperative malignancy developed in 11 patients (9.2 %), as PTLD in 7, breast cancer in 1, gastric cancer in 1, glioblastoma in 1, and adenocarcinoma of unknown primary in 1. Twenty-six (21.7 %) of the 120 transplant patients had a history of malignancy pre-transplant; however, the postoperative malignancies were all de novo without any recurrence of the original disease. The malignancies developed after LDLLT in six patients (9.7 %) and after CLT in 5 patients (8.6 %). Three of the four patients with solid organ malignancies had distant metastasis at diagnosis. Three patients died of PTLD and one patient died of gastric cancer. CONCLUSIONS: PTLD occurred after both LDLLT and CLT. There was no case of skin cancer in this series of Japanese patients, suggesting ethnic differences. Solid organ malignancies in lung transplant recipients tended to progress rapidly. PMID- 26983713 TI - Management of the unstable shoulder. PMID- 26983710 TI - A non-smooth tumor margin on preoperative imaging predicts microvascular invasion of hepatocellular carcinoma. AB - PURPOSES: Microvascular invasion (mVI) is known to be a risk factor of hepatocellular carcinoma (HCC) recurrence. Several factors such as the tumor grade, tumor size, tumor margin status on imaging studies, fluorine-18 fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) results, and tumor markers have been proposed to predict mVI of HCC. However, the values of these factors have not yet been validated. METHODS: Among the patients evaluated using enhanced CT/MRI, (18)F-FDG-PET, and tumor markers prior to hepatectomy from 2007 to 2012, 79 HCC patients without apparent macrovascular invasion in preoperative imaging were enrolled in this study. The image tumor margin status (smooth/non-smooth), (18)F-FDG-PET, and tumor markers, which were previously described as predictors for mVI, were evaluated. RESULTS: Fifteen patients had mVI (mVI+ group) and 64 patients had no evidence of mVI (mVI- group) on pathological examinations. A univariate analysis showed that the mVI+ group had a higher SUV and TNR (5.2 vs 3.8, p = 0.02 and 1.8 vs 1.3, p = 0.02, respectively) and a higher portion of non-smooth tumor margin (87 vs 27 %, p = 0.0001). There was no significant difference in the tumor markers. A multivariate analysis showed that non-smooth tumor margin alone could independently predict mVI (odds ratio 18.3, 95 % CI 3.27-102.6, p = 0.0009). CONCLUSION: A non-smooth tumor margin on preoperative imaging predicts microvascular invasion of HCC. PMID- 26983712 TI - The effects of roflumilast on the pancreas and remote organs in a cerulein induced experimental acute pancreatitis model in rats. AB - PURPOSE: Systemic damage in acute pancreatitis (AP) can be characterized by oxidative stress and the release of pro-inflammatory cytokines. Roflumilast has been shown to be a potent anti-inflammatory and antioxidant agent. In the present study, we aimed to investigate the effect of roflumilast in cerulein-induced AP. METHODS: Thirty-two male rats were divided into four groups: group 1 (sham), group 2 (Roflumilast), group 3 (AP), and group 4 (AP + Roflumilast). AP was induced by injecting 4 * 75 MUg/kg of body weight at an interval of 1 h. Rats were killed after 12 h following the last cerulein administration. AP was confirmed by measuring the serum amylase level and inflammatory features. RESULTS: Morphological changes were observed in the pancreas. Amylase levels were higher in the AP and AP + Roflumilast groups than the sham and Roflumilast groups. The serum levels of TNF-alpha, IL-1beta, and IL-6 increased in the AP group, whereas they decreased in the Roflumilast group. The total oxidant activity (TOA) was higher and the total antioxidant capacity (TAC) was lower in the AP group. The administration of roflumilast decreased the TOA and increased the TAC in comparison with the AP group (p < 0.05 for both). CONCLUSIONS: Roflumilast significantly decreases oxidative stress and inflammatory mediators in the plasma, pancreas, and lung in cerulein-induced AP rats. PMID- 26983714 TI - Bis(maltolato)oxovanadium(IV) (BMOV) Attenuates Apoptosis in High Glucose-Treated Cardiac Cells and Diabetic Rat Hearts by Regulating the Unfolded Protein Responses (UPRs). AB - Endoplasmic reticulum stress (ERS)-induced unfolded protein response (UPR) and the subsequent cell deaths are essential steps in the pathogenesis of diabetic cardiomyopathy (DCM), a main cause of diabetics' morbidity and mortalities. The bis(maltolato)oxovanadium(IV) (BMOV), a potent oral vanadium complex with anti diabetic properties and insulin-mimicking effects, was shown to improve cardiac dysfunctions in diabetic models. Here, we examined the effects of BMOV on UPR pathway protein expression and apoptotic cell deaths in both high glucose-treated cardiac H9C2 cells and in the hearts of diabetic rats. We show that in both the high glucose-treated cardiac cells and in the hearts of streptozotocin (STZ) diabetic rats, there was an overall activation of the UPR signaling, including both apoptotic (e.g., the cascades of PERK/EIf2alpha/ATF4/CHOP and of IRE1/caspase 12/caspase 3) and pro-survival (GRP78 and XBP1) signaling. A high amount of apoptotic cell deaths was also detected in both diabetic conditions. The administration of BMOV suppressed both the apoptotic and pro-survival UPR signaling and significantly attenuated apoptotic cell deaths in both conditions. The overall suppression of UPR signaling by BMOV suggests that the drug protects diabetic cardiomyopathy by counteracting reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. Our findings lend support to promote the use of BMOV in the treatment of diabetic heart diseases. PMID- 26983716 TI - Preparation and Photoluminescence of Sm (3+) Doped YAlO 3 Phosphor. AB - YAlO3: Sm(3+) phosphor has been synthesized by the solid state reaction method with calcium flouride used as a flux. The resulting YAlO3: Sm(3+) phosphor was characterized by X-ray diffraction (XRD) technique, Fourier transmission infrared spectroscopy (FTIR), photoluminescence . . PL excitation spectrum was found at 254,332,380,400,407, 603 and 713 nm. Under excitation of UV(713 nm) YAlO3: Sm(3+) (0-3 %) broad band emission were observed from 400 to 790 nm with a maximum around 713 nm of YAlO3 host lattice accompanied by weak emission of Sm(3+) ((4)G5/2 - (6)H5/2, (6)H7/2,(6)H9/2) transitions. The results of the XRD show that obtained YAlO3: Sm(3+) phosphor has a orthorhombic structure. The study suggested that Sm(3+) doped phosphors are potential luminescence material for laser diode pumping and inorganic scintillators. PMID- 26983715 TI - Melittin, the Major Pain-Producing Substance of Bee Venom. AB - Melittin is a basic 26-amino-acid polypeptide that constitutes 40-60% of dry honeybee (Apis mellifera) venom. Although much is known about its strong surface activity on lipid membranes, less is known about its pain-producing effects in the nervous system. In this review, we provide lines of accumulating evidence to support the hypothesis that melittin is the major pain-producing substance of bee venom. At the psychophysical and behavioral levels, subcutaneous injection of melittin causes tonic pain sensation and pain-related behaviors in both humans and animals. At the cellular level, melittin activates primary nociceptor cells through direct and indirect effects. On one hand, melittin can selectively open thermal nociceptor transient receptor potential vanilloid receptor channels via phospholipase A2-lipoxygenase/cyclooxygenase metabolites, leading to depolarization of primary nociceptor cells. On the other hand, algogens and inflammatory/pro-inflammatory mediators released from the tissue matrix by melittin's pore-forming effects can activate primary nociceptor cells through both ligand-gated receptor channels and the G-protein-coupled receptor-mediated opening of transient receptor potential canonical channels. Moreover, subcutaneous melittin up-regulates Nav1.8 and Nav1.9 subunits, resulting in the enhancement of tetrodotoxin-resistant Na(+) currents and the generation of long term action potential firing. These nociceptive responses in the periphery finally activate and sensitize the spinal dorsal horn pain-signaling neurons, resulting in spontaneous nociceptive paw flinches and pain hypersensitivity to thermal and mechanical stimuli. Taken together, it is concluded that melittin is the major pain-producing substance of bee venom, by which peripheral persistent pain and hyperalgesia (or allodynia), primary nociceptive neuronal sensitization, and CNS synaptic plasticity (or metaplasticity) can be readily induced and the molecular and cellular mechanisms underlying naturally-occurring venomous biotoxins can be experimentally unraveled. PMID- 26983717 TI - TPEN, a Specific Zn2+ Chelator, Inhibits Sodium Dithionite and Glucose Deprivation (SDGD)-Induced Neuronal Death by Modulating Apoptosis, Glutamate Signaling, and Voltage-Gated K+ and Na+ Channels. AB - Hypoxia-ischemia-induced neuronal death is an important pathophysiological process that accompanies ischemic stroke and represents a major challenge in preventing ischemic stroke. To elucidate factors related to and a potential preventative mechanism of hypoxia-ischemia-induced neuronal death, primary neurons were exposed to sodium dithionite and glucose deprivation (SDGD) to mimic hypoxic-ischemic conditions. The effects of N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a specific Zn2+-chelating agent, on SDGD-induced neuronal death, glutamate signaling (including the free glutamate concentration and expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor (GluR2) and N-methyl-D-aspartate (NMDA) receptor subunits (NR2B), and voltage-dependent K+ and Na+ channel currents were also investigated. Our results demonstrated that TPEN significantly suppressed increases in cell death, apoptosis, neuronal glutamate release into the culture medium, NR2B protein expression, and I K as well as decreased GluR2 protein expression and Na+ channel activity in primary cultured neurons exposed to SDGD. These results suggest that TPEN could inhibit SDGD-induced neuronal death by modulating apoptosis, glutamate signaling (via ligand-gated channels such as AMPA and NMDA receptors), and voltage-gated K+ and Na+ channels in neurons. Hence, Zn2+ chelation might be a promising approach for counteracting the neuronal loss caused by transient global ischemia. Moreover, TPEN could represent a potential cell-targeted therapy. PMID- 26983718 TI - Time-Dependent Changes in Apoptosis Upon Autophagy Inhibition in Astrocytes Exposed to Oxygen and Glucose Deprivation. AB - Recent studies have implicated the role of autophagy in brain ischemia pathophysiology. However, it remains unclear whether autophagy activation is protective or detrimental to astrocytes undergoing ischemic stress. This study evaluated the influence of ischemia-induced autophagy on cell death and the course of intrinsic and extrinsic apoptosis in primary cultures of rat cortical astrocytes exposed to combined oxygen-glucose deprivation (OGD). The role of autophagy was assessed by pharmacological inhibition with 3-methyladenine (3-MA). Cell viability was evaluated by measuring LDH release and through the use of the alamarBlue Assay. Apoptosis and necrosis were determined by fluorescence microscopy after Hoechst 33,342 and propidium iodide staining, respectively. The levels of apoptosis-related proteins were analyzed by immunoblotting. The downregulation of autophagy during OGD resulted in decreased cell viability and time-dependent changes in levels of apoptosis and necrosis. After short-term OGD (1, 4 h), cells treated with 3-MA showed higher level of cleaved caspase 3 compared with control cells. This result was consistent with an evaluation of apoptotic cell number by fluorescence microscopy. However, after prolonged exposure to OGD (8, 24 h), the number of apoptotic astrocytes (microscopically evaluated) did not differ or was even lower (as marked by caspase 3) in the presence of the autophagy inhibitor in comparison to the control. A higher level of necrosis was observed in 3-MA-treated cells compared to non-treated cells after 24 h OGD. The downregulation of autophagy caused time-dependent changes in both extrinsic (cleaved caspase 8, TNFalpha) and intrinsic (cleaved caspase 9) apoptotic pathways. Our results strongly indicate that the activation of autophagy in astrocytes undergoing ischemic stress is an adaptive mechanism, which allows for longer cell survival by delaying the initiation of apoptosis and necrosis. PMID- 26983719 TI - Suppressing H19 Modulates Tumorigenicity and Stemness in U251 and U87MG Glioma Cells. AB - Glioblastoma multiforme (GBM) is a type of malignant carcinoma found in the brain. Its high frequency of occurrence and poor survival rate have garnered much research attention in recent years. Long non-coding RNAs (lncRNAs) are known to be related to the formation and progression of several cancer types by both promoting and suppressing tumor transformation. H19 is one such lncRNA and has been shown to be upregulated in a few types of cancer. In this study, we discovered that the expression of H19 increased in GBM cell lines. H19 knocked down GBM cells also displayed decreased cellular proliferation and a higher apoptosis rate when induced by temozolomide. Interestingly, the GBM cell lines U87MG and U251 were found to express cancer stem cell markers CD133, NANOG, Oct4 and Sox2. Expression of these markers was downregulated in H19-deficient cells. Collectively, these data suggest a role for H19 in contributing to GBM malignancy and the maintenance of its stem cell properties. PMID- 26983720 TI - Cobalt serum levels differ in well functioning Birmingham resurfacing and Birmingham modular THA. AB - INTRODUCTION: Metal-on-metal (MoM) bearings are known to release metal ions secondary to wear and corrosion. This may cause local reactions (adverse soft tissue reactions and osteolysis) and systemic effects. Little is known about the exact pattern and the differences between large head MoM total hip replacements (THA) and resurfacings (HR). QUESTIONS: (1) Is there a difference in metal ion concentrations between HR and MoM-THR using the same bearing design (Birmingham Hip Resurfacing System, Smith & Nephew, Inc. Memphis, TN, USA)? (2) Are metal ion levels changing over time in MoM-THA or HR? (3) Do acetabular inclination angle and femoral component size influence cobalt and chromium levels? Is there a correlation between clinical outcome and metal ion levels? MATERIALS AND METHODS: A retrospective analysis was conducted in 77 well functioning unilateral Birmingham HR and 42 well functioning unilateral modular Birmingham MoM-THA (Smith & Nephew, Inc. Memphis, TN, USA) operated on between 2007 and 2012. Blood samples were taken at a minimum of 13 months and subsequent during annual follow ups. RESULTS: (1) Cobalt levels were significantly higher in MoM-THA compared to HR (p < 0.001). There was no significant difference in chromium levels (p = 0.313). (2) Cobalt is increasing over time in MoM-THA (p = 0.030) whereas metal ions remain stable in HR. (3) Metal ion levels were not affected by acetabular inclination angle and femoral component size in MoM-THA. Chromium levels correlate with the femoral component size (r = -0.240; p = 0.037), the UCLA activity score (r = -0.344; p = 0.003) and the VAS (r = 0.263; p = 0.38) in HR. CONCLUSION: Considering that HR and MoM-THA used the same MoM bearing design, increased cobalt levels may be related to trunnion wear or corrosion. Elevated cobalt levels should raise concern for corrosion related failure in MoM-THA. PMID- 26983722 TI - Letter to the Editor concerning "Incidence of adjacent segment degeneration in cervical disc arthroplasty versus anterior cervical decompression and fusion meta analysis of prospective studies" by Luo et al. (2015) Arch Orthop Trauma Surg 135(2):155-60. doi:10.1007/s00402-014-2125-2. PMID- 26983723 TI - A novel method to measure femoral component migration by computed tomography: a cadaver study. AB - INTRODUCTION: Radiostereometric analysis (RSA) is the most accurate technique to measure implant migration. However, it requires special equipment, technical expertise and analysis software and has not gained wide acceptance. The current paper analyzes a novel method to measure implant migration utilizing widely available computer tomography (CT). METHODS: Three uncemented total hip replacements were performed in three human cadavers and six tantalum beads were inserted into the femoral bone similar to RSA. Six different 28 mm heads (-3, 0, 2.5, 5.0, 7.5 and 10 mm) were added to simulate five reproducible translations (maximum total point migration) of the center of the head. Implant migration was measured in a 3-D analysis software (Geomagic Studio 7). Repeat manual reconstructions of the center of the head were performed by two investigators to determine repeatability and accuracy. RESULTS: The accuracy of measurements between the centers of two head sizes was 0.11 mm with a CI 95 % of 0.22 mm. The intra-observer repeatability was 0.13 mm (CI 95 % 0.25 mm). The interrater reliability was 0.943. CONCLUSION: CT based measurement of head displacement in a cadaver model were highly accurate and reproducible. PMID- 26983721 TI - Patch-augmented rotator cuff repair: influence of the patch fixation technique on primary biomechanical stability. AB - INTRODUCTION: There is an ongoing debate about the potential of patch augmentation to improve biomechanical stability and healing associated with rotator cuff repair. The biomechanical properties of three different patch augmented rotator cuff repair techniques were assessed in vitro and compared with a standard repair. Dermal collagen patch augmentation may increase the primary stability and strength of the repaired tendon in vitro, depending on the technique used for patch application. METHODS AND MATERIALS: Forty cadaveric sheep shoulders with dissected infraspinatus tendons were randomized into four groups (n = 10/group) for tendon repair using a knotless double-row suture anchor technique. A xenologous dermal extracellular matrix patch was used for augmentation in the three test groups using an "integrated", "cover", or "hybrid" technique. Tendons were preconditioned, cyclically loaded from 10 to 30 N at 1 Hz, and then loaded monotonically to failure. Biomechanical properties and the mode of failure were evaluated. RESULTS: Patch augmentation significantly increased the maximum load at failure by 61 % in the "cover" technique test group (225.8 N) and 51 % in the "hybrid" technique test group (211.4 N) compared with the non-augmented control group (140.2 N) (P <= 0.015). For the test group with "integrated" patch augmentation, the load at failure was 28 % lower (101.6 N) compared with the control group (P = 0.043). There was no significant difference in initial and linear stiffness among the four experimental groups. The most common mode of failure was tendon pullout. No anchor dislocation, patch disruption or knot breakage was observed. CONCLUSION: Additional patch augmentation with a collagen patch influences the biomechanical properties of a rotator cuff repair in a cadaveric sheep model. Primary repair stability can be significantly improved depending on the augmentation technique. PMID- 26983725 TI - The Role of Stress in the Self-Organized Growth of Porous Anodic Alumina. AB - Ridges and depressions were formed on the barrier layer during chemical and physical etching of porous anodic alumina (PAA) from the bottom side, indicating nonuniform etching rate around each cell. These behaviors cannot be explained solely by the well-known composition variation, but were in line with the hexagonal distribution of stress within the barrier layer of each cell. Such stress variation should be attributed to the interactions of neighboring cells undergoing volume expansion. These interactions could account for the self organization of PAA. PMID- 26983724 TI - Involvement of stakeholders in determining health priorities of adolescents in rural South Africa. AB - BACKGROUND: When developing intervention research, it is important to explore issues from the community perspective. Interventions that promote adolescent health in South Africa are urgently needed, and Project Ntshembo ('hope') aims to improve the health of young women and their offspring in the Agincourt sub district of rural northeast South Africa, actively using stakeholder involvement throughout the research process. OBJECTIVE: This study aimed to determine adolescent health priorities according to key stakeholders, to align stakeholder and researcher priorities, and to form a stakeholder forum, which would be active throughout the intervention. DESIGN: Thirty-two stakeholders were purposefully identified as community members interested in the health of adolescents. An adapted Delphi incorporating face-to-face discussions, as well as participatory visualisation, was used in a series of three workshops. Consensus was determined through non-parametric analysis. RESULTS: Stakeholders and researchers agreed that peer pressure and lack of information, or having information but not acting on it, were the root causes of adolescent health problems. Pregnancy, HIV, school dropout, alcohol and drug abuse, not accessing health services, and unhealthy lifestyle (leading to obesity) were identified as priority adolescent health issues. A diagram was developed showing how these eight priorities relate to one another, which was useful in the development of the intervention. A stakeholder forum was founded, comprising 12 of the stakeholders involved in the stakeholder involvement process. CONCLUSIONS: The process brought researchers and stakeholders to consensus on the most important health issues facing adolescents, and a stakeholder forum was developed within which to address the issues. Stakeholder involvement as part of a research engagement strategy can be of mutual benefit to the researchers and the community in which the research is taking place. PMID- 26983727 TI - An Introduction to Poliovirus: Pathogenesis, Vaccination, and the Endgame for Global Eradication. AB - Poliomyelitis is caused by poliovirus, which is a positive strand non-enveloped virus that occurs in three distinct serotypes (1, 2, and 3). Infection is mainly by the fecal-oral route and can be confined to the gut by antibodies induced either by vaccine, previous infection or maternally acquired. Vaccines include the live attenuated strains developed by Sabin and the inactivated vaccines developed by Salk; the live attenuated vaccine (Oral Polio Vaccine or OPV) has been the main tool in the Global Program of Polio eradication of the World Health Organisation. Wild type 2 virus has not caused a case since 1999 and type 3 since 2012 and eradication seems near. However most infections are entirely silent so that sophisticated environmental surveillance may be needed to ensure that the virus has been eradicated, and the live vaccine can sometimes revert to virulent circulating forms under conditions that are not wholly understood. Cessation of vaccination is therefore an increasingly important issue and inactivated polio vaccine (IPV) is playing a larger part in the end game. PMID- 26983726 TI - Effects of Habitual Physical Activity and Fitness on Tibial Cortical Bone Mass, Structure and Mass Distribution in Pre-pubertal Boys and Girls: The Look Study. AB - Targeted weight-bearing activities during the pre-pubertal years can improve cortical bone mass, structure and distribution, but less is known about the influence of habitual physical activity (PA) and fitness. This study examined the effects of contrasting habitual PA and fitness levels on cortical bone density, geometry and mass distribution in pre-pubertal children. Boys (n = 241) and girls (n = 245) aged 7-9 years had a pQCT scan to measure tibial mid-shaft total, cortical and medullary area, cortical thickness, density, polar strength strain index (SSIpolar) and the mass/density distribution through the bone cortex (radial distribution divided into endo-, mid- and pericortical regions) and around the centre of mass (polar distribution). Four contrasting PA and fitness groups (inactive-unfit, inactive-fit, active-unfit, active-fit) were generated based on daily step counts (pedometer, 7-days) and fitness levels (20-m shuttle test and vertical jump) for boys and girls separately. Active-fit boys had 7.3 7.7 % greater cortical area and thickness compared to inactive-unfit boys (P < 0.05), which was largely due to a 6.4-7.8 % (P < 0.05) greater cortical mass in the posterior-lateral, medial and posterior-medial 66 % tibial regions. Cortical area was not significantly different across PA-fitness categories in girls, but active-fit girls had 6.1 % (P < 0.05) greater SSIpolar compared to inactive-fit girls, which was likely due to their 6.7 % (P < 0.05) greater total bone area. There was also a small region-specific cortical mass benefit in the posterior medial 66 % tibia cortex in active-fit girls. Higher levels of habitual PA fitness were associated with small regional-specific gains in 66 % tibial cortical bone mass in pre-pubertal children, particularly boys. PMID- 26983728 TI - Poliovirus Laboratory Based Surveillance: An Overview. AB - World Health Assembly (WHA) in 1988 encouraged the member states to launch Global Polio Eradication Initiative (GPEI) (resolution WHA41.28) against "the Crippler" called poliovirus, through strong routine immunization program and intensified surveillance systems. Since its launch, global incidence of poliomyelitis has been reduced by more than 99 % and the disease squeezed to only three endemic countries (Afghanistan, Pakistan, and Nigeria) out of 125. Today, poliomyelitis is on the verge of eradication, and their etiological agents, the three poliovirus serotypes, are on the brink of extinction from the natural environment. The last case of poliomyelitis due to wild type 2 strain occurred in 1999 in Uttar Pradesh, India whereas the last paralytic case due to wild poliovirus type 3 (WPV3) was seen in November, 2012 in Yobe, Nigeria. Despite this progress, undetected circulation cannot fully rule out the eradication as most of the poliovirus infections are entirely subclinical; hence sophisticated environmental surveillance is needed to ensure the complete eradication of virus. Moreover, the vaccine virus in under-immunized communities can sometimes revert and attain wild type characteristics posing a big challenge to the program. PMID- 26983730 TI - Isolation and Characterization of Poliovirus in Cell Culture Systems. AB - The isolation and characterization of enteroviruses by cell culture was accepted as the "gold standard" by clinical virology laboratories. Methods for the direct detection of all enteroviruses by reverse transcription polymerase chain reaction, targeting a conserved region of the genome, have largely supplanted cell culture as the principal diagnostic procedure. However, the World Health Organization's Global Polio Eradication Initiative continues to rely upon cell culture to isolate poliovirus due to the lack of a reliable sensitive genetic test for direct typing of enteroviruses from clinical specimens. Poliovirus is able to infect a wide range of mammalian cell lines, with CD155 identified as the primary human receptor for all three seroytpes, and virus replication leads to an observable cytopathic effect. Inoculation of cell lines with extracts of clinical specimens and subsequent passaging of the cells leads to an increased virus titre. Cultured isolates of poliovirus are suitable for testing by a variety of methods and remain viable for years when stored at low temperature.This chapter describes general procedures for establishing a cell bank and routine passaging of cell lines. While the sections on specimen preparation and virus isolation focus on poliovirus, the protocols are suitable for other enteroviruses. PMID- 26983729 TI - Isolation and Characterization of Enteroviruses from Clinical Samples. AB - Enterovirus infections are common in humans worldwide. Enteroviruses are excreted in feces during infection and can be detected from stool specimens by isolation in continuous laboratory cell lines. Characterization of enteroviruses is based on their antigenic and/or genetic properties. PMID- 26983731 TI - Molecular Characterization of Polio from Environmental Samples: ISSP, The Israeli Sewage Surveillance Protocol. AB - Polioviruses are enteric viruses that cause paralytic poliomyelitis in less than 0.5 % of infections and are asymptomatic in >90 % infections of naive hosts. Environmental surveillance monitors polio in populations rather than in individuals. When this very low morbidity to infection ratio, drops drastically in highly vaccinated populations, environmental surveillance employing manual or automatic sampling coupled with molecular analysis carried out in well-equipped central laboratories becomes the surveillance method of choice since polioviruses are excreted by infected individuals regardless of whether or not the infection is symptomatic. This chapter describes a high throughput rapid turn-around time method for molecular characterization of polioviruses from sewage. It is presented in five modules: (1) Sewage collection and concentration of the viruses in the sewage; (2) Cell cultures for identification of virus in the concentrated sewage; (3) Nucleic acid extractions directly from sewage and from tissue cultures infected with aliquots of concentrated sewage; (4) Nucleic Acid Amplification for poliovirus serotype identification and intratypic differentiation (discriminating wild and vaccine derived polioviruses form vaccine strains); and (5) Molecular characterization of viral RNA by qRT-PCR, TR PCR, and Sequence analysis. Monitoring silent or symptomatic transmission of vaccine-derived polioviruses or wild polioviruses is critical for the endgame of poliovirus eradication. We present methods for adapting standard kits and validating the changes for this purpose based on experience gained during the recent introduction and sustained transmission of a wild type 1 poliovirus in Israel in 2013 in a population with an initial IPV vaccine coverage >90 %. PMID- 26983732 TI - Quality Assurance in the Polio Laboratory. Cell Sensitivity and Cell Authentication Assays. AB - The accuracy of poliovirus surveillance is largely dependent on the quality of the cell lines used for virus isolation, which is the foundation of poliovirus diagnostic work. Many cell lines are available for the isolation of enteroviruses, whilst genetically modified L20B cells can be used as a diagnostic tool for the identification of polioviruses. To be confident that cells can consistently isolate the virus of interest, it is necessary to have a quality assurance system in place, which will ensure that the cells in use are not contaminated with other cell lines or microorganisms and that they remain sensitive to the viruses being studied.The sensitivity of cell lines can be assessed by the regular testing of a virus standard of known titer in the cell lines used for virus isolation. The titers obtained are compared to previously obtained titers in the same assay, so that any loss of sensitivity can be detected.However, the detection of cell line cross contamination is more difficult. DNA bar coding is a technique that uses a short DNA sequence from a standardized position in the genome as a molecular diagnostic assay for species level identification. For almost all groups of higher animals, the cytochrome c oxidase subunit 1 of mitochondrial DNA (CO1) is emerging as the standard barcode region. This region is 648 nucleotide base pairs long in most phylogenetic groups and is flanked by regions of conserved sequences, making it relatively easy to isolate and analyze. DNA barcodes vary among individuals of the same species to a very minor degree (generally less than 1-2 %), and a growing number of studies have shown that the COI sequences of even closely related species differ by several per cent, making it possible to identify different species with high confidence. PMID- 26983733 TI - A Transgenic Mouse Model of Poliomyelitis. AB - Transgenic mice (tg mice) that express the human poliovirus receptor (PVR), CD155, are susceptible to poliovirus and develop a neurological disease that resembles human poliomyelitis. Assessment of the neurovirulence levels of poliovirus strains, including mutant viruses produced by reverse genetics, circulating vaccine-derived poliovirus, and vaccine candidates, is useful for basic research of poliovirus pathogenicity, the surveillance of circulating polioviruses, and the quality control of oral live poliovirus vaccines, and does not require the use of monkeys. Furthermore, PVR-tg mice are useful for studying poliovirus tissue tropism and host immune responses. PVR-tg mice can be bred with mice deficient in the genes involved in viral pathogenicity. This report describes the methods used to analyze the pathogenicity and immune responses of poliovirus using the PVR-tg mouse model. PMID- 26983735 TI - Molecular Properties of Poliovirus Isolates: Nucleotide Sequence Analysis, Typing by PCR and Real-Time RT-PCR. AB - Virologic surveillance is essential to the success of the World Health Organization initiative to eradicate poliomyelitis. Molecular methods have been used to detect polioviruses in tissue culture isolates derived from stool samples obtained through surveillance for acute flaccid paralysis. This chapter describes the use of realtime PCR assays to identify and serotype polioviruses. In particular, a degenerate, inosine-containing, panpoliovirus (panPV) PCR primer set is used to distinguish polioviruses from NPEVs. The high degree of nucleotide sequence diversity among polioviruses presents a challenge to the systematic design of nucleic acid-based reagents. To accommodate the wide variability and rapid evolution of poliovirus genomes, degenerate codon positions on the template were matched to mixed-base or deoxyinosine residues on both the primers and the TaqManTM probes. Additional assays distinguish between Sabin vaccine strains and non-Sabin strains. This chapter also describes the use of generic poliovirus specific primers, along with degenerate and inosine-containing primers, for routine VP1 sequencing of poliovirus isolates. These primers, along with nondegenerate serotype-specific Sabin primers, can also be used to sequence individual polioviruses in mixtures. PMID- 26983736 TI - Isolation and Characterization of Vaccine-Derived Polioviruses, Relevance for the Global Polio Eradication Initiative. AB - Stool specimens were collected from children with acute flaccid paralysis (AFP) and their contacts, and viral isolation was performed according to standard procedures. If the specimens tested positive for poliovirus, then intratypic differentiation (ITD) methods were performed on the viral isolates to determine whether the poliovirus isolates were wild or of vaccine origin, these include a poliovirus diagnostic ITD real-time PCR method and a vaccine-derived poliovirus (VDPV) screening real-time PCR method.Viral RNA was extracted from the poliovirus isolates by using the QIAamp Mini Viral RNA Extraction Kit (Qiagen) and was used for RT-PCR amplification by the standard method. The entire VP1 region of the poliovirus isolates was amplified by RT-PCR with primers that flanked the VP1 coding region. After purification of the PCR products by the QIAquick Gel Extraction Kit (Qiagen), the amplicons were bidirectionally sequenced with the ABI PRISM 3130 Genetic Analyzer (Applied Biosystems). A neurovirulence test of polioviruses isolates was carried out using PVR-Tg21 mice that expressed the human poliovirus receptor (CD155). And the temperature sensitivities of polioviruses isolates were assayed on monolayer RD cells in 24-well plates as described. PMID- 26983734 TI - Standardized Methods for Detection of Poliovirus Antibodies. AB - Testing for neutralizing antibodies against polioviruses has been an established gold standard for assessing individual protection from disease, population immunity, vaccine efficacy studies, and other vaccine clinical trials. Detecting poliovirus specific IgM and IgA in sera and mucosal specimens has been proposed for evaluating the status of population mucosal immunity. More recently, there has been a renewed interest in using dried blood spot cards as a medium for sample collection to enhance surveillance of poliovirus immunity. Here, we describe the modified poliovirus microneutralization assay, poliovirus capture IgM and IgA ELISA assays, and dried blood spot polio serology procedures for the detection of antibodies against poliovirus serotypes 1, 2, and 3. PMID- 26983737 TI - Phylogenetic Analysis of Poliovirus Sequences. AB - Comparative genomic sequencing is a major surveillance tool in the Polio Laboratory Network. Due to the rapid evolution of polioviruses (~1 % per year), pathways of virus transmission can be reconstructed from the pathways of genomic evolution. Here, we describe three main phylogenetic methods; estimation of genetic distances, reconstruction of a maximum-likelihood (ML) tree, and estimation of substitution rates using Bayesian Markov chain Monte Carlo (MCMC). The data set used consists of complete capsid sequences from a survey of poliovirus sequences available in GenBank. PMID- 26983738 TI - Generation of Infectious Poliovirus with Altered Genetic Information from Cloned cDNA. AB - The effect of specific genetic alterations on virus biology and phenotype can be studied by a great number of available assays. The following method describes the basic protocol to generate infectious poliovirus with altered genetic information from cloned cDNA in cultured cells.The example explained here involves generation of a recombinant poliovirus genome by simply replacing a portion of the 5' noncoding region with a synthetic gene by restriction cloning. The vector containing the full length poliovirus genome and the insert DNA with the known mutation(s) are cleaved for directional cloning, then ligated and transformed into competent bacteria. The recombinant plasmid DNA is then propagated in bacteria and transcribed to RNA in vitro before RNA transfection of cultured cells is performed. Finally, viral particles are recovered from the cell culture. PMID- 26983739 TI - A Rapid Method for Engineering Recombinant Polioviruses or Other Enteroviruses. AB - The cloning of large enterovirus RNA sequences is labor-intensive because of the frequent instability in bacteria of plasmidic vectors containing the corresponding cDNAs. In order to circumvent this issue we have developed a PCR based method that allows the generation of highly modified or chimeric full length enterovirus genomes. This method relies on fusion PCR which enables the concatenation of several overlapping cDNA amplicons produced separately. A T7 promoter sequence added upstream the fusion PCR products allows its transcription into infectious genomic RNAs directly in transfected cells constitutively expressing the phage T7 RNA polymerase. This method permits the rapid recovery of modified viruses that can be subsequently amplified on adequate cell-lines. PMID- 26983740 TI - Methods to Monitor Molecular Consistency of Oral Polio Vaccine. AB - Replication of viruses leads to emergence of mutations and their content in viral populations can increase by selection depending on growth conditions. Some of these mutations have deleterious effect on vaccine safety, such as neurovirulent reversions in the 5'-UTR of attenuated Sabin strains of poliovirus. Their content in vaccine batches must be tightly controlled during vaccine manufacture to ensure safety of the product. This chapter describes a quantitative molecular procedure called mutant analysis by PCR and restriction enzyme cleavage (MAPREC) that is used to monitor content of neurovirulent revertants in Oral Polio Vaccine (OPV). The method can be used for quantitative analysis of any other mutation in a viral population. PMID- 26983742 TI - Measuring Poliovirus Antigenicity by Surface Plasmon Resonance. Application for Potency Indicating Assays. AB - The D-antigen ELISA is the commonly accepted test for release of inactivated poliovirus containing vaccines. However, this test has a few drawbacks regarding the many variations in the method to quantify the D-unit. The result may depend on method and reagents used which makes standardization of inactivated polio vaccines, based on D-units, to a real challenge. This chapter describes a surface plasmon resonance based method to quantify D-units. The advantage of the calibrated D-antigen assay is the decrease in test variations because no labels, [no incubation times] and no washing steps are necessary. For standardization of both IPV and Sabin IPV, the calibration free concentration analysis could be an improvement as compared to ELISA or other SPR methods because this method combines quantity (particle concentration) and quality (antigenicity) in one assay. PMID- 26983741 TI - Methods for the Quality Control of Inactivated Poliovirus Vaccines. AB - Inactivated poliovirus vaccine (IPV) plays an instrumental role in the Global Poliovirus Eradication Initiative (GPEI). The quality of IPV is controlled by assessment of the potency of vaccine batches. The potency of IPV can be assessed by both in vivo and in vitro methods. In vitro potency assessment is based upon the assessment of the quantity of the D-Antigen (D-Ag) units in an IPV. The D-Ag unit is used as a measure of potency as it is largely expressed on native infectious virions and is the protective immunogen. The most commonly used in vitro test is the indirect ELISA which is used to ensure consistency throughout production.A range of in vivo assays have been developed in monkeys, chicks, guinea pigs, mice, and rats to assess the potency of IPV. All are based on assessment of the neutralizing antibody titer within the sera of the respective animal model. The rat potency test has become the favored in vivo potency test as it shows minimal variation between laboratories and the antibody patterns of rats and humans are similar. With the development of transgenic mice expressing the human poliovirus receptor, immunization-challenge tests have been developed to assess the potency of IPVs. This chapter describes in detail the methodology of these three laboratory tests to assess the quality of IPVs. PMID- 26983743 TI - Identification and Analysis of Antiviral Compounds Against Poliovirus. AB - The Global Polio Eradication Initiative, launched in 1988, had as its goal the eradication of polio worldwide by the year 2000 through large-scale vaccinations campaigns with the live attenuated oral PV vaccine (OPV) (Griffiths et al., Biologicals 34:73-74, 2006). Despite substantial progress, polio remains endemic in several countries and new imported cases are reported on a regular basis ( http://www.polioeradication.org/casecount.asp ).It was recognized by the poliovirus research community that developing antivirals against poliovirus would be invaluable in the post-OPV era. Here, we describe three methods essential for the identification of selective inhibitors of poliovirus replication and for determining their mode of action by time-of-drug-addition studies as well as by the isolation of compound-resistant poliovirus variants. PMID- 26983745 TI - Narrative self-constitution and vulnerability to co-authoring. AB - All people are vulnerable to having their self-concepts shaped by others. This article investigates that vulnerability using a theory of narrative self constitution. According to narrative self-constitution, people depend on others to develop and maintain skills of self-narration and they are vulnerable to having the content of their self-narratives co-authored by others. This theoretical framework highlights how vulnerability to co-authoring is essential to developing a self-narrative and, thus, the possibility of autonomy. However, this vulnerability equally entails that co-authors can undermine autonomy by contributing disvalued content to the agent's self-narrative and undermining her authorial skills. I illustrate these processes with the first-hand reports of several women who survived sexual abuse as children. Their narratives of survival and healing reveal the challenges involved in (re)developing the skills required to manage vulnerability to co-authoring and how others can help in this process. Finally, I discuss some of the implications of co-authoring for the healthcare professional and the therapeutic relationship. PMID- 26983744 TI - SPECT/CT Improves Detection of Metastatic Sentinel Lymph Nodes in Patients with Head and Neck Melanoma. AB - BACKGROUND: A positive sentinel lymph node (SLN) is the most important prognostic factor for predicting survival in cutaneous melanoma. This study aimed to evaluate how the addition of single-photon emission computed tomography (SPECT) and computed tomography (CT) to planar lymphoscintigraphy (PL) alters SLN identification, yield, and localization of metastatic nodes in head and neck melanoma. METHODS: This retrospective review examined patients undergoing SLN biopsy for cutaneous melanoma of the head and neck between July 2003 and December 2015. Patient demographics and pathologic outcomes were compared for patients undergoing SPECT-CT versus PL. A multivariable logistic regression analysis was used to identify factors associated with the identification of a positive SLN. RESULTS: Among 176 patients undergoing SLN biopsy, 91 underwent PL and 85 underwent SPECT-CT and PL. The patients in the SPECT-CT group were older than the PL patients (p = 0.050) but the groups did not differ in gender (p = 0.447), Breslow thickness (p = 0.744), or total number of SLNs identified (p = 0.633). As shown by the multivariate regression analysis, only Breslow thickness [odds ratio (OR) 1.47; 95 % confidence interval (CI) 1.17-1.84] and SPECT-CT (OR 3.58; 95 % CI 1.24-10.4) were associated with a positive SLN. CONCLUSION: The use of SPECT CT for patients with head and neck cutaneous melanoma significantly increases the likelihood of retrieving a positive SLN. Long-term follow-up evaluation is needed for further definition of the impact that SPECT-CT has on recurrence and survival. PMID- 26983746 TI - [Dyspnea, itching and depression in palliative medicine]. AB - Palliative medicine focuses on relieving burdening symptoms to improve quality of life. The most common symptoms are physical weakness, pain, loss of appetite, nausea as well as dyspnea, itching and depression. Frequently, good symptom control can be achieved using the most effective drug combination therapy or non medicinal interventions. This article specifically addresses the physical symptoms dyspnea, itching and the psychological symptom depression. PMID- 26983747 TI - Micronutrient Supplementation after Biliopancreatic Diversion with Duodenal Switch in the Long Term. AB - BACKGROUND: Malabsorptive bariatric surgery requires life-long micronutrient supplementation. Based on the recommendations, we assessed the number of adjustments of micronutrient supplementation and the prevalence of vitamin and mineral deficiencies at a minimum follow-up of 5 years after biliopancreatic diversion with duodenal switch (BPD-DS). METHODS: Between October 2010 and December 2013, a total of 51 patients at a minimum follow-up of 5 years after BPD DS were invited for a clinical check-up with a nutritional blood screening test for vitamins and minerals. RESULTS: Forty-three of fifty-one patients (84.3 %) completed the blood sampling with a median follow-up of 71.2 (range 60-102) months after BPD-DS. At that time, all patients were supplemented with at least one multivitamin. However, 35 patients (81.4 %) showed either a vitamin or a mineral deficiency or a combination of it. Nineteen patients (44.1 %) were anemic, and 17 patients (39.5 %) had an iron deficiency. High deficiency rates for fat-soluble vitamins were also present in 23.2 % for vitamin A, in 76.7 % for vitamin D, in 7.0 % for vitamin E, and in 11.6 % for vitamin K. CONCLUSIONS: The results of our study show that the prevalence of vitamin and mineral deficiencies after BPD-DS is 81.4 % at a minimum follow-up of 5 years. The initial prescription of micronutrient supplementation and further adjustments during the first follow-up were insufficient to avoid long-term micronutrient deficiencies. Life-long monitoring of micronutrients at a specialized bariatric center and possibly a better micronutrient supplementation, is crucial to avoid a deficient micronutrient status at every stage after malabsorptive bariatric surgery. PMID- 26983749 TI - Daily chocolate consumption is inversely associated with insulin resistance and liver enzymes in the Observation of Cardiovascular Risk Factors in Luxembourg study. AB - This study examined the association of chocolate consumption with insulin resistance and serum liver enzymes in a national sample of adults in Luxembourg. A random sample of 1153 individuals, aged 18-69 years, was recruited to participate in the cross-sectional Observation of Cardiovascular Risk Factors in Luxembourg study. Chocolate consumption (g/d) was obtained from a semi quantitative FFQ. Blood glucose and insulin levels were used for the homoeostasis model assessment of insulin resistance (HOMA-IR). Hepatic biomarkers such as serum gamma-glutamyl-transpeptidase (gamma-GT), serum aspartate transaminase and serum alanine transaminase (ALT) (mg/l) were assessed using standard laboratory assays. Chocolate consumers (81.8 %) were more likely to be younger, physically active, affluent people with higher education levels and fewer chronic co morbidities. After excluding subjects taking antidiabetic medications, higher chocolate consumption was associated with lower HOMA-IR (beta=-0.16, P=0.004), serum insulin levels (beta=-0.16, P=0.003) and gamma-GT (beta=-0.12, P=0.009) and ALT (beta=-0.09, P=0.004), after adjustment for age, sex, education, lifestyle and dietary confounding factors, including intakes of fruits and vegetables, alcohol, polyphenol-rich coffee and tea. This study reports an independent inverse relationship between daily chocolate consumption and levels of insulin, HOMA-IR and liver enzymes in adults, suggesting that chocolate consumption may improve liver enzymes and protect against insulin resistance, a well-established risk factor for cardiometabolic disorders. Further observational prospective research and well-designed randomised-controlled studies are needed to confirm this cross-sectional relationship and to comprehend the role and mechanisms that different types of chocolate may play in insulin resistance and cardiometabolic disorders. PMID- 26983750 TI - Erratum to: MicroRNAs involved in the browning process of adipocytes. PMID- 26983748 TI - A Time Interval of More Than 18 Months Between a Pregnancy and a Roux-en-Y Gastric Bypass Increases the Risk of Iron Deficiency and Anaemia in Pregnancy. AB - OBJECTIVE: The aim of the study is to explore the impact of time between Roux-en Y gastric bypass (RYGB) and pregnancy on obstetrical outcome and nutritional derangements. METHODS: In a retrospective cross-sectional study of pregnant women admitted for antenatal care at two tertiary hospitals, we examined 153 women with RYGB and a singleton pregnancy of at least 24 weeks. The women were stratified according to a pregnancy <18 months (40 women) or >=18 months (113 women) after RYGB. Main outcome measures were nutritional parameters and glycated haemoglobin 1Ac (HbA1c) in second and third trimester of pregnancy, gestational hypertension, length of pregnancy, mode of delivery and foetal birth weight. RESULTS: The two groups were comparable regarding age, parity and prepregnancy body mass index. The frequency of iron deficiency anaemia (ferritin <12 MUg/L and haemoglobin <6.5 mmol/L/10.5 g/dL) was significantly higher in the late group, 29 vs. 8 % in the early group, p = 0.010. No differences were found for vitamin B12, vitamin D and zinc. Median HbA1c was significantly higher in the late group than in the early group (33 vs. 31 mmol/mol, p = 0.027). There were no significant differences in the risk of adverse pregnancy outcome or birth weight between the two groups. CONCLUSION: A long surgery-to-pregnancy time interval after a RYGB increases the risk of iron deficiency anaemia but not of other nutritional deficits. Time interval does not seem to have an adverse effect on the obstetrical outcome, including intrauterine growth restriction. Specific attention is needed on iron deficit with increasing surgery-to-pregnancy time interval. PMID- 26983751 TI - Erythema of Rosacea Impairs Health-Related Quality of Life: Results of a Meta analysis. AB - INTRODUCTION: The central diagnostic feature of rosacea is diffuse central-facial erythema. The objective was to summarize published and unpublished health-related quality of life (HRQoL) data from seven previous studies in rosacea patients. METHODS: A meta-analysis was performed on baseline HRQoL data of subjects with erythema of rosacea from five randomized controlled trials, one open-label safety study and one epidemiological study. The data from four questionnaires were analyzed, including the Euro QoL 5-dimension (EQ5D) generic questionnaire, the Dermatology Life Quality Index (DLQI) dermatology-specific quality of life instrument, the Productivity and Social Life Questionnaire and the Facial Redness Questionnaire. RESULTS: The global EQ5D index score was 0.859 and the domains of pain/discomfort (31.5% moderate or extreme pain) and anxiety/depression (26.4% moderate or extreme) were most affected. Worse scores were observed with erythema of rosacea in the absence of inflammatory lesions (EQ5D score of 0.832 for no lesions vs 0.919 for subjects with >=1 lesion). Almost half (43%) the subjects had at least moderately impaired HRQoL, including 19.8% with a DLQI total score of >=11 indicating severely impaired HRQoL; symptoms/feelings was the most affected domain. Subjects with a patient self-assessment (PSA) of severe erythema of rosacea had a worse mean DLQI score than moderate PSA subjects (8.6 vs 6.0). Work life and social life were affected, especially in subjects with severe PSA (62% with social life at least somewhat affected). CONCLUSION: Erythema of rosacea causes a marked decrease in HRQoL in most patients, especially those with self-perceived severe erythema and without inflammatory lesions, and should thus be considered as an important medical problem requiring medical intervention. FUNDING: Galderma UK. PMID- 26983752 TI - Traumatic brain injury is not associated with significant myocardial dysfunction: an observational pilot study. AB - BACKGROUND: Myocardial dysfunction has been well described with catastrophic neurological events, such as subarachnoid hemorrhage and brain death. There is very limited data describing myocardial function in the context of traumatic brain injury (TBI), as no prospective study has yet examined this association. The objective of our study was to evaluate cardiac function using echocardiography in patients with clinically important TBI. METHODS: We conducted a prospective observational study of consecutive TBI patients admitted to the intensive care unit. All patients older than 16 years with moderate to severe TBI according to the Glascow Coma Scale (GCS) were eligible for the study. Only patients with a prior history of heart disease or cardiomyopathy or evidence of brain death on admission were excluded. A complete transthoracic echocardiogram was performed within 4 days of admission. RESULTS: Forty-nine patients (67% males, median age 34 years) were included in the study. Forty-one patients had severe TBI (84%) with a median GCS of six, 44 patients (90%) required mechanical ventilation and 36 (74%) intracranial pressure monitoring. Hospital mortality was 18%. No patients had global left ventricular dysfunction as defined by a left ventricular ejection fraction (LVEF) below 50% (95% CI, 0-0.07). Average LVEF was 65 +/- 4%. Four patients (8%) had regional wall motion abnormalities with preserved LVEF. DISCUSSION: The main finding of this study is the absence of clinically significant myocardial dysfunction in patients with moderate or severe TBI. Although myocardial dysfunction has been well described in a variety of neurological settings, it is possible that the young age of TBI patients and the absence of cardiovascular risk factors are protective against significant myocardial injury from catecholamine excess. CONCLUSIONS: In a group of patients with clinically important TBI, we did not identify any significant cardiac dysfunction. PMID- 26983753 TI - High pneumococcal density correlates with more mucosal inflammation and reduced respiratory syncytial virus disease severity in infants. AB - BACKGROUND: Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infections in infants. A small percentage of the infected infants develops a severe infection, while most of these severely ill patients were previously healthy. It remains unclear why these children develop severe RSV infections. In this study, we investigate whether pneumococcal nasopharyngeal carriage patterns correlate with mucosal inflammation and severity of disease. METHODS: In total, 105 infants hospitalized with RSV infection were included and recovery samples were taken from 42 patients. The presence and density of Streptococcus pneumoniae was determined by RT qPCR to study its relation to viral load, inflammation (MMP-9 and IL-6) and severity of RSV disease. RESULTS: We show that pneumococcal presence or absence in the nasopharynx does not correlate with viral load, inflammation or severity of disease. However, when pneumococcus is present in patients, a higher nasopharyngeal pneumococcal density was correlated with a higher RSV load, higher MMP-9 levels and a less severe course of disease. CONCLUSIONS: Our results show correlations between S. pneumoniae density and viral load, inflammation and disease severity, suggesting that pneumococcal density may be an indicator for severity in paediatric RSV disease. PMID- 26983754 TI - Xuebijing injection in the treatment of severe pneumonia: study protocol for a randomized controlled trial. AB - BACKGROUND: Severe pneumonia (SP) is a major complication of respiratory system diseases that is associated with high mortality and morbidity. If not treated correctly, it may rapidly lead to sepsis and multiple organ dysfunction syndrome. Despite continuous developments in antibiotic treatments for SP, the mortality rate remains high. Both basic and clinical research show that Xuebijing injection (XBJ) can improve the symptoms of SP. The aim of this study is to evaluate the effectiveness and safety of XBJ compared with placebo. METHODS/DESIGN: This multicenter, blinded, randomized controlled trial will be conducted with a total of 700 participants with SP. Using a central randomization system, participants will be randomized (1:1) into groups receiving either XBJ or placebo (within 24 h of diagnosis of SP) for 5-7 days with a 28-day follow-up. All participants will receive conventional treatment simultaneously. Both XBJ and placebo will be administered using a photophobic infusion set to avoid bias. The primary outcome is improvement of Pneumonia Severity Index risk rate. Adverse events will be monitored throughout the trial. DISCUSSION: This is the first and largest randomized trial done in China on SP treatment using a Chinese herbal extract. In this trial, we will use central randomization and an electronic case report form, and we have designed an innovative blinding method for the traditional Chinese medicine injection. The results of this trial may help to provide evidence-based recommendations to clinicians for treatment of SP. TRIAL REGISTRATION: Chinese Clinical Trials Registry ChiCTR-TRC-13003534 . Registered 24 June 2013. PMID- 26983755 TI - Coordinate regulatory osteogenesis effects of icariin, timosaponin B II and ferulic acid from traditional Chinese medicine formulas on UMR-106 osteoblastic cells and osteoblasts in neonatal rat calvaria cultures. AB - ETHNOPHARMACOLOGICAL SIGNIFICANCE: Icariin (I), ferulic acid (F) and timosaponin B II (T) derived respectively from the leaf of Epimedium brevicornu Maxim (EBM, Berberidaceae), rhizome of Anemarrhena asphodeloides Bunge (AAB, Liliaceae) and root of Angelica sinensis (Oliv.) Diels (ASD, Umbelliferae) are included in several traditional Chinese medicine (TCM) formulas for the treatment of osteoporosis. In addition, the medicinal materials and chemical constituents in many traditional Chinese formulas have been shown to have potential synergistic, additive and antagonistic effects. AIM OF STUDY: To explore the action mechanism and interactions between I, T and F as bone anabolic ingredients on osteoblasts, and fully understand their action mechanism and rationality of the formula design. MATERIALS AND METHODS: An osteoporotic model was established in bilaterally ovariectomized mice. Bone mineral density (BMD), bone mineral content (BMC) and serum biochemical parameters including alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRAP), osteoprotegerin (OPG) and deoxypyridinoline cross-links (DPD) were measured to evaluate the effects of I, T or F alone and their combinations on osteoporotic mice. UMR-106 osteoblastic cells and primary osteoblasts in neonatal rat calvarias were used to evaluate the osteogenesis effect. The immunohistochemical method and Western-blot analysis were used to detect the expression of critical proteins in the process of proliferation and differentiation of osteoblasts. RESULTS: IFT combinations enhanced the therapeutic effect without increasing the adverse effects on osteoporotic mice, synergistically increased the osteoblast proliferation, ALP activity and mineralized nodule formation, and promoted the expression of bone matrix by regulating BMP and Wnt/beta-catenin signaling pathways in osteoblasts. CONCLUSION: IFT combinations reinforced the therapeutic effect on osteoporosis by modulating multi-signaling pathways and action targets. PMID- 26983757 TI - When two are better than one: bright phosphorescence from non-stereogenic dinuclear iridium(III) complexes. AB - A new family of eight dinuclear iridium(iii) complexes has been prepared, featuring 4,6-diarylpyrimidines L(y) as bis-N^C-coordinating bridging ligands. The metal ions are also coordinated by a terminal N^C^N-cyclometallating ligand L(X) based on 1,3-di(2-pyridyl)benzene, and by a monodentate chloride or cyanide. The general formula of the compounds is {IrL(X)Z}2L(y) (Z = Cl or CN). The family comprises examples with three different L(X) ligands and five different diarylpyrimidines L(y), of which four are diphenylpyrimidines and one is a dithienylpyrimidine. The requisite proligands have been synthesised via standard cross-coupling methodology. The synthesis of the complexes involves a two-step procedure, in which L(X)H is reacted with IrCl3.3H2O to form dinuclear complexes of the form [IrL(X)Cl(MU-Cl)]2, followed by treatment with the diarylpyrimidine L(y)H2. Crucially, each complex is formed as a single compound only: the strong trans influence of the metallated rings dictates the relative disposition of the ligands, whilst the use of symmetrically substituted tridentate ligands eliminates the possibility of Lambda and Delta enantiomers that are obtained when bis-bidentate units are linked through bridging ligands. The crystal structure of one member of the family has been obtained using a synchrotron X-ray source. All of the complexes are very brightly luminescent, with emission maxima in solution varying over the range 517-572 nm, according to the identity of the ligands. The highest-energy emitter is the cyanide derivative whilst the lowest is the complex with the dithienylpyrimidine. The trends in both the absorption and emission energies as a function of ligand substituent have been rationalised accurately with the aid of TD-DFT calculations. The lowest-excited singlet and triplet levels correlate with the trend in the HOMO-LUMO gap. All the complexes have quantum yields that are close to unity and phosphorescence lifetimes - of the order of 500 ns - that are unusually short for complexes of such brightness. These impressive properties stem from an unusually high rate of radiative decay, possibly due to spin-orbit coupling pathways being facilitated by the second metal ion, and to low non-radiative decay rates that may be related to the rigidity of the dinuclear scaffold. PMID- 26983756 TI - CXCR4-antagonist Peptide R-liposomes for combined therapy against lung metastasis. AB - The chemokine CXCL12 activates CXCR4, initiating multiple pathways that control immune cell trafficking, angiogenesis and embryogenesis; CXCR4 is also overexpressed in multiple tumors affecting metastatic dissemination. While there has been great enthusiasm for exploiting the CXCR4-CXCL12 axis as a target in cancer therapy, to date the promise has yet to be fulfilled. A new class of CXCR4 antagonist cyclic peptides was recently developed and the compound named Peptide R was identified as the most active. With the intent to improve the efficacy and biodistribution of Peptide R, stealth liposomes decorated with Peptide R were developed (PL-Peptide R). In vitro PL-Peptide R efficiently inhibited CXCR4 dependent migration and in vivo it significantly reduced lung metastases and increased overall survival in B16-CXCR4 injected C57BL/6 mice. To evaluate if PL Peptide R could also be a drug delivery system for CXCR4 expressing tumors, the PL-Peptide R was loaded with doxorubicin (DOX) (PL-Peptide R-DOX). PL-Peptide R DOX efficiently delivered DOX to CXCR4 expressing cell lines with a consequent decrease in the DOX IC50 efficient dose. In vivo, B16-CXCR4 injected C57BL/6 mice treated with PL-Peptide R-DOX developed fewer lung metastases compared to PL-DOX treated mice. This work provides the proof-of-concept to prevent metastasis by using combined nanomedicine. PMID- 26983760 TI - Effect of alignment perturbations in a trans-tibial prosthesis user: A pilot study. AB - OBJECTIVE: A recurring complication in trans-tibial prosthetic limb users is "poor socket fit" with painful residuum-socket interfaces, a consequence of excess pressure. This is due to both poor socket fit and poor socket alignment; however, the interaction of these factors has not been quantified. Through evaluation of kinetic data this study aimed to articulate an interaction uniting socket design, alignment and interface pressures. The results will help to refine future studies and will hopefully help determine whether sockets can be designed, fitted and aligned to maximize mobility whilst minimizing injurious forces. METHODS: Interface pressures were recorded throughout ambulation in one user with "optimal (reference) alignment" followed by 5 malalignments in a patellar tendon bearing and a hydrocast socket. RESULTS: Marked differences in pressure distribution were discovered when equating the patellar tendon-bearing against the hydrocast socket and when comparing interface pressures from reference with offset alignment. Patellar tendon-bearing sockets were found to be more sensitive to alignment perturbations than hydrocast sockets. A complex interaction was found, with the most prominent finding demonstrating the requisite for attainment of optimal alignment: a translational alignment error of 10 mm can increase maximum peak pressures by 227% (mean 17.5%). CONCLUSION: Refinements for future trials are described and the necessity for future research into socket design, alignment and interface pressures has been estabilished. PMID- 26983759 TI - Syntheses and magnetic properties of a pyrimidyl-substituted nitronyl nitroxide radical and its cobalt(ii) complexes. AB - A new bis-bidentate nitronyl nitroxide radical with a pyrimidyl substituent group and two Co(ii) complexes of this ligand were synthesized and characterized. Field induced single-molecule magnet behavior was firstly observed in the nitronyl nitroxide radical-bridged complexes. PMID- 26983761 TI - Multiple look-alikes delusion. PMID- 26983762 TI - Descriptive diagnostic assessment of depression Categorical diagnosis, dimensional assessment, and instruments. AB - The descriptive diagnostics constitute the first step, the base and the prerequisite for the psychodiagnostic process and the treatment of depression. Within the descriptive diagnostics, two approaches are distinguished, namely (1) the differentiation between dimensional and categorical levels of measurement and (2) the consideration of the influence of the applied method: questionnaire versus interview. Departing from these approaches, a review of the most widely used instruments on depression is given, with a focus on the reliability and validity of the dimensional depression instruments, based on the findings of our research group. The importance of the differentiation between dimensional and categorical levels of measurement can also be recognised within the discussion on quantitative/dimensional versus qualitative/categorical taxonomic views on depression. The Integrated Threshold Model, which integrates both the quantitative and the qualitative view on the classification of depressive disorders, is considered. By way of conclusion, a diagnostic multi level/modality/method strategy is discussed and a specific test battery, which can be particularly useful within a research context, is presented. PMID- 26983758 TI - Human epithelial-type ovarian tumour marker beta-2-microglobulin is regulated by the TGF-beta signaling pathway. AB - BACKGROUND: Beta-2-microglobulin (B2M), a light chain subunit of the major histocompatibility complex (MHC) class I complex, has been implicated in tumorigenesis. However, whether it is expressed in different epithelial-type ovarian tumours remains unknown. This study was performed to examine the expression of B2M in different histopathological types of ovarian tumours, to explore the function of B2M in ovarian cancer (OC) cells and to investigate the mechanisms underlying the regulation of B2M by the TGF-beta signaling pathway. METHODS: B2M expression in normal ovarian tissues and epithelia-type ovarian tumours was detected by immunohistochemistry and Western blot, followed by the analysis of association with clinical features. OC cells were transfected with B2M-siRNA and cell proliferation, migration and invasion were determined by WST-1 assay, wound healing assay and Transwell invasion assay, respectively. The regulation of B2M by the TGF-beta signaling pathway in OC cells was examined by Western blot, ELISA and qRT-PCR. RESULTS: We found that B2M was overexpressed in ovarian borderline and malignant tumours compared with benign tumours and normal controls, but was not associated with age, tumour size, lymph node metastasis and clinical stage. Knocking down of B2M led to a decrease in OC cell proliferation, migration and invasion. The expression of B2M was downregulated by TGF-beta1 in OC cells, which was abolished in the presence of the inhibitor of TGF-beta type I receptor. CONCLUSION: Our findings suggest that B2M is a potential tissue biomarker and therapeutic target of borderline and malignant ovarian tumours and the dysregulation of B2M in these tumours may be mediated by the TGF-beta signaling pathway. PMID- 26983764 TI - Chronic pain and the psychiatrist. AB - Chronic pain is a phenomenon with important psychiatric aspects from a diagnostic as well as a therapeutic point of view. The place of chronic pain in the different versions of the Diagnostic and Statistical Manual of Mental Disorders, and the differential-diagnosis are critically discussed. The comorbidity with depression, anxiety disorders, substance abuse and personality disorders is extensively treated. Finally, the essential role of the psychiatrist in the multidisciplinary therapeutic approach of these patients is emphasised. PMID- 26983763 TI - Klinefelter syndroom en psychiatrische stoornissen: Twee gevalsbeschrijvingen en een literatuuroverzicht. AB - Klinefelter syndrome is a genetically determined disorder characterized by an additional X-chromosome. Apart from the phenotypical features, the literature about this disorder mentiones a psychopathological phenotype comprising mainly psychoses, depressive diseases and personality disorders. A substantial number of patients presents with mild to moderate mental retardation. In this paper, two case reports are described and their psychopathology is compared with the data from the existing literature. PMID- 26983765 TI - Psychiatric complications of drug treatment of Parkinson's disease. AB - Drug-induced psychiatric conditions are a common and severe problem in the treatment of patients with Parkinson's disease. Psychotic symptoms are the most frequent reason for nursing home placement of patients with Parkinson's disease. The psychotic symptoms seem to present themselves in a continuum where alterations in dreaming patterns often precede visual hallucinations, which often progress into delusional syndromes and, finally, into confusional organic syndromes. When evaluating a patient on dopaminergic treatment, it is important to inquire systematically about abnormal sleep related phenomena, for these are important clues in the early detection of psychotic symptoms. The pathogenesis of the psychotic symptoms is not yet fully understood but complex adaptations of various neurotransmitter systems seem to be involved. In the treatment of these drug-induced psychotic symptoms, the atypical antipsychotic drug clozapine plays an important role. Drug-induced mania, hypersexuality and anxiety, although less frequent than the psychotic symptoms, also occur as a complication of dopaminergic treatment. Depressive symptoms, although common in Parkinson's disease, are less likely to occur as a side effect of the drug treatment. PMID- 26983766 TI - Ultrasonography of the scrotum in adults. AB - Ultrasonography is the ideal noninvasive imaging modality for evaluation of scrotal abnormalities. It is capable of differentiating the most important etiologies of acute scrotal pain and swelling, including epididymitis and testicular torsion, and is the imaging modality of choice in acute scrotal trauma. In patients presenting with palpable abnormality or scrotal swelling, ultrasonography can detect, locate, and characterize both intratesticular and extratesticular masses and other abnormalities. A 12-17 MHz high frequency linear array transducer provides excellent anatomic detail of the testicles and surrounding structures. In addition, vascular perfusion can be easily assessed using color and spectral Doppler analysis. In most cases of scrotal disease, the combination of clinical history, physical examination, and information obtained with ultrasonography is sufficient for diagnostic decision-making. This review covers the normal scrotal anatomy as well as various testicular and scrotal lesions. PMID- 26983767 TI - Discrepancies between the ultrasonographic and gross pathological size of papillary thyroid carcinomas. AB - PURPOSE: The goal of this study was to investigate the level of agreement between tumor sizes measured on ultrasonography (US) and in pathological specimens of papillary thyroid carcinomas (PTCs) and to identify the US characteristics contributing to discrepancies in these measurements. METHODS: We retrospectively reviewed the US findings and pathological reports of 490 tumors in 431 patients who underwent surgery for PTC. Agreement was defined as a difference of <20% between the US and pathological tumor size measurements. Tumors were divided by size into groups of 0.5-1 cm, 1-2 cm, 2-3 cm, and >=3 cm. We compared tumors in which the US and pathological tumor size measurements agreed and those in which they disagreed with regard to the following parameters: taller-than-wide shape, infiltrative margin, echogenicity, microcalcifications, cystic changes in tumors, and the US diagnosis. RESULTS: The rate of agreement between US and the pathological tumor size measurements was 64.1% (314/490). Statistical analysis indicated that the US and pathological measurements significantly differed in tumors <1.0 cm in size (P=0.033), with US significantly overestimating the tumor size by 0.2 cm in such tumors (P<0.001). Cystic changes were significantly more frequent in the tumors where US and pathological tumor size measurements disagreed (P<0.001). CONCLUSION: Thyroid US may overestimate the size of PTCs, particularly for tumors <1.0 cm in size. This information may be helpful in guiding decision making regarding surgical extent. PMID- 26983768 TI - The platelet window: examining receptor regulated second messenger processes in psychosis and depression. AB - Peripheral markers of psychiatric illness provide a potentially important window into the pathophysiology of a number of psychiatric illnesses. Direct access to pathophysiological processes is fraught with difficulty. However, receptor regulated second messenger-mediated calcium shifts are an accessible and practical method by which to examine changes in a clinical population. This is possible because platelets and neurons share some physiological features. The platelet intracellular calcium response to receptor stimulation has previously been used as a peripheral marker of psychiatric illness across a range of neurotransmitters, including serotonin, dopamine and glutamate. This review considers the specificity and selectivity of this response and its use in psychotic and mood disorders. PMID- 26983770 TI - Glucocorticoids and glucocorticoid receptors: mediators of fatigue? AB - Fatigue is a common problem; when chronic and disabling, subjects can be categorized as having chronic fatigue syndrome (CFS). Whilst it is most likely a multifactorial condition of biopsychosocial origin, the nature of the pathophysiological component remains unclear. There has been a wealth of interest in the possible hypothalamo-pituitary-adrenal (HPA) axis dysfunction in CFS, and whether such changes may mediate fatigue. On balance, there appears to be reduced cortisol output in a proportion of patients, together with heightened negative feedback and glucocorticoid receptor function. There is evidence for impaired adrenocorticotropic hormone (ACTH) and cortisol responses to a variety of challenges. However, there is no evidence for a specific or uniform dysfunction of the HPA axis. Evidence that these changes may be related to symptom production comes from randomized controlled trials of glucocorticoid replacement therapy, which have shown improvements in fatigue and disability. Given the many factors that may impinge on the HPA axis in CFS, such as inactivity, sleep disturbance, psychiatric comorbidity, medication and ongoing stress, it seems likely that there is not a single or specific change to the HPA axis in CFS and that the observed HPA axis disturbances are of multifactorial etiology. This is further supported by a comparison of neuroendocrine findings in other conditions in which fatigue is prominent, showing both similarities and differences with the pattern in CFS. PMID- 26983769 TI - Molecular targets of lithium action. AB - Lithium is an effective drug for both the treatment and prophylaxis of bipolar disorder. However, the precise mechanism of lithium action is not yet well understood. Extensive research aiming to elucidate the molecular mechanisms underlying the therapeutic effects of lithium has revealed several possible targets. The behavioral and physiological manifestations of the illness are complex and are mediated by a network of interconnected neurotransmitter pathways. Thus, lithium's ability to modulate the release of serotonin at presynaptic sites and modulate receptor-mediated supersensitivity in the brain remains a relevant line of investigation. However, it is at the molecular level that some of the most exciting advances in the understanding of the long-term therapeutic action of lithium will continue in the coming years. The lithium cation possesses the selective ability, at clinically relevant concentrations, to alter the PI second-messenger system, potentially altering the activity and dynamic regulation of receptors that are coupled to this intracellular response. Subtypes of muscarinic receptors in the limbic system may represent particularly sensitive targets in this regard. Likewise, preclinical data have shown that lithium regulates arachidonic acid and the protein kinase C signaling cascades. It also indirectly regulates a number of factors involved in cell survival pathways, including cAMP response element binding protein, brain-derived neurotrophic factor, bcl-2 and mitogen-activated protein kinases, and may thus bring about delayed long-term beneficial effects via under-appreciated neurotrophic effects. Identification of the molecular targets for lithium in the brain could lead to the elucidation of the pathophysiology of bipolar disorder and the discovery of a new generation of mood stabilizers, which in turn may lead to improvements in the long-term outcome of this devastating illness (1). PMID- 26983772 TI - Mood disorders - review of structural MRI studies. AB - BACKGROUND: Mood disorders are related to considerable morbidity and mortality, and although there is little doubt that they are brain-based disorders, their neural correlates still remain elusive. A neuro-anatomic model of mood regulation comprising the prefrontal cortex, amygdala-hippocampus complex, thalamus, basal ganglia, and connections among these areas has been proposed. OBJECTIVE: We reviewed the evidence for regional brain abnormalities in bipolar disorder, and attempted to integrate available findings into a comprehensive pathophysiological model of illness. METHODS: A computerized Medline Ovid search was conducted for the period 1966-2002, and complemented by a manual search of bibliographical references from recent reviews. Articles meeting specified criteria were included. RESULTS: Hyperintense lesions in cortical and subcortical regions are the most consistently reported and widely studied structural abnormalities. Smaller prefrontal cortical volume is a common finding in bipolar disorder and unipolar depression. Enlarged amygdala (in bipolar disorder) and smaller hippocampus (in unipolar depression) have been reported by several groups. Decreased volumes (in unipolar depression) and increased or unaltered volumes (in bipolar disorder) of striatal structures have been reported. CONCLUSIONS: Bipolar and unipolar mood disorders are associated with detectable structural brain abnormalities. The histopathology underlying such anatomical changes remains to be elucidated. To reach more definitive conclusions about neuroanatomical changes that take place during the course of mood disorders, prospective longitudinal studies are needed. Also, integration with functional imaging is necessary in order to elucidate the relevance of identified structural abnormalities. PMID- 26983771 TI - Molecular mechanisms of glucocorticoid receptor sensitivity and relevance to affective disorders. AB - Changes in the hypothalamic-pituitary-adrenocortical (HPA) system are characteristic of depression, and in the majority of these patients these result in HPA axis hyperactivity. This is further supported by the reduced sensitivity to the inhibitory effects of the glucocorticoid, dexamethasone (DEX), on the production of adrenocorticotropic hormone (ACTH) and cortisol, during the DEX suppression test and the DEX-corticotropin-releasing hormone (DEX/CRH) test. Because the effects of glucocorticoids are mediated by intracellular receptors including, most notably, the glucocorticoid receptor (GR), several studies have examined the number and/or function of GRs in depressed patients. These studies have consistently demonstrated that GR function is impaired in major depression, resulting in reduced GR-mediated negative feedback on the HPA axis and increased production and secretion of CRH in various brain regions postulated to be involved in the causality of depression. This article summarizes the literature on GR in depression and on the impact of antidepressants on the GR in clinical and preclinical studies, and supports the concept that impaired GR signaling is a key mechanism in the pathogenesis of depression, in the absence of clear evidence of decreased GR expression. The data also indicate that antidepressants have direct effects on the GR, leading to enhanced GR function and increased GR expression. Hypotheses regarding the mechanism of these receptor changes involve non-steroid compounds that regulate GR function via second messenger pathways, such as cytokines and neurotransmitters. Moreover, we present recent evidence suggesting that membrane steroid transporters such as the multidrug resistance (MDR) p-glycoprotein, which regulate access of glucocorticoids to the brain, could be a fundamental target of antidepressant treatment. Research in this field will lead to new insights into the pathophysiology and treatment of affective disorders. PMID- 26983773 TI - Neurochemical brain imaging studies in bipolar disorder. AB - OBJECTIVE: We reviewed the neurochemical brain imaging literature in bipolar disorder to synthesize the findings and provide directions for future research. METHODS: Relevant articles were retrieved by computerized Medline Ovid search (up to and including 2002) and complemented by bibliographic manual searches of reviews known to the authors. RESULTS: PET and SPECT studies in bipolar disorder have identified changes in various aspects of dopaminergic and serotonergic neurotransmission. Ligands for other neurotransmitters are actively being pursued. Spectroscopy studies have utilized a number of MRS-sensitive nuclei to chemically 'biopsy' the brain of patients with bipolar disorder. Few consistent findings are emerging, however, the majority of nuclei that can be measured are not directly related to the pathophysiology of the disorder. CONCLUSIONS: Brain imaging has the potential to unravel the neurochemical underpinnings of bipolar disorder, however, there is a continuing need for clinical, technical and methodological sophistication. PMID- 26983774 TI - From genomics to proteomics: new directions in molecular neuropsychiatry. AB - Neuropsychiatry, like many other biomedical sciences, has been revolutionized by the advances in genomic technologies over the years. The advent of PCR (polymerase chain reaction) and the sequencing of the human genome have provided invaluable insights into the molecular genetics of the various psychiatric disorders through the study of candidate genes and linkage analyses. However, biological phenotype is dictated by protein expression, which has been shown to stray from the genetic blueprint designated by the genome. Consequently, the field of proteomics has recently emerged as a powerful means of exploring protein structure, function, and expression patterns. The ability to study disease at the gene and protein levels presents a tremendous opportunity for neuropsychiatric research, particularly in terms of the potential for developing therapeutic agents for novel protein targets. PMID- 26983776 TI - Selection of optimal chelator improves the contrast of GRPR imaging using bombesin analogue RM26. AB - Bombesin (BN) analogs bind with high affinity to gastrin-releasing peptide receptors (GRPRs) that are up-regulated in prostate cancer and can be used for the visualization of prostate cancer. The aim of this study was to investigate the influence of radionuclide-chelator complexes on the biodistribution pattern of the 111In-labeled bombesin antagonist PEG2-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta Leu-NH2 (PEG2-RM26) and to identify an optimal construct for SPECT imaging. A series of RM26 analogs N-terminally conjugated with NOTA, NODAGA, DOTA and DOTAGA via a PEG2 spacer were radiolabeled with 111In and evaluated both in vitro and in vivo. The conjugates were successfully labeled with 111In with 100% purity and retained binding specificity to GRPR and high stability. The cellular processing of all compounds was characterized by slow internalization. The IC50 values were in the low nanomolar range, with lower IC50 values for positively charged natIn NOTA-PEG2-RM26 (2.6 +/- 0.1 nM) and higher values for negatively charged natIn DOTAGA-PEG2-RM26 (4.8 +/- 0.5 nM). The kinetic binding studies showed KD values in the picomolar range that followed the same pattern as the IC50 data. The biodistribution of all compounds was studied in BALB/c nu/nu mice bearing PC-3 prostate cancer xenografts. Tumor targeting and biodistribution studies displayed rapid clearance of radioactivity from the blood and normal organs via kidney excretion. All conjugates showed similar uptake in tumors at 4 h p.i. The radioactivity accumulation in GRPR-expressing organs was significantly lower for DOTA- and DOTAGA-containing constructs compared to those containing NOTA and NODAGA. 111In-NOTA-PEG2-RM26 with a positively charged complex showed the highest initial uptake and the slowest clearance of radioactivity from the liver. At 4 h p.i., DOTA- and DOTAGA-coupled analogs showed significantly higher tumor-to-organ ratios compared to NOTA- and NODAGA-containing variants. The NODAGA conjugate demonstrated the best retention of radioactivity in tumors, and, at 24 h p.i., had the highest contrast to blood, muscle and bones. PMID- 26983777 TI - The 'SPARC' of life: Analysis of the role of osteonectin/SPARC in pancreatic cancer (Review). AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most clinically challenging cancers to manage. An estimated 48,960 people will be diagnosed with pancreatic cancer in 2015, of that population, 94% are projected to perish within 5 years. These dismal survival rates can be attributed, in part, to an advanced diagnosis occurring in 80% of cases. The heterogeneous and dynamic microenvironment of pancreatic cancer, and the lack of both specific risk factors and efficacious screening tools contribute to the challenge of diagnosing pancreatic cancer in its early stages. These clinical challenges have directed research into the unique characteristics that define PDAC. Recently, there has been an increased focus on the interaction of tumor cells with their microenvironment in the hope of identifying new therapeutic targets. One of the most promising avenues in this new vein of research is targeting protein communication between the cancer cells and the extracellular matrix. The secreted protein acidic and rich in cysteine (SPARC) is one such extracellular matrix protein that has shown potential as a therapeutic target due to its influence on PDAC invasion and metastasis. In this review, we discuss the complex interaction of SPARC with PDAC cells and its potential to guide treatment and eventually improve the survival of patients diagnosed with this devastating disease. PMID- 26983778 TI - A 2015 survey of established or potential epigenetic biomarkers for the accurate detection of human cancers. AB - Context The silencing or activation of cancer-associated genes by epigenetic mechanisms can ultimately lead to the clonal expansion of cancer cells. Objective The aim of this review is to summarize all relevant epigenetic biomarkers that have been proposed to date for the diagnosis of some prevalent human cancers. Methods A Medline search for the terms epigenetic biomarkers, human cancers, DNA methylation, histone modifications and microRNAs was performed. Results One hundred fifty-seven relevant publications were found and reviewed. Conclusion To date, a significant number of potential epigenetic cancer biomarkers of human cancer have been investigated, and some have advanced to clinical implementation. PMID- 26983779 TI - Sharing Information to Learn What Is Best Practice. PMID- 26983780 TI - News From the International Council on Women's Health Issues. PMID- 26983781 TI - Antioxidant and cytotoxic activity of carotenes produced by Dunaliella salina under stress. AB - Context Dunaliella salina Teodoresco (Dunaliellaceae) is one of the promising microalgae consumed as food and medicine for many years. Objective Dunaliella salina was grown under different stress conditions for enhancing carotene production. The carotene enriched extract was evaluated for antioxidant and cytotoxic activity. Materials and methods Carotene content was calculated under salinity, nitrogen and temperature stress conditions. Antioxidant activity was determined through DPPH assay by incubating the samples for 45 min with 250 MUg/mL of extract and reducing power assay was performed with 50, 100, 150 and 200 MUg/mL of extract. Cytotoxicity was determined by incubating ~2 * 10(4) MCF-7 (breast cancer) cells with 250 MUg of extract in each well for 72 h by MTT assay. Result Carotene content was significantly increased to 9.8 (3.5 M NaCl), 13.9 (37 degrees C), 8.2 (250 mM KNO3) and 10.6 MUg/mL (nitrogen-depleted medium) as compared with 3.2 MUg/mL in normal conditions (1.7 M NaCl, 0.75 mM KNO3 and 28 degrees C). Free radical scavenging activity increased at 3.0 and 3.5 M NaCl (27.8 and 57.5%, respectively), 37 degrees C (31.4%) and in nitrogen-depleted medium (41.9%) compared with normal (15%) conditions. Carotene content and scavenging activity were positively correlated under salinity (r = 0.97), temperature (r = 0.85) and nitrogen (r = 0.7) stress conditions. Cytotoxicity against MCF-7 cell lines increased due to increase in carotene content suggesting that cytotoxicity may be associated with carotene accumulation. Discussion and conclusions Carotene content enhanced by D. salina under stress conditions increased the antioxidant and cytotoxic activity. PMID- 26983782 TI - Evaluation of the revised Nipissing District Developmental Screening (NDDS) tool for use in general population samples of infants and children. AB - BACKGROUND: There is widespread interest in identification of developmental delay in the first six years of life. This requires, however, a reliable and valid measure for screening. In Ontario, the 18-month enhanced well-baby visit includes province-wide administration of a parent-reported survey, the Nipissing District Developmental Screening (NDDS) tool, to facilitate early identification of delay. Yet, at present the psychometric properties of the NDDS are largely unknown. METHOD: 812 children and their families were recruited from the community. Parents (most often mothers) completed the NDDS. A sub-sample (n = 111) of parents completed the NDDS again within a two-week period to assess test-retest reliability. For children 3 or younger, the criterion measure was the Bayley Scales of Infant Development, 3rd edition; for older children, a battery of other measures was used. All criterion measures were administered by trained assessors. Mild and severe delays were identified based on both published cut-points and on the distribution of raw scores. Sensitivity, specificity, positive and negative predictive values were calculated to assess agreement between tests. RESULTS: Test-retest reliability was modest (Spearman's rho = .62, p < 001). Regardless of the age of the child, the definition of delay (mild versus severe), or the cut point used on the NDDS, sensitivities (from 29 to 68 %) and specificities (from 58 to 88 %) were poor to moderate. CONCLUSION: The modest test-retest results, coupled with the generally poor observed agreement with criterion measures, suggests the NDDS should not be used on its own for identification of developmental delay in community or population-based settings. PMID- 26983783 TI - Improving the Welfare of a Zoo-Housed Male Drill (Mandrillus leucophaeus poensis) Aggressive Toward Visitors. AB - Improving the welfare of nonhuman animals in captivity and maintaining behavioral competence for future conservation purposes is of the highest priority for zoos. The behavior of an aggressive male drill (Mandrillus leucophaeus poensis) was assessed in Barcelona Zoo. The 2-year study presented in this article examined the effects of introducing changes in the exhibit of the drill to improve his welfare by analyzing scan behaviors. First, a partial visual barrier was applied and proved to be insufficient to decrease the long-term stress indicators assessed. Next, a feeding enrichment program was implemented. The results supported the hypothesis that feeding and explorative activities would increase, whereas apathetic and stereotypic behaviors would decrease. However, visitor directed aggression did not vary, indicating that more profound structural modifications were needed to reduce the negative impact of the agonistic interactions between the drill and the public. The study emphasized the usefulness of environmental enrichment evaluations in assessing captive animal welfare. PMID- 26983785 TI - Cutting Edge: Innate Lymphoid Cells Suppress Homeostatic T Cell Expansion in Neonatal Mice. AB - In adult mice, lymphopenia-induced proliferation (LIP) leads to T cell activation, memory differentiation, tissue destruction, and a loss of TCR diversity. Neonatal mice are lymphopenic within the first week of life. This enables some recent thymic emigrants to undergo LIP and convert into long-lived memory T cells. Surprisingly, however, most neonatal T cells do not undergo LIP. We therefore asked whether neonate-specific mechanisms prevent lymphopenia-driven T cell activation. In this study, we show that IL-7R-dependent innate lymphoid cells (ILCs) block LIP of CD8(+) T cells in neonatal but not adult mice. Importantly, CD8(+) T cell responses against a foreign Ag are not inhibited by neonatal ILCs. This ILC-based inhibition of LIP ensures the generation of a diverse naive T cell pool in lymphopenic neonates that is mandatory for the maintenance of T cell homeostasis and immunological self-tolerance later in life. PMID- 26983784 TI - Intravitreal administration of multipotent mesenchymal stromal cells triggers a cytoprotective microenvironment in the retina of diabetic mice. AB - BACKGROUND: Diabetic retinopathy is a common complication of diabetes and the leading cause of irreversible vision loss in the Western world. The reduction in color/contrast sensitivity due to the loss of neural cells in the ganglion cell layer of the retina is an early event in the onset of diabetic retinopathy. Multipotent mesenchymal stromal cells (MSCs) are an attractive tool for the treatment of neurodegenerative diseases, since they could differentiate into neuronal cells, produce high levels of neurotrophic factors and reduce oxidative stress. Our aim was to determine whether the intravitreal administration of adipose-derived MSCs was able to prevent the loss of retinal ganglion cells in diabetic mice. METHODS: Diabetes was induced in C57BL6 mice by the administration of streptozotocin. When retinal pro-damage mechanisms were present, animals received a single intravitreal dose of 2 * 10(5) adipose-derived MSCs or the vehicle. Four and 12 weeks later we evaluated: (a) retinal ganglion cell number (immunofluorescence); (b) neurotrophic factor levels (real-time quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA)); (c) retinal apoptotic rate (TUNEL); (d) retinal levels of reactive oxygen species and oxidative damage (ELISA); (e) electrical response of the retina (electroretinography); (f) pro-angiogenic and anti-angiogenic factor levels (RT-qPCR and ELISA); and (g) retinal blood vessels (angiography). Furthermore, 1, 4, 8 and 12 weeks post-MSC administration, the presence of donor cells in the retina and their differentiation into neural and perivascular-like cells were assessed (immunofluorescence and flow cytometry). RESULTS: MSC administration completely prevented retinal ganglion cell loss. Donor cells remained in the vitreous cavity and did not differentiate into neural or perivascular-like cells. Nevertheless, they increased the intraocular levels of several potent neurotrophic factors (nerve growth factor, basic fibroblast growth factor and glial cell line-derived neurotrophic factor) and reduced the oxidative damage in the retina. Additionally, MSC administration has a neutral effect on the electrical response of the retina and did not result in a pathological neovascularization. CONCLUSIONS: Intravitreal administration of adipose-derived MSCs triggers an effective cytoprotective microenvironment in the retina of diabetic mice. Thus, MSCs represent an interesting tool in order to prevent diabetic retinopathy. PMID- 26983787 TI - CD83 Modulates B Cell Activation and Germinal Center Responses. AB - CD83 is a maturation marker for dendritic cells. In the B cell lineage, CD83 is expressed especially on activated B cells and on light zone B cells during the germinal center (GC) reaction. The function of CD83 during GC responses is unclear. CD83(-/-) mice have a strong reduction of CD4(+) T cells, which makes it difficult to analyze a functional role of CD83 on B cells during GC responses. Therefore, in the present study we generated a B cell-specific CD83 conditional knockout (CD83 B-cKO) model. CD83 B-cKO B cells show defective upregulation of MHC class II and CD86 expression and impaired proliferation after different stimuli. Analyses of GC responses after immunization with various Ags revealed a characteristic shift in dark zone and light zone B cell numbers, with an increase of B cells in the dark zone of CD83 B-cKO mice. This effect was not accompanied by alterations in the level of IgG immune responses or by major differences in affinity maturation. However, an enhanced IgE response was observed in CD83 B-cKO mice. Additionally, we observed a strong competitive disadvantage of CD83-cKO B cells in GC responses in mixed bone marrow chimeras. Furthermore, infection of mice with Borrelia burgdorferi revealed a defect in bacterial clearance of CD83 B cKO mice with a shift toward a Th2 response, indicated by a strong increase in IgE titers. Taken together, our results show that CD83 is important for B cell activation and modulates GC composition and IgE Ab responses in vivo. PMID- 26983786 TI - HIV-1-Specific CD8 T Cells Exhibit Limited Cross-Reactivity during Acute Infection. AB - Prior work has demonstrated that HIV-1-specific CD8 T cells can cross-recognize variant epitopes. However, most of these studies were performed in the context of chronic infection, where the presence of viral quasispecies makes it difficult to ascertain the true nature of the original antigenic stimulus. To overcome this limitation, we evaluated the extent of CD8 T cell cross-reactivity in patients with acute HIV-1 clade B infection. In each case, we determined the transmitted founder virus sequence to identify the autologous epitopes restricted by individual HLA class I molecules. Our data show that cross-reactive CD8 T cells are infrequent during the acute phase of HIV-1 infection. Moreover, in the uncommon instances where cross-reactive responses were detected, the variant epitopes were poorly recognized in cytotoxicity assays. Molecular analysis revealed that similar antigenic structures could be cross-recognized by identical CD8 T cell clonotypes mobilized in vivo, yet even subtle differences in a single TCR-accessible peptide residue were sufficient to disrupt variant-specific reactivity. These findings demonstrate that CD8 T cells are highly specific for autologous epitopes during acute HIV-1 infection. Polyvalent vaccines may therefore be required to provide optimal immune cover against this genetically labile pathogen. PMID- 26983788 TI - Glial Cell-Elicited Activation of Brain Microvasculature in Response to Brucella abortus Infection Requires ASC Inflammasome-Dependent IL-1beta Production. AB - Blood-brain barrier activation and/or dysfunction are a common feature of human neurobrucellosis, but the underlying pathogenic mechanisms are largely unknown. In this article, we describe an immune mechanism for inflammatory activation of human brain microvascular endothelial cells (HBMEC) in response to infection with Brucella abortus Infection of HBMEC with B. abortus induced the secretion of IL 6, IL-8, and MCP-1, and the upregulation of CD54 (ICAM-1), consistent with a state of activation. Culture supernatants (CS) from glial cells (astrocytes and microglia) infected with B. abortus also induced activation of HBMEC, but to a greater extent. Although B. abortus-infected glial cells secreted IL-1beta and TNF-alpha, activation of HBMEC was dependent on IL-1beta because CS from B. abortus-infected astrocytes and microglia deficient in caspase-1 and apoptosis associated speck-like protein containing a CARD failed to induce HBMEC activation. Consistently, treatment of CS with neutralizing anti-IL-1beta inhibited HBMEC activation. Both absent in melanoma 2 and Nod-like receptor containing a pyrin domain 3 are partially required for caspase-1 activation and IL-1beta secretion, suggesting that multiple apoptosis-associated speck-like protein containing CARD-dependent inflammasomes contribute to IL-1beta-induced activation of the brain microvasculature. Inflammasome-mediated IL-1beta secretion in glial cells depends on TLR2 and MyD88 adapter-like/TIRAP. Finally, neutrophil and monocyte migration across HBMEC monolayers was increased by CS from Brucella-infected glial cells in an IL-1beta-dependent fashion, and the infiltration of neutrophils into the brain parenchyma upon intracranial injection of B. abortus was diminished in the absence of Nod-like receptor containing a pyrin domain 3 and absent in melanoma 2. Our results indicate that innate immunity of the CNS set in motion by B. abortus contributes to the activation of the blood-brain barrier in neurobrucellosis and IL-1beta mediates this phenomenon. PMID- 26983790 TI - NOD-Like Receptors: A Tail from Plants to Mammals Through Invertebrates. AB - NOD Like Receptors (NLRs) are the most abundant cytoplasmic immune receptors in plants and animals and they similarly act sensing pathogen invasion and activating immune response. Despite the fact that plant and mammals NLRs share homology.; with some protein structure differences.; for signalling pathway.; divergent evolution of the receptors has been hypothesized. Next generation genome sequencing has contributed to the description of NLRs in phyla others than plants and mammals and leads to new knowledge about NLRs evolution along phylogeny. Full comprehension of NLR-mediated immune response in plant could contribute to the understanding of animal NLRs physiology and/or pathology. PMID- 26983791 TI - Comparison of Retrograde Intrarenal Surgery and Micro-Percutaneous Nephrolithotomy in Moderately Sized Pediatric Kidney Stones. AB - PURPOSE: To compare the effectiveness and reliability of retrograde intrarenal surgery (RIRS) and micro-percutaneous nephrolithotomy (micro-perc) for the management of kidney stones in pediatric patients. MATERIALS AND METHODS: A retrospective analysis was made of pediatric patients aged <18 years with kidney stones that ranged from 10 to 20 mm in size, who underwent RIRS (n = 36) or micro perc (n = 45) in referral centers. RESULTS: In the RIRS group, the mean age of patients was 8.39 +/- 4.72 years and in the micro-perc group, it was 5.62 +/- 4.50 years (p = 0.01). The mean stone size was 12.80 +/- 3.03 mm in the RIRS group and 13.97 +/- 3.46 mm in the micro-perc group (p = 0.189). The success rate was 86.2% (n = 31) in the RIRS group and 80.0% (n = 36) in the micro-perc group (p = 0.47). The mean complication rate was 16.6% and 13.3% in the RIRS and micro perc groups, respectively (p = 0.675). Hospital stay and radiation exposure were significantly lower in the RIRS group (all p < 0.001). The mean anesthesia session was 1.94 in the RIRS group and 1.26 in the micro-perc group (p < 0.001). The mean hemoglobin drop was 0.53 +/- 0.87 g/dL in the micro-perc group, and none of the cases required blood transfusion. CONCLUSION: The results of this study suggested that micro-perc and RIRS were highly effective methods for the treatment of moderately sized renal stones in children, with comparable success and complication rates. Patients and their parents should be informed about the currently available treatment options, and of their efficacy and safety. However, further clinical trials are needed to support these results. PMID- 26983793 TI - Has Virginity Lost Its Virtue? Relationship Stigma Associated With Being a Sexually Inexperienced Adult. AB - While virginity prior to marriage has been historically valued, changing sociosexual scripts in the United States have made premarital sexual activity the norm for young adults, with sexual debut generally occurring in late adolescence. In the current research, we examined the impact of being developmentally off-time with first coitus (i.e., not yet engaging in coitus when most same-aged peers have done so). Specifically, we investigated stigma toward sexually inexperienced adults and discrimination regarding romantic relationship formation. Across three methodologically diverse studies we observed that sexually inexperienced adults perceived themselves to be stigmatized due to their inexperience and that sexually inexperienced adults were not highly desired as relationship partners. Even sexually inexperienced adults themselves did not find other inexperienced adults to be attractive relationship partners. Although abstaining from sexual activity may bestow some health advantages, our studies show that being a sexual "late bloomer" may result in negative interpersonal consequences such as limited opportunities for romantic relationships. PMID- 26983792 TI - Situation selection across adulthood: the role of arousal. AB - In this study, we investigated age differences in situation selection to understand the role stimulus arousal plays in motivating age differences in this type of emotion regulation. Participants freely selected from a set of affective videos using information about the valence and arousal of each stimulus. There were age differences both in the valence and arousal of selected stimuli. Older adults selected more neutral and low-arousal stimuli while younger adults selected more negative and high-arousal stimuli. We consider these results in light of recent theoretical models and conclude that studies of age differences in emotion regulation must consider both valence and arousal. PMID- 26983795 TI - Improving Physical Activity Ensures the Long-Term Survival of Pneumonia Patients in a Super-Aged Society: A Retrospective Study in an Acute-Care Hospital in Japan. AB - Pneumonia is the third largest cause of death in Japan. Chest physicians have been struggling to improve the outcome of pneumonia treatment in acute care settings. However, a poor long-term prognosis after pneumonia has not been well recognized. Furthermore, the factors related to the poor prognosis, especially the possible involvement of senescence-related disability, have not been identified. In this study, long-term outcomes after discharge from hospital were retrospectively analyzed to identify factors related to the poor long-term prognosis. Outcomes of 958 pneumonia patients who were discharged from South Miyagi Medical Center (Miyagi, Japan) from June 1, 2008 to March 31, 2014 were determined through patient surveys or medical record reviews on September 26, 2014. Survival curves were constructed and compared according to various factors. Multivariate analysis revealed that all levels of decrease in physical activity, an age of 80 years old or more, the most severe status in Japanese Respiratory Society pneumonia severity grading system, the presence of antibiotic-resistant bacteria, and comorbid malignancy significantly reduced long-term survival. The effects of dementia, neuromuscular disease, heart disease, and nursing care residency on long-term survival were detected only with univariate analysis. Physical activity influenced the acute-phase and the long-term prognosis of pneumonia. This report provides information to assist physicians in giving better suggestions to disabled older patients when choosing pneumonia treatment options. In conclusion, we propose that death related to pneumonia can be prevented in the same way as non-communicable diseases by improving physical activity. PMID- 26983794 TI - The Perioperative Educational Program for Improving Upper Arm Dysfunction in Patients with Breast Cancer at 1-Year Follow-Up: A Prospective, Controlled Trial. AB - The many women with breast cancer who underwent axillary lymph node dissection (ALND) suffer from the upper arm dysfunction. In this study, we investigated the effectiveness of a perioperative educational program for improving upper arm dysfunction in breast cancer patients following ALND. This study was a sub analysis of a previous controlled trial with an educational program. The subjects of this analysis included 64 patients following ALND who completed measurements at 12 months. The perioperative educational program consisted of monitoring of arm dysfunction, exercises, massage, and lifestyle adjustments. The intervention group (37 patients) received this perioperative educational program over 12 months, while 27 patients in the control group received written information about shoulder exercise from on-site staff only before surgery. Primary outcomes were shoulder range of motion (ROM), arm girth, and grip strength. Secondary outcomes were evaluated with the Subjective Perception of Post-Operative Functional Impairment of the Arm (SPOFIA) scores, the Disabilities of the Arm, Shoulder and Hand (DASH) scores, and the Medical Outcome Study 36-Item Short-Form Health Survey v2 (SF-36v2). The SF-36v2 measures health-related quality of life (QOL). Primary and secondary outcomes were compared between groups at 1 week (after drainage tube removal) and 12 months after surgery, using the Mann-Whitney U test. The horizontal extension was significantly improved only in the intervention group. Moreover, the SPOFIA score was significantly improved in the intervention group, and other scores of the secondary outcomes were similar between the two groups. The perioperative educational program may improve postoperative upper arm dysfunction and symptoms. PMID- 26983789 TI - Aging Converts Innate B1a Cells into Potent CD8+ T Cell Inducers. AB - B cell dysregulation in aging is thought to mostly occur in conventional B2 cells without affecting innate B1 cells. Elderly humans and mice also accumulate 4 1BBL(+)MHC class-I(Hi)CD86(Hi)B cells of unknown origin. In this article, we report that these cells, termed 4BL cells, are activated murine and possibly human B1a cells. The activation is mediated by aging human monocytes and murine peritoneal macrophages. They induce expression and activation of 4-1BBL and IFN gammaR1 on B1a cells to subsequently upregulate membrane TNF-alpha and CD86. As a result, activated B1a/4BL cells induce expression of granzyme B in CD8(+)T cells by targeting TNFR2 via membrane TNF-alpha and providing costimulation with CD86. Thus, for the first time, to our knowledge, these results indicate that aging affects the function of B1a cells. Upon aging, these cells lose their tumor supporting activity and become inducers of potentially antitumor and autoimmune CD8(+)T cells. PMID- 26983796 TI - Is paradoxical hair growth caused by low-level radiant exposure by home-use laser and intense pulsed light devices? AB - INTRODUCTION AND OBJECTIVES: This qualitative review of paradoxical hair growth, following professional treatments reviews, clarifies whether low fluence is the most probable cause of unwanted hair regrowth after at home light-based treatments. MATERIALS AND METHODS: The proposed causes of unexpected hair regrowth are examined, and our scientific understanding of absorption and scattering of light in turbid tissue is reviewed. Published reports of paradoxical hair growth are assessed. RESULTS: Early laser hair removal studies failed to record the occurrence of hair induction despite the significant numbers of subjects treated. Neither published paradoxical hair growth studies following home-based laser or intense pulsed light (IPL) hair removal treatments, nor randomised or controlled studies documenting paradoxical hair growth following professional treatments could be found. Several authors directly proposed inflammatory response to be the primary cause of hair growth induction. CONCLUSIONS: It is unlikely that hair regrowth several centimetres or more away from the irradiated tissue can be attributed to the laser or IPL used. In many cases of paradoxical hair growth, other causes may be responsible for the unexpected hair growth. The primary cause of instances of 'true' paradoxical hair growth is probably limited to darker phototypes with one or more other characteristics including polycystic ovarian syndrome or other androgen hormonal irregularities following high energy treatments with the corresponding inflammatory sequelae. PMID- 26983798 TI - Navigation: The long and short of teleporting. PMID- 26983797 TI - Correlation of bioelectrical impedance analysis phase angle with changes in oxidative stress on end-stage renal disease patients, before, during, and after dialysis. AB - Chronic kidney disease is a condition that promotes oxidative stress. There are conflicting evidence about the role of hemodialysis on oxidative stress, that are mostly related with the various types of membrane materials used, the quality and type of dialysate, the method used, etc. The phase angle (PhA), which is determined with bioelectrical impedance analysis (BIA), measures the functionality of cell membranes. In this study, the correlation of the PhA with parameters of oxidative stress is attempted for the first time. We evaluated parameters of oxidative status as total antioxidant capacity (TAC) in erythrocytes (RBCs) and plasma of patients with ESRD undergoing hemodialysis with low flux synthetic polysulfone membranes. Measurements were recorded from 30 patients (16 men and 14 women) aged 64 +/- 14 years before, during, and after dialysis, and in 15 healthy volunteers aged 56 +/- 12 years The PhA was obtained by BIA. The plasma TAC increased significantly (41%, p < 0.05). Intracellular TAC noted a non-significant increase. Total antioxidant capacity of the patients before and after hemodialysis was significantly lower from the healthy volunteers (p < 0.05) showing that ESRD patients are at the state of increased oxidative stress. The PhA increased in significantly positive correlation with plasma TAC at the end of hemodialysis. The process of hemodialysis with biocompatible synthetic membranes and bicarbonate dialysate improved plasma TAC. The positive correlation of PhA with extracellular TAC could evolve to a method of oxidative stress estimation by BIA but further research is needed. PMID- 26983799 TI - Fear Memory. AB - Fear memory is the best-studied form of memory. It was thoroughly investigated in the past 60 years mostly using two classical conditioning procedures (contextual fear conditioning and fear conditioning to a tone) and one instrumental procedure (one-trial inhibitory avoidance). Fear memory is formed in the hippocampus (contextual conditioning and inhibitory avoidance), in the basolateral amygdala (inhibitory avoidance), and in the lateral amygdala (conditioning to a tone). The circuitry involves, in addition, the pre- and infralimbic ventromedial prefrontal cortex, the central amygdala subnuclei, and the dentate gyrus. Fear learning models, notably inhibitory avoidance, have also been very useful for the analysis of the biochemical mechanisms of memory consolidation as a whole. These studies have capitalized on in vitro observations on long-term potentiation and other kinds of plasticity. The effect of a very large number of drugs on fear learning has been intensively studied, often as a prelude to the investigation of effects on anxiety. The extinction of fear learning involves to an extent a reversal of the flow of information in the mentioned structures and is used in the therapy of posttraumatic stress disorder and fear memories in general. PMID- 26983801 TI - Effects of carbon-to-sulfur (C/S) ratio and nitrate (N) dosage on Denitrifying Sulfur cycle-associated Enhanced Biological Phosphorus Removal (DS-EBPR). AB - In this study, the Denitrifying Sulfur cycle-associated Enhanced Biological Phosphorous Removal (DS-EBPR) with 20 mg P/L/d of the volumetric P removal rate was successfully achieved in a Sequencing Batch Reactor (SBR). The effects of carbon-to-sulfur (C/S) mass ratio and nitrate (N) dosage were investigated through two batch tests to reveal the role of wastewater compositions in DS-EBPR performance. The optimal specific P release and uptake rates (0.4 and 2.4 mg P/g VSS/h, respectively) were achieved at C/S/P/N mass ratio of 150/200/20/20, and poly-S is supplied as a potential electron and energy storage. The nitrate dosage in a range of 10-50 mg N/L had no significant influence on P uptake rates (2.1 ~ 2.4 mg P/g VSS/h), but significantly affected the storage of inclusion poly-S, the poly-S oxidation rate was increased about 16% while dosing nitrate from 20 to 30 mg N/L. It implies that nitrate is denitrified in the P uptake phase, and excess nitrate is further consumed by poly-S. Moreover, the microbial analysis showed that the functional bacteria should mostly belong to denitrifying bacteria or Unclassified genera. PMID- 26983800 TI - A new hand-held microfluidic cytometer for evaluating irradiation damage by analysis of the damaged cells distribution. AB - Space radiation brings uneven damages to cells. The detection of the distribution of cell damage plays a very important role in radiation medicine and the related research. In this paper, a new hand-held microfluidic flow cytometer was developed to evaluate the degree of radiation damage of cells. The device we propose overcomes the shortcomings (e.g., large volume and high cost) of commercial flow cytometers and can evaluate the radiation damage of cells accurately and quickly with potential for onsite applications. The distribution of radiation-damaged cells is analyzed by a simultaneous detection of immunofluorescence intensity of gamma-H2AX and resistance pulse sensor (RPS) signal. The gamma-H2AX fluorescence intensity provides information of the degree of radiation damage in cells. The ratio of the number of cells with gamma-H2AX fluorescence signals to the total numbers of cells detected by RPS indicates the percentage of the cells that are damaged by radiation. The comparison experiment between the developed hand-held microfluidic flow cytometer and a commercial confocal microscope indicates a consistent and comparable detection performance. PMID- 26983802 TI - Thermal niche estimators and the capability of poor dispersal species to cope with climate change. AB - For management strategies in the context of global warming, accurate predictions of species response are mandatory. However, to date most predictions are based on niche (bioclimatic) models that usually overlook biotic interactions, behavioral adjustments or adaptive evolution, and assume that species can disperse freely without constraints. The deep subterranean environment minimises these uncertainties, as it is simple, homogeneous and with constant environmental conditions. It is thus an ideal model system to study the effect of global change in species with poor dispersal capabilities. We assess the potential fate of a lineage of troglobitic beetles under global change predictions using different approaches to estimate their thermal niche: bioclimatic models, rates of thermal niche change estimated from a molecular phylogeny, and data from physiological studies. Using bioclimatic models, at most 60% of the species were predicted to have suitable conditions in 2080. Considering the rates of thermal niche change did not improve this prediction. However, physiological data suggest that subterranean species have a broad thermal tolerance, allowing them to stand temperatures never experienced through their evolutionary history. These results stress the need of experimental approaches to assess the capability of poor dispersal species to cope with temperatures outside those they currently experience. PMID- 26983803 TI - Tanshinone IIA induces TRAIL sensitization of human lung cancer cells through selective ER stress induction. AB - Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promised anticancer medicine targeting only the tumor, most cancers show resistance to TRAIL-induced apoptosis. For this reason, new therapeutic strategies to overcome the TRAIL resistance are required for more effective tumor treatment. In the present study, potential of tanshinone IIA as a TRAIL sensitizer was evaluated in human non-small cell lung cancer (NSCLC) cells. NSCLC cells showed resistance to TRAIL-mediated cell death, but combination treatment of Tanshinone IIA and TRAIL synergistically decreased cell viability and increased apoptosis in TRAIL-resistant NSCLC cells. Tanshinone IIA greatly induced death receptor 5 (DR5), but not death receptor 4 (DR4). Furthermore, DR5 knockdown attenuated the combination treatment of tanshinone IIA with TRAIL mediated cell death in human NSCLC cells. Tanshinone IIA also increased CHOP and activated the PERK-ATF4 pathway suggesting that tanshinone IIA increased DR5 and CHOP by activating the PERK-ATF4 pathway. Tanshinone IIA also downregulated phosphorylation of STAT3 and expression of survivin. Taken together, these results indicate that tanshinone IIA increases TRAIL-induced cell death via upregulating DR5 and downregulating survivin mediated by, respectively, selective activation of PERK/ATF4 and inhibition of STAT3, suggesting combinatorial intervention of tanshinone IIA and TRAIL as a new therapeutic strategy for human NSCLC. PMID- 26983804 TI - Broadband Tunability of Polarization-Insensitive Absorber Based on Frequency Selective Surface. AB - An innovative tunable and polarization-insensitive 1.6-8 GHz frequency selective surface (FSS) absorber was investigated in this study. The proposed FSS, which is in 4-axial symmetrical form, includes a novel array of PIN diodes with biasing lines including inductors. A gradually reduced equivalent resistor of PIN diodes can be achieved with increasing DC voltage, which characterizes tunable, multi resonance absorption peaks. Via this simplified design, small value resistor and equivalent capacitance of the gap between patterns can improve the absorber's performance in low frequencies; an active tunable absorber can be realized in a broad frequency range by employing adjustable devices. Changing the working state of the PIN diode allows the user to obtain strong absorption within the desired frequency. We analyzed the performance of the proposed absorber and found that it indeed shows very favorable absorption performance in low frequency (-10 dB in 1.6-4.3 GHz) and wideband (-8 dB in 4.3-5.4 GHz and -10 dB in 5.4-8.0 GHz) conditions. Calculation and simulation results also illustrated that the absorber is entirely polarization-insensitive. PMID- 26983805 TI - Optically responsive supramolecular polymer glasses. AB - The reversible and dynamic nature of non-covalent interactions between the constituting building blocks renders many supramolecular polymers stimuli responsive. This was previously exploited to create thermally and optically healable polymers, but it proved challenging to achieve high stiffness and good healability. Here we present a glass-forming supramolecular material that is based on a trifunctional low-molecular-weight monomer ((UPyU)3TMP). Carrying three ureido-4-pyrimidinone (UPy) groups, (UPyU)3TMP forms a dynamic supramolecular polymer network, whose properties are governed by its cross-linked architecture and the large content of the binding motif. This design promotes the formation of a disordered glass, which, in spite of the low molecular weight of the building block, displays typical polymeric behaviour. The material exhibits a high stiffness and offers excellent coating and adhesive properties. On account of reversible dissociation and the formation of a low-viscosity liquid upon irradiation with ultraviolet light, rapid optical healing as well as (de)bonding on demand is possible. PMID- 26983808 TI - Characterization and remediation of contamination: the influences of mining and other human activities. PMID- 26983806 TI - Novel roles for class II Phosphoinositide 3-Kinase C2beta in signalling pathways involved in prostate cancer cell invasion. AB - Phosphoinositide 3-kinases (PI3Ks) regulate several cellular functions such as proliferation, growth, survival and migration. The eight PI3K isoforms are grouped into three classes and the three enzymes belonging to the class II subfamily (PI3K-C2alpha, beta and gamma) are the least investigated amongst all PI3Ks. Interest on these isoforms has been recently fuelled by the identification of specific physiological roles for class II PI3Ks and by accumulating evidence indicating their involvement in human diseases. While it is now established that these isoforms can regulate distinct cellular functions compared to other PI3Ks, there is still a limited understanding of the signalling pathways that can be specifically regulated by class II PI3Ks. Here we show that PI3K-C2beta regulates mitogen-activated protein kinase kinase (MEK1/2) and extracellular signal regulated kinase (ERK1/2) activation in prostate cancer (PCa) cells. We further demonstrate that MEK/ERK and PI3K-C2beta are required for PCa cell invasion but not proliferation. In addition we show that PI3K-C2beta but not MEK/ERK regulates PCa cell migration as well as expression of the transcription factor Slug. These data identify novel signalling pathways specifically regulated by PI3K-C2beta and they further identify this enzyme as a key regulator of PCa cell migration and invasion. PMID- 26983809 TI - Estimation of PCB content in agricultural soils associated with long-term fertilization with organic waste. AB - Polychlorinated biphenyl (PCB) pollution related to the use of organic waste as fertilizers in agricultural soils is a cause of major concern. In the study presented herein, PCB concentration was studied through a field trial conducted in two agricultural soils in the province of Palencia (Spain) over a 4-year period, assessing the impact of irrigation and of different types of organic waste materials. The amounts of organic waste added to the soil were calculated according to the nitrogen needs of the crop, and the concentration of PCBs was determined before and after the application of the organic waste. The resulting persistence of the total PCB content in the agricultural soils, compared with the PCB concentration in the original soils, ranged from 27% to 90%, with the lowest value corresponding to irrigated soils treated with municipal solid waste compost (MSWC) and the highest value to non-irrigated soils treated with composted sewage sludge (CSS). An estimate of the PCB content in agricultural soils after the application of organic waste materials until year 2050 was obtained, resulting in a value below 5 ng.g(-1), considered a background value for soils in sites far away from potential pollution sources. PMID- 26983810 TI - Removing heavy metals from Isfahan composting leachate by horizontal subsurface flow constructed wetland. AB - Composting facility leachate usually contains high concentrations of pollutants including heavy metals that are seriously harmful to the environment and public health. The main purpose of this study was to evaluate heavy metals removal from Isfahan composting facility (ICF) leachate by a horizontal flow constructed wetland (HFCWs) system. Two horizontal systems were constructed, one planted with vetiver and the other without plant as a control. They both operated at a flow rate of 24 L/day with a 5-day hydraulic retention time (HRT). The average removal efficiencies for Cr (53 %), Cd (40 %), Ni (35 %), Pb (30 %), Zn (35 %), and Cu (40 %) in vetiver constructed wetland were significantly higher than those of the control (P < 0.05). Accumulations of heavy metals in roots were higher than shoots. Cd and Zn showed the highest and the lowest bioconcentration factor (BCF), respectively. Vetiver tolerates the extreme condition in leachate including high total dissolved solids. PMID- 26983811 TI - Transport stability of pesticides and PAHs sequestered in polyethylene passive sampling devices. AB - Research using low-density polyethylene (LDPE) passive samplers has steadily increased over the past two decades. However, such research efforts remain hampered because of strict guidelines, requiring that these samplers be quickly transported in airtight metal or glass containers or foil wrapped on ice. We investigate the transport stability of model pesticides and polycyclic aromatic hydrocarbons (PAHs) with varying physicochemical properties using polytetrafluoroethylene (PTFE) bags instead. Transport scenarios were simulated with transport times up to 14 days with temperatures ranging between -20 and 35 degrees C. Our findings show that concentrations of all model compounds examined were stable for all transport conditions tested, with mean recoveries ranging from 88 to 113 %. Furthermore, PTFE bags proved beneficial as reusable, lightweight, low-volume, low-cost alternatives to conventional containers. This documentation of stability will allow for more flexible transportation of LDPE passive samplers in an expanding range of research applications while maintaining experimental rigor. PMID- 26983812 TI - A multipoint (49 points) study of dry deposition of polycyclic aromatic hydrocarbons (PAHs) in Erzurum, Turkey by using surrogated snow surface samplers. AB - Dry deposition of atmospheric 18 polycyclic aromatic hydrocarbon (PAH) components was investigated in the scope of the study by using surrogate snow samplers at 49 different sampling points in and around the city center of Erzurum, Turkey. Snow was sampled twice, the first of which was taken immediately after the first fresh snow cover and placed into aluminum trays to obtain dry deposition surface while the second sample was taken from the snow cover (accumulated snow) exposed to an 8-day dry deposition period and then analyzed and extracted. All the samples taken from the samplers were extracted using solid and liquid phase extraction and analyzed through GC-MS. It was observed that at the end of an 8-day dry period, snow samples enriched 5.5 times more in PAH components than the baseline. PAH deposition was determined to be influenced mainly by coal, mixed source, traffic, diesel fuel, and petrol fuel at 43, 27, 20, 8, and 2 % of sampling points, respectively. Local polluting sources were found to be effective on the spatial distribution of dry deposition of PAH components in urban area. PMID- 26983813 TI - Transformation of acetaminophen during water chlorination treatment: kinetics and transformation products identification. AB - As a high-consumption drug in the world, acetaminophen (AAP) has been widely detected in natural waters and wastewaters. Its reactivity and the transformation products formed during chlorination may greatly threaten the safety of drinking water. The reaction kinetics of AAP during chlorination was investigated in this study. The results showed that the reaction kinetics could be well described with a kinetics model of -d[AAP]/dt = k app[AAP]t (0.63)[Cl2]t (1.37). The values of apparent rate constant (k app) were dependent on reaction temperature, ammonium, and pH. With the increase in reaction temperature from 5.0 +/- 1.0 to 40.0 +/- 1.0 degrees C, the removal efficiency of AAP increased from 60 to 100 %. When ammonium was present in the solution at 2.0 mg/L, the transformation of AAP was inhibited due to the rapid formation of chloramines. The maximum of k app was 0.58 * 10(2) M(-1) . min(-1) at pH 9.0, and the minimum was 0.27 M(-1) . min(-1) at pH 11.0. A low mineralization of AAP (about 7.2 %) with chlorination was observed through TOC analysis, implying the formation of plenty of transformation products during chlorination. The main transformation products, hydroquinone and two kinds of chlorinated compounds, monochlorinated acetaminophen and dichlorinated acetaminophen, were detected in gas chromatography-mass spectrometry analysis. PMID- 26983814 TI - The impact of Ni on the physiology of a Mediterranean Ni-hyperaccumulating plant. AB - High nickel (Ni) levels exert toxic effects on plant growth and plant water content, thus affecting photosynthesis. In a pot experiment, we investigated the effect of the Ni concentration on the physiological characteristics of the Ni hyperaccumulator Alyssoides utriculata when grown on a vermiculite substrate in the presence of different external Ni concentrations (0-500 mg Ni L(-1)). The results showed that the Ni concentration was higher in leaves than in roots, as evidenced by a translocation factor = 3 and a bioconcentration factor = 10. At the highest concentration tested (500 mg Ni L(-1)), A. utriculata accumulated 1100 mg Ni per kilogram in its leaves, without an effects on its biomass. Plant water content increased significantly with Ni accumulation. Ni treatment did not, or only slightly, affected chlorophyll fluorescence parameters. The photosynthetic efficiency (FV/FM) of A. utriculata was stable between Ni treatments (always >= 0.8) and the photosynthetic performance of the plant under Ni stress remained high (performance index = 1.5). These findings support that A. utriculata has several mechanisms to avoid severe damage to its photosynthetic apparatus, confirming the tolerance of this species to Ni under hyperaccumulation. PMID- 26983816 TI - Cone beam computed tomographic evaluation of nutrient canals and foramina in the anterior region of the mandible. AB - PURPOSE: To investigate the incidence and anatomical location of mandibular nutrient canals (NCs) originating from the mandibular canal using dental cone beam computed tomography (CBCT). METHODS: CBCT images from 105 patients were examined to evaluate the presence, number, diameter, and course of NCs. RESULTS: NCs and their foramina were bilaterally located in 17 (16.2 %) images. The mean diameters of NCs and foramina were 0.9 +/- 0.4 (range, 0.2-3.2) mm and 0.9 +/- 0.4 (0.2-2.1) mm, respectively. NCs coursed through the mandibular incisor region up to the lingual surface of the alveolar bone crest. CONCLUSION: The present study revealed the frequency and distribution of NCs using CBCT image analysis. NCs are important because surgical injury to the neurovascular bundle within these canals can lead to excessive bleeding and postoperative paresthesia. The identification of NC on CBCT images may be useful during the harvesting of bone blocks or placement of endosseous implants in the anterior region of the mandible. PMID- 26983815 TI - Exposure to a diet high in fat attenuates dendritic spine density in the medial prefrontal cortex. AB - A key factor in the development of obesity is the overconsumption of food calorically high in fat. Overconsumption of food high in fat not only promotes weight gain but elicits changes in reward processing. No studies to date have examined whether consumption of a high-fat (HF) diet alters structural plasticity in brain areas critical for reward processing, which may account for persistent changes in behavior and psychological function by reorganizing synaptic connectivity. To test whether dietary fat may induce structural plasticity we placed rats on one of three dietary conditions: ad libitum standard chow (SC), ad libitum 60 % HF (HF-AL), or calorically matched 60 % HF (HF-CM) for 3 weeks and then quantified dendritic spine density and type on basal and apical dendrites of pyramidal cells in layer V of the medial prefrontal cortex (mPFC) and medium spiny neurons (MSNs) of the nucleus accumbens. Our results demonstrate a significant reduction in the density of thin spines on the apical and basal segments of dendrites within the infralimbic, but not prelimbic, mPFC. PMID- 26983817 TI - New anatomo-radiological findings of the lateral pterygoid muscle. AB - PURPOSE: The discrepancies in the literature regarding the anatomy of the temporomandibular joint (TMJ), particularly at the level of the lateral pterygoid muscle, led us to compare plastinated section techniques and magnetic resonance imaging (MRI) to enable the better interpretation of both, and to describe the features of the lateral pterygoid muscle and the exact location of its insertions. METHODS: A total of 24 blocks of human TMJ were used. Seven were studied by MRI, obtaining images of the oblique-sagittal, oblique-coronal, and axial planes. Four of these blocks were then cut and processed by means of the E12 plastination technique. The remaining blocks were dissected. Finally, we performed a comparative morphological analysis of the different techniques used. RESULTS: New aspects about the morphology and the insertions of the lateral pterygoid muscle are described. The muscle is inserted into the disc, capsule, condyle, and the pterygoid fovea, through muscle and tendon fibres that alternate, giving it the characteristic of a multipennate muscle. This insertion caudally exceeded the pterygoid fovea and descends to near the lingula of mandible. A profuse pterygoid venous plexus surrounds the whole joint complex, and also the insertion zone of the lateral pterygoid muscle. CONCLUSIONS: We consider that the use of transparent-plastinated anatomical sections and its good correlation with MRI images (in axial and oblique-sagittal planes) led to an accurate identification of TMJ structures, especially in relation to the lateral pterygoid muscle, that is now described as a multipennate muscle. PMID- 26983818 TI - Community Violence Exposure and Generalized Anxiety Symptoms: Does Executive Functioning Serve a Moderating Role Among Low Income, Urban Youth? AB - Although community violence exposure (CVE) confers risk for generalized anxiety symptoms, not all youth who are exposed to violence exhibit such symptoms, suggesting that other factors moderate this relation. One candidate for moderation is executive functioning (EF), which is linked to both CVE and generalized anxiety symptoms. Nevertheless, little research has examined whether EF moderates the CVE-anxiety relation. To address this gap, we examined associations among CVE (i.e., direct victimization and witnessed violence), EF abilities (i.e., emotional control and shifting), and parent- and child-reported generalized anxiety disorder (GAD) symptoms among low income, urban youth (N = 104, 50 % male, M = 9.93 +/- 1.22 years). In terms of main effects, lower levels of emotional control were associated with increased parent-reported GAD symptoms, whereas lower levels of shifting abilities were associated with increased parent- and child-reported GAD symptoms across both subtypes of CVE. EF abilities moderated the relation between direct victimization and both parent- and child reported GAD symptoms, but did not moderate the relation between witnessed violence and GAD symptoms. Post-hoc probing indicated that when youth were exposed to higher levels of direct victimization, those with lower EF abilities exhibited elevated GAD symptoms. However, the level of direct victimization did not impact the level of GAD symptoms among youth with higher EF abilities. Findings have implications for prevention and intervention programs among at-risk youth who are exposed to community violence. PMID- 26983820 TI - [Significance of the German Act on the Reform of the Market for Medicinal Products for psychopharmacotherapy]. AB - The German Act on the Reform of the Market for Medicinal Products (AMNOG) will lead to rapid disappearance of many new psychotropic drugs from the market in Germany over the next few years or their not being introduced in the first place. This article lists the reasons and discusses possible solutions. In the long term, the AMNOG could not only lead to an improvement of psychopharmacology but also contribute to the development of psychiatry as a whole, especially if its standards become an international reference. PMID- 26983821 TI - The use of surgery for cervical degenerative disease in Norway in the period 2008 2014 : A population-based study of 6511 procedures. AB - BACKGROUND: The incidence rate of surgical treatment of cervical degenerative diseases (CDD) has increased in the USA and a large geographic variation has been shown. Little is known about such rates in Scandinavia and Europe. The aim of this population-based study was to (1) investigate annual incidence rates of operations performed in Norway, (2) to compare trends and variations in rates for surgical indications with and without myelopathy, and (3) to compare variations in the use of surgery between residential areas. METHODS: Patients operated for CDD and recorded in the Norwegian Patient Registry from 2008 to 2014 were evaluated according to residential areas (resident county and Regional Health Authority (RHA) area), age, gender, treating hospital, and whether myelopathy was present or not. Surgical rates were adjusted for age and gender. Data from private health care were also included. RESULTS: The annual surgical rates increased by 74.1 % from 2008 to 2014 (12.5/100,000 inhabitants). The largest increase was for surgical treatment of radiculopathy, 86.5 %. Surgical rates for CDD varied in 2014 with a ratio of 1.5 between the highest and lowest RHA and with a ratio of 2.5 between the different residential counties within one RHA. The treatment rates for myelopathy were relatively stable over time, but showed an increase of 2.1/100,000 (44.6 %) from 2013 to 2014. CONCLUSIONS: Our study shows that the rate of surgical treatment for radiculopathy due to CDD has increased substantially from 2008 to 2014 for all RHAs in Norway. The incidence rate for surgical treatment of myelopathy was more stable. An unexplained and moderate geographic variation was found. PMID- 26983824 TI - Simulation of Paramecium Chemotaxis Exposed to Calcium Gradients. AB - Paramecium or other ciliates have the potential to be utilized for minimally invasive surgery systems, making internal body organs accessible. Paramecium shows interesting responses to changes in the concentration of specific ions such as K(+), Mg(2+), and Ca(2+) in the ambient fluid. Some specific responses are observed as, changes in beat pattern of cilia and swimming toward or apart from the ion source. Therefore developing a model for chemotactic motility of small organisms is necessary in order to control the directional movements of these microorganisms before testing them. In this article, we have developed a numerical model, investigating the effects of Ca(2+) on swimming trajectory of Paramecium. Results for Ca(2+)-dependent chemotactic motility show that calcium gradients are efficient actuators for controlling the Paramecium swimming trajectory. After applying a very low Ca(2+) gradient, a directional chemotaxis of swimming Paramecium is observable in this model. As a result, chemotaxis is shown to be an efficient method for controlling the propulsion of these small organisms. PMID- 26983823 TI - Diverse Ecological Strategies Are Encoded by Streptococcus pneumoniae Bacteriocin Like Peptides. AB - The opportunistic pathogen Streptococcus pneumoniae is commonly carried asymptomatically in the human nasopharynx. Due to high rates of cocolonization with other pneumococcus strains, intraspecific competitive interactions partly determine the carriage duration of strains and thereby their potential to cause disease. These interactions may be mediated by bacteriocins, such as the type IIb bacteriocins encoded by the blp (bacteriocin-like peptide) locus. To understand blp diversity and evolution, we undertook a bioinformatic analysis of 4,418 pneumococcal genomes, including 168 newly sequenced genomes. We describe immense variation at all levels of genomic organization: Gene presence/absence, gene order, and allelic diversity. If we make the extreme and naive hypothesis that assumes all genes in this operon can assort randomly, this variation could lead to 10(15) distinct bacteriocin-related phenotypes, each potentially representing a unique ecological strategy; however, we provide several explanations for why this extreme is not realized. Although rarefaction analysis indicates that the number of unique strategies is not saturated, even after sampling thousands of genomes, we show that the variation is neither unbounded nor random. We delimit three bacteriocin groups, which contain group-specific bacteriocins, immunity genes, and blp operon gene order, and argue that this organization places a constraint on realized ecological strategies. We additionally show that ecological strategy diversity is significantly constrained by pneumococcal phylogeny and clonal structure. By examining patterns of association between alleles within the blp operon, we show that bacteriocin genes, which were believed to function in pairs, can be found with a broad diversity of partner alleles and immunity genes; this overall lack of allelic fidelity likely contributes to the fluid structure of this operon. Our results clarify the diversity of antagonistic ecological strategies in the global pneumococcal population and highlight the potential role of blp bacteriocins in competition within the nasopharynx. PMID- 26983822 TI - "Islands of Divergence" in the Atlantic Cod Genome Represent Polymorphic Chromosomal Rearrangements. AB - In several species genetic differentiation across environmental gradients or between geographically separate populations has been reported to center at "genomic islands of divergence," resulting in heterogeneous differentiation patterns across genomes. Here, genomic regions of elevated divergence were observed on three chromosomes of the highly mobile fish Atlantic cod (Gadus morhua) within geographically fine-scaled coastal areas. The "genomic islands" extended at least 5, 9.5, and 13 megabases on linkage groups 2, 7, and 12, respectively, and coincided with large blocks of linkage disequilibrium. For each of these three chromosomes, pairs of segregating, highly divergent alleles were identified, with little or no gene exchange between them. These patterns of recombination and divergence mirror genomic signatures previously described for large polymorphic inversions, which have been shown to repress recombination across extensive chromosomal segments. The lack of genetic exchange permits divergence between noninverted and inverted chromosomes in spite of gene flow. For the rearrangements on linkage groups 2 and 12, allelic frequency shifts between coastal and oceanic environments suggest a role in ecological adaptation, in agreement with recently reported associations between molecular variation within these genomic regions and temperature, oxygen, and salinity levels. Elevated genetic differentiation in these genomic regions has previously been described on both sides of the Atlantic Ocean, and we therefore suggest that these polymorphisms are involved in adaptive divergence across the species distributional range. PMID- 26983826 TI - Identification of cytoprotective constituents of the flower buds of Tussilago farfara against glucose oxidase-induced oxidative stress in mouse fibroblast NIH3T3 cells and human keratinocyte HaCaT cells. AB - A new cytoprotective compound, 1-[(4S)-3,4-dihydro-4-hydroxy-2,2-dimethyl-2H-1 benzopyran-6-yl]-ethanone (1) was isolated from the flower buds of Tussilago farfara L. (Compositae), together with eight known compounds, 3,4-dicaffeoyl isoquinic acid (2), trans-cinnamic acid (3), 4-hydroxyacetophenone (4), 4,5 dicaffeoylquinic acid methyl ester (5), 3,5-dicaffeoylquinic acid methyl ester (6), 4-hydroxybenzoic acid (7), isoquercetrin (8), and ligucyperonol (9). Compounds 2-4 were found in this plant for the first time. The isolates 1-9, were tested for their cytoprotective activities against glucose oxidase-induced oxidative stress in mouse fibroblast NIH3T3 cells and human keratinocyte HaCaT cells. Among them, 1 and 3 showed significant cytoprotective activities as determined by MTT assay and lactate dehydrogenase leakage, indicating their possibility as the potent cytoprotective agents. The structure of 1 was determined by spectroscopic data analysis including 1D- and 2D-NMR experiments, and its absolute configuration was elucidated by a circular dichroism. PMID- 26983825 TI - Gambling Problems Among Community Cocaine Users. AB - Cocaine use is highly prevalent and a major public health problem. While some studies have reported frequent comorbidity problems among cocaine users, few studies have included evaluation of gambling problems. This study aimed to estimate the prevalence of gambling problems and compare those who were at-risk gamblers with non-problem gamblers in terms of mental health problems, substance use problems, and some risk factors (i.e. family antecedents, erroneous perceptions and coping strategies) among individuals who smoke or inject cocaine. A total of 424 smoked or injected cocaine users recruited through community-based programs in Montreal (Quebec) completed the questionnaire, including the Canadian Pathological Gambling Index, the Composite International Diagnostic Interview, the CAGE, and the Severity Dependence Scale. Of the sample, 18.4 % were considered at-risk gamblers, of whom 7.8 % had problems gambling and 10.6 % were moderate-risk gamblers. The at-risk group was more likely to have experienced a recent phobic disorder and alcohol problems than the non-problem group. A multivariate analysis showed that, compared to those who were non-problem gamblers, the at-risk ones were more likely to have lost a large sum of money when they first started gambling, believed that their luck would turn, and gambled in reaction to painful life events. These results indicate the need to include routines for screening to identify gambling problem among cocaine users. PMID- 26983827 TI - Comparative metabolism of honokiol in mouse, rat, dog, monkey, and human hepatocytes. AB - Honokiol has antitumor, antioxidative, anti-inflammatory, and antithrombotic effects. Here we aimed to identify the metabolic profile of honokiol in mouse, rat, dog, monkey, and human hepatocytes and to characterize the enzymes responsible for the glucuronidation and sulfation of honokiol. Honokiol had a high hepatic extraction ratio in all five species, indicating that it was extensively metabolized. A total of 32 metabolites, including 17 common and 15 different metabolites, produced via glucuronidation, sulfation, and oxidation of honokiol allyl groups were tentatively identified using liquid chromatography high resolution quadrupole Orbitrap mass spectrometry. Glucuronidation of honokiol to M8 (honokiol-4-glucuronide) and M9 (honokiol-2'-glucuronide) was the predominant metabolic pathway in hepatocytes of all five species; however, interspecies differences between 4- and 2'-glucuronidation of honokiol were observed. UGT1A1, 1A8, 1A9, 2B15, and 2B17 played major roles in M8 formation, whereas UGT1A7 and 1A9 played major roles in M9 formation. Human cDNA-expressed SULT1C4 played a major role in M10 formation (honokiol-2'-sulfate), whereas SULT1A1*1, 1A1*2, and 1A2 played major roles in M11 formation (honokiol-4 sulfate). In conclusion, honokiol metabolism showed interspecies differences. PMID- 26983828 TI - Ciliary Extracellular Vesicles: Txt Msg Organelles. AB - Cilia are sensory organelles that protrude from cell surfaces to monitor the surrounding environment. In addition to its role as sensory receiver, the cilium also releases extracellular vesicles (EVs). The release of sub-micron sized EVs is a conserved form of intercellular communication used by all three kingdoms of life. These extracellular organelles play important roles in both short and long range signaling between donor and target cells and may coordinate systemic responses within an organism in normal and diseased states. EV shedding from ciliated cells and EV-cilia interactions are evolutionarily conserved phenomena, yet remarkably little is known about the relationship between the cilia and EVs and the fundamental biology of EVs. Studies in the model organisms Chlamydomonas and Caenorhabditis elegans have begun to shed light on ciliary EVs. Chlamydomonas EVs are shed from tips of flagella and are bioactive. Caenorhabditis elegans EVs are shed and released by ciliated sensory neurons in an intraflagellar transport dependent manner. Caenorhabditis elegans EVs play a role in modulating animal-to animal communication, and this EV bioactivity is dependent on EV cargo content. Some ciliary pathologies, or ciliopathies, are associated with abnormal EV shedding or with abnormal cilia-EV interactions. Until the 21st century, both cilia and EVs were ignored as vestigial or cellular junk. As research interest in these two organelles continues to gain momentum, we envision a new field of cell biology emerging. Here, we propose that the cilium is a dedicated organelle for EV biogenesis and EV reception. We will also discuss possible mechanisms by which EVs exert bioactivity and explain how what is learned in model organisms regarding EV biogenesis and function may provide insight to human ciliopathies. PMID- 26983832 TI - Oocytes affected by smooth endoplasmic reticulum aggregates: to discard or not to discard? AB - PURPOSE: Oocytes containing smooth endoplasmic reticulum aggregates (SERa) have been associated with reduced fertilization and clinical pregnancy rates as well as compromised neonatal outcomes. It was therefore recommended by an Alpha-ESHRE Consensus to discard oocytes presenting this dysmorphism. The data in the literature are nevertheless conflicting and healthy babies have recently been obtained from affected oocytes. The objectives of this study were to compare clinical outcomes between ICSI cycles with and without oocytes affected by smooth endoplasmic reticulum aggregates and to confirm whether affected oocytes can produce healthy babies. METHODS: A prospective observational study was performed comparing 714 SERa- ICSI cycles to 112 SERa+ cycles. Among the SERa+ cycles, 518 SERa- oocytes and 213 SERa+ oocytes were analyzed. Fertilization, embryo quality, and pregnancy rates as well as neonatal outcomes were compared between SERa+ and SERa- cycles as well as between SERa+ and SERa- oocytes. RESULTS: The presence of SERa was not associated with an adverse effect on embryological, clinical or neonatal data for SERa+ cycles and oocytes. Seven healthy babies were born from embryos originating from SERa+ oocytes. CONCLUSIONS: These results are encouraging and might contribute in the future to a revision of the Alpha-ESHRE Consensus. Larger studies, including a correlation between frequency and size of SERa, clinical outcomes and malformation rates, as well as the follow-up of babies born are nevertheless necessary. In the meantime, the currently conflicting data requires caution when considering transfers of embryos affected by SERa. PMID- 26983831 TI - Exosomes as Tools to Suppress Primary Brain Tumor. AB - Exosomes are small microvesicles released by cells that efficiently transfer their molecular cargo to other cells, including tumor. Exosomes may pass the blood-brain barrier and have been demonstrated to deliver RNAs contained within to brain. As they are non-viable, the risk profile of exosomes is thought to be less than that of cellular therapies. Exosomes can be manufactured at scale in culture, and exosomes can be engineered to incorporate therapeutic miRNAs, siRNAs, or chemotherapeutic molecules. As natural biological delivery vehicles, interest in the use of exosomes as therapeutic delivery agents is growing. We previously demonstrated a novel treatment whereby mesenchymal stromal cells were employed to package tumor-suppressing miR-146b into exosomes, which were then used to reduce malignant glioma growth in rat. The use of exosomes to raise the immune system against tumor is also drawing interest. Exosomes from dendritic cells which are antigen-presenting, and have been used for treatment of brain tumor may be divided into three categories: (1) exosomes for immunomodulation based therapy, (2) exosomes as delivery vehicles for anti-tumor nucleotides, and (3) exosomes as drug delivery vehicles. Here, we will provide an overview of these three applications of exosomes to treat brain tumor, and examine their prospects on the long road to clinical use. PMID- 26983834 TI - New Targets and New Treatments: Recent Advances in the Treatment of Musculoskeletal Disease. PMID- 26983829 TI - Study of Exosomes Shed New Light on Physiology of Amyloidogenesis. AB - Accumulation of toxic amyloid oligomers, a key feature in the pathogenesis of amyloid-related diseases, results from an imbalance between generation and clearance of amyloidogenic proteins. Cell biology has brought to light the key roles of multivesicular endosomes (MVEs) and their intraluminal vesicles (ILVs), which can be secreted as exosomes, in amyloid generation and clearance. To better understand these roles, we have investigated a relevant physiological model of amyloid formation in pigment cells. These cells have tuned their endosomes to optimize the formation of functional amyloid fibrils from the premelanosome protein (PMEL) and to avoid potential accumulation of toxic species. The functional amyloids derived from PMEL reveal striking analogies with the generation of Abeta peptides. We have recently strengthened these analogies using extracellular vesicles as reporters of the endosomal processes that regulate PMEL melanogenesis. We have shown that in pigmented cells, apolipoprotein E (ApoE) is associated with ILVs and exosomes, and regulates the formation of PMEL amyloid fibrils in endosomes. This process secures the generation of amyloid fibrils by exploiting ILVs as amyloid-nucleating platforms. This physiological model of amyloidogenesis could shed new light on the roles of MVEs and exosomes in conditions with pathological amyloid metabolism, such as Alzheimer's disease. PMID- 26983833 TI - Serious adverse events within 30 days of groin hernia surgery. AB - PURPOSE: To analyze severe complications after groin hernia repair with respect to age, ASA score, hernia anatomy, method of repair and method of anesthesia, using nationwide registers. The annual rate of 20 million groin hernia operations throughout the world renders severe complications, although rare, important both for the patient, the clinician, and the health economist. METHODS: Two nationwide registers, the Swedish Hernia Register and the National Swedish Patient Register were linked to find intraoperative complications, severe cardiovascular events and severe surgical adverse events within 30 days of groin hernia surgery. RESULTS: 143,042 patients, 8 % women and 92 % men, were registered between 2002 and 2011. Intraoperative complications occurred in 801 repair, 592 patients suffered from cardiovascular events and 284 patients from a severe surgical event within 30 days of groin hernia surgery. Emergency operation was a risk factor for both cardiovascular and severe surgical adverse events with odds ratios for cardiovascular events of 3.1 (2.5-4.0) for men and 2.8 (1.4-5.5) for women. Regional anesthesia was associated with an increase in cardiovascular morbidity compared with local anesthesia, odds ratio 1.4 (1.1-1.9). In men, bilateral hernia and sliding hernia approximately doubled the risk for severe surgical events; odds ratio 1.9 (1.1-3.5) and 2.2 (1.6-3.0), respectively. Methods other than open anterior mesh repair increased the risk for surgical complications. CONCLUSIONS: Awareness of the increased risk for cardiovascular or surgical complications associated with emergency surgery, bilateral hernia, sliding hernia, and regional anesthesia may enable the surgeon to further reduce their incidence. PMID- 26983836 TI - Selective Modulation of Protein Kinase C alpha over Protein Kinase C epsilon by Curcumin and Its Derivatives in CHO-K1 Cells. AB - Members of the protein kinase C (PKC) family of serine/threonine kinases regulate various cellular functions, including cell growth, differentiation, metabolism, and apoptosis. Modulation of isoform-selective activity of PKC by curcumin (1), the active constituent of Curcuma L., is poorly understood, and the literature data are inconsistent and obscure. The effect of curcumin (1) and its analogues, 4-[(2Z,6E)-3-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-5-oxohepta-2,6-dien-1-yl]-2 methoxyphenyl oleate (2), (9Z,12Z)-4-[(2Z,6E)-3-hydroxy-7-(4-hydroxy-3 methoxyphenyl)-5-oxohepta-2,6-dien-1-yl]-2-methoxyphenyl octadeca-9,12-dienoate (3), (9Z,12Z,15Z)-4-[(2Z,6E)-3-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-5-oxohepta 2,6-dien-1-yl]-2-methoxyphenyl octadeca-9,12,15-trienoate (4), and (1E,6E)-1-[4 (hexadecyloxy)-3-methoxyphenyl]-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5 dione (5), and didemethylcurcumin (6) on the membrane translocation of PKCalpha, a conventional PKC, and PKCepsilon, a novel PKC, has been studied in CHO-K1 cells, in which these PKC isoforms are endogenously expressed. Translocation of PKC from the cytosol to the membrane was measured using immunoblotting and confocal microscopy. 1 and 6 inhibited the TPA-induced membrane translocation of PKCalpha but not of PKCepsilon. Modification of the hydroxyl group of curcumin with a long aliphatic chain containing unsaturated double bonds in 2-4 completely abolished this inhibition property. Instead, 2-4 showed significant translocation of PKCalpha but not of PKCepsilon to the membrane. No membrane translocation was observed with 1, 6, or the analogue 5 having a saturated long chain for either PKCalpha or PKCepsilon. 1 and 6 inhibited TPA-induced activation of ERK1/2, and 2 4 activated it. ERK1/2 is the downstream readout of PKC. These results show that the hydroxyl group of curcumin is important for PKC activity and the curcumin template can be useful in developing isoform specific PKC modulators for regulating a particular disease state. PMID- 26983835 TI - Living with Intoxication-Type Inborn Errors of Metabolism: A Qualitative Analysis of Interviews with Paediatric Patients and Their Parents. AB - INTRODUCTION: Progress in diagnosis and treatment of patients with intoxication type inborn errors of metabolism (IT-IEM) such as urea cycle disorders, organic acidurias or maple syrup urine disease is resulting in a growing number of long term survivors. Consequently, health-related quality of life (HrQoL) of patients is increasingly regarded as a meaningful outcome parameter. To develop the first validated, disease-specific HrQoL questionnaire for IT-IEM, patients and parents were interviewed as content experts to identify major physical and psychosocial constraints and resources. METHODS: Focus group interviews with 19 paediatric IT IEM patients and 26 parents were conducted in four metabolic centres in Austria, Germany and Switzerland. Disease-specific HrQoL categories were established by qualitative content analysis. RESULTS: Fourteen disease-specific topics related to the three well-established generic HrQoL dimensions of physical, mental and social functioning were derived from the interview transcripts. Both patients and parents perceived dietary restrictions and social stigmatisation as major burdens. Dietary restrictions and emotional burdens were more important for young (<8 years) patients, whereas cognition, fatigue and social issues were more relevant to older patients (>=8 years). Treatment-related topics had a significant effect on social and emotional HrQoL. DISCUSSION: By exploring patients' and parents' perspectives, 14 HrQoL categories were identified. These new categories will allow the development of a disease-specific, standardised questionnaire to assess HrQoL in paediatric IT-IEM patients. Age-appropriate information on the disease and psychosocial support targeted to patients' individual burdens are essential to the delivery of personalised care that takes account of physical, mental and social dimensions of HrQoL. PMID- 26983838 TI - Defining Cyclic-Acyclic Exciton Transition at the Single-Molecule Level: Size Dependent Conformational Heterogeneity and Exciton Delocalization in Ethynylene Bridged Cyclic Oligothiophenes. AB - Conformational disorder in pi-conjugated cyclic systems plays a crucial role in controlling the extent of exciton delocalization in much the same way as that in linear counterparts. However, to date, there have been no detailed spectroscopic investigations on the nature of excitons in pi-conjugated cyclic systems at the single-molecule level. Herein, we studied the effect of conformational disorder on the excitonic behaviors of cyclic oligothiophenes composed of 6, 8, 10, and 12 subunits (C-6T, C-8T, C-10T, and C-12T, respectively) by employing single molecule fluorescence spectroscopy. We found that, due to the cyclic symmetry constraint which suppresses S1-S0 transition, small and rigid C-6T and C-8T exhibit extremely long fluorescence lifetimes, while short lifetimes typical of linear systems are dominant in large, flexible C-10T and C-12T. Two-dimensional correlation maps between fluorescence lifetimes and spectral positions show that, by torsional defects created through continued photoexcitation, fully delocalized cyclic excitons shrink to form acyclic excitons in the case of C-10T, while localized acyclic excitons from initial states are maintained in the case of C 12T. The distribution of linear dichroism values from C-6T to C-10T gradually broadens but narrows in C-12T, suggesting a cyclic-to-acyclic transition in excitonic nature between C-10T and C-12T. PMID- 26983830 TI - Extracellular Vesicles and MicroRNAs: Their Role in Tumorigenicity and Therapy for Brain Tumors. AB - MicroRNAs are small non-coding RNAs which mediate post-transcriptional gene regulation. Recently, microRNAs have also been found to be localized to the extracellular space, often encapsulated in secreted extracellular vesicles (EVs). This tandem of EVs and tissue-specific expressed/secreted microRNAs that can be taken up by neighboring or distant recipient cells, leading to changes in gene expression-suggests a cell-specialized role in physiological and pathological conditions. The complexity of solid tumors and their distinct pathophysiology relies on interactive communications between the various cell types in the neoplasm (tumor, endothelial, or macrophages, for instance). Understanding how such EV/microRNA-mediated communication occurs may actually lead to avenues for therapeutic exploitation and/or intervention, particularly for the most formidable cancers, such as those in the brain. In this review, the role of microRNAs/EVs in brain tumors will be discussed with emphasis on how these molecules could be utilized for tumor therapy. PMID- 26983837 TI - Oral microbiota species in acute apical endodontic abscesses. AB - BACKGROUND AND OBJECTIVES: Acute apical abscesses are serious endodontic diseases resulting from pulpal infection with opportunistic oral microorganisms. The objective of this study was to identify and compare the oral microbiota in patients (N=18) exhibiting acute apical abscesses, originating from the demographic region in Portland, Oregon. The study hypothesis is that abscesses obtained from this demographic region may contain unique microorganisms not identified in specimens from other regions. DESIGN: Endodontic abscesses were sampled from patients at the Oregon Health & Science University (OHSU) School of Dentistry. DNA from abscess specimens was subjected to polymerase chain reaction amplification using 16S rRNA gene-specific primers and Cy3-dCTP labeling. Labeled DNA was then applied to microbial microarrays (280 species) generated by the Human Oral Microbial Identification Microarray Laboratory (Forsyth Institute, Cambridge, MA). RESULTS: The most prevalent microorganisms, found across multiple abscess specimens, include Fusobacterium nucleatum, Parvimonas micra, Megasphaera species clone CS025, Prevotella multisaccharivorax, Atopobium rimae, and Porphyromonas endodontalis. The most abundant microorganisms, found in highest numbers within individual abscesses, include F. nucleatum, P. micra, Streptococcus Cluster III, Solobacterium moorei, Streptococcus constellatus, and Porphyromonas endodontalis. Strong bacterial associations were identified between Prevotella multisaccharivorax, Acidaminococcaceae species clone DM071, Megasphaera species clone CS025, Actinomyces species clone EP053, and Streptococcus cristatus (all with Spearman coefficients >0.9). CONCLUSIONS: Cultivable and uncultivable bacterial species have been identified in endodontic abscesses obtained from the Portland, Oregon demographic region, and taxa identifications correlated well with other published studies, with the exception of Treponema and Streptococcus cristae, which were not commonly identified in endodontic abscesses between the demographic region in Portland, Oregon and other regions. PMID- 26983839 TI - On the Spatiotemporal Material Anisotropy of the Vitreous Body in Tension and Compression. AB - Although linked to several vitreoretinal pathologies including traumatic retinal tears, breaks, and symptomatic vitreomacular traction, the dynamic material behavior of the vitreous body in response to mechanical loads is not well understood. The purpose of this study was to evaluate spatiotemporal patterns of collagen fiber reorganization and vitreous deformation (strain) in response to tensile and compressive forces. Using thick slabs of bovine eyes we examined collagen fiber reorganization following tensile and compressive step-loading with quantitative polarized light imaging. Strains were measured from sparse marker arrays and temporal collagen behavior was estimated from creep compliance rheological tests. Results showed that under applied loads (1) collagen fibers became significantly more aligned at the vitreous base (near the pars plana and the ciliary body), (2) vitreous located directly behind the lens deformed significantly more than surrounding regions, and (3) changes in collagen fiber alignment occurred on a short (<5 s) timescale. Together these results show that, despite a homogeneous visual appearance, the vitreous body exhibits anisotropic material behavior in tension and compression. Spatiotemporal patterns of collagen rearrangement were consistent with epidemiological patterns of traumatic retinal damage and vitreoretinal topology. High strains in the vitreous corresponded with locations of lower collagen content that are prone to age-related degeneration. These data suggest that differential fiber alignment and mechanical deformation could contribute to the pathogenesis of these diseases. Computational models that incorporate these experimental data will help improve our understanding of the biomechanical mechanisms that contribute to the pathogenesis of traumatic retinal damage, vitreous degeneration, and vitreoretinal disease. PMID- 26983841 TI - Cell-Instructive Graphene-Containing Nanocomposites Induce Multinucleated Myotube Formation. AB - Myoblast differentiation is a key step in myogenesis and has long been considered to be controlled mainly by biochemical cues such as growth factors. However, the tissue engineering approaches based on biochemical cues demonstrate low reproducibility as a precise spatial control over their bioactivity is challenging. Recently, substrate micro/nano-structure and electro-responsive properties are recognized for their important roles in myoblast differentiation. In this study, we hypothesized that engineering biophysical features such as nano/micro-fibrous structure and conductive properties into a single biomaterial scaffold will instruct the myoblasts to differentiate into multinucleated myotubes even in the absence of differentiation media. We fabricated nanocomposite scaffolds composed of conductive graphene nanosheets and polycaprolactone (PCL), a widely used biocompatible material. The resulting graphene-PCL scaffolds possess excellent conductivity due to graphene nanosheets and great processability, biodegradability and elastic mechanical properties conferred by PCL. Additionally, physicochemical and mechanical properties of nanocomposite scaffolds can be tuned by varying graphene concentration. Further, graphene-PCL nanocomposites and their 8-week degradation products exhibited remarkable cytocompatibility and promoted adhesion and proliferation of C2C12 mouse myoblast cells. Importantly, these nanocomposite scaffolds induced graphene concentration-dependent differentiation of C2C12 cells into multinucleated myotubes even in normal growth media suggesting their cell-instructive potential. Thus, graphene-PCL nanocomposite scaffolds can serve as a strategy to promote skeletal muscle regeneration without biochemical cues. PMID- 26983840 TI - A Novel Parameter for Predicting Arterial Fusion and Cutting in Finite Element Models. AB - Current efforts to evaluate the performance of laparoscopic arterial fusion devices are limited to costly, time consuming, empirical studies. Thus, a finite element (FE) model, with the ability to predict device performance would improve device design and reduce development time and costs. This study introduces a model of the heat transfer through an artery during electrosurgical procedures that accounts for changes in thermal material properties due to water loss and temperature. Experiments then were conducted by applying a known heat and pressure to carefully sectioned pieces of porcine splenic arteries and measuring cut completeness. From this data, equations were developed to predict at which temperature and pressure arterial tissue is cut. These results were then incorporated into a fully coupled thermomechanical FE model with the ability to predict whole artery cutting. An additional experiment, performed to examine the accuracy of the model, showed that the model predicted complete artery cut results correctly in 28 of 32 tests. The predictive ability of this FE model opens a gateway to more advanced electrosurgical fusion devices and modeling techniques of electrosurgical procedures by allowing for faster, cheaper and more comprehensive device design. PMID- 26983842 TI - A Concentric Tube Continuum Robot with Piezoelectric Actuation for MRI-Guided Closed-Loop Targeting. AB - This paper presents the design, modeling and experimental evaluation of a magnetic resonance imaging (MRI)-compatible concentric tube continuum robotic system. This system enables MRI-guided deployment of a precurved and steerable concentric tube continuum mechanism, and is suitable for clinical applications where a curved trajectory is needed. This compact 6 degree-of-freedom (DOF) robotic system is piezoelectrically-actuated, and allows simultaneous robot motion and imaging with no visually observable image artifact. The targeting accuracy is evaluated with optical tracking system and gelatin phantom under live MRI-guidance with Root Mean Square (RMS) errors of 1.94 and 2.17 mm respectively. Furthermore, we demonstrate that the robot has kinematic redundancy to reach the same target through different paths. This was evaluated in both free space and MRI-guided gelatin phantom trails, with RMS errors of 0.48 and 0.59 mm respectively. As the first of its kind, MRI-guided targeted concentric tube needle placements with ex vivo porcine liver are demonstrated with 4.64 mm RMS error through closed-loop control of the piezoelectrically-actuated robot. PMID- 26983844 TI - Predisposing Factors for Orthodontic Mini-Implant Failure Defined by Bone Strains in Patient-Specific Finite Element Models. AB - Factors responsible for the success or failure of orthodontic mini-implants (OMIs) in clinical settings are unclear. Failure of OMIs was found to be associated with increased maximum principal strain (MaxPN) when assessed using the subject-specific finite element (FE) modeling technique. The purpose of the present study was to identify factors that increase MaxPN and thereby predispose the OMI to failure. Using the FE method, MaxPN was calculated around 28 OMIs placed in orthodontic patients, 6 of which failed during the first 5 months. Sixteen potential risk factors related to patients or to OMI position were measured on computerized tomographic images or calculated in FE models. The impact of these factors on MaxPN was verified using regression analysis. Three factors were found to have significant nonlinear relationships with MaxPN: cortical bone quality, vertical angulation of the OMI, and proximity of the OMI to the tooth in the direction of force. In conclusion, failure of an OMI is a multifactorial problem, and position and angulation of the implant are among the affecting factors. Slight apical inclination and positioning at least 1 mm off the root in the direction of force may significantly decrease failure probability. PMID- 26983843 TI - Understanding the Role of ECM Protein Composition and Geometric Micropatterning for Engineering Human Skeletal Muscle. AB - Skeletal muscle lost through trauma or disease has proven difficult to regenerate due to the challenge of differentiating human myoblasts into aligned, contractile tissue. To address this, we investigated microenvironmental cues that drive myoblast differentiation into aligned myotubes for potential applications in skeletal muscle repair, organ-on-chip disease models and actuators for soft robotics. We used a 2D in vitro system to systematically evaluate the role of extracellular matrix (ECM) protein composition and geometric patterning for controlling the formation of highly aligned myotubes. Specifically, we analyzed myotubes differentiated from murine C2C12 cells and human skeletal muscle derived cells (SkMDCs) on micropatterned lines of laminin compared to fibronectin, collagen type I, and collagen type IV. Results showed that laminin supported significantly greater myotube formation from both cells types, resulting in greater than twofold increase in myotube area on these surfaces compared to the other ECM proteins. Species specific differences revealed that human SkMDCs uniaxially aligned over a wide range of micropatterned line dimensions, while C2C12s required specific line widths and spacings to do the same. Future work will incorporate these results to engineer aligned human skeletal muscle tissue in 2D for in vitro applications in disease modeling, drug discovery and toxicity screening. PMID- 26983845 TI - Effects of dietary supplementation with epidermal growth factor-expressing Saccharomyces cerevisiae on duodenal development in weaned piglets. AB - The aim of the present study was to assess the effects of dietary supplementation with epidermal growth factor (EGF)-expressing Saccharomyces cerevisiae on duodenal development in weaned piglets. In total, forty piglets weaned at 21-26 d of age were assigned to one of the five groups that were provided basic diet (control group) or diet supplemented with S. cerevisiae expressing either empty vector (INVSc1(EV) group), tagged EGF (T-EGF) (INVSc1-TE(-) group), extracellular EGF (EE-EGF) (INVSc1-EE(+) group) or intracellular EGF (IE-EGF) (INVSc1-IE(+) group). All treatments were delivered as 60.00 MUg/kg body weight EGF/d. On 0, 7, 14 and 21 d, eight piglets per treatment were sacrificed to analyse the morphology, activities and mRNA expressions of digestive enzymes, as well as Ig levels (IgA, IgM, IgG) in duodenal mucosa. The results showed significant improvement on 7, 14 and 21 d, with respect to average daily gain (P<0.05), mucosa morphology (villus height and crypt depth) (P<0.05), Ig levels (P<0.01), activities and mRNA expressions of digestive enzymes (creatine kinase, alkaline phosphatase, lactate dehydrogenase and sucrase) (P<0.05) and the mRNA expression of EGF-receptor (P<0.01) in NVSc1-TE(-), INVSc1-EE(+) and INVSc1-IE(+) groups compared with control and INVSc1(EV) groups. In addition, a trend was observed in which the INVSc1-IE(+) group showed an improvement in Ig levels (0.05160 mmol/L. Mortality was determined at 90 days after ICU admission. RESULTS: In 80,571 ICU patients, 913,272 serum sodium measurements were analyzed. A striking shift in the pattern of ICU-acquired dysnatremias was observed: The incidence of hyponatremia almost halved (47-25 %, p < 0.001), whereas the incidence of hypernatremia nearly doubled (13-24 %, p < 0.001). Most hypernatremias developed after ICU admission, and the incidence of severe hypernatremia (sodium > 155 mmol/L) increased dramatically over the years. On ICU day 10 this incidence was 0.7 % in the 1992-1996 period, compared to 6.3 % in the 2009-2012 period (p < 0.001). More severe dysnatremia was associated with significantly higher mortality throughout the 21-year study period (p < 0.001). CONCLUSIONS: In two large Dutch cohorts, we observed a marked shift in the incidence of dysnatremia from hyponatremia to hypernatremia over two decades. As hypernatremia was mostly ICU acquired, this strongly suggests changes in treatment as underlying causes. This shift may be related to the increased use of sodium-containing infusions, diuretics, and hydrocortisone. As ICU-acquired hypernatremia is largely iatrogenic, it should be-to an important extent preventable, and its incidence may be considered as an indicator of quality of care. Strategies to prevent hypernatremia deserve more emphasis; therefore, we recommend that further study should be focused on interventions to prevent the occurrence of dysnatremias during ICU stay. PMID- 26983859 TI - Are first-generation cephalosporins obsolete? A retrospective, non-inferiority, cohort study comparing empirical therapy with cefazolin versus ceftriaxone for acute pyelonephritis in hospitalized patients. AB - OBJECTIVES: Literature is lacking regarding the utilization of first-generation cephalosporins for the treatment of acute pyelonephritis. The aim of this study was to determine whether cefazolin is non-inferior to ceftriaxone for the empirical treatment of acute pyelonephritis in hospitalized patients. The primary outcome included a composite of symptomatic resolution plus either defervescence at 72 h or normalization of serum white blood cell count at 72 h (non-inferiority margin 15%). Secondary outcomes included length of stay and 30 day readmission. A subgroup analysis of the composite outcome was also conducted for imaging confirmed pyelonephritis. METHODS: This was a retrospective, non-inferiority, multicentre, cohort study comparing cefazolin versus ceftriaxone for the empirical treatment of acute pyelonephritis in hospitalized patients. RESULTS: Overall, 184 patients received one of the two treatments between July 2009 and March 2015. The composite outcome was achieved in 80/92 (87.0%) in the cefazolin group versus 79/92 (85.9%) in the ceftriaxone group (absolute difference 1.1%, 95% CI -11.1% to 8.9%, P = 0.83), meeting the pre-defined criteria for non inferiority. The composite outcome for patients with imaging-confirmed pyelonephritis was achieved in 46/56 (82.1%) versus 42/50 (84.0%) for the cefazolin group and the ceftriaxone group, respectively (absolute difference 1.9%, 95% CI -12.8% to 16.5%, P = 0.80). Additionally, there were no statistically significant differences in length of stay or 30 day readmission for cystitis or pyelonephritis. CONCLUSIONS: Cefazolin was non-inferior to ceftriaxone with regard to clinical response for the treatment of hospitalized patients with acute pyelonephritis in this study. No difference was observed for length of stay or 30 day readmission. PMID- 26983860 TI - A pharmacokinetic-pharmacodynamic (PKPD) model based on in vitro time-kill data predicts the in vivo PK/PD index of colistin. AB - OBJECTIVES: For antibiotics, extensive animal PKPD studies are often performed to evaluate the PK/PD driver for subsequent use when recommending dosing regimens. The aim of this work was to evaluate a PKPD model, developed based on in vitro time-kill data for colistin, in predicting the relationships between PK/PD indices and the bacterial killing previously observed in mice. METHODS: An in silico PKPD model for Pseudomonas aeruginosa exposed to colistin was previously developed based on static in vitro time-kill data. The model was here applied to perform an in silico replication of an in vivo study where the effect of colistin on P. aeruginosa was studied in the thigh infection model. Concentration-time profiles of unbound colistin were predicted and used as input to drive the bacterial killing in the PKPD model. The predicted bacterial count at 24 h was related to each of the PK/PD indices and the results were compared with reported observations in vivo. RESULTS: The model was found to adequately predict in vivo results from mice; both in terms of which PK/PD index best correlates to effect (fAUC/MIC) as well as the magnitude needed for a 2 log kill. The fAUC/MIC needed to achieve a 2 log reduction in bacterial counts after 24 h was here predicted to be 9 compared with 31 previously reported in vivo. CONCLUSIONS: This study provides further support that PKPD models based on longitudinal data can be a useful tool to make drug development more efficient within the infectious diseases area. PMID- 26983861 TI - Considering depression as a consequence of activation of the inflammatory response system. AB - This paper summarizes the possible interrelation between peripheral and/or cerebral inflammation and depression. Often, depression is regarded as a consequence of life events, including disabling diseases. The question addressed here is whether activation of the inflammatory response system (IRS) can cause depression. Epidemiological studies suggest that depression can be precipitated by bacterial or viral infections. In depressed patients, peripheral markers of the IRS are often increased. There is some evidence that some forms of depression are caused by a viral infection of the limbic system. More consistent are the observations that depression in diseases with active cerebral inflammatory processes (e.g. multiple sclerosis, Alzheimer's disease) may concur. Direct evidence of a relation between depression and inflammation was found in post mortem brain material of patients with a vascular depression. In both inflammatory brain diseases and in depression, a state-dependent increased hypothalamus-pituitary-adrenal axis activity is seen. Animals studies have shown that intact cerebral serotonin systems are required for the activation of the IRS following an endotoxin challenge and that long-term treatment with antidepressants may change such a response. Gender differences between the prevalence of depression and inflammatory diseases are similar, as more females are affected. We hypothesize that cerebral or peripheral activation of the IRS may contribute to the course of some antidepressant treatment-resistant depressions. Clinical trials combining antidepressants and drugs that reduce the activation of the IRS may provide evidence for such proposed depression subtypes. PMID- 26983858 TI - Horizontal transfer of beta-carbonic anhydrase genes from prokaryotes to protozoans, insects, and nematodes. AB - BACKGROUND: Horizontal gene transfer (HGT) is a movement of genetic information occurring outside of normal mating activities. It is especially common between prokaryotic endosymbionts and their protozoan, insect, and nematode hosts. Although beta carbonic anhydrase (beta-CA) plays a crucial role in metabolic functions of many living organisms, the origin of beta-CA genes in eukaryotic species remains unclear. METHODS: This study was conducted using phylogenetics, prediction of subcellular localization, and identification of beta-CA, transposase, integrase, and resolvase genes on the MGEs of bacteria. We also structurally analyzed beta-CAs from protozoans, insects, and nematodes and their putative prokaryotic common ancestors, by homology modelling. RESULTS: Our investigations of a number of target genomes revealed that genes coding for transposase, integrase, resolvase, and conjugation complex proteins have been integrated with beta-CA gene sequences on mobile genetic elements (MGEs) which have facilitated the mobility of beta-CA genes from bacteria to protozoan, insect, and nematode species. The prokaryotic origin of protozoan, insect, and nematode beta-CA enzymes is supported by phylogenetic analyses, prediction of subcellular localization, and homology modelling. CONCLUSION: MGEs form a complete set of enzymatic tools, which are relevant to HGT of beta-CA gene sequences from prokaryotes to protozoans, insects, and nematodes. PMID- 26983862 TI - Event-related potentials and white matter lesions in bipolar disorder. AB - OBJECTIVES: To investigate neurophysiological parameters which possibly distinguish subtypes I and II of patients with a bipolar disorder, and contrast the findings with observations from a group of schizophrenic patients and a group of healthy controls. METHODS: Sixty-six volunteers underwent a MRI scan to determine the number and location of white matter lesions (WSL). A electrophysiological registration was made while all volunteers performed a auditory 'oddball' task, and the amplitude of the resulting P300 wave was compared. RESULTS: Earlier reports of higher numbers of WSL in bipolar disorder were not replicated in this study. Subtypes I and II showed a different P300 amplitude and subtype I resembled the results of the schizophrenia group. CONCLUSION: Bipolar patients in remission have a functional brain disorder that is expressed by a change in physiological response to external stimuli. PMID- 26983863 TI - Seasonal variation and meteotropism in suicide: clinical relevance of findings and implications for research. AB - Seasonal asymmetry in yearly suicide occurrence is a long-observed phenomenon in psychiatric, suicidological and sociological research, and the effects of seasonal factors on suicidal behaviour have been the focus of a number of earlier studies. Taking into account limitations of data and methods, these studies have in general favoured interpretations based on psychosocial factors. Recent studies have challenged the widely held notion that seasonal effects on suicide are not influenced by age, gender or the circumstances of the act. The suicides committed with violent methods have been shown to follow clearer seasonal patterns than suicides by less violent methods, and differences have been found between male and female cycles of occurrence. The seasonal occurrence of suicides has also been found to differ significantly between the young and the elderly. The use of inappropriate statistics or age- and gender-biased samples may have hidden a seasonal component in some previous studies on attempted suicide. The absence of seasonality in earlier studies on attempted suicide was interpreted as depending upon the minor relevance of psychiatric and biological factors in non-fatal self harm. However, recent studies have reported clear seasonality in attempted suicide samples, with older people showing greater seasonal effect. Recent literature after 1985 on seasonal variation and weather or climate influence in attempted and completed suicide is reviewed. Suggestions for research and the development of more effective preventative strategies are offered. PMID- 26983864 TI - Effects of age and gender on the classification and phenomenology of unipolar depression. AB - AIM: The aim of the present study was to examine the effects of age and gender on depressive classification and phenomenology in unipolar depressed in-patients. METHODS: The authors have assessed 14 items relevant to depressive symptomatology from the Structured Clinical Interview for DSM-III (SCID) and the Hamilton Depression Rating Scale (HDRS) in 180 depressed in-patients. RESULTS: Melancholia was significantly more prominent in older depressed patients (>= 55 years), whereas minor depression (i.e. adjustment disorder with depressed mood and dysthymic disorder) in younger (< 55 years) depressed subjects. Older depressed subjects exhibited significantly more anorexia/weight loss, non-reactivity, depressed mood, loss of interest, early morning awakening, loss of energy, somatic anxiety, loss of insight, psychotic symptoms and retardation than younger depressed people. Male depressed subjects showed significantly more loss of interest, suicidal ideation and agitation than their female counterparts. Psychomotor disorders, a distinct quality of mood and early morning awakening were characteristics of older depressed males, while diurnal variation occurred more frequently in older depressed females. CONCLUSION: It is concluded that increasing age in unipolar depression may be accompanied by an increase in severity of illness, increased frequency of some melancholic symptoms, particularly in men and a higher frequency of major depression in women and of melancholia in men. PMID- 26983865 TI - Lipoma adhered to the corpus callosum in a schizophrenic patient with severe positive symptoms that responded to clozapine. PMID- 26983866 TI - Treatment of interictal psychiatric disorder in epilepsy. I. Affective and anxiety disorders. AB - BACKGROUND: Interictal affective disorders are common in patients with epilepsy and there is a need for evidence-based treatment guidelines. OBJECTIVE: This paper gives an overview of research concerning treatment of interictal affective disorders and interictal anxiety disorders in epilepsy. METHODS: Literature review supplemented by clinical experience. RESULTS: Interictal psychiatric disorder can be characterized as intermittent pleomorphic psychopathology. The most common manifestations are interictal dysphoric disorder (IDD) and depression. There is a lack of randomized control trials (RCTs) concerning effectiveness and side-effects of antidepressants in epilepsy patients. CONCLUSION: Treatment implications of the concept of IDD and other interictal disorders are an optimized dosage of anti-epileptics in combination with antidepressants. This coincides with recent guidelines concerning combinations of psychotropic medication, such as for depression and bipolar disorder, in general psychiatry. Systematic research involving the DSM-IV categories of generalized anxiety disorder, panic disorder and agoraphobia and depression is not yet available. Prevalence and treatment of interictal anxiety disorders and depressive disorder in epilepsy should be the subject of further research, in order to enable development of evidence-based treatment guidelines for these disorders in epilepsy patients. PMID- 26983867 TI - Treatment of interictal psychiatric disorder in epilepsy. II. Chronic psychosis. AB - BACKGROUND: Interictal psychosis is a serious comorbid condition in epilepsy patients that would benefit from treatment with psychotropic medication. OBJECTIVE: This paper gives an overview of the pathophysiology, symptomatology and treatment of the schizophrenia-like psychosis of epilepsy. Use of the term 'interictal chronic psychosis' is suggested, to conform to current DSM-IV classification of schizophrenia. METHODS: Literature review supplemented by clinical experience. There is a lack of randomized control trials (RCTs) concerning effectiveness and side-effects of neuroleptics in epilepsy patients. RESULTS: Hypotheses concerning the pathophysiology of the interictal chronic psychosis are discussed. The concept of forced normalization and alternative psychosis is based on case descriptions, and was not substantiated by systematic research. The kindling hypothesis seems promising, but was never confirmed in humans. A third theory, supported by some studies, suggests that inhibitory cerebral mechanisms enhance psychotic symptoms in epilepsy patients. Treatment strategies are based on case studies and open studies by lack of RCTs. Treatment should consider the optimalization of the dosage of antiepileptics in combination with one or two antidepressants, mood stabilizers and/or atypical neuroleptics. Surgery plays no significant role in the treatment of treatment-refractive epilepsy with interictal chronic psychotic symptoms. CONCLUSION: There is a prominent role of antidepressant or double antidepressant treatment strategies in patients with epilepsy and interictal chronic psychosis compared with treatment guidelines of chronic psychotic patients in general psychiatry. PMID- 26983868 TI - Treatment of interictal psychiatric disorder in epilepsy. III. Personality disorder, aggression and mental retardation. AB - BACKGROUND: Personality disorder, mental retardation and aggression are frequently encountered therapeutic problems in epilepsy patients. OBJECTIVE: This paper gives an overview of symptomatology and treatment of personality disorder, interictal aggression and mental retardation in epilepsy. METHODS: Literature review supplemented by clinical experience. RESULTS: Personality changes in patients with epilepsy are often symptoms of an organic psychosyndrome. Aggression is not more frequent among epilepsy patients than in the general population, but if it does happen it is often more severe. There is a need for controlled treatment studies. A treatment strategy is suggested. In the mentally retarded, diagnostic instruments should be used to overcome diagnostic difficulties. CONCLUSION: Prevalence studies based on DSM-IV personality disorder, conducted in the community, are needed, as well as systematic research on diagnosis and treatment of personality disorder in epilepsy patients. Randomized controlled trials (RCTs) considering the effectiveness and adverse effects of antidepressants and neuroleptics in epileptic patients with mental retardation are seriously needed. In the meantime, the Expert Consensus Guideline Series on Treatment of Psychiatric and Behavioural Problems in Mental Retardation is useful. The use of neuroleptics for the treatment of aggressive or destructive behaviour in nonpsychotic mentally retarded patients remains controversial. PMID- 26983869 TI - Liver Transplantation in Patients with Cryptogenic Cirrhosis Provides Excellent Long-Term Outcome. AB - BACKGROUND: Cryptogenic cirrhosis (CC) is an indication for liver transplantation in 5-9% of recipients. Diagnosis is made when other diagnostic possibilities have been ruled out. The aim of this study was to present long-term outcomes of liver transplantation for CC. MATERIAL AND METHODS: There have been 1367 liver transplantations performed during the years 1994-2013 in the Department of General, Transplant and Liver Surgery at the Medical University of Warsaw. This retrospective study comprised 55 patients after liver transplantation for CC (4.0%). Perioperative mortality (30 days) and patient and graft 1-, 5-, and 10 year survival rates were set as outcome measures. RESULTS: Peri-operative mortality reached 10.9% (6 of 55). The 1-, 5- and 10-year patient and graft survival rates were 85.2%, 78.8%, and 73.9%, respectively, and 83.3%, 74.5%, and 74.5%, respectively. In univariate analyses, the following parameters significantly influenced patient survival: pre-operative aspartate (AST; p=0.013) and alanine (ALT; p=0.043) aminotransferases activity, INR (p=0.040), bilirubin concentration (p=0.045), and donor age (p=0.033). Similarly, graft survival was significantly associated with AST (p=0.013), ALT (p=0.043), bilirubin concentration (p=0.044), INR (p=0.038), and recipient sex (p=0.049). In multivariable analyses, a tendency towards worse patient and graft survival was observed in patients with higher pre-operative AST (p=0.078 for patient survival and p=0.063 for graft survival). Analyses of the pathological reports indicated that underlying immunological processes were the most probable cause of liver damage in 16 of 51 patients (31.4%). CONCLUSIONS: Long-term outcomes of liver transplantation in patients with cryptogenic liver cirrhosis are encouraging. Analysis of the clinical course, biochemical parameters, and factors influencing outcomes suggest an underlying autoimmunological etiology of cirrhosis in this population of patients. PMID- 26983870 TI - Erratum to: Imported malaria including HIV and pregnant woman risk groups: overview of the case of a Spanish city 2004-2014. PMID- 26983871 TI - The epidemiology of substance misuse and comorbid psychiatric disorders. AB - The common co-occurrence of substance misuse and other psychiatric disorders and their intricate relationships have led to major community-based epidemiological studies in the US which showed high rates of current and lifetime comorbidity. Moreover, studies of clinical populations conducted in North America, Europe and Australia, showed even higher rates of comorbidity. The aetology of this comorbidity has also been investigated and important models have emerged with findings that inform its assessment and treatment. Future epidemiological studies should focus on the study of concurrent conditions rather than lifetime ones using research diagnostic instruments with high reliability providing information on a number of key outcomes. PMID- 26983873 TI - Psychopharmacology of substance misuse and comorbid psychiatric disorders. AB - The common occurrence of comorbid substance misuse and other psychiatric disorders has challenged the diagnostic and therapeutic skills of professionals concerned with the care of patients with these dual disorders. Combined pharmacological and psychological treatment approaches have evolved empirically drawing upon standard treatments with emphasis on psychosocial approaches to substance misuse for psychotic disorders and pharmacological approaches for mood disorders. Advances in the biology of both disorders have started to inform their psychopharmacology. The specific role of atypical antipscychotics is highlighted. Further studies of the biology of comorbidity will impact the use of effective pharmaceuticals such as clozapine with dual effects on schizophrenia and substance misuse. PMID- 26983872 TI - Diagnosing comorbidity: concepts, criteria, and methods. AB - BACKGROUND: The clinical and etiologic implications of comorbid psychiatric and substance-use disorders are relevant across countries and cultures. The DSM-IV now places greater emphasis on the clinical and research utility of the substance induced disorders classification, and clarifies several important diagnostic issues specific to primary and substance-induced disorders. However, no research consensus exists over the core problem of identifying and differentiating the drug and alcohol intoxication and withdrawal symptoms that can mimic psychiatric symptoms in heavy drinkers and drug users. OBJECTIVE: To investigate how various diagnostic instruments have measured comorbid psychiatric and substance-use disorders and how each instrument operationalizes the DSM-IV classification. METHOD: We review the evolution of the concept of comorbidity beginning with its formalization as the 'primary-secondary' distinction in the Feighner Criteria. We address the 'organic-non-organic' distinction found in the RDC, DSM-III, and DSM III-R; and finally, review the 'primary' and 'substance-induced' categories of DSM-IV, DSM-IV-TR and ICD-10. We describe how these distinctions have been operationalized in widely used diagnostic instruments. CONCLUSION: Further understanding of these classifications and the relationship of co-occurring psychiatric and substance disorders can be accomplished with the range of available measures, particularly the Psychiatric Research Interview for Substance and Mental Disorders (PRISM), which reliably utilizes and refines DSM-IV classification distinctions. PMID- 26983874 TI - Clinical interventions for severe mental illness and co-occurring substance use disorder. AB - In order to more effectively treat substance use disorders in persons with severe mental illness, integrated treatment models have been developed for these 'co occurring disorders.' The nature of clinical services provided in these programs is described in this article, with brief attention to research on these programs. Clinical services are generally guided by a stage model of change, in which the client's motivation to change (or stage of treatment: engagement, persuasion, active treatment, relapse prevention) informs the optimal selection of appropriate interventions. Psychotherapeutic services for co-occurring disorders include a range of individual (motivational interviewing, cognitive-behavioral counseling), group (stage-wise groups, social skills training, self-help), and family (single family, multifamily formats) interventions. Supplementary interventions are also commonly provided, including psychopharmacological, residential, coerced and involuntary, and vocational rehabilitation. Access to a range of different interventions for co-occurring disorders may improve the ability of clinicians to engage and tailor treatment to meet clients' unique needs. The research base supporting integrated treatment for co-occurring disorders is limited at this time owing to the small number of methodologically rigorous studies from which to draw conclusions. Nevertheless, the available evidence suggests that integrated treatment programs improve outcomes compared with nonintegrated approaches, and that more research is needed to evaluate the benefits of these programs. PMID- 26983875 TI - Evolving U.S. service model for patients with severe mental illness and co occurring substance use disorder. AB - Co-occurring severe mental illness and substance use disorder has been recognized as a common problem in the U.S. since the early 1980s (1-3). For these individuals with co-occurring disorders, research demonstrates the effectiveness of various forms of combining, blending, or integrating mental health and substance abuse treatments (4). The evolving U.S. service model for integrated dual disorders treatment emphasizes several key elements: implementation, leadership, training, engagement, assessment, counseling for all patients, ancillary treatments for those with multiple needs, secondary treatments for patients who are nonresponders, and quality assurance regarding process and outcomes. PMID- 26983876 TI - The British experience of dual diagnosis in the national health service. AB - The co-occurrence of substance misuse and other psychiatric disorder (dual diagnosis) has been increasingly recognized in the UK. Clinical studies of patients with severe mental disorders showed high rates of substance misuse with poor clinical and social outcome. These patients often fall 'between the cracks' of the separate general psychiatric and addiction services. This has necessitated the development of a national policy advocating the provision of integrated care within mainstream psychiatric services. There are emergent models of good practice that require evaluation of effectiveness and cost effectiveness. PMID- 26983877 TI - Comorbidity in young people: perspectives and challenges. AB - Trends in prevalence in substance misuse in young people in the UK are described: increased use over the last decade, the tendency to polydrug use, the narrowing of the gender gap. The complex issues relating to the description, definition and classification, and diagnosis of psychiatric comorbidity and substance misuse are outlined. The fact that there is no uniformly accepted definition of what constitutes 'dual diagnosis' or 'psychiatric comorbidity' in young people is highlighted: this variability impacts upon clinical assessment and study design. Despite these considerable drawbacks, a degree of consistency is beginning to emerge in the co-occurrence of some conditions, e.g. disruptive and suicidal behaviours. It is recognized that psychological distress and substance misuse are also associated with multiple social and physical complications. The rapid advances in treatment options are presented. At present the 'best practice' is implementation of what works for adults with addiction and young people with psychiatric disorder. This includes psychosocial interventions such as motivational enhancement techniques and cognitive behavioural treatment, as well as appropriate safe (usually), short-term use of a range of pharmacological agents. Very few comprehensive designated adolescent addiction services exist, while child and adolescent mental health services are under serious pressure. Thus the need for a longitudinal and multidisciplinary approach, with appropriate assessment instruments in young people, is required to further explore diagnostic classification which will classify the degrees and patterns of relationships between disorders. In this way it may be possible to build up a picture of the nature and extent of numerous complex, and sometimes overlapping, problems and needs in children and adolescents in a variety of settings: primary and secondary care, the criminal justice system and educational establishments. This might strengthen the development of innovative treatment services where novel interventions are tested as a priority. PMID- 26983878 TI - Dual Targeting of Bromodomain and Extraterminal Domain Proteins, and WNT or MAPK Signaling, Inhibits c-MYC Expression and Proliferation of Colorectal Cancer Cells. AB - Inhibitors of the bromodomain and extraterminal domain (BET) protein family attenuate the proliferation of several tumor cell lines. These effects are mediated, at least in part, through repression of c-MYC. In colorectal cancer, overexpression of c-MYC due to hyperactive WNT/beta-catenin/TCF signaling is a key driver of tumor progression; however, effective strategies to target this oncogene remain elusive. Here, we investigated the effect of BET inhibitors (BETi) on colorectal cancer cell proliferation and c-MYC expression. Treatment of 20 colorectal cancer cell lines with the BETi JQ1 identified a subset of highly sensitive lines. JQ1 sensitivity was higher in cell lines with microsatellite instability but was not associated with the CpG island methylator phenotype, c MYC expression or amplification status, BET protein expression, or mutation status of TP53, KRAS/BRAF, or PIK3CA/PTEN Conversely, JQ1 sensitivity correlated significantly with the magnitude of c-MYC mRNA and protein repression. JQ1 mediated c-MYC repression was not due to generalized attenuation of beta catenin/TCF-mediated transcription, as JQ1 had minimal effects on other beta catenin/TCF target genes or beta-catenin/TCF reporter activity. BETi preferentially target super-enhancer-regulated genes, and a super-enhancer in c MYC was recently identified in HCT116 cells to which BRD4 and effector transcription factors of the WNT/beta-catenin/TCF and MEK/ERK pathways are recruited. Combined targeting of c-MYC with JQ1 and inhibitors of these pathways additively repressed c-MYC and proliferation of HCT116 cells. These findings demonstrate that BETi downregulate c-MYC expression and inhibit colorectal cancer cell proliferation and identify strategies for enhancing the effects of BETi on c MYC repression by combinatorial targeting the c-MYC super-enhancer. Mol Cancer Ther; 15(6); 1217-26. (c)2016 AACR. PMID- 26983879 TI - Differential Effects of PI3K and Dual PI3K/mTOR Inhibition in Rat Prolactin Secreting Pituitary Tumors. AB - Aggressive pituitary tumors are rare but difficult to manage, as there is no effective chemotherapy to restrict their growth and cause their shrinkage. Within these tumors, growth-promoting cascades, like the PI3K/mTOR pathway, appear to be activated. We tested the efficacy of two inhibitors of this pathway, NVP-BKM120 (Buparlisib; pan-PI3K) and NVP-BEZ235 (dual PI3K/mTOR), both in vitro on immortalized pituitary tumor cells (GH3) and on primary cell cultures of human pituitary tumors and in vivo on a rat model of prolactin (PRL) tumors (SMtTW3). In vitro, NVP-BEZ235 had a potent apoptotic and cytostatic effect that was characterized by decreased cyclin D/E and Cdk4/2 protein levels and subsequent accumulation of cells in G1 In vivo, the effect was transient, with a decrease in mitotic index and increase in apoptosis; long-term treatment had no significant inhibitory effect on tumor growth. In contrast, while NVP-BKM120 had little effect in vitro, it dramatically limited tumor growth in vivo Increased Akt phosphorylation observed only in the NVP-BEZ235-treated tumors may explain the differential response to the two inhibitors. Primary cell cultures of human PRL pituitary tumors responded to NVP-BEZ235 with reduced cell viability and decreased hormone secretion, whereas NVP-BKM120 had little effect. Altogether, these results show a potential for PI3K inhibitors in the management of aggressive pituitary tumors. Mol Cancer Ther; 15(6); 1261-70. (c)2016 AACR. PMID- 26983881 TI - An Unbiased Oncology Compound Screen to Identify Novel Combination Strategies. AB - Combination drug therapy is a widely used paradigm for managing numerous human malignancies. In cancer treatment, additive and/or synergistic drug combinations can convert weakly efficacious monotherapies into regimens that produce robust antitumor activity. This can be explained in part through pathway interdependencies that are critical for cancer cell proliferation and survival. However, identification of the various interdependencies is difficult due to the complex molecular circuitry that underlies tumor development and progression. Here, we present a high-throughput platform that allows for an unbiased identification of synergistic and efficacious drug combinations. In a screen of 22,737 experiments of 583 doublet combinations in 39 diverse cancer cell lines using a 4 by 4 dosing regimen, both well-known and novel synergistic and efficacious combinations were identified. Here, we present an example of one such novel combination, a Wee1 inhibitor (AZD1775) and an mTOR inhibitor (ridaforolimus), and demonstrate that the combination potently and synergistically inhibits cancer cell growth in vitro and in vivo This approach has identified novel combinations that would be difficult to reliably predict based purely on our current understanding of cancer cell biology. Mol Cancer Ther; 15(6); 1155-62. (c)2016 AACR. PMID- 26983880 TI - TWIST1 Polymorphisms Predict Survival in Patients with Metastatic Colorectal Cancer Receiving First-Line Bevacizumab plus Oxaliplatin-Based Chemotherapy. AB - The epithelial-mesenchymal transition (EMT) is an important mechanism of resistance to angiogenesis inhibition. The ability of EMT pathway genetic variants to predict the efficacy of antiangiogenic therapy is unknown. We analyzed associations between functional SNPs in EMT-related genes and outcomes in metastatic colorectal cancer (mCRC) patients undergoing first-line bevacizumab based chemotherapy. A total of 220 mCRC patients were included in this study: 143 patients treated with first-line bevacizumab-based chemotherapy (bevacizumab cohort) and 77 patients treated with cetuximab-based chemotherapy (cetuximab cohort). SNPs in TWIST1 (rs2285682, rs2285681), ZEB1 (rs10826943, rs2839658), SNAIL (rs1543442, rs4647958), and E-cadherin (rs16260) genes were analyzed by PCR based direct sequencing. Patients carrying a TWIST1 rs2285682 G allele had a significantly longer median progression-free survival (PFS) of 18.1 months and overall survival (OS) of 44.1 months compared with those with the T/T genotype, who had a median PFS of 13.3 months (HR, 0.57; P = 0.003) and OS of 29.2 months (HR, 0.53; P = 0.001) in the bevacizumab cohort. In multivariate analysis, associations between TWIST1 rs2285682 and PFS and OS remained significant. Among women, the G allele of TWIST1 rs2285682 (PFS HR, 0.39; P = 0.007; OS HR, 0.30; P = 0.001) and TWIST1 rs2285681 (PFS HR, 0.27; P < 0.001; OS HR, 0.25; P < 0.001) was associated with improved survival. No significant associations were found in the cetuximab cohort. Our findings suggest that TWIST1 polymorphisms are associated with survival in mCRC patients treated with first-line bevacizumab based chemotherapy and may serve as clinically useful biomarkers for antiangiogenic therapy. Mol Cancer Ther; 15(6); 1405-11. (c)2016 AACR. PMID- 26983884 TI - Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of, Cardiovascular Imaging. PMID- 26983885 TI - Enzymatic Studies in Medicinal Chemistry of Neglected Diseases. PMID- 26983883 TI - Experimental ovine toxoplasmosis: influence of the gestational stage on the clinical course, lesion development and parasite distribution. AB - The relation between gestational age and foetal death risk in ovine toxoplasmosis is already known, but the mechanisms involved are not yet clear. In order to study how the stage of gestation influences these mechanisms, pregnant sheep of the same age and genetic background were orally dosed with 50 oocysts of Toxoplasma gondii (M4 isolate) at days 40 (G1), 90 (G2) and 120 (G3) of gestation. In each group, four animals were culled on the second, third and fourth week post infection (pi) in order to evaluate parasite load and distribution, and lesions in target organs. Ewes from G1 showed a longer period of hyperthermia than the other groups. Abortions occurred in all groups. While in G2 they were more frequent during the acute phase of the disease, in G3 they mainly occurred after day 20 pi. After challenge, parasite and lesions in the placentas and foetuses were detected from day 19 pi in G3 while in G2 or G1 they were only detected at day 26 pi. However, after initial detection at day 19 pi, parasite burden, measured through RT-PCR, in placenta or foetus of G3 did not increase significantly and, at in the third week pi it was lower than that measured in foetal liver or placenta from G1 to G3 respectively. These results show that the period of gestation clearly influences the parasite multiplication and development of lesions in the placenta and foetus and, as a consequence, the clinical course in ovine toxoplasmosis. PMID- 26983882 TI - The health belief model and number of peers with internet addiction as inter related factors of Internet addiction among secondary school students in Hong Kong. AB - BACKGROUND: Students are vulnerable to Internet addiction (IA). Influences of cognitions based on the Health Belief Model (HBM) and perceived number of peers with IA (PNPIA) affecting students' IA, and mediating effects involved, have not been investigated. METHODS: This cross-sectional study surveyed 9518 Hong Kong Chinese secondary school students in the school setting. RESULTS: In this self reported study, the majority (82.6%) reported that they had peers with IA. Based on the Chinese Internet Addiction Scale (cut-off =63/64), the prevalence of IA was 16.0% (males: 17.6%; females: 14.0%). Among the non-IA cases, 7.6% (males: 8.7%; females: 6.3%) perceived a chance of developing IA in the next 12 months. Concurring with the HBM, adjusted logistic analysis showed that the Perceived Social Benefits of Internet Use Scale (males: Adjusted odds ratio (ORa) = 1.19; females: ORa = 1.23), Perceived Barriers for Reducing Internet Use Scale (males: ORa = 1.26; females: ORa = 1.36), and Perceived Self-efficacy for Reducing Internet Use Scale (males: ORa = 0.66; females: ORa = 0.56) were significantly associated with IA. Similarly, PNPIA was significantly associated with IA ('quite a number': males: ORa = 2.85; females: ORa = 4.35; 'a large number': males: ORa = 3.90; females: ORa = 9.09). Controlling for these three constructs, PNPIA remained significant but the strength of association diminished ('quite a number': males: multivariate odds ratio (ORm) = 2.07; females: ORm = 2.44; 'a large number': males: ORm = 2.39; females: ORm = 3.56). Hence, the association between PNPIA and IA was partially mediated (explained) by the three HBM constructs. Interventions preventing IA should change these constructs. CONCLUSIONS: In sum, prevalence of IA was relatively high and was associated with some HBM constructs and PNPIA, and PNPIA also partially mediated associations between HBM constructs and IA. Huge challenges are expected, as social relationships and an imbalance of cost-benefit for reducing Internet use are involved. Perceived susceptibility and perceived severity of IA were relatively low and the direction of their associations with IA did not concur with the HBM. Group cognitive-behavioral interventions involving peers with IA or peers recovered from IA are potentially useful to modify the HBM constructs and should be tested for efficacy. PMID- 26983886 TI - Enzymatic Targets in Trypanosoma brucei. AB - One of the most neglected disease is the Sleeping sickness or Human African Trypanosomiasis (HAT), which is mostly restricted to poor regions of Africa. The disease is caused by parasitic infection with Trypanosoma brucei (T. brucei), and is acquired through the bite of the tsetse fly. In the first stage of the disease, the parasite is in the blood, but in stage 2, the infective form reaches the brain, causing great weakness and death. The few existing drugs against this infection, are highly toxic, and can cause the emergence of resistant forms of the parasite. Also, these drugs are not readily available. New drugs are needed. Many researchers are investigating new enzyme targets for the parasite, searching for more efficient and selective inhibitors that are capable to cause the parasite death with less toxicity to the host. Trypanothione reductase, farnesyl diphosphate synthase, 6-phospho-gluconate dehydrogenase, and UDP 4'-galactose epimerase are some of the enzymes involved in the studies reported on this review. In addition, we have applied ligandbased- virtual screening, using Random Forest associated with structure-based-virtual screening (docking), to a small dataset of 225 alkaloids from the Menispermaceae family (in-house data bank). The aim of this study is to select structures with potential inhibitory activity against trypanothione reductase from Trypanosoma brucei. The computer-aided drug design study selected certain alkaloids that might be worth further investigation. PMID- 26983888 TI - Metabolic Enzymes of Helminth Parasites: Potential as Drug Targets. AB - Metabolic pathways that extract energy from carbon compounds are essential for an organism's survival. Therefore, inhibition of enzymes in these pathways represents a potential therapeutic strategy to combat parasitic infections. However, the high degree of similarity between host and parasite enzymes makes this strategy potentially difficult. Nevertheless, several existing drugs to treat infections by parasitic helminths (worms) target metabolic enzymes. These include the trivalent antimonials that target phosphofructokinase and Clorsulon that targets phosphoglycerate mutase and phosphoglycerate kinase. Glycolytic enzymes from a variety of helminths have been characterised biochemically, and some inhibitors identified. To date none of these inhibitors have been developed into therapies. Many of these enzymes are externalised from the parasite and so are also of interest in the development of potential vaccines. Less work has been done on tricarboxylic acid cycle enzymes and oxidative phosphorylation complexes. Again, while some inhibitors have been identified none have been developed into drug-like molecules. Barriers to the development of novel drugs targeting metabolic enzymes include the lack of experimentally determined structures of helminth enzymes, lack of direct proof that the enzymes are vital in the parasites and lack of cell culture systems for many helminth species. Nevertheless, the success of Clorsulon (which discriminates between highly similar host and parasite enzymes) should inspire us to consider making serious efforts to discover novel anthelminthics, which target metabolic enzymes. PMID- 26983887 TI - Targeting Plasmodium Metabolism to Improve Antimalarial Drug Design. AB - Malaria is one of the main infectious diseases in tropical developing countries and represents high morbidity and mortality rates nowadays. The principal etiological agent P. falciparum is transmitted through the bite of the female Anopheles mosquito. The issue has escalated due to the emergence of resistant strains to most of the antimalarials used for the treatment including Chloroquine, Sulfadoxine-Pyrimethamine, and recently Artemisinin derivatives, which has led to diminished effectiveness and by consequence increased the severity of epidemic outbreaks. Due to the lack of effective compounds to treat these drug-resistant strains, the discovery or development of novel anti-malaria drugs is important. In this context, one strategy has been to find inhibitors of enzymes, which play an important role for parasite survival. Today, promising results have been obtained in this regard, involving the entire P. falciparum metabolism. These inhibitors could serve as leads in the search of a new chemotherapy against malaria. This review focuses on the achievements in recent years with regard to inhibition of enzymes used as targets for drug design against malaria. PMID- 26983890 TI - Shengmai injection attenuates the cerebral ischemia/reperfusion induced autophagy via modulation of the AMPK, mTOR and JNK pathways. AB - Context Shengmai injection (SMI) is a patented Chinese medicine originated from the ancient Chinese herbal compound Shengmai san, which is used extensively for the treatment of cardiovascular and cerebrovascular disease in the clinic. Objective To determine the neuroprotective effect of SMI, we investigated the effect of SMI on cerebral ischemia/reperfusion (I/R) injury in mice as well as the mechanisms underlying this effect. Materials and methods Right middle cerebral artery was occluded by inserting a thread through internal carotid artery for 1 h, and then reperfused for 24 h in mice. The neuroprotective effects were determined using transmission electron microscopic examination, the evaluation of infarct volume, neurological deficits and water brain content. Related mechanisms were evaluated by immunofluorescence staining and western blotting. SMI was injected intraperitoneally after 1 h of ischemia at doses of 1.42, 2.84 and 5.68 g/kg. The control group received saline as the SMI vehicle. Results Results showed that SMI (1.42, 2.84 and 5.68 g/kg) could significantly reduce the infarct volume, SMI (5.68 g/kg) could also significantly improve the neurological deficits, decreased brain water content, as well as the neuronal morphological changes. SMI (5.68g/kg) could significantly inhibit the expression of autophagy-related proteins: Beclin1 and LC3. It also reduced the increase in LC3-positive cells. SMI (5.68 g/kg) remarkably inhibited the phosphorylation of adenosine monophosphate activated protein kinase (AMPK), and down-regulated the phosphorylation of mammalian target of rapamycin (mTOR) and Jun N-terminal kinase (JNK) after 24 h of reperfusion. Discussion and conclusion The results indicate that SMI provides remarkable protection against cerebral ischemia/reperfusion injury, which may be partly due to the inhibition of autophagy and related signalling pathways. PMID- 26983891 TI - MicroRNA-9 suppresses cell migration and invasion through downregulation of TM4SF1 in colorectal cancer. AB - Transmembrane-4-L6 family 1 (TM4SF1) is upregulated in colorectal carcinoma (CRC). However, the mechanism leading to inhibition of the TM4SF1 is not known. In the present study, we investigated the regulation of TM4SF1 and function of microRNAs (miRNAs) in CRC invasion and metastasis. We analyzed 60 colon cancers and paired normal specimens for TM4SF1 and miRNA-9 (miR-9) expression using quantitative real-time PCR. A bioinformatics analysis identified a putative miR-9 binding site within the 3'-UTR of TM4SF1. We also found that TM4SF1 was upregulated in CRC tissues and CRC cell lines. The expression of TM4SF1 was positively correlated with clinical advanced stage and lymph node metastasis. Moreover, a luciferase assay revealed that miR-9 directly targeted 3'-UTR-TM4SF1. Overexpression of miR-9 inhibited expression of TM4SF1 mRNA and protein, wound healing, transwell migration and invasion of SW480 cells, whereas, overexpression of anti-miR-9 and siRNA-TM4SF1 inversely regulated the TM4SF1 mRNA and protein level in HCT116 cells. Furthermore, miR-9 suppressed not only TM4SF1 expression but also MMP-2, MMP-9 and VEGF expression. In clinical specimens, miR-9 was generally down-regulated in CRC and inversely correlated with TM4SF1 expression. These results suggest that miR-9 functions as a tumor-suppressor in CRC, and that its suppressive effects mediate invasion and metastasis by inhibition of TM4SF1 expression. Our results also indicate that miR-9 might be a novel target for the treatment of CRC invasion and metastasis. PMID- 26983892 TI - Toward Improving Transurethral Prostate Surgery: Development and Initial Experiments with a Prototype Concentric Tube Robotic Platform. AB - INTRODUCTION: Despite the potential clinical advantages of holmium laser enucleation of the prostate (HoLEP), there has been reluctance of the urologic community to adopt the procedure, as a result of a perceived steep learning curve. Thus, we sought to design and develop a transurethral endoscopic robotic platform for HoLEP. MATERIALS AND METHODS: We developed a novel transurethral, concentric tube robotic platform for HoLEP. We conducted magnetic tracking experiments to compare movements of the end effectors of the robot with those of a rigid endoscope. Additionally, we tested the robot on an HoLEP simulator and with a human cadaveric prostate to assess its ability to maneuver within a small working space. RESULTS: In the prostate scanning experiment, the area reached by the robot represents a 65% improvement vs the area accessible by a rigid endoscope without tissue deformation. Additionally, the robot performed well within the confines of the prostatic urethra and was able to successfully complete prostate lobe enucleation, on both the HoLEP simulator and with a human cadaveric prostate. CONCLUSIONS: We have developed a concentric tube robotic platform that is passed through a standard endoscope that is capable of producing complex movements of the end effectors. We have shown that these movements of the concentric tube manipulators are capable of performing tasks that may eventually translate into improved ease of performing HoLEP. PMID- 26983893 TI - Pain and sex hormones: a review of current understanding. AB - Multiple epidemiologic studies have demonstrated an increased prevalence for women in several chronic pain disorders. Clinical and experimental investigations have consistently demonstrated sex-specific differences in pain sensitivity and pain threshold. Even though the underlying mechanisms responsible for these differences have not yet been elucidated, the logical possibility of gonadal hormone influence on nociceptive processing has garnered recent attention. In this review, we evaluated the complex literature regarding gonadal hormones and their influence on pain perception. We reviewed the numerous functions of gonadal hormones, discussed the influence of these hormones on several common chronic pain syndromes (migraine, tension and cluster headaches, fibromyalgia, temporomandibular syndrome, rheumatoid arthritis and back pain, among others), and have attempted to draw conclusions from the available data. PMID- 26983894 TI - Low-level laser therapy attenuates the acute inflammatory response induced by muscle traumatic injury. AB - The purpose of this work was to investigate the effect of early and long-term low level laser therapy (LLLT) on oxidative stress and inflammatory biomarkers after acute-traumatic muscle injury in Wistar rats. Animals were randomly divided into the following four groups: control group (CG), muscle injury group (IG), CG + LLLT, and IG + LLLT: laser treatment with doses of 3 and 5 J/cm(2). Muscle traumatic injury was induced by a single-impact blunt trauma in the rat gastrocnemius. Irradiation for 3 or 5 J/cm(2) was initiated 2, 12, and 24 h after muscle trauma induction, and the treatment was continued for five consecutive days. All the oxidant markers investigated. namely thiobarbituric acid-reactive substance, carbonyl, superoxide dismutase, glutathione peroxidase, and catalase, were increased as soon as 2 h after muscle injury and remained increased up to 24 h. These alterations were prevented by LLLT at a 3 J/cm(2) dose given 2 h after the trauma. Similarly, LLLT prevented the trauma-induced proinflammatory state characterized by IL-6 and IL-10. In parallel, trauma-induced reduction in BDNF and VEGF, vascular remodeling and fiber-proliferating markers, was prevented by laser irradiation. In order to test whether the preventive effect of LLLT was also reflected in muscle functionality, we tested the locomotor activity, by measuring distance traveled and the number of rearings in the open field test. LLLT was effective in recovering the normal locomotion, indicating that the irradiation induced biostimulatory effects that accelerated or resolved the acute inflammatory response as well as the oxidant state elicited by the muscle trauma. PMID- 26983895 TI - The CagA toxin of Helicobacter pylori: abundant production but relatively low amount translocated. AB - CagA is one of the most studied pathogenicity factors of the bacterial pathogen Helicobacter pylori. It is injected into host cells via the H. pylori cag-Type IV secretion system. Due to its association with gastric cancer, CagA is classified as oncogenic protein. At the same time CagA represents the 4(th) most abundant protein produced by H. pylori, suggesting that high amounts of toxin are required to cause the physiological changes or damage observed in cells. We were able to quantify the injection of CagA into gastric AGS epithelial cells in vitro by the adaptation of a novel protease-based approach to remove the tightly adherent extracellular bacteria. After one hour of infection only 1.5% of the total CagA available was injected by the adherent bacteria, whereas after 3 hours 7.5% was found within the host cell. Thus, our data show that only a surprisingly small amount of the CagA available in the infection is finally injected under in vitro infection conditions. PMID- 26983896 TI - Transcriptional profiling of breast cancer cells in response to mevinolin: Evidence of cell cycle arrest, DNA degradation and apoptosis. AB - The merging of high-throughput gene expression techniques, such as microarray, in the screening of natural products as anticancer agents, is considered the optimal solution for gaining a better understanding of the intervention mechanism. Red yeast rice (RYR), a Chinese dietary product, contains a mixture of hypocholesterolemia agents such as statins. Typically, statins have this effect via the inhibition of HMG-CoA reductase, the key enzyme in the biosynthesis of cholesterol. Recently, statins have been shown to exhibit various beneficial antineoplastic properties through the disruption of tumor angiogenesis and metastatic processes. Mevinolin (MVN) is a member of statins and is abundantly present in RYR. Early experimental trials suggested that the mixed apoptotic/necrotic cell death pathway is activated in response to MVN exposure. In the current study, the cytotoxic profile of MVN was evaluated against MCF-7, a breast cancer-derived cell line. The obtained results indicated that MVN-induced cytotoxicity is multi-factorial involving several regulatory pathways in the cytotoxic effects of MVN on breast cancer cell lines. In addition, MVN-induced transcript abundance profiles inferred from microarrays showed significant changes in some key cell processes. The changes were predicted to induce cell cycle arrest and reactive oxygen species generation but inhibit DNA repair and cell proliferation. This MVN-mediated multi-factorial stress triggered specific programmed cell death (apoptosis) and DNA degradation responses in breast cancer cells. Taken together, the observed MVN-induced effects underscore the potential of this ubiquitous natural compound as a selective anticancer activity, with broad safety margins and low cost compared to benchmarked traditional synthetic chemotherapeutic agents. Additionally, the data support further pre-clinical and clinical evaluations of MVN as a novel strategy to combat breast cancer and overcome drug resistance. PMID- 26983897 TI - Effectiveness of Cognitive Behavioral Therapy for Veterans with Depression and Suicidal Ideation. AB - The current study examined suicidal ideation (SI) and depression outcomes among Veterans receiving Cognitive Behavioral Therapy for depression (CBT-D) throughout the Department of Veterans Affairs health care system. Patient outcomes included Beck Depression Inventory-II total score and SI item. Of 902 patients, 427 (47%) had no SI, 405 (45%) had SI but no suicidal intent, 26 (3%) indicated suicidal desire, 8 (1%) indicated suicide intent if they had the chance, and 36 (4%) did not answer this question at session one. The odds of SI decreased by 64% from 1.03 at session one to 0.37 at final assessment (OR = 0.36; 95% CI: 0.31, 0.43). Findings reveal that CBT-D was associated with significant decreases in SI and depression among Veterans. PMID- 26983898 TI - Biodegradable polymers for targeted delivery of anti-cancer drugs. AB - INTRODUCTION: Biodegradable polymers have been used for more than three decades in cancer treatment and have received increased interest in recent years. A range of biodegradable polymeric drug delivery systems designed for localized and systemic administration of therapeutic agents as well as tumor-targeting macromolecules has entered into the clinical phase of development, indicating the significance of biodegradable polymers in cancer therapy. AREAS COVERED: This review elaborates upon applications of biodegradable polymers in the delivery and targeting of anti-cancer agents. Design of various drug delivery systems based on biodegradable polymers has been described. Moreover, the indication of polymers in the targeted delivery of chemotherapeutic drugs via passive, active targeting, and localized drug delivery are also covered. EXPERT OPINION: Biodegradable polymer-based drug delivery systems have the potential to deliver the payload to the target and can enhance drug availability at desired sites. Systemic toxicity and serious side effects observed with conventional cancer therapeutics can be significantly reduced with targeted polymeric systems. Still, there are many challenges that need to be met with respect to the degradation kinetics of the system, diffusion of drug payload within solid tumors, targeting tumoral tissue and tumor heterogeneity. PMID- 26983899 TI - Cisplatin-induced CCL5 secretion from CAFs promotes cisplatin-resistance in ovarian cancer via regulation of the STAT3 and PI3K/Akt signaling pathways. AB - Currently, acquired resistance to cisplatin (DDP) is a substantial obstacle to reducing the morbidity and mortality due to ovarian malignant tumors. Nevertheless, cisplatin plays a vital role in killing the tumor cells while it may also be a 'primer' involved in chemotherapy resistance. We found that the cisplatin-induced chemokine (C-C motif) ligand 5 (CCL5) secretion derived from cancer-associated fibroblasts (CAFs) promoted ovarian cancer cell resistance to cisplatin. Via a cytokine chip assay, we identified a spectrum of secreted proteins that were derived from the CAFs through cisplatin-induced treatment. Among these, CCL5 significantly attenuated the cytotoxic effect of cisplatin chemotherapy in vitro and in vivo. Additionally, CCL5 expression was also detected in 62 serous ovarian cancer patient tissue specimens using IHC, and the results demonstrated that chemotherapy resistant patients displayed higher expression of CCL5 than the chemo-sensitive patients (P<0.05). Mechanistically, we found that CCL5 notably increased STAT3 and Akt phosphorylation levels in ovarian cancer cells. These results indicated that cisplatin- induced CCL5 secretion derived from the CAFs may promote cisplatin resistance, which was mediated by regulation of the STAT3 and PI3K/Akt signal pathways. PMID- 26983900 TI - Laboratory medicine and mobile health technologies at crossroads: Perspectives for the management of chronic diseases. AB - Management of chronic diseases represents a leading health and economic issue worldwide. Biomarkers are critical for the diagnosis and management of both communicable and non-communicable chronic diseases, and mobile health (mHealth) technologies are about to change the "game" with regard to the management of patients with such chronic diseases. The development of efficient, accurate and interactive solutions that integrate biomarkers and mHealth opens new perspectives for caregivers for the management of chronic illness. PMID- 26983901 TI - Translating immune targets into treatments for kidney disease. PMID- 26983902 TI - Concerted action of KCNJ15/Kir4.2 and intracellular polyamines in sensing physiological electric fields for galvanotaxis. PMID- 26983903 TI - Matrix metalloproteinases as candidate biomarkers in adults with congenital heart disease. AB - Context Matrix metalloproteinases (MMPs) are associated with diastolic dysfunction and heart failure in acquired heart disease. Objective To investigate the role of MMPs as novel biomarkers in clinically stable adults with congenital heart disease. Methods We measured serum MMP-2, -3, -9 and tissue inhibitor of matrix metalloproteinase-1 in 425 patients and analysed the association with cardiac function and exercise capacity. Results MMP-2 was significantly associated with exercise capacity, ventilatory efficiency and left ventricular deceleration time, independently of age, sex, body surface area and NT-proBNP. Conclusion MMP-2 may provide new information in the clinical evaluation of adults with congenital heart disease. PMID- 26983905 TI - Applications using high-Tc superconducting terahertz emitters. AB - Using recently-developed THz emitters constructed from single crystals of the high-Tc superconductor Bi2Sr2CaCu2O8+delta, we performed three prototype tests of the devices to demonstrate their unique characteristic properties for various practical applications. The first is a compact and simple transmission type of THz imaging system using a Stirling cryocooler. The second is a high-resolution Michelson interferometer used as a phase-sensitive reflection-type imaging system. The third is a system with precise temperature control to measure the liquid absorption coefficient. The detailed characteristics of these systems are discussed. PMID- 26983904 TI - A Randomized Clinical Trial Comparing Individual Cognitive Behavioral Therapy and Child-Centered Therapy for Child Anxiety Disorders. AB - This study compared individual cognitive behavioral therapy (CBT) and a supportive child-centered therapy (CCT) for child anxiety disorders on rates of treatment response and recovery at posttreatment and 1-year follow-up, as well as on real-world measures of emotional functioning. Youth (N = 133; ages 9-14) with anxiety disorders (generalized, separation, and/or social anxiety) were randomized using a 2:1 ratio to CBT (n = 90) or CCT (n = 43), which served as an active comparison. Treatment response and recovery at posttreatment and 1-year follow-up were assessed by Independent Evaluators, and youth completed ecological momentary assessment of daily emotions throughout treatment. The majority of youth in both CBT and CCT were classified as treatment responders (71.1% for CBT, 55.8% for CCT), but youth treated with CBT were significantly more likely to fully recover, no longer meeting diagnostic criteria for any of the targeted anxiety disorders and no longer showing residual symptoms (66.7% for CBT vs. 46.5% for CCT). Youth treated with CBT also reported significantly lower negative emotions associated with recent negative events experienced in daily life during the latter stages of treatment relative to youth treated with CCT. Furthermore, a significantly higher percentage of youth treated with CBT compared to CCT were in recovery at 1-year follow-up (82.2% for CBT vs. 65.1% for CCT). These findings indicate potential benefits of CBT above and beyond supportive therapy on the breadth, generalizability, and durability of treatment-related gains. PMID- 26983906 TI - Paricalcitol may improve oxidative DNA damage on experimental amikacin-induced nephrotoxicity model. AB - This study aimed to investigate the possible protective effect of paricalcitol on experimental amikacin-induced nephrotoxicity model in rats. Wistar albino rats (n = 32) were allocated into four equal groups of eight each, the control (Group C), paricalcitol (Group P), amikacin-induced nephrotoxicity (Group A), and paricalcitol-treated amikacin-induced nephrotoxicity (Group A + P) groups. Paricalcitol was given intra-peritoneally at a dose of 0.4 MUg/kg/d for 5 consecutive days prior to induction of amikacin-induced nephrotoxicity. Intra peritoneal amikacin (1.2 g/kg) was used to induce nephrotoxicity at day 4. Renal function parameters, oxidative stress biomarkers, oxidative DNA damage (8-hydroxy 2'-deoxyguanosine/deoxyguanosine ratio), kidney histology, and vascular endothelial growth factor (VEGF) immunoexpression were determined. Group A + P had lower mean fractional sodium excretion (p < 0.001) as well as higher creatinine clearance (p = 0.026) than the amikacin group (Group A). Renal tissue malondialdehyde levels (p = 0.035) and serum 8-hydroxy-2' deoxyguanosine/deoxyguanosine ratio (8-OHdG/dG ratio) (p < 0.001) were significantly lower; superoxide dismutase (p = 0.024) and glutathione peroxidase (p = 0.007) activities of renal tissue were significantly higher in group A + P than in group A. The mean scores of tubular necrosis (p = 0.024), proteinaceous casts (p = 0.038), medullary congestion (p = 0.035), and VEGF immunoexpression (p = 0.018) were also lower in group A + P when compared with group A. This study demonstrates the protective effect of paricalcitol in the prevention of amikacin induced nephrotoxicity in an experimental model. Furthermore, it is the first study to demonstrate that paricalcitol improves oxidative DNA damage in an experimental acute kidney injury model. PMID- 26983908 TI - Design of Advanced Photocatalysis System by Adatom Decoration in 2D Nanosheets of Group-IV and III-V Binary Compounds. AB - Searching for novel photocatalysts is one of the most important topic in photocatalytic fields. In the present work, we propose a feasible approach to improve the photocatalytic activities of 2D bilayers through surface decoration, i.e. hydrogenation, halogenation, and hydroxylation. Our investigations demonstrate that after surface modification, the optical adsorption expands into the visible region, while a built-in electric field is induced due to the interlayer coupling, which can promote the charge separation for photogenerated electron-hole pairs. Our results show that the indirect-direct band gap transition of SiC, SnC, BN and GaN can be realised through adatom decoration. Furthermore, the surface-modified 2D bilayers have suitable VBM and CBM alignments with the oxidation and reduction potentials for water splitting, suggesting powerful potentials in energy and environmental applications. PMID- 26983907 TI - In Vitro Characterization of Derrone as an Aurora Kinase Inhibitor. AB - Among mitotic kinases, Aurora kinases are the most widely studied, since their expression is restricted to mitosis. They play a key role in chromosome segregation and cell polyploidy. Aurora kinases are important therapeutic targets, and several research groups have directed their efforts toward the identification of kinase inhibitors. The aim of this study is to screen and characterize Aurora kinase inhibitors from natural substances extracted from plants that are used in the Vietnamese pharmacopoeia. We have characterized in vitro Derrone, extracted from Erythrina orientalis L. MURR, as a novel Aurora kinase inhibitor. This compound exhibited an ability to inhibit the phosphorylation of histone H3 at ser10 both in kinase assay and at the cellular level. The compound was more effective against Aurora kinase B, with a lower IC50 value as compared to Aurora A. Moreover, it impaired the mitotic spindle checkpoint and led to endoreduplication in cancer cells, a phenomenon caused by an Aurora B inhibitor. Interestingly, using the xCelligence system and real-time cell analysis (RTCA) software, we set up a comparison of cell proliferation profiles between cancer cells treated with Derrone and VX680-a well-known Aurora kinase inhibitor-and we found that these profiles exhibited considerable similarity in cell morphology, growth, and death. Additionally, Derrone significantly inhibited the formation and growth of MCF7 tumor spheroids. PMID- 26983909 TI - Contrasting responses of water use efficiency to drought across global terrestrial ecosystems. AB - Drought is an intermittent disturbance of the water cycle that profoundly affects the terrestrial carbon cycle. However, the response of the coupled water and carbon cycles to drought and the underlying mechanisms remain unclear. Here we provide the first global synthesis of the drought effect on ecosystem water use efficiency (WUE = gross primary production (GPP)/evapotranspiration (ET)). Using two observational WUE datasets (i.e., eddy-covariance measurements at 95 sites (526 site-years) and global gridded diagnostic modelling based on existing observation and a data-adaptive machine learning approach), we find a contrasting response of WUE to drought between arid (WUE increases with drought) and semi arid/sub-humid ecosystems (WUE decreases with drought), which is attributed to different sensitivities of ecosystem processes to changes in hydro-climatic conditions. WUE variability in arid ecosystems is primarily controlled by physical processes (i.e., evaporation), whereas WUE variability in semi-arid/sub humid regions is mostly regulated by biological processes (i.e., assimilation). We also find that shifts in hydro-climatic conditions over years would intensify the drought effect on WUE. Our findings suggest that future drought events, when coupled with an increase in climate variability, will bring further threats to semi-arid/sub-humid ecosystems and potentially result in biome reorganization, starting with low-productivity and high water-sensitivity grassland. PMID- 26983910 TI - Observation of Weyl nodes and Fermi arcs in tantalum phosphide. AB - A Weyl semimetal possesses spin-polarized band-crossings, called Weyl nodes, connected by topological surface arcs. The low-energy excitations near the crossing points behave the same as massless Weyl fermions, leading to exotic properties like chiral anomaly. To have the transport properties dominated by Weyl fermions, Weyl nodes need to locate nearly at the chemical potential and enclosed by pairs of individual Fermi surfaces with non-zero Fermi Chern numbers. Combining angle-resolved photoemission spectroscopy and first-principles calculation, here we show that TaP is a Weyl semimetal with only a single type of Weyl fermions, topologically distinguished from TaAs where two types of Weyl fermions contribute to the low-energy physical properties. The simple Weyl fermions in TaP are not only of fundamental interests but also of great potential for future applications. Fermi arcs on the Ta-terminated surface are observed, which appear in a different pattern from that on the As-termination in TaAs and NbAs. PMID- 26983911 TI - Smaller-loss planar SPP transmission line than conventional microstrip in microwave frequencies. AB - Transmission line is a basic component in all passive devices, integrated circuits, and systems. Microstrip is the most popular transmission line in the microwave and millimeter-wave frequencies, and has been widely used in current electronic devices, circuits, and systems. One of the important issues to be solved in such applications is the relatively large transmission loss of microstrip. Here, we propose a method to reduce the loss of microwave transmission line based on the designable wavenumber of spoof surface plasmon polaritons (SPPs). Using this characteristic, we analyze and experimentally demonstrate the low-loss feature of the SPP transmission line through the perturbation method and S-parameter measurements, respectively. Both simulation and experimental results show that the SPP transmission line has much smaller transmission loss than traditional microstrip with the same size in the microwave frequencies. Hence, the spoof SPP transmission line may make a big step forward in the low-loss circuits and systems. PMID- 26983912 TI - Value of FGFR2 expression for advanced gastric cancer patients receiving pazopanib plus CapeOX (capecitabine and oxaliplatin). AB - PURPOSE: The aim of this study was to use immunohistochemistry (IHC) to determine the effect of FGFR2 and VEGFR2 expression on treatment outcomes for patients with metastatic or recurrent advanced gastric cancer (AGC) receiving a combination of pazopanib with CapeOx (capecitabine and oxaliplatin). METHODS: We conducted a single-arm, open-label phase II study to determine the efficacy and toxicity of the combination of pazopanib with CapeOx in 66 patients with metastatic or recurrent AGC (ClinicalTrials.gov NCT01130805). IHC analysis of FGFR2 and VEGFR2 was possible in 54 patients (81.8 %). RESULTS: Among 54 patients, the median age was 51.5 years (range 23-72 years). Male patients were 59.3 %. Seven patients (13.5 %) had tumor tissues that expressed FGFR2 by IHC. No patients had tumors that expressed VEGFR2. Among seven patients with tumors with FGFR2 expression, six achieved partial response (PR) with a 85.7 % response rate and one patient with stable disease. Among 47 patients with tumors without FGFR2 expression, one had complete response and 27 had PR (59.5 %). A significant difference in PFS was seen between patients who were positive and negative for FGFR2 using IHC (8.5 vs. 5.6 months, P = 0.050). By prognostic analysis for PFS, only FGFR2 status by IHC (positive vs. negative) had significant prognostic value for predicting PFS. CONCLUSIONS: FGFR2 expression by IHC might be a useful biomarker for predicting treatment outcomes of patients with metastatic or recurrent AGC treated with a combination of pazopanib and CapeOx. PMID- 26983913 TI - Landfill site selection for municipal solid wastes in mountainous areas with landslide susceptibility. AB - Several cities across the world are located in mountainous and landslide prone areas. Any landfill siting without considering landslide susceptibility in such regions may impose additional environmental adversity. This study was aimed to propose a practical method for selecting waste disposal site that accounts for landslide exposure. The proposed method was applied to a city which is highly proneness to landslide due to its geology, morphology, and climatic conditions. First, information on the previously occurred landslides of the region was collected. Based on this information, proper landslide causative factors were selected and their thematic maps were prepared. Factors' classes were then standardized in 0-1 domain, and thematic layers were weighted by using analytical hierarchy process (AHP). The landslide susceptibility map was prepared afterwards. Unsuitable areas for landfill location were masked in GIS environment by Boolean method, retaining sufficient areas for further evaluation. Nine remaining alternatives were selected through comprehensive field visits and were ranked by using AHP. Consequently, 17 factors in three environmental, economical, and social perspectives were employed. Sensitivity analyses were performed to assess the stability of the alternatives ranking with respect to variations in criterion weights. Based on the obtained landslide susceptible map, nearly 36 % of the entire region is proneness to landslide. The prepared Boolean map indicates that potential areas for landfill construction cover 11 % of the whole region. The results further indicated that if landslide susceptible areas are not considered in landfill site selection, the potential landfill sites would become more than twice. It can be concluded that if any of these landslide prone sites are selected for landfilling, further environmental disaster would be terminated in the future. It can be further concluded that the proposed method could reasonably well be adjusted to consider landslide exposure when siting a solid waste landfill. PMID- 26983914 TI - Dynamic impact of urbanization, economic growth, energy consumption, and trade openness on CO 2 emissions in Nigeria. AB - The objective of this paper is to examine the dynamic impact of urbanization, economic growth, energy consumption, and trade openness on CO 2 emissions in Nigeria based on autoregressive distributed lags (ARDL) approach for the period of 1971-2011. The result shows that variables were cointegrated as null hypothesis was rejected at 1 % level of significance. The coefficients of long run result reveal that urbanization does not have any significant impact on CO 2 emissions in Nigeria, economic growth, and energy consumption has a positive and significant impact on CO 2 emissions. However, trade openness has negative and significant impact on CO 2 emissions. Consumption of energy is among the main determinant of CO 2 emissions which is directly linked to the level of income. Despite the high level of urbanization in the country, consumption of energy still remains low due to lower income of the majority populace and this might be among the reasons why urbanization does not influence emissions of CO 2 in the country. Initiating more open economy policies will be welcoming in the Nigerian economy as the openness leads to the reduction of pollutants from the environment particularly CO 2 emissions which is the major gases that deteriorate physical environment. PMID- 26983916 TI - Using a hybrid model to predict solute transfer from initially saturated soil into surface runoff with controlled drainage water. AB - The mixing layer theory is not suitable for predicting solute transfer from initially saturated soil to surface runoff water under controlled drainage conditions. By coupling the mixing layer theory model with the numerical model Hydrus-1D, a hybrid solute transfer model has been proposed to predict soil solute transfer from an initially saturated soil into surface water, under controlled drainage water conditions. The model can also consider the increasing ponding water conditions on soil surface before surface runoff. The data of solute concentration in surface runoff and drainage water from a sand experiment is used as the reference experiment. The parameters for the water flow and solute transfer model and mixing layer depth under controlled drainage water condition are identified. Based on these identified parameters, the model is applied to another initially saturated sand experiment with constant and time-increasing mixing layer depth after surface runoff, under the controlled drainage water condition with lower drainage height at the bottom. The simulation results agree well with the observed data. Study results suggest that the hybrid model can accurately simulate the solute transfer from initially saturated soil into surface runoff under controlled drainage water condition. And it has been found that the prediction with increasing mixing layer depth is better than that with the constant one in the experiment with lower drainage condition. Since lower drainage condition and deeper ponded water depth result in later runoff start time, more solute sources in the mixing layer are needed for the surface water, and larger change rate results in the increasing mixing layer depth. PMID- 26983917 TI - Sulfadimethoxine transport in soil columns in relation to sorbable and non sorbable tracers. AB - In this study, miscible displacement experiment and batch sorption experiments were performed with sulfadimethoxine, dye tracer, Brilliant Blue FCF (BB) and a conservative tracer (bromide) to depict, analyse and interpret transport paths of sulfadimethoxine in undisturbed and disturbed soil columns. Batch sorption experiment revealed that sorption potential increased in the order: Brilliant Blue FCF > sulfadimethoxine > bromide. The horizontal spatial patterns of sulfadimethoxine and the tracers were analysed in each depth, and selective samples were taken in horizontal cross-section. Non-adsorbable and conservative tracer, bromide spread more widely into longitudinal and horizontal direction than sulfadimethoxine and Brilliant Blue FCF, since adsorption reduced transversal dispersion of the sulfadimethoxine and dye. In non-stained area, residual concentrations of sulfadimethoxine were relatively lower than in stained areas. Therefore, Brilliant Blue FCF distribution can be used to approximate sulfadimethoxine movement in soil. However, presence of preferential flow networks found in undisturbed soil cores can enhance mobility of sulfadimethoxine and the tracers, due to faster flow velocities and non-equilibrium adsorption. Our findings showed that other dye tracers may also be applicable to identify transport pathways of various organic contaminants, of which physico-chemical properties are similar to those of the dye tracers. Preferential flow should be considered for drinking water managements and transport modelling, since this allows faster pollutants transport from their sources, and create critical consequences for groundwater quality and solute transport modelling. PMID- 26983915 TI - Degradation of the insecticide propoxur by electrochemical advanced oxidation processes using a boron-doped diamond/air-diffusion cell. AB - A solution with 0.38 mM of the pesticide propoxur (PX) at pH 3.0 has been comparatively treated by electrochemical oxidation with electrogenerated H2O2 (EO H2O2), electro-Fenton (EF), and photoelectro-Fenton (PEF). The trials were carried out with a 100-mL boron-doped diamond (BDD)/air-diffusion cell. The EO H2O2 process had the lowest oxidation ability due to the slow reaction of intermediates with *OH produced from water discharge at the BDD anode. The EF treatment yielded quicker mineralization due to the additional *OH formed between added Fe2+ and electrogenerated H2O2. The PEF process was the most powerful since it led to total mineralization by the combined oxidative action of hydroxyl radicals and UVA irradiation. The PX decay agreed with a pseudo-first-order kinetics in EO-H2O2, whereas in EF and PEF, it obeyed a much faster pseudo-first order kinetics followed by a much slower one, which are related to the oxidation of its Fe(II) and Fe(III) complexes, respectively. EO-H2O2 showed similar oxidation ability within the pH range 3.0-9.0. The effect of current density and Fe2+ and substrate contents on the performance of the EF process was examined. Two primary aromatic products were identified by LC-MS during PX degradation. PMID- 26983918 TI - On the potential role of DNMT1 in acute myeloid leukemia and myelodysplastic syndromes: not another mutated epigenetic driver. AB - DNA methylation is the most common epigenetic modification in the mammalian genome. DNA methylation is governed by the DNA methyltransferases mainly DNMT1, DNMT3A, and DNMT3B. DNMT1 methylates hemimethylated DNA ensuring accurate DNA methylation maintenance. DNMT1 is involved in the proper differentiation of hematopoietic stem cells (HSCs) through the interaction with effector molecules. DNMT1 is deregulated in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) as early as the leukemic stem cell stage. Through the interaction with fundamental transcription factors, non-coding RNAs, fusion oncogenes and by modulating core members of signaling pathways, it can affect leukemic cells biology. DNMT1 action might be also catalytic-independent highlighting a methylation-independent mode of action. In this review, we have gathered some current facts of DNMT1 role in AML and MDS and we also propose some perspectives for future studies. PMID- 26983919 TI - Learning with Technology: Video Modeling with Concrete-Representational-Abstract Sequencing for Students with Autism Spectrum Disorder. AB - The purpose of this study was to determine the effectiveness of a video modeling intervention with concrete-representational-abstract instructional sequence in teaching mathematics concepts to students with autism spectrum disorder (ASD). A multiple baseline across skills design of single-case experimental methodology was used to determine the effectiveness of the intervention on the acquisition and maintenance of addition, subtraction, and number comparison skills for four elementary school students with ASD. Findings supported the effectiveness of the intervention in improving skill acquisition and maintenance at a 3-week follow up. Implications for practice and future research are discussed. PMID- 26983920 TI - Differences in Social Motivation in Children with Smith-Magenis Syndrome and Down Syndrome. AB - Social excesses, characterised by heightened social motivation, are important for describing social functioning. Smith-Magenis syndrome (SMS) is a potential exemplar of a disorder where heightened social motivation is associated with negative behavioural outcomes. In Down syndrome (DS) strong social motivation is described, but less commonly associated with behavioural problems. Children with SMS (n = 21) and DS (n = 19) were observed during social situations, in which familiarity of adults present and level of attention available were manipulated. Motivation in SMS was characterised by comparatively frequent social initiations when adult attention was low, and stronger preference for familiar adults, compared to DS. Findings provide insight into the nature of social motivation in SMS and support an argument for nuanced consideration of motivation. PMID- 26983921 TI - Renaissance of leptin for obesity therapy. AB - Diet-induced obesity and its metabolic comorbidities constitute an overwhelming health crisis and there is an urgent need for safe and effective pharmacological interventions. Being largely shelved for decades, scientists are now revisiting the anti-obesity virtues of leptin. Whereas it remains evident that leptin as a stand-alone therapy is not an effective approach, the potential for employing sensitising pharmacology to unleash the weight-lowering properties of leptin has injected new hope into the field. Fascinatingly, these leptin-sensitising agents seem to act via distinct metabolic pathways and may thus, in parallel with their clinical development, serve as important research tools to progress our understanding of the molecular, physiological and behavioural pathways underlying energy homeostasis and obesity pathophysiology. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Thomas Meek and Gregory Morton, DOI: 10.1007/s00125-016-3898-3 , and by Gerald Shulman and colleagues, DOI: 10.1007/s00125-016-3909-4 ) and an overview by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016-3894-7 ). PMID- 26983923 TI - Bariatric surgery: traversing the CROSSROADS into mainstream diabetes care. PMID- 26983922 TI - Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-gamma and PPAR-alpha agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice. AB - AIMS/HYPOTHESIS: Pan-peroxisome proliferator-activated receptor (PPAR) agonists have long been sought as therapeutics against the metabolic syndrome, but current PPAR agonists show limited efficacy and adverse effects. Natural herbs provide a structurally untapped resource to prevent and treat complicated metabolic syndrome. METHODS: Natural PPAR agonists were screened using reporter gene, competitive binding and 3T3-L1 pre-adipocyte differentiation assays in vitro. The effects on metabolic phenotypes were verified in db/db and diet-induced obese mice. In addition, potentially synergistic actions of bavachinin (BVC, a novel natural pan-PPAR agonist from the fruit of the traditional Chinese glucose lowering herb malaytea scurfpea) and synthetic PPAR agonists were studied through nuclear magnetic resonance, molecular docking, reporter gene assays and mouse studies. RESULTS: BVC exhibited glucose-lowering properties without inducing weight gain and hepatotoxicity. Importantly, BVC synergised with thiazolidinediones, which are synthetic PPAR-gamma agonists, and fibrates, which are PPAR-alpha agonists, to induce PPAR transcriptional activity, as well as to lower glucose and triacylglycerol levels in db/db mice. We further found that BVC occupies a novel alternative binding site in addition to the canonical site of synthetic agonists of PPAR, and that the synthetic PPAR-gamma agonist rosiglitazone can block BVC binding to this canonical site but not to the alternative site. CONCLUSIONS/INTERPRETATION: This is the first report of a synergistic glucose- and lipid-lowering effect of BVC and synthetic agonists induced by unique binding with PPAR-gamma or -alpha. This combination may improve the efficacy and decrease the toxicity of marketed drugs for use as adjunctive therapy to treat the metabolic syndrome. PMID- 26983924 TI - Gastric bypass surgery vs intensive lifestyle and medical intervention for type 2 diabetes: the CROSSROADS randomised controlled trial. AB - AIMS/HYPOTHESIS: Mounting evidence indicates that Roux-en-Y gastric bypass (RYGB) ameliorates type 2 diabetes, but randomised trials comparing surgical vs nonsurgical care are needed. With a parallel-group randomised controlled trial (RCT), we compared RYGB vs an intensive lifestyle and medical intervention (ILMI) for type 2 diabetes, including among patients with a BMI <35 kg/m(2). METHODS: By use of a shared decision-making recruitment strategy targeting the entire at-risk population within an integrated community healthcare system, we screened 1,808 adults meeting inclusion criteria (age 25-64, with type 2 diabetes and a BMI 30 45 kg/m(2)). Of these, 43 were allocated via concealed, computer-generated random assignment in a 1:1 ratio to RYGB or ILMI. The latter involved >=45 min of aerobic exercise 5 days per week, a dietitian-directed weight- and glucose lowering diet, and optimal diabetes medical treatment for 1 year. Although treatment allocation could not be blinded, outcomes were determined by a blinded adjudicator. The primary outcome was diabetes remission at 1 year (HbA1c <6.0% [<42.1 mmol/mol], off all diabetes medicines). RESULTS: Twenty-three volunteers were assigned to RYGB and 20 to ILMI. Of these, 11 withdrew before receiving any intervention. Hence 15 in the RYGB group and 17 in the IMLI group were analysed throughout 1 year. The groups were equivalent regarding all baseline characteristics, except that the RYGB cohort had a longer diabetes duration (11.4 +/- 4.8 vs 6.8 +/- 5.2 years, p = 0.009). Weight loss at 1 year was 25.8 +/- 14.5% vs 6.4 +/- 5.8% after RYGB vs ILMI, respectively (p < 0.001). The ILMI exercise programme yielded a 22 +/- 11% increase in [Formula: see text] (p<0.0001), whereas [Formula: see text] after RYGB was unchanged. Diabetes remission at 1 year was 60.0% with RYGB vs 5.9% with ILMI (p = 0.002). The HbA1c decline over 1 year was only modestly more after RYGB than ILMI: from 7.7 +/- 1.0% (60.7 mmol/mol) to 6.4 +/- 1.6% (46.4 mmol/mol) vs 7.3 +/- 0.9% (56.3 mmol/mol) to 6.9 +/- 1.3% (51.9 mmol/mol), respectively (p = 0.04); however, this drop occurred with significantly fewer or no diabetes medications after RYGB. No life-threatening complications occurred. CONCLUSIONS/INTERPRETATION: Compared with the most rigorous ILMI yet tested against surgery in a randomised trial, RYGB yielded greater type 2 diabetes remission in mild-to-moderately obese patients recruited from a well-informed, population-based sample. TRIAL REGISTRATION: ClinicalTrials.gov NCT01295229. PMID- 26983926 TI - Epicardial Fat Thickness and Primary Aldosteronism. AB - Primary aldosteronism (PA) is associated with increased cardiovascular risk and left ventricle (LV) changes. Given its peculiar biomolecular and anatomic properties, excessive epicardial fat, the heart-specific visceral fat depot, can affect LV morphology. Whether epicardial fat can be associated with aldosterone and LV mass (LVM) in patients with PA is unknown. We performed ultrasound measurement of the epicardial fat thickness (EAT) in 79 consecutive newly diagnosed patients with PA, 59 affected by bilateral adrenal hyperplasia (IHA), 20 aldosterone-producing adenoma (APA), and 30 patients with essential hypertension (low renin hypertension) (EH). The 3 groups did not differ by age, sex distribution, body mass index (BMI), waist circumference (WC), or blood pressure values. EAT showed a trend of increase in both APA and IHA groups when compared to patients with EH (8.3+/-1.8 vs. 7.9+/-1.3 vs. 7.8+/-2 mm, respectively). EAT was significantly correlated with indexed LVM in the IHA group (r=0.35, p<005), better than BMI or WC were. Interestingly, EAT was highly associated with plasma aldosterone concentrations (PAC) and PAC/plasma renin activity (PRA) (PAC/PRA) in the APA group (p=0.58, p=0.37, p<0.01, for both), whereas BMI and WC were not. EAT was also correlated with PRA in the IHA group (p=-0.28, p<0.05). Our study indicates a novel and interesting interaction of EAT with PA, independent of obesity, abdominal fat and blood pressure control. EAT can locally affect LVM, at least in patients with IHA. Further studies in larger population will be required to confirm these findings. PMID- 26983925 TI - Temporary deafferentation evoked by cutaneous anesthesia: behavioral and electrophysiological findings in healthy subjects. AB - Motor function and motor excitability can be modulated by changes of somatosensory input. Here, we performed a randomized single-blind trial to investigate behavioral and neurophysiological changes during temporary deafferentation of left upper arm and forearm in 31 right-handed healthy adults. Lidocaine cream was used to anesthetize the skin from wrist to shoulder, sparing the hand. As control condition, on a different day, a neutral cream was applied to the same skin area. The sequence (first Lidocaine, then placebo or vice versa) was randomized. Behavioral measures included the Grating Orientation Task, the Von Frey hair testing and the Nine-hole-peg-test. Transcranial magnetic stimulation was used to investigate short-interval intracortical inhibition, stimulus response curves, motor evoked potential amplitudes during pre innervation and the cortical silent period (CSP). Recordings were obtained from left first dorsal interosseous muscle and from left flexor carpi radialis muscle. During deafferentation, the threshold of touch measured at the forearm was significantly worse. Other behavioral treatment-related changes were not found. The CSP showed a significant interaction between treatment and time in first dorsal interosseous muscle. CSP duration was longer during Lidocaine application and shorter during placebo exposure. We conclude that, in healthy subjects, temporary cutaneous deafferentation of upper and lower arm may have minor effects on motor inhibition, but not on sensory or motor function for the adjacent non anesthetized hand. PMID- 26983927 TI - ER Protein Processing Under Oxidative Stress: Implications and Prevention. AB - Elevated levels of mitochondrial nitrosative stress have been associated with the pathogenesis of both Parkinson's and Alzheimer's diseases. The mechanism involves catalytic poisoning of the endoplasmic reticulum (ER)-resident oxidoreductase chaperone, protein disulfide isomerase (PDI), and the subsequent accumulation of ER-processed substrate proteins. Using a model system to mimic mitochondrial oxidative and nitrosative stress, we demonstrate a PDI-independent mechanism whereby reactive oxygen species (ROS) compromise regeneration rates of disulfide bond-containing ER-processed proteins. Under ROS-duress, the secretion-destined traffic adopts disulfide-exposed structures making the protein flux retrotranslocation biased. We also demonstrate that ROS-compromised protein maturation rates can be rescued by the polyphenol ellagic acid (EA). Our results are significant in that they reveal an additional mechanism which could promote neurodegenerative disorders. Furthermore, our data reveal that EA possesses therapeutic potential as a lead prophylactic agent against oxidative/nitrosative stress-related neurodegenerative diseases. PMID- 26983928 TI - Amyloid Hydrogen Bonding Polymorphism Evaluated by (15)N{(17)O}REAPDOR Solid State NMR and Ultra-High Resolution Fourier Transform Ion Cyclotron Resonance Mass Spectrometry. AB - A combined approach, using Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) and solid-state NMR (Nuclear Magnetic Resonance), shows a high degree of polymorphism exhibited by Abeta species in forming hydrogen-bonded networks. Two Alzheimer's Abeta peptides, Ac-Abeta(16-22)-NH2 and Abeta(11-25), selectively labeled with (17)O and (15)N at specific amino acid residues were investigated. The total amount of peptides labeled with (17)O as measured by FTICR-MS enabled the interpretation of dephasing observed in (15)N{(17)O}REAPDOR solid-state NMR experiments. Specifically, about one-third of the Abeta peptides were found to be involved in the formation of a specific >C?(17)O...H-(15)N hydrogen bond with their neighbor peptide molecules, and we hypothesize that the rest of the molecules undergo +/- n off-registry shifts in their hydrogen bonding networks. PMID- 26983931 TI - Change of Guards. PMID- 26983929 TI - Building Tobacco Cessation Capacity in Homeless Shelters: A Pilot Study. AB - Tobacco use is common among homeless adults, yet few homeless shelters offer tobacco dependence treatment. Using a pre-intervention and post-intervention study design, we pilot tested the feasibility of a capacity building intervention that consisted of a 3.5-h training for shelter staff to provide cessation counseling. Staff (n = 12) and homeless clients (n = 46) completed questionnaires at pre-intervention, post-intervention (6 weeks), and at 12-weeks follow-up. Staff completed a questionnaire on tobacco-related knowledge, attitudes toward and practices around treating tobacco dependence, and self-efficacy in providing cessation counseling (score range 1-5). Clients completed a questionnaire on tobacco-related knowledge, attitudes toward tobacco dependence, and receipt of tobacco-related services from the program (score range 1-5). We used repeated measures linear regression analysis to examine change in scores over time. From pre-intervention to post-intervention, staff knowledge (beta coefficient 0.4, 95 % CI 0.1-0.8) and efficacy (beta coefficient 0.4, 95 % CI 0.2-0.7) in treating tobacco dependence increased. Client receipt of tobacco-related program services increased significantly from post-intervention to follow-up (beta coefficient 0.3, 95 % CI 0.1-0.5). A brief capacity building intervention has the potential to increase tobacco-related interventions among clients in homeless shelters. PMID- 26983930 TI - Increasing Community Awareness About Alzheimer's Disease in Puerto Rico Through Coffee Shop Education and Social Media. AB - Alzheimer's disease (AD) is the fourth leading cause of death in Puerto Rico. Using multi-media resources and in-person education may be an effective approach to improve knowledge and awareness of AD. The Un Cafe por el Alzheimer program in Puerto Rico incorporates an education component at coffee shops and a social media campaign using Facebook. The current study evaluates this initiative through an analysis of pre/post education survey results and social media content and use. Surveys contained close-ended and open-ended questions to understand participants' perceptions and knowledge about AD. Post-education surveys also included questions related to program satisfaction. Social media analysis of the Facebook community page examined posts from March 1 to September 30, 2015. Descriptive statistics were used to analyze survey and Facebook data. Four education sessions were conducted with a total of 212 participants. Fifty-one of the participants completed both pre- and post-surveys. Following the education program participants reported improved knowledge of risk and protective factors. All participants reported learning new information from the program. There were a total of 250 posts on the Un Cafe por el Alzheimer community Facebook page; 168 posts related to AD. The Facebook page reached 294,109 people, with 9963 page likes, 610 comments, 17,780 post clicks, and 3632 shares. There was an average increase of 64.8 % in number of people reached by the Facebook page following the education sessions. The approach of combining social media resources and in person education is beneficial to increase public awareness of AD and disseminate health information. PMID- 26983932 TI - Novel montelukast sodium-loaded stable oral suspension bioequivalent to the commercial granules in rats. AB - To develop a montelukast sodium-loaded stable oral suspension bioequivalent to the commercial granules in rats, several montelukast sodium-loaded suspensions were prepared with a suspending agent, stabilizers and anti-aggregation agents, and their stabilities were investigated by visually observing the sedimentation phenomenon and determining the concentration of the degradation product. Moreover, dissolution and pharmacokinetic studies of the optimized formulation were examined in rats compared to commercial montelukast sodium-loaded granules. Avicel RC-591 (Avicel), a suspending agent, prevented the sedimentation of these suspensions at >2.496 (w/v) per cent composition. Amongst the stabilizers tested, fumaric acid provided the lowest concentration of montelukast sulphoxide (a degradation product) in these suspensions at 40 degrees C, demonstrating its excellent stabilizing activity. Furthermore, as an anti-aggregation agent, glycerin gave lower amounts of degradation product than those with poloxamer 407 and Tween 80. In particular, montelukast-loaded oral suspension, an aqueous suspension containing montelukast sodium/Avicel/fumaric acid/glycerin at a concentration of 312/2496/15.6/62.4 (mg/100 ml), and the commercial granules exhibited similar dissolution profiles in 0.5% (w/v) aqueous solution of sodium lauryl sulphate. Moreover, the pharmacokinetics in rats provided by this suspension was comparable to that of the commercial granules, suggesting that they were bioequivalent. In addition, it was physically and chemically stable at 40 degrees C for at least 6 months. Thus, this montelukast sodium-loaded oral suspension, with bioequivalence to the commercial granules and excellent stability, could be a prospective dosage form for the treatment of asthma. PMID- 26983933 TI - 27-Hydroxycholesterol suppresses lipid accumulation by down-regulating lipogenic and adipogenic gene expression in 3T3-L1 cells. AB - Cholesterol oxidation products (oxycholesterols) are produced from cholesterol by automatic and/or enzymatic oxidation of the steroidal backbone and side-chain. Oxycholesterols are present in plasma and serum, suggesting that oxycholesterols are related to the development and progression of various diseases. However, limited information is available about the absolute amounts of oxycholesterols in organs and tissues, and the physiological significance of oxycholesterols in the body. In the present study, we quantified the levels of 13 oxycholesterols in white adipose tissue (WAT) of mice and then evaluated correlations between each oxycholesterol level and WAT weight. The sum of the levels of 13 oxycholesterols in WAT (white adipose tissue) was 15.9 +/- 3.4 MUg/g of WAT weight and approximately 1 % of cholesterol level. Among oxycholesterols, the levels of 27 hydroxycholesterol (27-OH), an endogenous oxycholesterol produced by enzymatic oxidation, and the relative WAT weights were significantly negatively correlated. Next, we evaluated the effects of 27-OH on lipogenesis and adipogenesis in 3T3-L1 cells. TO901317 (TO), a potent and selective agonist for LXRalpha, significantly increased intracellular TAG contents, while 27-OH significantly reduced the contents to half when compared with control (DMSO) and completely abolished the effect of TO. In addition, 27-OH significantly reduced the mRNA levels of lipogenic (LXRalpha and FAS) and adipogenic genes (PPARgamma and aP2) during adipocyte maturation of 3T3-L1 cells. In conclusion, our results indicate that 27 OH suppresses lipid accumulation by down-regulating lipogenic and adipogenic gene expression in 3T3-L1 cells. PMID- 26983936 TI - The impact of virtual fracture clinics on medical education - a medical student perspective. PMID- 26983934 TI - Exogenous expression of homeoprotein EGAM1N prevents in vitro cardiomyogenesis by impairing expression of T and Nkx2.5, but not Mef2c, in mouse embryonic stem cells. AB - Generation of multiple cell types from embryonic stem (ES) cells and induced pluripotent stem cells is crucial to provide materials for regenerative medicine. EGAM1N has been found in preimplantation mouse embryos and mouse ES cells as a functionally unclassified homeoprotein. Recently, we reported that expression of EGAM1N suppressed the in vitro differentiation of ES cells into progenitor cells that arise in early embryogenesis. To clarify the effect of EGAM1N on terminal differentiation, embryoid bodies (EBs) were prepared from ES cells expressing exogenous Egam1n. In EBs expressing Egam1n, cardiomyogenesis was inhibited by impairing the expression of crucial transcription factors Brachyury T and Nkx2.5 in the generation of mesoderm and cardiomyocytes, respectively. Expression levels of Mef2c, another crucial gene for cardiomyogenesis, were unaffected. Conversely, the expression levels of Gata6 and Plat, markers for the primitive endoderm lineage, and Cdx2, a marker for the trophectoderm lineage, were increased. These results suggested that certain cell populations in EBs expressing Egam1n preferentially differentiated to such cell lineages. Our results suggest that EGAM1N not only affects the generation of progenitor cells during early embryogenesis, but also the progression of terminal differentiation, such as cardiomyogenesis, in mouse ES cells. PMID- 26983935 TI - High variation in manufacturer-declared serving size of packaged discretionary foods in Australia. AB - Despite the potential of declared serving size to encourage appropriate portion size consumption, most countries including Australia have not developed clear reference guidelines for serving size. The present study evaluated variability in manufacturer-declared serving size of discretionary food and beverage products in Australia, and how declared serving size compared with the 2013 Australian Dietary Guideline (ADG) standard serve (600 kJ). Serving sizes were obtained from the Nutrition Information Panel for 4466 packaged, discretionary products in 2013 at four large supermarkets in Sydney, Australia, and categorised into fifteen categories in line with the 2013 ADG. For unique products that were sold in multiple package sizes, the percentage difference between the minimum and the maximum serving size across different package sizes was calculated. A high variation in serving size was found within the majority of food and beverage categories - for example, among 347 non-alcoholic beverages (e.g. soft drinks), the median for serving size was 250 (interquartile range (IQR) 250, 355) ml (range 100-750 ml). Declared serving size for unique products that are available in multiple package sizes also showed high variation, particularly for chocolate based confectionery, with median percentage difference between minimum and maximum serving size of 183 (IQR 150) %. Categories with a high proportion of products that exceeded the 600 kJ ADG standard serve included cakes and muffins, pastries and desserts (>=74 % for each). High variability in declared serving size may confound interpretation and understanding of consumers interested in standardising and controlling their portion selection. Future research is needed to assess if and how standardising declared serving size might affect consumer behaviour. PMID- 26983937 TI - Smartloss: A Personalized Mobile Health Intervention for Weight Management and Health Promotion. AB - BACKGROUND: Synonymous with increased use of mobile phones has been the development of mobile health (mHealth) technology for improving health, including weight management. Behavior change theory (eg, the theory of planned behavior) can be effectively encapsulated into mobile phone-based health improvement programs, which is fostered by the ability of mobile phones and related devices to collect and transmit objective data in near real time and for health care or research professionals and clients to communicate easily. OBJECTIVE: To describe SmartLoss, a semiautomated mHealth platform for weight loss. METHODS: We developed and validated a dynamic energy balance model that determines the amount of weight an individual will lose over time if they are adherent to an energy intake prescription. This model was incorporated into computer code that enables adherence to a prescribed caloric prescription determined from the change in body weight of the individual. Data from the individual are then used to guide personalized recommendations regarding weight loss and behavior change via a semiautomated mHealth platform called SmartLoss, which consists of 2 elements: (1) a clinician dashboard and (2) a mobile phone app. SmartLoss includes and interfaces with a network-connected bathroom scale and a Bluetooth-connected accelerometer, which enables automated collection of client information (eg, body weight change and physical activity patterns), as well as the systematic delivery of preplanned health materials and automated feedback that is based on client data and is designed to foster prolonged adherence with body weight, diet, and exercise goals. The clinician dashboard allows for efficient remote monitoring of all clients simultaneously, which may further increase adherence, personalization of treatment, treatment fidelity, and efficacy. RESULTS: Evidence of the efficacy of the SmartLoss approach has been reported previously. The present report provides a thorough description of the SmartLoss Virtual Weight Management Suite, a professionally programmed platform that facilitates treatment fidelity and the ability to customize interventions and disseminate them widely. CONCLUSIONS: SmartLoss functions as a virtual weight management clinic that relies upon empirical weight loss research and behavioral theory to promote behavior change and weight loss. PMID- 26983939 TI - NMR resonance assignments of caspase recruitment domain of RIP2 kinase. AB - Receptor interacting protein-2, RIP2, is a serine/threonine kinase and has sequence homology to RIP. It functions as an adaptor molecule for some members from the tumor necrosis factor receptor family and mediates divergent signaling pathways including NF-kappaB activation and cell death. RIP2 contains an N terminal kinases domain and a C-terminal caspase activation and recruitment domain (CARD). The apoptotic activity of RIP2 is restricted to its C-terminal CARD domain while NF-kappaB activation requires the intact RIP2 for binding. RIP2 CARD involved homotypic or heterotypic interactions with members of the death domains superfamily. Here I report backbone and sidechain (1)H, (13)C and (15)N resonance assignments of soluble RIP2 CARD as a basis for further structural and functional studies. PMID- 26983941 TI - A high performance three-phase enzyme electrode based on superhydrophobic mesoporous silicon nanowire arrays for glucose detection. AB - We describe here a high performance oxygen-rich three-phase enzyme electrode based on superhydrophobic mesoporous silicon nanowire arrays for glucose detection. We demonstrate that its linear detection upper limit is 30 mM, more than 15 times higher than that can be obtained on the normal enzyme-electrode. Notably, the three-phase enzyme electrode output is insensitive to the significant oxygen level fluctuation in analyte solution. PMID- 26983938 TI - Trypanosoma cruzi Polyamine Transporter: Its Role on Parasite Growth and Survival Under Stress Conditions. AB - Trypanosoma cruzi is the etiological agent of Chagas disease, a major health problem in Latin America. Polyamines are polycationic compounds that play a critical role as regulators of cell growth and differentiation. In contrast with other protozoa, T. cruzi is auxotrophic for polyamines because of its inability to synthesize putrescine due to the lack of both, arginine and ornithine decarboxylase; therefore, the intracellular availability of polyamines depends exclusively on transport processes. In this work, the polyamine transporter TcPAT12 was overexpressed in T. cruzi epimastigotes demonstrating that growth rates at different concentrations of polyamines strongly depend on the regulation of the polyamine transport. In addition, parasites overexpressing TcPAT12 showed a highly increased resistance to hydrogen peroxide and the trypanocidal drugs nifurtimox and benznidazole, which act by oxidative stress and interfering the synthesis of polyamine derivatives, respectively. Finally, the presence of putative polyamine transporters was analyzed in T. cruzi, Trypanosoma brucei, and Leishmania major genomes identifying 3-6 genes in these trypanosomatids. PMID- 26983940 TI - (1)H, (13)C and (15)N resonance assignments and secondary structure analysis of translation initiation factor 1 from Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen and a primary cause of infection in humans. P. aeruginosa can acquire resistance against multiple groups of antimicrobial agents, including beta-lactams, aminoglycosides and fluoroquinolones, and multidrug resistance is increasing in this organism which makes treatment of the infections difficult and expensive. This has led to the unmet need for discovery of new compounds distinctly different from present antimicrobials. Protein synthesis is an essential metabolic process and a validated target for the development of new antibiotics. Translation initiation factor 1 from P. aeruginosa (Pa-IF1) is the smallest of the three initiation factors that acts to establish the 30S initiation complex to initiate translation during protein biosynthesis, and its structure is unknown. Here we report the (1)H, (13)C and (15)N chemical shift assignments of Pa-IF1 as the basis for NMR structure determination and interaction studies. Secondary structure analyses deduced from the NMR chemical shift data have identified five beta-strands with an unusually extended beta-strand at the C-terminal end of the protein and one short alpha-helix arranged in the sequential order beta1-beta2-beta3-alpha1-beta4 beta5. This is further supported by (15)N-{(1)H} hetero NOEs. These secondary structure elements suggest the Pa-IF1 adopts the typical beta-barrel structure and is composed of an oligomer-binding motif. PMID- 26983942 TI - Enhancement of malate-production and increase in sensitivity to dimethyl succinate by mutation of the VID24 gene in Saccharomyces cerevisiae. AB - Malate in sake (a Japanese alcoholic beverage) is an important component for taste that is produced by yeasts during alcoholic fermentation. To date, many researchers have developed methods for breeding high-malate-producing yeasts; however, genes responsible for the high-acidity phenotype are not known. We determined the mutated gene involved in high malate production in yeast, isolated as a sensitive mutant to dimethyl succinate. In the comparative whole genome analysis between high-malate-producing strain and its parent strain, one of the non-synonymous substitutions was identified in the VID24 gene. The mutation of VID24 resulted in enhancement of malate-productivity and sensitivity to dimethyl succinate. The mutation appeared to lead to a deficiency in Vid24p function. Furthermore, disruption of cytoplasmic malate dehydrogenase (Mdh2p) gene in the VID24 mutant inhibited the high-malate-producing phenotype. Vid24p is known as a component of the multisubunit ubiquitin ligase and participates in the degradation of gluconeogenic enzymes such as Mdh2p. We suggest that the enhancement of malate-productivity results from an accumulation of Mdh2p due to the loss of Vid24p function. These findings propose a novel mechanism for the regulation of organic acid production in yeast cells by the component of ubiquitin ligase, Vid24p. PMID- 26983943 TI - Pyruvate kinase deletion as an effective phenotype to enhance lysine production in Corynebacterium glutamicum ATCC13032: Redirecting the carbon flow to a precursor metabolite. AB - Various attempts have been made to enhance lysine production in Corynebacterium glutamicum. Pyruvate kinase (PYK) defect is one of the strategies used to enhance the supply of oxaloacetic acid (OAA), a precursor metabolite for lysine biosynthesis. However, inconsistent effects of this mutation have been reported: positive effects of PYK defect in mutants having phosphoenolpyruvate carboxylase (PEPC) desensitized to feedback inhibition by aspartic acid, while negative effects in simple PYK gene (pyk) knockout mutants. To address these discrepancies, the effects of pyk deletion on lysine yield were investigated with or without the D299N mutation in ppc rendering PEPC desensitization. C. glutamicum ATCC13032 mutant strain P with a feedback inhibition-desensitized aspartokinase was used as the parent strain, producing 9.36 g/L lysine from 100 g/L glucose in a jar fermentor culture. Under these conditions, while the simple mutant D2 with pyk deletion or R2 with the PEPC-desensitization mutation showed marginally increased lysine yield (~1.1-fold, not significant), the mutant DR2 strain having both mutations showed synergistically increased lysine productivity (1.38-fold, 12.9 g/L). Therefore, the pyk deletion is effective under a PEPC desensitized background, which ensures enhanced supply of OAA, thus clarifying the discrepancies. A citrate synthase defective mutation (S252C in gltA) further increased the lysine yield in strain DR2 (1.68-fold, 15.7 g/L). Thus, these three mutations coordinately enhanced the lysine yield. Both the malate:quinone oxidoreductase activity and respiration rate were significantly reduced in strains D2 and DR2. Overall, these results provide valuable knowledge for engineering the anaplerotic reaction to increase lysine yield in C. glutamicum. PMID- 26983944 TI - Performance of a non-contact infrared thermometer in healthy newborns. AB - OBJECTIVE: To evaluate the performance of a non-contact infrared thermometer (NCIT) in comparison with digital axillary thermometer (DAT) and infrared tympanic thermometers (ITT) in a population of healthy at term and preterm newborns nursed in incubators. SETTING: 1 level III maternity hospital, and its intensive neonatal care unit. PARTICIPANTS: 119 healthy at term newborns and 70 preterm newborns nursed in incubators were consecutively enrolled. Exclusion criteria were unstable/critical conditions, polymalformative congenital syndromes and severe congenital syndromes. INTERVENTIONS: Body temperature readings were prospectively collected. Each participant underwent bilateral axillary temperature measurement with DAT, bilateral tympanic measurement with ITT and mid forehead temperature measurements using NCIT. PRIMARY OUTCOME MEASURES: Degree of agreement between methods was evaluated by the Bland and Altman method. RESULTS: 714 measurements in 119 healthy at term newborns and 420 measurements in 70 preterm newborns nursed in incubators were performed. Clinical reproducibility of NCIT was 0.0455 degrees C for infants in incubators and 0.0861 degrees C for infants outside an incubator. Bias was 0.029 degrees C for infants in incubators and <0.0001 degrees C for infants outside an incubator. Zero outliers were recorded. The mean difference between methods was good both for newborns at term (0.12 degrees C for NCIT vs DAT and 0.02 degrees C for NCIT vs ITT) and preterm newborns in incubators (0.10 degrees C for NCIT vs DAT and 0.14 degrees C for NCIT vs ITT). Limits of agreement were 0.99 to -0.75 and 0.78 to -0.75 in at term newborns and were particularly satisfactory in preterm newborns in incubators (95% CI: 0.48 to -0.27 and 0.68 to -0.40). CONCLUSIONS: Our results with Bland and Altman analysis demonstrate that NCIT is a very promising tool, especially in preterm newborns nursed in incubators. TRIAL REGISTRATION: The study was approved by the Careggi University Hospital Ethics Committee (07/2011). PMID- 26983945 TI - Effect of serotonin modulating pharmacotherapies on body mass index and dysglycaemia among children and adolescents: a systematic review and network meta analysis protocol. AB - INTRODUCTION: Serotonin-modulating medications are commonly prescribed for mental health issues. Currently, there is limited consensus on weight gain and dysglycaemia development among children using these medications. The objective of this study is to review and synthesise all the available evidence on serotonin modulating medications and their effects on body mass index (BMI), weight and glycaemic control. METHODS AND ANALYSIS: We will conduct a systematic review of all randomised controlled trials evaluating the use of serotonin-modulating medications in the treatment of children 2-17 years with mental health conditions. The outcome measures are BMI, weight and dysglycaemia. We will perform literature searches through Ovid Medline, Ovid Embase, PsycINFO and grey literature resources. Two reviewers from the team will independently screen titles and abstracts, assess the eligibility of full-text trials, extract information from eligible trials and assess the risk of bias and quality of the evidence. Results of this review will be summarised narratively and quantitatively as appropriate. We will perform a multiple treatment comparison using network meta-analysis to estimate the pooled direct, indirect and network estimate for all serotonin-modulating medications on outcomes if adequate data are available. ETHICS AND DISSEMINATION: Serotonin-modulating medications are widely prescribed for children with mental health diseases and are also used off label. This network meta-analysis will be the first to assess serotonin modulating antidepressants and their effects on weight and glycaemic control. We anticipate that our results will help physicians and patients make more informed choices while considering the side effect profile. We will disseminate the results of the systematic review and network meta-analysis through peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42015024367. PMID- 26983946 TI - ECG risk markers for atrial fibrillation and sudden cardiac death in minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised trial. AB - OBJECTIVE: Obstructive sleep apnoea (OSA), atrial fibrillation (AF) and sudden cardiac death (SCD) may occur concomitantly, and are of considerable epidemiological interest, potentially leading to morbidity and mortality. Effective treatment of OSA with continuous positive airway pressure (CPAP) could prevent progression and/or recurrence of AF and factors leading to SCD. Recently, a randomised controlled trial showed a statistically and clinically significant prolongation of measures of cardiac repolarisation after CPAP withdrawal in symptomatic patients with moderate to severe OSA. Whether or not CPAP therapy improves ECG risk markers of AF and SCD in patients with minimally symptomatic OSA as well, is unknown. METHODS: 3 centres taking part in the MOSAIC (Multicentre Obstructive Sleep Apnoea Interventional Cardiovascular) trial randomised 303 patients with minimally symptomatic OSA to receive either CPAP or standard care for 6 months. Treatment effects of CPAP on P-wave duration, P-wave dispersion, QT interval, QT dispersion, Tpeak-to-Tend (TpTe) and TpTe/QT ratio were analysed. RESULTS: Participants were primarily men (83%). Mean age was 57.8 (7.2) and mean ODI (Oxygen Desaturation Index) at baseline was 13.1/h (12.3). Full 12-lead ECG data was available in 250 patients. Mean (SD) baseline intervals of P-wave duration, P-wave dispersion, QTc interval, QT dispersion, TpTe and TpTe/QT ratio in ms were 87.4 (8.3), 42.3 (11.9), 397.8 (22.7), 43.1 (16.7), 73.5 (13.7) and 0.19 (0.0), respectively. No treatment effect of CPAP on risk markers for AF and SCD was found. CONCLUSIONS: There seems to be no effect of CPAP on ECG measures of arrhythmia risk in patients with minimally symptomatic OSA. TRIAL REGISTRATION NUMBER: ISRCTN34164388; Post-results. PMID- 26983948 TI - Qualitative study to conceptualise a model of interprofessional collaboration between pharmacists and general practitioners to support patients' adherence to medication. AB - OBJECTIVES: Pharmacists and general practitioners (GPs) face an increasing expectation to collaborate interprofessionally on a number of healthcare issues, including medication non-adherence. This study aimed to propose a model of interprofessional collaboration within the context of identifying and improving medication non-adherence in primary care. SETTING: Primary care; Sydney, Australia. PARTICIPANTS: 3 focus groups were conducted with pharmacists (n=23) and 3 with GPs (n=22) working in primary care. PRIMARY AND SECONDARY OUTCOME MEASURES: Qualitative investigation of GP and pharmacist interactions with each other, and specifically around supporting their patients' medication adherence. Audio-recordings were transcribed verbatim and transcripts thematically analysed using a combination of manual and computer coding. RESULTS: 3 themes pertaining to interprofessional collaboration were identified (1) frequency, (2) co collaborators and (3) nature of communication which included 2 subthemes (method of communication and type of communication). While the frequency of interactions was low, the majority were conducted by telephone. Interactions, especially those conducted face-to-face, were positive. Only a few related to patient non adherence. The findings are positioned within contemporary collaborative theory and provide an accessible introduction to models of interprofessional collaboration. CONCLUSIONS: This work highlighted that successful collaboration to improve medication adherence was underpinned by shared paradigmatic perspectives and trust, constructed through regular, face-to-face interactions between pharmacists and GPs. PMID- 26983950 TI - Correlates and Racial/Ethnic Differences in Bareback Sex Among Men Who Have Sex with Men with Unknown or Negative HIV Serostatus. AB - Men who have sex with men (MSM), particularly racial/ethnic minority MSM, are disproportionately affected by HIV in the United States and Texas. Bareback sex or condomless anal intercourse (CAI) can be a high HIV risk behavior. Despite this, a majority of MSM continues to engage in barebacking. Research suggests racial/ethnic differences in barebacking exist; however, these conclusions remain unclear due to insufficient sample sizes to compare racial/ethnic groups. Our cross-sectional correlational design explores barebacking correlates (substance use during sex, safe sex fatigue, and optimistic HIV treatment beliefs) within and between racial/ethnic groups among 366 MSM. Regression models are significant for Latino and African-American MSM alone and for all MSM combined, though not significant for European-American and Other Race/Ethnicity MSM alone. Our findings suggest motivations and behaviors underlying barebacking among MSM vary by racial/ethnic membership with clinical implications for informing culturally sensitive HIV interventions and prevention programs for target racial/ethnic groups. PMID- 26983947 TI - Role of community pharmacists in the use of antipsychotics for behavioural and psychological symptoms of dementia (BPSD): a qualitative study. AB - OBJECTIVE: This study aimed to use qualitative methodology to understand the current role of community pharmacists in limiting the use of antipsychotics prescribed inappropriately for behavioural and psychological symptoms of dementia. DESIGN: A qualitative study employing focus groups was conducted. Data were analysed using thematic analysis. SETTING: 3 different geographical locations in the England. PARTICIPANTS: Community pharmacists (n=22). RESULTS: The focus groups identified an array of factors and constraints, which affect the ability of community pharmacists to contribute to initiatives to limit the use of antipsychotics. 3 key themes were revealed: (1) politics and the medical hierarchy, which created communication barriers; (2) how resources and remit impact the effectiveness of community pharmacy; and (3) understanding the nature of the treatment of dementia. CONCLUSIONS: Our findings suggest that an improvement in communication between community pharmacists and healthcare professionals, especially general practitioners (GPs) must occur in order for community pharmacists to assist in limiting the use of antipsychotics in people with dementia. Additionally, extra training in working with people with dementia is required. Thus, an intervention which involves appropriately trained pharmacists working in collaboration with GPs and other caregivers is required. Overall, within the current environment, community pharmacists question the extent to which they can contribute in helping to reduce the prescription of antipsychotics. PMID- 26983949 TI - Health professionals' experiences of tuberculosis cohort audit in the North West of England: a qualitative study. AB - OBJECTIVES: Tuberculosis cohort audit (TBCA) was introduced across the North West (NW) of England in 2012 as an ongoing, multidisciplinary, systematic case review process, designed to improve clinical and public health practice. TBCA has not previously been introduced across such a large and socioeconomically diverse area in England, nor has it undergone formal, qualitative evaluation. This study explored health professionals' experiences of the process after 1515 cases had been reviewed. DESIGN: Qualitative study using semistructured interviews. Respondents were purposively sampled from 3 groups involved in the NW TBCA: (1) TB nurse specialists, (2) consultant physicians and (3) public health practitioners. Data from the 26 respondents were triangulated with further interviews with key informants from the TBCA Steering Group and through observation of TBCA meetings. ANALYSIS: Interview transcripts were analysed thematically using the framework approach. RESULTS: Participants described the evolution of a valuable 'community of practice' where interprofessional exchange of experience and ideas has led to enhanced mutual respect between different roles and a shared sense of purpose. This multidisciplinary, regional approach to TB cohort audit has promoted local and regional team working, exchange of good practices and local initiatives to improve care. There is strong ownership of the process from public health professionals, nurses and clinicians; all groups want it to continue. TBCA is regarded as a tool for quality improvement that improves patient safety. CONCLUSIONS: TBCA provides peer support and learning for management of a relatively rare, but important infectious disease through discussion in a no-blame atmosphere. It is seen as an effective quality improvement strategy which enhances TB care, control and patient safety. Continuing success will require increased engagement of consultant physicians and public health practitioners, a secure and ongoing funding stream and establishment of clear reporting mechanisms within the public health system. PMID- 26983951 TI - Pre-exposure Prophylaxis (PrEP) Use, Seroadaptation, and Sexual Behavior Among Men Who Have Sex with Men, San Francisco, 2004-2014. AB - The Food and Drug Administration approved pre-exposure prophylaxis (PrEP) to prevent HIV infection, and the Centers for Disease Control and Prevention has presented PrEP as a prevention option for groups at high risk such as men who have sex with men (MSM). Intervention data provide some information on how PrEP affects sexual behavior of MSM in trials, open label extensions, or clinics. However, it is unclear whether sexual risk and preventive behavioral patterns are changing in the population as a whole as PrEP becomes more widely available, whether due to PrEP use or other factors. We examined trends in PrEP use, numbers of condomless anal sex partners, consistent condom use, and seroadaptive strategies in San Francisco-a city which has actively promoted PrEP-using data from National HIV Behavioral Surveillance (NHBS). NHBS recruited 1211, 383, 373, and 268 HIV-negative MSM in 2004, 2008, 2011, and 2014, respectively. PrEP use increased from zero in 2004, 2008, and 2011 to 9.6 % in 2014. The proportion of men with no condomless anal sex partners dropped from 60.6 % in 2004, to 58.2 % in 2008, to 54.2 % in 2011, to 40.2 % in 2014. Consistent condom use decreased from 36.8 % in 2004, and 30.5 % in 2008 and 2011, to 18.3 % in 2014. PrEP's introduction and scale-up enters in a pre-existing trend of decreasing condom use and increasing sexually transmitted infections among MSM which may be accelerating in recent years. While PrEP use should be scaled up as a prevention option among those who would benefit most, we believe that public health officials need to be realistic about the possibility that condom use could very well continue to decline as PrEP use increases, and to an extent that may not be directly or indirectly offset by PrEP. PMID- 26983953 TI - VY6, a beta-lactoglobulin-derived peptide, altered metabolic lipid pathways in the zebra fish liver. AB - Today enormous research efforts are being focused on alleviating the massive, adverse effects of obesity. Short peptides are key targets for research as they can be generated from natural proteins, like milk. Here we conducted trypsinogen digestion of beta-lactoglobulin (beta-lg), the major mammalian milk protein, to release the hexamer VY6. It was assayed in vivo for its activities on lipid metabolism using zebra fish as a vertebrate model. Zebra fish juveniles were injected with two different doses of the peptide: 100 and 800 MUg per g fish and left for 5 days before sacrificing. Lipid measurements showed significant reduction in liver triglycerides and free cholesterol, as well as increased liver HDL cholesterol. Dose-dependent increases of the mRNA levels of the genes coding for the enzymes acyl coenzyme A oxidase 1 (acox1) and lipoprotein lipase (lpl) were also found. The complete results suggest significant anti-obesity activity of the beta-lg-derived VY6 peptide. Its use as a nutraceutical has been discussed. PMID- 26983952 TI - Phloretin induces cell cycle arrest and apoptosis of human glioblastoma cells through the generation of reactive oxygen species. AB - Phloretin, a flavonoid present in various plants, has been reported to exert anticarcinogenic effects. However, the mechanism of its chemo-preventive effect on human glioblastoma cells is not fully understood. This study aimed to investigate the molecular mechanism of phloretin and its associated chemo preventive effect in human glioblastoma cells. The results indicate that phloretin inhibited cell proliferation by inducing cell cycle arrest at the G0-G1 phase and induced apoptosis of human glioblastoma cells. Phloretin-induced cell cycle arrest was associated with increased expression of p27 and decreased expression of cdk2, cdk4, cdk6, cyclinD and cyclinE. Moreover, the PI3K/AKT/mTOR signaling cascades were suppressed by phloretin in a dose-dependent manner. In addition, phloretin triggered the mitochondrial apoptosis pathway and generated reactive oxygen species (ROS). This was accompanied by the up-regulation of Bax, Bak and c-PARP and the down-regulation of Bcl-2. The antioxidant agents N-acetyl L-cysteine and glutathione weakened the effect of phloretin on glioblastoma cells. In conclusion, these results demonstrate that phloretin exerts potent chemo-preventive activity in human glioblastoma cells through the generation of ROS. PMID- 26983954 TI - Transcatheter aortic valve implantation in a cancer patient denied for surgical aortic valve replacement-a case report. AB - BACKGROUND: Aortic stenosis is a progressive disease. Symptomatic aortic stenosis has a poor prognosis, which is frequently worse than that of a malignant disease. Cancer patients with severe aortic stenosis may be denied for optimal oncologic treatment because of high operative risk and for aortic valve replacement because of the significant comorbidity itself. In patients treated with medical therapy alone, 1-year-mortality exceeds 50 %. CASE REPORT: A 71-year-old woman with well differentiated, surgically treated, ovarian carcinoma and two relapses treated with chemo- and radiotherapy presented with symptomatic severe aortic stenosis (aortic valve area 0.6 cm(2), mean gradient 60 mmHg). The tumor was in stagnation. She was rejected for surgical valve replacement. We implanted a 29 mm CoreValve aortic prosthesis via transfemoral approach. After the procedure haemodynamic variables remain stable, patient's exertional capacity is excellent. CONCLUSION: Aortic valve replacement improves survival of cancer patients with symptomatic aortic stenosis. Transcatheter aortic valve replacement (TAVI) is a treatment option in inoperable patients and patients at high surgical risk. Symptoms should not be confused for the progression of the malignant disease. In patient selection emphasis should be made on their frailty and futility. Eligible patients must have a life expectancy of at least 1 year. Final decision has to be made by a multidisciplinary heart team. TAVI can reduce treatment risk and facilitate the oncologic treatment. PMID- 26983955 TI - External brain tamponade: a rare complication of decompressive craniectomy. PMID- 26983956 TI - Prevention programs for chronic kidney disease in low-income countries. AB - Chronic kidney disease (CKD) is an important determinant of the poor health outcome for major noncommunicable diseases that are the leading cause of death worldwide. Early recognition with screening programs of CKD and co-morbid conditions, like hypertension, diabetes, or toxic environments, can potentially slow progression to renal failure, improve quality of life and reduce healthcare cost. Effective multimodal tools are available to prevent CKD by managing its risk factors, and to slow or even halt disease progression to end-stage renal failure (ESRF). They can be adapted even to poor-resource settings of low- and middle-income countries for individual at high risk of CKD. CKD is also linked to acute kidney injury (AKI), that in poorest part of Africa, Asia and Latin America is preventable, treatable and often reversible, if managed adequately and in timely manner as proposed by the program "AKI 0by25" launched by the international Society of Nephrology in 2013. In addition to saving lives, prevention programs will create major heath gains, eventually reducing the current health inequity that arises from unaffordable or unobtainable renal replacement therapies in many part of the developing world if ESRF is not prevented. PMID- 26983957 TI - Allogeneic Stem Cell Transplantation for Non-Hodgkin Lymphoma. AB - Observational studies indicate a similar or higher probability of disease control, higher risk of non-relapse mortality (NRM), and similar overall survival (OS) with allogeneic stem cell transplantation (alloSCT), compared to autologous SCT, in relapsed or refractory non-Hodgkin lymphoma. Careful patient selection and utilization of reduced intensity conditioning (RIC) alloSCT may allow reduction in NRM. The optimal conditioning regimen and the roles of radioimmunotherapy, T cell depletion, and tandem SCT continue to be explored. Recent studies highlight comparable results with haploidentical SCT and cord blood SCT, thus providing alternate donor sources. Disease relapse and late effects continue to be major problems. Optimization of SCT techniques (e.g., improved graft-versus-host disease prophylaxis), post-transplant monitoring of minimal residual disease, and post-transplant maintenance, or pre-emptive therapy (e.g., with novel therapies) are emerging strategies to reduce the risk of relapse. Survivorship management using a multidisciplinary care approach, adoption of healthy lifestyle, and socioeconomic counseling are integral parts of a high-quality transplant program. PMID- 26983958 TI - Management of Patients with MYC-Altered Lymphomas. AB - Patients diagnosed with non-Burkitt high-grade B cell non-Hodgkin lymphomas demonstrating rearrangement in MYC, an oncogene promoting cellular proliferation, frequently do not achieve long-term disease-free survival due to a suboptimal response to standard front-line and salvage therapies. Double-hit lymphomas, harboring rearrangements in MYC as well as BCL2 and/or BCL6, appear to carry a particularly poor prognosis, although patients with this disease appear to achieve better survival outcomes when treated with intensified chemotherapy. Increased expression of MYC protein by immunohistochemistry as well as increased copy number or amplification of MYC may also be adverse pathologic features of non-Burkitt high-grade B cell non-Hodgkin lymphomas, although the benefit of treating these patients with intensified as opposed to standard dose chemotherapy remains unclear. Recognition and proper management of patients with MYC-altered lymphomas is crucial to improving patient outcomes. PMID- 26983961 TI - A High Performance Pulsatile Pump for Aortic Flow Experiments in 3-Dimensional Models. AB - Aortic pathologies such as coarctation, dissection, and aneurysm represent a particularly emergent class of cardiovascular diseases. Computational simulations of aortic flows are growing increasingly important as tools for gaining understanding of these pathologies, as well as for planning their surgical repair. In vitro experiments are required to validate the simulations against real world data, and the experiments require a pulsatile flow pump system that can provide physiologic flow conditions characteristic of the aorta. We designed a newly capable piston-based pulsatile flow pump system that can generate high volume flow rates (850 mL/s), replicate physiologic waveforms, and pump high viscosity fluids against large impedances. The system is also compatible with a broad range of fluid types, and is operable in magnetic resonance imaging environments. Performance of the system was validated using image processing based analysis of piston motion as well as particle image velocimetry. The new system represents a more capable pumping solution for aortic flow experiments than other available designs, and can be manufactured at a relatively low cost. PMID- 26983959 TI - Expression-Based Genome-Wide Association Study Links Vitamin D-Binding Protein With Autoantigenicity in Type 1 Diabetes. AB - Type 1 diabetes (T1D) is caused by autoreactive T cells that recognize pancreatic islet antigens and destroy insulin-producing beta-cells. This attack results from a breakdown in tolerance for self-antigens, which is controlled by ectopic antigen expression in the thymus and pancreatic lymph nodes (PLNs). The autoantigens known to be involved include a set of islet proteins, such as insulin, GAD65, IA-2, and ZnT8. In an attempt to identify additional antigenic proteins, we performed an expression-based genome-wide association study using microarray data from 118 arrays of the thymus and PLNs of T1D mice. We ranked all 16,089 protein-coding genes by the likelihood of finding repeated differential expression and the degree of tissue specificity for pancreatic islets. The top autoantigen candidate was vitamin D-binding protein (VDBP). T-cell proliferation assays showed stronger T-cell reactivity to VDBP compared with control stimulations. Higher levels and frequencies of serum anti-VDBP autoantibodies (VDBP-Abs) were identified in patients with T1D (n = 331) than in healthy control subjects (n = 77). Serum vitamin D levels were negatively correlated with VDBP-Ab levels in patients in whom T1D developed during the winter. Immunohistochemical localization revealed that VDBP was specifically expressed in alpha-cells of pancreatic islets. We propose that VDBP could be an autoantigen in T1D. PMID- 26983960 TI - Exercise Prevents Diet-Induced Cellular Senescence in Adipose Tissue. AB - Considerable evidence implicates cellular senescence in the biology of aging and chronic disease. Diet and exercise are determinants of healthy aging; however, the extent to which they affect the behavior and accretion of senescent cells within distinct tissues is not clear. Here we tested the hypothesis that exercise prevents premature senescent cell accumulation and systemic metabolic dysfunction induced by a fast-food diet (FFD). Using transgenic mice that express EGFP in response to activation of the senescence-associated p16(INK4a) promoter, we demonstrate that FFD consumption causes deleterious changes in body weight and composition as well as in measures of physical, cardiac, and metabolic health. The harmful effects of the FFD were associated with dramatic increases in several markers of senescence, including p16, EGFP, senescence-associated beta galactosidase, and the senescence-associated secretory phenotype (SASP) specifically in visceral adipose tissue. We show that exercise prevents the accumulation of senescent cells and the expression of the SASP while nullifying the damaging effects of the FFD on parameters of health. We also demonstrate that exercise initiated after long-term FFD feeding reduces senescent phenotype markers in visceral adipose tissue while attenuating physical impairments, suggesting that exercise may provide restorative benefit by mitigating accrued senescent burden. These findings highlight a novel mechanism by which exercise mediates its beneficial effects and reinforces the effect of modifiable lifestyle choices on health span. PMID- 26983965 TI - Assessment of borderline personality disorder: considering a diagnostic strategy. AB - BACKGROUND: Borderline personality disorder (BPD) represents a highly prevalent, severe and difficult-to-treat mental health problem. OBJECTIVE: This paper considers methods, instruments and strategies for assessing BPD as described within the frame of the DSM-IV classification. CONCLUSIONS: Following the general diagnostic approach introduced by Van Praag in biological psychiatry, a two-tier diagnostic strategy for the descriptive diagnostic assessment of BPD is recommended. Axis one results in a DSM-IV Axis II categorical diagnosis, whereas axis two refers to a symptomatological, dimensional or functional approach, in which the psychological dysfunctions of the nosological syndrome are depicted. Moreover, in a clinical context a basic aim of the diagnostic evaluation is to obtain therapeutically valid information that leads to a constructive conceptual framework, to a case formulation in which therapeutic interventions are understood, selected and implemented. This framework should be based on a biopsychosocial theoretical model and its application in the clinical context involves feedback to the patient, in which the descriptive evaluation is integrated with etiological; and pathogenic elements using an idiographic approach. This therapeutically orientated diagnostic strategy is illustrated by the use of the ADP-IV (Assessment of DSM-IV personality disorders) questionnaire within a cognitive behavioral orientation. PMID- 26983964 TI - A Chinese female Morvan patient with LGI1 and CASPR2 antibodies: a case report. AB - BACKGROUND: Morvan syndrome is a rare disorder characterized by the combination of peripheral nerve hyperexcitability, encephalopathy and dysautonomia with marked insomnia. It was reported to have association to antibodies to voltage gated potassium channels including contactin associated protein-like 2 antibodies (CASPR2-Ab) and leucine-rich glioma inactivated protein 1 antibodies (LGI1-Ab). LGI1-Ab was reported to associate with seizures, amnesia, confusion, hyponatraemia and a good prognosis, while CASPR2-Ab with peripheral presentations, probable risk for tumor and a poor prognosis. The vast majority of Morvan syndrome patients were male, with normal magnetic resonance imaging of the brain. CASE PRESENTATION: We report a female case presenting with a combination of bilateral leg pain, widespread myokymia, memory disturbance, seizure, hyperhidrosis and insomnia. She had antibodies targeting CASPR2 and LGI1, tested by the indirect immunofluorescence test, which demonstrated the diagnosis of typical Morvan syndrome as well as classical limbic encephalitis. Cranial MRI revealed bilateral hyper-intensity of the medial temporal lobe, insular lobe and basal ganglia on T2/FLAIR and DWI sequence. As the treatment carried on, her serum LGI1-Ab disappeared and her memory loss, seizure and confusion quickly relieved. But her peripheral presentations did not relieve until serum CASPR2-Ab turned negative. Intravenous immunoglobulin treatment showed limited efficacy while she achieved almost complete remission with corticosteroids therapy. CONCLUSIONS: This case provides a rare female resource of Morvan syndrome, which is the first patient with both CASPR2-Ab and LGI1-Ab positive Morvan syndrome in China and one of the few female patients with Morvan syndrome reported so far. Through the detailed analysis of her clinical course, the diverse and overlapping clinical phenotype of CASPR2-Ab and LGI1-Ab in patients with Morvan syndrome was obvious and interesting. PMID- 26983966 TI - Psychobiology and treatment of borderline personality disorder. AB - Borderline personality disorder can be characterized in terms of a profile of abnormal deviations on multiple personality dimensions using the temperament and character inventory (TCI). Borderline patients show poor character development, including low TCI self-directedness (irresponsible, blaming) and low TCI cooperativeness (hostile, intolerant). Their temperament is explosive or unstable due to a combination of high TCI harm avoidance (anxious, shy), high TCI novelty seeking (impulsive, quick-tempered), and low reward dependence (cold, aloof). Consequently they are usually dysthymic with an admixture of anxiety and anger, and regulate their social problems and intense emotions in immature ways. Genetic and psychobiological studies have led to identification of biological correlates of each of the TCI dimensions of personality, including individual differences in regional brain activity, psychophysiological variables, neuroendocrine abnormalities and specific gene polymorphisms. Each dimension of personality involves complex non-linear interaction of multiple genetic and environmental factors and, in turn, each personality dimension interacts with the others in influencing the way an individual directs and adapts to his or her life experiences. Systematic clinical trials have shown that these personality variables predict the response to pharmacological and psychotherapeutic treatments. For example, high harm avoidance and low self-directedness predict slower response and more rapid relapse with both antidepressants and cognitive behavioral therapy. Treatment with drugs and/or psychotherapy can be individually matched to the patient's profile of temperament and character traits, rather than treating a heterogeneous group of patients as if they had a discrete, homogeneous illness. Fundamental change in cognitive schemas depends on attention to all aspects of character, especially self-transcendence, which has previously been neglected in cognitive-behavioral therapy. Personality integration requires non resistance to our natural intuitive awareness, rather than intensified intellectual and emotional defenses. PMID- 26983962 TI - Chronic granulomatous disease. AB - INTRODUCTION: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent, life-threatening bacterial and fungal infections of the skin, the airways, the lymph nodes, the liver, the brain and the bones. Frequently found pathogens are Staphylococcus aureus, Aspergillus species, Klebsiella species, Burkholderia cepacia, Serratia marcescens and Salmonella species. SOURCES OF DATA: CGD is a rare (~1:250 000 individuals) disease caused by mutations in any one of the five components of the NADPH oxidase in phagocytic leucocytes. This enzyme generates superoxide and is essential for intracellular killing of pathogens by phagocytes. AREAS OF AGREEMENT: CGD patients suffer not only from life-threatening infections, but also from excessive inflammatory reactions. AREAS OF CONTROVERSY: Neither the cause of these inflammatory reactions nor the way to treat them is clear. AREAS TIMELY FOR DEVELOPING RESEARCH: Patient selection for and timing of bone marrow transplantation along with gene therapy. PMID- 26983967 TI - Serotonin, personality and borderline personality disorder. AB - Serotonin is one of the neurotransmitters implicated in normal personality. Many psychobiological models of personality include some dimensions related to serotonin. For instance, the harm avoidance dimension of the biosocial model developed by Cloninger is related to serotonergic activity. Higher scores on the harm avoidance dimension should theoretically reflect increased serotonergic activity. However, correlation studies related serotonin activity to harm avoidance dimension have not yielded consistent findings. These controversial results are probably related to the complexity of the neurotransmitter systems, and the different assessment techniques used in these studies. Finally, recent genetic studies have examined the association between personality dimensions and serotonergic receptor polymorphisms with mixed results. Serotonin is not only related to some dimensions of normal personality. Several psychopathological disorders are associated with serotonergic dysfunction. More particularly, borderline personality disorder (BPD) can be defined by many of the symptoms associated with serotonergic dysregulation, including affective lability, suicidal behaviours, impulsivity and loss of impulse control. Indeed, several reports have demonstrated the efficacy of selective serotonin re-uptake drugs in treating the depressive and impulsive symptoms of patients with BPD. Moreover, some challenge studies have reported a lower serotonergic activity in BPD. Because these challenges are not specific, we have assessed the serotonergic activity in BPD with the flesinoxan challenge. Preliminary results showed that the prolactine responses to flesinoxan were significantly lower in BPD patients compared to those observed in controls. PMID- 26983963 TI - The neglected role of abdominal compliance in organ-organ interactions. AB - This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901. PMID- 26983969 TI - An object relations perspective on borderline personality. AB - One of the principal formulations of borderline personality disorder is based on object relations theory, a component of psychoanalytic theory. To remain relevant, psychoanalytic formulations must find support from empirical research. After summarizing the object relations understanding of borderline personality, the authors review studies in biological neuroscience, developmental psychology and cognitive science related to the fundamental concepts of object relations theory as it aplies to borderline pathology. This review suggests that these empirical studies support psychoanalytic formulations originally derived from clinical practice and observation. PMID- 26983968 TI - Affect regulation in borderline personality disorder: experimental findings from psychophysiology and functional neuroimaging. AB - BACKGROUND: Intense and rapidly changing mood states are a major feature of borderline personality disorder (BPD), which is thought to arise from affective vulnerability. OBJECTIVE: There have been only a few studies investigating affective processing in BPD, and particularly neither psychophysiological nor neurofunctional correlates of abnormal emotional processing have been identified so far. METHODS: Studies are reported using psychophysiological or functional neuroimaging methodology. RESULTS: The psychophysiological study did not indicate a general emotional hyperresponsiveness in BPD. Low autonomic arousal seemed to reflect dissociative states in borderline subjects experiencing intense emotions. In the functional magnetic resonance imaging study enhanced amygdala activation was found in BPD, and it is suggested to reflect the intense and slowly subsiding emotions commonly observed in response to even low-level stressors. CONCLUSIONS: Implications for psychotherapy are discussed. PMID- 26983970 TI - In-patient treatment of borderline personality disorder: convergences and divergences between a psychoanalytical and a cognitive-behavioral approach. AB - For more than 20 years, patients with borderline personality disorder have been treated as in-patients in the UC St-Jozef in Kortenberg, Belgium. The majority of these patients were treated in a psychoanalytical or a behavior therapy ward. During these years, the treatment programs of these wards were gradually adjusted to the challenges provided by these patients. In this paper, we will describe the process of change that both wards have experienced. We will highlight similarities and differences between the approaches that are the result of an evolution over years. In both approaches, there is a strong emphasis on training and support for staff. While the psychoanalytical ward uses a group approach, the behavior therapy ward evolves towards a more individualized treatment. PMID- 26983971 TI - Psychiatric management of severe somatoform disorders in childhood and adolescence. AB - BACKGROUND: Unexplained medical symptoms are common in children. They constitute the main feature of somatoform disorders of childhood (i.e. pain disorders, conversion disorder and chronic fatigue syndrome or neurasthenia). OBJECTIVE: To describe assessment and treatment strategies for severe somatoform disorders of childhood. METHODS: Review of recommendations for clinical practice and clinical trials. RESULTS: A number of specific techniques have been described. Clinical accounts indicate that many children benefit and can recover. There is some empirical evidence supporting the beneficial effects of techniques such as family cognitive-behavioural therapy and relaxation technique for the less severe disorders. CONCLUSIONS: Existing helpful clinical guidelines require empiric validation. PMID- 26983972 TI - Outcome in adolescent anorexia nervosa. AB - The present paper compares course and outcome of adolescent anorexia nervosa to that of adult onset forms. In recent studies earlier onset of anorexia nervosa was associated with higher recovery rates and a lower mortality, although even in adolescent patients anorexia nervosa takes a prolonged course. A chronic eating disorder bears a high risk of other comorbid psychiatric or personality disorders. The most prevalent disturbances were anxiety and affective disorders and anxious-fearful-obsessive personality disorders, respectively. Patients who substantially overcame their eating disorder did not differ from normal controls in respect to psychosocial functioning, e.g. family relationships, partnership and occupational status. These results should encourage us to treat the eating disorder vigorously. PMID- 26983973 TI - Pathophysiology of autism: current opinions. AB - Research on the neurochemical aspects of the pathophysiology of autism is still increasing and publications are abundant. In this paper we reviewed significant data from the last decade and recent research results from our center. We focused on molecules influencing the central nervous system (CNS) and consecutively responsible for typical autistic behavior. We highlighted the mutual relationship between the serotonergic, immunological and endocrinological system and the interaction of these three pivotal systems with predisposing (genetic)and external (pre-, peri- and postnatal) conditions and xenobiotics. We stressed the influence of age, pubertal stage, sex, race and IQ on biological data. There is growing evidence that the complexity and variability of those interactions might be responsible for the heterogeneity of behavioral phenotypes and biological findings in Autism. Genetic, neuroanatomical and neurophysiological data were mentioned according their relevance to neurochemical opinions. PMID- 26983975 TI - Roles of Long Non-Coding RNA CCAT2 in Cervical Cancer Cell Growth and Apoptosis. AB - BACKGROUND: This study aimed to analyze the potential function of lncRNA CCAT2 in cervical cancer cell proliferation and apoptosis. MATERIAL/METHODS: Expression level of CCAT2 in cervical cancer cell lines (HeLa, CaSki, and SiHa) was detected by quantitative real-time PCR. CCAT2 knockdown was established by transfecting siRNA into human cervical cancer cells. Its effects on cell proliferation were studied using cell-counting kit-8 assay. The effect of CCAT2 on cervical cancer cells cycle and apoptosis was assessed by flow cytometry assay. RESULTS: CCK8 assay showed that CCAT2 knockdown inhibited cell proliferation in HeLa, CaSki, and SiHa cells. The flow cytometry confirmed the results that knockdown of CCAT2 could induce cervical cancer cells cycle G1 phase arrestment and trigger the cells apoptosis. CONCLUSIONS: LncRNA CCAT2 promoted the proliferation and survival of cervical cancer cells. PMID- 26983974 TI - Reasons for not starting antiretroviral therapy in HIV-1-infected individuals: a changing landscape. AB - PURPOSE: A cross-sectional survey was conducted to better understand why chronically HIV-1-infected individuals stratified by CD4 count (<=349; 350-499; >=500 cells/MUL) were not on antiretroviral therapy (ART). METHODS: Before the consultation, treatment-naive patients and their physicians independently completed a 90-item-questionnaire about barriers and their readiness to start/defer ART. The study was carried out at 34 sites in nine countries in Europe and Australia. RESULTS: Between December 2011 and October 2012, 508 pairs of patient- and physician-questionnaires were completed. 426 (84 %) patients were male and 39 (8 %), 138 (27 %), and 330 (65 %) were in the three stratified groups based on CD4 count, respectively. In the category 'Body and symptoms' the most commonly identified reason for patients not to start was: "As long as I feel good I don't have to take medication" (44 %). Less than 20 % of respondents indicated fears of side effects and toxicity or problems to manage pills. Most patients were in the lowest stage of treatment-readiness (N = 323, 68 %), especially patients with CD4 cells >=500 cells/MUL (N = 240, 79 %). Physicians answered in 92 (18 %) cases that ART was not indicated for CD4 cells <500 cells/MUL. Main reasons for physicians not starting treatment for these patients were their perception that patients were 'too depressed' (13 %) or that they had not known them long enough (13 %). CONCLUSIONS: Nowadays patient-barriers to ART are commonly related to health-and treatment-beliefs compared to fear of toxicity or ART manageability in the past. This new barrier pattern seems to reflect the era of well tolerated, easier ART regimens and has to be considered in light of the new recommendations to treat all HIV-infected individuals regardless of the CD4 cell count. PMID- 26983976 TI - Descemet's Membrane Endothelial Keratoplasty: Risk of Immunologic Rejection Episodes after Discontinuing Topical Corticosteroids. AB - PURPOSE: To assess the risk of immunologic rejection episodes if topical corticosteroids are discontinued 1 year after Descemet's membrane endothelial keratoplasty (DMEK) compared with continued once-per-day use. DESIGN: Prospective, longitudinal, parallel-group study. PARTICIPANTS: A total of 400 eyes of 259 DMEK recipients, aged 23 to 90 years. METHODS: Patients were enrolled 1 year after DMEK and allowed to choose whether to stop or continue once-daily topical corticosteroids to maximize compliance. Fellow eyes were eligible for enrollment because the donor grafts were independent. Participants were examined at 1, 3, 6, and 12 months during the second year after DMEK. Results were assessed using Kaplan-Meier survival analysis. MAIN OUTCOME MEASURES: Incidence of immunologic rejection episodes. RESULTS: Steroids were discontinued in 277 eyes (no steroid group) and continued once per day in 123 eyes (steroid group). The subject demographics were well balanced across groups; 99% of the subjects were white, and 95% of the grafts were performed to treat Fuchs' dystrophy. The cumulative incidence of rejection episodes was significantly greater in the no steroid group (6% vs. 0% in the steroid group; P = 0.013). Thirteen of 14 rejection episodes (all in the no steroid group) resolved with resumption of topical corticosteroids. Overall, 1 of 277 grafts (0.4%) failed in the no steroid group, and none failed in the steroid group during the second year after DMEK (P = 0.49). The endothelial cell loss between 1 and 2 years was comparable in the no steroid and steroid groups (6.4%+/-12% vs. 5.6%+/-14%, respectively; P = 0.67). CONCLUSIONS: Continued once-per-day use of a topical corticosteroid, even a weak one, was protective against rejection episodes during the second year after DMEK, whereas 6% experienced a rejection episode when steroids were discontinued. Among the 364 eyes that completed 12 months' follow-up, only 1 graft (0.27%) failed. PMID- 26983977 TI - Rectus Pulley Displacements without Abnormal Oblique Contractility Explain Strabismus in Superior Oblique Palsy. AB - PURPOSE: Using high-resolution magnetic resonance imaging (MRI), we investigated whether rectus pulleys are significantly displaced in superior oblique (SO) palsy and whether displacements account for strabismus patterns. DESIGN: Prospective case-control study. PARTICIPANTS: Twenty-four patients diagnosed with SO palsy based on atrophy of the SO muscle on MRI and 19 age-matched orthotropic control subjects. METHODS: High-resolution, surface coil MRI scans were obtained in multiple, contiguous, quasicoronal planes during monocular central gaze fixation. Pulley locations in oculocentric coordinates in the following subgroups of patients with SO palsy were compared with normal results in subgroups of patients with SO palsy: unilateral versus bilateral, congenital versus acquired, and isotropic (round) versus anisotropic (elongated) SO atrophy. Expected effects of pulley displacements were modeled using Orbit 1.8 (Eidactics, San Francisco, CA) computational simulation. MAIN OUTCOME MEASURES: Rectus pulley positions and ocular torsion. RESULTS: Rectus pulleys typically were displaced in SO palsy. In unilateral SO palsy, on average the medial rectus (MR) pulley was displaced 1.1 mm superiorly, the superior rectus (SR) pulley was displaced 0.8 mm temporally, and the inferior rectus (IR) pulley was displaced 0.6 mm superiorly and 0.9 mm nasally from normal. Displacements were similar in bilateral SO palsy, with the SR pulley additionally displaced 0.9 mm superiorly. However, the lateral rectus pulley was not displaced in either unilateral or bilateral SO palsy. The SR and MR pulleys were displaced in congenital SO palsy, whereas the IR and MR pulleys were displaced in acquired palsy. Pulley positions did not differ between isotropic and anisotropic palsy or between patients with cyclotropia of less than 7 degrees versus cyclotropia of 7 degrees or more. Simulations predicted that the observed pulley displacements alone could cause patterns of incomitant strabismus typical of SO palsy, without requiring any abnormality of SO or inferior oblique strength. CONCLUSIONS: Rectus pulley displacements alone, without abnormal oblique muscle contractility, can create the clinical patterns of incomitant strabismus in SO palsy. This finding supports accumulating evidence that clinical binocular misalignment patterns are not reliable indicators of contractile function of the SO muscle. Ocular torsion does not correlate with and thus cannot account for pulley displacements in SO palsy. PMID- 26983979 TI - A report that Fukushima residents are concerned about radiation from Land, Food and Radon. AB - The Great East Japan Earthquake and subsequent TEPCO Fukushima Daiichi nuclear disaster occurred on 11 March 2011, which caused the leakage of radioactive materials into the environment. In this study, we report public concerns about radiation in Fukushima and Tokyo almost one year after the nuclear disaster. We examined the public concerns by analyzing the data from 1022 participants, 555 in Fukushima and 467 in Tokyo. They were asked whether they were concerned about radiation from some of six different types of sources, which could be answered in a binary way, 'yes' or 'no'. We found not only similarities, but also significant differences in the degrees of concerns between Fukushima residents and Tokyo ones. Fukushima residents more concerned about radiation from land, food and radon in larger rate than that of Tokyo ones, while Tokyo residents were concerned about radiation from medical care. Residents in neither location were concerned about radiation from space. Our results suggested that careful risk communication should be undertaken, adaptively organized depending on location and other factors, e.g. comprehension about radiation, presence of the experience of evacuation, and also age and gender of the people. PMID- 26983978 TI - Stereotactic body radiotherapy for T3 and T4N0M0 non-small cell lung cancer. AB - To evaluate the outcomes and feasibility of stereotactic body radiotherapy (SBRT) for cT3 and cT4N0M0 non-small cell lung cancer (NSCLC), 25 patients with localized primary NSCLC diagnosed as cT3 or cT4N0M0, given SBRT between May 2005 and July 2013, were analyzed. All patients had inoperable tumors. The major reasons for tumors being unresectable were insufficient respiratory function for curative resection, advanced age (>80 years old) or technically inoperable due to invasion into critical organs. The median patient age was 79 years (range; 60 86). The median follow-up duration was 25 months (range: 5-100 months). The 2 year overall survival rates for T3 and T4 were 57% and 69%, respectively. The 2 year local control rates for T3 and T4 were 91% and 68%, respectively. As for toxicities, Grade 0-1, Grade 2 and Grade 3 radiation pneumonitis occurred in 23, 1 and 1 patient, respectively. No other acute or symptomatic late toxicities were reported. Thirteen patients who had no local, mediastinal or intrapulmonary progression at one year after SBRT underwent pulmonary function testing. The median variation in pre-SBRT and post-SBRT forced expiratory volume in 1 s (FEV1) values was -0.1 (-0.8-0.8). This variation was not statistically significant (P = 0.56). Forced vital capacity (FVC), vital capacity (VC), %VC and %FEV1 also showed no significant differences. SBRT for cT3 and cT4N0M0 NSCLC was both effective and feasible. Considering the favorable survival and low morbidity rate, SBRT is a potential treatment option for cT3 and cT4N0M0 NSCLC. PMID- 26983980 TI - Evaluation of the intake of radon through skin from thermal water. AB - The biokinetics of radon in the body has previously been studied with the assumption that its absorption through the skin is negligibly small. This assumption would be acceptable except in specific situations, such as bathing in a radon hot spring where the radon concentration in thermal water is far higher than that in air. The present study focused on such a situation in order to better understand the biokinetics of radon. To mathematically express the entry of radon through the skin into the body, we first modified the latest sophisticated biokinetic model for noble gases. Values of an important parameter for the model-the skin permeability coefficient K (m s(-1))-were derived using data from previous human studies. The analysis of such empirical data, which corresponded to radon concentrations in the air exhaled by subjects during and following bathing in radon-rich thermal water, revealed that the estimated K values had a log-normal distribution. The validity of the K values and the characteristics of the present model are then discussed. Furthermore, the impact of the intake of radon or its progeny via inhalation or skin absorption on radiation dose was also assessed for possible exposure scenarios in a radon hot spring. It was concluded that, depending on the radon concentration in thermal water, there might be situations in which the dose contribution resulting from skin absorption of radon is comparable to that resulting from inhalation of radon and its progeny. This conclusion can also apply to other therapeutic situations (e.g. staying in the pool for a longer period). PMID- 26983982 TI - Reirradiation using robotic image-guided stereotactic radiotherapy of recurrent head and neck cancer. AB - The purpose of this study was to examine the prognosis for patients with head and neck cancer after reirradiation using Cyberknife stereotactic body irradiation with special focus on mucosal ulceration. We conducted a retrospective multi institutional review of 107 patients with previously irradiated head and neck cancer. The median follow-up time for all patients was 15 months, and the 2-year overall survival rate was 35%. Significant prognostic factors for overall survival were primary site (nasopharynx versus other sites), presence of ulceration, and PTV volume. Detailed analysis of ulceration showed a lower response rate (28%) in the ulceration (+) group than the ulceration (-) group (63%; P = 0.0045). The 2-year overall survival rates were 8% in the ulceration (+) group and 42.7% (P = 0.0001) in the ulceration (-) group, respectively. We recorded 22 severe toxicities, including 11 patients with carotid blow-out syndrome (CBOS), which was fatal in 9 patients. CBOS occurred in 6 patients with ulceration (6/25; 24%), and 5 patients experienced CBOS without ulceration (5/82; 6%; P=0.027). In conclusion, ulceration is an important prognostic factor, not only for adverse events but also for survival after reirradiation using CyberKnife. PMID- 26983981 TI - Stereotactic body radiotherapy for patients with oligometastases from colorectal cancer: risk-adapted dose prescription with a maximum dose of 83-100 Gy in five fractions. AB - We previously reported that the local control of pulmonary metastases from colorectal cancer (CRC) following stereotactic body radiotherapy (SBRT) with moderate prescription dose was relatively worse. We investigated the treatment outcomes and toxicities of patients with oligometastases from CRC treated by SBRT using risk-adapted, very high- and convergent-dose regimens. Among patients referred for SBRT from August 2011 to January 2015, those patients were extracted who had liver or pulmonary metastases from CRC, and they were treated with a total dose of 50-60 Gy in five fractions prescribed to the 60% isodose line of the maximum dose covering the surface of the planning target volume. Concurrent administration of chemotherapy was not admitted during SBRT, while neoadjuvant or adjuvant chemotherapy was allowed. A total of 21 patients (12 liver, 9 lung) with 28 oligometastases were evaluated. The median follow-up duration was 27.5 months (range: 6.5-43.3 months). Four patients were treated with SBRT as a series of initial treatments, and 17 patients were treated after recurrent oligometastases. The local control rates at 1 and 2 years from the start of SBRT were 100%. The disease-free and actuarial overall survival rates were 62% and 55%, and 79% and 79%, respectively. No severe toxicities (>=grade 3) occurred during follow-up. The outcomes following high-dose SBRT were excellent. This treatment can provide an alternative to the surgical resection of oligometastases from CRC. Prospective studies are needed to validate the effectiveness of SBRT. PMID- 26983983 TI - Preliminary analysis of the sequential simultaneous integrated boost technique for intensity-modulated radiotherapy for head and neck cancers. AB - The aim of this study was to compare three strategies for intensity-modulated radiotherapy (IMRT) for 20 head-and-neck cancer patients. For simultaneous integrated boost (SIB), doses were 66 and 54 Gy in 30 fractions for PTVboost and PTVelective, respectively. Two-phase IMRT delivered 50 Gy in 25 fractions to PTVelective in the First Plan, and 20 Gy in 10 fractions to PTVboost in the Second Plan. Sequential SIB (SEQ-SIB) delivered 55 Gy and 50 Gy in 25 fractions, respectively, to PTVboost and PTVelective using SIB in the First Plan and 11 Gy in 5 fractions to PTVboost in the Second Plan. Conformity indexes (CIs) (mean +/- SD) for PTVboost and PTVelective were 1.09 +/- 0.05 and 1.34 +/- 0.12 for SIB, 1.39 +/- 0.14 and 1.80 +/- 0.28 for two-phase IMRT, and 1.14 +/- 0.07 and 1.60 +/ 0.18 for SEQ-SIB, respectively. CI was significantly highest for two-phase IMRT. Maximum doses (Dmax) to the spinal cord were 42.1 +/- 1.5 Gy for SIB, 43.9 +/- 1.0 Gy for two-phase IMRT and 40.3 +/- 1.8 Gy for SEQ-SIB. Brainstem Dmax were 50.1 +/- 2.2 Gy for SIB, 50.5 +/- 4.6 Gy for two-phase IMRT and 47.4 +/- 3.6 Gy for SEQ-SIB. Spinal cord Dmax for the three techniques was significantly different, and brainstem Dmax was significantly lower for SEQ-SIB. The compromised conformity of two-phase IMRT can result in higher doses to organs at risk (OARs). Lower OAR doses in SEQ-SIB made SEQ-SIB an alternative to SIB, which applies unconventional doses per fraction. PMID- 26983984 TI - The complexity of microRNAs in human cancer. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules that have key regulatory roles in cancer, acting as both oncogenes and tumor suppressors. Due to the potential roles of miRNAs in improving cancer prognostic, predictive, diagnostic and therapeutic approaches, they have become an area of intense research focus in recent years. MiRNAs harbor attractive features allowing for translation to the clinical world, such as relatively simple extraction methods, resistance to molecular degradation, and ability to be quantified. Numerous prognostic, predictive and diagnostic miRNA signatures have been developed. To date however, miRNA analysis has not been adopted for routine clinical use. The objectives of this article are to provide an overview of miRNA research and review a selection of miRNA studies in breast cancer, cervical cancer, sarcoma, and nasopharyngeal carcinoma to highlight advances and challenges in miRNA cancer research. PMID- 26983985 TI - Hypoxia-inducible factor 1-mediated characteristic features of cancer cells for tumor radioresistance. AB - Tumor hypoxia has been attracting increasing attention in the fields of radiation biology and oncology since Thomlinson and Gray detected hypoxic cells in malignant solid tumors and showed that they exert a negative impact on the outcome of radiation therapy. This unfavorable influence has, at least partly, been attributed to cancer cells acquiring a radioresistant phenotype through the activation of the transcription factor, hypoxia-inducible factor 1 (HIF-1). On the other hand, accumulating evidence has recently revealed that, even though HIF 1 is recognized as an important regulator of cellular adaptive responses to hypoxia, it may not become active and induce tumor radioresistance under hypoxic conditions only. The mechanisms by which HIF-1 is activated in cancer cells not only under hypoxic conditions, but also under normoxic conditions, through cancer specific genetic alterations and the resultant imbalance in intermediate metabolites have been summarized herein. The relevance of the HIF-1-mediated characteristic features of cancer cells, such as the production of antioxidants through reprogramming of the glucose metabolic pathway and cell cycle regulation, for tumor radioresistance has also been reviewed. PMID- 26983986 TI - Threshold doses and prediction of visually apparent liver dysfunction after stereotactic body radiation therapy in cirrhotic and normal livers using magnetic resonance imaging. AB - The purpose of the present study was to investigate the threshold dose for focal liver damage after stereotactic body radiation therapy (SBRT) in cirrhotic and normal livers using magnetic resonance imaging (MRI). A total of 64 patients who underwent SBRT for liver tumors, including 54 cirrhotic patients with hepatocellular carcinoma (HCC) and 10 non-cirrhotic patients with liver metastases, were analyzed. MRI was performed 3-6 months after SBRT, using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced T1-weighted sequences. All MRI datasets were merged with 3D dosimetry data. All dose distributions were corrected to the biologically effective dose using the linear quadratic model with an assumed alpha/beta ratio of 2 Gy. The development of liver dysfunction was validly correlated with isodose distribution. The median biologically effective dose (BED2) that provoked liver dysfunction was 57.3 (30.0 227.9) and 114.0 (70.4-244.9) Gy in cirrhotic and normal livers, respectively (P = 0.0002). The BED2 associated with a >5% risk of liver dysfunction was 38.5 in cirrhotic livers and 70.4 Gy in normal livers. The threshold BED2 for liver dysfunction was not significantly different between Child-Pugh A and B patients (P = 0.0719). Moreover, the fractionation schedule was not significantly correlated with threshold BED2 for liver dysfunction in the cirrhotic liver (P = 0.1019). In the cirrhotic liver, fractionation regimen and Child-Pugh classification did not significantly influence the threshold BED2 for focal liver damage after SBRT. We suggest that the threshold BED2 for liver dysfunction after SBRT is 40 and 70 Gy in the cirrhotic and normal liver, respectively. PMID- 26983988 TI - Two-fraction high-dose-rate brachytherapy within a single day combined with external beam radiotherapy for prostate cancer: single institution experience and outcomes. AB - We investigated the outcomes of treatment for patients with localized prostate cancer (PCa) treated with 3D conformal radiation therapy (3D-CRT) followed by two fraction high-dose-rate brachytherapy within a single day (2-fr.-HDR-BT/day) at a single institution. A total of 156 consecutive Asian males (median age, 67 years) were enrolled. To compare our findings with those of other studies, we analyzed our results using the D'Amico classification, assigning the patients to low- ( N =: 5; 3.2%), intermediate- ( N =: 36; 23.1%) and high-risk ( N =: 115; 73.7%) groups (Stage T3 PCa patients were classified as high-risk). One patient in the D'Amico low-risk group (20%), 13 intermediate-risk patients (36.1%) and 99 high risk patients (86.1%) underwent androgen deprivation therapy. We administered a prescription dose of 39 Gy in 13 fractions of 3D-CRT combined with 18 Gy of HDR BT in two 9-Gy fractions delivered within a single day. We did not distinguish between risk groups in determining the prescription dose. The median follow-up period was 38 months. Of the 156 patients, one died from primary disease and five died from other diseases. The 3-year overall survival (OS) rates were 100%, 100% and 93.7%, and the 3-year 'biochemical no evidence of disease (bNED)' rates were 100%, 100% and 96.9% for the D'Amico low-, intermediate- and high-risk groups, respectively. No patient developed >= Grade 3 early toxicity. The Grade 3 late genitourinary toxicity rate was 2.6%, and no >= Grade 3 late gastrointestinal toxicity occurred. The efficacy and safety of this study were satisfactory, and longer-term follow-up is necessary. PMID- 26983987 TI - The impact of hypoxia and its modification of the outcome of radiotherapy. AB - Since the initial observations made at the beginning of the last century, it has been established that solid tumors contain regions of low oxygenation (hypoxia). Tumor cells can survive in these hypoxic conditions and are a major factor in tumor radioresistance. This significance has resulted in hypoxia becoming the most cited biological topic in translational radiation oncology. Identifying hypoxic cells in human tumors has become paramount, and the ability to do this has been improved by the help of new imaging techniques and the use of predictive gene profiles. Substantial data confirm the presence of hypoxia in many types of human tumors, although with considerable heterogeneity among individual tumors. Various approaches have been investigated for eliminating the hypoxic population. These include increasing oxygen availability, directly radiosensitizing or killing the hypoxic cells, indirectly affecting them by targeting the tumor vascular supply, increasing the radiation dose to this resistant population, or by using radiation with a high linear energy transfer, for which hypoxia is believed to be less of an issue. Many of these approaches have undergone controlled clinical trials during the last 50 years, and the results have shown that hypoxic radiation resistance can indeed be overcome. Thus, ample data exists to support a high level of evidence for the benefit of hypoxic modification. However, such hypoxic modification still has no impact on general clinical practice. In this review we summarize the biological rationale, and the current activities and trials, related to identifying and overcoming hypoxia in modern radiotherapy. PMID- 26983990 TI - Characteristics of interventional cardiologists and their work practices for the study on radiation-induced lens opacities based on the methodology developed by ELDO-preliminary results. AB - Preliminary results of the Polish epidemiology study on eye lens opacities among interventional cardiologists (ICs), based on the methodology proposed by ELDO (epidemiological studies of radio-induced cataracts in interventional cardiologists and radiologists: methodology implementation), are presented. The aim of the study is to test the hypothesis concerning the excess risk of cataract in the group of ICs. The first results concern the study population characteristics, including the most important confounding factors for cataract, as well as a detailed description of the work practices in interventional cardiology needed in order to reconstruct the cumulative eye lens dose. The data from 69 ICs and 23 controls collected based on the general medical questionnaire and the occupational questionnaire (for ICs only) were analyzed. The mean age of ICs and of the control group was 41 and 44, respectively, while the mean duration of work for exposed physicians was 9 years. The analysis of the data from the occupational questionnaire concerning the procedures performed, the use of various access routes, as well as radiation protection tools (eye lens glasses, ceiling suspended transparent shield, etc.) are also presented. On the basis of this information and additional assumptions about the doses per procedure (as well as reduction factors for various types of radiation measures), the cumulative doses to the eye lens of ICs were evaluated. They ranged up to 1.55 Sv and 0.4 Sv for left and right eye, respectively; however, the dose to only 3% of ICs exceeded the new threshold for development of eye lens opacities (0.5 Gy) proposed by the ICRP. PMID- 26983989 TI - Opposing roles of RNF8/RNF168 and deubiquitinating enzymes in ubiquitination dependent DNA double-strand break response signaling and DNA-repair pathway choice. AB - The E3 ubiquitin ligases ring finger protein (RNF) 8 and RNF168 transduce the DNA double-strand break (DSB) response (DDR) signal by ubiquitinating DSB sites. The depletion of RNF8 or RNF168 suppresses the accumulation of DNA-repair regulating factors such as 53BP1 and RAP80 at DSB sites, suggesting roles for RNF8- and RNF168-mediated ubiquitination in DSB repair. This mini-review provides a brief overview of the RNF8- and RNF168-dependent DDR-signaling and DNA-repair pathways. The choice of DNA-repair pathway when RNF8- and RNF168-mediated ubiquitination dependent DDR signaling is negatively regulated by deubiquitinating enzymes (DUBs) is reviewed to clarify how the opposing roles of RNF8/RNF168 and DUBs regulate ubiquitination-dependent DDR signaling and the choice of DNA-repair pathway. PMID- 26983992 TI - Zinc-Finger Transcription Factor ZAT6 Positively Regulates Cadmium Tolerance through the Glutathione-Dependent Pathway in Arabidopsis. AB - Cadmium (Cd) is an environmental pollutant with high toxicity to animals and plants. It has been established that the glutathione (GSH)-dependent phytochelatin (PC) synthesis pathway is one of the most important mechanisms contributing to Cd accumulation and tolerance in plants. However, the transcription factors involved in regulating GSH-dependent PC synthesis pathway remain largely unknown. Here, we identified an Arabidopsis (Arabidopsis thaliana) Cd-resistant mutant xcd2-D (XVE system-induced cadmium-tolerance2) using a forward genetics approach. The mutant gene underlying xcd2-D mutation was revealed to encode a known zinc-finger transcription factor, ZAT6. Transgenic plants overexpressing ZAT6 showed significant increase of Cd tolerance, whereas loss of function of ZAT6 led to decreased Cd tolerance. Increased Cd accumulation and tolerance in ZAT6-overexpressing lines was GSH dependent and associated with Cd-activated synthesis of PC, which was correlated with coordinated activation of PC-synthesis related gene expression. By contrast, loss of function of ZAT6 reduced Cd accumulation and tolerance, which was accompanied by abolished PC synthesis and gene expression. Further analysis revealed that ZAT6 positively regulates the transcription of GSH1, GSH2, PCS1, and PCS2, but ZAT6 is capable of specifically binding to GSH1 promoter in vivo. Consistently, overexpression of GSH1 has been shown to restore Cd sensitivity in the zat6-1 mutant, suggesting that GSH1 is a key target of ZAT6. Taken together, our data provide evidence that ZAT6 coordinately activates PC synthesis-related gene expression and directly targets GSH1 to positively regulate Cd accumulation and tolerance in Arabidopsis. PMID- 26983991 TI - Pipeline for the identification and classification of ion channels in parasitic flatworms. AB - BACKGROUND: Ion channels are well characterised in model organisms, principally because of the availability of functional genomic tools and datasets for these species. This contrasts the situation, for example, for parasites of humans and animals, whose genomic and biological uniqueness means that many genes and their products cannot be annotated. As ion channels are recognised as important drug targets in mammals, the accurate identification and classification of parasite channels could provide major prospects for defining unique targets for designing novel and specific anti-parasite therapies. Here, we established a reliable bioinformatic pipeline for the identification and classification of ion channels encoded in the genome of the cancer-causing liver fluke Opisthorchis viverrini, and extended its application to related flatworms affecting humans. METHODS: We built an ion channel identification + classification pipeline (called MuSICC), employing an optimised support vector machine (SVM) model and using the Kyoto Encyclopaedia of Genes and Genomes (KEGG) classification system. Ion channel proteins were first identified and grouped according to amino acid sequence similarity to classified ion channels and the presence and number of ion channel like conserved and transmembrane domains. Predicted ion channels were then classified to sub-family using a SVM model, trained using ion channel features. RESULTS: Following an evaluation of this pipeline (MuSICC), which demonstrated a classification sensitivity of 95.2 % and accuracy of 70.5 % for known ion channels, we applied it to effectively identify and classify ion channels in selected parasitic flatworms. CONCLUSIONS: MuSICC provides a practical and effective tool for the identification and classification of ion channels of parasitic flatworms, and should be applicable to a broad range of organisms that are evolutionarily distant from taxa whose ion channels are functionally characterised. PMID- 26983997 TI - 25 years of Panic Disorder research at Maastricht University. PMID- 26983994 TI - Role of SKD1 Regulators LIP5 and IST1-LIKE1 in Endosomal Sorting and Plant Development. AB - SKD1 is a core component of the mechanism that degrades plasma membrane proteins via the Endosomal Sorting Complex Required for Transport (ESCRT) pathway. Its ATPase activity and endosomal recruitment are regulated by the ESCRT components LIP5 and IST1. How LIP5 and IST1 affect ESCRT-mediated endosomal trafficking and development in plants is not known. Here we use Arabidopsis mutants to demonstrate that LIP5 controls the constitutive degradation of plasma membrane proteins and the formation of endosomal intraluminal vesicles. Although lip5 mutants were able to polarize the auxin efflux facilitators PIN2 and PIN3, both proteins were mis-sorted to the tonoplast in lip5 root cells. In addition, lip5 root cells over-accumulated PIN2 at the plasma membrane. Consistently with the trafficking defects of PIN proteins, the lip5 roots showed abnormal gravitropism with an enhanced response within the first 4 h after gravistimulation. LIP5 physically interacts with IST1-LIKE1 (ISTL1), a protein predicted to be the Arabidopsis homolog of yeast IST1. However, we found that Arabidopsis contains 12 genes coding for predicted IST1-domain containing proteins (ISTL1-12). Within the ISTL1-6 group, ISTL1 showed the strongest interaction with LIP5, SKD1, and the ESCRT-III-related proteins CHMP1A in yeast two hybrid assays. Through the analysis of single and double mutants, we found that the synthetic interaction of LIP5 with ISTL1, but not with ISTL2, 3, or 6, is essential for normal plant growth, repression of spontaneous cell death, and post-embryonic lethality. PMID- 26983999 TI - The genetics of panic disorder: state of the art. AB - Panic disorder (PD) is a highly prevalent, debilitating disorder. The heritability of the disease has been estimated by twin studies to be between 30 and 60%. The vulnerability for PD overlaps with an increased risk of bipolar disorder in some families. Classical genetic methods such as linkage analysis and association studies have not yet identified genetic risk factors beyond doubt. However, two independent studies confirm linkage of a specific syndrome characterized by PD, bladder problems, severe headaches, mitral valve prolapse and thyroid dysfunction to genetic markers on chromosome 13q. Association studies, although showing divergent results, give some support to a causative role for the genes encoding for monoamine oxidase A (MAO-A), cholecystokinin (CCK) and catechol-O-methyltransferase (COMT). Finally, a somatic duplication of a 19-Mb region on chromosome 15 has been associated with PD, but this intriguing finding awaits confirmation. PMID- 26983998 TI - Panic disorder: from respiration to the homeostatic brain. AB - There is some experimental evidence to support the existence of a connection between panic and respiration. However, only recent studies investigating the complexity of respiratory physiology have revealed consistent irregularities in respiratory pattern, suggesting that these abnormalities might be a vulnerability factor to panic attacks. The source of the high irregularity observed, together with unpleasant respiratory sensations in patients with panic disorder (PD), is still unclear and different underlying mechanisms might be hypothesized. It could be the result of compensatory responses to abnormal respiratory inputs or an intrinsic deranged activity in the brainstem network shaping the respiratory rhythm. Moreover, since basic physiological functions in the organism are strictly interrelated, with reciprocal modulations and abnormalities in cardiac and balance system function having been described in PD, the respiratory findings might arise from perturbations of these other basic systems or a more general dysfunction of the homeostatic brain. Phylogenetically ancient brain circuits process physiological perceptions/sensations linked to homeostatic functions, such as respiration, and the parabrachial nucleus might filter and integrate interoceptive information from the basic homeostatic functions. These physiological processes take place continuously and subconsciously and only occasionally do they pervade the conscious awareness as 'primal emotions'. Panic attacks could be the expression of primal emotion arising from an abnormal modulation of the respiratory/homeostatic functions. PMID- 26984000 TI - The role of serotonin in panic: evidence from tryptophan depletion studies. AB - There has been growing interest in the role of serotonin (5-hydroxytryptamine, 5 HT) in anxiety, including pathological states such as panic disorder. The technique of tryptophan depletion (TD), which causes an acute, temporary and reversible reduction in brain 5-HT levels, is a useful minimally invasive paradigm to aid the research of the role of 5-HT in various disorders. This review discusses the evidence supporting the hypothesis that 5-HT function is of importance in the neurobiology of panic disorder and considers in more detail how our understanding has been influenced by work using the technique of TD. Possible avenues for future research are also discussed. PMID- 26983996 TI - The effects of attractive vs. repulsive instructional cuing on balance performance. AB - BACKGROUND: Torso-based vibrotactile feedback has been shown to improve postural performance during quiet and perturbed stance in healthy young and older adults and individuals with balance impairments. These systems typically include tactors distributed around the torso that are activated when body motion exceeds a predefined threshold. Users are instructed to "move away from the vibration". However, recent studies have shown that in the absence of instructions, vibrotactile stimulation induces small (~1 degrees ) non-volitional responses in the direction of its application location. It was hypothesized that an attractive cuing strategy (i.e., "move toward the vibration") could improve postural performance by leveraging this natural tendency. FINDINGS: Eight healthy older adults participated in two non-consecutive days of computerized dynamic posturography testing while wearing a vibrotactile feedback system comprised of an inertial measurement unit and four tactors that were activated in pairs when body motion exceeded 1 degrees anteriorly or posteriorly. A crossover design was used. On each day participants performed 24 repetitions of Sensory Organization Test condition 5 (SOT5), three repetitions each of SOT 1-6, three repetitions of the Motor Control Test, and five repetitions of the Adaptation Test. Performance metrics included A/P RMS, Time-in-zone and 95 % CI Ellipse. Performance improved with both cuing strategies but participants performed better when using repulsive cues. However, the rate of improvement was greater for attractive versus repulsive cuing. CONCLUSIONS: The results suggest that when the cutaneous signal is interpreted as an alarm, cognition overrides sensory information. Furthermore, although repulsive cues resulted in better performance, attractive cues may be as good, if not better, than repulsive cues following extended training. PMID- 26983995 TI - A Cation-Chloride Cotransporter Gene Is Required for Cell Elongation and Osmoregulation in Rice. AB - Rice (Oryza sativa) is characterized by having fibrous root systems; however, the molecular mechanisms underlying the root development are not fully understood. Here, we isolated a rice mutant with short roots and found that the mutant had a decreased cell size of the roots and shoots compared with wild-type rice. Map based cloning combined with whole-genome sequencing revealed that a single nucleotide mutation occurred in a gene, which encodes a putative cation-chloride cotransporter (OsCCC1). Introduction of OsCCC1 cDNA into the mutant rescued the mutant growth, indicating that growth defects of both the roots and shoots are caused by loss of function of OsCCC1. Physiological analysis showed that the mutant had a lower concentration of Cl(-) and K(+) and lower osmolality in the root cell sap than the wild type at all KCl supply conditions tested; however, the mutant only showed a lower Na(+) concentration at high external Na(+) Expression of OsCCC1 in yeast increased accumulation of K(+), Na(+), and Cl(-) The expression of OsCCC1 was found in both the roots and shoots, although higher expression was found in the root tips. Furthermore, the expression in the roots did not respond to different Na(+), K(+), and Cl(-) supply. OsCCC1 was expressed in all cells of the roots, leaf, and basal node. Immunoblot analysis revealed that OsCCC1 was mainly localized to the plasma membrane. These results suggest that OsCCC1 is involved in the cell elongation by regulating ion (Cl(-), K(+), and Na(+)) homeostasis to maintain cellular osmotic potential. PMID- 26984001 TI - Cholecystokinin and panic disorder. AB - Evidence for implication of cholecystokinin (CCK) in the neurobiology of panic disorder is reviewed through animal and human pharmacological studies. The results of these investigations raise two issues: (i) selectivity of action of CCK-2 agonists in anxiety disorders; and (ii) aberrations of the CCK system in anxiety disorders, both of which are discussed. PMID- 26984002 TI - Neuroimmunological parameters in panic disorder. AB - BACKGROUND: The interaction between immune cells, neurotransmitters and the neuroendocrinological systems plays a role in affective disorders, especially depression. Although panic disorder (PD) shares a lot of features with depression, it is clearly a distinct disorder. Reports on immunological parameters in PD don't provide a clear picture of the immunological status of PD patients. This can partly be attributed to methodological differences between studies and small patient groups. OBJECTIVE: The present study aims to assemble all studies on immunological parameters in PD in order to combine all available data to gain a broader perspective on this matter. METHOD: PubMed was searched for studies describing immunological parameters in PD patients without comorbid disorders or medication use. All studies had to include a healthy control group and the outcome measures had to be shared by at least one other study. RESULTS: Fourteen articles were found. Although the T-lymphocytic branch and the innate immune system were normal, the B-lymphocytic branch showed some differences between PD patients and healthy controls. B-cell counts were increased in PD patients, which was underlined by increased human leucocyte antigen (HLA)-DR counts and increased immunoglobulin A levels. However, B-cell activity following mitogen stimulation was normal. CONCLUSIONS: PD patients show increased B-cell numbers. The finding that B-cell activity is not increased can possibly be attributed to functional exhaustion of these cells. The meaning of this finding remains unclear, although it may be potentially important in affective disorders as the same has been found in depression. PMID- 26984003 TI - Symptom profiles of natural and laboratory panic attacks. AB - BACKGROUND: Little accurate information is available about the symptomatology of real-life panic attacks and about how well they are reproduced by an experimental model such as the 35% CO2 challenge. METHOD: Real-life panic symptoms were assessed in a group of 67 panic disorder patients, using daily life monitoring. Panic symptoms elicited by a 35% CO2 challenge were assessed in 61 panic disorder patients, and their frequency was compared with the real-life symptoms. RESULTS: The most frequent real-life symptoms were palpitations, dizziness and trembling. The 35% CO2 challenge reproduced well the majority of real-life symptoms. CONCLUSION: The findings suggest that the 35% CO2 challenge is a marker for spontaneous panic attacks, which are considered the core of panic disorder. PMID- 26983993 TI - Transcriptomic Signature of the SHATTERPROOF2 Expression Domain Reveals the Meristematic Nature of Arabidopsis Gynoecial Medial Domain. AB - Plant meristems, like animal stem cell niches, maintain a pool of multipotent, undifferentiated cells that divide and differentiate to give rise to organs. In Arabidopsis (Arabidopsis thaliana), the carpel margin meristem is a vital meristematic structure that generates ovules from the medial domain of the gynoecium, the female floral reproductive structure. The molecular mechanisms that specify this meristematic region and regulate its organogenic potential are poorly understood. Here, we present a novel approach to analyze the transcriptional signature of the medial domain of the Arabidopsis gynoecium, highlighting the developmental stages that immediately proceed ovule initiation, the earliest stages of seed development. Using a floral synchronization system and a SHATTERPROOF2 (SHP2) domain-specific reporter, paired with FACS and RNA sequencing, we assayed the transcriptome of the gynoecial medial domain with temporal and spatial precision. This analysis reveals a set of genes that are differentially expressed within the SHP2 expression domain, including genes that have been shown previously to function during the development of medial domain derived structures, including the ovules, thus validating our approach. Global analyses of the transcriptomic data set indicate a similarity of the pSHP2 expressing cell population to previously characterized meristematic domains, further supporting the meristematic nature of this gynoecial tissue. Our method identifies additional genes including novel isoforms, cis-natural antisense transcripts, and a previously unrecognized member of the REPRODUCTIVE MERISTEM family of transcriptional regulators that are potential novel regulators of medial domain development. This data set provides genome-wide transcriptional insight into the development of the carpel margin meristem in Arabidopsis. PMID- 26984004 TI - The influence of alcohol oral intake on the effects of 35% CO2 challenge. A study in healthy volunteers. AB - OBJECTIVE: Alcohol use disorders and panic disorder co-occur at a rate that exceeds chance significantly. The underlying mechanism of alcoholism associated with anxiety has rarely been examined using experimental methodologies. The present study in healthy volunteers tested whether alcohol consumption reduces anxiety associated with a panic-challenge procedure (35% CO2 challenge). METHODS: The study design was placebo-controlled, double-blind, randomized. Eight healthy volunteers were enrolled; all subjects had an alcohol and a placebo oral intake according to a crossover design. After each consumption the subjects underwent the 35% CO2 challenge and a series of anxiety symptom assessments. RESULTS: After the alcohol intake, the subjects presented a significant reduction in the anxiety state associated with the challenge procedure. The Panic Symptom List score is significantly lower after alcohol intake (P = 0.032), as compared with the placebo, and the Visual Analogue Anxiety Scale shows a trend to be lower after alcohol intake (P = 0.111). CONCLUSIONS: Moderate doses of alcohol acutely decrease the response to a 35% CO2 challenge in healthy volunteers. These results lend support to the pharmacological anxiolytic effect of alcohol and suggest that this property may reinforce the drinking behaviour among those with high levels of anxiety. PMID- 26984005 TI - New insights in cognitive behavioural therapy as treatment of panic disorder: a brief overview. AB - Cognitive behavioural therapy (CBT) has been proved to be very effective in the treatment of panic disorder. In this article we attempt to give a brief representation of more recent insights and techniques in the field of cognitive behavioural therapy in the treatment of panic disorder. PMID- 26984006 TI - Predicting the 10-year risk of hip and major osteoporotic fracture in rheumatoid arthritis and in the general population: an independent validation and update of UK FRAX without bone mineral density. AB - OBJECTIVES: FRAX incorporates rheumatoid arthritis (RA) as a dichotomous predictor for predicting the 10-year risk of hip and major osteoporotic fracture (MOF). However, fracture risk may deviate with disease severity, duration or treatment. Aims were to validate, and if needed to update, UK FRAX for patients with RA and to compare predictive performance with the general population (GP). METHODS: Cohort study within UK Clinical Practice Research Datalink (CPRD) (RA: n=11 582, GP: n=38 755), also linked to hospital admissions for hip fracture (CPRD-Hospital Episode Statistics, HES) (RA: n=7221, GP: n=24 227). Predictive performance of UK FRAX without bone mineral density was assessed by discrimination and calibration. Updating methods included recalibration and extension. Differences in predictive performance were assessed by the C-statistic and Net Reclassification Improvement (NRI) using the UK National Osteoporosis Guideline Group intervention thresholds. RESULTS: UK FRAX significantly overestimated fracture risk in patients with RA, both for MOF (mean predicted vs observed 10-year risk: 13.3% vs 8.4%) and hip fracture (CPRD: 5.5% vs 3.1%, CPRD HES: 5.5% vs 4.1%). Calibration was good for hip fracture in the GP (CPRD-HES: 2.7% vs 2.4%). Discrimination was good for hip fracture (RA: 0.78, GP: 0.83) and moderate for MOF (RA: 0.69, GP: 0.71). Extension of the recalibrated UK FRAX using CPRD-HES with duration of RA disease, glucocorticoids (>7.5 mg/day) and secondary osteoporosis did not improve the NRI (0.01, 95% CI -0.04 to 0.05) or C statistic (0.78). CONCLUSIONS: UK FRAX overestimated fracture risk in RA, but performed well for hip fracture in the GP after linkage to hospitalisations. Extension of the recalibrated UK FRAX did not improve predictive performance. PMID- 26984007 TI - Response to biological treatment and subsequent risk of coronary events in rheumatoid arthritis. AB - OBJECTIVES: Whether the increased risk of comorbidities, such as cardiovascular disease, in rheumatoid arthritis (RA) can be reverted by particular antirheumatic therapies, or response to these, is unclear but of critical clinical importance. We wanted to investigate whether response to tumour necrosis factor inhibitors (TNFi) translates into a reduced risk for acute coronary syndrome (ACS). METHODS: A cohort of patients with RA initiating a first TNFi 2001-2012 was identified in the Swedish Biologics Register. The association between European League Against Rheumatism (EULAR) response after 3-8 months of treatment (assessed using the first, the best and the measurement closest to 5 months, respectively), and the risk of incident ACS during the subsequent year was analysed in Cox regression models. Adjustments included cardiovascular risk factors, joint surgery, RA duration, education and work disability. RESULTS: During 6592 person-years among TNFi initiators (n=6864, mean age 55 years, 77% women), 47 ACS occurred. The adjusted HRs (95% CI), which were similar to the crude HRs, of the 1-year risk of ACS among EULAR good responders compared with non-responders were 0.5 (0.2 to 1.4), 0.4 (0.2 to 0.9) and 0.5 (0.2 to 1.2), for the first, the best and the evaluation closest to 5 months, respectively. EULAR moderate responders had equal risk to that of EULAR non-responders, who, compared with the general population referents (n=34 229), had a more than twice the risk of ACS. For good responders, there was no statistically significant difference in risk versus the general population. CONCLUSIONS: Optimised RA disease control has the potential to revert otherwise increased risks for ACS in RA. PMID- 26984009 TI - Motivated Implicit Theories of Personality: My Weaknesses Will Go Away, but My Strengths Are Here to Stay. AB - Across six studies, this research found consistent evidence for motivated implicit theories about personality malleability: People perceive their weaknesses as more malleable than their strengths. Moreover, motivation also influences how people see themselves in the future, such that they expect their present strengths to remain constant, but they expect their present weaknesses to improve in the future. Several additional findings suggest the motivational nature of these effects: The difference in perceived malleability for strengths versus weaknesses was only observed for the self, not for other people. When the desirability of possessing a certain trait was manipulated, that trait was perceived to be more malleable when it was depicted as undesirable. And these different beliefs that people have about how malleable their traits are, and how they will develop in the future, were associated with their desire for change, which is higher for weaknesses versus strengths. PMID- 26984008 TI - Points to consider for reporting, screening for and preventing selected comorbidities in chronic inflammatory rheumatic diseases in daily practice: a EULAR initiative. AB - In chronic inflammatory rheumatic diseases, comorbidities such as cardiovascular diseases and infections are suboptimally prevented, screened for and managed. The objective of this European League Against Rheumatism (EULAR) initiative was to propose points to consider to collect comorbidities in patients with chronic inflammatory rheumatic diseases. We also aimed to develop a pragmatic reporting form to foster the implementation of the points to consider. In accordance with the EULAR Standardised Operating Procedures, the process comprised (1) a systematic literature review of existing recommendations on reporting, screening for or preventing six selected comorbidities: ischaemic cardiovascular diseases, malignancies, infections, gastrointestinal diseases, osteoporosis and depression and (2) a consensus process involving 21 experts (ie, rheumatologists, patients, health professionals). Recommendations on how to treat the comorbidities were not included in the document as they vary across countries. The literature review retrieved 42 articles, most of which were recommendations for reporting or screening for comorbidities in the general population. The consensus process led to three overarching principles and 15 points to consider, related to the six comorbidities, with three sections: (1) reporting (ie, occurrence of the comorbidity and current treatments); (2) screening for disease (eg, mammography) or for risk factors (eg, smoking) and (3) prevention (eg, vaccination). A reporting form (93 questions) corresponding to a practical application of the points to consider was developed. Using an evidence-based approach followed by expert consensus, this EULAR initiative aims to improve the reporting and prevention of comorbidities in chronic inflammatory rheumatic diseases. Next steps include dissemination and implementation. PMID- 26984010 TI - Social-Class Differences in Consumer Choices: Working-Class Individuals Are More Sensitive to Choices of Others Than Middle-Class Individuals. AB - The present research shows that, when making choices, working-class Americans are more affected by others' opinions than middle-class Americans due to differences in independent versus interdependent self-construal. Experiment 1 revealed that when working-class Americans made decisions to buy products, they were more influenced by the choices of others than middle-class Americans. In contrast, middle-class Americans were more likely to misremember others' choices to be consistent with their own choices. In other words, working-class Americans adjusted their choices to the preference of others, whereas middle-class Americans distorted others' preferences to fit their choices. Supporting our prediction that this social-class effect is closely linked to the independent versus interdependent self-construal, we showed that the differences in self construal across cultures qualified the social-class effects on choices (Experiment 2). Moreover, when we experimentally manipulated self-construal in Experiment 3, we found that it mediated the corresponding changes in choices regardless of social class. PMID- 26984011 TI - Should Spouses Be Demanding Less From Marriage? A Contextual Perspective on the Implications of Interpersonal Standards. AB - How much should people ask of their relationships? Whereas several perspectives suggest high standards should make actual outcomes feel worse by comparison and thus harm relationships, other perspectives suggest high standards should motivate people to exert the effort necessary to cultivate quality partnerships. The current 4-year longitudinal study of newlywed couples reconciled these competing perspectives by testing a prediction implicit in Finkel, Hui, Carswell, and Larson's suffocation model of marriage-that spouses' standards interact with factors reflective of their abilities to meet those standards to predict subsequent satisfaction. Among spouses who either reported less severe problems or were in marriages observed to be characterized by lower levels of destructive behavior, standards were positively associated with satisfaction over time; among spouses who reported more severe problems or were in marriages characterized by higher levels of destructive behavior, in contrast, standards were negatively associated with satisfaction over time. PMID- 26984012 TI - Explaining Self and Vicarious Reactance: A Process Model Approach. AB - Research shows that people experience a motivational state of agitation known as reactance when they perceive restrictions to their freedoms. However, research has yet to show whether people experience reactance if they merely observe the restriction of another person's freedom. In Study 1, we activated realistic vicarious reactance in the laboratory. In Study 2, we compared people's responses with their own and others' restrictions and found the same levels of experienced reactance and behavioral intentions as well as aggressive tendencies. We did, however, find differences in physiological arousal: Physiological arousal increased quickly after participants imagined their own freedom being restricted, but arousal in response to imagining a friend's freedom being threatened was weaker and delayed. In line with the physiological data, Study 3's results showed that self-restrictions aroused more emotional thoughts than vicarious restrictions, which induced more cognitive responses. Furthermore, in Study 4a, a cognitive task affected only the cognitive process behind vicarious reactance. In contrast, in Study 4b, an emotional task affected self-reactance but not vicarious reactance. We propose a process model explaining the emotional and cognitive processes of self- and vicarious reactance. PMID- 26984013 TI - The Impact of Affect on Out-Group Judgments Depends on Dominant Information Processing Styles: Evidence From Incidental and Integral Affect Paradigms. AB - Two studies tested the affect-as-cognitive-feedback model, in which positive and negative affective states are not uniquely associated with particular processing styles, but rather serve as feedback about currently accessible processing styles. The studies extend existing work by investigating (a) both incidental and integral affect, (b) out-group judgments, and (c) downstream consequences. We manipulated processing styles and either incidental (Study 1) or integral (Study 2) affect and measured perceptions of out-group homogeneity. Positive (relative to negative) affect increased out-group homogeneity judgments when global processing was primed, but under local priming, the effect reversed (Studies 1 and 2). A similar interactive effect emerged on attributions, which had downstream consequences for behavioral intentions (Study 2). These results demonstrate that both incidental and integral affect do not directly produce specific processing styles, but rather influence thinking by providing feedback about currently accessible processing styles. PMID- 26984015 TI - The Rural-Urban Difference in Interpersonal Regret. AB - The present research examined rural-urban differences in interpersonal regret. In Study 1, participants who grew up in rural areas reported stronger interpersonal regret than those who grew up in large cities. In Study 2, we conducted an experiment and found that participants who were assigned to imagine a rural life reported greater interpersonal regret than those who were assigned to imagine an urban life. Moreover, this rural-urban difference was mediated by the degree to which participants wrote about informal social control such as gossip and reputation concerns. Finally, in Study 3, we used the pictorial eye manipulation, which evokes a concern for informal social control, and found that participants from large cities who were exposed to the eyes reported more intense interpersonal regret than those who were not exposed to the eyes. Together, these studies demonstrate that informal social control is a key to understanding rural urban differences in interpersonal regret. PMID- 26984014 TI - To Have Control Over or to Be Free From Others? The Desire for Power Reflects a Need for Autonomy. AB - The current research explores why people desire power and how that desire can be satisfied. We propose that a position of power can be subjectively experienced as conferring influence over others or as offering autonomy from the influence of others. Conversely, a low-power position can be experienced as lacking influence or lacking autonomy. Nine studies show that subjectively experiencing one's power as autonomy predicts the desire for power, whereas the experience of influence over others does not. Furthermore, gaining autonomy quenches the desire for power, but gaining influence does not. The studies demonstrated the primacy of autonomy across both experimental and correlational designs, across measured mediation and manipulated mediator approaches, and across three different continents (Europe, United States, India). Together, these studies offer evidence that people desire power not to be a master over others, but to be master of their own domain, to control their own fate. PMID- 26984016 TI - Humanizing Outgroups Through Multiple Categorization: The Roles of Individuation and Threat. AB - In three studies, we examined the impact of multiple categorization on intergroup dehumanization. Study 1 showed that perceiving members of a rival university along multiple versus simple categorical dimensions enhanced the tendency to attribute human traits to this group. Study 2 showed that multiple versus simple categorization of immigrants increased the attribution of uniquely human emotions to them. This effect was explained by the sequential mediation of increased individuation of the outgroup and reduced outgroup threat. Study 3 replicated this sequential mediation model and introduced a novel way of measuring humanization in which participants generated attributes corresponding to the outgroup in a free response format. Participants generated more uniquely human traits in the multiple versus simple categorization conditions. We discuss the theoretical implications of these findings and consider their role in informing and improving efforts to ameliorate contemporary forms of intergroup discrimination. PMID- 26984017 TI - The Immoral Assumption Effect: Moralization Drives Negative Trait Attributions. AB - Jumping to negative conclusions about other people's traits is judged as morally bad by many people. Despite this, across six experiments (total N = 2,151), we find that multiple types of moral evaluations--even evaluations related to open mindedness, tolerance, and compassion--play a causal role in these potentially pernicious trait assumptions. Our results also indicate that moralization affects negative-but not positive-trait assumptions, and that the effect of morality on negative assumptions cannot be explained merely by people's general (nonmoral) preferences or other factors that distinguish moral and nonmoral traits, such as controllability or desirability. Together, these results suggest that one of the more destructive human tendencies--making negative assumptions about others--can be caused by the better angels of our nature. PMID- 26984018 TI - Bizarre parosteal osteochondromatous proliferation (Nora's lesion) affecting the distal end of the ulna: a case report. AB - BACKGROUND: Bizarre parosteal osteochondromatous proliferation (BPOP), first described by Nora et al. in 1983 and therefore termed "Nora's lesion", is a rare lesion that occurs in the short bones of the hands and feet and eventually presents as a parosteal mass. Reports of BPOP in the long bones are very rare. A benign disease, BPOP does not become malignant, although a high rate of recurrence following surgical resection is reported. Because of its atypical imaging findings and histopathological appearance, a BPOP might be misdiagnosed as a malignant tumor such as an osteochondroma with malignant transformation, a parosteal osteosarcoma, or a periosteal osteosarcoma. CASE PRESENTATION: A 58 year-old woman complained of left ulnar wrist pain at the time of her initial presentation. Plain x-rays showed ectopic calcifications in and around the distal radioulnar joint, which supported the diagnosis of subacute arthritis with hydroxyapatite crystal deposition. She was initially given a wrist brace and directed to follow-up, but her persistent pain required the administration of corticosteroid injections into the distal radioulnar joint. Increasing ulnar wrist joint pain and limited forearm pronation and wrist flexion necessitated computed tomography and contrast-enhanced magnetic resonance imaging. BPOP was diagnosed based on the preoperative imaging studies, and a resection of the lesion was performed along with the decortication of the underlying the cortical bone to reduce recurrence rates. The diagnosis of BPOP was confirmed by pathologic examination. Two years after surgery, the patient has no subsequent pain complaints and an improved range of motion. CONCLUSIONS: BPOP affecting the distal end of the ulna is exceedingly rare. Because BPOP was diagnosed primarily based upon preoperative imaging findings in our patient, decortication of the underlying cortical bone was performed to reduce recurrence rates. Further careful follow-up in these patients is essential, despite the non-recurrence of the lesion. PMID- 26984021 TI - Asiatic acid exerts anticancer potential in human ovarian cancer cells via suppression of PI3K/Akt/mTOR signalling. AB - Context Asiatic acid, a triterpenoid compound extracted from the tropical medicinal plant Centella asiatica (Family: Apiaceae), has exhibited various biological activities. Objective This study was performed to investigate the cytotoxic effects of asiatic acid on human ovarian cancer cells. Materials and methods SKOV3 and OVCAR-3 ovarian cancer cells were exposed to different concentrations of asiatic acid (10-100 MUg/mL) for 72 or 48 h. Cell viability, colony formation, cell cycle distribution, apoptotic response were examined. Involvement of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was tested. Results At the concentration of 40 MUg/mL, asiatic acid caused about 50% reduction in the viability of ovarian cancer cells, but had little effect on the viability of normal human ovarian epithelial cells. Asiatic acid at 10 MUg/mL reduced colony formation of ovarian cancer cells by 25 30%. Asiatic acid-treated cells showed a cell cycle arrest at the G0/G1 phase and 7- to 10-fold increase in apoptosis. The phosphorylation levels of PI3K, Akt and mTOR were remarkably lower in asiatic acid-treated cells. Overexpression of constitutively active Akt partially reversed the cytotoxic effects of asiatic acid, as evidenced by increased cell viability and colony formation. Furthermore, knockdown of Akt mimicked the growth-suppressive activity of asiatic acid. Discussion and conclusion These results provide first the evidence for the anticancer potential of asiatic acid in ovarian cancer cells, partially via inactivation of the PI3K/Akt/mTOR pathway. Asiatic acid may represent a potential therapeutic agent for ovarian cancer. PMID- 26984022 TI - Erratum to: Synergistic anti-malarial action of cryptolepine and artemisinins. PMID- 26984023 TI - Targeting the MAP kinase pathway in astrocytoma cells using a recombinant anthrax lethal toxin as a way to inhibit cell motility and invasion. AB - Malignant astrocytomas are highly invasive into adjacent and distant regions of the normal brain. Understanding and targeting cancer cell invasion is an important therapeutic approach. Cell invasion is a complex process that replies on many signaling pathways including the mitogen-activated protein (MAP) kinase (MAPK). In many cell lines, the use of MAPK-targeted drugs proved to be a potential method to inhibit cancer cell motility. In the present study, we use a recombinant anthrax lethal toxin (LeTx), which selectively inhibits the MAPK pathway, in order to target invasion. LeTx proved ineffective on cell survival in astrocytoma (as well as normal cells). However, astrocytoma cells that were treated with LeTx showed a significant decrease in cell motility as seen by wound healing as well as random 2D motility in serum. The cells also showed a decrease in invasion across a collagen matrix. The effect of LeTx on cell migration was mediated though the deregulation of Rho GTPases, which play a role in cell motility. Finally, the effect of LeTx on cell migration and Rho GTPases was mimicked by the inhibition of the MAPK pathway. In this study, we describe for the first time the effect of the LeTx on cancer cell motility and invasion not cell survival making it a potentially selective brain tumor invasion inhibitor. PMID- 26984024 TI - Discharge interventions for older patients leaving hospital: protocol for a systematic meta-review. AB - BACKGROUND: There is an increased need for additional care and support services for the elderly population. It is important to identify what support older people need once they are discharged from hospital and to ensure continuity of care. There is a large evidence base focusing on enhanced discharge services and their impact on patients. The services show some potential benefits, but there are inconsistent findings across reviews. Furthermore, it is unclear what elements of enhanced discharge interventions could be most beneficial to older people. This meta-review aims to identify existing systematic reviews of discharge interventions for older people, identify potentially effective elements of enhanced discharge services for this patient group and identify areas where further work may still be needed. METHODS/DESIGN: The search will aim to identify English language systematic reviews that have assessed the effectiveness of discharge interventions for older people. The following databases will be searched: Medline, Embase, PsycINFO, HMIC, Social Policy and Practice, CINAHL, the Cochrane Library, ASSIA, Social Science Citation Index and the Grey Literature Report. The search strategy will comprise the keywords 'systematic reviews', 'older people' and 'discharge'. Discharge interventions must aim to support older patients before, during and/or after discharge from hospital. Outcomes of interest will include mortality, readmissions, length of hospital stay, patient health status, patient and carer satisfaction and staff views. Abstract, title and full text screening will be conducted independently by two reviewers. Data extracted from reviews will include review characteristics, patient population, review quality score, outcome measures and review findings, and a narrative synthesis will be conducted. DISCUSSION: This review will identify existing reviews of discharge interventions and appraise how these interventions can impact outcomes in older people such as readmissions, health status, length of hospital stay and mortality. The review could inform practice and will help identify where further research is needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015025737. PMID- 26984026 TI - Editorial Comment for Faragher et al. PMID- 26984025 TI - The Molecular Pharmacology of G Protein Signaling Then and Now: A Tribute to Alfred G. Gilman. AB - The recent, unfortunate death of Alfred G. ("Al") Gilman, M.D., Ph.D., represents a sad signpost for an era spanning over 40 years in molecular pharmacology. Gilman's discoveries, influence, and persona were dominant forces in research and training in pharmacology. Here, we review the progression of ideas and knowledge that spawned early work by Gilman and collaborators (among them, one of the authors) and later efforts (including those of the other author) that have recently yielded a comprehensive and precise structural understanding of fundamental topics in pharmacology: the binding of ligands to G protein-coupled receptors (GPCRs) and the interaction of GPCRs with heterotrimeric G proteins and effector molecules. Those data provide new and important insights into the molecular basis that underlies affinity and efficacy, two of the most important features of drug action, which represent the latest chapter in the saga that Al Gilman's work helped launch. PMID- 26984027 TI - Strategic directions for university hospitals in Saudi Arabia. AB - The kingdom of Saudi Arabia is currently witnessing a massive support for its healthcare services. This year's fiscal budget for health care is by far the largest in the history of the kingdom. While pursuing the conventional goals of healthcare delivery systems, such as equity, affordability and availability of services, the ministry of education (MOE), formerly called ministry of higher education (MOHE), is also seeking to achieve certain excellence standards, which are expected to set the bar for other countries in the region to follow suit. Almost all, under construction, university hospitals were adopting a paradigm shift in the standard of health care and training provided. This report summarizes these standards. PMID- 26984028 TI - Perceived barriers towards participation in undergraduate research activities among medical students at Alfaisal University-College of Medicine: A Saudi Arabian perspective. AB - BACKGROUND: The importance of undergraduate research (UR) to students is well acknowledged in literature; however, little is known about its perceived barriers. The aim of study is to explore the perceived barriers toward participation in UR activities among students at Alfaisal University-College of Medicine, Saudi Arabia. METHODS: An online, anonymous, cross-sectional, self rating survey was administered. A two-tailed Mann-Whitney U-test was used to compare the average five-point Likert scale responses between male and female students. RESULTS: Two-hundred and twenty-one students (n = 221/350) participated in the survey with a 63.1% response rate. The percentage of participation in UR significantly differed by gender (males vs. females: 68.6% vs. 45.4%; p < 0.0005, Chi-square test). The top three barriers toward participation in UR were "lack of time" (77.4%), "lack of formal UR courses in curriculum" (76%) and "lack of UR mentors" (70.1%). Statistically significant differences of means were identified between male and female students regarding the following statements: "lack of supervising research mentors" (p < 0.01), "lack of interest in research" (p < 0.04), "lack of finding same-gender research mentor" (p < 0.00) and "lack of UR opportunities" (p < 0.00). CONCLUSION: Our results were fairly comparable to the Western studies. Medical educators should carefully look into all UR barriers and consider implementing applicable solutions. PMID- 26984029 TI - Authentic leadership in a health sciences university. AB - AIM: To study authentic leadership characteristics between academic leaders in a health sciences university. METHODS: Cross-sectional study at a health sciences university in Saudi Arabia. The Authentic Leadership Questionnaire (ALQ) was utilized to assess authentic leadership. RESULTS: Out of 84 ALQs that were distributed, 75 (89.3%) were eligible. The ALQ scores showed consistency in the dimensions of self-awareness (3.45 +/- 0.43), internalized moral prospective (3.46 +/- 0.33) and balanced processing (3.42 +/- 0.36). The relational transparency dimension had a mean of 3.24 +/- 0.31 which was significantly lower than other domains. Academic leaders with medical background represented 57.3%, compared to 42.7% from other professions. Academic leaders from other professions had better ALQ scores that reached statistical significance in the internalized moral perspective and relational transparency dimensions with p values of 0.006 and 0.049, respectively. In reference to the impact of hierarchy, there were no significant differences in relation to ALQ scores. Almost one-third of academic leaders (34.7%) had Qualifications in medical education that did not show significant impact on ALQ scores. CONCLUSION: There was less-relational transparency among academic leaders that was not consistent with other ALQ domains. Being of medical background may enhance leaders' opportunity to be at a higher hierarchy status but it did not enhance their ALQ scores when compared to those from other professions. Moreover, holding a master in medical education did not impact leadership authenticity. PMID- 26984030 TI - Pre-admission criteria and pre-clinical achievement: Can they predict medical students performance in the clinical phase? AB - RATIONAL: Various factors affect medical students' performance during clinical phase. Identifying these factors would help in mentoring weak students and help in selection process for residency programmes. OBJECTIVE: Our study objective is to evaluate the impact of pre-admission criteria, and pre-clinical grade point average (GPA) on undergraduate medical students' performance during clinical phase. METHOD: This study has a cross-sectional design that includes fifth- and sixth-year female medical students (71). Data of clinical and pre-clinical GPA in medical school and pre-admission to medical school tests scores were collected. RESULTS: A significant correlation between clinical GPA with the pre-clinical GPA was observed (p < 0.05). Such significant correlation was not seen with other variables under study. A regression analysis was performed, and the only significant predictor of students clinical performance was the pre-clinical GPA (p < 0.001). However, no significant difference between students' clinical and pre-clinical GPA for both cohorts was observed (p > 0.05). CONCLUSION: Pre clinical GPA is strongly correlated with and can predict medical students' performance during clinical years. Our study highlighted the importance of evaluating the academic performances of students in pre-clinical years before they move into clinical years in order to identify weak students to mentor them and monitor their progress. PMID- 26984031 TI - Perceived influential factors toward participation in undergraduate research activities among medical students at Alfaisal University-College of Medicine: A Saudi Arabian perspective. AB - AIMS: (1) To explore correlations between medical students' participation in undergraduate research (UR) activities and their characteristics, and (2) to explore students' perceived influential factors toward participation in UR activities at Alfaisal University-College of Medicine, Saudi Arabia. METHODS: An online, anonymous, cross-sectional, self-rating survey was administered. Chi square test was used to correlate between participation in UR activities and students' characteristics (age, academic year and grade point average [GPA]). Two tailed Mann-Whitney U-test was used to compare the mean 5-point Likert scale responses between students with and without previous UR activities. RESULTS: About 218 students participated in the survey (n = 218/350; response rate: 62.3%). The top three influential factors to undertake UR activities were "facilitate entry into competitive residency programs," (88.1%) "improve curriculum vitae" (81.2%) and "publish in peer-reviewed journals" (79.8%). Percentage of participation in previous UR activities significantly differed by gender (p < 0.03825), academic year (p < 0.000003) and GPA (p < 0.02627). Students who had previous UR activities were more positively influenced to participate in future UR activities than those who did not (p < 0.0488). CONCLUSION: Students demonstrated positive attitudes toward UR activities. The relationships between participation in UR activities and male gender, increased number of years spent at medical college and higher GPA were directly proportional. PMID- 26984032 TI - Medical teachers' perception towards simulation-based medical education: A multicenter study in Saudi Arabia. AB - OBJECTIVE: This study aims to evaluate the perception of medical teachers toward the integration of simulation-based medical education (SBME) in undergraduate curriculum and also identify contextual barriers faced by medical teachers. METHODS: This cross-sectional observational study included medical teachers from three universities. A questionnaire was used to report teachers' perception. RESULTS: SBME was perceived by medical teachers (basic sciences/clinical, respectively) as enjoyable (71.1%/75.4%), effective assessment tool to evaluate students' learning (60%/73.9%) and can improve learning outcome (88.8%/79.7%). Similarly, (91.1%/71%) of teachers think that simulation should be part of the curriculum and not stand alone one time activity. Teachers' training for SBME has created a significant difference in perception (p < 0.05). Lack of teachers' training, time, resources and the need to integrate in medical curriculum are major perceived barriers for effective SBME. CONCLUSION: Results highlight the positive perception and attitude of medical teachers toward the integration of SBME in undergraduate curriculum. Prior formal training of teachers created a different perception. Top perceived barriers for effective SBME include teachers' formal training supported with time and resources and the early integration into the curriculum. These critical challenges need to be addressed by medical schools in order to enhance the integration SBME in undergraduate curricula. PMID- 26984034 TI - Public health education in Saudi Arabia: Needs and challenges. AB - In the last decade, public health (PH) has come to the frontlines in Saudi Arabia. The recent outbreak of a novel corona virus (MERS-CoV) highlighted the importance of PH services and the need for a competent PH workforce. The urgency and panic induced by infectious disease outbreaks explain the heightened interest. Decision makers' interest in public health was observed through a series of decisions, including creating a position for Deputy Minister for Public Health, changing the name of "Directorate of Primary Healthcare Centers" to "Directorate of Public Health" in all health regions and initiating a special scholarship program to prepare health administration professionals in collaboration with US-based universities. A distinguished group of PH leaders in Saudi Arabia was gathered in a structured workshop that was organized by the Al Imam Mohammad Ibn Saud Islamic University, college of medicine to discuss the current status and future needs of PH education in the Kingdom of Saudi Arabia. The workshop highlighted the need for PH education development and outlined the challenges ahead. The main challenges laid out by participants in the workshop were the development of an appropriate PH curriculum, appropriate training spots for practical placement, the development of research priorities for PH to satisfy the needs of PH programs and agencies, attracting the most qualified academic staff, the enrolment of highly motivated students and finally, the establishment of a quality assurance program to ensure the quality of PH education programs. The development of a framework for graduate competencies in PH was perceived to be a top priority. Moreover, setting a PH workforce surveillance system, building partnership between PH academic institutions and PH services providers, implementing national campaigns to explain what PH is about and illuminating the role of PH workers were also of utmost importance. PMID- 26984033 TI - Gathering validity evidence in the use of multiple mini-interviews as an admission tool for dental students: Preliminary evidence from Saudi Arabia. AB - AIMS: This study examined the validity evidence of noncognitive skills of incoming students in the Faculty of Dentistry at King Abdulaziz University using multiple mini-interviews (MMI). Validity evidence in response process, internal structure and relationship to other variables was investigated. METHODS: A total of 146 students were interviewed by faculty members over a two-day period. The interviews took the form of an MMI, which consisted of six objective structure clinical examination (OSCE) stations with two faculty interviewers per station. Each student rotated through the six stations and were asked 4-5 structured questions per station. Each student was rated on a three-point rating scale. RESULTS: The majority of dental students were rated to be acceptable. The inter rater reliability was 0.91 which was significantly high (range: 0.87-0.94). The total MMI score for all stations was 73.47 (SD = 8.49) with female students scoring significantly higher than males did (p < 0.001). Generalizability study results indicated good reliability (Phi-coefficient = 0.73; G-coefficient = 0.75). Moderate association was found between total MMI score and foundation year GPA (r = 0.30, p <= 0.001). CONCLUSIONS: Preliminary validity evidence supports the use of MMI scores as an admission tool for dental students, with respect to its response process, internal structure and relationship to other variables. PMID- 26984035 TI - Evaluation of a combined approach of clinical skills training utilizing near peers, in-campus faculty and clinicians: An innovative integrated model. AB - INTRODUCTION: Training clinical skills is essential in medicine. Different models of clinical skills courses have been previously suggested. Here, we report an innovative approach adopted to train junior medical students in clinical skills in a multimodal fashion by near-peers, basic scientists with clinical background and senior clinicians. METHODS: This quasi-experimental study was conducted at Alfaisal University College of Medicine at Riyadh. An electronic survey was conducted among year-2 and year-3 medical students seeking their perception about the (a) organization, (b) delivery, (c&d) self- and peer-assessment in clinical skills courses. Total 298 male and female medical students (91%), consisting of 164 from year 2 and 134 from year 3, participated by filling out a questionnaire (Cronbach's alpha 0.93). RESULTS: Out of maximum five, the average ratings for the course were 3.81, 3.72, 3.67 and 3.73 in organization, delivery, self evaluation and peer-assessment respectively, with no significant difference between both subgroups. The in-campus sessions rated higher than hospital sessions (p < 0.001). As tutors, interns were rated higher than clinicians (p < 0.001). The qualitative analysis suggested high satisfaction. CONCLUSIONS: The clinical skills course that was conducted in a multimodal fashion utilizing diverse tutors showed a positive attitude of students toward the organization and delivery of the course. PMID- 26984036 TI - Disaster medicine education for medical students: Is it a real need? AB - BACKGROUND: Disasters are serious public health problems that have increased over the last century. This study evaluated the familiarity and training needs of medical students regarding disaster medicine in Qassim University College of Medicine (QUCOM). METHODOLOGY: A mixed quantitative and qualitative study was conducted in which students in the clinical phase were asked to respond to a questionnaire. Clinical teachers of the college, emergency physicians and health administrators were interviewed for the qualitative part of the study. Data were analyzed using SPSS and relevant tool for the qualitative part. RESULTS: Two hundred twenty-nine students (91.6%) responded. Familiarity of students with disaster medicine was low with a mean score of 1.65 out of five points. However, male students demonstrated significantly higher mean scores in certain themes of disaster medicine. Students endorsed the idea that a training course is needed with a mean score of 3.66/5 and supported the idea that disaster medicine training should be provided to the general public as well (mean 3.85/5). Qualitative data affirmed inclusion of relevant topics in the curriculum based on students' inputs and needs and as defined by the community. CONCLUSION: Disaster medicine education for medical students is recommended by students and experts, while the applicability and feasibility needs further exploration. PMID- 26984037 TI - Physical activity and academic achievement among the medical students: A cross sectional study. AB - AIMS: To explore physical activity (PA) habits among the medical students and examine the correlation with their grade point average (GPA) achievement at College of Medicine, King Saud University, Riyadh, Saudi Arabia. METHODS: A cross sectional study was conducted among the medical students (n = 409), during the academic year 2012-2013. Students' physical activity habits were self-reported. GPA, body mass index (BMI) and body fat percent (BF%) were collected and analyzed with SPSS software. RESULTS: Out of 409 students, 193 (47.2%) students reported being physically active. Our result showed a significant positive association between students' PA habits and high-GPA achievement (chi(2 )= 10.65, p = 0.001). The greatest odds ratio of high GPA was found among the fourth year students (OR = 3.08, CI: 1.15-8.28, p = 0.025) and fifth year students (OR = 5.07, CI: 1.48 17.31, p = 0.010). In addition, significant association was found between the normal BMI and high-GPA achievers (chi(2 )= 8.30; p = 0.016). However, no statistically, significant association was found between BF% and GPA. CONCLUSIONS: The present study showed a positive associations was found between PA habits and high academic achievement. In addition, positive association was found between PA, obese students and GPA achievement. Therefore, there is a need for the establishment of physical activity education and public health programs to promote importance of PA in Saudi population. PMID- 26984038 TI - Dual-degree MBBS-PhD programs in Saudi Arabia: A call for implementation. AB - Engaging medical students in scholarly research activities and producing clinically competent and research-oriented medical workforces are essential demands, particularly in developing countries. Dual-degree MD-PhD programs offer simultaneous rigorous education in medicine and research, and train its graduates (physician-scientists) to successfully catalyze translational research evolutions. Literature fundamentally identifies dual-degree MD-PhD programs as the single most important, well-established, popular and influential programs toward commencing physician-scientist professions. While the physician-scientist population is alarmingly vanishing in the West with ongoing efforts to reverse this undesired trend, such population is largely nonexisting, unfortunately to start with, in Saudi Arabia. This is simply because no single dual-degree MBBS PhD program is yet established in Saudi Arabia. Herein, we call on the Saudi Higher Education bodies to implement dual-degree MBBS-PhD programs with anticipated generation of competent physician-scientists in Saudi Arabia. To the best of our knowledge, this is the first ever report to call for such innovative implementation. PMID- 26984039 TI - Cortical and subcortical modulation of pain. AB - Pain is more than merely nociception and response, but rather it encompasses emotional, behavioral and cognitive components that make up the pain experience. With the recent advances in imaging techniques, we now understand that nociceptive inputs can result in the activation of complex interactions among central sites, including cortical regions that are active in cognitive, emotional and reward functions. These sites can have a bimodal influence on the serotonergic and noradrenergic descending pain modulatory systems via communications among the periaqueductal gray, rostral ventromedial medulla and pontine noradrenergic nuclei, ultimately either facilitating or inhibiting further nociceptive inputs. Understanding these systems can help explain the emotional and cognitive influences on pain perception and placebo/nocebo effects, and can help guide development of better pain therapeutics. PMID- 26984040 TI - Understanding maladaptive responses to rejection: Aggression with an audience. AB - Logically, responding aggressively to rejection is maladaptive because one is unlikely to seek a relationship with an aggressor. We predict that when concealed, the illogical aggressive response to rejection is more likely, whereas when the rejected individuals' aggressive responses are perceived as public, the aggressive acts may be reduced. Participants were rejected by others (Experiment 1) or were either accepted or rejected during an online ball-tossing game (Experiment 2) and were then given an opportunity to aggress publicly or privately. Across experiments, when the opportunity to aggress was made public, rejected participants exhibited less aggressive behavior. When concerned about the perception of their public aggressive responses by others, rejected individuals' aggressive responses diminished compared with those whose actions were private. Crucially, this extended to aggression visible only to neutral others, suggesting that effects cannot solely be due to fear of retribution. PMID- 26984041 TI - Heteroepitaxial growth of Pt and Au thin films on MgO single crystals by bias assisted sputtering. AB - The crystallographic orientation of a metal affects its surface energy and structure, and has profound implications for surface chemical reactions and interface engineering, which are important in areas ranging from optoelectronic device fabrication to catalysis. However, it can be very difficult and expensive to manufacture, orient, and cut single crystal metals along different crystallographic orientations, especially in the case of precious metals. One approach is to grow thin metal films epitaxially on dielectric substrates. In this work, we report on growth of Pt and Au films on MgO single crystal substrates of (100) and (110) surface orientation for use as epitaxial templates for thin film photovoltaic devices. We develop bias-assisted sputtering for deposition of oriented Pt and Au films with sub-nanometer roughness. We show that biasing the substrate decreases the substrate temperature necessary to achieve epitaxial orientation, with temperature reduction from 600 to 350 degrees C for Au, and from 750 to 550 degrees C for Pt, without use of transition metal seed layers. In addition, this temperature can be further reduced by reducing the growth rate. Biased deposition with varying substrate bias power and working pressure also enables control of the film morphology and surface roughness. PMID- 26984043 TI - In silico and In vitro evaluation of the anti-inflammatory potential of Centratherum punctatum Cass-A. AB - Centratherum punctatum Cass., a herb belonging to the family Asteraceae has been traditionally used as a curative against diverse disorders like inflammation, tumor, depression, and hypertension. Though the medicinal properties of this plant have been attributed to the presence of flavonoids, glucosides, alkaloids, Vitamin C, etc., the molecular constituents of this plant and of the flavonoids that contribute to its medicinal activity have not been explored yet. This work attempts to evaluate the potential of Centratherum punctatum extract as an anti inflammatory agent. Ethanolic extracts of Centratherum punctatum analyzed by High Performance Thin Layer Chromatography (HPTLC) and Liquid Chromatography-Mass Spectrometry (LC-MS/MS) identified the presence of the flavones kaempferol, glycoside Isorhamnetin-3-O-rutinoside, and kaempferol-3-glucoside. The plant extract exhibited anti-oxidant property as confirmed by DPPH assay and IC50 value of 271.6 MUg/mL during inhibition of protein denaturation, 186.8 MUg/mL during RBC membrane stabilization, and 278.2 MUg/mL for proteinase inhibition. Membrane stabilizing functions of flavones and flavones glycosides validated the anti inflammatory potential of the extract. In silico evaluation using a rigorous molecular docking protocol with receptors of Cox2, TNF-alpha, Interleukin 1beta convertase, and Histamine H1 predicted high binding affinity of the isoflavones and isoflavone glycosides of Centratherum punctatum Cass. The interactions have also been shown to compare well with that of known drugs valdecoxib through Gln178, His342, and Gly340, desloratadine (through Lys191 and Thr194) and belnacasin (through Asp288 and Gly287) proven to function through the anti inflammatory pathway. This work establishes the anti-inflammatory potential of Centratherum punctatum Cass. extract as an alternative to existing therapeutic approach to inflammation through a systematic in silico approach supplementing the findings. PMID- 26984044 TI - Posttraumatic Stress Disorder and Suicidal Behavior: Indirect Effects of Impaired Social Functioning. AB - Social functioning is negatively impacted by the presence of PTSD, while increasing risk of suicidal behavior among individuals with PTSD. However, little research has examined the specific role of social functioning in the association between PTSD and suicidal behavior. Parallel multiple indirect effects analyses were performed to understand the unique indirect effects of four aspects of social functioning. Indirect effects of PTSD on suicidal ideation were significant through three pathways: interpersonal conflict, perceived family support, and interpersonal apprehension. Perceived family support was the only indirect pathway significantly associated with suicide attempt. Findings suggest that social functioning should be assessed and potentially targeted during treatment to help modify the risk for suicidal behavior among individuals with PTSD. PMID- 26984042 TI - Drug resistance originating from a TGF-beta/FGF-2-driven epithelial-to mesenchymal transition and its reversion in human lung adenocarcinoma cell lines harboring an EGFR mutation. AB - Epithelial-to-mesenchymal transition (EMT) is a malignant cancer phenotype characterized by augmented invasion and metastasis, chemoresistance, and escape from host-immunity. This study sought to identify efficient methods for inducing EMT reversion, to evaluate alterations in chemosensitivity and immune protectiveness, and to elucidate the underlying mechanisms. In this study, the human lung adenocarcinoma cell lines PC-9 and HCC-827, harboring an EGFR mutation, were treated with TGF-beta and FGF-2 to induce EMT. The phenotypic alterations were evaluated by RT-PCR, fluorescent immunohistochemistry, cell mobility, and flow cytometry. Chemosensitivity to gefitinib and cisplatin was evaluated using an MTT assay and apoptosis. Immune-protectiveness was evaluated by PD-L1 expression. A combination of TGF-beta and FGF-2 efficiently induced EMT in both cell lines: through Smad3 pathway in PC-9, and through Smad3, MEK/Erk, and mTOR pathways in HCC-827. The mTOR inhibitor PP242, metformin, and DMSO reverted EMT to different extent and through different pathways, depending on the cell lines. EMT induction reduced the sensitivity to gefitinib in both cell lines and to cisplatin in HCC-827, and it increased PD-L1 expression in both cell lines. EMT reversion using each of the 3 agents partly restored chemosensitivity and suppressed PD-L1 expression. Thus, chemoresistance and increased PD-L1 expression caused by EMT can be successfully reverted by EMT-reverting agents. PMID- 26984045 TI - Utilization of nanoemulsions to enhance bioactivity of pharmaceuticals, supplements, and nutraceuticals: Nanoemulsion delivery systems and nanoemulsion excipient systems. AB - INTRODUCTION: The efficacy of many hydrophobic bioactives (pharmaceuticals, supplements, and nutraceuticals) is limited due to their relatively low or highly variable bioavailability. Nanoemulsions consisting of small lipid droplets (r < 100 nm) dispersed in water can be designed to improve bioavailability. AREAS COVERED: The major factors limiting the oral bioavailability of hydrophobic bioactive agents are highlighted: bioaccessibility, absorption and transformation. Two nanoemulsion-based approaches to control these processes and improve bioavailability are discussed: nanoemulsion delivery systems (NDS) and nanoemulsion excipient systems (NES). In NDS, hydrophobic bioactives are dissolved within the lipid phase of oil-in-water nanoemulsions. In NES, the bioactives are present within a conventional drug, supplement, or food, which is consumed with an oil-in-water nanoemulsion. Examples of NDS and NES utilization to improve bioactive bioavailability are given. EXPERT OPINION: Considerable progress has been made in nanoemulsion design, fabrication, and testing. This knowledge facilitates the design of new formulations to improve the bioavailability of pharmaceuticals, supplements, and nutraceuticals. NDS and NES must be carefully designed based on the major factors limiting the bioavailability of specific bioactives. Research is still required to ensure these systems are commercially viable, and to demonstrate their safety and efficacy using animal and human feeding studies. PMID- 26984046 TI - Tetramethylpyrazine inhibits tumor growth of lung cancer through disrupting angiogenesis via BMP/Smad/Id-1 signaling. AB - The underlying mechanisms of inhibitory effects induced by tetramethylpyrazine (TMP) on angiogenesis and tumor growth of lung cancer were investigated. In vitro cell proliferation, migration, and tube formation of human microvascular endothelial cells (HMEC-1) were evaluated by a 3-(4,5-dimethylthiazol-2-yl)-2,5 dephenyltetrazolium bromide (MTT), wound healing, Transwell, and Matrigel assays. The expression of BMP/Smad/Id-1 signals was detected by RT-PCR and western blotting. In an A549 xenograft tumor model, TMP (40 and 80 mg/kg/day) was intraperitoneally injected into mice. The expressions of CD31, phosphorylated Smad1/5/8, and Id-1 were measured by immunohistochemistry. We demonstrated that TMP inhibited proliferation, migration, and capillary tube formation of HMEC-1 in a dose- and time-dependent manner. Furthermore, treatment of HMEC-1 cells with TMP (0.4 mg/ml) significantly upregulated BMP2 expression and downregulated BMPRIA, BMPRII, phosphorylated Smad1/5/8, and Id-1 expression. In addition, administrations of TMP remarkably inhibited tumor growth of A549 xenograft in nude mice. The CD31, phosphorylated Smad1/5/8, and Id-1 expression were significantly inhibited in TMP-treated xenograft tumors compared with the vehicle. In conclusion, our results indicated that TMP suppressed angiogenesis and tumor growth of lung cancer via blocking the BMP/Smad/Id-1 signaling. PMID- 26984047 TI - Sociocultural variation in attitudes toward use of genetic information and participation in genetic research by race in the United States: implications for precision medicine. AB - BACKGROUND: "Precision medicine" (PM) requires researchers to identify actionable genetic risks and for clinicians to interpret genetic testing results to patients. Whether PM will equally benefit all populations or exacerbate existing disparities is uncertain. METHODS: We ascertained attitudes toward genetic testing and genetic research by race in the United States using the online Amazon mTurk US workforce (n = 403 White; n = 56 African American (AA)). Generalized linear models were used to test differences in beliefs and preferences by race, adjusting for sociodemographics and prior genetic experience. RESULTS: AA were less likely than White to believe that genetic tests should be promoted or made available. Further, AA were less likely to want genetic testing results or to participate in genetic research. CONCLUSIONS: Important dimensions that underlay PM are not universally accepted by all populations. Without clear attention to concerns, AA communities may not equally benefit from the rapidly-emerging trend in PM-centered research and clinical practice. PMID- 26984048 TI - Balancing digital information-sharing and patient privacy when engaging families in the intensive care unit. AB - Patients in intensive care units (ICUs) may lack decisional capacity and may depend on proxy decision makers (PDMs) to make medical decisions on their behalf. High-quality information-sharing with PDMs, including through such means as health information technology, could improve communication and decision making and could potentially minimize the psychological consequences of an ICU stay for both patients and their family members. However, alongside these anticipated benefits of information-sharing are risks of unwanted disclosure of sensitive information. Approaches to identifying the optimal balance between access to digital health information to facilitate engagement and protecting patient privacy are urgently needed. We identified eight themes that should be considered in balancing health information access and patient privacy: 1) potential benefits to patients from PDM data access; 2) potential harms to patients from such access; 3) the moral status of families within the patient-clinician relationship; 4) the scope of relevant information provided to PDMs; 5) issues around defining PDMs' authority; 6) methods for eliciting and documenting patient preferences about their family's information access; 7) the relevance of methods for ascertaining the identity of PDMs; and 8) the obligations of hospitals to prevent privacy breaches by PDMs. We conclude that PDMs should typically have access to health information from the current episode of care when the patient is decisionally impaired, unless the patient has previously expressed a clear preference that PDMs not have such access. PMID- 26984049 TI - Data-driven health management: reasoning about personally generated data in diabetes with information technologies. AB - OBJECTIVE: To investigate how individuals with diabetes and diabetes educators reason about data collected through self-monitoring and to draw implications for the design of data-driven self-management technologies. MATERIALS AND METHODS: Ten individuals with diabetes (six type 1 and four type 2) and 2 experienced diabetes educators were presented with a set of self-monitoring data captured by an individual with type 2 diabetes. The set included digital images of meals and their textual descriptions, and blood glucose (BG) readings captured before and after these meals. The participants were asked to review a set of meals and associated BG readings, explain differences in postprandial BG levels for these meals, and predict postprandial BG levels for the same individual for a different set of meals. Researchers compared conclusions and predictions reached by the participants with those arrived at by quantitative analysis of the collected data. RESULTS: The participants used both macronutrient composition of meals, most notably the inclusion of carbohydrates, and names of dishes and ingredients to reason about changes in postprandial BG levels. Both individuals with diabetes and diabetes educators reported difficulties in generating predictions of postprandial BG; their predictions varied in their correlations with the actual captured readings from r = 0.008 to r = 0.75. CONCLUSION: Overall, the study showed that identifying trends in the data collected with self-monitoring is a complex process, and that conclusions reached by both individuals with diabetes and diabetes educators are not always reliable. This suggests the need for new ways to facilitate individuals' reasoning with informatics interventions. PMID- 26984050 TI - Osteoporosis: Not all BMD is created equal. PMID- 26984054 TI - Therapy: A fine conception -- BSR/BHPR guidelines on drugs in pregnancy. AB - Medical management of women with rheumatic diseases during pregnancy is challenging owing to incomplete information regarding medication safety. The British Society for Rheumatology and the British Health Professionals in Rheumatology committee published consensus guidelines that provide a good first step towards narrowing the knowledge gap in this important field. PMID- 26984055 TI - Therapy: Cell-type-specific approach to TNF inhibition. PMID- 26984056 TI - Azacitidine in the treatment of blastic plasmacytoid dendritic cell neoplasm: a report of 3 cases. PMID- 26984057 TI - The Capacity to Act in Trans Varies Among Drosophila Enhancers. AB - The interphase nucleus is organized such that genomic segments interact in cis, on the same chromosome, and in trans, between different chromosomes. In Drosophila and other Dipterans, extensive interactions are observed between homologous chromosomes, which can permit enhancers and promoters to communicate in trans Enhancer action in trans has been observed for a handful of genes in Drosophila, but it is as yet unclear whether this is a general property of all enhancers or specific to a few. Here, we test a collection of well-characterized enhancers for the capacity to act in trans Specifically, we tested 18 enhancers that are active in either the eye or wing disc of third instar Drosophila larvae and, using two different assays, found evidence that each enhancer can act in trans However, the degree to which trans-action was supported varied greatly between enhancers. Quantitative analysis of enhancer activity supports a model wherein an enhancer's strength of transcriptional activation is a major determinant of its ability to act in trans, but that additional factors may also contribute to an enhancer's trans-activity. In sum, our data suggest that a capacity to activate a promoter on a paired chromosome is common among Drosophila enhancers. PMID- 26984059 TI - Persistence of RNAi-Mediated Knockdown in Drosophila Complicates Mosaic Analysis Yet Enables Highly Sensitive Lineage Tracing. AB - RNA interference (RNAi) has emerged as a powerful way of reducing gene function in Drosophila melanogaster tissues. By expressing synthetic short hairpin RNAs (shRNAs) using the Gal4/UAS system, knockdown is efficiently achieved in specific tissues or in clones of marked cells. Here we show that knockdown by shRNAs is so potent and persistent that even transient exposure of cells to shRNAs can reduce gene function in their descendants. When using the FLP-out Gal4 method, in some instances we observed unmarked "shadow RNAi" clones adjacent to Gal4-expressing clones, which may have resulted from brief Gal4 expression following recombination but prior to cell division. Similarly, Gal4 driver lines with dynamic expression patterns can generate shadow RNAi cells after their activity has ceased in those cells. Importantly, these effects can lead to erroneous conclusions regarding the cell autonomy of knockdown phenotypes. We have investigated the basis of this phenomenon and suggested experimental designs for eliminating ambiguities in interpretation. We have also exploited the persistence of shRNA-mediated knockdown to design a sensitive lineage-tracing method, i TRACE, which is capable of detecting even low levels of past reporter expression. Using i-TRACE, we demonstrate transient infidelities in the expression of some cell-identity markers near compartment boundaries in the wing imaginal disc. PMID- 26984058 TI - Heterochromatin-Associated Proteins HP1a and Piwi Collaborate to Maintain the Association of Achiasmate Homologs in Drosophila Oocytes. AB - Accurate segregation of homologous chromosomes during meiosis depends on their ability to remain physically connected throughout prophase I. For homologs that achieve a crossover, sister chromatid cohesion distal to the chiasma keeps them attached until anaphase I. However, in Drosophila melanogaster wild-type oocytes, chromosome 4 never recombines, and the X chromosome fails to cross over in 6-10% of oocytes. Proper segregation of these achiasmate homologs relies on their pericentric heterochromatin-mediated association, but the mechanism(s) underlying this attachment remains poorly understood. Using an inducible RNA interference (RNAi) strategy combined with fluorescence in situ hybridization (FISH) to monitor centromere proximal association of the achiasmate FM7a/X homolog pair, we asked whether specific heterochromatin-associated proteins are required for the association and proper segregation of achiasmate homologs in Drosophila oocytes. When we knock down HP1a, H3K9 methytransferases, or the HP1a binding partner Piwi during mid-prophase, we observe significant disruption of pericentric heterochromatin-mediated association of FM7a/X homologs. Furthermore, for both HP1a and Piwi knockdown oocytes, transgenic coexpression of the corresponding wild-type protein is able to rescue RNAi-induced defects, but expression of a mutant protein with a single amino acid change that disrupts the HP1a-Piwi interaction is unable to do so. We show that Piwi is stably bound to numerous sites along the meiotic chromosomes, including centromere proximal regions. In addition, reduction of HP1a or Piwi during meiotic prophase induces a significant increase in FM7a/X segregation errors. We present a speculative model outlining how HP1a and Piwi could collaborate to keep achiasmate chromosomes associated in a homology-dependent manner. PMID- 26984061 TI - Peripheral blood collection: the first step towards gene expression profiling. AB - A crucial challenge for gene expression analysis in human biomonitoring studies on whole blood samples is rapid sample handling and mRNA stabilization. This study was designed to evaluate the impact of short bench times (less than 30 min) on yield, quality and gene expression of mRNA in the presence of different stabilization buffers (Tempus(TM) Blood RNA tube and RNAlater((r)) Stabilization Reagent). Microarray analyzes showed significant changes over short periods of time in expression of a considerate part of the transcriptome (2356 genes) with a prominent role for NFkB-, cancer- and glucocorticoid-mediated networks, and specifically interleukin-8 (IL-8). These findings suggest that even short bench times affect gene expression, requiring to carry out blood collection in a strictly standardized way. PMID- 26984062 TI - Women's empowerment: Finding strength in self-compassion. AB - Empowerment is often a desired outcome for health programs; however, it is rarely evaluated. One way to increase empowerment may be through self-compassion. The authors of the current study aimed to determine whether self-compassion and empowerment were positively related. Two hundred and five women (ages 18 to 48 years) were recruited from a pool of undergraduate students at a university in the southeastern United States in the summer/fall of 2012. Participants completed the study using Qualtrics, an online survey system. Participants wrote about a fight in a romantic relationship and were randomly assigned to write about the fight either self-compassionately or generally. Empowerment and perceptions of the fight were assessed as dependent measures. Hierarchical regression analyses investigated the relation of self-compassion, manipulated self-compassion, and their interaction with empowerment. A significant positive relationship was found between self-compassion and empowerment. However, manipulated self-compassion was not significantly related to empowerment. These findings suggested that self compassion and empowerment were strongly related, but using a short-term self compassion intervention may not be strong enough to influence empowerment. Empowerment-based practitioners may find empowerment increases more easily in women who are self-compassionate. If self-compassion is incorporated into empowerment settings, a long-term intervention may be necessary. PMID- 26984060 TI - A Pathway Analysis of Melanin Patterning in a Hemimetabolous Insect. AB - Diversity in insect pigmentation, encompassing a wide range of colors and spatial patterns, is among the most noticeable features distinguishing species, individuals, and body regions within individuals. In holometabolous species, a significant portion of such diversity can be attributed to the melanin synthesis genes, but this has not been formally assessed in more basal insect lineages. Here we provide a comprehensive analysis of how a set of melanin genes (ebony, black, aaNAT, yellow, and tan) contributes to the pigmentation pattern in a hemipteran, Oncopeltus fasciatus For all five genes, RNA interference depletion caused alteration of black patterning in a region-specific fashion. Furthermore, the presence of distinct nonblack regions in forewings and hindwings coincides with the expression of ebony and aaNAT in these appendages. These findings suggest that the region-specific phenotypes arise from regional employment of various combinations of the melanin genes. Based on this insight, we suggest that melanin genes are used in two distinct ways: a "painting" mode, using predominantly melanin-promoting factors in areas that generally lack black coloration, and, alternatively, an "erasing" mode, using mainly melanin suppressing factors in regions where black is the dominant pigment. Different combinations of these strategies may account for the vast diversity of melanin patterns observed in insects. PMID- 26984063 TI - Sibling Aggression Among Clinic-Referred Children and Adolescents. AB - Aggression against siblings has been associated with a number of negative outcomes within community samples of children and adolescents, but little is known about this phenomenon within clinical samples. The current study empirically identified subtypes of sibling aggression, assessed prevalence within a clinic-referred sample of children and adolescents, and described risk factors associated with sibling aggression. Surveys were administered as part of the intake procedures at a community mental health center serving children and adolescents. The current study analyzed reports of sibling-directed aggression and mother-to-child aggression, as well as symptom counts, from a sample of 346 matched pairs of mothers and children or adolescents. Ages of child/adolescent participants ranged from 7 to 18 (M = 12.92, SD = 2.82) and were 55.8% male. The sample was primarily Caucasian (90.2%), were lower income, and resided in a semirural midwestern county. Sibling-directed aggression was reported by 93.1% of mothers and 82.4% of children. Principal components analyses identified two subtypes of sibling aggression, mild and severe. Mother and child/adolescent reports of sibling aggression demonstrated only moderate agreement. Mother-to child verbal aggression and corporal punishment were more predictive of sibling aggression than more severe maternal aggression, and externalizing symptoms were also associated with sibling aggression. Sibling-directed aggression is very common among clinic-referred children and adolescents and may be an important target for treatment. Using multiple reports of sibling aggression could increase the chances of detection, as would awareness of other risk factors associated with sibling aggression. PMID- 26984066 TI - Assessed value of high-sensitivity cardiac troponin T for cardiovascular disease among CKD patients. AB - Objective To analyze the relationship between serum high-sensitivity cardiac troponin T (hs-cTnT) and cardiovascular disease (CVD) among non-dialysis chronic kidney disease (CKD) patients, and to further explore its value of evaluating and predicting CVD in this population. Methods Five hundred and fifty-seven non dialysis CKD patients were involved in this cross-sectional study. The relationship between serum hs-cTnT and CVD was analyzed using comparison between groups and regression analysis, and its value on assessing cardiac structure and function was evaluated by ROC curves. Results Median level of hs-cTnT was 13 (7 29) ng/L, with 1.7% undetectable, 46.4% greater than 99th percentile of the general population. Multivariate analysis suggested that compared with the lowest quartile of hs-cTnT, the highest quartile was approximately six times as likely to develop into LVH (OR, 6.515; 95% CI, 3.478-12.206, p < 0.05) and 18 times as likely to progress to left ventricular diastolic dysfunction(OR, 18.741; 95% CI, 2.422-145.017, p < 0.05). And Ln cTnT level had a more modest association with LVEF (OR, -1.117; 95% CI, -5.839 to -0.594; p < 0.05). When evaluated as a screening test, the area under the curve of ROC curves for hs-cTnT was 0.718, 0.788 and 0.736, respectively (p < 0.05). With a specificity of 90% as a diagnostic criterion, the value of hs-cTnT to evaluate LVH, LVEF < 50%, left ventricular diastolic dysfunction increased across CKD stages, from CKD 1 stage to CKD 5 stage. Conclusions In CKD non-dialysis population, hs-cTnT and NT-proBNP were valuable for evaluating LVH, left ventricular systolic dysfunction and left ventricular diastolic dysfunction. PMID- 26984064 TI - Far-red/near-infrared fluorescence light-up probes for specific in vitro and in vivo imaging of a tumour-related protein. AB - As lysosomal protein transmembrane 4 beta (LAPTM4B) is an important biomarker for many solid tumours, development of small-molecule fluorescence light-up probes for detection and imaging of LAPTM4B proteins is particularly valuable. In this work, we reported the design and synthesis of a far-red/near-infrared (FR/NIR) fluorescence light-up probe DBT-2EEGIHGHHIISVG, which could specifically visualize LAPTM4B proteins in cancer cells and tumour-bearing live mice. DBT 2EEGIHGHHIISVG was synthesized by the conjugation of two LAPTM4B-binding peptide ligands (EEGIHGHHIISVG) with one environment-sensitive fluorogen, 4,7-di(thiophen 2-yl)-2,1,3-benzothiadiazole (DBT). Owing to the intramolecular charge transfer character of DBT, DBT-2EEGIHGHHIISVG is weakly emissive in aqueous solution, but switches to fluoresce upon LAPTM4B proteins specifically bind to the peptide ligand of the probe, which provide the DBT with hydrophobic microenvironment, greatly reducing its charge transfer effect with water. It is found that DBT 2EEGIHGHHIISVG can achieve targeted imaging of LAPTM4B proteins in HepG2 cancer cells and visualize LAPTM4B protein-expressed tumour tissues of live mice in a selective and high-contrast manner. PMID- 26984065 TI - Facilitators and barriers to treatment adherence within PMTCT programs in Malawi. AB - In Malawi, an innovative prevention of mother-to-child transmission (PMTCT) of HIV program, Option B+, has greatly expanded access to antiretroviral treatment at no cost to women and their exposed infants. However, many women continue to experience social, cultural, and structural barriers impeding their ability to consistently access medical treatment. Understanding these women's perspectives may make programs more responsive to patients' needs. This qualitative study sought to explore factors influencing women's adherence within PMTCT programs in southern Malawi. Participants were current PMTCT patients (the first cohort following national implementation of Option B+), healthcare providers, community leaders, and patients who had dropped out of the program ("defaulters"). Qualitative interviews and focus groups were conducted to investigate barriers and facilitators to continued participation within PMTCT programs. Data were analyzed using content analysis. Barriers identified included fears of HIV disclosure to husbands, community-based HIV/AIDS stigma, and poor interactions with some health workers. Facilitators included the improved survival of PMTCT patients in recent years and the desire to remain healthy to care for one's children. This research highlights important sociocultural factors affecting adherence within HIV/AIDS treatment programs in Malawi. Recommendations to improve access to medical care for PMTCT patients include integrated services to increase attention to confidentiality and minimize stigma, shared HIV testing and counseling for couples to minimize conflict in gender-unequal relationships, and peer-led support groups to provide social support from other women with the shared experience of an HIV-positive serostatus. PMID- 26984068 TI - Antiphospholipid Antibodies as a Thrombotic Risk Factor in Connective Tissue Diseases and Idiopathic/immune Thrombocytopenic Purpura--Proposal for Altered Cut off values for Better Prediction. PMID- 26984069 TI - Clinical Application of the Forced Oscillation Technique. AB - The forced oscillation technique (FOT) is a noninvasive method with which to measure respiratory system resistance and reactance during tidal breathing. Recently, its clinical application has spread worldwide with the expansion of commercially available broadband frequency FOT devices, including MostGraph and Impulse Oscillometry. An increasing number of reports have supported the usefulness of the FOT in the management of asthma and chronic obstructive pulmonary disease (COPD). However, the FOT is not a surrogate test for spirometry, but should be used complementarily. Furthermore, reference values are not necessarily available and the interpretation of some measured data is controversial. There is a need to update the international statement for not only technical aspects but also the clinical use of the FOT. In this review, we summarize the previously published studies and discuss how to use the FOT in a clinical setting. PMID- 26984070 TI - Meningococcemia in Adults: A Review of the Literature. AB - We mainly refer to the acute setting of meningococcemia. Meningococcemia is an infection caused by Neisseria meningitidis, which has 13 clinically significant serogroups that are distinguishable by the structure of their capsular polysaccharides. N. meningitidis, also called meningococcus, is a Gram-negative, aerobic, diplococcus bacterium. The various consequences of severe meningococcal sepsis include hypotension, disseminated intravascular coagulation (DIC), multiple organ failure, and osteonecrosis due to DIC. The gold standard for the identification of meningococcal infection is the bacteriologic isolation of N. meningitidis from body fluids such as blood, cerebrospinal fluid (CSF), synovial fluid, and pleural fluid. Blood, CSF, and skin biopsy cultures are used for diagnosis. Meningococcal infection is a medical emergency that requires antibiotic therapy and intensive supportive care. Management of the systemic circulation, respiration, and intracranial pressure is vital for improving the prognosis, which has dramatically improved since the wide availability of antibiotics. This review of the literature provides an overview of current concepts on meningococcemia due to N. meningitidis infection. PMID- 26984071 TI - Clinical Search for Undiagnosed Mesenteric Phlebosclerosis at Outpatient Departments Specializing in Herbal (Kampo) Medicine. AB - OBJECTIVE: Mesenteric phlebosclerosis (MP) is a disease characterized by calcification of the mesenteric vein, which causes chronic mesenteric ischemia. Recently, the long-term intake of gardenia fruit ('Sanshishi' in Japanese) has been attracting attention as a possible cause. Usually, only advanced, severe MP cases get reported. However, we suspected that some latent cases of this disease may exist. We performed this study in order to determine the prediagnostic cases at our outpatient departments of herbal (Kampo) medicine, with particular attention paid to the initial changes, such as any slight color change of the colon, as shown in colonoscopy. METHODS: We recommend colonoscopy and computed tomography (CT) scans for patients with a long-term history of taking herbal medicines containing gardenia fruit. Clinical examinations were performed upon receiving patients' consent from December 2013 to November 2014. RESULTS: Of the 103 patients who took gardenia fruit long-term, 29 agreed to be checked for MP. 14 patients underwent colonoscopy. Four patients were confirmed to have MP due to the presence of fibrotic deposition of the colonic membrane on histological inspection. Twenty-one patients underwent abdominal CT screening. Characteristic calcification of the mesenteric vein was observed on CT scans in 2 patients. All 4 MP patients took Kampo formulas containing gardenia fruit for more than 6.8 years. The other patients did not develop MP, despite long-term gardenia fruit intake. CONCLUSION: We detected the latent and undiagnosed MP cases. All diagnoses were made while paying careful attention to any slight changes in colonoscopy and CT scans. PMID- 26984067 TI - Functionally different alpha-synuclein inclusions yield insight into Parkinson's disease pathology. AB - The formation of alpha-synuclein (alpha-S) amyloid aggregates, called Lewy bodies (LBs), is a hallmark of Parkinson's disease (PD). The function of LBs in the disease process is however still unclear; they have been associated with both neuroprotection and toxicity. To obtain insight into this contradiction, we induced the formation of alpha-S inclusions, using three different induction methods in SH-SY5Y cells and rat-derived primary neuronal cells. Using confocal and STED microscopy we observed induction-dependent differences in alpha-S inclusion morphology, location and function. The aggregation of alpha-S in functionally different compartments correlates with the toxicity of the induction method measured in viability assays. The most cytotoxic treatment largely correlates with the formation of proteasome-associated, juxta-nuclear inclusions. With less toxic methods cytosolic deposits that are not associated with the proteasome are more prevalent. The distribution of alpha-S over at least two different types of inclusions is not limited to cell models, but is also observed in primary neuronal cells and in human mesencephalon. The existence of functionally different LBs, in vivo and in vitro, gives important insights in the impact of Lewy Body formation on neuronal functioning and may thereby provide a platform for discovering therapeutics. PMID- 26984072 TI - Steroid Pulse Therapy for Blood Cell Recovery in Allogeneic Hematopoietic Stem Cell Transplantation. AB - OBJECTIVE: Steroid pulse therapy is used to relieve pancytopenias in our hospital and is effective in some patients. However, it is unclear which patients will benefit from such therapy. Thus, we retrospectively analyzed the clinical features of patients undergoing allogeneic hematopoietic stem cell transplantation who received steroid pulse therapy to facilitate recovery in their blood cell counts. METHODS: Between 2004 and 2012, 24 patients underwent steroid pulse therapy and the medical records of 17 of these evaluable patients (11 men, 6 women) were retrospectively reviewed. Bone marrow smears were assessed to calculate the proportion of hemophagocytic macrophages just prior to receiving pulse therapy. RESULTS: Steroid pulse therapy was started at a median of 15 days after transplantation (range, 10-28 days). The median white blood cell count was 0.02*10(3)/MUL (range, 0.01-0.4*10(3)/MUL). Eight patients responded to pulse therapy and subsequent engraftment was achieved in all responders. None of the patients who underwent cord blood transplantation responded to the pulse therapy. Among the non-responders, only two patients achieved engraftment and four of nine non-responders died within one month. When evaluating the efficacy of steroid pulse therapy according to the ferritin level and proportion of hemophagocytic macrophages among patients undergoing bone marrow or peripheral blood stem cell transplantation, both values were higher in responders than in non-responders. CONCLUSION: We speculate that responders have a hemophagocytic syndrome which is responsive to steroid pulse therapy. Thus, our results imply that the use of ferritin levels in combination with the proportion of hemophagocytic macrophages may be useful for the early detection of potential hemophagocytic syndrome after hematopoietic stem cell transplantation. PMID- 26984073 TI - Presence of Antiphospholipid Antibodies as a Risk Factor for Thrombotic Events in Patients with Connective Tissue Diseases and Idiopathic Thrombocytopenic Purpura. AB - OBJECTIVE: Antiphospholipid syndrome (APS) is a well-known complication of habitual abortion and/or thrombosis and is frequently associated with autoimmune diseases. METHODS: We retrospectively investigated the relationships between the presence of antiphospholipid antibodies (aPLs) and the incidence of thrombotic events (THEs) in 147 patients with various connective tissue diseases (CTD) suspected of having APS and 86 patients with idiopathic thrombocytopenic purpura (ITP). THEs were observed in 41 patients, including 14 cases of venous thrombosis, 21 cases of arterial thrombosis and eight cases of complications of pregnancy. RESULTS: The prevalence of THE was significantly high in the systemic lupus erythematosus (SLE) patients compared with the other CTD patients and ITP patients. The frequency of lupus anticoagulant (LA), anticardiolipin antibodies (aCL)-beta2-glycoprotein (GPI) complex IgG and aPL was significantly high in the SLE patients compared with the ITP patients. Subsequently, the rate of development of THE was significantly high in the patients with aPLs. In particular, the incidence of THE was significantly high in the SLE or ITP patients with LA, aCL-beta2GPI IgG or aPL. The optimal cut-off values for LA, aCL IgG and aCL-beta2GPI complex IgG for the risk of THEs were higher in the SLE patients in comparison to the values obtained when using the kit provided by the manufacturer. CONCLUSION: Although aPLs is frequently associated with SLE and is a causative factor for thrombosis, the optimal cut-off value for aPL for predicting the occurrence of THEs varies among different underlying diseases. PMID- 26984074 TI - The Clinical Characteristics of Neonatal Sepsis Infection in Southwest China. AB - OBJECTIVE: To identify the pathogens responsible for neonatal sepsis in a high volume women and children's hospital in Southwest China. METHODS: We retrospectively studied 133 neonates who were admitted to the West China Women and Children's Hospital between 2008 and 2012 for sepsis. The clinical characteristics of the patients were recorded, and the antibiotic sensitivities of the isolated bacteria were determined. RESULTS: All of the included patients had clinical symptoms of sepsis, and subsequent blood cultures confirmed the infection. Almost 80% of patients were infected with coagulase-negative staphylococci (52.8%), Escherichia coli (23.6%), Klebsiella pneumoniae (16.0%) or Staphylococcus aureus (7.5%). Neonates who were infected with gram-negative bacteria, particularly K. pneumoniae, had lower birth weights and were admitted to hospital within 24 hours of birth. Additionally, 87.5% of the isolated K. pneumoniae strains were resistant to third generation cephalosporins. CONCLUSION: Coagulase-negative staphylococci were the most common pathogens found in neonatal sepsis. Moreover, neonatal sepsis caused by gram-negative bacteria was more often observed in newborns of low birth weight. The isolated strains of gram-negative bacteria were highly resistant to cephalosporins. This observation highlights the issue of antibiotic-resistant pathogens in the clinical setting, which poses an added risk to infants presenting with sepsis. PMID- 26984075 TI - A Retrospective Analysis of Drug Fever Diagnosed during Infectious Disease Consultation. AB - OBJECTIVE: To clarify the current situation concerning drug fever (DF) in Japan, we retrospectively analyzed patients undergoing infectious disease consultation at our institution. METHODS: Between April 2014 and May 2015, we extracted the records of DF patients from among 388 patients who had obtained infectious disease consultations in Kurume University Hospital. We reviewed their medical charts and summarized the characteristics of DF. RESULTS: This study included the records of 16 patients. Clinical signs (relative bradycardia, the duration of the drug administration before becoming febrile, and the interval between the discontinuation of a drug and the alleviation of a fever), and laboratory tests (varied white blood cell count, low level of C-reactive protein, and a mild elevation of transaminases) were compatible with those from previous reports. Among the drug-confirmed cases, five involved the use of glycopeptides (vancomycin: 3, teicoplanin: 2), which were considered to be uncommon causes, and the another five cases involved the use of beta-lactams. In addition, the procalcitonin levels were either negative or low (<=0.25 ng/mL) in 10 of the 11 procalcitonin-measured cases. CONCLUSION: Our findings demonstrated that glycopeptides, similar to beta-lactams, may be the origin of DF. Furthermore, procalcitonin may be helpful in the diagnosis of DF, but only in combination with other detailed examinations. PMID- 26984076 TI - Efficacy of Intrathecal MTX/Ara-C Combined with Systemic Chemotherapy in a Gastric Cancer Patient with Meningeal Carcinomatosis. AB - A 35-year-old man was diagnosed to have gastric cancer by endoscopic and histological examinations. Staging laparoscopy detected peritoneal metastasis. Systemic chemotherapy was started, but the patient complained of severe headache. Subsequently, a lumbar puncture demonstrated adenocarcinoma cells in the spinal fluid, suggesting the occurrence of meningeal carcinomatosis (MC) from gastric cancer. MC occurs only rarely in patients with gastric cancer, but the prognosis is invariably poor. However, this patient nevertheless survived for 12 months after receiving intrathecal MTX/Ara-C together with systemic chemotherapy. Therefore, the early detection of meningeal irritation sign and intrathecal chemotherapy might greatly improve the prognosis of gastric cancer patients with MC. PMID- 26984077 TI - Localized Hepatic Tuberculosis with Imaging Changes Caused by the Progression of Tuberculosis. AB - Localized hepatic tuberculosis (LHTB) is difficult to diagnose preoperatively, and most cases of LHTB are diagnosed based on pathological findings. A relationship between imaging features and the pathological stage of hepatic tuberculosis (TB) has recently been reported, which could aid in the diagnosis of hepatic TB. We herein present a case study of a patient with LHTB diagnosed postoperatively who demonstrated imaging changes due to the progression of TB. An awareness of the presence of LHTB might have permitted a preoperative diagnosis. This is the first report of an LHTB patient who exhibited imaging changes during the course of the disease. PMID- 26984078 TI - The Coexistence of Somatostatinoma and Gastrointestinal Stromal Tumor in the Duodenum of a Patient with Von Recklinghausen's Disease. AB - We herein describe a case of somatostatinoma coexisting with a gastrointestinal stromal tumor (GIST) in the duodenum of an 81-year-old woman with Von Recklinghausen's disease (VRD) and common bile duct stone who presented with diarrhea of three months in duration. Gastroduodenoscopy revealed an ulcer on the second part of the duodenum. A 2.1-cm enhancing tumor was observed to extend from the ulcer on an abdominal computed tomography scan. Subtotal stomach-preserving pancreaticoduodenectomy revealed a somatostatinoma on the papilla of the vater and duodenal GIST. There have been only eight reports on VRD associated with ampullary somatostatinoma and GIST. An awareness of this possibility in patients with gastrointestinal lesions is necessary for proper treatment and patient management. PMID- 26984079 TI - Sorafenib-induced Acute Pancreatitis: A Case Report and Review of the Literature. AB - Sorafenib has been approved to increase the survival in patients with advanced hepatocellular carcinoma. Acute pancreatitis is an uncommon complication of sorafenib treatment. Only a few cases of sorafenib-induced acute pancreatitis have been reported in the English literature. We herein present the case of a 56 year-old man with hepatocellular carcinoma treated with sorafenib at 200 mg once daily. After six days of treatment, he suffered epigastric pain. Laboratory tests showed markedly elevated serum amylase and lipase levels. Imaging studies demonstrated negative findings. Sorafenib-induced acute pancreatitis was diagnosed after reviewing his history. The sorafenib treatment was discontinued, and his symptoms were resolved seven days later. To date, this case had the shortest duration and the lowest dosage of sorafenib to have induced acute pancreatitis. PMID- 26984080 TI - Attainment of a Long-term Favorable Outcome by Sunitinib Treatment for Pancreatic Neuroendocrine Tumor and Renal Cell Carcinoma Associated with von Hippel-Lindau Disease. AB - von Hippel-Lindau (VHL) disease, caused by germline mutations in the VHL gene, is a hereditary autosomal-dominant disorder which predisposes the individual to various malignant and benign tumors. VHL acts as a tumor suppressor, mainly through the negative regulation of hypoxia-inducible factors. Molecular-targeted drugs against vascular endothelial growth factor-signaling pathways, a target of hypoxia-inducible factors, have recently been introduced into clinical practice for the treatment of patients with sporadic renal cell carcinoma and pancreatic neuroendocrine tumors. However, whether such treatments are effective in patients with VHL disease remains to be elucidated. We herein report a Japanese patient with VHL disease who was successfully treated with sunitinib for approximately 5 years. PMID- 26984081 TI - Reversible Atrial Fibrillation with Bradycardia Associated with Primary Cardiac B Cell Lymphoma. AB - Primary cardiac lymphoma (PCL) only rarely occurs and it is defined as a lymphoma in which the bulk of the tumor is located within the heart and pericardium. A 53 year-old woman was referred due to dyspnea, and an electrocardiogram exhibited atrial fibrillation (AF). Echocardiography revealed no abnormal findings. Scintigraphy and a lymph node biopsy led to a diagnosis of PCL. After the start of chemotherapy, AF was converted to atrial tachycardia prior to sinus rhythm with a first-degree atrioventricular block, which was finally restored to a normal sinus rhythm. PCL is only rarely encountered, but it should be included in the differential diagnosis as a possible cause of AF, and such AF could be reversible if the patient can be treated in a timely manner. PMID- 26984082 TI - Acute Adrenal Insufficiency Associated with Rathke's Cleft Cyst. AB - Rathke's cleft cysts are known to cause hormone-related abnormalities. However, the natural history of this disorder is obscure, so it is rarely associated with acute adrenal insufficiency. We herein describe a case of Rathke's cleft cyst associated with acute adrenal insufficiency in a 27-year-old man. The patient experienced severe headaches due to acute adrenal insufficiency without changes in the size of the cyst. Glucocorticoid administration improved these symptoms, and the cyst spontaneously shrank before operation. This case led us to conclude that Rathke's cleft cysts should be considered in the differential diagnosis of patients who present with adrenal insufficiency, and that the cysts can be reduced by glucocorticoids. PMID- 26984083 TI - Fulminant Type 1 Diabetes Mellitus Associated with Coxsackie Virus Type A2 Infection: A Case Report and Literature Review. AB - A 65-year-old Japanese man presented to our hospital in June 2013 with a 6-day history of fever and fatigue, a 24-h history of thirst, and polyuria. His temperature was 37.8 degrees C and he was alert. However, laboratory tests revealed severe hyperglycemia, undetectable C-peptide levels, and diabetic ketoacidosis. Serum antibody testing confirmed a Coxsackie virus A2 infection. A variety of viral infections are reported to be involved in the development of fulminant type 1 diabetes mellitus (FT1D). Our patient is the first reported case of FT1D associated with Coxsackie virus A2 infection and supports the etiological role of common viral infections in FT1D. PMID- 26984084 TI - Streptococcal Infection-related Nephritis (SIRN) Manifesting Membranoproliferative Glomerulonephritis Type I. AB - We herein report the case of an 18-year-old boy who developed nephrotic syndrome and hypertension after upper airway inflammation. Post-streptococcal acute glomerulonephritis was diagnosed on the basis of a high antistreptolysin O titer, hypocomplementemia, proteinuria, and microscopic hematuria. A renal biopsy was performed due to persistent proteinuria, and the pathological diagnosis was membranoproliferative glomerulonephritis (MPGN) type I. Glomeruli showed positive staining for nephritis-associated plasmin receptor (NAPlr), a nephritogenic group A streptococcal antigen, and plasmin activity was found in a similar distribution as NAPlr deposition. This rare case of streptococcal infection-related nephritis (SIRN) manifesting MPGN type I supports the histological diversity of SIRN. PMID- 26984085 TI - Pulmonary Tumor Thrombotic Microangiopathy Caused by Urothelial Carcinoma Expressing Vascular Endothelial Growth Factor, Platelet-derived Growth Factor, and Osteopontin. AB - Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal cancer-related pulmonary complication. It is generally caused by gastric adenocarcinoma, and several molecules produced by tumor cells are reported to play important roles in its pathogenesis. We herein report an autopsy case of PTTM caused by urothelial carcinoma. Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and osteopontin were found to be expressed in both the primary tumor cells and metastatic cells in the PTTM lesions. These findings implicate the possible involvement of VEGF, PDGF, and osteopontin in the pathogenesis of PTTM caused by urothelial carcinoma. PMID- 26984086 TI - Marked Improvement with Pirfenidone in a Patient with Idiopathic Pulmonary Fibrosis. AB - A man in his mid-60's with idiopathic pulmonary fibrosis and hepatitis B-related liver cirrhosis developed exertional dyspnea and a dry cough lasting for three months. High-resolution computed tomography (HRCT) showed increasing bilateral ground-glass opacity superimposed on the usual interstitial pneumonia pattern. Six months after starting pirfenidone therapy, the partial pressure of arterial oxygen at rest increased from 81 to 101 torr, the predicted forced vital capacity (FVC) value increased from 75% to 94% and the ground-glass opacity on HRCT improved. The FVC value was subsequently maintained near or above baseline for 43 months. We concluded that our patient was a super-responder to pirfenidone therapy. PMID- 26984087 TI - Effective Management of Persistent Pneumothorax Using a Thopaz(r) Digital Drainage System Combined with an Endobronchial Watanabe Spigot. AB - A 72-year-old man with salivary gland cancer and multiple pulmonary metastases suffering from intractable pneumothorax was transferred to our institution; he was inoperable because of a low pulmonary function. A chest tube had been placed more than a month prior to this admission. A digital drainage system was used for 24-h monitoring of air leaks (Thopaz(r)). Using the Thopaz(r) system, we performed endoscopic bronchial occlusion using an endobronchial Watanabe spigot (EWS) to reduce air leaks. Finally, the air leaks ceased, and the chest tube was removed five days after EWS placement. We herein report a case of persistent pneumothorax that was successfully treated by endoscopic bronchial EWS placement with the aid of a Thopaz(r) system. PMID- 26984088 TI - Cord Blood Transplantation Following Reduced-intensity Conditioning for Adult onset Inherited Hemophagocytic Lymphohistiocytosis. AB - Inherited hemophagocytic lymphohistiocytosis (HLH) is a genetic anomaly disorder in which abnormally activated cytotoxic T lymphocytes cannot induce the apoptosis of target cells and antigen-presenting cells, leading to hemophagocytosis, pancytopenia, and a variety of symptoms such as a high fever. The present patient with adult-onset HLH developed refractory disease despite receiving immunosuppressive treatments. He underwent a reduced-intensity conditioning (RIC) regimen that comprised antithymocyte globulin (ATG) followed by cord blood transplantation (RIC-CBT). He achieved and maintained a complete donor type. The incorporation of ATG into RIC-CBT may prevent graft failure and control hemophagocytosis, however, further efforts are necessary to reduce infectious complications. PMID- 26984090 TI - Autoimmune Hemolytic Anemia Triggered by Infection with Human Parvovirus B19 after Total Abdominal Colectomy for Ulcerative Colitis. AB - A 50-year-old man was admitted to our hospital for an adhesive ileus 14 years after total abdominal colectomy for ulcerative colitis (UC). The ileus decreased with conservative treatment, however, autoimmune hemolytic anemia (AIHA) was diagnosed due to worsening anemia, a positive direct Coombs test, low haptoglobin, high lactase dehydrogenase, reticulocytosis, and an increase in the erythroblastic series in a bone-marrow examination. Human parvovirus B19 (PV-B19) IgM and PV-B19 DNA were present, indicating the development of AIHA triggered by an infection with PV-B19. The patient is currently being monitored after spontaneous remission. This is the first report of UC after total abdominal colectomy complicated by AIHA triggered by PV-B19 infection. PMID- 26984089 TI - Cytomegalovirus Pneumonia after Anti-CC-chemokine Receptor 4 Monoclonal Antibody (Mogamulizumab) Therapy in an Angioimmunoblastic T-cell Lymphoma Patient. AB - Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive T-cell lymphoma. A 63 year-old man was diagnosed with AITL. He received 6 cycles of CHOP therapy, but showed progressive disease. Subsequently, he received ESHAP chemotherapy; however, it was not effective. He received mogamulizumab (an anti-CCR4 monoclonal antibody). After 4 cycles, his respiratory condition worsened and he was diagnosed with cytomegalovirus (CMV) pneumonia. Despite antiviral and antibiotic therapy, he died. We speculate that the combination of progressive lymphoma with mogamulizumab and chemotherapy likely caused CMV pneumonia. Because mogamulizumab therapy causes immunosuppression, if CMV pneumonia is suspected, then rapid treatment should be initiated. PMID- 26984091 TI - Thrombocytopenia and Anemia with Anti-c-Mpl antibodies Effectively Treated with Cyclosporine in a Patient with Rheumatoid Arthritis and Chronic Renal Failure. AB - A 61-year-old woman with rheumatoid arthritis who was undergoing hemodialysis for end-stage renal failure was transferred to our hospital due to severe thrombocytopenia and anemia. A bone marrow biopsy showed the complete absence of megakaryocytes and erythroblasts. Cyclosporine treatment resulted in the improvement of her megakaryocyte and erythroblast levels, and a decrease in her serum level of anti-c-Mpl (thrombopoietin receptor) antibodies. After this initial improvement, her anemia progressively worsened, despite the continuous administration of immunosuppressive therapy with cyclosporine. Her platelet and leukocyte counts remained stable. This is the first report of a probable case of anti-c-Mpl antibody-associated pure red cell aplasia and acquired amegakaryocytic thrombocytopenic purpura. PMID- 26984092 TI - Juvenile-onset Sporadic Amyotrophic Lateral Sclerosis with a Frameshift FUS Gene Mutation Presenting Unique Neuroradiological Findings and Cognitive Impairment. AB - A 24-year-old Japanese woman developed anterocollis, weakness of the proximal arms, and subsequent cognitive impairment. A neurological examination revealed amyotrophic lateral sclerosis (ALS) without a family history. Systemic muscle atrophy progressed rapidly. Cerebral MRI clearly exhibited high signal intensities along the bilateral pyramidal tracts. An analysis of the FUS gene revealed a heterozygous two-base pair deletion, c.1507-1508delAG (p.G504WfsX515). A subset of juvenile-onset familial/sporadic ALS cases with FUS gene mutations reportedly demonstrates mental retardation or learning difficulty. Our study emphasizes the importance of conducting a FUS gene analysis in juvenile-onset ALS cases, even when no family occurrence is confirmed. PMID- 26984093 TI - Tubercular Spinal Epidural Abscess of the Lumbosacral Region without Osseous Involvement: Comparison of Spinal MRI and Pathological Findings of the Resected Tissue. AB - We herein present a case of tubercular spinal epidural abscess (SEA) without osseous involvement that mimicked an acute bacterial abscess. This case manifested quite unusual findings not only radiographically, but also clinically compared with previously reported cases of tubercular SEA. PMID- 26984094 TI - An Adult Case of Anti-Myelin Oligodendrocyte Glycoprotein (MOG) Antibody associated Multiphasic Acute Disseminated Encephalomyelitis at 33-year Intervals. AB - Acute disseminated encephalomyelitis (ADEM) followed by optic neuritis (ON) has been reported as a distinct phenotype associated with anti-myelin oligodendrocyte protein (MOG) antibody. We herein report the case of a 37-year-old woman who was diagnosed with ADEM at 4 years old of age and who subsequently developed ON followed by recurrent ADEM 33 years after the initial onset. A serum analysis showed anti-MOG antibody positivity. This phenotype has only previously been reported in pediatric cases. Neurologists thus need to be aware that the phenotype may occur in adult patients, in whom it may be assumed to be atypical multiple sclerosis. PMID- 26984096 TI - Asymptomatic Primary Malignant Melanoma of the Gastroesophageal Junction. PMID- 26984097 TI - Pyoderma Gangrenosum in a Patient with Multiple Myeloma. PMID- 26984098 TI - Relative Vasodilatory Change in Seizure-induced Crossed Cerebellar Diaschisis. PMID- 26984095 TI - Successful Additional Corticosteroid Treatment in a Patient with Mycoplasma pneumoniae Pneumonia in whom a Monobacterial Infection was Confirmed by a Molecular Method Using Bronchoalveolar Lavage Fluid. AB - A 23-year-old Japanese woman was admitted to A hospital due to pneumonia. IgM for Mycoplasma pneumoniae was positive, and the patient was treated with imipenem/cilastatin, clindamycin, pazufloxacin and minocycline. However, both the chest radiological findings and the symptoms became exacerbated, and she was therefore transferred to our hospital. The bronchoalveolar lavage fluid was obtained, and a 16S rRNA gene sequencing analysis revealed a monobacterial infection of Mycoplasma pneumoniae. Therefore, corticosteroid treatment in addition to minocycline was administered, and the patients symptoms, laboratory data and chest radiographs improved. Corticosteroid therapy may therefore be considered for patients with refractory M. pneumoniae pneumonia. PMID- 26984099 TI - Autoimmune Hemolytic Anemia Induced by Adalimumab. PMID- 26984100 TI - Autoimmune Hemolytic Anemia Induced by Adalimumab. PMID- 26984101 TI - Comparison of the cryo-tolerance of vitrified gorgonian oocytes. AB - Coral reefs have been declining considerably in recent years because of changes to the environment and climate. The cryopreservation of coral gametes is an essential alternative method that yields immense success in preserving corals. This study focuses on developing vitrification techniques for Junceella fragilis and Ellisella robusta oocytes, and presents a comparison on the cryotolerance of their vitrified oocytes. The results revealed that these coral oocytes could be preserved for a longer period in equilibration solution 2 and vitrification solution (VS) 2 at 5 degrees C than at 26 degrees C. Oocyte viability decreased significantly when VS2 was used for >4 min at 26 degrees C compared with the control. Cryoprotectant tolerance was higher in E. robusta oocytes than in J. fragilis oocytes. However, E. robusta was determined to be more cryo-tolerant, with differences attributed to their habitats, thus making E. robusta is likely a superior candidate species for further study. The results of this study on the effects of coral cryopreservation provide a foundation for developing protocols further for the cryopreservation of the oocytes of gorgonian corals. PMID- 26984102 TI - Design and synthesis of the superionic conductor Na10SnP2S12. AB - Sodium-ion batteries are emerging as candidates for large-scale energy storage due to their low cost and the wide variety of cathode materials available. As battery size and adoption in critical applications increases, safety concerns are resurfacing due to the inherent flammability of organic electrolytes currently in use in both lithium and sodium battery chemistries. Development of solid-state batteries with ionic electrolytes eliminates this concern, while also allowing novel device architectures and potentially improving cycle life. Here we report the computation-assisted discovery and synthesis of a high-performance solid state electrolyte material: Na10SnP2S12, with room temperature ionic conductivity of 0.4 mS cm(-1) rivalling the conductivity of the best sodium sulfide solid electrolytes to date. We also computationally investigate the variants of this compound where tin is substituted by germanium or silicon and find that the latter may achieve even higher conductivity. PMID- 26984103 TI - Correction: Nasrallah et al., Inhibitory Plasticity Permits the Recruitment of CA2 Pyramidal Neurons by CA3 (eNeuro July/August 2015, 2(4) 10.1523/ENEURO.0049 15.2015 1-12 http://dx.doi.org/10.1523/ENEURO.0049-15.2015). AB - [This corrects the article DOI: 10.1523/ENEURO.0049-15.2015.]. PMID- 26984106 TI - Paraneoplastic limbic encephalitis in B cell lymphoma unclassifiable with features intermediate between diffuse large B cell lymphoma and classical Hodgkin lymphoma. PMID- 26984104 TI - Anti-giardial therapeutic potential of dichloromethane extracts of Zingiber officinale and Curcuma longa in vitro and in vivo. AB - Giardiosis is one of the common parasitic diarrhoea in humans, especially in children, worldwide. Many drugs are used for its treatment, but there is evidence of drug resistance, insufficient efficacy and unpleasant side effects. Natural products are good candidates for discovering more effective anti-giardial compounds. This study evaluated the activity of extracts of Zingiber officinale (ginger) and Curcuma longa (curcumin) against Giardia lamblia in vitro and in vivo. Giardia cyst suspension was prepared from children faecal specimens. For the in vitro experiment, 1, 10 and 50 mg/mL dichloromethane extracts of ginger and curcumin separately were incubated with Giardia cysts for 5, 10, 30 and 60 min. The viability was distinguished by 0.1 % eosin and a haemocytometer. For the in vivo experiments, Balb/c mice were infected with Giardia cyst suspension containing 10,000 cysts/mL. Infected mice were administered 10 and 20 mg kg(-1) day(-1) ginger and curcumin extracts separately for 7 days post-infection. The effectiveness of the extracts was evaluated by faecal cyst and intestinal trophozoite counts and histopathological examination of the small intestine. In vitro ginger extract had a higher significant effect on cyst viability than curcumin, in a dose- and time-dependent manner. In vivo ginger (more effective) and curcumin extracts significantly treated infected mice, and this was evidenced by the faecal cyst and intestinal trophozoite counts reduction, in addition to evident improvement of intestinal mucosal damages induced by Giardia infection. Z. officinale and C. longa extracts may represent effective and natural therapeutic alternatives with low side effects and without drug resistance in the treatment of giardiosis. PMID- 26984105 TI - Effect of resistance training on muscular strength and indicators of abdominal adiposity, metabolic risk, and inflammation in postmenopausal women: controlled and randomized clinical trial of efficacy of training volume. AB - This study evaluated the effect of resistance training (RT) volume on muscular strength and on indicators of abdominal adiposity, metabolic risk, and inflammation in post-menopausal women (PW). Thirty-two volunteers were randomly allocated into the following three groups: control (CT, no exercise, n = 11), low volume RT (LV, three sets/exercise, n = 10), and high-volume RT (HV, six sets/exercise, n = 11). The LV and HV groups performed eight exercises at 70 % of one maximal repetition, three times a week, for 16 weeks. Muscular strength and indicators of abdominal adiposity, metabolic risk, and inflammation were measured at baseline and after 16 weeks. No differences were found in baseline measures between the groups. The PW showed excess weight and fat percentage (F%), large waist circumference (WC), high waist-hip ratio (WHR), and hypercholesterolemia and borderline values of glycated hemoglobin (HbA1c%). Following the RT, a similar increase in muscle strength and reduction in F% from baseline were found in both trained groups. In HV, a decrease in total cholesterol, LDL-c, WC, and WHR was noted. Moreover, the HV showed a lower change (delta%) of interleukin-6 (IL-6) when compared to CT (HV = 11.2 %, P 25-75 = -7.6-28.4 % vs. CT = 99.55 %, P 25-75 = 18.5-377.0 %, p = 0.049). In LV, a decrease was noted for HbA1c%. There were positive correlations (delta%) between WHR and IL-6 and between IL-6 and TC. These results suggest that while a low-volume RT improves HbA1c%, F%, and muscular strength, a high-volume RT is necessary to improve indicators of abdominal adiposity and lipid metabolism and also prevent IL-6 increases in PW. PMID- 26984107 TI - [Partial replacement of the knee joint with patient-specific instruments and implants (ConforMIS iUni, iDuo)]. AB - Knee arthroplasty is a successful standard procedure in orthopedic surgery; however, approximately 20 % of patients are dissatisfied with the clinical results as they suffer pain and can no longer achieve the presurgery level of activity. According to the literature the reasons are inexact fitting of the prosthesis or too few anatomically formed implants resulting in less physiological kinematics of the knee joint. Reducing the number of dissatisfied patients and the corresponding number of revisions is an important goal considering the increasing need for artificial joints. In this context, patient specific knee implants are an obvious alternative to conventional implants. For the first time implants are now matched to the individual bone and not vice versa to achieve the best possible individual situation and geometry and more structures (e.g. ligaments and bone) are preserved or only those structures are replaced which were actually destroyed by arthrosis. According to the authors view, this represents an optimal and pioneering addition to conventional implants. Patient-specific implants and the instruments needed for correct alignment and fitting can be manufactured by virtual 3D reconstruction and 3D printing based on computed tomography (CT) scans. The portfolio covers medial as well as lateral unicondylar implants, medial as well as lateral bicompartmental implants (femorotibial and patellofemoral compartments) and cruciate ligament preserving as well as cruciate ligament-substituting total knee replacements; however, it must be explicitly emphasized that the literature is sparse and no long-term data are available. PMID- 26984109 TI - [ALK-Diagnostics in NSCLC - Immunohistochemistry (IHC) and/or Fluorescence-in situ Hybridisation (FISH)]. AB - The EML4-ALK pathway plays an important role in a significant subset of non-small cell lung cancer patients. Treatment options such as tyrosine kinase inhibitors directed against the EML4-ALK signalling pathway lead to improved progression free and overall survival. These therapeutic options are chosen on the basis of the identification of the underlying genetic signature of the EML-ALK translocation. Efficient and easily accessible testing tools are required to identify the patients in time. While FISH techniques have been implemented to characterize this translocation for some time, the implementation of this testing is hampered by its broad use of resources. Immunohistochemical techniques to identify and screen for EML4-ALK translocations may play an important role in the near future. This consensus paper offers recommendations of the sequence and quality of the respective test approaches which are validated on the basis of the current literature. PMID- 26984108 TI - The pellet swim-up is the best technique for sperm preparation during in vitro fertilization procedures. AB - PURPOSE: The aim of this study was to investigate the most suitable sperm preparation technique to apply in order to obtain a spermatozoon population with minimal DNA damage during in vitro fertilization procedures. We compared four preparation techniques: direct swim-up (DSU), pellet swim-up (PSU), density gradient (DG), and density gradient followed by swim-up (DG-SU), evaluating the effects of each technique on the DNA damage rate, evaluated by DNA fragmentation index of the spermatozoa obtained. METHODS: In this observational study, 98 semen samples from couples undergoing IVF/ICSI cycles were included. Data were collected between April and November 2014 at the ANDROS Day Surgery Clinic, Palermo, Italy. RESULT(S): The percentages of DNA fragmentation were 18.30 +/- 10.8 in raw samples, 6.6 +/- 5.7 after DSU, 4.2 +/- 3.8 after PSU, 12.9 +/- 9.9 after DG, and 3.7 +/- 4.0 after DG-SU respectively. Compared to the raw evaluation, all the preparation techniques significantly decreased the total rate of the DNA fragmentation (DSU Z = -8.60, P < 0.008; PSU Z = -8.54, P < 0.008; DG Z = -6.42, P < 0.008, and DG-SU Z = -8.60, P < 0.008, respectively). Comparing them, spermatozoa with intact DNA after PSU and DG-SU were significantly higher than after DSU (Z = -7.12, P < 0.008; Z = -6.59, P < 0.008, respectively) and after DG (Z = -8.41, P < 0.008; Z = -8.60, P < 0.008, respectively). The difference between PSU and DG-SU was not significant (Z = -2.21, P = 0.03). CONCLUSION(S): There are, above all, two techniques of sperm preparation which allow for the recovery of spermatozoa with the lowest DNA fragmentation rate. Furthermore, given low costs and reduced time, we believe that PSU is the best option in the treatment of semen samples during IVF/ICSI. PMID- 26984111 TI - Dehydrogenative Cross-Coupling Reaction between N-Aryl alpha-Amino Acid Esters and Phenols or Phenol Derivative for Synthesis of alpha-Aryl alpha-Amino Acid Esters. AB - A novel dehydrogenative cross-coupling (DCC) reaction between N-arylglycine esters and phenols or 1,3,5-trimethoxybenzene was developed by copper catalysis using di-tert-butyl peroxide (DTBP) as an oxidant. Under optimized conditions, a range of N-arylglycine esters 1 underwent the DCC reaction smoothly with various phenols 2 or 1,3,5-trimethoxybenzene 4 to give desired alpha-aryl alpha -amino acid esters 3 or 5, respectively, with high ortho regioselectivities in a moderate to excellent yield. A possible mechanism involving aromatic electrophilic substitution is proposed. PMID- 26984110 TI - Contributions of Abiotic and Biotic Processes to the Aerobic Removal of Phenolic Endocrine-Disrupting Chemicals in a Simulated Estuarine Aquatic Environment. AB - The contributions of abiotic and biotic processes in an estuarine aquatic environment to the removal of four phenolic endocrine-disrupting chemicals (EDCs) were evaluated through simulated batch reactors containing water-only or water sediment collected from an estuary in South China. More than 90% of the free forms of all four spiked EDCs were removed from these reactors at the end of 28 days under aerobic conditions, with the half-life of 17alpha-ethynylestradiol (EE2) longer than those of propylparaben (PP), nonylphenol (NP) and 17beta estradiol (E2). The interaction with dissolved oxygen contributed to NP removal and was enhanced by aeration. The PP and E2 removal was positively influenced by adsorption on suspended particles initially, whereas abiotic transformation by estuarine-dissolved matter contributed to their complete removal. Biotic processes, including degradation by active aquatic microorganisms, had significant effects on the removal of EE2. Sedimentary inorganic and organic matter posed a positive effect only when EE2 biodegradation was inhibited. Estrone (E1), the oxidizing product of E2, was detected, proving that E2 was removed by the naturally occurring oxidizers in the estuarine water matrixes. These results revealed that the estuarine aquatic environment was effective in removing free EDCs, and the contributions of abiotic and biotic processes to their removal were compound specific. PMID- 26984112 TI - Comparison of baroreflex sensitivity estimated from ECG R-R and inter-systolic intervals obtained by finger plethysmography and radial tonometry. AB - Spontaneous BRS estimates may considerable vary according to the technique of blood pressure and heart rate assessment. To optimise and standardise BRS estimation for clinical use we evaluated possible differences between spontaneous BRS indices estimated from either finger plethysmography or radial tonometry. Forty-five healthy volunteers underwent simultaneous recordings of electrocardiogram, finger plethysmography and radial tonometry in supine position and during 60 degrees head-up tilt. BRS was computed by spectral analysis from either R-R time series and/or arterial pressure pulse. Radial tonometry generated higher mean BRS estimates than finger plethysmography. The difference decreased upon postural change from supine to upright. In the upright position, BRS estimates based on R-R interval proved to be generally lower compared to BRS indices estimated from arterial pressure pulse. The ratio of low-to-high frequency power of inter-systolic interval and systolic blood pressure from tonometry was lower than that from plethysmography in supine and approximated in upright position. Spectral parameters of inter-systolic interval and R-R interval did not differ in supine but diverged in upright position. Changes of spectral parameters were most pronounced in R-R interval. Arterial pressure pulse is adequate for estimation of BRS under resting conditions but it may distort BRS estimates under physical load. We, therefore, recommend using an ECG signal for BRS estimation especially in non-stationary conditions. PMID- 26984114 TI - Biomarkers of Resilience in Stress Reduction for Caregivers of Alzheimer's Patients. AB - Caregiving for a dementia patient is associated with increased risk of psychological and physical health problems. We investigated whether a mindfulness based stress reduction (MBSR) training course for caregivers that closely models the MBSR curriculum originally established by the Center of Mindfulness at the University of Massachusetts may improve the psychological resilience of non professional caregivers of Alzheimer's disease patients. Twenty adult non professional caregivers of dementia patients participated in an 8-week MBSR training course. Caregiver stress, depression, burden, grief, and gene expression profiles of blood mononuclear cells were assessed at baseline and following MBSR. MBSR training significantly improved the psychological resilience of some of the caregivers. We identified predictive biomarkers whose expression is associated with the likelihood of caregivers to benefit from MBSR, and biomarkers whose expression is associated with MBSR psychological benefits. Our biomarker studies provide insight into the mechanisms of health benefits of MBSR and a basis for developing a personalized medicine approach for applying MBSR for promoting psychological and cognitive resilience in caregivers of dementia patients. PMID- 26984113 TI - Identification of (poly)phenol treatments that modulate the release of pro inflammatory cytokines by human lymphocytes. AB - Diets rich in fruits and vegetables (FV), which contain (poly)phenols, protect against age-related inflammation and chronic diseases. T-lymphocytes contribute to systemic cytokine production and are modulated by FV intake. Little is known about the relative potency of different (poly)phenols in modulating cytokine release by lymphocytes. We compared thirty-one (poly)phenols and six (poly)phenol mixtures for effects on pro-inflammatory cytokine release by Jurkat T lymphocytes. Test compounds were incubated with Jurkat cells for 48 h at 1 and 30 um, with or without phorbol ester treatment at 24 h to induce cytokine release. Three test compounds that reduced cytokine release were further incubated with primary lymphocytes at 0.2 and 1 um for 24 h, with lipopolysaccharide added at 5 h. Cytokine release was measured, and generation of H2O2 by test compounds was determined to assess any potential correlations with cytokine release. A number of (poly)phenols significantly altered cytokine release from Jurkat cells (P<0.05), but H2O2 generation did not correlate with cytokine release. Resveratrol, isorhamnetin, curcumin, vanillic acid and specific (poly)phenol mixtures reduced pro-inflammatory cytokine release from T-lymphocytes, and there was evidence for interaction between (poly)phenols to further modulate cytokine release. The release of interferon-gamma induced protein 10 by primary lymphocytes was significantly reduced following treatment with 1 um isorhamnetin (P<0.05). These results suggest that (poly)phenols derived from onions, turmeric, red grapes, green tea and acai berries may help reduce the release of pro inflammatory mediators in people at risk of chronic inflammation. PMID- 26984115 TI - Recombinant Toxoplasma gondii phosphoglycerate mutase 2 confers protective immunity against toxoplasmosis in BALB/c mice. AB - Toxoplasmosis is one of the most widespread zoonoses worldwide. It has a high incidence and can result in severe disease in humans and livestock. Effective vaccines are needed to limit and prevent infection with Toxoplasma gondii. In this study, we evaluated the immuno-protective efficacy of a recombinant Toxoplasma gondii phosphoglycerate mutase 2 (rTgPGAM 2) against T. gondii infection in BALB/c mice. We report that the mice nasally immunised with rTgPGAM 2 displayed significantly higher levels of special IgG antibodies against rTgPGAM 2 (including IgG1, IgG2a and IgAs) and cytokines (including IFN-gamma, IL-2 and IL-4) in their blood sera and supernatant of cultured spleen cells compared to those of control animals. In addition, an increased number of spleen lymphocytes and enhanced lymphocyte proliferative responses were observed in the rTgPGAM 2 immunised mice. After chronic infection and lethal challenge with the highly virulent T. gondii RH strain by oral gavage, the survival time of the rTgPGAM 2 immunised mice was longer (P < 0.01) and the survival rate (70%) was higher compared with the control mice (P < 0.01). The reduction rate of brain and liver tachyzoites in rTgPGAM 2-vaccinated mice reached approximately 57% and 69% compared with those of the control mice (P < 0.01). These results suggest that rTgPGAM 2 can generate protective immunity against T. gondii infection in BALB/c mice and may be a promising antigen in the further development of an effective vaccine against T. gondii infection. PMID- 26984116 TI - Giardia duodenalis genetic assemblages and hosts. AB - Techniques for sub-classifying morphologically identical Giardia duodenalis trophozoites have included comparisons of the electrophoretic mobility of enzymes and of chromosomes, and sequencing of genes encoding beta-giardin, triose phosphate isomerase, the small subunit of ribosomal RNA and glutamate dehydrogenase. To date, G. duodenalis organisms have been sub-classified into eight genetic assemblages (designated A-H). Genotyping of G. duodenalis organisms isolated from various hosts has shown that assemblages A and B infect the largest range of host species, and appear to be the main (or possibly only) G. duodenalis assemblages that undeniably infect human subjects. In at least some cases of assemblage A or B infection in wild mammals, there is suggestive evidence that the infection had resulted from environmental contamination by G. duodenalis cysts of human origin. PMID- 26984117 TI - Lessons Learned from Community-Led Recruitment of Immigrants and Refugee Participants for a Randomized, Community-Based Participatory Research Study. AB - Ethnic minorities remain underrepresented in clinical trials despite efforts to increase their enrollment. Although community-based participatory research (CBPR) approaches have been effective for conducting research studies in minority and socially disadvantaged populations, protocols for CBPR recruitment design and implementation among immigrants and refugees have not been well described. We used a community-led and community-implemented CBPR strategy for recruiting 45 Hispanic, Somali, and Sudanese families (160 individuals) to participate in a large, randomized, community-based trial aimed at evaluating a physical activity and nutrition intervention. We achieved 97.7 % of our recruitment goal for families and 94.4 % for individuals. Use of a CBPR approach is an effective strategy for recruiting immigrant and refugee participants for clinical trials. We believe the lessons we learned during the process of participatory recruitment design and implementation will be helpful for others working with these populations. PMID- 26984118 TI - Potential Yield Increase of Hybrid Rice at Five Locations in Southern China. AB - BACKGROUND: A number of field studies have demonstrated that the yield potential of hybrid rice cultivars is higher than that of inbred cultivars, although the magnitude of difference between hybrid and inbred cultivars at different yield levels has not been described. The objective of this study is to compare the yield increase potential at different yield levels between hybrid and conventional rice. Ten field experiments were conducted at five locations in southern China in 2012 and 2013. At each location, two hybrid and two inbred cultivars were grown at three N levels: high (225 kg/hm(2)), moderate (161-191 kg/hm(2)) and the control, zero N (0 kg/hm(2)). RESULTS: Hybrid rice yielded approximately 8 % more grain than did inbred cultivars in Huaiji, Binyang and Haikou; approximately 7 % more in Changsha; and approximately 19 % more in Xingyi. The high grain yields observed for hybrid rice cultivars were attributed to high grain weight and biomass accumulation at maturity. On average, rice yields were approximately 6.0-7.5 t ha(-1) (medium yield) in Huaiji, Binyang and Haikou; approximately 9.0 t ha(-1) in Changsha (high yield); and approximately 12.0 t ha(-1) (super high yield) in Xingyi. The yield gaps among Huaiji, Binyang and Haikou and Changsha were attributed to the differences in spikelets m(-2) and biomass production, whereas the yield gap between Changsha and Xingyi was caused by the differences in grain-filling percentage, grain weight and harvest index. The differences in biomass production among sites were primarily due to variation in crop growth rate induced by varied temperatures and accumulative solar radiation. CONCLUSIONS: The yield superiority of hybrid rice was relatively small in comparison with that of inbred cultivars at medium and high yield levels, but the difference was large at super high yield levels. Improving rice yields from medium to high should focus on spikelets m(-2) and biomass, whereas further improvement to super high level should emphasize on grain-filling percentage, grain weight and harvest index. Favorable environmental conditions are essential for high yields in hybrid rice. PMID- 26984120 TI - Ultrafast triggered transient energy storage by atomic layer deposition into porous silicon for integrated transient electronics. AB - Here we demonstrate the first on-chip silicon-integrated rechargeable transient power source based on atomic layer deposition (ALD) coating of vanadium oxide (VOx) into porous silicon. A stable specific capacitance above 20 F g(-1) is achieved until the device is triggered with alkaline solutions. Due to the rational design of the active VOx coating enabled by ALD, transience occurs through a rapid disabling step that occurs within seconds, followed by full dissolution of all active materials within 30 minutes of the initial trigger. This work demonstrates how engineered materials for energy storage can provide a basis for next-generation transient systems and highlights porous silicon as a versatile scaffold to integrate transient energy storage into transient electronics. PMID- 26984119 TI - Resolution of Isolated, Aspergillus Colonization in a Deep Esophageal Ulcer in an Immunocompetent Patient with Ulcer Healing Without Specific Antifungal Therapy. PMID- 26984121 TI - Somatoform disorders in patients with chronic subjective tinnitus. AB - This study aimed to investigate the correlation of psychiatric disorders with tinnitus and tinnitus handicap scores. A total of 30 patients and 30 otherwise healthy people were enrolled for the study. Somatoform disorder questionnaire SDQ 20 was filled in by both the study and the control group. Tinnitus handicap scores were filled in study group. Tinnitus handicap scores were 28.1 +/- 19.8, and somatoform disorder questionnaire scores were 30.5 +/- 7.3 in the tinnitus group. In the control group the somatoform disorder questionnaire scores were 25.4 +/- 4.6. (1) We found a statistically significant difference between somatoform disorder questionnaire scores between groups (p < 0.05). (2) There was a statistically significant difference between tinnitus handicap scores and somatoform disorder questionnaire scores in study group (p = 0.0). The correlation between these tests was positively strong (R = 0.782). (3) There was no statistical difference between genders. We recommend investigating patients with long-lasting tinnitus for psychiatric comorbidity in relation to somatoform disorders in cooperation with psychiatric clinics. PMID- 26984122 TI - The Sexual Thoughts Questionnaire: Psychometric Evaluation of a Measure to Assess Self-Reported Thoughts During Exposure to Erotica Using Sexually Functional Individuals. AB - INTRODUCTION: Validated instruments for assessing specific thought content during exposure to sexually explicit material are lacking. AIM: To investigate the psychometric properties of a measure that assesses self-reported thoughts during exposure to sexual stimuli in laboratory settings, namely the Sexual Thoughts Questionnaire. The factorial structure of the questionnaire and its reliability and validity were examined. METHODS: One hundred sixty-seven sexually functional individuals (97 women and 70 men) were exposed to sexually explicit material while their genital arousal was being assessed. Subjective sexual arousal and thoughts during exposure to sexually explicit material also were assessed. MAIN OUTCOME MEASURES: Women's genital arousal was measured with a vaginal photoplethysmograph and men's genital arousal was measured with an indium-gallium strain gauge. Subjective sexual arousal and thoughts during exposure to erotica were assessed with self-report scales. RESULTS: Principal component analysis with varimax rotation identified five factors: sexual arousal thoughts, distractive and disengaging thoughts, body image and performance thoughts, actress's physical attractiveness thoughts, and sinful and lack of affection thoughts. Moreover, the scale showed satisfactory levels of internal consistency. Studies on convergent validity showed an association between self-reported thoughts and subjective sexual arousal levels in the women and men. CONCLUSION: The Sexual Thoughts Questionnaire showed adequate psychometric properties in a sexually functional sample. It could be useful in further experimental research on the role of cognitions in sexual response and allow further comparison between sexually functional and dysfunctional individuals, with possible significant implications for the assessment and treatment of sexual problems. PMID- 26984123 TI - Caching at a distance: a cache protection strategy in Eurasian jays. AB - A fundamental question about the complexity of corvid social cognition is whether behaviours exhibited when caching in front of potential pilferers represent specific attempts to prevent cache loss (cache protection hypothesis) or whether they are by-products of other behaviours (by-product hypothesis). Here, we demonstrate that Eurasian jays preferentially cache at a distance when observed by conspecifics. This preference for a 'far' location could be either a by product of a general preference for caching at that specific location regardless of the risk of cache loss or a by-product of a general preference to be far away from conspecifics due to low intra-species tolerance. Critically, we found that neither by-product account explains the jays' behaviour: the preference for the 'far' location was not shown when caching in private or when eating in front of a conspecific. In line with the cache protection hypothesis we found that jays preferred the distant location only when caching in front of a conspecific. Thus, it seems likely that for Eurasian jays, caching at a distance from an observer is a specific cache protection strategy. PMID- 26984124 TI - T-cell Lymphoma of Thyroid Gland with Lennert Type of Morphology: A Case Report and Review of the Literature. AB - The rare entity of primary T-cell lymphoma of thyroid gland may pose great diagnostic and therapeutic challenges to the pathologist and clinician. There are very few case and short series reports of these tumors describing their varied clinicopathologic features in English literature. We report a case of mature T cell lymphoma of thyroid in a 26 year old male, with unique pseudogranulomatous and lymphohistiocytic Lennert type of morphology, on a background of autoimmune thyroiditis. This man, diagnosed with Hashimoto's thyroiditis for the previous 2 years, underwent thyroidectomy for sudden onset of pressure symptoms. The diagnosis of T-cell lymphoma was made on the thyroid tissue based on histopathologic and immunophenotypic findings, in concert with the results of T cell receptor gene rearrangement studies by polymerase chain reaction. Later, after about 3 months, similar findings were confirmed in an excision biopsy from a left cervical lymph node in the patient. The patient has been started on chemotherapy with gemcitabine, dexamethasone, and cisplatin along with involved field radiotherapy; however, he has shown a rapid upstaging of disease from stage IE to IIIE in a short period of 3 months with relatively well preserved clinical parameters until the latest follow up. PMID- 26984125 TI - A Parapharyngeal Soft Tissue Chordoma Presenting with Synchronous Cervical Lymph Node Metastasis: An Unusual Presentation. AB - A 63 year old male presented with a three month history of dysphagia, neck swelling and an oropharyngeal swelling on examination. Initial fine needle aspiration cytology and magnetic resonance imaging (done at a peripheral hospital) suggested a salivary gland neoplasm with lymph node metastasis. An infra-temporal approach was employed to excise the tumour mass and a modified radical neck dissection undertaken to remove the cervical metastasis. Histopathological examination with immunohistochemistry confirmed this to be a soft tissue chordoma. To the best of our knowledge, this is the first documented report of an extra-axial soft tissue chordoma presenting with synchronous metastatic disease. Though rare, this adds to the list of differential diagnoses for complex parapharyngeal lesions. A multidisciplinary approach between head and neck surgery, histopathology, radiology and sarcoma teams is paramount for arriving at the correct diagnosis and to deliver optimal treatment. PMID- 26984126 TI - Optofluidic restricted imaging, spectroscopy and counting of nanoparticles by evanescent wave using immiscible liquids. AB - Conventional flow cytometry (FC) suffers from the diffraction limit for the detection of nanoparticles smaller than 100 nm, whereas traditional total internal reflection (TIR) microscopy can only detect few samples near the solid liquid interface mostly in static states. Here we demonstrate a novel on-chip optofluidic technique using evanescent wave sensing for single nanoparticle real time detection by combining hydrodynamic focusing and TIR using immiscible flows. The immiscibility of the high-index sheath flow and the low-index core flow naturally generate a smooth, flat and step-index interface that is ideal for the TIR effect, whose evanescent field can penetrate the full width of the core flow. Hydrodynamic focusing can focus on all the nanoparticles in the extreme centre of the core flow with a width smaller than 1 MUm. This technique enables us to illuminate every single sample in the running core flow by the evanescent field, leaving none unaffected. Moreover, it works well for samples much smaller than the diffraction limit. We have successfully demonstrated the scattering imaging and counting of 50 nm and 100 nm Au nanoparticles and also the fluorescence imaging and counting of 200 nm beads. The effective counting speeds are estimated as 1500, 2300 and 2000 particles per second for the three types of nanoparticles, respectively. The optical scattering spectra were also measured to determine the size of individual Au nanoparticles. This provides a new technique to detect nanoparticles and we foresee its application in the detection of molecules for biomedical analyses. PMID- 26984127 TI - Stability in Test-Usage Practices of Clinical Neuropsychologists in the United States and Canada Over a 10-Year Period: A Follow-Up Survey of INS and NAN Members. AB - As a 10-year follow up to our original study (Rabin, Barr, & Burton, 2005), we surveyed the test usage patterns of clinical neuropsychologists in the U.S and Canada. We expanded the original questionnaire to include additional cognitive and functional domains and to address current practice-related issues. Participants were randomly selected from the combined membership lists of the National Academy of Neuropsychology and the International Neuropsychological Society. Respondents were 512 doctorate-level members (25% usable response rate; 54% women) who had been practicing neuropsychology for 15 years on average. The Wechsler Adult Intelligence Scales, followed by the Wechsler Memory Scales, Trail Making Test, California Verbal Learning Test, and Wechsler Intelligence Scale for Children, were the most commonly used tests. These top five responses were identical and in the same order as those from 10 years ago. Participants respectively identified a lack of ecological validity and difficulty comparing the meaning of standardized scores across tests as the greatest challenges associated with the selection of neuropsychological instruments and interpretation of test data. Overall, we found great consistency in assessment practices over the 10-year period. We compare results to those of previous studies and discuss challenges and implications for neuropsychology. PMID- 26984131 TI - [Antrittsvorlesung zweier neuer Professoren an der Universitatszahnklinik Wien]. PMID- 26984129 TI - Synthesis and In Vitro Evaluation of Polyethylene Glycol-Paclitaxel Conjugates for Lung Cancer Therapy. AB - PURPOSE: Pulmonary drug delivery is considered an attractive route of drug administration for lung cancer chemotherapy. However, fast clearance mechanisms result in short residence time of small molecule drugs in the lung. Therefore, achieving a sustained presence of chemotherapeutics in the lung is very challenging. In this study, we synthesized two different polyethylene glycol paclitaxel ester conjugates with molecular weights of 6 and 20 kDa in order to achieve sustained release of paclitaxel in the lung. METHODS: One structure was synthesized with azide linker using "click" chemistry and the other structure was synthesized with a succinic spacer. The physicochemical and biological properties of the conjugates were characterized in vitro. RESULTS: Conjugation to polyethylene glycol improved the solubility of paclitaxel by up to four orders of magnitude. The conjugates showed good stability in phosphate buffer saline pH 6.9 (half-life >=72 h) and in bronchoalveolar lavage (half-life of 3 to 9 h) at both molecular weights, but hydrolyzed quickly in mouse serum (half-life of 1 to 3 h). The conjugates showed cytotoxicity to B16-F10 melanoma cells and LL/2 Lewis lung cancer cells but less than free paclitaxel or Taxol, the commercial paclitaxel formulation. CONCLUSIONS: These properties imply that the conjugates have the potential to retain paclitaxel in the lung for a prolonged duration and to sustain its release locally for a better efficacy. PMID- 26984132 TI - Editor's Letter. PMID- 26984130 TI - The use of cognitive behaviour therapy in the management of BPSD in dementia (Innovative practice). AB - Psychosocial approaches to the management of behavioural and psychological symptoms of dementia have received much support in the scientific literature. The following paper focuses on cognitive behaviour therapy as a valid framework in assessing and treating people with behavioural and psychological symptoms of dementia. The importance of identifying symptoms of depression and anxiety is emphasized, as cognitive behaviour therapy has been shown to be an effective intervention for these conditions in older adults. Modifications of cognitive behaviour therapy for those with dementia are discussed based on available evidence, with emphasis on incorporating nursing home staff in treatment programs and focusing on behavioural elements of cognitive behaviour therapy such as activity scheduling. The paper concludes with suggestions regarding how to incorporate and promote the use of cognitive behaviour therapy in dementia care settings. PMID- 26984128 TI - A Multi-Functional Tumor Theranostic Nanoplatform for MRI Guided Photothermal Chemotherapy. AB - PURPOSE: To develop a multi-functional theranostic nanoplatform with increased tumor retention, improving antitumor efficacy and decreased side effects of chemotherapy drugs. METHODS: GO@Gd nanocomposites was synthesized via decorating gadolinium (Gd) nanoparticles (GdNP) onto graphene oxide (GO), and then functionalized by polyethylene glycol (PEG2000), folic acid (FA), a widely used tumor targeting molecule, was linked to GO@Gd-PEG, finally, doxorubicin (DOX) was loaded onto GO@Gd-PEG-FA and obtained a tumor-targeting drug delivery system (GO@Gd-PEG-FA/DOX). GO@Gd-PEG-FA/DOX was characterized and explored its theranostic applications both in a cultured MCF-7 cells and tumor-bearing mice. RESULTS: GO@Gd-PEG-FA/DOX could efficiently cross the cell membranes, lead to more apoptosis and afford higher antitumor efficacy without obvious toxic effects to normal organs owing to its prolonged blood circulation and 7.6-fold higher DOX uptake of tumor than DOX. Besides, GO@Gd-PEG-FA/DOX also served as a powerful photothermal therapy (PTT) agent for thermal ablation of tumor and a strong T1 weighted contrast agent for tumor MRI diagnosis. The multi-functional nanoplatform also could selectively kill cancer cells in highly localized regions via the excellent tumor-targeting and MRI guided PTT abilities. CONCLUSIONS: GO@Gd-PEG-FA/DOX exhibited excellent photothermal-chemotherapeutic efficacy, tumor-targeting property and tumor diagnostic ability. PMID- 26984133 TI - Screaming Behind a Door: The Experiences of Individuals Incarcerated Without Medication-Assisted Treatment. AB - BACKGROUND AND PURPOSE: Medication-assisted treatment (MAT) is an evidence-based method of treating opioid addiction. Of incarcerated individuals in the United States, 50% to 85% have a history of substance abuse, and > 80% of inmates with opioid addiction history do not receive treatment. The purpose of this study was to explore individuals' experiences after being tapered from MAT upon incarceration. METHODS: Interpretative phenomenological analysis was employed using in-depth interviewing of 10 participants. RESULTS: Analysis identified six themes that captured the essence of the participants' experiences. IMPLICATIONS AND CONCLUSION: Losing MAT upon incarceration was described as an extremely stressful experience for many individuals and may create issues for both inmates and facility staff. Further research is needed to discover ways to improve addiction treatment in prison. PMID- 26984134 TI - Diagnostic Error in Correctional Mental Health: Prevalence, Causes, and Consequences. AB - While they have important implications for inmates and resourcing of correctional institutions, diagnostic errors are rarely discussed in correctional mental health research. This review seeks to estimate the prevalence of diagnostic errors in prisons and jails and explores potential causes and consequences. Diagnostic errors are defined as discrepancies in an inmate's diagnostic status depending on who is responsible for conducting the assessment and/or the methods used. It is estimated that at least 10% to 15% of all inmates may be incorrectly classified in terms of the presence or absence of a mental illness. Inmate characteristics, relationships with staff, and cognitive errors stemming from the use of heuristics when faced with time constraints are discussed as possible sources of error. A policy example of screening for mental illness at intake to prison is used to illustrate when the risk of diagnostic error might be increased and to explore strategies to mitigate this risk. PMID- 26984135 TI - Preparing Corrections Staff for the Future: Results of a 2-Day Training About Aging Inmates. AB - The aging of the prison population presents corrections staff with unique challenges in knowing how to support inmates while maintaining security. This article describes a 2-day training program to introduce the aging process to select staff at all levels. While the results of a pre-posttest measure, using a modified version of Palmore's Facts on Aging Quiz, did not produce a statistically significant difference at the conclusion of the training, attendees did express satisfaction with the training and their newfound insight into the challenges faced by aging inmates. They also offered recommendations for future training to include more practical suggestions for the work environment. PMID- 26984136 TI - Social Factors Related to the Utilization of Health Care Among Prison Inmates. AB - This study examines the demographic and social factors related to health care utilization in prisons using the 2004 Survey of Inmates in State Correctional Facilities. The findings show that education and employment, strong predictors of health care in the community, are not associated with health care in prisons. Although female inmates have a higher disease burden than male inmates, there are no sex differences in health care usage. The factors associated with health care, however, vary for women and men. Notably, Black men are significantly more likely to utilize health care compared to White and Latino men. The findings suggest that, given the constitutionally mandated health care for inmates, prisons can potentially minimize racial disparities in care and that prisons, in general, are an important context for health care delivery in the United States. PMID- 26984137 TI - Substance Use, Disordered Eating, and Weight Gain: Describing the Prevention and Treatment Needs of Incarcerated Women. AB - Weight-related concerns are associated with women's substance use and treatment relapse. The prevalence of overweight, obesity, disordered eating behavior, and substance abuse history was assessed among female inmates incarcerated for 6 to 24 months at an Oregon state prison, using a self-administered survey and physical measurements. Average weight gain was 20 pounds, 87% of women were overweight (39%) or obese (48%), and 24% reported using one or more unhealthy strategies to lose weight in the past 6 months. Women who used tobacco and illicit substances before incarceration gained more weight. Integrating nutrition and weight gain issues into substance abuse treatment could benefit incarcerated women--both soon after entering prison to prevent weight gain and close to release to prevent relapse into substance use. PMID- 26984138 TI - Goals and Plans of Incarcerated Men Postrelease. AB - Prior research has not examined the self-identified goals and plans of incarcerated people as they approach release from prison. This study analyzed the goals and plans generated during a motivational interviewing counseling session of incarcerated men who participated in a randomized controlled trial of a smoking abstinence intervention in a tobacco-free prison in the northeastern United States. Using thematic analysis, 53 written goals and plans were independently coded by trained research assistants to identify major themes that included (1) staying smoke-free or reducing the number of cigarettes smoked postrelease, (2) engaging in physical activities to improve health and wellness, and (3) spending time with family and/or friends. Implications for working with inmates to identify their plans and goals to remain smoke-free after incarceration are discussed. PMID- 26984140 TI - Journal of Correctional Health Care: Self-Study Program. PMID- 26984139 TI - Awareness and Environmental Exposures Related to Coccidioidomycosis Among Inmates at Two California Prisons, 2013. AB - Coccidioidomycosis (Valley fever) is a major cause of illness in inmates in some California prisons. This article discusses an investigation conducted at two prisons to describe potential environmental exposures. The study did not identify modifiable risk factors; limiting the type or duration of outdoor activity in these prisons may not decrease coccidioidomycosis morbidity. PMID- 26984141 TI - Statin Concentrations Below the Minimum Inhibitory Concentration Attenuate the Virulence of Rhizopus oryzae. AB - BACKGROUND: Mucormycosis is a destructive invasive mold infection afflicting patients with diabetes and hematologic malignancies. Patients with diabetes are often treated with statins, which have been shown to have antifungal properties. We sought to examine the effects of statins on Rhizopus oryzae, a common cause of mucormycosis. METHODS: Clinical strains of R. oryzae were exposed to lovastatin, atorvastatin, and simvastatin and the minimum inhibitory concentrations (MICs) were determined. R. oryzae germination, DNA fragmentation, susceptibility to oxidative stress, and ability to damage endothelial cells were assessed. We further investigated the impact of exposure to lovastatin on the virulence of R. oryzae RESULTS: All statins had MICs of >64 ug/mL against R. oryzae Exposure of R. oryzae to statins decreased germling formation, induced DNA fragmentation, and attenuated damage to endothelial cells independently of the expression of GRP78 and CotH. Additionally, R. oryzae exposed to lovastatin showed macroscopic loss of melanin, yielded increased susceptibility to the oxidative agent peroxide, and had attenuated virulence in both fly and mouse models of mucormycosis. CONCLUSIONS: Exposure of R. oryzae to statins at concentrations below their MICs decreased virulence both in vitro and in vivo. Further investigation is warranted into the use of statins as adjunctive therapy in mucormycosis. PMID- 26984142 TI - Genome-wide Screening Identifies Phosphotransferase System Permease BepA to Be Involved in Enterococcus faecium Endocarditis and Biofilm Formation. AB - Enterococcus faecium is a common cause of nosocomial infections, of which infective endocarditis is associated with substantial mortality. In this study, we used a microarray-based transposon mapping (M-TraM) approach to evaluate a rat endocarditis model and identified a gene, originally annotated as "fruA" and renamed "bepA," putatively encoding a carbohydrate phosphotransferase system (PTS) permease (biofilm and endocarditis-associated permease A [BepA]), as important in infective endocarditis. This gene is highly enriched in E. faecium clinical isolates and absent in commensal isolates that are not associated with infection. Confirmation of the phenotype was established in a competition experiment of wild-type and a markerless bepA mutant in a rat endocarditis model. In addition, deletion of bepA impaired biofilm formation in vitro in the presence of 100% human serum and metabolism of beta-methyl-D-glucoside. beta-glucoside metabolism has been linked to the metabolism of glycosaminoglycans that are exposed on injured heart valves, where bacteria attach and form vegetations. Therefore, we propose that the PTS permease BepA is directly implicated in E. faecium pathogenesis. PMID- 26984145 TI - Reimagining the Future of the Diagnosis of Viral Infections. PMID- 26984143 TI - Performance of Dengue Diagnostic Tests in a Single-Specimen Diagnostic Algorithm. AB - BACKGROUND: Anti-dengue virus (DENV) immunoglobulin M (IgM) seroconversion has been the reference standard for dengue diagnosis. However, paired specimens are rarely obtained, and the interval for this testing negates its usefulness in guiding clinical case management. The presence of DENV viremia and appearance of IgM during the febrile phase of dengue provides the framework for dengue laboratory diagnosis by using a single serum specimen. METHODS: Archived paired serum specimens (n = 1234) from patients with laboratory-confirmed dengue from 2005 through 2011 were used to determine the diagnostic performance of real-time reverse transcription polymerase chain reaction (RT-PCR), for detection of DENV serotypes 1-4, and enzyme-linked immunosorbent assays (ELISAs), for detection of DENV nonstructural protein 1 (NS1) antigen and anti-DENV IgM. RESULTS: During 1-3 days after illness onset, real-time RT-PCR and NS1 antigen testing detected 82% 69% and 90%-84% of cases, respectively, as viremia levels declined, while anti DENV IgM ELISA detected 5%-41% of cases as antibody appeared. Over the 10-day period of the febrile phase of dengue, the cumulative effect of using these 3 types of tests in a diagnostic algorithm confirmed >=90% of dengue cases. CONCLUSIONS: The use of molecular or NS1 antigen tests to detect DENV and one to detect anti-DENV IgM in a single serum specimen collected during the first 10 days of illness accurately identified >=90% of dengue primary and secondary cases. PMID- 26984146 TI - MicroRNAs Constitute a Negative Feedback Loop in Streptococcus pneumoniae-Induced Macrophage Activation. AB - Streptococcus pneumoniae causes high mortality as a major pneumonia-inducing pathogen. In pneumonia, control of innate immunity is necessary to prevent organ damage. We assessed the role of microRNAs (miRNAs) as regulators in pneumococcal infection of human macrophages. Exposure of primary blood-derived human macrophages with pneumococci resulted in transcriptional changes in several gene clusters and a significant deregulation of 10 microRNAs. Computational network analysis retrieved miRNA-146a as one putatively important regulator of pneumococci-induced host cell activation. Its induction depended on bacterial structural integrity and was completely inhibited by blocking Toll-like receptor 2 (TLR-2) or depleting its mediator MyD88. Furthermore, induction of miRNA-146a release did not require the autocrine feedback of interleukin 1beta and tumor necrosis factor alpha released from infected macrophages, and it repressed the TLR-2 downstream mediators IRAK-1 and TRAF-6, as well as the inflammatory factors cyclooxygenase 2 and interleukin 1beta. In summary, pneumococci recognition induces a negative feedback loop, preventing excessive inflammation via miR-146a and potentially other miRNAs. PMID- 26984147 TI - Dengue Viruses and Lifelong Immunity: Reevaluating the Conventional Wisdom. PMID- 26984149 TI - Mechanisms of interferon-alpha-induced depressive symptoms. PMID- 26984144 TI - Homotypic Dengue Virus Reinfections in Nicaraguan Children. AB - BACKGROUND: Infection with any of the 4 related dengue virus serotypes (DENV-1-4) is thought to result in lifelong immunity to homotypic reinfection (ie, reinfection with the same serotype). METHODS: Archived serum samples collected as part of an ongoing pediatric dengue cohort study in Nicaragua were tested for DENV by real-time reverse transcription polymerase chain reaction. Samples were collected from 2892 children who presented with an acute febrile illness clinically attributed to a non-DENV cause (hereafter, "C cases"). Test results were added to a database of previously identified symptomatic dengue cases in the cohort to identify repeat infections. RESULTS: Four patients with homotypic DENV reinfections were identified and confirmed among 29 repeat DENV infections (13.8%) with serotype confirmation. Homotypic reinfections with DENV-1, DENV-2, and DENV-3 occurred 325-621 days after the initial infection. Each patient experienced 1 symptomatic dengue case and 1 DENV-positive C case, and 2 patients presented with symptomatic dengue during their second infection. These DENV positive C cases did not elicit long-lived humoral immune responses, despite viremia levels of up to 6.44 log10 copies per mL of serum. CONCLUSIONS: We describe the first set of virologically confirmed homotypic DENV reinfections. Such cases challenge the current understanding of DENV immunity and have important implications for modeling DENV transmission. PMID- 26984150 TI - Low IQ scores in schizophrenia: primary or secondary deficit? AB - BACKGROUND: Schizophrenia is consistently associated with lower IQ compared to the IQ of control groups, or estimated premorbid IQ. It is not likely that the IQ scores deteriorate during the prodromal phase or first psychotic episode; they are already present before the onset of the prodromal phase and have been detected in childhood. METHODS: We investigated cognitive functioning and IQ levels in a group of 36 patients with schizophrenia or other psychotic disorders. RESULTS: The IQ scores in our sample were lower than average. The IQ showed a relation with attention, memory, speed of information processing and some aspects of executive functioning. However, when IQ scores were corrected for processing speed, they were no longer below average. CONCLUSIONS: These findings are important in considering the value of intelligence levels in schizophrenia. IQ scores should be judged in combination with cognitive functioning and school career to assess a patients capabilities in society. Cognitive functions and other variables might have a considerable influence on IQ scores. This rises the question of whether the low IQ scores are a primary or secondary deficit. Schizophrenia patients may have normal IQs, but could be less capable of making an IQ-test. PMID- 26984151 TI - Catatonia: the rise and fall of an intriguing psychopathological dimension. AB - BACKGROUND: For at least 125 years the discussion about the clinical relevance of catatonic symptoms in psychiatry continues. It started from the original description by Kahlbaum and was revived by modern factor analytical studies, that identified the catatonic dimension in about 10% of newly admitted patients. OBJECTIVE: Over a period of 2 years, four patients with an acute episodic psychosis and prominent catatonic symptoms were examined. METHODS: A clinical description is given of the psychopathology and classification is performed according to the various diagnostic instruments. RESULTS: All patients showed a circular fluctuation of their psychoses, with motor symptoms ranging from the excited to the inhibited pole within one episode. Their clinical pictures also comprised mood swings and anxieties as well as hallucinatory and delusional experiences, whereas the course of disease was characterized by complete recovery without residual symptoms. CONCLUSIONS: The significance of catatonic symptoms is not recognized in the current taxonomies despite the fact that this has major pharmacological treatment implications. PMID- 26984152 TI - Agitation in dementia due to hypothyroidism. PMID- 26984153 TI - Pteridines and affective disorders. AB - The pteridine tetrahydrobiopterin (BH4) is an essential cofactor in the biosynthesis of dopamine, (nor)epinephrine, serotonin and nitric oxide (NO). Furthermore, BH4 has a direct influence on release mechanisms of these neurotransmitters and on serotonin receptor binding activity immunology. The synthesis of BH4 is stimulated by interferon-gamma and hence there is a close relationship with the immune system HPA-axis. In animal experiments it was also found that the hypothalamus-pituitary-adrenal axis influences the pteridine metabolism. In clinical studies, so far, no evidence has been found for this relationship diseases. A congenital biopterin deficiency results in atypical phenylketonuria with severe neuropsychiatric symptoms. In several neurological diseases, such as Parkinson's disease, decreased levels of BH4 are found depression. Since 1984 there have been reports on decreased biopterin and increased neopterin levels in urine and plasma of depressed patients. Conflicting results have also been found, however, due probably to methodological problems therapy. Until now, oral administration of BH4 to depressed patients has been performed by two investigators, which resulted in mainly temporal clinical improvement discussion. Understanding of biochemical mechanisms in which pteridines are involved may contribute to our knowledge of the pathogenesis and treatment of affective disorders. This paper aims to provide an overview of the relevant literature and warrant for further research on this intriguing compound. PMID- 26984148 TI - Responder Interferon lambda Genotypes Are Associated With Higher Risk of Liver Fibrosis in HIV-Hepatitis C Virus Coinfection. AB - BACKGROUND: Liver fibrosis progresses faster in individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Interferon lambda3 (IFN lambda3) has both antiviral and proinflammatory properties. Genotypes at IFNL single-nucleotide proteins (SNPs; rs12979860CC and rs8099917TT) are linked to higher HCV clearance, potentially via rs8103142. We examined the relationship between IFN-lambda genotypes and significant liver fibrosis in HIV-HCV coinfection. METHODS: From the prospective Canadian Co-infection Cohort (n = 1423), HCV RNA-positive participants in whom IFN-lambda genotypes were detected and who were free of fibrosis, end-stage liver disease, and chronic hepatitis B at baseline (n = 485) were included. Time to significant fibrosis (defined as an aspartate transaminase level to platelet count ratio index [APRI] of >=1.5) by IFN-lambda genotypes was analyzed using Cox proportional hazards, with adjustment for age, sex, ethnicity, alcohol use, CD4(+) T-cell count, HCV genotype, gamma glutamyl transferase level, and baseline APRI. Haplotype analysis was performed, with adjustment for ethnicity. RESULTS: A total of 125 participants developed fibrosis over 1595 person-years (7.84 cases/100 person-years; 95% confidence interval [CI], 6.58-9.34 cases/100 person-years). Each genotype was associated with an increased fibrosis risk, with adjusted hazard ratios of 1.37 (95% CI, .94 2.02) for rs12979860CC, 1.34 (95% CI, .91-1.97) for rs8103142TT, and 1.79 (95% CI, 1.24-2.57) for rs8099917TT. Haplotype TCT was also linked with a higher risk (hazard ratio, 1.14 [95% CI, .73-1.77]). CONCLUSIONS: IFN-lambda SNPs rs12979860, rs8099917, and rs81013142 were individually linked to higher rates of fibrosis in individuals with HIV-HCV coinfection. IFN-lambda genotypes may be useful to target HCV treatments to people who are at higher risk of liver disease. PMID- 26984154 TI - Chronic fatigue syndrome in the psychiatric practice. AB - BACKGROUND: Chronic fatigue syndrome (CFS) is a complex syndrome with a psychiatric comorbidity of 70-80%. A psychiatric interview is necessary in order to exclude psychiatric illness and to identify psychiatric comorbidity. Studies have demonstrated that in general medical practice and in the non-psychiatric specialist practice, physicians tend to underdiagnose psychopathology in patients with CFS. There are many questions unanswered about the treatment of CFS Aim: Typical issues for the psychiatric practice are reviewed: psychiatric comorbidity, dysregulation of the PHA-axis and the treatment of CFS. CONCLUSIONS: Depression, somatization, sleeping disorders and anxiety disorders are the most important psychopathological symptoms found in CFS patients. CFS should not be regarded as a masked (somatoform) depression. Although the results from neuroendocrinological studies assessing the hypothalamic-pituitary-adrenal axis (HPA-axis) are inconsistent, they suggest that there is a subgroup of CFS patients suffering from a discrete dysregulation of the HPA-axis resulting in basal hypocortisolaemia. These findings, however, do not reveal a causal relationship. Antidepressants do not seem to have a positive influence on the symptom of fatigue, but appear to be beneficial in alleviating the symptoms of depression and social functioning. Cognitive behaviour therapy and graded exercise show a significant improvement on fatigue and other symptoms and are the only treatments available for CFS patients. PMID- 26984155 TI - The abnormal development of drive and guidance mechanisms in the brain: the pathogenesis of schizophrenia. AB - BACKGROUND: It remains a mystery as to how genetic and environmental factors cause schizophrenia. OBJECTIVE: To develop a pathophysiological model of schizophrenia that has greater explanatory power than existing hypotheses of the disorder. METHOD: Published findings on schizophrenia are integrated with more recent data from human and animal studies of striatal and cerebellar functions. RESULTS: The analysis shows that during phylo- and ontogenesis two primarily motor-control mechanisms are applied at the intentional (limbic) level of functioning to organize emotional and cognitive behavior: one for initiating and dosing (drive) and the other for the representational guidance (guidance) of both movements and intentions. The intentional drive and guidance mechanisms are organized through a ventral, respectively, a dorsal cortical-subcortical circuitry. CONCLUSIONS: A deficient implementation of these mechanisms at the limbic domain manifests itself as schizophrenia, whereby the heterogeneity in symptomatology is explained by the extent of the remaining cerebral activity and by the degree of indirect activation of these systems. In general, activation manifests itself as positive symptomatology and the absence of such activation as negative symptomatology. The model provides a more comprehensive explanation for existing clinical and epidemiological data than do the current alternatives. It is compatible with the major prevailing views on the illness, such as the theories that regard this as a progressive neurodevelopmental, or a connectivity disorder, or one resulting from a deficient cerebral lateralization, or an interrupted cortico-thalamo-cerebello-cortical circuitry. The model fits with recent theories in evolutionary psychology and evolutionary psychiatry. PMID- 26984156 TI - Depression and Parkinson's disease: a conceptual challenge. AB - AIM: To explore the relation between Parkinson's disease (PD) and depression from a conceptual point of view. METHODS: Discussion of the relevant literature on the conceptual, phenomenological and therapeutical aspects of depression in Parkinson's disease. RESULTS: Both semantic confusion and an erroneous belief in the mind-body distinction have contributed to some common misunderstandings of the nosology and etiology of depression in Parkinson's disease. CONCLUSION: The consequences of a different, integrated, neuropsychiatric approach for both diagnosis and treatment are discussed. PMID- 26984157 TI - Silibinin inhibits triple negative breast cancer cell motility by suppressing TGF beta2 expression. AB - Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates many biological events including cell motility and angiogenesis. Here, we investigated the role of elevated TGF-beta2 level in triple negative breast cancer (TNBC) cells and the inhibitory effect of silibinin on TGF-beta2 action in TNBC cells. Breast cancer patients with high TGF-beta2 expression have a poor prognosis. The levels of TGF-beta2 expression increased significantly in TNBC cells compared with those in non-TNBC cells. In addition, cell motility-related genes such as fibronectin (FN) and matrix metalloproteinase-2 (MMP-2) expression also increased in TNBC cells. Basal FN, MMP-2, and MMP-9 expression levels decreased in response to LY2109761, a dual TGF-beta receptor I/II inhibitor, in TNBC cells. TNBC cell migration also decreased in response to LY2109761. Furthermore, we observed that TGF-beta2 augmented the FN, MMP-2, and MMP-9 expression levels in a time- and dose-dependent manner. In contrast, TGF-beta2 induced FN, MMP-2, and MMP-9 expression levels decreased significantly in response to LY2109761. Interestingly, we found that silibinin decreased TGF-beta2 mRNA expression level but not that of TGF-beta1 in TNBC cells. Cell migration as well as basal FN and MMP-2 expression levels decreased in response to silibinin. Furthermore, silibinin significantly decreased TGF-beta2-induced FN, MMP-2, and MMP-9 expression levels and suppressed the lung metastasis of TNBC cells. Taken together, these results suggest that silibinin suppresses metastatic potential of TNBC cells by inhibiting TGF-beta2 expression in TNBC cells. Thus, silibinin may be a promising therapeutic drug to treat TNBC. PMID- 26984159 TI - Austerity is linked to rising mortality among older pensioners. PMID- 26984158 TI - Metabonomics and intensive care. AB - This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901. PMID- 26984161 TI - Statistical significance does not imply a real effect. PMID- 26984160 TI - Fetal heart rate monitoring of short term variation (STV): a methodological observational study. AB - BACKGROUND: Cardiotocography (CTG) has high sensitivity, but less specificity in detection of fetal hypoxia. There is need for adjunctive methods easy to apply during labor. Low fetal heart rate short term variation (STV) is predictive for hypoxia during the antenatal period. The objectives of our study were to methodologically evaluate monitoring of STV during labor and to compare two different monitors (SonicaidTM and EDANTM) for antenatal use. METHODS: A prospective observational study at the obstetric department, Karolinska University hospital, Stockholm (between September 2011 and April 2015). In 100 women of >= 36 weeks gestation, STV values were calculated during active labor. In a subset of 20 women we compared STV values between internal and external signal acquisition. Additionally we compared antenatal monitoring with two different monitors in another 20 women. RESULTS: Median STV in 100 fetuses monitored with scalp electrode during labor (EDANTM) was 7.1 msec (range 1.3 25.9) with no difference between early (3-6 cm) and late (7-10 cm) labor (7.1 vs 6.8 msec; p = 0.80). STV calculated from scalp electrode signals were positively correlated with delta-STV (STV internal -external) (R = 0.70; p < 0.01). No significant differences were found between SonicaidTM and EDANTM in antenatal external monitoring of STV (median difference 0.9 msec, Spearman Rank Correlation Sonicaid vs delta-STV; R = 0.35; p = 0.14). CONCLUSIONS: Median intrapartum STV was 7.1 msec. Significant differences were found between internal and external signal acquisition, a finding that suggests further intrapartum studies to be analysed separately depending upon type of signal acquisition. Antenatal external monitoring with SonicaidTM and EDANTM indicates that the devices perform equally well in the identification of acidemic fetuses. Further studies are needed to assess the clinical value of intrapartum STV. PMID- 26984162 TI - The impact of weight gain associated with atypical antipsychotic use in schizophrenia. AB - BACKGROUND: Atypical antipsychotics offer clear advantages in the management of schizophrenia, compared with conventional neuroleptics, but weight gain is a significant adverse effect with some of these agents. OBJECTIVE: To review the literature on weight gain associated with atypical antipsychotic treatment in schizophrenia. METHODS: Relevant sources were identified from Medline searches to February 2003 using combinations of keywords including 'schizophrenia', 'antipsychotics', 'weight gain', 'adverse events', 'obesity', and 'diabetes'. RESULTS: Most atypical antipsychotics induce some weight gain, but the magnitude of the effect varies markedly. The greatest increases are seen with clozapine and olanzapine: risperidone has a slight effect, comparable with that of conventional neuroleptics, while ziprasidone and aripiprazole appear from current data to have little effect. In addition, atypical antipsychotics have been associated with metabolic disturbances, particularly glucose dysregulation and dyslipidemia. These effects tend to be more marked with olanzapine and clozapine than with other agents. Weight gain associated with atypical antipsychotics imposes substantial morbidity, in addition to that associated with schizophrenia itself. Furthermore, weight gain can significantly impair patients' quality of life, and leads to non-adherence with treatment. Effective weight management should include the selection of an appropriate atypical antipsychotic and for effective weight management, as well both diet and exercise, formal weight management programs tailored to the needs of schizophrenic patients may be useful, and some patients may benefit from weight-reducing drugs. CONCLUSIONS: Weight gain associated with atypical antipsychotics is a common problem that requires effective management. The selection of an agent with a low risk of weight gain, such as risperidone or ziprasidone, is central to such management. PMID- 26984163 TI - Characteristics of sleep disturbances in Poland - results of the National Health Interview Survey. AB - BACKGROUND: Apart from insomnia, poor quality of sleep, decreased sleep duration, tiredness after awakening and frequency of using sleeping drugs are important indicators of sleep problems. OBJECTIVES: The aim of this study was to assess the prevalence of indicators of sleep disturbance, such as quality of sleep, sleep duration, feeling of restfulness in the morning and drug utilization in a randomly selected Polish adult population. METHODS: A stratified scheme of sampling involving two steps was used. A representative Polish population sample of 47 924 non-institutionalized adults was interviewed. Assessments of sleep related problems were based on six questions. Standardized prevalence ratios (SPRs and their 95% confidence intervals) were calculated. RESULTS: Almost one tenth of Polish inhabitants usually slept badly or very badly, a problem that was more common among women than men. Quality of sleep decreased together with ageing and this process was more rapid in women than in men over 40 years of age. Highly educated respondents had the highest quality of sleep. Up to one-fifth of the general Polish population usually woke up tired in the morning. Mean sleep duration was 7.7 h, with no gender differences. Usage of over-the-counter (OTC) medications was significantly lower than usage of those prescribed by the physician (5 vs. 16%). Women used OTC drugs twice as often as men. CONCLUSIONS: It would appear to be necessary to introduce educational programmes for the community as well as for general practitioners in order to correct improper attitudes. PMID- 26984164 TI - Effects of desmopressin (DDAVP) on memory impairment following electroconvulsive therapy (ECT). AB - BACKGROUND: Memory impairment is a common adverse effect of electroconvulsive therapy (ECT). Studies on animals and humans suggest that vasopressin improves the cognitive function, and positive effects of desmopressin on memory and learning have been reported. This research was performed for evaluation of the effects of desmopressin in the prevention of memory impairment following ECT. METHODS: This randomized, double-blind controlled clinical trial with placebo administration was performed on 50 patients with psychiatric disorders who were candidates for ECT. Subjects in the case group received 60 um of intranasal desmopressin daily (in three doses of 20 um). For the control group 0.9% saline solution was administered in the same way. Memory function was evaluated using Wechsler's Memory Scale three times a week (the first time before the start of ECT and the second and third times after the third and sixth sessions, respectively). Results were analyzed by t-test and Paired t-test. RESULTS: The mean age of patients was 29 years (range 20-40). During the course of ECT, patients in the control group demonstrated a meaningful decrease in memory scores (from a base score of 80.15-75.45 in the second test and 72.60 in the third test). Despite this, a meaningful increase in memory scores was observed during the treatment with desmopressin in the case group (from a base score of 73.27 75.70 and 79.13 in the second and the third tests, respectively). There was a meaningful difference between the two groups (P < 0.0001). CONCLUSION: This study confirms the protective effect of desmopressin against memory impairment. The results confirm that memory impairment is a common side-effect of ECT and suggest that desmopressin may prevent ECT-induced memory impairment by its effects on memory and the learning process. PMID- 26984165 TI - Changes in appearance and schizotypy in normal subjects. AB - BACKGROUND: Anecdotal reports suggest that drastic changes in physical appearance may signal psychotic decompensation in schizophrenic patients. OBJECTIVE: The current study sought to explore the association between changes in appearance and psychotic vulnerability in a more systematic fashion. METHODS: A sample of undergraduates (n = 171) completed the Changes in Appearance Scale (CAS), which assesses frequency and nature of changes in outlook, along with a Schizotypy Scale (STA), the Maudsley Obsessive Compulsive Inventory (MOCI), the Fear Questionnaire (FQ) and the Beck Depression Inventory (BDI). RESULTS: A modest but significant correlation was found between the CAS and STA scores. For the other symptom measures (MOCI, FQ, and BDI), no association with self-reported changes in physical appearance emerged. CONCLUSIONS: Changes in physical appearance are found to be significantly associated to mild (pre)psychotic symptoms. PMID- 26984166 TI - Focus on fillings: a qualitative health study of people medically diagnosed with mercury poisoning, linked to dental amalgam. AB - BACKGROUND: This paper reports a qualitative investigation of people who have considered removing their dental amalgam fillings following a medical diagnosis of mercury poisoning. OBJECTIVE: To document themes from patients' collective, subjective experience; and explore links between illness and dental amalgam. METHODS: Seven focus groups involved 35 participants selected by random, criteria sampling from the computerized patient records of one medical practice. RESULTS: The participants' experiences represented four scenarios, each with a distinct pattern of presenting illness, and developmental path for health beliefs linking mercury and illness. When discussing health outcomes following their diagnosis of mercury poisoning, 29 of the 32 participants who had begun amalgam removal reported enduring health gains. Participants compared sources of information on mercury poisoning, and explored issues related to medical practice: the focus on symptoms and not aetiology; how symptoms were monitored; the stigma of a psychosomatic label; suicide; and the problematic detoxification process. CONCLUSION: The placebo effect and reduced galvanism as explanations for recovery are considered. A 'toothless body' metaphor is proposed as a possible explanation for missed diagnosis of mercury poisoning. Participants reported that the experience was costly both financially and socially, and wanted health professionals to be more open to considering mercury in a causal role for chronic illness. PMID- 26984167 TI - Differential impairment of working memory performance in first-degree relatives of individuals with schizophrenia. AB - BACKGROUND: Numerous studies have reported neuropsychological impairment in schizophrenia and increasing evidence suggests that individuals with schizophrenia or schizophrenia spectrum disorders and their unaffected first degree family members exhibit similar deficits in some neuropsychological domains. Substantial modifications to the Wechsler Memory Scale (WMS) have resulted in more sensitive and reliable indicators of various aspects of memory functioning in the WMS-III, which enables generation of auditory, visual and working memory indices. OBJECTIVE: The aim of the present study was to examine the memory profile of individuals with schizophrenia or schizophrenia spectrum disorder (n = 19), their unaffected first-degree family members (n = 11), and healthy controls (n = 9). METHODS: The study involved neuropsychological testing, including the immediate and working memory subtests of the WMS-III, utilizing both auditory and visual domains. Symptom assessment was performed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN), version 2.0. Two multivariate analyses of covariance (mancova) were conducted: (i) comparing patients, relatives and controls; and (ii) comparing relatives and controls only. RESULTS: The first analysis indicated that the patient group obtained significantly lower index scores than both relatives and controls on all three indices. The second analysis indicated that the performance of relatives was significantly lower than controls on the working memory index, although there were no significant differences on the auditory and visual immediate index scores. CONCLUSIONS: The differential impairment in working memory performance in clinically asymptomatic family members suggests that the WMS-III working memory index score may be a potential phenotypic marker of schizophrenia. PMID- 26984168 TI - Abnormal speech perception in schizophrenia with auditory hallucinations. AB - BACKGROUND: The neurobiological mechanism of auditory hallucination (AH) in schizophrenia remains elusive, but AH can be caused by the abnormality in the speech perception system based on the speech perception neural network model. OBJECTIVES: The purpose of this study was to investigate whether schizophrenic patients with AH have the speech processing impairment as compared with schizophrenic patients without AH, and whether the speech perception ability could be improved after AH had subsided. METHODS: Twenty-four schizophrenic patients with AH were compared with 25 schizophrenic patients without AH. Narrative speech perception was assessed using a masked speech tracking (MST) task with three levels of superimposed phonetic noise. Sentence repetition task (SRT) and auditory continuous performance task (CPT) were used to assess grammar dependent verbal working memory and non-language attention, respectively. These tests were measured before and after treatment in both groups. RESULTS: Before treatment, schizophrenic patients with AH showed significant impairments in MST compared with those without AH. There were no significant differences in SRT and CPT correct (CPT-C) rates between both groups, but CPT incorrect (CPT-I) rate showed a significant difference. The low-score CPI-I group showed a significant difference in MST performance between the two groups, while the high-score CPI-I group did not. After treatment (after AH subsided), the hallucinating schizophrenic patients still had significant impairment in MST performance compared with non-hallucinating schizophrenic patients. CONCLUSIONS: Our results support the claim that schizophrenic patients with AH are likely to have a disturbance of the speech perception system. Moreover, our data suggest that non language attention might be a key factor influencing speech perception ability and that speech perception dysfunction might be a trait marker in schizophrenia with AH. PMID- 26984169 TI - Hypothalamic digoxin, hemispheric chemical dominance and sarcoidosis. AB - BACKGROUND/AIMS: The isoprenoid pathway produces three key metabolites: endogenous digoxin (membrane sodium-potassium ATPase inhibitor, immunomodulator and regulator of neurotransmitter/amino acid transport), dolichol (regulates N glycosylation of proteins) and ubiquinone (free radical scavenger). The role of the isoprenoid pathway in the pathogenesis of sarcoidosis in relation to hemispheric dominance was studied. METHODS: The isoprenoid pathway-related cascade was assessed in patients with systemic sarcoidosis with pulmonary involvement. The pathway was also assessed in patients with right hemispheric, left hemispheric and bihemispheric dominance for comparison to find out the role of hemispheric dominance in the pathogenesis of sarcoidosis. RESULTS: In patients with sarcoidosis there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites. There was an increase in the cholesterol:phospholipid ratio and a reduction in the glycoconjugate level of red blood cell (RBC) membrane in this group of patients. The same biochemical patterns were obtained in individuals with right hemispheric dominance. In individuals with left hemispheric dominance the patterns were reversed. CONCLUSIONS: Endogenous digoxin, by activating the calcineurin signal transduction pathway of T cells, can contribute to immune activation in sarcoidosis. An altered glycoconjugate metabolism can lead to the generation of endogenous self-glycoprotein antigens in the lung as well as other tissues. Increased free radical generation can also lead to immune activation. The role of a dysfunctional isoprenoid pathway and endogenous digoxin in the pathogenesis of sarcoidosis in relation to right hemispheric chemical dominance is discussed. All the patients with sarcoidosis were right-handed/left hemispheric dominant according to the dichotic listening test, but their biochemical patterns were suggestive of right hemispheric chemical dominance. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. PMID- 26984170 TI - Temperament and Character Inventory (TCI) in adolescents with anorexia nervosa. AB - BACKGROUND: Female patients with anorexia nervosa differ significantly from the control women in various dimensions of personality. OBJECTIVE: To investigate the personality dimensions measured with the Temperament and Character Inventory (TCI) in adolescent patients with restrictive-type and bulimic/purging-type anorexia nervosa (ANR and ANB, respectively), and contrast them with the results of control females. METHODS: Sixty-one patients with anorexia nervosa (36 ANR and 25 ANB) and 60 controls were tested with the TCI. A concomitant assessment of depression, body mass index and age was made to evaluate the possible correlation with personality dimensions. RESULTS: Adolescent ANR patients scored higher in persistence, harm avoidance and cooperativeness, and lower in novelty seeking and self-transcendence than control women. ANB patients scored in the middle between ANR and control females, but differences did not reach the significance level with either group, except for the self-transcendence dimension where they scored significantly higher than those with ANR. CONCLUSIONS: The deviations in temperamental profile of adolescent ANR are similar to those reported in adult patients. The ANB adolescent patients with anorexia nervosa show less prominent deviations from the personality of control women. With regard to the character dimension of cooperativeness, adolescents with ANR scored higher than controls, in contrast to the observations in adult patients. This may reflect the effect of illness on the development of character. PMID- 26984171 TI - Personality disorder comorbidity among patients with bipolar I disorder in remission. AB - BACKGROUND: Comorbid personality disorders have been shown to be a prominent factor affecting symptom severity and course in bipolar disorder (BD) patients. Bipolar patients with personality disorder had more relapses, poorer prognosis and worse treatment response than those without an axis II diagnosis. OBJECTIVE: We evaluated the prevalence rate of comorbid personality disorder in 74 bipolar I disorder cases who were in remission and tried to elucidate the possible relationship between comorbid axis II disorders and prognosis, severity and treatment features of BD cases. METHODS: Diagnosis of all personality disorder comorbidities was evaluated using the Structured Clinical Interview for DSM-III-R Axis-II Disorders (SCID-II), while the general psychopathology level was assessed using the Symptom Check List (SCL-90-R). A questionnaire for acquiring sociodemographic and clinical variables was also used. RESULTS: Sixty-two per cent of bipolar I patients in this sample had at least one comorbid axis II disorder. The most common comorbid cluster of personality disorder was cluster C (48.6%), followed by cluster A (25.7%) and cluster B (20.3%) personality disorders. Assessment of demographic and clinical variables revealed that bipolar patients with comorbid personality disorder were mainly female, had multiple affective episodes, and had attempted suicide more often than patients without personality disorder. CONCLUSIONS: The results of this study suggest that comorbid personality disorder might alter the course of BD and result in a poorer prognosis and more severe psychopathology. Further prospective controlled studies minimizing the bias of interviewers and other confounding factors would help us to understand the pure impact of personality disorder on the course of BD, its prognosis and response to treatment. PMID- 26984172 TI - Charles Bonnet syndrome and dementia. PMID- 26984173 TI - Visual hallucinations in CBS: reply from the author. PMID- 26984175 TI - Anisotropic Li intercalation in a Li(x)FePO4 nano-particle: a spectral smoothed boundary phase-field model. AB - A spectral smoothed boundary phase-field model is implemented to study lithium (Li) intercalation in a LixFePO4 nano-particle immersed in a Li(+) rich electrolyte. It takes into account different physical processes on the particle surface, such as heterogeneous nucleation, Li flux and stress-free boundary conditions. We show the nucleation and growth of plate-like Li-rich crystallites along the (010) plane due to the high Li mobility along [001]. Since such plate like crystallites, which are nucleated from (001) surfaces, align their phase boundaries along the (101) habit planes, a LixFePO4 nano-particle with prominent (010) and (001) surface facets and the longest axis length along [100] is proposed to exhibit great mechanical stability. PMID- 26984174 TI - Low Ten-eleven-translocation 2 (TET2) transcript level is independent of TET2 mutation in patients with myeloid neoplasms. AB - BACKGROUND: New sequencing technologies have enabled the identification of mutations in Ten-eleven-translocation 2 (TET2), an enzyme that catalyzes the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5-hmC) in myeloid neoplasms. We have recently identified reduced TET2 mRNA expression in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), which is associated with a poor overall survival in MDS. We herein aimed to investigate TET2 mutations and their impact on TET2 expression in a cohort of patients with myeloid neoplasms, including MDS and AML patients. FINDINGS: TET2 mutations were observed in 8 out of 19 patients (42 %) with myeloid neoplasms. The TET2 expression profile was similar between in wild type and in TET2 mutated patients. CONCLUSION: Our results suggest that TET2 expression is reduced in MDS/AML patients, independently of mutational status. PMID- 26984176 TI - In vitro immunomodulatory activity, cytotoxicity and chemistry of some central European polypores. AB - Context Some mushrooms of the order Polyporales are known for their immunomodulatory actions. Objective The objective of this study is to evaluate the in vitro phagocytic and cytotoxic effects of extracts from polyporales native to Central Europe. Materials and methods The effects of ethanol extracts from 27 polypore species on opsonized zymosan-induced phagocytosis of isolated human neutrophils were tested by a chemiluminescence method. Colon epithelial cell lines, Caco-2 and HT-29, were used for cytotoxicity assays, and extracts were chemically characterized in terms of total phenolic and beta-glucan content. Results We observed phagocytosis or respiratory burst enhancing activity in 17 extracts, of which five species, namely Aurantiporus fissilis (Berk. & M.A. Curtis) H. Jahn ex Ryvarden, Trametes gibbosa (Pers.) Fr., Piptoporus betulinus (Bull.) P. Karst, Neolentinus lepideus (Fr.) Redhead & Ginns, Polyporus squamosus (Huds.) Fr., significantly increased phagocytosis in granulocytes by 205, 181, 158, 155 and 141%, respectively. The beta-glucan content of the three most potent extracts was 58, 42 and 74 mg/g, respectively, and the polyphenol content was 155.6, 133.5 and 155.2 MUmol of gallic acid equivalent/g, respectively. Some extracts showed cytotoxic activity, with higher cytotoxicity in Caco-2 than in HT 29 cells. Pycnoporus cinnabarinus (Jacq.) P. Karst. extract was cytotoxic to both cell lines, with IC50 values of 81 and 31 MUg/mL, respectively. Discussion and conclusion The most promising extracts were from N. lepideus and Polyporus squamosus, which are edible species and may be considered safe. Our findings support their use as culinary preparations or food supplements for various immunological gut disorders. PMID- 26984177 TI - p75 neurotrophin receptor expression is a characteristic of the mitotically quiescent cancer stem cell population present in esophageal squamous cell carcinoma. AB - Mitotically quiescent cancer stem cells (CSC) are hypothesized to exhibit a more aggressive phenotype involving greater therapeutic resistance and metastasis. The aim of our study was to develop a method for identifying quiescent CSC in esophageal squamous cell carcinoma (ESCC) based on their expression of the p75 neurotrophin receptor (p75NTR) and other proposed CSC markers, such as CD44 and CD90. Double immunostaining of surgical ESCC specimens revealed that the mean Ki 67-labeling index of the p75NTR-positive cells was significantly lower than that of the p75NTR-negative cells. Real-time PCR analysis of sorted fractions of ESCC cell lines (KYSE cells) revealed that stem cell-related genes (Nanog, p63 and Bmi 1) and epithelial-mesenchymal transition (EMT)-related genes (N-cadherin and fibronectin) were expressed at significantly higher levels in the p75NTR-positive fractions than in the CD44-positive or CD90-positive fractions. In addition, the p75NTR-positive fractions exhibited significantly higher colony formation in vitro, significantly enhanced tumor formation in mice, and significantly greater chemoresistance against cisplatin (CDDP) than the CD44-positive or CD90-positive fractions. Furthermore, in both the cultured cells and those from the mouse xenograft tumors, the p75NTR-positive/CD44-negative and p75NTR-positive/CD90 negative KYSE cell fractions contained significantly higher proportions of mitotically quiescent cells. These results suggest that the mitotically quiescent CSC population in ESCC can be identified and isolated based on their p75NTR expression, providing researchers with a novel diagnostic and therapeutic target. PMID- 26984179 TI - The anti-tumor effects of cordycepin-loaded liposomes on the growth of hepatoma 22 tumors in mice and human hepatoma BEL-7402 cells in culture. AB - Liposomes have successfully been used for decades to encapsulate and protect drugs that are prone to deactivation in the body. The present study aimed to demonstrate the use of liposomes to encapsulate cordycepin, an adenosine analog that quickly loses its activity in vivo. The cordycepin-loaded liposomes were prepared by the ammonium sulfate gradient approach, and its in vitro and in vivo antitumour activities were evaluated using BEL-7402 cells and hepatocellular carcinoma H22 transplanted tumors, respectively. An MTT assay was used to observe the cytotoxicity of cells treated with cordycepin and cordycepin-loaded liposomes in vitro. High-content screening (HSC) was carried out using Hoechst 33342 to detect apoptotic cells and the ratio of cells in different cell cycle stages. The data demonstrated that both the cordycepin and the cordycepin-loaded liposomes resulted in clear cytotoxicity with IC50 values of 18.97 and 29.39 MUg/mL, respectively. The latter showed significantly strong inhibitory effects on H22 tumor growth in mice, while the former did not show any inhibitory effects on tumor growth. In addition, the HSC assay showed that the cordycepin-loaded liposomes resulted in a higher rate of apoptosis than the cordycepin alone in BEL 7402 cells. Further data analysis revealed that the cells treated with cordycepin loaded liposomes were predominately arrested at the G2/M phase (p < 0.05), while those treated with cordycepin alone were arrested in the G0/G1 phase (p < 0.05). In conclusion, these results suggest that liposomes can enhance and maintain the in vivo anti-tumor activity of cordycepin. PMID- 26984180 TI - Paralog analyses reveal gene duplication events and genes under positive selection in Ixodes scapularis and other ixodid ticks. AB - BACKGROUND: Hard ticks (family Ixodidae) are obligatory hematophagous ectoparasites of worldwide medical and veterinary importance. The haploid genomes of multiple species of ixodid ticks exceed 1 Gbp, prompting questions regarding gene, segmental and whole genome duplication in this phyletic group. The availability of the genome assembly for the black legged tick, Ixodes scapularis, and transcriptome datasets for multiple species of ticks offers an opportunity to assess the contribution of gene duplication to the genome. Here we developed a bioinformatics pipeline to identify and analyze duplicated genes (paralogs) using gene models from the prostriate tick, I. scapularis IscaW1.1 annotation and expressed sequence tags (ESTs) from I. scapularis and the metastriate ticks, Rhipicephalus microplus (southern cattle tick), R. appendiculatus (brown ear tick) and Amblyomma variegatum (tropical bont tick). RESULTS: Approximately 1-2% of I. scapularis gene models and 2-14% of ESTs from the four species represent duplicated genes. The ratio of non-synonymous to synonymous nucleotide substitution rates suggests ~ 25% of duplicated genes are under positive selection pressure in each species. Analyses of synonymous substitution rates provide evidence for two duplication events in I. scapularis and R. microplus involving several hundred genes. Conservative molecular clock estimates based on synonymous substitution rates for species of Anopheles mosquitoes and the fruit fly, Drosophila melanogaster, suggest these events occurred within the last 50 MYA. Mapping of paralogs to the I. scapularis genome assembly supports tandem, or possibly segmental duplication events. CONCLUSIONS: The present study marks the first genome-level analyses of gene duplication for the Ixodidae and provides insights into mechanisms shaping genome evolution in this group. At least two duplication events involving hundreds of genes may have occurred independently in the lineages prostriata and metastriata, with tandem and segmental duplication the most likely mechanisms for paralog generation. Duplicated genes under positive selection pressure may be linked to emerging functions in the tick and represent important candidates for further study. PMID- 26984178 TI - Developments in miRNA gene signaling pathways in pancreatic cancer. AB - Pancreatic cancer is a devastating malignancy that ranks as the fourth leading cause of cancer-related deaths worldwide. Dismal prognosis is mainly attributable to limited knowledge of the molecular pathogenesis of the disease. miRNAs have been found to be deregulated in pancreatic cancer, affecting several steps of initiation and aggressiveness of the disease by regulating important signaling pathways, such as the KRAS and Notch pathways. Moreover, the effect of miRNAs on regulating cell cycle events and expression of transcription factors has gained a lot of attention. Recent studies have highlighted the application of miRNAs as biomarkers and therapeutic tools. The current review focuses on latest advances with respect to the roles of miRNAs in pancreatic ductal adenocarcinoma associated signaling pathways and miRNA-based therapeutics. PMID- 26984182 TI - Influence of agglomeration and specific lung lining lipid/protein interaction on short-term inhalation toxicity. AB - Lung lining fluid is the first biological barrier nanoparticles (NPs) encounter during inhalation. As previous inhalation studies revealed considerable differences between surface functionalized NPs with respect to deposition and toxicity, our aim was to investigate the influence of lipid and/or protein binding on these processes. Thus, we analyzed a set of surface functionalized NPs including different SiO2 and ZrO2 in pure phospholipids, CuroSurf(TM) and purified native porcine pulmonary surfactant (nS). Lipid binding was surprisingly low for pure phospholipids and only few NPs attracted a minimal lipid corona. Additional presence of hydrophobic surfactant protein (SP) B in CuroSurf(TM) promoted lipid binding to NPs functionalized with Amino or PEG residues. The presence of the hydrophilic SP A in nS facilitated lipid binding to all NPs. In line with this the degree of lipid and protein affinities for different surface functionalized SiO2 NPs in nS followed the same order (SiO2 Phosphate ~ unmodified SiO2 < SiO2 PEG < SiO2 Amino NPs). Agglomeration and biomolecule interaction of NPs in nS was mainly influenced by surface charge and hydrophobicity. Toxicological differences as observed in short-term inhalation studies (STIS) were mainly influenced by the core composition and/or surface reactivity of NPs. However, agglomeration in lipid media and lipid/protein affinity appeared to play a modulatory role on short-term inhalation toxicity. For instance, lipophilic NPs like ZrO2, which are interacting with nS to a higher extent, exhibited a far higher lung burden than their hydrophilic counterparts, which deserves further attention to predict or model effects of respirable NPs. PMID- 26984184 TI - Evaluation of an Urban Farm-to-Preschool and Families Program. AB - Over the past 30 years, the rate of childhood obesity has risen dramatically. Despite recent declines in prevalence among preschool-aged children, child obesity is still a significant public health concern. Healthy People 2020 objectives include increasing fruit and vegetable consumption among children over 2 years of age and increasing the number of schools that offer access to fresh fruits and vegetables. To reach these objectives, farm-to-school programs are being implemented across the United States. The purpose of this evaluation was to: (a) identify factors that facilitate adoption of the Farm-to-Preschool and Families program in Springfield, MA, specifically; and (b) provide recommendations and guidelines for successful implementation of Farm-to-Preschool and Families programs generally. Using a combination of classroom observations of preschoolers, teacher and food service interviews, and administrator surveys, the findings suggest that having a strong programmatic infrastructure, administrative support, and external support from families is important to sustain a Farm-to Preschool and Families program. PMID- 26984181 TI - Does hemipelvis structure and position influence acetabulum orientation? AB - BACKGROUND: Although acetabulum orientation is well established anatomically and radiographically, its relation to the innominate bone has rarely been addressed. If explored, it could open the discussion on patomechanisms of such complex disorders as femoroacetabular impingement (FAI). We therefore evaluated the influence of pelvic bone position and structure on acetabular spatial orientation. We describe this relation and its clinical implications. METHODS: This retrospective study was based on computed tomography scanning of three dimensional models of 31 consecutive male pelvises (62 acetabulums). All measurements were based on CT spatial reconstruction with the use of highly specialized software (Rhinoceros). Relations between acetabular orientation (inclination, tilt, anteversion angles) and pelvic structure were evaluated. The following parameters were evaluated to assess the pelvic structure: iliac opening angle, iliac tilt angle, interspinous distance (ISD), intertuberous distance (ITD), height of the pelvis (HP), and the ISD/ITD/HP ratio. The linear and nonlinear dependence of the acetabular angles and hemipelvic measurements were examined with Pearson's product - moment correlation and Spearman's rank correlation coefficient. Correlations different from 0 with p < 0.05 were considered statistically significant. RESULTS: Comparison of the axis position with pelvis structure with orientation in the horizontal plane revealed a significant positive correlation between the acetabular anteversion angle and the iliac opening angle (p = 0.041 and 0.008, respectively). In the frontal plane, there was a positive correlation between the acetabular inclination angle and the iliac tilt angle (p = 0.025 and 0.014, respectively) and the acetabular inclination angle and the ISD/ITD/HP ratio (both p = 0.048). CONCLUSIONS: There is a significant correlation of the hemipelvic structure and acetabular orientation under anatomic conditions, especially in the frontal and horizontal planes. In the anteroposterior view, the more tilted-down innominate bone causes a more caudally oriented acetabulum axis, whereas in the horizontal view this relation is reversed. This study may serve as a basis for the discussion on the role of the pelvis in common disorders of the hip. PMID- 26984183 TI - Reusing larval rearing water and its effect on development and quality of Anopheles arabiensis mosquitoes. AB - BACKGROUND: There is growing interest in applying the sterile insect technique (SIT) against mosquitoes. Mass production of mosquitoes for large-scale releases demands a huge amount of water. Yet, many arid and/or seasonally arid countries face the difficulties of acute water shortage, deterioration of water quality and environmental constraints. The re-use of water to rear successive generations of larvae is attractive as a way to reduce water usage and running costs, and help to make this control method viable. METHODS: To determine whether dirty larval water was a suitable rearing medium for Anopheles arabiensis, in place of the 'clean' dechlorinated water routinely used, a series of three experiments was carried out to evaluate the effect of dirty water or mixed clean and dirty water on several parameters of insect quality. Batches of 100 fresh eggs were distributed in dirty water or added to clean water to test the effect of dirty water on egg hatching, whereas first-instar larvae were used to determine the effect on immature development time, pupation, adult emergence, body size, and longevity. Moreover, to assess the effect of dirty water on larval mortality, pupation rate, adult emergence, and longevity, L4 larvae collected after the tilting or larvae/pupae separation events were returned either to the dirty water or added to clean water. RESULTS: Results indicated that reusing dirty water or using a 50:50 mix of clean and dirty water did not affect egg hatching. Moreover, no difference was found in time to pupation, larval mortality or sex ratio when first-instar larvae were added to clean water, dirty water, or a 75:25, 50:50 or 25:75 mix of clean and dirty water and reared until emergence. When late-instar larvae were put back into their own rearing water, there was no effect on pupation rate, emergence rate or female longevity, though male longevity was reduced. When reared from first-instar larvae, however, dirty water decreased pupation rate, emergence rate, body size, and adult longevity. CONCLUSIONS: Re used larval-rearing water has no impact on egg hatching, development time or mortality of the immature stages of An. arabiensis. However, dirty water is not suitable for the production of high quality adult mosquitoes. Recycling processes to improve water quality and increase insect quality will be investigated, since it may have important implications for the implementation of the SIT in areas where clean water is a scarce or costly resource. PMID- 26984185 TI - Impact of an invasive nitrogen-fixing tree on arbuscular mycorrhizal fungi and the development of native species. AB - Arbuscular mycorrhizal fungi (AMF) are obligate soil biotrophs that establish intimate relationships with 80 % of terrestrial plant families. Arbuscular mycorrhizal fungi obtain carbon from host plants and contribute to the acquisition of mineral nutrients, mainly phosphorus. The presence of invasive plants has been identified as a soil disturbance factor, often conditioning the structure and function of soil microorganisms. Despite the investigation of many aspects related to the invasion ofAcacia dealbata, the effect produced on the structure of AMF communities has never been assessed. We hypothesize thatA. dealbatamodifies the structure of AMF community, influencing the establishment and growth of plants that are dependent on these mutualisms. To validate our hypothesis, we carried out denaturing gradient gel electrophoresis (DGGE) analysis and also grew plants ofPlantago lanceolatain pots using roots of native shrublands or fromA. dealbata, as inoculum of AMF. Cluster analyses from DGGE indicated an alteration in the structure of AMF communities in invaded soils. After 15 weeks, we found that plants grown in pots containing native roots presented higher stem and root growth and also produced higher biomass in comparison with plants grown withA. dealbatainoculum. Furthermore, plants that presented the highest biomass and growth exhibited the maximum mycorrhizal colonization and phosphorus content. Moreover, fluorescence measurements indicated that plants grown withA. dealbatainoculum even presented higher photosynthetic damage. Our results indicate that the presence of the invaderA. dealbatamodify the composition of the arbuscular fungal community, conditioning the establishment of native plants. PMID- 26984186 TI - TRPA1 mediates trigeminal neuropathic pain in mice downstream of monocytes/macrophages and oxidative stress. AB - Despite intense investigation, the mechanisms of the different forms of trigeminal neuropathic pain remain substantially unidentified. The transient receptor potential ankyrin 1 channel (encoded by TRPA1) has been reported to contribute to allodynia or hyperalgesia in some neuropathic pain models, including those produced by sciatic nerve constriction. However, the role of TRPA1 and the processes that cause trigeminal pain-like behaviours from nerve insult are poorly understood. The role of TRPA1, monocytes and macrophages, and oxidative stress in pain-like behaviour evoked by the constriction of the infraorbital nerve in mice were explored. C57BL/6 and wild-type (Trpa1(+/+)) mice that underwent constriction of the infraorbital nerve exhibited prolonged (20 days) non-evoked nociceptive behaviour and mechanical, cold and chemical hypersensitivity in comparison to sham-operated mice (P < 0.05-P < 0.001). Both genetic deletion of Trpa1 (Trpa1(-/-)) and pharmacological blockade (HC-030031 and A-967079) abrogated pain-like behaviours (both P < 0.001), which were abated by the antioxidant, alpha-lipoic acid, and the nicotinamide adenine dinucleotide phosphate oxidase inhibitor, apocynin (both P < 0.001). Nociception and hypersensitivity evoked by constriction of the infraorbital nerve was associated with intra- and perineural monocytic and macrophagic invasion and increased levels of oxidative stress by-products (hydrogen peroxide and 4-hydroxynonenal). Attenuation of monocyte/macrophage increase by systemic treatment with an antibody against the monocyte chemoattractant chemokine (C-C motif) ligand 2 (CCL2) or the macrophage-depleting agent, clodronate (both P < 0.05), was associated with reduced hydrogen peroxide and 4-hydroxynonenal perineural levels and pain-like behaviours (all P < 0.01), which were abated by perineural administration of HC-030031, alpha-lipoic acid or the anti-CCL2 antibody (all P < 0.001). The present findings propose that, in the constriction of the infraorbital nerve model of trigeminal neuropathic pain, pain-like behaviours are entirely mediated by the TRPA1 channel, targeted by increased oxidative stress by products released from monocytes and macrophages clumping at the site of nerve injury. PMID- 26984187 TI - Alterations in the hypothalamic melanocortin pathway in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis, the most common adult-onset motor neuron disease, leads to death within 3 to 5 years after onset. Beyond progressive motor impairment, patients with amyotrophic lateral sclerosis suffer from major defects in energy metabolism, such as weight loss, which are well correlated with survival. Indeed, nutritional intervention targeting weight loss might improve survival of patients. However, the neural mechanisms underlying metabolic impairment in patients with amyotrophic lateral sclerosis remain elusive, in particular due to the lack of longitudinal studies. Here we took advantage of samples collected during the clinical trial of pioglitazone (GERP-ALS), and characterized longitudinally energy metabolism of patients with amyotrophic lateral sclerosis in response to pioglitazone, a drug with well-characterized metabolic effects. As expected, pioglitazone decreased glycaemia, decreased liver enzymes and increased circulating adiponectin in patients with amyotrophic lateral sclerosis, showing its efficacy in the periphery. However, pioglitazone did not increase body weight of patients with amyotrophic lateral sclerosis independently of bulbar involvement. As pioglitazone increases body weight through a direct inhibition of the hypothalamic melanocortin system, we studied hypothalamic neurons producing proopiomelanocortin (POMC) and the endogenous melanocortin inhibitor agouti-related peptide (AGRP), in mice expressing amyotrophic lateral sclerosis-linked mutant SOD1(G86R). We observed lower Pomc but higher Agrp mRNA levels in the hypothalamus of presymptomatic SOD1(G86R) mice. Consistently, numbers of POMC-positive neurons were decreased, whereas AGRP fibre density was elevated in the hypothalamic arcuate nucleus of SOD1(G86R) mice. Consistent with a defect in the hypothalamic melanocortin system, food intake after short term fasting was increased in SOD1(G86R) mice. Importantly, these findings were replicated in two other amyotrophic lateral sclerosis mouse models based on TDP-43 (Tardbp) and FUS mutations. Finally, we demonstrate that the melanocortin defect is primarily caused by serotonin loss in mutant SOD1(G86R) mice. Altogether, the current study combined clinical evidence and experimental studies in rodents to provide a mechanistic explanation for abnormalities in food intake and weight control observed in patients with amyotrophic lateral sclerosis. Importantly, these results also show that amyotrophic lateral sclerosis progression impairs responsiveness to classical drugs leading to weight gain. This has important implications for pharmacological management of weight loss in amyotrophic lateral sclerosis. PMID- 26984189 TI - Effectiveness of eHealth interventions for the promotion of physical activity in older adults: a systematic review protocol. AB - BACKGROUND: It is known that regular physical activity (PA) is associated with improvements in physical, psychological, cognitive, and functional health outcomes. The World Health Organization recommends 150 min of moderate exercise per week for older adults to achieve these health benefits. However, only 20-60 % of adults aged 60 years and above currently meet these recommendations for exercise. The widespread use of the internet and mobile phones among older adults may open new opportunities to promote PA in this population. Findings of previous reviews suggest that eHealth interventions are effective in promoting PA in adults of various ages. However, to date, none of these reviews have provided a differentiated picture of engagement in such interventions and effects on PA among older adults. Also, we are unaware of any studies comparing effects of participation in eHealth vs. traditional paper-and-pencil interventions on PA in this population. The aim of this systematic review and meta-analysis is to compare the effectiveness of eHealth interventions promoting PA in older adults aged 55 years and above with either a non-eHealth PA intervention or a group that is not exposed to any intervention. METHODS: Eight electronic databases (MEDLINE, EMBASE, CINAHL, CENTRAL, PEI, PsycINFO, Web of Science, and OpenGrey) will be searched to identify experimental and quasi-experimental studies examining the effectiveness of eHealth interventions for PA promotion in adults aged 55 years and above. Two authors will independently select and review references, extract data, and assess the quality of the included studies by using the Cochrane Collaboration's risk of bias tool. Disagreements between authors will be resolved by discussion involving a third author. If feasible, a meta-analysis will be conducted. Narrative synthesis using harvest plots will be performed, should a meta-analysis not be feasible. DISCUSSION: The proposed systematic review will be the first review that compares the effectiveness of eHealth interventions promoting PA in older adults aged 55 years and above with control groups exposed to a non-eHealth intervention or to no intervention. The results of this review will provide new information regarding the question whether eHealth interventions are an effective intervention vehicle for PA promotion in this population. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015023875. PMID- 26984190 TI - Urban scaling in Europe. AB - Over the last few decades, in disciplines as diverse as economics, geography and complex systems, a perspective has arisen proposing that many properties of cities are quantitatively predictable due to agglomeration or scaling effects. Using new harmonized definitions for functional urban areas, we examine to what extent these ideas apply to European cities. We show that while most large urban systems in Western Europe (France, Germany, Italy, Spain, UK) approximately agree with theoretical expectations, the small number of cities in each nation and their natural variability preclude drawing strong conclusions. We demonstrate how this problem can be overcome so that cities from different urban systems can be pooled together to construct larger datasets. This leads to a simple statistical procedure to identify urban scaling relations, which then clearly emerge as a property of European cities. We compare the predictions of urban scaling to Zipf's law for the size distribution of cities and show that while the former holds well the latter is a poor descriptor of European cities. We conclude with scenarios for the size and properties of future pan-European megacities and their implications for the economic productivity, technological sophistication and regional inequalities of an integrated European urban system. PMID- 26984188 TI - Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging. AB - While emerging evidence suggests that neuroinflammation plays a crucial role in Alzheimer's disease, the impact of the microglia response in Alzheimer's disease remains a matter of debate. We aimed to study microglial activation in early Alzheimer's disease and its impact on clinical progression using a second generation 18-kDa translocator protein positron emission tomography radiotracer together with amyloid imaging using Pittsburgh compound B positron emission tomography. We enrolled 96 subjects, 64 patients with Alzheimer's disease and 32 controls, from the IMABio3 study, who had both (11)C-Pittsburgh compound B and (18)F-DPA-714 positron emission tomography imaging. Patients with Alzheimer's disease were classified as prodromal Alzheimer's disease (n = 38) and Alzheimer's disease dementia (n = 26). Translocator protein-binding was measured using a simple ratio method with cerebellar grey matter as reference tissue, taking into account regional atrophy. Images were analysed at the regional (volume of interest) and at the voxel level. Translocator protein genotyping allowed the classification of all subjects in high, mixed and low affinity binders. Thirty high+mixed affinity binders patients with Alzheimer's disease were dichotomized into slow decliners (n = 10) or fast decliners (n = 20) after 2 years of follow up. All patients with Alzheimer's disease had an amyloid positive Pittsburgh compound B positron emission tomography. Among controls, eight had positive amyloid scans (n = 6 high+mixed affinity binders), defined as amyloidosis controls, and were analysed separately. By both volumes of interest and voxel wise comparison, 18-kDa translocator protein-binding was higher in high affinity binders, mixed affinity binders and high+mixed affinity binders Alzheimer's disease groups compared to controls, especially at the prodromal stage, involving the temporo-parietal cortex. Translocator protein-binding was positively correlated with Mini-Mental State Examination scores and grey matter volume, as well as with Pittsburgh compound B binding. Amyloidosis controls displayed higher translocator protein-binding than controls, especially in the frontal cortex. We found higher translocator protein-binding in slow decliners than fast decliners, with no difference in Pittsburgh compound B binding. Microglial activation appears at the prodromal and possibly at the preclinical stage of Alzheimer's disease, and seems to play a protective role in the clinical progression of the disease at these early stages. The extent of microglial activation appears to differ between patients, and could explain the overlap in translocator protein binding values between patients with Alzheimer's disease and amyloidosis controls. PMID- 26984192 TI - Women in stroke, and cardiac devices in stroke management. PMID- 26984193 TI - Stroke incidence, prevalence and mortality in women worldwide. AB - BACKGROUND: The study of sex differences on stroke incidence, prevalence and mortality is an emerging field of stroke epidemiology and care. AIMS: This study sought to determine the information available on stroke epidemiology in women worldwide and possible sex differences in stroke epidemiology, and, if so, describe the nature of these differences and whether they are consistent across countries/groups of countries. SUMMARY: We searched the available literature in English published between 1 January 2008 and 5 May 2015. Out of 17.789 papers only 56 peer-reviewed papers (29 community-based studies, 17 retrospective studies, 6 reviews, and 4 cross-sectional studies) have been included in the study. This review adopted the epidemiologic transition theory, which classifies countries into four stages according to their levels of industrialization and economy. For the first and second stages, reliable registries and health certification are lacking, and therefore our sought after data were very limited.In the third stage, specifically for Eastern Europe (post-socialist countries), the burden from stroke in women was on the rise, while in the fourth stage, despite an aging population, decreases in stroke incidence, prevalence and mortality have been observed, even in subjects older than 80 years for both sexes. However, regarding studies of US populations, these trends for women were less pronounced for African Americans, and Hispanics as well as Indians. This suggests a "gender-gap" regarding access to treatment and care.In conclusion, identifying the presence of differing global burden between the sexes will allow us to better understand how to prevent, treat, and manage both men and women. PMID- 26984191 TI - Market analyses of livestock trade networks to inform the prevention of joint economic and epidemiological risks. AB - Conventional epidemiological studies of infections spreading through trade networks, e.g., via livestock movements, generally show that central large-size holdings (hubs) should be preferentially surveyed and controlled in order to reduce epidemic spread. However, epidemiological strategies alone may not be economically optimal when costs of control are factored in together with risks of market disruption from targeting core holdings in a supply chain. Using extensive data on animal movements in supply chains for cattle and swine in France, we introduce a method to identify effective strategies for preventing outbreaks with limited budgets while minimizing the risk of market disruptions. Our method involves the categorization of holdings based on position along the supply chain and degree of market share. Our analyses suggest that trade has a higher risk of propagating epidemics through cattle networks, which are dominated by exchanges involving wholesalers, than for swine. We assess the effectiveness of contrasting interventions from the perspectives of regulators and the market, using percolation analysis. We show that preferentially targeting minor, non-central agents can outperform targeting of hubs when the costs to stakeholders and the risks of market disturbance are considered. Our study highlights the importance of assessing joint economic-epidemiological risks in networks underlying pathogen propagation and trade. PMID- 26984194 TI - Coralie English: Asking the important clinical questions. PMID- 26984195 TI - Erratum to Inter-rater agreement analysis of the Precise Diagnostic Score for suspected transient ischemic attack. PMID- 26984197 TI - PL37: a new hope in the treatment of painful diabetic neuropathy? AB - Solomon Tesfaye speaks to Nick Ward, Commissioning Editor: Solomon Tesfaye, MB ChB, MD, FRCP, speaks about PL37; the first orally administered dual inhibitor of enkephalinases and its potential role in the treatment of painful diabetic neuropathy. Solomon Tesfaye is a Consultant Physician/Endocrinologist at Sheffield Teaching Hospitals and Honorary Professor of Diabetic Medicine at the University of Sheffield. His research projects include the epidemiology, risk factors, pathogenesis, CNS involvement and treatment of diabetic neuropathy and neuropathic pain. He was awarded the Prestigious Camillo Golgi Prize of the European Association for the Study of Diabetes (EASD) in 2014 for major scientific contributions in diabetic neuropathy. He has had international leadership roles including chairmanship of the International Expert Group on Diabetic Neuropathy, and of NEURODIAB (2006-2009). He is also a member of the Science and Research Committee of Diabetes UK; a review panel member for the MRC, a Board Member of the Global Quantitative Sensation Testing Society; a member of the Advisory Council of the Neuropathy Trust; and Secretary of International Insulin Foundation. He has served as a member of the MRC, JDRF, NIDDK and UK NIHR scientific review panels and as a member of a Diabetes and Neuropathic Pain Review Group for NICE. PMID- 26984196 TI - The M. tuberculosis HAD phosphatase (Rv3042c) interacts with host proteins and is inhibited by Clofazimine. AB - Mycobacterium tuberculosis codes for a HAD-phosphatase, Rv3042c (MtSerB2), that has earlier been characterized as a metabolic enzyme. Here we demonstrate that MtSerB2 is secreted into the cytosol of infected macrophages and is found in bronchoalveolar lavage samples of tuberculosis patients. MtSerB2 induces significant cytoskeleton rearrangements through cofilin activation and affects the expression of genes that regulate actin dynamics. It specifically interacts with HSP90, HSP70 and HSP27 that block apoptotic pathways and not with other HSPs. It actively dephosphorylates MAPK-p38 and NF-kappa B p65 that play crucial roles in inflammatory and immune responses. This in turn leads to down-regulation of Interleukin 8, a chemotactic and inflammatory cytokine. Finally, during evaluation of inhibitors against MtSerB2 we found that Clofazimine, a drug being evaluated for XDR and MDR tuberculosis, inhibits MtSerB2 phosphatase activity and reverses the above effects and interactions with host proteins. Overall, the study identifies that MtSerB2 has new functions that might help the pathogen to evade the host's immune response. PMID- 26984198 TI - Microbial Flavoprotein Monooxygenases as Mimics of Mammalian Flavin-Containing Monooxygenases for the Enantioselective Preparation of Drug Metabolites. AB - Mammalian flavin-containing monooxygenases, which are difficult to obtain and study, play a major role in detoxifying various xenobiotics. To provide alternative biocatalytic tools to generate flavin-containing monooxygenases (FMO) derived drug metabolites, a collection of microbial flavoprotein monooxygenases, sequence-related to human FMOs, was tested for their ability to oxidize a set of xenobiotic compounds. For all tested xenobiotics [nicotine, lidocaine, 3 (methylthio)aniline, albendazole, and fenbendazole], one or more monooxygenases were identified capable of converting the target compound. Chiral liquid chromatography with tandem mass spectrometry analyses of the conversions of 3 (methylthio)aniline, albendazole, and fenbendazole revealed that the respective sulfoxides are formed in good to excellent enantiomeric excess (e.e.) by several of the tested monooxygenases. Intriguingly, depending on the chosen microbial monooxygenase, either the (R)- or (S)-sulfoxide was formed. For example, when using a monooxygenase from Rhodococcus jostii the (S)-sulfoxide of albendazole (ricobendazole) was obtained with a 95% e.e. whereas a fungal monooxygenase yielded the respective (R)-sulfoxide in 57% e.e. For nicotine and lidocaine, monooxygenases could be identified that convert the amines into their respective N-oxides. This study shows that recombinantly expressed microbial monooxygenases represent a valuable toolbox of mammalian FMO mimics that can be exploited for the production of FMO-associated xenobiotic metabolites. PMID- 26984201 TI - Correction to "Pharmacological Discrimination of Calcitonin Receptor: Receptor Activity-Modifying Protein Complexes". PMID- 26984199 TI - Histological assessment for femora of ovariectomized obesity (db/db) mice carrying mutated leptin receptor. AB - In order to provide a clue to understand the interplay between leptin and estrogen, we have examined femoral metaphyses of ovariectomized db/db mice carrying a mutated leptin receptor. We performed ovariectomy (OVX) or sham operation (sham) on 12-week old female wild-type and db/db mice, and then, after 8 weeks, divided the animals into four groups: wild-type sham, wild-type OVX, db/db sham and db/db OVX. Samples from all groups were prepared for histochemical and ultrastructural examinations. As a result, db/db sham mice showed a reduced number and thickness of metaphyseal trabeculae and excessive adipose tissue when compared to wild-type sham mice. The wild-type OVX group exhibited markedly diminished trabecular number, as well as lower populations of osteoblasts and osteoclasts in comparison to wild-type sham group. On the other hand, trabecular numbers were similar for the two db/db groups, suggesting that the effect of the ovariectomy, i.e., estrogen deficiency may be lessened in this animal model. Leptin receptor was mainly found in osteoblasts and in bone marrow stromal cells including adipocytes. In addition, the expression of estrogen receptor did not seem to change after OVX in wild-type mice and in db/db mice. Both db/db sham and OVX mice featured many adipocytes close to the metaphyseal chondro-osseous junction, while osteoblasts accumulated glycogen granules and lipid droplets. Therefore, it seems likely that the disruption of leptin signaling in db/db mice shifts the cell differentiation cascade towards the adipocyte lineage, resulting in an osteoporotic bone independently of estrogen deficiency. PMID- 26984200 TI - Determination of Anticoagulant Rodenticides and alpha-Chloralose in Human Hair. Application to a Real Case. AB - Anticoagulant rodenticides are the largest group of poisons used to kill harmful rodents. Their fundamental mode of action consists in the inhibition of the vitamin K epoxide reductase, which causes blood-clotting alteration, ultimately leading to hemorrhagic events as the cause of death. In this study, we developed an UHPLC-MS-MS for the simultaneous determination of 10 anticoagulant hydroxycoumarine rodenticides, plus alpha-chloralose in human hair, with the scope of detecting potential trace of chronological poison exposure in clinical and forensic cases. The method was fully validated and applied to a case of intentional poisoning perpetrated by administration of difenacoum and alpha chloralose to a 97-year-old woman, who was hospitalized because of severe symptoms, including drowsiness, convulsions, pallor and hematoma. Hair sample from the victim was segmentally analyzed. Difenacoum was detected in the proximal 3-cm hair segment at the concentration of 2.9 pg/mg. To our knowledge, this is the first study to report that exposure to difenacoum is detectable in real hair samples. The other target analyte found in the hair sample was alpha-chloralose, which was detected in the 0-3 cm segment at the concentration of 85 pg/mg. The two subsequent and consecutive segments (3-6 cm and 6-9 cm) showed only traces of difenacoum (below LOQ) and low but quantifiable concentrations of alpha chloralose (29 and 6 pg/mg, respectively). Therefore, hair segmental analysis allowed us to conclude that the victim was repeatedly exposed to two poisons in the period corresponding to the first segment of hair. PMID- 26984202 TI - Helminth infections among long-term-residents and settled immigrants in Qatar in the decade from 2005 to 2014: temporal trends and varying prevalence among subjects from different regional origins. AB - BACKGROUND: Travel and migration from developing regions, where tropical diseases are common, to more developed industrialised nations can contribute to the introduction and subsequent spread of infections. With its rapidly expanding economy, Qatar has attracted vast numbers of immigrant workers in the last two decades, often from countries with poor socio-economic levels. Many used to arrive with patent intestinal parasitic infections. METHODS: We analysed the prevalence of helminth infections in a dataset of 29,286 records of subjects referred for stool examination at the Hamad Medical Corporation over the course of a decade (2005 to 2014, inclusive). RESULTS: Overall prevalence of combined helminth infections was low (1.86 %) but there were significant temporal trends, age and sex effects and those arising from the region of origin of the subjects. The most common helminths were hookworms (overall prevalence 1.22 %), which accounted for 70.1 % of cases, and therefore patterns for combined helminth infections were largely driven by hookworms. In both cases, and also in Trichuris trichiura and Ascaris lumbricoides, prevalence peaked in 2008, since when prevalence has been steadily falling. Helminth infections were largely concentrated among subjects from five Asian countries (Nepal, Bangladesh, Sri Lanka, India and Pakistan), and there was a highly biased prevalence in favour of male subjects in all cases. Prevalence of all three nematodes peaked in age class 7 (mean age 25.5 years, range = 20-29) and there were significant interactions between region of origin, sex of subjects and prevalence of hookworms. CONCLUSION: These results offer optimism that prevalence will continue to decline in the years ahead, especially if control is targeted at those most at risk of carrying infections. PMID- 26984203 TI - Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia in Adults. AB - The majority of adults with acute lymphoblastic leukemia will achieve a first complete remission (CR). However relapse is the most common cause of treatment failure. Outcomes after relapse remain poor, with long-term survival in the order of 10 %. Treatment decisions made at the time of first complete remission are thus critical to ensuring long-term survival. Allogeneic hematopoietic cell transplant (HCT) is effective at preventing relapse in many transplant recipients but is also associated with significant treatment related morbidity and mortality. Alternatively, ongoing systemic chemotherapy offers lower toxicity at the expense of increased relapse rates. Over the past decades, both the safety of transplant and the efficacy of non-transplant chemotherapy have improved. Emerging data show substantially improved outcomes for young adults treated with pediatric-inspired chemotherapy regimens that question the role of HCT in the upfront setting. In this review, we review the data supporting the role of allogeneic transplantation in adult acute lymphoblastic leukemia (ALL), and we propose a therapeutic algorithm for upfront therapy of adults with ALL. PMID- 26984205 TI - Dabigatran malabsorption in amiodarone-induced thyrotoxicosis: a clinical report. PMID- 26984206 TI - Self-inflicted, trans-optic canal, intracranial penetrating injury with a ballpoint pen. AB - Trans-orbital penetrating injuries are not common. If not promptly treated, these injuries can lead to serious disabilities and even death. A 60-year-old man, who had multiple underlying diseases, was admitted to our medical ward for the treatment of aspiration pneumonia; he attempted suicide by inserting a ballpoint pen into his left eye. CT of the brain showed a foreign body penetrating through the left optic canal into the intracranial parasellar region without obvious intracranial haemorrhage. The foreign body was withdrawn smoothly at bedside without a craniotomy. The patient was then transferred to the ICU for neuro observation. The patient recovered with complete left ophthalmoplegia but intact visual function. Acute management of a trans-orbital penetrating injury involves prompt neuroimaging examinations and knowledge of common recurring patterns of injury. All clinicians should be aware of the psychological condition of each patient, and suicide precautions should be considered during clinical practice. PMID- 26984207 TI - The life cycle of Neocladocystis intestinalis (Vaz, 1932) (Digenea: Cryptogonimidae), in Aylacostoma chloroticum (Prosobranchia: Thiaridae), and Salminus brasiliensis (Characiformes: Characidae), in Argentina. AB - The life cycle of Neocladocystis intestinalis (Vaz, 1932) was resolved experimentally. The prosobranchiate snail Aylacostoma chloroticum Hylton Scott (Thiaridae) collected in the Yacyreta Dam, Province of Misiones, Argentina, was found naturally infected with cercariae that possessed pigmented eye spots, 7 pairs of penetration glands, 12 pairs of flame cells, and a V-shaped, or Y-shaped excretory vesicle with very short stem. The cercariae developed in oval cysts, which were found on fin rays, and under scales of naturally and experimentally exposed tetragonopterid fish species and of experimentally exposed poecilid and prochilodont fish species. Adults were obtained experimentally from juvenile Salminus brasiliensis (Characidae), bred in captivity, and infected with metacercariae from albino Gymnocorymbus ternetzi (Tetragonopteridae), which had been exposed to emerging cercariae. PMID- 26984204 TI - Renin-angiotensin-aldosterone system blockade in chronic kidney disease: current strategies and a look ahead. AB - The Renin-Angiotensin-Aldosterone System (RAAS) is profoundly involved in the pathogenesis of renal and cardiovascular organ damage, and has been the preferred therapeutic target for renal protection for over 30 years. Monotherapy with either an Angiotensin Converting Enzime Inhibitor (ACE-I) or an Angiotensin Receptor Blocker (ARB), together with optimal blood pressure control, remains the mainstay treatment for retarding the progression toward end-stage renal disease. Combining ACE-Is and ARBs, or either one with an Aldosterone Receptor Antagonist (ARA), has been shown to provide greater albuminuria reduction, and to possibly improve renal outcome, but at an increased risk of potentially severe side effects. Moreover, combination therapy has failed to provide additional cardiovascular protection, and large prospective trials on hard renal endpoints are lacking. Therefore this treatment should, at present, be limited to selected patients with residual proteinuria and high renal risk. Future studies with novel agents, which directly act on the RAAS at multiple levels or have a more favourable side effect profile, are greatly needed to further explore and define the potential for and the limitations of profound pharmacologic RAAS inhibition. PMID- 26984209 TI - Novel TNF-related Apoptotic-inducing Ligand-based Immunotoxin for Therapeutic Targeting of CD25 Positive Leukemia. AB - BACKGROUND: Human TNF-related apoptotic-inducing ligand (TRAIL) has been used successfully for targeted therapy of almost all cancers. Leukemia is the most common type of cancer in children, and despite the advances in therapeutic strategies, the survival rate in leukemia cases is very low. Overexpression of interleukin 2 receptor (IL2R) in hematological malignancies has been utilized to target leukemia. Here, we report an immunotoxin fusion construct of human IL2alpha and TRAIL for targeting leukemia. AIM: Our aim was to develop an immunotoxin to target CD25+ leukemic cells. METHODS: Recombinant fusion construct comprising human IL2alpha and TRAIL114-281 was cloned, expressed and purified. Surface expression levels of IL2alpha and TRAIL receptors (CD25 and DR5 respectively) were compared in four leukemic cell lines and patient-derived peripheral blood mononuclear cells (PBMCs). Efficacy of immunotoxins was tested in cell lines and PBMCs by cell viability assay and compared with receptor expression. RESULTS: The efficacy of IL2-TRAIL was higher than TRAIL alone and showed an IC50 ranging from 0.2-0.8 MUM in cell lines. IL2-TRAIL induced cell death in PBMCs from leukemic patients in vitro, which was proportional to CD25 expression. Out of 34 leukemic samples, 24 samples were susceptible to immunotoxin-mediated cytotoxicity. The efficacy of IL2-TRAIL (87.5 %) was significantly high compared to TRAIL protein (29 %) in both myeloid and lymphoid leukemic patient samples. IL2-TRAIL fusion protein was highly specific for CD25+ leukemia and showed 100 % efficacy in lymphocytic leukemia [acute lymphoblastic leukemia and chronic lymphocytic leukemia] that overexpressed CD25. PMID- 26984210 TI - A phase I pharmacokinetics study comparing PF-06439535 (a potential biosimilar) with bevacizumab in healthy male volunteers. AB - PURPOSE: This study compared the pharmacokinetics of PF-06439535, a potential bevacizumab biosimilar, to bevacizumab sourced from the European Union (bevacizumab-EU) and USA (bevacizumab-US), and of bevacizumab-EU to bevacizumab US. METHODS: In this double-blind study, 102 healthy males, aged 21-55 years, were randomized 1:1:1 to receive a single 5 mg/kg intravenous dose of PF 06439535, bevacizumab-EU, or bevacizumab-US. Pharmacokinetic assessments were conducted for 71 days, with additional safety and immunogenicity assessments until day 100. Pharmacokinetic similarity was achieved if 90 % confidence intervals (CIs) for the test-to-reference ratios of the maximum serum concentration (C max), area under the serum concentration-time curve from zero to infinity (AUC0-infinity), and from zero to time of last quantifiable concentration (AUC0-t ) were within the 80.00-125.00 % bioequivalence acceptance window. RESULTS: The three study drugs exhibited similar pharmacokinetic properties. For the comparisons of PF-06439535 to bevacizumab-EU or bevacizumab US, and of bevacizumab-EU to bevacizumab-US, the 90 % CIs for the ratios of C max, AUC0-t , and AUC0-infinity were all within 80.00-125.00 %. Two, one, and two subjects treated with PF-06439535, bevacizumab-EU, and bevacizumab-US, respectively, tested positive for antidrug antibodies, none of whom tested positive for neutralizing antibodies. Treatment-related adverse events were reported in 15.2, 25.7, and 18.2 % of subjects in the PF-06439535, bevacizumab EU, and bevacizumab-US treatment arms, respectively. CONCLUSIONS: This study demonstrated the pharmacokinetic similarity of PF-06439535 to both bevacizumab-EU and bevacizumab-US, and of bevacizumab-EU to bevacizumab-US. The safety profile (including immunogenicity) was similar in the three treatment groups, with no significant safety findings reported. PMID- 26984212 TI - Vincent T. DeVita on His New Book, "The Death of Cancer," and the Current State of Cancer Care. PMID- 26984208 TI - Occurrence of Mesocestoides canislagopodis (Rudolphi, 1810) (Krabbe, 1865) in mammals and birds in Iceland and its molecular discrimination within the Mesocestoides species complex. AB - The life cycle of Mesocestoides tapeworms (Cestoda: Cyclophyllidea: Mesocestoididae) requires three hosts. The first intermediate host is unknown but believed to be an arthropod. The second intermediate host is a vertebrate. The primary definitive host is a carnivore mammal, or a bird of prey, that eats the tetrathyridium-infected second intermediate host. One representative of the genus, Mesocestoides canislagopodis, has been reported from Iceland. It is common in the arctic fox (Vulpes lagopus) and has also been detected in domestic dogs (Canis familiaris) and cats (Felis domestica). Recently, scolices of a non maturing Mesocestoides sp. have also been detected in gyrfalcon (Falco rusticolus) intestines, and tetrathyridia in the body cavity of rock ptarmigan (Lagopus muta). We examined the taxonomic relationship of Mesocestoides from arctic fox, gyrfalcon, and rock ptarmigan using molecular methods, both at the generic level (D1 domain LSU ribosomal DNA) and at the specific level (cytochrome c oxidase subunit I (COI) and 12S mitochondrial DNA). All stages belonged to Mesocestoides canislagopodis. Phylogenetic analysis of the combined 12S-COI at the specific level confirmed that M. canislagopodis forms a distinct clade, well separated from three other recognized representatives of the genus, M. litteratus, M. lineatus, and M. corti/vogae. This is the first molecular description of this species. The rock ptarmigan is a new second intermediate host record, and the gyrfalcon a new primary definitive host record. However, the adult stage seemed not to be able to mature in the gyrfalcon, and successful development is probably restricted to mammalian hosts. PMID- 26984211 TI - Results of a phase II study of vorinostat in combination with intravenous fludarabine, mitoxantrone, and dexamethasone in patients with relapsed or refractory mantle cell lymphoma: an interim analysis. AB - PURPOSE: Mantle cell lymphoma (MCL) is a disease that frequently relapses and primarily affects elderly people. We performed an open-label, multi-center, phase II study to investigate the effect and quality of life (QoL) of treatment with vorinostat in combination with fludarabine, mitoxantrone and dexamethasone (V FND) for relapsed or refractory MCL. METHODS: The treatment schedule was composed of four cycles of induction treatment with V-FND and subsequent consolidation therapy involving autologous hematopoietic stem cell transplantation or six cycles of vorinostat maintenance. QoL was assessed using EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) every 2 cycles. RESULTS: Data from a total of 20 patients were collected for an interim analysis. The median age was 67 years (range 49-75), and 14 or the patients (70 %) were male. The full course of V-FND induction treatment was completed in 11 patients, but only three completed all six cycles of maintenance therapy. Response to V-FND was not available in two patients. Among the other 18 patients, the objective response rate was 77.8 % (complete response in five patients + partial response in nine patients). Median progression-free survival was 9.3 months [95 % confidence interval (CI) 4.0 12.3]. Fifteen patients (75 %) experienced grade 3/4 toxicities. Analysis of QoL demonstrated significant deterioration of social functioning (p = 0.01), and significant aggravation of fatigue and nausea/vomiting (p = 0.04 and 0.01, respectively) after two cycles of V-FND induction. CONCLUSIONS: V-FND is effective in patients with relapsed or refractory MCL. However, significant toxicities were hurdles to sustained V-FND therapy. PMID- 26984213 TI - Vaccine Therapy, Oncolytic Viruses, and Gliomas. AB - After years of active research and refinement, vaccine therapy and oncolytic viruses are becoming part of the arsenal in the treatment of gliomas. In contrast to standard treatment with radiation therapy and chemotherapy, vaccines are more specific to the patient and the tumor. The majority of ongoing vaccine trials are investigating peptide, heat shock protein, and dendritic cell vaccines. The immunosuppression triggered by the tumor itself and by its treatment is a major obstacle to vaccine and oncolytic virus therapy. Thus, combination therapy with different agents that affect the immune system will probably be necessary. PMID- 26984214 TI - Vaccine Therapies Against Gliomas: Prime Time Yet? PMID- 26984215 TI - When to Combine Endocrine Therapy With a New Agent for Hormone Receptor-Positive Metastatic Breast Cancer in Postmenopausal Women. PMID- 26984216 TI - Favorable vs Unfavorable Intermediate-Risk Prostate Cancer: A Review of the New Classification System and Its Impact on Treatment Recommendations. AB - The population of patients with intermediate-risk prostate cancer are a large and heterogeneous group with highly variable prognoses, which present a challenge to efforts to develop standardized treatment recommendations. New classification systems have been proposed that modify the existing National Comprehensive Cancer Network guidelines and that subdivide men with intermediate-risk prostate cancer into favorable and unfavorable subgroups. This review will examine the changing landscape of intermediate-risk prostate cancer and the effects on treatment decisions that may result from this new classification. The literature provides evidence that men with favorable intermediate-risk prostate cancer have prostate cancer-specific mortality and all-cause mortality rates similar to the rates in patients with low-risk prostate cancer and thus may be candidates for active surveillance, dose-escalated radiation therapy without short-term androgen deprivation therapy (ADT), or, interestingly, standard-dose radiation therapy plus short-term ADT. Conversely, patients with unfavorable intermediate-risk prostate cancer have prostate cancer-specific mortality and all-cause mortality rates similar to the rates in patients with high-risk prostate cancer. These patients would not be candidates for active surveillance and may in fact require long-term ADT in addition to standard-dose or dose-escalated radiation therapy instead of 4 to 6 months of ADT. PMID- 26984217 TI - The Quest for an Evidence-Based Approach to Intermediate-Risk Prostate Cancer. PMID- 26984218 TI - Chemotherapy-Induced Peripheral Neuropathy. PMID- 26984219 TI - A Contemporary Review of HPV and Penile Cancer. AB - Human papillomavirus (HPV) is a widespread sexually transmitted infection. In both men and women, HPV infection can result in a spectrum of genitourinary manifestations ranging from genital warts to cancer. Cervical cancer is nearly always associated with high-risk HPV infection. For men, penile cancer can develop following or independently of HPV infection. Basaloid and warty subtypes of penile squamous cell carcinoma are most frequently associated with HPV infection. Further research into the molecular alterations caused by HPV infection may provide prognostic markers and future treatment targets. Until an effective treatment for HPV infection is developed, prevention will remain the focus of disease control. For women, vaccination is increasingly utilized to prevent HPV infection and subsequent cervical cancer development. New recommendations for routine male vaccination may further reduce cancers for both men and women. PMID- 26984220 TI - The Variegated Morphology of HPV-Related Neoplasms of the Penis. PMID- 26984221 TI - A 55-Year-Old Woman With New Triple-Negative Breast Mass, Less Than 2 cm on Both Mammogram and Ultrasound. PMID- 26984223 TI - More Opaque Than Clear: Reality Is Always Cloaked in Shades of Gray. PMID- 26984222 TI - Ground-Glass Opacity Lung Nodules in the Era of Lung Cancer CT Screening: Radiology, Pathology, and Clinical Management. AB - The advent of computed tomography screening for lung cancer will increase the incidence of ground-glass opacity (GGO) nodules detected and referred for diagnostic evaluation and management. GGO nodules remain a diagnostic challenge; therefore, a more systematic approach is necessary to ensure correct diagnosis and optimal management. Here we present the latest advances in the radiologic imaging and pathology of GGO nodules, demonstrating that radiologic features are increasingly predictive of the pathology of GGO nodules. We review the current guidelines from the Fleischner Society, the National Comprehensive Cancer Network, and the British Thoracic Society. In addition, we discuss the management and follow-up of GGO nodules in the light of experience from screening trials. Minimally invasive tissue biopsies and the marking of GGO nodules for surgery are new and rapidly developing fields that will yield improvements in both diagnosis and treatment. The standard-of-care surgical treatment of early lung cancer is still minimally invasive lobectomy with systematic lymph node dissection. However, recent research has shown that some GGO lesions may be treated with sublobar resections; these findings may expand the surgical treatment options available in the future. PMID- 26984224 TI - HPV and Penile Cancer: Perspectives on the Future Management of HPV-Positive Disease. PMID- 26984225 TI - Genome sequence analysis of five Canadian isolates of strawberry mottle virus reveals extensive intra-species diversity and a longer RNA2 with increased coding capacity compared to a previously characterized European isolate. AB - In this study, we report the genome sequence of five isolates of strawberry mottle virus (family Secoviridae, order Picornavirales) from strawberry field samples with decline symptoms collected in Eastern Canada. The Canadian isolates differed from the previously characterized European isolate 1134 in that they had a longer RNA2, resulting in a 239-amino-acid extension of the C-terminal region of the polyprotein. Sequence analysis suggests that reassortment and recombination occurred among the isolates. Phylogenetic analysis revealed that the Canadian isolates are diverse, grouping in two separate branches along with isolates from Europe and the Americas. PMID- 26984226 TI - Food Insecurity and Risk of Depression Among Refugees and Immigrants in South Africa. AB - South Africa's refugee population has grown considerably over the last decade. Both food insecurity and mental illness are common in developing countries, but this relationship remains unexamined in an African refugee population. 335 adult refugees in Durban, South Africa were interviewed using a self-report of food insecurity and the Hopkins Symptom Checklist-25. The proportion of those who responded 'often true' to not having enough food and eating less was 23.1 and 54.3 %, respectively. The proportion of individuals with a significant level of anxiety and depressive symptomatology was 49.4 and 54.6 %, respectively. The adjusted logistic regression indicated that not eating enough was significantly associated with anxiety (aOR = 4.52, 95 % CI: 2.09-9.80) and depression (aOR = 4.51, 95 % CI: 2.01-10.09). Similarly, eating less was significantly associated with anxiety (aOR = 2.88, 95 % CI: 1.56-5.31) and depression (aOR = 2.88, 95 % CI: 1.54-5.39). The high prevalence of food insecurity, and its relationship to mental illness, highlight the importance of addressing basic needs among this population. PMID- 26984227 TI - Dietary Patterns in Puerto Rican and Mexican-American Breast Cancer Survivors: A Pilot Study. AB - : Breast cancer is the leading cause of cancer death among Hispanic women. Certain dietary factors have been associated with the risk of breast cancer recurrence, but data in Hispanic survivors is scarce. OBJECTIVE: to examine dietary patterns and diet quality in two groups of Hispanic breast cancer survivors. METHODS: 23 Mexican-American (MA) and 22 Puerto Rican (PR) female breast cancer survivors completed a culturally adapted validated food frequency questionnaire. Intake was standardized per 1000 kcal and compared to US Dietary Guidelines and the DASH-style diet adherence score was calculated. RESULTS: Overweight/obese was 70 % in MA and 91 % in PR. PR consumed diets rich in fruit/100 % fruit juices and beans, while MA diets were high in vegetables, beans, and total grains. Both groups consumed high amounts of starchy vegetables, refined grains, animal protein and calories from solid fats and added sugars but low intakes of whole grains, dairy products and nuts and seeds. DASH scores were relatively low. CONCLUSION: MA and PR female breast cancer survivors have different dietary patterns but both groups had relatively low diet quality. These groups could benefit from culturally tailored interventions to improve diet quality, which could potentially reduce cancer recurrence. ClinicalTrials.gov Identifier NCT01504789. PMID- 26984229 TI - The influence of subscapularis tendon reattachment on range of motion in reversed shoulder arthroplasty: a clinical study. AB - PURPOSE: Reverse shoulder arthroplasty becomes more widely used as a treatment for patients with painful cuff arthropathy. As a part of the deltopectoral approach, the subscapularis tendon, if present, is (partly) detached. There is no consensus on repair of the tendon after placement of the prosthesis. We retrospectively describe the clinical effects of subscapularis tendon reattachment. Our hypothesis was that subscapularis repair has no clinical effects on range of motion and functional outcome scores. METHODS: A retrospective clinical study is performed. An Aequalis reverse shoulder prosthesis (Tornier, Montbonnot, France) was placed in 65 patients with a mean age of 73.8 years (range 47-90). In 40 patients (61.5 %), the quality of the tendon was initially insufficient for repair. The subscapularis was repaired in 25 patients (38.5 %). After a mean follow-up of 36 months with a minimum of 12 months, an ultrasound examination of the subscapularis was performed in patients with a repaired tendon. Range of motion, strength, Constant-Murley and Oxford scores were measured. RESULTS: On ultrasound examination, 10 (40 %) out of 25 repaired subscapularis tendons were still sufficient. Postoperatively, range of motion, strength, Constant-Murley and Oxford scores did not differ significantly between repair with present tendon, repair with absent tendon or no repair. CONCLUSION: In reverse shoulder arthroplasty, no significant differences on range of motion, functional outcome scores or strength were found between subscapularis repair or no repair, whether the tendon healed at follow-up or not. PMID- 26984230 TI - How Do We Manage Gastric Intestinal Metaplasia? A Survey of Clinical Practice Trends for Gastrointestinal Endoscopists in the United States. AB - BACKGROUND: Gastric intestinal metaplasia (GIM) is an accepted pathologic precursor to gastric adenocarcinoma (GAC). While surveillance of GIM in Europe and Asia is common, only limited recommendations related to endoscopic surveillance of GIM exist in the United States. AIM: To understand the clinical practice patterns of US gastroenterologists in the management and endoscopic surveillance of GIM. METHODS: A 23 item survey was developed to explore endoscopists' opinions regarding the surveillance of GIM and knowledge of current guidelines. Eight clinical vignettes were developed to address specific clinical scenarios where endoscopic surveillance of GIM might be considered. RESULTS: There were 227 respondents, with 60 % working primarily in the private sector and 40 % in academic medicine. While 68 % of the respondents refer to major society guidelines for guidance in patient management, almost 78 % of endoscopist responders believe that there are no specific US guidelines pertaining to surveillance of GIM. Only two-thirds of respondents believe that based on current data, patients at increased risk of GAC should be a part of an endoscopic surveillance program, while 15 % believe all patients with GIM should receive endoscopic surveillance. Respondents use a wide range of biopsy techniques and surveillance intervals for patients with GIM, with no consistent pattern of practice identified. CONCLUSIONS: There is variability in the knowledge and practice patterns of US endoscopists related to surveillance of gastric intestinal metaplasia. In the absence of detailed US GI society guidelines, many endoscopists perform surveillance endoscopy on patients with GIM using variable biopsy techniques and surveillance intervals. PMID- 26984231 TI - Endoscopic Detection of Gastric Carcinoma After Helicobacter pylori Eradication: More Difficult or Just Hype? PMID- 26984228 TI - nanoCAGE reveals 5' UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs. AB - The diversity of MTOR-regulated mRNA translation remains unresolved. Whereas ribosome-profiling suggested that MTOR almost exclusively stimulates translation of the TOP (terminal oligopyrimidine motif) and TOP-like mRNAs, polysome profiling indicated that MTOR also modulates translation of mRNAs without the 5' TOP motif (non-TOP mRNAs). We demonstrate that in ribosome-profiling studies, detection of MTOR-dependent changes in non-TOP mRNA translation was obscured by low sensitivity and methodology biases. Transcription start site profiling using nano-cap analysis of gene expression (nanoCAGE) revealed that not only do many MTOR-sensitive mRNAs lack the 5' TOP motif but that 5' UTR features distinguish two functionally and translationally distinct subsets of MTOR-sensitive mRNAs: (1) mRNAs with short 5' UTRs enriched for mitochondrial functions, which require EIF4E but are less EIF4A1-sensitive; and (2) long 5' UTR mRNAs encoding proliferation- and survival-promoting proteins, which are both EIF4E- and EIF4A1 sensitive. Selective inhibition of translation of mRNAs harboring long 5' UTRs via EIF4A1 suppression leads to sustained expression of proteins involved in respiration but concomitant loss of those protecting mitochondrial structural integrity, resulting in apoptosis. Conversely, simultaneous suppression of translation of both long and short 5' UTR mRNAs by MTOR inhibitors results in metabolic dormancy and a predominantly cytostatic effect. Thus, 5' UTR features define different modes of MTOR-sensitive translation of functionally distinct subsets of mRNAs, which may explain the diverse impact of MTOR and EIF4A inhibitors on neoplastic cells. PMID- 26984233 TI - Discrepant diagnosis rate of array comparative genomic hybridization in thawed euploid blastocysts. AB - PURPOSE: Preimplantation genetic screening (PGS) and diagnosis (PGD) with euploid embryo transfer is associated with improved implantation and live birth rates as compared to routine in vitro fertilization. However, misdiagnosis of the embryo is a potential risk. The purpose of this study was to investigate the clinical discrepant diagnosis rate associated with transfer of trophectoderm-biopsied blastocysts deemed to be euploid via array comparative genomic hybridization (aCGH). METHODS: This is a retrospective cohort study including cycles utilizing PGS or PGD with trophectoderm biopsy, aCGH, and euploid embryo transfer at a large university-based fertility center with known birth outcomes from November 2010 through July 2014 (n = 520). RESULTS: There were 520 embryo transfers of 579 euploid embryos as designated by aCGH. Five discrepant diagnoses were identified. Error rate per embryo transfer cycle was 1.0 %, 0.9 % per embryo transferred, and 1.5 % per pregnancy with a sac. The live birth (LB) error rate was 0.7 % (both sex chromosome errors), and the spontaneous abortion (SAB) error rate was 17.6 % (3/17 products of conception tested, but could range from 3/42 to 7/42). No single gene disorders were mistakenly selected for in any known cases. CONCLUSIONS: Although aCGH has been shown to be a highly sensitive method of comprehensive chromosome screening, several possible sources of error still exist. While the overall error rate is low, these findings have implications for counseling couples that are contemplating PGS and PGD with aCGH. PMID- 26984234 TI - Production of a biofunctional titanium surface using plasma electrolytic oxidation and glow-discharge plasma for biomedical applications. AB - In this study, the authors tested the hypotheses that plasma electrolytic oxidation (PEO) and glow-discharge plasma (GDP) would improve the electrochemical, physical, chemical, and mechanical properties of commercially pure titanium (cpTi), and that blood protein adsorption on plasma-treated surfaces would increase. Machined and sandblasted surfaces were used as controls. Standard electrochemical tests were conducted in artificial saliva (pHs of 3.0, 6.5, and 9.0) and simulated body fluid. Surfaces were characterized by scanning electron microscopy, energy-dispersive spectroscopy, x-ray photoelectron spectroscopy, atomic force microscopy, x-ray diffraction, profilometry, Vickers microhardness, and surface energy. For biological assay, the adsorption of blood serum proteins (i.e., albumin, fibrinogen, and fibronectin) was tested. Higher values of polarization resistance and lower values of capacitance were noted for the PEO and GDP groups (p < 0.05). Acidic artificial saliva reduced the corrosion resistance of cpTi (p < 0.05). PEO and GDP treatments improved the surface properties by enrichment of the surface chemistry with bioactive elements and increased surface energy. PEO produced a porous oxide layer (5-MUm thickness), while GDP created a very thin oxide layer (0.76-MUm thickness). For the PEO group, the authors noted rutile and anatase crystalline structures that may be responsible for the corrosion barrier improvement and increased microhardness values. Plasma treatments were able to enhance the surface properties and electrochemical stability of titanium, while increasing protein adsorption levels. PMID- 26984232 TI - Vitrification of in vitro matured oocytes collected from surplus ovarian medulla tissue resulting from fertility preservation of ovarian cortex tissue. AB - PURPOSE: The aim of the study was to investigate the maturation rate of immature oocytes collected from ovarian medulla tissue normally discarded during preparation of ovarian cortical tissue for fertility preservation. Further we evaluated survival of derived MII oocytes following vitrification and warming. METHODS: 36 patients aged from 8 to 41 years who had one ovary excised for fertility preservation were included. Oocytes were collected from the medulla tissue and matured in vitro 44-48 h followed by vitrification. Number of oocytes collected, the rates of maturation and post-warming survival were assessed. RESULTS: On average, 11 immature oocytes were collected per patient. The overall maturation rate was 29 % irrespective of whether the ovary was transported 4-5 h on ice or obtained immediately after oophorectomy. The maturation rate in patients below 20 years of age (55 %) was significantly higher than that of patients aged 20-30 years (29 %) and above 30 years (26 %). The post-warming survival rate was 64 %. No significant relationship was observed between the number of collected oocytes and the age of patients. CONCLUSIONS: Approximately three MII oocytes were obtained per patient following in vitro maturation (IVM) of immature oocytes collected from medulla tissue, of which two survived vitrification and warming. This approach represents an add-on method to potentially augment the fertility opportunity for cancer patients, especially in young women with cancer where transplantation of cortical tissue may pose a risk of relapse, but the IVM approach is currently too inefficient to be the only method used for fertility preservation. PMID- 26984235 TI - Role of flow for the deposition of platelets. AB - Implants inside the cardiovascular system are subjected to blood flow. Platelet deposition usually takes place, eventually leading to thrombus formation. Tests must be performed in order to select a suitable biomaterial, but no generally accepted test method exists for biomaterials in contact with blood. At a first glance, the flow appears to play only a minor role in the complex interaction between platelets and biomaterials. However, experiments and models have indeed demonstrated the importance of flow. Flow is the mechanism by which platelets are transported to the site of deposition, enabling deposition and forming the shape of a growing thrombus. This interaction is investigated here by means of two experimental models. The first model generates the simplest shear flow, the plane Couette flow. It serves to quantify the role of the shear rate. The second model, the stagnation point flow model, features a more complex shear flow. This model is used to understand the influence of a changing flow field along the wall over which the platelets travel. The platelet deposition is observed using the two experimental models, and a numerical model is developed to reproduce and simulate the experimental results. In the numerical model, the movement of platelets is computed with a combination of convective and stochastic movements due to diffusion. The combined motion brings some platelets close to the wall. The deposition of the platelet at the wall is modeled by a stochastic model. Probability determines whether the individual platelet deposits or flows onwards. This probability is the product of three different probabilities, which are the properties of the platelet, the wall, and the flow. The results of the models are compared with the experimental results and are used to understand the experiments. PMID- 26984236 TI - Predicting Change in Physical Activity: a Longitudinal Investigation Among Weight Concerned College Women. AB - BACKGROUND: Engaging in regular physical activity (PA) is critical for health, and adopting a consistent PA routine early in life is associated with greater PA over the lifespan. College women with weight concerns are at risk for weight gain, which may be prevented with regular PA. However, little is known about changes in PA engagement in this at-risk group. PURPOSE: Using an outcome expectancy framework, this study used a prospective longitudinal design to examine changes in PA during the first 2 years of college. We tested for concurrent and prospective within-person relations between body satisfaction/perceived eating behavior and PA to determine when weight-concerned college women may increase or decrease PA. METHODS: Women who reported weight concerns at the start of college (n = 294) completed five assessments over 2 years, including measured weight, body/eating experiences, and 4 days of pedometer steps (per assessment). Multilevel models addressed the resulting nested data structure (days within assessments within participants). RESULTS: Over 2 years, within-person change accounted for 65 % of PA variability (ICC = 0.35). PA was greatest at (and subsequent to) times when body satisfaction was lower, and when disinhibited eating and hedonic hunger were higher, than an individual's average (ps < 0.05). These changes were associated with 1-3 % of the recommended daily step totals. CONCLUSIONS: Weight-conscious college women show greater PA after negative eating and weight experiences. As these experiences change over time, health promotion efforts should help college women identify alternative, positive motivators for PA, which could facilitate consistent PA engagement. PMID- 26984237 TI - Role of Histological Criteria and Immunohistochemical Markers in Predicting Risk of Malignancy in Parathyroid Neoplasms. AB - Parathyroid carcinoma (PC) is a rare neoplasm accounting for 0.5-6 % of primary hyperparathyroidism. Histological criteria are currently considered as established means to diagnose malignancy in parathyroid neoplasms; however, it does not accurately predict the risk of aggressive behaviour of PC. Immunohistochemical (IHC) markers have been used in the literature with variable results. This work was planned to study whether IHC markers would have any added advantage over histology in predicting outcome in parathyroid neoplasms. Two hundred twenty-seven parathyroid neoplasms were reviewed according to older and revised histological criteria. IHC was performed for parafibromin, APC, galectin 3, PGP9.5 and Ki67. Diagnostic categories were correlated with clinical, biochemical, histological features and IHC markers. Chi-square test was used to analyse categorical variables. Review of histology by earlier and revised criteria showed a change in diagnosis of five cases of atypical adenoma (15.1 %), all of which were diagnosed as carcinoma according to earlier criteria. Change in diagnosis did not affect behaviour of disease as none of the cases showed recurrence or metastasis on follow-up. Combination of PF, Gal-3 and PGP9.5 showed 50 % sensitivity, 97.9 % specificity and 95.4 % predictive accuracy for PC. Histological criteria still remains the most established method for predicting risk of malignancy in parathyroid neoplasms irrespective of whether old or revised criteria are used. Combination of positive (Gal-3, PGP9.5) and negative (PF) IHC markers may be used as an adjunct to histology in histological, atypical and malignant parathyroid neoplasms to obviate the need for repeated follow-up. PMID- 26984238 TI - Potentially inappropriate drug prescribing in elderly hospitalized patients: an analysis and comparison of explicit criteria. AB - BACKGROUND: The management of therapy in elderly is a critical aspect of primary care. The physio-pathological complexity of the elderly involves the prescription of multiple drugs, exposing them to a higher risk of adverse reactions. OBJECTIVE: Aim of this study was to assess the medication use and (potential) inappropriate medications and prescribing omissions in the elderly before and during hospitalization, according to the main tools in literature described, and their relation to the number of comorbidities. SETTING: The study was carried out by the Clinical Pharmacists at ISMETT, an Italian Research Institute. METHODS: The prescriptions of elderly, admitted in ISMETT between January and December 2012, were analyzed. The information about clinical profile of elderly and prescriptions was obtained from the electronic medical records. 2012 Beers criteria, Screening Tool of Older Person's Prescriptions/Screening Tool to Alert doctors to Right Treatment criteria, and Improving Prescribing in the Elderly criteria were used to evaluate the appropriateness of prescriptions. The correlation between the number of comorbidities and the different tools was analyzed with the Spearman correlation coefficient. The frequency analysis was done with the Pearson Chi square test. MAIN OUTCOME MEASURE: Percentage of potentially inappropriate medications and prescribing omissions before/during hospitalization in elderly. RESULTS: 1027 elderly were admitted between January and December 2012. At admission and during hospitalization, according to Beers criteria 24 and 49 % of elderly had at least one potentially inappropriate medication, respectively; according to the Screening Tool of Older Person's Prescriptions criteria 21 and 27 %, respectively; according to the Improving Prescribing in the Elderly criteria 28 and 25 %, respectively; and then, according to Screening Tool to Alert doctors to Right Treatment criteria 28 and 33 % had at least one potentially prescribing omission, respectively. A significant correlation between comorbidities number and potentially inappropriate medications was found. CONCLUSION: The number of potentially inappropriate medications globally increased during hospitalization. Statistical analysis showed that the comorbidity affects the level of inappropriate prescriptions. Specific tools can guide clinicians toward a more rational use of medicines and minimize probable complications related to multi-treatments. PMID- 26984239 TI - Exploring dual inhibitory role of febrifugine analogues against Plasmodium utilizing structure-based virtual screening and molecular dynamic simulation. AB - Malaria is an endemic disease caused by the protozoan parasite Plasomodium falciparum. Febrifugine analogues are natural compound obtained from the traditional Chinese herbs have shown significant antimalarial and anticancerous efficacy in experimental model. Development of resistance against the existing antimalarial drug has alarmed the scientific innovators to find a potential antimalarial molecule which can be further used by endemic countries for the elimination of this disease. In this study, structure-based virtual screening and molecular dynamics (MD) base approaches were used to generate potential antimalarial compound against plasmepsin II and prolyl-tRNA synthetase of Plasmodium. Here, we have docked series of febrifugine analogues (n = 11,395) against plasmepsin II in three different docking modes and then it was compared with previously reported target prolyl-tRNA synthetase. Extra precision docking resulted into 235 ligands having better docking score were subject for QikProp analysis. Better ligands (n = 39) obtained from QikProp analysis were subject for ADMET prediction and docking protocol validation through the estimation of receiver operator characteristics. In the later stage, 24 ligands obtained from ADMET study were subject for the estimation of binding energy through MM-GBSA and same were also docked against prolyl-tRNA synthetase to get compounds with dual inhibitor role. Finally, MD simulation and 2D fingerprint MACCS study of two best ligands have shown significant interaction with plasmepsin II and homology against known active ligand with noteworthy MACCS index, respectively. This study concludes that FA12 could be potential drug candidate to fight against Plasmodium falciparum parasites. PMID- 26984241 TI - Adherence to treatment guidelines for cancer-associated thrombosis: a French hospital-based cohort study. AB - PURPOSE: French 2008 treatment guidelines recommend low-molecular-weight heparins (LMWH) for the treatment of cancer-associated thrombosis (CAT) with treatment duration of at least 3 months and up to 6 months and beyond if cancer remains active. Our aim was to assess adherence to guidelines in hospital clinical practice. METHODS: The French hospital database (PMSI) was used to identify patients with CAT admitted to three hospitals of the Paris region to be included in a retrospective cohort study. Adherence to guidelines was assessed in patients included from different treatment periods following the venous thromboembolism (VTE) episode i.e. first 10 days (T1), day 10 to 3 months (T2), months 3 to 6 (T3) and beyond 6 months (T4) when applicable. RESULTS: A total of 240 patients with CAT were included from January 2012 to December 2012 of whom 204 were analyzable. Treatment was adherent to guidelines in 55, 31 and 34 % of patients in T1, T2 and T3 treatment periods, respectively, while overall treatment adherence was found in 52 % of patients. Adherence rates were the highest among patients with pulmonary embolism (PE, 60.5 %), catheter-related thrombosis (62.5 %), class III/IV extended cancer (58.0 %) and metastatic malignancy (60.3 %) while only 40 % with deep vein thrombosis (DVT) received a treatment consistent with guidelines. CONCLUSION: Adherence to guidelines appears insufficient since only half of patients received an appropriate treatment. Adherence dropped significantly across treatment periods T2 and T3. VTE diagnosis and cancer characteristics influenced the anticoagulant prescription. Management of patients with CAT requires further education and information of health care professionals. PMID- 26984240 TI - Low level laser therapy/photobiomodulation in the management of side effects of chemoradiation therapy in head and neck cancer: part 1: mechanisms of action, dosimetric, and safety considerations. AB - PURPOSE: There is a large body of evidence supporting the efficacy of low level laser therapy (LLLT), more recently termed photobiomodulation (PBM), for the management of oral mucositis (OM) in patients undergoing radiotherapy for head and neck cancer (HNC). Recent advances in PBM technology, together with a better understanding of mechanisms involved, may expand the applications for PBM in the management of other complications associated with HNC treatment. This article (part 1) describes PBM mechanisms of action, dosimetry, and safety aspects and, in doing so, provides a basis for a companion paper (part 2) which describes the potential breadth of potential applications of PBM in the management of side effects of (chemo)radiation therapy in patients being treated for HNC and proposes PBM parameters. METHODS: This study is a narrative non-systematic review. RESULTS: We review PBM mechanisms of action and dosimetric considerations. Virtually, all conditions modulated by PBM (e.g., ulceration, inflammation, lymphedema, pain, fibrosis, neurological and muscular injury) are thought to be involved in the pathogenesis of (chemo)radiation therapy-induced complications in patients treated for HNC. The impact of PBM on tumor behavior and tumor response to treatment has been insufficiently studied. In vitro studies assessing the effect of PBM on tumor cells report conflicting results, perhaps attributable to inconsistencies of PBM power and dose. Nonetheless, the biological bases for the broad clinical activities ascribed to PBM have also been noted to be similar to those activities and pathways associated with negative tumor behaviors and impeded response to treatment. While there are no anecdotal descriptions of poor tumor outcomes in patients treated with PBM, confirming its neutrality with respect to cancer responsiveness is a critical priority. CONCLUSION: Based on its therapeutic effects, PBM may have utility in a broad range of oral, oropharyngeal, facial, and neck complications of HNC treatment. Although evidence suggests that PBM using LLLT is safe in HNC patients, more research is imperative and vigilance remains warranted to detect any potential adverse effects of PBM on cancer treatment outcomes and survival. PMID- 26984242 TI - Controlling chemotherapy-induced nausea requires further improvement: symptom experience and risk factors among Korean patients. AB - PURPOSE: The purpose of the present study is to describe the incidence and intensity of chemotherapy-induced nausea and vomiting (CINV) and patterns of symptom change after chemotherapy among Korean cancer patients for whom antiemetic guidelines were widely utilized and guideline-consistent antiemetics were available. The study also aimed to determine the contribution of known risk factors for CINV to the incidence and intensity of CINV, as well as patterns of symptom change. METHODS: A prospective observational descriptive study was conducted. A total of 332 adult cancer patients starting their first adjuvant chemotherapy participated in this study. Items of the Multinational Association of Supportive Care in Cancer Antiemesis Tool were utilized to generate a symptom diary. Descriptive statistics, logistic regression analyses, repeated measures ANOVA, and hierarchical generalized linear models were applied to analyze the data. RESULTS: Vomiting occurred, on average, less than once in the acute and delayed phases, and its frequency remained similar throughout 5 days after chemotherapy infusion in the first and second cycles. A quadratic pattern of nausea change was found. Nausea intensity increased to a peak on the third day after chemotherapy infusion (first-cycle incidence rate ratio (IRR) = 1.40 and second-cycle IRR = 1.27, both p < .001) and then changed gradually (first-cycle IRR = 0.69 and second-cycle and IRR = 0.76, both p < .001). Nausea experience in the previous cycle contributed to the subsequent nausea intensity (IRR = 2.78, p < .001). Younger age, consuming less alcohol, and expecting nausea were identified as risk factors for chemotherapy-induced nausea that needed to be considered from the start of the chemotherapy. CONCLUSIONS: Nausea control, especially in the delayed phase, has room for improvement. As the first chemotherapy-induced nausea experience contributes to subsequent symptom experience, intense control from the start of chemotherapy is necessary while considering patient-related risk factors. Future studies should evaluate the contribution of risk factors when antiemetic prophylaxis is fully provided in multiple settings. PMID- 26984244 TI - Supportive care vital in elderly cancer patients : A report from the 2015 annual conference of the International Society of Geriatric Oncology (SIOG), which focused on the role of supportive care in geriatric oncology. PMID- 26984245 TI - Linfotaping with Kinesio(r) Tape to manage and treat lymphedema patients: safety and tolerability are more important than efficacy? PMID- 26984243 TI - Implementation of a mobile inpatient quality of life (QoL) assessment for oncology nursing. AB - PURPOSE: Cancer patients suffer from a variety of symptoms, but little is known about changes during hospitalization and symptom burden at discharge. We implemented an electronic quality of life (QoL) assessment used by the nursing team in routine inpatient care. Feasibility, acceptance, and the course of QoL were investigated. METHODS: A self-administered electronic questionnaire based on the EQ-5D and the EORTC QLQ-C30 was applied in clinical routine. Cancer patients were approached by the nursing staff to complete the QoL assessment twice, at admission and at the day of discharge. Both the feedback of the nursing staff as well as characteristics of participants were used to evaluate the electronic assessment. RESULTS: Out of 210 patients from an oncologic ward, 85 patients (40 %) were invited to participate, 95 % of whom (n = 81) agreed to participate. Participation rate depended on the day of admission, the presence of the coordinating nurse, the overall morbidity assessed by patient clinical complexity level, and the patient age. Forty-six patients (56 %) asked for assistance in completing the questionnaire. Patients older than 53 years and male patients were more likely to need assistance. Twenty-two percent of the nursing staff (n = 5) use the information assessed for individual patient care. Fifty-two percent (n = 12) rated the additional workload as very little or little and 68 % (n = 15) agreed that handling for the patient was easy. Global QoL improved during the stay. Most severe symptoms at admission included fatigue, pain, appetite loss, and insomnia. CONCLUSIONS: The results of this study indicate that it is feasible to implement and use an electronic QoL assessment by the nursing staff in routine inpatient cancer care. Obstacles and worries of staff members have to be considered when further developing this program. PMID- 26984247 TI - Edentulism and transplant-associated complications in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation. AB - PURPOSE: Patients undergoing autologous hematopoietic stem cell transplantation (HSCT) are at risk for oral complications which may cause significant morbidity. The aim of this study was to compare the incidence of toxicities and complications in edentulous and dentate patients undergoing autologous HSCT for multiple myeloma. METHODS: We conducted a retrospective case-control study to analyze the incidence of bacteremia, fever, and oral mucositis, between edentulous and dentate patients. All patients underwent dental evaluation, received dental treatment if indicated, and were cleared before transplantation. The two groups were matched for age, gender, ethnicity, disease stage, time from diagnosis to transplant, performance status, and conditioning regimen. RESULTS: A total of 45 edentulous and 90 dentate patients were enrolled. All patients were male with a median age of 60 years and a mean performance status by Karnofsky score of 90 %. Two thirds had stage III MM with a median time from diagnosis to transplantation of 12 months, and all received melphalan as part of the conditioning regimen. The incidence of bacteremia (p = 0.553), fever (p = 0.245), severity of oral mucositis (p = 0.465), and other post-transplant toxicities were similar between both groups. CONCLUSIONS: There were no significant differences in the incidence of bacteremia, fever, severity of oral mucositis, or other complications between edentulous and dentate patients with multiple myeloma after autologous HSCT. PMID- 26984246 TI - The association between pre-treatment occupational skill level and mood and symptom burden in early-stage, postmenopausal breast cancer survivors during the first year of anastrozole therapy. AB - PURPOSE: Previous research has explored occupational activity of breast cancer survivors but has not examined the influence of occupational level on symptoms prospectively. The purpose of this study was to examine the relationship between occupational classification and changes in mood and symptom burden for postmenopausal breast cancer survivors during the first year of anastrozole therapy. METHODS: This was an exploratory secondary analysis in 49 postmenopausal women receiving anastrozole therapy for early-stage breast cancer. Participants reported their occupation at baseline and completed self-report questionnaires measuring mood and symptom burden at baseline, 6 months, and 12 months. Occupation was classified according to four major skill levels delineated by the International Standard Classification of Occupations (ISCO). RESULTS: Breast cancer survivors employed at occupational skill levels 1 through 3 reported significantly higher depressive symptoms, fatigue, and total symptoms on average than those employed at ISCO skill level 4. After adjusting for multiple comparisons, this pattern remained for the musculoskeletal, vasomotor, and gastrointestinal symptom subscales. CONCLUSIONS: Breast cancer survivors employed at lower skill levels (i.e., ISCO 1-3) reported poorer mood and greater symptom burden than breast cancer survivors employed at a higher skill level (i.e., ISCO 4). Assessing baseline occupation of occupationally active breast cancer survivors may improve understanding of the association between types of occupations and mood and symptom trajectories and may inform development of interventions to mitigate symptom severity in order to help breast cancer survivors maintain optimal occupational function and adherence to therapy. PMID- 26984248 TI - Pilot study of an interdisciplinary supportive care planning intervention in pancreatic cancer. AB - PURPOSE: A diagnosis of pancreatic cancer is often associated with higher symptom burden, lower functional status, and worse quality of life (QOL). To date, few interventions have focused on the unique QOL needs of patients with pancreatic cancer. The purpose of this pilot study is to determine the feasibility of an interdisciplinary supportive care planning intervention in patients with pancreatic cancer during disease-focused treatments. METHODS: Patients enrolled in this prospective, pre- and post-intervention pilot study received a supportive care intervention that included the following three components: comprehensive QOL assessment, case presentation at interdisciplinary care meetings, and two nurse administered educational sessions on QOL concerns. Patients completed outcome measures that included the FACT-Hep, FACIT-Sp-12, and self-report of finances and out-of-pocket costs since diagnosis. Measures were completed at baseline prior to receiving the intervention, and follow-up occurred at 1 and 2 months post intervention. RESULTS: A total of 10 patients were enrolled during a 4-month period who provided informed consent, received the intervention, and completed the study (58 % accrual). Examination of pre- and post-intervention QOL outcomes revealed changes across the three evaluation time points that were not statistically significant. Patients were highly satisfied with the intervention, with 80 % reporting that the intervention was "excellent." Discussions during the interdisciplinary care meetings and educational sessions were largely focused on physical and psychosocial needs. CONCLUSIONS: An interdisciplinary supportive care planning intervention was potentially feasible and acceptable for pancreatic cancer patients in an ambulatory care setting. PMID- 26984250 TI - Elaboration of a clinical and paraclinical score to estimate the probability of herpes simplex virus encephalitis in patients with febrile, acute neurologic impairment. AB - Herpes simplex virus (HSV) encephalitis is associated with a high risk of mortality and sequelae, and early diagnosis and treatment in the emergency department are necessary. However, most patients present with non-specific febrile, acute neurologic impairment; this may lead clinicians to overlook the diagnosis of HSV encephalitis. We aimed to identify which data collected in the first hours in a medical setting were associated with the diagnosis of HSV encephalitis. We conducted a multicenter retrospective case-control study in four French public hospitals from 2007 to 2013. The cases were the adult patients who received a confirmed diagnosis of HSV encephalitis. The controls were all the patients who attended the emergency department of Grenoble hospital with a febrile acute neurologic impairment, without HSV detection by polymerase chain reaction (PCR) in the cerebrospinal fluid (CSF), in 2012 and 2013. A multivariable logistic model was elaborated to estimate factors significantly associated with HSV encephalitis. Finally, an HSV probability score was derived from the logistic model. We identified 36 cases and 103 controls. Factors independently associated with HSV encephalitis were the absence of past neurological history (odds ratio [OR] 6.25 [95 % confidence interval (CI): 2.22 16.7]), the occurrence of seizure (OR 8.09 [95 % CI: 2.73-23.94]), a systolic blood pressure >=140 mmHg (OR 5.11 [95 % CI: 1.77-14.77]), and a C-reactive protein <10 mg/L (OR 9.27 [95 % CI: 2.98-28.88]). An HSV probability score was calculated summing the value attributed to each independent factor. HSV encephalitis diagnosis may benefit from the use of this score based upon some easily accessible data. However, diagnostic evocation and probabilistic treatment must remain the rule. PMID- 26984251 TI - Live surgery broadcast: who is benefiting? PMID- 26984252 TI - 16S-gyrB-rpoB multilocus sequence analysis for species identification in the genus Microbispora. AB - The genus Microbispora has been considered difficult to define taxonomically. While 16S rRNA gene analysis is required to determine phylogenetic relationships among species in this genus, most 16S rRNA gene-based phylogenetic tree topologies are not reliable. The genus Microbispora currently contains eight species along with six reclassified species (Microbispora chromogenes, Microbispora diastatica, Microbispora parva, Microbispora indica, Microbispora karnatakensis, Microbispora rosea) and Microbispora rosea subsp. aerata, a taxon composed of three further reclassified species (Microbispora aerata, Microbispora thermodiastatica, and Microbispora thermorosea). 16S rRNA, 23S rRNA, gyrB, and rpoB gene sequences were obtained for the type strains of Microbispora species, and eleven endophytic isolates from a Brazilian medicinal plant, Vochysia divergens. Using the concatenated sequence, most Microbispora type strains could be distinguished with high probability support. Based on these analyses, we propose that five of the species reclassified within the subspecies of M. rosea (M. chromogenes, M. karnatakensis, M. parva, M. aerata and M. thermorosea) are distinct from M. rosea and so should be retained as distinct species. The concatenated 16S-gyrB-rpoB gene phylogenic tree had significant probability support and topology. We propose the use of concatenated 16S-gyrB-rpoB gene sequences to determine phylogenetic relationships within the genus Microbispora. We also suggest that strains sharing >98.1 % 16S-gyrB-rpoB gene sequences similarity be defined as a single species, based on results from this analysis. Seven of the strains isolated from V. divergens were not related to any previously described Microbispora species. PMID- 26984254 TI - Marked eosinophilia as initial presentation of breast implant-associated anaplastic large cell lymphoma. PMID- 26984253 TI - Effect of Antibiotic Treatment on the Gastrointestinal Microbiome of Free-Ranging Western Lowland Gorillas (Gorilla g. gorilla). AB - The mammalian gastrointestinal (GI) microbiome, which plays indispensable roles in host nutrition and health, is affected by numerous intrinsic and extrinsic factors. Among them, antibiotic (ATB) treatment is reported to have a significant effect on GI microbiome composition in humans and other animals. However, the impact of ATBs on the GI microbiome of free-ranging or even captive great apes remains poorly characterized. Here, we investigated the effect of cephalosporin treatment (delivered by intramuscular dart injection during a serious respiratory outbreak) on the GI microbiome of a wild habituated group of western lowland gorillas (Gorilla gorilla gorilla) in the Dzanga Sangha Protected Areas, Central African Republic. We examined 36 fecal samples from eight individuals, including samples before and after ATB treatment, and characterized the GI microbiome composition using Illumina-MiSeq sequencing of the bacterial 16S rRNA gene. The GI microbial profiles of samples from the same individuals before and after ATB administration indicate that the ATB treatment impacts GI microbiome stability and the relative abundance of particular bacterial taxa within the colonic ecosystem of wild gorillas. We observed a statistically significant increase in Firmicutes and a decrease in Bacteroidetes levels after ATB treatment. We found disruption of the fibrolytic community linked with a decrease of Ruminoccocus levels as a result of ATB treatment. Nevertheless, the nature of the changes observed after ATB treatment differs among gorillas and thus is dependent on the individual host. This study has important implications for ecology, management, and conservation of wild primates. PMID- 26984249 TI - Low-level laser therapy/photobiomodulation in the management of side effects of chemoradiation therapy in head and neck cancer: part 2: proposed applications and treatment protocols. AB - PURPOSE: There is a large body of evidence supporting the efficacy of low-level laser therapy (LLLT), more recently termed photobiomodulation (PBM) for the management of oral mucositis (OM) in patients undergoing radiotherapy for head and neck cancer (HNC). Recent advances in PBM technology, together with a better understanding of mechanisms involved and dosimetric parameters may lead to the management of a broader range of complications associated with HNC treatment. This could enhance patient adherence to cancer therapy, and improve quality of life and treatment outcomes. The mechanisms of action, dosimetric, and safety considerations for PBM have been reviewed in part 1. Part 2 discusses the head and neck treatment side effects for which PBM may prove to be effective. In addition, PBM parameters for each of these complications are suggested and future research directions are discussed. METHODS: Narrative review and presentation of PBM parameters are based on current evidence and expert opinion. RESULTS: PBM may have potential applications in the management of a broad range of side effects of (chemo)radiation therapy (CRT) in patients being treated for HNC. For OM management, optimal PBM parameters identified were as follows: wavelength, typically between 633 and 685 nm or 780-830 nm; energy density, laser or light emitting diode (LED) output between 10 and 150 mW; dose, 2-3 J (J/cm(2)), and no more than 6 J/cm(2) on the tissue surface treated; treatment schedule, two to three times a week up to daily; emission type, pulsed (<100 Hz); and route of delivery, intraorally and/or transcutaneously. To facilitate further studies, we propose potentially effective PBM parameters for prophylactic and therapeutic use in supportive care for dermatitis, dysphagia, dry mouth, dysgeusia, trismus, necrosis, lymphedema, and voice/speech alterations. CONCLUSION: PBM may have a role in supportive care for a broad range of complications associated with the treatment of HNC with CRT. The suggested PBM irradiation and dosimetric parameters, which are potentially effective for these complications, are intended to provide guidance for well-designed future studies. It is imperative that such studies include elucidating the effects of PBM on oncology treatment outcomes. PMID- 26984255 TI - Ideal Cardiovascular Health and Cognitive Aging in the Northern Manhattan Study. AB - BACKGROUND: The American Heart Association defined target levels for 7 cardiovascular health (CVH) factors: smoking, body mass index, physical activity, diet, blood pressure, cholesterol, and glucose. We hypothesized that a greater number of American Heart Association ideal CVH metrics would be associated with less decline in cognitive performance in our multiethnic population. METHODS AND RESULTS: A subsample from the population-based Northern Manhattan Study underwent repeated neuropsychological testing (mean interval 6+/-2 years). Domain-specific Z scores were derived by using factor analysis for the domains of Episodic Memory, Semantic Memory, Executive Function, and Processing Speed, based on initial performance and decline over time. Linear regression models were constructed to examine the relationship between the number of ideal CVH metrics at enrollment with later cognitive performance and decline, adjusting for sociodemographics and magnetic resonance imaging brain markers. Among 1033 participants (mean age at initial cognitive assessment 72+/-8 years, 39% male, 19% black, 16% white, 65% Hispanic; n=722 with repeat testing), 3% had 0 ideal factors, 15% had 1 factor, 33% had 2 factors, 30% had 3 factors, 14% had 4 factors, 4% had 5 factors, 1% had 6 factors, and 0% had 7 factors. An increasing number of ideal CVH factors was associated with better processing speed at initial assessment and less decline. The association was driven by nonsmoking and glucose. Among those with better cognitive performance at initial assessment, positive associations were observed between the number of ideal CVH factors and less decline in the domains of Executive Function and Episodic Memory. CONCLUSIONS: The number of ideal CVH metrics was associated with less decline in the domains of Processing Speed and, to a lesser extent, of Executive Function and Episodic Memory. Ideal CVH promotion benefits brain health and cognitive aging. PMID- 26984256 TI - A MicroRNA-Mediated Insulin Signaling Pathway Regulates the Toxicity of Multi Walled Carbon Nanotubes in Nematode Caenorhabditis elegans. AB - The underlying mechanisms for functions of microRNAs (miRNAs) in regulating toxicity of nanomaterials are largely unclear. Using Illumina HiSeq(TM) 2000 sequencing technique, we obtained the dysregulated mRNA profiling in multi-walled carbon nanotubes (MWCNTs) exposed nematodes. Some dysregulated genes encode insulin signaling pathway. Genetic experiments confirmed the functions of these dysregulated genes in regulating MWCNTs toxicity. In the insulin signaling pathway, DAF-2/insulin receptor regulated MWCNTs toxicity by suppressing function of DAF-16/FOXO transcription factor. Moreover, we raised a miRNAs-mRNAs network involved in the control of MWCNTs toxicity. In this network, mir-355 might regulate MWCNTs toxicity by inhibiting functions of its targeted gene of daf-2, suggesting that mir-355 may regulate functions of the entire insulin signaling pathway by acting as an upregulator of DAF-2, the initiator of insulin signaling pathway, in MWCNTs exposed nematodes. Our results provides highlight on understanding the crucial role of miRNAs in regulating toxicity of nanomaterials in organisms. PMID- 26984257 TI - The benefits of systematic mapping to evidence-based environmental management. AB - Reviews of evidence are a vital means of summarising growing bodies of research. Systematic reviews (SRs) aim to reduce bias and increase reliability when summarising high priority and controversial topics. Similar to SRs, systematic maps (SMs) were developed in social sciences to reliably catalogue evidence on a specific subject. Rather than providing answers to specific questions of impacts, SMs aim to produce searchable databases of studies, along with detailed descriptive information. These maps (consisting of a report, a database, and sometimes a geographical information system) can prove highly useful for research, policy and practice communities, by providing assessments of knowledge gaps (subjects requiring additional research), knowledge gluts (subjects where full SR is possible), and patterns across the research literature that promote best practice and direct research resources towards the highest quality research. Here, we introduce SMs in detail using three recent case studies that demonstrate their utility for research and decision-making. PMID- 26984259 TI - CTGF mediates high-glucose induced epithelial-mesenchymal transition through activation of beta-catenin in podocytes. AB - OBJECTIVE: It is known that connective tissue growth factor (CTGF) and beta catenin are involved in DN; however, the underlying molecular mechanisms remain unknown. Here we hypothesized that podocytes undergo epithelial-mesenchymal transition (EMT) in high-glucose condition and CTGF mediates high-glucose induced EMT by activating beta-catenin in podocytes. METHODS: The differentiated podocytes were cultured and divided into three groups: the normal glucose group (5 mmol/L glucose), the high-glucose group (30 mmol/L glucose), and the osmotic control group (5 mmol/L glucose supplemented with 25 mmol/L mannitol). The morphology of cultured podocytes was observed under phase contrast microscopy. To study the relevant markers of EMT, as well as CTGF and beta-catenin, the mRNA and protein expressions were analyzed by real-time PCR and western blotting, respectively. In addition, the effects of inhibition CTGF by anti-CTGF antibody on high-glucose-induced EMT and beta-catenin expression in podocytes were studied. RESULTS: High glucose not only induced phenotypic transition of podocytes but also increased the expression of CTGF and beta-catenin. Under high glucose condition, podocytes underwent EMT, which were demonstrated by downregulation of nephrin and upregulation of desmin. Moreover, high-glucose induced EMT and beta-catenin overexpression in podocytes were attenuated by anti CTGF antibody. CONCLUSION: CTGF and beta-catenin are involved in the EMT of podocytes in diabetes. CTGF mediates high-glucose induced EMT through activation of beta-catenin in podocytes. CTGF inhibition may protect podocytes from EMT in diabetes. PMID- 26984258 TI - Changing Arctic snow cover: A review of recent developments and assessment of future needs for observations, modelling, and impacts. AB - Snow is a critically important and rapidly changing feature of the Arctic. However, snow-cover and snowpack conditions change through time pose challenges for measuring and prediction of snow. Plausible scenarios of how Arctic snow cover will respond to changing Arctic climate are important for impact assessments and adaptation strategies. Although much progress has been made in understanding and predicting snow-cover changes and their multiple consequences, many uncertainties remain. In this paper, we review advances in snow monitoring and modelling, and the impact of snow changes on ecosystems and society in Arctic regions. Interdisciplinary activities are required to resolve the current limitations on measuring and modelling snow characteristics through the cold season and at different spatial scales to assure human well-being, economic stability, and improve the ability to predict manage and adapt to natural hazards in the Arctic region. PMID- 26984261 TI - Do aggressive driving and negative emotional driving mediate the link between impulsiveness and risky driving among young Italian drivers? AB - The present study examined the contribution of impulsiveness and aggressive and negative emotional driving to the prediction of traffic violations and accidents taking into account potential mediation effects. Three hundred and four young drivers completed self-report measures assessing impulsiveness, aggressive and negative emotional driving, driving violations, and accidents. Structural equation modeling was used to assess the direct and indirect effects of impulsiveness on violations and accidents among young drivers through aggressive and negative emotional driving. Impulsiveness only indirectly influenced drivers' violations on the road via both the behavioral and emotional states of the driver. On the contrary, impulsiveness was neither directly nor indirectly associated with traffic accidents. Therefore, impulsiveness modulates young drivers' behavioral and emotional states while driving, which in turn influences risky driving. PMID- 26984260 TI - Kcne2 deletion causes early-onset nonalcoholic fatty liver disease via iron deficiency anemia. AB - Nonalcoholic fatty liver disease (NAFLD) is an increasing health problem worldwide, with genetic, epigenetic, and environmental components. Here, we describe the first example of NAFLD caused by genetic disruption of a mammalian potassium channel subunit. Mice with germline deletion of the KCNE2 potassium channel beta subunit exhibited NAFLD as early as postnatal day 7. Using mouse genetics, histology, liver damage assays and transcriptomics we discovered that iron deficiency arising from KCNE2-dependent achlorhydria is a major factor in early-onset NAFLD in Kcne2(?/?) mice, while two other KCNE2-dependent defects did not initiate NAFLD. The findings uncover a novel genetic basis for NAFLD and an unexpected potential factor in human KCNE2-associated cardiovascular pathologies, including atherosclerosis. PMID- 26984262 TI - Gastrin attenuates ischemia-reperfusion-induced intestinal injury in rats. AB - Intestinal ischemia-reperfusion (I/R) injury is a devastating complication when the blood supply is reflowed in ischemic organs. Gastrin has critical function in regulating acid secretion, proliferation, and differentiation in the gastric mucosa. We aimed to determine whether gastrin has an effect on intestinal I/R damage. Intestinal I/R injury was induced by 60-min occlusion of the superior mesenteric artery followed by 60-min reperfusion, and the rats were induced to be hypergastrinemic by pretreated with omeprazole or directly injected with gastrin. Some hypergastrinemic rats were injected with cholecystokinin-2 (CCK-2) receptor antagonist prior to I/R operation. After the animal surgery, the intestine was collected for histological analysis. Isolated intestinal epithelial cells or crypts were harvested for RNA and protein analysis. CCK-2 receptor expression, intestinal mucosal damage, cell apoptosis, and apoptotic protein caspase-3 activity were measured. We found that high gastrin in serum significantly reduced intestinal hemorrhage, alleviated extensive epithelial disruption, decreased disintegration of lamina propria, downregulated myeloperoxidase activity, tumor necrosis factor-alpha, and caspase-3 activity, and lead to low mortality in response to I/R injury. On the contrary, CCK-2 receptor antagonist L365260 could markedly impair intestinal protection by gastrin on intestinal I/R. Severe edema of mucosal villi with severe intestinal crypt injury and numerous intestinal villi disintegrated were observed again in the hypergastrinemic rats with L365260. The survival in the hypergastrinemic rats after intestinal I/R injury was shortened by L365260. Finally, gastrin could remarkably upregulated intestinal CCK-2 receptor expression. Our data suggest that gastrin by omeprazole remarkably attenuated I/R induced intestinal injury by enhancing CCK-2 receptor expression and gastrin could be a potential mitigator for intestinal I/R damage in the clinical setting. PMID- 26984263 TI - Predicting cardiorespiratory instability. AB - This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901. PMID- 26984264 TI - Fetuin A is down-regulated in rats during heterotopic ossification after Achilles tenotomy. AB - We investigated the role of fetuin A during heterotopic ossification (HO) in rats following Achilles tenotomy. We performed a right midpoint Achilles tenotomy on 24 rats. At 5 and 10 h after surgery, we investigated the formation of ectopic bone using X-ray and histological examination. We evaluated the mRNA level of fetuin A using real-time PCR. Presence of fetuin A in the Achilles tendon was assessed by immunohistochemical staining. We also measured the serum concentration of fetuin A using enzyme linked immunosorbent assay (ELISA). The expression of fetuin A was significantly decreased in both the liver and Achilles tendon during HO. ELISA showed a small amount of fetuin A in blood throughout the development of HO. Immunohistochemical staining showed that fetuin A was abundant in the ectopic bone. Fetuin A appears to be involved in the formation of ectopic bone induced by Achilles tenotomy, and a deficiency of fetuin A plays a role in the development of HO. PMID- 26984266 TI - Kaempferol induces ATM/p53-mediated death receptor and mitochondrial apoptosis in human umbilical vein endothelial cells. AB - Kaempferol is a member of the flavonoid compounds found in vegetables and fruits. It is shown to exhibit biological impact and anticancer activity, but no report exists on the angiogenic effect of kaempferol and induction of cell apoptosis in vitro. In this study, we investigated the role of kaempferol on anti-angiogenic property and the apoptotic mechanism of human umbilical vein endothelial cells (HUVECs). Our results demonstrated that kaempferol decreased HUVEC viability in a time- and concentration-dependent manner. Kaempferol also induced morphological changes and sub-G1 phase cell population (apoptotic cells). Kaempferol triggered apoptosis of HUVECs as detecting by DNA fragmentation, comet assay and immunofluorescent staining for activated caspase-3. The caspase signals, including caspase-8, -9 and -3, were time-dependently activated in HUVECs after kaempferol exposure. Furthermore, pre-treatment with a specific inhibitor of caspase-8 (Z-IETD-FMK) significantly reduced the activity of caspase-8, -9 and 3, indicating that extrinsic pathway is a major signaling pathway in kaempferol treated HUVECs. Importantly, kaempferol promoted reactive oxygen species (ROS) evaluated using flow cytometric assay in HUVECs. We further investigated the upstream extrinsic pathway and showed that kaempferol stimulated death receptor signals [Fas/CD95, death receptor 4 (DR4) and DR5] through increasing the levels of phosphorylated p53 and phosphorylated ATM pathways in HUVECs, which can be individually confirmed by N-acetylcysteine (NAC), ATM specific inhibitor (caffeine) and p53 siRNA. Based on these results, kaempferol-induced HUVEC apoptosis was involved in an ROS-mediated p53/ATM/death receptor signaling. Kaempferol might possess therapeutic effects on cancer treatment in anti-vascular targeting. PMID- 26984265 TI - GFRA3 promoter methylation may be associated with decreased postoperative survival in gastric cancer. AB - BACKGROUND: A large number of epigenetic alterations has been found to be implicated in the etiology of gastric cancer. We have studied the DNA methylation status of 27 500 gene promoter regions in 24 gastric adenocarcinomas from a Norwegian cohort, and aimed at identifying the hypermethylated regions. We have compared our findings to the gene expression in the same tissue, and linked our results to prognosis and survival. METHODS: Biopsies from gastric adenocarcinomas and adjacent normal gastric mucosa were obtained from 24 patients following surgical resection of the tumor. Genome-wide DNA methylation profiling of the tumor and matched non-cancerous mucosa was performed. The results were compared to whole transcriptome cDNA microarray analysis of the same material. RESULTS: Most of the gene promoter regions in both types of tissue showed a low degree of methylation, however there was a small, but significant hypermethylation of the tumors. Hierarchical clustering showed separate grouping of the tumor and normal tissue. Hypermethylation of the promoter region of the GFRA3 gene showed a strong correlation to post-operative survival and several of the clinicopathological parameters, however no difference was found between the two main histological types of gastric cancer. There was only a modest correlation between the DNA methylation status and gene expression. CONCLUSIONS: The different DNA methylation clusters of the tumors and normal tissue indicate that aberrant DNA methylation is a distinct feature of gastric cancer, although there is little difference in the overall, and low, methylation levels between the two tissue types. The GFRA3 promoter region showed marked hypermethylation in almost all tumors, and its correlation with survival and other clinicopathological parameters may have important prognostic significance. PMID- 26984267 TI - Uncertainty in Online U.S. News Coverage of Truvada. AB - The purpose of this study was to analyze the frequency of incidents of uncertainty in online news articles about Truvada, a drug used to prevent HIV infection. Using a coding scheme that synthesized uncertainty research from health disciplines and communication studies, we analyzed 235 articles from the most-read United States-based news websites. Our results showed that 80.4% of articles contained at least one incident of uncertainty, that articles contained significantly more incidents of uncertainty before the Centers for Disease Control and Prevention (CDC) endorsed Truvada compared to after the CDC endorsed the drug, and that articles mentioning men who have sex with men (MSM) contained significantly more incidents of uncertainty than articles in which they were not mentioned. PMID- 26984269 TI - Impact of occupation on stress and anxiety among Indian women. AB - The objectives of this study were to: (1) assess the prevalence of anxiety and stress in Indian women; and (2) evaluate the relationship of occupation to the prevalence of anxiety and stress. A cross-sectional study was performed from January 2013 to June 2014, on women (aged 18-50 years) randomly selected from different occupations in Gujarat, India. Anxiety was evaluated using Spielberg's State and Trait Anxiety Inventory scale and stress was assessed using the International Stress Management Association questionnaire. Serum cortisol concentration was measured in a sub-sample. The association of occupation with stress and anxiety was analyzed by a generalized linear model adjusted for age. Among all participants, 26% were the most prone and 66% were somewhat more prone to stress; 35% of women showed high anxiety levels. Homemakers had 1.2 times higher anxiety and 1.3 times higher stress than working women (p < .05). Prevalence of stress (37%, p < .001) and anxiety (40%, p = .068) were also higher in homemakers compared to working women and students. Serum cortisol levels did not differ significantly (p > .05) by occupation. This study revealed high prevalence rates of stress and anxiety in Indian women. Involvement in activities outside the home may help women to reduce stress. PMID- 26984270 TI - NMR- and GC/MS-based metabolomics of sulfur mustard exposed individuals: a pilot study. AB - Sulfur mustard (SM) is a potent alkylating agent and its effects on cells and tissues are varied and complex. Due to limitations in the diagnostics of sulfur mustard exposed individuals (SMEIs) by noninvasive approaches, there is a great necessity to develop novel techniques and biomarkers for this condition. We present here the first nuclear magnetic resonance (NMR) and gas chromatography mass spectrometry (GC/MS) metabolic profiling of serum from and healthy controls to identify novel biomarkers in blood serum for better diagnostics. Of note, SMEIs were exposed to SM 30 years ago and that differences between two groups could still be found. Pathways in which differences between SMEIs and healthy controls are observed are related to lipid metabolism, ketogenesis, tricarboxylic acid (TCA) cycle and amino acid metabolism. PMID- 26984271 TI - Erratum to: 'Evaluation of quality improvement for cesarean sections programmes through mixed methods'. PMID- 26984268 TI - CODV-Ig, a universal bispecific tetravalent and multifunctional immunoglobulin format for medical applications. AB - Bispecific immunoglobulins (Igs) typically contain at least two distinct variable domains (Fv) that bind to two different target proteins. They are conceived to facilitate clinical development of biotherapeutic agents for diseases where improved clinical outcome is obtained or expected by combination therapy compared to treatment by single agents. Almost all existing formats are linear in their concept and differ widely in drug-like and manufacture-related properties. To overcome their major limitations, we designed cross-over dual variable Ig-like proteins (CODV-Ig). Their design is akin to the design of circularly closed repeat architectures. Indeed, initial results showed that the traditional approach of utilizing (G4S)x linkers for biotherapeutics design does not identify functional CODV-Igs. Therefore, we applied an unprecedented molecular modeling strategy for linker design that consistently results in CODV-Igs with excellent biochemical and biophysical properties. CODV architecture results in a circular self-contained structure functioning as a self-supporting truss that maintains the parental antibody affinities for both antigens without positional effects. The format is universally suitable for therapeutic applications targeting both circulating and membrane-localized proteins. Due to the full functionality of the Fc domains, serum half-life extension as well as antibody- or complement dependent cytotoxicity may support biological efficiency of CODV-Igs. We show that judicious choice in combination of epitopes and paratope orientations of bispecific biotherapeutics is anticipated to be critical for clinical outcome. Uniting the major advantages of alternative bispecific biotherapeutics, CODV-Igs are applicable in a wide range of disease areas for fast-track multi-parametric drug optimization. PMID- 26984273 TI - Synthesis of SnO2 versus Sn crystals within N-doped porous carbon nanofibers via electrospinning towards high-performance lithium ion batteries. AB - The design of tin-based anode materials (SnO2 or Sn) has become a major concern for lithium ion batteries (LIBs) owing to their different inherent characteristics. Herein, particulate SnO2 or Sn crystals coupled with porous N doped carbon nanofibers (denoted as SnO2/PCNFs and Sn/PCNFs, respectively) are fabricated via the electrospinning method. The electrochemical behaviors of both SnO2/PCNFs and Sn/PCNFs are systematically investigated as anodes for LIBs. When coupled with porous carbon nanofibers, both SnO2 nanoparticles and Sn micro/nanoparticles display superior cycling and rate performances. SnO2/PCNFs and Sn/PCNFs deliver discharge capacities of 998 and 710 mA h g(-1) after 140 cycles (at 100, 200, 500 and 1000 mA g(-1) each for 10 cycles and then 100 cycles at 100 mA g(-1)), respectively. However, the Sn/PCNF electrodes show better cycling stability at higher current densities, delivering higher discharge capacities of 700 and 550 mA h g(-1) than that of SnO2/PCNFs (685 and 424 mA h g( 1)) after 160 cycles at 200 and 500 mA g(-1), respectively. The different superior electrochemical performance is attributed to the introduction of porous N-doped carbon nanofibers and their self-constructed networks, which, on the one hand, greatly decrease the charge-transfer resistance due to the high conductivity of N-doped carbon fibers; on the other hand, the porous carbon nanofibers with numerous voids and flexible one-dimensional (1D) structures efficiently alleviate the volume changes of SnO2 and Sn during the Li-Sn alloying dealloying processes. Moreover, the discussion of the electrochemical behaviors of SnO2vs. Sn would provide new insights into the design of tin-based anode materials for practical applications, and the current strategy demonstrates great potential in the rational design of metallic tin-based anode materials. PMID- 26984272 TI - Melatonin in Chronic Pain Syndromes. AB - Melatonin is a neurohormone secreted by epiphysis and extrapineal structures. It performs several functions including chronobiotic, antioxidant, oncostatic, immune modulating, normothermal, and anxiolytic functions. Melatonin affects the cardiovascular system and gastrointestinal tract, participates in reproduction and metabolism, and body mass regulation. Moreover, recent studies have demonstrated melatonin efficacy in relation to pain syndromes. The present paper reviews the studies on melatonin use in fibromyalgia, headaches, irritable bowel syndrome, chronic back pain, and rheumatoid arthritis. The paper discusses the possible mechanisms of melatonin analgesic properties. On one hand, circadian rhythms normalization results in sleep improvement, which is inevitably disordered in chronic pain syndromes, and activation of melatonin adaptive capabilities. On the other hand, there is evidence of melatonin-independent analgesic effect involving melatonin receptors and several neurotransmitter systems. PMID- 26984274 TI - Obesity may increase risk of rare type of stroke in women taking oral contraceptives. PMID- 26984275 TI - Adrenocortical cancer: mortality, hormone secretion, proliferation and urine steroids - experience from a single centre spanning three decades. AB - BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignant disease with a poor prognosis. Our aims were to study survival and to explore prognostic markers. METHODS: We retrospectively investigated the medical records of all 50 ACC patients at a single centre diagnosed between 1985 and 2012 and followed them up until 31/12/2014. RESULTS: Of this cohort, twenty six (52 %) were females. Adrenalectomy was performed in 48 patients (96 %), and twenty seven (54 %) were treated with adjuvant cytotoxic agents. The tumor sizes ranged from 6 to 20 cm. Overall survival time was 5.5 years (0.3-19.8), the two and five-year survival was 64 and 40 %, respectively. In ENSAT stage II 25/48 patients had a median survival of 7.0 years (0.7-15.5), in stage III 8/48 this was 1.9 (0.4 - 19.8), and in stage IV 15/48 it was 1.2 (0.3-3.6) years. Seventeen patients (34 %) were still alive at the end of 2014. The total follow-up time was 8.4 (0.3-19.8) years. Cell proliferation measured with Ki-67 had a median value of 15 % (2-80) and the urinary steroid profile was clearly pathologic in 29 of 43 (67 %) tested patients. The proliferation index did not significantly predict mortality (Ki-67 <= 10 vs. >10 %, 9.0 vs. 3.2 years, P = 0.0833), but resection margins did (R1 vs. R2, P = 0.0066; R0 vs. R2, P < 0.0001). The urinary steroid profile did not predict mortality (normal vs. pathologic urine profile: median survival 6.6 vs. 3.3 years, P = 0.261). CONCLUSIONS: The prognosis was generally poor and macroscopically positive resection margins resulted in a worse prognosis. However, some patients were still alive many years following primary surgery with no sign of residual disease. PMID- 26984276 TI - Construction site workers' malaria knowledge and treatment-seeking pattern in a highly endemic urban area of India. AB - BACKGROUND: Construction sites are potential breeding places for some species of mosquitoes. Construction workers usually stay at the construction sites, thus being extremely susceptible to malaria. For malaria control, a special focus on them is warranted as they often seek treatment from unregulated, private vendors, increasing their risk of exposure to substandard drugs. OBJECTIVES: To elicit the socio-demographic factors associated with comprehensive malaria knowledge (symptoms, mode of spread, and preventive measures) and treatment-seeking pattern (preferred source and type of treatment) among the construction workers in Mangaluru, India; and, to study the association among their comprehensive malaria knowledge, past suffering from malaria (within 1 year) and treatment-seeking pattern. METHODS: A community based cross-sectional study was conducted in nine randomly selected construction sites of Mangaluru, a high-risk city for malaria with an annual parasite incidence of >2/1000/year, from June-September 2012. A sample size of 132 was estimated assuming at least 30% of them have satisfactory malaria knowledge, 10% absolute precision, 95% confidence level, design effect of 1.5 and 10% non-responses. A semi-structured interview schedule was used, and knowledge scores were computed. Multivariate linear (for knowledge score) and logistic regressions (for preferred source and type of treatment) were applied. RESULTS: One hundred and nineteen workers participated in the study (total approached-138). 85% (n = 101) of them were males. Mean knowledge score was 9.95 +/- 3.19 (maximum possible score-16). The majority of them were aware of the symptoms and the mode of malaria transmission. However, <12% could explain the malaria preventive measures. Females workers (beta = -0.281, p = 0.001), self stated malaria within 1 year (beta = 0.276, p < 0.001) and who preferred allopathic treatment (beta = 0.283, P = 0.001) displayed better knowledge scores. Male workers (AdjOR 7.21, 95% CI 2.3-22.9) and those with self stated malaria within 1 year (AdjOR 11.21, 95% CI 2.38-52.8) showed favorable treatment-seeking pattern. CONCLUSIONS: There is an urgent need of intensifying and streamlining of ongoing malaria prevention activities for construction site workers in Mangaluru, India. Emphasizing the gender equity at every stage of programme implementation and addressing their treatment-seeking pattern is essential. Involvement of labour employers and building contractors in this regard is imperative. PMID- 26984277 TI - How rapid is rapid? Exemplary results of real-life rapid rule-out troponin timing in troponin-positive acute coronary syndromes without persistent ST-segment elevation in two contrasting German chest pain unit facilities. AB - AIM: To analyse the timing of cardiac troponin (cTn) measurements in high-risk and cTn-positive acute coronary syndromes without persistent ST-segment elevation (NSTE-ACS) in two structurally different German chest pain units (CPUs), contrasting an urban university maximum care and a rural regional primary care facility. METHODS: All patients encoded as NSTEMI during the year 2013 were retrospectively enrolled in two centres: site (I)--centre of maximum care in an urban university setting and site (II)--centre of primary care in a rural regional care setting. Data acquisition included time intervals from admission to baseline cTn and first and second cTn control as well as type and timing of invasive management. RESULTS: The median times (site I vs. site II) from admission to cTn result announcement were 26.5 vs. 33.0 min (p = 0.02) for baseline, 4 vs. 4 h (p = 0.43) for the first and 11.0 vs. 16.5 h (p = 0.03) for the second control. Timely announcement, as recommended by guidelines, was available in 86.9% at baseline, 59.4% for the first or 41.1% for the second cTn control. Rates and timing of invasive management were independent from the time point of positive cTn announcement (p = 0.51 and p = 0.68, respectively). CONCLUSIONS: German CPUs provide timely identification of cTn-positive patients in a narrow and guideline-adherent time frame using a rapid rule-out protocol. Especially, baseline and early cTn timing was comparable between the urban university maximum care and the rural regional primary care facility without relevant impact on guideline-conforming invasive management, underlining the high standard of care in those highly professional institutions. PMID- 26984278 TI - HIV-related stigma among African, Caribbean, and Black youth in Windsor, Ontario. AB - HIV-related stigma has been shown to undermine prevention, care, treatment, and the well-being of people living with HIV. A disproportion burden of HIV infection, as well as elevated levels of HIV-related stigma, is evidenced in sub Saharan African (SSA) and African-diasporic populations. This study explores factors that influence HIV-related stigma among 16- to 25-year-old youth residing in a Canadian city who identify as African, Caribbean, or Black. Stigma, as rooted in cultural norms and beliefs and related social institutions, combined with insights from research on stigma in SSA and African-diasporic populations, guided the development of a path analytic structural equation model predicting levels of HIV-related stigmatizing attitudes. The model was tested using survey responses of 510 youth to estimate the direct and indirect influences of ethno religious identity, religious service attendance, time in Canada, HIV/AIDS knowledge, HIV-testing history, sexual health service contact, and gender on HIV related stigma. Statistically significant negative associations were found between levels of stigma and knowledge and HIV-testing history. Ethno-religious identity and gender had both direct and indirect effects on stigma. African Muslim participants had higher levels of stigma, lower knowledge, and were less likely to have been tested for HIV infection than other ethno-religious groups. Male participants had higher levels of stigma and lower knowledge than women. Time in Canada had only indirect effects on stigma, with participants in Canada for longer periods having higher knowledge and less likely to have been tested than more recent arrivals. While the strength of the effect of knowledge on stigmatizing attitudes in this research is consistent with other research on stigma and evaluations of stigma-reduction programs, the path analytic results provide additional information about how knowledge and HIV-testing function as mediators of non-modifiable characteristics such as gender, ethnicity, religion, and time in a country. PMID- 26984279 TI - Inactivation of the ATMIN/ATM pathway protects against glioblastoma formation. AB - Glioblastoma multiforme (GBM) is the most aggressive human primary brain cancer. Using a Trp53-deficient mouse model of GBM, we show that genetic inactivation of the Atm cofactor Atmin, which is dispensable for embryonic and adult neural development, strongly suppresses GBM formation. Mechanistically, expression of several GBM-associated genes, including Pdgfra, was normalized by Atmin deletion in the Trp53-null background. Pharmacological ATM inhibition also reduced Pdgfra expression, and reduced the proliferation of Trp53-deficient primary glioma cells from murine and human tumors, while normal neural stem cells were unaffected. Analysis of GBM datasets showed that PDGFRA expression is also significantly increased in human TP53-mutant compared with TP53-wild-type tumors. Moreover, combined treatment with ATM and PDGFRA inhibitors efficiently killed TP53-mutant primary human GBM cells, but not untransformed neural stem cells. These results reveal a new requirement for ATMIN-dependent ATM signaling in TP53-deficient GBM, indicating a pro-tumorigenic role for ATM in the context of these tumors. PMID- 26984282 TI - Compliance with hand hygiene: reference data from the national hand hygiene campaign in Germany. AB - Hand hygiene is a key measure to prevent healthcare-associated infection. To promote hand hygiene nationally the German campaign 'Aktion Saubere Hande' was launched in January 2008, based on the World Health Organization's 'Clean Care is Safer Care' initiative. We report the first results from a full year of data collection on hand hygiene compliance recorded with the help of a renewed observation tool. Data were based on submissions from 109 participating hospitals collected from 576 wards between January 1st and December 31st, 2014. The overall median compliance was 73%, ranging from 55% (10th percentile) to 89% (90th percentile). The results demonstrated only small differences between adult and non-adult intensive care units (ICUs) with neonatal ICUs and paediatric non-ICUs maintaining higher compliance than adult care units. Performance among nurses was better than physicians, and overall rates of hand hygiene performance were significantly higher after patient contact than before. PMID- 26984280 TI - The nucleolar protein NIFK promotes cancer progression via CK1alpha/beta-catenin in metastasis and Ki-67-dependent cell proliferation. AB - Nucleolar protein interacting with the FHA domain of pKi-67 (NIFK) is a Ki-67 interacting protein. However, its precise function in cancer remains largely uninvestigated. Here we show the clinical significance and metastatic mechanism of NIFK in lung cancer. NIFK expression is clinically associated with poor prognosis and metastasis. Furthermore, NIFK enhances Ki-67-dependent proliferation, and promotes migration, invasion in vitro and metastasis in vivo via downregulation of casein kinase 1alpha (CK1alpha), a suppressor of pro metastatic TCF4/beta-catenin signaling. Inversely, CK1alpha is upregulated upon NIFK knockdown. The silencing of CK1alpha expression in NIFK-silenced cells restores TCF4/beta-catenin transcriptional activity, cell migration, and metastasis. Furthermore, RUNX1 is identified as a transcription factor of CSNK1A1 (CK1alpha) that is negatively regulated by NIFK. Our results demonstrate the prognostic value of NIFK, and suggest that NIFK is required for lung cancer progression via the RUNX1-dependent CK1alpha repression, which activates TCF4/beta-catenin signaling in metastasis and the Ki-67-dependent regulation in cell proliferation. PMID- 26984281 TI - Exciton-exciton annihilation and biexciton stimulated emission in graphene nanoribbons. AB - Graphene nanoribbons display extraordinary optical properties due to one dimensional quantum-confinement, such as width-dependent bandgap and strong electron-hole interactions, responsible for the formation of excitons with extremely high binding energies. Here we use femtosecond transient absorption spectroscopy to explore the ultrafast optical properties of ultranarrow, structurally well-defined graphene nanoribbons as a function of the excitation fluence, and the impact of enhanced Coulomb interaction on their excited states dynamics. We show that in the high-excitation regime biexcitons are formed by nonlinear exciton-exciton annihilation, and that they radiatively recombine via stimulated emission. We obtain a biexciton binding energy of ~ 250 meV, in very good agreement with theoretical results from quantum Monte Carlo simulations. These observations pave the way for the application of graphene nanoribbons in photonics and optoelectronics. PMID- 26984284 TI - Atrazine promotes RM1 prostate cancer cell proliferation by activating STAT3 signaling. AB - Atrazine, a widely used pesticide, is frequently detected in soil and surface water, which alarms epidemiologists and medical professionals because of its potential deleterious effects on health. Indeed, atrazine is a potent endocrine disruptor that increases aromatase expression in some human cancer cell lines. Both animal and human studies have suggested that atrazine is possibly carcinogenic, although discrepant results have been reported. In this study, RM1 cells were used to explore the atrazine effects on prostate cancer. Proliferation, migration and invasion of RM1 cells were assessed by colony formation, wound-healing and invasion assays, respectively, after in vitro exposure to atrazine. In addition, an RM1 cell xenograft model was generated to evaluate the effects of atrazine in vivo. To explore the molecular mechanisms, qRT-PCR, immunohistochemistry, and western blot analyses were employed to detect mRNA and protein levels of STAT3 signaling and cell cycle related proteins, including p53, p21, cyclin B1 and cyclin D1. Interestingly, RM1 cell proliferation was increased after treatment with atrazine, concomitantly with STAT3 signaling activation. These results suggest that atrazine promotes RM1 cell growth in vitro and in vivo by activating STAT3 signaling. PMID- 26984285 TI - Adjunctive use of intrapartum foetal ST-segment analysis (STAN) confers no benefit over conventional foetal heart rate monitoring. PMID- 26984283 TI - Indica rice genome assembly, annotation and mining of blast disease resistance genes. AB - BACKGROUND: Rice is a major staple food crop in the world. Over 80% of rice cultivation area is under indica rice. Currently, genomic resources are lacking for indica as compared to japonica rice. In this study, we generated deep sequencing data (Illumina and Pacific Biosciences sequencing) for one of the indica rice cultivars, HR-12 from India. RESULTS: We assembled over 86% (389 Mb) of rice genome and annotated 56,284 protein-coding genes from HR-12 genome using Illumina and PacBio sequencing. Comprehensive comparative analyses between indica and japonica subspecies genomes revealed a large number of indica specific variants including SSRs, SNPs and InDels. To mine disease resistance genes, we sequenced few indica rice cultivars that are reported to be highly resistant (Tetep and Tadukan) and susceptible (HR-12 and Co-39) against blast fungal isolates in many countries including India. Whole genome sequencing of rice genotypes revealed high rate of mutations in defense related genes (NB-ARC, LRR and PK domains) in resistant cultivars as compared to susceptible. This study has identified R-genes Pi-ta and Pi54 from durable indica resistant cultivars; Tetep and Tadukan, which can be used in marker assisted selection in rice breeding program. CONCLUSIONS: This is the first report of whole genome sequencing approach to characterize Indian rice germplasm. The genomic resources from our work will have a greater impact in understanding global rice diversity, genetics and molecular breeding. PMID- 26984288 TI - Successful surgical treatment of a giant right coronary artery aneurysm with a patent left internal thoracic artery graft. AB - We report a rare case of a giant right coronary artery aneurysm 13 years after coronary artery bypass grafting. Coronary angiography at the time of primary surgery demonstrated irregular aneurysmal dilatation in the mid-right coronary artery that expanded greatly over a 13-year period to a maximum diameter of 80 mm. The patient underwent aneurysmectomy and interposition using a saphenous vein graft through a right lateral thoracotomy. The patient did not undergo dissection or clamping of the left internal thoracic artery graft, and myocardial protection was obtained using systemic hypothermia and hyperkalaemia in addition to continuous antegrade cardioplegia. Postoperatively, coronary computed tomography showed a lack of residual aneurysm and good flow in the saphenous vein graft. The patient made an uneventful recovery. PMID- 26984287 TI - Thoracoscopic esophagectomy for esophageal cancer with situs inversus totalis: a case report and literature review. AB - A 63-year-old male visited our hospital, complaining of discomfort when swallowing. Upper gastrointestinal endoscopy revealed a type 2 tumor in the middle thoracic esophagus, which was diagnosed as squamous cell carcinoma by endoscopic biopsy. Computed tomography revealed situs inversus totalis (SIT). We assessed the relationship of the esophagus with neighboring organs using preoperative three-dimensional imaging. We performed thoracoscopic esophagectomy with radical lymph node dissection in the right decubitus position and hand assisted laparoscopic gastric mobilization in the supine position. The definitive diagnosis was squamous cell carcinoma, pT2N1M0, pStage IIB according to the Union for International Cancer Control. The patient's postoperative course was uneventful, and 5 years post-operation, he is alive without recurrence. In SIT patients, surgical procedures are difficult because of anatomic transposition. Three-dimensional imaging effectively assesses the anatomical structure and contributes to safer thoracoscopic esophagectomy for esophageal cancer patients with SIT. Relevant literature is also discussed and reviewed. PMID- 26984286 TI - Molecular detection and identification of piroplasms in sika deer (Cervus nippon) from Jilin Province, China. AB - BACKGROUND: Piroplasmosis is an important disease of domestic animals and wildlife and is caused by organisms from the genera Theileria and Babesia. Wildlife such as sika deer play an important role as reservoir hosts for several species of Theileria and Babesia. Using blood samples collected from sika deer, we investigated the epidemiology of Theileria spp. and Babesia spp. in sika deer from Jilin Province in China and identified those species that cause pathogenic infections in sika deer. METHODS: Sixty-eight blood samples of sika deer were collected from three areas of the Jilin Province in Northeast China. Genomic DNA was extracted, and the V4 hypervariable region of the 18S rRNA of the piroplasms was amplified using the nested PCR method. The selected positive samples were sequenced to identify species of Babesia and Theileria. RESULTS: PCR detection revealed that 24 samples were positive for Theileria and Babesia spp. (35.29 %, 95 % CI = 11.8-46.8). After alignment, a sequenced fragment for Theileria cervi was found to be the most prevalent from the obtained samples (22.06 %, 95 % CI = 11.8-49.6). Six sika deer samples were identified as being infected with a Theileria sp. that was similar to a Theileria sp. found from spotted deer in India. In addition to the results above, for the first time, we identified T. annulata infection from one sample of sika deer and Babesia sp. from two samples, which showed high identity with Babesia motasi found in sheep from China. CONCLUSION: The present study offers new data on the pathogens of piroplasmosis in sika deer in northeastern China. For the first time, sika deer was confirmed as a reservoir host for the T. annulata of cattle and the B. motasi of sheep, which was found in China. PMID- 26984290 TI - Validation of the Turkish Version of the Sexual Health Outcomes in Women Questionnaire (SHOW-Q) in Turkish-Speaking Women. AB - INTRODUCTION: The Sexual Health Outcomes in Women Questionnaire (SHOW-Q) is designed to evaluate the sexual life of women for satisfaction, orgasm, desire, and pelvic problem interference. The SHOW-Q is important for evaluating worsening of sexual life for patients with pelvic problems and the management of these women to improve their sexual life. AIMS: To validate the Turkish versions of the SHOW-Q for Turkish-speaking women. METHODS: The Turkish version of the SHOW-Q was generated by two independent professional English-to-Turkish translators. The translated version of the SHOW-Q was reverse translated by two bilingual translators whose native language was English. Women with at least one symptom related to pelvic problems (n = 71) and those with no symptoms (n = 38) were included in the present study. MAIN OUTCOME MEASURES: Test-retest reliability analysis, content-face validity, internal consistency reliability, item-total correlations, convergent validity, construct validity, and factorial validity were performed to assess the psychometric properties of the Turkish versions of the SHOW-Q. RESULTS: Test-retest reliability demonstrated good correlation for all subscales. Cronbach alpha values ranged from 0.735 to 0.892 and indicated high internal consistency. There was a strong correlation for the corresponding subscales between the SHOW-Q and the Female Sexual Function Index. The mean score of each SHOW-Q subscale showed significant differences between symptomatic and asymptomatic patients. CONCLUSION: The Turkish version of the SHOW-Q is a valid and reliable instrument that can be used to evaluate the sexual life of Turkish speaking women with different pelvic problems. PMID- 26984289 TI - An Aspect of the Capability for Suicide-Fearlessness of the Pain Involved in Dying-Amplifies the Association Between Suicide Ideation and Attempts. AB - The interpersonal theory of suicide posits that individuals who experience suicide ideation will only develop suicidal intent, and subsequently engage in suicidal behavior when they have concomitant fearlessness about death and tolerance for physical pain (i.e., the capability for suicide). The current studies examined the hypothesis that one aspect of the capability for suicide fearlessness of the pain involved in dying-would amplify the positive association between current suicide ideation and a previous suicide attempt in two samples at high risk for experiencing suicide ideation and suicide attempts. Study 1 examined this relation using self-report methods in a sample of adults entering treatment in a mental health outpatient clinic. Study 2 utilized similar methods in a sample of adults admitted to inpatient psychiatry. Both studies indicated that those individuals who reported suicide ideation were more likely than non ideators to report having attempted suicide only if they also reported greater fearlessness of the pain involved in dying. The current findings support the theorized role of the capability for suicide in the transition from ideation to attempt and also support assessing the capability for suicide in risk assessment. PMID- 26984291 TI - Intralesional Injection of Hyaluronic Acid in Patients Affected With Peyronie's Disease: Preliminary Results From a Prospective, Multicenter, Pilot Study. AB - INTRODUCTION: Hyaluronic acid has been shown to be efficacious in decreasing scar formation, inflammation, and oxidative stress. AIM: To assess the efficacy of intralesional injection of hyaluronic acid in patients affected by Peyronie's disease. METHODS: In this prospective, single-arm, self-controlled, interventional, multicenter pilot study, 65 patients underwent a 10-week cycle of weekly intraplaque injections with hyaluronic acid (0.8% highly purified sodium salt hyaluronic acid 16 mg/2 mL; Sinovial, IBSA, Lodi, Italy). Patients were re evaluated 2 months after the end of therapy. MAIN OUTCOME MEASURES: Plaque size (millimeters), penile curvature (degrees), International Index of Erectile Function (IIEF-5) score, visual analog scale (VAS) score for sexual satisfaction, and Patient's Global Impressions of Improvement (PGI-I) score. RESULTS: Median age was 57 years (range = 23-70). At baseline, mean plaque size was 10 mm (range = 3-30 mm), mean penile curvature was 30 degrees (range = 0 degrees -50 degrees ), and mean IIEF-5 score was 20 (range = 0-25), with slight to moderate erectile dysfunction (IIEF score < 21) in 36 of 65 patients (55%). A median VAS score of 6 (range = 2-10) was found. Mean follow-up was 12 months (range = 6-24 months). Statistically significant post-treatment improvements were detected for plaque size (before treatment = 10 mm [3-30 mm], after treatment = 8 mm [1-30 mm], P < .0001), penile curvature (before treatment = 30 degrees [0 degrees -50 degrees ], after treatment = 20 degrees [0 degrees -40 degrees ], P < .0001), IIEF-5 score (before treatment = 20 [11-25], after treatment = 21 [15-25], P < .0001), and VAS score (before treatment = 6 [2-10], after treatment 8 [2-10], P < .0001). After treatment, the rate of patients with an IIEF score lower than 21 decreased from 55% (36 patients) to 40% (25 patients). Overall improvement on the PGI-I questionnaire was 69%. CONCLUSION: Intralesional treatment with hyaluronic acid can improve plaque size, penile curvature, and overall sexual satisfaction and seems preferably indicated in the early (active) phase of the disease. Furthermore, it is easy to perform and well tolerated. PMID- 26984292 TI - Practice Update: Review of Anticonvulsant Therapy. AB - Since 2010, the Food and Drug Administration has approved the use of four new anti-epilepsy drugs (AEDs) for the treatment of epilepsy in the USA: clobazam (Onfi), ezogabine (Potiga), perampanel (Fycompa), and eslicarbazepine (Aptiom) as well as two extended release formulations, topiramate ER (Qudexy XR and Trokendi) and oxcarbazepine ER (Oxtellar). This not only provides practitioners ample choice to match medication profiles to their patients' preferences and co morbidities better, but also challenges us to be proficient in the use of all. In addition to providing a brief overview of these new medications and of the current medical management of epilepsy, this review discusses new data regarding vitamin D and AED-related osteoporosis, pregnancy registries, suicidality, marijuana-related compounds for epilepsy, and the recently published guidelines on the approach and management of a first unprovoked seizure in adults and guidelines for when to stop AEDs. PMID- 26984295 TI - Weighted Uncertainty Relations. AB - Recently, Maccone and Pati have given two stronger uncertainty relations based on the sum of variances and one of them is nontrivial when the quantum state is not an eigenstate of the sum of the observables. We derive a family of weighted uncertainty relations to provide an optimal lower bound for all situations and remove the restriction on the quantum state. Generalization to multi-observable cases is also given and an optimal lower bound for the weighted sum of the variances is obtained in general quantum situation. PMID- 26984294 TI - Divergent polo box domains underpin the unique kinetoplastid kinetochore. AB - Kinetochores are macromolecular machines that drive eukaryotic chromosome segregation by interacting with centromeric DNA and spindle microtubules. While most eukaryotes possess conventional kinetochore proteins, evolutionarily distant kinetoplastid species have unconventional kinetochore proteins, composed of at least 19 proteins (KKT1-19). Polo-like kinase (PLK) is not a structural kinetochore component in either system. Here, we report the identification of an additional kinetochore protein, KKT20, in Trypanosoma brucei. KKT20 has sequence similarity with KKT2 and KKT3 in the Cys-rich region, and all three proteins have weak but significant similarity to the polo box domain (PBD) of PLK. These divergent PBDs of KKT2 and KKT20 are sufficient for kinetochore localization in vivo. We propose that the ancestral PLK acquired a Cys-rich region and then underwent gene duplication events to give rise to three structural kinetochore proteins in kinetoplastids. PMID- 26984296 TI - Morphology, molecular and systematic analyses of Bychowskyella (Monogenea: Dactylogyridae) in siluriform fish from India. AB - Three species of genus Bychowskyella Akhmerov (1952), i.e. B. fossilisi Majumdar & Agarwal, 1989, B. tchangi Gusev, 1976 and B. wallagonia (Jain, 1959a) Gusev, 1961, were found to parasitize the gill filaments of siluriform fish in India. This redescription based on light microscopic examination of B. fossilisi, B. tchangi and B. wallagonia provides detailed taxonomic data for these species. We also amplified the 18S ribosomal RNA gene to evaluate the phylogenetic relationships of these three species. The morphological and genetic profiles confirmed the validation and taxonomical relationships of the above-mentioned species belonging to the genus Bychowskyella. PMID- 26984293 TI - Reciprocal regulation of Yersinia pestis biofilm formation and virulence by RovM and RovA. AB - RovA is known to enhance Yersinia pestis virulence by directly upregulating the psa loci. This work presents a complex gene regulatory paradigm involving the reciprocal regulatory action of RovM and RovA on the expression of biofilm and virulence genes as well as on their own genes. RovM and RovA enhance and inhibit Y. pestis biofilm production, respectively, whereas RovM represses virulence in mice. RovM directly stimulates the transcription of hmsT, hmsCDE and rovM, while indirectly enhancing hmsHFRS transcription. It also indirectly represses hmsP transcription. By contrast, RovA directly represses hmsT transcription and indirectly inhibits waaAE-coaD transcription, while RovM inhibits psaABC and psaEF transcription by directly repressing rovA transcription. rovM expression is significantly upregulated at 26 degrees C (the temperature of the flea gut) relative to 37 degrees C (the warm-blooded host temperature). We speculate that upregulation of rovM together with downregulation of rovA in the flea gut would promote Y. pestis biofilm formation while inhibiting virulence gene expression, leading to a more transmissible infection of this pathogen in fleas. Once the bacterium shifts to a lifestyle in the warm-blooded hosts, inhibited RovM production accompanied by recovered RovA synthesis would encourage virulence factor production and inhibit biofilm gene expression. PMID- 26984298 TI - Spontaneous Formation of Eutectic Crystal Structures in Binary and Ternary Charged Colloids due to Depletion Attraction. AB - Crystallization of colloids has extensively been studied for past few decades as models to study phase transition in general. Recently, complex crystal structures in multi-component colloids, including alloy and eutectic structures, have attracted considerable attention. However, the fabrication of 2D area-filling colloidal eutectics has not been reported till date. Here, we report formation of eutectic structures in binary and ternary aqueous colloids due to depletion attraction. We used charged particles + linear polyelectrolyte systems, in which the interparticle interaction could be represented as a sum of the electrostatic, depletion, and van der Waals forces. The interaction was tunable at a lengthscale accessible to direct observation by optical microscopy. The eutectic structures were formed because of interplay of crystallization of constituent components and accompanying fractionation. An observed binary phase diagram, defined by a mixing ratio and inverse area fraction of the particles, was analogous to that for atomic and molecular eutectic systems. This new method also allows the adjustment of both the number and wavelengths of Bragg diffraction peaks. Furthermore, these eutectic structures could be immobilized in polymer gel to produce self-standing materials. The present findings will be useful in the design of the optical properties of colloidal crystals. PMID- 26984297 TI - [Statement of the German Society for Pathology and the working group thoracic oncology of the working group oncology/German Cancer Society on ALK testing in NSCLC: Immunohistochemistry and/or FISH?]. PMID- 26984300 TI - Oxidation of NO by small oxygen species HO2(-) and O2(-): the role of negative charge, electronic spin and water solvation. AB - The reactions of HO2(-)(H2O)n and O2(-)(H2O)n clusters (n = 0-4) with NO were studied experimentally using mass spectrometry; the experimental work was supported by quantum chemical computations for the case n = 0, 1. It was found that HO2(-)(H2O)n clusters were efficient in oxidizing NO into NO2(-), although the reaction rate decreases rapidly with hydration above n = 1. Superoxide-water clusters did not oxidize NO into NO2(-) under the present experimental conditions (low pressure): instead a reaction occurred in which peroxynitrite, ONOO(-), was formed as a new cluster core ion. The latter reaction was found to need at least one water molecule present on the reactant cluster in order to enable the product to stabilize itself by evaporation of H2O. PMID- 26984301 TI - Empirical analysis of BMD metrics in genetic toxicology part II: in vivo potency comparisons to promote reductions in the use of experimental animals for genetic toxicity assessment. AB - Genotoxicity tests have traditionally been used only for hazard identification, with qualitative dichotomous groupings being used to identify compounds that have the capacity to induce mutations and/or cytogenetic alterations. However, there is an increasing interest in employing quantitative analysis of in vivo dose response data to derive point of departure (PoD) metrics that can be used to establish human exposure limits or margins of exposure (MOEs), thereby supporting human health risk assessments and regulatory decisions. This work is an extension of our companion article on in vitro dose-response analyses and outlines how the combined benchmark dose (BMD) approach across included covariates can be used to improve the analyses and interpretation of in vivo genetic toxicity dose-response data. Using the BMD-covariate approach, we show that empirical comparisons of micronucleus frequency dose-response data across multiple studies justifies dataset merging, with subsequent analyses improving the precision of BMD estimates and permitting attendant potency ranking of seven clastogens. Similarly, empirical comparisons of Pig-a mutant phenotype frequency data collected in males and females justified dataset merging across sex. This permitted more effective scrutiny regarding the effect of post-exposure sampling time on the mutagenicity of N-ethyl-N-nitrosourea observed in reticulocytes and erythrocytes in the Pig-a assay. The BMD-covariate approach revealed tissue specific differences in the induction of lacZ transgene mutations in MutaTMMouse specimens exposed to benzo[a]pyrene (BaP), with the results permitting the formulation of mechanistic hypotheses regarding the observed potency ranking. Lastly, we illustrate how historical dose-response data for assessments that examined numerous doses (i.e. induced lacZ mutant frequency (MF) across 10 doses of BaP) can be used to improve the precision of BMDs derived from datasets with far fewer doses (i.e. lacZ MF for 3 doses of dibenz[a,h]anthracene). Collectively, the presented examples illustrate how innovative use of the BMD approach can permit refinement of the use of in vivo data; improving the efficacy of experimental animal use in genetic toxicology without sacrificing PoD precision. PMID- 26984299 TI - The deadly line linking sympathetic overdrive, dipping status and vascular risk: critical appraisal and therapeutic implications. PMID- 26984302 TI - Metal mixture (As-Cd-Pb)-induced cell transformation is modulated by OLA1. AB - Environmental pollutants are complex mixtures in which metals are ubiquitous. Metal mixtures of arsenic, cadmium and lead are present in the occupational environment and generate health effects such as cardiovascular, renal and cancer diseases. Cell transformation induced by metal mixtures that depend on reactive oxygen species (ROS) generation, cell viability maintenance and avoidance of senescence was previously reported by our group. The aim of the present study was to explore the role of a Obg-like ATPase1 (OLA1) in the cell transformation of BALB/c 3T3 A31-1-1 clonal cells induced by a metal mixture (2 uM NaAsO2, 2 uM CdCl2 and 5 uM Pb(C2H3O2)2 3H2O) through ROS generation. The interest in OLA1 is justified because this protein has been proposed to be a negative regulator of the cellular antioxidant response. Small interfering RNA (siRNA) was used to knockdown OLA1 before the initiation stage of the transformation assay. We evaluated (ROS) and OLA1 protein expression throughout the initiation and promotion stages of transformation. OLA1 knockdown modulated metal mixture induced cell transformation more strongly when the metal mixture was an initiator stimulus than when it was a promoter. The ability of the metal mixture to initiate cell transformation was diminished by OLA1 knockdown, an effect that depended on intracellular ROS levels. The effect of OLA1 was synergistic with N Acetyl-l-cysteine (NAC) co-treatment. Oxidative stress-associated transcription factors Egr1 and Smad were also down-regulated by the OLA1 knockdown, contributing to the rescue of metal mixture cell transformation. PMID- 26984305 TI - Enhancing central noradrenergic function in depression: is there still a place for a new antidepressant? PMID- 26984303 TI - Editorial: Excessive Police Violence as a Public Health Issue. PMID- 26984304 TI - Pt and Pt-Rh supercrystals self-assembled in N,N-dimethylformamide. AB - <100>-oriented Pt and Pt-Rh supercrystals were directly synthesized in N,N dimethylformamide (DMF) solution. DMF was demonstrated to serve as the facet specific agent of the (100) facets and the driving force for the self-assembly of Pt and Pt-Rh building blocks due to the strong bonding interaction between metal atoms on the (100) facets and the carbonyl group of DMF. PMID- 26984306 TI - Contribution of the stress-induced degeneration of the locus coeruleus noradrenergic neurons to the pathophysiology of depression: a study on an animal model. AB - A novel theory on the pathophysiology of depression would be expected to resolve a contradiction between therapeutic time lag and monoamine hypothesis. On the basis of the fact that a subgroup of depression appears during or after stress, we exposed rats to a long-term (2 weeks) forced walking stress and produced depression-model rats in one group and spontaneous recovery rats in another. The density of axon terminals of the locus coeruleus (LC) neurons in the frontal cortex stained by dopamine beta-hydroxylase antiserum was lower in the depression model rats than in the spontaneous recovery rats and in the control rats without stress. The density was higher in the model rats daily treated with imipramine than in those treated with saline. Morphological projection (MP) index (a percentage of horseradish peroxidase-positive LC cells in total number of LC cells) and electrophysiological projection index (a percentage of LC neurons activated antidromically by electrical stimulation of the cerebral cortex) were lower in the depression-model rats than in the recovery and control rats. MP index was higher in the imipramine-treated rats than that in the saline-treated rats. Electron microscopic examination of the LC disclosed such degenerative changes as low-dense areas without structure, aggregation of intracellular organs, destroyed membranes around the rough endoplasmic reticulum (rER), a decreased number of deformed subsurface cisterns, glia invaginated into the LC neurons and prominent appearance of microglia containing increased number of lipofustin or lysosome in the model rats, but not in the spontaneous recovery rats. These findings suggest that the terminals and cell bodies of the LC noradrenergic neurons degenerate in the stress-induced depression-model rats and regenerate in the imipramine-treated model rats. This degenerative change may possibly contribute to the decrease in synthesis and metabolism of noradrenaline (NA), the slowing of axonal flow, the accumulation of NA in the neurons, the decrease in discharge rate of LC neurons without stress and the increase in release of NA in response to an additional stress. It may also explain the therapeutic time lag that is required to repair the noradrenergic neurons. PMID- 26984307 TI - The relationship between potency of oxidative stress and severity of depression. AB - BACKGROUND: Oxidative stress is one of the suggested mechanisms in major depression. OBJECTIVE: To determine the oxidative and antioxidative status of plasma of patients with major depression and to investigate whether there is a relationship between the potency of oxidative stress and the severity of depression. METHODS: To determine the antioxidative status of plasma, total and individual antioxidant levels which are total antioxidant potential (TAOP), total protein, albumin, uric acid, vitamin C and total bilirubin were measured. To determine the oxidative status, total peroxide level of plasma was measured in patients with drug-free depressive patients and compared with those of controls. Per cent ratio of total peroxide to TAOP was evaluated as oxidative stress index (OSI). RESULTS: Plasma TAOP and individual antioxidant levels were found to be lower in patients with depression than those of controls. On the contrary, the patients had high total plasma peroxide levels. OSI values of the patients were significantly higher than those of controls (P = 0.002), and a significant positive correlation between Hamilton Depression Rating Scale (HDRS) and OSI values was found (r = 0.54, P = 0.01). CONCLUSIONS: The patients with major depression are exposed to oxidative stress, and OSI may be useful to reflect the severity of the disease. PMID- 26984308 TI - Alcohol-dependent patients attempting and not attempting suicide: a comparison. AB - BACKGROUND: Alcohol dependence is a psychiatric disorder associated with an increased risk of suicidal behaviour. This is also associated with an increased number of suicide risk factors. OBJECTIVE: The current study examined the sociodemographic and clinical characteristics of a number of alcohol-dependent patients who attempted suicide. METHODS: We studied a consecutive series of 377 alcohol-dependent patients in our in-patient clinics. Their alcohol-use histories were assessed through semistructured interviews. The Suicidal Behaviors Questionnaire, the Childhood Trauma Questionnaire, the Michigan Alcoholism Screening Test and the Hamilton Depression Rating Scale were administered to all patients. Serum total cholesterol levels, mean corpuscular volume, the liver enzymes gamma glutamyl transferase, aspartate aminotransferase and alanine aminotransferase were routinely measured. In the statistical analyses, Student's t-test and chi-squared tests were applied. RESULTS: Of the 377 alcohol-dependent patients, 89 (23.6%) had histories of attempted suicide. Thirty-four (42.5%) of the 80 female alcohol-dependent patients and 55 (18.5%) of the 297 male alcohol dependent patients had attempted suicide; this gender difference was statistically significant (chi2 = 27.7, P < 0.001). A greater proportion of the suicide attempters than of the non-attempters met the Diagnostic Statistical Manual IV criteria for another psychiatric disorder (60.6%, n = 54, vs. 40.6%, n = 117; chi2 = 14.8; df = 6; P < 0.05). The difference of total cholesterol levels between female (mean = 144.0, SD = 58.3; mean = 158.0, SD = 83.9; t = 4.5; P < 0.05) and male (mean = 133.7, SD = 50.5; mean = 163.6, SD = 69.7; t = 11.7; P < 0.01) attempters and non-attempters was statistically significant. CONCLUSION: These results suggest that suicide attempts in alcohol-dependent patients are associated with more profound biopsychosocial pathology and decreased serum cholesterol levels. PMID- 26984309 TI - Categorization and validation of handedness using latent class analysis. AB - BACKGROUND: A view that handedness is not a dichotomous, i.e. left-right, phenomenon is shared by majority of researchers. However, there are different opinions about the exact number of hand-preference categories and criteria that should be used for their classification. OBJECTIVES: This study examined hand preference categories using the latent class analysis (LCA) and validated them against two external criteria (i.e. hand demonstration test and a series of arbitrary cut-off points). METHOD: The Edinburgh Handedness Inventory was applied to 354 individuals randomly selected from the general population, and the obtained data were analysed using the LatentGOLD software. RESULTS: Three discrete hand-preference clusters were identified, i.e. left-, right- and mixed handed category. Further subdivision of hand-preference clusters resulted in a non-parsimonious subcategorization of individuals. There was a good agreement between the LCA-based classification and classification based on hand-preference demonstration tests. The highest agreement between the LCA model and the different types of arbitrary classification criteria ranged between 0 +/- 50 and 0 +/- 70 of the laterality quotient. CONCLUSIONS: The study findings supported the view that handedness is not a bimodal phenomenon. However, definitions and subcategorizations of mixed-handedness using the cut-off points that are outside of the recommended range may lead to misclassification of cases. It is hoped that the categorization and validation of handedness developed in the context of this study will make future research in this area less dependent on arbitrary values and criteria. PMID- 26984310 TI - Neuroleptic malignant syndrome: risk factors, pathophysiology, and treatment. AB - Neuroleptic malignant syndrome (NMS) is associated with the administration of antipsychotic agents and other drugs such as l-dopa, antidepressants, and antihistaminic agents. Unexpected changes in mental status, new-onset catatonia, episodic tachycardia, tachypnea, hypertension, dysarthria, dysphagia, diaphoresis, sialorrhea, incontinence, low-grade temperature elevations, and rigidity should arouse suspicion. Several lines of evidence provide support for the involvement of dopamine. Most of the drugs implicated in NMS are D2 dopamine receptor antagonists. Central noradrenergic activity is also possibly related to the disorder, as sympathetic hyperactivity is associated with the active phase of NMS. Currently, the definitive role of GABA deficiency in NMS is yet to be established. Differential diagnosis should include malignant hyperthermia, lethal catatonia, lithium toxicity, serotonin syndrome, and heat stroke. A high degree of suspicion and the discontinuation of antipsychotic agents even if the diagnosis is not established are essential for the safety of the patient. Treatment of NMS should be individualized and be based empirically on the character, duration, and severity of the clinical signs and symptoms noted. The initial step in the treatment of NMS is the removal of the offending agent. Full blown NMS is a serious condition and requires immediate supportive, nutritive, and electrolyte therapies. The administration of drugs that can improve NMS, such as IV dantrolene and/or oral bromocriptine, may also be taken into consideration, based on the severity and nature of the NMS. PMID- 26984311 TI - Olanzapine metabolism by CYP1A2/CYP2D6 and hyperglycaemia. AB - The relationship between olanzapine metabolism by CYP1A2/CYP2D6 and hyperglycaemia was investigated. The higher blood olanzapine concentration may be effected by the abnormal metabolism, but not always caused by hyperglycaemia. PMID- 26984312 TI - The toxicity of the three antifouling biocides DCOIT, TPBP and medetomidine to the marine pelagic copepod Acartia tonsa. AB - Copepods, the largest group of pelagic grazers, are at risk from exposure to antifouling biocides. This study investigated the toxicity of the antifouling biocides 4,5-dichloro-2-octyl-1,2-thiazol-3(2H)-one (DCOIT), triphenylborane pyridine (TPBP) and 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (medetomidine) to the copepod Acartia tonsa, using mortality and egg production as endpoints. The toxicity ranking for mortality was as follows: DCOIT (LC50 57 nmol l(-1)) = TPBP (LC50 56 nmol l(-1)) > medetomidine (LC50 241 nmol l(-1)). Egg production was more sensitive than mortality to TPBP (EC50 3.2 nmol l(-1)), while DCOIT and medetomidine inhibited egg production at roughly the same concentrations (72 and 186 nmol l(-1) respectively). Furthermore, TPBP seems to affect egg hatching directly which was not the case for DCOIT and medetomidine. DCOIT and medetomidine might pose an environmental risk as they have been reported to occur in different exposure scenarios or analytical surveys at concentrations only 2-3 times lower than the respective EC10. Reported environmental concentrations of TPBP are few but clearly lower than the EC10 values reported here, suggesting current risk of TPBP to copepods to be moderate. PMID- 26984313 TI - Assessment of brachial artery reactivity, carotid intima-media thickness, and adhesion molecules in pediatric solid tumor patients treated with anthracyclines. AB - The aim of this study was to determine subclinical atherosclerosis and endothelial functional disturbance with measurement of carotid intima-media thickness (IMT), brachial artery reactivity (BAR), and levels of serum adhesion molecules in children with solid tumors who were treated with anthracyclines and are actually in complete remission. Fifty patients who were in remission and 30 healthy children were included in the study. Mean ages of patient and control groups were 13.5 +/- 4.7 years (range: 3-23 years) and 12.00 +/- 4.3 years (range: 4-21 years), respectively. The patients were divided into 3 groups according to cumulative doxorubicin dose: Group 1, <=100 mg/m(2); Group 2, 101 299 mg/m(2); Group 3, >=300 mg/m(2). The BAR and carotid IMT were measured in order to determine the endothelial function. The serum adhesion molecule levels in our patients and controls were also measured. The BAR of the patients with cumulative anthracycline dose >=300 mg/m(2) was significantly lower than the patients with cumulative anthracycline dose <=100 mg/m(2) and healthy controls (P =.005 and P =.003, respectively). Also, there was a negative correlation between brachial artery reactivity and increasing cumulative anthracycline dose (r = .287, P =.044). We also found significant difference between the mean carotid IMT of the patients and the healthy children (P =.041). No statistically significant difference was detected between the serum levels of sICAM-1 (soluble intercellular adhesion molecule-1), sVCAM-1 (soluble vascular cell adhesion molecule-1), sE-selectin of the patients and controls. The use of anthracyclines in pediatric patients with cancer could result in increase of the carotid IMT and endothelial dysfunction. PMID- 26984314 TI - Expert Consensus on the Management of Patients with Postmenopausal Osteoporosis in the Spanish Healthcare System. AB - INTRODUCTION: The management of postmenopausal osteoporosis (PMO) in routine clinical practice differs considerably from guideline recommendations. The objective of our study was to reach a consensus on the management of PMO, considering prevention, diagnosis, treatment and follow-up, according to expert opinion in Spain. METHODS: A two-round Delphi technique was conducted, including 38 experts. The questionnaire contained 35 sections, each one including 1-10 questions (n = 308) based on a literature review and contributions from the scientific steering committee. Each question was scored by experts from the current (1 = no occurrence, 9 = occurrence in all cases), wish (1 = total rejection; 9 = wish) and prediction (1 = no occurrence at all; 9 = occurs with maximum probability) perspectives. Consensus (wish and prediction perspectives) was considered when >=75% of experts scored 7-9 (agreement) or 1-3 (disagreement). RESULTS: Overall, consensus was achieved on 75% of questions. While protocols of clinical management and consultation/referral should be followed, their implementation is unlikely. Furthermore, the medical specialties currently involved in PMO management are poorly defined. PMO patients without fracture should be managed (prevention, diagnosis, treatment and follow-up) in both primary care and rheumatology settings; however, experts predicted that only treatment and follow-up will be assumed by these specialties. A multidisciplinary team should be involved in patients with fracture. No assessment tools are usually applied, and prediction indicated that they will not be used. CONCLUSION: Efforts should be focused on questions with high divergence between wishes and predictions, defining actions that will improve PMO management. Collaboration between scientific societies and health authorities to address the identified opportunities of improvement is proposed. FUNDING: Amgen S.A. PMID- 26984316 TI - Efficient total syntheses and biological activities of two teixobactin analogues. AB - The discovery of the new antibiotic teixobactin has been timely in the race for unearthing novel antibiotics wherein the emergence of drug resistant bacteria poses a serious threat worldwide. Herein, we present the total syntheses and biological activities of two teixobactin analogues. This approach is simple, efficient and has several advantages: it uses commercially available building blocks (except AllocHN-d-Thr-OH), has a single purification step and a good recovery (22%). By using this approach we have synthesised two teixobactin analogues and established that the d-amino acids are critical for the antimicrobial activity of these analogues. With continuing high expectations from teixobactin, this work can be regarded as a stepping stone towards an in depth study of teixobactin, its analogues and the quest for synthesising similar molecules. PMID- 26984315 TI - Impact of the Topical Ophthalmic Corticosteroid Loteprednol Etabonate on Intraocular Pressure. AB - Corticosteroids are a mainstay therapeutic option for the treatment of ocular inflammation. However, safety remains a concern for clinicians, particularly with long-term use. Though highly effective at suppressing inflammatory and allergic responses, topical ophthalmic corticosteroids carry an inherent risk of side effects, including elevated intraocular pressure (IOP), a risk factor for the development of glaucoma. The corticosteroid loteprednol etabonate (LE) contains an ester rather than a ketone at the C-20 position, minimizing the potential for side effects, including IOP elevation. In early pivotal clinical trials of LE ophthalmic suspension for conjunctivitis (allergic, giant papillary), anterior uveitis, and post-operative inflammation, LE had minimal impact on IOP over short term (<28 days) and long-term (>=28 days) use. Since then, new LE formulations including a gel, an ointment, and a suspension of LE in combination with tobramycin-have become commercially available. Multiple studies evaluating the safety and efficacy of LE for inflammatory conditions have been reported, including those requiring longer-term treatment such as photorefractive keratectomy, corneal transplantation, and dry eye disease. We review the available published data on the effect of LE on IOP and report on the cumulative incidence of clinically significant IOP elevations (>=10 mm Hg from baseline) with short-term and long-term LE use. In all studies, LE consistently demonstrated a low propensity to elevate IOP, regardless of formulation, dosage regimen, or treatment duration, including in known steroid responders. The cumulative proportion of patients exhibiting clinically significant IOP increases was 0.8% (14/1725 subjects) in studies evaluating short-term LE treatment and 1.5% (21/1386 subjects) in long-term studies. Furthermore, use of LE was associated with significantly lower rates of IOP elevation >=10 mm Hg as compared to prednisolone acetate or dexamethasone (when used in combination with tobramycin). The cumulative data to date substantiates a favorable IOP-safety profile for LE with both short-term and long-term use. PMID- 26984318 TI - What's new in ARDS: ARDS also exists in resource-constrained settings. PMID- 26984319 TI - The adsorption of amino acids and cations onto goethite: a prebiotic chemistry experiment. AB - Few prebiotic chemistry experiments have assessed the adsorption of biomolecules by iron oxide-hydroxides. The present work investigated the effects of cations in artificial seawaters on the adsorption of Gly, alpha-Ala and beta-Ala onto goethite, and vice versa. Goethite served to concentrate K and Mg cations from solution; these effects could have played important roles in peptide nucleoside formation. Goethite showed low adsorption of Gly and alpha-Ala. On the other hand, beta-Ala (a non-protein amino acid) was highly adsorbed by goethite. Because Gly and alpha-Ala are the most common amino acids in living beings, and iron oxide-hydroxides are widespread on Earth, additional iron oxides should be studied. Increased ionic strength in artificial seawaters decreased the adsorption of amino acids by goethite. Because Na was highly abundant in the artificial seawater, it showed the highest effect on amino acid adsorption. beta Ala increased the adsorption of K and Ca by goethite, this effect could have been important for peptide synthesis. PMID- 26984317 TI - Therapeutic management of peritonitis: a comprehensive guide for intensivists. AB - PURPOSE: The management of peritonitis in critically ill patients is becoming increasingly complex due to their changing characteristics and the growing prevalence of multidrug-resistant (MDR) bacteria. METHODS: A multidisciplinary panel summarizes the latest advances in the therapeutic management of these critically ill patients. RESULTS: Appendicitis, cholecystitis and bowel perforation represent the majority of all community-acquired infections, while most cases of healthcare-associated infections occur following suture leaks and/or bowel perforation. The micro-organisms involved include a spectrum of Gram positive and Gram-negative bacteria, as well as anaerobes and fungi. Healthcare associated infections are associated with an increased likelihood of MDR pathogens. The key elements for success are early and optimal source control and adequate surgery and appropriate antibiotic therapy. Drainage, debridement, abdominal cleansing, irrigation, and control of the source of contamination are the major steps to ensure source control. In life-threatening situations, a "damage control" approach is the safest way to gain time and achieve stability. The initial empirical antiinfective therapy should be prescribed rapidly and must target all of the micro-organisms likely to be involved, including MDR bacteria and fungi, on the basis of the suspected risk factors. Dosage adjustment needs to be based on pharmacokinetic parameters. Supportive care includes pain management, optimization of ventilation, haemodynamic and fluid monitoring, improvement of renal function, nutrition and anticoagulation. CONCLUSIONS: The majority of patients with peritonitis develop complications, including worsening of pre existing organ dysfunction, surgical complications and healthcare-associated infections. The probability of postoperative complications must be taken into account in the decision-making process prior to surgery. PMID- 26984321 TI - A novel liquid chromatography tandem mass spectrometry method for simultaneous determination of branched-chain amino acids and branched-chain alpha-keto acids in human plasma. AB - Branched-chain amino acids (BCAAs) and branched-chain alpha-keto acids (BCKAs) play significant biological roles as they are involved in protein and neurotransmitter synthesis as well as energy metabolism pathways. To routinely and accurately study the dynamics of BCAAs and BCKAs in human diseases, e.g. cerebral infarction, a novel liquid chromatography-tandem mass spectrometry (LC MS/MS) method has been developed and validated. The plasma samples were deproteinized with acetonitrile, and then separated on a reversed phase C18 column with a mobile phase of 0.1 % formic acid (solvent A)-methanol (solvent B) using gradient elution. The detection of BCAAs and BCKAs was conducted in multiple reaction monitoring with positive/negative electrospray ionization switching mode. Biologically relevant isomers such as leucine and isoleucine were individually quantified by combining chromatographic separation and fragmentation. Good linearity (R (2) > 0.99) was obtained for all six analytes with the limits of detection from 0.1 to 0.2 ug/mL. The intra-day and inter-day accuracy ranged from 93.7 to 108.4 % and the relative standard deviation (RSD) did not exceed 15.0 %. The recovery was more than 80 % with RSD less than 14.0 %. The main improvements compared to related, state-of-the-art methods included enhanced sensitivity, enhanced separation of isomers, and reduced complexity of sample processing. Finally, the validated method was applied to analyze the plasma samples of healthy volunteers and patients suffering cerebral infarction, and significant differences in the concentration levels of BCAAs and BCKAs were observed. PMID- 26984320 TI - Physiological and therapeutic effects of carnosine on cardiometabolic risk and disease. AB - Obesity, type 2 diabetes (T2DM) and cardiovascular disease (CVD) are the most common preventable causes of morbidity and mortality worldwide. They represent major public health threat to our society. Increasing prevalence of obesity and T2DM contributes to escalating morbidity and mortality from CVD and stroke. Carnosine (beta-alanyl-L-histidine) is a dipeptide with anti-inflammatory, antioxidant, anti-glycation, anti-ischaemic and chelating roles and is available as an over-the-counter food supplement. Animal evidence suggests that carnosine may offer many promising therapeutic benefits for multiple chronic diseases due to these properties. Carnosine, traditionally used in exercise physiology to increase exercise performance, has potential preventative and therapeutic benefits in obesity, insulin resistance, T2DM and diabetic microvascular and macrovascular complications (CVD and stroke) as well as number of neurological and mental health conditions. However, relatively little evidence is available in humans. Thus, future studies should focus on well-designed clinical trials to confirm or refute a potential role of carnosine in the prevention and treatment of chronic diseases in humans, in addition to advancing knowledge from the basic science and animal studies. PMID- 26984322 TI - Expression of apical Na(+)-L-glutamine co-transport activity, B(0)-system neutral amino acid co-transporter (B(0)AT1) and angiotensin-converting enzyme 2 along the jejunal crypt-villus axis in young pigs fed a liquid formula. AB - Gut apical amino acid (AA) transport activity is high at birth and during suckling, thus being essential to maintain luminal nutrient-dependent mucosal growth through providing AA as essential metabolic fuel, substrates and nutrient stimuli for cellular growth. Because system-B(0) Na(+)-neutral AA co-transporter (B(0)AT1, encoded by the SLC6A19 gene) plays a dominant role for apical uptake of large neutral AA including L-Gln, we hypothesized that high apical Na(+)-Gln co transport activity, and B(0)AT1 (SLC6A19) in co-expression with angiotensin converting enzyme 2 (ACE2) were expressed along the entire small intestinal crypt villus axis in young animals via unique control mechanisms. Kinetics of Na(+)-Gln co-transport activity in the apical membrane vesicles, prepared from epithelial cells sequentially isolated along the jejunal crypt-villus axis from liquid formula-fed young pigs, were measured with the membrane potential being clamped to zero using thiocyanate. Apical maximal Na(+)-Gln co-transport activity was much higher (p < 0.05) in the upper villus cells than in the middle villus (by 29 %) and the crypt (by 30 %) cells, whereas Na(+)-Gln co-transport affinity was lower (p < 0.05) in the upper villus cells than in the middle villus and the crypt cells. The B(0)AT1 (SLC6A19) mRNA abundance was lower (p < 0.05) in the crypt (by 40-47 %) than in the villus cells. There were no significant differences in B(0)AT1 and ACE2 protein abundances on the apical membrane among the upper villus, the middle villus and the crypt cells. Our study suggests that piglet fast growth is associated with very high intestinal apical Na(+)-neutral AA uptake activities via abundantly co-expressing B(0)AT1 and ACE2 proteins in the apical membrane and by transcribing the B(0)AT1 (SLC6A19) gene in the epithelia along the entire crypt-villus axis. PMID- 26984324 TI - H2O2 assisted room temperature oxidation of Ti2C MXene for Li-ion battery anodes. AB - Herein we demonstrate that a prominent member of the MXene family, Ti2C, undergoes surface oxidation at room temperature when treated with hydrogen peroxide (H2O2). The H2O2 treatment results in opening up of MXene sheets and formation of TiO2 nanocrystals on their surface, which is evidenced by the high surface area of H2O2 treated MXene and X-ray diffraction (XRD) analysis. We show that the reaction time and the amount of hydrogen peroxide used are the limiting factors, which determine the morphology and composition of the final product. Furthermore, it is shown that the performance of H2O2 treated MXene as an anode material in Li ion batteries (LIBs) was significantly improved as compared to as prepared MXenes. For instance, after 50 charge/discharge cycles, specific discharge capacities of 389 mA h g(-1), 337 mA h g(-1) and 297 mA h g(-1) were obtained for H2O2 treated MXene at current densities of 100 mA g(-1), 500 mA g( 1) and 1000 mA g(-1), respectively. In addition, when tested at a very high current density, such as 5000 mA g(-1), the H2O2 treated MXene showed a specific capacity of 150 mA h g(-1) and excellent rate capability. These results clearly demonstrate that H2O2 treatment of Ti2C MXene improves MXene properties in energy storage applications, such as Li ion batteries or capacitors. PMID- 26984323 TI - Ph(i-PrO)SiH2: An Exceptional Reductant for Metal-Catalyzed Hydrogen Atom Transfers. AB - We report the discovery of an outstanding reductant for metal-catalyzed radical hydrofunctionalization reactions. Observations of unexpected silane solvolysis distributions in the HAT-initiated hydrogenation of alkenes reveal that phenylsilane is not the kinetically preferred reductant in many of these transformations. Instead, isopropoxy(phenyl)silane forms under the reaction conditions, suggesting that alcohols function as important silane ligands to promote the formation of metal hydrides. Study of its reactivity showed that isopropoxy(phenyl)silane is an exceptionally efficient stoichiometric reductant, and it is now possible to significantly decrease catalyst loadings, lower reaction temperatures, broaden functional group tolerance, and use diverse, aprotic solvents in iron- and manganese-catalyzed hydrofunctionalizations. As representative examples, we have improved the yields and rates of alkene reduction, hydration, hydroamination, and conjugate addition. Discovery of this broadly applicable, chemoselective, and solvent-versatile reagent should allow an easier interface with existing radical reactions. Finally, isotope-labeling experiments rule out the alternative hypothesis of hydrogen atom transfer from a redox-active beta-diketonate ligand in the HAT step. Instead, initial HAT from a metal hydride to directly generate a carbon-centered radical appears to be the most reasonable hypothesis. PMID- 26984325 TI - Ultrasound versus 'clinical touch' for catheter guidance during embryo transfer in women. AB - BACKGROUND: Many women undergoing an assisted reproductive technology (ART) cycle will not achieve a live birth. Failure at the embryo transfer stage may be due to lack of good-quality embryo/s, lack of uterine receptivity, or the transfer technique itself. Numerous methods, including the use of ultrasound guidance for proper catheter placement in the endometrial cavity, have been suggested as more effective techniques of embryo transfer. This review evaluates the efficacy of ultrasound-guided embryo transfer (UGET) compared with 'clinical touch' (CTET), which is the traditional method of embryo transfer and relies on the clinician's tactile senses to judge when the transfer catheter is in the correct position. OBJECTIVES: To determine whether ultrasound guidance compared with clinical touch improves pregnancy outcomes in women undergoing embryo transfer during ART cycles. SEARCH METHODS: For the 2016 update of this review, we ran updated searches in the Cochrane Gynaecology and Fertility Group trials register (May 2015), the Cochrane Central Register of Controlled Trials (the Cochrane Library, May 2015), MEDLINE (2009 to May 2015), and EMBASE (2009 to May 2015). We also handsearched relevant conference proceedings: American Society for Reproductive Medicine (ASRM), European Society for Human Reproduction and Embryology (ESHRE), and International Federation of Gynecology and Obstetrics (FIGO). There were no language restrictions. SELECTION CRITERIA: We included only randomised controlled trials. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and quality of trials and extracted data from those selected. We calculated odds ratio (OR) and 95% confidence interval (CI) for dichotomous outcomes. No outcomes were reported using continuous data. We assessed the overall quality of the evidence for the main findings using the GRADE working group methods. MAIN RESULTS: This systematic review now has 21 included studies (four of which we added in the 2016 update), two studies awaiting assessment, and 47 excluded studies. In total, data for meta-analyses were available in 21 trials (n = 6218 women), of which only four reported live births.UGET was associated with an increased chance of a live birth/ongoing pregnancy compared with CTET (OR 1.47, 95% CI 1.30 to 1.65; 13 trials; n = 5859 women; I(2) = 74%; low-quality evidence). Sensitivity analysis by including only trials with low risk of selection bias or by using a random-effects model did not alter the effect. We estimate that for women with a chance of a live birth/ongoing pregnancy of 23% using CTET, this would increase to between 28% and 33% using UGET. We considered the quality of the evidence using GRADE methodology to be low.UGET was associated with an increase in the chance of a clinical pregnancy (OR 1.31, 95% CI 1.17 to 1.45; 20 trials; n = 6711 women; I(2) = 42%; moderate-quality evidence). We identified no differences between groups for the incidence of adverse events including multiple pregnancy, ectopic pregnancy, or miscarriage. These events were relatively rare, and sample sizes limited the ability to detect such differences. AUTHORS' CONCLUSIONS: The evidence suggests ultrasound guidance improves the chance of live birth/ongoing and clinical pregnancies compared with clinical touch, without increasing the chance of multiple pregnancy, ectopic pregnancy, or miscarriage. Methodological limitations included: only four studies reporting details of both computerised randomisation techniques and adequate allocation concealment, only four studies reported on the outcome of live birth, and none of the nine studies that reported on ongoing pregnancy reported on live birth, suggesting possible reporting bias. Adequate reporting of randomisation and allocation concealment will improve the quality of future studies. The primary outcome measure of future studies should be the reporting of live births per woman randomised. PMID- 26984327 TI - Stress in the brain: implications for treatment of depression. AB - A fundamental question in stress research is when the glucocorticoid stress hormone (cortisol in man) stops being neuroprotective and becomes harmful to the brain with negative consequences for cognition and mood. To address this question Section 1 focuses on the action mechanism of glucocorticoids. These hormones act via high and low affinity nuclear receptors, which regulate gene transcription in a coordinate manner. The receptors are expressed abundantly in hippocampus, amygdala and frontal cortex involved in cognitive processes. In Section 2 hypercortisolism is considered a potential disease factor for about 50% of the patients suffering from major depression. Recent data show that these patients recover within a few days when excess cortisol action is blocked with high doses of an antiglucocorticoid. Section 3 concerns animal models with 'depression-like' features of hypercorticism generated by manipulation of gene X environment inputs. Using gene expression profiling technology in the hippocampal transcriptome of these animals we identified about 700 potential targets for antidepressants out of 30 000 detectable gene products. One of our models is based on early life programming of the stress system. Rats exposed as pups to maternal deprivation display at senescence an enhanced individual difference in cognitive performance. The maternally deprived senescent animals age either successfully or become senile, at the expense of the average performance of non deprived controls. The essay is concluded with the notion that the new generation of antidepressants ameliorates specific psychic dysfunctions (e.g. cognitive performance) linked to aberrant stress hormone action in discrete brain regions. PMID- 26984326 TI - Workplace interventions for reducing sitting at work. AB - BACKGROUND: Office work has changed considerably over the previous couple of decades and has become sedentary in nature. Physical inactivity at workplaces and particularly increased sitting has been linked to increase in cardiovascular disease, obesity and overall mortality. OBJECTIVES: To evaluate the effects of workplace interventions to reduce sitting at work compared to no intervention or alternative interventions. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, OSH UPDATE, PsycINFO, Clinical trials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal up to 2 June, 2015. We also screened reference lists of articles and contacted authors to find more studies to include. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster-randomised controlled trials (cRCTs), and quasi randomised controlled trials of interventions to reduce sitting at work. For changes of workplace arrangements, we also included controlled before-and-after studies (CBAs) with a concurrent control group. The primary outcome was time spent sitting at work per day, either self-reported or objectively measured by means of an accelerometer-inclinometer. We considered energy expenditure, duration and number of sitting episodes lasting 30 minutes or more, work productivity and adverse events as secondary outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles, abstracts and full text articles for study eligibility. Two review authors independently extracted data and assessed risk of bias. We contacted authors for additional data where required. MAIN RESULTS: We included 20 studies, two cross-over RCTs, 11 RCTs, three cRCTs and four CBAs, with a total of 2180 participants from high income nations. The studies evaluated physical workplace changes (nine studies), policy changes (two studies), information and counselling (seven studies) and interventions from multiple categories (two studies). One study had both physical workplace changes and information and counselling components. We did not find any studies that had investigated the effect of periodic breaks or standing or walking meetings. Physical workplace changesA sit-stand desk alone compared to no intervention reduced sitting time at work per workday with between thirty minutes to two hours at short term (up to three months) follow-up (six studies, 218 participants, very low quality evidence). In two studies, sit-stand desks with additional counselling reduced sitting time at work in the same range at short term follow-up (61 participants, very low quality evidence). One study found a reduction at six months' follow-up of -56 minutes (95% CI -101 to -12, very low quality evidence) compared to no intervention. Also total sitting time at work and outside work decreased with sit-stand desks compared to no intervention (MD 78 minutes, 95% CI -125 to -31, one study) as did the duration of sitting episodes lasting 30 minutes or more (MD -52 minutes, 95% CI -79 to -26, two studies). This is considerably less than the two to four hours recommended by experts. Sit-stand desks did not have a considerable effect on work performance, musculoskeletal symptoms or sick leave. It remains unclear if standing can repair the harms of sitting because there is hardly any extra energy expenditure.The effects of active workstations were inconsistent. Treadmill desks combined with counselling reduced sitting time at work (MD -29 minutes, 95% CI -55 to -2, one study) compared to no intervention at 12 weeks' follow-up. Pedalling workstations combined with information did not reduce inactive sitting at work considerably (MD -12 minutes, 95% CI -24 to 1, one study) compared to information alone at 16 weeks' follow-up. The quality of evidence was low for active workstations. Policy changesTwo studies with 443 participants provided low quality evidence that walking strategies did not have a considerable effect on workplace sitting time at 10 weeks' (MD -16 minutes, 95% CI -54 to 23) or 21 weeks' (MD -17 minutes, 95% CI -58 to 25) follow-up respectively. Information and counsellingCounselling reduced sitting time at work (MD -28 minutes, 95% CI -52 to -5, two studies, low quality evidence) at medium term (three months to 12 months) follow-up. Mindfulness training did not considerably reduce workplace sitting time (MD -2 minutes, 95% CI -22 to 18) at six months' follow-up and at 12 months' follow-up (MD -16 minutes, 95% CI -45 to 12, one study, low quality evidence). There was no considerable increase in work engagement with counselling.There was an inconsistent effect of computer prompting on sitting time at work. One study found no considerable effect on sitting at work (MD -17 minutes, 95% CI -48 to 14, low quality evidence) at 10 days' follow-up, while another study reported a significant reduction in sitting at work (MD -55 minutes, 95% CI -96 to -14, low quality evidence) at 13 weeks' follow-up. Computer prompts to stand reduced sitting at work by 14 minutes more (95% CI 10 to 19, one study) compared to computer prompts to step at six days' follow-up. Computer prompts did not change the number of sitting episodes that last 30 minutes or longer. Interventions from multiple categories Interventions combining multiple categories had an inconsistent effect on sitting time at work, with a reduction in sitting time at 12 weeks' (25 participants, very low quality evidence) and six months' (294 participants, low quality evidence) follow-up in two studies but no considerable effect at 12 months' follow-up in one study (MD -47.98, 95% CI -103 to 7, 294 participants, low quality evidence). AUTHORS' CONCLUSIONS: At present there is very low to low quality evidence that sit-stand desks may decrease workplace sitting between thirty minutes to two hours per day without having adverse effects at the short or medium term. There is no evidence on the effects in the long term. There were no considerable or inconsistent effects of other interventions such as changing work organisation or information and counselling. There is a need for cluster-randomised trials with a sufficient sample size and long term follow-up to determine the effectiveness of different types of interventions to reduce objectively measured sitting time at work. PMID- 26984328 TI - Which depressions are related to life stress? AB - This paper examines the relationship of recent life events to specific kinds of depression using published studies and the author's own work. An overall effect of life events on depression has been found consistently and is moderate in degree. In suicide attempts there are stronger and more immediate effects than in depression. Life events precede both non-melancholic and melancholic depressions. It is only in recurrent depressions that life events are less common with melancholic pictures. Life events influence bipolar disorder as well as unipolar. Mania may be preceded by life events, particularly those involving social rhythm disruption, but it is harder to rule out events which are consequences of insidious development of illness. There are strong effects of life events and social support in postpartum depressions but in postpartum psychoses these effects are absent. Events precede depression comorbid with other disorders as well as pure depression. The course of depression is also influenced by life stress with less remission where negative events occur after onset and better outcome where earlier adverse events are neutralized. Relapse is related to immediately preceding life events. However, where depressions are both severe and recurrent life stress effects weaken and as the number of episodes increases preceding life events lessen. These findings suggest that some kinds of depression are more related to psychosocial causation and some are more biological in origin. PMID- 26984329 TI - Stress, norepinephrine and depression. AB - Experimental and clinical evidence implicates stress as a major predisposing factor in depression and other severe psychiatric disorders. In this review, evidence is presented to show how the impact of stress on the central sympathetic system leads to changes in the endocrine, immune and neurotransmitter axes which underlie the main clinical symptoms of depression. Thus it can be shown that the noradrenergic system is dysfunctional in depression, a situation which reflects the chronic hypersecretion of glucocorticoids and inflammatory mediators within the brain in addition to an enhanced activity of the locus ceruleus. With regard to the actions of antidepressants in modulating the stress response and alleviating depression it is now evident that, irrespective of the presumed specificity of the antidepressants for the noradrenergic or serotonergic systems, they all normalize noradrenergic function. This action is due partly to the regulation of tyrosine hydroxylase activity in the locus ceruleus but also enhances neuronal sprouting which counteracts the neurodegenerative effects of chronic stress. PMID- 26984330 TI - Neuroticism, alexithymia, negative affect and positive affect as predictors of medically unexplained symptoms in primary care. AB - BACKGROUND: Somatization has been defined in a number of ways. Despite their differences, these definitions have one element in common, namely the presence of somatic symptoms that cannot be explained (adequately) by organic findings. OBJECTIVE: The primary objectives of the dissertation were to gain a better insight into the concept of somatization, and to study (prospectively) the relationship between neuroticism and alexithymia, two personality traits that have been shown to be related to somatization, the affective state dimensions positive and negative affect (or psychological distress) and medically unexplained symptoms. METHOD: A selective review was conducted regarding conceptual and methodological issues related to somatization. A total number of 318 patients, presenting to their primary care physician with medically unexplained symptoms, participated in the prospective study. Both at baseline and at 6-month follow-up a number of measures were filled out with respect to somatization, neuroticism, alexithymia, negative and positive affect, anxiety and depression. RESULTS: The concept of somatization was clarified, thereby making use of the distinction between presenting and functional somatization. The personality traits neuroticism and alexithymia were found to have an indirect influence on symptom reports. Both the cross-sectional and follow-up data pointed to the importance of positive and negative affect as determinants of (changes in) number of symptoms (over time). Negative affect, together with the alexithymia dimension measuring difficulty identifying feelings, predicted symptom persistence. CONCLUSIONS: The theoretical as well as therapeutic implications of the present paper may give an impetus to new research in the domain of somatization. PMID- 26984331 TI - Stress, cortisol and memory as markers of serotonergic vulnerability. AB - OBJECTIVES: In the present paper the association of stress-induced cortisol with memory impairment is discussed Methods: An experiment is described in which an attempt is made to block stress-induced cortisol by lowering 5-HT neurotransmission by means of acute tryptophan depletion (ATD). Forty-five healthy control subjects participated in the experiment. RESULTS: Stress-induced peak cortisol and immediate memory performance were negatively associated. ATD tended to block stress-induced cortisol response. ATD also blocked the association between peak cortisol response and memory impairment. CONCLUSIONS: Stress-induced cortisol and its association with memory impairment is mediated at least partially by serotonin. PMID- 26984332 TI - The clinical application of the stress concept. AB - BACKGROUND: Knowledge on fundamental aspects of the influence of 'stress' on animal and human organisms is accumulating. In clinical situations, however, psychiatrists still do not use apropriate instruments to recognize and handle the impact of daily life stress. DSM-IV is insufficient in this respect. OBJECTIVE: A different approach is sketched for clinicians to be able to integrate knowledge from research more effectively. METHOD: Application of a 'broad' biological view may reveal the significance of interpretation, emotion, impulse and reaction as stages of a 'mental tract', which is involved in processing the input of stressful situations. RESULT: This may lead to a more rational 'targeting' of pharmacological and psychotherapeutic strategies in clinical practice. CONCLUSION: A re-orientation of clinical psychiatry from mere classification towards a 'broad' biological approach may pave the way for a more rational and purposeful application of research findings to therapy. PMID- 26984333 TI - Clinical models of stress. AB - BACKGROUND: Here we propose a stress model with disease-specific aspects and aspecific factors. The latter are subdivided into load (perception, psychic defence mechanisms), strain (psychophysiological responses) and stress sensu strictu (biological and behavioural compensation). Insufficiently compensated strain will result in being sick and precipitation of a specific disease according to one's predisposition. In the clinical practice, multiconditionality requires a multidimensional analysis, the the five-axial DSM-system being designed especially for this purpose. Multidisciplinary treatment is then organized accordingly, i.e. Axis I: case management, medication; Axis II, (focal) psychotherapy; Axis III, somatic specialists; Axis IV, social worker; Axis V, psychotherapy for coping deficits. OBJECTIVE: To test the efficacy of this multimethodical approach. METHOD: In a 1-year prospective study of 257 admissions in a department of psychiatry in a general hospital, the General Health Questionnaire (30 items) was filled out at admission, discharge and first polyclinical visit post-discharge. RESULTS: The 213 evaluable questionnaires at admission did not show differences (17-18.9) between the four groups, mood disorders (62%), alcoholism (17%), psychoses (15%) and anxiety disorders (6%). At discharge all four groups had reached the cut-off value for 'not-sick' (< 6), this remaining so at follow-up; the three measurements differed significantly throughout the patient groups. Hospitalization was definitely 28.2 days shorter than the Dutch mean of 42 days. CONCLUSIONS: Working to the proposed clinical model for multiconditionalty is effective on intensity and duration of disorders, sustained improvement is attained. PMID- 26984334 TI - Treatment of complex elbow fracture-dislocations. AB - Successful management of complex elbow fracture-dislocations requires, in part, recognition of the overall injury pattern, which can aid in the identification of concomitant bony and soft tissue injuries. Trans-olecranon fracture-dislocations are best treated surgically with stable anatomic restoration of the trochlear notch. Terrible triad elbow injuries are believed to be caused by a valgus posterolateral force. Although select terrible triad injuries can be managed non operatively, the majority of injuries are treated with stable surgical repair to allow early elbow motion. Unlike terrible triads, varus posteromedial forces are theorized to cause anteromedial coronoid fractures. These are usually associated with LCL disruptions, but do not have concomitant MCL or radial head injuries. A subset of anteromedial coronoid fractures can also be managed non-operatively. Internal fixation is recommended for injuries associated with large fracture fragments or elbow instability preventing early motion. PMID- 26984337 TI - Intra-familial Variation in Clinical Phenotype of CARD14-related Psoriasis. AB - Psoriasis is a multifactorial chronic inflammatory disease. Monogenic psoriasis has been described recently, including dominantly inherited plaque and generalized pustular types, related to activating mutations in the CARD14 gene. We describe here a family with CARD14-related psoriasis, exhibiting an extreme variability of clinical presentation (from mild plaque-type to generalized pustular psoriasis) and early disease onset. The affected family members harboured the c.349G>A [p.Gly117Ser] mutation in CARD14, which has not previously been linked to pustular psoriatic phenotype. Furthermore, most severely affected individuals carried 3 additional CARD14 coding region polymorphisms (rs2066964, rs34367357 and rs11652075), suggesting their possible effect on disease expression. Early-onset psoriasis co-segregated with the HLA-C*0602, indicating that HLA-C*0602 could potentially modulate the time of disease onset. In summary, this paper describes a family with CARD14-related psoriasis and discusses the possible influence of the specific haplotypes on intra-familial variation in the clinical phenotype of the disease. PMID- 26984338 TI - Preparation and evaluation of icariside II-loaded binary mixed micelles using Solutol HS15 and Pluronic F127 as carriers. AB - An effective anti-cancer drug, icariside II (IS), has been used to treat a variety of cancers in vitro. However, its poor aqueous solubility and permeability lead to low oral bioavailability. The aim of this work was to use Solutol(r)HS15 and Pluronic F127 as surfactants to develop novel mixed micelles to enhance the oral bioavailability of IS by improving permeability and inhibiting efflux. The IS-loaded mixed micelles were prepared using the method of ethanol thin-film hydration. The physicochemical properties, dissolution property, oral bioavailability of the male SD rats, permeability and efflux of Caco-2 transport models, and gastrointestinal safety of the mixed micelles were evaluated. The optimized IS-loaded mixed micelles showed that at 4:1 ratio of Solutol(r)HS15 and Pluronic F127, the particle size was 12.88 nm with an acceptable polydispersity index of 0.172. Entrapment efficiency (94.6%) and drug loading (9.7%) contributed to the high solubility (11.7 mg/mL in water) of IS, which increased about 900-fold. The SF-IS mixed micelle release profile showed a better sustained release property than that of IS. In Caco-2 cell monolayer models, the efflux ratio dramatically decreased by 83.5%, and the relative bioavailability of the mixed micelles (AUC0-infinity) compared with that of IS (AUC0-infinity) was 317%, indicating potential for clinical application. In addition, a gastrointestinal safety assay also provided reliable clinical evidence for the safe use of this micelle. PMID- 26984335 TI - Anterior cruciate ligament assessment using arthrometry and stress imaging. AB - Arthrometry and stress imaging are useful clinical tools for the objective assessment of anterior cruciate ligament (ACL) integrity. They are most frequently used for the diagnosis of a complete ACL tear when other workup is equivocal, in conjunction with history and clinical exam findings. Other applications include the diagnosis of partial ACL tears, injury prognosis, and post-operative monitoring. However, further studies are needed to validate these uses. Many different devices and techniques exist for objective examination, which have been compared in recent literature. Reliability and validity measures of these methods vary, and often depend upon examiner familiarity and skill. The KT series of devices is the current gold standard for arthrometry, although the newer robotic GNRB device shows promising early results. Newer methods of data interpretation have been developed for stress imaging, and portable technology may impact this field further. PMID- 26984339 TI - Physicochemical, Functional and Antioxidant Properties of Tropical Fruits Co products. AB - The aim of this study was to determine the physicochemical, functional and antioxidant properties of mango (MAC), pineapple (PAC) and passion fruit (PFC) co products in order to evaluate them as ingredients for food application. Proximate composition showed low fat content (0.95-5.64 g/100 g), and high levels of dietary fiber. In pineapple and passion fruit co-products, dietary fiber represented more than 50 % of the sample. Low pH, water activity, along with high acidity indicated that these co-products would not be easily susceptible to deterioration as food ingredients. Pineapple and passion fruit co-products had significant (p < 0.05) water holding capacity (4.96 and 4.31 g water/g sample, respectively), however oil holding capacity was low (1.59-1.85 g oil/g sample) for the three matrices studied. Regarding the phenolic content, values ranged from 3.78 to 4.67 mg gallic acid equivalent/g, with MAC showing the highest content. Through high performance liquid chromatography analysis, six compounds were identified and quantified (gallic acid, p-coumaric acid, ferulic acid, caffeic acid, epicatechin, and mangiferin) in the fruit co-products. As observed for the phenolic content, the highest antioxidant activity (p < 0.05) was found in MAC when measured by both DPPH and ABTS methods. The results indicated that the fruit co-products under evaluation could be used as functional ingredient to provide dietary fiber and natural antioxidants to food products. PMID- 26984336 TI - Co-administration of 3-Acetyl-11-Keto-Beta-Boswellic Acid Potentiates the Protective Effect of Celecoxib in Lipopolysaccharide-Induced Cognitive Impairment in Mice: Possible Implication of Anti-inflammatory and Antiglutamatergic Pathways. AB - Neuro-inflammation is known to initiate the underlying pathogenesis of several neurodegenerative disorders which may progress to cognitive, behavioral, and functional impairment. Boswellia serrata is a well-known powerful anti inflammatory agent used to treat several inflammatory diseases. The aim of the current study is to investigate the effect of the combination therapy of 3-acetyl 11-keto-beta-boswellic acid (AKBA), a 5-lipoxygenase (5-LOX) inhibitor and celecoxib, and a selective cyclooxygenase-2 (COX-2) inhibitor as dual enzyme inhibitors compared to monotherapies with celecoxib and AKBA. Cognitive dysfunction is induced by intraperational injection of lipopolysaccharide (LPS) in mice. Radial maze, Y maze, and novel object recognition (NOR) were performed to evaluate the possible behavioral changes. Moreover, estimation of glutamate and tumor necrosis factor-alpha (TNF-alpha), as well as an immunohistochemical investigation of amyloid beta peptide (Abeta) was performed to evaluate the molecular changes that followed the LPS or drug treatment. The results showed that the combination therapy of AKBA and celecoxib reversed the behavioral and molecular changes caused by LPS cognitive dysfunction model that predispose cognitive dysfunction in mice. This study showed the effectiveness of the dual therapy with AKBA and celecoxib as anti-inflammatory, antiglutamatergic, and anti amyloidogenic agents in the management of cognitive dysfunction. PMID- 26984340 TI - Impact of Cultivar on Profile and Concentration of Lipophilic Bioactive Compounds in Kernel Oils Recovered from Sweet Cherry (Prunus avium L.) by-Products. AB - Lipophilic bioactive compounds in oils recovered from the kernels of seven sweet cherry (Prunus avium L.) cultivars, harvested at single location in 2013, were studied. Oil yield in sweet cherry ranged between 30.3-40.3 % (w/w) dw. The main fatty acids were oleic acid (39.62-49.92 %), linoleic acid (31.13-38.81 %), alpha eleostearic acid (7.23-10.73 %) and palmitic acid (5.59-7.10 %), all four represented approximately 95 % of the total detected fatty acids. The ranges of total tocochromanols and sterols were between 83.1-111.1 and 233.6-419.4 mg/100 g of oil, respectively. Regardless of the cultivar, the gamma-tocopherol and beta sitosterol were the main lipophilic minor bioactive compounds. The content of the carotenoids and squalene were between 0.38-0.62 and 60.9-127.7 mg/100 g of oil, respectively. Three significant correlations were found between oil yield and total contents of sterols (r = -0.852), tocochromanols (r = -0.880) and carotenoids (r = -0.698) in sweet cherry kernel oils. The oil yield, as well as the content of lipophilic bioactive compounds in oil was significantly affected by the cultivar. PMID- 26984341 TI - Origin of B chromosomes in the genus Astyanax (Characiformes, Characidae) and the limits of chromosome painting. AB - Eukaryote genomes are frequently burdened with the presence of supernumerary (B) chromosomes. Their origin is frequently investigated by chromosome painting, under the hypothesis that sharing the repetitive DNA sequences contained in the painting probes is a sign of common descent. However, the intragenomic mobility of many anonymous DNA sequences contained in these probes (e.g., transposable elements) adds high uncertainty to this conclusion. Here we test the validity of chromosome painting to investigate B chromosome origin by comparing its results for seven B chromosome types in two fish species genus Astyanax, with those obtained (1) by means of the physical mapping of 18S ribosomal DNA (rDNA), H1 histone genes, the As51 satellite DNA and the (AC)15 microsatellite, and (2) by comparing the nucleotide sequence of one of these families (ITS regions from ribosomal DNA) between genomic DNA from B-lacking individuals in both species and the microdissected DNA from two metacentric B chromosomes found in these same species. Intra- and inter-specific painting suggested that all B chromosomes that were assayed shared homologous DNA sequences among them, as well as with a variable number of A chromosomes in each species. This finding would be consistent with a common origin for all seven B chromosomes analyzed. By contrast, the physical mapping of repetitive DNA sequences failed to give support to this hypothesis, as no more than two B-types shared a given repetitive DNA. Finally, sequence analysis of the ITS regions suggested that at least some of the B chromosomes could have had a common origin. PMID- 26984343 TI - Anti-Mullerian hormone levels do not predict response to pulsatile GnRH in women with hypothalamic amenorrhea. AB - Pulsatile GnRH is used to induce ovulation in women with hypothalamic amenorrhea (HA), but tools to predict response are lacking. We assessed whether baseline AMH levels are associated with response to pulsatile GnRH in 16 women with HA. AMH levels were compared between non-responders and women who achieved follicular development or pregnancy. Median AMH for the cohort was 2.2 ng/mL. AMH levels were undetectable or low in four women, normal in nine and high in three. Follicular development was observed in 13 (81%) women (82% of cycles) and pregnancy achieved in 10 (63%) women (29% of cycles). All four women with low or undetectable AMH had follicular response and three achieved pregnancy. Of the 12 women with normal or high AMH, 10 had a follicular response and seven achieved pregnancy. Median AMH levels were comparable in those who achieved follicular development and those who did not (2.2 ng/mL versus 1.3 ng/mL, p = 0.78) and in those who became pregnant and those who did not (2.2 ng/mL versus 1.9 ng/mL, p = 0.52). In summary, low AMH does not preclude response to ovulation induction in women with HA, suggesting that ovarian potential may not be the primary determinant of AMH concentrations in this population. PMID- 26984344 TI - Efficacy of fractional CO2 laser in treatment of atrophic scar of cutaneous leishmaniasis. AB - Cutaneous leishmaniasis is an endemic disease in Iran. Unfortunately, it can lead to unsightly atrophic scars with limited treatment options. Fractional CO2 laser is accepted for treatment of atrophic acne scars and recently has been used to treat cutaneous leishmaniasis, so we planned to use fractional CO2 laser on leishmaniasis scar. We conducted this study on 60 leishmaniasis scars on the face of 40 patients. The lesions were treated by a fractional CO2 laser with beam size of 120 MUm, with energy of 50-90 mJ, and 50-100 spots/cm(2) density with two passes in three monthly sessions. Evaluation was done in the first and second months after the first treatment and 3 and 6 months after the last treatment. Digital photography was performed at each visit. Assessment of improvement rate by patient and physician was rated separately as follows: no improvement (0%), mild (<25%), moderate (25-50%), good (51-75%), and excellent (76-100%). Based on patients' opinion, in the first and second follow-up, 48.3 and 90% of them reported moderate to excellent healing, respectively (p < 0.001). In 3 and 6 months follow-up after the end of the experiment, most of the patients (88.3 and 95%, respectively) reported moderate to excellent healing of scars. Based on two observers' opinion, healing in the first follow-up in most of the patients (65%) was mild to moderate and 33% were reported as having no healing. In the second follow-up, only 5% of the patients were reported with no healing and 60% were reported as having moderate healing (p < 0.001). In 3 and 6 months follow-up, most of the patients (95 and 96.6%) were reported as having moderate to excellent healing (p = <0.001). Our results underlined the high efficacy of fractional CO2 laser for leishmaniasis scar. No significant adverse effects were noted. PMID- 26984342 TI - Phylogenetic analysis and differential expression of EF1alpha genes in soybean during development, stress and phytohormone treatments. AB - The EF1alpha is a multifunctional protein with additional unrelated activities to its primary function in translation. This protein is encoded by a multigene family and few studies are still available in plants. Expression of six EF1alpha genes in Glycine max was performed using RT-qPCR and RNA-seq data to advance in the function of each gene during plant development, stress conditions and phytohormone treatments. A phylogenetic classification in Phaseoleae tribe was used to identify the G. max EF1alpha genes (EF1alpha 1a1, 1a2, 1b, 2a, 2b and 3). Three EF1alpha types (1-3) were found in Phaseoleae revealing duplications in G. max types 1 and 2. EF1alpha genes were expressed in all studied tissues, however, specific amount of each transcript was detected. In plant development, all EF1alpha transcripts were generally more expressed in younger tissues, however, in unifoliolate leaves and cotyledons a higher expression occurred in older tissues. Five EF1alpha genes (except 2a) were up-regulated under stress in a response tissue/stress/cultivar-dependent. EF1alpha 3 was the most stress-induced gene linked to cultivar stress tolerance mainly in aerial tissues. Auxin, salicylate and ethylene induced differentially the EF1alpha expression. Overall, this study provides a consistent EF1alpha classification in Phaseoleae tribe to better understand their functional evolution. The RT-qPCR and RNA-seq EF1alpha expression profiles were consistent, both exhibiting expression diversification of each gene (spatio-temporal, stress and phytohormone stimuli). Our results point out the EF1alpha genes, especially EF1alpha 3, as candidate for developing a useful tool for future G. max breeding. PMID- 26984345 TI - Treatment of primary cutaneous amyloidosis with laser: a review of the literature. AB - Primary cutaneous amyloidosis (PCA) is a condition characterized by tissue deposition of misfolded proteins. PCA can present in different forms, namely macular, lichen, and nodular amyloidosis. These lesions can be of cosmetic concern and are difficult to treat. Many therapeutic modalities have been suggested for the treatment of PCA, with variable efficacy, including topical and systemic medications, phototherapy, electrodessication, dermabrasion, cryosurgery, and lasers. Over the past decade, several studies have reported successful treatment of PCA with different types of lasers; however, a review of these studies has never been reported in the dermatologic literature. The aim of this study was to review the efficacy and safety of lasers in the treatment of PCA. A search of the National Library of Medicine's PubMed Database was performed. Studies were considered for inclusion based on their relevance, and specific data were extracted from all included studies. Eleven studies, comprising 64 patients, were included in this review. Significant improvements were observed in macular and lichen amyloidosis patients treated with carbon dioxide laser in two studies, while a number of case series and case reports showed good results with other types of laser in the treatment of PCA. This review was limited by the lack of large double-blinded randomized controlled trials and the overall small sample size. Laser treatment is a promising option in the treatment of PCA. Future randomized controlled trials are needed to compare the efficacy of different types of lasers and to select the best parameters for different types of PCA. PMID- 26984346 TI - Combined effects of low-level laser therapy and human bone marrow mesenchymal stem cell conditioned medium on viability of human dermal fibroblasts cultured in a high-glucose medium. AB - Low-level laser therapy (LLLT) exhibited biostimulatory effects on fibroblasts viability. Secretomes can be administered to culture mediums by using bone marrow mesenchymal stem cells conditioned medium (BM-MSCs CM). This study investigated the combined effects of LLLT and human bone marrow mesenchymal stem cell conditioned medium (hBM-MSCs CM) on the cellular viability of human dermal fibroblasts (HDFs), which was cultured in a high-glucose (HG) concentration medium. The HDFs were cultured either in a concentration of physiologic (normal) glucose (NG; 5.5 mM/l) or in HG media (15 mM/l) for 4 days. LLLT was performed with a continuous-wave helium-neon laser (632.8 nm, power density of 0.00185 W/cm(2) and energy densities of 0.5, 1, and 2 J/cm(2)). About 10% of hBM-MSCs CM was added to the HG HDF culture medium. The viability of HDFs was evaluated using dimethylthiazol-diphenyltetrazolium bromide (MTT) assay. A significantly higher cell viability was observed when laser of either 0.5 or 1 J/cm(2) was used to treat HG HDFs, compared to the control groups. The cellular viability of HG treated HDFs was significantly lower compared to the LLLT + HG HDFs, hBM-MSCs CM treated HG HDFs, and LLLT + hBM-MSCs CM-treated HG HDFs. In conclusion, hBM-MSCs CM or LLLT alone increased the survival of HG HDFs cells. However, the combination of hBM-MSCs CM and LLLT improved these results in comparison to the conditioned medium. PMID- 26984347 TI - 808-nm laser therapy with a flat-top handpiece photobiomodulates mitochondria activities of Paramecium primaurelia (Protozoa). AB - Photobiomodulation is proposed as a non-linear process, and only low-level laser therapy (LLLT) is assumed to stimulate exposed cells, whereas high powered laser and fluences can cause negative effects, exhausting the cell's energy reserve as a consequence of excessive photon-based stimulation. In our work, we investigated and compared the effects of 808-nm diode laser (CW) with a new flat-top handpiece. To this purpose, we tested the photobiomodulation effects of 1 and 3 J/cm(2) fluence, both generated by 100 mW or 1 W of laser power and of 64 J/cm(2) of fluence generated by 100 mW, 1 W, 1.5 W or 2 W, as expressed through oxygen consumption and ATP synthesis of Paramecium. Data collected indicates the incremental consumption of oxygen through irradiation with 3 J/cm(2)-100 mW or 64 J/cm(2)-1 W correlates with an increase in Paramecium ATP synthesis. The Paramecium respiration was inhibited by fluences 64 J/cm(2)-100 mW or 64 J/cm(2) 2 W and was followed by a decrease in the endogenous ATP concentration. The 1 J/cm(2)-100 mW or 1 W and 3 J/cm(2)-1 W did not affect mitochondrial activity. The results show that the fluence of 64 J/cm(2)-1 W more than the 3 J/cm(2)-100 mW causes greater efficiency in Paramecium mitochondria respiratory chain activity. Our results suggest that thanks to flat-top handpiece we used, high fluences by high-powered laser have to be reconsidered as an effective and non invasive therapy. Possible associated benefits of deeper tissue penetration would increase treatment effectiveness and reduced irradiation time. PMID- 26984348 TI - Low-level laser therapy modulates pro-inflammatory cytokines after partial tenotomy. AB - Tendon injuries give rise to substantial morbidity, and current understanding of the mechanisms involved in tendon injury and repair is limited. This lesion remains a clinical issue because the injury site becomes a region with a high incidence of recurrent rupture and has drawn the attention of researchers. We already demonstrated that low-level laser therapy (LLLT) stimulates the synthesis and organization of collagen I, MMP-9, and MMP-2 and improved the gait recovery of the treated animals. The aim of this study was to evaluate the effects of LLLT in the nitric oxide and cytokines profile during the inflammatory and remodeling phases. Adult male rats were divided into the following groups: G1--intact, G2-- injured, G3--injured + LLLT (4 J/cm(2) continuous), G4--injured + LLLT (4 J/cm(2) 20 Hz--pulsed laser). According to the analysis, the animals were euthanized on different dates (1, 4, 8, or 15 days after injury). ELISA assay of TNF-alpha, IL 1beta, IL-10, and TGF-beta was performed. Western blotting of isoform of nitric oxide synthase (i-NOS) and nitric oxide dosage experiments was conducted. Our results showed that the pulsed LLLT seems to exert an anti-inflammatory effect over injured tendons, with reduction of the release of proinflammatory cytokines, such as TNF-alpha and the decrease in the i-NOS activity. Thanks to the pain reduction and the facilitation of movement, there was a stimulation in the TGF beta and IL-1beta release. In conclusion, we believe that pulsed LLLT worked effectively as a therapy to reestablish the tendon integrity after rupture. PMID- 26984349 TI - Adjuvant thiamine improved standard treatment in patients with major depressive disorder: results from a randomized, double-blind, and placebo-controlled clinical trial. AB - Given that antidepressants (ADs) work slowly, there is interest in means to accelerate their therapeutic effect and to reduce side effects. In this regard, thiamine (vitamin B1) is attracting growing interest. Thiamine is an essential nutrient, while thiamine deficiency leads to a broad variety of disorders including irritability and symptoms of depression. Here, we tested the hypothesis that adjuvant thiamine would reduce depression, compared to placebo. A total of 51 inpatients (mean age: 35.2 years; 53 % females) with MDD (Hamilton Depression Rating Scale score (HDRS) at baseline: >24) took part in the study. A standardized treatment with SSRI was introduced and kept at therapeutic levels throughout the study. Patients were randomly assigned either to the thiamine or the placebo condition. Experts rated (HDRS) symptoms of depression at baseline, and after 3, 6, and 12 weeks (end of the study). Between baseline and the end of the study, depression had reduced in both groups. Compared to placebo, adjuvant thiamine improved symptoms of depression after 6 week of treatment, and improvements remained fairly stable until the end of the study, though mean differences at week 12 were not statistically significant anymore. No adverse side effects were reported in either group. Results suggest that among younger patients with MDD adjuvant thiamine alleviated symptoms of depression faster compared to placebo. Importantly, improvements were observed within 6 weeks of initiation of treatment. Thus, thiamine might have the potential to counteract the time lag in the antidepressant effects of ADs. PMID- 26984352 TI - Risungbinella massiliensis sp. nov., a new member of Thermoactinomycetaceae isolated from human gut. AB - A novel filamentous bacterium, designated GD1(T), was isolated from the gut microbiota of a 38-year-old male who suffered from a Coxiella burnetii vascular for which he received multiple a broad-spectrum antibiotic cocktail at the time of the stool collection. The strain was isolated as a part of culturomics study by cultivation on 5 % sheep blood agar in aerobic condition at 28 degrees C, after 14 days of incubation. Strain GD1(T) shows 16S rRNA gene sequence similarities of 98.01 % to the type strain of Risungbinella pyongyangensis. We describe here the features of this bacterium, together with the complete genome sequence and annotation. The G+C content of the genomic DNA was determined to be 40.1 mol %. The major fatty acids of strain GD1(T) were identified as iso-C15:0, iso-C17:0, anteiso-C15:0, iso-C14:0 and C16:0. The 3,440,191 bp long genome contains 3540 protein-coding and 67 RNA genes, including three rRNA genes. Strain GD1(T) (= DSM 46691 = CSUR P1082) sp. nov. is here classified as the type strain of a new species, Risungbinella massiliensis, within the family Thermoactinomycetaceae. To date, strain GD1(T) is the first member of the family Thermoactinomycetaceae isolated from human gut and the fourth from a human specimen. PMID- 26984353 TI - Altererythrobacter buctense sp. nov., isolated from mudstone core. AB - A yellow-pigmented, Gram-negative, non-flagellated, rod-shaped bacterial strain, designated M0322(T), was isolated from a mudstone core sample of the Mohe Basin, China. Growth of strain M0322(T) was observed at 15-40 degrees C (optimum, 30 degrees C), at pH 5.0-10.0, (optimum, pH 6.0-7.0) and in the presence 0-4 % NaCl (optimum, 0 %). Phylogenetic analyses of 16S rRNA gene sequences revealed that strain M0322(T) formed a distinct phyletic lineage with the members of the genus Altererythrobacter and is closely related to Altererythrobacter aestuarii JCM 16339(T) (96.1 %) and Altererythrobacter namhicola JCM 16345(T) (95.7 %). The only isoprenoid quinone was identified as ubiquinone 10 (Q-10), major polar lipids were determined to be phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, one unidentified glycolipid and three unidentified phospholipids, while major cellular fatty acids were summed feature 8 (C18:1 omega6c and/or C18:1 omega7c), summed feature 3 (C16:1 omega6c and/or C16:1 omega7c) and 11-Methyl C18:1 omega7c. The DNA G+C content of strain M0322(T) was determined to be 64.6 mol%. Based on the results of the polyphasic taxonomic study, strain M0322(T) is considered to represent a novel species of the genus Altererythrobacter, for which the name Altererythrobacter buctense sp. nov. is proposed. The type strain is M0322(T) (=CGMCC 1.12871(T) = JCM 30112(T)). PMID- 26984351 TI - Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance. AB - Kinase inhibitor resistance often involves upregulation of poorly understood "bypass" signaling pathways. Here, we show that extracellular proteomic adaptation is one path to bypass signaling and drug resistance. Proteolytic shedding of surface receptors, which can provide negative feedback on signaling activity, is blocked by kinase inhibitor treatment and enhances bypass signaling. In particular, MEK inhibition broadly decreases shedding of multiple receptor tyrosine kinases (RTK), including HER4, MET, and most prominently AXL, an ADAM10 and ADAM17 substrate, thus increasing surface RTK levels and mitogenic signaling. Progression-free survival of patients with melanoma treated with clinical BRAF/MEK inhibitors inversely correlates with RTK shedding reduction following treatment, as measured noninvasively in blood plasma. Disrupting protease inhibition by neutralizing TIMP1 improves MAPK inhibitor efficacy, and combined MAPK/AXL inhibition synergistically reduces tumor growth and metastasis in xenograft models. Altogether, extracellular proteomic rewiring through reduced RTK shedding represents a surprising mechanism for bypass signaling in cancer drug resistance. SIGNIFICANCE: Genetic, epigenetic, and gene expression alterations often fail to explain adaptive drug resistance in cancer. This work presents a novel post-translational mechanism of such resistance: Kinase inhibitors, particularly targeting MAPK signaling, increase tumor cell surface receptor levels due to widely reduced proteolysis, allowing tumor signaling to circumvent intended drug action. PMID- 26984354 TI - Imported cases of Chikungunya in Barcelona in relation to the current American outbreak. AB - BACKGROUND: The Chikungunya virus (CKIKV) is currently present in America. Travel between America and Europe is particularly intense and one of the main vectors of CHIKV, Aedes albopictus, is well established in the Mediterranean basin. We describe a series of imported cases that could originate a European outbreak. METHODS: We retrospectively studied cases of CHIKV originating in America and diagnosed in the last year in three Tropical Medicine Units of Barcelona of the International Health Program of the Catalan Health Institute (PROSICS). Clinical, microbiological and epidemiological data were analyzed. RESULTS: Forty-two CHIKV cases who had returned from 11 American countries were included. Fever was the most common symptom at onset (96.1%). Three months after symptom onset 50% continued with arthralgias, 35.3% fatigue and 11.8% arthritis. Three patients were viremic at the time of diagnosis by RT-PCR, and the remaining were diagnosed by serology (CHIKV IgM or IgG). Five (11.9%) patients had positive IgM for both dengue virus and CHIKV. CONCLUSIONS: The origin of the cases was diverse, the most frequent being initially the Dominican Republic, followed later by Venezuela and Colombia. Symptoms were not severe but persisted, accompanied by unremitting positive IgM. Diagnosis was mainly based on serology and RT-PCR, with the performance of the rapid immunochromatographic test being low. Phylogenetic studies showed that two viremic cases were caused by a strain of Asian lineage with a lower adaptability to Aedes albopictus. Co-infection with the dengue virus was common, but the clinical course was not affected by coinfection. Non steroidal anti-inflammatory drugs were administered to 71.4% and steroids to 21.4%. The number of imported cases of CHIKV in Spain is rising due to introduction of this virus in America, and this could lead to an autochthonous outbreak if Public Health measures are not taken. PMID- 26984356 TI - Keep children away from macaque monkeys! AB - To warn physicians and parents about the risk of macaque bites, we present two pediatric cases (a 4-year-old boy and a 10-year-old girl) of bites sustained while on holiday. The young boy developed febrile dermohypodermitis and was hospitalized for IV antibiotic treatment. He received an initial antirabies vaccine while still in the holiday destination. Except for local wound disinfection and antibiotic ointment, the girl did not receive any specific treatment while abroad. Both were negative for simian herpes PCR. When travelling in countries or cities with endemic simian herpes virus, parents should keep children away from monkeys. Travel agencies, pediatricians and family physicians should better inform families about the zoonotic risk. PMID- 26984357 TI - Ubiquitous Multicriteria Clinic Recommendation System. AB - Advancements in information, communication, and sensor technologies have led to new opportunities in medical care and education. Patients in general prefer visiting the nearest clinic, attempt to avoid waiting for treatment, and have unequal preferences for different clinics and doctors. Therefore, to enable patients to compare multiple clinics, this study proposes a ubiquitous multicriteria clinic recommendation system. In this system, patients can send requests through their cell phones to the system server to obtain a clinic recommendation. Once the patient sends this information to the system, the system server first estimates the patient's speed according to the detection results of a global positioning system. It then applies a fuzzy integer nonlinear programming-ordered weighted average approach to assess four criteria and finally recommends a clinic with maximal utility to the patient. The proposed methodology was tested in a field experiment, and the experimental results showed that it is advantageous over two existing methods in elevating the utilities of recommendations. In addition, such an advantage was shown to be statistically significant. PMID- 26984359 TI - The 27th European conference on biomaterials: facts and figures. PMID- 26984355 TI - Biomarkers of hypoxia, endothelial and circulatory dysfunction among climbers in Nepal with AMS and HAPE: a prospective case-control study. AB - BACKGROUND: The mechanisms underlying acute mountain sickness (AMS) and high altitude pulmonary edema (HAPE) are not fully understood. We hypothesized that regulators of endothelial function, circulatory homeostasis, hypoxia and cell stress contribute to the pathobiology of AMS and HAPE. METHODS: We conducted a prospective case-control study of climbers developing altitude illness who were evacuated to the CIWEC clinic in Kathmandu, compared to healthy acclimatized climbers. ELISA was used to measure plasma biomarkers of the above pathways. RESULTS: Of the 175 participants, there were 71 cases of HAPE, 54 cases of AMS and 50 acclimatized controls (ACs). Markers of endothelial function were associated with HAPE: circulating levels of endothelin-1 (ET-1) were significantly elevated and levels of sKDR (soluble kinase domain receptor) were significantly decreased in cases of HAPE compared to AC or AMS. ET-1 levels were associated with disease severity as indicated by oxygen saturation. Angiopoietin like 4 (Angptl4) and resistin, a marker of cell stress, were associated with AMS and HAPE irrespective of severity. Corin and angiotensin converting enzyme, regulators of volume homeostasis, were significantly decreased in HAPE compared to AC. CONCLUSION: Our findings indicate that regulators of endothelial function, vascular tone and cell stress are altered in altitude illness and may mechanistically contribute to the pathobiology of HAPE. PMID- 26984358 TI - Spherical porous hydroxyapatite granules containing composites of magnetic and hydroxyapatite nanoparticles for the hyperthermia treatment of bone tumor. AB - Spherical porous granules of hydroxyapatite (HA) containing magnetic nanoparticles would be suitable for the hyperthermia treatment of bone tumor, because porous HA granules act as a scaffold for bone regeneration, and magnetic nanoparticles generate sufficient heat to kill tumor cells under an alternating magnetic field. Although magnetic nanoparticles are promising heat generators, their small size makes them difficult to support in porous HA ceramics. We prepared micrometer-sized composites of magnetic and HA nanoparticles, and then supported them in porous HA granules composed of rod-like particles. The spherical porous HA granules containing the composites of magnetic and HA nanoparticle were successfully prepared using a hydrothermal process without changing the crystalline phase and heat generation properties of the magnetic nanoparticles. The obtained granules generated sufficient heat for killing tumor cells under an alternating magnetic field (300 Oe at 100 kHz). The obtained granules are expected to be useful for the hyperthermia treatment of bone tumors. PMID- 26984361 TI - Simultaneous Reduction in Both HbA1c and Body Weight with Canagliflozin Versus Glimepiride in Patients with Type 2 Diabetes on Metformin. AB - INTRODUCTION: Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has demonstrated sustained improvements in glycemic control and body weight reductions with treatment for up to 104 weeks in a broad range of patients with type 2 diabetes mellitus (T2DM). METHODS: This was a post hoc analysis of individual patient data (N = 1450) from a randomized, double-blind, placebo controlled, Phase 3 study comparing canagliflozin with glimepiride as add-on to metformin in patients with T2DM during a 52-week core period followed by a 52 week extension period. The number of patients who achieved a reduction from baseline in both HbA1c and body weight with canagliflozin 100 and 300 mg and glimepiride was assessed at Weeks 52 and 104. Safety was recorded as adverse events (AEs) during the study. RESULTS: Canagliflozin 100 and 300 mg provided durable glycemic improvements and body weight reductions compared with glimepiride over 104 weeks. At Week 52, the proportion of patients who achieved reductions in both HbA1c and body weight was 72.4% with canagliflozin 100 mg, 78.5% with canagliflozin 300 mg, and 26.8% with glimepiride; similar results were observed at Week 104 (65.5%, 71.1%, and 26.8% with canagliflozin 100 and 300 mg and glimepiride, respectively). The AE profile of canagliflozin was comparable to that observed in previous studies, with increased incidence of AEs related to the mechanism of SGLT2 inhibition (e.g., genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs) and a low risk of hypoglycemia. CONCLUSION: More patients treated with canagliflozin experienced reductions in both HbA1c and body weight compared with glimepiride for up to 104 weeks. Canagliflozin was generally well tolerated in patients with T2DM when used in combination with metformin. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00968812. FUNDING: Janssen Research & Development, LLC. PMID- 26984360 TI - Thermo-responsive methylcellulose hydrogels as temporary substrate for cell sheet biofabrication. AB - Methylcellulose (MC), a water-soluble polymer derived from cellulose, was investigated as a possible temporary substrate having thermo-responsive properties favorable for cell culturing. MC-based hydrogels were prepared by a dispersion technique, mixing MC powder (2, 4, 6, 8, 10, 12 % w/v) with selected salts (sodium sulphate, Na2SO4), sodium phosphate, calcium chloride, or phosphate buffered saline, to evaluate the influence of different compositions on the thermo-responsive behavior. The inversion test was used to determine the gelation temperatures of the different hydrogel compositions; thermo-mechanical properties and thermo-reversibility of the MC hydrogels were investigated by rheological analysis. Gelation temperatures and rheological behavior depended on the MC concentration and type and concentration of salt used in hydrogel preparation. In vitro cytotoxicity tests, performed using L929 mouse fibroblasts, showed no toxic release from all the tested hydrogels. Among the investigated compositions, the hydrogel composed of 8 % w/v MC with 0.05 M Na2SO4 had a thermo-reversibility temperature at 37 degrees C. For that reason, this formulation was thus considered to verify the possibility of inducing in vitro spontaneous detachment of cells previously seeded on the hydrogel surface. A continuous cell layer (cell sheet) was allowed to grow and then detached from the hydrogel surface without the use of enzymes, thanks to the thermo-responsive behavior of the MC hydrogel. Immunofluorescence observation confirmed that the detached cell sheet was composed of closely interacting cells. PMID- 26984363 TI - Supervising for Robust Hermeneutic Phenomenology: Reflexive Engagement Within Horizons of Understanding. AB - Undertaking philosophically hermeneutic research requires embodying the fundamental hermeneutic notions espoused by Heidegger, Gadamer, and other related philosophers. For both supervisors and students, there is "a way" of working that infuses a hermeneutic project with a particular kind of contemplative openness. In this article, I will draw from my own experience of coming to appreciate the nature of this approach. Reading Gadamer challenged me to see that, before interpreting the meanings inherent in research data, I first needed to grapple with the fact that I brought ready-made prejudices to the interpretation. Further, and perhaps more importantly, was the recognition that while prejudices may have a negative influence, they could also bring a positive view. Just as I needed to understand key Gadamerian notions to shed light on the interpretive nature of philosophical hermeneutics, I will unpack these to underpin the ongoing discussion of hermeneutic research strategies. In articulating "how" to be hermeneutic, I explain how I guide students embarking on hermeneutic research. Discussion centres on surfacing and engaging with preunderstandings through 'presuppositions interviewing', journalling and the careful selection of words that refine and crystallise meanings in ways that reflectively and reflexively engage and expand horizons of understanding. In this article, I use examples from my own experience as a doctoral student and supervisor of doctoral students to assist other supervisors and students understand both the importance of "being hermeneutic" and ways of achieving robust and philosophically congruent hermeneutic research. PMID- 26984362 TI - Nuclear medicine for imaging of epithelial ovarian cancer. AB - Cancer is one of the leading causes of mortality worldwide. Usually, the diagnosis of cancer at an early stage is important to facilitate proper treatment and survival. Nuclear medicine has been successfully used in the diagnosis, staging, therapy and monitoring of cancers. Single-photon emission computed tomography and PET-based companion imaging agents are in development for use as a companion diagnostic tool for patients with ovarian cancer. The present review discusses the basic and clinical studies related to the use of radiopharmaceuticals in the diagnosis and management of ovarian cancer, focusing on their utility and comparing them with other imaging techniques such as computed tomography and MRI. PMID- 26984364 TI - Personal Accounts of Discontinuing Neuroleptic Medication for Psychosis. AB - We conducted this study to explore personal accounts of making choices about taking medication prescribed for the treatment of psychosis (neuroleptics). There are costs and benefits associated with continuing and discontinuing neuroleptics. Service users frequently discontinue neuroleptics; therefore, we specifically considered these decisions. We used a grounded theory approach to analyze transcripts from interviews with 12 participants. We present a preliminary grounded theory of the processes involved in making choices about neuroleptic medication. We identified three tasks as important in mediating participants' choices: (a) forming a personal theory of the need for, and acceptability of taking, neuroleptic medication; (b) negotiating the challenges of forming alliances with others; and (c) weaving a safety net to safeguard well-being. Progress in the tasks reflected a developmental trajectory of becoming an expert over time and was influenced by systemic factors. Our findings highlight the importance of developing resources for staff to facilitate service user choice. PMID- 26984365 TI - Treatment Barriers and Support for Male Ex-Armed Forces Personnel in Prison: Professional and Service User Perspectives. AB - Ex-armed forces personnel represent a potentially vulnerable group within the prison population. To provide support to this group, we need to understand their needs and help-seeking behavior. A focus group with professionals and semi structured interviews with service users explored perspectives of the treatment barriers faced by this group and their support needs. Data were analyzed using constant comparison methods, and four primary themes were identified. The findings suggest ex-armed forces personnel consider prison an opportunity to access support but find it difficult to ask for help. Staff having an awareness of military issues was thought to encourage help-seeking, but the variability of provision across prison establishments was considered a barrier. Resettlement was a prominent concern, and access to support when preparing for, and after, release was felt by all participants to be important. Implications for the provision of support in prison are discussed along with recommendations for practice. PMID- 26984366 TI - The Social Reception of Women With Cancer. AB - Experiences of cancer are enmeshed with cultural understandings and social discourses around responsibility and causation. A cancer diagnosis can raise questions about its causation-including the role of the individual-whereas the disease and its treatment provide various social markers of illness. We present a sociological study of 81 women's accounts of living with cancer, with a focus on how women interpret their illness, in light of their interpersonal interactions and accounts of social relations. Our analysis reveals women's experiences of cancer diagnosis and treatment, the varied sociocultural meanings of cancer and the responses it elicits, the presence of moral assessments within everyday interactions, and the implications for the support and care they receive. We argue that the experience of cancer should be seen as intimately interwoven with its social reception and cultural sense-making practices, including normative constructs which promote ideas about (in)justice, responsibilization, and shame. PMID- 26984367 TI - Factors influencing the choice of anesthetic technique for primary hip and knee arthroplasty. AB - Despite evidence in the literature, continuing wide variation exists in anesthetic technique for primary joint arthroplasties. Recent evidence suggests that neuraxial anesthesia has advantages over general anesthesia in terms of mortality, major morbidity and healthcare utilization. Yet, despite the proposed benefits, utilization of these two techniques varies greatly across geographical locations, with general anesthesia being most common for total hip arthroplasty (THA) and total knee arthroplasty (TKA) in parts of the world. We uncover some factors that promote or hinder the use of neuraxial anesthesia in THA and TKA. Healthcare professionals should be familiarized with the evidence for neuraxial anesthesia, and unbiased educational material should be developed for patients regarding anesthetic options for THA and TKA in order to promote best practice. PMID- 26984368 TI - Biochemical and histopathological responses of the Swiss albino mice treated with uranyl nitrate and its recovery. AB - Uranium is a radioactive heavy metal ubiquitous in the natural environment. In its chemical form, it is known to induce nephrotoxicity both in human and in animals. Its toxicity is dose and time dependent, also varies with form of uranium. In the present study, we assessed the nephrotoxicity induced by a single dose of uranyl nitrate (UN) in mice at different time intervals and recovery from its toxicity. Two doses of 2 and 4 mg/kg body weight of uranyl nitrate was injected intraperitoneally and animals were sacrificed after 1, 3, 5, 14, and 28 d of administration. Histopathological and biochemical alterations of post-UN dosing in comparison to control were evaluated. Tubular damage to about 75% was observed after 3 d (4 mg/kg) and the biochemical parameters such as serum creatinine, urea, and blood urea nitrogen levels were also significantly increased. Progression of tubular damage was not found after 5 d. Dose-dependent recovery of uranyl nitrate-treated animals was observed after 14 and 28 d of dosing. The concentration of uranium retained in kidney correlates with biochemical and histopathological analysis. PMID- 26984369 TI - Corrigendum: A genome-wide search for epigenetically regulated genes in zebra finch using MethylCap-seq and RNA-seq. PMID- 26984371 TI - A new Bi-based visible-light-sensitive photocatalyst BiLa1.4Ca0.6O4.2: crystal structure, optical property and photocatalytic activity. AB - A new compound of BiLa1.4Ca0.6O4.2 is synthesized through solid state reaction, where the Ca substitutes, in part, the La site in a stable BiLa2O4.5 phase. The structure of the BiLa1.4Ca0.6O4.2 crystallizes in space group R3mH with a hexagonal lattice constants of a = 3.893(1) A, c = 9.891(1) A. Its optical absorption edge is about 2.05 eV, which just spans the visible light region. The photocatalytic activity of the BiLa1.4Ca0.6O4.2 powder to degradation of RhB under visible light irradiation is measured and improved more than 7 times by annealing in nitrogen ambient, indicating that annealing in nitrogen can effectively improve the photocatalytic activity by producing oxygen vacancy. Although the absolute photocatalytic activity obtained is low, there is great potential for enhancing the activity such as nanoscaling, doping, and coupling with other compounds. PMID- 26984370 TI - Critically ill patients with Middle East respiratory syndrome coronavirus infection. AB - This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901. PMID- 26984372 TI - Locally produced natural conditioners for dewatering of faecal sludge. AB - In urban areas of low-income countries, treatment of faecal sludge (FS) is insufficient or non-existent. This results in large amounts of FS being dumped into the environment. Existing treatment technologies for FS, such as settling thickening tanks and drying beds, are land intensive which is limiting in urban areas. Enhanced settling and dewatering by conditioning was evaluated in order to reduce the treatment footprint (or increase treatment capacity). Conventional wastewater conditioners, such as commercially available lime and polymers, are expensive, and commonly rely on complex supply chains for use in low-income countries. Therefore, the treatment performance of five conditioners which could be produced locally was evaluated: Moringa oleifera seeds and press cake, Jatropha curcas seeds, Jatropha Calotropis leaves and chitosan. M. oleifera seeds and press cake, and chitosan improved settling and dewatering and had a similar performance compared to lime and polymers. Optimal dosages were 400-500 kg M. oleifera/t TS, 300-800 kg lime/t TS and 25-50 kg polymer solution/t TS. In comparison, chitosan required 1.5-3.75 kg/t TS. These dosages are comparable to those recommended for wastewater (sludge). The results indicate that conditioning of FS can reduce total suspended solids (TSS) in the effluent of settling thickening tanks by 22-81% and reduce dewatering time with drying beds by 59-97%. This means that the area of drying beds could be reduced by 59-97% with end-use as soil conditioner, or 9-26% as solid fuel. Least expensive options and availability will depend on the local context. In Dakar, Senegal, chitosan produced from shrimp waste appears to be most promising. PMID- 26984375 TI - Could Watching TV Be Good for You? Examining How Media Consumption Patterns Relate to Salivary Cortisol. AB - This research explores whether media diet influences health, not through its effects on cognition and behavior but rather through its effects on biomarkers of stress, which are implicated in a host of acute and chronic illnesses. Two hundred and forty young adults completed assessments of their media consumption habits followed at least 2 days later by measures of the stress-related hormone cortisol. Results suggest that frequency of consuming different media and genres may decrease cortisol under certain conditions and increase them under others. Further, the patterns of results were wholly different from those found for perceived stress. The implications of these findings for health-related media effects and theoretical development are discussed. PMID- 26984373 TI - A unique subtype of diffuse large B-cell lymphoma primarily involving the bone marrow, spleen, and liver, defined by fluorodeoxyglucose-positron emission tomography combined with computed tomography. AB - We describe 10 cases of diffuse large B-cell lymphoma (DLBCL) confined to the bone marrow (BM), spleen, and liver, as evidenced by the uniformly increased uptake of fluorodeoxyglucose (FDG) on positron emission tomography combined with computed tomography (PET/CT). Ages ranged from 56 to 87. All, but one patient presented with 'B' symptoms, a poor performance status, and hepatosplenomegaly. All patients showed cytopenia and elevated lactate dehydrogenase levels and were classified into the high-risk category of the International Prognostic Index scoring. BM infiltration was diffuse, interstitial/intrasinusoidal, or mixed, and all showed the nongerminal center B immunophenotype. Five patients had a rearrangement involving 3q27/BCL6, while six had increased copies of MYC, BCL2, or BCL6. All patients were initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone, leading to complete responses in six out of eight evaluable patients. We propose BM, spleen, and liver-type DLBCL, which is defined by the findings of FDG-PET/CT. PMID- 26984374 TI - RepA-WH1, the agent of an amyloid proteinopathy in bacteria, builds oligomeric pores through lipid vesicles. AB - RepA-WH1 is a disease-unrelated protein that recapitulates in bacteria key aspects of human amyloid proteinopathies: i) It undergoes ligand-promoted amyloidogenesis in vitro; ii) its aggregates are able to seed/template amyloidosis on soluble protein molecules; iii) its conformation is modulated by Hsp70 chaperones in vivo, generating transmissible amyloid strains; and iv) causes proliferative senescence. Membrane disruption by amyloidogenic oligomers has been found for most proteins causing human neurodegenerative diseases. Here we report that, as for PrP prion and alpha-synuclein, acidic phospholipids also promote RepA-WH1 amyloidogenesis in vitro. RepA-WH1 molecules bind to liposomes, where the protein assembles oligomeric membrane pores. Fluorescent tracer molecules entrapped in the lumen of the vesicles leak through these pores and RepA-WH1 can then form large aggregates on the surface of the vesicles without inducing their lysis. These findings prove that it is feasible to generate in vitro a synthetic proteinopathy with a minimal set of cytomimetic components and support the view that cell membranes are primary targets in protein amyloidoses. PMID- 26984376 TI - Life at Age 100: An International Research Agenda for Centenarian Studies. AB - Living a long life is desired by many individuals, and this dream is likely to become reality in more and more industrialized societies. During the past 3 decades, the number of very old individuals has increased significantly, creating a global demographic challenge with consequences at the individual, family, and societal levels. Yet, life in very old age is still poorly understood in terms of its unique characteristics and challenges. Besides specific content areas, very old age represents an understudied field of research. This lack of knowledge may be one reason that the very old also are an underserved population. This special issue introduces an international network of three centenarian studies that describe and compare the life circumstances and characteristics of centenarians across Germany, Portugal, and the United States. Our parallel studies comprehensively assess centenarians' physical, cognitive, social, and psychological functioning to create a knowledge base regarding their capacities and needs. A specific focus lies in the investigation of psychological aspects, social resources, and societal/cultural contexts, factors that may contribute to longevity and successful aging. Determining key characteristics of this very old population and investigating similarities and differences across countries is timely and urgent, both from an applied and a policy standpoint. PMID- 26984377 TI - Body temperature rhythm and control of the time of the best physical condition by performing physical labor. AB - The initial examination of a male subject's body temperature revealed that it was highest during the evening. Based on this observation, I measured grasping power, calculation speed, performance time on a light sensory task and body temperature, all of which were highest or best during the evening. The time of this subject's best physical condition shifted from the evening to morning hours when the subject executed hard physical labor in the morning, and the shifted phase was maintained after the termination of the labor period. PMID- 26984379 TI - Mothers' factors associated with female genital mutilation in daughters in the Iraqi Kurdistan Region. AB - An important proactive factor for the continuation of female genital mutilation (FGM) is tradition and customs inherited in the family from mothers to daughters. Therefore, the aim of this study was to determine mothers' factors associated with the occurrence of FGM among their daughters. The datasets from the Iraq Multiple Indicator Cluster Survey 2011, on 5,184 women aged 15 to 49 years having at least one daughter, was used. Multivariate analysis based on a binary logistic regression model was applied. Mothers' age (adjusted odds ratio [aOR] = 8.18 at ages 25-34 years, aOR = 22.64 at ages 35-44 years, and aOR = 29.78 at ages 45-49 years, compared to the age group 15-24 years), educational level (aOR = 0.52 for primary education, aOR = 0.26 for secondary education, and aOR = 0.03 for higher education compared to uneducated), employment status (aOR = 0.55 for women having office work compared with unemployed), FGM status (aOR = 27.44 for circumcised mothers compared to uncircumcised), the governorate of residence (aOR = 18.73 for Suleimaniya and aOR = 33.23 for Erbil compared with Dohuk), and the wealth index of the household (aOR = 0.55 for richest group compared to the poorest) were significantly associated with the occurrence of FGM in daughters. Strategies aimed at preventing this harmful practice in the Iraqi Kurdistan Region should include female education and empowerment. PMID- 26984378 TI - XGFR*, a novel affinity-matured bispecific antibody targeting IGF-1R and EGFR with combined signaling inhibition and enhanced immune activation for the treatment of pancreatic cancer. AB - The epidermal growth factor receptor (EGFR) and the insulin-like growth factor-1 receptor (IGF-1R) play critical roles in tumor growth, providing a strong rationale for the combined inhibition of IGF-1R and EGFR signaling in cancer therapy. We describe the design, affinity maturation, in vitro and in vivo characterization of the bispecific anti-IGF-1R/EGFR antibody XGFR*. XGFR* is based on the bispecific IgG antibody XGFR, which enabled heterodimerization of an IGF-1R binding scFab heavy chain with an EGFR-binding light and heavy chain by the "knobs-into-holes" technology. XGFR* is optimized for monovalent binding of human EGFR and IGF-1R with increased binding affinity for IGF-1R due to affinity maturation and highly improved protein stability to oxidative and thermal stress. It bears an afucosylated Fc-portion for optimal induction of antibody-dependent cell-mediated cytotoxicity (ADCC). Stable Chinese hamster ovary cell clones with production yields of 2-3 g/L were generated, allowing for large scale production of the bispecific antibody. XGFR* potently inhibits EGFR- and IGF-1R-dependent receptor phosphorylation, reduces tumor cell proliferation in cells with heterogeneous levels of IGF-1R and EGFR receptor expression and induces strong ADCC in vitro. A comparison of pancreatic and colorectal cancer lines demonstrated superior responsiveness to XGFR*-mediated signaling and tumor growth inhibition in pancreatic cancers that frequently show a high degree of IGF 1R/EGFR co-expression. XGFR* showed potent anti-tumoral efficacy in the orthotopic MiaPaCa-2 pancreatic xenograft model, resulting in nearly complete tumor growth inhibition with significant number of tumor remissions. In summary, the bispecific anti-IGF-1R/EGFR antibody XGFR* combines potent signaling and tumor growth inhibition with enhanced ADCC induction and represents a clinical development candidate for the treatment of pancreatic cancer. PMID- 26984380 TI - Regulation of COX-2 expression and epithelial-to-mesenchymal transition by hypoxia-inducible factor-1alpha is associated with poor prognosis in hepatocellular carcinoma patients post TACE surgery. AB - Currently, it is not entirely clear whether hypoxia-inducible factor-1alpha (HIF 1alpha) is involved in the regulation of COX-2 expression and epithelial-to mesenchymal transition (EMT), and whether these events affect the prognosis of hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE). In this report the relationship between HIF-1alpha and COX-2 protein expression, EMT in tumor specimens from HCC patients after TACE surgery and the clinical significance of HIF-1alpha and COX-2 expression were analyzed using statistical approaches. HepG2 cells treated with CoCl2 was employed as a hypoxia cell model in vitro to study hypoxia-induced HIF-1alpha, COX-2 expression, and EMT alteration. The results showed that HIF-1alpha and COX 2 protein expression increased in HCC tissues after TACE surgery. Moreover, there was positive correlation between upregulation of HIF-1alpha and COX-2. Elevated expression of HIF-1alpha increased both Snail and Vimentin protein expression, while it reduced E-cadherin protein expression. It was further verified that hypoxia enhanced protein expression of HIF-1alpha and COX-2 in HepG2 cells treated with CoCl2. Upregulation of HIF-1alpha and COX-2, together with EMT alteration resulted in increased migration and invasion of HepG2 cells under hypoxia. In conclusion, TACE surgery results in aggravated hypoxia status, leading to increased HIF-1alpha protein expression in HCC tissue. To adapt to hypoxic environment, HIF-1alpha stimulates COX-2 protein expression and promotes EMT process in hepatocellular cancer cells, which enhances HCC invasion and metastasis, and might contribute to poor prognosis in HCC patients post TACE treatment. PMID- 26984383 TI - The glass and jamming transitions of soft polyelectrolyte microgel suspensions. AB - We explore the influence of particle softness on the state diagram of well characterized polyelectrolyte microgel suspensions using dynamic light scattering and rheology. Upon increasing the polymer concentration, we cross successively the well defined glass and jamming transitions which delimit four different states: dilute colloidal suspension, entropic glass, jammed glass, and dense glass. Each state has a specific dynamical fingerprint dictated by two key ingredients related to particle softness: elastic contact interactions, and osmotic or steric deswelling. Soft interactions control yielding and flow of the jammed glasses. The shrinkage of the microgels makes the glass transition look smoother than in hard sphere suspensions. We quantify the relationship between the polymer concentration and the volume fraction, and show that the glass transition behaviour of soft microgels can be mapped to that of hard sphere glasses once the volume fraction is used as the control parameter. PMID- 26984382 TI - Phenotypic variability and therapeutic implications of Candida species in patients with oral lichen planus. AB - We investigated the prevalence and phenotypic variation of Candida species in oral lichen planus (OLP) and the therapeutic implications of our findings. Eighty patients with clinically and histopathologically confirmed cases of OLP (64 non erosive, 16 erosive) and a control group of 80 healthy individuals with no predisposing factors for oral candidiasis were examined for evidence of Candida infection. Oral swabs and smears were obtained for cytology and culture. Identification, speciation and antifungal susceptibility tests of Candida isolates were performed using an automated microbial identification system. Fifty percent of erosive OLP cases, 28% of non-erosive cases and none of the controls showed evidence of Candida. Candida albicans was found predominantly in non erosive OLP, while other Candida species were predominate in erosive OLP. Non Candida albicans isolates (C. glabrata, C. krusei) were resistant to the commonly used antifungals, clotrimazole and fluconazole. Candida infection is common in cases of OLP. We recommend antifungal sensitivity testing prior to antifungal therapy for the erosive form of OLP. PMID- 26984381 TI - Epithelial cell adhesion molecule in human hepatocellular carcinoma cell lines: a target of chemoresistence. AB - BACKGROUND: The low survival rate of hepatocellular carcinoma (HCC) is partly attributable to its resistance to existing chemotherapeutic agents. Until now, there have been limited chemotherapeutic agents for liver cancer. Epithelial cell adhesion molecule (EpCAM) has been found to be over-expressed during stages of carcinogenesis and has been associated with poor overall survival in many cancers. The aim of this study was to evaluate EpCAM expression in HCC and evaluate the effects of EpCAM to established chemotherapy. METHODS: Three human hepatocellular carcinoma cell lines--HepG2, Hep3B and HuH-7--were pre- and post treated with doxorubicin, 5-fluorouracil (5-FU) and cisplatin. Cell viability and EpCAM protein expression were measured by MTT assay and Western Blotting respectively. EpCAM positive cells were analyzed by flow cytometry. To evaluate the effects of doxorubicin efficacy on EpCAM positive cells, a small interfering RNA (siRNA) specific to EpCAM was transfected into the cells and treated with doxorubicin. RESULTS: EpCAM was significantly down-regulated by doxorubicin treatment in all three HCC cell lines (P <0.05 or 0.01). EpCAM expression was down-regulated by the 5-FU and cisplatin in HepG2 cells, however the EpCAM expression was up-regulated by 5-FU and cisplatin in Hep3B cell line. EpCAM expression was down-regulated by 5-FU, and up-regulated by cisplatin in Huh-7 cell line. Flow cytometry assay showed doxorubicin exposure decreased EpCAM positive cell quantities in three HCC cell lines. EpCAM siRNA knock-down attenuated cell mortality after doxorubicin exposure. CONCLUSION: All of these findings demonstrate that EpCAM is one of targets of chemoresistence. PMID- 26984384 TI - How Do Evaluators Differentiate Successful From Less-Than-Successful Experiences With Collaborative Approaches to Evaluation? AB - OBJECTIVES: In this exploratory study, we wanted to know how evaluators differentiate collaborative approaches to evaluation (CAE) perceived to be successful from those perceived to be less-than-successful. METHOD: In an online questionnaire survey, we obtained 320 responses from evaluators who practice CAE (i.e., evaluations on which program stakeholders coproduce evaluation knowledge). Respondents identified two specific CAE projects from their own experience-one they believed to be "highly successful" and another they considered "far less successful than [they] had hoped."-and offered their comments and reflections about them. They rated the respective evaluations on 5-point opinion and frequency scales about (i) antecedent stakeholder perspectives, (ii) the purposes and justifications for collaborative inquiry, and (iii) the form such inquiry takes. FINDINGS: The results showed that successful evaluations, relative to their less-than-successful counterparts, tended to reflect higher levels of agreement among stakeholders about the focal program; higher intentionality estimates of evaluation justification and espoused purposes; and wider ranges and deeper levels of stakeholder participation. No differences were found for control of technical decision-making, and evaluators tended to lead evaluation decision making, regardless of success condition. DISCUSSION: The results are discussed in terms of implications for ongoing research on CAE. PMID- 26984385 TI - [(18)F]FDG-PET/CT metabolic parameters as useful prognostic factors in cervical cancer patients treated with chemo-radiotherapy. AB - BACKGROUND: To compare the prognostic value of different anatomical and functional metabolic parameters determined using [(18)F]FDG-PET/CT with other clinical and pathological prognostic parameters in cervical cancer (CC). METHODS: Thirty-eight patients treated with standard curative doses of chemo-radiotherapy (CRT) underwent pre- and post-therapy [(18)F]FDG-PET/CT. [(18)F]FDG-PET/CT parameters including mean tumor standardized uptake values (SUV), metabolic tumor volume (MTV) and tumor glycolytic volume (TGV) were measured before the start of CRT. The post-treatment tumor metabolic response was evaluated. These parameters were compared to other clinical prognostic factors. Survival curves were estimated by using the Kaplan-Meier method. Cox regression analysis was performed to determine the independent contribution of each prognostic factor. RESULTS: After 37 months of median follow-up (range, 12-106), overall survival (OS) was 71 % [95 % confidence interval (CI), 54-88], disease-free survival (DFS) 61 % [95 % CI, 44-78] and loco-regional control (LRC) 76 % [95 % CI, 62-90]. In univariate analyses the [(18)F]FDG-PET/CT parameters unfavorably influencing OS, DFS and LRC were pre-treatment TGV-cutoff >=562 (37 vs. 76 %, p = 0.01; 33 vs. 70 %, p = 0.002; and 55 vs. 83 %, p = 0.005, respectively), mean pre-treatment tumor SUV cutoff >=5 (57 vs. 86 %, p = 0.03; 36 vs. 88 %, p = 0.004; 65 vs. 88 %, p = 0.04, respectively) and a partial tumor metabolic response after treatment (9 vs. 29 %, p = 0.0008; 0 vs. 83 %, p < 0.0001; 22 vs. 96 %, p < 0.0001, respectively). After multivariate analyses a partial tumor metabolic response after treatment remained as an independent prognostic factor unfavorably influencing DFS and LRC (RR 1:7.7, p < 0.0001, and RR 1:22.6, p = 0.0003, respectively) while the pre treatment TGV-cutoff >=562 negatively influenced OS and DFS (RR 1:2, p = 0.03, and RR 1:2.75, p = 0.05). CONCLUSIONS: Parameters capturing the pre-treatment glycolytic volume and metabolic activity of [(18)F]FDG-positive disease provide important prognostic information in patients with CC treated with CRT. The post therapy [(18)F]FDG-PET/CT uptake (partial tumor metabolic response) is predictive of disease outcome. PMID- 26984387 TI - "Choice Set" for health behavior in choice-constrained settings to frame research and inform policy: examples of food consumption, obesity and food security. AB - OBJECTIVES: Using the nexus between food consumption, food security and obesity, this paper addresses the complexity of health behavior decision-making moments that reflect relational social dynamics in context-specific dialogues, often in choice-constrained conditions. METHODS: A pragmatic review of literature regarding social determinants of health in relation to food consumption, food security and obesity was used to advance this theoretical model. RESULTS AND DISCUSSION: We suggest that health choice, such as food consumption, is based on more than the capacity and volition of individuals to make "healthy" choices, but is dialogic and adaptive. In terms of food consumption, there will always be choice-constrained conditions, along a continuum representing factors over which the individual has little or no control, to those for which they have greater agency. These range from food store geographies and inventories and food availability, logistical considerations such as transportation, food distribution, the structure of equity in food systems, state and non-government food and nutrition programs, to factors where the individual exercises a greater degree of autonomy, such as sociocultural foodways, family and neighborhood shopping strategies, and personal and family food preferences. At any given food decision-making moment, many factors of the continuum are present consciously or unconsciously when the individual makes a decision. These health behavior decision-making moments are mutable, whether from an individual perspective, or within a broader social or policy context. We review the construct of "choice set", the confluence of factors that are temporally weighted by the differentiated and relationally-contextualized importance of certain factors over others in that moment. The choice transition represents an essential shift of the choice set based on the conscious and unconscious weighting of accumulated evidence, such that people can project certain outcomes. Policies and interventions should avoid dichotomies of "good and bad" food choices or health behaviors, but focus on those issues that contribute to the weightedness of factors influencing food choice behavior at a given decision-making moment and within a given choice set. PMID- 26984386 TI - Palatal fibroblasts reduce osteoclastogenesis in murine bone marrow cultures. AB - BACKGROUND: Preclinical studies support the assumption that connective tissue grafts preserve the alveolar bone from resorption; the underlying cellular mechanisms, however, remain unknown. The cellular mechanisms may be attributed to the paracrine activity of the palatal fibroblasts. It was thus reasonable to suggest that palatal connective tissue grafts reduce the formation of osteoclasts. METHODS: To test this hypothesis, human palatal fibroblasts were examined for their capacity to modulate the formation of osteoclasts in murine bone marrow cultures exposed to RANKL, M-CSF and TGF-beta1. Osteoclastogenesis was determined by tartrate-resistant acid phosphatase (TRAP) staining and gene expression analysis. The formation of antigen presenting cells was based on the expression of CD14 and costimmulatory molecules of antigen presenting cells. The paracrine interaction of fibroblasts and the bone marrow was modeled in vitro with inserts of cell-occlusive membranes. RESULTS: In cocultures without cell-to cell contact, palatal fibroblasts caused a decrease in the expression of the osteoclast marker genes in bone marrow cells; calcitonin receptors, cathepsin K, TRAP, and osteoclast-associated receptor. Also the number of TRAP positive multinucleated cells was decreased in the presence of fibroblasts. Notably, palatal fibroblasts increased the expression of CD14 and the co-stimulatory proteins CD40, CD80, and CD86 in bone marrow cells. Bone marrow cells had no considerable impact on fibroblast viability and proliferation marker genes. With regard to cell distribution, osteoclasts were most prominent in the center of the membranes, while fibroblasts accumulated immediately adjacent to the border of the insert forming a ring-like structure on the surface of the culture plate. CONCLUSION: The data suggest that palatal fibroblasts provide a paracrine environment that reduces osteoclastogenesis and increases markers of antigen presenting cells. Morover, the paracrine model revealed a joint activity between palatal fibroblasts and bone marrow cells visualized by the characteristic cell distribution in the two separated compartments. PMID- 26984388 TI - Cobimetinib Plus Vemurafenib: A Review in BRAF (V600) Mutation-Positive Unresectable or Metastatic Melanoma. AB - The MEK inhibitor cobimetinib (Cotellic((r))) is indicated for the treatment of patients with BRAF (V600) mutation-positive unresectable or metastatic melanoma, in combination with the BRAF inhibitor vemurafenib (Zelboraf((r))). In the pivotal coBRIM trial, previously untreated patients with BRAF (V600) mutation positive unresectable, stage IIIC or stage IV melanoma received cobimetinib 60 mg once daily for the first 21 days of each 28-day cycle plus vemurafenib 960 mg twice daily or vemurafenib alone. Compared with vemurafenib alone, cobimetinib plus vemurafenib significantly prolonged progression-free survival (primary endpoint) and was associated with a significantly higher overall response rate and significantly prolonged overall survival. Cobimetinib plus vemurafenib had a manageable tolerability profile. In conclusion, cobimetinib plus vemurafenib is a valuable option for use in BRAF (V600) mutation-positive unresectable or metastatic melanoma. PMID- 26984389 TI - Growing up in care. PMID- 26984390 TI - Association of Plasma Small-Molecule Intermediate Metabolites With Age and Body Mass Index Across Six Diverse Study Populations. AB - BACKGROUND: Older age and obesity are associated with metabolic dysregulation; the mechanism by which these factors impact metabolism across the lifespan is important, but relatively unknown. We evaluated a panel of amino acids (AAs) and acylcarnitines (ACs) to identify effects of age and adiposity (body mass index) on circulating small-molecule metabolites in a meta-analysis of six diverse study populations. METHODS: Targeted metabolic profiling was performed in six independent studies, representing 739 subjects with a broad range of age, body mass index, health states, and ethnic origin. Principal components analysis was performed on log-normalized values for AAs and ACs separately, generating one AC factor and two AA factors for each study. A common AC factor consisted primarily of acetylcarnitine, medium-chain AC, and several long-chain AC. AA Factor 1 consisted primarily of large neutral AAs. Glycine was its own factor. RESULTS: Metabolic profiling and factor analysis identified clusters of related metabolites of lipid and AA metabolism that were consistently associated with age and body mass in a series of studies with a broad range of age, body mass index, and health status. An inverse association of glycine with body mass index and male gender supports its role as a marker of favorable metabolic health. CONCLUSIONS: An important focus of future investigations should be to determine whether these clusters of metabolic intermediates are possible early predictors of health outcomes associated with body mass; are involved with accelerated aging; are involved in the causative pathway of aging; and how modification of these metabolic pathways impact the biology of aging. PMID- 26984391 TI - Disentangling Cognitive-Frailty: Results From the Gait and Brain Study. AB - BACKGROUND: Cognitive-frailty, defined as the presence of both frailty and cognitive impairment, is proposed as a distinctive entity that predicts dementia. However, it remains controversial whether frailty alone, cognitive-frailty, or the combination of cognitive impairment and slow gait pose different risks of incident dementia. METHODS: Two hundred and fifty-two older adults free of dementia at baseline (mean age 76.6+/-8.6 years) were followed up to 5 years with bi-annual visits including medical, cognitive, and gait assessments. Incident all cause of dementia and cognitive decline were the main outcomes. Frailty was defined using validated phenotypic criteria. Cognition was assessed using the Montreal Cognitive Assessment while gait was assessed using an electronic walkway. Cox Proportional Hazards models were used to estimate the risk of cognitive decline and dementia for frailty, cognitive-frailty, and gait and cognition models. RESULTS: Fifty-three participants experienced cognitive decline and 27 progressed to dementia (incident rate: 73/1,000 person-years). Frailty participants had a higher prevalence of cognitive impairment compared with those without frailty (77% vs. 54%, p = .02) but not significant risk to incident dementia. Cognitive-frailty increased incident rate (80/1,000 person-years) but not risk for progression to dementia. The combination of slow gait and cognitive impairment posed the highest risk for progression to dementia (hazard ratio: 35.9, 95% confidence interval: 4.0-319.2; p = 0.001, incident rate: 130/1,000 person-years). None of the models explored significantly predicted cognitive decline. CONCLUSIONS: Combining a simple motor test, such as gait velocity, with a reliable cognitive test like the Montreal Cognitive Assessment is superior than the cognitive-frailty construct to detect individuals at risk for dementia. Cognitive-frailty may embody two different manifestations, slow gait and low cognition, of a common underlying mechanism. PMID- 26984392 TI - Cross-Sectional and Longitudinal Associations Between Adiposity and Walking Endurance in Adults Age 60-79. AB - BACKGROUND: The impact of excess weight on current and future walking endurance in nondisabled persons is unclear. This study examines the association between obesity and walking endurance among nondisabled persons both in late mid-life and early old age. METHODS: Participants in the Baltimore Longitudinal Study of Aging aged 60-79 years (n = 406) who reported no walking limitations, and completed a 400-meter walk "as quickly as possible" without lower-extremity pain, and had a follow-up assessment within 1.7-4.2 years. Adiposity was assessed by weight, body mass index (BMI), BMI category, and percent fat mass by DXA. RESULTS: Adjusting for age, sex, race, height, and physical activity, all adiposity measures were cross-sectionally associated with slower 400 meter time in both 60-69 and 70 to 79-year-olds (weight: beta = 1.0 and 1.2; BMI: beta = 2.8 and 3.6; and percent fat mass: beta = 2.0 and 2.0, respectively, all p < .001). With additional adjustment for initial 400-meter performance and follow-up time, in 60- to 69 year-olds, change in 400-meter time (positive beta indicates decline) was associated with all adiposity measures (weight: beta = 0.4; BMI: beta = 1.0; and percent fat mass: beta = 0.5; all p <= .05) but not in the older group (weight: beta = -0.4; BMI: beta = -1.2; and percent fat mass: beta = -0.2; all p >= .17). CONCLUSION: Excess weight and adiposity were associated with worse walking endurance in nondisabled persons aged 60-79 years and predicted accelerated decline in endurance in late mid-life adults. Weight management for mobility independence may be best targeted in obese persons approaching traditional retirement age. PMID- 26984395 TI - MUC5B silencing reduces chemo-resistance of MCF-7 breast tumor cells and impairs maturation of dendritic cells. AB - Mucins participate in cancer progression by regulating cell growth, adhesion, signaling, apoptosis or chemo-resistance to drugs. The secreted mucin MUC5B, the major component of the respiratory tract mucus, is aberrantly expressed in breast cancer, where it could constitute a cancer biomarker. In this study we evaluated the role of MUC5B in breast cancer by gene silencing the MUC5B expression with short hairpin RNA on MCF-7 cells. We found that MUC5B-silenced MCF-7 cells have a reduced capacity to grow, adhere and form cell colonies. Interestingly, MUC5B knock-down increased the sensitivity to death induced by chemotherapeutic drugs. We also show that MUC5B silencing impaired LPS-maturation of DCs, and production of cytokines. Furthermore, MUC5B knock-down also influenced DC-differentiation and activation since it resulted in an upregulation of IL-1beta, IL-6 and IL-10, cytokines that might be involved in cancer progression. Thus, MUC5B could enhance the production of LPS-induced cytokines, suggesting that the use of MUC5B-based cancer vaccines combined with DC-maturation stimuli, could favor the induction of an antitumor immune response. PMID- 26984394 TI - Interrogating concepts of care in the HIV care continuum: ethnographic insights from the implementation of a "Universal Test and Treat" approach in South Africa. AB - South Africa currently sustains the largest antiretroviral treatment (ART) programme in the world. The number of people on ART is set to grow even more in the coming years as incidence remains stable, people on ART stay healthy, and guidelines for initiation become increasingly inclusive. The South African public health sector has increasingly relied on community- and home-based lay and professional "carers" to carry out the everyday tasks of rolling out the ART programme. Drawing on ethnographic research in one locality in the Western Cape, the paper explores the care practices of two such groups of carers implementing a 'Universal Test and Treat' (UTT) approach. The UTT approach being evlauated in this place is based on one model of the HIV treatment cascade, or care continuum, which focuses on the steps necessary to identify and link HIV-positive individuals to care and retain them in lifelong HIV treatment. In this context, community-based care workers are responsible for carrying out several discrete steps in the HIV care continuum, including testing people for HIV, linking HIV positive individuals to care, and supporting adherence. In order to retain clients within the continuum, however, carers also perform other forms of labour that stretch their care work beyond more bounded notions of a stepwise progression of care. These broader forms of care, which can be material, emotional, social or physical in nature, appear alongside the more structured technical and biomedical tasks formally expected of carers. We argue that understanding the dynamics of these more distributed and relational forms of care is essential for the effective implementation of the care continuum, and of the UTT approach, in diverse contexts. PMID- 26984396 TI - High Early Suicide Risk in Elderly Patients After Self-Poisoning. AB - This article reports the findings of a follow-up study of suicide mortality in elderly patients after an index episode of self-poisoning. A total of 222 consecutive patients (143 female) aged 65 years or older (mean age 76.5 years; range 65-100) presenting at the emergency department of the Karolinska University Hospital after self-poisoning during 1994-2000, were followed up for the cause of death by January 1, 2006. Survival analysis was applied to study suicide and death risk. Of the 15 suicides, 13 (87%) occurred during the first year after the index episode of self-poisoning (cumulative suicide risk 6.2%). The risk of dying of all causes during the first year was increased fourfold. Self-poisoning in both elderly men and women is associated with high early suicide risk. PMID- 26984393 TI - VCP and ATL1 regulate endoplasmic reticulum and protein synthesis for dendritic spine formation. AB - Imbalanced protein homeostasis, such as excessive protein synthesis and protein aggregation, is a pathogenic hallmark of a range of neurological disorders. Here, using expression of mutant proteins, a knockdown approach and disease mutation knockin mice, we show that VCP (valosin-containing protein), together with its cofactor P47 and the endoplasmic reticulum (ER) morphology regulator ATL1 (Atlastin-1), regulates tubular ER formation and influences the efficiency of protein synthesis to control dendritic spine formation in neurons. Strengthening the significance of protein synthesis in dendritic spinogenesis, the translation blocker cyclohexamide and the mTOR inhibitor rapamycin reduce dendritic spine density, while a leucine supplement that increases protein synthesis ameliorates the dendritic spine defects caused by Vcp and Atl1 deficiencies. Because VCP and ATL1 are the causative genes of several neurodegenerative and neurodevelopmental disorders, we suggest that impaired ER formation and inefficient protein synthesis are significant in the pathogenesis of multiple neurological disorders. PMID- 26984397 TI - Erratum: Histological criteria for atypical pituitary adenomas--data from the German pituitary adenoma registry suggests modifications. AB - The original version of this article unfortunately contained a mistake in the author list. The name of one co-author is written wrong in the final version of the article; Dr Hans Ulrich Knappe should be Ulrich Johannes Knappe. The updated author list is provided below: Christian P. Miermeister, Stephan Petersenn, Michael Buchfelder, Rudolf Fahlbusch, Dieter K.Ludecke, Annett Holsken, Markus Bergmann, Ulrich Johannes Knappe, Volkmar H. Hans, Jorg Flitsch, Wolfgang Saeger and Rolf Buslei. PMID- 26984398 TI - Genome-wide identification and characterization of Glyceraldehyde-3-phosphate dehydrogenase genes family in wheat (Triticum aestivum). AB - BACKGROUND: Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a central enzyme in glycolysi, we performed genome-wide identification of GAPDH genes in wheat and analyzed their structural characteristics and expression patterns under abiotic stress in wheat. RESULTS: A total of 22 GAPDH genes were identified in wheat cv. Chinese spring; the phylogenetic and structure analysis showed that these GAPDH genes could be divided into four distinct subfamilies. The expression profiles of GAPDH genes showed tissue specificity all over plant development stages. The qRT PCR results revealed that wheat GAPDHs were involved in several abiotic stress response. CONCLUSIONS: Wheat carried 22 GAPDH genes, representing four types of plant GAPDHs (gapA/B, gapC, gapCp and gapN). Whole genome duplication and segmental duplication might account for the expansion of wheat GAPDHs. Expression analysis implied that GAPDHs play roles in plants abiotic stress tolerance. PMID- 26984400 TI - [15 years of Competence Nets in Medicine]. PMID- 26984399 TI - [CAPNETZ. The competence network for community-acquired pneumonia (CAP)]. AB - CAPNETZ is a medical competence network for community-acquired pneumonia (CAP), which was funded by the German Ministry for Education and Research. It has accomplished seminal work on pneumonia over the last 15 years. A unique infrastructure was established which has so far allowed us to recruit and analyze more than 11,000 patients. The CAPNETZ cohort is the largest cohort worldwide and the results obtained relate to all relevant aspects of CAP management (epidemiology, risk stratification via biomarkers or clinical scores, pathogen spectrum, pathogen resistance, antibiotic management, prevention and health care research). Results were published in more than 150 journals and informed the preparation and update of the national S3-guideline. CAPNETZ was also the foundation for further networks like the Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis) (PROGRESS), the Systems Medicine of Community Acquired Pneumonia Network (CAPSyS) and SFB-TR84 (Sonderforschungsbereich - Transregio 84). The main recipients (Charite Berlin, University Clinic Ulm and the Hannover Medical School) founded the CAPNETZ foundation and transferred all data and materials rights to this foundation. Moreover, the ministry granted the CAPNETZ foundation the status of being eligible to apply for research proposals and receive research funds. Since 2013 the CAPNETZ foundation has been an associated member of the German Center for Lung Research (DZL). Thus, a solid foundation has been set up for CAPNETZ to continue its success story. PMID- 26984401 TI - Validation of two algorithms for managing children with a non-blanching rash. AB - BACKGROUND: Paediatricians are concerned that children who present with a non blanching rash (NBR) may have meningococcal disease (MCD). Two algorithms have been devised to help identify which children with an NBR have MCD. AIM: To evaluate the NBR algorithms' ability to identify children with MCD. METHODS: The Newcastle-Birmingham-Liverpool (NBL) algorithm was applied retrospectively to three cohorts of children who had presented with NBRs. This algorithm was also piloted in four hospitals, and then used prospectively for 12 months in one hospital. The National Institute for Health and Care Excellence (NICE) algorithm was validated retrospectively using data from all cohorts. RESULTS: The cohorts included 625 children, 145 (23%) of whom had confirmed or probable MCD. Paediatricians empirically treated 324 (52%) children with antibiotics. The NBL algorithm identified all children with MCD and suggested treatment for a further 86 children (sensitivity 100%, specificity 82%). One child with MCD did not receive immediate antibiotic treatment, despite this being suggested by the algorithm. The NICE algorithm suggested 382 children (61%) who should be treated with antibiotics. This included 141 of the 145 children with MCD (sensitivity 97%, specificity 50%). CONCLUSIONS: These algorithms may help paediatricians identify children with MCD who present with NBRs. The NBL algorithm may be more specific than the NICE algorithm as it includes fewer features suggesting MCD. The only significant delay in treatment of MCD occurred when the algorithms were not followed. PMID- 26984402 TI - Hunting dogs as sentinel animals for monitoring infections with Trichinella spp. in wildlife. AB - BACKGROUND: Nematode parasites of the genus Trichinella are important foodborne pathogens transmitted by ingestion of striated muscles harbouring infective larvae. Wild carnivorous and omnivorous animals are the most important reservoirs of these parasites. Hunting activities play an important role in Trichinella spp. EPIDEMIOLOGY: The aim of the present work was to assess if serological detection of anti-Trichinella IgG in hunting dogs can be a tool to indirectly monitor Trichinella spp. infections in wildlife. METHODS: An ELISA and a Western blot (Wb) were developed and validated. To validate the assays, serum samples were collected from 598 dogs considered to be Trichinella-free, 15 naturally infected dogs, and six experimentally infected foxes. Sera were tested by ELISA with Trichinella spiralis excretory/secretory antigens. The diagnostic sensitivity and specificity of ELISA were 100 % (95 % CI: 83.89-100 %) and 95.65 % (95 % CI: 93.69-97.14 %), respectively. Sera from Trichinella-infected dogs/foxes tested by Wb showed a three-band pattern ranging from 48 to 72 kDa. Since the prevalence of Toxocara canis is very high in dogs, the specificity of the ELISA and Wb was further assessed by testing sera for anti-T. canis IgG using T. canis excretory/secretory antigens. No cross-reactivity was observed. To evaluate the test's reliability in the field, serum samples were collected from wild boar hunting dogs from Central Italy where Trichinella britovi was circulating among wildlife. RESULTS: Out of 384 hunting dog sera, 189 (49.2 %) tested positive by ELISA and of these, 56 (29.6 %) tested positive by Wb, showing an overall prevalence of 14.6 % (56/384) in the wild boar hunting dog population of the investigated area. The serological prevalence in hunting dogs was significantly (P < 0.001) associated with the hunting district's altitude. This is in agreement with previous investigations, which had shown that the prevalence of T. britovi in wildlife was higher in mountainous areas than in lowland areas of Italy. CONCLUSION: The results suggest that the circulation of Trichinella spp. among wildlife can be monitored by testing sera from hunting dogs, which could act as sentinel animals of Trichinella spp. circulation in wildlife. PMID- 26984403 TI - ICP4-induced miR-101 attenuates HSV-1 replication. AB - Hepes simplex Virus type 1 (HSV-1) is an enveloped DNA virus that can cause lytic and latent infection. miRNAs post-transcriptionally regulate gene expression, and our previous work has indicated that HSV-1 infection induces miR-101 expression in HeLa cells. The present study demonstrates that HSV-1-induced miR-101 is mainly derived from its precursor hsa-mir-101-2, and the HSV-1 immediate early gene ICP4 (infected-cell polypeptide 4) directly binds to the hsa-mir-101-2 promoter to activate its expression. RNA-binding protein G-rich sequence factor 1 (GRSF1) was identified as a new target of miR-101; GRSF1 binds to HSV-1 p40 mRNA and enhances its expression, facilitating viral proliferation. Together, ICP4 induces miR-101 expression, which downregulates GRSF1 expression and attenuates the replication of HSV-1. This allows host cells to maintain a permissive environment for viral replication by preventing lytic cell death. These findings indicate that HSV-1 early gene expression modulates host miRNAs to regulate molecular defense mechanisms. This study provides novel insight into host-virus interactions in HSV-1 infection and may contribute to the development of antiviral therapeutics. PMID- 26984404 TI - Metabolite Regulation of Nuclear Localization of Carbohydrate-response Element binding Protein (ChREBP): ROLE OF AMP AS AN ALLOSTERIC INHIBITOR. AB - The carbohydrate-response element-binding protein (ChREBP) is a glucose responsive transcription factor that plays an essential role in converting excess carbohydrate to fat storage in the liver. In response to glucose levels, ChREBP is regulated by nuclear/cytosol trafficking via interaction with 14-3-3 proteins, CRM-1 (exportin-1 or XPO-1), or importins. Nuclear localization of ChREBP was rapidly inhibited when incubated in branched-chain alpha-ketoacids, saturated and unsaturated fatty acids, or 5-aminoimidazole-4-carboxamide ribonucleotide. Here, we discovered that protein-free extracts of high fat-fed livers contained, in addition to ketone bodies, a new metabolite, identified as AMP, which specifically activates the interaction between ChREBP and 14-3-3. The crystal structure showed that AMP binds directly to the N terminus of ChREBP-alpha2 helix. Our results suggest that AMP inhibits the nuclear localization of ChREBP through an allosteric activation of ChREBP/14-3-3 interactions and not by activation of AMPK. AMP and ketone bodies together can therefore inhibit lipogenesis by restricting localization of ChREBP to the cytoplasm during periods of ketosis. PMID- 26984405 TI - FoxO1 Deacetylation Decreases Fatty Acid Oxidation in beta-Cells and Sustains Insulin Secretion in Diabetes. AB - Pancreatic beta-cell dysfunction contributes to onset and progression of type 2 diabetes. In this state beta-cells become metabolically inflexible, losing the ability to select between carbohydrates and lipids as substrates for mitochondrial oxidation. These changes lead to beta-cell dedifferentiation. We have proposed that FoxO proteins are activated through deacetylation-dependent nuclear translocation to forestall the progression of these abnormalities. However, how deacetylated FoxO exert their actions remains unclear. To address this question, we analyzed islet function in mice homozygous for knock-in alleles encoding deacetylated FoxO1 (6KR). Islets expressing 6KR mutant FoxO1 have enhanced insulin secretion in vivo and ex vivo and decreased fatty acid oxidation ex vivo Remarkably, the gene expression signature associated with FoxO1 deacetylation differs from wild type by only ~2% of the >4000 genes regulated in response to re-feeding. But this narrow swath includes key genes required for beta-cell identity, lipid metabolism, and mitochondrial fatty acid and solute transport. The data support the notion that deacetylated FoxO1 protects beta-cell function by limiting mitochondrial lipid utilization and raise the possibility that inhibition of fatty acid oxidation in beta-cells is beneficial to diabetes treatment. PMID- 26984407 TI - Amidase Activity of AmiC Controls Cell Separation and Stem Peptide Release and Is Enhanced by NlpD in Neisseria gonorrhoeae. AB - The human-restricted pathogen Neisseria gonorrhoeae encodes a single N acetylmuramyl-l-alanine amidase involved in cell separation (AmiC), as compared with three largely redundant cell separation amidases found in Escherichia coli (AmiA, AmiB, and AmiC). Deletion of amiC from N. gonorrhoeae results in severely impaired cell separation and altered peptidoglycan (PG) fragment release, but little else is known about how AmiC functions in gonococci. Here, we demonstrated that gonococcal AmiC can act on macromolecular PG to liberate cross-linked and non-cross-linked peptides indicative of amidase activity, and we provided the first evidence that a cell separation amidase can utilize a small synthetic PG fragment as substrate (GlcNAc-MurNAc(pentapeptide)-GlcNAc-MurNAc(pentapeptide)). An investigation of two residues in the active site of AmiC revealed that Glu-229 is critical for both normal cell separation and the release of PG fragments by gonococci during growth. In contrast, Gln-316 has an autoinhibitory role, and its mutation to lysine resulted in an AmiC with increased enzymatic activity on macromolecular PG and on the synthetic PG derivative. Curiously, the same Q316K mutation that increased AmiC activity also resulted in cell separation and PG fragment release defects, indicating that activation state is not the only factor determining normal AmiC activity. In addition to displaying high basal activity on PG, gonococcal AmiC can utilize metal ions other than the zinc cofactor typically used by cell separation amidases, potentially protecting its ability to function in zinc-limiting environments. Thus gonococcal AmiC has distinct differences from related enzymes, and these studies revealed parameters for how AmiC functions in cell separation and PG fragment release. PMID- 26984410 TI - Brodie's abscess following percutaneous fixation of distal radius fracture in a child. AB - We report the case of a Brodie's abscess presenting five and a half years following closed reduction and percutaneous pinning of a distal radius fracture. The index surgery was complicated by a pin site infection that was treated successfully with antibiotics. The patient represented with forearm pain years later, and radiological investigations revealed a Brodie's abscess in the distal radius at the site of the previous Kirschner wires. The Brodie's abscess was managed through surgical curettage and antibiotics. Staphylococcus aureus and diphtheroid organisms were cultured from the intraoperative specimens. A Brodie's abscess is a form of localised subacute osteomyelitis, which usually occurs in the metaphysis of long bones and can mimic malignancy. Previous trauma or surgery has been implicated as predisposing factors. We have only identified one previously reported case of Brodie's abscess following percutaneous pinning. Ours is the first reported case in an adolescent. The aim of this paper is to raise awareness of this rare complication and review the current literature. PMID- 26984406 TI - Red Blood Cell Susceptibility to Pneumolysin: CORRELATION WITH MEMBRANE BIOCHEMICAL AND PHYSICAL PROPERTIES. AB - This study investigated the effect of the biochemical and biophysical properties of the plasma membrane as well as membrane morphology on the susceptibility of human red blood cells to the cholesterol-dependent cytolysin pneumolysin, a key virulence factor of Streptococcus pneumoniae, using single cell studies. We show a correlation between the physical properties of the membrane (bending rigidity and surface and dipole electrostatic potentials) and the susceptibility of red blood cells to pneumolysin-induced hemolysis. We demonstrate that biochemical modifications of the membrane induced by oxidative stress, lipid scrambling, and artificial cell aging modulate the cell response to the toxin. We provide evidence that the diversity of response to pneumolysin in diabetic red blood cells correlates with levels of glycated hemoglobin and that the mechanical properties of the red blood cell plasma membrane are altered in diabetes. Finally, we show that diabetic red blood cells are more resistant to pneumolysin and the related toxin perfringolysin O relative to healthy red blood cells. Taken together, these studies indicate that the diversity of cell response to pneumolysin within a population of human red blood cells is influenced by the biophysical and biochemical status of the plasma membrane and the chemical and/or oxidative stress pre-history of the cell. PMID- 26984408 TI - The beta-Arrestins: Multifunctional Regulators of G Protein-coupled Receptors. AB - The beta-arrestins (betaarrs) are versatile, multifunctional adapter proteins that are best known for their ability to desensitize G protein-coupled receptors (GPCRs), but also regulate a diverse array of cellular functions. To signal in such a complex fashion, betaarrs adopt multiple conformations and are regulated at multiple levels to differentially activate downstream pathways. Recent structural studies have demonstrated that betaarrs have a conserved structure and activation mechanism, with plasticity of their structural fold, allowing them to adopt a wide array of conformations. Novel roles for betaarrs continue to be identified, demonstrating the importance of these dynamic regulators of cellular signaling. PMID- 26984411 TI - The use of recombinant morphogenic protein-2(rhBMP-2) in children undergoing revision surgery for persistent non-union. AB - The purpose of the study was to evaluate the safety and efficacy with the use of BMP-2 for treating persistent non-unions in children with underlying complex conditions. Between October 2006 and November 2010 in our unit, 15 patients were treated with rhBMP-2 to enhance bone union. There were nine females and six males with a mean age of 9.5 years (range 4-15) at time of surgery. Seventy-five per cent of the patients required revision of internal fixation with insertion of rhBMP-2 to the non-union site, and the reminder had freshening of the non-union site with rhBMP-2 application. Patients had undergone a mean of 2 (1-5) operations prior to implantation of rhBMP-2. All the patients in the study group were available for review with mean follow-up of 44 months (range 21-70). The mean time to union was 16 weeks (range 10-28 weeks). No adverse events related to BMP-2 application were noted in our study group. Healing occurred clinically and radiographically in 16 of the 17 sites. Our study demonstrates that BMP-2 enhances healing of the persistent non-unions without any adverse events. PMID- 26984412 TI - Brain dopamine and serotonin transporter binding are associated with visual attention bias for food in lean men. AB - BACKGROUND: In rodents, the striatal dopamine (DA) system and the (hypo)thalamic serotonin (5-HT) system are involved in the regulation of feeding behavior. In lean humans, little is known about the relationship between these brain neurotransmitter systems and feeding. We studied the relationship between striatal DA transporters (DAT) and diencephalic 5-HT transporters (SERT), behavioral tasks and questionnaires, and food intake. METHOD: We measured striatal DAT and diencephalic SERT binding with [123I]FP-CIT SPECT in 36 lean male subjects. Visual attention bias for food (detection speed and distraction time) and degree of impulsivity were measured using response-latency-based computer tasks. Craving and emotional eating were assessed with questionnaires and ratings of hunger by means of VAS scores. Food intake was assessed through a self-reported online diet journal. RESULTS: Striatal DAT and diencephalic SERT binding negatively correlated with food detection speed (p = 0.008, r = -0.50 and p = 0.002, r = -0.57, respectively), but not with food distraction time, ratings of hunger, craving or impulsivity. Striatal DAT and diencephalic SERT binding did not correlate with free choice food intake, whereas food detection speed positively correlated with total caloric intake (p = 0.001, r = 0.60), protein intake (p = 0.01, r = 0.44), carbohydrate intake (p = 0.03, r = 0.39) and fat intake (p = 0.06, r = 0.35). CONCLUSIONS: These results indicate a role for the central 5-HT and DA system in the regulation of visual attention bias for food, which contributes to the motivation to eat, in non-obese, healthy humans. In addition, this study confirms that food detection speed, measured with the latency-based computer task, positively correlates with total food and macronutrient intake. PMID- 26984409 TI - p75 Neurotrophin Receptor Signaling Activates Sterol Regulatory Element-binding Protein-2 in Hepatocyte Cells via p38 Mitogen-activated Protein Kinase and Caspase-3. AB - Nerve growth factor (NGF) influences the survival and differentiation of a specific population of neurons during development, but its role in non-neuronal cells has been less studied. We observed here that NGF and its pro-form, pro-NGF, are elevated in fatty livers from leptin-deficient mice compared with controls, concomitant with an increase in low density lipoprotein receptors (LDLRs). Stimulation of mouse primary hepatocytes with NGF or pro-NGF increased LDLR expression through the p75 neurotrophin receptor (p75NTR). Studies using Huh7 human hepatocyte cells showed that the neurotrophins activate the sterol regulatory element-binding protein-2 (SREBP2) that regulates genes involved in lipid metabolism. The mechanisms for this were related to stimulation of p38 mitogen-activated protein kinase (p38 MAPK) and activation of caspase-3 and SREBP2 cleavage following NGF and pro-NGF stimulations. Cell fractionation experiments showed that caspase-3 activity was increased particularly in the membrane fraction that harbors SREBP2 and caspase-2. Experiments showed further that caspase-2 interacts with pro-caspase-3 and that p38 MAPK reduced this interaction and caused caspase-3 activation. Because of the increased caspase-3 activity, the cells did not undergo cell death following p75NTR stimulation, possibly due to concomitant activation of nuclear factor-kappaB (NF-kappaB) pathway by the neurotrophins. These results identify a novel signaling pathway triggered by ligand-activated p75NTR that via p38 MAPK and caspase-3 mediate the activation of SREBP2. This pathway may regulate LDLRs and lipid uptake particularly after injury or during tissue inflammation accompanied by an increased production of growth factors, including NGF and pro-NGF. PMID- 26984413 TI - Are all psychotherapies equally effective in the treatment of adult depression? The lack of statistical power of comparative outcome studies. AB - More than 100 comparative outcome trials, directly comparing 2 or more psychotherapies for adult depression, have been published. We first examined whether these comparative trials had sufficient statistical power to detect clinically relevant differences between therapies of d=0.24. In order to detect such an effect size, power calculations showed that a trial would need to include 548 patients. We selected 3 recent meta-analyses of psychotherapies for adult depression (cognitive behaviour therapy (CBT), interpersonal psychotherapy and non-directive counselling) and examined the number of patients included in the trials directly comparing other psychotherapies. The largest trial comparing CBT with another therapy included 178 patients, and had enough power to detect a differential effect size of only d=0.42. None of the trials in the 3 meta analyses had enough power to detect effect sizes smaller than d=0.34, but some came close to the threshold for detecting a clinically relevant effect size of d=0.24. Meta-analyses may be able to solve the problem of the low power of individual trials. However, many of these studies have considerable risk of bias, and if we only focused on trials with low risk of bias, there would no longer be enough studies to detect clinically relevant effects. We conclude that individual trials are heavily underpowered and do not even come close to having sufficient power for detecting clinically relevant effect sizes. Despite this large number of trials, it is still not clear whether there are clinically relevant differences between these therapies. PMID- 26984415 TI - Pathology and Surgical Treatment of High-Grade Pancreatic Neuroendocrine Carcinoma: an Evolving Landscape. AB - Pancreatic neuroendocrine neoplasms (PNENs) are rare, accounting for less than 5% of all pancreatic tumors. High-grade pancreatic neuroendocrine carcinomas (hgPNECs) represent about 5% of all PNENs. They show highly aggressive behavior with dismal prognosis. Throughout the last two decades, there has been a notable progress in basic and clinical research of PNENs and a therapeutic trend towards both more aggressive and minimally invasive surgery. Despite these advances, hgPNECs as a distinct clinical entity remains largely unexplored among surgeons. This review of current development in pathology reporting and surgical treatment of hgPNECs aims at increasing the awareness of an evolving field in pancreatic surgery. PMID- 26984416 TI - What Is the Place of PARP Inhibitors in Ovarian Cancer Treatment? AB - Poly-ADP-ribose polymerase (PARP) inhibitors have been one of the most exciting developments in the treatment of ovarian cancer in recent years. Demonstration of anti-cancer activity has led to the European Medicines Agency (EMA) approval of the PARP inhibitor (PARPi) olaparib as maintenance therapy in women with BRCA mutated (BRCAm) ovarian cancer with platinum-sensitive recurrence following response to platinum therapy and the US Food and Drug Administration (US FDA) approval of olaparib in relapsed germline BRCA-mutated (gBRCAm) ovarian cancer in women who have received at least three prior chemotherapy treatments, both occurring in 2014. Additional trials are underway or awaiting final analysis with olaparib, other PARPis, and PARPi combinations to further elucidate the activity of these drugs in various clinical settings. This review will focus on the current clinical experience and ongoing trials with PARPis in ovarian cancer. PMID- 26984417 TI - The Effect of Excess Electron and hole on CO2 Adsorption and Activation on Rutile (110) surface. AB - CO2 capture and conversion into useful chemical fuel attracts great attention from many different fields. In the reduction process, excess electron is of key importance as it participates in the reaction, thus it is essential to know whether the excess electrons or holes affect the CO2 conversion. Here, the first principles calculations were carried out to explore the role of excess electron on adsorption and activation of CO2 on rutile (110) surface. The calculated results demonstrate that CO2 can be activated as CO2 anions or CO2 cation when the system contains excess electrons and holes. The electronic structure of the activated CO2 is greatly changed, and the lowest unoccupied molecular orbital of CO2 can be even lower than the conduction band minimum of TiO2, which greatly facilities the CO2 reduction. Meanwhile, the dissociation process of CO2 undergoes an activated CO2(-) anion in bend configuration rather than the linear, while the long crossing distance of proton transfer greatly hinders the photocatalytic reduction of CO2 on the rutile (110) surface. These results show the importance of the excess electrons on the CO2 reduction process. PMID- 26984414 TI - Improving Systemic Chemotherapy for Bladder Cancer. AB - Systemic chemotherapy is integral to the management of muscle-invasive and metastatic bladder cancer (BCa). Neoadjuvant chemotherapy has been increasingly utilized for muscle-invasive BCa over the past several years, and several options for cisplatin-based regimens have emerged. Adjuvant chemotherapy may be considered for select patients who did not receive neoadjuvant therapy. Systemic chemotherapy added to radiotherapy is a critical component of a bladder preserving approach and superior to radiotherapy alone. Cisplatin-based chemotherapy has been the mainstay for metastatic BCa for more than three decades. Novel targeted agents are in development fueled by the recent molecular characterization of BCa. Recent trials of immunotherapy have demonstrated the possibility of a less toxic and potentially more effective treatment for metastatic disease. It is an extremely exciting time for BCa research, and much needed improvements in systemic treatment are most certainly on the horizon. PMID- 26984418 TI - Eating in mice with gastric bypass surgery causes exaggerated activation of brainstem anorexia circuit. AB - BACKGROUND/OBJECTIVE: Obesity and metabolic diseases are at an alarming level globally and increasingly affect children and adolescents. Gastric bypass and other bariatric surgeries have proven remarkably successful and are increasingly performed worldwide. Reduced desire to eat and changes in eating behavior and food choice account for most of the initial weight loss and diabetes remission after surgery, but the underlying mechanisms of altered gut-brain communication are unknown. SUBJECTS/METHODS: To explore the potential involvement of a powerful brainstem anorexia pathway centered around the lateral parabrachial nucleus (lPBN), we measured meal-induced neuronal activation by means of c-Fos immunohistochemistry in a new high-fat diet-induced obese mouse model of Roux-en Y gastric bypass (RYGB) at 10 and 40 days after RYGB or sham surgery. RESULTS: Voluntary ingestion of a meal 10 days after RYGB, but not after sham surgery, strongly and selectively activates calcitonin gene-related peptide neurons in the external lPBN as well as neurons in the nucleus tractus solitarius, area postrema and medial amygdala. At 40 days after surgery, meal-induced activation in all these areas was greatly diminished and did not reach statistical significance. CONCLUSIONS: The neural activation pattern and dynamics suggest a role of the brainstem anorexia pathway in the early effects of RYGB on meal size and food intake that may lead to adaptive neural and behavioral changes involved in the control of food intake and body weight at a lower level. However, selective inhibition of this pathway will be required for a more causal implication. PMID- 26984419 TI - Nitric oxide/cGMP/PKG signaling pathway activated by M1-type muscarinic acetylcholine receptor cascade inhibits Na+-activated K+ currents in Kenyon cells. AB - The interneurons of the mushroom body, known as Kenyon cells, are essential for the long-term memory of olfactory associative learning in some insects. Some studies have reported that nitric oxide (NO) is strongly related to this long term memory in Kenyon cells. However, the target molecules and upstream and downstream NO signaling cascades are not completely understood. Here we analyzed the effect of the NO signaling cascade on Na(+)-activated K(+) (KNa) channel activity in Kenyon cells of crickets (Gryllus bimaculatus). We found that two different NO donors, S-nitrosoglutathione (GSNO) and S-nitroso-N-acetyl-dl penicillamine (SNAP), strongly suppressed KNa channel currents. Additionally, this inhibitory effect of GSNO on KNa channel activity was diminished by 1H [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase (sGC), and KT5823, an inhibitor of protein kinase G (PKG). Next, we analyzed the role of ACh in the NO signaling cascade. ACh strongly suppressed KNa channel currents, similar to NO donors. Furthermore, this inhibitory effect of ACh was blocked by pirenzepine, an M1 muscarinic ACh receptor antagonist, but not by 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP) and mecamylamine, an M3 muscarinic ACh receptor antagonist and a nicotinic ACh receptor antagonist, respectively. The ACh-induced inhibition of KNa channel currents was also diminished by the PLC inhibitor U73122 and the calmodulin antagonist W-7. Finally, we found that ACh inhibition was blocked by the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME). These results suggested that the ACh signaling cascade promotes NO production by activating NOS and NO inhibits KNa channel currents via the sGC/cGMP/PKG signaling cascade in Kenyon cells. PMID- 26984420 TI - Muscle fatigue increases beta-band coherence between the firing times of simultaneously active motor units in the first dorsal interosseous muscle. AB - Synchronization between the firing times of simultaneously active motor units (MUs) is generally assumed to increase during fatiguing contractions. To date, however, estimates of MU synchronization have relied on indirect measures, derived from surface electromyographic (EMG) interference signals. This study used intramuscular coherence to investigate the correlation between MU discharges in the first dorsal interosseous muscle during and immediately following a submaximal fatiguing contraction, and after rest. Coherence between composite MU spike trains, derived from decomposed surface EMG, were examined in the delta (1 4 Hz), alpha (8-12 Hz), beta (15-30 Hz), and gamma (30-60 Hz) frequency band ranges. A significant increase in MU coherence was observed in the delta, alpha, and beta frequency bands postfatigue. In addition, wavelet coherence revealed a tendency for delta-, alpha-, and beta-band coherence to increase during the fatiguing contraction, with subjects exhibiting low initial coherence values displaying the greatest relative increase. This was accompanied by an increase in MU short-term synchronization and a decline in mean firing rate of the majority of MUs detected during the sustained contraction. A model of the motoneuron pool and surface EMG was used to investigate factors influencing the coherence estimate. Simulation results indicated that changes in motoneuron inhibition and firing rates alone could not directly account for increased beta-band coherence postfatigue. The observed increase is, therefore, more likely to arise from an increase in the strength of correlated inputs to MUs as the muscle fatigues. PMID- 26984421 TI - Local and global contributions to hemodynamic activity in mouse cortex. AB - Imaging techniques such as functional magnetic resonance imaging seek to estimate neural signals in local brain regions through measurements of hemodynamic activity. However, hemodynamic activity is accompanied by large vascular fluctuations of unclear significance. To characterize these fluctuations and their impact on estimates of neural signals, we used optical imaging in visual cortex of awake mice. We found that hemodynamic activity can be expressed as the sum of two components, one local and one global. The local component reflected presumed neural signals driven by visual stimuli in the appropriate retinotopic region. The global component constituted large fluctuations shared by larger cortical regions, which extend beyond visual cortex. These fluctuations varied from trial to trial, but they did not constitute noise; they correlated with pupil diameter, suggesting that they reflect variations in arousal or alertness. Distinguishing local and global contributions to hemodynamic activity may help understand neurovascular coupling and interpret measurements of hemodynamic responses. PMID- 26984422 TI - Metaplasticity in human primary somatosensory cortex: effects on physiology and tactile perception. AB - Theta-burst stimulation (TBS) over human primary motor cortex evokes plasticity and metaplasticity, the latter contributing to the homeostatic balance of excitation and inhibition. Our knowledge of TBS-induced effects on primary somatosensory cortex (SI) is limited, and it is unknown whether TBS induces metaplasticity within human SI. Sixteen right-handed participants (6 females, mean age 23 yr) received two TBS protocols [continuous TBS (cTBS) and intermittent TBS (iTBS)] delivered in six different combinations over SI in separate sessions. TBS protocols were delivered at 30 Hz and were as follows: a single cTBS protocol, a single iTBS protocol, cTBS followed by cTBS, iTBS followed by iTBS, cTBS followed by iTBS, and iTBS followed by cTBS. Measures included the amplitudes of the first and second somatosensory evoked potentials (SEPs) via median nerve stimulation, their paired-pulse ratio (PPR), and temporal order judgment (TOJ). Dependent measures were obtained before TBS and at 5, 25, 50, and 90 min following stimulation. Results indicate similar effects following cTBS and iTBS; increased amplitudes of the second SEP and PPR without amplitude changes to SEP 1, and impairments in TOJ. Metaplasticity was observed such that TOJ impairments following a single cTBS protocol were abolished following consecutive cTBS protocols. Additionally, consecutive iTBS protocols altered the time course of effects when compared with a single iTBS protocol. In conclusion, 30-Hz cTBS and iTBS protocols delivered in isolation induce effects consistent with a TBS-induced reduction in intracortical inhibition within SI. Furthermore, cTBS- and iTBS-induced metaplasticity appear to follow homeostatic and nonhomeostatic rules, respectively. PMID- 26984423 TI - Reactivation of visual-evoked activity in human cortical networks. AB - In the absence of sensory input, neuronal networks are far from being silent. Whether spontaneous changes in ongoing activity reflect previous sensory experience or stochastic fluctuations in brain activity is not well understood. Here we demonstrate reactivation of stimulus-evoked activity that is distributed across large areas in the human brain. We performed simultaneous electrocorticography recordings from occipital, parietal, temporal, and frontal areas in awake humans in the presence and absence of sensory stimulation. We found that, in the absence of visual input, repeated exposure to brief natural movies induces robust stimulus-specific reactivation at individual recording sites. The reactivation sites were characterized by greater global connectivity compared with those sites that did not exhibit reactivation. Our results indicate a surprising degree of short-term plasticity across multiple networks in the human brain as a result of repeated exposure to unattended information. PMID- 26984427 TI - Numerical density-to-potential inversions in time-dependent density functional theory. AB - We treat the density-to-potential inverse problem of time-dependent density functional theory as an optimization problem with a partial differential equation constraint. The unknown potential is recovered from a target density by applying a multilevel optimization method controlled by error estimates. We employ a classical optimization routine using gradients efficiently computed by the discrete adjoint method. The inverted potential has both a real and imaginary part to reduce reflections at the boundaries and other numerical artifacts. We demonstrate this method on model one-dimensional systems. The method can be straightforwardly extended to a variety of numerical solvers of the time dependent Kohn-Sham equations and to systems in higher dimensions. PMID- 26984424 TI - In vivo analysis of cerebellar Purkinje cell activity in SCA2 transgenic mouse model. AB - Cerebellar Purkinje cells (PCs) are primarily affected in many spinocerebellar ataxias (SCA). In this study we investigated functional activity of PCs in transgenic mouse model of SCA2, a polyglutamine neurodegenerative hereditary disorder. In our studies we used extracellular single-unit recording method to compare spontaneous activity of PCs in age-matched wild-type mice and SCA2-58Q transgenic mice. We discovered that the fraction of PCs with bursting and an irregular pattern of spontaneous activity dramatically increases in aged SCA2-58Q mice compared with wild-type littermates. Small-conductance calcium-activated potassium (SK) channels play an important role in determining firing rate of PCs. Indeed, we demonstrated that intraperitoneal (IP) injection of SK channel inhibitor NS8593 induces an irregular pattern of PC activity in wild-type mice. Furthermore, we demonstrated that IP injection of SK channel-positive modulator chlorzoxazone (CHZ) decreases spontaneous firing rate of cerebellar PCs. Finally, we have shown that IP injections with CHZ normalize firing activity of cerebellar PCs from aging SCA2-58Q mice. We propose that alterations in PC firing patterns is one of potential causes of ataxic symptoms in SCA2 and in other SCAs and that positive modulators of SK channels can be used to normalize activity of PCs and alleviate ataxic phenotype in patients with SCA. PMID- 26984425 TI - Network burst activity in hippocampal neuronal cultures: the role of synaptic and intrinsic currents. AB - The goal of this work was to define the contributions of intrinsic and synaptic mechanisms toward spontaneous network-wide bursting activity, observed in dissociated rat hippocampal cell cultures. This network behavior is typically characterized by short-duration bursts, separated by order of magnitude longer interburst intervals. We hypothesize that while short-timescale synaptic processes modulate spectro-temporal intraburst properties and network-wide burst propagation, much longer timescales of intrinsic membrane properties such as persistent sodium (Nap) currents govern burst onset during interburst intervals. To test this, we used synaptic receptor antagonists picrotoxin, 6-cyano-7 nitroquinoxaline-2,3-dione (CNQX), and 3-(2-carboxypiperazine-4-yl)propyl-1 phosphonate (CPP) to selectively block GABAA, AMPA, and NMDA receptors and riluzole to selectively block Nap channels. We systematically compared intracellular activity (recorded with patch clamp) and network activity (recorded with multielectrode arrays) in eight different synaptic connectivity conditions: GABAA + NMDA + AMPA, NMDA + AMPA, GABAA + AMPA, GABAA + NMDA, AMPA, NMDA, GABAA, and all receptors blocked. Furthermore, we used mixed-effects modeling to quantify the aforementioned independent and interactive synaptic receptor contributions toward spectro-temporal burst properties including intraburst spike rate, burst activity index, burst duration, power in the local field potential, network connectivity, and transmission delays. We found that blocking intrinsic Nap currents completely abolished bursting activity, demonstrating their critical role in burst onset within the network. On the other hand, blocking different combinations of synaptic receptors revealed that spectro-temporal burst properties are uniquely associated with synaptic functionality and that excitatory connectivity is necessary for the presence of network-wide bursting. In addition to confirming the critical contribution of direct excitatory effects, mixed-effects modeling also revealed distinct combined (nonlinear) contributions of excitatory and inhibitory synaptic activity to network bursting properties. PMID- 26984426 TI - Retinal cross talk in the mammalian visual system. AB - The existence and functional relevance of efferent optic nerve fibers in mammals have long been debated. While anatomical evidence for cortico-retinal and retino retinal projections is substantial, physiological evidence is lacking, as efferent fibers are few in number and are severed in studies of excised retinal tissue. Here we show that interocular connections contribute to retinal bioelectrical activity in adult mammals. Full-field flash electroretinograms (ERGs) were recorded from one or both eyes of Brown-Norway rats under dark adapted (n = 16) and light-adapted (n = 11) conditions. Flashes were confined to each eye by an opaque tube that blocked stray light. Monocular flashes evoked a small (5-15 MUV) signal in the nonilluminated eye, which was named "crossed ERG" (xERG). The xERG began under dark-adapted conditions with a positive (xP1) wave that peaked at 70-90 ms and ended with slower negative (xN1) and positive (xP2) waves from 200 to 400 ms. xN1 was absent under light-adapted conditions. Injection of tetrodotoxin in either eye (n = 15) eliminated the xERG. Intraocular pressure elevation of the illuminated eye (n = 6) had the same effect. The treatments also altered the ERG b-wave in both eyes, and the alterations correlated with xERG disappearance. Optic nerve stimulation (n = 3) elicited a biphasic compound action potential in the nonstimulated nerve with 10- to 13-ms latency, implying that the xERG comes from slow-conducting (W type) fibers. Monocular dye application (n = 7) confirmed the presence of retino-retinal ganglion cells in adult rats. We conclude that mammalian eyes communicate directly with each other via a handful of optic nerve fibers. The cross talk alters retinal activity in rats, and perhaps other animals. PMID- 26984428 TI - Hyponatremia in solid-tumor cancer patients: uncertainty regarding the use of vaptans. PMID- 26984429 TI - Diagnostic accuracy of triple-contrast multi-detector computed tomography for detection of penetrating gastrointestinal injury: a prospective study. AB - PURPOSE: Neither the performance of CT in diagnosing penetrating gastrointestinal injury nor its ability to discriminate patients requiring either observation or surgery has been determined. MATERIALS AND METHODS: This was a prospective, single-institutional observational study of patients with penetrating injury to the torso who underwent CT. Based on CT signs, reviewers determined the presence of a gastrointestinal injury and the need for surgery or observation. The primary outcome measures were operative findings and clinical follow-up. CT results were compared with the primary outcome measures. RESULTS: Of one hundred and seventy one patients (72 gunshot wounds, 99 stab wounds; age range, 18-57 years; median age, 28 years) with penetrating torso trauma who underwent CT, 45 % were followed by an operation and 55 % by clinical follow up. Thirty-five patients had a gastrointestinal injury at surgery. The sensitivity, specificity, and accuracy of CT for diagnosing a gastrointestinal injury for all patients were each 91 %, and for predicting the need for surgery, they were 94 %, 93 %, 93 %, respectively. Among the 3 % of patients who failed observation, 1 % had a gastrointestinal injury. CONCLUSION: CT is a useful technique to diagnose gastrointestinal injury following penetrating torso injury. CT can help discriminate patients requiring observation or surgery. KEY POINTS: * The most sensitive sign is wound tract extending up to gastrointestinal wall. * The most accurate sign is gastrointestinal wall thickening. * Triple-contrast CT is a useful technique to diagnose gastrointestinal injury. * Triple-contrast CT helps to discriminate patients requiring observation and surgery. PMID- 26984430 TI - MR-guided vacuum-assisted breast biopsy of MRI-only lesions: a single center experience. AB - PURPOSE: The purpose of this study was to compare three different biopsy devices on false-negative and underestimation rates in MR-guided, vacuum-assisted breast biopsy (VABB) of MRI-only lesions. METHODS: This retrospective, single-center study was IRB-approved. Informed consent was waived. 467 consecutive patients underwent 487 MR-guided VABB using three different 8-10-gauge-VABB devices (Atec 9-gauge,A; Mammotome-8-gauge,M; Vacora-10-gauge,V). VABB data (lesion-type, size, biopsy device, histopathology) were compared to final diagnosis (surgery, n = 210 and follow-up, n = 277). Chi-square, and Kruskal-Wallis tests were applied. P values < 0.05 were considered significant. RESULTS: Final diagnosis was malignant in 104 (21.4 %), high risk in 64 (13.1 %) and benign in 319 (65.5 %) cases. Eleven of 328 (3.4 %) benign-rated lesions were false-negative (1/95, 1.1 %, A; 2/73, 2.7 %, M; 8/160 5.0 % V; P = 0.095). Eleven high-risk (11/77, 14.3 %) lesions proved to be malignant (3/26, 11.5 % A; 4/12, 33.3 % M; 4/39, 10.3 % V; P = 0.228). Five of 34 (14.7 %) DCIS were upgraded to invasive cancer (2/15, 13.3 %, A; 1/6, 16.6 % M; 2/13, 15.3 %, V; P = 0.977). Lesion size (P = 0.05) and type (mass vs. non-mass, P = 0.107) did not differ significantly. CONCLUSION: MR guided VABB is an accurate method for diagnosis of MRI-only lesions. No significant differences on false-negative and underestimation rates were observed between three different biopsy devices. KEY POINTS: * MR-guided VABB is an accurate procedure for the diagnosis of MRI-only lesions. * Similar false negative and underestimation rates allow all three different MR-guided VABB devices for clinical application. * High-risk lesions should undergo surgery due to a substantial underestimation rate. * Agreement between MR-guided VABB and final diagnosis (benign/malignant) was 95.5% (465/487). PMID- 26984431 TI - Over-the-wire versus through-the-scope stents for the palliation of malignant gastric outlet obstruction: A retrospective comparison study. AB - OBJECTIVES: To compare the outcomes of over-the-wire (OTW) and through-the-scope (TTS) partially covered stents in patients with malignant gastric outlet obstruction (GOO). METHODS: A retrospective study was performed in 306 patients who had either OTW (n = 125) or TTS (n = 181) stents placed. Outcomes analysed included technical and clinical success, procedure time, complications, re intervention, stent patency and survival. RESULTS: One hundred and ninety-three patients met our inclusion criteria, including 125 patients in the OTW group and 68 patients in the TTS group. Technical and clinical outcomes were similar in the two groups. Stent migration rate was higher in the TTS than in the OTW group (P = 0.002) and was associated with straight stent and subsequent chemotherapy in the TTS group. Stent collapse was lower in the TTS than in the OTW group (P = 0.021). Six-month stent patency rate was higher in the OTW than in the TTS group (P = 0.044). CONCLUSIONS: TTS and OTW stents for the palliation of malignant GOO resulted in similar technical and clinical outcomes, stent patency and survival. TTS stents were associated with a higher migration rate, especially use of straight stents and subsequent chemotherapy, but a lower stent collapse rate than OTW stents. KEY POINTS: * OTW and TTS stents are equally effective in palliating GOO symptoms. * Six-month stent patency was higher for OTW than for TTS. * The straight stent and subsequent chemotherapy could increase stent migration. * Complication rates were lower for flared than for straight stents. * It is necessary to develop a multidisciplinary approach to integrate clinical experience. PMID- 26984435 TI - Long-term effects of pharmacotherapy on relapse prevention in alcohol dependence. AB - BACKGROUND: There is growing evidence that pharmacological treatment with two of the best validated anticraving drugs, acamprosate and naltrexone, is efficacious in promoting abstinence in recently detoxified alcohol-dependent subjects. OBJECTIVE: The stability of effects after termination of treatment remains to be answered, especially when combining both the drugs. METHOD: After detoxification, 160 alcohol-dependent subjects participated in a randomized, double-blind, placebo-controlled trial. Patients received naltrexone or acamprosate or a combination of naltrexone and acamprosate or placebo for 12 weeks. Patients were assessed weekly by interview, self-report, questionnaires and laboratory screening. Additionally, follow-up evaluation based on telephone interview of participants, general practitioners and relatives was conducted 12 weeks after terminating the medication. RESULTS: At week 12, the proportion of subjects relapsing to heavy drinking was significantly lower in the group with combined medication compared with both placebo and acamprosate (P < 0.05). No difference was detectable between acamprosate and naltrexone, both of which were superior to placebo (P < 0.05). Relapse rates were 28% (combined medication), 35% (naltrexone), 50% (acamprosate) and 75% (placebo). After follow-up (week 24), combined medication led to relapse rates significantly lower than placebo, but not lower than acamprosate. Again, both naltrexone and acamprosate were superior to placebo. Relapse rates were 80% (placebo), 54% (acamprosate), 53% (naltrexone) and 34% (combined medication). CONCLUSIONS: The results of this study highlight the stability of effects of pharmacotherapy on relapse prevention in alcohol dependence. PMID- 26984433 TI - Spatiotemporal characterization of brain infarction by sequential multimodal MR imaging following transient focal ischemia in a Rat model of intra-arterial middle cerebral artery occlusion. AB - OBJECTIVES: To assess spatiotemporal brain infarction evolution by sequential multimodal magnetic resonance (MR) imaging in an endovascular model of acute stroke in rats. MATERIALS AND METHODS: A microwire was selectively placed in the middle cerebral artery (MCA) in 16 consecutives rats during 90 minutes occlusion. Longitudinal 7-T MR imaging, including angiography, diffusion, and perfusion was performed during ischemia, immediately after reperfusion, 3 h and 24 h after subsequent reperfusion. RESULTS: MCA occlusion was complete in 75 % and partial in 18.7 %. Hypoperfusion (mean +/- SD) was observed in all animals during ischemia (-59 +/- 18 % of contralateral hemisphere, area 31 +/- 5 mm2). Infarction volume (mean +/- SD) was 90 +/- 64 mm3 during ischemia and 57 +/- 67 mm3 at 24 h. Brain infarction was fronto-parietal cortical in five animals (31 %), striatal in four animals (25 %), and cortico-striatal in seven animals (44 %) at 24 h. All rats survived at 24 h. CONCLUSION: This model is suitable to neuroprotection studies because of possible acute and close characterization of spatiotemporal evolution of brain infarction by MR imaging techniques, and evidence of ischemic penumbra, the target of neuroprotection agents. However, optimization of the brain infarct reproducibility needs further technical and neurointerventional tools improvements. KEY POINTS: * Nitinol microwire is MRI compatible allowing spatiotemporal characterization of brain infarction in rats. * Microwire selective placement in middle cerebral artery allows complete artery occlusion in 75 %. * A diffusion/perfusion mismatch during arterial occlusion is observed in 77 % of rats. PMID- 26984436 TI - Lofexidine for opiate detoxification. AB - The evolving role for lofexidine in the treatment of opiate detoxification over the last decade is reviewed. Lofexidine is no better than methadone or clonidine in attenuating withdrawal symptom severity, although it has a more favourable side-effect profile than clonidine. In conjunction with opiate antagonists, lofexidine may facilitate accelerated withdrawal, although activity and low liability for misuse, lofexidine may be more widely acceptable to clinicians than methadone, particularly those working in out-patient, non-specialist and prison treatment settings. Further studies in these treatment settings will be particularly apposite since, apart from the studies highlighted, the evidence base for the clinical value of lofexidine is mainly to be derived from in-patient trials. PMID- 26984432 TI - The diagnostic value of magnetic resonance urography using a balanced turbo field echo sequence. AB - OBJECTIVES: The aim of the study was to compare the inter-observer variability and the accuracy of magnetic resonance urography (MRU) using a thin sectional balanced-turbo field echo (B-TFE) sequence for detecting ureteral calculi and to determine the effect of additional factors (size, density and location of the calculus) on the sensitivity and specificity of the MRU. MATERIALS & METHODS: MRU and CT images were evaluated independently by two radiologists according to presence, density and localization of calculi. The degrees of inter-rater agreement for categorical items were evaluated by the Kappa coefficient. RESULTS: According to the 1st and 2nd observers, the sensitivity of MRU was 65.9 %, 71.8 % and the specificity of MRU was 95.9 %, 100 %, respectively. Inter-observer agreement was 84.6 % for stone detection. The larger size had a better effect on detectability (p < 0.05). Also, the higher density had a better impact on detectability (p < 0.05). CONCLUSION: Our study has shown that B-TFE MRU was useful to detect ureteral calculi. However, B-TFE MRU has low sensitivity and high specificity in comparison with CT images. MRU is a reasonable alternative imaging technique for follow-up periods of selective groups like patients with large urinary stones, children or pregnant patients when ionizing radiation is undesirable. KEY POINTS: * According to 1st and 2nd observers, sensitivity of MRU was 65.9 %, 71.8 %, respectively. * According to 1st and 2nd observers, MRU specificity was 95.9 %, 100 %, respectively. * Interobserver agreement was found to be over 84 % for stone detection. * B-TFE sequence provides calculus follow-up without radiation. * Larger calculi and more dense calculi individually have the better effect on detectability. PMID- 26984437 TI - The clinical use of buprenorphine in opiate addiction: evidence and practice. AB - Buprenorphine is a partial MU-opioid receptor agonist that is being increasingly used in clinical practice in the treatment of opioid dependence in the UK, USA, and, elsewhere. Its unique pharmacological properties mean it is a relatively safe drug, it can be given by alternate day dispensing, and it is associated with relatively mild symptoms on withdrawal. The interpretation of the research literature on buprenorphine is however, complex, and often appears to be in conflict with how buprenorphine is used in clinical practice. This article describes these apparent contradictions, their likely explanations, and how these may further inform our clinical practice. The article also describes the clinically relevant pharmacological properties of buprenorphine, compares it to methadone, relates the evidence to clinical experience, and provides practical advice on how to manage the most common clinical techniques. The best quality evidence suggests that very rapid buprenorphine induction is not associated with a higher drop-out rate than methadone, that buprenorphine is probably as good as methadone for maintenance treatment, and is superior to methadone and alpha-2 adrenergic agonists for detoxification. However, buprenorphine cannot yet be considered the 'gold standard' treatment for opiate dependence because of the higher drop-out rates that may occur on induction using current techniques, its high-cost relative to methadone, and because the place of buprenorphine in treatment is still continuing to evolve. PMID- 26984434 TI - Congenital cytomegalovirus infection: contribution and best timing of prenatal MR imaging. AB - OBJECTIVE: To predict sensorineural hearing loss (SNHL) and neurological impairment in congenital cytomegalovirus (cCMV) infection using MR imaging and define the best timing in pregnancy for prenatal assessment. METHODS: In 121 patients with confirmed cCMV infection, brain features at MR imaging were respectively graded from 1 to 5: normal; isolated frontal/parieto-occipital hyperintensity; temporal periventricular hyperintensity; temporal/occipital cysts and/or intraventricular septa; migration disorders. Grading was correlated with postnatal SNHL and neurological impairment using regression analysis. In 51 fetuses with MR examinations at 26.9 and 33.0 weeks, the predictive value of SNHL and neurological impairment was compared using ROC curves. RESULTS: Postnatal follow-up showed SNHL in 18 infants and neurological impairment in 10. MR grading was predictive of SNHL and of neurological impairment (P < 0.001). In grade 1 or 2, none had SNHL and 1/74 had neurological impairment. The areas under ROC curves for prediction of postnatal SNHL and of neurological impairment from first and second MR examination were comparable. CONCLUSION: Our data suggest that in cCMV infection, prediction of SNHL and neurological impairment is feasible by fetal MR imaging with a high negative predictive value and can equally be done at 27 or 33 weeks of gestation. KEY POINTS: * In cCMV, isolated periventricular T2-weighted signal hyperintensity has a good postnatal prognosis. * In cCMV, SNHL and neurological impairment can be predicted at 27 or 33 weeks. * In cCMV, fetal MR has a high NPV in predicting SNHL. * In cCMV, fetal MR has a high NPV in predicting neurological impairment. PMID- 26984438 TI - Heroin prescription for heroin addiction - an English view. AB - Heroin has been prescribed in England for the treatment of heroin addiction for almost 100 years. For many years, England was almost the only country where this occurred, and the British system was consequently the subject of international curiosity. In spite of this long history, very little research has been carried out locally, and until recently, there were no guidelines as to best practice. In 1965, it was decided that only doctors with a Home Office license could prescribe heroin. Since that time, the proportion of opiate addicts treated with heroin has greatly diminished, as has the number of doctors willing to prescribe. One doctor in particular remained an enthusiastic proponent of heroin prescription. His claims impressed some Swiss clinicians, who proceeded to establish a multicentre trial in Switzerland. This was followed by a similar trial in the Netherlands. These trials apparently indicated that a proportion of treatment-resistant opiate addicts could respond well to heroin, although the researchers' conclusions have been disputed. The National Treatment Agency in England is now developing guidelines for good practice based on this new information and is planning to set up some pilot sites. It is likely that practise in England will remain somewhat different from continental practice, particularly with respect to long-term supervised injecting. It is unclear how much funding will be released to support heroin prescription. Without adequate funding, it is likely to disappear. PMID- 26984439 TI - Is there an increased risk of metabolic syndrome among childhood acute lymphoblastic leukemia survivors? A developing country experience. AB - Data on metabolic syndrome (MS) in survivors of childhood acute lymphoblastic leukemia (ALL) from developing countries are lacking. The purpose of this single center, uncontrolled, observational study was to assess the frequency of MS in our survivors. The survivors of ALL <=15 years at diagnosis, who had completed therapy >=2 years earlier, were enrolled. Anthropometric measurements (weight, height, waist circumference), biochemistry (glucose, insulin, triglycerides, high density lipoprotein [HDL], thyroid function tests, C-reactive protein [CRP], magnesium), measurement of blood pressure, and Tanner staging were performed. MS was defined by International Diabetes Federation (IDF) and the National Cholesterol Education Program Third Adult Treatment Panel guidelines (NCEP ATP III) criteria, modified by Cook et al. (Arch Pediatr Adolesc Med. 2003;157:821 827) and Ford et al. (Diabetes Care. 2005;28:878-881). The median age of 76 survivors was 11.9 years (interquartile range [IQR]: 9.6-13.5). Twenty-four (32%) survivors were obese or overweight. The prevalence of insulin resistance (17%), hypertension (7%), hypertriglyceridemia (20%), and low HDL (37%) was comparable to the prevalence in children/adolescents in historical population-based studies from India. The prevalence of MS ranged from 1.3% to 5.2%, as per different defining criteria. Cranial radiotherapy, age at diagnosis, sex, or socioeconomic status were not risk factors for MS. The prevalence of MS in survivors of childhood ALL, at a median duration of 3 years from completion of chemotherapy, was comparable to the reference population. The prevalence of being obese or overweight was, however, greater than historical controls. PMID- 26984440 TI - About human taeniasis and Taenia saginata diagnosis by endoscopy. AB - La carta al editor se refiere al articulo de Canaval-Zuleta et al. aceptado para publicacion, titulado "Endoscopy as an alternative diagnostic and therapeutic technique for Taenia saginata". El trabajo presenta una serie de incorrecciones que deben ser aclaradas, o al menos parte de ellas en solo 300 palabras. La informacion sobre las vias de infeccion en taeniasis, asi como la patogenia y tecnicas de diagnostico, no se ajustan a la realidad. Asimismo, ya esta publicado que el diagnostico por endoscopia es una tecnica muy sensible pero nada especifica, pues no permite distinguir entre las 3 especies humanas del genero Taenia. PMID- 26984441 TI - Barriers to hand hygiene in ophthalmic outpatients in Uganda: a mixed methods approach. AB - BACKGROUND: Healthcare-associated infection rates are high in low-income countries and are associated with significant morbidity. There is a paucity of published data on infection control practice, attitudes or resources in these settings, particularly in ophthalmology. The aim of this study is to understand current hand washing practices, barriers to hand washing and facilities available in two Ugandan specialist eye hospitals. This study was undertaken through non participant observations of healthcare worker hand washing practices, documentation of hand hygiene facilities and semi-strucutured interviews with clinical staff. RESULTS: Eighty percent of the WHO opportunities for hand washing were missed through lack of attempted hand hygiene measures. Facilities for hand hygiene were inadequate with some key clinical areas having no provisions for hand hygiene. Training on effective hand hygiene varied widely with some staff reporting no training at all. The staff did not perceive the lack of facilities to be a barrier to hand washing but reported forgetfulness, lack of time and a belief that they could predict when transmission might occur and therefore did not wash hands as often as recommended. CONCLUSIONS: Hand hygiene at the two observed sites did not comply with WHO-recommended standards. The lack of facilities, variable training and staff perceptions were observable barriers to effective hand hygiene. Simple, low-cost interventions to improve hand hygiene could include increased provision of hand towels and running water and improved staff education to challenge their views and perceived barriers to hand hygiene. PMID- 26984442 TI - Structure-based identification of CaMKIIalpha-interacting MUPP1 PDZ domains and rational design of peptide ligands to target such interaction in human fertilization. AB - The recognition and association between Ca(2+)/calmodulin-activated protein kinase II-alpha (CaMKIIalpha) and multi-PDZ domain protein 1 (MUPP1) plays an important role in sperm acrosome reaction and human fertilization, which is mediated by the binding of CaMKIIalpha's C-terminal tail to one or more PDZ domains of the scaffolding protein MUPP1. In this study, we attempt to identify the CaMKIIalpha-interacting MUPP1 PDZ domains and to design peptide ligands that can potently target and then competitively disrupt such interaction. Here, a synthetic biology approach was proposed to systematically characterize the structural basis, energetic property, dynamic behavior and biological implication underlying the intermolecular interactions between the C-terminal peptide of CaMKIIalpha and all the 13 PDZ domains of MUPP1. These domains can be grouped into four clusters in terms of their sequence, structure and physiochemical profile; different clusters appear to recognize different classes of PDZ-binding motifs. The cluster 3 includes two members, i.e. MUPP1 PDZ 5 and 11 domains, which were suggested to bind class II motif Phi-X-Phi(-COOH) of the C-terminal peptide SGAPSV(-COOH) of CaMKIIalpha. Subsequently, the two domains were experimentally measured as the moderate- and high-affinity binders of the peptide by using fluorescence titration (dissociation constants K d = 25.2 +/- 4.6 and 0.47 +/- 0.08 uM for peptide binding to PDZ 5 and 11, respectively), which was in line with theoretical prediction (binding free energies DeltaG total = -7.6 and 9.2 kcal/mol for peptide binding to PDZ 5 and 11, respectively). A systematic mutation of SGAPSV(-COOH) residues suggested few favorable amino acids at different residue positions of the peptide, which were then combined to generate a number of potent peptide mutants for PDZ 11 domain. Consequently, two peptides (SIAPNV(-COOH) and SIVMNV(-COOH)) were identified to have considerably improved affinity with K d increase by ~tenfold relative to wild type peptide. Thus, the two peptides are considered as promising lead entities to develop therapeutic molecular agents with high efficacy and specificity to target CaMKIIalpha-MUPP1 interaction. Other five designed peptides (SILPSV(-COOH), SGLPNV(-COOH), SIVMSV( COOH), SIVPNV(-COOH) and SIAMNV(-COOH)) possessed comparable affinity with the wild type, and they may be further optimized to obtain higher potency. PMID- 26984443 TI - An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic organ prolapse (POP). AB - INTRODUCTION: The terminology for female pelvic floor prolapse (POP) should be defined and organized in a clinically-based consensus Report. METHODS: This Report combines the input of members of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS), assisted at intervals by external referees. Appropriate core clinical categories and a sub-classification were developed to give a coding to definitions. An extensive process of fourteen rounds of internal and external review was involved to exhaustively examine each definition, with decision-making by collective opinion (consensus). RESULTS: A Terminology Report for female POP, encompassing over 230 separate definitions, has been developed. It is clinically based with the most common diagnoses defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction and POP. Female-specific imaging (ultrasound, radiology and MRI) and conservative and surgical managements are major additions and appropriate figures have been included to supplement and clarify the text. Emerging concepts and measurements, in use in the literature and offering further research potential, but requiring further validation, have been included as an appendix. Interval (5-10 year) review is anticipated to keep the document updated and as widely acceptable as possible. CONCLUSION: A consensus-based Terminology Report for female POP has been produced to aid clinical practice and research. PMID- 26984444 TI - Early postoperative voiding dysfunction after insertion of retropubic midurethral tape. AB - INTRODUCTION AND HYPOTHESIS: A significant proportion of patients develop voiding dysfunction after midurethral tape (MUT) insertion, which reduces patient satisfaction. The study's purpose was to identify predictive factors of voiding dysfunction after a retropubic MUT procedure. METHODS: This was a retrospective study of 100 patients who underwent only a retropubic MUT procedure between January 2010 and December 2011. Early voiding dysfunction was defined when patients required a Foley catheter within 48 h. Data including demographic information, urogenital symptoms, previous surgery, preoperative uroflowmetry and urodynamic parameters were analysed using SPSS v22. Univariate analysis of all demographic variables was performed; those significant at 10 % were entered into a multivariate logistic regression. RESULTS: Fourteen patients required Foley catheter insertion, with a median age of 58 years (26-83 years), median BMI 28 kg/m(2) (20-48 kg/m2), and median parity 2 (0-4). Univariate analysis revealed peak flow rate <15 ml/s (OR 3.79; 1.07, 13.4; p = 0.046), bladder capacity (p = 0.044), stress incontinence versus mixed or urge incontinence (p = 0.064) and previous surgery (OR 4.39; 1.34, 14.41; p = 0.015) to be associated with voiding dysfunction. Multivariate analysis showed only previous pelvic floor surgery to be independently associated (OR 3.76; 1.14, 12.23, p = 0.029). CONCLUSIONS: Only previous pelvic-floor surgery was found to be a strong predictive factor of voiding dysfunction. The rate of voiding dysfunction was similar to those of published data. Previous studies revealed different predictive factors. A larger cohort is needed to provide a definite answer. Those with previous surgery appear to be those most at risk and pre-surgical counselling for these women could be suggested. PMID- 26984446 TI - The Other Side of Bad News. PMID- 26984445 TI - Electrocardiographic Characterization of Ramucirumab on the Corrected QT Interval in a Phase II Study of Patients With Advanced Solid Tumors. AB - LESSONS LEARNED: Cardiotoxicity can be a serious complication of anticancer therapies. To enable earlier identification of drug-related cardiac effects, the International Conference on Harmonization (ICH) adopted the ICH E14 Guidelines for evaluating the potential for QT/corrected QT (QTc) interval prolongation and proarrhythmic potential for nonantiarrhythmic drugs.The results of the evaluation of ramucirumab on the QT/QTc interval show a lack of effect on QTc prolongation in patients with advanced cancer. BACKGROUND: Ramucirumab is a human immunoglobulin G1 monoclonal antibody that specifically blocks vascular endothelial growth factor receptor-2 and is approved for the treatment of advanced gastric, non-small cell lung, and colorectal cancers. This phase II study was conducted to determine if treatment with ramucirumab causes prolongation of the corrected QT interval using Fridericia's formula (QTcF) in patients with advanced cancer. METHODS: Patients received intravenous ramucirumab (10 mg/kg) every 21 days for 3 cycles. The first 16 patients received moxifloxacin (400 mg orally), an antibiotic associated with mild QT prolongation as a positive control. During cycle 3, determination of QTcF prolongation was made with triplicate electrocardiograms at multiple time points to compare with baseline. RESULTS: Sixty-six patients received therapy; 51 patients completed 9 or more weeks of therapy for the complete QTcF evaluation period. The upper limit of the 90% two-sided confidence intervals for the least square means of change in QTcF from baseline at each time point was less than 10 milliseconds. Concentration-QTcF analysis showed a visible, but not significant, negative association between ramucirumab concentration and QTcF change from baseline. CONCLUSION: Ramucirumab at a dose of 10 mg/kg administered every 21 days for 3 cycles did not produce a statistically or clinically significant prolongation of QTcF. PMID- 26984447 TI - Curing Operable Stage I Non-Small Cell Lung Cancer With Stereotactic Ablative Body Radiotherapy: The Force Awakens. PMID- 26984448 TI - Enhanced Cardiac Testing in a Dual Anti-HER2 Regimen: What Have We Learned? PMID- 26984449 TI - FDA Approval Summary: Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With Progression On or After Platinum-Based Chemotherapy. AB - : On October 9, 2015, the U.S. Food and Drug Administration expanded the nivolumab metastatic non-small cell lung cancer (NSCLC) indication to include patients with nonsquamous NSCLC after a 3.25-month review timeline. Approval was based on demonstration of an improvement in overall survival (OS) in an international, multicenter, open-label, randomized trial comparing nivolumab to docetaxel in patients with metastatic nonsquamous NSCLC with progression on or after platinum-based chemotherapy. The CheckMate 057 trial enrolled 582 patients who were randomized (1:1) to receive nivolumab or docetaxel. Nivolumab demonstrated improved OS compared with docetaxel at the prespecified interim analysis with a hazard ratio (HR) of 0.73 (p = .0015), and a median OS of 12.2 months (95% CI: 9.7-15.0 months) in patients treated with nivolumab compared with 9.4 months (95% CI: 8.0-10.7 months) in patients treated with docetaxel. A statistically significant improvement in objective response rate (ORR) was also observed, with an ORR of 19% (95% CI: 15%-24%) in the nivolumab arm and 12% (95% CI: 9%-17%) in the docetaxel arm. The median duration of response was 17 months in the nivolumab arm and 6 months in the docetaxel arm. Progression-free survival was not statistically different between arms. A prespecified retrospective subgroup analysis suggested that patients with programmed cell death ligand 1 negative tumors treated with nivolumab had similar OS to those treated with docetaxel. The toxicity profile of nivolumab was consistent with the known immune mediated adverse event profile except for 1 case of grade 5 limbic encephalitis, which led to a postmarketing requirement study to better characterize immune mediated encephalitis. IMPLICATIONS FOR PRACTICE: Based on the results from the CheckMate 057 clinical trial, nivolumab represents a new treatment option for patients requiring second-line treatment for metastatic non-small cell lung cancer. The role of nivolumab in patients with sensitizing epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) alterations is less clear. Until dedicated studies are performed to better characterize the role and sequence of programmed cell death 1 (PD-1) therapy, patients with EGFR or ALK alterations should have progressed on appropriate targeted therapy before initiating PD-1 inhibitor therapy. Some patients whose tumors lack programmed cell death ligand 1 (PD-L1) expression also appear to have durable responses. The U.S. Food and Drug Administration granted approval to Dako's PD-L1 test, PD-L1 IHC 28-8 pharmDx, which the applicant claimed as a nonessential complementary diagnostic for nivolumab use. PMID- 26984451 TI - High quality reduced graphene oxide flakes by fast kinetically controlled and clean indirect UV-induced radical reduction. AB - This work highlights a surprisingly simple and kinetically controlled highly efficient indirect method for the production of high quality reduced graphene oxide (rGO) flakes via UV irradiation of aqueous dispersions of graphene oxide (GO), in which the GO is not excited directly. While the direct photoexcitation of aqueous GO (when GO is the only light-absorbing component) takes several hours of reaction time at ambient temperature (4 h) leading only to a partial GO reduction, the addition of small amounts of isopropanol and acetone (2% and 1%) leads to a dramatically shortened reaction time by more than two orders of magnitude (2 min) and a very efficient and soft reduction of graphene oxide. This method avoids the formation of non-volatile species and in turn contamination of the produced rGO and it is based on the highly efficient generation of reducing carbon centered isopropanol radicals via the reaction of triplet acetone with isopropanol. While the direct photolysis of GO dispersions easily leads to degradation of the carbon lattice of GO and thus to a relatively low electric conductivity of the films of flakes, our indirect photoreduction of GO instead largely avoids the formation of defects, keeping the carbon lattice intact. Mechanisms of the direct and indirect photoreduction of GO have been elucidated and compared. Raman spectroscopy, XPS and conductivity measurements prove the efficiency of the indirect photoreduction in comparison with the state-of-the-art reduction method for GO (hydriodic acid/trifluoroacetic acid). The rapid reduction times and water solvent containing only small amounts of isopropanol and acetone may allow easy process up-scaling for technical applications and low energy consumption. PMID- 26984450 TI - Cardiac Safety of Paclitaxel Plus Trastuzumab and Pertuzumab in Patients With HER2-Positive Metastatic Breast Cancer. AB - INTRODUCTION: Myocardial strain imaging and blood biomarkers have been proposed as adjuncts to left ventricular ejection fraction (LVEF) monitoring for the early detection of cardiotoxicity during cancer therapy. We report the results of a preplanned cardiac safety analysis of global longitudinal strain (GLS), and troponin-I (TnI) and brain natriuretic peptide (BNP) levels in the phase II study of paclitaxel, trastuzumab, and pertuzumab (THP) for metastatic HER2-positive breast cancer. PATIENTS AND METHODS: Patients with 0-1 lines of prior therapy were treated with weekly paclitaxel (80 mg/m(2)) plus trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and pertuzumab (840 mg loading dose followed by 420 mg) every 3 weeks. Exploratory endpoints were GLS measured with speckle tracking echocardiography every 3 months and TnI and BNP levels measured every 6 weeks (immediately pre- and postchemotherapy infusion) at 6 time points. RESULTS: Sixty-seven of 69 enrolled patients were treated with THP: 19 (28%) had hypertension, 8 (12%) had diabetes, 11 (16%) had hyperlipidemia, and 26 (38%) had smoking history. After a median follow-up of 21 months (range: 3-38 months), no patients developed symptomatic heart failure. Two patients (3.0%) experienced asymptomatic LVEF decline (grade 2). The mean GLS (+/-SD) was 19% +/- 2% (baseline), 19% +/- 2% (month 6), and 19% +/- 3% (month 12). Detectable TnI (>0.06 ng/mL) and elevated BNP (>100 pg/mL) levels were observed in 3 (4.3%) and 2 (3.0%) patients, respectively, but were not associated with LVEF decline. CONCLUSION: The absence of any significant changes in GLS and cardiac biomarkers (TnI and BNP) further support the cardiac safety of THP in patients with metastatic HER2-positive breast cancer. IMPLICATIONS FOR PRACTICE: Dual anti-HER2 therapy with trastuzumab and pertuzumab in combination with taxane-based chemotherapy improves overall survival in patients with metastatic HER2-positive breast cancer. There is a critical need to investigate the potential cardiotoxicity of dual anti-HER2 blockade, given the importance of HER2 signaling in cardiac homeostasis and stress response. Global longitudinal strain and cardiac biomarkers have been proposed as adjuncts to left ventricular ejection fraction for the early detection of cardiotoxicity. In this phase II study of combination trastuzumab and pertuzumab with paclitaxel, no clinically significant change was observed in global longitudinal strain or cardiac biomarkers. These results further support the cardiac safety of dual anti-HER2 blockade previously reported in the CLEOPATRA study. The findings in the current study also call into question the role of intensive cardiac monitoring among patients treated with anti-HER2 therapy in the absence of anthracyclines. Less frequent cardiac assessments could lead to a reduction in unnecessary treatment interruption and is an important consideration given the rise in medical expenditures, but this requires further investigation. PMID- 26984452 TI - Current Topics in Epilepsy Surgery. AB - This article reviews the current topics in the field of epilepsy surgery. Each type of epilepsy is associated with a different set of questions and goals. In mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS), postoperative seizure outcome is satisfactory. A recent meta-analysis revealed superior seizure outcome after anterior temporal lobectomy compared with selective amygdalohippocampectomy; in terms of cognitive outcome; however, amygdalohippocampectomy may be beneficial. In temporal lobe epilepsy with normal magnetic resonance imaging (MRI), postoperative seizure outcome is not as favorable as it is in MTLE with HS; further improvement of seizure outcome in these cases is necessary. Focal cortical dysplasia is the most common substrate in intractable neocortical epilepsy, especially in children, as well as in MRI invisible neocortical epilepsy. Postoperative seizure-free outcome is approximately 60-70%; further diagnostic and therapeutic improvement is required. Regarding diagnostic methodology, an important topic currently under discussion is wideband electroencephalogram (EEG) analysis. Although high-frequency oscillations and ictal direct current shifts are considered important markers of epileptogenic zones, the clinical significance of these findings should be clarified further. Regarding alternatives to surgery, neuromodulation therapy can be an option for patients who are not amenable to resective surgery. In addition to vagus nerve stimulation, intracranial stimulation such as responsive neurostimulation or anterior thalamic stimulation is reported to have a modest seizure suppression effect. Postoperative management such as rehabilitation and antiepileptic drug (AED) management is important. It has been reported that postoperative rehabilitation improves postoperative employment status. Pre- and post-operative comprehensive care is mandatory for postoperative improvement of quality of life. PMID- 26984453 TI - Current Opinion of Bone Marrow Stromal Cell Transplantation for Ischemic Stroke. AB - This article reviews recent advancement and perspective of bone marrow stromal cell (BMSC) transplantation for ischemic stroke, based on current information of basic and translational research. The author would like to emphasize that scientific approach would enable us to apply BMSC transplantation into clinical situation in near future. PMID- 26984454 TI - Kinetic Profile of Inflammation Markers in Human Skin In vivo Following Exposure to Ultraviolet B Indicates Synchronic Release of Cytokines and Prostanoids. AB - Ultraviolet B (UVB) irradiation affects epidermal cells, which respond via a cascade of inflammation markers. After initial in vitro and ex vivo experiments, this study used cutaneous microdialysis to generate a kinetic profile for 16 cytokines and 4 prostanoids in human skin in vivo. Skin areas 9 cm2 were irradiated with UVB (2* minimal erythematous dose) 16 h after catheter placement in the dermis of the volar forearms of healthy volunteers. Dialysates were collected at 4-h intervals up to 64 h and analysed for 5- and 8-iso-PGF2alpha, 9alpha,11alpha-PGF2alpha and PGE2 by gas chromatography-mass spectrometry (GC/MS). Dialysates were also analysed for interleukin (IL)-1beta, IL-2, IL-3, IL 4, IL-5, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, Fas ligand (FasL), interferon-gamma-inducible protein-10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), RANTES, eotaxin, and granulocyte-macrophage colony-stimulating factor (GM-CSF) using a multiplex-based cytometric-bead-array. In conclusion, 3 peaks with synchronic release of T helper (TH) 1-directed inflammatory cytokines and prostanoids could be detected post-UVB: an early phase (4-12 h), an intermediate phase (16-24 h) and a late phase (32-40 h). A TH2-directed cytokine response was detectable at intermediate and late phases. PMID- 26984455 TI - Research-based evidence in stroke rehabilitation: an investigation of its implementation by physiotherapists and occupational therapists. AB - PURPOSE: Stroke rehabilitation is a multidimensional process that is designed to facilitate restoration of and/or adaptation to loss of functioning. The use of research-based evidence in informed decision-making is insufficient. Occupational therapy and physiotherapy constitute important contributions to rehabilitation. The study aim was to investigate characteristics of the implementation of research-based evidence in stroke rehabilitation by occupational therapists and physiotherapists, using the International Classification of Functioning, Disability and Health as a conceptual framework. METHOD: A prospective cohort study, including all service levels within stroke rehabilitation. Consecutive patients with stroke admitted to a university hospital between May and December 2012 were enrolled by 13 therapists. Documentation of daily practice was collected from medical records. Analysis compared the therapists' documentation with the national clinical guidelines for physiotherapy and occupational therapy in the rehabilitation of adults with brain injury. RESULTS: The study included 131 patients. The therapists' praxis was seen to be in agreement with the majority of the national clinical guidelines. However, joint goal-setting and evaluation using standardized measures were seldom documented. CONCLUSIONS: Although the therapists recognize evidence-based practice as a framework for achieving quality in rehabilitation, findings suggest that they do not employ research-based evidence to the fullest extent. Implications for Rehabilitation In order to individualize the rehabilitation offered, more attention and focus on involving and giving words to patients' expectations, perceptions, experiences, and perspectives is needed. With the intention of enabling meaningful participation the health professionals need to pay more attention to the importance of environmental factors. Both guidelines and clinical practice should consider all components of the International Classification of Functioning, Disability and Health when formulating, and implementing, recommendations in rehabilitation praxis in order to aim for rehabilitation that is based both on evidence and a holistic approach. PMID- 26984458 TI - Influence of cognitive reserve on neuropsychological functioning in Parkinson's disease. AB - BACKGROUND: In recent years, attention has been drawn to the association between a low level of education and dementia, an almost generalized finding in the majority of studies on the prevalence of dementia where the level of education of the population was highly diversified. The protective effect of education is not limited to Alzheimer's disease but is also seen in other types of dementia, Parkinson's disease (PD), and even in the cognitive deterioration linked to aging Objective: To evaluate neuropsychological performance in (PD) subjects and to evaluate the influence of cognitive reserve (RC) on their neuropsychological performance. SUBJECTS: An extensive neuropsychological battery of tests was applied to a total of 79 subjects, 33 of whom were diagnosed with PD. MEASURES: RC scores were based on a combination of years of education, a measure of occupational attainment, and an estimate of premorbid intelligence. RESULTS: As regards the specific disturbances found in the clinical group subjects, a lower performance in memory, attention, visuospatial, visuoconstructive, and perceptive skills was seen. With respect to our second objective, our results showed that patients diagnosed with PD who had a high RC reached a higher neuropsychological level of performance than those subjects with a low reserve. CONCLUSIONS: Early neuropsychological impairments in PD are most evident in individuals with lower RC. As has been found in other neurological disorders, individuals with greater RC may be less sensitive to the initial clinical effects of the underlying neuropathological process. PMID- 26984457 TI - Lack of effect of eicosapentaenoic acid in the Porsolt forced swimming test model of depression. AB - BACKGROUND: Eicosapentaenoic acid (EPA) is one of the major components of fish oils. Omega-3 fatty acids, particularly EPA, have been hypothesized to play a role in the etiology, pathogenesis and treatment of mood disorders. Clinical studies have shown beneficial effects of omega-3 fatty acids in major depression, bipolar disorder and other psychiatric disorders. OBJECTIVE: The present study design evaluates the effect of EPA in the Porsolt forced swimming test. RESULTS: EPA alone did not reduce the immobility time and did not enhance the anti immobility effect of a low dose of imipramine. Contrary to the hypothesis, EPA slightly increased the immobility time, and in some experiments tended to reduce the anti-despair effect of imipramine. CONCLUSION: The present results do not provide an animal model for the antidepressant effect of EPA as demonstrated in clinical experiments. The mechanism of EPA antidepressant action is unknown and the Porsolt forced swimming test could be non-sensitive for its antidepressant properties. PMID- 26984459 TI - No allelic association between harm avoidance and the debrisoquine 4-hydroxylase gene. AB - BACKGROUND: Several reports suggest that variance in personality traits is inherited, but little is known about the genes responsible. It has been suggested that there is a relationship between personality characteristics and the gene responsible for the activity of the enzyme debrisoquine 4-hydroxylase (CYP2D6). OBJECTIVE: To examine the proportion of poor metabolizers in a group of personality disordered patients. METHODS: Blood samples were obtained from 23 patients with a high or very high score on the dimension 'harm avoidance' of the Temperament and Character Inventory (TCI). The samples were genotyped for the null alleles CYP2D6*3 and*4 by performing an allele-specific polymerase chain reaction. RESULTS: The frequencies of genotypes in the sample were very similar to the frequencies found in a general white population. CONCLUSIONS: The investigation produced no support for the idea that the CYP2D6 gene is related to personality by means of variations in the temperament dimension of harm avoidance. PMID- 26984456 TI - Identification of the -alpha(2.4) Deletion in One Family and in One Hb H Disease Patient in Guangxi, People's Republic of China. AB - The 2.4 kb (or -alpha(2.4)) deletion in the alpha-globin gene cluster (NG_000006.1) is an alpha(+)-thalassemia (alpha(+)-thal) allele. The molecular basis of -alpha(2.4) is a deletion from 36860 to 39251 of the alpha-globin gene cluster. It was reported by three research groups in 2005, 2012 and 2014, respectively. In routine thalassemia screening studies by this research group, we found an individual with the -alpha(2.4)/alphaalpha genotype and an Hb H (beta4) disease patient whose genotype was - -(SEA)/-alpha(2.4). Samples from the parents of the carrier of the -alpha(2.4)/alphaalpha genotype were collected to perform pedigree analysis, and the proband's mother's genotype was diagnosed to be - (SEA)/-alpha(2.4). The research revealed that the -alpha(2.4) allele exists in the population of southern Guangxi, People's Republic of China. PMID- 26984460 TI - Post-stroke quality of life and depression. AB - BACKGROUND: Studies on the determinants of the quality of life (QOL) after stroke bring differing results depending on the applied concept of QOL. This may lead to confusion about the contribution of various factors to the post-stroke QOL. OBJECTIVE: The aim of the study was: (i) to investigate functional and psychological QOL in the individuals after the first ischemic stroke; (ii) to identify the most important correlates of QOL; and (iii) to examine the significance of depression among the other possible predictors of QOL. METHODS: A hospital-based sample of 72 stroke patients was followed up to 6 months after stroke onset. QOL was assessed using the Polish version of the Quality of Life Index and the Sickness Impact Profile. A multiple regression procedure was performed to examine relationships between QOL and the study variables. RESULTS: In spite of good recovery, the psychological and functional QOL of the examined patients was impaired, although the negative impact of stroke was greater on the objective QOL than on the subjective QOL. Stroke-related impairment, depression, functional disability and marital status predicted 80% of the variance in the functional QOL. Emotional support, depression and functional disability explained 38% of the variance in psychological well-being. CONCLUSIONS: Depression and physical disability were the most important predictors of QOL after stroke since their impact on QOL was more robust in comparison to the remaining variables. For improving QOL, a comprehensive care for patients aimed at reducing physical dependence and ameliorating depressive symptoms could be recommended. PMID- 26984461 TI - Suppressive effect of TRH and antidepressants on human interferon-gamma production in vitro. AB - BACKGROUND: It has been established that thyrotropin-releasing hormone (TRH) affects several aspects of immunoreactivity, e.g. production of proinflammatory cytokines. It has been shown that TRH enhances the therapeutic efficiency of classical tricyclic antidepressants. Proinflammatory cytokines may play a role in the etiology of depression, whereas the therapeutic efficacy of antidepressants may be related to their negative immunoregulatory effects. OBJECTIVE: In order to verify the hypothesis that TRH-induced increase of therapeutic efficiency of classical tricyclic antidepressants results from synergistic inhibitory effects of these agents on the secretion of proinflammatory cytokines, we determine the effect of imipramine or fluoxetine with and without TRH on the production of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) by stimulated human whole blood cells. METHODS: Diluted whole blood of 17 volunteers was incubated with imipramine or fluoxetine (both in doses of 10-5 M) with or without TRH (in a dose of 10-5 M). The supernatants were collected 24 h later for the assay of TNF-alpha and after 72 h for the assays of IFN-gamma and IL-10. The three cytokines were assayed by ELISA methods. RESULTS: A significant decrease in production of IFN-gamma was observed in cells stimulated with mitogens and co-incubated with imipramine or fluoxetine and TRH. Under the same conditions, TRH alone did not change the production of these cytokines, whereas imipramine alone significantly decreases IFN-gamma production, and fluoxetine alone significantly decreases IFN-gamma and TNF-alpha production. CONCLUSION: Although a significant decrease in IFN-gamma production was observed after joint application of TRH and antidepressants, our data did not support the above-mentioned hypothesis. Indeed, we did not observe synergistic inhibitory effects of these agents on the secretion of proinflammatory cytokines. PMID- 26984463 TI - Psychiatric symptoms typical of patients with dementia with Lewy bodies - similarity to those of levodopa-induced psychosis. AB - We examined psychiatric symptoms in eight cases with dementia with Lewy bodies (DLB), which included visual hallucination of persons or small animals, visual illusion, metamorphosia, leibhaftige Bewusstheit, personal or topographical misidentification, Capgras' syndrome and reduplicative paramnesia as well as depressive state and delusion of persecution. These psychiatric symptoms are identical to those of levodopa-induced psychosis, although these symptoms appeared before medication with anti-Parkinson drugs. The hypersensitivity of the dopamine receptor in the meso-limbic dopaminergic system has been presumed in levodopa-induced psychosis. We previously showed disturbance of the nigro amygdaloid dopaminergic connections in DLB brains on pathological studies. Hypoperfusion or glucose hypometabolism in the occipital lobe has been demonstrated in DLB patients using SPECT or PET. The amygdala has reciprocal connections with the visual cortex in the occipital lobe. From these findings, it is supposed that the disturbance of the nigro-amygdaloid connections induces hypersensitivity of the dopamine receptor in the amygdala, causing psychiatric symptoms with dysfunction of the visuo-amygdaloid connections. PMID- 26984462 TI - Korsakoff's syndrome on the MMPI-2. AB - BACKGROUND: This article describes an exploratory study of MMPI-2 administration to 20 patients with Korsakoff's disease, all admitted to the Korsakoff unit of a major psychiatric hospital in the Netherlands. METHODS: We compared their MMPI-2 basic profiles with those of an inpatient alcohol-dependent non-Korsakoff group. Attention was also given to content scales and some selected supplementary scales. Furthermore, we explored the differences between MMPI-2 profiles of Korsakoff patients with and without insight into oneself and one's disease. RESULTS: Compared with both the Dutch norms and the scale means of the non Korsakoff alcoholics, Korsakoff patients showed an extraordinary flat profile. Illness insight appeared to be related to the levels of the various scales. DISCUSSION: The results show the potential usefulness of the MMPI-2 in the differential diagnosis of chronic alcoholism and Korsakoff's disease. PMID- 26984464 TI - Risperidone in the treatment of childhood autistic disorder: an open pilot study. AB - OBJECTIVE: To evaluate the tolerability and efficacy of risperidone in childhood autistic disorder. METHODS: A multicenter, open-label, dose-titration study involving seven autistic children (mean age 7.6 years) receiving risperidone for 4 weeks. RESULTS: Mean dose was 0.01 mg/kg/day on day 1, 0.019 mg/kg/day on day 7 (range 0.01-0.041 mg/kg/day) and 0.035 mg/kg/day on day 28 (range 0.014-0.064 mg/kg/day). Over the 4-week period, the Ritvo-Freeman Real Life Rating Scale total score measuring autistic behavior was significantly decreased (P = 0.019), as was the affectual reactions subscale (P = 0.029). Aberrant Behavior Checklist total score was significantly improved (P < 0.001), as were all subscales except inappropriate speech. Visual Analog Scale for individual target symptoms was significantly decreased (P = 0.001), and Clinical Global Impression severity of illness score was significantly improved (P = 0.006). The incidence of adverse effects was low, and no extrapyramidal symptoms were observed. No significant changes or clinically relevant abnormalities occurred in laboratory tests, vital signs or electrocardiograms. Plasma concentrations of the drug were similar to those in adult patients. CONCLUSIONS: These favorable results suggest that larger controlled trials of risperidone should be performed in autistic or mentally retarded patients with behavioral disturbances. PMID- 26984465 TI - Objective measures on knee instability: dynamic tests: a review of devices for assessment of dynamic knee laxity through utilization of the pivot shift test. AB - Current reconstructive methods used after anterior cruciate ligament (ACL) injury do not entirely restore native knee kinematics. Evaluation of dynamic knee laxity is important to accurately diagnose ACL deficiency, to evaluate reconstructive techniques, and to construct treatment algorithms for patients with ACL injury. The purpose of this study is to present recent progress in evaluation of dynamic knee laxity through utilization of the pivot shift test. A thorough electronic search was performed and relevant studies were assessed. Certain dynamic knee laxity measurement methods have been present for over 10 years (Navigation system, Electromagnetic sensor system) while other methods (Inertial sensor, Image analysis system) have been introduced recently. Methods to evaluate dynamic knee laxity through the pivot shift test are already potent. However, further refinement is warranted. In addition, to correctly quantify the pivot shift test, the involved forces need to be controlled through either standardization or mechanization of the pivot shift test. PMID- 26984466 TI - The posttraumatic stiff elbow: an update. AB - Posttraumatic elbow stiffness is a disabling condition that remains challenging to treat despite improvement of our understanding of the pathogenesis of posttraumatic contractures and new treatment regimens. This review provides an update and overview of the etiology of posttraumatic elbow stiffness, its classification, evaluation, nonoperative and operative treatment, and postoperative management. PMID- 26984467 TI - Anxiety and depression analyses of patients undergoing diagnostic cystoscopy. AB - PURPOSE: To prospectively assess anxiety and depression in patients undergoing diagnostic cystoscopy. METHODS: Patients presenting for outpatient diagnostic cystoscopy were recruited from four European urological departments. Anxiety and depression were assessed with the 'Hospital Anxiety and Depression Scale' (HADS) before cystoscopy and after 1 week. Statistical analyses, including the Chi square test, univariate, and multivariate logistic regression analyses, were carried out with SPSS v. 21 (IBM Corp., Armonk, NY). RESULTS: Prior to cystoscopy, 30.2 % of patients were anxious and 24.8 % depressive (n = 442). In the post-examination period, anxiety declined to 24.5 %, while depression was unchanged (24.4 %). Pre-cystoscopy anxiety was significantly more common in women (41.8 vs. 24.5 %, p < 0.0001), patients aged <65 years (34.9 vs. 25.9 %, p = 0.04), and in those being examined with rigid cystoscopes (35.7 vs. 23.9 %, p = 0.007). In multivariate regression analyses, female gender (OR 2.6, p < 0.0001), <65 years of age (OR 1.7, p = 0.03), and coexistence of depression (OR 7.8, p < 0.0001) were independently associated with elevated pre-cystoscopy anxiety. Anxious (OR 2.1, p = 0.03) and depressive (OR 2.1, p = 0.01) patients had higher odds of experiencing moderate or severe pain during cystoscopy. Bladder cancer diagnosis did not significantly change patient's anxiety (p = 0.23) or depression (p = 0.7) during the 1 week of follow-up. CONCLUSIONS: Women, patients aged <65 years, depressive patients and those being examined with rigid devices had higher rates of anxiety prior to cystoscopy. Anxious and depressive patients experienced more pain during cystoscopy. Bladder cancer diagnosis seems to have a minor effect on anxiety and depression during the first week after diagnosis. PMID- 26984468 TI - Expression of chemokine receptor CCR7 is a negative prognostic factor for patients with gastric cancer: a meta-analysis. AB - BACKGROUND: The prognostic significance of CC chemokine receptor type 7 (CCR7) for survival of patients with gastric cancer remains controversial. To investigate the impacts of CCR7 on clinicopathological findings and survival outcome in gastric cancer, we performed a meta-analysis. METHODS: A comprehensive search in PubMed, Embase, the Cochrane Library, and the CNKI database (1966 to November 2015) was undertaken for relevant studies. The relative risk and hazard ratios with their 95 % confidence intervals were used as measures to investigate the correlation between CCR7 expression and clinicopathological findings and overall survival rate. Sensitivity analysis was conducted to assess the stability of outcomes. RESULTS: Fifteen eligible studies comprising 1697 participants were included in our analysis. The pooled relative risks indicated CCR7 expression was significantly associated with deeper tumor invasion [0.61, 95 % confidence interval (CI) 0.45-0.84, p = 0.003], advanced stage (0.47, 95 % CI 0.32-0.69, p < 0.001), vascular invasion (2.12, 95 % CI 1.20-3.73, p = 0.009), lymph node metastasis (2.00, 95 % CI 1.48-2.70, p < 0.001), and lymphatic invasion (1.98, 95 % CI 1.43-2.72, p < 0.001) but not with age, tumor size, and histological type. The pooling of hazard ratios showed a significant relationship between positive CCR7 expression and worse 5-year overall survival rate (0.46, 95 % CI 0.31-0.70, p < 0.001). CONCLUSIONS: Our meta-analysis indicated high CCR7 expression is likely to be a negative clinicopathological prognostic factor for patients with gastric cancer and to predict a worse long-term survival outcome. PMID- 26984470 TI - Migraine and Meditation: Characteristics of Cortical Activity and Stress Coping in Migraine Patients, Meditators and Healthy Controls-An Exploratory Cross Sectional Study. AB - The aim of this exploratory cross-sectional study was to investigate the characteristics of cortical activity and stress coping in migraine patients, meditation experienced subjects, and healthy controls. 45 meditation experienced subjects, 46 migraine patients, and 46 healthy controls took part in the study. Cortical activity was measured with the contingent negative variation (CNV), a slow cortical event-related potential. Stress coping was examined with the standardized Stress Coping Questionnaire SVF-78. A one-way analysis of variance was used to investigate possible differences between the groups. CNV-amplitude was significantly higher in migraineurs than in controls. The meditators showed significantly lowest amplitudes. Migraine patients used negative stress-coping strategies significantly more often than meditators and healthy controls. Especially the application of the strategy "rumination" was most frequent in migraine patients and least frequent in meditators. Moreover, frequent rumination was significantly correlated with high CNV-amplitudes. Cortical and stress processing in people with meditation experience was improved compared to migraine patients and healthy controls. PMID- 26984469 TI - Microdosimetry of DNA conformations: relation between direct effect of (60)Co gamma rays and topology of DNA geometrical models in the calculation of A-, B- and Z-DNA radiation-induced damage yields. AB - In order to obtain the energy deposition pattern of ionizing radiation in the nanometric scale of genetic material and to investigate the different sensitivities of the DNA conformations, direct effects of (60)Co gamma rays on the three A, B and Z conformations of DNA have been studied. For this purpose, single-strand breaks (SSB), double-strand breaks (DSB), base damage (BD), hit probabilities and three microdosimetry quantities (imparted energy, mean chord length and lineal energy) in the mentioned DNA conformations have been calculated and compared by using GEometry ANd Tracking 4 (Geant4) toolkit. The results show that A-, B- and Z-DNA conformations have the highest yields of DSB (1.2 Gy(-1) Gbp(-1)), SSB (25.2 Gy(-1) Gbp(-1)) and BD (4.81 Gy(-1) Gbp(-1)), respectively. Based on the investigation of direct effects of radiation, it can be concluded that the DSB yield is largely correlated to the topological characteristics of DNA models, although the SSB yield is not. Moreover, according to the comparative results of the present study, a reliable candidate parameter for describing the relationship between DNA damage yields and geometry of DNA models in the theoretical radiation biology research studies would be the mean chord length (4 V/S) of the models. PMID- 26984472 TI - Fertility preservation in cancer patients with a poor prognosis: the controversy of posthumous reproduction. PMID- 26984471 TI - Body composition predictors of skeletal integrity in obesity. AB - OBJECTIVE: To determine body composition predictors of skeletal integrity in overweight/obese subjects using dual energy X-ray absorptiometry (DXA). We hypothesized that visceral adiposity would be negatively, and lean mass positively, associated with DXA measures of skeletal integrity in obesity. MATERIALS AND METHODS: Our study was institutional review board (IRB)-approved and Health Insurance Portability and Accountability Act (HIPAA)-compliant and written informed consent was obtained. We studied 82 overweight or obese, but otherwise healthy premenopausal women and men of similar age who were part of a clinical trial (mean age: 37 +/- 10 years, mean BMI: 34 +/- 7 kg/m(2)). All subjects underwent DXA of the spine and hip for assessment of bone mineral density (BMD), trabecular bone score (TBS), and hip structural analysis (HSA), and of the whole body for the assessment of body composition, including estimated visceral adipose tissue (VAT). RESULTS: Sixty-three subjects (77 %) had normal BMD and 19 subjects (23 %) had osteopenia. There were strong age-, sex-, and BMD independent positive associations between lean mass and HSA parameters (r = 0.50 to r = 0.81, p < 0.0001), whereas there was no association with TBS. There were strong age-, sex- and BMD-independent inverse associations between total fat and VAT mass and TBS (r = -0.60 and r = -0.72, p < 0.0001 for both correlations), whereas there were no associations with HSA parameters. CONCLUSION: Lean mass is a positive predictor of hip geometry, whereas fat and VAT mass are negative predictors of trabecular microarchitecture in overweight/obese subjects. PMID- 26984474 TI - Treatment of Myopia According to Sir Stewart Duke-Elder: Way Ahead of His Time! PMID- 26984475 TI - Neural Circuits Catch Fire. PMID- 26984476 TI - Optimization of protein samples for NMR using thermal shift assays. AB - Maintaining a stable fold for recombinant proteins is challenging, especially when working with highly purified and concentrated samples at temperatures >20 degrees C. Therefore, it is worthwhile to screen for different buffer components that can stabilize protein samples. Thermal shift assays or ThermoFluor((r)) provide a high-throughput screening method to assess the thermal stability of a sample under several conditions simultaneously. Here, we describe a thermal shift assay that is designed to optimize conditions for nuclear magnetic resonance studies, which typically require stable samples at high concentration and ambient (or higher) temperature. We demonstrate that for two challenging proteins, the multicomponent screen helped to identify ingredients that increased protein stability, leading to clear improvements in the quality of the spectra. Thermal shift assays provide an economic and time-efficient method to find optimal conditions for NMR structural studies. PMID- 26984478 TI - Multi-Shell Hollow Nanogels with Responsive Shell Permeability. AB - We report on hollow shell-shell nanogels with two polymer shells that have different volume phase transition temperatures. By means of small angle neutron scattering (SANS) employing contrast variation and molecular dynamics (MD) simulations we show that hollow shell-shell nanocontainers are ideal systems for controlled drug delivery: The temperature responsive swelling of the inner shell controls the uptake and release, while the thermoresponsive swelling of the outer shell controls the size of the void and the colloidal stability. At temperatures between 32 degrees C < T < 42 degrees C, the hollow nanocontainers provide a significant void, which is even larger than the initial core size of the template, and they possess a high colloidal stability due to the steric stabilization of the swollen outer shell. Computer simulations showed, that temperature induced switching of the permeability of the inner shell allows for the encapsulation in and release of molecules from the cavity. PMID- 26984479 TI - Evaluating the efficiency of a mixed culture biofilm for the treatment of black liquor and molasses in a mediator-less microbial fuel cell. AB - A microbial fuel cell (MFC) is an emerging environment-friendly technology to recover the useful energy available in waste by using microorganisms as catalyst. In this study, double chamber mediator-less MFCs separated by proton exchange membrane (PEM; Nafion) were constructed to determine the efficiency of mixed culture in using complex substrates (molasses and black liquor). It was found that activated sludge can serve as efficient source of electricigens for biofilm development on an anode. Power density of 2.425 W/m2 was generated from molasses with chemical oxygen demand (COD) removal efficiency of 67% as compared to power density of 3.55 W/m2 produced from black liquor along with COD removal efficiency of 78%. Moreover, it was demonstrated that surface area of PEM has a significant effect on power generation. An almost 5- to 8-fold increase in voltage was observed as the size of PEM was increased from 6.5 to 25 cm2. PMID- 26984477 TI - A novel hydroxyapatite film coated with ionic silver via inositol hexaphosphate chelation prevents implant-associated infection. AB - Various silver-coated implants have been developed to prevent implant-associated infections, and have shown dramatic effects in vitro. However, the in vivo results have been inconsistent. Recent in vitro studies showed that silver exerts antibacterial activity by mediating the generation of reactive oxygen species in the presence of oxygen. To maintain its antibacterial activity in vivo, the silver should remain in an ionic state and be stably bound to the implant surface. Here, we developed a novel bacteria-resistant hydroxyapatite film in which ionic silver is immobilized via inositol hexaphosphate chelation using a low-heat immersion process. This bacteria-resistant coating demonstrated significant antibacterial activity both in vitro and in vivo. In a murine bioluminescent osteomyelitis model, no bacteria were detectable 21 days after inoculation with S. aureus and placement of this implant. Serum interleukin-6 was elevated in the acute phase in this model, but it was significantly lower in the ionic-silver group than the control group on day 2. Serum C-reactive protein remained significantly higher in the control group than the ionic-silver group on day 14. Because this coating is produced by a low-heat immersion process, it can be applied to complex structures of various materials, to provide significant protection against implant-associated infections. PMID- 26984481 TI - Are behavioral practices for overcoming nature the hope for personalized medicine? PMID- 26984480 TI - Early human herpes virus type 6 reactivation in umbilical cord blood allogeneic stem cell transplantation. AB - Human herpes virus type 6 can reactivate in patients after allogeneic stem cell transplantation and has been associated with serious sequelae such as delayed engraftment and an increased risk of developing acute graft-versus-host disease (GVHD). This study investigated human herpes virus type 6 (HHV-6) reactivation within 60 days of transplantation in stem cell transplants utilizing single umbilical cord blood, double umbilical cord blood, or umbilical cord blood plus haploidentical stem cells. Of 92 patients, 60 (65%) had HHV-6 reactivation. Reactivation was not significantly influenced by any patient characteristics, disease characteristics, or by stem cell source (umbilical cord blood only versus haploidentical plus umbilical cord blood). We did not observe any impact of HHV-6 reactivation on neutrophil or platelet count recovery or on relapse-free survival. HHV-6 reactivation was associated with subsequent development of prerelapse acute GVHD (HR = 3.00; 95% CI, 1.4 to 6.4; p = 0.004). PMID- 26984473 TI - Trends in the Design and Development of Specific Aptamers Against Peptides and Proteins. AB - Aptamers are single stranded oligonucleotides, comparable to monoclonal antibodies (mAbs) in selectivity and affinity and have significant strategic properties in design, development and applications more than mAbs. Ease of design and development, simple chemical modification and the attachment of functional groups, easily handling and more adaptability with analytical methods, small size and adaptation with nanostructures are the valuable characteristics of aptamers in comparison to large protein based ligands. Among a broad range of targets that their specific aptamers developed, proteins and peptides have significant position according to the number of related studies performed so far. Since proteins control many of important physiological and pathological incidents in the living organisms, particularly human beings and because of the benefits of aptamers in clinical and analytical applications, aptamer related technologies in the field of proteins and peptides are under progress, exclusively. Currently, there is only one FDA approved therapeutic aptamer in the pharmaceutical market, which is specific to vascular endothelial growth factor and is prescribed for age related macular degenerative disease. Additionally, there are several aptamers in the different phases of clinical trials. Almost all of these aptamers are specific to clinically important peptide or protein targets. In addition, the application of protein specific aptamers in the design and development of targeted drug delivery systems and diagnostic biosensors is another interesting field of aptamer technology. In this review, significant efforts related to development and applications of aptamer technologies in proteins and peptides sciences were considered to emphasis on the importance of aptamers in medicinal and clinical applications. PMID- 26984482 TI - Urinary potassium excretion and risk of cardiovascular events. AB - BACKGROUND: Observational studies on dietary potassium and risk of cardiovascular disease (CVD) have reported weak-to-modest inverse associations. Long-term prospective studies with multiple 24-h urinary samples for accurate estimation of habitual potassium intake, however, are scarce. OBJECTIVE: We examined the association between urinary potassium excretion and risk of blood pressure related cardiovascular outcomes. DESIGN: We studied 7795 subjects free of cardiovascular events at baseline in the Prevention of Renal and Vascular End stage Disease study, a prospective, observational cohort with oversampling of subjects with albuminuria at baseline. Main cardiovascular outcomes were CVD [including ischemic heart disease (IHD), stroke, and vascular interventions], IHD, stroke, and new-onset heart failure (HF). Potassium excretion was measured in two 24-h urine specimens at the start of the study (1997-1998) and midway through follow-up (2001-2003). RESULTS: Baseline median urinary potassium excretion was 70 mmol/24 h (IQR: 56-84 mmol/24 h). During a median follow-up of 10.5 y (IQR: 9.9-10.8 y), a total of 641 CVD, 465 IHD, 172 stroke, and 265 HF events occurred. After adjustment for age and sex, inverse associations were observed between potassium excretion and risk [HR per each 26-mmol/24-h (1-g/d) increase; 95% CI] of CVD (0.87; 0.78, 0.97) and IHD (0.86; 0.75, 0.97), as well as nonsignificant inverse associations for risk of stroke (0.85; 0.68, 1.06) and HF (0.94; 0.80, 1.10). After further adjustment for body mass index, smoking, alcohol consumption, education, and urinary sodium and magnesium excretion, urinary potassium excretion was not statistically significantly associated with risk (multivariable-adjusted HR per 1-g/d increment; 95% CI) of CVD (0.96; 0.85, 1.09), IHD (0.90; 0.81, 1.04), stroke (1.09; 0.86, 1.39), or HF (0.99; 0.83, 1.18). No associations were observed between the sodium-to-potassium excretion ratio and risk of CVD, IHD, stroke, or HF. CONCLUSION: In this cohort with oversampling of subjects with albuminuria at baseline, urinary potassium excretion was not independently associated with a lower risk of cardiovascular events. PMID- 26984483 TI - Shadows of temperament in child eating patterns: implications for family and parenting research. PMID- 26984484 TI - Hippocampus as a mediator of the role of vitamin B-12 in memory. PMID- 26984485 TI - Cereals and pulse-based ready-to-use therapeutic food as an alternative to the standard milk- and peanut paste-based formulation for treating severe acute malnutrition: a noninferiority, individually randomized controlled efficacy clinical trial. AB - BACKGROUND: The cost of current standard ready-to-use therapeutic food (RUTF) is among the major obstacles to scaling up community-based management of acute malnutrition (CMAM), an important child survival strategy. Identifying a cheaper alternative is a global public health priority. OBJECTIVE: We sought to compare the efficacy of soya-maize-sorghum RUTF (SMS-RUTF) with that of standard peanut paste-based RUTF (P-RUTF). DESIGN: We used a nonblinded, parallel-group, simple randomized controlled trial along with a day care approach that enrolled 2 groups of children aged 6-23 and 24-59 mo, respectively, with severe acute malnutrition (SAM). RESULTS: Intention-to-treat (ITT) and per-protocol (PP) analyses showed noninferiority of SMS-RUTF compared with P-RUTF for the recovery rate [ITT: Delta = -2.0% (95% CI: -7.6%, 3.6%); PP: -1.9% (95% CI: -5.3%, 1.4%)], weight gain [Delta = -0.7 g . kg(-1). d(-1)(95% CI: -1.3, 0.0 g . kg(-1). d(-1))], and length of stay [Delta = 2.0 d (95% CI: -1.7, 5.8 d)] in children >=24 mo of age. In children <=23 mo of age, the recovery rate of SMS-RUTF was inferior to that of P RUTF [ITT: Delta = -20.8% (95% CI: -29.9%, -11.7%); PP: -17.2% (95% CI: -25.6%, 8.7%)]. Treatment with SMS-RUTF resulted in a greater increase in hemoglobin [0.670 g/dL (95% CI: 0.420, 0.921 g/dL);P< 0.001]. Treatment with both RUTFs resulted in the replenishment of all of the amino acids tested except for methionine. There were no differences at discharge between RUTF groups in fat mass [Delta = 0.3 kg (95% CI: -0.6, 1.6 kg);P= 0.341] or fat mass index [Delta = 0.4 kg/m(2)(95% CI: -0.3, 1.1 kg/m(2));P= 0.262]. By contrast, comparisons of fat free mass indicated lower concentrations than the community controls after treatment with either of the 2 RUTFs [Delta = -1.3 kg (95% CI: -2.4, -0.1 kg) andP= 0.034 for comparison between community controls and the SMS-RUTF group; Delta = -1.8 kg (95% CI: -2.9, -0.6 kg) andP= 0.003 for comparison between community controls and the P-RUTF group]. CONCLUSION: SMS-RUTF can be used to treat SAM in children aged >=24 mo to reduce the costs of CMAM programs. More research is required to optimize SMS-RUTF for younger children. This trial was registered in the Pan African Clinical Trial Registry as PACTR201303000475166. PMID- 26984486 TI - Low vitamin D status in Europe: moving from evidence to sound public health policies. PMID- 26984487 TI - Coffee and tea consumption in relation to estimated glomerular filtration rate: results from the population-based longitudinal Doetinchem Cohort Study. AB - BACKGROUND: Although coffee consumption and tea consumption have been linked to diabetes, the relation with kidney function is less clear and is underresearched. OBJECTIVE: We investigated the prospective associations of coffee and tea consumption with estimated glomerular filtration rate (eGFR). DESIGN: We included 4722 participants aged 26-65 y from the Doetinchem Cohort Study who were examined every 5 y for 15 y. Coffee and tea consumption (in cups/d) were assessed at each round. eGFR was assessed by using the Chronic Kidney Disease Epidemiology Collaboration equation based on both plasma creatinine and cystatin C. We determined the association between categories of coffee and tea intake and 1) eGFR and 2) subsequent annual changes in eGFR by using generalized estimating equation analyses. RESULTS: Baseline mean +/- SD eGFR was 108.0 +/- 14.7 mL . min(-1) . 1.73 m(-2) Tea consumption was not associated with eGFR. Those individuals who drank >6 cups coffee/d had a 1.33 (95% CI: 0.24, 2.43) mL . min( 1) . 1.73 m(-2) higher eGFR than those who drank <1 cup/d (P-trend = 0.02). This association was most apparent among those with a median age of >=46 y at baseline, with eGFR being 2.47 (95% CI: 0.42, 4.51) mL . min(-1) . 1.73 m(-2) higher in participants drinking >6 cups/d compared with <1 cup/d (P-trend = 0.02). Adjustment for biological risk factors and coffee constituents did not attenuate the associations. Neither coffee nor tea consumption was associated with changes in eGFR. CONCLUSIONS: Coffee consumption was associated with a slightly higher eGFR, particularly in those aged >=46 y. The absence of an association with eGFR changes suggests that the higher eGFR among coffee consumers is unlikely to be a result of glomerular hyperfiltration. Therefore, low to moderate coffee consumption is not expected to be a concern for kidney health in the general population. PMID- 26984488 TI - Solvent-Free Manufacturing of Electrodes for Lithium-ion Batteries. AB - Lithium ion battery electrodes were manufactured using a new, completely dry powder painting process. The solvents used for conventional slurry-cast electrodes have been completely removed. Thermal activation time has been greatly reduced due to the time and resource demanding solvent evaporation process needed with slurry-cast electrode manufacturing being replaced by a hot rolling process. It has been found that thermal activation time to induce mechanical bonding of the thermoplastic polymer to the remaining active electrode particles is only a few seconds. Removing the solvent and drying process allows large-scale Li-ion battery production to be more economically viable in markets such as automotive energy storage systems. By understanding the surface energies of various powders which govern the powder mixing and binder distribution, bonding tests of the dry deposited particles onto the current collector show that the bonding strength is greater than slurry-cast electrodes, 148.8 kPa as compared to 84.3 kPa. Electrochemical tests show that the new electrodes outperform conventional slurry processed electrodes, which is due to different binder distribution. PMID- 26984489 TI - The "Atlantis Forest hypothesis" does not explain Atlantic Forest phylogeography. PMID- 26984490 TI - Reply to Del Giudice et al., Chekroud et al., and Rosenblatt: Do brains of females and males belong to two distinct populations? PMID- 26984492 TI - Multivariate revisit to "sex beyond the genitalia". PMID- 26984491 TI - Patterns in the human brain mosaic discriminate males from females. PMID- 26984493 TI - Joel et al.'s method systematically fails to detect large, consistent sex differences. PMID- 26984494 TI - Reply to Raposo do Amaral et al.: The "Atlantis Forest hypothesis" adds a new dimension to Atlantic Forest biogeography. PMID- 26984495 TI - Insight into the flagella type III export revealed by the complex structure of the type III ATPase and its regulator. AB - FliI and FliJ form the FliI6FliJ ATPase complex of the bacterial flagellar export apparatus, a member of the type III secretion system. The FliI6FliJ complex is structurally similar to the alpha3beta3gamma complex of F1-ATPase. The FliH homodimer binds to FliI to connect the ATPase complex to the flagellar base, but the details are unknown. Here we report the structure of the homodimer of a C terminal fragment of FliH (FliHC2) in complex with FliI. FliHC2 shows an unusually asymmetric homodimeric structure that markedly resembles the peripheral stalk of the A/V-type ATPases. The FliHC2-FliI hexamer model reveals that the C terminal domains of the FliI ATPase face the cell membrane in a way similar to the F/A/V-type ATPases. We discuss the mechanism of flagellar ATPase complex formation and a common origin shared by the type III secretion system and the F/A/V-type ATPases. PMID- 26984497 TI - Microbes paired for biological gas-to-liquids (Bio-GTL) process. PMID- 26984496 TI - Soluble (pro)renin receptor via beta-catenin enhances urine concentration capability as a target of liver X receptor. AB - The extracellular domain of the (pro)renin receptor (PRR) is cleaved to produce a soluble (pro)renin receptor (sPRR) that is detected in biological fluid and elevated under certain pathological conditions. The present study was performed to define the antidiuretic action of sPRR and its potential interaction with liver X receptors (LXRs), which are known regulators of urine-concentrating capability. Water deprivation consistently elevated urinary sPRR excretion in mice and humans. A template-based algorithm for protein-protein interaction predicted the interaction between sPRR and frizzled-8 (FZD8), which subsequently was confirmed by coimmunoprecipitation. A recombinant histidine-tagged sPRR (sPRR His) in the nanomolar range induced a remarkable increase in the abundance of renal aquaporin 2 (AQP2) protein in primary rat inner medullary collecting duct cells. The AQP2 up-regulation relied on sequential activation of FZD8-dependent beta-catenin signaling and cAMP-PKA pathways. Inhibition of FZD8 or tankyrase in rats induced polyuria, polydipsia, and hyperosmotic urine. Administration of sPRR His alleviated the symptoms of diabetes insipidus induced in mice by vasopressin 2 receptor antagonism. Administration of the LXR agonist TO901317 to C57/BL6 mice induced polyuria and suppressed renal AQP2 expression associated with reduced renal PRR expression and urinary sPRR excretion. Administration of sPRR-His reversed most of the effects of TO901317. In cultured collecting duct cells, TO901317 suppressed PRR protein expression, sPRR release, and PRR transcriptional activity. Overall we demonstrate, for the first time to our knowledge, that sPRR exerts antidiuretic action via FZD8-dependent stimulation of AQP2 expression and that inhibition of this pathway contributes to the pathogenesis of diabetes insipidus induced by LXR agonism. PMID- 26984498 TI - Breaking the diffraction limit of light-sheet fluorescence microscopy by RESOLFT. AB - We present a plane-scanning RESOLFT [reversible saturable/switchable optical (fluorescence) transitions] light-sheet (LS) nanoscope, which fundamentally overcomes the diffraction barrier in the axial direction via confinement of the fluorescent molecular state to a sheet of subdiffraction thickness around the focal plane. To this end, reversibly switchable fluorophores located right above and below the focal plane are transferred to a nonfluorescent state at each scanning step. LS-RESOLFT nanoscopy offers wide-field 3D imaging of living biological specimens with low light dose and axial resolution far beyond the diffraction barrier. We demonstrate optical sections that are thinner by 5-12 fold compared with their conventional diffraction-limited LS analogs. PMID- 26984499 TI - Size and speed of the working stroke of cardiac myosin in situ. AB - The power in the myocardium sarcomere is generated by two bipolar arrays of the motor protein cardiac myosin II extending from the thick filament and pulling the thin, actin-containing filaments from the opposite sides of the sarcomere. Despite the interest in the definition of myosin-based cardiomyopathies, no study has yet been able to determine the mechanokinetic properties of this motor protein in situ. Sarcomere-level mechanics recorded by a striation follower is used in electrically stimulated intact ventricular trabeculae from the rat heart to determine the isotonic velocity transient following a stepwise reduction in force from the isometric peak force TP to a value T(0.8-0.2 TP). The size and the speed of the early rapid shortening (the isotonic working stroke) increase by reducing T from ~3 nm per half-sarcomere (hs) and 1,000 s(-1) at high load to ~8 nm?hs(-1) and 6,000 s(-1) at low load. Increases in sarcomere length (1.9-2.2 MUm) and external [Ca(2+)]o (1-2.5 mM), which produce an increase of TP, do not affect the dependence on T, normalized for TP, of the size and speed of the working stroke. Thus, length- and Ca(2+)-dependent increase of TP and power in the heart can solely be explained by modulation of the number of myosin motors, an emergent property of their array arrangement. The motor working stroke is similar to that of skeletal muscle myosin, whereas its speed is about three times slower. A new powerful tool for investigations and therapies of myosin-based cardiomyopathies is now within our reach. PMID- 26984502 TI - Breaking temporal symmetries for emission and absorption. AB - Time-reversal symmetries impose stringent constraints on emission and absorption. Antennas, from radiofrequencies to optics, are bound to transmit and receive signals equally well from the same direction, making a directive antenna prone to receive echoes and reflections. Similarly, in thermodynamics Kirchhoff's law dictates that the absorptivity and emissivity are bound to be equal in reciprocal systems at equilibrium, e(omega, theta)=a(omega, theta), with important consequences for thermal management and energy applications. This bound requires that a good absorber emits a portion of the absorbed energy back to the source, limiting its overall efficiency. Recent works have shown that weak time modulation or mechanical motion in suitably designed structures may largely break reciprocity and time-reversal symmetry. Here we show theoretically and experimentally that a spatiotemporally modulated device can be designed to have drastically different emission and absorption properties. The proposed concept may provide significant advances for compact and efficient radiofrequency communication systems, as well as for energy harvesting and thermal management when translated to infrared frequencies. PMID- 26984501 TI - A role for iron deficiency in dopaminergic neurodegeneration. PMID- 26984500 TI - Viral serine palmitoyltransferase induces metabolic switch in sphingolipid biosynthesis and is required for infection of a marine alga. AB - Marine viruses are the most abundant biological entities in the oceans shaping community structure and nutrient cycling. The interaction between the bloom forming alga Emiliania huxleyi and its specific large dsDNA virus (EhV) is a major factor determining the fate of carbon in the ocean, thus serving as a key host-pathogen model system. The EhV genome encodes for a set of genes involved in the de novo sphingolipid biosynthesis, not reported in any viral genome to date. We combined detailed lipidomic and biochemical analyses to characterize the functional role of this virus-encoded pathway during lytic viral infection. We identified a major metabolic shift, mediated by differential substrate specificity of virus-encoded serine palmitoyltransferase, a key enzyme of sphingolipid biosynthesis. Consequently, unique viral glycosphingolipids, composed of unusual hydroxylated C17 sphingoid bases (t17:0) were highly enriched in the infected cells, and their synthesis was found to be essential for viral assembly. These findings uncover the biochemical bases of the virus-induced metabolic rewiring of the host sphingolipid biosynthesis during the chemical "arms race" in the ocean. PMID- 26984503 TI - January Morning: An Autoethnographic Poem. PMID- 26984505 TI - Costs of Extending the Noncontributory Pension Program for Elderly: The Mexican Case. AB - Population aging coupled with high poverty rates among older persons and a lack of access to social-security benefits or traditional support systems have led governments in low and middle-income countries to introduce non-contributory pension programs for the elderly. This article reviews a non-contributory pension program introduced in Mexico in 2007 that has since expanded greatly. We use a variety of sources to estimate current and future costs of this program. PMID- 26984504 TI - Mechanical circulatory support in the new era: an overview. AB - This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901. PMID- 26984506 TI - The aging influence on cardiorespiratory, metabolic, and energy expenditure adaptations in head-out aquatic exercises: Differences between young and elderly women. AB - The purpose of this study was to: (1) establish the relationship between acute physiological responses and musical cadence; and (2) compare physiologic responses between young and older women. Eighteen older (mean = 65.06 +/- 5.77 years) and 19 young (mean = 22.16 +/- 2.63 years) women underwent an intermittent and progressive protocol performing the head-out aquatic exercise the "rocking horse." Results showed that older women demonstrated lower mean heart rate, blood lactate concentration (bLa), and oxygen uptake (VO2) at rest. Hierarchical linear modeling showed that variations in the rating of perceived effort and individual metabolic equivalent of task did not differ significantly by age group. However, during exercise, physiological responses of younger women were significantly different than for older women: in mean values, for each increased musical beat per minute, mean bLa was 0.003 mmol/l, VO2 was 0.024 ml/kg/min, and energy expenditure was 0.0001 kcal/kg/min higher for younger women. This study shows that increases in musical cadence increased the cardiorespiratory, metabolic, and energy expenditure responses. However, these responses during increasing intensity seemed to differ between young and older women, with lower values for the elderly group, when performing head-out aquatic exercises. PMID- 26984507 TI - DELLA proteins regulate expression of a subset of AM symbiosis-induced genes in Medicago truncatula. AB - The majority of the vascular flowering plants form symbiotic associations with fungi from the phylum Glomeromycota through which both partners gain access to nutrients, either mineral nutrients in the case of the plant, or carbon, in the case of the fungus. (1) The association develops in the roots and requires substantial remodeling of the root cortical cells where branched fungal hyphae, called arbuscules, are housed in a new membrane-bound apoplastic compartment. (2) Nutrient exchange between the symbionts occurs over this interface and its development and maintenance is critical for symbiosis. Previously, we showed that DELLA proteins, which are well known as repressors of gibberellic acid signaling, also regulate development of AM symbiosis and are necessary to enable arbuscule development. (3) Furthermore, constitutive overexpression of a dominant DELLA protein (della1-Delta18) is sufficient to induce transcripts of several AM symbiosis-induced genes, even in the absence of the fungal symbiont. (4) Here we further extend this approach and identify AM symbiosis genes that respond transcriptionally to constitutive expression of a dominant DELLA protein and also genes that do respond to this treatment. Additionally, we demonstrate that DELLAs interact with REQUIRED FOR ARBUSCULE DEVELOPMENT 1 (RAD1) which further extends our knowledge of GRAS factor complexes that have the potential to regulate gene expression during AM symbiosis. PMID- 26984508 TI - FAK tyrosine 407 organized with integrin alphaVbeta5 in Hs578Ts(i)8 advanced triple-negative breast cancer cells. AB - Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase known to promote cell migration and invasiveness. Overexpression and increased activity of FAK are closely associated with metastatic breast tumors and are linked to poor prognosis. This study discovered an inverse correlation between FAK activity and migratory and invasive behavior. We show decreased phosphorylation levels of FAK at tyrosine residues 397 and 861, and most prominently at Y407, in the more invasive Hs578Ts(i)8 subclone of the Hs578T breast cancer progression model. There is limited information available on FAK Y407, and here we demonstrate its presence in triple-negative breast cancer (TNBC) cell lines. Furthermore, our studies propose that localization of FAK Y407, rather than FAK expression and overall FAK Y407 phosphorylation levels, is crucial for the control of cell motility. FAK Y407 is found extensively at the cell periphery in focal adhesion like structures at each end of actin stress fibers and organized with integrin alphaVbeta5 receptors, linking the alphaVbeta5 integrin-mediated migratory behavior of Hs578Ts(i)8 cells to FAK Y407. These data suggest that subcellular localization, next to expression and activity levels, are important for understanding TNBC progression. Such an approach opens new avenues for further studies and may provide novel insight for the classification of TNBC and facilitate the discovery of effective biomarkers for diagnosis and therapy of TNBC. PMID- 26984509 TI - Experimental observation of the asymmetric instability of intermediate-reduced volume vesicles in extensional flow. AB - Vesicles provide an attractive model system to understand the deformation of living cells in response to mechanical forces. These simple, enclosed lipid bilayer membranes are suitable for complementary theoretical, numerical, and experimental analysis. A recent study [Narsimhan, Spann, Shaqfeh, J. Fluid Mech., 2014, 750, 144] predicted that intermediate-aspect-ratio vesicles extend asymmetrically in extensional flow. Upon infinitesimal perturbation to the vesicle shape, the vesicle stretches into an asymmetric dumbbell with a cylindrical thread separating the two ends. While the symmetric stretching of high-aspect-ratio vesicles in extensional flow has been observed and characterized [Kantsler, Segre, Steinberg, Phys. Rev. Lett., 2008, 101, 048101] as well as recapitulated in numerical simulations by Narsimhan et al., experimental observation of the asymmetric stretching has not been reported. In this work, we present results from microfluidic cross-slot experiments observing this instability, along with careful characterization of the flow field, vesicle shape, and vesicle bending modulus. The onset of this shape transition depends on two non-dimensional parameters: reduced volume (a measure of vesicle asphericity) and capillary number (ratio of viscous to bending forces). We observed that every intermediate-reduced-volume vesicle that extends forms a dumbbell shape that is indeed asymmetric. For the subset of the intermediate-reduced-volume regime we could capture experimentally, we present an experimental phase diagram for asymmetric vesicle stretching that is consistent with the predictions of Narsimhan et al. PMID- 26984510 TI - The relevance of tissue thiol histochemistry to diagnostic hematopathology. AB - Expression analyses suggest that alterations of the antioxidant state of some diffuse large B-cell lymphomas can assist prognosis; reversibly oxidized thiols may serve as a surrogate marker for identifying such cases. Little is known about the distribution of free thiols and reversibly oxidized thiols in human tissues. We developed a staining technique that enables visualization of tissue thiols in situ using bright field microscopy and validated it using gastrointestinal tissue specimens. We used our thiol staining technique to assess benign tonsillectomy and diffuse large B-cell lymphoma specimens. The gastrointestinal series revealed the presence of free thiols within epithelial cells and cells of the lamina propria. Staining for reversibly oxidized thiols was robust in gastric foveolar cells, intestinal goblet cells and the mucus they produce. Tonsillectomy specimens exhibited diffuse presence of free thiols. Staining for reversibly oxidized thiols was confined to germinal center macrophages and sinus histiocytes. Among the diffuse large B-cell lymphoma specimens, we observed strong staining for free thiols within malignant cells. By contrast to benign B cells, the malignant cells demonstrated pronounced and diffuse staining for reversibly oxidized thiols. We demonstrated intrinsic differences between benign and malignant cells. PMID- 26984511 TI - Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients. AB - BACKGROUND: 8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50%. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC). METHODS: SFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up. SFK inhibitors, dasatinib and saracatinib, were assessed in early ccRCC cell lines, 786-O and 769-P and a metastatic ccRCC cell line, ACHN (+/- Src) for effects on protein expression, apoptosis, proliferation and wound healing. RESULTS: High nuclear expression of Lyn and the downstream marker of activation, paxillin, were associated with decreased patient survival. Conversely, high cytoplasmic expression of other SFK members and downstream marker of activation, focal adhesion kinase (FAK) were associated with increased patient survival. Treatment of non-metastatic 786-O and 769-P cells with dasatinib, dose dependently reduced SFK activation, shown via SFK (Y(419)) and FAK (Y(861)) phosphorylation, with no effect in metastatic ACHN cells. Dasatinib also increased apoptosis, while decreasing proliferation and migration in 786-O and 769-P cell lines, both in the presence and absence of Src protein. CONCLUSIONS: Our data suggests that nuclear Lyn is a potential therapeutic target for ccRCC and dasatinib affects cellular functions associated with cancer progression via a Src kinase independent mechanism. PMID- 26984512 TI - Sandwich-like SnS/Polypyrrole Ultrathin Nanosheets as High-Performance Anode Materials for Li-Ion Batteries. AB - Sandwich-like SnS/polypyrrole ultrathin nanosheets were synthesized via a pyrrole reduction and in situ polymerization route, in which room-temperature synthesized ZnSn(OH)6 microcubes were used as the tin source. As anode materials for Li-ion batteries, they exhibit an extremely high reversible capacity (about 1000 mA h g( 1) at 0.1C), outstanding rate capability (with reversible capabilities of 878, 805, 747, 652, and 576 mA h g(-1) at 0.2C, 0.5C, 1C, 2C, and 5C, respectively), stable cycling performance, and high capacity retention (a high capacity of 703 mA h g(-1) at 1C after long 500 cycles). PMID- 26984513 TI - Feasibility of a 12-month-exercise intervention during and after radiation and chemotherapy in cancer patients: impact on quality of life, peak oxygen consumption, and body composition. AB - BACKGROUND: Accumulating evidence suggests that exercise is effective in treating many of the acute and chronic side effects of anti-cancer therapy. A recent meta analysis supported the use of exercise to prevent or treat fatigue and lymphoedema and to improve functional status in breast cancer patients. PATIENTS AND METHODS: This trial was intended as a controlled, prospective feasibility study evaluating the impact of physical exercise (PE) in cancer patients during and after treatment with radio- and chemotherapy. Inclusion criteria were previous or ongoing treatment for cancer, motivation for PE of 0.5-1hour duration at least twice weekly for at least 3 months. Continuation of PE was encouraged thereafter. Every three months the following endpoints were assessed: Peak oxygen consumption as measured by supervised cardiopulmonary exercise test, body composition and quality of life. RESULTS: A total of 45 patients were included with a median age of 49 years. Forty were female and five male. Cancer types were: Breast cancer (n = 30/67 %), gastrointestinal cancer (n = 5/12 %), other types (n = 10/22 %). Thirty-eight (84 %) of the patients were included during curative treatment of their disease. Seven (16 %) were considered palliative. Adherence to the PE-programme longer than 6 months was noted for 41/45 (91 %) of the patients. Intensity of PE was thrice weekly in 32/45 (71 %), twice weekly in 11/45 (24 %). Two of 45 patients (5 %) had no PE. Mean peak oxygen consumption increased from 18.8 +/- 5.6 ml/min/kg to 20.5 +/- 3 ml/min/kg and 19.9 +/- 4.7 ml/min/kg at 3 months (p = 0.005) and 12 months (p = 0.003), respectively. Median fat mass decreased from 30.7 +/- 15 kg to 28.9 +/- 15 kg and 29.5 +/- 13 kg at 3 months (p = 0.001) and 12 months (p = 0.017), respectively. Global health status scores increased from a median baseline value of 54.9 +/- 16.3 to 66.4 +/- 14 % and 68.0 +/- 20.3 % at 3 months (p = 0.001) and 12 months (p = 0.002), respectively. CONCLUSION: This exercise programme in cancer patients with 2-3 weekly supervised sessions over three months was well feasible and demonstrated measurable improvement of oxygen consumption, body composition and quality of life. In addition, a 90 %-adherence rate to the PE-programme beyond 6 months was encouraging. Further randomized prospective data in a larger patient population will be collected comparing the impact of two versus four months supervision. PMID- 26984514 TI - An analysis of the readability characteristics of oral health information literature available to the public in Tasmania, Australia. AB - BACKGROUND: The effectiveness of print-based health promotion materials is dependent on their readability. This study aimed to assess the characteristics of print-based oral health information literature publically available in Tasmania, Australia. METHODS: Oral health education brochures were collected from 11 dental clinics across Tasmania and assessed for structure and format, content and readability. Reading level was calculated using three widely-used measures: Flesch-Kincaid Grade Level (FKGL), Flesch Reading Ease, and Simple Measure of Gobbledygook (SMOG) reading grade level. RESULTS: The FKGL of the 67 brochures sampled ranged from grade 3 to 13. The grade level for government health department brochures (n = 14) ranged from grade 4 to 11 (5.6 +/- 1.8). Reading levels for materials produced by commercial sources (n = 22) ranged from 3 to 13 (8.3 +/- 2.1), those from professional associations (n = 22) ranged from grade 7 to 11 (8.9 +/- 0.9) and brochures produced by other sources (n = 9) ranged from 5 to 10 (7.6 +/- 1.5). The SMOG test was positively correlated with the FKGL (rs = 0.92, p < 0.001) though consistently rated materials 2-3 grades higher. The reading level required to comprehend brochures published by government sources were, on average, lower than those from commercial, professional and other sources. Government materials were also more likely to contain fewer words and professional jargon terms than brochures from the other sources. CONCLUSION: A range of oral health information brochures were publically available for patients in both public and private dental clinics. However, their readability characteristics differed. Many brochures required a reading skill level higher than that suited to a large proportion of the Tasmanian population. Readability and other characteristics of oral health education materials should be assessed to ensure their suitability for use with patients, especially those suspected of having low literacy skills. PMID- 26984515 TI - Taking Over Control From Highly Automated Vehicles in Complex Traffic Situations: The Role of Traffic Density. AB - OBJECTIVE: The aim of this study was to quantify the impact of traffic density and verbal tasks on takeover performance in highly automated driving. BACKGROUND: In highly automated vehicles, the driver has to occasionally take over vehicle control when approaching system limits. To ensure safety, the ability of the driver to regain control of the driving task under various driving situations and different driver states needs to be quantified. METHODS: Seventy-two participants experienced takeover situations requiring an evasive maneuver on a three-lane highway with varying traffic density (zero, 10, and 20 vehicles per kilometer). In a between-subjects design, half of the participants were engaged in a verbal 20-Questions Task, representing speaking on the phone while driving in a highly automated vehicle. RESULTS: The presence of traffic in takeover situations led to longer takeover times and worse takeover quality in the form of shorter time to collision and more collisions. The 20-Questions Task did not influence takeover time but seemed to have minor effects on the takeover quality. CONCLUSIONS: For the design and evaluation of human-machine interaction in takeover situations of highly automated vehicles, the traffic state seems to play a major role, compared to the driver state, manipulated by the 20-Questions Task. APPLICATION: The present results can be used by developers of highly automated systems to appropriately design human-machine interfaces and to assess the driver's time budget for regaining control. PMID- 26984516 TI - Multiplexed single-molecule force spectroscopy using a centrifuge. AB - We present a miniature centrifuge force microscope (CFM) that repurposes a benchtop centrifuge for high-throughput single-molecule experiments with high resolution particle tracking, a large force range, temperature control and simple push-button operation. Incorporating DNA nanoswitches to enable repeated interrogation by force of single molecular pairs, we demonstrate increased throughput, reliability and the ability to characterize population heterogeneity. We perform spatiotemporally multiplexed experiments to collect 1,863 bond rupture statistics from 538 traceable molecular pairs in a single experiment, and show that 2 populations of DNA zippers can be distinguished using per-molecule statistics to reduce noise. PMID- 26984517 TI - Serum CETP status is independently associated with reduction rates in LDL-C in pitavastatin-treated diabetic patients and possible involvement of LXR in its association. AB - BACKGROUND: Statins decrease cholesteryl ester transfer protein (CETP) levels, which have been positively associated with hepatic lipid content as well as serum low density lipoproteins-cholesterol (LDL-C) levels. However, the relationship between the CETP status and statin-induced reductions in LDL-C levels has not yet been elucidated in detail. We herein examined the influence of the CETP status on the lipid-reducing effects of pitavastatin in hypercholesterolemic patients with type 2 diabetes mellitus as well as the molecular mechanism underlying pitavastatin-induced modifications in CETP levels. METHODS: Fifty-three patients were treated with 2 mg of pitavastatin for 3 months. Serum levels of LDL-C, small dense (sd) LDL-C, and CETP were measured before and after the pitavastatin treatment. The effects of pitavastatin, T0901317, a specific agonist for liver X receptor (LXR) that reflects hepatic cholesterol contents, and LXR silencing on CETP mRNA expression in HepG2 cells were also examined by a real-time PCR assay. RESULTS: The pitavastatin treatment decreased LDL-C, sdLDL-C, and CETP levels by 39, 42, and 23%, respectively. Despite the absence of a significant association between CETP and LDL-C levels at baseline, baseline CETP levels and its percentage change were an independent positive determinant for the changes observed in LDL-C and sdLDL-C levels. The LXR activation with T0901317 (0.5 MUM), an in vitro condition analogous to hepatic cholesterol accumulation, increased CETP mRNA levels in HepG2 cells by approximately 220%, while LXR silencing markedly diminished the increased expression of CETP. Pitavastatin (5 MUM) decreased basal CETP mRNA levels by 21%, and this was completely reversed by T0901317. CONCLUSION: Baseline CETP levels may predict the lipid-reducing effects of pitavastatin. Pitavastatin-induced CETP reductions may be partially attributed to decreased LXR activity, predictable by the ensuing decline in hepatic cholesterol synthesis. TRIAL REGISTRATION: UMIN Clinical Trials Registry ID UMIN000019020. PMID- 26984521 TI - Corrigendum. PMID- 26984519 TI - MicroRNA analysis of breast ductal fluid in breast cancer patients. AB - Recent studies suggest that microRNAs show promise as excellent biomarkers for breast cancer; however there is still a high degree of variability between studies making the findings difficult to interpret. In addition to blood, ductal lavage (DL) and nipple aspirate fluids represent an excellent opportunity for biomarker detection because they can be obtained in a less invasive manner than biopsies and circumvent the limitations of evaluating blood biomarkers with regards to tissue of origin specificity. In this study, we have investigated for the first time, through a real-time PCR array, the expression of 742 miRNAs in the ductal lavage fluid collected from 22 women with unilateral breast tumors. We identified 17 differentially expressed miRNAs between tumor and paired normal samples from patients with ductal breast carcinoma. Most of these miRNAs have various roles in breast cancer tumorigenesis, invasion and metastasis, therapeutic response, or are associated with several clinical and pathological characteristics of breast tumors. Moreover, some miRNAs were also detected in other biological fluids of breast cancer patients such as serum (miR-23b, -133b, 181a, 338-3p, -625), plasma (miR-200a), and breast milk (miR-181a). A systems biology analysis of these differentially expressed miRNAs points out possible pathways and cellular processes previously described as having an important role in breast cancer such as Wnt, ErbB, MAPK, TGF-beta, mTOR, PI3K-Akt, p53 signaling pathways. We also observed a difference in the miRNA expression with respect to the histological type of the tumors. In conclusion, our findings suggest that miRNA analysis of breast ductal fluid is feasible and potentially very useful for the detection of breast cancer. PMID- 26984522 TI - Ara Darzi: Pet hate--procrastinators. PMID- 26984520 TI - A Systematic Review of Economic Evaluations of Pharmacogenetic Testing for Prevention of Adverse Drug Reactions. AB - BACKGROUND: Pharmacogenetics offers the potential to improve health outcomes by identifying individuals who are at greater risk of harm from certain medicines. Routine adoption of pharmacogenetic tests requires evidence of their cost effectiveness. OBJECTIVE: The present review aims to systematically review published economic evaluations of pharmacogenetic tests that aim to prevent or reduce the incidence of ADRs. METHODS: We conducted a systematic literature review of economic evaluations of pharmacogenetic tests aimed to reduce the incidence of adverse drug reactions. Literature was searched using Embase, MEDLINE and the NHS Economic Evaluation Database with search terms relating to pharmacogenetic testing, adverse drug reactions, economic evaluations and pharmaceuticals. Titles were screened independently by two reviewers. Articles deemed to meet the inclusion criteria were screened independently on abstract, and full texts reviewed. RESULTS: We identified 852 articles, of which 47 met the inclusion criteria. There was evidence supporting the cost effectiveness of testing for HLA-B*57:01 (prior to abacavir), HLA-B*15:02 and HLA-A*31:01 (prior to carbamazepine), HLA-B*58:01 (prior to allopurinol) and CYP2C19 (prior to clopidogrel treatment). Economic evidence was inconclusive with respect to TPMT (prior to 6-mercaptoputine, azathioprine and cisplatin therapy), CYP2C9 and VKORC1 (to inform genotype-guided dosing of coumarin derivatives), MTHFR (prior to methotrexate treatment) and factor V Leiden testing (prior to oral contraception). Testing for A1555G is not cost effective before prescribing aminoglycosides. CONCLUSIONS: Our systematic review identified robust evidence of the cost effectiveness of genotyping prior to treatment with a number of common drugs. However, further analyses and (or) availability of robust clinical evidence is necessary to make recommendations for others. PMID- 26984524 TI - The Relationship Between Mindfulness, Depressive Symptoms, and Non-Suicidal Self Injury Amongst Adolescents. AB - Mindfulness is often part of treatment for non-suicidal self-injury (NSSI); however, there has been limited research examining the role of mindfulness in NSSI. Thus, the current study sought to investigate the relationship among mindfulness, depressive symptoms, and NSSI (past year) in adolescents (N = 764; 56.8% female, M age = 14.42, SD = 0.64) with consideration of gender. Adolescents with recent NSSI (n = 74; 83.8% female, M age = 14.36, SD = 0.56) and a matched for age and gender no-NSSI group completed measures of mindfulness and depression. Findings revealed that mindfulness and depressive symptoms were negatively correlated, although significantly less so for the NSSI group. Second, the NSSI group reported greater depressive symptoms and less mindfulness. Finally, mindfulness was found to partially mediate the effect of depressive symptoms on NSSI. The present study is the first to provide empirical support for the protective role of mindfulness in NSSI. PMID- 26984523 TI - Cognitive Benefits of Online Social Networking for Healthy Older Adults. AB - Objectives: Research suggests that older adults who remain socially active and cognitively engaged have better cognitive function than those who are isolated and disengaged. This study examined the efficacy of learning and using an online social networking website, Facebook.com, as an intervention to maintain or enhance cognitive function in older adults. Method: Forty-one older adults were assigned to learn and use Facebook (n = 14) or an online diary website (active control, n = 13) for 8 weeks or placed on a waitlist (n = 14). Outcome measures included neuropsychological tests of executive functions, memory, and processing speed and self-report questionnaires about social engagement. Results: The Facebook group showed a significant increase in a composite measure of updating, an executive function factor associated with complex working memory tasks, compared to no significant change in the control groups. Other measures of cognitive function and social support showed no differential improvement in the Facebook group. Discussion: Learning and using an online social networking site may provide specific benefits for complex working memory in a group of healthy older adults. This may reflect the particular cognitive demands associated with online social networking and/or the benefits of social engagement more generally. PMID- 26984526 TI - RiboFR-Seq: a novel approach to linking 16S rRNA amplicon profiles to metagenomes. AB - 16S rRNA amplicon analysis and shotgun metagenome sequencing are two main culture independent strategies to explore the genetic landscape of various microbial communities. Recently, numerous studies have employed these two approaches together, but downstream data analyses were performed separately, which always generated incongruent or conflict signals on both taxonomic and functional classifications. Here we propose a novel approach, RiboFR-Seq (Ribosomal RNA gene flanking region sequencing), for capturing both ribosomal RNA variable regions and their flanking protein-coding genes simultaneously. Through extensive testing on clonal bacterial strain, salivary microbiome and bacterial epibionts of marine kelp, we demonstrated that RiboFR-Seq could detect the vast majority of bacteria not only in well-studied microbiomes but also in novel communities with limited reference genomes. Combined with classical amplicon sequencing and shotgun metagenome sequencing, RiboFR-Seq can link the annotations of 16S rRNA and metagenomic contigs to make a consensus classification. By recognizing almost all 16S rRNA copies, the RiboFR-seq approach can effectively reduce the taxonomic abundance bias resulted from 16S rRNA copy number variation. We believe that RiboFR-Seq, which provides an integrated view of 16S rRNA profiles and metagenomes, will help us better understand diverse microbial communities. PMID- 26984525 TI - Tat-dependent production of an HIV-1 TAR-encoded miRNA-like small RNA. AB - Evidence is accumulating that retroviruses can produce microRNAs (miRNAs). To prevent cleavage of their RNA genome, retroviruses have to use an alternative RNA source as miRNA precursor. The transacting responsive (TAR) hairpin structure in HIV-1 RNA has been suggested as source for miRNAs, but how these small RNAs are produced without impeding virus replication remained unclear. We used deep sequencing analysis of AGO2-bound HIV-1 RNAs to demonstrate that the 3' side of the TAR hairpin is processed into a miRNA-like small RNA. This ~21 nt RNA product is able to repress the expression of mRNAs bearing a complementary target sequence. Analysis of the small RNAs produced by wild-type and mutant HIV-1 variants revealed that non-processive transcription from the HIV-1 LTR promoter results in the production of short TAR RNAs that serve as precursor. These TAR RNAs are cleaved by Dicer and processing is stimulated by the viral Tat protein. This biogenesis pathway differs from the canonical miRNA pathway and allows HIV-1 to produce the TAR-encoded miRNA-like molecule without cleavage of the RNA genome. PMID- 26984527 TI - PolDIP2 interacts with human PrimPol and enhances its DNA polymerase activities. AB - Translesion synthesis (TLS) employs specialized DNA polymerases to bypass replication fork stalling lesions. PrimPol was recently identified as a TLS primase and polymerase involved in DNA damage tolerance. Here, we identify a novel PrimPol binding partner, PolDIP2, and describe how it regulates PrimPol's enzymatic activities. PolDIP2 stimulates the polymerase activity of PrimPol, enhancing both its capacity to bind DNA and the processivity of the catalytic domain. In addition, PolDIP2 stimulates both the efficiency and error-free bypass of 8-oxo-7,8-dihydrodeoxyguanosine (8-oxoG) lesions by PrimPol. We show that PolDIP2 binds to PrimPol's catalytic domain and identify potential binding sites. Finally, we demonstrate that depletion of PolDIP2 in human cells causes a decrease in replication fork rates, similar to that observed in PrimPol(-/ )cells. However, depletion of PolDIP2 in PrimPol(-/-)cells does not produce a further decrease in replication fork rates. Together, these findings establish that PolDIP2 can regulate the TLS polymerase and primer extension activities of PrimPol, further enhancing our understanding of the roles of PolDIP2 and PrimPol in eukaryotic DNA damage tolerance. PMID- 26984532 TI - Frozen-density embedding theory with average solvent charge densities from explicit atomistic simulations. AB - Besides molecular electron densities obtained within the Born-Oppenheimer approximation (rhoB(r)) to represent the environment, the ensemble averaged density ((r)) is also admissible in frozen-density embedding theory (FDET) [Wesolowski, Phys. Rev. A, 2008, 77, 11444]. This makes it possible to introduce an approximation in the evaluation of the solvent effect on quantum mechanical observables consisting of replacing the ensemble averaged observable by the observable evaluated at ensemble averaged rhoB(r). This approximation is shown to affect negligibly the solvatochromic shift in the absorption of hydrated acetone. The proposed model provides a continuum type of representation of the solvent, which reflects nevertheless its local structure, and it is to be applied as a post-simulation analysis tool in atomistic level simulations. PMID- 26984530 TI - An RNA trapping mechanism in Alphavirus mRNA promotes ribosome stalling and translation initiation. AB - During translation initiation, eukaryotic initiation factor 2 (eIF2) delivers the Met-tRNA to the 40S ribosomal subunit to locate the initiation codon (AUGi) of mRNA during the scanning process. Stress-induced eIF2 phosphorylation leads to a general blockade of translation initiation and represents a key antiviral pathway in mammals. However, some viral mRNAs can initiate translation in the presence of phosphorylated eIF2 via stable RNA stem-loop structures (DLP; Downstream LooP) located in their coding sequence (CDS), which promote 43S preinitiation complex stalling on the initiation codon. We show here that during the scanning process, DLPs of Alphavirus mRNA become trapped in ES6S region (680-914 nt) of 18S rRNA that are projected from the solvent side of 40S subunit. This trapping can lock the progress of the 40S subunit on the mRNA in a way that places the upstream initiator AUGi on the P site of 40S subunit, obviating the participation of eIF2. Notably, the DLP structure is released from 18S rRNA upon 60S ribosomal subunit joining, suggesting conformational changes in ES6Ss during the initiation process. These novel findings illustrate how viral mRNA is threaded into the 40S subunit during the scanning process, exploiting the topology of the 40S subunit solvent side to enhance its translation in vertebrate hosts. PMID- 26984528 TI - Suppression of gyrase-mediated resistance by C7 aryl fluoroquinolones. AB - Fluoroquinolones form drug-topoisomerase-DNA complexes that rapidly block transcription and replication. Crystallographic and biochemical studies show that quinolone binding involves a water/metal-ion bridge between the quinolone C3-C4 keto-acid and amino acids in helix-4 of the target proteins, GyrA (gyrase) and ParC (topoisomerase IV). A recent cross-linking study revealed a second drug binding mode in which the other end of the quinolone, the C7 ring system, interacts with GyrA. We report that addition of a dinitrophenyl (DNP) moiety to the C7 end of ciprofloxacin (Cip-DNP) reduced protection due to resistance substitutions in Escherichia coli GyrA helix-4, consistent with the existence of a second drug-binding mode not evident in X-ray structures of drug-topoisomerase DNA complexes. Several other C7 aryl fluoroquinolones behaved in a similar manner with particular GyrA mutants. Treatment of E. coli cultures with Cip-DNP selectively enriched an uncommon variant, GyrA-A119E, a change that may impede binding of the dinitrophenyl group at or near the GyrA-GyrA interface. Collectively the data support the existence of a secondary quinolone-binding mode in which the quinolone C7 ring system interacts with GyrA; the data also identify C7 aryl derivatives as a new way to obtain fluoroquinolones that overcome existing GyrA-mediated quinolone resistance. PMID- 26984529 TI - Exclusion of small terminase mediated DNA threading models for genome packaging in bacteriophage T4. AB - Tailed bacteriophages and herpes viruses use powerful molecular machines to package their genomes. The packaging machine consists of three components: portal, motor (large terminase; TerL) and regulator (small terminase; TerS). Portal, a dodecamer, and motor, a pentamer, form two concentric rings at the special five-fold vertex of the icosahedral capsid. Powered by ATPase, the motor ratchets DNA into the capsid through the portal channel. TerS is essential for packaging, particularly for genome recognition, but its mechanism is unknown and controversial. Structures of gear-shaped TerS rings inspired models that invoke DNA threading through the central channel. Here, we report that mutations of basic residues that line phage T4 TerS (gp16) channel do not disrupt DNA binding. Even deletion of the entire channel helix retained DNA binding and produced progeny phage in vivo On the other hand, large oligomers of TerS (11-mers/12 mers), but not small oligomers (trimers to hexamers), bind DNA. These results suggest that TerS oligomerization creates a large outer surface, which, but not the interior of the channel, is critical for function, probably to wrap viral genome around the ring during packaging initiation. Hence, models involving TerS mediated DNA threading may be excluded as an essential mechanism for viral genome packaging. PMID- 26984533 TI - The prevalence of visual hallucinations in non-affective psychosis, and the role of perception and attention. AB - BACKGROUND: Little is known about visual hallucinations (VH) in psychosis. We investigated the prevalence and the role of bottom-up and top-down processing in VH. The prevailing view is that VH are probably related to altered top-down processing, rather than to distorted bottom-up processing. Conversely, VH in Parkinson's disease are associated with impaired visual perception and attention, as proposed by the Perception and Attention Deficit (PAD) model. Auditory hallucinations (AH) in psychosis, however, are thought to be related to increased attention. METHOD: Our retrospective database study included 1119 patients with non-affective psychosis and 586 controls. The Community Assessment of Psychic Experiences established the VH rate. Scores on visual perception tests [Degraded Facial Affect Recognition (DFAR), Benton Facial Recognition Task] and attention tests [Response Set-shifting Task, Continuous Performance Test-HQ (CPT-HQ)] were compared between 75 VH patients, 706 non-VH patients and 485 non-VH controls. RESULTS: The lifetime VH rate was 37%. The patient groups performed similarly on cognitive tasks; both groups showed worse perception (DFAR) than controls. Non-VH patients showed worse attention (CPT-HQ) than controls, whereas VH patients did not perform differently. CONCLUSIONS: We did not find significant VH-related impairments in bottom-up processing or direct top-down alterations. However, the results suggest a relatively spared attentional performance in VH patients, whereas face perception and processing speed were equally impaired in both patient groups relative to controls. This would match better with the increased attention hypothesis than with the PAD model. Our finding that VH frequently co occur with AH may support an increased attention-induced 'hallucination proneness'. PMID- 26984531 TI - Polymorphism rs7278468 is associated with Age-related cataract through decreasing transcriptional activity of the CRYAA promoter. AB - CRYAA plays critical functional roles in lens transparency and opacity, and polymorphisms near CRYAA have been associated with age-related cataract (ARC). This study examines polymorphisms in the CRYAA promoter region for association with ARC and elucidates the mechanisms of this association. Three SNPs nominally associated with ARC were identified in the promoter region of CRYAA: rs3761382 (P = 0.06, OR (Odds ratio) = 1.5), rs13053109 (P = 0.04, OR = 1.6), rs7278468 (P = 0.007, OR = 0.6). The C-G-T haplotype increased the risk for ARC overall (P = 0.005, OR = 1.8), and both alleles and haplotypes show a stronger association with cortical cataract (rs3761382, P = 0.002, OR = 2.1; rs13053109, P = 0.002, OR = 2.1; rs7278468, P = 0.0007, OR = 0.5; C-G-T haplotype, P = 0.0003, OR = 2.2). The C-G-T risk haplotype decreased transcriptional activity through rs7278468, which lies in a consensus binding site for the transcription repressor KLF10. KLF10 binding inhibited CRYAA transcription, and both binding and inhibition were greater with the T rs7278468 allele. Knockdown of KLF10 in HLE cells partially rescued the transcriptional activity of CRYAA with rs7278468 T allele, but did not affect activity with the G allele. Thus, our data suggest that the T allele of rs7278468 in the CRYAA promoter is associated with ARC through increasing binding of KLF-10 and thus decreasing CRYAA transcription. PMID- 26984534 TI - Lifestyle-related effects of the web-based Kanker Nazorg Wijzer (Cancer Aftercare Guide) intervention for cancer survivors: a randomized controlled trial. AB - PURPOSE: The web-based Kanker Nazorg Wijzer (Cancer Aftercare Guide) responds to the needs of cancer survivors and oncology care providers to improve the counseling related to self-management of lifestyle and psychosocial challenges. In present study, overall intervention effects and the effects of using specific components were evaluated on vegetable, fruit, whole grain bread, and fish consumption, physical activity (PA), and smoking behavior. METHODS: Cancer survivors from 21 Dutch hospitals were recruited for a randomized controlled trial (N = 432). Intervention effects after 6 months were evaluated using multilevel linear regression analysis (complete cases and intention-to-treat). By conducting moderation analyses, additional effects of following the behavior related modules were explored. The false discovery rate correction was applied to account for multiple testing. RESULTS: After 6 months, 409 participants completed follow-up (dropout = 11.5 %). Indications were found that access to the intervention may result in increases of moderate PA and vegetable intake. The moderate PA increase was meaningful: 74.74 min p/w higher increase in the intervention condition. Effect sizes of moderate PA (d = .25) and vegetable (d = .37) consumption were comparable to prior effective interventions. Visiting behavior-related modules affected moderate PA, fruit, and fish consumption. However, after correction for multiple testing, significances expired. No significant intervention effect was found on smoking behavior due to low numbers of smokers. IMPLICATIONS FOR CANCER SURVIVORS: Although the effectiveness was only shown only to a limited extend, this study provided several indications that this theory-based, comprehensive, and personalized eHealth intervention provides valuable content to complement usual cancer aftercare. PMID- 26984537 TI - Plastic Deformation Modes of CuZr/Cu Multilayers. AB - We synthesized CuZr/Cu multilayers and performed nanoindentation testing to explore the dependence of plastic deformation modes on the thickness of CuZr layers. The Cu layers were 18 nm thick and the CuZr layers varied in thickness from 4 nm to 100 nm. We observed continuous plastic co-deformation in the 4 nm and 10 nm CuZr - 18 nm Cu multilayers and plastic-induced shear instability in thick CuZr layers (>20 nm). The plastic co-deformation is ascribed to the nucleation and interaction of shear transformation zones in CuZr layers at the adjacent interfaces, while the shear instability is associated with the nucleation and propagation of shear bands in CuZr layers. Shear bands are initialized in the CuZr layers due to the accumulated glide dislocations along CuZr-Cu interfaces, and propagate into adjacent Cu layers via slips on {111} plane non-parallel to the interface. Due to crystallographic constraint of the Cu layers, shear bands are approximately parallel to {111} plane in the Cu layer. PMID- 26984536 TI - Effect of dietary restriction and subsequent re-alimentation on the transcriptional profile of hepatic tissue in cattle. AB - BACKGROUND: Compensatory growth (CG) is an accelerated growth phenomenon observed in animals upon re-alimentation following a period of dietary restriction. It is typically utilised in livestock systems to reduce feed costs during periods of reduced feed availability. The biochemical mechanisms controlling this phenomenon, however, are yet to be elucidated. This study aimed to uncover the molecular mechanisms regulating the hepatic expression of CG in cattle, utilising RNAseq. RNAseq was performed on hepatic tissue of bulls following 125 days of dietary restriction (RES) and again following 55 days of subsequent re alimentation during which the animals exhibited significant CG. The data were compared with those of control animals offered the same diet on an ad libitum basis throughout (ADLIB). Elucidation of the molecular control of CG may yield critical information on genes and pathways which could be targeted as putative molecular biomarkers for the selection of animals with improved CG potential. RESULTS: Following a period of differential feeding, body-weight and liver weight were 161 and 4 kg higher, respectively, for ADLIB compared with RES animals. At this time RNAseq analysis of liver tissue revealed 1352 significantly differentially expressed genes (DEG) between the two treatments. DEGs indicated down-regulation of processes including nutrient transport, cell division and proliferation in RES. In addition, protein synthesis genes were up-regulated in RES following a period of restricted feeding. The subsequent 55 days of ad libitum feeding for both groups resulted in the body-weight difference reduced to 84 kg, with no difference in liver weight between treatment groups. At the end of 55 days of unrestricted feeding, 49 genes were differentially expressed between animals undergoing CG and their continuously fed counterparts. In particular, hepatic expression of cell proliferation and growth genes were greater in animals undergoing CG. CONCLUSIONS: Greater expression of cell cycle and cell proliferation genes during CG was associated with a 100 % recovery of liver weight during re-alimentation. Additionally, an apparent up-regulation in capacity for cellular protein synthesis during restricted feeding may contribute to and sustain CG during re-alimentation. DEGs identified are potential candidate genes for the identification of biomarkers for CG, which may be incorporated into future breeding programmes. PMID- 26984539 TI - Neck-Tongue Syndrome. AB - Neck-tongue syndrome (NTS) is a headache disorder often initiated by rapid axial rotation of the neck resulting in unilateral neck and/or occipital pain and transient ipsilateral tongue sensory disturbance. In this review, we examine reported cases of NTS since its initial description in 1980 to highlight the significance of this condition in the differential diagnosis of headache in patients presenting with neck pain and altered tongue sensation. The anatomical basis of NTS centers on the C1-C2 facet joint, C2 ventral ramus, and inferior oblique muscle in the atlanto-axial space. NTS may be categorized as complicated (secondary to another disease process) or uncomplicated (hereditary, related to trauma, or idiopathic). Diagnosis is based on clinical suspicion after a thorough history and physical without a pathognomonic radiologic finding. It is typically treated conservatively with medications, local injections, immobilization with cervical collars, or physical therapy; rarely is surgical intervention pursued. PMID- 26984540 TI - Sleep quality in schizophrenia and the effects of atypical antipsychotic medication. AB - BACKGROUND: Sleep disorders are widespread among patients with schizophrenia and contribute to adverse clinical outcomes. Antipsychotic drugs exert varying effects on sleep, and the effects of atypical agents may differ from those of conventional neuroleptics. OBJECTIVE: To review the literature on the effects of atypical medication on subjective and objective sleep quality in patients with schizophrenia. METHODS: A non-systematic literature review of Medline was performed in August 2003 searching the period from January 1985 to August 2003 for studies of the effects of atypical antipsychotics on sleep. RESULTS: We found published studies of clozapine, olanzapine, and risperidone, but none on quetiapine or ziprasidone. Studies with clozapine showed that it increased total sleep time, sleep efficiency, stage-2 non-rapid eye movement sleep and rapid eye movement (REM) sleep density, and decreased stage-4 sleep, slow wave sleep (SWS) and stage-1 sleep. Single-dose studies with olanzapine have shown that it increases SWS, sleep continuity, total sleeping time, subjective sleep quality, and delta sleep. Long-term studies with risperidone have shown improvements in total sleep, sleep efficiency, sleep continuity, SWS, and stage-2 sleep, and reductions in sleep latency, number of awakenings, and proportion of time awake. These benefits were paralleled by improvements in subjective sleep assessment and psychopathology, and psychosocial functioning. CONCLUSIONS: The evidence presented in this review suggests that atypical antipsychotics exert favorable effects on sleep profile compared with conventional agents, including improvement of subjective sleep quality and modification of specific sleep stages known to be associated with better clinical outcome. PMID- 26984541 TI - TNF-alpha and intPLA2 genes' polymorphism in anorexia nervosa. AB - OBJECTIVE: The aim of this study was the assessment of -308G/A tumor necrosis factor (TNF)-alpha gene polymorphism and intPLA2 gene polymorphism in patients with anorexia nervosa (AN) and healthy controls. SUBJECTS: We studied 91 non related patients with AN and 144 healthy women (blood donors and students). The mean age of women from study group was 18.22 years (SD +/- 3.13 years) and from control group was 31.71 years (SD +/- 8.22). METHODS: Gene polymorphisms were studied with the use of polymerase chain reaction-restriction fragment length polymorphism method. TNF-alpha gene polymorphism consists of G/A substitution in 308 promoter region. IntPLA2 gene polymorphism is related to intron 1, in which restrictive region is found and recognized by BanI enzyme. RESULTS: We did not obtain statistically significant differences in the frequency of genotypes and alleles of -308G/A TNF-alpha polymorphism between the study and control groups (genotypes: P = 0.106, alleles: P = 0.076). We did analogous analysis in the restrictive and bulimic subgroups. We did not observe statistically relevant differences in the frequency of genotypes (P = 0.700) and alleles (P = 0.305). We did not obtain statistically relevant difference in the frequency of genotypes and alleles of intPLA2 gene between the study group and controls (genotypes: P = 0.300, alleles: P = 0.331). We did analogous analysis in both subgroups of AN. We did not observe statistically relevant differences in the frequency of genotypes (P = 0.344) and alleles (P = 0.230). CONCLUSIONS: There was no statistically relevant trend for the association between TNF-alpha polymorphism and AN. We did not find association between studied polymorphism of intPLA2 gene and risk of AN. PMID- 26984542 TI - Prevalence of psychiatric morbidity in Polish population - national health interview survey. AB - OBJECTIVE: The aim was to evaluate the prevalence of psychiatric morbidity in Polish population. SUBJECTS AND METHODS: The national health interview survey was based on entire non-institutionalized Polish population by means of randomized, stratified (urban and rural census tracks) two-stage method (over 39 000 respondents). Prevalence of psychiatric morbidity was based on General Health Questionnaire-12. RESULTS: Psychiatric morbidity was noted in almost 1/4 of women and 1/5 of men in Poland, with small differences between urban and rural population. Every 10th woman reported such complaints at the age up to 25 years and every second above 75 years of age. Divorced and widowed respondents, irrespective of gender, have psychiatric disorders more frequently than compared groups. Higher prevalence of psychiatric morbidity was noted in out of work and especially disabled persons. The higher the level of education, the lower the frequency of psychiatric morbidity was observed. CONCLUSION: Presented survey enabled to evaluate prevalence of psychiatric morbidity in Polish representative sample. Findings should trigger more extended epidemiological studies. The requirement for epidemiological investigations increases in reform-awaiting health care system in Poland, for at least one reason that the improvement of the quality of services is closely associated with a detailed recognition of the problem. PMID- 26984543 TI - Switching atypical antipsychotics: a review. AB - BACKGROUND: Atypical antipsychotics are increasingly used in the treatment of diverse psychiatric disorders; however, there is little information on the 'why, when, and how' of switching between the different atypical antipsychotics currently available. OBJECTIVE: To review the data on switching and atypical antipsychotics. METHODS: A literature search was initially conducted using the key words followed by a search of relevant articles including conference abstracts; relevant pharmaceutical companies were also contacted. RESULTS: Clinical trial data are limited in terms of parameters measured, and case reports describe specific problems. Few studies are based on real world populations of psychiatric patients over the long-term. Careful patient and drug selections matched to a carefully supervised and appropriate cross titration based upon the pharmacodynamic and pharmacokinetic properties of all of the drugs involved is important to avoid potential complications such as re-emergence or worsening of psychosis and withdrawal, rebound, and emergent phenomena including new or uncovered side-effects. Psychoeducation and involvement of patients and caregivers in the process are also necessary for a successful switch. CONCLUSION: Despite the prevalence of switching in real world clinical practice, there is a paucity of data to guide clinicians with respect to effective and safe strategies. There are no criteria defining a successful switch. With the increasing range and formulations of atypical antipsychotics available, there is a rationale for their early use to avoid the practical problems associated with switching from conventional antipsychotics as well as the opportunity to maintain patients on an optimal atypical antipsychotic monotherapy. PMID- 26984538 TI - Molecular detection of Anaplasma platys infection in free-roaming dogs and ticks from Kenya and Ivory Coast. AB - BACKGROUND: Anaplasma platys is a bacterium parasitic in the canine platelets, representing the causative agent of canine cyclic thrombocytopenia, with a worldwide distribution, mainly in tropical countries. The agent has zoonotic potential, being reported in several human clinical cases. The suspected vector is the tick Rhipicephalus sanguineus (sensu lato), widely distributed in animals and humans in the tropical regions of South America, Africa, Asia and Australia, but also in southern Europe. Only few scattered data concerning the epidemiology of A. platys in sub-Saharan Africa are available. The aim of our study was to evaluate the epidemiological status of A. platys in dogs and cats from rural communities in eastern and western Africa, where dogs and their ticks live in close contact with humans. METHODS: A total of 216 canine and 22 feline blood samples and ticks feeding on them were collected in 2013 and 2014 from eight localities in Ivory Coast and four localities in Kenya. PCR was performed using specific primers targeting a portion of the 16S rRNA gene, followed by sequencing. RESULTS: The main results highlight the high prevalence of A. platys infection in dogs in both Eastern and Western Africa and report it for the first time in Eastern Africa and in Rhipicephalus camicasi. CONCLUSIONS: The presence of A. platys DNA in R. camicasi feeding on negative hosts together with the relatively high prevalence of A. platys, correlated with the absence of the probable vector Rhipicephalus sanguineus (s.l.) in Kenyan Island suggest the involvement of other tick species in the transmission of A. platys. PMID- 26984544 TI - Compliance and convenience: do physicians and patients see depot medication differently? AB - Physicians' attitudes to depot medication are often focused on improved compliance (adherence), and thus, short- and long-term treatment outcomes. By contrast, patients receiving such formulations tend to have a quite different viewpoint of medication. Factors such as convenience, side-effects and their beliefs about their illness play an important role in determining whether patients will adhere to their prescribed treatment regimen. The relationship between the patient and physician is of crucial importance in determining a patient's attitude to their medication; it is becoming increasingly clear that managing the illness in the long-term and avoiding relapse, while ensuring compliance, should be reframed as a collaborative process between the patient and physician. PMID- 26984545 TI - Sustained drug delivery optimizes long-term treatment of patients with schizophrenia. AB - Chronic disorders such as schizophrenia require long-term treatment programs in order to maintain patients at the lowest level of symptomatology, reduce the likelihood of psychotic relapse, and support achievement of remission and recovery. Evidence suggests that treatment with long-acting injectable antipsychotics reduces the impact of partial compliance and provides predictable release of medication, assuring continuous therapeutic coverage. Until recently, only conventional antipsychotic agents were available in long-acting formulations, thereby foregoing the advantages of the atypical class. Atypical agents which are given orally have been shown to provide long-term efficacy and tolerability benefits compared with conventional agents, but are limited by the need for daily administration. The most recent pharmacological strategy to achieve optimal maintenance treatment has been to combine the benefits of an atypical antipsychotic with delivery in a water-based long-acting formulation. The first antipsychotic to achieve this combination - long-acting risperidone - may thus represent an important advance in the optimization of long-term treatment outcomes in patients with schizophrenia. PMID- 26984535 TI - Chronic Toxoplasma gondii infection enhances beta-amyloid phagocytosis and clearance by recruited monocytes. AB - INTRODUCTION: Alzheimer's disease (AD) is associated with the accumulation of beta-amyloid (Abeta) as senile plaques in the brain, thus leading to neurodegeneration and cognitive impairment. Plaque formation depends not merely on the amount of generated Abeta peptides, but more importantly on their effective removal. Chronic infections with neurotropic pathogens, most prominently the parasite Toxoplasma (T.) gondii, are frequent in the elderly, and it has been suggested that the resulting neuroinflammation may influence the course of AD. In the present study, we investigated how chronic T. gondii infection and resulting neuroinflammation affect plaque deposition and removal in a mouse model of AD. RESULTS: Chronic infection with T. gondii was associated with reduced Abeta and plaque load in 5xFAD mice. Upon infection, myeloid-derived CCR2(hi) Ly6C(hi) monocytes, CCR2(+) Ly6C(int), and CCR2(+) Ly6C(low) mononuclear cells were recruited to the brain of mice. Compared to microglia, these recruited mononuclear cells showed highly increased phagocytic capacity of Abeta ex vivo. The F4/80(+) Ly6C(low) macrophages expressed high levels of Triggering Receptor Expressed on Myeloid cells 2 (TREM2), CD36, and Scavenger Receptor A1 (SCARA1), indicating phagocytic activity. Importantly, selective ablation of CCR2(+) Ly6C(hi) monocytes resulted in an increased amount of Abeta in infected mice. Elevated insulin-degrading enzyme (IDE), matrix metalloproteinase 9 (MMP9), as well as immunoproteasome subunits beta1i/LMP2, beta2i/MECL-1, and beta5i/LMP7 mRNA levels in the infected brains indicated increased proteolytic Abeta degradation. Particularly, LMP7 was highly expressed by the recruited mononuclear cells in the brain, suggesting a novel mechanism of Abeta clearance. CONCLUSIONS: Our results indicate that chronic Toxoplasma infection ameliorates beta amyloidosis in a murine model of AD by activation of the immune system, specifically by recruitment of Ly6C(hi) monocytes and by enhancement of phagocytosis and degradation of soluble Abeta. Our findings provide evidence for a modulatory role of inflammation-induced Abeta phagocytosis and degradation by newly recruited peripheral immune cells in the pathophysiology of AD. PMID- 26984546 TI - [Not Available]. PMID- 26984547 TI - [Not Available]. PMID- 26984548 TI - [Not Available]. PMID- 26984549 TI - Serotonin disrupts esophageal mucosal integrity: an investigation using a stratified squamous epithelial model. AB - BACKGROUND: Serotonin regulates gastrointestinal function, and mast cells are a potential nonneuronal source of serotonin in the esophagus. Tight junction (TJ) proteins in the esophageal epithelium contribute to the barrier function, and the serotonin signaling pathway may contribute to epithelial leakage in gastroesophageal reflux disease. Therefore, the aim of this study was to investigate the role of serotonin on barrier function, TJ proteins, and related signaling pathways. METHODS: Normal primary human esophageal epithelial cells were cultured with use of an air-liquid interface system. Serotonin was added to the basolateral compartment, and transepithelial electrical resistance (TEER) was measured. The expression of TJ proteins and serotonin receptor 7 (5-HT7) was assessed by Western blotting. The involvement of 5-HT7 was assessed with use of an antagonist and an agonist. The underlying cellular signaling pathways were examined with use of specific blockers. RESULTS: Serotonin decreased TEER and reduced the expression of TJ proteins ZO-1, occludin, and claudin 1, but not claudin 4. A 5-HT7 antagonist blocked the serotonin-induced decrease in TEER, and a 5-HT7 agonist decreased TEER. Inhibition of p38 mitogen-activated protein kinase (MAPK) reduced the serotonin-induced decrease in TEER. Inhibition of p38 MAPK blocked the decrease of ZO-1 levels, whereas extracellular-signal-regulated kinase (ERK) inhibition blocked the decrease in occludin levels. Cell signaling pathway inhibitors had no effect on serotonin-induced alterations in claudin 1 and claudin 4 levels. Serotonin induced phosphorylation of p38 MAPK and ERK, and a 5-HT7 antagonist partially blocked serotonin-induced phosphorylation of p38 MAPK but not that of ERK. CONCLUSIONS: Serotonin disrupted esophageal squamous epithelial barrier function by modulating the levels of TJ proteins. Serotonin signaling pathways may mediate the pathogenesis of gastroesophageal reflux disease. PMID- 26984551 TI - Device- and system-independent personal touchless user interface for operating rooms : One personal UI to control all displays in an operating room. AB - INTRODUCTION: In the modern day operating room, the surgeon performs surgeries with the support of different medical systems that showcase patient information, physiological data, and medical images. It is generally accepted that numerous interactions must be performed by the surgical team to control the corresponding medical system to retrieve the desired information. Joysticks and physical keys are still present in the operating room due to the disadvantages of mouses, and surgeons often communicate instructions to the surgical team when requiring information from a specific medical system. In this paper, a novel user interface is developed that allows the surgeon to personally perform touchless interaction with the various medical systems, switch effortlessly among them, all of this without modifying the systems' software and hardware. METHODS: To achieve this, a wearable RGB-D sensor is mounted on the surgeon's head for inside-out tracking of his/her finger with any of the medical systems' displays. Android devices with a special application are connected to the computers on which the medical systems are running, simulating a normal USB mouse and keyboard. When the surgeon performs interaction using pointing gestures, the desired cursor position in the targeted medical system display, and gestures, are transformed into general events and then sent to the corresponding Android device. Finally, the application running on the Android devices generates the corresponding mouse or keyboard events according to the targeted medical system. RESULTS AND CONCLUSION: To simulate an operating room setting, our unique user interface was tested by seven medical participants who performed several interactions with the visualization of CT, MRI, and fluoroscopy images at varying distances from them. Results from the system usability scale and NASA-TLX workload index indicated a strong acceptance of our proposed user interface. PMID- 26984550 TI - Carcinoma of the colon and rectum with deregulation of insulin-like growth factor 2 signaling: clinical and molecular implications. AB - BACKGROUND: Loss of imprinting (LOI) of the insulin-like growth factor 2 (IGF2) is an early event in the development of colorectal cancer (CRC). Whether LOI of IGF2 denotes a molecular or clinical cancer subgroup is currently unknown. METHODS: Tumor biopsies and paired normal mucosa from 399 patients with extensive clinical annotations were analyzed for LOI and IGF2 expression. LOI status in 140 informative cases was correlated with clinicopathologic parameters and outcome. RESULTS: LOI was frequent in normal mucosa and tumors and occurred throughout the large intestine. LOI was unrelated to microsatellite instability, KRAS mutation status, stage, and survival. However, CRC with LOI showed increased IGF2 protein levels and activation of AKT1. Gene expression analysis of tumors with and without LOI and knockdown of IGF2 in cell lines revealed that IGF2 induced distinct sets of activated and repressed genes, including Wnt5a, CEACAM6, IGF2BP3, KPN2A, BRCA2, and CDK1. Inhibition of AKT1 in IGF2-stimulated cells showed that the downstream effects of IGF2 on cell proliferation and gene expression were strictly AKT1-dependent. CONCLUSIONS: LOI of IGF2 is a frequent and early event in CRC that occurs both in the adenomatous polyposis coli (APC) gene-mutated and serrated route of carcinogenesis. LOI leads to overexpression of IGF2, activates IGF1R and AKT1, and is a powerful driver of cell proliferation. Moreover, our results suggest that IGF2 via AKT1 also contributes to non canonical wnt signaling. Although LOI had no significant impact on major clinical parameters and outcome, its potential as a target for preventive and therapeutic interventions merits further investigation. PMID- 26984552 TI - Registration of a statistical model to intraoperative ultrasound for scaphoid screw fixation. AB - PURPOSE: Volar percutaneous scaphoid fracture fixation is conventionally performed under fluoroscopy-based guidance, where surgeons need to mentally determine a trajectory for the insertion of the screw and its depth based on a series of 2D projection images. In addition to challenges associated with mapping 2D information to a 3D space, the process involves exposure to ionizing radiation. Three-dimensional ultrasound has been suggested as an alternative imaging tool for this procedure; however, it has not yet been integrated into clinical routine since ultrasound only provides a limited view of the scaphoid and its surrounding anatomy. METHODS: We propose a registration of a statistical wrist shape + scale + pose model to a preoperative CT and intraoperative ultrasound to derive a patient-specific 3D model for guiding scaphoid fracture fixation. The registered model is then used to determine clinically important intervention parameters, including the screw length and the trajectory of screw insertion in the scaphoid bone. RESULTS: Feasibility experiments are performed using 13 cadaver wrists. In 10 out of 13 cases, the trajectory of screw suggested by the registered model meets all clinically important intervention parameters. Overall, an average 94 % of maximum allowable screw length is obtained based on the measurements from gold standard CT. Also, we obtained an average 92 % successful volar accessibility, which indicates that the trajectory is not obstructed by the surrounding trapezium bone. CONCLUSIONS: These promising results indicate that determining clinically important screw insertion parameters for scaphoid fracture fixation is feasible using 3D ultrasound imaging. This suggests the potential of this technology in replacing fluoroscopic guidance for this procedure in future applications. PMID- 26984553 TI - User-friendly freehand ultrasound calibration using Lego bricks and automatic registration. AB - PURPOSE: As an inexpensive, noninvasive, and portable clinical imaging modality, ultrasound (US) has been widely employed in many interventional procedures for monitoring potential tissue deformation, surgical tool placement, and locating surgical targets. The application requires the spatial mapping between 2D US images and 3D coordinates of the patient. Although positions of the devices (i.e., ultrasound transducer) and the patient can be easily recorded by a motion tracking system, the spatial relationship between the US image and the tracker attached to the US transducer needs to be estimated through an US calibration procedure. Previously, various calibration techniques have been proposed, where a spatial transformation is computed to match the coordinates of corresponding features in a physical phantom and those seen in the US scans. However, most of these methods are difficult to use for novel users. METHODS: We proposed an ultrasound calibration method by constructing a phantom from simple Lego bricks and applying an automated multi-slice 2D-3D registration scheme without volumetric reconstruction. The method was validated for its calibration accuracy and reproducibility. RESULTS: Our method yields a calibration accuracy of [Formula: see text] mm and a calibration reproducibility of 1.29 mm. CONCLUSION: We have proposed a robust, inexpensive, and easy-to-use ultrasound calibration method. PMID- 26984554 TI - Joint registration of ultrasound, CT and a shape+pose statistical model of the lumbar spine for guiding anesthesia. AB - PURPOSE: Facet joint injections and epidural needle insertions are widely used for spine anesthesia. Accurate needle placement is important for effective therapy delivery and avoiding complications arising from damage of soft tissue and nerves. Needle guidance is usually performed by fluoroscopy or palpation, resulting in radiation exposure and multiple needle re-insertions. Several ultrasound (US)-based approaches have been proposed but have not found wide acceptance in clinical routine. This is mainly due to difficulties in interpretation of the complex spinal anatomy in US, which leads to clinicians' lack of confidence in relying only on information derived from US for needle guidance. METHODS: We introduce a multimodal joint registration technique that takes advantage of easy-to-interpret preprocedure computed topography (CT) scans of the lumbar spine to concurrently register a shape+pose model to the intraprocedure 3D US. Common shape coefficients are assumed between two modalities, while pose coefficients are specific to each modality. RESULTS: The joint method was evaluated on patient data consisting of ten pairs of US and CT scans of the lumbar spine. It was successfully applied in all cases and yielded an RMS shape error of 2.1 mm compared to the CT ground truth. The joint registration technique was compared to a previously proposed method of statistical model to US registration Rasoulian et al. (Information processing in computer-assisted interventions. Springer, Berlin, pp 51-60, 2013). The joint framework improved registration accuracy to US in 7 out of 17 visible vertebrae, belonging to four patients. In the remaining cases, the two methods were equally accurate. CONCLUSION: The joint registration allows visualization and augmentation of important anatomy in both the US and CT domain and improves the registration accuracy in both modalities. Observing the patient-specific model in the CT domain allows the clinicians to assess the local registration accuracy qualitatively, which is likely to increase their confidence in using the US model for deriving needle guidance decisions. PMID- 26984555 TI - Single-view X-ray depth recovery: toward a novel concept for image-guided interventions. AB - PURPOSE: X-ray imaging is widely used for guiding minimally invasive surgeries. Despite ongoing efforts in particular toward advanced visualization incorporating mixed reality concepts, correct depth perception from X-ray imaging is still hampered due to its projective nature. METHODS: In this paper, we introduce a new concept for predicting depth information from single-view X-ray images. Patient specific training data for depth and corresponding X-ray attenuation information are constructed using readily available preoperative 3D image information. The corresponding depth model is learned employing a novel label-consistent dictionary learning method incorporating atlas and spatial prior constraints to allow for efficient reconstruction performance. RESULTS: We have validated our algorithm on patient data acquired for different anatomy focus (abdomen and thorax). Of 100 image pairs per each of 6 experimental instances, 80 images have been used for training and 20 for testing. Depth estimation results have been compared to ground truth depth values. CONCLUSION: We have achieved around [Formula: see text] and [Formula: see text] mean squared error on abdomen and thorax datasets, respectively, and visual results of our proposed method are very promising. We have therefore presented a new concept for enhancing depth perception for image-guided interventions. PMID- 26984557 TI - Occurrence of (Z)-3,4-Dideoxyglucoson-3-ene in Different Types of Beer and Malt Beer as a Result of 3-Deoxyhexosone Interconversion. AB - In beer, 3-deoxyglucosone (3-DG) and 3-deoxygalactosone (3-DGal) are important sugar degradation products, but little is known about the relevance of the interconversion reaction between these compounds in different types of beer. In the present study, 3-DG was quantitated at concentrations of 12.9-52.7 mg/L and 3 DGal at concentrations of 6.0-26.4 mg/L in different types of beer (pilsner, wheat, bock, dark, and alcohol-free beers). The concentrations in malt beer tended to be higher. Largely overlapping concentration ranges precluded a classification of beers by their 3-deoxyglycosone contents. 3,4-Dideoxyglucoson-3 ene (3,4-DGE) was identified as an important intermediate and quantitated in beer and malt beer for the first time. The E and Z isomers of the corresponding quinoxaline were synthesized by a new synthetic approach and isolated by semipreparative HPLC. An assay was developed for quantitation of (E)- and (Z)-3,4 DGE by HPLC-MS/MS, and the Z isomer was determined at concentrations of 0.3-1.7 mg/L in beer and 0.5-4.8 mg/L in malt beer samples. The E isomer was shown to be of little importance. Concentrations of 5-hydroxymethylfurfural (HMF) were twice as high as those of (Z)-3,4-DGE in beer samples (0.4-3.7 mg/L) but much higher in malt beer samples (1.6-336 mg/L). PMID- 26984556 TI - Vessel-based registration of an optical shape sensing catheter for MR navigation. AB - PURPOSE: Magnetic resonance navigation (MRN), achieved with an upgraded MRI scanner, aims to guide therapeutic nanoparticles from their release in the hepatic vascular network to embolize highly vascularized liver tumors. Visualizing the catheter in real-time within the arterial network is important for selective embolization within the MR gantry. To achieve this, a new MR compatible catheter tracking technology based on optical shape sensing is used. METHODS: This paper proposes a vessel-based registration pipeline to co-align this novel catheter tracking technology to the patient's diagnostic MR angiography (MRA) with 3D roadmapping. The method first extracts the 3D hepatic arteries from a diagnostic MRA based on concurrent deformable models, creating a detailed representation of the patient's internal anatomy. Once the optical shape sensing fibers, inserted in a double-lumen catheter, is guided into the hepatic arteries, the 3D centerline of the catheter is inferred and updated in real-time using strain measurements derived from fiber Bragg gratings sensors. Using both centerlines, a diffeomorphic registration based on a spectral representation of the high-level geometrical primitives is applied. RESULTS: Results show promise in registration accuracy in five phantom models created from stereolithography of patient-specific vascular anatomies, with maximum target registration errors below 2 mm. Furthermore, registration accuracy with the shape sensing tracking technology remains insensitive to the magnetic field of the MR magnet. CONCLUSIONS: This study demonstrates that an accurate registration procedure of a shape sensing catheter with diagnostic imaging is feasible. PMID- 26984558 TI - Codeine in paediatrics: pharmacology, prescribing and controversies. AB - Codeine is a drug that until recently was widely used in children. It was endorsed by the WHO as the second step on the analgesic ladder for cancer pain and has been used routinely for postoperative and breakthrough pain. Recently, its safety and efficacy have been called into question, following deaths after adenotonsillectomy was associated with its use. This has led to regulation by the US Food and Drug Administration, European Medicines Agency and the UK Medicines and Healthcare products Regulatory Agency to place significant restrictions on its use, and some centres have stopped using it altogether.In this article, we discuss the developmental pharmacology underpinning its action, reviewing what is known about the pharmacokinetics, pharmacodynamics and pharmacogenetics in children, how this relates to prescribing, as well as the practical issues and the recent regulatory framework surrounding its use. PMID- 26984560 TI - Nineteen-year follow-up of a patient with severe glutathione synthetase deficiency. AB - Glutathione synthetase deficiency is a rare autosomal recessive disorder resulting in low levels of glutathione and an increased susceptibility to oxidative stress. Patients with glutathione synthetase deficiency typically present in the neonatal period with hemolytic anemia, metabolic acidosis and neurological impairment. Lifelong treatment with antioxidants has been recommended in an attempt to prevent morbidity and mortality associated with the disorder. Here, we present a 19-year-old female who was diagnosed with glutathione synthetase deficiency shortly after birth and who has been closely followed in our metabolic clinic. Despite an initial severe presentation, she has had normal intellectual development and few complications of her disorder with a treatment regimen that includes polycitra (citric acid, potassium citrate and sodium citrate), vitamin C, vitamin E and selenium. PMID- 26984559 TI - Fetal cell-free DNA fraction in maternal plasma is affected by fetal trisomy. AB - The purpose of this noninvasive prenatal testing (NIPT) study was to compare the fetal fraction of singleton gestations by gestational age, maternal characteristics and chromosome-specific aneuploidies as indicated by z-scores. This study was a multicenter prospective cohort study. Test data were collected from women who underwent NIPT by the massively parallel sequencing method. We used sequencing-based fetal fraction calculations in which we estimated fetal DNA fraction by simply counting the number of reads aligned within specific autosomal regions and applying a weighting scheme derived from a multivariate model. Relationships between fetal fractions and gestational age, maternal weight and height, and z-scores for chromosomes 21, 18 and 13 were assessed. A total of 7740 pregnant women enrolled in the study, of which 6993 met the study criteria. As expected, fetal fraction was inversely correlated with maternal weight (P<0.001). The median fetal fraction of samples with euploid result (n=6850) and trisomy 21 (n=70) were 13.7% and 13.6%, respectively. In contrast, the median fetal fraction values for samples with trisomies 18 (n=35) and 13 (n=9) were 11.0% and 8.0%, respectively. The fetal fraction of samples with trisomy 21 NIPT result is comparable to that of samples with euploid result. However, the fetal fractions of samples with trisomies 13 and 18 are significantly lower compared with that of euploid result. We conclude that it may make detecting these two trisomies more challenging. PMID- 26984563 TI - Accredited genetic testing in the Arab Gulf region: reinventing the wheel. PMID- 26984561 TI - MECP2 mutations in Czech patients with Rett syndrome and Rett-like phenotypes: novel mutations, genotype-phenotype correlations and validation of high resolution melting analysis for mutation scanning. AB - Rett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by developmental regression with loss of motor, communication and social skills, onset of stereotypic hand movements and often seizures. RTT is primarily caused by de novo mutations in the methyl-CpG-binding protein 2 gene (MECP2). We established a high-resolution melting (HRM) technique for mutation scanning of the MECP2 gene and performed analyses in Czech patients with RTT, autism spectrum conditions and intellectual disability with Rett-like features. In the cases with confirmed MECP2 mutations, we determined X-chromosome inactivation (XCI), examined the relationships between genotype and clinical severity and evaluated the modifying influence of XCI. Our results demonstrate that HRM analysis is a reliable method for the detection of point mutations, small deletions and duplications in the MECP2 gene. We identified 29 pathogenic mutations in 75 girls, including four novel mutations: c.155_1189del1035;909_932inv;insC, c.573delC, c.857_858dupAA and c.1163_1200del38. Skewed XCI (ratio >75%) was found in 19.3% of the girls, but no gross divergence in clinical severity was observed. Our findings confirm a high mutation frequency in classic RTT (92%) and a correlation between the MECP2 mutation type and clinical severity. We also demonstrate limitations of XCI in explaining all of the phenotypic differences in RTT. PMID- 26984562 TI - Spectrum of AGL mutations in Chinese patients with glycogen storage disease type III: identification of 31 novel mutations. AB - Glycogen storage disease type III (GSD III), a rare autosomal recessive disease characterized by hepatomegaly, fasting hypoglycemia, growth retardation, progressive myopathy and cardiomyopathy, is caused by deficiency of the glycogen debranching enzyme (AGL). Direct sequencing of human AGL cDNA and genomic DNA has enabled analysis of the underlying genetic defects responsible for GSD III. To date, the frequent mutations in different areas and populations have been described in Italy, Japan, Faroe Islands and Mediterranean area, whereas little has been performed in Chinese population. Here we report a sequencing-based mutation analysis in 43 Chinese patients with GSD III from 41 families. We identified 51 different mutations, including 15 splice-site (29.4%), 11 small deletions (21.6%), 12 nonsense (23.5%), 7 missense (13.7%), 5 duplication (9.8%) and 1 complex deletion/insertion (2.0%), 31 of which are novel mutations. The most common mutation is c.1735+1G>T (11.5%). The association of AGL missense and small in-frame deletion mutations with normal creatine kinase level was observed. Our study extends the spectrum of AGL mutations and suggests a genotype-phenotype correlation in GSD III. PMID- 26984566 TI - Human health risk assessment of heavy metals in a replaced urban industrial area of Qingdao, China. AB - The aim of this study was risk characterization of a replaced urban industrial land located north of Qingdao, in relation to heavy metals values. Soil concentrations of Cd, Pb, Cu, Ni, Cr, and Zn were analyzed. It was observed that the components of Cd, Pb, Cu, Ni, Cr, and Zn are about 2.22, 8.07, 4.70, 6.81, 2.65, and 3.0-folds, respectively, when compared with the local natural background values in Qingdao. The spatial distribution of heavy metals indicated that these hotspots for Cr and Zn located in the southwestern part, Ni and Cd in the middle of the south area, Pb in the northwest, and Cu in the middle of the east area. The values of pollution index and Nemerow integrated pollution index revealed that 100 % of soil samples were moderately or heavily contaminated by six heavy metals. From these results, human health risk assessment for sensitive population was performed according to two different land uses. For non carcinogenic risk, the direct oral ingestion appeared to be the main exposure pathway followed by dermal and inhalation absorption. The HI values of Pb and Cr characterized for children were larger than 1, while HI values of each metal for adults in two scenarios were lower than 1. Besides, carcinogenic risk from inhalation exposure to Cr for children and adults in two scenarios all exceeded the safety limit. PMID- 26984565 TI - [Influenza pandemic deaths in Germany from 1918 to 2009. Estimates based on literature and own calculations]. AB - BACKGROUND AND OBJECTIVE: Estimation of the number of deaths as a consequence of the influenza pandemics in the twentieth and twenty-first centuries (i.e. 1918 1919, 1957-1958, 1968-1970 and 2009) is a challenge worldwide and also in Germany. After conducting a systematic literature search complemented by our own calculations, values and estimates for all four pandemics were collated and evaluated. METHOD: A systematic literature search including the terms death, mortality, pandemic, epidemic, Germany, 1918, 1957, 1968, 2009 was performed. Hits were reviewed by title and abstract and selected for possible relevance. We derived our own estimates using excess mortality calculations, which estimate the mortality exceeding that to be expected. All identified values were evaluated by methodology and quality of the database. Numbers of pandemic deaths were used to calculate case fatality rates and were compared with global values provided by the World Health Organization. RESULTS: For the pandemic 1918-1919 we identified 5 relevant publications, 3 for the pandemics 1957-1958 and 1968-1970 and 3 for 2009. For all four pandemics the most plausible estimations were based on time series analyses, taken either from the literature or from our own calculations based on monthly or weekly all cause death statistics. For the four pandemics these estimates were in chronological order 426,600 (1918-1919), 29,100 (1957 1958), 46,900 (1968-1970) and 350 (2009) excess pandemic-related deaths. This translates to an excess mortality ranging between 691 per 100,000 (0.69 % in 1918 1919) and 0.43 per 100,000 (0.00043 % in 2009). Case fatality rates showed good agreement with global estimates. CONCLUSION: We have proposed plausible estimates of pandemic-related excess number of deaths for the last four pandemics as well as excess mortality in Germany. The heterogeneity among pandemics is large with a variation factor of more than 1000. Possible explanations include characteristics of the virus or host (immunity), social conditions, status of the healthcare system and medical advances. PMID- 26984567 TI - Treatment of pulmonary arterial hypertension in congenital heart disease in Singapore versus the Netherlands: age exceeds ethnicity in influencing clinical outcome. AB - BACKGROUND: Advanced treatment of pulmonary arterial hypertension (PAH) in congenital heart disease (CHD) is increasingly applied worldwide following the mainly Western world based-international PAH-CHD guidelines. However, studies comparing clinical presentation and outcome after the initiation of PAH-specific treatment are lacking. We aimed to analyse this in a Singaporean and Dutch cohort of PAH-CHD patients. METHODS: Adult CHD patients starting PAH-specific therapy, enrolled in two nationwide registries, were analysed. Patients received phosphodiesterase-type-5 inhibitors, endothelin receptor antagonists, or a combination. Change in six-minute walk test (6MWT) during follow-up was analysed using linear mixed model analysis. Determinants for mortality were assessed using Cox proportional hazard analyses. RESULTS: A total of 74 patients, 45 Dutch (mean age 47 +/- 14 years) and 29 Singaporean (mean age 41 +/- 14 years) were analysed. Despite a lower 6MWT (312 versus 395 metres, p = 0.01) and peak VO2 (35 versus 49 % of predicted, p = 0.01) at baseline in Singaporean patients, the treatment effect was similar in the two populations. Age at initiation of therapy (per 5 year lower age, beta = + 4.5, p = 0.017) was the strongest predictor of improvement in exercise capacity, corrected for ethnicity, baseline 6MWT, sex and CHD defect. CONCLUSIONS: Patients from Singapore had a worse clinical performance at baseline compared with the PAH-CHD patients from the Netherlands. No relation between ethnicity and improvement in 6MWT after PAH-specific therapy was found. Age at initiation of PAH-specific therapy was the strongest predictor of treatment efficacy and mortality, emphasising the need for early initiation of treatment in these patients. PMID- 26984568 TI - Erratum to: Medication therapy for attention deficit/hyperactivity disorder is associated with lower risk of fracture: a retrospective cohort study. PMID- 26984564 TI - Systematic molecular analyses of SHOX in Japanese patients with idiopathic short stature and Leri-Weill dyschondrosteosis. AB - The etiology of idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD) in European patients is known to include SHOX mutations and copy-number variations (CNVs) involving SHOX and/or the highly evolutionarily conserved non coding DNA elements (CNEs) flanking the gene. However, the frequency and types of SHOX abnormalities in non-European patients and the clinical importance of mutations in the CNEs remains to be clarified. Here, we performed systematic molecular analyses of SHOX for 328 Japanese patients with ISS or LWD. SHOX abnormalities accounted for 3.8% of ISS and 50% of LWD cases. CNVs around SHOX were identified in 16 cases, although the ~47 kb deletion frequently reported in European patients was absent in our cases. Probably damaging mutations and benign/silent substitutions were detected in four cases, respectively. Although CNE-linked substitutions were detected in 15 cases, most of them affected poorly conserved nucleotides and were shared by unaffected individuals. These results suggest that the frequency and mutation spectrum of SHOX abnormalities are comparable between Asian and European patients, with the exception of a European specific downstream deletion. Furthermore, this study highlights the clinical importance and genetic heterogeneity of the SHOX-flanking CNVs, and indicates a limited clinical significance of point mutations in the CNEs. PMID- 26984569 TI - Effect of twelve-month physical exercise program on patients with osteoporotic vertebral fractures: a randomized, controlled trial. AB - We performed a randomized clinical trial to evaluate the effect of a 12-month physical exercise program on quality of life, balance, and functional mobility in postmenopausal women with osteoporotic vertebral fractures. All three outcomes improved in the intervention group and were better than in the controls. INTRODUCTION: Th aim of this study was to evaluate the effectiveness of a structured physical exercise intervention on quality of life, functional mobility, and balance in patients with osteoporotic vertebral fractures and back pain. METHODS: Seventy-eight postmenopausal women with vertebral fractures were randomized into an exercise group (n = 40) and a control group (n = 38). The mean age was 69.2 +/- 7.7 years. All women had at least one osteoporotic vertebral fracture and suffered from chronic back pain. Patients with a history of vertebral and non-vertebral fracture within the past 6 months were excluded. The 40-min exercise program was conducted twice weekly for 1 year. Participants in the control group were instructed to continue their usual daily activities. Participants were assessed at baseline and at 12 months using the Quality of Life Questionnaire (QUALEFFO-41). Balance was measured with the Balance Master(r) System NeuroCom(r) and functional mobility was measured with the "timed up and go" test and "sit-to-stand" test. RESULTS: Total QUALEFFO-41 score after 12 months was significantly better in the exercise group (44.2 +/- 7.5) compared to the control group (56.6 +/- 9.4), p < 0.0001. Quality of life improved in domains: "Pain", "Physical function: Jobs around the house", "Physical function: Mobility", "Social function", "General health perception" in the exercise group as compared to the control group. After 12 months, balance as assessed by "Tandem Walk and Sway" became significantly better in the exercise group as compared to the control group (p = 0.02). A significant improvement in the "timed up and go" test (p = 0.02) and the "sit-to-stand" test (p = 0.01) was shown in the exercise group compared to the control group. CONCLUSIONS: This is the first 12 month randomized clinical trial of exercise in osteoporotic women with a vertebral fracture that demonstrates improvement of three key outcome measures: quality of life, functional mobility, and balance. PMID- 26984570 TI - The circulating sphingosine-1-phosphate level predicts incident fracture in postmenopausal women: a 3.5-year follow-up observation study. AB - A high level of circulating sphingosine-1-phosphate (S1P) is associated with a high incidence of osteoporotic fracture and a high rate of an insufficient response to bisphosphonate therapy. INTRODUCTION: Sphingosine-1-phosphate (S1P) is a significant regulator of bone metabolism. Recently, we found that a high plasma S1P level is associated with low bone mineral density (BMD), high levels of bone resorption markers (BRMs), and a high risk of prevalent vertebral fracture in postmenopausal women. We investigated the possibility that S1P is a predictor of incident fracture. METHODS: A total of 248 postmenopausal women participated in this longitudinal study and were followed up for a mean duration of 3.5 years (untreated [n = 76] or treated with bisphosphonate or hormone replacement therapy [n = 172]). The baseline plasma S1P level and prevalent and incident fracture occurrence were assessed. RESULTS: A high S1P level was significantly associated with a higher rate of prevalent fracture after adjusting for femoral neck (FN) BMD, BRM, and potential confounders (odds ratio = 2.05; 95 % confidence interval [CI] = 1.03-4.00). Incident fractures occurred more frequently in the highest S1P tertile (T3) than in the lower two tertiles (T1-2) after adjusting for confounders, including baseline FN BMD, prevalent fracture, antiosteoporotic medication, annualized changes in FN BMD, BRM, and potential confounders (hazard ratio = 5.52; 95 % CI = 1.04-56.54). Insufficient response to bisphosphonate therapy occurred more frequently in T3 than T1-2 (odds ratio = 4.43; 95 % CI = 1.02-21.25). CONCLUSIONS: The plasma S1P level may be a potential predictor of fracture occurrence and an insufficient response to bisphosphonate therapy in postmenopausal women. PMID- 26984573 TI - Stress, immunity, cytokines and depression. AB - The current issue of Acta Neuropsychiatrica presents a series of papers which together provide a broad overview relating stress, immunity, cytokine activity and depressive illness, as well as the influence of cytokines on other neurological disorders. This introduction to the issue presents a broad perspective of the impact of stressors on immune functioning in animal studies and in humans, considering the potential effects of acute, subchronic and chronic stressors, as well as the contribution of previous stressor experience in promoting neurochemical and immunological alterations. Given the supposition that cytokines may act as immunotransmitters, and immune challenge may be viewed as a stressor, a brief review is provided concerning the impact of stressors and cytokine challenges on central neurochemical functioning, with particular emphasis on the commonalties between the effects of these treatments. It is suggested that by virtue of the neurochemical changes imparted by cytokines, a depressive affect may be instigated, just as it is in response to psychogenic stressors. To this end, an overview is presented concerning the relationship between cytokines and depression, as well as the influence of cytokine treatments on behavioral changes in animal studies and among patients receiving immunotherapy. Provisionally, the data support the view that activation of the inflammatory response system may contribute to affective illness, and that cytokines may act as signaling molecules to activate central nervous system processes regulating mood states. PMID- 26984571 TI - Export controls and the life sciences: controversy or opportunity? Innovations in the life sciences' approach to export control suggest there are ways to disrupt biological weapons development by rogue states and terrorist groups without impeding research. PMID- 26984572 TI - Major involvement of trunk muscles in myotonic dystrophy type 1. AB - OBJECTIVES: The motor impairments in Myotonic Dystrophy 1 (DM1) are assumed to progress from distal toward proximal parts of the extremities in the Juvenile and Adult forms of DM1. On occasion and late in progress spine deformity is observed. In this study we have examined whether and to what extent trunk muscles are impaired in DM1, and if this impairment is correlated with the duration of the disorder, walking capacity, mobility, balance, and CTG-repeats. MATERIALS & METHODS: Manual muscle testing (MMT) of skeletal muscle strength in trunk and extremities, reassessment of the mutation size, time since first symptom, the 6 min walk test (6MWT), Rivermead mobility index (RIM) and Timed up & go (TUG) were sampled in 38 adult DM1 outpatients. RESULTS: We found significant impairment in trunk muscles. Trunk muscle strength decreased significantly with increasing mutation size (r = -0.64, P < 0.001). Reduced walking capacity, mobility and balance were significantly related to decreased trunk muscle strength. CONCLUSION: DM1 affects trunk muscle groups. The trunk impairments seem to occur relatively early in disease progression. Awareness of trunk impairments may be of importance for everyday functioning and for understanding the risk of injuries due to falls reported among DM1 patients. It may also help in identification of DM1 patients and considered outcome measure in future clinical trials. PMID- 26984574 TI - Brain cytokines and disease. AB - Cytokines (e.g. various interleukins and subfamily members, tumor necrosis factors, interferons, chemokines and growth factors) act in the brain as immunoregulators and neuromodulators. Over a decade ago, the integrative article 'Immunoregulators in the Nervous System' (Neurosci Biobehav Rev 1991; 15: 185 215) provided a comprehensive framework of pivotal issues on cytokines and the nervous system that recently have been extensively studied. Cytokine profiles in the brain, including cytokine generation and action, have been studied in multiple models associated with neuropathophysiological conditions. These include: (1) acute conditions and disorders such as stroke (cerebral ischemia or infarction and intracranial hemorrhage), traumatic brain injury, spinal cord injury and acute neuropathies; (2) chronic neurodegenerative disorders and chronic conditions, including Alzheimer's disease, Parkinson's disease, neuropathic pain, epilepsy and chronic neuropathies; (3) brain infections, including bacterial meningitis and encephalitis; (4) brain tumors; (5) neuroimmunological disorders per se, such as multiple sclerosis; (5) psychiatric disorders, including schizophrenia and depression; (6) neurological and neuropsychiatric manifestations associated with non- central nervous system (CNS) disorders such as peripheral cancer, liver, kidney and metabolic compromise, and peripheral infectious and inflammatory conditions; and (7) cytokine immunotherapy, which can be accompanied by neuropsychiatric manifestations when administered either via peripheral or brain routes. Cytokine profiles have also been studied in multiple animal models challenged with inflammatory, infectious, chemical, malignant and stressor insults. Essentially data show that cytokines play a pivotal role in multiple neuropathophysiological processes associated with different types of disorders and insults. Cytokine expression and action in the brain shows a different profile across conditions, but some similarities exist. Under a defined temporal sequence, cytokine involvement in neuroprotection or the induction of a deleterious pathophysiological cascade and in resolution/healing is proposed depending on the type of cytokine. In the brain, functional interactions among cytokines, balance between pro-inflammatory and anti inflammatory cytokines and functional interactions with neurotransmitters and neuropeptides play a pivotal role in the overall cytokine profile, pattern of neuropathophysiological cascades, and quality and magnitude of neuropsychiatric manifestations. In this brief review various selected cytokine-related issues with relevance to the brain are discussed. PMID- 26984575 TI - Stressor-induced modulation of immune function: a review of acute, chronic effects in animals. AB - The present paper reviews recent studies on the effects of stress on immune function in laboratory animals. The emphasis is on those studies where a simultaneous comparison of acute and chronic stress regimens was determined, although additional relevant studies are also reviewed. The effects of stress on basic measurements of cellular and humoral immune measures are discussed, including the growing number of studies that have reported alterations in macrophage functions. The latter are key elements in the innate immune response, and like measurements of T cell function and antibody production, are inhibited and enhanced by stressor exposure. This review does not focus on the mechanisms by which stress alters immune function, there being little to add conceptually in terms of what was reported previously (see Kusnecov AW, Rabin BS, Int Arch Allergy Immunol 1994;105:107-121.). However, a question is raised in the conclusion as to how stressor effects on immune function should be interpreted, for it is clear that immunological processes in and of themselves elicit central nervous system responses that neurochemically and endocrinologically do not differ from those produced in response to psychological stressors. Therefore, at least in the short term stressor-induced immune changes may not necessarily reflect maladaptive adjustments, although, as demonstrated by some studies reviewed in this paper, they may pose a serious risk to health should stressor exposure be persistent and uncontrolled. PMID- 26984576 TI - Early life environment: does it have implications for predisposition to disease? AB - Early life environmental factors have been associated with altered predisposition to a variety of pathologies. A considerable literature examines pre- and postnatal factors associated with increased risk of cardiovascular, metabolic (i.e. insulin resistance, hyperlipidemia) and psychiatric disease, and the importance of hormonal programming. The brain is exquisitely sensitive to environmental inputs during development and the stress responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to be both up- and down regulated by early life exposure to limited nutrition, stress, altered maternal behaviors, synthetic steroids and inflammation. It has been suggested that peri natal programming of HPA axis regulation might therefore contribute to metabolic and psychiatric disease etiology. In addition, glucocorticoids play modulatory roles regulating many aspects of immune function, notably controlling both acute and chronic inflammatory responses. Neuroendocrine-immune communication is bidirectional, and therefore it is expected that environmental factors altering HPA regulation have implications for stress effects on immune function and predisposition to inflammation. The impact of pre- and postnatal factors altering immune function, stress responsivity and predisposition to inflammatory disease are reviewed. It is also examined whether the early 'immune environment' might similarly influence predisposition to disease and alter neuroendocrine function. Evidence indicating a role for early life inflammation and infection as an important factor programming the neuroendocrine-immune axis and altering predisposition to disease is considered. PMID- 26984577 TI - Peripheral endotoxin causes long-lasting changes in locus coeruleus activity via IL-1 in the brain. AB - Activity of locus coeruleus (LC) neurons, the major noradrenergic cell-body group in the brain whose axons give rise to approximately 70% of norepinephrine (NE) in the brain, is believed to play an important role in attention/vigilance, cognitive functions and behavioral disorders, particularly depression. Results described here show that in the rat, intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, a bacterial endotoxin) causes long-lasting changes in electrophysiological activity of LC neurons that are mediated by interleukin-1 (IL-1) acting locally in the LC region. First, it was found that IL-1, when microinjected into the LC region or stimulated/expressed in that brain region, increased activity of LC neurons. The only exception to this was that a very low dose of microinjected IL-1 (5 pg) decreased LC activity, which could be blocked by an antagonist to corticotropin-releasing hormone (CRH), thus suggesting that the decrease was due to IL-1 stimulation of CRH release. All of these effects could be blocked by injection and/or infusion of IL-1 receptor antagonist (IL 1RA) specifically into the LC region. Next, intraperitoneal (i.p.) injection of a low dose of LPS(10 ug/kg or 100 ng/kg) was also found to increase LC activity. The excitation of LC produced by 10 ug/kg i.p. LPS increased progressively for at least 1 week, with LC neurons firing at more than twice their normal rate at 1 week after the i.p. LPS injection. Alteration of LC activity lasted for 3 weeks after a single i.p. injection of 10 ug/kg LPS. The effects of i.p. LPS on LC activity at any time after i.p. injection could be blocked by a brief microinfusion of IL-1RA into the LC region, thereby indicating that changes in LC activity seen after the i.p. LPS were caused by IL-1 acting in the LC region. Finally, i.p. injection of peptidoglycan, representing gram-positive bacteria, and polyinsinic-polycytidylic acid [poly(I):(C)], representing viral infection, also caused increases in LC activity, and the effects of peptidoglycan [but not those of poly(I):(C)] were blocked by microinfusion of IL-1RA into LC. These findings suggest that bacterial infections can give rise to prolonged changes in brain activity through cytokine action in brain. PMID- 26984578 TI - The acute and sensitization effects of tumor necrosis factor-alpha: implications for immunotherapy as well as psychiatric and neurological conditions. AB - In addition to their role as signaling molecules of the immune system, cytokines may participate in central neurotransmission. Variations of the central and/or peripheral levels of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-beta (IL-1beta), impact on neuroendocrine processes as well as central neurotransmitter activity. To a considerable extent, these effects are reminiscent of those elicited by psychogenic stressors. The current review describes recent findings consistent with a role for these cytokines in the neurochemical and behavioral manifestations of clinical depression, as well as the cellular death associated with cerebral ischemia. Moreover, the increasing use of cytokines in the immunotherapeutic treatment of various autoimmune diseases (e.g. rheumatoid arthritis) and cancers prompted us to consider the potential role of central processes in subserving the mood-related side-effects elicited by these treatments. Finally, a single administration of TNF-alpha has been shown to elicit a time-dependent sensitization effect, wherein the behavioral and neurochemical responses elicited by later cytokine treatment are greatly enhanced. Thus, particular attention was devoted to the possibility that elevated levels of TNF-alpha, through either exogenous (e.g. immunotherapy) or endogenous (e.g. brain damage or stressors) means may sensitize neurotransmitter or second messenger pathways important for the pathology. Given the time dependent nature of cytokine sensitization effects, the schedule of cytokine administration during immunotherapy, or the timing of cytokine up-regulation in response to traumatic or stressful events may favor the development of sensitized central processes, which may influence clinical outcome. PMID- 26984579 TI - Antidepressant treatment of cytokine-induced mood disorders. AB - Significant evidence suggests that the immune system is capable of profoundly affecting central nervous system (CNS) functioning in ways that may contribute to the development and expression of neuropsychiatric disorders, including disorders of mood. This paper reviews evidence that the production of proinflammatory cytokines, whether in the context of therapeutic administration (e.g. interferon alpha-2b for hepatitis C infection) or medical illness, induces a state of sickness behavior that closely resembles major depression. Antidepressants have been shown to abolish or attenuate cytokine-induced sickness behavior in laboratory animals and to protect against the development of major depression in the context of therapeutic cytokine administration in humans. Potential mechanisms by which antidepressants ameliorate depressive and/or sickness symptoms in the context of immune activation include direct effects on immune cell functioning, as well as modulatory effects on monoamine neurotransmitters, intracellular second messenger pathways and the neuroendocrine system, in particular the hypothalamic-pituitary-adrenal axis. PMID- 26984581 TI - Facile and quick preparation of carbon nanohorn-based counter electrodes for efficient dye-sensitized solar cells. AB - For the first time, Pt-free counter electrodes based on carbon nanohorns for highly efficient dye-sensitized solar cells were assembled by a facile and fast drop cast technique. These novel electrodes feature an effective catalytic behavior towards the reduction of I3(-) and, as such, afford even higher short circuit current densities compared to Pt-based references. In a final device, solar cells with 7.7% efficiency were achieved. PMID- 26984582 TI - Decision-making regarding place of birth in high-risk pregnancy: a qualitative study. AB - INTRODUCTION: Women consider factors including safety and the psychological impact of their chosen location when deciding whether to give birth in hospital or at home. The same is true for women with high-risk pregnancies who may plan homebirths against medical advice. This study investigated women's decision making during high-risk pregnancies. Half the participants were planning hospital births and half were planning homebirths. METHODS: A qualitative study using semi structured interviews set in a hospital maternity department in the UK. Twenty six participants with high-risk pregnancies, at least 32 weeks pregnant. Results were analysed using systematic thematic analysis. RESULTS: Three themes emerged: perceptions of birth at home and hospital; beliefs about how birth should be; and the decision process. Both groups were concerned about safety but they expressed different concerns. Women drew psychological comfort from their chosen birth location. Women planning homebirths displayed faith in the natural birth process and stressed the quality of the birth experience. Women planning hospital births believed the access to medical care outweighed their misgivings about the physical environment. DISCUSSION: Although women from both groups expressed similar concerns about safety they reached different decisions about how these should be addressed regarding birth location. These differences may be related to beliefs about the birth process. Commitment to their decisions may have helped reduce cognitive stress. PMID- 26984584 TI - Corrigendum. PMID- 26984583 TI - Muscle strengthening exercises during pregnancy are associated with increased energy and reduced fatigue. AB - INTRODUCTION: Physical inactivity likely contributes to fatigue and low energy during pregnancy but whether acute resistance exercise attenuates these symptoms is unknown. METHODS: Twenty-six women performed six low-to-moderate intensity resistance exercises twice per week from weeks 23 to 35 of pregnancy and measurements were made before and after each workout using the Mental and Physical State Energy and Fatigue Scales. RESULTS: Acute resistance exercise usually increased perceived physical and mental energy (92% to 96% of workouts, respectively). These increases did not differ significantly across the 24 exercise sessions for feelings of physical energy or mental energy, even after adjusting for variations in attendance (median = 22/24 workouts). Acute resistance exercise usually decreased perceived physical and mental fatigue (79% to 88% of workouts, respectively), and ANCOVA showed these decreases did not differ significantly across the 24 exercise sessions for feelings of physical fatigue or mental fatigue even after adjusting for variations in attendance. DISCUSSION: The results suggest acute, low-to-moderate intensity muscle strengthening exercise during pregnancy is effective for transiently improving feelings of energy and fatigue. PMID- 26984580 TI - Protein S-Glutathionylation Mediates Macrophage Responses to Metabolic Cues from the Extracellular Environment. AB - AIMS: Protein S-glutathionylation, the formation of a mixed disulfide between glutathione and protein thiols, is an oxidative modification that has emerged as a new signaling paradigm, potentially linking oxidative stress to chronic inflammation associated with heart disease, diabetes, cancer, lung disease, and aging. Using a novel, highly sensitive, and selective proteomic approach to identify S-glutathionylated proteins, we tested the hypothesis that monocytes and macrophages sense changes in their microenvironment and respond to metabolic stress by altering their protein thiol S-glutathionylation status. RESULTS: We identified over 130 S-glutathionylated proteins, which were associated with a variety of cellular functions, including metabolism, transcription and translation, protein folding, free radical scavenging, cell motility, and cell death. Over 90% of S-glutathionylated proteins identified in metabolically stressed THP-1 monocytes were also found in hydrogen peroxide (H2O2)-treated cells, suggesting that H2O2 mediates metabolic stress-induced protein S glutathionylation in monocytes and macrophages. We validated our findings in mouse peritoneal macrophages isolated from both healthy and dyslipidemic atherosclerotic mice and found that 52% of the S-glutathionylated proteins found in THP-1 monocytes were also identified in vivo. Changes in macrophage protein S glutathionylation induced by dyslipidemia were sexually dimorphic. INNOVATION: We provide a novel mechanistic link between metabolic (and thiol oxidative) stress, macrophage dysfunction, and chronic inflammatory diseases associated with metabolic disorders. CONCLUSION: Our data support the concept that changes in the extracellular metabolic microenvironment induce S-glutathionylation of proteins central to macrophage metabolism and a wide array of cellular signaling pathways and functions, which in turn initiate and promote functional and phenotypic changes in macrophages. Antioxid. Redox Signal. 25, 836-851. PMID- 26984585 TI - Hemoglobinopathies in the Cukurova Region and Neighboring Provinces. AB - To contribute to the creation of a mutation map of the region, we aimed to determine the mutation spectrum of thalassemias and abnormal hemoglobins (Hbs) in the Cukurova region and surrounding provinces. In this study, a total of 8135 samples from Adana, Hatay, Mersin, Konya and Kayseri provinces between 1993 and 2014 were analyzed. Complete blood cell (CBC) counts and Hb typing were carried out using automatic cell counters, cellulose acetate membrane electrophoresis and high performance liquid chromatography (HPLC), respectively. For the molecular analyses, genomic DNA was extracted using both manual and automated DNA extraction devices. Determination of Hb mutations were done by microarray, restriction fragment length polymorphism (RFLP), amplification refractory mutation system (ARMS) and gap-polymerase chain reaction (gap-PCR) methodologies. Samples were analyzed for abnormal Hb and thalassemia mutations. Out of 8135 samples, 1382 were observed to be carrying Hb mutations. It was identified that 826 mutation carriers included abnormal Hbs with a frequency of 59.7%, 416 carriers included beta-thalassemia (beta-thal) mutations with a frequency of 30.7% and 136 carriers included alpha-thalassemia (alpha-thal) mutations with a frequency of 9.9%. In this study, the most frequently observed abnormal Hb in the region was Hb S [beta6(A3)Glu->Val (GTG > GAG), HBB: c.20T > A], whereas the most commonly observed mutations were the IVS-I-110 (G > A) (HBB: c.93-21G > A) point mutation in beta-thal and the 3.7 kb deletion in alpha-thal. PMID- 26984586 TI - Developmental Origins of Cardiovascular Dysfunction - Doomed From Birth? PMID- 26984587 TI - Antithrombotic Therapy for Secondary Prevention in Patients With Diabetes Mellitus and Coronary Artery Disease. AB - Diabetes mellitus (DM) is a key risk factor for recurrent atherothrombotic events in patients with acute coronary syndrome (ACS) and in those undergoing percutaneous coronary intervention (PCI). The prothrombotic milieu that characterizes patients with DM underscores the importance of oral antithrombotic therapy for secondary prevention of recurrent events in these patients. Indeed, dual antiplatelet therapy (DAPT) with aspirin and the P2Y12inhibitor clopidogrel, which has represented the mainstay of treatment for many years, has significantly reduced the incidence of recurrent atherothrombotic events. However, recurrence rates in DM patients still remain high despite this treatment regimen, which may be partly related to inadequate platelet inhibition induced by standard DAPT with aspirin and clopidogrel. This underpins the need for more potent antithrombotic treatment regimens for secondary prevention of atherothrombotic events in DM patients following ACS or PCI. The development of antiplatelet therapies associated with more potent oral platelet P2Y12receptor inhibition, including prasugrel and ticagrelor, as well as platelet inhibitors blocking alternative pathways, such as thrombin-mediated platelet inhibition with vorapaxar, may represent potential treatment options in DM patients. Moreover, with the introduction of the target-specific oral anticoagulants, there has been a reappraisal of the use of anticoagulation in addition to antiplatelet therapy for secondary prevention in patients with ACS. This review provides an update on the recent advances and limitations of oral antithrombotic agents used for secondary prevention in DM patients following ACS or PCI. PMID- 26984588 TI - Testing in Patients With Stable Coronary Artery Disease - The Debate Continues. AB - The major guidelines on stable coronary artery disease recommend revascularizing patients with large areas of myocardium at risk. The algorithms on how to prove that such high risk is present differ considerably. The opinions on the use of coronary CT (calcium scoring and angiography) vary widely. This review aims to summarize the recommendations of the major guidelines, commenting on differences between the guidelines and discussing whether extending the role of coronary CT angiography should be considered in the light of new CT data. PMID- 26984589 TI - Clinical and Immunological Studies of 332 Japanese Patients Tentatively Diagnosed as Anti-BP180-type Mucous Membrane Pemphigoid: A Novel BP180 C-terminal Domain Enzyme-linked Immunosorbent Assay. AB - Diagnosis of anti-BP180-type mucous membrane pemphigoid (BP180-MMP) is frustrated by the difficulty of detecting BP180 reactivity. A total of 721 patients with suspected MMP, selected from a cohort of 4,698 patients with autoimmune bullous disease (AIBD), were included in this study. Of these, 332 patients were tentatively diagnosed as BP180-MMP if they showed IgG/IgA reactivity with the epidermal side of 1M NaCl-split-skin and/or positive reactivity with BP180 in at least one of our antigen detection methods. Clinically, a predominance of female patients was found. Oral mucosal and cutaneous lesions were found in 85.5% and 41.0% of patients, respectively, and frequent treatments were systemic steroids, tetracycline/minocycline and diaminodiphenyl sulfone. Various immunological methods, including a newly developed BP180 C-terminal domain enzyme-linked immunosorbent assay (ELISA), revealed frequent reactivity with BP180 C-terminal and NC16a domains. Some patients reacted with BP180 and other antigens, indicating that BP180-MMP tends to concur with other AIBDs. This large study of patients with suspected BP180-MMP indicates the difficulty of diagnosis of BP180 MMP and the diagnostic usefulness of BP180 C-terminal domain ELISA. PMID- 26984591 TI - The Relationship between Learning Style Preferences and Memory Strategy use in Adults. AB - Deficits in working memory are pervasive, resistant to remediation and significantly impact a persons ability to perform activities of daily living. Internal strategies are effective for improving working memory. Learning style preferences may influence the use of various internal working memory strategies. This study compares the use of internal working memory strategies among four different learning style preferences; converger, diverger, assimilator and accommodator. A non-experimental group design was used to compare the use of internal working memory strategies and learning style preferences among 110 adults. There were some significant differences in the types of strategies used according to learning style preferences. Knowing the learning style preference of clients may help occupational therapists better tailor cognitive rehabilitation treatments to meet the client's needs. PMID- 26984590 TI - Evaluation of shoulder function in clavicular fracture patients after six surgical procedures based on a network meta-analysis. AB - Purpose Using a network meta-analysis approach, our study aims to develop a ranking of the six surgical procedures, that is, Plate, titanium elastic nail (TEN), tension band wire (TBW), hook plate (HP), reconstruction plate (RP) and Knowles pin, by comparing the post-surgery constant shoulder scores in patients with clavicular fracture (CF). Methods A comprehensive search of electronic scientific literature databases was performed to retrieve publications investigating surgical procedures in CF, with the stringent eligible criteria, and clinical experimental studies of high quality and relevance to our area of interest were selected for network meta-analysis. Statistical analyses were conducted using Stata 12.0. Results A total of 19 studies met our inclusion criteria were eventually enrolled into our network meta-analysis, representing 1164 patients who had undergone surgical procedures for CF (TEN group = 240; Plate group = 164; TBW group = 180; RP group = 168; HP group = 245; Knowles pin group = 167). The network meta-analysis results revealed that RP significantly improved constant shoulder score in patients with CF when compared with TEN, and the post-operative constant shoulder scores in patients with CF after Plate, TBW, HP, Knowles pin and TEN were similar with no statistically significant differences. The treatment relative ranking of predictive probabilities of constant shoulder scores in patients with CF after surgery revealed the surface under the cumulative ranking curves (SUCRA) value is the highest in RP. Conclusion The current network meta-analysis suggests that RP may be the optimum surgical treatment among six inventions for patients with CF, and it can improve the shoulder score of patients with CF. Implications for Rehabilitation RP improves shoulder joint function after surgical procedure. RP achieves stability with minimal complications after surgery. RP may be the optimum surgical treatment for rehabilitation of patients with CF. PMID- 26984592 TI - Multiple myeloma with Russell bodies and needle-shaped crystalline inclusions. PMID- 26984593 TI - Transient ischemic attack as an unusual initial manifestation of acute promyelocytic leukemia. AB - Patients with acute promyelocytic leukemia (APL) are prone to both bleeding and thrombosis. Both of these have a significant impact on the morbidity and mortality of patients with this disease. Here we report a case of a 41-year-old male, who presented with transient ischemic attack (TIA) and early neurological deterioration (END) as initial manifestations prior to an ultimate diagnosis of APL. This patient had no cerebrovascular risk factors or familial cerebrovascular disease. The patient experienced an acute ischemic stroke, verified by magnetic resonance imaging (MRI), in less than 24 h after his second hospital admission. Some APL patients suffer from cerebral ischemia as an initial manifestation or during induction therapy, and patients presenting this condition may continue to deteriorate until their death during hospitalization. Thus, APL should be considered as a possible underlying disease in patients with TIA without cerebrovascular risk factors. Delayed diagnosis and treatment of APL can be fatal. PMID- 26984595 TI - Trends in the development of MET inhibitors for hepatocellular carcinoma. AB - Hepatocellular carcinoma is the third most common cause of cancer-related deaths worldwide. The multikinase inhibitor sorafenib has improved survival and is now considered the standard of care; however, the benefits are still disappointing, and thus, new effective treatments are required. In human hepatocellular carcinoma, MET, which is encoded by the HGFR gene, is activated by amplification, overexpression or mutation, and it has recently emerged as a possible therapeutic target in various tumors including hepatocellular carcinoma. In fact, some drugs targeting the HGF/MET axis are currently under investigation in clinical trials. Here, we review the role of MET and trends in the development of MET inhibitors for hepatocellular carcinoma. PMID- 26984594 TI - Comparison of prothrombin time tests used in the monitoring of edoxaban and their evaluation as indicators of the reversal effect. AB - Clinical demand for the prompt assessment of the activity of direct-acting factor Xa inhibitors in the emergency care setting is increasing. In the present study, we examined whether prothrombin time (PT) tests can serve as a clinically useful indicator of anti-factor Xa activity. In the first series, the in vitro effect of edoxaban on PT was evaluated by spiking human plasma with edoxaban and measuring PT using three different commercial PT tests. In the second series, the reversal effect of prothrombin complex concentrates (PCC) and activated PCC (aPCC) in edoxaban-spiked plasma was evaluated. In the third series, PT of plasma samples from patients administered either 15 or 30 mg/day of edoxaban was assessed, and the results were compared with edoxaban concentrations determined by a calibrated anti-factor Xa activity assay. The spike test revealed that all PT reagents positively correlated with edoxaban. The sensitivity to edoxaban varied among the three reagents and Triniclot((r)) Excel S showed the best performance. Prolonged PT by edoxaban was reversed by PCC and aPCC in a dose-dependent manner; however, complete reversal was not achieved. Positive correlation between anti-factor Xa activity and PT was shown in the clinical samples at the edoxaban range from 0 to >300 ng/mL. PMID- 26984596 TI - Nutritionally related blood metabolites and performance of finishing pigs fed on graded levels of dietary fibre. AB - The objective of the study was to determine effect of feeding fibrous diets on performance and biochemical profiles of finishing pigs. A total of 84 clinically healthy male pigs were used in the experiment. Body weight of the pigs at the beginning of the experiment was 85 +/- 10.1 kg. Maize cob (MC), sunflower hulls (SH), lucerne hay (LH) and dried citrus pulp (PU) were incorporated in a basal diet for finishing pigs at different inclusion levels of 0, 80, 160, 240, 320 and 400 g/kg. Effects of week of feeding, fibre source and inclusion level of fibre were significant (P < 0.05). Pigs consumed more LH compared to MC, SH and PU. Average daily gain was high for pigs consuming diets with inclusion levels of 0, 80, 160 and 240 g/kg and low for pigs consuming 320 and 400 g/kg inclusion level of fibre in a diet. There was an increase in serum total concentration (TP) with an increase in PU, MC and LH in pig diets (P < 0.05). Creatine kinase (CK) concentrations decreased as levels of PU, LH and MC increased (P < 0.05). Increasing inclusion level of LH and SH in pig diets resulted in an increase in glycated haemoglobin concentration (P < 0.05). It can be concluded that level of PU, LH, MC and SH in diets of finishing pigs negatively influences average daily feed intake, average daily gain and biochemical profiles. PMID- 26984597 TI - Anticoccidial effect of Piper sarmentosum extracts in experimental coccidiosis in broiler chickens. AB - To study the anticoccidial effect of Piper sarmentosum extracts (PSE) in experimental broiler coccidiosis, 270 one-day-old Wenchang broiler chickens were randomly assigned to six groups, each with three replicates (n = 15). The six groups were blank control group (BC), negative control group (NC), positive control group (PC), and another three PSE addition groups. Chickens in three control groups were fed a basal diet without PSE supplementation. Chickens in the three PSE addition groups were fed a basal diet supplemented with PSE at 100 (T100), 200 (T200), and 300 (T300) mg/kg of feed, respectively. At 15 days of age, chickens in group NC, PC, and three PSE addition groups were challenged with an oral dose of 1 * 10(5) Eimeria tenella oocysts each chick. Chickens in group PC were fed with diclazuril solution in water for 5 days after 48 h with oocysts inoculation. The results showed that PSE and diclazuril improved growth performance and significantly (P < 0.05) decreased oocysts per gram in inoculated broiler chickens. PSE and diclazuril significantly (P < 0.05) decreased nitric oxide at 6 and 9 days post-inoculation relative to the NC group, respectively. At 6 and 9 days post-inoculation, PSE supplementation at 200 mg/kg in the diet increased concentration of interleukin 2 (IL-2) and interferon gamma (IFN-gamma) (P < 0.05). PSE supplementation at 200 mg/kg in the diet significantly (P < 0.05) increased mRNA expressions of IFN-gamma and IL-2 in the cecum of chickens at 9 days post-inoculation relative to the BC and NC group. The current results showed the anticoccidial properties, and beneficial effect on intestinal mucosa damage of PSE in broiler chickens that had been challenged by coccidiosis. PMID- 26984598 TI - Estimates of effective population size and inbreeding in South African indigenous chicken populations: implications for the conservation of unique genetic resources. AB - Conservation of locally adapted indigenous livestock breeds has become an important objective in sustainable animal breeding, as these breeds represent a unique genetic resource. Therefore, the Agricultural Research Council of South Africa initiated a conservation programme for four South African indigenous chicken breeds. The evaluation and monitoring of the genetic constitution of these conservation flocks is important for proper management of the conservation programme. Using molecular genetic analyses, the effective population sizes and relatedness of these conservation flocks were compared to village (field) chicken populations from which they were derived. Genetic diversity within and between these populations are further discussed within the context of population size. The conservation flocks for the respective breeds had relatively small effective population sizes (point estimate range 38.6-78.6) in comparison to the field populations (point estimate range 118.9-580.0). Furthermore, evidence supports a transient heterozygous excess, generally associated with the occurrence of a recent population bottleneck. Genetic diversity, as measured by the number of alleles, heterozygosity and information index, was also significantly reduced in the conservation flocks. The average relatedness amongst the conservation flocks was high, whilst it remained low for the field populations. There was also significant evidence for population differentiation between field and conservation populations. F st estimates for conservation flocks were moderate to high with a maximum reached between VD_C and VD_F (0.285). However, F st estimates for field population were excessively low between the NN_C and EC_F (0.007) and between EC_F and OV_F (0.009). The significant population differentiation of the conservation flocks from their geographically correlated field populations of origin is further supported by the analysis of molecular variance (AMOVA), with 10.51 % of genetic diversity ascribed to population differences within groups (F SC = 0.106). The results suggest that significant genetic erosion has occurred within the conservation flocks due to inbreeding, pronounced effects of random drift and selection. It might be necessary to introduce new breeding individuals from the respective field populations in order to increase the effective population sizes of the conservation flocks and counter the effects of genetic erosion. PMID- 26984599 TI - Significance of Low Nanomolar Concentration of Zn2+ in Artificial Cerebrospinal Fluid. AB - Much less attention has been paid to Zn2+ in artificial cerebrospinal fluid (ACSF), i.e., extracellular medium, used for in vitro slice experiments than divalent cations such as Ca2+. Approximately 2 mM Ca2+ is added to conventional ACSF from essentiality of Ca2+ signaling in neurons and glial cells. However, no Zn2+ is added to it, even though the importance of Zn2+ signaling in them is recognizing. On the other hand, synaptic Zn2+ homeostasis is changed during brain slice preparation. Therefore, it is possible that not only neuronal excitation but also synaptic plasticity such as long-term potentiation is modified in ACSF without Zn2+, in which original physiology might not appear. The basal (static) levels of intracellular (cytosolic) Zn2+ and Ca2+ are not significantly different between brain slices prepared with conventional ACSF without Zn2+ and pretreated with ACSF containing 20 nM ZnCl2 for 1 h. In the case of mossy fiber excitation, however, presynaptic activity assessed with FM 4-64 is significantly suppressed in the stratum lucidum of brain slices pretreated with ACSF containing Zn2+, indicating that hippocampal excitability is enhanced in brain slices prepared with ACSF without Zn2+. The evidence suggests that low nanomolar concentration of Zn2+ is necessary for ACSF. Furthermore, exogenous Zn2+ has opposite effect on LTP induction between in vitro and in vivo experiments. It is required to pay attention to extracellular Zn2+ concentration to understand synaptic function precisely. PMID- 26984600 TI - Mechano-Transduction Signals Derived from Self-Assembling Peptide Nanofibers Containing Long Motif of Laminin Influence Neurogenesis in In-Vitro and In-Vivo. AB - Astroglial scaring and limited neurogenesis are two problematic issues in recovery of spinal cord injury (SCI). In the meantime, it seems that mechanical manipulations of scaffold to inhibit astroglial scarring and improve neurogenesis is worthy of value. In the present investigation, the effect of nanofiber (gel) concentration as a mechanical-stimuli in neurogenesis was investigated. Cell viability, membrane damage, and neural differentiation derived from endometrial stem cells encapsulated into self-assembling peptide nanofiber containing long motif of laminin were assessed. Then, two of their concentrations that had no significant difference of neural differentiation potential were selected for motor neuron investigation in SCI model of rat. MTT assay data showed that nanofibers at the concentrations of 0.125 and 0.25 % w/v induced higher and less cell viability than others, respectively, while cell viability derived from higher concentrations of 0.25 % w/v had ascending trend. Gene expression results showed that noggin along with laminin motif over-expressed TH gene and the absence of noggin or laminin motif did not in all concentrations. Bcl2 over expression is concomitant with the decrease of nanofiber stiffness, NF+ cells increment, and astrogenesis inhibition and dark neuron decrement in SCI model. It seems that stiffness affects on Bcl2 gene expression and may through beta Catenin/Wnt signaling pathway and BMP-4 inhibition decreases astrogenesis and improves neurogenesis. However, stiffness had a significant effect on upregulation of GFAP+ cells and motor neuron recovery in in vivo. It might be concluded that eventually there is a critical definitive point concentration that at less or higher than of it changes cell behavior and neural differentiation through different molecular pathways. PMID- 26984601 TI - miR-124 Regulates the Expression of BACE1 in the Hippocampus Under Chronic Cerebral Hypoperfusion. AB - Chronic cerebral hypoperfusion (CCH) is a high-risk factor of Alzheimer's disease (AD). MicroRNAs (miRNAs) are ideal mediators of hypoxic stress responses to facilitate cellular adaptation to long-term hypoxia. MiR-124 is a kind of nervous system-specific miRNAs, and one of its target genes is beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). In the present study, miR-124 was found to be inhibited all the time from early to late stage of cerebral hypoxia accompanying with the upregulation of BACE1 protein and overproduction of amyloid beta (Abeta) in the hippocampus from cerebral hypoperfusion rat models. Meanwhile, Abeta could further enhance the expression of BACE1 protein due to the inhibition of miR-124. Thus, miR-124 was the key factor in this hypoxia/Abeta-miR 124-BACE1-Abeta cycle. The activation of EPAC-Rap1 pathway was involved in the inhibition of miR-124 in hippocampus under hypoxia or Abeta insult. Our data suggest that, as an endogenous regulator of BACE1 protein, miR-124 may play a role in AD onset induced by CCH. PMID- 26984602 TI - The Visual Cycle in the Inner Retina of Chicken and the Involvement of Retinal G Protein-Coupled Receptor (RGR). AB - The vertebrate retina contains typical photoreceptor (PR) cones and rods responsible for day/night vision, respectively, and intrinsically photosensitive retinal ganglion cells (ipRGCs) involved in the regulation of non-image-forming tasks. Rhodopsin/cone opsin photopigments in visual PRs or melanopsin (Opn4) in ipRGCs utilizes retinaldehyde as a chromophore. The retinoid regeneration process denominated as "visual cycle" involves the retinal pigment epithelium (RPE) or Muller glial cells. Opn4, on the contrary, has been characterized as a bi/tristable photopigment, in which a photon of one wavelength isomerizes 11-cis to all-trans retinal (Ral), with a second photon re-isomerizing it back. However, it is unknown how the chromophore is further metabolized in the inner retina. Nor is it yet clear whether an alternative secondary cycle occurs involving players such as the retinal G-protein-coupled receptor (RGR), a putative photoisomerase of unidentified inner retinal activity. Here, we investigated the role of RGR in retinoid photoisomerization in Opn4x (Xenopus ortholog) (+) RGC primary cultures free of RPE and other cells from chicken embryonic retinas. Opn4x (+) RGCs display significant photic responses by calcium fluorescent imaging and photoisomerize exogenous all-trans to 11-cis Ral and other retinoids. RGR was found to be expressed in developing retina and in primary cultures; when its expression was knocked down, the levels of 11-cis, all-trans Ral, and all-trans retinol in cultures exposed to light were significantly higher and those in all trans retinyl esters lower than in dark controls. The results support a novel role for RGR in ipRGCs to modulate retinaldehyde levels in light, keeping the balance of inner retinal retinoid pools. PMID- 26984603 TI - The role of IL-1beta in Pseudomonas aeruginosa in lung infection. AB - This mini-review examines the role of the pro-inflammatory cytokine interleukin (IL)-1beta in the interaction of Pseudomonas aeruginosa and the host immune system during lung infection. Different studies show that the reduction of the inflammatory response, especially a decrease in IL-1beta, leads to a better outcome in acute lung infection with this bacterium. This includes a higher survival rate, reduced damage to the lung tissue and, in particular, a better clearance of the airways and the tissue of the lungs from P. aeruginosa. PMID- 26984604 TI - Duke-Elder's Views on Prognosis, Prophylaxis, and Treatment of Myopia: Way Ahead of His Time. AB - Sir Stewart Duke-Elder was probably the most influential ophthalmologist of the 20th century. One of his visionary pieces of work was his writing on myopia in the second edition of The Practice of Refraction, published in 1935. Many of his insights are now, 80 years later, supported by scientific proof. In terms of prognosis of myopia, he stated that this largely depended on the age of the patient. We now have epidemiologic evidence that age of onset is strongly related to final refractive error, and that high myopia carries a high risk of blindness. With respect to prophylaxis, he claimed that accessory risk factors were excessive near work, bad ocular hygiene, and physical debility in the early years of growth: "The regime of modern schools imposes far too much application to books upon young children at an age when they require all their available vitality for physical growth and development." He recommended open-air pursuits and avoidance of indoor activities, in particular for children with a hereditary tendency toward myopia. Current investigations indeed point to a crucial role for near work, although not all findings are consistent. The most established factor that is protective from myopia is outdoor exposure, more likely due to intense exposure to light rather than to "open-air." Ocular hygiene and physical activity have not been confirmed as protective factors, but Duke-Elder's views on gene environment interactions are truly insightful. Concerning treatment, he suggested that adequate correction by glasses, intake of vitamin D, and restriction of education in "myope classes" could halt progression of myopia. Optical correction is considered helpful nowadays, but sound statistical evidence has only been provided for orthokeratology. High vitamin D serum levels are indeed related to low refractive error, but it is not yet clear whether high dietary intake is beneficial. Restriction of education does not meet current moral standards, but in China, "myopia classrooms" in the form of large cubes of windows, admitting lots of light, have been built. In this report, we highlight Duke-Elder's insights into the causes and clinical care of myopia, and discuss their merit for ophthalmic care today. PMID- 26984606 TI - Acute amnestic syndrome due to MDMA exposure. PMID- 26984605 TI - Monitoring effectiveness and safety of Tafamidis in transthyretin amyloidosis in Italy: a longitudinal multicenter study in a non-endemic area. AB - Tafamidis is a transthyretin (TTR) stabilizer able to prevent TTR tetramer dissociation. There have been a few encouraging studies on Tafamidis efficacy in early-onset inherited transthyretin amyloidosis (ATTR) due to Val30Met mutation. However, less is known about its efficacy in later disease stages and in non Val30Met mutations. We performed a multi-center observational study on symptomatic ATTR patients prescribed to receive Tafamidis. We followed up patients according to a standardized protocol including general medical, cardiological and neurological assessments at baseline and every 6 months up to 3 years. Sixty-one (42 males) patients were recruited. Only 28 % of enrolled subjects had the common Val30Met mutation, mean age of onset was remarkably late (59 years) and 18 % was in advanced disease stage at study entry. Tafamidis proved safe and well-tolerated. One-third of patients did not show significant progression along 36 months, independently from mutation type and disease stage. Neurological function worsened particularly in the first 6 months but progression slowed significantly thereafter. Autonomic function remained stable in 33 %, worsened in 56 % and improved in 10 %. Fifteen percent of patients showed cardiac disease progression and 30 % new onset of cardiomyopathy. Overall, Tafamidis was not able to prevent functional progression of the disease in 23 (43 %) subjects, including 16 patients who worsened in their walking ability and 12 patients who reached a higher NYHA score during the follow-up period. A higher mBMI at baseline was associated with better preservation of neurological function. In conclusion, neuropathy and cardiomyopathy progressed in a significant proportion of patients despite treatment. However, worsening of neurological function slowed after the first 6 months and also subjects with more advanced neuropathy, as well as patients with non-Val30Met mutation, benefited from treatment. Body weight preservation is an important favorable prognostic factor. PMID- 26984607 TI - Acute vestibular syndrome: a critical review and diagnostic algorithm concerning the clinical differentiation of peripheral versus central aetiologies in the emergency department. AB - Almost 20 % of cerebral ischaemic strokes occur in the posterior circulation. Estimates are that 20 % of these patients present with isolated vertigo. In approximately one-sixth to one-third of these patients, this symptom is wrongly diagnosed to be peripheral vestibular in origin. As a result, these missed stroke patients are withheld from therapeutic and secondary prophylactic treatment, which may result in unnecessary morbidity and mortality. We therefore propose a diagnostic algorithm concerning the clinical differentiation of acute vestibular syndrome (AVS) patients based on a critical review of the available literature. PMID- 26984608 TI - Normalisation of brain spectroscopy findings in Niemann-Pick disease type C patients treated with miglustat. AB - Niemann-Pick disease type C (NP-C) is a fatal progressive neurolipidosis involving neuronal storage of cholesterol and gangliosides. Miglustat, an inhibitor of glycosphingolipid synthesis, has been approved to treat neurological manifestations in adults and children with NP-C. This open-label observational study in adults with confirmed NP-C evaluated the efficacy of miglustat (200 mg t.i.d.) based on composite functional disability (CFD) scores and brain proton magnetic resonance spectroscopy (H-MRS) measurement of choline (Cho)/N-acetyl aspartate (NAA) ratio in the centrum ovale. Overall, 16 patients were included and received miglustat for a mean period of 30.6 months: 12 continued on miglustat throughout follow up, and 4 discontinued miglustat because of adverse effects (n = 2) or perceived lack of efficacy (n = 2). In the 'continued' subgroup, the mean (SD) annual progression of CFD scores decreased from 0.75 (0.94) before treatment to 0.29 (1.29) during the period between miglustat initiation and last follow-up. In the discontinued subgroup, CFD progression increased from 0.48 (0.44) pre-treatment to 1.49 (1.31) at last follow up (off treatment). Mean (SD) Cho/NAA ratio [normal level 0.48 (0.076)] decreased during miglustat treatment in the continued subgroup: 0.64 (0.12) at baseline (miglustat initiation), 0.59 (0.17) at 12-month follow up, and 0.48 (0.09) at 24-month follow up. Cho/NAA ratio remained relatively stable in the discontinued subgroup: 0.57 (0.15), 0.53 (0.04) and 0.55 (0.09), respectively. In conclusion, H-MRS Cho/NAA ratio might serve as an objective, quantitative neurological marker of brain dysfunction in NP-C, allowing longitudinal analysis of the therapeutic effect of miglustat. PMID- 26984610 TI - Morphological features of Ixodes persulcatus and I. ricinus hybrids: nymphs and adults. AB - Our aim was to reveal morphological features of first-generation Ixodes persulcatus and I. ricinus hybrids (nymphs and adults) obtained under laboratory conditions for further study of natural populations of these species in sympatry foci. In 65 nymphs of three groups I. ricinus (23 specimens), I. persulcatus (21 specimens), and hybrids (21 specimens), 16 parameters were evaluated (length/width of the scutum and capitulum, length of the hypostome, palp, tarsus I, coxa I, sternal setae, and various scutal and alloscutal setae) and discrimination analysis was performed allowing differentiation of hybrid nymphs from original species. General effectiveness of classification of I. ricinus, I. persulcatus, and hybrids was >95 %. Discriminant functions are presented allowing classification of I. persulcatus, I. ricinus, and hybrid nymphs. For description of morphology, 27 adult hybrids (13 males and 14 females) were examined under a stereo microscope at 14-28* (without preparation of permanent mounts). The following morphological distinctions of hybrids from original species were described: posterior marginal groove is not clear (as in I. ricinus) and absence of syncoxa on coxa I (as in I persulcatus). In hybrid males, simultaneous absence of syncoxa on coxa I (as in I. persulcatus) and a long internal spur on coxa I (as in I. ricinus) can be used as a diagnostic feature. Based on the detected characteristics, 10 of 157 ticks collected in Karelia in I. ricinus and I. persulcatus sympatry area were classified as hybrids. PMID- 26984611 TI - Enhanced spontaneous functional connectivity of the superior temporal gyrus in early deafness. AB - Early auditory deprivation may drive the auditory cortex into cross-modal processing of non-auditory sensory information. In a recent study, we had shown that early deaf subjects exhibited increased activation in the superior temporal gyrus (STG) bilaterally during visual spatial working memory; however, the changes in the organization of the STG related spontaneous functional network, and their cognitive relevance are still unknown. To clarify this issue, we applied resting state functional magnetic resonance imaging on 42 early deafness (ED) and 40 hearing controls (HC). We also acquired the visual spatial and numerical n-back working memory (WM) information in these subjects. Compared with hearing subjects, the ED exhibited faster reaction time of visual WM tasks in both spatial and numerical domains. Furthermore, ED subjects exhibited significantly increased functional connectivity between the STG (especially of the right hemisphere) and bilateral anterior insula and dorsal anterior cingulated cortex. Finally, the functional connectivity of STG could predict visual spatial WM performance, even after controlling for numerical WM performance. Our findings suggest that early auditory deprivation can strengthen the spontaneous functional connectivity of STG, which may contribute to the cross modal involvement of this region in visual working memory. PMID- 26984609 TI - Coherence in resting-state EEG as a predictor for the recovery from unresponsive wakefulness syndrome. AB - We investigated differences of EEG coherence within (short-range), and between (long-range) specified brain areas as diagnostic markers for different states in disorders of consciousness (DOC), and their predictive value for recovery from unresponsive wakefulness syndrome (UWS). EEGs of 73 patients and 24 controls were recorded and coma recovery scale- revised (CRS-R) scores were assessed. CRS-R of UWS patients was collected after 12 months and divided into two groups (improved/unimproved). Frontal, parietal, fronto-parietal, fronto-temporal, and fronto-occipital coherence was computed, as well as EEG power over frontal, parietal, occipital, and temporal areas. Minimally conscious patients (MCS) and UWS patients could not be differentiated based on their coherence patterns or on EEG power. Fronto-parietal and parietal coherence could positively predict improvement of UWS patients, i.e. recovery from UWS to MCS. Parietal coherence was significantly higher in delta and theta frequencies in the improved group, as well as the coherence between frontal and parietal regions in delta, theta, alpha, and beta frequencies. High parietal delta and theta, and high fronto parietal theta and alpha coherence appear to provide strong early evidence for recovery from UWS with high predictive sensitivity and specificity. Short and long-range coherence can have a diagnostic value in the prognosis of recovery from UWS. PMID- 26984613 TI - Exploring Existential Coping Resources: The Perspective of Koreans with Cancer. AB - The present study aimed to explore the use of meaning-making coping (existential, spiritual, and religious coping) among cancer patients in Korea and to investigate the impact of culture on their choice of coping methods. Thirty-three participants with various kinds of cancer were interviewed. Four different kinds of coping resources emerged from analyses of the interview transcripts: (1) belief in the healing power of nature; (2) mind-body connection; (3) relying on transcendent power; and (4) finding oneself in relationships with others. The findings of this study suggest the importance of investigating cultural context when exploring the use of the meaning-making coping strategies in different countries. PMID- 26984612 TI - Cholinergic imaging in dementia spectrum disorders. AB - The multifaceted nature of the pathology of dementia spectrum disorders has complicated their management and the development of effective treatments. This is despite the fact that they are far from uncommon, with Alzheimer's disease (AD) alone affecting 35 million people worldwide. The cholinergic system has been found to be crucially involved in cognitive function, with cholinergic dysfunction playing a pivotal role in the pathophysiology of dementia. The use of molecular imaging such as SPECT and PET for tagging targets within the cholinergic system has shown promise for elucidating key aspects of underlying pathology in dementia spectrum disorders, including AD or parkinsonian dementias. SPECT and PET studies using selective radioligands for cholinergic markers, such as [(11)C]MP4A and [(11)C]PMP PET for acetylcholinesterase (AChE), [(123)I]5IA SPECT for the alpha4beta2 nicotinic acetylcholine receptor and [(123)I]IBVM SPECT for the vesicular acetylcholine transporter, have been developed in an attempt to clarify those aspects of the diseases that remain unclear. This has led to a variety of findings, such as cortical AChE being significantly reduced in Parkinson's disease (PD), PD with dementia (PDD) and AD, as well as correlating with certain aspects of cognitive function such as attention and working memory. Thalamic AChE is significantly reduced in progressive supranuclear palsy (PSP) and multiple system atrophy, whilst it is not affected in PD. Some of these findings have brought about suggestions for the improvement of clinical practice, such as the use of a thalamic/cortical AChE ratio to differentiate between PD and PSP, two diseases that could overlap in terms of initial clinical presentation. Here, we review the findings from molecular imaging studies that have investigated the role of the cholinergic system in dementia spectrum disorders. PMID- 26984616 TI - The BRaliBase dent-a tale of benchmark design and interpretation. AB - BRaliBase is a widely used benchmark for assessing the accuracy of RNA secondary structure alignment methods. In most case studies based on the BRaliBase benchmark, one can observe a puzzling drop in accuracy in the 40-60% sequence identity range, the so-called 'BRaliBase Dent'. In this article, we show this dent is owing to a bias in the composition of the BRaliBase benchmark, namely the inclusion of a disproportionate number of transfer RNAs, which exhibit a conserved secondary structure. Our analysis, aside of its interest regarding the specific case of the BRaliBase benchmark, also raises important questions regarding the design and use of benchmarks in computational biology. PMID- 26984614 TI - Prognostic implications of securin expression and sub-cellular localization in human breast cancer. AB - PURPOSE: Securin belongs to a class of cell cycle regulators that prevent metaphase-to-anaphase transition until sister chromatid separation is complete. Evidence is accumulating that securin has a prognostic impact on a variety of malignancies but, thus far, the role and regulation of securin expression and its sub-cellular localization have not been systematically addressed in breast cancer. METHODS: In total 470 breast cancer specimens with follow-up data for up to 22 years were included. Immunohistochemical staining and immunofluorescence double-staining were performed for securin and its regulating proteins PTTG1IP, CDC20 and BUBR1. Prognostic associations were evaluated between the expression patterns of these proteins and established prognosticators of invasive breast cancer and patient survival. RESULTS: We found that a high fraction of securin expressing cancer cells predicted an unfavorable clinical outcome of the breast cancer patients (p < 0.001). Also in multivariate analyses, the fraction of securin expressing cancer cells served as an independent prognosticator of a poor survival (p < 0.0001). We also found that the sub-cellular localization of securin exhibited prognostic power, since cytoplasmic securin expression in the cancer cells appeared to be associated with aggressive breast cancer subtypes and high breast cancer-associated mortality rates (p = 0.003). Through immunofluorescence double-staining, we found that PTTG1IP, CDC20 and BUBR1 exhibited distinct patterns of co-expression with securin, suggesting a regulatory role in the metaphase-to-anaphase transition in human breast cancer cells. We also noted that a subgroup of triple-negative breast carcinomas exhibited deviant expression patterns for the proteins studied. CONCLUSIONS: Our data indicate that securin expression may serve as a strong and independent prognosticator of breast cancer outcome and that a cytoplasmic localization of the protein may provide additional prognostic information, particularly in the biologically and clinically challenging subgroup of triple-negative breast carcinomas. The sub-cellular localization of securin appears to reflect the expression of PTTG1IP, CDC20 and BUBR1, which may participate in the regulation of securin activity and, ultimately, in the survival of breast cancer patients. PMID- 26984615 TI - Interaction of the amyloid beta peptide with sodium dodecyl sulfate as a membrane mimicking detergent. AB - The amyloid beta (A beta) peptide is important in the context of Alzheimer's disease, since it is one of the major components of the fibrils that constitute amyloid plaques. Agents that can influence fibril formation are important, and of those, membrane mimics are particularly relevant, because the hydrophobic part of A beta suggests a possible membrane activity of the peptide. We employed spin label EPR to investigate the aggregation process of A beta1-40 in the presence of the sodium dodecyl sulfate (SDS) detergent as a membrane-mimicking agent. In this work, the effect of SDS on A beta is studied using two positions of spin label, the N-terminus and position 26. By comparing the two label positions, the effect of local mobility of the spin label is eliminated, revealing A beta aggregation in the SDS concentration regime below the critical micelle concentration (CMC). We demonstrate that, at low SDS concentrations, the N-terminus of A beta participates in the solubilization, most likely by being located at the particle water interface. At higher SDS concentrations, an SDS-solubilized state that is a precursor to the one A beta/micelle state above the CMC of SDS prevails. We propose that A beta is membrane active and that aggregates include SDS. This study reveals the unique potential of EPR in studying A beta aggregation in the presence of detergent. PMID- 26984617 TI - A comprehensive study of RNA secondary structure alignment algorithms. AB - RNA secondary structure alignment has received more attention since the discovery of the structure-function relationships in some non-protein-encoding RNAs. However, unlike the pure sequence alignment problem, which has been solved in polynomial time, secondary structure alignment incorporates the base pairings as another information dimension in addition to the base sequence. This problem therefore becomes more challenging. In this study, we classify the selected approaches, and algorithmically illustrate how these methods address the alignment problems with different structure types. Other features such as the types of base pair edit operations supported and the time complexity are also compared. PMID- 26984618 TI - Towards an open, collaborative, reusable framework for sharing hands-on bioinformatics training workshops. AB - There is a clear demand for hands-on bioinformatics training. The development of bioinformatics workshop content is both time-consuming and expensive. Therefore, enabling trainers to develop bioinformatics workshops in a way that facilitates reuse is becoming increasingly important. The most widespread practice for sharing workshop content is through making PDF, PowerPoint and Word documents available online. While this effort is to be commended, such content is usually not so easy to reuse or repurpose and does not capture all the information required for a third party to rerun a workshop. We present an open, collaborative framework for developing and maintaining, reusable and shareable hands-on training workshop content. PMID- 26984619 TI - Problems modelling behavioural variation across Western North American Indian societies. PMID- 26984620 TI - Impacts of dispersal on rapid adaptation and dynamic stability of Daphnia in fluctuating environments. AB - Prior ecological research has shown that spatial processes can enhance the temporal stability of populations in fluctuating environments. Less explored is the effect of dispersal on rapid adaptation and its concomitant impact on population dynamics. For asexually reproducing populations, theory predicts that dispersal in fluctuating environments can facilitate asynchrony among clones and enhance stability by reducing temporal variability of total population abundance. This effect is predicted when clones exhibit heritable variation in environmental optima and when fluctuations occur asynchronously among patches. We tested this in the field using artificial ponds and metapopulations composed of a diverse assemblage of Daphnia pulex clones. We directly manipulated dispersal presence/absence and environmental fluctuations in the form of nutrient pulses. Consistent with predictions, dispersal enhanced temporal asynchrony among clones in the presence of nutrient pulses; this in turn stabilized population dynamics. This effect only emerged when patches experienced spatially asynchronous nutrient pulses (dispersal had no effect when patches were synchronously pulsed). Clonal asynchrony was driven by strong positive selection for a single clone that exhibited a performance advantage under conditions of low resource availability. Our work highlights the importance of dispersal as a driver of eco-evolutionary dynamics and population stability in variable environments. PMID- 26984621 TI - Mechanosensation in an adipose fin. AB - Adipose fins are found on approximately 20% of ray-finned fish species. The apparently rudimentary anatomy of adipose fins inspired a longstanding hypothesis that these fins are vestigial and lack function. However, adipose fins have evolved repeatedly within Teleostei, suggesting adaptive function. Recently, adipose fins were proposed to function as mechanosensors, detecting fluid flow anterior to the caudal fin. Here we test the hypothesis that adipose fins are mechanosensitive in the catfish Corydoras aeneus. Neural activity, recorded from nerves that innervate the fin, was shown to encode information on both movement and position of the fin membrane, including the magnitude of fin membrane displacement. Thus, the adipose fin of C. aeneus is mechanosensitive and has the capacity to function as a 'precaudal flow sensor'. These data force re-evaluation of adipose fin clipping, a common strategy for tagging fishes, and inform hypotheses of how function evolves in novel vertebrate appendages. PMID- 26984622 TI - Returns from matching management resolution to ecological variation in a coral reef fishery. AB - When managing heterogeneous socioecological systems, decision-makers must choose a spatial resolution at which to define management policies. Complex spatial policies allow managers to better reflect underlying ecological and economic heterogeneity, but incur higher compliance and enforcement costs. To choose the most appropriate management resolution, we need to characterize the relationship between management resolution and performance. We parameterize a model of the commercial coral trout fishery in the Great Barrier Reef, Australia, which is currently managed by a single, spatially homogeneous management policy. We use this model to estimate how the spatial resolution of management policies affect the amount of revenue generated, and assess whether a more spatially complex policy can be justified. Our results suggest that economic variation is likely to be a more important source of heterogeneity than ecological differences, and that the majority of this variation can be captured by a relatively simple spatial management policy. Moreover, while an increase in policy resolution can improve performance, the location of policy changes also needs to align with ecological and socioeconomic variation. Interestingly, the highly complex process of larval dispersal, which plays a critical ecological role in coral reef ecosystem dynamics, may not demand equally complex management policies. PMID- 26984624 TI - Silent oceans: ocean acidification impoverishes natural soundscapes by altering sound production of the world's noisiest marine invertebrate. AB - Soundscapes are multidimensional spaces that carry meaningful information for many species about the location and quality of nearby and distant resources. Because soundscapes are the sum of the acoustic signals produced by individual organisms and their interactions, they can be used as a proxy for the condition of whole ecosystems and their occupants. Ocean acidification resulting from anthropogenic CO2 emissions is known to have profound effects on marine life. However, despite the increasingly recognized ecological importance of soundscapes, there is no empirical test of whether ocean acidification can affect biological sound production. Using field recordings obtained from three geographically separated natural CO2 vents, we show that forecasted end-of century ocean acidification conditions can profoundly reduce the biological sound level and frequency of snapping shrimp snaps. Snapping shrimp were among the noisiest marine organisms and the suppression of their sound production at vents was responsible for the vast majority of the soundscape alteration observed. To assess mechanisms that could account for these observations, we tested whether long-term exposure (two to three months) to elevated CO2 induced a similar reduction in the snapping behaviour (loudness and frequency) of snapping shrimp. The results indicated that the soniferous behaviour of these animals was substantially reduced in both frequency (snaps per minute) and sound level of snaps produced. As coastal marine soundscapes are dominated by biological sounds produced by snapping shrimp, the observed suppression of this component of soundscapes could have important and possibly pervasive ecological consequences for organisms that use soundscapes as a source of information. This trend towards silence could be of particular importance for those species whose larval stages use sound for orientation towards settlement habitats. PMID- 26984623 TI - Stickleback embryos use ATP-binding cassette transporters as a buffer against exposure to maternally derived cortisol. AB - Offspring from females that experience stressful conditions during reproduction often exhibit altered phenotypes and many of these effects are thought to arise owing to increased exposure to maternal glucocorticoids. While embryos of placental vertebrates are known to regulate exposure to maternal glucocorticoids via placental steroid metabolism, much less is known about how and whether egg laying vertebrates can control their steroid environment during embryonic development. We tested the hypothesis that threespine stickleback (Gasterosteus aculeatus) embryos can regulate exposure to maternal steroids via active efflux of maternal steroids from the egg. Embryos rapidly (within 72 h) cleared intact steroids, but blocking ATP-binding cassette (ABC) transporters inhibited cortisol clearance. Remarkably, this efflux of cortisol was sufficient to prevent a transcriptional response of embryos to exogenous cortisol. Taken together, these findings suggest that, much like their placental counterparts, developing fish embryos can actively regulate their exposure to maternal cortisol. These findings highlight the fact that even in egg-laying vertebrates, the realized exposure to maternal steroids is mediated by both maternal and embryonic processes and this has important implications for understanding how maternal stress influences offspring development. PMID- 26984625 TI - Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum. AB - Infections with the malaria parasite Plasmodium falciparum typically comprise multiple strains, especially in high-transmission areas where infectious mosquito bites occur frequently. However, little is known about the dynamics of mixed strain infections, particularly whether strains sharing a host compete or grow independently. Competition between drug-sensitive and drug-resistant strains, if it occurs, could be a crucial determinant of the spread of resistance. We analysed 1341 P. falciparum infections in children from Angola, Ghana and Tanzania and found compelling evidence for competition in mixed-strain infections: overall parasite density did not increase with additional strains, and densities of individual chloroquine-sensitive (CQS) and chloroquine-resistant (CQR) strains were reduced in the presence of competitors. We also found that CQR strains exhibited low densities compared with CQS strains (in the absence of chloroquine), which may underlie observed declines of chloroquine resistance in many countries following retirement of chloroquine as a first-line therapy. Our observations support a key role for within-host competition in the evolution of drug-resistant malaria. Malaria control and resistance-management efforts in high transmission regions may be significantly aided or hindered by the effects of competition in mixed-strain infections. Consideration of within-host dynamics may spur development of novel strategies to minimize resistance while maximizing the benefits of control measures. PMID- 26984626 TI - Cuttlefish see shape from shading, fine-tuning coloration in response to pictorial depth cues and directional illumination. AB - Humans use shading as a cue to three-dimensional form by combining low-level information about light intensity with high-level knowledge about objects and the environment. Here, we examine how cuttlefish Sepia officinalis respond to light and shadow to shade the white square (WS) feature in their body pattern. Cuttlefish display the WS in the presence of pebble-like objects, and they can shade it to render the appearance of surface curvature to a human observer, which might benefit camouflage. Here we test how they colour the WS on visual backgrounds containing two-dimensional circular stimuli, some of which were shaded to suggest surface curvature, whereas others were uniformly coloured or divided into dark and light semicircles. WS shading, measured by lateral asymmetry, was greatest when the animal rested on a background of shaded circles and three-dimensional hemispheres, and less on plain white circles or black/white semicircles. In addition, shading was enhanced when light fell from the lighter side of the shaded stimulus, as expected for real convex surfaces. Thus, the cuttlefish acts as if it perceives surface curvature from shading, and takes account of the direction of illumination. However, the direction of WS shading is insensitive to the directions of background shading and illumination; instead the cuttlefish tend to turn to face the light source. PMID- 26984627 TI - Perspectives on optimal control of varicella and herpes zoster by mass routine varicella vaccination. AB - Herpes zoster arises from reactivation of the varicella-zoster virus (VZV), causing varicella in children. As reactivation occurs when cell-mediated immunity (CMI) declines, and there is evidence that re-exposure to VZV boosts CMI, mass varicella immunization might increase the zoster burden, at least for some decades. Fear of this natural zoster boom is the main reason for the paralysis of varicella immunization in Europe. We apply optimal control to a realistically parametrized age-structured model for VZV transmission and reactivation to investigate whether feasible varicella immunization paths that are optimal in controlling both varicella and zoster exist. We analyse the optimality system numerically focusing on the role of the cost functional, of the relative zoster varicella cost and of the planning horizon length. We show that optimal programmes will mostly be unfeasible for public health owing to their complex temporal profiles. This complexity is the consequence of the intrinsically antagonistic nature of varicella immunization programmes when aiming to control both varicella and zoster. However, we show that gradually increasing-hence feasible-vaccination schedules can perform better than routine programmes with constant vaccine uptake. Finally, we show the optimal profiles of feasible programmes targeting mitigation of the post-immunization natural zoster boom with priority. PMID- 26984628 TI - Cultural history, not ecological environment, is the main determinant of human behaviour. PMID- 26984629 TI - Correction to 'A theory of modern cultural shifts and meltdowns'. PMID- 26984630 TI - Corrigendum: Tunable continuous wave emission via phase-matched second harmonic generation in a ZnSe microcylindrical resonator. PMID- 26984631 TI - Increased 5-hydroxymethylcytosine in CD4(+) T cells in systemic lupus erythematosus. AB - One of the major disappointments in autoimmunity has been the relative lack of informative data when genomewide associations (GWAS) have been applied to patients with systemic lupus erythematosus (SLE). Indeed, there is increasing evidence that SLE is characterized by widespread epigenetic changes. 5 Hydroxymethylcytosine (5-hmC) is a newly discovered modified form of cytosine suspected to be an important epigenetic modification in embryonic development, cell differentiation and cancer. DNA methylation dynamics have already been implicated in the pathogenesis of SLE, while little is known about hydroxymethylation in this process. Here, we show an increased 5-hmC level in genomic DNA in CD4(+) T cells of patients with SLE compared with healthy controls, accompanied by the up-regulated expression of the Ten-eleven translocation TET2 and TET3, which can enzymatically convert 5-methylcytosine (5 mC) to 5-hmC. Moreover, we present the differential patterns of DNA hydroxymethylation in genome-wide promoter regions in SLE CD4(+) T cells compared with healthy controls. We identified 2748 genes with increased 5-hmC levels in promoter regions in SLE CD4(+) T cells, which were enriched in critical pathways, including neurotrophin signaling, WNT signaling, MAPK signaling, calcium signaling and the mTOR signaling pathway. Through a combined analysis of differential DNA hydroxymethylation profile and gene expression profile in SLE CD4(+) T cells, we found 131 genes with the increased 5-hmC in promoter regions and up-regulated expression in SLE CD4(+) T cells compared with healthy controls, including selected immune-related genes, i.e. SOCS1, NR2F6 and IL15RA, which were also confirmed by ChIP-qPCR. Furthermore, we demonstrate that CTCF, as a transcription factor, can mediate DNA hydroxymethylation and contribute to overexpression of SOCS1 in CD4(+) T cells through binding to the promoter region of SOCS1. Taken together, our study reveals a critical differential 5-hmC in the genome-wide promoter regions of SLE CD4(+) T cells and provides a novel mechanism that suggests that DNA hydroxymethylation contributes to the aberrant regulation of genes transcription in the pathogenesis of SLE. PMID- 26984632 TI - Octadecylamine-Mediated Versatile Coating of CoFe2O4 NPs for the Sustained Release of Anti-Inflammatory Drug Naproxen and in Vivo Target Selectivity. AB - Magnetic nanoparticles (MNPs) can play a distinct role in magnetic drug delivery via their distribution to the targeted area. The preparation of such MNPs is a challenging multiplex task that requires the optimization of size, magnetic, and surface properties for the achievement of desirable target selectivity, along with the sustained drug release as a prerequisite. In that context, CoFe2O4 MNPs with a small size of ~7 nm and moderate saturation magnetization of ~60 emu g(-1) were solvothermally synthesized in the presence of octadecylamine (ODA) with a view to investigate the functionalization route effect on the drug release. Synthetic regulations allowed us to prepare MNPs with aminated (AmMNPs) and amine free (FAmMNPs) surface. The addition of the nonsteroidal anti-inflammatory drug with a carboxylate donor, Naproxen (NAP), was achieved by direct coupling with the NH2 groups, rendered by ODA, through the formation of an amide bond in the case of AmMNPs. In the case of FAmMNPs, indirect coupling of NAP was performed through an intermediate linker (polyethylenimine) and on PEG-ylated MNPs. FT-IR, (1)H NMR, (13)C NMR, and UV-vis data confirmed the addition of NAP, whereas diverse drug-release behavior was observed for the different functionalization approaches. The biological behavior of the MNPs@NAP was evaluated in vitro in rat serum and in vivo in mice, after radiolabeling with a gamma-emitting radionuclide, (99m)Tc. The in vivo fate of MNPs@NAP carriers was in straightforward relation with the direct or indirect coupling of NAP. Furthermore, an inflammation was induced intramuscularly, where the directly coupled (99m)Tc-MNPs@NAP carriers showed increased accumulation at the inflammation site. PMID- 26984633 TI - Timosaponin A-III reverses multi-drug resistance in human chronic myelogenous leukemia K562/ADM cells via downregulation of MDR1 and MRP1 expression by inhibiting PI3K/Akt signaling pathway. AB - One of the major causes of failure in chemotherapy for patients with human chronic myelogenous leukemia (CML) is the acquisition of multidrug resistance (MDR). MDR is often associated with the overexpression of drug efflux transporters of the ATP-binding cassette (ABC) protein family. Timosaponin A-III (TAIII), a saponin isolated from the rhizome of Anemarrhena asphodeloides, has previously demonstrated the ability to suppress certain human tumor processes and the potential to be developed as an anticancer agent. Nevertheless, the ability of TAIII to reverse MDR has not yet been explored. In this study, the adriamycin (ADM) resistance reversal effect of TAIII in human CML K562/ADM cells and the underlying mechanism was investigated. The Cell Counting Kit-8 (CCK-8) assay showed that TAIII had a reversal effect on the drug resistance of K562/ADM cells. Flow cytometry assay showed increased intracellular accumulation of ADM after cells were pretreated with TAIII, and the changes in the accumulation of rhodamine-123 (Rho-123) and 5(6)-carboxyfluorescein diacetate (CFDA) dye in K562/ADM cells were determined to be similar to the changes of intracellular accumulation of ADM. After pretreatment of cells with TAIII, the decreasing expression of P-gp and MRP1 mRNA was examined by reverse transcription polymerase chain reaction (RT-PCR). Western blotting showed TAIII inhibiting P-gp and MRP1 expression depended on the PI3K/Akt signaling pathway by decreasing the activity of p-Akt. Moreover, wortmannin an inhibitor of PI3K/Akt signaling pathway has a strong inhibitory effect on the expression of p-Akt, P-gp and MRP1. Besides, the combined treatment with TAIII did not have an affect on wortmannin downregulation of p-Akt, P-gp and MRP1. Taken together, our findings demonstrate, for the first time, that TAIII induced MDR reversal through inhibition of P-gp and MRP1 expression and function with regained adriamycin sensitivity which might mainly correlate to the regulation of PI3K/Akt signaling pathway. PMID- 26984634 TI - Real-time high-resolution heterodyne-based measurements of spectral dynamics in fibre lasers. AB - Conventional tools for measurement of laser spectra (e.g. optical spectrum analysers) capture data averaged over a considerable time period. However, the generation spectrum of many laser types may involve spectral dynamics whose relatively fast time scale is determined by their cavity round trip period, calling for instrumentation featuring both high temporal and spectral resolution. Such real-time spectral characterisation becomes particularly challenging if the laser pulses are long, or they have continuous or quasi-continuous wave radiation components. Here we combine optical heterodyning with a technique of spatio temporal intensity measurements that allows the characterisation of such complex sources. Fast, round-trip-resolved spectral dynamics of cavity-based systems in real-time are obtained, with temporal resolution of one cavity round trip and frequency resolution defined by its inverse (85 ns and 24 MHz respectively are demonstrated). We also show how under certain conditions for quasi-continuous wave sources, the spectral resolution could be further increased by a factor of 100 by direct extraction of phase information from the heterodyned dynamics or by using double time scales within the spectrogram approach. PMID- 26984636 TI - The impairment of small nerve fibers in severe sepsis and septic shock. AB - BACKGROUND: A decrease of small nerve fibers in skin biopsies during the course of critical illness has been demonstrated recently. However, the diagnostic use of skin biopsies in sepsis and its time course is not known. METHODS: Patients (n=32) with severe sepsis or septic shock were examined using skin biopsies, neurological examination, nerve conduction studies, and sympathetic skin response in the first week after onset of sepsis, 2 weeks and 4 months later and compared to gender- and age-matched healthy controls. RESULTS: Skin biopsies at the ankle and thigh revealed a significant decrease of intraepidermal nerve fiber density (IENFD) during the first week of sepsis and 2 weeks later. All patients developed critical illness polyneuropathy (CIP) according to electrophysiological criteria and 11 showed IENFD values lower than the 0.05 quantile. Four patients were biopsied after 4 months and still showed decreased IENFD. Results of nerve conduction studies and IENFD did considerably change over time. No differences for survival time between patients with IEFND lower and larger than 3.5 fibers/mm were found. CONCLUSIONS: Skin biopsy is able to detect an impairment of small sensory nerve fibers early in the course of sepsis. However, it may not be suited as a prognostic parameter for survival. TRIAL REGISTRATION: German Clinical Trials Register, DRKS-ID: DRKS00000642, 12/17/2010. PMID- 26984635 TI - Runs of homozygosity and inbreeding in thyroid cancer. AB - BACKGROUND: Genome-wide association studies (GWASs) have identified several single-nucleotide polymorphisms (SNPs) influencing the risk of thyroid cancer (TC). Most cancer predisposition genes identified through GWASs function in a co dominant manner, and studies have not found evidence for recessively functioning disease loci in TC. Our study examines whether homozygosity is associated with an increased risk of TC and searches for novel recessively acting disease loci. METHODS: Data from a previously conducted GWAS were used for the estimation of the proportion of phenotypic variance explained by all common SNPs, the detection of runs of homozygosity (ROH) and the determination of inbreeding to unravel their influence on TC. RESULTS: Inbreeding coefficients were significantly higher among cases than controls. Association on a SNP-by-SNP basis was controlled by using the false discovery rate at a level of q* < 0.05, with 34 SNPs representing true differences in homozygosity between cases and controls. The average size, the number and total length of ROHs per person were significantly higher in cases than in controls. A total of 16 recurrent ROHs of rather short length were identified although their association with TC risk was not significant at a genome-wide level. Several recurrent ROHs harbor genes associated with risk of TC. All of the ROHs showed significant evidence for natural selection (iHS, Fst, Fay and Wu's H). CONCLUSIONS: Our results support the existence of recessive alleles in TC susceptibility. Although regions of homozygosity were rather small, it might be possible that variants within these ROHs affect TC risk and may function in a recessive manner. PMID- 26984637 TI - Distances between bony landmarks and adjacent nerves: anatomical factors that may influence retractor placement in total hip replacement surgery. AB - BACKGROUND: Retractor placement is a leading cause of intraoperative nerve injury during total hip replacement (THR) surgery. The sciatic nerve, femoral nerve, and superior gluteal nerve are most commonly affected. This study aimed to identify the distances from bony landmarks in the hip to the adjacent nerves on magnetic resonance imaging (MRI) and the associations between anatomical factors and these distances that would guide the placement of retractors during THR surgery, in order to minimize the risk of nerve injury. METHODS: We reviewed hip MRIs of 263 adults and recorded the distances from (1) the anterior acetabular rim to the femoral nerve; (2) the superior acetabular rim to the superior gluteal nerve; (3) the posterior acetabular rim to the sciatic nerve; and (4) the greater trochanter to the sciatic nerve. The effects of anatomical factors (i.e., gender, age, body height, body mass index (BMI), pelvic width, and acetabular version and morphology) on these distances were analyzed. RESULTS: Distances from bony landmarks to adjacent nerves (in cm) were 2.06 +/- 0.44, 2.23 +/- 0.28, 1.94 +/- 0.81, and 4.83 +/- 0.26 for the anterior acetabular rim, superior acetabular rim, posterior acetabular rim, and greater trochanter, respectively, and were shorter in women than in men (P < 0.001). Multivariate analysis identified body height as the most influential factor (P < 0.001). Linear regression demonstrated a strong positive linear correlation between body height and these distances (Pearson's r = 0.808, 0.823, 0.818, and 0.792, respectively (P < 0.001)). CONCLUSIONS: The distances from bony landmarks to adjacent nerves provide useful information for placing retractors without causing nerve injury during THR surgery. Shorter patients will have shorter distances from bony landmarks to adjacent nerves, prompting more careful placement of retractors. PMID- 26984639 TI - Associations of functional alanine-glyoxylate aminotransferase 2 gene variants with atrial fibrillation and ischemic stroke. AB - Asymmetric and symmetric dimethylarginines (ADMA and SDMA) impair nitric oxide bioavailability and have been implicated in the pathogenesis of atrial fibrillation (AF). Alanine-glyoxylate aminotransferase 2 (AGXT2) is the only enzyme capable of metabolizing both of the dimethylarginines. We hypothesized that two functional AGXT2 missense variants (rs37369, V140I; rs16899974, V498L) are associated with AF and its cardioembolic complications. Association analyses were conducted using 1,834 individulas with AF and 7,159 unaffected individuals from two coronary angiography cohorts and a cohort comprising patients undergoing clinical exercise testing. In coronary angiography patients without structural heart disease, the minor A allele of rs16899974 was associated with any AF (OR = 2.07, 95% CI 1.59-2.68), and with paroxysmal AF (OR = 1.98, 95% CI 1.44-2.74) and chronic AF (OR = 2.03, 95% CI 1.35-3.06) separately. We could not replicate the association with AF in the other two cohorts. However, the A allele of rs16899974 was nominally associated with ischemic stroke risk in the meta-analysis of WTCCC2 ischemic stroke cohorts (3,548 cases, 5,972 controls) and with earlier onset of first-ever ischemic stroke (360 cases) in the cohort of clinical exercise test patients. In conclusion, AGXT2 variations may be involved in the pathogenesis of AF and its age-related thromboembolic complications. PMID- 26984638 TI - The role of the aryl hydrocarbon receptor in the development of cells with the molecular and functional characteristics of cancer stem-like cells. AB - BACKGROUND: Self-renewing, chemoresistant breast cancer stem cells are believed to contribute significantly to cancer invasion, migration and patient relapse. Therefore, the identification of signaling pathways that regulate the acquisition of stem-like qualities is an important step towards understanding why patients relapse and towards development of novel therapeutics that specifically target cancer stem cell vulnerabilities. Recent studies identified a role for the aryl hydrocarbon receptor (AHR), an environmental carcinogen receptor implicated in cancer initiation, in normal tissue-specific stem cell self-renewal. These studies inspired the hypothesis that the AHR plays a role in the acquisition of cancer stem cell-like qualities. RESULTS: To test this hypothesis, AHR activity in Hs578T triple negative and SUM149 inflammatory breast cancer cells were modulated with AHR ligands, shRNA or AHR-specific inhibitors, and phenotypic, genomic and functional stem cell-associated characteristics were evaluated. The data demonstrate that (1) ALDH(high) cells express elevated levels of Ahr and Cyp1b1 and Cyp1a1, AHR-driven genes, (2) AHR knockdown reduces ALDH activity by 80%, (3) AHR hyper-activation with several ligands, including environmental ligands, significantly increases ALDH1 activity, expression of stem cell- and invasion/migration-associated genes, and accelerates cell migration, (4) a significant correlation between Ahr or Cyp1b1 expression (as a surrogate marker for AHR activity) and expression of stem cell- and invasion/migration-associated gene sets is seen with genomic data obtained from 79 human breast cancer cell lines and over 1,850 primary human breast cancers, (5) the AHR interacts directly with Sox2, a master regulator of self-renewal; AHR ligands increase this interaction and nuclear SOX2 translocation, (6) AHR knockdown inhibits tumorsphere formation in low adherence conditions, (7) AHR inhibition blocks the rapid migration of ALDH(high) cells and reduces ALDH(high) cell chemoresistance, (8) ALDH(high) cells are highly efficient at initiating tumors in orthotopic xenografts, and (9) AHR knockdown inhibits tumor initiation and reduces tumor Aldh1a1, Sox2, and Cyp1b1 expression in vivo. CONCLUSIONS: These data suggest that the AHR plays an important role in development of cells with cancer stem cell-like qualities and that environmental AHR ligands may exacerbate breast cancer by enhancing expression of these properties. PMID- 26984640 TI - Bioluminescent magnetic nanoparticles as potential imaging agents for mammalian spermatozoa. AB - BACKGROUND: Nanoparticles have emerged as key materials for developing applications in nanomedicine, nanobiotechnology, bioimaging and theranostics. Existing bioimaging technologies include bioluminescent resonance energy transfer conjugated quantum dots (BRET-QDs). Despite the current use of BRET-QDs for bioimaging, there are strong concerns about QD nanocomposites containing cadmium which exhibits potential cellular toxicity. RESULTS: In this study, bioluminescent composites comprised of magnetic nanoparticles and firefly luciferase (Photinus pyralis) are examined as potential light-emitting agents for imaging, detection, and tracking mammalian spermatozoa. Characterization was carried out using infrared spectroscopy, TEM and cryo-TEM imaging, and zeta potential measurements to demonstrate the successful preparation of these nanocomposites. Binding interactions between the synthesized nanoparticles and spermatozoon were characterized using confocal and atomic/magnetic force microscopy. Bioluminescence imaging and UV-visible-NIR microscopy results showed light emission from sperm samples incubated with the firefly luciferase-modified nanoparticles. Therefore, these newly synthesized luciferase-modified magnetic nanoparticles show promise as substitutes for QD labeling, and can potentially also be used for in vivo manipulation and tracking, as well as MRI techniques. CONCLUSIONS: These preliminary data indicate that luciferase-magnetic nanoparticle composites can potentially be used for spermatozoa detection and imaging. Their magnetic properties add additional functionality to allow for manipulation, sorting, or tracking of cells using magnetic techniques. PMID- 26984641 TI - Young Adults' Information Seeking Following Celebrity Suicide: Considering Involvement With the Celebrity and Emotional Distress in Health Communication Strategies. AB - Young adults (N = 357) were surveyed following the suicide of celebrity Robin Williams to better understand how involvement with the actor and emotional responses to his death influenced searches for information concerning depression, suicide, and mental health. Emotional distress following the actor's death mediated the relationship between involvement and certain types of information searches. Most respondents sought information about the celebrity's career, suicide, and depression using portable devices such as smartphones and laptop computers to access news websites for information. Those respondents who sought information about the suicide reported changes in their thoughts about suicide, most often dealing with the difficulty in spotting warning signs and the idea that "it can happen to anyone." Findings suggest placement of health messages within existing material about celebrity announcements on online websites and social media to drive more traffic toward general informational outlets. Messages that acknowledge emotional distress might be best placed within content specific to the celebrity's tragedy, rather than specific to the celebrity's career or performances. PMID- 26984642 TI - Novel Approach for Clinical Validation of the cobas KRAS Mutation Test in Advanced Colorectal Cancer. AB - AIM: Our objective was to assess the performance of the cobas test versus comparators for KRAS mutation status and predicting clinical response to anti epidermal growth factor receptor (EGFR) therapy in patients with metastatic colorectal cancer (mCRC). METHODS: mCRC samples from 398 patients from Roche study NO16968 (XELOXA) and 82 supplemental samples were tested with the cobas((r)) KRAS mutation test (cobas test), the therascreen((r)) KRAS RGQ PCR kit test (therascreen test), and Sanger sequencing as the reference method for detecting mutations in codons 12/13. RESULTS: For 461 eligible samples, the cobas test, therascreen test, and sequencing had invalid results for 5.2, 10.8, and 2.6 % of specimens, respectively. Valid cobas and therascreen test results had similar KRAS mutation-positive rates (37.3 vs. 36.3 %, respectively); sequencing was 28.5 %. Positive and negative percent agreement (PPA/NPA) between the cobas test and sequencing was 96.9 % (95 % confidence interval [CI] 92.2-98.8), and 88.7 % (95 % CI 84.7-91.8), respectively. PPA/NPA between the cobas and therascreen tests was 93.3 % (95 % CI 88.1-96.3) and 96.5 % (95 % CI 93.5-98.1), respectively. Bridging analysis from NCIC-CO.17 and NCT00113763 using the cobas test yielded modeled hazard ratios for overall survival and progression-free survival (PFS) of 0.558 (95 % CI 0.422-0.752) and 0.413 (95 % CI 0.304-0.550), respectively, for cetuximab and 0.989 (95 % CI 0.778-1.299) and 0.471 (95 % CI 0.360-0.626), respectively, for panitumumab, demonstrating significant efficacy in the KRAS-negative population for PFS. CONCLUSION: The cobas test showed similar accuracy to the therascreen test for detecting KRAS mutations and could appropriately identify mCRC patients ineligible for anti-EGFR therapy as demonstrated by bridging analysis results. PMID- 26984643 TI - Collective atomic scattering and motional effects in a dense coherent medium. AB - We investigate collective emission from coherently driven ultracold (88)Sr atoms. We perform two sets of experiments using a strong and weak transition that are insensitive and sensitive, respectively, to atomic motion at 1 MUK. We observe highly directional forward emission with a peak intensity that is enhanced, for the strong transition, by >10(3) compared with that in the transverse direction. This is accompanied by substantial broadening of spectral lines. For the weak transition, the forward enhancement is substantially reduced due to motion. Meanwhile, a density-dependent frequency shift of the weak transition (~10% of the natural linewidth) is observed. In contrast, this shift is suppressed to <1% of the natural linewidth for the strong transition. Along the transverse direction, we observe strong polarization dependences of the fluorescence intensity and line broadening for both transitions. The measurements are reproduced with a theoretical model treating the atoms as coherent, interacting radiating dipoles. PMID- 26984644 TI - Suicide Ideation Is Related to Therapeutic Alliance in a Brief Therapy for Attempted Suicide. AB - The objective of this study was to investigate the role of therapeutic alliance on suicide ideation as outcome measure in a brief therapy for patients who attempted suicide. Sixty patients received the 3-session therapy supplemented by follow-up contact through regular letters. Therapeutic alliance was measured with the Helping Alliance Questionnaire (HAQ). Outcome at 6 and 12 months was measured with the Beck Scale for Suicide Ideation (BSS). Therapeutic alliance increased from session 1 to session 3. Higher alliance measures correlated with lower suicidal ideation at 12 months follow-up. A history of previous attempts and depression had a negative affect on therapeutic alliance. The results suggest that in the treatment of suicidal patients therapeutic alliance may be a moderating factor for reducing suicide ideation. PMID- 26984645 TI - Effects of prenatal diclofenac sodium exposure on newborn testis: a histomorphometric study. AB - Diclofenac sodium (DS) is used primarily to treat fever and to alleviate pain and inflammation. We investigated the effects of DS exposure during gestation on the testes of rat pups to investigate the safety of its use during the prenatal period. Pregnant rats were separated into control, saline, low dose, medium dose and high dose groups. DS was given between weeks 15 and 21 of gestation. Total numbers of spermatogonia and Sertoli cells were counted in the testes of 7-day old male rats using the physical disector method. By the end of the study, the total number of Sertoli cells was decreased significantly in a dose dependent manner in the medium and high dose groups compared to controls. No significant differences were found in the total number of spermatogonia in the control, saline and low dose DS groups. Medium and high dose DS administration reduced the total number of spermatogonia compared to other groups. We suggest that prenatal administration of DS can cause deleterious effects on the testis development, especially in high doses. PMID- 26984647 TI - Novel structurally tuned DAMN receptor for "in situ" diagnosis of bicarbonate in environmental waters. AB - A new diaminomalenonitrile (DAMN) based charge transfer (CT) chromophore has been designed and synthesized. The receptor demonstrates highly specific and prompt bicarbonate anion (HCO3(-)) sensing in aqueous solution. Interaction with HCO3(-) triggers facile CT across the system, and enables the in situ recognition of water soluble carbonates. The recognition allows us to obtain qualitative as well as quantitative information from aqueous media. The inimitable potential of the receptor was further utilized for monitoring bicarbonate in a range of environmental waters. PMID- 26984646 TI - Poor sleep quality is observed in mild cognitive impairment and is largely unrelated to depression and anxiety. AB - BACKGROUND: Individuals with mild cognitive impairment (MCI) commonly experience a number of sleep quality related issues. However, it remains unclear if these issues are specific to MCI or are simply attributed to the elevated levels depression and anxiety symptoms frequently observed among those with MCI. The present study sought to examine group differences between participants with MCI and matched controls on self-reported measures of sleep quality while controlling for depression and anxiety levels. METHODS: Participants with MCI (N = 48) and demographically matched controls (N = 48) were administered with self-reported measures of anxiety, depression and sleep quality. Sleep quality between both groups were first analyzed using a Multivariate Analysis of Variance, and then subsequently a Multivariate Analysis of Covariance incorporating depression and anxiety scores as covariates. RESULTS: The MCI group had significantly higher levels of depression and anxiety than the controls. On the sleep-related measures, the MCI group had significantly worse outcomes in sleep duration, disturbances, latency, efficiency, quality and daytime dysfunction. After controlling for depression and anxiety levels, with the exception of daytime dysfunction, all other differences remain significant, and are also associated with moderate to large effect sizes. CONCLUSION: The results suggest that sleep quality issues are present in MCI and are largely independent of depression and anxiety. PMID- 26984648 TI - Is internal fixation of the intertrochanteric fractures reliable option in patients with cognitive dysfunction? AB - The purpose of this study was to compare the results of hemiarthroplasty with those of treatment internal fixation devices for stable intertrochanteric fractures in patients with moderate and severe cognitive dysfunction. 155 patients were evaluated retrospectively. 54 patients were treated with proximal femoral nail (PFN), 57 with dynamic hip screw (DHS) and 44 were underwent hemiarthroplasty (HA). Activities of daily living (ADL) were evaluated with the Barthel Activity Index (BI) score and the Health Related Quality of Life (HRQoL) with the Euroquol-5D (EQ-5D) test. The BI scores in HA patients were found to be at significantly high compared to the PFN and DHS groups both at the one and two years. A significant difference was also found in the EQ-5D scores in favor of HA group at one year. The most common complications in internal fixation patients were malunion (7/54 for PFN, 9/57 for DHS group), fixation failure (8/54 for PFN, 12/57 for DHS group) and dislocation (10/44), deep infection (8/44) for HA group. The strong predictive variables on ADL in dementia patients were, duration time to surgery and pre-operative MMSE score. In conclusion, HA is the prefered treatment for stable intertrochanteric fractures but that the dislocation (10/44) and infection rates (8/44) are very high in dementia. PMID- 26984650 TI - Patella component loosening--A case report. AB - Patellofemoral arthroplasty is a treatment option for the relatively young patient with isolated patellofemoral osteoarthritis where conservative treatment has failed. However, despite of reasonable long term results, complications could be challenging. Loosening of the polyethylene patella component is a serious complication and has been reported in 2%. Dislocation of the polyethylene patella component did -happen more often in the polyethylene patella metal backed LCS-PFA variant. In this case we describe the diagnostic and treatment challenges of this complication. PMID- 26984649 TI - Birmingham Hip Resurfacing--Patient reported outcomes pre and post 'Metal-on Metal' media attention. AB - We have investigated whether patient reported outcomes provided by patients with Birmingham Hip Resurfacing (BHR) changed after negative media coverage of metal on-metal (MOM) hip replacement. We also investigated whether patients whose procedures were performed by a designer surgeon behaved differently to those performed elsewhere. 1178 consecutive BHR procedures performed between January 2002 and December 2006, by one of the designer surgeons in his private practice, were reviewed. We also reviewed 402 BHRs undertaken by two non-designer surgeons in both their NHS and private practice. 150 of the latter cohort were undertaken at an NHS hospital and 252 at an independent private hospital. All patients had annual Oxford Hip Scores (OHS) collected. We chose 2007 as pre-"media attention" and compared scores from this year against subsequent years. We found no clinically significant change in OHS between 2007 and subsequent years, at all centres. We conclude that negative media reporting does not appear to have had an impact on patients' perceived outcome after BHR. In consequence, patients who have undergone this type of hip resurfacing and show deterioration should be investigated. PMID- 26984651 TI - Anterior lumbar inter-body fusion with instrumentation compared with posterolateral fusion for low grade isthmic-spondylolisthesis. AB - Spondylolisthesis presenting as low back pain is not an uncommon condition. Many of such patients are treated conservatively. For those that require surgical management, various treatment options are in vogue e.g. Postero-lateral fusion (PLF) with decompression or posterior fusion with instrumentation and anterior lumbar inter-body fusion (ALIF). Each technique has produced satisfactory outcome with benefits and disadvantages. AIM OF THE STUDY: To compare the outcome of surgical management of low grade spondylolisthesis with two treatments modalities -Postero-lateral fusion (PLF) and Anterior lumbar inter-body fusion (ALIF) with posterior instrumentation in similar patient profile. SETTINGS AND DESIGN: Prospective study to compare the results of two surgical treatment modalities. MATERIAL AND METHODS: The selected group of patients for surgery based on definite criteria was operated by the same surgeon by two modalities: Postero lateral fusion with decompression and Anterior Lumbar Inter-body fusion with posterior instrumentation. The outcomes were compared. STATISTICAL ANALYSIS USED: Analysis of variance (ANOVA) test. RESULTS: Follow up was done at twelve weekly intervals up to 2 years. Both groups showed good recovery in pain as seen in Visual analogue scale (VAS) and Oswestry low back pain scoring. Intra-operative bleeding was observed to be higher in Postero-lateral fusion group. Average length of hospital stay for the patients of PLF group was 6.6 days (Range: 4-7 days) as compared to 12.5 days (Range: 10-16 days) in case of ALIF group. Treatment cost was found to be higher in patients who undergone ALIF with instrumentation. CONCLUSIONS: ALIF with posterior instrumentation in low grade isthmic spondylolisthesis provides satisfactory outcome in patients requiring surgical treatment. The results of pain relief and disability index are comparable to time tested posterolateral fusion. ALIF shows a tendency to faster pain relief and return to activity with less intraoperative blood requirement in low grade isthmic spondylolisthesis. PMID- 26984653 TI - Adjustments in 2011 KSS increase the clinical suitability. AB - The 2011 KSS is a valid clinical TKA questionnaire, but with a low completion rate (42%). Adjustments, focusing on optimizing scale features, are required to improve its clinical use. The low completion rates, non-optimal scale features, lacking rules or a combination of these factors where addressed, leading to the development of the adjusted 2011 KSS (2011 KSS-A). Four-hundred-ninety-nine primary TKA patients were addressed pre- and postoperative by mail. Clinimetric quality was evaluated. Seventy percent responded and 90% completed the scale. Internal consistency proved excellent with Cronbach's Alpha>=0.79 for all subscales. Strong correlations were found between the Functional Activity subscales and KOOS-PS (r=-0.63 to -0.87). All subscales improved significantly after intervention (r-range 14-33%, effect size 0.50-2.85). Postoperatively, ceiling effects were found in the subscales Symptoms (16%) and Walking & Standing (26%). Adjustments led to a shortened and simplified questionnaire while maintaining its clinimetric quality. PMID- 26984652 TI - Results of a unicentric series of 15 wrist prosthesis implantations at a 5.2 year follow-up. AB - Our retrospective study aimed to evaluate functional and radiological results of a unicentric series of 17 total wrist prostheses implanted between 2001 and 2011. Nine women and seven men, mean age 59, underwent wrist joint arthroplasty, bilateral in one case. Universal Total Wrist and Remotion prostheses were used and followed-up at a mean of 5.2 years (1.1-10). Fifteen patients were reviewed. Four patients had postoperative complications, three of whom required arthrodesis. The rest obtained satisfactory pain relief. Grip strength nevertheless decreased compared to the contralateral side and mobility was reduced: flexion/extension=33 degrees , ulnar/radial deviation=20 degrees . The Quick DASH score was 29% and PRWE, 26%. Radiological assessment revealed carpal implant loosening in eight patients. Our series confirms the discordance generally observed between patients' subjective satisfaction and mediocre clinical and radiological results over the medium term. PMID- 26984654 TI - Percutaneous iliosacral screw fixation in vertically unstable pelvic injuries, a refined conventional method. AB - Percutaneous ilio-sacral screw fixation is a well-established method for fixation of unstable posterior pelvic lesions. Due to unavailability of the navigation system in our institute and the limits of using CT-guided method, we tried to refine the conventional method. Between March 2011 and Nov. 2012, twenty patients with closed vertical pelvic injuries were admitted. They were 17 males and three females with an average age of 34 years (range from 27 to 55). Percutaneous ilio sacral screw fixation was done in the supine position using a Schanz screw marking of a fixed entry point in the outer iliac table. Closed reduction was done in all cases with excellent reduction in 14 cases, good in two and fair in four cases. The mean duration of screw insertion was 17 minutes (ranged from 10 to 25). One case of injury of the superior gluteal vessels was present and one case with misplacement through the ventral part of contra-lateral sacral ala. No neurological complications were detected. Ilio-sacral screw fixation by this refined technique allows safe stabilization of vertical pelvic lesions with an acceptable complication rate. PMID- 26984655 TI - Press-fit versus threaded acetabular cups in total hip arthroplasty: Functional and radiological results after five years. AB - Prospectively the outcome after total hip replacement with a new threaded acetabular cup design was compared to an established press-fit cup. After 1, 2 and 5 years, the 36-item Short Form Health Survey, Western Ontario and McMaster University Osteoarthritis Index and Harris Hip Score revealed no significant differences between the two groups (each group: n=42 patients), except for a higher Harris Hip Score in the threaded cup group after five years (p=0.02). After five years, one threaded cup had a mild radiolucent line without further signs of loosening. All other cups of both groups (98.6%) showed a full osseous integration. The cup inclination angle ranged from 41-58 degrees (threaded cups) to 39-77 degrees (press-fit cups). The new threaded cup provides equivalent clinical outcomes and osseous integration but more precise implant positioning compared to the press-fit design. No complications typically ascribed to threaded cups (acetabular fractures, bone resorption, nerve impairment) occurred. PMID- 26984656 TI - Operative treatment of chondroblastoma: a study of 11 cases. AB - Aim of the study was to review the radiological, clinical results of 11 chondroblastoma cases treated at our institute between 2003-2013. All patients with chondroblastoma included in this study underwent intra-lesional curettage+/ bone grafting. Follow up for healing of chondroblastoma lesions and detection of any local recurrence was assessed on clinical and radiological bases. The functional outcome was assessed by the Musculoskeletal Tumour Society scoring system. The mean follow-up period was 6.1 years. There were three recurrences (two femoral head, one proximal tibia). The mean Musculoskeletal Tumour Society functional score was 21. First line aggressive treatment seems appropriate for chondroblastoma especially when localized at lower extremities. PMID- 26984657 TI - Role of anthropometric data in the prediction of 4-stranded hamstring graft size in anterior cruciate ligament reconstruction. AB - To evaluate whether pre-operative anthropometric data can predict the optimal diameter and length of hamstring tendon autograft for anterior cruciate ligament (ACL) reconstruction. This was a cohort study that involved 169 patients who underwent single-bundle ACL reconstruction (single surgeon) with 4-stranded MM Gracilis and MM Semi-Tendinosus autografts. Height, weight, body mass index (BMI), gender, race, age and -smoking status were recorded pre-operatively. Intra operatively, the diameter and functional length of the 4-stranded autograft was recorded. Multiple regression analysis was used to determine the relationship between the anthropometric measurements and the length and diameter of the implanted autografts. The strongest correlation between 4-stranded hamstring autograft diameter was height and weight. This correlation was stronger in females than males. BMI had a moderate correlation with the diameter of the graft in females. Females had a significantly smaller graft both in diameter and length when compared with males. Linear regression models did not show any significant correlation between hamstring autograft length with height and weight (p>0.05). Simple regression analysis demonstrated that height and weight can be used to predict hamstring graft diameter. The following regression equation was obtained for females: Graft diameter=0.012+0.034*Height+0.026*Weight (R2=0.358, p=0.004) The following regression equation was obtained for males: Graft diameter=5.130+0.012*Height+0.007*Weight (R2=0.086, p=0.002). Pre-operative anthropometric data has a positive correlation with the diameter of 4 stranded hamstring autografts but no significant correlation with the length. This data can be utilised to predict the autograft diameter and may be useful for pre operative planning and patient counseling for graft selection. PMID- 26984658 TI - How to treat a frozen shoulder? A survey among shoulder specialists in the Netherlands and Belgium. AB - A frozen shoulder is a common cause of a painful and stiff shoulder. A web-based survey was conducted to obtain insight in the current preferences about the diagnosis and treatment of a frozen shoulder. A response rate of 54% was reached among shoulder specialized orthopaedic surgeons from the Netherlands and Belgium. Non-steroidal anti-inflammatory drugs and intra-articular corticosteroid injections are used frequently in the first phase of the condition. Physiotherapy is assumed to be more important in the final phase. The results of the survey indicate a wide variety of treatment strategies in the different phases of a frozen shoulder. Three out of four respondents considered that the management of a frozen shoulder could benefit from a written guideline. The development of a written guideline should lead to an improved level of consensus and a more standardized approach in the treatment of a frozen shoulder among shoulder specialists in the Netherlands and Belgium. PMID- 26984660 TI - Infrapatellar fat pad syndrome: a review of anatomy, function, treatment and dynamics. AB - The infrapatellar (Hoffa's) fatpad is an important structure within the knee, whose function and role are both poorly understood. This review explores the anatomy, neural innervation, vascularity, role in biomechanics, pathology, imaging (stressing the importance of dynamic ultrasound assessment) and treatment of disorders presenting within this structure. PMID- 26984659 TI - LCP metaphyseal plate fixation for fractures of the distal third humeral shaft using brachialis splitting approach. AB - The authors retrospectively studied the clinical and radiographic outcomes of locking compressive plate (LCP) metaphyseal plate fixation through the anterolateral approach in patients treated surgically for unstable distal third humeral shaft fractures. Twenty seven patients were treated surgically with LCP metaphyseal plate using brachialis splitting methods through the anterolateral approach. The mean arc of elbow motion was 132.4 degrees with a mean flexion of 133.5 degrees and mean flexion contracture of 1.1 degrees . Three patients had a slight elbow flexion contracture with loss of 5 degrees (n=1), 10 degrees (n=1), and 15 degrees (n=1) of extension. The mean American Shoulder and Elbow Surgeons score was 92.6 points, which corresponded to excellent results in 26 shoulders and a good result in one. The mean Mayo Elbow Performance Score was 90.7 points, which corresponded to excellent results in 24 elbows, a good result in 2, and a fair result in 1. Treatment of distal third humeral shaft fracture using LCP metaphyseal plate through the anterolateral approach is an acceptable and alternative method that can provide good results. PMID- 26984661 TI - Exostoses, enchondromatosis and metachondromatosis; diagnosis and management. AB - We describe a 5 years old girl who presented to the multidisciplinary skeletal dysplasia clinic following excision of two bony lumps from her fingers. Based on clinical examination, radiolographs and histological results an initial diagnosis of hereditary multiple exostosis (HME) was made. Four years later she developed further lumps which had the radiological appearance of enchondromas. The appearance of both exostoses and enchondromas suggested a possible diagnosis of metachondromatosis. Genetic testing revealed a splice site mutation at the end of exon 11 on the PTPN11 gene, confirming the diagnosis of metachondromatosis. While both single or multiple exostoses and enchondromas occur relatively commonly on their own, the appearance of multiple exostoses and enchondromas together is rare and should raise the differential diagnosis of metachondromatosis. Making this diagnosis is important as the lesions in metachondromatosis may spontaneously resolve and therefore surgical intervention is often unnecessary. We discuss the diagnostic findings, genetic causes, treatment and prognosis of this rare condition of which less than thirty cases have previously been reported. PMID- 26984662 TI - Arthroscopic tibiotalocalcaneal arthrodesis in neurological pathologies: outcomes after at least one year of follow up. AB - The main complications of open tibiotalocalcaneal arthrodesis are wound healing disorders and nonunion. Our hypothesis was that arthroscopy and interlocking intramedullary nailing decrease these complications. We retrospectively reviewed six patients (mean age: 58 years; mean preoperative Kitaoka score: 51/100) having undergone arthroscopic tibiotalocalcaneal arthrodesis with retrograde intramedullary nailing between January and November 2011 for equinus deformity of the hindfoot and subtalar instability of neurological origin. Postoperative pain disappeared completely in four cases, one patient presented some pain associated with projection of the proximal locking screw head under the skin and the remaining patient presented fibular tendinitis that resolved after infiltration of anti-inflammatory drugs. The mean postoperative Kitaoka score was 64/100. None of the patients presented any wound healing complications or nonunion. The observed incidence of wound complications and bone consolidation disorders after tibiotalocalcaneal arthrodesis was lower than the ones reported for open tibiotalocalcaneal arthrodesis. Level of clinical evidence IV: retrospective case series. PMID- 26984663 TI - The Dutch version of the Forgotten Joint Score: test-retesting reliability and validation. AB - The aim of this study was to translate the Forgotten Joint Score (FJS) into the Dutch language. This -questionnaire was tested for internal consistency (Cronbach's alpha) and test-retest reliability (intraclass correlation coefficients (ICC)). 159 patients were included in this study; 74 with a total hip arthroplasty (THA) and 85 with a total knee arthroplasty (TKA). The FJS showed a high internal consistency (Cronbach's alpha=0.957; ICC=0.943). The FJS showed a significant correlation (r=0.751) with the WOMAC and low ceiling effects (3.1%). This study proved the Dutch FJS to be highly discriminative in patients treated with a THA or TKA. This makes the FJS a reliable patient related outcome measurement, measuring a new dimension in arthroplasty: the ability to forget an artificial joint in everyday life. PMID- 26984664 TI - Early failure of coracoclavicular ligament reconstruction using TightRope system. AB - This prospective study reports the results of early failure of coracoclavicular (CC) ligament reconstruction using TightRope. Nine consecutive patients who had CC ligament reconstruction using TightRope or GraftRope were assessed for radiological and functional outcomes using DASH and Oxford Shoulder scores. With an average age of 38.4 (21-70) years, four patients had type III injuries, two type IV and two type V injuries. The mean follow-up was 22.8 (12-42) months. In 7 out of 9 patients, secondary progressive loss of reduction was observed at an average of 3.1 (1-7) months. Three patients underwent revision. The mean DASH score at latest follow-up was 27.45 (19.6-35) & Oxford shoulder score was 30.5 (20-43). Coraco-clavicular reconstruction with TightRope or GraftRope appears to result in failure with progressive AC joint subluxation perhaps due to 'windscreen wiper' micromotion. Surgeons should be wary of this potential problem whilst choosing this method of -reconstruction for CC ligament reconstructions. PMID- 26984666 TI - The current role of coronal plane alignment in Total Knee Arthroplasty in a preoperative varus aligned population: an evidence based review. AB - BACKGROUND: Based on historical data, the current standard of care in Total Knee Arthroplasty (TKA) is to restore the overall alignment to a neutral mechanical axis of 0 degrees +/-3 degrees or even slight valgus. However, there is significant controversy in literature regarding intentionally placing the TKA in the patient's physiologic, rather than neutral (0+/-3 degrees ), mechanical alignment. QUESTIONS/PURPOSES: The goal of this review is to provide a concise update on the present knowledge of coronal plane alignment TKA in a varus population. METHODS: A systematic overview of the present literature was undertaken to determine basic science and clinical results in frontal plane alignment in primary TKA. RESULTS: Results of studies based on laboratory research, retrieval analysis, cadaver research, finite models, survival scores, clinical outcome, gait analysis and radiographic outcome upon today are provided. CONCLUSIONS: Currently placement of a TKA in neutral alignment of 0 degrees +/-3 degrees of frontal plane alignment is the standard of care. However, frontal plane alignment in neutral may not be as strongly correlated to survivorship as previously thought. Caution needs to be exercised before changing the standard of care, and more research needs to be performed. PMID- 26984665 TI - An alternative treatment method for defective pseudoarthrosis; evaluation of eight patients treated with Artelon+Kryptonite. AB - Pseudoarthrosis with bone loss is one of the most challenging orthopaedic problems for surgeons. Bone loss usually leads to technical difficulties during surgery due to instability in the fracture area. Eight patients with pseudoarthrosis of different long bones were operated on by the same surgeon. The median age was 53 years (25-61), and the median time period after the index operation was 21 months (12-72 months). Radiographic union was achieved in all patients in 3.62 months (2-5 months). Efficient healing with new bone formation was observed in all of the patients. The result of the current case series is promising. This treatment method can be used for the treatment of pseudoarthrosis without increasing morbidity. Long-term follow-up and larger case series are needed for evidence of the adequacy and reliability of this method of treatment. PMID- 26984667 TI - Outcome Predictors in Prosthetic Joint Infections--Validation of a risk stratification score for Prosthetic Joint Infections in 120 cases. AB - Prosthetic joint infections are a major challenge in total joint arthroplasty, especially in times of accumulating drug resistancies. Even though predictive risk classifications are a widely accepted tool to define a suitable treatment protocol a classification is still missing considering the difficulty in treating the -causative pathogen antibiotically. In this study, we present and evaluate a new predictive risk stratification for prosthetic joint infections in 120 cases, treated with a two-stage exchange. Treatment outcomes in 120 patients with proven prosthetic joint infections in hip and knee prostheses were regressed on time of infection, systemic risk factors, local risk factors and the difficulty in treating the causing pathogen. The main outcome variable was "definitely free of infection" after two years as published. Age, gender, and BMI were included as covariables and analyzed in a logistic regression model. 66 male and 54 female patients, with a mean age at surgery of 68.3 years+/-12.0 and a mean BMI of 26.05+/-6.21 were included in our survey and followed for 29.0+/-11.3 months. We found a significant association (p<0.001) between our score and the outcome parameters evaluated. Age, gender and BMI did not show a significant association with the outcome. These results show that our score is an independent and reliable predictor for the cure rate in prosthetic joint infections in hip and knee prostheses treated within a two-stage exchange protocol. Our score illustrates, that there is a statistically significant, sizable decrease in cure rate with an increase in score. In patients with prosthetic joint infections the validation of a risk score may help to identify patients with local and systemic risk factors or with infectious organisms identified as "difficult to treat" prior to the treatment or the decision about the treatment concept. Thus, appropriate extra care should be considered and provided. PMID- 26984668 TI - Ion transport in polycarbonate based solid polymer electrolytes: experimental and computational investigations. AB - Among the alternative host materials for solid polymer electrolytes (SPEs), polycarbonates have recently shown promising functionality in all-solid-state lithium batteries from ambient to elevated temperatures. While the computational and experimental investigations of ion conduction in conventional polyethers have been extensive, the ion transport in polycarbonates has been much less studied. The present work investigates the ionic transport behavior in SPEs based on poly(trimethylene carbonate) (PTMC) and its co-polymer with epsilon-caprolactone (CL) via both experimental and computational approaches. FTIR spectra indicated a preferential local coordination between Li(+) and ester carbonyl oxygen atoms in the P(TMC20CL80) co-polymer SPE. Diffusion NMR revealed that the co-polymer SPE also displays higher ion mobilities than PTMC. For both systems, locally oriented polymer domains, a few hundred nanometers in size and with limited connections between them, were inferred from the NMR spin relaxation and diffusion data. Potentiostatic polarization experiments revealed notably higher cationic transference numbers in the polycarbonate based SPEs as compared to conventional polyether based SPEs. In addition, MD simulations provided atomic-scale insight into the structure-dynamics properties, including confirmation of a preferential Li(+)-carbonyl oxygen atom coordination, with a preference in coordination to the ester based monomers. A coupling of the Li-ion dynamics to the polymer chain dynamics was indicated by both simulations and experiments. PMID- 26984669 TI - Adolescent cancer survivors' posttraumatic stress symptoms: Concordance between self-report and maternal-proxy report. AB - Subsyndromal posttraumatic stress among pediatric cancer survivors has been associated with negative physical and mental health outcomes. However, adolescent self-report and mother-proxy report of adolescents' posttraumatic stress symptoms evidenced varying concordance depending on methodology. There was moderate concordance, particularly among younger respondents, when total posttraumatic stress symptoms were viewed continuously and low-moderate concordance when viewed categorically; moderate-strong concordance for only one posttraumatic stress disorder symptom cluster; low-moderate agreement for high-frequency items; and no concordance for identifying caseness. Although a significant subset of pediatric cancer survivors experience posttraumatic stress, mothers and adolescents demonstrate limited symptom, categorical, and caseness agreement, potentially impacting adolescents' healthcare service utilization. PMID- 26984670 TI - 5-Caffeoylquinic acid inhibits invasion of non-small cell lung cancer cells through the inactivation of p70S6K and Akt activity: Involvement of p53 in differential regulation of signaling pathways. AB - In the present study, we investigated the effects and molecular mechanism of 5 caffeoylquinic acid (5-CQA), a natural phenolic compound isolated from Ligularia fischeri, on cell invasion, proliferation and adhesion in p53 wild-type A549 and p53-deficient H1299 non-small cell lung cancer (NSCLC) cells. 5-CQA abrogated mitogen-stimulated invasion, but not proliferation, in both A549 and H1299 cells. In addition, 5-CQA inhibited mitogen-stimulated adhesion in A549 cells only. Anti invasive activity of 5-CQA in A549 cells was mediated by the inactivation of p70(S6K)-dependent signaling pathway. In contrast, in H1299 cells the inactivation of Akt was found to be involved in 5-CQA-mediated inhibition of cell invasion. Collectively, these findings demonstrate the pharmacological roles and molecular targets of 5-CQA in regulating NSCLC cell fate, and suggest further evaluation and development of 5-CQA as a potential therapeutic agent for the treatment and prevention of lung cancer. PMID- 26984672 TI - Prevalence of Asymptomatic Bacteriuria in Hospitalized Patients. PMID- 26984671 TI - Cytokinin production by Pseudomonas fluorescens G20-18 determines biocontrol activity against Pseudomonas syringae in Arabidopsis. AB - Plant beneficial microbes mediate biocontrol of diseases by interfering with pathogens or via strengthening the host. Although phytohormones, including cytokinins, are known to regulate plant development and physiology as well as plant immunity, their production by microorganisms has not been considered as a biocontrol mechanism. Here we identify the ability of Pseudomonas fluorescens G20 18 to efficiently control P. syringae infection in Arabidopsis, allowing maintenance of tissue integrity and ultimately biomass yield. Microbial cytokinin production was identified as a key determinant for this biocontrol effect on the hemibiotrophic bacterial pathogen. While cytokinin-deficient loss-of-function mutants of G20-18 exhibit impaired biocontrol, functional complementation with cytokinin biosynthetic genes restores cytokinin-mediated biocontrol, which is correlated with differential cytokinin levels in planta. Arabidopsis mutant analyses revealed the necessity of functional plant cytokinin perception and salicylic acid-dependent defence signalling for this biocontrol mechanism. These results demonstrate microbial cytokinin production as a novel microbe-based, hormone-mediated concept of biocontrol. This mechanism provides a basis to potentially develop novel, integrated plant protection strategies combining promotion of growth, a favourable physiological status and activation of fine tuned direct defence and abiotic stress resilience. PMID- 26984676 TI - EPOS 35th Congress Meeting. PMID- 26984677 TI - EPOS 35th Congress Meeting. PMID- 26984674 TI - Massive pulmonary embolism with acute cor pulmonale. PMID- 26984673 TI - Improvement of the banana "Musa acuminata" reference sequence using NGS data and semi-automated bioinformatics methods. AB - BACKGROUND: Recent advances in genomics indicate functional significance of a majority of genome sequences and their long range interactions. As a detailed examination of genome organization and function requires very high quality genome sequence, the objective of this study was to improve reference genome assembly of banana (Musa acuminata). RESULTS: We have developed a modular bioinformatics pipeline to improve genome sequence assemblies, which can handle various types of data. The pipeline comprises several semi-automated tools. However, unlike classical automated tools that are based on global parameters, the semi-automated tools proposed an expert mode for a user who can decide on suggested improvements through local compromises. The pipeline was used to improve the draft genome sequence of Musa acuminata. Genotyping by sequencing (GBS) of a segregating population and paired-end sequencing were used to detect and correct scaffold misassemblies. Long insert size paired-end reads identified scaffold junctions and fusions missed by automated assembly methods. GBS markers were used to anchor scaffolds to pseudo-molecules with a new bioinformatics approach that avoids the tedious step of marker ordering during genetic map construction. Furthermore, a genome map was constructed and used to assemble scaffolds into super scaffolds. Finally, a consensus gene annotation was projected on the new assembly from two pre-existing annotations. This approach reduced the total Musa scaffold number from 7513 to 1532 (i.e. by 80%), with an N50 that increased from 1.3 Mb (65 scaffolds) to 3.0 Mb (26 scaffolds). 89.5% of the assembly was anchored to the 11 Musa chromosomes compared to the previous 70%. Unknown sites (N) were reduced from 17.3 to 10.0%. CONCLUSION: The release of the Musa acuminata reference genome version 2 provides a platform for detailed analysis of banana genome variation, function and evolution. Bioinformatics tools developed in this work can be used to improve genome sequence assemblies in other species. PMID- 26984678 TI - EPOS 35th Congress Meeting. PMID- 26984679 TI - Trypanosoma cruzi-infected Panstrongylus geniculatus and Rhodnius robustus adults invade households in the Tropics of Cochabamba region of Bolivia. AB - BACKGROUND: There are hardly any data available on the relationships between the parasite and the vector or regarding potential reservoirs involved in the natural transmission cycle of Trypanosoma cruzi in the Tropics of Cochabamba, Bolivia. Local families from communities were responsible for the capture of triatomine specimens, following a strategic methodology based on entomological surveillance with community participation developed by the National Chagas Programme of the Ministry of Health of Bolivia. FINDINGS: We describe the collection of adult Panstrongylus geniculatus and Rhodnius robustus naturally infected with Trypanosoma cruzi from houses and from the hospital of Villa Tunari municipality. The flagellates found in the digestive tract of P. geniculatus belong to genetic lineages or DTUs TcI and TcIII, whereas only lineage DTU TcI was found in R. robustus. The detection of these vectors infected with T. cruzi reveals the vulnerability of local communities. CONCLUSION: The results presented here highlight the risk of Chagas disease transmission in a region previously thought not to be endemic, indicating that the Tropics of Cochabamba should be placed under permanent entomological and epidemiological surveillance. PMID- 26984680 TI - Structure Calculation and Reconstruction of Discrete-State Dynamics from Residual Dipolar Couplings. AB - Residual dipolar couplings (RDCs) acquired by nuclear magnetic resonance (NMR) spectroscopy are an indispensable source of information in investigation of molecular structures and dynamics. Here, we present a comprehensive strategy for structure calculation and reconstruction of discrete-state dynamics from RDC data that is based on the singular value decomposition (SVD) method of order tensor estimation. In addition to structure determination, we provide a mechanism of producing an ensemble of conformations for the dynamical regions of a protein from RDC data. The developed methodology has been tested on simulated RDC data with +/-1 Hz of error from an 83 residue alpha protein (PDB ID 1A1Z ) and a 213 residue alpha/beta protein DGCR8 (PDB ID 2YT4 ). In nearly all instances, our method reproduced the structure of the protein including the conformational ensemble to within less than 2 A. On the basis of our investigations, arc motions with more than 30 degrees of rotation are identified as internal dynamics and are reconstructed with sufficient accuracy. Furthermore, states with relative occupancies above 20% are consistently recognized and reconstructed successfully. Arc motions with a magnitude of 15 degrees or relative occupancy of less than 10% are consistently unrecognizable as dynamical regions within the context of +/ 1 Hz of error. PMID- 26984682 TI - Comparative microRNA profiling in relation to urinary albumin excretion in newly diagnosed hypertensive patients. AB - Microalbuminuria is an established early marker of endothelial dysfunction and damage. MicroRNAs (miRNAs) are emerging as essential modulators of cardiovascular physiology and disease. In the present study, we sought an association between the differential expression of related miRNAs in the peripheral blood mononuclear cells of untreated patients with newly diagnosed essential hypertension and the levels of urinary albumin excretion. We assessed the expression of the miRNAs miRNA-1, miRNA-133a, miRNA-26b, miRNA-208b, miRNA-499 and miRNA-21 in consecutive subjects with untreated newly diagnosed essential hypertension (aged 62.5+/-9.7 years) and with no indications of other organic heart disease. MiRNA expression levels in peripheral blood mononuclear cells were quantified by real-time reverse transcription-polymerase chain reaction. The prevalence of microalbuminuria was 9.8%. miRNA-208b and miRNA-133a were independently correlated with 24-h urinary albumin excretion. More specifically, a strong association was found between the gene expression levels of miRNA-208b in our patients' peripheral blood cells and urinary albumin (r=0.72, P<0.001). A similar association was found for miRNA-133a (r=0.372, P<0.001). In conclusion, miRNA-208b and miRNA-133a show distinct profiling in peripheral blood cells isolated from untreated patients with recently diagnosed essential hypertension. Their gene expression levels reveal a strong correlation with urinary albumin excretion levels. Our findings provide new perspectives on the development of a new generation of biomarkers for the better monitoring of end-organ damage in hypertension. PMID- 26984681 TI - Volume-based growth tumor kinetics as a prognostic biomarker for patients with EGFR mutant lung adenocarcinoma undergoing EGFR tyrosine kinase inhibitor therapy: a case control study. AB - BACKGROUND: We aim to determine whether volumetric assessment has the potential to serve as a prognostic biomarker, and to assess the relationship between longitudinal tumor data during treatment and prognosis in lung adenocarcinoma patients with sensitizing EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKI). METHODS: We retrospectively assessed patients with EGFR-mutant stage IV lung adenocarcinoma who were treated with EGFR TKIs until disease progression. CT studies of 106 patients were quantitatively analyzed in terms of tumor size and volume by comparing baseline and follow-up CT scans obtained at every two treatment cycles. Tumor response was quantified using longitudinal measurements, and tumor growth kinetics was determined. Correlation with early surrogate parameters for tumor response evaluation such as change in size, volume, and response rate was performed. The Cox-proportional hazard model and Log-rank test were used to predict overall survival (OS). RESULTS: Responders based on the percent change in volume after four cycles of TKI therapy had a higher OS than non-responders (P = 0.035). The percent of volume and size changes after four cycles of TKI therapy were significantly correlated with TTP (P < 0.001). CONCLUSION: Volume measurements and corresponding rates of growth appear to be helpful adjuncts for predicting survival in patients undergoing EGFR-TKI therapy. PMID- 26984685 TI - Drunk on risk: how the chief medical officers' alcohol guidelines are demonising drink. PMID- 26984683 TI - Determinants of day-night difference in blood pressure, a comparison with determinants of daytime and night-time blood pressure. AB - Blunted day-night difference in blood pressure (BP) is an independent cardiovascular risk factor, although there is limited information on determinants of diurnal variation in BP. We investigated determinants of day-night difference in systolic (SBP) and diastolic (DBP) BP and how these compared with determinants of daytime and night-time SBP and DBP. We analysed the association of mean daytime, mean night-time and mean day-night difference (defined as (mean daytime mean night-time)/mean daytime) in SBP and DBP with clinical, lifestyle and biochemical parameters from 1562 adult individuals (mean age 38.6) from 509 nuclear families recruited in the GRAPHIC Study. We estimated the heritability of the various BP phenotypes. In multivariate analysis, there were significant associations of age, sex, markers of adiposity (body mass index and waist-hip ratio), plasma lipids (total and low-density lipoprotein cholesterol and triglycerides), serum uric acid, alcohol intake and current smoking status on daytime or night-time SBP and/or DBP. Of these, only age (P=4.7 * 10-5), total cholesterol (P=0.002), plasma triglycerides (P=0.006) and current smoking (P=3.8 * 10-9) associated with day-night difference in SBP, and age (P=0.001), plasma triglyceride (P=2.2 * 10-5) and current smoking (3.8 * 10-4) associated with day night difference in DBP. 24-h, daytime and night-time SBP and DBP showed substantial heritability (ranging from 18-43%). In contrast day-night difference in SBP showed a lower heritability (13%) while heritability of day-night difference in DBP was not significant. These data suggest that specific clinical, lifestyle and biochemical factors contribute to inter-individual variation in daytime, night-time and day-night differences in SBP and DBP. Variation in day night differences in BP is largely non-genetic. PMID- 26984684 TI - Alcohol and Drug Use and the Developing Brain. AB - Adolescence is an important neurodevelopmental period marked by rapidly escalating rates of alcohol and drug use. Over the past decade, research has attempted to disentangle pre- and post-substance use effects on brain development by using sophisticated longitudinal designs. This review focuses on recent, prospective studies and addresses the following important questions: (1) what neuropsychological and neural features predate adolescent substance use, making youth more vulnerable to engage in heavy alcohol or drug use, and (2) how does heavy alcohol and drug use affect normal neural development and cognitive functioning? Findings suggest that pre-existing neural features that relate to increased substance use during adolescence include poorer neuropsychological functioning on tests of inhibition and working memory, smaller gray and white matter volume, changes in white matter integrity, and altered brain activation during inhibition, working memory, reward, and resting state. After substance use is initiated, alcohol and marijuana use are associated with poorer cognitive functioning on tests of verbal memory, visuospatial functioning, psychomotor speed, working memory, attention, cognitive control, and overall IQ. Heavy alcohol use during adolescence is related to accelerated decreases in gray matter and attenuated increases in white matter volume, as well as increased brain activation during tasks of inhibition and working memory, relative to controls. Larger longitudinal studies with more diverse samples are needed to better understand the interactive effects of alcohol, marijuana, and other substances, as well as the role of sex, co-occurring psychopathology, genetics, sleep, and age of initiation on substance use. PMID- 26984686 TI - Eye spectral sensitivity in fresh- and brackish-water populations of three glacial-relict Mysis species (Crustacea): physiology and genetics of differential tuning. AB - Absorbance spectra of single rhabdoms were studied by microspectrophotometry (MSP) and spectral sensitivities of whole eyes by electroretinography (ERG) in three glacial-relict species of opossum shrimps (Mysis). Among eight populations from Fennoscandian fresh-water lakes (L) and seven populations from the brackish water Baltic Sea (S), L spectra were systematically red-shifted by 20-30 nm compared with S spectra, save for one L and one S population. The difference holds across species and bears no consistent adaptive relation to the current light environments. In the most extensively studied L-S pair, two populations of M. relicta (L(p) and S(p)) separated for less than 10,000 years, no differences translating into amino acid substitutions have been found in the opsin genes, and the chromophore of the visual pigments as analyzed by HPLC is pure A1. However, MSP experiments with spectrally selective bleaching show the presence of two rhodopsins (lambda(max) ~ 525-530 nm, MWS, and 565-570 nm, LWS) expressed in different proportions. ERG recordings of responses to "red" and "blue" light linearly polarized at orthogonal angles indicate segregation of the pigments into different cells differing in polarization sensitivity. We propose that the pattern of development of LWS and MWS photoreceptors is governed by an ontogenetic switch responsive to some environmental signal(s) other than light that generally differ(s) between lakes and sea, and that this reaction norm is conserved from a common ancestor of all three species. PMID- 26984687 TI - Quadratus lumborum catheters for breast reconstruction requiring transverse rectus abdominis myocutaneous flaps. AB - Patients diagnosed with breast cancer may opt to undergo surgical reconstructive flaps at the time of or after mastectomies. These surgeries leave patients with significant postoperative pain and sometimes involve large surgical beds including graft sites from the abdomen to reconstruct the breast. Consequently, multimodal methods of pain management have become highly favored. Quadratus lumborum catheters offer an opioid-sparing technique that can be performed easily and safely. We present a case of a patient who underwent a breast flap reconstruction and had bilateral quadratus lumborum catheters placed for perioperative pain control. PMID- 26984688 TI - Ketamine and propofol have opposite effects on postanesthetic sleep architecture in rats: relevance to the endogenous sleep-wakefulness substances orexin and melanin-concentrating hormone. AB - BACKGROUND: Anesthesia and surgery disturb sleep. Disturbed sleep adversely affects postoperative complications involving the cardiovascular system, diabetes, and infection. General anesthetics share neuronal mechanisms involving endogenous sleep-wakefulness-related substances, such as orexin (OX) and melanin concentrating hormone (MCH). We evaluated changes in sleep architecture and the concentration of OX and MCH during the peri-anesthetic period. METHODS: To examine sleep architecture, male Sprague-Dawley rats weighing 350-450 g received ketamine 100 mg/kg (n = 9) or propofol 80 mg/kg (n = 6) by intraperitoneal injection. Electroencephalography was recorded from 2 days pre- to 5 days postanesthesia. To quantify levels of OX and MCH, 144 similar rats received the same doses of ketamine (n = 80) or propofol (n = 64). Brain concentrations of these substances were determined at 0, 20, 60, and 120 min after anesthetic administration. RESULTS: Ketamine decreased OX content in the hypothalamus during the anesthesia period. OX content was restored to pre-anesthesia levels in the hypothalamus and pons. Both anesthetics increased brain MCH content in the postanesthetic period, with the degree of increase being greater with propofol. Ketamine enhanced wakefulness and inhibited non-rapid eye movement sleep (NREMS) immediately after anesthesia. Conversely, propofol inhibited wakefulness and enhanced NREMS in that period. Ketamine inhibited wakefulness and enhanced NREMS during the dark phase on the first postanesthesia day. CONCLUSIONS: Anesthetics affect various endogenous sleep-wakefulness-related substances; however, the modulation pattern may depend on the type of anesthetic. The process of postanesthetic sleep disturbance was agent specific. Our results provide fundamental evidence to treat anesthetic-related sleep disturbance. PMID- 26984690 TI - The Influence of Social Networks and Supports on Depression Symptoms: Differential Pathways for Older Korean Immigrants and Non-Hispanic White Americans. AB - OBJECTIVES: The current cross-cultural study examines the pathways underlying different formations of social networks and social support systems, which affect depression symptoms among older Korean immigrants and non-Hispanic Whites in the United States. METHOD: Data for this study came from a panel survey of 223 older Korean American immigrants and 201 non-Hispanic White older adults 65 years of age and older living in Los Angeles. Structural equation modeling (SEM) is used to test the proposed conceptual model designed to explain the direct and indirect relationships between social networks and social support on depression symptoms. RESULTS: Empirical evidence from this study indicated different effect of one's social networks and social support on depression by race/ethnicity. DISCUSSION: The work discussed in this article pointed to the need to recognize the role of culture in assessing the relationships between social networks, social support, and health among older adults. PMID- 26984689 TI - The Long-Term Effects of Participant Direction of Supports and Services for People With Disabilities. AB - Numerous studies have demonstrated the short-term effectiveness of the Cash and Counseling model option of participant-directed home and community-based personal care service programs for Medicaideligible recipients with disabilities requiring long-term care. However, long-term experiences with participant-directed services have yet to be examined for these individuals. We addressed this gap in the literature through participatory action research and qualitative content analysis. Working together as coresearchers with members of the National Participant Network, a peer organization for people interested in or enrolled in participant-directed services, we interviewed 17 adults enrolled in one state's Cash and Counseling-based program. Participants' ages ranged from 40 to 83 years, had been enrolled for at least 5 years, and acted as their own representative within the program. Our major findings show (a) the program's flexibility allowed for adaptation to meet participants' changing needs over time and (b) that program attendants helped connect participants with community in multiple ways. In this article, we provide important policy and practice implications for participant-directed programs for people with disabilities. PMID- 26984691 TI - Barriers and Facilitators to Coordinating Care With High-Risk, High-Cost Disabled Medicaid Beneficiaries: Perspectives of Frontline Staff and Participating Clients. AB - This evaluation was designed to examine the perspectives of 15 frontline staff who implemented a managed care program and 154 high-risk, high-cost disabled Medicaid clients who were participants in the program. Results indicated that positive relationships between staff and clients played a key role in facilitating program implementation. Challenges included finding ways to provide a wide breadth of services including food, shelter, and transportation; handling difficulties following from staff turnover; and creating transitions of care for clients to community health clinics. Staff identified training in motivational interviewing and having both nurse care managers and social workers collaboratively deliver the intervention as among the most powerful components of the program. Staff and clients expressed high levels of satisfaction with the program, and clients believed they were experiencing positive impacts of the program. Lessons learned from this study may inform the design of services as the Affordable Care Act continues to unfold. PMID- 26984692 TI - Hypertensive Black Men's Perceptions of a Nurse Protocol for Medication Self Administration. AB - A factor contributing to uncontrolled hypertension in older persons is medication nonadherence. Older Black men in a rural cardiology clinic were not taking blood pressure medication as prescribed resulting in uncontrolled hypertension. A nurse protocol to assist with self-administration of hypertensive medication was proposed to address the problem. This qualitative key informant study identified a purposive sample of 10 hypertensive Black men who were 65-70 years of age and nonadherent in taking their medication. The nurse conducted teaching sessions using the protocol to review evidence-based strategies for improving medication adherence. A follow-up phone call was done after 1 week. Participants were interviewed about their perceptions of taking hypertensive medication. The interviews were recorded, transcribed, and coded for themes using constant comparative analysis. Six themes emerged: Medication Bottle Guides Medication Usage, Confusion about Side Effects, Reasons for Not Taking Medications, New Behavior, Unchanged Behavior, and Discovery of Other Problems. The results showed that the nurse-administered protocol resulted in participants' changed attitudes about taking medication. PMID- 26984693 TI - Important Case Management Goals in Community Aged Care Practice and Key Influences. AB - AIM: To investigate important case management goals and key influences on the achievement of the goals in community aged care practice from the perspectives of case managers in Australia. METHODS: We surveyed 154 case managers, representing 17.1% of the target population in the State of Victoria, Australia. The key information collected was case managers' characteristics and their selections of important case management goals. We also conducted 33 interviews with 47 case managers to explore their perceptions of important case-managed community aged care goals and the key influences on the achievement of these goals. Descriptive analysis, logistic regression, and qualitative thematic analysis were performed. RESULTS: The survey findings showed that important case management goals included improving client outcomes, improving care quality, enhancing care coordination and accessibility, and reducing nursing home admissions. The interview findings indicated that important case management goals were divided into client-centered goals (e.g., maintaining clients safely at home), case managers' personal goals (e.g., gaining professional development), and organizational goals/expectations/values (e.g., expecting case managers to manage budgets wisely). Finally, the mixed research methods determined constraints of organizational resources and policies, clients' risky decisions, and case managers' work experience and employment status as key influences or significant factors associated with the achievement of case management goals. CONCLUSION: Client-centered goals are of particular importance among those important case management goals. Case managers helping clients establish reasonable expectations and organizations developing favorable professional development policies and establishing reasonable job requirements and expectations will facilitate the achievement of case management goals. PMID- 26984695 TI - Erratum to: Impact Total Psoas Volume on Short- and Long-Term Outcomes in Patients Undergoing Curative Resection for Pancreatic Adenocarcinoma: a New Tool to Assess Sarcopenia. PMID- 26984694 TI - Use of Prophylactic Antibiotics to Prevent Abscess Formation Following Hepatic Ablation in Patients with Prior Enterobiliary Manipulation. AB - INTRODUCTION: Prior enterobiliary manipulation confers a high risk for liver abscess formation after hepatic ablation. We aimed to determine if prophylactic antibiotics could prevent post-ablation abscess in patients with a history of hepaticojejunostomy. MATERIALS AND METHODS: This single-institution retrospective study identified 262 patients who underwent 307 percutaneous liver ablation sessions between January 2010 and August 2014. Twelve (4.6 %) patients with prior hepaticojejunostomy were included in this analysis. Ten (83> %) had received an aggressive prophylactic antibiotic regimen consisting of levofloxacin, metronidazole, neomycin, and erythromycin base. Two (16.6 %) had received other antibiotic regimens. Clinical, laboratory, and imaging findings were used to identify abscess formation and antibiotic-related side effects. RESULTS: Twelve ablation sessions were performed during the period studied. During a mean follow up period of 440 days (range, 77-1784 days), post-ablation abscesses had developed in 2 (16.6 %) patients, who both received the alternative antibiotic regimens. None of the 10 patients who received the aggressive prophylactic antibiotic regimen developed liver abscess. One of the 10 patients who received the aggressive prophylactic antibiotic regimen developed grade 2 antibiotic related diarrhea and arthralgia. CONCLUSION: An aggressive regimen of prophylactic antibiotics may be effective in preventing liver abscess formation after liver ablation in patients with prior hepaticojejunostomy. PMID- 26984698 TI - A literary dessert. AB - This paper contains an expression of gratitude towards the organizers of the congress 'Psychiatry, Food and Addiction', and the Board members of the Interdisciplinary Society for Biological Psychiatry, of the Sections 'Biological Psychiatry' and 'Psychiatry and Addiction' of the Dutch Society of Psychiatry and the former Editorial Board of Acta Neuropsychiatry. The author has been a long term board member of the society and cofounder of both sections and cofounder and editor-in-chief of this Journal from 1989 to 1999. PMID- 26984696 TI - Absence of a Periampullary Mass on Cross-sectional Imaging Delays Diagnosis and Time to Pancreatoduodenectomy But Does Not Impair Outcome. AB - BACKGROUND: The aim of this study was to assess whether the lack of a radiological mass in patients with periampullary malignancies led to protracted diagnosis, delayed resection, and an inferior outcome. METHODS: The departmental database was interrogated to identify all patients undergoing pancreatoduodenectomy during the period 2000-2014. The absence of a mass on cross sectional and endoscopic ultrasound was noted. The interval between imaging and surgery was evaluated and related to the absence of a mass. The relationship between mass/no mass and the pathological profile was also assessed. RESULTS: Among 490 patients who underwent pancreatoduodenectomy for periampullary malignancies, masses were detected in 299 patients. Patients with undetected mass on either endoscopic ultrasonography (EUS) or computed tomography (CT)/magnetic resonance imaging (MRI) had a longer median interval from initial imaging to resection than detected mass with no difference in survival (66 vs. 41 days, p = 0.001). The absence of a mass was more common in cholangiocarcinomas (p < 0.001). The absence of a mass on imaging was associated with smaller size on final histopathology (2.4 vs. 2.8 cm; p < 0.001). CONCLUSIONS: The absence of a mass with all modalities in patients with a periampullary malignancy leads to a delayed diagnosis without a significant effect on survival. PMID- 26984699 TI - Nutritional manipulation and psychiatric conditions: focus on mood and cognition. AB - In this paper, several experimental models of human depression and cognitive dysfunction, which are designed specifically to mimic the proposed mechanisms of action of many nutritional supplements, are illustrated. These mechanisms of interest are antioxidant effects, glucose utilization, neuronal membrane function and neurotransmitter effects, with particular reference to nutrient-based amino acid manipulations of neurotransmission, such as tryptophan depletion. It is concluded that the application of experimental human models of altered mood and cognitive function may illuminate substantially the quest for nutritional enhancement of human mood and cognitive function. PMID- 26984697 TI - C-Reactive Protein as a Predictor for Complications Following Esophagectomy : Comment on: Rising C-Reactive Protein and Procalcitonin Levels Precede Early Complications After Esophagectomy. PMID- 26984700 TI - Interferon, tryptophan and depression. AB - Depression is a frequent comorbid disorder of many inflammatory diseases and it is suggested that brain inflammatory processes have a pathogenic role in mood dysregulation. Several immunocompromised patients have been treated with cytokines and long-term treatments have resulted in a variety of neuropsychiatric side-effects. The objective of the study was to present evidence for an association between the induction of neuropsychiatric side-effects during treatment with interferon-alpha (IFN-alpha) and changes in serotonergic and immunological parameters. Moreover, the use of IFN-alpha-induced depression as a paradigm for research into the pathophysiology of depressive disorders in general will be discussed. This literature review focused on the relationships between tryptophan, serotonin, cytokines and depression associated with interferon treatment. Immunotherapy with IFN-alpha influences several immunological and serotonergic parameters, and induces in most patients neurovegetative, somatic and depressive symptoms. Literature findings indicate that the development of depressive symptoms in patients undergoing cytokine therapy are secondary to cytokine induction and could be mediated by a reduced availability of tryptophan to the brain, resulting ultimately in decreased serotonergic activity. Changes in the metabolism of tryptophan and consequently of serotonin may play a role in the pathophysiology of interferon-induced depression. Studies on interferon-induced neuropsychiatric side-effects may be a promising research paradigm and shed light on the role of immunological and serotonergic factors in the pathogenesis of depressive disorders in general. However, first the appropriate symptomatology of the interferon-induced depressive states has to be documented. PMID- 26984702 TI - On holy cows and golden calves. PMID- 26984701 TI - Polyunsaturated fatty acids in depression. PMID- 26984703 TI - Panic disorder and depression: relationship between psychological and biochemical aspects. AB - In a group of medication-free out-patients suffering from depression and/or panic disorder we investigated the interdependence between psychological parameters such as aggression and biochemical parameters such as serotonin and tryptophan. We compared the findings in the patient group with a reference group. In the group of patients as a whole negative correlations were observed between the concentration of serotonin in platelets and depression and with hostility and aggression against others. Serotonin in plasma and tryptophan correlated negatively with hostility. The findings support the suggested link between aggression and depression with a low functioning serotonergic system. PMID- 26984704 TI - Prader-Willi syndrome: cycloid psychosis in a genetic subtype? AB - Prader-Willi syndrome (PWS) is a genetically determined disorder associated with the loss of the paternal contribution to the proximal part of the long arm of chromosome 15. Its pathophysiology is dominated by hypothalamic dysfunctions. The psychopathological phenotype comprises affective and psychotic symptoms as well as an increase of pre-existent obsessive-compulsive behaviors. The present study comprises 19 PWS patients who were referred for neuropsychiatric evaluation because of psychotic deterioration. Patients were assessed by using the elements of semistructured symptom checklists. In the majority a genetic analysis was performed to detect the underlying chromosomal defect. In 16 of the 19 patients a diagnosis of cycloid psychosis could be established. The other three showed a bipolar affective disorder. Of the psychotic patients, 11 were diagnosed as UPD and one as del 15q11-13. The remaining four patients were diagnosed clinically. For various reasons the genetic etiology could not be established. In PWS patients with a psychotic disorder (cycloid psychosis) a disproportional number of UPD is found. PMID- 26984705 TI - The acute transient polymorphic psychosis: a biochemical subtype of the cycloid psychosis. AB - BACKGROUND: The pathogenesis of atypical psychoses, in particularly those characterized by polymorphic psychopathology, is hypothesized to be related to disturbances in amino acid metabolism. OBJECTIVE: In the present study, the role of the amino acid serine was investigated in patients with acute transient polymorphic psychosis. METHODS: Patients were loaded with serine and with the amino acids glycine and alanine as controls and subsequently evaluated for the development of psychopathological symptoms. In addition, plasma levels of amino acids were measured. RESULTS: In a subgroup of patients suffering from atypical psychoses, this biochemical challenge resulted in the reappearance of psychedelic symptoms in particular. Furthermore, significantly lower plasma concentrations of serine were found. In vitro experiments revealed a disturbance in the one-carbon metabolism. In another group of patients the loading provoked vegetative symptoms and fatigue. CONCLUSIONS: Disturbances in amino acid metabolism may be involved in the emergence of certain psychotic disorders. PMID- 26984706 TI - Stress, work and mental health: a global perspective. AB - BACKGROUND: The United Nations, WHO and the World Bank have called the current prevalence rate of neuro-psychiatric disorder approaches of 1 in 4 individuals worldwide and 'unheralded public health crisis'. Rates are driven by an early onset, high impairment and high chronicity of these disorders. Most importantly, detection and treatment rates are low, estimated at les than 10% worldwide resulting in 500 million people underserved. The related economic costs soared in 1999 to 120 billion dollars in Europe and North America, with over 60 billion dollars assigned to stress related disorders. Contributing factors are bio-psycho social and include rapid social change as well as the time compression of modern life resulting in the experience of increased work-life stress that parallels a decade long intensification of activities in the workplace. Coping with the requirements of the new economy of mental performance has lagged behind at many individual and social levels as we cling to adjustments made during the industrial economy of the last century. A climate of transition, and more recently, terror and fear have stressed the landscape of mental health and work already ravaged by the destructive forces of stigma. AIM: This presentation will examine the other side of prosperity from the point of view of stress in the workplace as two global problems converge at this time in history, the escalation of neuro-psychiatric disorders and the increasing dependence on the mental faculties of the world's citizens. In this paper we also discuss how the international community can work together to help reduce the burden of mental disorders worldwide and sketch the implications for research and policy. CONCLUSIONS: Ultimately the media will need to be enlisted to educate the public on the value of investments in mental health. PMID- 26984708 TI - Doing Interdisciplinary Mixed Methods Health Care Research: Working the Boundaries, Tensions, and Synergistic Potential of Team-Based Research. AB - Current trends in health care research point to a shift from disciplinary models to interdisciplinary team-based mixed methods inquiry designs. This keynote address discusses the problems and prospects of creating vibrant mixed methods health care interdisciplinary research teams that can harness their potential synergy that holds the promise of addressing complex health care issues. We examine the range of factors and issues these types of research teams need to consider to facilitate efficient interdisciplinary mixed methods team-based research. It is argued that concepts such as disciplinary comfort zones, a lack of attention to team dynamics, and low levels of reflexivity among interdisciplinary team members can inhibit the effectiveness of a research team. This keynote suggests a set of effective strategies to address the issues that emanate from the new field of research inquiry known as team science as well as lessons learned from tapping into research on organizational dynamics. PMID- 26984707 TI - Redox Pioneer: Professor Vadim N. Gladyshev. AB - Professor Vadim N. Gladyshev is recognized here as a Redox Pioneer, because he has published an article on antioxidant/redox biology that has been cited more than 1000 times and 29 articles that have been cited more than 100 times. Gladyshev is world renowned for his characterization of the human selenoproteome encoded by 25 genes, identification of the majority of known selenoprotein genes in the three domains of life, and discoveries related to thiol oxidoreductases and mechanisms of redox control. Gladyshev's first faculty position was in the Department of Biochemistry, the University of Nebraska. There, he was a Charles Bessey Professor and Director of the Redox Biology Center. He then moved to the Department of Medicine at Brigham and Women's Hospital, Harvard Medical School, where he is Professor of Medicine and Director of the Center for Redox Medicine. His discoveries in redox biology relate to selenoenzymes, such as methionine sulfoxide reductases and thioredoxin reductases, and various thiol oxidoreductases. He is responsible for the genome-wide identification of catalytic redox-active cysteines and for advancing our understanding of the general use of cysteines by proteins. In addition, Gladyshev has characterized hydrogen peroxide metabolism and signaling and regulation of protein function by methionine-R-sulfoxidation. He has also made important contributions in the areas of aging and lifespan control and pioneered applications of comparative genomics in redox biology, selenium biology, and aging. Gladyshev's discoveries have had a profound impact on redox biology and the role of redox control in health and disease. He is a true Redox Pioneer. Antioxid. Redox Signal. 25, 1-9. PMID- 26984709 TI - Huwa Rog, Parhej, and Desi Dawai: Women's Perceptions of Postpartum Maternal Morbidity and Care in Rajasthan, India. AB - Although more maternal deaths occur in the postpartum period, this period receives far less attention from the program managers. To understand how the women and their families perceive postpartum health problems, the culturally derived restrictions, and precautions controlling diets and behavior patterns, we conducted a mixed-method study in Rajasthan, India. The study methods included free listing of maternal morbidity conditions, interviews with 81 recently delivered women, case interviews with eight cases of huwa rog (postpartum illness), and interviews with nine key informants. The study showed that huwa rog refers to a broad category of serious postpartum illness, thought to affect women a few weeks to several months after delivery. Prevention of the illness involves a system of precautions referred to as parhej, which includes a distinctive set of "medicinal dietary items" referred to as desi dawai, or "country medicine," and restrictions about mobility and work patterns of a postpartum woman. This cultural framework around the concept of huwa rog and peoples' beliefs about it are of central importance for planning postpartum health interventions, including place of contact and communication messages. PMID- 26984711 TI - Prolonged exposure to low-dose microcystin induces nonalcoholic steatohepatitis in mice: a systems toxicology study. AB - Microcystin-LR (MCLR), a cyanotoxin widely present in freshwater, has been shown to have potent acute hepatotoxicity. However, the chronic toxicity of low-dose MCLR remains confusing by traditional measurements of toxicity. This has impeded understanding of the chronic liver damage of low-dose MCLR and corresponding safety risks of the human exposure guideline value. Here, iTRAQ-based proteomics and NMR-based metabonomics were used to decipher the molecular toxicological signatures of low doses of MCLR in mice exposed to this agent for 90 days. Low levels of MCLR, even under the reported no observed adverse effect level, significantly altered hepatic protein expression, especially of proteins associated with lipid metabolism, transport, immune and proteolysis. Coherently, MCLR induced marked perturbations in lipid metabolites in both liver and serum. Integrated analysis of proteomic, metabolic, histological and cytokine profiles revealed that MCLR significantly inhibited fatty acid beta-oxidation and hepatic lipoprotein secretion and promoted hepatic inflammation, resulting in nonalcoholic steatohepatitis disease (NASH). These findings for the first time provide compelling evidence that chronic exposure to low-level MCLR can induce NASH. These results also indicate that current guidelines for MCs in drinking water may be inadequate and associated with risks to human health. PMID- 26984713 TI - Higher Levels of Caregiver Strain Perceived by Indian Mothers of Children and Young Adults with Cerebral Palsy Who have Limited Self-Mobility. AB - AIM: Describe and compare the caregiver strain experienced among Indian mothers of children and young adults with cerebral palsy (CP) living in low resource settings. METHODS: 62 consecutive children and young adults with spastic CP (mean age 6.0 +/- 4.5, range 2-21) and their parents were recruited from an outpatient physiotherapy department for this cross-sectional study. Ability to walk was classified using the Gross Motor Function Classification System and mother's caregiver strain was measured using caregiver strain index (CSI). RESULTS: Mothers of children and young adults who have limited self-mobility perceived higher caregiver strain (mean CSI score 12.0 +/- 1.3, p < 0.05) than mothers of children who can walk (mean CSI score 4.5 +/- 3.0, p < 0.05). All 46 mothers of children and youth in GMFCS levels IV and V reported high levels of caregiver stress compared with only three of 16 mothers of children and youth who walk (levels I and II). CONCLUSIONS: Physiotherapists and occupational therapists serving children and youth with CP are encouraged to partner with families to identify goals for ease of caregiving, activity, and participation at home and in the community. PMID- 26984714 TI - The kinetics and mechanism of the organo-iridium-catalysed enantioselective reduction of imines. AB - The iridium complex of pentamethylcyclopentadiene and (S,S)-1,2-diphenyl-N' tosylethane-1,2-diamine is an effective catalyst for the asymmetric transfer hydrogenation of imine substrates under acidic conditions. Using the Ir catalyst and a 5 : 2 ratio of formic acid : triethylamine as the hydride source for the asymmetric transfer hydrogenation of 1-methyl-3,4-dihydroisoquinoline and its 6,7 dimethoxy substituted derivative, in either acetonitrile or dichloromethane, shows unusual enantiomeric excess (ee) profiles for the product amines. The reactions initially give predominantly the (R) enantiomer of the chiral amine products with >90% ee but which then decreases significantly during the reaction. The decrease in ee is not due to racemisation of the product amine, but because the rate of formation of the (R)-enantiomer follows first-order kinetics whereas that for the (S)-enantiomer is zero-order. This difference in reaction order explains the change in selectivity as the reaction proceeds - the rate formation of the (R)-enantiomer decreases exponentially with time while that for the (S) enantiomer remains constant. A reaction scheme is proposed which requires rate limiting hydride transfer from the iridium hydride to the iminium ion for the first-order rate of formation of the (R)-enantiomer amine and rate-limiting dissociation of the product for the zero-order rate of formation of the (S) enantiomer. PMID- 26984712 TI - Domestic violence against women as a risk factor for depressive and anxiety disorders: findings from domestic violence household survey in Tehran, Iran. AB - Domestic violence (DV) especially intimate partner violence is a global health problem responsible for significant part of burden of diseases in women. Mental health problems such as depression and anxiety are possibly results and resulted in IPV. To investigate correlation between IPV and depression and anxiety among married women, in a household survey of married women in Tehran, Iran, at summer 2011, we recruited 615 samples with cluster sampling method and they are directly asked about experience of 23 different types of physical and non-physical IPV during marital life and last 12 months. Depression and anxiety were assessed by Beck depression inventory II (BDI) and Beck Anxiety inventory (BAI). Multinominal regression model was used to assess the independent relationship of factor on IPV. Mean (+/-SE) age and duration of marriage were 42.6 +/- 0.9 and 22 +/- 0.8, respectively. Non-physical violence and physical violence during marital life reported in 77.2 and 35.1 %. Clinically significant depression and anxiety was reported in 15.3 and 32.7 % of women, respectively. The odds ratio (95 % CI) of clinically significant depression and anxiety in DV victims were 5.8 (2.3-14.6) and 2.6 (1.6-4.3). DV as a social factor is significantly correlated factor with depression and anxiety. Comprehensive view and collaborative work to detect and address social determinants of mental illness like DV is a crucial point in mental health promotion programs. PMID- 26984715 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for treatment of ovarian cancer. AB - Hyperthermic intraperitoneal chemotherapy (HIPEC), a strategy combining maximal cytoreductive surgery and maximal regional chemotherapy, has been applied to treat ovarian cancer resulting in long-term survival rates in selected patients. However, the status of HIPEC in ovarian cancer remains an experimental procedure, given the many variables among the data and trials reviewed, to enable us to derive strong conclusions about its role from this overview. In this review we discuss treatment with HIPEC in patients with ovarian cancer and future prospective of its use in clinical setting. HIPEC is an effective tool in the treatment of selected patients with peritoneal carcinomatosis from ovarian cancer. Unfortunately, due to the lack of randomised trials, the evidence of HIPEC is very limited. Future randomised studies are awaited to define the role and clinical impact of HIPEC in ovarian cancer. PMID- 26984710 TI - Morpho-histology of head kidney of female catfish Heteropneustes fossilis: seasonal variations in melano-macrophage centers, melanin contents and effects of lipopolysaccharide and dexamethasone on melanins. AB - In the catfish Heteropneustes fossilis, the anterior kidney is a hemopoietic tissue which surrounds the adrenal homologues, interrenal (IR) and chromaffin tissues corresponding to the adrenal cortical and adrenal medulla of higher mammals. The IR tissue is arranged in cell cords around the posterior cardinal vein (PCV) and its tributaries and secretes corticosteroids. The chromaffin tissue is scattered singly or in nests of one or more cells around the epithelial lining of the PCV or blood capillaries within the IR tissue. They are ferric ferricyanide-positive. Leukemia-inhibitory factor (LIF)-like reactivity was noticed in the lining of the epithelium of the IR cell cords and around the wall of the PCV and blood capillaries. No staining was observed in the hemopoietic cells. IL-1beta- and TNF-alpha-like immunoreactivity was seen in certain cells in the hemopoietic tissue but not in the IR region. Macrophages were identified with mammalian macrophage-specific MAC387 antibodies and are present in the hemopoietic mass but not in the IR tissue. Pigments accumulate in the hemopoietic mass as melano-macrophage centers (MMCs) and are PAS-, Schmorl's- and Perls' positive. The pigments contain melanin (black), hemosiderin (blue) and lipofuscin/ceroid (oxidized lipid, yellowish tan), as evident from the Perls' reaction. The MMCs were TUNEL-positive as evident from FITC fluorescence, indicating their apoptotic nature. The MMCs showed significant seasonal variation with their density increasing to the peak in the postspawning phase. Melanins were characterized spectrophotometrically for the first time in fish anterior kidney. The predominant form is pheomelanin (PM), followed by eumelanin (EM) and alkali-soluble melanin (ASM). Melanins showed significant seasonal variations with the level low in the resting phase and increasing to the peak in the postspawning phase. Under in vitro conditions, lipopolysaccharide (10 ug/mL) treatment increased significantly the levels of PM and EM levels both at 16 and at 32 h and the ASM level at 32 h. On the other hand, the synthetic glucocorticoid dexamethasone (100 nM) decreased significantly the levels of EM, PM and ASM time-dependently. The results indicate that the anterior kidney is an important site of immune-endocrine interaction. PMID- 26984716 TI - Left Atrial Appendage Occlusion in Non-Valvular Atrial Fibrillation in a Korean Multi-Center Registry. AB - BACKGROUND: The aim of this study was to evaluate clinical outcome after left atrial appendage (LAA) occlusion in real clinical practice and compare between Amplatzer cardiac plug (ACP) and Watchman. METHODS AND RESULTS: From October 2010 to February 2015, 96 successful LAA occlusion procedures were performed using either ACP (n=50) or Watchman device (n=46) in non-valvular atrial fibrillation (AF) patients (59 male; age, 65.1+/-9.4 years; CHADS2, 2.5+/-1.2; CHA2DS2-VASC, 3.9+/-1.6; HAS-BLED, 2.7+/-1.3). The procedure success rate was 96.8%. There were serious complications in 4 patients (4.1%; 2 cardiac tamponade, 1 device embolization, and 1 major bleed). The anticoagulation cessation rate after 6 weeks was 92.7%. During mean 21.9-month follow-up, the incidence of death, stroke, systemic embolization and major bleeding was 5.2%, 4.2%, 0% and 1.0%, respectively. On transesophageal echocardiography of 93 patients within 6 months after the procedure, 24 residual leaks were observed (25.8%; 2 mild, 18 moderate, and 4 major). Clinical outcome was similar for the 2 devices, but peridevice leakage was more frequent with the Watchman than the ACP. CONCLUSIONS: LAA occlusion was feasible in non-valvular AF patients with high risk of stroke and hemorrhage. The ACP and Watchman devices were similar in terms of procedural and clinical outcomes. (Circ J 2016; 80: 1123-1130). PMID- 26984717 TI - Native T1 Relaxation Time and Extracellular Volume Fraction as Accurate Markers of Diffuse Myocardial Fibrosis in Heart Valve Disease - Comparison With Targeted Left Ventricular Myocardial Biopsy. AB - BACKGROUND: The aim of our study was to investigate the relationship between the cardiac magnetic resonance (CMR)-derived native T1 relaxation time and myocardial extracellular volume (ECV) fraction and the extent of diffuse myocardial fibrosis (DMF) on targeted myocardial left ventricular (LV) biopsy. METHODS AND RESULTS: The study population consisted of 40 patients (age 63+/-8 years, 65% male) undergoing valve and/or ascending aorta surgery for severe aortic stenosis (77.5%), root dilatation (7.5%) or valve regurgitation (15%). The T1 relaxation time was assessed in the basal interventricular septum pre- and 10-min post contrast administration using the modified Look-Locker Inversion recovery sequence prior to surgery. LV myocardial biopsy specimen was obtained during surgery from the basal interventricular septal segment matched with the T1 mapping assessment. The percentage of myocardial collagen was quantified using picrosirius red staining. The average percentage of myocardial collagen was 22.0+/-14.8%. Both native T1 relaxation time with cutoff value >=1,010 ms (sensitivity=90%, specificity=73%, area under the curve=0.82) and ECV with cutoff value >=0.32 (sensitivity=80%, specificity=90%, area under the curve=0.85) showed high accuracy to identify severe (>30%) DMF. The native T1 relaxation time showed significant correlation with LV mass (P<0.01). CONCLUSIONS: Native T1 relaxation time and ECV at 10 min after contrast administration are accurate markers of DMF. (Circ J 2016; 80: 1202-1209). PMID- 26984719 TI - Deaths following prehospital safety incidents: an analysis of a national database. AB - INTRODUCTION: Ensuring patient safety in the prehospital environment is difficult due to the unpredictable nature of the workload and the uncontrolled situations that care is provided in. Studying previous safety incidents can help understand risks and take action to mitigate them. We present an analysis of safety incidents related to patient deaths in ambulance services in England. METHODS: All incidents related to a patient death reported to the National Reporting and Learning System from an ambulance service between 1 June 2010 and 31 October 2012 were subjected to thematic analysis to identify the failings that led to the incident. RESULTS: Sixty-nine incidents were analysed, equating to one safety incident-related death per 168 000 calls received. Just three event categories were identified: delayed response (59%, 41/69), shortfalls in clinical care (35%, 24/69) and injury during transit (6%, 4/69). Primary failures differed for the categories: problems with dispatch caused the majority of delays in response, with equipment problems and bad weather accounting for the remainder. Failure to provide necessary care was predominantly caused by clinical misjudgements by ambulance staff and equipment issues underlay incidents that led to a patient injury. CONCLUSIONS: Improvements intended to address safety related mortality in the ambulance service should include ensuring adequate equipping and resourcing of ambulance services, improving coordination and decision-making during dispatch and supporting individual staff members in the difficult decisions they are faced with. PMID- 26984718 TI - Throat Infections are Associated with Exacerbation in a Substantial Proportion of Patients with Chronic Plaque Psoriasis. AB - Streptococcal throat infections are known to trigger or exacerbate psoriasis, and several studies support the benefit of tonsillectomy. To evaluate the potential of tonsillectomy as a treatment, we used a retrospective study-specific questionnaire to assess the proportion of psoriasis patients with sore throat associated psoriasis exacerbations. Our survey sampled 275 psoriasis patients. Of patients with plaque psoriasis, 42% reported sore throat-associated psoriasis exacerbations, and of patients with confirmed streptococcal infections, 72% reported aggravation. Notably, women and patients with early onset psoriasis were more likely to report psoriasis exacerbation after a sore throat (p < 0.001, p = 0.046, respectively). Other psoriasis aggravation factors were more common in patients with sore throat-associated exacerbations (p < 0.01). Of tonsillectomized patients, 49% reported subsequent improvement and had more frequent sore throat-associated aggravation of psoriasis than patients who did not improve after tonsillectomy (p = 0.015). These findings suggest a closer association between sore throats, streptococcal throat infections and plaque psoriasis than reported previously. PMID- 26984720 TI - Refinements of the ICF Linking Rules to strengthen their potential for establishing comparability of health information. AB - : Purpose The content of and methods for collecting health information often vary across settings and challenge the comparability of health information across time, individuals or populations. The International Classification of Functioning, Disability and Health (ICF) contains an exhaustive set of categories of information which constitutes a unified and consistent language of human functioning suitable as a reference for comparing health information. Methods and results In two earlier papers, we have proposed rules for linking existing health information to the ICF. Further refinements to these existing ICF Linking Rules are presented in this paper to enhance the transparency of the linking process. The refinements involve preparing information for linking, perspectives from which information is collected and the categorization of response options. Issues regarding the linking of information not covered or unspecified within the ICF are also revisited in this paper. CONCLUSION: The ICF Linking Rules are valuable for enhancing comparability of health information to ensure that information is available in a consistent manner to serve as a foundation for evidence-based decision-making across all levels of health systems. The refinements presented in this paper enhance transparency in, and ultimately reliability of the process of, linking health information to the ICF. Implications for Rehabilitation The International Classification of Functioning, Disability and Health (ICF) constitutes a unified and consistent language of human functioning suitable as a reference for comparing health information. Comparability of information is essential to ensure that the widest range of information is available in a consistent manner for any decision-maker at all levels of the health system. The refined ICF Linking Rules presented in this article outline the method to establish comparability of health information based on the ICF. PMID- 26984721 TI - Detection of Broadly Neutralizing Activity within the First Months of HIV-1 Infection. AB - A fraction of HIV-1 patients are able to generate broadly neutralizing antibodies (bNAbs) after 2 to 4 years of infection. In rare occasions such antibodies are observed close to the first year of HIV-1 infection but never within the first 6 months. In this study, we analyzed the neutralization breadth of sera from 157 antiretroviral-naive individuals who were infected for less than 1 year. A range of neutralizing activities was observed with a previously described panel of six recombinant viruses from five different subtypes (M. Medina-Ramirez et al., J Virol 85:5804-5813, 2011, http://dx.doi.org/10.1128/JVI.02482-10). Some sera were broadly reactive, predominantly targeting envelope epitopes within the V2 glycan dependent region. The neutralization breadth was positively associated with time postinfection (P = 0.0001), but contrary to what has been reported for chronic infections, no association with the viral load was observed. Notably, five individuals within the first 6 months of infection (two as early as 77 and 96 days postinfection) showed substantial cross-neutralization. This was confirmed with an extended panel of 20 Env pseudoviruses from four different subtypes (two in tier 3, 14 in tier 2, and four in tier 1). Sera from these individuals were capable of neutralizing viruses from four different subtypes with a geometric mean 50% infective dose (ID50) between 100 and 800. These results indicate that induction of cross-neutralizing responses, albeit rare, is achievable even within 6 months of HIV-1 infection. These observations encourage the search for immunogens able to elicit this kind of response in preventive HIV-1 vaccine approaches. IMPORTANCE: There are very few individuals able to mount broadly neutralizing activity (bNA) close to the first year postinfection. It is not known how early in the infection cross-neutralizing responses can be induced. In the present study, we show that bNAbs, despite being rare, can be induced much earlier than previously thought. The identification of HIV-1-infected patients with these activities within the first months of infection and characterization of these responses will help in defining new immunogen designs and neutralization targets for vaccine-mediated induction of bNAbs. PMID- 26984722 TI - Protection of Cattle against Rinderpest by Vaccination with Wild-Type but Not Attenuated Strains of Peste des Petits Ruminants Virus. AB - Although rinderpest virus (RPV) has been eradicated in the wild, efforts are still continuing to restrict the extent to which live virus is distributed in facilities around the world and to prepare for any reappearance of the disease, whether through deliberate or accidental release. In an effort to find an alternative vaccine which could be used in place of the traditional live attenuated RPV strains, we have determined whether cattle can be protected from rinderpest by inoculation with vaccine strains of the related morbillivirus, peste des petits ruminants virus (PPRV). Cattle were vaccinated with wild-type PPRV or either of two established PPRV vaccine strains, Nigeria/75/1 or Sungri/96. All animals developed antibody and T cell immune responses to the inoculated PPRV. However, only the animals given wild-type PPRV were protected from RPV challenge. Animals given PPRV/Sungri/96 were only partially protected, and animals given PPRV/Nigeria/75/1 showed no protection against RPV challenge. While sera from animals vaccinated with the vaccine strain of RPV showed cross neutralizing ability against PPRV, none of the sera from animals vaccinated with any strain of PPRV was able to neutralize RPV although sera from animals inoculated with wild-type PPRV were able to neutralize RPV-pseudotyped vesicular stomatitis virus. IMPORTANCE: Rinderpest virus has been eradicated, and it is only the second virus for which this is so. Significant efforts are still required to ensure preparedness for a possible escape of RPV from a laboratory or its deliberate release. Since RPV vaccine protects sheep and goats from PPRV, it is important to determine if the reverse is true as this would provide a non-RPV vaccine for dealing with suspected RPV outbreaks. This is probably the last in vivo study with live RPV that will be approved. PMID- 26984723 TI - Enhancement of Ebola Virus Infection via Ficolin-1 Interaction with the Mucin Domain of GP Glycoprotein. AB - Ebola virus infection requires the surface viral glycoprotein to initiate entry into the target cells. The trimeric glycoprotein is a highly glycosylated viral protein which has been shown to interact with host C-type lectin receptors and the soluble complement recognition protein mannose-binding lectin, thereby enhancing viral infection. Similarly to mannose-binding lectin, ficolins are soluble effectors of the innate immune system that recognize particular glycans at the pathogen surface. In this study, we demonstrate that ficolin-1 interacts with the Zaire Ebola virus (EBOV) glycoprotein, and we characterized this interaction by surface plasmon resonance spectroscopy. Ficolin-1 was shown to bind to the viral glycoprotein with a high affinity. This interaction was mediated by the fibrinogen-like recognition domain of ficolin-1 and the mucin like domain of the viral glycoprotein. Using a ficolin-1 control mutant devoid of sialic acid-binding capacity, we identified sialylated moieties of the mucin domain to be potential ligands on the glycoprotein. In cell culture, using both pseudotyped viruses and EBOV, ficolin-1 was shown to enhance EBOV infection independently of the serum complement. We also observed that ficolin-1 enhanced EBOV infection on human monocyte-derived macrophages, described to be major viral target cells,. Competition experiments suggested that although ficolin-1 and mannose-binding lectin recognized different carbohydrate moieties on the EBOV glycoprotein, the observed enhancement of the infection likely depended on a common cellular receptor/partner. In conclusion, ficolin-1 could provide an alternative receptor-mediated mechanism for enhancing EBOV infection, thereby contributing to viral subversion of the host innate immune system. IMPORTANCE: A specific interaction involving ficolin-1 (M-ficolin), a soluble effector of the innate immune response, and the glycoprotein (GP) of EBOV was identified. Ficolin 1 enhanced virus infection instead of tipping the balance toward its elimination. An interaction between the fibrinogen-like recognition domain of ficolin-1 and the mucin-like domain of Ebola virus GP occurred. In this model, the enhancement of infection was shown to be independent of the serum complement. The facilitation of EBOV entry into target host cells by the interaction with ficolin 1 and other host lectins shunts virus elimination, which likely facilitates the survival of the virus in infected host cells and contributes to the virus strategy to subvert the innate immune response. PMID- 26984724 TI - Porcine Reproductive and Respiratory Syndrome Virus Utilizes Nanotubes for Intercellular Spread. AB - Intercellular nanotube connections have been identified as an alternative pathway for cellular spreading of certain viruses. In cells infected with porcine reproductive and respiratory syndrome virus (PRRSV), nanotubes were observed connecting two distant cells with contiguous membranes, with the core infectious viral machinery (viral RNA, certain replicases, and certain structural proteins) present in/on the intercellular nanotubes. Live-cell movies tracked the intercellular transport of a recombinant PRRSV that expressed green fluorescent protein (GFP)-tagged nsp2. In MARC-145 cells expressing PRRSV receptors, GFP-nsp2 moved from one cell to another through nanotubes in the presence of virus neutralizing antibodies. Intercellular transport of viral proteins did not require the PRRSV receptor as it was observed in receptor-negative HEK-293T cells after transfection with an infectious clone of GFP-PRRSV. In addition, GFP-nsp2 was detected in HEK-293T cells cocultured with recombinant PRRSV-infected MARC 145 cells. The intercellular nanotubes contained filamentous actin (F-actin) with myosin-associated motor proteins. The F-actin and myosin IIA were identified as coprecipitates with PRRSV nsp1beta, nsp2, nsp2TF, nsp4, nsp7-nsp8, GP5, and N proteins. Drugs inhibiting actin polymerization or myosin IIA activation prevented nanotube formation and viral clusters in virus-infected cells. These data lead us to propose that PRRSV utilizes the host cell cytoskeletal machinery inside nanotubes for efficient cell-to-cell spread. This form of virus transport represents an alternative pathway for virus spread, which is resistant to the host humoral immune response. IMPORTANCE: Extracellular virus particles transmit infection between organisms, but within infected hosts intercellular infection can be spread by additional mechanisms. In this study, we describe an alternative pathway for intercellular transmission of PRRSV in which the virus uses nanotube connections to transport infectious viral RNA, certain replicases, and certain structural proteins to neighboring cells. This process involves interaction of viral proteins with cytoskeletal proteins that form the nanotube connections. Intercellular viral spread through nanotubes allows the virus to escape the neutralizing antibody response and may contribute to the pathogenesis of viral infections. The development of strategies that interfere with this process could be critical in preventing the spread of viral infection. PMID- 26984725 TI - Internal Proteins of the Procapsid and Mature Capsids of Herpes Simplex Virus 1 Mapped by Bubblegram Imaging. AB - The herpes simplex virus 1 (HSV-1) capsid is a huge assembly, ~1,250 A in diameter, and is composed of thousands of protein subunits with a combined mass of ~200 MDa, housing a 100-MDa genome. First, a procapsid is formed through coassembly of the surface shell with an inner scaffolding shell; then the procapsid matures via a major structural transformation, triggered by limited proteolysis of the scaffolding proteins. Three mature capsids are found in the nuclei of infected cells. A capsids are empty, B capsids retain a shrunken scaffolding shell, and C capsids-which develop into infectious virions-are filled with DNA and ostensibly have expelled the scaffolding shell. The possible presence of other internal proteins in C capsids has been moot as, in cryo electron microscopy (cryo-EM), they would be camouflaged by the surrounding DNA. We have used bubblegram imaging to map internal proteins in all four capsids, aided by the discovery that the scaffolding protein is exceptionally prone to radiation-induced bubbling. We confirmed that this protein forms thick-walled inner shells in the procapsid and the B capsid. C capsids generate two classes of bubbles: one occupies positions beneath the vertices of the icosahedral surface shell, and the other is distributed throughout its interior. A likely candidate is the viral protease. A subpopulation of C capsids bubbles particularly profusely and may represent particles in which expulsion of scaffold and DNA packaging are incomplete. Based on the procapsid structure, we propose that the axial channels of hexameric capsomers afford the pathway via which the scaffolding protein is expelled. IMPORTANCE: In addition to DNA, capsids of tailed bacteriophages and their distant relatives, herpesviruses, contain internal proteins. These proteins are often essential for infectivity but are difficult to locate within the virion. A novel adaptation of cryo-EM based on detecting gas bubbles generated by radiation damage was used to localize internal proteins of HSV-1, yielding insights into how capsid maturation is regulated. The scaffolding protein, which forms inner shells in the procapsid and B capsid, is exceptionally bubbling-prone. In the mature DNA-filled C capsid, a previously undetected protein was found to underlie the icosahedral vertices: this is tentatively assigned as a storage form of the viral protease. We also observed a capsid species that appears to contain substantial amounts of scaffolding protein as well as DNA, suggesting that DNA packaging and expulsion of the scaffolding protein are coupled processes. PMID- 26984726 TI - Type I Interferons Regulate the Magnitude and Functionality of Mouse Polyomavirus Specific CD8 T Cells in a Virus Strain-Dependent Manner. AB - Mouse polyomavirus (MPyV) is a ubiquitous persistent natural mouse pathogen. A glutamic acid (E)-to-glycine (G) difference at position 91 of the VP1 capsid protein shifts the profile of tumors induced by MPyV from an epithelial to a mesenchymal cell origin. Here we asked if this tropism difference affects the MPyV-specific CD8 T cell response, which controls MPyV infection and tumorigenesis. Infection by the laboratory MPyV strain RA (VP1-91G) or a strain A2 mutant with an E-to-G substitution at VP1 residue 91 [A2(91G)] generated a markedly smaller virus-specific CD8 T cell response than that induced by A2(VP1 91E) infection. Mutant A2(91G)-infected mice showed a higher frequency of memory precursor (CD127(hi) KLRG1(lo)) CD8 T cells and a higher recall response than those of A2-infected mice. Using T cell receptor (TCR)-transgenic CD8 T cells and immunization with peptide-pulsed dendritic cells, we found that early bystander inflammation associated with A2 infection contributed to recruitment of the larger MPyV-specific CD8 T cell response. Beta interferon (IFN-beta) transcripts were induced early during A2 or A2(91G) infections. IFN-beta inhibited replication of A2 and A2(91G) in vitro Using mice lacking IFN-alphabeta receptors (IFNAR(-/-)), we showed that type I IFNs played a role in controlling MPyV replication in vivo but differentially affected the magnitude and functionality of virus-specific CD8 T cells recruited by A2 and A2(91G) viral infections. These data indicate that type I IFNs are involved in protection against MPyV infection and that their effect on the antiviral CD8 T cell response depends on capsid mediated tropism properties of the MPyV strain. IMPORTANCE: Isolates of the human polyomavirus JC virus from patients with the frequently fatal demyelinating brain disease progressive multifocal leukoencephalopathy (PML) carry single amino acid substitutions in the domain of the VP1 capsid protein that binds the sialic acid moiety of glycoprotein/glycolipid receptors on host cells. These VP1 mutations may alter neural cell tropism or enable escape from neutralizing antibodies. Changes in host cell tropism can affect recruitment of virus-specific CD8 T cells. Using mouse polyomavirus, we demonstrate that a single amino acid difference in VP1 known to shift viral tropism profoundly affects the quantity and quality of the anti-polyomavirus CD8 T cell response and its differentiation into memory cells. These findings raise the possibility that CD8 T cell responses to infections by human polyomaviruses may be influenced by VP1 mutations involving domains that engage host cell receptors. PMID- 26984727 TI - Generation of a More Immunogenic Measles Vaccine by Increasing Its Hemagglutinin Expression. AB - Imported measles virus (MV) outbreaks are maintained by poor vaccine responders and unvaccinated people. A convenient but more immunogenic vaccination strategy would enhance vaccine performance, contributing to measles eradication efforts. We report here the generation of alternative pediatric vaccines against MV with increased expression of the H protein in the background of the current MV vaccine strain. We generated two recombinants: MVvac2-H2, with increased full-length H expression resulting in a 3-fold increase in H incorporation into virions, and MVvac2-Hsol, vectoring a truncated, soluble form of the H protein that is secreted into the supernatants of infected cells. Replication fitness was conserved despite the duplication of the H cistron for both vectors. The modification to the envelope of MVvac2-H2 conferred upon this virus a measurable level of resistance to in vitro neutralization by MV polyclonal immune sera without altering its thermostability. Most interestingly, both recombinant MVs with enhanced H expression were significantly more immunogenic than their parental strain in outbred mice, while MVvac2-H2 additionally proved more immunogenic after a single, human-range dose in genetically modified MV susceptible mice. IMPORTANCE: Measles incidence was reduced drastically following the introduction of attenuated vaccines, but progress toward the eradication of this virus has stalled, and MV still threatens unvaccinated populations. Due to the contributions of primary vaccine failures and too-young-to-be-vaccinated infants to this problem, more immunogenic measles vaccines are highly desirable. We generated two experimental MV vaccines based on a current vaccine's genome but with enriched production of the H protein, the main MV antigen in provoking immunity. One vaccine incorporated H at higher rates in the viral envelope, and the other secreted a soluble H protein from infected cells. The increased expression of H by these vectors improved neutralizing responses induced in two small-animal models of MV immunogenicity. The enhanced immunogenicity of these vectors, mainly from the MV that incorporates additional H, suggests their value as potential alternative pediatric MV vaccines. PMID- 26984728 TI - Mutations in the Schmallenberg Virus Gc Glycoprotein Facilitate Cellular Protein Synthesis Shutoff and Restore Pathogenicity of NSs Deletion Mutants in Mice. AB - Serial passage of viruses in cell culture has been traditionally used to attenuate virulence and identify determinants of viral pathogenesis. In a previous study, we found that a strain of Schmallenberg virus (SBV) serially passaged in tissue culture (termed SBVp32) unexpectedly displayed increased pathogenicity in suckling mice compared to wild-type SBV. In this study, we mapped the determinants of SBVp32 virulence to the viral genome M segment. SBVp32 virulence is associated with the capacity of this virus to reach high titers in the brains of experimentally infected suckling mice. We also found that the Gc glycoprotein, encoded by the M segment of SBVp32, facilitates host cell protein shutoff in vitro Interestingly, while the M segment of SBVp32 is a virulence factor, we found that the S segment of the same virus confers by itself an attenuated phenotype to wild-type SBV, as it has lost the ability to block the innate immune system of the host. Single mutations present in the Gc glycoprotein of SBVp32 are sufficient to compensate for both the attenuated phenotype of the SBVp32 S segment and the attenuated phenotype of NSs deletion mutants. Our data also indicate that the SBVp32 M segment does not act as an interferon (IFN) antagonist. Therefore, SBV mutants can retain pathogenicity even when they are unable to fully control the production of IFN by infected cells. Overall, this study suggests that the viral glycoprotein of orthobunyaviruses can compensate, at least in part, for the function of NSs. In addition, we also provide evidence that the induction of total cellular protein shutoff by SBV is determined by multiple viral proteins, while the ability to control the production of IFN maps to the NSs protein. IMPORTANCE: The identification of viral determinants of pathogenesis is key to the development of prophylactic and intervention measures. In this study, we found that the bunyavirus Gc glycoprotein is a virulence factor. Importantly, we show that mutations in the Gc glycoprotein can restore the pathogenicity of attenuated mutants resulting from deletions or mutations in the nonstructural protein NSs. Our findings highlight the fact that careful consideration should be taken when designing live attenuated vaccines based on deletions of nonstructural proteins since single mutations in the viral glycoproteins appear to revert attenuated mutants to virulent phenotypes. PMID- 26984729 TI - Cellular Immune Responses against Simian T-Lymphotropic Virus Type 1 Target Tax in Infected Baboons. AB - There are currently 5 million to 10 million human T-lymphotropic virus type 1 (HTLV-1)-infected people, and many of them will develop severe complications resulting from this infection. A vaccine is urgently needed in areas where HTLV-1 is endemic. Many vaccines are best tested in nonhuman primate animal models. As a first step in designing an effective HTLV-1 vaccine, we defined the CD8(+) and CD4(+) T cell response against simian T-lymphotropic virus type 1 (STLV-1), a virus closely related to HTLV-1, in olive baboons (Papio anubis). Consistent with persistent antigenic exposure, we observed that STLV-1-specific CD8(+) T cells displayed an effector memory phenotype and usually expressed CD107a, gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha). To assess the viral targets of the cellular immune response in STLV-1-infected animals, we used intracellular cytokine staining to detect responses against overlapping peptides covering the entire STLV-1 proteome. Our results show that, similarly to humans, the baboon CD8(+) T cell response narrowly targeted the Tax protein. Our findings suggest that the STLV-1-infected baboon model may recapitulate some of the important aspects of the human response against HTLV-1 and could be an important tool for the development of immune-based therapy and prophylaxis. IMPORTANCE: HTLV-1 infection can lead to many different and often fatal conditions. A vaccine deployed in areas of high prevalence might reduce the incidence of HTLV-1-induced disease. Unfortunately, there are very few animal models of HTLV-1 infection useful for testing vaccine approaches. Here we describe cellular immune responses in baboons against a closely related virus, STLV-1. We show for the first time that the immune response against STLV-1 in naturally infected baboons is largely directed against the Tax protein. Similar findings in humans and the sequence similarity between the human and baboon viruses suggest that the STLV-1-infected baboon model might be useful for developing a vaccine against HTLV-1. PMID- 26984730 TI - The Large Marseillevirus Explores Different Entry Pathways by Forming Giant Infectious Vesicles. AB - Triggering the amoebal phagocytosis process is a sine qua non condition for most giant viruses to initiate their replication cycle and consequently to promote their progeny formation. It is well known that the amoebal phagocytosis process requires the recognition of particles of >500 nm, and most amoebal giant viruses meet this requirement, such as mimivirus, pandoravirus, pithovirus, and mollivirus. However, in the context of the discovery of amoebal giant viruses in the last decade, Marseillevirus marseillevirus (MsV) has drawn our attention, because despite its ability to successfully replicate in Acanthamoeba, remarkably it does not fulfill the >500-nm condition, since it presents an ~250-nm icosahedrally shaped capsid. We deeply investigated the MsV cycle by using a set of methods, including virological, molecular, and microscopic (immunofluorescence, scanning electron microscopy, and transmission electron microscopy) assays. Our results revealed that MsV is able to form giant vesicles containing dozens to thousands of viral particles wrapped by membranes derived from amoebal endoplasmic reticulum. Remarkably, our results strongly suggested that these giant vesicles are able to stimulate amoebal phagocytosis and to trigger the MsV replication cycle by an acidification-independent process. Also, we observed that MsV entry may occur by the phagocytosis of grouped particles (without surrounding membranes) and by an endosome-stimulated pathway triggered by single particles. Taken together, not only do our data deeply describe the main features of MsV replication cycle, but this is the first time, to our knowledge, that the formation of giant infective vesicles related to a DNA virus has been described. IMPORTANCE: Triggering the amoebal phagocytosis process is a sine qua non condition required by most giant viruses to initiate their replication cycle. This process requires the recognition of particles of >500 nm, and many giant viruses meet this requirement. However, MsV is unusual, as despite having particles of ~250 nm it is able to replicate in Acanthamoeba Our results revealed that MsV is able to form giant vesicles, containing dozens to thousands of viral particles, wrapped in membranes derived from amoebal endoplasmic reticulum. Remarkably, our results strongly suggest that these giant vesicles are able to stimulate phagocytosis using an acidification-independent process. Our work not only describes the main features of the MsV replication cycle but also describes, for the first time to our knowledge, the formation of huge infective vesicles in a large DNA viruses. PMID- 26984731 TI - Characterization of Glycoprotein-Mediated Entry of Severe Fever with Thrombocytopenia Syndrome Virus. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever with a high case fatality rate caused by SFTS virus (SFTSV). Effective vaccines and specific therapies for SFTS are urgently sought, and investigation into virus-host cell interactions is expected to contribute to the development of antiviral strategies. In this study, we have developed a pseudotype vesicular stomatitis virus (VSV) bearing the unmodified Gn/Gc glycoproteins (GPs) of SFTSV (SFTSVpv). We have analyzed the host cell entry of this pseudotype virus and native SFTSV. Both SFTSVpv and SFTSV exhibited high infectivity in various mammalian cell lines. The use of lysosomotropic agents indicated that virus entry occurred via pH-dependent endocytosis. SFTSVpv and SFTSV infectivity was neutralized by serial dilutions of convalescent-phase patient sera. Entry of SFTSVpv and growth of SFTSV were increased in Raji cells expressing not only the C-type lectin dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) but also DC-SIGN-related (DC-SIGNR) and liver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin). 25-Hydroxycholesterol (25HC), a soluble oxysterol metabolite, inhibited the cell entry of SFTSVpv and the membrane fusion of SFTSV. These results indicate that pH-dependent endocytosis of SFTSVpv and SFTSV is enhanced by attachment to certain C-type lectins. SFTSVpv is an appropriate model for the investigation of SFTSV-GP mediated cell entry and virus neutralization at lower biosafety levels. Furthermore, 25HC may represent a potential antiviral agent against SFTS. IMPORTANCE: SFTSV is a recently discovered bunyavirus associated with SFTS, a viral hemorrhagic fever with a high case fatality rate endemic to China, South Korea, and Japan. Because little is known about the characteristics of the envelope protein and entry mechanisms of SFTSV, further studies will be required for the development of a vaccine or effective therapies. In this study, we investigated the mechanism of SFTSV cell entry using SFTSVpv and the native virus. SFTSV can grow in nonsusceptible cell lines in the presence of certain C type lectins. Moreover, 25HC, an oxysterol metabolite, may represent a potential therapeutic inhibitor of SFTSV infection. PMID- 26984733 TI - Age-related differences in image quality of prospectively ECG-triggered axial and helical scans for coronary CT angiography. AB - We investigated the underlying reasons for the occurrence of misalignment artifacts in prospectively ECG-triggered axial coronary CT angiography scans. In this study we analyzed 56 consecutive patients scanned in axial mode and 66 consecutive patients scanned in helical mode. Predictors for the occurrence of misalignment artifacts were evaluated by multivariable logistic regression analysis for those patients scanned in the axial mode; advanced age was identified as the sole independent predictor (odds ratio: 1.088; 95 % CI: 1.012 1.170; p = 0.0228). In a comparison with the patients scanned in the helical mode, the image quality score for patients aged 65 years or older was significantly higher in helical mode than in axial mode (2.6 +/- 0.5 and 2.4 +/- 0.7, respectively; p = 0.0313). Misalignment artifacts in the image are more common in the elderly than in younger. Helical mode should be preferred in this older patient population to allow for good diagnostic image quality. PMID- 26984732 TI - HIV Provirus Stably Reproduces Parental Latent and Induced Transcription Phenotypes Regardless of the Chromosomal Integration Site. AB - Understanding the mechanisms of HIV proviral latency is essential for development of a means to eradicate infection and achieve a cure. We have previously described an in vitro latency model that reliably identifies HIV expression phenotypes of infected cells using a dual-fluorescence reporter virus. Our results have demonstrated that ~50% of infected cells establish latency immediately upon integration of provirus, a phenomenon termed early latency, which appears to occur by mechanisms that are distinct from epigenetic silencing observed with HIV provirus that establishes productive infections. In this study, we have used a mini-dual HIV reporter virus (mdHIV) to compare the long-term stability of provirus produced as early latent or productive infections using Jurkat-Tat T cell clones. Cloned lines bearing mdHIV provirus integrated at different chromosomal locations display unique differences in responsiveness to signaling agonists and chromatin-modifying compounds, and they also produce characteristic expression patterns from the 5' long terminal repeat (LTR) dsRed and internal EIF1alpha-enhanced green fluorescent protein (EIF1alpha-eGFP) reporters. Furthermore, reporter expression profiles of single cell sorted subcultures faithfully reproduce expression profiles identical to that of their original parental population, following prolonged growth in culture, without shifting toward expression patterns resembling that of cell subclones at the time of sorting. Comparison of population dispersion coefficient (CV) and mean fluorescence intensity (MFI) of the subcloned lines showed that both untreated and phorbol myristate acetate (PMA)-ionomycin-stimulated cultures produce expression patterns identical to those of their parental lines. These results indicate that HIV provirus expression characteristics are strongly influenced by the epigenetic landscape at the site of chromosomal integration. IMPORTANCE: There is currently considerable interest in development of therapies to eliminate latently infected cells from HIV-infected patients on antiretroviral therapy. One proposed strategy, known as "shock and kill," would involve treatment with therapies capable of inducing expression of latent provirus, with the expectation that the latently infected cells could be killed by a host immune response or virus-induced apoptosis. In clinical trials, histone deacetylase (HDAC) inhibitors were shown to cause reactivation of latent provirus but did not produce a significant effect toward eliminating the latently infected population. Results shown here indicate that integration of HIV provirus at different chromosomal locations produces significant effects on the responsiveness of virus expression to T cell signaling agonists and chromatin-modifying compounds. Given the variety of phenotypes produced by integrated provirus, it is unlikely that any single potential shock-and-kill therapy will be effective toward purging the latently infected population. PMID- 26984734 TI - Simple noise reduction for diffusion weighted images. AB - Our purpose in this study was to reduce the noise in order to improve the SNR of Dw images with high b-value by using two correction schemes. This study was performed with use of phantoms made from water and sucrose at different concentrations, which were 10, 30, and 50 weight percent (wt%). In noise reduction for Dw imaging of the phantoms, we compared two correction schemes that are based on the Rician distribution and the Gaussian distribution. The highest error values for each concentration with use of the Rician distribution scheme were 7.3 % for 10 wt%, 2.4 % for 30 wt%, and 0.1 % for 50 wt%. The highest error values for each concentration with use of the Gaussian distribution scheme were 20.3 % for 10 wt%, 11.6 % for 30 wt%, and 3.4 % for 50 wt%. In Dw imaging, the noise reduction makes it possible to apply the correction scheme of Rician distribution. PMID- 26984737 TI - The carboxyl-terminally truncated kidney anion exchanger 1 R901X dRTA mutant is unstable at the plasma membrane. AB - Mutations in the SLC4A1 gene coding for kidney anion exchanger 1 (kAE1) cause distal renal tubular acidosis (dRTA). We investigated the fate of the most common truncated dominant dRTA mutant kAE1 R901X. In renal epithelial cells, we found that kAE1 R901X is less abundant than kAE1 wild-type (WT) at the plasma membrane. Although kAE1 WT and kAE1 R901X have similar half-lives, the decreased abundance of kAE1 R901X at the surface is due to an increased endocytosis rate and a decreased recycling rate of endocytosed proteins. We propose that, in polarized renal epithelial cells, the apically mistargeted kAE1 R901X mutant is endocytosed faster than kAE1 WT and its recycling to the basolateral membrane is delayed. This resets the equilibrium, such that kAE1 R901X resides predominantly in an endomembrane compartment, thereby likely participating in development of dRTA disease. PMID- 26984738 TI - Development of a short version of the Aging Males' Symptoms scale: Mokken scaling analysis and Rasch analysis. AB - The aim of this study was to develop a psychometrically sound short version of the 17-item Aging Males' Symptoms (AMS) scale using Mokken scale analysis (MSA) and Rasch analysis. We recruited a convenient sample of 1787 men (age: mean (SD) = 43.8 (11.5) years) who visited a men's health polyclinic in Taiwan and completed the AMS scale. The scale was first assessed using MSA. The remaining items were assessed using Rasch analysis. We used a stepwise approach to remove items with chi(2) item statistics and mean square values while monitoring unidimensionality. The item reduction process resulted in a 6-item version of the AMS scale (AMS-6). The AMS-6 scale included a 5-item psychosomatic subscale (original items 1, 4, 5, 8, and 9) and a 1-item sexual subscale (original item 16). Analyses confirmed that the 5-item psychosomatic subscale was a Rasch scale. The AMS-6 correlated well with the AMS scales: the 5-item psychosomatic subscale correlated with the AMS scale (r between 0.50 and 0.92); the 1-item sexual subscale correlated with the sexual subscale of the AMS scale (r = 0.81). A 6 item short form of the AMS scale had satisfactory measurement properties. This version may be useful for estimating psychosomatic and sexual symptoms as well as health-related quality of life with a minimal burden on respondents. PMID- 26984735 TI - Human vascular endothelial cells transport foreign exosomes from cow's milk by endocytosis. AB - Encapsulation of microRNAs in exosomes confers protection against degradation and a vehicle for shuttling of microRNAs between cells and tissues, and cellular uptake by endocytosis. Exosomes can be found in foods including milk. Humans absorb cow's milk exosomes and deliver the microRNA cargo to peripheral tissues, consistent with gene regulation by dietary nucleic acids across species boundaries. Here, we tested the hypothesis that human vascular endothelial cells transport milk exosomes by endocytosis, constituting a step crucial for the delivery of dietary exosomes and their cargo to peripheral tissues. We tested this hypothesis by using human umbilical vein endothelial cells and fluorophore labeled exosomes isolated from cow's milk. Exosome uptake followed Michaelis Menten kinetics (Vmax = 0.057 +/- 0.004 ng exosome protein * 40,000 cells/h; Km = 17.97 +/- 3.84 MUg exosomal protein/200 MUl media) and decreased by 80% when the incubation temperature was lowered from 37 degrees C to 4 degrees C. When exosome surface proteins were removed by treatment with proteinase K, or transport was measured in the presence of the carbohydrate competitor d-galactose or measured in the presence of excess unlabeled exosomes, transport rates decreased by 45% to 80% compared with controls. Treatment with an inhibitor of endocytosis, cytochalasin D, caused a 50% decrease in transport. When fluorophore-labeled exosomes were administered retro-orbitally, exosomes accumulated in liver, spleen, and lungs in mice. We conclude that human vascular endothelial cells transport bovine exosomes by endocytosis and propose that this is an important step in the delivery of dietary exosomes and their cargo to peripheral tissues. PMID- 26984736 TI - Downregulation of LRRC8A protects human ovarian and alveolar carcinoma cells against Cisplatin-induced expression of p53, MDM2, p21Waf1/Cip1, and Caspase-9/-3 activation. AB - The leucine-rich repeat containing 8A (LRRC8A) protein is an essential component of the volume-sensitive organic anion channel (VSOAC), and using pharmacological anion channel inhibitors (NS3728, DIDS) and LRRC8A siRNA we have investigated its role in development of Cisplatin resistance in human ovarian (A2780) and alveolar (A549) carcinoma cells. In Cisplatin-sensitive cells Cisplatin treatment increases p53-protein level as well as downstream signaling, e.g., expression of p21(Waf1/Cip1), Bax, Noxa, MDM2, and activation of Caspase-9/-3. In contrast, Cisplatin-resistant cells do not enter apoptosis, i.e., their p53 and downstream signaling are reduced and caspase activity unaltered following Cisplatin exposure. Reduced LRRC8A expression and VSOAC activity are previously shown to correlate with Cisplatin resistance, and here we demonstrate that pharmacological inhibition and transient knockdown of LRRC8A reduce the protein level of p53, MDM2, and p21(Waf1/Cip1) as well as Caspase-9/-3 activation in Cisplatin sensitive cells. Cisplatin resistance is accompanied by reduction in total LRRC8A expression (A2780) or LRRC8A expression in the plasma membrane (A549). Activation of Caspase-3 dependent apoptosis by TNFalpha-exposure or hyperosmotic cell shrinkage is almost unaffected by pharmacological anion channel inhibition. Our data indicate 1) that expression/activity of LRRC8A is essential for Cisplatin induced increase in p53 protein level and its downstream signaling, i.e., Caspase 9/-3 activation, expression of p21(Waf1/Cip1) and MDM2; and 2) that downregulation of LRRC8A-dependent osmolyte transporters contributes to acquirement of Cisplatin resistance in ovarian and lung carcinoma cells. Activation of LRRC8A-containing channels is upstream to apoptotic volume decrease as hypertonic cell shrinkage induces apoptosis independent of the presence of LRRC8A. PMID- 26984739 TI - The relation of postprandial plasma glucose and serum endostatin to the urinary albumin excretion of residents with prediabetes: results from the Kyushu and Okinawa Population Study (KOPS). AB - BACKGROUND: Previous clinical studies have shown that the circulating level of endostatin is related to kidney injury. We hypothesized that the impact of HbA1c, fasting, and postprandial plasma glucose on urinary albumin excretion would be related to the serum endostatin level. METHODS: A cross-sectional, community based population study of 1057 Japanese residents was conducted. Of these subjects, 162 with a fasting plasma glucose value between 5.5 and 6.9 mmol/L and an HbA1c level of <6.5 % received an oral glucose tolerance test, had serum endostatin measured, and had the urinary albumin/creatinine ratio (UACR) calculated. RESULTS: In multivariate analysis, 2-h postprandial plasma glucose (beta = 0.26, P < 0.01) was significantly associated with log-transformed UACR, independently of fasting plasma glucose (beta = 0.14, P = 0.28) and HbA1c (beta = -0.08, P = 0.57). When divided by the median value of endostatin (82.2 ng/mL), 2 h postprandial plasma glucose (beta = 0.38, P = 0.01) remained significantly associated with the log-transformed UACR of the participants below the median, while the fasting plasma glucose (beta = 0.34, P = 0.046) was independently associated with the log-transformed UACR of participants above the median. CONCLUSION: Postprandial plasma glucose was independently associated with the urinary albumin excretion of the residents with prediabetes. Moreover, this relationship was limited to residents with a serum endostatin level below the median. PMID- 26984742 TI - Protein enrichment of brewery spent grain from Rhizopus oligosporus by solid state fermentation. AB - Brewery spent grain represents approximately 85 % of total by-products generated in a brewery. Consisting of carbohydrates, fiber, minerals and low amounts of protein, the use of brewery spent grain is limited to the feeding of ruminants; however, its potential use should be investigated. The reuse of this by-product using microorganisms by solid-state fermentation process as the case of protein enrichment by single-cell protein incorporation is an alternative to ensure sustainability and generate commercially interesting products. In this context, the aim of this study was to grow Rhizopus oligosporus in brewery spent grain under different initial moisture contents and nitrogen sources to increase the protein content of the fermented material. After 7 days of fermentation, increase of 2-4 times in the crude protein and soluble protein content was verified, respectively, compared to unfermented brewery spent grain. The kinetics of protein enrichment demonstrated the possibility of application of this technique, which can be a great alternative for use in diets for animals. PMID- 26984741 TI - Micheliolide inhibits LPS-induced inflammatory response and protects mice from LPS challenge. AB - Sepsis is the principal cause of fatality in the intensive care units worldwide. It involves uncontrolled inflammatory response resulting in multi-organ failure and even death. Micheliolide (MCL), a sesquiterpene lactone, was reported to inhibit dextran sodium sulphate (DSS)-induced inflammatory intestinal disease, colitis-associated cancer and rheumatic arthritis. Nevertheless, the role of MCL in microbial infection and sepsis is unclear. We demonstrated that MCL decreased lipopolysaccharide (LPS, the main cell wall component of Gram-negative bacteria) mediated production of cytokines (IL-6, TNF-alpha, MCP-1, etc) in Raw264.7 cells, primary macrophages, dendritic cells and human monocytes. MCL plays an anti inflammatory role by inhibiting LPS-induced activation of NF-kappaB and PI3K/Akt/p70S6K pathways. It has negligible impact on the activation of mitogen activated protein kinase (MAPK) pathways. In the acute peritonitis mouse model, MCL reduced the secretion of IL-6, TNF-alpha, IL-1beta, MCP-1, IFN-beta and IL-10 in sera, and ameliorated lung and liver damage. MCL down-regulated the high mortality rate caused by lethal LPS challenge. Collectively, our data illustrated that MCL enabled maintenance of immune equilibrium may represent a potentially new anti-inflammatory and immunosuppressive drug candidate in the treatment of sepsis and septic shock. PMID- 26984740 TI - Metabolic and Inflammatory Adaptation of Reactive Astrocytes: Role of PPARs. AB - Astrocyte-mediated inflammation is associated with degenerative pathologies such as Alzheimer's and Parkinson's diseases and multiple sclerosis. The acute inflammation and morphological and metabolic changes that astrocytes develop after the insult are known as reactive astroglia or astrogliosis that is an important response to protect and repair the lesion. Astrocytes optimize their metabolism to produce lactate, glutamate, and ketone bodies in order to provide energy to the neurons that are deprived of nutrients upon insult. Firstly, we review the basis of inflammation and morphological changes of the different cell population implicated in reactive gliosis. Next, we discuss the more active metabolic pathways in healthy astrocytes and explain the metabolic response of astrocytes to the insult in different pathologies and which metabolic alterations generate complications in these diseases. We emphasize the role of peroxisome proliferator-activated receptors isotypes in the inflammatory and metabolic adaptation of astrogliosis developed in ischemia or neurodegenerative diseases. Based on results reported in astrocytes and other cells, we resume and hypothesize the effect of peroxisome proliferator-activated receptor (PPAR) activation with ligands on different metabolic pathways in order to supply energy to the neurons. The activation of selective PPAR isotype activity may serve as an input to better understand the role played by these receptors on the metabolic and inflammatory compensation of astrogliosis and might represent an opportunity to develop new therapeutic strategies against traumatic brain injuries and neurodegenerative diseases. PMID- 26984743 TI - Tissue growth constrained by extracellular matrix drives invagination during optic cup morphogenesis. AB - In the early embryo, the eyes form initially as relatively spherical optic vesicles (OVs) that protrude from both sides of the brain tube. Each OV grows until it contacts and adheres to the overlying surface ectoderm (SE) via an extracellular matrix (ECM) that is secreted by the SE and OV. The OV and SE then thicken and bend inward (invaginate) to create the optic cup (OC) and lens vesicle, respectively. While constriction of cell apices likely plays a role in SE invagination, the mechanisms that drive OV invagination are poorly understood. Here, we used experiments and computational modeling to explore the hypothesis that the ECM locally constrains the growing OV, forcing it to invaginate. In chick embryos, we examined the need for the ECM by (1) removing SE at different developmental stages and (2) exposing the embryo to collagenase. At relatively early stages of invagination (Hamburger-Hamilton stage HH14[Formula: see text]), removing the SE caused the curvature of the OV to reverse as it 'popped out' and became convex, but the OV remained concave at later stages (HH15) and invaginated further during subsequent culture. Disrupting the ECM had a similar effect, with the OV popping out at early to mid-stages of invagination (HH14[Formula: see text] to HH14[Formula: see text]). These results suggest that the ECM is required for the early stages but not the late stages of OV invagination. Microindentation tests indicate that the matrix is considerably stiffer than the cellular OV, and a finite-element model consisting of a growing spherical OV attached to a relatively stiff layer of ECM reproduced the observed behavior, as well as measured temporal changes in OV curvature, wall thickness, and invagination depth reasonably well. Results from our study also suggest that the OV grows relatively uniformly, while the ECM is stiffer toward the center of the optic vesicle. These results are consistent with our matrix-constraint hypothesis, providing new insight into the mechanics of OC (early retina) morphogenesis. PMID- 26984744 TI - Supratentorial clear cell ependymomas with branching capillaries demonstrate characteristic clinicopathological features and pathological activation of nuclear factor-kappaB signaling. AB - BACKGROUND: Clear cell ependymoma is one of the 4 main histological subtypes of ependymomas defined by the World Health Organization (WHO) classification of tumors of the CNS. DNA methylation profiling can distinguish 4 subgroups of intracranial ependymomas, including supratentorial (ST) ependymomas with Yes associated protein 1 fusion (YAP1), ST ependymomas with fusion of v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), posterior fossa ependymomas with balanced genome, and posterior fossa ependymomas with chromosomal instability. In addition, trisomy 19 is a genomic hallmark of ependymomas with rich branching capillaries. However, the relation of histological and molecular subtypes is unclear. METHODS: Here, we report a series of 20 ependymomas histologically defined by clear cells and branching capillaries. RESULTS: We observed a strong male predominance. Median age at surgery was 10.4 years (range, 0.8-68.4). All cases were ST, cortical, contrast enhancing, and most often frontal, cystic, and calcified. All tumors qualified as WHO grade III. Some of them exhibited neuronal differentiation. Trisomy 19 was recorded in 13 cases. All samples strongly accumulated p65RelA protein within nuclei, indicating pathological activation of the nuclear factor-kappaB pathway. We identified causative C11ORF95-RELA fusion in almost all cases. Median progression-free survival and overall survival were 11.4 years (95% CI: 5.1-17.8) and not reached, respectively. CONCLUSION: ST clear cell ependymomas with branching capillaries display characteristic clinicopathological features and are associated with pathological activation of nuclear factor-kappaB signaling, which may indicate a potential novel target for therapy in these patients. PMID- 26984747 TI - Spherical aberration reduction in nuclear cataracts. AB - PURPOSE: To measure higher-order aberrations (HOAs) in nuclear cataracts and to investigate spherical aberration changes with nuclear cataract progression. METHODS: A total of 102 eyes of older subjects (>50 years) were classified based on the nuclear opalescence (NO) grading of the Lens Opacities Classification System III: Group 1 (< NO2, 35), 2 (NO2, 23), 3 (NO3, 23), and 4 (>= NO 4:21 eyes). Wave front measurements were performed with a Hartmann-Shack aberrometer. To investigate lenticular spherical aberration, HOAs were examined in 28 eyes before and after phacoemulsification, followed by insertion of an aberration-free intraocular lens. The relationship between lens opacity grade and ocular and lenticular spherical aberrations were investigated. RESULTS: Mean spherical aberrations in groups 1, 2, 3, and 4 were 0.25 +/- 0.10, 0.16 +/- 0.13, 0.12 +/- 0.15, and 0.10 +/- 0.20 MUm, respectively, and showed a significant difference with nuclear opacity grading (p = 0.001). The spherical aberration showed negative associations with nuclear opacity grading (r = -0.408, p < 0.001). The predominant change in HOAs after phacoemulsification was an increase in spherical aberration, and 86 % of lenticular spherical aberrations were presumed to have negative values. The lenticular spherical aberration was negatively correlated with nuclear opacity severity (r = -0.409, p = 0.031). CONCLUSIONS: Ocular spherical aberration decreases with the progression of nuclear cataracts due to the negative correlation between lenticular spherical aberration and nuclear opacity severity. PMID- 26984746 TI - Whole-brain spectroscopic MRI biomarkers identify infiltrating margins in glioblastoma patients. AB - BACKGROUND: The standard of care for glioblastoma (GBM) is maximal safe resection followed by radiation therapy with chemotherapy. Currently, contrast-enhanced MRI is used to define primary treatment volumes for surgery and radiation therapy. However, enhancement does not identify the tumor entirely, resulting in limited local control. Proton spectroscopic MRI (sMRI), a method reporting endogenous metabolism, may better define the tumor margin. Here, we develop a whole-brain sMRI pipeline and validate sMRI metrics with quantitative measures of tumor infiltration. METHODS: Whole-brain sMRI metabolite maps were coregistered with surgical planning MRI and imported into a neuronavigation system to guide tissue sampling in GBM patients receiving 5-aminolevulinic acid fluorescence-guided surgery. Samples were collected from regions with metabolic abnormalities in a biopsy-like fashion before bulk resection. Tissue fluorescence was measured ex vivo using a hand-held spectrometer. Tissue samples were immunostained for Sox2 and analyzed to quantify the density of staining cells using a novel digital pathology image analysis tool. Correlations among sMRI markers, Sox2 density, and ex vivo fluorescence were evaluated. RESULTS: Spectroscopic MRI biomarkers exhibit significant correlations with Sox2-positive cell density and ex vivo fluorescence. The choline to N-acetylaspartate ratio showed significant associations with each quantitative marker (Pearson's rho = 0.82, P < .001 and rho = 0.36, P < .0001, respectively). Clinically, sMRI metabolic abnormalities predated contrast enhancement at sites of tumor recurrence and exhibited an inverse relationship with progression-free survival. CONCLUSIONS: As it identifies tumor infiltration and regions at high risk for recurrence, sMRI could complement conventional MRI to improve local control in GBM patients. PMID- 26984745 TI - Immune responses and outcome after vaccination with glioma-associated antigen peptides and poly-ICLC in a pilot study for pediatric recurrent low-grade gliomas. AB - BACKGROUND: Low-grade gliomas (LGGs) are the most common brain tumors of childhood. Although surgical resection is curative for well-circumscribed superficial lesions, tumors that are infiltrative or arise from deep structures are therapeutically challenging, and new treatment approaches are needed. Having identified a panel of glioma-associated antigens (GAAs) overexpressed in these tumors, we initiated a pilot trial of vaccinations with peptides for GAA epitopes in human leukocyte antigen-A2+ children with recurrent LGG that had progressed after at least 2 prior regimens. METHODS: Peptide epitopes for 3 GAAs (EphA2, IL 13Ralpha2, and survivin) were emulsified in Montanide-ISA-51 and administered subcutaneously adjacent to intramuscular injections of polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose every 3 weeks for 8 courses, followed by booster vaccines every 6 weeks. Primary endpoints were safety and T lymphocyte responses against GAA epitopes. Treatment response was evaluated clinically and by MRI. RESULTS: Fourteen children were enrolled. Other than grade 3 urticaria in one child, no regimen-limiting toxicity was encountered. Vaccination induced immunoreactivity to at least one vaccine-targeted GAA in all 12 evaluable patients: to IL-13Ralpha2 in 3, EphA2 in 11, and survivin in 3. One child with a metastatic LGG had asymptomatic pseudoprogression noted 6 weeks after starting vaccination, followed by dramatic disease regression with >75% shrinkage of primary tumor and regression of metastatic disease, persisting >57 months. Three other children had sustained partial responses, lasting >10, >31, and >45 months, and one had a transient response. CONCLUSIONS: GAA peptide vaccination in children with recurrent LGGs is generally well tolerated, with preliminary evidence of immunological and clinical activity. PMID- 26984750 TI - A case of pseudomyxoma peritonei: visualization of septa using diffusion-weighted images with low b values. AB - Pseudomyxoma peritonei (PMP) is a rare disease with neoplastic growth of mucin secreting cells in the peritoneal cavity, resulting in mucinous ascites. The septum of intra-abdominal fluid collection is a key imaging finding characteristic to PMP. In magnetic resonance imaging (MRI), multi-b value diffusion-weighted imaging (DWI) is a method used to obtain an accurate apparent diffusion coefficient. The clinical utilities of DWI using lower b values as diagnostic imaging are rarely highlighted. This report describes a case of PMP in which DWI using b values of 100 and 500 s/mm(2) exclusively visualized many thick septa with low signal intensity in peritoneal effusion. The septa could not be recognized in DWIs with b values of zero or 1000 s/mm(2), as with ultrasonography, computed tomography, and conventional MRI. A discrepancy between DWI using lower b values and other MRI sequences or imaging modalities indicates a specific capability of DWI using low b values: the ability to visualize septa of intra-abdominal fluid collection much thicker than in real cases. Results for this case suggest that DWI using low b values might present clinical potential for the preoperative diagnosis of PMP. PMID- 26984748 TI - Quantitative thermophoretic study of disease-related protein aggregates. AB - Amyloid fibrils are a hallmark of a range of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. A detailed understanding of the physico-chemical properties of the different aggregated forms of proteins, and of their interactions with other compounds of diagnostic or therapeutic interest, is crucial for devising effective strategies against such diseases. Protein aggregates are situated at the boundary between soluble and insoluble structures, and are challenging to study because classical biophysical techniques, such as scattering, spectroscopic and calorimetric methods, are not well adapted for their study. Here we present a detailed characterization of the thermophoretic behavior of different forms of the protein alpha-synuclein, whose aggregation is associated with Parkinson's disease. Thermophoresis is the directed net diffusional flux of molecules and colloidal particles in a temperature gradient. Because of their low volume requirements and rapidity, analytical methods based on this effect have considerable potential for high throughput screening for drug discovery. In this paper we rationalize and describe in quantitative terms the thermophoretic behavior of monomeric, oligomeric and fibrillar forms of alpha synuclein. Furthermore, we demonstrate that microscale thermophoresis (MST) is a valuable method for screening for ligands and binding partners of even such highly challenging samples as supramolecular protein aggregates. PMID- 26984749 TI - Life cycle of Amblyomma integrum (Acari: Ixodidae) under laboratory conditions. AB - Amblyomma integrum is a hard tick infesting mainly buffalo and cattle and has been identified as an agent of human otoacariasis in Sri Lanka. Data on the life cycle pattern of A. integrum were collected by experimental infestation on New Zealand white rabbits under laboratory conditions. Wild-caught females laid 55 7389 eggs for 2-35 days after spending a latent period of 10-25 days. Egg incubation period was 31-105 days and the newly emerged larvae started feeding after 4-11 days. Larvae dropped off after feeding and they moulted into nymphs after 10-16 days. Nymphs actively fed on rabbits for 4-8 days and dropped off. Engorged nymphs took 11-25 days for moulting before emerging as adults. The male:female sex ratio of the adults moulted under laboratory conditions was 11:9. All the stages showed periodicity in engorgement and dropping off. The three-host life cycle was completed within 74-245 days with an average of 152.9 days. The mean Reproductive Efficiency Index (REI) and Reproductive Aptitude Index (RAI) were 3.6 and 1.1, respectively. Females hatched in the laboratory did not successfully feed on New Zealand white rabbits. The wild-caught females which fed on buffaloes had prolonged pre-oviposition and oviposition periods, low REI, low RAI and low eclosion under controlled laboratory conditions compared to other tick species. Although larva and nymphs of A. integrum successfully fed on New Zealand white rabbits under laboratory conditions, full life cycle was not completed because the adult females did not feed on rabbits. PMID- 26984751 TI - A practical primer on PI-RADS version 2: a pictorial essay. AB - Multiparametric magnetic resonance imaging has become an established method for evaluating the prostate for clinically significant prostate adenocarcinoma. Criteria have been developed for categorizing MRI findings, the most frequently used of which is the PI-RADS system. The PI-RADS V2 document provides separate image interpretation and clinical grading sections. Within this article we give an overview of the integrated, algorithmic way, we approach prostate MRI, show images corresponding to each PI-RADS category, and provide several illustrative cases. PMID- 26984752 TI - Spatial proximity as a determinant of context-specific attentional settings. AB - People implicitly encode the history of conflict associated with particular contexts and use this information to modulate attention to distractors. This manifests as a reduction in the compatibility effect in mostly incompatible locations compared to mostly compatible locations, a difference termed the context-specific proportion compatibility (CSPC) effect. CSPC effects are explained by an episodic retrieval account positing that abstract attentional settings bind to contextual cues-allowing rapid, context-driven modulation of attention. The current study interrogated this binding process by testing the influence of relative spatial proximity on the association of attentional settings with particular locations. In Experiment 1, like typical CSPC paradigms, biased locations appeared near top (e.g., mostly compatible) and bottom (e.g., mostly incompatible) edges of the screen. A novel feature was the addition of two mostly compatible (above fixation) and two mostly incompatible (below fixation) locations placed within close proximity at the middle of the screen. A CSPC effect was found for outer but not middle mostly compatible and mostly incompatible locations, suggesting the attentional setting bound to the middle locations reflected the average history of conflict (i.e., 50 % compatible) for the group of middle locations. In Experiment 2, distance between middle locations was increased, allowing middle locations to group with outer locations. The CSPC effect was found for outer and middle mostly compatible and mostly incompatible locations. Results support the relative proximity hypothesis, positing that attentional settings bound to a particular location are influenced by experience within a location and relatively close neighboring locations. PMID- 26984753 TI - The Impact of the Project K Youth Development Program on Self-Efficacy: A Randomized Controlled Trial. AB - A key issue for youth development programs is whether the learning they provide is transferred to participants' daily lives. It is also important that they are effective for the diverse range of participants they attract. This study used a randomized controlled trial design to measure the impact of Project K, a New Zealand-based youth development program, on academic and social self-efficacy. Project K combines a 3-week wilderness adventure, a 10 day community service component, and 1 year of mentoring to promote positive growth in 14-15 year olds with low self-efficacy. At baseline, the evaluation included 600 Project K (46 % female) and 577 Control participants (48 % female) and revealed that Project K was effective in improving both social and academic self-efficacy from pre- to post-program with effects being sustained 1 year later. Parents' perceptions of changes in the participants' interpersonal skills supported these findings. Differential program effects were found across participant subgroups, particularly 1 year after program completion. The implications of these differences are discussed. PMID- 26984754 TI - Evaluating the Psychological Concomitants of Other-Sex Crush Experiences During Early Adolescence. AB - Very little empirical attention has been paid to other-sex crush experiences during adolescence. As a result, it is not known whether such experiences, which appear to be relatively common, impact psychological adjustment outcomes. This two-wave (3 month interval) longitudinal study of 268 young adolescents (48 % girls; M age at Time 1 = 11.84 years) examined the psychological concomitants of other-sex crush experiences (having and being viewed by others as a crush). Anxious-withdrawal and gender were evaluated as moderators. Peer nomination measures at Time 1 assessed both types of crush experiences and mutual friendship involvement, and participants completed self-report measures of loneliness and depressive symptoms at Times 1 and 2. The results from regression analyses revealed significant associations between having an other-sex crush and depressive symptoms at Time 1 and loneliness at Time 2, after accounting for the effects of mutual friendship. Two interaction effects also revealed that crush status was a risk factor for depressive symptoms at low levels of anxious withdrawal but a protective factor at high levels. The findings provide the first empirical evidence that other-sex crush experiences are developmentally significant during early adolescence. PMID- 26984756 TI - Natural Product Vibsanin A Induces Differentiation of Myeloid Leukemia Cells through PKC Activation. AB - All-trans retinoic acid (ATRA)-based cell differentiation therapy has been successful in treating acute promyelocytic leukemia, a unique subtype of acute myeloid leukemia (AML). However, other subtypes of AML display resistance to ATRA based treatment. In this study, we screened natural, plant-derived vibsane-type diterpenoids for their ability to induce differentiation of myeloid leukemia cells, discovering that vibsanin A potently induced differentiation of AML cell lines and primary blasts. The differentiation-inducing activity of vibsanin A was mediated through direct interaction with and activation of protein kinase C (PKC). Consistent with these findings, pharmacological blockade of PKC activity suppressed vibsanin A-induced differentiation. Mechanistically, vibsanin A mediated activation of PKC led to induction of the ERK pathway and decreased c Myc expression. In mouse xenograft models of AML, vibsanin A administration prolonged host survival and inhibited PKC-mediated inflammatory responses correlated with promotion of skin tumors in mice. Collectively, our results offer a preclinical proof of concept for vibsanin A as a myeloid differentiation inducing compound, with potential application as an antileukemic agent. Cancer Res; 76(9); 2698-709. (c)2016 AACR. PMID- 26984755 TI - Autophagy in Plasma Cell Ontogeny and Malignancy. AB - Autophagy is a highly conserved pathway that recycles cytosolic material and organelles via lysosomal degradation. Once simplistically viewed as a non selective survival strategy in dire straits, autophagy has emerged as a tightly regulated process ensuring organelle function, proteome plasticity, cell differentiation and tissue homeostasis, with key roles in physiology and disease. Selective target recognition, mediated by specific adapter proteins, enables autophagy to orchestrate highly specialized functions in innate and adaptive immunity. Among them, the shaping of plasma cells for sustainable antibody production through a negative control on their differentiation program. Moreover, memory B cells and long-lived plasma cells require autophagy to exist. Further, the plasma cell malignancy, multiple myeloma deploys abundant autophagy, essential for homeostasis, survival and drug resistance. PMID- 26984757 TI - An Epigenetic Reprogramming Strategy to Resensitize Radioresistant Prostate Cancer Cells. AB - Radiotherapy is a mainstay of curative prostate cancer treatment, but risks of recurrence after treatment remain significant in locally advanced disease. Given that tumor relapse can be attributed to a population of cancer stem cells (CSC) that survives radiotherapy, analysis of this cell population might illuminate tactics to personalize treatment. However, this direction remains challenging given the plastic nature of prostate cancers following treatment. We show here that irradiating prostate cancer cells stimulates a durable upregulation of stem cell markers that epigenetically reprogram these cells. In both tumorigenic and radioresistant cell populations, a phenotypic switch occurred during a course of radiotherapy that was associated with stable genetic and epigenetic changes. Specifically, we found that irradiation triggered histone H3 methylation at the promoter of the CSC marker aldehyde dehydrogenase 1A1 (ALDH1A1), stimulating its gene transcription. Inhibiting this methylation event triggered apoptosis, promoted radiosensitization, and hindered tumorigenicity of radioresistant prostate cancer cells. Overall, our results suggest that epigenetic therapies may restore the cytotoxic effects of irradiation in radioresistant CSC populations. Cancer Res; 76(9); 2637-51. (c)2016 AACR. PMID- 26984761 TI - Photoprecursor Approach Enables Preparation of Well-Performing Bulk Heterojunction Layers Comprising a Highly Aggregating Molecular Semiconductor. AB - Active-layer morphology critically affects the performance of organic photovoltaic cells, and thus its optimization is a key toward the achievement of high-efficiency devices. However, the optimization of active-layer morphology is sometimes challenging because of the intrinsic properties of materials such as strong self-aggregating nature or low miscibility. This study postulates that the "photoprecursor approach" can serve as an effective means to prepare well performing bulk-heterojunction (BHJ) layers containing highly aggregating molecular semiconductors. In the photoprecursor approach, a photoreactive precursor compound is solution-deposited and then converted in situ to a semiconducting material. This study employs 2,6-di(2-thienyl)anthracene (DTA) and [6,6]-phenyl-C71-butyric acid methyl ester as p- and n-type materials, respectively, in which DTA is generated by the photoprecursor approach from the corresponding alpha-diketone-type derivative DTADK. When only chloroform is used as a cast solvent, the photovoltaic performance of the resulting BHJ films is severely limited because of unfavorable film morphology. The addition of a high boiling-point cosolvent, o-dichlorobenzene (o-DCB), to the cast solution leads to significant improvement such that the resulting active layers afford up to approximately 5 times higher power conversion efficiencies. The film structure is investigated by two-dimensional grazing-incident wide-angle X-ray diffraction, atomic force microscopy, and fluorescence microspectroscopy to demonstrate that the use of o-DCB leads to improvement in film crystallinity and increase in charge-carrier generation efficiency. The change in film structure is assumed to originate from dynamic molecular motion enabled by the existence of solvent during the in situ photoreaction. The unique features of the photoprecursor approach will be beneficial in extending the material and processing scopes for the development of organic thin-film devices. PMID- 26984759 TI - Measurement of Endogenous versus Exogenous Formaldehyde-Induced DNA-Protein Crosslinks in Animal Tissues by Stable Isotope Labeling and Ultrasensitive Mass Spectrometry. AB - DNA-protein crosslinks (DPC) arise from a wide range of endogenous and exogenous chemicals, such as chemotherapeutic drugs and formaldehyde. Importantly, recent identification of aldehydes as endogenous genotoxins in Fanconi anemia has provided new insight into disease causation. Because of their bulky nature, DPCs pose severe threats to genome stability, but previous methods to measure formaldehyde-induced DPCs were incapable of discriminating between endogenous and exogenous sources of chemical. In this study, we developed methods that provide accurate and distinct measurements of both exogenous and endogenous DPCs in a structurally specific manner. We exposed experimental animals to stable isotope labeled formaldehyde ([(13)CD2]-formaldehyde) by inhalation and performed ultrasensitive mass spectrometry to measure endogenous (unlabeled) and exogenous ((13)CD2-labeled) DPCs. We found that exogenous DPCs readily accumulated in nasal respiratory tissues but were absent in tissues distant to the site of contact. This observation, together with the finding that endogenous formaldehyde-induced DPCs were present in all tissues examined, suggests that endogenous DPCs may be responsible for increased risks of bone marrow toxicity and leukemia. Furthermore, the slow rate of DPC repair provided evidence for the persistence of DPCs. In conclusion, our method for measuring endogenous and exogenous DPCs presents a new perspective for the potential health risks inflicted by endogenous formaldehyde and may inform improved disease prevention and treatment strategies. Cancer Res; 76(9); 2652-61. (c)2016 AACR. PMID- 26984758 TI - HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors. AB - The stress-inducible chaperone protein HSP70 (HSPA1) is implicated in melanoma development, and HSP70 inhibitors exert tumor-specific cytotoxic activity in cancer. In this study, we documented that a significant proportion of melanoma tumors express high levels of HSP70, particularly at advanced stages, and that phospho-FAK (PTK2) and BRAF are HSP70 client proteins. Treatment of melanoma cells with HSP70 inhibitors decreased levels of phospho-FAK along with impaired migration, invasion, and metastasis in vitro and in vivo Moreover, the HSP70 inhibitor PET-16 reduced levels of mutant BRAF, synergized with the BRAF inhibitor PLX4032 in vitro, and enhanced the durability of response to BRAF inhibition in vivo Collectively, these findings provide strong support for HSP70 inhibition as a therapeutic strategy in melanoma, especially as an adjuvant approach for overcoming the resistance to BRAF inhibitors frequently observed in melanoma patients. Cancer Res; 76(9); 2720-30. (c)2016 AACR. PMID- 26984762 TI - Erratum. PMID- 26984760 TI - Reconstruction of thermotolerant yeast by one-point mutation identified through whole-genome analyses of adaptively-evolved strains. AB - Saccharomyces cerevisiae is used as a host strain in bioproduction, because of its rapid growth, ease of genetic manipulation, and high reducing capacity. However, the heat produced during the fermentation processes inhibits the biological activities and growth of the yeast cells. We performed whole-genome sequencing of 19 intermediate strains previously obtained during adaptation experiments under heat stress; 49 mutations were found in the adaptation steps. Phylogenetic tree revealed at least five events in which these strains had acquired mutations in the CDC25 gene. Reconstructed CDC25 point mutants based on a parental strain had acquired thermotolerance without any growth defects. These mutations led to the downregulation of the cAMP-dependent protein kinase (PKA) signaling pathway, which controls a variety of processes such as cell-cycle progression and stress tolerance. The one-point mutations in CDC25 were involved in the global transcriptional regulation through the cAMP/PKA pathway. Additionally, the mutations enabled efficient ethanol fermentation at 39 degrees C, suggesting that the one-point mutations in CDC25 may contribute to bioproduction. PMID- 26984763 TI - Proteomic identification of potential cancer markers in human urine using subtractive analysis. AB - Urine is an ideal medium in which to focus diagnostic cancer research due to the non-invasive nature and ease of sampling. Many large-scale proteomic studies have shown that urine is unexpectedly complex. We hypothesised that novel diagnostic cancer biomarkers could be discovered using a comparative proteomic analysis of pre-existing data. We assembled a database of 100 published datasets of 5,620 urinary proteins, as well as 46 datasets of 8,620 non-redundant proteins derived from kidney and blood proteome analyses. The data were then used to either subtract or compare molecules from a novel urinary proteome profiling dataset that we generated. We identified 1,161 unique proteins in samples from either cancer-bearing or healthy subjects. Subtractive analysis yielded a subset of 44 proteins that were found uniquely in urine from cancer patients, 30 of which were linked previously to cancer. In conclusion, this approach is useful in discovering novel biomarkers in tissues where unrelated profiling data is available. Only a limited disease-specific novel dataset is required to define new targets or substantiate previous findings. We have shared this discovery platform in the form of our Large Scale Screening Resource database, accessible through the Proteomic Analysis DataBase portal (www.PADB.org). PMID- 26984764 TI - Enhanced charge separation of rutile TiO2 nanorods by trapping holes and transferring electrons for efficient cocatalyst-free photocatalytic conversion of CO2 to fuels. AB - Modification with chloride and phosphate anions, and coupling with carbon nanotubes could effectively trap holes and transfer the electrons of rutile nanorods, respectively, so as to greatly promote photogenerated charge separation, leading to an obviously-improved cocatalyst-free photocatalytic conversion of CO2 to CH4 and CO, along with the positive effects of constructed phosphate bridges. PMID- 26984765 TI - Carbonate Doping in TiO2 Microsphere: The Key Parameter Influencing Others for Efficient Dye Sensitized Solar Cell. AB - Four key parameters namely light trapping, density of light harvesting centre, photoinduced electron injection and electron transport without self-recombination are universally important across all kinds of solar cells. In the present study, we have considered the parameters in the context of a model Dye Sensitized Solar Cell (DSSC). Our experimental studies reveal that carbonate doping of TiO2 mesoporous microspheres (doped MS) makes positive influence to all the above mentioned key parameters responsible for the enhanced solar cell efficiency. A simple method has been employed to synthesize the doped MS for the photoanode of a N719 (ruthenium dye)-based DSSC. A detail electron microscopy has been used to characterize the change in morphology of the MS upon doping. The optical absorption spectrum of the doped MS reveals significant shift of TiO2 (compared to that of the MS without doping) towards maximum solar radiance (~500 nm) and the excellent scattering in the entire absorption band of the sensitizing dye (N719). Finally, and most importantly, for the first time we have demonstrated that the solar cells with doped MS offers better efficiency (7.6%) in light harvesting compared to MS without doping (5.2%) and also reveal minimum self recombination of photoelectrons in the redox chain. PMID- 26984767 TI - Pink Ribbons and Red Dresses: A Mixed Methods Content Analysis of Media Coverage of Breast Cancer and Heart Disease. AB - This research examined media coverage of breast cancer (n = 145) and heart disease and stroke (n = 39) news articles, videos, advertisements, and images in a local Canadian context through quantitative and thematic content analyses. Quantitative analysis revealed significant differences between coverage of the diseases in placement, survivors as a source of information, health agency, human interest stories, citation of a research study, the inclusion of risk statistics, discussion of preventative behaviors, and tone used. The thematic analysis revealed themes that characterized a "typical" breast cancer survivor and indicated that "good" citizens and businesses should help the cause of breast cancer. Themes for heart disease and stroke articulated individual responsibility and the ways fundraising reinforced femininity and privilege. Findings provide insight on how these diseases are framed in local Canadian media, which might impact an individual's understanding of the disease. PMID- 26984768 TI - Enhanced superconductivity in atomically thin TaS2. AB - The ability to exfoliate layered materials down to the single layer limit has presented the opportunity to understand how a gradual reduction in dimensionality affects the properties of bulk materials. Here we use this top-down approach to address the problem of superconductivity in the two-dimensional limit. The transport properties of electronic devices based on 2H tantalum disulfide flakes of different thicknesses are presented. We observe that superconductivity persists down to the thinnest layer investigated (3.5 nm), and interestingly, we find a pronounced enhancement in the critical temperature from 0.5 to 2.2 K as the layers are thinned down. In addition, we propose a tight-binding model, which allows us to attribute this phenomenon to an enhancement of the effective electron-phonon coupling constant. This work provides evidence that reducing the dimensionality can strengthen superconductivity as opposed to the weakening effect that has been reported in other 2D materials so far. PMID- 26984769 TI - Testing the Efficacy of Attention Bias Modification for Suicidal Thoughts: Findings From Two Experiments. AB - This study explores whether four sessions of attention bias modification (ABM) decreases suicide-specific attentional bias. We conducted two experiments where suicide ideators completed either a Training or Control version of ABM, a computer-based intervention intended to target attentional bias. Suicide-specific attentional bias was measured using adapted Stroop and probe discrimination tasks. The first experiment with community-based suicide ideators did not show that ABM impacts attentional bias or suicidal ideation. The second experiment with clinically severe suicidal inpatients yielded similar results. Post-hoc findings suggest that the type of attentional bias targeted by the current intervention may differ from the type that marks suicide risk. There remains little to no evidence that the ABM intervention changes suicide-specific attentional bias or suicidal ideation. PMID- 26984766 TI - Clinical significance of the expression of autophagy-associated marker, beclin 1, in breast cancer patients who received neoadjuvant endocrine therapy. AB - BACKGROUND: Neoadjuvant endocrine therapy (NAE) has been employed to improve surgical outcomes for hormone receptor-positive breast cancers in postmenopausal women. Endocrine responsiveness is estimated by expressions of hormone receptors, but its heterogeneity has been recognized. Autophagy is an evolutionally conserved process associated with cell survival and cell death and has been implicated in cancer treatment. METHODS: In order to examine the possible association between autophagy and response to endocrine therapy, we evaluated the status of autophagy-associated markers, beclin 1 and LC3, and apoptosis associated markers, TUNEL and M30, in pre- and post-treatment specimens from 71 patients in a multicenter prospective study of neoadjuvant exemestane (JFMC34 0601). RESULTS: Immunoreactivity of the autophagy-associated markers, beclin 1 and LC3, in carcinoma cells increased in 14% and 52% of the patients, respectively, following the exemestane treatment. These increases were statistically significant (beclin 1, p = 0.016, N = 49; LC3, p < 0.0001, N = 33). The status of M30 immunoreactivity decreased (p = 0.008, N = 47) and TUNEL remained unchanged (N = 53). In addition, tumors with pre-treatment stromal beclin 1 immunoreactivity revealed poor clinical and pathological responses compared with those without stromal beclin 1 immunoreactivity (25% vs 67% for clinical response, p = 0.011, N = 51; 0% vs 41% for pathological response, p = 0.0081, N = 49). Tumors with positive pre-treatment stromal beclin 1 had a higher baseline Ki-67 labeling index (both hot spot and overall average) than those without (p = 0.042 and 0.0075, respectively, N = 53). Results of logistic regression analyses revealed that stromal beclin 1 was a predictor for clinical and pathological responses while ER, PR, Ki-67, and stromal LC3 expressions were not. CONCLUSIONS: Results of our present study demonstrated that beclin 1 and LC3 immunoreactivity increased in carcinoma cells following exemestane treatment and that the status of pre-treatment stromal beclin 1 is associated with higher carcinoma cell proliferation and poor clinical and pathological responses to NAE. TRIAL REGISTRATION: UMIN C000000345 (2006/03/06). PMID- 26984770 TI - The P42 peptide and Peptide-based therapies for Huntington's disease. AB - Huntington's disease (HD) is a progressive neurodegenerative hereditary disease clinically characterised by the presence of involuntary movements, behavioural problems and cognitive decline. The disease-onset is usually between 30 and 50 years of age. HD is a rare disorder affecting approximately 1.3 in 10,000 people in the European Union. It is caused by an expanded CAG repeat in the first exon of the Huntingtin (HTT) gene, leading to an abnormal form of the Huntingtin protein (Htt) (polyQHtt), containing N-terminus, enlarged polyglutamine strands of variable length that stick together to form aggregates and nuclear inclusions in the damaged brain cells. Treatments currently used for Huntington's disease are symptomatic and aimed at temporally relieving the symptoms of the disease; although some promising therapies are on study, there is no drug capable of stopping disease progression either in the form of delaying onset or slowing disability progression. The utilization of peptides interacting with polyQ stretches or with Htt protein to prevent misfolding and aggregation of the expanded polyQ protein is a fascinating idea, because of low potential toxicity and ability to target very initial steps in the pathophysiological cascade of the disease, such as aggregation or cleavage process. Indeed, several therapeutic peptides have been developed and were found to significantly slow down the progression of symptoms in experimental models of Huntington's disease. This review is essentially focusing on the latest development concerning peptide strategy. In particular, we focused on a 23aa peptide P42, which is a part of the Htt protein. It is expected to work principally by preventing the abnormal Htt protein from sticking together, thereby preventing pathological consequences of aggregation and improving the symptoms of the disease. In the meantime, as P42 is part of the Htt protein, some therapeutic properties might be linked to the physiological actions of the peptide itself, considered as a functional domain of the Htt protein. PMID- 26984771 TI - Low Plasma Levels of Adiponectin Do Not Explain Acute Respiratory Distress Syndrome Risk: a Prospective Cohort Study of Patients with Severe Sepsis. AB - BACKGROUND: Obesity is associated with the development of acute respiratory distress syndrome (ARDS) in at-risk patients. Low plasma levels of adiponectin, a circulating hormone-like molecule, have been implicated as a possible mechanism for this association. The objective of this study was to determine the association of plasma adiponectin level at ICU admission with ARDS and 30-day mortality in patients with severe sepsis and septic shock. METHODS: This is a prospective cohort study of patients admitted to the medical ICU at the Hospital of the University of Pennsylvania. Plasma adiponectin was measured at the time of ICU admission. ARDS was defined by Berlin criteria. Multivariable logistic regression was used to determine the association of plasma adiponectin with the development of ARDS and mortality at 30 days. RESULTS: The study included 164 patients. The incidence of ARDS within 5 days of admission was 45%. The median initial plasma adiponectin level was 7.62 mcg/ml (IQR: 3.87, 14.90) in those without ARDS compared to 8.93 mcg/ml (IQR: 4.60, 18.85) in those developing ARDS. The adjusted odds ratio for ARDS associated with each 5 mcg increase in adiponectin was 1.12 (95% CI 1.01, 1.25), p-value 0.025). A total of 82 patients (51%) of the cohort died within 30 days of ICU admission. There was a statistically significant association between adiponectin and mortality in the unadjusted model (OR 1.11, 95% CI 1.00, 1.23, p-value 0.04) that was no longer significant after adjusting for potential confounders. CONCLUSIONS: In this study, low levels of adiponectin were not associated with an increased risk of ARDS in patients with severe sepsis and septic shock. This argues against low levels of adiponectin as a mechanism explaining the association of obesity with ARDS. At present, it is unclear whether circulating adiponectin is involved in the pathogenesis of ARDS or simply represents an epiphenomenon of other unknown functions of adipose tissue or metabolic alterations in sepsis. PMID- 26984774 TI - Expression of ATP6V1C1 during oral carcinogenesis. AB - We investigated the gene and protein expressions of V-type ATPase protein subunit C1 (ATP6V1C1) in cases of oral squamous cell carcinoma (OSCC) and contralateral normal mucosa in smokers, nonsmokers and former smokers. Subjects were separated into five groups of 15: group 1, smokers with OSCC; group 2, normal contralateral mucosa of OSCC patients; group 3, chronic smokers; group 4, former smokers who had stopped smoking 1 year earlier; group 5, individuals who had never smoked. Exfoliative cytology specimens from oral mucosa of smokers, former smokers and nonsmokers showed normal gene and protein expression. We found significantly greater gene expression in the OSCC group than in the nonsmoker groups. No difference in gene expression was observed between normal contralateral mucosa and nonsmoker groups, smoker and nonsmoker groups or former smoker and nonsmoker groups. We observed intense immunostaining for ATP6V1C1 protein in all cases of OSCC and weak or no staining in smoker, former smoker and nonsmoker groups. Significantly greater expression of ATP6V1C1 protein was observed in the OSCC group compared to the other groups, which supports the role of ATP6V1C1 in effecting changes associated with oral cancer. Analysis of the mucosae of chronic smokers, former smokers and the normal contralateral mucosa of patients with OSCC showed unaltered ATP6V1C1 gene and protein expression. Early stages of carcinogenesis, represented by altered epithelium of chronic smokers, had neither gene nor protein alterations as seen in OSCC. Therefore, we infer that the changes in ATP6V1C1 occur during later stages of carcinogenesis. Our preliminary study provides a basis for future studies of using ATP6V1C1 levels for detecting early stage OSCC. PMID- 26984772 TI - Mesodermal ALK5 controls lung myofibroblast versus lipofibroblast cell fate. AB - BACKGROUND: Epithelial-mesenchymal cross talk is centerpiece in the development of many branched organs, including the lungs. The embryonic lung mesoderm provides instructional information not only for lung architectural development, but also for patterning, commitment and differentiation of its many highly specialized cell types. The mesoderm also serves as a reservoir of progenitors for generation of differentiated mesenchymal cell types that include alphaSMA expressing fibroblasts, lipofibroblasts, endothelial cells and others. Transforming Growth Factor beta (TGFbeta) is a key signaling pathway in epithelial-mesenchymal cross talk. Using a cre-loxP approach we have elucidated the role of the TGFbeta type I receptor tyrosine kinase, ALK5, in epithelial mesenchymal cross talk during lung morphogenesis. RESULTS: Targeted early inactivation of Alk5 in mesodermal progenitors caused abnormal development and maturation of the lung that included reduced physical size of the sub-mesothelial mesoderm, an established source of specific mesodermal progenitors. Abrogation of mesodermal ALK5-mediated signaling also inhibited differentiation of cell populations in the epithelial and endothelial lineages. Importantly, Alk5 mutant lungs contained a reduced number of alphaSMA(pos) cells and correspondingly increased lipofibroblasts. Elucidation of the underlying mechanisms revealed that through direct and indirect modulation of target signaling pathways and transcription factors, including PDGFRalpha, PPARgamma, PRRX1, and ZFP423, ALK5 mediated TGFbeta controls a process that regulates the commitment and differentiation of alphaSMA(pos) versus lipofibroblast cell populations during lung development. CONCLUSION: ALK5-mediated TGFbeta signaling controls an early pathway that regulates the commitment and differentiation of alphaSMA(pos) versus LIF cell lineages during lung development. PMID- 26984775 TI - A New Year, a new look for Avian Pathology and a special issue on necrotic enteritis. PMID- 26984773 TI - Setting targets for human resources for eye health in sub-Saharan Africa: what evidence should be used? AB - With a global target set at reducing vision loss by 25% by the year 2019, sub Saharan Africa with an estimated 4.8 million blind persons will require human resources for eye health (HReH) that need to be available, appropriately skilled, supported, and productive. Targets for HReH are useful for planning, monitoring, and resource mobilization, but they need to be updated and informed by evidence of effectiveness and efficiency. Supporting evidence should take into consideration (1) ever-changing disease-specific issues including the epidemiology, the complexity of diagnosis and treatment, and the technology needed for diagnosis and treatment of each condition; (2) the changing demands for vision-related services of an increasingly urbanized population; and (3) interconnected health system issues that affect productivity and quality. The existing targets for HReH and some of the existing strategies such as task shifting of cataract surgery and trichiasis surgery, as well as the scope of eye care interventions for primary eye care workers, will need to be re-evaluated and re-defined against such evidence or supported by new evidence. PMID- 26984782 TI - Adsorption of a single gold or silver atom on vanadium oxide clusters. AB - The bonding properties between a single atom and its support have a close relationship with the stability and reactivity of single-atom catalysts. As a model system, the structural and electronic properties of bimetallic oxide clusters MV3Oy(q) (M = Au or Ag, q = 0, +/-1, and y = 6-8) are systematically studied using density functional theory. The single noble metal atom Au or Ag tends to be adsorbed on the periphery of the V oxide clusters. Au prefers V sites for oxygen-poor clusters and O sites for oxygen-rich clusters, while Ag prefers O sites for most cases. According to natural population analysis, Au may possess positive or negative charges in the bimetallic oxide clusters, while Ag usually possesses positive charges. The bonding between Au and V has relatively high covalent character according to the bond order analysis. This work may provide some clues for understanding the bonding properties of single noble metal atoms on the support in practical single-atom catalysts, and serve as a starting point for further theoretical studies on the reaction mechanisms of related catalytic systems. PMID- 26984779 TI - Epidemiology of antimicrobial resistance in bloodstream infections. AB - Antimicrobial resistance in bacterial pathogens is a worldwide challenge leading high morbidity and mortality in clinical settings. Multidrug resistant patterns in gram-positive and -negative bacteria have resulted in difficult-to-treat or even untreatable infections with conventional antimicrobials. Since the early identification of causative microorganisms and their antimicrobial susceptibility patterns in patients with bacteremia and other serious infections is lacking in many healthcare institutions, broad spectrum antibiotics are liberally and mostly unnecessarily used. Such practice has, in turn, caused dramatic increases in emerging resistance and when coupled with poor practice of infection control, resistant bacteria can easily be disseminated to the other patients and the environment. Thus, availability of updated epidemiological data on antimicrobial resistance in frequently encountered bacterial pathogens will be useful not only for deciding on empirical treatment strategies, but also devising an effective antimicrobial stewardship program in hospitals. PMID- 26984783 TI - Factors Associated with Willingness to Use Mental Health Services in Korean Immigrants. AB - Responding to the concern about underutilization of mental health services in immigrant populations, the present study explored the factors associated with Korean immigrants' willingness to use mental health services. Guided by Andersen's behavioral model, consideration was given to the role of predisposing (age, gender, marital status, education, and years in the United States), need (depressive symptoms), and enabling (health insurance, acculturation, and personal beliefs about depression) variables. The study estimated, using data from a sample of 205 Korean immigrants (ages 18-45), a logistic regression model of willingness to use mental health services. Although participants experiencing more depressive symptoms tend to be less willing to use these services (odds ratio [OR] = .89, p < .05), an increase in the odds of willingness to use them are found among women (OR = 2.52, p < .01), highly acculturated individuals (OR = 1.09, p < .05), and individuals who believe that depression is a medical condition (OR = 4.71, p < .01). Educational interventions focused on increasing mental health literacy may be beneficial in promoting mental health services for Korean immigrants. PMID- 26984781 TI - First Morphological and Molecular Evidence of the Negative Impact of Diatom Derived Hydroxyacids on the Sea Urchin Paracentrotus lividus. AB - Oxylipins (including polyunsaturated aldehydes [PUAs], hydoxyacids, and epoxyalcohols) are the end-products of a lipoxygenase/hydroperoxide lyase metabolic pathway in diatoms. To date, very little information is available on oxylipins other than PUAs, even though they represent the most common oxylipins produced by diatoms. Here, we report, for the first time, on the effects of 2 hydroxyacids, 5- and 15-HEPE, which have never been tested before, using the sea urchin Paracentrotus lividus as a model organism. We show that HEPEs do induce developmental malformations but at concentrations higher when compared with PUAs. Interestingly, HEPEs also induced a marked developmental delay in sea urchin embryos, which has not hitherto been reported for PUAs. Recovery experiments revealed that embryos do not recover following treatment with HEPEs. Finally, we report the expression levels of 35 genes (involved in stress, development, differentiation, skeletogenesis, and detoxification processes) to identify the molecular targets affected by HEPEs. We show that the 2 HEPEs have very few common molecular targets, specifically affecting different classes of genes and at different times of development. In particular, 15-HEPE switched on fewer genes than 5-HEPE, upregulating mainly stress-related genes at a later pluteus stage of development. 5-HEPE was stronger than 15-HEPE, targeting 24 genes, mainly at the earliest stages of embryo development (at the blastula and swimming blastula stages). These findings highlight the differences between HEPEs and PUAs and also have important ecological implications because many diatom species do not produce PUAs, but rather these other chemicals are derived from the oxidation of fatty acids. PMID- 26984784 TI - Altered social attention in anorexia nervosa during real social interaction. AB - The capacity to devote attentional resources in response to body-related signals provided by others is still largely unexplored in individuals with Anorexia Nervosa (AN). Here, we tested this capacity through a novel paradigm that mimics a social interaction with a real partner. Healthy individuals (Experiment 1) and individuals with AN (Experiment 2) completed a task with another person which consisted in performing, alternatively, rapid aiming movements to lateralised targets. Generally, this task leads to a form of Inhibition of Return (IOR), which consists of longer reaction times when an individual has to respond to a location previously searched by either himself (individual IOR) or by the partner (social IOR) as compared to previously unexplored locations. IOR is considered as an important attentional mechanism that promotes an effective exploration of the environment during social interaction. Here, healthy individuals displayed both individual and social IOR that were both reliable and of the same magnitude. Individuals with AN displayed a non-significant individual IOR but a reliable social IOR that was also significantly stronger than individual IOR. These results suggest the presence of a reduced sensitivity in processing body-related stimuli conveyed by oneself in individuals with AN which is reflected in action based attentional processes. PMID- 26984785 TI - Completeness of Neisseria meningitidis reporting in New York City, 1989-2010. AB - Invasive meningococcal disease (IMD) completeness of reporting has never been assessed in New York City (NYC). We conducted a capture-recapture study to assess completeness of reporting, comparing IMD reports made to the NYC Department of Health and Mental Hygiene (DOHMH) and records identified in the New York State hospital discharge database [Statewide Planning and Research Cooperative System (SPARCS)] by ICD-9 codes from 1989 to 2010. Reporting completeness estimates were calculated for the entire study period, and stratified by year, age group, clinical syndrome, and reporting system. A chart review of hospital medical records from 2008 to 2010 was conducted to validate hospital coding and to adjust completeness estimates. Overall, 2194 unique patients were identified from DOHMH (n = 1300) and SPARCS (n = 1525); 631 (29%) were present in both. Completeness of IMD reporting was 41% [95% confidence interval (CI) 40-43]. Differences in completeness were found by age, clinical syndrome, and reporting system. The chart review found 33% of hospital records from 2008 to 2010 had no documentation of IMD. Removal of those records improved completeness of reporting to 51% (95% CI 49-53). Our data showed a low concordance between what is reported to DOHMH and what is coded by hospitals as IMD. Additional guidance to clinicians on IMD reporting criteria may improve completeness of IMD reporting. PMID- 26984780 TI - Activation of Constitutive Androstane Receptor (CAR) in Mice Results in Maintained Biliary Excretion of Bile Acids Despite a Marked Decrease of Bile Acids in Liver. AB - Activation of Constitutive Androstane Receptor (CAR) protects against bile acid (BA)-induced liver injury. This study was performed to determine the effect of CAR activation on bile flow, BA profile, as well as expression of BA synthesis and transport genes. Synthetic CAR ligand 1,4-bis-[2-(3,5 dichloropyridyloxy)]benzene (TCPOBOP) was administered to mice for 4 days. BAs were quantified by UPLC-MS/MS (ultraperformance liquid chromatography-tandem mass spectrometry). CAR activation decreases total BAs in livers of male (49%) and female mice (26%), largely attributable to decreases of the 12alpha-hydroxylated BA taurocholic acid (T-CA) (males (M) 65%, females (F) 45%). Bile flow in both sexes was increased by CAR activation, and the increases were BA-independent. CAR activation did not alter biliary excretion of total BAs, but overall BA composition changed. Excretion of muricholic (6-hydroxylated) BAs was increased in males (101%), and the 12alpha-OH proportion of biliary BAs was decreased in both males (37%) and females (28%). The decrease of T-CA in livers of males and females correlates with the decreased mRNA of the sterol 12alpha-hydroxylase Cyp8b1 in males (71%) and females (54%). As a response to restore BAs to physiologic concentrations in liver, mRNA of Cyp7a1 is upregulated following TCPOBOP (males 185%, females 132%). In ilea, mRNA of the negative feedback regulator Fgf15 was unaltered by CAR activation, indicating biliary BA excretion was sufficient to maintain concentrations of total BAs in the small intestine. In summary, the effects of CAR activation on BAs in male and female mice are quite similar, with a marked decrease in the major BA T-CA in the liver. PMID- 26984786 TI - Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design. AB - The discovery and optimization of non-nucleoside dengue viral RNA-dependent-RNA polymerase (RdRp) inhibitors are described. An X-ray-based fragment screen of Novartis' fragment collection resulted in the identification of a biphenyl acetic acid fragment 3, which bound in the palm subdomain of RdRp. Subsequent optimization of the fragment hit 3, relying on structure-based design, resulted in a >1000-fold improvement in potency in vitro and acquired antidengue activity against all four serotypes with low micromolar EC50 in cell-based assays. The lead candidate 27 interacts with a novel binding pocket in the palm subdomain of the RdRp and exerts a promising activity against all clinically relevant dengue serotypes. PMID- 26984788 TI - Harmonizing routinely collected health information for strengthening quality management in health systems: requirements and practice. AB - OBJECTIVE: Our aim was to specify the requirements of an architecture to serve as the foundation for standardized reporting of health information and to provide an exemplary application of this architecture. METHODS: The World Health Organization's International Classification of Functioning, Disability and Health (ICF) served as the conceptual framework. Methods to establish content comparability were the ICF Linking Rules. The Rasch measurement model, as a special case of additive conjoint measurement, which satisfies the required criteria for fundamental measurement, allowed for the development of a common metric foundation for measurement unit conversion. Secondary analysis of data from the North Yorkshire Survey was used to illustrate these methods. Patients completed three instruments and the items were linked to the ICF. The Rasch measurement model was applied, first to each scale, and then to items across scales which were linked to a common domain. RESULTS: Based on the linking of items to the ICF, the majority of items were grouped into two domains, Mobility and Self-care. Analysis of the individual scales and of items linked to a common domain across scales satisfied the requirements of the Rasch measurement model. The measurement unit conversion between items from the three instruments linked to the Mobility and Self-care domains, respectively, was demonstrated. CONCLUSIONS: The realization of an ICF-based architecture for information on patients' functioning enables harmonization of health information while allowing clinicians and researchers to continue using their existing instruments. This architecture will facilitate access to comprehensive and consistently reported health information to serve as the foundation for informed decision-making. PMID- 26984787 TI - The role of Fas-associated phosphatase 1 in leukemia stem cell persistence during tyrosine kinase inhibitor treatment of chronic myeloid leukemia. AB - Chronic myeloid leukemia (CML) is characterized by expression of Bcr-abl, a tyrosine kinase oncogene. Clinical outcomes in CML were revolutionized by development of Bcr-abl-targeted tyrosine kinase inhibitors (TKIs), but CML is not cured by these agents. CML leukemia stem cells (LSCs) are relatively TKI insensitive and persist even in remission. LSC persistence results in relapse upon TKI discontinuation, or drug resistance or blast crisis (BC) during prolonged treatment. We hypothesize that increased expression of Fas-associated phosphatase 1 (Fap1) in CML contributes to LSC persistence and BC. As Fap1 substrates include Fas and glycogen synthase kinase-3beta (Gsk3beta), increased Fap1 activity in CML is anticipated to induce Fas resistance and stabilization of beta-catenin protein. Resistance to Fas-induced apoptosis may contribute to CML LSC persistence, and beta-catenin activity increases during BC. In the current study, we directly tested the role of Fap1 in CML LSC persistence using in an in vivo murine model. In TKI-treated mice, we found that inhibiting Fap1, using a tripeptide or small molecule, prevented TKI resistance, BC and relapse after TKI discontinuation; all events observed with TKI alone. In addition, Fap1 inhibition increased Fas sensitivity and decreased beta-catenin activity in CD34(+) bone marrow cells from human subjects with CML. Therapeutic Fap1 inhibition may permit TKI discontinuation and delay in progression in CML. PMID- 26984789 TI - Erratum to: Development of a Multiplex-PCR probe system for the proper identification of Klebsiella variicola. PMID- 26984790 TI - A case report on desmoplastic ameloblastoma of anterior mandible. AB - BACKGROUND: Desmoplastic ameloblastoma (DA) is a rare variant that accounts for approximately 4-13% of ameloblastoma, displaying significant differences in anatomical site, imaging, and histologic appearance. It has been included in WHO classification of head and neck tumor (WHO-2005) as a variant of ameloblastoma. The tumor resembles benign fibro-osseous lesion for being frequently occurring in the anterior region of jaws as a mixed radiopaque-radiolucent lesion. CASE PRESENTATION: We present a case of DA in a 43-year-old female with a painless swelling in the anterior region of mandible. No fluid was evident on fine needle aspiration. A mixed lesion with multilocular appearance was evident on both panoramic radiographs as well as computed tomography scan. An incisional biopsy confirmed it to be a case of desmoplastic ameloblastoma. Segmental mandibulectomy was performed from teeth 35 to 44. The patient is on routine follow-up and is currently free of ailment. CONCLUSIONS: The present case deserves emphasis because of its unfamiliar appearance, potentially aggressive nature and deceptive radiologic appearance maximizing the chances of misdiagnosis. So, the clinician should be alert enough to include desmoplastic ameloblastoma in differential diagnosis of any lesion/growth with mixed radiolucent-radiopaque appearance having ill-defined borders and occurring in anterior maxilla or mandible. PMID- 26984791 TI - Lifestyle risk factors for cardiovascular disease and diabetic risk in a sedentary occupational group: the Galway taxi driver study. AB - BACKGROUND: Taxi drivers are at increased risk of cardiovascular disease (CVD), something which persists after correcting for the overrepresentation of traditional risk factors for CVD in this cohort. The contribution of lifestyle risk factors to this residually elevated CVD risk remains under-evaluated. AIMS: We aimed to determine the prevalence of lifestyle risk factors for CVD, self reported medical risk factors for CVD, and future risk of type 2 diabetes amongst Irish taxi drivers. METHODS: Male taxi drivers with no history of CVD and type 2 diabetes and working in Galway city in the west of Ireland were invited to participate. Physical activity levels, dietary patterns, anthropometry, smoking, hypertension, hypercholesterolaemia, and Finnish Diabetes Risk Score (FINDRISC) values were recorded in a cross-sectional manner. RESULTS: 41 taxi drivers (mean age 56.7 +/- 9.8 years) participated. 37 % were insufficiently active based on self-report, although only 8 % objectively achieved 10, 000 steps per day. Mean modified Mediterranean diet score (mMDS) was 4.6 +/- 2.2, and only 13 % of participants had a normal body mass index (BMI) or waist circumference (WC). Those who worked for taxi companies tended to have a higher BMI (p = .07) and WC (p = .04) by multivariable regression. 22 % were current smokers, although a quit rate of 72 % was observed amongst the 78 % of taxi drivers who had ever smoked. 25 % were at high or very high risk of future type 2 diabetes. CONCLUSION: Lifestyle risk factors for CVD and dysglycaemia are prevalent amongst Irish taxi drivers. PMID- 26984792 TI - Survival and clinical outcomes in patients with metastatic epidural spinal cord compression after spinal surgery: a prospective, multicenter, observational cohort study. AB - BACKGROUND: High quality studies have been challenging to undertake in patients with metastatic epidural spinal cord compression. Nonetheless, in the article "Survival and Clinical Outcomes in Surgically Treated Patients With Metastatic Epidural Spinal Cord Compression: Results of the Prospective Multicenter AOSpine Study" recently published in the Journal of Clinical Oncology, our team provided convincing evidence that spinal surgery improves overall quality of life in patients with this potentially devastating complication of cancer. Considering that metastatic spinal lesions treated with surgery have the highest mean cost among all oncological musculo-skeletal issues, it is essential to provide high quality data to optimize the therapeutic approaches and cost-effective use of health care resources. MAIN BODY: Although the AOSpine Study provided high quality prospective data, it was primarily limited by the lack of non-operative controls and the relatively small sample size. Given the dearth of medical equipoise and the fundamental difference between patients deemed to be adequate surgical candidates and those who are not amenable to operative intervention, conducting a randomized controlled trial in this patient population was not felt to be ethically or medically feasible. Consequently, the optimal option to overcome limitations of both the lack of controls and the relatively small sample size is through collection of large prospective datasets through rigorously developed and maintained registries. CONCLUSIONS: With the alarming increase in the incidence of cancer in China and China's parallel growing cancer control efforts, China would offer a fantastic platform to set up a national metastatic spinal lesion registry. Such registry would not only enhance metastatic epidural spinal cord compression translational research but also optimize patient care. PMID- 26984793 TI - Cerebral blood flow in alcohol withdrawal: relation to severity of dependence and cognitive impairment. AB - BACKGROUND: Alcohol dependence affects cerebral function in complex, still unsettled ways. METHODS: Thirty exclusively alcohol-dependent patients in various stages of withdrawal and 25 matched controls were examined for regional uptake of 99mTc-HMPAO in nine homologous regions of the cerebral cortex by single photon emission tomography (SPET). Image analysis reports regional uptake/uptake in homologous hemisphere. RESULTS: Alcohol dependence is associated with diminished perfusion in the anterior, and middle frontal regions, and increased perfusion in the posterior temporal regions. Frontal hypoperfusion is related to alcohol withdrawal because it disappears with longer time between imaging, last intake and correlates with a composite index of cognitive impairment at the time. Temporal hyperperfusion persists for longer periods. Severe dependence correlates with both frontal, and temporal altered perfusion. DISCUSSION: Alcohol withdrawal leads to redistribution of blood flow favouring the temporal, and more posterior regions of the cortex at the expense of frontal flow. PMID- 26984794 TI - The influence of folate serum levels on depressive mood and mental processing in patients with epilepsy treated with enzyme-inducing anti-epileptic drugs. AB - BACKGROUND: Folate deficiency is common in patients with epilepsy and also occurs in patients with depression or cognitive deficits. OBJECTIVE: This study investigates whether low serum folate levels may contribute to depressive mood and difficulties in mental processing in patients with epilepsy treated with anti epileptic drugs inducing the cytochrome P450. METHODS: We analysed the serum folate levels, the score in the Self Rating Depression Scale (SDS) and the results of a bedside test in mental processing in 54 patients with epilepsy. RESULTS: There was a significant negative correlation between the serum folate levels and the score in SDS and significant positive correlations between the score in SDS and the time needed to process an interference task or a letter reading task. CONCLUSIONS: Low serum folate levels may contribute to depressive mood and therefore to difficulties in mental processing. Further studies utilizing total plasma homocysteine as a sensitive measure of functional folate deficiency and more elaborate tests of mental processing are required to elucidate the impact of folate metabolism on depressive mood and cognitive function in patients with epilepsy. PMID- 26984795 TI - Prevalence of insomnia in Poland - results of the National Health Interview Survey. AB - BACKGROUND: Sleep disturbances are one of the most common underdiagnosed and undertreated health problems among the adult population. OBJECTIVES: The aim of the study was to assess the prevalence of sleeping problems and their relation to sociodemographic characteristics in the Polish population, based on the results of the National Health Interview Survey carried out by the Central Statistical Office in 1996. METHODS: A stratified sampling scheme, involving two steps, was used. Standardized prevalence ratios (SPRs and their 95% confidence intervals) were calculated. Assessment of sleep-related problems was based on six questions. A representative Polish sample (47 924 non-institutionalized, adult respondents) was interviewed. RESULTS: Nearly one-fourth of Polish inhabitants suffered from insomnia. The percentage was significantly higher among women (28.1%) than among men (18.1%). The prevalence of insomnia increased with age and was highest in divorced respondents. Respondents of both sexes with higher educational levels suffered from insomnia less often than individuals with lower levels of education. The problem of insomnia applies in a similar degree to inhabitants of both rural and urban regions. About one-twentieth of inhabitants of Poland experienced recent sleep deterioration related to problems. It was associated positively with age, female gender and lower education. About 20% of the population get up not rested in the morning, women significantly more often than men, urban residents more often than rural ones. CONCLUSIONS: Sleep-related problems are common and the results are comparable with those from other countries. The findings have important implications, such as the necessity of better education of the public community about the identification and possibilities of treatment of sleep disturbance. PMID- 26984796 TI - Hypothalamic digoxin and brain function. AB - BACKGROUND AND OBJECTIVES: The study assessed the biochemical differences between right hemispheric-dominant and left hemispheric-dominant individuals. The chemical hemispheric-dominance in various systemic and neuropsychiatric diseases was also studied. METHODS: The isoprenoid metabolites, digoxin, dolichol and ubiquinone, glycoconjugate metabolism, free radical metabolism and the RBC membrane composition, were studied in individuals with differing hemispheric dominance. The digoxin levels and RBC membrane Na+-K+ATPase activity were also studied in systemic and neuropsychiatric diseases. RESULTS: The results showed that right hemispheric-dominant individuals had elevated digoxin levels, increased free radical production and reduced scavenging, increased tryptophan catabolites and reduced tyrosine catabolites, increased glycoconjugate levels and increased cholesterol : phospholipid ratio of RBC membranes. Left hemispheric dominant individuals had the opposite patterns. This patterns could be correlated with various systemic and neuropsychiatric diseases. CONCLUSION: Right hemispheric-dominance represents a hyperdigoxinaemic state with membrane sodium potassium ATPase inhibition. Left hemispheric-dominance represents the reverse pattern with hypodigoxinaemia and membrane sodium-potassium ATPase stimulation. Hemispheric-dominance could predispose to various systemic and neuropsychiatric diseases. PMID- 26984797 TI - D3 dopamine receptor mRNA expression in lymphocytes: a peripheral marker for schizophrenia? AB - BACKGROUND: Identification of schizophrenia, a common neuropsychiatric disorder, is based on clinical examination. An easily measurable peripheral marker, which may enable a more rapid and more accurate diagnosis, is not available. A possible candidate is the D3 dopamine receptor on lymphocytes. OBJECTIVE: The D3 receptor is investigated for its clinical significance as a marker for diagnosing schizophrenia. METHODS: From eight schizophrenic patients and eight controls lymphocyte RNA was isolated. A semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) was carried out and the intensities of the specific D3 dopamine receptor bands of patients and controls were compared. RESULTS: No difference could be seen between the intensities of the bands from patients and controls. CONCLUSION: An aberrant D3 dopamine receptor mRNA expression in lymphocytes of schizophrenics could not be demonstrated. This might be caused by down-regulation of D3 receptor production by antipsychotic drug treatment. At present, the D3 receptor seems to have no diagnostic value in schizophrenia. PMID- 26984798 TI - Craniopharyngeoma presenting as psychosis, disinhibition and personality change without neurological signs. AB - Tumors of the pituitary are associated most commonly with visual changes or endocrine abnormalities. Although a significant proportion of such tumors cause cognitive abnormalities, only a small number of cases have been reported in which the presenting symptoms are primarily 'psychiatric' in nature. The case described below highlights the importance of ancillary investigations in the evaluation of patients admitted to psychiatric wards. Despite the size and extension of the tumor, the patient showed no clear neurological signs, and screening serology was normal except for an elevated prolactin level. Only diagnostic imaging was able to reveal the presence of a calcified, cystic suprasellar mass that was confirmed to be a craniopharyngeoma by histopathology. PMID- 26984799 TI - Diencephalic tumours presenting as psychosis. AB - BACKGROUND: Diencephalic tumours are usually presented with the sign and symptoms of increased intracranial pressure, endocrinological changes and visual disturbances. Psychiatric manifestation of such rare tumours is not well known. OBJECTIVE: To investigate the challenges and benefits of psychiatric evaluation on the diagnosis of diencephalic tumours and to emphasize the presence of psychosis as an initial phenomenon. METHODS AND RESULTS: Two cases who presented with the characteristic symptoms of psychosis and diagnosed diencephalic tumour are reported. A detailed radiological examination confirmed such diagnosis in both cases and surgical treatment was done. CONCLUSION: First, all patients who presented with a history of unexplained behaviour change must be evaluated by psychiatrists to exclude an organic pathology. Secondly, until the diagnosis of diencephalic tumour is confirmed, the surgical management must be performed. PMID- 26984800 TI - Letter to the Editor. PMID- 26984803 TI - Juvenile Fibromyalgia: Different from the Adult Chronic Pain Syndrome? AB - While a majority of research has focused on adult fibromyalgia (FM), recent evidence has provided insights into the presence and impact of FM in children and adolescents. Commonly referred as juvenile fibromyalgia (JFM), youths, particularly adolescent girls, present with persistent widespread pain and cardinal symptoms observed in adult FM. A majority of youth with JFM continue to experience symptoms into adulthood, which highlights the importance of early recognition and intervention. Some differences are observed between adult and juvenile-onset FM syndrome with regard to comorbidities (e.g., joint hypermobility is common in JFM). Psychological comorbidities are common but less severe in JFM. Compared to adult FM, approved pharmacological treatments for JFM are lacking, but non-pharmacologic approaches (e.g., cognitive-behavioral therapy and exercise) show promise. A number of conceptual issues still remain including (1) directly comparing similarities and differences in symptoms and (2) identifying shared and unique mechanisms underlying FM in adults and youths. PMID- 26984802 TI - Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome: a Review of the Pathogenesis. AB - PFAPA syndrome represents the most common cause of recurrent fever in children in European populations, and it is characterized by recurrent episodes of high fever, pharyngitis, cervical adenitis, and aphthous stomatitis. Many possible causative factors have been explored so far, including infectious agents, immunologic mechanisms and genetic predisposition, but the exact etiology remains unclear. Recent findings demonstrate a dysregulation of different components of innate immunity during PFAPA flares, such as monocytes, neutrophils, complement, and pro-inflammatory cytokines, especially IL-1beta, suggesting an inflammasome mediated innate immune system activation and supporting the hypothesis of an autoinflammatory disease. Moreover, in contrast with previous considerations, the strong familial clustering suggests a potential genetic origin rather than a sporadic disease. In addition, the presence of variants in inflammasome-related genes, mostly in NLRP3 and MEFV, suggests a possible role of inflammasome composing genes in PFAPA pathogenesis. However, none of these variants seem to be relevant, alone, to its etiology, indicating a high genetic heterogeneity as well as an oligogenic or polygenic genetic background. PMID- 26984804 TI - Racial/Ethnic Disparity in Rates and Outcomes of Total Joint Arthroplasty. AB - Racial/ethnic disparity in total joint arthroplasty (TJA) has grown over the last two decades as studies have documented the widening gap between Blacks and Whites in TJA utilization rates despite the known benefits of TJA. Factors contributing to this disparity have been explored and include demographics, socioeconomic status, patient knowledge, patient preference, willingness to undergo TJA, patient expectation of post-arthroplasty outcome, religion/spirituality, and physician-patient interaction. Improvement in patient knowledge by effective physician-patient communication and other methods can possibly influence patient's perception of the procedure. Such interventions can provide patient relevant data on benefits/risks and dispel myths related to benefits/risks of arthroplasty and possibly reduce this disparity. This review will summarize the literature on racial/ethnic disparity on TJA utilization and outcomes and the factors underlying this disparity. PMID- 26984805 TI - Mortality in Systemic Lupus Erythematosus: an Updated Review. AB - Both systemic lupus erythematosus (SLE) and its treatments can contribute to increased mortality rates. The focus of this review is recent studies on mortality and comorbidities during the last 5 years from around the world. The authors conducted a literature review, using PUBMED, for articles relating to SLE mortality with a specific focus on literature published within the last 5 years. Our analysis found that while mortality in SLE patients continues to improve, there are differences in survival based on ethnicity, socioeconomic status, age, and gender. The most common cause of mortality is cardiovascular disease, followed closely by infection and severe disease activity. To conclude, while there have been significant advances in the treatment of SLE and its associated comorbidities, increased mortality remains a major concern in patient management. PMID- 26984806 TI - Facial spasms, but not hemifacial spasm: a case report and review of literature. AB - INTRODUCTION: Facial spasms represent a complicated array of neurological motor disorders with unique diagnostic and treatment algorithms. Due to the rarity of many of these disorders in the pediatric population, special care must be taken in identifying subtle differences in presentation of these disorders. METHODS: We present a case of a 3-year-old boy diagnosed with a brainstem ganglioglioma, Chiari 1 malformation, and a 2-year history of left-sided facial spasms. Stereotyped facial contractions and subtle eye deviation occurred every 10 s, with downward movement rather than upward elevation of the eyebrow. RESULTS: MRI revealed absence of a clear compressive vessel of the centrally-myelinized portion of the facial nerve, and EMG of the left facial nerve demonstrated no abnormal motor response or evidence of "lateral spread." Given these findings, a diagnosis of hemifacial seizures was made. Microvascular decompression was not recommended, and botulinum toxin injection was not pursued; however, the patient has remained refractory to antiepileptic drugs, possibly due to biochemical alteration by his ganglioglioma. He may eventually require surgical debulking should his symptoms progress. CONCLUSION: Hemifacial spasm is a well-recognized disorder, but similar conditions can, at times, imitate its appearance. While our patient presented with facial spasms, his clinical history, examination, and radiographic and electrophysiological findings were more consistent with hemifacial seizures secondary to a brainstem lesion, rather than hemifacial spasms. It is important to distinguish the two entities, as misdiagnosis and inappropriate diagnostic or therapeutic measures may be taken inadvertently. PMID- 26984807 TI - Nightly oral administration of topiramate for benign childhood epilepsy with centrotemporal spikes. AB - OBJECTIVE: The objective of this study was to explore the feasibility of nightly oral administration of topiramate for treating benign childhood epilepsy with centrotemporal spikes (BECTS). METHODS: Eighty-five children with BECTS receiving topiramate treatment were randomly divided into A group (44 patients) and B group (41 patients). In A group, topiramate was orally administrated once a night, with a final dose of 2 mg/kg/day. In B group, topiramate was orally administrated twice a day, with a final dose of 4 mg/kg/day. At the end of the 12-month follow up period, clinical efficacy, changes in electroencephalographic (EEG) activity, and adverse reactions were analyzed. RESULTS: There was no significant difference in overall efficacy rate, percentages of patients achieving seizure free, or changes in EEG activity between the two groups (P > 0.05). The rate of adverse reactions for A group was 9.1 %, which was significantly lower than the 29.3 % for B group (chi (2) = 4.262, P < 0.05). CONCLUSION: Nightly oral administration of topiramate is a feasible strategy for the treatment of BECTS, with the advantages of comparable efficacy, convenience, and fewer adverse reactions. PMID- 26984808 TI - Intraspinal extradural benign fibrous histiocytoma of the lumbar spine in a pediatric patient. Case report and literature review. AB - INTRODUCTION: Benign fibrous histiocytoma (BFH) is a rare skeletal tumor. Spinal localizations have been previously described in 17 cases, and this is the first report of BFH occurring at the lumbar spine in a pediatric patient. CASE REPORT: A 13-year-old male complained lower limb motor and sensory impairment with severe claudication and urination disorders. A huge intraspinal, extradural mass at L4 L5 level, clearly evident on a preoperative MRI, caused dislocation and severe compression of the cauda equina nerve roots. After a biopsy, confirming BFH, a tumor resection and L4-S1 vertebral arthrodesis was carried out. At 1 year follow up, no recurrence was detached on postoperative MRI, with complete neurological recovery. DISCUSSION AND CONCLUSION: Review of the literature is discussed. Histological examination is mandatory for a correct diagnosis and plan of treatment. None of the pediatric patients treated for BFH have ever shown local relapse. PMID- 26984809 TI - Photon-absorbing charge-bridging states in organic bulk heterojunctions consisting of diketopyrrolopyrrole derivatives and PCBM. AB - We have investigated the photo- and electrochemical properties of five diketopyrrolopyrrole (DPP) derivatives both experimentally and theoretically. In the experimental study, we found that a blend of a DPP derivative named D2 and phenyl-C61-butyric acid methyl ester (PCBM) exhibits the highest internal quantum efficiency (IQE) and power convergence efficiency (PCE) among the five derivatives investigated. In the theoretical study, we found that the open circuit voltage can be estimated from the difference between the energy gap of frontier orbitals and the voltage loss and that the latter is suppressed when the IQE is large. Then, to investigate the factors that influence the IQE, investigations on charge recombination, hole transfer, and charge transfer induced by photoabsorption were conducted for the complexes of each DPP derivative and PCBM. It was found that D2/PCBM exhibits the largest charge bridging upon photoabsorption, which leads to the highest IQE and PCE among the five DPP derivatives. PMID- 26984812 TI - Bisphosphonates beyond five years. PMID- 26984813 TI - Pore emptying transition during nucleation in hydrophobic nanopores. AB - Using the 2D Ising model we study the generic properties of nucleation in hydrophobic nanopores. To explore the pathways to nucleation of a spin-up phase from a metastable spin-down phase we perform umbrella sampling and transition path sampling simulations. We find that for narrow pores the nucleation occurs on the surface outside the pore. For wide pores the nucleation starts in the pore, and continues outside the filled pore. Intriguingly, we observe a pore emptying transition for a range of intermediate pore widths: a pre-critical nucleus fills the pore, continues to expand outside of the filled pore, but then suddenly gets expelled from the pore before reaching its critical size. PMID- 26984811 TI - Moral Distress Amongst Physician Trainees Regarding Futile Treatments. PMID- 26984810 TI - Non-specific symbiotic germination of Cynorkis purpurea (Thouars) Kraezl., a habitat-specific terrestrial orchid from the Central Highlands of Madagascar. AB - Orchids, particularly terrestrial taxa, rely mostly on basidiomycete fungi in the Cantharellales and Sebacinales that trigger the process of seed germination and/or initiate the full development of the seedling. During the course of development, orchids may associate with the same fungus, or they may enlist other types of fungi for their developmental needs leading to resilience in a natural setting. This study examined in vitro seed germination and seedling developmental behavior of Cynorkis purpurea, a terrestrial orchid from the Central Highlands of Madagascar. This species is mostly restricted to gallery forests in the Itremo Massif, in moist substrate between rocks bordering streams. The main objective was to understand the influence of diverse mycorrhizal fungi on seed germination and further development of C. purpurea. The study aims to compare symbiotic versus asymbiotic germination and seedling development with seeds and fungi collected from a 13-km(2) area in the Itremo region. Seeds collected from the wild were sown with diverse orchid mycorrhizal fungi (OMF) spanning 12 operational taxonomic units (OTUs) in three genera (Tulasnella, Ceratobasidium, and Sebacina) acquired from different habitats. Treatments were assessed in terms of the percentage of germinated seeds and fully developed seedlings against those in asymbiotic control media treatments. Overall, OMF significantly improved seedling development within the 12-week experiment period. Sebacina as a genus was the most effective at promoting seedling development of C. purpurea, as well as having the ability to enter into successful symbiotic relationships with orchids of different life forms; this new knowledge may be especially useful for orchid conservation practiced in tropical areas like Madagascar. A Sebacina isolate from an epiphytic seedling of Polystachya concreta was the most effective at inducing rapid seedling development and was among the five that outperformed fungi isolated from roots of C. purpurea. C. purpurea was found to be a mycorrhizal generalist, despite its specific habitat preference, highlighting the complex interaction between the plant, fungi, and the environment. The potential impact on conservation strategies of understanding the requirements for orchid seed germination and development by identifying and using OMF from diverse sources is discussed in detail. PMID- 26984815 TI - Commentary: Transcervical Carotid Artery Stenting (CAS) With Flow Reversal: A Promising Technique for the Reduction of Strokes Associated With CAS. PMID- 26984814 TI - Molecular and in Silico Characterization of Achaea janata Granulovirus Granulin Gene. AB - Achaea janata granulovirus (AcjaGV), an insect virus belonging to Baculoviridae, infects semilooper, a widely distributed defoliating pest on castor beans (Ricinus communis L.) and several other plant hosts in India. The propagation and purification of the Hyderabad isolate AcjaGV were performed, granulin gene from this isolate was amplified, cloned and sequenced, and its homology with other known granulin genes was assessed. The 753-bp granulin ORF of AcjaGV encoded for a granulin protein of 250 amino acids with a molecular mass of 29.5 +/- 0.7 kDa. This amino acid sequence exhibited significant homology with Spodoptera litura granulovirus (SpliGV) and other GVs infecting insects in the same Noctuidae family of Lepidoptera. Peptide analysis of granulin protein indicated close homology with that of SpliGV. Virtual RFLP patterns from in silico digestions of granulin gene of 18 granuloviruses mapped by 12 restriction enzymes were used for simulated digestions. Implications of the phylogenetic relationships of granulin nucleotide and deduced amino acid sequence are discussed. We have established the sequence identity of granulin gene of AcjaGV and characterized its protein product and the phylogenetic relationship with other known GVs. Our results indicate the presence of unique restriction sites for three restriction enzymes, and this can be used as a tool for identification of AcjaGV from various sources. This is the first report from the Indian subcontinent to describe the complete granulin gene of a GV isolated from A. janata. PMID- 26984816 TI - Commentary: Proximal Uncovered Stent Disconnections With the Standard and Low Profile Zenith AAA Stent-Grafts. PMID- 26984817 TI - Commentary: Buttoning Up the Proximal Tear: Is a Vascular Plug the Answer to Achieving False Lumen Thrombosis? PMID- 26984818 TI - Debulking Plus Drug-Coated Balloon Combination as Revascularization Strategy for Complex Femoropopliteal Lesions: A New Standard Technique? PMID- 26984819 TI - A G4.K(+) hydrogel that self-destructs. AB - A G4-quartet based hydrogel formed by self-assembly of borate esters of 5'-deoxy 5'-iodoguanosine (5'-IG 2) undergoes in situ cyclization to give 5'-deoxy-N3,5' cycloguanosine (5'-cG 3). Formation of 5'-cG 3 causes self-destruction of the gel. This intramolecular cyclization can be used to release nucleoside analogs that have been pre-incorporated into the gel network. PMID- 26984820 TI - Lack of hippocampal CB1 receptor desensitization by Delta(9)-tetrahydrocannabinol in aged mice and by low doses of JZL 184. AB - Activation of cannabinoid CB1 receptors may offer new therapeutic strategies, but the efficiency of CB1 receptor agonists may be impaired by tolerance development upon prolonged administration. We compared the influence of repeated administration of Delta(9)-tetrahydrocannabinol (THC) 10 mg/kg on the motility and on basal and CB1 receptor-stimulated (35)S-GTPgammaS binding of adolescent and aged mice. Moreover, we determined the influence of JZL 184 (which inhibits the 2-arachidonoylglycerol, 2-AG, degrading enzyme monoacylglycerol lipase, MAGL) on (35)S-GTPgammaS binding and 2-AG levels of young adult mice. Mouse motility was tested in the open field. (35)S-GTPgammaS binding was studied in hippocampal membranes. THC and CP 55,940 were used as cannabinoid agonists in the behavioural and biochemical studies, respectively. 2-AG levels were quantified by liquid chromatography-multiple reaction monitoring. The THC (10 mg/kg)-induced hypomotility was stronger in untreated than in THC-pretreated adolescent mice but similar in both treatment groups of aged mice. Basal and stimulated (35)S GTPgammaS binding was decreased in membranes from THC-pretreated adolescent but not affected in membranes from aged mice. Treatment of young adult mice with JZL 184 (4, 10 and 40 mg/kg) for 14 days did not affect basal binding. Stimulated binding tended to be decreased by 25 % only in mice treated with JZL 184 (40 mg/kg). Hippocampal 2-AG level was increased by JZL 184 at 40 and 10 but not affected at 4 mg/kg. In conclusion, CB1 receptor tolerance does not occur in aged mice pretreated with THC and in young adult mice treated with a low dose of the MAGL inhibitor JZL 184. PMID- 26984822 TI - Neither self-reported ethnicity nor declared family origin are reliable indicators of genomic ancestry. AB - Ancestry information can be useful in investigations of diseases with a genetic or infectious background. As the Brazilian population is highly admixed physical traits tend to be poor indicators of ancestry. The assessment of ancestry by ancestry informative markers (AIMs) can exclude the subjectivity of self-declared ethnicity and reported family origin. We aimed to evaluate the reliability of self-reported ethnicity or reported family origin as indicators of genomic ancestry in a female population from the Southeast of Brazil. Two cohorts were included: 404 women asked to self-report their ethnicity (Pop1) and 234 women asked to report their family's origin (Pop2). Identification of AIMs was performed using a panel of 61 markers and results were plotted against parental populations-Amerindian, Western European and Sub-Saharan African-using Structure v2.3.4. In Pop1 57.4 % of women self-reported as white, 34.6 % as brown and 8.0 % as black. Median global European, Amerindian and African contributions were 66.8, 12.6 and 16.6 %. In Pop2, 66.4 % of women declared European origin, 23.9 % African origin and 26.9 % Amerindian. Median global European, Amerindian and African contributions were 80.8, 7.3 and 7.6 %, respectively. Only 31.0 and 21.0 % of the global variation in African and European contributions, respectively, could be explained by self-reported ethnicity and reported family origin only accounted for 20.0 and 5.0 % of the variations observed in African and European ancestries, respectively. Amerindian ancestry did not influence self-reported ethnicity or declared family origin. Neither self-reported ethnicity nor declared family origin are reliable indicators of genomic ancestry in these Brazilian populations. PMID- 26984823 TI - Microbial contamination in intraoral phosphor storage plates: the dilemma. AB - OBJECTIVES: The aims of this study were to evaluate microbial contamination in phosphor storage plates in dental radiology services and discuss the possible origin of this contamination. MATERIALS AND METHODS: The sample comprised 50 phosphor plates: 14 plates from service A, 30 from service B, and 6 in the control group, consisting of plates never used. Damp sterile swabs were rubbed on the phosphor plates, and then transferred to tests tubes containing sterile saline solution. Serial dilutions were made, and then inoculated in triplicate on Mueller Hinton agar plates and incubated at 37 degrees C/48 h, before counting the colony-forming units (CFU). The samples were also seeded in brain-heart infusion medium to confirm contamination by turbidity of the culture medium. All solutions, turbid and clean, were seeded in selective and non-selective media. RESULTS: At service A and B, 50 and 73.3 % of the phosphor plates were contaminated, respectively. This contamination was mainly due to bacteria of the genus Staphylococcus. CFU counts ranged from 26.4 to 80.0 CFU/plate. CONCLUSIONS: Most of the phosphor plates evaluated shown to be contaminated, mainly by Staphylococcus ssp. Quantitatively, this contamination occurred at low levels, possibly arising from handling of the plates. The use of a second plastic barrier may have diminished contamination by microorganisms from the oral cavity. CLINICAL RELEVANCE: There is a risk of cross-contamination by phosphor storage plates used in dental radiology services. PMID- 26984821 TI - Effect of pregabalin on contextual memory deficits and inflammatory state-related protein expression in streptozotocin-induced diabetic mice. AB - Diabetes mellitus is a metabolic disease characterized by hyperglycemia due to defects in insulin secretion or its action. Complications from long-term diabetes consist of numerous biochemical, molecular, and functional tissue alterations, including inflammation, oxidative stress, and neuropathic pain. There is also a link between diabetes mellitus and vascular dementia or Alzheimer's disease. Hence, it is important to treat diabetic complications using drugs which do not aggravate symptoms induced by the disease itself. Pregabalin is widely used for the treatment of diabetic neuropathic pain, but little is known about its impact on cognition or inflammation-related proteins in diabetic patients. Thus, this study aimed to evaluate the effect of intraperitoneal (ip) pregabalin on contextual memory and the expression of inflammatory state-related proteins in the brains of diabetic, streptozotocin (STZ)-treated mice. STZ (200 mg/kg, ip) was used to induce diabetes mellitus. To assess the impact of pregabalin (10 mg/kg) on contextual memory, a passive avoidance task was applied. Locomotor and exploratory activities in pregabalin-treated diabetic mice were assessed by using activity cages. Using Western blot analysis, the expression of cyclooxygenase-2 (COX-2), cytosolic prostaglandin E synthase (cPGES), nuclear factor (erythroid derived 2)-like 2 (Nrf2), nuclear factor-KB (NF-KB) p50 and p65, aryl hydrocarbon receptor (AhR), as well as glucose transporter type-4 (GLUT4) was assessed in mouse brains after pregabalin treatment. Pregabalin did not aggravate STZ-induced learning deficits in vivo or influence animals' locomotor activity. We observed significantly lower expression of COX-2, cPGES, and NF-kappaB p50 subunit, and higher expression of AhR and Nrf2 in the brains of pregabalin-treated mice in comparison to STZ-treated controls, which suggested immunomodulatory and anti inflammatory effects of pregabalin. Antioxidant properties of pregabalin in the brains of diabetic animals were also demonstrated. Pregabalin does not potentiate STZ-induced cognitive decline, and it has antioxidant, immunomodulatory, and anti inflammatory properties in mice. These results confirm the validity of its use in diabetic patients. Graphical abstract Effect of pregabalin on fear-motivated memory and markers of brain tissue inflammation in diabetic mice. PMID- 26984826 TI - Gender, age, and cultural differences in the Japanese version of the Infant Toddler Social and Emotional Assessment. AB - This study aimed to clarify the characteristics of the Japanese version of the Infant-Toddler Social and Emotional Assessment (J-ITSEA), a parentreport questionnaire concerning social-emotional/behavioral problems and delays in competence in 1- to 3-year-old children. The differences in score between genders, ages, and between the J-ITSEA and the original Infant-Toddler Social and Emotional Assessment were examined. The data of 617 participants recruited from Saitama prefecture through stratified two-stage sampling were analyzed. The Cronbach's alpha ranged from 0.76 to 0.93. Gender differences emerged for some problems and all competence scales, with boys rated higher in the Externalizing problem domain and Activity/Impulsivity subscale and girls rated higher in the Internalizing problem domain, Inhibition to Novelty subscale, and all Competence scales. The Competence domain score increased across age groups. Compared with a normative sample in the US, participants in this study rated higher in Aggression/Defiance and Separation Distress, and rated lower in Peer Aggression and most of the Competence scales. The results indicate that the J-ITSEA scores should be interpreted in comparison with standard scores assigned for gender and 6-month age groups, and that specific criteria for the cut-off points for the J ITSEA are required instead of those in the original questionnaire. PMID- 26984824 TI - Magnetic permeability as a predictor of the artefact size caused by orthodontic appliances at 1.5 T magnetic resonance imaging. AB - OBJECTIVES: Artefacts caused by orthodontic attachments limit the diagnostic value and lead to removal of these appliances before magnetic resonance imaging. Magnetic permeability can predict the artefact size. There is no standardised approach to determine the permeability of such attachments. The aim was to establish a reliable approach to determine artefact size caused by orthodontic attachments at 1.5 T MRI. MATERIALS AND METHODS: Artefact radii of 21 attachments were determined applying two prevalent sequences of the head and neck region (turbo spin echo and gradient echo). The instrument Ferromaster (Stefan Mayer Instruments, Dinslaken) is approved for permeability measurements of objects with a minimum size (d = 20 mm, h = 5 mm). Eleven small test specimens of known permeability between 1.003 and 1.431 were produced. They are slightly larger than the orthodontic attachments. Their artefacts were measured and cross tabulated against the permeability. The resulting curve was used to compare the orthodontic attachments with the test bodies. RESULTS: Steel caused a wide range of artefact size of 10-74 mm subject to their permeability. Titanium, cobalt-chromium and ceramic materials produced artefact radii up to 20 mm. Measurement of artefacts of the test bodies revealed an interrelationship according to a root function. The artefact size of all brackets was below that root function. CONCLUSIONS: The permeability can be reliably assessed by conventional measurement devices and the artefact size can be predicted. The radiologist is able to decide whether or not the orthodontic attachments should be removed. CLINICAL RELEVANCE: This study clarifies whether an orthodontic appliance must be removed before taking an MRI. PMID- 26984825 TI - Effect of Early Intervention to Promote Mother - Infant Interaction and Maternal Sensitivity in Japan: A Parenting Support Program based on Infant Mental Health. AB - This study investigated the effects of the Japanese Early Promotion Program (JEPP), which is based on the Infant Mental Health (IMH) program. The JEPP aims to promote mother-infant interactions by enhancing the mother's ability to respond appropriately her child. Mothers in the JEPP group (n = 15) received support from IMH nurses in a pediatric clinic until their infants reached 12 months of age. The nurses provided positive feedback that emphasized strength of parenting, and assisted the mothers in understanding the construct of their infants. Mother-infant interactions and mother's mental health status were assessed at intake (1-3 months), and at 6, 9, and 12 months of infants' age. The JEPP group data were compared with cross-sectional data of the control group (n = 120). Although JEPP dyads were not found to be significantly different from the control group in general dyadic synchrony, both before and after intervention, JEPP mothers significantly improved their ability to understand their infant's cues and to respond promptly. In the JEPP group, unresponsiveness to infants was reduced in mothers, while infants showed reduced passiveness and enhanced responsiveness to the mother. Furthermore, the intervention reduced the mothers' parenting stress and negative emotions, thereby enhancing their self-esteem. PMID- 26984827 TI - A Prospective Study of Factors Related to Mother-Infant Interaction in One-year old Infants with Retinoblastoma. AB - This study aimed to clarify the relationships among developmental characteristics of retinoblastoma (RB) infants, mother-infant interaction, and mental health of mothers. Prospective studies were conducted twice with 13 dyads of mothers and infants who were between one (Time 1) and two years old (Time 2). Cross-sectional and longitudinal analyses were performed. The mean Developmental Quotients (DQ) significantly decreased between Time 1 and Time 2 (p < .05). Four (30.8%) infants showed DQ p < 85 at Time 1. They showed a DQ below the borderline at Time 2 and their developmental changes were different from RB infants in the normal DQ range. Infant Behavior Checklist-R (IBC-R) scores negatively correlated with DQ (p < .05). The mothers' Japanese Nursing Child Assessment Teaching Scale (JNCATS) scores were significantly higher than the normative mean. The IBC-R scores negatively correlated with mothers' JNCATS scores at Time 1 (rho = -.66, p < .05) and positively correlated with the child domain scores on the Parenting Stress Index at Time 2 (rho = .62, p < .05). Some RB infants showed a developmental delay. Mother-child interactions were negatively affected and mothers recognized their infants' problem. The support needs to be provided in early infancy. PMID- 26984828 TI - A Case of Giant Primary Dermal Melanoma with BRAF V600E Mutation. PMID- 26984829 TI - Reply. PMID- 26984830 TI - Naegleria fowleri That Induces Primary Amoebic Meningoencephalitis: Rapid Diagnosis and Rare Case of Survival in a 12-Year-Old Caucasian Girl. AB - Primary amoebic meningoencephalitis (PAM) is a rare and almost always fatal disease that is caused by Naegleria fowleri, a freshwater thermophilic amoeba. Our case involves an adolescent female who presented with fever of unknown origin. A lumbar puncture was performed, and the Wright-Giemsa and Gram stained cerebrospinal fluid (CSF) cytospin slides showed numerous organisms. Experienced medical technologists in the microbiology and hematology laboratories identified the organisms as morphologically consistent with Naegleria species. The laboratory made a rapid diagnosis and alerted emergency department care providers within 75 minutes. The patient was treated for PAM with amphotericin, rifampin, azithromycin, fluconazole and aggressive supportive therapy including dexamethasone. The Centers for Disease Control and Prevention (CDC) was contacted, and miltefosine, an investigational medication, was started. Additional treatment included an intraventricular shunt and controlled hypothermia in order to mitigate potential cerebral edema. Our patient is a rare success story, as she was diagnosed swiftly, successfully treated, and survived PAM. PMID- 26984832 TI - Tissue Penetration of a Novel Spectinamide Antibiotic for the Treatment of Tuberculosis. AB - The in vivo biodistribution and pharmacokinetics of 1329, a novel spectinamide antibiotic with anti-tubercular activity, were studied during intravenous administration of an tritium-labeled compound for nine consecutive, 12-hourly doses to rats. Serial blood samples were collected after the first and the eighth dose, and major organs and tissues were collected 1 h after the ninth dose. Urinary and fecal excretion was monitored throughout the dosing period. Radioactivity in the collected samples was assessed by scintillation counting. During the course of treatment, 86.6% of the administered radioactivity was recovered in urine, feces, organs, and muscle tissue. Urinary excretion was the major route of elimination, with 70% of radioactivity recovered from urine and 12.6% from feces. The time profiles of radioactivity in serum after the first and the eighth dose were identical for the first 2 h post-dose, with similar Cmax (3.39 vs. 3.55 mCi/L) and AUC0-tau (5.08 vs. 5.17 mCi * h/L), indicating no substantial accumulation of 1329 during multiple dosing. Radioactivity in major target organs for pulmonary tuberculosis infection, the lungs and spleen, was 2.79- and 3.06-fold higher than in the blood. Similarly, the intracellular uptake of 1329 into macrophages was sixfold higher than for streptomycin. Overall, these observations suggest biodistribution properties favorable for targeting pulmonary tuberculosis infections. PMID- 26984833 TI - Priority topics for European multidisciplinary guidelines on the management of chronic kidney disease in older adults. AB - PURPOSE: To identify and prioritize potential topics to be addressed in the development of European multidisciplinary guidelines on the management of chronic kidney disease stage 3b-5 in older patients. METHODS: We composed a list of 47 potential guideline topics by reviewing the literature, consulting online 461 nephrologists and 107 geriatricians, and obtaining expert input. A multidisciplinary panel of twelve experts then prioritized the topics during a face-to-face consensus meeting, following a nominal group technique structure with two voting rounds. Topics were rated on a 9-point scale ranging from 1 ('not at all important') to 9 ('critically important'). RESULTS: The highest rating (median; range) was assigned to 'Screening and referral' (8.5; 2.0). Eight topics shared the second highest rating with a median priority score of 8.0 (2.0) and included 'Starting dialysis or not' and 'Accurate assessment of renal function.' 'Targets for and treatment of diabetes' received the lowest rating with (3.0; 6.0). CONCLUSIONS: This joint initiative of the European Renal Association European Dialysis Transplant Association (ERA-EDTA) and the European Union Geriatric Medicine Society (EUGMS) prioritized the development of guidance on interdisciplinary referral of older patients with chronic kidney disease stage 3b 5. Future guidance will therefore focus on identifying prognostic scores to predict death and progression to end-stage renal disease, as well as accurate tests for assessment of renal function in older kidney patients. This will contribute to more informed treatment decision making in this growing patient population. PMID- 26984834 TI - Screening tests for predicting the prognosis of oral intake in elderly patients with acute pneumonia. AB - Many elderly patients with pneumonia have aspiration pneumonia. Therefore they must temporarily abstain from oral intake. However, it is difficult to predict whether or not they will be able to start oral intake. The reason is the standard method to evaluate deglutition about pneumonia patients has not been established. In this study we aimed to develop a simple and convenient method that predicts the prognosis of oral intake as nutrition among elderly patients with acute stage pneumonia. Participants were 77 inpatients fasting due to aspiration risk with acute pneumonia. (86.0 +/- 7.7 years; range 68-105 years; men: n = 34, women: n = 43) during September 2011 and August 2013. Their consciousness levels were determined by Glasgow coma scale (GCS) and swallowing function and cough reflex were evaluated by repetitive saliva swallowing test (RSST), modified water swallow test, simple swallowing provocation test and cough test. Oral intake status at discharge was considered as the objective variable, and these tests were considered as explanatory variables. Then receiver operating characteristic (ROC) curve and the area under the curve (AUC) for each was done. From the ROC curve analysis, GCS >=14 had the largest AUC (0.79) with a sensitivity and specificity of 0.71 and 0.80. That was followed by RSST >=1, AUC (0.77) with a sensitivity and specificity of 0.81 and 0.67. These results suggest that GCS and RSST could be useful screening tests for prognostic prediction of oral intake capability in elderly patients with acute pneumonia. PMID- 26984835 TI - Association between hepatitis B virus basal core promoter/precore region mutations and the risk of hepatitis B-related acute-on-chronic liver failure in the Chinese population: an updated meta-analysis. AB - BACKGROUND: The relationship between hepatitis B virus (HBV) mutations in basal core promoter (BCP) and precore (PC) regions and the risk of hepatitis B-related acute-on-chronic liver failure (HB-ACLF) remains uncertain. METHODS: Databases were searched for papers that were published in English or Chinese until April 31, 2015. The odds ratios (ORs) of HBV mutation were pooled by using a fixed or random-effects model according to heterogeneity. RESULTS: Data for 13 studies with a total of 1,149 HB-ACLF and 1,867 chronic hepatitis B (CHB) cases were retrieved. Statistically significant summary ORs for HB-ACLF were obtained for T1753V (1.99; 95 % confidence interval 1.30-3.02) and A1762T/G1764A (2.11; 95 %, 1.75-2.54) in the BCP region and for A1846T (3.33; 95 %, 2.23-4.97), G1896A (2.78; 95 %, 2.07-3.74), and G1899A (3.09; 95 %, 1.82-5.25) in the PC region. In subgroup analysis, BCP mutations were found to have higher ORs in age-matched studies, but PC mutations were found to have higher ORs in age-unmatched studies; patients with the mutations in HBV genotype C were more susceptible to HB-ACLF; patients with pre-existing liver cirrhosis had a higher risk of HB-ACLF occurrence. In sensitivity, specificity, and accuracy analysis, A1762T/G1764A had the highest sensitivity (67.43 %); A1762T/G1764A + G1896A triple mutations had the highest specificity (93.70 %); and T1753V + A1762T + G1764A mutation had the highest accuracy (65.42 %). CONCLUSIONS: HBV T1753V, A1762T/G1764A, A1846T, G1896A, and G1899A mutations are correlated with an increase in the risk of HB ACLF. These mutations alone and in combination may be predictive of the susceptibility of patients with CHB to developing HB-ACLF. PMID- 26984836 TI - Predicting Maternal Health Care Use by Age at Marriage in Multiple Countries. AB - PURPOSE: In light of the global pervasiveness of child marriage and given that improving maternal health care use is an effective strategy in reducing maternal and child morbidity and mortality, the available empirical evidence on the association of child marriage with maternal health care utilization seems woefully inadequate. Furthermore, existing studies have not considered the interaction of type of place of residence and parity with child marriage, which can give added insight to program managers. METHODS: Demographic Health Survey data for seven countries are used to estimate logistic regression models including interactions of age at marriage with area of residence and birth order. Adjusted predicted probabilities at representative values and marginal effects are computed for each outcome. RESULTS: The results show a negative association between child marriage and maternal health care use in most study countries, and this association is more negative in rural areas and with higher orders of parity. However, the association between age at marriage and maternal health care use is not straightforward but depends on parity and area of residence and varies across countries. The marginal effects in use of delivery care services between women married at age 14 years or younger and those married at age 18 years or older are more than 10% and highly significant in Bangladesh, Burkina Faso, and Nepal. CONCLUSIONS: The study's findings call for the formulation of country-and age at marriage-specific recommendations to improve maternal and child health outcomes. PMID- 26984837 TI - Acupuncture for treating polycystic ovary syndrome: guidance for future randomized controlled trials. AB - OBJECTIVE: To provide guidance for future randomized controlled trials (RCTs) based on a review concerning acupuncture for treating polycystic ovary syndrome (PCOS). METHODS: A comprehensive literature search was conducted in October 2015 using MEDLINE, EMBASE, SCISEARCH, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Menstrual Disorders and Subfertility Group trials register, Allied and Complementary Medicine (AMED), China National Knowledge Infrastructure (CNKI), and the Wanfang databases. RCTs comparing either acupuncture with no/sham/pharmacological intervention or a combination of acupuncture and conventional therapy with conventional therapy in the treatment of PCOS were included in this review. A quality evaluation was performed for each of the included studies. RESULTS: Thirty-one RCTs were included in the review and were divided into four categories according to the type of intervention used in the comparator or control group. Menstrual frequency, hormones, anthropometrics, insulin sensitivity, blood lipids, and fertility were used as the main measurements to assess the effects of acupuncture on the patients with PCOS. Thirty trials, except for one, showed an improvement in at least one of the indicators of PCOS after acupuncture treatment. However, normalizing the methodological and reporting format remains an issue. CONCLUSIONS: Based upon this review of current clinical trials concerning acupuncture for treating PCOS, we provide guidelines for better clinical trial design in the future. PMID- 26984838 TI - 0.9% saline is neither normal nor physiological. AB - The purpose of this review is to objectively evaluate the biochemical and pathophysiological properties of 0.9% saline (henceforth: saline) and to discuss the impact of saline infusion, specifically on systemic acid-base balance and renal hemodynamics. Studies have shown that electrolyte balance, including effects of saline infusion on serum electrolytes, is often poorly understood among practicing physicians and inappropriate saline prescribing can cause increased morbidity and mortality. Large-volume (>2 L) saline infusion in healthy adults induces hyperchloremia which is associated with metabolic acidosis, hyperkalemia, and negative protein balance. Saline overload (80 ml/kg) in rodents can cause intestinal edema and contractile dysfunction associated with activation of sodium-proton exchanger (NHE) and decrease in myosin light chain phosphorylation. Saline infusion can also adversely affect renal hemodynamics. Microperfusion experiments and real-time imaging studies have demonstrated a reduction in renal perfusion and an expansion in kidney volume, compromising O2 delivery to the renal parenchyma following saline infusion. Clinically, saline infusion for patients post abdominal and cardiovascular surgery is associated with a greater number of adverse effects including more frequent blood product transfusion and bicarbonate therapy, reduced gastric blood flow, delayed recovery of gut function, impaired cardiac contractility in response to inotropes, prolonged hospital stay, and possibly increased mortality. In critically ill patients, saline infusion, compared to balanced fluid infusions, increases the occurrence of acute kidney injury. In summary, saline is a highly acidic fluid. With the exception of saline infusion for patients with hypochloremic metabolic alkalosis and volume depletion due to vomiting or upper gastrointestinal suction, indiscriminate use, especially for acutely ill patients, may cause unnecessary complications and should be avoided. More education regarding saline-related effects and adequate electrolyte management is needed. PMID- 26984839 TI - Antibiotic resistance mechanisms of Myroides sp. AB - Bacteria of the genus Myroides (Myroides spp.) are rare opportunistic pathogens. Myroides sp. infections have been reported mainly in China. Myroides sp. is highly resistant to most available antibiotics, but the resistance mechanisms are not fully elucidated. Current strain identification methods based on biochemical traits are unable to identify strains accurately at the species level. While 16S ribosomal RNA (rRNA) gene sequencing can accurately achieve this, it fails to give information on the status and mechanisms of antibiotic resistance, because the 16S rRNA sequence contains no information on resistance genes, resistance islands or enzymes. We hypothesized that obtaining the whole genome sequence of Myroides sp., using next generation sequencing methods, would help to clarify the mechanisms of pathogenesis and antibiotic resistance, and guide antibiotic selection to treat Myroides sp. infections. As Myroides sp. can survive in hospitals and the environment, there is a risk of nosocomial infections and pandemics. For better management of Myroides sp. infections, it is imperative to apply next generation sequencing technologies to clarify the antibiotic resistance mechanisms in these bacteria. PMID- 26984840 TI - Roles of microRNA and signaling pathway in osteoarthritis pathogenesis. AB - Osteoarthritis (OA) is a common chronic degenerative joint disease, with complicated pathogenic factors and undefined pathogenesis. Various signaling pathways play important roles in OA pathogenesis, including genetic expression, matrix synthesis and degradation, cell proliferation, differentiation, apoptosis, and so on. MicroRNA (miRNA) is a class of non-coding RNA in Eukaryon, regulating genetic expression on the post-transcriptional level. A great number of miRNAs are involved in the development of OA, and are closely associated with different signaling pathways. This article reviews the roles of miRNAs and signaling pathways in OA, looking toward having a better understanding of its pathogenesis mechanisms and providing new therapeutic targets for its treatment. PMID- 26984841 TI - Hydrogen sulfide from a NaHS source attenuates dextran sulfate sodium (DSS) induced inflammation via inhibiting nuclear factor-kappaB. AB - This study investigated the alleviating effects of hydrogen sulfide (H2S), derived from sodium hydrosulfide (NaHS), on inflammation induced by dextran sulfate sodium (DSS) in both in vivo and in vitro models. We found that NaHS injection markedly decreased rectal bleeding, diarrhea, and histological injury in DSS-challenged mice. NaHS (20 MUmol/L) reversed DSS-induced inhibition in cell viability in Caco-2 cells and alleviated pro-inflammation cytokine expression in vivo and in vitro, indicating an anti-inflammatory function for H2S. It was also found that H2S may regulate cytokine expression by inhibiting the nuclear factor kappaB (NF-kappaB) signaling pathway. In conclusion, our results demonstrated that H2S alleviated DSS-induced inflammation in vivo and in vitro and that the signal mechanism might be associated with the NF-kappaB signaling pathway. PMID- 26984842 TI - Association between polymorphisms of prokineticin receptor (PKR1 rs4627609 and PKR2 rs6053283) and recurrent pregnancy loss. AB - Recurrent pregnancy loss (RPL) is a condition with complex etiologies, to which both genetic and environmental factors may contribute. During the last decade, studies indicated that the expression patterns of the prokineticin receptor (PKR1 and PKR2) are closely related to early pregnancy. However, there are few studies on the role of PKR1 and PKR2 in RPL. In this study, we purpose to investigate the association between polymorphisms of the prokineticin receptor (PKR1 rs4627609 and PKR2 rs6053283) and RPL on a group of 93 RPL cases and 169 healthy controls. Genotyping of the single nucleotide polymorphisms (SNPs) was performed using a Sequenom MassARRAY iPLEX system. The results revealed a significant association between PKR2 rs6053283 polymorphism and RPL (P=0.003), whereas no association was observed between PKR1 rs4627609 polymorphism and RPL (P=0.929) in the Chinese Han population. PMID- 26984843 TI - Controversial opinion: evaluation of EGR1 and LAMA2 loci for high myopia in Chinese populations. AB - Functional studies have suggested the important role of early growth response 1 (EGR1) and Laminin alpha2-chain (LAMA2) in human eye development. Genetic studies have reported a significant association of the single nucleotide polymorphism (SNP) in the LAMA2 gene with myopia. This study aimed to evaluate the association of the tagging SNPs (tSNPs) in the EGR1 and LAMA2 genes with high myopia in two independent Han Chinese populations. Four tSNPs (rs11743810 in the EGR1 gene; rs2571575, rs9321170, and rs1889891 in the LAMA2 gene) were selected, according to the HapMap database (http://hapmap.ncbi.nlm.nih.gov), and were genotyped using the ligase detection reaction (LDR) approach for 167 Han Chinese nuclear families with extremely highly myopic offspring (<-10.0 diopters) and an independent group with 485 extremely highly myopic cases (<-10.0 diopters) and 499 controls. Direct sequencing was used to confirm the LDR results in twenty randomly selected subjects. Family-based association analysis was performed using the family-based association test (FBAT) software package (Version 1.5.5). Population-based association analysis was performed using the Chi-square test. The association analysis power was estimated using online software (http://design.cs.ucla.edu). The FBAT demonstrated that all four tSNPs tested did not show association with high myopia (P>0.05). Haplotype analysis of tSNPs in the LAMA2 genes also did not show a significant association (P>0.05). Meanwhile, population-based association analysis also showed no significant association results with high myopia (P>0.05). On the basis of our family- and population-based analyses for the Han Chinese population, we did not find positive association signals of the four SNPs in the LAMA2 and EGR1 genes with high myopia. PMID- 26984845 TI - John H. Gagnon (1931-2016). PMID- 26984846 TI - Couple Identity, Sacrifice, and Availability of Alternative Partners: Dedication in Friends With Benefits Relationships. AB - Friends with benefit relationships (FWB) combine elements of ongoing friendship and physical intimacy. Although many studies have examined predictors of who are likely to enter these relationships as well as their outcomes, we do not know what relational factors are associated with FWB relationship outcomes. This study examined the association between three commitment variables: couple identity, satisfaction with sacrifice, and alternative availability and FWB relationship adjustment and sexual satisfaction. In a young adult sample (n = 171), bivariate correlations demonstrated greater couple identity, more satisfaction with sacrifice, and less alternative availability which were associated with greater relationship adjustment, but not sexual satisfaction. In a multivariate context, satisfaction with sacrifice was the only significant predictor of FWB relationship adjustment. There was also a significant interaction between alternative availability and satisfaction with sacrifice in the prediction of sexual satisfaction. For those who perceived fewer alternative options, the degree to which they were satisfied with sacrificing for their partner was positively associated with sexual satisfaction. Implications for enhancing FWB relationships are discussed. PMID- 26984844 TI - Comparison of laparoscopic hepatectomy, percutaneous radiofrequency ablation and open hepatectomy in the treatment of small hepatocellular carcinoma. AB - OBJECTIVE: Three mainstream techniques--laparoscopic hepatectomy (LH), percutaneous radiofrequency ablation (pRFA), and open hepatectomy (OH)--were compared in this study, in terms of their efficacies in the treatment of small hepatocellular carcinoma (HCC). METHODS: A comparative study was performed within a total of 94 patients diagnosed with small HCC in our hospital from 2005 to 2010, who underwent LH (28), RFA (33), or OH (33). They had either a single tumor lesion of less than or up to three nodules with diameters of less than each. Outcomes were carefully evaluated throughout a 3-year follow-up interval and statistically interpreted. RESULTS: The pRFA group had a significantly lower disease-free survival rate compared with the two surgical groups (P=0.001) and significantly shorter overall survival (P=0.005), while the LH group and the OH group had no difference in survival results. For patients younger than 60 years old, surgical approaches offered a better long-term overall survival prognosis (P=0.008). There were no statistically significant differences among the three groups in overall survival for elderly patients (P=0.104). CONCLUSIONS: Among patients with small HCC, LH may provide better curative effects than pRFA without increasing complication rates. pRFA leads to faster recurrence than surgical resections. LH has similar therapeutic effects to OH and causes less trauma. For patients younger than 60 years old, LH may be the best curative treatment. Elderly patients may choose either surgery or pRFA. PMID- 26984847 TI - Tumor-derived factors modulating dendritic cell function. AB - Dendritic cells (DC) play unique and diverse roles in the tumor occurrence, development, progression and response to therapy. First of all, DC can actively uptake tumor-associated antigens, process them and present antigenic peptides to T cells inducing and maintaining tumor-specific T cell responses. DC interaction with different immune effector cells may also support innate antitumor immunity, as well as humoral responses also known to inhibit tumor development in certain cases. On the other hand, DC are recruited to the tumor site by specific tumor derived and stroma-derived factors, which may also impair DC maturation, differentiation and function, thus resulting in the deficient formation of antitumor immune response or development of DC-mediated tolerance and immune suppression. Identification of DC-stimulating and DC-suppressing/polarizing factors in the tumor environment and the mechanism of DC modulation are important for designing effective DC-based vaccines and for recovery of immunodeficient resident DC responsible for maintenance of clinically relevant antitumor immunity in patients with cancer. DC-targeting tumor-derived factors and their effects on resident and administered DC in the tumor milieu are described and discussed in this review. PMID- 26984848 TI - Premeltons in DNA. AB - Premeltons are examples of emergent-structures (i.e., structural-solitons) that arise spontaneously in DNA due to the presence of nonlinear-excitations in its structure. They are of two kinds: B-B (or A-A) premeltons form at specific DNA regions to nucleate site-specific DNA melting. These are stationary and, being globally-nontopological, undergo breather-motions that allow drugs and dyes to intercalate into DNA. B-A (or A-B) premeltons, on the other hand, are mobile, and being globally-topological, act as phase-boundaries transforming B- into A-DNA during the structural phase-transition. They are not expected to undergo breather motions. A key feature of both types of premeltons is the presence of an intermediate structural-form in their central regions (proposed as being a transition-state intermediate in DNA-melting and in the B- to A-transition), which differs from either A- or B-DNA. Called beta-DNA, this is both metastable and hyperflexible--and contains an alternating sugar-puckering pattern along the polymer backbone combined with the partial unstacking (in its lower energy-forms) of every-other base-pair. Beta-DNA is connected to either B- or to A-DNA on either side by boundaries possessing a gradation of nonlinear structural-change, these being called the kink and the antikink regions. The presence of premeltons in DNA leads to a unifying theory to understand much of DNA physical chemistry and molecular biology. In particular, premeltons are predicted to define the 5' and 3' ends of genes in naked-DNA and DNA in active-chromatin, this having important implications for understanding physical aspects of the initiation, elongation and termination of RNA-synthesis during transcription. For these and other reasons, the model will be of broader interest to the general-audience working in these areas. The model explains a wide variety of data, and carries with it a number of experimental predictions--all readily testable--as will be described in this review. PMID- 26984850 TI - Visceral Leishmaniasis May Unmask X-linked Hyper-IgM Syndrome. PMID- 26984849 TI - Dissecting Epigenetic Dysregulation of Primary Antibody Deficiencies. AB - Primary antibody deficiencies (PADs), the most prevalent inherited primary immunodeficiencies (PIDs), are associated with a wide range of genetic alterations (both monogenic or polygenic) in B cell-specific genes. However, correlations between the genotype and clinical manifestations are not evident in all cases indicating that genetic interactions, environmental and epigenetic factors may have a role in PAD pathogenesis. The recent identification of key defects in DNA methylation in common variable immunodeficiency as well as the multiple evidences on the role of epigenetic control during B cell differentiation, activation and during antibody formation highlight the importance of investing research efforts in dissecting the participation of epigenetic defects in this group of diseases. This review focuses on the role of epigenetic control in B cell biology which can provide clues for the study of potential novel pathogenic defects involved in PADs. PMID- 26984851 TI - Human Circulating T Follicular Helper Cell Subsets in Health and Disease. AB - T follicular helper (Tfh) cells are specialized to provide help to B cells and to induce durable antibody response. Our knowledge on the biology of Tfh cells and their contribution to disease has significantly increased in the past decade. In particular, recent discoveries of functionally distinct subsets within circulating Tfh (cTfh) cells in human blood have provided clues to assess the ongoing Tfh responses in healthy subjects after vaccinations and in patients with autoimmune diseases. The immune pathways associated with Tfh cell differentiation in humans are also getting revealed. In this review, I will first summarize the subsets within human cTfh cells, and discuss their alterations in patients with autoimmune diseases. Then I will discuss the mechanisms associated with the aberrant Tfh responses in human autoimmune diseases. PMID- 26984852 TI - Role and therapeutic potential of vascular stem/progenitor cells in pathological neovascularisation during chronic portal hypertension. AB - OBJECTIVE: Pathological neovascularisation is intimately involved in portal hypertension (PH). Here, we determined the contribution of vascular stem/progenitor cells (VSPCs) to neovessel growth in PH and whether the RNA binding protein cytoplasmic polyadenylation element binding protein-4 (CPEB4) was behind the mechanism controlling VSPC function. DESIGN: To identify and monitor VSPCs in PH rats (portal vein-ligated), we used a combinatorial approach, including sphere-forming assay, assessment of self-renewal, 5-bromo-2' desoxyuridine label retention technique, in vitro and in vivo stem/progenitor cell (SPC) differentiation and vasculogenic capability, cell sorting, as well as immunohistochemistry, immunofluorescence and confocal microscopy expression analysis. We also determined the role of CPEB4 on VSPC proliferation using genetically engineered mouse models. RESULTS: We demonstrated the existence in the mesenteric vascular bed of VSPCs displaying capability to form cellular spheres in suspension culture, self-renewal ability, expression of molecules commonly found in SPCs, slow-cycling features, in addition to other cardinal properties exhibited by SPCs, like capacity to differentiate into endothelial cells and pericytes with remarkable vasculogenic activity. Such VSPCs showed, after PH induction, an early switch in proliferation, and differentiated in vivo into endothelial cells and pericytes, contributing, structurally and functionally, to abnormal neovessel formation. Quantification of VSPC-dependent neovessel formation in PH further illustrated the key role played by VSPCs. We also demonstrated that CPEB4 regulates the proliferation of the activated VSPC progeny upon PH induction. CONCLUSIONS: These findings demonstrate that VSPC derived neovessel growth (ie, vasculogenesis) and angiogenesis cooperatively stimulate mesenteric neovascularisation in PH and identify VSPC and CPEB4 as potential therapeutic targets. PMID- 26984853 TI - Gut microbiota produce alcohol and contribute to NAFLD. PMID- 26984854 TI - Propranolol improves endothelial dysfunction in advanced cirrhosis: the 'endothelial exhaustion' hypothesis. PMID- 26984855 TI - Complexity of cardiac ion channel macromolecular complexes. PMID- 26984857 TI - If it were only that simple. PMID- 26984856 TI - Native American Death Taboo: Implications for Health Care Providers. AB - This study was conducted to highlight Native American (NA) perspectives on death taboo in order to examine the cultural appropriateness of hospice services for NA patients, if any. Searching literature that addressed taboo and death from historical, psychological, sociological, and anthropological aspects, a comparison of death perspectives was made between NAs and European Americans. A culturally sensitive transition from palliative care to hospice care was suggested for NA patients and their family. PMID- 26984858 TI - Reduction of LDL-cholesterol: important at all ages. PMID- 26984859 TI - FDG-PET reveals coronary artery inflammation proceeding to cardiac allograft vasculopathy progression. PMID- 26984860 TI - Optical coherence tomographic findings of myeloproliferative disorder presenting as acute myocardial infarction. PMID- 26984861 TI - Catheter ablation for atrial fibrillation is associated with lower incidence of stroke and death: data from Swedish health registries. AB - AIM: It is unclear if catheter ablation for atrial fibrillation (AF) affects the prognosis or merely is a symptomatic treatment. The aim is to study the association between ablation for AF, ischaemic stroke, and mortality. METHODS AND RESULTS: We identified all 361 913 patients with a diagnosis of AF in the Swedish Patient Register. During a 7-year period, 5176 AF ablations were performed among 4278 individuals. Patients who had undergone catheter ablation were younger (58.7 vs. 74.7 years, P < 0.001) and healthier (mean CHA2DS2-VASc scores 1.5 +/- 1.4 vs. 3.6 +/- 1.9, P < 0.001) than other patients with AF. Propensity score matching was used to construct two cohorts of equal size (n = 2836) with similar characteristics in 51 dimensions. Mean follow-up was 4.4 +/- 2.0 years (minimum 1 year). In the ablated group, 78 patients suffered ischaemic stroke compared with 112 in the non-ablated (annual rates 0.70 vs. 1.0%, P = 0.013). A total of 88 ablated and 184 non-ablated patients died (annual rates 0.77 vs. 1.62%, P < 0.001). After multivariable adjustments, catheter ablation was associated with lower risk of ischaemic stroke [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.51-0.93) and with lower mortality risk (HR 0.50, 95% CI 0.37-0.62). Stroke reduction was most pronounced among patients with CHA2DS2-VASc score >=2 (HR 0.39, 95% CI 0.19-0.78) and among patients without new cardioversions beyond 6 months after the ablation (HR 0.68, 95% CI 0.48-0.97). CONCLUSION: Ablation may be associated with lower incidence of ischaemic stroke and death in patients with AF. This beneficial finding appears more pronounced in patients with higher thromboembolic risk. PMID- 26984862 TI - Mapping and surgical ablation of persistent atrial fibrillation in cor triatriatum sinister. PMID- 26984863 TI - Cardiovascular safety of non-aspirin non-steroidal anti-inflammatory drugs: review and position paper by the working group for Cardiovascular Pharmacotherapy of the European Society of Cardiology. PMID- 26984865 TI - Chinese herbal drug natural indigo may cause pulmonary artery hypertension. PMID- 26984864 TI - Fluid status telemedicine alerts for heart failure: a randomized controlled trial. AB - AIMS: Hospital admissions are frequently preceded by increased pulmonary congestion in heart failure (HF) patients. This study evaluated whether early automated fluid status alert notification via telemedicine improves outcome in HF patients. METHODS AND RESULTS: Patients recently implanted with an implantable cardioverter defibrillator (ICD) with or without cardiac resynchronization therapy were eligible if one of three conditions was met: prior HF hospitalization, recent diuretic treatment, or recent brain natriuretic peptide increase. Eligible patients were randomized (1:1) to have fluid status alerts automatically transmitted as inaudible text message alerts to the responsible physician or to receive standard care (no alerts). In the intervention arm, following a telemedicine alert, a protocol-specified algorithm with remote review of device data and telephone contact was prescribed to assess symptoms and initiate treatment. The primary endpoint was a composite of all-cause death and cardiovascular hospitalization. We followed 1002 patients for an average of 1.9 years. The primary endpoint occurred in 227 patients (45.0%) in the intervention arm and 239 patients (48.1%) in the control arm [hazard ratio, HR, 0.87; 95% confidence interval (CI), 0.72-1.04; P = 0.13]. There were 59 (11.7%) deaths in the intervention arm and 63 (12.7%) in the control arm (HR, 0.89; 95% CI, 0.62 1.28; P = 0.52). Twenty-four per cent of alerts were not transmitted and 30% were followed by a medical intervention. CONCLUSION: Among ICD patients with advanced HF, fluid status telemedicine alerts did not significantly improve outcomes. Adherence to treatment protocols by physicians and patients might be challenge for further developments in the telemedicine field. PMID- 26984867 TI - Telestroke-the promise and the challenge. Part two-expansion and horizons. AB - Acute ischemic stroke remains a major public health concern, with low national treatment rates for the condition, demonstrating a disconnection between the evidence of treatment benefit and delivery of this treatment. Intravenous thrombolysis and endovascular thrombectomy are both strongly evidence supported and exquisitely time sensitive therapies. The mismatch between the distribution and incidence of stroke presentations and the availability of specialist care significantly affects access to care. Telestroke, the use of telemedicine for stroke, aims to surmount this hurdle by distributing stroke expertise more effectively, through video consultation with and examination of patients in locations removed from specialist care. This is the second of a two part review, and is focused on the challenges telestroke faces for wider adoption. It further details the anticipated evolution of this novel therapeutic platform, and the potential roles it holds in stroke prevention, ambulance based care, rehabilitation, and research. PMID- 26984868 TI - Telestroke-the promise and the challenge. Part one: growth and current practice. AB - Acute ischemic stroke remains a major public health concern, with low national treatment rates for the condition, demonstrating a disconnection between the evidence of treatment benefit and delivery of this treatment. Intravenous thrombolysis and endovascular thrombectomy are both strongly evidence supported and exquisitely time sensitive therapies. The mismatch between the distribution and incidence of stroke presentations and the availability of specialist care significantly affects access to care. Telestroke, the use of telemedicine for stroke, aims to surmount this hurdle by distributing stroke expertise more effectively, through video consultation with and examination of patients in locations removed from specialist care. This is the first of a detailed two part review, and explores the growth and current practice of telestroke, including the specific role it plays in the assessment and management of patients after emergent large vessel occlusion. PMID- 26984871 TI - April 2016 Update. PMID- 26984870 TI - Advancing non-directive pregnancy options counseling skills: A pilot Study on the use of blended learning with an online module and simulation. AB - OBJECTIVE: Limitations on didactic time pose barriers to teaching non-directive pregnancy options counseling. This study set out to explore the use of an online module to support trainee performance in a pregnancy options counseling standardized-patient exercise implemented among third-year medical students, and to examine the effect of clinical experience on student performance. STUDY DESIGN: An online module was developed. A convenience sample of forty-six student performances in a family medicine clerkship participated in a standardized patient exercise. Trained faculty rated performances. Students completed a self assessment and provided feedback on the online module. Chi-square and Mann Whitney-U tests were used to analyze data. Three coders qualitatively examined narrative student comments. RESULTS: Thirty-four students passed, 11 achieved a minimal pass, and one failed. The mean global rating from faculty was 2.8 (pass). Students with prior clinical experience significantly outperformed those without on the global rating scale with mean scores of 3.1 compared to 2.7, respectively (p=.044). All students agreed that the online module helped prepare them for the exercise. Qualitative analysis of students' feedback on the module revealed strengths in content and pedagogy. In their self-assessments, all but two students referred to content explicitly conveyed in the module. CONCLUSION: All students agreed that an online module supported their performance of non directive pregnancy options counseling skills. Prior clinical experience was associated with improved performance. This module, along with the simulated exercise, can be implemented as a blended learning exercise without additional faculty teaching effort in standardized patient resource centers. IMPLICATIONS: Students agreed that an online module facilitates simulated performance of non directive pregnancy options counseling skills. Future work should compare the impact of this approach to others, and explore the additional training needed to maintain and build on initial learning. PMID- 26984873 TI - Transition and Adaptation to the Continuing Care Retirement Community From a Life Course Perspective: Something Old, Something New, and Something Borrowed. AB - The study examined the accounts of older adults and their adult children concerning the transition to the continuing care retirement community (CCRC) and the adjustment to it, using a life course perspective. Up to three waves of interviews, consisting of a total of 187 interviews with older adults and their adult children, were conducted between 6 months and 6 years from the transition to the CCRC. Thematic analysis was employed using comparisons across groups of interviewees (older adults and adult children) and waves of interviews (up to three waves) to identify core categories of meaning. Time perception was an organizing principle across interviews. Both older adults and their adult children perceived themselves as moving forward and backward in time following the transition to the CCRC and future expectations for deterioration. The study emphasizes the linked-lives of older adults and their adult children. PMID- 26984869 TI - Thromboaspiration technique as first approach for endovascular treatment of acute ischemic stroke: initial experience at nine Italian stroke centers. AB - BACKGROUND AND PURPOSE: Aspiration thrombectomy of large vessel occlusions has made a comeback among recanalization techniques thanks to recent advances in catheter technology resulting in faster recanalization and promising clinical results when used either alone or as an adjunct to stent retriever. This multicenter retrospective study reports angiographic data, complications, and clinical outcome in patients treated with aspiration thrombectomy as the first line option. MATERIALS AND METHODS: We analysed the clinical and procedural data of patients treated from January 2014 to March 2015. Recanalization was assessed according to the Thrombolysis in Cerebral Infarction score. Clinical outcome was evaluated at discharge and after 3 months. RESULTS: Overall, 152 patients (mean age 68 years) were treated. Sites of occlusion were 90.8% anterior circulation (including 16.4% tandem extracranial/intracranial occlusions) and 9.2% basilar artery. In 79 patients administration of intravenous tissue plasminogen activator was attempted. Recanalization of the target vessel was obtained in 115/152 cases (75.6%) whereas direct aspiration alone was successful in 83/152 cases (54.6%) with an average puncture to revascularization time of 44.67 min. Symptomatic intracranial hemorrhage occurred in 7.8% and embolization to new territories in 1.9%. 77 patients (50.6%) had a good outcome at 90-day follow-up: 55/96 in the direct aspiration alone group and 22/56 in the aspiration-stent retriever group. CONCLUSIONS: Direct aspiration thrombectomy appears a feasible technique with good revascularization results achieved in more than half the patients. In light of the self-reported data, inhomogeneous patient selection, absence of a core imaging laboratory, and a non-standardized approach, the results should be validated in a larger trial. PMID- 26984872 TI - Flavored Intravenous Ondansetron Administered Orally for the Treatment of Persistent Vomiting in Children. AB - OBJECTIVE: To study the serum level of ondansetron after oral administration of intravenous ondansetron, and test the palatability of the drug after being flavored. METHOD: This is a single-center prospective study enrolling children aged 3-8 years with gastroenteritis treated for persistent vomiting; patients received single dose of flavored intravenous ondansetron orally. The primary outcome was ondansetron serum level at 4 hours. Secondary outcome was palatability of the drug. RESULTS: Forty previously healthy patients presenting with acute gastroenteritis were enrolled. The mean age was 4.86+/-1.37 years. Serum level at 4 h had a median of 26.23 ng/ml, range (8.3-52 ng/ml). Palatability of the drug had a mean of 3.23 (of 5) +/- 0.80, based on score from visual analog scale. CONCLUSIONS: Flavored intravenous ondansetron administered orally is a safe and an effective option and can be considered in the absence of the oral forms of the drug. PMID- 26984874 TI - The Ethics of Doing Ethics. AB - Ethicists have investigated ethical problems in other disciplines, but there has not been much discussion of the ethics of their own activities. Research in ethics has many ethical problems in common with other areas of research, and it also has problems of its own. The researcher's integrity is more precarious than in most other disciplines, and therefore even stronger procedural checks are needed to protect it. The promotion of some standpoints in ethical issues may be socially harmful, and even our decisions as to which issues we label as "ethical" may have unintended and potentially harmful social consequences. It can be argued that ethicists have an obligation to make positive contributions to society, but the practical implications of such an obligation are not easily identified. This article provides an overview of ethical issues that arise in research into ethics and in the application of such research. It ends with a list of ten practical proposals for how these issues should be dealt with. PMID- 26984875 TI - Cervical pedicle screw placement using intraoperative computed tomography imaging with a mobile scanner gantry. AB - PURPOSE: A multi-detector computed tomography (CT) imaging system with a mobile scanner gantry in the operating room can provide intraoperative reconstructed images with a high resolution. We devised a technique for cervical pedicle screw (CPS) placement using the mobile CT system and evaluated the accuracy of this technique. METHODS: Forty-eight patients who underwent cervical fixation using CPSs were prospectively enrolled in this study. Initial pedicle probing was performed approximately to the depth of the posterior aspect of the vertebral body using fluoroscopic lateral view, and a marking pin was put in place. Intraoperative CT images were obtained to confirm whether the position of the marking pin was accurate. After adequate modification of the trajectory was performed, an appropriately sized CPS was inserted. The accuracy of the CPS was evaluated using postoperative reconstructed CT images, and compared with a historical control group of 22 patients (CPS insertion using only fluoroscopy). RESULTS: A total of 193 CPSs were inserted. Intraoperative CT images demonstrated that 12.4 % of the initial probings were not accurate, and modification of the trajectory was required. On postoperative CT, 92.7 % of the CPSs were found to be placed accurately: the accuracy was significantly higher than the control group (80.9 %). In the cases using intraoperative CT images, only 1.0 % of the screws were judged to show grade 2 screw misplacement; no neurovascular complications associated with screw placement were observed. CONCLUSIONS: The technique of CPS placement using mobile CT was shown to be safe and effective in preventing catastrophic complications associated with CPS insertion. PMID- 26984877 TI - A retrospective observational study on the treatment outcomes of 26 patients with spinal cord astrocytoma including two cases of malignant transformation. AB - PURPOSE: To determine the biologic behavior and prognostic factors of spinal cord astrocytoma, we reviewed surgical and clinical outcomes. Due to the rarity of spinal cord astrocytoma, there is a lack of research regarding this type of tumor and malignant transformation. METHODS: We retrospectively reviewed the data from all patients on whom we performed spinal cord tumor removal between 1983 and 2014. Twenty-six patients were pathologically confirmed to have spinal cord astrocytoma or glioblastoma. Surgical extent and disease progression were confirmed by the surgeon based on operative findings, postoperative MRI, and outpatient department (OPD) follow-up. RESULTS: Pain or neurological deficit was the chief complaint for all patients. With MRI studies, there is a tendency for high-grade astrocytomas to show as enhanced and heterogeneous images. Two of the low-grade astrocytomas showed malignant transformation over the course of 4 and 11 months, respectively. The overall survival (OS) for low-grade astrocytoma was 28-480 months (mean 156.38 months); the OS for high-grade astrocytoma was 1-36 months (mean 12.00 months). CONCLUSIONS: Two of 12 low-grade cases showed malignant transformations at 4 and 11 months, respectively, based on pathological confirmation. With spinal cord astrocytomas, enhanced MRI results appeared similar to those of a malignant lesion. We suggest close observation and image correlation of low-grade astrocytomas, even when pathologically confirmed as low grade. In this review, we found that histologic grade is the most important prognostic factor, although it is not always concordant with biologic behaviors. PMID- 26984878 TI - Vertebral body fracture after TLIF: a new complication. AB - BACKGROUND: The transforaminal posterior approach (TLIF) procedure was first described in 1982. Current literature indicates its equality in outcomes for fusion constructs as other anterior-posterior procedures. As a procedure becomes more popular and is more frequently performed the types and number of complications that occur increase. We report on a two case series that underwent TLIF. Both patients had satisfactory postoperative imaging, but presented later with coronal plane vertebral body fractures in the caudal vertebral body of the TLIF construct. We believe the complication may be related to: (a) unrecognized fracture of the endplate during cage impaction; (b) overloading the endplates by maximizing the lordosis achieved by using the reverse jackknife position on a Jackson table; (c) underlying mineral bone disease in patients. As the TLIF procedure increases in popularity, caution should be exercised to avoid the same potential complications. PURPOSE: To describe a potential complication with the TLIF procedure. STUDY DESIGN: Case report. PATIENT SAMPLE: 2. OUTCOME MEASURE: Revision surgery. METHODS: Case series. RESULTS: Caudal vertebral body fracture is a potential complication after TLIF. CONCLUSION: TLIF procedures can result in an unstable vertebral body fracture potentially necessitating revision decompression & stabilization. We recommend extra caution in patients with mineral bone disease, as technical errors can be magnified. PMID- 26984880 TI - Letter to the Editor concerning "Surgery and survival outcomes of 30 patients with neurological deficit due to clear cell renal cell carcinoma spinal metastases" by Shuai Han et al. (Eur Spine J, 2015; DOI 10.1007/s00586-015-3912 3). PMID- 26984876 TI - Management of neck pain and associated disorders: A clinical practice guideline from the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. AB - PURPOSE: To develop an evidence-based guideline for the management of grades I III neck pain and associated disorders (NAD). METHODS: This guideline is based on recent systematic reviews of high-quality studies. A multidisciplinary expert panel considered the evidence of effectiveness, safety, cost-effectiveness, societal and ethical values, and patient experiences (obtained from qualitative research) when formulating recommendations. Target audience includes clinicians; target population is adults with grades I-III NAD <6 months duration. RECOMMENDATION 1: Clinicians should rule out major structural or other pathologies as the cause of NAD. Once major pathology has been ruled out, clinicians should classify NAD as grade I, II, or III. RECOMMENDATION 2: Clinicians should assess prognostic factors for delayed recovery from NAD. RECOMMENDATION 3: Clinicians should educate and reassure patients about the benign and self-limited nature of the typical course of NAD grades I-III and the importance of maintaining activity and movement. Patients with worsening symptoms and those who develop new physical or psychological symptoms should be referred to a physician for further evaluation at any time during their care. RECOMMENDATION 4: For NAD grades I-II <=3 months duration, clinicians may consider structured patient education in combination with: range of motion exercise, multimodal care (range of motion exercise with manipulation or mobilization), or muscle relaxants. In view of evidence of no effectiveness, clinicians should not offer structured patient education alone, strain counterstrain therapy, relaxation massage, cervical collar, electroacupuncture, electrotherapy, or clinic-based heat. RECOMMENDATION 5: For NAD grades I-II >3 months duration, clinicians may consider structured patient education in combination with: range of motion and strengthening exercises, qigong, yoga, multimodal care (exercise with manipulation or mobilization), clinical massage, low-level laser therapy, or non-steroidal anti-inflammatory drugs. In view of evidence of no effectiveness, clinicians should not offer strengthening exercises alone, strain-counterstrain therapy, relaxation massage, relaxation therapy for pain or disability, electrotherapy, shortwave diathermy, clinic-based heat, electroacupuncture, or botulinum toxin injections. RECOMMENDATION 6: For NAD grade III <=3 months duration, clinicians may consider supervised strengthening exercises in addition to structured patient education. In view of evidence of no effectiveness, clinicians should not offer structured patient education alone, cervical collar, low-level laser therapy, or traction. RECOMMENDATION 7: For NAD grade III >3 months duration, clinicians should not offer a cervical collar. Patients who continue to experience neurological signs and disability more than 3 months after injury should be referred to a physician for investigation and management. RECOMMENDATION 8: Clinicians should reassess the patient at every visit to determine if additional care is necessary, the condition is worsening, or the patient has recovered. Patients reporting significant recovery should be discharged. PMID- 26984882 TI - Should we treat subclinical hypothyroidism in obese children? PMID- 26984879 TI - Effect of surgical correction of adolescent idiopathic scoliosis on the quality of life: a prospective study with a minimum 5-year follow-up. AB - PURPOSE: To prospectively evaluate the quality of life (QoL), functionality, and body image of subjects who had undergone surgery for adolescent idiopathic scoliosis (AIS) 5-12 years previously, and to identify the outcome predictors. METHODS: The sample consisted of 87 patients for whom follow-up data were available out of a series of 91 patients who had surgery for AIS between 2002 and 2009. We assessed the preoperative, 1-year postoperative, and 5-year or more postoperative SF-36 and SRS-23 questionnaire scores. Longitudinal clinical and radiographic data also were evaluated. Changes in the patient-oriented outcomes were compared with age and sex-adjusted normative values. A multiple regression analysis was used to identify possible outcome predictors. RESULTS: Preoperatively, patients had impaired QoL, functionality, and body image compared to age- and sex-matched healthy controls. Surgery led to significant improvement of the SF-36 and SRS scores at the one-year and final control date, but the final scores on SF-36's physical indexes were lower than control subjects' scores. No clinically relevant differences with the normative values were detected in the final SRS scores. The height of the residual rib hump negatively predicted the total SRS and self-image scores; a more caudal level of fusion correlated with more postoperative pain. CONCLUSIONS: Patients who underwent surgery for AIS a minimum of 5 years earlier had impaired self-reported physical QoL compared to control subjects, but they nevertheless performed better than before their surgery. Greater size of the residual hump and greater distal extension of the fusion area are negatively correlated with final self reported outcome. PMID- 26984883 TI - A Pilot Study. AB - AIM: To examine the effectiveness of a bio-energy intervention on self-reported stress for a convenience sample of University students, faculty, and staff during finals week. We hypothesized that participants would report a decrease in stress after a 20 minute bio-energy intervention. STUDY DESIGN: A quasi-experimental, single-group, pretest-posttest design was used. METHOD: Thirty-nine faculty, staff, and students participated. Participants served as their own controls. A specific technique was provided by each bio-energy practitioner for 20 minutes after participants had completed a visual analogue scale identifying level of stress and listing two positive and negative behaviors they were currently using in response to stress. RESULTS: A one-sample t test indicates that bio-energy therapy significantly reduces stress, t(35) = 7.74, p < .0001. A multiple regression analysis further indicates that the decrease in stress levels is significantly greater for higher initial stress levels, t(31) = 4.748, p < .0001); decreases in stress are significantly greater for faculty and staff compared to students, t(31) = -2.223, p = .034; and decreases in stress levels are marginally significantly higher for older participants, t(31) =1.946, p = .061. CONCLUSION: Bio-energy therapy may have benefit in reducing stress for faculty, staff, and students during final examination week. Further research is needed. PMID- 26984881 TI - Distinguishing characteristics of stem cells derived from different anatomical regions of human degenerated intervertebral discs. AB - INTRODUCTION: Several types of stem cells have been successfully demonstrated to exist in the human degenerated intervertebral disc (IVD), which is composed of annulus fibrosus (AF), nucleus pulposus (NP) and cartilage endplate (CEP). However, the differences in the biological characteristics among these and bone marrow derived mesenchymal stem cells (BM-MSCs) remain unclear. MATERIALS AND METHODS: To investigate this issue, cells were harvested from human AF, NP, CEP, and bone marrow, respectively; passage 2 cells were selected using the agarose suspension culture system to obtain stem cell clones. Following expansion in vitro, stem cells from different anatomical regions were compared regarding the morphology, proliferation ability, immunophenotypic expression, and multi-lineage differentiation capacity. In addition, stem cell-alginate bead compositions were constructed for the comparison of DNA and sGAG content. RESULTS: There were subtle differences regarding cell morphology, but no significant differences in proliferation ability among the four types of stem cells. For the immunophenotypic analysis, all stem cells basically fulfilled the criteria for mesenchymal stem cells (MSCs), which have been published by the International Society for Cellular Therapy (ISCT), with a significant difference in CD105 expression. A comparison of the osteogenic capacities indicated: cartilage endplate-derived stem cells (CESCs) > annulus fibrosus-derived stem cells (AFSCs) > BM-MSCs > nucleus pulposus-derived stem cells (NPSCs). The chondrogenesis difference was similar to osteogenesis. For adipogenesis: BM-MSCs >NPSCs >CESCs >AFSCs. In the stem cell/alginate composition, the CESCs consistently showed the superior chondrogenic potential among all those cell types. CONCLUSIONS: Our data indicated that all the four types of stem cells shared some similar biological properties (regarding shape, proliferation ability and immunophenotypic expression). CESCs, which had the strongest osteogenic and chondrogenic potentials, may serve as excellent seed cells for NP/cartilage or bone tissue engineering. PMID- 26984884 TI - Carbamylated Erythropoietin Outperforms Erythropoietin in the Treatment of AKI-on CKD and Other AKI Models. AB - Erythropoietin (EPO) may be a beneficial tissue-protective cytokine. However, high doses of EPO are associate with adverse effects, including thrombosis, tumor growth, and hypertension. Carbamylated erythropoietin (CEPO) lacks both erythropoietic and vasoconstrictive actions. In this study, we compared the renoprotective, hemodynamic, and hematologic activities and survival effects of identical EPO and CEPO doses in rat models of clinically relevant AKI presentations, including ischemia-reperfusion-induced AKI superimposed on CKD (5000 U/kg EPO or CEPO; three subcutaneous injections) and ischemia-reperfusion induced AKI in old versus young animals and male versus female animals (1000 U/kg EPO or CEPO; three subcutaneous injections). Compared with EPO therapy, CEPO therapy induced greater improvements in renal function and body weight in AKI on CKD animals, with smaller increases in hematocrit levels and similarly improved survival. Compared with EPO therapy in the other AKI groups, CEPO therapy induced greater improvements in protection and recovery of renal function and survival, with smaller increases in systolic BP and hematocrit levels. Overall, old or male animals had more severe loss in kidney function and higher mortality rates than young or female animals, respectively. Notably, mRNA and protein expression analyses confirmed the renal expression of the heterodimeric EPO receptor/CD131 complex, which is required for the tissue-protective effects of CEPO signaling. In conclusion, CEPO improves renal function, body and kidney weight, and survival in AKI models without raising hematocrit levels and BP as substantially as EPO. Thus, CEPO therapy may be superior to EPO in improving outcomes in common forms of clinical AKI. PMID- 26984885 TI - Autoantibodies Targeting a Collecting Duct-Specific Water Channel in Tubulointerstitial Nephritis. AB - Tubulointerstitial nephritis is a common cause of kidney failure and may have diverse etiologies. This form of nephritis is sometimes associated with autoimmune disease, but the role of autoimmune mechanisms in disease development is not well understood. Here, we present the cases of three patients with autoimmune polyendocrine syndrome type 1 who developed tubulointerstitial nephritis and ESRD in association with autoantibodies against kidney collecting duct cells. One of the patients developed autoantibodies targeting the collecting duct-specific water channel aquaporin 2, whereas autoantibodies of the two other patients reacted against the HOXB7 or NFAT5 transcription factors, which regulate the aquaporin 2 promoter. Our findings suggest that tubulointerstitial nephritis developed in these patients as a result of an autoimmune insult on the kidney collecting duct cells. PMID- 26984887 TI - Glandular epithelial AR inactivation enhances PTEN deletion-induced uterine pathology. AB - Phosphatase and tensin homolog (PTEN) deletion induces uterine pathology, whereas androgen actions via androgen receptor (AR) support uterine growth and therefore may modify uterine cancer risk. We hypothesized that the androgen actions mediated via uterine glandular epithelial AR could modify PTEN deletion-induced uterine pathology. To test our hypothesis, we developed uterine glandular epithelium-specific PTEN and/or AR knockout mouse models comparing the uterine pathology among wild-type (WT), glandular epithelium-specific AR inactivation (ugeARKO), PTEN deletion (ugePTENKO), and the combined PTEN and AR knockout (ugePTENARKO) female mice. The double knockout restricted to glandular epithelium showed that AR inactivation enhanced PTEN deletion-induced uterine pathology with development of intraepithelial neoplasia by 20 weeks of age. In ugePTENARKO, 6/10 (60%) developed intraepithelial neoplasia, whereas 3/10 (30%) developed only glandular hyperplasia in ugePTENKO uterus. No uterine pathology was observed in WT (n=8) and ugeARKO (n=7) uteri. Uterine weight was significantly (P=0.002) increased in ugePTENARKO (374+/-97 mg (mean+/-s.e.)) compared with WT (97+/-6 mg), ugeARKO (94+/-12 mg), and ugePTENKO (205+/-33 mg). Estrogen receptor alpha (ERalpha) and P-AKT expression was modified by uterine pathology but did not differ between ugePTENKO and ugePTENARKO, suggesting that its expressions are not directly affected by androgens. However, progesterone receptor (PR) expression was reduced in ugePTENARKO compared to ugePTENKO uterus, suggesting that PR expression could be regulated by glandular epithelial AR inactivation. In conclusion, glandular epithelial AR inactivation (with persistent stromal AR action) enhanced PTEN deletion-induced uterine pathology possibly by downregulating PR expression in the uterus. PMID- 26984888 TI - Non-vitamin K antagonist oral anticoagulants (NOACs) for the management of venous thromboembolism. PMID- 26984886 TI - Integrated Omics and Computational Glycobiology Reveal Structural Basis for Influenza A Virus Glycan Microheterogeneity and Host Interactions. AB - Despite sustained biomedical research effort, influenza A virus remains an imminent threat to the world population and a major healthcare burden. The challenge in developing vaccines against influenza is the ability of the virus to mutate rapidly in response to selective immune pressure. Hemagglutinin is the predominant surface glycoprotein and the primary determinant of antigenicity, virulence and zoonotic potential. Mutations leading to changes in the number of HA glycosylation sites are often reported. Such genetic sequencing studies predict at best the disruption or creation of sequons for N-linked glycosylation; they do not reflect actual phenotypic changes in HA structure. Therefore, combined analysis of glycan micro and macro-heterogeneity and bioassays will better define the relationships among glycosylation, viral bioactivity and evolution. We present a study that integrates proteomics, glycomics and glycoproteomics of HA before and after adaptation to innate immune system pressure. We combined this information with glycan array and immune lectin binding data to correlate the phenotypic changes with biological activity. Underprocessed glycoforms predominated at the glycosylation sites found to be involved in viral evolution in response to selection pressures and interactions with innate immune-lectins. To understand the structural basis for site-specific glycan microheterogeneity at these sites, we performed structural modeling and molecular dynamics simulations. We observed that the presence of immature, high mannose type glycans at a particular site correlated with reduced accessibility to glycan remodeling enzymes. Further, the high mannose glycans at sites implicated in immune lectin recognition were predicted to be capable of forming trimeric interactions with the immune-lectin surfactant protein-D. PMID- 26984889 TI - Arterial stiffness of lifelong Japanese female pearl divers. AB - Japanese female pearl divers called Ama specialize in free diving in the cold sea for collecting foods and pearls in oysters. Exercising in the water combined with marked bradycardia and pressor responses provides a circulatory challenge to properly buffer or cushion elevated cardiac pulsations. Because Ama perform repeated free dives throughout their lives, it is possible that they may have adapted similar arterial structure and function to those seen in diving mammals. We compared arterial stiffness of lifelong Japanese pearl divers with age-matched physically inactive adults living in the same fishing villages. A total of 115 Japanese female pearl divers were studied. Additionally, 50 physically inactive adults as well as 33 physically active adults (participating in community fitness programs) living in the same coastal villages were also studied. There were no differences in age (~65 yr), body mass index, and brachial blood pressure between the groups. Measures of arterial stiffness, cardio-ankle vascular index and beta stiffness index were lower (P < 0.05) in pearl divers and physically active adults than in their physically inactive peers. Augmentation pressure and augmentation index adjusted for the heart rate of 75 beats/min were lower (P < 0.05) in pearl divers than in other groups. These results indicate that lifelong Japanese pearl divers demonstrate reduced arterial stiffness and arterial wave reflection compared with age-matched physically inactive peers living in the same fishing villages. PMID- 26984890 TI - Decreased excitability and voltage-gated sodium currents in aortic baroreceptor neurons contribute to the impairment of arterial baroreflex in cirrhotic rats. AB - Cardiovascular autonomic dysfunction, which is manifested by an impairment of the arterial baroreflex, is prevalent irrespective of etiology and contributes to the increased morbidity and mortality in cirrhotic patients. However, the cellular mechanisms that underlie the cirrhosis-impaired arterial baroreflex remain unknown. In the present study, we examined whether the cirrhosis-impaired arterial baroreflex is attributable to the dysfunction of aortic baroreceptor (AB) neurons. Biliary and nonbiliary cirrhotic rats were generated via common bile duct ligation (CBDL) and intraperitoneal injections of thioacetamide (TAA), respectively. Histological and molecular biological examinations confirmed the development of fibrosis in the livers of both cirrhotic rat models. The heart rate changes during phenylephrine-induced baroreceptor activation indicated that baroreflex sensitivity was blunted in the CBDL and TAA rats. Under the current clamp mode of the patch-clamp technique, cell excitability was recorded in DiI labeled AB neurons. The number of action potential discharges in the A- and C type AB neurons was significantly decreased because of the increased rheobase and threshold potential in the CBDL and TAA rats compared with sham-operated rats. Real-time PCR and Western blotting indicated that the NaV1.7, NaV1.8, and NaV1.9 transcripts and proteins were significantly downregulated in the nodose ganglion neurons from the CBDL and TAA rats compared with the sham-operated rats. Consistent with these molecular data, the tetrodotoxin-sensitive NaV currents and the tetrodotoxin-resistant NaV currents were significantly decreased in A- and C type AB neurons, respectively, from the CBDL and TAA rats compared with the sham operated rats. Taken together, these findings implicate a key cellular mechanism in the cirrhosis-impaired arterial baroreflex. PMID- 26984891 TI - Methylene blue prevents retinal damage in an experimental model of ischemic proliferative retinopathy. AB - Perinatal asphyxia induces retinal lesions, generating ischemic proliferative retinopathy, which may result in blindness. Previously, we showed that the nitrergic system was involved in the physiopathology of perinatal asphyxia. Here we analyze the application of methylene blue, a well-known soluble guanylate cyclase inhibitor, as a therapeutic strategy to prevent retinopathy. Male rats (n = 28 per group) were treated in different ways: 1) control group comprised born to-term animals; 2) methylene blue group comprised animals born from pregnant rats treated with methylene blue (2 mg/kg) 30 and 5 min before delivery; 3) perinatal asphyxia (PA) group comprised rats exposed to perinatal asphyxia (20 min at 37 degrees C); and 4) methylene blue-PA group comprised animals born from pregnant rats treated with methylene blue (2 mg/kg) 30 and 5 min before delivery, and then the pups were subjected to PA as above. For molecular studies, mRNA was obtained at different times after asphyxia, and tissue was collected at 30 days for morphological and biochemical analysis. Perinatal asphyxia produced significant gliosis, angiogenesis, and thickening of the inner retina. Methylene blue treatment reduced these parameters. Perinatal asphyxia resulted in a significant elevation of the nitrergic system as shown by NO synthase (NOS) activity assays, Western blotting, and (immuno)histochemistry for the neuronal isoform of NOS and NADPH-diaphorase activity. All these parameters were also normalized by the treatment. In addition, methylene blue induced the upregulation of the anti-angiogenic peptide, pigment epithelium-derived factor. Application of methylene blue reduced morphological and biochemical parameters of retinopathy. This finding suggests the use of methylene blue as a new treatment to prevent or decrease retinal damage in the context of ischemic proliferative retinopathy. PMID- 26984892 TI - Nitric oxide and fever: immune-to-brain signaling vs. thermogenesis in chicks. AB - Nitric oxide (NO) plays a role in thermogenesis but does not mediate immune-to brain febrigenic signaling in rats. There are suggestions of a different situation in birds, but the underlying evidence is not compelling. The present study was designed to clarify this matter in 5-day-old chicks challenged with a low or high dose of bacterial LPS. The lower LPS dose (2 MUg/kg im) induced fever at 3-5 h postinjection, whereas 100 MUg/kg im decreased core body temperature (Tc) (at 1 h) followed by fever (at 4 or 5 h). Plasma nitrate levels increased 4 h after LPS injection, but they were not correlated with the magnitude of fever. The NO synthase inhibitor (N(G)-nitro-l-arginine methyl ester, l-NAME; 50 mg/kg im) attenuated the fever induced by either dose of LPS and enhanced the magnitude of the Tc reduction induced by the high dose in chicks at 31-32 degrees C. These effects were associated with suppression of metabolic rate, at least in the case of the high LPS dose. Conversely, the effects of l-NAME on Tc disappeared in chicks maintained at 35-36 degrees C, suggesting that febrigenic signaling was essentially unaffected. Accordingly, the LPS-induced rise in the brain level of PGE2 was not affected by l-NAME. Moreover, l-NAME augmented LPS-induced huddling, which is indicative of compensatory mechanisms to run fever in the face of attenuated thermogenesis. Therefore, as in rats, systemic inhibition of NO synthesis attenuates LPS-induced fever in chicks by affecting thermoeffector activity and not by interfering with immune-to-brain signaling. This may constitute a conserved effect of NO in endotherms. PMID- 26984893 TI - pH buffering of single rat skeletal muscle fibers in the in vivo environment. AB - Homeostasis of intracellular pH (pHi) has a crucial role for the maintenance of cellular function. Several membrane transporters such as lactate/H(+) cotransporter (MCT), Na(+)/H(+) exchange transporter (NHE), and Na(+)/HCO3 (-) cotransporter (NBC) are thought to contribute to pHi regulation. However, the relative importance of each of these membrane transporters to the in vivo recovery from the low pHi condition is unknown. Using an in vivo bioimaging model, we pharmacologically inhibited each transporter separately and all transporters together and then evaluated the pHi recovery profiles following imposition of a discrete H(+) challenge loaded into single muscle fibers by microinjection. The intact spinotrapezius muscle of adult male Wistar rats (n = 72) was exteriorized and loaded with the fluorescent probe 2',7'-bis(2 carboxyethyl)-5(6)-carboxyfluorescein-acetoxymethyl ester (10 MUM). A single muscle fiber was then loaded with low-pH solution [piperazine-N,N'-bis(2 ethanesulfonic acid) buffer, pH 6.5, ~2.33 * 10(-3) MUl] by microinjection over 3 s. The rats were divided into groups for the following treatments: 1) no inhibitor (CONT), 2) MCT inhibition (by alpha-Cyano-4-hydroxyciannamic acid; 4 mM), 3) NHE inhibition (by ethylisopropyl amiloride; 0.5 mM), 4) NBC inhibition (by DIDS; 1 mM), and 5) MCT, NHE, and NBC inhibition (All blockade). The fluorescence ratio (F500 nm/F445 nm) was determined from images captured during 1 min (60 images/min) and at 5, 10, 15, and 20 min after injection. The pHi at 1-2 s after injection significantly decreased from resting pHi (DeltapHi = -0.73 +/- 0.03) in CONT. The recovery response profile was biphasic, with an initial rapid and close-to-exponential pHi increase (time constant, tau: 60.0 +/- 7.9 s). This initial rapid profile was not affected by any pharmacological blockade but was significantly delayed by carbonic anhydrase inhibition. In contrast, the secondary, more gradual, return toward baseline that restored CONT pHi to 84.2% of baseline was unimpeded by MCT, NHE, and NBC blockade separately but abolished by All blockade (DeltapHi = -0.60 +/- 0.07, 72.8% initial pHi, P < 0.05 vs. CONT). After injection of H(+) into, or superfusion onto, an adjacent fiber pHi of the surrounding fibers decreased progressively for the 20-min observation period (~7.0, P < 0.05 vs. preinjection/superfusion). In conclusion, these results support that, after an imposed H(+) load, the MCT, NHE, and NBC transporters are not involved in the initial rapid phase of pHi recovery. In contrast, the gradual recovery phase was abolished by inhibiting all three membrane transporter systems simultaneously. The alteration of pHi in surrounding fibers suggest that H(+) uptake by neighboring fibers can help alleviate the pH consequences of myocyte H(+) exudation. PMID- 26984894 TI - Deletion of GPR40 fatty acid receptor gene in mice blocks mercaptoacetate-induced feeding. AB - Both increased and decreased fatty acid (FA) availability contribute to control of food intake. For example, it is well documented that intestinal FA reduces feeding by triggering enterondocrine secretion of satietogenic peptides, such as cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1). In contrast, mechanisms by which decreased FA availability increase feeding are not well understood. Over the past three decades substantial research related to FA availability and increased feeding has involved use of the orexigenic compound mercaptoacetate (MA). Because MA reportedly inhibits FA oxidation, it has been assumed that reduced FA oxidation accounts for the orexigenic action of MA. Recently, however, we demonstrated that MA antagonizes G protein-coupled receptor 40 (GPR40), a membrane receptor for long and medium chain FA. We also demonstrated that, by antagonizing GPR40, MA inhibits GLP-1 secretion and attenuates vagal afferent activation by FA. Because both vagal afferent activation and GLP-1 inhibit food intake, we postulated that inhibition of GPR40 by MA might underlie the orexigenic action of MA. We tested this hypothesis using male and female GPR40 knockout (KO) and wild-type (WT) mice. Using several testing protocols, we found that MA increased feeding in WT, but not GPR40 KO mice, and that GPR40 KO mice gained more weight than WT on a high-fat diet. Metabolic monitoring after MA or saline injection in the absence of food did not reveal significant differences in respiratory quotient or energy expenditure between treatment groups or genotypes. These results support the hypothesis that MA stimulates food intake by blocking FA effects on GPR40. PMID- 26984897 TI - Sixty seconds on . . . the NHS Bill. PMID- 26984896 TI - Photoperiod- and Triiodothyronine-dependent Regulation of Reproductive Neuropeptides, Proinflammatory Cytokines, and Peripheral Physiology in Siberian Hamsters (Phodopus sungorus). AB - Seasonal trade-offs in reproduction and immunity are ubiquitous in nature. The mechanisms that govern transitions across seasonal physiological states appear to involve reciprocal switches in the local synthesis of thyroid hormone. In long day (LD) summer-like conditions, increased hypothalamic triiodothyronine (T3) stimulates gonadal development. Alternatively, short-day (SD) winter-like conditions increase peripheral leukocytes and enhance multiple aspects of immune function. These data indicate that the localized effects of T3 in the hypothalamus and leukocytes are photoperiod dependent. We tested the hypothesis that increased peripheral T3 in SD conditions would increase aspects of reproductive physiology and inhibit immune function, whereas T3 injections in LD conditions would facilitate aspects of immune function (i.e., leukocytes). In addition, we also examined whether T3 regulates hypothalamic neuropeptide expression as well as hypothalamic and splenic proinflammatory cytokine expression. Adult male Siberian hamsters were maintained in LD (15L:9D) or transferred to SD (9L:15D) for 8 weeks. A subset of LD and SD hamsters was treated daily with 5 ug T3 for 2 weeks. LD and SD controls were injected with saline. Daily T3 administration in SD hamsters (SD+T3) resulted in a rapid and substantial decrease in peripheral leukocyte concentrations and stimulated gonadal development. T3 treatment in LD (LD+T3) had no effect on testicular volumes but significantly increased leukocyte concentrations. Molecular analyses revealed that T3 stimulated interleukin 1beta messenger RNA (mRNA) expression in the spleen and inhibited RFamide Related Peptide-3 mRNA expression in the hypothalamus. Moreover, there was a photoperiod-dependent decrease in splenic tumor necrosis factor-alpha mRNA expression. These findings reveal that T3 has tissue-specific and photoperiod-dependent regulation of seasonal rhythms in reproduction and immune function. PMID- 26984898 TI - Is heart transplantation after circulatory death compatible with the dead donor rule? AB - Dalle Ave et al (2016) provide a valuable overview of several protocols for heart transplantation after circulatory death. However, their analysis of the compatibility of heart donation after circulatory death (DCD) with the dead donor rule (DDR) is flawed. Their permanence-based criteria for death, which depart substantially from established law and bioethics, are ad hoc and unfounded. Furthermore, their analysis is self-defeating, because it undercuts the central motivation for DDR as both a legal and a moral constraint, rendering the DDR vacuous and trivial. Rather than devise new and ad hoc criteria for death for the purpose of rendering DCD nominally consistent with DDR, we contend that the best approach is to explicitly abandon DDR. PMID- 26984895 TI - Predominance of Movement Speed Over Direction in Neuronal Population Signals of Motor Cortex: Intracranial EEG Data and A Simple Explanatory Model. AB - How neuronal activity of motor cortex is related to movement is a central topic in motor neuroscience. Motor-cortical single neurons are more closely related to hand movement velocity than speed, that is, the magnitude of the (directional) velocity vector. Recently, there is also increasing interest in the representation of movement parameters in neuronal population activity, such as reflected in the intracranial EEG (iEEG). We show that in iEEG, contrasting to what has been previously found on the single neuron level, speed predominates over velocity. The predominant speed representation was present in nearly all iEEG signal features, up to the 600-1000 Hz range. Using a model of motor cortical signals arising from neuronal populations with realistic single neuron tuning properties, we show how this reversal can be understood as a consequence of increasing population size. Our findings demonstrate that the information profile in large population signals may systematically differ from the single neuron level, a principle that may be helpful in the interpretation of neuronal population signals in general, including, for example, EEG and functional magnetic resonance imaging. Taking advantage of the robust speed population signal may help in developing brain-machine interfaces exploiting population signals. PMID- 26984899 TI - Influence of porcine circovirus type 2 vaccination on the level of antimicrobial consumption on 65 Austrian pig farms. AB - The administration of antibiotics to farm animals is an important contemporary topic. Veterinarians, pig producers, politicians, retailers and consumers all have a vested interest in reducing antimicrobial use on farm, while ensuring adequate health and welfare of food-producing animals. Vaccination programmes may be used to reduce the overall level of clinical disease in a population, subsequently leading to a decline in antimicrobial use. In 2008, a vaccination programme against porcine circovirus type 2 (PCV-2) was initiated in Austria. In the retrospective observational study presented here, farm medication records (2008-2011) from 65 conventional pig farms were evaluated. As PCV-2 has been shown to lead to generalised immunosuppression, enabling secondary bacterial infections to occur, the authors hypothesised that PCV-2 vaccination would decrease antimicrobial consumption at farm level. Firstly, we focused on the annual antimicrobial consumption expressed as the number of administered animal daily doses per kg liveweight (nADDkg/kg/year). Secondly, a linear mixed effects model was applied to evaluate the influence of PCV-2 vaccination on the antimicrobial consumption at farm level. The interaction between farm type and PCV-2 vaccination was found to be a highly significant factor (P=0.0002) influencing antimicrobial use at farm level. The estimated impact of PCV-2 vaccination revealed a highly significant (P<0.001) decline in total antimicrobial drug use from 1.72 ADDkg/kg/year to 0.56 ADDkg/kg/year on finishing farms, whereas only a negligible decline was detectable on farrow-to-finish farms. PMID- 26984900 TI - Seroprevalence and factors associated with equine herpesvirus type 1 and 4 in Spanish Purebred horses in Spain. AB - Equine herpesvirus type 1 (EHV-1) and type 4 (EHV-4) have a worldwide distribution and cause respiratory disease, abortion, neonatal death and myeloencephalopathy in susceptible horses. Given the scarcity of serological EHV 1/EHV-4 data in Spain, the objective of this cross-sectional study was to estimate the seroprevalence of EHV-1/EHV-4 and to identify potential horse-level and stud farm-level factors associated with EHV-1/EHV-4 in the breeding Spanish Purebred (SP) horse population in central Spain. Serum samples from 334 SP unvaccinated horses, collected between September 2011 and November 2013 at 30 stud farms, were tested using a commercially available EHV-1/EHV-4 antibody ELISA and seroneutralisation as the World Organisation for Animal Health reference confirmation test. Data on factors putatively associated with seropositivity to EHV-1/EHV-4 were collected via a questionnaire and examined using logistic regression analysis. EHV-1/EHV-4 seroprevalence in the SP breeding population in central Spain, standardised for the sex distribution of the reference horse population, was 53.9 per cent (95 per cent confidence interval 44.0 per cent to 63.8 per cent). Increasing age, southern location of the stud farm, temperate climate during the summer, and a smaller surface area used for breeding activities in the farm were associated with increased odds for EHV-1/EHV-4 seropositivity, whereas EHV-1/EHV-4 vaccination of other resident horses and separation of breeding mares from youngsters were protective factors. PMID- 26984902 TI - Overview of ICRP Committee 2: doses from radiation exposure. AB - The focus of the work of Committee 2 of the International Commission on Radiological Protection (ICRP) is the computation of dose coefficients compliant with Publication 103 A set of reference computational phantoms is being developed, based on medical imaging data, and used for radiation transport calculations. Biokinetic models used to describe the behaviour of radionuclides in body tissues are being updated, also leading to changes in organ doses and effective dose coefficients. Dose coefficients for external radiation exposure of adults calculated using the new reference phantoms were issued as Publication 116, jointly with the International Commission on Radiation Units and Measurements. Forthcoming reports will provide internal dose coefficients for radionuclide inhalation and ingestion by workers, and associated bioassay data. Work is in progress to revise internal dose coefficients for members of the public, and, for the first time, to provide reference values for external exposures of the public. Committee 2 is also working with Committee 3 on dose coefficients for radiopharmaceuticals, and leading a cross-Committee initiative to give advice on the use of effective dose. PMID- 26984903 TI - Are the core values of the radiological protection system shared across cultures? AB - In spite of ongoing globalisation in many fields, the ethics of radiological protection have long been discussed almost exclusively in terms of 'Western' moral philosophy concepts such as utilitarianism or deontology. A cross-cultural discourse in this field is only just beginning. In 'Principles of Biomedical Ethics', Beauchamp and Childress suggested that there exists a 'common morality' which is 'not relative to cultures or individuals, because it transcends both'. They proposed four cross-culturally valid principles for decision making in medicine: respect for autonomy, non-maleficence, beneficence, and justice. A similar approach is being developed by the International Commission on Radiological Protection Task Group 94 on the ethics of radiological protection. Here, the core values are: human dignity, beneficence/non-maleficence, prudence, and justice. Other values could be added, such as consideration for the interests of society as a whole or the interests of future generations, or procedural values such as transparency and accountability; this paper will include a brief discussion on how they relate to the four basic principles. The main question to be addressed here, however, is whether the proposed core values are indeed part of a 'common morality'. This, as it will be argued, cannot be decided by a global opinion poll, but has to be based on an analysis of the written and oral traditions that have provided ethical orientation throughout history, and are still considered seminal by the majority of people. It turns out that there are indeed many commonalities across cultures, and that the concept of globally shared core values for the radiological protection system is not hopelessly idealistic. PMID- 26984901 TI - Cysticidal Efficacy of Combined Treatment With Praziquantel and Albendazole for Parenchymal Brain Cysticercosis. AB - BACKGROUND: The efficacy of current antiparasitic treatment for cerebral Taenia solium cysticercosis with either albendazole (ABZ) or praziquantel (PZQ) is suboptimal. A recent study demonstrated that combining these 2 antiparasitic drugs improves antiparasitic efficacy. We present here the parasiticidal efficacy data obtained during a previous phase II pharmacokinetic study that compared combined ABZ plus PZQ with ABZ alone. METHODS: The study was a randomized, double blinded, placebo-controlled phase II evaluation of the pharmacokinetics of ABZ (15 mg/k/d, for 10 days) and PZQ (50 mg/k/d, for 10 days) in intraparenchymal brain cysticercosis. Patients received the usual concomitant medications, including an antiepileptic drug (phenytoin or carbamazepine), dexamethasone, and ranitidine. Randomization was stratified by antiepileptic drug. Patients underwent safety laboratory evaluations at days 4, 7, and 11, as well as magnetic resonance (MR) imaging at 6 months to assess parasiticidal efficacy. RESULTS: Thirty-two patients were included, 16 in each arm. All of them completed antiparasitic treatment and underwent follow-up brain MR imaging. Cysticidal efficacy was strikingly higher in the combined ABZ-plus-PZQ group than in the ABZ alone group (proportion of cysts resolved, 78 of 82 [95%] vs 23 of 77 [30%] [relative risk {RR}, 3.18; 95% confidence interval {CI}, 2.08-4.88; P < .001]; patients with complete cyst clearance, 12 of 16 [75%] vs 4 of 16 [25%] [RR, 3.00; 95% CI, 1.23-7.34; P = .005]). CONCLUSIONS: The combination of ABZ plus PZQ is more effective in destroying viable brain cysticercosis cysts than ABZ alone. CLINICAL TRIALS REGISTRATION: NCT00441285. PMID- 26984905 TI - The rewards of switching to digital. PMID- 26984904 TI - Dosimetry for animals and plants: contending with biota diversity. AB - Diversity of living organisms and their environmental radiation exposure conditions represents a special challenge for non-human dosimetry. In order to contend with such diversity, the International Commission on Radiological Protection (ICRP) has: (a) set up points of reference by providing dose conversion coefficients (DCCs) for reference entities known as 'Reference Animals and Plants' (RAPs); and (b) used dosimetric models that pragmatically assume simple body shapes with uniform composition and density, homogeneous internal contamination, a limited set of idealised external radiation sources, and truncation of the radioactive decay chains. This pragmatic methodology has been further developed and extended systematically. Significant methodological changes include: a new extended approach for assessing doses of external exposure for terrestrial animals, transition to the contemporary ICRP radionuclide database, assessment-specific consideration of the contribution of radioactive progeny to dose coefficients of parent nuclides, and the use of generalised allometric relationships in the estimation of biokinetic or metabolic parameters. The new methodological developments resulted in a revision of the DCCs for RAPs. Tables of the dose coefficients have now been complemented by a web-based software tool, which can be used to calculate a user-specific DCC for an organism of arbitrary mass and shape, located at user-defined height above the ground, and for an arbitrary radionuclide and its radioactive progeny. PMID- 26984906 TI - Fears from a medical student. PMID- 26984907 TI - Bayesian clinical classification from high-dimensional data: Signatures versus variability. AB - When data exhibit imbalance between a large number d of covariates and a small number n of samples, clinical outcome prediction is impaired by overfitting and prohibitive computation demands. Here we study two simple Bayesian prediction protocols that can be applied to data of any dimension and any number of outcome classes. Calculating Bayesian integrals and optimal hyperparameters analytically leaves only a small number of numerical integrations, and CPU demands scale as O(nd). We compare their performance on synthetic and genomic data to the mclustDA method of Fraley and Raftery. For small d they perform as well as mclustDA or better. For d = 10,000 or more mclustDA breaks down computationally, while the Bayesian methods remain efficient. This allows us to explore phenomena typical of classification in high-dimensional spaces, such as overfitting and the reduced discriminative effectiveness of signatures compared to intra-class variability. PMID- 26984908 TI - A Markov chain representation of the multiple testing problem. AB - The problem of multiple hypothesis testing can be represented as a Markov process where a new alternative hypothesis is accepted in accordance with its relative evidence to the currently accepted one. This virtual and not formally observed process provides the most probable set of non null hypotheses given the data; it plays the same role as Markov Chain Monte Carlo in approximating a posterior distribution. To apply this representation and obtain the posterior probabilities over all alternative hypotheses, it is enough to have, for each test, barely defined Bayes Factors, e.g. Bayes Factors obtained up to an unknown constant. Such Bayes Factors may either arise from using default and improper priors or from calibrating p-values with respect to their corresponding Bayes Factor lower bound. Both sources of evidence are used to form a Markov transition kernel on the space of hypotheses. The approach leads to easy interpretable results and involves very simple formulas suitable to analyze large datasets as those arising from gene expression data (microarray or RNA-seq experiments). PMID- 26984909 TI - Responsiveness-informed multiple imputation and inverse probability-weighting in cohort studies with missing data that are non-monotone or not missing at random. AB - Population-based cohort studies are invaluable to health research because of the breadth of data collection over time, and the representativeness of their samples. However, they are especially prone to missing data, which can compromise the validity of analyses when data are not missing at random. Having many waves of data collection presents opportunity for participants' responsiveness to be observed over time, which may be informative about missing data mechanisms and thus useful as an auxiliary variable. Modern approaches to handling missing data such as multiple imputation and maximum likelihood can be difficult to implement with the large numbers of auxiliary variables and large amounts of non-monotone missing data that occur in cohort studies. Inverse probability-weighting can be easier to implement but conventional wisdom has stated that it cannot be applied to non-monotone missing data. This paper describes two methods of applying inverse probability-weighting to non-monotone missing data, and explores the potential value of including measures of responsiveness in either inverse probability-weighting or multiple imputation. Simulation studies are used to compare methods and demonstrate that responsiveness in longitudinal studies can be used to mitigate bias induced by missing data, even when data are not missing at random. PMID- 26984910 TI - Outcomes of Unicompartmental Knee Arthroplasty After Aseptic Revision to Total Knee Arthroplasty: A Comparative Study of 768 TKAs and 578 UKAs Revised to TKAs from the Norwegian Arthroplasty Register (1994 to 2011). AB - BACKGROUND: The general recommendation for a failed primary unicompartmental knee arthroplasty (UKA) is revision to a total knee arthroplasty (TKA). The purpose of the present study was to compare the outcomes, intraoperative data, and mode of failure of primary UKAs and primary TKAs revised to TKAs. METHODS: The study was based on 768 failed primary TKAs revised to TKAs (TKA->TKA) and 578 failed primary UKAs revised to TKAs (UKA->TKA) reported to the Norwegian Arthroplasty Register between 1994 and 2011. Patient-reported outcome measures (PROMs) including the EuroQol EQ-5D, the Knee Injury and Osteoarthritis Outcome Score (KOOS), and visual analog scales assessing satisfaction and pain were used. We performed Kaplan-Meier and Cox regression analyses adjusting for propensity score to assess the survival rate and the risk of re-revision and multiple linear regression analyses to estimate the differences between the two groups in mean PROM scores. RESULTS: Overall, 12% in the UKA->TKA group and 13% in the TKA->TKA group underwent re-revision between 1994 and 2011. The ten-year survival percentage of UKA->TKA versus TKA->TKA was 82% versus 81%, respectively (p = 0.63). There was no difference in the overall risk of re-revision for UKA->TKA versus TKA->TKA (relative risk [RR] = 1.2; p = 0.19), or in the PROM scores. However, the risk of re-revision was two times higher for TKA->TKA patients who were greater than seventy years of age at the time of revision (RR = 2.1; p = 0.05). A loose tibial component (28% versus 17%), pain alone (22% versus 12%), instability (19% versus 19%), and deep infection (16% versus 31%) were major causes of re-revision for UKA->TKA versus TKA->TKA, respectively, but the observed differences were not significant, with the exception of deep infection, which was significantly greater in the TKA->TKA group (RR = 2.2; p = 0.03). The surgical procedure of TKA->TKA took a longer time (mean of 150 versus 114 minutes) and more of the procedures required stems (58% versus 19%) and stabilization (27% versus 9%) compared with UKA->TKA. CONCLUSIONS: Despite TKA >TKA seeming to be a technically more difficult surgical procedure, with a higher percentage of re-revisions due to deep infection compared with UKA->TKA, the overall outcomes of UKA->TKA and TKA->TKA were similar. PMID- 26984911 TI - OP-1 Compared with Iliac Crest Autograft in Instrumented Posterolateral Fusion: A Randomized, Multicenter Non-Inferiority Trial. AB - BACKGROUND: Spinal fusion with the use of autograft is a commonly performed procedure. However, harvesting of bone from the iliac crest is associated with complications. Bone morphogenetic proteins (BMPs) are extensively used as alternatives, often without sufficient evidence of safety and efficacy. The purpose of this study was to investigate non-inferiority of osteogenic protein-1 (OP-1, also known as BMP-7) in comparison with iliac crest bone graft in posterolateral fusions. METHODS: This study was a randomized, controlled multicenter trial. Patients who underwent a single-level instrumented posterolateral fusion of the lumbar spine for degenerative or isthmic spondylolisthesis with symptoms of neurological compression were randomized to receive OP-1 combined with local bone (OP-1 group) or autologous bone graft from the iliac crest combined with local bone (autograft group). The primary outcome was overall success, defined as a combination of clinical success and evidence of fusion on computed tomography (CT) scans, at one year postoperatively. RESULTS: One hundred and nineteen patients were included in the study, and analysis of the overall outcome was performed for 113. Non-inferiority of OP-1 compared with iliac crest autograft was not found at one year, with a success rate of 40% in the OP-1 group versus 54% in the autograft group (risk difference = -13.3%, 90% confidence interval [CI] = -28.6% to +2.10%). This was due to the lower rate of fusion (the primary aim of OP-1 application) seen on the CT scans in the OP-1 group (54% versus 74% in the autograft group, p = 0.03). There were no adverse events that could be directly related to the use of OP-1. CONCLUSIONS: OP-1 with a collagen carrier was not as effective as autologous iliac crest bone for achieving fusion and cannot be recommended in instrumented posterolateral lumbar fusion procedures. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 26984912 TI - C2 Vertebral Fractures in the Medicare Population: Incidence, Outcomes, and Costs. AB - BACKGROUND: Cervical 2 (C2) fractures in the elderly are common, and the incidence of these fractures has been increasing. Surgical and nonoperative treatments are associated with high complication and mortality rates, and these rates have not been evaluated at the population level, to our knowledge. The purpose of this study was to use the Medicare claims database to determine trends in treatment, surgical and nonoperative outcomes, and Medicare reimbursement for treatment of these fractures. METHODS: We examined the Medicare claims database from 2000 to 2011 to identify patients admitted for the treatment of a C2 fracture. The incidence of fractures and the rates of nonoperative and surgical treatment were determined across the study period. We compared rates of mortality and life-threatening complications between patients treated nonoperatively and surgically. Centers for Medicare & Medicaid Services (CMS) payments for the initial admission as well as for subsequent inpatient admissions during the ninety-day post-admission period were compared between treatment groups. We used multivariate analysis to control for differences in patient characteristics between groups. RESULTS: There were 81,596 admissions for C2 fracture identified, and 53,338 met inclusion criteria. The incidence of C2 fractures increased 135% from 2000 to 2011, but the rate of surgical treatment remained constant at 16%. There was significantly lower mortality at thirty days for the surgical group at 8.3% compared with the nonoperative group at 16.2% (p < 0.001) and at one year for the surgical group at 21.7% compared with the nonoperative group at 32.3% (p < 0.001). Life-threatening complications within thirty days of admission were slightly more common in the surgical group at 10.9% compared with the nonoperative group at 9.0% (p < 0.05). Medicare reimbursements for the initial inpatient admission were significantly higher (p < 0.001) in U.S. dollars for the surgical group at $21,487 compared with the nonoperative group at $8469, and this significant difference (p < 0.001) persisted in the ninety-day post-discharge period at $10,487 for the surgical group compared with $8410 for the nonoperative group. CONCLUSIONS: Although the incidence of C2 fractures in the Medicare population increased from 2000 to 2011, the rate of surgery stayed relatively constant. After controlling for baseline differences, patients treated with surgery had significantly lower thirty-day and one-year mortality rates compared with patients treated nonoperatively. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 26984913 TI - Inferior Cubital Artery Perforator Flap for Soft-Tissue Coverage of the Elbow: Anatomical Study and Clinical Application. AB - BACKGROUND: Soft-tissue defects surrounding the elbow can be a challenging problem for the orthopaedic surgeon. Reliable reconstruction with use of muscular flaps or even perforator flaps derived from the surrounding vessels has been described. The inferior cubital artery (ICA) is an indirect septocutaneous perforator branch that most frequently arises from the lateral side of the radial artery. The purposes of the present study were to characterize the capillary cutaneous perforators of the ICA and to evaluate the potential of a local perforator flap procedure for soft-tissue coverage of the elbow. METHODS: Twenty fresh cadaveric forearms were dissected in order to describe the ICA anatomy, and in ten additional forearms the ICA was selectively injected with a red ink solution to detail the ICA vascular territory. For each artery, we recorded the site of origin, the diameter of the artery at its source, the course of the artery, and the number, type, and diameter of capillary cutaneous perforators. RESULTS: A total of seventy-eight ICA capillary perforators were analyzed from the twenty dissected forearms: forty-six were in-transit capillary perforators, nineteen were terminal capillary perforators, and thirteen were musculocutaneous capillary perforators. Of these seventy-eight perforators, sixteen (21%) had a caliber of <0.5 mm and sixty-two capillary perforators (79%) had a caliber of >=0.5 mm. Ten ICAs were selectively injected, and the mean size of all stained skin areas was 30.9 +/- 11.9 cm(2). A perforator pedicled flap was readily feasible for all dissections. We also describe the case of a patient with a medial soft-tissue defect of the elbow that was covered with a pedicled perforator flap based on an ICA. The patient had satisfactory healing at two months. CONCLUSIONS: The ICA flap is a reliable and useful flap for elbow soft tissue reconstruction. CLINICAL RELEVANCE: The perforator flap procedure is a major advancement in reconstructive surgery. One potential application of the perforator flaps is the use of tissue adjacent to a defect as a perforator-based island flap. The use of this tissue allows for thinner flaps to be tailored for more accurate reconstruction. A flap that depends on a perforator branch of the radial artery called the inferior cubital artery seems to be an excellent solution for soft-tissue coverage of the elbow. PMID- 26984915 TI - A Vessel-Preserving Surgical Hip Dislocation Through a Modified Posterior Approach: Assessment of Femoral Head Vascularity Using Gadolinium-Enhanced MRI. AB - BACKGROUND: Surgical hip dislocation allows circumferential access to the femoral head and acetabulum and is utilized in the treatment of intra-articular hip disorders. Surgical hip dislocation is currently performed with a trochanteric osteotomy that reliably preserves the femoral head arterial supply; however, trochanteric nonunion or painful hardware requiring removal may occur. In a cadaveric model, using gadolinium-enhanced magnetic resonance imaging (MRI) and gross dissection, we evaluated whether modifications to the posterior approach preserve the femoral head arterial supply after a posterior surgical hip dislocation. METHODS: In eight fresh-frozen pelvic specimens, a surgical hip dislocation was performed through the posterolateral approach with modifications in the tenotomy of the short external rotators and a capsulotomy designed to preserve the medial femoral circumflex artery (MFCA). Modifications included tenotomies of the quadratus femoris, conjoined tendon of the short external rotators, and obturator externus made 2.5 cm medial to their insertion on the greater trochanter and a T-type capsulotomy originating below the cut edge of the obturator externus tendon and continuing circumferentially along the acetabular rim. After hip dislocation, the MFCA was cannulated and MRI scans were acquired before and after gadolinium enhancement for evaluation of femoral head perfusion, with the contralateral hip, which was left intact, used as a control. Anatomic gross dissection was performed after the injection of polyurethane in the MFCA and confirmed MFCA vessel integrity. RESULTS: Quantitative MRI showed that the operatively treated hip retained a mean perfusion (and standard deviation) of 95.6% +/- 9.7% in the femoral head and 94.7% +/- 21.5% in the femoral head-neck junction compared with the control hip (p = 0.66 and p = 0.85, respectively). Dissection after polyurethane injection confirmed that the superior retinacular and inferior retinacular arteries entering the femoral head were intact in all specimens. CONCLUSIONS: In a cadaveric model using gadolinium-enhanced MRI, we found that standardized modifications to the posterior approach, specifically with regard to the location of the short external rotator tenotomy and capsulotomy, successfully preserved the femoral head arterial supply after posterior surgical hip dislocation. CLINICAL RELEVANCE: While further research is necessary before these modifications can be recommended for widespread clinical use, the results of this study suggest the extracapsular vascular anatomy can be safely preserved during posterior surgical hip dislocation. PMID- 26984916 TI - Change in Size of Hamstring Grafts During Preparation for ACL Reconstruction: Effect of Tension and Circumferential Compression on Graft Diameter. AB - BACKGROUND: There is good consensus that anterior cruciate ligament (ACL) grafts should be pretensioned to remove creep prior to implantation, but the literature contains little information on the influence of graft preparation or circumferential compression on graft size. The purpose of this study was to investigate how the size of hamstring allografts changes as they are prepared for ACL reconstruction. We hypothesized that grafts decrease in diameter as they are prepared with both tension and circumferential compression. We also investigated the interrater reliability of graft diameter measurements during each step of graft preparation. METHODS: Twenty pairs of fresh-frozen human hamstring tendons obtained from an allograft supplier were prepared in a standardized fashion for ACL reconstruction (suturing followed by longitudinal tensioning followed by circumferential compression followed by relaxation). Four blinded raters measured each graft in a sequential manner after each graft preparation step. Interrater reliability was assessed using the intraclass correlation coefficient ICC(2,1). The mean allograft diameter at each time point was calculated and compared across all time points using repeated-measures analysis of variance (ANOVA). RESULTS: Subjecting the grafts to both tension and circumferential compression significantly decreased their mean diameter (to 7.38 mm compared with 8.28 mm at baseline; p = 0.044). Interrater reliability revealed almost perfect agreement at each measurement interval, with the ICC ranging from 0.933 to 0.961. CONCLUSIONS: The average diameter of hamstring ACL grafts decreases by almost 1 mm after they are subjected to both tension and circumferential compression within a standard cylindrical sizing block. CLINICAL RELEVANCE: Because ACL bone tunnels are drilled in 0.5-mm increments, preparing soft-tissue grafts with circumferential compression in addition to tension may allow creation of tunnels that are one to two incremental sizes smaller. This could permit less bone removal, which may be particularly applicable for certain reconstruction techniques such as pediatric, double-bundle, or revision ACL reconstruction, in which limited space is available for tunnel drilling. PMID- 26984917 TI - Foot and Ankle Function at Maturity After Ilizarov Treatment for Atrophic-Type Congenital Pseudarthrosis of the Tibia: A Comprehensive Outcome Comparison with Normal Controls. AB - BACKGROUND: The purpose of this study was to evaluate clinical outcomes and the biomechanical function of the foot and ankle at skeletal maturity of patients treated for atrophic-type congenital pseudarthrosis of the tibia (CPT) compared with healthy young adult controls. METHODS: Twenty-four patients (mean age of 19.1 years) who had undergone Ilizarov treatment for unilateral atrophic-type CPT were compared with twenty-four controls (mean age of 19.6 years). All participants were evaluated using validated outcome questionnaires, radiographs, physical examination, instrumented motion analysis including a multisegmental foot model, and pedobarographic measurement. RESULTS: Within the CPT group, the mean score of the American Orthopaedic Foot & Ankle Society (AOFAS) ankle hindfoot scale was 89.9 (range, 76 to 100), and the mean score of the Oxford Ankle Foot Questionnaire (OAFQ) was 42.8 (range, 15 to 60). Motion analysis and pedobarographic measurement showed differences in biomechanical function of the foot and ankle on the side affected by CPT: a slower walking speed due to the short stride length; decreased dorsiflexion in hallux motion; increased hindfoot pronation in the presence of forefoot supination; diminished ankle push-off power; delayed time to heel-rise; and decreased forefoot pressure relative to hindfoot pressure. However, sagittal motion of the hindfoot and forefoot on the affected side was relatively well preserved. Subgroup analysis demonstrated no significant differences in terms of clinical outcome scores and most biomechanical parameters between the tibiofibular synostosis group and the intact fibula group. CONCLUSIONS: Children with atrophic-type CPT can obtain satisfactory foot and ankle function at maturity after successful Ilizarov treatment. Early stabilization of the ankle mortise by fibular stabilization and preservation of ankle mobility during and after treatment is thought to be crucial to maintaining function of the ankle in patients with CPT. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 26984914 TI - Dynamic Stabilization with Active Locking Plates Delivers Faster, Stronger, and More Symmetric Fracture-Healing. AB - BACKGROUND: Axial dynamization of fractures can promote healing, and overly stiff fixation can suppress healing. A novel technology, termed active plating, provides controlled axial dynamization by the elastic suspension of locking holes within the plate. This prospective, controlled animal study evaluated the effect of active plates on fracture-healing in an established ovine osteotomy model. We hypothesized that symmetric axial dynamization with active plates stimulates circumferential callus and delivers faster and stronger healing relative to standard locking plates. METHODS: Twelve sheep were randomly assigned to receive a standard locking plate or an active locking plate for stabilization of a 3-mm tibial osteotomy gap. The only difference between plates was that locking holes of active plates were elastically suspended, allowing up to 1.5 mm of axial motion at the fracture. Fracture-healing was analyzed weekly on radiographs. After sacrifice at nine weeks postoperatively, callus volume and distribution were assessed by computed tomography. Finally, to determine their strength, healed tibiae and contralateral tibiae were tested in torsion until failure. RESULTS: At each follow-up, the active locking plate group had more callus (p < 0.001) than the standard locking plate group. At postoperative week 6, all active locking plate group specimens had bridging callus at the three visible cortices. In standard locking plate group specimens, only 50% of these cortices had bridged. Computed tomography demonstrated that all active locking plate group specimens and one of the six standard locking plate group specimens had developed circumferential callus. Torsion tests after plate removal demonstrated that active locking plate group specimens recovered 81% of their native strength and were 399% stronger than standard locking plate group specimens (p < 0.001), which had recovered only 17% of their native strength. All active locking plate group specimens failed by spiral fracture outside the callus zone, but standard locking plate group specimens fractured through the osteotomy gap. CONCLUSIONS: Symmetric axial dynamization with active locking plates stimulates circumferential callus and yields faster and stronger healing than standard locking plates. CLINICAL RELEVANCE: The stimulatory effect of controlled motion on fracture-healing by active locking plates has the potential to reduce healing complications and to shorten the time to return to function. PMID- 26984918 TI - Arterial Anatomy of the Posterior Tibial Nerve in the Tarsal Tunnel. AB - BACKGROUND: Both vascular and compression etiologies have been proposed as the source of neurologic symptoms in tarsal tunnel syndrome. Advancing the understanding of the arterial anatomy supplying the posterior tibial nerve (PTN) and its branches may provide insight into the cause of tarsal tunnel symptoms. The purpose of this study was to describe the arterial anatomy of the PTN and its branches. METHODS: Sixty adult cadaveric lower extremities (thirty previously frozen and thirty fresh specimens) were amputated distal to the knee. The vascular supply to the PTN and its branches was identified, measured, and described macroscopically (the thirty previously frozen specimens, prepared using a formerly described debridement technique) and microscopically (the thirty fresh specimens, processed using the Spalteholz technique). RESULTS: On both macroscopic and microscopic evaluation, the PTN and the medial and lateral plantar nerves were observed to have multiple entering vessels within the tarsal tunnel. On microscopic evaluation, a vessel was observed to enter the nerve at the bifurcation of the PTN into the medial and lateral plantar nerves in twenty two (73%) of the thirty specimens. There was a significant difference (p < 0.05) in vascular density between the PTN and each of its branches. CONCLUSIONS: The abundant blood supply to the PTN and its branches identified in this study is consistent with observations of other peripheral nerves. This rich vascular network may render the PTN and its branches susceptible to nerve compression related to vascular congestion. The combination of vascular and structural compression may also elicit neurologic symptoms. CLINICAL RELEVANCE: Advancing the understanding of the arterial anatomy supplying the PTN and its branches may provide insight into the cause and treatment of tarsal tunnel syndrome. PMID- 26984919 TI - Quality Measures in Upper Limb Surgery. AB - BACKGROUND: Quality measures are now commonplace and are increasingly tied to financial incentives. We reviewed the existing quality measures that address the upper limb and tested the null hypothesis that structure (capacity to deliver care), process (appropriate care), and outcome (the result of care) measures are equally represented. METHODS: We systematically reviewed MEDLINE/PubMed, Embase, Google Scholar, the American Academy of Orthopaedic Surgeons Clinical Practice Guidelines, the National Quality Forum, the Agency for Healthcare Research and Quality, and the Physician Quality Reporting System for quality measures addressing upper limb surgery. Measures were characterized as structure, process, or outcome measures and were categorized according to their developer and their National Strategy for Quality Improvement in Health Care (National Quality Strategy) priority as articulated by the U.S. Department of Health & Human Services. RESULTS: We identified 134 quality measures addressing the upper limb: 131 (98%) process and three (2%) outcome measures. The majority of the process measures address the National Quality Strategy priority of effective clinical care (90%), with the remainder addressing communication and care coordination (5%), person and caregiver-centered experience and outcomes (4%), and community/population health (1%). CONCLUSIONS: Our review identified opportunities to develop more measures in the structure and outcome domains as well as measures addressing patient and family engagement, public health, safety, care coordination, and efficient use of resources. The most common existing measures-process measures addressing care-might not be the best measures of upper limb surgery quality given the relative lack of evidence for their use in care improvement. PMID- 26984920 TI - What's New in Hand Surgery. PMID- 26984921 TI - Analysis of FDA-Approved Orthopaedic Devices and Their Recalls. AB - BACKGROUND: The U.S. Food and Drug Administration (FDA) evaluates medical devices by two main pathways. The more stringent Premarket Approval (PMA) review requires clinical trials, and the Premarket Notification 510(k) process generally exempts devices from clinical trials if they prove to be substantially equivalent to existing devices. We hypothesized that orthopaedic devices are more likely to be cleared through the 510(k) process and thus are more susceptible to being recalled. METHODS: Using the FDA's public database, we searched for the following: PMA and 510(k) clearances for orthopaedics and non-orthopaedic specialties, including General & Plastic Surgery, Gastroenterology/Urology, Obstetrics/Gynecology, and Ear Nose & Throat, from 1992 to 2012. Additionally, we searched for all device recall events from 2002 to 2012. For the top-twenty recall companies, we calculated the odds ratio that compares the likelihood of recall for 510(k)-approved devices with that for PMA-approved devices. RESULTS: From 1992 to 2012, the proportion of non-orthopaedic devices cleared via the 510(k) process decreased from 91% to 53%. However, that of orthopaedic devices decreased only from 94% to 88%. Furthermore, we found that from 2002 to 2012, the percentage of recalled devices was 17.8% for 510(k)-cleared devices and 1.6% for PMA-approved devices. When stratified on the basis of recall class, the odds ratios were 3.5 for class-I devices, 13.2 for class-II devices, and 8.5 for class III devices. CONCLUSIONS: Given that 510(k)-cleared devices were 11.5 times more likely to be recalled than PMA-approved devices, it is concerning that most orthopaedic devices are cleared through the 510(k) process with limited clinical trials data. CLINICAL RELEVANCE: When orthopaedic surgeons are considering using a new device clinically in their patients, it is important for them to consider how the new device was approved by the FDA. If the device was approved by the 510(k) pathway, then it may have been approved without additional clinical studies confirming efficacy or safety. PMID- 26984922 TI - Will There Be a Difference If Things Go Bad? Commentary on an article by Tesfaye H. Leta, MPhil, et al.: "Outcomes of Unicompartmental Knee Arthroplasty After Aseptic Revision to Total Knee Arthroplasty. A Comparative Study of 768 TKAs and 578 UKAs Revised to TKAs from the Norwegian Arthroplasty Register (1994 to 2011)". PMID- 26984923 TI - Are We at the End of the Bone Morphogenetic Protein Era? Commentary on an article by Diyar Delawi, MD, PhD, et al.: "OP-1 Compared with Iliac Crest Autograft in Instrumented Posterolateral Fusion. A Randomized, Multicenter Non-Inferiority Trial". PMID- 26984924 TI - The Challenge of Plate-Bone Construct Stiffness: A Swinging Pendulum: Commentary on an article by Michael Bottlang, PhD, et al.: "Dynamic Stabilization with Active Locking Plates Delivers Faster, Stronger, and More Symmetric Fracture Healing". PMID- 26984925 TI - Percutaneous Common Carotid Artery Access for Pediatric Interventional Cardiac Catheterization. AB - BACKGROUND: Surgical cutdown for access to the common carotid artery provides a more direct route for certain pediatric cardiac interventions and avoids femoral artery injury in small infants. The safety of percutaneous carotid access (PCA) in children is unknown. METHODS AND RESULTS: Retrospective review of PCA at Texas Children's Hospital and Children's Healthcare of Atlanta. From July 2006 to November 2014, 42 patients underwent 47 attempts at catheterization via PCA. Median (range) age was 20 days (0 days-2.9 years) and weight was 3.2 kg (1.1 12.2). Two patients had failed PCA with no sequelae. Of the 45 catheterizations with successful PCA and sheath placement, 44 interventions were performed, the most common being stenting or stent redilation of the ductus arteriosus, balloon aortic valvuloplasty, and stenting or angioplasty of Blalock-Taussig shunts. After sheath withdrawal, hemostasis was achieved with manual compression, with no need for surgical control of bleeding. Follow-up carotid imaging was performed in all. Acutely, 3 patients developed carotid thrombosis with resolution in 1 and mild residual narrowing in 2 after anticoagulation therapy. At follow-up, 40 of 42 patients (95%) had a normal carotid artery, with 2 instances of mild stenosis. There were no neurological sequelae attributable to PCA. CONCLUSIONS: PCA is safe even in small infants, and hemostasis can be achieved without surgical repair, with a carotid patency rate superior to published data after surgical cutdown. Surgical cutdown is not routinely required for pediatric cardiac catheterization via the carotid artery. PMID- 26984928 TI - Discovery of Enhancers of the Secretion of Leukemia Inhibitory Factor for the Treatment of Multiple Sclerosis. AB - Multiple sclerosis (MS) is an autoimmune neurodegenerative disease that involves activation of T cells, microglia, and astrocytes. There is a clear unmet medical need for MS, as current therapies reduce the relapse rate, but are unable to prevent the neurological deterioration. Leukemia inhibitory factor (LIF) is a proinflammatory cytokine that can also positively modulate the immune response, by inducing the inhibition of myelin-reactive TH17 differentiation, and by promoting oligodendrocyte-mediated myelination. The aim of this project was to find central nervous system (CNS)-permeable and orally available small molecules that upregulate production of endogenous LIF. We describe here the development of a phenotypic assay and screening of 1.7 million compounds to identify LIF enhancers using U87 MG cells. Five chemically tractable series of compounds and a few singletons were selected for further progression. Some of them were also active in a different LIF-expressing cell line and in primary rat astrocytes. Although further studies would be required to deconvolute the targets involved in LIF induction and to confirm activity of hits in more disease-relevant assays, our results have demonstrated the potential of the phenotypic approach to identify specific and chemically tractable small molecules that trigger the production of LIF in relevant cell lines. PMID- 26984927 TI - Development of a Scalable, High-Throughput-Compatible Assay to Detect Tau Aggregates Using iPSC-Derived Cortical Neurons Maintained in a Three-Dimensional Culture Format. AB - Tau aggregation is the pathological hallmark that best correlates with the progression of Alzheimer's disease (AD). The presence of neurofibrillary tangles (NFTs), formed of hyperphosphorylated tau, leads to neuronal dysfunction and loss, and is directly associated with the cognitive decline observed in AD patients. The limited success in targeting beta-amyloid pathologies has reinforced the hypothesis of blocking tau phosphorylation, aggregation, and/or spreading as alternative therapeutic entry points to treat AD. Identification of novel therapies requires disease-relevant and scalable assays capable of reproducing key features of the pathology in an in vitro setting. Here we use induced pluripotent stem cells (iPSCs) as a virtually unlimited source of human cortical neurons to develop a robust and scalable tau aggregation model compatible with high-throughput screening (HTS). We downscaled cell culture conditions to 384-well plate format and used Matrigel to introduce an extra physical protection against cell detachment that reduces shearing stress and better recapitulates pathological conditions. We complemented the assay with AlphaLISA technology for the detection of tau aggregates in a high-throughput compatible format. The assay is reproducible across users and works with different commercially available iPSC lines, representing a highly translational tool for the identification of novel treatments against tauopathies, including AD. PMID- 26984930 TI - Periprocedural Myocardial Injury and Long-Term Clinical Outcome in Patients Undergoing Percutaneous Coronary Interventions of Coronary Chronic Total Occlusion. AB - BACKGROUND: Periprocedural myocardial injury (PMI) after percutaneous coronary intervention (PCI) might occur more frequently during challenging procedures such as PCI of chronic coronary total occlusion (CTO). The prognostic implication of PMI in CTO-PCI remains unclear. METHODS: From January 2006 to September 2012, a total of 715 consecutive patients undergoing CTO-PCI were screened at three centers. Only patients with available pre-PCI and post-PCI troponin (cTn) were included (n = 442). PMI was defined as an elevation of cTn >5x the upper reference limit (URL), or a rise of cTn >20% if baseline values were elevated. RESULTS: Patients were grouped into: (1) successful CTO-PCI and no-PMI (Group A; n = 195); (2) successful CTO-PCI with PMI (Group B; n = 133); failed CTO-PCI (Group C; n = 114). Occurrence of major adverse cardiovascular event (MACE) was assessed in 431 patients (97%), at a median follow-up of 25 months, and were significantly lower in patients successfully treated without PMI occurrence, while increased in cases of PMI or failed CTO-PCI (Group A, 9%; Group B, 15%; Group C, 28%; hazard ratio, 1.57 (95% confidence interval, 1.12-2.18); P<.01). At Kaplan-Meier analysis, MACE-free survival was significantly higher in Group A (log-rank, 21.46; P<.001). CONCLUSION: Successful CTO revascularization is still associated with a better long-term clinical outcome vs patients in whom it failed, regardless of the occurrence of PMI. PMID- 26984931 TI - Using Discrete Event Simulation to Model the Economic Value of Shorter Procedure Times on EP Lab Efficiency in the VALUE PVI Study. AB - BACKGROUND: The VALUE PVI study demonstrated that atrial fibrillation (AF) ablation procedures and electrophysiology laboratory (EP lab) occupancy times were reduced for the cryoballoon compared with focal radiofrequency (RF) ablation. However, the economic impact associated with the cryoballoon procedure for hospitals has not been determined. OBJECTIVE: Assess the economic value associated with shorter AF ablation procedure times based on VALUE PVI data. METHODS AND RESULTS: A model was formulated from data from the VALUE PVI study. This model used a discrete event simulation to translate procedural efficiencies into metrics utilized by hospital administrators. A 1000-day period was simulated to determine the accrued impact of procedure time on an institution's EP lab when considering staff and hospital resources. The simulation demonstrated that procedures performed with the cryoballoon catheter resulted in several efficiencies, including: (1) a reduction of 36.2% in days with overtime (422 days RF vs 60 days cryoballoon); (2) 92.7% less cumulative overtime hours (370 hours RF vs 27 hours cryoballoon); and (3) an increase of 46.7% in days with time for an additional EP lab usage (186 days RF vs 653 days cryoballoon). Importantly, the added EP lab utilization could not support the time required for an additional AF ablation procedure. CONCLUSIONS: The discrete event simulation of the VALUE PVI data demonstrates the potential positive economic value of AF ablation procedures using the cryoballoon. These benefits include more days where overtime is avoided, fewer cumulative overtime hours, and more days with time left for additional usage of EP lab resources. PMID- 26984929 TI - TGFalpha expression in myeloid malignancies. AB - BACKGROUND: Transforming growth factor alpha (TGFalpha) is a peptide growth factor known to be expressed in normal haemopoiesis. It is also expressed in a range of epithelial neoplasms but has not been assessed in haemopoietic malignancies. We have performed an immunohistochemical evaluation of TGFalpha in acute and chronic myeloid malignancies. METHODS: TGFalpha expression was semiquantitatively assessed in 69 normal bone marrow trephines and 157 cases of myeloid malignancy using an immunohistochemical approach. RESULTS: Blast cells of myeloid origin in acute myeloid leukaemia (AML), myelodysplasia and accelerated and blast phases of chronic myeloid leukaemia (CML) were TGFalpha positive. In acute promyelocytic leukaemia the neoplastic cells had significantly weaker TGFalpha expression than seen in other forms of AML. The blast cells in CML accelerated and blast phases were positive with similar expression to AML. CONCLUSIONS: TGFalpha is expressed in neoplastic myeloblasts and could, therefore, be used as blast cell biomarker in diagnostic haematopathology. In addition, TGFalpha immunohistochemistry may be of use in identifying a therapeutic target. PMID- 26984926 TI - Methanobactin and the Link between Copper and Bacterial Methane Oxidation. AB - Methanobactins (mbs) are low-molecular-mass (<1,200 Da) copper-binding peptides, or chalkophores, produced by many methane-oxidizing bacteria (methanotrophs). These molecules exhibit similarities to certain iron-binding siderophores but are expressed and secreted in response to copper limitation. Structurally, mbs are characterized by a pair of heterocyclic rings with associated thioamide groups that form the copper coordination site. One of the rings is always an oxazolone and the second ring an oxazolone, an imidazolone, or a pyrazinedione moiety. The mb molecule originates from a peptide precursor that undergoes a series of posttranslational modifications, including (i) ring formation, (ii) cleavage of a leader peptide sequence, and (iii) in some cases, addition of a sulfate group. Functionally, mbs represent the extracellular component of a copper acquisition system. Consistent with this role in copper acquisition, mbs have a high affinity for copper ions. Following binding, mbs rapidly reduce Cu(2+) to Cu(1+). In addition to binding copper, mbs will bind most transition metals and near transition metals and protect the host methanotroph as well as other bacteria from toxic metals. Several other physiological functions have been assigned to mbs, based primarily on their redox and metal-binding properties. In this review, we examine the current state of knowledge of this novel type of metal-binding peptide. We also explore its potential applications, how mbs may alter the bioavailability of multiple metals, and the many roles mbs may play in the physiology of methanotrophs. PMID- 26984933 TI - High-yield fabrication of 60 nm Permalloy nanodiscs in well-defined magnetic vortex state for biomedical applications. AB - Permalloy disc structures in magnetic vortex state constitute a promising new type of magnetic nanoparticles for biomedical applications. They present high saturation magnetisation and lack of remanence, which ease the remote manipulation of the particles by magnetic fields and avoid the problem of agglomeration, respectively. Importantly, they are also endowed with the capability of low-frequency magneto-mechanical actuation. This effect has already been shown to produce cancer cell destruction using functionalized discs, about 1 MUm in diameter, attached to the cell membrane. Here, Permalloy nanodiscs down to 60 nm in diameter are obtained by hole-mask colloidal lithography, which is proved to be a cost-effective method for the uniform patterning of large substrate areas, with a high production yield of nanostructures. The characterisation of the magnetic behaviour of the nanodiscs, complemented with micromagnetic simulations, confirms that they present a very well defined magnetic vortex configuration, unprecedented, to our knowledge, for nanostructures of this size prepared by a high-yield method. The successful detachment of the gold-covered nanodiscs from the substrate is also demonstrated by the use of sacrificial layers. PMID- 26984932 TI - Outcomes After Orbital Atherectomy of Severely Calcified Left Main Lesions: Analysis of the ORBIT II Study. AB - OBJECTIVES: The ORBIT II trial reported excellent outcomes in patients with severely calcified coronary lesions treated with orbital atherectomy. Severe calcification of the left main (LM) artery represents a complex coronary lesion subset. This study evaluated the safety and efficacy of coronary orbital atherectomy to prepare severely calcified protected LM artery lesions for stent placement. METHODS: The ORBIT II trial was a prospective, multicenter clinical trial that enrolled 443 patients with severely calcified coronary lesions in the United States. The major adverse cardiac event (MACE) rate through 2 years post procedure, defined by cardiac death, myocardial infarction (CK-MB >3x upper limit of normal with or without a new pathologic Q-wave) and target-vessel revascularization, was compared in the LM and non-left main (NLM) groups. RESULTS: Among the 443 patients, a total of 10 underwent orbital atherectomy of protected LM artery lesions. At 2 years, there was no significant difference in the 2-year MACE rate in the LM and NLM groups (30.0% vs 19.1%, respectively; P=.36). Cardiac death was low in both groups (0% vs 4.4%, respectively; P=.99). Myocardial infarction occurred within 30 days in both groups (10.0% vs 9.7%, respectively; P=.99). Severe dissection, perforation, persistent slow flow, and persistent no reflow did not occur in the LM group. Abrupt closure occurred in 1 patient in the LM group. CONCLUSIONS: Orbital atherectomy for patients with heavily calcified LM coronary artery lesions is safe and feasible. Further studies are needed to assess the safety and efficacy of orbital atherectomy in patients with severely calcified LM artery lesions. PMID- 26984934 TI - Prothrombin Time Tests for the Monitoring of Direct Oral Anticoagulants and Their Evaluation as Indicators of the Reversal Effect. AB - INTRODUCTION: The prompt assessment and the reversal of direct oral anticoagulants (DOACs) are urgent matters in the emergency care setting. Thus, we planned to elucidate the adequate prothrombin time (PT) test for the evaluation of the anticoagulant effects of various DOACs. METHODS: The anticoagulant effects of rivaroxaban, apixaban, and edoxaban were measured with 3 PT tests (Triniclot PT Excel S, Neoplastin R, and Thromborel S). Human plasma was spiked with each DOAC at a range of 0 to 1000 ng/mL, and the PT was measured using each PT test. In another series, the reversal effect of either 4-factor prothrombin complex concentrate (PCC) or activated PCC (aPCC) was evaluated with each PT test. RESULTS: All PT reagents correlated with the concentrations of each DOAC, however, the reactivity was considerably different between the DOACs and the PT tests. A prolonged PT with DOACs was reversed both by PCC and aPCC in a dose dependent manner; however, Triniclot PT Excel S showed reprolongation of the PT with a higher dose of PCC. CONCLUSION: The proper choice of PT test is necessary for the assessments of the anticoagulant activity of DOACs. It is also important to understand the different characteristics of each PT test for the assessment of the reversal effects of PCC. PMID- 26984935 TI - Effects of LEP G2548A and LEPR Q223R Polymorphisms on Serum Lipids and Response to Simvastatin Treatment in Chinese Patients With Primary Hyperlipidemia. AB - OBJECTIVES: To investigate whether LEP G2548A and LEPR Q223R polymorphisms influence serum lipid levels and whether the 2 polymorphisms affect the efficacy of simvastatin treatment in Chinese patients with primary hyperlipidemia. METHODS: We used an extreme sampling approach by selecting 212 individuals from the top and bottom 15% of adjusted lipid-lowering response residuals to simvastatin (n = 106 in each group of good or bad response) from a total of 734 samples with primary hyperlipidemia. They were treated with simvastatin orally 20 mg/d. Fasting serum lipids were measured at baseline and after 4 and 8 weeks of treatment. Genotyping was carried out using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: More patients in the good response group (27%) had LEPR Q223R than in the bad response group (16%, P = .046). Secondary stratified analyses showed that patients carrying the RR genotype of the LEPR Q223R gene had significantly higher high-density lipoprotein cholesterol levels than those with the QR genotype at baseline ( P = .034) among good responders. After 29 consecutive days of treatment with simvastatin, patients carrying the RR genotype had a significantly larger decrease in triglycerides (change: -0.74 +/- 0.92, P = .036) and total cholesterol levels (change: -1.77 +/- 0.68, P = .023) compared with those carrying QR genotype among bad responders. After Bonferroni correction, the results were not statistically significant. CONCLUSION: LEPR Q223R polymorphism, but not LEP G2548A, could modulate the efficacy of simvastatin in Chinese patients with primary hyperlipidemia. PMID- 26984937 TI - Nano-patterned SU-8 surface using nanosphere-lithography for enhanced neuronal cell growth. AB - Mimicking the nanoscale surface texture of the extracellular matrix can affect the regulation of cellular behavior, including adhesion, differentiation, and neurite outgrowth. In this study, SU-8-based polymer surfaces with well-ordered nanowell arrays were fabricated using nanosphere lithography with polystyrene nanoparticles. We show that the SU-8 surface with nanowells resulted in similar neuronal development of rat pheochromocytoma (PC12) cells compared with an unpatterned poly-L-lysine (PLL)-coated SU-8 surface. Additionally, even after soaking the substrate in cell culture medium for two weeks, cells on the nanowell SU-8 surface showed long-term neurite outgrowth compared to cells on the PLL coated SU-8 surface. The topographical surface modification of the nanowell array demonstrates potential as a replacement for cell adhesive material coatings such as PLL, for applications requiring long-term use of polymer-based implantable devices. PMID- 26984936 TI - Delayed ALK5 inhibition improves functional recovery in neonatal brain injury. AB - Neuroinflammation subsequent to developmental brain injury contributes to a wave of secondary neurodegeneration and to reactive astrogliosis that can inhibit oligodendrocyte progenitor differentiation and subsequent myelination. Here we evaluated the therapeutic efficacy of a small molecule antagonist for a TGFbeta receptor in a model of moderate perinatal hypoxia-ischemia (H-I). Osmotic pumps containing SB505124, an antagonist of the type 1 TGFbeta1 receptor ALK5, or vehicle, were implanted three days after H-I induced at postnatal day 6. Perinatal H-I induced selective neuronal death, ventriculomegaly, elevated CNS levels of IL-6 and IL-1alpha, astrogliosis, and fewer proliferating oligodendrocyte progenitors. Myelination was reduced by ~50%. Anterograde tracing revealed extensive axonal loss in the corticospinal tract. These alterations correlated with functional impairments across a battery of behavioral tests. All of these parameters were brought back towards normal levels with SB505124 treatment. Notably, SB505124 preserved neurons in the hippocampus and thalamus. Our results indicate that inhibiting ALK5 signaling, even as late as three days after injury, creates an environment that is more permissive for oligodendrocyte maturation and myelination producing significant improvements in neurological outcome. This new therapeutic would be especially appropriate for moderately preterm asphyxiated infants, for whom there is presently no FDA approved neuroprotective therapeutic. PMID- 26984938 TI - Bone Morphogenetic Protein Receptor Type 2 Mutation in Pulmonary Arterial Hypertension: A View on the Right Ventricle. AB - BACKGROUND: The effect of a mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene on right ventricular (RV) pressure overload in patients with pulmonary arterial hypertension is unknown. Therefore, we investigated RV function in patients who have pulmonary arterial hypertension with and without the BMPR2 mutation by combining in vivo measurements with molecular and histological analysis of human RV and left ventricular tissue. METHODS AND RESULTS: In total, 95 patients with idiopathic or familial pulmonary arterial hypertension were genetically screened for the presence of a BMPR2 mutation: 28 patients had a BMPR2 mutation, and 67 patients did not have a BMPR2 mutation. In vivo measurements were assessed using right heart catheterization and cardiac MRI. Despite a similar mean pulmonary artery pressure (noncarriers 54+/-15 versus mutation carriers 55+/-9 mm Hg) and pulmonary vascular resistance (755 [483-1043] versus 931 [624-1311] dynes.s(-1).cm(-5)), mutation carriers presented with a more severely compromised RV function (RV ejection fraction: 37.6+/-12.8% versus 29.0+/-9%: P<0.05; cardiac index 2.7+/-0.9 versus 2.2+/-0.4 L.min(-1).m(-2)). Differences continued to exist after treatment. To investigate the role of transforming growth factor beta and bone morphogenetic protein receptor II signaling, human RV and left ventricular tissue were studied in controls (n=6), mutation carriers (n=5), and noncarriers (n=11). However, transforming growth factor beta and bone morphogenetic protein receptor II signaling, and hypertrophy, apoptosis, fibrosis, capillary density, inflammation, and cardiac metabolism, as well, were similar between mutation carriers and noncarriers. CONCLUSIONS: Despite a similar afterload, RV function is more severely affected in mutation carriers than in noncarriers. However, these differences cannot be explained by a differential transforming growth factor beta, bone morphogenetic protein receptor II signaling, or cardiac adaptation. PMID- 26984940 TI - Demonstration of Sn-seeded GaSb homo- and GaAs-GaSb heterostructural nanowires. AB - The particle-assisted epitaxial growth of antimonide-based nanowires has mainly been realized using gold as the seed material. However, the Au-seeded epitaxial growth of antimonide-based nanowires such as GaSb nanowires presents several challenges such as for example direct nucleation issues and crystal structure tuning. Therefore, it is of great importance to understand the role of seed material choice and properties in the growth behavior of antimonide-based nanowires to obtain a deeper understanding and a better control on their formation processes. In this report, we have investigated the epitaxial growth of GaSb and GaAs-GaSb nanowires using in situ-formed tin seeds by means of metalorganic vapor phase epitaxy technique. This comprehensive report covers the growth of in situ-formed tin seeds and Sn-seeded GaSb nanowires on both GaAs and GaSb (111)B substrates, as well as GaAs-GaSb nanowires on GaAs (111)B substrates. The growth behavior and structural properties of the obtained GaSb nanowires are further investigated and compared with the Au-seeded counterparts. The results provided by this study demonstrate that Sn is a promising seed material for the growth of GaSb nanowires. PMID- 26984939 TI - Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification. AB - BACKGROUND: The clinical use of doxorubicin is limited by cardiotoxicity. Histopathological changes include interstitial myocardial fibrosis and the appearance of vacuolated cardiomyocytes. Whereas dysregulation of autophagy in the myocardium has been implicated in a variety of cardiovascular diseases, the role of autophagy in doxorubicin cardiomyopathy remains poorly defined. METHODS AND RESULTS: Most models of doxorubicin cardiotoxicity involve intraperitoneal injection of high-dose drug, which elicits lethargy, anorexia, weight loss, and peritoneal fibrosis, all of which confound the interpretation of autophagy. Given this, we first established a model that provokes modest and progressive cardiotoxicity without constitutional symptoms, reminiscent of the effects seen in patients. We report that doxorubicin blocks cardiomyocyte autophagic flux in vivo and in cardiomyocytes in culture. This block was accompanied by robust accumulation of undegraded autolysosomes. We go on to localize the site of block as a defect in lysosome acidification. To test the functional relevance of doxorubicin-triggered autolysosome accumulation, we studied animals with diminished autophagic activity resulting from haploinsufficiency for Beclin 1. Beclin 1(+/-) mice exposed to doxorubicin were protected in terms of structural and functional changes within the myocardium. Conversely, animals overexpressing Beclin 1 manifested an amplified cardiotoxic response. CONCLUSIONS: Doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity. PMID- 26984941 TI - The Werner syndrome RECQ helicase targets G4 DNA in human cells to modulate transcription. AB - The Werner syndrome (WS) is a prototypic adult Mendelian progeroid syndrome in which signs of premature aging are associated with genomic instability and an elevated risk of cancer. The WRN RECQ helicase protein binds and unwinds G quadruplex (G4) DNA substrates in vitro, and we identified significant enrichment in G4 sequence motifs at the transcription start site and 5' ends of first introns (false discovery rate < 0.001) of genes down-regulated in WS patient fibroblasts. This finding provides strong evidence that WRN binds G4 DNA structures at many chromosomal sites to modulate gene expression. WRN appears to bind a distinct subpopulation of G4 motifs in human cells, when compared with the related Bloom syndrome RECQ helicase protein. Functional annotation of the genes and miRNAs altered in WS provided new insight into WS disease pathogenesis. WS patient fibroblasts displayed altered expression of multiple, mechanistically distinct, senescence-associated gene expression programs, with altered expression of disease-associated miRNAs, and dysregulation of canonical pathways that regulate cell signaling, genome stability and tumorigenesis. WS fibroblasts also displayed a highly statistically significant and distinct gene expression signature, with coordinate overexpression of nearly all of the cytoplasmic tRNA synthetases and associated ARS-interacting multifunctional protein genes. The 'non-canonical' functions of many of these upregulated tRNA charging proteins may together promote WS disease pathogenesis. Our results identify the human WRN RECQ protein as a G4 helicase that modulates gene expression in G4-dependent fashion at many chromosomal sites and provide several new and unexpected mechanistic insights into WS disease pathogenesis. PMID- 26984942 TI - Brain arterial aging and its relationship to Alzheimer dementia. AB - OBJECTIVE: To test the hypothesis that brain arterial aging is associated with the pathologic diagnosis of Alzheimer disease (AD). METHODS: Brain large arteries were assessed for diameter, gaps in the internal elastic lamina (IEL), luminal stenosis, atherosclerosis, and lumen-to-wall ratio. Elastin, collagen, and amyloid were assessed with Van Gieson, trichrome, and Congo red staining intensities, and quantified automatically. Brain infarcts and AD (defined pathologically) were assessed at autopsy. We created a brain arterial aging (BAA) score with arterial characteristics associated with aging after adjusting for demographic and clinical variables using cross-sectional generalized linear models. RESULTS: We studied 194 autopsied brains, 25 (13%) of which had autopsy evidence of AD. Brain arterial aging consisted of higher interadventitial and lumen diameters, thickening of the wall, increased prevalence of IEL gaps, concentric intima thickening, elastin loss, increased amyloid deposition, and a higher IEL proportion without changes in lumen-to-wall ratio. In multivariable analysis, a high IEL proportion (B = 1.96, p = 0.030), thick media (B = 3.50, p = 0.001), elastin loss (B = 6.16, p < 0.001), IEL gaps (B = 3.14, p = 0.023), and concentric intima thickening (B = 7.19, p < 0.001) were used to create the BAA score. Adjusting for demographics, vascular risk factors, atherosclerosis, and brain infarcts, the BAA score was associated with AD (B = 0.022, p = 0.002). CONCLUSIONS: Aging of brain large arteries is characterized by arterial dilation with a commensurate wall thickening, elastin loss, and IEL gaps. Greater intensity of arterial aging was associated with AD independently of atherosclerosis and brain infarcts. Understanding the drivers of arterial aging may advance the knowledge of the pathophysiology of AD. PMID- 26984943 TI - CNS demyelination and enhanced myelin-reactive responses after ipilimumab treatment. PMID- 26984944 TI - Occupational cognitive requirements and late-life cognitive aging. AB - OBJECTIVE: To examine whether occupational cognitive requirements, as a marker of adulthood cognitive activity, are associated with late-life cognition and cognitive decline. METHODS: Main lifetime occupation information for 7,637 participants aged >65 years of the Chicago Health and Aging Project (CHAP) was linked with standardized data on worker attributes and job characteristics from the Occupational Information Network (O*NET). Ratings of cognitive processes required in 10 work-related tasks were used to create a summary measure of occupational cognitive requirements (possible range 0-7). Multivariable-adjusted linear mixed models were used to estimate the association of occupational cognitive requirements score (OCRS) with cognitive function and rate of cognitive decline. RESULTS: Higher OCRS corresponded to significantly better late-life cognitive performance at baseline in 1993 (p < 0.001) and to slower decline in global cognitive function over time (p = 0.004). Within a genotyped subsample (n = 4,104), the associations of OCRS with rate of cognitive decline did not differ significantly by APOE epsilon4 carriership (p = 0.11). CONCLUSIONS: Findings suggest that occupational cognitive requirements are associated with better cognition and a slower rate of cognitive decline in older age. Adulthood cognitive activity may contribute to cognitive reserve in late life. PMID- 26984946 TI - Routine vs extended outpatient EEG for the detection of interictal epileptiform discharges. AB - OBJECTIVE: To compare the yield of epileptiform abnormalities on 30-minute recordings with those greater than 45 minutes. METHODS: We performed a prospective observational cross-sectional study of all outpatient routine EEGs comparing the rate of interictal epileptiform discharges (IEDs) and clinical events during the initial 30 minutes (routine) with those occurring in the remaining 30-60 minutes (extended). A relative increase of 10% was considered clinically significant. RESULTS: EEGs from 1,803 patients were included; overall EEG duration was 59.4 minutes (SD +/-6.5). Of 426 patients with IEDs at any time during the EEG, 81 (19.1%, 95% confidence interval 15.6-23) occurred only after the initial 30 minutes. The rate of late IEDs was not associated with age, indication, IED type, or sleep deprivation. Longer recording times also increased event capture rate by approximately 30%. CONCLUSIONS: The yield of IED and event detection is increased in extended outpatient EEGs compared to 30-minute studies. PMID- 26984947 TI - Serum and CSF GQ1b antibodies in isolated ophthalmologic syndromes. AB - OBJECTIVE: To establish the sensitivity and specificity of serum and CSF antibodies targeting the gangliosides GQ1b (GQ1bAb) in isolated ophthalmologic syndromes, such as acute ophthalmoplegia (AO) and optic neuritis (ON), caused by disorders other than Miller-Fisher syndrome (MFS). METHODS: We measured serum and CSF GQ1bAb in patients with MFS and with AO or ON caused by other disorders than MFS. RESULTS: Twenty-one patients with AO (21 serum, 9 CSF), 13 with ON (13 serum, 13 CSF), and 12 with MFS (12 serum, 10 CSF) were included in the study. There were no significant differences in age, sex, and CSF findings between the AO and MFS groups. Elevated serum GQ1b titers occurred in 11 of 12 patients with MFS but in only 1 of the 34 patients without MFS. Sensitivity was 92% (95% confidence interval [CI] 62%-100%) and specificity 97% (95% CI 85%-100%). In CSF, GQ1bAb were identified in 2 of 10 patients with MFS but in none with other disorders. Sensitivity was 20% (95% CI 2%-56%) and specificity 100% (95% CI 85% 100%). CONCLUSIONS: Increased serum GQ1bAb are highly specific for MFS. Measurement of GQ1bAb in CSF does not improve diagnosis. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that serum GQ1bAb accurately distinguish MFS from other disorders (sensitivity 92%, 95% CI 62%-100%; specificity 97%, 95% CI 85%-100%). PMID- 26984948 TI - Sex differences in cognition: Does the "fairer sex" need a fairer test? PMID- 26984949 TI - Towards a uniform and large-scale deposition of MoS2 nanosheets via sulfurization of ultra-thin Mo-based solid films. AB - Large-scale integration of MoS2 in electronic devices requires the development of reliable and cost-effective deposition processes, leading to uniform MoS2 layers on a wafer scale. Here we report on the detailed study of the heterogeneous vapor solid reaction between a pre-deposited molybdenum solid film and sulfur vapor, thus resulting in a controlled growth of MoS2 films onto SiO2/Si substrates with a tunable thickness and cm(2)-scale uniformity. Based on Raman spectroscopy and photoluminescence, we show that the degree of crystallinity in the MoS2 layers is dictated by the deposition temperature and thickness. In particular, the MoS2 structural disorder observed at low temperature (<750 degrees C) and low thickness (two layers) evolves to a more ordered crystalline structure at high temperature (1000 degrees C) and high thickness (four layers). From an atomic force microscopy investigation prior to and after sulfurization, this parametrical dependence is associated with the inherent granularity of the MoS2 nanosheet that is inherited by the pristine morphology of the pre-deposited Mo film. This work paves the way to a closer control of the synthesis of wafer-scale and atomically thin MoS2, potentially extendable to other transition metal dichalcogenides and hence targeting massive and high-volume production for electronic device manufacturing. PMID- 26984950 TI - Alternating faciobrachial dystonic seizures in LGI1-antibody limbic encephalitis. PMID- 26984951 TI - The clinical assessment of apraxia. PMID- 26984952 TI - 2016 Young Investigator Award of the American Physiological Society Renal Section. PMID- 26984953 TI - Measuring the intrarenal distribution of glomerular volumes from histological sections. AB - Glomerular volume is an important metric reflecting glomerular filtration surface area within the kidney. Glomerular hypertrophy, or increased glomerular volume, may be an important marker for renal stress. Current stereological techniques report the average glomerular volume (AVglom) within the kidney. These techniques cannot assess the spatial or regional heterogeneity common in developing renal pathology. Here, we report a novel "unfolding" technique to measure the actual distribution of individual glomerular volumes in a kidney from the two dimensional glomerulus profiles observed by optical microscopy. The unfolding technique was first developed and tested for accuracy with simulations and then applied to measure the number of glomeruli (Nglom), AVglom, and intrarenal distribution of individual glomerular volume (IVglom) in the oligosyndactyl (Os/(+)) mouse model compared with wild-type (WT) controls. The Os/(+) mice had fewer and larger glomeruli than WT mice: Nglom was 12,126 +/- 1,658 (glomeruli/kidney) in the WT mice and 5,516 +/- 899 in the Os/(+) mice; AVglom was 2.01 +/- 0.28 * 10(-4) mm(3) for the WT mice and 3.47 +/- 0.35 * 10(-4) mm(3) for the Os/(+) mice. Comparing the glomerular volume distributions in Os/(+) and WT kidneys, we observed that the Os/(+) distribution peaked at a higher value of IVglom than the WT distribution peak, and glomeruli with a radius greater than 55 MUm were more prevalent in the Os/(+) mice (3.4 +/- 1.6% of total glomeruli vs. 0.6 +/- 1.2% in WT). Finally, the largest profiles were more commonly found in the juxtamedullary region. Unfolding is a novel stereological technique that provides a new quantitative view of glomerular volume distribution in the individual kidney. PMID- 26984954 TI - The C-terminal tail of polycystin-1 regulates complement factor B expression by signal transducer and activator of transcription 1. AB - Inhibition of the overactivated alternative complement pathway in autosomal dominant polycystic kidney disease (ADPKD) retards disease progression in animal models; however, it remains unknown how complement factor B (CFB) is upregulated in ADPKD. Here, we showed that the overexpression of CFB in cystic kidneys is associated with increased JAK2/STAT1 activity and enhanced expression of the polycystin-1 C-terminal tail (PC1-CTT). Overexpression or blockage of STAT1 increased or decreased CFB expression and CFB promoter activity. Moreover, overexpression of PC1-CTT induced JAK2/STAT1 activation and CFB upregulation in renal tubular epithelial cells. Furthermore, PC1-CTT overexpression increased human CFB promoter activity, whereas dominant negative STAT1 plasmids or mutation of putative STAT1 responsive elements decreased PC1-CTT-induced CFB promoter activity. The effect of CFB on macrophage differentiation was tested on a mouse macrophage cell line. Bioactive CFB dose dependently promoted macrophage M2 phenotype conversion. In addition, conditioned media from renal epithelial cells promoted macrophage M2 phenotype conversion which was blocked by STAT1 inhibition in a dose-dependent manner. Conditioned media from PC1-CTT-transfected renal epithelial cells further promoted macrophage M2 phenotype conversion, which was suppressed by fludarabine or a CFB antibody. In addition, we show that NF-kappaB acts downstream of PC1-CTT and may partly mediate PC1-CTT-induced CFB expression. In conclusion, our study reveals possible mechanisms of CFB upregulation in ADPKD and a novel role of PC1-CTT in ADPKD-associated inflammation. Furthermore, our study suggests that targeting STAT1 may be a new strategy to prevent inflammation in the kidney of patients with ADPKD. PMID- 26984955 TI - COX-2 gene dosage-dependent defects in kidney development. AB - Deletion of cyclooxygenase (COX)-2 causes impairment of kidney development, including hypothrophic glomeruli and cortical thinning. A critical role for COX-2 is seen 4-8 days postnatally. The present study was aimed at answering whether different COX-2 gene dosage and partial pharmacological COX-2 inhibition impairs kidney development. We studied kidney development in COX-2(+/+), COX-2(+/-), and COX-2(-/-) mice as well as in C57Bl6 mice treated postnatally with low (5 mg.kg( 1).day(-1)) and high (10 mg.kg(-1).day(-1)) doses of the selective COX-2 inhibitor SC-236. COX-2(+/-) mice exhibit impaired kidney development leading to reduced glomerular size but, in contrast to COX-2(-/-) mice, only marginal cortical thinning. Moreover, in COX-2(+/-) and COX-2(-/-) kidneys, juxtamedullary glomeruli, which develop in the very early stages of nephrogenesis, also showed a size reduction. In COX-2(+/-) kidneys at the age of 8 days, we observed significantly less expression of COX-2 mRNA and protein and less PGE2 and PGI2 synthetic activity compared with COX-2(+/+) kidneys. The renal defects in COX-2( /-) and COX-2(+/-) kidneys could be mimicked by high and low doses of SC-236, respectively. In aged COX-2(+/-) kidneys, glomerulosclerosis was observed; however, in contrast to COX-2(-/-) kidneys, periglomerular fibrosis was absent. COX-2(+/-) mice showed signs of kidney insufficiency, demonstrated by enhanced serum creatinine levels, quite similar to COX-2(-/-) mice, but, in contrast, serum urea remained at the control level. In summary, function of both COX-2 gene alleles is absolutely necessary to ensure physiological development of the mouse kidney. Loss of one copy of the COX-2 gene or partial COX-2 inhibition is associated with distinct renal damage and reduced kidney function. PMID- 26984945 TI - Better verbal memory in women than men in MCI despite similar levels of hippocampal atrophy. AB - OBJECTIVE: To examine sex differences in the relationship between clinical symptoms related to Alzheimer disease (AD) (verbal memory deficits) and neurodegeneration (hippocampal volume/intracranial volume ratio [HpVR]) across AD stages. METHODS: The sample included 379 healthy participants, 694 participants with amnestic mild cognitive impairment (aMCI), and 235 participants with AD and dementia from the Alzheimer's Disease Neuroimaging Initiative who completed the Rey Auditory Verbal Learning Test (RAVLT). Cross-sectional analyses were conducted using linear regression to examine the interaction between sex and HpVR on RAVLT across and within diagnostic groups adjusting for age, education, and APOE epsilon4 status. RESULTS: Across groups, there were significant sex * HpVR interactions for immediate and delayed recall (p < 0.01). Women outperformed men among individuals with moderate to larger HpVR, but not among individuals with smaller HpVR. In diagnosis-stratified analyses, the HpVR * sex interaction was significant in the aMCI group, but not in the control or AD dementia groups, for immediate and delayed recall (p < 0.01). Among controls, women outperformed men on both outcomes irrespective of HpVR (p < 0.001). In AD dementia, better RAVLT performance was independently associated with female sex (immediate, p = 0.04) and larger HpVR (delayed, p = 0.001). CONCLUSION: Women showed an advantage in verbal memory despite evidence of moderate hippocampal atrophy. This advantage may represent a sex-specific form of cognitive reserve delaying verbal memory decline until more advanced disease stages. PMID- 26984957 TI - Monomeric C-reactive protein inhibits renal cell-directed complement activation mediated by properdin. AB - Previous studies have shown that complement activation on renal tubular cells is involved in the induction of interstitial fibrosis and cellular injury. Evidence suggests that the tubular cell damage is initiated by the alternative pathway (AP) of complement with properdin having an instrumental role. Properdin is a positive regulator of the AP, which can bind necrotic cells as well as viable proximal tubular epithelial cells (PTECs), inducing complement activation. Various studies have indicated that in the circulation there is an unidentified inhibitor of properdin. We investigated the ability of C-reactive protein (CRP), both in its monomeric (mCRP) and pentameric (pCRP) form, to inhibit AP activation and injury in vitro on renal tubular cells by fluorescent microscopy, ELISA, and flow cytometry. We demonstrated that preincubation of properdin with normal human serum inhibits properdin binding to viable PTECs. We identified mCRP as a factor able to bind to properdin in solution, thereby inhibiting its binding to PTECs. In contrast, pCRP exhibited no such binding and inhibitory effect. Furthermore, mCRP was able to inhibit properdin-directed C3 and C5b-9 deposition on viable PTECs. The inhibitory ability of mCRP was not unique for viable cells but also demonstrated for binding to necrotic Jurkat cells, a target for properdin binding and complement activation. In summary, mCRP is an inhibitor of properdin in both binding to necrotic cells and viable renal cells, regulating complement activation on the cell surface. We propose that mCRP limits amplification of tissue injury by controlling properdin-directed complement activation by damaged tissue and cells. PMID- 26984958 TI - Nanoembossed gold nanoshell with a fluorescence-like strong SERS signal. AB - We present a nanoembossed nanoshell with a new internal location for the formation of strong electromagnetic fields. The internally nanoembossed gold nanoshell (AuNS) is fabricated by electrostatically assembling smaller silica nanoparticles (~15.7 nm) around the silica core (~123.6 nm) followed by growing gold nanoseeds on the core in a wet process. FDTD calculations reveal the creation of a strong electromagnetic field (|E/Ein|max = 55 at 633 nm) at sharp edges formed by the contact between the nanoembosses and the silica core. The field formation is supported by measuring the SERS signal of Ru(bpy) encapsulated in the nanoembossing silica nanoparticles. SERS signals as strong as the corresponding fluorescence are obtained. The Raman enhancement factor (EF) is estimated to be up to 10(10) at 633 nm excitation, in addition to a comparable EF at 785 nm laser excitation. The SERS intensity of the nanoembossed nanoshell layer is sufficiently high compared to the outer or the core of the nanoshell. Finally, we fabricate all-in-one nanoparticles with all the three places where the reporter dyes are loaded and acquire the highest SERS intensity to potentially enable bio-medical applications of the nanoembossed AuNS as a sensitive and reliable labeling particle. PMID- 26984959 TI - Neuro-Physiological Psychotherapy (NPP): The development and application of an integrative, wrap-around service and treatment programme for maltreated children placed in adoptive and foster care placements. AB - This article describes the development and application of a wrap-around, multidisciplinary, brain-based, developmental and attachment-focussed intervention for children who have experienced significant trauma in the context of their early life. It outlines the presentation of the children and families who are referred to the service and the model of treatment that they receive. In doing so, it identifies the core components underpinning Neuro-Physiological Psychotherapy (NPP) and links the application of the integrative model to research and practice in the field of neuroscience and attachment and to the use of therapeutic approaches that are beneficial to maltreated children and their adoptive parents. It highlights the need for a neuro-sequential approach that impacts all aspects of the child's life in the effort to redress the impact of developmental trauma with the aim of improving their overall functioning and their ability to develop healthy relationships into the future. PMID- 26984956 TI - Effects of exercise training on urinary tract function after spinal cord injury. AB - Spinal cord injury (SCI) causes dramatic changes in the quality of life, including coping with bladder dysfunction which requires repeated daily and nightly catheterizations. Our laboratory has recently demonstrated in a rat SCI model that repetitive sensory information generated through task-specific stepping and/or loading can improve nonlocomotor functions, including bladder function (Ward PJ, Herrity AN, Smith RR, Willhite A, Harrison BJ, Petruska JC, Harkema SJ, Hubscher CH. J Neurotrauma 31: 819-833, 2014). To target potential underlying mechanisms, the current study included a forelimb-only exercise group to ascertain whether improvements may be attributed to general activity effects that impact target organ-neural interactions or to plasticity of the lumbosacral circuitry that receives convergent somatovisceral inputs. Male Wistar rats received a T9 contusion injury and were randomly assigned to three groups 2 wk postinjury: quadrupedal locomotion, forelimb exercise, or a nontrained group. Throughout the study (including preinjury), all animals were placed in metabolic cages once a week for 24 h to monitor water intake and urine output. Following the 10-wk period of daily 1-h treadmill training, awake cystometry data were collected and bladder and kidney tissue harvested for analysis. Metabolic cage frequency-volume measurements of voiding and cystometry reveal an impact of exercise training on multiple SCI-induced impairments related to various aspects of urinary tract function. Improvements in both the quadrupedal and forelimb trained groups implicate underlying mechanisms beyond repetitive sensory information from the hindlimbs driving spinal network excitability of the lumbosacral urogenital neural circuitry. Furthermore, the impact of exercise training on the upper urinary tract (kidney) underscores the health benefit of activity-based training on the entire urinary system within the SCI population. PMID- 26984960 TI - Clinical improvements in adopted children with fetal alcohol spectrum disorders through neurodevelopmentally informed clinical intervention: A pilot study. AB - Research on early intervention for young children (infants and toddlers) with fetal alcohol spectrum disorders (FASD), particularly children with comorbid maltreatment experiences, is limited. Existing research has primarily focused on structuring environments to be responsive to the needs experienced by children with FASD rather than improving their functioning. The purpose of this study is to present outcomes from an early psychosocial intervention with 10 adopted, maltreated young children diagnosed with FASD, aged 10-53 months (M = 35 months), and their adoptive parents. The potential for early, targeted interventions to improve developmental outcomes for children with prenatal alcohol exposure was examined, as well as improving the skills of and reducing stress experienced by their adoptive parents. Based on the outcomes of a neurodevelopmentally informed assessment protocol, the 10 children whose data are presented were recommended to receive a range of regulatory, somatosensory, relational, and cognitive enrichments. As part of their treatment, children and caregivers received Child Parent Psychotherapy (CPP), and caregivers (here, adoptive parents) also received Mindful Parenting Education (MPE). Related-samples Wilcoxon signed-rank tests indicated that scores of several measures of child developmental functioning improved from pre- to post-intervention and that parents' caregiving skills improved while their caregiving stress decreased. Reliable change analyses indicated that change observed from pre- to post-intervention was reliable. The promise of using neurodevelopmentally informed assessment strategies to sequence interventions for young children with diverse neurodevelopmental insults is discussed. PMID- 26984961 TI - Investigating affinity-maturation strategies and reproducibility of fluorescence activated cell sorting using a recombinant ADAPT library displayed on staphylococci. AB - During the past decades, advances in protein engineering have resulted in the development of variousin vitroselection techniques (e.g. phage display) to facilitate discovery of new and improved proteins. The methods are based on linkage between genotype and phenotype and are often performed in successive rounds of selection. Since the resulting output depends on the selection pressures used and the applied strategy, parameters in each round must be carefully considered. In addition, studies have reported biases that can cause enrichment of unwanted clones and/or low correlation between abundance in output and affinity. We have recently developed a selection method based on display of protein libraries onStaphylococcus carnosusand isolation of affinity proteins by fluorescence-activated cell sorting. Here, we compared duplicate selections for affinity maturation using equilibrium binding at different target concentrations and kinetic off-rate selection. The results showed that kinetic selection is efficient for isolation of high-affinity binders and that equilibrium selection at subnanomolar concentrations should be avoided. Furthermore, the reproducibility of the selection was high and a clear correlation was observed between enrichment and affinity. This work reports on the reproducibility of bacterial display in combination with FACS and provides insights into selection design to help guide the development of new affinity proteins. PMID- 26984962 TI - Body Mass Transitions Through Childhood and Early Adolescence: A Multistate Life Table Approach. AB - The growing prevalence of overweight and obesity among children is well documented, but prevalence estimates offer little insight into rates of transition to higher or lower body mass index (BMI; weight (kg)/height (m)(2)) categories. We estimated the expected numbers of years children would live as normal weight, overweight, and obese by race/ethnicity and sex, given rates of transition across BMI status levels. We used multistate life table methods and transition rates estimated from prospective cohort data (2007-2013) for Denver, Colorado, public schoolchildren aged 3-15 years. At age 3 years, normal-weight children could expect to live 11.1 of the following 13 years with normal weight status, and obese children could expect to live 9.8 years with obese status. At age 3 years, overweight children could expect to live 4.5 of the following 13 years with normal weight status, 5.1 years with overweight status, and 3.4 years with obese status. Whites and Asians lived more years at lower BMI status levels than did blacks or Hispanics; sex differences varied by race/ethnicity. Children who were normal weight or obese at age 3 years were relatively unlikely to move into a different BMI category by age 15 years. Overweight children are relatively likely to transition to normal weight or obese status. PMID- 26984963 TI - Non-intubated video-assisted thoracoscopic surgery under loco-regional anaesthesia for thoracic surgery: a meta-analysis. AB - OBJECTIVES: The short-term feasibility and safety of non-intubated video-assisted thoracoscopic surgery under loco-regional anaesthesia for thoracic surgery remains unknown. Therefore, we conducted a meta-analysis to provide evidence for the short-term efficacy and safety profile of non-intubated video-assisted thoracoscopic surgery under loco-regional anaesthesia for thoracic surgery. METHODS: We performed a systematic literature search in PubMed, Embase, Cochrane Library databases and Google Scholar, as well as American Society of Clinical Oncology to identify relevant studies comparing non-intubated video-assisted thoracoscopic surgery under loco-regional anaesthesia with conventionally intubated video-assisted thoracoscopic surgery under general anaesthesia, dated up to 31 August 2015. Data concerning global in-operating room time, hospital stays, rate of postoperative complications and perioperative mortality were extracted and analysed. We conducted a meta-analysis of the overall results and two subgroup analyses based on study design (a meta-analysis of randomized controlled trials and a second meta-analysis of observational studies). RESULTS: Four randomized controlled trials and six observational studies with a total of 1283 patients were included. We found that in the overall analysis, patients treated with non-intubated video-assisted thoracoscopic surgery under loco regional anaesthesia achieved significantly shorter global in-operating room time [weighted mean difference = -41.96; 95% confidence interval (CI) = (-57.26, 26.67); P < 0.001] and hospital stays [weighted mean difference = -1.24; 95% CI = (-1.46, -1.02); P < 0.001] as well as a lower rate of postoperative complications [relative risk = 0.55; 95% CI = (0.40, 0.74); P < 0.001] than patients treated with intubated video-assisted thoracoscopic surgery under general anaesthesia. Subgroup meta-analyses based on study design achieved the same outcomes as overall analysis. In our meta-analysis, no perioperative mortality was observed in patients treated with non-intubated video-assisted thoracoscopic surgery under loco-regional anaesthesia. CONCLUSIONS: Non-intubated video-assisted thoracoscopic surgery under loco-regional anaesthesia for thoracic surgery proved to be feasible and safe. Future multicentre and well-designed randomized controlled trials with longer follow-up are needed to confirm and update the findings of our study, as well as the long-term efficacy of non-intubated video assisted thoracoscopic surgery under loco-regional anaesthesia. PMID- 26984964 TI - The SYNTAX score is correlated with long-term outcomes of coronary artery bypass grafting for complex coronary artery lesions. AB - OBJECTIVES: We analysed retrospectively the long-term outcomes of conventional coronary artery bypass grafting (CABG) as employed routinely for complex coronary lesions by observing patients with low (0-22), intermediate (23-32) and high (>=33) SYNTAX scores. The purpose of this study was to evaluate the correlation between the SYNTAX score and long-term major adverse cardiac and cerebrovascular events (MACCEs) including all-cause death, stroke, myocardial infarction (MI) and repeat revascularization after CABG. METHODS: The study enrolled 396 consecutive patients with stable and untreated left main and/or three-vessel disease, who had been referred to our heart team from 2000 through 2009. They all routinely underwent conventional CABG. The three groups (low score; n = 159, intermediate score; n = 150, high score; n = 87) were compared, looking at the primary endpoint of MACCE and its components. We also analysed the effects of diverse variables on long-term MACCEs after the operation. RESULTS: The cumulative 10 year MACCE rates in patients with low, intermediate and high SYNTAX score were 25.3, 35.8 and 48.1%, respectively. The Kaplan-Meier cumulative event curves showed a significantly higher MACCE rate after CABG in patients with a higher SYNTAX score than in those with a lower score (log-rank P = 0.0012). This was mainly because of a significantly increased rate of repeat revascularization in the higher SYNTAX score group (log-rank P = 0.0032). The cumulative rate of repeat revascularization at 10 years in patients having low, intermediate and high SYNTAX score were, respectively, 4.6, 15.7 and 16.8%. The cumulative rates of the combined outcomes of death/stroke/MI at 10 years did not show statistical differences between the three groups (22.3% with low, 25.0% with intermediate and 38.4% with high score, log-rank P = 0.063). In the multivariable analysis, the SYNTAX score [hazard ratio (HR) 1.03, P = 0.0043] and logistic EuroSCORE II (HR 1.34, P = 0.0012) were found to be significant predictors of long-term MACCEs. CONCLUSIONS: The SYNTAX score is correlated with long-term outcomes, in terms of MACCEs, after conventional CABG for complex coronary lesions and is prognostic of long-term outcomes of CABG for patients with complex lesions. PMID- 26984966 TI - Information transfer in multidisciplinary operating room teams: a simulation based observational study. AB - BACKGROUND: Communication of clinically relevant information between members of the operating room (OR) team is critical for safe patient care. Formal communication processes, such as briefing, sign in and time out, are designed to promote this. AIMS: We investigated patterns of communication of clinically relevant information between OR staff in simulated surgical scenarios, to identify factors associated with effective information sharing. We focused on the influence of precase briefing, sign in and time out, which we defined as formal team communications. METHOD: Twenty teams of six participated in two scenarios during a day-long course. Participants each received unique, clinically relevant items of information (information probes) prior to simulations and were tested postscenario on recall of the information in the probe. Using videos of the simulations, we coded each time an information probe was mentioned against a structured framework. RESULTS: Of the 145 instances where a probe was mentioned at least once, 75 (51.7%) were mentioned during a formal team communication. However, there were 89 instances of a possible 234 (38%) where a probe was never mentioned. Some team members were more likely to mention the information than others. When probes were mentioned during formal team communications, significantly more team members were attentive (1.4 vs 2.3; p<0.001), the information was significantly more likely to be recalled and the team was five times more likely (p=0.01) to recall the information than if the information was only mentioned outside of a formal communication. CONCLUSIONS: While our study supports the value of formal team communications during precase briefing, sign in and time out in the Surgical Safety Checklist, our findings suggest suboptimal transmission of information between team members and unequal contributions of information by different professional groups. PMID- 26984965 TI - Predictive value of high-sensitivity troponin T in addition to EuroSCORE II in cardiac surgery. AB - OBJECTIVES: Plasma troponins, measured by fourth-generation assays, are associated with increased mortality and morbidity after cardiac surgery. They also offer predictive information in addition to EuroSCORE, a widely used risk model after cardiac surgery. However, preoperatively measured troponin has provided no additional information to postoperative values. Whether these facts hold true also for the high-sensitivity fifth-generation troponin assay and the better calibrated risk model, EuroSCORE II, is unknown. We hypothesized that preoperative and/or postoperative high-sensitivity troponin T (hs-TnT) would increase the predictive value of EuroSCORE II. METHODS: Consecutive coronary artery bypass grafting (CABG) and other cardiac surgical patients were prospectively enrolled in a university hospital. Plasma samples and EuroSCORE II variables were collected. The primary and secondary end-points were 180-day mortality and any major adverse event within 30 days, and 961-day mortality. The data were analysed by Kaplan-Meier survival curves, regression analyses, receiver operator characteristic curves and decision curve analysis. RESULTS: Mortality rates in 180 days were 3.5% (15/428) in CABG and 6.4% (14/220) in other cardiac surgical patients. Survival curves differed only in patients with not only high postoperative hs-TnT value (>500 ng/l), but also high preoperative hs-TnT value (>14 ng/l), compared with patients with both hs-TnT values low. Adding hs-TnT to EuroSCORE II improved the prediction of 180-day mortality in other cardiac surgical patients (maximum net benefit of 1.5%), but not in CABG patients. Regarding major adverse events, adding hs-TnT to EuroSCORE II improved the prediction in both CABG patients and other cardiac surgical patients (maximum net benefits of 3 and 7%). CONCLUSIONS: Elevated postoperative hs-TnT was predictive of mortality only when combined with elevated preoperative hs-TnT. Hs-TnT measurements added information to the EuroSCORE II regarding major adverse events in all cardiac surgical patients and regarding 180-day mortality in non-CABG patients. PMID- 26984968 TI - Comment on: Is palinopsia in migraineurs an enhanced physiological phenomenon? PMID- 26984969 TI - Reply to letter to the editor: Is palinopsia in migraineurs an enhanced physiological phenomenon? PMID- 26984967 TI - Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors' responses to stimulation of TRPV1 and TRPA1 channels: Are we getting closer to solving this puzzle? AB - BACKGROUND: Administration of onabotulinumtoxinA (BoNT-A) to peripheral tissues outside the calvaria reduces the number of days chronic migraine patients experience headache. Because the headache phase of a migraine attack, especially those preceded by aura, is thought to involve activation of meningeal nociceptors by endogenous stimuli such as changes in intracranial pressure (i.e. mechanical) or chemical irritants that appear in the meninges as a result of a yet-to-be discovered sequence of molecular/cellular events triggered by the aura, we sought to determine whether extracranial injections of BoNT-A alter the chemosensitivity of meningeal nociceptors to stimulation of their intracranial receptive fields. MATERIAL AND METHODS: Using electrophysiological techniques, we identified 161 C- and 135 Adelta-meningeal nociceptors in rats and determined their mechanical response threshold and responsiveness to chemical stimulation of their dural receptive fields with TRPV1 and TRPA1 agonists seven days after BoNT-A administration to different extracranial sites. Two paradigms were compared: distribution of 5 U BoNT-A to the lambdoid and sagittal sutures alone, and 1.25 U to the sutures and 3.75 U to the temporalis and trapezius muscles. RESULTS: Seven days after it was administered to tissues outside the calvaria, BoNT-A inhibited responses of C-type meningeal nociceptors to stimulation of their intracranial dural receptive fields with the TRPV1 agonist capsaicin and the TRPA1 agonist mustard oil. BoNT-A inhibition of responses to capsaicin was more effective when the entire dose was injected along the suture lines than when it was injected into muscles and sutures. As in our previous study, BoNT-A had no effect on non noxious mechanosensitivity of C-fibers or on responsiveness of Adelta-fibers to mechanical and chemical stimulation. DISCUSSION: This study demonstrates that extracranial administration of BoNT-A suppresses meningeal nociceptors' responses to stimulation of their intracranial dural receptive fields with capsaicin and mustard oil. The findings suggest that surface expression of TRPV1 and TRPA1 channels in dural nerve endings of meningeal nociceptors is reduced seven days after extracranial administration of BoNT-A. In the context of chronic migraine, reduced sensitivity to molecules that activate meningeal nociceptors through the TRPV1 and TRPA1 channels can be important for BoNT-A's ability to act as a prophylactic. PMID- 26984970 TI - Low psychological resilience is associated with depression in patients with cardiovascular disease. AB - BACKGROUND: Psychological resilience is associated with an improved capacity to cope with chronic health challenges such as cardiovascular disease. AIMS: The aim of this cross-sectional study was to examine the relationship between psychological resilience and symptoms of depression in a non-acute cardiac outpatient population. METHODS: A total of 419 adult cardiac outpatients (288 men; mean+/-SD age 66.26+/-14.04 years) attending cardiovascular clinics completed the Sense of Coherence (SOC13) scale as a measure of psychological resilience and the Cardiac Depression Scale (CDS26) prior to their consultation. RESULTS: The total SOC13 score (mean+/-SD 64.02+/-14.24, range 19-91) was within the moderate range. Older patients (?65 years) were significantly more resilient than those aged <65 ( p<0.01). Psychological resilience (SOC13) was negatively correlated with depression (CDS26) ( r=-0.79; p<0.001) and inversely associated with affective, cognitive and somatic symptoms of depression. Psychological resilience, particularly meaningfulness, accounted for more of the variance in affective features of depression than for somatic features. CONCLUSION: These findings show that low psychological resilience was related to depression in this cohort of cardiac outpatients, particularly affective symptoms such as anhedonia and hopelessness. The SOC13 scale offers a complementary measure of psychological status that could be used to monitor, and possibly predict, patient coping and response to treatment throughout the cardiovascular disease trajectory. PMID- 26984971 TI - A Universal Culture Medium for Screening Polymyxin-Resistant Gram-Negative Isolates. AB - The colistin-containing SuperPolymyxin medium was developed for screening polymyxin-resistant Gram-negative bacteria. It was evaluated with 88 polymyxin susceptible or polymyxin-resistant cultured Gram-negative isolates. Its sensitivity and specificity of detection were ca. 100%. The SuperPolymyxin medium is the first screening medium that is able to detect intrinsic and acquired polymyxin-resistant bacteria. PMID- 26984972 TI - Identification of Mycobacterial Antigens in Human Urine by Use of Immunoglobulin G Isolated from Sera of Patients with Active Pulmonary Tuberculosis. AB - Point-of-care (POC) diagnostic testing of tuberculosis (TB) is a tremendous unmet need. In this study, four urinary mycobacterial antigens were identified through two independent approaches using IgG capture and immunodepletion methods. Among these, ModC was validated by a multiple reaction monitoring (MRM) method. As expected, the biomarkers elevated the clinical validity of TB diagnosis when combined with preexisting markers. PMID- 26984973 TI - Rapid Antimicrobial Susceptibility Testing of Bacillus anthracis, Yersinia pestis, and Burkholderia pseudomallei by Use of Laser Light Scattering Technology. AB - Rapid methods to determine antimicrobial susceptibility would assist in the timely distribution of effective treatment or postexposure prophylaxis in the aftermath of the release of bacterial biothreat agents such as Bacillus anthracis, Yersinia pestis, or Burkholderia pseudomallei Conventional susceptibility tests require 16 to 48 h of incubation, depending on the bacterial species. We evaluated a method that is based on laser light scattering technology that measures cell density in real time. We determined that it has the ability to rapidly differentiate between growth (resistant) and no growth (susceptible) of several bacterial threat agents in the presence of clinically relevant antimicrobials. Results were available in <4 h for B. anthracis and <6 h for Y. pestis and B. pseudomallei One exception was B. pseudomallei in the presence of ceftazidime, which required >10 h of incubation. Use of laser scattering technology decreased the time required to determine antimicrobial susceptibility by 50% to 75% for B. anthracis, Y. pestis, and B. pseudomallei compared to conventional methods. PMID- 26984974 TI - Evaluation of Molecular Methods for Serotyping Shigella flexneri. AB - Shigella flexneri can be phenotypically serotyped using antisera raised to type specific somatic antigens and group factor antigens and genotypically serotyped using PCR targeting O-antigen synthesis or modification genes. The aim of this study was to evaluate a real-time PCR for serotyping S. flexneri and to use whole genome sequencing (WGS) to investigate the phenotypic and genotypic serotype identifications. Of the 244 cultures tested retrospectively, 226 (92.6%) had concordant results between phenotypic serotyping and PCR. Seventy of the 244 isolates (including 15 of the 18 isolates where a serotype-PCR mismatch was identified) were whole-genome sequenced, and the serotype was derived from the genome. Discrepant results between the phenotypic and genotypic tests were attributed to insertions/deletions or point mutations identified in O-antigen synthesis or modification genes, rendering them dysfunctional; inconclusive serotyping results due to nonspecific cross-reactions; or novel genotypes. Phylogenetic analysis of the WGS data indicated that the serotype, regardless of whether it was phenotypically or genotypically determined, was a weak predictor of phylogenetic relationships between strains of S. flexneri WGS data provided both genome-derived serotyping, thus supporting backward compatibility with historical data and facilitating data exchange in the community, and more robust and discriminatory typing at the single-nucleotide-polymorphism level. PMID- 26984975 TI - A Bacterial Glycoengineered Antigen for Improved Serodiagnosis of Porcine Brucellosis. AB - Brucellosis is a highly zoonotic disease that affects animals and human beings. Brucella suis is the etiological agent of porcine brucellosis and one of the major human brucellosis pathogens. Laboratory diagnosis of porcine brucellosis mainly relies on serological tests, and it has been widely demonstrated that serological assays based on the detection of anti O-polysaccharide antibodies are the most sensitive tests. Here, we validate a recombinant glycoprotein antigen, an N-formylperosamine O-polysaccharide-protein conjugate (OAg-AcrA), for diagnosis of porcine brucellosis. An indirect immunoassay based on the detection of anti-O-polysaccharide IgG antibodies was developed coupling OAg-AcrA to enzyme linked immunosorbent assay plates (glyco-iELISA). To validate the assay, 563 serum samples obtained from experimentally infected and immunized pigs, as well as animals naturally infected with B. suis biovar 1 or 2, were tested. A receiver operating characteristic (ROC) analysis was performed, and based on this analysis, the optimum cutoff value was 0.56 (relative reactivity), which resulted in a diagnostic sensitivity and specificity of 100% and 99.7%, respectively. A cutoff value of 0.78 resulted in a test sensitivity of 98.4% and a test specificity of 100%. Overall, our results demonstrate that the glyco-iELISA is highly accurate for diagnosis of porcine brucellosis, improving the diagnostic performance of current serological tests. The recombinant glycoprotein OAg-AcrA can be produced in large homogeneous batches in a standardized way, making it an ideal candidate for further validation as a universal antigen for diagnosis of "smooth" brucellosis in animals and humans. PMID- 26984976 TI - Molecular Characterization of Human Atypical Sorbitol-Fermenting Enteropathogenic Escherichia coli O157 Reveals High Diversity. AB - Alongside the well-characterized enterohemorrhagic Escherichia coli (EHEC) O157:H7, serogroup O157 comprises sorbitol-fermenting typical and atypical enteropathogenic E. coli (EPEC/aEPEC) strains that carry the intimin-encoding gene eae but not Shiga toxin-encoding genes (stx). Since little is known about these pathogens, we characterized 30 clinical isolates from patients with hemolytic uremic syndrome (HUS) or uncomplicated diarrhea with respect to their flagellin gene (fliC) type and multilocus sequence type (MLST). Moreover, we applied whole-genome sequencing (WGS) to determine the phylogenetic relationship with other eae-positive EHEC serotypes and the composition of the rfbO157 region. fliC typing resulted in five fliC types (H7, H16, H34, H39, and H45). Isolates of each fliC type shared a unique ST. In comparison to the 42 HUS-associated E. coli (HUSEC) strains, only the stx-negative isolates with fliCH7 shared their ST with EHEC O157:H7/H(-) strains. With the exception of one O157:H(-) fliCH16 isolate, HUS was exclusively associated with fliCH7. WGS corroborated the separation of the fliCH7 isolates, which were closely related to the EHEC O157:H7/H(-) isolates, and the diverse group of isolates exhibiting different fliC types, indicating independent evolution of the different serotypes. This was also supported by the heterogeneity within the rfbO157 region that exhibited extensive recombinations. The genotypic subtypes and distribution of clinical symptoms suggested that the stx-negative O157 strains with fliCH7 were originally EHEC strains that lost stx The remaining isolates form a distinct and diverse group of atypical EPEC isolates that do not possess the full spectrum of virulence genes, underlining the importance of identifying the H antigen for clinical risk assessment. PMID- 26984978 TI - Genetic variations of phenprocoumon metabolism in patients with ventricular assist devices. AB - OBJECTIVES: Anticoagulation in patients with ventricular assist device (VAD) support is crucial and to date, no alternative to vitamin K antagonists (VKAs) can be safely used. Genetic variances of cytochrome p450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC) have been recently connected with variation of VKA maintenance as well as loading doses. In this retrospective study, we assessed the incidence of genetic variations and the influence of different genotypes of CYP2C9 and VKORC1 in VAD patients. METHODS: A total of 161 patients received a VAD implant in our institution between January 2006 and July 2014. Of these, 63 consented to genetic analysis and completed an interview with standardized questions on phenprocoumon (PC) dosage, international normalized ratio and anticoagulation-related complications. Determination of VKORC (-1639 G > A; -1173 C > T) and of CYP2C9 (*2, 430 C > T; *3, 1075 A > C) polymorphisms was performed by polymerase chain reaction and restriction analysis. RESULTS: The most common VKORC-1639 allele combination was wild-type GG (41%) followed by GA (32%) and AA (27%). Patients with VKORC1 polymorphisms AA and GA needed less PC in the maintenance phase of anticoagulation (P < 0.001) compared with wild-type GG patients. In contrast, CYP2C9 polymorphisms showed no effect on PC doses. Similar findings were observed in the initiation phase of PC therapy. High complications rates under PC therapy were observed particularly at the beginning. CONCLUSIONS: VKORC polymorphism affects PC dosage in the initiation as well as the maintenance phase. High rates of bleeding complications and thromboembolic events were found at the beginning of PC therapy in VAD patients. Therefore, a genotype-guided dosage algorithm might be useful in VAD patients. PMID- 26984977 TI - Laboratory Diagnosis of Mycobacterium tuberculosis Infection and Disease in Children. AB - Diagnosis of tuberculosis in children is challenging; even with advanced technologies, the diagnosis is often difficult to confirm microbiologically in part due to the paucibacillary nature of the disease. Clinical diagnosis lacks standardization, and traditional and molecular microbiologic methods lack sensitivity, particularly in children. Immunodiagnostic tests may improve sensitivity, but these tests cannot distinguish tuberculosis disease from latent infection and some lack specificity. While molecular tools like Xpert MTB/RIF have advanced our ability to detect Mycobacterium tuberculosis and to determine antimicrobial resistance, decades old technologies remain the standard in most locales. Today, the battle against this ancient disease still poses one of the primary diagnostic challenges in pediatric laboratory medicine. PMID- 26984979 TI - Non-invasive spinal cord oxygenation monitoring: validating collateral network near-infrared spectroscopy for thoracoabdominal aortic aneurysm repair. AB - OBJECTIVES: Near-infrared spectroscopy of the collateral network (cnNIRS) has recently been trialled to monitor real-time tissue oxygenation of the paraspinous vasculature as a surrogate for spinal cord tissue oxygenation. This large animal study was designed to investigate the correlation between cnNIRS and spinal cord oxygenation by comparing it to laser Doppler flowmetry (LDF), a proven method for direct oxygenation and flow assessment. METHODS: Measurements were performed in seven animals. Four paravertebral cnNIRS optodes were positioned bilaterally at thoracic and lumbar levels to assess tissue oxygenation of the paraspinous vasculature. Paravertebral muscle and spinal cord oxygenation and microcirculatory flow were measured directly using LDF probes. LDF and cnNIRS were compared during consecutive repeated periods of descending aortic cross clamping for 8 min and recovery by clamp release. RESULTS: Following aortic cross clamping, lumbar cnNIRS signals instantaneously responded with a decrease to 85 +/- 4% within 30 s, and to a minimum of 69 +/- 6% after 8 min, returning to baseline values after clamp release within 40 s. Direct lumbar muscle and spinal cord oxygenation assessed by LDF responded analogously to cnNIRS (muscle and spinal cord oxygenation after cross-clamping 11.3 +/- 6 and 37.6 +/- 22% after 5 and 8 min, respectively). Comparison between lumbar cnNIRS and LDF muscle and spinal cord measurements showed a significant positive correlation (r = 0.51 0.52, P < 0.001). Thoracic cnNIRS signals remained relatively stable throughout the procedure. Lumbar paraspinous muscle oxygenation corresponded to direct spinal cord oxygenation (no significant difference, P = 0.296). CONCLUSIONS: These experiments confirm that the paraspinous vasculature in the presented large animal model is directly linked to spinal cord microcirculation and that the regional paraspinous muscle oxygenation status reflects spinal cord tissue oxygenation. As lumbar cnNIRS reproducibly depicts tissue oxygenation of the paraspinous vasculature, it can be used for non-invasive spinal cord oxygenation monitoring in real-time. PMID- 26984980 TI - Comparative study for surgical management of thymectomy for non-thymomatous myasthenia gravis from the French national database EPITHOR. AB - OBJECTIVES: Thymectomy may be part of the therapeutic strategy in patients with myasthenia gravis (MG) without thymoma. Median sternotomy is still considered as the gold standard, but during the last 15 years, several groups have demonstrated the non-inferiority of cervicotomy with upper sternotomy and minimally invasive techniques. To date, there is no consensus on surgical procedure choice. The aim of our study was to compare the morbidity and mortality of three techniques [cervicotomy with upper sternotomy versus sternotomy versus video-assisted thoracic surgery (VATS)/robotic-assisted thoracic surgery (RATS)] from the national database EPITHOR and to analyse French epidemiology. METHODS: From the national thoracic surgery database EPITHOR, we have extracted all the details regarding thymectomies performed for non-thymomatous MG. We have divided thymectomy into three groups: A-sternotomy; B-cervicotomy with upper sternotomy; C-VATS/RATS. We investigated the postoperative morbidity and mortality without analysis of the long-term evolution of the disease not available on EPITHOR. RESULTS: From 2005 to 2013, 278 patients were included: 131 (47%) in Group A, 31 (11%) in Group B and 116 (42%) in Group C. The sex ratio F/M was 2.3. The mean age was, respectively, 42 +/- 17, 42 +/- 16, 35 +/- 14 years old (P < 0.01). The number of patients without comorbidities was 63 (48%), 25 (81%) and 78 (65%), respectively (P < 0.01). The operative time was 94 +/- 37, 79 +/- 42 and 112 +/- 59 min, respectively (P < 0.01). The number of patients who presented at least one postoperative complication was 12 (14%), 0 and 3 (9%) (P= 0.03), respectively. The postoperative lengths of stay were 7.7 +/- 4.5, 5 +/- 1.7 and 4.5 +/- 2 days, respectively (P < 0.01). There was no death. CONCLUSIONS: In our study, we were unable to prove the superiority of minimally invasive techniques due to the important differences between the groups. However, this study shows us major changes in French surgical procedures during the last decade with an increase in minimally invasive procedures such as VATS and RATS. PMID- 26984981 TI - Early valve repair or replacement is not generally contraindicated in patients with infective endocarditis and stroke with or without intracranial haemorrhage. PMID- 26984982 TI - Ascending aortic elongation and the risk of dissection. AB - OBJECTIVES: Unlike aneurysm formation, the role of ascending aortic elongation in the pathogenesis of Type A aortic dissection (TAD) is largely unclear. We investigated the morphology of healthy, dissected and predissection aortas with a focus on ascending aortic length. METHODS: We retrospectively compared clinical and computer tomography angiography (CTA) data from TAD patients (n = 130), patients who developed a TAD in the further clinical course (preTAD, n = 16) and healthy control patients who received a CTA for non-aortic emergencies (n = 165). The length of the ascending aorta was defined as the distance between the sinotubular junction (STJ) and the brachiocephalic trunk (BCT) at the central line, the outer and inner curvature as well as the direct distance in the frontal and sagittal planes. Additionally, the aortic diameters were analysed. RESULTS: In the healthy controls, we found a positive correlation of age with the aortic diameter (r = 0.57) and aortic length (r = 0.42). The correlation of the respective parameters with the body size was negligible (r < 0.2). The median ascending aortic diameter at the height of the pulmonary artery in TAD (50 mm) was significantly (P < 0.001) larger compared with the respective diameter of the healthy aortas (34 mm). The diameter of the preTAD aortas (40 mm) was also significantly larger compared with the healthy controls. These proportions were similar in all the aortic diameters. The midline length of the healthy ascending aortas was 71 mm. In the preTAD and TAD aortas, the same values were 81 mm and 92 mm, respectively (both P < 0.001). We evaluated the linear distance between the STJ and the BCT in the frontal plane as an easy-to-measure parameter of aortic length. In the TAD aortas (108 mm) and preTAD aortas (97 mm), this distance was significantly longer compared with the healthy aortas (84 mm). CONCLUSIONS: Aortic diameter might not be an optimal parameter to predict dissection. Most aortas dissect at diameters below 55 mm. Both the TAD and preTAD aortas were elongated compared with the healthy controls. Thus, aortic elongation may play a role in the pathogenesis of and may be a risk factor for TAD. PMID- 26984983 TI - Durability after aortic valve replacement with the Mitroflow versus the Perimount pericardial bioprosthesis: a single-centre experience in 2393 patients. AB - OBJECTIVES: This study compares the durability and risk of reoperation in patients undergoing aortic valve replacement (AVR) with either a Mitroflow or a Carpentier-Edwards (CE) pericardial bioprosthesis. Since AVR with bioprosthetic valves has increased progressively in recent years as compared to mechanical valves, especially in patients aged 60-70 years, there has been renewed interest in the long-term durability of current pericardial bioprostheses. METHODS: We compared 440 AVR with Mitroflow valves with 1953 AVR with CE pericardial valves implanted from 1999 to 2014 with regard to reoperation, reoperation for structural valve deterioration (SVD) and all-cause mortality. RESULTS: Ten-year freedom from explant of any cause was higher for CE Perimount (98 +/- 0.7%) than for Mitroflow (95 +/- 1.4%, P < 0.01). Reasons for explant for CE Perimount were SVD (n = 2), endocarditis (n = 8) and paraprosthetic leak (n = 10). The reasons for explant for Mitroflow were SVD (n = 11), endocarditis (n = 3) SVD and pericarditis (n = 1) and paraprosthetic leak (n = 2). Ten-year freedom from explant due to SVD was higher for CE Perimount (100%) than for Mitroflow (96%) (P < 0.01). In small aortic annuli (bioprosthesis size 19-21 mm), freedom from SVD at 10 years for CE Perimount and Mitroflow was 100 versus 96%, respectively. By multivariate analysis, it was found that bioprosthesis size was not a risk factor for SVD. The choice of valve type could not be demonstrated to influence long term survival. CONCLUSIONS: The Mitroflow pericardial bioprosthesis provides less than optimal mid- and long-term durability compared with the CE Perimount pericardial valve, especially for small aortic diameter implants (19 and 21 mm). This study hereby confirms the existence of a real risk of valvular deterioration of the Mitroflow valve that might compromise the prognosis of the patients. PMID- 26984985 TI - Just because you get on a scale doesn't mean you lose weight: is Meetbaar Beter really measurably better? PMID- 26984984 TI - Surgical factors and complications affecting hospital outcome in redo mitral surgery: insights from a multicentre experience. AB - OBJECTIVES: Several single-centre experiences have reported significant operative mortality and morbidity after mitral valve surgery in redo scenarios (ReMVS). Several preoperative risk factors outlining 'high-risk' categories have been reported, but scanty data on the impact of different operative techniques for these major challenging procedures have been analysed to date. The aim of the study is to investigate those intraoperative factors and postoperative events affecting early survival after redo mitral procedures. METHODS: Operative mortality and major morbidity events from a large multicentre registry enrolling 832 consecutive redo mitral procedures were analysed. Intraoperative technical issues and postoperative complications impacting operative mortality were identified. RESULTS: ReMVS was associated with significant operative mortality (12.5%), acute myocardial infarction (AMI; 5.9%), stroke (4.9%), acute respiratory insufficiency (14.8%), pneumonia (7.0%), acute renal insufficiency (16.1%) and failure (12.6%), reintervention for bleeding (7.6%), massive transfusion (28.0%), need for permanent pacemaker (10.1%). Injury of a previous patent left internal mammary artery (LIMA) graft [odds ratio (OR) 4.2, 95% confidence interval (CI): 1.6-11.5; P = 0.005], major cardiovascular iatrogenic lesions at re-entry (OR 19.2, 95% CI: 9.2-39.9; P < 0.001), extracellular crystalloid cardioplegia (OR 7.3, 95% CI: 1.4-37.8; P = 0.018), and incremental cardiopulmonary bypass time (OR 1.1, 95% CI: 1.0-1.2; P = 0.001) independently predicted operative mortality, whereas combined antegrade + retrograde cardioplegia (OR 0.2, 95% CI: 0.09-0.4; P = 0.001) was the only protective factor against mortality. Among complications, AMI (OR 4.1, 95% CI: 1.8-9.6; P = 0.001), need for intra-aortic balloon pumping (IABP; OR 3.1, 95% CI: 1.5-6.1; P = 0.001), prolonged intubation >48 h (OR 5.3, 95% CI: 2.9-9.4; P = 0.001) and massive (>6 units) transfusions (OR 4.4, 95% CI: 2.4-8.0; P = 0.001) also predicted operative mortality. CONCLUSIONS: ReMVS still carries the risk of significant early mortality and major morbidity. Major lesion to cardiovascular structures is the most dreadful iatrogenic complication, and injury of a previous LIMA graft identifies patients at higher risk of operative mortality. Prolonged cross-clamp times, extracellular crystalloid cardioplegia and massive transfusions have profound impact on early outcome, as well as the development of perioperative AMI, eventually requiring IABP and prolonged intubation. The combination of antegrade and retrograde cardioplegia seems to offer a better myocardial protection in these high-risk patients. PMID- 26984986 TI - Factors associated with progression of right ventricular enlargement and dysfunction after repair of tetralogy of Fallot based on serial cardiac magnetic resonance imaging. AB - OBJECTIVES: Although progressive right ventricular (RV) enlargement (RVE) is common in patients with pulmonary regurgitation after tetralogy of Fallot (TOF) repair, the rate of RVE and progression of RV dysfunction varies among patients. The present study aimed to investigate the independent predictors of rapid RVE and RV dysfunction after the repair of TOF, using serial cardiac magnetic resonance imaging (MRI). METHODS: The study included consecutive patients who underwent serial cardiac MRI more than twice between January 2005 and March 2015 after the repair of TOF. Patients who underwent surgical pulmonary valve implantation or any transcatheter cardiac intervention between two consecutive MRI assessments were excluded. The study patients were divided into rapid RVE and non-rapid RVE groups according to the rate of RVE. The upper first quartile of the patients was considered to have rapid RV dilatation (defined as rapid RVE group). Remaining patients in other three quartiles were included in the non rapid RVE group. Additionally, the study patients were divided into rapid right ventricular ejection fraction (RVEF) change and non-rapid RVEF change groups according to the rate of change in the RVEF. The groups were compared, and multiple logistic regression analyses were performed to identify the independent risk factors for rapid RVE and RV dysfunction. RESULTS: The study included 116 patients. The mean number of cardiac MRI assessments performed in each patient was 2.8 +/- 0.8. The time to the initial MRI assessment after TOF repair was 14.2 +/- 10.3 years, and the interval between the initial and last MRI assessments was 4.5 +/- 2.2 years. The mean right ventricular end-diastolic volume index (RVEDVi) change rate was 2.7 +/- 6.1 ml/m(2)/year. The initial RVEDVi was not different between the rapid RVE and non-rapid RVE groups. Restrictive RV physiology was an independent risk factor for rapid RVE (odds ratio, 3.64; 95% confidence interval, 1.263-10.494; P = 0.02), and a previous palliative shunt procedure was a negative predictor for rapid RVE (odds ratio, 0.08; 95% confidence interval, 0.010-0.778; P = 0.03). We did not find any predictive factors for rapid RV dysfunction. CONCLUSIONS: In patients with rapid RV dilatation, restrictive RV physiology might be frequently noted at the initial MRI assessment. Therefore, careful follow-up may be necessary in patients with restrictive RV physiology to determine the optimal timing of pulmonary valve implantation. PMID- 26984987 TI - Bronchoscopic lung volume reduction: an alternative to repeated lung volume reduction surgery. PMID- 26984988 TI - Follow-up after tricuspid valve surgery in adult patients with systemic right ventricles. AB - OBJECTIVES: In patients with congenitally corrected transposition of the great arteries (ccTGA) or after atrial (Mustard or Senning) correction for transposition of the great arteries (acTGA), the right ventricle (RV) supports the systemic circulation. The tricuspid valve (TV) (systemic atrioventricular valve) is prone to regurgitation in these patients and this is associated with impending RV failure and decreased survival. This study evaluates mid-term functional improvements, echocardiographic findings and survival after TV surgery in this patient group. METHODS: From July 1999 to November 2014, 26 patients (mean age 37.1 +/- 12.3 years, 14 females) with ccTGA (n = 15) or acTGA (n = 11) had TV surgery. All patients had RV dysfunction and more-than-moderate TV regurgitation (TR); 14 underwent TV replacement (TVR) and 12 had valvuloplasty (TVP). Main outcomes were New York Heart Association (NYHA) functional class, TR and RV dysfunction at 1 year postoperatively and at latest follow-up. Complications and freedom from the composite end-point of death or recurrent TR were analysed. RESULTS: The median follow-up time was 5.9 years (range, 0-16.1 years). Mean NYHA functional class significantly improved to 1.7 [95% confidence interval (CI): 1.3-2.1] at 1 year (P= 0.004) and was 2.1 (95% CI: 1.7-2.6) at latest follow-up (P= 0.14). TV competence significantly improved to a mean TR grade of 1.1 (95% CI: 0.5-1.7) at latest follow-up (P< 0.001). The mean grade for RV function at latest follow-up was 2.7 (95% CI: 2.3-3.0). Most encountered postoperative complications were arrhythmias and temporary haemodynamic instability due to low cardiac output. Early mortality was 11.5% (n = 3); late mortality was 15.4% (n = 4). Estimated freedom from the composite end-point of death or recurrent TR was 76.9% (95% CI: 55.7-88.9%) at 1 year and 64.8% (95% CI: 43.2-79.9%) at 5 years. In TVP patients, TV function at 1 year and at latest follow-up was significantly worse than in TVR patients (P< 0.001 and P= 0.003, respectively). Also, TVP patients had a significantly lower composite end-point survival curve compared with TVR patients (P= 0.018). CONCLUSIONS: In this patient group, TV surgery showed stabilization of RV function and improvement of NYHA functional class for at least several years. In this series, TVR appears superior to TVP with respect to occurrence of recurrent TR. Early and late mortality after TV surgery is substantial, and we believe that patients with significant TR should be referred earlier for surgery for better outcome. PMID- 26984989 TI - Multicentre analysis of current strategies and outcomes in open aortic arch surgery: heterogeneity is still an issue. AB - OBJECTIVES: The study was conducted to evaluate, on the basis of a multicentre analysis, current results of elective open aortic arch surgery performed during the last decade. METHODS: Data of 1232 consecutive patients who underwent aortic arch repair with reimplantation of at least one supra-aortic artery between 2004 and 2013 were collected from 11 European cardiovascular centres, and retrospective statistical examination was performed using uni- and multi-variable analyses to identify predictors for 30-day mortality. Acute aortic dissections and arch surgeries not involving the supra-aortic arteries were not included. RESULTS: Arch repair involving all 3 arch arteries (total), 2 arch arteries (subtotal) or 1 arch artery (partial) was performed in 956 (77.6%), 155 (12.6%) and 121 (9.8%) patients, respectively. The patients' characteristics as well as the surgical techniques, including the method of cannulation, perfusion and protection, varied considerably between the clinics participating in the study. The in-hospital and 30-day mortality rates were 11.4 and 8.8% for the entire cohort, respectively, ranging between 1.7 and 19.0% in the surgical centres. Multivariable logistic regression analysis identified surgical centre, patient's age, number of previous surgeries with sternotomy and concomitant surgeries as independent risk factors of 30-day mortality. The follow-up of the study group was 96.5% complete with an overall follow-up duration of 3.3 +/- 2.9 years, resulting in 4020 patient-years. After hospital discharge, 176 (14.3%) patients died, yielding an overall mortality rate of 25.6%. The actuarial survival after 5 and 8 years was 72.0 +/- 1.5% and 64.0 +/- 2.0, respectively. CONCLUSIONS: The surgical risk in elective aortic arch surgery has remained high during the last decade despite the advance in surgical techniques. However, the patients' characteristics, numbers of surgeries, the techniques and the results varied considerably among the centres. The incompleteness of data gathered retrospectively was not effective enough to determine advantages of particular cannulation, perfusion, protection or surgical techniques; and therefore, we strongly recommend further prospective multicentre studies, preferably registries, in which all relevant data have to be clearly defined and collected. PMID- 26984990 TI - Cardiac resynchronization combined with coronary artery bypass grafting. PMID- 26984992 TI - Resilience, respite and general practice: taking a mindful approach to culture change. PMID- 26984991 TI - First results of a national initiative to enable quality improvement of cardiovascular care by transparently reporting on patient-relevant outcomes. AB - OBJECTIVES: The aims of this study were to assess patient-relevant outcomes of delivered cardiovascular care by focusing on disease management as determined by a multidisciplinary Heart Team, to establish and share best practices by comparing outcomes and to embed value-based decision-making to improve quality and efficiency in Dutch heart centres. METHODS: In 2014, 12 Dutch heart centres pooled patient-relevant outcome data, which resulted in transparent publication of the outcomes, including long-term follow-up up to 5 years, of approximately 86 000 heart patients. This study presents the results of both disease- and treatment patient-relevant outcome measures for coronary artery disease and aortic valve disease. The patients included were presented to a Heart Team and underwent invasive or operative treatment. In-hospital and out-of-hospital patient-relevant outcome measures were collected as well as initial conditions. Quality of life was assessed using the Short Form (SF)-36 or SF-12 health survey. RESULTS: In the Netherlands, patient-relevant and risk-adjusted outcomes of cardiovascular care in participating heart centres are published annually. Data were sufficiently reliable to enable comparisons and to subtract best practices. The statistically lower risk-adjusted mortality rate after coronary artery bypass grafting resulted in a voluntary roll-out of a perioperative safety check. The in depth analysis of outcomes after percutaneous coronary intervention resulted in process improvements in several heart centres, such as pre-hydration for patients with renal insufficiency and the need of target vessel revascularizations within a year. CONCLUSION: Annual data collection on follow-up of patient-relevant outcomes of cardiovascular care, initiated and organized by physicians, appears feasible. Transparent publication of outcomes drives the improvement of quality within heart centres. The system of using a limited set of patient-relevant outcome measures enables reliable comparisons and exposes the quality of decision making and the operational process. Transparent communication on outcomes is feasible, safe and cost-effective, and stimulates professional decision-making and disease management. PMID- 26984993 TI - Empiric antibiotic treatment for urinary tract infection in preschool children: susceptibilities of urine sample isolates. AB - BACKGROUND: Antibiotic treatment recommendations based on susceptibility data from routinely submitted urine samples may be biased because of variation in sampling, laboratory procedures and inclusion of repeat samples, leading to uncertainty about empirical treatment. OBJECTIVE: To describe and compare susceptibilities of Escherichia coli cultured from routinely submitted samples, with E. coli causing urinary tract infection (UTI) from a cohort of systematically sampled, acutely unwell children. METHODS: Susceptibilities of 1458 E. coli isolates submitted during the course of routine primary care for children <5 years (routine care samples), compared to susceptibilities of 79 E. coli isolates causing UTI from 5107 children <5 years presenting to primary care with an acute illness [systematic sampling: the Diagnosis of Urinary Tract infection in Young children (DUTY) cohort]. RESULTS: The percentage of E. coli sensitive to antibiotics cultured from routinely submitted samples were as follows: amoxicillin 45.1% (95% confidence interval: 42.5-47.7%); co-amoxiclav using the lower systemic break point (BP) 86.6% (84.7-88.3%); cephalexin 95.1% (93.9-96.1%); trimethoprim 74.0% (71.7-76.2%) and nitrofurantoin 98.2% (97.4 98.8%). The percentage of E. coli sensitive to antibiotics cultured from systematically sampled DUTY urines considered to be positive for UTI were as follows: amoxicillin 50.6% (39.8-61.4%); co-amoxiclav using the systemic BP 83.5% (73.9-90.1%); co-amoxiclav using the urinary BP 94.9% (87.7-98.4%); cephalexin 98.7% (93.2-99.8%); trimethoprim 70.9% (60.1-80.0%); nitrofurantoin 100% (95.3 100.0%) and ciprofloxacin 96.2% (89.4-98.7%). CONCLUSION: Escherichia coli susceptibilities from routine and systematically obtained samples were similar. Most UTIs in preschool children remain susceptible to nitrofurantoin, co amoxiclav and cephalexin. PMID- 26984994 TI - The Chronic Disease Self-Management Program: the experience of frequent users of health care services and peer leaders. AB - BACKGROUND: Large amount of evidence supports the contribution of the Stanford Chronic Disease Self-Management Program (CDSMP) to a global chronic disease management strategy. However, many studies have suggested further exploring of the factors influencing acceptance and completion of participants in this program. OBJECTIVE: This study aimed to describe and examine factors associated with acceptance and completion rates of the CDSMP among frequent users of health care services, and to highlight the experience of patients and peer leaders who facilitated the program. METHODS: A descriptive design with mixed sequential data was used. Acceptance and completion rates were calculated and their relationship with patient characteristics was examined in regression analysis (n = 167). Interviews were conducted among patients who accepted (n = 11) and refused (n = 13) to participate and with the program coordinator. Focus groups were held with the seven peer leaders who facilitated the program. Data were analysed using thematic analysis. RESULTS: Of the 167 patients invited, 60 (36%) accepted to participate in the program. Group format was the most frequent reason to decline the invitation to participate. Twenty-eight participants (47%) completed the program. Participants who dropped out during the program raised different reasons such as poor health and too much heterogeneity among participants. Factors such as location, schedule, content, group composition and facilitation were considered as important elements contributing to the success of the program. CONCLUSION: The CDSMP could therefore be considered as a self-management support option for this vulnerable clientele, while taking measures to avoid too much heterogeneity among participants to improve completion rates. PMID- 26984995 TI - GPs' and community pharmacists' opinions on medication management at transitions of care in Ireland. AB - OBJECTIVE: The aim of this study was to survey GPs and community pharmacists (CPs) in Ireland regarding current practices of medication management, specifically medication reconciliation, communication between health care providers and medication errors as patients transition in care. METHODS: A national cross-sectional survey was distributed electronically to 2364 GPs, 311 GP Registrars and 2382 CPs. Multivariable associations comparing GPs to CPs were generated and content analysis of free text responses was undertaken. RESULTS: There was an overall response rate of 17.7% (897 respondents-554 GPs/Registrars and 343 CPs). More than 90% of GPs and CPs were positive about the effects of medication reconciliation on medication safety and adherence. Sixty per cent of GPs reported having no formal system of medication reconciliation. Communication between GPs and CPs was identified as good/very good by >90% of GPs and CPs. The majority (>80%) of both groups could clearly recall prescribing errors, following a transition of care, they had witnessed in the previous 6 months. Free text content analysis corroborated the positive relationship between GPs and CPs, a frustration with secondary care communication, with many examples given of prescribing errors. CONCLUSIONS: While there is enthusiasm for the benefits of medication reconciliation there are limited formal structures in primary care to support it. Challenges in relation to systems that support inter-professional communication and reduce medication errors are features of the primary/secondary care transition. There is a need for an improved medication management system. Future research should focus on the identified barriers in implementing medication reconciliation and systems that can improve it. PMID- 26984996 TI - The Histone Demethylase FBXL10 Regulates the Proliferation of Spermatogonia and Ensures Long-Term Sustainable Spermatogenesis in Mice. AB - The F-box and leucine-rich repeat protein 10 (Fbxl10) gene encodes a protein that catalyzes demethylation of H3K4 and H3K36. In this study, we show the important roles of FBXL10 as a histone demethylase in sustainable sperm production using mice in which the JmjC domain of Fbxl10 was deleted (Fbxl10(DeltaJ/DeltaJ)). In histological analysis, testis sections from 10-wk-old Fbxl10(DeltaJ/DeltaJ) mice appeared normal. On the other hand, testes from 7-mo-old Fbxl10(DeltaJ/DeltaJ) mice contained a greater ratio of seminiferous tubules exhibiting degeneration of spermatogenesis. Further analysis using an in vitro spermatogonia culture system, that is, germline stem cells (GSCs), revealed that Fbxl10(DeltaJ/DeltaJ) GSCs expressed a significantly higher level of P21 and P19 mRNA, cyclin-dependent kinase inhibitors and also known as cellular senescence markers, than wild-type (WT) GSCs. Furthermore, the ratio of Fbxl10(DeltaJ/DeltaJ) GSCs in G0/G1 phase was higher and the ratios in S and G2/M phases were lower than the corresponding ratios of WT GSCs, and the doubling speed of Fbxl10(DeltaJ/DeltaJ) GSCs was significantly slower than that of WT GSCs. In addition to these in vitro results, an in vivo study indicated that recovery of spermatogenesis after a transient reduction in the number of testicular germ cells by busulfan treatment was significantly slower in Fbxl10(DeltaJ/DeltaJ) mice than in WT mice. These data suggest that Fbxl10 plays important roles in long-term sustainable spermatogenesis via regulating cell cycle. PMID- 26984997 TI - Three-Dimensional Distribution of UBF and Nopp140 in Relationship to Ribosomal DNA Transcription During Mouse Preimplantation Development. AB - The nucleolus is a dynamic nuclear compartment that is mostly involved in ribosome subunit biogenesis; however, it may also play a role in many other biological processes, such as stress response and the cell cycle. Mainly using electron microscopy, several studies have tried to decipher how active nucleoli are set up during early development in mice. In this study, we analyzed nucleologenesis during mouse early embryonic development using 3D immunofluorescent detection of UBF and Nopp140, two proteins associated with different nucleolar compartments. UBF is a transcription factor that helps maintain the euchromatic state of ribosomal genes; Nopp140 is a phosphoprotein that has been implicated in pre-rRNA processing. First, using detailed image analyses and the in situ proximity ligation assay technique, we demonstrate that UBF and Nopp140 dynamic redistribution between the two-cell and blastocyst stages (time of implantation) is correlated with morphological and structural modifications that occur in embryonic nucleolar compartments. Our results also support the hypothesis that nucleoli develop at the periphery of nucleolar precursor bodies. Finally, we show that the RNA polymerase I inhibitor CX-5461: 1) disrupts transcriptional activity, 2) alters preimplantation development, and 3) leads to a complete reorganization of UBF and Nopp140 distribution. Altogether, our results underscore that highly dynamic changes are occurring in the nucleoli of embryos and confirm a close link between ribosomal gene transcription and nucleologenesis during the early stages of development. PMID- 26984998 TI - Energy Utilization for Survival and Fertilization-Parsimonious Quiescent Sperm Turn Extravagant on Motility Activation in Rat. AB - Quiescent sperm survive in cauda epididymis for long periods of time under extreme crowding conditions and with a very limited energy substrate, while after ejaculation, motile sperm live for a much shorter period with an unlimited energy resource and without crowding. Thus, the energy metabolism in relation to the energy requirement of the two may be quite different. A simple physiological technique was evolved to collect viable quiescent sperm from rat cauda epididymis to compare its energy metabolism with motile sperm. Quiescent sperm exhibited 40% 60% higher activities of mitochondrial electron transport chain complexes I-IV and ATP synthase in comparison to motile sperm and accumulated Ca(2+) in the midpiece mitochondria to enhance oxidative phosphorylation (OxPhos). In contrast, motile sperm displayed up to 75% higher activities of key glycolytic enzymes and secreted more than two times the lactate than quiescent sperm. Quiescent sperm phosphorylated AMPK and MAPK-p38, while motile sperm phosphorylated AKT and MAPK/ERK. Glycolytic inhibitor iodoacetamide prevented motility activation of quiescent rat sperm and inhibited conception in rabbits more effectively than OxPhos uncoupler 2,4-dinitrophenol. Apparently, quiescent sperm employ the most energy efficient OxPhos to survive for extended periods of time under extreme conditions of nutrition and crowding. However, on motility initiation, sperm switch predominantly to glycolysis to cater to their high- and quick-energy requirement of much shorter periods. This study also presents a proof of concept for targeting sperm energy metabolism for contraception. PMID- 26984999 TI - Gonadotropin Inhibitory Hormone Down-Regulates the Brain-Pituitary Reproductive Axis of Male European Sea Bass (Dicentrarchus labrax). AB - Gonadotropin-inhibitory hormone (GnIH) inhibits gonadotropin synthesis and release from the pituitary of birds and mammals. However, the physiological role of orthologous GnIH peptides on the reproductive axis of fish is still uncertain, and their actions on the main neuroendocrine systems controlling reproduction (i.e., GnRHs, kisspeptins) have received little attention. In a recent study performed in the European sea bass, we cloned a cDNA encoding a precursor polypeptide that contained C-terminal MPMRFamide (sbGnIH-1) and MPQRFamide (sbGnIH-2) peptide sequences, developed a specific antiserum against sbGnIH-2, and characterized its central and pituitary GnIH projections in this species. In this study, we analyzed the effects of intracerebroventricular injection of sbGnIH-1 and sbGnIH-2 on brain and pituitary expression of reproductive hormone genes (gnrh1, gnrh2, gnrh3, kiss1, kiss2, gnih, lhbeta, fshbeta), and their receptors (gnrhr II-1a, gnrhr II-2b, kiss1r, kiss2r, and gnihr) as well as on plasma Fsh and Lh levels. In addition, we determined the effects of GnIH on pituitary somatotropin (Gh) expression. The results obtained revealed the inhibitory role of sbGnIH-2 on brain gnrh2, kiss1, kiss2, kiss1r, gnih, and gnihr transcripts and on pituitary fshbeta, lhbeta, gh, and gnrhr-II-1a expression, whereas sbGnIH-1 only down-regulated brain gnrh1 expression. However, at different doses, central administration of both sbGnIH-1 and sbGnIH-2 decreased Lh plasma levels. Our work represents the first study reporting the effects of centrally administered GnIH in fish and provides evidence of the differential actions of sbGnIH-1 and sbGnIH-2 on the reproductive axis of sea bass, the main inhibitory role being exerted by the sbGnIH-2 peptide. PMID- 26985000 TI - The Transcription Factor NFIL3 Is Essential for Normal Placental and Embryonic Development but Not for Uterine Natural Killer (UNK) Cell Differentiation in Mice. AB - Mice ablated for the gene encoding the transcription factor Nfil3 lack peripheral natural killer (NK) cells but retain tissue-resident NK cells, particularly in mucosal sites, including virgin uterus. We undertook a time course histological study of implantation sites from syngeneically (Nfil3(-/-)) and allogeneically (BALB/c) mated Nfil3(-/-) females. We also examined implantation sites from Rag2( /-)Il2rg(-/-) females preconditioned by adoptive transfer of Nfil3(-/-) marrow or uterine cell suspensions to identify the Nfil3(-/-) pregnancy aberrations that could be attributed to nonlymphoid cells. Uterine NKs (UNKs) reactive and nonreactive with the lectin Dolichos biflorus agglutinin (DBA) differentiate, localize, and mature within Nfil3(-/-) implantation sites, although at reduced abundance. The DBA nonreactive UNK cells were enriched following Nfil3(-/-) marrow transplantation. Uterine lumen closure, early embryonic development, and differentiation of antimesometrial decidua were delayed in Nfil3(-/-) implantation sites. Major disturbances to the decidual-trophoblast interface that did not lead to fetal death were attributed to NFIL3 deficiency in trophoblast. At midgestation, vessels of the placental labyrinth were enlarged, suggestive of reduced branching morphogenesis. A major term complication in most Nfil3(-/-) * Nfil3(-/-) pregnancies but not Nfil3(-/-) * Nfil3(+/-) pregnancies was dystocia. These studies highlight the differentiation potential and functions of Nfil3(-/-) UNK cell progenitors and illustrate that much of the implantation site histopathology associated with this strain is due to Nfil3 deletion in nonlymphoid cell lineages. PMID- 26985002 TI - A Prolactin Family Paralog Regulates Placental Adaptations to a Physiological Stressor. AB - The prolactin (PRL) family of hormones and cytokines participates in the regulation of optimal reproductive performance in the mouse and rat. Members of the PRL family are expressed in the anterior pituitary, uterus, and/or placenta. In the present study, we investigated the ontogeny of PRL family 7, subfamily b, member 1 (PRL7B1; also called PRL-like protein-N, PLP-N) expression in the developing mouse placenta and established a mouse model for investigating the biological function of PRL7B1. Transcripts for Prl7b1 were first detected on Gestation Day (d) 8.5. From gestation d8.5 through d14.5, Prl7b1 was expressed in trophoblast cells residing at the interface between maternal mesometrial decidua and the developing placenta. On gestation d17.5, the predominant cellular source of Prl7b1 mRNA was migratory trophoblast cells invading into the uterine mesometrial decidua. The Prl7b1 null mutant allele was generated via replacement of the endogenous Prl7b1 coding sequence with beta-galactosidase (LacZ) reporter and neomycin cassettes. The mutant Prl7b1 allele was successfully passed through the germline. Homozygous Prl7b1 mutant mice were viable and fertile. Under standard animal housing conditions, Prl7b1 had undetectable effects on placentation and pregnancy. Hypoxia exposure during pregnancy evoked adaptations in the organization of the wild-type placenta that were not observed in Prl7b1 null placentation sites. In summary, PRL7B1 is viewed as a part of a pathway regulating placental adaptations to physiological stressors. PMID- 26985005 TI - Physiotherapy assessment and diagnosis of musculoskeletal disorders of the knee via telerehabilitation. AB - Introduction Lower limb musculoskeletal disorders place a heavy burden on healthcare systems. Appropriate management of these conditions is critical, however access to appropriate physiotherapy services is difficult for those in geographically remote areas or those with mobility or transport difficulties. The aim of this study was to evaluate the accuracy and reliability of an online musculoskeletal physiotherapy assessment of the knee complex using telerehabilitation compared to traditional face-to-face assessment. Methods In a repeated-measures design, 18 subjects who sought treatment for knee pain underwent a traditional face-to-face assessment and a remote telerehabilitation assessment. Telerehabilitation assessments were conducted with participants performing facilitated self-palpation, self-applied modified orthopaedic tests, active movements and functional tasks. Results Primary pathoanatomical diagnoses were in exact agreement in 67% of cases and were similar in 89% of cases. The system of pathology was found to be in agreement in 17 out of 18 cases (94%). Comparisons of objective findings from the two physical assessments demonstrated substantial agreement (kappa = 0.635) for categorical data and binary data (chi squared = 400.36; p < 0.001). A high level of intra-rater (89%) and moderate level of inter-rater (67%) reliability was evident for telerehabilitation assessments. Discussion Telerehabilitation assessment of the knee complex appears to be feasible and reliable. This study has implications for clinical practice and the development of physiotherapy services to address the burden of lower limb musculoskeletal pain and disability. PMID- 26985004 TI - Investigating the preferences of older people for telehealth as a new model of health care service delivery: A discrete choice experiment. AB - Introduction Telehealth approaches to health care delivery can potentially improve quality of care and clinical outcomes, reduce mortality and hospital utilisation, and complement conventional treatments. However, substantial research into the potential for integrating telehealth within health care in Australia, particularly in the provision of services relevant to older people, including palliative care, aged care and rehabilitation, is lacking. Furthermore, to date, no discrete choice experiment (DCE) studies internationally have sought the views and preferences of older people about the basic features that should make up a telehealth approach to these services. Methods Using a DCE, we investigated the relative importance of six salient features of telehealth (what aspects of care are to be pursued during telehealth sessions, distance to the nearest hospital or clinic, clinicians' attitude to telehealth, patients' experience of using technology, what types of assessments should be conducted face-to-face versus via telehealth sessions and the costs associated with receiving telehealth). Data were obtained from an online panel of older people aged 65 years and above, drawn from the Australian general population. Results The mean age for 330 study participants was 69 years. In general, individuals expressed strong preferences for telehealth services that offered all aspects of care, were relatively inexpensive and targeted specifically at individuals living in remote regions without easy access to a hospital or clinic. Participants also preferred telehealth services to be offered to individuals with some prior experience of using technology, provided by clinicians who were positive about telehealth but wanted all or some pre-telehealth health assessments to take place in a hospital or clinic. Preferences only differed by gender. Additionally, respondents did not feel that telehealth led to loss of privacy and confidentiality. Discussion Our findings indicate a preference amongst respondents for face-to-face pre-telehealth health assessments and, thereafter, a comprehensive telehealth model (in terms of services offered) targeted at those with some technological know-how as a substitute for attendance at hospitals and clinics, especially where these health facilities were far away from older people's homes. The findings may be usefully incorporated into the design of future telehealth models of service delivery for older people. PMID- 26985001 TI - Multiple Mechanisms Cooperate to Constitutively Exclude the Transcriptional Co Activator YAP from the Nucleus During Murine Oogenesis. AB - Reproduction depends on the generation of healthy oocytes. Improving therapeutic strategies to prolong or rescue fertility depends on identifying the inter- and intracellular mechanisms that direct oocyte development under physiological conditions. Growth and proliferation of multiple cell types is regulated by the Hippo signaling pathway, whose chief effectors are the transcriptional co activator YAP and its paralogue WWTR1. To resolve conflicting results concerning the potential role of Hippo in mammalian oocyte development, we systematically investigated the expression and localization of YAP in mouse oocytes. We report that that YAP is expressed in the germ cells beginning as early as Embryonic Day 15.5 and subsequently throughout pre- and postnatal oocyte development. However, YAP is restricted to the cytoplasm at all stages. YAP is phosphorylated at serine 112 in growing and fully grown oocytes, identifying a likely mechanistic basis for its nuclear exclusion, and becomes dephosphorylated at this site during meiotic maturation. Phosphorylation at serine-112 is regulated by a mechanism dependent on cyclic AMP and protein kinase A, which is known to be active in oocytes prior to maturation. Growing oocytes also contain a subpopulation of YAP, likely dephosphorylated, that is able enter the oocyte nucleus, but it is not retained there, implying that oocytes lack the cofactors required to retain YAP in the nucleus. Thus, although YAP is expressed throughout oocyte development, phosphorylation-dependent and -independent mechanisms cooperate to ensure that it does not accumulate in the nucleus. We conclude that nuclear YAP does not play a significant physiological role during oocyte development in mammals. PMID- 26985003 TI - Knockdown of Progesterone Receptor (PGR) in Macaque Granulosa Cells Disrupts Ovulation and Progesterone Production. AB - Adenoviral vectors (vectors) expressing short-hairpin RNAs complementary to macaque nuclear progesterone (P) receptor PGR mRNA (shPGR) or a nontargeting scrambled control (shScram) were used to determine the role PGR plays in ovulation/luteinization in rhesus monkeys. Nonluteinized granulosa cells collected from monkeys (n = 4) undergoing controlled ovarian stimulation protocols were exposed to either shPGR, shScram, or no virus for 24 h; human chorionic gonadotropin (hCG) was then added to half of the wells to induce luteinization (luteinized granulosa cells [LGCs]; n = 4-6 wells/treatment/monkey). Cells/media were collected 48, 72, and 120 h postvector for evaluation of PGR mRNA and P levels. Addition of hCG increased (P < 0.05) PGR mRNA and medium P levels in controls. However, a time-dependent decline (P < 0.05) in PGR mRNA and P occurred in shPGR vector groups. Injection of shPGR, but not shScram, vector into the preovulatory follicle 20 h before hCG administration during controlled ovulation protocols prevented follicle rupture in five of six monkeys as determined by laparoscopic evaluation, with a trapped oocyte confirmed in three of four follicles of excised ovaries. Injection of shPGR also prevented the rise in serum P levels following the hCG bolus compared to shScram (P < 0.05). Nuclear PGR immunostaining was undetectable in granulosa cells from shPGR injected follicles, compared to intense staining in shScram controls. Thus, the nuclear PGR appears to mediate P action in the dominant follicle promoting ovulation in primates. In vitro and in vivo effects of PGR knockdown in LGCs also support the hypothesis that P enhances its own synthesis in the primate corpus luteum by promoting luteinization. PMID- 26985007 TI - Regulation of expression of venom toxins: silencing of prothrombin activator trocarin D by AG-rich motifs. AB - Trocarin D (TroD), a venom prothrombin activator from Tropidechis carinatus, shares similar structure and function with blood coagulation factor Xa [Tropidechis carinatus FX (TrFX) a]. Their distinct physiologic roles are due to their distinct expression patterns. The genes of TroD and TrFX are highly similar, except for promoter and intron 1, indicating that TroD has probably evolved by duplication of FX, the plasma counterpart. The promoter insertion in TroD accounts for the elevated but not venom gland-specific expression. Here we examined the roles of 3 insertions and 2 deletions in intron 1 of TroD in the regulation of expression using luciferase as a reporter. By systematic deletions, we showed that a 209 bp region within the second insertion silences expression in mammalian and unmilked venom gland cells. Through bioinformatics analysis, we identified 5 AG-rich motifs in this region. All except the 5th motif are important for silencing function. YY1, Sp3 and HMGB2 were identified to bind these AG-rich motifs and silence gene expression in mammalian cells. Similar AG rich motif clusters are also found in other toxin genes but not in their physiologic counterparts. Thus, AG-rich motifs contribute to regulation of expression of TroD, and probably other toxin genes.-Han, S. X., Kwong, S., Ge, R., Kolatkar, P. R., Woods, A. E., Blanchet, G., Kini, R. M. Regulation of expression of venom toxins: silencing of prothrombin activator trocarin D by AG rich motifs. PMID- 26985006 TI - Prenatal, but not early postnatal, exposure to a Western diet improves spatial memory of pigs later in life and is paired with changes in maternal prepartum blood lipid levels. AB - Maternal obesity and perinatal high-fat diets are known to affect cognitive development. We examined the effects of late prenatal and/or early postnatal exposure to a Western-type diet, high in both fat and refined sugar, on the cognition of pigs (Sus scrofa) in the absence of obesity. Thirty-six sows and their offspring were assigned to 1 of 4 treatments in a 2 * 2 factorial arrangement, with 8 wk prenatal and 8 wk postnatal exposure to a Western diet (enriched in fat, sucrose, and cholesterol) or control diets as factors. Compared to controls, piglets exposed to the prenatal Western diet showed enhanced working and reference memory during the acquisition and reversal phases of a spatial hole board task. Mothers fed the prenatal Western diet had higher prepartum blood cholesterol and free fatty acid levels. Postnatal exposure to the Western diet did not affect piglet cognitive performance, but it did increase postpartum maternal and postweaning piglet cholesterol levels. The Western diet had no effect on maternal or offspring insulin sensitivity or leptin levels. In conclusion, a prenatal Western diet improved memory function in pigs, which was paired with changes in prepartum maternal blood cholesterol levels. These findings highlight the key role of late fetal nutrition for long-term programming of cognition.-Clouard, C., Kemp, B., Val-Laillet, D., Gerrits, W. J. J., Bartels, A. C., Bolhuis, J. E. Prenatal, but not early postnatal, exposure to a Western diet improves spatial memory of pigs later in life and is paired with changes in maternal prepartum blood lipid levels. PMID- 26985009 TI - PhenoWorld: addressing animal welfare in a new paradigm to house and assess rat behaviour. AB - The use of animals is essential in biomedical research. The laboratory environment where the animals are housed has a major impact on them throughout their lives and influences the outcome of animal experiments. Therefore, there has been an increased effort in the refinement of laboratory housing conditions which is explicitly reflected in international regulations and recommendations. Since housing conditions affect behaviour and brain function as well as well being, the validation of an animal model or paradigm to study the brain and central nervous system disorders is not complete without an evaluation of its implication on animal welfare. Here we discuss several aspects of animal welfare, comparing groups of six rats living in the PhenoWorld (PhW), a recently developed and validated paradigm for studying rodent behaviour, with standard-housed animals (in cages of six rats or pair-housed). In this study we present new data on home-cage behaviour showing that PhW animals have a clearer circadian pattern of sleep and social interaction. We conclude that, by promoting good basic health and functioning, together with the performance of natural behaviours, and maintaining animals' control over some of their environment but still keeping some physical and social challenges, the PhW stimulates positive affective states and higher motivation in rats, which might contribute to an increased welfare for animals living in the PhW. PMID- 26985008 TI - Increased aldosterone-dependent Kv1.5 recycling predisposes to pacing-induced atrial fibrillation in Kcne3-/- mice. AB - Hyperaldosteronism is associated with an increased prevalence of atrial fibrillation (AF). Mutations in KCNE3 have been associated with AF, and Kcne3(-/ ) mice exhibit hyperaldosteronism. In this study, we used recently developed Kcne3(-/-) mice to study atrial electrophysiology with respect to development of aldosterone-dependent AF. In invasive electrophysiology studies, Kcne3(-/-) mice displayed a reduced atrial effective refractory period (AERP) and inducible episodes of paroxysmal AF. The cellular arrhythmogenic correlate for AF predisposition was a significant increase in atrial Kv currents generated by the micromolar 4-aminopyridine-sensitive Kv current encoded by Kv1.5. Electrophysiological alterations in Kcne3(-/-) mice were aldosterone dependent and were associated with increased Rab4, -5, and -9-dependent recycling of Kv1.5 channels to the Z-disc/T-tubulus region and lateral membrane via activation of the Akt/AS160 pathway. Treatment with spironolactone inhibited Akt/AS160 phosphorylation, reduced Rab-dependent Kv1.5 recycling, normalized AERP and atrial Kv currents to the wild-type level, and reduced arrhythmia induction in Kcne3(-/-) mice. Kcne3 deletion in mice predisposes to AF by a heretofore unrecognized mechanism-namely, increased aldosterone-dependent Kv1.5 recycling via Rab GTPases. The findings uncover detailed molecular mechanisms underpinning a channelopathy-linked form of AF and emphasize the inevitability of considering extracardiac mechanisms in genetic arrhythmia syndromes.-Lisewski, U., Koehncke, C., Wilck, N., Buschmeyer, B., Pieske, B., Roepke, T. K. Increased aldosterone dependent Kv1.5 recycling predisposes to pacing-induced atrial fibrillation in Kcne3(-/-) mice. PMID- 26985010 TI - Platelet-rich plasma: Renewed scientific understanding must guide appropriate use. PMID- 26985011 TI - Concordance between the tuberculin skin test and interferon gamma release assay (IGRA) for diagnosing latent tuberculosis infection in patients with systemic lupus erythematosus and patient characteristics associated with an indeterminate IGRA. AB - OBJECTIVE: We investigated the agreement between the tuberculin skin test (TST) and the QuantiFERON-TB gold (QFT-G) assay in the diagnosis of latent tuberculosis infection (LTBI) in patients with systemic lupus erythematosus (SLE). Furthermore, we evaluated the factors associated with indeterminate results in the QFT-G assay in patients with SLE. METHODS: We enrolled 136 patients with SLE prospectively, and compared them to 66 patients with rheumatoid arthritis (RA). In addition to the TST, QFT-G assay, patients' medications, and Bacillus Calmette Guerin (BCG) vaccination status were also investigated. A positive TST or QFT-G assay result without an active tuberculosis lesion on chest x-ray was considered to indicate a diagnosis of LTBI. RESULTS: The prevalence of LTBI was 26.5% in patients with SLE and 30.3% in patients with RA. The agreement between the TST and QFT-G assay was fair in SLE patients, but poor in RA patients. BCG vaccination was one factor associated with discordance between TST and QFT-G. Older age and higher SLE Disease Activity Index (SLEDAI) score were associated with a negative TST/positive QFT-G result in patients with SLE. Higher SLEDAI score and increased glucocorticoid dose were associated with an indeterminate result in the QFT-G assay for patients with SLE. CONCLUSIONS: Agreement between the QFT-G assay and TST in patients with SLE was found to be fair. However, BCG vaccination status, age, and SLEDAI score are all factors that could result in discordance between the two tests. Indeterminate results from the QFT-G assay may be caused by a higher SLEDAI score or increased glucocorticoid dose. PMID- 26985012 TI - Rumen bacterial communities shift across a lactation in Holstein, Jersey and Holstein * Jersey dairy cows and correlate to rumen function, bacterial fatty acid composition and production parameters. AB - Rumen bacteria form a dynamic, complex, symbiotic relationship with their host, degrading forages to provide volatile fatty acids (VFA) and other substrates as energy to the animal. The objectives were to characterize rumen bacteria in three genetic lines of primiparous dairy cattle, Holstein (HO, n = 7), Jersey (JE, n = 8), and HO * JE crossbreeds (CB, n = 7) across a lactation [3, 93, 183 and 273 days in milk (DIM)] and correlate these factors with VFA, bacterial cell membrane fatty acids (FA), and animal production (i.e. milk yield). This study employed Illumina MiSeq (v. 3) to investigate rumen bacterial communities and gas-liquid chromatography/mass spectroscopy to identify bacterial membrane FA. Lactation stage had a prominent effect on rumen bacterial communities, whereas genetics had a lesser effect on rumen bacteria. The FA composition of bacterial cell membranes was affected by both lactation stage and genetics. Few correlations existed between VFA and bacterial communities; however, moderate correlations occurred between milk yield, protein percentage, fat yield and rumen bacterial communities. Positive correlations were found between branched-chain FA (BCFA) in bacterial cell membranes and bacterial genera. In conclusion, bacterial communities and their FA compositions are more affected by stage of lactation than by genetics of dairy cow. PMID- 26985013 TI - Diversity and dynamics of algal Megaviridae members during a harmful brown tide caused by the pelagophyte, Aureococcus anophagefferens. AB - Many giant dsDNA algal viruses share a common ancestor with Mimivirus--one of the largest viruses, in terms of genetic content. Together, these viruses form the proposed 'Megaviridae' clade of nucleocytoplasmic large DNA viruses. To gauge Megaviridae diversity, we designed degenerate primers targeting the major capsid protein genes of algae-infecting viruses within this group and probed the clade's diversity during the course of a brown tide bloom caused by the harmful pelagophyte,Aureococcus anophagefferens We amplified target sequences in water samples from two distinct locations (Weesuck Creek and Quantuck Bay, NY) covering 12 weeks concurrent with the proliferation and demise of a bloom. In total, 475 amplicons clustered into 145 operational taxonomic units (OTUs) at 97% identity. One OTU contained 19 sequences with >=97% identity to AaV, a member of the Megaviridae clade that infects A. anophagefferens, suggesting AaV was present during the bloom. Unifrac analysis showed clear temporal patterns in algal Megaviridae dynamics, with a shift in the virus community structure that corresponded to the Aureococcus bloom decline in both locations. Our data provide insights regarding the environmental relevance of algal Megaviridae members and raise important questions regarding their phylodynamics across different environmental gradients. PMID- 26985014 TI - University of McGill massive open online course: pioneering sport and exercise medicine education. PMID- 26985015 TI - Factors Affecting Physicians' Intentions to Communicate Personalized Prognostic Information to Cancer Patients at the End of Life: An Experimental Vignette Study. AB - PURPOSE: To explore the effects of personalized prognostic information on physicians' intentions to communicate prognosis to cancer patients at the end of life, and to identify factors that moderate these effects. METHODS: A factorial experiment was conducted in which 93 family medicine physicians were presented with a hypothetical vignette depicting an end-stage gastric cancer patient seeking prognostic information. Physicians' intentions to communicate prognosis were assessed before and after provision of personalized prognostic information, while emotional distress of the patient and ambiguity (imprecision) of the prognostic estimate were varied between subjects. General linear models were used to test the effects of personalized prognostic information, patient distress, and ambiguity on prognostic communication intentions, and potential moderating effects of 1) perceived patient distress, 2) perceived credibility of prognostic models, 3) physician numeracy (objective and subjective), and 4) physician aversion to risk and ambiguity. RESULTS: Provision of personalized prognostic information increased prognostic communication intentions (P < 0.001, eta(2) = 0.38), although experimentally manipulated patient distress and prognostic ambiguity had no effects. Greater change in communication intentions was positively associated with higher perceived credibility of prognostic models (P = 0.007, eta(2) = 0.10), higher objective numeracy (P = 0.01, eta(2) = 0.09), female sex (P = 0.01, eta(2) = 0.08), and lower perceived patient distress (P = 0.02, eta(2) = 0.07). Intentions to communicate available personalized prognostic information were positively associated with higher perceived credibility of prognostic models (P = 0.02, eta(2) = 0.09), higher subjective numeracy (P = 0.02, eta(2) = 0.08), and lower ambiguity aversion (P = 0.06, eta(2) = 0.04). CONCLUSIONS: Provision of personalized prognostic information increases physicians' prognostic communication intentions to a hypothetical end-stage cancer patient, and situational and physician characteristics moderate this effect. More research is needed to confirm these findings and elucidate the determinants of prognostic communication at the end of life. PMID- 26985017 TI - Identification of microtubule growth deceleration and its regulation by conserved and novel proteins. AB - Microtubules (MTs) are cytoskeletal polymers that participate in diverse cellular functions, including cell division, intracellular trafficking, and templating of cilia and flagella. MTs undergo dynamic instability, alternating between growth and shortening via catastrophe and rescue events. The rates and frequencies of MT dynamic parameters appear to be characteristic for a given cell type. We recently reported that all MT dynamic parameters vary throughout differentiation of a smooth muscle cell type in intact Caenorhabditis elegans. Here we describe local differences in MT dynamics and a novel MT behavior: an abrupt change in growth rate (deceleration) of single MTs occurring in the cell periphery of these cells. MT deceleration occurs where there is a decrease in local soluble tubulin concentration at the cell periphery. This local regulation of tubulin concentration and MT deceleration are dependent on two novel homologues of human cylicin. These novel ORFs, which we name cylc-1 and -2, share sequence homology with stathmins and encode small, very basic proteins containing several KKD/E repeats. The TOG domain-containing protein ZYG-9(TOGp) is responsible for the faster polymerization rate within the cell body. Thus we have defined two contributors to the molecular regulation for this novel MT behavior. PMID- 26985016 TI - Understanding mechanisms of hypertension in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that predominately affects women of reproductive age. Hypertension is an important cardiovascular risk factor that is prevalent in this patient population. Despite the high incidence of hypertension in women with SLE, the pathophysiological mechanisms underlying the development of hypertension remain poorly understood. This review will focus on disease-related factors, including inflammation, autoantibodies, and sex hormones that may contribute to hypertension in patients with SLE. In addition, we will highlight studies performed by our laboratory using the female NZBWF1 (F1 hybrid of New Zealand Black and New Zealand White strains) mouse model, a spontaneous model of SLE that mimics human disease and develops hypertension and renal injury. Specifically, using female NZBWF1 mice, we have demonstrated that multiple factors contribute to the pathogenesis of hypertension, including the inflammatory cytokine, tumor necrosis factor (TNF) alpha, oxidative stress, as well as B-cell hyperactivity and autoantibody production. PMID- 26985018 TI - Tension on JAM-A activates RhoA via GEF-H1 and p115 RhoGEF. AB - Junctional adhesion molecule A (JAM-A) is a broadly expressed adhesion molecule that regulates cell-cell contacts and facilitates leukocyte transendothelial migration. The latter occurs through interactions with the integrin LFA-1. Although we understand much about JAM-A, little is known regarding the protein's role in mechanotransduction or as a modulator of RhoA signaling. We found that tension imposed on JAM-A activates RhoA, which leads to increased cell stiffness. Activation of RhoA in this system depends on PI3K-mediated activation of GEF-H1 and p115 RhoGEF. These two GEFs are further regulated by FAK/ERK and Src family kinases, respectively. Finally, we show that phosphorylation of JAM-A at Ser-284 is required for RhoA activation in response to tension. These data demonstrate a direct role of JAM-A in mechanosignaling and control of RhoA and implicate Src family kinases in the regulation of p115 RhoGEF. PMID- 26985020 TI - Mesophyll Chloroplast Investment in C3, C4 and C2 Species of the Genus Flaveria. AB - The mesophyll (M) cells of C4 plants contain fewer chloroplasts than observed in related C3 plants; however, it is uncertain where along the evolutionary transition from C3 to C4 that the reduction in M chloroplast number occurs. Using 18 species in the genus Flaveria, which contains C3, C4 and a range of C3-C4 intermediate species, we examined changes in chloroplast number and size per M cell, and positioning of chloroplasts relative to the M cell periphery. Chloroplast number and coverage of the M cell periphery declined in proportion to increasing strength of C4 metabolism in Flaveria, while chloroplast size increased with increasing C4 cycle strength. These changes increase cytosolic exposure to the cell periphery which could enhance diffusion of inorganic carbon to phosphenolpyruvate carboxylase (PEPC), a cytosolic enzyme. Analysis of the transcriptome from juvenile leaves of nine Flaveria species showed that the transcript abundance of four genes involved in plastid biogenesis-FtsZ1, FtsZ2, DRP5B and PARC6-was negatively correlated with variation in C4 cycle strength and positively correlated with M chloroplast number per planar cell area. Chloroplast size was negatively correlated with abundance of FtsZ1, FtsZ2 and PARC6 transcripts. These results indicate that natural selection targeted the proteins of the contractile ring assembly to effect the reduction in chloroplast numbers in the M cells of C4 Flaveria species. If so, efforts to engineer the C4 pathway into C3 plants might evaluate whether inducing transcriptome changes similar to those observed in Flaveria could reduce M chloroplast numbers, and thus introduce a trait that appears essential for efficient C4 function. PMID- 26985019 TI - Dermal Exposure to Cumene Hydroperoxide: Assessing Its Toxic Relevance and Oxidant Potential. AB - Cumene hydroperoxide (CHP) is a high production volume chemical that is used to generate phenol and acetone. Dermal exposure to CHP was hypothesized to result in systemic tissue toxicity, production of free radicals, and consequent decrease in plasma antioxidant levels. To evaluate the hypothesis and characterize the toxicity of CHP, male and female B6C3F1/N mice and F344/N rats were exposed to varying doses of CHP applied topically for 14 or 90 days. No significant changes in survival or body weight of mice and rats were observed following 14 days of exposure. However, 90 days of CHP exposure at the high dose (12 mg/kg) triggered a significant decrease (-15%) in the body weight of the male rat group only. Irritation of the skin was observed at the site of application and was characterized by inflammation and epidermal hyperplasia. In treated animals, histology of liver tissue, free radical generation, and antioxidant levels in blood plasma were not significantly changed as compared to the corresponding controls. Consistent with the lack of systemic damage, no increase in micronucleated erythrocytes was seen in peripheral blood. In conclusion, topical CHP application caused skin damage only at the application site and did not cause systemic tissue impairment. PMID- 26985022 TI - Dissociating Prediction Failure: Considerations from Music Perception. PMID- 26985021 TI - Co-overexpressing a Plasma Membrane and a Vacuolar Membrane Sodium/Proton Antiporter Significantly Improves Salt Tolerance in Transgenic Arabidopsis Plants. AB - The Arabidopsis gene AtNHX1 encodes a vacuolar membrane-bound sodium/proton (Na(+)/H(+)) antiporter that transports Na(+) into the vacuole and exports H(+) into the cytoplasm. The Arabidopsis gene SOS1 encodes a plasma membrane-bound Na(+)/H(+) antiporter that exports Na(+) to the extracellular space and imports H(+) into the plant cell. Plants rely on these enzymes either to keep Na(+) out of the cell or to sequester Na(+) into vacuoles to avoid the toxic level of Na(+) in the cytoplasm. Overexpression of AtNHX1 or SOS1 could improve salt tolerance in transgenic plants, but the improved salt tolerance is limited. NaCl at concentration >200 mM would kill AtNHX1-overexpressing or SOS1-overexpressing plants. Here it is shown that co-overexpressing AtNHX1 and SOS1 could further improve salt tolerance in transgenic Arabidopsis plants, making transgenic Arabidopsis able to tolerate up to 250 mM NaCl treatment. Furthermore, co overexpression of AtNHX1 and SOS1 could significantly reduce yield loss caused by the combined stresses of heat and salt, confirming the hypothesis that stacked overexpression of two genes could substantially improve tolerance against multiple stresses. This research serves as a proof of concept for improving salt tolerance in other plants including crops. PMID- 26985023 TI - A Role for the GIRK3 Subunit in Methamphetamine-Induced Attenuation of GABAB Receptor-Activated GIRK Currents in VTA Dopamine Neurons. AB - Repeated exposure to psychostimulants induces locomotor sensitization and leads to persistent changes in the circuitry of the mesocorticolimbic dopamine (DA) system. G-protein-gated inwardly rectifying potassium (GIRK; also known as Kir3) channels mediate a slow IPSC and control the excitability of DA neurons. Repeated 5 d exposure to psychostimulants decreases the size of the GABAB receptor (GABABR)-activated GIRK currents (IBaclofen) in ventral tegmental area (VTA) DA neurons of mice, but the mechanism underlying this plasticity is poorly understood. Here, we show that methamphetamine-dependent attenuation of GABABR GIRK currents in VTA DA neurons required activation of both D1R-like and D2R-like receptors. The methamphetamine-dependent decrease in GABABR-GIRK currents in VTA DA neurons did not depend on a mechanism of dephosphorylation of the GABAB R2 subunit found previously for other neurons in the reward pathway. Rather, the presence of the GIRK3 subunit appeared critical for the methamphetamine-dependent decrease of GABABR-GIRK current in VTA DA neurons. Together, these results highlight different regulatory mechanisms in the learning-evoked changes that occur in the VTA with repeated exposure to psychostimulants. SIGNIFICANCE STATEMENT: Exposure to addictive drugs such as psychostimulants produces persistent adaptations in inhibitory circuits within the mesolimbic dopamine system, suggesting that addictive behaviors are encoded by changes in the reward neural circuitry. One form of neuroadaptation that occurs with repeated exposure to psychostimulants is a decrease in slow inhibition, mediated by a GABAB receptor and a potassium channel. Here, we examine the subcellular mechanism that links psychostimulant exposure with changes in slow inhibition and reveal that one type of potassium channel subunit is important for mediating the effect of repeated psychostimulant exposure. Dissecting out the components of drug dependent plasticity and uncovering novel protein targets in the reward circuit may lead to the development of new therapeutics for treating addiction. PMID- 26985024 TI - Extrinsic and Intrinsic Brain Network Connectivity Maintains Cognition across the Lifespan Despite Accelerated Decay of Regional Brain Activation. AB - The maintenance of wellbeing across the lifespan depends on the preservation of cognitive function. We propose that successful cognitive aging is determined by interactions both within and between large-scale functional brain networks. Such connectivity can be estimated from task-free functional magnetic resonance imaging (fMRI), also known as resting-state fMRI (rs-fMRI). However, common correlational methods are confounded by age-related changes in the neurovascular signaling. To estimate network interactions at the neuronal rather than vascular level, we used generative models that specified both the neural interactions and a flexible neurovascular forward model. The networks' parameters were optimized to explain the spectral dynamics of rs-fMRI data in 602 healthy human adults from population-based cohorts who were approximately uniformly distributed between 18 and 88 years (www.cam-can.com). We assessed directed connectivity within and between three key large-scale networks: the salience network, dorsal attention network, and default mode network. We found that age influences connectivity both within and between these networks, over and above the effects on neurovascular coupling. Canonical correlation analysis revealed that the relationship between network connectivity and cognitive function was age-dependent: cognitive performance relied on neural dynamics more strongly in older adults. These effects were driven partly by reduced stability of neural activity within all networks, as expressed by an accelerated decay of neural information. Our findings suggest that the balance of excitatory connectivity between networks, and the stability of intrinsic neural representations within networks, changes with age. The cognitive function of older adults becomes increasingly dependent on these factors. SIGNIFICANCE STATEMENT: Maintaining cognitive function is critical to successful aging. To study the neural basis of cognitive function across the lifespan, we studied a large population-based cohort (n = 602, 18-88 years), separating neural connectivity from vascular components of fMRI signals. Cognitive ability was influenced by the strength of connection within and between functional brain networks, and this positive relationship increased with age. In older adults, there was more rapid decay of intrinsic neuronal activity in multiple regions of the brain networks, which related to cognitive performance. Our data demonstrate increased reliance on network flexibility to maintain cognitive function, in the presence of more rapid decay of neural activity. These insights will facilitate the development of new strategies to maintain cognitive ability. PMID- 26985025 TI - Interdependent Conductances Drive Infraslow Intrinsic Rhythmogenesis in a Subset of Accessory Olfactory Bulb Projection Neurons. AB - The accessory olfactory system controls social and sexual behavior. However, key aspects of sensory signaling along the accessory olfactory pathway remain largely unknown. Here, we investigate patterns of spontaneous neuronal activity in mouse accessory olfactory bulb mitral cells, the direct neural link between vomeronasal sensory input and limbic output. Both in vitro and in vivo, we identify a subpopulation of mitral cells that exhibit slow stereotypical rhythmic discharge. In intrinsically rhythmogenic neurons, these periodic activity patterns are maintained in absence of fast synaptic drive. The physiological mechanism underlying mitral cell autorhythmicity involves cyclic activation of three interdependent ionic conductances: subthreshold persistent Na(+) current, R-type Ca(2+) current, and Ca(2+)-activated big conductance K(+) current. Together, the interplay of these distinct conductances triggers infraslow intrinsic oscillations with remarkable periodicity, a default output state likely to affect sensory processing in limbic circuits. SIGNIFICANCE STATEMENT: We show for the first time that some rodent accessory olfactory bulb mitral cells-the direct link between vomeronasal sensory input and limbic output-are intrinsically rhythmogenic. Driven by >= 3 distinct interdependent ionic conductances, infraslow intrinsic oscillations show remarkable periodicity both in vitro and in vivo. As a novel default state, infraslow autorhythmicity is likely to affect limbic processing of pheromonal information. PMID- 26985026 TI - Mirror Neurons of Ventral Premotor Cortex Are Modulated by Social Cues Provided by Others' Gaze. AB - Mirror neurons (MNs) in the inferior parietal lobule and ventral premotor cortex (PMv) can code the intentions of other individuals using contextual cues. Gaze direction is an important social cue that can be used for understanding the meaning of actions made by other individuals. Here we addressed the issue of whether PMv MNs are influenced by the gaze direction of another individual. We recorded single-unit activity in macaque PMv while the monkey was observing an experimenter performing a grasping action and orienting his gaze either toward (congruent gaze condition) or away (incongruent gaze condition) from a target object. The results showed that one-half of the recorded MNs were modulated by the gaze direction of the human agent. These gaze-modulated neurons were evenly distributed between those preferring a gaze direction congruent with the direction where the grasping action was performed and the others that preferred an incongruent gaze. Whereas the presence of congruent responses is in line with the usual coupling of hand and gaze in both executed and observed actions, the incongruent responses can be explained by the long exposure of the monkeys to this condition. Our results reveal that the representation of observed actions in PMv is influenced by contextual information not only extracted from physical cues, but also from cues endowed with biological or social value. SIGNIFICANCE STATEMENT: In this study, we present the first evidence showing that social cues modulate MNs in the monkey ventral premotor cortex. These data suggest that there is an integrated representation of other's hand actions and gaze direction at the single neuron level in the ventral premotor cortex, and support the hypothesis of a functional role of MNs in decoding actions and understanding motor intentions. PMID- 26985027 TI - Neuropeptidergic Signaling and Active Feeding State Inhibit Nociception in Caenorhabditis elegans. AB - Food availability and nutritional status are important cues affecting behavioral states. Here we report that, in Caenorhabditis elegans, a cascade of dopamine and neuropeptide signaling acts to inhibit nociception in food-poor environments. In the absence of food, animals show decreased sensitivity and increased adaptation to soluble repellents sensed by the polymodal ASH nociceptors. The effects of food on adaptation are affected by dopamine and neuropeptide signaling; dopamine acts via the DOP-1 receptor to decrease adaptation on food, whereas the neuropeptide receptors NPR-1 and NPR-2 act to increase adaptation off food. NPR-1 and NPR-2 function cell autonomously in the ASH neurons to increase adaptation off food, whereas the DOP-1 receptor controls neuropeptide release from interneurons that modulate ASH activity indirectly. These results indicate that feeding state modulates nociception through the interaction of monoamine and neuropeptide signaling pathways. PMID- 26985028 TI - Defective Phagocytic Corpse Processing Results in Neurodegeneration and Can Be Rescued by TORC1 Activation. AB - The removal of apoptotic cell corpses is important for maintaining homeostasis. Previously, defects in apoptotic cell clearance have been linked to neurodegeneration. However, the mechanisms underlying this are still poorly understood. In this study, we report that the absence of the phagocytic receptor Draper in glia leads to a pronounced accumulation of apoptotic neurons in the brain of Drosophila melanogaster. These dead cells persist in the brain throughout the lifespan of the organism and are associated with age-dependent neurodegeneration. Our data indicate that corpses persist because of defective phagosome maturation, rather than recognition defects. TORC1 activation, or inhibition of Atg1, in glia is sufficient to rescue corpse accumulation as well as neurodegeneration. These results suggest that phagocytosis of apoptotic neurons by glia during development is essential for brain homeostasis in adult flies. Furthermore, it suggests that TORC1 regulates Draper-mediated phagosome maturation. SIGNIFICANCE STATEMENT: Previously, defects in dead cell clearance were linked to neurodegeneration, but the exact mechanisms are not well understood. In this study, we report that the absence of an engulfment receptor leads to a pronounced accumulation of dead neurons in the brain of the fruit fly Drosophila melanogaster. These dead cells persist in the brain throughout the lifespan of the organism and are associated with age-dependent neurodegeneration. Our data indicate that corpses persist because of defective degradation of cells rather than recognition of dead cells. PMID- 26985030 TI - High-Fat Diet-Induced Obesity Ablates Gastric Vagal Afferent Circadian Rhythms. AB - Rats with high-fat diet (HFD)-induced obesity increase daytime eating, suggesting an alteration in circadian food intake mechanisms. Gastric vagal afferents (GVAs) respond to mechanical stimuli to initiate satiety. These signals are dampened in HFD mice and exhibit circadian variations inversely with food intake in lean mice. Furthermore, leptin shows circadian variation in its circulating level and is able to modulate GVA mechanosensitivity. However, whether leptin's ability to modulate GVAs occurs in a circadian manner is unknown. Therefore, we investigated whether changes in the circadian intake of food in HFD-induced obesity is associated with a disruption in GVA circadian rhythms. Eight-week-old male C57BL/6 mice were fed a standard laboratory diet (SLD) or a HFD for 12 weeks. A subgroup of SLD and HFD mice were housed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 h intervals starting at zeitgeber time 0 (ZT0) and stomach content was measured. After 12 weeks, HFD mice consumed more food during the light phase through larger and more frequent meals compared with SLD mice. SLD mice exhibited circadian fluctuation in stomach content, which peaked at ZT18 and reached a nadir at ZT9. At these time points, both tension and mucosal receptor mechanosensitivity were the lowest and highest, respectively. HFD mice exhibited little circadian variation in stomach content or GVA mechanosensitivity. Leptin potentiated mucosal receptor mechanosensitivity only in SLD mice and with reduced potency during the dark phase. In conclusion, loss of circadian variation in GVA signaling may underpin changes in eating behavior in HFD-induced obesity. SIGNIFICANCE STATEMENT: Appropriate circadian control of food intake is vital for maintaining metabolic health. Diet-induced obesity is associated with strong circadian changes in food intake, but the contributing mechanisms have yet to be determined. Vagal afferents are involved in regulation of feeding behavior, particularly meal size, and have been shown to exhibit circadian fluctuation in mechanosensitivity, potentially allowing for time of day specific levels of satiety signaling. Our study indicates that, in diet-induced obesity, these circadian fluctuations in gastric vagal afferent mechanosensitivity are lost. This was accompanied by increased light phase eating, particularly increased meal size. This is the first evidence that diet induced disruption to vagal afferent signaling may cause a perturbation in circadian eating patterns. PMID- 26985029 TI - Store-Operated Calcium Entry in Muller Glia Is Controlled by Synergistic Activation of TRPC and Orai Channels. AB - The endoplasmic reticulum (ER) is at the epicenter of astrocyte Ca(2+) signaling. We sought to identify the molecular mechanism underlying store-operated calcium entry that replenishes ER stores in mouse Muller cells. Store depletion, induced through blockade of sequestration transporters in Ca(2+)-free saline, induced synergistic activation of canonical transient receptor potential 1 (TRPC1) and Orai channels. Store-operated TRPC1 channels were identified by their electrophysiological properties, pharmacological blockers, and ablation of the Trpc1 gene. Ca(2+) release-activated currents (ICRAC) were identified by ion permeability, voltage dependence, and sensitivity to selective Orai antagonists Synta66 and GSK7975A. Depletion-evoked calcium influx was initiated at the Muller end-foot and apical process, triggering centrifugal propagation of Ca(2+) waves into the cell body. EM analysis of the end-foot compartment showed high-density ER cisternae that shadow retinal ganglion cell (RGC) somata and axons, protoplasmic astrocytes, vascular endothelial cells, and ER-mitochondrial contacts at the vitreal surface of the end-foot. The mouse retina expresses transcripts encoding both Stim and all known Orai genes; Muller glia predominantly express stromal interacting molecule 1 (STIM1), whereas STIM2 is mainly confined to the outer plexiform and RGC layers. Elimination of TRPC1 facilitated Muller gliosis induced by the elevation of intraocular pressure, suggesting that TRPC channels might play a neuroprotective role during mechanical stress. By characterizing the properties of store-operated signaling pathways in Muller cells, these studies expand the current knowledge about the functional roles these cells play in retinal physiology and pathology while also providing further evidence for the complexity of calcium signaling mechanisms in CNS astroglia. SIGNIFICANCE STATEMENT: Store-operated Ca(2+) signaling represents a major signaling pathway and source of cytosolic Ca(2+) in astrocytes. Here, we show that the store-operated response in Muller cells, radial glia that perform key structural, signaling, osmoregulatory, and mechanosensory functions within the retina, is mediated through synergistic activation of transient receptor potential and Orai channels. The end-foot disproportionately expresses the depletion sensor stromal interacting molecule 1, which contains an extraordinarily high density of endoplasmic reticulum cisternae that shadow neuronal, astrocytic, vascular, and axonal structures; interface with mitochondria; but also originate store-operated Ca(2+) entry-induced transcellular Ca(2+) waves that propagate glial excitation into the proximal retina. These results identify a molecular mechanism that underlies complex interactions between the plasma membrane and calcium stores, and contributes to astroglial function, regulation, and response to mechanical stress. PMID- 26985032 TI - A Network of Three Types of Filaments Organizes Synaptic Vesicles for Storage, Mobilization, and Docking. AB - Synaptic transmission between neurons requires precise management of synaptic vesicles. While individual molecular components of the presynaptic terminal are well known, exactly how the molecules are organized into a molecular machine serving the storage and mobilization of synaptic vesicles to the active zone remains unclear. Here we report three filament types associated with synaptic vesicles in glutamatergic synapses revealed by electron microscope tomography in unstimulated, dissociated rat hippocampal neurons. One filament type, likely corresponding to the SNAREpin complex, extends from the active zone membrane and surrounds docked vesicles. A second filament type contacts all vesicles throughout the active zone and pairs vesicles together. On the third filament type, vesicles attach to side branches extending from the long filament core and form vesicle clusters that are distributed throughout the vesicle cloud and along the active zone membrane. Detailed analysis of presynaptic structure reveals how each of the three filament types interacts with synaptic vesicles, providing a means to traffic reserved and recycled vesicles from the cloud of vesicles into the docking position at the active zone. SIGNIFICANCE STATEMENT: The formation and release of synaptic vesicles has been extensively investigated. Explanations of the release of synaptic vesicles generally begin with the movement of vesicles from the cloud into the synaptic active zone. However, the presynaptic terminal is filled with filamentous material that would appear to limit vesicular diffusion. Here, we provide a systematic description of three filament types connecting synaptic vesicles. A picture emerges illustrating how the cooperative attachment and release of these three filament types facilitate the movement of vesicles to the active zone to become docked in preparation for release. PMID- 26985033 TI - Rivalry-Like Neural Activity in Primary Visual Cortex in Anesthetized Monkeys. AB - Two incongruent images viewed by the two eyes cause binocular rivalry, during which observers perceive continuous alternations between these two visual images. Previous studies in both humans and monkeys have shown that the primary visual cortex (V1) plays a critical role in the rivalry perception. However, it is unclear whether the rivalry activity observed in V1 relies on conscious influences. Here, we examine the responses of V1 in monkeys under general anesthesia. With intrinsic signal optical imaging and single-trial analysis, alternating activation of ocular dominance columns in V1 was observed during binocularly incongruent stimulation. Left- and right-eye columns exhibited counterphase activation, which were modulated by stimulus features in ways similar to those found in conscious human observers. These observations indicated that binocular rivalry occurs in V1 without consciousness, suggesting that the low-level automatic mechanisms play a more important role than previously believed in handling visual ambiguities. SIGNIFICANCE STATEMENT: When visual input is ambiguous, for example, in viewing bistable images, human subjects normally perceive one of the interpretations at a particular moment. Previous studies have shown that both low-level visual processing and high-level attention contribute to the establishment of the final visual perception. However, it is not clear whether attention is indispensable in such a process. Here we show that rivalry-like neural activity persisted in monkey V1 when the monkeys were anesthetized and viewed binocularly incongruent stimuli. Such activity has many key features similar to those observed in conscious human subjects. These findings indicate that low-level visual processes play a critical role in solving visual ambiguity such as binocular rivalry. PMID- 26985034 TI - Sensory Prioritization in Rats: Behavioral Performance and Neuronal Correlates. AB - Operating with some finite quantity of processing resources, an animal would benefit from prioritizing the sensory modality expected to provide key information in a particular context. The present study investigated whether rats dedicate attentional resources to the sensory modality in which a near-threshold event is more likely to occur. We manipulated attention by controlling the likelihood with which a stimulus was presented from one of two modalities. In a whisker session, 80% of trials contained a brief vibration stimulus applied to whiskers and the remaining 20% of trials contained a brief change of luminance. These likelihoods were reversed in a visual session. When a stimulus was presented in the high-likelihood context, detection performance increased and was faster compared with the same stimulus presented in the low-likelihood context. Sensory prioritization was also reflected in neuronal activity in the vibrissal area of primary somatosensory cortex: single units responded differentially to the whisker vibration stimulus when presented with higher probability compared with lower probability. Neuronal activity in the vibrissal cortex displayed signatures of multiplicative gain control and enhanced response to vibration stimuli during the whisker session. In conclusion, rats allocate priority to the more likely stimulus modality and the primary sensory cortex may participate in the redistribution of resources. SIGNIFICANCE STATEMENT: Detection of low amplitude events is critical to survival; for example, to warn prey of predators. To formulate a response, decision-making systems must extract minute neuronal signals from the sensory modality that provides key information. Here, we identify the behavioral and neuronal correlates of sensory prioritization in rats. Rats were trained to detect whisker vibrations or visual flickers. Stimuli were embedded in two contexts in which either visual or whisker modality was more likely to occur. When a stimulus was presented in the high-likelihood context, detection was faster and more reliable. Neuronal recording from the vibrissal cortex revealed enhanced representation of vibrations in the prioritized context. These results establish the rat as an alternative model organism to primates for studying attention. PMID- 26985031 TI - Cardinal Orientation Selectivity Is Represented by Two Distinct Ganglion Cell Types in Mouse Retina. AB - Orientation selectivity (OS) is a prominent and well studied feature of early visual processing in mammals, but recent work has highlighted the possibility that parallel OS circuits might exist in multiple brain locations. Although both classic and modern work has identified an OS mechanism in selective wiring from lateral geniculate nucleus (LGN) to primary visual cortex, OS responses have now been found upstream of cortex in mouse LGN and superior colliculus, suggesting a possible origin in the retina. Indeed, retinal OS responses have been reported for decades in rabbit and more recently in mouse. However, we still know very little about the properties and mechanisms of retinal OS in the mouse, including whether there is a distinct OS ganglion cell type, which orientations are represented, and what are the synaptic mechanisms of retinal OS. We have identified two novel types of OS ganglion cells in the mouse retina that are highly selective for horizontal and vertical cardinal orientations. Reconstructions of the dendritic trees of these OS ganglion cells and measurements of their synaptic conductances offer insights into the mechanism of the OS computation at the earliest stage of the visual system. SIGNIFICANCE STATEMENT: Orientation selectivity (OS) is one of the most well studied computations in the brain and has become a prominent model system in various areas of sensory neuroscience. Although the cortical mechanism of OS suggested by Hubel and Wiesel (1962) has been investigated intensely, other OS cells exist upstream of cortex as early as the retina and the mechanisms of OS in subcortical regions are much less well understood. We identified two ON retinal ganglion cells (RGCs) in mouse that compute OS along the horizontal (nasal-temporal) and vertical (dorsoventral) axes of visual space. We show the relationship between dendritic morphology and OS for each RGC type and reveal new synaptic mechanisms of OS computation in the retina. PMID- 26985035 TI - Synaptic Deficits at Neuromuscular Junctions in Two Mouse Models of Charcot-Marie Tooth Type 2d. AB - Patients with Charcot-Marie-Tooth Type 2D (CMT2D), caused by dominant mutations in Glycl tRNA synthetase (GARS), present with progressive weakness, consistently in the hands, but often in the feet also. Electromyography shows denervation, and patients often report that early symptoms include cramps brought on by cold or exertion. Based on reported clinical observations, and studies of mouse models of CMT2D, we sought to determine whether weakened synaptic transmission at the neuromuscular junction (NMJ) is an aspect of CMT2D. Quantal analysis of NMJs in two different mouse models of CMT2D (Gars(P278KY), Gars(C201R)), found synaptic deficits that correlated with disease severity and progressed with age. Results of voltage-clamp studies revealed presynaptic defects characterized by: (1) decreased frequency of spontaneous release without any change in quantal amplitude (miniature endplate current), (2) reduced amplitude of evoked release (endplate current) and quantal content, (3) age-dependent changes in the extent of depression in response to repetitive stimulation, and (4) release failures at some NMJs with high-frequency, long-duration stimulation. Drugs that modify synaptic efficacy were tested to see whether neuromuscular performance improved. The presynaptic action of 3,4 diaminopyridine was not beneficial, whereas postsynaptic-acting physostigmine did improve performance. Smaller mutant NMJs with correspondingly fewer vesicles and partial denervation that eliminates some release sites also contribute to the reduction of release at a proportion of mutant NMJs. Together, these voltage-clamp data suggest that a number of release processes, while essentially intact, likely operate suboptimally at most NMJs of CMT2D mice. SIGNIFICANCE STATEMENT: We have uncovered a previously unrecognized aspect of axonal Charcot-Marie-Tooth disease in mouse models of CMT2D. Synaptic dysfunction contributes to impaired neuromuscular performance and disease progression. This suggests that drugs which improve synaptic efficacy at the NMJ could be considered in treating the pathophysiology of CMT2D patients. PMID- 26985036 TI - Spontaneous Activity Defines Effective Convergence Ratios in an Inhibitory Circuit. AB - Many neurons fire spontaneously, and the rate of this firing is subject to neuromodulation. How this firing affects functional connectivity within a neural network remains largely unexplored. Here we show that changes in spontaneous firing of cartwheel interneurons in the mouse dorsal cochlear nucleus (DCN) alter the effective convergence ratio of interneurons onto their postsynaptic targets through short-term synaptic plasticity. Spontaneous firing of cartwheel cells led to activity-dependent synaptic depression of individual cartwheel synapses. Depression was rapid and profound at stimulation frequencies between 10 and 200 Hz, suggesting the presence of high release probability (Pr) vesicles at these inhibitory synapses. Weak, transient synaptic facilitation could be induced after synapses were predepressed, indicating that low-Pr vesicles are also recruited, and may thus support steady-state transmission. A two-pool vesicle depletion model with 10-fold differences in Pr could account for the synaptic depression over a wide range of stimulus conditions. As a result of depression during high spontaneous activity, more cartwheel interneurons were required for effective inhibition. Convergence of four interneurons was sufficient to compensate for the effects of depression during physiologically expected rates of activity. By simulating synaptic release during spontaneous firing, we found that recruitment of low-Pr vesicles at the synapse plays a critical role in maintaining effective inhibition within a small population of interneurons. The interplay between spontaneous spiking, short-term synaptic plasticity, and vesicle recruitment thus determines the effective size of a convergent neural network. SIGNIFICANCE STATEMENT: We examined the relationship between the structure of a small neural circuit and the properties of its individual synapses. Successful synaptic inhibition of a target cell firing requires a critical inhibitory synaptic strength. Synapses often become depressed during spontaneous presynaptic activity, and this increases the number of presynaptic neurons needed to mediate inhibition. We show that depression is limited by the presence of a pool of vesicles that resist depletion. Thus, the size of this vesicle pool determines the size of the circuit needed to mediate inhibition during different patterns of activity. PMID- 26985037 TI - Role of Ventral Subiculum in Context-Induced Relapse to Alcohol Seeking after Punishment-Imposed Abstinence. AB - In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive alcohol use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol drinking. We recently developed a rat model of this human condition in which we train alcohol preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and then test for relapse to alcohol seeking in Contexts A and B without alcohol or shock. Here, we studied the role of projections to nucleus accumbens (NAc) shell from ventral subiculum (vSub), basolateral amygdala, paraventricular thalamus, and ventral medial prefrontal cortex in context-induced relapse after punishment-imposed abstinence. First, we measured double-labeling of the neuronal activity marker Fos with the retrograde tracer cholera toxin subunit B (injected in NAc shell) and demonstrated that context-induced relapse is associated with selective activation of the vSub->NAc shell projection. Next, we reversibly inactivated the vSub with GABA receptor agonists (muscimol+baclofen) before the context-induced relapse tests and provided evidence for a causal role of vSub in this relapse. Finally, we used a dual-virus approach to restrict expression of the inhibitory kappa opioid-receptor based DREADD (KORD) in vSub->NAc shell projection neurons. We found that systemic injections of the KORD agonist salvinorin B, which selectively inhibits KORD-expressing neurons, decreased context-induced relapse to alcohol seeking. Our results demonstrate a critical role of vSub in context induced relapse after punishment-imposed abstinence and further suggest a role of the vSub->NAc projection in this relapse. SIGNIFICANCE STATEMENT: In many human alcoholics, abstinence is self-imposed because of the negative consequences of excessive use, and relapse is often triggered by exposure to environmental contexts associated with prior alcohol use. Until recently, an animal model of this human condition did not exist. We developed a rat model of this human condition in which we train alcohol-preferring P rats to self-administer alcohol in one context (A), punish the alcohol-reinforced responding in a different context (B), and test for relapse to alcohol seeking in Contexts A and B. Here, we used neuroanatomical, neuropharmacological, and chemogenetic methods to demonstrate a role of ventral subiculum and potentially its projections to nucleus accumbens in context-induced relapse after punishment-imposed abstinence. PMID- 26985040 TI - Anxiety Evokes Hypofrontality and Disrupts Rule-Relevant Encoding by Dorsomedial Prefrontal Cortex Neurons. AB - Anxiety is a debilitating symptom of most psychiatric disorders, including major depression, post-traumatic stress disorder, schizophrenia, and addiction. A detrimental aspect of anxiety is disruption of prefrontal cortex (PFC)-mediated executive functions, such as flexible decision making. Here we sought to understand how anxiety modulates PFC neuronal encoding of flexible shifting between behavioral strategies. We used a clinically substantiated anxiogenic treatment to induce sustained anxiety in rats and recorded from dorsomedial PFC (dmPFC) and orbitofrontal cortex (OFC) neurons while they were freely moving in a home cage and while they performed a PFC-dependent task that required flexible switches between rules in two distinct perceptual dimensions. Anxiety elicited a sustained background "hypofrontality" in dmPFC and OFC by reducing the firing rate of spontaneously active neuronal subpopulations. During task performance, the impact of anxiety was subtle, but, consistent with human data, behavior was selectively impaired when previously correct conditions were presented as conflicting choices. This impairment was associated with reduced recruitment of dmPFC neurons that selectively represented task rules at the time of action. OFC rule representation was not affected by anxiety. These data indicate that a neural substrate of the decision-making deficits in anxiety is diminished dmPFC neuronal encoding of task rules during conflict-related actions. Given the translational relevance of the model used here, the data provide a neuronal encoding mechanism for how anxiety biases decision making when the choice involves overcoming a conflict. They also demonstrate that PFC encoding of actions, as opposed to cues or outcome, is especially vulnerable to anxiety. SIGNIFICANCE STATEMENT: A debilitating aspect of anxiety is its impact on decision making and flexible control of behavior. These cognitive constructs depend on proper functioning of the prefrontal cortex (PFC). Understanding how anxiety affects PFC encoding of cognitive events is of great clinical and evolutionary significance. Using a clinically valid experimental model, we find that, under anxiety, decision making may be skewed by salient and conflicting environmental stimuli at the expense of flexible top-down guided choices. We also find that anxiety suppresses spontaneous activity of PFC neurons, and weakens encoding of task rules by dorsomedial PFC neurons. These data provide a neuronal encoding scheme for how anxiety disengages PFC during decision making. PMID- 26985039 TI - 17beta-Estradiol and Agonism of G-protein-Coupled Estrogen Receptor Enhance Hippocampal Memory via Different Cell-Signaling Mechanisms. AB - The ability of 17beta-estradiol (E2) to enhance hippocampal object recognition and spatial memory depends on rapid activation of extracellular signal-regulated kinase (ERK) in the dorsal hippocampus (DH). Although this activation can be mediated by the intracellular estrogen receptors ERalpha and ERbeta, little is known about the role that the membrane estrogen receptor GPER plays in regulating ERK or E2-mediated memory formation. In this study, post-training DH infusion of the GPER agonist G-1 enhanced object recognition and spatial memory in ovariectomized female mice, whereas the GPER antagonist G-15 impaired memory, suggesting that GPER activation, like E2, promotes hippocampal memory formation. However, unlike E2, G-1 did not increase ERK phosphorylation, but instead significantly increased phosphorylation of c-Jun N-terminal kinase (JNK) in the DH. Moreover, DH infusion of the JNK inhibitor SP600125 prevented G-1 from enhancing object recognition and spatial memory, but the ERK inhibitor U0126 did not. These data suggest that GPER enhances memory via different cell-signaling mechanisms than E2. This conclusion was supported by data showing that the ability of E2 to facilitate memory and activate ERK signaling was not blocked by G-15 or SP600125, which demonstrates that the memory-enhancing effects of E2 are not dependent on JNK or GPER activation in the DH. Together, these data indicate that GPER regulates memory independently from ERalpha and ERbeta by activating JNK signaling, rather than ERK signaling. Thus, the findings suggest that GPER in the DH may not function as an estrogen receptor to regulate object recognition and spatial memory. SIGNIFICANCE STATEMENT: Although 17beta-estradiol has long been known to regulate memory function, the molecular mechanisms underlying estrogenic memory modulation remain largely unknown. Here, we examined whether the putative membrane estrogen receptor GPER acts like the classical estrogen receptors, ERalpha and ERbeta, to facilitate hippocampal memory in female mice. Although GPER activation did enhance object recognition and spatial memory, it did so by activating different cell-signaling mechanisms from ERalpha, ERbeta, or 17beta-estradiol. These data indicate that 17beta-estradiol and GPER independently regulate hippocampal memory, and suggest that hippocampal GPER may not function as an estrogen receptor in the dorsal hippocampus. These findings are significant because they provide novel insights about the molecular mechanisms through which 17beta-estradiol modulates hippocampal memory. PMID- 26985042 TI - The Severity of Acute Stress Is Represented by Increased Synchronous Activity and Recruitment of Hypothalamic CRH Neurons. AB - The hypothalamo-pituitary-adrenocortical (HPA) axis regulates stress physiology and behavior. To achieve an optimally tuned adaptive response, it is critical that the magnitude of the stress response matches the severity of the threat. Corticotropin-releasing hormone (CRH) released from the paraventricular nucleus of the hypothalamus is a major regulator of the HPA axis. However, how CRH producing neurons in an intact animal respond to different stressor intensities is currently not known. Using two-photon calcium imaging on intact larval zebrafish, we recorded the activity of CRH cells, while the larvae were exposed to stressors of varying intensity. By combining behavioral and physiological measures, we first determined how sudden alterations in environmental conditions lead to different levels of stress axis activation. Then, we measured changes in the frequency and amplitude of Ca(2+) transients in individual CRH neurons in response to such stressors. The response magnitude of individual CRH cells covaried with stressor intensity. Furthermore, stressors caused the recruitment of previously inactive CRH neurons in an intensity-dependent manner, thus increasing the pool of responsive CRH cells. Strikingly, stressor-induced activity appeared highly synchronized among CRH neurons, and also across hemispheres. Thus, the stressor strength-dependent output of CRH neurons emerges by a dual mechanism that involves both the increased activity of individual cells and the recruitment of a larger pool of responsive cells. The synchronicity of CRH neurons within and across hemispheres ensures that the overall output of the HPA axis matches the severity of the threat. SIGNIFICANCE STATEMENT: Stressors trigger adaptive responses in the body that are essential for survival. How the brain responds to acute stressors of varying intensity in an intact animal, however, is not well understood. We address this question using two-photon Ca(2+) imaging in larval zebrafish with transgenically labeled corticotropin-releasing hormone (CRH) cells, which represent a major regulator of the stress axis. We show that stressor strength-dependent responses of CRH neurons emerge via an intensity-dependent increase in the activity of individual CRH cells, and by an increase in the pool of responsive CRH cells at the population level. Furthermore, we report striking synchronicity among CRH neurons even across hemispheres, which suggests tight intrahypothalamic and interhypothalamic coordination. Thus, our work reveals how CRH neurons respond to different levels of acute stress in vivo. PMID- 26985038 TI - More Docked Vesicles and Larger Active Zones at Basket Cell-to-Granule Cell Synapses in a Rat Model of Temporal Lobe Epilepsy. AB - Temporal lobe epilepsy is a common and challenging clinical problem, and its pathophysiological mechanisms remain unclear. One possibility is insufficient inhibition in the hippocampal formation where seizures tend to initiate. Normally, hippocampal basket cells provide strong and reliable synaptic inhibition at principal cell somata. In a rat model of temporal lobe epilepsy, basket cell-to-granule cell (BC->GC) synaptic transmission is more likely to fail, but the underlying cause is unknown. At some synapses, probability of release correlates with bouton size, active zone area, and number of docked vesicles. The present study tested the hypothesis that impaired GABAergic transmission at BC->GC synapses is attributable to ultrastructural changes. Boutons making axosomatic symmetric synapses in the granule cell layer were reconstructed from serial electron micrographs. BC->GC boutons were predicted to be smaller in volume, have fewer and smaller active zones, and contain fewer vesicles, including fewer docked vesicles. Results revealed the opposite. Compared with controls, epileptic pilocarpine-treated rats displayed boutons with over twice the average volume, active zone area, total vesicles, and docked vesicles and with more vesicles closer to active zones. Larger active zones in epileptic rats are consistent with previous reports of larger amplitude miniature IPSCs and larger BC->GC quantal size. Results of this study indicate that transmission failures at BC->GC synapses in epileptic pilocarpine-treated rats are not attributable to smaller boutons or fewer docked vesicles. Instead, processes following vesicle docking, including priming, Ca(2+) entry, or Ca(2+) coupling with exocytosis, might be responsible. SIGNIFICANCE STATEMENT: One in 26 people develops epilepsy, and temporal lobe epilepsy is a common form. Up to one third of patients are resistant to currently available treatments. This study tested a potential underlying mechanism for previously reported impaired inhibition in epileptic animals at basket cell-to-granule cell (BC->GC) synapses, which normally are reliable and strong. Electron microscopy was used to evaluate 3D ultrastructure of BC->GC synapses in a rat model of temporal lobe epilepsy. The hypothesis was that impaired synaptic transmission is attributable to smaller boutons, smaller synapses, and abnormally low numbers of synaptic vesicles. Results revealed the opposite. These findings suggest that impaired transmission at BC->GC synapses in epileptic rats is attributable to later steps in exocytosis following vesicle docking. PMID- 26985041 TI - Synaptic Mechanisms Generating Orientation Selectivity in the ON Pathway of the Rabbit Retina. AB - Neurons that signal the orientation of edges within the visual field have been widely studied in primary visual cortex. Much less is known about the mechanisms of orientation selectivity that arise earlier in the visual stream. Here we examine the synaptic and morphological properties of a subtype of orientation selective ganglion cell in the rabbit retina. The receptive field has an excitatory ON center, flanked by excitatory OFF regions, a structure similar to simple cell receptive fields in primary visual cortex. Examination of the light evoked postsynaptic currents in these ON-type orientation-selective ganglion cells (ON-OSGCs) reveals that synaptic input is mediated almost exclusively through the ON pathway. Orientation selectivity is generated by larger excitation for preferred relative to orthogonal stimuli, and conversely larger inhibition for orthogonal relative to preferred stimuli. Excitatory orientation selectivity arises in part from the morphology of the dendritic arbors. Blocking GABAA receptors reduces orientation selectivity of the inhibitory synaptic inputs and the spiking responses. Negative contrast stimuli in the flanking regions produce orientation-selective excitation in part by disinhibition of a tonic NMDA receptor-mediated input arising from ON bipolar cells. Comparison with earlier studies of OFF-type OSGCs indicates that diverse synaptic circuits have evolved in the retina to detect the orientation of edges in the visual input. SIGNIFICANCE STATEMENT: A core goal for visual neuroscientists is to understand how neural circuits at each stage of the visual system extract and encode features from the visual scene. This study documents a novel type of orientation selective ganglion cell in the retina and shows that the receptive field structure is remarkably similar to that of simple cells in primary visual cortex. However, the data indicate that, unlike in the cortex, orientation selectivity in the retina depends on the activity of inhibitory interneurons. The results further reveal the physiological basis for feature detection in the visual system, elucidate the synaptic mechanisms that generate orientation selectivity at an early stage of visual processing, and illustrate a novel role for NMDA receptors in retinal processing. PMID- 26985046 TI - Bringing in "The Ones Who Know Them": Informal Community and Safety Planning for Victims of Intimate Partner Violence in New Zealand. AB - Victim advocates help victims of intimate partner violence to plan for their safety and encourage them to find social support. In New Zealand, however, victims often bring supportive allies with them to safety planning meetings, and those allies help to plan for the victim's safety. Interviews were conducted with representatives from 24 refuges in New Zealand, and from their perspective, the inclusion of allies in safety planning meetings is beneficial not only for social support but also for enhancing the safety of the victim. The benefits and implications of enlisting informal community members to help keep victims safe are discussed. PMID- 26985043 TI - AMPA-Kainate Receptor Inhibition Promotes Neurologic Recovery in Premature Rabbits with Intraventricular Hemorrhage. AB - Intraventricular hemorrhage (IVH) in preterm infants leads to cerebral inflammation, reduced myelination of the white matter, and neurological deficits. No therapeutic strategy exists against the IVH-induced white matter injury. AMPA kainate receptor induced excitotoxicity contributes to oligodendrocyte precursor cell (OPC) damage and hypomyelination in both neonatal and adult models of brain injury. Here, we hypothesized that IVH damages white matter via AMPA receptor activation, and that AMPA-kainate receptor inhibition suppresses inflammation and restores OPC maturation, myelination, and neurologic recovery in preterm newborns with IVH. We tested these hypotheses in a rabbit model of glycerol-induced IVH and evaluated the expression of AMPA receptors in autopsy samples from human preterm infants. GluR1-GluR4 expressions were comparable between preterm humans and rabbits with and without IVH. However, GluR1 and GluR2 levels were significantly lower in the embryonic white matter and germinal matrix relative to the neocortex in both infants with and without IVH. Pharmacological blockade of AMPA-kainate receptors with systemic NBQX, or selective AMPA receptor inhibition by intramuscular perampanel restored myelination and neurologic recovery in rabbits with IVH. NBQX administration also reduced the population of apoptotic OPCs, levels of several cytokines (TNFalpha, IL-beta, IL-6, LIF), and the density of Iba1(+) microglia in pups with IVH. Additionally, NBQX treatment inhibited STAT-3 phosphorylation, but not astrogliosis or transcription factors regulating gliosis. Our data suggest that AMPA-kainate receptor inhibition alleviates OPC loss and IVH-induced inflammation and restores myelination and neurologic recovery in preterm rabbits with IVH. Therapeutic use of FDA-approved perampanel treatment might enhance neurologic outcome in premature infants with IVH. SIGNIFICANCE STATEMENT: Intraventricular hemorrhage (IVH) is a major complication of prematurity and a large number of survivors with IVH develop cerebral palsy and cognitive deficits. The development of IVH leads to inflammation of the periventricular white matter, apoptosis and arrested maturation of oligodendrocyte precursor cells, and hypomyelination. Here, we show that AMPA kainate receptor inhibition by NBQX suppresses inflammation, attenuates apoptosis of oligodendrocyte precursor cells, and promotes myelination as well as clinical recovery in preterm rabbits with IVH. Importantly, AMPA-specific inhibition by the FDA-approved perampanel, which unlike NBQX has a low side-effect profile, also enhances myelination and neurological recovery in rabbits with IVH. Hence, the present study highlights the role of AMPA-kainate receptor in IVH-induced white matter injury and identifies a novel strategy of neuroprotection, which might improve the neurological outcome for premature infants with IVH. PMID- 26985047 TI - The Influence of Non-Misogynous and Mixed Portrayals of Intimate Partner Violence in Music on Beliefs About Intimate Partner Violence. AB - In this study, we investigated the effect of songs that offer non-misogynous and ambivalent portrayals of intimate partner violence (IPV). Participants ( N = 103) were exposed to a misogynous song about IPV, a song critical of IPV, and a song that offered an ambivalent portrayal of IPV. Our results showed positive effects of the anti-IPV song, and both positive and negative effects of the ambivalent portrayal on participants' beliefs about a violent relationship. These findings suggest that the context in which IPV is portrayed should be considered when evaluating the impact of media depicting IPV. PMID- 26985044 TI - Cell Type-Specific Circuit Mapping Reveals the Presynaptic Connectivity of Developing Cortical Circuits. AB - The mammalian cerebral cortex is a dense network composed of local, subcortical, and intercortical synaptic connections. As a result, mapping cell type-specific neuronal connectivity in the cerebral cortex in vivo has long been a challenge for neurobiologists. In particular, the development of excitatory and inhibitory interneuron presynaptic input has been hard to capture. We set out to analyze the development of this connectivity in the first postnatal month using a murine model. First, we surveyed the connectivity of one of the earliest populations of neurons in the brain, the Cajal-Retzius (CR) cells in the neocortex, which are known to be critical for cortical layer formation and are hypothesized to be important in the establishment of early cortical networks. We found that CR cells receive inputs from deeper-layer excitatory neurons and inhibitory interneurons in the first postnatal week. We also found that both excitatory pyramidal neurons and inhibitory interneurons received broad inputs in the first postnatal week, including inputs from CR cells. Expanding our analysis into the more mature brain, we assessed the inputs onto inhibitory interneurons and excitatory projection neurons, labeling neuronal progenitors with Cre drivers to study discrete populations of neurons in older cortex, and found that excitatory cortical and subcortical inputs are refined by the fourth week of development, whereas local inhibitory inputs increase during this postnatal period. Cell type specific circuit mapping is specific, reliable, and effective, and can be used on molecularly defined subtypes to determine connectivity in the cortex. SIGNIFICANCE STATEMENT: Mapping cortical connectivity in the developing mammalian brain has been an intractable problem, in part because it has not been possible to analyze connectivity with cell subtype precision. Our study systematically targets the presynaptic connections of discrete neuronal subtypes in both the mature and developing cerebral cortex. We analyzed the connections that Cajal Retzius cells make and receive, and found that these cells receive inputs from deeper-layer excitatory neurons and inhibitory interneurons in the first postnatal week. We assessed the inputs onto inhibitory interneurons and excitatory projection neurons, the major two types of neurons in the cortex, and found that excitatory inputs are refined by the fourth week of development, whereas local inhibitory inputs increase during this postnatal period. PMID- 26985048 TI - Unusual tremor syndromes: know in order to recognise. AB - Tremor is a common neurological condition in clinical practice; yet, few syndromes are widely recognised and discussed in the literature. As a result, there is an overdiagnosis of well-known causes, such as essential tremor. Many important unusual syndromes should be considered in the differential diagnosis of patients with tremor. The objective of this review is to provide broad clinical information to aid in the recognition and treatment of various unusual tremor syndromes in the adult and paediatric populations. The review comprised of a comprehensive online search using PubMed, Ovid database and Google Scholar to identify the available literature for each unusual tremor syndrome. The review includes fragile X-associated tremor/ataxia syndrome, spinocerebellar ataxia type 12, tremors caused by autosomal recessive cerebellar ataxias, myorhythmia, isolated tongue tremor, Wilson's disease, slow orthostatic tremor, peripheral trauma-induced tremor, tardive tremor and rabbit syndrome, paroxysmal tremors (hereditary chin tremor, bilateral high-frequency synchronous discharges, head tremor, limb-shaking transient ischaemic attack), bobble-head doll syndrome, spasmus nutans and shuddering attacks. Rare tremors generally present with an action tremor and a variable combination of postural and kinetic components with resting tremors less frequently seen. The phenomenology of myorhythmia is still vague and a clinical definition is proposed. The recognition of these entities should facilitate the correct diagnosis and guide the physician to a prompt intervention. PMID- 26985049 TI - How to measure color using spectrometers and calibrated photographs. AB - The measurement of color in biology has become increasingly common. These measurements are not limited to color vision research, but are also found in studies of communication, signaling, camouflage, evolution and behavior, and in the examination of environmental, artificial and biogenic light. Although the recent availability of portable spectrometers has made it simpler to measure color, guidance on how to make these measurements has not kept pace. Because most biologists receive little training in optics, many measure the wrong thing, or measure the right thing in the wrong way. This Commentary attempts to give biologists a brief overview of how to measure light and color using spectrometers and calibrated photographs. It focuses in particular on the inherent ambiguities of many optical measurements, and how these can be addressed. PMID- 26985045 TI - Mindfulness-Meditation-Based Pain Relief Is Not Mediated by Endogenous Opioids. AB - Mindfulness meditation, a cognitive practice premised on sustaining nonjudgmental awareness of arising sensory events, reliably attenuates pain. Mindfulness meditation activates multiple brain regions that contain a high expression of opioid receptors. However, it is unknown whether mindfulness-meditation-based analgesia is mediated by endogenous opioids. The present double-blind, randomized study examined behavioral pain responses in healthy human volunteers during mindfulness meditation and a nonmanipulation control condition in response to noxious heat and intravenous administration of the opioid antagonist naloxone (0.15 mg/kg bolus + 0.1 mg/kg/h infusion) or saline placebo. Meditation during saline infusion significantly reduced pain intensity and unpleasantness ratings when compared to the control + saline group. However, naloxone infusion failed to reverse meditation-induced analgesia. There were no significant differences in pain intensity or pain unpleasantness reductions between the meditation + naloxone and the meditation + saline groups. Furthermore, mindfulness meditation during naloxone produced significantly greater reductions in pain intensity and unpleasantness than the control groups. These findings demonstrate that mindfulness meditation does not rely on endogenous opioidergic mechanisms to reduce pain. SIGNIFICANCE STATEMENT: Endogenous opioids have been repeatedly shown to be involved in the cognitive inhibition of pain. Mindfulness meditation, a practice premised on directing nonjudgmental attention to arising sensory events, reduces pain by engaging mechanisms supporting the cognitive control of pain. However, it remains unknown if mindfulness-meditation-based analgesia is mediated by opioids, an important consideration for using meditation to treat chronic pain. To address this question, the present study examined pain reports during meditation in response to noxious heat and administration of the opioid antagonist naloxone and placebo saline. The results demonstrate that meditation based pain relief does not require endogenous opioids. Therefore, the treatment of chronic pain may be more effective with meditation due to a lack of cross tolerance with opiate-based medications. PMID- 26985050 TI - Intestinal paracellular absorption is necessary to support the sugar oxidation cascade in nectarivorous bats. AB - We made the first measurements of the capacity for paracellular nutrient absorption in intact nectarivorous bats. Leptonycteris yerbabuenae (20 g mass) were injected with or fed inert carbohydrate probes L-rhamnose and D(+) cellobiose, which are absorbed exclusively by the paracellular route, and 3-O methyl-D-glucose (3OMD-glucose), which is absorbed both paracellularly and transcellularly. Using a standard pharmacokinetic technique, we collected blood samples for 2 h after probe administration. As predicted, fractional absorption (f) of paracellular probes declined with increasing Mr in the order of rhamnose (f=0.71)>cellobiose (f=0.23). Absorption of 3OMD-glucose was complete (f=0.85; not different from unity). Integrating our data with those for glucose absorption and oxidation in another nectarivorous bat, we conclude that passive paracellular absorption of glucose is extensive in nectarivorous bat species, as in other bats and small birds, and necessary to support high glucose fluxes hypothesized for the sugar oxidation cascade. PMID- 26985051 TI - Dose-dependent fluoxetine effects on boldness in male Siamese fighting fish. AB - As the use of pharmaceuticals and personal care products (PPCPs) continues to rise, these compounds enter the environment in increasing frequency. One such PPCP, fluoxetine, has been found in detectable amounts in aquatic ecosystems worldwide, where it may interfere with the behavior of exposed organisms. Fluoxetine exposure has been found to influence boldness and exploration in a range of fish species; however, how it might alter behavior in multiple contexts or over time is rarely examined. To this end, the effects of fluoxetine on boldness over time were studied in male Siamese fighting fish. Three different groups of males (0, 0.5 and 5 ug l(-1) fluoxetine) were tested in multiple boldness assays (empty tank, novel environment and shoal) once a week for 3 weeks to collect baseline measures and then at three different time points post exposure. The effects of these varying exposure amounts on behavior were then examined for overall response, consistency and across-context correlations. Unexposed males were bolder in all contexts, were more consistent within a context, and had stronger between-context correlations than exposed males. Fluoxetine had dose-dependent effects on behavior, as males that received the higher dose exhibited greater behavioral effects. This study stresses the potential fitness consequences of fluoxetine exposure and suggests that examining behavioral effects of PPCPs under different dosing regimens and in multiple contexts is important to gain an increased understanding of how exposure affects behavior. PMID- 26985052 TI - Resistance to nutritional stress in ants: when being fat is advantageous. AB - In ants, nutrient acquisition for the whole colony relies on a minority of workers, the foragers, which are often old and lean. Some studies have shown that the link between age, physiology and foraging activity is more flexible than once thought, especially in response to colony or environmental perturbations. This great plasticity offers the intriguing possibility to disentangle the effect of age, behaviour and physiology on the ants' abilities to cope with nutritional stresses. In this paper, we first looked at the capacity of groups of foragers and inner-nest workers to resist starvation and macronutrient imbalance. Second, we investigated whether behavioural task reversion modified the tolerance to nutritional stresses and by extension, changed mortality rate. We found that inner-nest workers live longer than foragers under nutritional stresses but not under optimal conditions. The reversion from foraging to inner-nest activities is followed by an increase in fat content and longevity. Finally, we demonstrated that changes in fat content associated with behavioural transition are highly flexible and strongly correlated to tolerance of nutritional stress. Our results have considerable implications for our understanding of the population dynamics of social insects under adverse nutritional conditions. PMID- 26985053 TI - Maximum-speed curve-running biomechanics of sprinters with and without unilateral leg amputations. AB - On curves, non-amputees' maximum running speed is slower on smaller radii and thought to be limited by the inside leg's mechanics. Similar speed decreases would be expected for non-amputees in both counterclockwise and clockwise directions because they have symmetric legs. However, sprinters with unilateral leg amputation have asymmetric legs, which may differentially affect curve running performance and Paralympic competitions. To investigate this and understand the biomechanical basis of curve running, we compared maximum curve running (radius 17.2 m) performance and stride kinematics of six non-amputee sprinters and 11 sprinters with a transtibial amputation. Subjects performed randomized, counterbalanced trials: two straight, two counterclockwise curves and two clockwise curves. Non-amputees and sprinters with an amputation all ran slower on curves compared with straight running, but with different kinematics. Non-amputees ran 1.9% slower clockwise compared with counterclockwise (P<0.05). Sprinters with an amputation ran 3.9% slower with their affected leg on the inside compared with the outside of the curve (P<0.05). Non-amputees reduced stride length and frequency in both curve directions compared with straight running. Sprinters with an amputation also reduced stride length in both curve running directions, but reduced stride frequency only on curves with the affected leg on the inside. During curve running, non-amputees and athletes with an amputation had longer contact times with their inside compared with their outside leg, suggesting that the inside leg limits performance. For sprinters with an amputation, the prolonged contact times of the affected versus unaffected leg seem to limit maximum running speed during both straight running and running on curves with the affected leg on the inside. PMID- 26985054 TI - Spatiotemporal distribution of essential elements through Populus leaf ontogeny. AB - We examined the spatiotemporal distribution and accumulation of calcium (Ca), potassium (K), and zinc (Zn) during the growth and maturation of grey poplar (Populus tremula * alba) leaves covering plastochrons 01 through 10. This period spans the sugar sink-to-source transition and requires coordinated changes of multiple core metabolic processes that likely involve alterations in essential and non-essential element distributions as tissues mature and effect a reversal in phloem flow direction. Whole-leaf elemental maps were obtained from dried specimens using micro X-ray fluorescence spectroscopy. Additional cross-sections of fresh leaves were scanned to check for tissue specificity in element accumulation. The anatomical distribution of Zn and K remains relatively consistent throughout leaf development; Ca accumulation varied across leaf developmental stages. The basipetal allocation of Ca to the leaf mesophyll matched spatially and temporally the sequence of phloem maturation, positive carbon balance, and sugar export from leaves. The accumulation of Ca likely reflects the maturation of xylem in minor veins and the enhancement of the transpiration stream. Our results independently confirm that xylem and phloem maturation are spatially and temporally coordinated with the onset of sugar export in leaves. PMID- 26985055 TI - Clinical Evaluation of 99mTc-Rituximab for Sentinel Lymph Node Mapping in Breast Cancer Patients. AB - The metastatic status of sentinel lymph nodes (SLNs) might be the most important prognostic factor in breast cancer. In this paper, we report to our knowledge the first study of (99m)Tc-rituximab as a radiotracer for imaging of SLNs using lymphoscintigraphy in both preoperative and intraoperative breast cancer patients. METHODS: (99m)Tc-rituximab was designed as an SLN tracer targeting the CD20 antigen, which expresses extensively in LNs. A retrospective study was performed on 2,317 patients with primary breast cancer who underwent lymphoscintigraphy and sentinel lymph node biopsy (SLNB). Before imaging, all patients were administered a preoperative peritumoral injection of 37 MBq of (99m)Tc-rituximab. RESULTS: (99m)Tc-rituximab was synthesized in both high radiolabeling yield and high radiochemical purity (>95%), with molecular integrity and immune activity well maintained. The initial study of 100 breast cancer patients showed that the success rate of SLN lymphoscintigraphy by injection of (99m)Tc-rituximab, as compared with SLNB, was 100%, and the sensitivity, specificity, accuracy, and false negative rate were 97.4%, 100%, 98.0%, and 2.60%, respectively. Of the following 2,217 patients studied, the success rate of lymphoscintigraphy and SLNB was 98.8% and 99.9%, and the average number of SLN was 1.78 (range, 1-10) and 2.85 (range, 1-15). Age was an independent predictor of the number of SLNs identified by lymphoscintigraphy and intraoperative handheld gamma-probe (P < 0.05), and other factors-such as sex, imaging time, primary tumor site, histopathologic subtype, clinical T stage, and immunochemistry-were not (P > 0.05). However, the SLN metastatic rates were different in patients with different histopathologic subtype, clinical T stage, and immunochemistry (P < 0.05). CONCLUSION: Here we report the first study of the new radiotracer (99m)Tc-rituximab for breast cancer lymphoscintigraphy. This tracer showed great feasibility, safety, and effectiveness for SLN mapping in breast cancer patients. PMID- 26985056 TI - PSMA-Targeted Radionuclide Therapy of Metastatic Castration-Resistant Prostate Cancer with 177Lu-Labeled PSMA-617. AB - Prostate-specific membrane antigen (PSMA) is an excellent target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). Besides high affinity and long tumor retention, the DOTA-conjugated ligand PSMA-617 has low kidney uptake, making it an excellent choice for therapeutic application. We retrospectively report our experience with (177)Lu-PSMA-617-targeted radionuclide therapy in a case series of mCRPC patients resistant to other treatments. METHODS: Patients with PSMA-positive tumor phenotypes were selected by molecular imaging. Thirty patients received 1-3 cycles of (177)Lu-PSMA-617. During therapy, pharmacokinetics and radiation dosimetry were evaluated. Blood cell count was checked every 2 wk after the first and every 4 wk after succeeding cycles. Prostate-specific antigen (PSA) was determined every 4 wk. Radiologic restaging was performed after 3 cycles. RESULTS: Twenty-one of 30 patients had a PSA response; in 13 of 30 the PSA decreased more than 50%. After 3 cycles, 8 of 11 patients achieved a sustained PSA response (>50%) for over 24 wk, which also correlated with radiologic response (decreased lesion number and size). Normally, acute hematotoxicity was mild. Diffuse bone marrow involvement was a risk factor for higher grade myelosuppression but could be identified by PSMA imaging in advance. Xerostomia, nausea, and fatigue occurred sporadically (<10%). Clearance of non-tumor-bound tracer was predominantly renal and widely completed by 48 h. Safety dosimetry revealed kidney doses of approximately 0.75 Gy/GBq, red marrow doses of 0.03 Gy/GBq, and salivary gland doses of 1.4 Gy/GBq, irrespective of tumor burden and consistent on subsequent cycles. Mean tumor-absorbed dose ranged from 6 to 22 Gy/GBq during cycle 1. CONCLUSION: (177)Lu-PSMA-617 is a promising new option for therapy of mCRPC and deserves more attention in larger prospective trials. PMID- 26985057 TI - Prediction of Posttransplantation Recurrence of Hepatocellular Carcinoma Using Metabolic and Volumetric Indices of 18F-FDG PET/CT. AB - (18)F-FDG PET is an effective method of predicting recurrence of hepatocellular carcinoma (HCC) after liver transplantation. We compared recently introduced metabolic and volumetric (18)F-FDG PET/CT indices with the current clinicopathologic predictors for ability to predict recurrence. METHODS: In total, 110 HCC patients who underwent (18)F-FDG PET and liver transplantation were enrolled. On PET, SUVs and tumor-to-background ratios (TBRs) were measured as metabolic activity indices. Various metabolic tumor volumes and uptake-volume products (UVP) were also measured as volumetric indices. The ability of these indices and other clinicopathologic factors to predict recurrence was compared. RESULTS: All metabolic and volumetric indices were significant for recurrence prediction on receiver-operating-characteristic curve analyses (P < 0.001). On univariate survival analyses, all PET indices-as well as tumor size, tumor number, the Milan criteria, tumor grade, vascular invasion, and T-stage-were significant factors. However, on multivariate analyses, tumor size, tumor grade, maximum TBR, and UVP calculated by inferior vena cava activity were significant factors (P = 0.004, 0.014, 0.009, and 0.021, respectively). When the Milan criteria and PET factors were included in the multivariate analysis, the Milan criteria (P = 0.029), maximum TBR (P < 0.001), and UVP (P = 0.016) were significant. CONCLUSION: Volumetric and metabolic activity indices of (18)F-FDG PET are effective predictors of posttransplantation HCC recurrence. In addition to clinicopathologic factors, these indices need to be considered in the selection of candidates for liver transplantation. PMID- 26985058 TI - PET Mapping of Neurofunctional Changes in a Posttraumatic Stress Disorder Model. AB - Posttraumatic stress disorder (PTSD) is an anxiety disorder that occurs after exposure to a traumatic event. This study aimed to investigate the neurobiologic changes before and after exposure-based therapy by PET in a rat model of PTSD. METHODS: Serial (18)F-FDG PET imaging studies were performed under the control (tone presentation), fear-conditioning, and extinction retrieval phases. Neuroactivity marker c-Fos protein was used for immunostaining. RESULTS: Increased glucose metabolism was observed in the bilateral amygdala after fear conditioning (P < 0.001) and in the right posterior insular cortex under extinction retrieval (P < 0.001) compared with the control phase. Increased c-Fos expression in the posterior insular cortex under extinction retrieval was positively correlated to the glucose metabolism (P < 0.01). CONCLUSION: Our results indicated that the amygdala plays a key role in fear memory formation and, most importantly, the insular cortex is related to the retrieval of extinction memory. (18)F-FDG PET may provide a promising in vivo approach for evaluating exposure-based therapy of PTSD. PMID- 26985059 TI - The Impact That Number of Analyzed Metastatic Breast Cancer Lesions Has on Response Assessment by 18F-FDG PET/CT Using PERCIST. AB - The PET Response Criteria in Solid Tumors (PERCIST) are not specific regarding the number of lesions that should be analyzed per patient. This study evaluated how the number of analyzed lesions affects response assessment in metastatic breast cancer. METHODS: In 60 patients, response was assessed by the change in SUVpeak, normalized to lean body mass, of the most (18)F-FDG-avid lesion (PERCIST 1) and by the change in the sum of normalized SUVpeak for up to 5 lesions (PERCIST 5). The correlation between response by PERCIST and progression-free and disease-specific survival was evaluated. RESULTS: In responders and nonresponders, the respective progression-free survival at 2 y was 37.26% and 6.43% for PERCIST 1 (P < 0.0001) and 33.65% and 7.14% for PERCIST 5 (P < 0.0001) and the respective disease-specific survival at 4 y was 58.96% and 25.44% for PERCIST 1 (P < 0.012) and 59.12% vs 20.01% for PERCIST 5 (P < 0.002). CONCLUSION: The number of analyzed lesions does not appear to have a major impact on the prognostic value of response assessment with (18)F-FDG PET/CT in metastatic breast cancer. PMID- 26985060 TI - Assessment of Minimum 124I Activity Required in Uptake Measurements Before Radioiodine Therapy for Benign Thyroid Diseases. AB - This study aimed to assess a hypothetical minimum administered activity of (124)I required to achieve comparability between pretherapeutic radioiodine uptake (RAIU) measurements by (124)I PET/CT and by (131)I RAIU probe, the clinical standard. In addition, the impact of different reconstruction algorithms on (124)I RAIU and the evaluation of pixel noise as a parameter for image quality were investigated. METHODS: Different scan durations were simulated by different reconstruction intervals of 600-s list-mode PET datasets (including 15 intervals up to 600 s and 5 different reconstruction algorithms: filtered-backprojection and 4 iterative techniques) acquired 30 h after administration of 1 MBq of (124)I. The Bland-Altman method was used to compare mean (124)I RAIU levels versus mean 3-MBq (131)I RAIU levels (clinical standard). The data of 37 patients with benign thyroid diseases were assessed. The impact of different reconstruction lengths on pixel noise was investigated for all 5 of the (124)I PET reconstruction algorithms. A hypothetical minimum activity was sought by means of a proportion equation, considering that the length of a reconstruction interval equates to a hypothetical activity. RESULTS: Mean (124)I RAIU and (131)I RAIU already showed high levels of agreement for reconstruction intervals of as short as 10 s, corresponding to a hypothetical minimum activity of 0.017 MBq of (124)I. The iterative algorithms proved generally superior to the filtered backprojection algorithm. (124)I RAIU showed a trend toward higher levels than (131)I RAIU if the influence of retrosternal tissue was not considered, which was proven to be the cause of a slight overestimation by (124)I RAIU measurement. A hypothetical minimum activity of 0.5 MBq of (124)I obtained with iterative reconstruction appeared sufficient both visually and with regard to pixel noise. CONCLUSION: This study confirms the potential of (124)I RAIU measurement as an alternative method for (131)I RAIU measurement in benign thyroid disease and suggests that reducing the administered activity is an option. CT information is particularly important in cases of retrosternal expansion. The results are relevant because (124)I PET/CT allows additional diagnostic means, that is, the possibility of performing fusion imaging with ultrasound. (124)I PET/CT might be an alternative, especially when hybrid (123)I SPECT/CT is not available. PMID- 26985061 TI - 18F-Choline PET/MRI: The Additional Value of PET for MRI-Guided Transrectal Prostate Biopsies. AB - We assessed the value of fusion (18)F-fluoromethylcholine ((18)F-choline) PET/MRI for image-guided (targeted) prostate biopsies to detect significant prostate cancer (Gleason >= 3 + 4) compared with standard (systematic 12-core) biopsies. METHODS: Within an ongoing prospective clinical trial, hybrid (18)F-choline PET/CT and multiparametric 3T MRI (mpMRI) of the pelvis were performed in 36 subjects with a rising prostate-specific antigen for known (n = 15) or suspected (n = 21) prostate cancer before a prostate biopsy procedure. PET and T2-weighted MR volumes of the prostate were spatially registered using commercially available software. Biopsy targets were selected on the basis of visual appearance on MRI and graded as low, intermediate, or high risk for significant disease. Volumes of interest were defined for MR-identified lesions. (18)F-choline uptake measures were obtained from the MR target and a mirrored background volume of interest. The biopsy procedure was performed after registration of real-time transrectal ultrasound with T2-weighted MR and included image-guided cores plus standard cores. Histologic results were determined from standard and targeted biopsy cores as well as prostatectomy specimens (n = 10). RESULTS: Fifteen subjects were ultimately identified with Gleason >= 3 + 4 prostate cancer, of which targeted biopsy identified significantly more (n = 12) than standard biopsies (n = 5; P = 0.002). A total of 52 lesions were identified by mpMRI (19 low, 18 intermediate, 15 high risk), and mpMRI-assigned risk was a strong predictor of final pathology (area under the curve = 0.81; P < 0.001). When the mean (18)F-choline target-to background ratio was used, the addition of (18)F-choline to mpMRI significantly improved the prediction of Gleason >= 3 + 4 cancers over mpMRI alone (area under the curve = 0.92; P < 0.001). CONCLUSION: Fusion PET/MRI transrectal ultrasound image registration for targeted prostate biopsies is clinically feasible and accurate. The addition of (18)F-choline PET to mpMRI improves the identification of significant prostate cancer. PMID- 26985062 TI - RAS isoforms and mutations in cancer at a glance. AB - RAS proteins (KRAS4A, KRAS4B, NRAS and HRAS) function as GDP-GTP-regulated binary on-off switches, which regulate cytoplasmic signaling networks that control diverse normal cellular processes. Gain-of-function missense mutations in RAS genes are found in ~25% of human cancers, prompting interest in identifying anti RAS therapeutic strategies for cancer treatment. However, despite more than three decades of intense effort, no anti-RAS therapies have reached clinical application. Contributing to this failure has been an underestimation of the complexities of RAS. First, there is now appreciation that the four human RAS proteins are not functionally identical. Second, with >130 different missense mutations found in cancer, there is an emerging view that there are mutation specific consequences on RAS structure, biochemistry and biology, and mutation selective therapeutic strategies are needed. In this Cell Science at a Glance article and accompanying poster, we provide a snapshot of the differences between RAS isoforms and mutations, as well as the current status of anti-RAS drug discovery efforts. PMID- 26985066 TI - Editor's Note. PMID- 26985064 TI - Cell adhesion molecule L1 contributes to neuronal excitability regulating the function of voltage-gated Na+ channels. AB - L1 (also known as L1CAM) is a trans-membrane glycoprotein mediating neuron-neuron adhesion through homophilic and heterophilic interactions. Although experimental evidence has implicated L1 in axonal outgrowth, fasciculation and pathfinding, its contribution to voltage-gated Na(+) channel function and membrane excitability has remained unknown. Here, we show that firing rate, single cell spiking frequency and Na(+) current density are all reduced in hippocampal excitatory neurons from L1-deficient mice both in culture and in slices owing to an overall reduced membrane expression of Na(+) channels. Remarkably, normal firing activity was restored when L1 was reintroduced into L1-deficient excitatory neurons, indicating that abnormal firing patterns are not related to developmental abnormalities, but are a direct consequence of L1 deletion. Moreover, L1 deficiency leads to impairment of action potential initiation, most likely due to the loss of the interaction of L1 with ankyrin G that produces the delocalization of Na(+) channels at the axonal initial segment. We conclude that L1 contributes to functional expression and localization of Na(+) channels to the neuronal plasma membrane, ensuring correct initiation of action potential and normal firing activity. PMID- 26985065 TI - Sleepiness, Fatigue, Behavioral Functioning, and Quality of Life in Survivors of Childhood Hematopoietic Stem Cell Transplant. AB - OBJECTIVES: To examine subjective fatigue and sleepiness as predictors of functional outcomes in long-term pediatric hematopoietic stem cell transplant (HSCT) survivors. METHODS: Participants included 76 survivors assessed 5-14 years post-HSCT. Self-report and parent-proxy (i.e., N = 38) measures of fatigue, excessive daytime sleepiness (EDS), emotional and behavioral functioning, executive functioning, and quality of life (QOL) were completed. Health-related correlates were obtained from medical records. RESULTS: Survivors exhibited significant fatigue for self (M = 69.21 +/- 20.14) and parent-proxy (M = 72.15 +/ 20.79) report. EDS was endorsed for 20-33% of survivors, depending on the respondent. EDS was not significant for parent-proxy outcomes, but was associated with poorer self-reported QOL and internalizing problems (p < .0016). Fatigue was associated with poorer functioning across all domains (p's < .0016). CONCLUSIONS: A substantial number of pediatric HSCT survivors exhibit sleepiness and fatigue. Fatigue is associated with statistically and clinically greater functional difficulties, highlighting the importance of examining sleep and fatigue and considering interventions to improve alertness. PMID- 26985063 TI - TAK1 determines susceptibility to endoplasmic reticulum stress and leptin resistance in the hypothalamus. AB - Sustained endoplasmic reticulum (ER) stress disrupts normal cellular homeostasis and leads to the development of many types of human diseases, including metabolic disorders. TAK1 (also known as MAP3K7) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family and is activated by a diverse set of inflammatory stimuli. Here, we demonstrate that TAK1 regulates ER stress and metabolic signaling through modulation of lipid biogenesis. We found that deletion of Tak1 increased ER volume and facilitated ER-stress tolerance in cultured cells, which was mediated by upregulation of sterol-regulatory-element binding protein (SREBP)-dependent lipogenesis. In the in vivo setting, central nervous system (CNS)-specific Tak1 deletion upregulated SREBP-target lipogenic genes and blocked ER stress in the hypothalamus. Furthermore, CNS-specific Tak1 deletion prevented ER-stress-induced hypothalamic leptin resistance and hyperphagic obesity under a high-fat diet (HFD). Thus, TAK1 is a crucial regulator of ER stress in vivo, which could be a target for alleviation of ER stress and its associated disease conditions. PMID- 26985068 TI - Response to "Comment on 'Nutrition Considerations in Duchenne Muscular Dystrophy' ". PMID- 26985067 TI - Comment on "Nutrition Considerations in Duchenne Muscular Dystrophy". PMID- 26985071 TI - Fingerprinting by fMRI: from populations to individual patterns of functional connectivity. PMID- 26985069 TI - Plasticity of Sensorimotor Networks: Multiple Overlapping Mechanisms. AB - Redundancy is an important feature of the motor system, as abundant degrees of freedom are prominent at every level of organization across the central and peripheral nervous systems, and musculoskeletal system. This basic feature results in a system that is both flexible and robust, and which can be sustainably adapted through plasticity mechanisms in response to intrinsic organismal changes and dynamic environments. While much early work of motor system organization has focused on synaptic-based plasticity processes that are driven via experience, recent investigations of neuron-glia interactions, epigenetic mechanisms and large-scale network dynamics have revealed a plethora of plasticity mechanisms that support motor system organization across multiple, overlapping spatial and temporal scales. Furthermore, an important role of these mechanisms is the regulation of intrinsic variability. Here, we review several of these mechanisms and discuss their potential role in neurorehabilitation. PMID- 26985072 TI - Management of stage IIIA (N2) non-small-cell lung cancer: a transatlantic perspective?. PMID- 26985076 TI - A rare case of single right coronary artery with absent left main coronary artery. PMID- 26985074 TI - Real-time respiratory triggered SPECT myocardial perfusion imaging using CZT technology: impact of respiratory phase matching between SPECT and low-dose CT for attenuation correction. AB - AIMS: To assess the impact of respiratory phase matching between single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) and low dose computed tomography (CT) for attenuation correction (AC). METHODS AND RESULTS: Forty patients underwent 1-day 99mTc-tetrofosmin pharmacological stress/rest SPECT-MPI using a cadmium-zinc-telluride gamma camera. Low-dose CT for AC was performed at deep-inspiration breath-hold. SPECT-MPI was acquired once with free-breathing (FB) and repeated at deep-inspiration breath-hold (BH) to match the respiratory phase of AC. From these acquisitions we reconstructed four data sets: free-breathing SPECT-MPI without AC (non-corrected; FB-NC), breath hold SPECT-MPI without AC (non-corrected; BH-NC), free-breathing SPECT-MPI with AC (FB-AC), and breath-hold SPECT-MPI with AC (BH-AC), the latter representing respiratory-phase-matched AC SPECT-MPI. We compared semi-quantitative segmental tracer uptake, visual diagnosis, inter-observer agreement, and image quality. Compared with FB-NC, deep-inspiration BH-NC increases inferior and lateral uptake, but decreases septal uptake. Addition of AC to FB increases inferior and septal uptake, but decreases anterolateral uptake. Combining breath-hold MPI with breath-hold CT AC (BH-AC) increases inferior, inferolateral, and septal uptake, but reduces apical uptake, without affecting anterolateral uptake, with significant differences to all other protocols. Frequency of normal scans increases across protocols: 10% with FB-NC, 21% with BH-NC, 38% with FB-AC, and 51% with BH-AC. Image quality and inter-observer agreement were highest for BH-AC among all protocols. CONCLUSION: Compared with non-corrected breath-hold SPECT MPI and with free-breathing AC SPECT-MPI, respiratory-phase-matched AC SPECT-MPI significantly affects segmental semi-quantitative uptake, increases the frequency of normal scans, yields the best inter-observer agreement, and significantly improves image quality. These findings suggest a potential role of respiratory triggered SPECT-MPI in clinical routine. PMID- 26985075 TI - Papillary fibro-elastoma as a rare cause of rate-dependent angina: importance of diastolic coronary perfusion. PMID- 26985077 TI - Prediction of atherosclerotic disease progression using LDL transport modelling: a serial computed tomographic coronary angiographic study. AB - AIM: To investigate the efficacy of low-density lipoprotein (LDL) transport simulation in reconstructed arteries derived from computed tomography coronary angiography (CTCA) to predict coronary segments that are prone to progress. METHODS AND RESULTS: Thirty-two patients admitted with an acute coronary event who underwent 64-slice CTCA after percutaneous coronary intervention and at 3 year follow-up were included in the analysis. The CTCA data were used to reconstruct the coronary anatomy of the untreated vessels at baseline and follow up, and LDL transport simulation was performed in the baseline models. The computed endothelial shear stress (ESS), LDL concentration, and CTCA-derived plaque characteristics were used to identify predictors of substantial disease progression (defined as an increase in the plaque burden at follow-up higher than two standard deviations of the intra-observer variability of the expert who performed the analysis). Fifty-eight vessels were analysed. High LDL concentration [odds ratio (OR): 2.16; 95% confidence interval (CI): 1.64-2.84; P = 0.0054], plaque burden (OR: 1.40; 95% CI: 1.13-1.72; P = 0.0017), and plaque area (OR: 3.46; 95% CI: 2.20-5.44; P<= 0.0001) were independent predictors of a substantial disease progression at follow-up. The ESS appears as a predictor of disease progression in univariate analysis but was not an independent predictor when the LDL concentration was entered into the multivariate model. The accuracy of the model that included the LDL concentration was higher than the accuracy of the model that included the ESS (65.1 vs. 62.5%). CONCLUSIONS: LDL transport modelling appears a better predictor of atherosclerotic disease progression than the ESS, and combined with the atheroma characteristics provided by CTCA is able to detect with a moderate accuracy segments that will exhibit a significant plaque burden increase at mid-term follow-up. PMID- 26985078 TI - Low dose in nuclear cardiology: state of the art in the era of new cadmium-zinc telluride cameras. AB - The use of myocardial perfusion imaging has seen a tremendous growth during the last decade and has become the most commonly used non-invasive imaging tool for risk stratification in patients with suspected and known coronary artery disease. Adherence to radiation safety best practices varied significantly between laboratories but the possibility to use the new cameras in nuclear cardiology can reduce dramatically the radiation dose without losing accuracy. Moreover, the physical characteristics of ultrafast technology could be able to open new doors for the evaluation of old parameters, changing the impact of nuclear cardiology in the diagnostic strategies. PMID- 26985079 TI - Where Deforestation Leads to Urbanization: How Resource Extraction is Leading to Urban Growth in the Brazilian Amazon. AB - Developing the Amazon into a major provider of internationally traded mineral and food commodities has dramatically transformed broad expanses of tropical forests to farm and pasturelands, and to mining sites. The environmental impacts of this transformation, as well as the drivers underlying the process, have already been well documented. In this article we turn our analytical lenses to another, less examined effect of Amazon land use and environmental change, namely the creation and development of new urban areas. Here we argue that urban growth in the Amazon is a direct residual of international interest in the production of traded commodities, and of the capacity of local urban residents to capture capital and value before it is extracted from the region. Specifically, we suggest that urban growth is occurring fastest where cities have access to both rural export commodities and export corridors. We also show correlations between urban growth and lower rural population density, and cities' capacities to draw migrants from beyond their immediate rural surroundings. More broadly, we argue that urbanization in the Amazon is better interpreted as a symptom rather than a driver of the region's land use and land cover change. PMID- 26985080 TI - What Drives Indirect Land Use Change? How Brazil's Agriculture Sector Influences Frontier Deforestation. AB - From 2000-2005 high returns to soybeans set off an unprecedented expansion of agricultural production across Brazil. The expansion occurred concurrently to a sharp rise in deforestation, leading academics and policy makers to question the extent and means by which the growing agricultural sector was driving regional forest loss. In this article we consider and question the underlying drivers of indirect land use change, namely the potential impact of soybean expansion on beef prices and of land use displacement, via migration. We then present field level results documenting the displacement process in northern Mato Grosso and western Para States of the Amazon. Our results question the extent to which tropical Amazon deforestation is attributable to land use displacement; however, we argue that the agricultural sector may drive deforestation through other channels, namely through regional land markets. PMID- 26985081 TI - Preparing Tomorrow's Pharmacists: Should All Institutional Pharmacists Be Willing and Able to Train Pharmacy Learners? PMID- 26985082 TI - [Not Available]. PMID- 26985083 TI - Interdisciplinary Systems-Based Intervention to Improve IV Hydration during Parenteral Administration of Acyclovir. AB - BACKGROUND: Intravenous (IV) hydration is considered a protective factor in reducing the incidence of acyclovir-induced nephrotoxicity. A systems-based review of cases of acyclovir-associated acute kidney injury can be used to examine institution-, care provider-, and task-related factors involved in administering the drug and can serve as a basis for developing a quality improvement intervention to achieve safer administration of acyclovir. OBJECTIVES: To explore the effectiveness of the study institution's inter disciplinary quality improvement intervention in increasing the dilution of acyclovir before IV administration. METHODS: After conducting a systems-based review for intervention development, a retrospective analysis was undertaken to compare IV administration of acyclovir in the 6-month periods before and after implementation of the intervention. The study population was a sequential sample of all patients over 18 years of age who were seen in the emergency department or admitted to a ward and who received at least one IV dose of acyclovir at the study institution. The primary outcome was the volume in which each acyclovir dose was delivered. The secondary outcomes were the hourly rate of fluid administration, the frequency of an increase in hourly hydration rate, and the incidence of acute kidney injury. RESULTS: Eighty-four patients (44 in the pre intervention period and 40 in the post-intervention period) received IV acyclovir and had evaluable data for the primary outcome. The median volume in which the acyclovir dose was administered was significantly higher in the post-intervention group (250 mL versus 100 mL, p < 0.001). CONCLUSIONS: In this study, an easily implemented intervention significantly increased the volume of IV fluid administered to patients receiving acyclovir. Adequately powered prospective studies are suggested to investigate the effectiveness of this intervention on the clinically relevant incidence of acyclovir-induced nephrotoxicity. PMID- 26985085 TI - Increasing Capacity for Experiential Rotations for Pharmacy Learners: Lessons Learned from a Multisite Teaching Hospital. PMID- 26985086 TI - [Not Available]. PMID- 26985084 TI - Bisphosphonates for Osteoporosis in Patients with Renal Insufficiency: Pharmacists' Practices and Beliefs. AB - BACKGROUND: Clinicians often face challenges in deciding how to treat osteoporosis in patients with chronic kidney disease. As background to offering guidance to health care providers, it is important to understand their practices and beliefs. OBJECTIVES: To describe the practices and beliefs of pharmacists regarding use of bisphosphonates for patients with osteoporosis and chronic kidney disease. METHODS: A cross-sectional survey of pharmacists working in hospitals and related health care settings was conducted. A 34-item online questionnaire was developed consisting of 4 sections: demographic characteristics, practices, beliefs, and comfort level with making decisions about osteoporosis treatment. An e-mail invitation was sent to members of the Canadian Society of Hospital Pharmacists (n = 2499) in November 2012. RESULTS: A total of 367 pharmacists completed the survey. Most of the respondents were women (258 [70%]), had more than 10 years in practice (213 [58%]), and were providing care to 1 or more osteoporosis patients per week (212 [58%]). Over one-third (150 [41%]) stated that they would use a bisphosphonate for patients with creatinine clearance (CrCl) of 15-30 mL/min, but more than half (207 [56%]) stated that they would avoid a bisphosphonate (and recommend another medication) for patients with CrCl below 15 mL/min. Forty-eight percent (176/363) agreed that oral bisphosphonates could be used for patients with renal failure (defined as CrCl < 30 mL/min), so long as dosage adjustments are made. More than half (206/363 [57%]) believed that the adverse effects of oral bisphosphonates increase for patients with renal failure. Respondents expressed a low level of comfort in assessing and initiating osteoporosis treatment for patients with renal failure. CONCLUSIONS: Pharmacists had varying beliefs about managing osteoporosis in patients with chronic kidney disease. This study highlights the need for practice tools and targeted education addressing the use of bisphosphonates for these patients. PMID- 26985087 TI - Health Care and Pharmacy Practice in South Africa. PMID- 26985088 TI - Interaction between Warfarin and Apple Juice. PMID- 26985090 TI - Dexamethasone 1 mg/mL Suspension Prepared from Crushed Tablets: Stability in Glass and Plastic Bottles and Plastic Syringes. PMID- 26985089 TI - Should Traditional Antimicrobial Stewardship (AMS) Models Incorporating Clinical Pharmacists with Full-Time AMS Responsibilities Be Replaced by Models in Which Pharmacists Simply Participate in AMS Activities as Part of Their Routine Ward or Team-Based Pharmaceutical Care? PMID- 26985091 TI - Tribute to the Reviewers of the Canadian Journal of Hospital Pharmacy. PMID- 26985092 TI - Back to the Future. PMID- 26985093 TI - [Not Available]. PMID- 26985095 TI - After the Launch of the CSHP Strategic Plan, What's Next? PMID- 26985094 TI - [Not Available]. PMID- 26985096 TI - Alcohol intake, morbidity, and mortality. PMID- 26985097 TI - Advances in schizophrenia genetics bring new challenges for clinicians and researchers. PMID- 26985098 TI - Twenty years of Internet addiction ... Quo Vadis? PMID- 26985099 TI - Stigma of tiger attack: Study of tiger-widows from Sundarban Delta, India. AB - AIMS: Human-tiger conflict (HTC) is a serious public health issue in Sundarban Reserve Forest, India. HTC is a continued concern for significant mortality and morbidity of both human and tiger population. This study examined 49 widows, whose husbands were killed by tigers, in order to explore the cultural stigma related with tiger-killing and consequent discrimination and social rejection. Different psychosocial aspects of community stigma associated with tiger-killings is discussed in the context of local culture. METHODS: A mix of both quantitative and qualitative methods was used in this ethnographic study in two mouzas of Sundarban adjacent to Reserve Forest, involving (1) Village Survey for Tiger widows, (2) In-depth interview of the widows, (3) Focus Group discussions, (4) Participatory mapping and (5) Stigma assessment by using a 28 item stigma scale especially devised for this research. For comparison of stigma-burden snake-bite widows and normal widows were taken from the same community. RESULTS: Tiger widows showed significantly higher stigma scores on all the clusters (fear, negative feelings, disclosure, discrimination, community attitudes, and spiritual dimension) than from both normal and snake-bite widows. They also showed higher total stigma score (65.9 +/- 9.8) than normal widows (35.8 +/- 8.0) and snake bite widows (40.1 +/- 7.1) and this difference was highly significant (P < 0.001). IDIs and FGDs helped to unfold the cultural construct of stigma related to tiger-killing. This can be seen in how the tiger-widows' quality of life has been negatively impacted with a multitude of post-trauma psychological scars, deprivation, abuse and exploitation. CONCLUSIONS: The study proposes that administrative strategy for sustainable alternative income generation and conservation policy with integrated participatory forest management may save both human and tiger. A community ecocultural mental health programme addressing to eradicate the cultural stigma related with tiger attack, with environmental awareness may help to reduce the social miseries of the tiger-widows. PMID- 26985100 TI - An Indian experience of neurocognitive endophenotypic markers in unaffected first degree relatives of schizophrenia patients. AB - CONTEXT: Multiple vulnerability genes interact with environmental factors to develop a range of phenotypes in the schizophrenia spectrum. Endophenotypes can help characterize the impact of risk genes by providing genetically relevant traits that are more complaisant than the behavioral symptoms that classify mental illness. AIMS: We aimed to investigate the neurocognitive endophenotypic markers for schizophrenia in Indian population. SETTINGS AND DESIGN: In a cross sectional study, we assessed neurocognitive functioning in 40 unaffected first degree relatives (FDR) of schizophrenia patients with an equal number of healthy controls. MATERIALS AND METHODS: FDR schizophrenia group was compared with the control group on measures of short-term memory, verbal working memory, auditory verbal memory on indices of immediate recall and recognition, visuospatial working memory, visual attention, and executive functions. RESULTS: The study found that FDR schizophrenia scored poorly on all tested measures of neurocognition except visual attention. On calculating composite score, we found that composite neurocognitive score better discriminated the FDR schizophrenia from the control group. CONCLUSIONS: Neurocognitive measures of short-term memory, verbal working memory, auditory verbal memory, visuospatial working memory, and executive functions significantly differentiate FDR of patients with schizophrenia from controls and can be considered as endophenotypic markers of schizophrenia in non-Caucasian population. The exactitude of this approach can be increased by calculating a composite neurocognitive score which combines various neurocognitive measures. PMID- 26985101 TI - Predictors of retention in treatment in a tertiary care de-addiction center. AB - CONTEXT: Retention in treatment can improve the outcomes of patients with substance use disorders. AIMS: This study aimed to assess the predictors of treatment retention in a set of patients admitted with substance use disorders. SETTING AND DESIGN: This record-based study was conducted among consecutive patients discharged from the inpatient unit of a tertiary care de-addiction facility in Northern India. MATERIALS AND METHODS: Patients were classified as being retained in treatment or drop-outs based on follow-up records. STATISTICAL ANALYSIS: Those who were retained and those who dropped out were compared using appropriate parametric and nonparametric tests. Logistic regression was used to find out the predictors of retention in treatment. RESULTS: A total of 88 case records were evaluated. All subjects were males and majority of the sample was married, educated up to 10(th) grade, employed, belonged to the nuclear family and urban background. Opioid dependence syndrome (96.6%) was the most common substance use disorder identified. Guilt feelings, general weakness of body, and loss of social respect were the most common substance-related complications experienced. Of the total sample, 40 (45.4%) were classified as retained into treatment. Higher socioeconomic status and having a family member with substance use was associated with higher chances of treatment retention. CONCLUSION: Identification of patient characteristics predicting drop-outs can help in targeting those individuals at higher risk. This can help in more favorable patient outcomes. PMID- 26985102 TI - Two decades of an indigenously developed brief-pulse electroconvulsive therapy device: A review of research work from National Institute of Mental Health and Neurosciences. AB - In 1993, a device to administer brief-pulse electroconvulsive therapy was indigenously developed through collaboration between the National Institution for Quality and Reliability and the National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India. The additional feature of computerized recording of the electroencephalograph and electrocardiograph for both online and offline use had substantial clinical and research implications. Over the past two decades, this device has been used extensively in different academic and nonacademic settings. A considerable body of research with clinical and heuristic interest has also emanated using this device. In this paper, we present the development of this device and follow it up with a review of research conducted at NIMHANS that validate the features and potentials of this device. PMID- 26985103 TI - Resilience: A psychobiological construct for psychiatric disorders. AB - Understanding of psychopathology of mental disorder is evolving, particularly with availability of newer insight from the field of genetics, epigenetics, social, and environmental pathology. It is now becoming clear how biological factors are contributing to development of an illness in the face of a number of psychosocial factors. Resilience is a psychobiological factor which determines individual's response to adverse life events. Resilience is a human capacity to adapt swiftly and successfully to stressful/traumatic events and manage to revert to a positive state. It is fundamental for growth of positive psychology which deals with satisfaction, adaptability, contentment, and optimism in people's life. Of late, there has been a paradigm shift in the understanding of resilience in context of stress risk vulnerability dimension. It is a neurobiological construct with significant neurobehavioral and emotional features which plays important role in deconstructing mechanism of biopsychosocial model of mental disorders. Resilience is a protective factor against development of mental disorder and a risk factor for a number of clinical conditions, e.g. suicide. Available information from scientific studies points out that resilience is modifiable factor which opens up avenues for a number of newer psychosocial as well as biological therapies. Early identification of vulnerable candidates and effectiveness of resilience-based intervention may offer more clarity in possibility of prevention. Future research may be crucial for preventive psychiatry. In this study, we aim to examine whether resilience is a psychopathological construct for mental disorder. PMID- 26985104 TI - Effectiveness of planned teaching program on knowledge regarding Alzheimer's disease among the family members of elderly in a selected urban community at Mangalore. AB - BACKGROUND: Alzheimer's disease is one of the debilitating chronic diseases among older persons. It is an irreversible condition that leads to progressive deterioration of cognitive, intellectual, physical, and psychosocial functions. The study was aimed to assess the knowledge of the family members of elderly regarding Alzheimer's disease in a selected urban community at Mangalore. MATERIALS AND METHODS: A preexperimental research design of one group pretest and posttest with an evaluative approach was adopted for the study. A total of 50 family members of elderly who met the inclusion criteria were selected through purposive sampling technique. The researcher developed a planned teaching program on Alzheimer's disease, and structured knowledge questionnaire on Alzheimer's disease was used to collect the data. RESULTS: Descriptive and inferential statistics was used to analyze the data. Analysis revealed that the mean posttest knowledge (20.78 +/- 3.31) was higher than mean pretest knowledge scores (12.90 +/- 2.43). Significance of difference between pretest and posttest was statistically tested using paired "t" test and it was found very highly significant (t = 40.85, P < 0.05). Majority of the variables showed no significant association between pretest and posttest knowledge score and with demographic variables. CONCLUSION: The findings revealed that the planned teaching program is an effective strategy for improving the knowledge of the subjects. PMID- 26985105 TI - A follow-up study of patients with Dhat syndrome: Treatment pattern, outcome, and reasons for dropout from treatment. AB - AIM: The aim of this study was to evaluate the treatment pattern and satisfaction with treatment provided to patients with Dhat syndrome. It was also aimed to study the follow-up rates and reasons for dropping out of treatment in patients with Dhat syndrome. MATERIALS AND METHODS: Sixty-four subjects diagnosed with Dhat syndrome were prospectively contacted to evaluate treatment satisfaction and reason for dropout after 6 months of baseline evaluation. Sociodemographic, clinical details were recorded at initial intake and Sex Knowledge and Attitude Questionnaire was applied. After 6 months, information on treatment received, number of follow-up visits to the clinic and the outcome were extracted from the treatment records. Treatment satisfaction using Patient Satisfaction Questionnaire and reasons for dropping out from treatment were assessed by a telephonic interview. RESULTS: Twenty-three patients were categorized as treatment completers, 14 as early drop-outs and 27 as late drop-out. The mean (standard deviation) number of visits over the period of 6 months was 3.81 (3.06). The outcome at 6 months was no change in 45.3%, improved in 32.8% and recovered in 21.9%. Higher proportion of treatment completers (52.2%) sought psychiatric help on their own compared to those who dropped out early from the treatment (7.1%). Treatment completers had better knowledge, and more positive attitude toward sex compared to late drop-out group. 34.4%of the subjects were fully satisfied with the various components of treatment. Level of satisfaction was highest for treatment completers. The most common reasons given by those who dropped out early were "not able to spare time for consultation" (21.4%) and "not prescribed medications" (21.4%). The most common reason given by those belonging to "late drop-out" group was 'no improvement with treatment in symptoms of Dhat syndrome (40.7%). CONCLUSIONS: Patients with Dhat syndrome frequently drop-out of the treatment network. There is a need to reorganize the services for these patients and understand their expectations from the treatment so as to provide better care. PMID- 26985106 TI - Circadian clock gene aryl hydrocarbon receptor nuclear translocator-like polymorphisms are associated with seasonal affective disorder: An Indian family study. AB - BACKGROUND AND AIM: Polymorphisms in aryl hydrocarbon receptor nuclear translocator-like (ARNTL) gene, the key component of circadian clock manifests circadian rhythm abnormalities. As seasonal affective disorder (SAD) is associated with disrupted circadian rhythms, the main objective of this study was to screen an Indian family with SAD for ARNTL gene polymorphisms. MATERIALS AND METHODS: In this study, 30 members of close-knit family with SAD, 30 age- and sex matched controls of the same caste with no prior history of psychiatric illness and 30 age- and sex-matched controls belonging to 17 different castes with no prior history of psychiatric illness were genotyped for five different single nucleotide polymorphisms (SNPs) in ARNTL gene by TaqMan allele-specific genotyping assay. STATISTICAL ANALYSIS: Statistical significance was assessed by more powerful quasi-likelihood score test-XM. RESULTS: Most of the family members carried the risk alleles and we observed a highly significant SNP rs2279287 (A/G) in ARNTL gene with an allelic frequency of 0.75. CONCLUSIONS: Polymorphisms in ARNTL gene disrupt circadian rhythms causing SAD and genetic predisposition becomes more deleterious in the presence of adverse environment. PMID- 26985107 TI - Do female patients with nonpathological vaginal discharge need the same evaluation as for Dhat syndrome in males? AB - AIM: The aim of this study was to evaluate the concept of female Dhat syndrome characterized by the complaint of nonpathological vaginal discharge in association with somatic, anxiety, and depressive symptoms. MATERIALS AND METHODS: A total of 26 female subjects with nonpathological vaginal discharge along with depressive and somatic complaints were assessed on a self-rated questionnaire modified from Comprehensive Questionnaire for Assessment of Dhat Syndrome designed for males. They were also assessed for psychiatric comorbidity as per ICD-10. RESULTS: All female subjects received an ICD-10 psychiatric diagnosis, with somatoform/dissociative disorder (57.7%) being the most common. The mean age of onset of vaginal discharge was 24.6 (standard deviation - 7.0) years, noted every day or for 2-3 times per week by more than two-third of the participants. Two-fifth (61.5%) of the women described it as a milky discharge. The most common reason reported for passage of vaginal discharge was that of urinary infection or problems of urinary tract infections (42.3%) followed by vaginal infection/disease (34.6%). More than half (53.8%) of the subjects considered vaginal discharge to be responsible for weakness in the body, weakness in stamina and thinness of physique, while slightly more than two-third (69.2%) of them reported bodily weakness and sleep disturbances. Overall the clinical picture in females was similar to male patients with Dhat syndrome on most of the account. CONCLUSIONS: Subgroup of patients with vaginal discharge attribute their somatic and mental symptoms to the passage of whitish vaginal discharge and are distressed due to the same. The clinical picture is similar to Dhat syndrome in males. There is a need to recognize female variant of Dhat syndrome as a culture bound syndrome. Identification of the same may help in managing this subgroup of patients seeking help from the gynecologists for their nonpathological vaginal discharge or from mental health professionals for their symptoms of common mental disorders. PMID- 26985108 TI - Perception, knowledge, and attitude toward mental disorders and psychiatry among medical undergraduates in Karnataka: A cross-sectional study. AB - CONTEXT: Globally, psychiatry as a subject, psychiatrists as professionals, and patients with psychiatric disorders are subjected to cultural stereotypes and negative attitude by the general population. What is of alarming concern is that these prejudices exist within the medical community as well. AIMS: This study aims at evaluating the perception, knowledge, and attitude toward psychiatric disorders, therapeutic modalities used in psychiatry, psychiatry as a subject and psychiatrists as professionals among undergraduate medical students in Karnataka. SETTINGS AND DESIGN: This is a descriptive, cross-sectional type of study conducted in three medical colleges located in Karnataka. MATERIALS AND METHODS: A sample of 500 students from all three professional phases of MBBS was selected using purposive sampling. A semistructured prevalidated questionnaire was used to assess the perception, knowledge, and attitude of undergraduate medical students toward psychiatric disorders and psychiatry. STATISTICAL ANALYSIS: Data were analyzed using Statistical Package for Social Sciences, version 16.0. RESULTS: The undergraduate medical student population had significant shortcomings in knowledge and attitude pertaining to psychiatric disorders, more glaring in the initial years of education. A comparatively positive opinion was obtained regarding psychiatry as a subject and psychiatrists as professionals, which may reflect the changing trends and concepts, both in society and medical community. CONCLUSION: This study highlights the need for better educational measures at undergraduate level in order to shape a positive attitude of the health care providers towards psychiatry, which is essential for ensuring better care for patients as well as reduction of stigma surrounding psychiatric disorders. PMID- 26985110 TI - Drug abuse in slum population. AB - Substance abuse is an important health problem throughout the world including India, but prevalence and pattern of abuse varies from country to country and in different types of population. Slums have their own social and economic problems so that substance abuse may be different in this population and might be related with these problems. The aim of the present study was to study the prevalence and pattern substances in slum population. Prakash Chandra Sethi Nagar slum area of Indore district was selected for the purpose of this study. In first phase of the study, first a camp was organized to sensitize local leaders, key persons, and local inhabitants about drug abuse at Chandra Prakash Sethi Nagar. After that basic information was gathered with the key persons in Chandra Prakash Sethi Nagar. In second phase by house-to-house survey, all members of the family were interviewed in detail and information was recorded on semi-structured proforma. We observed prevalence rate of 560/1000 populations, 78.2% were males, 28.2% were females, and two-third abusers were laborers (72%). In order of frequency, tobacco was the most common substance abused in 53.9% population followed by gutka (nontobacco pan masala). Other drugs in order of frequency were alcohol 46.5%, cannabis 8.9%, opiates 4.9%, sedative and hypnotic 2.0%, solvents 1.0%, and cocaine in 0.1%. Slum population has higher prevalence rates than general population. PMID- 26985111 TI - Iloperidone-induced ejaculatory dysfunction: A case series. AB - Disorders of ejaculation are the consequences of surgical procedures and with the use of various drugs. Until date, most drugs reported to induce ejaculatory dysfunctions such as retrograde ejaculation or dry orgasms share the capacity to significantly antagonize alpha 1-adrenergic receptor. Iloperidone, a new dopamine Type 2 and serotonin Type 2A antagonist similar to risperidone, provides better efficacy with lesser extra-pyramidal side effects. In addition, it also antagonize alpha 1-adrenergic receptor and alpha-2C receptors. Limited data is available for iloperidone-induced ejaculation dysfunction. This article features five schizophrenic patients which developed retrograde ejaculation during treatment with iloperidone. The ejaculatory dysfunction following treatment with iloperidone could be postulated due to blocking of alpha 1-adrenergic receptor. PMID- 26985109 TI - Presleep thoughts and dysfunctional beliefs in subjects of insomnia with or without depression: Implications for cognitive behavior therapy for insomnia in Indian context. AB - BACKGROUND: Presleep thoughts may vary between patients of insomnia with or without depression. They are important for cognitive behavior therapy for insomnia (CBT-I), but they have never been systemically examined in Indian population. MATERIALS AND METHODS: Patients with insomnia (>1 month) who were willing to undergo CBT-I were included in this study after obtaining informed consent. They were requested to fill a sleep diary and return after 15 days. At the time of intake, diagnosis of depression and anxiety disorders was made according to Diagnostic and Statistical Manual - IV-Text Revision. They were encouraged to provide information regarding presleep thoughts through open-ended and then, close-ended questions. Dysfunctional attitudes and beliefs about sleep were assessed with Hindi version of "dysfunctional beliefs and attitudes scale brief version". Hindi version of "insomnia severity index" was used to assess the severity of insomnia. Subjects were divided into two-groups - insomnia without depression (I) and insomnia with major depressive disorder (I-MDD+). STATISTICAL ANALYSIS: It was done with the help of SPSS v 21.0. Descriptive statistics was calculated. Proportions between groups were tested with Chi-square analysis and categorical variables were compared using independent sample t-test. RESULTS: This study included a total of 63 subjects, out of which 60% were women. Mean age of the whole group was 41.7 +/- 11.8 years. About 40% of all the subjects were diagnosed as having I-MDD+. Forty-one percent of the subjects had clinically significant anxiety. Both groups - I and I-MDD+ had comparable proportion of female subjects (chi(2) = 0.002; P = 0.96) and there was no difference regarding precipitating factors for insomnia (chi(2) = 0.97; P = 0.61). They were also comparable with regards to sleep-related measures, themes of presleep thoughts, and dysfunctional beliefs and attitudes about sleep and insomnia severity. Major themes of presleep thoughts included family issues and health issues. Only a small proportion had recurrent thoughts related to insomnia and its consequences. CONCLUSION: Insomnia is a co-morbid illness with depression and it needs to be separately addressed during therapy. CBT-I should include the element of problem solving technique, especially when we are dealing with the Indian population. PMID- 26985112 TI - Joubert syndrome with autism in two siblings: A rare presentation. AB - Joubert syndrome is a rare autosomal recessive disorder with partial or complete agenesis of cerebellar vermis. This syndrome is identified mainly by the presence of molar tooth sign in magnetic resonance imaging of the brain since it has a varied phenotypic presentation. Of the 200 cases reported so far in the literature, only three reports show the presence of autistic symptoms in siblings suggesting a link between the cerebellar vermis and autistic spectrum disorders. In this case report of two siblings, the female child satisfied the criterion for autistic spectrum disorder in accordance with Diagnostic and Statistical Manual of Mental Disorders Fifth Editon. The boy showed developmental delay with autistic features (not amounting to diagnostic threshold). This report is important in that it adds evidence to the literature that abnormalities of cerebellum are involved in the cognitive development and autistic symptoms. PMID- 26985113 TI - Drinking habits in ancient India. AB - Consumption of one or other form of intoxicating substances has been present throughout the history of the world. This article traces such use in the Indian subcontinent, both in North and South India. References to the use of intoxicants are to be found in the Vedas, the Great Epics, and the ancient Tamil literature. PMID- 26985114 TI - Delusion of pregnancy in a married male: A rare case report. PMID- 26985115 TI - Onychotillomania as manifestation for underlying depressive disorder. PMID- 26985116 TI - Psychopharmacological dinner: A metaphoric learning of psychedelics from gustatory revelations of a pillbox. PMID- 26985117 TI - Warfarin-quetiapine interaction causing hemorrhage. PMID- 26985118 TI - Divalproex sodium leading to sustained significant improvement in tardive dyskinesia in a patient with bipolar disorder. PMID- 26985119 TI - The integration of psychiatry and neurology. PMID- 26985120 TI - Risperidone-induced skin rash. PMID- 26985121 TI - Description of the larval stage of Drusus mixtus (Pictet, 1834) (Trichoptera: Limnephilidae: Drusinae) with notes on its ecology and zoogeography. AB - In the Swiss Jura adults of Drusus mixtus and unknown Drusinae larvae which could not be identified with existing keys were sampled. Based on ripe pupae, the unknown larvae were identified as D. mixtus. The association was confirmed by specimen rearing in aquaria. Based on morphology, larvae of Drusus mixtus key out together with D. croaticus in existing keys. D. mixtus is separated from the latter species by the shape of the anteromedian metanotal sclerites which are broadly triangular, whereas in D. croaticus the sclerites are almost parallel sided, resembling a stretched rectangle. In addition, the two species are geographically well separated: D. croaticus is restricted to the confines of Croatia and Slovenia, whereas D. mixtus is only present in Switzerland and eastern France. With this present paper, all Central European Drusinae species except Drusus chapmani McL, 1901 (France, Switzerland) and D. noricus Malicky, 1981, an endemic from the Saualpe (Carinthia, Austria), are known in the larval stage. PMID- 26985122 TI - The Relation Between Risk and Protective Factors for Problem Behaviors and Depressive Symptoms, Antisocial Behavior, and Alcohol Use in Adolescence. AB - Both externalizing and internalizing psychopathology increase throughout adolescence and a similar set of risk and protective factors may underlie depressive symptoms, antisocial behavior, and alcohol use. Analyses test how risk and protective factors for externalizing behavior in community, school, family, peer and individual domains are related to depressive symptoms, antisocial behavior, and alcohol use concurrently and longitudinally in a sample of 2002 students assessed in 8th and 10th grades (52% male; 58% Caucasian). Findings indicate that risk and protective factors for antisocial behavior and alcohol use are also associated with depressive symptoms, both concurrently and longitudinally. Prevention approaches that target risk and protective factors for externalizing problems may have crossover effects on depressive symptoms during adolescence. PMID- 26985123 TI - Joint confidence region estimation of L-moment ratios with an extension to right censored data. AB - L-moments, defined as specific linear combinations of expectations of order statistics, have been advocated by Hosking [7] and others in the literature as meaningful replacements to that of classic moments in a wide variety of applications. One particular use of L-moments is to classify distributions based on the so-called L-skewness and L-kurtosis measures and given by an L-moment ratio diagram. This method parallels the classic moment-based plot of skewness and kurtosis corresponding to the Pearson system of distributions. In general, these methods have been more descriptive in nature and failed to consider the corresponding variation and covariance of the point estimators. In this note, we propose two procedures to estimate the 100(1 - alpha)% joint confidence region of L-skewness and L-kurtosis, given both complete and censored data. The procedures are derived based on asymptotic normality of L-moment estimators or through a novel empirical characteristic function (c.f.) approach. Simulation results are provided for comparing the performance of these procedures in terms of their respective coverage probabilities. The new and novel c.f.-based confidence region provided superior coverage probability as compared to the standard bootstrap procedure across all parameter settings. The proposed methods are illustrated via an application to a complete Buffalo snow fall data set and to a censored breast cancer data set, respectively. PMID- 26985124 TI - Smooth bootstrap-based confidence intervals for one binomial proportion and difference of two proportions. AB - Constructing confidence intervals (CIs) for a binomial proportion and the difference between two binomial proportions is a fundamental and well-studied problem with respect to the analysis of binary data. In this note, we propose a new bootstrap procedure to estimate the CIs by resampling from a newly developed smooth quantile function in [11] for discrete data. We perform a variety of simulation studies in order to illustrate the strong performance of our approach. The coverage probabilities of our CIs in the one-sample setting are superior than or comparable to other well-known approaches. The true utility of our new and novel approach is in the two-sample setting. For the difference of two proportions, our smooth bootstrap CIs provide better coverage probabilities almost uniformly over the interval (-1, 1), particularly in the tail region as compared than other published methods included in our simulation. We illustrate our methodology via an application to several different binary data sets. PMID- 26985125 TI - A Rejection Principle for Sequential Tests of Multiple Hypotheses Controlling Familywise Error Rates. AB - We present a unifying approach to multiple testing procedures for sequential (or streaming) data by giving sufficient conditions for a sequential multiple testing procedure to control the familywise error rate (FWER). Together we call these conditions a "rejection principle for sequential tests," which we then apply to some existing sequential multiple testing procedures to give simplified understanding of their FWER control. Next the principle is applied to derive two new sequential multiple testing procedures with provable FWER control, one for testing hypotheses in order and another for closed testing. Examples of these new procedures are given by applying them to a chromosome aberration data set and to finding the maximum safe dose of a treatment. PMID- 26985126 TI - Outpatient Dialectical Behavior Therapy for Adolescents Engaged in Deliberate Self-Harm: Conceptual and Methodological Considerations. AB - The current review examines conceptual and methodological issues related to the use of dialectical behavior therapy for adolescents (DBT-A) in treating youth who engage in deliberate self-harm. A comprehensive review of the literature identified six studies appropriate for the review. Results indicated several inconsistencies and limitations across studies including the mixing of various forms of self-harm; variations in diagnostic inclusion/exclusion criteria, insufficient use of standardized self-harm outcome measures, variable lengths and intensity of provided treatment, and inadequate attention paid to DBT adherence. Each of these areas is reviewed along with a discussion of ways to improve the quality of future research. PMID- 26985127 TI - Sports genetics: the PPARA gene and athletes' high ability in endurance sports. A systematic review and meta-analysis. AB - A meta-analysis was performed with the aim of re-evaluating the role of the peroxisome proliferator activated receptor alpha (PPARA) gene intron 7 G/C polymorphism (rs4253778) in athletes' high ability in endurance sports. DESIGN: A meta-analysis of case control studies assessing the association between the G/C polymorphisms of the PPARA gene and endurance sports was conducted. The Cochrane Review Manager software was used to compare the genotype and allele frequencies between endurance athletes and controls to determine whether a genetic variant is more common in athletes than in the general population. Five studies, encompassing 760 endurance athletes and 1792 controls, fulfilled our inclusion criteria. The pooled odds ratio (and confidence intervals, CIs) for the G allele compared to the C allele was 1.65 (95% CI 1.39-1.96). The pooled OR for the GG genotype compared to the GC genotype was 1.79 (95% CI 1.44-2.22), and for the GG genotype compared to the CC genotype 2.37 (95% CI 1.40-3.99). There was no evidence of heterogeneity (I(2) =0%) or of publication bias. Athletes with high ability in endurance sports had a higher frequency of the GG genotype and G allele. PMID- 26985128 TI - High-intensity endurance training increases nocturnal heart rate variability in sedentary participants. AB - The effects of endurance training on endurance performance characteristics and cardiac autonomic modulation during night sleep were investigated during two 4 week training periods. After the first 4-week training period (3 x 40 min per week, at 75% of HRR) the subjects were divided into HIGH group (n = 7), who performed three high-intensity endurance training sessions per week; and CONTROL group (n = 8) who did not change their training. An incremental treadmill test was performed before and after the two 4-week training periods. Furthermore, nocturnal RR-intervals were recorded after each training day. In the second 4 week training period HIGH group increased their VO2max (P = 0.005) more than CONTROL group. At the same time, nocturnal HR decreased (P = 0.039) and high frequency power (HFP) increased (P = 0.003) in HIGH group while no changes were observed in CONTROL group. Furthermore, a correlation was observed between the changes in nocturnal HFP and changes in VO2max during the second 4-week training period (r = 0.90, P < 0.001). The present study showed that the increased HFP is related to improved VO2max in sedentary subjects suggesting that nocturnal HFP can provide a useful method in monitoring individual responses to endurance training. PMID- 26985129 TI - The IGF-1/cortisol ratio as a useful marker for monitoring training in young boxers. AB - Training effects on plasma insulin-like growth factor-1 (IGF-1)/cortisol ratio were investigated in boxers. Thirty subjects were assigned to either the training or the control group (n = 15 in both). They were tested before the beginning of training (T0), after 5 weeks of intensive training (T1), and after 1 week of tapering (T2). Physical performances (Yo-Yo intermittent recovery test level-1), training loads, and blood sampling were obtained at T0, T1, and T2. Controls were only tested for biochemical and anthropometric parameters at T0 and T2. A significantly higher physical performance was observed at T2 compared to T1. At T1, cortisol levels were significantly increased whereas IGF-1 and insulin-like growth factor binding protein-3 (IGFBP-3) levels remained unchanged compared to baseline. At T2, cortisol levels decreased while IGF-1 and IGFBP-3 levels increased. The IGF-1/cortisol ratio decreased significantly at T1 and increased at T2, and its variations were significantly correlated with changes in training loads and Yo-Yo intermittent recovery test level 1 (IRT1) performance over the training period. Cortisol variations correlated with changes in training load (r = 0.64; p < 0.01) and Yo-Yo IRT1 performance (r = 0.78; p < 0.001) at T1 whereas IGF-1 variations correlated only with changes in Yo-Yo IRT1 performance at T2 (r = 0.71; p < 0.001). It is concluded that IGF-1/cortisol ratio could be a useful tool for monitoring training loads in young trained boxers. PMID- 26985130 TI - The effect of cumulative endurance exercise on leptin and adiponectin and their role as markers to monitor training load. AB - Leptin and adiponectin play an essential role in energy metabolism. Leptin has also been proposed as a marker for monitoring training load. So far, no studies have investigated the variability of these hormones in athletes and how they are regulated during cumulative exercise. This study monitored leptin and adiponectin in 15 endurance athletes twice daily in the days before, during and after a 9-day simulated cycling stage race. Adiponectin significantly increased during the race (p = 0.001) and recovery periods (p = 0.002) when compared to the baseline, while leptin decreased significantly during the race (p < 0.0001) and returned to baseline levels during the recovery period. Intra-individual variability was substantially lower than inter-individual variability for both hormones (leptin 34.1 vs. 53.5%, adiponectin 19% vs. 37.2%). With regards to exercise, this study demonstrated that with sufficient, sustained energy expenditure, leptin concentrations can decrease within the first 24 hours. Under the investigated conditions there also appears to be an optimal leptin concentration which ensures stable energy homeostasis, as there was no significant decrease over the subsequent race days. In healthy endurance athletes the recovery of leptin takes 48-72 hours and may even show a supercompensation-like effect. For adiponectin, significant increases were observed within 5 days of commencing racing, with these elevated values failing to return to baseline levels after 3 days of recovery. Additionally, when using leptin and adiponectin to monitor training loads, establishing individual threshold values improves their sensitivity. PMID- 26985131 TI - Age- and gender-related development of stretch shortening cycle during a sub maximal hopping task. AB - The aim of this study was to analyse the effects of age and gender (and their interaction) on a stretch shortening cycle solicited during a hopping task. For this aim, 147 girls and 148 boys aged 11 to 20 years, who were enrolled in middle school or secondary school with no experience in sport activity, or training less than three times per week, performed 3*5 hops in place. Leg-stiffness, jump height and reactive-strength indices were assessed using an accelerometer (Myotest). The participants were selected in order to form five age groups: 11 12, 13-14, 15-16, 17-18 and 19-20 years. Regression analysis between force and centre of mass displacement revealed spring-mass behaviour for all groups (r(2)=.73-.89), meaning that beginning at the age of 11 years, children are able to perform complex inter-muscular coordination of the lower limbs, revealing efficient neural control early in childhood. Leg stiffness increased from 24.7 +/ 10.6 kN . m(-1) at 11-12 years to 44.1 +/- 14 kN . m(-1) in boys, with a small increase until 16 years (+17%) and a large increase between 17 and 20 years (+32.7%). In girls, leg stiffness increased from 26.6 +/- 9 kN . m(-1) at 11-12 years to 39.4 +/- 10.9 kN . m(-1) at 19-20 years, with a curious decrease in leg stiffness at 17-18 years, probably due to an increase in the percentage of fat at this age (25%). While no gender effect was found, the reactive-strength index revealed that, from 15-16 years onward, boys were better able to produce high levels of force in a shorter time than girls. The age of 15-16 years is a threshold of maturity and gender differentiation, where the boys investigated are more efficient in the stretch shortening cycle. PMID- 26985132 TI - Does small-sided-games' court area influence metabolic, perceptual, and physical performance parameters of young elite basketball players? AB - The purpose of this study was to investigate the effect of court size on physiological responses and physical performance of young elite basketball players. Twelve male basketball players (18.6 +/- 0.5 years; 88.8 +/- 14.5 kg; 192.6 +/- 6.5 cm) from an under-19 team performed two small-sided games (matches) with different court areas (28x15 m and 28x9 m; 28x15 and 28x9 protocols). The number of players (3x3) was kept the same in each protocol. The players performed a repeated-sprint ability (RSA) test before and after each match. Blood lactate concentration was collected before (pre) and after (post) the matches, and the session rating of perceived exertion (session-RPE) was determined 30 minutes after the match. Best and mean time in the RSA test were not different between the 28x15 and the 28x9 match protocols (p > 0.05). A significant difference was observed for lactate concentration from pre- to post-match (p < 0.05) in both protocols (28x15 and 28x9); however, there was no significant interaction between protocols. A similar session-RPE mean score (28x15: 7.2 +/- 1.4 and 28x9: 6.6 +/- 1.4) was detected for both protocols (p > 0.05, ES=0.41). In summary, the results of the current study suggest that the different court areas induced similar responses. Although there was no significant difference in effort perception, players tended to perceive a greater effort in the larger court size. PMID- 26985133 TI - Physiological, physical and on-ice performance criteria for selection of elite ice hockey teams. AB - The purpose of this study was to examine physiological and physical determinants of ice-hockey performance in order to assess their impact on the result during a selection for ice hockey. A total of 42 ice hockey players took part in the selection camp. At the end of the camp 20 best players were selected by team of expert coaches to the ice hockey team and created group G1, while the second group (G2) consisted of not selected players (non-successful group Evaluation of goodness of fit of the model to the data was based on the Hosmer Lemeshow test. Ice hockey players selected to the team were taller 181.95+/-4.02 cm, had lower% body fat 13.17+/-3.17%, a shorter time to peak power 2.47+/-0.35 s, higher relative peak power 21.34+/-2.41 W.kg(-1) and higher relative total work 305.18+/ 28.41 J.kg(-1). The results of the aerobic capacity test showed significant differences only in case of two variables. Ice hockey players in the G1 had higher VO2max 4.07+/-0.31 l.min(-1) values than players in the G2 as well as ice hockey players in G1 showed a higher level of relative VO2max 51.75+/-2.99 ml.min(-1).kg(-1) than athletes in G2. Ice hockey players selected to the team (G1) performed better in the 30 m Forwards Sprint 4.28+/-0.31 s; 6x9 Turns 12.19+/-0.75 s; 6x9 stops 12.79+/-0.49 s and Endurance test (6x30 m stops) 32.01+/-0.80 s than players in G2. The logistic regression model showed that the best predictors of success in the recruitment process of top level ice hockey players were time to peak power, relative peak power, VO2max and 30 m sprint forwards on ice. On the basis of the constructed predictive logistic regression model it will be possible to determine the probability of success of the athletes during following the selection processes to the team. PMID- 26985134 TI - Impact of Ramadan intermittent fasting on cognitive function in trained cyclists: a pilot study. AB - This study assessed selected measures of cognitive function in trained cyclists who observed daylight fasting during Ramadan. Eleven cyclists volunteered to participate (age: 21.6+/-4.8 years, VO2max: 57.7+/-5.6 ml kg(-1).min(-1)) and were followed for 2 months. Cognitive function (Cambridge Neuropsychological Test Automated Battery (CANTAB), Reaction Time index (RTI) and Rapid Visual Information Processing (RVP) tests) and sleep architecture (ambulatory EEG) were assessed: before Ramadan (BR), in the 1st week (RA1) and 4th week of Ramadan (RA4), and 2 weeks post-Ramadan (PR). Both cognitive tests were performed twice per day: before and after Ramadan at 8-10 a.m. and 4-6 p.m., and during Ramadan at 4-6 p.m. and 0-2 a.m., respectively. Training load (TL) by the rating of perceived exertion (RPE) method and wellness (Hooper index) were measured daily. If the TL increased over the study period, this variable was stable during Ramadan. The perceived fatigue and delayed onset muscle soreness (DOMS) increased at RA4. Sleep patterns and architecture showed clear disturbances, with significant increases in the number of awakenings and light sleep durations during Ramadan (RA1 and RA4), together with decreased durations of deep and REM sleep stages at PR. RTI (simple and multiple reaction index) reaction and movement times did not vary over the study period. The RVP test showed reduced false alarms during Ramadan, suggesting reduced impulsivity. Overall accuracy significantly increased at RA1, RA4 and PR compared to baseline. At RA4, the accuracy was higher at 0-2 a.m. compared to 4-6 p.m. Despite the observed disturbances in sleep architecture, Ramadan fasting did not negatively impact the cognitive performance of trained cyclists from the Middle East. PMID- 26985135 TI - Poor physical fitness is independently associated with mild cognitive impairment in elderly Koreans. AB - The purpose of this study was to investigate the association between physical fitness and mild cognitive impairment (MCI) in elderly Koreans. This was a cross sectional study that involved 134 men and 299 women aged 65 to 88 years. Six senior fitness tests were used as independent variables: 30 s chair stand for lower body strength, arm curl for upper body strength, chair-sit-and-reach for lower body flexibility, back scratch for upper body flexibility, 8-ft up-and-go for agility/dynamic balance, and 2-min walk for aerobic endurance. Global cognitive function was assessed using the Korean version of the Mini-Mental State Examination (MMSE). Potential covariates such as age, education levels, blood lipids, and insulin resistance (IR) markers were also assessed. Compared to individuals without MMSE-based MCI, individuals with MMSE-based MCI had poor physical fitness based on the senior fitness test (SFT). There were significant positive trends observed for education level (p=0.001) and MMSE score (p<0.001) across incremental levels of physical fitness in this study population. Individuals with moderate (OR=0.341, p=0.006) and high (OR=0.271, p=0.007) physical fitness based on a composite score of the SFT measures were less likely to have MMSE-based MCI than individuals with low physical fitness (referent, OR=1). The strength of the association between moderate (OR=0.377, p=0.038) or high (OR=0.282, p=0.050) physical fitness and MMSE-based MCI was somewhat attenuated but remained statistically significant even after adjustment for the measured compounding factors. We found that poor physical fitness was independently associated with MMSE-based MCI in elderly Koreans. PMID- 26985136 TI - Effect of ultra-endurance exercise on left ventricular performance and plasma cytokines in healthy trained men. AB - The purpose of this study was to investigate the effect of ultra-endurance exercise on left ventricular (LV) performance and plasma concentration of interleukin (IL)-6, IL-10, IL-18 and tumour necrosis factor alpha (TNF-alpha) as well as to examine the relationships between exercise-induced changes in plasma cytokines and those in echocardiographic indices of LV function in ultra-marathon runners. Nine healthy trained men (mean age 30+/-1.0 years) participated in a 100 km ultra-marathon. Heart rate, blood pressure, ejection fraction (EF), fractional shortening (FS), ratio of early (E) to late (A) mitral inflow peak velocities (E/A), ratio of early (E') to late (A') diastolic mitral annulus peak velocities (E'/A') and E-wave deceleration time (DT) were obtained by echocardiography before, immediately after and in the 90th minute of the recovery period. Blood samples were taken before each echocardiographic evaluation. The ultra-endurance exercise caused significant increases in plasma IL-6, IL-10, IL-18 and TNF-alpha. Echocardiography revealed significant decreases in both E and the E/A ratio immediately after exercise, without any significant changes in EF, FS, DT or the E/E' ratio. At the 90th minute of the recovery period, plasma TNF-alpha and the E/A ratio did not differ significantly from the pre-exercise values, whereas FS was significantly lower than before and immediately after exercise. The increases in plasma TNF-alpha correlated with changes in FS (r=0.73) and DT (r=-0.73). It is concluded that ultra-endurance exercise causes alterations in LV diastolic function. The present data suggest that TNF-alpha might be involved in this effect. PMID- 26985138 TI - It Takes Two to Fight in School Too: A Social Relations Model of the Psychometric Properties and Relative Variance of Dyadic Aggression and Victimization in Middle School. AB - Aggressive behavior has been well-studied in terms of interindividual differences among aggressors and victims, but has been understudied, especially within naturalistic contexts, in terms of aggressor-victim relationships. The Social Relations Model (SRM) is a powerful conceptual and analytic tool for studying dyadic phenomena, and we describe the use of multivariate SRM to study aggression. Boys and girls (N = 210) in middle schools (sixth and seventh grades) completed a newly created Dyadic Aggression and Victimization Inventory (DAVI). Results support the reliability and validity of the DAVI in assessing interindividual and interdyadic differences in aggression and victimization. Occurrences of aggression were accounted for primarily by interdyadic variability, indicating the importance of considering aggressor-victim relationships. We discuss the implications of this relationship focus for future research and intervention efforts. PMID- 26985137 TI - Exploring Potential Mechanisms Underlying the Lack of Uncertainty Monitoring in Capuchin Monkeys. AB - In a widely used animal-metacognition paradigm, monkeys are positively reinforced with food for correct classifications of stimuli as sparse or dense and punished with timeouts for incorrect responses, but they also have access to an "uncertainty" response that moves them to the next trial without either of these forms of feedback. Rhesus monkeys use this uncertainty response most often for trials on which they are at greatest risk for making an error, suggesting that they are monitoring their ability to make these classifications. Capuchin monkeys do not succeed to the same degree on these tasks-conceivably as a result of differential contingencies in place in all existing studies between the sparse/dense responses (food delivery or timeout) and the uncertainty response (avoidance of a timeout but also no chance for food reward). Here, we used a novel variation of this task in which the outcomes of the three response classes (sparse, dense, uncertain) were functionally equivalent. All responses simply determined the delay interval before presentation of a second task (matching-to sample), and that task yielded potential food rewards. Overall, capuchin monkeys used the dense and sparse responses appropriately, including some animals that had no prior experience in performing this classification task. However, none used the uncertainty response appropriately even when it was placed on the same contingency plane as the dense and sparse responses. This suggests that the failure of capuchin monkeys to use an uncertainty response is not the result of that response producing a qualitatively different outcome compared to the dense and sparse responses. PMID- 26985140 TI - A Small-Sample Choice of the Tuning Parameter in Ridge Regression. AB - We propose new approaches for choosing the shrinkage parameter in ridge regression, a penalized likelihood method for regularizing linear regression coefficients, when the number of observations is small relative to the number of parameters. Existing methods may lead to extreme choices of this parameter, which will either not shrink the coefficients enough or shrink them by too much. Within this "small-n, large-p" context, we suggest a correction to the common generalized cross-validation (GCV) method that preserves the asymptotic optimality of the original GCV. We also introduce the notion of a "hyperpenalty", which shrinks the shrinkage parameter itself, and make a specific recommendation regarding the choice of hyperpenalty that empirically works well in a broad range of scenarios. A simple algorithm jointly estimates the shrinkage parameter and regression coefficients in the hyperpenalized likelihood. In a comprehensive simulation study of small-sample scenarios, our proposed approaches offer superior prediction over nine other existing methods. PMID- 26985139 TI - Developmental Science and Executive Function. AB - Executive function abilities, including working memory, inhibitory control, and the flexible volitional shifting of the focus of attention provide a foundation for reflection on experience, reasoning, and the purposeful regulation of behavior. These abilities and their underlying neurobiology, however, are inherently malleable and influenced by characteristics of individuals and contexts. Implications of this malleability for research on the development of executive function in early childhood, for the prospect that these abilities can be fostered and promoted by specific types of activities, and for issues relating to the reliable and valid measurement of executive function are considered. PMID- 26985141 TI - Larval morphology of the Western Balkans endemic caddisflies Drusus krusniki Malicky 1981, D. vernonensis Malicky 1989, and D. vespertinus Marinkovic 1976 (Trichoptera, Limnephilidae, Drusinae). AB - Drusinae (Trichoptera, Limnephilidae) are highland caddisflies inhabiting high gradient, turbulent running water and spring habitats. They are disjunctly distributed over the Eurasian mountain ranges, and the majority of species is endemic to particular mountain areas. The most diverse of three main groups of the Drusinae, the grazer clade, consists of species in which larvae feed on epiltihic biofilm and algae. In this paper we describe three previously unknown grazer-clade Drusinae larvae: Drusus krusniki Malicky 1981 (endemic to the Dinaric western Balkans), D. vernonensis Malicky 1989 (endemic to the Hellenic western Balkans), and D. vespertinus Marinkovic 1976 (endemic to the Dinaric western Balkans). The larvae of these species have toothless mandibles typical of the Drusinae grazer clade. Larvae and adults were unambiguously associated using molecular genetic data, i.e., the mitochondrial cytochrome oxidase I gene fragment (mtCOI3-P). Morphological characteristics of the larvae are described and the diagnostic features enabling species-level identification are illustrated. We further discuss the ecology and distribution of three Western Balkan endemic species. PMID- 26985142 TI - Cost and resource utilization in cervical cancer management: a real-world retrospective cost analysis. AB - OBJECTIVES: We set out to assess the health care resource utilization and cost of cervical cancer from the perspective of a single-payer health care system. METHODS: Retrospective observational data for women diagnosed with cervical cancer in British Columbia between 2004 and 2009 were analyzed to calculate patient-level resource utilization patterns from diagnosis to death or 5-year discharge. Domains of resource use within the scope of this cost analysis were chemotherapy, radiotherapy, and brachytherapy administered by the BC Cancer Agency; resource utilization related to hospitalization and outpatient visits as recorded by the B.C. Ministry of Health; medically required services billed under the B.C. Medical Services Plan; and prescriptions dispensed under British Columbia's health insurance programs. Unit costs were applied to radiotherapy and brachytherapy, producing per-patient costs. RESULTS: The mean cost per case of treating cervical cancer in British Columbia was $19,153 (standard error: $3,484). Inpatient hospitalizations, at 35%, represented the largest proportion of the total cost (95% confidence interval: 32.9% to 36.9%). Costs were compared for subgroups of the total cohort. CONCLUSIONS: As health care systems change the way they manage, screen for, and prevent cervical cancer, cost-effectiveness evaluations of the overall approach will require up-to-date data for resource utilization and costs. We provide information suitable for such a purpose and also identify factors that influence costs. PMID- 26985143 TI - Cost-effectiveness analysis of whole-mount pathology processing for patients with early breast cancer undergoing breast conservation. AB - BACKGROUND: Obtaining accurate histopathologic detail for breast lumpectomy specimens is challenging because of sampling and loss of three-dimensional conformational features with conventional processing. The whole-mount (wm) technique is a novel method of serial pathologic sectioning designed to optimize cross-sectional visualization of resected specimens and determination of margin status. METHODS: Using a Markov chain cohort simulation cost-effectiveness model, we compared conventional processing with wm technique for breast lumpectomies. Cost-effectiveness was evaluated from the perspective of the Canadian health care system and compared using incremental cost-effectiveness ratios (icers) for cost per quality-adjusted life-year (qaly) over a 10-year time horizon. Deterministic and probabilistic sensitivity analyses were performed to test the robustness of the model with willingness-to-pay (wtp) thresholds of $0-$100,000. Costs are reported in adjusted 2014 Canadian dollars, discounted at a rate of 3%. RESULTS: Compared with conventional processing, wm processing is more costly ($19,989 vs. $18,427) but generates 0.03 more qalys over 10 years. The icer is $45,414, indicating that this additional amount is required for each additional qaly obtained. The model was robust to all variance in parameters, with the prevalence of positive margins accounting for most of the model's variability. CONCLUSIONS: After a wtp threshold of $45,414, wm processing becomes cost-effective and ultimately generates fewer recurrences and marginally more qalys over time. Excellent baseline outcomes for the current treatment of breast cancer mean that incremental differences in survival are small. However, the overall benefit of the wm technique should be considered in the context of achieving improved accuracy and not just enhancements in clinical effectiveness. PMID- 26985144 TI - Population-based trends in systemic therapy use and cost for cancer patients in the last year of life. AB - BACKGROUND: The use of systemic therapy near the end of life can expose cancer patients to severe toxicity for minimal survival gain and comes with a high cost. Early palliative care is recommended, but there is evidence that aggressive care remains common. To better understand those patterns, the present study set out to describe trends in systemic therapy use and cost for cancer patients in the last year of life. METHODS: Using the BC Cancer Registry, a retrospective population based cohort of cancer decedents (2002-2007) was identified and linked to systemic therapy records. The outcomes of interest were any systemic therapy use and total systemic therapy costs during the last year of life. Multiple logistic regression (systemic therapy use) and generalized linear regression (costs) were conducted, adjusting for age, sex, and survival. Subgroup analyses were performed for patients with primary colorectal, lung, prostate, or breast cancer. RESULTS: From 2002 to 2007, use of systemic therapy in the last 12-4 months of life increased by 21% (95% ci: 10% to 33%); no significant change in use in the last 3 months of life was observed. Costs for both periods increased over time, by 48% (95% ci: 36% to 63%) and by 33% (95% ci: 19% to 49%) respectively. The trends varied across cancer sites, with the greatest increases being observed for lung and colorectal cancer patients. CONCLUSIONS: The use and costs of systemic therapy have generally been increasing, putting pressure on health care providers and payers, but the quality-of-life implications for patients must be better understood. PMID- 26985146 TI - Original Canadian cancer costing research for cancer control sustainability, quality, and value. PMID- 26985145 TI - Temporal association between home nursing and hospital costs at end of life in three provinces. AB - BACKGROUND: Research has demonstrated that increases in palliative homecare nursing are associated with a reduction in the rate of subsequent hospitalizations. However, little evidence is available about the cost-savings potential of palliative nursing when accounting for both increased nursing costs and potentially reduced hospital costs. METHODS: Our retrospective cohort study included cancer decedents from British Columbia, Ontario, and Nova Scotia who received any palliative nursing in the last 6 months of life. A Poisson regression analysis was used to determine the association of increased nursing costs (in 2-week blocks) on the relative average hospital costs in the subsequent 2-week block and on the overall total cost (hospital costs plus nursing costs in the preceding 2-week block). RESULTS: The cohort included 58,022 cancer decedents. Results of the analysis for the last month of life showed an association between increased nursing costs and decreased relative hospital costs in comparisons with a reference group (>0 to 1 hour nursing in the block): the maximum decrease was 55% for Ontario, 31% for British Columbia, and 38% for Nova Scotia. Also, increased nursing costs in the last month were almost always associated with lower total costs in comparison with the reference. For example, cost savings per person-block ranged from $376 (>10 nursing hours) to $1,124 (>4 to 6 nursing hours) in British Columbia. CONCLUSIONS: In the last month of life, increased palliative nursing costs (compared with costs for >0 to 1 hour of nursing in the block) were associated with lower relative hospital costs and a lower total cost in a subsequent block. Our research suggests a cost-savings potential associated with increased community-based palliative nursing. PMID- 26985147 TI - Cost implications of unwarranted imaging for distant metastasis in women with early-stage breast cancer in Ontario. AB - INTRODUCTION: Despite the publication of multiple evidence-based guidelines recommending against routine imaging for distant metastasis in patients with early-stage (i/ii) breast cancer, such imaging is frequently performed. The present retrospective cohort study was conducted to estimate the cost of unnecessary imaging tests in women with stage i and ii breast cancer diagnosed between 1 January 2007 and 31 December 2012 in Ontario. METHODS: We obtained patient-level demographic and tumour data from a large provincial dataset. The total cost of unwarranted imaging tests (in 2015 Canadian dollars) was considered to be equal to the sum of imaging costs incurred between 2007 and 2012 and was stratified by disease stage, imaging modality, and body site. RESULTS: Of the 26,547 identified patients with early-stage breast cancer, 22,811 (85.9%) underwent at least 1 imaging test, with an average of 3.7 tests per patient (3.2 for stage i patients and 4.0 for stage ii patients) over 5 years. At least 1 imaging test was performed in 79.6% of stage i and 92.7% of stage ii patients. During a 5-year period, the cost of unwarranted imaging in patients with early stage breast cancer ranged from CA$4,418,139 to CA$6,865,856, depending on guideline recommendations. CONCLUSIONS: Our study highlights the substantial cost of excess imaging that could be saved and re-allocated to patient care if evidence-based guidelines are followed. Future studies should assess strategies to ensure that evidence-based guidelines are followed and to increase awareness of the cost implications of nonadherence to guidelines. PMID- 26985149 TI - Importance of cost estimates and cost studies. PMID- 26985148 TI - Using the Cancer Risk Management Model to evaluate the health and economic impacts of cytology compared with human papillomavirus DNA testing for primary cervical cancer screening in Canada. AB - BACKGROUND: In Canada, discussion about changing from cytology to human papillomavirus (hpv) dna testing for primary screening in cervical cancer is ongoing. However, the Canadian Task Force on Preventive Health Care has not yet made a recommendation, concluding that the evidence is insufficient. METHODS: We used the cervical cancer and hpv transmission models of the Cancer Risk Management Model to study the health and economic outcomes of primary cytology compared with hpv dna testing in 14 screening scenarios with varying screening modalities and intervals. Projected cervical cancer cases, deaths, colposcopies, screens, costs, and incremental cost-effectiveness were evaluated. We performed sensitivity analyses for hpv dna test costs. RESULTS: Compared with triennial cytology from age 25, 5-yearly hpv dna screening alone from age 30 resulted in equivalent incident cases and deaths, but 55% (82,000) fewer colposcopies and 43% (1,195,000) fewer screens. At hpv dna screening intervals of 3 years, whether alone or in an age-based sequence with cytology, screening costs are greater, but at intervals of more than 5 years, they are lower. Scenarios on the cost effectiveness frontier were hpv dna testing alone every 10, 7.5, 5, or 3 years, and triennial cytology starting at age 21 or 25 when combined with hpv dna testing every 3 years. CONCLUSIONS: Changing from cytology to hpv dna testing as the primary screening test for cervical cancer would be an acceptable strategy in Canada with respect to incidence, mortality, screening and diagnostic test volumes. PMID- 26985150 TI - Cost trajectories for cancer patients. AB - BACKGROUND: Health care spending is known to be highly skewed, with a small subset of the population consuming a disproportionate amount of health care resources. Patients with cancer are high-cost users because of high incremental health care costs for treatment and the growing prevalence of cancer. The objectives of the present study included characterizing cancer-patient trajectories by cost, and identifying the patient and health system characteristics associated with high health system costs after cancer treatment. METHODS: This retrospective cohort study identified Ontario adults newly diagnosed with cancer between 1 April 2009 and 30 September 2010. Costs of health care use before, during, and after cancer episodes were used to develop trajectories of care. Descriptive analyses examined differences between the trajectories in terms of clinical and health system characteristics, and a logistic regression approach identified predictors of being a high-cost user after a cancer episode. RESULTS: Ten trajectories were developed based on whether patients were high- or low-cost users before and after their cancer episode. The most common trajectory represented patients who were low-cost in the year before cancer, survived treatment, and continued to be low-cost in the year after cancer (31.4%); stage ii cancer of the male genital system was the most common diagnosis within that trajectory. Regression analyses identified increases in age and in multimorbidity and low continuity of care as the strongest predictors of high cost status after cancer. CONCLUSIONS: Findings highlight an opportunity to proactively identify patients who might transition to high-cost status after cancer treatment and to remediate that transition. PMID- 26985152 TI - Ileal tubular duplication; a rare cause of bowel obstruction in adults. AB - Gastrointestinal tract duplications (GSD) are rare congenital abnormalities. Eighty percent of GSDs are diagnosed in children less than two years of age. These lesions can be seen anywhere from the oral cavity to the anus, but ileum is the most commonly affected site. GSD can be long and tubular, but are usually in the form of cystic masses. The clinical manifestation of GSD in adults is variable, and they are rarely considered as part of differential diagnosis. In this case report, we presented a 20-year-old patient with ileal duplication. Despite medical tests and radiological examinations, the diagnosis could be made during the operation. PMID- 26985151 TI - Estimation of drug cost avoidance and pathology cost avoidance through participation in NCIC Clinical Trials Group phase III clinical trials in Canada. AB - BACKGROUND: Cost avoidance occurs when, because of provision of a drug therapy [drug cost avoidance (dca)] or a pathology test [pathology cost avoidance (pca)] during trial participation, health care payers need not pay for standard treatments or testing. The aim of our study was to estimate the total dca and pca for Canadian patients enrolled in relevant phase iii trials conducted by the ncic Clinical Trials Group. METHODS: Phase iii trials that had completed accrual and resulted in dca or pca were identified. The pca was calculated based on the number of patients screened and the test cost. The dca was estimated based on patients randomized, the protocol dosing regimen, drug cost, median dose intensity, and median duration of therapy. Costs are presented in Canadian dollars. No adjustment was made for inflation. RESULTS: From 1999 to 2011, 4 trials (1479 patients) resulted in pca and 17 trials (3195 patients) resulted in dca. The total pca was estimated at $4,194,849, which included testing for KRAS ($141,058), microsatellite instability ($18,600), and 21-gene recurrence score ($4,035,191). The total dca was estimated at $27,952,512, of which targeted therapy constituted 43% (five trials). The combined pca and dca was $32,147,361. CONCLUSIONS: Over the study period, trials conducted by the ncic Clinical Trials Group resulted in total cost avoidance (pca and dca) of approximately $7,518 per patient. Although not all trials lead to cost avoidance, such savings should be taken account when the financial impact of conducting clinical research is being considered. PMID- 26985153 TI - The risk of hypocalcemia in patients with parathyroid autotransplantation during thyroidectomy. AB - OBJECTIVE: Thyroidectomy is the most common cause of hypocalcemia. Preservation of parathyroid glands in situ is essential in preventing this complication. The aims of our study were to review patients who underwent parathyroid gland autotransplantation during thyroidectomy, and to compare hypocalcemia rates in patients with and without autotransplantation. MATERIAL AND METHODS: Parathyroid gland autotransplantation was performed in 43 (7.9%) of 543 patients who underwent thyroidectomy between 2008 and 2012. RESULTS: Forty-four parathyroid glands were autotransplanted in 43 patients, including 36 women and 7 men. The median age was 55 (range: 30 to 68). The most common cause of autotransplantation was vascular comprise of the parathyroid gland. Early postoperative hypocalcemia developed in 37% of patients with autotransplantation, and none developed permanent hypocalcemia. Transient and permanent hypocalcemia rates were 9.6% and 0.4% in patients without autotransplantation, respectively. The risk of transient hypocalcemia was significantly high in patients with parathyroid autotransplantation (p<0.001). There was no difference between the two groups in terms of permanent hypocalcemia (p=0.156). CONCLUSION: Despite meticulous dissection, parathyroid glands can be devascularized or removed inadvertently during thyroidectomy. Parathyroid autotransplantation is the best method to maintain parathyroid gland function. Although the risk of transient hypocalcemia is increased following parathyroid autotransplantation, long-term results are satisfactory. PMID- 26985154 TI - An evaluation of treatment results of emergency versus elective surgery in colorectal cancer patients. AB - OBJECTIVE: Colorectal cancer is still one of the most common causes of cancer related deaths in the world despite improvements in diagnosis and treatment modalities, and application of community-based screening methods. Symptoms of colorectal cancer are non-specific and usually manifest following local progression. A number of patients with advanced stage colorectal cancer present to emergency departments with obstruction as the first sign of disease without any previous symptoms. This presentation is an indication for emergency surgery that has a high rate of morbidity and mortality. In this study, we aimed to determine the factors associated with early diagnosis and survival by comparing postoperative results of colorectal cancer patients who underwent surgery under emergency or elective situation. MATERIAL AND METHODS: Files of colorectal patients treated between 2009-2013 were retrospectively analyzed. Data on patient age, gender, operation type, intraoperative results, length of hospital stay, co morbidities, postoperative complications and pathological results were evaluated and compared. RESULTS: There was no statistical difference between groups in terms of age, gender, and pathology results (p>0.05). The difference between groups in terms of postoperative length of hospital stay, presence of co-morbid diseases, pathological stage, and postoperative complications was statistically significant (p<0.05). Length of hospital stay, advanced stage on admission, complications such as surgical site infection, evisceration, and anastomosis leakage rates were higher in patients in the emergency surgery group. CONCLUSION: Risk groups should be determined in order to diagnose colorectal cancer patients at an early stage while they are still asymptomatic, and this information should be incorporated into effective screening programs. This approach will be beneficial to treatment outcomes, complication rates, length of hospital stay, and survival and treatment results. PMID- 26985155 TI - Comparison of laparoscopic sleeve gastrectomy and laparoscopic gastric plication: One year follow-up results. AB - OBJECTIVE: Various different surgical methods are used for obesity surgery. Among them, laparoscopic sleeve gastrectomy (LSG) and laparoscopic gastric plication (LGP) have been both successfully performed in recent years. In this study, we compared the treatment results of patients who underwent LGP, a method that was introduced later consisting of plication of gastric greater curvature to achieve volume reduction, with results of patients who underwent LSG. MATERIAL AND METHODS: We analyzed data on morbid obese patients who underwent bariatric surgery with either LSG or LPG in Konya Beyhekim Hospital between 2009 and 2012. Demographic features including age and sex, preoperative blood biochemistry, body mass index (BMI) before and after operation, duration of hospital stay, morbidity, mortality and complications were analyzed. RESULTS: Fifty-five patients who were operated for obesity between 2009 and 2012 were included in the study. 29 patients underwent LGP, and 26 patients LSG. The BMI in the LGP and LSG groups was 41.4+/-3 kg/m(2) and 42.0+/-3.1 kg/m(2), respectively. There was no significant difference between two groups in terms of BMI. Two groups were also similar in terms of age and gender. In the LGP group, one patient had postoperative necrosis of the suture line. One patient in the LSG group was re operated due to bleeding. Another patient in this group had leakage at the suture line. Postoperative BMI assessment of groups revealed significantly lower BMI levels in the LSG group. Length of hospital stay was significantly shorter in the LGP group. There was no significant difference in complication rates between two groups. CONCLUSION: In this study, we obtained similar results in patients who were treated with LGP or LSG. Moreover, LSG was more efficient in decreasing BMI in morbid obesity surgery when compared to LGP. However, duration of hospital stay was significantly shorter in LGP group. We concluded that both methods could be effectively and safely used in the surgical management of morbid obesity. PMID- 26985156 TI - Our intraoperative boost radiotherapy experience and applications. AB - OBJECTIVE: To present our experience since November 2013, and case selection criteria for intraoperative boost radiotherapy (IObRT) that significantly reduces the local recurrence rate after breast conserving surgery in patients with breast cancer. MATERIAL AND METHODS: Patients who were suitable for IObRT were identified within the group of patients who were selected for breast conserving surgery at our breast council. A MOBETRON (mobile linear accelerator for IObRT) was used for IObRt during surgery. RESULTS: Patients younger than 60 years old with <3 cm invasive ductal cancer in one focus (or two foci within 2 cm), with a histologic grade of 2-3, and a high possibility of local recurrence were admitted for IObRT application. Informed consent was obtained from all participants. Lumpectomy and sentinel lymph node biopsy was performed and advancement flaps were prepared according to the size and inclination of the conus following evaluation of tumor size and surgical margins by pathology. Distance to the thoracic wall was measured, and a radiation oncologist and radiation physicist calculated the required dose. Anesthesia was regulated with slower ventilation frequency, without causing hypoxia. The skin and incision edges were protected, the field was radiated (with 6 MeV electron beam of 10 Gy) and the incision was closed. In our cases, there were no major postoperative surgical or early radiotherapy related complications. CONCLUSION: The completion of another stage of local therapy with IObRT during surgery positively effects sequencing of other treatments like chemotherapy, hormonotherapy and radiotherapy, if required. IObRT increases disease free and overall survival, as well as quality of life in breast cancer patients. PMID- 26985157 TI - Analysis of the Istanbul Forensic Medicine Institute expert decisions on recurrent laryngeal nerve injuries due to thyroidectomy between 2008-2012. AB - OBJECTIVE: The aim of this study was to evaluate the approach of Forensic Medicine Institution for recurrent laryngeal nerve injuries. In addition, parameters that were taken into consideration by Forensic Medicine Institution in the differentiation of complication and malpractice were evaluated. MATERIAL AND METHODS: The files of 38 patients, with recurrent laryngeal nerve injury following thyroidectomy, that were referred to Istanbul Forensic Medicine Institute with request of expert opinion between 2008-2012 were retrospectively investigated. Data regarding expert decisions, age, gender, diagnosis, hospital type, preoperative vocal cord examination, intraoperative nerve monitoring (IONM), identification of nerve injury during operation, repair of nerve during operation, and type of injury were assessed. RESULTS: Surgeons were found to be faulty in all files with bilateral nerve injury, however, one-sided injury files were considered as a medical complication. Twenty-one (55.2%) patients were female, and 17 (44.8%) were male, with a mean age of 35,8 in women, and 34,1 in men. None of these patients had undergone preoperative vocal cord assessment. The recurrent laryngeal nerve was intraoperatively identified in 21 (55.2%) patients, while it was not seen in 17 (44.8%) patients. IONM was not applied in any patients. There was no attempt for nerve repair during any operation. Nineteen patients had unilateral, and 19 patients had bilateral nerve damage. CONCLUSION: Bilateral recurrent laryngeal nerve injuries are considered as malpractice, when imaging or pathology reports fail to state a cause for difficulty in nerve identification. PMID- 26985158 TI - Benefits of xiphoidectomy in total gastrectomy: Technical note. AB - OBJECTIVE: The esophago-gastric junction may be challenging during total gastrectomy due to gastric cancer. This situation may compromise the security of both the dissection and anastomosis. The purpose of this study was to investigate the usefulness of xiphoidectomy to overcome this issue. MATERIAL AND METHODS: The files of patients who underwent total gastrectomy + D2 lymph node dissection due to proximal gastric cancer or cardia cancer between April 2002-December 2013 were retrospectively evaluated. We assessed the outcome in patients with xiphoidectomy in addition to the midline incision in terms of xiphoidectomy technique, xiphoidectomy time, and operative and postoperative complications. RESULTS: Thirty cases were identified to undergo xiphoidectomy. Nineteen patients were male and 11 were female, with a mean age of 51 (21-80) years. The time required for xiphoidectomy was 7-15 minutes (mean 8.7 minutes). The mean additional time required for the closure of the incision in cases with xiphoidectomy was 2 minutes. There was minimal arterial bleeding from the diaphragmatic surface in one patient, which was controlled by electrocautery. Only two patients developed wound infection. CONCLUSION: Performing xiphoidectomy is quite easy, after a certain learning phase. The operative time was 7-15 minutes longer due to excision of xiphoid and closure of the related defect. Minor hemorrhage was a problem during surgery. There were no early or late post-operative complications. We suggest that the procedure is beneficial in selected cases with requirement of a wider operative field or better exposure of the esophago-gastric junction during total gastrectomy for gastric cancer, and recommend removal of the xiphoid bone. PMID- 26985160 TI - Intraoperative diagnosis of cecal diverticulitis during surgery for acute appendicitis: Case series. AB - OBJECTIVE: Cecal diverticulum is a rare entity, and can cause acute abdomen by the way of diverticulitis and perforation of diverticulitis. In this study, we aimed to perform an analysis of patients that have cecal diverticulitis, and presented with acute abdomen. MATERIAL AND METHODS: Patients who were admitted to emergency clinic between 2009-2012 and had acute abdomen due to cecal diverticulitis were included into study retrospectively. RESULTS: Six patients were included in the study with a mean age of 34 years (range 24-43). Four patients were male and two were female (male/female: 2). All six patients presented with abdominal pain, additional symptoms were nausea in five patients, and vomiting in one patient. The mean white blood cell count was 11.900/mm(3) (5850-17.400/mm(3)), while the remaining laboratory results were normal. There were no specific findings on abdominal X-ray or ultrasonography. The surgical exploration revealed an inflamed cecal diverticulitis and normal appendix in all patients. Five patients underwent appendectomy and diverticulectomy. Right hemicolectomy was performed in one patient due to suspicion of malignancy. The early postoperative period was uneventful in all patients. The mean length of hospital stay was 4.5 days with a range of 2-6 days. Histopathological examination showed acute perforated diverticulitis with underlying true diverticulum in three patients, and true diverticulum with acute diverticulitis in the remaining three patients. CONCLUSION: Pre-operative diagnosis of cecal diverticulitis is challenging due to symptoms and signs that resemble acute appendicitis. Diverticulectomy and incidental appendectomy is the treatment of choice in uncomplicated cases. PMID- 26985159 TI - Sentinel lymph node biopsy under fluorescent indocyanin green guidance: Initial experience. AB - OBJECTIVE: Sentinel lymph node biopsy can be applied by using either blue dye or radionuclide method or both in breast cancer. Fluorescent imaging with indocyanine green is a new defined method. This study evaluates the applicability of sentinel lymph node biopsy via fluorescent indocyanine green. MATERIAL AND METHODS: IC-VIEW (Pulsion Medical Systems AG, Munich, Germany) infrared visualization system was used for imaging. Two mL of indocyanine green was injected to visualize sentinel lymph nodes. After injection, subcutaneous lymphatics were traced and sentinel lymph nodes were found with simultaneous imaging. Sentinel lymph nodes were excised under fluorescent light guidance, and excised lymph nodes were examined histopathologically. Patients with sentinel lymph node metastases underwent axillary dissection. RESULTS: Four patients with sentinel lymph node biopsy due to breast cancer were included in the study. Sentinel lymph nodes were visualized with indocyanine green in all patients. The median number of excised sentinel lymph node was 2 (2-3). Two patients with lymph node metastasis underwent axillary dissection. No metastasis was detected in lymph nodes other than the sentinel nodes in patients with axillary dissection. There was no complication during and after the operation related to the method. CONCLUSION: According to our limited experience, sentinel lymph node biopsy under fluorescent indocyanine green guidance, which has an advantage of simultaneous visualization, is technically feasible. PMID- 26985161 TI - Missed retrosternal ectopic thyroid tissue in a patient operated for multinodular goiter. AB - Ectopic thyroid tissue has been found from the tongue to the diaphragm. The most common ectopic thyroid tissue has been found in the tongue, submandibular region, cervical lymph nodes, larynx, trachea, oesophagus, mediastinum, diaphragm and heart respectively. "Forgotten goiter" is an extremely rare disease which is defined as a mediastinal thyroid mass found after total thyroidectomy. In this case report, we discussed a 49 year-old female patient whose retrosternal ectopic thyroid tissue was detected by thyroid scintigraphy taken in postoperative period after total thyroidectomy performed with diagnosis of multinodular goiter. Papillary carcinoma was determined by the histopathological examination. Ectopic thyroid tissue was removed by performing sternotomy. We did not observe any postoperative surgical complications. 100 mCi dose of radioactive iodine was administered to the patient. Retrosternal ectopic thyroid tissue detected after total thyroidectomy is a rarely encountered condition. Therefore, retrosternal ectopic thyroid tissue existence should be definitely kept in mind in patients with no increase in thyroid stimulating hormone level after total thyroidectomy. PMID- 26985162 TI - Sarcoidosis mimicking metastatic breast cancer in a patient with early-stage breast cancer. AB - Sarcoidosis is a systemic granulomatous disorder of unknown origin that affects the lungs and mediastinal lymph nodes in most patients. The coexistence of sarcoidosis and breast cancer has been reported. An unfortunate consequence of the presence of both entities in the same patient is the risk of misdiagnosis. We report the case of a 70-year-old female with T1N0 cancer of the right breast that was initially diagnosed as stage IV because of mediastinal positron-emission tomography -positive lymphadenopathy. Biopsy of a mediastinal lymph node allowed us to diagnose sarcoidosis and correctly stage her disease as stage I breast cancer. PMID- 26985163 TI - Primary thyroid lymphoma. AB - Primary thyroid lymphoma is an uncommon thyroid malignancy. The treatment modalities significantly differ from other thyroid malignancies. Frequently it is accompanied by Hashimoto's thyroiditis, and it may be difficult to differentiate the two entities histologically. Patients typically present with suddenly growing mass in the thyroid gland. Discrimination between primary and secondary lymphoma is important due to variations in diagnostic tools, treatment modalities and prognosis. Surgery, chemotherapy, radiotherapy or combinations of these modalities may be applied in treatment. In this report, three cases with primary thyroid lymphoma in which three different treatment modalities have been applied are presented. PMID- 26985164 TI - Can heat shock protein 32 be used for the early diagnosis of acute mesenteric ischemia? AB - OBJECTIVE: Acute mesenteric ischemia is a challenging and fatal disease. The aim of this study was to detect the heat shock protein 32 (HSP32) response in intestinal tissue and systemic blood to intestinal ischemia and ischemia/reperfusion to define a tool for the early diagnosis of acute mesenteric ischemia. MATERIAL AND METHODS: Thirty female Wistar albino rats were equally divided into 3 groups. Group 1 rats underwent simple laparotomy and closure (control). In Group 2 rats, 1-hour intestinal ischemia followed by 5-hour reperfusion was performed, and Group 3 rats were subjected to 6-hour intestinal ischemia. The experiment was repeated with a 24-hour waiting period. At the end of the waiting period, blood was withdrawn from the tail veins of the rats and the rats were sacrificed via cardiac puncture. Re-laparotomy was subsequently performed and intestinal tissue and luminal samples were obtained for biochemical and pathological investigations. The HSP32 levels of intestinal tissues, luminal contents and blood levels were compared among the groups. RESULTS: At the end of the 24-hour waiting period, the median tissue HSP32 levels were 0.43 (0-6.6) ng/mL for Group 1, 9.51 (2.5-49.9) ng/mL for Group 2 and 43.13 (6.3-121.3) ng/mL for Group 3 (p=0.001). The median blood HSP32 levels were 0.11 (0.1-1.4) ng/mL for Group 1, 0.42 (0.1-0.7) ng/mL for Group 2, and 0.25 (0.1-1.2) ng/mL for Group 3 (p=0.047). The HSP levels in the luminal contents were undetectable. CONCLUSION: Both ischemia and ischemia/reperfusion significantly raised intestinal tissue HSP32 levels in comparison with the control group. However, this change was not reflected in the circulating blood or luminal contents. PMID- 26985165 TI - Prospective randomized comparison of single-incision laparoscopic cholecystectomy with new facilitating maneuver vs. conventional four-port laparoscopic cholecystectomy. AB - OBJECTIVE: We aimed to investigate the technical feasibility of single-incision laparoscopic cholecystectomy (SILC) with our new facilitative maneuver and to compare it with the gold standard four-port laparoscopic cholecystectomy (LC). MATERIAL AND METHODS: Operation time, cosmetic score and incisional hernia rates between LC (n=20) and SILC-1 (first 20 consecutive operations with the new technique) and 2 (subsequent 20 operations with the new technique) were compared. RESULTS: The median operation time for LC, SILC-1 and SILC-2 were; 35 min (12 75), 47.5 min (30-70), and 30 min (12-80), respectively (p=0.005). The operation duration was similar in LC and SILC-2 (p=0.277) groups. Wound seroma rate was higher in SILC-1 (45%) and SILC-2 (30%) groups than LC (5%) group (p=0.010). Cosmetic score was similar between all the groups. Hernia rates were 15.8% and 5.3% in the SILC-1 and SILC-2 groups, respectively, while there was no hernia in the LC group. CONCLUSION: SILC with new facilitating maneuver is comparable with classical four-port laparoscopic cholecystectomy in terms of ease, operation time, reproducibility and safety. Besides these advantages, the single-incision access technique must be optimized to provide comparable wound complication and postoperative hernia rates before being recommended to patients. PMID- 26985166 TI - Risk factors for the development of complicated appendicitis in adults. AB - OBJECTIVE: To investigate the patient's history and physical examination information to find out risk factors associated with complicated appendicitis. MATERIAL AND METHODS: Two hundred patients who were admitted with complicated appendicitis (including abscess, phlegmon, and generalized peritonitis) were retrieved from our database. Two hundred patients with non-complicated acute appendicitis were randomly selected from the same period. These two groups were compared in terms of demographic characteristics, past medical history, and presenting symptoms. We made a multivariate analysis model using binary logistic regression and backward stepwise elimination. RESULTS: Based on multivariate analysis, risk factors for complicated appendicitis included presenting with epigastric pain (OR=3.44), diarrhea (OR=23.4) or malaise (OR=49.7), history of RLQ pain within the past 6 months (OR=4.93), older age (OR=1.04), being married (OR=2.52), lack of anorexia (OR=4.63) and longer interval between onset of symptoms and admission (OR=1.46). Conversely, higher (academic) education was associated with decreased odds for complicated appendicitis (OR=0.26). CONCLUSION: Our findings suggest that a surgeon's clinical assessment is more reliable to make a judgment. "Bedside evaluation" is a useful, cheap, quick and readily available method for identifying those at risk for developing complicated acute appendicitis. PMID- 26985167 TI - Primary hyperparathyroidism. AB - Primary hyperparathyroidism is a common endocrine disorder caused by overactivation of parathyroid glands resulting in excessive release of parathyroid hormone. The resultant hypercalcemia leads to a myriad of symptoms. Primary hyperparathyroidism may increase a patient's morbidity and even mortality if left untreated. During the last few decades, disease presentation has shifted from the classic presentation of severe bone and kidney manifestations to most patients now being diagnosed on routine labs. Although surgery is the only curative therapy, many advances have been made over the past decades in the diagnosis and the surgical management of primary hyperparathyroidism. The aim of this review is to summarize the characteristics of the disease, the work up, and the treatment options. PMID- 26985168 TI - Using mid infrared technology as new method for the determination of the dwell time of salivary substitutes on three dimensional gingiva models. AB - BACKGROUND: Many people suffer from dry mouth (xerostomia) due to radiotherapy treatment of head and neck cancer, diseases like Sjogren's syndrome or as adverse effects to prescribed medications. Salivary substitute products like gels or sprays are often used for treatment. Efficacy of those oral care products are regularly assessed by validated or even not validated questionnaires. To determine the adhesion effect over time more objectively a new and sensitive method was established. The following study was designed to assess the dwell time of different oral care products in vitro. METHOD: Two different types of surfaces were covered with oral care products and washed using a definite protocol with artificial saliva salt solution. First, oral care gels or oral care sprays were spread to a polystyrene surface of 2.25 cm(2), then onto cell based three dimensional gingiva models. The surfaces were washed ten times with artificial saliva salt solution. The resulting washing solutions were examined using mid infrared spectroscopy in order to detect ingredients of the oral care products. RESULTS: All assessed oral care gels or oral care sprays and their components were detected very sensitive. Even traces of the products were detected in the eluent and thus enabled to differentiate the dwell times of the different products. In general, the dwell time of oral care gels on polystyrene or gingiva models was longer than that of oral care sprays. The use of gingiva models improved the differentiation between different products. CONCLUSIONS: MIR spectroscopy turned out to be a sensitive method to detect salivary substitutes. Differences between single components and different products can be detected. The described method is a simple, reliable and easy process to evaluate the dwell time of oral care products in vitro and thus a useful tool to design optimised salivary substitute products. ETHICS: This is an in vitro study. No ethics or consent was required for this study. PMID- 26985169 TI - Residential Mobility within Guangzhou City, China, 1990-2010: Local Residents Versus Migrants. AB - Drawing on residential history data from two household surveys conducted in Guangzhou in 2005 and 2010, this paper compares the pattern of intra-city residential moves of local residents and that of migrants. The findings show different trajectories of residential moves for the two groups. While migrants showed increasing mobility over time, residential moves of locals first rose until the early 2000s, then declined steadily afterward. Moreover, the determinants of residential moves of migrants differ from those of the local population. Also, whereas residential moves for the local population are subject to changing factors over time, drivers of relocation for migrants remain more or less stable. PMID- 26985170 TI - A larval key to the Drusinae species (Trichoptera: Limnephilidae) of Austria, Germany, Switzerland and the dinaric western Balkan. AB - A larval key of the Drusinae of Central Europe and the dinaric western Balkan is presented. Phylogeographic relationships are discussed in the light of molecular genetics, feeding ecology and larval morphology. PMID- 26985171 TI - Structural and biophysical characteristics of human skin in maintaining proper epidermal barrier function. AB - The complex structure of human skin and its physicochemical properties turn it into an efficient outermost defence line against exogenous factors, and help maintain homeostasis of the human body. This role is played by the epidermal barrier with its major part - stratum corneum. The condition of the epidermal barrier depends on individual and environmental factors. The most important biophysical parameters characterizing the status of this barrier are the skin pH, epidermal hydration, transepidermal water loss and sebum excretion. The knowledge of biophysical skin processes may be useful for the implementation of prophylactic actions whose aim is to restore the barrier function. PMID- 26985173 TI - Clinical characteristics of cutaneous lupus erythematosus. AB - INTRODUCTION: Lupus erythematosus (LE) shows a wide variety of clinical manifestations, skin involvement being one of the most important. AIM: To analyze the clinical presentation of cutaneous variants of lupus erythematosus in terms of skin lesion spectrum and extracutaneous involvement. MATERIAL AND METHODS: A total of 64 patients with cutaneous LE (CLE) were included. The study was based on the "Core Set Questionnaire" developed by the European Society of Cutaneous Lupus Erythematosus (EUSCLE). Clinical severity of skin lesions was evaluated with the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). All results were subjected to statistical analysis. RESULTS: Fifteen (23.4%) patients had an acute CLE (ACLE), 26 (40.6%) subacute CLE (SCLE) and 21 (32.8%) chronic CLE (CCLE). Two (3.2%) individuals only demonstrated urticarial vasculitis as a cutaneous manifestation of LE and these patients were excluded. Patients with ACLE were characterized by the earliest onset of the disease (mean age of 31.9 +/-15.0 years; p < 0.001). On average, 4.8 +/-1.8 criteria of systemic LE were found in the ACLE group compared to 2.7 +/-1.3 criteria in SCLE and 2.5 +/-1.5 criteria in CCLE (p < 0.001). The highest activity of skin lesions according to CLASI was found in the SCLE group (p = 0.002). On the other hand, the most severe skin damage was observed in CCLE (p < 0.01). CONCLUSIONS: Each variant of CLE differs significantly from the others in respect of various aspects of clinical manifestations. Due to a number of different variants of LE skin lesions, a unified classification of CLE still remains a challenge. PMID- 26985174 TI - Analysis of selected allergic reactions among psoriatic patients. AB - INTRODUCTION: Psoriasis is a chronic and recurrent inflammatory skin disease. The aetiology is still unknown in spite of numerous scientific researches. There is very little evidence which does not provide enough knowledge about allergic reactions in psoriatic patients. Based on the fact that the epidermal barrier damage allows different allergen types to penetrate into deep layers of epidermis and skin, we can assume that it may lead to immunological reactions. AIM: To investigate the allergic reaction indicators and hypersensitivity assessment about contact, inhalant and food allergens. The results were analysed with regard to clinical disease indicators and progression stage of dermal lesions. MATERIAL AND METHODS: Eighty patients with psoriasis were examined. The concentration of total IgE antibodies and allergen specific IgE antibodies (asIgE) were analysed. Standard epidermal tests and atopy patch tests were performed. All the patients were estimated for their dermatological condition based on the PASI scale. The control group consisted of 50 patients without psoriasis and allergic history. RESULTS: Significantly higher concentration of total E immunoglobulin has been stated in the patients with psoriasis. Higher concentrations of specific allergic IgE antibodies were more often observed in the examined group but the most frequently observed values were present in 1-3 class. The most common airborne allergens were birch, artemisia, timothy and rye pollens. There have not been any significant statistical differences in the case of positive epidermal test results. CONCLUSIONS: There is slightly expressed hypersensitivity in psoriatic patients. This hypersensitivity degree correlates with the intensification of symptoms. PMID- 26985172 TI - The role of antimicrobial peptides in chronic inflammatory skin diseases. AB - Antimicrobial peptides (AMPs) are effector molecules of the innate immune system of the skin. They present an activity against a broad spectrum of Gram-positive and Gram-negative bacteria as well as some fungi, parasites and enveloped viruses. Several inflammatory skin diseases including psoriasis, atopic dermatitis, acne vulgaris and rosacea are characterized by a dysregulated expression of AMPs. Antimicrobial peptides are excessively produced in lesional psoriatic scales or rosacea in contrast to the atopic skin that shows lower AMP levels when compared with psoriasis. The importance of the AMPs contribution to host immunity is indisputable as alterations in the antimicrobial peptide expression have been associated with various pathologic processes. This review discusses the biology and clinical relevance of antimicrobial peptides expressed in the skin and their role in the pathogenesis of inflammatory skin diseases. PMID- 26985175 TI - Oral mucosal manifestations in primary and secondary Sjogren syndrome and dry mouth syndrome. AB - INTRODUCTION: One of the most important symptoms of Sjogren syndrome is xerostomia. The oral cavity deprived of saliva and its natural lubricative, protective and antibacterial properties is prone to a number of unfavourable consequences. AIM: To present the most important lesions on the oral mucosa in primary and secondary Sjogren syndrome and in dry mouth syndrome. MATERIAL AND METHODS: The study group comprised 55 patients including 52 women and 3 men aged 20-72 years (average: 28.25 years). RESULTS: Basing on the accepted criteria, primary Sjogren syndrome was diagnosed in 22 (40%) patients, secondary Sjogren syndrome in 18 (32.7%) patients, and dry mouth syndrome in 15 (27.27%) patients. The physical examination and the examination of the mouth were performed and history was elicited from every patient. CONCLUSIONS: The most common pathologies appearing on the oral mucosa in primary and secondary Sjogren syndrome are angular cheilitis, cheilitis, increased lip dryness as well as non-specific ulcerations, aphthae and aphthoid conditions. PMID- 26985177 TI - The frequency of polymorphic variants of filaggrin gene and clinical atopic dermatitis. AB - INTRODUCTION: As far as pathogenesis of the atopic dermatitis (AD) is concerned, the roles of an impaired epidermal barrier and cornified cell envelope are widely emphasized. AIM: The assessment of mutations of the filaggrin gene and their connection with the clinical picture of AD as well as selected allergological and environmental indicators. MATERIAL AND METHODS: 105 patients with diagnosed AD on the basis of diagnostic criteria were included. For every patient of the examined group, quantitative determination of the total concentration of IgE and the concentration of IgE antibodies to selected allergens were examined. For all patients, studies were performed by means of analysis of two genomic gene variants of profilaggrin (FLG) - R501X and 2282del4. RESULTS: Loss-of-function mutations in the filaggrin gene were shown in 12 (11.4%) patients in the examined group. All patients in the study group who developed one of the tested loss-of function mutations in the filaggrin gene demonstrated an extrinsic, allergic form of atopic dermatitis. A significant association (p = 0.0002) between the presence of one of the tested loss-of-function mutations in the filaggrin gene and elevated levels of total concentration of immunoglobulin E was shown. CONCLUSIONS: Patients with AD of null mutations in the filaggrin gene demonstrate a relationship with the total and specific concentration of immunoglobulin E, specifically higher concentrations of IgE against aeroallergens and alimentary allergens as well as elevated levels of total immunoglobulin E. PMID- 26985176 TI - A study of the activity and effectiveness of recombinant fibroblast growth factor (Q40P/S47I/H93G rFGF-1) in anti-aging treatment. AB - INTRODUCTION: Fibroblast growth factor 1 (FGF-1) is a powerful mitogen involved in the stimulation of DNA synthesis and the proliferation of a wide variety of cell types. Fibroblast growth factor 1 was genetically modified to improve its thermal stability and resistance to protease degradation without losing its biological activity. AIM: To study the impact of Q40P/S47I/H93G rFGF-1 on skin cells, its penetration through the skin and the evaluation of the rFGF-1-cosmetic product properties. MATERIAL AND METHODS: In vitro studies included the examination of primary fibroblast and keratinocyte viability after the incubation with rFGF-1. The penetration abilities of rFGF-1 in various formulations and carrier systems were examined ex vivo by the Raman spectroscopy. In vivo studies HF Ultrasound and 3D Imaging System - were used to evaluate the anti-aging properties of creams containing rFGF-1. RESULTS: In vitro studies demonstrated that rFGF-1 strongly enhanced the viability of the treated cells. The Raman Spectroscopy analysis indicated that rFGF-1 encapsulated in lipid spheres penetrate through the stratum corneum to the depth of 60 um, and added to the o/w formulation - could penetrate to a depth of 90 um. The results obtained from Primos revealed the reduction of the volume and the depth of the wrinkles. Changes in the skin structure in the analyzed areas were evaluated by HF Ultrasonography. CONCLUSIONS: Recombinant FGF-1 strongly stimulated fibroblast and keratinocyte proliferation. However, the transition of this protein through the SC required an appropriate carrier system - lipid spheres. All tests - in vitro, ex vivo and in vivo - have proved that rFGF-1 is a substance with a potentially wide spectrum of use. PMID- 26985178 TI - Clinicopathological analysis of recurrent basal cell carcinoma of the eyelid. AB - INTRODUCTION: Basal cell carcinoma (BCC) is the most common malignant neoplasm of the eyelids and surrounding structures, usually developing in the area of the lower lid and medial canthus. Invasive forms of BCC are connected with a high risk of recurrence, often due to incomplete excision of these lesions. AIM: Clinical and pathological analysis of recurrent BCCs of the eyelids and surrounding structures. MATERIAL AND METHODS: We present clinical and pathological analysis including immunohistochemical reaction to Ki-67 antigen of 19 patients (11 women, 8 men) operated for recurrent BCCs of the eyelids in 2000 2012. RESULTS: In most cases, recurrences were present on the lower lid and in the medial canthus. In 15 patients the histopathological type did not change and in 4 cases it transformed into more invasive forms. The values of Ki-67 index for primary BCCs ranged between 1% and 20%, and for relapsing lesions between 11% and 48%. CONCLUSIONS: Proper clinical and pathological evaluation to determine the risk of relapse in BCCs of the eyelids and surrounding structures should include the analysis of prognostic factors, in particular location and size, histopathological type and radicalness of surgical treatment of primary BCCs. Clinical and pathological analysis of patients with recurrent BCC of the eyelids and surrounding structures should be combined with the evaluation of proliferation index Ki-67, which is essential for prognosis and choice of the appropriate therapeutic method. PMID- 26985180 TI - Skin toxicity in BRAF(V600) mutated metastatic cutaneous melanoma patients treated with vemurafenib. AB - INTRODUCTION: The use of orally available BRAF kinase inhibitor - vemurafenib is associated with numerous adverse skin reactions. AIM: To assess the safety and early side effects of vemurafenib treatment in the unselected group of patients treated at the outpatient clinic, in particular the assessment of the incidence of skin cancer. MATERIAL AND METHODS: We carried out a systematic study of patients (pts) treated with vemurafenib. Skin toxicity during vemurafenib therapy was analyzed. Toxicity was determined on the basis of the toxicity scale CTCAE, version 4.0. RESULTS: The most common cutaneous side effects were hyperkeratotic perifollicular rash (69%) and photosensitivity (15%). Skin rash developed more frequently in the first month of treatment. Squamous cell carcinoma occurred in 38% of patients. Patients with skin cancer development during vemurafenib therapy had non-significantly longer overall survival (OS) than patients without skin cancer, p = 0.4. Skin cancer developed more often in women than in men (60% vs. 25%), p = 0.249. It was detected only in patients with normal weight compared to overweight patients (55% vs. 0), p = 0.09. The median OS was 26 months and median OS from the time of distant metastases diagnosis was 9.8 months. In patients with a low body mass index, shorter OS was observed, p = 0.09. CONCLUSIONS: The incidence of squamous cell carcinoma was high (38%). This study has many limitations mostly due to a small group of patients. That is why the results should be taken into consideration with caution. The proper symptomatic treatment in cooperation with dermatologists allows to continue the vemurafenib therapy. PMID- 26985179 TI - Evaluation of serum concentrations of the selected cytokines in patients with localized scleroderma. AB - INTRODUCTION: Localized scleroderma is an autoimmune disease primarily affecting the skin. The cause of disease remains unexplained although environmental factors are implicated, which are likely to be responsible for activation of the endothelium and subsequent inflammation leading to excessive synthesis of collagen and extracellular matrix components. AIM: To determine concentrations of interleukin (IL)-27, transforming growth factor (TGF)-beta1, TGF-beta2, IL-6, and sIL-6R in patients with localized scleroderma compared to controls and to assess the relations between their levels and laboratory markers. MATERIAL AND METHODS: The study encompassed 17 females with localized scleroderma (aged 25-67). The control group consisted of 30 age-matched healthy women. The blood was sampled from the basilic vein. Serum levels of cytokines were determined using ELISA. RESULTS: The TGF-beta2 levels were found to be significantly lower in patients with localized scleroderma compared to controls. Concentrations of TGF-beta1 were decreased in scleroderma patients when compared to controls but without statistical significance. There were no significant differences in serum IL-6, sIL-6R and IL-27 levels between patients and the control group; however, we found a significant positive correlation between the level of sIL-6 and ESR among subjects with localized scleroderma. CONCLUSIONS: The findings of decreased serum levels of TGF-beta1 and TGF-beta2 in patients with localized scleroderma demonstrate a possible association of these cytokines with pathogenesis of the disease. The results suggest also that sIL-6R is likely to be involved in inflammation in patients with localized scleroderma. PMID- 26985182 TI - Occurrence of sleep-related breathing disorders in patients with chronic urticaria at its asymptomatic or oligosymptomatic stages. AB - INTRODUCTION: Chronic urticaria (CU), in view of its manifestations (pruritus, wheals), chronic and recurrent nature is very bothersome for patients and significantly influences their quality of life. AIM: To assess the importance of sleep problems and sleep-related breathing disorders (SRBDs) declared by CU patients, for their quality of life. MATERIAL AND METHODS: Twenty-eight patients with CU at an asymptomatic stage or with minimal symptoms and signs were qualified for the study. In these patients, assessment of urticaria severity, QoL and SRBDs incidence was carried out. RESULTS: In a questionnaire study (CU-Q2oL), about 54% of the patients with CU complained of sleeping problems, about 80% reported significant fatigue and lack of concentration in the daytime. Respiratory polygraphy, an objective measure of sleep-related breathing disorders (SRBDs) demonstrated their higher incidence in patients with CU than in the general population, but these disorders were mild and had no influence on the reduced quality of life of the study patients, compared with a group of patients without SRBDs. CONCLUSIONS: The occurrence of SRBDs was found in 25% of patients with CU at asymptomatic or oligosymptomatic stages. The SRBDs in those patients were mild, required no treatment and their occurrence did not cause any significant reduction in their quality of life. PMID- 26985183 TI - The flare-up phenomenon: recurrence of distant dermatitis during patch testing. PMID- 26985181 TI - Coexistence of 2282del4 FLG gene mutation and IL-18 -137G/C gene polymorphism enhances the risk of atopic dermatitis. AB - INTRODUCTION: Atopic dermatitis (AD) pathogenesis appears in the context of the correlation between cornified envelope proteins and immunological factors. AIM: To estimate the association between FLG R501X and 2282del4 gene mutations, -137 G/C IL-18 and -1112 C/T IL-13 gene polymorphisms and their influence on AD course and the risk in the Polish population. MATERIAL AND METHODS: One hundred and fifty-two AD patients and 123 healthy volunteers were included into the study. Amplification refractory mutation system - polymerase chain reaction method was used. RESULTS: 2282del4 FLG mutation, predominant (p = 0.04) in Polish AD patients, enhanced the risk of AD (OR = 2.35; p = 0.01) and was associated with itch (p = 0.023). GG genotype of IL-18 was prevailing in AD (p < 0.0001), associated with elevated IgE levels (p = 0.00074) and pruritus (p < 0.0001). GG genotype and G-allele in -137 position of IL-18 increased AD risk (OR = 5.4; p = 0.0001, respectively, OR = 5.3; p = 0.000029). -1112 C/T polymorphism of IL-13 was associated with elevated IgE levels (p = 0.00049), pruritus (p = 0.0005), SCORAD score (p = 0.02), concomitant asthma (p = 0.0087) and AD risk (OR = 2.02; p = 0.012). Coexistence of 2282del4 or R501X FLG gene mutation with GG genotype of IL-18 was associated with a 6-fold higher risk of AD (OR = 5.8; p = 0.00013), contrary to combined occurrence of FLG mutations with T-allele in -1112 position of IL-13 gene (OR = 0.12; p = 0.1). CONCLUSIONS: 2282del4 FLG mutation similarly to GG genotype and G-allele in -137 position of IL-18 gene enhance the risk of AD in the Polish population. Coexistence of FLG mutations with GG genotype of IL-18 may be helpful to estimate chances of AD development. PMID- 26985184 TI - A case of papular elastorrhexis. PMID- 26985185 TI - A case of Behcet's disease possibly triggered by beta-glucan. PMID- 26985186 TI - Snakebites notified to the poison control center of Morocco between 2009 and 2013. AB - BACKGROUND: Snakebites cause considerable death and injury throughout the globe, particularly in tropical regions, and pose an important yet neglected threat to public health. In 2008, the Centre Anti Poison et de Parmacovigilance du Maroc (CAPM) started to set up a specific strategy for the control of snakebites that was formalized in 2012. The aim of the present study is to describe and update the epidemiological characteristics of snakebites notified to CAPM between 2009 and 2013. METHODS: This retrospective five-year study included all cases of snakebites notified to CAPM by mail or phone. RESULTS: During the study period, 873 snakebite cases were reported to CAPM, an average incidence of 2.65 cases per 100,000 inhabitants with 218 cases each year. The highest incidence was found in Tangier-Tetouan region with 357 cases (40.9 %) followed by Souss Massa Draa region with 128 cases (14.6 %). The average age of patients was 26.8 +/- 17.2 years. The male to female sex ratio was 1.67:1 and 77 % of cases occurred in rural areas. The bites occurred mainly in spring (44 %) followed by summer (42 %). Snake species was identified in 54 cases (6.2 %): colubrids represented 31 % (n = 18) and vipers 67 % (n = 36), mainly Daboia mauritanica, Bitis arietans and Cerastes cerastes. In 311 cases (35.6 %), the patients showed viper syndrome. Thrombocytopenia was observed in 23.5 % of viper syndrome cases, whereas, compartment syndrome was observed in 7.6 % patients. FAV-Afrique(r) was administered in 41 patients (5 %). In patients treated with antivenom, 38 patients recovered and three died. Twenty-seven deaths were reported (3.9 %). CONCLUSION: Despite specific efforts to better understand the epidemiology of snakebites in Morocco (incidence, severity, snake species involved), it remains underestimated. Therefore, further work is still necessary to ensure accessibility of appropriate antivenom against venomous species and to improve the management of envenomation in Morocco. PMID- 26985187 TI - Epidemiology of snakebites in Kedougou region (eastern Senegal): comparison of various methods for assessment of incidence and mortality. AB - BACKGROUND: Although considered a public health issue in Senegal, the actual incidence and mortality from snakebite are not known. In the present study, an epidemiological survey was carried out in Kedougou region, southeastern Senegal, where envenomations, particularly by Echisocellatus, are frequent and severe. METHODS: Three sources of data were used: records from health centers and reports by health professionals; traditional healers; and household surveys. RESULTS: The annual incidence and mortality provided by health centers were 24.4 envenomations and 0.24 deaths per 100,000 population, respectively. The annual incidence recorded by traditional healers was 250 bites per 100,000 inhabitants, but the number of deaths was unknown. Finally, the household surveys reported an annual incidence of 92.8 bites per 100,000 inhabitants and an annual mortality rate of 2.2 deaths per 100,000 inhabitants. The differences in incidence and mortality between the different methods were explained by significant bias, resulting in particular from the complex patient's healthcare-seeking behavior. The incidence provided by health records should be used to specify the immediate quantitative requirements of antivenoms and places where they should be available first. CONCLUSION: Mandatory reporting of cases would improve the management of envenomation by simplifying epidemiological surveys. Patients' preference for traditional medicine should prompt health authorities to urge traditional healers to refer patients to health centers according to defined clinical criteria (mainly edema and bleeding or neurotoxic symptoms). Finally, household surveys were likely to reflect the actual epidemiological situation. Poison Control Center of Senegal should continue its work to sensitize stakeholders and train health staff. PMID- 26985188 TI - Retrospective study on the incidence of envenomation and accessibility to antivenom in Burkina Faso. AB - BACKGROUND: Snakebite is a common neglected public health issue, especially in poor rural areas of sub-Saharan Africa, Asia and Latin America. Passive immunotherapy with safe and effective antivenom is the only approved treatment for it. This study aimed to determine the incidence of snakebites, and to assess the availability and accessibility of antivenoms, from 2010 to 2014, in Burkina Faso. METHODS: The assessment of snakebite cases managed in all health facilities from 2010 to 2014 was performed from the Statistical Yearbook of the Ministry of Health. Antivenom consumption data were collected from the drug wholesalers established in Burkina Faso. RESULTS: Snakebites are among the five leading causes of consultations in health districts. From 2010 to 2014, 114,126 envenomation cases occurred in Burkina Faso, out of which 62,293 (54.6 %) victims have been hospitalized resulting in 1,362 (2 %) deaths. The annual incidence and mortality were respectively 130 bites and 1.75 deaths per 100,000 inhabitants. The amount of antivenom sold by wholesalers were 5,738 vials with a total cost of US$ 539,055 (annual average = US$ 107,811). The high cost of these antivenoms (between US$ 42 and 170 per dose according to brand) limited their use by rural people, the main victims of snakebites, whose income is insufficient. Thus, only 4 % of patients received antivenom treatment over the past five years. The price of antivenom was reduced in 2015 to US$ 3.4 by a public drug wholesaler. CONCLUSION: The study confirmed the high burden of snakebites in Burkina Faso. To better manage envenomation, Burkina Faso implemented a strategy consisting in seeking affordable sources of antivenom supply of good quality and innovative mechanisms of subsidy. PMID- 26985189 TI - The 6(th) international conference on envenomation by Snakebites and Scorpion Stings in Africa: a crucial step for the management of envenomation. AB - During the 6(th) International Conference on Envenomation by Snakebites and Scorpion Stings in Africa held in Abidjan, from 1 to 5 June 2015, the measures for the management of envenomation were discussed and new recommendations were adopted by the participants. The high incidence and severity of this affliction were confirmed by several studies conducted in African countries. The poor availability of antivenom, particularly because of the cost, was also highlighted. Some experiences have been reported, mainly those regarding the financial support of antivenom in Burkina Faso (more than 90 %) and Togo (up to 60 %) or the mandatory reporting of cases in Cameroon. Key recommendations concerned: improvement of epidemiological information based on case collection; training of health workers in the management of envenomation; policy to promote the use of effective and safe antivenom; and antivenom funding by sharing its costs with stakeholders in order to improve antivenom accessibility for low income patients. PMID- 26985190 TI - An audit of the management of childhood-onset growth hormone deficiency during young adulthood in Scotland. AB - BACKGROUND: Adolescents with childhood onset growth hormone deficiency (CO-GHD) require re-evaluation of their growth hormone (GH) axis on attainment of final height to determine eligibility for adult GH therapy (rhGH). AIM: Retrospective multicentre review of management of young adults with CO-GHD in four paediatric centres in Scotland during transition. PATIENTS: Medical records of 130 eligible CO-GHD adolescents (78 males), who attained final height between 2005 and 2013 were reviewed. Median (range) age at initial diagnosis of CO-GHD was 10.7 years (0.1-16.4) with a stimulated GH peak of 2.3 MUg/l (0.1-6.5). Median age at initiation of rhGH was 10.8 years (0.4-17.0). RESULTS: Of the 130 CO-GHD adolescents, 74/130(57 %) had GH axis re-evaluation by stimulation tests /IGF-1 measurements. Of those, 61/74 (82 %) remained GHD with 51/74 (69 %) restarting adult rhGH. Predictors of persistent GHD included an organic hypothalamic pituitary disorder and multiple pituitary hormone deficiencies (MPHD). Of the remaining 56/130 (43 %) patients who were not re-tested, 34/56 (61 %) were transferred to adult services on rhGH without biochemical retesting and 32/34 of these had MPHD. The proportion of adults who were offered rhGH without biochemical re-testing in the four centres ranged between 10 and 50 % of their total cohort. CONCLUSIONS: A substantial proportion of adults with CO-GHD remain GHD, particularly those with MPHD and most opt for treatment with rhGH. Despite clinical guidelines, there is significant variation in the management of CO-GHD in young adulthood across Scotland. PMID- 26985191 TI - Brachytherapy boost and cancer-specific mortality in favorable high-risk versus other high-risk prostate cancer. AB - PURPOSE: Recent retrospective data suggest that brachytherapy (BT) boost may confer a cancer-specific survival benefit in radiation-managed high-risk prostate cancer. We sought to determine whether this survival benefit would extend to the recently defined favorable high-risk subgroup of prostate cancer patients (T1c, Gleason 4 + 4 = 8, PSA < 10 ng/ml or T1c, Gleason 6, PSA > 20 ng/ml). MATERIAL AND METHODS: We identified 45,078 patients in the Surveillance, Epidemiology, and End Results database with cT1c-T3aN0M0 intermediate- to high-risk prostate cancer diagnosed 2004-2011 treated with external beam radiation therapy (EBRT) only or EBRT plus BT. We used multivariable competing risks regression to determine differences in the rate of prostate cancer-specific mortality (PCSM) after EBRT + BT or EBRT alone in patients with intermediate-risk, favorable high-risk, or other high-risk disease after adjusting for demographic and clinical factors. RESULTS: EBRT + BT was not associated with an improvement in 5-year PCSM compared to EBRT alone among patients with favorable high-risk disease (1.6% vs. 1.8%; adjusted hazard ratio [AHR]: 0.56; 95% confidence interval [CI]: 0.21-1.52, p = 0.258), and intermediate-risk disease (0.8% vs. 1.0%, AHR: 0.83, 95% CI: 0.59 1.16, p = 0.270). Others with high-risk disease had significantly lower 5-year PCSM when treated with EBRT + BT compared with EBRT alone (3.9% vs. 5.3%; AHR: 0.73; 95% CI: 0.55-0.95; p = 0.022). CONCLUSIONS: Brachytherapy boost is associated with a decreased rate of PCSM in some men with high-risk prostate cancer but not among patients with favorable high-risk disease. Our results suggest that the recently-defined "favorable high-risk" category may be used to personalize therapy for men with high-risk disease. PMID- 26985192 TI - Dosimetry of permanent interstitial prostate brachytherapy for an interoperative procedure, using O-arm based CT and TRUS. AB - PURPOSE: The aim of this report is dosimetric evaluation for an intraoperative fusion computed tomography (CT) as a superior predictor of 1-month CT based dosimetry in comparison to transrectal ultrasound (TRUS) in permanent interstitial prostate brachytherapy. MATERIAL AND METHODS: Data of 65 patients treated with seed implantation were analyzed. All procedures has been performed with patients in the lithotomy position inside the O-arm system. An end-fine probe is used as a landmark to fuse TRUS and O-arm-based CT images. There was no difference in the patient's position, probe position, and timing of image acquisition between the two imaging modalities. Dose-volume histogram (DVH) parameters such as the dose to 90% of prostate volume (D90) has been analyzed. RESULTS: The area under the curve of the receiver operating characteristic tended to be larger on fusion CT than on TRUS for most DVH parameters (71.85% vs. 59.59% for D90; p = 0.07). Significant relationships between fusion CT and 1-month CT were confirmed using Pearson's correlation coefficients for most DVH parameters (R = 0.48, p < 0.01 for D90), although the relationship between TRUS and 1-month CT was poor. Large dose reduction (35 Gy for D90) was seen from TRUS to fusion CT, especially in patients with high body weight and small prostate volume. CONCLUSIONS: Intraoperative fusion CT appears to have higher predictive power for 1-month CT-based dosimetry than TRUS. A prospective trial using fusion CT-based planning is warranted. PMID- 26985193 TI - WBRT vs. APBI: an interim report of patient satisfaction and outcomes. AB - PURPOSE: To determine differences in patient's reported quality of life and self reported breast cosmesis between whole breast radiation therapy (WBRT) and accelerated partial breast irradiation (APBI) via single and multi-lumen high dose-rate (HDR) brachytherapy for women with early stage breast cancer. MATERIAL AND METHODS: Patient information was retrospectively reviewed and survey data were prospectively collected for women treated between 2004 to 2014 (APBI) and 2012 to 2014 (WBRT). Criteria for APBI treatments were ER+ (after 2010), N0 (after 2010), T < 3 cm, and post-menopausal. All patients were given a survey with modified FACIT (Functional Assessment of Chronic Illness Therapy) breast quality of life questions to rate their amount of pain, self-consciousness, low energy, presence of lymphedema, and breast cosmesis. RESULTS: 242 APBI patients and 59 WBRT patients were identified. In the WBRT cohort, 34 women met departmental criteria for APBI treatment (WBRT who were APBI eligible). The FACIT survey was completed by 80 women treated with APBI (33%; mean follow-up time of 14 months), and 26 women treated with WBRT who were APBI eligible (76%; mean follow-up time of 26 months). During the first year post-treatment, low energy (p = 0.009), self-consciousness (p = 0.0004), and lymphedema (p = 0.0002) scores were significantly lower in the APBI cohort when compared to women treated with WBRT who were APBI eligible. During the second year post-treatment, women treated with APBI reported significantly better breast cosmesis (p = 0.04). The single lumen balloon (score = 6.3/10) was found to be associated with worse cosmesis compared to the multi-lumen balloons (Mammosite ML and Contura; score = 8.2/10; p = 0.002). There were no significant differences in rates of recurrence between balloons or treatments (p > 0.05). CONCLUSIONS: APBI treated patients reported higher cosmetic satisfaction than patients in the matched WBRT cohort. Quality of life scores tended to improve over time. Multi-lumen catheters provided superior cosmetic results compared to single-lumen catheters. PMID- 26985194 TI - Concomitant cervical and transperineal parametrial high-dose-rate brachytherapy boost for locally advanced cervical cancer. AB - PURPOSE: There is no consensus for parametrial boost technic while both transvaginal and transperineal approaches are discussed. A prototype was developed consisting of a perineal template, allowing transperineal needle insertion. This study analyzed acute toxicity of concomitant cervical and transperineal parametrial high-dose-rate brachytherapy (HDRB) boost for locally advanced cervical cancer. MATERIAL AND METHODS: From 01.2011 to 12.2014, 33 patients (pts) presenting a locally advanced cervical cancer with parametrial invasion were treated. After the first course of external beam radiation therapy with cisplatinum, HDRB was performed combining endocavitary and interstitial technique for cervical and parametrial disease. Post-operative delineation (CTV, bladder, rectum, sigmoid) and planification were based on CT-scan/MRI. HDRB was delivered in 3-5 fractions over 2-3 consecutive days. Acute toxicities occurring within 6 months after HDRB were retrospectively reviewed. RESULTS: Median age was 56.4 years (27-79). Clinical stages were: T2b = 23 pts (69.7%), T3a = 1 pt (3%), T3b = 6 pts (18.2%), and T4a = 3 pts (9.1%). Median HDRB prescribed dose was 21 Gy (21-27). Median CTVCT (16 pts) and HR-CTVMRI (17 pts) were 52.6 cc (28.5 74.3), 31.9 cc (17.1-58), respectively. Median EQD2alphabeta10 for D90CTV and D90HR-CTV were 82.9 Gy (78.2-96.5), 84.8 Gy (80.6-91.4), respectively. Median EQD2alphabeta3 (CT/MRI) for D2cc bladder, rectum and sigmoid were 75.5 Gy (66.6 90.9), 64.4 Gy (51.9-77.4), and 60.4 Gy (50.9-81.1), respectively. Median follow up was 14 months (ranged 6-51). Among the 24 pts with MFU = 24 months, 2-year LRFS rate, RRFS, and OS were 86.8%, 88.8%, and 94.1%, respectively. The rates of acute genitourinary and gastrointestinal toxicities were 36% (G1 dysuria = 8 pts, G2 infection = 2 pts, G3 infection = 2 pts), and 27% (G1 diarrhea = 9 pts), respectively. One patient presented vaginal bleeding at the time of applicator withdrawal (G3-blood transfusion); no bleeding was observed due to the parametrial implant. CONCLUSIONS: Concomitant cervical and transperineal parametrial HDRB boost for locally advanced cervical cancer appears feasible and safe with no specific acute toxicity compare to cervical HDRB alone. Longer follow-up and larger patient cohort will be needed. PMID- 26985195 TI - Interstitial high-dose-rate brachytherapy in locally advanced and recurrent vulvar cancer. AB - PURPOSE: The aim of the study was to report our experience with high-dose-rate interstitial brachytherapy (HDR-ISBT) in locally advanced and recurrent vulvar cancer. MATERIAL AND METHODS: Between 2004 and 2014, fourteen women with locally advanced or recurrent vulvar cancer were treated using HDR-ISBT in our Centre. High-dose-rate interstitial brachytherapy was performed as a separate treatment or in combination with external beam radiotherapy (EBRT) (given prior to brachytherapy). RESULTS: Patients were divided into: group I (n = 6) with locally advanced tumors, stages III-IVA after an incisional biopsy only, and group II (n = 8) with recurrent vulvar cancer after previous radical surgery. In group I, median follow up was 12 months (range 7-18 months); 1-year overall survival (OS) was 83%. Transient arrest of cancer growth or tumor regression was noticed in all patients but 4/6 developed relapse. Median time to failure was 6.3 months (range 3-11 months). The 1-year progression-free survival (PFS) was 33%. In group II, median follow up was 28 months (range 13-90 months). The 1-year and 3-year OS was 100% and 80%, respectively. The arrest of cancer growth or tumor regression was achieved in all patients. In 4/8 patients neither clinical nor histological symptoms of relapse were observed but 4/8 women experienced relapse. Median time to failure was 31 months (range 13-76 months). The 1-year and 3-year PFS was 100% and 62.5%, respectively. Two patients (14.3%) in group II had severe late toxicity (G3). CONCLUSIONS: High-dose-rate interstitial brachytherapy is a well tolerated treatment option in selected patients with advanced or recurrent vulvar cancer. It is a safe and effective treatment modality for advanced and recurrent vulvar cancer, yielding good local control with acceptable late treatment related side effects. In our study, patients with recurrent vulvar cancer had better results in HDR-ISBT treatment, probably because of the smaller tumor volume. This hypothesis should be verified in a larger group of patients. PMID- 26985196 TI - High-dose-rate interstitial brachytherapy for female peri-urethral cancer. AB - PURPOSE: Peri-urethral cancer (PUC) in females is a rare malignancy. Surgery is not usually contemplated due to associated morbidity. Radiation therapy (RT) can be employed in the form of interstitial brachytherapy (IBT) alone for early lesions, and external beam radiation therapy (EBRT) with or without IBT for advanced lesions. We report our first experience in the literature to evaluate the role of high-dose-rate (HDR) IBT in female PUC. MATERIAL AND METHODS: Between 2008 and 2013, 10 female patients with PUC (5 primary and 5 recurrent) were treated with HDR-IBT with or without EBRT at our center. Size of the lesion ranged from 1.5 cm to 5.0 cm. A 2-3 plane free-hand implant was performed using plastic catheters. The prescribed dose of HDR-IBT was 42 Gy in 14 fractions for brachytherapy alone (5 patients), and 18-21 Gy for the boost along with EBRT (5 patients). Patients were followed up regularly for assessment of disease control and toxicity. RESULTS: At a median follow up of 25 months, six patients were disease free at their last follow up. Four patients developed recurrence: 2 at inguinal nodes, 1 at local site, and 1 at both local as well as inguinal nodes. Moist desquamation was the commonest acute toxicity observed in all 5 patients treated with IBT alone, which healed within 4 weeks' time. Overall, grade II delayed complication rate was 30%. CONCLUSIONS: Though small sample size, the results of our study have shown that HDR-IBT provides good loco-regional control with acceptable toxicity for female PUC. PMID- 26985197 TI - Electronic brachytherapy for superficial and nodular basal cell carcinoma: a report of two prospective pilot trials using different doses. AB - PURPOSE: Basal cell carcinoma (BCC) is a very common cancer in the Caucasian population. Treatment aims to eradicate the tumor with the lowest possible functional and aesthetic impact. Electronic brachytherapy (EBT) is a treatment technique currently emerging. This study aims to show the outcomes of two consecutive prospective pilot clinical trials using different radiation doses of EBT with Esteya((r)) EB system for the treatment of superficial and nodular basal cell carcinoma. MATERIAL AND METHODS: Two prospective, single-center, non randomized, pilot studies were conducted. Twenty patients were treated in each study with different doses. The first group (1) was treated with 36.6 Gy in 6 fractions of 6.1 Gy, and the second group (2) with 42 Gy in 6 fractions of 7 Gy. Cure rate, acute toxicity, and late toxicity related to cosmesis were analyzed in the two treatment groups. RESULTS: In group 1, a complete response in 90% of cases was observed at the first year of follow-up, whereas in group 2, the complete response was 95%. The differences with reference to acute toxicity and the cosmetic results between the two treatment groups were not statistically significant. CONCLUSIONS: Our initial experience with Esteya((r)) EB system to treat superficial and nodular BCC shows that a dose of 36.6 Gy and 42 Gy delivered in 6 fraction of 7 Gy achieves a 90% and 95% clinical cure rate at 1 year, respectively. Both groups had a tolerable toxicity and a very good cosmesis. The role of EBT in the treatment of BCC is still to be defined. It will probably become an established option for selected patients in the near future. PMID- 26985198 TI - High-dose-rate interstitial brachytherapy in early stage oral tongue cancer - 15 year experience from a tertiary care institute. AB - PURPOSE: To determine outcomes of interstitial high-dose-rate brachytherapy (HDR BT) in patients with early stage oral tongue cancer. MATERIAL AND METHODS: Ninety two patients with stage I and II oral tongue cancer were treated with HDR-BT between 1999 and 2014: brachytherapy alone = 62 (67.4%), and combination of external beam radiotherapy (EBRT) and brachytherapy = 30 (32.6%). Median follow up was 53.5 months. Patterns of failure, overall survival (OS), disease-free survival (DFS), local control rates (LCR), and nodal control rates (NCR) were determined. RESULTS: 5-year OS, DFS, LCR, and NCR were 73.2%, 58.2%, 64.2%, and 83.8%, respectively. In total, 43 patients (46.7%) failed treatment: isolated local failures = 28 (30.4%), isolated nodal failures = 8 (8.7%), both local and regional failures = 7 (7.6%). While in T1 stage, 5 year LCR were significantly higher in brachytherapy alone group compared to combined EBRT and brachytherapy group (81.7% vs. 62.5%, p = 0.04), the isolated nodal failure rates were not significantly different among the two groups. For T2 stage, NCR were higher in combined EBRT and brachytherapy group compared to brachytherapy alone (92.9% vs. 74.3%). Acute mucositis (grade >= 2) was seen more in brachytherapy alone group compared to the combined modality group (87% vs. 66%), and this correlated significantly with the higher biological equivalent dose (BED) in the brachytherapy alone group. CONCLUSIONS: Our study recommends treating patients with brachytherapy alone in T1 stage, and demonstrates the need for addressing nodal region either by neck dissection or nodal irradiation in T2 stage patients. Also, the study highlights the need for dose escalation (from the doses used in the study) in both T1 and T2 stage tumors when using interstitial brachytherapy either as sole modality or as a boost. PMID- 26985199 TI - Ruthenium-106 brachytherapy for thick uveal melanoma: reappraisal of apex and base dose radiation and dose rate. AB - PURPOSE: To evaluate the outcomes of ruthenium-106 ((106)Ru) brachytherapy in terms of radiation parameters in patients with thick uveal melanomas. MATERIAL AND METHODS: Medical records of 51 patients with thick (thickness >= 7 mm and < 11 mm) uveal melanoma treated with (106)Ru brachytherapy during a ten-year period were reviewed. Radiation parameters, tumor regression, best corrected visual acuity (BCVA), and treatment-related complications were assessed. RESULTS: Fifty one eyes of 51 consecutive patients including 25 men and 26 women with a mean age of 50.5 +/- 15.2 years were enrolled. Patients were followed for 36.1 +/- 26.5 months (mean +/- SD). Mean radiation dose to tumor apex and to sclera were 71 (+/ 19.2) Gy and 1269 (+/- 168.2) Gy. Radiation dose rates to tumor apex and to sclera were 0.37 (+/- 0.14) Gy/h and 6.44 (+/- 1.50) Gy/h. Globe preservation was achieved in 82.4%. Preoperative mean tumor thickness of 8.1 (+/- 0.9) mm decreased to 4.5 (+/- 1.6) mm, 3.4 (+/- 1.4) mm, and 3.0 (+/- 1.46) mm at 12, 24, and 48 months after brachytherapy (p = 0.03). Four eyes that did not show regression after 6 months of brachytherapy were enucleated. Secondary enucleation was performed in 5 eyes because of tumor recurrence or neovascular glaucoma. Tumor recurrence was evident in 6 (11.8%) patients. Mean Log MAR (magnification requirement) visual acuity declined from 0.75 (+/- 0.63) to 0.94 (+/- 0.5) (p = 0.04). Best corrected visual acuity of 20/200 or worse was recorded in 37% of the patients at the time of diagnosis and 61.7% of the patients at last exam (p = 0.04). Non-proliferative and proliferative radiation-induced retinopathy was observed in 20 and 7 eyes. CONCLUSIONS: Thick uveal melanomas are amenable to (106)Ru brachytherapy with less than recommended apex radiation dose and dose rates. PMID- 26985200 TI - A comparison study on various low energy sources in interstitial prostate brachytherapy. AB - PURPOSE: Low energy sources are routinely used in prostate brachytherapy. (125)I is one of the most commonly used sources. Low energy (131)Cs source was introduced recently as a brachytherapy source. The aim of this study is to compare dose distributions of (125)I, (103)Pd, and (131)Cs sources in interstitial brachytherapy of prostate. MATERIAL AND METHODS: ProstaSeed (125)I brachytherapy source was simulated using MCNPX Monte Carlo code. Additionally, two hypothetical sources of (103)Pd and (131)Cs were simulated with the same geometry as the ProstaSeed (125)I source, while having their specific emitted gamma spectra. These brachytherapy sources were simulated with distribution of forty-eight seeds in a phantom including prostate. The prostate was considered as a sphere with radius of 1.5 cm. Absolute and relative dose rates were obtained in various distances from the source along the transverse and longitudinal axes inside and outside the tumor. Furthermore, isodose curves were plotted around the sources. RESULTS: Analyzing the initial dose profiles for various sources indicated that with the same time duration and air kerma strength, (131)Cs delivers higher dose to tumor. However, relative dose rate inside the tumor is higher and outside the tumor is lower for the (103)Pd source. CONCLUSIONS: The higher initial absolute dose in cGy/(h.U) of (131)Cs brachytherapy source is an advantage of this source over the others. The higher relative dose inside the tumor and lower relative dose outside the tumor for the (103)Pd source are advantages of this later brachytherapy source. Based on the total dose the (125)I source has advantage over the others due to its longer half-life. PMID- 26985201 TI - The air matters - sleeve air cavity as a marker guiding image-guided helical tomotherapy to target cervical cancer. AB - PURPOSE: Radiotherapy with concurrent chemotherapy has been recommended as standard treatment for locally advanced cervical cancer. To validate the main tumor location before each high-precision helical tomotherapy (HT) fraction, the development of a more reliable marker or indicator is of clinical importance to avoid inadequate coverage of the main tumor. MATERIAL AND METHODS: A 61-year-old woman with cervical cancer, TMN stage cT2b2N1M1, FIGO stage IVB was presented. Extended field external beam radiotherapy (EBRT) with concurrent chemotherapy and the interdigitated delivery of intracavitary brachytherapy was performed. Helical tomotherapy equipped with megavoltage cone beam computed tomography (MV-CBCT) was used for image-guided radiotherapy. For the insertion of tandem of brachytherapy applicator, a silicone sleeve with a central hollow canal was placed into the endocervical canal with the caudal end stopping at the outer surface of the cervical os, and making contact with the distal boundary of the cervical tumor during the entire brachytherapy course. RESULTS: In the remaining EBRT fractions, we found that the air cavity inside the central hollow canal of the sleeve could be clearly identified in daily CBCT images. The radiation oncologists matched the bony markers to adjust the daily setup errors because the megavoltage of the CBCT images could not provide a precise boundary between the soft tissue and the tumor, but the sleeve air cavity, with a clear boundary, could be used as a surrogate and reliable marker to guide the daily setup errors, and to demonstrate the primary tumor location before delivery of each HT fraction. CONCLUSIONS: The application of the sleeve during the interdigitated course of HT and brachytherapy in this patient provided information for the feasibility of using the sleeve air cavity as a surrogate marker for the localization of the main primary tumor before the daily delivery of image-guided HT. PMID- 26985202 TI - Accelerated partial breast irradiation utilizing brachytherapy: patient selection and workflow. AB - Accelerated partial breast irradiation (APBI) represents an evolving technique that is a standard of care option in appropriately selected woman following breast conserving surgery. While multiple techniques now exist to deliver APBI, interstitial brachytherapy represents the technique used in several randomized trials (National Institute of Oncology, GEC-ESTRO). More recently, many centers have adopted applicator-based brachytherapy to deliver APBI due to the technical complexities of interstitial brachytherapy. The purpose of this article is to review methods to evaluate and select patients for APBI, as well as to define potential workflow mechanisms that allow for the safe and effective delivery of APBI. Multiple consensus statements have been developed to guide clinicians on determining appropriate candidates for APBI. However, recent studies have demonstrated that these guidelines fail to stratify patients according to the risk of local recurrence, and updated guidelines are expected in the years to come. Critical elements of workflow to ensure safe and effective delivery of APBI include a multidisciplinary approach and evaluation, optimization of target coverage and adherence to normal tissue guideline constraints, and proper quality assurance methods. PMID- 26985203 TI - DELIBERATE SELF-HARM PATIENTS VISITING PUBLIC AND PRIVATE EMERGENCY DEPARTMENTS OF KARACHI. AB - OBJECTIVE: To study the mode of attempted deliberate self-harm (DSH) in patients presenting to the Emergency Departments (ED) of public and private hospitals of Karachi, Pakistan. DESIGN: A cross sectional study. PLACE AND DURATION OF STUDY: Aga Khan University Hospital Karachi, Jinnah Post Graduate Medical Centre Karachi and Civil Hospital Karachi; March 2011 to February 2012. SUBJECTS AND METHODS: One hundred DSH cases from ED of a private sector hospital were compared with 101 patients from two public sector hospitals. RESULTS: DSH patients in the private hospital were mostly females (70%), had higher level of education (32%), did not share their problems (67%) with someone and had more mental disorders (28%). Patients from public hospitals were treated more for physical illnesses compared to private facility. Organophosphorus poisoning (90%) was a common mode of DSH in patients presenting to public hospitals; however significant number of organophosphorus poisoning (40%) was also seen in private hospital besides the benzodiazepine overdose (32%). CONCLUSION: Emergency Physicians working in the EDs, both public and private sector hospitals of Karachi, should have adequate knowledge of managing organophosphorus poisoning. As more and more cases are presenting to the EDs, there should be a public health initiative to control the illegal sale and availability of such compounds in Pakistan. PMID- 26985204 TI - A Risk-Scoring Model to Predict One-year Major Adverse Cardiac Events after Percutaneous Coronary Intervention. AB - BACKGROUND: The aim of the present study was to develop a scoring system for predicting 1-year major adverse cardiac events (MACE), including mortality, target vessel or target lesion revascularization, coronary artery bypass graft surgery, and non-fatal myocardial infarction after percutaneous coronary intervention (PCI). METHODS: The data were extracted from a single center PCI registry. The score was created based on the clinical, procedural, and laboratory characteristics of 8206 patients who underwent PCI between April 2004 and October 2009. Consecutive patients undergoing PCI between November 2009 and February 2011 (n= 2875) were included as a validation data set. RESULTS: Diabetes mellitus, increase in the creatinine level, decrease in the left ventricular ejection fraction, presentation with the acute coronary syndrome, number of diseased vessels, primary PCI, PCI on the left anterior descending artery and saphenous vein graft, and stent type and diameter were identified as the predictors of the outcome and used to develop the score (R2 = 0.795). The models had adequate goodness of fit (Hosmer-Lemeshow statistic; p value = 0.601) and acceptable ability of discrimination (c-statistics = 0.63). The score categorized the individual patients as low-, moderate-, and high-risk for the occurrence of MACE. The validation of the model indicated a good agreement between the observed and expected risks. CONCLUSION: An individual risk-scoring system based on both clinical and procedural variables can be used conveniently to predict 1-year MACE after PCI. Risk classification based on this score can assist physicians in decision-making and postprocedural health care. PMID- 26985205 TI - Effect of Cardiac Rehabilitation Program on Heart Rate Recovery in Coronary Heart Disease. AB - BACKGROUND: It has been suggested that the autonomic system function and the metabolic syndrome can significantly affect patients' survival. The aim of the current study was to investigate the impact of the cardiac rehabilitation program on the autonomic system balance in patients with coronary artery disease. METHODS: Patients with a previous diagnosis of coronary artery disease who were referred to the Cardiovascular Rehabilitation Center of Afshar Hospital (Yazd, Iran) between March and November 2011 were enrolled. All the patients participated in rehabilitation sessions 3 times a week for 12 weeks. Heart rate recovery (HRR) was measured as an indicator of the autonomic system balance. In order to calculate HRR, the maximum heart rate during the exercise test was recorded. At the end of the exercise test, the patients were asked to sit down without having a cooldown period and their heart rate was recorded again after 1 minute. The difference between these 2 measurements was considered as HRR. RESULTS: A total of 108 patients, including 86 (79.6%) men and 22 (20.4%) women, completed the rehabilitation course. The mean age of the study participants was 58.25 +/- 9.83 years. A statistically significant improvement was observed in HRR (p value = 0.040). Significant declines were also observed in the patients' waist circumference (p value < 0.001) and systolic and diastolic blood pressures (p value = 0.018 and 0.003, respectively). A decreasing trend was observed in the patients' body mass index, but it failed to reach statistical significance (p value = 0.063). No statistically meaningful changes were noted in fasting blood glucose (p value = 0.171), high-density lipoprotein (p value = 0.070), or triglyceride concentrations (p value = 0.149). CONCLUSION: The cardiac rehabilitation program may help to improve HRR and several components of the metabolic syndrome in patients with coronary heart disease. PMID- 26985206 TI - Mid-term Follow-up of the Transcatheter Closure of Perimembranous Ventricular Septal Defects in Children Using the Amplatzer. AB - BACKGROUND: The ventricular septal defect (VSD) is the most common form of congenital heart defects. The purpose of this study was to evaluate the results of the early complications and mid-term follow-up of the transcatheter closure of the VSD using the Amplatzer VSD Occluder. METHODS: Between April 2012 and October 2013, 110 patients underwent the percutaneous closure of the perimembranous VSD. During the procedure, the size and type of the VSD were obtained via ventriculography. A device at least 2 mm larger than the VSD diameter measured via ventriculography was deployed. The size of the VSD, size of the Amplatzer, and device-size to VSD-size ratio were calculated. After the confirmation of the suitable position of the device via echocardiography and left ventriculography, the device was released. Follow-up evaluations were done at discharge as well as at 1, 6, and 12 months and yearly thereafter for the VSD occlusion and complete heart block. RESULTS: The study population comprised 62 females and 48 males. The mean age and weight of the patients at procedure were 4.3 +/- 5.6 years (range: 2 to 14) and 14.9 +/- 10.8 kg (range: 10 to 43). The average device size was 7.0 +/ 2.5 mm (range: 4 to 14). The VSD occlusion rate was 72.8% at the completion of the procedure and rose up to 99.0% during the follow-up. The most serious significant complication was complete atrioventricular block, which was seen in 2 patients. The mean follow-up duration was 10.9 +/- 3.6 months. CONCLUSION: The transcatheter closure of the perimembranous VSD was a safe and effective treatment with excellent closure rates in our study population. This procedure had neither mortality nor serious complications. PMID- 26985209 TI - Bridging to Heart Transplantation from the Biventricular Pulsatile Berlin Heart EXCOR Assist Device Support in a Patient with Advanced End-Organ Failure. AB - Long-term mechanical circulatory support is a life-saving technology while briding to heart transplantation. It increases the quality of life and preserves end-organ function for patients with advanced heart failure. The number of patients with advanced heart failure scheduled for heart transplantation before comorbidities escalate is on the rise. However, the device function is complicated by the bleeding-thrombosis and infection paradigm, hence the interest in understanding device thrombosis and infection. We describe a 27-year-old man with idiopathic cardiomyopathy, advanced end-organ failure, and severe infection, who was bridged to heart transplantation after 8 months on the Berlin Heart EXCOR (Berlin Heart AG, Berlin, Germany) biventricular support. The patient was discharged from the hospital in the third postoperative week after the recovery of his end-organ functions. At 29 months' post-transplantation follow-up, his last cardiac biopsy was grade 0, his ejection fraction was 60%, and he was enjoying a good quality of life. PMID- 26985207 TI - Transseptal Approach versus Left Atrial Approach to Mitral Valve: A Propensity Score Matching Study. AB - BACKGROUND: Many patients with mitral valve diseases need surgical procedures for the repair or replacement of their mitral valve. There is a great deal of controversy over the outcomes of the transseptal (TS) and left atrial (LA) approaches to the mitral valve. We sought to evaluate the outcomes of each approach more accurately by eliminating the possible biases in case selection and matching. METHODS: This retrospective study included patients who had surgery for mitral valve diseases via either the TS approach or the LA approach between 2004 and 2011 in Tehran Heart Center. Patients with surgical approaches other than the TS and LA were excluded. To control for the confounding effects, a propensity score matching technique was applied and the patients were matched for 14 demographic and preoperative variables. After the selection of controls, the effect of the TS approach (163 patients) versus the LA approach (652 patients) on the outcomes was presented through odds ratio (OR) with 95% confidence intervals (CI). RESULTS: The mean age of the patients was 53.15 +/- 12.02 years in the TS group and 52.93 +/- 13.56 years in the LA group. Females comprised 119 (73.0%) patients in the TS group and 462 (70.9%) in the LA group. There was a significant association in the prevalence of new postoperative atrial fibrillation in the two groups (OR = 1.539, 95%CI: 1.072-2.210; p value = 0.019). Temporary pacemaker placement had no statistically significant difference between the two groups (p value = 0.418). The TS patients had significantly longer pump (p value < 0.001) and cross-clamp (p value < 0.001) times. The mortality rate was 4.1% (27 patients) in the LA group and 6.1% (10 patients) in the TS group (p value = 0.274). CONCLUSION: In our study population, the TS approach was associated with higher pump and cross-clamp times as well as risk of postoperative atrial fibrillation, but it did not increase the rates of permanent pacemaker placement, re-operations, and mortality. PMID- 26985210 TI - Acute ST-Elevation Myocardial Infarction after Coronary Stent Fracture. AB - The invention of the drug-eluting stent (DES) has brought about revolutionary changes in the field of interventional cardiology. In the DES era, in-stent restenosis has declined but new issues such as stent thrombosis have emerged. One of the emerging paradigms in the DES era is stent fracture. There are reports about stent fracture leading to in-stent restenosis or stent thrombosis. Most of these reports concern the Sirolimus-eluting stent. The present case is a representation of a Biolimus-eluting stent fracture. We introduce a 64-year-old male patient, for whom the BioMatrix stent was deployed in the right coronary artery. Five months after the implantation, he experienced acute myocardial infarction, with stent fracture leading to stent thrombosis being the causative mechanism. Another DES (Cypher) was used to manage this situation, and the final result was good. PMID- 26985208 TI - Systolic Longitudinal Function of the Left Ventricle Assessed by Speckle Tracking in Heart Failure Patients with Preserved Ejection Fraction. AB - BACKGROUND: Echocardiographic evaluations of the longitudinal axis of the left ventricular (LV) function have been used in the diagnosis and assessment of heart failure with normal ejection fraction (HFNEF). The evaluation of the global and segmental peak systolic longitudinal strains (PSLSs) by two-dimensional speckle tracking echocardiography (STE) may correlate with conventional echocardiography findings. We aimed to use STE to evaluate the longitudinal function of the LV in patients with HFNEF. METHODS: In this study, 126 patients with HFNEF and diastolic dysfunction and 60 normal subjects on conventional echocardiography underwent STE evaluations, including LV end-diastolic and end-systolic dimensions; interventricular septal thickness; posterior wall thickness; LV volume; LV ejection fraction; left atrial volume index; early diastolic peak flow velocity (??); late diastolic peak flow velocity (??); ??/?? ratio; deceleration time of ??; early diastolic myocardial velocity (e'); late diastolic myocardial velocity (A'); systolic myocardial velocity (S); and global, basal, mid, and apical PSLSs. The correlations between these methods were assessed. RESULTS: The mean age was 57.50 +/- 10.07 years in the HFNEF patients and 54.90 +/- 7.17 years in the control group. The HFNEF group comprised 69.8% males and 30.2% females, and the normal group consisted of 70% males and 30% females. The global, basal, mid, and apical PSLSs were significantly lower in the HFNEF group (p value < 0.001 for all). There was a significant positive correlation between the global PSLS and the septal e' (p value < 0.001). There was a negative correlation between the global PSLS and the E/e' ratio (p value = 0.001). There was a significant negative correlation between the E/e' ratio and the mid PSLS (p value = 0.002) and the basal PSLS (p value = 0.001). There was a weak positive correlation between the septal e' and the mid PSLS (p value = 0.001) and the basal PSLS (p value < 0.001). There were also weak negative correlations between the isovolumic relaxation time and the global PSLS (p value = 0.022) and the mid PSLS (p value = 0.018) and also between the New York Heart Association functional class and the mid PSLS (p value = 0.041) and the basal PSLS (p value = 0.009). CONCLUSION: Our HFNEF patients on conventional echocardiography had different STE findings compared to our normal subjects, which is indicative of diastolic dysfunction. The longitudinal systolic function of the LV, which was measured by STE, was reduced in all the segments, denoting some degree of subclinical systolic dysfunction in these patients. PMID- 26985211 TI - The GuideLiner Catheter: A Useful Tool in the Armamentarium of the Interventional Cardiologist. AB - Regardless of the clinical setting, a good back-up represents one of the most important conditions to ensure guide wire and balloon advancement and stent delivery. As a "mother and child" system, the GuideLiner catheter (Vascular Solutions Inc., Minneapolis, MN, USA) provides an extension to the guide catheter with better coaxial alignment and stability. We report two didactic cases showing the usefulness of the GuideLiner device in everyday catheterization laboratory practice. The first case was a primary percutaneous coronary intervention (PCI) in a 71-year-old diabetic man admitted for inferior ST-elevation myocardial infarction, related to tight proximal stenosis in a dominant tortuous and calcified left circumflex. The second case was an elective PCI in a 76-year-old man admitted for stable angina (Canadian Cardiovascular Society [CCS] class III), related to focal intra-stent restenosis of a saphenous venous graft to the left anterior descending. In both cases, the GuideLiner catheter provided a good back up insuring the success of PCI and drug-eluting stents implantation, with a good in-hospital outcome. PMID- 26985212 TI - Emergency Coronary Artery Bypass Graft Surgery for Iatrogenic Left Main Coronary Artery Dissection. AB - Iatrogenic coronary artery dissection during coronary angiography with or without rupture is a rare but feared complication. We herein report a case of iatrogenic left main coronary artery dissection in a 49-year-old female. Admitted to our hospital with a recent history of severe hypotension, she develpled apnea during angiography. She was intubated and resuscitated with an Epinephrine infusion in the Cath-Lab. The diagnosis was iatrogenic left main coronary artery dissection based on angiography. Immediately, the patient was transferred to the operating room in a lethargic state with an Epinephrine infusion and prepared for emergency coronary artery bypass graft surgery. In the ICU, she was completely alert with no hemodynamic complications and finally was discharged in a good overall condition. At 18 months' follow-up, the patient was in a stable situation with good daily function. PMID- 26985214 TI - Relationship between Season and Acute Myocardial Infarction, In Iran. PMID- 26985213 TI - Senile Calcification of the Trachea, Aortic Arch, and Mitral Annulus: An Incidental Finding on Chest X-Ray. AB - A 94-year-old woman presented with dizziness and hypotension of 2 days' duration. She denied any syncope, presyncope, or angina. She had received a permanent pacemaker 12 years previously for the management of complete heart block (CHB), but she failed to program it. Twelve-lead electrocardiography revealed CHB with ventricular escape rhythm (40/min), so we inserted a temporary pacemaker. Anteroposterior chest X-ray showed trachea, aortic arch, and severe mitral valve calcification. Tracheal calcification is usually seen after 40 years old without clinical importance. However, it is seen in patients with renal failure, metastases, and prolonged use of warfarin as well as in pregnancy.(1) (-) (3). PMID- 26985215 TI - Other Probable Explanations for Acute Neurological Deficits after the Removal of a Central Venous Catheter. PMID- 26985217 TI - Association between nurses' personality characteristics and their attitude toward the older adults. AB - BACKGROUND: Administration of quality care in the aged people requires having a positive attitude toward them. Numerous factors including nurses' personality characteristics may play a role in their attitude toward the aged people. Therefore, the present study investigated the association between nurses' personality characteristics and their attitude toward the aged people. MATERIALS AND METHODS: This is a cross-sectional study conducted on 261 nurses selected through random stratified sampling. Kogan's Attitudes toward Older People Scale (KAOPS) was adopted to measure nurses' attitude toward the aged people, and five factor personality inventory was used to detect their personality dimensions. The data were analyzed by descriptive and inferential statistical tests (Pearson correlation coefficient and multiple linear regression). P < 0.05 was considered significant. RESULTS: Results showed that the predictive model of nurses' attitude toward aged people based on their five-factor personality dimensions was significant (P = 0.001). Overall, the variables, entered in the model, predicted 13% of variance of nurses' attitude toward aged people. Among the predicting variables, two dimensions of personality, including agreeableness (P = 0.046) and neuroticism (P = 0.003), significantly predicted nurses' attitude toward aged people. CONCLUSIONS: The results showed that nurses with higher agreeableness and lower neuroticism can be an appropriate option in caring for the aged people. Therefore, nurse managers are suggested to take steps toward creating a more positive attitude toward the aged people among nurses, in addition to holding educational programs for them with the goal of agreeableness empowerment. PMID- 26985216 TI - Nurses' human dignity in education and practice: An integrated literature review. AB - BACKGROUND: Human dignity, as a fundamental human right and a moral obligation, has been emphasized in different fields of nursing. The aim of the present integrative review was to explore the nature of nurses' human dignity in educational and clinical settings. MATERIALS AND METHODS: A literature review was conducted on quantitative and qualitative research papers in English and Persian using the PubMed, ProQuest, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Google Scholar, SID, and Irandoc databases from the year 2000 to 2013. Keywords for the search included dignity, nursing, faculty, nurse clinicians, nursing student, and humanism. In total, 12 research papers met the inclusion criteria for the integrative review. RESULTS: From this review, four key themes emerged. The themes consisted of concept of human dignity (it was as an expression of the professional value in nursing settings), factors affecting human dignity (including respect, communication, autonomy and power, competency and ability, structure of the workplace, and value-based education), dimensions of human dignity (including intrinsic and professional domains), and consequences of human dignity [positive (individual and professional growth and caring professional behavior) and negative (loss of motivation, intention to leave the profession, and non-professional image of nursing in the minds of people)]. CONCLUSIONS: The small number of studies found for the review indicates the need for further research in the field of nurses' dignity. Recognizing nurses' dignity can help to improve the nursing practice and provide them a dignified workplace. PMID- 26985218 TI - The effect of education based on the main concepts of logotherapy approach on the quality of life in patients after coronary artery bypass grafting surgery. AB - BACKGROUND: Improving the patients' quality of life (QOL) after coronary artery bypass grafting (CABG) is one of the main concerns of the treatment team. Educational interventions may affect the aspects of QOL in various ways. The present study aimed to investigate the effect of education based on the main concepts of logotherapy approach on the CABG patients' quality of life. MATERIALS AND METHODS: In this quasi-experimental study, a convenient sample of 67 patients who had undergone CABG in Isfahan Chamran hospital were randomly allocated to two groups of experimental (n = 35) and control (n = 32). While the control group received routine care, the experiment group benefitted from logotherapy-based education program (six 90-min sessions, twice a week). SF-36 questionnaire was completed by both two groups (before and 1 month after intervention). Descriptive and inferential statistical tests (consisting of independent t-test) were employed to analyze data in SPSS version 13. RESULTS: The pre-test mean total score of SF-36 questionnaire and also the mean scores of its eight dimensions were not significantly different between the two groups. The post-test mean score change [Standard Error (SE)] in the intervention group was 24.95 (3) and in the control group was 9.27 (0.82). There were significant differences between the two groups (P < 0.001). Moreover, the mean scores of six dimensions of QOL (vitality, bodily pain, general health, emotional role, social functioning, and mental health) changed significantly in the intervention group. CONCLUSIONS: Our findings indicated that the intervention has improved the patients' QOL after CABG. Integration of such an intervention in these patients' rehabilitation programs is recommended. PMID- 26985219 TI - A self-efficacy questionnaire regarding leisure time physical activity: Psychometric properties among Iranian male adolescents. AB - BACKGROUND: Attention to different aspects of self-efficacy leads to actual evaluation of self-efficacy about physical activity. This study was carried out in order to design and determine psychometric characteristics of a questionnaire for evaluation of self-efficacy about leisure time physical activity (SELPA) among Iranian adolescent boys, with an emphasis on regulatory self-efficacy. MATERIALS AND METHODS: This descriptive-analytic study was conducted in 734 male adolescents aged 15-19 years in Isfahan. After item generation and item selection based on review of literature and other questionnaires, content validity index (CVI) and content validity ratio (CVR) were determined and items were modified employing the opinions of expert panel (N = 10). Comprehensibility of the questionnaire was determined by members of target group (N = 35). Exploratory factors analysis (EFA) was operated on sample 1 (N 1 = 325) and confirmatory factors analysis (CFA) on sample 2 (N 2 = 347). Reliability of SELPA was estimated via internal consistency method. RESULTS: According to EFA, barrier self-efficacy and scheduling self-efficacy are the two main aspects of SELPA with the total variance of 65%. The suggested model was confirmed by CFA and all fitness indices of the corrected model were good. Cronbach's alpha was totally estimated as 0.89 and for barrier and scheduling self-efficacy, it was 0.86 and 0.81, respectively. CONCLUSIONS: The results provide some evidence for acceptable validity and reliability of SELPA in Iranian adolescent boys. However, further investigations, especially for evaluation of predictive power of the questionnaire, are necessary. PMID- 26985221 TI - The effect of neuro-linguistic programming on occupational stress in critical care nurses. AB - BACKGROUND: The use of coping strategies in reducing the adverse effects of stress can be helpful. Nero-linguistic programming (NLP) is one of the modern methods of psychotherapy. This study aimed to determine the effect of NLP on occupational stress in nurses working in critical care units of Urmia. MATERIALS AND METHODS: This study was carried out quasi-experimentally (before-after) with control and experimental groups. Of all the nurses working in the critical care units of Urmia Imam Khomeini and Motahari educational/therapeutic centers, 60 people participated in this survey. Eighteen sessions of intervention were done, each for 180 min. The experimental group received NLP program (such as goal setting, time management, assertiveness skills, representational system, and neurological levels, as well as some practical and useful NLP techniques). Expanding Nursing Stress Scale (ENSS) was used as the data gathering tool. Data were analyzed using SPSS version 16. Descriptive statistics and Chi-square test, Mann-Whitney test, and independent t-test were used to analyze the data. RESULTS: The baseline score average of job stress was 120.88 and 121.36 for the intervention and control groups, respectively (P = 0.65). After intervention, the score average of job stress decreased to 64.53 in the experimental group while that of control group remained relatively unchanged (120.96). Mann-Whitney test results showed that stress scores between the two groups was statistically significant (P = 0.0001). CONCLUSIONS: The results showed that the use of NLP can increase coping with stressful situations, and it can reduce the adverse effects of occupational stress. PMID- 26985222 TI - Iranian entrepreneur nurses' perceived barriers to entrepreneurship: A qualitative study. AB - BACKGROUND: To respond efficiently to the increasing and new needs of people in health issues, it is necessary for nurses to develop their knowledge from hospital to society and to be equipped to play entrepreneur role in different levels of care. The present study was conducted to describe Iranian entrepreneur nurses' perceived barriers to entrepreneurship, in order to identify the existing barriers. MATERIALS AND METHODS: This is a qualitative study in which Graneheim and Lundman's content analysis method was employed. Thirteen entrepreneur nurses were chosen purposively, and data were gathered by unstructured interviews. RESULTS: As a result of the data analysis, five major themes were extracted: Traditional nursing structure, legal limitations, traditional attitudes of governmental managers, unprofessional behaviors of colleagues, and immoral business. CONCLUSIONS: The findings of the present study show that Iranian nurses are confronted with various problems and barriers to enter entrepreneur nursing and keep going in this area. By focusing on such barriers and applying appropriate changes, policymakers and planners in health can facilitate nurses entering into this activity. PMID- 26985220 TI - Adherence to HIV/AIDS antiretroviral therapy among drug users: A qualitative study in Iran. AB - BACKGROUND: The introduction of antiretroviral therapy has caused a remarkable decrease in the occurrence of diseases and mortality among HIV-positive patients, while this success has not been achieved among injection addicts due to a low adherence to antiretroviral medicine. This study aims at clarifying the important factors affecting adherence to treatment in addicts suffering from HIV. MATERIALS AND METHODS: In this qualitative research, data were gathered through in-depth interviews and field notes, and were interpreted through content analysis in the form of constant comparison. The participants were 16 drug addicts living with HIV/AIDS. Most of them had records of imprisonment and were receiving Highly Active Antiretroviral Therapy (HAART) drug treatments in the AIDS center of Imam Khomeini Hospital complex, affiliated to Tehran University of Medical Sciences. Sampling was started in a purposive method and was continued until data were saturated. RESULTS: Four main categories including psychological reactions, contradictory beliefs, perceived support, and individual and environmental barriers were extracted from the data, each having some sub-categories. CONCLUSIONS: The obtained results indicated that adherence to the treatment of HIV is not constant and mono-dimensional, but is a function of different factors. Hence, an individual having feeble adherence in a specific time and under specific circumstances may show desirable adherence under a different circumstance. Thus, treatment of addicts living with HIV/AIDS requires physical, psychological, and social attention along with drug treatments. PMID- 26985223 TI - Determining the disease management process for epileptic patients: A qualitative study. AB - BACKGROUND: Epilepsy exposes patients to many physical, social, and emotional challenges. Thus, it seems to portray a complex picture and needs holistic care. Medical treatment and psychosocial part of epilepsy remain central to managing and improving the patient's qualify of life through team efforts. Some studies have shown the dimensions of self-management, but its management process of epilepsy patients, especially in Iran, is not clear. This study aimed to determine the disease management process in patients with epilepsy in Iran. MATERIALS AND METHODS: This qualitative approach and grounded theory study was conducted from January 2009 to February 2012 in Isfahan city (Iran). Thirty-two participants were recruited by the goal-oriented, and snowball sample selection and theoretical sampling methods. After conducting a total of 43 in-depth interviews with the participants, the researchers reached data saturation. Data were analyzed using Strauss and Corbin method. RESULTS: With a focus on disease management process, researchers found three main themes and seven sub-themes as a psychosocial process (PSP). The main themes were: perception of threat to self identity, effort to preserve self-identity, and burn out. The psychosocial aspect of the disease generated one main variable "the perception of identity loss" and one central variable "searching for self-identity." CONCLUSIONS: Participants attributed threat to self-identity and burn out to the way their disease was managed requiring efforts to preserve their identity. Recommendations consist of support programs and strategies to improve the public perception of epilepsy in Iran, help patients accept their condition and preserve self-identity, and most importantly, enhance medical management of epilepsy. PMID- 26985224 TI - Requirements for nurse supervisor training: A qualitative content analysis. AB - BACKGROUND: Supervisors should have certain characteristics and adequate preparation for their roles. Yet, there are no well-educated experts knowing about the supervisor's role and responsibilities and how to train them. So, this research was conducted with the purpose of finding the factors affecting nursing supervisor training. MATERIALS AND METHODS: This research is an inductive content analysis. Participants were 25 in number, consisting of nurses and supervisors in Shahid Sadoughi University hospitals. The participants were chosen by a purposive sampling method. Data collection was done by semi-structured interviews and reviewing documents. Data were analyzed using conventional content analysis. RESULTS: Findings included two main themes: Firstly, establishment of a supervisory infrastructure that includes "making the appointments and retention of supervisors, clarifying the duties and authority of supervisor, developing supervisory culture, specializing supervision, and conducting practice-based training" and secondly, comprehensive supervisory competencies that include "acquiring scientific, managing, communicative, professional, ethical, pedagogical, and supporting adequacy." CONCLUSIONS: Clinical supervisor has a major role in ensuring the quality of nursing care. This leads to improvements in patient care and nurses' personal and professional development. So, it is necessary that for effective supervision in nursing, first an infrastructure is provided for supervision and then the comprehensive competency of a supervisor is enhanced to apply effective supervision. PMID- 26985225 TI - Relationship between parent-infant attachment and parental satisfaction with supportive nursing care. AB - BACKGROUND: Parent-infant attachment is an important factor in accepting parenting role, accelerating infant survival, and adjusting to the environment outside the uterus. Since family supportive interventions can strengthen the parent-infant caring relationship, this study sought to investigate the relationship between mother-infant attachment and satisfaction of the mothers with the supportive nursing care received in the neonatal intensive care unit (NICU). MATERIALS AND METHODS: In this descriptive-correlational study, 210 mothers with premature infants who were hospitalized in the NICUs affiliated to Isfahan Medical University hospitals took part. The data were collected via Maternal Postnatal Attachment Scale and researcher's self-tailored questionnaire based on Nurse Parent Support Tool. Pearson correlation coefficient and multiple linear regressions were used to analyze the collected data. RESULTS: The results showed that the overall score of mother-infant attachment and the overall score of maternal satisfaction correlated with a correlation coefficient of r = 0.195. Also, the overall score of mother-infant attachment and mothers' satisfaction scores in the emotional, communicative-informative, and self-confidence domains correlated with correlation coefficients of r = 0.182, r = 0.0.189, and r = 0.0.304, respectively. The results of multiple regression analysis revealed that about 15% of changes in the dependent variable (mother-infant attachment) could be explained by different dimensions of mothers' satisfaction. CONCLUSIONS: The results of the study showed that mother-infant attachment improved by increasing mothers' satisfaction of supportive nursing care. Therefore, it seems necessary to increase maternal satisfaction through given nursing care support, in order to promote mother-infant attachment. PMID- 26985226 TI - Effects of hope promoting interventions based on religious beliefs on quality of life of patients with congestive heart failure and their families. AB - BACKGROUND: Heart failure is one of the most important and prevalent diseases that may have negative effects on the quality of life (QOL). Today, the promotion of QOL in patients with heart failure is important in nursing care programs. This research aimed to determine the efficacy of hope-promoting interventions based on religious beliefs on the QOL of patients with congestive heart failure (CHF). MATERIALS AND METHODS: In this randomized clinical trial (IRCT2014100619413N1) conducted in Isfahan, Iran, 46 adult patients with CHF were selected and randomly assigned to study and control groups. Ferrans and Powers Quality of Life Index (QLI) was completed by both groups before, immediately after, and 1 month after the intervention. For the study group participants and their families, 60-min sessions of hope-promoting interventions based on religious beliefs were held twice a week for 3 weeks. Independent t, repeated measures analysis of variance (ANOVA), Chi-square, Mann-Whitney, and Fisher's exact tests were adopted for data analysis. RESULTS: The mean (standard deviation) overall QOL score in the area of satisfaction significantly increased in the study group, compared to the controls, immediately [70.7 (8.5) vs. 59.2 (12.5)] and 1 month after the intervention [75.2 (7.4) vs. 59.4 (12.9)] (P < 0.05). There was also a similar difference between the two groups in the area of importance immediately [73.6 (5.8) vs. 65.7 (7.5)] and 1 month after the intervention [76.3 (8.1) vs. 66.8 (8.5)] (P < 0.05). CONCLUSIONS: Hope-promoting intervention based on religious beliefs is a useful method for improving QOL in patients with CHF. PMID- 26985227 TI - The implementation of kangaroo mother care and nurses' perspective of barriers in Iranian' NICUs. AB - BACKGROUND: Kangaroo mother care (KMC) is the most implementation intervention in caring of the infants, as in this method, both the mothers and infants are cared. The World Health Organization recommends implementation of KMC for all infants. However, there are some barriers in the way of its application. The purpose of this study was evaluation of the practical application of KMC and nurses' perspective about its implantation barriers in the neonatal intensive care units (NICUs) in Iran. MATERIALS AND METHODS: The descriptive study was conducted on 96 infants and 80 nurses working in the NICUs of two university hospitals in Isfahan, Iran. Data were collected by a two-section questionnaire and analyzed by t-test through SPSS 14. RESULTS: Study findings indicated that mean weight and age of the infants with KMC were 1510 g and 32 weeks, respectively. KMC was implantation for 32 min in a day. From nurses' perspective, mother-related barriers were the main barriers in the implantation of KMC as mothers were not present by their infants. Another barrier was the mothers' fear of touching their infants. In the domain of organizational barriers, physician's order was found to be the most important barrier in application of KMC. CONCLUSIONS: Identifying barriers in implantation of KMC is essential to support the mothers. Regarding mother-related barriers, organizational barriers, and the need for a physician's order for implementation of KMC, policy makers must provide facilities and equipment for applying KMC practice for mothers and improve the protocol of KMC in the NICU. PMID- 26985228 TI - The effect of incentive spirometry on arterial blood gases after coronary artery bypass surgery (CABG). AB - BACKGROUND: After coronary artery bypass surgery, pulmonary complications and oxygenation disorders are common, which have an important role in mortality and morbidity. Different methods are used for the improvement of pulmonary function and oxygenation, of which incentive spirometry (IS) has been investigated here. The aim of this study is to evaluate the effects of IS on arterial blood gases after coronary artery bypass graft (CABG). MATERIALS AND METHODS: This was a clinical trial. Fifty patients who were candidates for CABG were chosen. The patients had been allocated to two random groups of intervention and control. The intervention was done through IS. These two groups were compared for the arterial blood gases' preoperative level, and the levels on first (after extubation), second, and third postoperative days. RESULTS: The study findings showed that on the third postoperative day, there was a significant difference between the intervention and control groups in the mean amount of arterial blood oxygen (82.3 +/- 4.7 vs. 72.7 +/- 7.1, respectively, P = 0.02), arterial blood carbon dioxide (36.8 +/- 2 vs. 43.7 +/- 3.2, respectively, P = 0.007), and oxygen saturation (96.8 +/- 1.4 vs. 90.5 +/- 1.4, respectively, P = 0.03). CONCLUSIONS: This investigation shows that using IS is significantly effective in the improvement of blood arterial gas parameters. PMID- 26985229 TI - Exploring the risk factors contributing to suicide attempt among adolescents: A qualitative study. AB - BACKGROUND: Since suicide attempt among adolescents is a major challenge and the reasons why this age group attempt suicide are complex, the aim of this study was to investigate the risk factors that contribute to suicide attempt among adolescents. MATERIALS AND METHODS: In this qualitative content analysis, 14 adolescents (12-19 years old) who were admitted in two hospitals in Shiraz, Iran, were interviewed. Participants who tried attempt suicide with medication were selected by purposive sampling and the data were gathered by semi-structured interviews. Data analysis was guided by the conventional approach of qualitative content analysis. RESULTS: Three major themes and 13 subthemes emerged from data analysis. The main themes were: (a) Individual factors and experiences (psycho emotional problems, puberty, religious beliefs, stress management strategies, marriage and love, field and level of education); (b) family factors (family structure, family relationship, family economic features, family health conditions); and (c) social factors (suicidal behavior in others, media influence, professional support). CONCLUSIONS: This study identified three major themes related to suicide attempt among adolescents in the context. As a result, suicide prevention and care provision should formulate a comprehensive method, considering the interaction of medical besides individual, familiar, and social factors in their assessment and care provision. PMID- 26985230 TI - The effect of vitamin D supplementation on blood sugar and different indices of insulin resistance in patients with non-alcoholic fatty liver disease (NAFLD). AB - BACKGROUND: Vitamin D supplementation has been shown to decrease insulin resistance through which it might cause fatty liver. Fatty liver increasingly results in type 2 diabetes mellitus (T2DM). Insulin resistance and fatty liver are particularly closely related. The aim of present study is to examine the effect of vitamin D supplementation on blood sugar and different indices of insulin resistance in patients with non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: This randomized placebo-controlled clinical trial was conducted on 60 patients with NAFLD, who were divided equally into intervention and control groups. Patients in the intervention group received vitamin D3 (50,000 IU) and patients in the control group received placebo capsules every week for 10 weeks. Blood sugar, homeostatic model assessment-insulin resistance (HOMA-IR), and homeostatic model assessment-beta cell (HOMA-B) were checked at baseline and after 10 weeks of the intervention. Adjustment for variables was performed by analysis of covariance (ANCOVA). RESULTS: Vitamin D supplementation resulted in increased serum 25-hydroxy vitamin D [25(OH) D] concentration in the intervention group compared to the control group [+68 (12) vs. -1.9 (2.44); P = 0.001]. Intake of vitamin D supplements led to a marginally significant decrease in fasting blood glucose [FBS: -12 (4) in the intervention group compared to - 3 (2) in the control group; P = 0.055]. Also, HOMA-IR decreased in the intervention group compared to the control group [-1.75 (0.23) vs. 0.12 (0.41); P = 0.066]. CONCLUSIONS: Vitamin D supplementation resulted in decreased HOMA-IR and FBS concentration in patients with NAFLD; however, it did not affect the insulin level and HOMA-B significantly. PMID- 26985231 TI - Ebola outbreak in West Africa: Bridging the gap between the public health authorities and the community. PMID- 26985232 TI - Effect of a synbiotic on the response to seasonal influenza vaccination is strongly influenced by degree of immunosenescence. AB - BACKGROUND: Ageing increases risk of respiratory infections and impairs the response to influenza vaccination. Pre- and probiotics offer an opportunity to modulate anti-viral defenses and the response to vaccination via alteration of the gut microbiota. This study investigated the effect of a novel probiotic, Bifidobacterium longum bv. infantis CCUG 52,486, combined with a prebiotic, gluco oligosaccharide (B. longum + Gl-OS), on the response to seasonal influenza vaccination in young and older subjects in a double-blind, randomized controlled trial, taking into account the influence of immunosenescence markers at baseline. RESULTS: Vaccination resulted in a significant increase in total antibody titres, vaccine-specific IgA, IgM and IgG and seroprotection to all three subunits of the vaccine in both young and older subjects, and in general, the increases in young subjects were greater. There was little effect of the synbiotic, although it tended to reduce seroconversion to the Brisbane subunit of the vaccine and the vaccine-specific IgG response in older subjects. Immunological characterization revealed that older subjects randomized to the synbiotic had a significantly higher number of senescent (CD28(-)CD57(+)) helper T cells at baseline compared with those randomized to the placebo, and they also had significantly higher plasma levels of anti-CMV IgG and a greater tendency for CMV seropositivity. Moreover, higher numbers of CD28(-)CD57(+) helper T cells were associated with failure to seroconvert to Brisbane, strongly suggesting that the subjects randomized to the synbiotic were already at a significant disadvantage in terms of likely ability to respond to the vaccine compared with those randomized to the placebo. CONCLUSIONS: Ageing was associated with marked impairment of the antibody response to influenza vaccination in older subjects and the synbiotic failed to reverse this impairment. However, the older subjects randomized to the synbiotic were at a significant disadvantage due to a greater degree of immunosenscence at baseline compared with those randomized to the placebo. Thus, baseline differences in immunosenescence between the randomized groups are likely to have influenced the outcome of the intervention, highlighting the need for detailed immunological characterization of subjects prior to interventions. TRIAL REGISTRATION: Clinicaltrials.gov NCT01066377. PMID- 26985233 TI - Dietary L-arginine intake and the incidence of coronary heart disease: Tehran lipid and glucose study. AB - BACKGROUND: We investigated the association of regular dietary intake of L arginine and both the incidence of coronary heart disease (CHD) and changes of blood pressure. METHODS: Eligible adults (n = 2284) who participated in the Tehran Lipid and Glucose Study were followed for a mean of 4.7 years. Dietary intake of L-arginine was assessed at baseline (2006-2008); biochemical variables were evaluated at baseline and the follow-up examination. Multivariate Cox proportional hazard regression models adjusted for potential confounders were used to estimate the risk of CHD across tertiles of L-arginine intake. Linear regression models were also used to indicate the association of L-arginine intake with changes of serum lipids and blood pressure during the follow-up. RESULTS: Mean age of participants (42.8 % men) was 38.2 +/- 13.4, at baseline. During a mean 4.7 +/- 1.4 y of follow-up, 57 participants experienced CHD events. A significant negative association was observed between plant-derived L-arginine intake and changes of both systolic and diastolic blood pressure, whereas animal derived L-arginine intake was related to increased levels of diastolic blood pressure (P < 0.01). Participants in the 2(nd) tertile (1.45-1.78 g/d) had a significantly increased risk of CHD events compared to the participants in the 1(st) tertile (<1.45 g/d) (HR = 1.90, 95 % CI = 1.03-3.58). The risk of CHD had a decreasing trend across increasing plant-derived L-arginine intake (HR = 1.0, HR = 0.91, 95 % CI = 0.51-1.62, HR = 0.72, 95 % CI = 0.39-1.32, P for trend = 0.03). CONCLUSION: Higher intake of plant derived L-arginine may have a protective effect whereas animal-derived L-arginine may be a risk factor for development of hypertension and CHD events. PMID- 26985234 TI - On the (In)Validity of Tests of Simple Mediation: Threats and Solutions. AB - Mediation analysis is a popular framework for identifying underlying mechanisms in social psychology. In the context of simple mediation, we review and discuss the implications of three facets of mediation analysis: (a) conceptualization of the relations between the variables, (b) statistical approaches, and (c) relevant elements of design. We also highlight the issue of equivalent models that are inherent in simple mediation. The extent to which results are meaningful stem directly from choices regarding these three facets of mediation analysis. We conclude by discussing how mediation analysis can be better applied to examine causal processes, highlight the limits of simple mediation, and make recommendations for better practice. PMID- 26985235 TI - Barefoot therapists: barriers and facilitators to delivering maternal mental health care through peer volunteers in Pakistan: a qualitative study. AB - BACKGROUND: Perinatal depression is a public health problem in low and middle income countries. Although effective psychosocial interventions exist, a major limitation to their scale up is the scarcity of mental health professionals. The aim of this study was to explore the facilitators and barriers to the acceptability of peer volunteers (PVs)-volunteer lay women from the community with shared socio-demographic and life experiences with the target population-as delivery agents of a psychosocial intervention for perinatal depression in a rural area of Pakistan. METHODS: This qualitative study was embedded in the pilot phase of a larger peer-delivered mental health programme. Forty nine participants were included: depressed mothers (n = 21), PVs (n = 8), primary health care staff (n = 5), husbands (n = 5) and mothers-in-law (n = 10). Data were collected through in-depth interviews and focus groups and analysed using the Framework Analysis approach. RESULTS: The PVs were accepted as delivery agents by all key stakeholders. Facilitators included the PVs' personal attributes such as being local, trustworthy, empathetic, and having similar experiences of motherhood. The perceived usefulness and cultural appropriateness of the intervention and linkages with the primary health care (PHC) system was vital to their legitimacy and credibility. The PVs' motivation was important, and factors influencing this were: appropriate selection; effective training and supervision; community endorsement of their role, and appropriate incentivisation. Barriers included women's lack of autonomy, certain cultural beliefs, stigma associated with depression, lack of some mothers' engagement and resistance from some families. CONCLUSION: PVs are a potential human resource for the delivery of a psychosocial intervention for perinatal depression in this rural area of Pakistan. The use of such delivery agents could be considered for other under-resourced settings globally. PMID- 26985238 TI - Autonomic hyperreflexia after spinal cord injury managed successfully with intravenous lidocaine: a case report. AB - BACKGROUND: Some paraplegic patients may wish undergo some surgical procedures, like urological procedures, without anesthesia. However, these patients can develop autonomic hyperreflexia if cystoscopy is performed without anesthesia. CASE PRESENTATION: We present a case of severe autonomic hyperreflexia in a 44 year-old male with spinal cord injury at the level of T4 during urologic procedure under sedation and analgesia successfully treated with intravenous lidocaine. CONCLUSIONS: This case illustrates that patients with spinal cord injuries are likely to develop autonomic hyperreflexia during urological procedures performed without anesthesia. Health professionals should educate spinal cord injury patients regarding risks of this serious condition and be aware to prevent and manage autonomic hyperreflexia. In an acute episode, nifedipine, nitrates and captopril are the most commonly used and recommended agents. To our knowledge, this is the first case report of severe autonomic hyperreflexia treated successfully with intravenous lidocaine. PMID- 26985239 TI - Thyroid research: stepping forward. AB - It is eight years since Thyroid Research was launched with an aim to enhance opportunities for scientists and clinicians, working in the rapidly advancing field of thyroidology, to publish their research (Thyroid Res 1(1):1, 2008). Right from the outset, Thyroid Research aspired to become a prominent journal in thyroidology with high quality publications. Over the years, the journal has not only survived in the increasingly competitive field of open-access academic journal publication, it has also been making a steady progress towards achieving this ambitious goal. Now, Thyroid Research is ready to step forward to begin a new chapter in its publication. PMID- 26985236 TI - Mental health and cerebellar volume during adolescence in very-low-birth-weight infants: a longitudinal study. AB - BACKGROUND: Preterm birth at very low birth weight (VLBW) poses a risk for cerebellar abnormalities and increased psychiatric morbidity compared with reference populations. We aimed to study cerebellar volumes (grey and white matter; GM, WM) and mental health in VLBW individuals and controls at 15 and 19 years of age, as well as changes between the two time points. METHODS: Forty VLBW (<=1500 g) and 56 control adolescents were included in the study at 15 years of age, and 44 VLBW and 60 control adolescents at 19 years of age. We had longitudinal data for 30 VLBW participants and for 37 controls. Clinical diagnoses were assessed following the schedule for affective disorders and schizophrenia for school-age children (KSADS). Psychiatric symptoms and function were further investigated with the Achenbach System of Empirically Based Assessment (ASEBA), ADHD Rating Scale-IV and the children's global assessment scale (CGAS). An automatic segmentation of cerebellar GM and WM volumes was performed in FreeSurfer. The MRI scans were obtained on the same 1.5T scanner at both ages. RESULTS: The VLBW group had higher rates of psychiatric disorders at both ages. Cerebellar growth trajectories did not differ between VLBW adolescents and controls, regardless of psychiatric status. However, VLBW adolescents who had a psychiatric diagnosis at both ages or developed a psychiatric disorder from 15 to 19 years had maintained smaller cerebellar WM and GM volumes than controls and also smaller volumes than VLWB adolescents who were or became healthy in this period. Moreover, there were no differences in cerebellar WM and GM volumes between controls and those VLBW who were healthy or became healthy. In the VLBW group, cerebellar WM and GM volumes correlated positively with psycho-social function at both 15 and 19 years of age, and smaller GM volumes were associated with inattention at 15 years. CONCLUSIONS: Smaller cerebellar volume in adolescents born very preterm and with VLBW may be a biomarker of increased risk of psychiatric problems in young adulthood. PMID- 26985237 TI - Microalgal TAG production strategies: why batch beats repeated-batch. AB - BACKGROUND: For a commercially feasible microalgal triglyceride (TAG) production, high TAG productivities are required. The operational strategy affects TAG productivity but a systematic comparison between different strategies is lacking. For this, physiological responses of Nannochloropsis sp. to nitrogen (N) starvation and N-rich medium replenishment were studied in lab-scale batch and repeated-batch (part of the culture is periodically harvested and N-rich medium is re-supplied) cultivations under continuous light, and condensed into a mechanistic model. RESULTS: The model, which successfully described both strategies, was used to identify potential improvements for both batch and repeated-batch and compare the two strategies on optimized TAG yields on light (amount of TAGs produced per mol of supplied PAR photons). TAG yields on light, for batch, from 0.12 (base case at high light) to 0.49 g molph (-1) (at low light and with improved strain) and, for repeated-batch, from 0.07 (base case at high light) to 0.39 g molph (-1) (at low light with improved strain and optimized repeated-batch settings). The base case yields are in line with the yields observed in current state-of-the-art outdoor TAG production. CONCLUSIONS: For continuous light, an optimized batch process will always result in higher TAG yield on light compared to an optimized repeated-batch process. This is mainly because repeated-batch cycles start with N-starved cells. Their reduced photosynthetic capacity leads to inefficient light use during the regrowth phase which results in lower overall TAG yields compared to a batch process. PMID- 26985240 TI - DASPfind: new efficient method to predict drug-target interactions. AB - BACKGROUND: Identification of novel drug-target interactions (DTIs) is important for drug discovery. Experimental determination of such DTIs is costly and time consuming, hence it necessitates the development of efficient computational methods for the accurate prediction of potential DTIs. To-date, many computational methods have been proposed for this purpose, but they suffer the drawback of a high rate of false positive predictions. RESULTS: Here, we developed a novel computational DTI prediction method, DASPfind. DASPfind uses simple paths of particular lengths inferred from a graph that describes DTIs, similarities between drugs, and similarities between the protein targets of drugs. We show that on average, over the four gold standard DTI datasets, DASPfind significantly outperforms other existing methods when the single top ranked predictions are considered, resulting in 46.17 % of these predictions being correct, and it achieves 49.22 % correct single top ranked predictions when the set of all DTIs for a single drug is tested. Furthermore, we demonstrate that our method is best suited for predicting DTIs in cases of drugs with no known targets or with few known targets. We also show the practical use of DASPfind by generating novel predictions for the Ion Channel dataset and validating them manually. CONCLUSIONS: DASPfind is a computational method for finding reliable new interactions between drugs and proteins. We show over six different DTI datasets that DASPfind outperforms other state-of-the-art methods when the single top-ranked predictions are considered, or when a drug with no known targets or with few known targets is considered. We illustrate the usefulness and practicality of DASPfind by predicting novel DTIs for the Ion Channel dataset. The validated predictions suggest that DASPfind can be used as an efficient method to identify correct DTIs, thus reducing the cost of necessary experimental verifications in the process of drug discovery. DASPfind can be accessed online at: http://www.cbrc.kaust.edu.sa/daspfind.Graphical abstractThe conceptual workflow for predicting drug-target interactions using DASPfind. PMID- 26985241 TI - Clinical and laboratory data of a large series of patients with congenital generalized lipodystrophy. AB - BACKGROUND: Berardinelli-Seip congenital lipodystrophy (BSCL) was initially described by Berardinelli in Brazil in 1954 and 5 years later by Seip in Norway. It is an autosomal recessive disease that leads to a generalized deficit of body fat, evolving with diabetes and hypertriglyceridemia. The aim of this study was to describe the clinical and laboratory characteristics of a large series of patients with BSCL. METHODS: This is a cross-sectional study of patients with BSCL. A total of 54 cases of BSCL were diagnosed, treated and followed for the past 17 years. We report clinical and laboratorial data of 44 of those patients. RESULTS: There was a predominance of female patients (27 patients), and the mean age was 21.3 +/- 13.7 years old. The majority of patients (30/44; 68.2 %) were diabetic, and almost half of them (14/30 patients, 46.7 %) were on insulin. The mean body mass index was 19.6 +/- 3.3 and the mean body fat measured by dual energy X-ray absorptiometry (DEXA) was 5.4 +/- 0.8 %. Acanthosis nigricans, acromegaloid facies, atrophic cheeks, prognathism, phlebomegaly, and muscle hypertrophy were the most common clinical features. Only two patients had triglyceridemia lower than 150 mg/dl without the use of lipid-lowering drugs. Hyperinsulinemia was present in the majority of patients, and leptin values were very low in all patients. CONCLUSIONS: We report one of the largest series of patients with BSCL treated at a single medical center. Earlier identification of the mutations and a better understanding of the pathophysiology can aid to better treatment and decrease complications, potentially improving life quality and expectancy. PMID- 26985242 TI - A pilot study of scanning acoustic microscopy as a tool for measuring arterial stiffness in aortic biopsies. AB - This study explores the use of scanning acoustic microscopy (SAM) as a potential tool for characterisation of arterial stiffness using aortic biopsies. SAM data is presented for human tissue collected during aortic bypass graft surgery for multi-vessel coronary artery disease. Acoustic wave speed as determined by SAM was compared to clinical data for the patients namely, pulse wave velocity (PWV), blood pressure, cholesterol and glucose levels. There was no obvious trend relating acoustic wave speed to PWV values, and an inverse relationship was found between systolic and diastolic blood pressure and acoustic wave speed. However, in patients with a higher cholesterol or glucose level, the acoustic wave speed increased. A more detailed investigation is needed to relate SAM data to clinical measurements. PMID- 26985243 TI - Importance of Delphian Lymph Node Evaluation in Autoimmune Thyroiditis: Fact or Fiction? AB - BACKGROUND: Our main objective was to evaluate the association between autoimmune thyroiditis and the Delphian lymph node during different stages of thyroiditis. MATERIAL/METHODS: The relationships between the ultrasonography (US) results of thyroiditis and characteristics of the Delphian lymph node in different stages of AT were evaluated. Thyroid hormone and antibody levels were assessed. A total of 126 patients were divided into four groups according to the thyroid US findings: Group 1: control cases; Group 2: indeterminate cases; Group 3: established thyroiditis cases; Group 4: advanced-late stage thyroiditis cases. Indeterminate cases attended a 1-year follow-up, and the cases with a sonographic finding matching thyroiditis formed Group 2. RESULTS: The rate of Delphian lymph node presence in Group 4 was significantly higher than in Groups 1 and 2 (p<0.01). In addition, its presence was significantly higher in Group 3 than in Group 1 (p<0.05). Although there was a difference in Delphian lymph node presence between Groups 2 and 3, it was not significant (p=0.052), nor was there a significant difference between Groups 1 and 2 (p>0.05). Both the long and short axis measurements were significantly higher in Groups 2, 3, and 4 compared to those in the control group. However, the same increase was not observed in the long/short axis ratio. CONCLUSIONS: Both the presence and dimensions of the Delphian lymph node were highly correlated with the progress of autoimmune thyroiditis. Evaluating the Delphian lymph nodes might prevent missing a diagnosis of autoimmune thyroiditis. PMID- 26985244 TI - Non-Invasive and Minimally Invasive Imaging Evaluation of CSF Rhinorrhoea - a Retrospective Study with Review of Literature. AB - BACKGROUND: Localization of a cerebrospinal fluid [CSF] fistula is a diagnostic challenge. The choice of an optimal imaging technique is necessary to locate the site of CSF leak which is required for surgical/endoscopic repair of the CSF fistula. MATERIAL/METHODS: Retrospective analysis of imaging was performed in 33 patients who presented with symptoms suggestive of CSF rhinorrhoea over a period of two years. Either a bone defect on high resolution CT [HRCT] or CSF column extending extracranially from the subarachnoid space with or without brain/ meningeal herniation on magnetic resonance [MR] cisternography was considered positive for CSF leak. The MR imaging technique included 1-mm heavily T2-weighted [TR 2000 ms; TE-200 ms] fast spin echo study in coronal and sagittal planes. HRCT sections involved 0.625 to 0.8-mm sections in the coronal plane, with or without axial planes, through the paranasal sinuses, reconstructed in a sharp algorithm and acquired with the patient in prone position. Imaging findings were compared with endoscopic findings, being the gold standard for the assessment of CSF rhinorrhea. RESULTS: A total of 25 patients had a combination of HRCT and MR cisternography. The sensitivity, specificity, positive predictive value [PPV] and negative predictive value [NPV] of both MR cisternography and HRCT together were 93%, 100%, 100% and 50% respectively. Two patients underwent only MR cisternography, 5 patients underwent only HRCT and one patient underwent HRCT, MR cisternography and CT cisternography. Though PPV was 100% in the groups with HRCT alone, MR cisternography alone and combined CT cisternography, HRCT and MR cisternography, the results were not statistically significant as the number of patients in those groups was lower. CONCLUSIONS: Combination of MR cisternography and HRCT appears to be complementary, accurate and non-invasive and should be considered as optimal imaging modality for pre-op imaging in the evaluation of CSF rhinorrhoea. PMID- 26985245 TI - Infantile Type Sandhoff Disease with Striking Brain MRI Findings and a Novel Mutation. AB - BACKGROUND: Sandhoff disease is an autosomal recessive disorder caused by beta hexosaminidase deficiency in which the ganglioside GM2 and other glycolipids accumulate intracellularly within lysosomes. This process results in progressive motor neuron manifestations, death from respiratory failure and infections in infantiles. CASE REPORT: This report presents a 22-month-old girl with infantile type Sandhoff disease that was hospitalized for generalized seizures and psychomotor retardation. She was diagnosed with a genetically proven novel mutation and by demonstrating it's specific imaging findings. CONCLUSIONS: Determination of spesific changes in neuroimaging which are initial findings for GM2 gangliosidosis is important from the point of diagnosis and follow-up in infants suspected of having a neurodegenerative disease. PMID- 26985246 TI - Systemic Immunosuppression in High-Risk Penetrating Keratoplasty: A Systematic Review. AB - Cornea transplantation has a high success rate and typically only requires topical immunomodulation. However, in high-risk cases, systemic immunosuppression can be used. We conducted a systematic review on the efficacy and side effects of systemic immunosuppression for high-risk cornea transplantation. The study population was 18 years old or older with a high-risk transplant (two or more clock hours of cornea vascularization or a previous failed graft or a graft needed because of herpes simplex keratitis). A comprehensive search strategy was performed with the help of an information specialist and content experts from ophthalmology. All study designs were accepted for assessment. Level 1 and level 2 screening was performed by two reviewers followed by data abstraction. Forest plots were created whenever possible to synthesize treatment effects. Quality assessment was done with a Downs and Blacks score. From 1,150 articles, 29 were ultimately used for data abstraction. The odds ratios (ORs) for clear graft survival in cyclosporine and controls were 2.43 (95% CI: 1.00 - 5.88) and 3.64 (95% CI: 1.48 - 8.91) for rejection free episodes. Mycophenolate mofetil (MMF) significantly improved the rejection free graft survival rates at 1 year (OR: 4.05, 95% CI: 1.83 - 8.96). The overall results suggested that both systemic cyclosporine and MMF improved 1-year rejection free graft survival in high-risk keratoplasty. Cyclosporine also significantly improved clear graft survival rates at 1 year; however, there were insufficient data to analyze the same in the MMF group. Higher quality studies are needed to understand this issue better. PMID- 26985247 TI - Use of Sodium Bicarbonate in Cardiac Arrest: Current Guidelines and Literature Review. AB - The aim of the review was to summarize the literature over the last 25 years regarding bicarbonate administration in out-of-hospital cardiac arrest. A PubMed search was conducted using the terms "bicarbonates" and "cardiac arrest", limited to human studies and reviews published in English (or at least with a meaningful abstract in English) in the last 25 years. Clinical and experimental data raised questions regarding the safety and effectiveness of sodium bicarbonate (SB) administration during cardiac arrest. Earlier advanced cardiac life support (ACLS) guidelines recommended routine bicarbonate administration as part of the ACLS algorithm, but recent guidelines no longer recommend its use. The debate in the literature is ongoing, but at the present time, SB administration is only recommended for cardiac arrest related to hypokalemia or overdose of tricyclic antidepressants. Several studies challenge the assumption that bicarbonate administration is beneficial for treatment of acidosis in cardiac arrest. At the present time, there is a trend against using bicarbonates in cardiac arrest, and this trend is supported by guidelines published by professional societies and organizations. PMID- 26985250 TI - Temporal Trends of the Clinical, Resource Use and Outcome Attributes of ICU Managed Candidemia Hospitalizations: A Population-Level Analysis. AB - BACKGROUND: There are mixed findings on the longitudinal patterns of the incidence of intensive care unit (ICU)-managed candidemia, with scarcity of reports on the corresponding evolving patterns of patients' clinical characteristics and outcomes. No population-level data were reported on the temporal trends of the attributes, care and outcomes of ICU-managed adults with candidemia. METHODS: The Texas Inpatient Public Use Data File was used to identify hospitalizations aged 18 years or older with a diagnosis of candidemia and ICU admission (C-ICU hospitalizations) between 2001 and 2010. Temporal trends of the demographics, clinical features, use of healthcare resources, and short term outcomes were examined. Average annual percent changes (AAPCs) were derived. RESULTS: C-ICU hospitalizations (n = 7,552) became (AAPC) increasingly younger (age >= 65 years: -1.0%/year). The Charslon comorbidity index rose 4.2%/year, while the mean number of organ failures (OFs) increased by 8.2%/year, with a fast rise in the rate of those developing >= 3 OFs (+15.5%/year). Between 2001 and 2010, there was no significant change in utilization of mechanical ventilation and new hemodialysis among C-ICU hospitalizations with reported respiratory and renal failures (68.9% vs. 73.3%, P = 0.3653 and 15.5% vs. 21.8%, P = 0.8589, respectively). Hospital length of stay or total hospital charges remained unchanged during study period. Hospital mortality decreased between 2001 and 2010 from 39.3% to 23.8% (-5.2%/year). The majority of hospital survivors (61.6%) were discharged to another facility, and increasingly to long-term acute care hospitals, with routine home discharge decreasing to 11% by 2010. CONCLUSIONS: C ICU hospitalizations demonstrated increasing comorbidity burden and rising development of OF, and matching rise in use of selected life-support interventions, though with unchanged in-hospital fiscal impact. There has been marked decrease in hospital mortality, but survivors had substantial residual morbidity with the majority discharged increasingly to another post-acute care facility. PMID- 26985249 TI - The Changes of HIF-1alpha and VEGF Expression After TACE in Patients With Hepatocellular Carcinoma. AB - As a common malignant tumor, hepatocellular carcinoma (HCC) has a high prevalence and is a serious threat to human health. The surgical resection rate of HCC is low, and the prognosis is poor. Although transarterial chemoembolization (TACE) is the main treatment for HCC patients who are not candidates for surgical resection, it is not considered a curative procedure. For HCC, poor TACE efficacy or TACE failure may be related to tumor angiogenesis of the residual disease. Among the many regulatory factors in tumor angiogenesis, hypoxia-inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) play vital roles in this process. In this paper, we conducted a review of the dynamic change and relevance of HIF-1alpha and VEGF levels after TACE of HCC patients. PMID- 26985251 TI - Resting and Post-Exercise Ankle-Brachial Index Measurements to Diagnose Asymptomatic Peripheral Arterial Disease in Middle Aged and Elderly Chronic Obstructive Pulmonary Disease Patients: A Pilot Study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients are at risk for asymptomatic peripheral arterial disease (PAD) because smoking is a risk factor for COPD and PAD. The objectives of this study were to determine the proportion of COPD patients with asymptomatic PAD and to investigate whether the estimated risk of asymptomatic PAD in subjects with COPD differs using resting and exercise ankle-brachial index (ABI) in smokers. METHODS: Using a cross-sectional study design, consecutive smokers > 50 years old were recruited over 2 months from the inpatient units and the outpatient clinics. Subjects previously diagnosed with PAD, unstable angina, recent (< 3 months) myocardial infarction or abdominal, intracranial, eye or lung surgery, and palliative care patients were excluded. Vascular risk factors, ABI (supine and post-3-minute walk supine), self-reported PAD symptoms, and spirometry were obtained. Two measurements of systolic blood pressure on all limbs were obtained using a sphygmomanometer and a Doppler ultrasound, and the ABI was calculated. Data were expressed as means +/- standard deviation (SD). Dichotomous outcomes were assessed using Chi-square statistics; P values of < 0.05 were considered significant. RESULTS: Thirty patients with no previous diagnosis of PAD were recruited. Mean age was 67.7 years (SD: 10.5). Overall, 21 subjects (70%) had spirometry-proven COPD. Significant ABI for PAD (< 0.9) was seen in 7/21 COPD (33.5%) and 0/9 non-COPD subjects in the supine resting position (P = 0.07), and in 9/21 COPD (42.9%) vs. 0/9 non-COPD subjects after exercise (P = 0.03). CONCLUSIONS: A significant proportion of patients with spirometry-proven COPD screened positive for asymptomatic PAD after exercise. Resting ABI may not be very sensitive to diagnose asymptomatic PAD in COPD subjects. ABI may be a reliable, sensitive and practical screening tool to assess cardiovascular risk in COPD patients. Future large-scale studies are required to confirm this finding. PMID- 26985248 TI - Signaling Pathways in Thyroid Cancer and Their Therapeutic Implications. AB - Thyroid cancer is a common malignancy of endocrine system, and has now become the fastest increasing cancer among all the malignancies. The development, progression, invasion, and metastasis are closely associated with multiple signaling pathways and the functions of related molecules, such as Src, Janus kinase (JAK)-signal transducers and activators of transcription (STAT), mitogen activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt, NF-kappaB, thyroid stimulating hormone receptor (TSHR), Wnt-beta-catenin and Notch signaling pathways. Each of the signaling pathways could exert its function singly or through network with other pathways. These pathways could cooperate, promote, antagonize, or interact with each other to form a complex network for the regulation. Dysfunction of this network could increase the development, progression, invasion, and metastasis of thyroid cancer. Inoperable thyroid cancer still has a poor prognosis. However, signaling pathway-related targeted therapies offer the hope of longer quality of meaningful life for this small group of patients. Signaling pathway-related targets provide unprecedented opportunities for further research and clinical development of novel treatment strategies for this cancer. In the present work, the advances in these signaling pathways and targeted treatments of thyroid cancer were reviewed. PMID- 26985252 TI - Efficacy of Stem Cell Therapy in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Published studies seeking to improve survival in amyotrophic lateral sclerosis (ALS) have poor results in humans, although there are several studies in animal models with positive results. METHODS: We conducted a systematic review and meta-analysis of studies that were published between March 2009 and March 2015 on stem cell therapy and survival in animal models and patients with ALS. A total of 714 articles were identified, and from these, we selected preclinical in vivo studies and retrospective clinical studies. RESULTS AND CONCLUSIONS: A meta analysis confirmed the efficacy of stem cell therapy in improving survival in preclinical trials, where a mean difference of 9.79 days (95% confidence interval: 4.45 - 15.14) in lifespan favored stem cell therapy. In contrast, the number of clinical studies is still insufficient to assess their effectiveness, and these studies only demonstrate the absence of serious adverse events. However, even this conclusion should be interpreted with caution because clinical studies are retrospective and heterogeneous and have an unsatisfactory quality. PMID- 26985253 TI - The Impact of Admission Serum Creatinine Derived Estimated Glomerular Filtration Rate on Major Adverse Cardiac Events in ST-Segment Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention. AB - BACKGROUND: The impact of Cockroft-Gault (C-G) derived estimated glomerular filtration rate (eGFR) on mortality and major adverse cardiac events (MACEs) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) was assessed. METHODS: A total of 884 patients were classified into four categories according to admission creatine derived eGFR: < 60, 60 - < 90, 90 - < 120, and >= 120 mL/min/1.73 m(2). RESULTS: In-hospital and long-term MACEs were significantly higher in eGFR < 60 mL/min/1.73 m(2) subgroup (P < 0.001 and P = 0.028). Multivariate analysis demonstrated 7.78-fold (95% CI: 0.91 - 66.8) higher mortality risk in eGFR < 60 mL/min/1.73 m(2) subgroup. CONCLUSION: As an easily applicable bedside method, C G derived eGFR could be important for prediction of in-hospital and long-term mortality and MACE in STEMI patients undergoing primary PCI. PMID- 26985254 TI - Single Fetal Demise at 10 - 14 Weeks of Monochorionic and Dichorionic Twin Pregnancy. AB - BACKGROUND: We examined the perinatal outcomes in cases of at least one fetal demise in monochorionic and diamniotic twin pregnancies. METHODS: We reviewed the obstetric records of all Japanese twin pregnancies managed beyond 9 weeks' gestation at Japanese Red Cross Katsushika Maternity Hospital between 2008 and 2014. RESULTS: The incidence in the monochorionic twin pregnancies was significantly higher than that in the dichorionic twin pregnancies (8.3% vs. 2.6%, odds ratio: 3.40, 95% confidence interval: 1.5 - 7.6, P < 0.01). Of these, 60.0% were diagnosed as fetal demise of both fetuses at the same time (vs. dichorionic twin pregnancy: odds ratio: 12.0, 95% confidence interval: 1.3 - 120, P = 0.04). The rate of "vanishing twin" in cases of at least one fetal demise at 10 - 14 weeks' gestation in the monochorionic twin pregnancies was significantly lower than that in the diamniotic twin pregnancies (30.0% vs. 88.9%, odds ratio: 0.05, 95% confidence interval: 0.01 - 0.53, P = 0.01). CONCLUSION: The incidence of fetal demise and the influence on the co-twin in monochorionic twin pregnancy is greater than those in dichorionic twin pregnancy. PMID- 26985255 TI - Long-Term Efficacy of Adalimumab in Patients With Intestinal Behcet's Disease: Eight Consecutive Cases. AB - The long-term efficacy and safety of adalimumab (ADA) for the treatment of intestinal Behcet's disease (BD) in the clinical setting have not been evaluated previously. This retrospective study evaluated the 52-week efficacy of ADA in BD patients. A total of eight patients who were refractory to conventional therapy were given ADA (160/80/40 mg every other week). Marked improvement (MI) was achieved by 10 weeks in five patients (62.5%), and by 52 weeks in six patients (75%). In addition, complete remission was obtained in two patients (25%) at both 10 and 52 weeks. Improvement of global gastrointestinal (GI) symptoms to score 0 was observed in three patients (37.5%) at 10 weeks and four patients (50%) at 52 weeks. Moreover, improvement of endoscopic assessment to score 0 was also seen in four patients (50%) at both 10 and 52 weeks. No adverse events were observed in any patients during the 52 weeks. In conclusion, ADA offers an effective, well tolerated treatment for intestinal BD in patients who are refractory to conventional therapy. PMID- 26985256 TI - Postoperative Massive Pulmonary Embolism Due to Superficial Vein Thrombosis of the Upper Limb. AB - It is well known that deep vein thrombosis of the upper extremities is linked to high morbidity/mortality, resulting in 12-20% of all documented pulmonary embolism; however, there are few data about thromboembolism originating from a vein and/or a branch of a superficial vein of the upper extremities. Pulmonary embolism secondary to upper limb superficial vein thrombosis (not combined with upper extremities deep vein thrombosis) is a very rare clinical manifestation with few cases reported in the literature. We report a rare case of thrombophlebitis in departure from a superficial branch of the cephalic vein of the right arm, complicated by cardiac arrest secondary to a massive pulmonary embolism in a patient who underwent major surgery for ovarian cancer. We discuss on the numerous thrombotic risk factors, triggering a cascade of reactions and resulting in a potential fatal clinical manifestation. PMID- 26985257 TI - Cavernous Sinus Dural Arteriovenous Fistula Patients Presenting With Headache as an Initial Symptom. AB - Cavernous sinus (CS) dural arteriovenous fistula (dAVF) patients presenting with only headache as an initial symptom are not common. Patients with CS-dAVF commonly present with symptoms related to their eyes. In all three patients, headache was the initial symptom. Other symptoms related to the eyes developed 1 7 months after headache. In one patient, headache was controlled by sumatriptan succinate, but not diclofenac sodium or loxoprofen sodium. In another patient, headache was controlled by loxoprofen sodium. In the third patient, headache was improved by stellate ganglion block. In all patients, magnetic resonance angiography (MRA) in the early stage of the clinical course showed abnormal blood flow in the CS. However, reflux to the superior ophthalmic vein (SOV) was not detected. As treatment, transarterial and transvenous embolizations were necessary for one patient, and transvenous embolization was performed for another patient with significant blood flow to the SOV and cortical veins. On the other hand, manual compression of the bilateral carotid arteries at the neck resulted in disappearance of the fistula in the third patient. In all patients, the symptoms improved after the disappearance of blood reflux to the CS. The refluxed blood to the CS might cause elevation of the CS pressure and stimulate the trigeminal nerve in the dural membrane, resulting in headache before developing reflux in an anterior direction. CS-dAVF could induce both migraine and common headache. In cases with blood reflux to the CS on magnetic resonance imaging and/or MRA even without eye symptoms, a differential diagnosis of CS-dAVF should be taken into consideration. PMID- 26985258 TI - Focal Epithelial Hyperplasia (Heck's Disease) in a 57-Year-Old Brazilian Patient: A Case Report and Literature Review. AB - Focal epithelial hyperplasia (FEH), or Heck's disease, is a rare disease of the oral mucosa associated with infection by some subtypes of human papilloma virus, especially subtypes 13 or 32. The disease is predominantly found in children and adolescents with indigenous heritage, but other ethnic groups can be affected worldwide. To the best of the authors' knowledge, it has not been reported in Brazil's elderly population. This article describes a case of FEH in a 57-year old Brazilian patient presenting since childhood, with multiple lesions in the lips, buccal mucosa and tongue. The solitary tongue lesion underwent excisional biopsy and the histopathological analysis showed parakeratosis, acanthosis, rete pegs with a club-shaped appearance, koilocytosis and the presence of mitosoid cells. These microscopic findings in conjunction with clinical presentation were sufficient to establish the accurate diagnosis of FEH. Polymerase chain reaction (PCR) was performed, but no one human papillomavirus (HPV) subtype could be identified. Clinicians must be aware of this rare oral disease, which can even affect elderly patients, as we described here. Treatment may be indicated in selected cases due to esthetic and/or functional problems. PMID- 26985259 TI - Percutaneous Mitral Valvotomy in a Case of Situs Inversus Totalis and Juvenile Rheumatic Critical Mitral Stenosis: Case Report. AB - Situs inversus totalis is a rare congenital disorder where the heart being a mirror image is situated on the right side of the body. Distorted cardiac anatomy makes fluoroscopy-guided percutaneous mitral valvotomy (PMV) technically challenging and there are only few reports of PMV in situs inversus totalis. Here we report a case where PMV was successfully done for situs inversus totalis with rare coincidence of juvenile rheumatic severe mitral stenosis in a 12-year-old boy with a few modifications of standard Inoue technique. He had exertional dyspnea of NYHA class III with initial mitral valve area (MVA) of 0.6 cm(2) and severe pulmonary arterial hypertension with features suitable for PMV. Femoral vein was accessed from the left side to align the septal puncture needle and balloon to facilitate left ventricular entry. Septal descent and puncture by Brockenbrough needle was performed in the right anterior oblique view with the needle facing 5 o'clock position. Accura balloon was negotiated across mitral valve in left anterior oblique and procedure was successfully executed. Echocardiography showed a well-divided anterior commissure with an MVA of 2.0 cm(2) and mild mitral regurgitation. In summary, PMV is safe and feasible in the rare patient with situs inversus totalis with few modifications of the Inoue technique. PMID- 26985261 TI - [Traumatic rupture of the quadriceps tendon: a report of 3 cases]. PMID- 26985262 TI - [Tethered cord syndrome]. PMID- 26985260 TI - [Nasosinusal malignant tumors: about 32 cases and literature reviews]. PMID- 26985263 TI - [Cerebral Langerhans cell histiocytosis]. PMID- 26985264 TI - [Rectal duplication in adults: a rare cause of pelvic mass]. PMID- 26985265 TI - [Cushing syndrome in adolescents: report of 18 patients]. PMID- 26985266 TI - [Peculiarity of infantile cystinosis in Tunisian children]. PMID- 26985267 TI - [Acute compartment syndrome secondary to an intravenous injection of heroin in a drug abuser: report of a case]. PMID- 26985268 TI - [Evaluation of the quality of the management of dyspnea by GPs in Parakou in 2013]. PMID- 26985269 TI - Improving community based AEFI (Adverse Events Following Immunization) reporting rate through telephone "beep" in a Cameroon health district: a randomized field trial. AB - INTRODUCTION: AEFIs underreporting is one of different barriers to achieving objectives of pharmaco vigilance of vaccine worldwide. Studies describe it as being related to limited awareness of health personnel and of vaccinees or of their parents. The objective was to assess the effect of telephone "beep" on community based reporting rates of AEFIs during routine immunization sessions in a Cameroon Health District. METHODS: It was a randomized control trial implemented during routine EPI in Biyem-Assi health district (Cameroon). Parents of vaccinated children were randomly assigned: i) to receive the telephone contact of the investigation team and was advised to ''beep''(short phone call not picked up) the investigators team in the case any medical incidence occurs within the 30 days following the immunization (intervention group) or; ii) to return to the health facility in case any medical incidence occurs within the same period (control group). The main outcome was AEFI incidence rate. RESULTS: 236 parents were assigned to the intervention group and 235 to the control group. Of 1192 doses of EPI vaccines administered, 20 AEFIs (392 AEFIs/100000 doses/week) were reported within 30 days after vaccine administration. These included 19 (829 AEFIs/100000 doses/week) AEFIs in the intervention group and 1 (43 AEFIs/100000 doses/week) AEFI in the control group. The AEFIs reporting rate in the intervention group was significantly higher than that in the control group [RR = 18.9; CI95 (2.5; 140.0) (P=0.0004)]. CONCLUSION: The use of telephone "beep" significantly increases at affordable cost community based AEFI reporting rate in routine EPI. PMID- 26985270 TI - Urethral cavernous hemangioma in a female patient: a rare entity. AB - Genitourinary hemangiomas are rare entities of the urinary system. We reported a female patient who suffered dyspareunia and intermitant hematuria that was proved as urethral cavernous hemangioma. Despite its benign nature, hemangiomas may recur due to incomplet excision. PMID- 26985271 TI - [Posterior dislocation of the shoulder in an athlete treated with pedicle transfer of the subscapularis]. PMID- 26985272 TI - Perceptions about medical male circumcision and sexual behaviours of adults in rural Uganda: a cross sectional study. AB - INTRODUCTION: Medical male circumcision is currently recognized as an additional important HIV preventive intervention to reduce the risk of heterosexually acquired HIV infection in men. However, sexual behaviours after medical circumcision can potentially reduce the expected benefits of the practice. This study explored the perceptions about medical male circumcision and sexual behaviours of adults in Kayunga district, Uganda. METHODS: A cross-sectional study was carried out among 393 respondents using a semi structured questionnaire. In addition, four focus group discussions were conducted. Quantitative data was analysed using STATA 12. Univariate, bivariate and multivariate analyses were carried out. Qualitative data was analysed thematically. RESULTS: The study established various perceptions about medical male circumcision and sexual behaviours. Majority 247 (64.5%) did not perceive circumcision as a practice that can lead men to have multiple sexual partners. Males were 3 times more likely to think that circumcision would lead to having multiple sexual partners than females (AOR=2.99, CI: 1.93-4.61). Only 89 (23.2%) believed that circumcision would lead to complacency and compromise the use of condoms to prevent against infection with HIV. Respondents who had education above primary were less likely to think that circumcision would compromise the use of condoms (AOR=0.49, CI: 0.31- 0.79). The perception that circumcised youths were less likely to abstain from sexual intercourse was less held among those with education above primary (AOR=0.58, CI: 0.37-0.91) and those older than 30 years (AOR=0.59, CI: 0.38-0.92). CONCLUSION: There were gaps in knowledge and negative perceptions about MMC in the study community. Measures are needed to avert the negative perceptions by equipping communities with sufficient, accurate and consistent information about medical male circumcision and sexual behaviour. PMID- 26985274 TI - [Tearing of the anterior superior and lower anterior iliac spines in teenage athletes: report of two cases]. PMID- 26985273 TI - [Hydatid cyst of the liver complicated with ischemic stroke: report of a case]. PMID- 26985275 TI - Nontyphoidal Salmonella septic arthritis of the elbow in a healthy infant. AB - A case of rarely encountered nontyphoidal Salmonella septic arthritis of the elbow in an infant with no preexisting disease is reported. Salmonella etiology was not suspected in this case, and the diagnosis was made only after bacterial isolation. Aspiration of the infected joint with radiological guidance initially failed to give a good clinical response. Arthrotomy was done with intravenous cefotaxime for 4 weeks followed by 2 weeks oral ciprofloxacin therapy to which the child responded favorably. Up to our knowledge this is the first case of nontyphoidal salmonella elbow septic arthritis in an infant in Saudi Arabia to be reported in the English literature. PMID- 26985276 TI - [Endocrine osteoporosis: report of a series of cases]. PMID- 26985278 TI - [Large osteochondroma of the scapula: report of a case]. PMID- 26985277 TI - [Leprosy ulnar claw treated by Lasso Zancolli tendon transfer: report of a case]. PMID- 26985280 TI - [Fragmented appendix, diagnostic and therapeutic problems: about 26 cases]. PMID- 26985279 TI - [Pseudopapillary and solid tumor of the pancreas: a rare cause of abdominal mass]. PMID- 26985283 TI - Epigenetic Medicinal Chemistry. AB - The past decade has seen tremendous growth in our understanding of epigenetics and chromatin remodeling. Small, organic molecule modulators of a number of chromatin modifying proteins (CMPs) have been reported over this time frame and several of these have advanced to human clinical trials. In this Viewpoint, I summarize the current state of medicinal chemistry efforts focused on epigenetic targets and attempt to provide some insight into future directions on which the community may wish to focus. PMID- 26985281 TI - Giant cell reparative granuloma of the hallux following enchondroma. AB - Giant cell reparative granuloma (GCRG) is a rare, benign intra osseous lytic lesion occurring especially in gnathis bone but also seen in feet and hands. It has similar clinical and radiological presentations than giant cell tumor, chondroblastoma, aneurysmal bone cyst, and hyperparathyroidism brown tumors but with specific histological findings We report a case of a GCRG of hallux phalanx in 18 years old patient appearing many years after enchondroma curettage and grafting. Radiographs showed a multiloculated osteolytic lesions involving whole phalanx with cortical thinning and without fluid-fluid levels in CT view. Expected to be an enchondroma recurrence, second biopsy confirmed diagnosis of GCRG with specific histological findings. Although if aetiopathogeny remains unknown, GCRG is reported to be a local non neoplasic reaction to an intraosseous hemorrhage. Our exceptional case claims that this tumor can appear in reaction to cellular disturbance primary or secondary. PMID- 26985284 TI - Inhibition of Histone Demethylases Offers a Novel and Promising Approach for the Treatment of Cancer and Other Diseases. PMID- 26985285 TI - Dihydropteridinone Inhibitors of BRD4. PMID- 26985282 TI - Hierarchically-coupled hidden Markov models for learning kinetic rates from single-molecule data. AB - We address the problem of analyzing sets of noisy time-varying signals that all report on the same process but confound straightforward analyses due to complex inter-signal heterogeneities and measurement artifacts. In particular we consider single-molecule experiments which indirectly measure the distinct steps in a biomolecular process via observations of noisy time-dependent signals such as a fluorescence intensity or bead position. Straightforward hidden Markov model (HMM) analyses attempt to characterize such processes in terms of a set of conformational states, the transitions that can occur between these states, and the associated rates at which those transitions occur; but require ad-hoc post processing steps to combine multiple signals. Here we develop a hierarchically coupled HMM that allows experimentalists to deal with inter-signal variability in a principled and automatic way. Our approach is a generalized expectation maximization hyperparameter point estimation procedure with variational Bayes at the level of individual time series that learns an single interpretable representation of the overall data generating process. PMID- 26985286 TI - Aminotriazole and Aminotetrazole Inhibitors of LSD1 as Epigenetic Modulators. PMID- 26985287 TI - Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor. AB - SMYD3 has been implicated in a range of cancers; however, until now no potent selective small molecule inhibitors have been available for target validation studies. A novel oxindole series of SMYD3 inhibitors was identified through screening of the Epizyme proprietary histone methyltransferase-biased library. Potency optimization afforded two tool compounds, sulfonamide EPZ031686 and sulfamide EPZ030456, with cellular potency at a level sufficient to probe the in vitro biology of SMYD3 inhibition. EPZ031686 shows good bioavailability following oral dosing in mice making it a suitable tool for potential in vivo target validation studies. PMID- 26985288 TI - Selective Inhibition of CBX6: A Methyllysine Reader Protein in the Polycomb Family. AB - The polycomb paralogs CBX2, CBX4, CBX6, CBX7, and CBX8 are epigenetic readers that rely on "aromatic cage" motifs to engage their partners' methyllysine side chains. Each CBX carries out distinct functions, yet each includes a highly similar methyllysine-reading chromodomain as a key element. CBX7 is the only chromodomain that has yet been targeted by chemical inhibition. We report a small set of peptidomimetic agents in which a simple chemical modification switches the ligands from one with promiscuity across all polycomb paralogs to one that provides selective inhibition of CBX6. The structural basis for this selectivity, which involves occupancy of a small hydrophobic pocket adjacent to the aromatic cage, was confirmed through molecular dynamics simulations. Our results demonstrate the increases in affinity and selectivity generated by ligands that engage extended regions of chromodomain binding surfaces. PMID- 26985289 TI - Discovery of Benzotriazolo[4,3-d][1,4]diazepines as Orally Active Inhibitors of BET Bromodomains. AB - Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of therapeutic relevance to cancer and inflammatory disease, respectively. Herein we report substituted benzo[b]isoxazolo[4,5-d]azepines and benzotriazolo[4,3 d][1,4]diazepines as fragment-derived novel inhibitors of the bromodomain of BRD4. Compounds from these series were potent and selective in cells, and subsequent optimization of microsomal stability yielded representatives that demonstrated dose- and time-dependent reduction of plasma IL-6 in mice. PMID- 26985290 TI - Characterizing the Covalent Targets of a Small Molecule Inhibitor of the Lysine Acetyltransferase P300. AB - C646 inhibits the lysine acetyltransferases (KATs) p300 and CBP and represents the most potent and selective small molecule KAT inhibitor identified to date. To gain insights into the cellular activity of this epigenetic probe, we applied chemoproteomics to identify covalent targets of the C646 chemotype. Modeling and synthetic derivatization was used to develop a clickable analogue (C646-yne) that inhibits p300 similarly to the parent compound and enables enrichment of bound proteins. LC-MS/MS identified the major covalent targets of C646-yne as highly abundant cysteine-containing proteins, and follow-up studies found that C646 can inhibit tubulin polymerization in vitro. Finally, we provide evidence that thiol reactivity of C646 may limit its ability to antagonize acetylation in cells. These findings should enable a more precise interpretation of studies utilizing C646 as a chemical probe of KAT activity and suggest that an underappreciated liability of electrophile-containing inhibitors is a reduction in their cellular potency due to consumption by abundant protein and metabolite thiol sinks. PMID- 26985291 TI - Beyond PAINs: Chemotype Sensitivity of Protein Methyltransferases in Screens. AB - Screening of the relatively new target class, the lysine and arginine methyltransferases (MTases), presents unique challenges in the identification and confirmation of active chemical matter. Examination of high throughput screening data generated using Scintillation Proximity Assay (SPA) format for a number of protein MTase targets reveals sensitivity to both the known pan assay interference compounds (PAINS) and also other scaffolds not currently precedented as assay interferers. We find that, in general, true actives show significant selectivity within the MTase family. With the exception of slight modifications of SAM-like compounds, scaffolds that are observed frequently in multiple MTase assays should be viewed with caution and should be carefully validated before following up. PMID- 26985292 TI - Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666. AB - The recent publication of a potent and selective inhibitor of protein methyltransferase 5 (PRMT5) provides the scientific community with in vivo-active tool compound EPZ015666 (GSK3235025) to probe the underlying pharmacology of this key enzyme. Herein, we report the design and optimization strategies employed on an initial hit compound with poor in vitro clearance to yield in vivo tool compound EPZ015666 and an additional potent in vitro tool molecule EPZ015866 (GSK3203591). PMID- 26985293 TI - Design, Synthesis, and Immunological Evaluation of Benzyloxyalkyl-Substituted 1,2,3-Triazolyl alpha-GalCer Analogues. AB - Replacement of the amide moiety in the structure of alpha-GalCer with a 1,2,3 triazole linker is known to elicit a response skewed toward Th2 immunity, and glycolipids containing an aromatic ring in the terminus of their acyl or phytosphingosine structural component exhibit an enhanced Th1 immune response. In the current study, synthesis and immunological screening of a focused library of benzyloxyalkyl-substituted 1,2,3-triazolyl alpha-GalCer analogues are reported. The novel alpha-GalCer analogues activate invariant natural killer T (iNKT) cells via CD1d mediated presentation, which was confirmed by in vitro tests performed on iNKT hybridomas incubated with CD1d proteins. When tested on isolated murine splenocytes, the T1204B and T1206B compounds stimulated higher levels of both IFN gamma and IL-4 cytokine expression in vitro compared to that of alpha-GalCer. PMID- 26985294 TI - Design and Synthesis of Nonpeptide Inhibitors of Hepatocyte Growth Factor Activation. AB - In this letter we report first nonpeptide inhibitors of hepatocyte growth factor (HGF) activation. These compounds inhibit the three proteases (matriptase, hepsin, and HGF activator) required for HGF maturation. We show that 6, 8a, 8b, and 8d block activation of fibroblast-derived pro-HGF, thus preventing fibroblast induced scattering of DU145 prostate cancer cells. Compound 6 (SRI 31215) is very soluble (91 MUM) and has excellent microsome stability (human t 1/2 = 162 min; mouse t 1/2 = 296 min). In mouse 6 has an in vivo t 1/2 = 5.8 h following IV administration. The high solubility of 6 and IV t 1/2 make this compound a suitable prototype "triplex inhibitor" for the study of the inhibition of HGF activation in vivo. PMID- 26985295 TI - Allosteric Indole Amide Inhibitors of p97: Identification of a Novel Probe of the Ubiquitin Pathway. AB - A high-throughput screen to discover inhibitors of p97 ATPase activity identified an indole amide that bound to an allosteric site of the protein. Medicinal chemistry optimization led to improvements in potency and solubility. Indole amide 3 represents a novel uncompetitive inhibitor with excellent physical and pharmaceutical properties that can be used as a starting point for drug discovery efforts. PMID- 26985297 TI - Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists. AB - 2-Aminooxazolines were discovered as a novel structural class of TAAR1 ligands. Starting from a known adrenergic compound 1, structural modifications were made to obtain highly potent and selective TAAR1 ligands such as 12 (RO5166017), 18 (RO5256390), 36 (RO5203648), and 48 (RO5263397). These compounds exhibit drug like physicochemical properties, have good oral bioavailability, and display in vivo activity in a variety of animal models relevant for psychiatric diseases and addiction. PMID- 26985296 TI - New Colchicine-Derived Triazoles and Their Influence on Cytotoxicity and Microtubule Morphology. AB - A series of new colchicinoids with a variable triazole unit at C-7 was synthesized through Cu(I)-catalyzed 1,3-dipolar cycloaddition (click-chemistry) of a colchicine-derived azide with various alkynes and the cytotoxicity against THP-1 and Jurkat cancer cell lines was used for structural optimization. Three particularly active compounds (IC50 <= 5 nM) were additionally investigated with respect to their efficacy against relevant solid tumor cell lines (HeLa, A549, and SK MES 1). Besides distorting the microtubule morphology by tubulin depolymerization, one compound also exhibited a pronounced centrosome declustering effect in triple negative breast cancer cells (MDA-MB-231) and nonsmall cell lung cancer cells (H1975). PMID- 26985299 TI - Novel Therapeutics Targeting Epigenetics: New Molecules, New Methods. PMID- 26985298 TI - Discovery of 8-Amino-imidazo[1,5-a]pyrazines as Reversible BTK Inhibitors for the Treatment of Rheumatoid Arthritis. AB - Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition and for the treatment of B cell related diseases. We report a series of compounds based on 8-amino-imidazo[1,5-a]pyrazine that are potent reversible BTK inhibitors with excellent kinase selectivity. Selectivity is achieved through specific interactions of the ligand with the kinase hinge and driven by aminopyridine hydrogen bondings with Ser538 and Asp539, and by hydrophobic interaction of trifluoropyridine in the back pocket. These interactions are evident in the X-ray crystal structure of the lead compounds 1 and 3 in the complex with the BTK enzyme. Our lead compounds show desirable PK profiles and efficacy in the preclinical rat collagen induced arthritis model. PMID- 26985300 TI - Cathepsin B Inhibitors: Combining Dipeptide Nitriles with an Occluding Loop Recognition Element by Click Chemistry. AB - An active site mapping of human cathepsin B with dipeptide nitrile inhibitors was performed for a combinatorial approach by introducing several points of diversity and stepwise optimizing the inhibitor structure. To address the occluding loop of cathepsin B by a carboxylate moiety, click chemistry to generate linker-connected molecules was applied. Inhibitor 17 exhibited K i values of 41.3 nM, 27.3 nM, or 19.2 nM, depending on the substrate and pH of the assay. Kinetic data were discussed with respect to the conformational selection and induced fit models. PMID- 26985302 TI - MALT1 Inhibitors May Potentially Treat Lymphomas and Autoimmune Disorders. PMID- 26985301 TI - Discovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors. AB - A novel series of potent and selective hexokinase 2 (HK2) inhibitors, 2,6 disubstituted glucosamines, has been identified based on HTS hits, exemplified by compound 1. Inhibitor-bound crystal structures revealed that the HK2 enzyme could adopt an "induced-fit" conformation. The SAR study led to the identification of potent HK2 inhibitors, such as compound 34 with greater than 100-fold selectivity over HK1. Compound 25 inhibits in situ glycolysis in a UM-UC-3 bladder tumor cell line via (13)CNMR measurement of [3-(13)C]lactate produced from [1,6 (13)C2]glucose added to the cell culture. PMID- 26985303 TI - Glutaminase GLS1 Inhibitors as Potential Cancer Treatment. PMID- 26985304 TI - Potential Use of Inhibitors of Tankyrases and PARP-1 as Treatment for Cancer and Other Diseases. PMID- 26985305 TI - Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells. AB - Beginning with promiscuous COT inhibitors, which were found to inhibit CDK8, a series of 6-aza-benzothiophene containing compounds were developed into potent, selective CDK8 inhibitors. When cocrystallized with CDK8 and cyclin C, these compounds exhibit an unusual binding mode, making a single hydrogen bond to the hinge residue A100, a second to K252, and a key cation-pi interaction with R356. Structure-based drug design resulted in tool compounds 13 and 32, which are highly potent, kinase selective, permeable compounds with a free fraction >2% and no measurable efflux. Despite these attractive properties, these compounds exhibit weak antiproliferative activity in the HCT-116 colon cancer cell line. Further examination of the activity of 32 in this cell line revealed that the compound reduced phosphorylation of the known CDK8 substrate STAT1 in a manner identical to a CDK8 knockout clone, illustrating the complex effects of inhibition of CDK8 kinase activity in proliferation in these cells. PMID- 26985306 TI - Structure-Activity Relationship Studies and Molecular Modeling of Naphthalene Based Sphingosine Kinase 2 Inhibitors. AB - The two isoforms of sphingosine kinase (SphK1 and SphK2) are the only enzymes that phosphorylate sphingosine to sphingosine-1-phosphate (S1P), which is a pleiotropic lipid mediator involved in a broad range of cellular processes including migration, proliferation, and inflammation. SphKs are targets for various diseases such as cancer, fibrosis, and Alzheimer's and sickle cell disease. Herein, we disclose the structure-activity profile of naphthalene containing SphK inhibitors and molecular modeling studies that reveal a key molecular switch that controls SphK selectivity. PMID- 26985307 TI - 2-(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible and Drug Resistant Mycobacterium tuberculosis Strains. AB - 2-(Quinolin-4-yloxy)acetamides have been described as potent in vitro inhibitors of Mycobacterium tuberculosis growth. Herein, additional chemical modifications of lead compounds were carried out, yielding highly potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.05 MUM. Further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to Vero and HaCat cells (IC50s >= 20 MUM). In addition, the 2-(quinolin-4-yloxy)acetamides showed intracellular activity against the bacilli in infected macrophages with action similar to rifampin, low risk of drug-drug interactions, and no sign of cardiac toxicity in zebrafish (Danio rerio) at 1 and 5 MUM. Therefore, these data indicate that this class of compounds may furnish candidates for future development to, hopefully, provide drug alternatives for tuberculosis treatment. PMID- 26985309 TI - Astemizole Derivatives as Fluorescent Probes for hERG Potassium Channel Imaging. AB - The detection and imaging of hERG potassium channels in living cells can provide useful information for hERG-correlation studies. Herein, three small-molecule fluorescent probes, based on the potent hERG channel inhibitor astemizole, for the imaging of hERG channels in hERG-transfected HEK293 cells (hERG-HEK293) and human colorectal cancer cells (HT-29), are described. These probes are expected to be applied in the physiological and pathological studies of hERG channels. PMID- 26985308 TI - Aloperine and Its Derivatives as a New Class of HIV-1 Entry Inhibitors. AB - A quinolizidine-type alkaloid aloperine was found to inhibit HIV-1 infection by blocking HIV-1 entry. Aloperine inhibited HIV-1 envelope-mediated cell-cell fusion at low micromolar concentrations. To further improve the antiviral potency, more than 30 aloperine derivatives with a variety of N12-substitutions were synthesized. Among them, 12d with an N-(1-butyl)-4-trifluoromethoxy benzamide side chain showed the most potent anti-HIV-1 activity with EC50 at 0.69 MUM. Aloperine derivatives inhibited both X4 and R5 HIV-1 Env-mediated cell-cell fusions. In addition, both BMS-806, a compound representing a class of HIV-1 gp120-targeting small molecules in clinical trials, and resistant and sensitive HIV-1 Env-mediated cell-cell fusions were equally sensitive to aloperine derivatives. These results suggest that aloperine and its derivatives are a new class of anti-HIV-1 entry inhibitors. PMID- 26985311 TI - Kinetic ESI-MS Studies of Potent Anti-HIV Aptamers Based on the G-Quadruplex Forming Sequence d(TGGGAG). AB - To investigate what properties make tetramolecular G-quadruplex ODNs good anti HIV aptamers, we studied the stoichiometry and the self-assembly kinetics of the highly active 5'-end modified G-quadruplexes based on the d(TGGGAG) sequence. Our results demonstrate that the 5'-end conjugation does not necessarily increase the folding rate of the G-quadruplex; indeed, it ascribes anti-HIV activity. Unexpectedly, the G4-folding kinetics of the inactive G4 is similar to that of the 5'-end modified sequences. ESI-MS studies also revealed the formation of higher order G4 structures identified as octameric complexes along with tetramolecular G-quadruplexes. PMID- 26985310 TI - Synthesis and Evaluation of Macrocyclic Peptide Aldehydes as Potent and Selective Inhibitors of the 20S Proteasome. AB - This research explores the first design and synthesis of macrocyclic peptide aldehydes as potent inhibitors of the 20S proteasome. Two novel macrocyclic peptide aldehydes based on the ring-size of the macrocyclic natural product TMC 95 were prepared and evaluated as inhibitors of the 20S proteasome. Both compounds inhibited in the low nanomolar range and proved to be selective for the proteasome over other serine and cysteine proteases, particularly when compared to linear analogues with similar amino acid sequences. In HeLa cells, both macrocycles efficiently inhibited activation of nuclear factor-kappaB (NF-kappaB) transcription factor by blocking proteasomal degradation of the inhibitor protein IkappaBalpha after cytokine stimulation. Due to their covalent mechanism of binding these compounds represent a 1000-fold increase in inhibitory potency over previously reported noncovalently binding TMC-95 analogues. Molecular modeling of the macrocyclic peptides confirms the preference of the large S3 pocket for large, hydrophobic residues and the ability to exploit this to improve selectivity of proteasome inhibitors. PMID- 26985312 TI - Discovery of Novel Indoline Cholesterol Ester Transfer Protein Inhibitors (CETP) through a Structure-Guided Approach. AB - Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharmacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from (1)H NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK-PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay. PMID- 26985313 TI - Design, Syntheses, and Anti-TB Activity of 1,3-Benzothiazinone Azide and Click Chemistry Products Inspired by BTZ043. AB - Electron deficient nitroaromatic compounds such as BTZ043 and its closest congener, PBTZ169, and related agents are a promising new class of anti-TB compounds. Herein we report the design and syntheses of 1,3-benzothiazinone azide (BTZ-N3) and related click chemistry products based on the molecular mode of activation of BTZ043. Our computational docking studies indicate that BTZ-N3 binds in the essentially same pocket as that of BTZ043. Detailed biochemical studies with cell envelope enzyme fractions of Mycobacterium smegmatis combined with our model biochemical reactivity studies with nucleophiles indicated that, in contrast to BTZ043, the azide analogue may have a different mode of activation for anti-TB activity. Subsequent enzymatic studies with recombinant DprE1 from Mtb followed by MIC determination in NTB1 strain of Mtb (harboring Cys387Ser mutation in DprE1 and is BTZ043 resistant) unequivocally indicated that BTZ-N3 is an effective reversible and noncovalent inhibitor of DprE1. PMID- 26985315 TI - Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of NaV1.7 with Efficacy in Rodent Pain Models. AB - We report on a novel series of aryl sulfonamides that act as nanomolar potent, isoform-selective inhibitors of the human sodium channel hNaV1.7. The optimization of these inhibitors is described. We aimed to improve potency against hNaV1.7 while minimizing off-target safety concerns and generated compound 3. This agent displayed significant analgesic effects in rodent models of acute and inflammatory pain and demonstrated that binding to the voltage sensor domain 4 site of NaV1.7 leads to an analgesic effect in vivo. Our findings corroborate the importance of hNaV1.7 as a drug target for the treatment of pain. PMID- 26985314 TI - Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Abeta Reduction in Rodents. AB - By targeting the flap backbone of the BACE1 active site, we discovered 6 dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain Abeta reduction in rat dose-response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer's disease. PMID- 26985316 TI - Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P1 Receptor Modulator in Clinical Trials. AB - Clinical validation of S1P receptor modulation therapy was achieved with the approval of fingolimod (Gilenya, 1) as the first oral therapy for relapsing remitting multiple sclerosis. However, 1 causes a dose-dependent reduction in the heart rate (bradycardia), which occurs within hours after first dose. We disclose the identification of clinical compound BMS-986104 (3d), a novel S1P1 receptor modulator, which demonstrates ligand-biased signaling and differentiates from 1 in terms of cardiovascular and pulmonary safety based on preclinical pharmacology while showing equivalent efficacy in a T-cell transfer colitis model. PMID- 26985317 TI - Discovery and Preclinical Evaluation of BMS-955829, a Potent Positive Allosteric Modulator of mGluR5. AB - Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are of interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe the discovery and optimization of a novel oxazolidinone-based chemotype to identify BMS-955829 (4), a compound with high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. The low fold shift and absence of agonist activity proved critical in the identification of a molecule with an acceptable preclinical safety profile. Despite its low fold shift, 4 retained efficacy in set shifting and novel object recognition models in rodents. PMID- 26985318 TI - Identification of a Small Molecule Cyclophilin D Inhibitor for Rescuing Abeta Mediated Mitochondrial Dysfunction. AB - Cyclophilin D (CypD), a peptidylprolyl isomerase F (PPIase), plays a central role in opening the mitochondrial membrane permeability transition pore leading to cell death. CypD resides in the mitochondrial matrix, associates with the inner mitochondrial membrane, interacts with amyloid beta to exacerbate mitochondrial and neuronal stress and has been linked to Alzheimer's disease (AD). We report the biological activity of a small-molecule CypD inhibitor (C-9), which binds strongly to CypD and attenuates mitochondrial and cellular perturbation insulted by Abeta and calcium stress. Binding affinities for C-9 were determined using in vitro surface plasmon resonance. This compound antagonized calcium-mediated mitochondrial swelling, abolished Abeta-induced mitochondrial dysfunction as shown by increased cytochrome c oxidase activity and adenosine-5'-triphosphate levels, and inhibited CypD PPIase enzymatic activity by real-time fluorescence capture assay using Hamamatsu FDSS 7000. Compound C-9 seems a good candidate for further investigation as an AD drug. PMID- 26985319 TI - Potent and Selective CK2 Kinase Inhibitors with Effects on Wnt Pathway Signaling in Vivo. AB - The Wnt pathway is an evolutionarily conserved and tightly regulated signaling network with important roles in embryonic development and adult tissue regeneration. Impaired Wnt pathway regulation, arising from mutations in Wnt signaling components, such as Axin, APC, and beta-catenin, results in uncontrolled cell growth and triggers oncogenesis. To explore the reported link between CK2 kinase activity and Wnt pathway signaling, we sought to identify a potent, selective inhibitor of CK2 suitable for proof of concept studies in vivo. Starting from a pyrazolo[1,5-a]pyrimidine lead (2), we identified compound 7h, a potent CK2 inhibitor with picomolar affinity that is highly selectivity against other kinase family enzymes and inhibits Wnt pathway signaling (IC50 = 50 nM) in DLD-1 cells. In addition, compound 7h has physicochemical properties that are suitable for formulation as an intravenous solution, has demonstrated good pharmacokinetics in preclinical species, and exhibits a high level of activity as a monotherapy in HCT-116 and SW-620 xenografts. PMID- 26985321 TI - Optimization of Novel Aza-benzimidazolone mGluR2 PAMs with Respect to LLE and PK Properties and Mitigation of CYP TDI. AB - Investigation of a novel amino-aza-benzimidazolone structural class of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 2 (mGluR2) identified [2.2.2]-bicyclic amine 12 as an intriguing lead structure due to its promising physicochemical properties and lipophilic ligand efficiency (LLE). Further optimization led to chiral amide 18, which exhibited strong in vitro activity and attractive pharmacokinetic (PK) properties. Hypothesis-driven target design identified compound 21 as a potent, highly selective, orally bioavailable mGluR2 PAM, which addressed a CYP time-dependent inhibition (TDI) liability of 18, while maintaining excellent drug-like properties with robust in vivo activity in a clinically validated model of antipsychotic potential. PMID- 26985322 TI - Electrophilic Oxidation and [1,2]-Rearrangement of the Biindole Core of Birinapant. AB - Birinapant/TL32711 (1) is a bivalent antagonist of the inhibitor of apoptosis (IAP) family of proteins and was designed to mimic AVPI, the N-terminal tetrapeptide of the second mitochondria-derived activator of caspases (Smac/DIABLO). Birinapant bound to the BIR3 domains of cIAP1, cIAP2, and XIAP with K i values of 1, 36, and 45 nM, respectively. Birinapant-mediated activation of cIAP1 resulted in cIAP1 autoubiquitylation and degradation and correlated with inhibition of TNF-mediated NF-kappaB activation, induction of tumor cell death in vitro, and tumor regression in vivo. Birinapant is being evaluated in Phase 1/2 trials for the treatment of cancer and hepatitis B virus (HBV) infection. After one year at accelerated storage conditions, a formulation of 1 afforded four degradants in >0.1% abundance by HPLC analysis. The primary degradants (2 and 3) were formed via oxidation of the biindole core, while the secondary degradants (5 and 6) arose via [1,2]-rearrangement of 3 and 2, respectively. Forced degradation conditions were developed, which allowed the isolation of 2 and 3 in multigram quantities. Novel deuterated analogues of 1 were prepared to determine the site of oxidation, and NMR experiments confirmed the chemical structures of 5 and 6. The de novo synthesis of 2, 3, 5, and 6 confirmed these experimental findings. PMID- 26985320 TI - Discovery of G Protein-Biased EP2 Receptor Agonists. AB - To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the omega chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the omega chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors. PMID- 26985324 TI - Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition. AB - The optimization, based on computational, thermodynamic, and crystallographic data, of a series of small-molecule ligands of the Phe43 cavity of the envelope glycoprotein gp120 of human immunodeficiency virus (HIV) has been achieved. Importantly, biological evaluation revealed that the small-molecule CD4 mimics (4 7) inhibit HIV-1 entry into target cells with both significantly higher potency and neutralization breadth than previous congeners, while maintaining high selectivity for the target virus. Their binding mode was characterized via thermodynamic and crystallographic studies. PMID- 26985325 TI - Discovery of 3-Substituted 1H-Indole-2-carboxylic Acid Derivatives as a Novel Class of CysLT1 Selective Antagonists. AB - The indole derivative, 3-((E)-3-((3-((E)-2-(7-chloroquinolin 2yl)vinyl)phenyl)amino)-3-oxoprop-1-en-1-yl)-7-methoxy-1H-indole-2-carboxylic acid (17k), was identified as a novel and highly potent and selective CysLT1 antagonist with IC50 values of 0.0059 +/- 0.0011 and 15 +/- 4 MUM for CysLT1 and CysLT2, respectively. PMID- 26985323 TI - Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors. AB - A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23-ligand interaction led to the identification of 2 (trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described. PMID- 26985327 TI - Overview of techniques applicable to self-interference incoherent digital holography. AB - Self-interference incoherent digital holography (SIDH) retrieves the complex hologram from the object illuminated by the incoherent light. Supported by the adaptive optic feature, SIDH is readily applicable to the ocular imaging to investigate the human retinal cells. Considering the practical issues, issues related to resolution, phase-shifting, and contrast should be addressed to implement the viable SIDH system which is capable of recording the holographic information of human retinal cells under the incoherent illumination. Super resolution image reconstruction technique can be directly applied to SIDH to enhance the resolution of the system without any change of configuration. We present the improved way to incorporate the phase-shifting itself into the lateral shift required by the super resolution technique. To deal with the phase shifting issue, we present an arbitrary phase shift retrieval algorithm which can reduce the number of phase-shift and accept the blind phase-shift. The single shot imaging is also possible by adopting the off-axis configuration of SIDH. We will provide the detailed procedures to retrieve the complex hologram using the proposed arbitrary phase shifting algorithm and the off-axis configuration. PMID- 26985326 TI - Detecting Depression Severity from Vocal Prosody. AB - To investigate the relation between vocal prosody and change in depression severity over time, 57 participants from a clinical trial for treatment of depression were evaluated at seven-week intervals using a semi-structured clinical interview for depression severity (Hamilton Rating Scale for Depression: HRSD). All participants met criteria for Major Depressive Disorder at week 1. Using both perceptual judgments by naive listeners and quantitative analyses of vocal timing and fundamental frequency, three hypotheses were tested: 1) Naive listeners can perceive the severity of depression from vocal recordings of depressed participants and interviewers. 2) Quantitative features of vocal prosody in depressed participants reveal change in symptom severity over the course of depression. And 3) Interpersonal effects occur as well; such that vocal prosody in interviewers shows corresponding effects. These hypotheses were strongly supported. Together, participants' and interviewers' vocal prosody accounted for about 60% of variation in depression scores, and detected ordinal range of depression severity (low, mild, and moderate-to-severe) in 69% of cases (kappa = 0.53). These findings suggest that analysis of vocal prosody could be a powerful tool to assist in depression screening and monitoring over the course of depressive disorder and recovery. PMID- 26985328 TI - An Update on Ovarian Aging and Ovarian Reserve Tests. AB - Ovaries are the female organs that age more quickly than other tissues such as the uterus, the pituitary gland or pancreas. Different from males, an interesting question is why and how the females lose fertility so rapidly. During the aging process, both the number and quality of the oocytes in the ovaries decrease and reach to a point beyond that no more viable offspring may be produced and the associated cyclic endocrinological activities cease, entering the menopause in females at an average age of 50 years. Females who delayed childbearing with or without their willing until their 30 years or 40 years constitute the largest portion of the total infertility population. Ovarian reserve tests (ORTs) provide an indirect estimate of a female's diminishing ovarian reserve or remaining follicular pool. This article briefly reviews recent progresses in relation to ovarian aging and ORTs. PMID- 26985330 TI - Epidemiology of Uterine Myomas: A Review. AB - Myomas are the most common benign tumors of the genital organs in women of childbearing age, causing significant morbidity and impairing their quality of life. In our investigation, we have reviewed the epidemiological data related to the development of myomas in order to homogenize the current data. Therefore, a MEDLINE and PubMed search, for the years 1990-2013, was conducted using a combination of keywords, such as "myoma," "leiomyoma," "fibroids," "myomectomy," "lifestyle," "cigarette," "alcohol," "vitamins," "diet," and "hysterectomy". Randomized controlled studies were selected based upon the authors' estimation. Peer-reviewed articles examining myomas were sorted by their relevance and included in this research. Additional articles were also identified from the references of the retrieved papers and included according to authors' estimation. Many epidemiologic factors are linked to the development of myomas; however, many are not yet fully understood. These factors include age, race, heritage, reproductive factors, sex hormones, obesity, lifestyle (diet, caffeine and alcohol consumption, smoking, physical activity and stress), environmental and other influences, such as hypertension and infection. Some of the epidemiological data is conflicting. Thus, more research is needed to understand all the risk factors that contribute to myoma formation and how they exactly influence their onset and growth. PMID- 26985331 TI - A Preliminary Report of A Low-Dose Step-Up Regimen of Recombinant Human FSH for Young Women Undergoing Ovulation Induction with IUI. AB - BACKGROUND: The aim of this study was to evaluate the efficacy and safety of a recombinant human follicle stimulating hormone (r-FSH) low-dose step-up regimen for controlled ovarian hyperstimulation in patients undergoing ovulation induction (OI) with intrauterine insemination (IUI). MATERIALS AND METHODS: The study was conducted in the Department of Obstetrics and Gynecology, Far Eastern Memorial Hospital, New Taipei, Taiwan. In this prospective, observational study, consecutive infertile women (20-35 years) with regular menstrual cycles and a normal baseline FSH level were prospectively enrolled between January 2010 and September 2010. A starting dose of 112.5 IU/day r-FSH was administered on day 3 and increased by 37.5 IU/day every 2 days until a follicle >=11 mm in diameter was present. Recombinant human chorionic gonadotropin (r-hCG) was administered when a follicle >=18 mm was noted. Monifollicular development was defined as only one follicle with a diameter >=16 mm. Clinical pregnancy was defined as a pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs. RESULTS: A total of 29 women and 30 cycles were included. The mean daily dose of r-FSH to achieve a follicle of >=11 mm in diameter was 131.3 +/- 23.6 IU and the mean total dose was 1030.0 +/- 383.2 IU. Approximately 41% of the cycles were monofollicular. Clinical pregnancy was observed in 9 (30.0%) cycles, and a fetal heart beat was observed in 7 (23.3%). There were no multiple pregnancies. Mild ovarian hyperstimulation syndrome, which was resolved with conservative management, was observed in 3 (10.0%) cycles. CONCLUSION: This r-FSH low-dose step-up regimen seems to be a feasible and practical method for OI in younger infertile women undergoing IUI. PMID- 26985333 TI - Sexual Satisfaction and Sexual Reactivity in Infertile Women: The Contribution of The Dyadic Functioning and Clinical Variables. AB - BACKGROUND: Infertility is a factor which has been linked to higher prevalence of sexual dysfunctions in women; however, ambiguous results have been reported about the impact of infertility on women's sexual satisfaction. The purpose of this study was to compare sexual and dyadic functioning in infertile and fertile women. Furthermore, the associations between sexual variables and clinical variables (depressive symptoms, period trying to conceive, and treatment period) were assessed in infertile women sample. MATERIALS AND METHODS: The cross sectional study involved 50 women with the history of infertility and 50 fertile women recruited from the general population. The Sexual Satisfaction Scale (SSS), Mell-Krat Scale (women's version), Family Assessment Measure (FAM-III), and Beck Depression Inventory (BDI) were administered to all participants. RESULTS: Infertile women reported lower sexual satisfaction and more maladaptive patterns of dyadic functioning in comparison to the control group. As many as 45 (90%) of infertile women, compared to 13 (26%) of the control group, reported the scores on the Mell-Krat Scale indicative of the presence of dysfunctions in sexual reactivity (P<=0.001). Infertile women reported significantly higher levels of depressive symptoms than the women from the control group (P<=0.001). Negative correlations were observed between sexual satisfaction and dyadic functioning in both groups (P<=0.05); however, the patterns of these associations were different in infertile and fertile women. For example, negative correlations were found between satisfaction with control and task accomplishment, role performance, affective involvement, and values and norms in infertile women. However, these relationships were not observed in the control group. No correlations were revealed between sexual reactivity and dyadic functioning in infertile women and the control group. Negative correlations were observed between satisfaction with control and relationship duration and treatment period as well as between sexual reactivity and period of trying to conceive. Multiple regression analyses also revealed different predictors of sexual satisfaction in both groups: affective involvement (P<=0.05) and relationship duration (P<=0.05) in infertile women, whereas communication (P<=0.05), affective expression (P<=0.05) and depressive symptoms (P<=0.05) in the control group. CONCLUSION: Infertility is an important factor affecting sexual and dyadic functioning and is linked to higher depressive symptoms in infertile women. PMID- 26985329 TI - Oxidative Stress during Ovarian Torsion in Pediatric and Adolescent Patients: Changing The Perspective of The Disease. AB - Among the different causes of gynecological acute pelvic pain, ovarian torsion represents a surgical emergency. It is a rare case in the pediatric/adolescent aged group that must be included in the differential diagnosis of any girl with abdominal pain or pelvic/abdominal mass. Current recommendations suggest that laparoscopic detorsion should be performed in order to preserve the integrity of the ovaries and fertility, although oophoropexy may be considered in case of severe necrosis. Nevertheless, maintaining the circulation of the ovary after detorsion deteriorates the tissue injury and leads to a pathologic process called ischaemia/reperfusion (I/R) injury, which is characterized by oxidative stress. During the detorsion process, an excess amount of molecular oxygen is supplied to the tissues, and reactive species of oxygen (ROS) such as superoxide radical (O2 (-)), hydrogen peroxide (H2O2), hydroxyl radical (OH*), as well as reactive nitrogen species (RNS) are produced in excess. ROS, RNS and their toxic products cause DNA damage and lipid peroxidation in the cellular and mitochondrial membranes, leading to cell death. In spite of attention on this topic, currently there is no shared and clear evidence about the use of anti-inflammatory and antioxidant agents to prevent I/R damage after laparoscopic ovarian detorsion. Considering this element, future research should aim to develop shared protocols for the clinical use (route of application, dosage and time of application) of antioxidants after laparoscopic management of this condition. PMID- 26985332 TI - Effect of In Vitro Maturation Technique and Alpha Lipoic Acid Supplementation on Oocyte Maturation Rate: Focus on Oxidative Status of Oocytes. AB - BACKGROUND: Therapeutic potential of in vitro maturation (IVM) in infertility is growing with great promise. Although significant progress is obtained in recent years, existing IVM protocols are far from favorable results. The first aim of this study was to investigate whether two step IVM manner change reactive oxygen species (ROS) and total anti- oxidant capacity (TAC) levels. The second aim was to find the effect of alpha lipoic acid (ALA) supplementation on oocyte maturation rate and on ROS/TAC levels during IVM. MATERIALS AND METHODS: In this experimental study, mouse germinal vesicle (GV) oocytes divided into cumulus denuded oocytes (DOs) and cumulus oocyte complexes (COCs) groups. GVs were matured in vitro in the presence or absence of ALA only for 18 hours (control) or with pre-culture of forskolin plus cilostamide for an additional 18 hours. Matured oocytes obtained following 18 and 36 hours based on experimental design. In parallel, the ROS and TAC levels were measured at different time (0, 18 and 36 hours) by 2',7'-dichlorodihydrofluorescein (DCFH) probe and ferric reducing/antioxidant power (FRAP) assay, respectively. RESULTS: Maturation rate of COCs was significantly higher than DOs in control group (P<0.05), while there was no significant difference between COCs and DOs when were pre-cultured with forskolin plus cilostamide. ROS and TAC levels was increased and decreased respectively in DOs after 18 hours while in COCs did not change at 18 hours and showed a significant increase and decrease respectively at 36 hours (P<0.05). ROS and TAC levels in the presence of ALA were significantly decreased and increased respectively after 36 hours (P<0.05) whereas, maturation rates of COCs and DOs were similar to their corresponding control groups. CONCLUSION: ALA decreased ROS and increased TAC but could not affect maturation rate of both COCs and DOs in one or two step IVM manner. PMID- 26985334 TI - Menstrual Pattern following Tubal Ligation: A Historical Cohort Study. AB - BACKGROUND: Tubal ligation (TL) is recommended for women who have completed their family planning. The existence of the menstrual disorders following this procedure has been the subject of debate for decades. This study was conducted to identify the relationship between tubal ligation and menstrual disorders. MATERIALS AND METHODS: A historical cohort study was carried out on 140 women undergoing tubal ligation (TL group) and on 140 women using condom as the main contraceptive method (Non-TL group). They aged between 20 and 40 years and were selected from a health care center in Rudsar, Guilan Province, Iran, during 2013 2014. The two groups were comparable in demographic characteristics, obstetrical features and menstrual bleeding pattern using a routine questionnaire. A validated pictorial blood loss assessment chart (PBLAC) was also used to measure the menstrual blood loss. RESULTS: Women with TL had more menstrual irregularity than those without TL (24.3 vs. 10%, P=0.002). Women with TL had more polymenorrhea (9.3 vs. 1.4%, P=0.006), hypermenorrhea (12.1 vs. 2.1%, P=0.002), menorrhagia (62.9 vs. 22.1%, P<0.0001) and menometrorrhagia (15.7 vs. 3.6%, P=0.001) than those without TL. There is a significant difference in the PBLAC score between women with and without TL (P<0.0001). According to logistic regression, age odds ratio [(OR=1.08, con- fidence interval (CI):1.07-1.17, P=0.03)], TL (OR=5.95, CI:3.45-10.26, P<0.0001) and cesarean section (OR=2.72, CI:1.49-4.97, P=0.001) were significantly associated with menorrhagia. CONCLUSION: We found significant differences in menstrual disorders between women with and without TL. Therefore, women should be informed by the health providers regarding the advantages and disadvantages of TL before the procedures. PMID- 26985335 TI - Performance of Circulating Placental Growth Factor as A Screening Marker for Diagnosis of Ovarian Endometriosis: A Pilot Study. AB - BACKGROUND: The aim of this study is to compare the circulating placental growth factor (PlGF) concentration in women with and without endometrioma to verify the performance of this marker to diagnose the disease. MATERIALS AND METHODS: In this case-control study, thirteen women with histological diagnosis of ovarian endometriosis were compared with women without endometriosis disease. PlGF plasma levels of endometriotic patients and controls were investigated using a fluorescence immunoassay technique. RESULTS: PlGF showed a direct correlation with body mass index (BMI) only in the control group (P=0.013). After adjustment for BMI values, PlGF median value in endometriosis group (14.7 pg/mL) resulted higher than in control group (13.8 pg/ mL, P=0.004). CONCLUSION: PlGF is a promising peripheral blood marker that can discriminate between patients with and without ovarian endometriosis. PMID- 26985336 TI - Metabolic Syndrome in Patients with Polycystic Ovary Syndrome in Iran. AB - BACKGROUND: The prevalence of metabolic syndrome (MetS) in polycystic ovary syndrome (PCOS) has been studied in different populations, but their results were so controversial regarding Iranian women. These controversial data indicated the need for more investigation of MetS characteristics in PCOS patients in our population. So this study aimed to evaluate the clinical and laboratory characteristics and metabolic features of patients with PCOS in Rasht. MATERIALS AND METHODS: This prospective cross sectional study was conducted on 215 PCOS women who lived in Rasht, north of Iran, from March 2010 to July 2012. The participants were then divided into two groups of women with MetS (n=62) and women without MetS (n=153). The diagnosis of PCOS and MetS were based on the Rotterdam 2003 criteria and the Adult Treatment Panel III (ATP III) criteria, respectively. Demographic characteristics, fertility characteristics, family history and laboratory findings were assessed. RESULTS: The prevalence of MetS in women with PCOS was 28.8%. In PCOS women of both groups, the waist circumference (WC) exceeded 88cm in 72.6%, hypertension [systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) >=130/85mm Hg] was prevalent in 9.3%, fasting blood sugar (FBS) level was >=110 mg/dl in 6%, triglycerides (Tg) level were >=150 mg/dl in 47%, and high-density lipoprotein (HDL) level was <50 mg/dl in 86%. The values of WC, SBP, DBP, body mass index (BMI), ovarian size, Tg, cholesterol, FBS, 2-hour blood sugar, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were significantly greater in PCOS women with MetS than women without MetS. Also HDL and luteinizing hormone (LH) levels in women with MetS were significantly lower than women without MetS. CONCLUSION: Prevalence of MetS in PCOS women was 28.8%, indicating that this value is higher than other studies conducted on PCOS women in Iran and other studies conducted on general population in Iran. PCOS women are considered as a high-risk population for MetS. The special strategies are required to prevent MetS and its associated complications in PCOS women. PMID- 26985337 TI - Comparison of Pregnancy Outcome between Ultrasound- Guided Tubal Recanalization and Office-Based Microhysteroscopic Ostial Dilatation in Patients with Proximal Blocked Tubes. AB - BACKGROUND: The current research to the best of my knowledge is the first to compare the pregnancy outcome between ultrasound-guided tubal recanalization (UGTR) using a special fallopian tubal catheter, and office-based micrhysteroscopic ostial dilatation (MHOD) using the same tubal catherter in infertile women with previously diagnosed bilateral proximal tubal obstruction (PTO). MATERIALS AND METHODS: This prospective study reported the pregnancy outcomes for 200 women in private infertility care center in Arafa hospital in Fayoum and in El Minya University Hospital in the period between January 2010 and October 2013 treated as outpatients for their bilateral PTO after the routine hysterosalpingography (HSG). A Cook's catheter, special fallopian tubal catheter, were used to recanalize the blocked tubes in 100 women (group A) under UGTR, and the same Cook's tubal catheter was used through 2mm microhysteroscope to cannulate both ostia using MHOD in another 100 women (group B). Pregnancy outcome was determined after the procedures for a 12-month period follow-up. RESULTS: The number of the recanalization of PTO was not significantly different between two groups. As of the 200 blocked fallopian tubes in group A, 140 tubes (70%) were successfully recanalized by passing the ultrasound-guided special cannula, while 150 tubes (75%) were successfully recanalized in group B, using the same tubal catheter through a 2mm microhysteroscope. The cumulative pregnancy rate after the two procedures was not statistically different between two groups. It was 25.9% in group A, while it was 26.3% in group B, after a 12-month period follow-up. CONCLUSION: UGTR is highly recommended as the first step to manage infertile women due to PTO, as it is easier procedure; however, there is possible to obtain nearly similar results after MHOD. PMID- 26985338 TI - Correlation of Serum CA-125 and Progesterone Levels with Ultrasound Markers in The Prediction of Pregnancy Outcome in Threatened Miscarriage. AB - BACKGROUND: The aim of this study was to evaluate the relationship between ultrasonographic findings and serum progesterone and cancer antigen-125 (CA-125) levels in threatened miscarriage and to predict pregnancy outcome. MATERIALS AND METHODS: In a prospective comparative case-control study, serum CA-125 and progesterone levels were measured for 100 pregnant women with threatened miscarriage who attended the outpatient clinic or the causality department of Obstetrics and Gynecology at Kasr El-Aini Hospital, Giza, Egypt, during the period from March 2013 to October 2013. Ultrasound was performed for fetal viability, crown-rump length (CRL), gestational sac diameter (GSD) and fetal heart rate (FHR). The patients were followed up and divided into two groups based on the outcome: 20 women who miscarried (group 1), and 80 women who continued pregnancy (group 2). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy were tested for CA 125 and progesterone levels in prediction of the pregnancy outcome. Correlation of these chemical markers with the ultrasound markers was also examined. RESULTS: In the group that miscarried, CA-125 level was significantly higher (P<0.001) and serum progesterone level was significantly lower (P<0.001). For prediction of the outcome of pregnancy, the cut-off limit of 31.2 IU/ml for CA-125 level yielded sensitivity, specificity and an overall accuracy of 96.2, 100 and 99.4% respectively. The cut-off limit of 11.5 ng/ml for progesterone level yielded sensitivity, specificity and an overall accuracy of 97.5, 100 and 99.8% respectively. CA-125 level had a negative correlation with progesterone level and FHR levels (r=-0.716, P<0.001) and (r=-0.414, P<0.001) respectively. Serum progesterone level correlated with GSD (r=0.521, P<0.001) and with CRL (r=0.407, P<0.001) and FHR (r=0.363, P<0.001). CA-125 level was significantly higher in the group that showed hematoma as compared with the group without hematoma (P<0.001). Also, serum progesterone level was significantly lower in the group that showed hematoma as compared with the group without hematoma (P=0.017). CONCLUSION: Serum CA-125 and progesterone levels are valid early predictors of the outcome of pregnancy in women with threatened miscarriage. They are correlated with some ultrasonographic markers (GSD, CRL, and FHR). PMID- 26985339 TI - Comparison of Toxicity of CdSe: ZnS Quantum Dots on Male Reproductive System in Different Stages of Development in Mice. AB - BACKGROUND: Quantum dots (QDs) are new types of fluorescent materials for biological labeling. QDs toxicity study is an essential requirement for future clinical applications. Therefore, this study aimed to evaluate cytotoxic effects of CdSe: ZnS QDs on male reproductive system. MATERIALS AND METHODS: In this experimental study, the different concentrations of CdSe: ZnS QDs (10, 20 and 40 mg/kg) were injected to 32 male mice (adult group) and 24 pregnant mice (embryo group) on day 8 of gestation. The histological changes of testis and epididymis were studied by a light microscopy, and the number of seminiferous tubules between two groups was compared. One-way analysis of variance (one-way Anova) using the Statistical Package for the Social Sciences (SPSS, SPSS Inc., USA) version 16 were performed for statistical analysis. RESULTS: In adult group, histological studies of testis tissues showed a high toxicity of CdSe: ZnS in 40 mg/kg dose followed by a decrease in lamina propria; destruction in interstitial tissue; deformation of seminiferous tubules; and a reduction in number of spermatogonia, spermatocytes, and spermatids. However, there was an interesting result in fetal testis development, meaning there was no significant effect on morphology and structure of the seminiferous tubules and number of sperm stem cells. Also histological study of epididymis tissues in both groups (adult and embryo groups) showed no significant effect on morphology and structure of tubule and epithelial cells, but there was a considerable reduction in number of spermatozoa in the lumen of the epididymal duct in 40 mg/kg dose of adult group. CONCLUSION: The toxicity of QDs on testicular tissue of the mice embryo and adult are different before and after puberty. Due to lack of research in this field, this study can be an introduction to evaluate the toxicity of QDs on male reproduction system in different stages of development. PMID- 26985340 TI - Effects of Adding Sodium Nitroprusside to Semen Diluents on Motility, Viability and Lipid Peroxidation of Sperm in Holstein Bulls. AB - BACKGROUND: Nitric oxide (NO) that plays important role in all sexual activities of animals is made from the amino acid L-arginine by the enzymatic action of NO synthase (NOS). NO makes a band with sulfur-iron complexes, but due to production of steroid sexual hormones related to the enzymes involved in this complex, NO can change the activity of these enzymes. NO affects many cells including vein endothelial cells, macrophages and mast cells. These cells are also found in Leydig cells; therefore, they are important source of NO in testis tissue. Therefore, minimizing damages to sperm at the time of freezing thawing process are really important. The aim of this study was to determine the appropriate NO concentration to be added to the freezing extender to improve the quality of thawed sperm. MATERIALS AND METHODS: In this experimental randomized study, sperms of four Holstein bulls with an average age of 4 were collected twice a week for 3 weeks. They received sodium nitroprusside (SNP) in concentrations of 0, 10, 50 and 100 nmol/ml. Data analysis was performed using the special issue and static (SAS) 98 software. Also, mean comparison was done using Duncan's multiple ranges test (P<0.05).This research was conducted at the laboratory of Science and Research Branch, Islamic Azad University, Tehran at spring and summer of 2013. RESULTS: All concentrations of SNP used was found to increase motility and viability of spermatozoa at 1, 2 and 3 hours after thawing, significantly (P<0.05), but there was no significant difference at zero time. Different concentrations of SNP reduced the membrane lipid peroxidation level of sperm and increased acrosome membranes integrity, implying that SNP generally improved samples membranes, especially in 50 and 100 nmol/ml concentrations. CONCLUSION: According to the obtained results, addition of SNP to semen diluents increases motility and viability of spermatozoa. Also, it reduces membrane lipid peroxidation level that leads to improved sperm function. PMID- 26985341 TI - Accuracy Evaluation of The Depth of Six Kinds of Sperm Counting Chambers for both Manual and Computer-Aided Semen Analyses. AB - BACKGROUND: Although the depth of the counting chamber is an important factor influencing sperm counting, no research has yet been reported on the measurement and comparison of the depth of the chamber. We measured the exact depths of six kinds of sperm counting chambers and evaluated their accuracy. MATERIALS AND METHODS: In this prospective study, the depths of six kinds of sperm counting chambers for both manual and computer-aided semen analyses, including Makler (n=24), Macro (n=32), Geoffrey (n=34), GoldCyto (n=20), Leja (n=20) and Cell-VU (n=20), were measured with the Filmetrics F20 Spectral Reflectance Thin-Film Measurement System, then the mean depth, the range and the coefficient of variation (CV) of each chamber, and the mean depth, relative deviation and acceptability of each kind of chamber were calculated by the closeness to the nominal value. Among the 24 Makler chambers, 5 were new and 19 were used, and the other five kinds were all new chambers. RESULTS: The depths (mean +/- SD, MUm) of Makler (new), Macro and Geoffrey chambers were 11.07 +/- 0.41, 10.19 +/- 0.48 and 10.00 +/- 0.28, respectively, while those of GoldCyto, Leja and Cell-VU chambers were 23.76 +/- 2.15, 20.49 +/- 0.22 and 24.22 +/- 2.58, respectively. The acceptability of Geoffrey chambers was the highest (94.12%), followed by Macro (65.63%), Leja (35%) and Makler (20%), while that of the other two kinds and the used Makler chamber was zero. CONCLUSION: There existed some difference between the actual depth and the corresponding nominal value for sperm counting chambers, and the overall acceptability was very low. Moreover, the abrasion caused by the long use, as of Makler chamber, for example, may result in unacceptability of the chamber. In order to ensure the accuracy and repeatability of sperm concentration results, the depth of the sperm counting chamber must be checked regularly. PMID- 26985342 TI - Reducing Inter-Laboratory Differences between Semen Analyses Using Z Score and Regression Transformations. AB - BACKGROUND: Standardization of the semen analysis may improve reproducibility. We assessed variability between laboratories in semen analyses and evaluated whether a transformation using Z scores and regression statistics was able to reduce this variability. MATERIALS AND METHODS: We performed a retrospective cohort study. We calculated between-laboratory coefficients of variation (CVB) for sperm concentration and for morphology. Subsequently, we standardized the semen analysis results by calculating laboratory specific Z scores, and by using regression. We used analysis of variance for four semen parameters to assess systematic differences between laboratories before and after the transformations, both in the circulation samples and in the samples obtained in the prospective cohort study in the Netherlands between January 2002 and February 2004. RESULTS: The mean CVBwas 7% for sperm concentration (range 3 to 13%) and 32% for sperm morphology (range 18 to 51%). The differences between the laboratories were statistically significant for all semen parameters (all P<0.001). Standardization using Z scores did not reduce the differences in semen analysis results between the laboratories (all P<0.001). CONCLUSION: There exists large between-laboratory variability for sperm morphology and small, but statistically significant, between-laboratory variation for sperm concentration. Standardization using Z scores does not eliminate between-laboratory variability. PMID- 26985343 TI - Protective Effects of Thymoquinone against Methotrexate-Induced Germ Cell Apoptosis in Male Mice. AB - BACKGROUND: Toxic effects of anti-cancer and other drugs on the normal tissues could be reduced by the herbal plants and their fractions. This study investigated the protective effect of thymoquinone (TQ) as a fraction of Nigella sativa on methotrexate (MTX)- induced germ cell apoptosis in male mice. MATERIALS AND METHODS: In this experimental study, thirty male Balb/c mice were divided randomly into 5 groups (n=6). A single dose of MTX (20 mg/kg) and different concentrations of TQ were administrated for 4 consecutive days. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed on paraffin embedded tissue sections to analysis the occurrence of apoptosis in the testis. Reverse transcription polymerase chain reaction (RT-PCR) of apoptosis related genes was performed with RNA extracted from testes of the mice. Statistical analysis was done using one-way ANOVA. RESULTS: In the MTX group, there was a significant increase in morphologic sign of germ cell degeneration of tubules (48 +/- 0.6%), apoptotic index (AI; 2.3 +/- 0.6%), as well as mRNA expression of p53 (P=0.008), caspase 8 (P=0.002), caspase 3 (P=0.005), caspase 9 (P=0.000), bax (P=0.004) and the ratio of bax/bcl-2 (P=0.000), whereas there was an decrease in the expression of bcl-2 (P=0.003), as compared to control group. In MTX+TQ groups, the data showed that different concentrations of TQ could improve the harmful effects caused by the MTX. The best protective effects were achieved in MTX+TQ (10 mg/kg). CONCLUSION: TQ protects testicular germ cell against MTX-induced apoptosis by affecting related genes regulation. PMID- 26985345 TI - Prenatal Caffeine Exposure Impairs Pregnancy in Rats. AB - BACKGROUND: In recent years, concerns have been raised about human reproductive disorders. Caffeine consumption is increasing by the world's population and there is a relationship between caffeine intake and adverse reproductive outcomes. The aim of this study was to evaluate the effects of caffeine on implantation sites, number of live births, birth weight, crown-rump length (CRL) and abnormality in pregnant rats. MATERIALS AND METHODS: In this experimental study, 40 female albino rats (170-190 g) were randomly divided into two experimental and two control groups (n=10/each group). In both experimental groups, animals received caffeine intraperitoneally (IP: 150 mg/kg/day) on days 1-5 of pregnancy. In experimental group 1, treated animals were euthanized on day 7of pregnancy and the number of implantation sites was counted. In experimental group 2, treated animals maintained pregnant and after delivery, the number of live births, birth weight, CRL and abnormality of neonates were investigated. In control group, animals received IP injections of distilled water. Data were analyzed by independent t test. RESULTS: Results showed that administration of caffeine significantly decreased the number of implantation sites, number of live births and CRL as compared with control group (P<0.05). There were no significant differences regarding birth weight and abnormality of neonate rats between experimental and control groups. CONCLUSION: These results suggest that caffeine caused anti-fertility effect and significantly decreased CRL in neonate rats. PMID- 26985344 TI - Protection against Cyclosporine-Induced Reprotoxicity by Satureja khuzestanica Essential Oil in Male Rats. AB - BACKGROUND: The effects of cyclosporine (Cs), a fungal cyclic polypeptide with potent immunosuppressive activity, on fertility have assumed greater significance with the increasing numbers of transplantations being performed all over the world. Current study was undertaken to investigate the potential of Satureja khuzestanica Essential Oil (SEO) as an antioxidant to mitigate Cs-induced reprotoxicity. MATERIALS AND METHODS: In this experimental study (April-July 2012), thirty-two adult male Wistar rats were randomly divided into 4 groups of 8 animals each. Two groups of rats were administered Cs [40 mg/kg/day, per oral (p.o.)] for 45 days. One of these groups received SEO (225 mg/kg/day, p.o.) four hours after Cs administration. A vehicle-treated control group and a SEO control group were also included. Epididymal sperm characteristics, in vitro fertilizing capacity as well as embryo development were evaluated. For statistical analysis, one-way ANOVA and Tukey's post-hoc test were used, and the value of P<0.05 was considered as the criterion for statistical significance. RESULTS: Sperm count and viability along with fertilization and blastocyst development rates were significantly decreased by Cs treatment. Moreover, Cs-treated group showed significant increases in DNA damage, protamine deficiency of the sperm cells and proportion of spermatozoa with cytoplasmic droplet. Notably, aforementioned parameters were improved to near normal level by SEO co-administration. CONCLUSION: These results suggest that SEO has a protective action against Cs induced reprotoxicity in a rat model. PMID- 26985346 TI - The Effect of Prolonged Culture of Chromosomally Abnormal Human Embryos on The Rate of Diploid Cells. AB - BACKGROUND: A decrease in aneuploidy rate following a prolonged co-culture of human blastocysts has been reported. As co-culture is not routinely used in assisted reproductive technology, the present study aimed to evaluate the effect of the prolonged single culture on the rate of diploid cells in human embryos with aneuploidies. MATERIALS AND METHODS: In this cohort study, we used fluorescence in situ hybridi- zation (FISH) to reanalyze surplus blastocysts undergoing preimplantation genetic diagnosis (PGD) on day 3 postfertilization. They were randomly studied on days 6 or 7 following fertilization. RESULTS: Of the 30 analyzed blastocysts, mosaicism was observed in 26(86.6%), while 2(6.7%) were diploid, and 2(6.7%) were triploid. Of those with mosaicism, 23(88.5%) were determined to be diploid-aneuploid and 3(11.5%) were aneuploid mosaic. The total frequency of embryos with more than 50% diploid cells was 33.3% that was lower on day 7 in comparison with the related value on day 6 (P<0.05); however, there were no differences when the embryos were classified according to maternal age, blastocyst developmental stage, total cell number on day 3, and embryo quality. CONCLUSION: Although mosaicism is frequently observed in blastocysts, the prolonged single culture of blastocysts does not seem to increase the rate of normal cells. PMID- 26985349 TI - Nanofiber Expansion of Umbilical Cord Blood Hematopoietic Stem Cells. AB - BACKGROUND: The aim of this study was the ex vivo expansion of Umbilical Cord Blood hematopoietic stem cells on biocompatible nanofiber scaffolds. MATERIALS AND METHODS: CD133+ hematopoietic stem cells were separated from umbilical cord blood using MidiMacs (positive selection) system by means of monocolonal antibody CD133 (microbeads); subsequently, flowcytometry method was done to assess the purity of separated cells. Isolated cells were cultured on plate (2 Dimensional) and fibronectin conjugated polyethersulfon nanofiber scaffold, simultaneously (3 Dimensional). Colony assay test was performed to show colonization ability of expanded cells. RESULTS: Cell count analysis revealed that expansion of hematopoietic stem cells in 2dimensional (2D) environment was greater than 3dimensional (3D) condition (p= 0.01). Assessment of stem cell- phenotype after expansions was performed by flowcytometric analysis which is showed that the maintenance of CD133 marker in expanded cells in 3 dimensional condition were higher than expanded cells in 2 dimensional condition (p=0.01). Moreover, colony assay test was performed before and after of expansion to show colonization ability of expanded cells both in 3D and 2D culture and results revealed more ability of 3D culture compared with 2D culture (p= 0.03). CONCLUSION: The results of current study confirmed that umbilical cord blood CD133+ haematopoietic stem cells are able to expand on fibronectin conjugated polyethersulfon scaffold. These findings indicated that 3D is a proper and valuable cell culture system for hematopoietic stem cells expansion, compared to 2D in invitro situation. PMID- 26985348 TI - Molecular Dissection Using Array Comparative Genomic Hybridization and Clinical Evaluation of An Infertile Male Carrier of An Unbalanced Y;21 Translocation: A Case Report and Review of The Literature. AB - Chromosomal defects are relatively frequent in infertile men however, translocations between the Y chromosome and autosomes are rare and less than 40 cases of Y-autosome translocation have been reported. In particular, only three individuals has been described with a Y;21 translocation, up to now. We report on an additional case of an infertile man in whom a Y;21 translocation was associated with the deletion of a large part of the Y chromosome long arm. Applying various techniques, including conventional cytogenetic procedures, fluorescence in situ hybridisation (FISH) analysis and array comparative genomic hybridization (array-CGH) studies, we identified a derivative chromosome originating from a fragment of the short arm of the chromosome Y translocated on the short arm of the 21 chromosome. The Y chromosome structural rearrangement resulted in the intactness of the entire short arm, including the sex-determining region Y (SRY) and the short stature homeobox (SHOX) loci, although translocated on the 21 chromosome, and the loss of a large part of the long arm of the Y chromosome, including azoospermia factor-a (AZFa), AZFb, AZFc and Yq heterochromatin regions. This is the first case in which a (Yp;21p) translocation has been ascertained using an array-CGH approach, thus reporting details of such a rearrangement at higher resolution. PMID- 26985347 TI - A Case of Bilateral Testicular Tumors Subsequently Diagnosed as Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. AB - 21-hydroxylase deficiency (21-OHD) caused congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic disorders resulting from mutations in genes involved with cortisol (CO) synthesis in the adrenal glands. Testicular adrenal rest tumors (TARTs) are rarely the presenting symptoms of CAH. Here, we describe a case of simple virilizing CAH with TARTs, in a 15-year-old boy. The patient showed physical signs of precocious puberty. The levels of blood adrenocorticotropic hormone (ACTH), urinary 17-ketone steroids (17-KS), dehydroepiandrosterone sulfate (DHEA-S), and serum progesterone (PRGE) were elevated, whereas those of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and CO were reduced. Computed tomography (CT) of the adrenal glands and magnetic resonance imaging (MRI) of the testes showed a soft tissue density (more pronounced on the right side) and an irregularly swollen mass (more pronounced on the left side), respectively. Pathological examination of a specimen of the mass indicated polygonal/circular eosinophilic cytoplasm, cord like arrangement of interstitial cells, and lipid pigment in the cytoplasm. Immunohistochemistry results precluded a diagnosis of Leydig cell tumors. DNA sequencing revealed a hackneyed homozygous mutation, I2g, on intron 2 of the CYP21A2 gene. The patient's symptoms improved after a three-month of dexamethasone therapy. Recent radiographic data showed reduced hyperplastic adrenal nodules and testicular tumors. A diagnosis of TART should be considered and prioritized in CAH patients with testicular tumors. Replacement therapy using a sufficient amount of dexamethasone in this case helps combat TART. PMID- 26985350 TI - Evaluation of Nosocomial Infection in Patients at hematology-oncology ward of Dr. Sheikh children's hospital. AB - BACKGROUND: Infections in critical care unit are high, and they are serious hospital problems. Infections acquired during the hospital stay are generally called nosocomial infections, initially known as infections arising after 48 h of hospital admission. The mostfrequent nosocomial infections (urinary, respiratory, gastroenteritis and blood stream infection) were common in patients at hospital.The aim was to study, the current status of nosocomial infection, rate of infection among hospitalized children at hematology-oncology ward of Dr. Sheikh children's hospital, Mashhad, Iran. MATERIALS AND METHODS: Data were collected from 200 patient's records presented with symptoms of nosocomial infection at hematology-oncology ward of Dr. Sheikh children's hospital from March 2014 to September 2014. Descriptive statistics using percentage was calculated. RESULTS: Incidence of nosocomial infections inpatients athematology oncology ward was 31% (62/200). Of which 69.35% (43/62) blood stream infection being the most frequent; followed by 30.64% (19/62) was urinary tract infection (UTI), and the most common blood culture isolate was been Staphylococcus epidermidis 18 (41.86%), andour study showed that large numbers ofnosocomial UTIs causing by Gram-negative bacteria. CONCLUSION: This study showed blood stream infection and UTI are the common nosocomial infections among patients athematology-oncology ward. Early recognition of infections and short term use of invasive devices along with proper infection control procedures can significantly decrease the incidence of nosocomial infections in patients. PMID- 26985351 TI - ABO and Rh Blood Type Relationship in Parents with more than One Disabled Child. AB - BACKGROUND: Parental blood variables are one of the most important medical biological causes of intellectual and physical-movement disabilities. The purpose of this study was to identify the relationship between parents' blood variables (ABO and Rh blood type) and their relationship with frequency of intellectual and physical-movement disabilities in Isfahan province. MATERIALS AND METHODS: This was a descriptive-analytical study and 494 samples were selected from mothers with more than one disabled child and mothers with normal child using simple and multistage random methods. The data collection was done through questionnaire. Based on Kuder-Richardson Formula 20 (KR-20), the reliability of questionnaire was 0.88. The statistical model in this study was a hierarchical log-linear method. RESULTS: There was a significant relationship between mother's Rh blood and having disabled child (P=0.002). However no significant relationship between having disabled children and the following variables was found: the father's Rh blood (p=0.2), father and mother's Rh blood together (P=0.5), father blood type (P=0.56), mother blood type (P=0.42), and mother and father blood types together (P=0.7). CONCLUSION: Maternal and fetal blood incompatibility (motherwith negative Rh blood and fetus with positive Rh blood) increased the likelihood of being born with disabilities. PMID- 26985352 TI - Health Related Quality of Life, Depression, Anxiety and Stress in Patients with Beta-Thalassemia Major. AB - BACKGROUND: Awareness of factors associated with quality of life (QOL) in patients with beta-Thalassemia major (beta-TM) is necessary to develop clinical programs in order to improve social support and QOL in beta-TM patients. This study aimed to examine QoL, depression, anxiety, and stress in beta-TM patients in Ahvaz, Iran. MATERIALS AND METHODS: A cross-sectional study was conducted on173 beta-TM patients aged >=12 years (12-18=55, >=19=118). Subjects were selected using a census method. Data collection instrument consisted of three parts including: demographic questions, SF-36 questionnaire and depression, anxiety, and stress scale (DAS-21). RESULTS: The participants obtained a mean score of 64.38+/-18.20 for QOL, 6.4+/-5.1 for depression, 4.8+/-3.9 for anxiety, and 7.3+/-4.9 for stress. Significant relationship was found between QOL and employment (P=0.02) and education level (P<0.001). Patients in the age group of 12-18 years old had higher mean scores in the majority of QoL dimensions than those aged <=19. The mean scores of depression, anxiety, and stress were higher in patients aged <=19. No significant correlation was observed between QOL and depression, anxiety, stress scores, and other demographic variables. Moreover, a significant inverse correlation was found between QOL and depression (P<0.001,r= 0.62), anxiety (P<0.001,r= -0.55), and stress scores (P<0.001, r= -0.5) . CONCLUSION: This study showed that beta-TM patients experienced a considerable decrease both in their overall QoL and in its dimensions. A majority of the beta TM patients were also suffered from mild to severe depression, anxiety, and stress. PMID- 26985353 TI - Cardiac and Hepatic T2*-Weighted Magnetic Resonance Imaging in Transfusion Dependent Hemoglobinopathy in North West of Iran. AB - BACKGROUND: Iron overload is the main transfusion related side effects in patients with transfusion dependent hemoglobinopathies. Severe iron deposition in tissues leads to organ dysfunction. Many organs can be affected such as heart, liver, and endocrine organs. Cardiac failure and liver fibrosis are the consequent of Iron overload in transfusion dependent hemoglobinopathy. Magnetic Resonance Imaging (MRI) is a safe, noninvasive, and accurate method for the assessment of iron deposition in different tissues. This study assessed iron levels in liver and heart of the patients with transfusion dependent hemoglobinopathies. MATERIALS AND METHODS: The studied population consisted of 12 patients (7 male and 5 female) with transfusion dependent hemoglobinopathies, aged between 10-18 years old. Then, Cardiac and liver T2*- weighted magnetic resonance imaging (MRI) were obtained. RESULTS: In current study, 1patient (8.33%) had severe, 2 patients (16.66%) had moderate and 2(16.66%) had mild cardiac iron deposition. Out of 12 patients, 1 had severe iron deposition in liver (8.33%), 5(41.66%) and 4(33.33%) had moderate and mild hepatic iron deposition, respectively. Differences between Hepatic and cardiac iron levels were not significant between males and females (p>0.05). CONCLUSION: Since cardiac and liver iron levels were higher than normal in most of the study group, checking ferritin level and liver function test and also echocardiography in shorter intervals (each 3 months) in involved group is suggested instead of checking routinely in 6 month intervals in patients with transfusion dependent hemoglobinopathies. PMID- 26985354 TI - Maternal Hemoglobin Levels during Pregnancy and their Association with Birth Weight of Neonates. AB - BACK GROUND: Anemia in pregnancy is associated with increased rates of maternal and perinatal mortality, premature delivery, low birth weight, and other adverse outcomes. MATERIALS AND METHODS: A prospective study was conducted on 1405 Iranian pregnant women who delivered during 2015. Blood was collected from all the subjects to measure the hemoglobin (Hb) during 16-19 weeks, 22-24 weeks, and 34-36 weeks of gestation. According to the level of hemoglobin, it is divided into 4 groups. Group 1; Hb > 10.1 gm/100ml (control group), Group 2; Hb= 8.1-10 gm/100ml (mild anemia) Group 3; Hb= 6.5-8 gm/100ml (moderate anemia) Group 4; Hb <6.5 gm/100ml (severe anemia). After delivery, the neonates were weighted within 24 hours after birth. Maternal hemoglobin and birth weights were compared. RESULTS: The anemia prevalence was 20.2% (Hb<10g/dl). Out of them, 16.2 % hadmoderate anemia (Hb=6.5-8 g/dl) and 83.8% had mild anemia (Hb=8.1-10 g/dl). Severe anemia did not detect in pregnant women. The hemoglobin levels in non anemic group showed a drop in the second trimester. Pregnant women with hemoglobin less than 10 g/dl, considered as anemic gave birth to neonates with birth weight of 2.6kg, while pregnant women with higher hemoglobin level (>10 g/dl), considered as normal gave birth to heavier and normal babies (3.3 kg). The severity of anemia during three trimesters was closely associated with birth weight of newborns. CONCLUSION: The low hemoglobin values during three trimesters of pregnancy were associated with low birth weight in Iran. The anemia can lead to intra uterine growth retardation. PMID- 26985355 TI - Is there any relation between Duration of breastfeeding and anemia? AB - BACKGROUND: In the early months of life, Breastfeeding increases chance of survival, reduces recovery time after disease and mortality due to infections such as diarrhea and acute respiratory infections. However, infants who are exclusively breast-fed for more than 6 months in developing countries may be at increased risk of anemia. Therefore, the aim of study was to assess the relation between duration of breastfeeding and anemia. MATERIALS AND METHODS: In this analytical cross-sectional study, 400 neonates registered in primary health care system since birth time. Complete blood count and serum ferritin were obtained. Data were analyzed by chi- square test and regression analysis. P-value less than 0.05 was considered significant and 95% confidence interval was noted. RESULTS: Results of this study showed that 199 infants were anemic (Hemoglobin (Hb) concentration <11 mg/dl). Ten percent of anemic patients reported Ferritin< 12ng/dl and %25 of anemic children had iron deficiency anemia (IDA). In Binominal logistic regression, merely kind of delivery and duration of breastfeeding were effective factors. Binominal logistic regression also showed that natural vaginal delivery and exclusive breastfeeding up to 6 months had a significant influence on anemia. Exclusive breast feeding for 6 months or more increased the likelihood of anemia. In addition, 4 months exclusive breastfeeding decreased 0.686 fold the likelihood of anemia. CONCLUSION: According to the results, it seems that revision of health program recommendations for iron supplementation can be constructive. National planning to promote the level of knowledge regarding natural vaginal delivery and appropriate period for clamping can be recommended. PMID- 26985356 TI - The Association of Mean Platelet Volume with Intra Ventricular Hemorrhage and Broncho Pulmonary Dysplasia in Preterm Infants. AB - BACKGROUND: Interventricular hemorrhage (IVH) and Broncho pulmonary dysplasia(BPD) commonly occur in premature infants and they associate with platelet dysfunction. The aim of this study was to investigate the association of MPV and occurrence of IVH and BPD. MATERIALS AND METHODS: In this cross sectional study, 3 groups including IVH, BPD and control were compared. All participants were preterm neonates with <35 weeks of gestation. MPV was recorded during the first 48 hours of life for all cases. Data were reported by descriptive statistics and analyzed by Pearson correlation coefficient, spearman correlation coefficient, paired T test and multinomial regression analysis in SPSS version 17. RESULTS: Higher MPV level was noted in BPD and IVH groups versus control group (9.79+/-0.73 fl and 10+/-1.04 fl versus 8.33+/-0,91 fl p<0.0001). Also, most participants in BPD (93.3%) and IVH (73.3%) groups had MPV >9 fl compared to controls (16.7%) (p<0.0001). Regression analysis showed that only MPV related to the occurrence of IVH (OR=2.200 95%CI p=0.013) and elevated MPV significantly increased duration of O2 therapy (p<0.0001) and mechanical ventilation (p=0.0010). CONCLUSION: MPV value at first 48 hours of life can be noted as a simple biomarker for occurrence of BPD and specially IVH in preterm infants. PMID- 26985358 TI - Trismus Resulting from Infantile Hemangioma of the Parotid: A Rare Case Report. AB - Vascular abnormalities are characterized by increasing number of vessels. Salivary gland tumors are uncommon and their overall incidence is about 3 per 100000 per year. Salivary gland hemangioma makes up 1 % of all salivary gland tumors. Trismus resulting from parotid hemangioma is so rare. The patient was a 6 month-old boy with a huge lesion in his right parotid who referred to Shahid sadoughi hospital of Yazd, Iran. The lesion appeared at 4 months of age and had rapid growth and was suspected as hemangioma after clinical examination and patient had trismus. The lesion was excised without any complications. Five months after surgery, area of the lesion appeared normal. Parotid hemangioma has low potential to turn into malignant form but early detection and biopsy are necessary for decreasing complications. Removal of the mass was the best treatment for the patients with large or complicated hemangioma; however, it should be performed with caution because the tissues may bleed profusely. Patients may have long term survival after surgery. PMID- 26985357 TI - Nanotechnology and Pediatric Cancer: Prevention, Diagnosis and Treatment. AB - Despite development of new approaches for the treatment of cancer disease, it is the second cause of mortality in world. Annually, 30000 persons die in Iran due to cancer diseases. Eighty percent of cancer patients are children which about 50% children lead to death. Given the high rate of cancer-related death, the new approaches for prevention, control, early diagnosis, and treatment of this disease seem necessary. Investigation of new strategies is the major challenge for scientists at recent century. Nanotechnology as a new scientific field with novel and small compounds utilized different fields over the past ten years especially in medicine. This science has come to the forefront in the areas of medical diagnostics, imaging, and therapeutic scheduls. Therefore, it has the potential applications for cancer detection and therapy. This review will discuss the therapeutic applications of different nano-materials in diagnosis, imaging, and delivery of therapeutic agents for the treatment of cancer with a major focus on their applications for the treatment of cancer and cancer- related diseases in children. The advancements in established nanoparticle technologies such as liposomes, polymer micelles, and functionalization regarding tumor targeting and controlled release strategies as well as drug delivery were discussed. It will also review the blood toxicity of used nanostructures. PMID- 26985360 TI - Type I interferon inhibits varicella-zoster virus replication by interfering with the dynamic interaction between mediator and IE62 within replication compartments. AB - BACKGROUND: Varicella-zoster virus (VZV) is the causative agent of varicella and zoster. The immediate-early protein, IE62 is the predominant VZ virion tegument protein, transactivating the expression of all kinetic classes of VZV genes. IE62 is localized to punctae that form DNA replication compartments in the nuclei of VZV infected cells. The morphological changes and the increase in the size of replication compartments that express IE62 are correlated with production of VZ virions. Mammalian Mediator serves as a coactivator of IE62 and functions by bridging DNA-binding transcription factors RNA polymerase II (RNAP II) and their target DNAs for VZV replication. While VZV is highly sensitive to type I interferons (IFNs), how IFN-alpha inhibits early events during VZV replication is poorly understood. RESULTS: In this study, we performed in situ analysis to investigate the effects of IFN-alpha on the dynamic interactions of IE62 with the Mediator MED25 subunit and the RNAP II negative regulator cycle-dependent kinase 8 (CDK8) in VZV infected cells by confocal immunofluorescence. We found that in addition to dose-dependent inhibition of the yields of infectious virus by IFN treatment, IFN-alpha prominently impeded the development of large IE62(+) nuclear compartments and significantly decreased transcription of VZV genes. Both the expression level and stable recruitment of MED25 to IE62(+) replication compartments were inhibited by IFN-alpha. While IFN-alpha treatment upregulated CDK8 expression, redistribution and recruitment of CDK8 to IE62(+) replication compartments in infected cells was not affected by VZV. CONCLUSION: IFN-alpha exerts multiple inhibitory activities against virus infections. In this study, we provide visionary demonstration that continuous translocation of MED25 into VZV replication compartments ensures production of virions. IFN-alpha greatly impedes the formation of a stable complex between IE62 and the Mediator complex thereby suppresses VZV gene transcription. Our demonstration that IFN-alpha-induced antiviral effect against VZV infection is through inhibiting the reorganization of nuclear components uncovers a novel function of IFN-alpha. Targeting the interaction between IE62 and MED25 may offer a novel approach to the development of antiviral agents against VZV infection. PMID- 26985361 TI - The impact of facility characteristics on the use of antipsychotic medications in nursing homes: a cross-sectional study. AB - BACKGROUND: Antipsychotic medications (APMs) are commonly prescribed in nursing homes (NHs) and their excessive use raises concerns about the quality of care. They are often seen as "chemical restraints", and were shown to increase morbidity and mortality risks in NH residents. The objective of this study was to investigate the variability in prevalence in APM use in a sample of Israeli NHs and to examine the effect of facility characteristics on the use of APMs. METHODS: A retrospective cross-sectional study was conducted in 2011 using data which were collected in a sample of NHs in the Tel Aviv district during the annual certification process. Prevalence of APMs was determined on the basis of all residents using antipsychotics on a regular basis. The association between facility characteristics and APM use was assessed by multivariate analysis. RESULTS: Forty-four NHs providing care for 2372 residents were investigated. The prevalence of APM use varied between facilities from 14.8 to 70.6 %, with an overall prevalence of 37.3 %. Multiple linear regression analysis revealed that greater use of APMs was associated with for-profit facilities, facilities in which most of the residents were self-pay, the presence of a "mentally frail" unit, a medical director non-specialized in geriatrics, shortage of social workers and occupational therapists, presence of unsafe/non-fitting equipment or self-aids (e.g., unsafe bath/toilet seats, unsuitable height of tables) and shortage of recreational activities. CONCLUSIONS: A wide variation in APM use was recorded in NHs in the Tel Aviv district. This variation was associated with facility characteristics that undermine quality of care. Application of APM use as a measure of quality in NHs and publicizing their utilization may decrease their overall use. PMID- 26985363 TI - Analysis of the operation of on farm emergency slaughter of bovine animals in the Republic of Ireland. AB - BACKGROUND: On Farm Emergency Slaughter (OFES) is the slaughter outside the slaughterhouse, of an otherwise healthy animal, which has suffered an accident that, for welfare reasons, prevented its transport to a slaughterhouse. The procedure is designed to prevent the transport of welfare compromised animals, which may have veterinary certification to slaughterhouses for Casualty Slaughter (CS), and provides an alternative to the euthanasia and disposal of injured animals that are otherwise fit for human consumption. The aim of this study was to analyse the operation of OFES in the Republic of Ireland between 1st January 2011 and 31st December 2013. METHODS: Data were obtained from the Animal Identification and Movement electronic database of the Department of Agriculture, Food and the Marine. Two structured surveys were designed, one for Official Veterinarians (OVs) who work in slaughterhouses and the second for Private Veterinary Practitioners (PVPs) who work in food animal practice in the Republic of Ireland. Surveys were administered through SurveyMonkey. The total number of bovines slaughtered and the number that underwent OFES in Northern Ireland and the Netherlands were obtained from the Northern Ireland Department of Agriculture and Rural Development and the Netherlands Food and Consumer Safety Authority. RESULTS: OFES is neither widely available nor used in the Republic of Ireland. Results from the OV survey showed that Food Business Operators consider that facilitation of OFES would be detrimental to business. Data from the 5 slaughterhouses which offer OFES showed that acceptance criteria are not standardised. Results from the PVP survey showed that 77 % (n = 79) of PVPs were willing to certify animals for OFES. Fifty four percent (n = 49) were aware of slaughterhouses in their area that provided the service of OFES and 64 % (n = 57) stated a willingness to certify the transport of acutely injured animals to slaughterhouses for CS. Data from the Northern Ireland Department of Agriculture and Rural Development and the Netherlands Food and Consumer Safety Authority indicated a low level of uptake of OFES in the Republic of Ireland compared to Northern Ireland and the Netherlands. CONCLUSION: Based on results reported here, criteria for assessment of risk associated with accepting animals for OFES should be reconsidered. A review of the systems pertaining to OFES and its implementation should be undertaken, including the level and quality of training of all stakeholders, with a view to making OFES more widely available in the Republic of Ireland. PMID- 26985359 TI - Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression. AB - BACKGROUND: Intellectual disability (ID), autism, and epilepsy share frequent yet variable comorbidities with one another. In order to better understand potential genetic divergence underlying this variable risk, we studied genes responsible for monogenic IDs, grouped according to their autism and epilepsy comorbidities. METHODS: Utilizing 465 different forms of ID with known molecular origins, we accessed available genetic databases in conjunction with gene ontology (GO) to determine whether the genetics underlying ID diverge according to its comorbidities with autism and epilepsy and if genes highly penetrant for autism or epilepsy share distinctive features that set them apart from genes that confer comparatively variable or no apparent risk. RESULTS: The genetics of ID with autism are relatively enriched in terms associated with nervous system-specific processes and structural morphogenesis. In contrast, we find that ID with highly comorbid epilepsy (HCE) is modestly associated with lipid metabolic processes while ID without autism or epilepsy comorbidity (ID only) is enriched at the Golgi membrane. Highly comorbid autism (HCA) genes, on the other hand, are strongly enriched within the nucleus, are typically involved in regulation of gene expression, and, along with IDs with more variable autism, share strong ties with a core protein-protein interaction (PPI) network integral to basic patterning of the CNS. CONCLUSIONS: According to GO terminology, autism-related gene products are integral to neural development. While it is difficult to draw firm conclusions regarding IDs unassociated with autism, it is clear that the majority of HCA genes are tightly linked with general dysregulation of gene expression, suggesting that disturbances to the chronology of neural maturation and patterning may be key in conferring susceptibility to autism spectrum conditions. PMID- 26985362 TI - Importance of psychological factors for the recovery from a first episode of acute non-specific neck pain - a longitudinal observational study. AB - BACKGROUND: The influence of psychological factors on acute neck pain is sparsely studied. In a secondary analysis of prospectively collected data, this study investigated how several psychological factors develop in the first three months of acute neck pain and how these factors influence self-perceived recovery. METHODS: Patients were recruited in various chiropractic practices throughout Switzerland between 2010 and 2014. The follow-up telephone interviews were conducted for all patients by research assistants in the coordinating university hospital following a standardized procedure. The population of this study consisted of 103 patients (68 female; mean age = 38.3 +/- 13.8 years) with a first episode of acute (<4 weeks) neck pain. Prior to the first treatment, the patients filled in the Bournemouth Questionnaire (BQ). One week and 1 and 3 months later, they completed the BQ again along with the Patient Global Impression of Change (PGIC). The temporal development (repeated measure ANOVA) of the BQ questions 4 (anxiety), 5 (depression), 6 (fear-avoidance) and 7 (pain locus of control) as well as the influence of these scores on the PGIC were investigated (binary logistic regression analyses, receiver operating curves (ROC)). RESULTS: All psychological parameters showed significant reduction within the first month. The parameter 'anxiety' was associated with outcome at 1 and 3 months (p = 0.013, R(2) = 0.40 and p = 0.039, R(2) = 0.63, respectively). Baseline depression (p = 0.037, R(2) = 0.21), but not baseline anxiety, was a predictor for poor outcome. A high reduction in anxiety within the first month was a significant predictor for favorable outcome after 1 month (p < 0.001; R(2) = 0.57). CONCLUSIONS: Psychological factors emerged from this study as relevant in the early phase of acute neck pain. Particularly persistent anxiety and depression at baseline might be risk factors for a transition to chronic pain that should be addressed in the early management of neck pain patients. PMID- 26985364 TI - Micro-computed tomography scan and virtual histological slide data for the land planarian Obama otavioi (Platyhelminthes). AB - BACKGROUND: We investigated whether images obtained through X-ray micro-computed tomography (MUCT) can be used in conjunction with traditional methods for morphological studies of soft-bodied land planarians. MUCT is non-invasive and provides true-to-scale three-dimensional imagery at high resolution. We compared MUCT-based images of a recently described land planarian species of Obama otavioi (Platyhelminthes) with those obtained from light microphotography of histological sections, most of which were also digitized at high magnification. FINDINGS: The specimens studied were collected in 2012. Subsequent MUCT-based images of the stained body of a paratype show nearly all morphological features provided by traditional histology, with the exception of particularly minute structures, smaller than 5 MUm, such as the sensory pits and single muscle fibers, which are best visible on traditional histological sections. Because the technique is non destructive, the scanned specimen is preserved without damage. The raw and derivative MUCT data and virtual histological sections are freely available in GigaDB. CONCLUSIONS: The MUCT datasets of these stained soft-bodied organisms reveal images of external and internal structures that support previous taxonomic studies. This technique can be particularly important for non-destructively revealing internal details of whole museum specimens at a faster rate than histology alone. High-resolution virtual histological slides also allow further searches for new, previously unstudied morphological features. The use of X-ray equipment with higher resolution can enable smaller sensory organ and muscle fiber details to be seen. The image sets, MUCT-based images and digitized histological slides can be disseminated without the constraints of specimen loans. PMID- 26985365 TI - A need for a systematic genetic evaluation of hereditary polyuric patients. PMID- 26985366 TI - Persistent severe polyuria after renal transplant. AB - Polydipsia and polyuria are common symptoms in patients with diabetes insipidus (DI), which can be due to inadequate vasopressin production (cranial DI) or vasopressin insensitivity (nephrogenic DI). Clinical diagnosis of the subtypes of DI can be tricky. We present a 44-year-old man with a strong family history of DI who had been diagnosed with autosomal dominant nephrogenic DI from infancy. At the age of 40, he had progressed to end-stage renal failure. When he experienced unresolving severe polyuria after renal transplant, further investigations revealed that he was misdiagnosed and that he had a novel mutation causing autosomal dominant cranial DI. PMID- 26985367 TI - Outcome in patients with idiopathic retroperitoneal fibrosis treated with corticosteroid or tamoxifen monotherapy. AB - BACKGROUND: Although corticosteroids (CS) are used primarily in idiopathic retroperitoneal fibrosis (iRPF), tamoxifen (TMX) may be a suitable alternative. We compared outcome with CS or TMX monotherapy for first presentation in a large group of patients with iRPF disease. METHODS: Of all patients with iRPF disease who were seen at our tertiary care referral centre from February 1999 to December 2011, 118 patients were eligible for this retrospective study. Treatment success was defined as the composite of (i) amelioration of symptoms, (ii) computed tomography (CT)-documented mass regression and, if applicable, (iii) definitive removal of ureteral stent or nephrostomy tube. Recurrence was defined as recurrence of signs and symptoms and/or CT-documented mass increase after initial treatment success with primary treatment. RESULTS: Presenting signs and symptoms did not differ between patients treated with CS (n = 50) or TMX (n = 68). Time to amelioration of symptoms after treatment initiation was shorter in CS-treated patients [CS, 2.0 (0.8-3.8) weeks versus TMX, 4.0 (2.0-6.0) weeks; P < 0.01]. Short-term percentual decrease in acute-phase reactant levels (P < 0.001 for both erythrocyte sedimentation rate and C-reactive protein) and serum creatinine level (P < 0.01) following treatment initiation was greater in CS-treated patients compared with that in TMX-treated patients. Mass regression at first follow-up CT scan was observed more frequently in CS-treated patients (CS, 84.0% versus TMX, 68.3%; P = 0.05) with no difference in time interval from treatment initiation to first follow-up CT between groups [CS, 5 (2-7) months versus TMX, 4 (4-5) months; P = 0.34]. Definite treatment success was non-significantly higher in CS-treated patients (CS, 72.7% versus TMX, 58.3%; P = 0.15). In patients with initial treatment success with primary treatment, recurrence rate was lower in TMX treated patients (CS, 62.5% versus TMX, 21.4%; P < 0.01). CONCLUSIONS: CS are superior to TMX in treating iRPF disease. However, in patients with initial treatment success with primary treatment, recurrence rate was lower in TMX treated patients. PMID- 26985368 TI - Acute kidney injury, long-term renal function and mortality in patients undergoing major abdominal surgery: a cohort analysis. AB - BACKGROUND: Acute kidney injury (AKI) is frequent during hospitalization and may contribute to adverse consequences. We aimed to evaluate long-term adverse renal function and mortality after postoperative AKI in a cohort of patients undergoing major abdominal surgery. METHODS: We performed a retrospective analysis of adult patients who underwent major non-vascular abdominal surgery between January 2010 and February 2011 at the Department of Surgery II of Hospital de Santa Maria Centro Hospitalar Lisboa Norte, Portugal. Exclusion criteria were as follows: chronic kidney disease on renal replacement therapy, undergoing renal replacement therapy the week before surgery, death before discharge and loss to follow-up through January 2014. Patients were categorized according to the development of postoperative AKI in the first 48 h after surgery using the Kidney Disease: Improving Global Outcomes classification. AKI was defined by an increase in absolute serum creatinine (SCr) >=0.3 mg/dL or by a percentage increase in SCr >=50% and/or by a decrease in urine output to <0.5 mL/kg/h for >6 h. Adverse renal outcomes (need for long-term dialysis and/or a 25% decrease in estimated glomerular filtration rate after hospital discharge) and mortality after discharge were evaluated. Cumulative mortality was analysed with the Kaplan-Meier method and log-rank test and outcome predictive factors with the Cox regression. Significance was set at P < 0.05. RESULTS: Of 390 selected patients, 72 (18.5%) developed postoperative AKI. The median follow-up was 38 months. Adverse renal outcomes and death after hospital discharge were more frequent among AKI patients (47.2 versus 22.0%, P < 0.0001; and 47.2 versus 20.5%, P < 0.0001, respectively). The 4 year cumulative probability of death was 44.4% for AKI patients, while it was 19.8% for patients with no AKI (log-rank test, P < 0.0001). In multivariate analysis, AKI was a risk factor for adverse renal outcomes (adjusted hazard ratio 1.6, P = 0.046) and mortality (adjusted hazard ratio 1.4, P = 0.043). CONCLUSIONS: AKI after major abdominal surgery was independently associated with the risk of long-term need for dialysis and/or renal function decline and with the risk of death after hospital discharge. PMID- 26985369 TI - Wasp sting-induced acute kidney injury. AB - BACKGROUND: Wasp stings are a common form of envenomation in tropical countries, especially in farmers. The aim of this study was to document the clinical presentation, treatment and outcomes of patients with acute kidney injury (AKI) due to multiple wasp stings in a tertiary care hospital. METHODS: We conducted a retrospective observational study of patients with multiple wasp stings and AKI at the Department of Nephrology between July 2011 and August 2015. The clinical features, laboratory data, treatment details and outcomes were noted. RESULTS: A total of 11 patients were included. All were from rural areas. All of them were males with age ranging from 21 to 70 years, mean age 45 +/- 23 years. Six had oliguria and two had hypotension. All 11 patients had evidence of rhabdomyolysis and three also had hemolysis. Ten patients required hemodialysis with a mean number of hemodialysis sessions of 8.7 +/- 2.8. Renal biopsy carried out on four patients, showed acute interstitial nephritis (AIN) in one patient, acute tubular necrosis (ATN) in two patients, and one patient had both AIN and ATN. The two patients with AIN were given steroids, while all other patients were managed with supportive measures. One patient died within 48 h of presentation due to shock. At a mean follow-up of 24 months, one had progressed to chronic kidney disease and the remaining nine had normal renal function. CONCLUSIONS: Wasp sting is an occupational hazard. AKI was most commonly due to rhabdomyolysis. Early renal biopsy is indicated in those patients who do not respond to supportive measures. Timely dialysis and steroid in the case of AIN improves renal survival. PMID- 26985370 TI - Phoxilium((r)) reduces hypophosphataemia and magnesium supplementation during continuous renal replacement therapy. AB - BACKGROUND: Although associated with severe clinical complications, phosphate remains a neglected ion. Additionally, phosphate balance during continuous renal replacement therapy (CRRT) is complex and multifunctional. The present retrospective study investigated the effects of phosphate-containing CRRT fluid on phosphate homeostasis. METHODS: We retrospectively analysed 112 patients treated with CRRT at Skane University Hospital, Sweden. The control group was treated with Hemosol((r)) B0 (no phosphate; n = 36) as dialysis and replacement fluid, while the study group received Phoxilium((r)) (phosphate; n = 76) as dialysis fluid and Hemosol((r)) B0 as replacement fluid. RESULTS: Hypophosphataemia (<0.7 mM) occurred in 15% of the treatment days in the control group compared with 7% in the study group (P = 0.027). Magnesium substitution was reduced by 40% in the study group (P < 0.001). No differences in acid-base parameters were detected between the groups. CONCLUSIONS: In this larger cohort, we could confirm that Phoxilium((r)) reduced the episodes of hypophosphataemia during CRRT. A beneficial effect on magnesium balance could also be observed. PMID- 26985371 TI - Atypical anti-glomerular basement membrane disease. AB - BACKGROUND: Anti-glomerular basement membrane (anti-GBM) disease classically presents with aggressive necrotizing and crescentic glomerulonephritis, often with pulmonary hemorrhage. The pathologic hallmark is linear staining of GBMs for deposited immunoglobulin G (IgG), usually accompanied by serum autoantibodies to the collagen IV alpha-3 constituents of GBMs. METHODS: Renal pathology files were searched for cases with linear anti-GBM to identify cases with atypical or indolent course. Histopathology, laboratory studies, treatment and outcome of those cases was reviewed in detail. RESULTS: Five anti-GBM cases with atypical clinicopathologic features were identified (accounting for ~8% of anti-GBM cases in our laboratory). Kidney biopsies showed minimal glomerular changes by light microscopy; one patient had monoclonal IgG deposits in an allograft (likely recurrent). Three patients did not have detectable serum anti-GBM by conventional assays. Three patients had indolent clinical courses after immunosuppressive treatment. One patient, untreated after presenting with brief mild hematuria, re presented after a short interval with necrotizing and crescentic glomerulonephritis. CONCLUSIONS: Thorough clinicopathologic characterization and close follow-up of patients with findings of atypical anti-GBM on renal biopsy are needed. Review of the literature reveals only rare well-documented atypical anti-GBM cases to date, only one of which progressed to end-stage kidney disease. PMID- 26985372 TI - Post-infectious glomerulonephritis with crescents in adults: a retrospective study. AB - BACKGROUND: Crescent formation generally reflects severe glomerular injury. There is sparse literature on post-infectious glomerulonephritis (PIGN) with crescents in adults. This retrospective study looked at nine such cases to see if there is a correlation between the severity of presentation, steroid treatment, histological severity and outcome. METHODS: Biopsy reports of all the adults who underwent kidney biopsy from February 2010 to June 2014 in a tertiary care hospital were screened and all the cases with the diagnosis of PIGN with crescents were selected. Clinical presentation, laboratory data, histology, treatment and outcome were analysed. RESULTS: Six patients had evidence of recent/current infection, but all except two were non-streptococcal. The mean creatinine was 360.67 MUmol/L (range 70.72-770.85) and the mean estimated glomerular filtration rate (MDRD eGFR) was 30.28 mL/min/1.73 m(2) (range 6.4 111.1) on presentation. All five patients who were treated with steroids had an excellent response. Among the four patients who did not receive steroids, two were left with significant renal impairment (mean MDRD eGFR 23.5 mL/min/1.73 m(2)) at a mean follow-up of 15.5 months (range 10-21). The mean percentage of glomeruli with crescents was 36.13% (range 11.76-100) and except in one, there was no tubular atrophy or interstitial fibrosis and none had glomerulosclerosis. None of the patients progressed to end-stage renal disease. CONCLUSION: Non streptococcal infections are more common precipitants. There was no correlation between histological and clinical severity. Patients treated with steroids had better renal outcomes. PMID- 26985373 TI - Treatment pattern in patients with idiopathic membranous nephropathy-practices in Sweden at the start of the millennium. AB - BACKGROUND: Idiopathic membranous nephropathy (MN) is one of the leading causes of nephrotic syndrome in adults and may result in end-stage renal disease (ESRD). In this retrospective study, we describe the outcomes and treatment patterns of patients with idiopathic MN in six nephrology clinics in the western part of Sweden. METHODS: Seventy-three consecutive patients with biopsy-proven MN in the years 2000-12 were classified as idiopathic, i.e. secondary forms were excluded. The patients were followed retrospectively for a mean period of 83 months and clinical data were collected through the medical files. RESULTS: A high proportion (88%) of the patients received supportive treatment with angiotensin converting enzyme inhibition, angiotensin receptor blockade and/or statins. At the end of follow-up, 43 patients were in complete remission, 12 in partial remission, 10 patients had developed ESRD and 8 patients had on-going proteinuria. Fifty-one per cent of the patients received immunosuppressive therapy and the choice of therapy varied between and within the clinics. There was a tendency to initiate specific treatment at an early point instead of awaiting a possible spontaneous remission (21% of the patients), and non recommended therapy such as corticosteroids only was used in a high proportion of these cases (47%). CONCLUSIONS: Even though the treatment recommendations in idiopathic MN have not changed the last decade, the question of whom and when to treat seems to lead to uncertainty. Recent studies have presented promising results supporting the PLA2R antibody the predictive marker needed for this patient group. The diverse treatment approach presented in this study might have resulted in a worse outcome than expected. Hopefully, unnecessary exposure to immunosuppressive therapy or delayed treatment can be avoided through better support, education and treatment forums, and thus result in an improved outcome. PMID- 26985374 TI - Necrotizing and crescentic glomerulonephritis with membranous nephropathy in a patient exposed to levamisole-adulterated cocaine. AB - Levamisole is an antihelminthic agent widely used as an adulterant of illicit cocaine recently implicated as a cause of antineutrophil cytoplasmic antibody (ANCA)-associated microscopic polyangiitis in cocaine abusers. An isolated case of membranous nephropathy (MN) associated with levamisole exposure has also been reported. We report the first case, to our knowledge, of a patient with both microscopic polyangiitis manifest as a pauci-immune necrotizing and crescentic glomerulonephritis and concurrent MN in the setting of chronic cocaine abuse and presumed levamisole exposure, raising the hypothesis that levamisole was the causative agent in the development of this rare dual glomerulopathy. PMID- 26985375 TI - Minimal change disease onset observed after bevacizumab administration. AB - This is a report of a patient with minimal change disease (MCD) onset after bevacizumab administration. A 72-year-old man with inoperable Grade 3 astrocytoma was treated with a combination of temozolomide and the vascular endothelial growth factor monoclonal antibody bevacizumab. After two biweekly treatments, he developed nephrotic syndrome. Despite cessation of bevacizumab, his renal function deteriorated and a renal biopsy disclosed MCD. Thereafter, he was started on high-dose oral prednisone and renal function immediately improved. Within weeks, the nephrotic syndrome resolved. Although rare, biologic agents can cause various glomerulopathies that can have important therapeutic implications. MCD should be considered in patients who develop nephrotic syndrome while exposed to antiangiogenic agents. PMID- 26985376 TI - Renal effects of BRAF inhibitors: a systematic review by the Cancer and the Kidney International Network. AB - Advanced melanoma has been traditionally unresponsive to standard chemotherapy agents and used to have a dismal prognosis. Genetically targeted small-molecule inhibitors of the oncogenic BRAF V600 mutation or a downstream signaling partner (MEK mitogen-activated protein kinase) are effective treatment options for the 40 50% of melanomas that harbor mutations in BRAF. Selective BRAF and MEK inhibitors induce frequent and dramatic objective responses and markedly improve survival compared with cytotoxic chemotherapy. In the past decade after discovery of this mutation, drugs such as vemurafenib and dabrafenib have been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of V600-mutated melanomas. While the initial trials did not signal any renal toxicities with the BRAF inhibitors, recent case reports, case series and FDA adverse reporting systems have uncovered significant nephrotoxicities with these agents. In this article, we systematically review the nephrotoxicities of these agents. Based on recently published data, it appears that there are lower rates of kidney disease and cutaneous lesions seen with dabrafenib compared with vemurafenib. The pathology reported in the few kidney biopsies done so far are suggestive of tubulo interstitial damage with an acute and chronic component. Electrolyte disorders such as hypokalemia, hyponatremia and hypophosphatemia have been reported as well. Routine monitoring of serum creatinine and electrolytes and calculation of glomerular filtration rate prior to the first administration when treating with dabrafenib and vemurafenib are essential. PMID- 26985377 TI - Can we routinely measure patient involvement in treatment decision-making in chronic kidney care? A service evaluation in 27 renal units in the UK. AB - BACKGROUND: Shared decision making is considered an important aspect of chronic disease management. We explored the feasibility of routinely measuring kidney patients' involvement in making decisions about renal replacement therapy (RRT) in National Health Service settings. METHODS: We disseminated a 17-item paper questionnaire on involvement in decision-making among adult patients with established kidney failure who made a decision about RRT in the previous 90 days (Phase 1) and patients who had been receiving RRT for 90-180 days (Phase 2). Recruitment rates were calculated as the ratio between the number of included and expected eligible patients (I : E ratio). We assessed our sample's representativeness by comparing demographics between participants and incident patients in the UK Renal Registry. RESULTS: Three hundred and five (Phase 1) and 187 (Phase 2) patients were included. For Phase 1, the I : E ratio was 0.44 (range, 0.08-2.80) compared with 0.27 (range, 0.04-1.05) in Phase 2. Study participants were more likely to be white compared with incident RRT patients (88 versus 77%; P < 0.0001). We found no difference in age, gender or social deprivation. In Phases 1 and 2, the majority reported a collaborative decision making style (73 and 69%), and had no decisional conflict (85 and 76%); the median score for shared decision-making experience was 12.5 (Phase 1) and 10 (Phase 2) out of 20. CONCLUSION: Our study shows the importance of assessing the feasibility of data collection in a chronic disease context prior to implementation in routine practice. Routine measurement of patient involvement in established kidney disease treatment decisions is feasible, but there are challenges in selecting the measure needed to capture experience of involvement, reducing variation in response rate by service and identifying when to capture experience in a service managing people's chronic disease over time. PMID- 26985379 TI - Does lower urine-specific gravity predict decline in renal function and hypernatremia in older adults exposed to psychotropic medications? An exploratory analysis. AB - BACKGROUND: Exposure to psychotropic agents, including lithium, antipsychotics and antidepressants, has been associated with nephrogenic diabetes insipidus (NDI). This is especially concerning in older adults already at risk of developing chronic kidney disease (CKD) and hypernatremia with advanced aging. This study investigates whether commonly performed random urine-specific gravity (USG) tests can predict adverse NDI outcomes (CKD and hypernatremia) in psychotropic-exposed older adults. METHODS: This was a retrospective longitudinal study of 173 geriatric psychiatry patients (age >=65 years) exposed to psychotropic medications. Our main continuous outcome was 'decrease in estimated glomerular filtration rate (eGFR) >10 mL/min/1.73 m(2)' over 5-year follow-up. Hypernatremia and acute kidney injury (AKI) were secondary outcomes. Whether baseline USG <1.010 predicted outcomes was assessed in bivariate and multivariate analyses. RESULTS: USG <1.010 predicted hypernatremia episodes (sodium concentration >=150 mmol/L-28.1 versus 12%, chi(2) = 4.7, P = 0.03). USG <1.010 [odds ratio 2.36 (95% confidence interval 0.93-6.0), P = 0.07], baseline eGFR and typical antipsychotic use independently predicted decrease in eGFR >10 mL/min/1.73 m(2). Patients with a single baseline sodium concentration of >=140 mmol/L and USG <1.010 have a 26.3% incidence of AKI and a 57.9% incidence of hypernatremia over the ensuing 5 years. CONCLUSIONS: In psychotropic-exposed older adults, there appears to be a clinically important association between low USG and developing both hypernatremia and CKD. USG may be a useful surrogate measure for NDI-related outcomes in large administrative database studies, where ideal measures such as 24-h urine volume may not be available. PMID- 26985380 TI - The effects of vitamin K supplementation and vitamin K antagonists on progression of vascular calcification: ongoing randomized controlled trials. AB - BACKGROUND: The extent and the progression of vascular calcification (VC) are independent predictors of cardiovascular risk in the haemodialysis population. Vitamin K is essential for the activation of matrix gla protein (MGP), a powerful inhibitor of tissue calcification. Functional vitamin K deficiency may contribute to the high VC burden in haemodialysis patients. In addition, haemodialysis patients are frequently treated with vitamin K antagonists, mainly to prevent stroke in atrial fibrillation, potentially compounding the cardiovascular risk in these already vulnerable patients. New oral anticoagulants (NOACs) are valuable alternatives to vitamin K antagonists in the general population, but their use in dialysis has been encumbered by substantial renal clearance. However, a recent pharmacokinetic study provided information on how to use rivaroxaban in haemodialysis patients. METHODS: We conduct a randomized, prospective, multicentre, open-label interventional clinical trial that will include 117 chronic haemodialysis patients with non-valvular atrial fibrillation, treated with or candidates for treatment with vitamin K antagonists. Patients will be randomized to a vitamin K antagonist titrated weekly to an international normalized ratio between 2 and 3, a daily dose of rivaroxaban of 10 mg, or a daily dose of rivaroxaban 10 mg with a thrice weekly supplement of 2000 ug vitamin K2. Cardiac computed tomography, pulse wave velocity (PWV) measurements and MGP sampling will be performed at baseline, 6 months, 12 months and 18 months. Primary endpoints include progression of coronary artery and thoracic aorta calcification and changes in PWV. Secondary endpoints are progression of aortic and mitral valve calcification, all-cause mortality, major adverse cardiovascular events, stroke and bleeding. The ClinicalTrials.gov database was searched to retrieve related trials. RESULTS: Seven trials, three of which are performed in the haemodialysis population, evaluate whether pharmacological doses of vitamin K1 or K2 retard progression of VC. Five studies compare the effect of warfarin and NOACs on progression of VC, the present study being the only conducted in the dialysis population. CONCLUSION: Vitamin K deficiency may be a modifiable cardiovascular risk factor in the haemodialysis population. Conversely, vitamin K antagonists may aggravate VC burden in haemodialysis patients. Several ongoing trials may provide an answer to these questions in the near future. PMID- 26985378 TI - Safety concerns about intravenous iron therapy in patients with chronic kidney disease. AB - Anaemia in chronic kidney disease (CKD) is managed primarily with erythropoiesis stimulating agents (ESAs) and iron therapy. Following concerns around ESA therapy, intravenous (IV) iron is being administered more and more worldwide. However, it is still unclear whether this approach is safe at very high doses or in the presence of very high ferritin levels. Some observational studies have shown a relationship between either high ferritin level or high iron dose and increased risk of death, cardiovascular events, hospitalization or infection. Others have not been able to confirm these findings. However, they suffer from indication biases. On the other hand, the majority of randomized clinical trials have only a very short follow-up (and thus drug exposure) and are inadequate to assess the mortality risk. None of them have tested the role of different iron doses on hard end points. With the lack of clear evidence coming from well designed and large-scale studies, several data suggest that excessive iron therapy may be toxic in several aspects, ranging from iron overload to tissue damage from labile iron. A number of experimental and clinical data suggest that either excessive iron therapy or iron overload may be a possible culprit of atherogenesis. The process seems to be mediated by oxidative stress. Iron therapy should also be used cautiously in the presence of active infections, since iron is essential for bacterial growth. Recently, the European Medicines Agency officially raised concerns about rare hypersensitivity reactions following IV iron administration. The balance has been in favour of benefits. In several European countries, this has created a lot of confusion and somewhat slowed the run towards excessive use. Altogether, IV iron remains a mainstay of anaemia treatment in CKD patients. However, in our opinion, its excessive use should be avoided, especially in patients with high ferritin levels and when ESA agents are not contraindicated. PMID- 26985381 TI - Calcifying circulating cells: an uncharted area in the setting of vascular calcification in CKD patients. AB - Vascular calcification, occurring during late-stage vascular and valvular disease, is highly associated with chronic kidney disease-mineral and bone disorders (CKD-MBD), representing a major risk factor for cardiovascular morbidity and mortality. The hallmark of vascular calcification, which involves both media and intima, is represented by the activation of cells committed to an osteogenic programme. Several studies have analysed the role of circulating calcifying cells (CCCs) in vascular calcification. CCCs are bone marrow (BM) derived cells with an osteogenic phenotype, participating in intima calcification processes and defined by osteocalcin and bone alkaline phosphatase expression. The identification of CCCs in diabetes and atherosclerosis is the most recent, intriguing and yet uncharted chapter in the scenario of the bone-vascular axis. Whether osteogenic shift occurs in the BM, the bloodstream or both, is not known, and also the factors promoting CCC formation have not been identified. However, it is possible to recognize a common pathogenic commitment of inflammation in atherosclerosis and diabetes, in which metabolic control may also have a role. Currently available studies in patients without CKD did not find an association of CCCs with markers of bone metabolism. Preliminary data on CKD patients indicate an implication of mineral bone disease in vascular calcification, as a consequence of functional and anatomic integrity interruption of BM niches. Given the pivotal role that parathyroid hormone and osteoblasts play in regulating expansion, mobilization and homing of haematopoietic stem/progenitors cells, CKD MBD could promote CCC formation. PMID- 26985382 TI - Early changes in body weight and blood pressure are associated with mortality in incident dialysis patients. AB - BACKGROUND: While much research is devoted to identifying novel biomarkers, addressing the prognostic value of routinely measured clinical parameters is of great interest. We studied early blood pressure (BP) and body weight (BW) trajectories in incident haemodialysis patients and their association with all cause mortality. METHODS: In a cohort of 357 incident patients, we obtained all records of BP and BW during the first 90 days on dialysis (over 12 800 observations) and analysed trajectories using penalized B-splines and mixed linear regression models. Baseline comorbidities and all-cause mortality (median follow-up: 2.2 years) were obtained from the French Renal Epidemiology and Information Network (REIN) registry, and the association with mortality was assessed by Cox models adjusting for baseline comorbidities. RESULTS: During the initial 90 days on dialysis, there were non-linear decreases in BP and BW, with milder slopes after 15 days [systolic BP (SBP)] or 30 days [diastolic BP (DBP) and BW]. SBP or DBP levels at dialysis initiation and changes in BW occurring in the first month or during the following 2 months were significantly associated with survival. In multivariate models adjusting for baseline comorbidities and prescriptions, higher SBP value and BW slopes were independently associated with a lower risk of mortality. Hazard ratios of mortality and 95% confidence intervals were 0.92 (0.85-0.99) for a 10 mmHg higher SBP and 0.76 (0.66-0.88) for a 1 kg/month higher BW change on Days 30-90. CONCLUSIONS: BW loss in the first weeks on dialysis is a strong and independent predictor of mortality. Low BP is also associated with mortality and is probably the consequence of underlying cardiovascular diseases. These early markers appear to be valuable prognostic factors. PMID- 26985384 TI - Improving vascular access outcomes: attributes of arteriovenous fistula cannulation success. AB - BACKGROUND: Arteriovenous fistulas (AVFs) are the preferred access for hemodialysis (HD) yet they are underutilized. Cannulation of the fistula is a procedure requiring significant skill development and refinement and if not done well can have negative consequences for patients. The nurses' approach, attitude and skill with cannulation impacts greatly on the patient experience. Complications from miscannulation or an inability to needle fistulas can result in the increased use of central venous catheters. Some nurses remain in a state of a 'perpetual novice' resulting in a viscous cycle of negative patient consequences (bruising, pain), further influencing patients' decisions not to pursue a fistula or abandon cannulation. METHOD: This qualitative study used organizational development theory (appreciative inquiry) and research method to determine what attributes/activities contribute to successful cannulation. This can be applied to interventions to promote change and skill development in staff members who have not advanced their proficiency. Eighteen HD nurses who self identified with performing successful cannulation participated in audio-recorded interviews. The recordings were transcribed verbatim. The data were analyzed using content analysis. RESULTS: Four common themes, including patient-centered care, teamwork, opportunity and skill and nurse self-awareness, represented successful fistula cannulation. Successful cannulation is more than a learned technique to correctly insert a needle, but rather represents contextual influences and interplay between the practice environment and personal attributes. CONCLUSIONS: Practice changes based on these results may improve cannulation, decrease complications and result in better outcomes for patients. Efforts to nurture positive patient experiences around cannulation may influence patient decision-making regarding fistula use. PMID- 26985383 TI - Hemodialysis outcomes in a global sample of children and young adult hemodialysis patients: the PICCOLO MONDO cohort. AB - BACKGROUND: The aim of this study was to describe the experience of pediatric and young adult hemodialysis (HD) patients from a global cohort. METHODS: The Pediatric Investigation and Close Collaborative Consortium for Ongoing Life Outcomes for MONitoring Dialysis Outcomes (PICCOLO MONDO) study provided de identified electronic information of 3244 patients, ages 0-30 years from 2000 to 2012 in four regions: Asia, Europe, North America and South America. The study sample was categorized into pediatric (<=18 years old) and young adult (19-30 years old) groups based on the age at dialysis initiation. RESULTS: For those with known end-stage renal disease etiology, glomerular disease was the most common diagnosis in children and young adults. Using Europe as a reference group, North America [odds ratio (OR) 2.69; CI 1.29, 5.63] and South America (OR 4.21; CI 2.32, 7.63) had the greatest mortality among young adults. North America also had higher rates of overweight, obesity, hypertension, cardiovascular disease, hospitalizations and secondary diabetes compared with all other regions. Initial catheter use was greater for North American (86.4% in pediatric patients and 75.2% in young adults) and South America (80.6% in pediatric patients and 75.9% in young adults). Catheter use at 1-year follow-up was most common in North American children (77.3%) and young adults (62.9%). Asia had the lowest rate of catheter use. For both age groups, dialysis adequacy (equilibrated Kt/V) ranged between 1.4 and 1.5. In Asia, patients in both age groups had significantly longer treatment times than in any other region. CONCLUSIONS: The PICCOLO MONDO study has provided unique baseline and 1-year follow-up information on children and young adults receiving HD around the globe. This cohort has brought to light aspects of care in these age groups that warrant further investigation. PMID- 26985386 TI - Therapeutic drug monitoring of enteric-coated mycophenolate sodium by limited sampling strategies is associated with a high rate of failure. AB - BACKGROUND: Therapeutic drug monitoring of mycophenolic acid (MPA) is usually performed with a limited sampling strategy (LSS), which relies on a limited number of blood samples and subsequent extrapolation of the global exposure to MPA. LSS is usually performed successfully with mycophenolate mofetil (MMF), but data on enteric-coated mycophenolate sodium (EC-MPS) are scarce. Here, we evaluated the feasibility of 6-h LSS therapeutic drug monitoring with EC-MPS compared with MMF monitoring among kidney transplant recipients. METHODS: Sixty two patients who received EC-MPS during the first 6 months of transplantation were compared with a matched group of 64 MMF-treated kidney transplant recipients. The area under the curve (AUC) was computed by LSS using multiple concentration time points (0, 1, 2, 3 and 6 h post-dose) and a trapezoidal rule. Patients had MPA therapeutic drug monitoring performed on two occasions, one within 2 weeks and the second after 3-4 months of transplantation. RESULTS: EC MPS monitoring and MMF therapeutic drug monitoring were not interpretable in 34.5% (n = 40/116) and 1.8% (n = 2/112) of patients, respectively {relative risk [RR] 19.3 [95% confidence interval (CI) 4.8-78.0]; P < 0.0001}. The main cause of abnormal EC-MPS therapeutic drug monitoring was delayed absorption of both the previous evening and the morning dose, resulting in MPA plasma levels before the next morning dose being higher than MPA plasma levels measured at 1, 2 and 3 h after taking EC-MPS. Cyclosporin in association with MMF significantly increased the risk of low AUC values (<30 mg h/L) in comparison with tacrolimus [55% (n = 11/20) and 10% (n = 9/88), respectively; RR 5.4 (95% CI 2.6-11.2); P < 0.0001]. CONCLUSIONS: The risk of therapeutic drug monitoring failure with EC-MPS is >30% during the first 6 months of renal transplantation. Delayed pharmacokinetics was the main reason. In contrast, the risk of therapeutic drug monitoring failure was substantially lower with MMF. PMID- 26985385 TI - BK polyoma virus infection and renal disease in non-renal solid organ transplantation. AB - BK virus (BKV) is a non-enveloped DNA virus of the polyomaviridae family that causes an interstitial nephritis in immunosuppressed patients. BKV nephropathy is now a leading cause of chronic kidney disease and early allograft failure following kidney transplantation. It is also known to cause renal disease with a progressive decline in kidney function in non-renal solid organ transplant (NRSOT) recipients, although the disease may not be recognized nor its impact appreciated in this patient population. In this report, we review the existing literature to highlight our current understanding of its incidence in NRSOT populations, the approaches to diagnosis and the potential treatment options. PMID- 26985387 TI - Frailty and comorbidity are independent predictors of outcome in patients referred for pre-dialysis education. AB - BACKGROUND: The incidence of chronic kidney disease (CKD) is rising and is likely to continue to do so for the foreseeable future, with the fastest growth seen among adults >=75 years of age. Elderly patients with advanced CKD are likely to have a higher burden of comorbidity and frailty, both of which may influence their disease outcome. For these patients, treatment decisions can be complex, with the current lack of robust prognostic tools hindering the shared decision making process. The current study aims to assess the impact of comorbidity and frailty on the outcomes of patients referred for pre-dialysis education. METHODS: We performed a single-centre study of patients (n = 283) referred for pre dialysis education between 2010 and 2012. The Charlson Comorbidity Index (CCI) and Clinical Frailty Scale (CFS) were used to assess comorbid disease burden and frailty, respectively. Follow-up data were collected until February 2015. RESULTS: The CCI and CFS scores at the time of referral to the pre-dialysis service were independent predictors of mortality. Within the study follow-up period, 76% of patients with a high CFS score at the time of pre-dialysis education had died, with 63% of these patients not commencing dialysis before death. CONCLUSION: A relatively simple frailty scale and comorbidity score could be used to predict survival and better inform the shared decision-making process for patients with advanced kidney disease. PMID- 26985388 TI - Teaching renal physiology in the 21st century: focus on acid-base physiology. AB - A thorough understanding of renal physiology, and in particular acid-base physiology, is essential for an understanding of nephrology. Difficulties in both teaching and learning this material are major impediments to attracting medical trainees into nephrology. Approaches to teaching renal physiology include collaborative learning, computer-based learning and laboratory-based learning. Computer-based learning applications are becoming increasingly popular and can be useful, but are most successful when they incorporate interactive components. Students also note that the presence of a live instructor remains desirable. Some concepts of renal and in particular acid-base physiology can be taught using structured self-experimentation, a practice with a long tradition that possibly should be revitalized. PMID- 26985390 TI - The Health Experts onLine at Portsmouth (HELP) system: One-year review of adult and Pediatric Asynchronous Telehealth Consultations. AB - INTRODUCTION: The Health Experts onLine at Portsmouth teleconsultation system is designed to connect health providers in the Navy Medicine East Region to specialists at Naval Medical Center Portsmouth. METHODS: A review of the first year of the Health Experts onLine at Portsmouth system was performed. Data on each teleconsultation were extracted from the Health Experts onLine at Portsmouth system database and analyzed. RESULTS: From June 2014 to May 2015 there have been 585 teleconsultations. Providers stationed on 36 ships/submarines and at 28 remote military treatment facilities have utilized the Health Experts onLine at Portsmouth system. Over 280 specialists in 34 different specialties were consulted. The median time to first response from a specialist was 6 h and 8 min, with 75% of all consults being addressed within 24 h. Eighteen medevacs were recommended. Thirty-nine potential medevacs were prevented, and 100 potential civilian network deferrals were prevented, resulting in an estimated savings of over US$580,000. DISCUSSION: Based on the 1-year metrics, Health Experts onLine at Portsmouth has provided improved access and quality of care to service members and their families throughout the Navy Medicine East Region. It has helped avoid over US$580,000 in unnecessary cost burden. Further review at the 2-year time interval will demonstrate the continued growth and effectiveness of the Health Experts onLine at Portsmouth system. PMID- 26985389 TI - The financial burden of out-of-pocket expenses in the United States and Canada: How different is the United States? AB - BACKGROUND: This article compares the burden that medical cost-sharing requirements place on households in the United States and Canada. It estimates the probability that individuals with similar demographic features in the two countries have large medical expenses relative to income. METHOD: The study uses 2010 nationally representative household survey data harmonized for cross national comparisons to identify individuals with high medical expenses relative to income. Using logistic regression, it estimates the probability of high expenses occurring among 10 different demographic groups in the two countries. RESULTS: The results show the risk of large medical expenses in the United States is 1.5-4 times higher than it is in Canada, depending on the demographic group and spending threshold used. The United States compares least favorably when evaluating poorer citizens and when using a higher spending threshold. CONCLUSION: Recent health care reforms can be expected to reduce Americans' catastrophic health expenses, but it will take very large reductions in out-of pocket expenditures-larger than can be expected-if poorer and middle-class families are to have the financial protection from high health care costs that their counterparts in Canada have. PMID- 26985391 TI - Gastric siderosis: An under-recognized and rare clinical entity. AB - The increased deposition of iron in gastric mucosa is known as gastric siderosis. It is believed that the only regulated step of the iron metabolism cycle occurs during absorption in the small intestine. Once this system becomes overwhelmed due to either local or widespread iron levels, then iron can be absorbed very quickly by a passive concentration-dependent mechanism. This excess iron is initially stored in the liver but later can be found in the pancreas, heart and joints. Excess iron is not expected to deposit in the gastric mucosa. This gastric deposition has been found in association with hemochromatosis, oral iron medications, alcohol abuse, blood transfusions, hepatic cirrhosis and spontaneous portacaval shunt with esophageal varices. The precise mechanism of this iron deposition in gastric epithelial and stromal cells is still not well understood; thus, identification of iron in gastric mucosa raises many questions. On histology, the pattern of deposition is variable, and recognition of the pattern is often useful to choose the appropriate workup for the patient and to diagnose and possibly treat the cause of iron overload. In this article, we have described a well-referenced review of this rare clinical entity with different histological patterns, diagnostic tests and the clinical significance of the different patterns of iron deposition. PMID- 26985392 TI - Medication regimen complexity and readmissions after hospitalization for heart failure, acute myocardial infarction, pneumonia, and chronic obstructive pulmonary disease. AB - OBJECTIVES: Readmission rate is increasingly being viewed as a key indicator of health system performance. Medication regimen complexity index scores may be predictive of readmissions; however, few studies have examined this potential association. The primary objective of this study was to determine whether medication regimen complexity index is associated with all-cause 30-day readmission after admission for heart failure, acute myocardial infarction, pneumonia, or chronic obstructive pulmonary disease. METHODS: This study was an institutional review board-approved, multi-center, case-control study. Patients admitted with a primary diagnosis of heart failure, acute myocardial infarction, pneumonia, or chronic obstructive pulmonary disease were randomly selected for inclusion. Patients were excluded if they discharged against medical advice or expired during their index visit. Block randomization was utilized for equal representation of index diagnosis and site. Discharge medication regimen complexity index scores were compared between subjects with readmission versus those without. Medication regimen complexity index score was then used as a predictor in logistic regression modeling for readmission. RESULTS: Seven hundred and fifty-six patients were randomly selected for inclusion, and 101 (13.4%) readmitted within 30 days. The readmission group had higher medication regimen complexity index scores than the no-readmission group (p < 0.01). However, after controlling for demographics, disease state, length of stay, site, and medication count, medication regimen complexity index was no longer a significant predictor of readmission (odds ratio 0.99, 95% confidence interval 0.97-1.01) or revisit (odds ratio 0.99, 95% confidence interval 0.98-1.02). CONCLUSION: There is little evidence to support the use of medication regimen complexity index in readmission prediction when other measures are available. Medication regimen complexity index may lack sufficient sensitivity to capture an effect of medication regimen complexity on all-cause readmission. PMID- 26985393 TI - A cell-based microarray to investigate combinatorial effects of microparticle encapsulated adjuvants on dendritic cell activation. AB - Experimental vaccine adjuvants are being designed to target specific toll-like receptors (TLRs) alone or in combination, expressed by antigen presenting cells, notably dendritic cells (DCs). There is a need for high-content screening (HCS) platforms to explore how DC activation is affected by adjuvant combinations. Presented is a cell-based microarray approach, "immunoarray", exposing DCs to a large number of adjuvant combinations. Microparticles encapsulating TLR ligands are printed onto arrays in a range of doses for each ligand, in all possible dose combinations. Dendritic cells are then co-localized with physisorbed microparticles on the immunoarray, adherent to isolated islands surrounded by a non-fouling background, and DC activation is quantified. Delivery of individual TLR ligands was capable of eliciting high levels of specific DC activation markers. For example, either TLR9 ligand, CpG, or TLR3 ligand, poly I:C, was capable of inducing among the highest 10% expression levels of CD86. In contrast, MHC-II expression in response to TLR4 agonist MPLA was among the highest, whereas either MPLA or poly I:C, was capable of producing among the highest levels of CCR7 expression, as well as inflammatory cytokine IL-12. However, in order to produce robust responses across all activation markers, adjuvant combinations were required, and combinations were more represented among the high responders. The immunoarray also enables investigation of interactions between adjuvants, and each TLR ligand suggested antagonism to other ligands, for various markers. Altogether, this work demonstrates feasibility of the immunoarray platform to screen microparticle-encapsulated adjuvant combinations for the development of improved and personalized vaccines. PMID- 26985395 TI - Residential radon and environmental burden of disease among Non-smokers. AB - BACKGROUND: Lung cancer was the second highest absolute cancer incidence globally and the first cause of cancer mortality in 2014. Indoor radon is the second leading risk factor of lung cancer after cigarette smoking among ever smokers and the first among non-smokers. Environmental burden of disease (EBD) attributable to residential radon among non-smokers is critical for identifying threats to population health and planning health policy. METHODS: To identify and retrieve literatures describing environmental burden of lung cancer attributable to residential radon, we searched databases including Ovid-MEDLINE, -EMBASE from 1980 to 2016. Search terms included patient keywords using 'lung', 'neoplasm', exposure keywords using 'residential', 'radon', and outcomes keywords using 'years of life lost', 'years of life lost due to disability', 'burden'. Searching through literatures identified 261 documents; further 9 documents were identified using manual searching. Two researchers independently assessed 271 abstracts eligible for inclusion at the abstract level. Full text reviews were conducted for selected publications after the first assessment. Ten studies were included in the final evaluation. REVIEW: Global disability-adjusted life years (DALYs)(95 % uncertainty interval) for lung cancer were increased by 35.9 % from 23,850,000(18,835,000-29,845,000) in 1900 to 32,405,000(24,400,000-38,334,000) in 2000. DALYs attributable to residential radon were 2,114,000(273,000-4,660,000) DALYs in 2010. Lung cancer caused 34,732,900(33,042,600 ~ 36,328,100) DALYs in 2013. DALYs attributable to residential radon were 1,979,000(1,331,000-2,768,000) DALYs for in 2013. The number of attributable lung cancer cases was 70-900 and EBD for radon was 1,000-14,000 DALYs in Netherland. The years of life lost were 0.066 years among never-smokers and 0.198 years among ever-smoker population in Canada. CONCLUSION: In summary, estimated global EBD attributable to residential radon was 1,979,000 DALYs for both sexes in 2013. In Netherlands, EBD for radon was 1,000-14,000 DALYs. Smoking population lost three times more years than never smokers in Canada. There was no study estimating EBD of residential radon among never smokers in Korea and Asian country. In addition, there were a few studies reflecting the age of building, though residential radon exposure level depends on the age of building. Further EBD study reflecting Korean disability weight and the age of building is required to estimate EBD precisely. PMID- 26985394 TI - Context-sensitive fluid therapy in critical illness. AB - Microcirculatory alterations are frequently observed in critically ill patients undergoing major surgery and those who suffer from trauma or sepsis. Despite the need for adequate fluid administration to restore microcirculation, there is no consensus regarding optimal fluid therapy for these patients. The recent recognition of the importance of the endothelial glycocalyx layer in capillary fluid and solute exchange has largely changed our views on fluid therapy in critical illness. Given that disease status largely differs among critically ill patients, fluid therapy must not be considered generally, but rather tailored to the clinical condition of each patient. This review outlines the current understanding of context-sensitive volume expansion by fluid solutions and considers its clinical implications for critically ill patients. The modulation of capillary hydrostatic pressure through the appropriate use of vasopressors may increase the effectiveness of fluid infusion and thereby reduce detrimental effects resulting from excessive fluid administration. PMID- 26985396 TI - Gene mutation discovery research of non-smoking lung cancer patients due to indoor radon exposure. AB - Although the incidence and mortality for most cancers such as lung and colon are decreasing in several countries, they are increasing in several developed countries because of an unhealthy western lifestyles including smoking, physical inactivity and consumption of calorie-dense food. The incidences for lung and colon cancers in a few of these countries have already exceeded those in the United States and other western countries. Among them, lung cancer is the main cause of cancer death in worldwide. The cumulative survival rate at five years differs between 13 and 21 % in several countries. Although the most important risk factors are smoking for lung cancer, however, the increased incidence of lung cancer in never smokers(LCINS) is necessary to improve knowledge concerning other risk factors. Environmental factors and genetic susceptibility are also thought to contribute to lung cancer risk. Patients with lung adenocarcinoma who have never smoking frequently contain mutation within tyrosine kinase domain of the epidermal growth factor receptor(EGFR) gene. Also, K-ras mutations are more common in individuals with a history of smoking use and are related with resistance to EFGR-tyrosine kinase inhibitors. Recently, radon(Rn), natural and noble gas, has been recognized as second common reason of lung cancer. In this review, we aim to know whether residential radon is associated with an increased risk for developing lung cancer and regulated by several genetic polymorphisms. PMID- 26985397 TI - Toward a Relationship Perspective on Aggression among Schoolchildren: Integrating Social Cognitive and Interdependence Theories. AB - The traditional psychological approach of studying aggression among schoolchildren in terms of individual differences in aggression and in victimization has been valuable in identifying prevalence rates, risk, and consequences of involvement in aggression. However, it is argued that a focus on aggressor-victim relationships is warranted based on both conceptual and empirical grounds. Such a shift in focus requires modification and integration of existing theories of aggression, and this paper integrates social cognitive theory and interdependence theory to suggest a new, interdependent social cognitive theory of aggression. Specifically, this paper identifies points of overlap and different foci between these theories, and it illustrates their integration through a proposed model of the emergence of aggressor-victim interactions and relationships. The paper concludes that expanding consideration to include aggressor-victim relationships among schoolchildren offers considerable theoretical, empirical, and intervention opportunities. PMID- 26985399 TI - Designing Interventions Informed by Scientific Knowledge About Effects of Early Adversity: A Translational Neuroscience Agenda for Next Generation Addictions Research. AB - In spite of extensive scientific knowledge about the neurobiological systems and neural pathways underlying addictions, only limited progress has been made to reduce the population-level incidence of addictions by using prevention and treatment programs. In this area of research the translation of basic neuroscience of causal mechanisms to effective interventions has not been fully realized. In this article we describe how an understanding of the effects of early adverse experiences on brain and biological development may provide new opportunities to achieve impact at scale with respect to reduction of addictions. We propose four categories of new knowledge that translational neuroscience investigations of addictions should incorporate to be successful. We then describe a translational neuroscience-informed smoking cessation intervention based on this model. PMID- 26985398 TI - Spatial separation of the processing and MHC class I loading compartments for cross-presentation of the tumor-associated antigen HER2/neu by human dendritic cells. AB - Cross-presentation is the process by which professional antigen presenting cells (APCs) (B cells, dendritic cells (DCs) and macrophages) present endocytosed antigens (Ags) via MHC-I to CD8+ T cells. This process is crucial for induction of adaptive immune responses against tumors and infected cells. The pathways and cellular compartments involved in cross-presentation are unresolved and controversial. Among the cells with cross-presenting capacity, DCs are the most efficient, which was proposed to depend on prevention of endosomal acidification to block degradation of the epitopes. Contrary to this view, we show in this report that some cargoes induce strong endosomal acidification following uptake by human DCs, while others not. Moreover, processing of the tumor-associated antigen HER2/neu delivered in nanoparticles (NP) for cross-presentation of the epitope HER2/neu369-377 on HLA-A2 depended on endosomal acidification and cathepsin activity as well as proteasomes, and newly synthesized HLA class I. However, the HLA-A*0201/HER2/neu369-377 complexes were not found in the endoplasmic reticulum (ER) nor in endolysosomes but in hitherto not described vesicles. The data thus indicate spatial separation of antigen processing and loading of MHC-I for cross-presentation: antigen processing occurs in the uptake compartment and the cytosol whereas MHC-I loading with peptide takes place in a distinct subcellular compartment. The findings further elucidate the cellular pathways involved in the cross-presentation of a full-length, clinically relevant tumor-associated antigen by human DCs, and the impact of the vaccine formulation on antigen processing and CD8+ T cell induction. PMID- 26985400 TI - A comparison of the recoverable proportion of methicillin-resistant Staphylococcus aureus from two different types of papers. AB - AIM: Paper is used for various purposes in hospitals. Generally, there are two different types of paper, which are commonly used in our facility: wood-free paper, and paper containing wood. We compared the recoverable proportion of methicillin-resistant Staphylococcus aureus (MRSA; ATCC 43300) from the surface of such papers. METHOD: The papers were divided into two groups: Group 1: wood free paper; Group 2: paper containing wood. The papers were contaminated in a standardized procedure with 0.1 mL of a 5*10(7) CFU MRSA/mL stock solution. RESULTS: The recoverable proportion of MRSA was higher in the wood-containing papers than in the papers without wood (P=0.043). CONCLUSION: This study indicates that if paper is purchased for healthcare facilities it should not contain wood, but rather wood-free paper types should be considered. PMID- 26985402 TI - Healthcare is primary. AB - India is undergoing a rapid transformation in terms of governance, administrative reforms, newer policy develoment, and social movements. India is also considered one of the most vibrant economies in the world. The current discourse in public space is dominated by issues such as economic development, security, corruption free governance, gender equity, and women safety. Healthcare though remains a pressing need of population; seems to have taken a backseat. In the era of decreasing subsidies and cautious investment in social sectors, the 2(nd) National Conference on Family Medicine and Primary Care 2015 (FMPC) brought a focus on "healthcare" in India. The theme of this conference was "Healthcare is Primary." The conference participants discussed on the theme of why healthcare should be a national priority and why strong primary care should remain at the center of healthcare delivery system. The experts recommended that India needs to strengthen the "general health system" instead of focusing on disease based vertical programs. Public health system should have capacity and skill pool to be able to deliver person centered comprehensive health services to the community. Proactive implementation of policies towards human resource in health is the need of the hour. As the draft National Health Policy 2015 is being debated, "family medicine" (academic primary care), the unfinished agenda of National Health Policy 2002, remains a priority area of implementation. PMID- 26985403 TI - The revised guidelines of the Medical Council of India for academic promotions: Need for a rethink. AB - Note: This editorial is being published simultaneously in the Indian Heart Journal, Indian Journal of Anaesthesia, Indian Journal of Gastroenterology, Indian Journal of Medical Ethics, Indian Journal of Medical Microbiology, Indian Journal of Occupational and Environmental Medicine, Indian Journal of Pathology and Microbiology, Indian Journal of Pharmacology, Indian Journal of Physiology and Pharmacology, Indian Journal of Urology, Indian Pediatrics, International Journal of Health Research & Medicolegal Practice, Journal of Anaesthesiology Clinical Pharmacology, Journal of Ayurveda and Integrative Medicine, Journal of Clinical and Scientific Research, Journal of Conservative Dentistry, Journal of Family Medicine and Primary Care, Journal of Indian Academy of Forensic Medicine, Journal of Mahatma Gandhi Institute of Medical Sciences, Journal of Postgraduate Medicine, National Journal of Integrated Research in Medicine, and The National Medical Journal of India. It may also be published in forthcoming issues of other journals. This editorial is not endorsed by all members of the Indian Association of Medical Journal Editors (IAMJE). PMID- 26985404 TI - "Health system approach" for improving immunization program performance. AB - Immunization programs are one of the most well-recognized and successful public health programs across the world. The immunization programs have achieved significant successes in a number of countries; however, the coverage with available vaccines remains sub-optimal in many low- and middle-income countries (LMICs). This article, based upon extensive review of literature and using universal immunization program (UIP) in India as a case study, summarizes the latest developments and initiatives in the area of vaccination and immunization in the last few years. The article analyzes initiatives under UIP in India from the "health system approach" and argues that it is possible to increase coverage with available vaccines and overall program performance by focused attention on various functions of health systems. It also discusses the emerging evidence that health systems could be strengthened prior to the introduction of new interventions (vaccines included) and the introduction of new interventions (including vaccines) could be planned in a way to strengthen the health systems. It concludes that immunization programs could be one of the entry points for strengthening health systems in the countries and lessons from vaccine introduction could pave pathway for scaling up other health interventions and therefore, could contribute to advancing Universal Health Coverage (UHC). PMID- 26985405 TI - Family medicine education in India: A panoramic view. AB - INTRODUCTION: In the recent years, there has been renewed interest in strengthening primary care for improved health services delivery. Family medicine with its holistic principles is an effective approach for building primary care workforce in resource constraint settings. Even though this discipline is well established and mainstreamed in Western countries, the same is yet to occur in low- and middle-income nations. India with its paradigm shift for universal health coverage is strategically poised to embrace family medicine as a core component of its health system. However, till date, a clear picture of family medicine teaching across the country is yet to be available. METHODS: This paper makes an attempt to assess the landscape of family medicine teaching in India with an aim to contribute to a framework for bolstering its teaching and practice in coming years. The objective was to obtain relevant information through a detailed scan of the health professional curricula as well as mapping independent academic programs. Specific areas of interest included course content, structure, eligibility criteria, and accreditation. RESULTS: Our findings indicate that teaching of family medicine is still in infancy in India and yet to be mainstreamed in health professional education. There are variations in family medicine teaching across academic programs. CONCLUSION: It is suggested that both medical and nursing colleges should develop dedicated Departments of Family Medicine for both undergraduate and postgraduate teaching. Further, more number of standalone diploma courses adopting blended learning methods should be made available for in-service practitioners. PMID- 26985401 TI - Molecular imaging of bacterial infections in vivo: the discrimination of infection from inflammation. AB - Molecular imaging by definition is the visualization of molecular and cellular processes within a given system. The modalities and reagents described here represent a diverse array spanning both pre-clinical and clinical applications. Innovations in probe design and technologies would greatly benefit therapeutic outcomes by enhancing diagnostic accuracy and assessment of acute therapy. Opportunistic pathogens continue to pose a worldwide threat, despite advancements in treatment strategies, which highlights the continued need for improved diagnostics. In this review, we present a summary of the current clinical protocol for the imaging of a suspected infection, methods currently in development to optimize this imaging process, and finally, insight into endocarditis as a model of infectious disease in immediate need of improved diagnostic methods. PMID- 26985406 TI - Diagnosis and management of preeclampsia in community settings in low and middle income countries. AB - Hypertensive disorders of pregnancy contribute significantly to maternal mortality and morbidity. Preeclampsia belongs to the spectrum of hypertensive disorders of pregnancy and if undiagnosed and/or untreated leads to fatal consequences for both the mother and the baby. Early detection and prevention of preeclampsia is limited by uncertainty in the knowledge about its etiopathogenesis. While much work has been done in establishing clinical guidelines for management of preeclampsia in the hospital or tertiary care settings, there is considerable lack of work in the domain of evidence-based guidelines for screening, identification and management of preeclampsia at the community-level. The article reviews these issues with special considerations and to challenges faced in low and middle-income countries. There is a need to focus on low-cost screening and interventions in the community to achieve a significant impact on preventable maternal and fetal mortality in order to control the burden of preeclampsia significantly as well as investing on more research at primary care level to improve the evidence base for community-level interventions. PMID- 26985407 TI - Identifying gaps in research prioritization: The global burden of neglected tropical diseases as reflected in the Cochrane database of systematic reviews. AB - BACKGROUND: Neglected tropical diseases (NTDs) impact disadvantaged populations in resource-scarce settings. Availability of synthesized evidence is paramount to end this disparity. The aim of the study was to determine whether NTD systematic reviews or protocols in the Cochrane Database of Systematic Reviews (CDSR) reflect disease burden. METHODS: Two authors independently searched the CDSR for reviews/protocols regarding the NTDs diseases. Each review or protocol was classified to a single NTD category. Any discrepancy was solved by consensus with third author. NTD systematic review or protocol from CDSR were matched with disability-adjusted life year (DALY) metrics from the Global Burden of Disease 2010 Study. Spearman's rank correlation coefficient and associated P values were used to assess for correlation between the number of systematic reviews and protocols and the %2010 DALY associated with each NTD. RESULTS: Overall, there was poor correlation between CDSR representation and DALYs. Yellow fever, echinococcus, onchocerciasis, and schistosomiasis representation was well-aligned with DALY. Leprosy, trachoma, dengue, leishmaniasis, and Chagas disease representation was greater, while cysticercosis, human African trypanosomiasis, ascariasis, lymphatic filariasis, and hookworm representation was lower than DALY. Three of the 18 NTDs had reviews/protocols of diagnostic test accuracy. CONCLUSIONS: Our results indicate the need for increased prioritization of systematic reviews on NTDs, particularly diagnostic test accuracy reviews. PMID- 26985408 TI - What are we drinking? Assessment of water quality in an urban city of Punjab, India. AB - INTRODUCTION: Ground water is the ultimate and most suitable fresh water resource for human consumption in the urban areas of India. Studies regarding ground water quality have shown that the higher rate of exploration as compared to the rate of recharging, inappropriate dumping of solid, as well as liquid waste, lack of strict enforcement of law has led to the deterioration of ground water quality. The present study was thus, carried out to evaluate physicochemical, as well as a microbiological profile of tap water, and filtered water in urban areas of Patiala, Punjab. MATERIALS AND METHODS: The three zones under Municipal Corporation and two areas under Public Health Department were chosen according to the simple random sampling from Patiala city. From each area, 10 houses were chosen according to the systematic random sampling technique (n = 50). Water was taken from two sources, tap water, and from the water filter. Two samples were taken from each source one for the physicochemical analysis and another for bacteriological analysis. The samples which were sent for bacteriological assessment were collected in a sterile container. RESULTS: The number of water samples found to be within desirable limits with respect to physicochemical parameters were significantly more with the filter water sample than the tap water samples. Suspicious/unsatisfactory microbiological quality of water was observed in 28% and 4% of tap and filter water samples, respectively. CONCLUSION: The results indicate that certain chemical parameters such as hardness, chloride, and fluoride levels were beyond the permissible limits. Therefore, we recommend that home filters should be installed, serviced appropriately, and their water quality should be checked routinely. Also, any leak from sewage pipes should be promptly repaired to prevent contamination of drinking water. PMID- 26985409 TI - Musculoskeletal disorders among municipal solid waste workers in India: A cross sectional risk assessment. AB - BACKGROUND: Waste management is a necessary activity around the world, but involves a variety of health hazards. In a developing country like India, municipal solid waste is collected manually requiring heavy physical activity. Among all occupational health issues, musculoskeletal problems are common among waste collectors in the form of nonfatal injuries because of the presence of such risk factors (lifting, carrying, pulling, and pushing). We have thus conducted this study to evaluate musculoskeletal disorders (MSDs) among municipal solid waste (MSW) workers. METHODOLOGY: A cross-sectional study using probability proportionate to size sampling, recruited 220 MSW workers from the Chennai Municipal Corporation, India for this study. A pretested validated questionnaire has been used to collect data on demographic and occupational history and information on musculoskeletal pain. Data analysis was performed using R software (3.0.1 version). RESULTS: 70% of the participants reported that they had been troubled with musculoskeletal pain in one or more of the 9 defined body regions during the last 12 months, whereas 91.8% had pain during the last 7 days. Higher prevalence of symptoms in knees, shoulders, and lower back was found to be 84.5%, 74.5%, and 50.9% respectively. Female illiterate workers with lower socioeconomic status were found to have higher odds for MSDs. Similarly, higher body mass index having no physical activity increases the chance of odds having MSDs. CONCLUSION: The higher percentage of musculoskeletal symptoms among MSW workers could be attributed to the long duration of employment, the low job control, and the nature of their job, which is physically demanding. A workplace of health promotion model integration can minimize the reported high prevalence, and a prospective cohort study could be recommended further. PMID- 26985410 TI - Same day sputum smear microscopy for the diagnosis of pulmonary tuberculosis: Ziehl-Neelsen versus fluorescent staining. AB - BACKGROUND: Sputum smear microscopy is the main tool for the diagnosis of pulmonary tuberculosis (TB), especially in low- and middle-income countries (LMICs). Limited sensitivity of smear microscopy and patient dropouts (PDs) are the important obstacles of national TB control programs. OBJECTIVES: (1) To assess the diagnostic utility of the same day (SS2) approach (2) To compare the smear results of the spot morning (SM) and the SS2 approaches. MATERIALS AND METHODS: The study was conducted in the Department of Microbiology, GSL Medical College, Rajahmundry, Andhra Pradesh, India from January 2011 to February 2015. Three sputum samples were collected [spot (S), second spot (S2) 1 h after S, and morning sample (M)] from the volunteers. The sputum smears were stained by Ziehl Neelsen (ZN), modified ZN (MZN), and fluorescent staining (FS) techniques and the results were pooled and compared under SM and SS2 approaches. RESULTS: Of the 3,186 study participants, sputum smear positivity (SSP) for SM approach was 9.6% and 10.8% and for SS2 approach, it was 9.4% and 10.6%, respectively, with ZN and FS and the results were statistically insignificant (Mann-Whitney U test, P > 0.05). CONCLUSION: Technically SSP was similar for both the approaches and no improvement was observed with the SS2 approach. Hence, there is an urgent need to improve SSP. PMID- 26985412 TI - Epidemiological predictors of metabolic syndrome in urban West Bengal, India. AB - INTRODUCTION: Metabolic syndrome is one of the emerging health problems of the world. Its prevalence is high in urban areas. Though pathogenesis is complex, but the interaction of obesity, sedentary lifestyle, dietary, and genetic factors are known as contributing factors. Community-based studies were very few to find out the prevalence or predictors of the syndrome. OBJECTIVES: To ascertain the prevalence and epidemiological predictors of metabolic syndrome. MATERIALS AND METHODS: A total of 690 study subjects were chosen by 30 clusters random sampling method from 43 wards of Durgapur city. Data were analyzed in SPSS version 20 software and binary logistic regression was done to find out statistical significance of the predictors. RESULTS: Among 32.75% of the study population was diagnosed as metabolic syndrome according to National Cholesterol Education Program Adult Treatment Panel III definition with a modification for Asia Pacific cut-off of waist circumference. Odds were more among females (2.43), upper social class (14.89), sedentary lifestyle (17.00), and positive family history. CONCLUSION: The overall prevalence of metabolic syndrome was high in urban areas of Durgapur. Increased age, female gender, higher social status, sedentary lifestyle, positive family history, and higher education were the statistically significant predictors of metabolic syndrome. PMID- 26985413 TI - Process evaluation of community monitoring under national health mission at Chandigarh, union territory: Methodology and challenges. AB - BACKGROUND: Community monitoring was introduced on a pilot mode in 36 selected districts of India in a phased manner. In Chandigarh, it was introduced in the year 2009-2010. A preliminary evaluation of the program was undertaken with special emphasis on the inputs and the processes. METHODOLOGY: Quantitative methods included verification against checklists and record reviews. Nonparticipant observation was used to evaluate the conduct of trainings, interviews, and group discussions. Health system had trained health system functionaries (nursing students and Village Health Sanitation Committee [VHSC] members) to generate village-based scorecards for assessing community needs. Community needs were assessed independently for two villages under the study area to validate the scores generated by the health system. RESULTS: VHSCs were formed in all 22 villages but without a chairperson or convener. The involvement of VHSC members in the community monitoring process was minimal. The conduct of group discussions was below par due to poor moderation and unequal responses from the group. The community monitoring committees at the state level had limited representation from the non-health sector, lower committees, and the nongovernmental organizations/civil societies. Agreement between the report cards generated by the investigator and the health system in the selected villages was found to be to be fair (0.369) whereas weighted kappa (0.504) was moderate. CONCLUSION: In spite of all these limitations and challenges, the government has taken a valiant step by trying to involve the community in the monitoring of health services. The dynamic nature of the community warrants incorporation of an evaluation framework into the planning of such programs. PMID- 26985414 TI - A retrospective review of 911 calls to a regional poison control center. AB - BACKGROUND: There is little data as to what extent national Emergency Medical Services (EMS; 911) utilize poison control centers (PCCs). A review of data from our PCC was done to better understand this relationship and to identify potential improvements in patient care and health care savings. METHODS: Retrospective chart review of a single PCC to identify calls originating from 911 sources over a 4-year study period (1/1/08-12/31/11). Recorded variables included the origin of call to the PCC, intent of exposure, symptoms, management site, hospital admission, and death. Odds ratios (OR) were developed using multiple logistic regressions to identify risk factors for EMS dispatch, management site, and the need for hospital admission. RESULTS: A total of 7556 charts were identified; 4382 (58%) met inclusion criteria. Most calls (63.3%) involved accidental exposures and 31% were self-harm or misuse. A total of 2517 (57.4%) patients had symptoms and 2044 (50.8%) were transported to an Emergency Department (ED). Over 38% of calls (n = 1696) were handled primarily by the PCC and did not result in EMS dispatch; only 6.5% of cases (n = 287) with initial PCC involvement resulted in crew dispatch. There were 955 (21.8%) cases that resulted in admission, and five deaths. The OR for being transported to an ED was 45.4 (95% confidence interval [CI]: 30.2-68.4) when the crew was dispatched by the PCC. Hospital admission was predicted by intent for self-harm (OR 5.0; 95% CI: 4.1-6.2) and the presence of symptoms (OR 2.43; 95% CI: 1.9-3.0). The ORs for several other predictive variables are also reported. CONCLUSIONS: When 911 providers contact a PCC about poisoning-related emergencies, a history of intentional exposure and the presence of symptoms each predicted EMS dispatch by the PCC, patient transport to an ED, and hospital admission. Early involvement of a PCC may prevent the need for EMS activation or patient transfer to a health care facility. PMID- 26985411 TI - Patient safety in maternal healthcare at secondary and tertiary level facilities in Delhi, India. AB - BACKGROUND: There is insufficient information on causes of unsafe care at facility levels in India. This study was conducted to understand the challenges in government hospitals in ensuring patient safety and to propose solutions to improve patient care. MATERIALS AND METHODS: Desk review, in-depth interviews, and focused group discussions were conducted between January and March 2014. Healthcare providers and nodal persons for patient safety in Gynecology and Obstetrics Departments of government health facilities from Delhi state of India were included. Data were analyzed using qualitative research methods and presented adopting the "health system approach." RESULTS: The patient safety was a major concern among healthcare providers. The key challenges identified were scarcity of resources, overcrowding at health facilities, poor communications, patient handovers, delay in referrals, and the limited continuity of care. Systematic attention on the training of care providers involved in service delivery, prescription audits, peer reviews, facility level capacity building plan, additional financial resources, leadership by institutional heads and policy makers were suggested as possible solutions. CONCLUSIONS: There is increasing awareness and understanding about challenges in patient safety. The available local information could be used for selection, designing, and implementation of measures to improve patient safety at facility levels. A systematic and sustained approach with attention on all functions of health systems could be beneficial. Patient safety could be used as an entry point to improve the quality of health care services in India. PMID- 26985415 TI - Physician's self-perceived abilities at primary care settings in Indonesia. AB - BACKGROUND: Southeast Asian countries with better-skilled primary care physicians have been shown to have better health outcomes. However, in Indonesia, there has been a large number of inappropriate referrals, leading to suboptimal health outcomes. This study aimed to examine the reasons underlying the unnecessary referrals as related to Indonesian physicians' standard of abilities. MATERIALS AND METHODS: This was a multiple-case study that explored physicians' self evaluation of their abilities. Self-evaluation questionnaires were constructed from the Indonesian Standards of Physicians Competences of 2006-2012 (ISPC), which is a list of 155 diseases. This study was undertaken in three cities, three towns, and one "border-less developed" area during 2011-2014. The study involved 184 physicians in those seven districts. Data were collected using one-on-one, in depth interviews, focus group discussions (FGDs), and clinical observations. RESULTS: This study found that primary care physicians in Indonesia felt that they were competent to handle less than one-third of "typical" primary care cases. The reasons were limited understanding of person-centered care principles and limited patient care services to diagnosis and treatment of common biomedical problems. Additionally, physical facilities in primary care settings are lacking. DISCUSSIONS AND CONCLUSIONS: Strengthening primary health care in Indonesia requires upscaling doctors' abilities in managing health problems through more structured graduate education in family medicine, which emphasizes the bio-psycho socio-cultural background of persons; secondly, standardizing primary care facilities to support physicians' performance is critical. Finally, a strong national health policy that recognizes the essential role of primary care physicians in health outcomes is an urgent need. PMID- 26985417 TI - Modified measles versus rubella versus atypical measles: One and same thing. AB - INTRODUCTION: In outbreak settings, more than one virus may be infecting the given population. In twin or triple outbreak of measles, German measles (rubella), and varicella in highly immunized hilly areas, maximal number of the case patients in all the hilly villages belonged to the older age group. It suggested an obvious shift to the higher age group, warranting second dose opportunity in such case scenario. The clinical presentations of viral diseases are too similar to differentiate. The aim is to clearly categorize the case patients of modified measles, rubella, and atypical measles in outbreak settings. RESULTS: Four outbreaks are listed. In the first one, sixty case patients were identified from 1026 people in 5 villages. Of these, 41 were diagnosed by clinically, 8 were laboratory confirmed as measles and 11 were epidemiologically linked German measles case patients. Seventy percent of the cases were vaccinated for measles. In second case, we identified 29/35 measles and 6/35 were confirmed as epidemiologically linked unvaccinated chickenpox case patients. In third one, we identified 116 cases in eight villages (112/116 clinically and 04/116 laboratory confirmed). Majority of cases were immunized against measles, but only minor cases for rubella. In fourth case, we identified 505 case patients from mixed outbreaks of varicella, measles and rubella (30/505 clinically, 467/505 epidemiologically linked and 8/505 laboratory confirmed case patients from a study population of 3280). In all the four outbreaks, prima facie, the clinical presentations of both rubella and modified measles were difficult to differentiate. DISCUSSION: On the basis of outbreak investigation and analytical inference, it has been observed that the symtomatology of modified measles and laboratory confirmed rubella case patients/epidemiologically linked cases are so similar placed that many a time, it becomes much difficult to line list the cases in one section of modified measles or rubella or atypical cases. CONCLUSION: Similarities of morphological symptoms between modified measles and rubella is the point of challenge and it causes debate between pediatrician and field epidemiologist to differentiate and classify them. PMID- 26985416 TI - System level approaches for mainstreaming tobacco control into existing health programs in India: Perspectives from the field. AB - INTRODUCTION: India is the second largest consumer of tobacco in the world, and varieties of both smoked and smokeless tobacco products are widely available. The national program for tobacco control is run like a vertical stand-alone program. There is a lack of understanding of existing opportunities and barriers within the health programs that influence the integration of tobacco control messages into them. The present formative research identifies such opportunities and barriers. METHODS: We conducted a multi-step, mixed methodological study of primary care personnel and policy-makers in two Indian states of Andhra Pradesh and Gujarat. The primary purpose of our study was to investigate health worker and policy-maker perceptions on the integration of tobacco control intervention. We systematically collected data in three steps: In Step I, we conducted in-depth interviews (IDIs) and focus group discussions with primary care health personnel, Step II consists of a quantitative survey among health care providers (n = 1457) to test knowledge, attitudes and practices in tobacco control and Step III we conducted 75 IDIs with program heads and policy-makers to evaluate the relative congruence of their views on integration of the tobacco control program. RESULTS: Majority of the health care providers recognized tobacco use as a major health problem. There was a general consensus for the need of training for effective dissemination of information from health care providers to patients. Almost 92% of the respondents opined that integration of tobacco control with other health programs will be highly effective to downscale the tobacco epidemic. CONCLUSIONS: Our findings suggest the need for integration of tobacco control program into existing health programs. Integration of tobacco control strategies into the health care system within primary and secondary care will be more effective and counseling for tobacco cessation should be available for population at large. PMID- 26985419 TI - Depression and anxiety among middle-aged women: A community-based study. AB - BACKGROUND: Anxiety and depressive disorders constitute a substantial proportion of the global burden of disease and are projected to form the second most common cause of disability by 2020. OBJECTIVE: To assess the level of depression and anxiety among middle age women and the possible factors behind it. MATERIALS AND METHODS: A total of 180 women aged 40-60 years were selected by proportionate sampling technique. Age, education, marital status, socioeconomic status, age at marriage, age at menopause, weight and height were noted. Zung-self-rating scales were used for calculating levels of depression and anxiety in these women. The data were analyzed by using statistical software SPSS. RESULTS: The level of syndromal depression and anxiety was found to be 86.7% and 88.9%, respectively. Most of the subjects had the moderate type of depression (49.5%) followed by mild (29.4%) and severe depression (7.8%). While in case of anxiety, most of the subjects (69.4%) had a mild form of anxiety and 17.8% had moderate anxiety level. A significant difference was observed in the level of depression with respect to marital status (P = 0.009) and in the level of anxiety with respect to age (P = 0.021) in the study subjects. On applying logistic regression, none of the factors studied were found to be significant variables for anxiety or depression in the study population. CONCLUSION: Depression and anxiety are prevalent among the middle-aged women in rural Punjab. Provision of mental health services in this group is essential. PMID- 26985418 TI - A synergistic role of ischemia modified albumin and high-sensitivity troponin T in the early diagnosis of acute coronary syndrome. AB - AIM: The aim was to evaluate the role of high sensitivity troponin T and ischemia modified albumin (IMA) and in the early diagnosis of acute coronary syndrome (ACS). MATERIALS AND METHODS: This was a cross-sectional study that comprised of 120 individuals of which 75 were cases and 45 healthy controls. On the basis of clinical history and 12-lead electrocardiogram, initial diagnosis of ACS was made in the cases. High sensitive cardiac troponin T (hs-cTnT) and IMA were measured in all the individuals. RESULTS: Levels of IMA were significantly higher in patients of ACS as compared to those in control group (means: 101.83 [95% confidence interval (CI): 91.96-111.70] vs. 41.11 [95% CI: 38.55-43.67]). By taking the cut-off as >65.23 U/mL for IMA, which was obtained from receiver operating characteristic (ROC) curve, the sensitivity was 91.3%, specificity was 81.1%, positive predictive value (PPV) was 74.4%, and negative predictive value (NPV) was 93.9%. Positive likelihood ratio was 4.83 while negative likelihood ratio was 0.11, whereas the corresponding values in case of hs-cTnT were 95.6% (95% CI: 85.2-99.5), 61.3% (95% CI: 49.5-72.6), 59.7%, 95.8%, 2.47 and 0.07 by taking cut-off as >14 pg/mL. The area under the ROC curves (AUC) of IMA and hs cTnT at 0-6 h were 0.932 (95% CI: 0.87-0.97, P < 0.001) and 0.797 (95% CI: 0.71 0.86, P < 0.001), respectively. The logistic model combining the two markers yielded sensitivity, specificity, PPV, and NPV of 95.7%, 81.1%, 88.6%, and 92.5% respectively. CONCLUSION: hs-cTnT and IMA may be useful tools for risk stratification of ACS and can be used together with better accuracy in the early diagnosis of ACS. PMID- 26985421 TI - Seatbelt submarining injury and its prevention countermeasures: How a cantilever seat pan structure exacerbate submarining. AB - The purpose of this study and a case report was to demonstrate seat belt webbing induced injury due to seatbelt submarining during the frontal motor vehicle crash. Submarining is an undesired phenomenon during a frontal crash scenario and is dependent on design features of the seat pan and seatbelt system. The lack of adequate anti-submarining features at any seating position with three-point restraint can cause abdominal solid and hollow organ injuries. This paper reports a case of submarining and factors that exacerbated this phenomenon leading to critical occupant abdominal injury. This case report and the following injury causation analysis demonstrate the shortcomings of a cantilever seat pan design in context to the occupant safety. The inadequate seat pan anti-submarining feature in association with lack of seatbelt load-limiter and Pretensioner reduces the level of occupant protection offered by the seat belt system in the rear seat. This case report shows the dangers of cantilever seat pan design and its association with increased risk of submarining causing severe abdominal injuries. PMID- 26985420 TI - Knowledge of hand hygiene in undergraduate medical, dental, and nursing students: A cross-sectional survey. AB - BACKGROUND: Hand hygiene is of paramount importance for the prevention of healthcare associated infections and the spread of antimicrobial resistance. There is a need to explore the concept of hand hygiene among the cross disciplinary undergraduate healthcare students. AIM: To evaluate and compare the knowledge of hand hygiene among medical, dental, and nursing undergraduate students. MATERIALS AND METHODS: A cross-sectional survey was conducted among 84 medical, 74 dental, and 40 nursing undergraduate students in a Tertiary Care Teaching Institute in Navi Mumbai, Maharashtra, India. Knowledge was assessed using the World Health Organization hand hygiene questionnaire. The scores for each were calculated and compared. The scores were further graded as low, moderate, and good. RESULTS: Overall, only 7.5% of the participants had good knowledge regarding hand hygiene while majority (69.1%) had moderate knowledge. Medical students' hand hygiene knowledge was significantly (P < 0.01) higher than that of dental and nursing students. CONCLUSION: The overall low scores on hand hygiene knowledge indicate that undergraduate healthcare students require increased emphasis on hand hygiene education, behavior, and improvement in their current primary training as well as undergraduate curricula. PMID- 26985422 TI - Some interesting observations regarding TB patient management from a rural area of Madhya Pradesh: TB case series. AB - Despite many serious efforts, tuberculosis (TB) is still a recognized public health problem. The Government of India has adopted the Directly Observed Treatment, Short-Course (DOTS) strategy for the entire country through the Revised National Tuberculosis Control Programme (RNTCP) for the treatment of TB. In this report, we have presented the trajectories for care seeking of two TB cases who suffered from either "patient level delays" or "health system-related delays" in seeking DOTS for the treatment of TB. PMID- 26985423 TI - Concurrent meningitis and vivax malaria. AB - Malaria is an endemic infectious disease in India. It is often associated with other infective conditions but concomitant infection of malaria and meningitis are uncommon. We present a case of meningitis with vivax malaria infection in a 24-year-old lady. This case emphasizes the importance of high index of clinical suspicion to detect other infective conditions like meningitis when fever does not improve even after anti-malarial treatment in a patient of malaria before switching therapy suspecting drug resistance, which is quite common in this part of world. PMID- 26985425 TI - An undiagnosed cause of chronic cough. AB - Tracheomalacia (TM) refers to loss of tracheal rigidity and resulting susceptibility to collapse. It is usually an incidental finding during investigations of other illness. The main symptoms are dyspnoea, cough, sputum production and hemoptysis. Most cases are considered as respiratory infection and are treated symptomatically. Acquired TM results from damage to trachea due to various conditions such as inflammation, chronic pressure, or medical/surgical procedures. The diagnosis is done by end-expiratory dynamic tracheal imaging, which demonstrates typical crescentric narrowing of trachea and reduced antero posterior diameter <50% of normal. Management include conservative measures like cough suppressants or surgical measures like tracheoplasty, stenting or surgical repair. We are reporting a case of chronic cough, which was subsequently diagnosed as TM. PMID- 26985424 TI - Immune reconstitution syndrome in a human immunodeficiency virus infected child due to giardiasis leading to shock. AB - Human immunodeficiency virus (HIV)-associated immune reconstitution inflammatory syndrome has been reported in association with tuberculosis, herpes zoster (shingles), Cryptococcus neoformans, Kaposi's sarcoma, Pneumocystis pneumonia, hepatitis B virus, hepatitis C virus, herpes simplex virus, Histoplasma capsulatum, human papillomavirus, and Cytomegalovirus. However, it has never been documented with giardiasis. We present a 7-year-old HIV infected girl who developed diarrhea and shock following the initiation of antiretroviral therapy, and her stool showed the presence of giardiasis. PMID- 26985426 TI - Spontaneous puerperal extraperitoneal bladder wall rupture in young woman with diagnostic dilemma. AB - A young female presented with an acute abdominal pain and oliguria for 1 week following normal vaginal delivery. No history of hematuria was present. Patient was having lochia rubra. Sealed uterine rupture was suspected clinically. Initial ultrasound of the patient showed distended urinary bladder containing Foley catheter ballon with clamping of Foley catheter and particulate ascites. Abdominal paracentesis revealed hemorrhagic fluid. Contrast-enhanced computed tomography of abdomen revealed ascites, distended urinary bladder and no extraluminal contrast extravasation in delayed scan. As patient condition deteriorated, repeat ultrasound guided abdominal paracentesis was done which revealed transudative peritoneal collection with distended bladder. Cystoscopy revealed urinary bladder ruptures with exudate sealing the rupture site. Exploratory laparotomy was done and a diagnosis of extraperitoneal bladder rupture was confirmed. The rent was repaired in layers. She was put on continuous bladder drainage for 3 weeks followed by bladder training. It presented in a unique way as there was hemorrhagic peritoneal tap, no macroscopic hematuria and urinary bladder was distended in spite of urinary bladder wall rupture which delayed the diagnosis and treatment. Complete emptying of urinary bladder before second stage of labor and during postpartum period with perineal repair is mandatory to prevent urinary bladder rupture. PMID- 26985427 TI - Challenges of parents having developmentally challenged children: An intervention approach using acceptance and commitment therapy. PMID- 26985428 TI - Why do some parents prefer private vaccine providers in urban area? PMID- 26985429 TI - Scientometric analysis: A technical need for medical science researchers either as authors or as peer reviewers. AB - The nature of performing a scientific research is a process that has several different components which consist of identifying the key research question(s), choices of scientific approach for the study and data collection, data analysis, and finally reporting on results. Generally, peer review is a series of procedures in the evaluation of a creative work or performance by other people, who work in the same or related field, with the aim of maintaining and improving the quality of work or performance in that field. The assessment of the achievement of every scientist, and thus indirectly determining his reputation in the scientific community of these publications, especially journals, is done through the so-called impact factor index. The impact factor predicts or estimates that how many annual citations article may receive after its publication. Evaluation of scientific productivity and assessment of the published articles of researchers and scientists can be made through the so called H-index. The quality of published results of scientific work largely depends on knowledge sources that are used in the preparation, which means that it should be considered to serve the purpose and the very relevance of the information used. Scientometrics as a field of science covers all aforementioned issues, and scientometric analysis is obligatory for quality assessment of the scientific validity of published articles and other type of publications. PMID- 26985432 TI - Omega-3 and Zinc supplementation as complementary therapies in children with attention-deficit/hyperactivity disorder. AB - OBJECTIVE: The aim of this study is to evaluate the effect of zinc and omega-3 supplements as adjunctive drugs in the treatment of attention deficit/hyperactivity disorder (ADHD) of children. METHODS: This study is a randomized, double-blind clinical trial conducted on 150 children aged 6-15 years old that diagnosed as new cases of ADHD. Study subjects were evaluated for 8 weeks. Besides of drug of choice (methylphenidate) for the ADHD, patients received placebo in the control group (n = 50), zinc sulfate in second group (n = 50), and omega-3 (n = 50) in third group. Clinical improvement was checking by Conners' Parent and Teacher Rating Scales before and in 2(nd), 4(th), and 8(th) week of treatment. Results were analyzed with SPSS version 16 software. FINDINGS: In this study, mean scores of Conners' scale showed significant improvement during treatment in the zinc group compared to control group in children that affected to attention-deficit disorder subtype of ADHD (P = 0.02). Moreover, in omega-3 group, better clinical response was seen than other groups (P < 0.05). However, there was no significant difference between omega-3 group compared to placebo group in the mean scores of Conners' scale (P = 0.89). CONCLUSION: Zinc supplementation accompanied by the main treatment significantly improves symptom of attention-deficit disorder subtype of ADHD. However, omega-3 supplementation was superior to zinc and placebo in the clinical improvement of ADHD. PMID- 26985431 TI - Prophylactic antiemetic effects of Midazolam, Ondansetron, and their combination after middle ear surgery. AB - OBJECTIVE: The purpose of the present study was to evaluate the efficacy of midazolam-ondansetron combination in prevention of postoperative nausea and vomiting (PONV) after middle ear surgery and its comparison with using midazolam or ondansetron alone. METHODS: One hundred and forty patients were enrolled in four groups to receive midazolam 0.75 mg/kg in group M, ondansetron 4 mg in group O, midazolam 0.75 mg/kg and ondansetron 4 mg in group MO, and saline 0.90% in group S intravenously just before anesthesia. Assessment of nausea, vomiting, rescue antiemetic, and side effects of study drugs such as headache and dizziness was carried out postoperatively for 24 h. FINDINGS: The incidence of PONV was significantly smaller in group MO than group M and group O, while there was no significant difference between group M and group O during the first 24 h postoperatively. Requirement to the additional antiemetic was significantly more in group S (71.4%) compared to other groups, while in group MO (11.4%) was lower than group M (31.4%) and group O (34.3%). CONCLUSION: Our study showed that prophylactic administration of midazolam 0.75 mg/kg combined with ondansetron 4 mg was more effective than using midazolam or ondansetron alone in prevention of PONV after middle ear surgery. PMID- 26985430 TI - A review of Vitamin D effects on common respiratory diseases: Asthma, chronic obstructive pulmonary disease, and tuberculosis. AB - Despite the classic role of Vitamin D in skeletal health, new aspects of Vitamin D have been discovered in tissues and organs other than bones. Epidemiological and observational studies demonstrate a link between Vitamin D deficiency and risk of developing respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD), and tuberculosis (TB). To review the literature, we searched the terms "Vitamin D" (using the set operator) and "asthma," "COPD" and "TB" in electronic databases, including PubMed/MEDLINE, Scopus, and Google Scholar until July 2015. Non-English articles or articles with unavailable full text were excluded. Both in vivo and in vitro studies were included. All the reviewed articles state that Vitamin D deficiency is very common among patients with respiratory diseases. The present data regarding Vitamin D and asthma is still controversial, but data about COPD and TB are more encouraging. The relevant studies have been conducted in different populations therefore it is not particularly possible to compare the data due to genetic variations. In order to point out a role for Vitamin D, large clinical trials with Vitamin D deficient subjects and sufficient Vitamin D supplementation are needed. PMID- 26985433 TI - The effect of neutral oligosaccharides on fecal microbiota in premature infants fed exclusively with breast milk: A randomized clinical trial. AB - OBJECTIVE: This study was designed to compare the efficacy and safety of enteral supplementation of a prebiotic mixture (SCGOS/LCFOS) on faecal microbiota in very premature infants who fed exclusively with human-milk. METHODS: This double center randomized control trial was conducted from December 2012 to November 2013 in the tertiary Neonatal Intensive Care Units of the Isfahan University of Medical Sciences. Fifty preterm infants (birth weight <=1500 g who were not fed with formula) were randomly allocated to have enteral (tube feeding) supplementation with a prebiotic mixture (SCGOS/LCFOS; 9:1) or receive no prebiotics. FINDINGS: The primary outcome (e.g., the effect of the prebiotic mixture on fecal microbiota pattern) was clearly different between the two groups. Despite greater coliforms colony counts in first stool cultures in the prebiotic group (Group P) (P = 0.67), coliforms were significantly lower in the third stool cultures in the Group P (P < 0.001). Furthermore, despite the much higher Lactobacillus colony counts, in the first stool cultures, in the control group (Group C) (P = 0.005); there was a trend toward significantly increased Lactobacillus colony counts in the Group P during the study, but the difference between Lactobacillus colony counts, in the third stool cultures, between two groups was no longer statistically significant (P = 0.11). Interestingly, the median length of hospital stay was significantly less in the Group P (16 [12.50 23.50] vs. 25 [19.50-33.00] days; P = 0.003). CONCLUSION: This suggests that it might have been "the complete removal of formula" which manifests a synergistic effect between nonhuman neutral oligosaccharides (prebiotics) and human oligosaccharides, which in turn, led to the rapid growth of beneficial Lactobacillus colonies in the gut of breast milk-fed preterm infants, while decreasing the number of pathogenic coliforms microorganisms. Therefore, further studies with larger sample sizes are recommended to investigate the issue. PMID- 26985434 TI - Pharmaceutical strategic purchasing requirements in Iran: Price interventions and the related effective factors. AB - OBJECTIVE: Pharmaceutical access for the poor is an essential factor in developing countries that can be improved through strategic purchasing. This study was conducted to identify the elements affecting price in order to enable insurance organizations to put strategic purchasing into practice. METHODS: This was a qualitative study conducted through content analysis with an inductive approach applying a five-stage framework analysis (familiarization, identifying a thematic framework, indexing, mapping, and interpretation). Data analysis was started right after transcribing each interview applying ATLAS.ti. Data were saturated after 32 semi-structured interviews by experts. These key informants were selected purposefully and through snowball sampling. FINDINGS: Findings showed that there are four main themes as Pharmaceutical Strategic Purchasing Requirements in Iran as follows essential and structural factors, international factors, economical factors, and legal factors. Moreover, totally 14 related sub themes were extracted in this area as the main effective variables. CONCLUSION: It seems that paying adequate attention to the four present themes and 14 sub themes affecting price can enable health system policy-makers of developing countries like Iran to make the best decisions through strategic purchasing of drugs by the main insurers in order to improve access and health in the country. PMID- 26985435 TI - Antibiotic resistance patterns of microorganisms isolated from nephrology and kidney transplant wards of a referral academic hospital. AB - OBJECTIVE: Antibiotic use pattern and emergence of resistant bacteria are major concerns in clinical settings. This study aimed to detect common bacteria and their antibiotic sensitivity patterns in nephrology and kidney transplant wards. METHODS: This 1-year, observational study was performed in the nephrology and kidney transplant wards of Imam Khomeini Hospital Complex, Tehran, Iran. All patients treated with antimicrobial agents for confirmed or suspected infections were included. Their demographic, clinical, and laboratory data (including biological media used for microbial culture, growth organisms, and antibiograms) were collected. Adherence of antimicrobial regimen to standard guidelines was also assessed. FINDINGS: About half of the patients received antibiotic. The most common infecting bacteria were Escherichia coli followed by Enterococcus sp. and Staphylococcus aureus. E. coli showed high rate of sensitivity to carbapenems and nitrofurantoin and high rate of resistance to co-trimoxazole and ciprofloxacin. Enterococcus sp. in both wards had high rate of resistance to ampicillin and were all sensitive to linezolid. Unlike to the nephrology ward, more than 50% of Enterococcus sp. from kidney transplant ward was resistant to vancomycin. The most common type of S. aureus in this nephrology ward was methicillin-resistant S. aureus (MRSA). Most commonly-prescribed antibiotics were carbapenems followed by vancomycin, ciprofloxacin, and ceftriaxone. Antibiotic regimens were 75% and 83%, 85% and 91%, and 80% and 87% compatible with international guidelines in antibiotic types, dosages, and treatment durations, respectively, in nephrology and kidney transplant wards, respectively. CONCLUSION: MRSA, fluoroquinolone resistant E. coli, and vancomycin resistant Enterococcus species are major threats in nephrology and kidney transplant wards. Most commonly-prescribed antibiotics were carbapenems that necessitate providing internal guidelines by the teamwork of clinical pharmacist, infectious disease specialists, and nephrologists to avoid the widespread use of broad-spectrum antibiotics. PMID- 26985436 TI - Adherence to prescribed medications of Iranian traditional medicine in a group of patients with chronic disease. AB - OBJECTIVE: The extent to which a person's health-related behavior corresponds with medical instructions (adherence) is an important modifier of health system effectiveness. This study was designed to determine the patients' adherence to Iranian traditional medicine in a group of patients with chronic disease. METHODS: Convenience sampling was used to enroll 320 patients with chronic diseases from January 2014 to January 2015 in clinics of traditional medicine affiliated with medical universities in Tehran. Morisky Medication Adherence Scale (MMAS) was used to measure the adherence. After describing the variables and the frequency of adherence, logistic regression analysis was used to determine the influencing factors. FINDINGS: Mean age was 40.8 (standard deviation [SD] =13) years. The mean of the duration of disease was 54.6 (SD = 56.1) months and mean of the duration of referring to the clinics 6.5 (SD = 6.9) months. Total score of MMAS was zero in 33 (10.3%) of patients (high adherence), one or two in 128 (40%) of patients (moderate adherence), and more than two in 159 (49.7%) of patients (low adherence). Forgetfulness, bad taste, not availability, and the high cost of the drugs were the most commonly reported causes of non-adherence. Adherence was associated with age (odds ratio [OR] =1.05, 95% confidence interval [95% CI] 1-1.1), marriage (OR = 10.8, 95% CI 2.05 57.6), number of prescribed drugs (OR = 0.05, 95% CI 0.02-0.14), and duration of disease (OR = 1.01, 95% CI 1-1.02). CONCLUSION: Considering the low adherence in users of medications of Iranian traditional medicine, health care practitioners need to be trained in adherence and the influencing factors and also to use some interventions to increase the adherence. PMID- 26985437 TI - Development of a community pharmacy program in Iran with a focus on Logbook application. AB - OBJECTIVE: Community pharmacy educational program needs to be completed because of gradual transition in pharmacist responsibilities from traditional roles such as dispensing and compounding medications to give professional patient-based care. To further develop the community pharmacy program, this study was designed to involve Logbook in pharmacy training courses. METHODS: For this study, at first, Logbook for community pharmacy practice was designed to develop educational program of this course in Isfahan University of Medical Sciences. Thereafter, in a 6-month prospective study, this Logbook was incorporated to the pharmacy practice course of Doctor of Pharmacy (PharmD) educational program, and students' feedbacks were gained after final examination to improve the Logbook accordingly. Students described their opinions about different sections of this program as unnecessary, necessary, and necessary with revision. FINDINGS: A total of 65 PharmD students were included in this study. More than 90% of the students gave complete answers to the evaluation of this pharmacy training program. The results showed that more than 70% of students considered this program of pharmacy training was necessary (with or without revisions) in PharmD courses. They recommended more time to be included for prescription reading and analyses during these courses. CONCLUSION: Developing pharmacy training program by using Logbook which was presented in this study was considered necessary and efficient for PharmD students. However, it is a prototype system, and we are committed to using initial students and preceptors' feedbacks to improve Logbook in future courses. PMID- 26985438 TI - The risk factors for cytomegalovirus reactivation following stem cell transplantation. AB - OBJECTIVE: Opportunistic infections like cytomegalovirus (CMV) are among the primary causes of morbidity and mortality in patients undergoing hematipoetic stem cell transplantation (HSCT). This infection is frequently seen in early postengraftment period. So we determined to find the risk factors associated with CMV reactivation. METHODS: We retrospectively evaluated the medical records of 126 consecutive patients who underwent allogenic-HSCT from peripheral blood stem cells from August 2011 to February 2013 in Shariati Hospital. We included HSCT patients with 15 years of age or older, who survived at least 100 days after transplantation. CMV reactivation was detected based on the weekly PP65 assessment. Patients with 10 or more positive cells per 50,000 cells were defined as having high-level antigenemia. FINDINGS: From 126 patients which included in this study, 76 were male (60%). CMV antigenemia was documented in 43 patients (34%). The median time to CMV infection was 40 days (range: 3-77) after transplantation. The incidence of high-level antigenemia during the first 100 days following HSCT was 11%. CONCLUSION: We found that the significant risk factor for CMV antigenemia in multivariate analysis was prior graft-versus-host disease (GVHD) experience and higher donor age. For high-level antigenemia, GVHD or duration of its treatment was significant determinant. PMID- 26985439 TI - Drug reaction with eosinophilia and systemic symptoms syndrome associated with Nitrofurantoin. AB - Drug reaction with eosinophilia and systemic symptom (DRESS) is a severe adverse drug-induced reaction with a prolonged latency period which is characterized by a variety of clinical manifestations, usually fever, rash, lymphadenopathy, eosinophilia, and a wide range of mild-to-severe systemic presentations. Drugs are an important cause of DRESS in most of the cases. It is challenging to diagnose DRESS because of the diversity of cutaneous eruption and visceral organs involvement. We hereby report a 34-year-old female who developed DRESS syndrome following ingestion of nitrofurantoin for the treatment of urinary tract infection. She was managed conservatively and recovered after few weeks. Our aim of this study is to raise awareness to suspect DRESS syndrome in patients who present with unusual clinical features with skin involvement after initiating any drug. PMID- 26985440 TI - Silymarin therapy and improvement of cardiac outcome in patients with beta thalassemia major. PMID- 26985441 TI - The Current State of Poison Control Centers in Pakistan and the Need for Capacity Building. AB - BACKGROUND: Chemical exposure is a major health problem globally. Poison control centers (PCCs) play a leading role both in developed and developing countries in the prevention and control of poisonous chemical exposures. In this study, we aimed to assess the current state of PCCs in Pakistan and highlight capacity building needs in these centers. METHODS: A cross-sectional survey of the two registered PCCs was done during August - December 2011. Necessary services of the PCCs were evaluated and the data were recorded on a predesigned checklist. RESULTS: Both PCCs are affiliated to a tertiary care hospital. Clinical services to poisoned patients were available 24 hours a day / 7 days a week. Information on common local products was available to poison center staff. Both centers were involved in undergraduate and post graduate teaching. Telephone poison information service was not available in either of centers. There was a limited capacity for qualitative and analytical toxicology. Common antidotes were available. There were limited surveillance activities to capture toxic risks existing in the community and also a deficiency was observed in chemical disaster planning. CONCLUSION: PCCs in Pakistan need capacity building for specialized training in toxicology, toxicovigilance, chemical disaster planning, analytical laboratory tests and telephone service for consultation in poisoning cases. PMID- 26985443 TI - Application of linker technique to trap transiently interacting protein complexes for structural studies. AB - Protein-protein interactions are key events controlling several biological processes. We have developed and employed a method to trap transiently interacting protein complexes for structural studies using glycine-rich linkers to fuse interacting partners, one of which is unstructured. Initial steps involve isothermal titration calorimetry to identify the minimum binding region of the unstructured protein in its interaction with its stable binding partner. This is followed by computational analysis to identify the approximate site of the interaction and to design an appropriate linker length. Subsequently, fused constructs are generated and characterized using size exclusion chromatography and dynamic light scattering experiments. The structure of the chimeric protein is then solved by crystallization, and validated both in vitro and in vivo by substituting key interacting residues of the full length, unlinked proteins with alanine. This protocol offers the opportunity to study crucial and currently unattainable transient protein interactions involved in various biological processes. PMID- 26985444 TI - Single Clinical Practice's Report of Testing Initiation, Antibody Clearance, and Transmission of Hepatitis C Virus (HCV) in Infants of Chronically HCV-Infected Mothers. AB - Background. Perinatally acquired hepatitis C virus (HCV) is the main source of pediatric HCV infection. However, the best time for initiation of screening and follow up of these infants is still unknown. Analysis of the clinical data of infants born to HCV-infected mothers, transmission rates, and pathway of HCV testing could be important for optimization of their management. Methods. Children of mothers with chronic HCV infection, who were observed between 1998 and 2013 at the pediatric infectious disease clinic for the first 18 months of their life, were eligible for enrollment. We analyzed the factors influencing initiation of HCV testing in these children and rate of HCV transmission as demonstrated by consecutive HCV antibody and HCV ribonucleic acid (RNA) amplification testing. Results. One hundred and forty-two mother-infant pairs were enrolled. The majority of mothers were intravenous drug users, had carried to term, and delivered vaginally. A high proportion of infants had at least 1 positive anti-HCV antibody assay without viremia. True HCV infection and intermittent viremia were recorded in 3.5% and 1.4% of infants, respectively. Initiation of HCV testing after 10 months of age was associated with a significant decline in the probability of obtaining a positive HCV antibody of maternal origin. Conclusions. The low likelihood for detection and confirmation of true HCV transmission before 10 months of age could challenge the early initiation of HCV screening of infants exposed to maternal HCV infection but may affect the parental need for early monitoring and counseling. PMID- 26985446 TI - Opioid System Modulates the Immune Function: A Review. AB - Opioid receptors and their ligands produce powerful analgesia that is effective in perioperative period and chronic pain managements accompanied with various side effects including respiratory depression, constipation and addiction etc. Opioids can also interfere with the immune system, not only participating in the function of the immune cells, but also modulating innate and acquired immune responses. The traditional notion of opioids is immunosuppressive. Recent studies indicate that the role of opioid receptors on immune function is complicated, working through various different mechanisms. Different opioids or opioids administrations show various effects on the immune system: immunosuppressive, immunostimulatory, or dual effect. It is important to elucidate the relationship between opioids and immune function, since immune system plays critical role in various physiological and pathophysiological processes, including the inflammation, tumor growth and metastasis, drug abuse, and so on. This review article tends to have an overview of the recent work and perspectives on opioids and the immune function. PMID- 26985445 TI - Asymmetric Dimethylarginine in Adult Falciparum Malaria: Relationships With Disease Severity, Antimalarial Treatment, Hemolysis, and Inflammation. AB - Background. Endothelial nitric oxide (NO) bioavailability is impaired in severe falciparum malaria (SM). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase (NOS), contributes to endothelial dysfunction and is associated with mortality in adults with falciparum malaria. However, factors associated with ADMA in malaria, including the NOS-substrate l-arginine, hemolysis, and antimalarial treatment, are not well understood. Methods. In a prospective observational study of Malaysian adults with SM (N = 22) and non-SM (NSM; N = 124) and healthy controls (HCs), we investigated factors associated with plasma ADMA including the effects of antimalarial treatment. Results. Compared with HCs, ADMA levels were lower in NSM (0.488 uM vs 0.540 uM, P = .001) and in the subset of SM patients enrolled before commencing treatment (0.453 uM [N = 5], P = .068), but levels were higher in SM patients enrolled after commencing antimalarial treatment (0.610 uM [N = 17], P = .026). In SM and NSM, ADMA levels increased significantly to above-baseline levels by day 3. Baseline ADMA was correlated with arginine and cell-free hemoglobin in SM and NSM and inversely correlated with interleukin-10 in NSM. Arginine and the arginine/ADMA ratio (reflective of arginine bioavailability) were lower in SM and NSM compared with HCs, and the arginine/ADMA ratio was lower in SM compared with NSM. Conclusions. Pretreatment ADMA concentrations and l-arginine bioavailability are reduced in SM and NSM. Asymmetric dimethylarginine increases to above-baseline levels after commencement of antimalarial treatment. Arginine, hemolysis, and posttreatment inflammation all likely contribute to ADMA regulation, with ADMA likely contributing to the reduced NO bioavailability in SM. PMID- 26985447 TI - Significance of Proline Residue on Short Mucin Peptide Interactions with Mouse MUC1 Monoclonal Antibody Studied by Saturation Transfer Difference NMR Spectroscopy. AB - In this study we investigated to see whether or not a shortened MUC1 mucin peptide epitope with the sequence GVTSAPD containing a single prolyl residue would still bind specific monoclonal antibody as its native sequence (e.g., PDTRP), known to be the specific recognition site on the Variable Number Tandem Repeat (VNTR) region of MUC1 mucin by the immune system. The affinity of GVTSAPD peptide to a mouse Muc1 mucin specific monoclonal antibody (clone 6A4, IgG1 isotype) was investigated by Saturation Transfer Difference NMR spectroscopy (STD NMR). Results showed that the shortened mucin epitope GVTSAPD still retained affinity to Muc1 specific monoclonal antibody (mAb) while one that lacks the prolyl residue at position 6 lost its affinity, which suggests that P6 is necessay for antibody binding. The interactions observed by STD NMR occurred strongest at the P6 side chain 1H's (betaH and gammaH); the P6Halpha showed lower degree of saturation transfer effect. Minor interactions also occurred at the methyl groups of V2' T3 and A5. Mucin peptides derived from the VNTR region have been the target of cancer vaccine research, thus properties associated with mucin peptide structure, conformation and antibody interaction are central to peptide design or engineering towards that end. PMID- 26985448 TI - Characterization of molecular and cellular phenotypes associated with a heterozygous CNTNAP2 deletion using patient-derived hiPSC neural cells. AB - Neurodevelopmental disorders, such as autism spectrum disorders (ASD) and schizophrenia (SZ), are complex disorders with a high degree of heritability. Genetic studies have identified several candidate genes associated with these disorders, including contactin-associated protein-like 2 (CNTNAP2). Traditionally, in animal models or in vitro, the function of CNTNAP2 has been studied by genetic deletion or transcriptional knockdown, which reduce the expression of the entire gene; however, it remains unclear whether the mutations identified in clinical settings are sufficient to alter CNTNAP2 expression in human neurons. Here, using human induced pluripotent stem cells (hiPSCs) derived from two individuals with a large (289kb) and heterozygous deletion in CNTNAP2 (affecting exons 14-15) and discordant clinical outcomes, we have characterized CNTNAP2 expression patterns in hiPSC neural progenitor cells (NPCs), two independent populations of hiPSC-derived neurons and hiPSC-derived oligodendrocyte precursor cells (OPCs). First, we observed exon-specific changes in CNTNAP2 expression in both carriers; although the expression of exons 14-15 is significantly decreased, the expression of other exons is upregulated. Second, we observed significant differences in patterns of allele-specific expression in CNTNAP2 carriers that were consistent with clinical outcome. Third, we observed a robust neural migration phenotype that correlated with diagnosis and exon- and allele-specific CNTNAP2 expression patterns, but not with genotype. In all, our data highlight the importance of considering the nature, location and regulation of mutated alleles when attempting to connect GWAS studies to gene function. PMID- 26985449 TI - EVALUATION RETREAT: A SENSIBLE METHOD FOR PROGRAM'S ASSESSMENT. AB - PURPOSE: The University of Puerto Rico (UPR), Medical Sciences Campus (MSC) post doctoral Master of Science in Clinical and Translational Research (MSc) program aims to train Hispanic post-doctoral candidates to advance their careers and become successful clinical and translational researchers geared to help eliminate health disparities. Its curriculum highlights the use of technology and online resources to maximize time use of time and efforts. As part of the assessment efforts, the program's Evaluation Committee leads an annual activity, Evaluation Retreat (ER), to evaluate the program's curriculum, research component, and mentoring experience according to Scholars' perspective. Results are used by the Program Executive committee for further planning and improvement. This analysis presents the most relevant results from these activities. DESIGN METHODS: Data collection (from last 5 years), include quantitative (online surveys) and qualitative approaches (a group meeting with Scholars.) Questionnaires request Scholars to rate specific features of the program's research component, mentoring experience and curriculum. It also includes questions about the program in general (major strengths and challenges, and recommendations for improvement. During the group meeting, Scholars discuss these results and present consensus in a plenary session. Quantitative data are managed and analyzed using the statistical software SPSS. Qualitative data are examined using content analysis. RESULTS: Scholars identified as program's strengths the networking opportunities (local and with U.S. experts), the diversity of peers and faculty, the faculty support, the technical and audiovisual support, the physical facilities and resources, the guest speakers and consultants, and the quality of the curriculum. Challenges vary as cohorts change, but time limitations and the need for technical/statistical support are always highlighted. Recommendations for improvement emphasize the need for a greater pool of experienced mentors, and more hands-on approaches to address particular skills such as, manuscript development, institutional and federal guidelines for proposal submission, and issues related to the research project management. DISCUSSION: Evaluation Retreats provide a valuable input to improve a program geared to develop competent clinical researchers. Findings evidence the program's commitment with providing the foundation for an enhanced mass of clinical researchers. PMID- 26985450 TI - Individually tailored light intervention through closed eyelids to promote circadian alignment and sleep health. AB - BACKGROUND: Light is most effective at changing the timing of the circadian clock when applied close to the core body temperature minimum. The present study investigated, in a home setting, if individually tailored light treatment using flashing blue light delivered through closed eyelids during the early part of the sleep period delayed circadian phase and sleep in a population of healthy older adults and in those suffering from early awakening insomnia. METHODS: Twenty eight participants (9 early awakening insomniacs) completed an 8-week, within subjects study. Twice, participants collected data during two baseline weeks and one intervention week. During the intervention week, participants wore a flashing blue (active) or a flashing red (control) light mask during sleep. Light was expected to delay circadian phase. Saliva samples for dim light melatonin onset (DLMO) were collected at the end of each baseline and intervention week. Wrist actigraphy and Daysimeter, a calibrated light and activity meter, data were collected during the entire study. RESULTS: Compared to baseline, flashing blue light, but not flashing red light, significantly (p<0.05) delayed DLMO. The mean +/- standard deviation phase shift (minutes) was 0:06 +/- 0:30 for the flashing red light and 0:34 +/- 0:30 for the flashing blue light. Compared to Day 1, sleep start times were significantly delayed (by approximately 46 minutes) at Day 7 after the flashing blue light. The light intervention did not affect sleep efficiency. CONCLUSIONS: The present study demonstrated the feasibility of using light through closed eyelids during sleep for promoting circadian alignment and sleep health. PMID- 26985451 TI - REGENERATIVE ENGINEERING: APPROACHES TO LIMB REGENERATION AND OTHER GRAND CHALLENGES. AB - The clinical grand challenge to regenerate complex tissue and organ systems call for a paradigm shift that requires a transdisciplinary approach. The field of regenerative engineering puts forward a Convergence approach to create a regenerative toolbox to move beyond individual tissue repair to the regeneration of complex tissues and organ systems. Here we discuss the regenerative tool box currently under development to address grand opportunities in complex tissue/organ regeneration. PMID- 26985452 TI - Metabolic reprogramming of pyruvate dehydrogenase is essential for the proliferation of glioma cells expressing mutant IDH1. AB - Mutations in isocitrate dehydrogenase 1 (IDH1) characterize most adult low-grade gliomas. Mutant IDH1 catalyzes production of the oncometabolite 2 hydroxyglutarate (2-HG). We recently discovered that the IDH1 mutation also reprograms pyruvate metabolism in a 2-HG-dependent manner, and reprogramming of pyruvate metabolism is essential for cell proliferation in mutant IDH1 glioma cells. PMID- 26985453 TI - Editorial: Introducing Research Resource Identification Initiative at eNeuro. PMID- 26985455 TI - Nanogel-Mediated RNAi Against Runx2 and Osx Inhibits Osteogenic Differentiation in Constitutively Active BMPR1A Osteoblasts. AB - Trauma-induced heterotopic ossification (HO) and fibrodysplasia ossificans progressiva (FOP) are acquired and genetic variants of pathological bone formation occurring in soft tissues. Conventional treatment modalities target the inflammatory processes preceding bone formation. We investigated the development of a prophylaxis for heterotopic bone formation by addressing the biological basis for HO - dysregulation in the bone morphogenetic protein (BMP) signaling pathway. We previously reported the synthesis of cationic nanogel nanostructured polymers (NSPs) for efficient delivery of short interfering ribonucleic acids (siRNAs) and targeted gene silencing. Results suggested that nanogel:siRNA weight ratios of 1:1 and 5:1 silenced Runx2 and Osx gene expression in primary mouse osteoblasts with a constitutively active (ca) BMP Receptor 1A (BMPR1A) by the Q233D mutation. Repeated RNAi treatments over 14 days significantly inhibited alkaline phosphatase activity in caBMPR1A osteoblasts. Hydroxyapatite (HA) deposition was diminished over 28 days in culture, though complete suppression of HA deposition was not achieved. Outcome data suggested minimal cytotoxicity of nanogel-based RNAi therapeutics, and the multistage disruption of BMP-induced bone formation processes. This RNAi based approach to impeding osteoblastic differentiation and subsequent bone formation may form the basis of a clinical therapy for heterotopic bone formation. PMID- 26985454 TI - Network Analysis Reveals Sex- and Antibiotic Resistance-Associated Antivirulence Targets in Clinical Uropathogens. AB - Increasing antibiotic resistance among uropathogenic Escherichia coli (UPEC) is driving interest in therapeutic targeting of nonconserved virulence factor (VF) genes. The ability to formulate efficacious combinations of antivirulence agents requires an improved understanding of how UPEC deploy these genes. To identify clinically relevant VF combinations, we applied contemporary network analysis and biclustering algorithms to VF profiles from a large, previously characterized inpatient clinical cohort. These mathematical approaches identified four stereotypical VF combinations with distinctive relationships to antibiotic resistance and patient sex that are independent of traditional phylogenetic grouping. Targeting resistance- or sex-associated VFs based upon these contemporary mathematical approaches may facilitate individualized anti-infective therapies and identify synergistic VF combinations in bacterial pathogens. PMID- 26985456 TI - "Compassion Cultivation in Chronic Pain May Reduce Anger, Pain, and Increase Acceptance: Study Review and Brief Commentary". PMID- 26985458 TI - Enhanced fluorescent resonant energy transfer of DNA conjugates complexed with surfactants and divalent metal ions. AB - Dimerization and resultant quenching of donor and acceptor dyes conjugated on DNA causes loss of fluorescent resonant energy transfer (FRET) efficiency. However, when complexed with surfactants and divalent metal ions, sheathing effects insulate and shield the DNA structures, reducing dimerization and quenching which leads to significant enhancement of FRET efficiency. PMID- 26985457 TI - Effect of MRP2 and MRP3 Polymorphisms on Anastrozole Glucuronidation and MRP2 and MRP3 Gene Expression in Normal Liver Samples. AB - Anastrozole is an aromatase inhibitor (AI) used as adjuvant therapy for breast cancer. Anastrozole is subject to direct glucuronidation catalyzed by UDP glucuronosyltransferase1A4 (UGT1A4). Interindividual variability in anastrozole glucuronidation may be affected by UGT1A4 SNPs. Interplay between drug metabolizing genes such as UGT1A4 and transporter genes may also be affected by genetic variability. Thus, we hypothesize that genetic variability in MRPs could influence anastrozole glucuronidation. The correlation between UGT1A4 and MRP2 or MRP3 transporter gene expressions and the correlation between MRP2 or MRP3 mRNA and anastrozole glucuronidation were analyzed in normal human liver samples. MRP2 and MRP3 mRNA levels were significantly correlated with UGT1A4 mRNA, with anastrozole glucuronidation and with each other (p<0.05). The data also demonstrated that MRP2 SNPs are positively correlated with MRP2 mRNA expression, while there was no association between MRP3 SNPs from this study and MRP3 expression. Significant correlations (p<0.05) between certain MRP2 SNPs (3972C>T, 2366C>T and -24C>T) and anastrozole glucuronidation were observed. There were no observed correlations between MRP3 SNPs and anastrozole glucuronidation. MRP2 polymorphisms have been identified as playing a role in the disposition of other drugs, and the data presented here indicate for the first time that MRP2 SNPs could influence anastrozole metabolism and contribute to interindividual variation in treatment responses. PMID- 26985459 TI - HEALTHY INNOVATION: VAPING, SMOKING, AND PUBLIC POLICY. PMID- 26985460 TI - RECOMMENDATIONS FOR U.S. PUBLIC POLICIES REGULATING ELECTRONIC CIGARETTES. PMID- 26985461 TI - HEALTH REGULATION. PMID- 26985462 TI - COMPREHENSIVE E-CIGARETTE REGULATION AS A STEP TOWARD HARM REDUCTION. PMID- 26985463 TI - Retraction notice to "Triptolide, histone acetyltransferase inhibitor, suppresses growth and chemosensitizes leukemic cells through inhibition of gene expression regulated by TNF-TNFR1-TRADD-TRAF2-NIK-TAK1-IKK pathway" [Biochem. Pharmacol. 82 (2011) 1134-1144]. PMID- 26985464 TI - Retraction notice to "Cyclodextrin-complexed curcumin exhibits anti-inflammatory and antiproliferative activities superior to those of curcumin through higher cellular uptake" [Biochem. Pharmacol. 80 (2010) 1021-1032]. PMID- 26985465 TI - Retraction notice to "Design of curcumin-loaded PLGA nanoparticles formulation with enhanced cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo" [Biochem. Pharmacol. 79 (2010) 330-338]. PMID- 26985466 TI - Retraction notice to "Suppression of pro-inflammatory and proliferative pathways by diferuloylmethane (curcumin) and its analogues dibenzoylmethane, dibenzoylpropane, and dibenzylideneacetone: Role of Michael acceptors and Michael donors" [Biochem. Pharmacol. 82 (2011) 1901-1909]. PMID- 26985467 TI - Retraction notice to "Curcumin potentiates the antitumor effects of gemcitabine in an orthotopic model of human bladder cancer through suppression of proliferative and angiogenic biomarkers" [Biochem. Pharmacol. 79 (2010) 218-228]. PMID- 26985468 TI - Retraction notice to "Thymoquinone poly(lactide-co-glycolide) nanoparticles exhibit enhanced anti-proliferative, anti-inflammatory, and chemosensitization potential" [Biochem. Pharmacol. 79 (2010) 1640-1647]. PMID- 26985469 TI - Retraction notice to "Curcumin induces the degradation of cyclin E expression through ubiquitin-dependent pathway and up-regulates cyclin-dependent kinase inhibitors p21 and p27 in multiple human tumor cell lines" [Biochem. Pharmacol. 73 (2007) 1024-1032]. PMID- 26985471 TI - Reflections: neurology and the humanities. The Theory of Everything The extraordinary and the ordinary. PMID- 26985470 TI - The authors respond. PMID- 26985472 TI - Author Response. PMID- 26985474 TI - rRNA sequencing for bacterial identification. PMID- 26985473 TI - Author Response. PMID- 26985475 TI - [Young patient with palpitations. Which arrhythmia is the cause - and what would you do?]. PMID- 26985476 TI - [Work on the stress axis brings relief. Helping the highly sensitive patient]. PMID- 26985477 TI - [Sports tax for sedentary persons]. PMID- 26985478 TI - [A prescription with broad effective spectrum. Properly prescribing motor activity]. PMID- 26985479 TI - [Sports in tumor after care. Moderate exercise therapy for better prognosis]. PMID- 26985480 TI - [Knee injuries. What is broken: meniscus, ligaments or cartilage?]. PMID- 26985481 TI - [Quo vadis sports medicine?]. PMID- 26985482 TI - [Spontaneous pneumothorax. Thoracic drainage: what can go wrong?]. PMID- 26985483 TI - [Diagnosis and admission criteria updated. New guideline pericarditis]. PMID- 26985484 TI - [Cystitis. Ultrasound only in complicated anamnesis]. PMID- 26985486 TI - [Severe atopic dermatitis. Antibodies revolutionize therapy]. PMID- 26985487 TI - [Atopic dermatitis. Probiotics in primary prevention]. PMID- 26985489 TI - [The silent potentials of no.01622 EBM]. PMID- 26985488 TI - [Therapy of deep venous thrombosis. Effective without stockings?]. PMID- 26985490 TI - [Small GOA trick in exclusion of no. 8]. PMID- 26985491 TI - [Physician assistant pregnant - what should be done?]. PMID- 26985492 TI - [Even with sensory aids there is a regress risk]. PMID- 26985493 TI - [This grimacing patient I have offended]. PMID- 26985494 TI - [Even Hahnemann did not anticipate this]. PMID- 26985495 TI - [Mecklenburg-Vorpommern physician network. Bypass for health care stenosis]. PMID- 26985496 TI - [ GOA accounting. Patient will not pay injections and cannula]. PMID- 26985497 TI - [Remedies. Subsequent prescription is the responsibility of the first prescriber ]. PMID- 26985498 TI - [Endless reform. GOA: offsetting inflation personally]. PMID- 26985499 TI - [Reader survey. Antibiotics in respiratory infections are unpopular]. PMID- 26985500 TI - [Approach to multiple targets]. PMID- 26985501 TI - [In atrial fibrillation weight loss is effective]. PMID- 26985502 TI - [Multidimensional prevention of dementia diseases]. PMID- 26985503 TI - [Overdiagnosis in gynecomastia in the man]. PMID- 26985504 TI - [Lady in red seeks reproductive partners]. PMID- 26985505 TI - [Suspending anticoagulation for operation without substitutes]. PMID- 26985506 TI - [Even in COPD beta blockers can be administered - but not all]. PMID- 26985507 TI - [Passive smoking damages blood vessels the same as active smoking]. PMID- 26985508 TI - [Things are different in nursing homes. Take care of the elderly]. PMID- 26985509 TI - [Multiresistant bacteria in nursing homes for the elderly]. PMID- 26985510 TI - [Self determined planning at the end of life]. PMID- 26985511 TI - [Diagnostic and treatment principles of iron deficiency anaemia]. PMID- 26985512 TI - [Suffering from hemorrhoids: "I am even afraid to go to the bathroom"]. PMID- 26985513 TI - [Dietary recommendations for patients with type 2 diabetes]. PMID- 26985514 TI - [Migraine]. PMID- 26985515 TI - [Diagnostic sonography for assessment of shoulder pain]. PMID- 26985516 TI - [Acute uncomplicated respiratory tract infections. Phytotherapy with mustard oils recommended by expert panel]. PMID- 26985517 TI - [SGLT2 inhibition in type 2 diabetes. New study data for reducing cardiovascular risk]. PMID- 26985567 TI - Quantification of adipose volume reduction with a prospective study analyzing the application of external radiofrequency energy and high voltage ultrashort pulse duration electrical fields. AB - To date, there have been no objective measurements of subcutaneous volume loss following treatments with a noninvasive radiofrequency (RF)-based device. Twenty female patients were treated with a suction-coupled bipolar RF device using external RF energy combined with pulsed electromagnetic RF energy for subcutaneous fat reduction. Parameters followed included weight, Vectra measurements of abdominal circumference and torso volume, and high-definition ultrasound measurements of fat thickness. Measurements were taken before treatment and three times following treatment. Analysis of the measured parameters showed that mean circumference reduction of 2.30 cm was noted at three months post-treatment. Independent volumetric analysis showed a mean subcutaneous volume reduction of 428 cc three months following RF treatment. High-resolution ultrasound fat thickness was reduced by a mean of 39.6% three months following the final BodyFX treatment. Independent and paired-sample t-tests showed a p value of < 0.05. Repeated measures of analysis of covariance (ANCOVA) adjusted for differences in age, as well as height and weight (proxy for body mass index) to minimize individual differences and control for extraneous variables that may affect the pre- and post-treatment results were analyzed. No confounding variables were found. All analyses were conducted using IBM SPSS 21.0. PMID- 26985569 TI - Usefulness of sentinel lymph node biopsy for prognostic prediction in extramammary Paget's disease. AB - Complete excision of the primary lesion has long been considered the standard treatment for extramammary Paget's disease (EMPD). However, the presence of lymph node metastases has been reported as an important prognostic factor. We evaluated the association between lymph node metastasis and prognosis for EMPD using sentinel lymph node (SLN) biopsy. This retrospective study included 59 patients with histopathologically-confirmed primary EMPD. A total of 45 patients with microinvasion to the papillary dermis and deep invasion into the reticular dermis or subcutaneous tissue were included in the analysis. The survival curves of the SLN-negative group and the SLN-positive group were compared and we examined the risk factors for SLN positivity. A total of 139 SLNs were excised from one (28 patients) or both inguinal regions (31 patients). The average number of detected SLNs was 2.4. The incidence of SLN metastases was 16.9%. SLN positivity rates according to level of invasion were 0% for intraepithelial lesions, 4.1% for microinvasion, and 42.8% for dermal invasion. The five-year survival rates were 100% in the SLN-negative and 24% in the SLN-positive groups (p = 0.0001). Reticular dermis or subcutaneous tissue invasion was a significant independent risk factor for SLN positivity according to multivariate analysis. The result of SLN biopsy affected prognosis. It is extremely important to accurately ascertain the presence, i.e. the number, or absence of regional lymph node metastases in patients with EMPD. We conclude that SLN biopsy may be appropriate for cases where invasion is suspected. PMID- 26985568 TI - Stability of stereognosis after pediatric repetitive transcranial magnetic stimulation and constraint-induced movement therapy clinical trial. AB - OBJECTIVE: Poor sensibility affecting stereognosis, the ability to discriminate objects without visual input, can potentiate disuse of the paretic limb following stroke. The purpose of this study was to examine potential change in stereognosis after intervention. METHODS: Stereognosis testing in a secondary subgroup of 10 children with hemiparesis and baseline stereognosis deficits (ages 11-16) after a 13-day clinical trial of real or sham repetitive transcranial magnetic stimulation (rTMS) and constraint-induced movement therapy (CIMT) is reported. All children received 10 h of CIMT while wearing a cast full-time. RESULTS: Post trial, 80% of participants from both intervention groups demonstrated improvement in stereognosis (95% CI: 44.4%-97.5%). Pre-trial to long-term follow-up (range: 21-57 months), 60% retained gains or improved (95% CI: 26.2%-87.8%). Between group differences were not detected. DISCUSSION: Children demonstrated stereognosis change following intervention. Research on this change and potential minimal clinically important differences are indicated. PMID- 26985570 TI - Effect of brefeldin A and castanospermine on resistant cell lines as supplements in anticancer therapy. AB - In the present study, we analyzed the influence of brefeldin A (BFA) and castanospermine (CAS) on the activity, stability and localization of P glycoprotein (Pgp) and breast cancer resistance protein (BCRP) in various resistant cell lines. The impact of BFA and CAS on cell viability was assessed using the MTT test. Western blotting (WB) was performed to assess the effect of the inhibitors on the expression of the investigated proteins. Immunofluorescence was employed to assess the effect of BFA and CAS on the cellular localization of the proteins. Flow cytometry was used to verify the functional role of inhibitors on drug uptake and efflux. The MTT test showed that BFA had a significant effect on cell viability in LoVo/Dx and W1PR cell lines. WB analysis demonstrated that BFA partially blocked Pgp N-glycosylation and induced BCRP degradation and CASP 3 dependent apoptosis in W1TR cells; however, the BFA activity was p53-independent. CAS had no effect on the stability of Pgp but increased the level of non glycosylated BCRP. The expression of p53 protein decreased in all of the cells that were treated with CAS. Immunofluorescence revealed that BFA caused a more granular Pgp signal in W1PR and BCRP in A2780T1 cells. Furthermore, BFA caused morphological changes in LoVo/Dx and W1TR cell lines. CAS also induced a granular signal in all of the cell lines, except W1TR. The flow cytometry showed higher dye accumulation in sensitive cell lines. We observed an increase in the mean fluorescence intensity (MFI) of Rho123 in LoVo/Dx cells treated with BFA and CAS, but no differences were observed in W1PR. BFA had no effect on the MFI of W1TR, but CAS led to an increase in the level of intracellular H33342 in W1TR and A2780T1 cells. These results suggest that these compounds are likely to be useful as supplements in anticancer therapy. PMID- 26985571 TI - Inhibitory effects of benzimidazole containing new phenolic Mannich bases on human carbonic anhydrase isoforms hCA I and II. AB - New phenolic mono and bis Mannich bases incorporating benzimidazole, such as 2 (aminomethyl)-4-(1H-benzimidazol-2-yl)phenol and 2,6-bis(aminomethyl)-4-(1H benzimidazol-2-yl)phenol were synthesized starting from 4-(1H-benzimidazol-2 yl)phenol. Amines used for the synthesis included dimethylamine, pyrrolidine, piperidine, N-methylpiperazine and morpholine. The CA inhibitory properties of these compounds were tested on the human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I and hCA II. These new compounds, as many phenols show moderate CA inhibitory properties. PMID- 26985572 TI - Functionalization, preparation and use of cell-laden gelatin methacryloyl-based hydrogels as modular tissue culture platforms. AB - Progress in advancing a system-level understanding of the complexity of human tissue development and regeneration is hampered by a lack of biological model systems that recapitulate key aspects of these processes in a physiological context. Hence, growing demand by cell biologists for organ-specific extracellular mimics has led to the development of a plethora of 3D cell culture assays based on natural and synthetic matrices. We developed a physiological microenvironment of semisynthetic origin, called gelatin methacryloyl (GelMA) based hydrogels, which combine the biocompatibility of natural matrices with the reproducibility, stability and modularity of synthetic biomaterials. We describe here a step-by-step protocol for the preparation of the GelMA polymer, which takes 1-2 weeks to complete, and which can be used to prepare hydrogel-based 3D cell culture models for cancer and stem cell research, as well as for tissue engineering applications. We also describe quality control and validation procedures, including how to assess the degree of GelMA functionalization and mechanical properties, to ensure reproducibility in experimental and animal studies. PMID- 26985573 TI - A LC-MS-based workflow for measurement of branched fatty acid esters of hydroxy fatty acids. AB - Branched fatty acid esters of hydroxy fatty acids (FAHFAs) are a recently discovered class of endogenous mammalian lipids with antidiabetic and anti inflammatory effects. We previously identified 16 different FAHFA families, such as branched palmitic acid esters of hydroxy stearic acids (PAHSAs); each family consists of multiple isomers in which the branched ester is at different positions (e.g., 5- and 9-PAHSA). We anticipate increased need for PAHSA measurements as markers of metabolic and inflammatory health. In this protocol, we provide a detailed description of the extraction of FAHFAs from human or mouse tissues, their enrichment by solid-phase extraction and subsequent analysis by LC MS. For a sample size of 6-12, the time frame is 2-3 d. PMID- 26985575 TI - Number-specific and general cognitive markers of preschoolers' math ability profiles. AB - Different number-specific and general cognitive markers have been claimed to underlie preschoolers' math ability. It is unclear, however, whether similar/different cognitive markers, or combinations of them, are associated with different patterns of emerging math abilities (i.e., different patterns of strength and weakness). To examine this question, 103 preschoolers (40-60 months of age) completed six math tasks (count sequence, object counting, give a number, naming numbers, ordinal relations, and arithmetic), three number-specific markers of math ability (dot enumeration, magnitude comparison, and spontaneous focusing on numerosity), and four general markers (working memory, response inhibition, attention, and vocabulary). A three-step latent profile modeling procedure identified five math ability profiles that differed in their patterns of math strengths and weaknesses; specifically, the profiles were characterized by (a) excellent math ability on all math tasks, (b) good arithmetic ability, (c) good math ability but relatively poor count sequence recitation ability, (d) average ability on all math tasks, and (e) poor ability on all math tasks. After controlling for age, only dot enumeration and spontaneous focusing on numerosity were associated with the math ability profiles, whereas vocabulary was also marginally significant, and these markers were differentially associated with different profiles; that is, different cognitive markers were associated with different patterns of strengths and weaknesses in math abilities. Findings are discussed in terms of their implications for the development of math cognition. PMID- 26985574 TI - Automated screening for small organic ligands using DNA-encoded chemical libraries. AB - DNA-encoded chemical libraries (DECLs) are collections of organic compounds that are individually linked to different oligonucleotides, serving as amplifiable identification barcodes. As all compounds in the library can be identified by their DNA tags, they can be mixed and used in affinity-capture experiments on target proteins of interest. In this protocol, we describe the screening process that allows the identification of the few binding molecules within the multiplicity of library members. First, the automated affinity selection process physically isolates binding library members. Second, the DNA codes of the isolated binders are PCR-amplified and subjected to high-throughput DNA sequencing. Third, the obtained sequencing data are evaluated using a C++ program and the results are displayed using MATLAB software. The resulting selection fingerprints facilitate the discrimination of binding from nonbinding library members. The described procedures allow the identification of small organic ligands to biological targets from a DECL within 10 d. PMID- 26985577 TI - Age-related differences in working memory updating components. AB - The aim of this study was to investigate possible age-related changes throughout childhood and adolescence in different component processes of working memory updating (WMU): retrieval, transformation, and substitution. A set of numerical WMU tasks was administered to four age groups (8-, 11-, 14-, and 21-year-olds). To isolate the effect of each of the WMU components, participants performed different versions of a task that included different combinations of the WMU components. The results showed an expected overall decrease in response times and an increase in accuracy performance with age. Most important, specific age related changes in the retrieval component were found, demonstrating that the effect of retrieval on accuracy was larger in children than in adolescents or young adults. These findings indicate that the availability of representations from outside the focus of attention may change with age. Thus, the retrieval component of updating could contribute to the age-related changes observed in the performance of many updating tasks. PMID- 26985578 TI - Human Rabies - Missouri, 2014. AB - On September 18, 2014, the Missouri Department of Health and Senior Services (MDHSS) was notified of a suspected rabies case in a Missouri resident. The patient, a man aged 52 years, lived in a rural, deeply wooded area, and bat sightings in and around his home were anecdotally reported. Exposure to bats poses a risk for rabies. After two emergency department visits for severe neck pain, paresthesia in the left arm, upper body tremors, and anxiety, he was hospitalized on September 13 for encephalitis of unknown etiology. On September 24, he received a diagnosis of rabies and on September 26, he died. Genetic sequencing tests confirmed infection with a rabies virus variant associated with tricolored bats. Health care providers need to maintain a high index of clinical suspicion for rabies in patients who have unexplained, rapidly progressive encephalitis, and adhere to recommended infection control practices when examining and treating patients with suspected infectious diseases. PMID- 26985576 TI - Cultural differences in visual object recognition in 3-year-old children. AB - Recent research indicates that culture penetrates fundamental processes of perception and cognition. Here, we provide evidence that these influences begin early and influence how preschool children recognize common objects. The three tasks (N=128) examined the degree to which nonface object recognition by 3-year olds was based on individual diagnostic features versus more configural and holistic processing. Task 1 used a 6-alternative forced choice task in which children were asked to find a named category in arrays of masked objects where only three diagnostic features were visible for each object. U.S. children outperformed age-matched Japanese children. Task 2 presented pictures of objects to children piece by piece. U.S. children recognized the objects given fewer pieces than Japanese children, and the likelihood of recognition increased for U.S. children, but not Japanese children, when the piece added was rated by both U.S. and Japanese adults as highly defining. Task 3 used a standard measure of configural progressing, asking the degree to which recognition of matching pictures was disrupted by the rotation of one picture. Japanese children's recognition was more disrupted by inversion than was that of U.S. children, indicating more configural processing by Japanese than U.S. children. The pattern suggests early cross-cultural differences in visual processing; findings that raise important questions about how visual experiences differ across cultures and about universal patterns of cognitive development. PMID- 26985579 TI - Does valproic acid affect tumor growth and improve survival in glioblastomas? PMID- 26985580 TI - Computer Simulations Reveal Substrate Specificity of Glycosidic Bond Cleavage in Native and Mutant Human Purine Nucleoside Phosphorylase. AB - Purine nucleoside phosphorylase (PNP) catalyzes the reversible phosphorolysis of purine ribonucleosides and 2'-deoxyribonucleosides, yielding the purine base and (2'-deoxy)ribose 1-phosphate as products. While this enzyme has been extensively studied, several questions with respect to the catalytic mechanism have remained largely unanswered. The role of the phosphate and key amino acid residues in the catalytic reaction as well as the purine ring protonation state is elucidated using density functional theory calculations and extensive empirical valence bond (EVB) simulations. Free energy surfaces for adenosine, inosine, and guanosine are fitted to ab initio data and yield quantitative agreement with experimental data when the surfaces are used to model the corresponding enzymatic reactions. The cognate substrates 6-aminopurines (inosine and guanosine) interact with PNP through extensive hydrogen bonding, but the substrate specificity is found to be a direct result of the electrostatic preorganization energy along the reaction coordinate. Asn243 has previously been identified as a key residue providing substrate specificity. Mutation of Asn243 to Asp has dramatic effects on the substrate specificity, making 6-amino- and 6-oxopurines equally good as substrates. The principal effect of this particular mutation is the change in the electrostatic preorganization energy between the native enzyme and the Asn243Asp mutant, clearly favoring adenosine over inosine and guanosine. Thus, the EVB simulations show that this particular mutation affects the electrostatic preorganization of the active site, which in turn can explain the substrate specificity. PMID- 26985581 TI - Conducting polymer-silk biocomposites for flexible and biodegradable electrochemical sensors. AB - Approaches to form flexible biosensors require strategies to tune materials for various biomedical applications. We report a facile approach using photolithography to fabricate poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) ( PEDOT: PSS) sensors on a fully biodegradable and flexible silk protein fibroin support. A benchtop photolithographic setup is used to fabricate high fidelity and high resolution PEDOT: PSS microstructures over a large (cm) area using only water as the solvent. Using the conductive micropatterns as working electrodes, we demonstrate biosensors with excellent electrochemical activity and stability over a number of days. The fabricated biosensors display excellent nonspecific detection of dopamine and ascorbic acid with high sensitivity. These devices are mechanically flexible, optically transparent, electroactive, cytocompatible and biodegradable. The benign fabrication protocol allows the conducting ink to function as a matrix for enzymes as shown by a highly sensitive detection of glucose. These sensors can retain their properties under repeated mechanical deformations, but are completely degradable under enzymatic action. The reported technique is scalable and can be used to develop sensitive, robust, and inexpensive biosensors with controllable biodegradability, leading to applications in transient or implantable bioelectronics and optoelectronics. PMID- 26985582 TI - Label-free and enzyme-free colorimetric detection of microRNA by catalyzed hairpin assembly coupled with hybridization chain reaction. AB - In this study, a simple, label-free, and enzyme-free colorimetric biosensor has been developed for amplified detection of let-7a microRNA (miRNA) on the basis of dual signal amplification strategy. The sensing system mainly consists of four unlabeled hairpin probes termed H1, H2, H3, and H4. Upon sensing of the target miRNA, hairpin H1 is opened. Then hairpin H2 hybridizes with H1 forming H1-H2 duplex and frees the target miRNA that can be recycled to trigger another reaction cycle. In addition, the newly formed H1-H2 duplex hybridizes with hairpin H3, and this triggers the autonomous cross-opening of the two hairpins H3 and H4 through hybridization chain reaction. During this process, numerous split G-quadruplex structures are generated and further associate with cofactor hemin to form massive peroxidase-mimicking DNAzymes. The resulting DNAzymes catalyze the H2O2-mediated oxidation of colorless 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulfonic acid) (ABTS(2-)) to the green-colored ABTS(*-), inducing a remarkably amplified colorimetric signal. This newly developed sensing system exhibits high sensitivity toward miRNA with a detection limit of 7.4fM and a large dynamic range of 6 orders of magnitude from 10fM to 10nM. Furthermore, it exhibits a good performance to discriminate single-base difference among the miRNA family members and holds a great potential for early diagnosis in gene-related diseases. PMID- 26985583 TI - Invading stacking primer: A trigger for high-efficiency isothermal amplification reaction with superior selectivity for detecting microRNA variants. AB - Searching for a strategy to enhance the efficiency of nucleic acid amplification and achieve exquisite discrimination of nucleic acids at the single-base level for biological detection has become an exciting research direction in recent years. Here, we have developed a simple and universal primer design strategy which produces a fascinating effect on isothermal strand displacement amplification (iSDA). We refer to the resultant primer as "invading stacking primer (IS-Primer)" which is based on contiguous stacking hybridization and toehold-mediated exchange reaction and function by merely changing the hybridization location of the primer. Using the IS-Primer, the sensitivity in detecting the target miR-21 is improved approximately five fold compared with the traditional iSDA reaction. It was further demonstrated that the IS-Primer acts as an invading strand to initiate branch migration which can increase the efficiency of the untwisting of the hairpin probe. This effect is equivalent to reducing the free energy of the stem, and the technique shows superior selectivity for single base mismatches. By demonstrating the enhanced effect of the IS-Primer in the iSDA reaction, this work may provide a potentially new avenue for developing more sensitive and selective nucleic acids assays. PMID- 26985584 TI - Point-of-care and visual detection of P. aeruginosa and its toxin genes by multiple LAMP and lateral flow nucleic acid biosensor. AB - This study describes a simple and sensitive approach for visual and point-of-care detection of P. aeruginosa and its toxin genes based on multiple loop-mediated isothermal amplification (mLAMP) and lateral flow nucleic acid biosensor (LFNAB). Differentiation of the internal standard gene ecfX and toxin genes (ExoS and ExoU) in P. aeruginosa was determined using FITC-, hex-and digoxin-modified primers in the mLAMP process. In the presence of biotin-and FITC- (hex-, digoxin ) modified primers and Bst DNA polymerase large fragments, the mLAMP produced numerous biotin- and FITC- (hex-, digoxin-) attached duplex DNA products. The products were detected by LFNAB through dual immunoreactions (anti-biotin antibodies on the gold nanoparticle (Au-NP) and biotin on the duplex, anti-FITC (hex, digoxin) antibodies on the LFNAB test line and FITC (hex, digoxin) on the duplex). The accumulation of Au-NPs produced a characteristic red band, enabling visual detection of P. aeruginosa and its toxin genes without instrumentation. After systematic optimization of LFNAB preparation and detecting conditions, the current approach was capable of detecting concentrations as low as 20 CFU/mL P. aeruginosa or its toxin genes within 50min without complicated instrument, which is more sensitive than PCR. Therefore, this approach provides a simple, pollution free, sensitive, and low-cost point-of-care test for the detection of P. aeruginosa and its toxin genes. PMID- 26985585 TI - Enzyme-coupled nanoplasmonic biosensing of cancer markers in human serum. AB - As the use of biosensors for early in-vitro diagnosis of malignant diseases has expanded, issues associated with ultra-sensitivity and wide dynamic range have become paramount. In this study, we designed a sub-zeptomolar sensor for detecting the alpha-feto protein (AFP) that utilizes localized surface plasmon resonance (LSPR) assisted by bio-catalytic reaction and a self-controlled detection scheme. A gold nanodot array (GNA), serving as a plasmonic material, was fabricated using an improved UV nanoimprint lithography (NIL) method that employs a sacrificial layer. In the new approach, LSPR observation is highly stable because it employs a back reflection mode, which avoids passing the signal through the sample solution. An enzyme-precipitation reaction was conducted on the AFP antigen-antibody complex on the surface of the gold nanodot (nano-ELISA) using a procedure that was described previously. To extend the AFP detection limit below femtomolar concentrations, a scheme involving self-controlled detection was employed to lower the limit. In this method, the sample including the target simultaneously plays the role of both sample and negative control. Using this scheme, AFP can be detected at concentrations as low as 14 aM (0.7 zeptomole in 50MUL serum) and with the wide dynamic range of 10fgmL(-1)-10ngmL( 1). Importantly, the new method provides a platform for studying and monitoring interactions between biochemically active substances that are present in very low concentrations. Finally, the general strategy used to design the detection method can be easily adapted to the ultra-sensitive detection of other biomarkers and pathogens. PMID- 26985586 TI - A sensitive electrochemiluminescence immunosensor based on luminophore capped Pd@Au core-shell nanoparticles as signal tracers and ferrocenyl compounds as signal enhancers. AB - In this work, N-(aminobutyl)-N-(ethylisoluminol) (ABEI), an analogue of luminol, is served as both the reductant and luminescence reagent to synthesize ABEI capped Pd@Au core-shell nanoparticles (ABEI-Pd@AuNPs). The nanoparticles not only exhibit inherent electrochemiluminescence (ECL) property, but also possess advantages of noble-metal nanomaterials such as outstanding electronic property, high specific surface area and good biocompatibility. In order to enhance the luminescence efficiency, ferrocene monocarboxylic acid (Fc) as catalyzer is grafted on the surface of ABEI-Pd@AuNPs with the aid of l-cysteine (l-Cys). When the Fc is electrochemically oxidized to ferricinium cation species (Fc(+)), the decomposition of H2O2 which existed in detection solution can be catalyzed by Fc(+) to generate oxygen-related free radicals, resulting effective signal amplification for ABEI-H2O2 system. For potential applications, the Pd@Au core shell nanoparticles bifunctionalized by ABEI and catalyzer are employed as nano carriers to immobilize detection antibody (Ab2). Based on sandwiched immunoreactions, a "signal-on" ECL immunosensor is developed for detection of human collagen type IV (Col IV), a potential biomarker associated with diabetic nephropathy. Consequently, the proposed immunosensor provides a wide linear detection ranging from 1pgmL(-1) to 10ngmL(-1) with a relatively low detection limit of 0.3pgmL(-1) (S/N=3). PMID- 26985588 TI - [On hip fracture and ageing[Editorial]]. PMID- 26985587 TI - [Zika virus - a relatively new human pathogen[Editorial]]. PMID- 26985589 TI - [Treatment and outcome of patients with hip fracture]. AB - INTRODUCTION: Hip fractures are common amongst the elderly, often with serious consequences and increased mortality. The aim of this study was to describe treatment and outcome of patients with hip fractures. MATERIAL AND METHODS: Retrospective study on all hip fracture patients >=60 years of age operated at Landspitali University Hospital in the year 2011. RESULTS: The study group was made up of 255 patients (mean age 82 +/- 8 years, women 65%). Mean delay to operation was 22 +/- 14 hours. Mean length of hospital stay for those living at a nursing home before hip fracture was 4 +/- 2 days but if they had lived at home 14 +/- 10 days (p<0.001). Before the fracture 68% of the patients lived at home but 54% at the end of follow-up (p<0.001). Mortality one year after hip fracture was 27% and on average eightfold compared to the general population >=60 years. A multivariate analysis showed that age, time from fracture to arrival at hospital, ASA-classification and living in a nursing home before fracture were linked to an increased risk of death. CONCLUSION: The mean delay to surgery was within recommended guidelines, but one- third waited longer than 24 hours. Resources outside hospital seemed to decide hospital length of stay. Mortality of hip fracture patients was manifold compared to the general population of the same age and within higher range compared to other countries. Significantly fewer lived in their own home after the fracture. Hip fractures cause serious debilitation and are demanding for society. PMID- 26985590 TI - [Epidemiology of the two types of gastric adenocarcinoma in Iceland according to the Lauren histological classification 1990-2009]. AB - BACKGROUND: In the mid twentieth century gastric cancer was the most common type of cancer in Iceland. In recent decades, however, the incidence rate of gastric cancer has decreased markedly and currently only represents 2-3% of cancer cases. The Lauren classification system classifies adenocarcinoma into two types, intestinal and diffuse. The main purpose of our study was to describe the epidemiology of the two types of gastric adenocarcinoma in Iceland between the years 1990-2009. METHODS: This is a retrospective cohort study. Information on patients diagnosed with gastric cancer in Iceland between 1990 and 2009 was collected from the population based Cancer Registry. Histological descriptions were reviewed and classified according to the Lauren classification system. The records of patients diagnosed with either having intestinal or diffuse adenocarcinomas were reviewed and epidemiological information gathered. RESULTS: Between 1990 and 2009, 730 patients were diagnosed with gastric adenocarcinoma in Iceland, 447 had intestinal adenocarcinoma and 168 diffuse adenocarcinoma. Patients diagnosed with diffuse adenocarcinoma were significantly younger at diagnosis than those diagnosed with intestinal adenocarcinoma. The sex ratio for intestinal adenocarcinoma was 2.3:1 (M:F) and 1.1:1 (M:F) for diffuse adenocarcinoma. The incidence of intestinal adenocarcinoma decreased more rapidly than that of diffuse adenocarcinoma during this period (0.92/100,000 vs. 0.12/100,000). Median survival rates of intestinal and diffuse adenocarcinomas were 23.7 and 20.6 months, respectively. The difference in survival was found to be statistically significant. The hazard ratio between the two groups was 1.31 (CI 1.03-1.67), corrected for age, sex, stage, year of diagnosis and surgical outcome (radical, non-radical or no operation). CONCLUSION: The overall incidence rate of gastric cancer has decreased dramatically in the past 20 years. However, the reduction is largely limited to the intestinal adenocarcinoma sub-group. We conclude that the Lauren classification predicts prognosis in gastric adenocarcinoma with diffuse adenocarcinoma having worse prognosis. KEY WORDS: gastric cancer, Lauren classification, survival, incidence. Correspondence: Halla Sif Olafsdottir, hsolafsdottir@gmail.com. PMID- 26985591 TI - [Visits of patients with exertional rhabdomyolysis to the Emergency Department at Landspitali, The National University Hospital of Iceland in the years 2008-2012]. AB - INTRODUCTION: Overexertion and too much training are among the -multiple etiologies of rhabdomyolysis. Creatine kinase (CK) and myo-globine, released from skeletal muscle cells, are useful for diagnosis and follow-up. Acute kidney injury is a serious complication of myoglobinemia. Literature on exertional rhabdomyolysis in the general population is scarce. The aim of this study was to investigate the epidemiology of exertional rhabdomyolysis among patients diagnosed at Landspitali The National University Hospital of Iceland in 2008 2012. MATERIALS AND METHODS: The study was retrospective and observational. All patients presenting with muscle pain after exertion and elevated creatine kinase >1000 IU/L, during the period from 1 January 2008 to 31 December 2012, were included. Patients with CK elevations secondary to causes other than exertion were excluded. Variables included: patient number and gender, CK-levels, date of hospital admission, cause of rhabdomyolysis, location of injured muscle groups, length of hospital stay, complications and means of fluid replacement. Population figures of the capital region were gathered from Statistics Iceland and information on sport practice in the capital region from The National Olympic and Sports Association of Iceland. RESULTS: Exertional rhabdomyolysis was diagnosed in 54 patients, 18 females (33,3%) and 36 males (66,7%), or 8,3% of rhabdomyolysis cases from all causes in the study period (648 cases). Incidence in the capital region was 5,0/100.000 inhabitants per year in the study period. Median age was 28 years and median CK-level was 24.132 IU/L. CK-levels were higher among females but the difference between genders was not significant. Muscle groups of the upper and lower extremities were most frequently affected (89%). Thirty patients received intravenous fluids. They had significantly higher CK values than other patients. One patient developed acute kidney injury. Information on sport practice and physical training in the capital region was not available. CONCLUSION: Exertional rhabdomyolysis is uncommon but mostly affects younger people. Information on the practice of exertion among males and females is not available but CK-levels were not significantly different between genders, age groups or different muscle groups. CK-levels were high but complications uncommon. Studies of exertional rhabdomyolysis in the general population are lacking. KEY WORDS: Rhabdomyolysis, exertion, sports, physical training, CK elevation. Correspondence: Brynjolfur Mogensen, brynmog@landspitali.is. PMID- 26985592 TI - HCV false positive immunoassays in patients with LVAD: A potential trap! AB - BACKGROUND: Left ventricular assist devices (LVAD) are a therapeutic choice for patients with advanced heart failure prior cardiac transplantation. Patients with a LVAD implant are frequently monitored for hepatitis C virus (HCV) as a positive result may be an exclusion criterion for transplantation. OBJECTIVES: To determine the rate of false positive results with immunoassays for HCV antibodies in a LVAD population. STUDY DESIGN: Between June 2011 and January 2015, HCV antibody testing using a chemiluminescent immunoassay (CLIA) (Liaison, Diasorin) was performed for 32 patients prior and post LVAD implantation. A HCV reactive result by CLIA was repeated and further tested by an enzyme linked fluorescent assay (ELFA) (VIDAS, bioMerieux). For patients with a positive HCV CLIA and ELFA test, immunoblot and HCV RNA detection were performed. RESULTS: Prior to LVAD implantation, all patients showed a negative HCV serology. After LVAD implantation, 19 patients (59%) had positive results for HCV antibody using CLIA and ELFA technologies. The HCV immunoblot was negative for 17 patients and indeterminate for two patients. For 15 patients, HCV RNA detection was performed and was undetectable. Actually, no HCV infections were observed among those who were tested for HCV RNA. CONCLUSIONS: HCV serological tests routinely used in our laboratories are not reliable in patients with cardiac devices. A positive CLIA and/or ELFA reaction in patients with a LVAD should be confirmed by HCV immunoblot and by HCV RNA PCR detection in order to rule out a HCV infection. PMID- 26985593 TI - HHV-8 DNA replication correlates with the clinical status in AIDS-related Kaposi's sarcoma. AB - BACKGROUND: The value of plasma levels of human herpesvirus 8 (HHV-8) DNA as a marker of clinical status in acquired immunodeficiency syndrome-related Kaposi's sarcoma (AIDS-KS) remains to be elucidated. OBJECTIVES: To investigate the relationship between the plasma HHV-8 DNA viral load and the clinical status of AIDS-KS. STUDY DESIGN: A total of 378 blood samples were obtained from 62 patients with AIDS-KS followed longitudinally. All patients received antiretroviral therapy (ART) or anti-neoplastic therapy. The patients were divided into four groups according to their clinical status: onset disease (OD), progressive disease (PD), stable or partial remission (S/PR) and complete remission (CR). RESULTS: Plasma HHV-8 DNAaemia was detected in all samples obtained from patients with OD or PD (100%); in contrast, HHV-8 DNAaemia was found only in a minority of patients with CR (8%) and was invariably undetectable in patients with stable CR. HHV-8 DNA detection in plasma was strongly associated with an unfavourable outcome (odds ratio=231.9; p<0.0001). Conversely, neither the HIV-1 viral load nor peripheral CD4(+) T-cell counts were associated with the KS clinical status, though both parameters did affect HHV-8 DNAaemia levels (p<0.0001). Multivariate analysis confirmed that HHV-8 DNAaemia was strongly and independently correlated with both clinical status (p<0.05) and HIV-1 plasma viraemia (p=0.027). CONCLUSIONS: The strong association of plasma HHV-8 DNAaemia with onset or progressive disease is compatible with an active role of replicating virus in clinically active AIDS-KS. An accurate evaluation of the plasma HHV-8 load might be useful for monitoring AIDS-KS under antiretroviral or antineoplastic therapy. PMID- 26985594 TI - Adenovirus related lymphohistiocytic hemophagocytosis: Case report and literature review. AB - INTRODUCTION: Adenoviral infection is a classic cause of lymphohistiocytic hemophagocytosis (LH) in bone marrow transplantation but is rare outside this setting. CASE REPORT: A 31-year-old female, with a history of treated mesencephalic astrocytoma, was hospitalized for fever, pancytopenia, elevated liver enzymes, hyperferritinemia and hypertriglyceridemia. Adenovirus viral load in blood was 7.3*10(9) copies/mL. Bone marrow aspirate examination confirmed LH. The patient recovered without specific LH or adenovirus-directed treatment. CONCLUSION: Adenovirus-related LH, common in bone marrow transplant recipients, should also be considered in patients with chemotherapy in solid tumors. PMID- 26985595 TI - Shape Evolution of Metal Nanoparticles in Water Vapor Environment. AB - The structures of the metal nanoparticles are crucial for their catalytic activities. How to understand and even control the shape evolution of nanoparticles under reaction condition is a big challenge in heterogeneous catalysis. It has been proved that many reactive gases hold the capability of changing the structures and properties of metal nanoparticles. One interesting question is whether water vapor, such a ubiquitous environment, could induce the shape evolution of metal nanoparticles. So far this question has not received enough attention yet. In this work, we developed a model based on the density functional theory, the Wulff construction, and the Langmuir adsorption isotherm to explore the shape of metal nanoparticle at given temperature and water vapor pressure. By this model, we show clearly that water vapor could notably increase the fraction of (110) facets and decrease that of (111) facets for 3-8 nm Cu nanoparticles, which is perfectly consistent with the experimental observations. Further investigations indicate the water vapor has different effects on the different metal species (Cu, Au, Pt, and Pd). This work not only helps to understand the water vapor effect on the structures of metal nanoparticles but also proposes a simple but effective model to predict the shape of nanoparticles in certain environment. PMID- 26985596 TI - Androgen receptor splice variant 7 (AR-V7) and drug efficacy in castration resistant prostate cancer: Biomarker for treatment selection exclusion or inclusion? AB - Currently there are no molecular biomarkers used to help guide treatment selection for those patients with castration-resistant prostate cancer. A recent study published in JAMA Oncology (Antonarakis et al.) presents evidence supporting the potential use of androgen receptor splice variant 7 as a biomarker for optimal treatment selection in this population. PMID- 26985598 TI - Implications of Mexican Health Care Reform on the Health Coverage of Nonmigrants and Returning Migrants. AB - OBJECTIVES: To assess health coverage among Mexicans with US migration experience, before and after the implementation of Mexico's universal health care program, Seguro Popular. METHODS: I used data from the 2000 and 2010 Mexican Censuses to generate nationally representative estimates of health coverage among working-age Mexicans by migrant status. RESULTS: In 2000, before the implementation of Seguro Popular, 56% of Mexicans aged 15 to 60 years with no recent US migrations were uninsured compared with 80% of recently returned migrants. By 2010, the proportion uninsured declined from 56% to 35% (-38%) among nonmigrants and from 80% to 54% (-33%) among return migrants. CONCLUSIONS: Seguro Popular has increased health coverage among Mexican return migrants, but they remain substantially underinsured. A creative and multifaceted approach likely will be needed to address Mexican immigrants' health care needs. PMID- 26985597 TI - Sexual Identity Disparities in Smoking and Secondhand Smoke Exposure in California: 2003-2013. AB - OBJECTIVES: To determine smoking prevalence, smoking behavior, and secondhand smoke (SHS) exposure of lesbian, gay, and bisexual (LGB)-identified Californians; compare these with that of heterosexuals; and analyze changes over time. METHODS: We analyzed self-reported variables from 111 965 heterosexual, 1667 lesbian, and 1706 bisexual women, and 79 881 heterosexual, 2505 gay, and 911 bisexual men, aged 18 to 70 years, in the 2003-2013 California Health Interview Surveys. RESULTS: Sexual minority women had higher smoking prevalence, and female bisexual smokers were less likely to be light smokers, than heterosexuals. Smoking prevalence was higher among sexual minority men, and gay smokers were more likely to be daily smokers than were heterosexuals; and male bisexual smokers were more likely to be light smokers than were gay or heterosexual smokers. Sexual minority adults were more likely to have SHS exposure at home than were heterosexuals. Current smoking prevalence decreased annually 4% and 7% for lesbian and bisexual women, and 5% and 6% for gay and bisexual men, respectively. Exposure to SHS fell an average of 11% annually for sexual minority men and women. CONCLUSIONS: Sexual identity disparities in smoking and SHS exposure exist in California, with bisexuals particularly at risk. PMID- 26985599 TI - Applying Community Organizing Principles to Assess Health Needs in New Haven, Connecticut. AB - The Affordable Care Act added requirements for nonprofit hospitals to conduct community health needs assessments. Guidelines are minimal; however, they require input and representation from the broader community. This call echoes 2 decades of literature on the importance of including community members in all aspects of research design, a tenet of community organizing. We describe a community-engaged research approach to a community health needs assessment in New Haven, Connecticut. We demonstrate that a robust community organizing approach provided unique research benefits: access to residents for data collection, reliable data, leverage for community-driven interventions, and modest improvements in behavioral risk. We make recommendations for future community-engaged efforts and workforce development, which are important for responding to increasing calls for community health needs assessments. PMID- 26985600 TI - Validity of Single-Item Screening for Limited Health Literacy in English and Spanish Speakers. AB - OBJECTIVES: To evaluate 3 single-item screening measures for limited health literacy in a community-based population of English and Spanish speakers. METHODS: We recruited 324 English and 314 Spanish speakers from a community research registry in Dallas, Texas, enrolled between 2009 and 2012. We used 3 screening measures: (1) How would you rate your ability to read?; (2) How confident are you filling out medical forms by yourself?; and (3) How often do you have someone help you read hospital materials? In analyses stratified by language, we used area under the receiver operating characteristic (AUROC) curves to compare each item with the validated 40-item Short Test of Functional Health Literacy in Adults. RESULTS: For English speakers, no difference was seen among the items. For Spanish speakers, "ability to read" identified inadequate literacy better than "help reading hospital materials" (AUROC curve = 0.76 vs 0.65; P = .019). CONCLUSIONS: The "ability to read" item performed the best, supporting use as a screening tool in safety-net systems caring for diverse populations. Future studies should investigate how to implement brief measures in safety-net settings and whether highlighting health literacy level influences providers' communication practices and patient outcomes. PMID- 26985601 TI - Benzodiazepine Use and Hepatitis C Seroconversion in a Cohort of Persons Who Inject Drugs. AB - OBJECTIVES: To examine the relationship between benzodiazepine (BZD) use and HCV seroconversion in 2 linked prospective cohorts of persons who inject drugs (PWID). METHODS: We examined prospective cohorts of 440 PWID (baseline BZD users: n = 102; 23.2%) from the AIDS Care Cohort to Evaluate Access to Survival Services (ACCESS) and the Vancouver Injection Drug Users Study (VIDUS) cohorts, followed up from 1996 to 2013 in Vancouver, Canada. RESULTS: At baseline, the prevalence of HCV was higher among those who used BZD (80.5% vs 61.5%; P < .001). After adjustment, BZD use remained independently associated with increased rates of HCV seroconversion (adjusted rate ratio = 1.67; 95% confidence interval = 1.05, 2.66). CONCLUSIONS: BZD use is independently associated with HCV seroconversion in a population of PWID. PMID- 26985603 TI - Impact of Clinic Closures on Women Obtaining Abortion Services After Implementation of a Restrictive Law in Texas. AB - OBJECTIVES: To evaluate the additional burdens experienced by Texas abortion patients whose nearest in-state clinic was one of more than half of facilities providing abortion that had closed after the introduction of House Bill 2 in 2013. METHODS: In mid-2014, we surveyed Texas-resident women seeking abortions in 10 Texas facilities (n = 398), including both Planned Parenthood-affiliated clinics and independent providers that performed more than 1500 abortions in 2013 and provided procedures up to a gestational age of at least 14 weeks from last menstrual period. We compared indicators of burden for women whose nearest clinic in 2013 closed and those whose nearest clinic remained open. RESULTS: For women whose nearest clinic closed (38%), the mean one-way distance traveled was 85 miles, compared with 22 miles for women whose nearest clinic remained open (P <= .001). After adjustment, more women whose nearest clinic closed traveled more than 50 miles (44% vs 10%), had out-of-pocket expenses greater than $100 (32% vs 20%), had a frustrated demand for medication abortion (37% vs 22%), and reported that it was somewhat or very hard to get to the clinic (36% vs 18%; P < .05). CONCLUSIONS: Clinic closures after House Bill 2 resulted in significant burdens for women able to obtain care. PMID- 26985604 TI - Impact of State Ignition Interlock Laws on Alcohol-Involved Crash Deaths in the United States. AB - OBJECTIVES: To investigate the impact on alcohol-involved crash deaths of universal ignition interlock requirements, which aim to prevent people convicted of driving under the influence of alcohol from driving while intoxicated. METHODS: We used data from the National Highway Traffic Safety Administration for 1999 to 2013. From 2004 to 2013, 18 states made interlocks mandatory for all drunk-driving convictions. We compared alcohol-involved crash deaths between 18 states with and 32 states without universal interlock requirements, accounting for state and year effects, and for clustering within states. RESULTS: Policy impact was apparent 3 years after implementation. The adjusted rate of alcohol involved crash deaths was 4.7 (95% confidence interval [CI] = 4.0, 5.4) per 100,000 in states with the universal interlock requirement, compared with 5.5 (95% CI = 5.48, 5.53) in states without, an absolute reduction of 0.8 (95% CI = 0.1, 1.5) deaths per 100,000 per year. CONCLUSIONS: Requiring ignition interlocks for all drunk-driving convictions was associated with 15% fewer alcohol-involved crash deaths, compared with states with less-stringent requirements. Interlocks are a life-saving technology that merit wider use. PMID- 26985602 TI - Health Disparities in Drug- and Alcohol-Use Disorders: A 12-Year Longitudinal Study of Youths After Detention. AB - OBJECTIVES: To examine sex and racial/ethnic differences in the prevalence of 9 substance-use disorders (SUDs)--alcohol, marijuana, cocaine, hallucinogen or PCP, opiate, amphetamine, inhalant, sedative, and unspecified drug--in youths during the 12 years after detention. METHODS: We used data from the Northwestern Juvenile Project, a prospective longitudinal study of 1829 youths randomly sampled from detention in Chicago, Illinois, starting in 1995 and reinterviewed up to 9 times in the community or correctional facilities through 2011. Independent interviewers assessed SUDs with Diagnostic Interview Schedule for Children 2.3 (baseline) and Diagnostic Interview Schedule version IV (follow ups). RESULTS: By median age 28 years, 91.3% of males and 78.5% of females had ever had an SUD. At most follow-ups, males had greater odds of alcohol- and marijuana-use disorders. Drug-use disorders were most prevalent among non Hispanic Whites, followed by Hispanics, then African Americans (e.g., compared with African Americans, non-Hispanic Whites had 32.1 times the odds of cocaine use disorder [95% confidence interval = 13.8, 74.7]). CONCLUSIONS: After detention, SUDs differed markedly by sex, race/ethnicity, and substance abused, and, contrary to stereotypes, did not disproportionately affect African Americans. Services to treat substance abuse--during incarceration and after release--would reach many people in need, and address health disparities in a highly vulnerable population. PMID- 26985605 TI - Educational Interventions to Promote Healthy Nutrition and Physical Activity Among Older Chinese Americans: A Cluster-Randomized Trial. AB - OBJECTIVES: To evaluate the efficacy of an in-language intervention of 2 lectures plus printed materials versus printed materials alone on knowledge and adherence to nutrition and physical activity guidelines among older Chinese Americans in San Francisco, California. METHODS: From August 2010 to September 2013, we randomized 756 Chinese Americans aged 50 to 75 years to either lectures plus print (n = 361) or print (n = 357). Clusters were the participants recruited by each lay health worker. Intervention outcomes were changes in knowledge of recommended vegetable intake, fruit intake, and physical activity level and adherence to those recommendations from pre- to 6 months postintervention. RESULTS: The retention rate was 99%. At baseline, knowledge and adherence to recommendations were low. Print yielded increases in knowledge of recommended vegetable intake and physical activity level and adherence to fruit intake and physical activity recommendations. Lectures plus print had significant increases in all 6 outcomes. In multivariable models, lectures plus print was superior to print for knowledge of vegetable (adjusted odds ratio [AOR] = 12.61; 95% confidence interval [CI] = 6.50, 24.45) and fruit (AOR = 16.16; 95% CI = 5.61, 46.51) intake recommendations and adherence to vegetable intake recommendations (AOR = 5.53; 95% CI = 1.96, 15.58). CONCLUSIONS: In-language print materials, alone and combined with lectures, increased nutrition and physical activity knowledge and behaviors among older Chinese Americans. PMID- 26985606 TI - Impacts of Urban Water Conservation Strategies on Energy, Greenhouse Gas Emissions, and Health: Southern California as a Case Study. AB - OBJECTIVES: To determine how urban water conservation strategies in California cities can affect water and energy conservation efforts, reduce greenhouse gas emissions, and benefit public health. METHODS: We expanded upon our 2014 health impact assessment of California's urban water conservation strategies by comparing the status quo to 2 options with the greatest potential impact on the interrelated issues of water and energy in California: (1) banning landscape irrigation and (2) expanding alternative water sources (e.g., desalination, recycled water). RESULTS: Among the water conservation strategies evaluated, expanded use of recycled water stood out as the water conservation strategy with potential to reduce water use, energy use, and greenhouse gas emissions, with relatively small negative impacts for the public's health. CONCLUSIONS: Although the suitability of recycled water for urban uses depends on local climate, geography, current infrastructure, and finances, analyses similar to that presented here can help guide water policy decisions in cities across the globe facing challenges of supplying clean, sustainable water to urban populations. PMID- 26985607 TI - Community Health Workers Versus Nurses as Counselors or Case Managers in a Self Help Diabetes Management Program. AB - OBJECTIVES: To confirm the effectiveness of community health workers' involvement as counselors or case managers in a self-help diabetes management program in 2009 to 2014. METHODS: Our open-label, randomized controlled trial determined the effectiveness of a self-help intervention among Korean Americans aged 35 to 80 years in the Baltimore-Washington metropolitan area with uncontrolled type 2 diabetes. We measured and analyzed physiological and psychobehavioral health outcomes of the community health worker-counseled (n = 54) and registered nurse (RN)-counseled (n = 51) intervention groups in comparison with the control group (n = 104). RESULTS: The community health workers' performance was comparable to that of the RNs for both psychobehavioral outcomes (e.g., self-efficacy, quality of life) and physiological outcomes. The community health worker-counseled group showed hemoglobin A1C reductions from baseline (-1.2%, -1.5%, -1.3%, and -1.6%, at months 3, 6, 9, and 12, respectively), all of which were greater than reductions in the RN-counseled (-0.7%, -0.9%, -0.9%, and -1.0%) or the control ( 0.5%, -0.5%, -0.6%, and -0.7%) groups. CONCLUSIONS: Community health workers performed as well as or better than nurses as counselors or case managers in a self-help diabetes management program in a Korean American community. PMID- 26985608 TI - Sexual Orientation Disparities in Preventable Disease: A Fundamental Cause Perspective. AB - OBJECTIVES: To determine whether fundamental cause theory (which posits that, in societal conditions of unequal power and resources, members of higher-status groups experience better health than members of lower-status groups because of their disproportionate access to health-protective factors) might be relevant in explaining health disparities related to sexual orientation. METHODS: We used 2001 to 2011 morbidity data from the Stockholm Public Health Cohort, a representative general population-based study in Sweden. A total of 66 604 (92.0%) individuals identified as heterosexual, 848 (1.2%) as homosexual, and 806 (1.1%) as bisexual. To test fundamental cause theory, we classified diseases in terms of preventability potential (low vs high). RESULTS: There were no sexual orientation differences in morbidity from low-preventable diseases. By contrast, gay or bisexual men (adjusted odds ratio [OR] = 1.48; 95% confidence interval [CI] = 1.13, 1.93) and lesbian or bisexual women (adjusted OR = 1.64; 95% CI = 1.28, 2.10) had a greater risk of high-preventable morbidity than heterosexual men and women, respectively. These differences were sustained in analyses adjusted for covariates. CONCLUSIONS: Our findings support fundamental cause theory and suggest that unequal distribution of health-protective resources, including knowledge, prestige, power, and supportive social connections, might explain sexual orientation health disparities. PMID- 26985609 TI - Direct Engagement With Communities and Interprofessional Learning to Factor Culture Into End-of-Life Health Care Delivery. AB - Aging patients with advanced or terminal illnesses or at the end of their lives become highly vulnerable when their cultural needs-in terms of ethnic habits, religious beliefs, and language-are unmet. Cultural diversity should be taken into account during palliative care delivery (i.e., noncurative, supportive care during advanced illness or at the end of life). Providers and systems deliver disparate palliative care to diverse patients. I present 2 strategies to improve how culturally diverse populations are served during advanced illness: (1) health service provider assessment of local populations to understand service populations' cultural needs and guide services and policy; and (2) interprofessional education to improve multicultural understanding among the health care workforce. PMID- 26985610 TI - Sexual Orientation and All-Cause Mortality Among US Adults Aged 18 to 59 Years, 2001-2011. AB - To determine whether sexual minorities have an earlier mortality than do heterosexuals, we investigated associations between sexual orientation assessed in the 2001 to 2010 National Health and Nutrition Examination Surveys (NHANES) and mortality in the 2011 NHANES-linked mortality file. Mortality follow-up time averaged 69.6 months after NHANES. By 2011, 338 individuals had died. Sexual minorities evidenced greater all-cause mortality than did heterosexuals after adjusting for demographic confounding. These effects generally disappeared with further adjustment for NHANES-detected health and behavioral differences. PMID- 26985611 TI - Homicides by Police: Comparing Counts From the National Violent Death Reporting System, Vital Statistics, and Supplementary Homicide Reports. AB - OBJECTIVE: To evaluate the National Violent Death Reporting System (NVDRS) as a surveillance system for homicides by law enforcement officers. METHODS: We assessed sensitivity and positive predictive value of the NVDRS "type of death" variable against our study count of homicides by police, which we derived from NVDRS coded and narrative data for states participating in NVDRS 2005 to 2012. We compared state counts of police homicides from NVDRS, Vital Statistics, and Federal Bureau of Investigation Supplementary Homicide Reports. RESULTS: We identified 1552 police homicides in the 16 states. Positive predictive value and sensitivity of the NVDRS "type of death" variable for police homicides were high (98% and 90%, respectively). Counts from Vital Statistics and Supplementary Homicide Reports were 58% and 48%, respectively, of our study total; gaps varied widely by state. The annual rate of police homicide (0.24/100,000) varied 5-fold by state and 8-fold by race/ethnicity. CONCLUSIONS: NVDRS provides more complete data on police homicides than do existing systems. POLICY IMPLICATIONS: Expanding NVDRS to all 50 states and making 2 improvements we identify will be an efficient way to provide the nation with more accurate, detailed data on homicides by law enforcement. PMID- 26985612 TI - Neighborhood Walkability and Body Mass Index Trajectories: Longitudinal Study of Canadians. AB - OBJECTIVES: To assess the impact of neighborhood walkability on body mass index (BMI) trajectories of urban Canadians. METHODS: Data are from Canada's National Population Health Survey (n = 2935; biannual assessments 1994-2006). We measured walkability with the Walk Score. We modeled body mass index (BMI, defined as weight in kilograms divided by the square of height in meters [kg/m(2)]) trajectories as a function of Walk Score and sociodemographic and behavioral covariates with growth curve models and fixed-effects regression models. RESULTS: In men, BMI increased annually by an average of 0.13 kg/m(2) (95% confidence interval [CI] = 0.11, 0.14) over the 12 years of follow-up. Moving to a high walkable neighborhood (2 or more Walk Score quartiles higher) decreased BMI trajectories for men by approximately 1 kg/m(2) (95% CI = -1.16, -0.17). Moving to a low-walkable neighborhood increased BMI for men by approximately 0.45 kg/m(2) (95% CI = 0.01, 0.89). There was no detectable influence of neighborhood walkability on body weight for women. CONCLUSIONS: Our study of a large sample of urban Canadians followed for 12 years confirms that neighborhood walkability influences BMI trajectories for men, and may be influential in curtailing male age-related weight gain. PMID- 26985614 TI - Reducing Sexual Assault on Campus: Lessons From the Movement to Prevent Drunk Driving. AB - I examined similarities and differences between the movement to prevent drunk driving of the 1980s, and current efforts to prevent and address campus sexual assault. As college and university administrators design policies and initiatives to reduce campus sexual assault in response to new federal legislation and regulation, they can apply lessons from successful public health initiatives to reduce drunk driving initiated more than 3 decades ago. I illustrate how interventions at the 5 levels of the social-ecological model, and messages that address entrenched cultural attitudes condoning sexual assault and blaming its victims can be used to combat campus sexual assault as a crime and a public health problem. I also show how efforts to promote community engagement can change behavioral norms and reduce offenses. PMID- 26985613 TI - Emergency Care for Homeless Patients: A French Multicenter Cohort Study. AB - OBJECTIVES: To determine whether homeless patients experience suboptimal care in the emergency department (ED) by the provision of fewer health care resources. METHODS: We conducted a prospective multicenter cohort study in 30 EDs in France. During 72 hours in March 2015, all homeless patients that visited the participating EDs were included in the study. The primary health care service measure was the order by the physician of a diagnostic investigation or provision of a treatment in the ED. Secondary measures of health care services included ED waiting time, number and type of investigations per patient, treatment in the ED, and discharge disposition. RESULTS: A total of 254 homeless patients and 254 nonhomeless patients were included. After excluding homeless patients that attended the ED for the sole purpose of housing, we analyzed 214 homeless and 214 nonhomeless. We found no significant difference between the 2 groups in terms of health care resource consumption, and for our secondary endpoints. CONCLUSIONS: We did not find significant differences in the level of medical care delivered in French EDs to homeless patients compared with matched nonhomeless patients. PMID- 26985615 TI - Prevalence and Co-Occurrence of Heavy Drinking and Anxiety and Mood Disorders Among Gay, Lesbian, Bisexual, and Heterosexual Canadians. AB - OBJECTIVES: To investigate the prevalence and co-occurrence of heavy drinking, anxiety, and mood disorders among Canadians who self-identified as gay, lesbian, bisexual, or heterosexual. METHODS: Pooled data from the 2007 to 2012 cycles of the Canadian Community Health Survey (n = 222 548) were used to fit logistic regression models controlling for sociodemographic characteristics. RESULTS: In adjusted logistic regression models, gay or lesbian respondents had greater odds than heterosexual respondents of reporting anxiety disorders, mood disorders, and anxiety-mood disorders. Bisexual respondents had greater odds of reporting anxiety disorders, mood disorders, anxiety-mood disorders, and heavy drinking. Gay or lesbian and bisexual respondents had greater odds than heterosexuals of reporting co-occurring anxiety or mood disorders and heavy drinking. The highest rates of disorders were observed among bisexual respondents, with nearly quadruple the rates of anxiety, mood, and combined anxiety and mood disorders relative to heterosexuals and approximately twice the rates of gay or lesbian respondents. CONCLUSIONS: Members of sexual minority groups in Canada, in particular those self-identifying as bisexual, experience disproportionate rates of anxiety and mood disorders, heavy drinking, and co-occurring disorders. PMID- 26985616 TI - State and Local Policies as a Structural and Modifiable Determinant of HIV Vulnerability Among Latino Migrants in the United States. AB - We explore how state and local policies in labor, health, education, language, community and neighborhood environments, deportation, and state-authorized identification can reduce or exacerbate HIV vulnerability among Latino migrants in the United States. We reviewed literature on Latino migrants and HIV risk, on the structural-environmental contexts experienced by Latino migrants, and on the many domains in which policies influence those contexts. To illustrate the pathways through which policies across multiple sectors are relevant to HIV vulnerability, we describe how policies shape 2 mediating domains (a climate of hostility toward Latino migrants and the relative ease or difficulty of access to beneficial institutions) and how those domains influence behavioral risk practices, which increase vulnerability to HIV. This argument demonstrates the utility of considering the policy context as a modifiable element of the meso level through which structural factors shape vulnerability to HIV. This approach has specific relevance to the consideration of HIV prevention for Latino migrants, and more generally, to structural approaches to HIV prevention. PMID- 26985617 TI - Environmental Nutrition: A New Frontier for Public Health. AB - Food systems must operate within environmental constraints to avoid disastrous consequences for the biosphere. Such constraints must also take into account nutritional quality and health outcomes. Given the intrinsic relationships between the environmental sciences and nutritional sciences, it is imperative that public health embraces environmental nutrition as the new frontier of research and practice and begins a concerted focus on the new discipline of environmental nutrition, which seeks to comprehensively address the sustainability of food systems. We provide an overview to justify our proposition, outline a research and practice agenda for environmental nutrition, and explore how the complex relationships within food systems that affect public health could be better understood through the environmental nutrition model. PMID- 26985618 TI - Promoting Nature-Based Activity for People With Mental Illness Through the US "Exercise Is Medicine" Initiative. AB - Nature-based physical activity programming (e.g., countryside walks, hiking, horseback riding) has been found to be an effective way to help improve the health of people with mental illness. Exercise referral initiatives, whereby health practitioners prescribe exercise in an attempt to prevent or treat chronic illnesses, have helped make such nature-based activities accessible to this population in the United Kingdom and Australia; however, there is a dearth of research related to the most prominent exercise referral program in the United States: Exercise is Medicine. Taking into account the barriers to physical activity faced by people with mental illness, we explore how nature-based programming for this population might be mobilized in the United States through the growing Exercise is Medicine initiative. PMID- 26985619 TI - Disability-Free Life Expectancy Over 30 Years: A Growing Female Disadvantage in the US Population. AB - OBJECTIVES: To examine changes in active life expectancy in the United States over 30 years for older men and women (aged >= 65 years). METHODS: We used the 1982 and 2004 National Long Term Care Survey and the 2011 National Health and Aging Trends Study to estimate age-specific mortality and disability rates, the overall chances of survival and of surviving without disability, and years of active life for men and women. RESULTS: For older men, longevity has increased, disability has been postponed to older ages, disability prevalence has fallen, and the percentage of remaining life spent active has increased. However, for older women, small longevity increases have been accompanied by even smaller postponements in disability, a reversal of a downward trend in moderate disability, and stagnation of active life as a percentage of life expectancy. As a consequence, older women no longer live more active years than men, despite their longer lives. CONCLUSIONS: Neither a compression nor expansion of late-life disability is inevitable. Public health measures directed at older women to postpone disability may be needed to offset impending long-term care pressures related to population aging. PMID- 26985621 TI - Food Gardeners' Productivity in Laramie, Wyoming: More Than a Hobby. AB - OBJECTIVES: We quantified the productivity of food gardens in Laramie, Wyoming, over 3 growing seasons. METHODS: From 2012 to 2014, 33 participating gardening households weighed and recorded each harvest. Academic partners measured plot sizes and converted reported harvest weights to volume in cups. RESULTS: The yield of the average 253-square-foot plot was enough to supply an adult with the daily US Department of Agriculture-recommended amount of vegetables for 9 months. CONCLUSIONS: Gardeners produced nutritionally meaningful quantities of food; thus, food gardening offers promise as an effective public health intervention for improving food security and nutritional health. PMID- 26985620 TI - A Longitudinal Study of Multiple Drug Use and Overdose Among Young People Who Inject Drugs. AB - OBJECTIVES: To determine the association between multiple drug use and nonfatal overdose among young people (younger than 30 years) who inject drugs. METHODS: We completed a longitudinal study of 173 injection drug users younger than 30 years living in San Francisco, California, between April 2012 and February 2014. RESULTS: The odds of nonfatal overdose increased significantly as heroin and benzodiazepine pill-taking days increased and when alcohol consumption exceeded 10 drinks per day compared with 0 drinks per day. CONCLUSIONS: Heroin, benzodiazepine, and alcohol use were independently associated with nonfatal overdose over time among young people who inject drugs. Efforts to address multiple central nervous system depressant use remain an important component of a comprehensive approach to overdose, particularly among young people. PMID- 26985622 TI - Food Environments and Obesity: Household Diet Expenditure Versus Food Deserts. AB - OBJECTIVES: To examine the associations between obesity and multiple aspects of the food environments, at home and in the neighborhood. METHODS: Our study included 38,650 individuals nested in 18,381 households located in 2104 US counties. Our novel home food environment measure, USDAScore, evaluated the adherence of a household's monthly expenditure shares of 24 aggregated food categories to the recommended values based on US Department of Agriculture food plans. The US Census Bureau's County Business Patterns (2008), the detailed food purchase information in the IRi Consumer Panel scanner data (2008-2012), and its associated MedProfiler data set (2012) constituted the main sources for neighborhood-, household-, and individual-level data, respectively. RESULTS: After we controlled for a number of confounders at the individual, household, and neighborhood levels, USDAScore was negatively linked with obesity status, and a census tract-level indicator of food desert status was positively associated with obesity status. CONCLUSIONS: Neighborhood food environment factors, such as food desert status, were associated with obesity status even after we controlled for home food environment factors. PMID- 26985623 TI - Barriers to Health Care Among Adults Identifying as Sexual Minorities: A US National Study. AB - OBJECTIVES: To assess the extent to which lesbian, gay, and bisexual (LGB) adults aged 18 to 64 years experience barriers to health care. METHODS: We used 2013 National Health Interview Survey data on 521 gay or lesbian (291 men, 230 women), 215 bisexual (66 men, 149 women), and 25 149 straight (11 525 men, 13 624 women) adults. Five barrier-to-care outcomes were assessed (delayed or did not receive care because of cost, did not receive specific services because of cost, delayed care for noncost reasons, trouble finding a provider, and no usual source of care). RESULTS: Relative to straight adults, gay or lesbian and bisexual adults had higher odds of delaying or not receiving care because of cost. Bisexual adults had higher odds of delaying care for noncost reasons, and gay men had higher odds than straight men of reporting trouble finding a provider. By contrast, gay or lesbian women had lower odds of delaying care for noncost reasons than straight women. Bisexual women had higher odds than gay or lesbian women of reporting 3 of the 5 barriers investigated. CONCLUSIONS: Members of sexual minority groups, especially bisexual women, are more likely to encounter barriers to care than their straight counterparts. PMID- 26985624 TI - Breast free flap complications related to haematoma formation - do the risks of multiple antithrombotics outweigh the benefits today? AB - Background Free flap reconstruction is today a common operation for many breast cancer patients, but local protocols for microsurgery still predict the use of antithrombotic agents. Reduced operation times and complication rates together with faster mobilisation, after introduction of perforator flaps, call for less comprehensive antithrombotic regimens. It was hypothesised that multiple antithrombotics was a risk factor for bleeding-related flap complications. Methods A retrospective cohort study was conducted to study the association between reoperation for haematoma and flap-related complications after free flap breast reconstruction. A combination of heparin, low-molecular-weight heparin and dextran were used as antithrombotics. A sub-analysis was performed to compare non dextran to dextran treated patients. Results One hundred and thirty-nine patients were identified, reconstructed with 150 consecutive perforator free flaps to the breast. Reoperation for breast haematoma (13%) was associated with concomitant re operation for venous congestion (8.6%) (p < 0.001), but also for flap thrombosis (2.9%) (p = 0.007), highlighting haematoma as a risk factor for flap-related complications. An increased rate of haematoma re-operations of the breast was noted among the flap-related complications in the dextran (n = 79), compared to the non-dextran group (p = 0.011). Conclusion The current study highlights the use of multiple antithrombotics as a risk factor for haematoma reoperation. Liberal use of drains and evacuation of breast haematomas are, therefore, indicated together with limitation of antithrombotic agents. The highly variable use of antithrombotic agents worldwide call for evidence-based guidelines in standardised free flap breast reconstruction. PMID- 26985625 TI - Snapshot of Teleretinal Screening for Diabetic Retinopathy at the West Los Angeles Medical Center. AB - INTRODUCTION: The West Los Angeles Veterans Affairs Medical Center is a large urban facility with a robust teleretinal screening program in primary care clinic, established in 2006. The purpose of this article is to provide a snapshot of teleretinal screening at this site. METHODS: Diabetic patients from 2012 were analyzed with a prospective cohort study. Demographic information, results of teleretinal screening, referral to eye clinic, and loss to follow-up (defined as no eye care within 2 years) were collected. RESULTS: Of 516 patients with diabetes screened with teleretinal imaging, 120 patient charts were reviewed for data analysis. Teleretinal imaging diagnosed 15% (18/120) of patients with varying stages of nonproliferative diabetic retinopathy (DR). Of patients screened, 55.8% (67/120) of the patients were referred to an eye clinic for further ophthalmic evaluation. Nondiabetic retinopathy reasons for eye clinic referral included glaucoma suspect (13.3%, 16/120) and age-related macular degeneration (10.0%, 12/120). Of all patients screened, 37.5% (45/120) of them were lost to follow-up, defined as no teleretinal screening or eye clinic appointment within 2 years. Patients who lived farther away from clinic had a higher risk of loss to follow-up (p = 0.04). DISCUSSION: We found, although only 15% of patients were diagnosed with DR from teleretinal screening, more than 50% of patients were referred to eye clinic. In addition, of all screened patients, there was a high rate of not returning to the Veterans Affairs (VA) for eye care. PMID- 26985626 TI - Effects of additives on the co-pyrolysis of municipal solid waste and paper sludge by using thermogravimetric analysis. AB - By using thermogravimetric analysis (TGA), the effects of different additives (MgO, Al2O3 and ZnO) on the pyrolysis characteristics and activation energy of municipal solid waste (MSW), paper sludge (PS) and their blends in N2 atmosphere had been investigated in this study. The experiments resulted that these additives were effective in reducing the initial temperature and activation energy. However, not all the additives were beneficial to reduce the residue mass and enhance the index D. For the different ratios of MSW and PS, the same additive even had the different influences. The catalytic effects of additives were not obvious and the pyrolysis became difficult with the increase of the proportion of PS. Based on all the contrast of the pyrolysis characteristics, MgO was the best additive and 70M30P was the best ratio, respectively. PMID- 26985627 TI - Study on product distributions and char morphology during rapid co-pyrolysis of platanus wood and lignite in a drop tube fixed-bed reactor. AB - The rapid co-pyrolytic behavior of platanus wood and Pingzhuang lignite was explored in a drop tube fixed-bed reactor under nitrogen atmosphere. Synergistic effects were evaluated using the deviations between experimental and predicted values of product yields and gas components. Surface morphology of residual chars were also investigated applying the scanning electron microscopy technique (SEM). This study found that the experimental values of gas volume yields were greater than the predicted, and the maximum gas volume yield exhibited with 50% biomass blending ratio at 1000 degrees C. Positive or negative synergistic effects happened in gas components at different blending ratios and temperatures. The SEM results indicated that the differences of char surface morphology were evident. The fractal dimensions of residual chars increased with increasing biomass blending ratio, which may improve their gasification or combustion reactivity. The change in product yields and gas components was attributed to the secondary reactions and tar cracking. PMID- 26985628 TI - Ammonia-LCFA synergetic co-inhibition effect in manure-based continuous biomethanation process. AB - In the current study it has been hypothesized that, when organic loading of an anaerobic reactor is increased, the additional cell biomass biosynthesis would capture more ammonia nitrogen and thereby reduce the ammonia toxicity. Therefore, the alleviation of the toxicity of high ammonia levels using lipids (glycerol trioleate-GTO) or carbohydrates (glucose-GLU) as co-substrates in manure-based thermophilic continuous stirred-tank reactors (R(GTO) and R(GLU), respectively) was tested. At 5gNH4(+)-NL(-1), relative methane production of R(GTO) and R(GLU), was 10.5% and 41% compared to the expected uninhibited production, respectively. At the same time control reactor (R(CTL)), only fed with manure, reached 32.7% compared to the uninhibited basis production. Therefore, it seems that using lipids to counteract the ammonia effect in CSTR reactors creates an "ammonia-LCFA (long chain fatty acids) synergetic co-inhibition" effect. Moreover, co-digestion with glucose in R(GLU) was more robust to ammonia toxicity compared to R(CTL). PMID- 26985629 TI - Safety and Efficacy of Intratympanic Ciprofloxacin Otic Suspension in Children With Middle Ear Effusion Undergoing Tympanostomy Tube Placement: Two Randomized Clinical Trials. AB - IMPORTANCE: Otorrhea after tympanostomy tube placement (TTP) in children is common. Although not approved by the US Food and Drug Administration, antibiotic ear drops are routinely used intraoperatively and prescribed for multidose, multiday postoperative administration by caregivers. OBJECTIVE: To investigate the safety and efficacy of a single-dose intratympanic, intraoperative, thermosensitive, otic suspension of ciprofloxacin (OTO-201) in children requiring TTP. DESIGN, SETTING, AND PARTICIPANTS: Two identically designed, prospective, double-blind, sham-controlled, multicenter phase 3 randomized clinical trials included 532 patients aged 6 months to 17 years with middle ear effusions. Patients with confirmed bilateral effusions on the day of TTP were randomized to TTP alone or to TTP with OTO-201 injection. Children underwent a 28-day observation period. Data were collected from November 14, 2013, to June 3, 2014. Final follow-up was completed on June 16, 2014, and intent-to-treat data were analyzed from June 10 to August 27, 2014. MAIN OUTCOMES AND MEASURES: Efficacy was assessed as treatment failure, including the presence of otorrhea, use of otic or systemic antibiotics, loss to follow-up, or missed visits. Safety was assessed for serious adverse events and treatment-emergent adverse events using audiometry, otoscopy, and tympanometry. RESULTS: Among the 532 patients included in the trials, 175 were randomized to TTP only and 357 to OTO-201 treatment (304 boys [57.1%]; 228 girls [42.9%]; mean [SD] age, 2.4 [2.1]). At day 15, the cumulative proportion of treatment failures (primary end point) was 24.6% (44 of 179 patients) in trial 1 and 21.3% (38 of 178 patients) in trial 2 in the OTO-201 groups vs 44.8% (39 of 87 patients) in trial 1 and 45.5% (40 of 88 patients) in trial 2 in the TTP-alone groups. At day 15 otorrhea-only treatment failures in trial 1 included 21 of 179 (11.7%) in the OTO-201 group vs 22 of 87 (25.3%) in the TTP-only group; in trial 2, 17 of 178 (9.6%) in the OTO-201 group vs 29 of 88 (33.0%) in the TTP-only group. The odds of otorrhea-only failure were significantly reduced in the OTO-201 groups compared with the TTP-only groups in both trials (age-adjusted odds ratios, 0.38 [95% CI, 0.19-0.75] and 0.19 [95% CI, 0.09-0.38]; P < .001 for both trials, post hoc analysis). No drug-related serious adverse events were seen, and most adverse events were mild or moderate. No evidence of increased tube occlusion and no negative effect on results of audiometry, tympanometry, or otoscopy were noted with OTO-201 administration. CONCLUSIONS AND RELEVANCE: Two large phase 3 randomized clinical trials demonstrate the safety and efficacy of a single intraoperative administration of OTO-201 for middle ear effusion at the time of TTP. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT01949142 and NCT01949155. PMID- 26985632 TI - Managing the Risks of Concurrent Surgeries. PMID- 26985631 TI - Stressful events and coping related to acute and sub-acute whiplash-associated disorders. AB - Purpose To describe daily stressors affecting and coping strategies employed by individuals with whiplash-associated disorders (WAD) immediately to one month (acute) and three to four months (sub-acute) after injury events using a daily coping assessment. Levels of pain, anxiety, depressed mood and activity are also compared between phases. Method A descriptive prospective design with a content analysis approach was used. Participants completed daily coping assessments for one week during both acute and sub-acute phases. Main measure was whiplash associated disorders-daily coping assessment (WAD-DCA). Results Nine participants used words describing recovery in the sub-acute phase; 31 described stressful events during both phases. Most frequently reported stressors were related to "symptoms", "emotions" and "occupations/studies". These were equally reported during both phases. Cognitive coping strategies were employed more often during the sub-acute phase (p = 0.008). The only behavioral strategy that increased in prevalence over time was the "relaxed" strategy (p = 0.001). Anxiety levels declined over time (p = 0.022). Conclusion The reported stressors were largely uniform across both acute and sub-acute phases; however, the use of cognitive coping strategies increased over time. The WAD-DCA captures individual stressors and coping strategies employed during a vulnerable phase of rehabilitation and can thus provide information that is useful to clinical practice. Implications for rehabilitation The WAD-DCA provides valuable information for clinical practice when employed during early phases of whiplash-associated disorder development. Reported stressors during the acute and sub-acute phases are essentially the same, whereas cognitive coping strategies grow in prevalence over time. Tailored treatments in early phases of whip-lash associated disorders may benefit from strategies aimed at matching patient-specific stressors with contextually adapted coping strategies. PMID- 26985630 TI - Structure-based design of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoates as selective inhibitors of the Mcl-1 oncoprotein. AB - Structure-based drug design was utilized to develop novel, 1-hydroxy-2-naphthoate based small-molecule inhibitors of Mcl-1. Ligand design was driven by exploiting a salt bridge with R263 and interactions with the p2 pocket of the protein. Significantly, target molecules were accessed in just two synthetic steps, suggesting further optimization will require minimal synthetic effort. Molecular modeling using the Site-Identification by Ligand Competitive Saturation (SILCS) approach was used to qualitatively direct ligand design as well as develop quantitative models for inhibitor binding affinity to Mcl-1 and the Bcl-2 relative Bcl-xL as well as for the specificity of binding to the two proteins. Results indicated hydrophobic interactions in the p2 pocket dominated affinity of the most favourable binding ligand (3bl: Ki = 31 nM). Compounds were up to 19 fold selective for Mcl-1 over Bcl-xL. Selectivity of the inhibitors was driven by interactions with the deeper p2 pocket in Mcl-1 versus Bcl-xL. The SILCS-based SAR of the present compounds represents the foundation for the development of Mcl 1 specific inhibitors with the potential to treat a wide range of solid tumours and hematological cancers, including acute myeloid leukemia. PMID- 26985634 TI - A New (-)-5',6-dimethoxyisolariciresinol-(3",4"-dimethoxy)-3alpha-O-beta-D glucopyranoside from the bark of Aglaia eximia (Meliaceae). AB - New (-)-5',6-dimethoxyisolariciresinol-(3",4"-dimethoxy)-3alpha-O-beta-d glucopyranoside compound was isolated from the methanol extract of the bark of Aglaia eximia (Meliaceae). The chemical structure of the new compound were elucidated on the basis of spectroscopic data including, UV, IR, HR-ESI-TOFMS, 1D NMR, 2D-NMR and comparison with those related compounds previously reported. PMID- 26985633 TI - cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response. AB - Activation and proliferation of T cells are tightly regulated during the immune response. We show here that kinetics of proliferation of PHA activated T cells follows the expression of cMyc. Expression of p53 is also elevated and remains high several days after activation. To investigate the role of p53 in activated T cells, its expression was further elevated with nultin-3 treatment, a small molecule that dissociates the E3 ubiquitin protein ligase MDM2 from p53. Concomitantly, cMyc expression and proliferation decreased. At the other end of the cMyc-p53 axis, inhibition of cMyc with 10058-F4 led to down regulation of p53, likely through the lower level of cMyc induced p14ARF, which is also known to dissociate the p53-MDM2 complex. Both compounds induced cell cycle arrest and apoptosis. We conclude that the feedback regulation between cMyc and p53 is important for the T cell homeostasis. We also show that the two compounds modulating p53 and cMyc levels inhibited proliferation without abolishing the cytotoxic function, thus demonstrating the dichotomy between proliferation and cytotoxicity in activated T cells. PMID- 26985635 TI - Prediction of 60-Day Case Fatality After Aneurysmal Subarachnoid Hemorrhage: External Validation of a Prediction Model. AB - OBJECTIVE: External validation of prognostic models is crucial but rarely done. Our aim was to externally validate a prognostic model to predict 60-day case fatality after aneurysmal subarachnoid hemorrhage developed from the International Subarachnoid Aneurysm Trial in a retrospective unselected cohort of subarachnoid hemorrhage patients. DESIGN: The model's predictors were age, aneurysm size, Fisher grade, and World Federation of Neurological Surgeons grade. Two versions of the model were validated: one with World Federation of Neurological Surgeons grade scored at admission and the other with World Federation of Neurological Surgeons grade at treatment decision. The outcome was 60-day case fatality. Performance of the model was assessed by studying discrimination, expressed by the area under the receiver operating characteristic curve, and calibration. SETTING: University hospital. PATIENTS: We analyzed data from 307 consecutive aneurysmal subarachnoid hemorrhage patients admitted between 2007 and 2011 (validation cohort). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The observed 60-day case fatality rate was 30.6%. Discrimination was good, and differed between the model with World Federation of Neurological Surgeons grade at treatment decision (area under the receiver operating characteristic curve, 0.89) and at admission (area under the receiver operating characteristic curve, 0.82). Mean predicted probabilities were lower than observed: 17.0% (model with World Federation of Neurological Surgeons grade at admission) and 17.7% (model with World Federation of Neurological Surgeons grade at treatment decision). CONCLUSIONS: The model discriminated well between patients who died or survived within 60 days. In addition, we found that using World Federation of Neurological Surgeons grade at moment of treatment decision of the ruptured aneurysm improved model performance. However, since predicted probabilities were much lower than observed probabilities, the International Subarachnoid Aneurysm Trial prediction model needs to be adapted to be used in clinical practice. PMID- 26985637 TI - FTY720-induced enhancement of autophagy protects cells from FTY720 cytotoxicity in colorectal cancer. AB - FTY720, also known as fingolimod, is a widely used immunomodulator in multiple sclerosis and multiple organ transplantation. It is also an important protein phosphatase 2A (PP2A) activator. Based on this, a number of studies have recently demonstrated the cytotoxic effect of FTY720 in various cancers. Yet in colorectal cancer (CRC), the underlying mechanisms of FTY720 cytotoxicity remain less clear, especially the relationship between a drug and autophagy. We demonstrate here for the first time that FTY720 promotes the appearance of autophagic hallmarks such as autophagosome formation and light chain 3 (LC3)-II accumulation, indicating the participation of autophagy in FTY720 cytotoxicity on CRC. Moreover, inhibition of autophagy using 3-methyladenine (3-MA), a specific inhibitor of autophagy, enhanced FTY720 cytotoxicity, indicating the protective role of autophagy against the drug's own cytotoxic effect. The protective autophagy was likely affected by cancerous inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor that is closely related with poor prognosis and drug resistance. Consequently, our data not only demonstrate a new mechanism underlying the cytotoxic effect of FTY720 in CRC, but also a new strategy for CRC treatment, especially in cases resistant to conventional chemotherapies because of high CIP2A levels. PMID- 26985638 TI - Direct Uniaxial Alignment of a Donor-Acceptor Semiconducting Polymer Using Single Step Solution Shearing. AB - The alignment of organic semiconductors (OSCs) in the active layers of electronic devices can confer desirable properties, such as enhanced charge transport properties due to better ordering, charge transport anisotropy for reduced device cross-talk, and polarized light emission or absorption. The solution-based deposition of highly aligned small molecule OSCs has been widely demonstrated, but the alignment of polymeric OSCs in thin films deposited directly from solution has typically required surface templating or complex pre- or postdeposition processing. Therefore, single-step solution processing and the charge transport enhancement afforded by alignment continue to be attractive. We report here the use of solution shearing to tune the degree of alignment in poly(diketopyrrolopyrrole-terthiophene) thin films by controlling the coating speed. A maximum dichroic ratio of ~7 was achieved on unpatterned substrates without any additional pre- or postdeposition processing. The degree of polymer alignment was found to be a competition between the shear alignment of polymer chains in solution and the complex thin film drying process. Contrary to previous reports, no charge transport anisotropy was observed because of the small crystallite size relative to the channel length, a meshlike morphology, and the likelihood of increased grain boundaries in the direction transverse to coating. In fact, the lack of aligned morphological structures, coupled with observed anisotropy in X-ray diffraction data, suggests the alignment of polymer molecules in both the crystalline and the amorphous regions of the films. The shear speed at which maximum dichroism is achieved can be controlled by altering deposition parameters such as temperature and substrate treatment. Modest changes in molecular weight showed negligible effects on alignment, while longer polymer alkyl side chains were found to reduce the degree of alignment. This work demonstrates that solution shearing can be used to tune polymer alignment in a one-step deposition process not requiring substrate patterning or any postdeposition treatment. PMID- 26985643 TI - Bimetallic rare-earth/platinum complexes ligated by phosphinoamides. AB - The heterometallic early-late 5d/4f binuclear phosphinoamido Ln/Pt(0) complexes [(Ph2PNHPh)Pt{MU-(Ph2PNPh)}3Ln(MU-Cl)Li(THF)3] (Ln = Y (1a), Lu (1b)) were obtained by reaction of [Li(THF)4][(Ph2PNPh)4Ln] (Ln = Y, Lu) with the Pt(0) complex [Pt(tBu3P)2] in the presence of LiCl. In the absence of LiCl the corresponding Ln/Pt(0) complexes [(Ph2PNHPh)Pt{MU-(Ph2PNPh)}3Ln{eta(2) (Ph2PNPh)}][Li(THF)4] (Ln = Y (2a), Lu (2b)) were isolated. Both kind of complexes decompose in solution. The Pt(0) complex [Pt(Ph2PNHPh)4] (3) was identified as one of these decomposition products. PMID- 26985636 TI - Nutritional Status Based on Body Mass Index Is Associated With Morbidity and Mortality in Mechanically Ventilated Critically Ill Children in the PICU. AB - OBJECTIVE: To determine the influence of admission anthropometry on clinical outcomes in mechanically ventilated children in the PICU. DESIGN: Data from two multicenter cohort studies were compiled to examine the unique contribution of nutritional status, defined by body mass index z score, to 60-day mortality, hospital-acquired infections, length of hospital stay, and ventilator-free days, using multivariate analysis. SETTING: Ninety PICUs from 16 countries with eight or more beds. PATIENTS: Children aged 1 month to 18 years, admitted to each participating PICU and requiring mechanical ventilation for more than 48 hours. MEASUREMENTS AND MAIN RESULTS: Data from 1,622 eligible patients, 54.8% men and mean (SD) age 4.5 years (5.1), were analyzed. Subjects were classified as underweight (17.9%), normal weight (54.2%), overweight (14.5%), and obese (13.4%) based on body mass index z score at admission. After adjusting for severity of illness and site, the odds of 60-day mortality were higher in underweight (odds ratio, 1.53; p < 0.001) children. The odds of hospital-acquired infections were higher in underweight (odds ratio, 1.88; p = 0.008) and obese (odds ratio, 1.64; p < 0.001) children. Hazard ratios for hospital discharge were lower among underweight (hazard ratio, 0.71; p < 0.001) and obese (hazard ratio, 0.82; p = 0.04) children. Underweight was associated with 1.3 (p = 0.001) and 1.6 (p < 0.001) fewer ventilator-free days than normal weight and overweight, respectively. CONCLUSIONS: Malnutrition is prevalent in mechanically ventilated children on admission to PICUs worldwide. Classification as underweight or obese was associated with higher risk of hospital-acquired infections and lower likelihood of hospital discharge. Underweight children had a higher risk of mortality and fewer ventilator-free days. PMID- 26985644 TI - Proteomic strategies in the search for novel pancreatic cancer biomarkers and drug targets: recent advances and clinical impact. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers; despite a low incidence rate it is the fourth leading cause of cancer-related death in the world. Improvement of the diagnosis, prognosis and treatment remains the main focus of pancreatic cancer research. Rapid developments in proteomic technologies has improved our understanding of the pancreatic cancer proteome. Here, the authors summarise the recent proteomic strategies undertaken in the search for: novel biomarkers for early diagnosis, pancreatic cancer-specific proteins which may be used for novel targeted therapies and proteins which may be useful for monitoring disease progression post-therapy. Recent advances and findings discussed here provide great promise of having a significant clinical impact and improving the outcome of patients with this malignancy. PMID- 26985645 TI - Weeding Out the Truth: Adolescents and Cannabis. AB - The use of cannabis for both legal (similar to alcohol) and medical purposes is becoming more common. Although cannabis remains an illegal Schedule 1 drug federally, as of November 2015, 23 states and the District of Columbia have legalized "medical" cannabis, and 4 states and the District of Columbia have legalized the use of cannabis for adults aged 21 years and older. It is very likely that more and more states will sooner rather than later allow cannabis for both medical and legal purposes. This review article will focus on a variety of issues relevant to the current debate about cannabis, and will address the following. PMID- 26985646 TI - Weeding Out the Truth: Adolescents and Cannabis: Case and Discussion. AB - This clinical case conference discusses the case of an adolescent presenting with a marijuana use disorder. Information about a real patient is presented to expert clinicians, who respond to the information by sharing their reasoning and recommendations, followed by a summary of the clinical discussion. PMID- 26985647 TI - Sources of Prescription Opioids for Nonmedical Use. PMID- 26985648 TI - Controlled Substances and Prescribers. PMID- 26985649 TI - Methadone and Buprenorphine for Opioid Dependence During Pregnancy: A Retrospective Cohort Study: Re: Meyer et al. PMID- 26985651 TI - ER stress and autophagy are involved in the apoptosis induced by cisplatin in human lung cancer cells. AB - Cisplatin [cis-diamminedichloroplatinum II (CDDP)] is one of the most classical and effective chemotherapeutic drugs for the treatment of cancers including lung cancer. However, the presence of cisplatin resistance in cancer lowers its curative effect and limits its usage in the clinic. The aim of the present study was to investigate the underlying mechanisms of cisplatin resistance in lung cancer involving endoplasmic reticulum (ER) stress and autophagy. In the present study, we detected the effect of cisplatin on cell viability, ER stress and autophagy in lung cancer cell lines A549 and H460. We also tested the effects of ER stress and autophagy on apoptosis induced by cisplatin. The results showed that cisplatin induced apoptosis, ER stress and autophagy in lung cancer cell lines. In addition, the inhibition of ER stress by 4-phenylbutyric acid (4-PBA) or tauroursodeoxycholic acid sodium (TUDC) enhanced cisplatin-induced apoptosis in the human lung cancer cells. Meanwhile, combination treatment with the autophagic inhibitor 3-methyladenine (3-MA) or chloroquine (CQ) further increased the apoptosis induced by cisplatin in the human lung cancer cells. The present study provides a novel treatment strategy - cisplatin in combination with an autophagic inhibitor or an ER stress inhibitor leads to increased apoptosis in human lung cancer cells. PMID- 26985652 TI - Determining whether curcumin degradation/condensation is actually bioactivation (Review). AB - Curcumin has been shown to exert therapeutic or protective effects against a variety of diseases, such as cancer, pulmonary diseases, neurological, liver, metabolic, autoimmune, cardiovascular diseases and numerous other chronic ailments. Over 116 clinical studies on curcumin in humans were registered with the US National Institutes of Health in 2015. However, it is mystifying how curcumin can be so effective in the treatment of many diseases since it has very low water solubility and bioavailability. Furthermore, curcumin is not stable under various conditions; its degradation or condensation into different bioactive compounds may be responsible for its biological activities rather than curcumin itself. In this review, we provide evidence of curcumin degradation and condensation into different compounds which have or may have health benefits themselves. Literature reviews strongly suggest that these molecules contribute to the observed health benefits, rather than curcumin itself. PMID- 26985653 TI - Antisense non-coding RNAs and regulation of gene transcription. AB - Transcriptome analyses have revealed the existence of a large variety of non coding RNAs (ncRNAs) that, although specifically expressed, are largely unknown in function. The best-studied role of ncRNAs is the regulation of gene expression, mostly participating in transcription. We report here the role of an antisense ncRNA that represses transcription of LEF1 by recruiting Polycomb repressive complex 2 (PRC2), which trimethylates H3K27. This antisense LEF1 transcript undergoes splicing losing its inhibitory function. We also discuss the possible general relevance of this finding. PMID- 26985654 TI - Next-generation ecological risk assessment: Predicting risk from molecular initiation to ecosystem service delivery. AB - Ecological risk assessment is the process of evaluating how likely it is that the environment may be impacted as the result of exposure to one or more chemicals and/or other stressors. It is not playing as large a role in environmental management decisions as it should be. A core challenge is that risk assessments often do not relate directly or transparently to protection goals. There have been exciting developments in in vitro testing and high-throughput systems that measure responses to chemicals at molecular and biochemical levels of organization, but the linkage between such responses and impacts of regulatory significance - whole organisms, populations, communities, and ecosystems - are not easily predictable. This article describes some recent developments that are directed at bridging this gap and providing more predictive models that can make robust links between what we typically measure in risk assessments and what we aim to protect. PMID- 26985656 TI - Validation of Software Measurements of Eyelid Position From Digital Photographs. PMID- 26985655 TI - Risk management of viral infectious diseases in wastewater reclamation and reuse: Review. AB - Inappropriate usage of reclaimed wastewater has caused outbreaks of viral infectious diseases worldwide. International and domestic guidelines for wastewater reuse stipulate that virus infection risks are to be regulated by the multiple-barrier system, in which a wastewater treatment process composed of sequential treatment units is designed based on the pre-determined virus removal efficiency of each unit. The objectives of this review were to calculate representative values of virus removal efficiency in wastewater treatment units based on published datasets, and to identify research topics that should be further addressed for improving implementation of the multiple-barrier system. The removal efficiencies of human noroviruses, rotaviruses and enteroviruses in membrane bioreactor (MBR) and conventional activated sludge (CAS) processes were obtained by a systematic review protocol and a meta-analysis approach. The log10 reduction (LR) of norovirus GII and enterovirus in MBR were 3.35 (95% confidence interval: 2.39, 4.30) and 2.71 (1.52, 3.89), respectively. The LR values of rotavirus, norovirus GI and GII in CAS processes were 0.87 (0.20, 1.53), 1.48 (0.96, 2.00) and 1.35 (0.52, 2.18), respectively. The systematic review process eliminated a substantial number of articles about virus removal in wastewater treatment because of the lack of information required for the meta-analysis. It is recommended that future publications should explicitly describe their treatment of left-censored datasets. Indicators, surrogates and methodologies appropriate for validating virus removal performance during daily operation of wastewater reclamation systems also need to be identified. PMID- 26985657 TI - Photoluminescence properties of AgInS2-ZnS nanocrystals: the critical role of the surface. AB - AgInS2-ZnS (ZAIS) nanocrystals are very good candidates for easily synthesized, highly efficient cadmium-free nano-phosphors. They can be employed for the development of next generation white-LED technologies, taking advantage of their nanometric size. This paper describes the combined use of time-resolved emission spectroscopy and photoluminescence quantum yield measurements to quantitatively compare the efficiency of each recombination pathway involved in the photoluminescence of ZAIS nanocrystals. This approach, applied to nanocrystals of different sizes, compositions and surface chemistry revealed the critical role of surface effects. Moreover, we developed a new type of surface passivation that increases the photoluminescence quantum yield of all nanocrystal compositions by 15 to 20%. This molecular surface passivation can be applied as a replacement or in addition to the already established ZnS shell passivation method. PMID- 26985658 TI - Dual Roles of Methyl Ketones in Radziszewski-Type Reaction: Formal [2 + 1 + 1 + 1] Synthesis of 1,2,5-Trisubstituted Imidazoles. AB - A highly efficient molecular iodine mediated Radziszewski-type reaction of methyl ketones, anilines, and tosylmethyl isocyanide has been developed. This protocol represents an elegant molecular fragment assembly of imidazoles via a formal [2 + 1 + 1 + 1] annulation. It is the first example where methyl ketones serve as the alpha-dicarbonyl compounds and aldehydes in Radziszewski-type reactions. PMID- 26985659 TI - Anthocyanins inhibit trastuzumab-resistant breast cancer in vitro and in vivo. AB - Trastuzumab (Herceptin(r)) is a recombinant humanized monoclonal antibody that is targeted against the human epidermal growth factor receptor 2 (HER2) tyrosine kinase receptor. Trastuzumab has been successfully used to treat patients with HER2-positive breast cancer, which accounts for ~25% of invasive breast cancer. However, the majority of patients who initially respond to trastuzumab demonstrate disease progression within 1 year of treatment. Therefore, identifying alternative drugs that overcome trastuzumab resistance and target HER2 may increase the magnitude and duration of response. Through a high throughput screening approach, we previously identified numerous anthocyanins that exert activity in HER2-positive human breast cancer cell lines. The present study aimed to evaluate the anti-tumor properties of anthocyanins against parental HER2-positive cells and derivative trastuzumab-resistant cells in vitro and in vivo. Cell proliferation, western blotting, Annexin V staining, migration and invasion assays were used to determine the effects of anthocyanins in vitro. Cyanidin-3-glucoside and peonidin-3-glucoside were able to inhibit phosphorylation of HER2, induce apoptosis, suppress migration and invasion, and inhibit tumor cell growth. Coupled with the fact that anthocyanins have been used for decades as supplements for the treatment of various types of cancer in Asia, the present study may have established a framework for the development and testing of anthocyanins as a novel treatment paradigm used to overcome classical trastuzumab-resistance and to improve the outcome of this disease. PMID- 26985660 TI - Localizing Tortoise Nests by Neural Networks. AB - The goal of this research is to recognize the nest digging activity of tortoises using a device mounted atop the tortoise carapace. The device classifies tortoise movements in order to discriminate between nest digging, and non-digging activity (specifically walking and eating). Accelerometer data was collected from devices attached to the carapace of a number of tortoises during their two-month nesting period. Our system uses an accelerometer and an activity recognition system (ARS) which is modularly structured using an artificial neural network and an output filter. For the purpose of experiment and comparison, and with the aim of minimizing the computational cost, the artificial neural network has been modelled according to three different architectures based on the input delay neural network (IDNN). We show that the ARS can achieve very high accuracy on segments of data sequences, with an extremely small neural network that can be embedded in programmable low power devices. Given that digging is typically a long activity (up to two hours), the application of ARS on data segments can be repeated over time to set up a reliable and efficient system, called Tortoise@, for digging activity recognition. PMID- 26985661 TI - Botulinum Toxin Type A and the Prevention of Hypertrophic Scars on the Maxillofacial Area and Neck: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: The purpose of the meta-analysis was to evaluate the efficiency of therapeutic botulinum toxin type A (BTX-A) in the prevention of maxillofacial and neck scars. METHODS AND FINDINGS: Information came from the following electronic databases: Medline, PubMed, Cochrane Library, and EMBASE (time was ended by August 31, 2015) to retrieve RCTs evaluating the effect of the BTX-A for hypertrophic scar on the maxillofacial or neck. All languages were included as long as they met the inclusion criteria. Here the effects of BTX-A were evaluated by comparing the width of the scar, patient satisfaction, and the visual analysis scores (VAS), respectively. Pooled weighted mean differences (WMDs), pooled odds ratios (ORs), and 95% confidence intervals (CI) were calculated. Nine RCTs covering a total of 539 patients were included. A statistically significant difference in scar width was identified between the BTX-A group and control group (non-BTX-A used) (WMD = -0.41, 95% CI = -0.68 to -0.14, P = 0.003). A statistically significant difference in patient satisfaction was observed between the BTX-A group and control group (OR = 25.76, 95% CI = 2.58 to 256.67, P = 0.006). And in patients regarding visual analysis scores (VAS), a statistically significant difference was also observed between the BTX-A group and control group (WMD = 1.30, 95% CI = 1.00 to 1.60, P < 0.00001). CONCLUSIONS: This meta analysis evaluates the efficacy of the BTX-A and confirms that BTX-A is a suitable potential therapy for the prevention of hypertrophic scars in patients in the maxillofacial and neck areas. PMID- 26985663 TI - Genetically Engineered Yeast Expressing a Lytic Peptide from Bee Venom (Melittin) Kills Symbiotic Protozoa in the Gut of Formosan Subterranean Termites. AB - The Formosan subterranean termite, Coptotermes formosanus Shiraki, is a costly invasive urban pest in warm and humid regions around the world. Feeding workers of the Formosan subterranean termite genetically engineered yeast strains that express synthetic protozoacidal lytic peptides has been shown to kill the cellulose digesting termite gut protozoa, which results in death of the termite colony. In this study, we tested if Melittin, a natural lytic peptide from bee venom, could be delivered into the termite gut via genetically engineered yeast and if the expressed Melittin killed termites via lysis of symbiotic protozoa in the gut of termite workers and/or destruction of the gut tissue itself. Melittin expressing yeast did kill protozoa in the termite gut within 56 days of exposure. The expressed Melittin weakened the gut but did not add a synergistic effect to the protozoacidal action by gut necrosis. While Melittin could be applied for termite control via killing the cellulose-digesting protozoa in the termite gut, it is unlikely to be useful as a standalone product to control insects that do not rely on symbiotic protozoa for survival. PMID- 26985662 TI - A Sensorimotor Model for Computing Intended Reach Trajectories. AB - The presumed role of the primate sensorimotor system is to transform reach targets from retinotopic to joint coordinates for producing motor output. However, the interpretation of neurophysiological data within this framework is ambiguous, and has led to the view that the underlying neural computation may lack a well-defined structure. Here, I consider a model of sensorimotor computation in which temporal as well as spatial transformations generate representations of desired limb trajectories, in visual coordinates. This computation is suggested by behavioral experiments, and its modular implementation makes predictions that are consistent with those observed in monkey posterior parietal cortex (PPC). In particular, the model provides a simple explanation for why PPC encodes reach targets in reference frames intermediate between the eye and hand, and further explains why these reference frames shift during movement. Representations in PPC are thus consistent with the orderly processing of information, provided we adopt the view that sensorimotor computation manipulates desired movement trajectories, and not desired movement endpoints. PMID- 26985664 TI - A SNP-Based Molecular Barcode for Characterization of Common Wheat. AB - Wheat is grown as a staple crop worldwide. It is important to develop an effective genotyping tool for this cereal grain both to identify germplasm diversity and to protect the rights of breeders. Single-nucleotide polymorphism (SNP) genotyping provides a means for developing a practical, rapid, inexpensive and high-throughput assay. Here, we investigated SNPs as robust markers of genetic variation for typing wheat cultivars. We identified SNPs from an array of 9000 across a collection of 429 well-known wheat cultivars grown in China, of which 43 SNP markers with high minor allele frequency and variations discriminated the selected wheat varieties and their wild ancestors. This SNP based barcode will allow for the rapid and precise identification of wheat germplasm resources and newly released varieties and will further assist in the wheat breeding program. PMID- 26985665 TI - Identification of an Alternative Splicing Product of the Otx2 Gene Expressed in the Neural Retina and Retinal Pigmented Epithelial Cells. AB - To investigate the complexity of alternative splicing in the retina, we sequenced and analyzed a total of 115,706 clones from normalized cDNA libraries from mouse neural retina (66,217) and rat retinal pigmented epithelium (49,489). Based upon clustering the cDNAs and mapping them with their respective genomes, the estimated numbers of genes were 9,134 for the mouse neural retina and 12,050 for the rat retinal pigmented epithelium libraries. This unique collection of retinal of messenger RNAs is maintained and accessible through a web-base server to the whole community of retinal biologists for further functional characterization. The analysis revealed 3,248 and 3,202 alternative splice events for mouse neural retina and rat retinal pigmented epithelium, respectively. We focused on transcription factors involved in vision. Among the six candidates suitable for functional analysis, we selected Otx2S, a novel variant of the Otx2 gene with a deletion within the homeodomain sequence. Otx2S is expressed in both the neural retina and retinal pigmented epithelium, and encodes a protein that is targeted to the nucleus. OTX2S exerts transdominant activity on the tyrosinase promoter when tested in the physiological environment of primary RPE cells. By overexpressing OTX2S in primary RPE cells using an adeno associated viral vector, we identified 10 genes whose expression is positively regulated by OTX2S. We find that OTX2S is able to bind to the chromatin at the promoter of the retinal dehydrogenase 10 (RDH10) gene. PMID- 26985667 TI - Association between Serum Uric Acid and Mortality among Chinese Patients with Coronary Artery Disease. AB - OBJECTIVES: Several studies have investigated the association between serum uric acid (SUA) and the risks of coronary artery disease (CAD) but have yielded inconsistent results. The aim of this study was to assess whether there is an independent association of SUA with all-cause and cardiovascular disease (CVD) mortality in Chinese patients with CAD. METHODS: A prospective cohort study of 1,799 patients was conducted. Cox regression models were used to estimate the association of SUA with the risk of death. RESULTS: During a median follow-up of 3.9 years, 177 deaths were recorded and 126 of these were due to CVD. Patients in the highest SUA quartile had a 2.43-fold risk of all-cause mortality and a 2.44 fold risk of CVD mortality compared with those in the lowest quartile. In the subpopulation analysis, the association between SUA and mortality remained similar when participants were stratified by age, gender, body mass index and type of CAD. In contrast, we found a significant interaction with estimated glomerular filtration rate (eGFR). There was a stronger association between SUA and the risk of all-cause and CVD mortality among patients with an eGFR >=60 ml/min/1.73 m2, but no significant association was found in the population with an eGFR <60 ml/min/1.73 m2. CONCLUSIONS: Elevated SUA levels were positively associated with an increased risk of all-cause and CVD mortality among CAD patients. PMID- 26985668 TI - Wild Ungulate Decision-Making and the Role of Tiny Refuges in Human-Dominated Landscapes. AB - Wildlife conservation in human-dominated landscapes requires that we understand how animals, when making habitat-use decisions, obtain diverse and dynamically occurring resources while avoiding risks, induced by both natural predators and anthropogenic threats. Little is known about the underlying processes that enable wild animals to persist in densely populated human-dominated landscapes, particularly in developing countries. In a complex, semi-arid, fragmented, human dominated agricultural landscape, we analyzed the habitat-use of blackbuck, a large herbivore endemic to the Indian sub-continent. We hypothesized that blackbuck would show flexible habitat-use behaviour and be risk averse when resource quality in the landscape is high, and less sensitive to risk otherwise. Overall, blackbuck appeared to be strongly influenced by human activity and they offset risks by using small protected patches (~3 km2) when they could afford to do so. Blackbuck habitat use varied dynamically corresponding with seasonally changing levels of resources and risks, with protected habitats registering maximum use. The findings show that human activities can strongly influence and perhaps limit ungulate habitat-use and behaviour, but spatial heterogeneity in risk, particularly the presence of refuges, can allow ungulates to persist in landscapes with high human and livestock densities. PMID- 26985666 TI - Functional Connectivity of the Caudal Anterior Cingulate Cortex Is Decreased in Autism. AB - The anterior cingulate cortex (ACC) is frequently reported to have functionally distinct sub-regions that play key roles in different intrinsic networks. However, the contribution of the ACC, which is connected to several cortical areas and the limbic system, to autism is not clearly understood, although it may be involved in dysfunctions across several distinct but related functional domains. By comparing resting-state fMRI data from persons with autism and healthy controls, we sought to identify the abnormalities in the functional connectivity (FC) of ACC sub-regions in autism. The analyses found autism-related reductions in FC between the left caudal ACC and the right rolandic operculum, insula, postcentral gyrus, superior temporal gyrus, and the middle temporal gyrus. The FC (z-scores) between the left caudal ACC and the right insula was negatively correlated with the Stereotyped Behaviors and Restricted Interests scores of the autism group. These findings suggest that the caudal ACC is recruited selectively in the pathomechanism of autism. PMID- 26985670 TI - Simultaneous Determination of Glass Transition Temperatures of Several Polymers. AB - AIMS: A simple and easy optical method is proposed for the determination of glass transition temperature (Tg) of polymers. METHODS & RESULTS: Tg was determined using the technique of microsphere imaging to monitor the variation of the refractive index of polymer microsphere as a function of temperature. It was demonstrated that the method can eliminate most thermal lag and has sensitivity about six fold higher than the conventional method in Tg determination. So the determined Tg is more accurate and varies less with cooling/heating rate than that obtained by conventional methods. The most attractive character of the method is that it can simultaneously determine the Tg of several polymers in a single experiment, so it can greatly save experimental time and heating energy. CONCLUSION: The method is not only applicable for polymer microspheres, but also for the materials with arbitrary shapes. Therefore, it is expected to be broadly applied to different fundamental researches and practical applications of polymers. PMID- 26985669 TI - Natural Genetic Variation Influences Protein Abundances in C. elegans Developmental Signalling Pathways. AB - Complex traits, including common disease-related traits, are affected by many different genes that function in multiple pathways and networks. The apoptosis, MAPK, Notch, and Wnt signalling pathways play important roles in development and disease progression. At the moment we have a poor understanding of how allelic variation affects gene expression in these pathways at the level of translation. Here we report the effect of natural genetic variation on transcript and protein abundance involved in developmental signalling pathways in Caenorhabditis elegans. We used selected reaction monitoring to analyse proteins from the abovementioned four pathways in a set of recombinant inbred lines (RILs) generated from the wild-type strains N2 (Bristol) and CB4856 (Hawaii) to enable quantitative trait locus (QTL) mapping. About half of the cases from the 44 genes tested showed a statistically significant change in protein abundance between various strains, most of these were however very weak (below 1.3-fold change). We detected a distant QTL on the left arm of chromosome II that affected protein abundance of the phosphatidylserine receptor protein PSR-1, and two separate QTLs that influenced embryonic and ionizing radiation-induced apoptosis on chromosome IV. Our results demonstrate that natural variation in C. elegans is sufficient to cause significant changes in signalling pathways both at the gene expression (transcript and protein abundance) and phenotypic levels. PMID- 26985671 TI - No Spillover Effect of the Foreclosure Crisis on Weight Change: The Diabetes Study of Northern California (DISTANCE). AB - The emerging body of research suggests the unprecedented increase in housing foreclosures and unemployment between 2007 and 2009 had detrimental effects on health. Using data from electronic health records of 105,919 patients with diabetes in Northern California, this study examined how increases in foreclosure rates from 2006 to 2010 affected weight change. We anticipated that two of the pathways that explain how the spike in foreclosure rates affects weight gain increasing stress and declining salutary health behaviors- would be acute in a population with diabetes because of metabolic sensitivity to stressors and health behaviors. Controlling for unemployment, housing prices, temporal trends, and time-invariant confounders with individual fixed effects, we found no evidence of an association between the foreclosure rate in each patient's census block of residence and body mass index. Our results suggest, although more than half of the population was exposed to at least one foreclosure within their census block, the foreclosure crisis did not independently impact weight change. PMID- 26985673 TI - FoodChain-Lab: A Trace-Back and Trace-Forward Tool Developed and Applied during Food-Borne Disease Outbreak Investigations in Germany and Europe. AB - FoodChain-Lab is modular open-source software for trace-back and trace-forward analysis in food-borne disease outbreak investigations. Development of FoodChain Lab has been driven by a need for appropriate software in several food-related outbreaks in Germany since 2011. The software allows integrated data management, data linkage, enrichment and visualization as well as interactive supply chain analyses. Identification of possible outbreak sources or vehicles is facilitated by calculation of tracing scores for food-handling stations (companies or persons) and food products under investigation. The software also supports consideration of station-specific cross-contamination, analysis of geographical relationships, and topological clustering of the tracing network structure. FoodChain-Lab has been applied successfully in previous outbreak investigations, for example during the 2011 EHEC outbreak and the 2013/14 European hepatitis A outbreak. The software is most useful in complex, multi-area outbreak investigations where epidemiological evidence may be insufficient to discriminate between multiple implicated food products. The automated analysis and visualization components would be of greater value if trading information on food ingredients and compound products was more easily available. PMID- 26985672 TI - Racial Differences in Left Atrial Size: Results from the Coronary Artery Risk Development in Young Adults (CARDIA) Study. AB - Whites have an increased risk of atrial fibrillation (AF) compared to Blacks. The mechanism underlying this association is unknown. Left atrial (LA) size is an important AF risk factor, and studies in older adults suggest Whites have larger LA diameters. However, because AF itself causes LA dilation, LA size differences may be due to greater subclinical AF among older Whites. We therefore assessed for racial differences in LA size among young adults at low AF risk. The Coronary Artery Risk Development in Young Adults (CARDIA) study enrolled White and Black participants between 18 and 30 years of age. LA diameter was measured in a subset of participants using echocardiography at Year 5 (n = 4,201) and Year 25 (n = 3,373) of follow up. LA volume was also assessed at Year 5 (n = 2,489). Multivariate linear regression models were used to determine the adjusted association between race and LA size. In unadjusted analyses, mean LA diameter was significantly larger among Blacks compared to Whites both at Year 5 (35.5 +/- 4.8 mm versus 35.1 +/- 4.5 mm, p = 0.01) and Year 25 (37.4 +/- 5.1 mm versus 36.8 +/- 4.9 mm, p = 0.002). After adjusting for demographics, comorbidities, and echocardiographic parameters, Whites demonstrated an increased LA diameter (0.7 mm larger at Year 5, 95% CI 0.3-1.1, p<0.001; 0.6 mm larger at Year 25, 95% CI 0.3-1.0, p<0.001). There was no significant association between race and adjusted Year 5 LA volume. In conclusion, in a young, well-characterized cohort, the larger adjusted LA diameter among White participants suggests inherent differences in atrial structure may partially explain the higher risk of AF in Whites. The incongruent associations between race, LA diameter, and LA volume suggest that LA geometry, rather than size alone, may have implications for AF risk. PMID- 26985674 TI - Exploring Climate Niches of Ponderosa Pine (Pinus ponderosa Douglas ex Lawson) Haplotypes in the Western United States: Implications for Evolutionary History and Conservation. AB - Ponderosa pine (Pinus ponderosa Douglas ex Lawson) occupies montane environments throughout western North America, where it is both an ecologically and economically important tree species. A recent study using mitochondrial DNA analysis demonstrated substantial genetic variation among ponderosa pine populations in the western U.S., identifying 10 haplotypes with unique evolutionary lineages that generally correspond spatially with distributions of the Pacific (P. p. var. ponderosa) and Rocky Mountain (P. p. var. scopulorum) varieties. To elucidate the role of climate in shaping the phylogeographic history of ponderosa pine, we used nonparametric multiplicative regression to develop predictive climate niche models for two varieties and 10 haplotypes and to hindcast potential distribution of the varieties during the last glacial maximum (LGM), ~22,000 yr BP. Our climate niche models performed well for the varieties, but haplotype models were constrained in some cases by small datasets and unmeasured microclimate influences. The models suggest strong relationships between genetic lineages and climate. Particularly evident was the role of seasonal precipitation balance in most models, with winter- and summer-dominated precipitation regimes strongly associated with P. p. vars. ponderosa and scopulorum, respectively. Indeed, where present-day climate niches overlap between the varieties, introgression of two haplotypes also occurs along a steep clinal divide in western Montana. Reconstructed climate niches for the LGM suggest potentially suitable climate existed for the Pacific variety in the California Floristic province, the Great Basin, and Arizona highlands, while suitable climate for the Rocky Mountain variety may have existed across the southwestern interior highlands. These findings underscore potentially unique phylogeographic origins of modern ponderosa pine evolutionary lineages, including potential adaptations to Pleistocene climates associated with discrete temporary glacial refugia. Our predictive climate niche models may inform strategies for further genetic research (e.g., sampling design) and conservation that promotes haplotype compatibility with projected changes in future climate. PMID- 26985675 TI - A case of pigmented pilomatricoma (calcifying epithelioma): the role of mast cells in pigmentation. PMID- 26985676 TI - Hyperglycemia-Induced Modulation of the Physiognomy and Angiogenic Potential of Fibroblasts Mediated by Matrix Metalloproteinase-2: Implications for Venous Stenosis Formation Associated with Hemodialysis Vascular Access in Diabetic Milieu. AB - PURPOSE: It is hypothesized that venous stenosis formation associated with hemodialysis vascular-access failure is caused by hypoxia-mediated fibroblast-to myofibroblast differentiation accompanied by proliferation and migration, and that diabetic patients have worse clinical outcomes. The aim of this study was to determine the functional and gene expression outcomes of matrix metalloproteinase 2 (Mmp-2) silencing in fibroblasts cultured under hyperglycemia and euglycemia with hypoxic and normoxic stimuli. MATERIALS AND METHODS: AKR-2B fibroblasts were stably transduced using lentivirus-mediated shRNA-Mmp-2 or scrambled controls and subjected to hypoxia or normoxia under hyperglycemic or euglycemic conditions for 24 and 72 h. Gene expression of vascular endothelial growth factor-A (Vegf-A), Vegfr-1, Mmp-2, Mmp-9 and tissue inhibitors of matrix metalloproteinases (Timps) were determined by RT-PCR. Collagen I and IV secretion and cellular proliferation and migration were determined. RESULTS: Under hyperglycemic conditions, there is a significant reduction in the average gene expression of Vegf-A and Mmp-9, with an increase in Timp-1 at 24 h of hypoxia (p < 0.05) in Mmp-2-silenced fibroblasts when compared to controls. In addition, there is a decrease in collagen I and IV secretion and cellular migration. The euglycemic cells were able to reverse these findings. CONCLUSION: These findings demonstrate the rationale for using anti-Mmp 2 therapy in dialysis patients with hemodialysis vascular access in helping to reduce stenosis formation. PMID- 26985677 TI - Human alveolar epithelial cells expressing tight junctions to model the air-blood barrier. AB - This paper describes a new human alveolar epithelial cell line (hAELVi - human Alveolar Epithelial Lentivirus immortalized) with type I-like characteristics and functional tight junctions, suitable to model the air-blood barrier of the peripheral lung. Primary human alveolar epithelial cells were immortalized by a novel regimen, grown as monolayers on permeable filter supports and characterized morphologically, biochemically and biophysically. hAELVi cells maintain the capacity to form tight intercellular junctions, with high trans-epithelial electrical resistance (> 1000 Omega*cm2). The cells could be kept in culture over several days, up to passage 75, under liquid-liquid as well as air-liquid conditions. Ultrastructural analysis and real time PCR revealed type I-like cell properties, such as the presence of caveolae, expression of caveolin-1, and absence of surfactant protein C. Accounting for the barrier properties, inter digitations sealed with tight junctions and desmosomes were also observed. Low permeability of the hydrophilic marker sodium fluorescein confirmed the suitability of hAELVi cells for in vitro transport studies across the alveolar epithelium. These results suggest that hAELVi cells reflect the essential features of the air-blood barrier, as needed for an alternative to animal testing to study absorption and toxicity of inhaled drugs, chemicals and nanomaterials. PMID- 26985678 TI - Strong inflammatory response and Th1-polarization profile in children with acute lymphoblastic leukemia without apparent infection. AB - Children with acute lymphoblastic leukemia (ALL) often present fever. Febrile states are usually associated with infectious processes that generate an inflammatory response involving various molecules, including cytokines. However, an inflammatory response may also occur in the absence of infection. We hypothesized that the levels of inflammatory cytokines are increased in children with ALL without apparent infection. The serum levels of 13 cytokines in 99 patients with ALL and 48 non-oncological patients without apparent infection were measured using multiplex analyte profiling technology (Luminex(r)). The concentration of circulating pro-inflammatory cytokines associated with fever was similar between patients with ALL and fever at diagnosis and those without fever. The levels of tumor necrosis factor alpha, interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and IL-10 were higher in patients with ALL vs. the control group (P<0.05). Moreover, the levels of the T helper 1 (interferon gamma and IL-12) cytokines were higher in patients with ALL vs. the control group. Transforming growth factor beta was lower in patients with ALL vs. the control group (P<0.05). The levels of IL-1beta, IL-2, IL-4, IL-13, and IL-17 were similar in the two groups. Our results indicate that the circulating levels of seven of the important studied cytokines are elevated in patients with newly diagnosed ALL without apparent infection, reflecting a strong and deregulated inflammatory state in this disease, with a Th1-polarization profile. PMID- 26985680 TI - Interest in technology-based therapies hampered by access: A survey of veterans with serious mental illnesses. AB - OBJECTIVE: Computer technology is used in various ways to deliver and enhance health care. It is therefore important to understand technology use patterns among underserved populations such as persons with serious mental illnesses who often experience inequitable care. METHODS: A survey was administered to 210 veterans with serious mental illnesses attending programs at a Department of Veterans Affairs community care center, with data collected on demographics, psychiatric diagnoses, access, use, and willingness to use cell phones, smart phones, Internet-based online social networking, and computerized therapies. Descriptive and multivariable analyses were conducted to determine utilization and interest in different technologies. RESULTS: Although 80.4% of the respondents reported owning a cellphone, only 30.3% reported they had a computer and 13.1% reported owning a smartphone. Although 56.7% reported using the Internet and 47.6% indicated they used e-mail, 68.6% of respondents reported that they were interested in using computer programs for mental health-related problems. Older, less educated veterans, and those with alcohol use disorders were less likely to use the Internet. Veterans who were White or had PTSD diagnoses were less willing to use any computerized therapy. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Lower rates of computer use, Internet, and cell phone technologies were observed among veterans with serious mental illnesses compared to general population surveys. Sociodemographic barriers likely impede access to technology among veterans with serious mental illnesses. Providing financial resources and associated education and training to veterans with serious mental illnesses could increase access to helpful technology-based interventions in a population that traditionally experiences service gaps. (PsycINFO Database Record PMID- 26985679 TI - Use of Vaccinia Virus Smallpox Vaccine in Laboratory and Health Care Personnel at Risk for Occupational Exposure to Orthopoxviruses - Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2015. AB - On June 25, 2015, the Advisory Committee on Immunization Practices (ACIP) recommended routine vaccination with live smallpox (vaccinia) vaccine (ACAM2000) for laboratory personnel who directly handle 1) cultures or 2) animals contaminated or infected with replication-competent vaccinia virus, recombinant vaccinia viruses derived from replication-competent vaccinia strains (i.e., those that are capable of causing clinical infection and producing infectious virus in humans), or other orthopoxviruses that infect humans (e.g., monkeypox, cowpox, and variola) (recommendation category: A, evidence type 2 [Box]). Health care personnel (e.g., physicians and nurses) who currently treat or anticipate treating patients with vaccinia virus infections and whose contact with replication-competent vaccinia viruses is limited to contaminated materials (e.g., dressings) and persons administering ACAM2000 smallpox vaccine who adhere to appropriate infection prevention measures can be offered vaccination with ACAM2000 (recommendation category: B, evidence type 2 [Box]). These revised recommendations update the previous ACIP recommendations for nonemergency use of vaccinia virus smallpox vaccine for laboratory and health care personnel at risk for occupational exposure to orthopoxviruses (1). Since 2001, when the previous ACIP recommendations were developed, ACAM2000 has replaced Dryvax as the only smallpox vaccine licensed by the U.S. Food and Drug Administration (FDA) and available for use in the United States (2). These recommendations contain information on ACAM2000 and its use in laboratory and health care personnel at risk for occupational exposure to orthopoxviruses. PMID- 26985681 TI - Human-centered risk management for medical devices - new methods and tools. AB - Studies regarding adverse events with technical devices in the medical context showed, that in most of the cases non-usable interfaces are the cause for use deficiencies and therefore a potential harm for the patient and third parties. This is partially due to the lack of suitable methods for interlinking usability engineering and human-centered risk management. Especially regarding the early identification of human-induced errors and the systematic control of these failures, medical device manufacturers and in particular the developers have to be supported in order to guarantee reliable design and error-tolerant human machine interfaces (HMI). In this context, we developed the HiFEM methodology and a corresponding software tool (mAIXuse) for model-based human risk analysis. Based on a two-fold approach, HiFEM provides a task-type-sensitive modeling structure with integrated temporal relations in order to represent and analyze the use process in a detailed way. The approach can be used from early developmental stages up to the validation process. Results of a comparative study with the HiFEM method and a classical process-failure mode and effect analysis (FMEA) depict, that the new modeling and analysis technique clearly outperforms the FMEA. Besides, we implemented a new method for systematic human risk control (mAIXcontrol). Accessing information from the method's knowledge base enables the operator to detect the most suitable countermeasures for a respective risk. Forty one approved generic countermeasure principles have been indexed as a resulting combination of root causes and failures in a matrix. The methodology has been tested in comparison to a conventional approach as well. Evaluation of the matrix and the reassessment of the risk priority numbers by a blind expert demonstrate a substantial benefit of the new mAIXcontrol method. PMID- 26985682 TI - Thermodynamic effects after Diode and Er:YAG laser irradiation of grade IV and V titanium implants placed in bone - an ex vivo study. Preliminary report. AB - Many inserted implants are affected by peri-implantitis. The aim of our study was to evaluate increases in implant temperature, depending on the diameter and chemical composition of implants. In particular we measured the time it takes for the temperature of an implant to rise by 10 degrees C and evaluated laser power settings required to prevent thermal injury when an implant surface is decontaminated during the treatment of peri-implantitis. The study analysed six implants placed in porcine ribs and divided into two groups according to their diameter and chemical composition (grade IV and grade V titanium). The implants were irradiated with Diode and Er:YAG lasers using different laser parameters. The temperature was measured with a K-type thermocouple. The temperature on the implant surface rose as the laser power increased and the implant diameter decreased. The time required to increase the temperature of an implant by 10 degrees C was less than it was for titanium grade IV. The temperature gradient was below 10 degrees C for all implants treated using a laser power up to 1 W. It is important to choose the correct laser parameters, depending on the chemical composition and diameter of the implant, so that decontamination of the implant surface is thorough, effective and safe. PMID- 26985683 TI - Numerical assessment of the reduction of specific absorption rate by adding high dielectric materials for fetus MRI at 3 T. AB - The specific absorption rate (SAR) is an important issue to be considered in fetus MRI at 3 T due to the high radiofrequency energy deposited inside the body of pregnant woman. The high dielectric material (HDM) has shown its potential for enhancing B1 field and reducing SAR in MRI. The aim of this study is to assess the feasibility of SAR reduction by adding an HDM to the fetus MRI. The feasibility of SAR reduction is numerically assessed in this study, using a birdcage coil in transmission loaded with an electromagnetic pregnant woman model in the SEMCAD-EM solver. The HDMs with different geometric arrangements and dielectric constants are manually optimized. The B1+ ${B_1}^ + $ homogeneity is also considered while calculating the optimized fetus 10 g local SAR among different strategies in the application of HDM. The optimum maximum fetus 10 g local SAR was obtained as 2.25 W/kg, by using two conformal pads placed left and right with the dielectric constant to be 400, reduced by 24.75% compared to that without the HDM. It indicated that the SAR can be significantly reduced with strategic placement of the HDM and the use of HDM may provide a simple, effective and low-cost method for reducing the SAR for the fetus MRI at 3 T. PMID- 26985684 TI - Congenital diaphragmatic hernia - a Belgrade single center experience. AB - OBJECTIVE: Though the outcome for children with congenital diaphragmal hernia (CDH) is improving, management of seriously compromised respiratory and cardiovascular function remains a great challenge. The aim of this study was to review a tertiary center experience in treating children with CDH. DESIGN: Retrospective observational study from January 2005 to December 2014. SETTING: Neonatal Intensive Care Unit (NICU) of University Children Hospital (UCH), Belgrade, Serbia. PATIENTS: Children with CDH. RESULTS: The CDH was diagnosed prenatally in 23% patients. An overall survival rate was 62%. Among those patients who underwent surgical repair 29 (90%) survived. There was statistically significant difference in survival rate between operated patients and total examined population (P=0.020). Prenatally diagnosed neonates with CDH had significantly lower survival rate comparing to those who were postnatally diagnosed (20% vs. 75%; P=0.002). Fatal outcome was more frequent in patients with small birth weight comparing to those with normal birth weight (67% vs. 30%; P=0.046). CONCLUSIONS: Our center survival rate for CDH is in accordance with other reported studies. Based on our experience there are potential points for further improvement. First, further increase of prenatal detection, planning for delivery, and coordinated transfer to tertiary institution, in order to avoid transfer of near death patients. Second, preoperative management in the NICU. This could be done by more uniform implementation of current consensual guidelines in monitoring, mechanical ventilation and circulatory support of these delicate patients, together with rationale use of newer therapeutic resources. PMID- 26985685 TI - Chemical constituents and antiproliferative effects of cultured Mougeotia nummuloides and Spirulina major against cancerous cell lines. AB - In this study, the effect of Mougeotia nummuloides and Spirulina major on Vero cells (African green monkey kidney), C6 cells (rat brain tumor cells) and HeLa cells (human uterus carcinoma) was investigated in vitro. The antiproliferative effect of the methanol extract of M. nummuloides and S. major compared with 5 fluorourasil (5-FU) and cisplatin was tested at various concentrations using the BrdU Cell Proliferation ELISA. Both M. nummuloides and S. major extracts significantly inhibited the proliferation of Vero, HeLa and C6 cancer cell lines with IC50 and IC75 values. The M. nummuloides extract exhibited higher activity than 5-FU and cisplatin on Vero and C6 cells at high concentrations. The S. major extract revealed better antifproliferative activity than standards against Vero cells at 500 MUg/mL. The compounds of methanol extracts were determined by GC-MS after the silylation process. Trehalose, monostearin and 1-monopalmitin were detected as major products in the M. nummuloides extract where as in the S. major extract; monostearin, 1-monopalmitin and hexyl alcohol were the main constituents. PMID- 26985686 TI - Hybrid minigene splicing assay verified the pathogenicity of a novel splice site variant in the dystrophin gene of a Chinese patient with typical Duchenne muscular dystrophy phenotype. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is typically caused by disrupting the reading frame of the dystrophin gene: approximately 70%-80% of mutational events are represented by deletions or duplications of one or more exons in the dystrophin gene, and the remaining cases by subtle mutations, including point mutations, small indels, small inversions, and complex small rearrangements. The dystrophin gene is the largest known gene with one of the highest known rates of new mutations. METHODS: Deletions and duplications were detected in the DMD gene of the proband by using multiple ligation-dependent probe amplification (MLPA). Targeted next-generation sequencing (NGS) was used in the subtle mutation detection, followed by Sanger sequencing confirmation. The effect of the mutation on the splicing of the DMD gene was assessed by bioinformatics prediction and hybrid minigene splicing assay (HMSA). RESULTS: Neither duplication nor deletion was found in the DMD gene of the proband. While a novel splice site mutation c.6762+1G>C was identified in the proband by NGS and Sanger sequencing, and his mother was heterozygous at the same site. Bioinformatics predicted that the 5' donor splice site of intron 46 disappeared because of the mutation, which would lead to aberrant splicing and introduce premature stop codon. The HMSA results were in agreement with the prediction. CONCLUSIONS: The novel splice site mutation caused DMD in the proband by aberrant splicing. We suggested that combined applications of MLPA, NGS, HMSA and bioinformatics are comprehensive and effective methods for diagnosis and aberrant splicing study of DMD. PMID- 26985687 TI - Molecular diagnosis and precision medicine in allergy management. AB - Precision medicine (PM) can be defined as a structural model aimed at customizing healthcare, with medical decisions/products tailored on an individual patient at a highly detailed level. In this sense, allergy diagnostics based on molecular allergen components allows to accurately define the patient's IgE repertoire. The availability of highly specialized singleplexed and multiplexed platforms support allergists with an advanced diagnostic armamentarium. The therapeutic intervention, driven by the standard diagnostic approach, but further supported by these innovative tools may result, for instance, in a more appropriate prescription of allergen immunotherapy (AIT). Also, the phenotyping of patients, which may have relevant effects on the treatment strategy, could be take advantage by the molecular allergy diagnosis. PMID- 26985688 TI - The dietary protein, IGF-I, skeletal health axis. AB - Dietary protein represents an important nutrient for bone health and thereby for the prevention of osteoporosis. Besides its role as a brick provider for building the organic matrix of skeletal tissues, dietary protein stimulates the production of the anabolic bone trophic factor IGF-I (insulin-like growth factor I). The liver is the main source of circulating IGF-I. During growth, protein undernutrition results in reduced bone mass and strength. Genetic defect impairing the production of IGF-I markedly reduces bone development in both length and width. The serum level of IGF-I markedly increases and then decreases during pubertal maturation in parallel with the change in bone growth and standing height velocity. The impact of physical activity on bone structure and strength is enhanced by increased dietary protein consumption. This synergism between these two important environmental factors can be observed in prepubertal boys, thus modifying the genetically determined bone growth trajectory. In anorexia nervosa, IGF-I is low as well as bone mineral mass. In selective protein undernutrition, there is a resistance to the exogenous bone anabolic effect of IGF-I. A series of animal experiments and human clinical trials underscore the positive effect of increased dietary intake of protein on calcium-phosphate economy and bone balance. On the contrary, the dietary protein-induced acidosis hypothesis of osteoporosis is not supported by several experimental and clinical studies. There is a direct effect of amino acids on the local production of IGF-I by osteoblastic cells. IGF-I is likely the main mediator of the positive effect of parathyroid hormone (PTH) on bone formation, thus explaining the reduction in fragility fractures as observed in PTH-treated postmenopausal women. In elderly women and men, relatively high protein intake protects against spinal and femoral bone loss. In hip fracture patients, isocaloric correction of the relatively low protein intake results in: increased IGF-I serum level, significant attenuation of postsurgical bone loss, improved muscle strength, better recovery, and shortened hospital stay. Thus, dietary protein contributes to bone health from early childhood to old age. An adequate intake of protein should be recommended in the prevention and treatment of osteoporosis. PMID- 26985689 TI - The pathophysiological basis of bone tissue alterations associated with eating disorders. AB - Anorexia nervosa (AN) and obesity are two major eating disorders present nowadays in Western countries. They are both characterized by striking body composition variations and hormonal alterations, which impact on skeletal metabolism, inducing bone tissue modifications and, thus, often cause an increased risk for fractures. AN and obesity are characterized by a severe reduction in fat mass and a high expression of it, respectively, and in both conditions hormones secreted or modulated by body fat content are important determinants of low bone density, impaired bone structure and reduced bone strength. In addition, in both AN and obesity, increased marrow adiposity, which correlates with low bone density, has been observed. This review will discuss the pathophysiological basis of bone alterations associated with AN and obesity, conditions of extreme energy deficiency and excess, respectively. PMID- 26985690 TI - Double-Strand Displacement Biosensor and Quencher-Free Fluorescence Strategy for Rapid Detection of MicroRNA. AB - We describe a facile quencher-free fluorescence strategy for rapid detection of microRNAs (miRNAs) by using a novel double-strand displacement sensor. The sensor is designed with an outstanding 2-aminopurine (2-AP) fluorophore as a probe and a predesigned cDNA, which can completely complement the target miRNA and partly complement the 2-AP probe. When the target miRNA is added, the cDNA can be competed off from the cDNA?2-AP probe duplex, thereby forming a cDNA?RNA heteroduplex. The free 2-AP probe induces an increase in the fluorescent signal. A limit of detection of 5 nM and a wide linear range from 5 to 1000 nM (R(2) = 0.9971) are achieved by this assay. The rapid detection strategy can be accomplished within 2 h without expensive nanoparticles and complicated instruments for the whole procedure, thus, offering a significant potential for clinical application. PMID- 26985691 TI - Synthesis and inhibitory properties of some carbamates on carbonic anhydrase and acetylcholine esterase. AB - A series of carbamate derivatives were synthesized and their carbonic anhydrase I and II isoenzymes and acetylcholinesterase enzyme (AChE) inhibitory effects were investigated. All carbamates were synthesized from the corresponding carboxylic acids via the Curtius reactions of the acids with diphenyl phosphoryl azide followed by addition of benzyl alcohol. The carbamates were determined to be very good inhibitors against for AChE and hCA I, and II isoenzymes. AChE inhibition was determined in the range 0.209-0.291 nM. On the other hand, tacrine, which is used in the treatment of Alzheimer's disease possessed lower inhibition effect (Ki: 0.398 nM). Also, hCA I and II isoenzymes were effectively inhibited by the carbamates, with inhibition constants (Ki) in the range of 4.49-5.61 nM for hCA I, and 4.94-7.66 nM for hCA II, respectively. Acetazolamide, which was clinically used carbonic anhydrase (CA) inhibitor demonstrated Ki values of 281.33 nM for hCA I and 9.07 nM for hCA II. The results clearly showed that AChE and both CA isoenzymes were effectively inhibited by carbamates at the low nanomolar levels. PMID- 26985692 TI - Purification and Characterization of Plantaricin JLA-9: A Novel Bacteriocin against Bacillus spp. Produced by Lactobacillus plantarum JLA-9 from Suan-Tsai, a Traditional Chinese Fermented Cabbage. AB - Bacteriocins are ribosomally synthesized peptides with antimicrobial activity produced by numerous bacteria. A novel bacteriocin-producing strain, Lactobacillus plantarum JLA-9, isolated from Suan-Tsai, a traditional Chinese fermented cabbage, was screened and identified by its physiobiochemical characteristics and 16S rDNA sequence analysis. A new bacteriocin, designated plantaricin JLA-9, was purified using butanol extraction, gel filtration, and reverse-phase high-performance liquid chromatography. The molecular mass of plantaricin JLA-9 was shown to be 1044 Da by MALDI-TOF-MS analyses. The amino acid sequence of plantaricin JLA-9 was predicted to be FWQKMSFA by MALDI-TOF MS/MS, which was confirmed by Edman degradation. This bacteriocin exhibited broad spectrum antibacterial activity against Gram-positive and Gram-negative bacteria, especially Bacillus spp., high thermal stability (20 min, 121 degrees C), and narrow pH stability (pH 2.0-7.0). It was sensitive to alpha-chymotrypsin, pepsin, alkaline protease, and papain. The mode of action of this bacteriocin responsible for outgrowth inhibition of Bacillus cereus spores was studied. Plantaricin JLA-9 had no detectable effects on germination initiation over 1 h on monitoring the hydration, heat resistance, and 2,6-pyridinedicarboxylic acid (DPA) release of spores. Rather, germination initiation is a prerequisite for the action of plantaricin JLA-9. Plantaricin JLA-9 inhibited growth by preventing the establishment of oxidative metabolism and disrupting membrane integrity in germinating spores within 2 h. The results suggest that plantaricin JLA-9 has potential applications in the control of Bacillus spp. in the food industry. PMID- 26985693 TI - Naked Polyamidoamine Polymers Intrinsically Inhibit Angiotensin II-Mediated EGFR and ErbB2 Transactivation in a Dendrimer Generation- and Surface Chemistry Dependent Manner. AB - The effects of naked polyamidoamine (PAMAM) dendrimers on renin-angiotensin system (RAS) signaling via Angiotensin (Ang) II-mediated transactivation of the epidermal growth factor receptor (EGFR) and the closely related family member ErbB2 (HER2) were investigated. In primary aortic vascular smooth muscle cells, a cationic fifth-generation (G5) PAMAM dendrimer dose- and time-dependently inhibited Ang II/AT1 receptor-mediated transactivation of EGFR and ErbB2 as well as their downstream signaling via extracellular-regulated kinase 1/2 (ERK1/2). Inhibition even occurred at noncytotoxic concentrations at short (1 h) exposure times and was dependent on dendrimer generation (G7 > G6 > G5 > G4) and surface group chemistry (amino > carboxyl > hydroxyl). Mechanistically, the cationic G5 PAMAM dendrimer inhibited Ang II-mediated transactivation of EGFR and ErbB2 via inhibition of the nonreceptor tyrosine kinase Src. This novel, early onset, intrinsic biological action of PAMAM dendrimers as inhibitors of the Ang II/AT1/Src/EGFR-ErbB2/ERK1/2 signaling pathway could have important toxicological and pharmacological implications. PMID- 26985694 TI - Does Graded Prognostic Assessment outperform Recursive Partitioning Analysis in patients with moderate prognosis brain metastases? AB - AIM: To compare the clinical utility of the Recursive Partitioning Analysis (RPA) and Graded Prognostic Assessment (GPA) in predicting outcomes for moderate prognosis patients with brain metastases. METHODS & MATERIALS: We reviewed 101 whole brain radiotherapy cases. RPA and GPA were calculated. Overall survival was compared. RESULTS: Sixty-eight patients had moderate prognosis. RPA patient characteristics for increased death hazard were <=10 WBRT fractions or no surgery/radiosurgery. GPA patients had increased death risk with no surgery/radiosurgery or lower Karnofsky Performance Status. CONCLUSION: The indices have similar predicted survival. Patients scored by RPA with longer radiation schedules had longer survival; patients scored by GPA did not. This indicates GPA is more clinically useful, leaving less room for subjective treatment choices. PMID- 26985695 TI - Computer Modelling Using Prehospital Vitals Predicts Transfusion and Mortality. AB - OBJECTIVE: Test computer-assisted modeling techniques using prehospital vital signs of injured patients to predict emergency transfusion requirements, number of intensive care days, and mortality, compared to vital signs alone. METHODS: This single-center retrospective analysis of 17,988 trauma patients used vital signs data collected between 2006 and 2012 to predict which patients would receive transfusion, require 3 or more days of intensive care, or die. Standard transmitted prehospital vital signs (heart rate, blood pressure, shock index, and respiratory rate) were used to create a regression model (PH-VS) that was internally validated and evaluated using area under the receiver operating curve (AUROC). Transfusion records were matched with blood bank records. Documentation of death and duration of intensive care were obtained from the trauma registry. RESULTS: During the course of their hospital stay, 720 of the 17,988 patients in the study population died (4%), 2,266 (12.6%) required at least a 3-day stay in the intensive care unit (ICU), 1,171 (6.5%) required transfusions, and 210 (1.2%) received massive transfusions. The PH-VS model significantly outperformed any individual vital sign across all outcomes (average AUROC = 0.82), The PH-VS model correctly predicted that 512 of 777 (65.9%) and 580 of 931 (62.3%) patients in the study population would receive transfusions within the first 2 and 6 hours of admission, respectively. CONCLUSIONS: The predictive ability of individual vital signs to predict outcomes is significantly enhanced with the model. This could support prehospital triage by enhancing decision makers' ability to match critically injured patients with appropriate resources with minimal delays. PMID- 26985696 TI - Comparison of effect between high intense focused ultrasound devices for facial tightening: Evaluator-blinded, split-face study. AB - BACKGROUND: Various high intense focused ultrasound (HIFU) devices have been introduced in recent years for improving skin laxity, with satisfactory results. However, there is no comparative study on the efficacy and safety of available HIFU devices. OBJECTIVE: To compare the efficacy and safety of two HIFU devices for facial skin tightening and subsequently, to validate the quantitative assessment. METHODS AND MATERIALS: We performed a split-face comparative study in 20 Korean patients. Two different HIFU devices were used on each side of the face. Patients received one treatment session on the same number of coagulative zones. Patient assessments were recorded. Three blinded clinicians evaluated paired pretreatment and post-treatment photographs. Quantitative assessment using a fixed point as well as a variable point was additionally performed for objective evaluation. RESULTS: Qualitative assessments of both HIFU devices conducted by both clinicians and patients generally showed mild to moderate improvement, similar to previous studies. The two devices had similar efficacy in blinded clinician and quantitative assessment, although there were some differences in patient satisfaction and degree of pain. There was a correlation between clinician qualitative scores and quantitative values, which suggests successful skin tightening. CONCLUSION: To the author's knowledge, both HIFU devices tested can be used safely and effectively for facial tightening. PMID- 26985697 TI - Planning sentences while doing other things at the same time: effects of concurrent verbal and visuospatial working memory load. AB - This study investigated to what extent advance planning during sentence production is affected by a concurrent cognitive load. In two picture-word interference experiments in which participants produced subject-verb-object sentences while ignoring auditory distractor words, we assessed advance planning at a phonological (lexeme) and at an abstract-lexical (lemma) level under visuospatial or verbal working memory (WM) load. At the phonological level, subject and object nouns were found to be activated before speech onset with concurrent visuospatial WM load, but only subject nouns were found to be activated with concurrent verbal WM load, indicating a reduced planning scope as a function of type of WM load (Experiment 1). By contrast, at the abstract lexical level, subject and object nouns were found to be activated regardless of type of concurrent load (Experiment 2). In both experiments, sentence planning had a more detrimental effect on concurrent verbal WM task performance than on concurrent visuospatial WM task performance. Overall, our results suggest that advance planning at the phonological level is more affected by a concurrently performed verbal WM task than advance planning at the abstract-lexical level. Also, they indicate an overlap of resources allocated to phonological planning in speech production and verbal WM. PMID- 26985698 TI - Membrane-Anchored Cyclic Peptides as Effectors of Mitochondrial Oxidative Phosphorylation. AB - The echinocandins are membrane-anchored, cyclic lipopeptides (CLPs) with antifungal activity due to their ability to inhibit a glucan synthase located in the plasma membrane of fungi such as Candida albicans. A hydrophobic tail of an echinocandin CLP inserts into a membrane, placing a six-amino acid cyclic peptide near the membrane surface. Because processes critical for the function of the electron transfer complexes of mitochondria, such as proton uptake and release, take place near the surface of the membrane, we have tested the ability of two echinocandin CLPs, caspofungin and micafungin, to affect the activity of electron transfer complexes in isolated mammalian mitochondria. Indeed, caspofungin and micafungin both inhibit whole chain electron transfer in isolated mitochondria at low micromolar concentrations. The effects of the CLPs are fully reversible, in some cases simply via the addition of bovine serum albumin to bind the CLPs via their hydrophobic tails. Each CLP affects more than one complex, but they still exhibit specificity of action. Only caspofungin inhibits complex I, and the CLP inhibits liver but not heart complex I. Both CLPs inhibit heart and liver complex III. Caspofungin inhibits complex IV activity, while, remarkably, micafungin stimulates complex IV activity nearly 3-fold. Using a variety of assays, we have developed initial hypotheses for the mechanisms by which caspofungin and micafungin alter the activities of complexes IV and III. The dication caspofungin partially inhibits cytochrome c binding at the low-affinity binding site of complex IV, while it also appears to inhibit the release of protons from the outer surface of the complex, similar to Zn(2+). Anionic micafungin appears to stimulate complex IV activity by enhancing the transfer of protons to the O2 reduction site. For complex III, we hypothesize that each CLP binds to the cytochrome b subunit and the Fe-S subunit to inhibit the required rotational movement of the latter. PMID- 26985699 TI - Long-Range Energy Transport via Plasmonic Propagation in a Supramolecular Organic Waveguide. AB - Energy transport in organic materials is dependent on the coherent migration of optically induced excited states. For instance, in active organic waveguides, the tight packing of dye molecules allows delocalization of excitons over a distance generally limited to at most several hundred nanometers. Here, we demonstrate an alternative mechanism of energy transport in a triarylamine-based supramolecular organic waveguide that is plasmonic in nature and results in coherent energy propagation superior to 10 MUm. The optical, electric, and magnetic properties of the doped material support the presence of metallic electrons that couple with and transport incident light. These results show that organic metals constitute a novel class of materials with efficient energy transport and are of potential interest for optoelectronics, plasmonics, and artificial light-energy harvesting systems. PMID- 26985700 TI - Dexamethasone Implant for the Treatment of Type 1 Idiopathic Macular Telangiectasia. AB - PURPOSE: To report our results of 4 patients about the efficacy and safety of intravitreal dexamethasone implant for type 1 idiopathic macular telangiectasia (IMT). METHODS: Four patients' charts with type 1 IMT treated with intravitreal dexamethasone implant were retrospectively reviewed. All patients underwent full ophthalmic examination including best corrected visual acuity (BCVA), spectral domain optical coherence tomography, and fluorescein angiography. BCVA, central macular thickness (CMT), and macular volume (MV) were evaluated. RESULTS: The median BCVA was logMAR 0.55 (range 0.2-1.3) at baseline, improved to logMAR 0.45 (range 0.2-1) at 2 months after the first injection, and deteriorated to logMAR 0.7 (range 0.2-1) at final visit. The median CMT was 393 MUm (range 283-410 MUm) and MV was 2.70 mm(3) (range 1.96-2.87 mm(3)) at baseline. Two months after the first injection median CMT decreased to 327 MUm (range 269-356 MUm) and MV decreased to 2.45 mm(3) (range 1.93-2.57 mm(3)). At final visit median CMT slightly increased to 342 MUm (range 258-444 MUm) and MV slightly increased to 2.56 mm(3) (range 1.93-2.89 mm(3)). None of the changes were statistically significant. CONCLUSION: Considering the effects of dexamethasone on macular edema intravitreal dexamethasone implant can be used in selected cases. Randomized clinical trials with larger sample size are needed for further evaluation. PMID- 26985701 TI - Quality of information for women seeking breast augmentation in the Internet. AB - Background Recently published data show that many women interested in breast augmentation (BA) actively search the Internet for information. The Internet is currently the main source of information on this topic. Objectives Little is known about the quality of available information on the Internet concerning BA. The goal was to evaluate this in a systematic manner using a validated and reproducible tool. Methods Women (n = 96) unrelated to medicine were asked which keywords they would use to search the Internet if they were interested in BA. Five keywords were used. Qualitative and quantitative assessment was performed with the modified Ensuring Quality Information for Patients (EQIP) tool. A total of 2500 websites containing information on BA were identified using Google, Bing, Yahoo, Ask, and AOL. Results Out of 623 eligible websites, only 153 (25%) addressed more than 20 EQIP items. Scores were higher for encyclopaedias and academic websites compared to hospital and practitioner websites. The median EQIP score was only 15 (IQR = 12-20), and quantitative postoperative morbidity and mortality risk estimates were available in only 38% and 25% of the websites, respectively. Major complications (e.g. capsular contraction, implant safety) were mentioned in only 156 (25%) of the websites. Conclusions This is the first assessment of online patient information on BA using the EQIP tool. This analysis demonstrated several shortcomings in the quality of information provided to BA candidates. There is an immediate need for better informative and educational websites regarding BA procedures that are compatible with international quality standards for plastic surgery. PMID- 26985702 TI - Laparoscopic cholecystostomy tube-guided hepatotomy and cholecystolithotomy: alternative strategy for treatment of severe chronic cholecystitis. AB - Laparoscopic cholecystectomy can be a challenging procedure in gallbladders with chronic disease. We describe a patient with chronic cholecystitis and difficult visualisation of the gallbladder at surgery who underwent laparoscopic hepatotomy along the drainage tube of the cholecystostomy. In this way, the gallbladder was identified to avoid non-visualisation of ductal anatomy. This exceptional solution should be added to the surgical options if anatomical recognition is difficult and complete removal of the gallbladder is too risky. PMID- 26985705 TI - Physical and social factors determining quality of life for veterans with lower limb amputation(s): a systematic review. AB - PURPOSE: Most veterans live for many years after their war-related traumatic lower-limb amputation, which is why understanding which factors influence health related quality of life (HRQoL) remains important to their long-term management. The objective of this study was to perform a review of the literature to summarize any evidence on the physical and social determinants for HRQoL in veterans with uni- or bilateral lower-limb amputation(s). METHOD: MEDLINE, EMBASE, PEDro, CINAHL, Scopus and Cochrane databases were searched systematically for eligible studies. Inclusion criteria were: traumatic lower-limb amputation(s), HRQoL outcome and veterans. Physical and social factors that influence HRQoL were extracted. RESULTS: The literature search identified 2073 citations, leading to the inclusion of 10 studies in the systematic review. Physical activity level, sport participation, level of amputation, back pain, years of education, as well as duration and severity of phantom pain were found to be determining factors for HRQoL among veterans with lower-limb amputation. CONCLUSIONS: The identified physical and social determinants were similar to those found in civilian traumatic amputees. More high quality research designs, interventions and complex statistical analyses are warranted to identify the physical and social factors that influence the HRQoL of veteran amputees. Implications for Rehabilitation Rehabilitation staff should promote physical activity and participation in sport among veterans with lower-limb amputation(s). Level of amputation, back pain severity, years of education, duration of phantom pain and severity of phantom pain have been found to be determining factors for HRQoL and should be taken into consideration when planning rehabilitation programs for veterans with lower-limb amputations. PMID- 26985703 TI - Current State and Model for Development of Technology-Based Care for Attention Deficit Hyperactivity Disorder. AB - INTRODUCTION: Care (i.e., evaluation and intervention) delivered through technology is used in many areas of mental health services, including for persons with attention deficit hyperactivity disorder (ADHD). Technology can facilitate care for individuals with ADHD, their parents, and their care providers. The adoption of technological tools for ADHD care requires evidence-based studies to support the transition from development to integration into use in the home, school, or work for persons with the disorder. The initial phase, which is development of technological tools, has begun in earnest; however, the evidence base for many of these tools is lacking. In some instances, the uptake of a piece of technology into home use or clinical practice may be further along than the research to support its use. METHODS: In this study, we review the current evidence regarding technology for ADHD and also propose a model to evaluate the support for other tools that have yet to be tested. RESULTS: We propose using the Research Domain Criteria as a framework for evaluating the tools' relationships to dimensions related to ADHD. CONCLUSION: This article concludes with recommendations for testing new tools that may have promise in improving the evaluation or treatment of persons with ADHD. PMID- 26985707 TI - fMRI investigation of working memory in adolescents with surgically treated congenital heart disease. AB - Adolescents and young adults with surgically treated congenital heart disease (CHD) have been shown to exhibit difficulties with executive functions; however, the neural underpinnings of these impairments have not been previously examined with functional magnetic resonance imaging (fMRI). The current study employed fMRI to examine the neural mechanisms during a letter n-back task of working memory compared to vigilance. Seventeen participants with CHD (Mage = 17.76 +/- 1.72 years; 88% Caucasian; 30% female; mean IQ = 104.12 +/- 15.15) were compared to 17 controls (Mage = 18.40 +/- 1.74 years; 70% Caucasian; 30% female; mean IQ = 110.59 +/- 5.28) with similar declining performance as the n-back became more challenging. Overall, both groups activated similar frontal-parietal working memory networks as seen in previous literature; however, some significant differences were detected between the groups. Specifically, the participants with CHD demonstrated differences within the left precuneus and the right inferior frontal gyrus. Secondary analyses indicated that this difference appeared to be due to less task-induced deactivation (TID) in the CHD group during working memory and greater working-memory TID in the control group. In CHD, prefrontal fMRI deactivation on working-memory tasks correlated with improved working-memory performance. Future complementary neuroimaging research with functional connectivity is warranted to further examine the neural underpinnings of disrupted executive function in the long-term outcomes of CHD. PMID- 26985706 TI - ABCE1 is essential for S phase progression in human cells. AB - ABCE1 is a highly conserved protein universally present in eukaryotes and archaea, which is crucial for the viability of different organisms. First identified as RNase L inhibitor, ABCE1 is currently recognized as an essential translation factor involved in several stages of eukaryotic translation and ribosome biogenesis. The nature of vital functions of ABCE1, however, remains unexplained. Here, we study the role of ABCE1 in human cell proliferation and its possible connection to translation. We show that ABCE1 depletion by siRNA results in a decreased rate of cell growth due to accumulation of cells in S phase, which is accompanied by inefficient DNA synthesis and reduced histone mRNA and protein levels. We infer that in addition to the role in general translation, ABCE1 is involved in histone biosynthesis and DNA replication and therefore is essential for normal S phase progression. In addition, we analyze whether ABCE1 is implicated in transcript-specific translation via its association with the eIF3 complex subunits known to control the synthesis of cell proliferation-related proteins. The expression levels of a few such targets regulated by eIF3A, however, were not consistently affected by ABCE1 depletion. PMID- 26985713 TI - High-speed detection of DNA translocation in nanopipettes. AB - We present a high-speed electrical detection scheme based on a custom-designed CMOS amplifier which allows the analysis of DNA translocation in glass nanopipettes on a microsecond timescale. Translocation of different DNA lengths in KCl electrolyte provides a scaling factor of the DNA translocation time equal to p = 1.22, which is different from values observed previously with nanopipettes in LiCl electrolyte or with nanopores. Based on a theoretical model involving electrophoresis, hydrodynamics and surface friction, we show that the experimentally observed range of p-values may be the result of, or at least be affected by DNA adsorption and friction between the DNA and the substrate surface. PMID- 26985709 TI - Autophagy Plays a Protective Role in Tumor Necrosis Factor-alpha-Induced Apoptosis of Bone Marrow-Derived Mesenchymal Stem Cells. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) are being broadly investigated for treating numerous inflammatory diseases. However, the low survival rate of BMSCs during the transplantation process has limited their application. Autophagy can maintain cellular homeostasis and protect cells against environmental stresses. Tumor necrosis factor-alpha (TNF-alpha) is an important inflammatory cytokine that can induce both autophagy and apoptosis of BMSCs. However, the actual role of autophagy in TNF-alpha-induced apoptosis of BMSCs remains poorly understood. In the current study, BMSCs were treated with TNF-alpha/cycloheximide (CHX), and cell death was examined by the Cell Counting Kit-8, Hoechst 33342 staining, and flow cytometric analysis as well as by the level of caspase-3 and caspase-8. Meanwhile, autophagic flux was examined by analyzing the level of microtubule-associated protein light chain 3 B (LC3B)-II and SQSTEM1/p62 and by examining the amount of green fluorescent protein-LC3B by fluorescence microscopy. Then, the cell death and autophagic flux of BMSCs were examined after pretreatment and cotreatment with 3-methyladenine (3-MA, autophagy inhibitor) or rapamycin (Rap, autophagy activator) together with TNF-alpha/CHX. Moreover, BMSCs pretreated with lentiviruses encoding short hairpin RNA of beclin-1 (BECN1) were treated with TNF-alpha/CHX, and then cell death and autophagic flux were detected. We showed that BMSCs treated with TNF-alpha/CHX presented dramatically elevated autophagic flux and cell death. Furthermore, we showed that 3-MA and shBECN1 treatment accelerated TNF-alpha/CHX-induced apoptosis, but that Rap treatment ameliorated cell death. Our results demonstrate that autophagy protects BMSCs against TNF-alpha-induced apoptosis. Enhancing the autophagy of BMSCs may elevate cellular survival in an inflammatory microenvironment. PMID- 26985714 TI - Two-semiconductive-component hybrid coordination polymers with controllable photo induced electron-transfer properties. AB - Two semiconductive inorganic-organic hybrid coordination polymers constructed from metal iodide clusters and naphthalene diimide semiconductive components, [Cu2I2(DPNDI)]n () and [PbI2(DPNDI)]n () (DPNDI = N,N'-di-(4-pyridyl)-1,4,5,8 naphthalene diimide), have been synthesized and characterized. Although possessing similar 2D heterostructures, hybrids exhibited different photo-induced electron-transfer properties. Due to the higher HOMO energy level of the [Cu2I2]n chain than that of the [PbI2]n cluster, only hybrid can easily undergo intramolecular electron transfer to form a long-lived charge separated state, which may be applied in artificial photosynthesis. PMID- 26985708 TI - Curcumin inhibits tumor epithelial-mesenchymal transition by downregulating the Wnt signaling pathway and upregulating NKD2 expression in colon cancer cells. AB - Tumor invasion and metastasis are closely associated with epithelial-mesenchymal transition (EMT). EMT refers to epithelial cells under physiological and pathological conditions that are specific to mesenchymal transition. Curcumin inhibits EMT progression via Wnt signaling. The Wnt signaling pathway is a conservative EMT-related signaling pathway that is involved in the development of various tumors. In the present study, MTS assays were employed to analyze the proliferation of curcumin-treated cells. Naked cuticle homolog 2 (NKD2), chemokine receptor 4 (CXCR4) and antibodies associated with EMT were examined in SW620 colorectal cancer cell lines using western blot analysis and real-time qPCR. NKD2 small-interfering RNA (siRNA) and CXCR4 expression plasmid was synthesized and transfected into the colorectal cancer cell lines, and NKD2 and CXCR4 expression levels were detected. The results showed that curcumin significantly inhibited the proliferation of colorectal cancer cells and upregulated the expression of NKD2 in SW620 colorectal cancer cells and in the xenograft, resulting in the downregulation of key markers in the Wnt signaling. In addition, the progression of ETM was inhibited due to the overexpression of E cadherin as well as the downregulation of vimentin. Curcumin also inhibited tumor metastasis by downregulating the expression of CXCR4 significantly. The results suggested involvement of the NKD2-Wnt-CXCR4 signaling pathway in colorectal cancer cells. In addition, curcumin is inhibit this signaling and the development of colorectal cancer. PMID- 26985716 TI - Valsartan ameliorates podocyte loss in diabetic mice through the Notch pathway. AB - The Notch pathway is known to be linked to diabetic nephropathy (DN); however, its underlying mechanism was poorly understood. In the present study, we examined the effect of Valsartan, an angiotensin II type 1 receptor antagonist, on the Notch pathway and podocyte loss in DN. Diabetes was induced in mice by an intraperitoneal injection of streptozotocin and and this was followed by treatment with Valsartan. Levels of blood glucose, kidney weight and body weight, as well as proteinuria were measured. Samples of the kidneys were also histologically examined. The relative levels of Jagged1, Notch1, Notch intracellular domain 1 (NICD1), Hes family BHLH transcription factor 1 (Hes1) and Hes-related family BHLH transcription factor with YRPW motif 1 expression (Hey1) in the glomeruli were determined by immunohistochemical analysis, western blot analysis and RT-qPCR. The B-Cell CLL/Lymphoma 2 (Bcl-2) and p53 pathways were examined by western blot analysis. Apoptosis and detachment of podocytes from the glomerular basement membrane were examined using a TUNEL assay, flow cytometric analysis and ELISA. The number of podocytes was quantified by measuring Wilms tumor-1 (WT-1) staining. We noted that the expression of Jagged1, Notch1, NICD1, Hes1 and Hey1 was increased in a time-dependent manner in the glomeruli of mice with streptozotocin (STZ)-induced diabetes. Moreover, in diabetic mice, Valsartan significantly reduced kidney weight and proteinuria, and mitigated the pathogenic processes in the kidneys. Valsartan also inhibited the activation of Notch, Bcl-2 and p53 pathways and ameliorated podocyte loss in the glomeruli of mice with STZ induced diabetes. Taken together, these findings indicated that Valsartan exerted a beneficial effect on reducing podocyte loss, which is associated with inhibition of Notch pathway activation in the glomeruli of diabetic mice. PMID- 26985715 TI - Loss of Runt-related transcription factor 3 induces resistance to 5-fluorouracil and cisplatin in hepatocellular carcinoma. AB - Runt-related transcription factor 3 (RUNX3) is known to function as a tumor suppressor in gastric cancer and other types of cancers, including hepatocellular carcinoma (HCC). However, its role has not been fully elucidated. In the present study, we aimed to evaluate the role of RUNX3 in HCC. We used the human HCC cell lines Hep3B, Huh7 and HLF; RUNX3 cDNA was introduced into Hep3B and Huh7 cells, which were negative for endogenous RUNX3 expression, and RUNX3 siRNA was transfected into HLF cells, which were positive for endogenous RUNX3. We analyzed the expression of RUNX3 and multidrug resistance-associated protein (MRP) by immunoblotting. MTT assays were used to determine the effects of RUNX3 expression on 5-fluorouracil (5-FU) and cisplatin (CDDP) sensitivity. Finally, 23 HCC specimens resected from patients with HCC at Okayama University Hospital were analyzed, and correlations among immunohistochemical expression of RUNX3 protein and MRP protein were evaluated in these specimens. Exogenous RUNX3 expression reduced the expression of MRP1, MRP2, MRP3 and MRP5 in the RUNX3-negative cells, whereas knockdown of RUNX3 in the HLF cells stimulated the expression of these MRPs. An inverse correlation between RUNX3 and MRP expression was observed in the HCC tissues. Importantly, loss of RUNX3 expression contributed to 5-FU and CDDP resistance by inducing MRP expression. These data have important implications in the study of chemotherapy resistance in HCC. PMID- 26985717 TI - A single flexible RNAPII-CTD integrates many different transcriptional programs. AB - The RNAPII-CTD functions as a binding platform for coordinating the recruitment of transcription associated factors. Altering CTD function results in gene expression defects, although mounting evidence suggests that these effects likely vary among species and loci. Here we highlight emerging evidence of species- and loci-specific functions for the RNAPII-CTD. PMID- 26985718 TI - Human Hippocampal Theta Oscillations during Movement without Visual Cues. AB - The hippocampus exhibits theta oscillations when animals navigate. Vass et al. (2016) discovered that theta oscillations are also present when humans are moved through a virtual environment without sensory feedback, indicating that theta oscillations have a general role in spatial cognition beyond sensorimotor processing. PMID- 26985719 TI - A Cool Approach to Probing Speech Cortex. AB - In this issue of Neuron, Long et al. (2016) employ a novel technique of intraoperative cortical cooling in humans during speech production. They demonstrate that cooling Broca's area interferes with speech timing but not speech quality. PMID- 26985720 TI - Tracking Down Mutations Cell by Cell. AB - Using somatic cell nuclear transfer, Hazen et al. (2016) examined clonally expanded single neurons for mutations and found ~100 mutations from a variety of classes. Post-mitotic mutations in individual neurons represent an exploratory direction for finding fundamental origins of neurodegeneration. PMID- 26985721 TI - Plug-N-Play: Mechanotransduction Goes Modular. AB - Mechanosensitive ion channels initiate sensory signals by converting mechanical information into electrochemical signals. In this issue of Neuron (Zhao et al., 2016), a data-rich structure-function study on mammalian mechanosensitive Piezo channels reveals a modular protein architecture that includes a central pore module surrounded by a force-sensing module. PMID- 26985723 TI - Chloride Regulation: A Dynamic Equilibrium Crucial for Synaptic Inhibition. AB - Fast synaptic inhibition relies on tight regulation of intracellular Cl(-). Chloride dysregulation is implicated in several neurological and psychiatric disorders. Beyond mere disinhibition, the consequences of Cl(-) dysregulation are multifaceted and best understood in terms of a dynamical system involving complex interactions between multiple processes operating on many spatiotemporal scales. This dynamical perspective helps explain many unintuitive manifestations of Cl(-) dysregulation. Here we discuss how taking into account dynamical regulation of intracellular Cl(-) is important for understanding how synaptic inhibition fails, how to best detect that failure, why Cl(-) regulation is energetically so expensive, and the overall consequences for therapeutics. PMID- 26985725 TI - Melatonin attenuates hLRRK2-induced sleep disturbances and synaptic dysfunction in a Drosophila model of Parkinson's disease. AB - Sleep problems are the most common non-motor symptoms in Parkinson's disease (PD), and are more difficult to treat than the motor symptoms. In the current study, the role of human leucine-rich repeat kinase 2 (hLRRK2), the most common genetic cause of PD, was investigated with regards to sleep problems, and the therapeutic potential of melatonin in hLRRK2-associated sleep problems was explored in Drosophila. hLRRK2 was selectively expressed in the mushroom bodies (MBs) in Drosophila and sleep patterns were measured using the Drosophila Activity Monitoring System. MB expression of hLRRK2 resulted in sleep problems, presynaptic dysfunction as evidenced by reduced miniature excitatory postsynaptic current (mEPSC) and excitatory postsynaptic potential (EPSP) frequency, and excessive synaptic plasticity such as increased axon bouton density. Treatment with melatonin at 4 mM significantly attenuated the sleep problems and rescued the reduction in mEPSC and EPSP frequency in the hLRRK2 transgenic flies. The present study demonstrates that MB expression of hLRRK2 in flies recapitulates the clinical features of the sleep disturbances in PD, and that melatonin attenuates hLRRK2-induced sleep disorders and synaptic dysfunction, suggesting the therapeutic potential of melatonin in PD patients carrying LRRK2 mutations. PMID- 26985724 TI - A Role for Synaptic Input Distribution in a Dendritic Computation of Motion Direction in the Retina. AB - The starburst amacrine cell in the mouse retina presents an opportunity to examine the precise role of sensory input location on neuronal computations. Using visual receptive field mapping, glutamate uncaging, two-photon Ca(2+) imaging, and genetic labeling of putative synapses, we identify a unique arrangement of excitatory inputs and neurotransmitter release sites on starburst amacrine cell dendrites: the excitatory input distribution is skewed away from the release sites. By comparing computational simulations with Ca(2+) transients recorded near release sites, we show that this anatomical arrangement of inputs and outputs supports a dendritic mechanism for computing motion direction. Direction-selective Ca(2+) transients persist in the presence of a GABA-A receptor antagonist, though the directional tuning is reduced. These results indicate a synergistic interaction between dendritic and circuit mechanisms for generating direction selectivity in the starburst amacrine cell. PMID- 26985726 TI - Brief motivational intervention to reduce alcohol and HIV/sexual risk behavior in emergency department patients: A randomized controlled trial. AB - OBJECTIVE: Given the prevalence of co-occurring risky sexual behavior and drinking among emergency department (ED) patients, we developed a motivational intervention (MI) to address both behaviors. This study tested efficacy of a single-session MI compared to brief advice (BA) for reducing heavy drinking and condomless sex in adult ED patients screening positive for both. METHOD: We randomized 372 patients to MI (n = 184) or BA (n = 188). Alcohol and sex risk outcomes were assessed over 9 months. RESULTS: Generalized estimating equations models analyzing 327 patients with follow-up data provided strong support for efficacy of this integrated alcohol and sex-risk MI. Compared to BA, and after controlling for baseline covariates, those in MI reported significantly fewer heavy drinking days, drinks per week, and were less likely to engage in excessive drinking over follow-up (all ps < .05). MI was also favored over BA for reducing sex risk. Compared to BA, those in MI reported significantly fewer days on which they engaged in condomless sex with casual partners, had lower odds of reporting any condomless sex with a casual partner, and reported fewer days of sex under the influence of alcohol/other drugs (all ps < .05). CONCLUSION: This innovative MI was acceptable, feasible, and successfully delivered in 2 community hospitals and thus shows great promise for scalability and dissemination into complex health settings where newly insured at-risk individuals are likely to seek care. (PsycINFO Database Record PMID- 26985722 TI - Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops. AB - Understanding the mechanisms underlying autism spectrum disorders (ASDs) is a challenging goal. Here we review recent progress on several fronts, including genetics, proteomics, biochemistry, and electrophysiology, that raise motivation for forming a viable pathophysiological hypothesis. In place of a traditionally unidirectional progression, we put forward a framework that extends homeostatic hypotheses by explicitly emphasizing autoregulatory feedback loops and known synaptic biology. The regulated biological feature can be neuronal electrical activity, the collective strength of synapses onto a dendritic branch, the local concentration of a signaling molecule, or the relative strengths of synaptic excitation and inhibition. The sensor of the biological variable (which we have termed the homeostat) engages mechanisms that operate as negative feedback elements to keep the biological variable tightly confined. We categorize known ASD-associated gene products according to their roles in such feedback loops and provide detailed commentary for exemplar genes within each module. PMID- 26985729 TI - Integrating motivational interviewing with cognitive-behavioral therapy for severe generalized anxiety disorder: An allegiance-controlled randomized clinical trial. AB - OBJECTIVE: Although integrating motivational interviewing (MI) and cognitive behavioral therapy (CBT) has been recommended for treating anxiety, few well controlled tests of such integration exist. METHOD: In the present randomized trial for severe generalized anxiety disorder (GAD), we compared the efficacy of 15 sessions of CBT alone (N = 43) versus 4 MI sessions followed by 11 CBT sessions integrated with MI to address client resistance/ambivalence (N = 42). Clients were adults, predominantly female and Caucasian, with a high rate of diagnostic comorbidity. To control for allegiance, therapists were nested within treatment group and supervised separately by experts in the respective treatments. RESULTS: Piecewise multilevel models revealed no between-groups differences in outcomes from pre- to posttreatment; however, there were treatment effects over the follow-up period with MI-CBT clients demonstrating a steeper rate of worry decline (gamma = -0.13, p = .03) and general distress reduction (gamma = -0.12, p = .01) than CBT alone clients. Also, the odds of no longer meeting GAD diagnostic criteria were ~5 times higher at 12-months for clients receiving MI-CBT compared with CBT alone. There were also twice as many dropouts in CBT alone compared with MI-CBT (23% vs. 10%); a difference that approached significance (p = .09). The treatments were competently delivered, and intraclass correlations revealed negligible between-therapist effects on the outcomes. CONCLUSIONS: The findings support the integration of MI with CBT for severe GAD and point to the importance of training therapists in appropriate responsivity to in-session markers of resistance and ambivalence. (PsycINFO Database Record PMID- 26985728 TI - A randomized clinical trial of Motivational Interviewing to reduce alcohol and drug use among patients with depression. AB - OBJECTIVE: This study examined the efficacy of Motivational Interviewing (MI) to reduce hazardous drinking and drug use among adults in treatment for depression. METHOD: Randomized controlled trial based in a large outpatient psychiatry program in an integrated health care system in Northern California. The sample consisted of 307 participants ages 18 and over who reported hazardous drinking, drug use (primarily cannabis) or misuse of prescription drugs in the prior 30 days, and who scored >=5 on the Patient Health Questionnaire (PHQ-9). Participants were randomized to receive either 3 sessions of MI (1 in person and 2 by phone) or printed literature about alcohol and drug use risks (control), as an adjunct to usual outpatient depression care. Measures included alcohol and drug use in the prior 30 days and PHQ-9 depression symptoms. Participants completed baseline in-person interviews and telephone follow-up interviews at 3 and 6 months (96 and 98% of the baseline sample, respectively). Electronic health records were used to measure usual care. RESULTS: At 6 months, MI was more effective than control in reducing rate of cannabis use (p = .037); and hazardous drinking (>=4 drinks in a day for women, >=5 drinks in a day for men; p = .060). In logistic regression, assignment to MI predicted lower cannabis use at 6 months (p = .016) after controlling for covariates. Depression improved in both conditions. CONCLUSIONS: MI can be an effective intervention for cannabis use and hazardous drinking among patients with depression. (PsycINFO Database Record PMID- 26985727 TI - A church-based intervention for families to promote mental health and prevent HIV among adolescents in rural Kenya: Results of a randomized trial. AB - OBJECTIVE: To evaluate a family- and church-based intervention for adolescents and caregivers in rural Kenya to improve family relationships, reduce HIV risk, and promote mental health. METHOD: The intervention was developed using community based participatory methods and focused on strengthening family communication. Modules addressed economic, relationship, and HIV-related topics using evidence based behavioral strategies alongside culturally grounded content. A stepped wedge cluster randomized trial was conducted with 124 families (237 adolescents ages 10 to 16; 203 caregivers) from 4 churches. Participants completed interviewer-administered surveys over 5 rounds. Primary outcomes included family communication, HIV risk knowledge, self-efficacy, and beliefs. Secondary outcomes included parenting, social support, mental health, and adolescent sexual behavior. We estimated intent-to-treat effects via ordinary least squares regression with clustered standard errors. RESULTS: Relative to controls, the intervention group reported better family communication across domains at 1- and 3-months postintervention and higher self-efficacy for risk reduction skills and HIV-related knowledge at 1-month postintervention. Sexually active youth in the intervention reported fewer high-risk behaviors at 1-month postintervention, including unprotected sex or multiple partners. Male caregivers in the intervention reported higher parental involvement at both time points, and youth reported more social support from male caregivers at 3-months postintervention. No effects on secondary outcomes of parenting, social support, and mental health were detected. CONCLUSIONS: This intervention holds promise for strengthening positive family processes to protect against negative future outcomes for adolescents. Implementation with religious congregations may be a promising strategy for improving sustainability and scalability of interventions in low resource settings. (PsycINFO Database Record PMID- 26985730 TI - Exploring effective sampling design for monitoring soil organic carbon in degraded Tibetan grasslands. AB - The effects of climate change and human activities on grassland degradation and soil carbon stocks have become a focus of both research and policy. However, lack of research on appropriate sampling design prevents accurate assessment of soil carbon stocks and stock changes at community and regional scales. Here, we conducted an intensive survey with 1196 sampling sites over an area of 190 km(2) of degraded alpine meadow. Compared to lightly degraded meadow, soil organic carbon (SOC) stocks in moderately, heavily and extremely degraded meadow were reduced by 11.0%, 13.5% and 17.9%, respectively. Our field survey sampling design was overly intensive to estimate SOC status with a tolerable uncertainty of 10%. Power analysis showed that the optimal sampling density to achieve the desired accuracy would be 2, 3, 5 and 7 sites per 10 km(2) for lightly, moderately, heavily and extremely degraded meadows, respectively. If a subsequent paired sampling design with the optimum sample size were performed, assuming stock change rates predicted by experimental and modeling results, we estimate that about 5-10 years would be necessary to detect expected trends in SOC in the top 20 cm soil layer. Our results highlight the utility of conducting preliminary surveys to estimate the appropriate sampling density and avoid wasting resources due to over-sampling, and to estimate the sampling interval required to detect an expected sequestration rate. Future studies will be needed to evaluate spatial and temporal patterns of SOC variability. PMID- 26985731 TI - Anaerobic digestion of sulfate-acidified cattle slurry: One-stage vs. two-stage. AB - Two strategies to include acidified cattle manure (AcCM) in co-digestion with normal cattle manure (CM) are presented in this work. The strategies are a single thermophilic (50 degrees C) continuous stirred tank reactor (CSTR) anaerobic digestion and a two-step (65 degrees C + 50 degrees C) CSTR process. In both strategies, two different inclusion levels of H2SO4-acidified CM (10% and 20%) in co-digestion with normal CM were tested and compared with a control CSTR fed only CM. Important enhancement of methane (CH4) yield and solid reductions were observed in the thermophilic one-step CSTR working with 10% AcCM. However, a higher inclusion level of AcCM (20%) caused volatile fatty acid accumulation in the reactor and a more than 30% reduction in CH4 production. In terms of CH4 production, when 10% of AcCM was co-digested with 90% of CM, the two-step anaerobic co-digestion yielded less than the single step. During the first step of the two-step CSTR process, acidogenesis and a partial sulfate reduction were achieved. However, sulfide stripping between the first and the second step must be promoted in order to advance this technology. PMID- 26985732 TI - Ancestors of modern plant crops. AB - Recent accumulation of plant genomic resources offers the opportunity to compare modern genomes and model their evolutionary history from their reconstructed Most Recent Common Ancestors (MRCAs) that can be used as a guide to unveil the forces driving the evolutionary success of angiosperms and ultimately to perform applied translational research from models to crops. This article reviews the current state of art of recent structural comparative genomics studies through ancestral genome reconstruction, that is, the field of in silico paleogenomics. PMID- 26985733 TI - Maternal sensitivity and the empathic brain: Influences of early life maltreatment. AB - One of the most striking characteristics of early life maltreatment (ELM) is the risk of transmission across generations, which could be linked to differences in maternal behavior. Maternal sensitivity includes appropriate and positive affective exchanges between mother and child. Mothers with a history of ELM have been found to show a lower sensitivity representing a significant risk factor for maltreating their own children. 25 mothers with and 28 mothers without sexual and/or physical childhood maltreatment (as assessed with the Childhood Experience of Care and Abuse interview) and their children participated in a standardized mother-child interaction task. Videotaped interactions were rated by two independent trained raters based on the Emotional Availability Scales. In addition, empathic capabilities were assessed with the Interpersonal Reactivity Index. High resolution structural magnetic resonance brain images of the mothers were analyzed with unbiased voxel-based morphometry and correlated with maternal sensitivity. Results indicate that mothers with ELM were less sensitive in the standardized interaction with their own child. In non-maltreated control mothers, maternal sensitivity was positively related to anterior insular grey matter volume, a region which is crucially involved in emotional empathy, while there was a positive association between maternal sensitivity and grey matter volume in parts of the cognitive empathy network such as the superior temporal sulcus and temporal pole region in mothers with ELM. These results implicate that neurostructural alterations associated with poor maternal sensitivity might be a sequelae of ELM and that mothers with ELM may try to compensate deficits in emotional empathy by recruiting brain regions involved in cognitive empathy when interacting with their child. Thus, findings suggest possible coping strategies of mother with ELM to prevent an intergenerational transmission of abuse. PMID- 26985734 TI - Anticancer studies of synthesized ZnO nanoparticles against human cervical carcinoma cells. AB - A metal oxide nanoparticle has been widely investigated for its potential use in the biomedical application. The present study investigates the cytotoxicity of ZnO nanoparticle in human cervical carcinoma cells. Cell viability was determined, and it showed the possible cytotoxic effect of ZnO nanoparticles. The characteristic apoptotic features such as rounding and loss of adherence were observed in the treated cells. Fluorescence and Confocal Laser Scanning Microscope (CLSM) studies have showed reduced nuclear volume and condensed cytoplasm. The mRNA expression of apoptotic gene p53 and caspase 3 was up regulated following ZnO nanoparticle exposure, which confirms the occurrence of apoptosis at the transcriptional level. Reactive oxygen species (ROS) was increased in a dose-dependent manner, and initiate lipid peroxidation of the liposomal membrane, which in turn regulate several signaling pathways and influencing the cytokinetic movements of cells. ZnO nanoparticles showed a dynamic cytotoxic effect in cervical carcinoma cells. ZnO nanoparticle might induce the apoptosis through increased intracellular ROS level. Moreover, up regulated apoptotic gene expression confirms the occurrence of apoptosis. Taking all these data together, it may be concluded that ZnO nanoparticle may exert cytotoxicity on HeLa cell through the apoptotic pathway, implies the probable utility of ZnO nanoparticle in the cancer treatment and therapy. PMID- 26985735 TI - Stability of curcumin in different solvent and solution media: UV-visible and steady-state fluorescence spectral study. AB - In aqueous solution, curcumin is photodegradable (light sensitive), it is also self-degradable in the dark. In basic medium, the second process is enhanced. The dark process has been studied in water and also in a number of protic and aprotic solvents, and aqueous solutions of ionic liquids, pluronics, reverse micelles and salt. The kinetics of the process followed the first order rate law; a comparative as well as individual assessment of which has been made. The kinetics of curcumin self-degradation has been found to be fairly dependent on salt (NaCl) concentration. Curcumin molecules in solution may remain in the enol or keto-enol form. From the visible spectral analysis, an estimate of the proportions of these forms in aqueous ethanol medium has been made. The temperature effect on the visible and fluorescence spectra of curcumin has been also studied. The steady state fluorescence anisotropy of the photoactive curcumin has been evaluated in different solvent and solution media. The reversibility of the steady state fluorescence anisotropy of curcumin on heating and cooling conditions has been examined. The results herein presented are new and ought to be useful as the study of physicochemistry of curcumin has been gaining importance in the light of its biological importance. PMID- 26985736 TI - Synthesis, characterization, crystal structure, DNA and BSA binding, molecular docking and in vitro anticancer activities of a mononuclear dioxido-uranium(VI) complex derived from a tridentate ONO aroylhydrazone. AB - A mononuclear dioxido-uranium(IV) complex [UO2(L)(DMSO)2], was prepared from the reaction of (2-hydroxy-3-methoxybenzylidene)benzohydrazide [HL] with UO2(OAc)2.2H2O in DMSO. The obtained complex was fully characterized. Single crystal X-ray diffraction analysis of [UO2(L)(DMSO)2] revealed that U(VI) ion has been coordinated by ONO donor atoms of the dianionic ligand (L(2-)), oxo groups and two DMSO molecules in a pentagonal bipyramid geometry. In addition, interactions of the complex with salmon sperm DNA and bovine serum albumin (BSA) were thoroughly investigated using UV-vis absorption, voltammetry and molecular docking methods. The experimental studies showed an intercalative mode of interaction between the complex and DNA. Experiments on BSA interaction indicated a change in the polarity of the environment surrounded the complex as a result of the interaction between BSA and [UO2(L)(DMSO)2]. Finally, MTT assays indicated that the U(VI) complex had excellent cytotoxicity against human carcinoma cell lines of MCF-7, HPG-2, and HT-29, with IC50 values of 8.4, 10.6 and 10.0MUM, respectively. PMID- 26985737 TI - Effects of enhanced UV-B radiation on the nutritional and active ingredient contents during the floral development of medicinal chrysanthemum. AB - The paper mainly studied the effects of enhanced UV-B radiation on the nutritional and active ingredient contents during the floral development of medicinal chrysanthemum. The experiment included two levels of UV-B radiation (0 and 400MUWcm(-2)). The contents of hydrogen peroxide (H2O2), anthocyanin, UV-B absorbing compounds, total chlorophyll and carotenoids, and the activities of phenylalanine ammonia lyase enzyme (PAL) and cinnamic acid-4-hydroxylase enzyme (C4H) in flowers significantly decreased with the floral development. However, the contents of soluble sugar, amino acid and total vitamin C in flowers significantly increased with the floral development. The contents of flavonoid and chlorogenic acid were significantly different in the four stages of floral development, and their highest contents were found in the bud stage (stage 2). In the four stages of floral development, enhanced UV-B radiation significantly increased the contents of H2O2, UV-B absorbing compounds, chlorophyll, carotenoids, soluble sugar, amino acid, vitamin C, flavonoid and chlorogenic acid, and the activities of PLA and C4H in flowers. The results indicated that the highest contents of active and nutrient ingredients in flowers were found not to be in the same developmental stages of flowers. Comprehensive analysis revealed that the best harvest stage of chrysanthemum flowers was between the bud stage and the young flower stage (stage 2 and stage 3), which could simultaneously gain the higher contents of active and nutritional ingredients in flowers. PMID- 26985738 TI - Highly efficient generation of glutamatergic/cholinergic NT2-derived postmitotic human neurons by short-term treatment with the nucleoside analogue cytosine beta D-arabinofuranoside. AB - The human NTERA2/D1 (NT2) cells generate postmitotic neurons (NT2N cells) upon retinoic acid (RA) treatment and are functionally integrated in the host tissue following grafting into the rodent and human brain, thus representing a promising source for neuronal replacement therapy. Yet the major limitations of this model are the lengthy differentiation procedure and its low efficiency, although recent studies suggest that the differentiation process can be shortened to less than 1 week using nucleoside analogues. To explore whether short-term exposure of NT2 cells to the nucleoside analogue cytosine beta-d-arabinofuranoside (AraC) could be a suitable method to efficiently generate mature neurons, we conducted a neurochemical and morphometric characterization of AraC-differentiated NT2N (AraC/NT2N) neurons and improved the differentiation efficiency by modifying the cell culture schedule. Moreover, we analyzed the neurotransmitter phenotypes of AraC/NT2N neurons. Cultures obtained by treatment with AraC were highly enriched in postmitotic neurons and essentially composed of dual glutamatergic/cholinergic neurons, which contrasts with the preferential GABAergic phenotype that we found after RA differentiation. Taken together, our results further reinforce the notion NT2 cells are a versatile source of neuronal phenotypes and provide a new encouraging platform for studying mechanisms of neuronal differentiation and for exploring neuronal replacement strategies. PMID- 26985739 TI - Uptake of caprolactam and its influence on growth and oxygen production of Desmodesmus quadricauda algae. AB - The consumption of polyamides produced from caprolactam is increasing continuously, and for that reason the danger of environmental contamination by this lactam is also rising. This study's aim was to evaluate the influence of caprolactam on the growth and oxygen production of the green alga Desmodesmus quadricauda and on caprolactam uptake by this alga. The presence of caprolactam in water was observed to cause the algae significantly to increase its oxygen production. Caprolactam concentration of 5,000 mg/L stopped algae growth after 6 days and influenced coenobia structure (seen as disappearance of pyrenoids, deformation of cells) but did not decrease the number of cells in the coenobia. Caprolactam uptake is probably passive but relatively rapid. Maximum concentration in the algae was reached after 18-24 h. PMID- 26985740 TI - Risk of depressive disorders following sudden sensorineural hearing loss: A nationwide population-based retrospective cohort study. AB - BACKGROUND: Sudden sensorineural hearing loss (SSNHL) occurs as an unexplained, rapid loss of hearing that can cause significant stress in the affected individual. This study aims to assess the risk of depressive disorders in SSNHL patients. METHODS: From the National Health Insurance Research Database (NHIRD) in Taiwan, we identified new SSNHL patients diagnosed by an otolaryngologist between January 01, 2000, and December 31, 2008. A control group was composed of individuals who had never suffered from SSNHL. A total of 1717 SSNHL patients and 6868 individuals without SSNHL who were matched by sex, age and index date were followed until December 31, 2009, unless otherwise diagnosed with depressive disorders by a psychiatrist or deceased. RESULTS: The results found that after adjusting for patients' age, sex, comorbidities, urbanization, and monthly income, SSNHL patients are 2.17 times more at risk (95% confidence interval [CI], 1.51-3.08, p<.001) for depressive disorders then control patients, especially in younger age groups (<60 years old). CONCLUSIONS: Our study indicated an increased risk of developing depressive disorders in patients with SSNHL, particularly for younger patients. Symptoms of depression should be regularly evaluated in patients with SSNHL. PMID- 26985741 TI - Zinc and imipramine reverse the depression-like behavior in mice induced by chronic restraint stress. AB - Depression is a common psychopathological disorders. Studies of depression have indicated that zinc play a role in the depression pathophysiology and treatment. In present study, we examined the effects of zinc and imipramine supplement alone or combination of zinc and imipramine in mice induced by chronic restraint stress (CRS). Moreover, the possible roles of zinc receptor (G protein-coupled receptor 39, GPR39)-related pathway was investigated. Decreased weight and increased corticosterone (CORT) were observed after 3 weeks CRS exposure. It was shown that CRS induced lower serum zinc, higher hippocampal zinc, increased immobility time in tail suspension test and decreased movement distance in spontaneous activity test, which could be normalized by zinc (30 mg/kg) and imipramine (20 mg/kg) supplement alone and combination of zinc (15 mg/kg) and imipramine (5 mg/kg) for 3 weeks after CRS exposure. Moreover, the changes in mRNA expressions of GPR39, cAMP-response element binding protein (CREB), brain-derived neurotropic factor (BDNF) and n-methytl-d-aspartate receptors (NMDAR) could be reversed by the same treatment mentioned above. These results suggested that zinc dyshomeostasis in serum and hippocampus and depression-like behavior in CRS exposure animals observed in present study could be normalized by zinc and imipramine. The combination of zinc and imipramine in low dose has synergetic effects. The possible mechanism might be correlated to GPR39 receptor-related pathway. PMID- 26985742 TI - Evaluation and Management of Pulmonary Hypertension in Kidney Transplant Candidates and Recipients: Concepts and Controversies. AB - Although cardiac evaluation before kidney transplantation commonly focuses on coronary artery disease, a comprehensive pretransplant cardiac evaluation must consider other prognostically important cardiac conditions including functional and structural heart disease. Pulmonary hypertension (PH) is increasingly recognized among patients with kidney failure and may be driven by left heart failure, high cardiac output from arteriovenous fistula, hypoxic lung diseases, and metabolic derangements associated with renal disease. In this article, we examine several key concepts and controversies relevant to optimizing the assessment and management of PH in kidney transplant candidates and recipients. First, categorizing PH according to underlying pathophysiologies, hemodynamic characteristics, and treatment responses as currently defined by the World Health Organization can be challenging in this population, but should be pursued to direct appropriate management. Second, echocardiographic PH (based on variable definitions) has been reported in 13% to 50% of selected pretransplant cohorts, but use of more precise diagnostic methods is needed to better define epidemiology and underlying etiologies. Third, although measures of PH have been associated with adverse patient and graft outcomes after kidney transplantation, pilot data suggest that PH may improve with successful transplantation. Fourth, recent advances in PH treatment in the general population focus on World Health Organization group 1 pulmonary arterial hypertension, and the efficacy of management strategies for any PH type in patients with renal failure is largely unproven. Broader prospective data, including attention to the impact of transplantation, are needed to advance understanding of the frequency, causes, and optimal management of PH in kidney transplant candidates and recipients. PMID- 26985743 TI - Quantification of Alloantibody-Mediated Cytotoxicity In Vivo. AB - BACKGROUND: Preexisting, donor-specific antibodies (DSAs) are culprits of hyperacute rejection. Donor-specific antibodies are also formed de novo, and their role in acute and chronic rejection is increasingly appreciated. However, it is difficult to assess damage inflicted exclusively by DSAs when alloreactive T cell and B cell responses coincide. We reasoned that allosensitization with "costimulation-deficient" cells should induce DSA synthesis but not naive cytotoxic T lymphocyte (CTL) precursors' priming via direct allorecognition. Accordingly, we have developed a novel model to quantify DSA-mediated cytotoxicity in vivo. METHODS: C57BL/6 (H-2b) mice were sensitized with H-2 kidney epithelial cells, and a cytofluorimetric killing assay was tailored to the measurement of allocytotoxicity. We took cell/complement depletion, costimulation blockade, and serum transfer approaches to reveal the mediators of cytotoxicity. "Third-party" controls and a skin allotransplantation model were used to confirm DSAs' specificity for allo-major histocompatibility complex. We validated our experimental approach in other mouse strains primed with different allogeneic cell types, including endothelial cells. To demonstrate the usefulness of our model/method for drug efficacy testing, we examined the effect of CTLA4-Ig and rapamycin on DSA-mediated cytolysis. RESULTS: Allosensitization of MHC-disparate mouse strains with costimulation-deficient cells led to robust cytotoxicity mediated by complement-fixing DSAs and phagocytic cells. This response was independent of CTLs, natural killer or natural killer T cells. It required CD4 T cell help, CD40 signaling and CD28-based costimulation during allosensitization and could be reversed by sustained rapamycin treatment. CONCLUSIONS: The unique model described herein should enable mechanistic studies on sensitization and effector phases of humoral alloreactivity as well as efficacy testing of future immunotherapies to prevent DSA-induced pathology. PMID- 26985744 TI - Liver Transplantation for Alcoholic Liver Disease. AB - Alcohol-related liver disease is the second most frequent indication for liver transplantation (LT), yet as many as 90% to 95% of patients with alcohol-related end-stage liver disease are never formally evaluated for LT. Furthermore, despite its significance as a cause of chronic liver disease and indication for LT, it has received little attention in recent years for several reasons, including the good posttransplant short-term results, and the lack of specific "drugs" used for this disease. A writing group, endorsed by the International Liver Transplant Society, was convened to write guidelines on Liver Transplantation for Alcoholic Liver Disease to summarize current knowledge and provide answers to controversial and delicate ethical as well as clinical problems. We report here a short version of the guidelines (long version available at www.ilts.org) with the final recommendations graded for level of evidence. The writing group membership is expected to remain active for 5 years, reviewing the guideline annually, and updating the online version when appropriate. PMID- 26985746 TI - Living Donation Has a Greater Impact on Renal Allograft Survival Than HLA Matching in Pediatric Renal Transplant Recipients. AB - BACKGROUND: Living donor (LD) kidney transplantation accounts for around half of all pediatric renal transplant recipients and results in improved renal allograft survival. The aim of this study was to determine the effect of HLA matching on deceased and LD renal allograft outcomes in pediatric recipients. METHODS: Data were obtained from the UK Transplant Registry held by NHS Blood and Transplant on all children who received a donation after brain death (DBD) or LD kidney-only transplant between 2000 and 2011. HLA-A, HLA-B and HLA-DR mismatches were categorized into 4 levels and 2 groups. Data were fully anonymized. RESULTS: One thousand three hundred seventy-eight pediatric renal transplant recipients were analyzed; 804 (58%) received a DBD donor kidney, 574 (42%) received an LD kidney. Five-year renal allograft survival was superior for children receiving a poorly HLA-matched LD kidney transplant (88%, 95% confidence interval [95% CI], 84-91%) compared with children receiving a well HLA-matched DBD kidney transplant (83%, 95% CI, 80-86%, log rank test P = 0.03). Five-year renal allograft survival was superior for children receiving an LD kidney with 1 or 2 HLA-DR mismatches (88%, 95% CI, 84-91%) compared with children receiving a DBD kidney with 0 HLA-DR mismatches (83%, 95% CI, 80-86%, log rank test P = 0.03). CONCLUSIONS: In children, poorly HLA-matched LD renal transplant outcomes are not inferior when compared with well HLA-matched DBD renal transplants. It is difficult to justify preferentially waiting for an improved HLA-matched DBD kidney when a poorer HLA matched LD kidney transplant is available. PMID- 26985745 TI - The Risk of Cardiovascular Disease Is Not Increasing Over Time Despite Aging and Higher Comorbidity Burden of Kidney Transplant Recipients. AB - BACKGROUND: Cardiovascular death remains the leading cause of mortality in kidney transplant recipients. Cardiovascular events are associated with significant morbidity. However, current trends in cardiovascular events after kidney transplantation are poorly understood. METHODS: We conducted a retrospective study using healthcare databases in Ontario, Canada, to determine whether the incidence of cardiovascular events after kidney transplantation has changed from 1994 to 2009. Our primary endpoint was a 3-year composite outcome of posttransplant death or major cardiovascular event (myocardial infarction, coronary angioplasty, coronary artery bypass graft surgery, stroke). RESULTS: Recipients (n = 4954) were older and had more baseline comorbidity in recent years. A total of 445 recipients (9.0%) died or experienced a major cardiovascular event within 3 years of transplantation. There was no significant change in the incidence of the composite outcome or death-censored cardiovascular events over time (P = 0.41 and 0.92, respectively). After adjusting for age, sex, and comorbidities, the risk of death or major cardiovascular event steadily declined across the years of transplant (2006-2009 adjusted hazard ratio, 0.70; P = 0.009; referent 1994-1997). When recipients were matched on age, sex, and date of cohort entry to members of the general population and to the chronic kidney disease population, the risk was lowest in the general population and highest in the chronic kidney disease population. CONCLUSION: Despite transplant centers accepting recipients who are older with more comorbidities in recent years, the 3 year cumulative incidence of death or major cardiovascular event has remained stable over time. PMID- 26985747 TI - Subclinical Rejection in Renal Transplantation: Reappraised. AB - Short-term outcomes in renal transplantation have improved significantly in the past few years. However, the improvement in long-term outcomes has been modest. The reasons for graft failure beyond the first year of transplantation have been attributed to several different factors. We believe that subclinical rejection (SCR) may be 1 of the factors that contribute to graft loss in the long run. We also believe that there are data to suggest that SCR leads to progressive fibrosis and loss of graft function. This has been demonstrated even in patients who have mild degrees of subclinical inflammation. This review outlines the major studies that have been published on this important topic. It also outlines potential risk factors for the development of SCR. The current approach and diagnostic methods are discussed as well as their pros and cons. Newer noninvasive methods of diagnosis as well as molecular diagnostics and their merits and shortcomings are also discussed in some depth. Thus, the proposed state of the art review on SCR will create a renewed interest at all levels including transplant clinicians, transplant researchers, pharmaceutical industries as well as regulatory organizations. PMID- 26985748 TI - Going Gray. PMID- 26985749 TI - Creating a Nurse-Led Culture to Minimize Horizontal Violence in the Acute Care Setting: A Multi-Interventional Approach. AB - Horizontal violence (HV) is prevalent in nursing. However, few strategies are identified to address this phenomenon that undermines communication and patient safety. Nurses at an acute care hospital implemented multiple interventions to address HV resulting in increased knowledge of hospital policies regarding HV, and significantly (p < .05) less HV prevalence than was reported by nurses in other organizations throughout New York State. With the aid and oversight of nursing professional development specialists, evidence-based interventions to address HV were developed including policies, behavioral performance reviews, and staff/manager educational programs. PMID- 26985750 TI - Standardizing Assessment of Competences and Competencies of Oncology Nurses Working in Ambulatory Care. AB - A nursing quality consortium standardized nursing practice across 17 independently functioning ambulatory oncology sites. Programs were developed to validate both competences and competencies. One program assessed nine competences needed to develop systems of care to detect and treat treatment-related side effects. A second program was developed to assess competencies needed to prevent harm to oncology patients. This manuscript describes a successful approach to standardizing nursing practice across geographically distant academic and community sites. PMID- 26985751 TI - Exploration of Learning Strategies Associated With Aha Learning Moments. AB - Educators recognize aha moments as powerful aspects of learning. Yet limited research has been performed regarding how to promote these learning moments. This article describes an exploratory study of aha learning moments as experienced and described by participants. Findings showed use of visuals, scenarios, storytelling, Socratic questions, and expert explanation led to aha learning moments. The findings provide guidance regarding the types of learning strategies that can be used to promote aha moments. PMID- 26985752 TI - Navigations: The Road to a Better Orientation. AB - A team of nursing professional development specialists from a large Magnet(r) healthcare network transformed new employee orientation using a themed, interdisciplinary, learner-centered approach. Guided by project management principles, the nursing professional development team created an engaging program that serves as an interactive guide for new hires' orientation journey. This unique approach differs from traditional orientation programs through its incorporation of gaming, video clips, and group discussions. PMID- 26985753 TI - The Professionalism of Critical Care Nurse Fellows After Completion of the Critical Care Nurse Fellowship Program. AB - Professionalism is paramount to the formation and functioning of new graduate critical care nurses. In this project, a sample of 110 new graduate nurses used a descriptive self-report electronic survey with Hall's Professionalism Inventory Scale. A great percentage of these new graduate critical care nurse fellows with high professionalism scores may be related to their participation in the Critical Care Nurse Fellowship orientation program. Perhaps, Nursing Professional Development specialists should incorporate classes on professional advancement planning for new graduate nurses. PMID- 26985755 TI - Interprofessional Simulation: Creative Ways to Integrate Education and Goal Setting in the Practice Environment. PMID- 26985754 TI - Pressure Ulcer Prevention: Where Practice and Education Meet. AB - This article describes the processes used to implement a pressure ulcer management program in a Midwest academic medical center, which led to a decrease in reportable pressure ulcers. A learning needs assessment was completed, and a workgroup was formed to address the learning needs. Methods, materials, and processes included lectures, technology-enhanced learning, and interactive stations with mannequins and pressure ulcer moulages. The processes and outcome measures used to measure effectiveness of the program are discussed. PMID- 26985756 TI - Reviving the Journal Club as a Nursing Professional Development Strategy. PMID- 26985757 TI - The Golden Rule of Three. PMID- 26985758 TI - Implementing Nursing Professional Development. AB - Sandra Bruce is the Nurse Education Program Manager, Air Force Personnel Center, Joint Base San Antonio-Randolph in Texas, and is responsible for the Air Force Continuing Nursing Education program and facilitation of selection boards for graduate education and fellowship programs. She served as editor for the third and fourth editions of the Association for Nursing Professional Development (ANPD) Core Curriculums for Nursing Professional Development. Sandy previously served as the Education Consultant to the Air Force Surgeon General for Nursing Education programs for over 3,000 Air Force Nurse Corps members. She received her BSN from Mercy College of Detroit in 1976 and entered the Air Force in 1982. The Air Force sponsored her Master's Degree in Nursing as a Clinical Nurse Specialist. PMID- 26985759 TI - ANPD Strategic Plan: Organizational Transformation. PMID- 26985760 TI - Research Champions: An Initiative to Improve Use of Research Evidence in Nursing Practice. AB - The implementation of the Research Champions program was an effective strategy to increase the confidence of direct care nurses in research skills, a goal for staff development educators. Postprogram questionnaires conducted at 12 months assessed participants' confidence in specific areas: critique of research manuscripts, comprehension of research statistics, knowledge of the ethics of research, and using research in practice. Data supported that participants' confidence increased in all areas assessed. PMID- 26985763 TI - Latent tuberculosis infection: diagnostic update before introduction of biological drugs. PMID- 26985762 TI - Identifying Care Coordination Interventions Provided to Community-Dwelling Older Adults Using Electronic Health Records. AB - Although care coordination is a popular intervention, there is no standard method of delivery. Also little is known about who benefits most, or characteristics that predict the amount of care coordination needed, especially with chronically ill older adults. The purpose of this study was to identify types and amount of nurse care coordination interventions provided to 231 chronically ill older adults who participated in a 12-month home care medication management program in the Midwest. For each participant, the nurse care coordinator spent an average of 134 min/mo providing in-person home care, 48 min/mo of travel, and 18 min/mo of indirect care occurring outside the home visit. This accounted for 67.2%, 23.8%, and 9.0% of nursing time, respectively, for home visits, travel, and indirect care. Four of 11 nursing interventions focused on medication management were provided to all participants. Seven of the 11 main interventions were individualized according to each person's special needs. Wide variations were observed in time provided with in-person home care and communications with multiple stakeholders. Study findings indicate the importance of individualizing interventions and the variability in the amount of nursing time needed to provide care coordination to chronically ill older adults. PMID- 26985764 TI - A Study of Serum Soluble CD 163 Levels in Women with Polycystic Ovary Syndrome. AB - The aim of this study was to determine serum soluble CD163 levels in patients with polycystic ovary syndrome and its relation to clinical and metabolic parameters. Eighty-four women aged 18-45 years, 43 with polycystic ovary syndrome and 41 controls were recruited in this case-control study. Serum sCD163 levels of the groups were compared. Other metabolic, hormonal, and clinical parameters including, body mass index, HOMA-IR, highly sensitive C- reactive protein, glucose, glycated hemoglobin, lipids, luteinizing hormone, and total testosterone and waist/hip circumference were also investigated. Patients were further subgrouped according to body mass index and sCD163 levels were investigated in obese and normal weight subjects. We performed a multiple regression analysis to investigate the independent predictors affecting soluble CD163 levels. Significantly higher soluble CD163 levels were found in patients with polycystic ovary syndrome (2.11+/-0.65 ng/ml vs. 1.69+/-0.85 ng/ml, p=0.012). We detected positive correlations of sCD163 with total testosterone, total cholesterol, and luteinizing hormone (r=0.330, p=0.002, r=0.356, p<0.001 and r=0.239, p=0.030, respectively). In the multiple linear regression analysis, total testosterone was the variable associated with the elevation of serum soluble CD163 levels. Soluble CD163, which is identified as a marker of inflammation and type II diabetes, is elevated in polycystic ovary syndrome. Elevated sCD163 levels were found to be associated with total testosterone. Further studies to elucidate the exact mechanism underlying the elevation of serum soluble CD163 in polycystic ovary syndrome are needed. PMID- 26985765 TI - Expression of D-type cyclins in mantle cell and diffuse large B-cell lymphomas. AB - D-type cyclins are involved in cell cycle regulation and play an important role in the pathogenesis of lymphomas. Aberrant expression of cyclin D1 is associated with mantle cell lymphoma (MCL) and serves as a diagnostic marker of MCL. Analysis of cyclin D expression in tumor tissues of patients with diffuse large B cell lymphoma (DLBCL) which comprises a heterogeneous group of tumors may contribute to their stratification. We analyzed expression of cyclin D1, D2, and D3 mRNAs in 30 MCL and 104 DLBCL patients using qRT-PCR and addressed their significance for disease outcome. We confirmed a high level of cyclin D1 mRNA in 29 MCL cases (97%). One case (3%) was identified as positive for cyclin D2. Expression of cyclin D1 was limited to MCL and did not occur in DLBCL. Overexpression of cyclin D2, which is rare in MCL, occurred more frequently in DLBCL (11 cases, 10.6%). We showed that high expression of cyclin D2 in DLBCL cases de novo decreased the overall survival rate (P=0.016) and progression-free survival (P=0.009). The expression pattern of cyclin D3 was similar in both types of studied lymphomas and it did not affect the disease outcome. PMID- 26985766 TI - Building and Strengthening Infection Control Strategies to Prevent Tuberculosis - Nigeria, 2015. AB - Tuberculosis (TB) is the leading cause of infectious disease mortality worldwide, accounting for more than 1.5 million deaths in 2014, and is the leading cause of death among persons living with human immunodeficiency virus (HIV) infection (1). Nigeria has the fourth highest annual number of TB cases among countries, with an estimated incidence of 322 per 100,000 population (1), and the second highest prevalence of HIV infection, with 3.4 million infected persons (2). In 2014, 100,000 incident TB cases and 78,000 TB deaths occurred among persons living with HIV infection in Nigeria (1). Nosocomial transmission is a significant source of TB infection in resource-limited settings (3), and persons with HIV infection and health care workers are at increased risk for TB infection because of their routine exposure to patients with TB in health care facilities (3-5). A lack of TB infection control in health care settings has resulted in outbreaks of TB and drug-resistant TB among patients and health care workers, leading to excess morbidity and mortality. In March 2015, in collaboration with the Nigeria Ministry of Health (MoH), CDC implemented a pilot initiative, aimed at increasing health care worker knowledge about TB infection control, assessing infection control measures in health facilities, and developing plans to address identified gaps. The approach resulted in substantial improvements in TB infection control practices at seven selected facilities, and scale-up of these measures across other facilities might lead to a reduction in TB transmission in Nigeria and globally. PMID- 26985767 TI - High leukocyte mtDNA content contributes to poor prognosis through ROS-mediated immunosuppression in hepatocellular carcinoma patients. AB - Compelling epidemiological evidences indicate a significant association between leukocyte mitochondrial DNA (mtDNA) content and incidence risk of several malignancies, including hepatocellular carcinoma (HCC). However, whether leukocyte mtDNA content affect prognosis of HCC patients and underlying mechanism has never been explored. In our study, leukocyte mtDNA content was measured in 618 HCC patients and its prognostic value was analyzed. Moreover, we detected the immunophenotypes of peripheral blood mononuclear cells (PBMCs) and plasma concentrations of several cytokines in 40 HCC patients and assessed the modulating effects of mtDNA content on immunosuppression in cell models. Our results showed that HCC patients with high leukocyte mtDNA content exhibited a significantly worse recurrence-free survival (RFS) and overall survival (OS) than those with low leukocyte mtDNA content. Leukocyte mtDNA content and TNM stage exhibited a notable joint effect in prognosis prediction. Furthermore, we found that patients with high leukocyte mtDNA content exhibited a higher frequency of CD4+CD25+FOXP3+ regulatory T (Treg) cells and lower frequency of NK cells in PBMCs and had higher TGF-beta1 and lower TNF-alpha and IFN-gamma plasma concentration when compared with those with low leukocyte mtDNA content, which suggests an immunosuppressive status. High leukocyte mtDNA content significantly enhanced the ROS-mediated secretion of TGF-beta1, which accounted for higher Treg and lower NK frequency in PBMCs. In a conclusion, our study for the first time demonstrates that leukocyte mtDNA content is an independent prognostic marker complementing TNM stage and associated with an ROS-mediated immunosuppressive phenotype in HCC patients. PMID- 26985768 TI - CCR5 knockout suppresses experimental autoimmune encephalomyelitis in C57BL/6 mice. AB - Multiple sclerosis (MS) is an inflammatory disease in which myelin in the spinal cord is damaged. C-C chemokine receptor type 5 (CCR5) is implicated in immune cell migration and cytokine release in central nervous system (CNS). We investigated whether CCR5 plays a role in MS progression using a murine model, experimental autoimmune encephalomyelitis (EAE), in CCR5 deficient (CCR5-/-) mice. CCR5-/- and CCR5+/+ (wild-type) mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) followed by pertussis toxin, after which EAE paralysis was scored for 28 days. We found that clinical scoring and EAE neuropathology were lower in CCR5-/- mice than CCR5+/+ mice. Immune cells (CD3+, CD4+, CD8+, B cell, NK cell and macrophages) infiltration and astrocytes/microglial activation were attenuated in CCR5-/- mice. Moreover, levels of IL-1beta, TNF-alpha, IFN-gamma and MCP-1 cytokine levels were decreased in CCR5-/- mice spinal cord. Myelin basic protein (MBP) and CNPase were increased while NG2 and O4 were decreased in CCR5-/- mice, indicating that demyelination was suppressed by CCR5 gene deletion. These findings suggest that CCR5 is likely participating in demyelination in the spinal cord the MS development, and that it could serve as an effective therapeutic target for the treatment of MS. PMID- 26985770 TI - STARD13-correlated ceRNA network inhibits EMT and metastasis of breast cancer. AB - Competing endogenous RNAs (ceRNAs) network has been correlated with the initiation and development of cancer. Here, we identify CDH5, HOXD1, and HOXD10 as putative STARD13 ceRNAs and they display concordant patterns with STARD13 in different metastatic potential breast cancer cell lines and tissues. Notably, 3'UTRs of these genes suppress breast cancer metastasis via inhibiting epithelial mesenchymal transition (EMT) in vitro and in vivo, which are activated through the crosstalk between STARD13 and its ceRNAs in 3'UTR- and miRNA-dependent manners. In addition, Kaplan-Meier survival analysis reveals that mRNA level of STARD13 and its ceRNAs is remarkably associated with survival of breast cancer patients. These results suggest that 3'UTRs of CDH5, HOXD1, and HOXD10 inhibit breast cancer metastasis via serving as STARD13 ceRNAs. PMID- 26985772 TI - Identification of new anti-Candida compounds by ligand-based pharmacophore virtual screening. AB - Candida albicans represents the most prevalent microbial population in mucosal and systemic infections, usually confined to severely immunocompromised people. Considering the increase of resistant strains and the demand for new antifungal drugs endowed with innovative mechanism of action, we performed a ligand-based virtual screening in order to identify new anti-Candida compounds. Starting from a large library of natural/semisynthetic products and several published synthesized compounds, three coumarin derivatives were discovered in silico as new hit compounds and submitted to the in vitro assay in order to confirm their predicted biological activity. PMID- 26985771 TI - Multiple genetic imaging study of the association between cholesterol metabolism and brain functional alterations in individuals with risk factors for Alzheimer's disease. AB - Alzheimer's disease (AD) is a clinically and genetically heterogeneous neurodegenerative disease. Genes involved in cholesterol metabolism may play a role in the pathological changes of AD. However, the imaging genetics-based endophenotypes derived from polymorphisms in multiple functionally related genes are unclear in individuals with risk factors for AD. Forty-three amnestic mild cognitive impairment (aMCI) subjects and 30 healthy controls underwent resting state functional magnetic resonance imaging (fMRI) measurements of brain topological organization. Thirty-three previously suggested tagging single nucleotide polymorphisms (SNPs) from 12 candidate genes in the cholesterol metabolism pathway were further investigated. A cholesterol metabolism pathway gene-based imaging genetics approach was then utilized to investigate disease related differences between the groups based on genotype-by-aMCI interactions. The cholesterol metabolism pathway genes exerted widespread effects on the cortico-subcortical-cerebellar spontaneous brain activity. Meanwhile, left lateralization of global brain connectivity was associated with cholesterol metabolism pathway genes. The APOE rs429358 variation significantly influenced the brain network characteristics, affecting the activation of nodes as well as the connectivity of edges in aMCI subjects.The cholesterol metabolism pathway gene-based imaging genetics approach may provide new opportunities to understand the mechanisms underlying AD and suggested that APOE rs429358 is a core genetic variation that is associated with disease-related differences in brain function. PMID- 26985773 TI - COI1-Regulated Hydroxylation of Jasmonoyl-L-isoleucine Impairs Nicotiana attenuata's Resistance to the Generalist Herbivore Spodoptera litura. AB - The phytohormone jasmonoyl-L-isoleucine (JA-Ile) is well-known as the key signaling molecule that elicits plant defense responses after insect herbivory. Oxidation, which is catalyzed by the cytochrome P450s of the CYP94 family, is thought to be one of the main catabolic pathways of JA-Ile. In this study, we identified four CYP94B3 homologues in the wild tobacco plant Nicotiana attenuata. Individually silencing the four homologues revealed that NaCYP94B3 like-1 and NaCYP94B3 like-2, but not NaCYP94B3 like-3 and NaCYP94B3 like-4, are involved in the C-12-hydroxylation of JA-Ile. Simultaneously silencing three of the NaCYP94B3 like genes, NaCYP94B3 like-1, -2, and -4, in the VIGS-NaCYP94B3s plants doubled herbivory-induced JA-Ile levels and greatly enhanced plant resistance to the generalist insect herbivore, Spodoptera litura. The poor larval performance was strongly correlated with the high concentrations of several JA-Ile-dependent direct defense metabolites in VIGS-NaCYP94B3s plants. Furthermore, we show that the abundance of 12-hydroxy-JA-Ile was dependent on JA-Ile levels as well as COI1, the receptor of JA-Ile. COI1 appeared to transcriptionally control NaCYP94B3 like-1 and -2 and thus regulates the catabolism of its own ligand molecule, JA-Ile. These results highlight the important role of JA-Ile degradation in jasmonate homeostasis and provide new insight into the feedback regulation of JA-Ile catabolism. Given that silencing these CYP94 genes did not detectably alter plant growth and highly increased plant defense levels, we propose that CYP94B3 genes can be potential targets for genetic improvement of herbivore-resistant crops. PMID- 26985774 TI - Proficient Detection of Multi-Drug-Resistant Mycobacterium tuberculosis by Padlock Probes and Lateral Flow Nucleic Acid Biosensors. AB - Tuberculosis is a major communicable disease. Its causative agent, Mycobacterium tuberculosis, becomes resistant to antibiotics by acquisition of point mutations in the chromosome. Multi-drug-resistant tuberculosis (MDR-TB) is an increasing public health threat, and prompt detection of such strains is of critical importance. As rolling circle amplification of padlock probes can be used to robustly distinguish single-nucleotide variants, we combined this technique with a sensitive lateral flow nucleic acid biosensor to develop a rapid molecular diagnostic test for MDR-TB. A proof-of-concept test was established for detection of the most common mutations [rpoB 531 (TCG/TTG) and katG 315 (AGC/ACC)] causing MDR-TB and verification of loss of the respective wild type. The molecular diagnostic test produces visual signals corresponding to the respective genotypes on lateral flow strips in approximately 75 min. By detecting only two mutations, the test can detect about 60% of all MDR-TB cases. The padlock probe-lateral flow (PLP-LF) test is the first of its kind and can ideally be performed at resource limited clinical laboratories. Rapid information about the drug-susceptibility pattern can assist clinicians to choose suitable treatment regimens and take appropriate infection control actions rather than prescribing empirical treatment, thereby helping to control the spread of MDR-TB in the community. PMID- 26985769 TI - The application of the fibroblast activation protein alpha-targeted immunotherapy strategy. AB - Cancer immunotherapy has primarily been focused on attacking tumor cells. However, given the close interaction between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), CAF-targeted strategies could also contribute to an integrated cancer immunotherapy. Fibroblast activation protein alpha (FAP alpha) is not detectible in normal tissues, but is overexpressed by CAFs and is the predominant component of the stroma in most types of cancer. FAP alpha has both dipeptidyl peptidase and endopeptidase activities, cleaving substrates at a post-proline bond. When all FAP alpha expressing cells (stromal and cancerous) are destroyed, tumors rapidly die. Furthermore, a FAP alpha antibody, FAP alpha vaccine, and modified vaccine all inhibit tumor growth and prolong survival in mouse models, suggesting FAP alpha is an adaptive tumor-associated antigen. This review highlights the role of FAP alpha in tumor development, explores the relationship between FAP alpha and immune suppression in the TME, and discusses FAP alpha as a potential immunotherapeutic target. PMID- 26985776 TI - Bilateral Endogenous Endophthalmitis Caused by Candida albicans After Breast Implant Surgery. PMID- 26985777 TI - Preoperative Imaging for Thyroid Cancer: Beyond Ultrasonography. PMID- 26985779 TI - Social Media Sites, Part 1: The Dark Side. PMID- 26985775 TI - In Vivo Evaluation of Site-Specifically PEGylated Chemically Self-Assembled Protein Nanostructures. AB - Chemically self-assembled nanorings (CSANs) are made of dihydrofolate reductase (DHFR) fusion proteins and have been successfully used in vitro for cellular cargo delivery and cell surface engineering applications. However, CSANs have yet to be evaluated for their in vivo stability, circulation, and tissue distribution. In an effort to evaluate CSANs in vivo, we engineered a site specifically PEGylated epidermal growth factor receptor (EGFR) targeting DHFR molecules, characterized their self-assembly into CSANs with bivalent methotrexates (bis-MTX), visualized their in vivo tissue localization by microPET/CT imaging, and determined their ex vivo organ biodistribution by tissue based gamma counting. A dimeric DHFR (DHFR(2)) molecule fused with a C-terminal EGFR targeting peptide (LARLLT) was engineered to incorporate a site-specific ketone functionality using unnatural amino acid mutagenesis. Aminooxy-PEG, of differing chain lengths, was successfully conjugated to the protein using oxime chemistry. These proteins were self-assembled into CSANs with bis-MTX DHFR dimerizers and characterized by size exclusion chromatography and dynamic light scattering. In vitro binding studies were performed with fluorescent CSANs assembled using bis-MTX-FITC, while in vivo microPET/CT imaging was performed with radiolabeled CSANs assembled using bis-MTX-DOTA[(64)Cu]. PEGylation reduced the uptake of anti-EGFR CSANs by mouse macrophages (RAW 264.7) up to 40% without altering the CSAN's binding affinity toward U-87 MG glioblastoma cells in vitro. A significant time dependent tumor accumulation of (64)Cu labeled anti-EGFR-CSANs was observed by microPET/CT imaging and biodistribution studies in mice bearing U 87 MG xenografts. PEGylated CSANs demonstrated a reduced uptake by the liver, kidneys, and spleen resulting in high contrast tumor imaging within an hour of intravenous injection (9.6% ID/g), and continued to increase up to 24 h (11.7% ID/g) while the background signal diminished. CSANs displayed an in vivo profile between those of rapidly clearing small molecules and slow clearing antibodies. Thus, CSANs offer a modular, programmable, and stable protein based platform that can be used for in vivo drug delivery and imaging applications. PMID- 26985778 TI - Relations Among Detection of Syllable Stress, Speech Abnormalities, and Communicative Ability in Adults With Autism Spectrum Disorders. AB - PURPOSE: To date, the literature on perception of affective, pragmatic, and grammatical prosody abilities in autism spectrum disorders (ASD) has been sparse and contradictory. It is interesting to note that the primary perception of syllable stress within the word structure, which is crucial for all prosody functions, remains relatively unexplored in ASD. Thus, in the current study, we explored syllable stress perception sensitivity and its relationship to speech production abnormalities and communicative ability in adults with ASD. METHOD: A same-different syllable stress perception task using pairs of identical 4 syllable words was delivered to 42 adults with/without high-functioning ASD, matched for age, to investigate primary speech perception ability in ASD. Speech production and communicative ability in ASD was measured using the Autism Diagnostic Observation Schedule (Lord et al., 2000). RESULTS: As predicted, the results showed that adults with ASD were less sensitive in making judgments about syllable stress relative to controls. Also, partial correlations revealed a key association of speech production abnormalities with stress perception sensitivity, rather than communicative ability. CONCLUSIONS: Our findings provide empirical evidence for deficits on primary syllable stress perception in ASD and its role on sociocommunicative difficulties. This information could facilitate the development of effective interventions for speech and language therapy and social communication. PMID- 26985780 TI - The Persuasive Effect of Social Network Feedback on Mediated Communication: A Case Study in a Real Organization. AB - This study focuses on social feedback, namely on information on the outcome of users' online activity indirectly generated by other users, and investigates in a real setting whether it can affect subsequent activity and, if so, whether participants are aware of that. SkyPas, an application that calculates, transmits, and displays social feedback, was embedded in a common instant messaging service (Skype(TM)) and used during a 7-week trial by 24 office workers at a large business organization. The trial followed an ABA scheme in which the B phase was the feedback provision phase. Results show that social feedback affects users' communication activity (participation, inward communication, outward communication, and reciprocity), sometimes even after the feedback provision phase. At the same time, users were poorly aware of this effect, showing a discrepancy between self-reported and observational measures. These results are then discussed in terms of design transparency and task compatibility. PMID- 26985781 TI - The Immersive Virtual Reality Experience: A Typology of Users Revealed Through Multiple Correspondence Analysis Combined with Cluster Analysis Technique. AB - Immersive virtual reality is thought to be advantageous by leading to higher levels of presence. However, and despite users getting actively involved in immersive three-dimensional virtual environments that incorporate sound and motion, there are individual factors, such as age, video game knowledge, and the predisposition to immersion, that may be associated with the quality of virtual reality experience. Moreover, one particular concern for users engaged in immersive virtual reality environments (VREs) is the possibility of side effects, such as cybersickness. The literature suggests that at least 60% of virtual reality users report having felt symptoms of cybersickness, which reduces the quality of the virtual reality experience. The aim of this study was thus to profile the right user to be involved in a VRE through head-mounted display. To examine which user characteristics are associated with the most effective virtual reality experience (lower cybersickness), a multiple correspondence analysis combined with cluster analysis technique was performed. Results revealed three distinct profiles, showing that the PC gamer profile is more associated with higher levels of virtual reality effectiveness, that is, higher predisposition to be immersed and reduced cybersickness symptoms in the VRE than console gamer and nongamer. These findings can be a useful orientation in clinical practice and future research as they help identify which users are more predisposed to benefit from immersive VREs. PMID- 26985782 TI - The Online Version of the Chinese Intolerance of Uncertainty Scale: Psychometric Properties. AB - The Intolerance of Uncertainty Scale (IUS) is widely used to assess the implications of being uncertain, attempts to control the future, and emotional, cognitive, and behavioral reactions to ambiguous situations. Several language versions of the paper-and-pencil test have shown satisfactory psychometric properties. This study is intended to explore whether the IUS is suited to being administered on the Internet. We examined the factor structure, reliability, and validity of the online version of the Chinese IUS in a sample of college students (N = 905). The results showed a four-factor structure model, excellent internal consistency reliability (alpha = 0.91), re-tested reliability (r = 0.82), and convergent and divergent validity. We can conclude that the online version of the Chinese IUS is appropriate for measurement and its psychometric properties are similar to the paper-and-pencil version. PMID- 26985783 TI - Who Multitasks on Smartphones? Smartphone Multitaskers' Motivations and Personality Traits. AB - This study aimed to explore the psychological determinants of smartphone multitasking. Smartphone multitasking comprises the following three different subtypes: multitasking with nonmedia activities, cross-media multitasking with nonsmartphone media, and single-device multitasking within the smartphone. The primary motivations for smartphone multitasking were first identified- efficiency, utility, and positive affect--and the ways in which they are associated with the three subtypes were examined; among the primary motivations, efficiency and positive affect predicted the degree of total smartphone multitasking behavior. The personality traits that are pertinent to all of the primary motivations--need for cognition (NFC) and sensation seeking (SS)--were also investigated. Further analyses revealed that the motivations for and the extent of smartphone multitasking can vary as functions of a user's NFC and SS. In this study, NFC was not only a meaningful predictor of the cognitive needs that drive smartphone multitasking but also increased the likelihood of multitasking through its interaction with SS. PMID- 26985786 TI - Guidance Document for the Prehospital Use of Tranexamic Acid in Injured Patients. AB - Tranexamic acid (TXA) is being administered already in many prehospital air and ground systems. Insufficient evidence exists to support or refute the prehospital administration of TXA, and results are pending from several prehospital studies currently in progress. We have created this document to aid agencies and systems in best practices for TXA administration based on currently available best evidence. This document has been endorsed by the American College of Surgeons Committee on Trauma, the American College of Emergency Physicians, and the National Association of EMS Physicians. PMID- 26985788 TI - Editorial. PMID- 26985789 TI - Chemical Biology in the Embryo: In Situ Imaging of Sulfur Biochemistry in Normal and Proteoglycan-Deficient Cartilage Matrix. AB - Proteoglycans (PGs) are heavily glycosylated proteins that play major structural and biological roles in many tissues. Proteoglycans are abundant in cartilage extracellular matrix; their loss is a main feature of the joint disease osteoarthritis. Proteoglycan function is regulated by sulfation-sulfate ester formation with specific sugar residues. Visualization of sulfation within cartilage matrix would yield vital insights into its biological roles. We present synchrotron-based X-ray fluorescence imaging of developing zebrafish cartilage, providing the first in situ maps of sulfate ester distribution. Levels of both sulfur and sulfate esters decrease as cartilage develops through late phase differentiation (maturation or hypertrophy), suggesting a functional link between cartilage matrix sulfur content and chondrocyte differentiation. Genetic experiments confirm that sulfate ester levels were due to cartilage proteoglycans and support the hypothesis that sulfate ester levels regulate chondrocyte differentiation. Surprisingly, in the PG synthesis mutant, the total level of sulfur was not significantly reduced, suggesting sulfur is distributed in an alternative chemical form during lowered cartilage proteoglycan production. Fourier transform infrared imaging indicated increased levels of protein in the mutant fish, suggesting that this alternative sulfur form might be ascribed to an increased level of protein synthesis in the mutant fish, as part of a compensatory mechanism. PMID- 26985787 TI - No laughing matter: How the presence of laughing witnesses changes the perception of insults. AB - Insults always sting, but the context in which they are delivered can make the effects even worse. Here we test how the brain processes insults, and whether and how the neurocognitive processing of insults is changed by the presence of a laughing crowd. Event-related potentials showed that insults, compared to compliments, evoked an increase in N400 amplitude (indicating increased lexical semantic processing) and LPP amplitude (indicating emotional processing) when presented in isolation. When insults were perceived in the presence of a laughing crowd, the difference in N400 amplitude disappeared, while the difference in LPP activation increased. These results show that even without laughter, verbal insults receive additional neural processing over compliments, both at the lexical-semantic and emotional level. The presence of a laughing crowd has a direct effect on the neurocognitive processing of insults, leading to stronger and more elongated emotional processing. PMID- 26985790 TI - Templated Self-Assembly of Ultrathin Gold Nanowires by Nanoimprinting for Transparent Flexible Electronics. AB - We fabricated flexible, transparent, and conductive metal grids as transparent conductive materials (TCM) with adjustable properties by direct nanoimprinting of self-assembling colloidal metal nanowires. Ultrathin gold nanowires (diameter below 2 nm) with high mechanical flexibility were confined in a stamp and readily adapted to its features. During drying, the wires self-assembled into dense bundles that percolated throughout the stamp. The high aspect ratio and the bundling yielded continuous, hierarchical superstructures that connected the entire mesh even at low gold contents. A soft sintering step removed the ligand barriers but retained the imprinted structure. The material exhibited high conductivities (sheet resistances down to 29 Omega/sq) and transparencies that could be tuned by changing wire concentration and stamp geometry. We obtained TCMs that are suitable for applications such as touch screens. Mechanical bending tests showed a much higher bending resistance than commercial ITO: conductivity dropped by only 5.6% after 450 bending cycles at a bending radius of 5 mm. PMID- 26985791 TI - Impaired Retinal Perfusion Resulting From Vitreoretinal Traction: A Mechanism of Retinal Vascular Insufficiency. AB - BACKGROUND AND OBJECTIVE: To demonstrate vitreoretinal traction as a mechanism of abnormal retinal vascular perfusion. PATIENTS AND METHODS: Retrospective report of three cases demonstrating vitreoretinal traction concurrent with abnormal retinal perfusion. Subjects were retrospectively identified based on clinical records from two tertiary care retina subspecialty practices. All subjects underwent complete ophthalmic examination and ancillary testing as necessary for their standard clinical care. Vascular perfusion was assessed by one or more methods, including wide-field fluorescein angiography and optical coherence tomography angiography (OCTA). Vitreoretinal traction was assessed by clinical examination; intraoperative surgical observations; and fundus imaging, including wide-field, red-free, and color images as well as OCT. RESULTS: Three cases are shown in which vitreoretinal traction was clearly documented and correlated with abnormal retinal vascular perfusion. Abnormal vascular perfusion correlated with the distribution of vessels affected by vitreoretinal traction in all cases. Vascular perfusion normalized in all cases after surgery was used to relieve vitreoretinal traction. CONCLUSION: The authors demonstrate that vitreoretinal traction can alter retinal vascular perfusion in a reversible fashion. These results suggest that there can be a direct mechanical effect of vitreous traction on retinal vascular perfusion. Further advances in wide-field imaging, wide-field OCT, and OCTA will help better evaluate this cause of retinal vascular insufficiency. PMID- 26985793 TI - Erratum for "Epiretinal Membrane Peeling After Uncomplicated Primary Retinal Detachment Repair". PMID- 26985792 TI - Multimodal Imaging in Retinal Disease: A Consensus Definition. PMID- 26985794 TI - Hydroxychloroquine: A Brief Review on Screening, Toxicity, and Progression. PMID- 26985795 TI - Predictors of Macular Atrophy Detected by Fundus Autofluorescence in Patients With Neovascular Age-Related Macular Degeneration After Long-Term Ranibizumab Treatment. AB - BACKGROUND AND OBJECTIVE: To study the relationship between baseline morphologic characteristics of the choroidal neovascular (CNV) lesion and long-term development of macular atrophy in eyes with neovascular age-related macular degeneration (AMD) treated with ranibizumab (Lucentis; Genentech, South San Francisco, CA). PATIENTS AND METHODS: Certified graders evaluated baseline and 7 year follow-up (SEVEN-UP study) images of 41 eyes from the MARINA/ANCHOR and HORIZON trials. Using GRADOR software and stepwise linear regression, graders correlated lesion characteristics on fluorescein angiography (FA) at both visits with areas of definite decreased autofluorescence (DDAF) on fundus autofluorescence (FAF) imaging at the SEVEN-UP visit. RESULTS: Three of 41 eyes (7.3%) had macular atrophy on FA at baseline (mean +/- standard deviation [SD] size: 0.29 mm(2) +/- 1.50 mm(2)), 29 (70.7%) at SEVEN-UP (mean +/- standard deviation [SD] area: 7.42 mm(2) +/- 7.97 mm(2)). On FAF imaging at the SEVEN-UP visit, all 41 eyes (100%) had DDAF (mean +/- SD size: 10.29 mm(2) +/- 8.07 mm(2)). Variables significantly associated with area of DDAF at the SEVEN-UP visit were the area of leaking CNV lesion components (coefficient: 0.953; P < .001), the area of other lesion components (coefficient: 1.094; P = .038), and the area of retinal pigment epithelial (RPE) atrophy (coefficient: 1.334; P = .040) on baseline FA imaging. CONCLUSION: The area of DDAF at more than 7 years after initiation of ranibizumab therapy was 35% larger than the original CNV lesion. The baseline area of leaking CNV and other components of the CNV lesion and the baseline area of RPE atrophy were important predictors of the area of definite decreased autofluorescence, presumably corresponding to areas of photoreceptor and RPE loss. The findings from this study may guide hypothesis generation for future AMD trials. PMID- 26985796 TI - A Comparison of Intraoperative Dexamethasone Intravitreal Implant and Triamcinolone Acetonide Used During Vitrectomy and Epiretinal Membrane Peeling: A Case Control Study. AB - BACKGROUND AND OBJECTIVE: Intravitreal corticosteroids may accelerate the normalization of macular morphology after vitrectomy and epiretinal membrane (ERM) peeling. The authors compared the visual and anatomic outcomes of eyes undergoing this procedure with the intraoperative use of the dexamethasone intravitreal implant (DEX) (Ozurdex; Allergan, Irvine, CA) versus triamcinolone acetonide (IVTA) (Triesence; Alcon, Fort Worth, TX). PATIENTS AND METHODS: Interventional, retrospective, consecutive, case-control study. RESULTS: Fifty five participants were included (DEX = 19; IVTA = 36). Best-corrected visual acuity (BCVA) improved at 1, 2, 3, and 6 months in both the DEX (P = .40, .45, .02, .08, respectively) and IVTA (P < .01, = .10, < .01, < .01) arms. Similarly, central macular thickness (CMT) improved at 1, 2, 3, and 6 months in both the DEX (P < .01, = .03, < .01, < .01) and IVTA (P < .01, < .01, < .01, < .01) arms. There were no statistical differences between DEX and IVTA regarding BCVA and CMT. CONCLUSION: Both intraoperative DEX and IVTA, used at the completion of vitrectomy and at membrane peeling for epiretinal membrane, were effective in improving visual and anatomic outcomes, though there was a trend toward greater significance with IVTA. PMID- 26985797 TI - Effect of Fluid Status at Week 12 on Visual and Anatomic Outcomes at Week 52 in the VIEW 1 and 2 Trials. AB - BACKGROUND AND OBJECTIVE: To evaluate effect of retinal fluid status at week 12 on visual and anatomic outcomes at week 52 in patients with neovascular age related macular degeneration from the VIEW studies. PATIENTS AND METHODS: Post hoc analysis included 1,465 eyes treated with intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) 2 mg every 4 weeks (2q4) or every 8 weeks following three initial monthly injections (2q8) or ranibizumab (Lucentis; Genentech, South San Francisco, CA) 0.5 mg every 4 weeks (Rq4), which had known retinal fluid status at weeks 12 and 52. RESULTS: At 12 weeks, 512 (35%) eyes had fluid and 953 (65%) were fluid-free. Two hundred three (41.5%), 148 (29.8%), and 161 (33.5%) eyes had fluid in Rq4, 2q4, and 2q8, respectively. Best-corrected visual acuity (BCVA) change at week 52 from baseline was independent of retinal fluid status at week 12 or treatment assignment. Eyes were more likely to remain fluid-free at week 52 if absent of fluid at week 12. CONCLUSION: At week 52, 2q4, 2q8, and Rq4 improved BCVA independent of fluid status at week 12. PMID- 26985799 TI - Mobile Health in the Retinal Clinic Population: Access to and Interest in Self Tracking. AB - BACKGROUND AND OBJECTIVE: Implementation of mobile health-tracking programs for retinal pathology requires both access to mobile devices and patient motivation to participate in self-tracking. The authors' study aimed to evaluate the prevalence of smartphone and tablet ownership and patient interest in self tracking among a retinal clinic population. PATIENTS AND METHODS: This is an institutional, prospective, cross-sectional survey of 103 retinal clinic outpatients. Consenting patients underwent a one-on-one interview conducted in the examination room during their waiting period by one researcher. RESULTS: Overall, 75 of 103 participants (72.2%) reported either owning a smartphone and/or tablet or having access at their household to a device that could be used to track eye health. The majority of participants (69 of 103 participants; 67%) reported interest in using a mobile application (smartphone or tablet) to track their eye health. CONCLUSION: These data suggest strong patient interest in the use of mobile devices to track eye health. PMID- 26985801 TI - Multi-Modal Longitudinal Evaluation of Subthreshold Laser Lesions in Human Retina, Including Scanning Laser Ophthalmoscope-Adaptive Optics Imaging. AB - BACKGROUND AND OBJECTIVE: Subthreshold retinal laser therapy is efficacious for a variety of retinovascular disorders. Currently, it is unknown which laser parameters can ensure no detectable damage to human retina tissue. MATERIALS AND METHODS: One informed physician participant with a normal retina was treated with three levels (75%, 50%, and 25%) of subthreshold 577-nm laser (PASCAL; Topcon, Santa Clara, CA) at 20-millisecond (ms) duration and 100 um spot size. Several high-resolution retinal imaging modalities, including spectral-domain optical coherence tomography (SD-OCT) and scanning laser ophthalmoscope-adaptive optics (SLO-AO), were used to longitudinally image retinal laser lesions during a 9 month period. RESULTS: SLO-AO and SD-OCT imaging of subthreshold laser therapy in human retina showed no cone cell or RPE damage at all time points during a 9 month period using the 25% threshold power 577-nm laser in the human retina. CONCLUSION: It is likely that subthreshold laser therapy with 577-nm laser at 20 ms duration in the human retina is safe at the 25% of threshold power level. PMID- 26985800 TI - Diabetic Macular Edema Diagnosis and Treatment in the Real World: An Analysis of Medicare Claims Data (2008 to 2010). AB - BACKGROUND AND OBJECTIVE: To characterize vascular endothelial growth factor (VEGF) inhibitor treatment patterns in patients with diabetic macular edema (DME) using a Medicare Standard Analytic Files Part B or Outpatient Claims database to understand treatment frequency and DME persistence. PATIENTS AND METHODS: A retrospective analysis of treatment patterns for patients diagnosed with DME receiving their first anti-VEGF injection was performed. RESULTS: The average number of anti-VEGF injection claims for DME per patient rose from 3.1 to 4.6 per year (mean: 4.2). Within 1 year of diagnosis, 46% of patients received their final DME diagnosis (mean: 1.9 anti-VEGF claims), and 65% of patients received their final anti-VEGF treatment for DME. Patients who received treatment for DME through years 2 and 3 submitted a mean of four and 7.2 anti-VEGF claims, respectively. CONCLUSION: VEGF inhibitor treatment was less frequent than in landmark trials, but did resolve DME in a proportion of patients. PMID- 26985798 TI - Evaluating Efficacy of Aflibercept in Refractory Exudative Age-Related Macular Degeneration With OCT Segmentation Volumetric Analysis. AB - BACKGROUND AND OBJECTIVE: To use automated segmentation software to analyze spectral-domain optical coherence tomography (SD-OCT) scans and evaluate the effectiveness of aflibercept (Eylea; Regeneron, Tarrytown, NY) in the treatment of patients with exudative age-related macular degeneration (AMD) refractory to other treatments. PATIENTS AND METHODS: Retrospective chart review of 16 patients refractory to bevacizumab (Avastin; Genentech, South San Francisco, CA)/ranibizumab (Lucentis; Genentech, San Francisco, CA) treatment was conducted. Visual acuity, central foveal thickness (CFT), maximum fluid height, pigment epithelial detachment (PED) volume, sub-retinal fluid (SRF) volume, fluid-free time interval, and adverse effects were evaluated. Automated segmentation analysis was used to quantify improvement. RESULTS: With aflibercept treatment, there was a statistically significant improvement in visual acuity by 1 line (P = .020), in CFT by 74.02 um (P = .001), and in maximum fluid height by 31.9 um (P= .011). Total PED and SRF volume also decreased significantly by 1.50 um(3) * 10(8) um(3) (P = .013). Anatomic improvement was confirmed by automated segmentation analysis. CONCLUSION: This study demonstrates utility of automated segmentation software in quantifying anatomic improvement with aflibercept treatment in exudative AMD refractory to other anti-vascular endothelial growth factor treatments. PMID- 26985802 TI - Subconjunctival Bevacizumab for the Treatment of Keratoprosthesis-Associated Cystoid Macular Edema. AB - The authors present a case of keratoprosthesis-associated cystoid macular edema (CME) responsive to subconjunctival bevacizumab (Avastin; Genentech, South San Francisco, CA). A 40-year-old woman with a history of Stevens-Johnson syndrome (SJS) and Boston keratoprosthesis type I implantation developed CME 10 months after surgery and received sub-Tenon's kenalog with minimal improvement. Sixteen months after surgery, she received a subconjunctival injection of bevacizumab and demonstrated visual and anatomic improvement. Ten weeks later, she received a second subconjunctival injection of bevacizumab for worsening CME and again demonstrated a favorable response. Subconjunctival bevacizumab may be an effective and less-invasive alternative to intravitreal injections for the treatment of postoperative CME. PMID- 26985804 TI - Retinal Pigment Epithelium Hyperplasia After Unsuccessful Surgery for Macular Hole. AB - An 81-year-old woman presented with a retinal tumor after unsuccessful surgery was performed for a macular hole (MH) in the 1990s. A histopathological analysis revealed retinal pigment epithelium hyperplasia with no evidence of neoplastic cells. This case highlights two points: first, MHs that remain open after unsuccessful MH surgery can cause retinal tumors, leading to further visual loss; and second, in this case, the MH-associated tumor showed no evidence of neoplastic cells. PMID- 26985803 TI - Very Late Reactivation of Retinopathy of Prematurity After Monotherapy With Intravitreal Bevacizumab. AB - The authors report a case of very late reactivation of retinopathy of prematurity (ROP) after bevacizumab monotherapy. A female born at 630 g and 24 weeks received two bilateral treatment of bevacizumab (Avastin; Genentech, South San Francisco, CA) for aggressive posterior ROP (APROP). At 2.5 years of age, ROP reactivated in the form of tractional retinal detachment in one eye and milder reactivation in the other. Although intravitreal bevacizumab treatment is effective in inducing regression of ROP, late reactivation and retinal detachments can occur after initial extended quiescence. Due to alterations of disease progression after bevacizumab, close follow-up by peripheral fluorescein angiography and laser ablation of persistent avascular retina is recommended to prevent disease reactivation and progression to retinal detachment. PMID- 26985805 TI - A Novel Approach to Understanding Pathogenesis and Treatment of Capillary Dropout in Retinal Vascular Diseases. AB - Capillary dropout is a common sequela of endothelial cell dysfunction that underlies the pathology of multiple retinal vascular diseases, including familial exudative vitreoretinopathy (FEVR). Wide-field fluorescein angiography allowed for identification of areas of capillary inflammatory changes and late-phase angiographic posterior and peripheral vascular leakage (LAPPEL). We propose LAPPEL as a precursor in pathogenesis of capillary dropout and a marker of endothelial cell inflammation in the retina. The authors describe a case of FEVR with significant macular edema associated with LAPPEL, which was successfully treated with topical and intravitreal steroids. The implication for disease mechanism and potential future treatment applications are also discussed. PMID- 26985807 TI - 8 Questions with Dr. Puliafito. PMID- 26985806 TI - The Origin of Subretinal Fluid in Optic Disc Pit Maculopathy. AB - A surgical approach for the drainage of fluid leaking over the pit in optic disc pit maculopathy is described, and a theory of the origin of fluid is discussed. In two cases, complete fluid-air exchange was performed. The air infusion pressure was decreased to 5 mm Hg, and the collected fluid was drained by raising the infusion pressure to 25 mm Hg. The fluid inside the back-flush needle was routed via a microcentrifuge tube. Biochemical analyses of the fluids were conducted in order to find their origin. Results of the first and second case were comparable to normal cerebrospinal fluid (CSF) levels (chloride: 125 mmol/L, 122 mmol/L; sodium: 146 mmol/L, 147 mmol/L; potassium: 2.8 mmol/L, 3.0 mmol/L; protein: 29 mg/dL, 18.4 mg/ dL; and glucose: 60 mg/dL, 57 mg/dL, respectively). These findings suggest that the origin of subretinal fluid found in the submacular space in optic disc pit maculopathy is CSF. PMID- 26985809 TI - The Spanish "Century XXI" academy for developing elite level basketballers: design, monitoring and training methodologies. AB - OBJECTIVES: The XXI Century Academy was a 6-year state-initiated intervention program that served as an alternative to basketball clubs for players in the u-14 and u-18 age groups in Spain, under guidelines established by the Spanish Basketball Federation. It was an important and unique project on talent development in basketball. To the best of the authors' knowledge, no evidence has been reported on long-term athlete development programs in basketball worldwide. The main aim of this report is to describe the design and evaluation methods used for the XXI Century Academy as a long-term intervention program in the elite Spanish Basketball Academy, aiming to prepare basketball players to compete at the elite level. METHODS: The monitoring time lasted from 1996 to 2001. A total of 55 players were assigned to the intervention groups based on age, position, maturation level, and country of origin. During this process, participants competed in up to two categories in addition to playing competitive official matches worldwide in international tournaments in their categories and with the national team in the European and World Championships (u-14 - u-18). Participants included 1 NBA player, 3 national A Team players, 10 ACB (First Spanish League) players, 5 LEB (second League) players and 39 LEB-2 EBA (third League) players. Assessments took place in a High-Performance Sports Center (CPT FADURA-GETXO- Basque Government, Getxo, Vizcaya, Spain) and consisted of health questionnaires, anthropometric measures, blood parameters, maturation level, birth age, fitness tests, training volume and intensity, physical activity, technical and tactical training, dietary intake, supplementation and injuries. Each player was assessed 4 times per year (September, December, April, June) for 4 years (16 data points). RESULTS: This is a purely methodological paper describing the design and evaluation methods used in the XXI Century Project, which will be used as a basis for future reporting of results. Therefore, the results of the project will be reported in subsequent publications. CONCLUSION: The viability of the Century XXI Project protocols has been described. This national project of training in basketball closely replicates the physical and technical match-play conditions for professionals and may constitute a useful training tool. PMID- 26985811 TI - Sociocultural aspects of risk to pregnant women during the 2013-2015 multinational Ebola virus outbreak in West Africa. AB - Researchers reflect on sociocultural aspects of the Ebola outbreak in West Africa and critically analyze the epidemic's effects on pregnant mothers and their babies. We address structural inequalities contributing to poor maternal health in lower-income countries, while reflecting on how the Ebola outbreak highlights the still-marginalized role of pregnant women. Drawing on prior research in West and East Africa, we discuss health care providers' responses to risk of infection during maternity work under normal circumstances and in times of crisis. We end with recommendations for preventing such detrimental effects on the health of pregnant women in the case of another epidemic. PMID- 26985808 TI - Emerging nexus between RAB GTPases, autophagy and neurodegeneration. AB - The RAB class of small GTPases includes the major regulators of intracellular communication, which are involved in vesicle generation through fusion and fission, and vesicular trafficking. RAB proteins also play an imperative role in neuronal maintenance and survival. Recent studies in the field of neurodegeneration have also highlighted the process of autophagy as being essential for neuronal maintenance. Here we review the emerging roles of RAB proteins in regulating macroautophagy and its impact in the context of neurodegenerative diseases. PMID- 26985812 TI - Challenges in publication ethics. PMID- 26985814 TI - Intraoperative localisation of schottle's point without fluoroscopy during medial patellofemoral ligament reconstruction. PMID- 26985815 TI - A novel technique for sealing de-roofed renal allograft cysts. PMID- 26985813 TI - Meta-analysis of the diagnostic accuracy of laparoscopic ultrasonography and intraoperative cholangiography in detection of common bile duct stones. AB - Introduction During laparoscopic cholecystectomy, intraoperative cholangiography (IOC) is currently regarded as the gold standard in the detection of choledocholithiasis. Laparoscopic ultrasonography (LUS) is an attractive alternative with several potential advantages. Methods A systematic review was undertaken of the published literature comparing LUS with IOC in the assessment of common bile duct (CBD) stones. Results Twenty-one comparative studies were analysed. There were 4,566 patients in the IOC group and 5,044 in the LUS group. The combined sensitivity and specificity of IOC in the detection of CBD stones were 0.87 (95% confidence interval [CI]: 0.83-0.89) and 0.98 (95% CI: 0.98-0.98) respectively with a pooled area under the curve (AUC) of 0.985 and a diagnostic odds ratio (OR) of 260.65 (95% CI: 160.44-423.45). This compares with a sensitivity and specificity for LUS of 0.90 (95% CI: 0.87-0.92) and 0.99 (95% CI: 0.99-0.99) respectively with a pooled AUC of 0.982 and a diagnostic OR of 765.15 (95% CI: 450.78-1,298.76). LUS appeared to be more successful in terms of coming to a clinical decision regarding CBD stones than IOC (random effects, risk ratio: 0.95, 95% CI: 0.93-0.98, df=20, z=-3.7, p<0.005). Furthermore, LUS took less time (random effects, standardised mean difference: 0.95, 95% CI: 0.93-0.98, df=20, z= 3.7, p<0.005). Conclusions LUS is comparable with IOC in the detection of CBD stones. The main advantages of LUS are that it does not involve ionising radiation, is quicker to perform, has a lower failure rate and can be repeated during the procedure as required. PMID- 26985816 TI - Bilateral obstruction of bilaterally duplicated collecting systems requiring upper and lower moiety drainage. AB - A 60-year-old woman with a history of breast cancer presented with bilateral obstruction of bilaterally duplicated renal collecting systems secondary to extrinsic compression from metastatic pelvic lymphadenopathy. Bilateral JJ ureteric stents were inserted, resulting in some improvement of renal function but a failure to normalise completely. Repeat computed tomography demonstrated bilateral duplex collecting systems with persisting obstruction of the undrained moieties. Selective puncture was performed to decompress the obstructed renal moieties for bilateral nephrostomy catheter insertion. This allowed renal function to improve sufficiently for the patient to be discharged and commence chemotherapy. This is the first reported case of bilaterally obstructed partially duplicated collecting systems and it illustrates the importance of recognising anatomical variants to tailor treatment appropriately. It also highlights the important relationship between urology and interventional radiology in the management of such complex patients. PMID- 26985817 TI - Aortic bypass surgery using synthetic conduits in a child with mycotic aneurysmal disease. AB - A six-year-old child developed multiple aortic aneurysms as a consequence of fungal infection following thoracic aortic surgery for coarctation. Several repairs of both the thoracic and abdominal aorta were carried out using synthetic material combined with long-term postoperative antifungal treatment. We describe the surgical interventions performed and follow-up. The choice of conduit continues to be the main concern; however, when other alternatives are not available, synthetic material combined with indefinite antifungal treatment can produce satisfactory medium-term results. PMID- 26985818 TI - Perineal herniation of an ileal neobladder following radical cystectomy and consecutive rectal resection for recurrent bladder carcinoma. AB - Secondary perineal herniation of intraperitoneal contents represents a rare complication following procedures such as abdominoperineal rectal resection or cystectomy. We present a case of a perineal hernia formation with prolapse of an ileum neobladder following radical cystectomy and rectal resection for recurrent bladder cancer. Following consecutive resections in the anterior and posterior compartment of the lesser pelvis, the patient developed problems emptying his neobladder. Clinical examination and computed tomography revealed perineal herniation of his neobladder through the pelvic floor. Through a perineal approach, the hernial sac could be repositioned, and via a combination of absorbable and non-absorbable synthetic mesh grafts, the pelvic floor was stabilised. Follow-up review at one year after hernia fixation showed no signs of recurrence and no symptoms. In cases of extensive surgery in the lesser pelvis with associated weakness of the pelvic compartments, meshes should be considered for closure of the pelvic floor. Development of biological meshes with reduced risk of infection might be an interesting treatment option in these cases. PMID- 26985819 TI - Interspecific Interactions and the Scope for Parent-Offspring Conflict: High Mite Density Temporarily Changes the Trade-Off between Offspring Size and Number in the Burying Beetle, Nicrophorus vespilloides. AB - Parents have a limited amount of resources to invest in reproduction and commonly trade-off how much they invest in offspring size (or quality) versus brood size. A negative relationship between offspring size and number has been shown in numerous taxa and it underpins evolutionary conflicts of interest between parents and their young. For example, previous work on vertebrates shows that selection favours mothers that produce more offspring, at the expense of individual offspring size, yet favours offspring that have relatively few siblings and therefore attain a greater size at independence. Here we analyse how this trade off is temporarily affected by stochastic variation in the intensity of interspecific interactions. We examined the effect of the mite Poecilochirus carabi on the relationship between offspring size and number in the burying beetle, Nicrophorus vespilloides. We manipulated the initial number of mites in the reproductive event (by introducing either no mites, 4 mites, 10 mites, or 16 mites), and assessed the effect on the brood. We found a similar trade-off between offspring size and number in all treatments, except in the '16 mite' treatment where the correlation between offspring number and size flattened considerably. This effect arose because larvae in small broods failed to attain a high mass by dispersal. Our results show that variation in the intensity of interspecific interactions can temporarily change the strength of the trade-off between offspring size and number. In this study, high densities of mites prevented individual offspring from attaining their optimal weight, thus potentially temporarily biasing the outcome of parent-offspring conflict in favour of parents. PMID- 26985820 TI - TESTIN Induces Rapid Death and Suppresses Proliferation in Childhood B Acute Lymphoblastic Leukaemia Cells. AB - BACKGROUND: Childhood acute lymphoblastic leukaemia (ALL) is the most common malignancy in children. Despite high cure rates, side effects and late consequences of the intensive treatments are common. Unquestionably, the identification of new therapeutic targets will lead to safer, more effective treatments. We identified TES promoter methylation and transcriptional silencing as a very common molecular abnormality in childhood ALL, irrespective of molecular subtype. The aims of the present study were to demonstrate that TES promoter methylation is aberrant, to determine the effects of TES re-expression in ALL, and to determine if those effects are mediated via TP53 activity. METHODS: Normal fetal and adult tissue DNA was isolated and TES promoter methylation determined by Sequenom MassARRAY. Quantitative RT-PCR and immunoblot were used to confirm re-expression of TES in ALL cell lines after 5'-aza-2' deoxycytidine (decitabine) exposure or transfection with TES expression plasmids. The effects of TES re-expression on ALL cells were investigated using standard cell proliferation, cell death and cell cycle assays. RESULTS: In this study, we confirm that the TES promoter is unmethylated in normal adult and fetal tissues. We report that decitabine treatment of ALL cell lines results in demethylation of the TES promoter and attendant expression of TES mRNA. Re-expression of TESTIN protein in ALL cells using expression plasmid transfection results in rapid cell death or cell cycle arrest independent of TP53 activity. CONCLUSIONS: These results suggest that TES is aberrantly methylated in ALL and that re-expression of TESTIN has anti-leukaemia effects which point to novel therapeutic opportunities for childhood ALL. PMID- 26985821 TI - Profiling Ethylene-Responsive Genes Expressed in the Latex of the Mature Virgin Rubber Trees Using cDNA Microarray. AB - Ethylene is commonly used as a latex stimulant of Hevea brasiliensis by application of ethephon (chloro-2-ethylphosphonic acid); however, the molecular mechanism by which ethylene increases latex production is not clear. To better understand the effects of ethylene stimulation on the laticiferous cells of rubber trees, a latex expressed sequence tag (EST)-based complementary DNA microarray containing 2,973 unique genes (probes) was first developed and used to analyze the gene expression changes in the latex of the mature virgin rubber trees after ethephon treatment at three different time-points: 8, 24 and 48 h. Transcript levels of 163 genes were significantly altered with fold-change values >= 2 or <= -2 (q-value < 0.05) in ethephon-treated rubber trees compared with control trees. Of the 163 genes, 92 were up-regulated and 71 down-regulated. The microarray results were further confirmed using real-time quantitative reverse transcript-PCR for 20 selected genes. The 163 ethylene-responsive genes were involved in several biological processes including organic substance metabolism, cellular metabolism, primary metabolism, biosynthetic process, cellular response to stimulus and stress. The presented data suggest that the laticifer water circulation, production and scavenging of reactive oxygen species, sugar metabolism, and assembly and depolymerization of the latex actin cytoskeleton might play important roles in ethylene-induced increase of latex production. The results may provide useful insights into understanding the molecular mechanism underlying the effect of ethylene on latex metabolism of H. brasiliensis. PMID- 26985822 TI - Guideline Adherence in Outpatient Clinics for Chronic Obstructive Pulmonary Disease: Results from a Clinical Audit. AB - OBJECTIVES: Previous clinical audits of COPD have provided relevant information about medical intervention in exacerbation admissions. The present study aims to evaluate adherence to current guidelines in COPD through a clinical audit. METHODS: This is a pilot clinical audit performed in hospital outpatient respiratory clinics in Andalusia, Spain (eight provinces with more than 8 million inhabitants), including 9 centers (20% of the public centers in the area) between 2013 and 2014. Cases with an established diagnosis of COPD based on risk factors, clinical symptoms, and a post-bronchodilator FEV1/FVC ratio of less than 0.70 were deemed eligible. The performance of the outpatient clinics was benchmarked against three guidance documents available at the time of the audit. The appropriateness of the performance was categorized as excellent (>80%), good (60 80%), adequate (40-59%), inadequate (20-39%), and highly inadequate (<20%). RESULTS: During the audit, 621 clinical records were audited. Adherence to the different guidelines presented a considerable variability among the different participating hospitals, with an excellent or good adherence for symptom recording, MRC or CAT use, smoking status evaluation, spirometry, or bronchodilation therapy. The most outstanding areas for improvement were the use of the BODE index, the monitoring of treatments, the determination of alpha1 antitrypsin, the performance of exercise testing, and vaccination recommendations. CONCLUSIONS: The present study reflects the situation of clinical care for COPD patients in specialized secondary care outpatient clinics. Adherence to clinical guidelines shows considerable variability in outpatient clinics managing COPD patients, and some aspects of the clinical care can clearly be improved. PMID- 26985824 TI - Focal Plant Observations as a Standardised Method for Pollinator Monitoring: Opportunities and Limitations for Mass Participation Citizen Science. AB - BACKGROUND: Recently there has been increasing focus on monitoring pollinating insects, due to concerns about their declines, and interest in the role of volunteers in monitoring pollinators, particularly bumblebees, via citizen science. METHODOLOGY / PRINCIPAL FINDINGS: The Big Bumblebee Discovery was a one year citizen science project run by a partnership of EDF Energy, the British Science Association and the Centre for Ecology & Hydrology which sought to assess the influence of the landscape at multiple scales on the diversity and abundance of bumblebees. Timed counts of bumblebees (Bombus spp.; identified to six colour groups) visiting focal plants of lavender (Lavendula spp.) were carried out by about 13 000 primary school children (7-11 years old) from over 4000 schools across the UK. 3948 reports were received totalling 26 868 bumblebees. We found that while the wider landscape type had no significant effect on reported bumblebee abundance, the local proximity to flowers had a significant effect (fewer bumblebees where other flowers were reported to be >5m away from the focal plant). However, the rate of mis-identifcation, revealed by photographs uploaded by participants and a photo-based quiz, was high. CONCLUSIONS / SIGNIFICANCE: Our citizen science results support recent research on the importance of local flocal resources on pollinator abundance. Timed counts of insects visiting a lure plant is potentially an effective approach for standardised pollinator monitoring, engaging a large number of participants with a simple protocol. However, the relatively high rate of mis-identifications (compared to reports from previous pollinator citizen science projects) highlights the importance of investing in resources to train volunteers. Also, to be a scientifically valid method for enquiry, citizen science data needs to be sufficiently high quality, so receiving supporting evidence (such as photographs) would allow this to be tested and for records to be verified. PMID- 26985826 TI - A Directed Acyclic Graph-Large Margin Distribution Machine Model for Music Symbol Classification. AB - Optical Music Recognition (OMR) has received increasing attention in recent years. In this paper, we propose a classifier based on a new method named Directed Acyclic Graph-Large margin Distribution Machine (DAG-LDM). The DAG-LDM is an improvement of the Large margin Distribution Machine (LDM), which is a binary classifier that optimizes the margin distribution by maximizing the margin mean and minimizing the margin variance simultaneously. We modify the LDM to the DAG-LDM to solve the multi-class music symbol classification problem. Tests are conducted on more than 10000 music symbol images, obtained from handwritten and printed images of music scores. The proposed method provides superior classification capability and achieves much higher classification accuracy than the state-of-the-art algorithms such as Support Vector Machines (SVMs) and Neural Networks (NNs). PMID- 26985823 TI - Phthalates Are Metabolised by Primary Thyroid Cell Cultures but Have Limited Influence on Selected Thyroid Cell Functions In Vitro. AB - Phthalates are plasticisers added to a wide variety of products, resulting in measurable exposure of humans. They are suspected to disrupt the thyroid axis as epidemiological studies suggest an influence on the peripheral thyroid hormone concentration. The mechanism is still unknown as only few in vitro studies within this area exist. The aim of the present study was to investigate the influence of three phthalate diesters (di-ethyl phthalate, di-n-butyl phthalate (DnBP), di-(2 ethylhexyl) phthalate (DEHP)) and two monoesters (mono-n-butyl phthalate and mono (2-ethylhexyl) phthalate (MEHP)) on the differentiated function of primary human thyroid cell cultures. Also, the kinetics of phthalate metabolism were investigated. DEHP and its monoester, MEHP, both had an inhibitory influence on 3'-5'-cyclic adenosine monophosphate secretion from the cells, and MEHP also on thyroglobulin (Tg) secretion from the cells. Results of the lactate dehydrogenase measurements indicated that the MEHP-mediated influence was caused by cell death. No influence on gene expression of thyroid specific genes (Tg, thyroid peroxidase, sodium iodine symporter and thyroid stimulating hormone receptor) by any of the investigated diesters could be demonstrated. All phthalate diesters were metabolised to the respective monoester, however with a fall in efficiency for high concentrations of the larger diesters DnBP and DEHP. In conclusion, human thyroid cells were able to metabolise phthalates but this phthalate exposure did not appear to substantially influence selected functions of these cells. PMID- 26985825 TI - Systems Pharmacology and Rational Polypharmacy: Nitric Oxide-Cyclic GMP Signaling Pathway as an Illustrative Example and Derivation of the General Case. AB - Impaired nitric oxide (NO)-cyclic guanosine 3', 5'-monophosphate (cGMP) signaling has been observed in many cardiovascular disorders, including heart failure and pulmonary arterial hypertension. There are several enzymatic determinants of cGMP levels in this pathway, including soluble guanylyl cyclase (sGC) itself, the NO activated form of sGC, and phosphodiesterase(s) (PDE). Therapies for some of these disorders with PDE inhibitors have been successful at increasing cGMP levels in both cardiac and vascular tissues. However, at the systems level, it is not clear whether perturbation of PDE alone, under oxidative stress, is the best approach for increasing cGMP levels as compared with perturbation of other potential pathway targets, either alone or in combination. Here, we develop a model-based approach to perturbing this pathway, focusing on single reactions, pairs of reactions, or trios of reactions as targets, then monitoring the theoretical effects of these interventions on cGMP levels. Single perturbations of all reaction steps within this pathway demonstrated that three reaction steps, including the oxidation of sGC, NO dissociation from sGC, and cGMP degradation by PDE, exerted a dominant influence on cGMP accumulation relative to other reaction steps. Furthermore, among all possible single, paired, and triple perturbations of this pathway, the combined perturbations of these three reaction steps had the greatest impact on cGMP accumulation. These computational findings were confirmed in cell-based experiments. We conclude that a combined perturbation of the oxidatively-impaired NO-cGMP signaling pathway is a better approach to the restoration of cGMP levels as compared with corresponding individual perturbations. This approach may also yield improved therapeutic responses in other complex pharmacologically amenable pathways. PMID- 26985827 TI - Acute High-Dose and Chronic Lifetime Exposure to Alcohol Consumption and Differentiated Thyroid Cancer: T-CALOS Korea. AB - BACKGROUND: This study evaluated the effects of acute high-dose and chronic lifetime exposure to alcohol and exposure patterns on the development of differentiated thyroid cancer (DTC). METHODS: The Thyroid Cancer Longitudinal Study (T-CALOS) included 2,258 DTC patients (449 men and 1,809 women) and 22,580 healthy participants (4,490 men and 18,090 women) who were individually matched by age, gender, and enrollment year. In-person interviews were conducted with a structured questionnaire to obtain epidemiologic data. Clinicopathologic features of the patients were obtained by chart reviews. Odds ratios (ORs) and 95% confidence intervals (95%CI) were estimated using conditional regression models. RESULTS: While light or moderate drinking behavior was related to a reduced risk of DTC, acute heavy alcohol consumption (151 g or more per event or on a single occasion) was associated with increased risks in men (OR = 2.22, 95%CI = 1.27 3.87) and women (OR = 3.61, 95%CI = 1.52-8.58) compared with never-drinkers. The consumption of alcohol for 31 or more years was a significant risk factor for DTC for both men (31-40 years: OR = 1.58, 95%CI = 1.10-2.28; 41+ years: OR = 3.46, 95%CI = 2.06-5.80) and women (31-40 years: OR = 2.18, 95%CI = 1.62-2.92; 41+ years: OR = 2.71, 95%CI = 1.36-5.05) compared with never-drinkers. The consumption of a large amount of alcohol on a single occasion was also a significant risk factor, even after restricting DTC outcomes to tumor size, lymph node metastasis, extrathyroidal extension and TNM stage. CONCLUSION: The findings of this study suggest that the threshold effects of acute high-dose alcohol consumption and long-term alcohol consumption are linked to an increased risk of DTC. PMID- 26985829 TI - Phenotypically Dormant and Immature Leukaemia Cells Display Increased Ribosomal Protein S6 Phosphorylation. AB - Mechanistic/mammalian target of rapamycin (mTOR) activity drives a number of key metabolic processes including growth and protein synthesis. Inhibition of the mTOR pathway promotes cellular dormancy. Since cells from patients with acute myeloid leukaemia (AML) can be phenotypically dormant (quiescent), we examined biomarkers of their mTOR pathway activity concurrently with Ki-67 and CD71 (indicators of cycling cells) by quantitative flow cytometry. Using antibodies to phosphorylated epitopes of mTOR (S2448) and its downstream targets ribosomal protein S6 (rpS6, S235/236) and 4E-BP1 (T36/45), we documented that these phosphorylations were negligible in lymphocytes, but evident in dormant as well as proliferating subsets of both mobilised normal stem cell harvest CD34+ cells and AML blasts. Although mTOR phosphorylation in AML blasts was lower than that of the normal CD34+ cells, p-4E-BP1 was 2.6-fold higher and p-rpS6 was 22-fold higher. Moreover, in contrast to 4E-BP1, rpS6 phosphorylation was higher in dormant than proliferating AML blasts, and was also higher in the immature CD34+CD38- blast subset. Data from the Cancer Genome Atlas show that rpS6 expression is associated with that of respiratory chain enzymes in AML. We conclude that phenotypic quiescence markers do not necessarily predict metabolic dormancy and that elevated rpS6 ser235/236 phosphorylation is characteristic of AML. PMID- 26985828 TI - Differential Growth Responses of Marine Phytoplankton to Herbicide Glyphosate. AB - Glyphosate is a globally popular herbicide to kill weeds and its wide applications may lead to accumulation in coastal oceans as a source of phosphorus (P) nutrient or growth inhibitor of phytoplankton. We studied the physiological effects of glyphosate on fourteen species representing five major coastal phytoplankton phyla (haptophyta, bacillariophyta, dinoflagellata, raphidophyta, and chlorophyta). Based on growth responses to different concentrations of glyphosate under contrasting dissolved inorganic phosphorus (DIP) conditions, we found that phytoplankton species could be classified into five groups. Group I (Emiliania huxleyi, Skeletonema costatum, Phaeodactylum tricornutum) could utilize glyphosate as sole P-source to support growth in axenic culture, but in the presence of DIP, they were inhibited by both 36-MUM and 360-MUM glyphosate. Group II (Karenia mikimotoi, Prorocentrum minimum, Dunaliella tertiolecta, Symbiodinium sp., Heterosigma akashiwo and Alexandrium catenella) could not utilize glyphosate as sole P-source to support growth, and in the presence of DIP growth was not affected by 36-MUM but inhibited by 360-MUM glyphosate. Glyphosate consistently enhanced growth of Group III (Isochrysis galbana) and inhibited Group IV (Thalassiosira weissflogii, Thalassiosira pseudonana and Chattonella marina) regardless of DIP condition. Group V (Amphidinium carterae) exhibited no measurable response to glyphosate regardless of DIP condition. This grouping is not congruent with the phylogenetic relationships of the phytoplankton species suggesting functional differentiation driven by environmental pressure. We conclude that glyphosate could be used as P-source by some species while is toxic to some other species and yet has no effects on others. The observed differential effects suggest that the continued use of glyphosate and increasing concentration of this herbicide in the coastal waters will likely exert significant impact on coastal marine phytoplankton community structure. PMID- 26985830 TI - Effects of Stormwater and Snowmelt Runoff on ELISA-EQ Concentrations of PCDD/PCDF and Triclosan in an Urban River. AB - The aim of the study was to determine the effects of stormwater and snowmelt runoff on the ELISA EQ PCDD/PCDF and triclosan concentrations in the small urban Sokolowka River (Central Poland). The obtained results demonstrate the decisive influence of hydrological conditions occurring in the river itself and its catchment on the quoted PCDD/PCDF ELISA EQ concentrations. The lowest PCDD/PCDF values of 87, 60 and 67 ng EQ L-1 in stormwater, the river and its reservoirs, respectively, were associated with the highest river flow of 0.02 m3 s-1 and high precipitation (11.2 mm) occurred five days before sampling. In turn, the highest values of 353, 567 and 343 ng EQ L-1 in stormwater, the river and its reservoirs, respectively, were observed during periods of intensive snow melting (stormwater samples) and spring rainfall preceded by a rainless phase (river and reservoir samples) followed by low and moderate river flows of 0.01 and 0.005 m3 s-1. An analogous situation was observed for triclosan, with higher ELISA EQ concentrations (444 to 499 ng EQ L-1) noted during moderate river flow and precipitation, and the lowest (232 to 288 ng EQ L-1) observed during high river flow and high precipitation preceded by violent storms. Stormwater was also found to influence PCDD/PCDF EQ concentrations of the river and reservoirs, however only during high and moderate flow, and no such effect was observed for triclosan. The study clearly demonstrates that to mitigate the high peaks of the studied pollutants associated with river hydrology, the increased in-site stormwater infiltration and purification, the development of buffering zones along river course and the systematic maintenance of reservoirs to avoid the accumulation of the studied micropollutants and their subsequent release after heavy rainfall are required. PMID- 26985832 TI - High Mortality of Disseminated Non-Tuberculous Mycobacterial Infection in HIV Infected Patients in the Antiretroviral Therapy Era. AB - BACKGROUND: Little information is available on the mortality and risk factors associated with death in disseminated non-tuberculous mycobacterial infection (dNTM) in HIV-infected patients in the ART-era. METHODS: In a single-center study, HIV-infected dNTM with positive NTM culture from sterile sites between 2000 and 2013 were analysed. The clinical characteristics at commencement of anti mycobacterial treatment (baseline) were compared between those who survived and died. RESULTS: Twenty-four patients were analyzed. [The median CD4 27/MUL (range 2-185)]. Mycobacterium avium and M. intracellulare accounted for 20 (83%) and 3 (13%) of isolated NTM. NTM bacteremia was diagnosed in 15 (63%) patients. Seven (29%) patients died, and NTM bacteremia was significantly associated with mortality (p = 0.022). The baseline CD4 count was significantly lower in the non survivors than the survivors (median 7/MUL versus 49, p = 0.034). Concomitant AIDS-defining diseases or malignancies were not associated with mortality. Immune reconstitution syndrome (IRS) occurred to 19 (79%) patients (8 paradoxical and 11 unmasking), and prognosis tended to be better in unmasking-IRS than the other patients (n = 13) (p = 0.078). Patients with paradoxical-IRS had marginally lower CD4 count and higher frequency of bacteremia than those with unmasking-IRS (p = 0.051, and 0.059). Treatment with systemic corticosteroids was applied in 63% and 55% of patients with paradoxical and unmasking-IRS, respectively. CONCLUSION: dNTM in HIV-infected patients resulted in high mortality even in the ART-era. NTM bacteremia and low CD4 count were risk factors for death, whereas patients presented with unmasking-IRS had marginally better prognosis. IRS occurred in 79% of the patients, suggesting difficulty in the management of dNTM. PMID- 26985833 TI - Recent advances in the neuroimaging and neuropsychology of cerebral palsy. AB - This article reviews the recent advances in understanding of cerebral palsy (CP) and outlines how these advances could inform pediatric neuropsychological rehabilitation. Three main areas are discussed: the improved delineation of differing presentations resulting from more advanced imaging techniques with emerging links to function; a brief review of research examining neuropsychological functioning of children with CP and their quality of life and participation; and lastly, some of the evidence for efficacious interventions and the extent to which these interventions are derived from neuropsychological theory and practice. Advances and gaps in knowledge in addition to suggestions of areas for future focus in research and practice are discussed throughout the article. PMID- 26985834 TI - Vascular endothelial growth factor inhibitor use and treatment approach for choroidal neovascularization secondary to pathologic myopia. AB - INTRODUCTION: Myopic choroidal neovascularization (CNV) is the most common cause of CNV in those under 50 years of age. It is a significant cause of visual loss in those with pathologic myopia. The current standard of care involves therapy with intravitreal inhibitors of vascular endothelial growth factor (VEGF). AREAS COVERED: The epidemiology of myopia, high myopia, pathologic myopia, and myopic CNV is reviewed, along with a brief discussion of historical treatments. The pharmacology of the three most commonly used anti-VEGF agents is discussed, with an emphasis on the licensed drugs, ranibizumab and aflibercept. A comprehensive clinical approach to diagnosis and treatment of myopic CNV is presented. EXPERT OPINION: The current standard of care for myopic CNV is intravitreal inhibition of VEGF, with ranibizumab and aflibercept licensed for intraocular use. The diagnosis, OCT features of disease activity and retreatment algorithm for myopic CNV is different from wet age-related macular degeneration. In the long-term, myopic CNV may be associated with gradual, irreversible visual loss due to progressive chorioretinal atrophy, for which there is currently no treatment. PMID- 26985831 TI - Probiotic Gut Microbiota Isolate Interacts with Dendritic Cells via Glycosylated Heterotrimeric Pili. AB - Mapping of the microbial molecules underlying microbiota-host interactions is key to understand how microbiota preserve mucosal homeostasis. A pivotal family of such bacterial molecules are pili. Pili are proteinaceous cell wall appendages with a well-documented role in adhesion, whilst their role in immune interaction with the host is less established. Gram-positive pili are often posttranslationally modified by sortase-specific cleavage reactions and the formation of intramolecular peptide bonds. Here we report glycosylation as a new level of posttranslational modification of sortase-dependent pili of a beneficial microbiota species and its role in immune modulation. We focused on the SpaCBA pili of the model probiotic and beneficial human gut microbiota isolate Lactobacillus rhamnosus GG. A unique combination of molecular techniques, nanoscale mechanical and immunological approaches led to the identification of mannose and fucose residues on the SpaCBA pili. These glycans on the pili are recognized by human dendritic cells via the C-type lectin receptor DC-SIGN, a key carbohydrate-dependent immune tailoring pattern recognition receptor. This specific lectin-sugar interaction is moreover of functional importance and modulated the cytokine response of dendritic cells. This provides insight into the direct role bacterial glycoproteins can play in the immunomodulation of the host. Modification of the complex heterotrimeric pili of a model probiotic and microbiota isolate with mannose and fucose is of importance for the functional interaction with the host immune lectin receptor DC-SIGN on human dendritic cells. Our findings shed light on the yet underappreciated role of glycoconjugates in bacteria-host interactions. PMID- 26985836 TI - Self-sampling HPV testing versus mainstream cervical screening and HPV testing. PMID- 26985837 TI - A warning against heart disease complacency in 2016. PMID- 26985838 TI - Integrative medicine: more than the promotion of unproven treatments? PMID- 26985839 TI - Recording consultations: a win-win situation for physicians and patients. PMID- 26985840 TI - "Good kid, mad system": the role for health in reforming justice for vulnerable communities. PMID- 26985841 TI - Identifying low-value care: the Royal Australasian College of Physicians' EVOLVE initiative. PMID- 26985842 TI - A case of acute phosphate nephropathy. PMID- 26985844 TI - Antioxidant supplementation and cancer patients receiving curative-intent chemotherapy. PMID- 26985845 TI - First report of Zika virus infection in a returned traveller from the Solomon Islands. PMID- 26985843 TI - HPV vaccine impact in Australian women: ready for an HPV-based screening program. PMID- 26985846 TI - Barriers to reforming low-value care. PMID- 26985847 TI - Gene panel testing for hereditary breast cancer. AB - Inherited predisposition to breast cancer is explained only in part by mutations in the BRCA1 and BRCA2 genes. Most families with an apparent familial clustering of breast cancer who are investigated through Australia's network of genetic services and familial cancer centres do not have mutations in either of these genes. More recently, additional breast cancer predisposition genes, such as PALB2, have been identified. New genetic technology allows a panel of multiple genes to be tested for mutations in a single test. This enables more women and their families to have risk assessment and risk management, in a preventive approach to predictable breast cancer. Predictive testing for a known family specific mutation in a breast cancer predisposition gene provides personalised risk assessment and evidence-based risk management. Breast cancer predisposition gene panel tests have a greater diagnostic yield than conventional testing of only the BRCA1 and BRCA2 genes. The clinical validity and utility of some of the putative breast cancer predisposition genes is not yet clear. Ethical issues warrant consideration, as multiple gene panel testing has the potential to identify secondary findings not originally sought by the test requested. Multiple gene panel tests may provide an affordable and effective way to investigate the heritability of breast cancer. PMID- 26985849 TI - Impact of HPV sample self-collection for underscreened women in the renewed Cervical Screening Program. AB - OBJECTIVES: In 2017, the National Cervical Screening Program in Australia will transition to 5-yearly primary HPV screening for all women, irrespective of human papillomavirus (HPV) vaccination status. As an adjunct to the mainstream program, HPV testing on self-collected samples will be offered under practitioner supervision to all unscreened and underscreened women aged 30-74 years. We quantified how different screening decisions affect the future risk of cervical cancer. DESIGN: Simulation of outcomes for 100 000 previously unscreened women, aged 30 years and eligible for self-collection, using a well-established model of HPV natural history and cervical screening. MAIN OUTCOME MEASURES: Cumulative cancer diagnoses and deaths averted (compared with remaining unscreened) to age 84, number needed to treat for pre-cancer (NNT) to avert each cancer diagnosis. RESULTS: One round of self-collected HPV screening at age 30 years would avert 908 cancer diagnoses and 364 cancer deaths in the cohort by age 84 (NNT, 5.8). Benefits would still be achieved were self-collected screening delayed to age 40 (922 fewer diagnoses; 426 fewer deaths; NNT, 3.7) or 50 (684 fewer diagnoses; 385 fewer deaths; NNT, 3.2). However, the benefits associated with joining the mainstream screening program would be substantially larger (2002, 1623 or 1091 fewer diagnoses and NNT of 4.9, 3.7 or 3.4 by joining at age 30, 40 or 50 years respectively). The relative benefits of joining the mainstream program were similar for cohorts who had been offered vaccination. CONCLUSIONS: Offering HPV self-collection has the potential to considerably improve outcomes for unscreened and underscreened women. Nevertheless, these findings underscore the need for concerted strategies to encourage these women to join the mainstream HPV screening program. PMID- 26985848 TI - Clinical practice guidelines for dementia in Australia. AB - About 9% of Australians aged 65 years and over have a diagnosis of dementia. Clinical practice guidelines aim to enhance research translation by synthesising recent evidence for health and aged care professionals. New clinical practice guidelines and principles of care for people with dementia detail the optimal diagnosis and management in community, residential and hospital settings. The guidelines have been approved by the National Health and Medical Research Council. The guidelines emphasise timely diagnosis; living well with dementia and delaying functional decline; managing symptoms through training staff in how to provide person-centred care and using non-pharmacological approaches in the first instance; and training and supporting families and carers to provide care. PMID- 26985850 TI - The Burns Registry of Australia and New Zealand: progressing the evidence base for burn care. AB - OBJECTIVE: Analysis of data from the Burns Registry of Australia and New Zealand (BRANZ) to determine the extent of variation between participating units in treatment and in specific outcomes during the first 4 years of its operation. DESIGN: BRANZ, an initiative of the Australian and New Zealand Burn Association, is a clinical quality registry developed in accordance with the Australian Commission on Safety and Quality in Healthcare national operating principles. SETTING: Patients with burn injury who fulfil pre-defined criteria are transferred to and managed in designated burn units. There are 17 adult and paediatric units in Australia and New Zealand that manage almost all patients with significant burn injury. Twelve of these units treat adult patients. PARTICIPANTS: Data on 7184 adult cases were contributed by ten acute adult burn units to the registry between July 2010 and June 2014.Major outcomes: In-hospital mortality, hospital length of stay, skin grafting rates, and rates of admission to intensive care units. RESULTS: Considerable variations in unit profiles (including numbers of patients treated), in treatment and in outcomes were identified. CONCLUSIONS: Despite the highly centralised delivery of care to patients with severe or complex burn injury, and the relatively small number of specialist burn units, we found significant variation between units in clinical management and in outcomes. BRANZ data from its first 4 years of operation support its feasibility and the value of further development of the registry. Based on these results, the focus of ongoing research is to improve understanding of the reasons for variations in practice and of their effect on outcomes for patients, and to develop evidence-informed clinical guidelines for burn management in Australia and New Zealand. PMID- 26985851 TI - Economic evaluation of Indigenous health worker management of poorly controlled type 2 diabetes in north Queensland. AB - OBJECTIVE: To conduct an economic evaluation of intensive management by Indigenous health workers (IHWs) of Indigenous adults with poorly controlled type 2 diabetes in rural and remote north Queensland. DESIGN: Cost-consequence analysis alongside a cluster randomised controlled trial of an intervention delivered between 1 March 2012 and 5 September 2013. SETTING: Twelve primary health care services in rural and remote north Queensland communities with predominantly Indigenous populations. PARTICIPANTS: Indigenous adults with poorly controlled type 2 diabetes (HbA1c >= 69 mmol/mol) and at least one comorbidity (87 people in six IHW-supported communities (IHW-S); 106 in six usual care (UC) communities). MAIN OUTCOME MEASURES: Per person cost of the intervention; differential changes in mean HbA1c levels, percentage with extremely poor HbA1c level control, quality of life, disease progression, and number of hospitalisations. RESULTS: The mean cost of the 18-month intervention trial was $10 060 per person ($6706 per year). The intervention was associated with a non significantly greater reduction in mean HbA1c levels in the IHW-S group (-10.1 mmol/mol v -5.4 mmol/mol in the UC group; P = 0.17), a significant reduction in the proportion with extremely poor diabetes control (HbA1c >= 102 mmol/mol; P = 0.002), and a sub-significant differential reduction in hospitalisation rates for type 2 diabetes as primary diagnosis (-0.09 admissions/person/year; P = 0.06), with a net reduction in mean annual hospital costs of $646/person (P = 0.07). Quality of life utility scores declined in both groups (between-group difference, P = 0.62). Rates of disease progression were high in both groups (between-group difference, P = 0.73). CONCLUSION: Relative to the high cost of the intervention, the IHW-S model as implemented is probably a poor investment. Incremental cost effectiveness might be improved by a higher caseload per IHW, a longer evaluation time frame, and improved service integration. Further approaches to improving chronic disease outcomes in this very unwell population need to be explored, including holistic approaches that address the complex psychosocial, pathophysiological and environmental problems of highly disadvantaged populations. TRIAL REGISTRATION: ANZCTR12610000812099. PMID- 26985852 TI - Effectiveness of the Koorliny Moort out-of-hospital health care program for Aboriginal and Torres Strait Islander children in Western Australia. AB - OBJECTIVES: To determine whether the Koorliny Moort program could reduce emergency department presentations, hospital admissions and length of stay, and improve attendance at out-of-hospital appointments for Aboriginal and Torres Strait Islander children in Western Australia. DESIGN: Children were enrolled in the program from 1 August 2012. Each child acted as their own control. Evaluation data were collected from 1 August 2010 to 31 July 2014. Occasions of service and person-time in days were compared for each child before and after referral to the program. SETTING AND PARTICIPANTS: Aboriginal children aged 0-16 years residing in three WA regions (Kimberley, Pilbara, Perth metropolitan) who were referred to the Koorliny Moort program. INTERVENTIONS: Partnerships with primary care providers; nurse-led care coordination; and outreach care by paediatricians, nurses and social workers closer to the home of the child. MAIN OUTCOME MEASURES: Emergency department presentations; hospital admissions; length of hospital stay; non-attended appointments. RESULTS: A total of 942 children were referred to the program. There were significant decreases after referral to the program in the incidence of emergency department presentations (incident rate ratio [IRR], 0.47; 95% CI, 0.43-0.53; P < 0.001), of hospitalisation (IRR, 0.70; 95% CI, 0.62-0.79; P < 0.001), and of non-attended appointments (IRR, 0.83; 95% CI, 0.74-0.94; P < 0.001), as well as in the mean length of hospital stay (IRR, 0.23; 95% CI, 0.21 0.25; P < 0.001). CONCLUSIONS: Health-seeking behaviour and health outcomes for Aboriginal children can be improved by engaging Aboriginal families in their health care, providing effective communication between health service providers, and delivering a coordinated program of Aboriginal service provider-led care. PMID- 26985854 TI - Henry Krum: clinician, researcher and scientist. PMID- 26985853 TI - Teledermatology and clinical photography: safeguarding patient privacy and mitigating medico-legal risk. AB - Capturing clinical images is becoming more prevalent in everyday clinical practice, and dermatology lends itself to the use of clinical photographs and teledermatology. "Store-and-forward", whereby clinical images are forwarded to a specialist who later responds with an opinion on diagnosis and management is a popular form of teledermatology. Store-and-forward teledermatology has proven accurate and reliable, accelerating the process of diagnosis and treatment and improving patient outcomes. Practitioners' personal smartphones and other devices are often used to capture and communicate clinical images. Patient privacy can be placed at risk with the use of this technology. Practitioners should obtain consent for taking images, explain how they will be used, apply appropriate security in their digital communications, and delete images and other data on patients from personal devices after saving these to patient health records. Failing to use appropriate security precautions poses an emerging medico-legal risk for practitioners. PMID- 26985856 TI - SKA1 regulates the metastasis and cisplatin resistance of non-small cell lung cancer. AB - Currently, chemotherapy with platinum-based drugs including cisplatin is the most effective therapy for the treatment of non-small cell lung carcinoma (NSCLC). However, the efficacy of chemotherapy is limited due to commonly developed drug resistance. Spindle and kinetochore-associated complex subunit 1 (SKA1) is part of a complex essential for stabilizing the attachment of spindle microtubules to kinetochores and for maintaining the metaphase plate during mitosis. In the present study, we aimed to investigate the role of SKA1 in the process of metastasis and drug resistance of NSCLC. We completed a series of experiments to investigate the function of SKA1 in NSCLC metastasis and drug resistance including qRT-PCR, immunohistochemistry and western blotting, as well as MTT, BrdU, wounded healing, Transwell and gelatin zymography assays. We demonstrated that the expression levels of SKA1 were elevated in NSCLC and were correlated with cancer progression and malignancy. We also reported that SKA1 positively regulated the proliferation and metastatic ability of NSCLC cells. In addition, we determined that SKA1 contributed to cisplatin resistance in NSCLC cells by protecting these cells from cisplatin-induced cell apoptosis. SKA1 also appeared to regulate the ERK1/2 and the Akt-mediated signaling pathways in NSCLC cells. SKA1 is required for metastasis and cisplatin resistance of non-small cell lung cancer. PMID- 26985855 TI - CDKIs p18(INK4c) and p57(Kip2) are involved in quiescence of CML leukemic stem cells after treatment with TKI. AB - Chronic Myeloid Leukemia (CML) is sustained by a small population of cells with stem cell characteristics known as Leukemic Stem Cells that are positive to BCR ABL fusion protein, involved with several abnormalities in cell proliferation, expansion, apoptosis and cell cycle regulation. Current treatment options for CML involve the use of Tirosine Kinase Inhibitor (Imatinib, Nilotinib and Dasatinib), that efficiently reduce proliferation proliferative cells but do not kill non proliferating CML primitive cells that remain and contributes to the persistence of the disease. In order to understand the role of Cyclin Dependent Kinase Inhibitors in CML LSC permanence after TKI treatment, in this study we analyzed cell cycle status, the levels of several CDKIs and the subcellular localization of such molecules in different CML cell lines, as well as primary CD34(+)CD38( )lin(-) LSC and HSC. Our results demonstrate that cellular location of p18(INK4c) and p57(Kip2) seems to be implicated in the antiproliferative activity of Imatinib and Dasatinib in CML cells and also suggest that the permanence of quiescent stem cells after TKI treatment could be associated with a decrease in p18(INK4c) and p57(Kip2) nuclear location. The differences in p18(INK4c)and p57(Kip2)activities in CML and normal stem cells suggest a different cell cycle regulation and provide a platform that could be considered in the development of new therapeutic options to eliminate LSC. PMID- 26985857 TI - Clinical Observation on Hemogram Variation of Allogeneic Donors from Chinese Population for Peripheral Hematopoietic Stem Cell Collection. AB - Peripheral blood stem cell (PBSC) collection has been increasingly more popular than bone marrow donation, but little side effects induced by hemogram variation of donors for PBSC collection were reported. The peripheral blood cells were counted pre- and post-collection of PBSC from 166 allogeneic-related donors. Donors' hemoglobin concentration decreased from 144.95 (+/-16.175) g/L to 139.12 (+/-13.684) g/L (P < 0.05) and platelet counts decreased from 234.51 (+/-60.925) * 10(9)/L to 93.00 (+/-28.439) * 10(9)/L (P < 0.001) after sequential PBSC collections. The anemia condition was weakly correlated (r = 0.297, P < 0.02) and the decrease of platelet counts was strongly correlated (r = 0.719, P < 0.001) to the blood cells in the collection products. The hemoglobin concentration decrease had no significant difference in all four age groups between pre- and post collection (P >= 0.05), but was significantly decreased between pre-collection and post-first collection, post-second collection (P < 0.05 and P < 0.001) in all the body mass index (BMI) groups, among which the underweight group was highly decreased. Neither of the BMI groups nor age groups indicated any statistical difference on platelet counts (P > 0.05). A slight decrease of hemoglobin and a significant decrease of platelet counts occurred after sequential PBSC collection, which was tolerable for donors younger than 60 years old. The collection characteristic of underweight persons should be fine-tuned to ensure their safety. The platelet decrease was independent of ages or BMI values. PMID- 26985863 TI - Pharmaceuticals and personal care products (PPCPs) in urban and suburban rivers of Beijing, China: occurrence, source apportionment and potential ecological risk. AB - This study analyzed 15 pharmaceuticals and personal care products (PPCPs) in two rivers with different urbanization levels in the surrounding watershed (urban and suburb) in Beijing, China. Along the rivers, effluent samples from wastewater treatment plants (WWTPs) and wastewater samples from direct discharge outlets were also collected to reveal their possible contribution to the occurrence of PPCPs in these two rivers. Among the 15 PPCPs, 14 compounds were detected with caffeine (maximum 11,900 ng L(-1)) being the dominant compound. The total concentration of the detected PPCPs in direct discharge outlets (median 4706 ng L(-1)) was much higher than that in river waters (2780 ng L(-1)) and WWTP effluents (1971 ng L(-1)). The suburban-influenced Liangshui River had significantly higher PPCP concentrations compared to the urban-influenced Qing River due to more input of untreated wastewater from direct discharge outlets. Source apportionment showed that approximately 55% of the total PPCPs were contributed by untreated wastewater in the suburban-influenced river. Finally, ecological risk assessment has been regarded as a necessary part of general research. According to the environmental risk assessment results, caffeine, trimethoprim and metoprolol were found to be the most critical compounds, due to their high risk quotient values. The results of the present study can provide useful information for future PPCP pollution control and sustainable water management in Beijing, China. PMID- 26985865 TI - Assessment of the Correlation between Endoscopic Activity and Histological Activity in Ulcerative Colitis Patients. AB - OBJECTIVE: The aim of this study was to assess the concordance between the Rachmilewitz endoscopic activity index (EAI) and the Harpaz histopathological activity scoring system (HSS), which are used for evaluating the disease activity of ulcerative colitis (UC). SUBJECTS AND METHODS: This study included 109 patients with UC. Based on the disease extent, patients were divided into two groups as left-sided colitis and pancolitis. Patients were grouped as inactive, mild, moderate and severe depending on the Rachmilewitz EAI and Harpaz HSS. Kendal's tau and kappa (x03BA;) statistics were used to assess the agreement between endoscopic and histopathological scores. A receiver operating characteristic (ROC) curve was also analyzed to evaluate the sensitivity and specificity of endoscopic scores to predict inactive histopathological disease. RESULTS: In the left-sided colitis group, there were slight and poor agreements in the inactive endoscopic subscores (ESS) with inactive Harpaz HSS (x03BA;: 0.598, p < 0.001) and moderate ESS with moderate Harpaz HSS (x03BA;: 0.236, p = 0.046). There was no agreement between mild ESS and mild Harpaz HSS and between severe ESS and severe Harpaz HSS (x03BA;: 0.071, p = 0.573 and x03BA;: 0.160, p = 0.151, respectively). In the pancolitis group, there was no significant agreement between inactive, mild, moderate and severe ESS and the equivalent Harpaz HSS grades (x03BA;: -0.194, p = 0.187; x03BA;: 0.125, p = 0.397; x03BA;: 0.148, p = 0.175 and x03BA;: 0.174, p = 0.153, respectively). The ROC curve showed that the ESS indicating inactive disease had a low sensitivity to predict histologically inactive disease. CONCLUSION: The concordance between the endoscopic and histopathological indices was poor. Using both scores in the follow-up of patients with UC is necessary for treatment planning. PMID- 26985866 TI - Tripartite Motif Protein 72 Regulates the Proliferation and Migration of Rat Cardiac Fibroblasts via the Transforming Growth Factor-beta Signaling Pathway. AB - BACKGROUND: The proliferation and migration of cardiac fibroblasts are critical for the progress of cardiac fibrosis. Tripartite motif protein 72 (Trim72), also known as MG53, mediates the dynamic process of membrane fusion and exocytosis in striated muscle. However, the role of Trim72 in the proliferation and migration of cardiac fibroblasts is unknown. METHODS: In the present study, we used small interference RNA (siRNA) to silence Trim72 and then investigated the effects of Trim72 on cardiac fibroblast proliferation and migration, which were activated during cardiac remodeling after myocardial infarction. Cardiac fibroblasts were isolated from 2- to 3-day-old neonatal Sprague-Dawley rats and transfected with siRNA. A cell-counting assay was used to determine the proliferation of cardiac fibroblasts. A Boyden chamber assay was performed to determine the migration of cardiac fibroblasts. RESULTS: Our study has, for the first time, demonstrated that Trim72 regulates the cell proliferation and migration of rat cardiac fibroblasts. Furthermore, the data from the gene expression profile microarray analysis indicate that Trim72 depletion can cause downregulation of the transforming growth factor (TGF)-beta signaling pathway, suggesting that Trim72 regulates the proliferation and migration of cardiac fibroblasts probably via the TGF-beta signaling pathway. CONCLUSIONS: We have demonstrated that Trim72 might play a pivotal role in the proliferation of neonatal rat cardiac fibroblasts, which could be a potential target for the treatment of cardiac fibrosis. However, the involvement of other signaling pathways and factors in the formation of cardiac fibrosis cannot be excluded. PMID- 26985867 TI - Upregulation of miRNA-155 expression by OxLDL in dendritic cells involves JAK1/2 kinase and transcription factors YY1 and MYB. AB - Dendritic cells (DCs) have been implicated in the pathogenesis of atherosclerosis (AS). Whereas the pathogenic role of oxidized low-density lipoprotein (oxLDL) in the development and progression of AS has been recognized previously, the contribution of microRNA-155 (miR-155) to AS was previously not fully understood. It had also been noted that miR-155 levels were upregulated by oxLDL in various cell types under different (patho)physiological conditions, but its underlying mechanisms had not been examiend in detail. Thus, in the present study, we observed that oxLDL treatment increased miR-155 expression in DCs, and transfecting DCs with siRNA against scavenger receptor A (SRA) revealed that repression of SRA attenuated this upregulation. We also noted that miR-155 negatively regulated SRA expression by suppressing the JNK pathway. Furthermore, we noted that Yin Yang 1 (YY1) and V-Myb avian myeloblastosis viral oncogene homolog (MYB), which were also upregulated by oxLDL, directly bound to the cognate sequences of the promoter region of miR-155 to activate its transcription. In addition, using SP600125, a specific inhibitor for c-Jun N terminal kinase (JNK) signaling, we demonstrated that JNK signaling was involved in the miR-155-mediated suppression of SRA expression. Thus, in the present study we uncovered the molecular mechanism through which miR-155 expression is regulated by oxLDL, and we also identified a negative feedback loop, miR-155-JNK SRA-miR-155. Our findings thus provide novel insights into the regulatory network underlying the expression and activity of miR-155 in DCs. PMID- 26985861 TI - In Vivo Imaging of Human Neuroinflammation. AB - Neuroinflammation is implicated in the pathophysiology of a growing number of human disorders, including multiple sclerosis, chronic pain, traumatic brain injury, and amyotrophic lateral sclerosis. As a result, interest in the development of novel methods to investigate neuroinflammatory processes, for the purpose of diagnosis, development of new therapies, and treatment monitoring, has surged over the past 15 years. Neuroimaging offers a wide array of non- or minimally invasive techniques to characterize neuroinflammatory processes. The intent of this Review is to provide brief descriptions of currently available neuroimaging methods to image neuroinflammation in the human central nervous system (CNS) in vivo. Specifically, because of the relatively widespread accessibility of equipment for nuclear imaging (positron emission tomography [PET]; single photon emission computed tomography [SPECT]) and magnetic resonance imaging (MRI), we will focus on strategies utilizing these technologies. We first provide a working definition of "neuroinflammation" and then discuss available neuroimaging methods to study human neuroinflammatory processes. Specifically, we will focus on neuroimaging methods that target (1) the activation of CNS immunocompetent cells (e.g. imaging of glial activation with TSPO tracer [(11)C]PBR28), (2) compromised BBB (e.g. identification of MS lesions with gadolinium-enhanced MRI), (3) CNS-infiltration of circulating immune cells (e.g. tracking monocyte infiltration into brain parenchyma with iron oxide nanoparticles and MRI), and (4) pathological consequences of neuroinflammation (e.g. imaging apoptosis with [(99m)Tc]Annexin V or iron accumulation with T2* relaxometry). This Review provides an overview of state-of-the-art techniques for imaging human neuroinflammation which have potential to impact patient care in the foreseeable future. PMID- 26985864 TI - Curcumin inhibits intracellular fatty acid synthase and induces apoptosis in human breast cancer MDA-MB-231 cells. AB - High levels of fatty acid synthase (FAS) expression have been found in many tumors, including prostate, breast, and ovarian cancers, and inhibition of FAS has been reported to obstruct tumor growth in vitro and in vivo. Curcumin is one of the major active ingredients of Curcuma longa, which has been proven to inhibit the growth of cancer cells. In the present study, we investigated the potential activity of curcumin as a FAS inhibitor for chemoprevention of breast cancer. As a result, curcumin induced human breast cancer MDA-MB-231 cell apoptosis with the half-inhibitory concentration value of 3.63 +/- 0.26 ug/ml, and blocked FAS activity, expression and mRNA level in a dose-dependent manner. Curcumin also regulated B-cell lymphoma 2 (Bcl-2), Bax and p-Akt protein expression in MDA-MB-231 cells. Moreover, FAS knockdown showed similar effect as curcumin. All these results suggested that curcumin may induce cell apoptosis via inhibiting FAS. PMID- 26985868 TI - Establishment and Characterization of a New Muscle Cell Line of Zebrafish (Danio rerio) as an In Vitro Model for Gene Expression Studies. AB - A new continuous fibroblast cell line was established from the muscle tissue of healthy juvenile Danio rerio (Zebrafish) through explant method. Fish cell lines serve as useful tool for investigating basic fish biology, as a model for bioassay of environmental toxicant, toxicity ranking, and for developing molecular biomarkers. The cell line was continuously subcultured for a period of 12 months (61 passages) and maintained at 28 degrees C in L-15 medium supplemented with 10% FBS and 10 ng/mL of basic fibroblastic growth factor (bFGF) without use of antibiotics. Its growth rate was proportional to the FBS concentration, with optimum growth at 15% FBS. DNA barcoding (16SrRNA and COX1) was used to authenticate the cell line. Cells were incubated with propidium iodide and sorted via flow cytometry to calculate the DNA content to confirm the genetic stability. Significant green fluorescent protein (GFP) signals confirmed the utility of cell line in transgenic and genetic manipulation studies. In vitro assay was performed with MTT to examine the growth potential of the cell line. The muscle cell line would provide a novel invaluable in vitro model to identify important genes to understand regulatory mechanisms that govern the molecular regulation of myogenesis and should be useful in biomedical research. PMID- 26985862 TI - Vaccines for the prevention against the threat of MERS-CoV. AB - First identified in 2012, Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) is listed as a new Category C Priority Pathogen. While the high mortality of MERS-CoV infection is further intensified by potential human-to human transmissibility, no MERS vaccines are available for human use. This review explains immune responses resulting from MERS-CoV infection, describes MERS vaccine criteria, and presents available small animal models to evaluate the efficacy of MERS vaccines. Current advances in vaccine development are summarized, focusing on specific applications and limitations of each vaccine category. Taken together, this review provides valuable guidelines toward the development of an effective and safe MERS vaccine. This article is written for a Special Focus Issue of Expert Review of Vaccines on 'Vaccines for Biodefence'. PMID- 26985869 TI - Expression of MIF and c-erbB-2 in endometrial cancer. AB - The aim of the present study was to investigate the expression of c-erbB-2 and macrophage migration inhibitory factor (MIF) in endometrial cancer and to elucidate the significance of the early diagnosis and prognosis of endometrial cancer. The gene copy number of c-erbB-2 and MIF was characterized by reverse transcription quantitative polymerase chain reaction and the reactivity was assessed by immunohistochemistry in 70 patients using a polyclonal antibody, and evaluated semiquantitatively according to the percentage of cells demonstrating membranous or diffuse cytoplasmic staining. A correlation between age, tumor stage, grade, myometrial invasion and lymph node metastasis was observed. The mRNA expression of c-erbB-2 and MIF was high in endometrial carcinoma. The positive expression rate of MIF protein in normal endometrium, atypical hyperplasia and endometrial carcinoma significantly increased along with the degree of aggravation of the disease by 20 (3/15), 45 (9/20) and 70% (35/50), respectively. The positive expression of MIF and c-erbB-2 was highest in endometrial cancer and a significantly higher level of protein was observed in tumors at stage I, stage G1, with a depth of myometrial invasion <0.4 cm and no lymph node metastasis. The protein expression of c-erbB-2 in endometrial cancer was higher in tumors at the G2-3 phase, clinical stage III-IV, lymph node metastasis, and had no association with the depth of myometrial invasion and age. MIF and c-erbB-2 were correlated with the occurrence and the development of endometrial cancer, and thus can be used for the early diagnosis and prognosis of endometrial cancer. The present study laid the foundation for identifying new treatments for endometrial cancer. PMID- 26985870 TI - Confirmatory evidence for a multidimensional model of racial-ethnic socialization for transracially adoptive families. AB - OBJECTIVES: The purpose of the current study is to test a recently established model of racial-ethnic socialization (Langrehr, 2014) among 2 samples of White transracially adoptive parents and to assess whether the proposed model functions similarly after accounting for adopted child race. METHOD: Based on a modified version of the Racial Bias Preparation Scale (Fisher, Wallace, & Fenton, 2000), confirmatory factor analysis was used to test the 3-factor model (i.e., Prejudice Awareness, Racial-Ethnic Pride, and Egalitarianism) among 172 White transracially adoptive parents with Asian children (Mage = 45.72) and 140 White transracially adoptive parents with Black children (Mage = 42.62). In addition, multigroup invariance testing was used to assess whether the proposed model functioned similarly across the 2 groups of parents. RESULTS: Results indicate that the proposed 3-factor model demonstrated partial measurement invariance such that the subconstruct of Egalitarianism functioned similarly across groups, whereas Racial Ethnic Pride and Prejudice Awareness were deemed noninvariant. CONCLUSIONS: Findings are intended to help expand the concept of racial-ethnic socialization for transracially adoptive families and address the degree to which current research on racial-ethnic socialization can be applied to different transracially adoptive families. Results are intended to highlight ways that various social cultural dimensions of family can culminate into different socialization experiences. (PsycINFO Database Record PMID- 26985871 TI - Evaluation of overpressure prediction models for air blast above the triple point. AB - The increase of blast exposures leads to the need for better assessment of the blast threat. Empirical models describing the blast propagation in ideal conditions as free-field or surface detonations are commonly employed, but in some configurations the ground-reflected shock should be treated explicitly. Empirical models permit the prediction of the blast characteristics with the ground-reflected shock. The present study uses some original experimental data to evaluate the accuracy of the predicted overpressure with time regarding the reflected shock characteristics. Three methods are tested. The first method, called method of images (MOI) and linearly adding a virtual ground-symmetrical source blast to the free-field blast, is quick but lacks accuracy regarding the reflected shock characteristics. The second method, based on the LOAD_BLAST_ENHANCED function of the commercial LS-DYNA framework, better captures the reflected shock compared to the MOI, but the overall differences with experimental data are of the same order of magnitude as for the MOI. An original fit is introduced, based on standard physical parameters. The accuracy of this fit on the reflected shock characteristics, and the better match with the overall overpressure time series, shows its potential as a new empirical blast predicting tool. PMID- 26985873 TI - Liberation characteristics after cryogenic modification and air table separation of discarded printed circuit boards. AB - Liberating useful materials from printed circuit boards (PCBs) is challenging because PCBs are flexible and complex in terms of materials and components. In this study, the crushing of PCBs at low-temperature was investigated. The results indicated that when the temperature was decreased to approximately -20 degrees C, the strength of PCBs decreased and their brittleness increased, making them easier to crush. A double roll crusher was selected to crush the PCBs. The particle size distribution and power consumption were studied under different working conditions. The results showed that the particle size of most of the lumps was in the range 15*20-25*20 mm, and that power consumption was minimal when the frequency of the crusher was 40-50 Hz. A small shredder was used for cryogenic grinding, and it was found that its power consumption strongly depended on the cooling temperature. An orthogonal experiment was conducted, which revealed that a smaller cutter gap and higher rotational speed could achieve higher yield. Furthermore, the results indicated that the air table developed to liberate PCB materials could effectively separate 2.8-0.5mm grade materials. Overall, the results of this study provide an experimental foundation for more effectively recycling discarded PCBs. PMID- 26985872 TI - Effect of energetic materials wettability on their outdoor effective elution rate. AB - Energetic materials (EM) contained in military ammunitions have been found in the surface soil and water of training areas and may potentially represent a threat to human health and the environment. EM wettability is an essential physical parameter to characterize because it controls EM dissolution rate. This paper was conducted to determine the wettability of conventional and new EM formulations used in military ammunition. Wettability was estimated in the laboratory via contact angle measurements of water droplets on different EM surfaces. Results show that 2,4,6-trinitrotoluene (TNT), 1,3,5-trinitro-1,3,5-triazinane (RDX), Octol and energetic thermoplastic elastomer (ETPE) 1000 are hydrophilic while Composition B, XRT, GIM, CX-85, ETPE 2000, and C4 are hydrophobic whereas HELOVA gun propellant has a mixed wettability oscillating between hydrophilic and hydrophobic. The present study demonstrates that wettability of EM formulation is generally controlled by their matrix constituents. Results indicate that hydrophobic formulations have a much slower outdoor environmental effective elution rate than hydrophilic ones, with the exception of the hydrophobic C4 formulation whose elution rate is extremely high. The addition of hydrophobic components into EM formulations is recommended to diminish the environmental impact on water, as it has already been done with XRT, GIM and CX-85 formulations. PMID- 26985874 TI - Gaseous trichloroethylene removal using an electrochemically generated homogeneous low-valent ligand-free Co(I) electrocatalyst by electro-scrubbing. AB - The interest in heterogeneous Co(OH)2 electrocatalysts for energy applications has increased steadily. This study focused on a ligand-free homogeneous electrocatalyst for the degradation of gaseous trichloroethylene (TCE) in NaOH in a divided electrolytic cell. The initial electrolysis results revealed a change in the oxidation reduction potential (ORP) of [Co(II)(OH)4](2-) (Co(II)) from 267 mV to -800 mV on anodized Ti during electrolytic reduction identifies low valent homogeneous [Co(I)(OH)4](3-)(Co(I)) formation in 10 M NaOH. Cyclic voltammetry analysis of Co(II) at different anodized electrodes, Ag, carbon and Ti, in a 10 M NaOH solution, showed no stripping like peak in the reverse scan only the Ti electrode, supporting the formation of low-valent Co(I). UV-vis spectral analysis of the electrolyzed solution showed an enhanced peak corresponding to metal-to-ligand transition, demonstrates Co(I) formation. Co(II) reduction reached a maximum yield of 18% at 30 mA cm(-2) on an anodized Ti cathode. For gaseous TCE removal, continuous mode electro-scrubbing was adopted and degradation was monitored using an online FTIR gas analyzer that showed 99.75% degradation of TCE in the presence of homogeneous Co(I). Three consecutive regenerations of Co(I) and degradation steps of TCE confirmed the possibility of industrial applications in a sustainable manner. PMID- 26985875 TI - Indole-containing new types of dyes and their UV-vis and NMR spectra and electronic structures: Experimental and theoretical study. AB - Indole containing dyes were synthesized via a simple method with high yield. These molecules have different colors and UV-vis spectra of them were recorded. Impact of solvents on absorbances was investigated and it was observed that basic solvent such as DMF and pyridine have blue shift. TD-DFT calculations were done and results were compared with experimental data. NMR data of molecules were analyzed and tautomeric forms of colorants and their ratio were determined. It was find out that two tautomers might be formed in solution, called indole and indolenine form. HOMO-LUMO and energy gaps were calculated and plotted. Furthermore, molecular electrostatic potentials were simulated to find out electrophilic and nucleophilic regions. PMID- 26985876 TI - Dielectric spectroscopic studies on the water hyacinth plant collected from agriculture drainage. AB - The present paper aims to investigate the sensitivity of dielectric spectroscopy to changes in concentrations of pollutants (heavy metals and metal oxides) uptake by the water hyacinth plant collected from agriculture wastewater drainage. The measurements were carried out on the dried root and shoot plant parts before and after subjecting to different microwave heating powers for different times. Dielectric properties of the untreated root were investigated at temperature range (30-90 degrees C). X-ray fluorescence spectroscopy (XRF) results showed that the concentration of metals and metals oxides are higher in plant root than in plant shoot. Accordingly, the obtained dielectric properties were found to depend on the applied electric field frequency, magnitude of heating power as well as concentrations of pollutants. Analysis of experimental data represented by the imaginary part of the dielectric modulus M" (omega) revealed to the presence of three different relaxation processes. The lower frequency relaxation process was associated to charge carriers conduction whereas those appeared at higher frequencies were associated to different types of interfacial polarization. The plant ability for removing heavy metals and metal oxides from the aquatic environments would be enhanced upon subjecting to microwave heating power with 400 W for 30 min. PMID- 26985877 TI - Chromatographic and spectroscopic identification and recognition of ammoniacal cochineal dyes and pigments. AB - In this work a combined chromatographic and spectroscopic approach is used to provide a diagnostic assessment of semi-synthetic ammoniacal cochineal through the syntheses of its dyes and lakes according to art historical recipes. Commercially introduced in the late XIX century as a dye and pigment, it was used to obtain a brilliant purplish/violet nuance which provided a more stable option over carminic acid although its evidenced use in manufacts and artworks of heritage importance have been scarcely documented. Through HPLC-DAD, it has been possible to identify 4-aminocarminic acid as the main component of ammoniacal cochineal highlighting a chemical formula analogous to acid stable carmine, a recent patented food dye. FTIR clearly distinguishes the amine group in the ammoniacal cochineal dye preparation and TLC-SERS allows for an adequate separation and spectral differentiation in its main components to be evidenced. Colloidal SERS has permitted spectral markers useful in discerning ammoniacal cochineal over carminic acid to be highlighted and discussed. Finally, the methods experimented in this study for the identification of ammoniacal cochineal have been validated on analyzing a sample of dyed wool. PMID- 26985878 TI - Which therapeutic strategy will achieve a cure for HIV-1? AB - Strategies to achieve a cure for HIV-1 infection can be broadly classified into three categories: eradication cure (elimination of all viral reservoirs), functional cure (immune control without reservoir eradication), or a hybrid cure (reservoir reduction with improved immune control). The many HIV-1 cure strategies being investigated include modification of host cells to resist HIV-1, engineered T cells to eliminate HIV-infected cells, broadly HIV-1 neutralizing monoclonal antibodies, and therapeutic vaccination, but the 'kick and kill' strategy to expose latent HIV-1 with latency reversing agents (LRAs) and kill the exposed cells through immune effector functions is currently the most actively pursued. It is unknown, however, whether LRAs can deplete viral reservoirs in vivo or whether current LRAs are sufficiently safe for clinical use. PMID- 26985879 TI - Virus assembly factories in a lipid world. AB - Many viruses build specialized structures known as viral factories, a protected environment in which viral genome replication and morphogenesis take place. Recent findings show that viruses manipulate lipid flows to assemble these replication platforms. Viruses are thus able to create new membranes by interfering with lipid metabolism, targeting and transport; they make use of specific lipid transfer proteins (LTP) at membrane contact sites, and frequently recruit endoplasmic reticulum (ER), ER export sites, and mitochondria. Some factories, such as those built by plant and certain animal viruses, are motile membranous structures involved in intracellular or intercellular transport of the replicated viral genome. The identification of lipids and LTP subverted by viruses might lead to better understand and fight viral infections. PMID- 26985880 TI - Bad is freer than good: Positive-negative asymmetry in attributions of free will. AB - Recent findings support the idea that the belief in free will serves as the basis for moral responsibility, thus promoting the punishment of immoral agents. We theorized that free will extends beyond morality to serve as the basis for accountability and the capacity for change more broadly, not only for others but also for the self. Five experiments showed that people attributed higher freedom of will to negative than to positive valence, regardless of morality or intent, for both self and others. In recalling everyday life situations and in classical decision making paradigms, negative actions, negatives outcomes, and negative framing were attributed higher free will than positive ones. Free will attributions were mainly driven by action or outcome valence, but not intent. These findings show consistent support for the idea that free will underlies laypersons' sense-making for accountability and change under negative circumstances. PMID- 26985881 TI - The influence of retrieval practice on metacognition: The contribution of analytic and non-analytic processes. AB - People may change their memory predictions after retrieval practice using naive theories of memory and/or by using subjective experience - analytic and non analytic processes respectively. The current studies disentangled contributions of each process. In one condition, learners studied paired-associates, made a memory prediction, completed a short-run of retrieval practice and made a second prediction. In another condition, judges read about a yoked learners' retrieval practice performance but did not participate in retrieval practice and therefore, could not use non-analytic processes for the second prediction. In Study 1, learners reduced their predictions following moderately difficult retrieval practice whereas judges increased their predictions. In Study 2, learners made lower adjusted predictions than judges following both easy and difficult retrieval practice. In Study 3, judge-like participants used analytic processes to report adjusted predictions. Overall, the results suggested non-analytic processes play a key role for participants to reduce their predictions after retrieval practice. PMID- 26985882 TI - Self-reference recollection effect and its relation to theory of mind: An investigation in healthy controls and schizophrenia. AB - This study explores the links between the Self-Reference Effect (SRE) and Theory of Mind (ToM) in typical adults and patients with schizophrenia. Participants were assessed with a self-referential memory paradigm investigating the mnemonic effect of both semantic and episodic self-reference with a recognition task associated with the Remember/Know/Guess paradigm. They also completed a self descriptive scale and shortened versions of the attribution of intention task and the reading the mind in the eyes test as measures of cognitive and affective ToM respectively. Unlike typical adults, the patients showed no semantic SRRE (correct recognition associated with remembering), and there was no episodic SRRE and no SRE (on the number of correct recognitions) in either group. Semantic SRRE was correlated with the affective ToM in patients and with the positivity of the self-concept in the healthy group. We discuss that patients and typical adults use different strategies during self and other-reflection. PMID- 26985883 TI - Metacognitive monitoring and control processes in children with autism spectrum disorder: Diminished judgement of confidence accuracy. AB - Metacognition consists of monitoring processes (the ability to accurately represent one's own mental states) and control processes (the ability to control one's cognitive processes effectively). Both processes play vital roles in self regulated learning. However, currently it is unclear whether these processes are impaired in individuals with autism spectrum disorders (ASDs). This study aimed to assess metacognition in thirty-two children with ASD, and 30 IQ-/age-matched neurotypical children, using a judgment of confidence task. It was found that children with ASD showed diminished accuracy in their judgments of confidence, indicating metacognitive monitoring impairments in ASD. Children with ASD also used monitoring to influence control processes significantly less than neurotypical children, despite little evidence of impairments in overall control ability. PMID- 26985885 TI - Chitosan Nanoparticles as Carriers for the Delivery of PhiKAZ14 Bacteriophage for Oral Biological Control of Colibacillosis in Chickens. AB - The use of chitosan as a delivery carrier has attracted much attention in recent years. In this study, chitosan nanoparticles (CS-NP) and chitosan-PhiKAZ14 bacteriophage-loaded nanoparticles (C-PhiKAZ14 NP) were prepared by a simple coercavation method and characterized. The objective was to achieve an effective protection of bacteriophage from gastric acids and enzymes in the chicken gastrointestinal tract. The average particle sizes for CS-NP and C-PhiKAZ14 NP were 188 +/- 7.4 and 176 +/- 3.2 nm, respectively. The zeta potentials for CS-NP and C-PhiKAZ14 NP were 50 and 60 mV, respectively. Differential scanning calorimetry (DSC) of C-PhiKAZ14 NP gave an onset temperature of -17.17 degrees C with a peak at 17.32 degrees C and final end set of 17.41 degrees C, while blank chitosan NP had an onset of -20.00 degrees C with a peak at -19.78 degrees C and final end set at -20.47. FT-IR spectroscopy data of both CS-NP and C-PhiKAZ14 NP were the same. Chitosan nanoparticles showed considerable protection of PhiKAZ14 bacteriophage against degradation by enzymes as evidenced in gel electrophoresis, whereby PhiKAZ14 bacteriophage encapsulated in chitosan nanoparticles were protected whereas the naked PhiKAZ14 bacteriophage were degraded. C-PhiKAZ14 NP was non-toxic as shown by a chorioallantoic membrane (CAM) toxicity assay. It was concluded that chitosan nanoparticles could be a potent carrier of PhiKAZ14 bacteriophage for oral therapy against colibacillosis in poultry. PMID- 26985884 TI - Approaches to preventative and therapeutic HIV vaccines. AB - Novel strategies are being researched to discover vaccines to prevent and treat HIV-1. Non-efficacious preventative vaccine approaches include bivalent recombinant gp120 alone, HIV gene insertion into an Adenovirus 5 (Ad5) virus vector and the DNA prime/Ad5 boost vaccine regimen. However, the ALVAC-HIV prime/AIDSVAX(r) B/E gp120 boost regimen showed 31.2% efficacy at 3.5 years, and is being investigated as clade C constructs with an additional boost. Likewise, although multiple therapeutic vaccines have failed in the past, in a non-placebo controlled trial, a Tat vaccine demonstrated immune cell restoration, reduction of immune activation, and reduced HIV-1 DNA viral load. Monoclonal antibodies for passive immunization or treatment show promise, with VRC01 entering advanced clinical trials. PMID- 26985886 TI - Nanopore Event-Transduction Signal Stabilization for Wide pH Range under Extreme Chaotrope Conditions. AB - Operation of an alpha-hemolysin nanopore transduction detector is found to be surprisingly robust over a critical range of pH (6-9), including physiological pH = 7.4 and polymerase chain reaction (PCR) pH = 8.4, and extreme chaotrope concentration, including 5 M urea. The engineered transducer molecule that is captured in the standard alpha-hemolysin nanopore detector, to transform it into a transduction detector, appears to play a central role in this stabilization process by stabilizing the channel against gating during its capture. This enables the nanopore transduction detector to operate as a single molecule "nanoscope" in a wide range of conditions, where tracking on molecular state is possible in a variety of different environmental conditions. In the case of streptavidin biosensing, results are shown for detector operation when in the presence of extreme (5 M) urea concentration. Complications involving degenerate states are encountered at higher chaotrope concentrations, but since the degeneracy is only of order two, this is easily absorbed into the classification task as in prior work. This allows useful detector operation over a wide range of conditions relevant to biochemistry, biomedical engineering, and biotechnology. PMID- 26985887 TI - Use of a Ceramic Membrane to Improve the Performance of Two-Separate-Phase Biocatalytic Membrane Reactor. AB - Biocatalytic membrane reactors (BMR) combining reaction and separation within the same unit have many advantages over conventional reactor designs. Ceramic membranes are an attractive alternative to polymeric membranes in membrane biotechnology due to their high chemical, thermal and mechanical resistance. Another important use is their potential application in a biphasic membrane system, where support solvent resistance is highly needed. In this work, the preparation of asymmetric ceramic hollow fibre membranes and their use in a two separate-phase biocatalytic membrane reactor will be described. The asymmetric ceramic hollow fibre membranes were prepared using a combined phase inversion and sintering technique. The prepared fibres were then used as support for lipase covalent immobilization in order to develop a two-separate-phase biocatalytic membrane reactor. A functionalization method was proposed in order to increase the density of the reactive hydroxyl groups on the surface of ceramic membranes, which were then amino-activated and treated with a crosslinker. The performance and the stability of the immobilized lipase were investigated as a function of the amount of the immobilized biocatalytst. Results showed that it is possible to immobilize lipase on a ceramic membrane without altering its catalytic performance (initial residual specific activity 93%), which remains constant after 6 reaction cycles. PMID- 26985888 TI - New Anti-HBV C-Boivinopyranosyl Flavones from Alternanthera philoxeroides. AB - C-boivinopyranosyl flavones have rarely been isolated from nature. In the search for anti-HBV (hepatitis b virus) constituents of Alternanthera philoxeroides, two new compounds, luteolin-6-C-beta-D-boivinopyranosyl-3'-O-beta-D-glucopyranoside (1) and chrysoeriol-6-C-beta-D-boivinopyranosyl-4'-O-beta-D-glucopyranoside (2), along with three known C-boivinopyranosyl flavones (compounds 3-5) were isolated. Their structures were determined by spectroscopic analyses including 1D and 2D NMR, HR-ESI-MS, IR spectra. Compounds 1, 2 and 3 showed significant anti-HBV activities through specifically inhibiting the secretion of HBsAg in HepG2.2.15. PMID- 26985889 TI - Large Scale Screening of Ethnomedicinal Plants for Identification of Potential Antibacterial Compounds. AB - The global burden of bacterial infections is very high and has been exacerbated by increasing resistance to multiple antibiotics. Antibiotic resistance leads to failed treatment of infections, which can ultimately lead to death. To overcome antibiotic resistance, it is necessary to identify new antibacterial agents. In this study, a total of 662 plant extracts (diverse parts) from 222 plant species (82 families, 177 genera) were screened for antibacterial activity using the agar cup plate method. The aqueous and methanolic extracts were prepared from diverse plant parts and screened against eight bacterial (two Gram-positive and six Gram negative) species, most of which are involved in common infections with multiple antibiotic resistance. The methanolic extracts of several plants were shown to have zones of inhibition >= 12 mm against both Gram-positive and Gram-negative bacteria. The minimum inhibitory concentration was calculated only with methanolic extracts of selected plants, those showed zone of inhibition >= 12 mm against both Gram-positive and Gram-negative bacteria. Several extracts had minimum inhibitory concentration <= 1 mg/mL. Specifically Adhatoda vasica, Ageratum conyzoides, Alangium salvifolium, Alpinia galanga, Andrographis paniculata, Anogeissus latifolia, Annona squamosa, A. reticulate, Azadirachta indica, Buchanania lanzan, Cassia fistula, Celastrus paniculatus, Centella asiatica, Clausena excavate, Cleome viscosa, Cleistanthus collinus, Clerodendrum indicum, Croton roxburghii, Diospyros melanoxylon, Eleutherine bulbosa, Erycibe paniculata, Eryngium foetidum, Garcinia cowa, Helicteres isora, Hemidesmus indicus, Holarrhena antidysenterica, Lannea coromandelica, Millettia extensa, Mimusops elengi, Nyctanthes arbor-tristis, Oroxylum indicum, Paederia foetida, Pterospermum acerifolium, Punica granatum, Semecarpus anacardium, Spondias pinnata, Terminalia alata and Vitex negundo were shown to have significant antimicrobial activity. The species listed here were shown to have anti-infective activity against both Gram-positive and Gram-negative bacteria. These results may serve as a guide for selecting plant species that could yield the highest probability of finding promising compounds responsible for the antibacterial activities against a broad spectrum of bacterial species. Further investigation of the phytochemicals from these plants will help to identify the lead compounds for drug discovery. PMID- 26985890 TI - Carbapenems to Treat Multidrug and Extensively Drug-Resistant Tuberculosis: A Systematic Review. AB - BACKGROUND: Carbapenems (ertapenem, imipenem, meropenem) are used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB), even if the published evidence is limited, particularly when it is otherwise difficult to identify the recommended four active drugs to be included in the regimen. No systematic review to date has ever evaluated the efficacy, safety, and tolerability of carbapenems. METHODS: A search of peer-reviewed, scientific evidence was carried out, aimed at evaluating the efficacy/effectiveness, safety, and tolerability of carbapenem-containing regimens in individuals with pulmonary/extra-pulmonary disease which was bacteriologically confirmed as M/XDR TB. We used PubMed to identify relevant full-text, English manuscripts up to the 20 December 2015, excluding editorials and reviews. RESULTS: Seven out of 160 studies satisfied the inclusion criteria: two on ertapenem, one on imipenem, and four on meropenem, all published between 2005 and 2016. Of seven studies, six were retrospective, four were performed in a single center, two enrolled children, two had a control group, and six reported a proportion of XDR-TB cases higher than 20%. Treatment success was higher than 57% in five studies with culture conversion rates between 60% and 94.8%. CONCLUSIONS: The safety and tolerability is very good, with the proportion of adverse events attributable to carbapenems below 15%. PMID- 26985891 TI - Mesenchymal Stem Cells Increase Neo-Angiogenesis and Albumin Production in a Liver Tissue-Engineered Engraftment. AB - The construction of a three-dimensional (3D) liver tissue is limited by many factors; one of them is the lack of vascularization inside the tissue-engineered construct. An engineered liver pocket-scaffold able to increase neo-angiogenesis in vivo could be a solution to overcome these limitations. In this work, a hyaluronan (HA)-based scaffold enriched with human mesenchymal stem cells (hMSCs) and rat hepatocytes was pre-conditioned in a bioreactor system, then implanted into the liver of rats. Angiogenesis and hepatocyte metabolic functions were monitored. The formation of a de novo vascular network within the HA-based scaffold, as well as an improvement in albumin production by the implanted hepatocytes, were detected. The presence of hMSCs in the HA-scaffold increased the concentration of growth factors promoting angiogenesis inside the graft. This event ensured a high blood vessel density, coupled with a support to metabolic functions of hepatocytes. All together, these results highlight the important role played by stem cells in liver tissue-engineered engraftment. PMID- 26985895 TI - Effect of Bismuth Oxide on the Microstructure and Electrical Conductivity of Yttria Stabilized Zirconia. AB - Bismuth oxide (Bi2O3)-doped yttria-stabilized zirconia (YSZ) were prepared via the solid state reaction method. X-ray diffraction and electron diffraction spectroscopy results indicate that doping with 2 mol% Bi2O3 and adding 10 mol% yttria result in a stable zirconia cubic phase. Adding Bi2O3 as a dopant increases the density of zirconia to above 96%, while reducing its normal sintering temperature by approximately 250 degrees C. Moreover, electrical impedance analyses show that adding Bi2O3 enhances the conductivity of zirconia, improving its capability as a solid electrolyte for intermediate or even lower temperatures. PMID- 26985892 TI - Extracellular Vesicles: A New Frontier in Biomarker Discovery for Non-Alcoholic Fatty Liver Disease. AB - In recent years, the global burden of obesity and diabetes has seen a parallel rise in other metabolic complications, such as non-alcoholic fatty liver disease (NAFLD). This condition, once thought to be a benign accumulation of hepatic fat, is now recognized as a serious and prevalent disorder that is conducive to inflammation and fibrosis. Despite the rising incidence of NAFLD, there is currently no reliable method for its diagnosis or staging besides the highly invasive tissue biopsy. This limitation has resulted in the study of novel circulating markers as potential candidates, one of the most popular being extracellular vesicles (EVs). These submicron membrane-bound structures are secreted from stressed and activated cells, or are formed during apoptosis, and are known to be involved in intercellular communication. The cargo of EVs depends upon the parent cell and has been shown to be changed in disease, as is their abundance in the circulation. The role of EVs in immunity and epigenetic regulation is widely attested, and studies showing a correlation with disease severity have made these structures a favorable target for diagnostic as well as therapeutic purposes. This review will highlight the research that is available on EVs in the context of NAFLD, the current limitations, and projections for their future utility in a clinical setting. PMID- 26985893 TI - A RNA-DNA Hybrid Aptamer for Nanoparticle-Based Prostate Tumor Targeted Drug Delivery. AB - The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient's health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA), was designed. A super paramagnetic iron oxide nanoparticle-aptamer-doxorubicin (SPIO-Apt-Dox) was fabricated and employed as a targeted drug delivery platform for cancer therapy. This DNA RNA hybridized aptamer antitumor agent was able to enhance the cytotoxicity of targeted cells while minimizing collateral damage to non-targeted cells. This SPIO-Apt-Dox nanoparticle has specificity to PSMA+ prostate cancer cells. Aptamer inhibited nonspecific uptake of membrane-permeable doxorubic to the non-target cells, leading to reduced untargeted cytotoxicity and endocytic uptake while enhancing targeted cytotoxicity and endocytic uptake. The experimental results indicate that the drug delivery platform can yield statistically significant effectiveness being more cytotoxic to the targeted cells as opposed to the non targeted cells. PMID- 26985894 TI - Genetic Diversity and Population Structure of Broomcorn Millet (Panicum miliaceum L.) Cultivars and Landraces in China Based on Microsatellite Markers. AB - Broomcorn millet (Panicum miliaceum L.), one of the first domesticated crops, has been grown in Northern China for at least 10,000 years. The species is presently a minor crop, and evaluation of its genetic diversity has been very limited. In this study, we analyzed the genetic diversity of 88 accessions of broomcorn millet collected from various provinces of China. Amplification with 67 simple sequence repeat (SSR) primers revealed moderate levels of diversity in the investigated accessions. A total of 179 alleles were detected, with an average of 2.7 alleles per locus. Polymorphism information content and expected heterozygosity ranged from 0.043 to 0.729 (mean = 0.376) and 0.045 to 0.771 (mean = 0.445), respectively. Cluster analysis based on the unweighted pair group method of mathematical averages separated the 88 accessions into four groups at a genetic similarity level of 0.633. A genetic structure assay indicated a close correlation between geographical regions and genetic diversity. The uncovered information will be valuable for defining gene pools and developing breeding programs for broomcorn millet. Furthermore, the millet-specific SSR markers developed in this study should serve as useful tools for assessment of genetic diversity and elucidation of population structure in broomcorn millet. PMID- 26985896 TI - Wearable Sensor Localization Considering Mixed Distributed Sources in Health Monitoring Systems. AB - In health monitoring systems, the base station (BS) and the wearable sensors communicate with each other to construct a virtual multiple input and multiple output (VMIMO) system. In real applications, the signal that the BS received is a distributed source because of the scattering, reflection, diffraction and refraction in the propagation path. In this paper, a 2D direction-of-arrival (DOA) estimation algorithm for incoherently-distributed (ID) and coherently distributed (CD) sources is proposed based on multiple VMIMO systems. ID and CD sources are separated through the second-order blind identification (SOBI) algorithm. The traditional estimating signal parameters via the rotational invariance technique (ESPRIT)-based algorithm is valid only for one-dimensional (1D) DOA estimation for the ID source. By constructing the signal subspace, two rotational invariant relationships are constructed. Then, we extend the ESPRIT to estimate 2D DOAs for ID sources. For DOA estimation of CD sources, two rational invariance relationships are constructed based on the application of generalized steering vectors (GSVs). Then, the ESPRIT-based algorithm is used for estimating the eigenvalues of two rational invariance matrices, which contain the angular parameters. The expressions of azimuth and elevation for ID and CD sources have closed forms, which means that the spectrum peak searching is avoided. Therefore, compared to the traditional 2D DOA estimation algorithms, the proposed algorithm imposes significantly low computational complexity. The intersecting point of two rays, which come from two different directions measured by two uniform rectangle arrays (URA), can be regarded as the location of the biosensor (wearable sensor). Three BSs adopting the smart antenna (SA) technique cooperate with each other to locate the wearable sensors using the angulation positioning method. Simulation results demonstrate the effectiveness of the proposed algorithm. PMID- 26985897 TI - Development of Mobile Mapping System for 3D Road Asset Inventory. AB - Asset Management is an important component of an infrastructure project. A significant cost is involved in maintaining and updating the asset information. Data collection is the most time-consuming task in the development of an asset management system. In order to reduce the time and cost involved in data collection, this paper proposes a low cost Mobile Mapping System using an equipped laser scanner and cameras. First, the feasibility of low cost sensors for 3D asset inventory is discussed by deriving appropriate sensor models. Then, through calibration procedures, respective alignments of the laser scanner, cameras, Inertial Measurement Unit and GPS (Global Positioning System) antenna are determined. The efficiency of this Mobile Mapping System is experimented by mounting it on a truck and golf cart. By using derived sensor models, geo referenced images and 3D point clouds are derived. After validating the quality of the derived data, the paper provides a framework to extract road assets both automatically and manually using techniques implementing RANSAC plane fitting and edge extraction algorithms. Then the scope of such extraction techniques along with a sample GIS (Geographic Information System) database structure for unified 3D asset inventory are discussed. PMID- 26985898 TI - A Novel Semi-Supervised Electronic Nose Learning Technique: M-Training. AB - When an electronic nose (E-nose) is used to distinguish different kinds of gases, the label information of the target gas could be lost due to some fault of the operators or some other reason, although this is not expected. Another fact is that the cost of getting the labeled samples is usually higher than for unlabeled ones. In most cases, the classification accuracy of an E-nose trained using labeled samples is higher than that of the E-nose trained by unlabeled ones, so gases without label information should not be used to train an E-nose, however, this wastes resources and can even delay the progress of research. In this work a novel multi-class semi-supervised learning technique called M-training is proposed to train E-noses with both labeled and unlabeled samples. We employ M training to train the E-nose which is used to distinguish three indoor pollutant gases (benzene, toluene and formaldehyde). Data processing results prove that the classification accuracy of E-nose trained by semi-supervised techniques (tri training and M-training) is higher than that of an E-nose trained only with labeled samples, and the performance of M-training is better than that of tri training because more base classifiers can be employed by M-training. PMID- 26985899 TI - Spatially Analyzing the Inequity of the Hong Kong Urban Heat Island by Socio Demographic Characteristics. AB - Recent studies have suggested that some disadvantaged socio-demographic groups face serious environmental-related inequities in Hong Kong due to the rising ambient urban temperatures. Identifying heat-vulnerable groups and locating areas of Surface Urban Heat Island (SUHI) inequities is thus important for prioritizing interventions to mitigate death/illness rates from heat. This study addresses this problem by integrating methods of remote sensing retrieval, logistic regression modelling, and spatial autocorrelation. In this process, the SUHI effect was first estimated from the Land Surface Temperature (LST) derived from a Landsat image. With the scale assimilated to the SUHI and socio-demographic data, a logistic regression model was consequently adopted to ascertain their relationships based on Hong Kong Tertiary Planning Units (TPUs). Lastly, inequity "hotspots" were derived using spatial autocorrelation methods. Results show that disadvantaged socio-demographic groups were significantly more prone to be exposed to an intense SUHI effect: over half of 287 TPUs characterized by age groups of 60+ years, secondary and matriculation education attainment, widowed, divorced and separated, low and middle incomes, and certain occupation groups of workers, have significant Odds Ratios (ORs) larger than 1.2. It can be concluded that a clustering analysis stratified by age, income, educational attainment, marital status, and occupation is an effective way to detect the inequity hotspots of SUHI exposure. Additionally, inequities explored using income, marital status and occupation factors were more significant than the age and educational attainment in these areas. The derived maps and model can be further analyzed in urban/city planning, in order to mitigate the physical and social causes of the SUHI effect. PMID- 26985900 TI - Exploring Associations between Problematic Internet Use, Depressive Symptoms and Sleep Disturbance among Southern Chinese Adolescents. AB - The primary aim of this study was to examine associations between problematic Internet use, depression and sleep disturbance, and explore whether there were differential effects of problematic Internet use and depression on sleep disturbance. A total of 1772 adolescents who participated in the Shantou Adolescent Mental Health Survey were recruited in 2012 in Shantou, China. The Chinese version of the Internet Addiction Test (IAT) was used to evaluate the prevalence and severity of Internet addiction. The Chinese version of the Pittsburgh Sleep Quality Index (PSQI), a 10-item version of the Center for Epidemiologic Studies Depression Scale (CESD-10), and other socio-demographic measures were also completed. Multiple regression analysis was used to test the mediating effect of problematic Internet use and depression on sleep disturbance. Among the participants, 17.2% of adolescents met the criteria for problematic Internet use, 40.0% were also classified as suffering from sleep disturbance, and 54.4% of students had depressive symptoms. Problematic Internet use was significantly associated with depressive symptoms and sleep disturbance. The correlation between depressive symptoms and sleep disturbance was highly significant. Both problematic Internet use (beta = 0.014; Sobel test Z = 12.7, p < 0.001) and depression (beta = 0.232; Sobel test Z = 3.39, p < 0.001) had partially mediating effects on sleep disturbance and depression was of greater importance for sleep disturbance than problematic Internet use. There is a high prevalence of problematic Internet use, depression and sleep disturbance among high school students in southern China, and problematic Internet use and depressive symptoms are strongly associated with sleep disturbance. This study provides evidence that problematic Internet use and depression have partially mediating effects on sleep disturbance. These results are important for clinicians and policy makers with useful information for prevention and intervention efforts. PMID- 26985901 TI - The Inflammation Response to DEHP through PPARgamma in Endometrial Cells. AB - Epidemiological studies have shown the possible link between phthalates and endometrium-related gynecological diseases, however the molecular mechanism(s) behind this is/are still unclear. In the study, both primary cultured endometrial cells and an endometrial adenocarcinoma cell line (Ishikawa) were recruited to investigate the effects of di-(2-ethylhexyl) phthalate (DEHP) at human-relevant concentrations. The results showed that DEHP did not affect the viability of either type of cell, which showed different responses to inflammation. Primary cultured cells showed stronger inflammatory reactions than the Ishikawa cell line. The expression of inflammatory factors was induced both at the mRNA and protein levels, however the inflammation did not induce the progress of epithelial-mesenchymal transition (EMT) as the protein levels of EMT markers were not affected after exposure to either cell type. Further study showed that the mRNA levels of peroxisome proliferator-activated receptor gamma (PPARgamma) wereup-regulated after exposure. In all, our study showed that human-relevant concentrations of DEHP could elicit the inflammatory response in primary cultured endometrial cells rather than in Ishikawa cell line. PPARgamma may act as the mediating receptor in the inflammation reaction. PMID- 26985902 TI - Characterization of Intra-Type Variants of Oncogenic Human Papillomaviruses by Next-Generation Deep Sequencing of the E6/E7 Region. AB - Different human papillomavirus (HPV) types are characterized by differences in tissue tropism and ability to promote cell proliferation and transformation. In addition, clinical and experimental studies have shown that some genetic variants/lineages of high-risk HPV (HR-HPV) types are characterized by increased oncogenic activity and probability to induce cancer. In this study, we designed and validated a new method based on multiplex PCR-deep sequencing of the E6/E7 region of HR-HPV types to characterize HPV intra-type variants in clinical specimens. Validation experiments demonstrated that this method allowed reliable identification of the different lineages of oncogenic HPV types. Advantages of this method over other published methods were represented by its ability to detect variants of all HR-HPV types in a single reaction, to detect variants of HR-HPV types in clinical specimens with multiple infections, and, being based on sequencing of the full E6/E7 region, to detect amino acid changes in these oncogenes potentially associated with increased transforming activity. PMID- 26985903 TI - Long Terminal Repeat Circular DNA as Markers of Active Viral Replication of Human T Lymphotropic Virus-1 in Vivo. AB - Clonal expansion of human T-lymphotropic virus type-1 (HTLV-1) infected cells in vivo is well documented. Unlike human immunodeficiency virus type 1 (HIV-1), HTLV 1 plasma RNA is sparse. The contribution of the "mitotic" spread of HTLV-1 compared with infectious spread of the virus to HTLV-1 viral burden in established infection is uncertain. Since extrachromosomal long terminal repeat (LTR) DNA circles are indicators of viral replication in HIV-1 carriers with undetectable plasma HIV RNA, we hypothesised that HTLV-1 LTR circles could indicate reverse transcriptase (RT) usage and infectious activity. 1LTR and 2LTR DNA circles were measured in HTLV-1 cell lines and peripheral blood mononuclear cells (PBMC) of asymptomatic carriers (ACs) and patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) or adult T cell leukaemia/lymphoma (ATLL). 1LTR DNA circles were detected in 14/20 patients at a mean of 1.38/100 PBMC but did not differentiate disease status nor correlate with HTLV-1 DNA copies. 2LTR DNA circles were detected in 30/31 patients and at higher concentrations in patients with HTLV-1-associated diseases, independent of HTLV-1 DNA load. In an incident case the 2LTR DNA circle concentration increased 2.1 fold at the onset of HAM/TSP compared to baseline. Detectable and fluctuating levels of HTLV-1 DNA circles in patients indicate viral RT usage and virus replication. Our results indicate HTLV-1 viral replication capacity is maintained in chronic infection and may be associated with disease onset. PMID- 26985906 TI - Mechanisms of Nuclear Export in Cancer and Resistance to Chemotherapy. AB - Tumour suppressor proteins, such as p53, BRCA1, and ABC, play key roles in preventing the development of a malignant phenotype, but those that function as transcriptional regulators need to enter the nucleus in order to function. The export of proteins between the nucleus and cytoplasm is complex. It occurs through nuclear pores and exported proteins need a nuclear export signal (NES) to bind to nuclear exportin proteins, including CRM1 (Chromosomal Region Maintenance protein 1), and the energy for this process is provided by the RanGTP/RanGDP gradient. Due to the loss of DNA repair and cell cycle checkpoints, drug resistance is a major problem in cancer treatment, and often an initially successful treatment will fail due to the development of resistance. An important mechanism underlying resistance is nuclear export, and a number of strategies that can prevent nuclear export may reverse resistance. Examples include inhibitors of CRM1, antibodies to the nuclear export signal, and alteration of nuclear pore structure. Each of these are considered in this review. PMID- 26985905 TI - Altered Skeletal Muscle Fatty Acid Handling in Subjects with Impaired Glucose Tolerance as Compared to Impaired Fasting Glucose. AB - Altered skeletal muscle fatty acid (FA) metabolism contributes to insulin resistance. Here, we compared skeletal muscle FA handling between subjects with impaired fasting glucose (IFG; n = 12 (7 males)) and impaired glucose tolerance (IGT; n = 14 (7 males)) by measuring arterio-venous concentration differences across forearm muscle. [2H2]-palmitate was infused intravenously, labeling circulating endogenous triacylglycerol (TAG) and free fatty acids (FFA), whereas [U-(13)C]-palmitate was incorporated in a high-fat mixed-meal, labeling chylomicron-TAG. Skeletal muscle biopsies were taken to determine muscle TAG, diacylglycerol (DAG), FFA, and phospholipid content, their fractional synthetic rate (FSR) and degree of saturation, and gene expression. Insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp. Net skeletal muscle glucose uptake was lower (p = 0.018) and peripheral insulin sensitivity tended to be reduced (p = 0.064) in IGT as compared to IFG subjects. Furthermore, IGT showed higher skeletal muscle extraction of VLDL-TAG (p = 0.043), higher muscle TAG content (p = 0.025), higher saturation of FFA (p = 0.004), lower saturation of TAG (p = 0.017) and a tendency towards a lower TAG FSR (p = 0.073) and a lower saturation of DAG (p = 0.059) versus IFG individuals. Muscle oxidative gene expression was lower in IGT subjects. In conclusion, increased liver-derived TAG extraction and reduced lipid turnover of saturated FA, rather than DAG content, in skeletal muscle accompany the more pronounced insulin resistance in IGT versus IFG subjects. PMID- 26985908 TI - Convective Mixing in Distal Pipes Exacerbates Legionella pneumophila Growth in Hot Water Plumbing. AB - Legionella pneumophila is known to proliferate in hot water plumbing systems, but little is known about the specific physicochemical factors that contribute to its regrowth. Here, L. pneumophila trends were examined in controlled, replicated pilot-scale hot water systems with continuous recirculation lines subject to two water heater settings (40 degrees C and 58 degrees C) and three distal tap water use frequencies (high, medium, and low) with two pipe configurations (oriented upward to promote convective mixing with the recirculating line and downward to prevent it). Water heater temperature setting determined where L. pneumophila regrowth occurred in each system, with an increase of up to 4.4 log gene copies/mL in the 40 degrees C system tank and recirculating line relative to influent water compared to only 2.5 log gene copies/mL regrowth in the 58 degrees C system. Distal pipes without convective mixing cooled to room temperature (23-24 degrees C) during periods of no water use, but pipes with convective mixing equilibrated to 30.5 degrees C in the 40 degrees C system and 38.8 degrees C in the 58 degrees C system. Corresponding with known temperature effects on L. pneumophila growth and enhanced delivery of nutrients, distal pipes with convective mixing had on average 0.2 log more gene copies/mL in the 40 degrees C system and 0.8 log more gene copies/mL in the 58 degrees C system. Importantly, this work demonstrated the potential for thermal control strategies to be undermined by distal taps in general, and convective mixing in particular. PMID- 26985907 TI - From Prebiotics to Probiotics: The Evolution and Functions of tRNA Modifications. AB - All nucleic acids in cells are subject to post-transcriptional chemical modifications. These are catalyzed by a myriad of enzymes with exquisite specificity and that utilize an often-exotic array of chemical substrates. In no molecule are modifications more prevalent than in transfer RNAs. In the present document, we will attempt to take a chemical rollercoaster ride from prebiotic times to the present, with nucleoside modifications as key players and tRNA as the centerpiece that drove the evolution of biological systems to where we are today. These ideas will be put forth while touching on several examples of tRNA modification enzymes and their modus operandi in cells. In passing, we submit that the choice of tRNA is not a whimsical one but rather highlights its critical function as an essential invention for the evolution of protein enzymes. PMID- 26985911 TI - A Quality Improvement Project in Balance and Vestibular Rehabilitation and Its Effect on Clinical Outcomes. AB - BACKGROUND AND PURPOSE: Unwarranted variation in practice is among the principal contributors of suboptimal outcomes in health care. This variation can be minimized via quality improvement initiatives. However, quality improvement projects focus mostly on assessing processes, and less attention is given to the effect of the variation on clinical outcomes. An effective implementation of a clinical treatment algorithm (CTA) could improve care for individuals with balance and vestibular disorders. The first aim of this quality improvement project was to examine adherence to a CTA developed by physical therapists who treat persons with balance and vestibular disorders. The second aim was to examine the effect of adherence on patient outcomes. METHODS: Twenty-three physical therapists who provided rehabilitation for individuals with balance and vestibular disorders participated in the quality improvement project. All physical therapists worked for the same health care provider, and developed the minimum data set and CTA. The physical therapists were cluster randomized into 2 groups; both groups received educational training and reminders regarding adherence to the CTA. The first group received the training and reminders after an 8-week baseline period (initial group), and the second group (delayed group) after a 12-week baseline period. The prescribed interventions were classified as being adherent or nonadherent to the CTA. Clinical outcomes, including the Activities-Specific Balance Confidence (ABC) scale, Dizziness Handicap Inventory (DHI), and the Global Rating of Change (GRC), were recorded at the initial evaluation and discharge for 454 individual with balance or vestibular disorders. RESULTS: Across the 16-week project, adherence rates improved significantly by 9% and 12% for the initial and delayed groups, respectively (P = 0.008), but there was no difference between groups related to the timing of the educational training and adherence reminders. Clinical outcomes improved for individuals, with balance or vestibular disorders but there was no differences in the change in ABC, DHI, and GRC scores based on whether the interventions were or were not adherent to the CTA. DISCUSSION AND CONCLUSIONS: This quality improvement project was effective in increasing the adherence to the CTA in both groups. Although on average individuals with balance and vestibular disorders showed improvement on the clinical outcomes, there was no additional benefit in the clinical outcome for adherent interventions.Video abstract is available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A125). PMID- 26985913 TI - Epithelial skin cancers after kidney transplantation: a retrospective single centre study of 376 recipients. AB - Post-transplant non-melanoma skin cancers (NMSC) are the most common malignancies in kidney transplant recipients. To analyse risk factors associated with the occurrence of basal cell carcinomas (BBC) and squamous cell carcinomas (SCC) in kidney transplant recipients. Statistical analysis was performed on 376 kidney transplant recipients screened for NMSC in 2002-2009 and followed until 2013. NMSC developed in 23.67% of individuals with an SCC/BCC ratio of 2.15:1 and an age-standardised incidence ratio (IR) of 2.71 cases (95% CI: 1.97-3.46) per 100 patients/year. Based on multivariable analysis, NMSC occurrence significantly correlated with higher age (p<0.001), fair skin type (p = 0.01), and particularly SCCs with male gender (p = 0.001). Patients with >10 actinic keratoses were at higher risk of developing NMSCs (IRR = 2.95; 95% CI: 1.97-4.42; p<0.001) and more prone to SCCs, compared to BCCs (p = 0.04). Also, more SCC carriers had high counts of warty lesions (p = 0.006). Calcineurin inhibitors were associated with higher NMSC incidence (IRR = 2.81; 95% CI: 1.1-7.01; p = 0.03), while no difference was seen with the mammalian target of rapamycin (mTOR) inhibitors. Our results confirm an influence of the individual immunosuppressive regimen, in addition to the duration of immunosuppression, and suggest that older patients, males, fair skinned recipients or those affected with high counts of actinic keratoses (field cancerisation) are particularly prone to development of NMSC. PMID- 26985910 TI - Aryl Diazonium Chemistry for the Surface Functionalization of Glassy Biosensors. AB - Nanostring resonator and fiber-optics-based biosensors are of interest as they offer high sensitivity, real-time measurements and the ability to integrate with electronics. However, these devices are somewhat impaired by issues related to surface modification. Both nanostring resonators and photonic sensors employ glassy materials, which are incompatible with electrochemistry. A surface chemistry approach providing strong and stable adhesion to glassy surfaces is thus required. In this work, a diazonium salt induced aryl film grafting process is employed to modify a novel SiCN glassy material. Sandwich rabbit IgG binding assays are performed on the diazonium treated SiCN surfaces. Fluorescently labelled anti-rabbit IgG and anti-rabbit IgG conjugated gold nanoparticles were used as markers to demonstrate the absorption of anti-rabbit IgG and therefore verify the successful grafting of the aryl film. The results of the experiments support the effectiveness of diazonium chemistry for the surface functionalization of SiCN surfaces. This method is applicable to other types of glassy materials and potentially can be expanded to various nanomechanical and optical biosensors. PMID- 26985915 TI - Multi-trait BLUP model indicates sorghum hybrids with genetic potential for agronomic and nutritional traits. AB - The breeding of sorghum, Sorghum bicolor (L.) Moench, aimed at improving its nutritional quality, is of great interest, since it can be used as a highly nutritive alternative food source and can possibly be cultivated in regions with low rainfall. The objective of the present study was to evaluate the potential and genetic diversity of grain-sorghum hybrids for traits of agronomic and nutritional interest. To this end, the traits grain yield and flowering, and concentrations of protein, potassium, calcium, magnesium, sulfur, iron, manganese, and zinc in the grain were evaluated in 25 grain-sorghum hybrids, comprising 18 experimental hybrids of Embrapa Milho e Sorgo and seven commercial hybrids. The genetic potential was analyzed by a multi-trait best linear unbiased prediction (BLUP) model, and cluster analysis was accomplished by squared Mahalanobis distance using the predicted genotypic values. Hybrids 0306037 and 0306034 stood out in the agronomic evaluation. The hybrids with agronomic prominence, however, did not stand out for the traits related to the nutritional quality of the grain. Three clusters were formed from the dendrogram obtained with the unweighted pair group method with arithmetic mean method. From the results of the genotypic BLUP and the analysis of the dendrogram, hybrids 0577337, 0441347, 0307651, and 0306037 were identified as having the potential to establish a population that can aggregate alleles for all the evaluated traits of interest. PMID- 26985909 TI - New Insights into the Crossroads between EMT and Stemness in the Context of Cancer. AB - The epithelial-mesenchymal transition (EMT) is an example of cellular plasticity, where an epithelial cell acquires a mesenchymal-like phenotype that increases its migratory and invasive properties. Stemness is the ability of stem cells to proliferate in an asymmetric way that allows them to maintain the reservoir of undifferentiated cells with stem cell identity, but also to produce new differentiated cells. Initial works revealed that activation of the EMT program in epithelial cells induces the acquisition of stem cell properties, which in the context of cancer may contribute to the appearance of tumor initiating cells (TIC). However, a number of groups have recently reported that mesenchymal epithelial transition (MET) is required for efficient metastatic colonization and that EMT may be not necessarily associated with stemness. In this review, we summarize recent findings that extend our knowledge about the crossroads between EMT and stemness and their relevance under physiological or pathological conditions. PMID- 26985904 TI - Micronutrients in Oncological Intervention. AB - Nutritional supplements are widely used among patients with cancer who perceive them to be anticancer and antitoxicity agents. Depending on the type of malignancy and the gender 30%-90% of the cancer patients supplement their diets with antioxidant and immuno-stabilizing micronutrients, such as selenium, vitamin C, and vitamin D, often without the knowledge of the treating physician. From the oncological viewpoint, there are justifiable concerns that dietary supplements decrease the effectiveness of chemotherapy and radiotherapy. Recent studies, however, have provided increasing evidence that treatment is tolerated better with an increase in patient compliance and a lower rate of treatment discontinuations-when micronutrients, such as selenium, are added as appropriate to the patient's medication. Nutritional supplementation tailored to an individual's background diet, genetics, tumor histology, and treatments may yield benefits in subsets of patients. Clinicians should have an open dialogue with patients about nutritional supplements. Supplement advice needs to be individualized and come from a credible source, and it is best communicated by the physician. PMID- 26985916 TI - Association between angiotensin-converting enzyme insertion/deletion polymorphisms and the risk of heart disease: an updated meta-analysis. AB - Insertion/deletion (I/D) polymorphisms of the gene encoding angiotensin converting enzyme (ACE) are a controversial risk factor for heart diseases (HDs). ACE I/D polymorphism has been reported to be associated with various cardiovascular diseases. However, some studies have presented conflicting results. In this study, we aim to explore the association between ACE I/D polymorphisms and the risk of coronary HD (CHD), coronary artery disease (CAD), and myocardial infarction (MI). A meta-analysis was conducted, which included 12,533 cases and 20,726 controls from 75 case-control studies. We performed overall analysis on the entire dataset and found that the D allele of ACE was significantly associated with increased risk of HDs in three different comparison models (dominant, recessive, and homozygote). We also performed analyses on subgroups based on ethnicity as well as disease type. Our results showed that the D allele of ACE was significantly associated with an increased risk of HDs in the Asian and European groups but not in the American group. In addition, in all three subgroups (CHD, CAD, and MI), the D allele of ACE was found to be significantly associated with increased risk of disease. Begg's funnel plots were generated to evaluate publication biases, but no obvious publication bias was found in the studies included in our meta-analysis. In conclusion, our meta analysis demonstrated that the D allele of ACE was significantly associated with an increased risk of HDs. PMID- 26985914 TI - Radiofrequency thermal treatment with chemoradiotherapy for advanced rectal cancer. AB - We previously reported that patients with a clinical complete response (CR) following radiofrequency thermal treatment exhibit significantly increased body temperature compared with other groups, whereas patients with a clinical partial response or stable disease depended on the absence or presence of output limiting symptoms. The aim of this study was to evaluate the correlation among treatment response, Hidaka radiofrequency (RF) output classification (HROC: termed by us) and changes in body temperature. From December 2011 to January 2014, 51 consecutive rectal cancer cases were included in this study. All patients underwent 5 RF thermal treatments with concurrent chemoradiation. Patients were classified into three groups based on HROC: with <=9, 10-16, and >=17 points, calculated as the sum total points of five treatments. Thirty-three patients received surgery 8 weeks after treatment, and among them, 32 resected specimens were evaluated for histological response. Eighteen patients did not undergo surgery, five because of progressive disease (PD) and 13 refused because of permanent colostomy. We demonstrated that good local control (ypCR + CR + CRPD) was observed in 32.7% of cases in this study. Pathological complete response (ypCR) was observed in 15.7% of the total 51 patients and in 24.2% of the 33 patients who underwent surgery. All ypCR cases had >=10 points in the HROC, but there were no patients with ypCR among those with <=9 points in the HROC. Standardization of RF thermal treatment was performed safely, and two types of patients were identified: those without or with increased temperatures, who consequently showed no or some benefit, respectively, for similar RF output thermal treatment. We propose that the HROC is beneficial for evaluating the efficacy of RF thermal treatment with chemoradiation for rectal cancer, and the thermoregulation control mechanism in individual patients may be pivotal in predicting the response to RF thermal treatment. PMID- 26985917 TI - Isolation and characterization of white and brown adipocytes in Kunming mice. AB - White adipose tissue and brown adipose tissue play critical roles in controlling energy homeostasis and the development of obesity and diabetes. We isolated mouse white adipocytes from inguinal white fat tissues and brown adipocytes from interscapular brown fat tissues, and employed a variety of approaches, including immunofluorescent staining, quantitative real-time PCR, western blotting analysis, and differentiation assay, to characterize those adipocytes. Both white and brown adipocytes stained positively for CD44 and CD29, and lipid droplets were observed after the induction of adipogenesis. The Asc1 expression level in the white adipocytes was 2.5-fold higher than that in the brown adipocytes (P < 0.05), and the expression of Ucp1 in the white adipocytes was approximately 50% of that in the brown adipocytes (P < 0.05). The expression of alpha-tubulin in the brown adipocytes was approximately 70% of that in the white adipocytes. The brown adipocytes had a higher Cidea mRNA level (P < 0.05) and a lower Ppargamma mRNA level (P < 0.05) than the white adipocytes. The results demonstrate that white and brown adipocytes have different gene expression signatures, and may represent two useful cell models to study the mechanisms involved in obesity. PMID- 26985918 TI - Karyotype studies on Lycoris radiata populations from China. AB - Lycoris radiata is an important medicinal and ornamental plant of China. In the present study, somatic chromosome counts and karyotype analyses, which are important aspects of plant phylogeny and evolution, were performed in 466 individuals from 25 L. radiata populations by root tip squash method. Chromosome counts revealed that 10 populations were diploid (2n = 2x = 22) and 15 were triploid (2n = 3x = 33). Except for one diploid population containing some triploid plants, the remaining 24 populations showed a single cytotype. Karyotype analysis showed that the karyotypes of L. radiata varied in different populations and even within the same population. However, based on the Stebbins' system, the karyotype of all the populations could be classified in 4A classes. The cluster analysis and ordination methods demonstrated that the L. radiata populations grouped in two major clusters. Previous research has shown that the triploid strain of L. radiata is a genetically identical species. However, the cluster analysis revealed that the triploid strains clustered in two groups instead of one, which indicates that these strains may not be identical species, genetically. This study is expected to improve the understanding of the genetic diversity in L. radiata and provide a basis for future studies on species differentiation, speciation, and taxonomy. PMID- 26985920 TI - Epistasis in intra- and inter-gene pool crosses of the common bean. AB - Epistasis has been shown to have an important role in the genetic control of several quantitative traits in the common bean. This study aimed to investigate the occurrence of epistasis in intra- and inter-pool gene crosses of the common bean. Four elite lines adapted to Brazilian conditions were used as parents, two from the Andean gene pool (ESAL 686; BRS Radiante) and two from the Mesoamerican gene pool (BRSMG Majestoso; BRS Valente). Four F2 populations were obtained: "A" (ESAL 686 x BRS Radiante), "B" (BRSMG Majestoso x BRS Valente), "C" (BRS Radiante x BRSMG Majestoso), and "D" (BRS Valente x ESAL 686). A random sample of F2 plants from each population was backcrossed to parents and F1 individuals, according to the triple test cross. Three types of progenies from each population were evaluated in contiguous trials. Seed yield and 100-seed weight were evaluated. Dominance genetic variance was predominant in most cases. However, the estimates of genetic variance may be biased by the occurrence of linkage disequilibrium and epistasis. Epistasis was detected for both traits; however, the occurrence differed among the populations and between the two traits. The results of this study reinforce the hypothesis that epistasis is present in the genetic control of traits in the common bean and suggest that the phenomenon is more frequent in inter-gene pool crosses than in intra-gene pool crosses. PMID- 26985919 TI - Effect of puerarin on the expression of NMU, NPY, and POMC genes in the hypothalamus. AB - The hypothalamus is an important component of the nervous system, and neuropeptide Y (NPY), proopiomelanocortin (POMC), and neuromedin U (NMU) are key players in physiological regulation. Puerarin is important for nerve regulation. We investigated the effect of puerarin on the expression of NMU, NPY, and POMC genes in the hypothalamus. The results showed that the puerarin low-dose group and the other groups were significantly different (P < 0.05). However, there was no significant difference in NMU, POMC, and NPY among the groups. PMID- 26985921 TI - Investigation of mycoviruses in endophytic and phytopathogenic strains of Colletotrichum from different hosts. AB - Fungi belonging to the Colletotrichum genus can be categorized as endophytic or phytopathogenic. These fungi can be infected by viruses, termed mycoviruses, which are know to promote hypovirulence in infected fungi. However, there are few studies that have described mycoviral infections of endophytes. The production of secondary metabolites by endophytes with antimicrobial potential in inhibiting numerous pathogens has gained increasing attention. The aim of the current study was to investigate the presence of mycoviruses in endophytic and phytopathogenic fungi of the Colletotrichum genus, as well as to analyze the antimicrobial activity of crude extracts obtained from these samples. To detect the presence of mycoviruses in the samples, dsRNA was extracted, treated with enzymes, and analyzed following electrophoresis in agarose gel. Furthermore, isometric mycoviral particles were observed by transmission electron microscopy. Serial microdilution methodology was used to test crude extracts of Colletotrichum spp for antibacterial activity against Escherichia coli and Staphylococcus aureus, and antifungal activity against Fusarium solani. The results of the molecular and microscopic analyses indicated that a phytopathogenic strain presented infection by mycovirus. The antibacterial activity analysis revealed that the minimum inhibitory concentrations and minimum bactericidal concentrations were low for the fungal extracts of the two endophytes, indicating that these extracts were effective antibacterial agents. However, their antifungal activity against F. solani was not statistically different compared to that of the negative control. PMID- 26985922 TI - Therapeutic effect of Pleurotus eryngii cellulose on experimental fatty liver in rats. AB - The aim of this study was to explore the therapeutic effect of Pleurotus eryngii cellulose on experimental fatty liver in rats. Rats were fed high-fat fodder to establish a rat fatty liver model, and were then fed different concentrations of Pleurotus eryngii cellulose for six weeks. Lipitor was used as a positive control. Measured levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), and total triglyceride (TG); the activity of malondialdehyde (MDA), superoxide dismutase (SOD), hepatic lipase (HL), and lipoprotein lipase; and liver histopathological changes. Successfully established rat fatty liver model after feeding high-fat fodder for one week. A diet of P. eryngii cellulose for six weeks significantly reduced ALT, AST, TC, and TG levels in rat serum (P < 0.01); TC and AST levels in P. eryngii cellulose high-dose group and Lipitor group were not significantly different from those of the control (P > 0.05). SOD activity increased significantly, while MDA and HL activity decreased (P < 0.05); fatty degeneration and fat accumulation both decreased in hepatic tissue. Hepatic protection of P. eryngii cellulose showed dose-related effect. P. eryngii cellulose can affect lipid metabolism, having therapeutic effects on fatty liver in rats. PMID- 26985923 TI - Relationship between CYP17 gene polymorphisms and risk of prostate cancer. AB - Cytochrome P450 17a-hydroxylase (CYP17) plays a critical role in androgen biosynthesis. Polymorphisms of the CYP17 promoter have been proposed as risk factors for prostate cancer; however, some studies have produced inconclusive or controversial results. We investigated the relationship between polymorphisms of the CYP17 gene and the risk of prostate cancer. A total of 176 patients with prostate cancer were enrolled in the study, and 168 healthy individuals acted as the control group. The participants were divided into those <71 years old and those >=71 years old. Restriction fragment length polymorphism-polymerase chain reaction was used to confirm the genotype of CYP17 in the samples. The prostate specific antigen (PSA) concentrations were also measured in all subjects. When T/C and C/C were compared with T/T, the ORs were 0.478 (P = 0.489) and 0.814 (P = 0.367), respectively. There was no significant difference in PSA concentration among the three genotypes in the <71 group, whereas there were statistically significant differences in the >=71 group (P = 0.003 and 0.012, respectively). There was no significant difference in free PSA and total PSA levels between the three groups and the control group. The T/C and C/C genotypes were not associated with the risk of prostate cancer, and there were no significant differences between them. In the >=71 group, the T/C and C/C genotypes were closely associated with prostate cancer, which suggests that the CYP17 gene might be a risk factor for prostate cancer in males of advanced age. PMID- 26985924 TI - Salt stress alters DNA methylation levels in alfalfa (Medicago spp). AB - Modification of DNA methylation status is one of the mechanisms used by plants to adjust gene expression at both the transcriptional and posttranscriptional levels when plants are exposed to suboptimal conditions. Under abiotic stress, different cultivars often show heritable phenotypic variation accompanied by epigenetic polymorphisms at the DNA methylation level. This variation may provide the raw materials for plant breeding programs that aim to enhance abiotic stress tolerance, including salt tolerance. In this study, methylation-sensitive amplified polymorphism (MSAP) analysis was used to assess cytosine methylation levels in alfalfa (Medicago spp) roots exposed to increasing NaCl concentrations (0.0, 8.0, 12.0, and 20.0 dS/m). Eleven indigenous landraces were analyzed, in addition to a salt-tolerant cultivar that was used as a control. There was a slight increase in DNA methylation upon exposure to high levels of soil salinity. Phylogenetic analysis using MSAP showed epigenetic variation within and between the alfalfa landraces when exposed to saline conditions. Based on MSAP and enzyme linked immunosorbent assay results, we found that salinity increased global DNA methylation status, particularly in plants exposed to the highest level of salinity (20 dS/m). Quantitative reverse transcription-polymerase chain reaction indicated that this might be mediated by the overexpression of methyltransferase homolog genes after exposure to saline conditions. DNA demethylation using 5 azacytidine reduced seedling lengths and dry and fresh weights, indicating a possible decrease in salinity tolerance. These results suggest that salinity affects DNA methylation flexibility. PMID- 26985925 TI - RETRACTION of "Immune memory responses to HBV vaccine 13-18 years after primary vaccination" by L. Hou, W. Li, X. Wei, Y. Zhou, Y. Zhuo, H. Wu, B. Shen. Genet. Mol. Res. 14 (3): 8466-8472 (2015). AB - The article "Immune memory responses to HBV vaccine 13-18 years after primary vaccination" by L. Hou, W. Li, X. Wei, Y. Zhou, Y. Zhuo, H. Wu, B. Shen published in 2015 in Genetics and Molecular Research 14(3): 8466-8472 (http://dx.doi.org/10.4238/2015.July.28.14) has been found to be substantially equal to the article "Immune memory response induced in vitro by recombinant hepatitis B surface antigen challenge 13-18 years after primary vaccination" published in the Journal of Medical Virology 86:1700-1704 (2014) from Andrea do Livramento et al. (DOI: 10.1002/jmv.24012). The corresponding author of the article published in Genetics and Molecular Research, Baosheng Shen, alerted our editorial staff about this situation and requested the retraction of the article. The Publisher and Editor retract this article in Accordance with the recommendations of the Committee on Publication Ethics (COPE). After a thorough investigation, we have strong reasons to believe que the peer review process was failure and after review and contacting the authors, the editors of Genetics and Molecular Research have decided to retract the article. The authors and their institutions have been advised of this serious breach of ethics. PMID- 26985926 TI - Corrigendum: Association between TAP1 gene polymorphisms and alopecia areata in a Korean population - Genet. Mol. Res. 14 (4): 18820-18827. PMID- 26985927 TI - Antimicrobial potential of actinobacteria isolated from the rhizosphere of the Caatinga biome plant Caesalpinia pyramidalis Tul. AB - Actinobacteria are known to produce various secondary metabolites having antibiotic effects. This study assessed the antimicrobial potential of actinobacteria isolated from the rhizosphere of Caesalpinia pyramidalis Tul. from the Caatinga biome. Sixty-eight actinobacteria isolates were evaluated for antimicrobial activity against different microorganisms by disk diffusion and submerged fermentation, using different culture media, followed by determination of minimum inhibitory concentration (MIC) and chemical prospecting of the crude extract. Of the isolates studied, 52.9% of those isolated at 37 degrees C and 47.05% of those isolated at 45 degrees C had activity against Bacillus subtilis, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Fusarium moniliforme, and Candida albicans. When compared with others actinobacteria, the isolate C1.129 stood out with better activity and was identified by 16S rDNA gene analysis as Streptomyces parvulus. The crude ethanol extract showed an MIC of 0.97 MUg/mL for MRSA and B. subtilis, while the ethyl acetate extract showed MIC of 3.9 MUg/mL for S. aureus and MRSA, showing the greatest potential among the metabolites produced. Chemical prospecting revealed the presence of mono/sesquiterpenes, proanthocyanidin, triterpenes, and steroids in both crude extracts. This study evaluates S. parvulus activity against multi-resistant microorganisms such as MRSA. Thus, it proves that low-fertility soil, as is found in the Caatinga, may contain important microorganisms for the development of new antimicrobial drugs. PMID- 26985928 TI - Validation of EST-derived microsatellite markers for two Cerrado-endemic Campomanesia (Myrtaceae) species. AB - We assessed the transferability of 120 EST-derived Eucalyptus microsatellite primers to Campomanesia adamantium and C. pubescens. Both species are berry trees native to the Brazilian Cerrado, and population genetic information is poor. Twelve markers were used to analyze the genetic variability of four sampled populations. Regarding DNA extraction, we sampled leaf tissues from two populations of each species (80 individuals). Of the 120 primers evaluated, 87 did not amplify any PCR products, and 21 rendered nonspecific amplification. Twelve primers were successfully transferred, providing a low combined probability of genetic identity for both species (5.718 x 10(-10) for C. adamantium; 1.182 x 10(-11) for C. pubescens) and a high probability of paternity exclusion (0.99939 for C. adamantium; 0.99982 for C. pubescens). The average number of alleles in the polymorphic loci was 6.8 for C. adamantium and 7.8 for C. pubescens, ranging from 2 to 16 alleles per locus. The observed heterozygosity values for C. adamantium and C. pubescens were 0.504 and 0.503, respectively, and the expected heterozygosity values for C. adamantium and C. pubescens were 0.517 and 0.579, respectively. The populations exhibited structured genetic variability with qP values of 0.105 for C. adamantium and 0.249 for C. pubescens. Thus, we concluded that these 12 microsatellite markers, transferred from Eucalyptus, were efficient for population genetic studies of C. adamantium and C. pubescens. PMID- 26985929 TI - rs3918242 MMP9 gene polymorphism is associated with myocardial infarction in Mexican patients. AB - Several studies have demonstrated that matrix metalloproteinases (MMPs) play a major role in atherosclerotic plaque disruption and lead to myocardial infarction (MI). We investigated the association between the MMP1 -1607 1G/2G (rs1799750), MMP3 -1612 5A/6A (rs3025058), and MMP9 -1562 C/T (rs3918242) polymorphisms and the risk of developing MI in a Mexican mestizo cohort. The genotype analysis was performed using the restriction fragment length polymorphism-polymerase chain reaction technique in a group of 236 patients with a history of MI and 285 healthy controls. Similar distributions of rs1799750 and rs3025058 were observed in both groups; however, the MMP9 rs3918242 T allele and the CT genotype were associated with the risk of developing MI (OR = 2.32, pC = 0.02 and OR = 2.40, pC = 0.02, respectively). Multiple logistic analysis was performed between MI patients and controls to estimate the risk, and after adjusting for identified risk factors, the CT + TT genotypes of MMP9 rs3918242 were found to be significantly associated with increased risk of developing MI than those with the CC genotype (OR = 2.88, P < 0.01). In summary, our results reveal that the rs3918242 polymorphism of the MMP9 gene plays a major role in the risk of developing MI. PMID- 26985930 TI - Desmoglein 4 diversity and correlation analysis with coat color in goat. AB - Desmoglein 4 (DSG4) has an important role in the development of wool traits in domestic animals. The full-length DSG4 gene, which contains 3918 bp, a complete open-reading-frame, and encodes a 1040-amino acid protein, was amplified from Liaoning cashmere goat. The sequence was compared with that of DSG4 from other animals and the results show that the DSG4 coding region is consistent with interspecies conservation. Thirteen single-nucleotide polymorphisms (SNPs) were identified in a highly variable region of DSG4, and one SNP (M-1, G>T) was significantly correlated with white and black coat color in goat. Haplotype distribution of the highly variable region of DSG4 was assessed in 179 individuals from seven goat breeds to investigate its association with coat color and its differentiation among populations. However, the lack of a signature result indicates DGS4 haplotypes related with the color of goat coat. PMID- 26985931 TI - Effects of probucol on cultured human umbilical vein endothelial cells injured by hypoxia/reoxygenation. AB - There is increasing evidence suggesting that endoplasmic reticulum stress (ERS) plays an important role in the initiation and development of atherosclerosis. This study was designed to examine the effect of probucol on cultured human umbilical vein endothelial cells (HUVECs) injured by hypoxia/reoxygenation (H/R) and the potential mechanisms involving ERS. Injured HUVECs induced by Na2S2O4 served as an H/R model in vitro. The concentration of probucol in this study ranged from 3 to 27 MUM. Cell viability was analyzed using MTT and a lactate dehydrogenase (LDH) assay. The expression of GRP78, X-box-binding protein (XBP) 1, and CHOP (c/EBP-hemologous protein) were quantified using western blot. Compared to cells with H/R injury alone, the results showed that the cell viability increased significantly with probucol, while the LDH leakage rate was significantly lower as analyzed by the LDH assay. Furthermore, the expression levels of GRP78, XBP-1, and CHOP were significantly downregulated. These results indicated that probucol effectively protected HUVEC from injury induced by H/R and that the mechanism might be related to attenuation of ERS. PMID- 26985932 TI - Effect of ST2825 on the proliferation and apoptosis of human hepatocellular carcinoma cells. AB - The purpose of this study was to investigate the effect of ST2825, an inhibitor of myeloid differentiation factor 88 (MyD88), on the proliferation and apoptosis of human hepatocellular carcinoma (HCC) cells as well as the potential mechanism and clinical significance of ST2825 in the treatment of HCC. Immunohistochemical staining with an MyD88 antibody was performed on tissues from 80 human HCC patients and adjacent normal tissues. In the in vitro experiment, human HCC HepG 2 cells cultured in vitro were divided into the following groups: blank, control (1% DMSO), low-dose (2 MUM), medium-dose (10 MUM), and high-dose ST2825 (20 MUM). Cell apoptosis was detected by the Annexin V-FITC assay, and HepG-2 cell proliferation was detected by the MTT assay. The expression of IkappaB, p65, cyclin D1, caspase-3, and bcl-2 in the cells after a 48-h treatment was assayed by western blot analysis. MyD88 expression in the HCC tissue was significantly higher than that in the adjacent normal tissue (P < 0.05). The proliferation and apoptosis rates of control HCC cells displayed no significant differences compared with those of the blank group (P > 0.05). Compared with the control, ST2825 significantly inhibited the proliferation of and promoted the apoptosis of HCC cells. Moreover, ST2825 significantly decreased bcl-2 expression, increased cleaved caspase-3 expression (P < 0.05), and reduced p65 nuclear expression (P < 0.05) in a dose-dependent manner. ST2825 inhibits the proliferation of and promotes the apoptosis of HCC cells, thereby suggesting that ST2825 may be a new drug for HCC treatment. PMID- 26985933 TI - Association of N-acetyltransferase-2 polymorphism with an increased risk of coronary heart disease in a Chinese population. AB - We investigated the possible correlations between N-acetyltransferase-2 (NAT2) gene polymorphisms and the risk of coronary heart disease (CHD). CHD patients (113) and healthy controls (118) were enrolled from the First People's Hospital of Yuhang between January 2013 and June 2014. The patients were divided into mild CHD (N = 72) and severe CHD (N = 41) subgroups. DNA samples were extracted and the distributions of NAT2 polymorphisms were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Clinical characteristic indexes of severe CHD patients were also examined for relevant statistical analysis. WT, M1, M2, and M3 alleles were observed in both case and control groups. PCR-RFLP identified a wild-type homozygote, WT/WT; a mutant heterozygote, WT/Mx; and a mutant homozygote, Mx/Mx (x = 1, 2, and 3) variant of the NAT2 genotype. Mx/Mx differed significantly between case and control groups (P < 0.05); the frequencies of all four alleles did not differ significantly between case and control groups (P > 0.05). Slow acetylator genotype frequencies were notably higher in the case group than in the control group (P < 0.05). Individuals with the slow acetylator genotype were at 1.97-times higher risk of CHD and also displayed higher triglyceride and lower high-density lipoprotein cholesterol levels than those with the rapid acetylator genotype (P < 0.05). Therefore, the NAT2 polymorphism was believed to be associated with increased risk of CHD, with the NAT2 slow acetylator genotype serving as a risk factor for severe CHD in a Chinese population. PMID- 26985934 TI - 5-Fluorouracil induces apoptosis of colorectal cancer cells. AB - 5-Fluorouracil (5-FU) is widely used in chemotherapy for treatment of colorectal cancer. Leucine-rich repeat-containing G protein-coupled receptor (LGR) is known to participate in the occurrence and development of breast cancer by regulating the rebirth of tumor vessels. This study aimed to explore the proliferation and apoptosis of HCT116 colorectal cancer cells treated with 5-FU and related molecular mechanisms. 5-FU (20 MUg/mL) was used to treat cultured HCT116 cells. An MTT test, flow cytometry, and colony formation assays were used to examine the proliferation and apoptosis of HCT116 cells. Western blotting was applied to detect the expression of the LGR4 protein in HCT116 cells. Small interference RNA or over-expression techniques were used to manipulate LGR4 expression in HCT116 cells and describe the proliferation and apoptosis of HCT116 treated with 5-FU. A dosage of 20 MUg/mL 5-FU resulted in a significant decrease in the proliferation and apoptosis of HCT116 cells and significantly decreased expression levels of LGR4. The specific gene silence or over-expression of LGR4 in HCT116 cells increased and decreased the levels of apoptosis in HCT116, respectively. 5-FU induces apoptosis of colorectal cancer cells and inhibits proliferation by suppressing LGR4 proteins. PMID- 26985935 TI - Comparative evaluation of total RNA extraction methods in Theobroma cacao using shoot apical meristems. AB - Theobroma cacao is a species of great economic importance with its beans used for chocolate production. The tree has been a target of various molecular studies. It contains many polyphenols, which complicate the extraction of nucleic acids with the extraction protocols requiring a large amount of plant material. These issues, therefore, necessitate the optimization of the protocols. The aim of the present study was to evaluate different methods for extraction of total RNA from shoot apical meristems of T. cacao 'CCN 51' and to assess the influence of storage conditions for the meristems on the extraction. The study also aimed to identify the most efficient protocol for RNA extraction using a small amount of plant material. Four different protocols were evaluated for RNA extraction using one shoot apical meristem per sample. Among these protocols, one that was more efficient was then tested to extract RNA using four different numbers of shoot apical meristems, subjected to three different storage conditions. The best protocol was tested for cDNA amplification using reverse transcription-polymerase chain reaction; the cDNA quality was determined to be satisfactory for molecular analyses. The study revealed that with the best RNA extraction protocol, one shoot apical meristem was sufficient for extraction of high-quality total RNA. The results obtained might enable advances in genetic analyses and molecular studies using reduced amount of plant material. PMID- 26985936 TI - Vasculogenic mimicry and hypoxia-inducible factor-1alpha expression in cervical squamous cell carcinoma. AB - In this study, the existence of vasculogenic mimicry (VM) in cervical squamous cell carcinoma was investigated. To this end, the relationship between hypoxia inducible factor 1alpha (HIF-1alpha) and the development, infiltration, and metastasis of cervical squamous cell carcinoma was studied. Between January 2010 and December 2010, 67 human cervical squamous carcinoma tissue samples were collected and stained by CD34/periodic acid-Schiff double staining to detect the existence of VM. HIF-1alpha expression was analyzed by immunohistochemistry. The relationship between VM and HIF-1alpha was also analyzed. Normal cervical tissues (20 cases) from patients who had uterine surgeries in the same period were collected as controls. In the cervical squamous carcinoma tissues, positive rates of VM and HIF-1alpha were 38.81% (26/67) and 64.18% (43/67), respectively. This was significantly higher than those in the normal cervical tissues [0 (0/20); P < 0.05]. VM rates in cervical squamous carcinoma tissues from patients with different pathological grades, Federation of Gynecology and Obstetrics (FIGO) stages, and lymph node metastasis states were also significantly different (P < 0.05). In addition, significant differences in HIF-1alpha positivity rates were observed among patients with varying tumor sizes and lymph node metastasis states (P < 0.05). Positive correlation was found between VM and HIF-1alpha (r = 0.339, P < 0.05). To summarize, we found VM in cervical squamous carcinoma; high expression of HIF-1alpha may promote VM formation, as well as cervical squamous cell infiltration and metastasis. PMID- 26985937 TI - CsSAD: a fatty acid desaturase gene involved in abiotic resistance in Camellia sinensis (L.). AB - Tea (Camellia sinensis L.) is a thermophilic evergreen woody plant that has poor cold tolerance. The SAD gene plays a key role in regulating fatty acid synthesis and membrane lipid fluidity in response to temperature change. In this study, full-length SAD cDNA was cloned from tea leaves using rapid amplification of cDNA ends and polymerase chain reaction (PCR)-based methods. Sequence analysis demonstrated that CsSAD had a high similarity to other corresponding cDNAs. At 25 degrees C, the CsSAD transcriptional level was highest in the leaf and lowest in the stem, but there was no obvious difference between the root and stem organs. CsSAD expression was investigated by reverse transcription-PCR, which showed that CsSAD was upregulated at 4 degrees and -5 degrees C. At 25 degrees C, CsSAD was induced by polyethylene glycol, abscisic acid, and wounding, and a similar trend was observed at 4 degrees C, but the mean expression level at 4 degrees C was lower than that at 25 degrees C. Under natural cold acclimation, the 'CsCr05' variety's CsSAD expression level increased before decreasing. The CsSAD expression level in variety 'CsCr06' showed no obvious change at first, but rapidly increased to a maximum when the temperature was very low. Our study demonstrates that CsSAD is upregulated in response to different abiotic conditions, and that it is important to study the stress resistance of the tea plant, particularly in response to low temperature, drought, and wounding. PMID- 26985938 TI - Expression of MMP-1, -2, and -8 in longissimus dorsi muscle and their relationship with meat quality traits in cattle. AB - The extracellular matrix (ECM) is the major macromolecule in skeletal muscle, which affects meat quality greatly. The remodeling of the ECM is mainly regulated by matrix metalloproteinases (MMPs). The expression patterns of MMP-1, -2, and -8 in longissimus dorsi muscle were explored using quantitative real-time polymerase chain reaction. The results show that the expression of MMP-1, -2, and -8 decreased significantly from 135 days of pregnancy to postnatal 30 months. While the expression of MMP-1, -2, and -8 showed no significant relationships with intramuscular fat contents, MMP-1 and -2 showed significant negative correlations with the shearing force of the longissimus dorsi muscle in cattle. The expression of MMP-1 also showed a significant negative correlation with cooking loss and a positive correlation with water holding capacity. The expression levels of MMP-1 and -2 were usually higher in fat than in skeletal muscle tissue. The expression of MMP-8 was significantly higher in the mammary fat pad and the longissimus dorsi muscle than in all other tissues. This study indicates that the remodeling of the ECM has important effects both on the development of postnatal skeletal muscle and on meat quality. PMID- 26985939 TI - Differential expression of FUT1 and FUT2 in Large White, Meishan, and Sutai porcine breeds. AB - To assess the relationship between the expression of a(1,2)-fucosyltransferase (FUT1 and FUT2) genes and resistance to Escherichia coli F18 in weaned pigs, FUT1 and FUT2 expression levels in Large White, Meishan, and Sutai pigs (with resistance to E. coli F18) were determined using real-time PCR. The results revealed that FUT1 and FUT2 expression levels were higher in the liver, lungs, kidneys, stomach, duodenum, and jejunum than in the muscle and heart. Medium FUT2 expression levels were detected in the spleen, thymus, and lymph nodes. Intestinal FUT1 expression levels were higher in Sutai pigs than in Large White and Meishan pigs (P < 0.05). However, intestinal FUT2 expression levels were lower in Sutai pigs than in Large White and Meishan pigs (P < 0.05). FUT1 and FUT2 expression levels did not differ between Large White and Meishan pigs (P > 0.05). The results revealed that high FUT1 expression levels and low FUT2 expression levels in the intestines of Sutai pigs affected FUT1 and FUT2 enzymes, the synthesis of type 2 H and type 1 H antigens, and E. coli F18 adhesion. Moreover, low FUT2 expression levels conferred resistance to E. coli F18. PMID- 26985940 TI - Common genetic risk factors of venous thromboembolism in Western and Asian populations. AB - Venous thromboembolism (VTE) is a multifactorial disorder involving both acquired and genetic risk factors. The common genetic factors in Western populations have been studied and reported for several decades, while studies on Asian populations are relatively scarce. Evidence suggests that the prevalence and genetic risk factors of VTE vary significantly among ethnic populations. In this review, we summarize the common genetic risk factors of VTE in both Western and Asian populations. In addition to the development of DNA sequencing technology, genome wide association studies have many advantages and are becoming more important in identifying new genetic risk factors and susceptible loci. They can therefore help in the prediction and prevention of VTE. PMID- 26985941 TI - Effects of grafting on key photosynthetic enzymes and gene expression in the citrus cultivar Huangguogan. AB - Grafting influences scion photosynthetic capacity and fruit quality. Ribulose-1,5 bisphosphate carboxylase/oxygenase (Rubisco), which strongly affects photosynthetic rate, and Rubisco activase (RCA), which regulates Rubisco activity, are two key photosynthetic enzymes. However, little information is available regarding the effect of grafting on the concentration and expression of Rubisco and RCA in the citrus cultivar Huangguogan. The objective of this study was to investigate the effect of grafting Huangguogan plants onto trifoliate orange, tangerine, and orange on: 1) the concentration of Rubisco and RCA; 2) the mRNA levels of rbcL, rbcS, and rca; and 3) fruit quality. Overall, the results showed that when Huangguogan plants budded on tangerine and orange, they had better fruit quality, while on trifoliate orange they had higher Rubisco concentration. Tangerine and orange are probably the most suitable rootstocks for Huangguogan plants given the environmental conditions of Sichuan Province, China. PMID- 26985942 TI - Expression of microRNA-210 in tissue and serum of renal carcinoma patients and its effect on renal carcinoma cell proliferation, apoptosis, and invasion. AB - This study investigated the expression of microRNA-210 (miR-210) in tissue and serum of renal carcinoma patients and its effect on renal carcinoma cell proliferation, apoptosis, and invasion. Thirty-two renal carcinoma patients in our hospital were selected as the study group and 32 people receiving a physical examination were selected as the control group. miR-210 expression in the serum of renal carcinoma patients and in healthy subjects was quantified by real-time polymerase chain reaction. After miR-210 overexpression and inhibition in ACHN cells in human renal carcinoma, ACHN cell proliferation, apoptosis, and invasion were detected by CCK-8, flow cytometry, and a transwell invasion assay. The expression of miR-210 was significantly higher in renal carcinoma than in corresponding paracarcinoma tissues (P < 0.001). The expression of miR-210 was significantly higher in the serum of renal carcinoma than in the control group (P < 0.001). ACHN cell proliferation and invasion were significantly increased and apoptosis was significantly decreased (P < 0.05) when miR-210 was overexpressed. ACHN cell proliferation and invasion were significantly decreased and apoptosis was significantly increased (P < 0.05) when miR-210 was inhibited. In conclusion, miR-210 was highly expressed in tissues and serum of renal carcinoma patients. miR-210 could promote the proliferation and invasion of renal carcinoma cells and inhibit the apoptosis of renal cell carcinoma cells. PMID- 26985944 TI - Paclitaxel induces apoptosis in leukemia cells through a JNK activation-dependent pathway. AB - Paclitaxel (PTX) is a mitotic inhibitor widely used in chemotherapy for many types of cancers, including solid tumors and hematological malignancies. However, the molecular basis of the anti-proliferation activity of PTX is not fully understood. In this paper, we focused on the role of c-Jun N-terminal kinase (JNK) pathways in PTX-induced apoptosis and proliferation inhibition. The effects of PTX were examined in human leukemia cell lines and patients' chronic lymphocytic leukemia (CLL) cells in relation to mitochondrial events, apoptosis, and perturbation of JNK activation using flow cytometry, siRNA, mitochondrial membrane potential determination, and western blotting. Exposure of cells to PTX at concentrations >= 10 nM for 18 or 24 h resulted in a significant release of cytochrome c from mitochondria to the cytosol, cleavages of procaspase 3 and poly (ADP-ribose) polymerase (PARP), and JNK activation, leading to apoptosis. The pan caspase inhibitor BOC-D-FMK blocked the PTX-induced apoptosis but had no effect on cytochrome c release, suggesting that cytochrome c had been released before caspase activation. Moreover, both pharmacological JNK inhibitors SP600125 and JNK siRNA dramatically blocked PTX-induced apoptosis, cytochrome c release, caspase 3, and PARP cleavage. These findings demonstrate that JNK activation plays a critical role in the induction of apoptosis mediated by PTX in human leukemia cell lines and CLL patient-derived primary cancer cells, and this event is upstream of cytochrome c release, caspase 3, and PARP cleavage. PMID- 26985943 TI - Characterization of the inaA gene and expression of ice nucleation phenotype in Pantoea ananatis isolates from Maize White Spot disease. AB - Maize White Spot (MWS), a foliar disease caused by Pantoea ananatis, could cause up to 60% yield loss. Some strains of P. ananatis harboring the ice nucleation gene inaA catalyze the formation of ice nuclei, causing tissue damage at temperatures slightly below freezing. Little is known about the relationship between the presence of the ina gene in this maize pathogen and its expression during the phenomenon of ice nucleus formation. Here, we attempted to verify the presence of the inaA gene and the expression of phenotype in vitro. The identity of the isolates and the presence of the inaA gene were determined by P. ananatis species-specific primers. The expression of the inaA gene was assessed in vitro by the visualization of ice-crystal formation in water at subzero temperatures. A total of ninety P. ananatis isolates from MWS lesions were characterized. The presence of the inaA gene was confirmed by gel electrophoresis of the 350-400-bp PCR products. The inaA primers did not lead to DNA fragment amplification in three isolates. The ice nucleation phenotype was expressed in 83.34% of the isolates carrying the inaA gene. Our study showed that the ice nucleation in P. ananatis isolated from MWS lesions was dependent on the presence of a functional ina gene in the genome. We also found evidence indicating that some P. ananatis strains have a mutated form of the inaA gene, producing a non-functional ice nucleation protein. This is the first report on inaA gene characterization in P. ananatis isolates from Maize White Spot. PMID- 26985945 TI - Process of Bipolaris sorghicola invasion of host cells. AB - Target leaf spot is a sorghum leaf disease caused by Bipolaris sorghicola, a species of fungus with a global distribution. In this study, we investigated the process by which B. sorghicola invades cells of barley, onion, Arabidopsis thaliana species, and sorghum. The results showed that within 8 h of coming into contact with host cells, the hyphal ends of B. sorghicola expand and form a uniform infective penetration pegbolt-like structure; a primary infection mycelium can be formed inside host cells within 24 h after contact, which can infect closed cells after 48 h. A mycelium can grow within the gap between cells and form infective hyphae. The pathogen infection process was the same in different host cells. B. sorghicola can affect root cells through soil infection, indicating that it may also have characteristics of soil-borne pathogens. PMID- 26985946 TI - Selecting soybean resistant to the cyst nematode Heterodera glycines using simple sequence repeat (microssatellite) markers. AB - The soybean cyst nematode (SCN) is a major cause of soybean yield reduction. The objective of this study was to evaluate the efficiency of marker-assisted selection to identify genotypes resistant to SCN race 3 infection, using Sat_168 and Sat-141 resistance quantitative trait loci. The experiment was carried out under greenhouse conditions, using soybean populations originated from crosses between susceptible and resistant parent stock: CD-201 (susceptible) and Foster IAC (resistant), Conquista (susceptible) and S83-30 (resistant), La-Suprema (susceptible) and S57-11 (resistant), and Parecis (susceptible) and S65-50 (resistant). Plants were inoculated with SCN and evaluated according to the female index (FI), those with FI < 10% were classified as resistant to nematode infection. Plants were genotyped for SCN resistance using microsatellite markers Sat-141 and Sat_168. Marker selection efficiency was analyzed by a contingency table, taking into account genotypic versus phenotypic evaluations for each line. These markers were shown to be useful tool for selection of SCN race 3. PMID- 26985947 TI - Effect of retinoic acid on aquaporin 3 expression in keratinocytes. AB - To explore the possible mechanism of the third-generation retinoic acid drugs (isotretinoin, acitretin, adapalene) in inducing skin and mucosa dryness and rhagades; specifically, mechanism by which these drugs influence keratinocyte cell culture models in vitro (HaCaT) and aquaporin channel (AQP3) protein expression was investigated. Isotretinoin, acitretin, and adapalene were applied to human keratinocyte HaCaT cells. Immunohistochemistry, reverse transcriptase polymerase chain reaction, and western blotting were used to detect their effects on AQP3 expression in HaCaT cells at different concentrations (0.000, 0.001, 0.010, 0.060, and 0.100 mg/mL) or different at times (0, 6, 12, 24, and 48 h). At 0.010 mg/mL, maximal AQP3 expression was observed in HaCaT cells; this was significantly higher than the expressions at the other concentrations (P < 0.05). After treatment with isotretinoin, acitretin, or adapalene at 0.010 mg/mL for 12 h, the expression of AQP3 was the highest in the isotretinoin group, followed by the acitretin group, with the lowest expression in the adapalene group. However, the differences were not statistically significant (P > 0.05). Retinoic acid can increase AQP3 expression in HaCaT cells, with significant effects observed with 0.010 mg/mL isotretinoin treatment for 12 h. The side effects, namely skin and mucosa dryness caused by retinoic acid might be related to its effects on AQP3 expression. PMID- 26985949 TI - Contribution of microsatellites markers in the clarification of the origin, genetic risk factors, and implications for conservation of Tunisian native sheep breeds. AB - The genetic diversity and genetic relationship of the two main groups of African sheep, thin-tailed and fat-tailed sheep, represented by the indigenous Tunisian sheep breeds "Barbarine" (BAR, fat-tailed) and "Queue Fine de l'Ouest" (QFO, thin tailed) were investigated. The genotypes of 110 animals belonging to these two breeds and their crossbreed (CRO) were assessed using 17 microsatellite markers. The results showed high levels of genetic diversity and a total of 256 alleles were identified in the whole population. The mean values of observed and expected heterozygosity were 0.719 and 0.789, respectively, and the mean allelic richness estimate was 10.89. The average FIS (0.112) and FIT (0.118) values over all loci indicated a notable level of inbreeding within the whole population. However, the FST value (0.007) showed a low level of genetic differentiation between these two native breeds. The high level of both gene flow and molecular coancestry coefficient detected between the two breeds and their CRO revealed an old miscegenation between the BAR and QFO breeds. The clustering analysis performed with the STRUCTURE software confirmed gene flow between these two breeds. Results arising from this study provide evidence regarding the genetic structure and variability of the two main local sheep breeds, and the implications of their actual management, which indicates the need for an urgent conservation strategy in order to prevent significant gene flow and preserve the remaining breed specificity for future generations. PMID- 26985948 TI - Correlation analysis between an IL-6 genetic polymorphism and non-small cell lung cancer prognosis. AB - Interleukin-6 (IL-6) is a multifunctional cytokine that is involved in tumor cell proliferation, apoptosis, and differentiation. The purpose of this study was to evaluate the impact of the single nucleotide polymorphism (SNP) -174G/C in IL-6 on the prognosis and pain tolerance of non-small cell lung cancer (NSCLC) patients. DNA was extracted from the peripheral blood of 434 patients with NSCLC, which was diagnosed by cytology or histology. Polymerase chain reaction restriction fragment length polymorphism was used to detect the IL-6 -174G/C genotypes and their correlation with survival was analyzed. The IL-6 -174G/C genotypes were high IL-6 production type (G carriers - GG or GC genotypes) and low IL-6 production type (CC genotype). The correlation between the IL-6 SNP and pain level/analgesic use was also analyzed. Survival analysis showed that patients carrying the G allele (CG/GG) had a shorter survival time than patients with the CC genotype. The -174G/C SNP is in the promoter region of the IL-6 gene and may be associated with changes in gene transcription and serum cytokine levels. Presence of the IL-6 -174G/C SNP is significantly correlated with morphine equivalent daily dose. Patients with the CC genotype needed a higher opioid dose than patients with the GG or GC genotypes. In conclusion, we found that the IL-6 -174G/C SNP is closely related to survival, analgesic use and pain tolerance in NSCLC patients. However, it is necessary to further validate the results with a larger patient cohort and elucidate the mechanisms of this SNP. PMID- 26985950 TI - Protective mechanism of quercetin on acute myocardial infarction in rats. AB - To investigate the protective mechanism of quercetin on acute myocardial infarction (AMI) rats, an AMI rat model was established by ligating the left coronary anterior descending branch. The rats were randomly divided into the model group and low- and high-dose quercetin groups. The control group comprised sham-operated rats. The rats in the low- and high-dose quercetin groups were administered 100 and 400 mg/kg quercetin, respectively, by gavage. The rats in the control and model groups were administered isometric normal saline once daily for one week. The mRNA and protein levels of TNF-alpha and IL-1beta in the myocardial tissue of rats were detected in each group by real time polymerase chain reaction and enzyme-linked immunosorbent assay. Malondialdehyde (MDA) content in the myocardial tissue and superoxide dismutase (SOD) and catalase (CAT) activities were detected using a colorimetric method. The level of apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling. Compared with those in the control group, the mRNA and protein levels of TNF-alpha, IL-1beta and MDA content in the model, low-, and high-dose groups significantly increased. SOD and CAT activities decreased significantly. The cell apoptosis index increased significantly (P < 0.05). Compared with those in the model group, the mRNA and protein levels of TNF-alpha and IL-1beta and MDA content in myocardial tissue of rats in the low-dose and high-dose groups decreased significantly. SOD and CAT activities increased significantly. The cell apoptosis index significantly reduced (P < 0.05). In conclusion, quercetin has significant anti-inflammatory, antioxidant, and anti-apoptotic effects on AMI rats and can effectively protect against myocardium damage. PMID- 26985951 TI - Molecular characterization, tissue expression profile, and single nucleotide polymorphism analysis of the periostin gene in swine. AB - Periostin, also called osteoblast-specific factor 2, is an important regulator of bone, cardiac development, and wound healing. A recent study revealed that periostin plays an important role in tumor development and is upregulated in a wide variety of cancers. However, little is known about periostin in swine. Therefore, the cDNA sequence of the porcine periostin gene was obtained by rapid amplification of cDNA ends (RACE). One C/T single nucleotide polymorphism anchored in intron 9 was identified and genotyped by PCR-RFLP-HaeIII. In Daweizi, Shaziling, Ningxiang, Taoyuan, Wuzhishan, Landrace, and Yorkshire pigs, the C allele was dominant, while the T allele was dominant in the Duroc pig. Quantitative PCR analysis showed that the periostin gene was expressed in all examined tissues from 25-day-old Shaziling and Yorkshire piglets, with mRNA expression in the longissimus dorsi muscle being the highest in these two breeds, and that in the kidney and lungs being the lowest. There was a significant difference in periostin gene expression in the intestines, heart, and spleen (P < 0.05). These findings might contribute to our understanding of the function of periostin in swine. PMID- 26985952 TI - Genomic breeding value prediction for simple maize hybrid yield using total effects of associated markers, under different imbalance levels and environments. AB - The main objective of a maize breeding program is to generate hybrid combinations that are more productive than those pre-existing in the market. However, the number of parents, and consequently the number of crosses, increases so rapidly that the phenotypic evaluation of all the possible combinations becomes economically and technically infeasible. In this context, predicting the performance of the most promising genotypes may increase the genetic gains with increased selection intensity and reduced breeding cycles. Thus, the present study aimed to use the total effects of associated markers method to predict genomic breeding values (GBVs) via cross-validation and by using different imbalance levels (10, 30, 50, and 70%). A set of 51 genotyped strains was used with 79 microsatellite markers and 273 hybrids that were generated by a partial diallel. A total of 186 and 272 hybrids were analyzed in the experiments within the southern and central regions of Brazil, respectively. The GBVs were, thus, predicted for each location in both the regions, and for training in one region and validation in another region. The correlation between the predicted and observed GBVs ranged from 0.48 to 0.91, depending on the imbalance level and the region analyzed. Overall, the results obtained in the present study were promising, particularly considering that a small number of markers were used and that the training and predictions occurred in the very distinct regions of southern and central Brazil. PMID- 26985953 TI - Identification of a Panax ginseng fruit fingerprint by HPLC-ESI-MS. AB - Over many years, parts of Panax ginseng (root and rhizome) have been identified and applied for medical purposes as traditional Chinese herbal medicine. Recently, research has indicated that ginseng fruit also contains similar compounds and is as rich as the other parts of the ginseng. This discovery may dramatically improve the efficient of outputs derived from ginseng products. Here, a new technique combining high-performance liquid chromatography (HPLC) with electrospray ionization tandem mass spectrometry (ESI-MS) was employed to identify the fingerprint of P. ginseng fruit. Using HPLC, compounds that are important for medical purposes were extracted and purified. Combined with ESI-MS, the characteristic peaks (nine common peaks) of those compounds were identified, and the accuracy was confirmed by analysis using the Chromatographic Fingerprint Similarity Evaluation System (2004A edition). Overall, 15 batches of ginseng fruit had a similarity of more than 0.80, 13 batches of samples had a similarity between 0.97 and 0.99, and two batches had a similarity less than 0.90. The test solution and mobile phase selection was discussed. The HPLC-ESI-MS method can produce repeatable and reliable results and can be applied in the quality control of P. ginseng fruit. PMID- 26985954 TI - Association between ERCC1 and ERCC2 polymorphisms and breast cancer risk in a Chinese population. AB - We conducted a case-control study to investigate the role of ERCC1 rs3212986 and ERCC2 rs13181 gene polymorphisms in the development of breast cancer. Between March 2012 and March 2014, a total of 242 newly diagnosed breast cancer patients with histopathologically confirmed primary breast cancer and 242 healthy controls were recruited. Genotyping of ERCC1 rs3212986 and ERCC2 rs13181 polymorphisms was carried out using polymerase chain reaction-restriction fragment length polymorphism analysis. Unconditional logistic regression analyses indicated that the TT genotype of rs3212986 was associated with a higher risk of breast cancer compared to that associated with the GG genotype (OR = 2.05, 95%CI = 1.13-3.78). In dominant and recessive models, we found that the rs3212986 polymorphism was associated with increased risk of breast cancer, and the ORs were 1.50 (95%CI = 1.03-2.18) and 1.74 (95%CI = 1.01-3.11), respectively. In summary, we found that the ERCC1 rs3212986 polymorphism was associated with the development of breast cancer. PMID- 26985955 TI - Population genetic analysis and trichothecene profiling of Fusarium graminearum from wheat in Uruguay. AB - Fusarium graminearum sensu stricto (F. graminearum s.s.) is the major causal agent of Fusarium head blight of wheat worldwide, and contaminates grains with trichothecene mycotoxins that cause serious threats to food safety and animal health. An important aspect of managing this pathogen and reducing mycotoxin contamination of wheat is knowledge regarding its population genetics. Therefore, isolates of F. graminearum s.s. from the major wheat-growing region of Uruguay were analyzed by amplified fragment length polymorphism assays, PCR genotyping, and chemical analysis of trichothecene production. Of the 102 isolates identified as having the 15-ADON genotype via PCR genotyping, all were DON producers, but only 41 strains were also 15-ADON producers, as determined by chemical analysis. The populations were genotypically diverse but genetically similar, with significant genetic exchange occurring between them. Analysis of molecular variance indicated that most of the genetic variability resulted from differences between isolates within populations. Multilocus linkage disequilibrium analysis suggested that the isolates had a panmictic population genetic structure and that there is significant recombination occurs in F. graminearum s.s. In conclusion, tour findings provide the first detailed description of the genetic structure and trichothecene production of populations of F. graminearum s.s. from Uruguay, and expands our understanding of the agroecology of F. graminearum and of the correlation between genotypes and trichothecene chemotypes. PMID- 26985956 TI - Molecular characterization and tissue expression profile of porcine Ephrin-B2. AB - Ephrin-B2 (EFNB2) is a signaling molecule that plays an important role in cell adhesion, proliferation, and migration in humans. However, little is known about this molecule in pigs. In order to investigate whether EFNB2 is associated with the skeletal muscle in pigs, we cloned the full-length cDNA of EFNB2 (GenBank accession No. KF500033) from the longissimus dorsi muscle of Yorkshire pigs by rapid amplification of cDNA ends. The results indicated that its full-length cDNA comprises 1991 bp, with an open reading frame of 1002 bp, a 5' end of 88 bp, and a 3' end of 901 bp. We analyzed the homology of porcine EFNB2 with sequences from other species, and the phylogenetic tree showed that pig EFNB2 was most closely related to that from sheep, followed by domestic cats and wolf, with mackerel being the most distantly related. Porcine EFNB2 is a water-soluble protein with a theoretical molecular weight of 36,928.1 Da, an isoelectric point of 8.98, and a hydrophilic transmembrane-spanning region. It contains 19 glycosylation sites and eight phosphorylation sites. The tertiary structure of the EFNB2 protein showed a forniciform helix structure. The porcine EFNB2 gene was expressed in ten different tissues from 25-day-old Shaziling and Yorkshire piglets, with the highest expression observed in the longissimus dorsi. These results lay the foundation for further study on the EFNB2 gene in pigs. PMID- 26985957 TI - Association of interleukin-8 gene polymorphisms in HIV patients with opportunistic infections in Limpopo Province, South Africa. AB - Opportunistic infections (OIs) are common among human immunodeficiency virus (HIV) patients; however, genetic susceptibility to these infections has not been studied. Recent studies have shown that interleukin-8 (IL-8) A/T genotype carriers are more susceptible to a variety of diseases. In this study, we showed the effects of IL-8 gene polymorphisms on OIs and symptoms such as sexually transmitted diseases (STDs), tuberculosis (TB), diarrhea, shortness of breath, weight loss, and viral load, in HIV and acquired immunodeficiency syndrome patients. Genomic DNA was purified from mouthwash samples collected from patients attending HIV centers in the Vhembe district. The IL-8 (-251) A/T locus was genotyped using allele-specific polymerase chain reaction followed by agarose gel electrophoresis. The results showed a weak association between the IL-8 AA genotype and OIs such as STDs (P = 0.143), diarrhea (P = 0.906), and TB (P = 0.762). Significant associations were found between the IL-8 AT genotype and weight loss (P = 0.019), shortness of breath (P = 0.043), and skin problems (P = 0.003). Low viral load was also found to be significantly associated with IL-8 AA genotype (P = 0.009). The present study suggests that different IL-8 genotypes are associated with resistance to various OIs. However, further studies using larger samples sizes are needed to confirm this hypothesis. PMID- 26985958 TI - Mutations in WT1 in boys with sporadic isolated steroid-resistant nephrotic syndrome. AB - Mutations in the Wilms' tumor gene, WT1, can lead to syndromic steroid-resistant nephrotic syndrome and isolated steroid-resistant nephrotic syndrome. WT1 mutations have been identified in the majority of children with Denys-Drash or Frasier syndrome. WT1 mutations have not previously been identified in boys with sporadic isolated steroid-resistant nephrotic syndrome, but, recently, four boys with isolated nephrotic syndrome were identified to have WT1 mutations. However, whether boys with sporadic isolated steroid-resistant nephrotic syndrome should be routinely subjected to mutation analysis of WT1 has not been established. We examined 35 boys with sporadic isolated steroid-resistant nephrotic syndrome for mutations in WT1. Mutation analysis of all 10 exons of WT1 was performed by polymerase chain reaction and direct sequencing. Karyotype analysis or Y chromosome identification was performed for all patients. A Y chromosome or a 46, XY karyotype was demonstrated for all 35 patients. No causative WT1 mutation was identified in any of the patients. The WT1 mutation, IVS4+14T>C, which is not predicted to affect splicing, was identified in one patient who achieved complete remission after 8 weeks of oral prednisone treatment, indicating that IVS4+14T>C is not a causative mutation. Five WT1 polymorphisms were also identified in some patients and controls. Our results suggest that mutation analysis of WT1 should not be routinely performed for genetically defined boys with sporadic isolated steroid-resistant nephrotic syndrome. PMID- 26985960 TI - Whole-exome sequencing reveals a novel COL2A1 mutation in a patient with spondylo epiphyseal dysplasia congenita. AB - Skeletal dysplasia is a group of disorders with more than 450 entities, many of which cannot be differentiated, especially during infancy, but could lead to different clinical courses and prognoses. In this study, we have described a case of a Thai infant with short stature, flat face, pectus carinatum, indirect inguinal hernia, platyspondyly, and generalized delayed endochondral ossification. Using whole-exome sequencing (WES), we successfully identified a de novo heterozygous mutation, c.2024G>A (p.G675D), in the COL2A1 gene, which, to our knowledge, has not been previously reported. These molecular findings helped provide a definite diagnosis of spondyloepiphyseal dysplasia congenita, aiding in proper management of the disease and improved genetic counseling. We demonstrated that WES is an efficient and cost-effective tool for molecular diagnosis for a type II collagenopathy. PMID- 26985959 TI - E2F, HSF2, and miR-26 in thyroid carcinoma: bioinformatic analysis of RNA sequencing data. AB - In this study, we examined the molecular mechanism of thyroid carcinoma (THCA) using bioinformatics. RNA-sequencing data of THCA (N = 498) and normal thyroid tissue (N = 59) were downloaded from The Cancer Genome Atlas. Next, gene expression levels were calculated using the TCC package and differentially expressed genes (DEGs) were identified using the edgeR package. A co-expression network was constructed using the EBcoexpress package and visualized by Cytoscape, and functional and pathway enrichment of DEGs in the co-expression network was analyzed with DAVID and KOBAS 2.0. Moreover, modules in the co expression network were identified and annotated using MCODE and BiNGO plugins. Small-molecule drugs were analyzed using the cMAP database, and miRNAs and transcription factors regulating DEGs were identified by WebGestalt. A total of 254 up-regulated and 59 down-regulated DEGs were identified between THCA samples and controls. DEGs enriched in biological process terms were related to cell adhesion, death, and growth and negatively correlated with various small-molecule drugs. The co-expression network of the DEGs consisted of hub genes (ITGA3, TIMP1, KRT19, and SERPINA1) and one module (JUN, FOSB, and EGR1). Furthermore, 5 miRNAs and 5 transcription factors were identified, including E2F, HSF2, and miR 26. miR-26 may participate in THCA by targeting CITED1 and PLA2R1; E2F may participate in THCA by regulating ITGA3, TIMP1, KRT19, EGR1, and JUN; HSF2 may be involved in THCA development by regulating SERPINA1 and FOSB; and small-molecule drugs may have anti-THCA effects. Our results provide novel directions for mechanistic studies and drug design of THCA. PMID- 26985962 TI - Selection and validation of reference house-keeping genes in the J774A1 macrophage cell line for quantitative real-time PCR. AB - Macrophages are essential components of the innate and adaptive immune responses, playing a decisive role in atherosclerosis, asthma, obesity, and cancer. The differential gene expression resulting from adhesion of macrophages to the extra cellular matrix (ECM) has been studied in the J774A1 murine macrophage cell line using quantitative polymerase chain reaction (qPCR). The goal of this study was to identify housekeeping genes (HKGs) that remain stable and unaltered under normal culture conditions and in the presence of laminin after a time lapse of 6 and 24 h. The expression stabilities of eight commonly used reference genes were analyzed by determining the comparative threshold cycle ((DeltaDelta)Ct) values, and using the BestKeeper, NormFinder, and geNorm algorithms. BestKeeper analysis revealed that the glyceraldehyde-3-phosphate dehydrogenase (GAPDH), peptidylprolyl isomerase A (PPIA), and ribosomal protein L13a (RPL13A) genes were highly stable, confirming the results of the (DeltaDelta)Ct analysis. On the other hand, NormFinder proposed RPL13A and beta-glucuronidase (GUSB) to be the most suitable combination, and geNorm adjudged RPL13A, PPIA, and GUSB to be the most stable across all culture conditions. All programs discarded the use of actin beta and beta-2-microglobulin for normalization. The collected data indicated that RPL13A, PPIA, GAPDH, and GUSB as highly suitable as reference genes for qPCR analysis of murine macrophages under normal and ECM-simulated culture conditions. This study also emphasizes the importance of evaluating HKGs used for normalization to ensure the accuracy of qPCR data. PMID- 26985961 TI - Bayesian approach increases accuracy when selecting cowpea genotypes with high adaptability and phenotypic stability. AB - This study aimed to verify that a Bayesian approach could be used for the selection of upright cowpea genotypes with high adaptability and phenotypic stability, and the study also evaluated the efficiency of using informative and minimally informative a priori distributions. Six trials were conducted in randomized blocks, and the grain yield of 17 upright cowpea genotypes was assessed. To represent the minimally informative a priori distributions, a probability distribution with high variance was used, and a meta-analysis concept was adopted to represent the informative a priori distributions. Bayes factors were used to conduct comparisons between the a priori distributions. The Bayesian approach was effective for selection of upright cowpea genotypes with high adaptability and phenotypic stability using the Eberhart and Russell method. Bayes factors indicated that the use of informative a priori distributions provided more accurate results than minimally informative a priori distributions. PMID- 26985963 TI - Analysis of POU1F1 gene DdeI polymorphism in Chinese goats. AB - As a member of the POU-domain family, the POU1F1 is a positive regulator for growth hormone, prolactin and thyroid-stimulating hormone b, by binding to target DNA promoters as a dimer in mammals. This study described the polymorphisms at the goat POU1F1-DdeI locus and analyzed the distribution of alleles in 15 indigenous Chinese goat breeds. The PCR-RFLP analysis showed a predominance of the D1D1 genotype and the D1 allele, with average frequencies of 0.550 and 0.790, respectively, irrespective of goat utility type. The D1D2 genotype was the second most frequent, with a mean frequency of 0.371. The distributions of genotypic and allelic frequencies at this locus were found to be significantly different among populations based on a Chi square test (P < 0.001), suggesting that the breed factor significantly affected the molecular genetic character of the POU1F1 gene. The genetic diversity analysis revealed that Chinese indigenous populations had a wide spectrum of genetic diversity at the goat POU1F1-DdeI locus. However, an ANOVA analysis revealed no significant differences in gene homozygosity, gene heterozygosity, effective allele numbers, or polymorphism information content among meat, dairy, and cashmere utility types (P > 0.05). This suggests that the goat utility types had no significant effect on the spectrum of genetic diversity. PMID- 26985964 TI - Development of a thematic collection of Musa spp accessions using SCAR markers for preventive breeding against Fusarium oxysporum f. sp cubense tropical race 4. AB - Bananas are one of the most consumed fruits worldwide, but are affected by many pests and diseases. One of the most devastating diseases is Fusarium wilt, caused by Fusarium oxysporum f. sp cubense (Foc). Recently, Fusarium tropical race 4 (Foc TR4) has been causing irreparable damage, especially in Asia and Africa where it has devastated entire plantations, including areas with Cavendish, which is known to be resistant to Foc race 1. Although this race is not yet present in Brazil, results obtained by Embrapa in partnership with the University of Wageningen, The Netherlands, indicate that 100% of the cultivars used by Brazilian growers are susceptible to Foc TR 4. In our study, 276 banana accessions were screened with sequence characterized amplified region (SCAR) markers that have been linked to the resistance of Foc TR 4. Two SCAR primers were tested and the results revealed that SCAR ScaU1001 was efficient at discriminating accessions with possible resistance in 36.6% of the evaluated accessions. This is the first attempt to develop a thematic collection of possible Foc TR 4 resistant banana accessions in Brazil, which could be tested in Asian or African countries to validate marker-assisted selection (MAS), and for use in the preventive breeding of the crop to safeguard our banana plantations against Foc TR 4. We believe that this is an important step towards the prevention of this devastating disease, especially considering that our banana plantations are at risk. PMID- 26985965 TI - Revision to CDC's Zika Travel Notices: Minimal Likelihood for Mosquito-Borne Zika Virus Transmission at Elevations Above 2,000 Meters. AB - Since May 2015, when Zika virus, a flavivirus transmitted primarily by Aedes aegypti mosquitoes, was reported in Brazil, the virus has rapidly spread across the Region of the Americas and the Caribbean. The association between maternal Zika virus infection and adverse fetal and reproductive outcomes, including microcephaly, prompted CDC to issue a Level 2 alert travel notice* for the 37 countries and U.S. territories (at the national and territorial level) that have reported recent Zika virus transmission as of March 11, 2016. In addition to mosquito bite precautions for all travelers, CDC advises that pregnant women postpone travel to affected countries and U.S. territories. Within a nation's borders, ecologic characteristics, which determine the distribution of mosquito vectors, can vary considerably. CDC conducted a spatial analysis, focusing on the probability of occurrence of Ae. aegypti, to support the demarcation for subnational travel alerts. Based on results of this analysis, travel that is limited to elevations higher than 2,000 m (6,562 ft) above sea level is considered to have minimal (approximately 1%) likelihood for mosquito-borne Zika virus transmission, even within countries reporting active transmission. Women who are pregnant should avoid travel to elevations <2,000 m in countries with active Zika virus transmission. PMID- 26985966 TI - Sources of self-efficacy in academic contexts: A longitudinal perspective. AB - The formation of self-efficacy, according to Bandura's (1997) social-cognitive theory, is an important area of inquiry. This theoretical tenet posits the importance of enactive learning experience, followed by lesser influences of vicarious experience, verbal persuasion, and emotional and physiological states. Quantitative research, predominantly, has produced clear and consistent evidence that supports this position. We argue that the elementary school years may indicate differently, whereby children's limited cognitive maturity and learning experiences could compel them to rely on other psychosocial informational sources. To date and to our knowledge, very few studies, if any, have explored the sustained influence of enactive learning experience across time. In this study, consequently, we tested a sequential predictive model that involved the differential influences of the 4 major informational sources on self-efficacy and then self-efficacy on academic achievement. Three time points of data (N = 328, Year 6) were collected across the calendar year, and Mplus 7.3 (Muthen & Muthen, 1998-2012) was used to assist us in our structural modeling testing. At Time 1, only enactive learning experience and vicarious experience positively influenced self-efficacy. At Time 2, after controlling for prior variance of Time 1 corresponding factors, only enactive learning experience remained significant. At Time 3, after controlling for autoregressive paths, enactive learning experience remained significant, and both verbal persuasion and emotional and physiological states positively influenced self-efficacy. The impact of self-efficacy on academic achievement was significant across the 3 occasions (betas = .20-.46). (PsycINFO Database Record PMID- 26985967 TI - Double Methotrexate-Modified Neuropeptide Y Analogues Express Increased Toxicity and Overcome Drug Resistance in Breast Cancer Cells. AB - Bioconjugates containing the neuropeptide Y (NPY) analogue [F(7),P(34)]-NPY as targeting moiety are able to deliver toxic agents specifically to breast cancer cells that overexpress the human Y1-receptor (hY1R). To increase their activity, multiple toxophores can be attached to one peptide. Herein, synthesis and characterization of [F(7),P(34)]-NPY conjugates containing two methotrexate (MTX) molecules are presented. First, carboxytetramethylrhodamine was linked to [F(7),P(34)]-NPY by amide or enzymatic linkage. The conjugate containing the enzymatic cleavage site showed high extracellular stability and fast intracellular release. Then, MTX was introduced at positions four and 22 of [F(7),P(34)]-NPY, connected by enzymatic or amide linkage. The toxicity of the analogues on breast cancer cells was hY1R-mediated and dependent on the used linkage and amount of toxophores. Furthermore, conjugates revealed higher potency than MTX on MTX-resistant cells. These results emphasize that peptide-drug conjugates can overcome drug resistance and that the attachment of multiple cleavable toxophores enhances the efficiency of this smart delivery system. PMID- 26985968 TI - Automated In-Injector Derivatization Combined with High-Performance Liquid Chromatography-Fluorescence Detection for the Determination of Semicarbazide in Fish and Bread Samples. AB - Semicarbazide (1) is a widespread genotoxic food contaminant originating as a metabolic byproduct of the antibiotic nitrofurazone used in fish farming or as a thermal degradation product of the common flour additive azodicarbonamide. The goal of this study is to develop a simple and sensitive high-performance liquid chromatography coupled with fluorescence detection (HPLC-FLD) method for the detection of compound 1 in food products. In comparison to existing methods for the determination of compound 1, the reported method combining online precolumn derivatization and HPLC-FLD is less labor-intensive, produces higher sample throughput, and does not require the use of expensive analytical instruments. After validation of accuracy and precision, this method was applied to determine the amount of compound 1 in fish and bread samples. Comparative studies using an established liquid chromatography coupled with tandem mass spectrometry method did not yield systematically different results, indicating that the developed HPLC-FLD method is accurate and suitable for the determination of compound 1 in fish and bread samples. PMID- 26985969 TI - Novel psychoactive substances: the pharmacology of stimulants and hallucinogens. AB - There are increasing levels of concern relating to the rapidly evolving novel psychoactive substances/NPS and web markets' scenarios. The paper aims at providing an overview of the clinical pharmacological issues related to some of the most popular NPS categories, e.g. stimulants and hallucinogens. NPS intake is typically associated with the imbalance of a complex range of neurotransmitter pathways/receptors, namely: dopamine; cannabinoid/CB1; and 5-HT2A. The intake is almost invariably undetectable with standard screening tests. Hence, it may frequently occur that the acute management of NPS misusers will need to focus on decreasing levels of both self/outward-directed aggression and agitation. Benzodiazepines may be considered as first line treatment. Alternatively, propofol and/or antipsychotics can be administered. Focus will be as well on treatment of possible rhabdomyolysis and hyperthermia. Indeed, future studies should inform better tailored management/treatment strategies. PMID- 26985970 TI - Screening of Toxic Chemicals in a Single Drop of Human Whole Blood Using Ordered Mesoporous Carbon as a Mass Spectrometry Probe. AB - Surface-enhanced laser desorption/ionization (SELDI) is a versatile and high throughput mass spectrometry (MS) technique that uses a probe for extraction, enrichment, desorption, and ionization of target analytes. Here we report ordered mesoporous carbon as a new SELDI probe for rapid screening and identification of trace amount of toxic chemicals in a single drop of human whole blood without complicated sample preparation procedures. We demonstrate that ordered mesoporous carbon not only can selectively enrich a wide variety of low-mass toxic compounds from whole blood samples but also can be used as an excellent matrix to assist the laser desorption/ionization process of small molecules with low background noise, high repeatability, and good salt tolerance. High sensitivity (detection limits at ppt levels) and good reproducibility for typical toxic compounds were obtained. With CMK-8 as a SELDI probe, we successfully identified and screened six perfluorinated compounds in a single drop of whole blood collected from workers in a perfluorochemical plant. The method was also validated with complex samples such as human urine and environmental water samples. With distinct advantages such as simplicity, rapidness, minimal sample requirement, and high reliability, this method keeps great promise for various aspects of application. PMID- 26985972 TI - Validation of Software Measurements of Eyelid Position From Digital Photographs Reply. PMID- 26985973 TI - Eosinophilic, Polymorphic, and Pruritic Eruption Associated With Radiotherapy on the Skin of the Right Breast. PMID- 26985976 TI - Best of JAMA Facial Plastic Surgery: Top Viewed Articles of 2015. PMID- 26985971 TI - MALDI TOF/TOF-Based Approach for the Identification of d- Amino Acids in Biologically Active Peptides and Proteins. AB - Several biologically active peptides contain a d- amino acid in a well-defined position, which is position 2 in all peptide epimers isolated to date from vertebrates and also some from invertebrates. The detection of such D- residues by standard analytical techniques is challenging. In tandem mass spectrometric (MS) analysis, although fragment masses are the same for all stereoisomers, peak intensities are known to depend on chirality. Here, we observe that the effect of a d- amino acid in the second N-terminal position on the fragmentation pattern in matrix assisted laser desorption time-of-flight spectrometry (MALDI-TOF/TOF MS) strongly depends on the peptide sequence. Stereosensitive fragmentation (SF) is correlated to a neighborhood effect, but the d- residue also exerts an overall effect influencing distant bonds. In a fingerprint analysis, multiple peaks can thus serve to identify the chirality of a sample in short time and potentially high throughput. Problematic variations between individual spots could be successfully suppressed by cospotting deuterated analogues of the epimers. By identifying the [d-Leu2] isomer of the predicted peptide GH-2 (gene derived bombininH) in skin secretions of the toad Bombina orientalis, we demonstrated the analytical power of SF-MALDI-TOF/TOF measurements. In conclusion, SF-MALDI TOF/TOF MS combines high sensitivity, versatility, and the ability to complement other methods. PMID- 26985977 TI - Use of FACE-Q to Measure Quality of Life Following Aesthetic Facial Treatments. PMID- 26985978 TI - Use of FACE-Q to Measure Quality of Life Following Aesthetic Facial Treatments Reply. PMID- 26985979 TI - Elevated glucose levels in early puerperium, and association with high cortisol levels during parturition. AB - Background Gestational diabetes is one of the commonest metabolic problems associated with pregnancy and an accurate diagnosis is critical for the care. Research has shown that pregnant women have high levels of cortisol during the last stage of parturition. As cortisol is a diabetogenic hormone causing increased glucose levels, we wanted to study the association between cortisol and glucose levels during parturition. Materials and methods Glucose and cortisol were analyzed during parturition in 50 females divided according to slow (n = 11) and normal labors (n = 39). Blood samples were analyzed three times during the parturition and four times in the first day after delivery. Glucose levels were also measured once in each trimester. Results In the normal group, the glucose concentration increased from 6.2 (IQR 5.6-8.0) mmol/L in the latency phase to 11.6 (10.0-13.3) mmol/L at aftercare (p < 0.05). After parturition the glucose concentrations decreased gradually. There were significant Spearman rank correlations between glucose and cortisol values. Conclusions The changes associated with birth cause significant elevations of cortisol and glucose around parturition. PMID- 26985980 TI - Computed tomography (CT) in the selection of treatment for root-filled maxillary molars with apical periodontitis. AB - OBJECTIVES: The aims of this study were to evaluate whether the use of CT facilitates agreement among endodontists in selecting treatments for root-filled maxillary molars with apical periodontitis and to assess the efficacy of CT in choosing a treatment for such teeth. METHODS: 39 root-filled maxillary molars from 34 patients with suspected apical periodontitis were independently evaluated by 4 endodontists and 1 postgraduate student (decision-makers). Treatment decisions were made based on intra-oral radiographs and a fictive clinical history. After 1-3 months, the same decision-makers repeated the examination of the same teeth but with additional information from a CT examination. Agreement between decision-makers with or without the availability of the CT results was measured with Cohen's kappa coefficient. Differences in selected treatments with or without accessibility to the CT results were plotted for the same endodontists using descriptive statistics. RESULTS: The agreement in assessments among endodontists was slight or fair before the CT results were available (range: 0.081-0.535). No increase was observed after reviewing the CT results (range: 0.116-0.379). After the use of CT, the treatment plan was changed 38-76% of the time by all decision-makers, and the changes affected 57.8% of the cases in the study. CONCLUSIONS: The endodontists in this study exhibited a low degree of agreement when choosing a treatment for root-filled maxillary molars with apical periodontitis. A CT examination of the investigated teeth did not result in a significantly higher degree of agreement, and CT frequently contributed to a shift in the selected therapy. PMID- 26985981 TI - Therapeutic Hypothermia for Patients with Out-of-Hospital Cardiac Arrest in North Carolina. AB - INTRODUCTION: While therapeutic hypothermia has been the standard of care for patients who suffer out-of-hospital cardiac arrest (OHCA), recent trials have led to an advisory statement recommending a focus on targeted in-hospital temperature management and against initiation of prehospital hypothermia with rapid infusion of cooled saline. The aim of this study is to review the experience with therapeutic hypothermia in North Carolina. METHODS: We studied patients who suffered OHCA in North Carolina in 2012 captured in the CARES database as part of the Heart Rescue Project. We excluded patients without return of spontaneous circulation and patients without an advanced airway placed in the field to reduce selection bias. Bivariate distributions and multivariate logistic regression models were used to examine differences in survival to discharge and positive neurological outcome. RESULTS: 847 patients were included in the analysis of pre hospital hypothermia. Of these patients, 55% received prehospital hypothermia. Prehospital initiation of hypothermia was associated with higher survival to hospital discharge (OR 1.55, 95% CI 1.03-2.32) and improved neurologic outcome at discharge (OR 1.56 95% CI 1.01-2.40). In patients who survived to hospital admission (n = 537), in-hospital hypothermia was associated with a non significant trend toward better survival to discharge (p = 0.18). CONCLUSION: We found that patients who received prehospital hypothermia had improved outcomes, a finding that may be due to a greater likelihood of receiving in-hospital hypothermia or a reflection of higher quality of pre-hospital care. These findings support ongoing efforts to improve all aspects of the chain of survival after cardiac arrest. PMID- 26985982 TI - Cost-effectiveness of continuous subcutaneous insulin infusion in people with type 2 diabetes in the Netherlands. AB - AIMS: Up to 30% of insulin-treated type 2 diabetes patients are unable to achieve HbA1c targets despite optimization of insulin multiple daily injections (MDI). For these patients the use of continuous subcutaneous insulin infusion (CSII) represents a useful but under-utilized alternative. The aim of the present analysis was to examine the cost-effectiveness of initiating CSII in type 2 diabetes patients failing to achieve good glycemic control on MDI in the Netherlands. METHODS: Long-term projections were made using the IMS CORE Diabetes Model. Clinical input data were sourced from the OpT2mise trial. The analysis was performed over a lifetime time horizon. The discount rates applied to future costs and clinical outcomes were 4% and 1.5% per annum, respectively. RESULTS: CSII was associated with improved quality-adjusted life expectancy compared with MDI (9.38 quality-adjusted life years [QALYs] vs 8.95 QALYs, respectively). The breakdown of costs indicated that ~50% of costs were attributable to diabetes related complications. Higher acquisition costs of CSII vs MDI were partially offset by the reduction in complications. The ICER was estimated at EUR 62,895 per QALY gained and EUR 60,474 per QALY gained when indirect costs were included. CONCLUSIONS: In the Netherlands, CSII represents a cost-effective option in patients with type 2 diabetes who continue to have poorly-controlled HbA1c despite optimization of MDI. Since the ICER falls below the willingness-to-pay threshold of EUR 80,000 per QALY gained, CSII is likely to represent good-value for money in the treatment of poorly-controlled T2D patients compared with MDI. PMID- 26985983 TI - When Nanowires Meet Ultrahigh Ferroelectric Field-High-Performance Full-Depleted Nanowire Photodetectors. AB - One-dimensional semiconductor nanowires (NWs) have been widely applied in photodetector due to their excellent optoelectronic characteristics. However, intrinsic carrier concentration at certain level results in appreciable dark current, which limits the detectivity of the devices. Here, we fabricated a novel type of ferroelectric-enhanced side-gated NW photodetectors. The intrinsic carriers in the NW channel can be fully depleted by the ultrahigh electrostatic field from polarization of P(VDF-TrFE) ferroelectric polymer. In this scenario, the dark current is significantly reduced and thus the sensitivity of the photodetector is increased even when the gate voltage is removed. Particularly, a single InP NW photodetector exhibits high-photoconductive gain of 4.2 * 10(5), responsivity of 2.8 * 10(5) A W(-1), and specific detectivity (D*) of 9.1 * 10(15) Jones at lambda = 830 nm. To further demonstrate the universality of the configuration we also demonstrate ferroelectric polymer side-gated single CdS NW photodetectors with ultrahigh photoconductive gain of 1.2 * 10(7), responsivity of 5.2 * 10(6) A W(-1) and D* up to 1.7 * 10(18) Jones at lambda = 520 nm. Overall, our work demonstrates a new approach to fabricate a controllable, full depleted, and high-performance NW photodetector. This can inspire novel device structure design of high-performance optoelectronic devices based on semiconductor NWs. PMID- 26985984 TI - KLHL20 links the ubiquitin-proteasome system to autophagy termination. AB - Autophagy is a dynamic and self-limiting process. The amplitude and duration of this process need to be properly controlled to maintain cell homeostasis, and excessive or insufficient autophagy activity could each lead to disease states. Compared to our understanding of the molecular mechanisms of autophagy induction, little is known about how the autophagy process is turned off after its activation. We recently identified KLHL20 as a key regulator of autophagy termination. By functioning as a substrate-binding subunit of CUL3 ubiquitin ligase, KLHL20 targets the activated ULK1 and phagophore-residing PIK3C3/VPS34 and BECN1 for ubiquitination and proteasomal degradation, which in turn triggers a destabilization of their complex components ATG13 and ATG14. These hierarchical degradation events cause the exhaustion of the autophagic pool of ULK1 and PIK3C3/VPS34 complexes, thereby preventing persistent and excessive autophagy activity. Impairment of KLHL20-dependent feedback regulation of autophagy enhances cell death under prolonged starvation and aggravates muscle atrophy in diabetic mice, which highlights the pathophysiological significance of this autophagy termination mechanism in cell survival and tissue homeostasis. Modulation of this autophagy termination pathway may be effective for treating diseases associated with deregulation of autophagy activity. PMID- 26985985 TI - Unimolecular Decomposition Rate of the Criegee Intermediate (CH3)2COO Measured Directly with UV Absorption Spectroscopy. AB - The unimolecular decomposition of (CH3)2COO and (CD3)2COO was measured by direct detection of the Criegee intermediate at temperatures from 283 to 323 K using time-resolved UV absorption spectroscopy. The unimolecular rate coefficient kd for (CH3)2COO shows a strong temperature dependence, increasing from 269 +/- 82 s(-1) at 283 K to 916 +/- 56 s(-1) at 323 K with an Arrhenius activation energy of ~6 kcal mol(-1). The bimolecular rate coefficient for the reaction of (CH3)2COO with SO2, kSO2, was also determined in the temperature range 283 to 303 K. Our temperature-dependent values for kd and kSO2 are consistent with previously reported relative rate coefficients kd/kSO2 of (CH3)2COO formed from ozonolysis of tetramethyl ethylene. Quantum chemical calculations of kd for (CH3)2COO are consistent with the experiment, and the combination of experiment and theory for (CD3)2COO indicates that tunneling plays a significant role in (CH3)2COO unimolecular decomposition. The fast rates of unimolecular decomposition for (CH3)2COO measured here, in light of the relatively slow rate for the reaction of (CH3)2COO with water previously reported, suggest that thermal decomposition may compete with the reactions with water and with SO2 for atmospheric removal of the dimethyl-substituted Criegee intermediate. PMID- 26985988 TI - Impaired handgrip exercise-induced brachial artery flow-mediated dilation in young obese males. AB - Flow mediated dilation (FMD) stimulated by different shear stress stimulus profiles may recruit distinct transduction mechanisms, and provide distinct information regarding endothelial function. The purpose of this study was to determine whether obesity influences brachial artery FMD differently depending on the shear stress profile used for FMD assessment. The FMD response to a brief, intermediate, and sustained shear stress profile was assessed in obese (n = 9) and lean (n = 19) young men as follows: brief stimulus, standard reactive hyperemia (RH) following a 5 min forearm occlusion (5 min RH); intermediate stimulus, RH following a 15 min forearm occlusion (15 min RH); sustained stimulus, 10 min of handgrip exercise (HGEX). Brachial artery diameter and mean shear stress were assessed using echo and Doppler ultrasound, respectively, during each FMD test. There was no group difference in HGEX shear stress (p = 0.390); however, the obese group had a lower HGEX-FMD (5.2 +/- 3.0% versus 11.5 +/- 4.4%, p < 0.001). There was no group difference in 5 min RH-FMD (p = 0.466) or 15 min RH-FMD (p = 0.181); however, the shear stress stimulus was larger in the obese group. After normalization to the stimulus the 15 min RH-FMD (p = 0.002), but not the 5 min RH-FMD (p = 0.118) was lower in the obese group. These data suggest that obesity may have a more pronounced impact on the endothelium's ability to respond to prolonged increases in shear stress. PMID- 26985986 TI - Intra-articular treatment of knee osteoarthritis: from anti-inflammatories to products of regenerative medicine. AB - OBJECTIVES: Knee osteoarthritis (OA) is a debilitating condition that may ultimately require total knee arthroplasty (TKA). Non-operative treatments are bracing, oral analgesics, physical therapy, and intra-articular knee injection (IAKI). The objective of this paper is to provide a systematic literature review regarding intra-articular treatment of knee OA and insight into promising new products of regenerative medicine that may eventually have a substantial effect on treatment. METHODS: A literature search was executed using Medline, Cochrane, and Embase with keywords "knee osteoarthritis" and "injection." Specifically, 45 articles that discussed intra-articular knee injection using corticosteroids, hyaluronic acid, analgesics, local anesthetics, and newer products of regenerative medicine, such as platelet-rich plasma (PRP) and mesenchymal stem cells (MSC), were analyzed. Of these, eleven were level 1, three were level 2, twelve were level 3, two were level 4, and seventeen were level 5 evidence. Papers included animal models. RESULTS: Local anesthetics have potential side effects and may only be effective for a few hours. Morphine and ketorolac may provide significant pain relief for 24 hours. Corticosteroids may give patients weeks to months of effective analgesia, but complications may occur, such as systemic hyperglycemia, septic arthritis, and joint degradation . Hyaluronic acid is a natural component of synovial fluid, but efficacy with respect to analgesia is controversial. Platelet-rich plasma formulations, autologous conditioned serum, autologous protein solution, and mesenchymal stem cell injections contain anti-inflammatory molecules and have been proposed to attenuate joint destruction or potentially remodel the joint. CONCLUSIONS: Currently, knee OA treatment does not address the progressively inflammatory environment of the joint. More investigation is needed regarding products of regenerative medicine, but they may ultimately have profound implications in the way knee OA is managed. PMID- 26985989 TI - Neural Tuning Size in a Model of Primate Visual Processing Accounts for Three Key Markers of Holistic Face Processing. AB - Faces are an important and unique class of visual stimuli, and have been of interest to neuroscientists for many years. Faces are known to elicit certain characteristic behavioral markers, collectively labeled "holistic processing", while non-face objects are not processed holistically. However, little is known about the underlying neural mechanisms. The main aim of this computational simulation work is to investigate the neural mechanisms that make face processing holistic. Using a model of primate visual processing, we show that a single key factor, "neural tuning size", is able to account for three important markers of holistic face processing: the Composite Face Effect (CFE), Face Inversion Effect (FIE) and Whole-Part Effect (WPE). Our proof-of-principle specifies the precise neurophysiological property that corresponds to the poorly-understood notion of holism, and shows that this one neural property controls three classic behavioral markers of holism. Our work is consistent with neurophysiological evidence, and makes further testable predictions. Overall, we provide a parsimonious account of holistic face processing, connecting computation, behavior and neurophysiology. PMID- 26985991 TI - Correction: Congruent Deep Relationships in the Grape Family (Vitaceae) Based on Sequences of Chloroplast Genomes and Mitochondrial Genes via Genome Skimming. PMID- 26985990 TI - Development and Genetic Control of Plant Architecture and Biomass in the Panicoid Grass, Setaria. AB - The architecture of a plant affects its ability to compete for light and to respond to environmental stresses, thus affecting overall fitness and productivity. Two components of architecture, branching and height, were studied in 182 F7 recombinant inbred lines (RILs) at the vegetative, flowering and mature developmental stages in the panicoid C4 model grass system, Setaria. The RIL population was derived from a cross between domesticated S. italica (foxtail millet) and its wild relative S. viridis (green foxtail). In both field and greenhouse trials the wild parent was taller initially, started branching earlier, and flowered earlier, while the domesticated parent was shorter initially, but flowered later, producing a robust tall plant architecture with more nodes and leaves on the main culm and few or no branches. Biomass was highly correlated with height of the plant and number of nodes on the main culm, and generally showed a negative relationship with branch number. However, several of the RILs with the highest biomass in both trials were significantly more branched than the domesticated parent of the cross. Quantitative trait loci (QTL) analyses indicate that both height and branching are controlled by multiple genetic regions, often with QTL for both traits colocalizing in the same genomic regions. Genomic positions of several QTL colocalize with QTL in syntenic regions in other species and contain genes known to control branching and height in sorghum, maize, and switchgrass. Included in these is the ortholog of the rice SD-1 semi dwarfing gene, which underlies one of the major Setaria height QTL. Understanding the relationships between height and branching patterns in Setaria, and their genetic control, is an important step to gaining a comprehensive knowledge of the development and genetic regulation of panicoid grass architecture. PMID- 26985992 TI - Inflammatory Kidney and Liver Tissue Response to Different Hydroxyethylstarch (HES) Preparations in a Rat Model of Early Sepsis. AB - BACKGROUND: Tissue hypoperfusion and inflammation in sepsis can lead to organ failure including kidney and liver. In sepsis, mortality of acute kidney injury increases by more than 50%. Which type of volume replacement should be used is still an ongoing debate. We investigated the effect of different volume strategies on inflammatory mediators in kidney and liver in an early sepsis model. MATERIAL AND METHODS: Adult male Wistar rats were subjected to sepsis by cecal ligation and puncture (CLP) and assigned to three fluid replenishment groups. Animals received 30mL/kg of Ringer's lactate (RL) for 2h, thereafter RL (75mL/kg), hydroxyethyl starch (HES) balanced (25mL/kg), containing malate and acetate, or HES saline (25mL/kg) for another 2h. Kidney and liver tissue was assessed for inflammation. In vitro rat endothelial cells were exposed to RL, HES balanced or HES saline for 2h, followed by stimulation with tumor necrosis factor alpha (TNF-alpha) for another 4h. Alternatively, cells were exposed to malate, acetate or a mixture of malate and acetate, reflecting the according concentration of these substances in HES balanced. Pro-inflammatory cytokines were determined in cell supernatants. RESULTS: Cytokine mRNA in kidney and liver was increased in CLP animals treated with HES balanced compared to RL, but not after application of HES saline. MCP-1 was 3.5fold (95% CI: 1.3, 5.6) (p<0.01) and TNF-alpha 2.3fold (95% CI: 1.2, 3.3) (p<0.001) upregulated in the kidney. Corresponding results were seen in liver tissue. TNF-alpha-stimulated endothelial cells co-exposed to RL expressed 3529+/-1040pg/mL MCP-1 and 59+/-23pg/mL CINC-1 protein. These cytokines increased by 2358pg/mL (95% CI: 1511, 3204) (p<0.001) and 29pg/ml (95% CI: 14, 45) (p<0.01) respectively when exposed to HES balanced instead. However, no further upregulation was observed with HES saline. PBS supplemented with acetate increased MCP-1 by 1325pg/mL (95% CI: 741, 1909) (p<0.001) and CINC-1 by 24pg/mL (95% CI: 9, 38) (p<0.01) compared to RL. Malate as well as HES saline did not affect cytokine expression. CONCLUSION: We identified HES balanced and specifically its component acetate as pro inflammatory factor. How important this additional inflammatory burden on kidney and liver function is contributing to the sepsis-associated inflammatory burden in early sepsis needs further evaluation. PMID- 26985993 TI - Pepsin Egg White Hydrolysate Ameliorates Obesity-Related Oxidative Stress, Inflammation and Steatosis in Zucker Fatty Rats. AB - The aim of this work was to evaluate the effect of the administration of egg white hydrolysates on obesity-related disorders, with a focus on lipid metabolism, inflammation and oxidative stress, in Zucker fatty rats. Obese Zucker rats received water, pepsin egg white hydrolysate (750 mg/kg/day) or Rhizopus aminopeptidase egg white hydrolysate (750 mg/kg/day) for 12 weeks. Lean Zucker rats received water. Body weight, solid and liquid intakes were weekly measured. At the end of the study, urine, faeces, different organs and blood samples were collected. The consumption of egg white hydrolysed with pepsin significantly decreased the epididymal adipose tissue, improved hepatic steatosis, and lowered plasmatic concentration of free fatty acids in the obese animals. It also decreased plasma levels of tumor necrosis factor-alpha and reduced oxidative stress. Pepsin egg white hydrolysate could be used as a tool to improve obesity related complications. PMID- 26985994 TI - The RIP1-RIP3 Complex Mediates Osteocyte Necroptosis after Ovariectomy in Rats. AB - Osteocyte apoptosis has been reported to play a central role in bone remodeling. In addition to apoptosis, other mechanisms may be involved in osteocyte loss. This study aimed to investigate the effect of necroptosis on osteocytes in ovariectomized (OVX) rats. Ninety-six female Sprague-Dawley rats were randomly divided into an OVX group and a sham group. At 0, 4, 8 and 12 weeks after surgery, specimens from each group (n = 12 each) were harvested. Bone mineral density (BMD) and body weight were measured. Transmission electron microscopy (TEM) and micro-CT were used to observe the changes in cellular morphology and bone microarchitecture induced by estrogen deficiency. Osteocyte apoptosis and necroptosis were evaluated via TUNEL and immunofluorescence staining for active caspase-3. At 8 weeks after ovariectomy, a greater number of osteocytes with typical necrotic morphological features were TUNEL positive but negative for active caspase-3. Western blotting, quantitative real-time PCR and immunofluorescence assessments demonstrated that the levels of receptor interacting serine/threonine protein kinase 1 (RIP1) and RIP3 in osteocytes were significantly increased at 8 weeks after ovariectomy. These data are the first to suggest that necroptosis accelerates osteocyte loss under conditions of estrogen deficiency-induced osteoporosis in OVX rats. These findings provide evidence of a potential mechanism through which osteocyte necroptosis is associated with postmenopausal osteoporosis. PMID- 26985995 TI - Prospects for Moxidectin as a New Oral Treatment for Human Scabies. PMID- 26985996 TI - Invariant Feature Matching for Image Registration Application Based on New Dissimilarity of Spatial Features. AB - An invariant feature matching method is proposed as a spatially invariant feature matching approach. Deformation effects, such as affine and homography, change the local information within the image and can result in ambiguous local information pertaining to image points. New method based on dissimilarity values, which measures the dissimilarity of the features through the path based on Eigenvector properties, is proposed. Evidence shows that existing matching techniques using similarity metrics--such as normalized cross-correlation, squared sum of intensity differences and correlation coefficient--are insufficient for achieving adequate results under different image deformations. Thus, new descriptor's similarity metrics based on normalized Eigenvector correlation and signal directional differences, which are robust under local variation of the image information, are proposed to establish an efficient feature matching technique. The method proposed in this study measures the dissimilarity in the signal frequency along the path between two features. Moreover, these dissimilarity values are accumulated in a 2D dissimilarity space, allowing accurate corresponding features to be extracted based on the cumulative space using a voting strategy. This method can be used in image registration applications, as it overcomes the limitations of the existing approaches. The output results demonstrate that the proposed technique outperforms the other methods when evaluated using a standard dataset, in terms of precision-recall and corner correspondence. PMID- 26985998 TI - The Goals and Effects of Music Listening and Their Relationship to the Strength of Music Preference. AB - Individual differences in the strength of music preference are among the most intricate psychological phenomena. While one person gets by very well without music, another person needs to listen to music every day and spends a lot of temporal and financial resources on listening to music, attending concerts, or buying concert tickets. Where do these differences come from? The hypothesis presented in this article is that the strength of music preference is mainly informed by the functions that music fulfills in people's lives (e.g., to regulate emotions, moods, or physiological arousal; to promote self-awareness; to foster social relatedness). Data were collected with a diary study, in which 121 respondents documented the goals they tried to attain and the effects that actually occurred for up to 5 music-listening episodes per day for 10 successive days. As expected, listeners reporting more intense experience of the functional use of music in the past (1) had a stronger intention to listen to music to attain specific goals in specific situations and (2) showed a larger overall strength of music preference. It is concluded that the functional effectiveness of music listening should be incorporated in existing models and frameworks of music preference to produce better predictions of interindividual differences in the strength of music preference. The predictability of musical style/genre preferences is also discussed with regard to the present results. PMID- 26985997 TI - Metagenomic Analysis from the Interior of a Speleothem in Tjuv-Ante's Cave, Northern Sweden. AB - Speleothems are secondary mineral deposits normally formed by water supersaturated with calcium carbonate percolating into underground caves, and are often associated with low-nutrient and mostly non-phototrophic conditions. Tjuv Ante's cave is a shallow-depth cave formed by the action of waves, with granite and dolerite as major components, and opal-A and calcite as part of the speleothems, making it a rare kind of cave. We generated two DNA shotgun sequencing metagenomic datasets from the interior of a speleothem from Tjuv Ante's cave representing areas of old and relatively recent speleothem formation. We used these datasets to perform i) an evaluation of the use of these speleothems as past biodiversity archives, ii) functional and taxonomic profiling of the speleothem's different formation periods, and iii) taxonomic comparison of the metagenomic results to previous microscopic analyses from a nearby speleothem of the same cave. Our analyses confirm the abundance of Actinobacteria and fungi as previously reported by microscopic analyses on this cave, however we also discovered a larger biodiversity. Interestingly, we identified photosynthetic genes, as well as genes related to iron and sulphur metabolism, suggesting the presence of chemoautotrophs. Furthermore, we identified taxa and functions related to biomineralization. However, we could not confidently establish the use of this type of speleothems as biological paleoarchives due to the potential leaching from the outside of the cave and the DNA damage that we propose has been caused by the fungal chemical etching. PMID- 26985999 TI - Effects of age and school type on unconstrained, phonemic, and semantic verbal fluency in children. AB - Biological and cultural factors have been found to have a significant influence on cognitive development and performance in neuropsychological instruments such as verbal fluency tasks (VFT). Variations of traditional VFT, involving unconstrained word production and increased retrieval times, may provide further data regarding the executive, attentional, mnemonic, and linguistic abilities involved in VFT. As such, the aim of this study was to investigate the impact of age and school type on the performance of 6- to 12-year-old children in unconstrained, phonemic, and semantic VFT. The VFT were administered to 460 participants. The effects of age and school type on verbal fluency (VF) performance were analyzed using a two-way analysis of variance, followed by Bonferroni post-hoc tests (p <= .05). A repeated-measures analysis was also used to evaluate VF performance over time (p <= .05). Main effects of age and school type were identified on all measures (effect sizes ranged from .05 to .32, p <= .05). VF scores increased with age and were higher among private school students. The influence of age on VFT may be associated with the development of executive functions. The impact of type of school on VF performance may be explained by the greater availability of cognitive stimulation (semantic knowledge) provided by private schools and families with better socioeconomic levels. PMID- 26986000 TI - The Allometry of Bee Proboscis Length and Its Uses in Ecology. AB - Allometric relationships among morphological traits underlie important patterns in ecology. These relationships are often phylogenetically shared; thus quantifying allometric relationships may allow for estimating difficult-to measure traits across species. One such trait, proboscis length in bees, is assumed to be important in structuring bee communities and plant-pollinator networks. However, it is difficult to measure and thus rarely included in ecological analyses. We measured intertegular distance (as a measure of body size) and proboscis length (glossa and prementum, both individually and combined) of 786 individual bees of 100 species across 5 of the 7 extant bee families (Hymenoptera: Apoidea: Anthophila). Using linear models and model selection, we determined which parameters provided the best estimate of proboscis length. We then used coefficients to estimate the relationship between intertegular distance and proboscis length, while also considering family. Using allometric equations with an estimation for a scaling coefficient between intertegular distance and proboscis length and coefficients for each family, we explain 91% of the variance in species-level means for bee proboscis length among bee species. However, within species, individual-level intertegular distance was a poor predictor of individual proboscis length. To make our findings easy to use, we created an R package that allows estimation of proboscis length for individual bee species by inputting only family and intertegular distance. The R package also calculates foraging distance and body mass based on previously published equations. Thus by considering both taxonomy and intertegular distance we enable accurate estimation of an ecologically and evolutionarily important trait. PMID- 26986001 TI - Cell-mediated drug delivery by gingival interdental papilla mesenchymal stromal cells (GinPa-MSCs) loaded with paclitaxel. AB - OBJECTIVE: Gingival tissue is composed of cell types that contribute to the body's defense against many agents in oral environment, wound healing and tissue regeneration. Thanks to their easy and scarcely invasive withdrawal procedure, interdental papilla provide a good source of mesenchymal stromal cells (GinPa MSCs). We isolated GinPa-MSCs and verified their ability to uptake/release the anticancer agent Paclitaxel (PTX). METHODS: In vitro expanded GinPa-MSCs were characterized for CD markers by FACS, tested for differentiation ability and analyzed by TEM. Their ability to uptake/release PTX was assessed according to a standardized procedure. RESULTS: The CD expression and chondro-adipo-osteo differentiation ability confirmed the mesenchymal feature of GinPa-MSCs. Surprisingly, 28% of GinPa-MSCs expressed CD14 marker and had an impressive pinocytotic activity. GinPa-MSCs were able to take up and release a sufficient amount of PTX to demonstrate effective in vitro activity against pancreatic carcinoma cells, suggesting that the drug was not inactivated. CONCLUSIONS: The procedure to obtain MSCs from interdental papilla is less invasive than that used for both bone marrow and adipose tissue, GinPa-MSCs are easy to expand and can be efficiently loaded with PTX. Taken together these qualities suggest that GinPa MSCs may prove to be a good tool for cell-mediated drug delivery in cancer, particularly if related to stomatognathic system. PMID- 26986002 TI - Quantitative Risk Assessment for African Horse Sickness in Live Horses Exported from South Africa. AB - African horse sickness (AHS) is a severe, often fatal, arbovirus infection of horses, transmitted by Culicoides spp. midges. AHS occurs in most of sub-Saharan Africa and is a significant impediment to export of live horses from infected countries, such as South Africa. A stochastic risk model was developed to estimate the probability of exporting an undetected AHS-infected horse through a vector protected pre-export quarantine facility, in accordance with OIE recommendations for trade from an infected country. The model also allows for additional risk management measures, including multiple PCR tests prior to and during pre-export quarantine and optionally during post-arrival quarantine, as well as for comparison of risk associated with exports from a demonstrated low risk area for AHS and an area where AHS is endemic. If 1 million horses were exported from the low-risk area with no post-arrival quarantine we estimate the median number of infected horses to be 5.4 (95% prediction interval 0.5 to 41). This equates to an annual probability of 0.0016 (95% PI: 0.00015 to 0.012) assuming 300 horses exported per year. An additional PCR test while in vector protected post-arrival quarantine reduced these probabilities by approximately 12 fold. Probabilities for horses exported from an area where AHS is endemic were approximately 15 to 17 times higher than for horses exported from the low-risk area under comparable scenarios. The probability of undetected AHS infection in horses exported from an infected country can be minimised by appropriate risk management measures. The final choice of risk management measures depends on the level of risk acceptable to the importing country. PMID- 26986004 TI - Andean Condor (Vultur gryphus) in Ecuador: Geographic Distribution, Population Size and Extinction Risk. AB - The Andean Condor (Vultur gryphus) in Ecuador is classified as Critically Endangered. Before 2015, standardized and systematic estimates of geographic distribution, population size and structure were not available for this species, hampering the assessment of its current status and hindering the design and implementation of effective conservation actions. In this study, we performed the first quantitative assessment of geographic distribution, population size and population viability of Andean Condor in Ecuador. We used a methodological approach that included an ecological niche model to study geographic distribution, a simultaneous survey of 70 roosting sites to estimate population size and a population viability analysis (PVA) for the next 100 years. Geographic distribution in the form of extent of occurrence was 49 725 km2. During a two-day census, 93 Andean Condors were recorded and a population of 94 to 102 individuals was estimated. In this population, adult-to-immature ratio was 1:0.5. In the modeled PVA scenarios, the probability of extinction, mean time to extinction and minimum population size varied from zero to 100%, 63 years and 193 individuals, respectively. Habitat loss is the greatest threat to the conservation of Andean Condor populations in Ecuador. Population size reduction in scenarios that included habitat loss began within the first 15 years of this threat. Population reinforcement had no effects on the recovery of Andean Condor populations given the current status of the species in Ecuador. The population size estimate presented in this study is the lower than those reported previously in other countries where the species occur. The inferences derived from the population viability analysis have implications for Condor management in Ecuador. This study highlights the need to redirect efforts from captive breeding and population reinforcement to habitat conservation. PMID- 26986003 TI - Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development. AB - The multi-subunit chromatin-remodeling SWI/SNF (known as BAF for Brg/Brm associated factor) complexes play essential roles in development. Studies have shown that the loss of individual BAF subunits often affects local chromatin structure and specific transcriptional programs. However, we do not fully understand how BAF complexes function in development because no animal mutant had been engineered to lack entire multi-subunit BAF complexes. Importantly, we recently reported that double conditional knock-out (dcKO) of the BAF155 and BAF170 core subunits in mice abolished the presence of the other BAF subunits in the developing cortex. The generated dcKO mutant provides a novel and powerful tool for investigating how entire BAF complexes affect cortical development. Using this model, we found that BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3. Here, we present further insights into how the scaffolding ability of the BAF155 and BAF170 core subunits maintains the stability of BAF complexes in the forebrain and throughout the embryo during development. Furthermore, we show that the loss of BAF complexes in the above-described model up-regulates H3K27me3 and impairs forebrain development and embryogenesis. These findings improve our understanding of epigenetic mechanisms and their modulation by the chromatin-remodeling SWI/SNF complexes that control embryonic development. PMID- 26986007 TI - Highlights from the 11th ISCB Student Council Symposium 2015. Dublin, Ireland. 10 July 2015. PMID- 26986005 TI - Association of Cytomegalovirus End-Organ Disease with Stroke in People Living with HIV/AIDS: A Nationwide Population-Based Cohort Study. AB - OBJECTIVES: Cytomegalovirus (CMV) infection might increase the risk of cardiovascular event. However, data on the link between incident stroke and co infections of CMV and human immunodeficiency virus (HIV) are limited and inconsistent. This nationwide population-based cohort study analyzed the association of CMV end-organ disease and stroke among people living with HIV/AIDS (PLWHA). METHODS: From January 1, 1998, this study identified adult HIV individuals with and without CMV end-organ disease in the Taiwan National Health Insurance Research Database. All patients were observed for incident stroke and were followed until December 31, 2012. Time-dependent analysis was used to evaluate associations of CMV end-organ disease with stroke. RESULTS: Of the 22,581 PLWHA identified (439 with CMV end-organ disease and 22,142 without CMV end-organ disease), 228 (1.01%) had all-cause stroke during a mean follow-up period of 4.85 years, including 169 (0.75%) with ischemic stroke and 59 (0.26%) with hemorrhagic stroke. After adjusting for age, sex, comorbidities, opportunistic infections after HIV diagnosis, and antiretroviral treatment, CMV end-organ disease was found to be an independent risk factor for incident all cause stroke (adjusted hazard ratio [AHR], 3.07; 95% confidence interval [CI], 1.70 to 5.55). When stroke type was considered, CMV end-organ disease was significantly positively associated with the risk of ischemic stroke (AHR, 3.14; 95% CI, 1.49 to 6.62) but not hemorrhagic stroke (AHR, 2.52; 95% CI, 0.64 to 9.91). CONCLUSIONS: This study suggested that CMV end-organ disease was an independent predictor of ischemic stroke among PLWHA. PMID- 26986006 TI - Functional stability and structural transitions of Kallikrein: spectroscopic and molecular dynamics studies. AB - Kallikrein, a physiologically vital serine protease, was investigated for its functional and conformational transitions during chemical (organic solvents, Gdn HCl), thermal, and pH induced denaturation using biochemical and biophysical techniques and molecular dynamics (MD) simulations approach. The enzyme was exceptionally stable in isopropanol and ethanol showing 110% and 75% activity, respectively, after 96 h, showed moderate tolerance in acetonitrile (45% activity after 72 h) and much lower stability in methanol (40% activity after 24 h) (all the solvents [90% v/v]). Far UV CD and fluorescence spectra indicated apparent reduction in compactness of KLKp structure in isopropanol system. MD simulation studies of the enzyme in isopropanol revealed (1) minimal deviation of the structure from native state (2) marginal increase in radius of gyration and solvent accessible surface area (SASA) of the protein and the active site, and (3) loss of density barrier at the active site possibly leading to increased accessibility of substrate to catalytic triad as compared to methanol and acetonitrile. Although kallikrein was structurally stable up to 90 degrees C as indicated by secondary structure monitoring, it was functionally stable only up to 45 degrees C, implicating thermolabile active site geometry. In GdnHCl [1.0 M], 75% of the activity of KLKp was retained after incubation for 4 h, indicating its denaturant tolerance. A molten globule-like structure of KLKp formed at pH 1.0 was more thermostable and exhibited interesting structural transitions in organic solvents. The above results provide deeper understanding of functional and structural stability of the serine proteases at molecular level. PMID- 26986008 TI - UV-dependent phosphorylation of COP9/signalosome in UV-induced apoptosis. AB - The COP9/signalosome (CSN) multi-protein complex regulates the activity of cullin RING ubiquitin ligases (CRLs), including the DDB2 and CSA CRL4 ligases (CRL4DDB2 and CRL4CSA), which are involved in the repair of UV-induced DNA damages. In the present study, we demonstrated that the protein kinase ATM, a key component of the DNA damage response (DDR), phosphorylates CSN1 and CSN7a, two subunits of the CSN complex, in a UV-dependent manner. The phosphorylation of CSN1 on serine 474 was detected as early as 3 h after UV-exposure, peaked at 8 h and persisted until 48 h post-UV irradiation. Such a time course suggests a role in late DDR rather than in DNA repair. Consistently, overexpression of a phosphorylation-resistant S474A CSN1 mutant reduced UV-induced apoptosis. Thus, CSN1 appears to play a role not only in DNA repair but also in UV-induced apoptosis. PMID- 26986015 TI - Proceedings of the 5th Kuwait International Pharmacy Conference, February 1-3, 2015. PMID- 26986016 TI - Clinical Prediction Score for Successful Retrograde Procedure in Chronic Total Occlusion Percutaneous Coronary Intervention. AB - OBJECTIVE: To develop and validate a prediction score for a successful retrograde procedure in chronic total occlusion (CTO) percutaneous coronary intervention (PCI). METHODS: A total of 228 CTO lesions in 223 patients who underwent PCI by retrograde approach were analyzed. All subjects were randomly grouped to a derivation set and a validation set at a ratio of 2:1. A successful retrograde procedure was set as the end point. Each of the identified predictors for the end point by logistic regression was assigned 1 point and summed. RESULTS: Independent predictors of a successful retrograde procedure were Werner's score [odds ratio (OR) 4.841, 95% confidence interval (CI) 1.952-12.005, p = 0.001], diameter of distal CTO segment (OR 5.263, 95% CI 2.067-13.398, p < 0.001) and tortuous collateral (type b; OR 0.119, 95% CI 0.032-0.444, p = 0.002). The predictive model developed in the derivation set stratified the difficulty of achieving a successful retrograde procedure into 4 grades - very difficult (10.5%), difficult (23.7%), intermediate (50.7%) and easy (15.1%) - and was demonstrated significantly in the validation set: very difficult (15.8%), difficult (18.4%), intermediate (47.4%) and easy (18.4%). The area under the receiver-operating characteristic curve was 0.832 +/- 0.042 for the derivation set and 0.912 +/- 0.041 for the validation set with an almost equal performance. CONCLUSIONS: According to the experience of our center, this model performed excellently in predicting the difficulty in achieving a successful retrograde procedure. PMID- 26986017 TI - Energy Sources for Laparoscopic Colorectal Surgery: Is One Better than the Others? AB - BACKGROUND: Wide acceptance of the laparoscopic approach in both benign and malignant colorectal diseases has led to the development of several multifunctional tools aiming to overcome the limitations of conventional electrosurgery (ES). The aim of this study was to compare ES, ultrasonic coagulating shears (US), electrothermal bipolar vessel sealers (EBVS), and a relatively new energy device that combines both ultrasonic and bipolar energy (Thunderbeat, TB) in terms of safety, efficacy, and cost-effectiveness in patients undergoing laparoscopic colorectal resection (LCR). MATERIALS AND METHODS: A review of the literature was performed in Medline and the Cochrane Library. Only randomized controlled trials (RCTs) and cohort studies were considered for inclusion. RESULTS: Four RCTs, one retrospective, and two prospective cohort studies were eligible for inclusion. Bleeding control was better with US compared with ES and operative time was shorter with both US and EBVS compared with ES. These advantages were more evident in challenging colorectal resections, such as low anterior resections. US and EBVS seemed to be more cost-effective compared with ES, although supporting data are limited. US and EBVS appeared to be equivalent with regard to different outcome parameters. Preliminary data on the efficacy and safety of TB are promising. CONCLUSION: Although US and EBVS have the advantages of less blood loss and/or a shorter operative time compared with ES, the current evidence does not demonstrate which multifunctional instrument is the most effective in LCR. High-quality RCTs are required to confirm the preliminary promising results with the use of TB in LCR. PMID- 26986014 TI - Prediction of the molecular mechanisms and potential therapeutic targets for diabetic nephropathy by bioinformatics methods. AB - In this study, we aimed to explore the molecular mechanisms of and genetic factors influencing diabetic nephropathy (DN). Gene expression profiles associated with DN were obtained from the GEO database (Accession no. GSE20844). The differentially expressed genes (DEGs) between diabetic mice and non-diabetic mice were screened. Subsequently, the DEGs were subjected to functional and pathway analysis. The protein-protein interaction (PPI) network was constructed and the transcription factors (TFs) were screened among the DEGs. A total of 92 upregulated and 118 downregulated genes were screened. Pathway analysis revealed that the p53 signaling pathway, the transforming growth factor (TGF)-beta signaling pathway and the mitogen-activated protein kinase (MAPK) signaling pathway were significantly enriched by upregulated genes. Serpine1 (also known as plasminogen activator inhibitor-1), early growth response 1 (Egr1) and Mdk were found to be significant nodes in the PPI network by three methods. A total of 12 TFs were found to be differentially expressed, of which nuclear receptor subfamily 4, group A, member 1 (Nr4a1) and peroxisome proliferator-activated receptor gamma (Pparg) were found to have multiple interactions with other DEGs. We demonstrated that the p53 signaling pathway, the TGF-beta signaling pathway and the MAPK signaling pathway were dysregulated in the diabetic mice. The significant nodes (Serpine1, Egr1 and Mdk) and differentially expressed TFs (Nr4a1 and Pparg) may provide a novel avenue for the targeted therapy of DN. PMID- 26986013 TI - Chemically induced skin carcinogenesis: Updates in experimental models (Review). AB - Skin cancer is one of the most common malignancies affecting humans worldwide, and its incidence is rapidly increasing. The study of skin carcinogenesis is of major interest for both scientific research and clinical practice and the use of in vivo systems may facilitate the investigation of early alterations in the skin and of the mechanisms involved, and may also lead to the development of novel therapeutic strategies for skin cancer. This review outlines several aspects regarding the skin toxicity testing domain in mouse models of chemically induced skin carcinogenesis. There are important strain differences in view of the histological type, development and clinical evolution of the skin tumor, differences reported decades ago and confirmed by our hands-on experience. Using mouse models in preclinical testing is important due to the fact that, at the molecular level, common mechanisms with human cutaneous tumorigenesis are depicted. These animal models resemble human skin cancer development, in that genetic changes caused by carcinogens and pro-inflammatory cytokines, and simultaneous inflammation sustained by pro-inflammatory cytokines and chemokines favor tumor progression. Drugs and environmental conditions can be tested using these animal models. keeping in mind the differences between human and rodent skin physiology. PMID- 26986018 TI - "The role of redundant information in cultural transmission and cultural stabilization": Correction to Acerbi and Tennie (2016). AB - Reports an error in "The role of redundant information in cultural transmission and cultural stabilization" by Alberto Acerbi and Claudio Tennie (Journal of Comparative Psychology, 2016[Feb], Vol 130[1], 62-70). In the article the copyright should have been "(c) 2016 The Author(s)". The author note also should have included the following license statement "This article has been published under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s). Author(s) grant(s) the American Psychological Association the exclusive right to publish the article and identify itself as the original publisher." The online version of this article has been corrected. (The following abstract of the original article appeared in record 2016-07004-005.) Redundant copying has been proposed as a manner to achieve the high-fidelity necessary to pass on and preserve complex traits in human cultural transmission. There are at least 2 ways to define redundant copying. One refers to the possibility of copying repeatedly the same trait over time, and another to the ability to exploit multiple layers of information pointing to the same trait during a single copying event. Using an individual-based model, we explore how redundant copying (defined as in the latter way) helps to achieve successful transmission. The authors show that increasing redundant copying increases the likelihood of accurately transmitting a behavior more than either augmenting the number of copying occasions across time or boosting the general accuracy of social learning. They also investigate how different cost functions, deriving, for example, from the need to invest more energy in cognitive processing, impact the evolution of redundant copying. The authors show that populations converge either to high-fitness/high-costs states (with high redundant copying and complex culturally transmitted behaviors; resembling human culture) or to low-fitness/low-costs states (with low redundant copying and simple transmitted behaviors; resembling social learning forms typical of nonhuman animals). This outcome may help to explain why cumulative culture is rare in the animal kingdom. (PsycINFO Database Record (c) 2016 APA, all rights reserved). PMID- 26986019 TI - Overcoming associative learning. AB - Thorndike (1898, 1911) rejected the idea that animal behavior was the consequence of reasoning, and suggested instead that the gradual acquisition of associations formed the basis of behavior-a contention that has had a significant impact on the development of animal learning theory. Despite this, comparative psychology provides a number of examples of behaviors that have been considered to be above and beyond the explanation of associative-, or reinforcement-learning mechanisms. These behaviors have motivated some researchers to propose higher-order cognitive abilities in animals, including (but not limited to) reasoning, sensitivity to ambiguity, and metacognition. However, other authors have questioned this claim, and provided alternative explanations for these behaviors from an associative perspective. With relevant examples, the steps that must be taken in order to overcome an associative explanation of behavior are described. (PsycINFO Database Record PMID- 26986021 TI - The effect of length scale on the determination of geometrically necessary dislocations via EBSD continuum dislocation microscopy. AB - Electron backscatter diffraction (EBSD) dislocation microscopy is an important, emerging field in metals characterization. Currently, calculation of geometrically necessary dislocation (GND) density is problematic because it has been shown to depend on the step size of the EBSD scan used to investigate the sample. This paper models the change in calculated GND density as a function of step size statistically. The model provides selection criteria for EBSD step size as well as an estimate of the total dislocation content. Evaluation of a heterogeneously deformed tantalum specimen is used to asses the method. PMID- 26986020 TI - Osteo-/odontogenic differentiation of BMP2 and VEGF gene-co-transfected human stem cells from apical papilla. AB - Stem cells from apical papilla (SCAP) possess clear osteo-/odontogenic differentiation capabilities, and are regarded as the major cellular source for root dentin development. Bone morphogenetic protein 2 (BMP2) and vascular endothelial growth factor (VEGF) serve pivotal roles in the modulation of tooth development and dentin formation. However, the synergistic effects of BMP2 and VEGF on osteo-/odontogenic differentiation of SCAP remain unclear. The current study aimed to investigate the proliferative and osteo-/odontogenic differentiating capabilities of BMP2 and VEGF gene-co-transfected SCAP (SCAP-BMP2 VEGF) in vitro. The basic characteristics of the isolated SCAP were identified by the induction of multipotent differentiation and by flow cytometry. Lentiviral vector-mediated gene transfection was conducted with SCAP in order to construct blank vector-transfected SCAP (SCAP-green fluorescent protein), BMP2 gene transfected SCAP (SCAP-BMP2), VEGF gene-transfected SCAP (SCAP-VEGF) and SCAP BMP2-VEGF. The Cell Counting Kit 8 assay was used to analyze the proliferative capacities of the four groups of cells. The expression of osteo-/odontogenic genes and proteins in the cells were evaluated by reverse transcription quantitative polymerase chain reaction and western blotting. The mineralized nodules formed by the four group cells were visualized by alkaline phosphatase (ALP) staining. Among the four groups of cells, SCAP-VEGF was demonstrated to exhibit increased proliferation, and SCAP-BMP2-VEGF exhibited reduced proliferation during eight days observation. SCAP-BMP2-VEGF exhibited significantly increased expression levels of ALP, osteocalcin, dentin sialophosphoprotein, dentin matrix acidic phosphoprotein gene 1 and dentin sialoprotein than the other three groups at the majority of the time points. Furthermore, the SCAP-BMP2-VEGF group exhibited a significantly greater number of ALP-positive mineralized nodules than the other groups following 16 days culture in vitro. In conclusion, lentiviral vector-mediated BMP2 and VEGF gene co transfection significantly activated the osteo-/odontogenic differentiation of human SCAP. PMID- 26986023 TI - Facile analysis of contents and compositions of the chondroitin sulfate/dermatan sulfate hybrid chain in shark and ray tissues. AB - The chondroitin sulfate (CS)/dermatan sulfate (DS) hybrid chain was extracted from specific tissues of several kinds of sharks and rays. The contents and sulfation patterns of the CS/DS hybrid chain were precisely analyzed by digestion with chondroitinases ABC and AC. All samples predominantly contained the A- and C units. Furthermore, all samples characteristically contained the D-unit. Species specific differences were observed in the contents of the CS/DS hybrid chain, which were the highest in Mako and Blue sharks and Sharpspine skates, but were lower in Hammerhead sharks. Marked differences were observed in the ratio of the C-unit/A-unit between sharks and rays. The contents of the CS/DS hybrid chain and the ratio of the C-unit/A-unit may be related to an oxidative stress-decreasing ability. PMID- 26986022 TI - Driver state examination--Treading new paths. AB - A large proportion of crashes in road driving can be attributed to driver fatigue. Several types of fatigue are discussed, comprising sleep-related fatigue, active task-related fatigue (as a consequence of workload in demanding driving situations) as well as passive task-related fatigue (as related to monotonous driving situations). The present study investigated actual states of fatigue in a monotonous driving situation, using EEG measures and a long-lasting driving simulation experiment, in which drivers had to keep the vehicle on track by compensating crosswind of different strength. Performance data and electrophysiological correlates of mental fatigue (EEG Alpha and Theta power, Inter Trial Coherence (ITC), and auditory event-related potentials to short sound stimuli) were analyzed. Driving errors and driving lane variability increased with time on task and with increasing crosswind. The posterior Alpha and Theta power also increased with time on task, but decreased with stronger crosswind. The P3a to sound stimuli decreased with time on task when the crosswind was weak, but remained stable when the crosswind was strong. The analysis of ITC revealed less frontal Alpha and Theta band synchronization with time on task, but no effect of crosswind. The results suggest that Alpha power in monotonous driving situations reflects boredom or attentional withdrawal due to monotony rather than the decline of processing abilities as a consequence of high mental effort. A more valid indicator of declining mental resources with increasing time on task seems to be provided by brain oscillatory synchronization measures and event related activity. PMID- 26986025 TI - Laparoscopic cholecystectomy using the PINPOINT endoscopic fluorescence imaging system with intraoperative fluorescent imaging: A case report. AB - We report on a laparoscopic cholecystectomy performed using the PINPOINT endoscopic fluorescence imaging system (Novadaq, Mississauga, ON, Canada), which enables surgery to be performed while simultaneously viewing fluorescent images. The patient was a 43-year-old man diagnosed with cholecystolithiasis. Indocyanine green (ICG) was administered 18h prior to surgery. The PINPOINT system made it possible to perform the procedure while viewing ICG fluorescence in the cystic duct. As the gallbladder was also imaged with this technique, it was easy to determine at which layer to detach the gallbladder from the liver bed. The operative time was 1h and 32min, and blood loss was 5ml. There were no perioperative complications. PMID- 26986024 TI - Histopathology investigation on the Vardar chub (Squalius vardarensis) populations captured from the rivers impacted by mining activities. AB - Many natural freshwater ecosystems, especially in the north eastern Macedonia, are polluted with heavy metals, which are released by active mines. Long-term exposure to high levels of dissolved metals might result in increased metal bioaccumulation in organs of aquatic organisms, and consequently might cause various sub-toxic and toxic effects. The aim of this study was to assess the health of Vardar chub (Squalius vardarensis) inhabiting mining impacted rivers Zletovska and Kriva, in comparison with chub from the reference Bregalnica River. It was done by use of indicators of tissue damage (histopathology of liver and gonads) and general indicators of exposure to environmental stressors (condition factor, organo-somatic indices and external/internal macroscopic lesions). Histological assessment of gonads revealed good reproductive health in all three rivers, indicating high tolerance of gonads to contaminant exposure. Contrary, several external/internal lesions were more pronounced in chub from severely metal contaminated Zletovska River. Prevalence of hepatic lesions was also higher in mining impacted rivers (in Kriva, 70%; in Zletovska, 59%) compared to Bregalnica River (38%). The spectrum of histological lesions observed in chub liver varied from non-specific minor degenerative conditions, such as lymphocyte infiltration, fibrosis, parasites, granulomas and lipidosis, to extensive and/or more severe changes such as bile duct proliferation, necrosis, megalocytosis, light-dark hepatocytes and hepatocytes regeneration. The results of histopathological investigation for all three rivers showed clear signs of water contamination, especially prominent in mining influenced rivers. More research efforts should be devoted to study of environmental conditions and metal contamination in the mining impacted rivers worldwide, especially of their effects on health of local ichthyofauna. PMID- 26986026 TI - Adsorption and separation of HCV particles by novel affinity aptamer functionalized adsorbents. AB - A novel type of aptamer-functionalized immunoadsorbent was prepared and characterized to remove HCV particles, a promising option of extracorporeal immunoadsorption (ECI) therapy against HCV. Herein, we fabricated a HCV-specific immunoadsorbent where single-stranded DNA aptamers reported and studied previously, modified with amino group at the 5' terminus, was immobilized covalently onto surfaces of carboxylated-derivative sepharose 4FF beads through N hydroxysuccinimide (NHS) linkage. Then the adsorbents was evaluated and characterized by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). Subsequently, we also confirmed that proposed immunoadsorbents exhibited a favorable biocompatibility as well as specificity. In addition, time-dependent effects of the eradication capacity of aptamer functionalized sepharose beads against HCV was investigated. With the optimized time point, the decontamination performance of HCV particles was assessed by real time quantitative PCR (qPCR) followed by nucleic acid-based hybridization (NAH), which shows sorbents with an aptamer density of 2nmolligand/ml resin could remove approximately 80% (i.e. 8.9*10(6) HCV particles/ml resin) of the HCV genotype 2a cultivated in vitro and 75% (vary with the intial concentration of HCV from about 7.5*10(4)-4.4*10(5) HCV particles/ml resin) of the HCV samples from human plasma samples. All these results indicated that the novel aptamer-based adsorbents could effectively remove HCV particles and likely serve as a novel therapy option or at least supplementary for the treatment regimen of HCV. PMID- 26986027 TI - Optimize and refine therapeutic index in radiation therapy: Overview of a century. AB - In 1936, Holthusen theorized the probability of achieving tumor control and of developing normal tissue complications after radiotherapy as a function of radiation dose. This concept was formalized and further developed in 1975. Several concepts for improving the therapeutic gain had been anticipated, including the possibility of modulating the tumor/normal tissue differential response. Eight decades later, it is possible to review and analyze progress achieved in the knowledge of radiation-induced toxicity. The clinical developments using new technologies and biological modulators of radiation response have corroborated a posteriori this model, however, many questions remain unanswered. A few randomized trials have validated the benefit of modern irradiation techniques for improving the therapeutic index; but the level I evidence of a survival improvement is still lacking. In the field of bio modulation, large meta-analyses have shown that concurrent chemotherapy improves local control in many cancer types. Clinical investigations using molecularly targeted therapies have been rather disappointing, with only one exception: head and neck squamous cell carcinoma. Numerous recent biological findings question the possibility to target tumor tissue without impacting normal tissue response. Moreover, the abscopal and bystander effects suggest that normal tissue irradiation should not be perceived only as a source of toxicity, but may also result in downstream therapeutic effects. This paper reexamines the multiple efforts made to modulate the tumor versus normal tissue differential response, which have translated into incremental therapeutic gain and highlights the ongoing effort to better understand the optimal integration of radiation biology, chemotherapeutic, novel drugs and novel technologies. PMID- 26986028 TI - Exocrine pancreatic insufficiency in a child with Netherton syndrome. PMID- 26986030 TI - Tardy ulnar nerve palsy caused by chronic radial head dislocation after Monteggia fracture: a report of two cases. AB - Dislocation of the radial head is often encountered as a result of a pediatric Monteggia fracture. We report two rare cases of tardy ulnar nerve palsy associated with anterior radial head dislocation combined with anterior bowing of the ulna. They had cubitus valgus deformity, valgus instability, and osteoarthritis of the elbow, and had elbow injury more than 40 years back. They were diagnosed with chronic radial head dislocation long after a Bado type 1 Monteggia fracture. Anterior subcutaneous ulnar nerve transposition yielded favorable results. It is important to recognize the possibility of tardy ulnar nerve palsy caused by an improperly treated Monteggia fracture. PMID- 26986031 TI - Revision pediatric anterior cruciate ligament reconstruction after failure of iliotibial band technique treated with all-epiphyseal technique in a prepubescent with Ehlers-Danlos syndrome: a case report. AB - The increasing number of pediatric anterior cruciate ligament (ACL) injuries and the failure of nonoperative management of these patients has elicited a concordant response in the surgical community to devise reconstruction techniques that stabilize the knee joint without causing iatrogenic growth disturbances. Likewise, the rise in pediatric ACL reconstructions forecasts a consequent rise in revision ACL reconstructions in patients with open physes. In this case report, we describe a prepubescent with Ehlers-Danlos syndrome and congenital ACL deficiency, who underwent physeal-sparing iliotibial band ACL reconstruction and revision to an all-epiphyseal ACL reconstruction with allograft. We also underscore the lack of evidence addressing graft choice and outcomes for ACL reconstructions in patients with connective tissue disorders. PMID- 26986029 TI - Protective Role of Grape Seed Proanthocyanidins Against Ccl4 Induced Acute Liver Injury in Mice. AB - BACKGROUND: We investigated the effect of grape seed proanthocyanidins (GSPs) on carbon tetrachloride (CCl4)-induced acute liver injury. MATERIAL/METHODS: Sixty SPF KM mice were randomly divided into 6 groups: the control group, CCl4-model group, bifendate group (DDB group), and low-, moderate-, and high-dose GSP groups. The following parameters were measured: serum levels of alanine aminotransferase (ALT); aspartate aminotransferase (AST); tumor necrosis factor (TNF)-alpha; interleukin-6 (IL-6); high-mobility group box (HMGB)-1; body weight; liver, spleen, and thymus indexes; superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity; HMGB1 mRNA; malondialdehyde (MDA) content; hepatocyte proliferation; and changes in liver histology. RESULTS: Compared to the CCl4-model group, decreases in liver index and increases in thymus index significantly increased SOD and GSH-Px activities and reduced MDA content, and higher hepatocyte proliferative activity was found in all GSP dose groups and the DDB group (all P<0.001). Compared with the CCl4-model group, serum TNF-alpha and IL-6 levels and HMGB 1 mRNA and protein expressions decreased significantly in the high GSP dose group (all P<0.05). CONCLUSIONS: Our results provide strong evidence that administration of GSPs might confer significant protection against CCl4-induced acute liver injury in mice. PMID- 26986032 TI - Humeral lateral condyle fractures in children: redefining the criteria for displacement. AB - The aim of this study is to define paediatric lateral humeral condyle fractures prone to later displacement. The authors reviewed 106 children who were treated surgically for this fracture. There were 74 boys and 32 girls with an age range of 3-10 years. The study included 27 minimally displaced and 79 displaced fractures. The average follow-up was 50 months. Binary logistic regression model indicated that 6-8-year-old children with minimally displaced fractures and who underwent immediate surgery have a better chance for satisfactory results. The authors concluded that routine use of 2 mm displacement for treatment decisions should be changed to avoid delayed surgery. PMID- 26986033 TI - Eight-year follow-up findings of surgical treatment for severe dystrophic changes in the cervical spine associated with neurofibromatosis type I: a case report. AB - Long-term follow-up findings for dystrophic changes in the cervical spine caused by neurofibromatosis type 1 have been rarely reported. A 13-year-old boy with severe dural ectasia in the cervical spine underwent cervical posterior fusion from C1 to C5 for prevention of cervical spine fracture and spinal injury. We followed him up for 8 years after surgery. We measured the progression of the destruction on yearly MRI. The dural ectasia gradually progressed until 3 years postoperatively. Subsequently, no further enlargement of the dural sac occurred. At the 8-year follow-up examination, the patient had no limitations in the activities of daily life. PMID- 26986034 TI - Role of the tumor microenvironment in tumor progression and the clinical applications (Review). AB - Oncogene activation and tumor-suppressor gene inactivation are considered as the main causes driving the transformation of normal somatic cells into malignant tumor cells. Cancer cells are the driving force of tumor development and progression. Yet, cancer cells are unable to accomplish this alone. The tumor microenvironment is also considered to play an active role rather than simply acting as a by-stander in tumor progression. Through different pathways, tumor cells efficiently recruit stromal cells, which in turn, provide tumor cell growth signals, intermediate metabolites, and provide a suitable environment for tumor progression as well as metastasis. Through reciprocal communication, cancer cells and the microenvironment act in collusion leading to high proliferation and metastatic capability. Understanding the role of the tumor microenvironment in tumor progression provides us with novel approaches through which to target the tumor microenvironment for efficient anticancer treatment. In this review, we summarize the mechanisms involved in the recruitment of stromal cells by tumor cells to the primary tumor site and highlight the role of the tumor microenvironment in the regulation of tumor progression. We further discuss the potential approaches for cancer therapy. PMID- 26986036 TI - Discovery and Structure-Activity Relationship of a Bioactive Fragment of ELABELA that Modulates Vascular and Cardiac Functions. AB - ELABELA (ELA) was recently discovered as a novel endogenous ligand of the apelin receptor (APJ), a G protein-coupled receptor. ELA signaling was demonstrated to be crucial for normal heart and vasculature development during embryogenesis. We delineate here ELA's structure-activity relationships and report the identification of analogue 3 (ELA(19-32)), a fragment of ELA that binds to APJ, activates the Galphai1 and beta-arrestin-2 signaling pathways, and induces receptor internalization similarly to its parent endogenous peptide. An alanine scan performed on 3 revealed that the C-terminal residues are critical for binding to APJ and signaling. Finally, using isolated-perfused hearts and in vivo hemodynamic and echocardiographic measurements, we demonstrate that ELA and 3 both reduce arterial pressure and exert positive inotropic effects on the heart. Altogether, these results present ELA and 3 as potential therapeutic options in managing cardiovascular diseases. PMID- 26986037 TI - Comparison of ketamine-propofol and remifentanil in terms of hemodynamic variables and patient satisfaction during monitored anaesthesia care. AB - BACKGROUND: This study aimed to compare remifentanil and ketamine-propofol in terms of hemodynamic response, duration of recovery and patient satisfaction in operative hysteroscopy cases who underwent monitored anaesthesia care in combination with paracervical block. METHODS: Monitored anaesthesia care was used in 60 ASA I-II female patients. The patients were divided into two groups as remifentanil (Group R) and ketamine-propofol (Group K-P). The hemodynamic effects of remifentanil and ketamine-propofol, and duration of recovery were recorded and compared. The patient satisfaction was also recorded and the two groups were compared. RESULTS: Age, body mass, ASA status, duration of anaesthesia and type of surgery were found to be similar between groups. The time of the Aldrete score reaching >= 9 was found to be shorter in Group R when compared with Group KP (Group R: 4.1 +/- 1.9 min, Group K-P: 6.1 +/- 2.6 min) (P< 0.05). The incidence of postoperative nausea and vomiting was found to be significantly higher in the remifentanil group (P <= 0.05). When the groups were compared in terms of patient satisfaction, in both groups this was found to be similar. CONCLUSION: Sedation with remifentanil combined with a paracervical block during monitored anaesthesia care provides early recovery with effective sedation and analgesia in hysteroscopy procedures. PMID- 26986038 TI - The influence of regional anaesthesia and local anaesthetics on cardiac repolarization. AB - The normal function of the heart muscle is the result of electro-mechanic and hemodynamic coupling. Modification of the structure and activity of ion channels within the cardiomyocytes may induce cardiac arrhythmias. Electrophysiological mechanisms of arrhythmia, generated by a prolonged period of repolarization, result either from conduction disturbances (reentry mechanism) and/or the induction of beats (early after-depolarizations). Local anaesthetic drug deposition does not affect the repolarization period, as long as the concentration of the free drug in the plasma does not reach the critical value to cause toxic effects in the cardiomyocytes. When analyzing the effect of regional anaesthesia on the repolarization period it is essential to acknowledge the activity or blockade of adrenergic fibres. Blocking the sympathetic fibres', including level T1 to T4, leads to a shortening of the QT interval and a reduction of QT dispersion. Adrenergic blockade as a result of spinal anaesthesia causes severe adrenergic activity above the level of the block and therefore prolongs repolarization. Stellate ganglion block on the right side causes a significant prolongation of the QT interval and QT dispersion. Regardless of the reasons for prolongation of the repolarization period (congenital or acquired), vigilance is required within the perioperative anaesthetic management of a patient, so as not to lead to the occurrence of ventricular arrhythmias. Regional anaesthesia techniques and properly used local anaesthetic drugs are regarded as being safe in these patients. PMID- 26986039 TI - Entropy production in mesoscopic stochastic thermodynamics: nonequilibrium kinetic cycles driven by chemical potentials, temperatures, and mechanical forces. AB - Nonequilibrium thermodynamics (NET) investigates processes in systems out of global equilibrium. On a mesoscopic level, it provides a statistical dynamic description of various complex phenomena such as chemical reactions, ion transport, diffusion, thermochemical, thermomechanical and mechanochemical fluxes. In the present review, we introduce a mesoscopic stochastic formulation of NET by analyzing entropy production in several simple examples. The fundamental role of nonequilibrium steady-state cycle kinetics is emphasized. The statistical mechanics of Onsager's reciprocal relations in this context is elucidated. Chemomechanical, thermomechanical, and enzyme-catalyzed thermochemical energy transduction processes are discussed. It is argued that mesoscopic stochastic NET in phase space provides a rigorous mathematical basis of fundamental concepts needed for understanding complex processes in chemistry, physics and biology. This theory is also relevant for nanoscale technological advances. PMID- 26986041 TI - Heat-Resistant Crack-Free Superhydrophobic Polydivinylbenzene Colloidal Films. AB - Highly cross-linked poly(divinylbenzene) (PDVB) spherical colloidal particles with nano-, submicron-, and micron-sizes of 157.2 nm, 602.1 nm, and 5.1 MUm were synthesized through emulsion and dispersion polymerization methods. The influences of particle size on the surface morphology, roughness, superhydrophobicity, and critical cracking thickness of colloidal films were studied in detail. The results show that PDVB colloidal films possess large water contact angle (CA) over 151 degrees , belonging to superhydrophobic materials. Moreover, it is interesting to observe that the highly cross-linked network structure leads to PDVB film's excellent heat-resistance. The CA and rough surface morphology remain nearly unchanged after thermal-treatment of films at 150 degrees C for 24 h. In addition, no cracks were observed in films with thicknesses up to 8.1 MUm, exceeding most of polymer and inorganic particle films reported in the literature. The simple and scalable preparation method, low-cost, superhydrophobicity, and excellent thermal stability endow the PDVB colloidal films with promising applications in advanced coating fields, especially when employed in the high-temperature service environment. PMID- 26986040 TI - Functional architecture of visual emotion recognition ability: A latent variable approach. AB - Emotion recognition has been a focus of considerable attention for several decades. However, despite this interest, the underlying structure of individual differences in emotion recognition ability has been largely overlooked and thus is poorly understood. For example, limited knowledge exists concerning whether recognition ability for one emotion (e.g., disgust) generalizes to other emotions (e.g., anger, fear). Furthermore, it is unclear whether emotion recognition ability generalizes across modalities, such that those who are good at recognizing emotions from the face, for example, are also good at identifying emotions from nonfacial cues (such as cues conveyed via the body). The primary goal of the current set of studies was to address these questions through establishing the structure of individual differences in visual emotion recognition ability. In three independent samples (Study 1: n = 640; Study 2: n = 389; Study 3: n = 303), we observed that the ability to recognize visually presented emotions is based on different sources of variation: a supramodal emotion-general factor, supramodal emotion-specific factors, and face- and within modality emotion-specific factors. In addition, we found evidence that general intelligence and alexithymia were associated with supramodal emotion recognition ability. Autism-like traits, empathic concern, and alexithymia were independently associated with face-specific emotion recognition ability. These results (a) provide a platform for further individual differences research on emotion recognition ability, (b) indicate that differentiating levels within the architecture of emotion recognition ability is of high importance, and (c) show that the capacity to understand expressions of emotion in others is linked to broader affective and cognitive processes. PMID- 26986042 TI - Challenges in the pharmacological treatment of geriatric asthma. AB - Asthma in older populations is characterized by frequent comorbid conditions, which increase the risk of side effects and of detrimental interactions between respiratory and non-respiratory drugs. These observations lead to the need to manage asthma in older populations by applying a multidimensional assessment and a multidisciplinary treatment; therefore, we favor the use of the 'geriatric' term to define asthma in the elderly. Geriatric asthma is a complex disease, which may not necessarily imply that it is also complicated, although the two conditions may often coexist. On this basis, the switch from an organ-driven management to the holistic approach may be the key factor to attain optimal control of the disease in this age range. The current review discusses the age related factors affecting asthma treatment in the oldest individuals, such as the comorbid conditions, and age-related changes of metabolism and excretion that can impair the efficacy and safety of drugs. PMID- 26986044 TI - Incorrect Sentence in the Abstract. PMID- 26986043 TI - Analysis of Inner and Outer Retinal Thickness in Patients Using Hydroxychloroquine Prior to Development of Retinopathy. AB - Importance: Retinopathy is a known risk of long-term use of hydroxychloroquine sulfate. However, whether the inner as well as outer retina are involved before retinopathy develops and whether changes in the retina might signal impending toxic effects during screening remain unknown. Objective: To determine the degree of inner and outer retinal involvement in short- and long-term use of hydroxychloroquine before the development of retinopathy. Design, Setting, and Participants: This retrospective medical record review of spectral-domain optical coherence tomography (SD-OCT) findings was performed at an academic medical center. Thirty-two patients without retinopathy and with high-quality SD-OCT images were studied. Twenty-seven patients were age matched (49-65 years old) for comparison of retinal layers among patients who used the drug less than 5 years (n = 12) or longer than 15 years (n = 15) at the initial visit. Populations were also defined (without age limitation) for comparison of change during 25 to 52 months of follow-up among patients with initial use of less than 5 years (n = 7) or longer than 15 years (n = 8). Data were collected from 2010 to 2015. Main Outcomes and Measures: Measurements of inner and outer retinal thickness in SD OCT images using commercial software and a Stanford pixel-by-pixel segmentation software that also provided topographic maps of thickness dimensions and change. Results: Thirty-two patients (5 men and 27 women) were included in the analysis. Measurements of inner retinal thickness between short- and long-term hydroxychloroquine users (n = 27) in different retinal regions, and during a median 39 months of follow-up (n = 15), showed no statistically significant differences or change. Similarly, no significant differences or changes were identified in outer retinal thickness except for the final visit of 1 patient who developed focal parafoveal thinning, a toxic effect of hydroxychloroquine use. Cirrus ganglion cell analysis measurements were inaccurate in the presence of outer retinal damage. Conclusions and Relevance: The inner retina appears not to be involved in hydroxychloroquine-induced retinopathy to any clinically relevant degree within the limitations of our sample size. No clinically apparent warning of outer retinal damage was seen in the SD-OCT images of long-term hydroxychloroquine users until the actual appearance of focal retinopathy. Early detection of hydroxychloroquine-induced retinopathy is known to prevent visual acuity loss and serious progression after the therapy is stopped, and these data suggest that screening should seek distinct new areas of retinopathy (shown by topographic thickness maps) rather than long-term progressive thinning. PMID- 26986045 TI - FTY720 Attenuates Retinal Inflammation and Protects Blood-Retinal Barrier in Diabetic Rats. AB - PURPOSE: FTY720 has shown a protective effect in several diseases via inhibiting inflammation and decreasing vascular permeability. The purpose of this study was to assess the impact of FTY720 on inflammation and the blood-retinal barrier (BRB) in diabetic rats. METHODS: Male Wister rats were induced to develop diabetes by streptozotocin, and FTY720 was administered by oral gavage daily for 12 weeks. All experiments were performed at 12 weeks after model establishment. Gene expression was assessed by real-time PCR. Protein expression and/or distribution were assessed by Western blotting and/or immunohistochemistry. The BRB breakdown was determined by staining of retinal whole mounts and quantified using Evans blue. RESULTS: FTY720 induced lymphopenia in diabetic rats. Proinflammatory cytokines (TNF-alpha, IL-6, and IL-1beta) and adhesion molecules (inter-cellular cell adhesion molecule-1 and vascular cell adhesion molecule-1) were increased in retinas of diabetic rats. FTY720 significantly inhibited the up regulation of these inflammatory factors. FTY720 also suppressed nuclear factor kappaB activation seen in retinas of diabetic rats. Additionally, FTY720 prevented BRB breakdown and reduction of tight junction proteins (ZO-1, Occludin, and Claudin-5) in the retinas of diabetic rats. Down-regulation of S1P1 and S1P3 was also reversed by FTY720 in retinas of diabetic rats. CONCLUSIONS: FTY720 provides protection against diabetic retinopathy (DR), which may involve its anti inflammatory and barrier-enhancing effects. The S1PR modulation may serve as a novel approach to treat patients with DR. PMID- 26986046 TI - Arthroscopic suture bridge rotator cuff repair: functional outcome, repair integrity, and preoperative factors related to postoperative outcome. AB - OBJECTIVES: To assess the retear rate, retear size and location, the clinical impact of a retear, and preoperative patient factors related to postoperative outcome after arthroscopic suture bridge rotator cuff repair. METHODS: Fifty six patients with an isolated, full-thickness supraspinatus tendon tear who underwent arthroscopic suture bridge rotator cuff repair were retrospectively identified. Patients were evaluated and rotator cuff integrity was assessed using ultrasonography. Visual analog score (VAS), the American Shoulder and Elbow Surgeon (ASES) score, shoulder range of motion and strength were used for clinical evaluation. Retears were assessed for size and location on ultrasonography. RESULTS: Forty two patients (75%) aged a mean 59.7 +/- 8.6 years (range 41-79 years) were available for follow-up at a mean 13.5 months. Postoperative evaluation indicated significant improvements in ASES score (49.76 +/- 18.2 to 86.57 +/- 13.4, P < 0.001), VAS pain score (4.69 +/- 2.17 to 0.63 +/- 1.29, P < 0.001), forward elevation range of motion (144.1 degrees +/- 29.9 to 159.69 degrees +/- 13.9, P = 0.002), and internal rotation ROM (44.13 degrees +/- 12.0 to 52.09 degrees +/- 12.0, P = 0.003). The retear rate was 14.28% (6/42). Patients with retears were not older (P = 0.526) but had a larger preoperative tear size (3.25 cm +/- 0.5 vs. 2.05 cm +/- 0.48, P < 0.001). Preoperative tear size was significantly associated with a postoperative retear (P < 0.001). The duration of preoperative symptoms was significantly associated with pain (P = 0.029), pain improvement (P = 0.013), internal rotation ROM (P = 0.002), and internal rotation strength (P = 0.004). CONCLUSIONS: Arthroscopic suture bridge repair provides good clinical results with a low retear rate. The duration of preoperative symptoms was associated with postoperative outcome, indicating that delaying surgery may result in inferior outcomes. LEVEL OF EVIDENCE: IV, Case Series. PMID- 26986048 TI - Prognostic Value of Cardiac MR Imaging for Preoperative Assessment of Patients with Severe Functional Tricuspid Regurgitation. AB - Purpose To explore the prognostic value of cardiac magnetic resonance (MR) imaging in predicting postoperative cardiac death in patients with severe functional tricuspid regurgitation (TR). Materials and Methods This study was approved by the institutional review board, and written informed consent was obtained from all patients. Prospectively collected data included cardiac MR images, New York Heart Association (NYHA) functional class, a comprehensive laboratory test, and clinical events over the follow-up period in 75 consecutive patients (61 women and 14 men; mean age +/- standard deviation, 59 years +/- 9) undergoing corrective surgery for severe functional TR. Cox proportional hazards models were used to assess the association between cardiac MR parameters and outcomes. Results During a median follow-up period of 57 months (range, 21-82 months), cardiac mortality and all-cause mortality were 17.3% and 26.7%, respectively, with a surgical mortality of 6.7%. Cardiac death risk was lower with a higher right ventricular (RV) ejection fraction (EF) on cardiac MR images (hazard ratio per 5% higher EF = 0.790, P = .048). By adjusting for confounding variables, RV EF remained a significant predictor for cardiac death (P < .05) and major postoperative cardiac events (P < .05). The area under the receiver operating characteristic curve (AUC) confirmed the incremental role of RV EF on cardiac MR images in the prediction of postoperative cardiac death (AUC, 0.681 0.771; P = .041) and major postoperative cardiac events (AUC, 0.660-0.745; P = .044) on top of NYHA class. RV end-systolic volume index was also independently associated with these outcomes but failed to increase the AUC significantly. Conclusion Preoperative assessment of cardiac MR imaging-based RV EF provides independent and incremental prognostic information in patients undergoing corrective surgery for severe functional TR. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 26986047 TI - Nonthermal Ablation by Using Intravascular Oxygen Radical Generation with WST11: Dynamic Tissue Effects and Implications for Focal Therapy. AB - Purpose To examine the hypothesis that vascular-targeted photodynamic therapy (VTP) with WST11 and clinically relevant parameters can be used to ablate target tissues in a non-tumor-bearing large-animal model while selectively sparing blood vessels and collagen. Materials and Methods By using an institutional animal care and use committee-approved protocol, 68 ablations were performed in the kidneys (cortex and medulla) and livers of 27 adult pigs. Posttreatment evaluation was conducted with contrast material-enhanced computed tomography in the live animals at 24 hours. Immunohistochemistry was evaluated and histologic examination with hematoxylin-eosin staining was performed at 4 hours, 24 hours, and 7 days. Intravenous infusion of WST11 (4 mg per kilogram of body weight) was followed by using near-infrared illumination (753 nm for 20 minutes) through optical fibers prepositioned in target tissues by using a fixed template. Treated areas were scanned, measured, and statistically analyzed by using the Student t test and two way analysis of variance. Results Focal WST11 VTP treatment in the liver and kidney by using a single optical fiber resulted in well-demarcated cylindrical zones of nonthermal necrosis concentrically oriented around the light-emitting diffuser, with no intervening viable parenchymal cells. The radius of ablated tissue increased from approximately 5 mm at 150 mW to approximately 7 mm at 415 mW (P < .01). Illumination through fiber triads at 1-cm separation resulted in confluent homogeneous necrosis. Patterns of acute injury within 24 hours were consistent with microcirculatory flow arrest and collagen preservation (demonstrated with trichrome staining). In the peripheral ablation zone, blood vessels at least 40 MUm in diameter were selectively preserved and remained functional at 7 days. Ablated tissues exhibited progressive fibrosis and chronic inflammatory cell infiltrates. No histologic changes consistent with thermal injury were observed in blood vessels or collagen. The renal hilum and collecting system did not show treatment effect, despite treatment proximity. Conclusion WST11 VTP induces nonthermal tissue ablation in target tissue while preserving critical organ structures and bystander blood vessels within solid organs. ((c)) RSNA, 2016 Online supplemental material is available for this article. PMID- 26986050 TI - Quasi-ballistic Electronic Thermal Conduction in Metal Inverse Opals. AB - Porous metals are used in interfacial transport applications that leverage the combination of electrical and/or thermal conductivity and the large available surface area. As nanomaterials push toward smaller pore sizes to increase the total surface area and reduce diffusion length scales, electron conduction within the metal scaffold becomes suppressed due to increased surface scattering. Here we observe the transition from diffusive to quasi-ballistic thermal conduction using metal inverse opals (IOs), which are metal films that contain a periodic arrangement of interconnected spherical pores. As the material dimensions are reduced from ~230 nm to ~23 nm, the thermal conductivity of copper IOs is reduced by more than 57% due to the increase in surface scattering. In contrast, nickel IOs exhibit diffusive-like conduction and have a constant thermal conductivity over this size regime. The quasi-ballistic nature of electron transport at these length scales is modeled considering the inverse opal geometry, surface scattering, and grain boundaries. Understanding the characteristics of electron conduction at the nanoscale is essential to minimizing the total resistance of porous metals for interfacial transport applications, such as the total electrical resistance of battery electrodes and the total thermal resistance of microscale heat exchangers. PMID- 26986051 TI - Performance of Density Functional Theory and Relativistic Effective Core Potential for Ru-Based Organometallic Complexes. AB - Herein a performance assessment of density functionals used for calculating the structural and energetic parameters of bi- and trimetallic Ru-containing organometallic complexes has been performed. The performance of four popular relativistic effective core potentials (RECPs) has also been assessed. On the basis of the calculated results, the MN12-SX (range-separated hybrid functional) demonstrates good performance for calculating the molecular structures, while MN12-L (local functional) performs well for calculating the energetics, including that of the Ru-Ru bond breaking process. The choice of appropriate density functional is a crucial factor for calculating the energetics. The LANL08 demonstrates the lowest performance of the RECPs for calculating the molecular structures, especially the Ru-Ru bond length. PMID- 26986049 TI - Association of interleukin-6 methylation in leukocyte DNA with serum level and the risk of ischemic heart disease. AB - Background Interleukin-6 (IL-6), a multifunctional cytokine, plays an important role in the development of ischemic heart disease (IHD), and DNA hypomethylation of 2 CpGs, located downstream in the proximity of the IL-6 gene promoter, has been associated with risk factor for IHD. This study was to examine the association of blood leukocyte DNA methylation of the 2 CpGs in IL-6 with the risk of IHD and the serum IL-6 level. Methods IL-6 methylation levels of 582 cases and 673 controls were measured using the bisulfite pyrosequencing technology. Serum level of IL-6 was measured using enzyme-linked immunosorbent assay. Results The IL-6 methylation was significantly lower in IHD cases than in the controls, irrespective of CpG site. After multivariate adjustment, lower (< median) average IL-6 methylation was associated with an increased risk of IHD (OR 1.57, 95% CI 1.22-2.02, p < 0.001). Average IL-6 methylation level was inversely associated with serum IL-6 level (beta = -1.02 pg/mL per increase in IL-6 methylation, p = 0.002) among IHD cases. This significant relationship was not observed among controls. Conclusions DNA hypomethylation of IL-6 gene measured in blood leukocytes was associated with increased risk of IHD. IL-6 demethylation may upregulate its expression, whereby exerting its risk effect on the development of IHD. PMID- 26986052 TI - GABARAP activates ULK1 and traffics from the centrosome dependent on Golgi partners WAC and GOLGA2/GM130. AB - WAC and GOLGA2/GM130 are 2 Golgi proteins that affect autophagy; however, their mechanism of action was unknown. We have shown that WAC binding to GOLGA2 at the Golgi displaces GABARAP from GOLGA2 to allow the maintenance of a nonlipidated centrosomal GABARAP pool. Centrosomal GABARAP can traffic to autophagic structures during starvation. In addition GABARAP specifically promotes ULK1 activation and this is independent of GABARAP lipidation but likely requires a LIR-mediated GABARAP-ULK1 interaction. PMID- 26986055 TI - Electromyographic Activity of Scapular Muscle Control in Free-Motion Exercise. AB - CONTEXT: The appropriate resistance intensity to prescribe for shoulder rehabilitative exercise is not completely known. Excessive activation of the deltoid and upper trapezius muscles could be counterproductive for scapulohumeral rhythm during humeral elevation. OBJECTIVE: To identify the effects of different exercise intensities on the scapular muscles during a free-motion "robbery" exercise performed in different degrees of shoulder abduction in seated and standing positions. DESIGN: Descriptive laboratory study. SETTING: Kinesiology Adapted Physical Education Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 15 healthy male college students (age = 20.5 +/- 2.2 years, height = 174.5 +/- 5.3 cm, mass = 63.8 +/- 6.0 kg). INTERVENTION(S): Participants performed 5 repetitions of a randomized exercise sequence of the robbery exercise in 2 body positions (seated, standing), 2 shoulder-abducted positions (W [20 degrees ], 90/90 [90 degrees ]) at 3 intensities (0%, 3%, and 7% body weight). MAIN OUTCOME MEASURE(S): Electromyographic (EMG) activity of the upper trapezius, lower trapezius, serratus anterior, anterior deltoid, and infraspinatus muscles of the upper extremity was collected. All EMG activities were normalized by the maximal voluntary isometric contraction of each corresponding muscle (%). RESULTS: The serratus anterior, anterior deltoid, and infraspinatus EMG activities were greater at 7% body weight in the seated position compared with the standing position (P < .05). The EMG activities in all 5 muscles were greater in the 90/90 position than in the W position (P < .05). CONCLUSIONS: Scapular muscle activity modulated relative to changes in body posture and resistance intensity. These findings will enable clinicians to prescribe the appropriate level of exercise intensity and positioning during shoulder rehabilitation. PMID- 26986058 TI - Correction: Enrollment in HIV Care Two Years after HIV Diagnosis in the Kingdom of Swaziland: An Evaluation of a National Program of New Linkage Procedures. PMID- 26986053 TI - Factors Associated with the Use of Helicopter Inter-facility Transport of Trauma Patients to Tertiary Trauma Centers within an Organized Rural Trauma System. AB - OBJECTIVE: A review of the literature yielded little information regarding factors associated with the decision to use ground (GEMS) or helicopter (HEMS) emergency medical services for trauma patients transferred inter-facility. Furthermore, studies evaluating the impact of inter-facility transport mode on mortality have reported mixed findings. Since HEMS transport is generally reserved for more severely injured patients, this introduces indication bias, which may explain the mixed findings. Our objective was to identify factors at referring non-tertiary trauma centers (NTC) influencing transport mode decision. METHODS: This was a case-control study of trauma patients transferred from a Level III or IV NTC to a tertiary trauma center (TTC) within 24-hours reported to the Oklahoma State Trauma Registry between 2005 and 2012. Multivariable logistic regression was used to determine clinical and non-clinical factors associated with the decision to use HEMS. RESULTS: A total of 7380 patients met the study eligibility. Of these, 2803(38%) were transported inter-facility by HEMS. Penetrating injury, prehospital EMS transport, severe torso injury, hypovolemic shock, and TBI were significant predictors (p<0.05) of HEMS use regardless of distance to a TTC. Association between HEMS use and male gender, Level IV NTC, and local ground EMS resources varied by distance from the TTC. Many HEMS transported patients had minor injuries and normal vital signs. CONCLUSIONS: Our results suggest that while distance remains the most influential factor associated with HEMS use, significant differences exist in clinical and non clinical factors between patients transported by HEMS versus GEMS. To ensure comparability of study groups, studies evaluating outcome differences between HEMS and GEMS should take factors determining transport mode into account. The findings will be used to develop propensity scores to balance baseline risk between GEMS and HEMS patients for use in subsequent studies of outcomes. PMID- 26986056 TI - Structural Pathways between Child Abuse, Poor Mental Health Outcomes and Male Perpetrated Intimate Partner Violence (IPV). AB - BACKGROUND: Violent trauma exposures, including child abuse, are risk factors for PTSD and comorbid mental health disorders. Child abuse experiences of men exacerbate adult male-perpetrated intimate partner violence (IPV). The relationship between child abuse, poor mental health and IPV perpetration is complex but research among the general population is lacking. This study describes the relationship and pathways between history of child abuse exposure and male-perpetrated IPV while exploring the potentially mediating effect of poor mental health. METHODS: We analysed data from a randomly selected, two-stage clustered, cross-sectional household survey conducted with 416 adult men in Gauteng Province of South Africa. We used multinomial regression modelling to identify associated factors and Structural Equation Modelling (SEM) to test the primary hypothesis that poor mental health (defined as abusing alcohol or having PTSD or depressive symptoms) mediates the relationship between child abuse and IPV perpetration. RESULTS: Eighty eight percent of men were physically abused, 55% were neglected, 63% were emotionally abused and 20% were sexually abused at least once in their childhood. Twenty four percent of men had PTSD symptoms, 24% had depressive symptoms and 36% binge drank. Fifty six percent of men physically abused and 31% sexually abused partners at least once in their lifetime. Twenty two percent of men had one episode and 40% had repeat episodes of IPV perpetration. PTSD symptomatology risk increased with severity of child trauma and other trauma. PTSD severity increased the risk for binge drinking. Child trauma, other trauma and PTSD symptomatology increased the severity of depressive symptoms. PTSD symptomatology was comorbid with alcohol abuse and depressive symptoms. Child trauma, having worked in the year before the survey, other trauma and PTSD increased the risk of repeat episodes of IPV perpetration. Highly equitable gender attitudes were protective against single and repeat episodes of IPV perpetration. There was a direct path between the history of child trauma and IPV perpetration and three other indirect paths showing the mediating effects of PTSD, other trauma and gender attitudes. CONCLUSIONS: Child trauma is a risk factor for both poor mental health and male-perpetrated IPV among men in Gauteng. Male-perpetrated IPV in these settings should be explained through a combination of the Trauma, Feminist, and Intergenerational Transmission of Family Violence theories. Prevention interventions for male- perpetrated IPV in South Africa need to incorporate strategies and therapies to address poor mental health conditions. PMID- 26986057 TI - Specific Monoclonal Antibody Overcomes the Salmonella enterica Serovar Typhimurium's Adaptive Mechanisms of Intramacrophage Survival and Replication. AB - Salmonella-specific antibodies play an important role in host immunity; however, the mechanisms of Salmonella clearance by pathogen-specific antibodies remain to be completely elucidated since previous studies on antibody-mediated protection have yielded inconsistent results. These inconsistencies are at least partially attributable to the use of polyclonal antibodies against Salmonella antigens. Here, we developed a new monoclonal antibody (mAb)-449 and identified its related immunogen that protected BALB/c mice from infection with Salmonella enterica serovar Typhimurium. In addition, these data indicate that the mAb-449 immunogen is likely a major protective antigen. Using in vitro infection studies, we also analyzed the mechanism by which mAb-449 conferred host protection. Notably, macrophages infected with mAb-449-treated S. Typhimurium showed enhanced pathogen uptake compared to counterparts infected with control IgG-treated bacteria. Moreover, these macrophages produced elevated levels of pro-inflammatory cytokine TNFalpha and nitric oxide, indicating that mAb-449 enhanced macrophage activation. Finally, the number of intracellular bacteria in mAb-449-activated macrophages decreased considerably, while the opposite was found in IgG-treated controls. Based on these findings, we suggest that, although S. Typhimurium has the potential to survive and replicate within macrophages, host production of a specific antibody can effectively mediate macrophage activation for clearance of intracellular bacteria. PMID- 26986059 TI - Percutaneous Mitral Valve Repair in Mitral Regurgitation Reduces Cell-Free Hemoglobin and Improves Endothelial Function. AB - BACKGROUND AND OBJECTIVE: Endothelial dysfunction is predictive for cardiovascular events and may be caused by decreased bioavailability of nitric oxide (NO). NO is scavenged by cell-free hemoglobin with reduction of bioavailable NO up to 70% subsequently deteriorating vascular function. While patients with mitral regurgitation (MR) suffer from an impaired prognosis, mechanisms relating to coexistent vascular dysfunctions have not been described yet. Therapy of MR using a percutaneous mitral valve repair (PMVR) approach has been shown to lead to significant clinical benefits. We here sought to investigate the role of endothelial function in MR and the potential impact of PMVR. METHODS AND RESULTS: Twenty-seven patients with moderate-to-severe MR treated with the MitraClip(r) device were enrolled in an open-label single-center observational study. Patients underwent clinical assessment, conventional echocardiography, and determination of endothelial function by measuring flow mediated dilation (FMD) of the brachial artery using high-resolution ultrasound at baseline and at 3-month follow-up. Patients with MR demonstrated decompartmentalized hemoglobin and reduced endothelial function (cell-free plasma hemoglobin in heme 28.9+/-3.8 MUM, FMD 3.9+/-0.9%). Three months post-procedure, PMVR improved ejection fraction (from 41+/-3% to 46+/-3%, p = 0.03) and NYHA functional class (from 3.0+/-0.1 to 1.9+/-1.7, p<0.001). PMVR was associated with a decrease in cell free plasma hemoglobin (22.3+/-2.4 MUM, p = 0.02) and improved endothelial functions (FMD 4.8+/-1.0%, p<0.0001). CONCLUSION: We demonstrate here that plasma from patients with MR contains significant amounts of cell-free hemoglobin, which is accompanied by endothelial dysfunction. PMVR therapy is associated with an improved hemoglobin decompartmentalization and vascular function. PMID- 26986060 TI - The association of gender, age, and intelligence with neuropsychological functioning in young typically developing children: The Generation R study. AB - Although early childhood is a period of rapid neurocognitive development, few studies have assessed neuropsychological functioning in various cognitive domains in young typically developing children. Also, results regarding its association with gender and intelligence are mixed. In 853 typically developing children aged 6 to 10 years old, the association of gender, age, and intelligence with neuropsychological functioning in the domains of attention, executive functioning, language, memory, sensorimotor functioning, and visuospatial processing was explored. Clear positive associations with age were observed. In addition, gender differences were found and showed that girls generally outperformed boys, with the exception of visuospatial tasks. Furthermore, IQ was positively associated with neuropsychological functioning, which was strongest in visuospatial tasks. Performance in different neuropsychological domains was associated with age, gender, and intelligence in young typically developing children, and these factors should be taken into account when assessing neuropsychological functioning in clinical or research settings. PMID- 26986061 TI - Pre-cut Filter Paper for Detecting Anti-Japanese Encephalitis Virus IgM from Dried Cerebrospinal Fluid Spots. AB - BACKGROUND: The use of filter paper as a simple, inexpensive tool for storage and transportation of blood, 'Dried Blood Spots' or Guthrie cards, for diagnostic assays is well-established. In contrast, there are a paucity of diagnostic evaluations of dried cerebrospinal fluid (CSF) spots. These have potential applications in low-resource settings, such as Laos, where laboratory facilities for central nervous system (CNS) diagnostics are only available in Vientiane. In Laos, a major cause of CNS infection is Japanese encephalitis virus (JEV). We aimed to develop a dried CSF spot protocol and to evaluate its diagnostic performance using the World Health Organisation recommended anti-JEV IgM antibody capture enzyme-linked immunosorbent assay (JEV MAC-ELISA). METHODOLOGY AND PRINCIPAL FINDINGS: Sample volumes, spotting techniques and filter paper type were evaluated using a CSF-substitute of anti-JEV IgM positive serum diluted in Phosphate Buffer Solution (PBS) to end-limits of detection by JEV MAC-ELISA. A conventional protocol, involving eluting one paper punch in 200 MUl PBS, did not detect the end-dilution, nor did multiple punches utilising diverse spotting techniques. However, pre-cut filter paper enabled saturation with five times the volume of CSF-substitute, sufficiently improving sensitivity to detect the end dilution. The diagnostic accuracy of this optimised protocol was compared with routine, neat CSF in a pilot, retrospective study of JEV MAC-ELISA on consecutive CSF samples, collected 2009-15, from three Lao hospitals. In comparison to neat CSF, 132 CSF samples stored as dried CSF spots for one month at 25-30 degrees C showed 81.6% (65.7-92.3 95%CI) positive agreement, 96.8% (91.0-99.3 95%CI) negative agreement, with a kappa coefficient of 0.81 (0.70-0.92 95%CI). CONCLUSIONS/SIGNIFICANCE: The novel design of pre-cut filter paper saturated with CSF could provide a useful tool for JEV diagnostics in settings with limited laboratory access. It has the potential to improve national JEV surveillance and inform vaccination policies. The saturation of filter paper has potential use in the wider context of pathogen detection, including dried spots for detecting other analytes in CSF, and other body fluids. PMID- 26986064 TI - Analysis of the Velocity Distribution in Partially-Filled Circular Pipe Employing the Principle of Maximum Entropy. AB - The flow velocity distribution in partially-filled circular pipe was investigated in this paper. The velocity profile is different from full-filled pipe flow, since the flow is driven by gravity, not by pressure. The research findings show that the position of maximum flow is below the water surface, and varies with the water depth. In the region of near tube wall, the fluid velocity is mainly influenced by the friction of the wall and the pipe bottom slope, and the variation of velocity is similar to full-filled pipe. But near the free water surface, the velocity distribution is mainly affected by the contractive tube wall and the secondary flow, and the variation of the velocity is relatively small. Literature retrieval results show relatively less research has been shown on the practical expression to describe the velocity distribution of partially filled circular pipe. An expression of two-dimensional (2D) velocity distribution in partially-filled circular pipe flow was derived based on the principle of maximum entropy (POME). Different entropies were compared according to fluid knowledge, and non-extensive entropy was chosen. A new cumulative distribution function (CDF) of partially-filled circular pipe velocity in terms of flow depth was hypothesized. Combined with the CDF hypothesis, the 2D velocity distribution was derived, and the position of maximum velocity distribution was analyzed. The experimental results show that the estimated velocity values based on the principle of maximum Tsallis wavelet entropy are in good agreement with measured values. PMID- 26986062 TI - In Situ Staining and Laser Capture Microdissection of Lymph Node Residing SIV Gag Specific CD8+ T cells--A Tool to Interrogate a Functional Immune Response Ex Vivo. AB - While a plethora of data describes the essential role of systemic CD8+ T cells in the control of SIV replication little is known about the local in situ CD8+ T cell immune responses against SIV at the intact tissue level, due to technical limitations. In situ staining, using GagCM9 Qdot 655 multimers, were here combined with laser capture microdissection to detect and collect SIV Gag CM9 specific CD8+ T cells in lymph node tissue from SIV infected rhesus macaques. CD8+ T cells from SIV infected and uninfected rhesus macaques were also collected and compared to the SIV GagCM9 specific CD8+ T cells. Illumina bead array and transcriptional analyses were used to assess the transcriptional profiles and the three different CD8+ T cell populations displayed unique transcriptional patterns. This pilot study demonstrates that rapid and specific immunostaining combined with laser capture microdissection in concert with transcriptional profiling may be used to elucidate phenotypic differences between CD8+ T cells in SIV infection. Such technologies may be useful to determine differences in functional activities of HIV/SIV specific T cells. PMID- 26986063 TI - Morbidity and Mortality in 7,684 Women According to Personal Hair Dye Use: The Copenhagen City Heart Study followed for 37 Years. AB - BACKGROUND: Permanent hair dye contains aromatic amines which are carcinogenic, and can cause allergic skin reactions. In the long term personal use of hair dye might therefore influence both morbidity and mortality. OBJECTIVES: We tested the hypothesis that personal use of hair dye in women is associated with increased morbidity and mortality in the general population. METHODS: We included 7,684 women from the Copenhagen City Heart Study with information on the use of personal hair dye. We assessed the risk of cancer, skin diseases, other morbidities, and mortality during a median follow-up of 27 years (range 0-37). RESULTS: The multivariable adjusted hazard ratio for malignant melanoma in women with versus without personal use of hair dye was 2.07 (95% confidence interval 1.25-3.42). There was no increased risk of other cancer types. For other skin diseases and other major causes of morbidity we found no differences between the two groups, except for a minor excess of digestive diseases and increased risk of Parkinson's disease among women using hair dye. Finally, we found no difference in all-cause mortality comparing women using personal hair dye or not. After correction for multiple comparisons, none of the results remained significant. However, in sensitivity analysis the excess risk of malignant melanoma remained increased with a hazard ratio of 2.58 (95%CI 1.33-5.03) among users of personal hair dye. CONCLUSIONS: Personal use of hair dye does not have major influences on morbidity and mortality. Our finding of a 2-fold risk of malignant melanoma in women using hair dye is hypothesis generating. PMID- 26986067 TI - Adverse events following immunization: real causality and myths. AB - INTRODUCTION: To assure the highest safety of immunization programs, detect adverse events following immunization (AEFIs), eliminate concerns, and reduce the risk of low vaccination coverage, authorities in industrialized countries have collected years of reports of suspected AEFIs and have systematically assessed their clinical importance. AREAS COVERED: In this paper, the methods used to assess vaccine safety and the results obtained by the analysis of reports, studies, and meta-analyses are discussed. EXPERT OPINION: Severe AEFIs are rare, and all evaluations of safety of vaccines recommended for both children and adults have demonstrated that the advantages of vaccines are always significantly higher than the problems that they cause, and there is no need to modify recommendations. However, the definition of AEFI is dependent on the vaccines themselves, complicating the definition of an AEFI and explaining why doubts and concerns have been raised. Presently, disease epidemiology data collected in healthy people and in subjects with underlying disease, general vaccine coverage, and the vaccination status of subjects with AEFIs are managed by many independent institutions. Only strict co-operation between these institutions will lead to the successful identification of AEFIs and to a reduction of the weight of anti vaccine arguments. PMID- 26986065 TI - Anti-Retroviral Therapy Increases the Prevalence of Dyslipidemia in South African HIV-Infected Patients. AB - PURPOSE: Data on the prevalence of dyslipidaemia and associated risk factors in HIV-infected patients from sub-Saharan Africa is sparse. We performed a cross sectional analysis in a cohort of HIV-infected South African adults. METHODS: We studied HIV-infected patients who were either antiretroviral therapy (ART)-naive or receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based or protease inhibitor (PI)-based ART. Evaluation included fasting lipograms, oral glucose tolerance tests and clinical anthropometry. Dyslipidemia was defined using the NCEP ATPIII guidelines. RESULTS: The median age of the participants was 34 years (range 19-68 years) and 78% were women. The prevalence of dyslipidemia in 406 ART-naive and 551 participants on ART was 90.0% and 85%, respectively. Low HDL-cholesterol (HDLC) was the most common abnormality [290/406 (71%) ART-naive and 237/551 (43%) ART- participants]. Participants on ART had higher triglycerides (TG), total cholesterol (TC), LDL-cholesterol (LDLC) and HDLC than the ART-naive group. Severe dyslipidaemia, (LDLC> 4.9 mmol/L or TG >5.0 mmol/L) was present in <5% of participants. In multivariate analyses there were complex associations between age, gender, type and duration of ART and body composition and LDLC, HDLC and TG, which differed between ART-naive and ART-participants. CONCLUSION: Participants on ART had higher TG, TC, LDLC and HDLC than those who were ART-naive but severe lipid abnormalities requiring evaluation and treatment were uncommon. PMID- 26986066 TI - Muscle Damage following Maximal Eccentric Knee Extensions in Males and Females. AB - AIM: To investigate whether there is a sex difference in exercise induced muscle damage. MATERIALS AND METHOD: Vastus Lateralis and patella tendon properties were measured in males and females using ultrasonography. During maximal voluntary eccentric knee extensions (12 reps x 6 sets), Vastus Lateralis fascicle lengthening and maximal voluntary eccentric knee extensions torque were recorded every 10 degrees of knee joint angle (20-90 degrees ). Isometric torque, Creatine Kinase and muscle soreness were measured pre, post, 48, 96 and 168 hours post damage as markers of exercise induced muscle damage. RESULTS: Patella tendon stiffness and Vastus Lateralis fascicle lengthening were significantly higher in males compared to females (p<0.05). There was no sex difference in isometric torque loss and muscle soreness post exercise induced muscle damage (p>0.05). Creatine Kinase levels post exercise induced muscle damage were higher in males compared to females (p<0.05), and remained higher when maximal voluntary eccentric knee extension torque, relative to estimated quadriceps anatomical cross sectional area, was taken as a covariate (p<0.05). CONCLUSION: Based on isometric torque loss, there is no sex difference in exercise induced muscle damage. The higher Creatine Kinase in males could not be explained by differences in maximal voluntary eccentric knee extension torque, Vastus Lateralis fascicle lengthening and patella tendon stiffness. Further research is required to understand the significant sex differences in Creatine Kinase levels following exercise induced muscle damage. PMID- 26986069 TI - Young Male Patients with Atrial Fibrillation and CHA2DS2-VASc Score of 1 May Not Need Anticoagulants: A Nationwide Population-Based Study. AB - BACKGROUND: It is unclear whether oral anticoagulants are beneficial for atrial fibrillation (AF) patients with low CHA2DS2-VASc score. Age could be important in determining the risk of thromboembolism in low risk AF patients (CHA2DS2-VASc score of 1 for male or 2 for female). METHODS: The Taiwan National Health Insurance Research Database (NHIRD) was used and 27,521 AF patients with CHA2DS2 VASc score of 1 (male) or 2 (female) not receiving anticoagulants were acquired as the study cohort, which were classified into three age groups: 20-49, 50-64, and 65-74 years. The clinical endpoint was the occurrence of ischemic thromboembolism within one year of follow up. RESULTS: During the follow-up of 0.94 +/- 0.19 years, 385 (2.19%) male patients experienced ischemic thromboembolism, with annual rate of 2.32%. The annual risk ranged from 1.29%, 2.43% to 2.77% for male patients aged 20-49, 50-64 and 65-74 years respectively. Of the female patients, 218 (2.20%) experienced clinical event with annual rate of 2.32%. The annual risk increased from 1.87%, 2.28% to 2.64% for female patients aged 20-49, 50-64 and 65-74 years respectively. There was no difference in risk between the male patients aged 20-49 years with CHA2DS2-VASc score of 1 and overall male patients with CHA2DS2-VASc score of 0. (P = 0.631) The female patients aged 20-49 years with CHA2DS2-VASc score of 2 was associated with a higher risk of thromboembolic events than overall female patients with CHA2DS2 VASc score of 1 (HR = 1.93; P = 0.008). CONCLUSIONS: Age is important in determining the risk of thromboembolism in AF patients with single risk factor. In male patients <50 years old with CHA2DS2-VASc score of 1, the risk of ischemic thromboembolism was low. Considering the benefits and the risk of bleeding, oral anticoagulation therapy may not be favorable in these patients. PMID- 26986068 TI - The metabolic interaction of cancer cells and fibroblasts - coupling between NAD(P)H and FAD, intracellular pH and hydrogen peroxide. AB - Alteration in the cellular energy metabolism is a principal feature of tumors. An important role in modifying cancer cell metabolism belongs to the cancer associated fibroblasts. However, the regulation of their interaction has been poorly studied to date. In this study we monitored the metabolic status of both cell types by using the optical redox ratio and the fluorescence lifetimes of the metabolic co-factors NAD(P)H and FAD, in addition to the intracellular pH and the hydrogen peroxide levels in the cancer cells, using genetically encoded sensors. In the co-culture of human cervical carcinoma cells HeLa and human fibroblasts we observed a metabolic shift from oxidative phosphorylation toward glycolysis in cancer cells, and from glycolysis toward OXPHOS in fibroblasts, starting from Day 2 of co-culturing. The metabolic switch was accompanied by hydrogen peroxide production and slight acidification of the cytosol in the cancer cells in comparison with that of the corresponding monoculture. Therefore, our HeLa-huFb system demonstrated metabolic behavior similar to Warburg type tumors. To our knowledge, this is the first time that these 3 parameters have been investigated together in a model of tumor-stroma co-evolution. We propose that determination of the start-point of the metabolic alterations and understanding of the mechanisms of their realization can open a new ways for cancer treatment. PMID- 26986070 TI - Characterization of Disease-Associated Mutations in Human Transmembrane Proteins. AB - Transmembrane protein coding genes are commonly associated with human diseases. We characterized disease causing mutations and natural polymorphisms in transmembrane proteins by mapping missense genetic variations from the UniProt database on the transmembrane protein topology listed in the Human Transmembrane Proteome database. We found characteristic differences in the spectrum of amino acid changes within transmembrane regions: in the case of disease associated mutations the non-polar to non-polar and non-polar to charged amino acid changes are equally frequent. In contrast, in the case of natural polymorphisms non-polar to charged amino acid changes are rare while non-polar to non-polar changes are common. The majority of disease associated mutations result in glycine to arginine and leucine to proline substitutions. Mutations to positively charged amino acids are more common in the center of the lipid bilayer, where they cause more severe structural and functional anomalies. Our analysis contributes to the better understanding of the effect of disease associated mutations in transmembrane proteins, which can help prioritize genetic variations in personal genomic investigations. PMID- 26986072 TI - Cultural scripts surrounding young people's sexual and romantic relationships in the Western Highlands of Guatemala. AB - Guatemala has one of the world's highest teenage pregnancy rates and 92% of young people report not using contraception for first sex. We conducted narrative-based thematic analysis of a sample of narratives (n = 40; 15 male-authored, 25 female authored) on HIV and sexuality, submitted to a 2013 scriptwriting competition by young people aged 15-19 years from Guatemala's Western Highlands. Our objective was to identify dominant cultural scripts and narratives that deviated positively from that norm with a view to informing the development of educational curricula and communication materials promoting youth sexual and reproductive health. The narratives are characterised by romantic themes and melodramatic plotlines: three in four had tragic endings. Rigid gender norms and ideologies of enduring love make female characters blind to the potential consequences of unprotected sex and vulnerable to betrayal and abandonment. Unprotected sex is the norm, with contraception and sexually transmitted infection protection mentioned rarely. In the four positively deviant narratives, female and male characters' interaction is based on mutual respect, dialogue and genuine affection. The narratives reveal opportunities for action to increase sexual health knowledge and access to services and to challenge harmful cultural scripts, potentially by leveraging the positive value attached to romantic love by authors of both sexes. PMID- 26986071 TI - Improvement of Rice Biomass Yield through QTL-Based Selection. AB - Biomass yield of rice (Oryza sativa L.) is an important breeding target, yet it is not easy to improve because the trait is complex and phenotyping is laborious. Using progeny derived from a cross between two high-yielding Japanese cultivars, we evaluated whether quantitative trait locus (QTL)-based selection can improve biomass yield. As a measure of biomass yield, we used plant weight (aboveground parts only), which included grain weight and stem and leaf weight. We measured these and related traits in recombinant inbred lines. Phenotypic values for these traits showed a continuous distribution with transgressive segregation, suggesting that selection can affect plant weight in the progeny. Four significant QTLs were mapped for plant weight, three for grain weight, and five for stem and leaf weight (at alpha = 0.05); some of them overlapped. Multiple regression analysis showed that about 43% of the phenotypic variance of plant weight was significantly explained (P < 0.0001) by six of the QTLs. From F2 plants derived from the same parental cross as the recombinant inbred lines, we divergently selected lines that carried alleles with positive or negative additive effects at these QTLs, and performed successive selfing. In the resulting F6 lines and parents, plant weight significantly differed among the genotypes (at alpha = 0.05). These results demonstrate that QTL-based selection is effective in improving rice biomass yield. PMID- 26986073 TI - MiR-99a regulates ROS-mediated invasion and migration of lung adenocarcinoma cells by targeting NOX4. AB - miR-99a is frequently downregulated in various types of human malignancies including lung adenocarcinoma. Recent studies have reported that miR-99a regulates cell growth and cell cycle progression by targeting mTOR, AKT1 and FGFR3. However, the underlying mechanisms involved in the modulation of invasion and migration by miR-99a remain elusive. In this study, we analyzed the relationship between the expression of miR-99a and clinical stage or metastasis in 90 matched lung adenocarcinoma and adjacent non-tumor lung tissues. Downregulation of miR-99a was significantly associated with advanced stage and tumor metastasis in lung adenocarcinoma patients, and it was found to be a poor prognostic factor in lung adenocarcinoma. Furthermore, functional experiments found that overexpression of miR-99a inhibited the proliferation, migration and invasion of lung adenocarcinoma A549 and Calu3 cells in vitro. We then identified NOX4 as a target gene of miR-99a and NOX4 mediated the inhibition of invasion and migration of lung adenocarcinoma cells by miR-99a. By targeting NOX4-mediated ROS production, miR-99a regulated the invasion and migration of lung adenocarcinoma cells. Moreover, overexpression of miR-99a significantly inhibited tumor growth in vivo. Immunohistochemical staining analysis of the mouse tumor tissues revealed that NOX4 levels were downregulated in the miR-99a treatment group, confirming the in vitro data of NOX4 as a direct target gene of miR-99a. Taken together, these data indicate for the first time that miR-99a directly regulates the invasion and migration in lung adenocarcinoma by targeting NOX4 and that overexpression of miR-99a may become a therapeutic strategy for lung adenocarcinoma. PMID- 26986077 TI - Intracultural Differences in Local Botanical Knowledge and Knowledge Loss among the Mexican Isthmus Zapotecs. AB - This study reports on the socio-demographic and locality factors that influence ethnobiological knowledge in three communities of Zapotec indigenous people of the Isthmus of Tehuantepec, Mexico. It uses local botanical nomenclature as a proxy for general ethnobiological knowledge. In each of these communities (one urban and two rural), 100 adult men were interviewed aided with a field herbarium. Fifty had a background in farming, and 50 worked in the secondary or tertiary sector as their main economic activity, totaling 300 interviews. Using a field herbarium with samples of 30 common and rare wild regional species, we documented visual recognition, knowledge of the local life form, generic and specific names and uses (five knowledge levels measuring knowledge depth). The relationship between sociodemographic variables and knowledge was analyzed with simple correlations. Differences between the three communities and the five knowledge levels were then evaluated with a discriminant analysis. A general linear analysis identified factors and covariables that influenced the observed differences. Differences between the groups with different economic activities were estimated with a t-test for independent samples. Most of the relationships found between sociodemographic variables and plant knowledge were expected: age and rurality were positively related with knowledge and years of formal schooling was negatively related. However, the somewhat less rural site had more traditional knowledge due to local circumstances. The general linear model explained 70-77% of the variation, a high value. It showed that economic activity was by far the most important factor influencing knowledge, by a factor of five. The interaction of locality and economic activity followed. The discriminant analysis assigned interviewees correctly to their localities in 94% of the cases, strengthening the evidence for intracultural variation. Both sociodemographic and historic intracultural differences heavily influence local knowledge. PMID- 26986078 TI - Earlier Initiation of Therapeutic Hypothermia by Non-Tertiary Neonatal Units in Victoria, Australia. AB - BACKGROUND: Therapeutic hypothermia is an effective treatment for moderate or severe hypoxic-ischaemic encephalopathy (HIE), with maximal neuroprotective benefit when initiated soon after birth. Early initiation of therapeutic hypothermia in infants with HIE born in geographically distant settings is challenging. OBJECTIVE: To audit temperature control in infants with HIE treated with hypothermia during neonatal transport in Victoria, Australia. METHODS: A retrospective database review from September 1, 2008 to August 31, 2012 compared temperatures of transported outborn infants with HIE treated with hypothermia initiated by the referring non-tertiary neonatal unit, with hypothermia initiated by the transport team. RESULTS: 123 infants received therapeutic hypothermia during the study period. Hypothermia treatment commenced significantly earlier [median (interquartile range [IQR]) 1.1 h (0.6-1.7) vs. 3.3 h (2.1-4.5); p < 0.01] with the target temperature (33-34 degrees C) achieved sooner [median (IQR) 3.4 h (2.4-4.6) vs. 4.5 h (3.6-5.5)] when initiated by the referring hospital (n = 71) than by the transport team (n = 52). There was no statistically significant difference in achieving the target temperature before admission to the tertiary neonatal intensive care unit when hypothermia was initiated by the referring unit, compared with by the transport team [51/71 (71.8%) vs. 28/52 (53.9%), odds ratio (95% CI) 2.19 (0.96, 4.96)]. Infants in whom hypothermia was initiated by the referring hospital were more likely to have a recorded temperature below 33 degrees C [22/71 (31.0%) vs. 4/52 (7.7%), odds ratio (95% CI) 5.39 (1.64, 22.83)]. CONCLUSIONS: The target temperature is achieved sooner in infants with moderate or severe HIE when therapeutic hypothermia is initiated by referring non tertiary neonatal units under guidance from the regional transport service. This practice may enhance neuroprotection for infants with HIE born in non-tertiary units, particularly in remote locations. PMID- 26986079 TI - NaF Inhibits Matrix-Bound Cathepsin-Mediated Dentin Matrix Degradation. AB - Matrix metalloproteinases (MMPs) and cysteine cathepsins (CCs) degrade the collagen fibrils of demineralized dentin. Sodium fluoride (NaF) has previously been shown to inhibit recombinant MMP-2 and MMP-9. This study aimed to evaluate the efficacy of NaF on the inhibition of dentin-bound MMPs and CCs. Dentin beams were completely demineralized in 10% phosphoric acid. The baseline total MMP activity and dry masses were measured. Beams were assigned to test groups based on similar MMP activity and dry mass (n = 10/group), and incubated in artificial saliva (control) or artificial saliva with NaF containing 6-238 mM fluoride for 1, 7 and 21 days. The dry mass loss and MMP activities were reassessed at each time point. The proteolytic activity was screened by gelatin zymography. ICTP and CTX released to the incubation medium were analyzed as indices of MMP and cathepsin K activity, respectively. The beams were examined under scanning electron microscopy. All NaF doses reduced the dry mass loss after 21 days (p < 0.05). NaF inhibition of the total MMP activity ranged between 5 and 80%. In gelatin zymography, the bands of MMP-2 and MMP-9 became less prominent with increasing NaF levels. NaF did not decrease the released ICTP (p > 0.05). Less CTX release was detected with F >=179 mM (p < 0.05). CaF2-like minerals were observed on the beams. High levels of NaF may slow the degradation of the dentin matrix due to the inhibition of cathepsin K. Fluoride does not seem effective in the direct inhibition of proteolysis by dentin matrix-bound MMPs. PMID- 26986080 TI - Reliability generalization of the Multigroup Ethnic Identity Measure-Revised (MEIM-R). AB - [Correction Notice: An Erratum for this article was reported in Vol 63(5) of Journal of Counseling Psychology (see record 2016-33161-001). The name of author Erika Feinauer was misspelled as Erika Feinhauer. All versions of this article have been corrected.] Individuals' strength of ethnic identity has been linked with multiple positive indicators, including academic achievement and overall psychological well-being. The measure researchers use most often to assess ethnic identity, the Multigroup Ethnic Identity Measure (MEIM), underwent substantial revision in 2007. To inform scholars investigating ethnic identity, we performed a reliability generalization analysis on data from the revised version (MEIM-R) and compared it with data from the original MEIM. Random-effects weighted models evaluated internal consistency coefficients (Cronbach's alpha). Reliability coefficients for the MEIM-R averaged alpha = .88 across 37 samples, a statistically significant increase over the average of alpha = .84 for the MEIM across 75 studies. Reliability coefficients for the MEIM-R did not differ across study and participant characteristics such as sample gender and ethnic composition. However, consistently lower reliability coefficients averaging alpha = .81 were found among participants with low levels of education, suggesting that greater attention to data reliability is warranted when evaluating the ethnic identity of individuals such as middle-school students. Future research will be needed to ascertain whether data with other measures of aspects of personal identity (e.g., racial identity, gender identity) also differ as a function of participant level of education and associated cognitive or maturation processes. (PsycINFO Database Record PMID- 26986082 TI - Influence of material stretchability on the equilibrium shape of a Mobius band. AB - We use a two-dimensional discrete, lattice-based model to show that Mobius bands made with stretchable materials are less likely to crease or tear. This stems from a delocalization of twisting strain that occurs if stretching is allowed. The associated low-energy configurations provide strategic target shapes for the guided assembly of nanometer and micron scale Mobius bands. To predict macroscopic band shapes for a given material, we establish a connection between stretchability and relevant continuum moduli, leading to insight regarding the practical feasibility of synthesizing Mobius bands from materials with continuum parameters that can be measured experimentally or estimated by upscale averaging. PMID- 26986081 TI - MicroRNA-335-5p inhibits osteoblast apoptosis induced by high glucose. AB - Diabetic osteoporosis represents a serious health condition with increasing incidence. Previous studies have shown that microRNA (miR)-335-5p is highly expressed in MC3T3-E1 osteoblasts and promotes their differentiation via downregulating the expression of dickkopf-1 (DKK1). The present study investigated the effects of miR-335-5p on apoptosis of osteoblasts induced by high glucose (HG), as well as the underlying molecular mechanisms. MC3T3-E1 osteoblasts were transfected with miR-335-5p mimics or control miR and cultured under HG conditions for seven days. Reverse-transcription PCR and showed that, compared with the control group, the expression levels of miR-335-5p were significantly downregulated in the HG group. However, no significant differences were observed in the mRNA expression levels of DKK1 between these groups. Furthermore, flow cytometric analysis showed that the apoptotic rate was increased by >2-fold in the HG group compared with that in the control group, while miR-335-5p overexpression significantly decreased the apoptotic rate in these model cells by ~40%. In addition, western blot analysis revealed that the protein expression levels of DKK1 and caspase-3 were significantly elevated in the HG group, which was significantly inhibited by overexpression of miR-335-5p. These results may indicate that miR-335-5p overexpression inhibited HG-induced apoptosis of MC3T3-E1 osteoblasts through decreasing the protein expression levels of DKK1. The results of the present study suggested that miR-335-5p may represent a potential target for the treatment of diabetic osteoporosis. PMID- 26986083 TI - Adipose tissue-derived stem cells promote the reversion of non-alcoholic fatty liver disease: An in vivo study. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver injury and seriously affects human health. In the present study, we aimed to investigate whether adipose tissue-derived stem cell (ADSC) transplantation in combination with dietary modification was capable of reversing the progression of NAFLD. After establishing a rat model of NAFLD by feeding them a high-fat diet (HFD), ADSCs were transplanted via the portal vein into rats with HFD-induced NAFLD, and simultaneously fed a modified diet. Thereafter, gross liver morphology, the hepatosomatic (HSI) index and indicators of liver function, including alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) were evaluated. Subsequently, the serum levels of total cholesterol (TC), triglycerides (TGs) and fatty acids (FAs) were also assayed. Furthermore, H&E and oil red O staining were used to confirm the pathological effects of NAFLD in the rat livers. Although dietary modification alone caused liver function to recover, ADSC transplantation in combination with dietary modification further decreased the HSI index, the serum levels of ALT, TBIL, TC, TGs, FAs, reduced lipid accumulation to normal levels, and reversed the hepatic pathological changes in the rat livers. Taken together, these findings suggest that ADSC transplantation assists in the reversion of NAFLD by improving liver function and promoting lipid metabolism, thereby exerting hepatoprotective effects. Thus, we suggest that ADSC transplantation is a promising, potential therapeutic strategy for NAFLD treatment. PMID- 26986084 TI - Cantharidin inhibits cell proliferation and induces apoptosis through G2/M phase cell cycle arrest in hepatocellular carcinoma stem cells. AB - The present study was designed to investigate the effect of cantharidin on cell proliferation, ability of selfrenewal, cell cycle arrest and induction of apoptosis in HepG2 hepatocellular carcinoma stem cells (HCSCs). It was observed that cantharidin treatment exhibited dose- and time-dependent inhibitory effect on the viability of HCSCs. The inhibition of cell viability by cantharidin in HepG2 CD133+ and parental cells was significant at the concentration 5 and 15 uM, respectively after 48 h. Cantharidin treatment inhibited the self-renewal ability of the HCSCs and the expression of beta-catenin and cyclin D1. Flow cytometry revealed that cantharidin treatment at 5 uM concentration significantly increased the cell population in G2/M phase and decreased the population in the G1 phase. Cantharidin treatment in the HCSCs for 48 h increased expression of histone H2AX, Myt1, cyclin A2, cyclin B1, p53 and cdc2 (Tyr15) phosphorylation significantly compared to the parental cells. Exposure of the HCSCs to cantharidin for 48 h at a concentration of 5 uM caused a significant increase in the proportion of apoptotic cells. Therefore, cantharidin is a promising agent for the hepatocellular carcinoma treatment. PMID- 26986085 TI - Impact of surface porosity and topography on the mechanical behavior of high strength biomedical polymers. AB - The ability to control the surface topography of orthopedic implant materials is desired to improve osseointegration but is often at the expense of mechanical performance in load bearing environments. Here we investigate the effects of surface modifications, roughness and porosity, on the mechanical properties of a set of polymers with diverse chemistry and structure. Both roughness and surface porosity resulted in samples with lower strength, failure strain and fatigue life due to stress concentrations at the surface; however, the decrease in ductility and fatigue strength were greater than the decrease in monotonic strength. The fatigue properties of the injection molded polymers did not correlate with yield strength as would be traditionally observed in metals. Rather, the fatigue properties and the capacity to maintain properties with the introduction of surface porosity correlated with the fracture toughness of the polymers. Polymer structure impacted the materials relative capacity to maintain monotonic and cyclic properties in the face of surface texture and porosity. Generally, amorphous polymers with large ratios of upper to lower yield points demonstrated a more significant drop in ductility and fatigue strength with the introduction of porosity compared to crystalline polymers with smaller ratios in their upper to lower yield strength. The latter materials have more effective dissipation mechanisms to minimize the impact of surface porosity on both monotonic and cyclic damage. PMID- 26986086 TI - Molecular modeling and snake venom phospholipase A2 inhibition by phenolic compounds: Structure-activity relationship. AB - In our earlier study, we have reported that a phenolic compound 2-hydroxy-4 methoxybenzaldehyde from Janakia arayalpatra root extract was active against Viper and Cobra envenomations. Based on the structure of this natural product, libraries of synthetic structurally variant phenolic compounds were studied through molecular docking on the venom protein. To validate the activity of eight selected compounds, we have tested them in in vivo and in vitro models. The compound 21 (2-hydroxy-3-methoxy benzaldehyde), 22 (2-hydroxy-4 methoxybenzaldehyde) and 35 (2-hydroxy-3-methoxybenzylalcohol) were found to be active against venom-induced pathophysiological changes. The compounds 20, 15 and 35 displayed maximum anti-hemorrhagic, anti-lethal and PLA2 inhibitory activity respectively. In terms of SAR, the presence of a formyl group in conjunction with a phenolic group was seen as a significant contributor towards increasing the antivenom activity. The above observations confirmed the anti-venom activity of the phenolic compounds which needs to be further investigated for the development of new anti-snake venom leads. PMID- 26986087 TI - Metal exposure in cows grazing pasture contaminated by iron industry: Insights from magnetic particles used as tracers. AB - Magnetic particles (MP) emitted by an iron smelter were used to investigate the exposure of cows grazing on a grassland polluted by these MP and by large amounts of potentially toxic elements (PTE). The morphology as well as the chemical composition of the MP separated from cow dung were studied. Large amounts of typical MP were found (1.1 g kg(-1) dry weight) in the cow dung sampled from the exposed site, whereas these particles were absent from the reference unpolluted site. The ingested MP were mainly technogenic magnetic particles (TMP) emitted by the smelter. Considering the MP concentration in the grazed grass on the exposed site, it was concluded that cows absorb the MP not only from the grass but also from the soil surface. The results of a mild acidic leaching of the MP suggested that the particles were possibly submitted to a superficial dissolution in the abomasum, pointing at a potential route of transfer of the PTE originating from the TMP and leading into food chains. TMP were only a small part of the anthropogenic contamination having affected the soil and the dung. However, due to their unequivocal signature, TMP are a powerful tracer of the distribution of PTE in the different compartments constituting the food chains and the ecosystems. Furthermore, the measurement of the particle sizes gave evidence that a noticeable proportion of the MP could enter the respiratory tract. PMID- 26986088 TI - Subcellular distribution of trace elements and liver histology of landlocked Arctic char (Salvelinus alpinus) sampled along a mercury contamination gradient. AB - We sampled landlocked Arctic char (Salvelinus alpinus) from four lakes (Small, 9 Mile, North, Amituk) in the Canadian High Arctic that span a gradient of mercury contamination. Metals (Hg, Se, Tl, and Fe) were measured in char tissues to determine their relationships with health indices (relative condition factor and hepatosomatic index), stable nitrogen isotope ratios, and liver histology. A subcellular partitioning procedure was employed to determine how metals were distributed between potentially sensitive and detoxified compartments of Arctic char livers from a low- and high-mercury lake (Small Lake and Amituk Lake, respectively). Differences in health indices and metal concentrations among char populations were likely related to differences in feeding ecology. Concentrations of Hg, Se, and Tl were highest in the livers of Amituk char, whereas concentrations of Fe were highest in Small and 9-Mile char. At the subcellular level we found that although Amituk char had higher concentrations of Tl in whole liver than Small Lake char, they maintained a greater proportion of this metal in detoxified fractions, suggesting an attempt at detoxification. Mercury was found mainly in potentially sensitive fractions of both Small and Amituk Lake char, indicating that Arctic char are not effectively detoxifying this metal. Histological changes in char livers, mainly in the form of melano-macrophage aggregates and hepatic fibrosis, could be linked to the concentrations and subcellular distributions of essential or non-essential metals. PMID- 26986089 TI - Fate of engineered cerium oxide nanoparticles in an aquatic environment and their toxicity toward 14 ciliated protist species. AB - The potential environmental impacts of engineered cerium oxide nanoparticles (CeO2 NPs) on aquatic organisms have remained largely unknown. Therefore, the laboratory study featured herein was performed to determine the fate of CeO2 NPs in an aquatic environment and their toxicity towards 14 different ciliated protist species at a specified population level. An investigation of 48 h aggregation kinetics in the Dryl's solution showed the CeO2 NPs to be relatively stable. The pH values in three test medium were too far away from PZC, which explained the stability of CeO2 NPs. CeO2 NPs generally elicited more toxicity with increasing NP concentration, following certain dose-response relationships. Nano-CeO2 resulted in greater toxicity in a particle state than when added as bulk material. LC50 values showed a negative correlation with the surface-to volume ratio for these protists, suggesting that surface adsorption of CeO2 NPs might contribute to the observed toxicity. Additionally, acute toxic responses of 14 ciliated protist species to CeO2 NPs were not significantly phylogenetically conserved. The results of these observations provide a better insight into the potential risks of CeO2 NPs in an aquatic environment. PMID- 26986090 TI - When ambient noise impairs parent-offspring communication. AB - Ambient noise has increased in extent, duration and intensity with significant implications for species' lives. Birds especially, because they heavily rely on vocal communication, are highly sensitive towards noise pollution. Noise can impair the quality of a territory or hamper the transmission of vocal signals such as song. The latter has significant fitness consequences as it may erode partner preferences in the context of mate choice. Additional fitness costs may arise if noise masks communication between soliciting offspring and providing parents during the period of parental care. Here, we experimentally manipulated the acoustic environment of blue tit (Cyanistes caeruleus) families within their nest boxes with playbacks of previously recorded highway noise and investigated the consequences on parent-offspring communication. We hypothesized that noise interferes with the acoustic cues of parental arrival and vocal components of offspring begging. As such we expected an increase in the frequency of missed detections, when nestlings fail to respond to the returning parent, and a decrease in parental provisioning rates. Parents significantly reduced their rate of provisioning in noisy conditions compared to a control treatment. This reduction is likely to be the consequence of a parental misinterpretation of the offspring hunger level, as we found that nestlings fail to respond to the returning parent more frequently in the presence of noise. Noise also potentially masks vocal begging components, again contributing to parental underestimation of offspring requirements. Either way, it appears that noise impaired parent offspring communication is likely to reduce reproductive success. PMID- 26986091 TI - Memory response to oxytocin predicts relationship dissolution over 18 months. AB - BACKGROUND: Oxytocin is known for its role in pair bonding in non-human animals. To examine the role of oxytocin in human romantic bonding, we examined its effect on recall of memories of past and current romantic experiences as predictors of relationship dissolution. METHOD: In a placebo-controlled, within-subject, randomized experiment, 48 participants (24?; 16 single) self-administered intranasal oxytocin and completed an autobiographical memory test. Participants in a current romantic relationship reported on their relationship status 18 months later. RESULTS: Participants in a relationship recalled fewer memories of past romantic partners following oxytocin administration relative to placebo. Participants who responded to oxytocin by recalling more conflict memories of their current romantic partner, relative to placebo, were more likely to have ended their relationship over 18 months than those who did not show this response. CONCLUSION: These results suggest that the memory response to an intranasal oxytocin challenge may represent an index of relationship outcome over time. PMID- 26986093 TI - [Epidemiology of schistosomiasis in the periurban area of Sotuba, 10 years mass treatment began in Mali]. AB - OBJECTIVE: The objective of this work was to describe the epidemiology of schistosomiasis 10 years after mass administration of praziquantel began in Sotuba, Mali. METHODOLOGY/RESULTS: This observational cross-sectional survey in Sotuba, a periurban village in the Bamako district, took place from July to September 2010 and collected stool and urine samples from residents at least one year old. Kato-Katz (for stool) and urine filtration techniques were used to detect Schistosoma mansoni and S. haematobium eggs, respectively. Overall, 335 urine samples and 300 stool samples were examined. The prevalence rate was 5.4% (18/335) for S. haematobium and 8.7% (26/300) for S. mansoni. Excretion of these eggs was most frequent in the 6-15 year-old group: 4.8% (16/335) for S. haematobium and 7.7% (23/300) for S. mansoni. Snails of the Biomphalaria pfeifferi and Bulinus truncatus species were the intermediate hosts, captured in the fields at water contact points. The principal clinical symptoms reported by participants were abdominal pain 27.2% (61/169) and headaches 23.2% (52/169). CONCLUSION: Despite the implementation of mass drug administration in Mali a decade ago, our results show that schistosomiasis transmission continues in Sotuba. Assessment of the risk factors for this persistent transmission is strongly needed. PMID- 26986092 TI - Trait positive and negative emotionality differentially associate with diurnal cortisol activity. AB - Inter-individual variability in metrics of hypothalamic-pituitary-adrenocortical (HPA) activity, such as the slope of the diurnal decline in cortisol, cortisol awakening response (CAR), and total cortisol output, have been found to associate inversely with trait ratings of extraversion and positive affect (E/PA) and positively with neuroticism and negative affect (N/NA) in some, but not all, investigations. These inconsistencies may partly reflect varied intensity of cortisol sampling among studies and reliance on self-rated traits, which are subject to reporting biases and limitations of introspection. Here, we further examined dispositional correlates of HPA activity in 490 healthy, employed midlife volunteers (M age=43 years; 54% Female; 86% white). Trait ratings were requested from participants and 2 participant-elected informants using the Positive and Negative Affect Schedule (PANAS) and Extraversion and Neuroticism dimensions of NEO personality inventories. CAR was assessed as percent increase in cortisol levels from awakening to 30min after awakening; and the diurnal slope and total output of cortisol [Area Under the Curve (AUC)] were determined from cortisol measurements taken at awakening, +4 and +9h later, and bedtime, across 3 workdays. Structural equation modeling was used to estimate multi-informant E/PA and N/NA factors. We used 3days of measurement as indicators to model each of the three latent cortisol factors (slope, CAR, and AUC). With the two latent emotionality and three latent cortisol indices included there was good fit to the data (chi(2)(200)=278.38, p=0.0002; RMSEA=0.028, 90% CI=0.02-0.04; CFI/TLI=0.97/0.96; SRMR=0.04). After controlling for covariates (age, sex, race), results showed higher latent E/PA associated with a steeper diurnal slope (Standardized beta=-0.19, p=0.02) and smaller CAR (Standardized beta=-0.26, p=0.004), whereas N/NA did not associate with any cortisol metric (Standardized beta's=-0.12 to 0.13, p's=0.10 to 0.53). These findings suggest that positive emotionality may be more closely associated with indices of diurnal cortisol release than negative emotionality. PMID- 26986094 TI - Abdominal Obesity and Association With Atherosclerosis Risk Factors: The Uberlandia Heart Study. AB - Ectopic visceral fat (VF) and subcutaneous fat (SCF) are associated with cardiovascular risk factors. Gender differences in the correlations of cardiovascular disease risk factors and ectopic fat in the Brazilian population still lacking. Cross-sectional study with 101 volunteers (50.49% men; mean age 56.5 +/- 18, range 19-74 years) drawn from the Uberlandia Heart Study underwent ultrasonography assessment of abdominal visceral adipose tissue with convex transducer of 3.5 MHz of frequency. The thickness of VF was ultrasonographically measured by the distance between the inner face of the abdominal muscle and the posterior face of abdominal aorta, 1 cm above the umbilicus. The SCF thickness was measured with a 7.5 MHz linear transducer transversely positioned 1 cm above the umbilical scar. The exams were always performed by the same examiner. Ectopic fat volumes were examined in relation to waist circumference, blood pressure, and metabolic risk factors. The VF was significantly associated with the levels of triglycerides (P < 0.01, r = 0.10), HDL cholesterol (P < 0.005, r = 0.15), total cholesterol (P < 0.01, r = 0.10), waist circumference (P < 0.0001, r = 0.43), systolic blood pressure (P < 0.001, r = 0.41), and diastolic blood pressure (P < 0.001, r = 0.32) in women, and with the levels of triglycerides (P < 0.002, r = 0,14), HDL cholesterol (P < 0.032, r = 0.07), glucose (P < 0.001, r = 0.15), alanine aminotransferase (ALT) (P < 0.008, r = 0.12), gamma-GT (P < 0.001, r = 0.30), waist circumference (P < 0.001, r = 0.52), systolic blood pressure (P < 0.001, r = 0.32), and diastolic blood pressure (P < 0.001, r = 0.26) in men. SCF was significantly associated with the levels of triglycerides (P < 0.01, r = 0.34), LDL cholesterol (P < 0.001, r = 0.36), total cholesterol (P < 0.05, r = 0.36), waist circumference (P < 0.0001, r = 0.62), systolic and diastolic blood pressure (P < 0.05, r = 0.34) in women, and with the waist circumference (P < 0.001, r = 0.065)), and MetS (P < 0.05, r = 0.11) in men. The VF and SCF were correlated with most cardiovascular risk factors in both genders but our findings support the idea that there are gender differences in the correlations between ectopic fat deposition and the cardiovascular risk factors. PMID- 26986095 TI - The Incidence and Risk of Herpes Zoster in Patients With Sleep Disorders: A Population-Based Cohort Study. AB - Lack of sleep can compromise the immune system, which may reactivate latent varicella-zoster virus. Studies on sleep disorders and the risk of herpes zoster (HZ) are scant.We conducted a population-based cohort study to evaluate the risk of HZ in patients with sleep disorders and potential risk factors for HZ development. We identified patients with sleep disorders without apnea from 2002 to 2005 by using the Taiwan Longitudinal Health Insurance Database. The patients without sleep disorders were randomly selected and frequency matched with patients with sleep disorders according to age, sex, and index year. We estimated the follow-up time in person-years for the patients from the entry date until HZ diagnosis, loss to follow-up, or the end of 2010. We used Cox proportional hazards regression models and a sensitivity analysis to estimate the risk of HZ while controlling for demographic characteristics and comorbidities. A total of 131,001 study participants (follow-up, 948,177 person-years; mean age, 51.2 +/- 16.5 years; 62.2% women) were included in the study. Patients with sleep disorders exhibited a higher incidence of HZ compared with a comparison cohort when stratified by age, sex, and comorbidities. After adjustment for covariates, the sleep disorder cohort exhibited a 1.23-fold greater risk of HZ compared with the comparison cohort (95% confidence interval [CI] = 1.17-1.30). The incidence of HZ increased with age. Adults ages 65 years and older exhibited a 6.11-fold greater risk of HZ development compared with their younger counterparts (95% CI = 5.34-7.00). Cancers and autoimmune diseases were independent risk factors of HZ development. The patients with sleep disorders may carry an increased risk of developing HZ. PMID- 26986096 TI - A Pilot Randomized Controlled Study of Dexlansoprazole MR-Based Triple Therapy for Helicobacter Pylori Infection. AB - Dexlansoprazole MR is the R-enantiomer of lansoprazole that is delivered by a dual delayed release formulation. It is effective for symptom control of patients with gastroesophageal reflux disease. However, its efficacy in the treatment of Helicobacter pylori infection remains unclear. This pilot, randomized, controlled, head-to-head study was conducted to investigate whether the efficacy of single-dose dexlansoprazole MR-based triple therapy was noninferior to double dose rabeprazole-based triple therapy in the treatment of H pylori infection. Consecutive H pylori-infected subjects were randomly allocated to either 7-day dexlansoprazole MR-based standard triple therapy (dexlansoprazole MR 60 mg once daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily) or rabeprazole-based triple therapy (rabeprazole 20 mg twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily). H pylori status was assessed 6 weeks after the end of treatment. A total of 177 H pylori-infected patients were randomized to receive dexlansoprazole MR-based (n = 90) or rabeprazole-based (n = 87) triple therapy. Intention-to-treat analysis demonstrated no differences between eradication rates of the 2 study groups (83.3% vs 81.6%; P = 0.736). Per-protocol analysis yielded comparable results (85.1% vs 81.2%; P = 0.497). Both groups exhibited similar frequencies of adverse events (7.8% vs 4.6%; P = 0.536) and drug compliance (98.9% vs 97.7%; P = 0.496). Multivariate analysis disclosed that the presence of clarithromycin resistance was the only independent factors predictive of treatment failure with an odds ratio of 6.8 (95% confidence interval: 1.2-37.6). This work demonstrates that single-dose dexlansoprazole MR-based triple therapy yields a similar eradication rate as double-dose rabeprazole-based therapy. Since the pharmaceutical cost of the single-dose dexlansoprazole MR regime is lower than that of the double-dose rabeprazole regimen, dexlansoprazole-based therapy can reasonably be recommended in the first-line treatment of H pylori infection. PMID- 26986097 TI - Effectiveness of Autologous Stem Cell Therapy for the Treatment of Lower Extremity Ulcers: A Systematic Review and Meta-Analysis. AB - Primary studies in animal models and humans have suggested the therapeutic potential of autologous stem cell for treating chronic lower extremity ulcers. However, the results of pilot randomized controlled trials (RCTs) in humans have been inconsistent. A meta-analysis of RCTs was performed to evaluate the role of autologous stem cell-based therapy for lower extremity ulcers.Studies were identified during a systematic search of Medline, Embase, Cochrane's library, and references cited in related reviews and studies. Studies were included if they were RCTs published in English, recruited patients with lower extremity ulcers who were assigned to either a group for the topical therapy with autologous stem cells, and reported data regarding the healing of the ulcers.Relative risks (RRs) for healing rate and standardized mean differences (SMDs) for the changes in the mean sizes of ulcers were evaluated with a random-effects model. Overall, autologous stem cell-based therapy was associated with better healing of lower extremity ulcers (12 comparisons, 290 patients, RR for partial healing = 3.07, 95% confidence interval [CI] = 1.14-8.24, P = 0.03; RR for complete healing = 2.26, 95% CI = 1.48-3.16, P < 0.001) with little heterogeneity (I = 0%). Moreover, autologous stem cell-based therapy was associated with a greater reduction in mean ulcer size (SMD = -0.63, 95% CI = -1.03 to -0.22, P = 0.002). Subgroup analyses indicated that stem cells from peripheral blood and bone marrow seemed to exert similar beneficial effects on the healing of ulcers. Stem cell therapy was not associated with any increased risks for adverse events. The optimized sources, amounts, and delivery methods of stem cell -based therapy for patients with chronic lower extremity ulcers need to be determined, and the long term effects of stem cell-based therapy on clinical outcomes need further exploration.Autologous stem cell-based therapy is effective and safe for improving the healing of chronic lower extremity ulcers and large-scale RCTs are needed to confirm our findings. PMID- 26986098 TI - Influence of Parental Monitoring, Sensation Seeking, Expected Social Benefits, and Refusal Efficacy on Tobacco and Alcohol Use in Chinese Adolescents. AB - The relationships between parental monitoring (PM), sensation seeking (SS), expected social benefits (ESB), refusal efficacy (RE), and tobacco and alcohol use (TAU) have been well documented among adolescents. However, the mechanisms by which these 4 determinants affect TAU remain unclear. Based on the Theory of Triadic Influence, this study aimed to explore how PM, SS, ESB, and RE simultaneously influenced TAU in Chinese adolescents. From September 2013 to June 2014, we used multistage cluster sampling to select 6269 students from 179 classes of 7 vocational high schools in 3 cities of China. Each student completed a battery of 5 measures: PM, SS, ESB, RE, and TAU. Then, we used structural equation modeling techniques and mediation analyses to investigate the relationships among these 5 measures, with TAU as the final dependent variable. Results demonstrated that the relationship between PM and TAU was fully mediated by ESB and RE (b = -0.18, P < 0.001), that SS influenced TAU directly (b = 0.10, P < 0.001) and indirectly through ESB and RE (b = 0.15, P < 0.001), and that ESB influenced TAU directly (b = 0.09, P < 0.001) and indirectly through RE (b = 0.28, P < 0.001).These findings indicate that the link between PM and SS to TAU among Chinese adolescents can be explained by ESB and RE. These 4 precursory determinants can play an important role in TAU prevention among adolescents in China. PMID- 26986100 TI - Endoscopic Findings of Small-Bowel Lesions in Familial Amyloid Polyneuropathy: A Case Report. AB - Familial amyloid polyneuropathy (FAP) is an autosomal dominant disease associated with the mutations in the transthyretin gene. To date, the endoscopic findings of the small-bowel lesions of FAP have never been described. We report a rare case of FAP with gastrointestinal involvement. A 71-year-old woman complaining of refractory diarrhea for 1 year was referred to our institution. She had sensory disturbance, movement disorder due to muscle weakness, and autonomic nervous system disorders including orthostatic hypotension and dysuria. Her eldest sister had cardiac amyloidosis. Small-bowel radiography and retrograde double-balloon endoscopy (DBE) revealed that fine granular protrusions were diffusely observed both in the jejunum and ileum. Histologic examination of the biopsy specimens obtained from the small bowel revealed perivascular amyloid deposits mainly in the muscularis mucosae and submucosa, which were immunoreactive with transthyretin antibodies. Analysis of the genomic DNA showed a heterozygous Gly47Val mutation in the transthyretin gene. Thus a diagnosis of FAP was established. Diffuse fine granular protrusions in the jejunum and the ileum visualized by small-bowel radiography and DBE may be characteristic of FAP. Multiple biopsies from the gastrointestinal mucosa are recommended for the definitive histologic diagnosis of FAP. PMID- 26986099 TI - Association of Increased Epicardial Adipose Tissue Thickness With Adverse Cardiovascular Outcomes in Patients With Atrial Fibrillation. AB - The thickness of epicardial adipose tissue (EAT) was reported to be highly associated with the incidence and severity of atrial fibrillation (AF). This study was conducted to analyze the ability of EAT thickness in predicting adverse cardiovascular (CV) events in AF. In 190 persistent AF patients, we performed a comprehensive transthoracic echocardiographic examination with assessment of EAT thickness. The definition of CV events included CV mortality, hospitalization for heart failure, myocardial infarction, and stroke. There were 69 CV events including 19 CV deaths, 32 hospitalizations for heart failure, 3 myocardial infarctions, and 15 strokes during a mean follow-up of 29 (25th-75th percentile: 17-36) months. The multivariable analysis demonstrates that chronic heart failure, increased left ventricular (LV) mass index and the ratio of transmitral E-wave velocity to early diastolic mitral annulus velocity, decreased body mass index, and increased EAT thickness (per 1-mm increase, odds ratio 1.224, 95% confidence interval [CI] 1.096-1.368, P < 0.001) were associated with adverse CV events. Additionally, the addition of EAT thickness to a model containing CHA2DS2 VASc score, left atrial volume index, and LV systolic and diastolic function significantly improved the values in predicting CV events (global chi increase 14.65, P < 0.001 and integrated discrimination improvement 0.10, 95% CI 0.04 0.16, P < 0.001). In AF, EAT thickness was useful in predicting adverse CV events. Additionally, EAT thickness could provide incremental value for CV outcome prediction over traditional clinical and echocardiographic parameters in AF. PMID- 26986101 TI - Expression of Phosphorylated AMP-Activated Protein Kinase Predicts Response to Transarterial Chemoembolization in Postoperative Cases of Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in the world. Transcatheter arterial chemoembolization (TACE) was commonly used for HCC patients postoperatively. However, the survival benefits of adjuvant TACE were controversial due to the extensive heterogeneity of HCC. Hence, there is a critical need to explore potential biomarkers that can predict the clinical response to TACE. The AMP-activated protein kinase (AMPK) is a highly conserved heterotrimeric serine/threonine kinase that plays a central role in linking metabolism and cancer development. In this study, we aimed at evaluating the association of pAMPKalpha (Thr172) status with clinical outcomes in HCC patients treated with or without postoperative adjuvant TACE.pAMPKalpha (Thr172) expression was assessed using immunohistochemical analysis in a cohort of 378 Chinese HCC patients who had undergone tumor resection. Kaplan-Meier analysis and multivariate Cox proportional hazards models were used to study the impact on clinical outcomes.High pAMPKalpha (Thr172) expression was associated with improved disease-free and overall survival and was an independent prognostic factor for overall survival by multivariate analysis. Furthermore, low pAMPKalpha (Thr172) expression level was correlated with high percentage of OV6 tumor initiating cells (T-ICs) in HCC specimens.To our knowledge, it can be demonstrated for the first time that pAMPKalpha (Thr172) status is associated with response to postoperative adjuvant TACE. High pAMPKalpha (Thr172) level in HCC may serve as a positive predictor of survival in HCC patients undergoing TACE. PMID- 26986102 TI - Tuberculous Spondylitis Following Kyphoplasty: A Case Report and Review of the Literature. AB - Tuberculous spondylitis of the augmented vertebral column following percutaneous vertebroplasty or kyphoplasty has rarely been described. We report an unusual case of tuberculous spondylitis diagnosed after percutaneous kyphoplasty (PKP). A 61-year-old woman presented to our institution complaining of back pain following a fall 7 days before. Radiologic studies revealed an acute osteoporotic compression L1 fracture. The patient denied history of pulmonary tuberculosis (TB) and there were no signs of infection. The patient was discharged from hospital 4 days after undergoing L1 PKP with a dramatic improvement in her back pain. Two years later, the patient was readmitted with a 1 year history of recurrent back pain. Imaging examinations demonstrated long segmental bony destruction involving L1 vertebra with massive paravertebral abscess formation. The tentative diagnosis of tuberculous spondylitis was made, after a serum T SPOT. The TB test was found to be positive. Anterior debridement, L1 corpectomy, decompression, and autologous rib graft interposition, and posterior T8-L4 instrumentation were performed. The histologic examination of the resected tissue results confirmed the diagnosis of spinal TB. Anti-TB medications were administered for 12 months and the patient recovered without sequelae. Spinal TB and osteoporotic vertebral compression fractures are similar clinically and radiologically. Spinal surgeons should consider this disease entity to avoid misdiagnosis or complications. Early surgical intervention and anti-TB treatment should be instituted as soon as the diagnosis of spinal TB after vertebral augmentation is made. PMID- 26986104 TI - Sitagliptin/Metformin Versus Insulin Glargine Combined With Metformin in Obese Subjects With Newly Diagnosed Type 2 Diabetes. AB - To compare the therapeutic effects of different regimens in Chinese obese type 2 diabetic mellitus (T2DM) patients. From October 2013 to July 2014, a total of 166 T2DM outpatients who attended the Shanghai Changhai Hospital and the Yijishan Hospital of Wannan Medical College were randomly assigned into an experimental sitagliptin/metformin combined with low caloric diet group (n = 115) and an insulin glargine combined with metformin control group (n = 51). Inclusion criteria were body mass index (BMI) >= 25 kg/m and diagnosed with T2DM with glycosylated hemoglobin (glycated hemoglobin A1C [HbA1c]) >9%. Main outcome parameters were fasting plasma glucose, postprandial plasma glucose, BMI, HbA1c, fasting C-peptide, 2-h postprandial C-peptide, triglyceride (TG), total cholesterol (TC), high-density cholesterol (HDL-C), and low-density cholesterol (LDL-C), which were determined by the 75 g steamed-bun meal tolerance test before and 4, 8, 12, and 24 weeks after the treatment started. Treatment costs and life quality were also assessed. BMI, HbA1C, TG, TC, and LDL were significantly more reduced (P < 0.000) and HbA1c significantly better improved in the experimental group than in the control group (<6.5% in 24 [20.87%] vs 2 [3.92%], P < 0.001; <7% in 65 [56.52%] vs 12 [23.53%], P < 0.001). Quality of life scores in the experimental group increased more than in the control group (P < 0.001). The costs for the experimental group medication were less than for other regimens. For obese T2DM patients diagnosed with a glycosylated hemoglobin level >9%, oral sitagliptin/metformin combined with a low caloric diet effectively and economically maintained glycemic control and significantly improved life quality. PMID- 26986103 TI - Neutrophilic Dermatoses in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A French Multicenter Study of 17 Cases and Literature Review. AB - A few reports suggest combination of ANCA-associated vasculitis (AAV) and neutrophilic dermatoses (ND). We aimed to describe the main characteristics of patients presenting with both AAV and ND in a French cohort and through a systematic literature review, and to discuss the possible common pathogenic process involved. We conducted a retrospective study of patients with both conditions. Patients were selected via the French Internal Medicine Society (SNFMI) and the French Vasculitis Study Group (FVSG). A literature review focusing on a combination of both conditions, concentrated only on publications with well-established diagnoses and individual detailed data. Seventeen patients diagnosed with AAV and ND were identified in this cohort. Twelve patients had granulomatosis with polyangiitis (GPA), 4 had microscopic polyangiitis (MPA) and one had eosinophilic GPA (EGPA). Eight patients, all with GPA, displayed pyoderma gangrenosum (PG). Sweet's syndrome was observed in 6 patients (4 with MPA, one with GPA and one with EGPA) and erythema elevatum diutinum in the other three (2 with GPA and 1 with MPA). The literature review identified 33 additional patients with both conditions, including 26 with GPA. Altogether, of the 50 patients (17 from our study and 33 from the literature review), 33 (66%) patients presented with PG associated with GPA in 29 cases (89%). Corticosteroids were the first line treatment in conjunction with an immunosuppressive agent in most cases. Outcomes were good and a total of 15 patients experienced a relapse. Patients who relapsed were more likely to have ear, nose and throat manifestation than patients who did not [12/15 (80%) relapsing patients vs. 15/35 (43%) non relapsing patients; p = 0.03)]. In our stud, the most frequent association concerned GPA and PG. ND should be considered and specifically researched within the spectrum of cutaneous manifestations observed in AAV. PMID- 26986105 TI - A Preoperative Nutritional Index for Predicting Cancer-Specific and Overall Survival in Chinese Patients With Laryngeal Cancer: A Retrospective Study. AB - Pinato prognostic nutritional index (PNI) adequately predicts long-term outcomes of various malignancies. However, its value in predicting outcomes in laryngeal squamous cell carcinoma (LSCC) is unknown. All patients newly diagnosed with LSCC presenting to the Department of Head and Neck Oncology at Sun Yat-sen University Cancer Center between January 1, 1990 and July 31, 2010 were eligible. The PNI was calculated as serum albumin (g/L) + 5 * total lymphocyte count/L. The Cutoff Finder software program was used to classify the patients into 3 groups for which the PNI score was at least 70% sensitive, at least 70% specific, or equivocal. Cancer-specific survival was estimated using the Kaplan-Meier method, and predictors were assessed with Cox regression analysis. Median time between surgery and PNI administration for the 975 eligible patients was 83 months. Index score groups were significantly associated with age, T stage, TNM stage, and type of surgery. Five-year CSS and OS were 57.3% and 56.6% in patients with PNI scores below 48.65 (low-probability of survival), 72.8% and 71.3% with scores between 48.65 and 56.93 (moderate-probability of survival), and 77.6% and 75.3% with scores above 56.93 (high-probability of survival); 10-year CSS and OS were 44.2% and 42.7%, 61.6% and 55.6%, 68.3% and 63.5%, respectively. The PNI score groups significantly predicted CSS and OS (P < 0.001). The PNI is an inexpensive and readily available score that predicted survival in patients with LSCC after curative laryngectomy. PMID- 26986106 TI - Slow Recovery of Weight Bearing After Stabilization of Long-Bone Fractures Using Elastic Stable Intramedullary Nails in Children. AB - Stabilization of diaphyseal long-bone fractures using elastic stable intramedullary nails (ESIN) in children promises early mobilization and rapid resumption of full weight bearing. We evaluated the duration of postoperative functional rehabilitation after ESIN, measured by the time from stabilization until first partial weight bearing, full weight bearing, and resumption of school sports. Fifty children with unstable, displaced fractures of the femur or lower leg treated with ESIN between 2002 and 2012 were included in this retrospective analysis. We classified fractures according to the pediatric comprehensive classification of fractures (PCCF). Thirty-five children sustained a femur fracture, and 15 children had a fracture of the lower leg or tibia. The surgeons in charge applied an additional plaster cast in 7 of 15 children who suffered a lower leg fracture. The postoperative time interval until full weight bearing in the group of children who had suffered transverse or short oblique femur fractures was significantly shorter (median: 4.4 weeks; range: 0.1-9.1 weeks) than that in the group who had sustained more complex fracture patterns (median: 6.8 weeks; range: 2.9-13.9 weeks; P = 0.04). Similarly, transverse and short oblique lower leg and tibia fractures required less time until full weight bearing (median: 4.1 weeks; range 2.7-6.0 weeks) than complex lower leg fractures (median: 6.1 weeks; range: 1.3-12.9 weeks; P = 0.04). ESIN proved fairly effective in restoring full weight bearing in transverse or short oblique fractures of the lower extremities but was less effective in complex fractures. PMID- 26986107 TI - What Can Emergency Medicine Learn From Kinetics: Introducing an Alternative Evaluation and a Universal Criterion Standard for Emergency Department Performance. AB - This research focuses on developing an improved and robust measurement for emergency department (ED) performance and a criterion standard for global use via kinetic analysis. Based on kinetic approach, the input-throughput-output conceptual model of ED crowding is compared to the procedure of enzyme catalysis. All in average, the retented patients in EDs are defined as substrate (S), whereas the patients who depart the EDs as product (P). Therefore, the average ED departure velocity (V) can be presented as (P)divided by a given time (t) of the ED length of stay (LOS). The S-V and S2-P plots are depicted hourly for the kinetic analysis. The long-term stability of the kinetic parameters is ascertained by the method of coefficient of variation (CV). The participants collected for this study are from the EDs of Changhua Christian Medical Center and the five branched hospitals, all located in Taiwan. Based on the S-V plot analysis, the results clearly show 2 curves, an upper and a lower curve. The timeline of the lower curve includes approximately the total ED busy hours, and thus it can be used for the subsequent kinetic analysis. In order to explore the adequate kinetic parameters for ED performance, the try-and-error process was followed in this study. As a result, the S2-V plots adapted from the lower curves show the best linear regression of S2 on V with a good coefficient of determination (R). The Pan-Wen constant (PW), which is the slope of the liner regression line, and the ED medical personnel unit turnover number (EDMPU TON) were deduced from the kinetic meanings of (Equation is included in full-text article.)plots. In this research, the 2 kinetic parameters, PW and EDMPU TON were applied for the ED performance evaluations. An innovative relationship between the ED retented patients and the ED departure velocity is verified as PW; whereas, a feasible kinetic parameter, the EDMPU TON explicates the teamwork efficiency of the ED providers. Moreover, the EDMPU TON may not only be a reliable universal criterion standard for the ED performance, but also a valuable reference for both ED providers and payers. PMID- 26986108 TI - Haploidentical Transplantation Without In Vitro T-Cell Depletion Results in Outcomes Equivalent to Those of Contemporaneous Matched Sibling and Unrelated Donor Transplantation for Acute Leukemia. AB - The aim of the study is to determine whether HLA-haploidentical-related donor (HRD) transplant can achieve equivalent outcomes and have stronger GVL compared to HLA-matched sibling donor (MSD) and HLA-matched unrelated donor (MUD) transplants. A total of 355 consecutive patients with acute leukemia undergoing allogeneic transplant at our single institute between March 2008 and March 2014 were enrolled in this retrospective investigation. Of the 355 patients, 96 cases received HRD, 153 MSD, and 106 MUD transplants. HRD transplant was associated with higher incidences of grade II to IV aGVHD (40.6%) compared with MSD (23.5%, P = 0.002) and MUD transplants (34.0%, P = 0.049), whereas incidences of grade III to IV aGVHD (11.4%, 7.8%, 10.5%, respectively; P = 0.590) and cGVHD (29.5%, 24.0%, 29.5%, respectively; P = 0.538) did not differ among 3 groups. Five-year relapse rates were 19.2%, 26.8%, and 23.0% in 3 groups, respectively (P = 0.419). However, of 206 high-risk patients, the relapse rate in HRD transplant was lower than in MSD transplant (23.8% vs 41.9%, P = 0.026). Multivariate analysis showed that HRD had beneficial impact on relapse (for MSD: P = 0.006). Five-year transplant-related mortality was lower in MSD transplant compared with those in HRD (17.3% vs 26.4%, P = 0.041) and MUD transplants (17.3% vs 24.1%, P = 0.037). Five-year overall survival were 60.4%, 64.6%, and 61.0%, respectively, in HRD, MSD, and MUD groups (P = 0.371); 5-year disease-free survival were 59.6%, 58.8%, and 54.9%, respectively (P = 0.423). Our results suggest that HRD transplant results in outcomes equivalent to MSD and MUD transplants. HRD might carry a superior GVL effect compared to MSD for high-risk patients. PMID- 26986109 TI - Effects of an Exhaustive Exercise on Motor Skill Learning and on the Excitability of Primary Motor Cortex and Supplementary Motor Area. AB - We examined, on 28 healthy adult subjects, the possible correlations of an exhaustive exercise, and the consequent high blood lactate levels, on immediate (explicit) and delayed (implicit) motor execution of sequential finger movements (cognitive task). Moreover, we determined with transcranial magnetic stimulation whether changes in motor performance are associated with variations in excitability of primary motor area (M1) and supplementary motor area (SMA). We observed that, after an acute exhaustive exercise, the large increase of blood lactate is associated with a significant worsening of both explicit and implicit sequential visuomotor task paradigms, without gender differences. We also found that, at the end of the exhaustive exercise, there is a change of excitability in both M1 and SMA. In particular, the excitability of M1 was increased whereas that of SMA decreased and, also in this case, without gender differences. These results support the idea that an increase of blood lactate after an exhaustive exercise appears to have a protective effect at level of primary cortical areas (as M1), although at the expense of efficiency of adjacent cortical regions (as SMA). PMID- 26986110 TI - The Association of Ursodeoxycholic Acid Use With Colorectal Cancer Risk: A Nationwide Cohort Study. AB - Data from preclinical studies suggest that ursodeoxycholic acid (UDCA) has a chemopreventive effect on colorectal cancer (CRC) development, but no large observational study has examined this possibility. The aim of this study was to investigate the association of UDCA use with CRC risk in a nationwide population based cohort. This nationwide population-based cohort study used data from the Taiwan National Health Insurance Research Database for the period from 2000 through 2010. This study included data from 7119 Taiwanese adults who received >=28 cumulative defined daily doses (cDDDs) of UDCA and 14,238 patients who did not receive UDCA (<28 cDDDs). UDCA nonusers were matched 1:2 for age, sex, enrollment date, and presence of chronic liver disease, viral hepatitis, cholelithiasis, and alcoholic liver disease. The 2 cohorts were followed until December 31, 2010 or occurrence of CRC. Cox proportional hazards regression with robust Sandwich variance estimator, which can cooperate with matching design, was used to examine the association between UDCA use and CRC risk. During 109,312 person-years of follow-up (median, 5 years), 121 patients had newly diagnosed CRC: 28 UDCA users (76.7 per 100,000 person-years) and 93 nonusers (127.7 per 100,000 person-years) (log-rank test, P = 0.0169). After multivariate adjustment for age, UDCA use was associated with a reduced risk of CRC (hazard ratio, 0.60; 95% confidence interval [CI], 0.39-0.92). The adjusted hazard ratios were 0.55 (95% CI, 0.35-0.89), 0.89 (95% CI, 0.36-2.20), and 0.63 (95% CI, 0.16-2.53) for patients with 28 to 180, 181 to 365, and >365 cDDDs, respectively, relative to nonusers. UDCA use was associated with reduced risk of CRC in a cohort mainly comprising patients with chronic liver diseases. However, further studies are needed to determine the optimal dosage of UDCA. PMID- 26986111 TI - Increasing Level of Leisure Physical Activity Could Reduce the Risk of Hip Fracture in Older Women: A Dose-Response Meta-analysis of Prospective Cohort Studies. AB - We carried out the study to investigate and quantitatively assess the potential association between current level of physical activity and the risk of osteoporosis hip fracture in older women. Relevant publications before October 2015 were identified using the PubMed and Ovid searching tools. A dose-response meta-analysis was carried out to combine and analysis results. Fourteen prospective studies were included in the meta-analysis. A general analysis of 9 studies showed a significant inverse relationship between increasing level of physical activity and risk of hip fracture in older women [relative risk (RR) = 0.93, 95% confidence interval (95% CI): 0.91-0.96]. The result of a sensitivity analysis was consistent with the general analysis (RR = 0.94, 95% CI: 0.93-0.96). The association between increasing level of physical activity and risk of wrist fracture was not statistically significant in a general analysis of three studies (RR = 1.004, 95% CI: 0.98-1.03). A potential direct association between increasing level of physical activity and risk of wrist fracture was observed after removing 1 study with the greatest weight (RR = 1.01, 95% CI: 1.00-1.03). No significant publication bias was observed in our analysis. Our results show that increasing level of physical activity within an appropriate range may reduce the risk of hip fracture but not the risk of wrist fracture in older women. PMID- 26986112 TI - A Novel Risk Score to the Prediction of 10-year Risk for Coronary Artery Disease Among the Elderly in Beijing Based on Competing Risk Model. AB - The study aimed to construct a risk prediction model for coronary artery disease (CAD) based on competing risk model among the elderly in Beijing and develop a user-friendly CAD risk score tool. We used competing risk model to evaluate the risk of developing a first CAD event. On the basis of the risk factors that were included in the competing risk model, we constructed the CAD risk prediction model with Cox proportional hazard model. Time-dependent receiver operating characteristic (ROC) curve and time-dependent area under the ROC curve (AUC) were used to evaluate the discrimination ability of the both methods. Calibration plots were applied to assess the calibration ability and adjusted for the competing risk of non-CAD death. Net reclassification index (NRI) and integrated discrimination improvement (IDI) were applied to quantify the improvement contributed by the new risk factors. Internal validation of predictive accuracy was performed using 1000 times of bootstrap re-sampling. Of the 1775 participants without CAD at baseline, 473 incident cases of CAD were documented for a 20-year follow-up. Time-dependent AUCs for men and women at t = 10 years were 0.841 [95% confidence interval (95% CI): 0.806-0.877], 0.804 (95% CI: 0.768-0.839) in Fine and Gray model, 0.784 (95% CI: 0.738-0.830), 0.733 (95% CI: 0.692-0.775) in Cox proportional hazard model. The competing risk model was significantly superior to Cox proportional hazard model on discrimination and calibration. The cut-off values of the risk score that marked the difference between low-risk and high risk patients were 34 points for men and 30 points for women, which have good sensitivity and specificity. A sex-specific multivariable risk factor algorithm based competing risk model has been developed on the basis of an elderly Chinese cohort, which could be applied to predict an individual's risk and provide a useful guide to identify the groups at a high risk for CAD among the Chinese adults over 55 years old. PMID- 26986113 TI - Combined Direct and Indirect CT Venography (Combined CTV) in Detecting Lower Extremity Deep Vein Thrombosis. AB - This study aimed to evaluate the diagnostic accuracy of combined direct and indirect CT venography (combined CTV) in the detection of lower extremity deep vein thrombosis (LEDVT). The institutional review board approved the study protocol, and patients or qualifying family members provided informed consent. A total of 96 consecutive patients undergoing combined CTV were prospectively enrolled. A combined examination with digital subtraction angiography (DSA) plus duplex ultrasonography (US) was used as the criterion standard. Three observers were blinded to clinical, DSA, and US results, and they independently analyzed all combined CTV datasets. Interobserver agreement was expressed in terms of the Cohen k value for categorical variables. Accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of combined CTV in the detection of LEDVT were determined by using patient- and location based evaluations. Of the 96 patients, DSA plus US revealed LEDVT in 125 segmental veins in 63 patients. Patient-based evaluation with combined CTV yielded an accuracy of 96.9% to 97.9%, a sensitivity of 95.2% to 96.8%, a specificity of 100% to 100%, a PPV of 100% to 100%, and an NPV of 91.7% to 94.3% in the detection of LEDVT. Location-based evaluation yielded similar results. Through combined direct and indirect CTV, patients obtained a combined CT angiogram on the diseased limb and an indirect CT angiogram on the opposite side. The image quality of combined CTV was superior to an indirect venogram. Combined CTV shows promising diagnostic accuracy in the detection of LEDVT with 3 dimensional modeling of the lower limb venous system. PMID- 26986114 TI - Risk Factors for Development and Progression of Chronic Kidney Disease: A Systematic Review and Exploratory Meta-Analysis. AB - The risk factors influencing the natural course of chronic kidney disease (CKD) are complex and heterogeneous, and few systematic reviews to date have focused on this issue. The aim of the study is to identify the risk factors for disease development and progression in each stage of CKD. We conducted electronic literature searches of PubMed, MEDLINE, Scopus, and the Cochrane Library up to October 15, 2012, for observational studies evaluating the risk factors on the development or progression of CKD. Eligible studies should have collected repeated information that could evaluate changes in renal function. Extracted information from all the included studies was synthesized narratively. Quality assessments were performed using the Newcastle-Ottawa Scale. An exploratory random-effects meta-analysis was performed where feasible to pool effect sizes across studies for a specific risk factor in a specific outcome. We identified 38 cohort studies and 2 case-control studies from 40 articles, with a total of 318,898 participants from 14 countries. The follow-up duration ranged from 1.5 to 16 years. The majority of the included studies were of high quality. The baseline CKD stages of the included studies ranged from normal to later stages, and only 19 studies could be classified into a specific range of CKD stages during follow up. Three risk factors from studies of the same baseline and follow-up CKD stages were eligible for the exploratory meta-analysis, including male sex, substantial proteinuria, and diabetes. The hazard ratios for the progression from CKD stages 3-5 to end-stage renal disease (ESRD) were 1.37 (95% confidence interval 1.17 1.62), 1.64 (1.01-2.66), and 1.16 (0.98-1.38) for male sex, substantial proteinuria, and diabetes, respectively. In conclusion, our analyses comprehensively summarize the initiating and perpetuating factors for CKD. Male sex and substantial proteinuria are significant perpetuating factors for the progression from late stage CKD to ESRD, and diabetes may play a minor role for the outcome of ESRD among patients with later stages of CKD. PMID- 26986115 TI - Multimodality Treatment for Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Large-Scale, Multicenter, Propensity Mathching Score Analysis. AB - The optimal treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) remains controversial. We aimed to investigate the best treatment for patients with HCC with PVTT. From January 2002 to January 2014, the data from all consecutive patients with HCC with PVTT who underwent surgical treatment (ST),TACE,TACE combined with sorafenib (TACE-Sor), or TACE combined with radiotherapy (TACE-RT) in the 4 largest tertiary hospitals in China were analyzed retrospectively. The patients were divided into 3 subtypes according to the extent of PVTT in the portal vein (type I-III). The primary endpoint was overall survival (OS). A total of 1580 patients with HCC with PVTT were included in the study. The median survival times (MST) for ST (n = 745) for type I, II, and III patients (95% CI) were 15.9 (13.3-18.5), 12.5 (10.7-14.3), and 6.0 (4.3-7.7) months, respectively. The corresponding figures for patients after TACE (n = 604) were 9.3 (5.6-12.9), 4.9 (4.1-5.7), and 4.0 (3.1-4.9), respectively; for patients after TACE-Sor (n = 113) 12.0 (6.6-17.4), 8.9 (6.7-11.1), and 7.0 (3.0-10.9), respectively; and for patients after TACE-RT (n = 118) 12.2 (0-24.7), 10.6 (6.8 14.5), and 8.9 (5.2-12.6), respectively. Comparison among the different treatments for the 3 subtypes of PVTT patients after propensity score (PS) matching showed the effectiveness of ST to be the best for type I and type II PVTT patients, and TACE-RT was most beneficial for type III patients. Treatment was an independent risk factor of OS. ST was the best treatment for type I and II PVTT patients with Child-Pugh A and selected B liver function. TACE-RT should be given to type III PVTT patients. PMID- 26986116 TI - Surgery for Patients With Spontaneous Deep Supratentorial Intracerebral Hemorrhage: A Retrospective Case-Control Study Using Propensity Score Matching. AB - Spontaneous intracerebral hemorrhage (sICH) is one of the most dangerous cerebrovascular diseases, especially when in deep brain. The treatment of spontaneous deep supratentorial intracerebral hemorrhage is still controversial. We conducted a retrospective case-control study using propensity score matching to compare the efficacy of surgery and conservative treatment for patients with deep surpatentorial hemorrhage. We observed the outcomes of consecutive patients with spontaneous deep supratentorial hemorrhage retrospectively from December 2008 to July 2013. Clinical outcomes of surgery and conservative treatments were compared in patients with deep sICH using propensity score matching method. The primary outcome was neurological function status at 6 months post ictus. The second outcomes included mortality at 30 days and 6 months, and the incidence of complications. Subgroup analyses of 6-month outcome were conducted. Sixty-three (22.66%) of the 278 patients who received surgery had a favorable neurological function status at 6 months, whereas in the conservative group, 66 of 278 (23.74%) had the same result (P = 0.763). The 30-day mortality in the surgical group was 19.06%, whereas 30.58% in the conservative group (P = 0.002). There was significant difference in the mortality at 6 months after ictus as well (23.38% vs 36.33%, P = 0.001). The subgroup analyses showed significantly better outcomes for the surgical group when hematoma was >40 mL (13.33% vs 0%, P = 0.005) or complicated with intraventricular hemorrhage (16.67% vs 7.27%, P = 0.034). For complications, the risk of pulmonary infection, gastrointestinal hemorrhage, urinary infection, pulmonary embolus, and need for tracheostomy/long term ventilation in the surgical group was higher than the conservative group (31.29% vs 15.47%, P < 0.001; 6.83% vs 3.96%, P = 0.133; 2.88% vs 1.80%, P = 0.400; 1.80% vs 1.08%, P = 0.476; 32.73% vs 23.38%, P = 0.014). Surgery could reduce the short term mortality as well as long-term mortality in patients with spontaneous deep supratentorial hemorrhage. Moreover, surgery might improve the functional outcome in patients with large hematoma or with IVH compared with conservative treatment. Surgery might be a beneficial choice for part of the patients with spontaneous deep supratentorial hemorrhage, but further detailed research is still needed. PMID- 26986118 TI - Systolic Blood Pressure Variability is a Novel Risk Factor for Rebleeding in Acute Subarachnoid Hemorrhage: A Case-Control Study. AB - Rebleeding of an aneurysm is a major cause of morbidity and mortality after subarachnoid hemorrhage (SAH). Whereas numerous studies have demonstrated predictors of rebleeding and effect of systolic blood pressure variability (SBPV) on stroke, few data on the association between SBPV and rebleeding. Here, we sought to identify the effect of SBPV on rebleeding in acute aneurysmal SAH. Case control study. From January 2010 to June 2015, 612 patients with aneurysmal SAH were enrolled in our tertiary care medical center. MAIN OUTCOME MEASURES: Consecutive patients with acute (<3 days from ictus) aneurismal rebleeding or repair or death were retrospectively included. Antihypertensive therapy based on a predefined standardized protocol was prescribed to lower and maintain SBP between 120 and 160 mm Hg. SBP was measured hourly until a censoring event occurred. SBPV was determined as standard deviation (SD) and successive variation (SV). Binary logistic regression was used to assess the association between SBPV and rebleeding. Rebleeding occurred in 61 (10.0%) of the 612 patients. We identified 47 acute rebleeding as cases and 382 early repair or early death as controls. On binary logistic regression analysis, rebleeding was associated with the SD of SBP (odds ratio [OR], 1.254; 95% confidence interval [CI], 1.131-1.391; P < 0.001) and the SV of SBP (OR, 1.131; 95% CI, 1.039-1.231; P = 0.004). No significant difference was seen between rebleeding and mean systolic blood pressure (MSBP). SBPV is associated with increased rates of acute aneurysmal rebleeding. Further prospective research is warranted to confirm that SBP stability prevents acute aneurysm rebleeding. PMID- 26986117 TI - Observational Study of a French and Belgian Multicenter Cohort of 23 Patients Diagnosed in Adulthood With Mevalonate Kinase Deficiency. AB - The aim of this study was to describe the clinical and biological features of Mevalonate kinase deficiency (MKD) in patients diagnosed in adulthood. This is a French and Belgian observational retrospective study from 2000 to 2014. To constitute the cohort, we cross-check the genetic and biochemical databases. The clinical, enzymatic, and genetic data were gathered from medical records. Twenty three patients were analyzed. The mean age at diagnosis was 40 years, with a mean age at onset of symptoms of 3 years. All symptomatic patients had fever. Febrile attacks were mostly associated with arthralgia (90.9%); lymphadenopathy, abdominal pain, and skin lesions (86.4%); pharyngitis (63.6%); cough (59.1%); diarrhea, and hepatosplenomegaly (50.0%). Seven patients had psychiatric symptoms (31.8%). One patient developed recurrent seizures. Three patients experienced renal involvement (13.6%). Two patients had angiomyolipoma (9.1%). All but one tested patients had elevated serum immunoglobulin (Ig) D level. Twenty-one patients had genetic diagnosis; most of them were compound heterozygote (76.2%). p.Val377Ile was the most prevalent mutation. Structural articular damages and systemic AA amyloidosis were the 2 most serious complications. More than 65% of patients displayed decrease in severity and frequency of attacks with increasing age, but only 35% achieved remission. MKD diagnosed in adulthood shared clinical and genetic features with classical pediatric disease. An elevated IgD concentration is a good marker for MKD in adults. Despite a decrease of severity and frequency of attacks with age, only one-third of patients achieved spontaneous remission. PMID- 26986119 TI - Epidural Cystic Spinal Meningioma: A Case Report. AB - Cystic spinal meningioma (CSM) is an uncommon meningioma variant. Extradural CSMs are particularly rare and difficult to distinguish from other intraaxial tumors. This study presents a case of a 36-year-old woman with intraspinal extradual CSM at the thoracolumbar spine. She experienced persistent weakness, progressive numbness, and sensory disturbance in the right lower limb. Magnetic resonance imaging (MRI) of the patient revealed an irregular cystic mass at the thoracic 11 to lumbar 3 levels dorsally. This case was misdiagnosed as other neoplasms prior to surgery because of the atypical radiographic features and location of the tumor. Extradural CSMs should be considered in the differential diagnosis of intraspinal extradural cystic neoplasms. Complete removal of cystic wall provides an optimal outcome, rendering the lesion curable. PMID- 26986120 TI - What Do Stroke Patients Look for in Game-Based Rehabilitation: A Survey Study. AB - Stroke is one of the most common causes of physical disability, and early, intensive, and repetitive rehabilitation exercises are crucial to the recovery of stroke survivors. Unfortunately, research shows that only one third of stroke patients actually perform recommended exercises at home, because of the repetitive and mundane nature of conventional rehabilitation exercises. Thus, to motivate stroke survivors to engage in monotonous rehabilitation is a significant issue in the therapy process. Game-based rehabilitation systems have the potential to encourage patients continuing rehabilitation exercises at home. However, these systems are still rarely adopted at patients' places. Discovering and eliminating the obstacles in promoting game-based rehabilitation at home is therefore essential. For this purpose, we conducted a study to collect and analyze the opinions and expectations of stroke patients and clinical therapists. The study is composed of 2 parts: Rehab-preference survey - interviews to both patients and therapists to understand the current practices, challenges, and expectations on game-based rehabilitation systems; and Rehab-compatibility survey - a gaming experiment with therapists to elaborate what commercial games are compatible with rehabilitation. The study is conducted with 30 outpatients with stroke and 19 occupational therapists from 2 rehabilitation centers in Taiwan. Our surveys show that game-based rehabilitation systems can turn the rehabilitation exercises more appealing and provide personalized motivation for various stroke patients. Patients prefer to perform rehabilitation exercises with more diverse and fun games, and need cost-effective rehabilitation systems, which are often built on commodity hardware. Our study also sheds light on incorporating the existing design-for-fun games into rehabilitation system. We envision the results are helpful in developing a platform which enables rehab compatible (i.e., existing, appropriately selected) games to be operated on commodity hardware and brings cost-effective rehabilitation systems to more and more patients' home for long-term recovery. PMID- 26986122 TI - Beyond Volume: Hospital-Based Healthcare Technology for Better Outcomes in Cerebrovascular Surgical Patients Diagnosed With Ischemic Stroke: A Population Based Nationwide Cohort Study From 2002 to 2013. AB - We examined whether the level of hospital-based healthcare technology was related to the 30-day postoperative mortality rates, after adjusting for hospital volume, of ischemic stroke patients who underwent a cerebrovascular surgical procedure. Using the National Health Insurance Service-Cohort Sample Database, we reviewed records from 2002 to 2013 for data on patients with ischemic stroke who underwent cerebrovascular surgical procedures. Statistical analysis was performed using Cox proportional hazard models to test our hypothesis. A total of 798 subjects were included in our study. After adjusting for hospital volume of cerebrovascular surgical procedures as well as all for other potential confounders, the hazard ratio (HR) of 30-day mortality in low healthcare technology hospitals as compared to high healthcare technology hospitals was 2.583 (P < 0.001). We also found that, although the HR of 30-day mortality in low healthcare technology hospitals with high volume as compared to high healthcare technology hospitals with high volume was the highest (10.014, P < 0.0001), cerebrovascular surgical procedure patients treated in low healthcare technology hospitals had the highest 30-day mortality rate, irrespective of hospital volume. Although results of our study provide scientific evidence for a hospital volume/30-day mortality rate relationship in ischemic stroke patients who underwent cerebrovascular surgical procedures, our results also suggest that the level of hospital-based healthcare technology is associated with mortality rates independent of hospital volume. Given these results, further research into what components of hospital-based healthcare technology significantly impact mortality is warranted. PMID- 26986121 TI - Parental Use and Educational Campaigns on Sunbed Use Among Teenagers and Adolescents. AB - This study aimed to evaluate the prevalence of sunbed use among teenagers and the association between familial behavior and the adoption of UV-protective practices in this age group. We also assessed the impact of an educational program on students' knowledge about the potential risks of sunbed use. The educational intervention focused on: (i) skin effects of UV radiation, (ii) photoaging and photocarcinogenesis, (iii) risk factors for skin cancer, (iv) indoor sun tanning and misleading concepts such as possible protective effect of sunbed use on skin cancer risk, (v) sun protection and relation with skin phototype, and (vi) early diagnosis of melanoma using the ABCDE check list and the ugly duckling sign. We carried out a survey of 3098 students and found a strong association between parental sunbed use and students' use of the same (P < 0.0001). Students who attended the educational intervention were more aware that sunbed use cannot prevent sunburns (P = 0.03) than those who did not attend, making adjustments for confounding variables. However, sunbed use by parents influenced the desire to use a sunbed more than participation in the educational intervention (P < 0.0001). In conclusion, although our results indicate that educational interventions can improve knowledge of the risk of sunbed use. They also reveal a strong correlation between sunbed use by teenagers and parental behavior that highlights the importance of educational interventions involving families. PMID- 26986124 TI - Diagnostic Difficulties in a Pediatric Insulinoma: A Case Report. AB - Insulinomas are functional neuroendocrine pancreatic tumors rarely encountered in pediatric pathology. Insulinomas are usually solitary and sporadic, but may occur in association with multiple endocrine neoplasia type 1. Whipple's triad hypoglycemia, simultaneous compatible adrenergic and/or neurological signs, and relief of symptoms upon the administration of glucose-remains the fundamental diagnostic tool. We report a case of insulinoma in an 11-year-old boy with malnutrition and mild psychic retardation. History revealed neuroglycopenic symptoms associated with hypoglycemia that returned to normal values after glucose intravenous infusion; before admission in our unit, the levels of circulating insulin, as well as the abdominal ultrasound and abdominal computed tomography scan, were reported within normal range. During hospitalization in our service, the glycemic curves showed recurring low values associated with low glycated hemoglobin, positive fasting test, and elevated C-peptide. The pancreatic ultrasound was inconclusive, but the magnetic resonance imaging revealed a high signal focal area with a diameter of 1 cm, located in the tail of pancreas. Conventional enucleation of the lesion prompted a spectacular normalization of glucose metabolism and the alleviation of the main clinical symptoms. The child had a favorable evolution in the clinical follow-up, presenting with weight gain and progressive remission to complete disappearance of most symptoms-except for the mental impairments. Although in our case Whipple's triad was apparent from the beginning, the diagnosis was delayed due to the failure of conventional imaging methods in locating the tumor. Weight loss and mental impairment contributed to the diagnosis pitfalls. Pediatricians should be aware of confusing and nonspecific symptoms, especially when children with insulinoma present mental or neurological retardation. Despite the existence of medical regimens, surgery remains the gold standard for the therapeutic approach to this condition. PMID- 26986126 TI - Preventable Adverse Events in Surgical Care in Sweden: A Nationwide Review of Patient Notes. AB - Adverse events (AEs) occur in health care and may result in harm to patients especially in the field of surgery. Our objective was to analyze AEs in surgical patient care from a nationwide perspective and to analyze the frequency of AEs that may be preventable. In total 19,141 randomly selected admissions in 63 Swedish hospitals were reviewed each month during 2013 using a 2-stage record review method based on the identification of predefined triggers. The subgroup of 3301 surgical admissions was analyzed. All AEs were categorized according to site, type, level of severity, and degree of preventability. We reviewed 3301 patients' records and 507 (15.4%) were associated with AEs. A total of 62.5% of the AEs were considered probably preventable, over half contributed to prolonged hospital care or readmission, and 4.7% to permanent harm or death. Healthcare acquired infections composed of more than one third of AEs. The majority of the most serious AEs composed of healthcare acquired infections and surgical or other invasive AEs. The incidence of AEs was 13% in patients 18 to 64 years old and 17% in >=65 years. Pressure sores and drug-related AEs were more common in patients being >=65 years. Urinary retention and pressure sores showed the highest degree of preventability. Patients with probably preventable AEs had in median 7.1 days longer hospital stay. We conclude that AEs are common in surgical care and the majority are probably preventable. PMID- 26986125 TI - Protective Effect of Hand-Washing and Good Hygienic Habits Against Seasonal Influenza: A Case-Control Study. AB - Previous observational studies have reported protective effects of hand-washing in reducing upper respiratory infections, little is known about the associations between hand-washing and good hygienic habits and seasonal influenza infection. We conducted a case-control study to test whether the risk of influenza transmission associated with self-reported hand-washing and unhealthy hygienic habits among residents in Fujian Province, southeastern China.Laboratory confirmed seasonal influenza cases were consecutively included in the study as case-patients (n = 100). For each case, we selected 1 control person matched for age and city of residence. Telephone interview was used to collect information on hand-washing and hygienic habits. The associations were analyzed using conditional logistic regression. Compared with the poorest hand-washing score of 0 to 3, odds ratios of influenza infection decreased progressively from 0.26 to 0.029 as hand-washing score increased from 4 to the maximum of 9 (P < 0.001). Compared with the poorest hygienic habit score of 0 to 2, odds ratios of influenza infection decreased from 0.10 to 0.015 with improving score of hygienic habits (P < 0.001). Independent protective factors against influenza infection included good hygienic habits, higher hand-washing score, providing soap or hand cleaner beside the hand-washing basin, and receiving influenza vaccine. Regular hand-washing and good hygienic habits were associated with a reduced risk of influenza infection. These findings support the general recommendation for nonpharmaceutical interventions against influenza. PMID- 26986123 TI - A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. AB - von Willebrand disease (VWD) is a genetic bleeding disease due to a defect of von Willebrand factor (VWF), a glycoprotein crucial for platelet adhesion to the subendothelium after vascular injury. VWD include quantitative defects of VWF, either partial (type 1 with VWF levels <50 IU/dL) or virtually total (type 3 with undetectable VWF levels) and also qualitative defects of VWF (type 2 variants with discrepant antigenic and functional VWF levels). The most bleeding forms of VWD usually do not concern type 1 patients with the mildest VWF defects (VWF levels between 30 and 50 IU/dL). The French reference center for VWD performed a laboratory phenotypic and genotypic analysis in 1167 VWD patients (670 families) selected by their basic biologic phenotype: type 3, type 2, and type 1 with VWF levels <30 IU/dL. In these patients indeed, to achieve an accurate diagnosis of VWD type and subtype is crucial for the management (treatment and genetic counseling). A phenotype/genotype correlation was present in 99.3% of cases; 323 distinct VWF sequence variations (58% of novel) were identified (missense 67% versus truncating 33%). The distribution of VWD types was: 25% of type 1, 8% of type 3, 66% of type 2 (2A: 18%, 2B: 17%, 2M: 19%, 2N: 12%), and 1% of undetermined type. Type 1 VWD was related either to a defective synthesis/secretion or to an accelerated clearance of VWF. In type 3 VWD, bi allelic mutations of VWF were found in almost all patients. In type 2A, the most frequent mechanism was a hyper-proteolysis of VWF. Type 2B showed 85% of patients with deleterious mutations (distinct from type 2B New York). Type 2M was linked to a defective binding of VWF to platelet glycoprotein Ib or to collagen. Type 2N VWD included almost half type 2N/3. This biologic study emphasizes the complex mechanisms for both quantitative and qualitative VWF defects in VWD. In addition, this study provides a new epidemiologic picture of the most bleeding forms of VWD in which qualitative defects are predominant. PMID- 26986127 TI - High Fibroblast Growth Factor 23 Levels Associated With Low Hemoglobin Levels in Patients With Chronic Kidney Disease Stages 3 and 4. AB - In chronic kidney disease (CKD), decreased erythropoietin production, low serum active vitamin D levels, and high renin-angiotensin-aldosterone activities had been regarded as major causes of renal anemia. At present, no clinical data are available to elucidate the association between renal anemia and fibroblast growth factor 23 (FGF23) levels in CKD. This study aimed to access whether FGF23 is involved in the pathogenesis of renal anemia. This cross-sectional observational study included 53 stable outpatients with CKD stages 3 and 4. Our primary predictor was serum FGF23 levels and outcome was hemoglobin levels. Measurements contained hemoglobin, FGF23, 25-hydroxyvitamin D, intact parathyroid hormone, plasma renin, serum aldosterone, HbA1C levels, lipid and iron profiles, and serum and urine electrolytes. Mean age of our patients was 66.4 +/- 12.8 (SD) years, mean estimated glomerular filtration rate 33.5 +/- 13.9 mL/min/1.73 m, median FGF23 level 200 (25th-75th percentile, 124-303) pg/mL, vitamin D level 19.5 (25th 75th percentile, 14.0-25.9) ng/mL, and hemoglobin level 12.7 (25th-75th percentile, 10.7-13.75) g/dL. Even after adjusting multiple variables, lower hemoglobin levels correlated significantly with FGF23 levels that were higher than the median value (>200 pg/mL). Moreover, after adjusting for aldosterone, but not 25-hydroxyvitamin D, it decreased the association with FGF23 that higher than median level and hemoglobin levels. We also observed a significant decrease of hemoglobin level in the higher FGF23 group who had a diabetes history. High FGF23 levels were observed to be associated with low hemoglobin levels, which may be partially mediated through the effects of serum aldosterone levels in our patients with CKD stages 3 and 4. Furthermore, we also presumed that diabetes itself may have an impact on the loop among FGF23, hemoglobin, and aldosterone levels in these CKD patients. PMID- 26986129 TI - Treatments for the Fifth Metacarpal Neck Fractures: A Network Meta-analysis of Randomized Controlled Trials. AB - The fifth metacarpal neck fractures (commonly termed boxer's fractures) are the most common type of metacarpal fractures. Many types of treatments are available in clinical practice, some of which have already been compared with other treatments by various researchers. However, a comprehensive treatment comparison is lacking. We estimated the comparative efficacy of different interventions for total complications, through a network meta-analysis of randomized controlled trials. We conducted a systematic search of the literature through October 2015. The outcome measurements were the total complications. We used a Bayesian network meta-analysis to combine direct and indirect evidence and to estimate the relative effects of treatment. We identified 6 RCTs registering a total of 288 patients who were eligible for our network meta-analysis. The literature's quality is relatively high. The median Structured Effectiveness for Quality Evaluation of Study score for the included trials was 33.8. The overall methodological quality was high. Of the 6 studies, all were 2-arm controlled trials comparing active intervention. Among the 4 treatments--conservative treatment (CT), antegrade intramedullary nailing (AIMN), transverse pinning (TP) with K-wires, and plate fixation (PF)--CT had the best rankings (ie, lowest risk of total complications), followed by PF, AIMN, and TP (ie, highest risk of total complications). Furthermore, we also presented the results using surface under the cumulative ranking curve. The surface under the cumulative ranking curve probabilities were 94.1%, 52.9%, 37.3%, and 15.7% for CT, PF, AIMN, and TP, respectively. In conclusion, current evidence suggested that conservative treatment is the optimum treatment for the fifth metacarpal neck fractures because of reduced total complication rates. Moreover, the TP with K-wires is the worst option with highly total complication rates. PF and AIMN therapy should be considered as the first-line choices. Larger and higher-quality randomized controlled trials are required to confirm these conclusions and better inform clinical decision-making. PMID- 26986128 TI - Antiretroviral Therapy and Viral Suppression Among Foreign-Born HIV-Infected Persons Receiving Medical Care in the United States: A Complex Sample, Cross Sectional Survey. AB - Immigrants to the United States are more likely to be diagnosed with human immunodeficiency virus (HIV) infection compared with native-born persons. Navigating access to healthcare in the United States can be challenging for foreign-born persons, and HIV treatment outcomes may be suboptimal for these persons. We compared characteristics of and assessed disparities in clinical outcomes of foreign-born persons in care for HIV in the United States. The Medical Monitoring Project is a complex sample, cross-sectional survey designed to be nationally representative of HIV-infected adults receiving medical care in the United States. Using data from 2009, 2010, and 2011, we conducted descriptive analyses and multivariable logistic regression to assess associations between foreign-born status and antiretroviral therapy (ART) prescription, and between foreign-born status and viral suppression. In all, 13.4% of HIV-infected persons were self-identified as foreign-born; the most common regions of birth were Central America and Mexico (45.4%) and the Caribbean (16.0%). Nearly 90% of foreign-born persons were diagnosed with HIV after entry into the United States. Compared with US-born persons, foreign-born persons were more likely to be younger, Hispanic, less educated, and uninsured. The prevalence of ART prescription (prevalence ratio 1.00; 95% confidence interval 0.98-1.02) was not significantly different between foreign-born and US-born persons. A higher percentage of foreign-born persons achieved viral suppression compared with US born persons (prevalence ratio 1.05; 95% confidence interval 1.00-1.09). No major disparities in ART prescription and viral suppression were found between foreign born and US-born HIV-infected persons receiving medical care, despite higher percentages being uninsured. PMID- 26986130 TI - Comparative Effectiveness of Biologic Therapy Regimens for Ankylosing Spondylitis: A Systematic Review and a Network Meta-Analysis. AB - To establish the comparative effectiveness of all available biologic therapy regimens for ankylosing spondylitis, we performed a systematic review and a Bayesian network meta-analysis of randomized controlled trials. PubMed, Medline, Embase, Cochrane library, and ClinicalTrials.gov were searched from the inception of each database to June 2015. Systematic review and network meta-analysis was reported according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses. The primary outcome was 20% improvement of Assessments in SpondyloArthritis International Society Response Criteria (ASAS20) at Week 12 or 14; secondary outcomes were ASAS40, ASAS5/6, ASAS partial remission and 50% improvement in baseline Bath ankylosing spondylitis (AS) disease activity index. We reported relative risks and 95% confidence intervals from direct meta analysis and 95% credible intervals from Bayesian network meta-analysis, and ranked the treatment for outcomes. We also used Grading of Recommendations Assessment, Development and Evaluation criteria to appraise quality of evidence. Fourteen RCTs comprising 2672 active AS patients were included in the network meta-analysis. Most biologic therapy regimens were more effective than placebo regarding all the outcomes assessed, except for secukinumab and tocilizumab. No differences between biologic therapies in the treatment of AS could be found, except for the finding that infliximab 5 mg was superior to tocilizumab. Infliximab 5 mg/kg had the highest probability of being ranked the best for achieving ASAS20, whereas notably, secukinumab had the highest probability of being ranked the second best. Our study suggests that no differences between biologic therapies in the treatment of AS could be found except that infliximab 5 mg was superior to tocilizumab. Infliximab 5 mg/kg seems to be the better biologic therapy regimen for AS. Secukinumab appears promising, though additional data is warranted. Nevertheless, these interpretations should be accepted very cautiously. PMID- 26986131 TI - Human Cytokine Genetic Variants Associated With HBsAg Reverse Seroconversion in Rituximab-Treated Non-Hodgkin Lymphoma Patients. AB - Hepatitis B virus (HBV) reactivation has been noted in HBV surface antigen (HBsAg)-seronegative patients with CD20 B-cell non-Hodgkin lymphoma (NHL) undergoing rituximab treatment. Clinically, hepatitis flares are usually associated with the reappearance of HBsAg (reverse seroconversion of HBsAg, HBV RS). It is unclear whether human genetic factors are related to rituximab associated HBV reactivation. Unvaccinated HBsAg-seronegative adults (n = 104) with CD20 NHL who had received rituximab-containing therapy without anti-HBV prophylaxis were enrolled. Eighty-nine candidate single nucleotide polymorphisms (SNPs) of 49 human cytokine genes were chosen and were analyzed using the iPLEX technique. Competing risk regression was used to identify the factors associated with HBV-RS. Participants had a median age of 66.1 years and 56.7% were male (n = 59). The anti-HBs and anti-HBc positivity rates were 82.4% and 94.1%, respectively, among patients for whom data were available (approximately 81%). A mean of 7.14 cycles of rituximab therapy were administered, and a total of 14 (13.4%) patients developed HBV-RS. Nine SNPs showed significant differences in frequency between patients with or without HBV-RS: CD40 rs1883832, IL4 rs2243248 and rs2243263, IL13 rs1295686, IL18 rs243908, IL20 rs1518108, and TNFSF13B rs12428930 and rs12583006. Multivariate analysis showed that >=6 cycles of rituximab therapy, IL18 rs243908, and the IL4 haplotype rs2243248~rs2243263 were independently associated with HBV-RS. The IL4 haplotype rs2243248~rs2243263 was significantly associated with HBV-RS regardless of anti-HBs status. Polymorphisms in human cytokine genes impact the risk of rituximab-associated HBV-RS. PMID- 26986132 TI - Nonapnea Sleep Disorders and the Risk of Acute Kidney Injury: A Nationwide Population-Based Study. AB - Nonapnea sleep disorders (NASDs) and associated problems, which are highly prevalent in patients with kidney diseases, are associated with unfavorable medical sequelae. Nonetheless, whether NASDs are associated with acute kidney injury (AKI) development has not been thoroughly analyzed. We examined the association between NASD and AKI. We conducted a population-based study by using 1,000,000 representative data from the Taiwan National Health Insurance Research Database for the period from January 1, 2000, to December 31, 2010. We studied the incidence and risk of AKI in 9178 newly diagnosed NASD patients compared with 27,534 people without NASD matched according to age, sex, index year, urbanization level, region of residence, and monthly income at a 1:3 ratio. The NASD cohort had an adjusted hazard ratio (hazard ratio [HR]; 95% confidence interval [CI] = 1.15-2.63) of subsequent AKI 1.74-fold higher than that of the control cohort. Older age and type 2 diabetes mellitus were significantly associated with an increased risk of AKI (P < 0.05). Among different types of NASDs, patients with insomnia had a 120% increased risk of developing AKI (95% CI = 1.38-3.51; P = 0.001), whereas patients with other sleep disorders had a 127% increased risk of subsequent AKI (95% CI = 1.07-4.80; P = 0.033). Men with NASDs were at a high risk of AKI (P < 0.05). This nationwide population-based cohort study provides evidence that patients with NASDs are at higher risk of developing AKI than people without NASDs. PMID- 26986133 TI - Primary Intraosseous Cavernous Hemangioma in the Skull. AB - Primary intraosseous cavernous hemangiomas (PICHs) are benign vascular tumors that may involve any part of the body. PICH occurs more frequently in the spine and less commonly in skull. The earliest description in the English literature was in 1845 by Toynbee, who reported a vascular tumor arising in the confines of the parietal bone. Skull PICHs do not always have typical radiologic features and should always be considered in the differential diagnosis of malignant skull lesions. We now reviewed and analyzed related literatures in detail with reporting a rare case of PICH in the left front bone that was surgically resected. PMID- 26986134 TI - Surgical Versus Nonsurgical Treatment for High-Grade Spondylolisthesis in Children and Adolescents: A Systematic Review and Meta-Analysis. AB - The optimal management of high-grade spondylolisthesis in children and adolescent is controversial. There is a paucity of literature regarding operatively or nonoperative management in this setting. To assessment of the current state of evidence regarding high-grade spondylolisthesis treatment with the goal of obtaining outcome comparisons in these patients managed either operatively or nonoperatively. We performed a systematic literature search up to November 2014, using Medline, Embase, and The Cochrane Library. The analysis and eligibility criteria were documented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-guidelines) and Cochrane Back Review Group editorial board. We used the Newcastle-Ottawa quality assessment scale (NOS scale) to assess the quality. Five observational studies were considered eligible for analysis based on the evaluation of 1596 identified papers. The mean overall difference in the Scoliosis Research Society questionnaire 22 between the surgical and nonsurgical groups was not statistically significant (95% CI: -0.17 to 0.21, P = 0.84). The pooled mean difference in progression of slip between the surgical and nonsurgical groups was no significant difference (OR: 0.47, 95% CI: 0.12-1.81, P = 0.27, I = 0%). Because of the preponderance of uncontrolled case series, low-quality evidence indicates that the quality of life and progression of slips was no significant difference between surgery and nonoperation group. Nonoperative patients had no radiologic progression of their slip during the follow-up period. PMID- 26986135 TI - Elevated Serum Leptin Levels are Associated With an Increased Risk of Sentinel Lymph Node Metastasis in Cutaneous Melanoma. AB - The metabolic hormone leptin has been implicated in the pathogenesis of various malignancies and may contribute to the high rate of cancer in obese individuals. We reported that leptin and its receptor are expressed by melanoma tumors and cell lines, and that leptin stimulates proliferation of cultured melanoma cells. Here, we tested the hypothesis that leptin contributes to early melanoma progression by assessing its association with sentinel node positivity in cutaneous melanoma patients. The study enrolled 72 patients who were scheduled to undergo lymphatic mapping and sentinel node biopsy. Fasting blood was obtained before surgery, and serum leptin levels were measured by enzyme-linked immunosorbent assay (ELISA) with a "raw" (assay value) and an "adjusted" value (raw value divided by body mass index). Leptin levels and other clinicopathologic parameters were compared between sentinel node positive and negative groups. Logistic regression models were used to predict sentinel node status using leptin and other relevant clinical parameters. The raw and adjusted leptin levels were significantly higher in the 15 patients with positive sentinel nodes. These findings could not be attributed to differences in body mass indices. Univariate models revealed raw leptin, adjusted leptin, Breslow thickness, and mitotic rate as significant predictors of sentinel node status. Leptin levels and Breslow thickness remained significant in multivariate models. Survival and follow-up analysis revealed more aggressive disease in diabetic patients. Elevated serum leptin levels predict sentinel node metastasis in melanoma. Validation of this finding in larger cohorts should enable better stratification of early stage melanoma patients. PMID- 26986136 TI - The Association Between Genetic Variants in the Dopaminergic System and Posttraumatic Stress Disorder: A Meta-Analysis. AB - Posttraumatic stress disorder (PTSD) is a complex mental disorder and can severely interfere with the normal life of the affected people. Previous studies have examined the association of PTSD with genetic variants in multiple dopaminergic genes with inconsistent results. To perform a systematic literature search and conduct meta-analysis to examine whether genetic variants in the dopaminergic system is associated with PTSD. Data Sources: PubMed, Cochrane Library, Embase, Google Scholar, and HuGE. Study eligibility criteria and participants: The studies included subjects who had been screened for the presence of PTSD; the studies provided data for genetic variants of genes involved in the dopaminergic system; the outcomes of interest included diagnosis status of PTSD; and the studies were case-control studies. Study appraisal and synthesis methods: Odds ratio was used as a measure of association. We used random-effects model in all the meta-analyses. Between-study heterogeneity was assessed using I2, and publication bias was evaluated using Egger test. Findings from meta-analyses were confirmed using random-effects meta-analyses under the framework of generalized linear model (GLM). A total of 19 studies met the eligibility criteria and were included in our analyses. We found that rs1800497 in DRD2 was significantly associated with PTSD (OR = 1.96, 95% CI: 1.15-3.33; P = 0.014). The 3'-UTR variable number tandem repeat (VNTR) in SLC6A3 also showed significant association with PTSD (OR = 1.62, 95% CI: 1.12-2.35; P = 0.010), but there was no association of rs4680 in COMT with PTSD (P = 0.595). Sample size is limited for some studies; type and severity of traumatic events varied across studies; we could not control for potential confounding factors, such as age at traumatic events and gender; and we could not examine gene-environment interaction due to lack of data. We found that rs1800497 in DRD2 and the VNTR in SLC6A3 showed significant association with PTSD. Future studies controlling for confounding factors, with large sample sizes and more homogeneous traumatic exposure, are needed to validate the findings from this study. PMID- 26986137 TI - Chinese Herbal Products for Female Infertility in Taiwan: A Population-Based Cohort Study. AB - Female infertility and low birth rate are significant public health issues with profound social, psychological, and economic consequences. Some infertile women resort to conventional, complementary, or alternative therapies to conceive. The aim of this study was to identify the Chinese herbal products (CHPs) most commonly used for female infertility in Taiwan. The usage of traditional Chinese medicine (TCM) and the frequency of CHP prescriptions to infertile women were determined based on a nationwide 1-million randomly sampled cohort of National Health Insurance Research Database beneficiaries. Descriptive statistics and multiple logistic regression analysis were employed to estimate the adjusted odds ratio (aOR) for TCM usage and potential risk factors. In total, 8766 women with newly diagnosed infertility were included in this study. Of those, 8430 (96.17%) had sought TCM treatment in addition to visiting the gynecologist. We noted that female infertility patients with risk factors (e.g., endometriosis, uterine fibroids, or irregular menstrual cycle) were more likely to use TCM than those without TCM medication (aOR = 1.83, 1.87, and 1.79, respectively). The most commonly used formula and single CHP were Dang-Gui-Sha-Yao-San (17.25%) and Semen Cuscutae (27.40%), respectively. CHP formula combinations (e.g., Dang-Gui-Sha-Yao San plus Wen-Jing-Tang 3.10%) or single Chinese herbal combinations (e.g., Semen Cuscutae plus Leonurus japonicus 6.31%) were also commonly used to treat female infertility. Further well-conducted, double-blind, randomized, placebo-controlled studies will be needed to evaluate the efficacy and safety of these CHP combinations for female infertility. PMID- 26986139 TI - Infectious Complications and Morbidities After Neonatal Bloodstream Infections: An Observational Cohort Study. AB - Few data are available on the clinical characteristics of complications and morbidities after neonatal bloodstream infections (BSIs), understood as any newly infectious focus or organ dysfunction directly related to BSIs but not occur concurrently. However, these bloodstream-associated infectious complications (BSICs) contribute significantly to increased hospital stay, cost, and final mortality. We performed an observational cohort study of unselected neonatal intensive care unit (NICU) patients based on records in a large clinical database. All neonates hospitalized in our NICU with BSI between 2006 and 2013 were reviewed, and those who developed BSICs were analyzed to identify the clinical characteristics and outcomes. Multivariate logistic regression was used to identify independent risk factors for BSICs. Of 975 episodes of neonatal BSI, 101 (10.4%) BSICs occurred in 93 neonates with a median interval of 3 days (range, 0-17 days) after onset of BSI and included newly infectious focuses in 40 episodes (39.6%), major organ dysfunctions after septic shock in 36 episodes (35.6%), and neurological complications after meningitis or septic shock in 34 episodes (33.7%). All patients with BSICs encountered various morbidities, which subsequently resulted in in-hospital death in 30 (32.3%) neonates, critical discharge in 4 (4.3%), and persistent sequelae in 17 (18.3%). After multivariate logistic regression analysis, independent risk factors for BSICs included initial inappropriate antibiotics (odds ratio [OR], 5.54; 95% confidence interval [CI], 3.40-9.01), BSI with septic shock (OR, 5.75; 95% CI, 3.51-9.40), and BSI concurrent with meningitis (OR, 9.20; 95% CI, 4.33-19.56). It is worth noting that a percentage of neonates with BSI encountered subsequent sequelae or died of infections complications, which were significantly associated with initial inappropriate antibiotic therapy, septic shock, and the occurrence of meningitis. Further investigation is warranted to decrease the occurrence of BSICs due to their significant contribution toward final mortality. PMID- 26986138 TI - Pre-transplant Evaluation of Donor Urinary Biomarkers can Predict Reduced Graft Function After Deceased Donor Kidney Transplantation. AB - Several recipient biomarkers are reported to predict graft dysfunction, but these are not useful in decision making for the acceptance or allocation of deceased donor kidneys; thus, it is necessary to develop donor biomarkers predictive of graft dysfunction. To address this issue, we prospectively enrolled 94 deceased donors and their 109 recipients who underwent transplantation between 2010 and 2013 at 4 Korean transplantation centers. We investigated the predictive values of donor urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and L-type fatty acid binding protein (L-FABP) for reduced graft function (RGF). We also developed a prediction model of RGF using these donor biomarkers. RGF was defined as delayed or slow graft function. Multiple logistic regression analysis was used to generate a prediction model, which was internally validated using a bootstrapping method. Multiple linear regression analysis was used to assess the association of biomarkers with 1-year graft function. Notably, donor urinary NGAL levels were associated with donor AKI (P = 0.014), and donor urinary NGAL and L-FABP were predictive for RGF, with area under the receiver-operating characteristic curves (AUROC) of 0.758 and 0.704 for NGAL and L-FABP, respectively. The best-fit model including donor urinary NGAL, L FABP, and serum creatinine conveyed a better predictive value for RGF than donor serum creatinine alone (P = 0.02). In addition, we generated a scoring method to predict RGF based on donor urinary NGAL, L-FABP, and serum creatinine levels. Diagnostic performance of the RGF prediction score (AUROC 0.808) was significantly better than that of the DGF calculator (AUROC 0.627) and the kidney donor profile index (AUROC 0.606). Donor urinary L-FABP levels were also predictive of 1-year graft function (P = 0.005). Collectively, these findings suggest donor urinary NGAL and L-FABP to be useful biomarkers for RGF, and support the use of a new scoring system based on donor biomarkers to facilitate decision-making in acceptance and allocation of deceased donor kidneys and contribute to maximal organ utilization. PMID- 26986140 TI - Diagnostic Accuracy of Procalcitonin in Bacterial Meningitis Versus Nonbacterial Meningitis: A Systematic Review and Meta-Analysis. AB - Several studies have investigated the diagnostic accuracy of procalcitonin (PCT) levels in blood or cerebrospinal fluid (CSF) in bacterial meningitis (BM), but the results were heterogeneous. The aim of the present study was to ascertain the diagnostic accuracy of PCT as a marker for BM detection. A systematic search of the EMBASE, Scopus, Web of Science, and PubMed databases was performed to identify studies published before December 7, 2015 investigating the diagnostic accuracy of PCT for BM. The quality of the eligible studies was assessed using the revised Quality Assessment for Studies of Diagnostic Accuracy method. The overall diagnostic accuracy of PCT detection in CSF or blood was pooled using the bivariate model. Twenty-two studies involving 2058 subjects were included in this systematic review and meta-analysis. The overall specificities and sensitivities were 0.86 and 0.80 for CSF PCT, and 0.97 and 0.95 for blood PCT, respectively. Areas under the summary receiver operating characteristic curves were 0.90 and 0.98 for CSF PCT and blood PCT, respectively. The major limitation of this systematic review and meta-analysis was the small number of studies included and the heterogeneous diagnostic thresholds adopted by eligible studies. Our meta analysis shows that PCT is a useful biomarker for BM diagnosis. PMID- 26986141 TI - Impact of Obliterative Portal Venopathy Associated With Human Immunodeficiency Virus. AB - HIV-associated obstructive portopathy (HIVOP) is an obstruction of the hepatic microvasculature of unknown origin. The purpose of this study was to describe the clinical and paraclinical presentation of the disease and its impact in terms of morbidity. Twenty-nine HIV1-infected patients (average 12 years of infection, nadir of CD4 210/mm, including 7 patients with a history of opportunistic infection) with a biopsy-proven or likely HIVOP have been followed up for an average of 6.1 years. Modes of revelation of the HIVOP were: cytolysis and/or cholestasis (60%), occult (14%) or symptomatic (37%) portal hypertension (esophageal varices 17%, ascites 10%, cytopenia 10%), or fortuitous (8%). Hypoalbuminemia (<=35 g/L) was present in (31%), thrombocytopenia (<150,000 platelets) in 52% and prothrombin rate <70% in 10%. Esophageal varices were detected in 71%. Thrombophilia was present in 23 patients (80%): in head, protein S deficiency (87%). MRI showed in 82% at least 1 morphological abnormality. The average value of the liver stiffness by Fibroscan was 8.3 kPa. During follow-up, there was no radiological improvement, 15 (52%) patients presented with variceal hemorrhage, 10 patients (34%) ascites, 10 (34%) portal vein thrombosis, 7 (24%) an iron deficiency, and 2 (7%) with a protein-losing enteropathy, including 14 patients (48%) with several events. Four patients (14%) were transplanted, 1 (25%) recurred the HIVOP on the graft, and 1 patient is waiting for a transplant. HIVOP is a severe disease associated with high morbidity related to symptomatic portal hypertension, which occurred in 50% and required liver transplantation in 14%. PMID- 26986142 TI - Chemokine-Like Factor 1 (CKLF-1) is Overexpressed in Keloid Patients: A Potential Indicating Factor for Keloid-Predisposed Individuals. AB - Chemokine-like factor 1 (CKLF-1) is a novel cytokine which have a crucial role in immune and inflammatory responses. In this study, the expression level of CKLF-1 was measured to assess the difference between keloid patients and people without keloid. Fifty samples were taken from 30 patients: 10 keloid patients; 10 scar patients; and 10 patients without obvious scarring. Patients were randomly selected from the hospitalized patients of Peking Union Medical College Hospital from September 2013 to July 2015. Five groups of samples were established: keloid samples from keloid patients (K); normal skin samples from keloid patients (KS); scar samples from scar patients (C); normal skin samples from scar patients (CS); and normal skin samples from patients without obvious scarring (S). Hematoxylin and eosin (H&E) staining was used to observe morphological changes. CKLF-1, IL-6, IL-8, IL-18, and TGF-beta were detected by immunohistochemical and western blot technology. The expression of CKLF-1's mRNA was also measured by the real-time quantitative polymerase chain reaction (RT-qPCR). Compared to the K group, the other 4 groups presented significantly less inflammatory infiltration and lower expression levels of CKLF-1, IL-6, IL-8, IL-18, and TGF-beta. Among the 3 normal skin groups, the expression level of CKLF-1 was significantly higher in the KS group than in the CS or S group. The mRNA expression was also obvious in the K and KS groups. CKLF-1 and other inflammatory factors were overexpressed in the samples from keloid patients, indicating that the formation of keloid may be related to inflammation and that CKLF-1 may play an important role in this process. PMID- 26986143 TI - Reproducibility of Kidney Perfusion Measurements With Arterial Spin Labeling at 1.5 Tesla MRI Combined With Semiautomatic Segmentation for Differential Cortical and Medullary Assessment. AB - Magnetic resonance imaging with arterial spin labeling (ASL) is a noninvasive approach to measure organ perfusion. The purpose of this study was to evaluate the reproducibility of ASL kidney perfusion measurements with semiautomatic segmentation, which allows separate quantification of cortical and medullary perfusion. The right kidneys of 14 healthy volunteers were examined 6 times on 2 occasions (3 times at each occasion). There was a 10-minute pause between each examination and a 14-day interval between the 2 occasions. Cortical, medullary, and whole kidney parenchymal perfusion was determined with customized semiautomatic segmentation software. Coefficient of variances (CVs) and intraclass correlations (ICCs) were calculated. Mean whole, cortical, and medullary kidney perfusion was 307.26 +/- 25.65, 337.10 +/- 34.83, and 279.61 +/- 26.73 mL/min/100 g, respectively. On session 1, mean perfusion for the whole kidney, cortex, and medulla was 307.08 +/- 26.91, 336.79 +/- 36.54, and 279.60 +/ 27.81 mL/min/100 g, respectively, and on session 2, 307.45 +/- 24.65, 337.41 +/- 33.48, and 279.61 +/- 25.94 mL/min/100 g, respectively (P > 0.05; R2 = 0.60/0.59/0.54). For whole, cortical, and medullary kidney perfusion, the total ICC/CV were 0.97/3.43 +/- 0.86%, 0.97/4.19 +/- 1.33%, and 0.96/4.12 +/- 1.36%, respectively. Measurements did not differ significantly and showed a very good correlation (P > 0.05; R2 = 0.75/0.76/0.65). ASL kidney measurements combined with operator-independent semiautomatic segmentation revealed high correlation and low variance of cortical, medullary, and whole kidney perfusion. PMID- 26986144 TI - Association Between Autonomic Impairment and Structural Deficit in Parkinson Disease. AB - Patients with Parkinson disease (PD) have impaired autonomic function and altered brain structure. This study aimed to evaluate the relationship of gray matter volume (GMV) determined by voxel-based morphometry (VBM) to autonomic impairment in patients with PD. Whole-brain VBM analysis was performed on 3-dimensional T1 weighted images in 23 patients with PD and 15 sex- and age-matched healthy volunteers. The relationship of cardiovascular autonomic function (determined by survey) to baroreflex sensitivity (BRS) (determined from changes in heart rate and blood pressure during the early phase II of the Valsalva maneuver) was tested using least-squares regression analysis. The differences in GMV, autonomic parameters, and clinical data were correlated after adjusting for age and sex. Compared with controls, patients with PD had low BRS, suggesting worse cardiovascular autonomic function, and smaller GMV in several brain locations, including the right amygdala, left hippocampal formation, bilateral insular cortex, bilateral caudate nucleus, bilateral cerebellum, right fusiform, and left middle frontal gyri. The decreased GMVs of the selected brain regions were also associated with increased presence of epithelial progenitor cells (EPCs) in the circulation. In patients with PD, decrease in cardiovascular autonomic function and increase in circulating EPC level are associated with smaller GMV in several areas of the brain. Because of its possible role in the modulation of the circulatory EPC pool and baroreflex control, the left hippocampal formation may be a bio-target for disease-modifying therapy and treatment monitoring in PD. PMID- 26986145 TI - Association of the Transcription Factor 7 Like 2 (TCF7L2) Polymorphism With Diabetic Nephropathy Risk: A Meta-Analysis. AB - It is assumed that genetic factors may participate in the development of diabetic nephropathy (DN). The association between TCF7L2 gene polymorphism and DN risk is still unclear. To evaluate the relationship, we performed this meta-analysis. Eligible relevant studies were searched and selected from PubMed, Embase, and ISI Web of Science. Summary effect estimates were derived using a random effects model, with attention to study quality and publication bias. Ethnical approval was not necessary, because this meta-analysis was based on published articles, and did not involve patient consent. A total of 7 studies were identified. Analysis of all studies indicated significant association between TCF7L2 gene polymorphism and DN risk (odds ratio [OR] = 1.31, 95% confidence interval (CI) = 1.10-1.56, Pheterogeneity < 0.00001, P = 0.002). Subgroup analysis showed similar results in Asian (OR = 1.33, 95% CI = 1.10-1.62, Pheterogeneity = 0.03, P = 0.004), in Caucasian (OR = 2.27, 95% CI = 1.78-2.90, Pheterogeneity = 0.17, P < 0.00001), in rs7903146 mutation (OR = 1.61, 95% CI = 1.25-2.07, Pheterogeneity < 0.00001, P = 0.0002), However, no association was observed in Negroid (OR = 1.10, 95% CI = 0.90-1.35, Pheterogeneity < 00001, P = 0.36). Our results suggest that TCF7L2 gene polymorphism may contribute to the risk of DN. However, more studies should be launched in the future. PMID- 26986146 TI - Duodenal Adenocarcinoma Metastatic to the Breast: A Case Report. AB - Duodenal adenocarcinoma, a very rare malignant gastrointestinal tumor, mainly metastasizes via the lymphatic system. Metastases from duodenal adenocarcinomas to the breast are very uncommon. A 31-year-old woman presented at our department with a left breast tumor. She had a past medical history of duodenal adenocarcinoma. Physical examination on admission confirmed a 2.5-cm-diameter tumor in the outer lower quadrant of the left breast. Computed tomography (CT) examination showed a soft lesion with tissue-like density and enlarged axillary lymph nodes. Local excision was performed to remove the breast lesion. The findings of cytologic, histologic, and immunohistochemistry examination indicated a breast metastasis from the previous duodenal adenocarcinoma. The patient was treated with palliative chemotherapy. Metastases from duodenal adenocarcinoma to the breast are rare. The diagnosis depends on medical history, imaging, and pathologic examination including immunohistochemistry. An accurate diagnosis is important to avoid unnecessary surgery. PMID- 26986147 TI - Clinical Significance of HLA-DQ Antibodies in the Development of Chronic Antibody Mediated Rejection and Allograft Failure in Kidney Transplant Recipients. AB - With the development of the single antigen beads assay, the role of donor specific alloantibody (DSA) against human leukocyte antigens in kidney transplantation (KT) has been highlighted. This study aimed to investigate the clinical significance of DQ-DSA detected at renal allograft biopsy. We evaluated 263 KT recipients who underwent allograft biopsy and DSA detection at the same time. Among them, 155 patients who were nonsensitized before transplantation were selected to investigate the role of de-novo DQ-DSA. Both the total and nonsensitized subgroup was categorized into 4 groups each according to DSA results as: DQ only, DQ + non-DQ, non-DQ, and no DSA. In the total patient group, post-KT DSA was positive in 79 (30.0%) patients and DQ-DSA was most prevalent (64.6%). In the nonsensitized subgroup, de-novo DSAs were detected in 45 (29.0%) patients and DQ-DSA was also most prevalent (73.3%). The DQ only group showed a significantly longer post-KT duration compared to the other groups (P < 0.05). The overall incidence of antibody-mediated rejection (AMR) was 17.9%. B-DSA, DR DSA, and DQ-DSA were associated with AMR (P < 0.05), but in the analysis for chronic AMR, only DQ-DSA showed significance in both the total and the nonsensitized subgroup (P < 0.05). On comparison of Banff scores among groups, those representing humoral immunity were significantly dominant in all DSA positive groups compared to the no DSA group (P < 0.05), and higher scores of markers representing chronic tissue injury were more frequently detected in the groups with DQ-DSA. The worst postbiopsy survival was seen in the DQ + non-DQ group of the total patient group, and patients with de-novo DQ-DSA showed poorer graft survival in the nonsensitized subgroup compared to the no DSA group (P < 0.05). In the multivariate analysis, de-novo DQ-DSA was the only significant risk factor associated with late allograft failure (P < 0.05). Our study is the first to demonstrate the association of DQ-DSA with detailed histological findings representing chronic AMR. These findings suggest that the detection of DQ-DSA in nonsensitized patients is significantly associated with the development of chronic AMR and late allograft failure. Therefore monitoring of DQ-DSA not only in sensitized patients, but also nonsensitized patients may be necessary to improve long-term allograft outcomes. PMID- 26986148 TI - Systematic Review of Acupuncture for Chronic Prostatitis/Chronic Pelvic Pain Syndrome. AB - Acupuncture is a promising therapy for relieving symptoms in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), which affects >15% of adult men worldwide. The aim of the study was to assess the effects and safety of the use of acupuncture for CP/CPPS. MEDLINE, EMBASE, CENTRAL, Web of Science, CBM, CNKI, Wang-Fang Database, JCRM, and CiNii were searched from their inception through 30 November 2015. Grey literature databases and websites were also searched. No language limits were applied. Only randomized controlled trials (RCTs) with CP/CPPS treated by acupuncture were included. Two reviewers extracted data and assessed the risk of bias of RCTs using the Cochrane Risk of Bias Tools, respectively. Seven trials were included, involving 471 participants. The result of meta-analysis indicated that compared with sham acupuncture (MD: -6.09 [95%CI: -8.12 to -5.68]) and medicine (Levofloxacinand, Ibuprofen, and Tamsulosin) (MD: 4.57 [95%CI: -7.58 to -1.56]), acupuncture was more effective at decreasing the total NIH-CPSI score. Real acupuncture was superior to sham acupuncture in improving symptoms (pain, voiding) and quality of life (Qof) domain subscores. Compared to sham acupuncture and medicine, acupuncture appears to be more effective at improving the global assessment. Two trials found that there is no significant difference between acupuncture and sham acupuncture in decreasing the IPSS score. Acupuncture failed to show more favorable effects in improving both symptoms and the Qof domain compared with medicine. Overall, current evidence supports acupuncture as an effective treatment for CP/CPPS-induced symptoms, particularly in relieving pain. Based on the meta-analysis, acupuncture is superior to sham acupuncture in improving symptoms and Qof. Acupuncture might be similar to medicine (Levofloxacinand, Ibuprofen, and Tamsulosin) in its long-term effects, but evidence was limited due to high ROB among included trials as well as potential heterogeneity. Acupuncture is associated with rare and slightly adverse events. Protocol registration PROSPERO CRD42015027522. PMID- 26986149 TI - Gemcitabine-Based Regional Intra-Arterial Infusion Chemotherapy in Patients With Advanced Pancreatic Adenocarcinoma. AB - The present study was carried out to investigate the prognostic factors in patients who received intra-arterial infusion for advanced pancreatic cancer. In addition, the detailed procedure of intra-arterial infusion chemotherapy was described. A total of 354 patients with advanced unresectable pancreatic adenocarcinoma were recruited from January 2012, to April 2015, at Zhongshan Hospital Fudan University, Shanghai, China. Demographic and clinic characteristics of the patients were extracted from electronic medical records. Restricted cubic spline was used to assess the nonliner regression between baseline CA19-9 value and overall survival. Kaplan-Meier analysis and Cox proportional hazard models were used to estimate the association between overall survival and clinical characteristics. Of all 354 included patients, 230 (65%) were male (male/female ratio = 1.8), and 72 (20%) patients were diagnosed with detectable distant metastases. Pretreatment CA19-9 value of patients with metastases was significantly higher as compared to those with locally advanced cancer (median: 922.30 vs 357.00 U/mL, P = 0.0090). Totally 274 patients completed 1 cycle of intra-arterial infusion, whereas 80 patients received 2 or more cycles of the chemotherapy. For all the 354 patients, median OS was 7.0 months (95% CI: 6.0, 8.0 months) with a 6-, 12-, and 18-month survival rate of 0.48, 0.28, and 0.18, respectively. The median OS of patients, who received 1 cycle of intra-arterial infusion therapy, was 6.0 months (95% CI: 5.0, 8.0 months), which was similar to 7.0 months (95% CI: 6.0, 9.0 months) in patients who received 2 or more cycles. Restricted cubic spline revealed the nonline association between baseline CA19-9 and prognosis. The Cox proportional hazard model showed that age, CA19-9 baseline, CA19-9 value, and tumor location were significantly associated with the OS. In conclusion, the gemcitabine-based RIAC presented a potential treatment method for advanced pancreatic adenocarcinoma. Young age, pretreatment CA19-9 value <1000 U/mL, and tumor located at the head of pancreas indicated better response to the regional intra-arterial chemotherapy and better overall survival. PMID- 26986150 TI - Increased APRIL Expression Induces IgA1 Aberrant Glycosylation in IgA Nephropathy. AB - Aberrant glycosylated IgA1 molecules, mainly galactose-deficient IgA1 (Gd-IgA1), are important causal factors in IgA nephropathy; however, the underlying mechanism for the production of aberrantly glycosylated IgA1 is unknown. A recent genome-wide association study identified a novel IgAN susceptibility gene, TNFSF13, which encoded a proliferation-inducing ligand (APRIL) that promotes lymphocyte proliferation and IgA class switching. We aimed to explore the mechanism of APRIL's involvement in IgAN. We enrolled 166 patients with IgAN and 77 healthy controls and detected the plasma APRIL levels by the ELISA method, identified the mRNA expression of APRIL and its receptors by relative quantitative PCR, and confirmed by in vitro experiment. We identified increased plasma APRIL levels in IgAN, which was further proved by upregulated mRNA expression in B-lymphocytes from 27 IgAN patients. Analysis of the clinical characteristics of patients with IgAN showed that higher plasma APRIL level was associated with more severe clinical presentations (high proteinuria and low eGFR). The plasma APRIL level was positively correlated with Gd-IgA1 levels. Furthermore, exogenous APRIL could induce more production of Gd-IgA1 in cultured lymphocytes from patients with IgAN, compared with that from healthy controls. And, the relative higher expression of receptors of APRIL, that is, BCMA and TACI, in B-lymphocytes from IgAN patients were observed. Our findings implied that in patients with IgAN, increased APRIL is accompanied elevated expression of its receptors in B-lymphocytes, which induces overproduction of Gd-IgA1, ultimately contributing to the pathogenesis of IgAN. PMID- 26986151 TI - Sex-Related Differences Between Patients With Symptomatic Acute Aortic Dissection. AB - We designed a retrospective cohort study to assess sex-related differences in clinical manifestations, incidence, and outcomes of patients with symptomatic acute aortic dissection (AAD). We collected clinical data from 2010 to 2015 of 400 patients with AAD. Patients' clinical characteristics, treatment, and outcomes were analyzed as a function of sex. Among 400 patients with AAD, the ratio of men to women was 3.18:1; the incidence of atherosclerosis was higher in women (P = 0.02). Dysphoria (P = 0.01), focal neurological deficits (P = 0.04), and pulse deficits (P = 0.03) were more frequent in men. Imaging findings revealed that pleural effusion (P < 0.01), celiac trunk involvement (P < 0.01), and superior mesenteric artery involvement (P = 0.02) were more frequent in men. Dissection-related pneumonia (P = 0.02), pulmonary atelectasis (P = 0.01), aortic intramural hematoma (P < 0.01), ischemic electrocardiographic changes (P = 0.03), and in-hospital complications such as myocardial ischemia (P = 0.03), hypoxemia (P < 0.01), cardiac tamponade (P = 0.01) occurred more frequently in women. Women with type A dissection had higher in-hospital mortality than men (P < 0.01). The presentation of AAD varies with a patient's sex. Women with AAD had clinical features different from men as follows: higher age of onset, more frequent inpatient complications, and higher in-hospital mortality. These findings may lead to a better understanding of aortic dissection in women that will improve their outcomes. PMID- 26986152 TI - Disrupted Intrinsic Local Synchronization in Poststroke Aphasia. AB - Evidence has accumulated from the task-related and task-free (i.e., resting state) studies that alternations of intrinsic neural networks exist in poststroke aphasia (PSA) patients. However, information is lacking on the changes in the local synchronization of spontaneous functional magnetic resonance imaging blood oxygen level-dependent fluctuations in PSA at rest. We investigated the altered intrinsic local synchronization using regional homogeneity (ReHo) on PSA (n = 17) and age- and sex-matched healthy controls (HCs) (n = 20). We examined the correlations between the abnormal ReHo values and the aphasia severity and language performance in PSA. Compared with HCs, the PSA patients exhibited decreased intrinsic local synchronization in the right lingual gyrus, the left calcarine, the left cuneus, the left superior frontal gyrus (SFG), and the left medial of SFG. The local synchronization (ReHo value) in the left medial of SFG was positively correlated with aphasia severity (r = 0.55, P = 0.027) and the naming scores of Aphasia Battery of Chinese (r = 0.66, P = 0.005). This result is consistent with the important role of this value in language processing even in the resting state. The pathogenesis of PSA may be attributed to abnormal intrinsic local synchronous in multiple brain regions. PMID- 26986153 TI - Atrial Fibrillation is Associated With Morphine Treatment in Female Breast Cancer Patients: A Retrospective Population-Based Time-Dependent Cohort Study. AB - We investigated the relationship between morphine treatment and the risk of atrial fibrillation (AF) in female patients with breast cancer. We identified a malignancy cohort of 73,917 female breast cancer patients without an AF history before the date of breast cancer diagnosis between 2000 and 2010 by using the Longitudinal Health Insurance Database for Catastrophic Illness Patients in Taiwan. This malignancy cohort was divided into morphine and comparison cohorts comprising 18,671 and 55,246 patients, respectively, and the incidences of newly diagnosed AF were calculated. We used the Cox proportional hazard model with time dependent exposure covariates to estimate the risk of AF. The effect of morphine was assessed through multivariable Cox proportional hazard regression controlling for age, the Charlson comorbidity index (CCI) score, and the use of bisphosphonates and paclitaxel. Compared with nonmorphine users, patients who received morphine exhibited a 4.37-fold (95% CI = 3.56-5.36) increase in the risk of developing AF. The risk of AF increased as the CCI score increased, but decreased in patients with tamoxifen treatment. This risk is especially significant in current morphine users of all ages and with low CCI score. AF risk increased as the duration of morphine use lengthened (P for trend <0.0001). The incidence of AF in female breast cancer patients in Taiwan is associated with morphine, but prevented by tamoxifen treatment. PMID- 26986154 TI - Comparisons of Prognosis between Surgically and Clinically Diagnosed Idiopathic Pulmonary Fibrosis Using Gap Model: A Korean National Cohort Study. AB - Although a multidisciplinary approach has become an important criterion for an idiopathic pulmonary fibrosis (IPF) diagnosis, lung biopsies remain crucial. However, the prognosis of patients with surgically diagnosed IPF (sIPF) is uncertain. We aimed to investigate the prognosis of patients with clinically diagnosed IPF (cIPF) and sIPF. In this retrospective observational study, the Korean Interstitial Lung Disease Study Group conducted a national survey to evaluate the clinical, physiological, radiological, and survival characteristics of patients with IPF from January 1, 2003 to December 31, 2007. Patients were recruited from 54 universities and teaching hospitals across the Republic of Korea. IPF diagnoses were established according to the 2002 American Thoracic Society (ATS)/European Respiratory Society criteria (ERS) guideline. A total of 1685 patients with IPF (1027 cIPF and 658 sIPF) were enrolled. Patients with sIPF were significantly younger, predominantly female, and nonsmokers (all P < 0.001). sIPF group had significantly better initial pulmonary function. The proportion of computed tomography-based honeycomb findings of patients with cIPF was higher than in those with sIPF (P < 0.001). A Kaplan-Meier analysis showed that the sIPF group had a better prognosis (P = 0.001). A survival analysis showed that age, pulmonary function parameters, pulmonary oxygen tension, honeycombing change, and combined lung cancer had a significant influence on patient prognosis. However, there was no significant difference in prognosis between the cIPF and sIPF groups after adjusting for GAP (gender, age, physiology) stage. The patients with sIPF had better clinical features than those with cIPF. However, after adjusting for GAP stage, the sIPF group showed similar prognoses as the cIPF group. This study showed that after adjusting for GAP stage, the prognosis of patients with IPF is the same regardless of the diagnostic method used. PMID- 26986155 TI - Comparative Impact of Suppressive Antiretroviral Regimens on the CD4/CD8 T-Cell Ratio: A Cohort Study. AB - Although different factors have been implicated in the CD4/CD8 T-cell ratio recovery in HIV-infected patients who receive effective antiretroviral therapy (ART), limited information exists on the influence of the regimen composition. A longitudinal study carried out in a prospective, single-center cohort of HIV infected patients. ART regimens including non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), or integrase strand transfer inhibitors (INSTI) from patients who achieved long-term (>=6-month duration) virological suppression (HIV-RNA < 400 copies/mL) from January 1998 to June 2014 were analyzed. The impact of ART composition on the changes of the CD4/CD8 T-cell ratio was modeled using a mixed linear approach with adjustment for possible confounders. A total of 1068 ART regimens from 570 patients were analyzed. Mean (SD) age of the patients was 42.15 (10.68) years and 276 (48.42%) had hepatitis C virus (HCV) coinfection. Five hundred fifty-eight (52.25%) regimens were PI based, 439 (40.10%) NNRTI-based, and 71 (6.65%) INSTI-based; 487 (45.60%) were initial regimens, 476 (44.57%) simplification, and 105 (9.83%) salvage regimens. Median (IQR) number of regimens was 1 (1-2) per patient, of 29 (14-58) months duration, and 4 (3-7) CD4/CD8 measurements per regimen. The median baseline CD4/CD8 ratio was 0.42, 0.50, and 0.54, respectively, with the PI-, NNRTI-, and INSTI-based regimens (P = 0.0073). Overall median (IQR) increase of CD4/CD8 ratio was 0.0245 (-0.0352-0.0690) per year, and a CD4/CD8 ratio >=1 was achieved in 19.35% of the cases with PI-based, 25.97% with NNRTI-based, and 22.54% with INSTI based regimens (P = 0.1406). In the adjusted model, the mean CD4/CD8 T-cell ratio increase was higher with NNRTI-based regimens compared for PI-based (estimated coefficient for PI [95% CI], -0.0912 [-0.1604 to -0.0219], P = 0.009). Also, a higher CD4/CD8 baseline ratio was associated with higher CD4/CD8 increase in the adjusted model (P = 0.001); by contrast, higher age (P = 0.020) and simplification of ART regimen (P = 0.003) had a negative impact on the CD4/CD8 ratio. Antiretroviral regimen composition has a differential impact on the CD4/CD8 T-cell ratio; NNRTI-based regimens are associated with enhanced CD4/CD8 T cell ratio recovery compared to PI-based antiretroviral regimens. PMID- 26986156 TI - A Case Report of Esophageal Bronchogenic Cyst and Review of the Literature With an Emphasis on Endoscopic Ultrasonography Appearance. AB - Esophageal bronchogenic cysts are extremely rare. Here we report a more rare type of both presence of intra- and paraesophageal bronchogenic cyst that was safely removed via surgical resection. A 31-year-old male patient with space-occupying lesions in the mediastinum suddenly presented with persistent chest pain for 2 days and then transferred to dysphagia >1 week. Preoperative diagnosis is difficult. Endoscopic ultrasonography (EUS) showed a hypoechoic cystic-solid mass arising from the muscularis propria and local hyperechoic area in the deeper portion of cyst, concomitant with a heterogeneous center and tube-like structure lesion in mediastinum. Turbid coffee color paste contents were aspirated inside the tumor under endoscopic ultrasonography guided-fine needle aspiration (EUS FNA). A subsequent surgery was performed and histologic finding was diagnostic of esophageal bronchogenic cyst. Immunohistochemical staining confirmed the cyst was positive for carbohydrate antigen 199 (CA199) and carbohydrate antigen 125 (CA125). At a follow-up visit 3 months later, the patient had a regular diet and no complaint. This study is to summarize the clinical manifestations and EUS features of esophageal bronchogenic cyst by retrospectively reviewing the literature and simultaneously to provide guide for the correct examination scheme. The appearance of esophageal bronchogenic cyst can be great variation; EUS seems to be a valuable option for diagnosis and surveillance. PMID- 26986157 TI - Late-Life Risk Factors for All-Cause Dementia and Differential Dementia Diagnoses in Women: A Prospective Cohort Study. AB - Since the first evidence of a decline in dementia incidence was reported in 2011, the focus on modifiable risk factors has increased. The possibility of risk factor intervention as a prevention strategy has been widely discussed; however, further evidence in relation to risk factors is still needed. The Prospective Epidemiologic Risk Factor (PERF I) study was an observational prospective study of postmenopausal Danish women who were initially examined between 1999 and 2001 (n = 5855). Follow-up data on diagnosis and survival as of December 31, 2014 was retrieved from the National Danish Patient Registry and the National Danish Causes of Death Registry. Cox proportional hazards regression model was applied to calculate adjusted hazard ratios (HR) for selected risk factors for dementia. Of 5512 eligible subjects, 592 developed dementia within the follow-up period of maximum 15 years. The independent factors associated with increased risk of all cause dementia were depression (HR = 1.75 [95% CI 1.32-2.34]) and impaired fasting glucose levels. A dose-response relationship was observed between fasting glucose level and risk of dementia with HRs of 1.25 [1.05-1.49] and 1.45 [1.03 2.06] for impaired (5.6-6.9 mmol/L) and hyperglycemic (>=7.0 mmol/L) glucose levels, respectively. The factors associated with a decreased risk of dementia were overweight in late-life (HR = 0.75 [0. 62-0.89]) and physical activity at least once weekly (HR = 0.77 [0.61-0.96]). The identified risk factors for dementia in women in late-life are all considered modifiable. This supports the notion that prevention strategies may improve the poor future prospects for dementias in the ageing population. PMID- 26986158 TI - Long-Term Breast Cancer Patient Outcomes After Adjuvant Radiotherapy Using Intensity-Modulated Radiotherapy or Conventional Tangential Radiotherapy. AB - The aim of the article is to analyze breast cancer patient clinical outcomes after long-term follow-up using intensity-modulated radiotherapy (IMRT) or conventional tangential radiotherapy (cRT). We retrospectively reviewed patients with stage 0-III breast cancer who received breast conserving therapy between April 2004 and December 2007. Of the 234 patients, 103 (44%) were treated with IMRT and 131 (56%) were treated with cRT. A total prescription dose of 45 to 50 Gy (1.8-2 Gy per fraction) was delivered to the whole breast. A 14 Gy boost dose was delivered in 7 fractions. The median follow-up was 8.2 years. Five of 131 (3.8%) cRT-treated patients and 2 of 103 (1.9%) IMRT-treated patients had loco regional failure. The 8-year loco-regional failure-free survival rates were 96.7% and 97.6% (P = 0.393) in the cRT and IMRT groups, respectively, whereas the 8 year disease-free survival (DFS) rates were 91.2% and 93.1%, respectively (P = 0.243). Patients treated with IMRT developed >= grade 2 acute dermatitis less frequently than patients treated with cRT (40.8% vs 56.5%; P = 0.017). There were no differences in late toxicity. IMRT reduces >= grade 2 acute skin toxicity. Local control, DFS, and overall survival were equivalent with IMRT and cRT. IMRT can be considered a standard technique for breast cancer treatment. PMID- 26986159 TI - Red Blood Cell Distribution Width to Platelet Ratio is Related to Histologic Severity of Primary Biliary Cirrhosis. AB - We aimed to investigate whether red blood cell distribution width (RDW) and RDW to platelet ratio (RPR) were related to the histologic severity of primary biliary cirrhosis (PBC). Seventy-three treatment-naive PBC patients who had undergone a liver biopsy between January 2010 and January 2015 were enrolled in our study. The patients' histological stages were based on the classifications of Ludwig and Scheuer. The patients were divided into early stage (Stage I) and advanced stage (Stage II, III, and IV) hepatic fibrosis according to their histological stage. All common patient demographics, clinical characteristics, hematological parameters, liver biochemistry, and antimitochondrial M2 antibody levels (AMA-M2) were retrospectively analyzed, and RDW, RPR, aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis index based on the 4 factors (FIB-4) were calculated. A total of 28 (38.4%) patients had early stage PBC, whereas 45 (62.6%) were classified as advanced stage. Regarding age, no significant differences between the early and advanced stages were observed. Patients with advanced stage PBC had significantly higher RDW (13.6 vs 14.4; P = 0.019), conjugated bilirubin (10.1 vs 23.4; P = 0.029), and significantly lower cholinesterase (7901.1 vs 6060.8; P = 0.001) and platelets (212.6 vs 167.0; P = 0.006). However, no significant differences (P > 0.05) in other routine parameters previously evaluated in PBC, including aspartate aminotransferase (AST) and mean platelet volume, were found between the groups. The sensitivity and specificity of RDW were 33.3% and 92.9%, respectively, and the area under the receiver-operating characteristic curve (AUROC) was 0.66. However, the sensitivity and specificity of RPR were 46.7% and 96.4%, respectively, and the corresponding AUROC was 0.74 (P < 0.001). Hence, compared with preexisting indicators, RPR showed a higher AUROC than APRI (0.648; P = 0.035) and FIB-4 (0.682; P = 0.009). RDW and RPR may be a new noninvasive marker for predicting histologic severity of PBC. PMID- 26986160 TI - Echocardiographic Diagnosis and Outcome of Pseudoaneurysm of the Mitral-Aortic Intervalvular Fibrosa: Results of a Single-Center Experience in Beijing. AB - Pseudoaneurysm of the mitral-aortic intervalvular fibrosa (P-MAIVF) is a rare but potentially fatal entity. Early diagnosis and surgical treatment are particularly important to decrease risk of mortality. The purpose of this study was to explore the echocardiographic characteristics and outcome of P-MAIVF and to evaluate the potential application of three-dimensional (3D) echocardiography in the evaluation of P-MAIVF. Clinical and echocardiographic characteristics were retrospectively evaluated in 9 patients with P-MAIVF, 5 of them assessed by 3D echocardiography. P-MAIVF was identified on echocardiography and located in the posterior aspect of the aortic root, expanding in systole and collapsing in diastole. Of the 9 cases examined, 8 were associated with endocarditis and 1 was caused by radio frequency catheter ablation of atrial fibrillation. Five cases were associated with bicuspid aortic valve, and rupture of P-MAIVF was identified in 3 patients. The morphology of P-MAIVF was clearly demonstrated on 3D echocardiography in 5 cases. In conclusion, echocardiography provides a useful tool in the diagnosis of P-MAIVF. Color Doppler flow imaging can ease identification of the ostium in cases of ruptured pseudoaneurysms. Three dimensional echocardiography shows the relationship between P-MAIVF and the adjacent anatomic structures. PMID- 26986161 TI - The Prognosis of Patients With Nonobstructive Coronary Artery Disease Versus Normal Arteries Determined by Invasive Coronary Angiography or Computed Tomography Coronary Angiography: A Systematic Review. AB - Limited data exist regarding the outcomes of patients with nonobstructive coronary artery disease (CAD) detected by computed tomography coronary angiography (CTCA) or invasive coronary angiography (ICA). Our aim was to compare the prognosis of patients with nonobstructive coronary artery plaques with that of patients with entirely normal arteries. The MEDLINE, Cochrane Library, and Embase databases were searched. Studies comparing the prognosis of individuals with nonobstructive CAD versus normal coronary arteries detected by CTCA or ICA were included. The primary outcome was major adverse cardiac events (MACE) including cardiac death, nonfatal myocardial infarction, hospitalization due to unstable angina or revascularization. A fixed effects model was chosen to pool the estimates of odds ratios (ORs). Forty-eight studies with 64,905 individuals met the inclusion criteria. Patients in the nonobstructive CAD arm had a significantly higher risk of MACE compared to their counterparts in the normal artery arm (pooled OR, 3.17, 95% confidence interval, 2.77-3.63). When excluding revascularization as an endpoint, hard cardiac composite outcomes were also more frequent among patients with nonobstructive CAD (pooled OR, 2.10; 95%CI, 1.79 2.45). All subgroups (age, sex, follow-up duration, different outcomes, diagnostic modality, and CAD risk factor) consistently showed a poorer prognosis with nonobstructive CAD than with normal arteries. When dividing the studies into a CTCA and ICA group for further analysis based on the indications for diagnostic tests, we also found nonobstructive CAD to be associated with a higher risk of MACE in both stable and acute chest pain. Patients with nonobstructive CAD had a poorer prognosis compared with their counterparts with normal arteries. PMID- 26986163 TI - Posterior Ciliary Artery Occlusion Caused by Hyaluronic Acid Injections Into the Forehead: A Case Report. AB - Although cosmetic facial soft tissue fillers are generally safe and effective, improper injections can lead to devastating and irreversible consequences. We represent the first known case of posterior ciliary artery occlusion caused by hyaluronic acid. A 41-year-old female presented with right visual loss 7 hours after receiving cosmetic hyaluronic acid injections into her forehead. Examination revealed no light perception in the right eye and multiple dark ischemic area of injection over the forehead and nose. The right fundus revealed a pink retina with optic nerve edema. Fluorescein angiogram showed several filling defects in the choroidal circulation and late hyperfluorescence in the choroid. A right posterior ciliary artery occlusion and embolic occlusion of facial artery braches was diagnosed. With hyaluronidase injection, hyperbaric oxygen therapy, oral aspirin, oral acetazolamide and dexamethasone venotransfuse treatment, the patient's forehead and nasal skin improved and vision recovered to hand movements. With proper technique, vascular occlusion is rare following facial filler injection. Vision consequences can be severe if filler emboli enter the ocular circulation. Physicians should be aware of this potential side effect, recognize its presentation, and be knowledgeable of effective management. PMID- 26986162 TI - Glycemic Control Modifies Difference in Mortality Risk Between Hemodialysis and Peritoneal Dialysis in Incident Dialysis Patients With Diabetes: Results From a Nationwide Prospective Cohort in Korea. AB - Although numerous studies have tried to elucidate the best dialysis modality in end-stage renal disease patients with diabetes, results were inconsistent and varied with the baseline characteristics of patients. Furthermore, none of the previous studies on diabetic dialysis patients accounted for the impact of glycemic control. We explored whether glycemic control had modifying effect on mortality between hemodialysis (HD) and peritoneal dialysis (PD) in incident dialysis patients with diabetes. A total of 902 diabetic patients who started dialysis between August 2008 and December 2013 were included from a nationwide prospective cohort in Korea. Based on the interaction analysis between hemoglobin A1c (HbA1c) and dialysis modalities for patient survival (P for interaction = 0.004), subjects were stratified into good and poor glycemic control groups (HbA1c< or >=8.0%). Differences in survival rates according to dialysis modalities were ascertained in each glycemic control group after propensity score matching. During a median follow-up duration of 28 months, the relative risk of death was significantly lower in PD compared with HD in the whole cohort and unmatched patients (whole cohort, hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.47-0.90, P = 0.01; patients with available HbA1c [n = 773], HR = 0.64, 95% CI = 0.46-0.91, P = 0.01). In the good glycemic control group, there was a significant survival advantage of PD (HbA1c <8.0%, HR = 0.59, 95% CI = 0.37 0.94, P = 0.03). However, there was no significant difference in survival rates between PD and HD in the poor glycemic control group (HbA1c >=8.0%, HR = 1.21, 95% CI = 0.46-2.76, P = 0.80). This study demonstrated that the degree of glycemic control modified the mortality risk between dialysis modalities, suggesting that glycemic control might partly contribute to better survival of PD in incident dialysis patients with diabetes. PMID- 26986164 TI - Impact of Preoperative Neutrophil to Lymphocyte Ratio and Postoperative Infectious Complications on Survival After Curative Gastrectomy for Gastric Cancer: A Single Institutional Cohort Study. AB - Although postoperative complications are associated with a poor long-term prognosis after resection of several solid tumors via an undetermined mechanism, there are few related reports in gastric cancer patients. Preoperative elevated neutrophil to lymphocyte ratio (NLR) reflects a systemic inflammatory response and is a predictor of poor survival in gastric cancer. The relationship between preoperative NLR and postoperative complications and the impact of these 2 factors on survival in gastric cancer remains unclear. Our aim is to examine the association between postoperative complications and survival, and preoperative NLR in patients undergoing curative resection for gastric cancer. We enrolled a total of 404 consecutive patients with gastric cancer undergoing curative gastrectomy between January 1, 2000 and December 31, 2011. Multivariable analyses were performed to correlate preoperative and operative variables with postoperative complications and to correlate complications with long-term survival after gastrectomy. Postoperative infectious and noninfectious complication rates were 17.6% and 7.9%, respectively. Preoperative NLR independently predicted the development of postoperative infectious complication, but not the development of postoperative noninfectious complications after gastrectomy. Both elevated NLR and postoperative infectious complication were independently associated with long-term survival. Also, patients with both elevated NLR and the development of postoperative infectious complication had the worst long-term survival. NLR independently predicted the development of postoperative infectious complication and lower survival after gastrectomy. Elevated NLR could trigger postoperative infectious complication and increase the risk of recurrence in patients with postoperative infectious complication after gastrectomy. PMID- 26986165 TI - Tigecycline Treatment for Carbapenem-Resistant Enterobacteriaceae Infections: A Systematic Review and Meta-Analysis. AB - Carbapenem-resistant Enterobacteriaceae (CRE) infections are prevalent worldwide; they have few effective treatments and this jeopardizes public health. Clinicians often use tigecycline to combat CRE, but its clinical efficacy remains controversial. Therefore, to compare the efficacy and safety of tigecycline in treating CRE infections compared with that of other antimicrobial agents, and to evaluate whether combination therapy and high-dose regimens are beneficial, we performed a systematic review and meta-analysis. PubMed and Embase were searched for controlled trials or cohort studies reporting the efficacy and/or safety of tigecycline-based regimens to treat CRE infections. Statistical analyses were performed using the Comprehensive Meta-Analysis V2.2. All meta-analyses were performed based on fixed- or random-effects model, and the I method was used to assess heterogeneity. Twenty-one controlled studies and 5 single-arm studies were included in this systematic review. With regard to the controlled studies, the tigecycline groups did not differ significantly from the control groups in terms of overall mortality (Odds ratio (OR) = 0.96 [95% confidence interval (CI) = 0.75 1.22; P = 0.73]), clinical response rate (OR = 0.58 [95% CI = 0.31-1.09; P = 0.09]), or microbiological response rate (OR = 0.46 [95% CI = 0.15-1.44; P = 0.18]). Subgroup analyses showed that 30-day mortality was significantly lower in patients who received tigecycline combination therapy than in those who received monotherapy (OR = 1.83 [95% CI = 1.07-3.12; P = 0.03]) and other antibiotic regimens (OR = 0.59 [95% CI = 0.39-0.88; P = 0.01]), respectively. In addition, high-dose tigecycline regimens differed significantly from standard dose schedules in terms of ICU mortality (OR = 12.48 [95% CI = 2.06-75.43; P = 0.006]). The results of the 5 single-arm studies corroborated the findings of the controlled studies. Our results indicated that the efficacy of tigecycline in treating CRE infections is similar to that of other antibiotics. Tigecycline combination therapy and high-dose regimens may be more effective than monotherapy and standard-dose regimens, respectively. Nonetheless, considering that the current available evidence is limited, well-designed randomized controlled trials are urgently needed to clarify the comparative efficacy of tigecycline in treating CRE infections. PMID- 26986166 TI - Leptospirosis and Peripheral Artery Occlusive Disease: A Nationwide Cohort Analysis. AB - Data on the association between peripheral artery occlusive disease (PAOD) and leptospirosis are limited. We conducted a retrospective cohort study for determining whether leptospirosis is one of the possible risk factors for PAOD. Patients diagnosed with leptospirosis by using 2000 to 2010 data from the Taiwan National Health Insurance Research Database. Patients with leptospirosis without a history of PAOD were selected. For each leptospirosis patient, 4 controls without a history of leptospirosis and PAOD were randomly selected and frequency matched for sex, age, the year of the index date, and comorbidity diseases. The follow-up period was from the time of the initial diagnosis of leptospirosis to the diagnosis date of PAOD, or December 31, 2011. The Cox proportional hazard regression models were used for analyzing the risk of PAOD. During the follow-up period, the cumulative incidence of PAOD was higher among the patients from the leptospirosis cohort than among the nonleptospirosis cohort (log-rank test, P < 0.001). In total, 29 patients with PAOD from the leptospirosis cohort and 81 from the nonleptospirosis cohort were observed with the incidence rates of 2.1 and 1.3 per 1000 person-years, respectively, yielding a crude hazards ratio (HR) of 1.62 (95% confidence interval [CI] = 1.44-1.81) and adjusted HR (aHR) of 1.75 (95% CI = 1.58-1.95).The risk of PAOD was 1.75-fold higher in the patients with leptospirosis than in the general population. PMID- 26986167 TI - Disseminated Mycobacterium marinum Infection With a Destructive Nasal Lesion Mimicking Extranodal NK/T Cell Lymphoma: A Case Report. AB - Mycobacterium marinum is a ubiquitous waterborne organism that mainly causes skin infection in immunocompetent patients, and its disseminated infection is rare. Extranodal NK/T cell lymphoma, nasal type (ENKL) usually localizes at the nasal and/or paranasal area, but occasionally disseminates into the skin/soft tissue and gastrointestinal tract. Compromised immunity is a risk factor for developing nontuberculous mycobacterial (NTM) infection and malignant lymphoma, and the 2 diseases may share similar clinical presentation; however, only a few reports have described NTM infection mimicking malignant lymphoma.A 43-year-old Japanese man presented to our hospital complaining of multiple progressive skin nodules and purulent nasal discharge for 3 weeks. He was diagnosed with Crohn disease with refractory enteropathic arthritis and has been treated with anti-tumor necrosis factor alpha agents for 25 years. Fiberoptic nasal examination revealed septal perforation with hemorrhagic mucus and purulent rhinorrhea. Histological examination of the nasal septum revealed the infiltration of atypical medium-to large-sized cells with erosion. The cells were positive for cytoplasmic CD3, granzyme B, and Epstein-Barr virus-encoded small RNA. Histological examination of the skin nodules and auricle also showed infiltration of atypical lymphocytes. The patient was tentatively diagnosed with ENKL, and chemotherapy was considered. However, the skin lesions decreased in size after discontinuation of immunosuppressive agents and minocycline administration. Two weeks later, nasal septum and lavage fluid and left leg skin cultures were positive for M marinum, and minocycline was discontinued. The skin and the nasal lesions improved after 2 months. To the best of our knowledge, this is the first case of disseminated M marinum infection with a destructive nasal lesion mimicking ENKL. The differentiation between M marinum infection and ENKL is clinically important because misdirected treatment leads to a poor prognosis. NTM infections including M marinum should be considered in differential diagnosis of ENKL. Bacterial cultures, pathological analysis, and close monitoring are required for the differentiation of ENKL and disseminated M marinum infection; both are serious diseases and early diagnostic distinction between them and immediate appropriate treatment will improve the patient's prognosis. PMID- 26986168 TI - Epigastric Distress Caused by Esophageal Candidiasis in 2 Patients Who Received Sorafenib Plus Radiotherapy for Hepatocellular Carcinoma: Case Report. AB - Sorafenib followed by fractionated radiotherapy (RT) has been shown to decrease the phagocytic and candidacidal activities of antifungal agents due to radiosensitization. Moreover, sorafenib has been shown to suppress the immune system, thereby increasing the risk for candida colonization and infection. In this study, we present the 2 hepatocellular carcinoma (HCC) patients suffered from epigastric distress caused by esophageal candidiasis who received sorafenib plus RT. Two patients who had received sorafenib and RT for HCC with bone metastasis presented with hiccups, gastric ulcer, epigastric distress, anorexia, heart burn, and fatigue. Empiric antiemetic agents, antacids, and pain killers were ineffective at relieving symptoms. Panendoscopy revealed diffuse white lesions in the esophagus. Candida esophagitis was suspected. Results of periodic acid-Schiff staining were diagnostic of candidiasis. Oral fluconazole (150 mg) twice daily and proton-pump inhibitors were prescribed. At 2-weak follow-up, esophagitis had resolved and both patients were free of gastrointestinal symptoms. Physicians should be aware that sorafenib combined with RT may induce an immunosuppressive state in patients with HCC, thereby increasing their risk of developing esophagitis due to candida species. PMID- 26986170 TI - Tumor-Like Liver Abscess Mimicking Malignancy With Lung Metastases in a Patient With Acute Renal Failure: A Case Report. AB - The worldwide incidence of Klebsiella pneumoniae liver abscess (KLA) is increasing. It is important to accurately diagnose this life-threatening disease to provide timely and appropriate treatment. Here we report the case of a 38-year old man with acute renal failure and a tumor-like liver abscess and septic pulmonary embolism. Initially, his clinical symptoms, laboratory tests, and radiological findings presented equivocal results of malignancy with metastases. Fine needle aspiration of liver tumor was performed, which showed purulent material with a culture positive for K pneumoniae. KLA symptoms are atypical, and radiological findings may mimic a malignancy with tumor necrosis. In some circumstances, liver aspiration biopsy may be necessary to confirm the real etiology, leading to prompt and timely treatment. Moreover, we should be alert for the impression of KLA when facing a diabetic patient with liver mass lesion and acute renal failure. PMID- 26986169 TI - The Efficacy and Safety of Programmed Cell Death 1 and Programmed Cell Death 1 Ligand Inhibitors for Advanced Melanoma: A Meta-Analysis of Clinical Trials Following the PRISMA Guidelines. AB - The purpose of this study was to investigate the efficacy and safety of programmed cell death 1 (PD-1) and programmed cell death 1 ligand (PD-L1) inhibitors using a meta-analysis of present trials for advanced melanoma. A fully recursive literature search of the primary electronic databases for available trials was performed. The objective response rate (ORR) and the median progression-free survival (PFS) of clinical responses were considered the main endpoints to evaluate the efficacy, whereas Grade 3-4 adverse effects (AEs) were analyzed to evaluate safety. The ORR of PD-1 and PD-L1 inhibitors was 30% (95% CI: 25-35%). No significant difference in the ORR was observed after the comparisons of low-dose, median-dose, and high-dose cohorts. In addition, the rate of Grade 3-4 AEs was 9% (95% CI: 6-12%). According to the 3 randomized controlled trials that compared PD-1 inhibitors with chemotherapy, the difference between these 2 groups was found to be statistically significant with respect to the ORR, PFS and the incidence of Grade 3-4 AEs; that is, the relative risk (RR) of the ORR was 3.42 (95% CI: 2.49-4.69, P < 0.001), the hazard ratio (HR) of the PFS was 0.50 (95% CI: 0.44-0.58, P < 0.001), and the RR of Grade 3-4 AEs was 0.45 (95% CI: 0.31-0.65, P < 0.001). According to a meta-analysis of limited concurrent studies, PD-1 and PD-L1 inhibitors appear to be associated with improved response rates, superior response durability and tolerable toxicity in patients with advanced melanoma. PMID- 26986171 TI - Calculation of Blood Dose in Patients Treated With 131I Using MIRD, Imaging, and Blood Sampling Methods. AB - Radioiodine therapy is known as the most effective treatment of differentiated thyroid carcinoma (DTC) to ablate remnant thyroid tissue after surgery. In patients with DTC treated with radioiodine, internal radiation dosimetry of radioiodine is useful for radiation risk assessment. The aim of this study is to describe a method to estimate the absorbed dose to the blood using medical internal radiation dosimetry methods. In this study, 23 patients with DTC with different administrated activities, 3.7, 4.62, and 5.55 GBq after thyroidectomy, were randomly selected. Blood dosimetry of treated patients was performed with external whole body counting using a dual-head gamma camera imaging device and also with blood sample activity measurements using a dose calibrator. Absorbed dose to the blood was measured at 2, 6, 12, 24, 48, and 96 hours after the administration of radioiodine with the 2 methods. Based on the results of whole body counting and blood sample activity dose rate measurements, 96 hours after administration of 3.7, 4.62, and 5.55 GBq of radioiodine, absorbed doses to patients' blood were 0.65 +/- 0.20, 0.67 +/- 0.18, 0.79 +/- 0.51 Gy, respectively. Increasing radioiodine activity from 3.7 to 5.55 GBq increased blood dose significantly, while there was no significant difference in blood dose between radioiodine dosages of 3.7 and 4.62 GBq. Our results revealed a significant correlation between the blood absorbed dose and blood sample activity and between the blood absorbed dose and whole body counts 24 to 48 hours after the administration of radioiodine. PMID- 26986172 TI - Clonal Spread of a Unique Strain of Macrolide-Resistant Mycoplasma Pneumoniae Within a Single Family in Italy. AB - Macrolide-resistant Mycoplasma pneumoniae (MR-MP) is an increasing problem worldwide. This study describes the clonal spread of a unique strain of MR-MP within a single family. On January 23, 2015, nasopharyngeal swabs and sputum samples were collected from the index case (a 9-year-old girl) in southern Italy. The patient had pneumonia and was initially treated with clarithromycin. MR-MP infection was suspected due to prolonged symptoms despite appropriate antibiotic therapy. Two further cases of pneumonia occurred in relatives (a 7-year-old cousin and the 36-year-old mother of the index case); therefore, respiratory samples were also collected from other family members. Sequence analysis identified mutations associated with resistance to macrolides. Both P1 major adhesion protein typing and multiple loci variable-number tandem repeat analysis (MLVA) typing were performed to assess the relatedness of the strains. The index case, the cousin, the mother, and another 4 family members (twin siblings of the index case, a 3-year-old cousin, and the grandmother) were positive for MR-MP. All strains harbored the mutation A2063G, had the same P1 subtype (1), and were MLVA (7/4/5/7/2) type Z. In addition, the index case's aunt (31 years of age and the probable source of infection) harbored an M pneumoniae strain with the same molecular profile; however, this strain was susceptible to macrolides. This cluster of MR-MP infection/carriage caused by a clonal strain suggests a high transmission rate within this family and highlights the need for increased awareness among clinicians regarding the circulation of MR-MP. Novel strategies for the treatment and prevention of M pneumoniae infections are required. PMID- 26986174 TI - EVF HOW Education in Venous Disease on the Move The 7th EVF HOW is returning to Limassol, Cyprus Advanced courses, EVF HOW Plus, will continue during 2016. PMID- 26986175 TI - Early lung cancer detection, mucosal, and alveolar imaging. AB - PURPOSE OF REVIEW: Lung cancer is the leading cause of cancer deaths worldwide. Early detection is essential for long-term survival. Screening of high-risk individuals with low-dose computed tomography screening has proven to increase survival. However, current radiological imaging techniques have poor specificity for lung cancer detection and poor sensitivity for detection of mucosal or alveolar preinvasive malignant lesions. Bronchoscopy allows imaging and sampling of early lung cancer, with the highest safety profile and high diagnostic accuracy. RECENT FINDINGS: Available technologies, such as autofluorescence bronchoscopy, narrow band imaging, and radial ultrasound bronchoscopy can significantly increase the yield and diagnostic accuracy of bronchoscopy for early cancer detection in the central airways. Newer technologies such as optical coherence tomography, confocal bronchoscopy, and Raman spectroscopy may significantly increase the diagnostic yield of both central and parenchymal early cancer lesions. SUMMARY: Although some of these technologies are still investigational and are not readily available in most centers, they may identify early mucosal and alveolar cancer lesions accurately in the least invasive manner to provide appropriate therapy and prolong patient survival from lung cancer. PMID- 26986173 TI - (1->3)-beta-D-Glucan Levels Correlate With Neurocognitive Functioning in HIV Infected Persons on Suppressive Antiretroviral Therapy: A Cohort Study. AB - Microbial translocation from the gut is associated with immune dysfunction, persistent inflammation, and likely plays a role in the pathogenesis of neurocognitive dysfunction during HIV infection. (1->3)-beta-D-Glucan (BDG) is a component of most fungal cell walls and might be a useful indicator of gut mucosal barrier impairment. The objective of this study was to evaluate whether higher blood BDG levels correlate with impaired neurocognitive functioning in a cohort of HIV-infected adults with suppressed levels of HIV RNA in blood plasma. In this cross-sectional cohort study, we measured levels of BDG in blood plasma and cerebrospinal fluid (CSF) supernatant samples in a cohort of adults with acute/early HIV infection, who initiated antiretroviral therapy (ART) during the earliest phase of infection and achieved suppressed levels of HIV RNA in blood plasma (<50 copies/mL) thereafter. We compared BDG with established biomarkers of microbial translocation, immune activation, and cognitive dysfunction (evaluated by global deficit score). We found that higher blood BDG levels were significantly related to higher global deficit scores, reflecting worse neurocognitive performance (Spearman r = 0.47; P = 0.042) among HIV-infected adults with suppressed viral loads who initiated ART early in infection. Two CSF samples presented elevated BDG levels. Interestingly, these 2 samples originated from the 2 subjects with the highest global deficit scores of the cohort. BDG may be a promising independent biomarker associated with neurocognitive functioning in virologically suppressed HIV-infected individuals. PMID- 26986176 TI - Nobiletin inhibits epithelial-mesenchymal transition of human non-small cell lung cancer cells by antagonizing the TGF-beta1/Smad3 signaling pathway. AB - Epithelial-mesenchymal transition (EMT) is a critical cellular process in cancer metastasis, during which epithelial polarized cells become motile mesenchymal cells. Since transforming growth factor-beta (TGF-beta) is a potent inducer of EMT, blocking of TGF-beta/Smad signaling has become a promising cancer therapy. Nobiletin, a polymethoxy flavonoid from Citrus depressa, has been shown to be valuable for cancer treatment, yet the mechanism remains unclear. In the present study, lung adenocarcinoma A549 and H1299 cells were used to evaluate the effect of nobiletin on EMT induced by TGF-beta1. Nobiletin successfully inhibited TGF beta1-induced EMT, migration, invasion and adhesion in vitro, accompanied by attenuation of MMP-2, MMP-9, p-Src, p-FAK, p-paxillin, Snail, Slug, Twist and ZEB1 expression. Nobiletin inhibited the transcriptional activity of Smads without changing the phosphorylation status or translocation of Smads induced by TGF-beta1. Moreover, Smad3 is requisite in TGF-beta1-stimulated EMT. Smad3 overexpression meaningfully impaired the ability of nobiletin to reverse TGF beta1-induced EMT. In vivo, nobiletin prohibited the growth of metastatic nodules in the lungs of nude mice. Moreover, nobiletin inhibited tumor growth and reversed EMT in mice bearing A549-Luc xenografts, as revealed by IVIS imaging and immunohistochemical analysis. Collectively, the data suggest that nobiletin prevents EMT by inactivating TGF-beta1/Smad3 signaling. PMID- 26986178 TI - Synthesis and Pharmacological Characterization of Novel Glucagon-like Peptide-2 (GLP-2) Analogues with Low Systemic Clearance. AB - Glucagon-like peptide-2 receptor agonists have therapeutic potential for the treatment of intestinal diseases. The native hGLP-2, a 33 amino acid gastrointestinal peptide, is not a suitable clinical candidate, due to its very short half-life in humans. In search of GLP-2 receptor agonists with better pharmacokinetic characteristics, a series of GLP-2 analogues containing Gly substitution at position 2, norleucine in position 10, and hydrophobic substitutions in positions 11 and/or 16 was designed and synthesized. In vitro receptor potency at the human GLP-2, selectivity vs the human GLP-1 and GCG receptors, and PK profile in rats were determined for the new analogues. A number of compounds more potent at the hGLP-2R than the native hormone, showing excellent receptor selectivity and very low systemic clearance (CL) were discovered. Analogues 69 ([Gly(2),Nle(10),D-Thi(11),Phe(16)]hGLP-2-(1-30)-NH2), 72 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-OH), 73 ([Gly(2),Nle(10),D Phe(11),Leu(16)]hGLP-2-(1-33)-NH2), 81 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2 (1-33)-NHEt), and 85 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NH ((CH2)2O)4-(CH2)2-CONH2) displayed the desired profiles (EC50 (hGLP-2R) < 100 pM, CL in rat <0.3 mL/min/kg, selective vs hGLP-1R and hGCGR). Compound 73 (FE 203799) was selected as a candidate for clinical development. PMID- 26986179 TI - Melatonin as add-on treatment for epilepsy. AB - BACKGROUND: This is an updated version of the original Cochrane review published in Issue 6, 2012.Epilepsy is one of the most common chronic neurological disorders. Despite the plethora of antiepileptic drugs (AEDs) currently available, 30% of people continue having seizures. This group of people requires a more aggressive treatment, since monotherapy, the first choice scheme, fails to control seizures. Nevertheless, polytherapy often results in a number of unwanted effects, including neurological disturbances (somnolence, ataxia, dizziness), psychiatric and behavioural symptoms, and metabolic alteration (osteoporosis, inducement or inhibition of hepatic enzymes, etc.). The need for better tolerated AEDs is even more urgent in this group of people. Reports have suggested an antiepileptic role of melatonin with a good safety profile. OBJECTIVES: To assess the efficacy and tolerability of melatonin as add-on treatment for epilepsy. SEARCH METHODS: For the latest update, we searched the Cochrane Epilepsy Group's Specialized Register (12 January 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 12 January 2016), and MEDLINE (Ovid, 11 January 2016). We searched the bibliographies of any identified study for further references. We handsearched selected journals and conference proceedings. We applied no language restrictions. In addition, we contacted melatonin manufacturers (i.e. Nathura) and original investigators to identify any unpublished studies. SELECTION CRITERIA: Randomized controlled trials; double, single, or unblinded trials; parallel group or cross-over studies. People with epilepsy regardless of age and gender, including children and adults with disabilities. Administration of melatonin as add-on treatment to any AED(s) compared to add-on placebo or no add on treatment. DATA COLLECTION AND ANALYSIS: Review authors independently selected trials for inclusion according to pre-defined criteria, extracted relevant data, and evaluated the methodological quality of trials. We assessed the following outcomes: at least 50% seizure reduction, seizure freedom, adverse events, and quality of life. MAIN RESULTS: We included six publications, with 125 participants (106 aged under 18 years). Two different comparisons were available: melatonin versus placebo and melatonin 5 mg versus melatonin 10 mg. Despite our primary intention, due to insufficient information on outcomes, we were unable to perform any meta-analyses, but summarized data narratively. Four studies were randomized, double-blind, cross-over, placebo-controlled trials and two were randomized, double-blind, parallel, placebo-controlled trials. Only two studies provided the exact number of seizures during the trial compared to the baseline: none of the participants with seizures during the trial had a change in seizure frequency compared with the baseline. Two studies systematically evaluated adverse effects (worsening of headache was reported in a child with migraine under melatonin treatment). Only one study systematically evaluated quality of life, showing no statistically significant improvement in quality of life in the add-on melatonin group. AUTHORS' CONCLUSIONS: Included studies were of poor methodological quality, and did not systematically evaluate seizure frequency and adverse events, so that it was impossible to summarize data in a meta-analysis. It is not possible to draw any conclusion about the role of melatonin in reducing seizure frequency or improving quality of life in people with epilepsy. PMID- 26986180 TI - Does the crossed-limb deficit affect the uncrossed portions of limbs? AB - When locating touch, we remap its location from skin-based to external coordinates as a function of body posture. While remapping is thought to occur whenever there is tactile input, research has focused on a special case, the crossed-hands deficit, where tactile localization is impaired when the limbs are crossed compared with uncrossed. To date, these studies have always stimulated portions of the limbs that are crossed, such as a finger of each hand. It is therefore unknown whether the deficit induced by arm crossing is specific to the crossed portion of the limb or affects the limb as a whole. In Experiments 1 and 2, we stimulated the shoulders and elbows and found that tactile localization, measured with temporal order judgments, was unaffected by crossing the forearms. In Experiment 3, a crossed-limbs deficit was observed for touches on a single skin location when that location was distal-but not proximal-to the crossing point of the arms. In Experiment 4, we found a similar crossed-limbs deficit irrespective of how far distally to the crossing point touch was applied. Together, these results demonstrate that crossing the limbs affects tactile perception only distal to the point of crossing. The process of remapping tactile events does not take into account the end-point location of the limb, but an extremely precise metric description of the touch relative to the configuration of both arms. (PsycINFO Database Record PMID- 26986181 TI - The Conformation of Thermoresponsive Polymer Brushes Probed by Optical Reflectivity. AB - We describe a microscope-based optical setup that allows us to perform space- and time-resolved measurements of the spectral reflectance of transparent substrates coated with ultrathin films. This technique is applied to investigate the behavior in water of thermosensitive polymer brushes made of poly(N isopropylacrylamide) grafted on glass. We show that spectral reflectance measurements yield quantitative information about the conformation and axial structure of the brushes as a function of temperature. We study how parameters such as grafting density and chain length affect the hydration state of a brush, and provide one of the few experimental evidences for the occurrence of vertical phase separation in the vicinity of the lower critical solution temperature of the polymer. The origin of the hysteretic behavior of poly(N-isopropylacrylamide) brushes upon cycling the temperature is also clarified. We thus demonstrate that our optical technique allows for in-depth characterization of stimuli-responsive polymer layers, which is crucial for the rational design of smart polymer coatings in actuation, gating, or sensing applications. PMID- 26986183 TI - Error in Breast Cancer Detection Rate. PMID- 26986182 TI - Associations Between Methylenetetrahydrofolate Reductase Polymorphisms, Serum Homocysteine Levels, and Incident Cortical Cataract. AB - Importance: Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been shown to influence homocysteine levels; homocysteine has been implicated as a cataractogenic stressor. Objective: To investigate the associations of MTHFR polymorphisms and serum homocysteine levels with incident cortical cataract in an older population. Design, Setting, and Participants: From 1992 to 1994, a population-based cohort study, the Blue Mountains Eye Study, was conducted with 3654 residents (82.4% of eligible participants) of the Blue Mountains region aged 49 years and older. At the second (1997-1999, 5-year follow-up) and third (2002 2004, 10-year follow-up) surveys, 2334 (75.8% of survivors) and 1952 (76.7% of survivors) were examined, respectively. For this report, the second survey serves as baseline when homocysteine levels were assessed, and 5-year incidence of cataract refers to incidence estimated from the second to the third survey. After excluding participants with no follow-up data or DNA or who had previous cortical cataract or cataract surgery, 757 participants were included in gene and environment analyses. This current project on associations with cataract was designed initially March 19, 2013, and completed April 14, 2014. Cataract was assessed using the Wisconsin Cataract Grading system. Two MTHFR polymorphisms, C677T (rs1801133) and A1298C (rs1801131), were included. Serum homocysteine levels were assessed following standard methods. Main Outcomes and Measures: Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals for incident cortical cataract, after adjusting for age, sex, smoking status, hypertension, diabetes, education, and myopia. Path analysis was performed to explore a possible pathway of MTHFR polymorphisms via homocysteine levels to cortical cataract. Results: The mean (SD) age of the 1726 participants in the Blue Mountains Eye Study 2 cohort with normal homocysteine levels was 68.3 (8.1) years and 73.2 (8.5) years for those with elevated homocysteine levels. Both the C677T polymorphism (CT/TT vs CC: OR = 1.50; 95% CI = 1.01-2.23) and elevated homocysteine levels (>15 umol/L: OR = 2.24; 95% CI = 1.38-3.63) were independently associated with increased risk of cortical cataract. Path analysis showed that the genetic effect on cortical cataract was partially mediated via homocysteine levels. Combined CT/TT genotypes and elevated homocysteine levels were associated with a 3-fold risk of cortical cataract (OR = 3.74; 95% CI = 1.79-7.80). The synergy index of both exposures was 1.34 (95% CI = 0.44-4.01). Conclusions and Relevance: MTHFR polymorphism and elevated homocysteine levels contributed separately and jointly to increased risk of cortical cataract. If these findings are confirmed, homocysteine levels may be a therapeutic target to reduce risk of cortical cataract in persons carrying genetic risk. PMID- 26986187 TI - Incorrect Sentences in the Results. PMID- 26986184 TI - Degenerative and regenerative morphological aspects in peri-implantitis. AB - The purpose of this study was to describe the tissues surrounding two early failed dental implants morphologically and ultrastructurally. In the first case, the implant's surface was analyzed by scanning electron microscopy (SEM) using an environmental scanning electron microscope and the surrounding tissues were analyzed by light microscopy (LM) and transmission electron microscopy. In the second case we used only LM. By SEM analysis, very thin connective tissue was seen at the implant's apex; in the middle part, highly vascularized connective tissue and poorly mineralized areas were found, and there were fewer mineralized areas at the implant's base. Histologically and ultrastructurally, we identified a heterogeneous cellular population including fibroblast-like cells and osteoblasts with abundant amorphous extracellular matrix, as well as a number of inflammatory cells, predominantly neutrophils. In a small area around the implant, microorganisms classified as Actinomyces were identified. In this case, degenerative aspects were predominantly caused by infection. In the second case, our observations focused on recruitment of mesenchymal stem cells, their proliferation and differentiation into epithelial cells with keratinocyte phenotype, and formation of de novo capillaries from mesenchymal progenitors of endothelial cells. These regenerative events were accompanied by multiple areas of mineralization, culminating in bone formation around the implant. Correlative microscopic observations are necessary to conduct in future studies, in various clinical conditions and post-operative stages, to better define the cellular events involved in healing and osseointegration; our observations clearly depict significant regenerative aspects despite the degenerative ones. PMID- 26986188 TI - The effect of transcutaneous electrical nerve stimulation on post-thoracotomy pain. AB - BACKGROUND: Pain guidelines suggest transcutaneous electrical nerve stimulation (TENS) as a reliable analgesic method in postoperative pain. OBJECTIVES: This study was conducted as a randomized controlled study to determine the effect of TENS on postoperative pain and analgesic consumption in patients who have undergone posterolateral thoracotomy (PLT). DESIGN: The study was conducted in the Thoracic Surgery Clinic of a university hospital with 40 patients (test group: 20, control group: 20) and its power was 99%. While, test group patients were administered TENS, the control group patients were not. The pain assessment and analgesic consumption in both groups were recorded. RESULTS: The pain levels and analgesic consumption of the test group were lower than that of the control group (p < .05). CONCLUSIONS: TENS reduced PLT pain and analgesic consumption. Thus, TENS can be recommended as an easy and reliable analgesic method in PLT. PMID- 26986189 TI - A theory of generalized Bloch oscillations. AB - Bloch oscillations of electrons are shown to occur for cases when the energy spectrum does not consist of the traditional evenly-spaced ladders and the potential gradient does not result from an external electric field. A theory of such generalized Bloch oscillations is presented and an exact calculation is given to confirm this phenomenon. Our results allow for a greater freedom of design for experimentally observing Bloch oscillations. For strongly coupled oscillator systems displaying Bloch oscillations, it is further demonstrated that reordering of oscillators leads to destruction of Bloch oscillations. We stipulate that the presented theory of generalized Bloch oscillations can be extended to other systems such as acoustics and photonics. PMID- 26986190 TI - Prevalence and co-prevalence of comorbidities among patients with type 2 diabetes mellitus. AB - OBJECTIVE: Patients with type 2 diabetes (T2DM) often have multiple comorbidities which may impact the selection of antihyperglycemic therapies. The purpose of this study was to quantify the prevalence and co-prevalence of common comorbidities. RESEARCH DESIGN AND METHODS: A retrospective study was conducted using the Quintiles Electronic Medical Record database. Adult patients with T2DM who had >=1 encounter from July 2014 to June 2015 (index period) with >=1 year medical history available were included. The index date was defined as the most recent encounter date during the 1 year index period. MAIN OUTCOME MEASURES: Comorbid conditions were assessed using all data available prior to and including the index date. Patient characteristics, laboratory measures, and comorbidities were summarized via descriptive analyses, overall and by subgroups of age (<65, 65-74, 75+ years) and gender. RESULTS: Of the 1,389,016 eligible patients, 53% were female and the median age was 65 years. 97.5% of patients had at least one comorbid condition in addition to T2DM and 88.5% had at least two. The comorbidity burden tended to increase in older age groups and was higher in men than women. The most common conditions in patients with T2DM included hypertension (HTN) in 82.1%; overweight/obesity in 78.2%; hyperlipidemia in 77.2%; chronic kidney disease (CKD) in 24.1%; and cardiovascular disease (CVD) in 21.6%. The highest co-prevalence was demonstrated for the combination of HTN and hyperlipidemia (67.5%), followed by overweight/obesity and HTN (66.0%), overweight/obesity and hyperlipidemia (62.5%), HTN and CKD (22.4%), hyperlipidemia and CKD (21.1%), HTN and CVD (20.2%), hyperlipidemia and CVD (20.1%), overweight/obesity and CKD (19.1%) and overweight/obesity and CVD (17.0%). LIMITATIONS: Limitations include the potential for misclassification/underreporting due to the use of diagnostic codes, drug codes, or laboratory measures for identification of medical conditions. CONCLUSIONS: The vast majority of patients with T2DM have multiple comorbidities. To ensure a comprehensive approach to patient management, the presence of multimorbidity should be considered in the context of clinical decision making. PMID- 26986191 TI - Tunable Metasurface and Flat Optical Zoom Lens on a Stretchable Substrate. AB - A mechanically reconfigurable metasurface that can continuously tune the wavefront is demonstrated in the visible frequency range by changing the lattice constant of a complex Au nanorod array fabricated on a stretchable polydimethylsiloxane substrate. It is shown that the anomalous refraction angle of visible light at 632.8 nm interacting with the tunable metasurface can be adjusted from 11.4 degrees to 14.9 degrees by stretching the substrate by ~30%. An ultrathin flat 1.7* zoom lens whose focal length can continuously be changed from 150 to 250 MUm is realized, which also demonstrates the potential of utilizing metasurfaces for reconfigurable flat optics. PMID- 26986193 TI - Conformational Changes in Thiazole-2-carboxylic Acid Selectively Induced by Excitation with Narrowband Near-IR and UV Light. AB - Conformers and photoinduced conformational transformations were studied for monomers of thiazole-2-carboxylic acid (TCA). The matrix-isolation technique and excitations with narrowband near-IR and UV light, tuned in an optical parametric oscillator, were used for this purpose. Form I, with the carboxylic moiety in the trans orientation and with the hydrogen atom of the OH group directed toward the nitrogen atom of the ring, was the most abundant in low-temperature argon or nitrogen matrixes. Conformer II, differing from I by 180 degrees rotation of the OH group around the C-O bond, was also trapped in the matrixes, but in much smaller amount. The abundance of form II was experimentally determined as ~6% of the total amount of TCA molecules. Selective excitation of I with narrowband near IR laser light resulted in I -> II transformation. This near-IR-induced conformational change was photoreversible: form II converted back to I upon selective excitation of II with near-IR light of different wavelength. Conformational conversions of I into II, or vice versa, were also induced in TCA monomers by narrowband UV excitations at 300 nm (for I -> II transformation) and at 305 nm (for II -> I transformation). A spontaneous conversion of photogenerated II into the most stable form I was observed for the compound trapped in the matrix at 15 K and kept in the dark. This process was very slow; the estimated half-life time of conformer II was longer than 50 h. Finally, TCA was shown to thermally decompose at room temperature, yielding CO2 and thiazole. PMID- 26986192 TI - ATR-101, a Selective and Potent Inhibitor of Acyl-CoA Acyltransferase 1, Induces Apoptosis in H295R Adrenocortical Cells and in the Adrenal Cortex of Dogs. AB - ATR-101 is a novel, oral drug candidate currently in development for the treatment of adrenocortical cancer. ATR-101 is a selective and potent inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase 1 (ACAT1), an enzyme located in the endoplasmic reticulum (ER) membrane that catalyzes esterification of intracellular free cholesterol (FC). We aimed to identify mechanisms by which ATR 101 induces adrenocortical cell death. In H295R human adrenocortical carcinoma cells, ATR-101 decreases the formation of cholesteryl esters and increases FC levels, demonstrating potent inhibition of ACAT1 activity. Caspase-3/7 levels and terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeled-positive cells are increased by ATR-101 treatment, indicating activation of apoptosis. Exogenous cholesterol markedly potentiates the activity of ATR-101, suggesting that excess FC that cannot be adequately esterified increases caspase 3/7 activation and subsequent cell death. Inhibition of calcium release from the ER or the subsequent uptake of calcium by mitochondria reverses apoptosis induced by ATR-101. ATR-101 also activates multiple components of the unfolded protein response, an indicator of ER stress. Targeted knockdown of ACAT1 in an adrenocortical cell line mimicked the effects of ATR-101, suggesting that ACAT1 mediates the cytotoxic effects of ATR-101. Finally, in vivo treatment of dogs with ATR-101 decreased adrenocortical steroid production and induced cellular apoptosis that was restricted to the adrenal cortex. Together, these studies demonstrate that inhibition of ACAT1 by ATR-101 increases FC, resulting in dysregulation of ER calcium stores that result in ER stress, the unfolded protein response, and ultimately apoptosis. PMID- 26986194 TI - Time-dependent dysregulation of autophagy: Implications in aging and mitochondrial homeostasis in the kidney proximal tubule. AB - Autophagy plays an essential role in cellular homeostasis through the quality control of proteins and organelles. Although a time-dependent decline in autophagic activity is believed to be involved in the aging process, the issue remains controversial. We previously demonstrated that autophagy maintains proximal tubular cell homeostasis and protects against kidney injury. Here, we extend that study and examine how autophagy is involved in kidney aging. Unexpectedly, the basal autophagic activity was higher in the aged kidney than that in young kidney; short-term cessation of autophagy in tamoxifen-inducible proximal tubule-specific autophagy-deficient mice increased the accumulation of SQSTM1/p62- and ubiquitin-positive aggregates in the aged kidney. By contrast, autophagic flux in response to metabolic stress was blunted with aging, as demonstrated by the observation that transgenic mice expressing a green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3B fusion construct, showed a drastic increase of GFP-positive puncta in response to starvation in young mice compared to a slight increase observed in aged mice. Finally, proximal tubule-specific autophagy-deficient mice at 24 mo of age exhibited a significant deterioration in kidney function and fibrosis concomitant with mitochondrial dysfunction as well as mitochondrial DNA abnormalities and nuclear DNA damage, all of which are hallmark characteristics of cellular senescence. These results suggest that age-dependent high basal autophagy plays a crucial role in counteracting kidney aging through mitochondrial quality control. Furthermore, a reduced capacity for upregulation of autophagic flux in response to metabolic stress may be associated with age-related kidney diseases. PMID- 26986195 TI - Hospitalized Traumatic Brain Injury: Low Trauma Center Utilization and High Interfacility Transfers among Older Adults. AB - OBJECTIVE: Guidelines suggest that Traumatic Brain Injury (TBI) related hospitalizations are best treated at Level I or II trauma centers because of continuous neurosurgical care in these settings. This population-based study examines TBI hospitalization treatment paths by age groups. METHODS: Trauma center utilization and transfers by age groups were captured by examining the total number of TBI hospitalizations from National Inpatient Sample (NIS) and the number of TBI hospitalizations and transfers in the Trauma Data Bank National Sample Population (NTDB-NSP). TBI cases were defined using diagnostic codes. RESULTS: Of the 351,555 TBI related hospitalizations in 2012, 47.9% (n = 168,317) were directly treated in a Level I or II trauma center, and an additional 20.3% (n = 71,286) were transferred to a Level I or II trauma center. The portion of the population treated at a trauma center (68.2%) was significantly lower than the portion of the U.S. population who has access to a major trauma center (90%). Further, nearly half of all transfers to a Level I or II trauma center were adults aged 55 and older (p < 0.001) and that 20.2% of pediatric patients arrive by non-ambulatory means. CONCLUSION: Utilization of trauma center resources for hospitalized TBIs may be low considering the established lower mortality rate associated with treatment at Level I or II trauma centers. The higher transfer rate for older adults may suggest rapid decline amid an unrecognized initial need for a trauma center care. A better understanding of hospital destination decision making is needed for patients with TBI. PMID- 26986198 TI - Definition of a visuospatial dimension as a step forward in the diagnostic puzzle of nonverbal learning disability. AB - Although clinically recognized for almost 50 years, the categorical distinction of specific learning disabilities due to an impairment of the nonverbal domain (nonverbal learning disability [NLD]) is still debated and controversial. Unsolved issues involve theoretical models, diagnostic criteria, rehabilitative interventions, and moderator factors. These issues are briefly overviewed to sustain the need for a shift toward dimensional approaches, as suggested by research domain criteria, as a step forward in the diagnostic puzzle of NLD. With this aim, a visuospatial dimension, or spectrum, is proposed, and then clinical conditions that may fit with its impaired side are systemized, while specifying in which conditions a visuospatial impairment may be considered an NLD. PMID- 26986197 TI - Preclinical evaluations of peptide-conjugate vaccines targeting the antigenic domain-2 of glycoprotein B of human cytomegalovirus. AB - The Antigenic Domain 2 (AD-2) is a short region near the N-terminus of glycoprotein B of human cytomegalovirus (HCMV). AD-2 has been shown to contain linear epitopes that are targets for neutralizing monoclonal antibodies from human subjects with natural HCMV infection. However, AD-2 appears to be masked by the adjacent immunodominant AD-1 region. We assessed a serum panel from HCMV seropositive individuals and found a wide range of antibody titers to AD-2; these did not correlate to serum neutralization. To expose potential epitopes in AD-2, we constructed a series of AD-2 peptide-conjugate vaccines. Mice were immunized 3 times and produced high and sustained antibody titers to AD-2 peptides, but neutralization was weak even after a single boost with whole HCMV virions. Rabbits were likewise immunized with AD-2 peptide vaccines, and produced a robust antibody response, but neutralization was inferior to a recombinant gB vaccine with an oil-in-water adjuvant. These results highlight the challenges of developing a peptide-based vaccine specific to the HCMV gB AD-2 region. PMID- 26986200 TI - Changes in the Chemical Composition and Decay Resistance of Thermally-Modified Hevea brasiliensis Wood. AB - In this study the effect of thermal treatment on the equilibrium moisture content, chemical composition and biological resistance to decay fungi of juvenile and mature Hevea brasiliensis wood (rubber wood) was evaluated. Samples were taken from a 53-year-old rubber wood plantation located in Tabapua, Sao Paulo, Brazil. The samples were thermally-modified at 180 degrees C, 200 degrees C and 220 degrees C. Results indicate that the thermal modification caused: (1) a significant increase in the extractive content and proportional increase in the lignin content at 220 degrees C; (2) a significant decrease in the equilibrium moisture content, holocelluloses, arabinose, galactose and xylose content, but no change in glucose content; and (3) a significant increase in wood decay resistance against both Pycnoporus sanguineus (L.) Murrill and Gloeophyllum trabeum (Pers.) Murrill decay fungi. The greatest decay resistance was achieved from treatment at 220 degrees C which resulted in a change in wood decay resistance class from moderately resistant to resistant. Finally, this study also demonstrated that the influence of thermal treatment in mature wood was lower than in juvenile wood. PMID- 26986201 TI - Modelling Population Dynamics in Realistic Landscapes with Linear Elements: A Mechanistic-Statistical Reaction-Diffusion Approach. AB - We propose and develop a general approach based on reaction-diffusion equations for modelling a species dynamics in a realistic two-dimensional (2D) landscape crossed by linear one-dimensional (1D) corridors, such as roads, hedgerows or rivers. Our approach is based on a hybrid "2D/1D model", i.e, a system of 2D and 1D reaction-diffusion equations with homogeneous coefficients, in which each equation describes the population dynamics in a given 2D or 1D element of the landscape. Using the example of the range expansion of the tiger mosquito Aedes albopictus in France and its main highways as 1D corridors, we show that the model can be fitted to realistic observation data. We develop a mechanistic statistical approach, based on the coupling between a model of population dynamics and a probabilistic model of the observation process. This allows us to bridge the gap between the data (3 levels of infestation, at the scale of a French department) and the output of the model (population densities at each point of the landscape), and to estimate the model parameter values using a maximum-likelihood approach. Using classical model comparison criteria, we obtain a better fit and a better predictive power with the 2D/1D model than with a standard homogeneous reaction-diffusion model. This shows the potential importance of taking into account the effect of the corridors (highways in the present case) on species dynamics. With regard to the particular case of A. albopictus, the conclusion that highways played an important role in species range expansion in mainland France is consistent with recent findings from the literature. PMID- 26986199 TI - Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary. AB - OBJECTIVE: The objective of this study was to evaluate the antitumor effects of lurbinectedin as a single agent or in combination with existing anticancer agents for clear cell carcinoma (CCC) of the ovary, which is regarded as an aggressive, chemoresistant, histological subtype. METHODS: Using human ovarian CCC cell lines, the antitumor effects of lurbinectedin, SN-38, doxorubicin, cisplatin, and paclitaxel as single agents were assessed using the MTS assay. Then, the antitumor effects of combination therapies involving lurbinectedin and 1 of the other 4 agents were evaluated using isobologram analysis to examine whether these combinations displayed synergistic effects. The antitumor activity of each treatment was also examined using cisplatin-resistant and paclitaxel-resistant CCC sublines. Finally, we determined the effects of mTORC1 inhibition on the antitumor activity of lurbinectedin-based chemotherapy. RESULTS: Lurbinectedin exhibited significant antitumor activity toward chemosensitive and chemoresistant CCC cells in vitro. An examination of mouse CCC cell xenografts revealed that lurbinectedin significantly inhibits tumor growth. Among the tested combinations, lurbinectedin plus SN-38 resulted in a significant synergistic effect. This combination also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Everolimus significantly enhanced the antitumor activity of lurbinectedin-based chemotherapies. CONCLUSIONS: Lurbinectedin, a new agent that targets active transcription, exhibits antitumor activity in CCC when used as a single agent and has synergistic antitumor effects when combined with irinotecan. Our results indicate that lurbinectedin is a promising agent for treating ovarian CCC, both as a first-line treatment and as a salvage treatment for recurrent lesions that develop after platinum-based or paclitaxel treatment. PMID- 26986202 TI - Correction: Activation of alpha-7 Nicotinic Acetylcholine Receptor Reduces Ischemic Stroke Injury through Reduction of Pro-Inflammatory Macrophages and Oxidative Stress. PMID- 26986204 TI - Genome Update. Let the consumer beware: Streptomyces genome sequence quality. AB - A genome sequence assembly represents a model of a genome. This article explores some tools and methods for assessing the quality of an assembly, using publicly available data for Streptomyces species as the example. There is great variability in quality of assemblies deposited in GenBank. Only in a small minority of these assemblies are the raw data available, enabling full appraisal of the assembly quality. PMID- 26986203 TI - Co-infection of Ticks: The Rule Rather Than the Exception. AB - INTRODUCTION: Ticks are the most common arthropod vectors of both human and animal diseases in Europe, and the Ixodes ricinus tick species is able to transmit a large number of bacteria, viruses and parasites. Ticks may also be co infected with several pathogens, with a subsequent high likelihood of co transmission to humans or animals. However few data exist regarding co-infection prevalences, and these studies only focus on certain well-known pathogens. In addition to pathogens, ticks also carry symbionts that may play important roles in tick biology, and could interfere with pathogen maintenance and transmission. In this study we evaluated the prevalence of 38 pathogens and four symbionts and their co-infection levels as well as possible interactions between pathogens, or between pathogens and symbionts. METHODOLOGY/PRINCIPAL FINDINGS: A total of 267 Ixodes ricinus female specimens were collected in the French Ardennes and analyzed by high-throughput real-time PCR for the presence of 37 pathogens (bacteria and parasites), by rRT-PCR to detect the presence of Tick-Borne encephalitis virus (TBEV) and by nested PCR to detect four symbionts. Possible multipartite interactions between pathogens, or between pathogens and symbionts were statistically evaluated. Among the infected ticks, 45% were co-infected, and carried up to five different pathogens. When adding symbiont prevalences, all ticks were infected by at least one microorganism, and up to eight microorganisms were identified in the same tick. When considering possible interactions between pathogens, the results suggested a strong association between Borrelia garinii and B. afzelii, whereas there were no significant interactions between symbionts and pathogens. CONCLUSION/SIGNIFICANCE: Our study reveals high pathogen co infection rates in ticks, raising questions about possible co-transmission of these agents to humans or animals, and their consequences to human and animal health. We also demonstrated high prevalence rates of symbionts co-existing with pathogens, opening new avenues of enquiry regarding their effects on pathogen transmission and vector competence. PMID- 26986206 TI - Arthrobacter and related genera: An annotated selection of World Wide Web sites relevant to the topics in environmental microbiology. PMID- 26986207 TI - Differences Found in the Macroinvertebrate Community Composition in the Presence or Absence of the Invasive Alien Crayfish, Orconectes hylas. AB - Introductions of alien species into aquatic ecosystems have been well documented, including invasions of crayfish species; however, little is known about the effects of these introductions on macroinvertebrate communities. The woodland crayfish (Orconectes hylas (Faxon)) has been introduced into the St. Francis River watershed in southeast Missouri and has displaced populations of native crayfish. The effects of O. hylas on macroinvertebrate community composition were investigated in a fourth-order Ozark stream at two locations, one with the presence of O. hylas and one without. Significant differences between sites and across four sampling periods and two habitats were found in five categories of benthic macroinvertebrate metrics: species richness, percent/composition, dominance/diversity, functional feeding groups, and biotic indices. In most seasons and habitat combinations, the invaded site had significantly higher relative abundance of riffle beetles (Coleoptera: Elmidae), and significantly lower Missouri biotic index values, total taxa richness, and both richness and relative abundance of midges (Diptera: Chironomidae). Overall study results indicate that some macroinvertebrate community differences due to the O. hylas invasion were not consistent between seasons and habitats, suggesting that further research on spatial and temporal habitat use and feeding ecology of Ozark crayfish species is needed to improve our understanding of the effects of these invasions on aquatic communities. PMID- 26986205 TI - Understanding butanol tolerance and assimilation in Pseudomonas putida BIRD-1: an integrated omics approach. AB - Pseudomonas putida BIRD-1 has the potential to be used for the industrial production of butanol due to its solvent tolerance and ability to metabolize low cost compounds. However, the strain has two major limitations: it assimilates butanol as sole carbon source and butanol concentrations above 1% (v/v) are toxic. With the aim of facilitating BIRD-1 strain design for industrial use, a genome-wide mini-Tn5 transposon mutant library was screened for clones exhibiting increased butanol sensitivity or deficiency in butanol assimilation. Twenty-one mutants were selected that were affected in one or both of the processes. These mutants exhibited insertions in various genes, including those involved in the TCA cycle, fatty acid metabolism, transcription, cofactor synthesis and membrane integrity. An omics-based analysis revealed key genes involved in the butanol response. Transcriptomic and proteomic studies were carried out to compare short and long-term tolerance and assimilation traits. Pseudomonas putida initiates various butanol assimilation pathways via alcohol and aldehyde dehydrogenases that channel the compound to central metabolism through the glyoxylate shunt pathway. Accordingly, isocitrate lyase - a key enzyme of the pathway - was the most abundant protein when butanol was used as the sole carbon source. Upregulation of two genes encoding proteins PPUBIRD1_2240 and PPUBIRD1_2241 (acyl CoA dehydrogenase and acyl-CoA synthetase respectively) linked butanol assimilation with acyl-CoA metabolism. Butanol tolerance was found to be primarily linked to classic solvent defense mechanisms, such as efflux pumps, membrane modifications and control of redox state. Our results also highlight the intensive energy requirements for butanol production and tolerance; thus, enhancing TCA cycle operation may represent a promising strategy for enhanced butanol production. PMID- 26986208 TI - Is Serum Total LDH Evaluation Able to Differentiate between Alimentary Lymphoma and Inflammatory Bowel Disease in a Real World Clinical Setting? AB - CONTEXT: An increase in enzyme lactate dehydrogenase (LDH) in serum is a negative prognostic factor for survival in cats affected by lymphoma. Measuring LDH at the time of diagnosis has been studied for differentiating neoplastic disease from non-neoplastic disease in dogs. Inflammatory bowel disease (IBD) and alimentary lymphoma are common diseases in cats. OBJECTIVE: The aim of this study was to determine whether elevation of total LDH occurred in cats with alimentary lymphoma and non-neoplastic gastrointestinal disease, such as IBD, and to evaluate whether this enzyme is useful in supporting the differential diagnosis of these specific diseases. MATERIALS AND METHODS: A prospective non-randomized controlled study was carried-out in a real world setting of three Italian private veterinary clinics. Seventy-one client-owned cats with a history of chronic gastrointestinal symptoms were enrolled; 33 cats were histologically diagnosed as having alimentary lymphoma and 38 cats as having IBD. Serum samples of total LDH analysis were measured. RESULTS: Gender (P = 0.016) and age (P = 0.046) were found to be significant factors influencing the differentiation of serum total LDH between cats with alimentary lymphoma and those with IBD. Despite low diagnostic accuracy in the overall population (63%), a cut-off value of serum total LDH ranging from 0.85- to 1.04-times the upper reference limit showed good capability (accuracy >80%) of differentiating these two conditions in neutered males and cats younger than 8 years of age (AUC: 0.805, 0.833; sensitivities: 76.9%, 83.3%; specificities: 80.0%, 76.5%; PPV: 76.9%, 55.6%; NPV: 80.0%, 92.9%; respectively). CONCLUSIONS: Although our study showed that gender and age are significant factors in differentiating serum total LDH between cats with alimentary lymphoma and those with IBD, this test had poor diagnostic accuracy in differentiating between these two conditions in the overall population. PMID- 26986209 TI - Relationship between antipsychotic medication, serum prolactin levels and osteoporosis/osteoporotic fractures in patients with schizophrenia: a critical literature review. AB - INTRODUCTION: Using an antipsychotic medication can increase prolactin (PRL) levels, causing hyperprolactinemia (HPRL). Although the occurrence of osteoporosis within the population of patients with schizophrenia has been recognized, the precise nature of the association between antipsychotic treatment, PRL, osteoporosis, and the disease itself seems to be elusive. AREAS COVERED: The aim of this review is to critically review the literature regarding the association between osteoporosis and PRL and to summarize the available evidence with respect to the impact of PRL-elevating antipsychotics on bone mineral density (BMD) and fractures in non-elderly patients with schizophrenia. EXPERT OPINION: Although long-standing HPRL can have an impact on the rate of bone metabolism and, when associated with hypogonadism, may lead to decreased bone density in both female and male subjects, the relative contribution of antipsychotic-induced HPRL in bone mineral loss in patients with schizophrenia remains unclear. Methodological shortcomings of existing studies, including the lack of prospective data and the focus on measurements of BMD instead of bone turnover markers, preclude definitive conclusions regarding the relationship between PRL-raising antipsychotics and BMD loss in patients with schizophrenia. Therefore, more well conducted prospective trials of these biomarkers are necessary to establish the precise relationship between antipsychotics, PRL levels and osteoporosis/osteoporotic risk. PMID- 26986210 TI - Critical reanalysis of the methods that discriminate the activity of CDK2 from CDK1. AB - Cyclin dependent kinases 1 and 2 (CDK1 and CDK2) play crucial roles in regulating cell cycle progression from G1 to S, through S, and G2 to M phase. Both inhibition and aberrant activation of CDK1/2 can be detrimental to cancer cell growth. However, the tools routinely employed to discriminate between the activities of these 2 kinases do not have the selectivity commonly attributed to them. Activation of these kinases is often assayed as a decrease of the inhibitory tyrosine-15 phosphorylation, yet the antibodies used cannot discriminate between phosphorylated CDK1 and CDK2. Inhibitors of these kinases, while partially selective against purified kinases, may lack selectivity when applied to intact cells. High levels of cyclin E are often considered a marker of increased CDK2 activity, yet active CDK2 targets cyclin E for degradation, hence high levels usually reflect inactive CDK2. Finally, inhibition of CDK2 does not arrest cells in S phase suggesting CDK2 is not required for S phase progression. Furthermore, activation of CDK2 in S phase can rapidly induce DNA double-strand breaks in some cell lines. The misunderstandings associated with the use of these tools has led to misinterpretation of results. In this review, we highlight these challenges in the field. PMID- 26986211 TI - Meis1 Is Required for Adult Mouse Erythropoiesis, Megakaryopoiesis and Hematopoietic Stem Cell Expansion. AB - Meis1 is recognized as an important transcriptional regulator in hematopoietic development and is strongly implicated in the pathogenesis of leukemia, both as a Hox transcription factor co-factor and independently. Despite the emerging recognition of Meis1's importance in the context of both normal and leukemic hematopoiesis, there is not yet a full understanding of Meis1's functions and the relevant pathways and genes mediating its functions. Recently, several conditional mouse models for Meis1 have been established. These models highlight a critical role for Meis1 in adult mouse hematopoietic stem cells (HSCs) and implicate reactive oxygen species (ROS) as a mediator of Meis1 function in this compartment. There are, however, several reported differences between these studies in terms of downstream progenitor populations impacted and effectors of function. In this study, we describe further characterization of a conditional knockout model based on mice carrying a loxP-flanked exon 8 of Meis1 which we crossed onto the inducible Cre localization/expression strains, B6;129 Gt(ROSA)26Sor(tm1(Cre/ERT)Nat)/J or B6.Cg-Tg(Mx1-Cre)1Cgn/J. Findings obtained from these two inducible Meis1 knockout models confirm and extend previous reports of the essential role of Meis1 in adult HSC maintenance and expansion and provide new evidence that highlights key roles of Meis1 in both megakaryopoiesis and erythropoiesis. Gene expression analyses point to a number of candidate genes involved in Meis1's role in hematopoiesis. Our data additionally support recent evidence of a role of Meis1 in ROS regulation. PMID- 26986212 TI - Cuf2 Is a Transcriptional Co-Regulator that Interacts with Mei4 for Timely Expression of Middle-Phase Meiotic Genes. AB - The Schizosaccharomyces pombe cuf2+ gene encodes a nuclear regulator that is required for timely activation and repression of several middle-phase genes during meiotic differentiation. In this study, we sought to gain insight into the mechanism by which Cuf2 regulates meiotic gene expression. Using a chromatin immunoprecipitation approach, we demonstrate that Cuf2 is specifically associated with promoters of both activated and repressed target genes, in a time-dependent manner. In case of the fzr1+ gene whose transcription is positively affected by Cuf2, promoter occupancy by Cuf2 results in a concomitant increased association of RNA polymerase II along its coding region. In marked contrast, association of RNA polymerase II with chromatin decreases when Cuf2 negatively regulates target gene expression such as wtf13+. Although Cuf2 operates through a transcriptional mechanism, it is unable to perform its function in the absence of the Mei4 transcription factor, which is a member of the conserved forkhead protein family. Using coimmunoprecipitation experiments, results showed that Cuf2 is a binding partner of Mei4. Bimolecular fluorescence complementation experiments brought further evidence that an association between Cuf2 and Mei4 occurs in the nucleus. Analysis of fzr1+ promoter regions revealed that two FLEX-like elements, which are bound by the transcription factor Mei4, are required for chromatin occupancy by Cuf2. Together, results reported here revealed that Cuf2 and Mei4 co-regulate the timely expression of middle-phase genes during meiosis. PMID- 26986214 TI - When Geometry Constrains Vision: Systematic Misperceptions within Geometrical Configurations. AB - How accurate are we in reproducing a point within a simple shape? This is the empirical question we addressed in this work. Participants were presented with a tiny disk embedded in an empty circle (Experiment 1 and 3) or in a square (Experiment 2). Shortly afterwards the disk vanished and they had to reproduce the previously seen disk position within the empty shape by means of the mouse cursor, as accurately as possible. Several loci inside each shape were tested. We found that the space delimited by a circle and by a square is not homogeneous and the observed distortion appears to be consistent across observers and specific for the two tested shapes. However, a common pattern can be identified when reproducing geometrical loci enclosed in a shape: errors are shifted toward the periphery in the region around the center and toward the center in the region nearby the edges. The error absolute value declines progressively as we approach an equilibrium contour line between the center and the outline of the shape where the error is null. These results suggest that enclosing an empty space within a shape imposes an organization to it and warps its metrics: not only the perceived loci inside a shape are not the same as the geometrical loci, but they are misperceived in a systematic way that is functional to the correct identification of the center of the shape. Eye movements recordings (Experiment 3) are consistent with this interpretation of the data. PMID- 26986215 TI - Nitro Lignin-Derived Nitrogen-Doped Carbon as an Efficient and Sustainable Electrocatalyst for Oxygen Reduction. AB - The use of lignin as a precursor for the synthesis of materials is nowadays considered very interesting from a sustainability standpoint. Here we illustrate the synthesis of a micro-, meso-, and macroporous nitrogen-doped carbon (NDC) using lignin extracted from beech wood via alkaline hydrothermal treatment and successively functionalized via aromatic nitration. The so obtained material is thus carbonized in the eutectic salt melt KCl/ZnCl2. The final NDC shows an excellent activity as electrocatalyst for the oxygen reduction reaction. PMID- 26986213 TI - Immune-Mediated Inflammation May Contribute to the Pathogenesis of Cardiovascular Disease in Mucopolysaccharidosis Type I. AB - BACKGROUND: Cardiovascular disease, a progressive manifestation of alpha-L iduronidase deficiency or mucopolysaccharidosis type I, continues in patients both untreated and treated with hematopoietic stem cell transplantation or intravenous enzyme replacement. Few studies have examined the effects of alpha-L iduronidase deficiency and subsequent glycosaminoglycan storage upon arterial gene expression to understand the pathogenesis of cardiovascular disease. METHODS: Gene expression in carotid artery, ascending, and descending aortas from four non-tolerized, non-enzyme treated 19 month-old mucopolysaccharidosis type I dogs was compared with expression in corresponding vascular segments from three normal, age-matched dogs. Data were analyzed using R and whole genome network correlation analysis, a bias-free method of categorizing expression level and significance into discrete modules. Genes were further categorized based on module-trait relationships. Expression of clusterin, a protein implicated in other etiologies of cardiovascular disease, was assessed in canine and murine mucopolysaccharidosis type I aortas via Western blot and in situ immunohistochemistry. RESULTS: Gene families with more than two-fold, significant increased expression involved lysosomal function, proteasome function, and immune regulation. Significantly downregulated genes were related to cellular adhesion, cytoskeletal elements, and calcium regulation. Clusterin gene overexpression (9 fold) and protein overexpression (1.3 to 1.62-fold) was confirmed and located specifically in arterial plaques of mucopolysaccharidosis-affected dogs and mice. CONCLUSIONS: Overexpression of lysosomal and proteasomal-related genes are expected responses to cellular stress induced by lysosomal storage in mucopolysaccharidosis type I. Upregulation of immunity-related genes implicates the potential involvement of glycosaminoglycan-induced inflammation in the pathogenesis of mucopolysaccharidosis-related arterial disease, for which clusterin represents a potential biomarker. PMID- 26986216 TI - Critical involvement of the alpha(1,2)-fucosyltransferase in multidrug resistance of human chronic myeloid leukemia. AB - The fucosyltransferases are key enzymes in cell surface antigen synthesis during multidrug resistance (MDR) development. The aim of the present study was to analyze the alteration of alpha(1,2)-fucosyltransferase involved in MDR development in human chronic myeloid leukemia (CML). FUT1 was overexpressed in three CML/MDR cell lines and peripheral blood mononuclear cells (PBMC) of CML patients. However, no significant changes of FUT2 were observed. The altered levels of FUT1 had a significant impact on the phenotypic variation of MDR of K562 and K562/ADR cells, the activity of EGFR/MAPK pathway and P-glycoprotein (P gp) expression. Blocking the EGFR/MAPK pathway by its specific inhibitor PD153035 or EGFR small interfering RNA (siRNA) resulted in the reduced MDR of K562/ADR cells. This study indicated that alpha(1,2)-fucosyltransferase involved in the development of MDR of CML cells probably through FUT1 regulated the activity of EGFR/MAPK signaling pathway and the expression of P-gp. PMID- 26986221 TI - Perspectives on intimate relationships among young people in rural South Africa: the logic of risk. AB - This paper explores how young people in rural South Africa understand gender, dating, sexuality and risk-taking in adolescence. The empirical material drawn upon consists of 20 interviews with young men and women (aged 18-19) and reflects normative gender patterns characterised by compulsory heterosexuality and dating as obligatory, and representing key symbols of normality. However, different meanings of heterosexual relationships are articulated in the interviews, for example in the recurring concept of 'passing time', and these meanings show that a relationship can be something arbitrary: a way to reduce boredom and have casual sex. Such a rationale for engaging in a relationship reflects one of several other normative gender patterns, which relate to the trivialisation of dating and sexual risk-taking, and which entail making compromises and legitimising deviations from the 'ideal' life-script and the hope of a better future. However, risks do not exclusively represent something bad, dangerous or immoral, because they are also used as excuses to avoid sex, HIV acquisition and early pregnancy. In conclusion, various interrelated issues can both undermine and/or reinforce risk awareness and subsequent risk behaviour. Recognition of this tension is essential when framing policies to support young people to reduce sexual risk-taking behaviour. PMID- 26986217 TI - UVB Radiation Delays Tribolium castaneum Metamorphosis by Influencing Ecdysteroid Metabolism. AB - Ultraviolet B (UVB) radiation is an important environmental factor. It is generally known that UVB exhibits high genotoxicity due to causing DNA damage, potentially leading to skin carcinogenesis and aging in mammals. However, little is known about the effects of UVB on the development and metamorphosis of insects, which are the most abundant terrestrial animals. In the present study, we performed dose-response analyses of the effects UVB irradiation on Tribolium castaneum metamorphosis, assessed the function of the T. castaneum prothoracicotropic hormone gene (Trcptth), and analyzed ecdysteroid pathway gene expression profile and ecdysterone titers post-UVB irradiation. The results showed that UVB not only caused death of T. castaneum larvae, but also delayed larval-pupal metamorphosis and reduced the size and emergence rate of pupae. In addition, we verified the function of Trcptth, which is responsible for regulating metamorphosis. It was also found that the expression profiles of Trcptth as well as ecdysteroidogenesis and response genes were influenced by UVB radiation. Therefore, a disturbance pulse of ecdysteroid may be involved in delaying development under exposure to irradiation. To our knowledge, this is the first report indicating that UVB can influence the metamorphosis of insects. This study will contribute to a better understanding of the impact of UVB on signaling mechanisms in insect metamorphosis. PMID- 26986222 TI - Age-Related Changes of Intraocular Pressure in Elderly People in Southern China: Lingtou Eye Cohort Study. AB - PURPOSE: To study age-related changes of intraocular pressure (IOP) and assess the cohort effect in both cross-sectional and longitudinal settings among elderly Chinese adults. METHODS: Participants were enrolled from the Lingtou Eye Cohort Study with Chinese government officials aged 40 years and older at baseline and received physical check-up and ocular examinations from 2010 to 2012. IOP was measured using a non-contact tonometer according to standardized protocols, as well as systolic blood pressure (SBP), diastolic blood pressure (DBP) and body mass index (BMI). Participants who had attended IOP measurements in both 2010 and 2012 were included in this study. Cross-sectional association of IOP with age was assessed using multivariate liner regression analyses and based on the data of 2010. Longitudinal changes in IOP were assessed by paired t-test. RESULTS: A total of 3372 subjects were enrolled in the current analysis (2010 mean [SD] age, 61.9 [7.1] years; 60.2% men). The mean IOP in 2010 was 15.4 +/- 2.3 mmHg for women and 15.2 +/- 2.3 mmHg for men with an intersex difference (P = 0.029). Cross-sectional analysis showed that IOP was negatively associated with age (P = 0.003, beta = -0.033 for women and P<0.001, beta = -0.061 for men) adjusted for baseline SBP, DBP and BMI. Paired t-test suggested that IOP was higher in the year 2012 than 2010 in women (P = 0.006) but did not change significantly in men within 2 years (P = 0.345). In addition, the 2-year changes of IOP were not associated with age adjusted for baseline IOP in 2010 (P = 0.249). CONCLUSION: Cross-sectional data suggests that IOP is lower in people with older age. Longitudinal data does not support such findings and thus the identified decreasing pattern with age in cross-sectional analysis is likely caused by cohort effects. PMID- 26986223 TI - A Rapid and Quantitative Flow Cytometry Method for the Analysis of Membrane Disruptive Antimicrobial Activity. AB - We describe a microbial flow cytometry method that quantifies within 3 hours antimicrobial peptide (AMP) activity, termed Minimum Membrane Disruptive Concentration (MDC). Increasing peptide concentration positively correlates with the extent of bacterial membrane disruption and the calculated MDC is equivalent to its MBC. The activity of AMPs representing three different membranolytic modes of action could be determined for a range of Gram positive and negative bacteria, including the ESKAPE pathogens, E. coli and MRSA. By using the MDC50 concentration of the parent AMP, the method provides high-throughput, quantitative screening of AMP analogues. A unique feature of the MDC assay is that it directly measures peptide/bacteria interactions and lysed cell numbers rather than bacteria survival as with MIC and MBC assays. With the threat of multi-drug resistant bacteria, this high-throughput MDC assay has the potential to aid in the development of novel antimicrobials that target bacteria with improved efficacy. PMID- 26986225 TI - Endoscopic Improvement of the Adenoma Detection Rate during Colonoscopy - Where Do We Stand in 2015? AB - BACKGROUND: The presence of colorectal adenomas is considered a major risk factor for colorectal cancer development. The implementation of screening colonoscopy programs in the Western world has led to a substantial reduction of colorectal cancer death. Many efforts have been made to reduce the adenoma miss rates by the application of new endoscopic devices and techniques for better adenoma visualization. SUMMARY: This special review gives the readership an overview of current endoscopic innovations that can aid in the increase of the adenoma detection rate (ADR) during colonoscopy. These innovations include the use of devices like EndoCuff(r) and EndoRings(r) as well as new technical equipment like third-eye endoscope(r) and full-spectrum endoscopy (FUSE(r)). KEY MESSAGE: Technical improvements and newly developed accessories are able to improve the ADR. However, additional costs and a willingness to invest into potentially expensive equipment might be necessary. Investigator-dependent skills remain the backbone in the ADR detection. PMID- 26986224 TI - Is Modified Radical Hysterectomy Needed for Patients with Clinical Stage I/II Endometrial Cancers? A Historical Control Study. AB - OBJECTIVE: The aim of the present study was to assess whether hysterectomy with wider resection could improve survival by preventing local recurrence. METHODS: Medical charts of the patients with clinical stage I/II endometrial cancers treated at our hospital between 1990 and 2009 were retrospectively analyzed. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and adverse effects according to the type of hysterectomy. RESULTS: A total of 247 patients were identified: 46 patients treated with total abdominal hysterectomy (TAH group) and 201 patients with modified radical hysterectomy (mRH group). No significant differences were observed in OS (p = 0.52) and PFS (p = 0.67) between the two groups. Also, there was no significant difference in the distribution of recurrent sites between the two groups. The patients treated with mRH had a longer operation time and more frequently developed severe adverse events, such as blood loss and lymphedema. CONCLUSION: In our cohorts, there were no significant differences in both PFS and OS according to surgical procedures, and the mRH group more frequently developed severe adverse events. Overall, clinical benefit was not obtained by mRH in patients with clinical stage I/II endometrial carcinomas. PMID- 26986226 TI - Research and development of antibiotics: insights from patents and citation network. AB - INTRODUCTION: Bacterial resistance to antibiotics develops at an alarming rate and leads to the increasing morbidity and health-care costs in recent years. However, the global research and development (R&D) of antibiotics has fallen behind the emergence and spread of bacterial resistance and the world is heading towards a 'post-antibiotic era'. In this context, systematic understanding of the technology landscape and evolving process of antibiotic R&D may help to provide insights for discovering future antibiotics more rationally. AREAS COVERED: Patents and patent citations are broadly believed to be powerful tools in representing the technology advances and capturing technology flows. In all, 707 U.S. patents related to antibiotic R&D are collected and analyzed. Furthermore, patent citations are visualized by a network-based approach, while the inter relationship between patented technologies on antibiotics is further revealed. EXPERT OPINION: The current dry pipeline of antibiotic development requires substantial awareness and political support. It is essential to build an attractive and supportive environment for investment. Thus, a new antibiotic business model is needed to chase the balance between the market-oriented investment and public health goals. Additionally, drug development targeting Gram negative bacteria, especially resistant Gram-negative bacteria, demands attentions from stakeholders because of their unmet medical needs. PMID- 26986227 TI - Social anxiety and alcohol use across the university years: Adaptive and maladaptive groups. AB - University/college can be a challenging time as students face developmental tasks such as building new social networks and achieving academically. Social anxiety may be disadvantageous in this setting given that social situations often include drinking and individuals with social anxiety tend to self-medicate through alcohol use. However, findings are mixed as to whether the association between social anxiety and alcohol use is positive or negative. To clarify the nature of this association, we used a person-centered longitudinal analysis to identify student groups based on levels of social anxiety symptoms and alcohol consumption. Undergraduates (N = 1132, 70.5% female, Mage = 19.06 at Time 1) enrolled in university completed a survey assessing social anxiety and alcohol use over 3 years, and psychosocial functioning and emotion coping behaviors at Time 1. Two out of 5 groups were identified with higher levels of social anxiety, 1 with moderately low alcohol use, and the other with moderately high alcohol use. Both groups reported higher levels of general anxiety, depressive symptoms, behavioral inhibition, emotional reactivity, daily hassles, and lower levels of social ties at Time 1 than the 3 groups with lower levels of social anxiety. Furthermore, the social anxiety-alcohol use group reported significantly lower academic grades and was more likely to endorse problematic emotion coping behaviors (e.g., self-injury) than the social anxiety-low alcohol use group. These results not only help explain the mixed findings in the literature but indicate that 1 group of socially anxious students may be particularly vulnerable to negative adjustment difficulties. (PsycINFO Database Record PMID- 26986229 TI - Emotionally numb: Desensitization to community violence exposure among urban youth. AB - Community violence exposure (CVE) is associated with numerous psychosocial outcomes among youth. Although linear, cumulative effects models have typically been used to describe these relations, emerging evidence suggests the presence of curvilinear associations that may represent a pattern of emotional desensitization among youth exposed to chronic community violence. This study uses longitudinal data to investigate relations between CVE and both internalizing and externalizing symptoms among 3,480 youth ages 3 to 12 at baseline and 9 to 18 at outcome. Results support desensitization models, as evidenced by longitudinal quadratic associations between Wave 2 CVE and Wave 3 anxiety/depressive symptoms, alongside cross-sectional linear associations between Wave 3 CVE and Wave 3 aggression. Neither age nor gender moderated the associations between CVE and well-being. (PsycINFO Database Record PMID- 26986228 TI - Ethnic identity trajectories among Mexican-origin girls during early and middle adolescence: Predicting future psychosocial adjustment. AB - We examined trajectories of ethnic identity exploration, resolution, and affirmation and their associations with depressive symptoms and self-esteem 3.5 years later among early and middle adolescent Mexican-origin girls (N = 338). Findings indicated that exploration, resolution, and affirmation increased over time for both cohorts. Among early adolescents, growth in exploration was associated with more depressive symptoms during middle adolescence, whereas higher initial levels and greater rates of change of affirmation predicted fewer subsequent depressive symptoms. Among middle adolescents, higher baseline levels of exploration and affirmation predicted fewer depressive symptoms in late adolescence. Higher initial levels and greater change in affirmation predicted higher self-esteem among both cohorts. Findings highlight the developmental and multifaceted quality of ethnic identity and that associations between ethnic identity and adjustment may vary by adolescent developmental stage. (PsycINFO Database Record PMID- 26986230 TI - A hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS) based metabolomics study on colour stability of ovine meat. AB - Meat colour is one of the cues available to the consumer to gauge overall meat quality and wholesomeness. Colour stability of meat is determined by several factors both inherent to the animal and post-slaughter conditions, including ageing, storage/packaging and display times. A hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS) based metabolomics study was undertaken to identify and compare polar metabolites between ovine meat samples that were exposed to different durations of ageing, storage conditions, and display times. Primary metabolites comprising amino acids, sugars, nucleotides, nucleosides, organic acids and their breakdown products were mainly identified as discriminating factors. For the first time, boron complexes of sugar and malic acid were also tentatively identified. As expected, most compounds identified were related to myoglobin chemistry, and compounds with antioxidant properties were found in higher levels in colour stable samples. Supplementary studies identifying semi-polar, non-polar and volatile compounds will provide a holistic understanding of the chemical basis of colour stability in ovine meat. PMID- 26986231 TI - Aloe vera: A review of toxicity and adverse clinical effects. AB - The Aloe plant is employed as a dietary supplement in a variety of foods and as an ingredient in cosmetic products. The widespread human exposure and its potential toxic and carcinogenic activities raise safety concerns. Chemical analysis reveals that the Aloe plant contains various polysaccharides and phenolic chemicals, notably anthraquinones. Ingestion of Aloe preparations is associated with diarrhea, hypokalemia, pseudomelanosis coli, kidney failure, as well as phototoxicity and hypersensitive reactions. Recently, Aloe vera whole leaf extract showed clear evidence of carcinogenic activity in rats, and was classified by the International Agency for Research on Cancer as a possible human carcinogen (Group 2B). This review presents updated information on the toxicological effects, including the cytotoxicity, genotoxicity, carcinogenicity, and adverse clinical effects of Aloe vera whole leaf extract, gel, and latex. PMID- 26986232 TI - MicroRNA-200b inhibits the proliferation of hepatocellular carcinoma by targeting DNA methyltransferase 3a. AB - Aberrant microRNA (miRNA or miR) expression has been reported to contribute to the pathogenesis of hepatocellular carcinoma (HCC). However, the involvement of specific miRNAs in HCC remains to be elucidated. The present study aimed to investigate the potential role of miR-200b and the mechanism underlying its function in hepatocarcinogenesis. The results of the present study demonstrated that the expression levels of miR-200b were significantly reduced in HCC tissue samples, as compared with normal liver (NL) and para-tumorous (PT) tissue samples. The results also revealed that miR-200b expression levels in HepG2 cells were significantly decreased compared with those in L02 cells. In addition, western blotting and reverse transcription-quantitative polymerase chain reaction demonstrated that the expression levels of DNA methyltransferase 3a (DNMT3a), a possible target gene for miR-200b, were significantly higher in HCC tissue samples, as compared with those in NL and PT tissue samples. Furthermore, the data suggested that DNMT3a was a direct target gene of miR-200b. Upregulated miR 200b expression in HepG2 cells led to a decrease in DNMT3a expression levels, and an inhibition of cell proliferation. These results suggested that miR-200b has an important role in hepatocarcinogenesis and acts by downregulating DNMT3a expression. Thus, miR-200b may be a promising target for HCC treatment. PMID- 26986233 TI - Overexpression of miR-155 promotes the proliferation and invasion of oral squamous carcinoma cells by regulating BCL6/cyclin D2. AB - Although microRNA-155 (miR-155) is known to play an important role in many cancers, its expression and function in oral squamous cell carcinoma (OSCC) was not fully understood. Thus, in the present study, we investigated the expression of miR-155 and also the role this miR plays in OSCC. We used the OSCC cell line (CAL27) and paired tumor and non-tumor tissue samples from patients with OSCC in order to detect the expression of miR-155. Cell proliferation, migration and invasion assays were then undertaken in order to determine the effect of miR-155 on the biological behavior of CAL27 cells following transient transfection with miR-155 mimic and antagomir. The regulatory effect of miR-155 on its target gene B-cell CLL/lymphoma 6 (BCL6) and downstream gene cyclin D2 (CCND2) was also analyzed. We found that miR-155 expression in OSCC cell and tumor tissues was significantly higher than that of the controls. We noted that the miR-155 mimic enhanced CAL27 cell proliferation, migration and invasion ability, downregulated BCL6 levels, and increased cyclin D2 expression. However, we noted that abrogating miR-155 with the miR-155 antagomir suppressed CAL27 cell proliferation, migration and invasion, upregulated BCL6 and reduced cyclin D2 expression. These results indicate that miR-155 plays a tumor-promoting role in OSCC by regulating the BCL6/cyclin D2 axis. PMID- 26986234 TI - Clinical and therapeutic significance of sirtuin-4 expression in colorectal cancer. AB - Several members of the sirtuin family (SIRT1-7), which are a highly conserved family of NAD+-dependent enzymes, play an important role in tumor formation. Recent studies indicate that SIRT4 acts as a tumor suppressor by regulating glutamine metabolism. In the present study, we investigated the expression and activity of SIRT4 in colorectal cancer. Using a tissue microarray of 89 colorectal cancer cases, we found that SIRT4 was significantly downregulated in colorectal cancer tissues compared with that noted in the corresponding normal tissue (P<0.001). Lower SIRT4 levels were associated with worse pathological differentiation (P=0.031) and poorer post-operative overall survival rate (P=0.041). We found that SIRT4 overexpression inhibited the proliferation of colorectal cancer cells in vitro and in vivo. SIRT4 inhibited the glutamine metabolism of colorectal cancer cells and synergistically with glycolysis inhibitors induced cell death. SIRT4 also increased the sensitivity of colorectal cancer cells to chemotherapeutic drug 5-fluorouracil by inhibiting the cell cycle. Together, these results highlight the prognostic value of SIRT4 in colorectal cancer and the potential application of SIRT4 in colorectal cancer treatment. PMID- 26986237 TI - Growth and (137)Cs uptake and accumulation among 56 Japanese cultivars of Brassica rapa, Brassica juncea and Brassica napus grown in a contaminated field in Fukushima: Effect of inoculation with a Bacillus pumilus strain. AB - Fifty six local Japanese cultivars of Brassica rapa (40 cultivars), Brassica juncea (10 cultivars) and Brassica napus (6 cultivars) were assessed for variability in growth and (137)Cs uptake and accumulation in association with a Bacillus pumilus strain. Field trial was conducted at a contaminated farmland in Nihonmatsu city, in Fukushima prefecture. Inoculation resulted in different responses of the cultivars in terms of growth and radiocesium uptake and accumulation. B. pumilus induced a significant increase in shoot dry weight in 12 cultivars that reached up to 40% in one B. rapa and three B. juncea cultivars. Differences in radiocesium uptake were observed between the cultivars of each Brassica species. Generally, inoculation resulted in a significant increase in (137)Cs uptake in 22 cultivars, while in seven cultivars it was significantly decreased. Regardless of plant cultivar and bacterial inoculation, the transfer of (137)Cs to the plant shoots (TF) varied by a factor of up to 5 and it ranged from to 0.011 to 0.054. Five inoculated cultivars, showed enhanced shoot dry weights and decreased (137)Cs accumulations, among which two B. rapa cultivars named Bitamina and Nozawana had a significantly decreased (137)Cs accumulation in their shoots. Such cultivars could be utilized to minimize the entry of radiocesium into the food chain; however, verifying the consistency of their radiocesium accumulation in other soils is strongly required. Moreover, the variations in growth and radiocesium accumulation, as influenced by Bacillus inoculation, could help selecting well grown inoculated Brassica cultivars with low radiocesium accumulation in their shoots. PMID- 26986236 TI - Determinants of early life immune responses to RSV infection. AB - Respiratory syncytial virus causes significant morbidity and mortality in both developed and developing countries, and a vaccine that adequately protects from severe disease remains an important unmet need. RSV disease has an inordinate impact on the very young, and the physical and immunological immaturity of early life complicates vaccine design. Defining and targeting the functional capacities of early life immune responses and controlling responses during primary antigen exposure with selected vaccine delivery approaches will be important for protecting infants by active immunization. Alternatively, vaccination of older children and pregnant mothers may ameliorate disease burden indirectly until infants reach about six months of age, when they can generate more effective anti RSV immune responses. PMID- 26986238 TI - The roles of specialisation and evidence-based practice in inter-professional jurisdictions: A qualitative study of stroke services in England, Sweden and Poland. AB - This paper investigates how the concepts of clinical specialisation and evidence influence the jurisdictional power of doctors, nurses and therapists involved in stroke care in Sweden, England and Poland. How stroke care has become a distinct specialism across Europe and the role that evidence has played in this development are critically analysed. Five qualitative case studies were undertaken across the three countries, consisting of 119 semi-structured interviews with a range of healthcare workers. The informants were purposively selected and their perspectives of evidence-based practice (EBP) within stroke care were explored. The data were analysed through thematic content analysis. The two key themes that emerged from the data were the health professionals' degrees of EBP and specialisation. The results illustrate how the two concepts of clinical specialisation and evidence are interrelated and work together to influence the different professions' degree of professional jurisdiction. It is concluded that doctors' professional dominance gives them full jurisdiction in stroke care and that nurses' and therapists' degrees of jurisdiction is dependent on their ability to specialise. PMID- 26986235 TI - Interspecies transmission and chikungunya virus emergence. AB - Chikungunya virus (CHIKV) causes severe, debilitating, often chronic arthralgia with high attack rates, resulting in severe morbidity and economic costs to affected communities. Since its first well-documented emergence in Asia in the 1950s, CHIKV has infected millions and, since 2007, has spread widely, probably via viremic travelers, to initiate urban transmission in Europe, the South Pacific, and the Americas. Some spread has been facilitated by adaptive envelope glycoprotein substitutions that enhance transmission by the new vector, Aedes albopictus. Although epistatic constraints may prevent the impact of these mutations in Asian strains now circulating in the Americas, as well as in African CHIKV strains imported into Brazil last year, these constraints could eventually be overcome over time to increase the transmission by A. albopictus in rural and temperate regions. Another major determinant of CHIKV endemic stability in the Americas will be its ability to spill back into an enzootic cycle involving sylvatic vectors and nonhuman primates, an opportunity exploited by yellow fever virus but apparently not by dengue viruses. PMID- 26986239 TI - Change and stability in work-family conflict and mothers' and fathers' mental health: Longitudinal evidence from an Australian cohort. AB - Work-family conflict (WFC) occurs when work or family demands are 'mutually incompatible', with detrimental effects on mental health. This study contributes to the sparse longitudinal research, addressing the following questions: Is WFC a stable or transient feature of family life for mothers and fathers? What happens to mental health if WFC increases, reduces or persists? What work and family characteristics predict WFC transitions and to what extent are they gendered? Secondary analyses of 5 waves of data (child ages 4-5 to 12-13 years) from employed mothers (n = 2693) and fathers (n = 3460) participating in the Longitudinal Study of Australian Children were conducted. WFC transitions, across four two-year intervals (Waves 1-2, 2-3, 3-4, and 4-5) were classified as never, conscript, exit or chronic. Significant proportions of parents experienced change in WFC, between 12 and 16% of mothers and fathers for each transition 'type'. Parents who remained in chronic WFC reported the poorest mental health (adjusted multiple regression analyses), followed by those who conscripted into WFC. When WFC was relieved (exit), both mothers' and fathers' mental health improved significantly. Predictors of conscript and chronic WFC were somewhat distinct for mothers and fathers (adjusted logit regressions). Poor job quality, a skilled occupation and having more children differentiated chronic fathers' from those who exited WFC. For mothers, work factors only (skilled occupation; work hours; job insecurity) predicted chronic WFC. Findings reflect the persistent, gendered nature of work and care shaped by workplaces, but also offer tailored opportunities to redress WFC for mothers and fathers. We contribute novel evidence that mental health is directly influenced by the WFC interface, both positively and negatively, highlighting WFC as a key social determinant of health. PMID- 26986240 TI - "Drop dead ... I need your job": An exploratory study of intra-professional conflict amongst nurses in two Ontario cities. AB - Past studies have focused on inter-professional conflict and its implication for professional status and work. However, there is a dearth of research on intra professional conflict and its implications for professions. This study explores intra-professional conflicts among nurses in Ontario, using a qualitative research design, drawing on in-depth interviews with 66 nurses. The study identifies conflicts along race and age: Visible minority and younger nurses report more conflict, with visible minority nurses particularly vulnerable and racially marginalized. Members of Visible minorities and young nurses responded to workplace conflict by demonstrating competence, seeking support from colleagues, and either ignoring the abuse or standing up for themselves. These strategies do nothing to challenge professional unity. Nonetheless, intra professional conflict has negative consequences for professionals and their work. PMID- 26986241 TI - Understanding kidney transplant patients' treatment choices: The interaction of emotion with medical and social influences on risk preferences. AB - Following renal transplantation patients experience on-going immunosuppressant medication to reduce the risk of graft rejection. Over the long term the side effects of immunosuppressive drugs may affect graft survival and significantly increase risks of cancers, stroke and cardiovascular disease. To reduce these risks research is underway to develop a biomarker test to identify those patients who are likely to be 'tolerant' to their graft and therefore able to reduce immunosuppression. Biomarker tests may however incorrectly identify some patients as tolerant, thus jeopardising their graft. Following a quantitative assessment of risk preferences we undertook a qualitative study to investigate the range of influences that shaped the substantial variations found in the level of risk transplant recipients were hypothetically willing to take. In-depth interviews were carried out in the United Kingdom between May 2013 and July 2014 with 24 transplant recipients all of whom had stable kidney graft function. These interviews identified a range of factors that patients take into account when making risk assessments, including familial views, trust and the ritual of 'gift exchange' that permeates the social space of kidney transplantation. Our data support the notion that emotion is not part of a linear process, preceding and separate to reason, but is intertwined with personal understanding and perception of risk and involves a complex interplay between different influences on decision making. Our data also support Lupton's view that risk judgements are shared and collective rather than located within the individual and suggests that patient choice rather than involving a purely rational weighing of medical benefit is often based on influences that may not accord with the framework nor intention of medical professionals and medical research. PMID- 26986242 TI - [Impediments to HIV testing in HIV-infected children and teenagers in Africa: look for them where they are!]. AB - A huge number of HIV-infected children and teenagers have no access to care or receive it very late. Of the 3.2 million infected children, 2.8 million should be receiving highly active antiretroviral treatment (HAART) but only around 700,000 actually are. The first reason for this failure is the lack of HIV testing among HIV-exposed infants and thus early diagnosis or, even more frequently, the lack of testing among older children and teenagers. The objectives of this article are twofold: to review the current situation and to advocate routine offers of HIV testing to HIV-exposed children and teenagers (exposed either through mother-to child transmission or repeated transfusions) and those suspected to be HIV infected (because of malnutrition, tuberculosis, or other associated diseases). Finally, adults living with HIV should be made aware of the need for routine HIV screening of their children, even when asymptomatic. PMID- 26986243 TI - Training Increases Muscle O2 Diffusing Capacity Intrinsic to the Elevated VO2max. PMID- 26986244 TI - Response. PMID- 26986246 TI - Vaccinations for rheumatoid arthritis. AB - PURPOSE OF REVIEW: Rheumatoid arthritis (RA) patients experience increased infectious disease-related morbidity and mortality, and vaccinations represent an important element in their care. However, vaccine immunogenicity can be affected by disease-modifying antirheumatic drug (DMARD) therapy, such that vaccine choice and timing can be clinically challenging. We review the indications, safety, and immunogenicity of vaccines in the setting of RA. RECENT FINDINGS: Recent recommendations highlight the use of influenza, pneumococcal, and shingles vaccines in RA patients. Studies suggest influenza and pneumococcal vaccines are underutilized, but well tolerated in RA patients and generally immunogenic during DMARD use with the exception of rituximab. Though data for other nonlive vaccines are more limited, hepatitis B virus and human papilloma virus vaccines also appear well tolerated and immunogenic in this population. Live vaccines for shingles and yellow fever remain contraindicated in some RA patients; however, limited data suggest they might be well tolerated in certain individuals. SUMMARY: The review updates rheumatologists on the optimal use and timing of routine vaccinations in the care of RA. PMID- 26986247 TI - How compelling are the data for Epstein-Barr virus being a trigger for systemic lupus and other autoimmune diseases? AB - PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) is caused by a combination of genetic and acquired immunodeficiencies and environmental factors including infections. An association with Epstein-Barr virus (EBV) has been established by numerous studies over the past decades. Here, we review recent experimental studies on EBV, and present our integrated theory of SLE development. RECENT FINDINGS: SLE patients have dysfunctional control of EBV infection resulting in frequent reactivations and disease progression. These comprise impaired functions of EBV-specific T-cells with an inverse correlation to disease activity and elevated serum levels of antibodies against lytic cycle EBV antigens. The presence of EBV proteins in renal tissue from SLE patients with nephritis suggests direct involvement of EBV in SLE development. As expected for patients with immunodeficiencies, studies reveal that SLE patients show dysfunctional responses to other viruses as well. An association with EBV infection has also been demonstrated for other autoimmune diseases, including Sjogren's syndrome, rheumatoid arthritis, and multiple sclerosis. SUMMARY: Collectively, the interplay between an impaired immune system and the cumulative effects of EBV and other viruses results in frequent reactivation of EBV and enhanced cell death, causing development of SLE and concomitant autoreactivities. PMID- 26986245 TI - Development of a high-resolution melting method for the screening of TNFAIP3 gene mutations. AB - Tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) which encodes a ubiquitin-modifying enzyme (A20), acts as a negative regulator of the NF-kappaB pathway, and in lymphoma and autoimmune diseases it is frequently inactivated by mutations and/or deletions. We investigated the prevalence of the inactivation of TNFAIP3 in oral squamous cell carcinoma (OSCC). DNA was extracted from 81 cases of OSCC and 50 peripheral blood samples from normal controls. A high-resolution melting (HRM) analysis was used to characterize TNFAIP3 mutations, and the results were confirmed by direct DNA sequencing. Three mutations and three single nucleotide polymorphisms (SNPs) were found to be associated with OSCC; the TNFAIP3 mutation occurred in 3.7% (3/81) of the OSCC cases examined. All mutations were in exon 7 [c.1081G>A (p.E361K), c.1398C>G (p.S466R) (rs200878487) and c.1760C>T (p.P587L) (rs150056192)], and p.E361K was identified as a novel mutation. We further used SIFT and PolyPhen-2 software to assess potentially functional mutations. Two SNPs, c.296-20_296-18delCTC (rs71670547) and c.380T>G (p.F127C) (rs2230926), were located in exon 3, and c.2140C>T (p.P714S) was located in exon 9. A novel SNP, p.P714S differed from the one reported previously (p.P714A) (rs369155845) at that site. We also identified five SNPs in 50 normal Taiwanese individuals, and two of them [c.296-15C>T (rs377482653) and c.305A>G (p.N102S) (rs146534657)] were not found in our OSCC tissue. HRM facilitated the screening of genetic changes. In addition, our results indicate that the prevalence of the TNFAIP3 mutation is low in OSCC. PMID- 26986249 TI - Intermittent axillary temperature measurement fails to detect fever in critically ill patients. PMID- 26986250 TI - Where we are in training of residents: results from a standardized evaluation approach. PMID- 26986254 TI - Why we need more algal genomes. PMID- 26986252 TI - Hexokinase 2 is a determinant of neuroblastoma metastasis. AB - BACKGROUND: Intersecting a genome-wide expression profile of metastatic and nonmetastatic human neuroblastoma xenograft variants with expression profiles of tumours from stage 1 and 4 neuroblastoma patients, we previously characterised hexokinase 2 (HK2) as a gene whose expression was upregulated in both metastatic neuroblastoma variants and tumours from stage 4 neuroblastoma patients. METHODS: Local and metastatic neuroblastoma cell variants as well as metastatic neuroblastoma cells genetically manipulated to downregulate the expression of HK2 were utilised for in vitro and in vivo examinations of the involvement of HK2 in neuroblastoma. RESULTS: Hexokinase 2 expression and its activity levels were increased in neuroblastoma metastatic variants as compared with the local variants. The upregulation of HK2 confers upon the metastatic cells high resistance to the antiproliferative effect of the HK2 inhibitor 3-BrPa and to the chemotherapy agent Deferoxamine. The inhibition of HK2 transcript lowered the proliferation and motility of sh-HK2 cells as compared with sh-control cells. Mice that were inoculated with sh-HK2 cells had a lower incidence of local tumours, smaller tumour volumes and a diminished load of lung metastasis compared with mice inoculated with sh-control cells. CONCLUSIONS: Hexokinase 2 plays a significant role in shaping the malignant phenotype of neuroblastoma and influences the progression of this disease. PMID- 26986251 TI - The incidence of leukaemia in women with BRCA1 and BRCA2 mutations: an International Prospective Cohort Study. AB - BACKGROUND: Germline mutations in BRCA1 and BRCA2 increase the susceptibility to develop breast and ovarian cancers as well as increase the risk of some other cancers. Primary objective was to estimate the risk of leukaemia in BRCA1 and BRCA2 mutation carriers. METHODS: We followed 7243 women with a BRCA1 or a BRCA2 mutation for incident cases of leukaemia. We used the standardised incidence ratio (SIR) to estimate the relative risk of leukaemia, according to mutation and history of breast cancer. RESULTS: We identified five incident cases of leukaemia (two BRCA1, three BRCA2). All five women had a prior history of breast cancer and four had received chemotherapy. The mean time from breast cancer diagnosis to the development of leukaemia was 10.2 years (range 3-18 years). The SIR for BRCA1 carriers was 0.66 (95% CI: 0.11-2.19, P=0.61) and the SIR for BRCA2 carriers was 2.42 (95% CI: 0.61-6.58, P=0.17). The SIR was significantly higher than expected for women with a BRCA2 mutation and breast cancer (SIR=4.76, 95% CI:1.21-12.96, P=0.03), in particular for women who received chemotherapy (SIR=8.11, 2.06-22.07, P=0.007). CONCLUSIONS: We observed an increased risk of leukaemia in women with a BRCA2 mutation who receive chemotherapy for breast cancer. PMID- 26986253 TI - Pre-diagnostic circulating sex hormone levels and risk of prostate cancer by ERG tumour protein expression. AB - BACKGROUND: Experimental studies have shown androgen receptor stimulation to facilitate formation of the TMPRSS2:ERG gene fusion in prostate cell lines. No study has tested whether higher pre-diagnostic circulating sex hormone levels in men increase risk of developing TMPRSS2:ERG-positive prostate cancer specifically. METHODS: We conducted a nested case-control study of 200 prostate cancer cases and 1057 controls from the Physicians' Health Study and Health Professionals Follow-up Study. We examined associations between pre-diagnostic circulating levels of total testosterone, free testosterone, DHT, androstanediol glucuronide, estradiol, and SHBG and risk of prostate cancer by TMPRSS2:ERG status. TMPRSS2:ERG was estimated by ERG immunohistochemistry. We used multivariable unconditional polytomous logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of ERG-positive (n=94) and, separately, ERG-negative (n=106) disease. RESULTS: Free testosterone was significantly associated with the risk of ERG-positive prostate cancer (OR: 1.37, 95% CI: 1.05-1.77), but not ERG-negative prostate cancer (OR: 1.09, 95% CI: 0.86 1.38) (Pdiff=0.17). None of the remaining hormones evaluated showed clear differential associations with ERG-positive vs ERG-negative disease. CONCLUSIONS: These findings provide some suggestive evidence that higher pre-diagnostic free testosterone levels are associated with an increased risk of developing TMPRSS2:ERG-positive prostate cancer. PMID- 26986255 TI - Coralline algae (Rhodophyta) in a changing world: integrating ecological, physiological, and geochemical responses to global change. AB - Coralline algae are globally distributed benthic primary producers that secrete calcium carbonate skeletons. In the context of ocean acidification, they have received much recent attention due to the potential vulnerability of their high Mg calcite skeletons and their many important ecological roles. Herein, we summarize what is known about coralline algal ecology and physiology, providing context to understand their responses to global climate change. We review the impacts of these changes, including ocean acidification, rising temperatures, and pollution, on coralline algal growth and calcification. We also assess the ongoing use of coralline algae as marine climate proxies via calibration of skeletal morphology and geochemistry to environmental conditions. Finally, we indicate critical gaps in our understanding of coralline algal calcification and physiology and highlight key areas for future research. These include analytical areas that recently have become more accessible, such as resolving phylogenetic relationships at all taxonomic ranks, elucidating the genes regulating algal photosynthesis and calcification, and calibrating skeletal geochemical metrics, as well as research directions that are broadly applicable to global change ecology, such as the importance of community-scale and long-term experiments in stress response. PMID- 26986256 TI - Intra-thallus differentiation of fatty acid and pigment profiles in some temperate Fucales and Laminariales. AB - Intra-thallus variation in fatty acid and pigment contents and profiles was investigated in five species of Laminariales (Alaria esculenta, Laminaria digitata, Laminaria hyperborea, Saccharina latissima, and Saccorhiza polyschides), and three Fucales (Ascophyllum nodosum, Fucus serratus, and Himanthalia elongata). Significant variation occurred across all species and compounds examined. Total fatty acids were generally higher in the fronds, with highest levels and largest variability observed in A. nodosum (1.5% of dry weight (DW) in the base, 6.3% of DW in frond tips). Percentages of the omega-3 fatty acids 18:4 n-3 and 20:5 n-3 were generally higher in more distal parts, while 20:4 n-6 exhibited a contrasting pattern, with higher levels in basal structures and holdfasts. Trends for pigments were similar to those for fatty acids in Laminariales. In the Fucales, highest levels were detected in the mid-fronds, with lower concentrations in meristematic areas. Highest levels and greatest variability in pigments (e.g., chl a) was observed in F. serratus (1.07 mg . g( 1) DW in the base, 3.04 mg . g(-1) DW in the mid frond). Intra-thallus variability was attributed to physiological functions of the respective thallus sections, e.g., photosynthetic activity, meristematic tissue, and to variations in physical attributes of the structures investigated. Regarding potential commercial nutritional applications, fronds appeared to represent most suitable source materials, due to higher levels of pigments, polyunsaturated fatty acids, and more preferable omega-3/omega-6 ratios. PMID- 26986257 TI - Finding of 13(2) , 17(3) -cyclopheophorbide a enol as a degradation product of chlorophyll in shrunk zooxanthellae of the coral Montipora digitata. AB - We examined the morphology and pigment composition of zooxanthellae in corals subjected to normal temperature (27 degrees C) and thermal stress (32 degrees C). We observed several normal and abnormal morphological types of zooxanthellar cells. Normal cells were intact and their chloroplasts were unbroken (healthy); abnormal cells were shrunken and had partially degraded or broken chloroplasts, or they were bleached and without chloroplasts. At 27 degrees C, most healthy zooxanthellar cells were retained in the coral tissue, whereas shrunken zooxanthellae were expelled. Under thermal stress, the abundance of healthy zooxanthellae declined and the proportion of shrunken/abnormal cells increased in coral tissues. The rate of algal cell expulsion was reduced under thermal stress. Within the shrunken cells, we detected the presence of a chl-like pigment that is not ordinarily found in healthy zooxanthellae. Analysis of the absorption spectrum, absorption maxima, and retention time (by HPLC) indicated that this pigment was 13(2) , 17(3) -cyclopheophorbide a enol (cPPB-aE), which is frequently found in marine and lacustrine sediments, and in protozoans that graze on phytoplankton. The production of cPPB-aE in shrunken zooxanthellae suggests that the chls have been degraded to cPPB-aE, a compound that is not fluorescent. The lack of a fluorescence function precludes the formation of reactive oxygen species. We therefore consider the formation of cPPB-aE in shrunken zooxanthellae to be a mechanism for avoiding oxidative stress. PMID- 26986258 TI - Variability in nitrogen stable isotope ratios of macroalgae: consequences for the identification of nitrogen sources. AB - In our research, we collected and analyzed numerous macroalgal specimens (738) for isotopic analysis sampled over a year at monthly intervals across 20 sites within the Urias lagoon complex, a typical subtropical coastal ecosystem located in the Gulf of California. We quantified and characterized (chemically and isotopically) the N loads received by Urias throughout a year. We studied the spatial-temporal variation of the chemical forms and isotopic signals of the available N in the water column, and we monitored in situ different environmental variables and other hydrodynamic parameters. Multiple N sources (e.g., atmospheric, sewage, seafood processing, agriculture and aquaculture effluents) and biogeochemical reactions related to the N cycle (e.g., ammonia volatilization, nitrification and denitrification) co-occurring across the ecosystem, result in a mixture of chemical species and isotopic compositions of available N in the water column. Increased variability was observed in the delta(15) N values of macroalgae (0.410/00-22.670/00). Based on our results, the variation in delta(15) N was best explained by spatio-temporal changes in available N and not necessarily related to the N sources. The variability was also explained by the differences in macroalgal biology among functional groups, species and/or individuals. Although the delta(15) N-macroalgae technique was a useful tool to identify N sources, its application in coastal ecosystems receiving multiple N sources, with changing environmental conditions influencing biogeochemical processes, and high diversity of ephemeral macroalgal species, could be less sensitive and have less predictive power. PMID- 26986259 TI - Characterization and comparison of toxin-producing isolates of Dinophysis acuminata from New England and Canada. AB - Following the identification of the first toxic isolate of Dinophysis acuminata from the northwestern Atlantic, we conducted detailed investigations into the morphology, phylogeny, physiology, and toxigenicity of three isolates from three sites within the northeastern U.S./Canada region: Eel Pond and Martha's Vineyard, Massachusetts, and the Bay of Fundy. Another isolate, collected from the Gulf of Mexico, was grown under the same light, temperature, and prey conditions for comparison. Despite observed phenotypic heterogeneity, morphometrics and molecular evidence classified the three northwestern Atlantic isolates as D. acuminata Claparede & Lachmann, whereas the isolate from the Gulf of Mexico was morphologically identified as D. cf. ovum. Physiological and toxin analyses supported these classifications, with the three northwestern Atlantic isolates being more similar to each other with respect to growth rate, toxin profile, and diarrhetic shellfish poisoning (DSP) toxin content (okadaic acid + dinophysistoxin 1/cell) than they were to the isolate from the Gulf of Mexico, which had toxin profiles similar to those published for D. cf. ovum F. Schutt. The DSP toxin content, 0.01-1.8 pg okadaic acid (OA) + dinophysistoxin (DTX1) per cell, of the three northwestern Atlantic isolates was low relative to other D. acuminata strains from elsewhere in the world, consistent with the relative scarcity of shellfish harvesting closures due to DSP toxins in the northeastern U.S. and Canada. If this pattern is repeated with the analyses of more geographically and temporally dispersed isolates from the region, it would appear that the risk of significant DSP toxin outbreaks in the northwestern Atlantic is low to moderate. Finally, the morphological, physiological, and toxicological variability within D. acuminata may reflect spatial (and/or temporal) population structure, and suggests that sub-specific resolution may be helpful in characterizing bloom dynamics and predicting toxicity. PMID- 26986261 TI - Temperature and light interactively modulate gene expression in Saccharina latissima (Phaeophyceae). AB - Macroalgae of the order Laminariales (kelp) are important components of cold temperate coastal ecosystems. Major factors influencing their distribution are light (including UV radiation) and temperature. Therefore, future global environmental changes potentially will impact their zonation, distribution patterns, and primary productivity. Many physiological studies were performed on UV radiation and temperature stress in kelp but combinatory effects have not been analyzed and so far no study is available on the molecular processes involved in acclimation to these stresses. Therefore, sporophytes of Saccharina latissima were exposed for 2 weeks to 12 combinations of photosynthetically active radiation (PAR), UV radiation and temperature. Subsequently, microarray hybridizations were performed to determine changes in gene expression patterns. Several effects on the transcriptome were observed after exposure experiments. The strongest effect of temperature on gene expression was observed at 2 degrees C. Furthermore, UV radiation had stronger effects on gene expression than high PAR, and caused stronger induction genes correlated with categories such as photosynthetic components and vitamin B6 biosynthesis. Higher temperatures ameliorated the negative effects of UV radiation in S. latissima. Regulation of reactive oxygen species (ROS) scavenging seems to work in a compartment specific way. Gene expression profiles of ROS scavengers indicated a high amount of oxidative stress in response to the 2 degrees C condition as well as to excessive light at 12 degrees C. Interestingly, stress levels that did not lead to physiological alterations already caused by a transcriptomic response. PMID- 26986260 TI - Diel variation of the cellular carbon to nitrogen ratio of Chlorella autotrophica (Chlorophyta) growing in phosphorus- and nitrogen-limited continuous cultures. AB - We investigated the relationship between daily growth rates and diel variation of carbon (C) metabolism and C to nitrogen (N) ratio under P- and N-limitation in the green algae Chlorella autotrophica. To do this, continuous cultures of C. autotrophica were maintained in a cyclostat culture system under 14:10 light:dark cycle over a series of P- and N-limited growth rates. Cell abundance, together with cell size, as reflected by side scatter signal from flow cytometric analysis demonstrated a synchronized diel pattern with cell division occurring at night. Under either type of nutrient limitation, the cellular C:N ratio increased through the light period and decreased through the dark period over all growth rates, indicating a higher diel variation of C metabolism than that of N. Daily average cellular C:N ratios were higher at lower dilution rates under both types of nutrient limitation but cell enlargement was only observed at lower dilution rates under P-limitation. Carbon specific growth rates during the dark period positively correlated with cellular daily growth rates (dilution rates), with net loss of C during night at the lowest growth rates under N-limitation. Under P limitation, dark C specific growth rates were close to zero at low dilution rates but also exhibited an increasing trend at high dilution rates. In general, diel variations of cellular C:N were low when dark C specific growth rates were high. This result indicated that the fast growing cells performed dark C assimilation at high rates, hence diminished the uncoupling of C and N metabolism at night. PMID- 26986262 TI - Phylogeny and toxicology of Lyngbya wollei (Cyanobacteria, Oscillatoriales) from north-eastern Australia, with a description of Microseira gen. nov. AB - Three populations of the freshwater filamentous cyanobacterium Lyngbya wollei (Farlow ex Gomont) Speziale and Dyck have been putatively identified from north eastern Australia and found to produce the potent cyanotoxin cylindrospermopsin (CYN) and its analog deoxy-cylindrospermopsin (deoxy-CYN). We investigated the phylogeny and toxicology of strains and mats isolated from two of these populations using a combination of molecular and morphological techniques. Morphologically the strains corresponded to the type description, however, the frequency of false-branching was low, and variable over time. Strains and mat samples from both sites were positive for the cyrF and cyrJ genes associated with CYN biosynthesis. Phylogenetic analysis of these genes from Australian L. wollei sequences and comparable cyanobacterial sequences revealed that the genes in L. wollei were more closely related to homologous genes in Oscillatoria sp. PCC 6506 than to homologs in Nostocalean CYN-producers. These data suggest a common evolutionary origin of CYN biosynthesis in L. wollei and Oscillatoria. In both the 16S rRNA and nifH phylogenies, the Australian L. wollei strains formed well supported clades with United States L. wollei (= Plectonema wollei) strains. Pair wise sequence similarities within the 16S rRNA clade containing all eleven L. wollei strains were high, ranging from 97% to 100%. This group was distantly related (<92% nucleotide similarity) to other taxa within the group previously considered under the genus Lyngbya sensu lato (C. Agardh ex Gomont). Collectively, these results suggest that this toxigenic group is evolutionarily distinct and sufficiently distant as to be considered a separate genus, which we have described as Microseira gen. nov. and hence transfer to it the type M. wollei comb. nov. PMID- 26986263 TI - An association network analysis among microeukaryotes and bacterioplankton reveals algal bloom dynamics. AB - Algal blooms are a worldwide phenomenon and the biological interactions that underlie their regulation are only just beginning to be understood. It is established that algal microorganisms associate with many other ubiquitous, oceanic organisms, but the interactions that lead to the dynamics of bloom formation are currently unknown. To address this gap, we used network approaches to investigate the association patterns among microeukaryotes and bacterioplankton in response to a natural Scrippsiella trochoidea bloom. This is the first study to apply network approaches to bloom dynamics. To this end, terminal restriction fragment (T-RF) length polymorphism analysis showed dramatic changes in community compositions of microeukaryotes and bacterioplankton over the blooming period. A variance ratio test revealed significant positive overall associations both within and between microeukaryotic and bacterioplankton communities. An association network generated from significant correlations between T-RFs revealed that S. trochoidea had few connections to other microeukaryotes and bacterioplankton and was placed on the edge. This lack of connectivity allowed for the S. trochoidea sub-network to break off from the overall network. These results allowed us to propose a conceptual model for explaining how changes in microbial associations regulate the dynamics of an algal bloom. In addition, key T-RFs were screened by principal components analysis, correlation coefficients, and network analysis. Dominant T-RFs were then identified through 18S and 16S rRNA gene clone libraries. Results showed that microeukaryotes clustered predominantly with Dinophyceae and Perkinsea while the majority of bacterioplankton identified were Alphaproteobacteria, Gammaproteobacteria, and Bacteroidetes. The ecologi-cal roles of both were discussed in the context of these findings. PMID- 26986264 TI - Flood disturbance effects on benthic diatom assemblage structure in a semiarid river network. AB - Disturbances such as floods and droughts play a central role in determining the structure of riverine benthic biological assemblages. Extreme disturbances from flash floods are often restricted to part of the river network and the magnitude of the flood disturbance may lessen as floods propagate downstream. The present study aimed to characterize the impact of summer monsoonal floods on the resistance and resilience of the benthic diatom assemblage structure in nine river reaches of increasing drainage size within the Gila River in the southwestern United States. Monsoonal floods had a profound effect on the diatom assemblage in the Gila River, but the effects were not related to drainage size except for the response of algal biomass. During monsoons, algal biomass was effectively reduced in smaller and larger systems, but minor changes were observed in medium systems. Resistance and resilience of the diatom assemblage to floods were related to specific species traits, mainly to growth forms. Tightly adhered, adnate and prostrate species (Achnanthidium spp., Cocconeis spp.) exhibited high resistance to repeated scour disturbance. Loosely attached diatoms, such as Nitzschia spp. and Navicula spp., were most susceptible to drift and scour. However, recovery of the diatom assemblage was very quick indicating a high resilience, especially in terms of biomass and diversity. Regional hydroclimatic models predict greater precipitation variability, which will select for diatoms resilient to bed-mobilizing disturbances. The results of this study may help anticipate future benthic diatom assemblage patterns in the southwestern United States resulting from a more variable climate. PMID- 26986265 TI - Spermatogenesis and auxospore structure in the multipolar centric diatom Hydrosera. AB - Spermatogenesis and auxospore development were studied in the freshwater centric diatom Hydrosera triquetra. Spermatogenesis was unusual, lacking depauperating cell divisions within the spermatogonangium. Instead, a series of mitoses occurred within an undivided cell to produce a multinucleate plasmodium with peripheral nuclei, which then underwent meiosis. 32 or 64 sperm budded off from the plasmodium leaving a large residual cell containing all the chloroplasts. Similar development apparently occurs in Pleurosira, Aulacodiscus, and Guinardia, these being so distantly related that independent evolution of plasmodial spermatogenesis seems likely. After presumed fertilization, the Hydrosera egg cell expanded distally to form a triangular end part. However, unlike in other triangular diatoms (Lithodesmium, Triceratium), the development of triradiate symmetry was not controlled by the "canonical" method of a perizonium that constrains expansion to small terminal areas of the auxospore wall. Instead, the auxospore wall lacked a perizonium and possessed only scales and a dense mat of thin, apparently entangled strips of imperforate silica. No such structures have been reported from any other centric diatoms, the closest analogs being instead the incunabular strips of some raphid diatoms (Nitzschia and Pinnularia). Whether these silica structures are formed by the normal method (intracellular deposition within a silica deposition vesicle) is unknown. As well as being more rounded than vegetative cells, the initial cell is aberrant in its structure, since it has a less polarized distribution of the "triptych" pores characteristic of the species. PMID- 26986266 TI - Intraspecific diversity and distribution of the cosmopolitan species Pseudo nitzschia pungens (Bacillariophyceae): morphology, genetics, and ecophysiology of the three clades. AB - Three clades of Pseudo-nitzschia pungens, determined by the internal transcribed space (ITS) region, are distributed throughout the world. We studied 15 P. pungens clones from various geographical locations and confirmed the existence of the three clades within P. pungens, based on ITS sequencing and described the three subgroups (IIIaa, IIIab, and IIIb) of clade III. Clade III (clade IIIaa) populations were reported for the first time in Korean coastal waters and the East China Sea. In morphometric analysis, we found the ultrastructural differences in the number of fibulae, striae, and poroids that separate the three clades. We carried out physiological tests on nine clones belonging to the three clades growing under various culture conditions. In temperature tests, only clade III clones could not grow at lower temperatures (10 degrees C and 15 degrees C), although clade I and II clones grew well. The estimated optimal growth range of clade I clones was wider than that of clades II and III. Clade II clones were considered to be adapted to lower temperatures and clade III to higher temperatures. In salinity tests, clade II and III clones did not grow well at a salinity of 40. Clade I clones were regarded as euryhaline and clade II and III clones were stenohaline. This supports the hypothesis that P. pungens clades have different ecophysiological characteristics based on their habitats. Our data show that physiological and morphological features are correlated with genetic intraspecific differentiation in P. pungens. PMID- 26986267 TI - Are Prorocentrum hoffmannianum and Prorocentrum belizeanum (DINOPHYCEAE, PROROCENTRALES), the same species? An integration of morphological and molecular data. AB - The taxonomic assignment of Prorocentrum species is based on morphological characteristics; however, morphological variability has been found for several taxa isolated from different geographical regions. In this study, we evaluated species boundaries of Prorocentrum hoffmannianum and Prorocentrum belizeanum based on morphological and molecular data. A detailed morphological analysis was done, concentrating on the periflagellar architecture. Molecular analyses were performed on partial Small Sub-Unit (SSU) rDNA, partial Large Sub-Unit (LSU) rDNA, complete Internal Transcribed Spacer Regions (ITS1-5.8S-ITS2), and partial cytochrome b (cob) sequences. We concatenated the SSU-ITS-LSU fragments and constructed a phylogenetic tree using Bayesian Inference (BI) and maximum likelihood (ML) methods. Morphological analyses indicated that the main characters, such as cell size and number of depressions per valve, normally used to distinguish P. hoffmannianum from P. belizeanum, overlapped. No clear differences were found in the periflagellar area architecture. Prorocentrum hoffmannianum and P. belizeanum were a highly supported monophyletic clade separated into three subclades, which broadly corresponded to the sample collection regions. Subtle morphological overlaps found in cell shape, size, and ornamentation lead us to conclude that P. hoffmanianum and P. belizeanum might be considered conspecific. The molecular data analyses did not separate P. hoffmannianum and P. belizeanum into two morphospecies, and thus, we considered them to be the P. hoffmannianum species complex because their clades are separated by their geographic origin. These geographic and genetically distinct clades could be referred to as ribotypes: (A) Belize, (B) Florida-Cuba, (C1) India, and (C2) Australia. PMID- 26986268 TI - DNA sequencing, anatomy, and calcification patterns support a monophyletic, subarctic, carbonate reef-forming Clathromorphum (Hapalidiaceae, Corallinales, Rhodophyta). AB - For the first time, morpho-anatomical characters that were congruent with DNA sequence data were used to characterize several genera in Hapalidiaceae-the major eco-engineers of Subarctic carbonate ecosystems. DNA sequencing of three genes (SSU, rbcL, ribulose-1, 5-bisphosphate carboxylase/oxygenase large subunit gene and psbA, photosystem II D1 protein gene), along with patterns of cell division, cell elongation, and calcification supported a monophyletic Clathromorphum. Two characters were diagnostic for this genus: (i) cell division, elongation, and primary calcification occurred only in intercalary meristematic cells and in a narrow vertical band (1-2 MUm wide) resulting in a "meristem split" and (ii) a secondary calcification of interfilament crystals was also produced. Neopolyporolithon was resurrected for N. reclinatum, the generitype, and Clathromorphum loculosum was transferred to this genus. Like Clathromorphum, cell division, elongation, and calcification occurred only in intercalary meristematic cells, but in a wider vertical band (over 10-20 MUm), and a "meristem split" was absent. Callilithophytum gen. nov. was proposed to accommodate Clathromorphum parcum, the obligate epiphyte of the northeast Pacific endemic geniculate coralline, Calliarthron. Diagnostic for this genus were epithallial cells terminating all cell filaments (no dorsi-ventrality was present), and a distinct "foot" was embedded in the host. Leptophytum, based on its generitype, L. laeve, was shown to be a distinct genus more closely related to Clathromorphum than to Phymatolithon. All names of treated species were applied unequivocally by linking partial rbcL sequences from holotype, isotype, or epitype specimens with field collected material. Variation in rbcL and psbA sequences suggested that multiple species may be passing under each currently recognized species of Clathromorphum and Neopolyporolithon. PMID- 26986269 TI - Identification of the resting cyst of Cochlodinium polykrikoides Margalef (Dinophyceae, Gymnodiniales) in Korean coastal sediments. AB - This study provides the first morphological features of resting cysts of Cochlodinium polykrikoides collected from Korean coastal sediments. Evidence for the existence of resting cysts of C. polykrikoides is based on the morphological and molecular phylogenetic data of the germinated cells and a resting cyst. The morphology of the resting cysts differed from that reported previously in sediments and culture experiments. The distinct feature is that the cyst body was covered by the reticulate ornaments and spines. PMID- 26986270 TI - First report of fossilized cysts produced by the benthic Bysmatrum subsalsum (Dinophyceae) from a shallow Mexican lagoon in the Gulf of Mexico. AB - Cysts belonging to the benthic dinoflagellate Bysmatrum subsalsum were recovered from palynologically treated sediments collected in the Alvarado Lagoon (southwestern Gulf of Mexico). The cysts are proximate, reflecting the features of the parent thecal stage, and their autofluorescence implies a dinosporin composition similar to the cyst walls of phototrophic species. This finding is important for our understanding of B. subsalsum life cycle transitions and ecology. Encystment may play an important role in the bloom dynamics of this species as it can enable the formation of a sediment cyst bank that allows reinoculation of the water column when conditions become favorable. This is the first report of a fossilized cyst produced by a benthic dinoflagellate recovered from sub-recent sediments. PMID- 26986271 TI - Single integrodifferential wave equation for a Levy walk. AB - We derive the single integrodifferential wave equation for the probability density function of the position of a classical one-dimensional Levy walk with continuous sample paths. This equation involves a classical wave operator together with memory integrals describing the spatiotemporal coupling of the Levy walk. It is valid at all times, not only in the long time limit, and it does not involve any large-scale approximations. It generalizes the well-known telegraph or Cattaneo equation for the persistent random walk with the exponential switching time distribution. Several non-Markovian cases are considered when the particle's velocity alternates at the gamma and power-law distributed random times. In the strong anomalous case we obtain the asymptotic solution to the integrodifferential wave equation. We implement the nonlinear reaction term of Kolmogorov-Petrovsky-Piskounov type into our equation and develop the theory of wave propagation in reaction-transport systems involving Levy diffusion. PMID- 26986272 TI - Macroscopic fluctuation theory and first-passage properties of surface diffusion. AB - We investigate nonequilibrium fluctuations of a solid surface governed by the stochastic Mullins-Herring equation with conserved noise. This equation describes surface diffusion of adatoms accompanied by their exchange between the surface and the bulk of the solid, when desorption of adatoms is negligible. Previous works dealt with dynamic scaling behavior of the fluctuating interface. Here we determine the probability that the interface first reaches a large given height at a specified time. We also find the optimal time history of the interface conditional on this nonequilibrium fluctuation. We obtain these results by developing a macroscopic fluctuation theory of surface diffusion. PMID- 26986273 TI - Universal structure of two- and three-dimensional self-gravitating systems in the quasiequilibrium state. AB - We study a universal structure of two- and three-dimensional self-gravitating systems in the quasiequilibrium state. It is shown numerically that the two dimensional self-gravitating system in the quasiequilibrium state has the same kind of density profile as the three-dimensional one, especially when null virial conditions are fulfilled. It is unveiled why the conditions are necessary for the universal structure by the envelope equation. We develop a phenomenological model to describe this universal structure by using a special Langevin equation with a distinctive random noise to self-gravitating systems. We find that the density profile derived theoretically is very consistent with results of observations and simulations. PMID- 26986274 TI - Onset of time dependence in ensembles of excitable elements with global repulsive coupling. AB - We consider the effect of global repulsive coupling on an ensemble of identical excitable elements. An increase of the coupling strength destabilizes the synchronous equilibrium and replaces it with many attracting oscillatory states, created in the transcritical heteroclinic bifurcation. The period of oscillations is inversely proportional to the distance from the critical parameter value. If the elements interact with the global field via the first Fourier harmonics of their phases, the stable equilibrium is in one step replaced by the attracting continuum of periodic motions. PMID- 26986275 TI - Spiral wave chimeras in locally coupled oscillator systems. AB - The recently discovered chimera state involves the coexistence of synchronized and desynchronized states for a group of identical oscillators. In this work, we show the existence of (inwardly) rotating spiral wave chimeras in the three component reaction-diffusion systems where each element is locally coupled by diffusion. A transition from spiral waves with the smooth core to spiral wave chimeras is found as we change the local dynamics of the system or as we gradually increase the diffusion coefficient of the activator. Our findings on the spiral wave chimera in the reaction-diffusion systems suggest that spiral chimera states may be found in chemical and biological systems that can be modeled by a large population of oscillators indirectly coupled via a diffusive environment. PMID- 26986276 TI - Impact of BaTiO(3) nanoparticles on pretransitional effects in liquid crystalline dodecylcyanobiphenyl. AB - The pretransitional behavior of dodecylcyanobiphenyl (12CB) (isotropic-smectic-A solid mesomorphism) with d=50nmBaTiO(3) nanoparticles (NPs) linked to the cubic phase was monitored via temperature studies of dielectric constant. Tests were carried out in the isotropic, liquid crystal mesomorphic, and solid phases. For each phase transition the same value of the critical exponent alpha~0.5 was obtained, including nanocolloids. All phase transitions show the weakly discontinuous nature. The temperature metric of the discontinuity DeltaT notably decreases when adding nanoparticles. The addition of nanoparticles first decreases the dielectric constant by approximately 50% in comparison with pure 12CB, but already for a concentration ~x=0.4% NP an increase over 50% takes place. It is notable that for the latter concentration unique hallmarks of the pretransitional effect emerge also for the solid-mesophase transition. All these indicate the important impact of nanoparticles on multimolecular mesoscale fluctuations. PMID- 26986277 TI - Modifying self-assembly and species separation in three-dimensional systems of shape-anisotropic particles. AB - The behaviors of large, dynamic assemblies of macroscopic particles are of direct relevance to geophysical and industrial processes and may also be used as easily studied analogs to micro- or nano-scale systems, or model systems for microbiological, zoological, and even anthropological phenomena. We study vibrated mixtures of elongated particles, demonstrating that the inclusion of differing particle "species" may profoundly alter a system's dynamics and physical structure in various diverse manners. The phase behavior observed suggests that our system, despite its athermal nature, obeys a minimum free energy principle analogous to that observed for thermodynamic systems. We demonstrate that systems of exclusively spherical objects, which form the basis of numerous theoretical frameworks in many scientific disciplines, represent only a narrow region of a wide, multidimensional phase space. Thus, our results raise significant questions as to whether such models can accurately describe the behaviors of systems outside this highly specialized case. PMID- 26986278 TI - Dynamic self-assembly of non-Brownian spheres studied by molecular dynamics simulations. AB - Granular self-assembly of confined non-Brownian spheres under gravity is studied by molecular dynamics simulations. Starting from a disordered phase, dry or cohesive spheres organize, by vibrational annealing, into body-centered tetragonal or face-centered-cubic structures, respectively. During the self assembling process, isothermal and isodense points are observed. The existence of such points indicates that both granular temperature and packing fraction undergo an inversion process that may be in the core of crystal nucleation. Around the isothermal point, a sudden growth of granular clusters having the maximum coordination number takes place, indicating the outcome of a first-order phase transition. We propose a heuristic equation that successfully describes the dynamic evolution of the local packing fraction in terms of the local granular temperature, along the entire crystallization process. PMID- 26986279 TI - Acoustically levitated dancing drops: Self-excited oscillation to chaotic shedding. AB - We experimentally demonstrate self-excited oscillation and shedding of millimeter sized water drops, acoustically levitated in a single-node standing waves cavity, by decreasing the steady acoustic wave intensity below a threshold. The perturbation of the acoustic field by drop motion is a possible source for providing an effective negative damping for sustaining the growing amplitude of the self-excited motion. Its further interplay with surface tension, drop inertia, gravity and acoustic intensities, select various self-excited modes for different size of drops and acoustic intensity. The large drop exhibits quasiperiodic motion from a vertical mode and a zonal mode with growing coupling, as oscillation amplitudes grow, until falling on the floor. For small drops, chaotic oscillations constituted by several broadened sectorial modes and corresponding zonal modes are self-excited. The growing oscillation amplitude leads to droplet shedding from the edges of highly stretched lobes, where surface tension no longer holds the rapid expanding flow. PMID- 26986280 TI - Low-dimensional representations of exact coherent states of the Navier-Stokes equations from the resolvent model of wall turbulence. AB - We report that many exact invariant solutions of the Navier-Stokes equations for both pipe and channel flows are well represented by just a few modes of the model of McKeon and Sharma [J. Fluid Mech. 658, 336 (2010)]. This model provides modes that act as a basis to decompose the velocity field, ordered by their amplitude of response to forcing arising from the interaction between scales. The model was originally derived from the Navier-Stokes equations to represent turbulent flows and has been used to explain coherent structure and to predict turbulent statistics. This establishes a surprising new link between the two distinct approaches to understanding turbulence. PMID- 26986282 TI - Conditional reversibility in nonequilibrium stochastic systems. AB - For discrete-state stochastic systems obeying Markovian dynamics, we establish the counterpart of the conditional reversibility theorem obtained by Gallavotti for deterministic systems [Ann. de l'Institut Henri Poincare (A) 70, 429 (1999)]. Our result states that stochastic trajectories conditioned on opposite values of entropy production are related by time reversal, in the long-time limit. In other words, the probability of observing a particular sequence of events, given a long trajectory with a specified entropy production rate sigma, is the same as the probability of observing the time-reversed sequence of events, given a trajectory conditioned on the opposite entropy production, -sigma, where both trajectories are sampled from the same underlying Markov process. To obtain our result, we use an equivalence between conditioned ("microcanonical") and biased ("canonical") ensembles of nonequilibrium trajectories. We provide an example to illustrate our findings. PMID- 26986283 TI - Heat conduction and energy diffusion in momentum-conserving one-dimensional full lattice ding-a-ling model. AB - The ding-a-ling model is a kind of half lattice and half hard-point-gas (HPG) model. The original ding-a-ling model proposed by Casati et al. does not conserve total momentum and has been found to exhibit normal heat conduction behavior. Recently, a modified ding-a-ling model which conserves total momentum has been studied and normal heat conduction has also been claimed. In this work, we propose a full-lattice ding-a-ling model without hard point collisions where total momentum is also conserved. We investigate the heat conduction and energy diffusion of this full-lattice ding-a-ling model with three different nonlinear inter-particle potential forms. For symmetrical potential lattices, the thermal conductivities diverges with lattice length and their energy diffusions are superdiffusive signaturing anomalous heat conduction. For asymmetrical potential lattices, although the thermal conductivity seems to converge as the length increases, the energy diffusion is definitely deviating from normal diffusion behavior indicating anomalous heat conduction as well. No normal heat conduction behavior can be found for the full-lattice ding-a-ling model. PMID- 26986281 TI - On-ground detection of an electron-positron annihilation line from thunderclouds. AB - Thunderclouds can produce bremsstrahlung gamma-ray emission, and sometimes even positrons. At 00:27:00 (UT) on 13 January 2012, an intense burst of gamma rays from a thundercloud was detected by the GROWTH experiment, located in Japan, facing the Sea of Japan. The event started with a sharp gamma-ray flash with a duration of <300 ms coincident with an intracloud discharge, followed by a decaying longer gamma-ray emission lasting for ~60 s. The spectrum of this prolonged emission reached ~10 MeV, and contained a distinct line emission at 508+/-3(stat.)+/-5(sys.) keV, to be identified with an electron-positron annihilation line. The line was narrow within the instrumental energy resolution (~80keV), and contained 520+/-50 photons which amounted to ~10% of the total signal photons of 5340+/-190 detected over 0.1-10 MeV. As a result, the line equivalent width reached 280+/-40 keV, which implies a nontrivial result. The result suggests that a downward positron beam produced both the continuum and the line photons. PMID- 26986284 TI - Slow Levy flights. AB - Among Markovian processes, the hallmark of Levy flights is superdiffusion, or faster-than-Brownian dynamics. Here we show that Levy laws, as well as Gaussian distributions, can also be the limit distributions of processes with long-range memory that exhibit very slow diffusion, logarithmic in time. These processes are path dependent and anomalous motion emerges from frequent relocations to already visited sites. We show how the central limit theorem is modified in this context, keeping the usual distinction between analytic and nonanalytic characteristic functions. A fluctuation-dissipation relation is also derived. Our results may have important applications in the study of animal and human displacements. PMID- 26986285 TI - Crossover from localized to diffusive water dynamics in carbon nanohorns: A comprehensive quasielastic neutron-scattering analysis. AB - Incoherent neutron scattering by water confined in carbon nanohorns was measured with the backscattering spectrometer SPHERES and analyzed in exemplary breadth and depth. Quasielastic spectra admit delta-plus-Kohlrausch fits over a wide q and T range. From the q and T dependence of fitted amplitudes and relaxation times, however, it becomes clear that the fits do not represent a uniform physical process, but that there is a crossover from localized motion at low T to diffusive alpha relaxation at high T. The crossover temperature of about 210 to 230 K increases with decreasing wave number, which is incompatible with a thermodynamic strong-fragile transition. Extrapolated diffusion coefficients D(T) indicate that water motion is at room temperature about 2.5 times slower than in the bulk; in the supercooled state this factor becomes smaller. At even higher temperatures, where the alpha spectrum is essentially flat, a few percentages of the total scattering go into a Lorentzian with a width of about 1.6MUeV, probably due to functional groups on the surface of the nanohorns. PMID- 26986286 TI - Conductivity estimates of spherical-particle suspensions based on triplet structure factors. AB - In this paper, we present an estimation of the conductivity of composites constituted of identical spheres embedded in a host material. A family of polarization integral equations for the localization problem is constructed and the operator is then minimized to yield an optimal integral equation. As a result, the corresponding Neumann series converges with the fastest rate and can be used to estimate the effective conductivity. By combining this series and integral approximation, one can derive explicit expressions for the overall property using expansions in Fourier domain. For random hard-sphere systems, relations to structure factors and triplet structure factors have been made and Kirkwood superposition approximation is used to evaluate the effective conductivity, taking into account third-order correlations. This presents an original means to account for the statistical information up to third-order correlation when determining the effective properties of composite materials. PMID- 26986287 TI - Characterization of stationary states in random walks with stochastic resetting. AB - It is known that introducing a stochastic resetting in a random-walk process can lead to the emergence of a stationary state. Here we study this point from a general perspective through the derivation and analysis of mesoscopic (continuous time random walk) equations for both jump and velocity models with stochastic resetting. In the case of jump models it is shown that stationary states emerge for any shape of the waiting-time and jump length distributions. The existence of such state entails the saturation of the mean square displacement to an universal value that depends on the second moment of the jump distribution and the resetting probability. The transient dynamics towards the stationary state depends on how the waiting time probability density function decays with time. If the moments of the jump distribution are finite then the tail of the stationary distributions is universally exponential, but for Levy flights these tails decay as a power law whose exponent coincides with that from the jump distribution. For velocity models we observe that the stationary state emerges only if the distribution of flight durations has finite moments of lower order; otherwise, as occurs for Levy walks, the stationary state does not exist, and the mean square displacement grows ballistically or superdiffusively, depending on the specific shape of the distribution of movement durations. PMID- 26986288 TI - Generalized maximum entropy approach to quasistationary states in long-range systems. AB - Systems with long-range interactions display a short-time relaxation towards quasistationary states (QSSs) whose lifetime increases with the system size. In the paradigmatic Hamiltonian mean-field model (HMF) out-of-equilibrium phase transitions are predicted and numerically detected which separate homogeneous (zero magnetization) and inhomogeneous (nonzero magnetization) QSSs. In the former regime, the velocity distribution presents (at least) two large, symmetric bumps, which cannot be self-consistently explained by resorting to the conventional Lynden-Bell maximum entropy approach. We propose a generalized maximum entropy scheme which accounts for the pseudoconservation of additional charges, the even momenta of the single-particle distribution. These latter are set to the asymptotic values, as estimated by direct integration of the underlying Vlasov equation, which formally holds in the thermodynamic limit. Methodologically, we operate in the framework of a generalized Gibbs ensemble, as sometimes defined in statistical quantum mechanics, which contains an infinite number of conserved charges. The agreement between theory and simulations is satisfying, both above and below the out-of-equilibrium transition threshold. A previously unaccessible feature of the QSSs, the multiple bumps in the velocity profile, is resolved by our approach. PMID- 26986289 TI - Lifshitz-Matsubara sum formula for the Casimir pressure between magnetic metallic mirrors. AB - We examine the conditions of validity for the Lifshitz-Matsubara sum formula for the Casimir pressure between magnetic metallic plane mirrors. As in the previously studied case of nonmagnetic materials [Guerout et al., Phys. Rev. E 90, 042125 (2014)], we recover the usual expression for the lossy model of optical response, but not for the lossless plasma model. We also show that the modes associated with the Foucault currents play a crucial role in the limit of vanishing losses, in contrast to expectations. PMID- 26986290 TI - Initial condition of stochastic self-assembly. AB - The formation of a stable protein aggregate is regarded as the rate limiting step in the establishment of prion diseases. In these systems, once aggregates reach a critical size the growth process accelerates and thus the waiting time until the appearance of the first critically sized aggregate is a key determinant of disease onset. In addition to prion diseases, aggregation and nucleation is a central step of many physical, chemical, and biological process. Previous studies have examined the first-arrival time at a critical nucleus size during homogeneous self-assembly under the assumption that at time t=0 the system was in the all-monomer state. However, in order to compare to in vivo biological experiments where protein constituents inherited by a newly born cell likely contain intermediate aggregates, other possibilities must be considered. We consider one such possibility by conditioning the unique ergodic size distribution on subcritical aggregate sizes; this least-informed distribution is then used as an initial condition. We make the claim that this initial condition carries fewer assumptions than an all-monomer one and verify that it can yield significantly different averaged waiting times relative to the all-monomer condition under various models of assembly. PMID- 26986291 TI - Finite-temperature mechanical instability in disordered lattices. AB - Mechanical instability takes different forms in various ordered and disordered systems and little is known about how thermal fluctuations affect different classes of mechanical instabilities. We develop an analytic theory involving renormalization of rigidity and coherent potential approximation that can be used to understand finite-temperature mechanical stabilities in various disordered systems. We use this theory to study two disordered lattices: a randomly diluted triangular lattice and a randomly braced square lattice. These two lattices belong to two different universality classes as they approach mechanical instability at T=0. We show that thermal fluctuations stabilize both lattices. In particular, the triangular lattice displays a critical regime in which the shear modulus scales as G~T(1/2), whereas the square lattice shows G~T(2/3). We discuss generic scaling laws for finite-T mechanical instabilities and relate them to experimental systems. PMID- 26986292 TI - Universal behavior of crystalline membranes: Crumpling transition and Poisson ratio of the flat phase. AB - We revisit the universal behavior of crystalline membranes at and below the crumpling transition, which pertains to the mechanical properties of important soft and hard matter materials, such as the cytoskeleton of red blood cells or graphene. Specifically, we perform large-scale Monte Carlo simulations of a triangulated two-dimensional phantom network which is freely fluctuating in three dimensional space. We obtain a continuous crumpling transition characterized by critical exponents which we estimate accurately through the use of finite-size techniques. By controlling the scaling corrections, we additionally compute with high accuracy the asymptotic value of the Poisson ratio in the flat phase, thus characterizing the auxetic properties of this class of systems. We obtain agreement with the value which is universally expected for polymerized membranes with a fixed connectivity. PMID- 26986293 TI - Validity of the third law of thermodynamics for the Tsallis entropy. AB - Bento et al. [Phys. Rev. E 91, 022105 (2015)] recently stated that the Tsallis entropy violates the third law of thermodynamics for 01 is already inherent in the fundamental incomplete structure of the deformed logarithms and exponentials underlying the Tsallis entropy. Then, we provide the complete deformed functions and show that the Tsallis entropy conforms to the third law of thermodynamics for both superadditive q<1 and subadditive q>1 regimes. Finally, we remark that the Tsallis entropy does not require the use of an escort-averaging scheme once it is expressed in terms of the complete deformed functions. PMID- 26986294 TI - Linear relaxation in large two-dimensional Ising models. AB - Critical dynamics in two-dimension Ising lattices up to 2048*2048 is simulated on field-programmable-gate-array- based computing devices. Linear relaxation times are measured from extremely long Monte Carlo simulations. The longest simulation has 7.1*10(16) spin updates, which would take over 37 years to simulate on a general purpose computer. The linear relaxation time of the Ising lattices is found to follow the dynamic scaling law for correlation lengths as long as 2048. The dynamic exponent z of the system is found to be 2.179(12), which is consistent with previous studies of Ising lattices with shorter correlation lengths. It is also found that Monte Carlo simulations of critical dynamics in Ising lattices larger than 512*512 are very sensitive to the statistical correlations between pseudorandom numbers, making it even more difficult to study such large systems. PMID- 26986295 TI - Thermodynamic aspects of information transfer in complex dynamical systems. AB - From the Horowitz-Esposito stochastic thermodynamical description of information flows in dynamical systems [J. M. Horowitz and M. Esposito, Phys. Rev. X 4, 031015 (2014)], it is known that while the second law of thermodynamics is satisfied by a joint system, the entropic balance for the subsystems is adjusted by a term related to the mutual information exchange rate between the two subsystems. In this article, we present a quantitative discussion of the conceptual link between the Horowitz-Esposito analysis and the Liang-Kleeman work on information transfer between dynamical system components [X. S. Liang and R. Kleeman, Phys. Rev. Lett. 95, 244101 (2005)]. In particular, the entropic balance arguments employed in the two approaches are compared. Notwithstanding all differences between the two formalisms, our work strengthens the Liang-Kleeman heuristic balance reasoning by showing its formal analogy with the recent Horowitz-Esposito thermodynamic balance arguments. PMID- 26986296 TI - Derivation of a one-way radiative transfer equation in random media. AB - We derive from first principles a one-way radiative transfer equation for the wave intensity resolved over directions (Wigner transform of the wave field) in random media. It is an initial value problem with excitation from a source which emits waves in a preferred, forward direction. The equation is derived in a regime with small random fluctuations of the wave speed but long distances of propagation with respect to the wavelength, so that cumulative scattering is significant. The correlation length of the medium and the scale of the support of the source are slightly larger than the wavelength, and the waves propagate in a wide cone with an opening angle less than 180 degrees , so that the backward and evanescent waves are negligible. The scattering regime is a bridge between that of radiative transfer, where the waves propagate in all directions, and the paraxial regime, where the waves propagate in a narrow angular cone. We connect the one-way radiative transfer equation with the equations satisfied by the Wigner transform of the wave field in these regimes. PMID- 26986297 TI - Sensory capacity: An information theoretical measure of the performance of a sensor. AB - For a general sensory system following an external stochastic signal, we introduce the sensory capacity. This quantity characterizes the performance of a sensor: sensory capacity is maximal if the instantaneous state of the sensor has as much information about a signal as the whole time series of the sensor. We show that adding a memory to the sensor increases the sensory capacity. This increase quantifies the improvement of the sensor with the addition of the memory. Our results are obtained with the framework of stochastic thermodynamics of bipartite systems, which allows for the definition of an efficiency that relates the rate with which the sensor learns about the signal with the energy dissipated by the sensor, which is given by the thermodynamic entropy production. We demonstrate a general trade-off between sensory capacity and efficiency: if the sensory capacity is equal to its maximum 1, then the efficiency must be less than 1/2. As a physical realization of a sensor we consider a two-component cellular network estimating a fluctuating external ligand concentration as signal. This model leads to coupled linear Langevin equations that allow us to obtain explicit analytical results. PMID- 26986298 TI - Transition radiation on a dynamic periodic interface. AB - We investigate the transition radiation on a periodically deformed interface between two dielectric media. Under the assumption that the dielectric permittivities of the media are close, a formula is derived for the spectral angular distribution of the radiated energy in the general case of a nonstatic profile function for the separating boundary. In particular, the latter includes the case of surface waves propagating along the boundary. The numerical examples are given for triangular grating and for sinusoidal profile. We show that instead of a single peak in the backward transition radiation on a flat interface, for periodic interface one has a set of peaks. The number and the locations of the peaks depend on the incidence angle of the charge and on the period of the interface. The conditions are specified for their appearance. PMID- 26986299 TI - Surface growth on percolation networks by a conserved-noise restricted solid-on solid growth model. AB - Surface growth by the conserved-noise restricted solid-on-solid model is investigated on diluted lattices, i.e., on percolation networks that are embedded in two spatial dimensions. The growth exponent beta and the roughness exponent alpha are defined, respectively, by the mean-square surface width via W(2)(t)~t(2beta) and the mean-square saturated width via W(sat)(2)(L)~L(2alpha), where L is the system size. These are measured on both an infinite network and a backbone network and the results are compared with power-counting predictions obtained using the fractional Langevin equation. While the Monte Carlo results on deterministic fractal substrates show excellent agreement with the predictions [D. H. Kim and J. M. Kim, Phys. Rev. E 84, 011105 (2011)], the results on critical percolation networks deviate by 8%-12% from these predictions. PMID- 26986300 TI - Bimodal and Gaussian Ising spin glasses in dimension two. AB - An analysis is given of numerical simulation data to size L=128 on the archetype square lattice Ising spin glasses (ISGs) with bimodal (+/-J) and Gaussian interaction distributions. It is well established that the ordering temperature of both models is zero. The Gaussian model has a nondegenerate ground state and thus a critical exponent eta=0, and a continuous distribution of energy levels. For the bimodal model, above a size-dependent crossover temperature T(*)(L) there is a regime of effectively continuous energy levels; below T(*)(L) there is a distinct regime dominated by the highly degenerate ground state plus an energy gap to the excited states. T(*)(L) tends to zero at very large L, leaving only the effectively continuous regime in the thermodynamic limit. The simulation data on both models are analyzed with the conventional scaling variable t=T and with a scaling variable tau(b)=T(2)/(1+T(2)) suitable for zero-temperature transition ISGs, together with appropriate scaling expressions. The data for the temperature dependence of the reduced susceptibility chi(tau(b),L) and second moment correlation length xi(tau(b),L) in the thermodynamic limit regime are extrapolated to the tau(b)=0 critical limit. The Gaussian critical exponent estimates from the simulations, eta=0 and nu=3.55(5), are in full agreement with the well-established values in the literature. The bimodal critical exponents, estimated from the thermodynamic limit regime analyses using the same extrapolation protocols as for the Gaussian model, are eta=0.20(2) and nu=4.8(3), distinctly different from the Gaussian critical exponents. PMID- 26986301 TI - Random field disorder at an absorbing state transition in one and two dimensions. AB - We investigate the behavior of nonequilibrium phase transitions under the influence of disorder that locally breaks the symmetry between two symmetrical macroscopic absorbing states. In equilibrium systems such "random-field" disorder destroys the phase transition in low dimensions by preventing spontaneous symmetry breaking. In contrast, we show here that random-field disorder fails to destroy the nonequilibrium phase transition of the one- and two-dimensional generalized contact process. Instead, it modifies the dynamics in the symmetry broken phase. Specifically, the dynamics in the one-dimensional case is described by a Sinai walk of the domain walls between two different absorbing states. In the two-dimensional case, we map the dynamics onto that of the well studied low temperature random-field Ising model. We also study the critical behavior of the nonequilibrium phase transition and characterize its universality class in one dimension. We support our results by large-scale Monte Carlo simulations, and we discuss the applicability of our theory to other systems. PMID- 26986302 TI - Surface properties and scaling behavior of a generalized ballistic deposition model. AB - The surface exponents, scaling behavior, and bulk porosity of a generalized ballistic deposition (GBD) model are studied. In nature, there exist particles with varying degrees of stickiness ranging from completely nonsticky to fully sticky. Such particles may adhere to any one of the successively encountered surfaces, depending on a sticking probability that is governed by the underlying stochastic mechanism. The microscopic configurations possible in this model are much larger than those allowed in existing models of ballistic deposition and competitive growth models that seek to mix ballistic and random deposition processes. In this article, we find the scaling exponents for surface width and porosity for the proposed GBD model. In terms of scaled width W[over ] and scaled time t[over ], the numerical data collapse onto a single curve, demonstrating successful scaling with sticking probability p and system size L. Similar scaling behavior is also found for the porosity. PMID- 26986303 TI - Otto engine beyond its standard quantum limit. AB - We propose a quantum Otto cycle based on the properties of a two-level system in a realistic out-of-thermal-equilibrium electromagnetic field acting as its sole reservoir. This steady configuration is produced without the need of active control over the state of the environment, which is a noncoherent thermal radiation, sustained only by external heat supplied to macroscopic objects. Remarkably, even for nonideal finite-time transformations, it largely over performs the standard ideal Otto cycle and asymptotically achieves unit efficiency at finite power. PMID- 26986304 TI - Efficient variants of the minimal diffusion formulation of Markov chain ensembles. AB - This study is concerned with ensembles of continuous-time Markov chains evolving independently under a common transition rate matrix in some finite state space. In this context, our prior work [Phys. Rev. E 91, 062116 (2015)] has formulated an approximation scheme, called the minimal diffusion formulation, to deduce how the number of chains in a prescribed relevant state evolves in time. The formulation consists of two specifically coupled Ornstein-Uhlenbeck processes in a stochastic differential equation representation; it is minimal in the sense that its structure does not change with the state space size or the transition matrix density, and it requires no matrix square-root operations. In the present study, we first calculate the autocorrelation function of the relevant state density in the minimal diffusion formulation, which is fundamental to the identification of the ensemble dynamics. The obtained autocorrelation function is then employed to develop two diffusion formulations that reduce the structural complexity of the minimal diffusion formulation without significant loss of accuracy in the dynamics. One of these variant formulations includes one less noise term than the minimal diffusion formulation and still satisfies the above mentioned autocorrelation function in its dynamics. The second variant is in the form of a one-dimensional Langevin equation, therefore it is the simplest possible diffusion formulation one can obtain for the problem, yet its autocorrelation function is first-order accurate in time gap. Numerical simulations supporting the theoretical analysis are delivered. PMID- 26986305 TI - Tight-binding approach to overdamped Brownian motion on a bichromatic periodic potential. AB - We present a theoretical treatment of overdamped Brownian motion on a time independent bichromatic periodic potential with spatially fast- and slow-changing components. In our approach, we generalize the Wannier basis commonly used in the analysis of periodic systems to define a basis of S states that are localized at local minima of the potential. We demonstrate that the S states are orthonormal and complete on the length scale of the periodicity of the fast-changing potential, and we use the S-state basis to transform the continuous Smoluchowski equation for the system to a discrete master equation describing hopping between local minima. We identify the parameter regime where the master equation description is valid and show that the interwell hopping rates are well approximated by Kramers' escape rate in the limit of deep potential minima. Finally, we use the master equation to explore the system dynamics and determine the drift and diffusion for the system. PMID- 26986306 TI - Anisotropic four-state clock model in the presence of random fields. AB - A four-state clock ferromagnetic model is studied in the presence of different configurations of anisotropies and random fields. The model is considered in the limit of infinite-range interactions, for which the mean-field approach becomes exact. Both representations of Cartesian spin components and two Ising variables are used, in terms of which the physical properties and phase diagrams are discussed. The random fields follow bimodal probability distributions and the richest criticality is found when the fields, applied in the two Ising systems, are not correlated. The phase diagrams present new interesting topologies, with a wide variety of critical points, which are expected to be useful in describing different complex phenomena. PMID- 26986307 TI - Beyond heat baths: Generalized resource theories for small-scale thermodynamics. AB - Thermodynamics has recently been extended to small scales with resource theories that model heat exchanges. Real physical systems exchange diverse quantities: heat, particles, angular momentum, etc. We generalize thermodynamic resource theories to exchanges of observables other than heat, to baths other than heat baths, and to free energies other than the Helmholtz free energy. These generalizations are illustrated with "grand-potential" theories that model movements of heat and particles. Free operations include unitaries that conserve energy and particle number. From this conservation law and from resource-theory principles, the grand-canonical form of the free states is derived. States are shown to form a quasiorder characterized by free operations, d majorization, the hypothesis-testing entropy, and rescaled Lorenz curves. We calculate the work distillable from-and we bound the work cost of creating-a state. These work quantities can differ but converge to the grand potential in the thermodynamic limit. Extending thermodynamic resource theories beyond heat baths, we open diverse realistic systems to modeling with one-shot statistical mechanics. Prospective applications such as electrochemical batteries are hoped to bridge one-shot theory to experiments. PMID- 26986308 TI - Percolation thresholds for discrete-continuous models with nonuniform probabilities of bond formation. AB - We introduce a class of discrete-continuous percolation models and an efficient Monte Carlo algorithm for computing their properties. The class is general enough to include well-known discrete and continuous models as special cases. We focus on a particular example of such a model, a nanotube model of disintegration of activated carbon. We calculate its exact critical threshold in two dimensions and obtain a Monte Carlo estimate in three dimensions. Furthermore, we use this example to analyze and characterize the efficiency of our algorithm, by computing critical exponents and properties, finding that it compares favorably to well known algorithms for simpler systems. PMID- 26986309 TI - Nonzero-temperature entanglement negativity of quantum spin models: Area law, linked cluster expansions, and sudden death. AB - We show that the bipartite logarithmic entanglement negativity (EN) of quantum spin models obeys an area law at all nonzero temperatures. We develop numerical linked cluster (NLC) expansions for the "area-law" logarithmic entanglement negativity as a function of temperature and other parameters. For one-dimensional models the results of NLC are compared with exact diagonalization on finite systems and are found to agree very well. The NLC results are also obtained for two dimensional XXZ and transverse field Ising models. In all cases, we find a sudden onset (or sudden death) of negativity at a finite temperature above which the negativity is zero. We use perturbation theory to develop a physical picture for this sudden onset (or sudden death). The onset of EN or its magnitude are insensitive to classical finite-temperature phase transitions, supporting the argument for absence of any role of quantum mechanics at such transitions. On approach to a quantum critical point at T=0, negativity shows critical scaling in size and temperature. PMID- 26986310 TI - Influence of the aspect ratio and boundary conditions on universal finite-size scaling functions in the athermal metastable two-dimensional random field Ising model. AB - This work studies universal finite size scaling functions for the number of one dimensional spanning avalanches in a two-dimensional (2D) disordered system with boundary conditions of different nature and different aspect ratios. To this end, we will consider the 2D random field Ising model at T=0 driven by the external field H with athermal dynamics implemented with periodic and forced boundary conditions. We have chosen a convenient scaling variable z that accounts for the deformation of the distance to the critical point caused by the aspect ratio. In addition, assuming that the dependence of the finite size scaling functions on the aspect ratio can be accounted for by an additional multiplicative factor, we have been able to collapse data for different system sizes, different aspect ratios, and different types of the boundary conditions into a single scaling function Q. PMID- 26986311 TI - Formulation of Liouville's theorem for grand ensemble molecular simulations. AB - Liouville's theorem in a grand ensemble, that is for situations where a system is in equilibrium with a reservoir of energy and particles, is a subject that, to our knowledge, has not been explicitly treated in literature related to molecular simulation. Instead, Liouville's theorem, a central concept for the correct employment of molecular simulation techniques, is implicitly considered only within the framework of systems where the total number of particles is fixed. However, the pressing demand of applied science in treating open systems leads to the question of the existence and possible exact formulation of Liouville's theorem when the number of particles changes during the dynamical evolution of the system. The intention of this paper is to stimulate a debate about this crucial issue for molecular simulation. PMID- 26986312 TI - Aspects of quantum work. AB - Various approaches of defining and determining work performed on a quantum system are compared. Any operational definition of work, however, must allow for two facts: first, that work characterizes a process rather than an instantaneous state of a system and, second, that quantum systems are sensitive to the interactions with a measurement apparatus. We compare different measurement scenarios on the basis of the resulting postmeasurement states and the according probabilities for finding a particular work value. In particular, we analyze a recently proposed work meter for the case of a Gaussian pointer state and compare it with the results obtained by two projective and, alternatively, two Gaussian measurements. In the limit of a strong effective measurement strength the work distribution of projective two energy measurements can be recovered. In the opposite limit the average of work becomes independent of any measurement. Yet the fluctuations about this value diverge. The performance of the work meter is illustrated by the example of a spin in a suddenly changing magnetic field. PMID- 26986313 TI - Microscopic description of quantum Lorentz gas and extension of the Boltzmann equation to entire space-time scale. AB - Irreversible processes of weakly coupled one-dimensional quantum perfect Lorentz gas are studied on the basis of the fundamental laws of physics in terms of the complex spectral analysis associated with the resonance state of the Liouville von Neumann operator. Without any phenomenological operations, such as a coarse graining of space-time, or a truncation of the higher order correlation, we obtained irreversible processes in a purely dynamical basis in all space and time scale including the microscopic atomic interaction range that is much smaller than the mean-free length. Based on this solution, a limitation of the usual phenomenological Boltzmann equation, as well as an extension of the Boltzmann equation to entire space-time scale, is discussed. PMID- 26986314 TI - First-passage phenomena in hierarchical networks. AB - In this paper we study Markov processes and related first-passage problems on a class of weighted, modular graphs which generalize the Dyson hierarchical model. In these networks, the coupling strength between two nodes depends on their distance and is modulated by a parameter sigma. We find that, in the thermodynamic limit, ergodicity is lost and the "distant" nodes cannot be reached. Moreover, for finite-sized systems, there exists a threshold value for sigma such that, when sigma is relatively large, the inhomogeneity of the coupling pattern prevails and "distant" nodes are hardly reached. The same analysis is carried on also for generic hierarchical graphs, where interactions are meant to involve p-plets (p>2) of nodes, finding that ergodicity is still broken in the thermodynamic limit, but no threshold value for sigma is evidenced, ultimately due to a slow growth of the network diameter with the size. PMID- 26986315 TI - Quantum thermal machine acting on a many-body quantum system: Role of correlations in thermodynamic tasks. AB - We study the functioning of a three-level thermal machine when acting on a many qubit system, the entire system being placed in an electromagnetic field in a stationary out-of-thermal-equilibrium configuration. This realistic setup stands between the two so-far-explored cases of single-qubit and macroscopic object targets, providing information on the scaling with system size of purely quantum properties in thermodynamic contexts. We show that, thanks to the presence of robust correlations among the qubits induced by the field, thermodynamic tasks can be delivered by the machine both locally to each qubit and collectively to the many-qubit system: This allows a task to be delivered also on systems much bigger than the machine size. PMID- 26986316 TI - Transition in the decay rates of stationary distributions of Levy motion in an energy landscape. AB - The time evolution of random variables with Levy statistics has the ability to develop jumps, displaying very different behaviors from continuously fluctuating cases. Such patterns appear in an ever broadening range of examples including random lasers, non-Gaussian kinetics, or foraging strategies. The penalizing or reinforcing effect of the environment, however, has been little explored so far. We report a new phenomenon which manifests as a qualitative transition in the spatial decay behavior of the stationary measure of a jump process under an external potential, occurring on a combined change in the characteristics of the process and the lowest eigenvalue resulting from the effect of the potential. This also provides insight into the fundamental question of what is the mechanism of the spatial decay of a ground state. PMID- 26986317 TI - Ballistic annihilation with superimposed diffusion in one dimension. AB - We consider a one-dimensional system with particles having either positive or negative velocity, and these particles annihilate on contact. Diffusion is superimposed on the ballistic motion of the particle. The annihilation may represent a reaction in which the two particles yield an inert species. This model has been the subject of previous work, in which it was shown that the particle concentration decays faster than either the purely ballistic or the purely diffusive case. We report on previously unnoticed behavior for large times when only one of the two species remains, and we also unravel the underlying fractal structure present in the system. We also consider in detail the case in which the initial concentration of right-going particles is 1/2+E, with E?0. It is shown that remarkably rich behavior arises, in which two crossover times are observed as E->0. PMID- 26986318 TI - Nonconservative dynamics of optically trapped high-aspect-ratio nanowires. AB - We investigate the dynamics of high-aspect-ratio nanowires trapped axially in a single gradient force optical tweezers. A power spectrum analysis of the dynamics reveals a broad spectral resonance of the order of kHz with peak properties that are strongly dependent on the input trapping power. A dynamical model incorporating linear restoring optical forces, a nonconservative asymmetric coupling between translational and rotational degrees of freedom, viscous drag, and white noise provides an excellent fit to experimental observations. A persistent low-frequency cyclical motion around the equilibrium trapping position, with a frequency distinct from the spectral resonance, is observed from the time series data. PMID- 26986319 TI - Quantifying group specificity of animal vocalizations without specific sender information. AB - Recordings of animal vocalization can lack information about sender and context. This is often the case in studies on marine mammals or in the increasing number of automated bioacoustics monitorings. Here, we develop a framework to estimate group specificity without specific sender information. We introduce and apply a bag-of-calls-and-coefficients approach (BOCCA) to study ensembles of cepstral coefficients calculated from vocalization signals recorded from a given animal group. Comparing distributions of such ensembles of coefficients by computing relative entropies reveals group specific differences. Applying the BOCCA to ensembles of calls recorded from group of long-finned pilot whales in northern Norway, we find that differences of vocalizations within social groups of pilot whales (Globicephala melas) are significantly lower than intergroup differences. PMID- 26986320 TI - Thermostat algorithm for generating target ensembles. AB - We present a deterministic algorithm called contact density dynamics that generates any prescribed target distribution in the physical phase space. Akin to the famous model of Nose and Hoover, our algorithm is based on a non-Hamiltonian system in an extended phase space. However, the equations of motion in our case follow from contact geometry and we show that in general they have a similar form to those of the so-called density dynamics algorithm. As a prototypical example, we apply our algorithm to produce a Gibbs canonical distribution for a one dimensional harmonic oscillator. PMID- 26986321 TI - Ab initio calculation of thermodynamic potentials and entropies for superionic water. AB - We construct thermodynamic potentials for two superionic phases of water [with body-centered cubic (bcc) and face-centered cubic (fcc) oxygen lattice] using a combination of density functional theory (DFT) and molecular dynamics simulations (MD). For this purpose, a generic expression for the free energy of warm dense matter is developed and parametrized with equation of state data from the DFT-MD simulations. A second central aspect is the accurate determination of the entropy, which is done using an approximate two-phase method based on the frequency spectra of the nuclear motion. The boundary between the bcc superionic phase and the ices VII and X calculated with thermodynamic potentials from DFT-MD is consistent with that directly derived from the simulations. Differences in the physical properties of the bcc and fcc superionic phases and their impact on interior modeling of water-rich giant planets are discussed. PMID- 26986322 TI - Fermionic thermocoherent state: Efficiency of electron transport. AB - On the basis of the fermionic coherent state of Cahill and Glauber [Phys. Rev. A 59, 1538 (1999)], we have introduced here the fermionic thermocoherent state in terms of the quasiprobability distribution which shows the appropriate thermal and coherent limits as in the bosonic case or the Glauber-Lachs state. It is shown that the fermionic thermocoherent state can be realized as a displaced thermal state of fermions. Its relation with the fermionic displaced number state and the fermion-added coherent state are explored in the spirit of the bosonic case. We have investigated the nature of the average current and the suppression of noise due to the thermocoherent character of the source. The theory is applied to the problem of electronic conduction. A modification of the Landauer conductance formula is suggested which reflects the role of nonzero coherence of the source in electron transport. PMID- 26986323 TI - Anomalously slow relaxation of interacting liquid nanoclusters confined in a porous medium. AB - Anomalously slow relaxation of clusters of a liquid confined in a disordered system of pores has been studied for the (water-L23 nanoporous medium) system. The evolution of the system of confined liquid clusters consists of a fast formation stage followed by slow relaxation of the system and its decay. The characteristic time for the formation of the initial state is tau(p)~10 s after the reduction of excess pressure after complete filling. Anomalously slow relaxation has been observed for times of 10(1)-10(5) s, and decay has been observed at times of >10(5) s. The time dependence of the volume fraction theta of pores filled with the confined liquid is described by a power law theta~t( alpha) with the exponent alpha<0.15. The exponent alpha and temperature dependence alpha(T) are qualitatively described theoretically for the case of a slightly polydisperse medium in a mean-field approximation with the inclusion of the interaction of liquid clusters and averaging over various degenerate local configurations of clusters. In this approximation, slow relaxation is represented as a continuous transition through a sequence of metastable states of the system of clusters with a decreasing barrier. PMID- 26986324 TI - Elusive present: Hidden past and future dependency and why we build models. AB - Modeling a temporal process as if it is Markovian assumes that the present encodes all of a process's history. When this occurs, the present captures all of the dependency between past and future. We recently showed that if one randomly samples in the space of structured processes, this is almost never the case. So, how does the Markov failure come about? That is, how do individual measurements fail to encode the past? and How many are needed to capture dependencies between the past and future? Here, we investigate how much information can be shared between the past and the future but not reflected in the present. We quantify this elusive information, give explicit calculational methods, and outline the consequences, the most important of which is that when the present hides past future correlation or dependency we must move beyond sequence-based statistics and build state-based models. PMID- 26986325 TI - Regular modes in a mixed-dynamics-based optical fiber. AB - A multimode optical fiber with a truncated transverse cross section acts as a powerful versatile support to investigate the wave features of complex ray dynamics. In this paper, we concentrate on the case of a geometry inducing mixed dynamics. We highlight that regular modes associated with stable periodic orbits present an enhanced spatial intensity localization. We report the statistics of the inverse participation ratio whose features are analogous to those of Anderson localized modes. Our study is supported by both numerical and experimental results on the spatial localization and spectral regularity of the regular modes. PMID- 26986326 TI - Solitons riding on solitons and the quantum Newton's cradle. AB - The reduced dynamics for dark and bright soliton chains in the one-dimensional nonlinear Schrodinger equation is used to study the behavior of collective compression waves corresponding to Toda lattice solitons. We coin the term hypersoliton to describe such solitary waves riding on a chain of solitons. It is observed that in the case of dark soliton chains, the formulated reduction dynamics provides an accurate an robust evolution of traveling hypersolitons. As an application to Bose-Einstein condensates trapped in a standard harmonic potential, we study the case of a finite dark soliton chain confined at the center of the trap. When the central chain is hit by a dark soliton, the energy is transferred through the chain as a hypersoliton that, in turn, ejects a dark soliton on the other end of the chain that, as it returns from its excursion up the trap, hits the central chain repeating the process. This periodic evolution is an analog of the classical Newton's cradle. PMID- 26986327 TI - Hysteresis and drift of spiral waves near heterogeneities: From chemical experiments to cardiac simulations. AB - Dissipative patterns in excitable reaction-diffusion systems can be strongly affected by spatial heterogeneities. Using the photosensitive Belousov Zhabotinsky reaction, we show a hysteresis effect in the transition between free and pinned spiral rotation. The latter state involves the rotation around a disk shaped obstacle with an impermeable and inert boundary. The transition is controlled by changes in light intensity. For permeable heterogeneities of higher excitability, we observe spiral drift along both linear and circular boundaries. Our results confirm recent theoretical predictions and, in the case of spiral drift, are further reproduced by numerical simulations with a modified Oregonator model. Additional simulations with a cardiac model show that orbital motion can also exist in anisotropic and three-dimensional systems. PMID- 26986328 TI - Symmetry reduction in high dimensions, illustrated in a turbulent pipe. AB - Equilibrium solutions are believed to structure the pathways for ergodic trajectories in a dynamical system. However, equilibria are atypical for systems with continuous symmetries, i.e., for systems with homogeneous spatial dimensions, whereas relative equilibria (traveling waves) are generic. In order to visualize the unstable manifolds of such solutions, a practical symmetry reduction method is required that converts relative equilibria into equilibria, and relative periodic orbits into periodic orbits. In this article we extend the fixed Fourier mode slice approach, previously applied one-dimensional PDEs, to a spatially three-dimensional fluid flow, and show that it is substantially more effective than our previous approach to slicing. Application of this method to a minimal flow unit pipe leads to the discovery of many relative periodic orbits that appear to fill out the turbulent regions of state space. We further demonstrate the value of this approach to symmetry reduction through projections (projections only possible in the symmetry-reduced space) that reveal the interrelations between these relative periodic orbits and the ways in which they shape the geometry of the turbulent attractor. PMID- 26986329 TI - Dynamics of a passively mode-locked semiconductor laser subject to dual-cavity optical feedback. AB - We study the influence of dual-cavity optical feedback on the emission dynamics and timing stability of a passively mode-locked semiconductor laser using a delay differential equation model and verify the timing stability results by an initial experiment. By bifurcation analysis in dependence of the feedback delay times and feedback strength bistability, quasiperiodic and chaotic dynamics, as well as fundamental mode-locking are investigated, yielding a comprehensive overview on the nonlinear emission dynamics arising due to dual-cavity optical feedback. Optimum self-locking ranges for improving the timing stability by dual-cavity optical feedback are identified. A timing jitter reduction and an increase of the repetition rate tuning range of up to a factor of three, compared with single cavity feedback, are predicted for the parameter ranges investigated. Improved timing stability on short and long timescales is predicted for dual-cavity feedback through the suppression of noise-induced fluctuations. Based on the numerical predictions, experimentally, a maximum timing jitter reduction up to a factor of 180 is found, accompanied by a side-band reduction by a factor of 58 dB, when both feedback cavities are resonant. PMID- 26986330 TI - Chaos synchronization by resonance of multiple delay times. AB - Chaos synchronization may arise in networks of nonlinear units with delayed couplings. We study complete and sublattice synchronization generated by resonance of two large time delays with a specific ratio. As it is known for single-delay networks, the number of synchronized sublattices is determined by the greatest common divisor (GCD) of the network loop lengths. We demonstrate analytically the GCD condition in networks of iterated Bernoulli maps with multiple delay times and complement our analytic results by numerical phase diagrams, providing parameter regions showing complete and sublattice synchronization by resonance for Tent and Bernoulli maps. We compare networks with the same GCD with single and multiple delays, and we investigate the sensitivity of the correlation to a detuning between the delays in a network of coupled Stuart-Landau oscillators. Moreover, the GCD condition also allows detection of time-delay resonances, leading to high correlations in nonsynchronizable networks. Specifically, GCD-induced resonances are observed both in a chaotic asymmetric network and in doubly connected rings of delay coupled noisy linear oscillators. PMID- 26986331 TI - Nonparametric causal inference for bivariate time series. AB - We introduce new quantities for exploratory causal inference between bivariate time series. The quantities, called penchants and leanings, are computationally straightforward to apply, follow directly from assumptions of probabilistic causality, do not depend on any assumed models for the time series generating process, and do not rely on any embedding procedures; these features may provide a clearer interpretation of the results than those from existing time series causality tools. The penchant and leaning are computed based on a structured method for computing probabilities. PMID- 26986332 TI - Short-time-delay limit of the self-coupled FitzHugh-Nagumo system. AB - We analyze the FitzHugh-Nagumo equations subject to time-delayed self-feedback in the activator variable. Parameters are chosen such that the steady state is stable independent of the feedback gain and delay tau. We demonstrate that stable large-amplitude tau-periodic oscillations can, however, coexist with a stable steady state even for small delays, which is mathematically counterintuitive. In order to explore how these solutions appear in the bifurcation diagram, we propose three different strategies. We first analyze the emergence of periodic solutions from Hopf bifurcation points for tau small and show that a subcritical Hopf bifurcation allows the coexistence of stable tau-periodic and stable steady state solutions. Second, we construct a tau-periodic solution by using singular perturbation techniques appropriate for slow-fast systems. The theory assumes tau=O(1) and its validity as tau->0 is investigated numerically by integrating the original equations. Third, we develop an asymptotic theory where the delay is scaled with respect to the fast timescale of the activator variable. The theory is applied to the FitzHugh-Nagumo equations with threshold nonlinearity, and we show that the branch of tau-periodic solutions emerges from a limit point of limit cycles. PMID- 26986333 TI - Floquet topological semimetal phases of an extended kicked Harper model. AB - Recent discoveries on topological characterization of gapless systems have attracted interest in both theoretical studies and experimental realizations. Examples of such gapless topological phases are Weyl semimetals, which exhibit three-dimensional (3D) Dirac cones (Weyl points), and nodal line semimetals, which are characterized by line nodes (two bands touching along a line). Inspired by our previous discoveries that the kicked Harper model exhibits many fascinating features of Floquet topological phases, in this paper we consider a generalization of the model, where two additional periodic system parameters are introduced into the Hamiltonian to serve as artificial dimensions, so as to simulate a 3D periodically driven system. We observe that by increasing the hopping strength and the kicking strength of the system, many new Floquet band touching points at Floquet quasienergies 0 and pi will start to appear. Some of them are Weyl points, while the others form line nodes in the parameter space. By taking open boundary conditions along the physical dimension, edge states analogous to Fermi arcs in static Weyl semimetal systems are observed. Finally, by designing an adiabatic pumping scheme, the chirality of the Floquet-band Weyl points and the pi Berry phase around Floquet-band line nodes can be manifested. PMID- 26986334 TI - Variational principle for nonlinear wave propagation in dissipative systems. AB - The dynamics of many natural systems is dominated by nonlinear waves propagating through the medium. We show that in any extended system that supports nonlinear wave fronts with positive surface tension, the asymptotic wave-front dynamics can be formulated as a gradient system, even when the underlying evolution equations for the field variables cannot be written as a gradient system. The variational potential is simply given by a linear combination of the occupied volume and surface area of the wave front and changes monotonically over time. PMID- 26986335 TI - Spectral decomposition of nonlinear systems with memory. AB - We present an alternative approach to the analysis of nonlinear systems with long term memory that is based on the Koopman operator and a Levy transformation in time. Memory effects are considered to be the result of interactions between a system and its surrounding environment. The analysis leads to the decomposition of a nonlinear system with memory into modes whose temporal behavior is anomalous and lacks a characteristic scale. On average, the time evolution of a mode follows a Mittag-Leffler function, and the system can be described using the fractional calculus. The general theory is demonstrated on the fractional linear harmonic oscillator and the fractional nonlinear logistic equation. When analyzing data from an ill-defined (black-box) system, the spectral decomposition in terms of Mittag-Leffler functions that we propose may uncover inherent memory effects through identification of a small set of dynamically relevant structures that would otherwise be obscured by conventional spectral methods. Consequently, the theoretical concepts we present may be useful for developing more general methods for numerical modeling that are able to determine whether observables of a dynamical system are better represented by memoryless operators, or operators with long-term memory in time, when model details are unknown. PMID- 26986336 TI - Cooperative dynamics in coupled systems of fast and slow phase oscillators. AB - We propose a coupled system of fast and slow phase oscillators. We observe two step transitions to quasiperiodic motions by direct numerical simulations of this coupled oscillator system. A low-dimensional equation for order parameters is derived using the Ott-Antonsen ansatz. The applicability of the ansatz is checked by the comparison of numerical results of the coupled oscillator system and the reduced low-dimensional equation. We investigate further several interesting phenomena in which mutual interactions between the fast and slow oscillators play an essential role. Fast oscillations appear intermittently as a result of excitatory interactions with slow oscillators in a certain parameter range. Slow oscillators experience an oscillator-death phenomenon owing to their interaction with fast oscillators. This oscillator death is explained as a result of saddle node bifurcation in a simple phase equation obtained using the temporal average of the fast oscillations. Finally, we show macroscopic synchronization of the order 1:m between the slow and fast oscillators. PMID- 26986337 TI - Granger-causality maps of diffusion processes. AB - Granger causality is a statistical concept devised to reconstruct and quantify predictive information flow between stochastic processes. Although the general concept can be formulated model-free it is often considered in the framework of linear stochastic processes. Here we show how local linear model descriptions can be employed to extend Granger causality into the realm of nonlinear systems. This novel treatment results in maps that resolve Granger causality in regions of state space. Through examples we provide a proof of concept and illustrate the utility of these maps. Moreover, by integration we convert the local Granger causality into a global measure that yields a consistent picture for a global Ornstein-Uhlenbeck process. Finally, we recover invariance transformations known from the theory of autoregressive processes. PMID- 26986339 TI - Delocalization and quantum chaos in atom-field systems. AB - Employing efficient diagonalization techniques, we perform a detailed quantitative study of the regular and chaotic regions in phase space in the simplest nonintegrable atom-field system, the Dicke model. A close correlation between the classical Lyapunov exponents and the quantum Participation Ratio of coherent states on the eigenenergy basis is exhibited for different points in the phase space. It is also shown that the Participation Ratio scales linearly with the number of atoms in chaotic regions and with its square root in the regular ones. PMID- 26986338 TI - Collective dynamics of a spin-orbit-coupled Bose-Einstein condensate. AB - We study the collective dynamics of the spin-orbit coupled two pseudospin components of a Bose-Einstein condensate trapped in a quasi-one-dimensional harmonic potential, by using variational and directly numerical approach of binary mean-field Gross-Pitaevskii equations. The results show that, because of strong coupling of spin-orbit coupling (SOC), Rabi coupling, and atomic interaction, the collective dynamics of the system behave as complex characters. When the Rabi coupling is absent, the density profiles of the system preserve the Gauss type and the wave packets do harmonic oscillations. The amplitude of the collective oscillations increases with SOC. Furthermore, when the SOC strength increases, the dipole oscillations of the two pseudospin components undergo a transition from in-phase to out-of-phase oscillations. When the Rabi coupling present, there will exist a critical value of SOC strength (which depends on the Rabi coupling and atomic interaction). If the SOC strength is less than this critical value, the density profiles of the system can preserve the Gauss type and the wave packets do anharmonic (the frequency of dipole oscillations depends on SOC) oscillations synchronously (i.e., in-phase oscillations). However, if the SOC strength is larger than this critical value, the wave packets are dynamically fragmented and the stable dipole oscillations of the system can not exist. The collective dynamics of the system can be controlled by adjusting the atomic interaction, SOC, and Rabi-coupling strength. PMID- 26986340 TI - Dynamical thermalization of Frenkel-Kontorova model in the thermodynamic limit. AB - We study numerically the process of dynamical thermalization in the Frenkel Kontorova (FK) model with weak nonlinearity. The total energy has initially equidistributed among some of the lowest frequency linear modes. It is found that the energy transfers continuously to the high-frequency modes and finally evolves towards energy equipartition in the FK model. However, the metastable state, which was found in Fermi-Pasta-Ulam (FPU) model and phi(4) model in a relatively short time scale, is not found in the FK model. We further perform a very accurate systematic study of the equipartition time T(eq) as functions of the particle number N, the nonlinear parameter beta, and the energy density E. In the thermodynamic limit, the dependence of T(eq) on beta and E is found to display a power law behavior: T(eq)?beta(a)E(b). The exponents a and b are numerically found to be approximately -2.0 and 1.43. This scaling law is also quite different from those of the FPU-beta model and phi(4) model. PMID- 26986341 TI - Controlling chimera states: The influence of excitable units. AB - We explore the influence of a block of excitable units on the existence and behavior of chimera states in a nonlocally coupled ring-network of FitzHugh Nagumo elements. The FitzHugh-Nagumo system, a paradigmatic model in many fields from neuroscience to chemical pattern formation and nonlinear electronics, exhibits oscillatory or excitable behavior depending on the values of its parameters. Until now, chimera states have been studied in networks of coupled oscillatory FitzHugh-Nagumo elements. In the present work, we find that introducing a block of excitable units into the network may lead to several interesting effects. It allows for controlling the position of a chimera state as well as for generating a chimera state directly from the synchronous state. PMID- 26986342 TI - Phase-shift-controlled logic gates in Y-shaped nonlinearly coupled chains. AB - We introduce a model system composed of two input discrete chains nonlinearly coupled to a single output chain which mimics the geometry of Y-shaped carbon nanotubes, photonic crystal wave guides, and DNA junctions. We explore the capability of the proposed system to perform logic gate operations based on the transmission of phase-shifted harmonic incoming waves. Within a tight-binding approach, we determine the exact transmission spectrum which exhibits a nonlinear induced bistability. Using a digitalization scheme of the output signal based on amplitude modulation, we show that AND, OR, and XOR logic operations can be achieved. Nonlinearity strongly favors the realization of logic operations in the regime of large wavelengths, while phase shifting is required for the OR logic gate to be realizable. A detailed analysis of the contrast ratio shows that optimal operation of the AND and OR logic gates takes place when the nonlinear response is the predominant physical property distinguishing the coupling and regular sites. These results point towards the possibility of Y-branched junctions to perform logic operations based on the transmission of traveling waves. PMID- 26986343 TI - Phase coherence induced by correlated disorder. AB - We consider a mean-field model of coupled phase oscillators with quenched disorder in the coupling strengths and natural frequencies. When these two kinds of disorder are uncorrelated (and when the positive and negative couplings are equal in number and strength), it is known that phase coherence cannot occur and synchronization is absent. Here we explore the effects of correlating the disorder. Specifically, we assume that any given oscillator either attracts or repels all the others, and that the sign of the interaction is deterministically correlated with the given oscillator's natural frequency. For symmetrically correlated disorder with zero mean, we find that the system spontaneously synchronizes, once the width of the frequency distribution falls below a critical value. For asymmetrically correlated disorder, the model displays coherent traveling waves: the complex order parameter becomes nonzero and rotates with constant frequency different from the system's mean natural frequency. Thus, in both cases, correlated disorder can trigger phase coherence. PMID- 26986344 TI - Dynamical behavior and peak power reduction in a pair of energy storage oscillators coupled by delayed power price. AB - This paper investigates dynamics of a management system for controlling a pair of energy storages. The system involves the following two characteristics: each storage behaves in a manner that reduces the number of charge noncharge cycles and begins to be charged when the price of power is lower than a particular price threshold. The price is proportional to the past total power flow from a power grid to all storages. A peak of the total power flow occurs when these storages are charged simultaneously. From the viewpoint of nonlinear dynamics, the energy storages can be considered as relaxation oscillators coupled by a delay connection. Our analytical results suggest that the peak can be reduced by inducing an antiphase synchronization in coupled oscillators. We confirm these analytical results through numerical simulations. In addition, we numerically investigate the dynamical behavior in 10 storages and find that time delay in the connection is important in reducing the peak. PMID- 26986345 TI - Leveraging information storage to select forecast-optimal parameters for delay coordinate reconstructions. AB - Delay-coordinate reconstruction is a proven modeling strategy for building effective forecasts of nonlinear time series. The first step in this process is the estimation of good values for two parameters, the time delay and the embedding dimension. Many heuristics and strategies have been proposed in the literature for estimating these values. Few, if any, of these methods were developed with forecasting in mind, however, and their results are not optimal for that purpose. Even so, these heuristics-intended for other applications-are routinely used when building delay coordinate reconstruction-based forecast models. In this paper, we propose an alternate strategy for choosing optimal parameter values for forecast methods that are based on delay-coordinate reconstructions. The basic calculation involves maximizing the shared information between each delay vector and the future state of the system. We illustrate the effectiveness of this method on several synthetic and experimental systems, showing that this metric can be calculated quickly and reliably from a relatively short time series, and that it provides a direct indication of how well a near neighbor based forecasting method will work on a given delay reconstruction of that time series. This allows a practitioner to choose reconstruction parameters that avoid any pathologies, regardless of the underlying mechanism, and maximize the predictive information contained in the reconstruction. PMID- 26986346 TI - Comprehensive spectral approach for community structure analysis on complex networks. AB - A simple but efficient spectral approach for analyzing the community structure of complex networks is introduced. It works the same way for all types of networks, by spectrally splitting the adjacency matrix into a "unipartite" and a "multipartite" component. These two matrices reveal the structure of the network from different perspectives and can be analyzed at different levels of detail. Their entries, or the entries of their lower-rank approximations, provide measures of the affinity or antagonism between the nodes that highlight the communities and the "gateway" links that connect them together. An algorithm is then proposed to achieve the automatic assignment of the nodes to communities based on the information provided by either matrix. This algorithm naturally generates overlapping communities but can also be tuned to eliminate the overlaps. PMID- 26986349 TI - Complex quantum networks: From universal breakdown to optimal transport. AB - We study the transport efficiency of excitations on complex quantum networks with loops. For this we consider sequentially growing networks with different topologies of the sequential subgraphs. This can lead either to a universal complete breakdown of transport for complete-graph-like sequential subgraphs or to optimal transport for ringlike sequential subgraphs. The transition to optimal transport can be triggered by systematically reducing the number of loops of complete-graph-like sequential subgraphs in a small-world procedure. These effects are explained on the basis of the spectral properties of the network's Hamiltonian. Our theoretical considerations are supported by numerical Monte Carlo simulations for complex quantum networks with a scale-free size distribution of sequential subgraphs and a small-world-type transition to optimal transport. PMID- 26986347 TI - Low-dimensional dynamics of structured random networks. AB - Using a generalized random recurrent neural network model, and by extending our recently developed mean-field approach [J. Aljadeff, M. Stern, and T. Sharpee, Phys. Rev. Lett. 114, 088101 (2015)], we study the relationship between the network connectivity structure and its low-dimensional dynamics. Each connection in the network is a random number with mean 0 and variance that depends on pre- and postsynaptic neurons through a sufficiently smooth function g of their identities. We find that these networks undergo a phase transition from a silent to a chaotic state at a critical point we derive as a function of g. Above the critical point, although unit activation levels are chaotic, their autocorrelation functions are restricted to a low-dimensional subspace. This provides a direct link between the network's structure and some of its functional characteristics. We discuss example applications of the general results to neuroscience where we derive the support of the spectrum of connectivity matrices with heterogeneous and possibly correlated degree distributions, and to ecology where we study the stability of the cascade model for food web structure. PMID- 26986348 TI - Meta-food-chains as a many-layer epidemic process on networks. AB - Notable recent works have focused on the multilayer properties of coevolving diseases. We point out that very similar systems play an important role in population ecology. Specifically we study a meta-food-web model that was recently proposed by Pillai et al. [Theor. Ecol. 3, 223 (2009)]. This model describes a network of species connected by feeding interactions, which spread over a network of spatial patches. Focusing on the essential case, where the network of feeding interactions is a chain, we develop an analytical approach for the computation of the degree distributions of colonized spatial patches for the different species in the chain. This framework allows us to address ecologically relevant questions. Considering configuration model ensembles of spatial networks, we find that there is an upper bound for the fraction of patches that a given species can occupy, which depends only on the networks mean degree. For a given mean degree there is then an optimal degree distribution that comes closest to the upper bound. Notably scale-free degree distributions perform worse than more homogeneous degree distributions if the mean degree is sufficiently high. Because species experience the underlying network differently the optimal degree distribution for one particular species is generally not the optimal distribution for the other species in the same food web. These results are of interest for conservation ecology, where, for instance, the task of selecting areas of old growth forest to preserve in an agricultural landscape, amounts to the design of a patch network. PMID- 26986350 TI - Velocity statistics of the Nagel-Schreckenberg model. AB - The statistics of velocities in the cellular automaton model of Nagel and Schreckenberg for traffic are studied. From numerical simulations, we obtain the probability distribution function (PDF) for vehicle velocities and the velocity velocity (vv) covariance function. We identify the probability to find a standing vehicle as a potential order parameter that signals nicely the transition between free congested flow for a sufficiently large number of velocity states. Our results for the vv covariance function resemble features of a second-order phase transition. We develop a 3-body approximation that allows us to relate the PDFs for velocities and headways. Using this relation, an approximation to the velocity PDF is obtained from the headway PDF observed in simulations. We find a remarkable agreement between this approximation and the velocity PDF obtained from simulations. PMID- 26986351 TI - Network nestedness as generalized core-periphery structures. AB - The concept of nestedness, in particular for ecological and economical networks, has been introduced as a structural characteristic of real interacting systems. We suggest that the nestedness is in fact another way to express a mesoscale network property called the core-periphery structure. With real ecological mutualistic networks and synthetic model networks, we reveal the strong correlation between the nestedness and core-periphery-ness (likeness to the core periphery structure), by defining the network-level measures for nestedness and core-periphery-ness in the case of weighted and bipartite networks. However, at the same time, via more sophisticated null-model analysis, we also discover that the degree (the number of connected neighbors of a node) distribution poses quite severe restrictions on the possible nestedness and core-periphery parameter space. Therefore, there must exist structurally interwoven properties in more fundamental levels of network formation, behind this seemingly obvious relation between nestedness and core-periphery structures. PMID- 26986352 TI - Comparison of minimum-action and steepest-descent paths in gradient systems. AB - On high-dimensional and complex potential energy surfaces, the identification of the most likely mechanism for the transition between local minima is a challenging task. Usually the steepest-descent path is used interchangeably with the minimum-energy path and is associated with the most likely path. Here we compare the meaning of the steepest-descent path in complex energy landscapes to the path integral formulation of a trajectory that minimizes the action functional for Brownian dynamics. In particular, for energy landscapes with bifurcation points and multiple minima and saddle points, there can be several steepest-descent paths associated with specific saddles that connect two predetermined states but largely differ from the path of maximum likelihood. The minimum-action path, however, additionally takes into account the scalar work along the trajectory. Minimizing the scalar work can be less ambiguous in the identification of the most likely path in different gradient systems. It can also be used to distinguish between multiple steepest-descent paths that connect reactant and product states. We illustrate that in systems with complex energy landscapes a careful assessment of the steepest-descent path is thus advisable. Here the evaluation of the action can provide valuable information on the analysis and description of the most likely path. PMID- 26986353 TI - Growth and containment of a hierarchical criminal network. AB - We model the hierarchical evolution of an organized criminal network via antagonistic recruitment and pursuit processes. Within the recruitment phase, a criminal kingpin enlists new members into the network, who in turn seek out other affiliates. New recruits are linked to established criminals according to a probability distribution that depends on the current network structure. At the same time, law enforcement agents attempt to dismantle the growing organization using pursuit strategies that initiate on the lower level nodes and that unfold as self-avoiding random walks. The global details of the organization are unknown to law enforcement, who must explore the hierarchy node by node. We halt the pursuit when certain local criteria of the network are uncovered, encoding if and when an arrest is made; the criminal network is assumed to be eradicated if the kingpin is arrested. We first analyze recruitment and study the large scale properties of the growing network; later we add pursuit and use numerical simulations to study the eradication probability in the case of three pursuit strategies, the time to first eradication, and related costs. Within the context of this model, we find that eradication becomes increasingly costly as the network increases in size and that the optimal way of arresting the kingpin is to intervene at the early stages of network formation. We discuss our results in the context of dark network disruption and their implications on possible law enforcement strategies. PMID- 26986354 TI - Dynamical network model for age-related health deficits and mortality. AB - How long people live depends on their health, and how it changes with age. Individual health can be tracked by the accumulation of age-related health deficits. The fraction of age-related deficits is a simple quantitative measure of human aging. This quantitative frailty index (F) is as good as chronological age in predicting mortality. In this paper, we use a dynamical network model of deficits to explore the effects of interactions between deficits, deficit damage and repair processes, and the connection between the F and mortality. With our model, we qualitatively reproduce Gompertz's law of increasing human mortality with age, the broadening of the F distribution with age, the characteristic nonlinear increase of the F with age, and the increased mortality of high-frailty individuals. No explicit time-dependence in damage or repair rates is needed in our model. Instead, implicit time-dependence arises through deficit interactions so that the average deficit damage rates increase, and deficit repair rates decrease, with age. We use a simple mortality criterion, where mortality occurs when the most connected node is damaged. PMID- 26986355 TI - Continuous utility factor in segregation models. AB - We consider the constrained Schelling model of social segregation in which the utility factor of agents strictly increases and nonlocal jumps of the agents are allowed. In the present study, the utility factor u is defined in a way such that it can take continuous values and depends on the tolerance threshold as well as the fraction of unlike neighbors. Two models are proposed: in model A the jump probability is determined by the sign of u only, which makes it equivalent to the discrete model. In model B the actual values of u are considered. Model A and model B are shown to differ drastically as far as segregation behavior and phase transitions are concerned. In model A, although segregation can be achieved, the cluster sizes are rather small. Also, a frozen state is obtained in which steady states comprise many unsatisfied agents. In model B, segregated states with much larger cluster sizes are obtained. The correlation function is calculated to show quantitatively that larger clusters occur in model B. Moreover for model B, no frozen states exist even for very low dilution and small tolerance parameter. This is in contrast to the unconstrained discrete model considered earlier where agents can move even when utility remains the same. In addition, we also consider a few other dynamical aspects which have not been studied in segregation models earlier. PMID- 26986357 TI - From individual spiking neurons to population behavior: Systematic elimination of short-wavelength spatial modes. AB - Mean-field models of the brain approximate spiking dynamics by assuming that each neuron responds to its neighbors via a naive spatial average that neglects local fluctuations and correlations in firing activity. In this paper we address this issue by introducing a rigorous formalism to enable spatial coarse-graining of spiking dynamics, scaling from the microscopic level of a single type 1 (integrator) neuron to a macroscopic assembly of spiking neurons that are interconnected by chemical synapses and nearest-neighbor gap junctions. Spiking behavior at the single-neuron scale l~10MUm is described by Wilson's two-variable conductance-based equations [H. R. Wilson, J. Theor. Biol. 200, 375 (1999)], driven by fields of incoming neural activity from neighboring neurons. We map these equations to a coarser spatial resolution of grid length Bl, with B?1 being the blocking ratio linking micro and macro scales. Our method systematically eliminates high-frequency (short-wavelength) spatial modes q(->) in favor of low frequency spatial modes Q(->) using an adiabatic elimination procedure that has been shown to be equivalent to the path-integral coarse graining applied to renormalization group theory of critical phenomena. This bottom-up neural regridding allows us to track the percolation of synaptic and ion-channel noise from the single neuron up to the scale of macroscopic population-average variables. Anticipated applications of neural regridding include extraction of the current-to-firing-rate transfer function, investigation of fluctuation criticality near phase-transition tipping points, determination of spatial scaling laws for avalanche events, and prediction of the spatial extent of self organized macrocolumnar structures. As a first-order exemplar of the method, we recover nonlinear corrections for a coarse-grained Wilson spiking neuron embedded in a network of identical diffusively coupled neurons whose chemical synapses have been disabled. Intriguingly, we find that reblocking transforms the original type 1 Wilson integrator into a type 2 resonator whose spike-rate transfer function exhibits abrupt spiking onset with near-vertical takeoff and chaotic dynamics just above threshold. PMID- 26986356 TI - Translocation frequency of double-stranded DNA through a solid-state nanopore. AB - Solid-state nanopores are single-molecule sensors that measure changes in ionic current as charged polymers such as DNA pass through. Here, we present comprehensive experiments on the length, voltage, and salt dependence of the frequency of double-stranded DNA translocations through conical quartz nanopores with mean opening diameter 15 nm. We observe an entropic barrier-limited, length dependent translocation frequency at 4M LiCl salt concentration and a drift dominated, length-independent translocation frequency at 1M KCl salt concentration. These observations are described by a unifying convection diffusion equation, which includes the contribution of an entropic barrier for polymer entry. PMID- 26986358 TI - Stochastic model for gene transcription on Drosophila melanogaster embryos. AB - We examine immunostaining experimental data for the formation of stripe 2 of even skipped (eve) transcripts on D. melanogaster embryos. An estimate of the factor converting immunofluorescence intensity units into molecular numbers is given. The analysis of the eve dynamics at the region of stripe 2 suggests that the promoter site of the gene has two distinct regimes: an earlier phase when it is predominantly activated until a critical time when it becomes mainly repressed. That suggests proposing a stochastic binary model for gene transcription on D. melanogaster embryos. Our model has two random variables: the transcripts number and the state of the source of mRNAs given as active or repressed. We are able to reproduce available experimental data for the average number of transcripts. An analysis of the random fluctuations on the number of eves and their consequences on the spatial precision of stripe 2 is presented. We show that the position of the anterior or posterior borders fluctuate around their average position by ~1% of the embryo length, which is similar to what is found experimentally. The fitting of data by such a simple model suggests that it can be useful to understand the functions of randomness during developmental processes. PMID- 26986360 TI - Interplay of migratory and division forces as a generic mechanism for stem cell patterns. AB - In many adult tissues, stem cells and differentiated cells are not homogeneously distributed: stem cells are arranged in periodic "niches," and differentiated cells are constantly produced and migrate out of these niches. In this article, we provide a general theoretical framework to study mixtures of dividing and actively migrating particles, which we apply to biological tissues. We show in particular that the interplay between the stresses arising from active cell migration and stem cell division give rise to robust stem cell patterns. The instability of the tissue leads to spatial patterns which are either steady or oscillating in time. The wavelength of the instability has an order of magnitude consistent with the biological observations. We also discuss the implications of these results for future in vitro and in vivo experiments. PMID- 26986361 TI - Self-adaptive formation of uneven node spacings in wild bamboo. AB - Bamboo has a distinctive structure wherein a long cavity inside a cylindrical woody section is divided into many chambers by stiff diaphragms. The diaphragms are inserted at nodes and thought to serve as ring stiffeners for bamboo culms against the external load; if this is the case, the separation between adjacent nodes should be configured optimally in order to enhance the mechanical stability of the culms. Here, we reveal the hitherto unknown blueprint of the optimal node spacings used in the growth of wild bamboo. Measurement data analysis together with theoretical formulations suggest that wild bamboos effectively control their node spacings as well as other geometric parameters in accord with the lightweight and high-strength design concept. PMID- 26986362 TI - Evolutionary dynamics of general group interactions in structured populations. AB - The evolution of populations is influenced by many factors, and the simple classical models have been developed in a number of important ways. Both population structure and multiplayer interactions have been shown to significantly affect the evolution of important properties, such as the level of cooperation or of aggressive behavior. Here we combine these two key factors and develop the evolutionary dynamics of general group interactions in structured populations represented by regular graphs. The traditional linear and threshold public goods games are adopted as models to address the dynamics. We show that for linear group interactions, population structure can favor the evolution of cooperation compared to the well-mixed case, and we see that the more neighbors there are, the harder it is for cooperators to persist in structured populations. We further show that threshold group interactions could lead to the emergence of cooperation even in well-mixed populations. Here population structure sometimes inhibits cooperation for the threshold public goods game, where depending on the benefit to cost ratio, the outcomes are bistability or a monomorphic population of defectors or cooperators. Our results suggest, counterintuitively, that structured populations are not always beneficial for the evolution of cooperation for nonlinear group interactions. PMID- 26986359 TI - Extending the dynamic range of transcription factor action by translational regulation. AB - A crucial step in the regulation of gene expression is binding of transcription factor (TF) proteins to regulatory sites along the DNA. But transcription factors act at nanomolar concentrations, and noise due to random arrival of these molecules at their binding sites can severely limit the precision of regulation. Recent work on the optimization of information flow through regulatory networks indicates that the lower end of the dynamic range of concentrations is simply inaccessible, overwhelmed by the impact of this noise. Motivated by the behavior of homeodomain proteins, such as the maternal morphogen Bicoid in the fruit fly embryo, we suggest a scheme in which transcription factors also act as indirect translational regulators, binding to the mRNA of other regulatory proteins. Intuitively, each mRNA molecule acts as an independent sensor of the input concentration, and averaging over these multiple sensors reduces the noise. We analyze information flow through this scheme and identify conditions under which it outperforms direct transcriptional regulation. Our results suggest that the dual role of homeodomain proteins is not just a historical accident, but a solution to a crucial physics problem in the regulation of gene expression. PMID- 26986363 TI - Torque generation through the random movement of an asymmetric rotor: A potential rotational mechanism of the gamma subunit of F(1)-ATPase. AB - The rotation of the gamma subunit of F(1)-ATPase is stochastic, processive, unidirectional, reversible through an external torque, and stepwise with a slow rotation. We propose a mechanism that can explain these properties of the rotary molecular motor, and that can determine the direction of rotation. The asymmetric structures of the gamma subunit, both at the tip of the shaft (C and N termini) and at the part (epsilon subunit) protruding from the alpha(3)beta(3) subunits, are critical. The torque required for stochastic rotation is generated from the impulsive reactive force due to the random collisions between the gamma subunit and the quasihexagonal alpha(3)beta(3) subunits. The rotation is the result of the random motion of the confined asymmetric gamma subunit. The steps originate from the chemical reactions of the gamma subunit and physical interaction between the gamma subunit and the flexible protrusions of the alpha(3)beta(3) subunits. An external torque as well as a configurational modification in the gamma subunit (the central rotor) can reverse the rotational direction. We demonstrate the applicability of the mechanism to a macroscopic simulation system, which has the essential ingredients of the F(1)-ATPase structure, by reproducing the dynamic properties of the rotation. PMID- 26986364 TI - Gene expression dynamics with stochastic bursts: Construction and exact results for a coarse-grained model. AB - We present a theoretical framework to analyze the dynamics of gene expression with stochastic bursts. Beginning with an individual-based model which fully accounts for the messenger RNA (mRNA) and protein populations, we propose an expansion of the master equation for the joint process. The resulting coarse grained model reduces the dimensionality of the system, describing only the protein population while fully accounting for the effects of discrete and fluctuating mRNA population. Closed form expressions for the stationary distribution of the protein population and mean first-passage times of the coarse grained model are derived and large-scale Monte Carlo simulations show that the analysis accurately describes the individual-based process accounting for mRNA population, in contrast to the failure of commonly proposed diffusion-type models. PMID- 26986365 TI - Spontaneous chiral symmetry breaking in collective active motion. AB - Chiral symmetry breaking is ubiquitous in biological systems, from DNA to bacterial suspensions. A key unresolved problem is how chiral structures may spontaneously emerge from achiral interactions. We study a simple model of active swimmers in three dimensions that effectively incorporates hydrodynamic interactions. We perform large-scale molecular dynamics simulations (up to 10(6) particles) and find long-lived metastable collective states that exhibit chiral organization although the interactions are achiral. We elucidate under which conditions these chiral states will emerge and grow to large scales. To explore the complex phase space available to the system, we perform nonequilibrium quenches on a one-dimensional Lebwohl-Lasher model with periodic boundary conditions to study the likelihood of formation of chiral structures. PMID- 26986366 TI - Competition between B-Z and B-L transitions in a single DNA molecule: Computational studies. AB - Under negative torsion, DNA adopts left-handed helical forms, such as Z-DNA and L DNA. Using the random copolymer model developed for a wormlike chain, we represent a single DNA molecule with structural heterogeneity as a helical chain consisting of monomers which can be characterized by different helical senses and pitches. By Monte Carlo simulation, where we take into account bending and twist fluctuations explicitly, we study sequence dependence of B-Z transitions under torsional stress and tension focusing on the interaction with B-L transitions. We consider core sequences, (GC)_{n} repeats or (TG)_{n} repeats, which can interconvert between the right-handed B form and the left-handed Z form, imbedded in a random sequence, which can convert to left-handed L form with different (tension dependent) helical pitch. We show that Z-DNA formation from the (GC)_{n} sequence is always supported by unwinding torsional stress but Z-DNA formation from the (TG)_{n} sequence, which are more costly to convert but numerous, can be strongly influenced by the quenched disorder in the surrounding random sequence. PMID- 26986367 TI - Identification of drug resistance mutations in HIV from constraints on natural evolution. AB - Human immunodeficiency virus (HIV) evolves with extraordinary rapidity. However, its evolution is constrained by interactions between mutations in its fitness landscape. Here we show that an Ising model describing these interactions, inferred from sequence data obtained prior to the use of antiretroviral drugs, can be used to identify clinically significant sites of resistance mutations. Successful predictions of the resistance sites indicate progress in the development of successful models of real viral evolution at the single residue level and suggest that our approach may be applied to help design new therapies that are less prone to failure even where resistance data are not yet available. PMID- 26986368 TI - Stochastic model of tumor-induced angiogenesis: Ensemble averages and deterministic equations. AB - A recent conceptual model of tumor-driven angiogenesis including branching, elongation, and anastomosis of blood vessels captures some of the intrinsic multiscale structures of this complex system, yet allowing one to extract a deterministic integro-partial-differential description of the vessel tip density [Phys. Rev. E 90, 062716 (2014)]. Here we solve the stochastic model, show that ensemble averages over many realizations correspond to the deterministic equations, and fit the anastomosis rate coefficient so that the total number of vessel tips evolves similarly in the deterministic and ensemble-averaged stochastic descriptions. PMID- 26986369 TI - Superradiance at the localization-delocalization crossover in tubular chlorosomes. AB - We study the effect of disorder on spectral properties of tubular chlorosomes in green sulfur bacteria Cf. aurantiacus. Employing a Frenkel-exciton Hamiltonian with diagonal and off-diagonal disorder consistent with spectral and structural studies, we analyze excitonic localization and spectral statistics of the chlorosomes. A size-dependent localization-delocalization crossover is found to occur as a function of the excitonic energy. The crossover energy region coincides with the more optically active states with maximized superradiance and is, consequently, more conducive for energy transfer. PMID- 26986370 TI - Dynamics of nanoparticle assembly from disjointed images of nanoparticle-polymer composites. AB - Understanding how nanoparticles (NPs) diffuse, stick, and assemble into larger structures within polymers is key to the design and fabrication of NP-polymer composites. Here we describe an approach for inferring the dynamic parameters of NP assembly from spatially and temporally disjointed images of composites. The approach involves iterative adjustment of the parameters of a kinetic model of assembly until the computed size statistics of NP clusters match those obtained from high-throughput analysis of the experimental images. Application of this approach to the assembly of shaped, metal NPs in polymer films suggests that NP structures grow via a cluster-cluster aggregation mechanism, where NPs and their clusters diffuse with approximately Stokes-Einstein diffusivity and stick to other NPs or clusters with a probability that depends strongly on the size and shape of the NPs and the molecular weight of the polymer. PMID- 26986371 TI - Equilibrium fluid-crystal interfacial free energy of bcc-crystallizing aqueous suspensions of polydisperse charged spheres. AB - The interfacial free energy is a central quantity in crystallization from the metastable melt. In suspensions of charged colloidal spheres, nucleation and growth kinetics can be accurately measured from optical experiments. In previous work, from these data effective nonequilibrium values for the interfacial free energy between the emerging bcc nuclei and the adjacent melt in dependence on the chemical potential difference between melt phase and crystal phase were derived using classical nucleation theory (CNT). A strictly linear increase of the interfacial free energy was observed as a function of increased metastability. Here, we further analyze these data for five aqueous suspensions of charged spheres and one binary mixture. We utilize a simple extrapolation scheme and interpret our findings in view of Turnbull's empirical rule. This enables us to present the first systematic experimental estimates for a reduced interfacial free energy, sigma(0,bcc), between the bcc-crystal phase and the coexisting equilibrium fluid. Values obtained for sigma(0,bcc) are on the order of a few k(B)T. Their values are not correlated to any of the electrostatic interaction parameters but rather show a systematic decrease with increasing size polydispersity and a lower value for the mixture as compared to the pure components. At the same time, sigma(0) also shows an approximately linear correlation to the entropy of freezing. The equilibrium interfacial free energy of strictly monodisperse charged spheres may therefore be still greater. PMID- 26986372 TI - Interaction modes between asymmetrically and oppositely charged rods. AB - The interaction of oppositely and asymmetrically charged rods in salt-a simple model of (bio)macromolecular assembly-is observed via simulation to exhibit two free energy minima, separated by a repulsive barrier. In contrast to similar minima in the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory, the governing mechanism includes electrostatic attraction at large separation, osmotic repulsion at close range, and depletion attraction near contact. A model accounting for ion condensation and excluded volume is shown to be superior to a mean-field treatment in predicting the effect of charge asymmetry on the free energy profile. PMID- 26986373 TI - Singular electrostatic energy of nanoparticle clusters. AB - The binding of clusters of metal nanoparticles is partly electrostatic. We address difficulties in calculating the electrostatic energy when high charging energies limit the total charge to a single quantum, entailing unequal potentials on the particles. We show that the energy at small separation h has a singular logarithmic dependence on h. We derive a general form for this energy in terms of the singular capacitance of two spheres in near contact c(h), together with nonsingular geometric features of the cluster. Using this form, we determine the energies of various clusters, finding that more compact clusters are more stable. These energies are proposed to be significant for metal-semiconductor binary nanoparticle lattices found experimentally. We sketch how these effects should dictate the relative abundances of metal nanoparticle clusters in nonpolar solvents. PMID- 26986374 TI - Capillary force and torque on spheroidal particles floating at a fluid interface beyond the superposition approximation. AB - By means of a perturbative scheme, we determine analytically the capillary energy of a spheroidal colloid floating on a deformed fluid interface in terms of the local curvature tensor of the background deformation. We validate our results, that hold for small ellipticity of the particle and small deformations of the surface, by an exact numerical calculation. As an application of our perturbative approach, we determine the asymptotic interaction, for large separations d, between two different spheroidal particles. The dominant contribution is quadrupolar and proportional to d(-4). It coincides with the known superposition approximation and is zero if one of the two particles is spherical. The next to leading approximation, proportional to d(-8), is always attractive and independent of the orientation of the two colloids. It is the dominant contribution to the interaction between a spheroidal and a spherical colloid. PMID- 26986375 TI - Viscoelastic properties of marginal networks in a solvent. AB - Polymer networks at the margins of mechanical stability are known to be highly sensitive to applied forces and fields and to exhibit an anomalously large resistance to deformation. In this paper, we study the effects of hydrodynamic interactions on the behavior of marginal networks using a hybrid molecular dynamics and multiparticle collision dynamics simulation technique. We examine how the filament and solvent properties affect the response of marginal networks to shear. We find that the stiffening of the network shows a stronger dependence on the shear frequency when hydrodynamic interactions are present than when they are not. The network shear modulus scales as G'~omega(alpha(c)), with a critical stiffening exponent alpha(c) that can be controlled by varying the relative concentrations of the network and the solvent. Our results show that this arises due to the solvent aiding the relaxation of the network and suppressing the network nonaffinity, with the system deforming more affinely when hydrodynamic interactions are maximized. PMID- 26986376 TI - Thinning and thickening in active microrheology. AB - When pulling a probe particle in a many-particle system at a fixed velocity, the probe's effective friction, defined as the average external force over its velocity, gamma(eff):=/u, first stays constant (linear response), then decreases (thinning), and, finally, increases again (thickening). We propose a three-time-scale picture to describe the thinning and thickening behavior. There are three distinct time scales for the bath particles: diffusion, damping, and single probe-bath collision. The dominating time scales are controlled by the pulling velocity and determine the behavior of the probe's friction. We test and confirm this description with a Langevin dynamics simulation. Microscopically, we find that for computing the effective friction, the Maxwellian distribution of bath particles' velocities fails in the regime of high Reynolds and Peclet numbers. This can be understood based on the microscopic mechanism of thickening obtained in the T=0 limit. The dynamic regimes defined by the ratio of different time scales can explain several observations of thinning and thickening in literature. PMID- 26986378 TI - Surface forces between colloidal particles at high hydrostatic pressure. AB - It was recently suggested that the electrostatic double-layer force between colloidal particles might weaken at high hydrostatic pressure encountered, for example, in deep seas or during oil recovery. We have addressed this issue by means of a specially designed optical trapping setup that allowed us to explore the interaction of a micrometer-sized glass bead and a solid glass wall in water at hydrostatic pressures of up to 1 kbar. The setup allowed us to measure the distance between bead and wall with a subnanometer resolution. We have determined the Debye lengths in water for salt concentrations of 0.1 and 1 mM. We found that in the pressure range from 1 bar to 1 kbar the maximum variation of the Debye lengths was <1 nm for both salt concentrations. Furthermore, the magnitude of the zeta potentials of the glass surfaces in water showed no dependency on pressure. PMID- 26986377 TI - Magnetic interaction of Janus magnetic particles suspended in a viscous fluid. AB - We studied the magnetic interaction between circular Janus magnetic particles suspended in a Newtonian fluid under the influence of an externally applied uniform magnetic field. The particles are equally compartmentalized into paramagnetic and nonmagnetic sides. A direct numerical scheme is employed to solve the magnetic particulate flow in the Stokes flow regime. Upon applying the magnetic field, contrary to isotropic paramagnetic particles, a single Janus particle can rotate due to the magnetic torque created by the magnetic anisotropy of the particle. In a two-particle problem, the orientation of each particle is found to be an additional factor that affects the critical angle separating the nature of magnetic interaction. Using multiparticle problems, we show that the orientation of the particles has a significant influence on the dynamics of the particles, the fluid flow induced by the actuated particles, and the final conformation of the particles. Straight and staggered chain structures observed experimentally can be reproduced numerically in a multiple particle problem. PMID- 26986379 TI - Characterization, nanoparticle self-organization, and Monte Carlo simulation of magnetoliposomes. AB - In this work we have developed and implement a new approach for the study of magnetoliposomes using Monte Carlo simulations. Our model is based on interaction among nanoparticles considering magnetic dipolar, van der Waals, ionic-steric, and Zeeman interaction potentials. The ionic interaction between nanoparticles and the lipid bilayer is represented by an ionic repulsion electrical surface potential that depends on the nanoparticle-lipid bilayer distance and the concentration of ions in the solution. A direct comparison among transmission electron microscopy, vibrating sample magnetometer, dynamic light scattering, nanoparticle tracking analysis, and experimentally derived static magnetic birefringence and simulation data allow us to validate our implementation. Our simulations suggest that confinement plays an important role in aggregate formation. PMID- 26986380 TI - Getting drowned in a swirl: Deformable bead-spring model microswimmers in external flow fields. AB - Deformability is a central feature of many types of microswimmers, e.g., for artificially generated self-propelled droplets. Here, we analyze deformable bead spring microswimmers in an externally imposed solvent flow field as simple theoretical model systems. We focus on their behavior in a circular swirl flow in two spatial dimensions. Linear (straight) two-bead swimmers are found to circle around the swirl with a slight drift to the outside with increasing activity. In contrast to that, we observe for triangular three-bead or squarelike four-bead swimmers a tendency of being drawn into the swirl and finally getting drowned, although a radial inward component is absent in the flow field. During one cycle around the swirl, the self-propulsion direction of an active triangular or squarelike swimmer remains almost constant, while their orbits become deformed exhibiting an "egglike" shape. Over time, the swirl flow induces slight net rotations of these swimmer types, which leads to net rotations of the egg-shaped orbits. Interestingly, in certain cases, the orbital rotation changes sense when the swimmer approaches the flow singularity. Our predictions can be verified in real-space experiments on artificial microswimmers. PMID- 26986381 TI - Transient cluster formation in sheared non-Brownian suspensions. AB - We perform numerical simulations of non-Brownian suspensions in the laminar flow regime to study the scaling behavior of particle clusters and collisions under shear. As the particle fraction approaches the maximum packing fraction, large transient clusters appear in the system. We use methods from percolation theory to discuss the cluster size distribution. We also give a scaling relation for the percolation threshold as well as system size effects through time-dependent fluctuations of this threshold and relate them to system size. System size effects are important close to the maximum packing fraction due to the divergence of the cluster length scale. We then investigate the transient nature of the clusters through characterization of particle collisions and show that collision times exhibit scale-invariant properties. Finally, we show that particle collision times can be modeled as first-passage processes. PMID- 26986382 TI - Electroclinic effect in a chiral paranematic liquid-crystal layer above the bulk nematic-to-isotropic transition temperature. AB - Electroclinic measurements are reported for two chiral liquid crystals above their bulk chiral isotropic-nematic phase transition temperatures. It is found that an applied electric field E induces a rotation theta [?Epsilon] of the director in the very thin paranematic layers that are induced by the cell's two planar-aligning substrates. The magnitude of the electroclinic coefficient dtheta/dE close to the transition temperature is comparable to that of a bulk chiral nematic, as well as to that of a parasmectic region above a bulk isotropic to-chiral smectic-A phase. However, dtheta/dE in the paranematic layer varies much more slowly with temperature than in the parasmectic phase, and its relaxation time is slower by more than three orders of magnitude than that of the bulk chiral nematic electroclinic effect. PMID- 26986383 TI - Consequences of director-density coupling theory for flexoelectricity in nematic liquid crystals. AB - We theoretically study how the measurements of the flexoelectric coefficients in nematic liquid crystals are affected by the inclusion of the director-density coupling energy. It is shown that this investigation is quite relevant for interpreting the data of experiments. PMID- 26986384 TI - Nematoelastic crawlers. AB - A propagating "beam" triggering a local phase transition in a nematic elastomer sets it into a crawling motion, which may morph due to buckling. We consider the motion of the various configurations of slender rods and thin stripes with both uniform and splayed nematic order in cross-section and detect the dependence of the gait and speed on flexural rigidity and substrate friction. PMID- 26986385 TI - Short-range smectic fluctuations and the flexoelectric model of modulated nematic liquid crystals. AB - We show that the flexoelectric model of chiral and achiral modulated nematics predicts the compression modulus that is by orders of magnitude lower than the measured values. The discrepancy is much larger in the chiral modulated nematic phase, in which the measured value of the compression modulus is of the same order of magnitude as in achiral modulated nematics, even though the heliconical pitch is by an order of magnitude larger. The relaxation of a one-constant approximation in the biaxial elastic model used for chiral modulated nematics does not solve the problem. Therefore, we propose a structural model of the modulated nematic phase, which is consistent with the current experimental evidence and can also explain large compression modulus: the structure consists of short-range smectic clusters with a fourfold symmetry and periodicity of two molecular distances. In chiral systems, chiral interactions lead to a helicoidal structure of such clusters. PMID- 26986386 TI - Positronium formation and annihilation in liquid crystalline smectic-E phase revisited. AB - The results of the positron lifetime measurements of the quenched smectic-E (Sm E) phase of 4-butyl-4'-isothiocyano-1,1'-biphenyl (4TCB) are revisited. The sites of positronium formation and annihilation, according to the model with nanosegregated layered structure of the Sm-E phase and molten state of alkyl chains of molecules, are identified in the sublayer containing alkyl chains of molecules. The possibility of vitrification of the Sm-E phase for 4TCB consisting in freezing of the alkyl chain motions is considered as a cause of the thermally activated creation of sites where o-Ps is formed and annihilates in the quenched Sm-E phase. The description of the temperature dependence of ortho-positronium intensity is performed using the glass transition model which assumes that the molecules occupy two thermodynamic states: solidlike or liquidlike regarding mobility of their alkyl chains. The equilibrium temperature between solidlike and liquidlike domains of the model obtained from positron lifetime measurements coincides with the exothermic effect in the temperature dependence of the heat capacity. PMID- 26986387 TI - Effect of waveform of the driving field on electroconvection near the dielectric inversion frequency. AB - This paper concerns the instability behavior of a nematic liquid crystal in the region of dielectric inversion frequency for different waveforms of the exciting electric field. The critical frequency separating the regimes of dielectric and electroconvective primary bifurcation states shows a notable dependence on the waveform. In particular, it is found to undergo a large downshift for square-wave and sawtooth-wave fields as compared to sine-wave and triangle-wave fields. This seems to underscore the significance of harmonics in nonsinusoidal fields for the evolution of patterned electroconvective states. The study also deals with the flow pattern associated with the periodic state and the sequence of secondary instabilities occurring at higher fields to emphasize the role of the Carr Helfrich mechanism for the instabilities in this region. The relevance of dielectric heating to the formation of transient structures is also pointed out. PMID- 26986388 TI - Stochastic analysis of nucleation rates. AB - We show that approximating the Becker-Doring equations with a Langevin equation results in multiplicative noise, which in turn leads to a family of possible Fokker-Planck equations according to the Ito-Stratonovich dilemma. Using a simple and general model for the attachment and detachment rates, we find that the Ito choice approximates the nucleation rate best and also coincides with the Fokker Planck equation resulting from the common way to Taylor expand the original set of rate equations. PMID- 26986389 TI - Dynamics of bubble breakup at a T junction. AB - The gas-liquid interfacial dynamics of bubble breakup in a T junction was investigated. Four regimes were observed for a bubble passing through the T junction. It was identified by the stop flow that a critical width of the bubble neck existed: if the minimum width of the bubble neck was less than the critical value, the breakup was irreversible and fast; while if the minimum width of the bubble neck was larger than the critical value, the breakup was reversible and slow. The fast breakup was driven by the surface tension and liquid inertia and is independent of the operating conditions. The minimum width of the bubble neck could be scaled with the remaining time as a power law with an exponent of 0.22 in the beginning and of 0.5 approaching the final fast pinch-off. The slow breakup was driven by the continuous phase and the gas-liquid interface was in the equilibrium stage. Before the appearance of the tunnel, the width of the depression region could be scaled with the time as a power law with an exponent of 0.75; while after that, the width of the depression was a logarithmic function with the time. PMID- 26986390 TI - Scaling of alloy interfacial properties under compositional strain. AB - Complex morphologies and microstructures that emerge during materials growth and solidification are often determined by both equilibrium and kinetic properties of the interface and their crystalline anisotropies. However, limited knowledge is available on alloying and, particularly, compositionally generated elastic effects on these interface characteristics. Here we systematically investigate such compositional effects on the interfacial properties of an alloy model system based on a phase-field-crystal analysis, including the solid-liquid interfacial free energy, kinetic coefficient, and lattice pinning strength. Scaling relations for these interfacial quantities over various ranges of material parameters are identified and predicted. Our results indicate the important effects of couplings among mesoscopic and microscopic length scales of alloy structure and concentration, and the influence of compressive and tensile interface stresses induced by composition variations. The approach developed here provides an efficient way to systematically identify these key material properties beyond the traditional atomistic and continuum methods. PMID- 26986391 TI - Force of adhesion on supersolvophobic surfaces: The role of capillary necks. AB - We study theoretically the force of adhesion of pinned liquid drops in contact with supersolvophobic surfaces. We develop a method to calculate the contact and excess surface areas vs compression of the drops against surfaces characterized by an effective interfacial energy in the Cassie-Baxter wetting regime. We find that a 9 degrees difference in contact angle can increase the force of adhesion by almost three orders of magnitude. We investigate the role that the inevitable formation of capillary necks has on this force, which has the same functional form of Derjaguin's result for elastic solids. Our results suggest that measuring the force of adhesion directly on nearly perfectly solvophobic surfaces may be a more precise technique to quantify the effective interfacial energy than traditional contact angle measurements on macroscopic drops. PMID- 26986392 TI - Hybrid Cassie-Wenzel model for droplets on surfaces with nanoscale roughness. AB - Several models have been developed to predict the contact angle of a droplet sitting on a roughened surface; however, no such model has been developed for substrates with nanoscale surface structures. In this paper we propose a hybrid Cassie-Wenzel model, which considers two factors attributed to the breakdown of macroscopic predictions, including the width of the wall-fluid depletion region and the coexistence of Cassie and Wenzel states in cases where the wall-fluid interface presents nanoscale structures. At the molecular scale, the parameter of surface roughness can be corrected by treating the wall-fluid interface as a hybrid Cassie-Wenzel state in which the fraction in the Wenzel state depends on fluid density within the cavities. A more general model developed using data fitted to fluid density is able to account for deviating tendencies induced by nanoscale surface features. A comparison of predicted results obtained in this study with those from previous works demonstrates that the proposed hybrid Cassie Wenzel model is applicable to the evaluation of wettability in a wide range of substrates with nanoscale surface structures, corresponding to a Cassie state, a Wenzel state, and a mixed state. More importantly, the present work provides a quantitative approach to the estimation of wettability even amidst nanoscale effects, which can have a significant influence in cases with surface features at the molecular scale. PMID- 26986393 TI - Effect of viscosity on the shaking-induced fluidization in a liquid-immersed granular medium. AB - A liquid-immersed granular medium is shaken vertically under a wide range of accelerations (Gamma in dimensionless form) and frequencies (f) and its fluidization process is studied. The granular medium is formed by settling and consists of two size-graded layers (particle diameter d) such that the upper layer is fine grained and is less permeable. When Gamma>Gamma(c), a liquid-rich layer formed by the accumulated liquid at the two-layer boundary causes a gravitational instability. The upwellings of the instability are separated horizontally by a distance (wavelength) lambda, and their amplitude grows exponentially with time [?exp(pt)] at a growth rate p. We conduct experiments for two liquid viscosity cases such that the particle settling velocity (V(s)) of the same particle differs by a factor of 17. We find that for both cases, Gamma(c) is at a minimum in an optimum frequency band centered at f~100 Hz. However, the high viscosity (HV) case has a smaller Gamma(c), a shorter lambda, and a faster dimensionless growth rate [p'=p/(V(s)/d)]. We also measure granular rheology under an oscillatory shear and find that (i) interparticle friction decreases when the strain amplitude becomes large and (ii) friction is smaller for the HV case. From (i), we infer that the shear strain of the shaking experiments becomes largest at around f~100 Hz. We consider that (ii) is a consequence of liquid lubrication and is a reason for a smaller Gamma(c) for the HV case. We show that the low- and high-frequency limits of the optimum frequency band can be explained by introducing critical values of dimensionless jerk (i.e., time derivative of acceleration) J and dimensionless shaking energy S. The low-frequency limit corresponds to the requirement that in order to unjam the particles, the period of shaking (1/f) must be shorter than the time needed for the particles to rearrange by settling (d/V(s)), which also explains why the HV case is fluidized at a lower f compared to the LV case. We apply the results of the linear stability analyses for Rayleigh-Taylor instability. Using the measured lambda and p, we infer that (i) only a thin layer beneath the two-layer boundary is mobile and the rest of the lower layer remains jammed and (ii) the effective viscosity of the upper granular layer relative to the liquid is smaller for the HV case as a result of smaller friction. PMID- 26986394 TI - Superdiffusive transport and energy localization in disordered granular crystals. AB - We study the spreading of initially localized excitations in one-dimensional disordered granular crystals. We thereby investigate localization phenomena in strongly nonlinear systems, which we demonstrate to differ fundamentally from localization in linear and weakly nonlinear systems. We conduct a thorough comparison of wave dynamics in chains with three different types of disorder-an uncorrelated (Anderson-like) disorder and two types of correlated disorders (which are produced by random dimer arrangements)-and for two types of initial conditions (displacement excitations and velocity excitations). We find for strongly precompressed (i.e., weakly nonlinear) chains that the dynamics depend strongly on the type of initial condition. In particular, for displacement excitations, the long-time asymptotic behavior of the second moment m(2) of the energy has oscillations that depend on the type of disorder, with a complex trend that differs markedly from a power law and which is particularly evident for an Anderson-like disorder. By contrast, for velocity excitations, we find that a standard scaling m(2)~t(gamma) (for some constant gamma) applies for all three types of disorder. For weakly precompressed (i.e., strongly nonlinear) chains, m(2) and the inverse participation ratio P(-1) satisfy scaling relations m(2)~t(gamma) and P(-1)~t(-eta), and the dynamics is superdiffusive for all of the cases that we consider. Additionally, when precompression is strong, the inverse participation ratio decreases slowly (with eta<0.1) for all three types of disorder, and the dynamics leads to a partial localization around the core and the leading edge of a propagating wave packet. For an Anderson-like disorder, displacement perturbations lead to localization of energy primarily in the core, and velocity perturbations cause the energy to be divided between the core and the leading edge. This localization phenomenon does not occur in the sonic-vacuum regime, which yields the surprising result that the energy is no longer contained in strongly nonlinear waves but instead is spread across many sites. In this regime, the exponents are very similar (roughly gamma~1.7 and eta~1) for all three types of disorder and for both types of initial conditions. PMID- 26986395 TI - Energy transport in one-dimensional disordered granular solids. AB - We investigate the energy transport in one-dimensional disordered granular solids by extensive numerical simulations. In particular, we consider the case of a polydisperse granular chain composed of spherical beads of the same material and with radii taken from a random distribution. We start by examining the linear case, in which it is known that the energy transport strongly depends on the type of initial conditions. Thus, we consider two sets of initial conditions: an initial displacement and an initial momentum excitation of a single bead. After establishing the regime of sufficiently strong disorder, we focus our study on the role of nonlinearity for both sets of initial conditions. By increasing the initial excitation amplitudes we are able to identify three distinct dynamical regimes with different energy transport properties: a near linear, a weakly nonlinear, and a highly nonlinear regime. Although energy spreading is found to be increasing for higher nonlinearities, in the weakly nonlinear regime no clear asymptotic behavior of the spreading is found. In this regime, we additionally find that energy, initially trapped in a localized region, can be eventually detrapped and this has a direct influence on the fluctuations of the energy spreading. We also demonstrate that in the highly nonlinear regime, the differences in energy transport between the two sets of initial conditions vanish. Actually, in this regime the energy is almost ballistically transported through shocklike excitations. PMID- 26986396 TI - Role of inertia in the rheology of amorphous systems: A finite-element-based elastoplastic model. AB - A simple finite-element analysis with varying damping strength is used to model the athermal shear rheology of densely packed glassy systems at a continuum level. We focus on the influence of dissipation on bulk rheological properties. Our numerical studies, done over a wide range of damping coefficients, identify two well-separated rheological regimes along with a crossover region controlled by a critical damping. In the overdamped limit, inertial effects are negligible and the rheological response is well described by the commonly observed Herschel Bulkley equation. In stark contrast, inertial vibrations in the underdamped regime prompt a significant drop in the mean-stress level, leading to a nonmonotonic constitutive relation. The observed negative slope in the flow curve, which is a signature of mechanical instability and thus permanent shear banding, arises from the sole influence of inertia, in qualitative agreement with the recent molecular dynamics study of Nicolas et al., Phys. Rev. Lett. 116, 058303 (2016). PMID- 26986397 TI - Declustering in a granular gas as a finite-size effect. AB - The existence of dense clusters has been shown to be a transient phenomenon for realistic models of granular collisions, where the coefficient of restitution depends on the impact velocity. We report direct numerical simulations that elucidate the conditions for the disappearance of structures. We find that upon cluster formation the granular temperature and the convective kinetic energy couple and both follow Haff's law. Furthermore, we show that clusters will eventually dissolve in all finite-size systems. We find the strong power law t'?L(12) for the dependency of the declustering time on system size. Our results imply that only in systems close to the initial critical system size both clustering and declustering transitions are observable. PMID- 26986398 TI - Influence of rough and smooth walls on macroscale granular segregation patterns. AB - Size bidisperse granular materials in a spherical tumbler segregate into two different patterns of three bands with either small particles at the equator and large particles at the poles or vice versa, depending upon the fill level in the tumbler. Here we use discrete element method simulations with supporting qualitative experiments to explore the effect of the tumbler wall roughness on the segregation pattern, modeling the tumbler walls as either a closely packed monolayer of fixed particles resulting in a rough wall or a frictional geometrically smooth wall. Even though the tumbler wall is in contact with the flowing layer only at its periphery, the impact of wall roughness is profound. Smooth walls tend toward a small-large-small (SLS) band pattern at the pole equator-pole at all but the highest fill fractions; rough walls tend toward a large-small-large (LSL) band pattern at all but the lowest fill fractions. This comes about because smooth walls induce poleward axial drift of small particles and an equator-directed drift for large particles, resulting in an SLS band pattern. On the other hand, rough walls result in both sizes of particles moving poleward at the surface of the flow. Due to radial segregation, small particles percolate lower in the flowing layer and when arriving near the pole are caught in the return current drift that carries them back toward the equator incrementally with each passage through the flowing layer, while large particles remain at the surface near the pole, resulting in an LSL band pattern. The tendency toward either of the two segregation patterns depends on the fill level in the tumbler and the roughness of the tumbler's bounding wall. PMID- 26986399 TI - Critical wind speed at which trees break. AB - Data from storms suggest that the critical wind speed at which trees break is constant (?42m/s), regardless of tree characteristics. We question the physical origin of this observation both experimentally and theoretically. By combining Hooke's law, Griffith's criterion, and tree allometry, we show that the critical wind speed indeed hardly depends on the height, diameter, and elastic properties of trees. PMID- 26986400 TI - Resonance vector soliton of the Rayleigh wave. AB - A theory of acoustic vector solitons of self-induced transparency of the Rayleigh wave is constructed. A thin resonance transition layer on an elastic surface is considered using a model of a two-dimensional gas of impurity paramagnetic atoms or quantum dots. Explicit analytical expressions for the profile and parameters of the Rayleigh vector soliton with two different oscillation frequencies is obtained, as well as simulations of this nonlinear surface acoustic wave with realistic parameters, which can be used in acoustic experiments. It is shown that the properties of a surface vector soliton of the Rayleigh wave depend on the parameters of the resonance layer, the elastic medium, and the transverse structure of the surface acoustic wave. PMID- 26986401 TI - Origami building blocks: Generic and special four-vertices. AB - Four rigid panels connected by hinges that meet at a point form a four-vertex, the fundamental building block of origami metamaterials. Most materials designed so far are based on the same four-vertex geometry, and little is known regarding how different geometries affect folding behavior. Here we systematically categorize and analyze the geometries and resulting folding motions of Euclidean four-vertices. Comparing the relative sizes of sector angles, we identify three types of generic vertices and two accompanying subtypes. We determine which folds can fully close and the possible mountain-valley assignments. Next, we consider what occurs when sector angles or sums thereof are set equal, which results in 16 special vertex types. One of these, flat-foldable vertices, has been studied extensively, but we show that a wide variety of qualitatively different folding motions exist for the other 15 special and 3 generic types. Our work establishes a straightforward set of rules for understanding the folding motion of both generic and special four-vertices and serves as a roadmap for designing origami metamaterials. PMID- 26986402 TI - Finite-size effects in a model for plasticity of amorphous composites. AB - We discuss the plastic behavior of an amorphous matrix reinforced by hard particles. A mesoscopic depinning-like model accounting for Eshelby elastic interactions is implemented. Only the effect of a plastic disorder is considered. Numerical results show a complex size dependence of the effective flow stress of the amorphous composite. In particular, the departure from the mixing law shows opposite trends associated to the competing effects of the matrix and the reinforcing particles, respectively. The reinforcing mechanisms and their effects on localization are discussed. Plastic strain is shown to gradually concentrate on the weakest band of the system. This correlation of the plastic behavior with the material structure is used to design a simple analytical model. The latter nicely captures reinforcement size effects in (logN/N)(1/2), where N is the linear size of the system, observed numerically. Predictions of the effective flow stress accounting for further logarithmic corrections show a very good agreement with numerical results. PMID- 26986404 TI - Boson peak and Ioffe-Regel criterion in amorphous siliconlike materials: The effect of bond directionality. AB - The vibrational properties of model amorphous materials are studied by combining complete analysis of the vibration modes, dynamical structure factor, and energy diffusivity with exact diagonalization of the dynamical matrix and the kernel polynomial method, which allows a study of very large system sizes. Different materials are studied that differ only by the bending rigidity of the interactions in a Stillinger-Weber modelization used to describe amorphous silicon. The local bending rigidity can thus be used as a control parameter, to tune the sound velocity together with local bonds directionality. It is shown that for all the systems studied, the upper limit of the Boson peak corresponds to the Ioffe-Regel criterion for transverse waves, as well as to a minimum of the diffusivity. The Boson peak is followed by a diffusivity's increase supported by longitudinal phonons. The Ioffe-Regel criterion for transverse waves corresponds to a common characteristic mean-free path of 5-7 A (which is slightly bigger for longitudinal phonons), while the fine structure of the vibrational density of states is shown to be sensitive to the local bending rigidity. PMID- 26986403 TI - Optical mechanical analogy and nonlinear nonholonomic constraints. AB - In this paper we establish a connection between particle trajectories subject to a nonholonomic constraint and light ray trajectories in a variable index of refraction. In particular, we extend the analysis of systems with linear nonholonomic constraints to the dynamics of particles in a potential subject to nonlinear velocity constraints. We contrast the long time behavior of particles subject to a constant kinetic energy constraint (a thermostat) to particles with the constraint of parallel velocities. We show that, while in the former case the velocities of each particle equalize in the limit, in the latter case all the kinetic energies of each particle remain the same. PMID- 26986406 TI - Surface waves in granular phononic crystals. AB - The existence of surface elastic waves at a mechanically free surface of granular phononic crystals is studied. The granular phononic crystals are made of spherical particles distributed periodically on a simple cubic lattice. It is assumed that the particles are interacting by means of normal, shear, and bending contact rigidities. First, Rayleigh-type surface acoustic waves, where the displacement of the particles takes place in the sagittal plane while the particles possess one rotational and two translational degrees of freedom, are analyzed. Second, shear-horizontal-type waves, where the displacement of the particles is normal to the sagittal plane while the particles possess one translational and two rotational degrees of freedom are studied. The existence of zero-group-velocity surface acoustic waves of Rayleigh type is theoretically predicted and interpreted. A comparison with surface waves predicted by the reduced Cosserat theory is performed, and some limitations of the latter are established. PMID- 26986405 TI - Devil's staircase in an optomechanical cavity. AB - We study self-excited oscillations (SEOs) in an on-fiber optomechanical cavity. While the phase of SEOs randomly diffuses in time when the laser power injected into the cavity is kept constant, phase locking may occur when the laser power is periodically modulated in time. We investigate the dependence of phase locking on the amplitude and frequency of the laser-power modulation. We find that phase locking can be induced with a relatively low modulation amplitude provided that the ratio between the modulation frequency and the frequency of SEOs is tuned close to a rational number of relatively low hierarchy in the Farey tree. To account for the experimental results, a one-dimensional map, which allows evaluating the time evolution of the phase of SEOs, is theoretically derived. By calculating the winding number of the one-dimensional map, the regions of phase locking can be mapped in the plane of modulation amplitude and modulation frequency. Comparison between the theoretical predictions and the experimental findings yields a partial agreement. PMID- 26986407 TI - Hydrodynamic slip length as a surface property. AB - Equilibrium and nonequilibrium molecular dynamics simulations were conducted in order to evaluate the hypothesis that the hydrodynamic slip length is a surface property. The system under investigation was water confined between two graphite layers to form nanochannels of different sizes (3-8 nm). The water-carbon interaction potential was calibrated by matching wettability experiments of graphitic-carbon surfaces free of airborne hydrocarbon contamination. Three equilibrium theories were used to calculate the hydrodynamic slip length. It was found that one of the recently reported equilibrium theories for the calculation of the slip length featured confinement effects, while the others resulted in calculations significantly hindered by the large margin of error observed between independent simulations. The hydrodynamic slip length was found to be channel size independent using equilibrium calculations, i.e., suggesting a consistency with the definition of a surface property, for 5-nm channels and larger. The analysis of the individual trajectories of liquid particles revealed that the reason for observing confinement effects in 3-nm nanochannels is the high mobility of the bulk particles. Nonequilibrium calculations were not consistently affected by size but by noisiness in the smallest systems. PMID- 26986408 TI - Asymptotic-preserving Boltzmann model equations for binary gas mixture. AB - An improved system of Boltzmann model equations is developed for binary gas mixture. This system of model equations has a complete asymptotic preserving property that can strictly recover the Navier-Stokes equations in the continuum limit with the correct constitutive relations and the correct viscosity, thermal conduction, diffusion, and thermal diffusion coefficients. In this equation system, the self- and cross-collision terms in Boltzmann equations are replaced by single relaxation terms. In monocomponent case, this system of equations can be reduced to the commonly used Shakhov equation. The conservation property and the H theorem which are important for model equations are also satisfied by this system of model equations. PMID- 26986409 TI - Fingering dynamics driven by a precipitation reaction: Nonlinear simulations. AB - A fingering instability can develop at the interface between two fluids when the more mobile fluid is injected into the less-mobile one. For example, viscous fingering appears when a less viscous (i.e., more mobile) fluid displaces a more viscous (and hence less mobile) one in a porous medium. Fingering can also be due to a local change in mobility arising when a precipitation reaction locally decreases the permeability. We numerically analyze the properties of the related precipitation fingering patterns occurring when an A+B->C chemical reaction takes place, where A and B are reactants in solution and C is a solid product. We show that, similarly to reactive viscous fingering patterns, the precipitation fingering structures differ depending on whether A invades B or vice versa. This asymmetry can be related to underlying asymmetric concentration profiles developing when diffusion coefficients or initial concentrations of the reactants differ. In contrast to reactive viscous fingering, however, precipitation fingering patterns appear at shorter time scales than viscous fingers because the solid product C has a diffusivity tending to zero which destabilizes the displacement. Moreover, contrary to reactive viscous fingering, the system is more unstable with regard to precipitation fingering when the high-concentrated solution is injected into the low-concentrated one or when the faster diffusing reactant displaces the slower diffusing one. PMID- 26986410 TI - Viscous Rayleigh-Taylor instability in spherical geometry. AB - We consider viscous fluids in spherical geometry, a lighter fluid supporting a heavier one. Chandrasekhar [Q. J. Mech. Appl. Math. 8, 1 (1955)] analyzed this unstable configuration providing the equations needed to find, numerically, the exact growth rates for the ensuing Rayleigh-Taylor instability. He also derived an analytic but approximate solution. We point out a weakness in his approximate dispersion relation (DR) and offer a somewhat improved one. A third DR, based on transforming a planar DR into a spherical one, suffers no unphysical predictions and compares reasonably well with the exact work of Chandrasekhar and a more recent numerical analysis of the problem [Terrones and Carrara, Phys. Fluids 27, 054105 (2015)]. PMID- 26986411 TI - Effect of added mass on the interaction of bubbles in a low-Reynolds-number shear flow. AB - Equal size air bubbles that are entrapped by a Taylor vortex of the secondary flow in a Couette device, thereby defying buoyancy, slowly form a stable ordered ring with equal separation distances between all neighbors. We present two models of the process dynamics based on force balance on a bubble in the presence of other bubbles positioned on the same streamline in a simple shear flow. The forces taken into account are the viscous resistance, the added mass force, and the inertia-induced repulsing force between two bubbles in a low-Reynolds-number shear flow obtained in Prakash et al. [J. Prakash et al., Phys. Rev. E 87, 043002 (2013)]. The first model of the process assumes that each bubble interacts solely with its nearest neighbors. The second model takes into account pairwise interactions among all the bubbles in the ring. The performed dynamic simulations were compared to the experimental results reported in Prakash et al. [J. Prakash et al., Phys. Rev. E 87, 043002 (2013)] and to the results of quasistationary models (ignoring the added mass effect) suggested in that paper. It is demonstrated that taking into account the effect of added mass, the models describe the major effect of the bubbles' ordering, provide good estimation of the relaxation time, and also predict nonmonotonic behavior of the separation distance between the bubbles, which exhibit over- and undershooting of equilibrium separations. The latter effects were observed in experiments, but are not predicted by the quasistationary models. PMID- 26986412 TI - Droplet migration characteristics in confined oscillatory microflows. AB - We analyze the migration characteristics of a droplet in an oscillatory flow field in a parallel plate microconfinement. Using phase field formalism, we capture the dynamical evolution of the droplet over a wide range of the frequency of the imposed oscillation in the flow field, drop size relative to the channel gap, and the capillary number. The latter two factors imply the contribution of droplet deformability, commonly considered in the study of droplet migration under steady shear flow conditions. We show that the imposed oscillation brings an additional time complexity in the droplet movement, realized through temporally varying drop shape, flow direction, and the inertial response of the droplet. As a consequence, we observe a spatially complicated pathway of the droplet along the transverse direction, in sharp contrast to the smooth migration under a similar yet steady shear flow condition. Intuitively, the longitudinal component of the droplet movement is in tandem with the flow continuity and evolves with time at the same frequency as that of the imposed oscillation, although with an amplitude decreasing with the frequency. The time complexity of the transverse component of the movement pattern, however, cannot be rationalized through such intuitive arguments. Towards bringing out the underlying physics, we further endeavor in a reciprocal identity based analysis. Following this approach, we unveil the time complexities of the droplet movement, which appear to be sufficient to rationalize the complex movement patterns observed through the comprehensive simulation studies. These results can be of profound importance in designing droplet based microfluidic systems in an oscillatory flow environment. PMID- 26986413 TI - Mixing of spherical bubbles with time-dependent radius in incompressible flows. AB - The motion of contracting and expanding bubbles in an incompressible chaotic flow is analyzed in terms of the finite-time Lyapunov exponents. The viscous forces acting on the bubble surface depend not only on the relative acceleration but also on the time dependence of the bubble volume, which is modeled by the Rayleigh-Plesset equation. The effect of bubble coalescence on the coherent structures that develop in the flow is studied using a simplified bubble merger model. Contraction and expansion of the bubbles is favored in the vicinity of the coherent structures. Time evolution of coalescence bubbles follows a Levy distribution with an exponent that depends on the initial distance between bubbles. Mixing patterns were found to depend heavily on merging and on the time dependent volume of the bubbles. PMID- 26986414 TI - Characterization of azimuthal and radial velocity fields induced by rotors in flows with a low Reynolds number. AB - We theoretically and experimentally investigate the flow field that emerges from a rodlike microrotor rotating about its center in a nonaxisymmetric manner. A simple theoretical model is proposed that uses a superposition of two rotlets as a fundamental solution to the Stokes equation. The predictions of this model are compared to measurements of the azimuthal and radial microfluidic velocity field components that are induced by a rotor composed of fused microscopic spheres. The rotor is driven magnetically and the fluid flow is measured with the help of a probe particle fixed by an optical tweezer. We find considerable deviations of the mere azimuthal flow pattern induced by a single rotating sphere as it has been reported by Di Leonardo et al. [Phys. Rev. Lett. 96, 134502 (2006)]. Notably, the presence of a radial velocity component that manifests itself by an oscillation of the probe particle with twice the rotor frequency is observed. These findings open up a way to discuss possible radial transport in microfluidic devices. PMID- 26986415 TI - Effects of shear rate, confinement, and particle parameters on margination in blood flow. AB - The effects of flow and particle properties on margination of particles in red blood cell (RBC) suspensions is investigated using direct numerical simulation (DNS) of cellar blood flow. We focus on margination of particles in the flow of moderately dense suspensions of RBCs. We hypothesize that margination rate in nondilute suspensions is mainly driven by the RBC-enhanced diffusion of marginating particles in the RBC-filled region. We derive a scaling law for margination length in a straight channel. Margination length increases cubically with channel height and is independent of shear rate. We verify this scaling law for margination length by DNS of flowing RBCs and marginating particles. We also show that rigidity and size both lead to particle margination with rigidity having a more significant effect compared to size within the range of parameters in this study. PMID- 26986416 TI - Principal curvature effects on the early evolution of three-dimensional single mode Richtmyer-Meshkov instabilities. AB - The Richtmyer-Meshkov instability (RMI) of single-mode air-SF(6) interfaces is studied numerically and the emphasis is placed on the effect of the principal curvature on the early evolution of the shocked interface. Two three-dimensional initial interfaces with opposite (3D-) and identical (3D+) principal curvatures and a traditional two-dimensional interface (2D) are considered. The weighted essentially nonoscillatory scheme and the Level-Set method combined with the real ghost fluid method are adopted. For comparison, perturbations on the initial interfaces with the same wavelength and amplitude in the symmetry plane are employed. The numerical results confirm the experimental finding that the growth rate of perturbations in the symmetry plane at the linear stage in the 3D- case is much smaller than that in the 2D and 3D+ cases. The difference among them can be ascribed to the different pressure and vorticity distributions associated with the principal curvatures of the initial interface. On the one hand, the high pressure zones in the vicinity of the deformed interface are significantly different for three cases especially in the very beginning. The shock convergence and divergence at the interface are more severe in the 3D+ case than those in the 2D case, while the wave pattern in the 3D- case is more complex. On the other hand, the baroclinic vorticity distribution plays a leading role in the interface deformation of the 3D RMI after the passage of the planar shock. The accumulated vorticity changes the movement of the deformed interface and makes the local growth of perturbations different among three cases. PMID- 26986417 TI - Coalescence dynamics of viscous conical drops. AB - When two oppositely charged drops come into light contact, a liquid meniscus bridge with double-cone geometry forms between the drops. Recent experiments have demonstrated the existence of a critical cone angle above which the meniscus bridge pinches off and the drops do not coalesce. This striking behavior-which has implications for processes ranging from the coarsening of emulsions to electrospray ionization in mass spectrometry-has been studied theoretically and experimentally for inertial liquid drops. Little is known, however, about the influence of the liquid viscosity on the critical cone angle. Here, we use high fidelity numerical simulations to gain insight into the coalescence dynamics of conical drops at intermediate Reynolds numbers. The simulations, which account for viscous, inertial, and surface tension effects, predict that the critical cone angle increases as the viscosity of the drops decreases. When approaching the inertial regime, however, the predicted critical angle quickly stabilizes at approximately 27 degrees , as observed in experiments. PMID- 26986418 TI - Convection flows driven by laser heating of a liquid layer. AB - When a fluid is heated by the absorption of a continuous laser wave, the fluid density decreases in the heated area. This induces a pressure gradient that generates internal motion of the fluid. Due to mass conservation, convection eddies emerge in the sample. To investigate these laser-driven bulk flows at the microscopic scale, we built a setup to perform temperature measurements with a fluorescent-sensitive dye on the one hand, and measured the flow pattern at different beam powers, using a particle image velocimetry technique on the other hand. Temperature measurements were also used in numerical simulations in order to compare predictions to the experimental velocity profiles. The combination of our numerical and experimental approaches allows a detailed description of the convection flows induced by the absorption of light, which reveals a transition between a thin and a thick liquid layer regime. This supports the basis of optothermal approaches for microfluidic applications. PMID- 26986419 TI - Transient elasticity and polymeric fluids: Small-amplitude deformations. AB - Transient elasticity (TE) is a concept useful for a systematic generalization of viscoelasticity. Due to its thermodynamic consistency, it naturally leads to a simple description of non-Newtonian effects displayed by polymeric fluids, granular media, and other soft matter. We employ a continuum-mechanical theory that is derived from TE and tailored to polymeric fluids, showing how it captures a surprisingly large number of phenomena in shear and elongational flows, including stationary, oscillatory, and transient ones, as well as the flow down an inclined channel. Even the Weissenberg effect is well accounted for. This theory is applicable for small- as well as large-amplitude deformations. We concentrate on the former in the present article, leaving the latter to a companion article. PMID- 26986420 TI - Transient elasticity and the rheology of polymeric fluids with large amplitude deformations. AB - Transient elasticity is a systematic generalization of viscoelasticity. Its purpose is to give a coherent description of non-Newtonian effects displayed by soft-matter systems, especially polymer melts and solutions. Using the concept of transient elasticity we describe here a hydrodynamic model for polymeric fluids, which is applicable for large amplitude deformations. We present an energy density with only two independent parameters, which is compatible with all thermodynamic requirements and which reduces for small deformations to models studied previously. The expression discussed is simple enough to allow full analytic treatment and shows semiquantitative agreement with experimental data. This model is used to capture many of the interesting effects thought to be characteristic of polymer rheology for large deformations including viscosity overshoot near the onset of shear flow, the onset of elongational flows in situations for which there is no stationary solution as well as shear thinning and normal stress differences for a large range of shear rates. In addition, we analyze how well our model accounts for empirical relations including the Cox Merz rule, the Yamamoto relation, and Gleibetale's mirror relations. PMID- 26986421 TI - Convection-driven kinematic dynamos at low Rossby and magnetic Prandtl numbers: Single mode solutions. AB - The onset of dynamo action is investigated within the context of a newly developed low Rossby, low magnetic Prandtl number, convection-driven dynamo model. This multiscale model represents an asymptotically exact form of an alpha^{2} mean field dynamo model in which the small-scale convection is represented explicitly by finite amplitude, single mode solutions. Both steady and oscillatory convection are considered for a variety of horizontal planforms. The kinetic helicity is observed to be a monotonically increasing function of the Rayleigh number. As a result, very small magnetic Prandtl number dynamos can be found for sufficiently large Rayleigh numbers. All dynamos are found to be oscillatory with an oscillation frequency that increases as the strength of the convection is increased and the magnetic Prandtl number is reduced. Kinematic dynamo action is strongly controlled by the profile of the helicity; single mode solutions which exhibit boundary layer behavior in the helicity show a decrease in the efficiency of dynamo action due to the enhancement of magnetic diffusion in the boundary layer regions. For a given value of the Rayleigh number, lower magnetic Prandtl number dynamos are excited for the case of oscillatory convection in comparison to steady convection. With regard to planetary dynamos, these results suggest that the low magnetic Prandtl number dynamos typical of liquid metals are more easily driven by thermal convection than by compositional convection. PMID- 26986423 TI - Ability of a low-dimensional model to predict geometry-dependent dynamics of large-scale coherent structures in turbulence. AB - We test the ability of a general low-dimensional model for turbulence to predict geometry-dependent dynamics of large-scale coherent structures, such as convection rolls. The model consists of stochastic ordinary differential equations, which are derived as a function of boundary geometry from the Navier Stokes equations [Brown and Ahlers, Phys. Fluids 20, 075101 (2008); Phys. Fluids 20, 105105 (2008)]. We test the model using Rayleigh-Benard convection experiments in a cubic container. The model predicts a mode in which the alignment of a convection roll stochastically crosses a potential barrier to switch between diagonals. We observe this mode with a measured switching rate within 30% of the prediction. PMID- 26986422 TI - Flow-induced compaction of a deformable porous medium. AB - Fluid flowing through a deformable porous medium imparts viscous drag on the solid matrix, causing it to deform. This effect is investigated theoretically and experimentally in a one-dimensional configuration. The experiments consist of the downwards flow of water through a saturated pack of small, soft, hydrogel spheres, driven by a pressure head that can be increased or decreased. As the pressure head is increased, the effective permeability of the medium decreases and, in contrast to flow through a rigid medium, the flux of water is found to increase towards a finite upper bound such that it becomes insensitive to changes in the pressure head. Measurements of the internal deformation, extracted by particle tracking, show that the medium compacts differentially, with the porosity being lower at the base than at the upper free surface. A general theoretical model is derived, and the predictions of the model give good agreement with experimental measurements from a series of experiments in which the applied pressure head is sequentially increased. However, contrary to theory, all the experimental results display a distinct and repeatable hysteresis: the flux through the material for a particular applied pressure drop is appreciably lower when the pressure has been decreased to that value compared to when it has been increased to the same value. PMID- 26986424 TI - Stochastic dynamics of particles trapped in turbulent flows. AB - The long-time dynamics of large particles trapped in two nonhomogeneous turbulent shear flows is studied experimentally. Both flows present a common feature, a shear region that separates two colliding circulations, but with different spatial symmetries and temporal behaviors. Because large particles are less and less sensitive to flow fluctuations as their size increases, we observe the emergence of a slow dynamics corresponding to back-and-forth motions between two attractors, and a super-slow regime synchronized with flow reversals when they exist. Such dynamics is substantially reproduced by a one-dimensional stochastic model of an overdamped particle trapped in a two-well potential, forced by a colored noise. An extended model is also proposed that reproduces observed dynamics and trapping without potential barrier: the key ingredient is the ratio between the time scales of the noise correlation and the particle dynamics. A total agreement with experiments requires the introduction of spatially nonhomogeneous fluctuations and a suited confinement strength. PMID- 26986425 TI - Interfacial wave dynamics of a drop with an embedded bubble. AB - This article describes how an embedded bubble changes the surface wave of a suspended liquid drop, and how such modifications, if recorded experimentally, can be used to detect voids in typically opaque interior of the fluid. The analysis uses a matrix formalism to predict the frequencies for natural oscillation and the deformation for acoustically induced forced vibration. The theory shows that the embedded cavity causes major shifts in the frequency and amplitude values as well as twofold increase in number of natural modes, indicating multifacetted utility of the results in process diagnostics, material characterizations, and combustion technology. PMID- 26986426 TI - Demonstrating universal scaling for dynamics of Yukawa one-component plasmas after an interaction quench. AB - The Yukawa one-component plasma (OCP) model is a paradigm for describing plasmas that contain one component of interest and one or more other components that can be treated as a neutralizing, screening background. In appropriately scaled units, interactions are characterized entirely by a screening parameter, kappa. As a result, systems of similar kappa show the same dynamics, regardless of the underlying parameters (e.g., density and temperature). We demonstrate this behavior using ultracold neutral plasmas (UNPs) created by photoionizing a cold (T<=10 mK) gas. The ions in UNP systems are well described by the Yukawa model, with the electrons providing the screening. Creation of the plasma through photoionization can be thought of as a rapid quench of the interaction potential from kappa=infinity to a final kappa value set by the electron density and temperature. We demonstrate experimentally that the postquench dynamics are universal in kappa over a factor of 30 in density and an order of magnitude in temperature. Results are compared with molecular-dynamics simulations. We also demonstrate that features of the postquench kinetic energy evolution, such as disorder-induced heating and kinetic-energy oscillations, can be used to determine the plasma density and the electron temperature. PMID- 26986427 TI - Calibrated simulations of Z opacity experiments that reproduce the experimentally measured plasma conditions. AB - Recently, frequency-resolved iron opacity measurements at electron temperatures of 170-200 eV and electron densities of (0.7-4.0)*10(22)cm(-3) revealed a 30-400% disagreement with the calculated opacities [J. E. Bailey et al., Nature (London) 517, 56 (2015)]. The discrepancies have a high impact on astrophysics, atomic physics, and high-energy density physics, and it is important to verify our understanding of the experimental platform with simulations. Reliable simulations are challenging because the temporal and spatial evolution of the source radiation and of the sample plasma are both complex and incompletely diagnosed. In this article, we describe simulations that reproduce the measured temperature and density in recent iron opacity experiments performed at the Sandia National Laboratories Z facility. The time-dependent spectral irradiance at the sample is estimated using the measured time- and space-dependent source radiation distribution, in situ source-to-sample distance measurements, and a three dimensional (3D) view-factor code. The inferred spectral irradiance is used to drive 1D sample radiation hydrodynamics simulations. The images recorded by slit imaged space-resolved spectrometers are modeled by solving radiation transport of the source radiation through the sample. We find that the same drive radiation time history successfully reproduces the measured plasma conditions for eight different opacity experiments. These results provide a quantitative physical explanation for the observed dependence of both temperature and density on the sample configuration. Simulated spectral images for the experiments without the FeMg sample show quantitative agreement with the measured spectral images. The agreement in spectral profile, spatial profile, and brightness provides further confidence in our understanding of the backlight-radiation time history and image formation. These simulations bridge the static-uniform picture of the data interpretation and the dynamic-gradient reality of the experiments, and they will allow us to quantitatively assess the impact of effects neglected in the data interpretation. PMID- 26986428 TI - Electron heating in radiation-pressure-driven proton acceleration with a circularly polarized laser. AB - Dynamics of electron heating in the radiation-pressure-driven acceleration through self-induced transparency (SIT) is investigated with the help of particle in-cell simulations. The SIT is achieved through laser filamentation which is seeded by the transverse density modulations due to the Rayleigh-Taylor-like instability. We observe stronger SIT induced electron heating for the longer duration laser pulses leading to deterioration of accelerated ion beam quality (mainly energy spread). Such heating can be controlled to obtain a quasimonoenergetic beam by cascaded foils targets where a second foil behind the main accelerating foil acts as a laser reflector to suppress the SIT. PMID- 26986429 TI - Temperature relaxation in dense plasmas. AB - We present a model to calculate temperature-relaxation rates in dense plasmas. The electron-ion interaction potential and the thermodynamic data of interest are provided by an average-atom model. This approach allows the study of the temperature relaxation in a two-temperature electron-ion system. PMID- 26986430 TI - Formation of current singularity in a topologically constrained plasma. AB - Recently a variational integrator for ideal magnetohydrodynamics in Lagrangian labeling has been developed. Its built-in frozen-in equation makes it optimal for studying current sheet formation. We use this scheme to study the Hahm-Kulsrud Taylor problem, which considers the response of a 2D plasma magnetized by a sheared field under sinusoidal boundary forcing. We obtain an equilibrium solution that preserves the magnetic topology of the initial field exactly, with a fluid mapping that is non-differentiable. Unlike previous studies that examine the current density output, we identify a singular current sheet from the fluid mapping. These results are benchmarked with a constrained Grad-Shafranov solver. The same signature of current singularity can be found in other cases with more complex magnetic topologies. PMID- 26986431 TI - Weakly nonlinear ion-acoustic excitations in a relativistic model for dense quantum plasma. AB - The dynamics of linear and nonlinear ionic-scale electrostatic excitations propagating in a magnetized relativistic quantum plasma is studied. A quantum hydrodynamic model is adopted and degenerate statistics for the electrons is taken into account. The dispersion properties of linear ion acoustic waves are examined in detail. A modified characteristic charge screening length and "sound speed" are introduced, for relativistic quantum plasmas. By employing the reductive perturbation technique, a Zakharov-Kuznetzov-type equation is derived. Using the small-k expansion method, the stability profile of weakly nonlinear slightly supersonic electrostatic pulses is also discussed. The effect of electron degeneracy on the basic characteristics of electrostatic excitations is investigated. The entire analysis is valid in a three-dimensional as well as in two-dimensional geometry. A brief discussion of possible applications in laboratory and space plasmas is included. PMID- 26986432 TI - Electron dynamics and gamma and e(-)e(+) production by colliding laser pulses. AB - The dynamics of an electron bunch irradiated by two focused colliding super intense laser pulses and the resulting gamma and e(-)e(+) production are studied. Due to attractors of electron dynamics in a standing wave created by colliding pulses the photon emission and pair production, in general, are more efficient with linearly polarized pulses than with circularly polarized ones. The dependence of the key parameters on the laser intensity and wavelength allows us to identify the conditions for the cascade development and gammae(-)e(+) plasma creation. PMID- 26986433 TI - Nonparametric estimation of Fisher information from real data. AB - The Fisher information matrix (FIM) is a widely used measure for applications including statistical inference, information geometry, experiment design, and the study of criticality in biological systems. The FIM is defined for a parametric family of probability distributions and its estimation from data follows one of two paths: either the distribution is assumed to be known and the parameters are estimated from the data or the parameters are known and the distribution is estimated from the data. We consider the latter case which is applicable, for example, to experiments where the parameters are controlled by the experimenter and a complicated relation exists between the input parameters and the resulting distribution of the data. Since we assume that the distribution is unknown, we use a nonparametric density estimation on the data and then compute the FIM directly from that estimate using a finite-difference approximation to estimate the derivatives in its definition. The accuracy of the estimate depends on both the method of nonparametric estimation and the difference Deltatheta between the densities used in the finite-difference formula. We develop an approach for choosing the optimal parameter difference Deltatheta based on large deviations theory and compare two nonparametric density estimation methods, the Gaussian kernel density estimator and a novel density estimation using field theory method. We also compare these two methods to a recently published approach that circumvents the need for density estimation by estimating a nonparametric f divergence and using it to approximate the FIM. We use the Fisher information of the normal distribution to validate our method and as a more involved example we compute the temperature component of the FIM in the two-dimensional Ising model and show that it obeys the expected relation to the heat capacity and therefore peaks at the phase transition at the correct critical temperature. PMID- 26986434 TI - Interface control and snow crystal growth. AB - The growth of snow crystals is dependent on the temperature and saturation of the environment. In the case of dendrites, Reiter's local two-dimensional model provides a realistic approach to the study of dendrite growth. In this paper we obtain a new geometric rule that incorporates interface control, a basic mechanism of crystallization that is not taken into account in the original Reiter model. By defining two new variables, growth latency and growth direction, our improved model gives a realistic model not only for dendrite but also for plate forms. PMID- 26986435 TI - Lattice Boltzmann model for numerical relativity. AB - In the Z4 formulation, Einstein equations are written as a set of flux conservative first-order hyperbolic equations that resemble fluid dynamics equations. Based on this formulation, we construct a lattice Boltzmann model for numerical relativity and validate it with well-established tests, also known as "apples with apples." Furthermore, we find that by increasing the relaxation time, we gain stability at the cost of losing accuracy, and by decreasing the lattice spacings while keeping a constant numerical diffusivity, the accuracy and stability of our simulations improve. Finally, in order to show the potential of our approach, a linear scaling law for parallelization with respect to number of CPU cores is demonstrated. Our model represents the first step in using lattice kinetic theory to solve gravitational problems. PMID- 26986436 TI - Fast solution of elliptic partial differential equations using linear combinations of plane waves. AB - Given an arbitrary elliptic partial differential equation (PDE), a procedure for obtaining its solution is proposed based on the method of Ritz: the solution is written as a linear combination of plane waves and the coefficients are obtained by variational minimization. The PDE to be solved is cast as a system of linear equations Ax=b, where the matrix A is not sparse, which prevents the straightforward application of standard iterative methods in order to solve it. This sparseness problem can be circumvented by means of a recursive bisection approach based on the fast Fourier transform, which makes it possible to implement fast versions of some stationary iterative methods (such as Gauss Seidel) consuming O(NlogN) memory and executing an iteration in O(Nlog(2)N) time, N being the number of plane waves used. In a similar way, fast versions of Krylov subspace methods and multigrid methods can also be implemented. These procedures are tested on Poisson's equation expressed in adaptive coordinates. It is found that the best results are obtained with the GMRES method using a multigrid preconditioner with Gauss-Seidel relaxation steps. PMID- 26986437 TI - Tracking vortices in superconductors: Extracting singularities from a discretized complex scalar field evolving in time. AB - In type-II superconductors, the dynamics of magnetic flux vortices determine their transport properties. In the Ginzburg-Landau theory, vortices correspond to topological defects in the complex order parameter field. Earlier, in Phillips et al. [Phys. Rev. E 91, 023311 (2015)], we introduced a method for extracting vortices from the discretized complex order parameter field generated by a large scale simulation of vortex matter. With this method, at a fixed time step, each vortex [simplistically, a one-dimensional (1D) curve in 3D space] can be represented as a connected graph extracted from the discretized field. Here we extend this method as a function of time as well. A vortex now corresponds to a 2D space-time sheet embedded in 4D space time that can be represented as a connected graph extracted from the discretized field over both space and time. Vortices that interact by merging or splitting correspond to disappearance and appearance of holes in the connected graph in the time direction. This method of tracking vortices, which makes no assumptions about the scale or behavior of the vortices, can track the vortices with a resolution as good as the discretization of the temporally evolving complex scalar field. Additionally, even details of the trajectory between time steps can be reconstructed from the connected graph. With this form of vortex tracking, the details of vortex dynamics in a model of a superconducting materials can be understood in greater detail than previously possible. PMID- 26986438 TI - Finite-volume versus streaming-based lattice Boltzmann algorithm for fluid dynamics simulations: A one-to-one accuracy and performance study. AB - A finite-volume (FV) discretization method for the lattice Boltzmann (LB) equation, which combines high accuracy with limited computational cost is presented. In order to assess the performance of the FV method we carry out a systematic comparison, focused on accuracy and computational performances, with the standard streaming lattice Boltzmann equation algorithm. In particular we aim at clarifying whether and in which conditions the proposed algorithm, and more generally any FV algorithm, can be taken as the method of choice in fluid dynamics LB simulations. For this reason the comparative analysis is further extended to the case of realistic flows, in particular thermally driven flows in turbulent conditions. We report the successful simulation of high-Rayleigh number convective flow performed by a lattice Boltzmann FV-based algorithm with wall grid refinement. PMID- 26986439 TI - Effects of viscosity and acoustic streaming on the interparticle radiation force between rigid spheres in a standing wave. AB - The total acoustic radiation force acting on interacting spheres in a viscous fluid consists of the primary and secondary forces. The primary force pushes rigid spheres to the pressure node due to the incident standing wave. The secondary force is the interparticle force caused by the interaction between spheres in the standing wave. In this study, an algorithm based on the multipole series expansion and Stokeslet method is proposed for calculating the primary and secondary radiation forces acting on a pair of spheres in a viscous fluid. It is concluded that the acoustical interaction between a pair of spheres is considerably stronger in a viscous fluid compared to the inviscid case due to the streaming effects in the viscous fluid. For spheres located far from each other, the interaction becomes considerably weak; thus, the spheres move mainly due to the primary radiation force. PMID- 26986440 TI - Finite-volume method with lattice Boltzmann flux scheme for incompressible porous media flow at the representative-elementary-volume scale. AB - Based on the Darcy-Brinkman-Forchheimer equation, a finite-volume computational model with lattice Boltzmann flux scheme is proposed for incompressible porous media flow in this paper. The fluxes across the cell interface are calculated by reconstructing the local solution of the generalized lattice Boltzmann equation for porous media flow. The time-scaled midpoint integration rule is adopted to discretize the governing equation, which makes the time step become limited by the Courant-Friedricks-Lewy condition. The force term which evaluates the effect of the porous medium is added to the discretized governing equation directly. The numerical simulations of the steady Poiseuille flow, the unsteady Womersley flow, the circular Couette flow, and the lid-driven flow are carried out to verify the present computational model. The obtained results show good agreement with the analytical, finite-difference, and/or previously published solutions. PMID- 26986441 TI - Lattice Boltzmann model for Coulomb-driven flows in dielectric liquids. AB - In this paper, we developed a unified lattice Boltzmann model (LBM) to simulate electroconvection in a dielectric liquid induced by unipolar charge injection. Instead of solving the complex set of coupled Navier-Stokes equations, the charge conservation equation, and the Poisson equation of electric potential, three consistent lattice Boltzmann equations are formulated. Numerical results are presented for both strong and weak injection regimes, and different scenarios for the onset and evolution of instability, bifurcation, and chaos are tracked. All LBM results are found to be highly consistent with the analytical solutions and other numerical work. PMID- 26986442 TI - Molecular Understanding and Structural-Based Design of Polyacrylamides and Polyacrylates as Antifouling Materials. AB - Design and synthesis of highly bioinert and biocompatible antifouling materials are crucial for a broad range of biomedical and engineering applications. Among antifouling materials, polyacrylamides and polyacrylates have proved so promising because of cheap raw materials, ease of synthesis and applicability, and abundant functional groups. The strong surface hydration and the high surface packing density of polyacrylamides and polyacrylates are considered to be the key contributors to their antifouling property. In this article, we review our studies on the design and synthesis of a series of polyacrylamides and polyacrylates with different molecular structures. These polymers can be fabricated into different architectural forms (brushes, nanoparticles, nanogels, and hydrogels), all of which are highly resistant to the attachment of proteins, cells, and bacteria. We find that small structural changes in the polymers can lead to large enhancement in surface hydration and antifouling performance, both showing a positive correlation. This reveals a general design rule for effective antifouling materials. Furthermore, polyacrylamides and polyacrylates are readily functionalized with other bioactive compounds to achieve different new multifunctionalities. PMID- 26986443 TI - Intra-arterial Chemotherapy for Retinoblastoma: A Systematic Review. AB - Importance: Intra-arterial chemotherapy has emerged as a treatment for intraocular retinoblastoma and has been quickly adopted by centers worldwide. Objective: To conduct a systematic review and attempt a meta-analysis to summarize the reported outcomes of intra-arterial chemotherapy. Evidence Review: In January 2015, we performed comprehensive searches in Medline, Embase, Cochrane, and Web of Science from inception through January 2015, including any peer-reviewed English-language publication that described outcomes related to toxicity or efficacy in at least 4 patients. Findings: From a total of 208 identified publications, 28 met inclusion criteria. Twelve reports with discernable nonduplicative information were included, reporting 655 patients, 757 eyes, and 2350 catheterizations. All were single-arm case series, and 67% (8 of 12) were retrospective. Across all studies, globe salvage was achieved for 502 (66%) of all eyes. Most common reported toxicities were chorioretinal atrophy and vascular occlusions. There were at least 13 reports of children with metastases. After publication, 7 additional children had metastases. The 4 different classification systems used challenged the comparison of disease severity at presentation. Visual outcome was not addressed in most studies. Meta-analyses were not possible because no study had a comparative group. Assessment of risk of bias was not possible because no validated tool for single-arm studies was available. Conclusions and Relevance: Intra-arterial chemotherapy is a promising new treatment associated with high rates of globe salvage. However, the literature is limited by the predominance of retrospective case series, absence of comparison groups, short median follow-up, heterogeneous definitions and tumor classifications, and frequent duplicate reporting. Metastases have been observed, and long-term follow-up is needed. Until the results of clinical, prospective studies are available, it is recommended that intra-arterial chemotherapy be offered selectively among other options, with fully informed discussion about all possible risks, benefits, and uncertainties. PMID- 26986444 TI - Dielectric Matrix Formulation of Correlation Energies in the Random Phase Approximation: Inclusion of Exchange Effects. AB - Starting from the general expression for the ground state correlation energy in the adiabatic-connection fluctuation-dissipation theorem (ACFDT) framework, it is shown that the dielectric matrix formulation, which is usually applied to calculate the direct random phase approximation (dRPA) correlation energy, can be used for alternative RPA expressions including exchange effects. Within this famework, the ACFDT analog of the second order screened exchange (SOSEX) approximation leads to a logarithmic formula for the correlation energy similar to the direct RPA expression. Alternatively, the contribution of the exchange can be included in the kernel used to evaluate the response functions. In this case, the use of an approximate kernel is crucial to simplify the formalism and to obtain a correlation energy in logarithmic form. Technical details of the implementation of these methods are discussed, and it is shown that one can take advantage of density fitting or Cholesky decomposition techniques to improve the computational efficiency; a discussion on the numerical quadrature made on the frequency variable is also provided. A series of test calculations on atomic correlation energies and molecular reaction energies shows that exchange effects are instrumental for improvement over direct RPA results. PMID- 26986446 TI - Tumor-Treating Fields-A Fundamental Change in Locoregional Management for Glioblastoma. PMID- 26986445 TI - Fixed-dose combination therapy of nebivolol and valsartan for the treatment of hypertension. AB - Recent large clinical trials have refuted earlier suggestions from the Joint National Committee 8 committee that less aggressive targets for blood pressure control were all that could be justified in most hypertensive patients. It now does appear that in fact "lower is better," with blood pressure targets < 120/80 mm Hg appropriate for many hypertensive patients. Two drug combinations are often indicated as initial therapy if a 20/10 mm Hg or greater blood pressure reduction is necessary to reach target. Combinations consisting of beta-blockers and renin angiotensin-aldosterone system inhibitors have previously been deemed "less effective," based on partially overlapping mechanisms of action and limited clinical trial evidence. Nebivolol is a vasodilating beta1-selective blocker and beta3- adrenoceptor agonist; beta3-adrenoceptor activation increases nitric oxide concentrations and thus explains the vasodilatory effect. A recent 8-week randomized trial (N=4,161) in individuals with stage 1-2 hypertension demonstrated that single-pill fixed dose combinations (FDC) of nebivolol and valsartan, an angiotensin II subtype 1 receptor blocker, were more effective in reducing blood pressure than the corresponding monotherapies, with comparable tolerability. In addition, an ABPM-biomarkers substudy from that trial (n=805) demonstrated that the FDC prevented a valsartan-induced increase in plasma renin activity, and that the nebivolol/valsartan 20/320 mg/day dose reduced plasma aldosterone concentration significantly more than valsartan 320 mg/day. This article will describe the properties of nebivolol that make it unique and separate it from other beta-blockers, and will further support the pharmacological advantages of this particular combination. PMID- 26986447 TI - Immunohistological study of tight junction protein expression in mal de Meleda. AB - Mal de Meleda (MdM, MIM: 248300) is a rare autosomal recessive skin disorder characterized by diffuse palmoplantar keratoderma and transgressive keratosis with onset in early infancy. The gene responsible for MdM, ARS, encodes for Secreted Lys6/Plaur domain-containing protein 1 which is essential for epidermal homeostasis. Tight junctions have been proposed to have two mutually exclusive functions: a fence function which prevents the mixing of membrane proteins between the apical and basolateral membranes; and a gate function which controls the paracellular passage of ions and solutes between cells. In this study we report immunohistochemical investigations of tight junction proteins claudin-1 and occludin in MdM Tunisian families. Nine skin biopsies from patients with MdM were analyzed. The control group was formed by skin biopsies belonging to healthy individuals. Immunohistochemical study was performed on fixed sections from biopsies of four microns with the following polyclonal antibodies: anti-claudin-1 and anti-occludin. In control skin, claudin-1 exhibited membrane expression throughout the epidermis with increasing and upward intensity, whereas occludin was detected in the cell membrane of keratinocytes of the stratum granulosum. In MdM skin, claudin-1 was expressed throughout the thickness of the spinous layers with membrane staining, and occludin had cytoplasmic staining in the granular layer. The immunohistochemical expression of TJ proteins in MdM patients harbors premature expression of occludin and decreased expression of claudin-1, highlighting further evidence for disorders in epidermal homeostasis. PMID- 26986448 TI - Exploring the effects of substituting basketball players in high-level teams. AB - Substituting basketball players during competition is a key process to optimise collective performance. Available research on this topic is scarce, probably due to the difficulty in isolating these effects; thus, the aim of this study was to identify the temporal effects of substitutions in basketball (Spanish professional basketball league). The sample was composed of 1118 substitutions gathered from 21 basketball games. The analysed variables were coach-controlled (player and team's personal fouls, player in and player out roles, player's in and out minutes on-court and timeout situation); on-court (foul committed, free throws, 2- and 3-point field-goal effectiveness) and situational variables (scoreline, quality of opposition, game location and game quarter). The results showed positive scoring performances after the substitution for all the analyses. During the first quarter, there were significant effects for fouls committed, scoreline and game location after the substitution. The player's out personal fouls, free-throw effectiveness, player in, minutes on-court player in, timeout situation and 3-point field-goal effectiveness were significant during the second quarter. The team's personal fouls, game location, and scoreline were identified as important in the third quarter. The fourth quarter did not show significant effects on the independent variables. Current findings allow optimising coaches' plans and team management of on-court and bench players throughout the game. PMID- 26986450 TI - Oxidative Dearomatization of Indoles via Pd-Catalyzed C-H Oxygenation: An Entry to C2-Quaternary Indolin-3-ones. AB - An oxidative dearomatization chemistry of 2-arylindole via a unique pathway involving Pd-catalyzed C-H peroxygenation is documented. Coupled with cascade transformation, it provides a new route to access indolin-3-ones bearing a C2 quaternary functionality, including a chiral center (indoxyls), a motif prevalent in indole alkaloids but synthetically underexplored. The method is chemo- and regioselective and compatible with versatile substrates. A mechanism has been outlined on the basis of results of control experiments, isolation/use of intermediates, and spectroscopic studies. PMID- 26986449 TI - Comparison of real-world outcomes of adalimumab and infliximab for patients with ulcerative colitis in the United States. AB - OBJECTIVE: We compared the real-world effectiveness of initiating adalimumab and infliximab among patients in the US who were naive to tumor necrosis factor (TNF) inhibitors. METHODS: A retrospective chart review was conducted to evaluate the real-world effectiveness among adults with ulcerative colitis (UC) initiating adalimumab or infliximab. Charts of patients with UC were abstracted by treating physicians (randomly selected from a nationally representative panel) in April 2014. Patient eligibility criteria included: adalimumab or infliximab initiation on/after 1 October 2012; no prior anti-TNF therapy, history of Crohn's disease, or colectomy; and >=6 months of follow-up. Information on clinical outcomes (partial Mayo score, remission rate, physician global assessment (PGA), stool frequency, and rectal bleeding) and treatment patterns (dose escalations, discontinuations, switches, and treatment augmentations) were retrospectively reported by treating physicians. Kaplan-Meier curves and multivariate Cox proportional hazards regression models were used to assess the time to clinical outcomes and treatment changes for each therapy. RESULTS: Overall, 170 physicians participated, contributing data on 380 and 424 patients who initiated adalimumab and infliximab, respectively. Baseline clinical characteristics were similar between groups. Both adalimumab- and infliximab-treated patients showed substantial improvements from baseline to follow-up in effectiveness measures; results of these measures were similar between the adalimumab and infliximab cohorts. Time to remission (p = 0.5241), no rectal bleeding (p = 0.7648), normal stool count (p = 0.9941), and normal PGA (p = 0.7697) showed no significant differences between therapies in unadjusted and adjusted comparisons. Unadjusted and adjusted time to event analysis of discontinuation (p = 0.7151), dose escalation (p = 0.6310), treatment augmentation (p = 0.1209), and switching (p = 0.7975) showed no significant differences between the two cohorts. LIMITATIONS: Retrospective, observational design. CONCLUSIONS: Adalimumab and infliximab were similarly effective in the treatment of moderate-to-severe UC in the real-world clinical setting. PMID- 26986452 TI - S((1)D) + ortho-D2 Reaction Dynamics at Low Collision Energies: Complementary Crossed Molecular Beam Experiments and Theoretical Investigations. AB - The excitation function of the S((1)D) + D2 reaction was determined in a crossed molecular beam apparatus for collision energies ranging from 1817 to 47 J mol(-1) in the near-cold regime. A very good overall agreement was found between experimental data and the theoretical results obtained using the ab initio potential energy surface built by Ho and coworkers and different methods: time independent quantum dynamics (QM), semiclassical mean potential capture theory (sc-MPCT), and quasi-classical trajectories (QCT). The general trend of the experimental excitation function is well reproduced in most of the range by a simple capture calculation with an R(-6) dispersion potential. The present results are discussed in the light of previous studies on the isotopic variants S((1)D) + H2 and HD. PMID- 26986451 TI - Caveolin-1-mediated Japanese encephalitis virus entry requires a two-step regulation of actin reorganization. AB - AIM: To investigate the detailed mechanism of Japanese encephalitis virus (JEV) cell entry. MATERIALS & METHODS: Utilize a siRNA library targeting cellular membrane trafficking genes to identify key molecules that mediate JEV entry into human neuronal cells. RESULTS: JEV enters human neuronal cells by caveolin-1 mediated endocytosis, which depends on a two-step regulation of actin cytoskeleton remodeling triggered by RhoA and Rac1: RhoA activation promoted the phosphorylation of caveolin-1, and then Rac1 activation facilitated caveolin associated viral internalization. Specifically, virus attachment activates the EGFR-PI3K signaling pathway, thereby leading to RhoA activation. CONCLUSION: This work provides a detailed picture of the entry route and intricate cellular events following the entry of JEV into human neuronal cells, and promotes a better understanding of JEV entry. PMID- 26986454 TI - The Role of Fine Needle Aspiration of Orbital Lesions: A Case Series. AB - OBJECTIVE: This paper analyzes a series of ultrasound (US)-guided orbital fine needle aspirations (FNAs) which provide diagnostic information that cytopathologists approaching orbital lesions for the first time can find useful and underlines the importance of teamwork. STUDY DESIGN: The investigators retrospectively obtained data from 24 consecutive orbital FNAs. For all patients, a complete clinicoradiological database was created. FNAs were performed under US guidance with 25-gauge needles and an aspiration biopsy syringe gun, and sent to the Department of Pathology for examination and data management. RESULTS: The mean age of the patients was 54 years. Imaging studies included US, magnetic resonance imaging and computed tomography scans; 9 lesions involved the right orbit and 15 the left orbit. The mean lesion size was 23.6 +/- 7.2 mm. After microscopic examination, 7 smears were labeled as 'nondiagnostic', while in 17 cases a definitive diagnosis was proposed, which always proved to be correct (70.8%, specificity = 100%). CONCLUSIONS: The investigators believe that FNA biopsy of orbital masses is a necessary step; its weaknesses lie in the particularly delicate site of sampling and the extreme heterogeneity of lesions. Nevertheless, when orbital FNA is performed within a well-coordinated multidisciplinary team, it is a powerful tool that can be used to define the most appropriate management of these patients. PMID- 26986455 TI - High-Resolution Spectroscopic Studies of Complexes Formed by Medium-Size Organic Molecules. AB - A wealth of structural and dynamical information has been obtained in the last 30 years from the study of high-resolution spectra of molecular clusters generated in a cold supersonic expansion by means of highly resolved spectroscopic methods. The data obtained, generally lead to determination of the structures of stable conformations. In addition, in the case of weakly bound molecular complexes, it is usual to observe the effects of internal motions due to the shallowness of the potential energy surfaces involved and the flexibility of the systems. In the case of electronic excitation experiments, also the effect of electronic distribution changes on both equilibrium structures and internal motions becomes accessible. The structural and dynamical information that can be obtained by applying suitable theoretical models to the analysis of these unusually complex spectra allows the determination and understanding of the driving forces involved in formation of the molecular complex. In this way, many types of non-covalent interactions have been characterized, from pure van der Waals interactions in complexes of rare gases to moderate-strength and weak hydrogen bonds and to the most recent halogen bonds and n-pi interactions. The aim of this review is to underline how the different experimental and theoretical methods converge in giving a detailed picture of weak interactions in small molecular adducts involving medium-size molecules. The conclusions regarding geometries and energies can contribute to understanding of the different driving forces involved in the dynamics of the processes and can be exploited in all fields of chemistry and biochemistry, from design of new materials with novel properties to rational design of drugs. PMID- 26986453 TI - Sexual dimorphism in activation of placental autophagy in obese women with evidence for fetal programming from a placenta-specific mouse model. AB - The incidence of maternal obesity and its co-morbidities (diabetes, cardiovascular disease) continues to increase at an alarming rate, with major public health implications. In utero exposure to maternal obesity has been associated with development of cardiovascular and metabolic diseases in the offspring as a result of developmental programming. The placenta regulates maternal-fetal metabolism and shows significant changes in its function with maternal obesity. Autophagy is a cell-survival process, which is responsible for the degradation of damaged organelles and misfolded proteins. Here we show an activation of autophagosomal formation and autophagosome-lysosome fusion in placentas of males but not females from overweight (OW) and obese (OB) women vs. normal weight (NW) women. However, total autophagic activity in these placentas appeared to be decreased as it showed an increase in SQSTM1/p62 and a decrease in lysosomal biogenesis. A mouse model with a targeted deletion of the essential autophagy gene Atg7 in placental tissue showed significant placental abnormalities comparable to those seen in human placenta with maternal obesity. These included a decrease in expression of mitochondrial genes and antioxidants, and decreased lysosomal biogenesis. Strikingly, the knockout mice were developmentally programmed as they showed an increased sensitivity to high-fat diet-induced obesity, hyperglycemia, hyperinsulinemia, increased adiposity, and cardiac remodeling. In summary, our results indicate a sexual dimorphism in placental autophagy in response to maternal obesity. We also show that autophagy plays an important role in placental function and that inhibition of placental autophagy programs the offspring to obesity, and to metabolic and cardiovascular diseases. PMID- 26986456 TI - Repulsive guidance molecule a blockade exerts the immunoregulatory function in DCs stimulated with ABP and LPS. AB - Repulsive guidance molecule a (RGMa) is an axonal guidance molecule that has recently found to exert function in immune system. This study evaluated the function of RGMa in modulation of dendritic cells (DCs) function stimulated with Achyranthes bidentata polysaccharide (ABP) and lipopolysaccharide (LPS) using a RGMa-neutralizing antibody. Compared with the Control-IgG/ABP and Control-IgG/LPS groups, DCs in the Anti-RGMa/ABP and Anti-RGMa/LPS groups 1) showed small, round cells with a few cell processes and organelles, and many pinocytotic vesicles; 2) had decreased MHC II, CD86, CD80, and CD40 expression; 3) displayed the decreased IL-12p70, IL-1beta and TNF-alpha levels and increased IL-10 secretion; 4) had a high percentage of FITC-dextran uptake; and 5) displayed a reduced ability to drive T cell proliferation and reinforced T cell polarization toward a Th2 cytokine pattern. We conclude that DCs treated with RGMa-neutralizing antibodies present with tolerogenic and immunoregulatory characteristics, which provides new insights into further understanding of the function of RGMa. PMID- 26986457 TI - Hypofractionated 3D radiotherapy for inoperable T1-3 N0-1 non-small-cell lung cancer. AB - OBJECTIVE: This study assessed the toxicity and clinical outcomes of three dimensional (3D) hypofractionated radiotherapy (HFRT) for medically inoperable T1 3 N0-1 non-small-cell lung cancer (NSCLC). METHODS: 34 patients with inoperable early-stage NSCLC were treated from August 2008 to April 2013. Prior to enrolment, patients were required to be evaluated by an experienced thoracic surgeon to determine the "operability". All received 57 Gy in 19 fractions followed by escalated doses of 3-Gy fractions, up to a total dose of 66 Gy using a 3D conformal technique. Toxicities were measured using the Common Terminology Criteria for Adverse Effects v. 4.0. RESULTS: The median follow-up was 33 months (7-74 months). Toxicity grades >=3 were not observed. Local control (LC) was 80.4% at 2 years, whereas regional control (RC) was 78%. The overall survival (OS), time to progression (TTP) and time to distant metastasis (TTM) at 2 years were 60%, 59% and 80%, respectively. For patients with T1-2 N0 and a tumour size <45 mm (n = 19), rates of OS, TTP and TTM at 2 years were 71%, 75% and 94%, respectively. LC and RC at 2 years were 85% and 94%, respectively. CONCLUSION: HFRT using 3.0-Gy fractions amounting to a total dose of 66 Gy is the recommended dose. A Phase 2 trial is warranted in order to assess the safety and efficacy of this fractionation scheme. ADVANCES IN KNOWLEDGE: HFRT results in a favourable outcome in early-stage lung cancer without the usual restrictions in tumour size and/or location associated with previous treatment methods. No special equipment is required, therefore permitting its application in any centre. PMID- 26986458 TI - Quality of search strategies reported in systematic reviews published in stereotactic radiosurgery. AB - OBJECTIVE: Systematic reviews require comprehensive literature search strategies to avoid publication bias. This study aimed to assess and evaluate the reporting quality of search strategies within systematic reviews published in the field of stereotactic radiosurgery (SRS). METHODS: Three electronic databases (Ovid MEDLINE((r)), Ovid EMBASE((r)) and the Cochrane Library) were searched to identify systematic reviews addressing SRS interventions, with the last search performed in October 2014. Manual searches of the reference lists of included systematic reviews were conducted. The search strategies of the included systematic reviews were assessed using a standardized nine-question form based on the Cochrane Collaboration guidelines and Assessment of Multiple Systematic Reviews checklist. Multiple linear regression analyses were performed to identify the important predictors of search quality. RESULTS: A total of 85 systematic reviews were included. The median quality score of search strategies was 2 (interquartile range = 2). Whilst 89% of systematic reviews reported the use of search terms, only 14% of systematic reviews reported searching the grey literature. Multiple linear regression analyses identified publication year (continuous variable), meta-analysis performance and journal impact factor (continuous variable) as predictors of higher mean quality scores. CONCLUSION: This study identified the urgent need to improve the quality of search strategies within systematic reviews published in the field of SRS. ADVANCES IN KNOWLEDGE: This study is the first to address how authors performed searches to select clinical studies for inclusion in their systematic reviews. Comprehensive and well-implemented search strategies are pivotal to reduce the chance of publication bias and consequently generate more reliable systematic review findings. PMID- 26986460 TI - Current artefacts in cardiac and chest magnetic resonance imaging: tips and tricks. AB - Currently MRI is extensively used for the evaluation of cardiovascular and thoracic disorders because of the well-established advantages that include use of non-ionizing radiation, good contrast and high spatial resolution. Despite the advantages of this technique, numerous categories of artefacts are frequently encountered. They may be related to the scanner hardware or software functionalities, environmental factors or the human body itself. In particular, some artefacts may be exacerbated with high-field-strength MR machines (e.g. 3 T). Cardiac imaging poses specific challenges with respect to breath-holding and cardiac motion. In addition, new cardiac MR-conditional devices may also be responsible for peculiar artefacts. The image quality may thus be impaired and give rise to a misdiagnosis. Knowledge of acquisition and reconstruction techniques is required to understand and recognize the nature of these artefacts. This article will focus on the origin and appearance of the most common artefacts encountered in cardiac and chest MRI along with possible correcting methods to avoid or reduce them. PMID- 26986462 TI - Commentary on "Assessing the Risk of Prehospital Administration of Naloxone with Subsequent Refusal of Care". PMID- 26986461 TI - Clinical outcomes of adaptive radiotherapy in head and neck cancers. AB - OBJECTIVE: The present study evaluated the efficacy and toxicity of adaptive radiotherapy (RT) among patients with head and neck cancer. METHODS: 36 patients eligible for radical RT underwent RT planning scans and were planned for 54-Gy dose to both high-risk and low-risk target volumes in Phase I. All patients underwent a second (adaptive) scan during the fifth week of RT. Phase II plans for 16 Gy to high-risk planning target volume were developed on these mid treatment scans. The primary end point was local response. Disease-free survival (DFS), overall survival (OS) and treatment-related morbidity were secondary end points. RESULTS: Median reductions in gross primary and nodal disease volumes on mid-treatment scans were 34% and 43.2%, respectively. 16 patients experienced grade 3 acute mucositis. No patient had grade 3 or above haematologic toxicity. Four patients developed local recurrences, all within the RT field. Median DFS and OS were 17.5 and 23.5 months, respectively. CONCLUSION: Adaptation to changes in the anatomic and tumour volume or shape may help tilt the balance towards more efficient dose delivery as well as better normal tissue sparing. ADVANCES IN KNOWLEDGE: This study supports the need for adaptive replanning for minimizing normal tissue toxicity without compromising local control and adds to the existing body of literature. PMID- 26986459 TI - Accelerated hypofractionated radiotherapy with concomitant chemotherapy in locally advanced squamous cell carcinoma of lung: evaluation of response, survival, toxicity and quality of life from a Phase II randomized study. AB - OBJECTIVE: To evaluate the feasibility and efficacy of accelerated hypofractionated radiation with concomitant chemotherapy (AHFx-RT-CT) in locally advanced squamous cell carcinoma (SCC) of the lung. METHODS: 36 patients were enrolled in this study (CTRI/2013/11/004143). Patients in Arm A (n = 18) received neoadjuvant chemotherapy (NACT) (paclitaxel 200 mg m(-2) and carboplatin area under the curve 5) followed by external radiotherapy (60 Gy/30 fractions/6 weeks). Patients in Arm B (n = 18) received NACT as in Arm A followed by AHFx-RT (48 Gy/20 fractions/4 weeks) with concomitant chemotherapy (cisplatin 30 mg m(-2) weekly). Primary end points included comparative evaluation of overall locoregional response rates (ORRs) and progression-free survival (PFS). Secondary end points included toxicity, quality of life (QOL) and overall survival (OS). RESULTS: The median follow-up duration was 15 months. The ORR at first follow-up (72.2% vs 44%, p = 0.06) and at 1 year after treatment completion (61% vs 5.5%, p = 0.04) were superior in Arm B. The median PFS (17 vs 5.36 months; p = 0.053) and OS (24.73 vs 12.33 months; p = 0.007) were also superior in Arm B. Grade >=3 acute pharyngitis/oesophagitis was less in Arm B (p = 0.05). Improvement of emotional function, cognitive function and chest pain was observed in Arm B. CONCLUSION: The study suggests that AHFx-RT-CT is feasible for locally advanced SCC of the lung with improved response rate, survival, QOL and favourable toxicity. ADVANCES IN KNOWLEDGE: To the best of our knowledge, this is the first study comparing conventionally fractionated radiation with AHFx-RT-CT. Addition of low-dose weekly cisplatin as radiosensitizer may be the potential factor responsible for improved response rate, survival and favourable toxicity in the study arm despite lower biological effective dose. PMID- 26986463 TI - Synthesis and biological evaluation of N-naphthoyl-phenylglyoxamide-based small molecular antimicrobial peptide mimics as novel antimicrobial agents and biofilm inhibitors. AB - Antimicrobial peptides (AMPs) are a key component of the human immune system. Synthetic AMP mimics represent a novel strategy to counteract the increasing incidence of antimicrobial resistance. Here, we describe the synthesis of novel glyoxamide derivatives via ring-opening reactions of N-hexanoyl, N-benzoyl and N naphthoylisatins with N,N-dimethylethane-1,2-diamine and N,N-dimethylpropane-1,3 diamine. These were converted to both the hydrochloric acid (HCl) or quaternary ammonium iodide (MeI) salts and their antibacterial activity against Staphylococcus aureus was investigated by their zone-of-inhibition and minimum inhibitory concentration (MIC). The HCl salt 22b exhibited the lowest MIC of 16 MUg mL(-1), whereas the corresponding MeI salt 22c had a MIC of 39 MUg mL(-1). We also investigated the in vitro toxicity of active compounds against the MRC-5 normal human lung fibroblasts and their activity against established biofilm in S. aureus. PMID- 26986464 TI - Scrutinizing Immutability: Research on Sexual Orientation and U.S. Legal Advocacy for Sexual Minorities. AB - We review scientific research and legal authorities to argue that the immutability of sexual orientation should no longer be invoked as a foundation for the rights of individuals with same-sex attractions and relationships (i.e., sexual minorities). On the basis of scientific research as well as U.S. legal rulings regarding lesbian, gay, and bisexual (LGB) rights, we make three claims: First, arguments based on the immutability of sexual orientation are unscientific, given what we now know from longitudinal, population-based studies of naturally occurring changes in the same-sex attractions of some individuals over time. Second, arguments based on the immutability of sexual orientation are unnecessary, in light of U.S. legal decisions in which courts have used grounds other than immutability to protect the rights of sexual minorities. Third, arguments about the immutability of sexual orientation are unjust, because they imply that same-sex attractions are inferior to other-sex attractions, and because they privilege sexual minorities who experience their sexuality as fixed over those who experience their sexuality as fluid. We conclude that the legal rights of individuals with same-sex attractions and relationships should not be framed as if they depend on a certain pattern of scientific findings regarding sexual orientation. PMID- 26986465 TI - Diagnostic Performance of Alpha-Fetoprotein, Protein Induced by Vitamin K Absence, Osteopontin, Dickkopf-1 and Its Combinations for Hepatocellular Carcinoma. AB - BACKGROUND & AIMS: Alpha-fetoprotein (AFP) is the most widely used serum biomarker for hepatocellular carcinoma (HCC), despite its limitations. As complementary biomarkers, protein induced by vitamin K absence (PIVKA-II), osteopontin (OPN), and Dickkopf-1 (DKK-1) have been proposed. This study aimed to perform a head-to-head comparison of the diagnostic performance of AFP, PIVKA-II, OPN and DKK-1 as single or in combination to seek the best biomarker or panel, and to investigate the clinical factors affecting their performance. METHODS: Using 401 stored plasma samples obtained from 208 HCC patients and 193 liver cirrhosis control patients, plasma AFP, PIVKA-II, OPN and DKK-1 levels were measured by ELISA, and receiver operating characteristic curve analyses were performed for each biomarker and for every combination of two to four markers. RESULTS: Of the four biomarkers, AFP showed the highest area under the curve (0.786). The sensitivity and specificity for each single biomarker was 62% and 90.2% (AFP>20 ng/mL), 51.0% and 91.2% (PIVKA-II>10 ng/mL), 46.2% and 80.3% (OPN>100 ng/mL), and 50.0% and 80.8% (DKK-1>500 pg/mL), respectively. Among the combinations of two biomarkers, AFP>20 ng/mL or DKK-1>500 pg/mL showed the best diagnostic performance (sensitivity 78.4%, specificity 72.5%). Triple or quadruple combination did not improve the diagnostic performance further. The patient's age, etiology and tumor invasiveness of HCC affected the performance of each marker. CONCLUSIONS: AFP was the most useful single biomarker for HCC diagnosis, and the combined measurement of AFP and DKK-1 could maximize the diagnostic yield. Clinical decision should be based on the consideration of various factors affecting the diagnostic performance of each biomarker. Efforts to seek novel HCC biomarkers should be continued. PMID- 26986466 TI - Modified Early Warning Score (MEWS) Identifies Critical Illness among Ward Patients in a Resource Restricted Setting in Kampala, Uganda: A Prospective Observational Study. AB - INTRODUCTION: Providing optimal critical care in developing countries is limited by lack of recognition of critical illness and lack of essential resources. The Modified Early Warning Score (MEWS), based on physiological parameters, is validated in adult medical and surgical patients as a predictor of mortality. The objective of this study performed in Uganda was to determine the prevalence of critical illness on the wards as defined by the MEWS, to evaluate the MEWS as a predictor of death, and to describe additional risk factors for mortality. METHODS: We conducted a prospective observational study at Mulago National Referral Teaching Hospital in Uganda. We included medical and surgical ward patients over 18 years old, excluding patients discharged the day of enrolment, obstetrical patients, and patients who self-discharged prior to study completion. Over a 72-hour study period, we collected demographic and vital signs, and calculated MEWS; at 7-days we measured outcomes. Patients discharged prior to 7 days were assumed to be alive at study completion. Descriptive and inferential statistical analyses were performed. RESULTS: Of 452 patients, the median age was 40.5 (IQR 29-54) years, 53.3% were male, 24.3% were HIV positive, and 45.1% had medical diagnoses. MEWS ranged from 0 to 9, with higher scores representing hemodynamic instability. The median MEWS was 2 [IQR 1-3] and the median length of hospital stay was 9 days [IQR 4-24]. In-hospital mortality at 7-days was 5.5%; 41.4% of patients were discharged and 53.1% remained on the ward. Mortality was independently associated with medical admission (OR: 7.17; 95% CI: 2.064-24.930; p = 0.002) and the MEWS >= 5 (OR: 5.82; 95% CI: 2.420-13.987; p<0.0001) in the multivariable analysis. CONCLUSION: There is a significant burden of critical illness at Mulago Hospital, Uganda. Implementation of the MEWS could provide a useful triage tool to identify patients at greatest risk of death. Future research should include refinement of MEWS for low-resource settings, and development of appropriate interventions for patients identified to be at high risk of death based on early warning scores. PMID- 26986467 TI - Oral Samples as Non-Invasive Proxies for Assessing the Composition of the Rumen Microbial Community. AB - Microbial community analysis was carried out on ruminal digesta obtained directly via rumen fistula and buccal fluid, regurgitated digesta (bolus) and faeces of dairy cattle to assess if non-invasive samples could be used as proxies for ruminal digesta. Samples were collected from five cows receiving grass silage based diets containing no additional lipid or four different lipid supplements in a 5 x 5 Latin square design. Extracted DNA was analysed by qPCR and by sequencing 16S and 18S rRNA genes or the fungal ITS1 amplicons. Faeces contained few protozoa, and bacterial, fungal and archaeal communities were substantially different to ruminal digesta. Buccal and bolus samples gave much more similar profiles to ruminal digesta, although fewer archaea were detected in buccal and bolus samples. Bolus samples overall were most similar to ruminal samples. The differences between both buccal and bolus samples and ruminal digesta were consistent across all treatments. It can be concluded that either proxy sample type could be used as a predictor of the rumen microbial community, thereby enabling more convenient large-scale animal sampling for phenotyping and possible use in future animal breeding programs aimed at selecting cattle with a lower environmental footprint. PMID- 26986469 TI - Cooperation and Conflict in the Plant Immune System. PMID- 26986470 TI - Adrenaline in anaphylaxis treatment. Balancing benefits and harms. AB - INTRODUCTION: Although anaphylaxis is a relatively common disorder, clinicians and scientists have debated on how to best define and manage this condition. The current recommendations are focused on the central role of adrenaline, but evidence in support of this therapeutic approach is modest, mainly for the lack of well-designed trials. Conversely, serious adverse effects are commonly reported following adrenaline use, especially when given intravenously. These include hypertension, ventricular arrhythmias, myocardial infarction, pulmonary edema. AREAS COVERED: Anaphylaxis treatment, with special focus on adrenaline utilization, both in pre-hospital and in-hospital settings. Aim is to examine in depth the balance between benefits and harms of this important drug. EXPERT OPINION: Due to the lack of solid evidence supporting the use of adrenaline in patients with anaphylaxis, except in severe cases, the strength of recommendations should be readdressed, limiting administration to selected categories of patients. Caregivers should promptly act in pre-hospital setting, given the shortness of time and lack of technology. In the hospital setting, and more specifically in the ED, clinicians should consider the prompt use of adrenaline in severe anaphylaxis cases, but they should also be able to judiciously wait in the vast majority of milder anaphylactic reactions, which may resolve spontaneously. PMID- 26986472 TI - A Global Perspective on Drinking-Water and Sanitation Classification: An Evaluation of Census Content. AB - Following the recent expiry of the United Nations' 2015 Millennium Development Goals (MDGs), new international development agenda covering 2030 water, sanitation and hygiene (WASH) targets have been proposed, which imply new demands on data sources for monitoring relevant progress. This study evaluates drinking water and sanitation classification systems from national census questionnaire content, based upon the most recent international policy changes, to examine national population census's ability to capture drinking-water and sanitation availability, safety, accessibility, and sustainability. In total, 247 censuses from 83 low income and lower-middle income countries were assessed using a scoring system, intended to assess harmonised water supply and sanitation classification systems for each census relative to the typology needed to monitor the proposed post-2015 indicators of WASH targets. The results signal a lack of international harmonisation and standardisation in census categorisation systems, especially concerning safety, accessibility, and sustainability of services in current census content. This suggests further refinements and harmonisation of future census content may be necessary to reflect ambitions for post-2015 monitoring. PMID- 26986473 TI - Lanthanide upconversion luminescence at the nanoscale: fundamentals and optical properties. AB - Upconversion photoluminescence is a nonlinear effect where multiple lower energy excitation photons produce higher energy emission photons. This fundamentally interesting process has many applications in biomedical imaging, light source and display technology, and solar energy harvesting. In this review we discuss the underlying physical principles and their modelling using rate equations. We discuss how the understanding of photophysical processes enabled a strategic influence over the optical properties of upconversion especially in rationally designed materials. We subsequently present an overview of recent experimental strategies to control and optimize the optical properties of upconversion nanoparticles, focussing on their emission spectral properties and brightness. PMID- 26986471 TI - User and Provider Acceptability of Intermittent Screening and Treatment and Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine to Prevent Malaria in Pregnancy in Western Kenya. AB - BACKGROUND: The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) alongside long lasting insecticide-treated nets (LLIN) and case management for reducing the risks associated with malaria in pregnancy in areas of moderate-to-high transmission in sub-Saharan Africa. Due to increasing Plasmodium falciparum resistance to SP, the search for alternative drugs or strategies to control malaria in pregnancy is a priority. We assessed the acceptability among pregnant women and health providers of intermittent screening and treatment (ISTp) and IPTp with dihydroartemisinin-piperaquine (DP) as alternative strategies in the context of an un-blinded clinical trial. METHODS: Qualitative data were collected through ten focus group discussions with women participating in a randomized controlled trial to evaluate ISTp or IPTp with DP (multi-day regimen) versus IPTp with SP (single dose) in western Kenya. Individual in-depth interviews were conducted with 26 health providers working in the trial facilities and trial staff. RESULTS: Women appreciated the advantages of being tested with a rapid diagnostic test (RDT) at every ANC visit (although a few women disliked finger pricks) and accepted that they would not receive any antimalarial when tested RDT negative. There were differences in women's experiences of the efficacy of antimalarials between the trial arms, with more women in the IPTp-SP arm reporting they had experienced malaria episodes. Side effects were experienced among women taking DP and SP. Although women and trial staff reported adherence to the full DP regimen within the trial, health providers were not confident that women would adhere to multi-day regimens in non-trial settings. Health providers recognized the advantages of ISTp in reducing unnecessary exposure to drugs, but lacked confidence in the reliability of RDTs compared to microscopy. CONCLUSIONS: Our findings indicate that, within a trial context, ISTp-DP and IPTp-DP were generally acceptable among both users and providers and were regarded as potentially valuable alternatives to IPTp-SP. Several challenges were identified the most important of which was concerns with achieving adherence to DP in non trial settings, requiring operational feasibility studies in routine health systems. Policy adoption of ISTp with RDTs would require a major shift in thinking among health providers due to lack of confidence in RDTs. PMID- 26986468 TI - Is Dengue Vector Control Deficient in Effectiveness or Evidence?: Systematic Review and Meta-analysis. AB - BACKGROUND: Although a vaccine could be available as early as 2016, vector control remains the primary approach used to prevent dengue, the most common and widespread arbovirus of humans worldwide. We reviewed the evidence for effectiveness of vector control methods in reducing its transmission. METHODOLOGY/PRINCIPAL FINDINGS: Studies of any design published since 1980 were included if they evaluated method(s) targeting Aedes aegypti or Ae. albopictus for at least 3 months. Primary outcome was dengue incidence. Following Cochrane and PRISMA Group guidelines, database searches yielded 960 reports, and 41 were eligible for inclusion, with 19 providing data for meta-analysis. Study duration ranged from 5 months to 10 years. Studies evaluating multiple tools/approaches (23 records) were more common than single methods, while environmental management was the most common method (19 studies). Only 9/41 reports were randomized controlled trials (RCTs). Two out of 19 studies evaluating dengue incidence were RCTs, and neither reported any statistically significant impact. No RCTs evaluated effectiveness of insecticide space-spraying (fogging) against dengue. Based on meta-analyses, house screening significantly reduced dengue risk, OR 0.22 (95% CI 0.05-0.93, p = 0.04), as did combining community-based environmental management and water container covers, OR 0.22 (95% CI 0.15-0.32, p<0.0001). Indoor residual spraying (IRS) did not impact significantly on infection risk (OR 0.67; 95% CI 0.22-2.11; p = 0.50). Skin repellents, insecticide-treated bed nets or traps had no effect (p>0.5), but insecticide aerosols (OR 2.03; 95% CI 1.44 2.86) and mosquito coils (OR 1.44; 95% CI 1.09-1.91) were associated with higher dengue risk (p = 0.01). Although 23/41 studies examined the impact of insecticide based tools, only 9 evaluated the insecticide susceptibility status of the target vector population during the study. CONCLUSIONS/SIGNIFICANCE: This review and meta-analysis demonstrate the remarkable paucity of reliable evidence for the effectiveness of any dengue vector control method. Standardised studies of higher quality to evaluate and compare methods must be prioritised to optimise cost effective dengue prevention. PMID- 26986475 TI - Inflammation Activation Contributes to Adipokine Imbalance in Patients with Acute Coronary Syndrome. AB - Inflammation can be activated as a defensive response by the attack of acute coronary syndrome (ACS) for ischemic tissue injury. The aim of the present study was to investigate the impact of ACS-activated inflammation on adipokine imbalance and the effects of statins on the crosstalk between inflammation and adipokine imbalance during ACS. In this study, 586 subjects were categorized into: (1) control group; (2) SA (stable angina) group; and (3) ACS group. Circulating levels of hs-CRP, adiponectin and resistin were measured by ELISA. Furthermore, forty C57BL/6 mice were randomized into: sham, AMI, low-statin (atorvastatin, 2 mg/kg/day) and high-statin (atorvastatin, 20 mg/kg/day) group. After 3 weeks, AMI models were established by surgical coronary artery ligation. Circulating levels and adipose expressions of adiponectin and resistin were assessed in animals. Besides, we investigate the effects of atorvastatin on ox LDL-induced adipokine imbalance in vitro. As a result, we found that ACS patients had higher hs-CRP and resistin levels and lower adiponectin levels. Our correlation analysis demonstrated hs-CRP concentrations were positively correlated with resistin but negatively with adiponectin levels in humans. Our animal findings indicated higher circulating hs-CRP and resistin levels and lower adiponectin levels in AMI mice. Atorvastatin pre-treatment dose-dependently decreased hs-CRP and resistin levels but increased adiponectin levels in mice. The consistent findings were observed about the adipose expressions of resistin and adiponectin in mice. In study in vitro, ox-LDL increased cellular resistin expressions and otherwise for adiponectin expressions, which dose-dependently reversed by the addition of atorvastatin. Therefore, our study indicates that the ACS attack activates inflammation leading to adipokine imbalance that can be ameliorated by anti-inflammation of atorvastatin. PMID- 26986476 TI - PTEN enhances G2/M arrest in etoposide-treated MCF-7 cells through activation of the ATM pathway. AB - As an effective tumor suppressor, phosphatase and tensin homolog (PTEN) has attracted the increased attention of scientists. Recent studies have shown that PTEN plays unique roles in the DNA damage response (DDR) and can interact with the Chk1 pathway. However, little is known about how PTEN contributes to DDR through the ATM-Chk2 pathway. It is well-known that etoposide induces G2/M arrest in a variety of cell lines, including MCF-7 cells. The DNA damage-induced G2/M arrest results from the activation of protein kinase ataxia telangiectasia mutated (ATM), followed by the activation of Chk2 that subsequently inactivates CDC25C, resulting in G2/M arrest. In the present study, we assessed the contribution of PTEN to the etoposide-induced G2/M cell cycle arrest. PTEN was knocked down in MCF-7 cells by specific shRNA, and the effects of PTEN on the ATM Chk2 pathway were investigated through various approaches. The results showed that knockdown of PTEN strongly antagonized ATM activation in response to etoposide treatment, and thereby reduced the phosphorylation level of ATM substrates, including H2AX, P53 and Chk2. Furthermore, depletion of PTEN reduced the etoposide-induced phosphorylation of CDC25C and strikingly compromised etoposide-induced G2/M arrest in the MCF-7 cells. Altogether, we demonstrated that PTEN plays a unique role in etoposide-induced G2/M arrest by facilitating the activation of the ATM pathway, and PTEN was required for the proper activation of checkpoints in response to DNA damage in MCF-7 cells. PMID- 26986477 TI - Bioinspired, Highly Stretchable, and Conductive Dry Adhesives Based on 1D-2D Hybrid Carbon Nanocomposites for All-in-One ECG Electrodes. AB - Here we propose a concept of conductive dry adhesives (CDA) combining a gecko inspired hierarchical structure and an elastomeric carbon nanocomposite. To complement the poor electrical percolation of 1D carbon nanotube (CNT) networks in an elastomeric matrix at a low filler content (~1 wt %), a higher dimensional carbon material (i.e., carbon black, nanographite, and graphene nanopowder) is added into the mixture as an aid filler. The co-doped graphene and CNT in the composite show the lowest volume resistance (~100 ohm.cm) at an optimized filler ratio (1:9, total filler content: 1 wt %) through a synergetic effect in electrical percolation. With an optimized conductive elastomer, gecko-inspired high-aspect-ratio (>3) microstructures over a large area (~4 in.(2)) are successfully replicated from intaglio-patterned molds without collapse. The resultant CDA pad shows a high normal adhesion force (~1.3 N/cm(2)) even on rough human skin and an excellent cycling property for repeatable use over 30 times without degradation of adhesion force, which cannot be achieved by commercial wet adhesives. The body-attachable CDA can be used as a metal-free, all-in-one component for measuring biosignals under daily activity conditions (i.e., underwater, movements) because of its superior conformality and water-repellent characteristic. PMID- 26986474 TI - Rosuvastatin Treatment Affects Both Basal and Glucose-Induced Insulin Secretion in INS-1 832/13 Cells. AB - Rosuvastatin is a member of the statin family. Like the other statins it is prescribed to lower cholesterol levels and thereby reduce the risk of cardiovascular events. Rosuvastatin lowers the cholesterol levels by inhibiting the key enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) in the cholesterol producing mevalonate pathway. It has been recognized that apart from their beneficial lipid lowering effects, statins also exhibit diabetogenic properties. The molecular mechanisms behind these remain unresolved. To investigate the effects of rosuvastatin on insulin secretion, we treated INS-1 832/13 cells with varying doses (20 nM to 20 MUM) of rosuvastatin for 48 h. At concentrations of 2 MUM and above basal insulin secretion was significantly increased. Using diazoxide we could determine that rosuvastatin did not increase basal insulin secretion by corrupting the KATP channels. Glucose-induced insulin secretion on the other hand seemed to be affected differently at different rosuvastatin concentrations. Rosuvastatin treatment (20 MUM) for 24-48 h inhibited voltage-gated Ca(2+) channels, which lead to reduced depolarization induced exocytosis of insulin-containing granules. At lower concentrations of rosuvastatin (<= 2 MUM) the stimulus-secretion coupling pathway was intact downstream of the KATP channels as assessed by the patch clamp technique. However, a reduction in glucose-induced insulin secretion could be observed with rosuvastatin concentrations as low as 200 nM. The inhibitory effects of rosuvastatin on glucose-induced insulin secretion could be reversed with mevalonate, but not squalene, indicating that rosuvastatin affects insulin secretion through its effects on the mevalonate pathway, but not through the reduction of cholesterol biosynthesis. Taken together, these data suggest that rosuvastatin has the potential to increase basal insulin secretion and reduce glucose-induced insulin secretion. The latter is possibly an unavoidable side effect of rosuvastatin treatment as it occurs through the same mechanisms as the lipid-lowering effects of the drug. PMID- 26986478 TI - Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans. AB - Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers), amlodipine (AML), nifedipine (NIF), benidipine (BEN) and flunarizine (FNZ) with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1) expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI) <0.5, but no interaction against sensitive strains (FICI = 0.56 ~ 2). The mechanism studies revealed that fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin) and YVC1 (encoding calcium channel protein in vacuole membrane). PMID- 26986479 TI - A Next-Generation Sequencing Data Analysis Pipeline for Detecting Unknown Pathogens from Mixed Clinical Samples and Revealing Their Genetic Diversity. AB - Forty-two cytopathic effect (CPE)-positive isolates were collected from 2008 to 2012. All isolates could not be identified for known viral pathogens by routine diagnostic assays. They were pooled into 8 groups of 5-6 isolates to reduce the sequencing cost. Next-generation sequencing (NGS) was conducted for each group of mixed samples, and the proposed data analysis pipeline was used to identify viral pathogens in these mixed samples. Polymerase chain reaction (PCR) or enzyme linked immunosorbent assay (ELISA) was individually conducted for each of these 42 isolates depending on the predicted viral types in each group. Two isolates remained unknown after these tests. Moreover, iteration mapping was implemented for each of these 2 isolates, and predicted human parechovirus (HPeV) in both. In summary, our NGS pipeline detected the following viruses among the 42 isolates: 29 human rhinoviruses (HRVs), 10 HPeVs, 1 human adenovirus (HAdV), 1 echovirus and 1 rotavirus. We then focused on the 10 identified Taiwanese HPeVs because of their reported clinical significance over HRVs. Their genomes were assembled and their genetic diversity was explored. One novel 6-bp deletion was found in one HPeV-1 virus. In terms of nucleotide heterogeneity, 64 genetic variants were detected from these HPeVs using the mapped NGS reads. Most importantly, a recombination event was found between our HPeV-3 and a known HPeV-4 strain in the database. Similar event was detected in the other HPeV-3 strains in the same clade of the phylogenetic tree. These findings demonstrated that the proposed NGS data analysis pipeline identified unknown viruses from the mixed clinical samples, revealed their genetic identity and variants, and characterized their genetic features in terms of viral evolution. PMID- 26986484 TI - Oxidative Dissolution of Silver Nanoparticles by Chlorine: Implications to Silver Nanoparticle Fate and Toxicity. AB - The kinetics of oxidative dissolution of silver nanoparticles (AgNPs) by chlorine is investigated in this work, with results showing that AgNPs are oxidized in the presence of chlorine at a much faster rate than observed in the presence of dioxygen and/or hydrogen peroxide. The oxidation of AgNPs by chlorine occurs in air-saturated solution in stoichiometric amounts with 2 mol of AgNPs oxidized for each mole of chlorine added. Dioxygen plays an important role in OCl(-)-mediated AgNP oxidation, especially at lower OCl(-) concentrations, with the mechanism shifting from stoichiometric oxidation of AgNPs by OCl(-) in the presence of dioxygen to catalytic removal of OCl(-) by AgNPs in the absence of dioxygen. These results suggest that the presence of chlorine will mitigate AgNP toxicity by forming less-reactive AgCl(s) following AgNP oxidation, although the disinfection efficiency of OCl(-) may not be significantly impacted by the presence of AgNPs because a chlorine-containing species is formed on OCl(-) decay that has significant oxidizing capacity. Our results further suggest that the antibacterial efficacy of nanosilver particles embedded on fabrics may be negated when treated with detergents containing strong oxidants, such as chlorine. PMID- 26986483 TI - Immunological Characterization of Plant-Based HIV-1 Gag/Dgp41 Virus-Like Particles. AB - It is widely anticipated that a prophylactic vaccine may be needed to control the HIV/AIDS epidemic worldwide. Despite over two decades of research, a vaccine against HIV-1 remains elusive, although a recent clinical trial has shown promising results. Recent studies have focused on highly conserved domains within HIV-1 such as the membrane proximal external region (MPER) of the envelope glycoprotein, gp41. MPER has been shown to play critical roles in mucosal transmission of HIV-1, though this peptide is poorly immunogenic on its own. Here we provide evidence that plant-produced HIV-1 enveloped virus-like particles (VLPs) consisting of Gag and a deconstructed form of gp41 comprising the MPER, transmembrane, and cytoplasmic domains (Dgp41) provides an effective platform to display MPER for use as an HIV vaccine candidate. Prime-boost strategies combining systemic and mucosal priming with systemic boosting using two different vaccine candidates (VLPs and CTB-MPR--a fusion of MPER and the B-subunit of cholera toxin) were investigated in BALB/c mice. Serum antibody responses against both the Gag and gp41 antigens were elicited when systemically primed with VLPs. These responses could be recalled following systemic boosting with VLPs. In addition, mucosal priming with VLPs allowed for a boosting response against Gag and gp41 when boosted with either candidate. Importantly, the VLPs also induced Gag-specific CD4 and CD8 T-cell responses. This report on the immunogenicity of plant-based Gag/Dgp41 VLPs may represent an important milestone on the road towards a broadly efficacious and inexpensive subunit vaccine against HIV-1. PMID- 26986485 TI - Fibroblast Growth Factor 21 (FGF-21) in Peritoneal Dialysis Patients: Natural History and Metabolic Implications. AB - BACKGROUND: Human fibroblast growth factor 21 (FGF-21) is an endocrine liver hormone that stimulates adipocyte glucose uptake independently of insulin, suppresses hepatic glucose production and is involved in the regulation of body fat. Peritoneal dialysis (PD) patients suffer potential interference with FGF-21 status with as yet unknown repercussions. OBJECTIVES: The aim of this study was to define the natural history of FGF-21 in PD patients, to analyze its relationship with glucose homeostasis parameters and to study the influence of residual renal function and peritoneal functional parameters on FGF-21 levels and their variation over time. METHODS: We studied 48 patients with uremia undergoing PD. Plasma samples were routinely obtained from each patient at baseline and at 1, 2 and 3 years after starting PD therapy. RESULTS: Plasma FGF-21 levels substantially increased over the first year and were maintained at high levels during the remainder of the study period (253 pg/ml (59; 685) at baseline; 582 pg/ml (60.5-949) at first year and 647 pg/ml (120.5-1116.6) at third year) (p<0.01). We found a positive correlation between time on dialysis and FGF-21 levels (p<0.001), and also, those patients with residual renal function (RRF) had significantly lower levels of FGF-21 than those without RRF (rho -0.484, p<0.05). Lastly, there was also a significant association between FGF-21 levels and peritoneal protein losses (PPL), independent of the time on dialysis (rho 0.410, p<0.05). CONCLUSION: Our study shows that FGF-21 plasma levels in incident PD patients significantly increase during the first 3 years. This increment is dependent on or is associated with RRF and PPL (higher levels in patients with lower RRF and higher PPL). FGF-21 might be an important endocrine agent in PD patients and could act as hormonal signaling to maintain glucose homeostasis and prevent potential insulin resistance. These preliminary results suggest that FGF 21 might play a protective role as against the development of insulin resistance over time in patients undergoing a continuous glucose load. PMID- 26986488 TI - Valence-specific emotion transmission: Potential influences on parent-adolescent emotion coregulation. AB - The current study tested if proximal transmission of positive and negative affect occurs bidirectionally between mothers and their adolescent children in valence specific patterns (e.g., maternal positive affect to adolescent positive, but not negative, affect) across a period of 7 minutes and between minutes. Whether adolescent gender moderated transmission effects was also explored. One hundred thirty-5 mothers (29-60 years old) and their children (12-16 years old, 49% female) independently completed questionnaires and then jointly engaged in a naturalistic 7-min problem-solving discussion. Transmission was examined by testing how 1 person's expressed affect (assessed observationally) changed the other person's self-reported state affect across the task. In path analyses, support for bidirectional transmission of negative affect emerged. Transmission was valence-specific, however, evidence for transmission of positive affect was not found. Results also supported cross-valence transmission of negative affect specifically from adolescents to their mothers, such that adolescent expressed negative affect predicted reduced maternal self-reported positive affect. Utilizing cross-lagged path analyses to further examine these findings between minutes revealed that transmission did not occur between specific minutes. Results largely support previous theoretical work on the orthogonal structure of affect and the bidirectionality of parent-adolescent affective interactions. Given this evidence for reciprocal transmission of affect across (not between) minutes in a microsocial context, implications for successful emotion coregulation in parent-adolescent interactions and how these mechanisms may predict long-term outcomes are discussed. (PsycINFO Database Record PMID- 26986487 TI - Long noncoding RNAs related to the odontogenic potential of dental mesenchymal cells in mice. AB - OBJECTIVES: The purpose of this study is to identify the lncRNAs that are associated with the odontogenic potential in mouse dental mesenchymal cells. DESIGN: The odontogenic potential of dental mesenchymal cells was found to be lost in the course of in vitro culture, so the lncRNA profiles were subsequently compared between freshly-isolated and cultured dental mesenchymal cells using RNA sequencing. A co-expression analysis of differentially expressed lncRNAs and coding RNAs was performed to understand their potential functions. The expression of several selected lncRNAs was also examined in developing tooth germs. RESULTS: Compared with cultured dental mesenchymal cells, 108 lncRNAs were upregulated and 36 lncRNAs were downregulated in freshly-isolated dental mesenchymal cells. Coding genes correlated with the lncRNAs were mainly associated with DNA and protein metabolic processes and cytoskeletal anchorage. Meg3, Malat1, Xist, and Dlx1as were significantly downregulated in cultured dental mesenchymal cells but were upregulated in odontogenic dental mesenchymal tissues. Moreover, the levels of Dlx1as were negatively correlated with that of Dlx1 in dental mesenchymal cells and dental mesenchymal tissues. CONCLUSIONS: The lncRNA profiles of dental mesenchymal cells are significantly changed during culturing, and the dysregulation of lncRNAs is associated with the loss of odontogenic potential. PMID- 26986486 TI - beta-COP as a Component of Transport Vesicles for HDL Apolipoprotein-Mediated Cholesterol Exocytosis. AB - OBJECTIVE: HDL and its apolipoproteins protect against atherosclerotic disease partly by removing excess cholesterol from macrophage foam cells. But the underlying mechanisms of cholesterol clearance are still not well defined. We investigated roles of vesicle trafficking of coatomer beta-COP in delivering cholesterol to the cell surface during apoA-1 and apoE-mediated lipid efflux from fibroblasts and THP-1 macrophages. METHODS: shRNA knockout, confocal and electron microscopy and biochemical analysis were used to investigate the roles of beta COP in apolipoprotein-mediated cholesterol efflux in fibroblasts and THP-1 macrophages. RESULTS: We showed that beta-COP knockdown by lentiviral shRNA resulted in reduced apoA-1-mediated cholesterol efflux, while increased cholesterol accumulation and formation of larger vesicles were observed in THP-1 macrophages by laser scanning confocal microscopy. Immunogold electron microscopy showed that beta-COP appeared on the membrane protrusion complexes and colocalized with apoA-1 or apoE during cholesterol efflux. This was associated with releasing heterogeneous sizes of small particles into the culture media of THP-1 macrophage. Western blotting also showed that apoA-1 promotes beta-COP translocation to the cell membrane and secretion into culture media, in which a total of 17 proteins were identified by proteomics. Moreover, beta-COP exclusively associated with human plasma HDL fractions. CONCLUSION: ApoA-1 and apoE promoted transport vesicles consisting of beta-COP and other candidate proteins to exocytose cholesterol, forming the protrusion complexes on cell surface, which were then released from the cell membrane as small particles to media. PMID- 26986489 TI - Expression Profiles of Endometrial Carcinoma by Integrative Analysis of TCGA Data. AB - BACKGROUND: This study was to explore the expression profile of endometrial carcinoma (EC) and identify the potential molecular mechanism and therapeutic targets. METHODS: Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified in EC using mRNA and miRNA sequencing data released by the Cancer Genome Atlas database; then, gene function and pathway of DEGs were analyzed based on the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway databases; finally, the transcription factors (TFs) latently regulating the DEGs and DEMs were predicted and a TF-miRNA-Gene network was then established to summarize the regulatory links between TFs, DEMs and DEGs. RESULTS: One thousand five hundred and forty two upregulated and 1,885 downregulated DEGs, 34 upregulated and 12 downregulated DEMs were identified. The principal DEGs-enriched functions were cell differentiation, cell migration, and cell surface receptor signaling pathway. The DEGs-enriched cell signaling pathways including the MAPK, Wnt signaling pathway, and the p53 signaling pathway. As shown in the TF-miRNA-Gene network, TFs such as CPBP and GKLF, miRNAs such as miR-141-3p and miR-130b-3p, regulated most of DEGs and DEMs. CONCLUSION: These results may contribute to the study of the molecular mechanism and therapeutic targets in EC, and facilitate the discovery of new biomarkers for screening, diagnosis and monitoring. PMID- 26986490 TI - The Role of Adjuvant Radiation Therapy for Locoregionally Advanced Papillary Thyroid Carcinoma. AB - OBJECTIVES: To investigate the role of adjuvant radiation therapy in locoregional control in patients with locoregionally advanced papillary thyroid carcinoma (pT4 or pN1b) based on a comparison of a group that received radiation therapy and a group that did not receive radiation therapy. METHODS: A retrospective analysis was performed on 165 patients with locoregionally advanced papillary thyroid carcinoma who underwent treatment between 2002 and 2011. Of these, 32 patients received adjuvant radiation therapy, and 133 patients did not receive radiation therapy. RESULTS: The median follow-up period was 7.2 years (range, 3.4-13.6) for the overall study population. The 10-year locoregional recurrence-free survival rates for patients in the radiation therapy and no radiation therapy groups were 83.9 and 60.8%, respectively (p = 0.037). The overall survival rate and distant recurrence-free survival rate were not different between the two groups (p = 0.076 and p = 0.813, respectively). Multivariate analysis showed that adjuvant radiation therapy was an independent prognostic factor for locoregional recurrence-free survival (p = 0.040). CONCLUSIONS: Adjuvant radiation therapy for patients with either pT4 or pN1b disease improved locoregional recurrence-free survival and might be of benefit for patients with these high-risk features by reducing the need for additional salvage treatment after locoregional recurrence. PMID- 26986491 TI - New clues on carcinogenicity-related substructures derived from mining two large datasets of chemical compounds. AB - In this study, new molecular fragments associated with genotoxic and nongenotoxic carcinogens are introduced to estimate the carcinogenic potential of compounds. Two rule-based carcinogenesis models were developed with the aid of SARpy: model R (from rodents' experimental data) and model E (from human carcinogenicity data). Structural alert extraction method of SARpy uses a completely automated and unbiased manner with statistical significance. The carcinogenicity models developed in this study are collections of carcinogenic potential fragments that were extracted from two carcinogenicity databases: the ANTARES carcinogenicity dataset with information from bioassay on rats and the combination of ISSCAN and CGX datasets, which take into accounts human-based assessment. The performance of these two models was evaluated in terms of cross-validation and external validation using a 258 compound case study dataset. Combining R and H predictions and scoring a positive or negative result when both models are concordant on a prediction, increased accuracy to 72% and specificity to 79% on the external test set. The carcinogenic fragments present in the two models were compared and analyzed from the point of view of chemical class. The results of this study show that the developed rule sets will be a useful tool to identify some new structural alerts of carcinogenicity and provide effective information on the molecular structures of carcinogenic chemicals. PMID- 26986493 TI - The adiabatic strictly-correlated-electrons functional: kernel and exact properties. AB - We investigate a number of formal properties of the adiabatic strictly-correlated electrons (SCE) functional, relevant for time-dependent potentials and for kernels in linear response time-dependent density functional theory. Among the former, we focus on the compliance to constraints of exact many-body theories, such as the generalised translational invariance and the zero-force theorem. Within the latter, we derive an analytical expression for the adiabatic SCE Hartree exchange-correlation kernel in one dimensional systems, and we compute it numerically for a variety of model densities. We analyse the non-local features of this kernel, particularly the ones that are relevant in tackling problems where kernels derived from local or semi-local functionals are known to fail. PMID- 26986492 TI - Rubus coreanus Miquel extract causes apoptosis of doxorubicin-resistant NCI/ADR RES ovarian cancer cells via JNK phosphorylation. AB - Cancer cells can acquire an anticancer, drug-resistant phenotype following chemotherapy, which is tightly linked to cancer malignancy and patient survival rates. Therefore, the identification of options to treat chemotherapy-resistant cancer cells is an urgent requirement. Rubus coreanus Miquel (RCM) has long been used as a source of food. In addition, it has been reported that RCM has effective functions against particular diseases, including cancer and inflammation. In the present study, it was demonstrated that RCM extract caused the apoptotic cell death of doxorubicin-resistant NCI/ADR-RES ovarian cancer cells by phosphorylating c-Jun N-terminal kinase (JNK). The RCM-mediated reduction of cell viability showed no synergism with doxorubicin. In addition, ellagic acid and quercetin, which are phytochemicals found in RCM, also caused apoptosis of the NCI/ADR-RES cells. In subsequent investigations of the RCM altered signaling pathway, RCM extract, ellagic acid and quercetin were found to commonly induce the phosphorylation of JNK and AKT. Additionally, the inhibition of JNK with SP600125 repressed the apoptotic cell death induced by RCM extract, ellagic acid and quercetin, and the inhibition of JNK appeared to switch apoptosis to necrosis. JNK inhibition also reduced the phosphorylation of AKT, which was induced by RCM extract, ellagic acid and quercetin, suggesting that the phosphorylation of JNK is required for AKT phosphorylation in RCM-, ellagic acid- or quercetin-induced apoptotic cell death. Therefore, the data obtained in the present study led to the conclusion that RCM caused apoptosis of doxorubicin resistant NCI/ADR-RES ovarian cancer cells via JNK phosphorylation, and suggested that RCM may be effective in the treatment of chemotherapy-resistant cancer cells. PMID- 26986494 TI - In situ generated polysiloxanes stabilizing MU3-oxo bridged Sb3 triangles. AB - The reaction of RSbO3H2 with t-butylsilanetriol has led to the isolation of organoantimony(v) based molecular triangles stabilized by siloxane frameworks. Depending on the reaction conditions employed or the substituents present on the antimony atom, either a combination of a disiloxane and a tetrasiloxane framework or a trisiloxane framework was generated in situ leading to the stabilization of the Sb3 triangle. PMID- 26986495 TI - Lab-scale demonstration of recuperative thickening technology for enhanced biogas production and dewaterability in anaerobic digestion processes. AB - There is growing interest in the use of high performance anaerobic digestion (AD) processes for the production of biogas at wastewater treatment facilities to offset the energy demands associated with wastewater treatment. Recuperative thickening (RT) is a promising technique which involves recycling a portion of the digested solids back to the incoming feed. In general there exists a significant number of knowledge gaps in the field of RT because the studies that have been conducted to date have almost exclusively occurred in pilot plant or full scale trials; this approach greatly limits the amount of process optimization that can be done in a given trial. In this work, a detailed and comprehensive study of RT was conducted at the lab scale; two custom designed digesters (capacity = 1.5 L) were operated in parallel with one acting as a 'control' digester and the other operating under a semi-batch RT mode. There was no significant change in biogas methane composition for the two digesters, however the RT digester had an average biogas productivity over two times higher than the control one. It was found that the recycling of the polymer flocculant back into the RT digester resulted in a significant improvement in dewatering performance. At the highest polymer concentration tested, the capillary suction time (CST) values for flocculated samples for the RT digester were over 6 times lower than the corresponding values for the control digester. Thus, there exists an opportunity to decrease the overall consumption of polymer flocculants through judicious selection of the dose of polymer flocculant that is used both for the thickening and end-stage dewatering steps in RT processes. PMID- 26986496 TI - Nitrification at different salinities: Biofilm community composition and physiological plasticity. AB - This paper describes an experimental study of microbial communities of three moving bed biofilm reactors (MBBR) inoculated with nitrifying cultures originated from environments with different salinity; freshwater, brackish (200/00) and seawater. All reactors were run until they operated at a conversion efficiency of >96%. The microbial communities were profiled using 454-pyrosequencing of 16S rRNA gene amplicons. Statistical analysis was used to investigate the differences in microbial community structure and distribution of the nitrifying populations with different salinity environments. Nonmetric multidimensional scaling analysis (NMDS) and the PERMANOVA test based on Bray-Curtis similarities revealed significantly different community structure in the three reactors. The brackish reactor showed lower diversity index than fresh and seawater reactors. Venn diagram showed that 60 and 78% of the total operational taxonomic units (OTUs) in the ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB) guild, respectively, were unique OTUs for a given reactor. Similarity Percentages (SIMPER) analysis showed that two-thirds of the total difference in community structure between the reactors was explained by 10 OTUs, indicating that only a small number of OTUs play a numerically dominant role in the nitrification process. Acute toxicity of salt stress on ammonium and nitrite oxidizing activities showed distinctly different patterns, reaching 97% inhibition of the freshwater reactor for ammonium oxidation rate. In the brackish culture, inhibition was only observed at maximal level of salinity, 320/00. In the fully adapted seawater culture, higher activities were observed at 320/00 than at any of the lower salinities. PMID- 26986497 TI - A review on chitosan-based flocculants and their applications in water treatment. AB - In recent years, the use of chitosan and its derivatives as flocculants in water treatment has received considerable attention due to their many advantages, including their widespread availability, environmental friendliness, biodegradability, and prominent structural features. However, it is a significant strategy for selection and design of the high-performance materials on the basis of their structure-activity relationships. Here we describe several of the chemical modification methods commonly used to prepare chitosan-based flocculants. These methods allow convenient control and adjustment of the structures of the obtained materials to meet the different practical requirements. The influence of structural elements of the chitosan-based flocculants on their flocculation properties are emphasized in this review by examining different flocculation mechanisms and their applications in the treatment of various wastewaters containing different pollutants (insoluble suspended colloids but also dissolved matters). Above all, the chitosan-based flocculants with proper structures by precise structure control bear great application potentials in water treatment. PMID- 26986498 TI - Effect of climate change on runoff of Campylobacter and Cryptosporidium from land to surface water. AB - Faeces originating from wildlife, domestic animals or manure-fertilized fields, is considered an important source of zoonotic pathogens to which people may be exposed by, for instance, bathing or drinking-water consumption. An increase in runoff, and associated wash-off of animal faeces from fields, is assumed to contribute to the increase of disease outbreaks during periods of high precipitation. Climate change is expected to increase winter precipitation and extreme precipitation events during summer, but has simultaneously also other effects such as temperature rise and changes in evapotranspiration. The question is to what extent the combination of these effects influence the input of zoonotic pathogens to the surface waters. To quantitatively analyse the impacts of climate change on pathogen runoff, pathogen concentrations reaching surface waters through runoff were calculated by combining an input model for catchment pathogen loads with the Wageningen Lowland Runoff Simulator (WALRUS). Runoff of Cryptosporidium and Campylobacter was evaluated under different climate change scenarios and by applying different scenarios for sources of faecal pollution in the catchments, namely dairy cows and geese and manure fertilization. Model evaluation of these scenarios shows that climate change has little overall impact on runoff of Campylobacter and Cryptosporidium from land to the surface waters. Even though individual processes like runoff fluxes, pathogen release and dilution are affected, either positively or negatively, the net effect on the pathogen concentration in surface waters and consequently also on infection risks through recreation seems limited. PMID- 26986499 TI - Efficacy of carbonaceous nanocomposites for sorbing ionizable antibiotic sulfamethazine from aqueous solution. AB - This paper investigated the key factors and mechanisms of sulfamethazine (SMT) sorption on a novel carbonaceous nanocomposite, and the effects of harsh aging on SMT sorption in the presence and absence of soil and before as well as after aging. The carbonaceous nanocomposites were synthesized by dip-coating straw biomass in carboxyl functionalized multi-walled carbon nanotubes solution and then pyrolyzed at 300 degrees C and 600 degrees C in the absence of air. The sorption performance of high temperature carbonaceous nanocomposite on SMT was excellent, as measured sorption distribution coefficient in the order of 10(3) 10(5.5) L kg(-1). Carbonaceous nanocomposites were aged either alone or mixed with soil via exposure to nutrients and soil extract (biological aging) or 80 degrees C for 100 d (chemical aging). No obvious effects of harsh aging on SMT sorption were observed in the presence of soil and/or biological and chemical aging. The primary mechanisms for SMT sorption included partition caused by Van der Waals forces and adsorption caused by hydrogen bonding and pi-pi electron donor-acceptor interaction. Comprehensively considering the cost, renewability, and the application to real water samples, the carbonaceous nanocomposites have potential in removal of SMT and possibly other persistent organic pollutants from wastewater. PMID- 26986500 TI - Continuous-release beads of natural allelochemicals for the long-term control of cyanobacterial growth: Preparation, release dynamics and inhibitory effects. AB - The effects of allelochemicals on cyanobacterial blooms have been observed for more than 20 years; however, the use of these compounds, usually involving a "direct-added" mode, has clear disadvantages, such as a short activity period or temporarily excessive localized concentration. Here, a simulated-allelopathy mode to facilitate the application of allelochemicals was proposed and tested on Microcystis aeruginosa. The continuous-release beads of 5,4'-dihydroxyflavone (DHF) were constitutive of a polymer matrix and showed a high drug-loading rate (47.18%) and encapsulation efficiency (67.65%) with a theoretical release time of approximately 120 d. Cyanobacterial growth tests showed that the DHF beads had long-term inhibition effects (>30 d), whereas those of "direct-added" DHF to cells lasted a maximum of 10 d. The beads also continuously affected the superoxide dismutase, catalase, and lipid peroxidation of M. aeruginosa. The inhibitory effects of DHF beads on cyanobacterial growth increased as initial cell densities of M. aeruginosa decreased, suggesting that the beads inhibit cyanobacterial activity more effectively in the early bloom phase. Consequently, the anti-cyanobacterial beads represent a novel application mode of allelochemicals with long-term inhibitory effects on cyanobacterial growth. Our study demonstrates that the successful application of allelochemicals offers great potential to control harmful cyanobacterial blooms, especially at the initial stage of development. PMID- 26986501 TI - Roles of iron species and pH optimization on sewage sludge conditioning with Fenton's reagent and lime. AB - Conditioning sewage sludge with Fenton's reagent could effectively improve its dewaterability. However, drawbacks of conditioning with Fenton's reagent are requirement of acidic conditions to prevent iron precipitation and subsequent neutralization with alkaline additive to obtain the pH of the filtrate close to neutrality. In this study, roles of pH were thoroughly investigated in the acidification pretreatment, Fenton reaction, and the final filtrate after conditioning. Through the response surface methodology (RSM), the optimal dosages of H2SO4, Fe(2+), H2O2, and lime acted as a neutralizer were found to be 0 (no acidification), 47.9, 34.3 and 43.2 mg/g DS (dry solids). With those optimal doses, water content of the dewatered sludge cakes could be reduced to 55.8 +/- 0.6 wt%, and pH of the final filtrate was 6.6 +/- 0.2. Fenton conditioning without initial acidification can simplify the conditioning process and reduce the usage of lime. The Fe(3+) content in the sludge cakes showed a close correlation with the dewaterability of conditioned sludge, i.e., the water content of sludge cakes, SRF (specific resistance to filtration), CST (capillary suction time), bound water content, and specific surface area. It indicated that the coagulation by Fe(3+) species in Fenton reaction could play an important role, compared to traditional Fenton oxidation effect on sludge conditioning. Thus, a two-step mechanism of Fenton oxidation and Fe(III) coagulation was proposed in sewage sludge conditioning. The mechanisms include the following: (1) extracellular polymeric substances (EPS) were firstly degraded into dissolved organics by Fenton oxidation; (2) bound water was converted to free water due to degradation of EPS; (3) the sludge particles were disintegrated into small ones by oxidation; (4) Fe(3+) generated from Fenton reaction acted as a coagulant to agglomerate smaller sludge particles into larger dense particles with less bond water; (5) finally, the dewatered sludge cakes were obtained, with less small pores (1-10 nm) that contributed to water affinity, but with more large pores (>10 nm) that contributed to a permeable, rigid lattice structure. Morphology of the Fenton-conditioned sludge cake exhibited a porous structure. The estimated cost of the composite conditioner, Fenton's reagent and lime, is USD$ 43.8/t DS, which is less than that of ferric chloride and lime (USD$ 54/t DS). Furthermore, pH of the final filtrate using this composite conditioner is about 6.6. Comparatively, that using ferric chloride and lime is as high as 12.4. PMID- 26986502 TI - Optimization of a cationic liposome-based gene delivery system for the application of miR-145 in anticancer therapeutics. AB - In order to improve the delivery efficiency of microRNA (miRNA or miR)-145, the present study examined several factors which may affect cationic liposome (CL) based transfection, including the hydration medium used for the preparation of liposomes, the quantity of the plasmid, the molar ratio of N-[1-(2,3 dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTAP)/cholesterol (chol), or DOTAP/chol, and the weight ratio of DOTAP/DNA. In order to enhance the transfection efficiency, protamine was selected as a DNA-condensing agent to form liposome-protamine-DNA (LPD) ternary complexes. An agarose gel retardation assay was used to examine the DNA binding affinity of the CLs. Following transfection, GFP fluorescence images were captured and flow cytometry was performed to determine the transfection efficiency. Furthermore, an MTT assay was performed to determine the cytotoxicity of the liposome complexes. The final optimal conditions were as follows: 5% glucose as the hydration medium, a molar ratio of DOTAP/chol at 3:1 for the preparation of CLs, a weight ratio of DOTAP/protamine/DNA of 3:0.5:1, with 8 ug plasmid added for the preparation of the LPD complexes. In vitro, the LPD complexes exhibited an enhanced transfection efficiency and low cytotoxicity, which indicated that the presented LPD vector enhanced the transfection efficiency of the CLs. The HepG2 cells were found to have the lowest expression levels of miR-145 out of the cell lines tested (A549, BGC-823, HepG2, HeLa, LoVo and MCF-7). Following the transient transfection of the HepG2 cells with miR-145, the results revealed that the overexpression of miR 145 inhibited the proliferation of the HepG2 cells and downregulated the expression of cyclin-dependent kinase 6 (CDK6), cyclinD1, c-myc, and Sp1 transcription factor (Sp1). In conclusion, in this study, we optimized a liposome based delivery system for the efficient delivery of miR-145 into cancer cells. This may provide a foundation for further research into the use of miR-145 in anticancer therapeutics. PMID- 26986503 TI - BLCAP arrests G1/S checkpoint and induces apoptosis through downregulation of pRb1 in HeLa cells. AB - BLCAP (bladder cancer-associated protein) gene exhibited tumor suppressor function in different tumors and is regarded as a candidate tumor suppressor gene; however, the mechanism by which BLCAP exerts its function remains elusive. This study investigated the functional association between BLCAP and proliferation or apoptosis in cervical cancer cells, to identify the functional motifs of BLCAP. The BLCAP-shRNA expression vector based on pRNA-U6.1/Hygro plasmid was used to specifically inhibit BLCAP activity in HeLa cells. The optimal shRNA plasmid was selected to knock down BLCAP expression and the biological effects were investigated. The effects on cell cycle and apoptosis were detected by flow cytometric or Annexin V-FITC staining analysis. The gene expression profiles of HeLa cells transfected with blcap-wt and BLCAP-shRNA were analyzed using human signal pathway gene Oligochips. The levels of protein expression and interaction of BLCAP with Rb1 proteins were determined by western blotting and Co-IP assays. The site-specific mutagenesis assay was used to identify amino acid residues important for BLCAP. Significantly differentially expressed genes were found by gene Oligo chips analysis. These genes were all correlated with proliferation, cell cycle and apoptosis. The results of western blotting and Co-IP assays confirmed that overexpression of BLCAP could interact with Rb1 and inhibit Rb1 phosphorylation. Further investigation revealed that SAXX mutation in the key regions of BLCAP suppressed the function of BLCAP and significantly increased the level of phosphorylated Rb1 protein. Here our findings suggested that the functional association of BLCAP and Rb1 might play important roles in proliferation and apoptosis of HeLa cells. It suggested that BLCAP could be a novel therapeutic target for cervical cancer. PMID- 26986504 TI - [Metastatic epiduritis in neurosurgery: Hospital data from the Abidjan teaching hospital, 2007-2012]. AB - INTRODUCTION: Metastatic epiduritis is the most frequent extrinsic epidural cause of spinal cord compression. Although neurosurgery is essential to its management, the exact role of this discipline in the treatment of spinal cancer in sub Saharan Africa has not yet been assessed. AIM: To analyze recent hospital data of patients with metastatic epiduritis managed in the Abidjan neurosurgery department. METHODOLOGY: We conducted a retrospective analysis of files of 56 patients admitted from January 2007 through December 2012. Our data are discussed in the light of the literature. RESULTS: The primary cancers in men were mostly lung (16%) and prostate (34%) cancers, and in women, breast cancer (23%). The two age brackets mainly involved were those aged 31-45 years (21%) and 46-60 years (39%). The reason for admission in all cases was functional disability of the lower limbs. Magnetic resonance imaging (MRI) was performed for 57%. The thoracic topography was dominant (60%), and vertebral damage was often associated with epiduritis (78%). This metastatic epiduritis was the initial sign leading to cancer diagnosis for 39%. Decompressive laminectomy with biopsy or lesionectomy was performed for 62%. Postoperative neurologic improvement was noted for 36%, and remained satisfactory at one year for 14 patients. Prostate-specific hormone therapy was performed for 30%. CONCLUSION: This study underlines the crucial importance of neurosurgery in management of metastatic epiduritis in our center. Our findings emphasize the need to improve access to neuroradiologic diagnostic resources and optimize surgical treatment in the sub-Saharan region. PMID- 26986505 TI - Sensitive liquid chromatography/tandem mass spectrometry method for the simultaneous determination of nine local anesthetic drugs. AB - A high-performance liquid chromatography-tandem mass spectrometry (LC/MS/MS) with electrospray ionization (ESI) procedure for the simultaneous determination of nine local anesthetic drugs (procaine, mepivacaine, lidocaine, ropivacaine, oxybuprocaine, tetracaine, bupivacaine, T-caine and dibucaine) in human serum is described. The chromatographic separation was performed on a Mightysil-RP-18 GP II column (2.0mm*150mm, particle size 5MUm). The mobile phase consisted of 10mM acetic ammonium buffer (pH 5.4) and acetonitrile and was delivered at a flow rate of 0.20mL/min. The triple quadrupole mass spectrometer was operated in positive ion mode, and multiple reaction monitoring was used for drug quantification. Solid-phase extraction of the nine local anesthetic drugs added to the human serum was performed with an Oasis((r)) HLB extraction cartridges column. The method was linear for the investigated drugs over the concentration range of 10 100ng/mL. The recoveries of these drugs were in the range of 81.4-144%. The standard deviation (SD) values for all analytes were <0.10 for both intraday and interday accuracy and precision. The selectivity, accuracy and precision of this method are satisfactory for clinical and forensic applications. The sensitive and selective method offers the opportunity for the simultaneous screening and quantification, for clinical and forensic purposes, of almost all local anesthetics available in Japan. PMID- 26986506 TI - Shaping prestimulus neural activity with auditory rhythmic stimulation improves the temporal allocation of attention. AB - Human attention fluctuates across time, and even when stimuli have identical physical characteristics and the task demands are the same, relevant information is sometimes consciously perceived and at other times not. A typical example of this phenomenon is the attentional blink, where participants show a robust deficit in reporting the second of two targets (T2) in a rapid serial visual presentation (RSVP) stream. Previous electroencephalographical (EEG) studies showed that neural correlates of correct T2 report are not limited to the RSVP period, but extend before visual stimulation begins. In particular, reduced oscillatory neural activity in the alpha band (8-12 Hz) before the onset of the RSVP has been linked to lower T2 accuracy. We therefore examined whether auditory rhythmic stimuli presented at a rate of 10 Hz (within the alpha band) could increase oscillatory alpha-band activity and improve T2 performance in the attentional blink time window. Behaviourally, the auditory rhythmic stimulation worked to enhance T2 accuracy. This enhanced perception was associated with increases in the posterior T2-evoked N2 component of the event-related potentials and this effect was observed selectively at lag 3. Frontal and posterior oscillatory alpha-band activity was also enhanced during auditory stimulation in the pre-RSVP period and positively correlated with T2 accuracy. These findings suggest that ongoing fluctuations can be shaped by sensorial events to improve the allocation of attention in time. PMID- 26986507 TI - MiR-218 impedes IL-6-induced prostate cancer cell proliferation and invasion via suppression of LGR4 expression. AB - Prostate cancer is the most common solid-organ malignancy and the second leading cause of cancer-related death in males. The oncogenic effect of leucine-rich repeat-containing G protein-coupled receptor (LGR) 4 has been recognized in the formation of various types of cancers, yet its regulatory mechanism in prostate cancer is still not fully understood. Previous study has shown that LGR4 may be a new responsive gene of interleukin-6 (IL-6) in cancer progression. In the present study, we established the LNCaP-IL-6+ cell subline by long-term incubation with a low concentration of IL-6 and explored the regulatory role of miR-218, a tumor suppressing miRNA, in IL-6-induced LGR4 expression and LNCaP-IL-6+ cell proliferation and invasion. The results showed that miR-218 expression was gradually decreased and IL-6 expression was gradually increased in the process of prostate cancer progression from normal prostate, benign prostatic hyperplasia to prostate cancer, and from LNCaP to LNCaP-IL-6+ cells. Notably, we also found that miR-218 inhibited the expression of cell cycle regulatory protein cyclin A1 and invasion-related matrix metalloproteinase-9 protein induced by IL-6, and impeded the accelerative effect of IL-6 on LNCaP-IL-6+ cell proliferation, cell cycle progression and cell invasion. Moreover, our results confirmed that miR-218 directly targets LGR4 and modulated the PI3K/Akt and Wnt/beta-catenin pathways in the LNCaP-IL-6+ cells. Taken together, these data clearly demonstrated the involvement of the miR-218/LGR4 regulatory pathway in IL-6-induced cell proliferation and invasion in LNCaP-IL-6+ cells via PI3K/Akt and Wnt/beta-catenin signaling, providing new insight into therapeutics for inflammation-induced prostate cancer. PMID- 26986508 TI - Toll-like receptors in the pathogenesis of chemotherapy-induced gastrointestinal toxicity. AB - PURPOSE OF REVIEW: Intestinal mucositis represents a common complication and dose limiting toxicity of cancer chemotherapy. So far chemotherapy-induced intestinal mucositis remains poorly treatable resulting in significant morbidity and reduced quality of life in cancer patients. This review discusses recent insights into the pathophysiology of chemotherapy-induced intestinal mucositis. Novel mechanisms linking gut microbiota, host innate immunity and anticancer drug metabolism are highlighted. RECENT FINDINGS: Gut microbiota may affect xenobiotic metabolism by direct and indirect mechanisms, critically modulating gut toxicity of chemotherapy drugs. Composition and metabolic function of the gut microbiome as well as innate immune responses of the intestinal mucosa are severely altered during chemotherapy. Commensal-mediated innate immune signaling via Toll-like receptors (TLRs) ambiguously shapes chemotherapy-induced genotoxic damage in the gastrointestinal tract. TLR2 may accelerate host detoxification by activating the multidrug transporter ATP-binding cassette 1 (ABCB1)/MDR1 P-glycoprotein to efflux harmful drugs, thus controlling the severity of cancer therapy-induced mucosal damage in the gastrointestinal tract. In contrast, selective chemotherapy drugs may drive LPS hyperresponsiveness via TLR4, which exacerbates mucosal injury through aberrant cytokine storms. Broad-spectrum antibiotic treatment does not seem to represent a valid therapeutic option, as drastic reduction in global gut microbiota may enhance risk of gastrointestinal toxicity and reduce efficacy of some chemotherapy drugs, at least in murine models. SUMMARY: Several variables (environment, metabolism, dysbiosis, infections and/or genetics) influence the outcome of mucosal TLR signaling during cancer treatment. Differences in innate immune responses also reflect chemotherapy drug-specific effects. Future studies must investigate in more detail whether manipulating the delicate balance between gut microbiota and host immune responses by either monotherapy or combinations of different TLR agonists and antagonists may be indeed useful to limit the toxic side-effects of complex chemotherapy regimens, accelerate mucosal tissue regeneration and improve the anticancer treatment response. PMID- 26986509 TI - Adipogenic placenta-derived mesenchymal stem cells are not lineage restricted by withdrawing extrinsic factors: developing a novel visual angle in stem cell biology. AB - Current evidence implies that differentiated bone marrow mesenchymal stem cells (BMMSCs) can act as progenitor cells and transdifferentiate across lineage boundaries. However, whether this unrestricted lineage has specificities depending on the stem cell type is unknown. Placental-derived mesenchymal stem cells (PDMSCs), an easily accessible and less invasive source, are extremely useful materials in current stem cell therapies. No studies have comprehensively analyzed the transition in morphology, surface antigens, metabolism and multilineage potency of differentiated PDMSCs after their dedifferentiation. In this study, we showed that after withdrawing extrinsic factors, adipogenic PDMSCs reverted to a primitive cell population and retained stem cell characteristics. The mitochondrial network during differentiation and dedifferentiation may serve as a marker of absent or acquired pluripotency in various stem cell models. The new population proliferated faster than unmanipulated PDMSCs and could be differentiated into adipocytes, osteocytes and hepatocytes. The cell adhesion molecules (CAMs) signaling pathway and extracellular matrix (ECM) components modulate cell behavior and enable the cells to proliferate or differentiate during the differentiation, dedifferentiation and redifferentiation processes in our study. These observations indicate that the dedifferentiated PDMSCs are distinguishable from the original PDMSCs and may serve as a novel source in stem cell biology and cell-based therapeutic strategies. Furthermore, whether PDMSCs differentiated into other lineages can be dedifferentiated to a primitive cell population needs to be investigated. PMID- 26986510 TI - Cdc42 deficiency induces podocyte apoptosis by inhibiting the Nwasp/stress fibers/YAP pathway. AB - Podocyte apoptosis is a major mechanism that leads to proteinuria in many chronic kidney diseases. However, the concert mechanisms that cause podocyte apoptosis in these kidney diseases are not fully understood. The Rho family of small GTPases has been shown to be required in maintaining podocyte structure and function. Recent studies have indicated that podocyte-specific deletion of Cdc42 in vivo, but not of RhoA or Rac1, leads to congenital nephrotic syndrome and glomerulosclerosis. However, the underlying cellular events in podocyte controlled by Cdc42 remain unclear. Here, we assessed the cellular mechanisms by which Cdc42 regulates podocyte apoptosis. We found that the expression of Cdc42 and its activity were significantly decreased in high glucose-, lipopolysaccharide- or adriamycin-injured podocytes. Reduced Cdc42 expression in vitro and in vivo by small interfering RNA and selective Cdc42 inhibitor ML-141, respectively, caused podocyte apoptosis and proteinuria. Our results further demonstrated that insufficient Cdc42 or Nwasp, its downstream effector, could decrease the mRNA and protein expression of YAP, which had been regarded as an anti-apoptosis protein in podocyte. Moreover, our data indicated that the loss of stress fibers caused by Cdc42/Nwasp deficiency also decreased Yes-associated protein (YAP) mRNA and protein expression, and induced podocyte apoptosis. Podocyte apoptosis induced by Cdc42/Nwasp/stress fiber deficiency was significantly inhibited by overexpressing-active YAP. Thus, the Cdc42/Nwasp/stress fibers/YAP signal pathway may potentially play an important role in regulating podocyte apoptosis. Maintaining necessary Cdc42 would be one potent way to prevent proteinuria kidney diseases. PMID- 26986511 TI - From fighting depression to conquering tumors: a novel tricyclic thiazepine compound as a tubulin polymerization inhibitor. AB - A novel tricyclic thiazepine derivative, 6-(p-tolyl)benzo[f] pyrido[2,3-b][1,4] thiazepine 11,11-dioxide (TBPT), exhibits potent inhibitory effects in two non small-cell lung cancer cell lines, H460 and its drug-resistant variant, H460(TaxR), while exhibiting much less toxic effects on normal human fibroblasts. After five injections of TBPT at a dose of 60 mg/kg, it inhibits H460(TaxR) tumor growth in xenografted mouse models by 66.7% without causing observable toxicity to normal tissues. Based on gene perturbation data and a series of investigations, we reveal that TBPT is not a P-glycoprotein substrate and it inhibits microtubule formation by targeting tubulin, thereby causing cell cycle arrest at the G2/M stage and eventually inducing apoptosis. This redeployment of anti-depressant compound scaffold for anticancer applications provides a promising future for conquering drug-resistant tumors with fewer side effects. PMID- 26986512 TI - Functional genetics-directed identification of novel pharmacological inhibitors of FAS- and TNF-dependent apoptosis that protect mice from acute liver failure. AB - shRNA-mediated gene-silencing technology paired with cell-based functional readouts reveals potential targets directly, providing an opportunity to identify drugs against the target without knowing the precise role of the target in the pathophysiological processes of interest. By screening a lentiviral shRNA library targeting for major components of human signaling pathways and known drug targets, we identified and validated both canonical as well as 52 novel mediators of FAS and TNF ligand-induced apoptosis. Presence of potential therapeutic targets among these mediators was confirmed by demonstration of in vivo activity of siRNAs against four identified target candidates that protected mice from acute liver failure (ALF), a life-threatening disease with known involvement of death receptor (DR)-mediated apoptosis. Network-based modeling was used to predict small-molecule inhibitors for several candidate apoptosis mediators, including somatostatin receptor 5 (SSTR5) and a regulatory subunit of PP2A phosphatase, PPP2R5A. Remarkably, pharmacological inhibition of either SSTR5 or PPP2R5A reduced apoptosis induced by either FASL or TNF in cultured cells and dramatically improved survival in several mouse models of ALF. These results demonstrate the utility of loss-of-function genetic screens and network-based drug-repositioning methods for expedited identification of targeted drug candidates and revealed pharmacological agents potentially suitable for treatment of DR-mediated pathologies. PMID- 26986513 TI - NORE1A induction by membrane-bound CD40L (mCD40L) contributes to CD40L-induced cell death and G1 growth arrest in p21-mediated mechanism. AB - Membrane-bound CD40L (mCD40L) but not soluble CD40L (sCD40L) has been implicated in direct cell death induction and apoptosis in CD40-expressing carcinomas. In this study, we show that mCD40L but not sCD40L induces NORE1A/Rassf5 expression in an NFkappaB-dependant mechanism. NORE1A expression appeared to contribute to mCD40L-induced cell death and enhance cell transition from G1 to S phase of the cell cycle in a p21-dependent mechanism. The upregulation of p21 protein was attributed to NORE1A expression, since NORE1A inhibition resulted in p21 downregulation. p21 upregulation was concomitant with lower p53 expression in the cytoplasmic fraction with no detectable increase at the nuclear p53 level. Moreover, mCD40L-induced cell death mediated by NORE1A expression appeared to be independent of mCD40L-induced cell death mediated by sustained JNK activation since NORE1A inhibition did not affect JNK phosphorylation and vice versa. The presented data allow better understanding of the mechanism by which mCD40L induces cell death which could be exploited in the clinical development of CD40 targeted anti-cancer therapies. PMID- 26986516 TI - The ghost plastid of Choreocolax polysiphoniae. AB - Parasitism has evolved innumerable times among eukaryotes. Red algal parasites alone have independently evolved over 100 times. The accepted evolutionary paradigm proposes that red algal parasites arise by first infecting a close relative and over time diversifying and infecting more distantly related species. This provides a natural evolutionary gradient of relationships between hosts and parasites that share a photosynthetic common ancestor. Upon infection, the parasite deposits its organelles into the host cell and takes over, spreading through cell-cell connections. Microscopy and molecular studies have demonstrated that the parasites do not maintain their own plastid, but rather abscond with a dedifferentiated host plastid as they pack up spores for dispersal. We sequenced a ~90 kb plastid genome from the parasite Choreocolax polysiphoniae, which has lost genes for light harvesting and photosynthesis. Furthermore, the presence of a native C. polysiphoniae plastid indicates that not all red algal parasites follow the same evolutionary pathway to parasitism. Along with the 167 kb plastid genome of its host, Vertebrata lanosa, these plastids are the first to be sequenced from the Ceramiales. PMID- 26986515 TI - p53MutaGene: an online tool to estimate the effect of p53 mutational status on gene regulation in cancer. AB - p53MutaGene is the first online tool for statistical validation of hypotheses regarding the effect of p53 mutational status on gene regulation in cancer. This tool is based on several large-scale clinical gene expression data sets and currently covers breast, colon and lung cancers. The tool detects differential co expression patterns in expression data between p53 mutated versus p53 normal samples for the user-specified genes. Statistically significant differential co expression for a gene pair is indicative that regulation of two genes is sensitive to the presence of p53 mutations. p53MutaGene can be used in 'single mode' where the user can test a specific pair of genes or in 'discovery mode' designed for analysis of several genes. Using several examples, we demonstrate that p53MutaGene is a useful tool for fast statistical validation in clinical data of p53-dependent gene regulation patterns. The tool is freely available at http://www.bioprofiling.de/tp53. PMID- 26986514 TI - Necroptosis in Niemann-Pick disease, type C1: a potential therapeutic target. AB - Niemann-Pick disease, type C1 (NPC1) is a neurodegenerative, lysosomal storage disorder due to mutation of the NPC1 gene. The NPC1 phenotype is characterized by progressive neuronal dysfunction, including cerebellar ataxia and dementia. There is histological evidence of neuroinflammation and progressive neuronal loss, with cerebellar Purkinje cells particularly vulnerable to loss of NPC1 function. Necroptosis was evaluated as a mechanism of neuronal loss. Receptor-interacting protein kinase 1 (RIP1) and RIP3 are key components of the necrosomal complex that regulates necroptotic cell death. We report increased expression of RIP1 and RIP3 in NPC1 fibroblasts, NPC1 iPS cell-derived neuronal precursors, and in cerebellar tissue from both NPC1 mice and patients. Our data suggest a positive correlation between NPC1 neurological disease severity and assembly of the necrosome complex. Furthermore, we demonstrate that pharmacological inhibition of RIP1 decreases cell death both in vitro and in vivo. Treatment of Npc1-mutant mice with necrostatin-1, an allosteric inhibitor of RIP1, significantly delayed cerebellar Purkinje cell loss, progression of neurological symptoms, and death. Collectively, our data identified necroptosis as a key component of the molecular network that contributes to neuronal loss in NPC1 and establish that inhibition of necroptosis is a potential therapeutic intervention. PMID- 26986517 TI - Compartmentation of defensive compound synthesis in a red alga. PMID- 26986518 TI - Mevalonosomes: specific vacuoles containing the mevalonate pathway in Plocamium brasiliense cortical cells (Rhodophyta). AB - This paper has identified, for the first time in a member of the Rhodophyta, a vacuolar organelle containing enzymes that are involved in the mevalonate pathway an important step in red algal isoprenoid biosynthesis. These organelles were named mevalonosomes (Mev) and were found in the cortical cells (CC) of Plocamium brasiliense, a marine macroalgae that synthesizes several halogenated monoterpenes. P. brasiliense specimens were submitted to a cytochemical analysis of the activity of the 3-hydroxy-3-methylglutaryl-CoA synthase (HMGS). Using transmission electron microscopy (TEM), we confirmed the presence of HMGS activity within the Mev. Because HMGS is necessary for the biosynthesis of halogenated monoterpenes, we isolated a hexanic fraction (HF) rich in halogenated monoterpenes from P. brasiliense that contained a pentachlorinated monoterpene as a major metabolite. Because terpenes are often related to chemical defense, the antifouling (AF) activity of pentachlorinated monoterpene was tested. We found that the settlement of the mussel Perna perna was reduced by HF treatment (2.25 times less than control; 40% and 90% of fouled surface, respectively; P = 0.001; F9,9 = 1.13). The HF (at 10 MUg . mL(-1) ) also inhibited three species of fouling microalgae (Chlorarachnion reptans, Cylindrotheca cloisterium, and Exanthemachrysis gayraliae), while at a higher concentration (50 MUg . mL(-1) ), it inhibited the bacteria Halomonas marina, Polaribacter irgensii, Pseudoalteromonas elyakovii, Shewanella putrefaciens, and Vibrio aestuarianus. The AF activity of P. brasiliense halogenated monoterpenes and the localization of HMGS activity inside Mev suggest that this cellular structure found in CC may play a role in thallus protection against biofouling. PMID- 26986520 TI - ATP and related purines stimulate motility, spatial congregation, and coalescence in red algal spores. AB - Adenosine 5'-triphosphate (ATP) is a versatile extracellular signal along the tree of life, whereas cAMP plays a major role in vertebrates as an intracellular messenger for hormones, transmitters, tastants, and odorants. Since red algal spore coalescence may be considered analogous to the congregation process of social amoeba, which is stimulated by cAMP, we ascertained whether exogenous applications of ATP, cAMP, adenine, or adenosine modified spore survival and motility, spore settlement and coalescence. Concentration-response studies were performed with carpospores of Mazzaella laminarioides (Gigartinales), incubated with and without added purines. Stirring of algal blades released ADP/ATP to the cell media in a time-dependent manner. 10-300 MUM ATP significantly increased spore survival; however, 1,500 MUM ATP, cAMP or adenine induced 100% mortality within less than 24 h; the exception was adenosine, which up to 3,000 MUM, did not alter spore survival. ATP exposure elicited spore movement with speeds of 2.2 2.5 MUm . s(-1) . 14 d after 1,000 MUM ATP addition, spore abundance in the central zone of the plaques was increased 2.7-fold as compared with parallel controls. Likewise, 1-10 MUM cAMP or 30-100 MUM adenine also increased central zone spore abundance, albeit these purines were less efficacious than ATP; adenosine up to 3,000 MUM did not influence settlement. Moreover, 1,000 MUM ATP markedly accelerated coalescence, the other purines caused a variable effect. We conclude that exogenous cAMP, adenine, but particularly ATP, markedly influence red algal spore physiology; effects are compatible with the expression of one or more membrane purinoceptor(s), discarding adenosine receptor participation. PMID- 26986519 TI - A molecular investigation of the genus Ecklonia (Phaeophyceae, Laminariales) with special focus on the Southern Hemisphere. AB - Brown algae of the order Laminariales, commonly referred to as kelps, are the largest and most productive primary producers in the coastal inshore environment. The genus Ecklonia (Lessoniaceae, Phaeophyceae) consists of seven species with four species in the Northern Hemisphere and three in the Southern Hemisphere. It was recently transferred to the family Lessoniaceae based on phylogenetic analyses of nuclear and chloroplastic markers, though the type of the genus was not included and its relationship with allied genera Eckloniopsis and Eisenia remained unresolved. The present study is the first to produce a phylogeny focussed on the genus Ecklonia. It included sequences from nuclear, mitochondrial, and chloroplastic DNA, for most of the distribution range of the three current Southern Hemisphere species (Ecklonia radiata, Ecklonia maxima, and a sample of a putative Ecklonia brevipes specimen), sequences for East Asiatic species (Ecklonia cava, Ecklonia kurome, and Ecklonia stolonifera), as well as the closely related genera Eckloniopsis and Eisenia. Results confirmed E. radiata and E. maxima as two distinct species in South Africa, E. radiata as a single species throughout the Southern Hemisphere (in South Africa, Australia, and New Zealand) and East Asiatic species as a distinct lineage from the Southern Hemisphere clade. Results further pointed out a close sister relationship between Eckloniopsis radicosa and two Eisenia species (including the type species: Eisenia arborea) to the genus Ecklonia suggesting that the genera Eckloniopsis and Eisenia are superfluous. PMID- 26986521 TI - Size scaling of extracellular carbonic anhydrase activity in centric marine diatoms. AB - Many microalgae have a surface-associated extracellular carbonic anhydrase (eCA) that converts HCO3 (-) to CO2 for uptake and subsequent photosynthetic fixation. We investigated eCA activity and assessed its importance for photosynthetic CO2 supply in six centric diatom species spanning nearly the full range of cell sizes for centric diatoms (equivalent spherical radius 3-67 MUm). Since larger cells are more susceptible to diffusion limitation, we hypothesized that eCA activity would increase with cell size as would its importance for CO2 supply. eCA activity did increase with cell size, increasing with cell radius by a size scaling exponent of 2.6 +/- 0.3. The rapid increase in eCA activity with cell radius keeps the absolute CO2 concentration difference between bulk seawater and the cell surface very low (<~0.2 MUM) allowing high rates of CO2 uptake even for large diatoms. Although inhibiting eCA did reduce photosynthesis in the diatoms, there was no overall relationship between the extent of inhibition of photosynthesis and cell size. The only indication that eCA may be more important for larger diatoms was that photosynthesis in the smallest diatoms (<4 MUm radius) was only affected by eCA inhibition when CO2 concentrations were very low, while photosynthesis in some larger diatoms was affected even at typical seawater CO2 concentrations. eCA is ubiquitous in centric marine diatoms, in contrast to other taxa where its presence is irregularly distributed among different species, and plays an important role in supplying CO2 for photosynthesis across the size spectrum. PMID- 26986522 TI - Lipidomic analysis can distinguish between two morphologically similar strains of Nannochloropsis oceanica. AB - The two morphologically similar microalgae NMBluh014 and NMBluh-X belong to two different strains of Nannochloropsis oceanica. They possess obviously different feeding effects on bivalves, but are indistinguishable by 18S rRNA and morphological features. In this work, lipidomic analysis followed by principal component analysis and orthogonal projections to latent structures discriminant analysis provided a clear distinction between these strains. Metabolites that definitively contribute to the classification were selected as potential biomarkers. The most important difference in polar lipids were sulfoquinovosyldiacylglycerol (containing 18:1/16:0 and 18:3/16:0) and monogalactosyldiacylglycerol (containing 18:3/16:3 and 20:5/14:0), which were detected only in NMBluh-X. Additionally, an exhaustive qualitative and quantitative profiling of the neutral lipid triacylglycerol (TAG) in the two strains was carried out. The predominant species of TAG containing 16:1/16:1/16:1 acyl groups was detected only in NMBluh-X with a content of ~93.67 +/- 11.85 nmol . mg(-1) dry algae at the onset of stationary phase. Meanwhile, TAG containing 16:0/16:0/16:0 was the main TAG in NMBluh014 with a content of 40.25 +/- 3.92 nmol . mg(-1) . These results provided the most straightforward evidence for differentiating the two species. The metabolomic profiling indicated that NMBluh X underwent significant chemical and physiological changes during the growth process, whereas NMBluh014 did not show such noticeable time-dependent metabolite change. This study is the first using Ultra Performance Liquid Chromatography coupled with Electrospray ionization-Quadrupole-Time of Flight Mass Spectrometry (UPLC-Q-TOF-MS) for lipidomic profiling with multivariate statistical analysis to explore lipidomic differences of plesiomorphous microalgae. Our results demonstrate that lipidomic profiling is a valid chemotaxonomic tool in the study of microalgal systematics. PMID- 26986523 TI - Restricted use of nitrate and a strong preference for ammonium reflects the nitrogen ecophysiology of a light-limited red alga. AB - Ammonium and nitrate are important sources of inorganic nitrogen for coastal primary producers. Nitrate has higher energy requirement for uptake and assimilation, compared with ammonium, suggesting that it might be a more efficient nitrogen source for slow-growing, light-limited macroalgae. To address this hypothesis, we examined the nitrogen ecophysiology of Anotrichium crinitum, a rhodophyte macroalgae common in low-light habitats in New Zealand. We measured seasonal changes in seawater nitrate and ammonium concentrations and the concentration of nitrate and ammonium stored internally by A. crinitum. We determined the maximal uptake rates of nitrate and ammonium seasonally and grew A. crinitum in the laboratory with these nitrogen sources under two ecologically relevant saturating light levels. Our results show that field-harvested A. crinitum has a high affinity for ammonium and although it will grow when supplied exclusively with nitrate, internal nitrate pools are low and it is unable to take up nitrate without several days of acclimation to saturating light. Our data predict that A. crinitum would be able to sustain growth with ammonium as the sole source of nitrogen, a strategy that would help it survive under low-light conditions that prevail in the field. PMID- 26986524 TI - Phylogenetic analysis of cultivation-resistant terrestrial cyanobacteria with massive sheaths (Stigonema spp. and Petalonema alatum, Nostocales, Cyanobacteria) using single-cell and filament sequencing of environmental samples. AB - Molecular assessment of a large portion of traditional cyanobacterial taxa has been hindered by the failure to isolate and grow them in culture. In this study, we developed an optimized protocol for single cell/filament isolation and 16S rRNA gene sequencing of terrestrial cyanobacteria with large mucilaginous sheaths, and applied it to determine the phylogenetic position of typical members of the genera Petalonema and Stigonema. A methodology based on a glass-capillary isolation technique and a semi-nested PCR protocol enabled reliable sequencing of the 16S rRNA gene from all samples analyzed. Ten samples covering seven species of Stigonema from Europe, North and Central America, and Hawaii, and the type species of Petalonema from Slovakia were sequenced. Contrary to some previous studies, which proposed a relationship with heteropolar nostocalean cyanobacteria, Petalonema appeared to belong to the family Scytonemataceae. Analysis of Stigonema specimens recovered a unique coherent phylogenetic cluster, substantially broadening our knowledge of the molecular diversity within this genus. Neither the uni- to biseriate species nor the multiseriate species formed monophyletic subclusters within the genus. Typical multiseriate species of Stigonema clustered in a phylogenetic branch derived from uni- to biseriate S. ocellatum Thuret ex Bornet & Flahault in our analysis, suggesting that species with more complex thalli may have evolved from the more simple ones. We propose the technique tested in this study as a promising tool for a future revision of the molecular taxonomy in cyanobacteria. PMID- 26986525 TI - Sexual resting cyst production by the dinoflagellate Akashiwo sanguinea: a potential mechanism contributing to the ubiquitous distribution of a harmful alga. AB - The dinoflagellate Akashiwo sanguinea is a well known, cosmopolitan harmful microalga that frequently forms harmful algal blooms (HABs) in marine estuaries from temperate to tropical waters, and has posed a severe threat to fish, shellfish, and sea birds. Therefore, it is important to understand the ecology of this species, particularly the mechanisms regulating its ubiquitous geographic distribution and frequent recurrence of. To date, the mechanisms regulating distribution and recurrence of HABs by this species have been poorly understood. While resting cyst production can play a central role in the geographic expansion and initiation of HABs, studies of the life cycle of this alga, including cyst production, have been lacking. Here, we demonstrate that A. sanguinea produces sexual resting cysts homothallically. We present evidence for cell pairs in sexual mating, biflagellated planozygote formation, and cysts of different morphologies, and we describe time series for germination of cysts to germlings with two longitudinal flagella, along with studies of possible factors affecting cyst production. Phylogenetic analysis of large sub-unit rDNA sequences revealed a monophyly of this species and thus possibly a recent common ancestor for all global populations. The discovery of resting cyst production by A. sanguinea suggests its frequent recurrence of blooms and global distribution may have been facilitated by the natural and anthropogenic transport of resting cysts. PMID- 26986526 TI - Oospore dimensions and morphology in North American Tolypella (Charophyceae, Charophyta). AB - Characteristics of the oospores have been used to delimit sections and, in some cases, species in the genus Tolypella A. Braun. To test the utility of oospore characters for identifying North American species of Tolypella, we investigated oospores from field-collected and herbarium specimens. Oospore dimensions (length, width, and length to width ratio) and morphology (color, ridge number and shape, wall ornamentation, and basal impression number) were measured. Oospore dimensions were statistically analyzed and oospore morphology was studied with light and scanning electron microscopy. Statistical analyses showed significant differences in length, width, and length to width ratios among most Tolypella species and populations but there was considerable overlap, which suggested that species identification based on oospore measurements alone is not wholly reliable. In addition, oospore morphology was not unique for every species. PMID- 26986527 TI - Glycerol-3-phosphate metabolism plays a role in stress response in the red alga Pyropia haitanensis. AB - Glycerol-3-phosphate (G3P) has been suggested as a novel regulator of plant defense signaling, however, its role in algal resistance remains largely unknown. The glycerol kinase (also designated as NHO1) and NAD-dependent G3P dehydrogenase (GPDH) are two key enzymes involved in the G3P biosynthesis. In our study, we cloned the full-length cDNA of NHO1 (NHO1Ph ) and GPDH (GPDHP h ) from the red alga Pyropia haitanensis (denoted as NHO1Ph and GPDHP h ) and examined their expression level under flagellin peptide 22 (flg22) stimulation or heat stress. We also measured the level of G3P and floridoside (a downstream product of G3P in P. haitanensis) under flg22 stimulation or heat stress. Both NHO1Ph and GPDHP h shared high sequence identity and structural conservation with their orthologs from different species, especially from red algae. Phylogenetic analysis showed that NHO1s and GPDHs from red algae were closely related to those from animals. Under flg22 stimulation or heat stress, the expression levels of NHO1Ph and GPDHP h were up-regulated, G3P levels increased, and the contents of floridoside decreased. But the floridoside level increased in the recovery period after heat stress. Taken together, we found that G3P metabolism was associated with the flg22-induced defense response and heat stress response in P. haitanensis, indicating the general conservation of defense response in angiosperms and algae. Furthermore, floridoside might also participate in the stress resistance of P. haitanensis. PMID- 26986528 TI - Stimulated rejuvenation of dormant Aulacoseira granulata (Bacillariophyta) by Gloeocystis planctonica (Chlorophyta) in a eutrophic river. AB - The abundance of Aulacoseira granulata (Ehrenburg) Simonsen and Gloeocystis planctonica (West & G.S.West) Lemmermann was assessed during the summers of 2005 and 2010 in the eutrophic Fox River, Wisconsin, USA. In both years, a mid-summer bloom of G. planctonica was followed by the rapid growth of A. granulata. Laboratory experiments in which A. granulata was grown in cell-free filtrate of a G. planctonica culture revealed that the growth of A. granulata was stimulated in the G. planctonica-treated medium relative to controls. This effect was detected when dormant A. granulata cells were used as the source culture for the experiment but not when actively growing cells were used. Dormant A. granulata also grew more rapidly in river water collected after the 2010 G. planctonica bloom relative to river water collected before the bloom. These results suggest that the summer bloom of A. granulata in the river was stimulated by G. planctonica. This relationship can be described as stimulated rejuvenation, an interaction where the transition of an algal resting stage into active growth is triggered by exposure to another species. PMID- 26986529 TI - Biofilm and capsule formation of the diatom Achnanthidium minutissimum are affected by a bacterium. AB - Photoautotrophic biofilms play an important role in various aquatic habitats and are composed of prokaryotic and/or eukaryotic organisms embedded in extracellular polymeric substances (EPS). We have isolated diatoms as well as bacteria from freshwater biofilms to study organismal interactions between representative isolates. We found that bacteria have a strong impact on the biofilm formation of the pennate diatom Achnanthidium minutissimum. This alga produces extracellular capsules of insoluble EPS, mostly carbohydrates (CHO), only in the presence of bacteria (xenic culture). The EPS themselves also have a strong impact on the aggregation and attachment of the algae. In the absence of bacteria (axenic culture), A. minutissimum did not form capsules and the cells grew completely suspended. Fractionation and quantification of CHO revealed that the diatom in axenic culture produces large amounts of soluble CHO, whereas in the xenic culture mainly insoluble CHO were detected. For investigation of biofilm formation by A. minutissimum, a bioassay was established using a diatom satellite Bacteroidetes bacterium that had been shown to induce capsule formation of A. minutissimum. Interestingly, capsule and biofilm induction can be achieved by addition of bacterial spent medium, indicating that soluble hydrophobic molecules produced by the bacterium may mediate the diatom/bacteria interaction. With the designed bioassay, a reliable tool is now available to study the chemical interactions between diatoms and bacteria with consequences for biofilm formation. PMID- 26986530 TI - Phylogeny of Gracilariaceae (Rhodophyta): evidence from plastid and mitochondrial nucleotide sequences. AB - Gracilariaceae are mostly pantropical red algae and include ~230 species in seven genera. Infrafamilial classification of the group has long been based on reproductive characters, but previous phylogenies have shown that traditionally circumscribed groups are not monophyletic. We performed phylogenetic analyses using two plastid (universal plastid amplicon and rbcL) and one mitochondrial (cox1) loci from a greatly expanded number of taxa to better assess generic relationships and understand patterns of character distributions. Our analyses produce the most well-supported phylogeny of the family to date, and indicate that key characteristics of spermatangia and cystocarp type do not delineate genera as commonly suggested. Our results further indicate that Hydropuntia is not monophyletic. Given their morphological overlap with closely related members of Gracilaria, we propose that Hydropuntia be synonymized with the former. Our results additionally expand the known ranges of several Gracilariaceae species to include Brazil. Lastly, we demonstrate that the recently described Gracilaria yoneshigueana should be synonymized as G. domingensis based on morphological and molecular characters. These results demonstrate the utility of DNA barcoding for understanding poorly known and fragmentary materials of cryptic red algae. PMID- 26986531 TI - DNA barcoding the genus Chara: molecular evidence recovers fewer taxa than the classical morphological approach. AB - Charophytes (Charales) are benthic algae with a complex morphology. They are vulnerable to ecosystem changes, such as eutrophication, and are red-listed in many countries. Accurate identification of Chara species is critical for understanding their diversity and for documenting changes in species distribution. Species delineation is, however, complicated, because of high phenotypic plasticity. We used barcodes of the ITS2, matK and rbcL regions to test if the distribution of barcode haplotypes among individuals is consistent with species boundaries as they are currently understood. The study included freshly collected and herbarium material of 91 specimens from 10 European countries, Canada and Argentina. Results showed that herbarium specimens are useful as a source of material for genetic analyses for aquatic plants like Chara. rbcL and matK had highest sequence recoverability, but rbcL had a somewhat lower discriminatory power than ITS2 and matK. The tree resulting from the concatenated data matrix grouped the samples into six main groups contrary to a traditional morphological approach that consisted of 14 different taxa. A large unresolved group consisted of C. intermedia, C. hispida, C. horrida, C. baltica, C. polyacantha, C. rudis, C. aculeolata, and C. corfuensis. A second unresolved group consisted of C. virgata and C. strigosa. The taxa within each of the unresolved groups shared identical barcode sequences on the 977 positions of the concatenated data matrix. The morphological differences of taxa within both unresolved groups include the number and length of spine cells, stipulodes, and bract cells. We suggest that these morphological traits have less taxonomic relevance than hitherto assumed. PMID- 26986532 TI - Transparent exopolymer particle production and aggregation by a marine planktonic diatom (Thalassiosira weissflogii) at different growth rates. AB - Transparent exopolymer particles (TEP) play an important role in the ocean carbon cycle as they are sticky and affect particle aggregation and the biological carbon pump. We investigated the effect of growth rate on TEP production in nitrogen limited semi-continuous cultures of the diatom Thalassiosira weissflogii (Grunow) G. Fryxell & Hasle. Steady-state diatom concentrations and other indicators of biomass (chl a, and total carbohydrate) were inversely related to growth rate, while individual cell volume increased with growth rate. There was no change in total TEP area with growth rate; however, individual TEP were larger at high growth rates and the number of individual TEP particles was lower. TEP concentration per cell was higher at higher growth rates. SYTOX Green staining showed that <5% of the diatom population had permeable cell membranes, with the proportion increasing at low growth rates. However, TEP production rates were greater at high growth rates, refuting our hypothesis that TEP formation is dependent on dying cells with compromised cell membranes in a diatom population. Measurements of particle size distribution in the cultures using laser scattering showed that they were most aggregated at high growth rates. These results indicate a coupling between TEP production and growth rate in diatoms under N limitation, with fast growing T. weissflogii producing more TEP and aggregates. PMID- 26986533 TI - Genetic variability and taxonomic revision of the genus Auxenochlorella (Shihira et Krauss) Kalina et Puncocharova (Trebouxiophyceae, Chlorophyta). AB - The monotypic genus Auxenochlorella with its type species A. protothecoides is so far only known from specific habitats such as the sap of several tree species. Several varieties were described according to physiological performances in culture on different organic substrates. However, two strains designated as Auxenochlorella were isolated from other habitats (an endosymbiont of Hydra viridis and an aquatic strain from an acidic volcano stream). We studied those isolates and compared them with six strains of Auxenochlorella belonging to different varieties. The integrative approach used in this study revealed that all strains showed similar morphology but differed in their SSU and ITS rDNA sequences. The Hydra endosymbiont formed a sister taxon to A. protothecoides, which included the varieties protothecoides, galactophila, and communis. The variety acidicola is not closely related to Auxenochlorella and represented its own lineage within the Trebouxiophyceae. In view of these results, we propose a new species of Auxenochlorella, A. symbiontica, for the Hydra symbiont, and a new genus Pumiliosphaera, with its type species, P. acidophila, for acidophilic strain. These results are supported by several compensatory base changes in the conserved region of ITS-2 and ITS-2 DNA barcodes. PMID- 26986534 TI - Mindfulness--What Works for Whom? Referral, Feasibility, and User Perspectives Regarding Patients with Mixed Chronic Pain. AB - OBJECTIVE: The purpose of this study was to describe and predict the patients who would benefit from a mindfulness-based stress reduction (MBSR) course and those for whom the conditions or timing are not optimal. The hypothesis was that patients' sociodemographic status would affect the effectiveness of MBSR. METHODS: Data were collected by using mixed methods. Quantitative data were collected from a group of 58 patients who completed health-related questionnaires and from an evaluation 6 months after completion of a mindfulness course. Qualitative data were collected from three focus group interviews and seven case stories. RESULTS: There were no significant differences in positive or negative outcomes after MBSR regarding any sociodemographic variables, and no clear predictors to identify patients best suited for participating in mindfulness were found. Techniques used by most patients (with or without positive outcome) were meditation and focus on breathing. Patients expressed positive feedback and reported positive changes they felt would last for the rest of their lives. Focusing on the issue of what works, four categories of interest were identified from the transcribed interviews: lessons learned, being oneself, permanence, and continuity as a condition for success. CONCLUSIONS: Mindfulness meditation makes a difference for patients. Patients felt rested and in better control of their pain and its role in their life. Only older age predicted better outcome, but patients who recognized that pain is part of their life and were living under stable conditions may have been more likely to learn and put forth personal effort, which may have made change possible. More specific variables have to be developed to study good match between the specific intervention and the specific patient. PMID- 26986535 TI - Water-Soluble Phosphine-Protected Au11 Clusters: Synthesis, Electronic Structure, and Chiral Phase Transfer in a Synergistic Fashion. AB - Synthesis of atomically precise, water-soluble phosphine-protected gold clusters is still currently limited probably due to a stability issue. We here present the synthesis, magic-number isolation, and exploration of the electronic structures as well as the asymmetric conversion of triphenylphosphine monosulfonate (TPPS) protected gold clusters. Electrospray ionization mass spectrometry and elemental analysis result in the primary formation of Au11(TPPS)9Cl undecagold cluster compound. Magnetic circular dichroism (MCD) spectroscopy clarifies that extremely weak transitions are present in the low-energy region unresolved in the UV-vis absorption, which can be due to the Faraday B-terms based on the magnetically allowed transitions in the cluster. Asymmetric conversion without changing the nuclearity is remarkable by the chiral phase transfer in a synergistic fashion, which yields a rather small anisotropy factor (g-factor) of at most (2.5-7.0) * 10(-5). Quantum chemical calculations for model undecagold cluster compounds are then used to evaluate the optical and chiroptical responses induced by the chiral phase transfer. On this basis, we find that the Au core distortion is ignorable, and the chiral ion-pairing causes a slight increase in the CD response of the Au11 cluster. PMID- 26986536 TI - Isolated Sphenoid Lesion. PMID- 26986537 TI - Advanced PCR-based molecular diagnosis of gastrointestinal infections: challenges and opportunities. AB - Acute infections of the gastrointestinal tract are among the most common infectious diseases. The etiological agents of gastroenteritis may be bacteria, viruses or protozoa. Identification of the etiological agents of acute diarrhea is important for the treatment and management of diarrheal diseases. Conventional stool culture for bacteria shows a low sensitivity and requires more than 24 hours. In addition, other approaches to detect viruses and protozoa mainly involve antigen detection, but this is not available for all enteropathogens, and microscopic observation requires training and is of low sensitivity. In this review, the authors describe currently available molecular methods to detect different enteropathogens and analyze the main advantages and disadvantages of these methods for laboratory diagnosis of gastroenteritis. PMID- 26986538 TI - The Neo-Bioscore Update for Staging Breast Cancer Treated With Neoadjuvant Chemotherapy: Incorporation of Prognostic Biologic Factors Into Staging After Treatment. AB - IMPORTANCE: We previously described and validated a breast cancer staging system (CPS+EG, clinical-pathologic scoring system incorporating estrogen receptor negative disease and nuclear grade 3 tumor pathology) for assessing prognosis after neoadjuvant chemotherapy using pretreatment clinical stage, posttreatment pathologic stage, estrogen receptor (ER) status, and grade. Development of the CPS+EG staging system predated routine administration of trastuzumab in patients with ERBB2-positive disease (formerly HER2 or HER2/neu). OBJECTIVE: To validate the CPS+EG staging system using the new definition of ER positivity (>=1%) and to develop an updated staging system (Neo-Bioscore) that incorporates ERBB2 status into the previously developed CPS+EG. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of data collected prospectively from January 2005 through December 2012 on patients with breast cancer treated with neoadjuvant chemotherapy at The University of Texas MD Anderson Cancer Center. MAIN OUTCOMES AND MEASURE: Prognostic scores were computed using 2 versions of the CPS+EG staging system, one with ER considered positive if it measured 10% or higher, the other with ER considered positive if it measured 1% or higher. Fits of the Cox proportional hazards model for the 2 sets of prognostic scores were compared using the Akaike Information Criterion (AIC). Status of ERBB2 was added to the model, and the likelihood ratio test was used to determine improvement in fit. RESULTS: A total of 2377 patients were included; all were women (median age, 50 years [range, 21-87 years]); ER status was less than 1% in 28.9%, 1% to 9% in 8.3%, and 10% or higher in 62.8%; 591 patients were ERBB2 positive. Median follow up was 4.2 years (range, 0.5-11.7 years). Five-year disease-specific survival was 89% (95% CI, 87%-90%). Using 1% or higher as the cutoff for ER positivity, 5-year disease-specific survival estimates determined using the CPS+EG stage ranged from 52% to 98%, thereby validating our previous finding that the CPS+EG score facilitates more refined categorization into prognostic subgroups than clinical or final pathologic stage alone. The AIC value for this model was 3333.06, while for a model using 10% or higher as the cutoff for ER positivity, it was 3333.38, indicating that the model fits were nearly identical. The improvement in fit of the model when ERBB2 status was added was highly significant, with 5-year disease specific survival estimates ranging from 48% to 99% (P < .001). Incorporating ERBB2 into the staging system defined the Neo-Bioscore, which provided improved stratification of patients with respect to prognosis. CONCLUSIONS AND RELEVANCE: The Neo-Bioscore improves our previously validated staging system and allows its application in ERBB2-positive patients. We recommend that treatment response and biologic markers be incorporated into the American Joint Committee on Cancer staging system. PMID- 26986539 TI - De novo C3 glomerulonephritis in a renal allograft. AB - C3 glomerulonephritis (C3GN) is a recently described, rare glomerular disease characterized by predominant or sole glomerular C3 deposits. Morphologic features of C3GN are similar to those of dense deposit disease (DDD); however, ribbon-like intramembranous electron-dense deposits are absent in the former. We report a case of de novo C3GN in a renal allograft with morphologic transformation to DDD. A 6-year-old boy presented with congenital left renal agenesis and right ureteropelvic junction obstruction. The patient underwent pyeloplasty but experienced recurrent urinary tract infections. At the age of 22 years, he received a renal allograft from a living related donor. C3GN was diagnosed after 1 year of transplantation; initial histology showed minimal mesangiopathy and this progressed to mesangial proliferation and membranoproliferative features over the next 7 years. Serum creatinine levels were stabilized with anti rejection treatments for combating repeated episodes of acute rejection; however, glomerular and tubular band-like electron-dense deposits became evident. PMID- 26986540 TI - Time to RE-AIM: Why Community Weight Loss Programs Should Be Included in Academic Obesity Research. AB - Despite decades of efficacy-based research on weight loss interventions, the obesity epidemic in the United States persists, especially in underserved populations. We used the RE-AIM (Reach, Efficacy/Effectiveness, Adoption, Implementation, and Maintenance) framework to describe the limitations of the current paradigm of efficacy-based research for weight loss interventions. We also used RE-AIM to propose that existing weight loss interventions (community based programs) such as Jenny Craig, Take Off Pounds Sensibly (TOPS), and Weight Watchers be studied to supplement the efficacy-based research approaches to achieve population-level impact on obesity. PMID- 26986541 TI - Dissemination as Dialogue: Building Trust and Sharing Research Findings Through Community Engagement. AB - A fundamental feature of community-based participatory research (CBPR) is sharing findings with community members and engaging community partners in the dissemination process. To be truly collaborative, dissemination should involve community members in a two-way dialogue about new research findings. Yet little literature describes how to engage communities in dialogue about research findings, especially with historically marginalized communities where mistrust of researchers may exist because of past or present social injustices. Through a series of interactive community presentations on findings from a longitudinal study, we developed a process for community dissemination that involved several overlapping phases: planning, outreach, content development, interactive presentations, and follow-up. Through this process, we built on existing and new community relationships. Following each interactive presentation, the research team debriefed and reviewed notes to identify lessons learned from the process. Key themes included the importance of creating a flexible dissemination plan, tailoring presentations to each community group, establishing a point person to serve as a community liaison, and continuing dialogue with community members after the presentations. Core strategies for developing trust during dissemination included engaging community members at every step, reserving ample time for discussion during presentations, building rapport by sharing personal experiences, being receptive to and learning from criticism, and implementing input from community members. This process led to a deeper understanding of research findings and ensured that results reached community members who were invested in them. PMID- 26986542 TI - Improvements and Disparities in Types of Foods and Milk Beverages Offered in Elementary School Lunches, 2006-2007 to 2013-2014. AB - INTRODUCTION: Children consume much of their daily energy intake at school. School district policies, state laws, and national policies, such as revisions to the US Department of Agriculture's school meals standards, may affect the types of foods and beverages offered in school lunches over time. METHODS: This study evaluated changes and disparities in school lunch characteristics from 2006-2007 to 2013-2014. Data were obtained from annual cross-sectional surveys at 4,630 public elementary schools participating in the National School Lunch Program. Multivariate logistic regressions were conducted to examine lunch characteristics. RESULTS: The percentage of schools regularly offering healthful items such as vegetables (other than potatoes), fresh fruit, salad bars, whole grains, and more healthful pizzas increased significantly from 2006-2007 to 2013 2014, and the percentage of schools offering less healthful items such as fried potatoes, regular pizza, and high-fat milks decreased significantly. Nevertheless, disparities were evident in 2013-2014. Schools in the West were significantly more likely to offer salad bars than were schools in the Northeast, Midwest, or South (adjusted prevalence: West, 66.3%; Northeast, 22.3%; Midwest, 20.8%; South, 18.3%). Majority-black or majority-Latino schools were significantly less likely to offer fresh fruit than were predominantly white schools (adjusted prevalence: majority black, 61.3%; majority Latino, 73.0%; predominantly white, 87.8%). Schools with low socioeconomic status were significantly less likely to offer salads regularly than were schools with middle or high socioeconomic status (adjusted prevalence: low, 38.5%; middle, 47.4%; high, 59.3%). CONCLUSION: Much progress has been made in improving the quality of school lunches in US public elementary schools, but additional opportunities for improvement remain. PMID- 26986543 TI - Influence of sex and limb dominance on lower extremity joint mechanics during unilateral land-and-cut manoeuvres. AB - Limb dominance theory suggests that females tend to be more one-leg dominant and exhibit greater kinematic and kinetic leg asymmetries than their male counterparts, contributing to the increased risk of anterior cruciate ligament injury among female athletes. Thus, the purpose of this study was to examine the influences of sex and limb dominance on lower extremity joint mechanics during unilateral land-and-cut manoeuvres. Twenty-one women and 21 men completed land and-cut manoeuvres on their dominant limb as well as their nondominant limb. Three-dimensional kinematics and kinetics were calculated bilaterally for the entire stance phase of the manoeuvre. Women performed land-and-cut manoeuvres with altered hip motions and loads as well as greater knee abduction at touchdown compared to men. Dominant limb land-and-cut manoeuvres where characterised by decreased hip flexion at touchdown as well as decreased hip flexion and adduction range of motion compared to nondominant land-and-cuts regardless of sex. The observed sex differences are consistent with previous research regarding mechanisms underlying the sex disparity in anterior cruciate ligament injury rates. However, observed differences regarding limb dominances appear somewhat arbitrary and did not suggest that the dominant or nondominant limb would be at increased risk of anterior cruciate ligament injury. PMID- 26986544 TI - Hypoglycemia, diabetes therapies and driving categories in type 2 diabetes. AB - OBJECTIVE: To assess the experiences of hypoglycemia in drivers with type 2 diabetes according to types of diabetes treatment; to determine experiences in different driving groups; and to ascertain whether UK-based Driving and Vehicle Licensing Agency (DVLA) guidance concerning hypoglycemia and driving is understood. Research, design, and methods: An online questionnaire was sent to UK drivers with type 2 diabetes between June and September 2014. Study limitations included selection bias inherent in online surveys, and lack of validation of the definition of hypoglycemic symptoms by an expert patient group. RESULTS: The survey was completed by 1569 (457 social, 590 commuters, and 522 business/work) drivers. Vocational drivers were more likely to be treated with an insulin secretagogue (sulfonylureas and glinides) (52%) than diet alone (18%), a non insulin secretagogue (26%) or insulin (16%). Symptoms of hypoglycemia (both mild and severe) were reported by 62% of the total cohort in the past year. Risk was greatest in those with poor diabetes self-management behavior and those receiving an insulin secretagogue. Among the 1112 respondents commuting or driving for a living, 16.8% had poor, 49.6% average, and 33.6% good diabetes self-management. Poor self-management was more frequent among vocational drivers and those receiving insulin secretagogues. Following a hypoglycemic episode, only 24% of insulin-secretagogue-treated drivers and 39% of insulin-treated drivers would discontinue driving for the DVLA-recommended 45 minutes. Insulin-treated drivers were best informed about diabetes and driving. Healthcare providers were the preferred source of information on driving and diabetes for 78% of drivers. CONCLUSION: Hypoglycemia risk is highest among drivers with poor diabetes self management, those commuting or driving for a living and those taking insulin secretagogues. There is an educational need for all drivers concerning driving and hypoglycemia. PMID- 26986545 TI - Highly Stereo- and Regioselective Hydrocarboxylation of Diynes with Carbon Dioxide. AB - A nickel-catalyzed three-component hydrocarboxylation of diynes with ZnEt2 and CO2 (1 atm) is disclosed. With this method, symmetric/nonsymmetric diynes could be reacted smoothly with very high stereo- and regioselectivity, affording conjugated 2,4-alkadienoic acids incorporated with five- or six-membered rings efficiently. A stepwise non-oxidative cyclometalation mechanism was proposed based on careful mechanistic studies. PMID- 26986546 TI - Does the donor matter? Donor vs patient effects in the outcome of a next generation microbiota-based drug trial for recurrent Clostridium difficile infection. AB - AIM: To evaluate the impact of the donor material versus the patient in outcomes achieved with RBX2660, a microbiota-based drug under study for recurrent Clostridium difficile infection (CDI). METHODS: RBX2660 was administered to patients enrolled in the previously reported Phase II PUNCH CD study under Rebiotix's Investigational New Drug submission to the US FDA. Four donors were used to prepare the RBX2660 drug product used in the study. The product was manufactured in individual, donor-specific batches that could be tracked to individual patients and their outcomes. Donor products were randomized to patients for both first and second doses. RESULTS: The individual donor or donor dose order did not significantly affect the outcome of RBX2660 treatment in 34 patients (mean age 68.8 years). CONCLUSION: The specific donor did not affect the outcomes achieved with administration of RBX2660 for recurrent CDI. PMID- 26986547 TI - The Atg17-Atg31-Atg29 complex and Atg11 regulate autophagosome-vacuole fusion. AB - The macroautophagy (hereafter autophagy) process involves de novo formation of double-membrane autophagosomes; after sequestering cytoplasm these transient organelles fuse with the vacuole/lysosome. Genetic studies in yeasts have characterized more than 40 autophagy-related (Atg) proteins required for autophagy, and the majority of these proteins play roles in autophagosome formation. The fusion of autophagosomes with the vacuole is mediated by the Rab GTPase Ypt7, its guanine nucleotide exchange factor Mon1-Ccz1, and soluble N ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. However, these factors are not autophagosome-vacuole fusion specific. We recently showed that 2 autophagy scaffold proteins, the Atg17-Atg31-Atg29 complex and Atg11, regulate autophagosome-vacuole fusion by recruiting the vacuolar SNARE Vam7 to the phagophore assembly site (PAS), where an autophagosome forms in yeast. PMID- 26986548 TI - OX133, a monoclonal antibody recognizing protein-bound N-ethylmaleimide for the identification of reduced disulfide bonds in proteins. AB - In vivo, enzymatic reduction of some protein disulfide bonds, allosteric disulfide bonds, provides an important level of structural and functional regulation. The free cysteine residues generated can be labeled by maleimide reagents, including biotin derivatives, allowing the reduced protein to be detected or purified. During the screening of monoclonal antibodies for those specific for the reduced forms of proteins, we isolated OX133, a unique antibody that recognizes polypeptide resident, N-ethylmaleimide (NEM)-modified cysteine residues in a sequence-independent manner. OX133 offers an alternative to biotin maleimide reagents for labeling reduced/alkylated antigens and capturing reduced/alkylated proteins with the advantage that NEM-modified proteins are more easily detected in mass spectrometry, and may be more easily recovered than is the case following capture with biotin based reagents. PMID- 26986549 TI - Increased 1-year survival and discharge to independent living in overweight hip fracture patients: A prospective study of 843 patients. AB - BACKGROUND AND PURPOSE: Hip fracture patients usually have low body mass index (BMI), and suffer further postoperative catabolism. How BMI relates to outcome in relatively healthy hip fracture patients is not well investigated. We investigated the association between BMI, survival, and independent living 1 year postoperatively. PATIENTS AND METHODS: This prospective multicenter study involved 843 patients with a hip fracture (mean age 82 (SD 7) years, 73% women), without severe cognitive impairment and living independently before admission. We investigated the relationship between BMI and both 1-year mortality and ability to return to independent living. RESULTS: Patients with BMI > 26 had a lower mortality rate than those with BMI < 22 and those with BMI 22-26 (6%, 16%, and 18% respectively; p = 0.006). The odds ratio (OR) for 1-year survival in the group with BMI > 26 was 2.6 (95% CI: 1.2-5.5) after adjustment for age, sex, and physical status. Patients with BMI > 26 were also more likely to return to independent living after the hip fracture (OR = 2.6, 95% CI: 1.4-5.0). Patients with BMI < 22 had similar mortality and a similar likelihood of independent living to those with BMI 22-26. INTERPRETATION: In this selected group of patients with hip fracture, the overweight and obese patients (BMI > 26) had a higher survival rate at 1 year, and returned to independent living to a higher degree than those of normal (healthy) weight. The obesity paradox and the recommendations for optimal BMI need further consideration in patients with hip fracture. PMID- 26986550 TI - Similar mortality with general or regional anesthesia in elderly hip fracture patients. AB - BACKGROUND AND PURPOSE: There is continuing confusion among practitioners with regard to the optimal choice of anesthetic type for repair of hip fractures. We investigated whether type of anesthetic was associated with short-term mortality after hip fracture surgery. PATIENTS AND METHODS: We conducted a retrospective cohort study of patients with surgically treated hip fractures, performed between January 1, 2009 and December 31, 2012. Exposure of interest was anesthesia type (general, spinal/neuroaxial, and mixed). Endpoints were 30-, 90-, and 365-day post-surgery mortality. Multivariable conditional logistic regression models were used and odds ratios (ORs) and 95% confidence intervals (CIs) are reported. RESULTS: Of the 7,585 participants, 5,412 (71%) were women and the median age was 80 (IQR: 72-85) years old. Of the total cohort, 4,257 (56%) received general anesthesia, 3,059 (40%) received spinal/neuroaxial, and 269 (4%) received mixed anesthesia. Overall, the incidence of 30-, 90-, and 365-day mortality was 4% (n = 307), 8% (n = 583), and 15% (n = 1,126), respectively. When compared with general anesthesia, the 365-day odds of mortality was marginally lower in patients with spinal/neuroaxial anesthesia (OR = 0.84, CI: 0.70-1.0), but it was similar in patients with mixed anesthesia (OR = 1.3, CI: 0.70-2.3). No other statistically significant differences were observed. INTERPRETATION: Regarding mortality, this study does not support specific recommendations regarding the type of anesthetic in surgery of fractured hips. PMID- 26986552 TI - Medial scapular winging following trauma--a case report. PMID- 26986551 TI - Surgery of non-spinal skeletal metastases in renal cell carcinoma: No effect of preoperative embolization? AB - BACKGROUND AND PURPOSE: Surgery for metastases of renal cell carcinoma has increased in the last decade. It carries a risk of massive blood loss, as tumors are hypervascular and the surgery is often extensive. Preoperative embolization is believed to facilitate surgery. We evaluated the effect of preoperative embolization and resection margin on intraoperative blood loss, operation time, and survival in non-spinal skeletal metastases of renal cell carcinoma. PATIENTS AND METHODS: This retrospective study involved 144 patients, 56 of which were treated preoperatively with embolization. The primary outcome was intraoperative blood loss. We also identified factors affecting operating time and survival. RESULTS: We did not find statistically significant effects on intraoperative blood loss of preoperative embolization of skeletal non-spinal metastases. Pelvic localization and large tumor size increased intraoperative blood loss. Marginal resection compared to intralesional resection, nephrectomy, level of hemoglobin, and solitary metastases were associated with better survival. INTERPRETATION: Tumor size, but not embolization, was an independent factor for intraoperative blood loss. Marginal resection rather than intralesional resection should be the gold standard treatment for skeletal metastases in non-spinal renal cell carcinoma, especially in the case of a solitary lesion, as this improved the overall survival. PMID- 26986553 TI - Emergency Medical Services Utilization among Patients with ST-Segment Elevation Myocardial Infarction: Observations from the Singapore Myocardial Infarction Registry. AB - OBJECTIVE: Early activation of emergency medical services (EMS), rapid transport, and treatment of patients experiencing ST-segment elevation myocardial infarction (STEMI) can improve outcomes. The Singapore Myocardial Infarction Registry (SMIR) is a nation-wide registry that collects data on STEMI. We aimed to determine the prevalence, predictors, and outcomes of EMS utilization among STEMI patients presenting to Emergency Departments (ED) in Singapore. METHODS: We analyzed STEMI patients enrolled by SMIR from January 2010 to December 2012. We excluded patients who were transferred, developed STEMI in-hospital or suffered cardiac arrest out-of-hospital or in the ED. Primary outcome was process-of-care timings. Secondary outcomes included the occurrence of cardiac complications. Multivariate analysis was used to examine independent factors associated with EMS transport. RESULTS: 6412 patients were enrolled into the study; 4667 patients were eligible for analysis. 49.8% of patients utilized EMS transport. EMS transport was associated with higher rate of reperfusion therapy (74.3% vs. 65.1%, p < 0.01), shorter median symptom-to-door time (119 vs. 182 minutes, p < 0.01), door-to balloon time (59 vs. 70 minutes, p < 0.01), and symptom-to-balloon time (185 vs. 233 minutes, p < 0.01). EMS transport had more patients with Killip Class 4 (7.5% vs 4.0%, p < 0.01) and was associated with greater presentation of heart failure, arrhythmias, and complete heart block. Independent predictors of EMS transport were age, syncope and Killip score; after-office-hour presentation was a negative predictor. CONCLUSION: Less than half of STEMI patients utilized EMS and EMS patients had faster receipt of initial reperfusion therapies. Targeted public education to reduce time to treatment may improve the care of STEMI patients. PMID- 26986554 TI - Clozapine for Drug-Refractory Irritability in Individuals with Developmental Disability. AB - OBJECTIVES: In this case series, we describe the acute clinical impact and tolerability of rapid titration of clozapine for treatment of refractory irritability in five hospitalized youth with developmental disability. We offer this descriptive report in an effort to expand the evidence base guiding treatment of refractory aggression in this population. METHODS: Five youth with developmental disability and severe irritability were admitted to a 10-bed psychiatric crisis stabilization unit where they received thorough psychiatric and medical evaluation. Informed consent was obtained in each case, and each patient underwent rapid titration onto clozapine. Clozapine monitoring guidelines were followed for all patients throughout treatment, and clinical severity at baseline and improvement with treatment was measured by use of the Clinical Global Impressions-Severity scale (CGI-S) and the Clinical Global Impressions Improvement scale (CGI-I). RESULTS: One female and four males diagnosed with developmental disability and at least one other psychiatric diagnosis, mean age of 13.1 +/- 2.1 years, and mean CGI-S at baseline of 5.8, each received clozapine treatment by rapid titration. The mean therapeutic total daily dose of clozapine was 380 +/- 200 mg. All patients demonstrated acute clinical improvement with the mean final CGI-I of 2.0, or "much improved." CONCLUSION: These initial results support the potential utility of clozapine rapid titration for treatment of severe refractory irritability in youth with developmental disability. These patients tolerated clozapine treatment in the short term. Future studies are needed to thoroughly evaluate the long-term safety of clozapine treatment in this population. PMID- 26986555 TI - The beta-phosphorus hyperfine coupling constant in nitroxides: 6. Solvent effects in non-cyclic nitroxides. AB - In two recent articles (Org. Biomol. Chem., 2015 and 2016), we showed that changes in the phosphorus hyperfine coupling constant aP at position beta in beta phosphorylated nitroxides can be dramatic. Such changes were applied to the titration of water in organic solvents and conversely of organic solvents in water. One of the molecules tested was a non-cyclic nitroxide meaning that a thorough investigation of the solvent effect on the EPR hyperfine coupling constant is timely due. In this article, we show that the aP of persistent non cyclic beta-phosphorylated nitroxides decrease with the normalized polarity Reichardt's constant E(N)T. The Koppel-Palm and Kalmet-Abboud-Taft relationships were applied to gain deeper insight into the effects influencing aN and aP: polarity/polarizability, hydrogen bond donor properties, and the structuredness of the cybotactic region. PMID- 26986556 TI - Cytopathology of Vitreous Humor Samples in Routine Practice. AB - OBJECTIVE: To describe findings in vitreous fluid samples in routine cytology practice. STUDY DESIGN: The pathology archives from 1988 to 2008 at our institution were searched for vitreous samples. The slides were reviewed and clinical and follow-up information was obtained. RESULTS: One hundred and eighty two vitreous fluid samples from 166 patients were analyzed. Most of the samples had been collected for vitreous hemorrhage (75 cases). The second reason for vitreous sample cytological evaluation was an intraocular inflammatory process (55 cases). A specific cause of inflammation was found by combining clinical, microbiological and cytopathological findings in 19 cases, i.e. infection in 7, sarcoidosis in 3, retinal necrosis in 3, lens-induced endophthalmitis in 2, uveitis associated with systemic disease in 2, retrobulbar neuritis in 1 and sympathetic ophthalmia in 1. Among the 19 samples from 16 patients collected to rule out malignancy, 8 had a confirmed intraocular malignancy. Malignant cells were observed in 5 cases (3 lymphomas, 1 melanoma and 1 carcinoma). Undiagnosed malignancies included 2 lymphomas and 1 choroidal melanoma. Other samples were collected during surgery for retinal detachment and cataracts. CONCLUSIONS: In routine practice, cytology of the vitreous fluid is performed in many and varied situations that are most often nonneoplastic. In nonneoplastic cases, cytology is a useful adjunct to vitrectomy, in spite of its limitations. PMID- 26986558 TI - Themenubersicht. PMID- 26986557 TI - Sexual Intimacy Constructions of Heterosexual Couples Living in a Low-Income, "Colored," Farmworker Community in South Africa. AB - This study has been motivated by the scarcity of research that adopts an unproblematic focus on sexuality in South African Black and Colored low-income communities. We explored the sexual intimacy constructions of 15 Colored married/cohabiting couples who live in a low-income, historical South African farmworker community. Using a social constructionist thematic analysis method, we identified four themes: (a) metaphoric and indirect sexual language; (b) the use of a romantic discourse to talk about sexual experiences; (c) male-centered sexual relationships; and (d) lack of privacy brings both restriction and pleasure. We consider how these themes may be linked to the participants' community context and colonial and apartheid history. Finally, we emphasize the need for research that also explores positive sex functions and experiences rather than focuses narrowly on problematic sexual behavior. PMID- 26986560 TI - Autorenverzeichnis. PMID- 26986561 TI - Inhaltsverzeichnis. PMID- 26986563 TI - Institutional Delivery Service Utilization among Women from Rural Districts of Wolaita and Dawro Zones, Southern Ethiopia; a Community Based Cross-Sectional Study. AB - INTRODUCTION: The highest number of maternal deaths occur during labour, delivery and the first day after delivery highlighting the critical need for good quality care during this period. Therefore, for the strategies of institutional delivery to be effective, it is essential to understand the factors that influence individual and household factors to utilize skilled birth attendance and institutions for delivery. This study was aimed to assess factors affecting the utilization of institutional delivery service of women in rural districts of Wolaita and Dawro Zones. METHODS: A community based cross-sectional study was done among mothers who gave birth within the past one year preceding the survey in Wolaita and Dawro Zones, from February 01 -April 30, 2015 by using a three stage sampling technique. Initially, 6 districts were selected randomly from the total of 17 eligible districts. Then, 2 kebele from each district was selected randomly cumulating a total of 12 clusters. Finally, study participants were selected from each cluster by using systematic sampling technique. Accordingly, 957 mothers were included in the survey. Data was collected by using a pretested interviewer administered structured questionnaire. The questionnaire was prepared by including socio-demographic variables and variables of maternal health service utilization factors. Data was entered using Epi-data version 1.4.4.0 and exported to SPSS version 20 for analysis. Bivariate and multiple logistic regressions were applied to identify candidate and predictor variables respectively. RESULT: Only 38% of study participants delivered the index child at health facility. Husband's educational status, wealth index, average distance from nearest health facility, wanted pregnancy, agreement to follow post-natal care, problem faced during delivery, birth order, preference of health professional for ante-natal care and maternity care were predictors of institutional delivery. CONCLUSION: The use of institutional delivery service is low in the study community. Eventhough antenatal care service is high; nearly two in every three mothers delivered their index child out of health facility. Improving socio-economic status of mothers as well as availing modern health facilities to the nearest locality will have a good impact to improve institutional delivery service utilization. Similarly, education is also a tool to improve awareness of mothers and their husbands for the improvement of health care service utilization. PMID- 26986562 TI - Proposal to inform European institutions regarding the regulation of conscientious objection to abortion. AB - The aim of this paper is to define a set of proposals to inform European institutions in the regulation of Conscientious Objection to abortion. The board of the European Society of Contraception and Reproductive Health Care (ESC) was informed on the elements that should in the opinion of the authors be included in a future regulation of Conscientious Objection to abortion in Europe. These elements are outlined in this paper and the debate about them could form the basis for recommendations to the international scientific community and the European institutions. As current measures governing the principle of conscientious objection result in negative consequences regarding women's access to sexual and reproductive health services, they should be changed. Healthcare services should adopt measures to guarantee that a woman's right to voluntary abortion is not limited by the practitioner's stance on the principle of conscientious objection. In the countries where conscientious objection is allowed, the regulation must clearly delineate the extent of the duties and the exemptions of professionals based on the principles of established social consensus. The recommendations included in this document specify measures on the rights of women, the rights and duties of the practitioner, the role of institutions and the role of professional associations. PMID- 26986564 TI - Electrical Impedance Myography to Detect the Effects of Electrical Muscle Stimulation in Wild Type and Mdx Mice. AB - OBJECTIVE: Tools to better evaluate the impact of therapy on nerve and muscle disease are needed. Electrical impedance myography (EIM) is sensitive to neuromuscular disease progression as well as to therapeutic interventions including myostatin inhibition and antisense oligonucleotide-based treatments. Whether the technique identifies the impact of electrical muscle stimulation (EMS) is unknown. METHODS: Ten wild-type (wt) C57B6 mice and 10 dystrophin deficient (mdx) mice underwent 2 weeks of 20 min/day EMS on left gastrocnemius and sham stimulation on the right gastrocnemius. Multifrequency EIM data and limb girth were obtained before and at the conclusion of the protocol. Muscle weight, in situ force measurements, and muscle fiber histology were also assessed at the conclusion of the study. RESULTS: At the time of sacrifice, muscle weight was greater on the EMS-treated side than on the sham-stimulated side (p = 0.018 for wt and p = 0.007 for mdx). Similarly, in wt animals, EIM parameters changed significantly compared to baseline (resistance (p = 0.009), reactance (p = 0.0003) and phase (p = 0.002); these changes were due in part to reductions in the EIM values on the EMS-treated side and elevations on the sham-simulated side. Mdx animals showed analogous but non-significant changes (p = 0.083, p = 0.064, and p = 0.57 for resistance, reactance and phase, respectively). Maximal isometric force trended higher on the stimulated side in wt animals only (p = 0.06). Myofiber sizes in wt animals were also larger on the stimulated side than on the sham-stimulated side (p = 0.034); no significant difference was found in the mdx mice (p = 0.79). CONCLUSION: EIM is sensitive to stimulation-induced muscle alterations in wt animals; similar trends are also present in mdx mice. The mechanisms by which these EIM changes develop, however, remains uncertain. Possible explanations include longer-term trophic effects and shorter-term osmotic effects. PMID- 26986565 TI - Do Males Form Social Associations Based on Sexual Attractiveness in a Fission Fusion Fish Society? AB - Recent theory predicts that males should choose social environments that maximize their relative attractiveness to females by preferentially associating with less attractive rivals, so as to enhance their mating success. Using the Trinidadian guppy (Poecilia reticulata), a highly social species, we tested for non-random social associations among males in mixed-sex groups based on two phenotypic traits (body length and coloration) that predict relative sexual attractiveness to females and sexual (sperm) competitiveness. Based on a well-replicated laboratory dichotomous-choice test of social group preference, we could not reject the null hypothesis that focal males chose randomly between a mixed-sex group that comprised a female and a rival male that was less sexually attractive than themselves and another mixed-sex group containing a sexually more attractive male. The same conclusion was reached when females were absent from the two groups. As might be expected from these laboratory findings, free-ranging males in the field were not assorted by either body length or colour in mixed-sex shoals. The apparent lack of an evolved and expressed preference in wild male guppies from our study population to form social associations with other males based on their relative sexual attractiveness and competitiveness might be due to the fission-fusion dynamics of guppy shoals in nature. Such social dynamics likely places constraints on the formation of stable phenotype-based social associations among males. This possibility is supported by a simulation model which assumes group departure rules based on relative body size and coloration in males. PMID- 26986566 TI - Recombinant Salivary Proteins of Phlebotomus orientalis are Suitable Antigens to Measure Exposure of Domestic Animals to Sand Fly Bites. AB - BACKGROUND: Certain salivary proteins of phlebotomine sand flies injected into the host skin during blood-feeding are highly antigenic and elicit strong antibody-mediated immune responses in repeatedly-exposed hosts. These antibodies can be measured by enzyme-linked immuno sorbent assays (ELISAs) using salivary gland homogenates (SGHs) as the source of antigens and serve as a markers for exposure to biting sand flies. Large-scale screening for anti-sand fly saliva antibodies requires replacement of SGH with recombinant salivary proteins. In East Africa, Phlebotomus orientalis is the main vector of Leishmania donovani, a trypanosomatid parasite causing visceral leishmaniasis. We tested recombinant salivary proteins derived from Ph. orientalis saliva to study exposure of domestic animals to this sand fly species. METHODOLOGY/PRINCIPAL FINDINGS: Antigenic salivary proteins from Ph. orientalis were identified by immunoblot and mass spectrometry. Recombinant apyrase rPorSP15, yellow-related protein rPorSP24, ParSP25-like protein rPorSP65, D7-related protein rPorSP67, and antigen 5-related protein rPorSP76 were tested using ELISA with sera of domestic animals from L. donovani foci in Ethiopia where Ph. orientalis is present. Our results highlighted recombinant yellow-related protein rPorSP24 as the most promising antigen, displaying a high positive correlation coefficient as well as good sensitivity and specificity when compared to SGH. This recombinant protein was the most suitable one for testing sera of dogs, sheep, and goats. In addition, a different antigen, rPorSP65 was found efficacious for testing canine sera. CONCLUSIONS/SIGNIFICANCE: Recombinant salivary proteins of Ph. orientalis, specifically rPorSP24, were shown to successfully substitute SGH in serological experiments to measure exposure of domestic animals to Ph. orientalis, the vector of L. donovani. The results suggest that rPorSP24 might be a suitable antigen for detecting anti-Ph. orientalis antibody-mediated reactions also in other host species. PMID- 26986567 TI - In Vivo Molecular Dissection of the Effects of HIV-1 in Active Tuberculosis. AB - Increased risk of tuberculosis (TB) associated with HIV-1 infection is primarily attributed to deficient T helper (Th)1 immune responses, but most people with active TB have robust Th1 responses, indicating that these are not sufficient to protect against disease. Recent findings suggest that favourable outcomes following Mycobacterium tuberculosis infection arise from finely balanced inflammatory and regulatory pathways, achieving pathogen control without immunopathology. We hypothesised that HIV-1 and antiretroviral therapy (ART) exert widespread changes to cell mediated immunity, which may compromise the optimal host protective response to TB and provide novel insights into the correlates of immune protection and pathogenesis. We sought to define these effects in patients with active TB by transcriptional profiling of tuberculin skin tests (TST) to make comprehensive molecular level assessments of in vivo human immune responses at the site of a standardised mycobacterial challenge. We showed that the TST transcriptome accurately reflects the molecular pathology at the site of human pulmonary TB, and used this approach to investigate immune dysregulation in HIV-1/TB co-infected patients with distinct clinical phenotypes associated with TST reactivity or anergy and unmasking TB immune reconstitution inflammatory syndrome (IRIS) after initiation of ART. HIV-1 infected patients with positive TSTs exhibited preserved Th1 responses but deficient immunoregulatory IL10-inducible responses. Those with clinically negative TSTs revealed profound anergy of innate as well as adaptive immune responses, except for preservation of type 1 interferon activity, implicated in impaired anti mycobacterial immunity. Patients with unmasking TB IRIS showed recovery of Th1 immunity to normal levels, but exaggerated Th2-associated responses specifically. These mechanisms of immune dysregulation were localised to the tissue microenvironment and not evident in peripheral blood. TST molecular profiling categorised different mechanisms of immunological dysfunction in HIV-1 infection beyond the effects on CD4 T cells, each associated with increased risk of TB disease and amenable to host-directed therapies. PMID- 26986569 TI - Finding Potent Sirt Inhibitor in Coffee: Isolation, Confirmation and Synthesis of Javamide-II (N-Caffeoyltryptophan) as Sirt1/2 Inhibitor. AB - Recent studies suggest that Sirt inhibition may have beneficial effects on several human diseases such as neurodegenerative diseases and cancer. Coffee is one of most popular beverages with several positive health effects. Therefore, in this paper, potential Sirt inhibitors were screened using coffee extract. First, HPLC was utilized to fractionate coffee extract, then screened using a Sirt1/2 inhibition assay. The screening led to the isolation of a potent Sirt1/2 inhibitor, whose structure was determined as javamide-II (N-caffeoyltryptophan) by NMR. For confirmation, the amide was chemically synthesized and its capacity of inhibiting Sirt1/2 was also compared with the isolated amide. Javamide-II inhibited Sirt2 (IC50; 8.7 MUM) better than Sirt1(IC50; 34MUM). Since javamide-II is a stronger inhibitor for Sirt2 than Sirt1. The kinetic study was performed against Sirt2. The amide exhibited noncompetitive Sirt2 inhibition against the NAD+ (Ki = 9.8 MUM) and showed competitive inhibition against the peptide substrate (Ki = 5.3 MUM). Also, a docking simulation showed stronger binding pose of javamide-II to Sirt2 than AGK2. In cellular levels, javamide-II was able to increase the acetylation of total lysine, cortactin and histone H3 in neuronal NG108-15 cells. In the same cells, the amide also increased the acetylation of lysine (K382) in p53, but not (K305). This study suggests that Javamide-II found in coffee may be a potent Sirt1/2 inhibitor, probably with potential use in some conditions of human diseases. PMID- 26986570 TI - The Effects of Acute Exercise and Exercise Training on Plasma Homocysteine: A Meta-Analysis. AB - BACKGROUND: Although studies have demonstrated that physical exercise alters homocysteine levels in the blood, meta-analyses of the effects of acute exercise and exercise training on homocysteine blood concentration have not been performed, especially regarding the duration and intensity of exercise, which could affect homocysteine levels differently. OBJECTIVE: The aim of this meta analysis was to ascertain the effects of acute exercise and exercise training on homocysteine levels in the blood. METHOD: A review was conducted according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta Analyses using the online databases PubMed, SPORTDiscus, and SciELO to identify relevant studies published through June 2015. Review Manager was used to calculate the effect size of acute exercise and exercise training using the change in Hcy plasmaserum concentration from baseline to post-acute exercise and trained vs. sedentary control groups, respectively. Weighted mean differences were calculated using random effect models. RESULTS: Given the abundance of studies, acute exercise trials were divided into two subgroups according to exercise volume and intensity, whereas the effects of exercise training were analyzed together. Overall, 22 studies with a total of 520 participants indicated increased plasma homocysteine concentration after acute exercise (1.18 MUmol/L, 95% CI: 0.71 to 1.65, p < .01). Results of a subgroup analysis indicated that either long-term exercise of low-to-moderate intensity (1.39 MUmol/L, 95% CI: 0.9 to 1.89, p < .01) or short-term exercise of high intensity (0.83 MUmol/L, 95% CI: 0.19 to 1.40, p < .01) elevated homocysteine levels in the blood. Increased homocysteine induced by exercise was significantly associated with volume of exercise, but not intensity. By contrast, resistance training reduced plasma homocysteine concentration (-1.53 MUmol/L, 95% CI: -2.77 to -0.28, p = .02), though aerobic training did not. The cumulative results of the seven studies with a total of 230 participants in exercise training analysis did not demonstrate a significant impact on homocysteine levels in the blood (-0.56 MUmol/L, 95% CI: 1.61 to 0.50, p = .23). CONCLUSIONS: Current evidence demonstrates that acute exercise increases homocysteine levels in the blood independent of exercise duration and intensity. Resistance, but not aerobic training decreases plasma homocysteine levels. PMID- 26986571 TI - Anticancer effect of metformin on estrogen receptor-positive and tamoxifen resistant breast cancer cell lines. AB - Acquisition of tamoxifen resistance (TR) during anti-estrogenic therapy using tamoxifen is a major obstacle in the treatment of estrogen receptor (ER)-positive breast cancer. As a biguanide derivative, metformin is commonly used to treat type II diabetes. It has recently emerged as a potential anticancer agent. The objective of the present study was to investigate the anticancer activity of metformin in relation to ERalpha expression and its signaling pathway in ERalpha positive MCF-7 and MDA-MB-361 breast cancer cells as well as TR MCF-7 breast cancer cells. Metformin inhibited both protein and mRNA levels of ERalpha in the presence or absence of estrogen (E2) in the MCF-7, TR MCF-7 and MDA-MB-361 cells. Metformin repressed E2-inducible estrogen response element (ERE) luciferase activity, protein levels and mRNA levels of E2/ERalpha-regulated genes [including c-Myc, cyclin D1, progesterone receptor (PR) and pS2] to a greater degree than tamoxifen, resulting in inhibition of cell proliferation of MCF-7, TR MCF-7 and MDA-MB-361 cells. Collectively, our results suggest that one of the anticancer mechanisms of metformin could be attributable to the repression of expression and transcriptional activity of ERalpha. Metformin may be a good therapeutic agent for treating ERalpha-positive breast cancer by inhibiting the expression and function of ERalpha. In addition, metformin may be useful to treat tamoxifen resistant breast cancer. PMID- 26986572 TI - De Novo Transcriptome Analysis Provides Insights into Immune Related Genes and the RIG-I-Like Receptor Signaling Pathway in the Freshwater Planarian (Dugesia japonica). AB - BACKGROUND: The freshwater planarian Dugesia japonica (D. japonica) possesses extraordinary ability to regenerate lost organs or body parts. Interestingly, in the process of regeneration, there is little wound infection, suggesting that D. japonica has a formidable innate immune system. The importance of immune system prompted us to search for immune-related genes and RIG-I-like receptor signaling pathways. RESULTS: Transcriptome sequencing of D. japonica was performed on an IlluminaHiSeq2000 platform. A total of 27,180 transcripts were obtained by Trinity assembler. CEGMA analysis and mapping of all trimmed reads back to the assembly result showed that our transcriptome assembly covered most of the whole transcriptome. 23,888 out of 27,180 transcripts contained ORF (open reading fragment), and were highly similar to those in Schistosoma mansoni using BLASTX analysis. 8,079 transcripts (29.7%) and 8,668 (31.9%) were annotated by Blast2GO and KEGG respectively. A DYNLRB-like gene was cloned to verify its roles in the immune response. Finally, the expression patterns of 4 genes (RIG-I, TRAF3, TRAF6, P38) in the RIG-I-like receptor signaling pathway were detected, and the results showed they are very likely to be involved in planarian immune response. CONCLUSION: RNA-Seq analysis based on the next-generation sequencing technology was an efficient approach to discover critical genes and to understand their corresponding biological functions. Through GO and KEGG analysis, several critical and conserved signaling pathways and genes related to RIG-I-like receptor signaling pathway were identified. Four candidate genes were selected to identify their expression dynamics in the process of pathogen stimulation. These annotated transcripts of D. japonica provide a useful resource for subsequent investigation of other important pathways. PMID- 26986617 TI - Behavioral Reactivity Associated With Electronic Monitoring of Environmental Health Interventions--A Cluster Randomized Trial with Water Filters and Cookstoves. AB - Subject reactivity--when research participants change their behavior in response to being observed--has been documented showing the effect of human observers. Electronics sensors are increasingly used to monitor environmental health interventions, but the effect of sensors on behavior has not been assessed. We conducted a cluster randomized controlled trial in Rwanda among 170 households (70 blinded to the presence of the sensor, 100 open) testing whether awareness of an electronic monitor would result in a difference in weekly use of household water filters and improved cookstoves over a four-week surveillance period. A 63% increase in number of uses of the water filter per week between the groups was observed in week 1, an average of 4.4 times in the open group and 2.83 times in the blind group, declining in week 4 to an insignificant 55% difference of 2.82 uses in the open, and 1.93 in the blind. There were no significant differences in the number of stove uses per week between the two groups. For both filters and stoves, use decreased in both groups over four-week installation periods. This study suggests behavioral monitoring should attempt to account for reactivity to awareness of electronic monitors that persists for weeks or more. PMID- 26986573 TI - Metagenomic Survey of Viral Diversity Obtained from Feces of Subantarctic and South American Fur Seals. AB - The Brazilian South coast seasonally hosts numerous marine species, observed particularly during winter months. Some animals, including fur seals, are found dead or debilitated along the shore and may harbor potential pathogens within their microbiota. In the present study, a metagenomic approach was performed to evaluate the viral diversity in feces of fur seals found deceased along the coast of the state of Rio Grande do Sul. The fecal virome of two fur seal species was characterized: the South American fur seal (Arctocephalus australis) and the Subantarctic fur seal (Arctocephalus tropicalis). Fecal samples from 10 specimens (A. australis, n = 5; A. tropicalis, n = 5) were collected and viral particles were purified, extracted and amplified with a random PCR. The products were sequenced through Ion Torrent and Illumina platforms and assembled reads were submitted to BLASTx searches. Both viromes were dominated by bacteriophages and included a number of potentially novel virus genomes. Sequences of picobirnaviruses, picornaviruses and a hepevirus-like were identified in A. australis. A rotavirus related to group C, a novel member of the Sakobuvirus and a sapovirus very similar to California sea lion sapovirus 1 were found in A. tropicalis. Additionally, sequences of members of the Anelloviridae and Parvoviridae families were detected in both fur seal species. This is the first metagenomic study to screen the fecal virome of fur seals, contributing to a better understanding of the complexity of the viral community present in the intestinal microbiota of these animals. PMID- 26986618 TI - The Nutritional Balancing Act of a Large Herbivore: An Experiment with Captive Moose (Alces alces L). AB - The nutrient balancing hypothesis proposes that, when sufficient food is available, the primary goal of animal diet selection is to obtain a nutritionally balanced diet. This hypothesis can be tested using the Geometric Framework for nutrition (GF). The GF enables researchers to study patterns of nutrient intake (e.g. macronutrients; protein, carbohydrates, fat), interactions between the different nutrients, and how an animal resolves the potential conflict between over-eating one or more nutrients and under-eating others during periods of dietary imbalance. Using the moose (Alces alces L.), a model species in the development of herbivore foraging theory, we conducted a feeding experiment guided by the GF, combining continuous observations of six captive moose with analysis of the macronutritional composition of foods. We identified the moose's self-selected macronutrient target by allowing them to compose a diet by mixing two nutritionally complementary pellet types plus limited access to Salix browse. Such periods of free choice were intermixed with periods when they were restricted to one of the two pellet types plus Salix browse. Our observations of food intake by moose given free choice lend support to the nutrient balancing hypothesis, as the moose combined the foods in specific proportions that provided a particular ratio and amount of macronutrients. When restricted to either of two diets comprising a single pellet type, the moose i) maintained a relatively stable intake of non-protein energy while allowing protein intakes to vary with food composition, and ii) increased their intake of the food item that most closely resembled the self-selected macronutrient intake from the free choice periods, namely Salix browse. We place our results in the context of the nutritional strategy of the moose, ruminant physiology and the categorization of food quality. PMID- 26986621 TI - Supported Tetrahedral Oxo-Sn Catalyst: Single Site, Two Modes of Catalysis. AB - Mild calcination in ozone of a (POSS)-Sn-(POSS) complex grafted on silica generated a heterogenized catalyst that mostly retained the tetrahedral coordination of its homogeneous precursor, as evidenced by spectroscopic characterizations using EXAFS, NMR, UV-vis, and DRIFT. The Sn centers are accessible and uniform and can be quantified by stoichiometric pyridine poisoning. This Sn-catalyst is active in hydride transfer reactions as a typical solid Lewis acid. However, the Sn centers can also create Bronsted acidity with alcohol by binding the alcohol strongly as alkoxide and transferring the hydroxyl H to the neighboring Sn-O-Si bond. The resulting acidic silanol is active in epoxide ring opening and acetalization reactions. PMID- 26986622 TI - Pharmacist medication reviews to improve safety monitoring in primary care patients. AB - OBJECTIVE: Patients prescribed psychotropic medications within primary care are at risk of suboptimal monitoring. It is unknown whether pharmacists can improve medication safety through targeted monitoring of at risk populations. Access Community Health Centers implemented a quality improvement pilot project that included pharmacists on an integrated care team to provide medication reviews for patients. Aims were to determine whether inclusion of a pharmacist performing medication reviews within a primary care behavioral health (PCBH) practice is feasible and facilitates safe medication use. METHOD: Pharmacists performed medication reviews of the electronic health record for patients referred for psychiatry consultation. Reviews were performed 1-3 months following consultation and focused on medications with known suboptimal monitoring rates. Reviews were documented within the EHR and routed to the primary care provider. Primary outcome measures were change in percentage up-to-date on monitoring and AIMS assessment, and at risk of experiencing drug interaction(s) between baseline and 3 months postreview. Secondary outcome was provider opinion of medication reviews collected via electronic survey. RESULTS: Reviews were performed for 144 patients. Three months postreview, percentage up-to-date on recommended monitoring increased 18% (p = .0001), at risk for drug interaction decreased 20% (p < .0001), and up-to-date on AIMS decreased 12% (p = .2113). The majority of surveyed providers wanted medication reviews to continue. CONCLUSION: Pharmacist population-level monitoring within an integrated care team is feasible and associated with improved safety monitoring of psychotropic medications. Results identify key areas for improvement that other clinics considering integration of similar pharmacy services should consider. (PsycINFO Database Record PMID- 26986620 TI - Protective effects of Alpha-lipoic acid on MeHg-induced oxidative damage and intracellular Ca(2+) dyshomeostasis in primary cultured neurons. AB - Methylmercury (MeHg) is one of the ubiquitous environmental toxicant that leads to long-lasting neurological deficits in animals and humans. However, the mechanisms of MeHg-induced neuronal cell death are incompletely understood. Treatment of neuronal cells with MeHg (0-2 MUM) for 0.5-12 h, or pretreated with LA (12.5-100 MUM) for 0.5-6 h resulted in toxic effects of primary cultured neurons concentration- and time-dependently. For further experiments, 12.5, 25, and 50 MUM of LA pretreatment for 3 h followed by 1 MUM MeHg for 6 h were performed for the examination of the responses of neurons. Exposure of MeHg resulted in damages of neurons, which were shown by a loss of cell viability, and supported by high levels of lactate dehydrogenase (LDH) release, apoptosis, and morphological changes. In addition, neurons were sensitive to MeHg-mediated oxidative stress, a finding that is consistent with ROS over-production, leading to decrease Ca(2+)-ATPase activity and increase intracellular free calcium. Moreover, expressions of NMDA receptor subunits in neurons were down-regulated after MeHg exposure, and expression of NR2A mRNA and protein were much more sensitive to MeHg than those of NR1 and NR2B. On the contrary, pretreatment with LA presented a concentration-dependent prevention against MeHg-mediated cytotoxic effects of neurons. In conclusion, present results showed that oxidative stress and intracellular Ca(2+ )dyshomeostasis resulting from MeHg exposure contributed to neuronal injury. LA could attenuate MeHg-induced neuronal toxicity via its antioxidant properties in primary cultured neurons. PMID- 26986619 TI - Lactoferrin Is an Allosteric Enhancer of the Proteolytic Activity of Cathepsin G. AB - Protease-mediated degradation of proteins is critical in a plethora of physiological processes. Neutrophils secrete serine proteases including cathepsin G (CatG), neutrophile elastase (NE), and proteinase 3 (PR3) together with lactoferrin (LF) as a first cellular immune response against pathogens. Here, we demonstrate that LF increases the catalytic activity of CatG at physiological concentration, with its highest enhancing capacity under acidic (pH 5.0) conditions, and broadens the substrate selectivity of CatG. On a functional level, the enzymatic activity of CatG was increased in the presence of LF in granulocyte-derived supernatant. Furthermore, LF enhanced CatG-induced activation of platelets as determined by cell surface expression of CD62P. Consequently, LF mediated enhancement of CatG activity might promote innate immunity during acute inflammation. PMID- 26986623 TI - Do perceptions of family-centered care differ in older and younger family/caregivers of U.S. veterans? AB - INTRODUCTION: Family-centered care (FCC) involves partnering with patients and family/caregivers ("caregivers"), engaging them in decisions, and providing support. FCC may be measured across 3 dimensions: respect, collaboration, and support and needs likely vary by caregiver age. The objective was to examine and compare caregiver perceptions of FCC by age. METHOD: We mailed surveys to family/caregivers of Veterans. We collected demographics and measured respect, collaboration, and support using the Family-Centered Care Survey (FCCS). We calculated mean values and conducted bivariate comparisons, dichotomized by caregiver age (>=60 vs. <60), of demographics and FCC constructs. We completed thematic analysis on open-ended text. RESULTS: Caregivers (n = 2,111) aged >=60 versus <60 were more likely to be spouses (81% vs. 62%, p < .0001) and White (74% vs. 50%, p < .0001). Overall FCC subscales values were high: respect (3.30), collaboration (3.07), and support (2.99). Older caregivers reported higher respect (3.36 vs. 3.22, p < .001), collaboration (3.12 vs. 2.98, p < .0001), and support (3.06 vs. 2.88, p < .0001). Qualitative analysis revealed collaboration, communication, hospital climate, and physical environment as important to FCC and supplemented quantitative findings on age. Examples highlighted both positive perceptions of FCC and areas of concern, such as feeling "unheard" and "like I am bothering providers," and needing "more comfortable seating" and "better parking." DISCUSSION: Caregivers perceived high FCC levels at VA facilities, reporting highest on respect and lowest on support. Older caregivers perceived better FCC compared with younger caregivers. Several concerns identified can be used to target improvements to FCC including: improved support, collaboration between patient/family/provider, and climate/environmental enhancements. (PsycINFO Database Record PMID- 26986625 TI - Interferon gamma-Induced Nuclear Interleukin-33 Potentiates the Release of Esophageal Epithelial Derived Cytokines. AB - BACKGROUND: Esophageal epithelial cells are an initiating cell type in esophageal inflammation, playing an essential role in the pathogenesis of gastroesophageal reflux disease (GERD). A new tissue-derived cytokine, interleukin-33 (IL-33), has been shown to be upregulated in esophageal epithelial cell nuclei in GERD, taking part in mucosal inflammation. Here, inflammatory cytokines secreted by esophageal epithelial cells, and their regulation by IL-33, were investigated. METHODS: In an in vitro stratified squamous epithelial model, IL-33 expression was examined using quantitative RT-PCR, western blot, ELISA, and immunofluorescence. Epithelial cell secreted inflammatory cytokines were examined using multiplex flow immunoassay. IL-33 was knocked down with small interfering RNA (siRNA) in normal human esophageal epithelial cells (HEECs). Pharmacological inhibitors and signal transducers and activators of transcription 1 (STAT1) siRNA were used to explore the signaling pathways. RESULTS: Interferon (IFN)gamma treatment upregulated nuclear IL-33 in HEECs. Furthermore, HEECs can produce various inflammatory cytokines, such as IL-6, IL-8, monocyte chemoattractant protein 1 (MCP-1), regulated on activation normal T-cell expressed and presumably secreted (RANTES), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in response to IFNgamma. Nuclear, but not exogenous IL-33, amplified IFN induction of these cytokines. P38 mitogen-activated protein kinase (MAPK) and janus protein tyrosine kinases (JAK)/STAT1 were the common signaling pathways of IFNgamma mediated induction of IL-33 and other cytokines. CONCLUSIONS: Esophageal epithelial cells can actively participate in GERD pathogenesis through the production of various cytokines, and epithelial-derived IL-33 might play a central role in the production of these cytokines. PMID- 26986624 TI - Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade. AB - Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose) polymerase 1 (PARP1). Biguanides and angiotensin II receptor blockers (ARBs) such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothelial cells (ECs), diabetic and hypertensive rodent models, and AMPKalpha2-knockout mice to investigate whether metformin and telmisartan have a beneficial effect on the endothelium via AMP-activated protein kinase (AMPK) phosphorylation of PARP1 and thus inhibition of PARP1 activity. The results showed that metformin and telmisartan, but not glipizide and metoprolol, activated AMPK, which phosphorylated PARP1 Ser-177 in cultured ECs and the vascular wall of rodent models. Experiments using phosphorylated/de-phosphorylated PARP1 mutants show that AMPK phosphorylation of PARP1 leads to decreased PARP1 activity and attenuated protein poly(ADP-ribosyl)ation (PARylation), but increased endothelial nitric oxide synthase (eNOS) activity and silent mating type information regulation 2 homolog 1 (SIRT1) expression. Taken together, the data presented here suggest biguanides and ARBs have a beneficial effect on the vasculature by the cascade of AMPK phosphorylation of PARP1 to inhibit PARP1 activity and protein PARylation in ECs, thereby mitigating endothelial dysfunction. PMID- 26986626 TI - Prolonged Cerebral Circulation Time Is the Best Parameter for Predicting Vasospasm during Initial CT Perfusion in Subarachnoid Hemorrhagic Patients. AB - PURPOSE: We sought to imitate angiographic cerebral circulation time (CCT) and create a similar index from baseline CT perfusion (CTP) to better predict vasospasm in patients with subarachnoid hemorrhage (SAH). METHODS: Forty-one SAH patients with available DSA and CTP were retrospectively included. The vasospasm group was comprised of patients with deterioration in conscious functioning and newly developed luminal narrowing; remaining cases were classified as the control group. The angiography CCT (XA-CCT) was defined as the difference in TTP (time to peak) between the selected arterial ROIs and the superior sagittal sinus (SSS). Four arterial ROIs were selected to generate four corresponding XA-CCTs: the right and left anterior cerebral arteries (XA-CCTRA2 and XA-CCTLA2) and right- and left-middle cerebral arteries (XA-CCTRM2 and XA-CCTLM2). The CCTs from CTP (CT-CCT) were defined as the differences in TTP from the corresponding arterial ROIs and the SSS. Correlations of the different CCTs were calculated and diagnostic accuracy in predicting vasospasm was evaluated. RESULTS: Intra-class correlations ranged from 0.96 to 0.98. The correlations of XA-CCTRA2, XA-CCTRM2, XA-CCTLA2, and XA-CCTLM2 with the corresponding CT-CCTs were 0.64, 0.65, 0.53, and 0.68, respectively. All CCTs were significantly prolonged in the vasospasm group (5.8-6.4 s) except for XA-CCTLA2. CT-CCTA2 of 5.62 was the optimal cut-off value for detecting vasospasm with a sensitivity of 84.2% and specificity 82.4. CONCLUSION: CT-CCTs can be used to interpret cerebral flow without deconvolution algorithms, and outperform both MTT and TTP in predicting vasospasm risk. This finding may help facilitate management of patients with SAH. PMID- 26986627 TI - Functional outcome at school age of neonatal post-hemorrhagic ventricular dilatation. AB - BACKGROUND: Specific knowledge about the functional outcome of preterm born children with post-hemorrhagic ventricular dilatation (PHVD) is lacking. OBJECTIVES: To determine functional outcome at school age in children with post hemorrhagic ventricular dilatation and to identify whether PHVD characteristics increased the risk for deficits. METHODS: Single-center case-control study. Included were preterm children born between 1996 and 2003 who had PHVD in their neonatal period. The controls were children matched for gestation, gender, and year of birth. At school age, using standardized tests and questionnaires, we assessed intelligence, attention, verbal memory, executive functioning, visual perception, visuomotor integration, motor skills, and behavior. RESULTS: Of 34 children with PHVD 28 survived, three of whom could not be tested at school age (one child's parents declined and two were lost to follow-up). At a mean age of 10years (6-14years) the total and verbal IQs of the remaining 25 children (17 boys, 8 girls) were significantly lower compared to controls (difference in total IQ-14 points, verbal IQ-9 points, P=0.001and P=0.009, respectively). After adjustment for possible confounders, the performance of the PHVD group was poorer on visual perception and attention tests. Selective attention showed a trend toward risk of borderline and abnormal scores (OR 4.03, 95%-CI 0.84-19.2). Within the PHVD group, total IQ was significantly lower (P=0.048) in those who had undergone surgical intervention (n=12). CONCLUSION: At school age, intelligence, attention, and visual perception were more affected in the PHVD group than in the matched controls. Surgical intervention was associated with lower IQ scores. PMID- 26986628 TI - Antimetabolites: A First Synthesis of a New Class of Cytosine Thioglycoside Analogs. AB - A first synthesis of a new class of novel cytosine thioglycoside analogs from readily available starting materials has been described. The key step of this protocol is the formation of sodium pyrimidine-4-thiolate via condensation of N' arylidene-2-cyanoacetohydrazides with sodium cyanocarbonimidodithioate salt, followed by coupling with halo sugars to give the corresponding cytosine thioglycoside analogs. Ammonolysis of the latter compounds afforded the free thioglycosides. PMID- 26986630 TI - Hydrogen bonding in DPD: application to low molecular weight alcohol-water mixtures. AB - In this work we propose a computational approach to mimic hydrogen bonding in a widely used coarse-grained simulation method known as dissipative particle dynamics (DPD). The conventional DPD potential is modified by adding a Morse potential term to represent hydrogen bonding attraction. Morse potential parameters are calculated by a mapping of energetic and structural properties to those of atomistic scale simulations. By the addition of hydrogen bonding to DPD and with the proposed parameterization, the volumetric mixing behavior of low molecular weight alcohols and water is studied and experimentally observed negative volume excess is successfully predicted, contrary to the conventional DPD implementation. Moreover, the density-dependent DPD parameterization employed provides the asymmetrical shapes of the excess volume curves. In addition, alcohol surface enrichment at the air interface and self-assembly in the bulk is studied. The surface concentrations of alcohols at the air interface compare favorably with the experimental observations at all bulk-phase alcohol fractions and, in consonance with experiment, some clustering is observed. PMID- 26986629 TI - S-Adenosylmethionine suppresses the expression of Smad3/4 in activated human hepatic stellate cells via Rac1 promoter methylation. AB - The aim of the present study was to investigate whether S-adenosylmethionine (SAM) was able to suppress activated human hepatic stellate cells (HSCs). Human LX-2 HSCs were cultured with SAM or NSC23766, and were transfected with plasmids encoding ras-related C3 botulinum toxin substrate 1 (Rac1) protein or an empty expression vector. Cell proliferation was detected by Cell Counting Kit-8. Cell migration and invasion were determined using the Transwell assay. The expression levels of Rac1 and Smad3/4 were detected by reverse transcription-quantitative polymerase chain reaction (PCR) or western blotting. The methylation status of Rac1 promoters was measured by methylation-specific PCR. The results demonstrated that SAM and NSC23766 suppressed the expression of Smad3/4 in LX-2 cells. The overexpression of Rac1 enhanced the proliferation, migration and invasion of LX-2 cells. In addition, compared with the control groups, a marked increase was observed in the protein expression levels of Smad3/4 in the LX-2 cells transfected with Rac1 plasmids. The methylation-specific PCR findings showed that SAM increased the methylation of Rac1 promoters. The results of the present study suggested that Rac1 enhanced the expression of Smad3/4 in activated HSCs; however, this increase may be suppressed by SAM-induced methylation of Rac1 promoters. PMID- 26986632 TI - GABAA Receptor Modulation by Phenyl Ring Compounds Is Associated with a Water Solubility Cut-Off Value. AB - BACKGROUND: The modulation of N-methyl-D-aspartate receptors is associated with a molar water solubility cut-off effect of approximately 1.1 mmol/l and hence are unaffected by significantly less soluble compounds. However, compounds with this molar water solubility are still able to modulate x03B3;-aminobutyric acid type A (GABAA) receptors. We hypothesized that GABAA receptor modulation by phenolic compounds would exhibit cut-off at a molar water solubility value less than 1.1 mmol/l. METHODS: GABAA receptors consisting of human alpha1 and rat beta2 and x03B3;2s subunits were expressed in Xenopus laevis oocytes, and drug responses were measured using standard 2-electrode voltage clamp techniques. Twenty substituted phenols and benzenes of similar size and molecular volume were studied at saturated aqueous concentrations. Reversible and statistically significant change in GABAA receptor current that was 10% or greater in magnitude from the baseline response defined a positive drug effect. RESULTS: All phenyl ring compounds with a molar water solubility value equal to or greater than 0.46 mmol/l positively modulated GABAA receptor currents. No compounds with a molar water solubility value equal to or less than 0.10 mmol/l had any effect on GABAA receptor currents. Saturated solutions of phenols with 2,6-dimethyl and 2,6 diisopropyl substituents also caused channel opening in the absence of GABA. CONCLUSIONS: The molar water solubility cut-off for GABAA receptor modulation by phenyl ring compounds lies between 0.10 and 0.46 mmol/l. Data suggest that hydrocarbons, perhaps including inhaled anesthetics, might modulate GABAA receptors by displacing water from one or more low-affinity amphipathic binding sites to induce conformational changes that increase ion conductance. PMID- 26986633 TI - Scaling-down antibody radiolabeling reactions with zirconium-89. AB - The most widely cited procedures for radiolabeling antibodies with zirconium-89 for immuno-PET require multi-milligram amounts of antibody which can be cost prohibitive, particularly during the research and development process. We therefore sought to develop a reliable (89)Zr-radiolabeling procedure that provides high radiochemical yields at the microgram scale. PMID- 26986634 TI - Selective suppression of Notch1 inhibits proliferation of renal cell carcinoma cells through JNK/p38 pathway. AB - The present study was performed to explore the effects of Notch1 inhibition selectively by siRNA on the proliferation and cell cycle of renal carcinoma cells. Human renal carcinoma cell lines, 786-0 and Caki-1, were treated with Si Notch1 or negative control (NC). RT-PCR and western blotting were used to confirm the efficiency of siRNA on Notch1 expression. MTT, cell cycle analysis, colony formation as well as migration and invasion assays were performed. The expression levels of p38 and SAPK/JNK were measured by western blotting. For both cell lines, as compared with the NC group, the cell growth was markedly reduced, and colony formation was restricted in the Si-Notch1-treated group. After incubated with Si-Notch1 or NC for 48 h, Si-Notch1-treated cells arrested the cell cycle at G1/S phase. The Si-Notch1 group also had a reduced rate of migration as well as invasion. Moreover, we observed a reduction in p-SAPK/JNK and p-p38 in Si-Notch1 transfected cells. The present study indicated that Notch signaling is important in the tumorigenesis of renal cell carcinoma. Notch1 may be a potential therapeutic regimen towards renal cell carcinoma, and JNK/p38 may serve as an important molecular mechanism for Notch1-mediated carcinogenesis. PMID- 26986635 TI - Synthesis, characterization, molecular modeling, and potential antimicrobial and anticancer activities of novel 2-aminoisoindoline-1,3-dione derivatives. AB - In an effort to establish new drug candidates with improved antimicrobial and anticancer activities, we report here synthesis, molecular modeling, and in vitro biological evaluation of novel substituted N-amino phthalamide derivatives (3a-b, 4a-b, 5a-j, and 6). Structures of the newly synthesized compounds were described by IR, (1)H &(13)CNMR and LC-MS spectral data. The novel compounds were evaluated for their antibacterial activity against four types of Gm+ve and two for Gm-ve types, and antifungal activity against three fungi microorganisms by well diffusion method. Of these novel compounds, Schiff bases showed mostly promising antibacterial activity compared to reference drugs. A successful step was done for explanation of their mode of action through molecular docking of most active molecules at DNA gyrase B enzyme and further were biologically tested. Moreover, the antiproliferative activity was tested against two human carcinoma cell lines (Human colon carcinoma (HCT-116) and human breast adenocarcinoma (MCF-7)) showing promising anticancer activity compared to doxorubicin drug. The data from structure-activity relationship (SAR) analysis revealed that the lypophilic properties of these compounds might be essential parameter for their activity and suggest that 2-amino phthalamide scaffold derivatives 5g and 5h exhibited good antimicrobial and anticancer activities and might used as leads for further optimization. PMID- 26986636 TI - Novel analogs of alloferon: Synthesis, conformational studies, pro-apoptotic and antiviral activity. AB - In this study, we report the structure-activity relationships of novel derivatives of the insect peptide alloferon (H-His-Gly-Val-Ser-Gly-His-Gly-Gln His-Gly-Val-His-Gly-OH). The peptide structure was modified by exchanging His at position 9 or 12 for natural or non-natural amino acids. Biological properties of these peptides were determined in antiviral in vitro test against Human Herpes Virus 1 McIntrie strain (HHV-1MC) using a Vero cell line. The peptides were also evaluated for the pro-apoptotic action in vivo on hemocytes of the Tenebrio molitor beetle. Additionally, the structural properties of alloferon analogs were examined by the circular dichroism in water and methanol. It was found that most of the evaluated peptides can reduce the HHV-1 titer in Vero cells. [Ala(9)] alloferon exhibits the strongest antiviral activity among the analyzed compounds. However, no cytotoxic activity against Vero cell line was observed for all the studied peptides. In vivo assays with hemocytes of T. molitor showed that [Lys(9)]-, [Phg(9)]-, [Lys(12)]-, and [Phe(12)]-alloferon exhibit a twofold increase in caspases activity in comparison with the native peptide. The CD conformational studies indicate that the investigated peptides seem to prefer the unordered conformation. PMID- 26986638 TI - A comparative life cycle assessment of material handling systems for sustainable mining. AB - In this comprehensive LCA comparison study, main objectives are to investigate life cycle environmental impacts of off-highway mining trucks and belt conveyors in surface mining. The research methodology essentially entails determination of the functional unit as 20,000 tons/day coal production transported for 5 km distance. After the system boundary was selected as the entire life cycle of material handling systems including pre-manufacturing of steel parts and plastic components, manufacturing, transportation, and utilization data was compiled from equipment manufacturers and the Eco-invent database. Life cycle impact categories for both material-handling systems were identified and the developed model was implemented using SIMAPRO 7.3. Climate change and acidification were selected as major impact categories as they were considered to be major concerns in mining industry. Although manufacturing stage had a significant impact on all of the environmental parameters, utilization stage was the hotspot for the selected impact categories. The results of this study revealed that belt conveyors have a greater environmental burden in climate change impact category when compared to the trucks. On the other hand, trucks have a greater environmental burden in acidification impact category when compared to the belt conveyors. This study implied that technological improvement in fuel combustion and electricity generation is crucial for the improvement of environmental profiles of off highway trucks and belt conveyors in the mining industry. The main novelty of this study is that it is the first initiative in applying LCA in the Turkish mining industry. PMID- 26986637 TI - 5,7-Dihydroxy-6-geranylflavanone improves insulin sensitivity through PPARalpha/gamma dual activation. AB - In the present study, we demonstrate that 5,7-dihydroxy-6-geranylflavanone (DGF) isolated from Amorpha fruticosa (A. fruticosa) is a novel peroxisome proliferator activated receptor (PPAR)alpha/gamma dual agonist which may be used to improve insulin sensitivity. The extract from A. fruticosa increased the transcriptional activity of both PPARalpha and PPARgamma which was, in part, driven by the active ingredient DGF. Treatment with DGF markedly enhanced the adipogenesis of 3T3-L1 preadipocytes, which was comparable to the effect of the PPARgamma agonist, troglitazone. In addition, DGF was found to enhance fatty acid oxidation and glucose utilization through the dual activation of PPARalpha/gamma. In addition treatment with DGF led to an improvement in insulin sensitivity, resulting in enhanced glucose uptake in muscle cells. The findings of our study data suggest that DGF may be used as potential therapeutic agent in the treatment of type 2 diabetes and related metabolic disorders by enhancing glucose and lipid metabolism. PMID- 26986639 TI - HPLC method development for the online-coupling of chromatographic Perilla frutescens extract separation with xanthine oxidase enzymatic assay. AB - Enzyme-regulatory effects of compounds contained in complex mixtures can be unveiled by coupling a continuous-flow enzyme assay to a chromatographic separation. A temperature-elevated separation was developed and the performance was tested using Perilla frutescens plant extracts of various polarity (water, methanol, ethanol/water). Owning to the need of maintaining sufficient enzymatic activity, only low organic solvent concentrations can be added to the mobile phase. Hence, to broaden the spectrum of eluting compounds, two different organic solvents and various contents were tested. The chromatographic performance and elution was further improved by the application of a moderate temperature gradient to the column. By taking the effect of eluent composition as well as calculated logD values and molecular structure of known extract compounds into account, unknown features were tentatively assigned. The method used allowed the successful observation of an enzymatic inhibition caused by P. frutescens extract. PMID- 26986641 TI - New Insights Into the Genomic Alterations in Glioma Progression. PMID- 26986642 TI - High-Resolution Computational Modeling of Somatosensory Cortex. PMID- 26986643 TI - New Targeted Treatment for Ankylosing Spondylitis. PMID- 26986644 TI - Comprehensive Genomic Analysis of Infiltrative Gliomas Based on Molecular Profile. PMID- 26986646 TI - Genomic Characterization of Isocitrate Dehydrogenase-1-Mutant Glioma Malignant Progression. PMID- 26986648 TI - Detection of Human Brain Tumor Infiltration With Quantitative Stimulated Raman Scattering Microscopy. PMID- 26986647 TI - 2-Hydroxy-Glutarate 3-Dimensional Functional Spectroscopy in the Evaluation of Isocitrate Dehydrogenase-Mutant Glioma Response to Therapy. PMID- 26986649 TI - Rhapontigenin inhibits TGF-beta-mediated epithelial-mesenchymal transition via the PI3K/AKT/mTOR pathway and is not associated with HIF-1alpha degradation. AB - The epithelial-mesenchymal transition (EMT) is a pivotal event in cancer cell invasion and metastasis. Emerging evidence suggests that rhapontigenin (Rha) may impede the progression of cancer by disrupting angiogenesis and the EMT. However, the underlying mechanism of Rha has not yet been clarified. In this study, we used transforming growth factor beta (TGF-beta) to trigger EMT in diverse types of cancer cells and revealed that Rha inhibited TGF-beta-induced EMT and derived cell invasiveness. The effects of TGF-beta were blocked by Rha via interference with the PI3K/AKT/mTOR/GSK3beta/beta-catenin signaling pathway. Furthermore, Rha also inhibited TGF-beta-induced expression of transcription regulators Snail and hypoxia-inducible factor 1alpha (HIF-1alpha) by causing their degradation by the 26S proteasome. Surprisingly, although HIF-1alpha was degraded with Snail as a result of Rha exposure, HIF-1alpha was not a key factor involved in TGF-beta mediated EMT induced by Rha. Knocking-down Snail expression, but not HIF-1alpha expression, by RNA interference dramatically reversed TGF-beta-mediated EMT. Moreover, Rha abolished TGF-beta-triggered cell invasiveness. Our results demonstrate that Rha inhibits TGF-beta-induced EMT in cancer cells by suppressing the activity of the PI3K/AKT/mTOR pathway. Therefore, Rha may represent a new route for therapeutic intervention in cancer patients and merits future studies to assess its potential. PMID- 26986651 TI - A comparison between r-LH and urinary supplements containing LH activity in patients undergoing the microdose GnRH agonist flare protocol for in-vitro fertilization: a pilot study. AB - BACKGROUND: The aim of this study was to compare pregnancy rates and stimulation parameters in patients with diminished ovarian reserve, who were treated with recombinant human luteinizing hormone (r-LH) or menopausal gonadotropins (hMG), as part of a microdose flare protocol. METHODS: A retrospective cohort study was performed. Comparisons between the group that was stimulated with r-LH plus follicle stimulating hormone (FSH) to those treated with hMG and FSH, were performed. Measurements included: medication doses, number of oocyte collected, number of embryos obtained, pregnancy and clinical pregnancy rates. RESULTS: Patients in the r-LH group (N.=40) had significant higher clinical pregnancy rates (33% vs. 14%; P=0.04) and used lower dose of LH (1938 IU vs. 2807 IU; P=0.02) compared to patients that were stimulated with hMG (N.=39). CONCLUSIONS: r-LH may offer advantages for the treatment of diminished ovarian reserve when performing a microdose flare protocol when compared to hMG. Both larger and prospective studies should be carried out to confirm these findings. PMID- 26986652 TI - [1]Benzothieno[3,2-b]benzothiophene-Based Organic Dyes for Dye-Sensitized Solar Cells. AB - Three new metal-free organic dyes with the [1]benzothieno[3,2-b]benzothiophene (BTBT) pi-bridge, having the structure donor-pi-acceptor (D-pi-A) and labeled as 19, 20 and 21, have been designed and synthesized for application in dye sensitized solar cells (DSSC). Once the design of the pi-acceptor block was fixed, containing the BTBT as the pi-bridge and the cyanoacrylic group as the electron acceptor and anchoring unit, we selected three donor units with different electron-donor capacity, in order to assemble new chromophores with high molar extinction coefficients (epsilon), whose absorption features well reflect the good performance of the final DSSC devices. Starting with the 19 dye, which shows a molar extinction coefficient epsilon of over 14,000 M(-1) cm(-1) and takes into account the absorption maximun at the longer wavelength, the substitution of the BFT donor unit with the BFA yields a great enhancement of absorptivity (molar extinction coefficient epsilon > 42,000 M(-1) cm(-1)), until reaching the higher value (epsilon > 69,000 M(-1) cm(-1)) with the BFPhz donor unit. The good general photovoltaic performances obtained with the three dyes highlight the suitable properties of electron-transport of the BTBT as the pi bridge in organic chromophore for DSSC, making this very cheap and easy to synthesize molecule particularly attractive for efficient and low-cost photovoltaic devices. PMID- 26986650 TI - Molecular subtyping of prostate cancer. AB - PURPOSE OF REVIEW: The recent publication of The Cancer Genome Atlas molecular taxonomy of primary prostate cancer highlights the increased understanding of the genomic basis of human prostate cancer, but also emphasizes the complexity and heterogeneity of prostate cancer. RECENT FINDINGS: Seven molecular subclasses have been defined on the basis of early genomic alterations, which are largely mutually exclusive. SUMMARY: We review the recent advances in the genomic understanding of human prostate cancer, with focus on molecular subclassification. Broadly, prostate cancer can be classified based upon whether specific genomic rearrangements, such as the Transmembrane Protease, Serine 2-ETS related gene fusion occur or whether specific alterations such as Speckle-type POZ protein and forkhead box A1 mutations occur. The molecular drivers remain to be identified in a further quarter of human prostate cancers. Depending upon the molecular subclassification and the coincident genomic alterations, specific clinical insights can be gained from this information, including associations with pathologic factors, race, and prognosis, as well as the possibility for future precision therapies. PMID- 26986654 TI - Lymphangiogenesis in Inflammatory Bowel Disease; A New Therapeutic Target? PMID- 26986653 TI - A Novel Resolvin-Based Strategy for Limiting Acetaminophen Hepatotoxicity. AB - OBJECTIVES: Acetaminophen (APAP)-induced hepatotoxicity is a major cause of morbidity and mortality. The current pharmacologic treatment for APAP hepatotoxicity, N-acetyl cysteine (NAC), targets the initial metabolite-driven injury but does not directly affect the host inflammatory response. Because of this, NAC is less effective if given at later stages in the disease course. Resolvins, a novel group of lipid mediators shown to attenuate host inflammation, may be a therapeutic intervention for APAP hepatotoxicity. METHODS: The temporal patterns of liver injury and neutrophil activation were investigated in a murine model of APAP hepatotoxicity. In addition, the effect of neutrophil depletion and resolvin administration on the severity of liver injury induced by APAP was studied. In vitro studies to investigate the mechanism of resolvin effect on hepatocyte injury and neutrophil adhesion were performed. RESULTS: We demonstrate that hepatic neutrophil activation occurs secondary to the initial liver injury induced directly by APAP. We also show that neutrophil depletion attenuates APAP induced liver injury, and administration of resolvins hours after APAP challenge not only attenuates liver injury, but also extends the therapeutic window eightfold compared to NAC. Mechanistic in vitro analysis highlights resolvins' ability to inhibit neutrophil attachment to endothelial cells in the presence of the reactive metabolite of APAP. CONCLUSIONS: This study highlights the ability of resolvins to protect against APAP-induced liver injury and extend the therapeutic window compared to NAC. Although the mechanism for resolvin-mediated hepatoprotection is likely multifactorial, inhibition of neutrophil infiltration and activation appears to play an important role. PMID- 26986658 TI - A metagenome for lacustrine Cladophora (Cladophorales) reveals remarkable diversity of eukaryotic epibionts and genes relevant to materials cycling. AB - Periphyton dominated by the cellulose-rich filamentous green alga Cladophora forms conspicuous growths along rocky marine and freshwater shorelines worldwide, providing habitat for diverse epibionts. Bacterial epibionts have been inferred to display diverse functions of biogeochemical significance: N-fixation and other redox reactions, phosphorus accumulation, and organic degradation. Here, we report taxonomic diversity of eukaryotic and prokaryotic epibionts and diversity of genes associated with materials cycling in a Cladophora metagenome sampled from Lake Mendota, Dane Co., WI, USA, during the growing season of 2012. A total of 1,060 distinct 16S, 173 18S, and 351 28S rRNA operational taxonomic units, from which >220 genera or species of bacteria (~60), protists (~80), fungi (6), and microscopic metazoa (~80), were distinguished with the use of reference databases. We inferred the presence of several algal taxa generally associated with marine systems and detected Jaoa, a freshwater periphytic ulvophyte previously thought endemic to China. We identified six distinct nifH gene sequences marking nitrogen fixation, >25 bacterial and eukaryotic cellulases relevant to sedimentary C-cycling and technological applications, and genes encoding enzymes in aerobic and anaerobic pathways for vitamin B12 biosynthesis. These results emphasize the importance of Cladophora in providing habitat for microscopic metazoa, fungi, protists, and bacteria that are often inconspicuous, yet play important roles in ecosystem biogeochemistry. PMID- 26986655 TI - An Overview of the Diagnosis and Management of Eosinophilic Esophagitis. AB - Eosinophilic esophagitis (EoE) is a chronic inflammatory condition characterized by symptoms of esophageal dysfunction and eosinophilic infiltration of the esophageal mucosa. The diagnosis requires esophageal biopsies demonstrating at least 15 eosinophils per high-powered field following a course of high-dose proton pump inhibitors. Management of EoE consists of the three Ds: drugs, dietary therapy, and esophageal dilation. In this review, we discuss the epidemiology, pathogenesis, diagnosis, and treatment of EoE to include the role of emerging therapies. PMID- 26986657 TI - Discovery of the mineral brucite (magnesium hydroxide) in the tropical calcifying alga Polystrata dura (Peyssonneliales, Rhodophyta). AB - Red algae of the family Peyssonneliaceae typically form thin crusts impregnated with aragonite. Here, we report the first discovery of brucite in a thick red algal crust (~1 cm) formed by the peyssonnelioid species Polystrata dura from Papua New Guinea. Cells of P. dura were found to be infilled by the magnesium rich mineral brucite [Mg(OH)2 ]; minor amounts of magnesite and calcite were also detected. We propose that cell infill may be associated with the development of thick (> ~5 mm) calcified red algal crusts, integral components of tropical biotic reefs. If brucite infill within the P. dura crust enhances resistance to dissolution similarly to crustose coralline algae that infill with dolomite, then these crusts would be more resilient to future ocean acidification than crusts without infill. PMID- 26986656 TI - More Is Not Always Better: A Randomized Trial Of Low Volume Oral Laxative, Enemas, And Combination Of Both Demonstrate That Enemas Alone Are Most Efficacious For Preparation For Flexible Sigmoidoscopy. AB - OBJECTIVES: Colon cleansing for flexible sigmoidoscopy using a standard fleet enema does not provide adequate cleansing in a significant number of patients. We tested whether the addition of a low-volume oral cleansing agent could mitigate this challenge without significantly compromising patient tolerance. HYPOTHESIS: Oral picosulfate with magnesium citrate (P/MC) would enhance the colon cleansing of patients undergoing sigmoidoscopy, as assessed by the modified Ottawa Bowel Preparation Score. METHODS: A randomized single blinded trial comparing (1) a single dose (i.e., one sachet) of oral sodium picosulfate plus magnesium citrate (P/MC) administered the night before, (2) a single dose oral P/MC the night before plus sodium phosphate enema 1 h before leaving home, and (3) sodium phosphate enema alone 1 h before leaving home for flexible sigmoidoscopy was conducted on outpatients referred for sigmoidoscopy for symptom assessment. RESULTS: A total 120 patients were randomized to the study groups. The main indication for sigmoidoscopy was investigation of rectal bleeding (n=80). There was no significant difference in bowel cleansing quality, measured by the endoscopist blinded to preparation, between P/MC, P/MC plus enema, and enema alone as measured by the modified Ottawa Bowel Preparation Scale (P=0.34) or the Aronchick Scale (P=0.13). Both oral P/MC regimens were associated with higher incidence of nausea, abdominal pain, bloating, and interrupted sleep than enema alone (P<0.05). CONCLUSIONS: A single dose of oral P/MC administered the night before did not result in better colon cleansing for sigmoidoscopy when used alone or with an enema and was associated with more side effects (NCT 01554111). PMID- 26986660 TI - The immediate wound-induced oxidative burst of Saccharina latissima depends on light via photosynthetic electron transport. AB - Reactive oxygen species (ROS) produced by an oxidative burst are an important component of the wound response in algae, vascular plants, and animals. In all taxa, ROS production is usually attributed solely to a defense-related enzyme like NADPH-oxidase (Nox). However, here we show that the initial, wound-induced oxidative burst of the kelp Saccharina latissima depends on light and photosynthetic electron transport. We measured oxygen evolution and ROS production at different light levels and in the presence of a photosynthetic inhibitor, and we used spin trapping and electron paramagnetic resonance as an orthogonal method. Using an in vivo chemical probe, we provide data suggesting that wound-induced ROS production in two distantly related and geographically isolated species of Antarctic macroalgae may be light dependent as well. We propose that electron transport chains are an important and as yet unaddressed component of the wound response, not just for photosynthetic organisms, but for animals via mitochondria as well. This component may have been obscured by the historic use of diphenylene iodonium, which inhibits not only Noxes but also photosynthetic and respiratory electron transport as well. Finally, we anticipate physiological and/or ecological consequences of the light dependence of macroalgal wound-induced ROS since pathogens and grazers do not disappear in the dark. PMID- 26986661 TI - Process optimization and modeling for the cultivation of Nannochloropsis sp. and Tetraselmis striata via response surface methodology. AB - The aim of this study was to determine the optimal physical process conditions for the cultivation of locally isolated strains of Nannochloropsis sp. and Tetraselmis striata to achieve maximum growth rate. It was essential to evaluate biomass production at different agitation rates, light intensities, and temperature levels. Central composite design and response surface methodology were applied to design the experiments and optimize the cultivation process for Nannochloropsis sp. and T. striata. The specific growth rate of 0.250 d(-1) was obtained for Nannochloropsis sp. cells under the light intensity of 54 MUmol photons . m(-2) . s(-1) , at the agitation rate of 151 rpm in 24.5 degrees C. The optimal physical process conditions for T. striata were obtained under the light intensity of 56 MUmol photons . m(-2) . s(-1) in 25.5 degrees C at the agitation rate of 151 rpm in 25.5 degrees C, resulting in a specific growth rate of 0.226 d(-1) . The predicted values were justified by the verification tests. Good agreement between the predicted values and the experimental values confirmed the validity of the models for the cultivation of microalgal strains. In this article, the noteworthy result was that temperature was a dominant factor in obtaining high chl-a content for Nannochloropsis sp., whereas the growth of T. striata strongly depended on light exposure. PMID- 26986662 TI - Multi-gene phylogenetic analyses of New Zealand coralline algae: Corallinapetra Novaezelandiae gen. et sp. nov. and recognition of the Hapalidiales ord. nov. AB - Coralline red algae from the New Zealand region were investigated in a study focused on documenting regional diversity. We present a multi-gene analysis using sequence data obtained for four genes (nSSU, psaA, psbA, rbcL) from 68 samples. The study revealed cryptic diversity at both genus and species levels, confirming and providing further evidence of problems with current taxonomic concepts in the Corallinophycidae. In addition, a new genus Corallinapetra novaezelandiae gen. et sp. nov. is erected for material from northern New Zealand. Corallinapetra is excluded from all currently recognized families and orders within the Corallinophycidae and thus represents a previously unrecognized lineage within this subclass. We discuss rank in the Corallinophycidae and propose the order Hapalidiales. PMID- 26986659 TI - Meiotic genes and sexual reproduction in the green algal class Trebouxiophyceae (Chlorophyta). AB - Sexual reproduction is widespread in eukaryotes and is well documented in chlorophytan green algae. In this lineage, however, the Trebouxiophyceae represent a striking exception: in contrast to its relatives Chlorophyceae and Ulvophyceae this group appears to be mostly asexual, as fertilization has been rarely observed. Assessments of sexual reproduction in the Trebouxiophyceae have been based on microscopic observation of gametes fusing. New genomic data offer now the opportunity to check for the presence of meiotic genes, which represent an indirect evidence of a sexual life cycle. Using genomic and transcriptomic data for 12 taxa spanning the phylogenetic breadth of the class, we tried to clarify whether genuine asexuality or cryptic sexuality is the most likely case for the numerous putatively asexual trebouxiophytes. On the basis of these data and a bibliographic review, we conclude that the view of trebouxiophytes as primarily asexual is incorrect. In contrast to the limited number of reports of fertilization, meiotic genes were found in all genomes and transcriptomes examined, even in species presumed asexual. In the taxa examined the totality or majority of the genes were present, Helicosporidium and Auxenochlorella being the only partial exceptions (only four genes present). The evidence of sex provided by the meiotic genes is phylogenetically widespread in the class and indicates that sexual reproduction is not associated with any particular morphological or ecological trait. On the basis of the results, we expect that the existence of the meiotic genes will be documented in all trebouxiophycean genomes that will become available in the future. PMID- 26986663 TI - Morphology and molecular phylogeny of Chaetoceros dayaensis sp. nov. (Bacillariophyceae), characterized by two 90 degrees rotations of the resting spore during maturation. AB - Recent studies suggest that a high species diversity of Chaetoceros exists in tropical waters. Based on plankton samples from Chinese tropical waters, Daya Bay of the South China Sea, a new species, Chaetoceros dayaensis sp. nov., is described. Vegetative cells and resting spores were examined by light microscopy as well as transmission and scanning electron microscopy. The nuclear rDNA molecular markers SSU, ITS and D1-D3 of LSU, and the chloroplast rbcL gene were sequenced for information on phylogenetic relationships. The species is characterized by the presence of two 90 degrees rotations of the resting spore during maturation. First a rotation in the apical plane of the mother cell resulting in the valvar plane of the resting spore turning from parallel to perpendicular to that of the mother cell, and a second 90 degrees rotation in the valvar plane of the mother cell resulting in the valve faces of the resting spore turning from facing narrow girdle view to broad girdle view of the mother cell. It is the first report of two 90 degrees rotations of resting spores during maturation in Chaetoceros. Based on this, the maturation rotation of the resting spore of C. rotosporus was reevaluated. C. dayaensis belongs to the subgenus Hyalochaete Gran and we suggest placing it in the section Laciniosa, although a new subdivision of Chaetoceros is needed. The description of C. dayaensis was based on analyses of the phylogenetic relationships combined with morphological comparisons with other similar species. PMID- 26986664 TI - Molecular evidence for the coexistence of two sibling species in Pylaiella littoralis (Ectocarpales, Phaeophyceae) along the Brittany coast. AB - The great phenotypic variability and the lack of diagnostic characters in the genus Pylaiella render the systematic study of this genus problematic. In this study, we investigated the diversity of Pylaiella littoralis along the Brittany (France) coast using a DNA barcoding multilocus approach with mitochondrial (cox1, nad1, and atp9) and chloroplastic (rbcL and atpB) markers associated with a population genetics approach using 10 microsatellite markers. In addition, spatio-temporal sampling was conducted along the Brittany coast. We sampled 140 individuals from four sites located between Saint-Malo and Concarneau (380 km) from April to October. Mitochondrial sequence data revealed the occurrence of two sibling species, with a minimum of 2.4% divergence between them. Microsatellite genotypic data congruently revealed two well-supported clusters matching the two mitochondrial clades of Pylaiella. Although gene flow is limited between species, occurrence of genetic admixtures in some populations suggested that reproductive isolation is not complete. Our study highlighted the complementarity of barcoding and population genetics approaches to shed light on the evolutionary processes that lead to speciation. PMID- 26986665 TI - Diversity of nitrogen assimilation pathways among microbial photosynthetic eukaryotes. AB - In an effort to better understand the diversity of genes coding for nitrogen (N) uptake and assimilation pathways among microalgae, we analyzed the transcriptomes of five phylogenetically diverse single celled algae originally isolated from the same high arctic marine region. The five photosynthetic flagellates (a pelagophyte, dictyochophyte, chrysoph-yte, cryptophyte and haptophyte) were grown on standard media and media with only urea or nitrate as a nitrogen source; cells were harvested during late exponential growth. Based on homolog protein sequences, transcriptomes of each alga were interrogated to retrieve genes potentially associated with nitrogen uptake and utilization pathways. We further investigated the phylogeny of poorly characterized genes and gene families that were identified. While the phylogeny of the active urea transporter (DUR3) was taxonomically coherent, those for the urea transporter superfamily, putative nitrilases and amidases indicated complex evolutionary histories, and preliminary evidence for horizontal gene transfers. All five algae expressed genes for ammonium assimilation and all but the chrysophyte expressed genes involved in nitrate utilization and the urea cycle. Among the four algae with nitrate transporter transcripts, we detected lower expression levels in three of these (the dictyochophyte, pelagophyte, and cryptophyte) grown in the urea only medium compared with cultures from the nitrate only media. The diversity of N pathway genes in the five algae, and their ability to grow using urea as a nitrogen source, suggest that these flagellates are able to use a variety of organic nitrogen sources, which would be an advantage in an inorganic nitrogen - limited environment, such as the Arctic Ocean. PMID- 26986666 TI - Assembling the challenging puzzle of algal biodiversity: species delimitation within the genus Asterochloris (Trebouxiophyceae, Chlorophyta). AB - The genus Asterochloris represents one of the most common, widespread, and diverse taxa of lichen photobionts. In this report, we describe and characterize six new species (A. echinata, A. friedlii, A. gaertneri, A. leprarii, A. lobophora, and A. woessiae) that were identified during our recent investigation of photobiont diversity. We found that the species differed genetically, morphologically, ecologically, and with respect to their mycobiont partners. Statistical analyses revealed significant morphological differentiation of all six newly described species, as well as their separation from previously described Asterochloris species. Chloroplast morphology represented the best morphological marker for species delineation. In fact, each species can be recognized by the dominance and unique assemblage of particular chloroplast types. Although genetically well recognized by rapidly evolving internal transcribed spacer rDNA and actin intron markers, all 13 investigated Asterochloris species shared identical small subunit rDNA sequences. We therefore demonstrated that morphologically and ecologically diverse species can frequently be grouped into a single taxonomic unit in whole-transcriptome sequencing studies, considerably affecting the resulting estimates of species diversity. Finally, we demonstrated the presence of isogamous sexual reproduction in Asterochloris, disputing the current symbiotic dogma of the loss of sexual reproduction in algal symbionts. PMID- 26986667 TI - The role of light availability and herbivory on algal responses to nutrient enrichment in a riparian wetland, Alaska. AB - We investigated how the relative availability of solar radiation in the presence or absence of grazing alters the ability of benthic algae to respond to nutrient enrichment in an Alaskan marsh. We used a factorial mesocosm experiment that included nutrient enrichment (enriched or control), grazing (grazed or ungrazed), and light (unshaded or shaded) to simulate shading by macrophytes early and late in the growing season, respectively. We found stronger effects of grazers and nutrients compared to light on benthic algal biomass and taxonomic composition. Algal biomass increased in nutrient-enriched treatments and was reduced by grazing. Shading did not have an effect on algal biomass or taxonomic composition, but the concentration of chl a per algal biovolume increased with shading, demonstrating the ability of algae to compensate for changes in light availability. Algal taxonomic composition was more affected by grazer presence than nutrients or light. Grazer-resistant taxa (basal filaments of Stigeoclonium) were replaced by diatoms (Nitzschia) and filamentous green algae (Ulothrix) when herbivores were removed. The interacting and opposing influences of nutrients and grazing indicate that the algal community is under dual control from the bottom up (nutrient limitation) and from the top-down (consumption by herbivores), although grazers had a stronger influence on algal biomass and taxonomic composition than nutrient enrichment. Our results suggest that low light availability will not inhibit the algal response to elevated nutrient concentrations expected with ongoing climate change, but grazers rapidly consume algae following enrichment, masking the effects of elevated nutrients on algal production. PMID- 26986668 TI - Indirect and direct effects of salinity on the quantity and quality of total amino acids in Ulva ohnoi (Chlorophyta). AB - Salinity can affect the quantity and quality of total amino acids (TAAs) in seaweeds indirectly by altering growth rates and thereby diluting or concentrating the amino acid content of the biomass, or directly by altering the synthesis of specific amino acids and osmolytes. This study attempted to partition the indirect and direct effects of salinity on the quantity and quality of TAAs in the green seaweed Ulva ohnoi by culturing it under a range of salinities without nutrient limitation. Both the quantity and quality of TAAs varied across the salinity treatments. Quantity was most strongly related to the growth rate of the seaweed and was highest in the slowest growing seaweed. In contrast, the quality of TAAs (individual amino acids as a proportion of total content) was most strongly related to salinity for all amino acids, although this varied substantially among individual amino acids. Increases in salinity were positively correlated with the proportion of proline (46% increase), tyrosine (36% increase), and histidine (26% increase), whereas there was a negative correlation with alanine (29% decrease). The proportion of methionine, with strong links to the synthesis of the osmolyte dimethylsulfoniopropionate, did not correlate linearly with salinity and instead was moderately higher at the optimal salinities for growth. These results show that salinity simultaneously affects the quantity and quality of TAAs in seaweed through both indirect and direct mechanisms, with growth rates playing the overarching role in determining the quantity of TAAs. PMID- 26986669 TI - A phylogenetic re-appraisal of the family Liagoraceae sensu lato (Nemaliales, Rhodophyta) based on sequence analyses of two plastid genes and postfertilization development. AB - The marine red algal family Liagoraceae sensu lato is shown to be polyphyletic based on analyses of a combined rbcL and psaA data set and the pattern of carposporophyte development. Fifteen of eighteen genera analyzed formed a monophyletic lineage that included the genus Liagora. Nemalion did not cluster with Liagoraceae sensu stricto, and Nemaliaceae is reinstated, characterized morphologically by the formation of the primary gonimolobes by longitudinal divisions of the gonimoblast initial. Yamadaella and Liagoropsis, previously placed in the Dermonemataceae, are shown to be independent lineages and are recognized as two new families Yamadaellaceae and Liagoropsidaceae. Yamadaellaceae is characterized by two gonimoblast initials cut off bilaterally from the fertilized carpogonium and diffusely spreading gonimoblast filaments. Liagoropsidaceae is characterized by at least three gonimoblast initials cut off by longitudinal septa from the fertilized carpogonium. In contrast, Liagoraceae sensu stricto is characterized by a single gonimoblast initial cut off transversely or diagonally from the fertilized carpogonium. Reproductive features, such as diffuse gonimoblasts and unfused carpogonial branches following postfertilization, appear to have evolved on more than one occasion in the Nemaliales and are therefore not taxonomically diagnostic at the family level, although they may be useful in recognizing genera. PMID- 26986670 TI - Relationship between the dinoflagellate cyst Spiniferites pachydermus and Gonyaulax ellegaardiae sp. nov. from Izmir Bay, Turkey, and molecular characterization. AB - Here, we established the cyst-motile stage relation-ship for Spiniferites pachydermus through incubation of cysts with a characteristically microreticulate/perforate surface isolated from Izmir Bay in the eastern Aegean Sea of the eastern Mediterranean. The morphology of the motile stage was similar to Gonyaulax spinifera but had a different size, overhang, displacement and reticulations. Based on the distinct morphology of the cyst and morphological differences in motile cells, we assigned S. pachydermus from Izmir Bay to the new species Gonyaulax ellegaardiae. We elucidate the phylogenetic relationship of G. ellegaardiae through large and small subunit ribosomal DNA and show that it forms a clade with other species that belong to the G. spinifera complex. PMID- 26986671 TI - Contrasting patterns of population structure and demographic history in cryptic species of Bostrychia intricata (Rhodomelaceae, Rhodophyta) from New Zealand. AB - Spatial patterns of genetic diversity provide insight into the demography and history of species. Morphologically similar but genetically distinct "cryptic" species are increasingly being recognized in marine organisms through molecular analyses. Such species are, on closer inspection, often discovered to display contrasting life histories or occasionally minor morphological differences; molecular tools can thus be useful indicators of diversity. Bostrychia intricata, a marine red alga, is widely distributed throughout the Southern Hemisphere and comprises many cryptic species. We used mitochondrial cytochrome c oxidase I gene sequences to assess the genetic variation, population genetic structure, and demographic history of B. intricata in New Zealand. Our results supported the existence of three cryptic species of B. intricata (N2, N4, and N5) in New Zealand. Cryptic species N4, which was found throughout New Zealand, showed a higher genetic diversity and wider distribution than the other two species, which were only found in the North Island and northern South Island. Our analyses showed low to moderate genetic differentiation among eastern North Island populations for cryptic species N2, but high differentiation among North and South Island populations for N4, suggesting different population structure between these cryptic species. Data also indicated that N2 has recently undergone population expansion, probably since the Last Glacial Maximum (LGM), while the higher genetic diversity in N4 populations suggests persistence in situ through the LGM. The contrasting population structures and inferred demographic histories of these species highlight that life history can vary greatly even among morphologically indistinguishable taxa. PMID- 26986672 TI - The plastid genome of the red alga Laurencia. AB - We present the 174,935 nt long plastid genome of the red alga Laurencia sp. JFC0032. It is the third plastid genome characterized for the largest order of red algae (Ceramiales). The circular-mapping plastid genome is small compared to most florideophyte red algae, and our comparisons show a trend toward smaller plastid genome sizes in the family Rhodomelaceae, independent from a similar trend in Cyanidiophyceae. The Laurencia genome is densely packed with 200 annotated protein-coding genes (188 widely conserved, 3 open reading frames shared with other red algae and 9 hypothetical coding regions). It has 29 tRNAs, a single-copy ribosomal RNA cistron, a tmRNA, and the RNase P RNA. PMID- 26986673 TI - Long-Term Effectiveness of Combined Treatment with Traditional Chinese Medicine and Western Medicine on the Prognosis of Patients with Lung Cancer. AB - OBJECTIVES: The study aim was to compare the long-term effect of Western medicine and combined treatment with Traditional Chinese Medicine (TCM) and Western medicine on the prognosis (survival rate, symptom distress, physical function, and quality of life) of patients with lung cancer. DESIGN: Longitudinal study. SETTING/LOCATION: Two medical centers, one each in Northern and Southern Taiwan. PATIENTS: Patients newly diagnosed with lung cancer and treated with Western medicine (n = 54) or TCM plus Western medicine (n = 30). OUTCOME MEASURES: Symptom distress, physical function, and quality of life were measured by using the Symptom Distress Scale, Eastern Cooperative Oncology Group-Performance Status Rating, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ-C30 and EORTC QLQ-LC13), respectively. Data on these measures were collected at baseline (before treatment) and 1, 3, 6, and 12 months after starting treatment. Survival was estimated by Kaplan-Meier curves. Group differences in outcomes were analyzed by generalized estimating equations. RESULTS: Treatment groups did not differ significantly at baseline for demographic information; disease severity; symptom distress; or EORTC QLQ-C30 and QLQ-LC13 scores, except for pain and dyspnea. After adjustment for these baseline effects, the combined-treatment group had better physical function and role function than the Western medicine group at 6 months (p < 0.05). The combined treatment group had better cumulative survival, but this difference did not reach significance. CONCLUSIONS: To more precisely estimate the long-term effectiveness of combined treatment on the prognosis of patients with lung cancer, future studies should standardize the number of TCM visits; increase the number of participants by continuous recruitment; and ask patients to complete daily logs with single-item measures of outcomes, such as symptom distress, quality of life, and physical function. Similar studies are suggested in patients with different cancers to develop a collaborative model using Western medicine and TCM. PMID- 26986675 TI - Parapharyngeal Space Mass. PMID- 26986674 TI - Reconstitution of Fusion Proteins in Supported Lipid Bilayers for the Study of Cell Surface Receptor-Ligand Interactions in Cell-Cell Contact. AB - Bioactive molecules such as adhesion ligands, growth factors, or enzymes play an important role in modulating cell behavior such as cell adhesion, spreading, and differentiation. Deciphering the mechanism of ligand-mediated cell adhesion and associated signaling is of great interest not only for fundamental biophysical investigations but also for applications in medicine and biotechnology. In the presented work, we developed a new biomimetic platform that enables culturing primary neurons and testing cell surface-receptor ligand interactions in cell cell contacts as, e.g., in neuronal synapses. This platform consists of a supported lipid bilayer modified with incorporated neuronal adhesion proteins conjugated with the Fc-domain of IgG (ephrin A5 Fc-chimera). We extensively characterized properties of these protein containing bilayers using fluorescence recovery after photobleaching (FRAP), quartz crystal microbalance with dissipation (QCM-D), and immunostaining. We conclude that the Fc-domain is the part responsible for the incorporation of the protein into the bilayer. The biomimetic platform prepared by this new approach was able to promote neuronal cell adhesion and maintain growth as well as facilitate neuronal maturation as shown by electrophysiological measurements. We believe that our approach can be extended to insert other proteins to create a general culture platform for neurons and other cell types. PMID- 26986677 TI - Medical Marijuana Use in Oncology: A Review. AB - Importance: Medicinal marijuana use is currently legal in 23 states and the District of Columbia. As more states approve marijuana use for medical indications, physicians will be asked by their patients for more information regarding the risks and benefits of use. This article reviews the history, adverse effects, and proposed mechanisms of action of marijuana and summarizes the available literature regarding symptom relief and therapeutic value in patients with cancer. Observations: Marijuana in oncology may have potential for use as an antiemetic, for refractory cancer pain, and as an antitumor agent. However, much of the data are based on animal data, small trials, or are outdated. Conclusions and Relevance: More research is needed in all areas related to the therapeutic use of marijuana in oncology. PMID- 26986676 TI - Variations in costs and use of provincially-funded testosterone replacement therapy across Canada: a population-based study. AB - INTRODUCTION: Provincial drug-program policies for the reimbursement of testosterone replacement therapy (TRT) vary across Canada, which may result in marked regional variability in use. METHODS: We conducted a population-based cross-sectional analysis of provincially funded TRT spending and utilization in eight provinces across Canada in 2012. We reported the annual cost per user, total cost, and rate of use of TRT overall and by formulation. RESULTS: We identified 23,544 provincially-funded recipients of TRT in 2012 in the eight provinces studied. Average annual cost per person varied by 3-fold, ranging from $173 (Prince Edward Island) to $485 (Ontario). Ontario also had the highest rate of use (1,105 users per 100,000 eligible) and the most liberal listing. Provinces with more restricted access (Alberta, British Columbia, and PEI) had lower annual costs per user ($293, $206, $173, respectively). CONCLUSIONS: Differing reimbursement policies for TRT products across Canada are likely contributing to variation in the rate of use and cost per recipient. PMID- 26986679 TI - Twenty years young. PMID- 26986678 TI - Concomitant use of Congo red staining and confocal laser scanning microscopy to detect amyloidosis in oral biopsy: A clinicopathological study of 16 patients. AB - Twenty oral biopsies from 16 patients were analyzed both by traditional microscopy and by confocal laser scanning microscopy. Using conventional histopathological techniques, the diagnosis of amyloidosis was confirmed only in 15 biopsies. Using confocal laser scanning microscopy, amyloid deposits were detected in all of the samples. The current study shows that confocal laser scanning analysis helps to identify minimal amyloid deposits that could be overlooked using traditional microscopy, thus raising the sensitivity of oral biopsy up to 100%. PMID- 26986681 TI - President's message. Vision, mission, action. PMID- 26986683 TI - Rural cardiac rehabilitation: a 20-year success story. AB - INTRODUCTION: Data are lacking on long-term participation in a clinically supervised cardiac rehabilitation program in a rural setting. We sought to determine whether there were sustained improvements in physiologic measures and discover what restorative and deteriorative processes took place over time. METHODS: We retrospectively analyzed the records of patients who were enrolled for a least 1 year in the Healthy Hearts Cardiac Rehabilitation Program. Data from stress tests were tracked for up to 18 years to determine whether there were any sustained improvements and what factors were associated with restorative and deteriorative processes. RESULTS: We analyzed data from 85 participants. The mean age of the participants was 72 years, and the mean length of participation was 8 years. Duration of stress testing significantly (p < 0.01) increased by a mean of 15% from the first year to the second year, with a corresponding increase in estimated metabolic equivalent of task (MET) level (Cohen d = 0.82). The increase in duration was sustained into the ninth year, with an overall increase of 35% compared with the first year of testing. After the ninth year, the duration and estimated MET levels declined. CONCLUSION: Participants in the cardiac rehabilitation program demonstrated improved duration of stress testing, and stable rate-pressure product, blood pressure and resting heart rate during long term participation in the program. PMID- 26986684 TI - Should I apply to medical school? High school students and barriers to application. AB - INTRODUCTION: A major goal of the Faculty of Medicine at the Memorial University of Newfoundland is to produce physicians who will return to rural areas that are currently underserviced. Research shows that the strongest indicator of practice in a rural area is a rural background, and thus it is important that rural students apply to medical school. We investigated what high school students believe to be preventing them from pursuing medical education. METHODS: Between September 2013 and June 2014, we administered a paper survey to high school students in Newfoundland and Labrador, New Brunswick and Prince Edward Island. RESULTS: A total of 665 participants completed the survey. We found that fewer rural students (75.6%) than urban students (98.6%) believed that they could gain admission to medical school (p < 0.01) and that medicine was promoted as a career choice in fewer rural schools (55.7%) than urban schools (69.7%). Also, 55.4% of urban students, but only 44.4% of rural students, believed that rural students were disadvantaged when applying to medical school. CONCLUSION: In our study, rural students believed they were less likely to be accepted into medical school than urban students, and fewer rural students felt that medicine was promoted as a potential career choice. Our results may be explained by a lack of role models or perhaps by financial barriers, although further research is needed. PMID- 26986685 TI - The occasional digital nerve block. PMID- 26986686 TI - Country cardiograms case 56. PMID- 26986688 TI - Seeds of hope. PMID- 26986689 TI - LTX-315, CAPtivating immunity with necrosis. PMID- 26986690 TI - Abnormalities in the basement membrane structure promote basal keratinocytes in the epidermis of hypertrophic scars to adopt a proliferative phenotype. AB - The majority of studies on scar formation have mainly focused on the dermis and little is known of the involvement of the epidermis. Previous research has demonstrated that the scar tissue-derived keratinocytes are different from normal cells at both the genetic and cell biological levels; however, the mechanisms responsible for the fundamental abnormalities in keratinocytes during scar development remain elusive. For this purpose, in this study, we used normal, wound edge and hypertrophic scar tissue to examine the morphological changes which occur during epidermal regeneration as part of the wound healing process and found that the histological structure of hypertrophic scar tissues differed from that of normal skin, with a significant increase in epidermal thickness. Notably, staining of the basement membrane (BM) appeared to be absent in the scar tissues. Moreover, immunofluorescence staining for cytokeratin (CK)10, CK14, CK5, CK19 and integrin-beta1 indicated the differential expression of cell markers in the epidermal keratinocytes among the normal, wound edge and hypertrophic scar tissues, which corresponded with the altered BM structures. By using a panel of proteins associated with BM components, we validated our hypothesis that the BM plays a significant role in regulating the cell fate decision of epidermal keratinocytes during skin wound healing. Alterations in the structure of the BM promote basal keratinocytes to adopt a proliferative phenotype both in vivo and in vitro. PMID- 26986691 TI - Characteristics and experiences of interns in strength and conditioning. AB - Student coaches undertake internships to develop practical skills and gain experience to improve employability prospects. The characteristics of the coaches who undertake these internships, their experiences and the nature of the work being performed are currently unknown. The purpose of this study was to report the characteristics of strength and conditioning (S&C) coaches who have undertaken internships and their experiences during their respective placements. A total of 113 men and 6 women completed an online survey. Placements generally lasted 6-12 months (66%), were unpaid (93%) and took place at professional teams (63%). All respondents had a standard of experience prior to commencement (82%); a higher-education degree (bachelor's degree 56%; master's degree 18%) and others were qualified S&C coaches (16%). Activities consisted largely of coaching (47%), data collection (22%) and equipment set-up (25%) but lacked provision of appropriate training. Mentors were allocated to interns; however, often developmental objectives were not discussed, meetings were rarely documented, and in some cases, no meetings took place. This study suggests that internships offer worthwhile experiences and assistance in skill development to progress in S&C. However, clearer guidelines are required to define the responsibilities of employers and interns, to maximise these experiential learning opportunities and avoid the exploitation of willing students. PMID- 26986693 TI - Correction to "Stereocomplex Crystallization and Homocrystallization of Star Shaped Four-Armed Stereo Diblock Poly(lactide)s with Different l-Lactyl Unit Contents: Isothermal Crystallization from the Melt". PMID- 26986694 TI - Diastereoselective Passerini Reaction of Biobased Chiral Aldehydes: Divergent Synthesis of Various Polyfunctionalized Heterocycles. AB - Lewis acid catalyzed Passerini reactions on chiral aldehydes derived from desymmetrized erythritol take place with unprecedented diastereoselectivity. The resulting adducts have been selectively and efficiently converted into a variety of densely functionalized, polyoxygenated heterocycles. PMID- 26986692 TI - Does the Presence of Endometriosis Affect Prognosis of Ovarian Cancer? AB - Ovarian cancers diagnosed between 2000 and 2013 were examined and cases with and without endometriosis compared. Among 139 epithelial ovarian, there were 49 (35%) with endometriosis and 90 (65%) without endometriosis. Endometriosis associated ovarian cancers were more likely to be confined to the pelvis (54% vs. 9%, p < 0.0001) and lower grade (51% vs. 29%, p = 0.014). Younger age and earlier stage independently predicted the presence of endometriosis (p = 0.0011 and p < 0.0001, respectively). Ovarian cancer patients with endometriosis had improved PFS and OS [(HR = 0.20; 95% CI, 0.09-0.43), (HR = 0.18; 95% CI, 0.04-0.81)], compared to patients without endometriosis; however, endometriosis had no independent prognostic significance. PMID- 26986696 TI - Football Equipment Removal Improves Chest Compression and Ventilation Efficacy. AB - OBJECTIVE: Airway access recommendations in potential catastrophic spine injury scenarios advocate for facemask removal, while keeping the helmet and shoulder pads in place for ensuing emergency transport. The anecdotal evidence to support these recommendations assumes that maintaining the helmet and shoulder pads assists inline cervical stabilization and that facial access guarantees adequate airway access. Our objective was to determine the effect of football equipment interference on performing chest compressions and delivering adequate ventilations on patient simulators. We hypothesized that conditions with more football equipment would decrease chest compression and ventilation efficacy. METHODS: Thirty-two certified athletic trainers were block randomized to participate in six different compression conditions and six different ventilation conditions using human patient simulators. Data for chest compression (mean compression depth, compression rate, percentage of correctly released compressions, and percentage of adequate compressions) and ventilation (total ventilations, mean ventilation volume, and percentage of ventilations delivering adequate volume) conditions were analyzed across all conditions. RESULTS: The fully equipped athlete resulted in the lowest mean compression depth (F5,154 = 22.82; P < 0.001; Effect Size = 0.98) and delivery of adequate compressions (F5,154 = 15.06; P < 0.001; Effect Size = 1.09) compared to all other conditions. Bag-valve mask conditions resulted in delivery of significantly higher mean ventilation volumes compared to all 1- or 2-person pocketmask conditions (F5,150 = 40.05; P < 0.001; Effect Size = 1.47). Two-responder ventilation scenarios resulted in delivery of a greater number of total ventilations (F5,153 = 3.99; P = 0.002; Effect Size = 0.26) and percentage of adequate ventilations (F5,150 = 5.44; P < 0.001; Effect Size = 0.89) compared to one-responder scenarios. Non chinstrap conditions permitted greater ventilation volumes (F3,28 = 35.17; P < 0.001; Effect Size = 1.78) and a greater percentage of adequate volume (F3,28 = 4.85; P = 0.008; Effect Size = 1.12) compared to conditions with the chinstrap buckled or with the chinstrap in place but not buckled. CONCLUSIONS: Chest compression and ventilation delivery are compromised in equipment-intense conditions when compared to conditions whereby equipment was mostly or entirely removed. Emergency medical personnel should remove the helmet and shoulder pads from all football athletes who require cardiopulmonary resuscitation, while maintaining appropriate cervical spine stabilization when injury is suspected. Further research is needed to confirm our findings supporting full equipment removal for chest compression and ventilation delivery. PMID- 26986695 TI - Activation of the EIF2AK4-EIF2A/eIF2alpha-ATF4 pathway triggers autophagy response to Crohn disease-associated adherent-invasive Escherichia coli infection. AB - The intestinal mucosa of Crohn disease (CD) patients is abnormally colonized by adherent-invasive E. coli (AIEC). Upon AIEC infection, autophagy is induced in host cells to restrain bacterial intracellular replication. The underlying mechanism, however, remains unknown. Here, we investigated the role of the EIF2AK4-EIF2A/eIF2alpha-ATF4 pathway in the autophagic response to AIEC infection. We showed that infection of human intestinal epithelial T84 cells with the AIEC reference strain LF82 activated the EIF2AK4-EIF2A-ATF4 pathway, as evidenced by increased phospho-EIF2AK4, phospho-EIF2A and ATF4 levels. EIF2AK4 depletion inhibited autophagy activation in response to LF82 infection, leading to increased LF82 intracellular replication and elevated pro-inflammatory cytokine production. Mechanistically, EIF2AK4 depletion suppressed the LF82 induced ATF4 binding to promoters of several autophagy genes including MAP1LC3B, BECN1, SQSTM1, ATG3 and ATG7, and this subsequently inhibited transcription of these genes. LF82 infection of wild-type (WT), but not eif2ak4(-/-), mice activated the EIF2AK4-EIF2A-ATF4 pathway, inducing autophagy gene transcription and autophagy response in enterocytes. Consequently, eif2ak4(-/-) mice exhibited increased intestinal colonization by LF82 bacteria and aggravated inflammation compared to WT mice. Activation of the EIF2AK4-EIF2A-ATF4 pathway was observed in ileal biopsies from patients with noninflamed CD, and this was suppressed in inflamed CD, suggesting that a defect in the activation of this pathway could be one of the mechanisms contributing to active disease. In conclusion, we show that activation of the EIF2AK4-EIF2A-ATF4 pathway upon AIEC infection serves as a host defense mechanism to induce functional autophagy to control AIEC intracellular replication. PMID- 26986698 TI - Effects of trehalose supplementation on the growth performance and intestinal innate immunity of juvenile chicks. AB - Trehalose is composed of two molecules of D-glucose joined by an alpha,alpha-1,1 glucosidic linkage and has antioxidative and anti-inflammatory effects. The present study investigated the effect of feeding a trehalose-supplemented diet on the growth performance, as well as the oxidative status and the intestinal innate immunity of juvenile chicks. A total of 16 d-old male broiler chicks were used in this study: two groups of 8 birds were fed on a 0% (control) or 0.5% trehalose supplemented diet for 18 d. The mean body weight of the trehalose group was significantly greater than that of the control group, but feed efficiency was not altered by feeding the trehalose-supplemented diet. No differences in the levels of lipid peroxidation in skeletal muscle, liver and plasma were observed between the control and trehalose-supplemented groups. The mRNA levels of interferon gamma, tumour necrosis factor-like ligand 1A, interleukin-10, NADPH oxidase 4 and inducible NO synthase were significantly reduced by the trehalose supplementation. Our results suggest that dietary supplementation with trehalose after hatching may have beneficial effects on the growth performance of juvenile chicks, probably by improving their intestinal innate immunity. PMID- 26986699 TI - [An exotic non-tropical lung disease]. AB - We report a case of pulmonary blastomycosis in a young man recently returned from a journey in Canada. He had acute pneumonia resistant to various antibiotics. Blastomycosis is an endemic mycosis in Canada and the United States, most frequently affecting the lungs, although extrapulmonary dissemination occurs in approximately one third of cases. Diagnosis is made by identification of Blastomyces dermatidis at direct examination or in culture. The lack of precise knowledge concerning the natural habitat of this microorganism is an obstacle to effective prevention. PMID- 26986697 TI - Prevalence of overweight and obesity among students with intellectual disabilities in Taiwan: A secondary analysis. AB - PURPOSE: The study aims to investigate the prevalence and likelihood of overweight and obesity in a large sample of students with intellectual disabilities (ID) from Taiwan. METHOD: A secondary analysis of a cross sectional study was employed to examine the body weight status among 7 to 18 year-old students with ID enrolled in public special education schools in 2013. The students were divided into three age groups (7-12 yrs, 13-15 yrs, and 16-18 yrs), four ID levels (mild, moderate, severe, and profound) and six comorbidities of ID (ID only, ID caused by genetic disorders, ID with physical disability, ID with multiple disabilities without physical disabilities, ID with autism spectrum disorders, and others with rare diseases). RESULTS: The sample represented 34.8% of students with ID attending public special education schools in Taiwan. Within this sample, 35.2% were identified as being overweight or obese. The 16 to 18 year-old age group were approximately two times (AOR=2.02, more likely to be obese than the 7-12 year-old group. Students with ID caused by genetic disorders such as Down syndrome (AOR=2.00) appeared to be more overweight or obese in comparison to those with ID only. Students with moderate (AOR=1.64) and severe ID (AOR=1.49) were more overweight/obese compared to those with profound ID. CONCLUSION: The findings not only highlight the high prevalence of overweight/obesity but also stress the need for health promotion initiatives to address issues of overweight/obesity within this population. PMID- 26986700 TI - Reduced TiO2-Graphene Oxide Heterostructure As Broad Spectrum-Driven Efficient Water-Splitting Photocatalysts. AB - The reduced TiO2-graphene oxide heterostructure as an alternative broad spectrum driven efficient water splitting photocatalyst has become a really interesting topic, however, its syntheses has many flaws, e.g., tedious experimental steps, time-consuming, small scale production, and requirement of various additives, for example, hydrazine hydrate is widely used as reductant to the reduction of graphene oxide, which is high toxicity and easy to cause the second pollution. For these issues, herein, we reported the synthesis of the reduced TiO2-graphene oxide heterostructure by a facile chemical reduction agent-free one-step laser ablation in liquid (LAL) method, which achieves extended optical response range from ultraviolet to visible and composites TiO(2-x) (reduced TiO2) nanoparticle and graphene oxide for promoting charge conducting. 30.64% Ti(3+) content in the reduced TiO2 nanoparticles induces the electronic reconstruction of TiO2, which results in 0.87 eV decrease of the band gap for the visible light absorption. TiO(2-x)-graphene oxide heterostructure achieved drastically increased photocatalytic H2 production rate, up to 23 times with respect to the blank experiment. Furthermore, a maximum H2 production rate was measured to be 16 mmol/h/g using Pt as a cocatalyst under the simulated sunlight irradiation (AM 1.5G, 135 mW/cm(2)), the quantum efficiencies were measured to be 5.15% for wavelength lambda = 365 +/- 10 nm and 1.84% for lambda = 405 +/- 10 nm, and overall solar energy conversion efficiency was measured to be 14.3%. These findings provided new insights into the broad applicability of this methodology for accessing fascinate photocatalysts. PMID- 26986701 TI - Expedient and generic synthesis of imidazole nucleosides by enzymatic transglycosylation. AB - A straightforward route to original imidazole-based nucleosides that makes use of an enzymatic N-transglycosylation step is reported in both the ribo- and deoxyribo-series. To illustrate the scope of this approach, a diverse set of 4 aryl and 4-heteroaryl-1H-imidazoles featuring variable sizes and hydrogen-bonding patterns was prepared using a microwave-assisted Suzuki-Miyaura cross-coupling reaction. These imidazole derivatives were examined as possible substrates for the nucleoside 2'-deoxyribosyltransferase from L. leichmannii and the purine nucleoside phosphorylase from E. coli. The optimum transglycosylation conditions, including the use of co-adjuvants to address solubility issues, were defined. Enzymatic conversion of 4-(hetero)arylimidazoles to 2'-deoxyribo- or ribo nucleosides proceeded in good to high conversion yields, except bulky hydrophobic imidazole derivatives. Nucleoside deoxyribosyltransferase of class II was found to convert the widest range of functionalized imidazoles into 2' deoxyribonucleosides and was even capable of bis-glycosylating certain heterocyclic substrates. Our findings should enable chemoenzymatic access to a large diversity of flexible nucleoside analogues as molecular probes, drug candidates and original building blocks for synthetic biology. PMID- 26986702 TI - Will Zika Virus and Microcephaly Epidemics Emerge After Ebola in West Africa? The Need for Prospective Studies Now. PMID- 26986704 TI - Endovascular-first strategy for acute and subacute limb ischaemia: Potential benefits of a pure mechanical thrombectomy approach Comment on Stanek et al, p. 49-56. PMID- 26986703 TI - Ankle-brachial index measurement: Skill cannot be taken for granted. Comment on Chaudru et al, p. 37-41 and Monti et al, p. 43-48. PMID- 26986706 TI - Inflammatory diseases of the aorta. AB - Inflammatory aortic diseases may occur with and without dilatation and are complicated by obstruction, rupture and dissection. Infections originate from periaortic foci or septicaemia and tend to result in the rapid development of aneurysms. Large vessel vasculitis due to Takayasu arteritis in younger and giant cell arteritis (GCA) in older patients is located in all layers of the aortic wall and prevails in the thoracic section. GCA patients are prone to developing aortic complications in the late course of disease. In Behcet's disease, aneurysms may have an unusual morphology and localisation. The diagnosis of aortitis is usually obtained by vascular imaging, but partly made only by biopsy on occasion of an operation, especially in case of isolated aortitis of the ascending aorta which mostly remains inapparent until dissection or large aneurysms have developed. Periaortitis typically occurs in the abdominal aorta and may lead to inflammatory aortic aneurysm (IAA). It is looked upon as a special form of vasculitis, with an overlap to primary retroperitoneal fibrosis (RF). An identical pathology is discussed for the three diseases. On the other hand, about 50% of isolated aortitides and periaortitides as well as retroperitoneal fibroses can be classed among IgG4-related diseases. Periaortitis also is observed after treatment of aortic aneurysms by stent-graft implantation. Special attention should be paid to ureteral obstruction along with RF or IAA. Once infection is ruled out, immunosuppression is applied to all forms of inflammatory aortic diseases, primarily with glucocorticoids. However, after successful surgery for isolated thoracic aortitis or inflammatory aortic aneurysm immunosuppression may be dispensable and it is not required if periaortic tissue enlargement persists in chronic inactive disease. For some patients with periaortitis and RF, tamoxifen may be a valuable alternative. PMID- 26986705 TI - Gender differences in patients with carotid stenosis. AB - This overview analyses gender differences in prevalence, epidemiology, risk factors and therapy in patients with carotid stenosis in a systematic review. Ischemic stroke is a leading cause of death in Western society, where about 20% of cases are triggered by a carotid stenosis or occlusion, which occurs more frequently in men than in women. The stroke-protective effect of carotid endarterectomy is greater in men. Men have lower peri-procedural stroke and death rates. Particularly men with carotid stenosis and a life expectancy of at least 5 years benefit from surgical treatment. Also, the recurrence rate of ipsilateral stroke 5 years after initial surgery is lower in men than in women. It is not yet fully clarified whether there are significant gender differences regarding the outcome after endovascular versus surgical treatment. Gender differences in the outcome of carotid artery repair may be caused by biological, anatomical (smaller vessel diameter in women) or hormonal differences as well as a protracted development of atherosclerotic changes in women and different plaque morphology. Moreover, women are on average older at the time of surgery and their surgical treatment is often delayed. To reduce the risk of stroke and to improve treatment outcome especially for women, further research on gender differences and their causes is mandatory and promising. PMID- 26986707 TI - Predicting the prevalence of peripheral arterial diseases: modelling and validation in different cohorts. AB - BACKGROUND: To develop models for prevalence estimation of peripheral arterial disease (PAD) and to validate them in an external cohort. METHODS: Model training cohort was a population based cross-sectional survey. Age, sex, smoking status, body mass index, total cholesterol (TC), high density lipoprotein (HDL), TC/HDL ratio, low density lipoprotein, fasting glucose, diabetes, hypertension, pulse pressure, and stroke history were considered candidate predicting variables. Ankle brachial index <= 0.9 was defined as the presence of peripheral arterial disease. Logistic regression method was used to build the prediction models. The likelihood ratio test was applied to select predicting variables. The bootstrap method was used for model internal validation. Model performance was validated in an external cohort. RESULTS: The final models included age, sex, pulse pressure, TC/HDL ratio, smoking status, diabetes, and stroke history. Area under receiver operating characteristics (AUC) with 95% confidence interval (CI) of the final model from the training cohort was 0.74 (0.70, 0.77). Model validation in another cohort revealed AUC (95% CI) of 0.72 (0.70, 0.73). P value of Hosmer-Lemeshow's model goodness of fit test was 0.75 indicating good model calibration. CONCLUSIONS: The developed model yielded a moderate usefulness for predicting the prevalence of PAD in general population. PMID- 26986709 TI - Accuracy of in-patients ankle-brachial index measurement by medical students. AB - BACKGROUND: Ankle brachial index (ABI) is a first line non-invasive screening tool for peripheral arterial disease (PAD) in at risk populations. The need to extend ABI use in large population screening has urged its use by professionals other than vascular physicians. As advocated by the American Heart Association, ABI teaching is part of medical curriculum in several countries. We determine accuracy in ABI measurement by trained medical students compared with an experienced angiologist. METHODS: Twelve 6th year medical students underwent 9 days of training at Lausanne University Hospital. Students and an experienced angiologist, blinded to students' results, screened consecutive hospitalised patients aged >= 65 or >= 50 with at least one cardiovascular risk factor during a 6-week period. RESULTS: A total of 249 patients were screened of whom 59 (23.7%) met the inclusion criteria. Median age was 80, 45.8% were women, and 6.8% were symptomatic. In total, 116 ABIs were available for analysis. Agreement between students and angiologist was moderate with a k-value of 0.498 (95% confidence interval: 0.389-0.606). Overall accuracy and precision of PAD screening performed by students showed sensitivity of 73.2% and specificity of 88.0%. Positive and negative predictive values were 76.9% and 85.7%, respectively; positive and negative likelihood ratios were 6.3 and 3, respectively. CONCLUSIONS: A nine day training program on ABI measurement is not sufficient for inexperienced medical students to achieve an acceptable diagnostic accuracy in detecting PAD in at risk populations. PMID- 26986708 TI - Knowledge about ankle-brachial index procedure among residents: being experienced is beneficial but is not enough. AB - BACKGROUND: Ankle-brachial index (ABI) at rest is the main clinical tool to diagnose the presence of lower extremity peripheral artery disease (PAD). The method for ABI procedure (i.e., measurement, calculation and interpretation) is standardised and guidelines were published in 2012. This study sought to: i) assess knowledge about the three major steps of the ABI procedure (i.e., measurement, calculation and interpretation) among residents from different medical schools, ii) compare the ABI knowledge of experienced residents (i.e., who have already performed ABI procedure more than 20 times) with the knowledge of inexperienced residents, and iii) describe the most common errors by residents. METHODS: Residents from six medical schools were invited to complete a questionnaire about the ABI procedure. RESULTS: Sixty-eight residents completed the questionnaire. None of them knew how to perform the entire ABI procedure. Overall, 22%, 13% and 41% of residents correctly answered questions about ABI measurement, ABI calculation and ABI interpretation, respectively. Score comparisons underlined the fact that experienced residents (n = 26) answered ABI measurement questions to a significantly better level and had a significantly higher total score than inexperienced residents (n = 42) (P = 0.0485 and P = 0.0332, respectively). Errors were similar for most of the residents. CONCLUSIONS: Our study confirms that experienced residents have significantly better ABI procedure knowledge than inexperienced residents. However, none of them are able to perform the entire ABI procedure without any mistake with regard to current guidelines. It is important that training be given to residents in medical schools in order to improve their ABI procedure knowledge. PMID- 26986710 TI - Percutaneous mechanical thrombectomy in the treatment of acute and subacute occlusions of the peripheral arteries and bypasses. AB - BACKGROUND: The aim of this prospective single-centre study was to analyse the immediate results, failures and complications of percutaneous mechanical thrombectomy using the Rotarex catheter in the treatment of acute and subacute occlusions of peripheral arteries and bypasses, as well as to evaluate long-term outcomes of this method. PATIENTS AND METHODS: Patients with acute (duration of symptoms < 14 days) or subacute (duration of symptoms > 14 days and < 3 months) occlusions of peripheral arteries and bypasses were selected consecutively for treatment. The cohort consisted of 113 patients, aged 18-92 years (median 72 years). In all, 128 procedures were performed. RESULTS: Angiographic success was obtained in 120 interventions (93.8%). Reasons for failures were rethrombosis of a partially recanalised segment in six procedures, and embolism into crural arteries in one intervention--percutaneous aspiration thromboembolectomy (PAT) and/or thrombolysis were ineffective in all these cases. Breakage of the Rotarex catheter happened in one procedure. Embolisation into crural arteries as a transitory complication solvable with PAT and/or thrombolysis occurred in four cases. Rethrombosis was more frequent in bypasses than in native arteries (p = 0.0069), in patients with longer occlusions (p = 0.026) and those with poorer distal runoff (p = 0.048). Embolisation happened more often in patients with a shorter duration of symptoms (p = 0.0001). Clinical success was achieved in 82.5%. Major amputation was performed in 10% of cases. Cumulative patency rates were 75% after one month, 71% after six months, 38% after 12 months, 33% after 18 months and 30% after 24, 30, 36 and 42 months. CONCLUSIONS: Rotarex thrombectomy has excellent immediate results with a low rate of failures and complications. In comparison to thrombolysis, it enables the fast and efficient treatment of acute and subacute occlusions of peripheral arteries in one session. PMID- 26986711 TI - Paroxysmal finger haematoma--a benign acrosyndrome occurring in middle-aged women. AB - BACKGROUND: Paroxysmal finger haematoma (PFH) is an under-recognised vascular acrosyndrome with no epidemiological description to date. The aim of this work was to evaluate the prevalence, risk factors and clinical correlates of PFH in a population-based sample of subjects and to describe their semiological characteristics. PATIENTS AND METHODS: This cross-sectional study of random samples of the general population in three geographic areas of France involved 802 subjects, 548 women and 254 men, aged 18 to 84 years. The diagnosis of PFH was made from a report by the subject of a history of recurrent haematoma in the fingers with a sudden, painful and unexpected occurrence. Diagnosis of associated conditions and evaluation of lifestyle variables were obtained through standardised medical interview and examination. RESULTS: A history of PFH was detected in 71 subjects, with a prevalence of 1.2% in men and 12.4% in women; there was no significant regional variation. Onset before 40 years of age was rare. Besides female sex and age, no socio-economical nor lifestyle risk factors were detected. PFH was associated with Raynaud phenomenon and a history of chilblains, but no link with any health threatening disease was found. In addition to the sudden onset of pain and hematoma, the main clinical features were a frequent digital swelling during the painful attack, and their predominant location on the volar side of the first and second phalanges of the third or second fingers of the dominant hand. CONCLUSIONS: PFH is a benign phenomenon, frequently found in middle-aged women, to be classified among the vascular acrosyndromes. Patients seeking medical evaluation for this disorder should be reassured. PMID- 26986712 TI - Risk factors for superficial vein thrombosis in patients with primary chronic venous disease. AB - BACKGROUND: Primary chronic venous disease (CVD) is associated with an increased risk of superficial vein thrombosis (SVT). While CVD is a predominant factor in SVT, there is a range of additional predisposing factors. The objective was to investigate the association between age, gender, BMI, smoking, oestrogen hormone therapy, family history of venous thromboembolism (VTE) and CEAP clinical classification in patients with CVD and a history of SVT. PATIENTS AND METHODS: In a retrospective observational study on consecutive patients with primary CVD, 641 outpatients were enrolled (152 men, 23.7%; 489 women, 76.3%). The prevalence of SVT was evaluated according to age, BMI, smoking, presence of family history of VTE, use of hormone therapy, and clinical class of CVD. RESULTS: Risk of SVT was significantly increased in women (OR 1.68, 95% CI = 1.02-2.76; p = 0.041), older patients (46-69 years, OR 1.57, 95% CI = 1.03-2.4; p = 0.036, >= 70 years, OR 2.93, 95% CI = 1.5-5.76; p = 0.001), smokers (OR 1.69, 95% CI = 1.1-2.58; p = 0.015) and in persons with first-degree siblings diagnosed with VTE (OR 2,28, 95% CI = 1.28-4.05; p = 0.004). The risk was significantly increased in older male smokers (p - 0.042). In women, smoking and oestrogen therapy (p = 0.495) did not increase the risk of SVT even older women or in those with increased BMI. In CVD (C0-C3), a history of episodes of SVT was found in 103/550 (18.7%), in chronic venous insufficiency (CVI) in 27/91 (29.7%). There was a significantly higher prevalence of SVT in patients with CVI (OR 1.70, 95% CI = 1.1-2.5; p = 0.016). CONCLUSIONS: In patients with primary CVD, SVT was significantly associated with female gender. In men, older age, smoking and positive family history of VTE were relevant SVT risk factors. In women, risk factors were older age, BMI >= 25 kg/m2 and positive family history of VTE. Compared with C0-C3 clinical classes, CVI significantly increases the risk of SVT. PMID- 26986713 TI - Coil embolization of a posterior circumflex humeral aneurysm in a volleyball player. PMID- 26986714 TI - Pushing the limits of endovascular intervention: favourable results of recent intracranial trials. PMID- 26986716 TI - Nickel Disulfide-Graphene Nanosheets Composites with Improved Electrochemical Performance for Sodium Ion Battery. AB - Nickel disulfide-graphene nanosheets (NiS2-GNS) composites were successfully synthesized via a simple and mild hydrothermal method. It was revealed by scanning electron microscopy and transmission electron microscopy images that the spherical NiS2 nanoparticles with a diameter of 200-300 nm were uniformly dispersed on graphene nanosheets. Na(+) electrochemical storage properties including cycling performance and high-rate capability of NiS2-GNS composites were investigated, demonstrating a superior reversible capacity of 407 mAh g(-1) with the capacity retention of 77% over 200 cycles at a current density of 0.1 C. Furthermore, even at a large current density of 2 C, a high capacity of 168 mAh g(-1) can still remain, which is much higher than that of pristine NiS2 materials. The enhancement in electrochemical properties might be attributed to the synergetic effect endowed by high conductivity of graphene and novel structure of the electrode material. Combined with the advantages of low cost and environmental benignity, NiS2-GNS composite would be a potential anode material for sodium ion batteries. PMID- 26986717 TI - A phosphatidylinositol 3-kinase inhibitor strongly suppressed pulmonary vascular remodeling of allergic vasculitis in a murine model. AB - OBJECTIVES: We investigated the effects of pan-class I PI3K inhibitor, ZSTK474 on vascular remodeling using a murine model of allergic vasculitis with eosinophil infiltration. METHODS: C57BL/6 mice were sensitized with OVA. The positive controls were exposed to aerosolized OVA daily for 7 days. The other group of mice were administered ZSTK474 (30 mg/kg, p.o. daily) in parallel with daily exposure to aerosolized OVA for 7 days. On the 3rd and 7th day, bronchoalveolar lavage (BAL) was performed and the lungs were excised for pathological analysis. Cell differentials were determined and the concentrations of IL-4, IL-5, IL-13 and TGF-betain BAL fluid were measured. RESULTS: The total cell numbers and eosinophil numbers in BALF were greatly reduced in the ZSTK474-treated group on the 3rd and 7th day after exposure to OVA. The numbers of total white blood cells and eosinophils in the peripheral blood were significantly reduced in the ZSTK474 treated group on the 3rd and 7th day after exposure to OVA. The concentrations of IL-4, IL-5, and IL-13 in BAL fluids were also reduced significantly on the 3rd day in the ZSTK474-treated group. The concentrations of TGF-beta in BAL fluids were also reduced significantly on the 3rd and 7th day in the ZSTK474-treated group. The pathological scores reduced significantly in the ZSTK474-treated group compared to the control group. CONCLUSION: The PI3K inhibitor, ZSTK474 suppressed pulmonary vascular remodeling in the murine model of allergic vasculitis with eosinophil infiltration. PI3K signal transduction may have a critical role in the immunological process that induces allergic vasculitis. PMID- 26986718 TI - Very Early versus Delayed Rehabilitation for Acute Ischemic Stroke Patients with Intravenous Recombinant Tissue Plasminogen Activator: A Nationwide Retrospective Cohort Study. AB - BACKGROUND: Although the safety and feasibility of very early rehabilitation for stroke are well recognized, the initiation of rehabilitation is sometimes delayed after thrombolysis. The purpose of this study was to clarify the association between very early rehabilitation and outcomes in acute ischemic stroke patients who received tissue plasminogen activator, using a national inpatient database in Japan. METHODS: We identified patients who were admitted to acute-care hospitals with ischemic stroke and were treated with intravenous recombinant tissue plasminogen activator on the same day of stroke onset and received rehabilitation within 3 days from admission. The primary outcome was functional independence on discharge. We compared the outcomes of a very early rehabilitation group with a comparison group. RESULTS: We identified 6,153 eligible patients, of whom 4,266 received very early rehabilitation. The proportion of functional independence on discharge was 41.2 and 36.6% in the very early rehabilitation group and the comparison group, respectively. Multivariable logistic regression analysis showed that the very early rehabilitation was significantly associated with a higher proportion of functional independence after adjustment for confounding factors. There was no significant difference in 7-, 30-, 90-day mortality or incidence of intracerebral hemorrhage between the groups after adjusting for baseline characteristics. Instrumental variable analysis confirmed a higher proportion of functionally independent patients in the very early rehabilitation group. CONCLUSION: Patients with acute ischemic stroke undergoing very early rehabilitation after thrombolysis were more likely to achieve functional independence without an increase in adverse outcomes. PMID- 26986719 TI - Spatial Organization of Epigenomes. AB - The role of genome architecture in transcription regulation has become the focus of an increasing number of studies over the past decade. Chromatin organization can have a significant impact on gene expression by promoting or restricting the physical proximity between regulatory DNA elements. Given that any change in chromatin state has the potential to alter DNA folding and the proximity between control elements, the spatial organization of chromatin is inherently linked to its molecular composition. In this review, we explore how modulators of chromatin state and organization might keep gene expression in check. We discuss recent findings and present some of the less well-studied aspects of spatial genome organization such as chromatin dynamics and regulation by non-coding RNAs. PMID- 26986721 TI - Precision wildlife monitoring using unmanned aerial vehicles. AB - Unmanned aerial vehicles (UAVs) represent a new frontier in environmental research. Their use has the potential to revolutionise the field if they prove capable of improving data quality or the ease with which data are collected beyond traditional methods. We apply UAV technology to wildlife monitoring in tropical and polar environments and demonstrate that UAV-derived counts of colony nesting birds are an order of magnitude more precise than traditional ground counts. The increased count precision afforded by UAVs, along with their ability to survey hard-to-reach populations and places, will likely drive many wildlife monitoring projects that rely on population counts to transition from traditional methods to UAV technology. Careful consideration will be required to ensure the coherence of historic data sets with new UAV-derived data and we propose a method for determining the number of duplicated (concurrent UAV and ground counts) sampling points needed to achieve data compatibility. PMID- 26986720 TI - Bioinformatic analyses of sense and antisense expression from terminal inverted repeat transposons in Drosophila somatic cells. AB - Understanding regulation of transposon movement in somatic cells is important as mobile elements can cause detrimental genomic rearrangements. Generally, transposons move via one of 2 mechanisms; retrotransposons utilize an RNA intermediate, therefore copying themselves and amplifying throughout the genome, while terminal inverted repeat transposons (TIR Tns) excise DNA sequences from the genome and integrate into a new location. Our recently published work indicates that retrotransposons in Drosophila tissue culture cells are actively transcribed in the antisense direction. Our data support a model in which convergent transcription of retrotransposons from intra element transcription start sites results in complementary RNAs that hybridize to form substrates for Dicer-2, the endogenous small interfering (esi)RNA generating enzyme. Here, we extend our previous analysis to TIR Tns. In contrast to retrotransposons, our data show that antisense TIR Tn RNAs result from transcription of intronic TIR Tns oriented antisense to their host genes. Also, disproportionately less esiRNAs are generated from TIR transcripts than from retrotransposons and transcription of very few individual TIR Tns could be confirmed. Collectively, these data support a model in which TIR Tns are regulated at the level of Transposase production while retrotransposons are regulated with esiRNA post-transcriptional mechanisms in Drosophila somatic cells. PMID- 26986722 TI - Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors. AB - The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05) (S2 Table). Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17 gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition. PMID- 26986724 TI - MicroRNA miR-93-5p regulates expression of IL-8 and VEGF in neuroblastoma SK-N-AS cells. AB - The role of the microRNA miR-93-5p on the secretome profile and the expression levels of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) was investigated in the neuroblastoma SK-N-AS cell line by Bio-Plex analysis and RT qPCR. The results indicate that VEGF and IL-8 are the major miR-93-5p molecular targets. This conclusion was based on in vitro transfection with pre-miR-93-5p and anti-miR-93-5p; these treatments inversely modulated both VEGF and IL-8 gene expression and protein release in the neuroblastoma SK-N-AS cell line. Computational analysis showed the presence of miR-93-5p consensus sequences in the 3'UTR region of both VEGF and IL-8 mRNAs, predicting possible interaction with miR-93-5p and confirming a potential regulatory role of this microRNA. PMID- 26986723 TI - Mechanism of Notch Pathway Activation and Its Role in the Regulation of Olfactory Plasticity in Drosophila melanogaster. AB - The neural plasticity of sensory systems is being increasingly recognized as playing a role in learning and memory. We have previously shown that Notch, part of an evolutionarily conserved intercellular signaling pathway, is required in adult Drosophila melanogaster olfactory receptor neurons (ORNs) for the structural and functional plasticity of olfactory glomeruli that is induced by chronic odor exposure. In this paper we address how long-term exposure to odor activates Notch and how Notch in conjunction with chronic odor mediates olfactory plasticity. We show that upon chronic odor exposure a non-canonical Notch pathway mediates an increase in the volume of glomeruli by a mechanism that is autonomous to ORNs. In addition to activating a pathway that is autonomous to ORNs, chronic odor exposure also activates the Notch ligand Delta in second order projection neurons (PNs), but this does not appear to require acetylcholine receptor activation in PNs. Delta on PNs then feeds back to activate canonical Notch signaling in ORNs, which restricts the extent of the odor induced increase in glomerular volume. Surprisingly, even though the pathway that mediates the increase in glomerular volume is autonomous to ORNs, nonproductive transsynaptic Delta/Notch interactions that do not activate the canonical pathway can block the increase in volume. In conjunction with chronic odor, the canonical Notch pathway also enhances cholinergic activation of PNs. We present evidence suggesting that this is due to increased acetylcholine release from ORNs. In regulating physiological plasticity, Notch functions solely by the canonical pathway, suggesting that there is no direct connection between morphological and physiological plasticity. PMID- 26986726 TI - Visual Perception-Based Statistical Modeling of Complex Grain Image for Product Quality Monitoring and Supervision on Assembly Production Line. AB - Computer vision as a fast, low-cost, noncontact, and online monitoring technology has been an important tool to inspect product quality, particularly on a large scale assembly production line. However, the current industrial vision system is far from satisfactory in the intelligent perception of complex grain images, comprising a large number of local homogeneous fragmentations or patches without distinct foreground and background. We attempt to solve this problem based on the statistical modeling of spatial structures of grain images. We present a physical explanation in advance to indicate that the spatial structures of the complex grain images are subject to a representative Weibull distribution according to the theory of sequential fragmentation, which is well known in the continued comminution of ore grinding. To delineate the spatial structure of the grain image, we present a method of multiscale and omnidirectional Gaussian derivative filtering. Then, a product quality classifier based on sparse multikernel-least squares support vector machine is proposed to solve the low-confidence classification problem of imbalanced data distribution. The proposed method is applied on the assembly line of a food-processing enterprise to classify (or identify) automatically the production quality of rice. The experiments on the real application case, compared with the commonly used methods, illustrate the validity of our method. PMID- 26986725 TI - Enhancing Maternal and Perinatal Health in Under-Served Remote Areas in Sub Saharan Africa: A Tanzanian Model. AB - BACKGROUND: In Tanzania, maternal mortality ratio (MMR), unmet need for emergency obstetric care and health inequities across the country are in a critical state, particularly in rural areas. This study was established to determine the feasibility and impact of decentralizing comprehensive emergency obstetric and neonatal care (CEmONC) services in underserved rural areas using associate clinicians. METHODS: Ten health centres (HCs) were upgraded by constructing and equipping maternity blocks, operating rooms, laboratories, staff houses and installing solar panels, standby generators and water supply systems. Twenty three assistant medical officers (advanced level associate clinicians), and forty four nurse-midwives and clinical officers (associate clinicians) were trained in CEmONC and anaesthesia respectively. CEmONC services were launched between 2009 and 2012. Monthly supportive supervision and clinical audits of adverse pregnancy outcomes were introduced in 2011 in these HCs and their respective district hospitals. FINDINGS: After launching CEmONC services from 2009 to 2014 institutional deliveries increased in all upgraded rural HCs. Mean numbers of monthly deliveries increased by 151% and obstetric referrals decreased from 9% to 3% (p = 0.03) in HCs. A total of 43,846 deliveries and 2,890 caesarean sections (CS) were performed in these HCs making the mean proportion of all births in EmONC facilities of 128% and mean population-based CS rate of 9%. There were 190 maternal deaths and 1,198 intrapartum and very early neonatal deaths (IVEND) in all health facilities. Generally, health centres had statistically significantly lower maternal mortality ratios and IVEND rates than district hospitals (p < 0.00 and < 0.02 respectively). Of all deaths (maternal and IVEND) 84% to 96% were considered avoidable. CONCLUSIONS: These findings strongly indicate that remotely located health centres in resource limited settings hold a great potential to increase accessibility to CEmONC services and to improve maternal and perinatal health. PMID- 26986737 TI - Haplotypes of the D-Amino Acid Oxidase Gene Are Significantly Associated with Schizophrenia and Its Neurocognitive Deficits. AB - D-amino acid oxidase (DAO) has been reported to be associated with schizophrenia. This study aimed to search for genetic variants associated with this gene. The genomic regions of all exons, highly conserved regions of introns, and promoters of this gene were sequenced. Potentially meaningful single-nucleotide polymorphisms (SNPs) obtained from direct sequencing were selected for genotyping in 600 controls and 912 patients with schizophrenia and in a replicated sample consisting of 388 patients with schizophrenia. Genetic associations were examined using single-locus and haplotype association analyses. In single-locus analyses, the frequency of the C allele of a novel SNP rs55944529 located at intron 8 was found to be significantly higher in the original large patient sample (p = 0.016). This allele was associated with a higher level of DAO mRNA expression in the Epstein-Barr virus-transformed lymphocytes. The haplotype distribution of a haplotype block composed of rs11114083-rs2070586-rs2070587-rs55944529 across intron 1 and intron 8 was significantly different between the patients and controls and the haplotype frequencies of AAGC were significantly higher in patients, in both the original (corrected p < 0.0001) and replicated samples (corrected p = 0.0003). The CGTC haplotype was specifically associated with the subgroup with deficits in sustained attention and executive function and the AAGC haplotype was associated with the subgroup without such deficits. The DAO gene was a susceptibility gene for schizophrenia and the genomic region between intron 1 and intron 8 may harbor functional genetic variants, which may influence the mRNA expression of DAO and neurocognitive functions in schizophrenia. PMID- 26986739 TI - Crystal Structure and Band Gap Engineering in Polyoxometalate-Based Inorganic Organic Hybrids. AB - We have demonstrated engineering of the electronic band gap of the hybrid materials based on POMs (polyoxometalates), by controlling its structural complexity through variation in the conditions of synthesis. The pH- and temperature-dependent studies give a clear insight into how these experimental factors affect the overall hybrid structure and its properties. Our structural manipulations have been successful in effectively tuning the optical band gap and electronic band structure of this kind of hybrids, which can find many applications in the field of photovoltaic and semiconducting devices. We have also addressed a common crystallographic disorder observed in Keggin-ion (one type of heteropolyoxometalate [POMs])-based hybrid materials. Through a combination of crystallographic, spectroscopic, and theoretical analysis of four new POM-based hybrids synthesized with tactically varied reaction conditions, we trace the origin and nature of the disorder associated with it and the subtle local structural coordination involved in its core picture. While the crystallography yields a centrosymmetric structure with planar coordination of Si, our analysis with XPS, IR, and Raman spectroscopy reveals a tetrahedral coordination with broken inversion symmetry, corroborated by first-principles calculations. PMID- 26986738 TI - Branching Shoots and Spikes from Lateral Meristems in Bread Wheat. AB - Wheat grain yield consists of three components: spikes per plant, grains per spike (i.e. head or ear), and grain weight; and the grains per spike can be dissected into two subcomponents: spikelets per spike and grains per spikelet. An increase in any of these components will directly contribute to grain yield. Wheat morphology biology tells that a wheat plant has no lateral meristem that forms any branching shoot or spike. In this study, we report two novel shoot and spike traits that were produced from lateral meristems in bread wheat. One is supernumerary shoot that was developed from an axillary bud at the axil of leaves on the elongated internodes of the main stem. The other is supernumerary spike that was generated from a spikelet meristem on a spike. In addition, supernumerary spikelets were generated on the same rachis node of the spike in the plant that had supernumerary shoot and spikes. All of these supernumerary shoots/spikes/spikelets found in the super wheat plants produced normal fertility and seeds, displaying huge yield potential in bread wheat. PMID- 26986740 TI - Queen Specific Exocrine Glands in Legionary Ants and Their Possible Function in Sexual Selection. AB - The colonies of army ants and some other legionary ant species have single, permanently wingless queens with massive post petioles and large gasters. Such highly modified queens are called dichthadiigynes. This paper presents the unusually rich exocrine gland endowment of dichthadiigynes, which is not found in queens of other ant species. It has been suggested these kinds of glands produce secretions that attract and maintain worker retinues around queens, especially during migration. However, large worker retinues also occur in non-legionary species whose queens do not have such an exuberance of exocrine glands. We argue and present evidence in support of our previously proposed hypothesis that the enormous outfit of exocrine glands found in dichthadiigynes is due to sexual selection mediated by workers as the main selecting agents. PMID- 26986741 TI - Moribund Ants Do Not Call for Help. AB - When an antlion captures a foraging ant, the victim's nestmates may display rescue behaviour. This study tested the hypothesis that the expression of rescue behaviour depends on the life expectancy of the captured ant. This hypothesis predicts that the expression of rescue behaviour will be less frequent when the captured ant has a lower life expectancy than when it has a higher life expectancy because such a response would be adaptive at the colony level. Indeed, significant differences were found in the frequency of rescue behaviours in response to antlion victims with differing life expectancies. In agreement with prediction, victims with lower life expectancies were rescued less frequently, and those rescues had a longer latency and shorter duration. There was also a qualitative difference in the behaviour of rescuers to victims from the low and high life expectancy groups. Several explanations for these findings are proposed. PMID- 26986742 TI - Does the use of gonadotropin-releasing hormone antagonists in natural IVF cycles for poor responder patients cause more harm than benefit? AB - Poor ovarian response to controlled ovarian stimulation (COS) is one of the most critical factors that substantially limits the success of assisted reproduction techniques (ARTs). Natural and modified natural cycle IVF are two options that could be considered as a last resort. Blocking gonadotropin-releasing hormone (GnRH) actions in the endometrium via GnRH receptor antagonism may have a negative impact on endometrial receptivity. We analysed IVF outcomes in 142 natural (n = 30) or modified natural (n = 112) IVF cycles performed in 82 women retrospectively. A significantly lower proportion of natural cycles reached follicular aspiration compared to modified natural cycles (56.7% vs. 85.7%, p < 0.001). However, the difference between the numbers of IVF cycles ending in embryo transfer (26.7% vs. 44.6%) was not statistically significant between natural cycle and modified natural IVF cycles. Clinical pregnancy (6.7% vs. 7.1%) and live birth rates per initiated cycle (6.7% vs. 5.4%) were similar between the two groups. Notably, the implantation rate was slightly lower in modified natural cycles (16% vs. 25%, p > 0.05). There was a trend towards higher clinical pregnancy (25% vs. 16%) and live birth (25% vs. 12%) rates per embryo transfer in natural cycles compared to modified natural cycles, but the differences did not reach statistical significance. PMID- 26986743 TI - Frequency-dependent loudness balancing in bimodal cochlear implant users. AB - Conclusion In users of a cochlear implant (CI) and a hearing aid (HA) in contralateral ears, frequency-dependent loudness balancing between devices did, on average, not lead to improved speech understanding as compared to broadband balancing. However, nine out of 15 bimodal subjects showed significantly better speech understanding with either one of the fittings. Objectives Sub-optimal fittings and mismatches in loudness are possible explanations for the large individual differences seen in listeners using bimodal stimulation. Methods HA gain was adjusted for soft and loud input sounds in three frequency bands (0-548, 548-1000, and >1000 Hz) to match loudness with the CI. This procedure was compared to a simple broadband balancing procedure that reflected current clinical practice. In a three-visit cross-over design with 4 weeks between sessions, speech understanding was tested in quiet and in noise and questionnaires were administered to assess benefit in real world. Results Both procedures resulted in comparable HA gains. For speech in noise, a marginal bimodal benefit of 0.3 +/- 4 dB was found, with large differences between subjects and spatial configurations. Speech understanding in quiet and in noise did not differ between the two loudness balancing procedures. PMID- 26986744 TI - Energetic Chromophores: Low-Energy Laser Initiation in Explosive Fe(II) Tetrazine Complexes. AB - The synthesis and characterization of air stable Fe(II) coordination complexes with tetrazine and triazolo-tetrazine ligands and perchlorate counteranions have been achieved. Time-dependent density functional theory (TD-DFT) was used to model the structural, electrochemical, and optical properties of these materials. These compounds are secondary explosives that can be initiated with Nd:YAG laser light at lower energy thresholds than those of PETN. Furthermore, these Fe(II) tetrazine complexes have significantly lower sensitivity than PETN toward mechanical stimuli such as impact and friction. The lower threshold for laser initiation was achieved by altering the electronic properties of the ligand scaffold to tune the metal ligand charge transfer (MLCT) bands of these materials from the visible into the near-infrared region of the electromagnetic spectrum. Unprecedented decrease in both the laser initiation threshold and the mechanical sensitivity makes these materials the first explosives that are both safer to handle and easier to initiate than PETN with NIR lasers. PMID- 26986746 TI - Some people are "More Lexical" than others. AB - People can understand speech under poor conditions, even when successive pieces of the waveform are flipped in time. Using a new method to measure perception of such stimuli, we show that words with sounds based on rapid spectral changes (stop consonants) are much more impaired by reversing speech segments than words with fewer such sounds, and that words are much more resistant to disruption than pseudowords. We then demonstrate that this lexical advantage is more characteristic of some people than others. Participants listened to speech that was degraded in two very different ways, and we measured each person's reliance on lexical support for each task. Listeners who relied on the lexicon for help in perceiving one kind of degraded speech also relied on the lexicon when dealing with a quite different kind of degraded speech. Thus, people differ in their relative reliance on the speech signal versus their pre-existing knowledge. PMID- 26986745 TI - Adaptation to number operates on perceived rather than physical numerosity. AB - Humans share with many animals a number sense, the ability to estimate rapidly the approximate number of items in a scene. Recent work has shown that like many other perceptual attributes, numerosity is susceptible to adaptation. It is not clear, however, whether adaptation works directly on mechanisms selective to numerosity, or via related mechanisms, such as those tuned to texture density. To disentangle this issue we measured adaptation of numerosity of 10 pairs of connected dots, as connecting dots makes them appear to be less numerous than unconnected dots. Adaptation to a 20-dot pattern (same number of dots as the test) caused robust reduction in apparent numerosity of the connected-dot pattern, but not of the unconnected dot-pattern. This suggests that adaptation to numerosity, at least for relatively sparse dot-pattern, occurs at neural levels encoding perceived numerosity, rather than at lower levels responding to the number of elements in the scene. PMID- 26986747 TI - Affective experience and motivated behavior in schizophrenia spectrum disorders: Evidence from clinical and nonclinical samples. AB - OBJECTIVE: Individuals with schizophrenia have been found to exhibit emotion behavior decoupling, particularly with respect to anticipated, rather than experienced events. However, previous research has focused on how emotion valence translates into motivated behavior, ignoring the fact that emotion arousal should also modulate emotion-behavior coupling. Few studies have examined emotion behavior coupling in prepsychotic conditions. This investigation aimed to examine the nature and extent of emotion valence- and arousal-behavior coupling across the schizophrenia spectrum. METHOD: We examine how emotional valence and arousal couple with behavior in 3 groups of individuals (25 individuals with chronic schizophrenia; 27 individuals early in the disease course, and 31 individuals reporting negative schizotypal symptoms). Participants completed a task using slides to elicit emotion and evoke motivated behavior. We compared participants with their respective matched control groups to determine differences in the correspondence between self-reported emotion valence/arousal and motivated behavior. RESULTS: Both groups with schizophrenia reported similar affective experiences as their controls, whereas individuals reporting negative schizotypal symptoms showed "in-the-moment" anhedonia but not emotion-behavior decoupling. In addition, the schizophrenia groups' affective experiences corresponded less well to their behavior relative to controls. CONCLUSIONS: Our findings suggest emotion behavior decoupling along both valence and arousal dimensions in schizophrenia but not in participants with high levels of schizotypal symptoms. Findings appear to support the idea that emotion-behavior decoupling differs in nature and extent across the schizophrenia spectrum. Interventions to recouple emotion and behavior may be particularly helpful in allowing people with schizophrenia to gain functional independence. (PsycINFO Database Record PMID- 26986748 TI - Is APOE epsilon4 associated with poorer cognitive outcome following traumatic brain injury? A meta-analysis. AB - OBJECTIVE: Cognitive impairment is a common sequelae of traumatic brain injury (TBI); however, predicting who will experience poorer outcomes remains challenging. A potential risk factor that has gained attention is the APOE gene, with the epsilon4 allele hypothesized to have a detrimental effect on post-TBI cognitive outcome. The aim of this meta-analysis was to evaluate the effect of APOE epsilon4 both in terms of general cognitive function and within specific domains known to be prone to impairment following TBI (executive function, working memory, verbal memory and visual memory). METHOD: A literature search was undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA), resulting in the inclusion of 10 studies (epsilon4-carriers n = 143, noncarriers n = 510). Neuropsychological tasks were identified, and Cohen's d was calculated and pooled. Meta-analyses were conducted on general cognitive functioning and for the specific cognitive domains of interest. RESULTS: No significant differences were found between APOE epsilon4 carriers or noncarriers, either in general cognitive function or in the cognitive domains of executive function, working memory, verbal memory, or visual memory. CONCLUSIONS: This meta-analysis indicates that APOE epsilon4 does not have a detrimental effect on cognitive performance following TBI. We propose that the relationship between APOE and cognitive function following TBI is complex, and a more-nuanced exploration of APOE genotypes is needed. (PsycINFO Database Record PMID- 26986749 TI - Early onset marijuana use is associated with learning inefficiencies. AB - OBJECTIVE: Verbal memory difficulties are the most widely reported and persistent cognitive deficit associated with early onset marijuana use. Yet, it is not known what memory stages are most impaired in those with early marijuana use. METHOD: Forty-eight young adults, aged 18-25, who used marijuana at least once per week and 48 matched nonusing controls (CON) completed the California Verbal Learning Test, Second Edition (CVLT-II). Marijuana users were stratified by age of initial use: early onset users (EMJ), who started using marijuana at or before age 16 (n = 27), and late onset marijuana user group (LMJ), who started using marijuana after age 16 (n = 21). Outcome variables included trial immediate recall, total learning, clustering strategies (semantic clustering, serial clustering, ratio of semantic to serial clustering, and total number of strategies used), delayed recall, and percent retention. RESULTS: Learning improved with repetition, with no group effect on the learning slope. EMJ learned fewer words overall than LMJ or CON. There was no difference between LMJ and CON in total number of words learned. Reduced overall learning mediated the effect on reduced delayed recall among EMJ, but not CON or LMJ. Learning improved with greater use of semantic versus serial encoding, but this did not vary between groups. EMJ was not related to delayed recall after adjusting for encoding. CONCLUSIONS: Young adults reporting early onset marijuana use had learning weaknesses, which accounted for the association between early onset marijuana use and delayed recall. No amnestic effect of marijuana use was observed. (PsycINFO Database Record PMID- 26986750 TI - Individual differences in reasoning and visuospatial attention are associated with prefrontal and parietal white matter tracts in healthy older adults. AB - OBJECTIVE: Although reasoning and attention are 2 cognitive processes necessary for ensuring the efficiency of many everyday activities in older adults, the role of white matter integrity in these processes has been little studied. This is an important question due to the role of white matter integrity as a neural substrate of cognitive aging. Here, we sought to examine the white matter tracts subserving reasoning and visuospatial attention in healthy older adults. METHOD: Sixty-one adults ages 60 and older completed a battery of cognitive tests to assess reasoning and visuospatial attention. In addition, diffusion tensor images were collected to assess fractional anisotropy (FA), a measure of white matter integrity. A principle components analysis of the test scores yielded 2 components: reasoning and visuospatial attention. Whole-brain correlations between FA and the cognitive components were submitted to probabilistic tractography analyses for visualization of cortical targets of tracts. RESULTS: For reasoning, bilateral thalamo-anterior prefrontal, anterior corpus callosum, and corpus callosum body tracts interconnecting the superior frontal cortices and right cingulum bundle were found. For visuospatial attention, a right inferior fronto-parietal tract and bilateral parietal and temporal connections were found. CONCLUSIONS: We conclude that in older adults, prefrontal cortex white matter tracts and interhemispheric communication are important in higher order cognitive functioning. On the other hand, right-sided fronto-parietal tracts appear to be critical for supporting control of cognitive processes, such as redirecting attention. Researchers may use our results to develop neuroscience-based interventions for older adults targeting brain mechanisms involved in cognitive plasticity. (PsycINFO Database Record PMID- 26986752 TI - Regulating Emotions during Difficult Multiattribute Decision Making: The Role of Pre-Decisional Coherence Shifting. AB - Almost all real-life decisions entail attribute conflict; every serious choice alternative is better than its competitors on some attribute dimensions but worse on others. In pre-decisional "coherence shifting," the decision maker gradually softens that conflict psychologically to the point where one alternative is seen as dominant over its competitors, or nearly so. Specifically, weaknesses of the eventually chosen alternative come to be perceived as less severe and less important while its strengths seem more desirable and significant. The research described here demonstrates that difficult multiattribute decision problems are aversive and that pre-decisional coherence shifting aids individuals in regulating that emotional discomfort. Across three studies, attribute conflict was confirmed to be aversive (Study 1), and skin conductance responses and ratings of decision difficulty both decreased in participants who coherence shifted (Study 2). Coherence shifting was also diminished among decision makers who were depleted of regulatory resources, known to be required for common emotion regulation mechanisms. Further, coherence shifting was shown to be relatively common among people who reported strong suppression tendencies in everyday emotion regulation (Study 3). Overall, the data suggest that, at least in part, coherence shifting serves as a tool that helps decision makers manage the pre-decisional discomfort generated by attribute conflict. Theoretical and practical implications are discussed. PMID- 26986751 TI - Adenovirus-Mediated Expression of the p14 Fusion-Associated Small Transmembrane Protein Promotes Cancer Cell Fusion and Apoptosis In Vitro but Does Not Provide Therapeutic Efficacy in a Xenograft Mouse Model of Cancer. AB - Adenoviruses (Ads) are used in numerous preclinical and clinical studies for delivery of anti-cancer therapeutic genes. Unfortunately, Ad has a poor ability to distribute throughout a tumor mass after intratumoral injection, and infects cells primarily within the immediate area of the injection tract. Thus, Ad encoded transgene expression is typically limited to only a small percentage of cells within the tumor. One method to increase the proportion of the tumor impacted by Ad is through expression of fusogenic proteins. Infection of a single cell with an Ad vector encoding a fusogenic protein should lead to syncytium formation with adjacent cells, effectively spreading the effect of Ad and Ad encoded therapeutic transgenes to a greater percentage of the tumor mass. Moreover, syncytium formation can be cytotoxic, suggesting that such proteins may be effective sole therapeutics. We show that an early region 1 (E1)-deleted Ad expressing reptilian reovirus p14 fusion-associated small transmembrane (FAST) protein caused extensive cell fusion in the replication-permissive 293 cell line and at high multiplicity of infection in non-permissive human lung adenocarcinoma A549 cells in vitro. FAST protein expression in the A549 cancer cell line led to a loss of cellular metabolic activity and membrane integrity, which correlated with induction of apoptosis. However, in an A549 xenograft CD-1 nude mouse cancer model, Ad-mediated FAST gene delivery did not induce detectable cell fusion, reduce tumor burden nor enhance mouse survival compared to controls. Taken together, our results show that, although AdFAST can enhance cancer cell killing in vitro, it is not effective as a sole therapeutic in the A549 tumor model in vivo. PMID- 26986753 TI - Thromboprophylaxis in multiple myeloma patients treated with lenalidomide - A systematic review. AB - BACKGROUND: Studies have consistently demonstrated the need for venous thromboembolism (VTE) prophylaxis in patients with newly diagnosed multiple myeloma (NDMM) or relapsed refractory multiple myeloma (RRMM), receiving lenalidomide-based therapy. However, the optimal approach has not yet been established. OBJECTIVE: To compare the efficacy of aspirin (ASA) and low molecular weight heparin (LMWH) prophylaxis in patients with myeloma using lenalidomide-based therapy. RESULTS: Six studies were included with 1125 adult participants with NDMM or RRMM treated with lenalidomide-based therapy with thromboprophylaxis with ASA or LMWH. Pooled data of studies of NDMM showed that the risk of VTE in patients on ASA was 1.5 per 100 patient-cycles with a total risk of VTE of 98 of 915 (10.7%) [95% CI: 8.86-12.88] compared to 3 of 211 (1.4%) [95% CI: 0.48-4.09] with LMWH in NDMM and RRMM patients. Our study demonstrated a significantly higher VTE risk for patients receiving lenalidomide plus high-dose dexamethasone (RD) on ASA prophylaxis compared to lenalidomide plus low-dose dexamethasone (Rd) [RR=2.5 (95% CI: 1.68-3.96), P<0.0001]. Furthermore, patients who received lenalidomide and dexamethasone alone had a significantly higher risk of VTE compared to those on MPR while on ASA prophylaxis (RR=6.4 [(95% CI: 4.11 9.91), P<0.0001]). CONCLUSION: The most frequent thromboprophylaxis option used for myeloma patients on lenalidomide-based therapy is ASA. However, ASA may not confer appropriate thromboprophylaxis in patients using RD, but may be a safe option with MPR. In future studies, the IMWG VTE risk stratification criteria should be validated, incorporating the thromboprophylaxis option accordingly. More studies comparing the efficacy and safety of ASA to LMWH are warranted. PMID- 26986754 TI - Post-thrombotic syndrome and the risk of subsequent recurrent thromboembolism. PMID- 26986755 TI - Biotransformation of penicillin V to 6-aminopenicillanic acid using immobilized whole cells of E. coli expressing a highly active penicillin V acylase. AB - The production of 6-aminopenicillanic acid (6-APA) is a key step in the manufacture of semisynthetic antibiotics in the pharmaceutical industry. The penicillin G acylase from Escherichia coli has long been utilized for this purpose. However, the use of penicillin V acylases (PVA) presents some advantages including better stability and higher conversion rates. The industrial application of PVAs has so far been limited due to the nonavailability of suitable bacterial strains and cost issues. In this study, whole-cell immobilization of a recombinant PVA enzyme from Pectobacterium atrosepticum expressed in E. coli was performed. Membrane permeabilization with detergent was used to enhance the cell-bound PVA activity, and the cells were encapsulated in calcium alginate beads and cross-linked with glutaraldehyde. Optimization of parameters for the biotransformation by immobilized cells showed that full conversion of pen V to 6-APA could be achieved within 1 hr at pH 5.0 and 35 degrees C, till 4% (w/v) concentration of the substrate. The beads could be stored for 28 days at 4 degrees C with minimal loss in activity and were reusable up to 10 cycles with 1-hr hardening in CaCl2 between each cycle. The high enzyme productivity of the PVA enzyme system makes a promising case for its application for 6-APA production in the industry. PMID- 26986756 TI - Altered function of monocytes/macrophages in patients with autoimmune hepatitis. AB - The pathogenesis of autoimmune hepatitis (AIH) involves the intervention of the innate and adaptive immune responses. In the current study, the alterations in monocytes/Kupffer cells (KCs) were investigated in patients with AIH. A total of 21 patients with AIH at different stages of the disease, and 7 controls with non alcoholic fatty liver disease were selected. The abundance of VAV1 and p21 activated kinase 1 (PAK1) in the liver and KCs was analyzed. In addition, the expression levels of HLA-DR and CD80 in the peripheral blood monocytes (PBMs) were measured, and phagocytosis of PBMs was assessed. KCs of AIH patients exhibited higher expression levels of VAV1 and PAK1. This upregulated expression was associated with disease progression. A reduced expression of HLA-DR and CD80, and reduced capacity of E. coli phagocytosis in PBMs was observed for patients with AIH. This downregulated expression was associated with disease progression. The results of the current study indicated that defective function of KCs and PBMs may be involved in the pathogenesis of AIH. PMID- 26986759 TI - Characterisation of the surface of freshly prepared precious metal catalysts. AB - A combination of electron microscopy, X-ray and neutron spectroscopies and computational methods has provided new insights into the species present on the surface of freshly prepared precious metal catalysts. The results show that in all cases, at least half of the surface is metallic or nearly so, with the remainder covered by oxygen, largely as hydroxide. Water is also present and is strongly held; weeks of pumping under high vacuum is insufficient to remove it. The hydroxyls are reactive as shown by their reaction with or displacement by CO and can be removed by hydrogenation. This clearly has implications for how precious metal catalysts are activated after preparation. PMID- 26986757 TI - Amelioration of Diabetic Mouse Nephropathy by Catalpol Correlates with Down Regulation of Grb10 Expression and Activation of Insulin-Like Growth Factor 1 / Insulin-Like Growth Factor 1 Receptor Signaling. AB - Growth factor receptor-bound protein 10 (Grb10) is an adaptor protein that can negatively regulate the insulin-like growth factor 1 receptor (IGF-1R). The IGF1 1R pathway is critical for cell growth and apoptosis and has been implicated in kidney diseases; however, it is still unknown whether Grb10 expression is up regulated and plays a role in diabetic nephropathy. Catalpol, a major active ingredient of a traditional Chinese medicine, Rehmannia, has been reported to possess anti-inflammatory and anti-aging activities and then used to treat diabetes. Herein, we aimed to assess the therapeutic effect of catalpol on a mouse model diabetic nephropathy and the potential role of Grb10 in the pathogenesis of this diabetes-associated complication. Our results showed that catalpol treatment improved diabetes-associated impaired renal functions and ameliorated pathological changes in kidneys of diabetic mice. We also found that Grb10 expression was significantly elevated in kidneys of diabetic mice as compared with that in non-diabetic mice, while treatment with catalpol significantly abrogated the elevated Grb10 expression in diabetic kidneys. On the contrary, IGF-1 mRNA levels and IGF-1R phosphorylation were significantly higher in kidneys of catalpol-treated diabetic mice than those in non-treated diabetic mice. Our results suggest that elevated Grb10 expression may play an important role in the pathogenesis of diabetic nephropathy through suppressing IGF-1/IGF-1R signaling pathway, which might be a potential molecular target of catalpol for the treatment of this diabetic complication. PMID- 26986760 TI - Gestalt Reasoning with Conjunctions and Disjunctions. AB - Reasoning, solving mathematical equations, or planning written and spoken sentences all must factor in stimuli perceptual properties. Indeed, thinking processes are inspired by and subsequently fitted to concrete objects and situations. It is therefore reasonable to expect that the mental representations evoked when people solve these seemingly abstract tasks should interact with the properties of the manipulated stimuli. Here, we investigated the mental representations evoked by conjunction and disjunction expressions in language picture matching tasks. We hypothesised that, if these representations have been derived using key Gestalt principles, reasoners should use perceptual compatibility to gauge the goodness of fit between conjunction/disjunction descriptions (e.g., the purple and/ or the green) and corresponding binary visual displays. Indeed, the results of three experimental studies demonstrate that reasoners associate conjunction descriptions with perceptually-dependent stimuli and disjunction descriptions with perceptually-independent stimuli, where visual dependency status follows the key Gestalt principles of common fate, proximity, and similarity. PMID- 26986761 TI - Increasing Diagnostic Value of Transbronchial Lung Cryobiopsy. PMID- 26986758 TI - Modeling HIV-1 Induced Neuroinflammation in Mice: Role of Platelets in Mediating Blood-Brain Barrier Dysfunction. AB - The number of HIV-1 positive individuals developing some form of HIV-associated neurocognitive disorder (HAND) is increasing. In these individuals, the integrity of the blood-brain barrier (BBB) is compromised due to an increase in exposure to pro-inflammatory mediators, viral proteins, and virus released from infected cells. It has been shown that soluble CD40L (sCD40L) is released upon platelet activation and is an important mediator of the pathogenesis of HAND but the underlying mechanisms are unclear, emphasizing the need of an effective animal model. Here, we have utilized a novel animal model in which wild-type (WT) mice were infected with EcoHIV; a derivative of HIV-1 that contains a substitution of envelope protein gp120 with that of gp80 derived from murine leukemia virus-1 (MuLV-1). As early as two-weeks post-infection, EcoHIV led to increased permeability of the BBB associated with decreased expression of tight junction protein claudin-5, in CD40L and platelet activation-dependent manner. Treatment with an antiplatelet drug, eptifibatide, in EcoHIV-infected mice normalized BBB function, sCD40L release and platelet activity, thus implicating platelet activation and platelet-derived CD40L in virally induced BBB dysfunction. Our results also validate and underscore the importance of EcoHIV infection mouse model as a tool to explore therapeutic targets for HAND. PMID- 26986763 TI - Fouling-release and chemical activity effects of a siloxane-based material on tunicates. AB - The antifouling performance of a siloxane-based elastomeric impression material (EIM) was compared to that of two silicone fouling-release coatings, Intersleek 757 and RTV-11. In field immersion trials, the EIM caused the greatest reduction in fouling by the solitary tunicate Ciona intestinalis and caused the longest delay in the progression of fouling by two species of colonial tunicate. However, in pseudobarnacle adhesion tests, the EIM had higher attachment strengths. Further laboratory analyses showed that the EIM leached alkylphenol ethoxylates (APEs) that were toxic to C. intestinalis larvae. The EIM thus showed the longest duration of chemical activity measured to date for a siloxane-based coating (4 months), supporting investigations of fouling-release coatings that release targeted biocides. However, due to potential widespread effects of APEs, the current EIM formulation should not be considered as an environmentally-safe antifoulant. Thus, the data also emphasize consideration of both immediate and long-term effects of potentially toxic constituents released from fouling-release coatings. PMID- 26986762 TI - Human umbilical cord blood mononuclear cells and chorionic plate-derived mesenchymal stem cells promote axon survival in a rat model of optic nerve crush injury. AB - The use of mesenchymal stem cells (MSCs) in cell therapy in regenerative medicine has great potential, particularly in the treatment of nerve injury. Umbilical cord blood (UCB) reportedly contains stem cells, which have been widely used as a hematopoietic source and may have therapeutic potential for neurological impairment. Although ongoing research is dedicated to the management of traumatic optic nerve injury using various measures, novel therapeutic strategies based on the complex underlying mechanisms responsible for optic nerve injury, such as inflammation and/or ischemia, are required. In the present study, a rat model of optic nerve crush (ONC) injury was established in order to examine the effects of transplanting human chorionic plate-derived MSCs (CP-MSCs) isolated from the placenta, as well as human UCB mononuclear cells (CB-MNCs) on compressed rat optic nerves. Expression markers for inflammation, apoptosis, and optic nerve regeneration were analyzed, as well as the axon survival rate by direct counting. Increased axon survival rates were observed following the injection of CB-MNCs at at 1 week post-transplantation compared with the controls. The levels of growth associated protein-43 (GAP-43) were increased after the injection of CB-MNCs or CP-MSCs compared with the controls, and the expression levels of hypoxia inducible factor-1alpha (HIF-1alpha) were also significantly increased following the injection of CB-MNCs or CP-MSCs. ERM-like protein (ERMN) and SLIT-ROBO Rho GTPase activating protein 2 (SRGAP2) were found to be expressed in the optic nerves of the CP-MSC-injected rats with ONC injury. The findings of our study suggest that the administration of CB-MNCs or CP-MSCs may promote axon survival through systemic concomitant mechanisms involving GAP-43 and HIF-1alpha. Taken together, these findings provide further understanding of the mechanisms repsonsible for optic nerve injury and may aid in the development of novel cell based therapeutic strategies with future applications in regenerative medicine, particularly in the management of optic nerve disorders. PMID- 26986764 TI - Heavy metal accumulation related to population density in road dust samples taken from urban sites under different land uses. AB - Soil pollution is a key component of the land degradation process, but little is known about the impact of soil pollution on human health in the urban environment. The heavy metals Pb, Zn, Cu, Cr, Cd and Ni were analyzed by acid digestion (method EPA 3050B) and a total of 15 dust samples were collected from streets of three sectors of the city with different land uses; commercial, residential and a highway. The purpose was to measure the concentrations of heavy metals in road sediment samples taken from urban sites under different land uses, and to assess pollution through pollution indices, namely the ecological risk index and geoaccumulation index. Heavy metals concentrations (mg/kg) followed the following sequences for each sector: commercial sector Pb (1289.4)>Cu (490.2)>Zn (387.6)>Cr (60.2)>Ni (54.3); highway Zn (133.3)>Cu (126.3)>Pb (87.5)>Cr (9.4)>Ni (5.3); residential sector Zn (108.3)>Pb (26.0)>Cu (23.7)>Cr (7.3)>Ni (7.2). The geoaccumulation index indicated that the commercial sector was moderately to strongly polluted while the other sectors fell into the unpolluted category. Similarly, using the ecological risk index the commercial sector fell into the considerable category while the other sectors classified as low risk. Road dust increased along with city growth and its dynamics, additionally, road dust might cause a number of negative environmental impacts, therefore the monitoring this dust is crucial. PMID- 26986766 TI - Effort to reduce postural sway affects both cognitive and motor performances in individuals with Parkinson's disease. AB - OBJECTIVES: To assess the effects of voluntarily reducing postural sway on postural control and to determine the attention level needed to do so in healthy adults (n=16, 65.9+/-9.7) and persons with PD (n=25, 65.8+/-9.5 years). Tasks: quiet and still standing conditions with and without a category task. Cognitive performance, center of pressure (CoP) displacement variability (RMSCoP) and velocity (VCoP) were assessed in the anterior-posterior (AP) and medial-lateral (ML) directions. Controls showed larger RMSCoP (AP) and VCoP (AP and ML) during still versus quiet standing (p<0.01), while the PD group demonstrated no changes. In the PD group, RMSCoP and VCoP (ML) increased in still standing when performed with the cognitive task (p<0.05). In both groups, cognitive responses decreased in still standing (p<0.05). In PD, attempting to reduce postural sway did not affect postural control under single task conditions, however ML CoP variability and velocity did increase as a dual task. In older adults, increased displacement and velocity in both AP and ML directions was observed during single, but not dual task conditions. Therefore standing still might not be an adequate postural strategy as it increases the attentional demand and affects motor performance, putting persons with PD at greater risk for falls. PMID- 26986765 TI - Prognostic and predictive effects of diabetes, hypertension, and coronary artery disease among women on extended adjuvant letrozole: NCIC CTG MA.17. AB - BACKGROUND: Women with breast cancer and diabetes mellitus (DM) have poorer survival. Mechanisms include insulin dysregulation and/or DM related co morbidities (CM). In MA.17 adjuvant letrozole (LET) after 5 years of tamoxifen (TAM) reduced the risk of recurrence and improved survival. We evaluated DM, hypertension (HTN), and coronary artery disease (CAD) as prognostic and predictive factors in MA.17. PATIENTS AND METHODS: Disease free survival, distant disease free survival (DDFS) and overall survival (OS) were compared using Cox regression model adjusting for other prognostic factors: in women treated by placebo (PLAC) based on the presence or absence of baseline DM (n = 462), HTN (n = 1627), CAD (n = 604) or any one of these CM (n = 2049), and between LET and PLAC groups in each CM. Analyses based on nodal status were performed. RESULTS: DM was neither prognostic nor predictive for women on extended LET. Women with one CM had similar outcomes on LET compared to women free of CM. For node positive women, the difference between LET and PLAC in DDFS was greater among women with one CM (hazard ratio [HR] = 0.30 [0.15-0.60], p = 0.001) compared to those without CM (HR = 0.72 [0.45-1.16], p = 0.17, p interaction = 0.04). Women on PLAC with HTN trended towards lower DDFS (HR = 1.50 [0.98-2.3], p = 0.06) and OS (HR = 1.61 [0.95-2.72], p = 0.08) than non-HTN women. HTN women had better DDFS on LET than non-HTN women. Women with one CM on PLAC had lower OS (HR = 2.10 [1.26-3.51], p = 0.004) than those free of CM. CONCLUSIONS: DM was not prognostic or predictive of outcomes. Women with CM who remain disease free after 5 years of TAM should be offered LET. HTN trended towards a negative prognosticator and outcomes among this group were improved on LET. More studies are needed to assess impact of adrenergic stimulation as a possible link to poorer breast cancer outcomes. PMID- 26986767 TI - Epigenetic targeting of glioma stem cells: Short-term and long-term treatments with valproic acid modulate DNA methylation and differentiation behavior, but not temozolomide sensitivity. AB - Glioblastoma (GBM) is the most aggressive tumor of the central nervous system. GBM is a fatal tumor, incurable by conventional therapies. One of the factors underlying tumor recurrence and poor long-term survival is the presence of a cancer stem-like cell population, termed glioma stem cells (GSCs), which is particularly resistant to chemotherapy and radiotherapy and supports tumor self renewal. The aim of the present study was to evaluate the impact and difference in effects of short-term and long-term treatments with valproic acid (VPA), a histone deacetylase inhibitor, on seven GSC lines. We investigated for the first time the changes in the genome-wide DNA methylation profile and the differentiation behavior of GSCs induced by short-term and long-term VPA treatments. Moreover, we verified VPA sensitivity after long-term VPA pretreatment and, notably, the results provide evidence of a subpopulation more resistant to further VPA treatments. Finally, since short-term VPA treatment induced a reversal of the MGMT methylation status, we aimed to sensitize GSCs to temozolomide, the drug commonly used for this tumor, using this regimen. The overall data highlighted the heterogeneous behavior of GSC lines that is representative of tumor heterogeneity in GBM. The VPA effects were variable among these cell lines in terms of pro-differentiating ability and DNA methylation switch. Here, we attempted to identify a suitable therapy for the eradication of the stem cell subpopulation, which is mandatory to achieve an effective treatment for this tumor. Differentiation-inducing and epigenetic therapies are the most promising approaches to affect the multiple properties of GSCs and, finally, defeat GBM. PMID- 26986768 TI - Lung Mass in a Teenage Male With Asthma. PMID- 26986769 TI - Risk Factors for Severity of Chikungunya in Children: A Prospective Assessment. AB - Chikungunya appeared during the second half of 2014 in Colombia. A prospective cohort study was carried to detect differences and severity between neonates and older children. Of 54 children with chikungunya, neonates had a higher viral load and greater frequency of severe laboratory and clinical findings. PMID- 26986770 TI - Predicting Outcome of Childhood Bacterial Meningitis With a Single Measurement of C-Reactive Protein. AB - INTRODUCTION: C-reactive protein (CRP), a marker of inflammation, shows high serum levels in invasive bacterial infections. We investigated the potential of a single CRP measurement at different phases of acute childhood bacterial meningitis to predict outcomes. METHODS: Using whole-blood finger-prick samples with no centrifugation, CRP was measured quantitatively on arrival and on day 3 or 4 in children participating in 2 prospective, randomized, double-blind treatment studies conducted in Latin America or Angola. The results were compared with patient outcomes. RESULTS: Although initial CRP values from 669 children gave useful prognostic information, the 3rd or 4th day measurements taken from 275 children associated significantly with seizures, slow recovery and low scores on the Glasgow Outcome Scale, with odds ratios for CRP values above the median (62 mg/L) ranging from 2 to 6, 2 to 5, and 3 to 5 (Latin America-Angola), respectively. Hearing impairment, although not full deafness, was 3 to 7 times more likely if CRP was above the median soon after hospitalization. CONCLUSIONS: Especially in resource-poor settings, clinicians have few simple-enough tools to identify the child with meningitis who requires maximum attention. CRP is a worthy addition. PMID- 26986771 TI - Travelers' Diarrhea in Children: What Have We Learnt? PMID- 26986772 TI - Infections With Biofilm Formation: Selection of Antimicrobials and Role of Prolonged Antibiotic Therapy. PMID- 26986773 TI - Denouement. PMID- 26986774 TI - Short-axis/out-of-plane or long-axis/in-plane ultrasound-guided arterial cannulation in children: A randomised controlled trial. AB - BACKGROUND: Even with ultrasound guidance, arterial cannulation in children can be challenging. OBJECTIVE: To compare the short-axis/out-of-plane (SAX) with the long-axis/in-plane (LAX) technique for ultrasound-guided arterial cannulation in children. DESIGN: A randomised controlled trial. SETTING: A tertiary university hospital, from 5 January 2015 to 21 April 2015. PATIENTS: 101 children, American Society of Anesthesiologists' physical status 1 or 2 and younger than 5 years of age. INTERVENTIONS: All were randomised into one of four groups according to age and ultrasound guidance technique: infants with SAX technique (n = 25), infants with LAX technique (n = 25), children with SAX technique (n = 25) and children with LAX technique (n = 26). Ultrasound-guided arterial cannulation was performed under general anaesthesia via the radial or posterior tibial artery, depending on individual position and operative field. MAIN OUTCOME MEASURES: The primary outcome was the total time to successful cannulation. Secondary outcomes included diameter and depth of the artery, time variables (imaging time, time to first successful puncture and time between first successful puncture and cannulation), number of puncture attempts, success rates (first puncture and final cannulation), posterior wall puncture rate and complications. RESULTS: Ultrasound guided arterial cannulation was successful in 97 children (96.0%). There were no significant differences in the total time to successful cannulation between the two groups. Ultrasound imaging time was significantly longer in the LAX group than in the SAX group (46.5 +/- 39.2 vs 16.0 +/- 17.6 s; 95% confidence interval of mean difference, -42.7 to -18.3; P = 0.000). However, the posterior wall puncture rate was significantly higher in the SAX group than in the LAX group (95.7% vs 18.0%; P = 0.000; odds ratio 0.01; 95% confidence interval, 0.002 to 0.048). There were no statistically significant differences in other secondary outcomes. CONCLUSION: Despite the longer imaging time with the LAX approach, there was no significant difference in the total time to successful cannulation between the two techniques. The posterior wall puncture rate was lower in the LAX group than in the SAX group. TRIAL REGISTRATION: Clinicaltrials.gov (identifier: NCT02333786). PMID- 26986775 TI - Anaesthesia and orphan disease: Bloom's syndrome. PMID- 26986776 TI - Effect of head position on laryngeal visualisation with the McGrath MAC videolaryngoscope in paediatric patients: A randomised controlled trial. AB - BACKGROUND: The McGrath MAC video laryngoscope can improve visualisation of the glottis compared with the Macintosh direct laryngoscope. However, good visualisation of the glottis does not guarantee rapid or successful intubation because of difficulty in handling the McGrath device. OBJECTIVE: We evaluated the effect of head elevation, aligning the positions of the external auditory meatus and sternal notch in the horizontal plane, on visualisation of the glottis and handling of the McGrath laryngoscope in paediatric patients. DESIGN: A randomised controlled trial. SETTING: The operating rooms of our tertiary care hospital. PATIENTS: Forty-six children, American Society of Anaesthesiologists' physical status 1 or 2, aged 3 to 7 years. INTERVENTION: Videolaryngoscopy using the McGrath device was performed with the head either flat or elevated. MAIN OUTCOME MEASURES: The percentage of glottis opening score, the use of optimisation manoeuvre and time to successful tracheal intubation were recorded. RESULTS: The median (IQR) percentage of glottis opening score was higher after head elevation than when the head was flat in all patients [100 (100 to 100)% vs. 100 (90 to 100)%, P = 0.0001). The need for use of optimisation procedures (50 vs. 9%, P = 0.004) and mean (SD) time to intubation (17 +/- 4 s vs. 15 +/- 3 s, P = 0.008) were lower in the head-elevated group. CONCLUSION: Visualisation of the glottis and handling of the McGrath MAC video laryngoscope were significantly better when the external auditory meatus and sternal notch were aligned in the horizontal plane. TRIAL REGISTRATION: http://cris.nih.go.kridentifier:KCT0001443. PMID- 26986777 TI - Regional haemodynamic changes after selective block of the four principal nerves in the arm: A double-blind randomised controlled study. PMID- 26986778 TI - Unraveling a generic growth pattern in structure evolution of thiolate-protected gold nanoclusters. AB - Precise control of the growth of thiolate-protected gold nanoclusters is a prerequisite for their applications in catalysis and bioengineering. Here, we bring to bear a new series of thiolate-protected nanoclusters with a unique growth pattern, i.e., Au20(SR)16, Au28(SR)20, Au36(SR)24, Au44(SR)28, and Au52(SR)32. These nanoclusters can be viewed as resulting from the stepwise addition of a common structural motif [Au8(SR)4]. The highly negative values of the nucleus-independent chemical shift (NICS) in the center of the tetrahedral Au4 units suggest that the overall stabilities of these clusters stem from the local stability of each tetrahedral Au4 unit. Generalization of this growth pattern rule to large-sized nanoclusters allows us to identify the structures of three new thiolate-protected nanoclusters, namely, Au60(SR)36, Au68(SR)40, and Au76(SR)44. Remarkably, all three large-sized nanoclusters possess relatively large HOMO-LUMO gaps and negative NICS values, suggesting their high chemical stability. Further extension of the growth-pattern rule to the infinitely long nanowire limit results in a one-dimensional (1D) thiolate-protected gold nanowire (RS-AuNW) with a band gap of 0.78 eV. Such a unique growth-pattern rule offers a guide for precise synthesis of a new class of large-sized thiolate-protected gold nanoclusters or even RS-AuNW which, to our knowledge, has not been reported in the literature. PMID- 26986779 TI - The relationship between family functioning and the crime types in incarcerated children. AB - BACKGROUND: We investigated the relationship between the family functioning and crime types in incarcerated children. METHODS: One hundred eighty two incarcerated children aged between 13-18 years who were confined in child-youth prisons and child correctional facilities were enrolled into this descriptive study. Participants completed demographic questions and the McMaster Family Assessment Device (Epstein, Baldwin, & Bishop, 1983) (FAD) with face to face interviews. RESULTS: The crime types were theft, assault (bodily injury), robbery, sexual assault, drug trafficker and murder. The socio-demographic characteristics were compared by using FAD scale, and growing up in a nuclear family had statistically significant better scores for problem solving and communication subscales and the children whose parents had their own house had significantly better problem solving scores When we compared the crime types of children by using problem solving, communication and general functioning subscales of FAD, we found statistical lower scores in assault (bodily injury) group than in theft, sexual assault, murder groups and in drug trafficker group than in murder group, also we found lower scores in drug trafficker group than in theft group for problem solving and general functioning sub-scales, also there were lower scores in bodily injury assault group than in robbery, theft groups and in drug trafficker than in theft group for problem solving subscale. CONCLUSIONS: The communication and problem solving sub-scales of FAD are firstly impaired scales for the incarcerated children. We mention these sub-scales are found with unplanned and less serious crimes and commented those as cry for help of the children. PMID- 26986780 TI - The value of pancreatic stone protein in the prediction of infected neonates. AB - BACKGROUND: The aim of this study was to determine serum pancreatic stone protein (PSP) levels in the neonates with highly probable or probable sepsis and assess their possible value in predicting infected neonates. METHODS: This was a prospective study involving 119 neonates who were admitted with suspected sepsis. The study population was divided into two groups, a infected group (N.=40, with highly probable sepsis or probable sepsis) and control group (N.=79, with possible or no sepsis). The blood samples were obtained at 24, 72 and 168 hours after birth. The amount of serum PSP were detected by enzyme linked immunosorbent (ELISA). RESULTS: PSP serum concentrations were higher in the infected group comparison to the control group at all time points (all P=0.000). In addition the sequential comparison between the infected group and control group at all of time points was significantly different (F=48.558, P=0.000). ROC area under the curve (AUC) was 0.791 [95% CI: 0.71-0.87; P=0.000] for PSP at 24 hours after birth and 0.790 (95% CI: 0.79-0.88; P=0.000) 72 hours after birth and combination of the two time points (24 and 72 hours), the AUC was 0.819 (95% CI: 0.74-0.90; P=0.000). CONCLUSIONS: PSP is a valuable biomarker in predicting infected neonates. Combination of PSP at each time point within 72 hours after birth might be better. PMID- 26986781 TI - Stereoselective Synthesis of Spiro Bis-C,C-alpha-arylglycosides by Tandem Heck Type C-Glycosylation and Friedel-Crafts Cyclization. AB - Spiro bis-C,C-alpha-arylglycosides were synthesized in three steps in 78-85% overall yields starting from exo-glycals. The initial Heck type C-aryl addition of exo-glycals with arylboronic acids afforded alpha-aryl-beta-substituted C glycosides with exclusive alpha-stereoselectivity. Among the products, beta ethanal alpha-aryl C-glycosides further reacted with alkylthiol in the presence of InCl3, followed by in situ Friedel-Crafts cyclization to yield the desirable final products. We proposed a mechanism to explain how the alpha-aryl group serves as a main determinant of the cyclization. PMID- 26986783 TI - Fifty years of the Journal of Phycology: What's the impact? PMID- 26986784 TI - Slow-flow habitats as refugia for coastal calcifiers from ocean acidification. AB - The pH of the oceans' surface water is dropping, termed ocean acidification (OA), and the 0.4 unit reduction in pH by 2100 is projected to negatively impact benthic coastal organisms that produce calcium carbonate "skeletons." Research has focussed on identifying species that are susceptible to OA, but there is an urgent need to discover refuge habitats that will afford protection to vulnerable species. The susceptibility of calcium carbonate skeletons to dissolution by OA depends on the pH at their surface, and this is controlled by the interaction between seawater velocity and organismal metabolism. This perspective considers how seawater velocity modifies the responses of calcifying organisms (seaweed, shellfish, and tropical corals) to OA through its action on controlling diffusion boundary layer thickness and thereby the pH and calcium carbonate saturation state (Omega) at the organisms' surface. Evidence is presented to support the idea that slow-flow habitats, such as wave-sheltered bays or the within canopies of seaweed/seagrass beds, might provide inexpensive refugia from OA for vulnerable coastal calcifiers. PMID- 26986785 TI - Ecological niche models of invasive seaweeds. AB - Ecological niche models (ENMs) are commonly used to calculate habitat suitability from species' occurrence and macroecological data. In invasive species biology, ENMs can be applied to anticipate whether invasive species are likely to establish in an area, to identify critical routes and arrival points, to build risk maps and to predict the extent of potential spread following an introduction. Most studies using ENMs focus on terrestrial organisms and applications in the marine realm are still relatively rare. Here, we review some common methods to build ENMs and their application in seaweed invasion biology. We summarize methods and concepts involved in the development of niche models, show examples of how they have been applied in studies on algae and discuss the application of ENMs in invasive algae research and to predict effects of climate change on seaweed distributions. PMID- 26986782 TI - Cistromic and genetic evidence that the vitamin D receptor mediates susceptibility to latitude-dependent autoimmune diseases. AB - The vitamin D receptor (VDR) is a ligand-activated transcription factor that regulates gene expression in many cell types, including immune cells. It requires binding of 1,25 dihydroxy vitamin D3 (1,25D3) for activation. Many autoimmune diseases show latitude-dependent prevalence and/or association with vitamin D deficiency, and vitamin D supplementation is commonly used in their clinical management. 1,25D3 is regulated by genes associated with the risk of autoimmune diseases and predominantly expressed in myeloid cells. We determined the VDR cistrome in monocytes and monocyte-derived inflammatory (DC1) and tolerogenic dendritic cells (DC2). VDR motifs were highly overrepresented in ChIP-Seq peaks in stimulated monocyte (40%), DC1 (21%) and DC2 (47%), P0.1 g . L(-1) ), and this effect did not significantly differ among the five sargassacean species. When the carpospores were combined with blades from the five species, many of the spores attached and germinated on every blade. Because N. harveyi penetrated rhizoids into basiphyte tissues, cuticle peeling observed in all five sargassacean species could not remove this epiphyte after germination. However, in S. siliquastrum, the blade tissues around the germlings became swollen and disintegrative, and were removed together with the germlings. The spores normally grew on the dead blades, suggesting that the tissue degradation of S. siliquastrum is triggered by the infection of N. harveyi. PMID- 26986792 TI - A non-toxigenic but morphologically and phylogenetically distinct new species of Pseudo-nitzschia, P. sabit sp. nov. (Bacillariophyceae). AB - A new species of Pseudo-nitzschia (Bacillariophyceae) is described from plankton samples collected from Port Dickson (Malacca Strait, Malaysia) and Manzanillo Bay (Colima, Mexico). The species possesses a distinctive falcate cell valve, from which they form sickle-like colonies in both environmental samples and cultured strains. Detailed observation of frustules under TEM revealed ultrastructure that closely resembles P. decipiens, yet the new species differs by the valve shape and greater ranges of striae and poroid densities. The species is readily distinguished from the curve-shaped P. subcurvata by the presence of a central interspace. The morphological distinction is further supported by phylogenetic discrimination. We sequenced and analyzed the nuclear ribosomal RNA genes in the LSU and the second internal transcribed spacer, including its secondary structure, to infer the phylogenetic relationship of the new species with its closest relatives. The results revealed a distinct lineage of the new species, forming a sister cluster with its related species, P. decipiens and P. galaxiae, but not with P. subcurvata. We examined the domoic acid (DA) production of five cultured strains from Malaysia by Liquid chromatography-mass spectrometry (LC MS), but they showed no detectable DA. Here, we present the taxonomic description of the vegetative cells, document the sexual reproduction, and detail the molecular phylogenetics of Pseudo-nitzschia sabit sp. nov. PMID- 26986793 TI - The 24 hour recovery kinetics from n starvation in Phaeodactylum tricornutum and Emiliania huxleyi. AB - The response of N (nitrate) starved cells of the diatom Phaeodactylum tricornutum and the coccolithophore Emiliania huxleyi to a pulse of new N were measured to investigate rapid cellular and photosynthetic recovery kinetics. The changes of multiple parameters were followed over 24 h. In P. tricornutum, the recovery of Fv /Fm (the maximum quantum yield of PS II) and sigmaPSII (the functional absorption cross-section for PSII) started within the first hour, much earlier than other parameters. Cellular pigments did not recover during the 24 h but the chlorophyll (chl) a/carotenoid ratios increased to levels measured in the controls. Cell division was independent of the recovery of chl a. In E. huxleyi, the recovery of Fv /Fm and sigmaPSII started after an hour, synchronous with the increase in cellular organic N and chl a with pigments fully recovered within 14 h. P. tricornutum prioritized the recovery of its photosynthetic functions and cell divisions while E. huxleyi did not follow this pattern. We hypothesize that the different recovery strategies between the two species allow P. tricornutum to be more competitive when N pulses are introduced into N-limited water while E. huxleyi is adapted to N scarce waters where such pulses are infrequent. These findings are consistent with successional patterns observed in coastal environments. This is one of only a few studies exploring recovery kinetics of cellular functions and photosynthesis after nitrogen stress in phytoplankton. Our results can be used to enhance ecological models linking phytoplankton traits to species diversity and community structure. PMID- 26986794 TI - Nutrient limitation of algal periphyton in streams along an acid mine drainage gradient. AB - Metal oxyhydroxide precipitates that form from acid mine drainage (AMD) may indirectly limit periphyton by sorbing nutrients, particularly P. We examined effects of nutrient addition on periphytic algal biomass (chl a), community structure, and carbon and nitrogen content along an AMD gradient. Nutrient diffusing substrata with treatments of +P, +NP and control were placed at seven stream sites. Conductivity and SO4 concentration ranged over an order of magnitude among sites and were used to define the AMD gradient, as they best indicate mine discharge sources of metals that create oxyhydroxide precipitates. Aqueous total phosphorous (TP) ranged from 2 to 23 MUg . L(-1) and significantly decreased with increasing SO4 . Mean chl a concentrations at sites ranged from 0.2 to 8.1 MUg . cm(-2) . Across all sites, algal biomass was significantly higher on +NP than control treatments (Co), and significantly increased with +NP. The degree of nutrient limitation was determined by the increase in chl a concentration on +NP relative to Co (response ratio), which ranged from 0.6 to 9.7. Response to nutrient addition significantly declined with increasing aqueous TP, and significantly increased with increasing SO4 . Thus, nutrient limitation of algal biomass increased with AMD impact, indicating metal oxyhydroxides associated with AMD likely decreased P availability. Algal species composition was significantly affected by site but not nutrient treatment. Percent carbon content of periphyton on the Co significantly increased with AMD impact and corresponded to an increase in the relative abundance of Chlorophytes. Changes in periphyton biomass and cellular nutrient content associated with nutrient limitation in AMD streams may affect higher trophic levels. PMID- 26986795 TI - Phylogeography of the freshwater raphidophyte Gonyostomum semen confirms a recent expansion in northern Europe by a single haplotype. AB - Gonyostmum semen is a freshwater raphidophyte that has increased in occurrence and abundance in several countries in northern Europe since the 1980s. More recently, the species has expanded rapidly also in north-eastern Europe, and it is frequently referred to as invasive. To better understand the species history, we have explored the phylogeography of G. semen using strains from northern Europe, United States, and Japan. Three regions of the ribosomal RNA gene (small subunit [SSU], internal transcribed spacer [ITS] and large subunit [LSU]) and one mitochondrial DNA marker (cox1) were analyzed. The SSU and partial LSU sequences were identical in all strains, confirming that they belong to the same species. The ITS region differentiated the American from the other strains, but showed high intra-strain variability. In contrast, the mitochondrial marker cox1 showed distinct differences between the European, American, and Japanese strains. Interestingly, only one cox1 haplotype was detected in European strains. The overall low diversity and weak geographic structure within northern European strains supported the hypothesis of a recent invasion of new lakes by G. semen. Our data also show that the invasive northern European lineage is genetically distinct from the lineages from the other continents. Finally, we concluded that the mitochondrial cox1 was the most useful marker in determining large-scale biogeographic patterns in this species. PMID- 26986796 TI - Novel psychrotolerant picocyanobacteria isolated from Chesapeake Bay in the winter. AB - Picocyanobacteria are major primary producers in the ocean, especially in the tropical or subtropical oceans or during warm seasons. Many "warm" picocyanobacterial species have been isolated and characterized. However, picocyanobacteria in cold environments or cold seasons are much less studied. In general, little is known about the taxonomy and ecophysiology of picocyanobacteria living in the winter. In this study, 17 strains of picocyanobacteria were isolated from Chesapeake Bay, a temperate estuarine ecosystem, during the winter months. These winter isolates belong to five distinct phylogenetic lineages, and are distinct from the picocyanobacteria previously isolated from the warm seasons. The vast majority of the winter isolates were closely related to picocyanobacteria isolated from other cold environments like Arctic or subalpine waters. The winter picocyanobacterial isolates were able to maintain slow growth or prolonged dormancy at 4 degrees C. Interestingly, the phycoerythrin-rich strains outperformed the phycocyanin-rich strains at cold temperature. In addition, winter picocyanobacteria changed their morphology when cultivated at 4 degrees C. The close phylogenetic relationship between the winter picocyanobacteria and the picocyanobacteria living in high latitude cold regions indicates that low temperature locations select specific ecotypes of picocyanobacteria. PMID- 26986797 TI - Sequencing type material resolves the identity and distribution of the generitype Lithophyllum incrustans, and related European species L. hibernicum and L. bathyporum (Corallinales, Rhodophyta). AB - DNA sequences from type material in the nongeniculate coralline genus Lithophyllum were used to unambiguously link some European species names to field collected specimens, thus providing a great advance over morpho-anatomical identifi-cation. In particular, sequence comparisons of rbcL, COI and psbA genes from field-collected specimens allowed the following conclusion: the generitype species, L. incrustans, occurs mostly as subtidal rhodoliths and crusts on both Atlantic and Mediterranean coasts, and not as the common, NE Atlantic, epilithic, intertidal crust reported in the literature. The heterotypic type material of L. hibernicum was narrowed to one rhodolith belonging in Lithophyllum. As well as occurring as a subtidal rhodolith, L. hibernicum is a common, epilithic and epizoic crust in the intertidal zone from Ireland south to Mediterranean France. A set of four features distinguished L. incrustans from L. hibernicum, including epithallial cell diameter, pore canal shape of sporangial conceptacles and sporangium height and diameter. An rbcL sequence of the lectotype of Lithophyllum bathyporum, which was recently proposed to accommodate Atlantic intertidal collections of L. incrustans, corresponded to a distinct taxon hitherto known only from Brittany as the subtidal, bisporangial, lectotype, but also occurs intertidally in Atlantic Spain. Specimens from Ireland and France morpho anatomically identified as L. fasciculatum and a specimen from Cornwall likewise identified as L. duckerae were resolved as L. incrustans and L. hibernicum, respectively. PMID- 26986798 TI - Trade-offs between life-history traits at range-edge and central locations. AB - The allocation of resources to different life-history traits should represent the best compromise in fitness investment for organisms in their local environment. When resources are limiting, the investment in a specific trait must carry a cost that is expressed in trade-offs with other traits. In this study, the relative investment in the fitness-related traits, growth, reproduction and defence were compared at central and range-edge locations, using the seaweed Ascophyllum nodosum as a model system. Individual growth rates were similar at both sites, whereas edge populations showed a higher relative investment in reproduction (demonstrated by a higher reproductive allocation and extended reproductive periods) when compared to central populations that invested more in defence. These results show the capability of A. nodosum to differentially allocate resources for different traits under different habitat conditions, suggesting that reproduction and defence have different fitness values under the specific living conditions experienced at edge and central locations. However, ongoing climate change may threaten edge populations by increasing the selective pressure on specific traits, forcing these populations to lower the investment in other traits that are also potentially important for population fitness. PMID- 26986799 TI - Corrigendum. PMID- 26986801 TI - Encapsulation of Antioxidant Gallate Derivatives in Biocompatible Poly(epsilon caprolactone)-b-Pluronic-b-Poly(epsilon-caprolactone) Micelles. AB - Formulation of antioxidant agents is still a challenge that limits their application in the biomedical field. Pentablock copolymers obtained through modification of two common PEO-PPO-PEO copolymers (Pluronic F127 and F68) with poly(epsilon-carprolactone) (PCL) were evaluated regarding their capability to form nanocarriers suitable for gallic acid, methyl gallate, and ethyl gallate. Applying a dialysis method, PCL/F127/PCL and PCL/F68/PCL self-assembled into spherical micelles in 0.9% NaCl aqueous solution but notably differed in critical micellar concentration (CMC), micelle core hydrophobicity, and micelle size, as evidenced by pyrene fluorescence, transmission electron microscopy, and dynamic light scattering. Cytotoxicity studies showed that the copolymers were safe at concentrations well above the CMC. Transfer of gallic acid and derivatives from aqueous medium to the micelle phase was characterized in terms of distribution constant and free energy of transference, which were shown to be strongly dependent on the hydrophobicity of the gallate derivatives and the length of PCL in the pentablock copolymer. Antioxidant activity of gallates was challenged against DPPH previously loaded in PCL/F127/PCL and PCL/F68/PCL micelles. The more the hydrophobicity of the gallate derivative, the greater the capability to enter in the micelle and to consume free radicals. In vitro release studies of gallic acid, methyl gallate, and ethyl gallate from the pentablock copolymer micelles also evidenced the influence of the hydrophobicity of both the gallate derivative and the micelle core on release rate, recording a variety of release patterns. Overall, PCL/F127/PCL and PCL/F68/PCL appear as suitable nanocarriers of potent antioxidant agents in a wide range of polarities, which may be useful for diverse therapeutic applications. PMID- 26986802 TI - A Highly Vascularized Supraglottic Neoplasm. PMID- 26986800 TI - Increases in NKG2C Expression on T Cells and Higher Levels of Circulating CD8+ B Cells Are Associated with Sterilizing Immunity Provided by a Live Attenuated SIV Vaccine. AB - Vaccines based on live attenuated viruses are highly effective immunogens in the simian immunodeficiency virus (SIV)/rhesus macaque animal model and offer the possibility of studying correlates of protection against infection with virulent virus. We utilized a tether system for studying, in naive macaques and animals vaccinated with a live-attenuated vaccine, the acute events after challenge with pathogenic SIV. This approach allowed for the frequent sampling of small blood volumes without sedation or restraining of the animals, thus reducing the confounding effect of sampling stress. Before challenge, vaccinated animals presented significantly higher levels of proliferating and activated B cells than naive macaques, which were manifested by high expression of CD8 on B cells. After SIV challenge, the only changes observed in protected vaccinated macaques were significant increases in expression of the NK marker NKG2C on CD4 and CD8 T cells. We also identified that infection of naive macaques with SIV resulted in a transient peak of expression of CD20 on CD8 T cells and a constant rise in the number of B cells expressing CD8. Finally, analysis of a larger cohort of vaccinated animals identified that, even when circulating levels of vaccine virus are below the limit of detection, live attenuated vaccines induce systemic increases of IP-10 and perforin. These studies indicate that components of both the innate and adaptive immune systems of animals inoculated with a live attenuated SIV vaccine respond to and control infection with virulent virus. Persistence of the vaccine virus in tissues may explain the elevated cytokine and B-cell activation levels. In addition, our report underpins the utility of the tether system for the intensive study of acute immune responses to viral infections. PMID- 26986805 TI - PD-L1 Testing and Lack of Benefit to Guide Treatment With Immune Checkpoint Inhibitors in Patients With Non-Small-Cell Lung Cancer. PMID- 26986804 TI - Concentrated growth factor promotes Schwann cell migration partly through the integrin beta1-mediated activation of the focal adhesion kinase pathway. AB - Nerve injury is a serious complication associated with dental implant surgery. Following nerve injury, the migration of Schwann cells (SCs) supports nerve regeneration. Concentrated growth factor (CGF) belongs to a new generation of biomaterials that contain fibrin matrix, as well as a number of growth factors that affect the migration of various types of cells, including endothelial cells and cancer cells. To the very best of our knowledge, there are no available studies to date on the promoting effect of CGF on the migration of SCs. Thus, the aim of the present study was to characterize the structure of CGF and growth factor release, examine the effects of CGF on the migration of SCs, and to examine the role of integrin beta1 and the focal adhesion kinase (FAK) pathway in the CGF-induced migration of SCs. For this purpose, CGF was prepared by centrifuging rat venous blood, which produced a fiber-like matrix capable of releasing transforming growth factor-beta1 (TGF-beta1) over a sustained period of time (at least 13 days). The soluble component of CGF was used to produce conditioned media to treat the SC cells in culture. The results demonstrated that CGF promoted the migration of SCs and increased the expression of integrin beta1. These effects appeared to involve FAK phosphorylation, which occurred downstream of integrin beta1 activation. The short-interfering RNA (siRNA)-mediated downregulation of integrin beta1 expression did not block the ability of CGF to promote the migration of SCs. These data suggest that CGF promotes the migration of SCs partly through the integrin beta1-mediated activation of the FAK pathway. PMID- 26986803 TI - The Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) trial: a randomised controlled trial of a protease inhibitor monotherapy strategy for long term management of human immunodeficiency virus infection. AB - BACKGROUND: Standard-of-care antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection uses a combination of drugs, until now considered essential to minimise treatment failure and development of drug resistance. Protease inhibitors (PIs) are potent with a high genetic barrier to resistance and have the potential for use as monotherapy after viral load (VL) suppression achieved on combination therapy. However, longer-term resistance and toxicity risks are uncertain. OBJECTIVE: To compare the effectiveness, toxicity profile and cost-effectiveness of PI monotherapy with those of standard-of-care triple therapy in a pragmatic long-term clinical trial. DESIGN: Open-label, parallel-group, randomised controlled trial. SETTING: Forty-three HIV clinical centres in the UK NHS. PARTICIPANTS: HIV-positive adults taking standard combination ART with a suppressed VL for >= 6 months. INTERVENTIONS: Patients were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected ritonavir-boosted PI monotherapy (PI-mono), with prompt return to combination therapy in the event of VL rebound. MAIN OUTCOME MEASURES: The primary outcome was reduction of future drug options, defined as new intermediate-/high-level resistance to one or more drugs to which the patient's virus was considered to be sensitive at trial entry (non-inferiority comparison, 10% margin). Secondary outcomes included confirmed virological rebound, serious drug- or disease-related complications, total grade 3 or 4 adverse events (AEs), neurocognitive function change, cluster of differentiation 4 (CD4) cell count change, change in health-related quality of life, cardiovascular risk change, health-care costs and health economic analysis. RESULTS: In total, 587 participants were randomised (77% male, 68% white) to OT (n = 291) or PI-mono (n = 296) and followed for a median of 44 months, of whom 2.7% withdrew/were lost to follow-up. One or more episodes of confirmed VL rebound were observed in eight patients (Kaplan-Meier estimate 3.2%) in the OT group and 95 patients (35.0%) in the PI-mono group [absolute risk difference 31.8%, 95% confidence interval (CI) 24.6% to 39.0%; p < 0.001]. PI-mono patients who changed to ART after VL rebound all resuppressed (median 3.5 weeks). The proportions with loss of a future drug option at 3 years were 0.7% in the OT group and 2.1% in the PI-mono group (difference 1.4%, (95% CI -0.4% to 3.4%); non-inferiority demonstrated). There were no significant differences in serious disease complications between groups or in the frequency of grade 3 or 4 clinical AEs (16.8% OT group vs. 22% PI-mono group; absolute risk difference 5.1%, 95% CI -1.3% to 11.5%; p = 0.12). Overall, the PI-mono strategy was shown to be cost-effective compared with OT under most scenarios explored. PI-mono was cost saving because of the large savings in ART drug costs while being no less effective in terms of quality-adjusted life-years in the within-trial analysis and only marginally less effective when extrapolated to lifetime outcomes. CONCLUSIONS: PI monotherapy, with prompt reintroduction of combination therapy for VL rebound, was non-inferior to combination therapy in preserving future treatment options and is an acceptable and cost-effective alternative for long-term management of HIV infection. TRIAL REGISTRATION: Current Controlled Trials ISRCTN04857074. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 21. See the NIHR Journals Library website for further project information. PMID- 26986806 TI - How methylglyoxal kills bacteria: An ultrastructural study. AB - Antibacterial activity of honey is due to the presence of methylglyoxal (MGO), H2O2, bee defensin as well as polyphenols. High MGO levels in manuka honey are the main source of antibacterial activity. Manuka honey has been reported to reduce the swarming and swimming motility of Pseudomonas aeruginosa due to de flagellation. Due to the complexity of honey it is unknown if this effect is directly due to MGO. In this ultrastructural investigation the effects of MGO on the morphology of bacteria and specifically the structure of fimbriae and flagella were investigated. MGO effectively inhibited Gram positive (Bacillus subtilis; MIC 0.8 mM and Staphylococcus aureus; MIC 1.2 mM) and Gram negative (P. aeruginosa; MIC 1.0 mM and Escherichia coli; MIC 1.2 mM) bacteria growth. The ultrastructural effects of 0.5, 1.0 and 2 mM MGO on B. substilis and E. coli morphology was then evaluated. At 0.5 mM MGO, bacteria structure was unaltered. For both bacteria at 1 mM MGO fewer fimbriae were present and the flagella were less or absent. Identified structures appeared stunted and fragile. At 2 mM MGO fimbriae and flagella were absent while the bacteria were rounded with shrinkage and loss of membrane integrity. Antibacterial MGO causes alterations in the structure of bacterial fimbriae and flagella which would limit bacteria adherence and motility. PMID- 26986807 TI - H2AX and EMT: deciphering beyond DNA repair. PMID- 26986808 TI - Abnormal expression of leiomyoma cytoskeletal proteins involved in cell migration. AB - Uterine leiomyomas are monoclonal tumors. Several factors are involved in the neoplastic transformation of the myometrium. In our study we focused on dysregulated cytoskeletal proteins in the leiomyoma as compared to the myometrium. Paired tissue samples of ten leiomyomas and adjacent myometria were obtained and analyzed by two-dimensional gel electrophoresis (2-DE). Mass spectrometry was used for protein identification, and western blotting for 2-DE data validation. The values of ten cytoskeletal proteins were found to be significantly different: eight proteins were upregulated in the leiomyoma and two proteins were downregulated. Three of the upregulated proteins (myosin regulatory light polypeptide 9, four and a half LIM domains protein 1 and LIM and SH3 domain protein 1) are involved in cell migration, while downregulated protein transgelin is involved in replicative senescence. Myosin regulatory light polypeptide 9 (MYL9) was further validated by western blotting because it is considered to be a cell migration marker in several cancers and could play a key role in leiomyoma development. Our data demonstrate significant alterations in the expression of cytoskeletal proteins involved in leiomyoma growth. A better understanding of the involvement of cytoskeletal proteins in leiomyoma pathogenesis may contribute to the identification of new therapeutic targets and the development of new pharmacological approaches. PMID- 26986809 TI - Radiation Duration in Women with Cervical Cancer Treated with Primary Chemoradiation: A Population-Based Analysis. AB - This study examines factors associated with prolonged radiation duration and its impact on survival in women with cervical cancer treated with primary chemoradiation. Women in the National Cancer Database with stage IB2-IVA cervical cancer from 2003 to 2011 who received radiation and chemotherapy were included. Of 7209 women, who met inclusion criteria, 3401 (47.1%) and 3808 (52.8%) completed radiation in <= 8 and > 8 weeks, respectively. There was no overall survival difference for radiation duration <= 8 vs. > 8 weeks. Sensitivity analyses showed that inferior overall survival is only seen with radiation duration of > 10-12 weeks. PMID- 26986810 TI - Delivery of mesenchymal stem cells in biomimetic engineered scaffolds promotes healing of diabetic ulcers. AB - AIM: We hypothesized that delivery of mesenchymal stem cells (MSCs) in a biomimetic collagen scaffold improves wound healing in a diabetic mouse model. MATERIALS & METHODS: Rolled collagen scaffolds containing MSCs were implanted or applied topically to diabetic C57BL/6 mice with excisional wounds. RESULTS: Rolled scaffolds were hypoxic, inducing MSC synthesis and secretion of VEGF. Diabetic mice with wounds treated with rolled scaffolds containing MSCs showed increased healing compared with controls. Histologic examination showed increased cellular proliferation, increased VEGF expression and capillary density, and increased numbers of macrophages, fibroblasts and smooth muscle cells. Addition of laminin to the collagen scaffold enhanced these effects. CONCLUSION: Activated MSCs delivered in a biomimetic-collagen scaffold enhanced wound healing in a translationally relevant diabetic mouse model. PMID- 26986812 TI - Drug metabolism: Comparison of biodistribution profile of holmium in three different compositions in healthy Wistar rats. AB - Radioisotope holmium is a candidate to be used in cancer treatment and diagnosis. There are different holmium salts and they present distinct solubility and consequently different biodistribution profiles. In this work, we aimed to evaluate the biodistribution profiles of two holmium salts (chloride and sulfate) and holmium nanoparticles (oxide) through an in vivo biodistribution assay using animal model. Samples were labeled with technetium-99m and administered in Wistar rats by retro-orbital route. Holmium chloride is highly soluble in water and it was quickly filtered by the kidneys while holmium sulfate that presents lower solubility in water was mainly found in the liver and the spleen. However, both the salts showed a similar biodistribution profile. On the other hand, holmium oxide showed a very different biodistribution profile since it seemed to interact with all organs. Due to its particle size range (approximately 100nm) it was not intensively filtered by the kidneys being found in high quantities in many organs, for this reason its use as a nanoradiopharmaceutical could be promising in the oncology field. PMID- 26986813 TI - A plastic scintillator-based 2D thermal neutron mapping system for use in BNCT studies. AB - In this study, a scintillator-based measurement instrument is proposed which is capable of measuring a two-dimensional map of thermal neutrons within a phantom based on the detection of 2.22MeV gamma rays generated via nth+H->D+gamma reaction. The proposed instrument locates around a small rectangular water phantom (14cm*15cm*20cm) used in Birmingham BNCT facility. The whole system has been simulated using MCNPX 2.6. The results confirm that the thermal flux peaks somewhere between 2cm and 4cm distance from the system entrance which is in agreement with previous studies. PMID- 26986811 TI - Autophagy is required for ectoplasmic specialization assembly in sertoli cells. AB - The ectoplasmic specialization (ES) is essential for Sertoli-germ cell communication to support all phases of germ cell development and maturity. Its formation and remodeling requires rapid reorganization of the cytoskeleton. However, the molecular mechanism underlying the regulation of ES assembly is still largely unknown. Here, we show that Sertoli cell-specific disruption of autophagy influenced male mouse fertility due to the resulting disorganized seminiferous tubules and spermatozoa with malformed heads. In autophagy-deficient mouse testes, cytoskeleton structures were disordered and ES assembly was disrupted. The disorganization of the cytoskeleton structures might be caused by the accumulation of a negative cytoskeleton organization regulator, PDLIM1, and these defects could be partially rescued by Pdlim1 knockdown in autophagy deficient Sertoli cells. Altogether, our works reveal that the degradation of PDLIM1 by autophagy in Sertoli cells is important for the proper assembly of the ES, and these findings define a novel role for autophagy in Sertoli cell-germ cell communication. PMID- 26986814 TI - A Novel Artificial Intelligence System for Endotracheal Intubation. AB - OBJECTIVE: Adequate visualization of the glottic opening is a key factor to successful endotracheal intubation (ETI); however, few objective tools exist to help guide providers' ETI attempts toward the glottic opening in real-time. Machine learning/artificial intelligence has helped to automate the detection of other visual structures but its utility with ETI is unknown. We sought to test the accuracy of various computer algorithms in identifying the glottic opening, creating a tool that could aid successful intubation. METHODS: We collected a convenience sample of providers who each performed ETI 10 times on a mannequin using a video laryngoscope (C-MAC, Karl Storz Corp, Tuttlingen, Germany). We recorded each attempt and reviewed one-second time intervals for the presence or absence of the glottic opening. Four different machine learning/artificial intelligence algorithms analyzed each attempt and time point: k-nearest neighbor (KNN), support vector machine (SVM), decision trees, and neural networks (NN). We used half of the videos to train the algorithms and the second half to test the accuracy, sensitivity, and specificity of each algorithm. RESULTS: We enrolled seven providers, three Emergency Medicine attendings, and four paramedic students. From the 70 total recorded laryngoscopic video attempts, we created 2,465 time intervals. The algorithms had the following sensitivity and specificity for detecting the glottic opening: KNN (70%, 90%), SVM (70%, 90%), decision trees (68%, 80%), and NN (72%, 78%). CONCLUSIONS: Initial efforts at computer algorithms using artificial intelligence are able to identify the glottic opening with over 80% accuracy. With further refinements, video laryngoscopy has the potential to provide real-time, direction feedback to the provider to help guide successful ETI. PMID- 26986815 TI - Antidifferentiation Noncoding RNA Regulates the Proliferation of Osteosarcoma Cells. AB - BACKGROUND: Antidifferentiation noncoding RNA (ANCR), a newly identified long noncoding RNA (lncRNA), plays a critical role for stem cells to maintain undifferentiated cell state. However, the functions of ANCR in human cancers have not been reported. This study is designed to explore the role of ANCR in osteosarcoma. METHODS: Lentivirus-mediated (shRNA) was applied to silence ANCR in the human osteosarcoma cell lines U2OS and Saos-2. Cell viability was measured by MTT assay. Colony-forming ability was measured by colony formation assay. Cell cycle progression was determined by flow cytometry with propidium iodide staining. In addition, cell cycle makers, including p21, CDK2, and CDK4, were investigated in ANCR silencing U2OS cells by real time PCR (RT-PCR) analysis. RESULTS: In this study, we first proved that lentivirus-mediated shRNA specifically suppressed the expression level of ANCR in U2OS and Saos-2 cells. Further investigations revealed that knockdown of ANCR significantly inhibited the proliferation of U2OS and Saos cells and colony formation of U2OS cells. Moreover, the cell cycle of U2OS cells was arrested at G0/G1 phase after ANCR knockdown. Furthermore, the expression level of p21 was increased and CDK2 was decreased in ANCR knock-down cells. CONCLUSIONS: Our data indicated that ANCR might be an oncogenic lncRNA that promoted proliferation of osteosarcoma. The potential application of ANCR-targeted therapy using the lentivirus-mediated shRNA approach is worth further investigations in preclinical and clinical studies. PMID- 26986816 TI - The Result of Multiple I-131 Treatments on the Effective Half-Life of Retained Radioactivity in Patients Ablated for Differentiated Thyroid Cancer: Possible Evidence for Thyroid Remnant Function Impairment. AB - The ablation of differentiated thyroid cancer by ingested I-131 depends on the activity absorbed by the remnant. This depends on the function of the thyroid cells and on the rate that radioactivity is excreted from the blood. The reduction of radioiodine is described by the effective half-life (EHL), which is the time taken to half the retained radioactivity. If the tumor recurs, more treatments are prescribed, often with escalating activities. Patients may receive several treatments during the evolution of the disease, and the total radioactivity administered (TRA) is the sum of all such activities. The patients' archived information permitted the calculation of EHL and TRA. The patient cohort processed here comprised 274 females and 101 males treated during 1997 to 2015. The TRA to the patients ranged between 1.1 and 129.5 GBq (average = 7.93 +/- 9.9 GBq) and the EHL varied between 5.06 and 43.87 hours (average = 14.13 +/- 5.7 hours). The data were processed as follows: (a) the EHL corresponding to the last treatment of each patient was plotted against TRA to patients who were treated once and to those treated several times for comparison and (b) using a small subgroup of 16 patients who were treated at least 5 times, the EHL and TRA corresponding to each treatment of each patient were plotted. A function of the form y = p-k.ln(x) was fitted on the data in all graphs and k was calculated. For patients treated once, EHL was independent of TRA. A decrease was seen in (a) multitreated patients, with the gradient (k) ranging between -0.541 and -13.880 and (b) 13 out of 16 patients, with the gradient (k) ranging between -5.55 and 31.17, both indicating an impairment of the remnant function, perhaps identified as "stunning." Since this is not avoidable, the uptake may be boosted by splitting the prescribed activity into low radioactivity fractions, which will also reduce patient hospitalization. PMID- 26986817 TI - Complete Remission of Unresectable Hepatocellular Carcinoma After Combined Sorafenib and Adjuvant Yttrium-90 Radioembolization. AB - Sorafenib has improved the median overall survival of unresectable or otherwise untreatable hepatocellular carcinoma (HCC) of ~3 months, compared to supportive cares. Complete response, although rare, has been reported. The authors reported herein a case of complete biochemical and radiological remission of advanced unresectable HCC with lymph node metastasis and tumoral portal vein thrombosis treated by 5 months therapy with sorafenib followed by adjuvant Yttrium-90 radioembolization. At 12 months follow-up, there is no evidence of HCC recurrence. PMID- 26986818 TI - Transpo-mAb display: Transposition-mediated B cell display and functional screening of full-length IgG antibody libraries. AB - In vitro antibody display and screening technologies geared toward the discovery and engineering of clinically applicable antibodies have evolved from screening artificial antibody formats, powered by microbial display technologies, to screening of natural, full-IgG molecules expressed in mammalian cells to readily yield lead antibodies with favorable properties in production and clinical applications. Here, we report the development and characterization of a novel, next-generation mammalian cell-based antibody display and screening platform called Transpo-mAb Display, offering straightforward and efficient generation of cellular libraries by using non-viral transposition technology to obtain stable antibody expression. Because Transpo-mAb Display uses DNA-transposable vectors with substantial cargo capacity, genomic antibody heavy chain expression constructs can be utilized that undergo the natural switch from membrane bound to secreted antibody expression in B cells by way of alternative splicing of Ig heavy chain transcripts from the same genomic expression cassette. We demonstrate that stably transposed cells co-express transmembrane and secreted antibodies at levels comparable to those provided by dedicated constructs for secreted and membrane-associated IgGs. This unique feature expedites the screening and antibody characterization process by obviating the need for intermediate sequencing and re-cloning of individual antibody clones into separate expression vectors for functional screening purposes. In a series of proof-of-concept experiments, we demonstrate the seamless integration of antibody discovery with functional screening for various antibody properties, including binding affinity and suitability for preparation of antibody-drug conjugates. PMID- 26986820 TI - [Risk factors and allergic manifestations associated with atopic dermatitis in Lome (Togo): a multicenter study of 476 children aged 0-15 years]. AB - OBJECTIVE: The aim of this study was to determine the prevalence and document the risk factors and allergic reactions associated with atopic dermatitis (AD) in children in Lome. METHOD: This cross-sectional multicenter study took place from March to June 2013 in four health facilities in Lome. It applied the criteria of the United Kingdom Working Party (UKWP). RESULTS: We included 476 children aged 0 15 years who came for a vaccination or pediatric consultation; 31.3% were diagnosed with AD. The mean age of the children with AD was 33.91 +/- 37 months, and the sex ratio (M/F) 0.96. In the univariate analysis, several risk factors and allergic reactions were significantly associated with AD including weaning, asthma, allergic conjunctivitis, allergic rhinitis, food allergy, alopecia, seborrheic dermatitis in infants, and prurigo. In the multivariate analysis, AD was associated with prurigo (aOR = 15.59, 95% CI = 7.54 to 32.21), allergic rhinitis (aOR = 7.51, 95% CI = 4.31 to 13.10), and food allergy (aOR = 5.32 95% CI = 1.20 to 23.48) were associated with AD. CONCLUSION: AD is common in children in Lome. Prurigo, allergic rhinitis and food allergy are allergic manifestations associated with it. These results deserve confirmation by a prospective study over a longer period. PMID- 26986821 TI - Integrating 3D Flower-Like Hierarchical Cu2NiSnS4 with Reduced Graphene Oxide as Advanced Anode Materials for Na-Ion Batteries. AB - Development of an anode material with high performance and low cost is crucial for implementation of next-generation Na-ion batteries (NIBs) electrode, which is proposed to meet the challenges of large scale renewable energy storage. Metal chalcogenides are considered as promising anode materials for NIBs due to their high theoretical capacity, low cost, and abundant sources. Unfortunately, their practical application in NIBs is still hindered because of low conductivity and morphological collapse caused by their volume expansion and shrinkage during Na(+) intercalation/deintercalation. To solve the daunting challenges, herein, we fabricated novel three-dimensional (3D) Cu2NiSnS4 nanoflowers (CNTSNs) as a proof of-concept experiment using a facile and low-cost method. Furthermore, homogeneous integration with reduced graphene oxide nanosheets (RGNs) endows intrinsically insulated CNTSNs with superior electrochemical performances, including high specific capacity (up to 837 mAh g(-1)), good rate capability, and long cycling stability, which could be attributed to the unique 3D hierarchical structure providing fast ion diffusion pathway and high contact area at the electrode/electrolyte interface. PMID- 26986819 TI - Accessing Elaborated 2,1-Borazaronaphthalene Cores Using Photoredox/Nickel Dual Catalytic Functionalization. AB - A highly effective method for derivatizing 2,1-borazaronaphthalene cores using ammonium alkylbis(catecholato)silicates via photoredox/nickel dual catalysis is reported. By forging C(sp)(3)-C(sp)(2) bonds via this approach, alkyl fragments with various functional groups can be introduced to the azaborine core, affording previously inaccessible heterocyclic isosteres in good to excellent yields. The base-free, room-temperature conditions outlined allow sensitive functional group tolerance, even permitting the cross-coupling of unprotected primary and secondary amines. PMID- 26986822 TI - [Changes in the epidemiology of gastroenteritis caused by Salmonella during 2005 2014 in Salamanca, Spain]. AB - OBJECTIVE: In Spain there are not many updated population studies about salmonellosis, despite being one of the most common etiologies of acute gastroenteritis (AGEs) caused by bacteria in the world. The aim of the study was to know the most relevant epidemiological features of AGEs produced by Salmonella spp. between 2005 and 2014 in Salamanca (Spain). METHODS: Descriptive cross sectional study carried out through review of the clinical microbiologic records at Complejo Asistencial Universitario de Salamanca. Culture, isolation, identification and serotyping were performed according to standard methodology. RESULTS: Salmonella was isolated in 1,477 patients, representing 47.7% of all positive stool cultures and 53.3% of all income bacterial AGE. The average prevalence was 42.1 cases/100,000 people per year. The mean age was 23 +/- 28 years and the median 7 years. 40.2% of all isolates occurred in children under 5 years, with an average prevalence of 45.1 cases/ 10,000 people per year. Overall, the most frequently isolated serotype was S. Typhimurium with 57%, followed by S. Enteritidis with 35.8%. CONCLUSIONS: The prevalence of Salmonella decreased over time. The group aged 0-4 years had the highest rate throughout the period. However, Salmonella produced the highest percentage of hospitalizations for bacterial AGE. In recent years, S. Typhimurium serotype has replaced S. Enteritidis serotype and predominates in younger patients. It is observed under reporting of cases of salmonellosis produced in Salamanca despite being mandatory notification of these since 2007. PMID- 26986824 TI - Blood Brain Barrier Disruption in Diabetic Stroke Related to Unfavorable Outcome. AB - BACKGROUND: Diabetes mellitus (DM) is associated with a wide range of microvascular abnormalities in the brain. These include the dysfunction of the blood brain barrier (BBB). In this study, we test the hypotheses that disruption of the BBB in patients presenting with acute stroke is common in patients with DM and is related to outcome. METHODS: Sixty-two consecutive patients with ischemic stroke in the middle cerebral artery territory were enrolled within 3-7 days after onset. In ischemic lesion, BBB disruption was detected by parenchymal enhancement (PE) on 5 min delayed post-contrast T1 weighted imaging. National Institute of Health Stroke Score (NIHSS) assessed neurologic impairment on admission. Clinical outcome at 3 months was classified as unfavorable if the modified Rankin scale was >1. The independent factors associated with clinical outcome were analyzed using multivariate logistic regression analysis and OR with its 95% CIs were estimated. RESULTS: An unfavorable stroke outcome was found in 19 diabetic patients and 21 non-diabetic patients. Diabetic patients had a significantly higher frequency of PE than non-diabetic patients (58.6 vs. 27.3%, p = 0.013) and DM was independently associated with PE (OR 4.40; 95% CI 1.22 15.83; p = 0.023). PE was significantly more common in diabetic patients with unfavorable stroke outcome (73.7%) than in other 3 subgroups: diabetic patients with favorable stroke outcome (30.0%), non-diabetic patients with favorable stroke outcome (38.1%) and unfavorable stroke outcome (8.3%; p = 0.002). PE was independently associated with unfavorable outcome (UO) in diabetic stroke (DS; OR 7.04; 95% CI 1.20-41.52; p = 0.031). Admission NIHSS score was associated with UO in non-DS (NDS) (OR 1.71; 95% CI 1.10-2.66; p = 0.017). CONCLUSIONS: Compared with NDS, DS had increased BBB disruption defined by the presence of PE. A different form of the relationship between admission NIHSS and UO in NDS, BBB disruption was related with UO in diabetic patients after stroke. PMID- 26986825 TI - Dynamic changes in circulating miRNA levels in response to antitumor therapy of lung cancer. AB - PURPOSE: Expression levels of cancer-associated microRNAs were reported to be altered in serum/plasma samples from lung cancer patients compared with healthy subjects. The purpose of this study was to estimate the value of five selected miRNAs plasma levels as markers of response to antitumor therapy in lung cancer patients. MATERIALS AND METHODS: Expression levels of miR-19b, miR-126, miR-25, miR-205, and miR-125b have been evaluated by quantitative reverse transcription PCR versus control miR-16 in blood plasma samples from 23 lung cancer (LC) patients. Plasma samples were obtained from LC patients before treatment (untreated-UT), within 30 days after completing two courses of chemotherapy (postchemotherapy-PC) and 15 days after surgery (postoperative-PO). RESULTS: Repeated Measures ANOVA demonstrated that miR-19b expression levels were decreased in PC and increased in PO samples. These changes were characterized by a significant quadratic trend (p = 0.03). Expression levels of miR-125b increased both after chemotherapy and again after surgery and demonstrated a significant linear trend (p = 0.03). The miR-125b/miR-19b ratio changed during the course of the antitumor treatment with a significant linear trend (p = 0.04). Individual analysis in the groups of patients with partial response to chemotherapy and patients with stable or progressive disease showed different trends for miR-19b, miR-125b, and miR-125b/miR-19b ratio between the groups. The Kaplan-Meier survival curves demonstrated an association of miR-125b/miR-19b ratio value with the survival time without the tumor relapse (p < 0.1). CONCLUSIONS: Dynamic change of trends for miR-19b and miR-125b expression levels and miR-125b/miR-19b ratio in the blood plasma have shown a potentiality to discriminate types of response to antitumor therapy in lung cancer patients. Further in-depth investigation is needed to establish a direct link the miRNAs expression levels in blood plasma with therapy response and patient's survival. PMID- 26986823 TI - Allele-Specific Quantitative PCR for Accurate, Rapid, and Cost-Effective Genotyping. AB - Customizable endonucleases such as transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) enable rapid generation of mutant strains at genomic loci of interest in animal models and cell lines. With the accelerated pace of generating mutant alleles, genotyping has become a rate limiting step to understanding the effects of genetic perturbation. Unless mutated alleles result in distinct morphological phenotypes, mutant strains need to be genotyped using standard methods in molecular biology. Classic restriction fragment length polymorphism (RFLP) or sequencing is labor-intensive and expensive. Although simpler than RFLP, current versions of allele-specific PCR may still require post-polymerase chain reaction (PCR) handling such as sequencing, or they are more expensive if allele-specific fluorescent probes are used. Commercial genotyping solutions can take weeks from assay design to result, and are often more expensive than assembling reactions in-house. Key components of commercial assay systems are often proprietary, which limits further customization. Therefore, we developed a one-step open-source genotyping method based on quantitative PCR. The allele-specific qPCR (ASQ) does not require post PCR processing and can genotype germline mutants through either threshold cycle (Ct) or end-point fluorescence reading. ASQ utilizes allele-specific primers, a locus-specific reverse primer, universal fluorescent probes and quenchers, and hot start DNA polymerase. Individual laboratories can further optimize this open source system as we completely disclose the sequences, reagents, and thermal cycling protocol. We have tested the ASQ protocol to genotype alleles in five different genes. ASQ showed a 98-100% concordance in genotype scoring with RFLP or Sanger sequencing outcomes. ASQ is time-saving because a single qPCR without post-PCR handling suffices to score genotypes. ASQ is cost-effective because universal fluorescent probes negate the necessity of designing expensive probes for each locus. PMID- 26986826 TI - Evaluation of the Septifast MGrade Test on Standard Care Wards--A Cohort Study. AB - BACKGROUND: The immediate need for appropriate antimicrobial therapy in septic patients requires the detection of the causative pathogen in a timely and reliable manner. In this study, the real-time PCR Septifast MGrade test was evaluated in adult patients meeting the systemic inflammatory response syndrome (SIRS) criteria that were treated at standard care wards. METHODS: Patients with clinical suspected infection, drawn blood cultures (BC), the Septifast M(Grade) test (SF) and sepsis biomarkers were prospectively screened for fulfillment of SIRS criteria and evaluated using the criteria of the European Centre of Disease Control (ECDC) for infection point prevalence studies. RESULTS: In total, 220 patients with SIRS were prospectively enrolled, including 56 patients with detection of bacteria in the blood (incidence: 25.5%). BC analysis resulted in 75.0% sensitivity (95% confidence interval, CI: 61.6%- 85.6%) with 97.6% specificity (CI: 93.9%- 99.3%) for detecting bacteria in the blood. In comparison to BC, SF presented with 80.4% sensitivity (CI: 67.6%- 89.8%) and with 97.6% specificity (CI: 93.9%- 99.3%). BC and SF analysis yielded comparable ROC-AUCs (0.86, 0.89), which did not differ significantly (p = 0.558). A trend of a shorter time-to-positivity of BC analysis was not seen in bacteremic patients with a positive SF test than those with a negative test result. Sepsis biomarkers, including PCT, IL-6 or CRP, did not help to explain discordant test results for BC and SF. CONCLUSION: Since negative results do not exclude bacteremia, the Septifast M(Grade) test is not suited to replacing BC, but it is a valuable tool with which to complement BC for faster detection of pathogens. PMID- 26986828 TI - Love at second sight: Sequential dependence of facial attractiveness in an on line dating paradigm. AB - Millions of people use online dating sites each day, scanning through streams of face images in search of an attractive mate. Face images, like most visual stimuli, undergo processes whereby the current percept is altered by exposure to previous visual input. Recent studies using rapid sequences of faces have found that perception of face identity is biased towards recently seen faces, promoting identity-invariance over time, and this has been extended to perceived face attractiveness. In this paper we adapt the rapid sequence task to ask a question about mate selection pertinent in the digital age. We designed a binary task mimicking the selection interface currently popular in online dating websites in which observers typically make binary decisions (attractive or unattractive) about each face in a sequence of unfamiliar faces. Our findings show that binary attractiveness decisions are not independent: we are more likely to rate a face as attractive when the preceding face was attractive than when it was unattractive. PMID- 26986829 TI - Serotonin transporter promoter polymorphism is associated with executive function impairments in patients with obsessive compulsive disorder. AB - OBJECTIVE: In the present study, we investigate the association between the 5 HTTLPR polymorphism and executive functions in a sample of patients with obsessive compulsive disorder (OCD). METHOD: A total of 98 unmedicated patients diagnosed with OCD according to DSM-IV criteria and 80 healthy controls were included in this study. The genotype frequencies of 5-HTTLPR polymorphism were compared in OCD and healthy control groups. The four subgroups of OCD and healthy control participants, determined according to having LaLa genotype (high expressing) or S- and/or Lg alleles (low expressing), were also compared using neuropsychological tests of executive functions. RESULTS: The frequency of SLa genotype of 5-HTTLPR polymorphism was found to be higher in patients with OCD compared with healthy controls. The mean scores of conceptual level responses of the Wisconsin Card Sorting Test (WCST) were significantly lower in the OCD-high expressing subgroup compared with the low-expressing control group. The mean scores of the number of moves of the Tower of London were found to be significantly higher in the OCD-high-expressing subgroup, compared with the high expressing subgroup of healthy controls. CONCLUSION: Our findings suggest that the high-expressing variant may be associated with lower performance on some abstraction and planning measures in OCD patients. PMID- 26986827 TI - Biochemistry and Crystal Structure of Ectoine Synthase: A Metal-Containing Member of the Cupin Superfamily. AB - Ectoine is a compatible solute and chemical chaperone widely used by members of the Bacteria and a few Archaea to fend-off the detrimental effects of high external osmolarity on cellular physiology and growth. Ectoine synthase (EctC) catalyzes the last step in ectoine production and mediates the ring closure of the substrate N-gamma-acetyl-L-2,4-diaminobutyric acid through a water elimination reaction. However, the crystal structure of ectoine synthase is not known and a clear understanding of how its fold contributes to enzyme activity is thus lacking. Using the ectoine synthase from the cold-adapted marine bacterium Sphingopyxis alaskensis (Sa), we report here both a detailed biochemical characterization of the EctC enzyme and the high-resolution crystal structure of its apo-form. Structural analysis classified the (Sa)EctC protein as a member of the cupin superfamily. EctC forms a dimer with a head-to-tail arrangement, both in solution and in the crystal structure. The interface of the dimer assembly is shaped through backbone-contacts and weak hydrophobic interactions mediated by two beta-sheets within each monomer. We show for the first time that ectoine synthase harbors a catalytically important metal co-factor; metal depletion and reconstitution experiments suggest that EctC is probably an iron-dependent enzyme. We found that EctC not only effectively converts its natural substrate N gamma-acetyl-L-2,4-diaminobutyric acid into ectoine through a cyclocondensation reaction, but that it can also use the isomer N-alpha-acetyl-L-2,4-diaminobutyric acid as its substrate, albeit with substantially reduced catalytic efficiency. Structure-guided site-directed mutagenesis experiments targeting amino acid residues that are evolutionarily highly conserved among the extended EctC protein family, including those forming the presumptive iron-binding site, were conducted to functionally analyze the properties of the resulting EctC variants. An assessment of enzyme activity and iron content of these mutants give important clues for understanding the architecture of the active site positioned within the core of the EctC cupin barrel. PMID- 26986830 TI - Activation of ERK/IER3/PP2A-B56gamma-positive feedback loop in lung adenocarcinoma by allelic deletion of B56gamma gene. AB - In order to investigate the involvement of the IER3/PP2A-B56gamma/ERK-positive feedback loop, which leads to sustained phosphorylation/activation of ERK in carcinogenesis, we immunohistochemically examined the expression of IER3 and phosphorylated ERK in lung tumor tissues. IER3 was overexpressed in all cases of adenocarcinomas examined, but was not overexpressed in squamous cell carcinomas. Phosphorylated ERK (pERK) was also overexpressed in almost all adenocarcinomas. EGFR and RAS, whose gene product is located upstream of ERK, were sequenced. Activating mutation of EGFR, which is a possible cause of overexpression of IER3 and pERK, was found only in 5 adenocarcinomas (42%). No mutation of RAS was found. We further examined the sequences of all exons of B56gamma gene (PPP2R5C) and IER3, but no mutation was found. Using a single nucleotide insertion in intron 1 of PPP2R5C, which was found in the process of sequencing, allelic deletion of PPP2R5C was examined. Eight cases were informative (67%), and the deletion was found in 4 of them (50%). Three cases having deletion of PPP2R5C did not have EGFR mutation. Finally, PPP2R5C deletion or EGFR mutation that could be responsible for IER3/pERK overexpression was found in at least 8 cases (67% or more). This is the first report of a high incidence of deletion of PPP2R5C in human carcinomas. PMID- 26986833 TI - Influence of Structural Disorder on Hollandites A(x)Ru4O8 (A(+) = K, Rb, Rb(1 x)Na(x)). AB - Structural disorder can play an important role in the electrical properties of correlated materials. In this work we examine the average and local disorder in hollandites A(x)Ru4O8 (A(+) = K, Rb, Rb(1-x)Na(x)) through neutron total scattering techniques. Samples with A(+) = Rb, Rb(1-x)Na(x) exhibit the largest amount of local disorder as evidenced by higher atomic displacement parameters, and as a result, a weakened temperature dependence of the resistivity is observed upon cooling as compared to K(x)Ru4O8. All samples exhibit anisotropic resistivity that is dominated by metallic conductivity at lower temperatures, and this is corroborated by Pauli paramagnetic behavior throughout the measured temperature regime. PMID- 26986832 TI - Failure of Passive Immune Transfer in Calves: A Meta-Analysis on the Consequences and Assessment of the Economic Impact. AB - Low colostrum intake at birth results in the failure of passive transfer (FPT) due to the inadequate ingestion of colostral immunoglobulins (Ig). FPT is associated with an increased risk of mortality and decreased health and longevity. Despite the known management practices associated with low FPT, it remains an important issue in the field. Neither a quantitative analysis of FPT consequences nor an assessment of its total cost are available. To address this point, a meta-analysis on the adjusted associations between FPT and its outcomes was first performed. Then, the total costs of FPT in European systems were calculated using a stochastic method with adjusted values as the input parameters. The adjusted risks (and 95% confidence intervals) for mortality, bovine respiratory disease, diarrhoea and overall morbidity in the case of FPT were 2.12 (1.43-3.13), 1.75 (1.50-2.03), 1.51 (1.05-2.17) and 1.91 (1.63-2.24), respectively. The mean (and 95% prediction interval) total costs per calf with FPT were estimated to be ?60 (?10-109) and ?80 (?20-139) for dairy and beef, respectively. As a result of the double-step stochastic method, the proposed economic estimation constitutes the first estimate available for FPT. The results are presented in a way that facilitates their use in the field and, with limited effort, combines the cost of each contributor to increase the applicability of the economic assessment to the situations farm-advisors may face. The present economic estimates are also an important tool to evaluate the profitability of measures that aim to improve colostrum intake and FPT prevention. PMID- 26986831 TI - The Relevance of a Novel Quantitative Assay to Detect up to 40 Major Streptococcus pneumoniae Serotypes Directly in Clinical Nasopharyngeal and Blood Specimens. AB - For epidemiological and surveillance purposes, it is relevant to monitor the distribution and dynamics of Streptococcus pneumoniae serotypes. Conventional serotyping methods do not provide rapid or quantitative information on serotype loads. Quantitative serotyping may enable prediction of the invasiveness of a specific serotype compared to other serotypes carried. Here, we describe a novel, rapid multiplex real-time PCR assay for identification and quantification of the 40 most prevalent pneumococcal serotypes and the assay impacts in pneumonia specimens from emerging and developing countries. Eleven multiplex PCR to detect 40 serotypes or serogroups were optimized. Quantification was enabled by reference to standard dilutions of known bacterial load. Performance of the assay was evaluated to specifically type and quantify S. pneumoniae in nasopharyngeal and blood samples from adult and pediatric patients hospitalized with pneumonia (n = 664) from five different countries. Serogroup 6 was widely represented in nasopharyngeal specimens from all five cohorts. The most frequent serotypes in the French, South African, and Brazilian cohorts were 1 and 7A/F, 3 and 19F, and 14, respectively. When both samples were available, the serotype in blood was always present as carriage with other serotypes in the nasopharynx. Moreover, the ability of a serotype to invade the bloodstream may be linked to its nasopharyngeal load. The mean nasopharyngeal concentration of the serotypes that moved to the blood was 3 log-fold higher than the ones only found in the nasopharynx. This novel, rapid, quantitative assay may potentially predict some of the S. pneumoniae serotypes invasiveness and assessment of pneumococcal serotype distribution. PMID- 26986834 TI - Bed rest following embryo transfer might negatively affect the outcome of IVF/ICSI: a systematic review and meta-analysis. AB - The majority of patients undergoing in vitro fertilization (IVF) and intracytoplasmatic sperm injection (ICSI) treatment will reach the stage of embryo transfer (ET), but only a small proportion of transferred embryos implant. Bed rest following ET has been recommended as a way to prevent embryo expulsion by gravity. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) published prior to May 2014 reporting the effect of bed rest following ET, and irrespective of language, country of origin, blinding or sample size. Four RCTs, including 757 women met the inclusion criteria. Bed rest following ET did not improve clinical pregnancy and live birth rates, but reduced the implantation rate. The quality of the trials included was moderate because of attrition bias and possible reporting bias. The findings of this systematic review and meta-analysis are concordant with previously published literature and suggest that bed rest is not beneficial following ET. Moreover, it might negatively affect the outcome of IVF/ICSI cycles via stress/anxiety mechanisms. PMID- 26986835 TI - The effect of inlay butterfly cartilage tympanoplasty technique on compliance. AB - CONCLUSION: IBCT technique should be preferred owing to its high graft survival rate and ABG gain. While no significant difference was found in middle ear pressures between ears that underwent IBCT and normal ears, compliance values were found to be decreased in patients undergoing IBCT. However, the lack of correlation between ABG gain and compliance values indicated that compliance increase had no effect on post-operative ABG results. OBJECTIVE: The aim of the present study was to compare tympanometric and audiological parameters in patients undergoing inlay butterfly cartilage tympanoplasty (IBCT) with their normal ears and to determine their difference with normal ear tympanometric parameters. METHODS: Overall, 25 patients that underwent an operation between August 2010-May 2014 were included in the present study. In 13 of these patients, the ear that did not undergo operation was normal. 0.5, 1, 2, 4 kHz pure sound average values, tympanometric measurements and compliance values of normal and operated ears were compared. RESULTS: The graft survival rate in patients was found to be 92%. Mean pre-operative air-bone gap (ABG) was 16.4 +/- 5.4 in patients, while mean post-operative ABG was 10.9 +/- 5.8, with a statistically significant difference (p = 0.001) While there was no significant difference between operated and normal ears of patients in terms of middle ear pressure (0.441), compliance values were significantly higher in normal ears than those in operated ears (0.032). When post-operative ABG gain was compared with compliance values, no significant correlation was found between ABG gain and compliance measurements (r = -0.025 and p = 0.936). PMID- 26986836 TI - AtNHX5 and AtNHX6 Are Required for the Subcellular Localization of the SNARE Complex That Mediates the Trafficking of Seed Storage Proteins in Arabidopsis. AB - The SNARE complex composed of VAMP727, SYP22, VTI11 and SYP51 is critical for protein trafficking and PSV biogenesis in Arabidopsis. This SNARE complex directs the fusion between the prevacuolar compartment (PVC) and the vacuole, and thus mediates protein trafficking to the vacuole. In this study, we examined the role of AtNHX5 and AtNHX6 in regulating this SNARE complex and its function in protein trafficking. We found that AtNHX5 and AtNHX6 were required for seed production, protein trafficking and PSV biogenesis. We further found that the nhx5 nhx6 syp22 triple mutant showed severe defects in seedling growth and seed development. The triple mutant had short siliques and reduced seed sets, but larger seeds. In addition, the triple mutant had numerous smaller protein storage vacuoles (PSVs) and accumulated precursors of the seed storage proteins in seeds. The PVC localization of SYP22 and VAMP727 was repressed in nhx5 nhx6, while a significant amount of SYP22 and VAMP727 was trapped in the Golgi or TGN in nhx5 nhx6. AtNHX5 and AtNHX6 were co-localized with SYP22 and VAMP727. Three conserved acidic residues, D164, E188, and D193 in AtNHX5 and D165, E189, and D194 in AtNHX6, were essential for the transport of the storage proteins, indicating the importance of exchange activity in protein transport. AtNHX5 or AtNHX6 did not interact physically with the SNARE complex. Taken together, AtNHX5 and AtNHX6 are required for the PVC localization of the SNARE complex and hence its function in protein transport. AtNHX5 and AtNHX6 may regulate the subcellular localization of the SNARE complex by their transport activity. PMID- 26986837 TI - Resorcinol Crystallization from the Melt: A New Ambient Phase and New "Riddles". AB - Structures of the alpha and beta phases of resorcinol, a major commodity chemical in the pharmaceutical, agrichemical, and polymer industries, were the first polymorphic pair of molecular crystals solved by X-ray analysis. It was recently stated that "no additional phases can be found under atmospheric conditions" (Druzbicki, K. et al. J. Phys. Chem. B 2015, 119, 1681). Herein is described the growth and structure of a new ambient pressure phase, epsilon, through a combination of optical and X-ray crystallography and by computational crystal structure prediction algorithms. alpha-Resorcinol has long been a model for mechanistic crystal growth studies from both solution and vapor because prisms extended along the polar axis grow much faster in one direction than in the opposite direction. Research has focused on identifying the absolute sense of the fast direction-the so-called "resorcinol riddle"-with the aim of identifying how solvent controls crystal growth. Here, the growth velocity dissymmetry in the melt is analyzed for the beta phase. The epsilon phase only grows from the melt, concomitant with the beta phase, as polycrystalline, radially growing spherulites. If the radii are polar, then the sense of the polar axis is an essential feature of the form. Here, this determination is made for spherulites of beta resorcinol (epsilon, point symmetry 222, does not have a polar axis) with additives that stereoselectively modify growth velocities. Both beta and epsilon have the additional feature that individual radial lamellae may adopt helicoidal morphologies. We correlate the appearance of twisting in beta and epsilon with the symmetry of twist-inducing additives. PMID- 26986839 TI - Mandated reporters' perceptions of and encounters with domestic minor sex trafficking of adolescent females in the United States. AB - This is the first study to explore whether mandated reporters who work with adolescent females, ages 10 to 17, recognize domestic minor sex trafficking (DMST) and associated risk factors. Because mandated reporters are required by law to report child abuse, neglect, and child exploitation, lack of specific DMST training or not believing DMST exists in communities continues to place young females at risk for revictimization. Results indicate that 60% of mandated reporters in the sample (N = 577) had no specific training on DMST. Furthermore, almost 25% of respondents did not believe DMST existed in their communities. Implications for practice are discussed. (PsycINFO Database Record PMID- 26986838 TI - Importance of human right inferior frontoparietal network connected by inferior branch of superior longitudinal fasciculus tract in corporeal awareness of kinesthetic illusory movement. AB - It is generally believed that the human right cerebral hemisphere plays a dominant role in corporeal awareness, which is highly associated with conscious experience of the physical self. Prompted by our previous findings, we examined whether the right frontoparietal activations often observed when people experience kinesthetic illusory limb movement are supported by a large-scale brain network connected by a specific branch of the superior longitudinal fasciculus fiber tracts (SLF I, II, and III). We scanned brain activity with functional magnetic resonance imaging (MRI) while nineteen blindfolded healthy volunteers experienced illusory movement of the right stationary hand elicited by tendon vibration, which was replicated after the scanning. We also scanned brain activity when they executed and imagined right hand movement, and identified the active brain regions during illusion, execution, and imagery in relation to the SLF fiber tracts. We found that illusion predominantly activated the right inferior frontoparietal regions connected by SLF III, which were not substantially recruited during execution and imagery. Among these regions, activities in the right inferior parietal cortices and inferior frontal cortices showed right-side dominance and correlated well with the amount of illusion (kinesthetic illusory awareness) experienced by the participants. The results illustrated the predominant involvement of the right inferior frontoparietal network connected by SLF III when people recognize postural changes of their limb. We assume that the network bears a series of functions, specifically, monitoring the current status of the musculoskeletal system, and building-up and updating our postural model (body schema), which could be a basis for the conscious experience of the physical self. PMID- 26986840 TI - How subjective well-being is associated with material deprivation and social exclusion in Israeli 12-year-olds. AB - The literature examining the relations between economic situation and happiness has focused almost exclusively on a household's income as a proxy for economic situation and, accordingly, also focused chiefly on the adult population, excluding children and adolescents. To fill this gap, this study examines the relation between economic deprivation and happiness by using 2 alternative proxies: material deprivation and social exclusion. The study tests the relation of these measures to the most common measure for happiness-subjective well-being (SWB)-in a sample of Israeli 12-year-olds (N = 1,081). The study also examines the effects of culture and life circumstances on these complex relations. Findings show that both material deprivation and social exclusion are negatively associated with children's SWB. Social exclusion explained a much larger percentage of children's SWB, adding up to 20%. Furthermore, children who were identified as materially deprived and socially excluded were found to be at much greater risk for unhappiness. Material deprivation was found to be significantly more important to the SWB of males compared with females, and for Jews compared with Arabs. Finally, some implications for social policy and regarding the relation of economic situation and happiness are discussed. (PsycINFO Database Record PMID- 26986841 TI - Effects of Salivary Oxidative Markers on Edentulous Patients' Satisfaction with Prosthetic Denture Treatments: A Pilot Study. AB - OBJECTIVES: The purpose of this study was to assess relationships among periodontal conditions, salivary antioxidant levels, and patients' satisfaction with their prostheses. METHODS: This study was conducted at the Division of Prosthodontics, Department of Dentistry, Taipei Medical University Hospital. The periodontal condition of patients was based on an assessment of the plaque index (PI) and gingival index (GI). The pH value, flow rate, and buffer capacity of the saliva were estimated. The salivary total antioxidant status (TAS) and superoxide dismutase (SOD) level were also determined. Patients' satisfaction with prosthetic treatments was evaluated using the Chinese version of the short-form Oral Health Impact Profile (OHIP-14C). A multivariate regression model was used to determine whether patients' satisfaction with prosthetic treatment was affected by their oral health status. RESULTS: In total, 35 edentulous patients were recruited. In the Spearman correlation analysis, salivary pH (r = -0.36, p = 0.03) and the buffer ability (r = -0.48, p<0.01) were associated with OHIP-14C scores. In the multivariate analysis, patients who had a higher GI also had a higher score of physical disabilities (beta = 1.38, p = 0.04). Levels of SOD increased with the scores of psychological discomfort (beta = 0.33 U/g protein, p = 0.04). CONCLUSIONS: This study suggested that both the GI and SOD levels were associated with patients' satisfaction with prosthetic treatments. To the best of our knowledge, this is the first study to elucidate the relationship between OHIP scores and salivary oxidative markers in edentulous patients. PMID- 26986843 TI - Does worry moderate the relation between aggression and depression in adolescent girls? AB - Aggressive girls, more so than aggressive boys, are at an increased risk for depression. Despite disconcerting outcomes, few researchers have examined factors that may attenuate or exacerbate the relation between aggression and depression. Competing hypotheses for explaining the role of worry in the relation between aggressive behaviour and depressive symptoms, commonly co-occurring problems in girls, have been proposed. In the present study, we examined worry as a possible moderator in the relation between girls nominated as aggressive by their peers and self-reported depressive symptoms in a sample of 226 girls aged 13 (M = 12.92, SD = 1.28) at Time 1. We found that worry exacerbated the risk of depressive symptoms concurrently and one year later for physically aggressive girls, but not relationally aggressive girls. These results suggest that worry plays an important role in the prediction of depression for aggressive girls, which varies by the form aggression takes. PMID- 26986842 TI - Functional Analysis of Novel Candidate Regulators of Insulin Secretion in the MIN6 Mouse Pancreatic beta Cell Line. AB - Elucidating the regulation of glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells is important for understanding and treating diabetes. The pancreatic beta cell line, MIN6, retains GSIS but gradually loses it in long-term culture. The MIN6 subclone, MIN6c4, exhibits well-regulated GSIS even after prolonged culture. We previously used DNA microarray analysis to compare gene expression in the parental MIN6 cells and MIN6c4 cells and identified several differentially regulated genes that may be involved in maintaining GSIS. Here we investigated the potential roles of six of these genes in GSIS: Tmem59l (Transmembrane protein 59 like), Scgn (Secretagogin), Gucy2c (Guanylate cyclase 2c), Slc29a4 (Solute carrier family 29, member 4), Cdhr1 (Cadherin-related family member 1), and Celsr2 (Cadherin EGF LAG seven-pass G-type receptor 2). These genes were knocked down in MIN6c4 cells using lentivirus vectors expressing gene specific short hairpin RNAs (shRNAs), and the effects of the knockdown on insulin expression and secretion were analyzed. Suppression of Tmem59l, Scgn, and Gucy2c expression resulted in significantly decreased glucose- and/or KCl-stimulated insulin secretion from MIN6c4 cells, while the suppression of Slc29a4 expression resulted in increased insulin secretion. Tmem59l overexpression rescued the phenotype of the Tmem59l knockdown MIN6c4 cells, and immunostaining analysis indicated that the TMEM59L protein colocalized with insulin and GM130, a Golgi complex marker, in MIN6 cells. Collectively, our findings suggested that the proteins encoded by Tmem59l, Scgn, Gucy2c, and Slc29a4 play important roles in regulating GSIS. Detailed studies of these proteins and their functions are expected to provide new insights into the molecular mechanisms involved in insulin secretion. PMID- 26986844 TI - Expression of nerve growth factor and its receptors in the uterus of rabbits: functional involvement in prostaglandin synthesis. AB - The aim of the present study was to evaluate: (1) the presence of nerve growth factor (NGF), neurotrophic tyrosine kinase receptor 1 (NTRK1), and nerve growth factor receptor (NGFR) in the rabbit uterus; and (2) the in vitro effects of NGF on PGF2alpha and PGE2 synthesis and on the PGE2-9-ketoreductase (PGE2-9-K) activity by the rabbit uterus. Nerve growth factor, NTRK1, and NGFR were immunolocalized in the luminal and glandular epithelium and stroma cells of the endometrium. reverse transcriptase polymerase chain reaction indicated the presence of messenger RNA for NGF, NTRK1, and NGFR in the uterus. Nerve growth factor increased (P < 0.01) in vitro secretions of PGF2alpha and PGE2 but coincubation with either NTRK1 or oxide nitric synthase (NOS) inhibitors reduced (P < 0.01) PGF2alpha production and blocked (P < 0.01) PGE2 secretion. Prostaglandins releases were lower (P < 0.01) than control when uterine samples were treated with NGF plus cyclooxygenase inhibitor. However, addition of NGFR inhibitor reduced (P < 0.01) PGF2alpha secretion less efficiently than NTRK1 or NOS inhibitors but had no effect on PGE2 yield. Nerve growth factor increased (P < 0.01) the activity of PGE2-9-K, whereas coincubation with NTRK1 or NOS inhibitors abolished (P < 0.01) this increase in PGE2-9-K activity. However, cotreatment with either cyclooxygenase or NGFR inhibitors had no effect on PGE2-9 K activity. This is the first study to document the distribution of NGF/NTRK1 and NGFR systems and their effects on prostaglandin synthesis in the rabbit uterus. NGF/NTRK1 increases PGF2alpha and PGE2 productions by upregulating NOS and PGE2-9 K activities, whereas NGF/NGFR augments only PGF2alpha secretion, through an intracellular mechanism that is still unknown. PMID- 26986845 TI - Increased expression of pentraxin 3 after in vivo and in vitro stimulation with gonadotropins in porcine oocyte-cumulus complexes and granulosa cells. AB - It has been previously shown that multimeric pentraxin 3 (PTX3) is a key component of the cumulus oophorus extracellular matrix (ECM) in mice. In response to the ovulatory LH surge, the cumulus cells assemble a unique ECM that envelopes the oocyte and cumulus cell complex. Importantly, cumuli from PTX3(-/-) mice were defective in their ECM organization and their fertility was impaired. It has been demonstrated that tumor necrosis factor alpha-induced protein 6 catalyzes the formation of heavy chains of (inter-alpha-trypsin inhibitor) -hyaluronan complexes and these are then cross-linked via PTX3. This process is tightly regulated and requires the proteins to meet/interact in the correct order. Finally, in this way, the above-listed proteins form the cumulus oophorus ECM. We investigated whether PTX3 is expressed in the porcine preovulatory follicle. Porcine oocyte-cumulus complexes (OCC) and mural granulosa cells (MGC) from gilts were obtained either after stimulation in vivo with eCG/hCG (4, 8, 16, 24, and 32 h) or culture in vitro (4, 24, and 44 h) in FSH/LH-supplemented medium. The methods performed were real-time reverse transcriptase-polymerase chain reaction, Western blot analysis, and immunostaining. The expression of PTX3 transcripts was significantly increased 24 h after either in vivo hCG stimulation or in vitro FSH/LH treatment in both OCC and MGC. Western blot analysis with PTX3 antibody revealed that not only matrix extracts from in vivo-stimulated gilts contain high levels of PTX3 protein but also matrix extracts of FSH/LH-stimulated OCC cultured in medium supplemented either with follicular fluid or with porcine serum. The localization of PTX3 in the cumulus oocyte complex was confirmed by immunostaining. In conclusion, PTX3 is produced by porcine OCC and MGC both in vivo and in vitro with gonadotropin stimuli inducing cumulus expansion. PMID- 26986846 TI - PRIMA-1MET induces apoptosis through accumulation of intracellular reactive oxygen species irrespective of p53 status and chemo-sensitivity in epithelial ovarian cancer cells. AB - There is an intensive need for the development of novel drugs for the treatment of epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy due to the high recurrence rate. TP53 mutation is a common event in EOC, particularly in high-grade serous ovarian cancer, where it occurs in more than 90% of cases. Recently, PRIMA-1 and PRIMA-1MET (p53 reactivation and induction of massive apoptosis and its methylated form) were shown to have an antitumor effect on several types of cancer. Despite that PRIMA-1MET is the first compound evaluated in clinical trials, the antitumor effects of PRIMA-1MET on EOC remain unclear. In this study, we investigated the therapeutic potential of PRIMA-1MET for the treatment of EOC cells. PRIMA-1MET treatment of EOC cell lines (n=13) resulted in rapid apoptosis at various concentrations (24 h IC50 2.6-20.1 uM). The apoptotic response was independent of the p53 status and chemo-sensitivity. PRIMA-1MET treatment increased intracellular reactive oxygen species (ROS), and PRIMA-1MET induced apoptosis was rescued by an ROS scavenger. Furthermore, RNA expression analysis revealed that the mechanism of action of PRIMA-1MET may be due to inhibition of antioxidant enzymes, such as Prx3 and GPx-1. In conclusion, our results suggest that PRIMA-1MET represents a novel therapeutic strategy for the treatment of ovarian cancer irrespective of p53 status and chemo-sensitivity. PMID- 26986847 TI - Phylogenetic Analysis of Different Ploidy Saccharum spontaneum Based on rDNA-ITS Sequences. AB - Saccharum spontaneum L. is a crucial wild parent of modern sugarcane cultivars whose ploidy clones have been utilized successfully in improving the stress resistance and yield related traits of sugarcane cultivars. To establish knowledge regarding the genetic variances and evolutional relationships of ploidy clones of Saccharum spontaneum collected in China, the rDNA-ITS sequences of 62 ploidy clones including octaploid clones (2n = 64), nonaploid clones (2n = 72), decaploid clones (2n = 80), and dodecaploid clones (2n = 96), were obtained and analyzed. The rDNA-ITS sequences of four species from Saccharum and Sorghum bicolor selected as controls. The results showed that decaploid clones (2n = 80) possess the most abundant variances with 58 variable sites and 20 parsim informative sites in ITS sequences, which were then followed by octaploid clones with 43 variable sites and 17 parsim-informative sites. In haplotype diversity, all four population exhibited high diversity, especially nonaploid and decaploid populations. By comparing the genetic distances among four ploidy populations, the dodecaploid population exhibited the closest relationship with the nonaploid population, and then the relationship strength decreased successively for the decaploid population and then for the octaploid population. Population differentiation analysis showed that the phenomena of population differentiation were not found among different ploidy populations, and low coefficient of gene differentiation(Gst) and high gene flow(Nm) occur among these populations possessing close genetic relationship. These results mentioned above will contribute to the understanding of the evolution of different ploidy populations of Saccharum spontaneum and provide vital knowledge for their utilization in sugarcane breeding and innovation. PMID- 26986849 TI - Copper complexes as catalyst precursors in the electrochemical hydrogen evolution reaction. AB - Herein, we report the synthesis and species distribution of copper(ii) complexes based on two different ligand scaffolds and the application of the two complexes in the electrochemical proton reduction catalysis. The ligands bind to one or two copper(II) ions and the pH-dependent mono/dinuclear equilibrium depends on the steric bulk of the ligands. The two water soluble copper(II) complexes were investigated for their activities in the electrochemical hydrogen evolution reaction (HER). In both complexes the copper(ii) ions have a N4-coordination environment composed of N-heterocycles, although in different coordination geometries (SPY-5 and TBPY-5). The solutions of the complexes were highly active catalysts in water at acidic pH but the complexes decompose under catalytic conditions. They act as precursors for highly active copper(0) and Cu2O deposits at the electrode surface, which are in turn the active catalysts. The absence or presence of the ligands has neither an influence on the catalytic activity of the solutions nor an influence on the activity of the deposit formed during controlled potential electrolysis. Finally, we can draw some conclusions on the stability of copper catalysts in the aqueous electrochemical HER. PMID- 26986848 TI - Effect of Fee on Cervical Cancer Screening Attendance--ScreenFee, a Swedish Population-Based Randomised Trial. AB - BACKGROUND: Attendance in the cervical cancer screening programme is one of the most important factors to lower the risk of contracting the disease. Attendance rates are often low in areas with low socioeconomic status. Charging a fee for screening might possibly decrease attendance in this population. Screening programme coverage is low in low socio-economic status areas in Gothenburg, Sweden, but has increased slightly after multiple interventions in recent years. For many years, women in the region have paid a fee for screening. We studied the effect of abolishing this fee in a trial emanating from the regular cervical cancer screening programme. METHOD: Individually randomised controlled trial. All 3 124 women in three low-resource areas in Gothenburg, due for screening during the study period, were randomised to receive an offer of a free test or the standard invitation stating the regular fee of 100 SEK (~11 ?). The study was conducted during the first six months of 2013. Attendance was defined as a registered Pap smear within 90 days from the date the invitation was sent out. RESULTS: Attendance did not differ significantly between women who were charged and those offered free screening (RR 0.93; CI 0.85-1.02). No differences were found within the districts or as an effect of age, attendance after the most recent previous invitation or previous experience of smear taking. CONCLUSION: Abolishment of a modest screening fee in socially disadvantaged urban districts with low coverage, after previous multiple systematic interventions, does not increase attendance in the short term. Other interventions might be more important for increasing attendance in low socio-economic status areas. TRIAL REGISTRATION: ClinicalTrials.gov NCT02378324. PMID- 26986850 TI - Activation of G Proteins by Guanine Nucleotide Exchange Factors Relies on GTPase Activity. AB - G proteins are an important family of signalling molecules controlled by guanine nucleotide exchange and GTPase activity in what is commonly called an 'activation/inactivation cycle'. The molecular mechanism by which guanine nucleotide exchange factors (GEFs) catalyse the activation of monomeric G proteins is well-established, however the complete reversibility of this mechanism is often overlooked. Here, we use a theoretical approach to prove that GEFs are unable to positively control G protein systems at steady-state in the absence of GTPase activity. Instead, positive regulation of G proteins must be seen as a product of the competition between guanine nucleotide exchange and GTPase activity--emphasising a central role for GTPase activity beyond merely signal termination. We conclude that a more accurate description of the regulation of G proteins via these processes is as a 'balance/imbalance' mechanism. This result has implications for the understanding of intracellular signalling processes, and for experimental strategies that rely on modulating G protein systems. PMID- 26986851 TI - GPU-Accelerated Molecular Dynamics Simulation to Study Liquid Crystal Phase Transition Using Coarse-Grained Gay-Berne Anisotropic Potential. AB - Gay-Berne (GB) potential is regarded as an accurate model in the simulation of anisotropic particles, especially for liquid crystal (LC) mesogens. However, its computational complexity leads to an extremely time-consuming process for large systems. Here, we developed a GPU-accelerated molecular dynamics (MD) simulation with coarse-grained GB potential implemented in GALAMOST package to investigate the LC phase transitions for mesogens in small molecules, main-chain or side chain polymers. For identical mesogens in three different molecules, on cooling from fully isotropic melts, the small molecules form a single-domain smectic-B phase, while the main-chain LC polymers prefer a single-domain nematic phase as a result of connective restraints in neighboring mesogens. The phase transition of side-chain LC polymers undergoes a two-step process: nucleation of nematic islands and formation of multi-domain nematic texture. The particular behavior originates in the fact that the rotational orientation of the mesogenes is hindered by the polymer backbones. Both the global distribution and the local orientation of mesogens are critical for the phase transition of anisotropic particles. Furthermore, compared with the MD simulation in LAMMPS, our GPU accelerated code is about 4 times faster than the GPU version of LAMMPS and at least 200 times faster than the CPU version of LAMMPS. This study clearly shows that GPU-accelerated MD simulation with GB potential in GALAMOST can efficiently handle systems with anisotropic particles and interactions, and accurately explore phase differences originated from molecular structures. PMID- 26986852 TI - Temperature Affects the Use of Storage Fatty Acids as Energy Source in a Benthic Copepod (Platychelipus littoralis, Harpacticoida). AB - The utilization of storage lipids and their associated fatty acids (FA) is an important means for organisms to cope with periods of food shortage, however, little is known about the dynamics and FA mobilization in benthic copepods (order Harpacticoida). Furthermore, lipid depletion and FA mobilization may depend on the ambient temperature. Therefore, we subjected the temperate copepod Platychelipus littoralis to several intervals (3, 6 and 14 days) of food deprivation, under two temperatures in the range of the normal habitat temperature (4, 15 degrees C) and under an elevated temperature (24 degrees C), and studied the changes in FA composition of storage and membrane lipids. Although bulk depletion of storage FA occurred after a few days of food deprivation under 4 degrees C and 15 degrees C, copepod survival remained high during the experiment, suggesting the catabolization of other energy sources. Ambient temperature affected both the degree of FA depletion and the FA mobilization. In particular, storage FA were more exhausted and FA mobilization was more selective under 15 degrees C compared with 4 degrees C. In contrast, depletion of storage FA was limited under an elevated temperature, potentially due to a switch to partial anaerobiosis. Food deprivation induced selective DHA retention in the copepod's membrane, under all temperatures. However, prolonged exposure to heat and nutritional stress eventually depleted DHA in the membranes, and potentially induced high copepod mortality. Storage lipids clearly played an important role in the short-term response of the copepod P. littoralis to food deprivation. However, under elevated temperature, the use of storage FA as an energy source is compromised. PMID- 26986853 TI - rs621554 single nucleotide polymorphism of DLC1 is associated with breast cancer susceptibility and prognosis. AB - Deleted in liver cancer 1 (DLC1) on chromosome 8p22, is an important tumor suppressor gene originally identified to be deleted in hepatocellular carcinoma. It can regulate the structure of the actin cytoskeleton and inhibit cell proliferation, motility and angiogenesis, which predominantly depends on its homology to rat RhoGAP. There are many genetic variants in DLC1, which may influence its antitumor efficacy. The rs621554 (IVS19+108C>T) polymorphism is a synonymous single nucleotide polymorphism (SNP) previously found to be associated with hepatocellular carcinoma. In the present study, 453 patients with breast cancer and 330 healthy females were analyzed using a cycling probe method. It was determined that the rs621554 polymorphism of DLC1 was associated with breast cancer susceptibility, with the CC and CT genotypes resulting in a higher risk of developing breast cancer. In regard to clinicopathological variables, it was demonstrated that the CT and CC genotype were associated with tumor size, lymph node metastasis and progesterone receptor status. Patients with the CT and CC genotype had shorter disease-free survival and overall survival rates compared with those with the TT genotype. Additionally, it was demonstrated that the rs621554 polymorphism was correlated with DLC1 expression at the mRNA level. These results suggested that the rs621554 polymorphism is associated with breast cancer susceptibility and prognosis, and may serve as a biomarker for breast cancer development and progression. PMID- 26986855 TI - Structural recovery of the retina in a retinoschisin-deficient mouse after gene replacement therapy by solid lipid nanoparticles. AB - X-linked juvenile retinoschisis (XLRS) is a retinal degenerative disorder caused by mutations in the RS1 gene encoding a protein termed retinoschisin. The disease is an excellent candidate for gene replacement therapy as the majority of mutations have been shown to lead to a complete deficiency of the secreted protein in the retinal structures. In this work, we have studied the ability of non-viral vectors based on solid lipid nanoparticles (SLN) to induce the expression of retinoschisin in photoreceptors (PR) after intravitreal administration to Rs1h-deficient mice. We designed two vectors prepared with SLN, protamine, and dextran (DX) or hyaluronic acid (HA), bearing a plasmid containing the human RS1 gene under the control of the murin opsin promoter (mOPS). In vitro, the nanocarriers were able to induce the expression of retinoschisin in a PR cell line. After injection into the murine vitreous, the formulation prepared with HA induced a higher transfection level in PR than the formulation prepared with DX. Moreover, the level of retinoschisin in the inner nuclear layer (INL), where bipolar cells are located, was also higher. Two weeks after vitreal administration into Rs1h-deficient mice, both formulations showed significant improvement of the retinal structure by inducing a decrease of cavities and PR loss, and an increase of retinal and outer nuclear layer (ONL) thickness. HA-SLN resulted in a significant higher increase in the thickness of both retina and ONL, which can be explained by the higher transfection level of PR. In conclusion, we have shown the structural improvement of the retina of Rs1h deficient mice with PR specific expression of the RS1 gene driven by the specific promoter mOPS, after successful delivery via SLN-based non-viral vectors. PMID- 26986856 TI - Silk matrices promote formation of insulin-secreting islet-like clusters. AB - Ex vivo expansion of endocrine cells constitutes an interesting alternative to be able to match the unmet need of transplantable pancreatic islets. However, endocrine cells become fragile once removed from their extracellular matrix (ECM) and typically become senescent and loose insulin expression during conventional 2D culture. Herein we develop a protocol where 3D silk matrices functionalized with ECM-derived motifs are used for generation of insulin-secreting islet-like clusters from mouse and human primary cells. The obtained clusters were shown to attain an islet-like spheroid shape and to maintain functional insulin release upon glucose stimulation in vitro. Furthermore, in vivo imaging of transplanted murine clusters showed engraftment with increasing vessel formation during time. There was no sign of cell death and the clusters maintained or increased in size throughout the period, thus suggesting a suitable cluster size for transplantation. PMID- 26986854 TI - CdSe/ZnS quantum dots induce hepatocyte pyroptosis and liver inflammation via NLRP3 inflammasome activation. AB - Increased biomedical applications of quantum dots (QDs) have raised considerable concern regarding their toxicological impact. However, the toxicity of QDs is largely unknown and the underlying mechanism is still undefined. This study was conducted to examine the hepatotoxicity of CdSe/ZnS core/shell QDs and the underlying mechanism. In hepatic L02 cells, the QDs caused cytotoxicity in a dose dependent manner. The QDs were then shown to activate the NLR pyrin domain containing 3 (NLRP3) inflammasome in hepatocytes, leading to a novel pro inflammatory form of cell death named pyroptosis. Further experiments demonstrated that the QDs induced mitochondrial reactive oxygen species (mtROS) production, and that both a mtROS and a total ROS scavenger attenuated QDs induced NLRP3 activation and pyroptosis. In addition, QDs increased cytoplasmic calcium (Ca(2+)) levels, while a Ca(2+) release antagonist and chelator alleviated QDs-induced mtROS, NLRP3 activation and subsequent pyroptosis in hepatocytes. In vivo, QDs administration induced liver inflammation and dysfunction. Moreover, the QDs also resulted in NLRP3 activation in liver tissue. However, QDs-induced liver inflammation and dysfunction were abolished in NLRP3 knockout mice. Also, an elevation in mtROS was observed in liver after QDs administration, and the mtROS scavenger suppressed liver NLRP3 activation, inflammation and dysfunction induced by QDs. Our data suggest that QDs induced hepatocyte pyroptosis, liver inflammation and dysfunction via NLRP3 activation, which was caused by QDs-triggered mtROS production and Ca(2+) mobilization. Our results provide novel insights into QDs-induced hepatotoxicity and the underlying mechanism, facilitating control of the side effects of QDs. PMID- 26986858 TI - 39-YEAR-OLD FEMALE WITH MILD RESPIRATORY DISTRESS AND HYPOXIA. AB - The diagnosis of cryptogenic organizing pneumonia is usually delayed for several weeks due to treatment for presumed infectious pneumonia. We present a case of cryptogenic organizing pneumonia in a 39-year-old female who presented with shortness of breath and cough. She had both rapid clinical and radiological response to treatment with corticosteroids. PMID- 26986859 TI - A SEVEN-YEAR-OLD MALE WITH CIRCULATING RED BLOOD CELLS SHOWING A THERMAL INJURY LIKE MORPHOLOGY. AB - A seven-year-old African-American male presented with a history of hematuria, proteinuria, jaundice, and anemia occasionally treated with transfusions since early childhood. The family history included a father and sister with similar symptoms of anemia, both of which had been diagnosed with hereditary pyropoikilocytosis. Due to the patient's family history and symptoms indicating a possible hematologic problem, a blood draw was performed. Laboratory studies showed an elevated alkaline phosphatase and bilirubin, and hemolytic anemia with unusual erythrocyte indices. The patient's vital signs and abdominal ultrasound were normal, and he had no known allergies. Examination of the patient's peripheral blood smear revealed extreme erythrocyte poikilocytosis with bizarre forms resembling the erythrocyte morphology sometimes seen in individuals with severe thermal burns. PMID- 26986857 TI - Hydroxychloroquine-conjugated gold nanoparticles for improved siRNA activity. AB - Current technology of siRNA delivery relies on pharmaceutical dosage forms to route maximal doses of siRNA to the tumor. However, this rationale does not address intracellular bottlenecks governing silencing activity. Here, we tested the impact of hydroxychloroquine conjugation on the intracellular fate and silencing activity of siRNA conjugated PEGylated gold nanoparticles. Addition of hydroxychloroquine improved endosomal escape and increased siRNA guide strand distribution to the RNA induced silencing complex (RISC), both crucial obstacles to the potency of siRNA. This modification significantly improved gene downregulation in cellulo. Altogether, our data suggest the benefit of this modification for the design of improved siRNA delivery systems. PMID- 26986860 TI - ABSOLUTE PLATELET REFRACTORINESS ASSOCIATED WITH HLA ANTIBODIES: A CASE REPORT. AB - Refractoriness to platelet transfusion is a complex process that can be due to a diverse array of etiologies. We report a case of refractoriness in a patient with acute myelogenous leukemia (AML) and the diagnostic challenge associated with it. During the course of myeloablative therapy the patient demonstrated no response to multiple sequential platelet transfusions given to prevent the onset of bleeding complications in the setting of severe thrombocytopenia. Diagnostic evaluation revealed multiple potential underlying etiologies and contributing factors, with alloimmunity to HLA antigens determined to be the most probable cause after thorough laboratory investigation. PMID- 26986861 TI - ATYPICAL HEMOLYTIC UREMIC SYNDROME IN AN ADULT SUCCESSFULLY TREATED WITH ECULIZUMAB. AB - Atypical Hemolytic Uremic Syndrome is a triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure not associated with diarrhea. It is a rare condition associated with complement disorders in about 50 percent of cases. The first line of treatment is therapeutic plasma exchange. However, because clinical response to TPE varies, an anti-complement drug, eculizumab has been tried. We report a case of atypical HUS successfully treated with eculizumab. PMID- 26986862 TI - THERAPY-RELATED T/MYELOID MIXED PHENOTYPE ACUTE LEUKEMIA IN A PATIENT TREATED WITH CHEMOTHERAPY FOR CUTANEOUS DIFFUSE LARGE B CELL LYMPHOMA. AB - Mixed-phenotype acute leukemia is a rare form of leukemia that is associated with a poor prognosis. Most cases of mixed-phenotype acute leukemia are de novo. However, therapy-related mixed-phenotype acute leukemia can occur, and are often associated with exposure to topoisomerase-II inhibitors and alkylating agents. There are no known treatment guidelines for therapy-related mixed-phenotype acute leukemia. We present a patient with T/myeloid mixed-phenotype acute leukemia secondary to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone R-CHOP chemotherapy for primary cutaneous diffuse large B-cell lymphoma. The patient's leukemic cells express CD34, an immaturity marker, CD3, a T-cell marker, and myeloperoxidase, a myeloid marker, and her history of chemotherapy for previous lymphoma supports the diagnosis of therapy-related T/myeloid mixed phenotype acute leukemia. Clinicians should be aware that this entity could be associated with R-CHOP chemotherapy. Given the complexity in diagnosis, and lack of treatment guidelines, a further understanding of the pathological and genetic principles of therapy-related mixed-phenotype acute leukemia will assist in future efforts to treat and categorize these patients. Mixed phenotype acute leukemia is a rare entity that accounts for two to five percent of all acute leukemias. Therapy- related mixed phenotype acute leukemia is an exceedingly rare hematological neoplasm that accounts for less than one percent of acute leukemias. We describe a case of therapy-related T/myeloid mixed phenotype acute leukemia following rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone R-CHOP chemotherapy for primary cutaneous diffuse large B-cell lymphoma DLBCL. The patient is a 63-year-old female who presented with several cutaneous nodules diagnosed as primary cutaneous DLBCL. The patient received R-CHOP chemotherapy and achieved remission. She remained in remission for four years until she presented with dyspnea, night sweats, weakness, and diffuse lymphadenopathy. Her presentation was initially concerning for recurrent lymphoma; however, a bone marrow biopsy and aspirate and a lymph node biopsy revealed a distinct blast population consistent with T/myeloid mixed phenotype acute leukemia T/M-MPAL. Given the patient's history of previous chemotherapy exposure, our patient represents a case of therapy-related T/myeloid mixed phenotype acute leukemia t-MPAL. PMID- 26986863 TI - WEST NILE VIRUS MENINGO-ENCEPHALITIS: POSSIBLE SEXUAL TRANSMISSION. AB - PURPOSE: We report a previously healthy middle aged woman who developed West Nile virus meningo-encephalitis within two weeks of unprotected vaginal intercourse with her husband. SUBJECT: This patient's husband had serologically confirmed West Nile virus infection manifested by a flu-like illness and rash with the sexual contact one day before the onset of his symptoms. RESULT: This well documented neuroinvasive West Nile virus infection in our patient was within the incubation period of transmission and there was no reported mosquito bite exposure. CONCLUSION: The timeframe of infection raises the possibility that her illness was sexually transmitted. PMID- 26986864 TI - Clinical Case of the Month: PERSISTENT HYPERTENSION IN A YOUNG WOMAN: A CLASSIC PRESENTATION OF CONN'S SYNDROME. AB - Primary aldosteronism PA is a secondary cause of hypertension that is often missed due to inadequate clinical evaluation and the lack of classically described laboratory abnormalities. Based on guidelines from the Endocrine Society, primary aldosteronism should be suspected in young patients with moderate to severe hypertension, patients with hypertension and coexisting hypokalemia, any patient with hypertension and an incidental adrenal adenoma, and hypertension in the setting of a significant family history of early onset hypertension or cerebral vascular accident in a first degree relative less than 40 years of age.1 In previous years, primary aldosteronism was attributed to less than one percent of all causes of secondary hypertension. However, recent research and increased utilization of aldosterone plasma renin ratio ARR as a method for screening has led to the understanding that majority of patients with PA are not hypokalemic, and the current literature now places the incidence of PA between 5-13 percent. Additionally, a growing body of evidence has demonstrated inflammatory, fibrotic, and remodeling effects on the cardiovascular and renal tissue that appear to be independent of PA- induced hypertension. Therefore a high suspicion for PA must be incorporated into evaluation of hypertensive patients, as diagnosis and subsequent treatment not only improves blood pressure control, but also acts to diminish cardiovascular morbidity and mortality. Here we present a case of a young woman with a seven-year history of hypertension prior to receiving a diagnosis of Conn's Syndrome. PMID- 26986865 TI - ECG Case of the Month: IRREGULARLY IRREGULAR CARDIAC RHYTHM IN AN 87-YEAR-OLD WOMAN. MULTIFOCAL ATRIAL TACHYCARDIA; RIGHT BUNDLE BRANCH BLOCK. AB - DIAGNOSIS: Multifocal atrial tachycardia; right bundle branch block. The rhythm is totally irregular at a rate of 103 beats/min and originally was read as atrial fibrillation. Close examination, however, reveals a P wave before each QRS and >= 3 different P- wave morphologies with no dominant morphology. These are the criteria for multifocal atrial tachycardia MAT, also known as chaotic atrial rhythm,1 chaotic atrial tachycardia,2 and chaotic atrial mechanism.3 The wide QRS complexes >= 0.12 s with broad S waves in leads I, aVL, and the lateral precordial leads and broad R or R' waves in leads aVR and V1 indicate right bundle branch block. MAT is frequently seen in patients with acute pulmonary or other non-cardiac disease and tends to resolve when the underlying disease is brought under control. Patients with MAT also tend to have bouts of other arrhythmias,2 and 3 months earlier this. PMID- 26986866 TI - RADIOLOGY CASE OF THE MONTH: A CASE OF IDIOPATHIC BASAL GANGLIA CALCIFICATION AND BRIEF REVIEW OF THE LITERATURE. AB - A 39-year-old woman was incidentally found to have extensive bilateral basal ganglia calcifications after a motor vehicle accident. Laboratory work-up was unremarkable. She was diagnosed with idiopathic basal ganglia calcifications, formerly known as Fahr's disease. A brief review of the literature is presented. PMID- 26986867 TI - Exploring the Mechanism Responsible for Cellulase Thermostability by Structure Guided Recombination. AB - Cellulases from Bacillus and Geobacillus bacteria are potentially useful in the biofuel and animal feed industries. One of the unique characteristics of these enzymes is that they are usually quite thermostable. We previously identified a cellulase, GsCelA, from thermophilic Geobacillus sp. 70PC53, which is much more thermostable than its Bacillus homolog, BsCel5A. Thus, these two cellulases provide a pair of structures ideal for investigating the mechanism regarding how these cellulases can retain activity at high temperature. In the present study, we applied the SCHEMA non-contiguous recombination algorithm as a novel tool, which assigns protein sequences into blocks for domain swapping in a way that lessens structural disruption, to generate a set of chimeric proteins derived from the recombination of GsCelA and BsCel5A. Analyzing the activity and thermostability of this designed library set, which requires only a limited number of chimeras by SCHEMA calculations, revealed that one of the blocks may contribute to the higher thermostability of GsCelA. When tested against swollen Avicel, the highly thermostable chimeric cellulase C10 containing this block showed significantly higher activity (22%-43%) and higher thermostability compared to the parental enzymes. With further structural determinations and mutagenesis analyses, a 310 helix was identified as being responsible for the improved thermostability of this block. Furthermore, in the presence of ionic calcium and crown ether (CR), the chimeric C10 was found to retain 40% residual activity even after heat treatment at 90 degrees C. Combining crystal structure determinations and structure-guided SCHEMA recombination, we have determined the mechanism responsible for the high thermostability of GsCelA, and generated a novel recombinant enzyme with significantly higher activity. PMID- 26986868 TI - Plasma concentrations of transforming growth factor beta 1 in non-progressive HIV 1 infection correlates with markers of disease progression. AB - The human immunodeficiency virus (HIV) infection shows variable rate of disease progression. The underlying biological and molecular mechanisms involved in determining progression of HIV infection are not fully understood. The aims of this study were to determine plasma concentrations of active TGF beta 1, Th1 and Th2 cytokines in patients with non-progressive and those with progressive HIV-1 infection, as well as to determine if there is an association of these cytokines to disease progression. In a cross-sectional study of 61 HIV-1 infected individuals categorized according to disease progression as having non progressive HIV-1 infection (n=14) and progressive infection (n=47), plasma levels of active TGF beta 1, INF-gamma, TNF-alpha, IL-10, IL-1beta, IL-12p70 and IL-13 were compared with HIV uninfected healthy controls (n=12). Plasma concentration of these cytokines was measured using a highly sensitive luminex200 XMAP assay. Pearson correlation test was used to assess the correlation of cytokines with CD4+ and CD8+ T cells, CD4:CD8 ratio and plasma HIV-1 RNA in the different study groups. Plasma concentrations of TGF beta 1 and IL-10 were significantly decreased while IL-1beta, IL-12p70 and TNF-alpha were increased in patients with non-progressive HIV-1 infection compared to patients with progressive infection. Plasma levels of TGF beta 1 and IL-10 showed an inverse correlation with CD8+ T cell counts and CD4:CD8 ratios in patients with non progressive HIV-1 infection, while plasma HIV-1 RNA positively correlated with CD4+ T cell counts. Plasma levels of TNF-alpha, IL-1beta, IL-12p70 and IL-13 positively correlated with CD4+ T cell counts and inversely correlated with plasma HIV-1 RNA, CD8+ T cell count and CD4:CD8 ratio in patients with non progressive infection. The correlation of cytokines to the state of T-lymphocyte and plasma HIV-1 RNA found in this study may provide insight into the role of cytokines in both progressive and non-progressive HIV-1 infection. Additionally, these findings may have implications for systemic cytokine-based therapies in HIV 1 infection. PMID- 26986869 TI - Seasonal development of cambial activity in relation to xylem formation in Chinese fir. AB - The vascular cambium is a lateral meristem which can differentiate into secondary phloem and xylem. The secondary growth of woody plants resulting from vascular cambium activity has been a focus of considerable attention, but the quantitative relationships between cambial activity and secondary xylem formation have been little studied. Our analysis of cytological changes in the cambium of Chinese fir (Cunninghamia lanceolata), revealed a significant positive correlation between vascular cambium cell numbers and cambium zone width through the seasonal cycle. Cambium cell numbers and the cambium cell radial diameter were closely related to xylem formation. Immuno-labeling showed that de-esterified homogalacturonan and (1-4)-beta-d-galactan epitopes were highly abundant in cell walls of dormant stage cambium, whereas high methylesterified homogalacturonan was strongly labeled in the active stage. Raman spectroscopy detected significant changes in the chemical composition of cell walls during the active-dormant stage transition. More pectin and less monolignols occurred in radial cell walls than in tangential walls during the dormant stage, but no significant changes were found in other stages, indicating that pectin accumulation facilitates cell wall expansion, with cambium activity transition. Our quantitative analysis of the relationship between cambial activity and xylem formation, as well as the cell wall modification during the active stage provides useful information about cambial characteristics and xylogenesis. PMID- 26986870 TI - Paclitaxel enhances tumoricidal potential of TRAIL via inhibition of MAPK in resistant gastric cancer cells. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) holds promise for cancer therapy due to its unique capacity to selectively trigger apoptosis in cancer cells. However, TRAIL therapy is greatly hampered by its resistance. A preclinical successful strategy is to identify combination treatments that sensitize resistant cancers to TRAIL. In the present study, we fully assessed TRAIL sensitivity in 9 gastric cancer cell lines. We found combined administration of paclitaxel (PTX) markedly enhanced TRAIL-induced apoptosis in resistant cancer cells both in vitro and in vivo. The sensitization to TRAIL was accompanied by activation of mitochondrial apoptotic pathway, upregulation of TRAIL receptors and downregulation of anti-apoptotic proteins including C-IAP1, C IAP2, Livin and Mcl-1. Noticeably, we found PTX could suppress the activation of mitogen-activated protein kinases (MAPKs). Inhibition of MAPKs using specific inhibitors (ERK inhibitor U0126, JNK inhibitor SP600125 and P38 inhibitor SB202190) facilitated TRAIL-mediated apoptosis and cytotoxicity. Additionally, SP600125 upregulated TRAL receptors as well as downregulated C-IAP2 and Mcl-1 suggesting the anti-apoptotic role of JNK. Thus, PTX-induced suppression of MAPKs may contribute to restoring TRAIL senstitivity. Collectively, our comprehensive analyses gave new insight into the role of PTX on enhancing TRAIL sensitivity, and provided theoretical references on the development of combination treatment in TRAIL-resistant gastric cancer. PMID- 26986871 TI - Benign Paroxysmal Positional Vertigo in 2 Children: A Case Series. AB - PURPOSE: The purpose of this case report is to present the cases of 2 boys with benign paroxysmal positional vertigo (BPPV). KEY POINTS: Patient A (11 years old) and Patient B (9 years old) had complaints of vertigo with position changes. Both exhibited left torsion upbeating nystagmus in the left Dix-Hallpike (DH) test and complaints of vertigo with reproduction of their symptoms, indicating BPPV. Both were treated with a left canalith repositioning maneuver and reported decreased incidence of positional vertigo upon reevaluation. Scores on the Dizziness Handicap Inventory and the Visual Analog Scale for Dizziness decreased after treatment for 1 of the boys. CONCLUSION: Benign paroxysmal positional vertigo is considered rare in children. Migraines may also cause vertigo. Differential diagnosis in these cases was made by performing the DH test. RECOMMENDATIONS FOR CLINICAL PRACTICE: Children with vertigo should be screened for BPPV through use of history taking, and the DH test. PMID- 26986872 TI - The Excess Winter Deaths Measure: Why Its Use Is Misleading for Public Health Understanding of Cold-related Health Impacts. AB - BACKGROUND: Excess winter deaths, the ratio between average daily deaths in December-March versus other months, is a measure commonly used by public health practitioners and analysts to assess health burdens associated with wintertime weather. We seek to demonstrate that this measure is fundamentally biased and can lead to misleading conclusions about health impacts associated with current and future winter climate. METHODS: Time series regression analysis of 779,372 deaths from natural causes in London over 15 years (1 August 1997-31 July 2012),collapsed by day of death and linked to daily temperature values. The outcome measures were the excess winter deaths index, and daily and annual deaths attributable specifically to cold. RESULTS: Most of the excess winter deaths are driven by cold: The excess winter deaths index decreased from 1.19 to 1.07 after excluding deaths attributable to low temperatures. Over 40% of cold-attributable deaths occurred outside of the December-March period, leading to bias in the excess winter deaths measure. Although there was no relationship between winter severity and annual excess winter deaths, there was a clear correlation with annual cold-attributable deaths. CONCLUSIONS: Excess winter deaths is not an appropriate indicator of cold-related health impacts, and its use should be discontinued. We advocate alternative measures. The findings we present bring into doubt previous claims that cold-related deaths in the UK will not reduce in future as a result of climate change. PMID- 26986873 TI - Commentary: Osteoarthritis and Mortality: Answering Questions or Questioning Answers? PMID- 26986874 TI - All-cause Mortality in Knee and Hip Osteoarthritis and Rheumatoid Arthritis. AB - BACKGROUND: While increased mortality in rheumatoid arthritis (RA) is well established, there is conflicting evidence on the association between osteoarthritis (OA) and mortality. Our aim was to estimate all-cause mortality in Swedish patients with RA and OA compared with the general population. METHODS: Cohort study of the population of Skane region, Sweden (1.3 million), based on physicians' diagnostic codes in a mandatory register covering all health care. We included all subjects aged >=45 years who between 1998 and 2012 consulted any physician at least once. We identified those who received a diagnosis of RA, knee OA, or hip OA. We followed all subjects until death, relocation outside Skane region, or end of 2013, and analyzed data using Cox proportional hazard regression with attained age as time scale. RESULTS: We identified 8,067 patients with RA, 51,939 with knee OA and 29,442 with hip OA among 524,136 in the population aged >=45 years. The mortality rates adjusted for sex, socioeconomic status, and comorbidities were elevated for RA, hazard ratio 1.86 (95% confidence interval = 1.78, 1.94) but not in knee or hip OA compared with the general population seeking health care, hazard ratio 0.87 (0.85, 0.89) and 0.90 (0.87, 0.92), respectively. Extensive sensitivity analyses supported the conclusion of no increased mortality in OA. CONCLUSIONS: In Sweden, RA is associated with about doubled mortality rate, but we found no increased mortality in patients with knee and hip OA. Possible selection of those seeking physician care for knee or hip pain and/or OA management in health care are plausible explanations. PMID- 26986875 TI - Microwaves and Aqueous Solvents Promote the Reaction of Poorly Nucleophilic Anilines with a Zincke Salt. AB - The Zincke reaction allows the transformation of primary amines into their respective N-alkylated or N-arylated pyridinium salts. While nucleophilic primary amines (typically, aliphatic primary amines) often lead to quantitative reactions and has been documented profusely, the use of poorly nucleophilic amines still requires an in depth account. To date, the lack of nucleophilicity of the amines is redhibitory. The subject addressed in this article is a series of primary amines deriving from aniline having been engaged in Zincke reactions. Efficient transformations were obtained, even when conducted on electronically deactivated, eventually also sterically hindered, substrates. This was achieved by the combined use of microwave activation and aqueous solvents. Under our conditions, the role of water revealed indeed crucial to avoid the self-degradation of the Zincke salt, the reagent of the reaction. PMID- 26986876 TI - Selective Ionic Transport Pathways in Phosphorene. AB - Despite many theoretical predictions indicating exceptionally low energy barriers of ionic transport in phosphorene, the ionic transport pathways in this two dimensional (2D) material has not been experimentally demonstrated. Here, using in situ aberration-corrected transmission electron microscopy (TEM) and density functional theory, we studied sodium ion transport in phosphorene. Our high resolution TEM imaging complemented by electron energy loss spectroscopy demonstrates a precise description of anisotropic sodium ions migration along the [100] direction in phosphorene. This work also provides new insight into the effect of surface and the edge sites on the transport properties of phosphorene. According to our observation, the sodium ion transport is preferred in zigzag edge rather than the armchair edge. The use of this highly selective ionic transport property may endow phosphorene with new functionalities for novel chemical device applications. PMID- 26986878 TI - An openly available online tool for implementing the ACMG/AMP standards and guidelines for the interpretation of sequence variants. PMID- 26986879 TI - Overcalling secondary findings. PMID- 26986881 TI - Polyamines in macroalgae: advances and future perspectives. AB - Polyamines (PA) are ubiquitous, small, aliphatic cations found in all living cells. In recent years the importance of these molecules for macroalgae has become evident and a substantial body of knowledge has been accumulated over the last three decades. This review summarizes research on the PAs found in macroalgae, their transport and metabolism, and their biological significance in processes such as cell division, chloroplast development, and reproduction. The involvement of PAs in environmental stress responses in macroalgae is also addressed. The discussion of PAs in this review not only demonstrates that PAs play an important role in physiological processes in macroalgae, but also clearly demonstrates the similarities and differences between PA metabolism in macroalgae and higher plants. Key areas for future research are also discussed. PMID- 26986880 TI - Prospects and challenges for industrial production of seaweed bioactives. AB - Large-scale seaweed cultivation has been instrumental in globalizing the seaweed industry since the 1950s. The domestication of seaweed cultivars (begun in the 1940s) ended the reliance on natural cycles of raw material availability for some species, with efforts driven by consumer demands that far exceeded the available supplies. Currently, seaweed cultivation is unrivaled in mariculture with 94% of annual seaweed biomass utilized globally being derived from cultivated sources. In the last decade, research has confirmed seaweeds as rich sources of potentially valuable, health-promoting compounds. Most existing seaweed cultivars and current cultivation techniques have been developed for producing commoditized biomass, and may not necessarily be optimized for the production of valuable bioactive compounds. The future of the seaweed industry will include the development of high value markets for functional foods, cosmeceuticals, nutraceuticals, and pharmaceuticals. Entry into these markets will require a level of standardization, efficacy, and traceability that has not previously been demanded of seaweed products. Both internal concentrations and composition of bioactive compounds can fluctuate seasonally, geographically, bathymetrically, and according to genetic variability even within individual species, especially where life history stages can be important. History shows that successful expansion of seaweed products into new markets requires the cultivation of domesticated seaweed cultivars. Demands of an evolving new industry based upon efficacy and standardization will require the selection of improved cultivars, the domestication of new species, and a refinement of existing cultivation techniques to improve quality control and traceability of products. PMID- 26986882 TI - New species of Clade B Symbiodinium (Dinophyceae) from the greater Caribbean belong to different functional guilds: S. aenigmaticum sp. nov., S. antillogorgium sp. nov., S. endomadracis sp. nov., and S. pseudominutum sp. nov. AB - Molecular approaches have begun to supersede traditional morphometrics in the species delineation of micro-eukaryotes. In addition to fixed differences in DNA sequences, recent genetics-based descriptions within the dinoflagellate genus Symbiodinium have incorporated confirmatory morphological, physiological, and ecological evidence when possible. However, morphological and physiological data are difficult to collect from species that have not been cultured, while the natural ecologies of many cultured species remain unknown. Here, we rely on genetic evidence-the only data consistently available among all taxa investigated to describe four new Clade B Symbiodinium species. The 'host-specialized' species (S. antillogorgium sp. nov. and S. endomadracis sp. nov.) engage in mutualisms with specific cnidarian hosts, but exhibit differences in our ability to culture them in vitro. The ecologically 'cryptic' species (S. aenigmaticum sp. nov. and S. pseudominutum sp. nov.) thrive in culture, but their roles or functions in the ecosystem (i.e., niches) are yet to be documented. These new species call further attention to the spectrum of ecological guilds among Symbiodinium. PMID- 26986877 TI - The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations. AB - PURPOSE: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal dominant disorder characterized by optic atrophy and intellectual disability caused by loss-of-function mutations in NR2F1. We report 20 new individuals with BBSOAS, exploring the spectrum of clinical phenotypes and assessing potential genotype-phenotype correlations. METHODS: Clinical features of individuals with pathogenic NR2F1 variants were evaluated by review of medical records. The functional relevance of coding nonsynonymous NR2F1 variants was assessed with a luciferase assay measuring the impact on transcriptional activity. The effects of two start codon variants on protein expression were evaluated by western blot analysis. RESULTS: We recruited 20 individuals with novel pathogenic NR2F1 variants (seven missense variants, five translation initiation variants, two frameshifting insertions/deletions, one nonframeshifting insertion/deletion, and five whole-gene deletions). All the missense variants were found to impair transcriptional activity. In addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%). CONCLUSION: BBSOAS encompasses a broad range of clinical phenotypes. Functional studies help determine the severity of novel NR2F1 variants. Some genotype-phenotype correlations seem to exist, with missense mutations in the DNA-binding domain causing the most severe phenotypes.Genet Med 18 11, 1143-1150. PMID- 26986883 TI - Environmental correlates of phenotypic variation: do variable tidal regimes influence morphology in intertidal seaweeds? AB - Seaweed morphology is often shaped by the hydrodynamic environment. However, exposure to air at low tide represents an additional factor potentially affecting the morphology of intertidal species. Here, we examined the relationships between the morphology of Hormosira banksii, an important intertidal habitat-forming seaweed in southern Australia, and environmental factors across multiple spatial scales around the island of Tasmania, Australia. Tasmania is surrounded by a diverse coastline with differences in wave exposure, tidal parameters, and temperature. We sampled Hormosira from four regions (100s km apart), three sites (10s km apart) within each region, and two zones (meters apart; eulittoral and sublittoral) at each site, and measured multiple morphological variables to test for differences in morphology at those different spatial scales. Thirteen environmental variables reflecting wave exposure, tidal conditions, and temperature for each site were generated to assess the relationship between Hormosira morphology and environmental variation. Morphology varied at all spatial scales examined. Most notably, north coast individuals had a distinct morphology, generally having smaller vesicles and shorter fronds, compared to other regions. Tidal conditions were the main environmental factors separating north coast sites from other sites and tidal regime was identified as the best predictor of morphological differences between regions. In contrast to other studies, we found little evidence that wave exposure was associated with morphological variation. Overall, our study emphasizes the role of tidal conditions, associated with emersion stress during low tide, in affecting the morphology of intertidal seaweeds. PMID- 26986884 TI - Comparison of population growth and photosynthetic apparatus changes in response to different nutrient status in a diatom and a coccolithophore. AB - In many marine ecosystems, diatoms dominate in nutrient-rich coastal waters while coccolithiophores are found offshore in areas where nutrients may be limiting. In lab-controlled batch cultures, mixed-species competition between the diatom Phaeodactylum tricornutum and the coccolithophore Emiliana huxleyi and the response of each species were examined under nitrate (N) and phosphate (P) starvation. Based on the logistic growth model and the Lotka-Volterra competition model, E. huxleyi showed higher competitive abilities than P. tricornutum under N and P starvation. For both species, cell growth was more inhibited by P starvation, while photosynthetic functions (chl a fluorescence parameters) and cellular constituents (pigments) were impaired by N starvation. The decline of photosynthetic functions occurred later in E. huxleyi (day 12) than in P. tricornutum (day 9); this time difference was associated with greater damage of the photosynthetic apparatus in P. tricornutum compared with E. huxleyi. Xanthophyll cycle pigment accumulation and the transformation from diadinoxanthin to diatoxanthin was more active in E. huxleyi than P. tricornutum, under similar N and P starvation. We concluded that E. huxleyi and P. tricornutum have different mechanisms to allocate resources and energy under nutrient starvation. It appears that E. huxleyi has a more economic strategy to adapt to nutrient depleted environments than P. tricornutum. These findings provided additional evidence explaining how N versus P limitation differentially support diatom and coccolithophore blooms in natural environments. PMID- 26986885 TI - Nutritional stress effects under different nitrogen sources on the genes in microalga Isochrysis zhangjiangensis and the assistance of Alteromonas macleodii in releasing the stress of amino acid deficiency. AB - The expressions of nine nitrogen assimilation-associated genes, NRT2, NAR1, NIA2, NIR, GLN2, GLSF, GSN1, GDH, and AAT2, in the microalga Isochrysis zhangjiangensis were investigated to unveil the effects of limitations of various nitrogen sources (NaNO3 , NH4 Cl, NaNO2 , and an amino acid mixture) on the microalgae. The results demonstrated that the NRT2, NAR1, GLN2, GSN1, and AAT2 genes were highly expressed in lipid-rich microalgae under inorganic nitrogen-deficient conditions and they decreased after nitrogen resupply. Significant increases in the expressions of NAR1, GLN2, and GLSF were found in nitrate-depleted microalgae, whereas significant increases in the expressions of NRT2, NAR1, GLN2, and GSN1 were found in nitrite-depleted microalgae. Significant increases in the expressions of only NRT2 and GSN1 were found in ammonium-depleted microalgae (P < 0.05). Except for the NRT2, other genes were expressed at lower levels under amino acid-deficient conditions compared with amino acid-sufficient controls. The expression of the NIA2 gene decreased in nitrogen-depleted microalgae regardless of the initial nitrogen source. However, the results of fatty acid analyses showed that the features of fatty acid profiles followed a similar mode, in which the percentage compositions of C16:0 and C18:1Delta(9) increased in nitrogen depleted cells and that of C16:1Delta(9) , C18:3Delta(9,12,15) , C18:4Delta(6,9,12,15) , and C18:5Delta(3,6,9,12,15) decreased, regardless of the type of nitrogen source applied. It was also found that the epiphytic bacterium Alteromonas macleodii played a particularly important role in releasing microalgae from the stress of amino acid deficiency. These findings also provide a foundation for regulating microalgal lipid production through manipulation of the nitrogen assimilation-associated genes. PMID- 26986886 TI - Phenotypic plasticity and biogeographic variation in physiology of habitat forming seaweed: response to temperature and nitrate. AB - Southeastern Australian waters are warming at nearly four times the global average rate (~0.7 degrees C . century(-1) ) driven by strengthening incursions of the warm oligotrophic East Australian Current. The growth rate hypothesis (GRH) predicts that nutrient depletion will impact more severely on seaweeds at high latitudes with compressed growth seasons. This study investigates the effects of temperature and nutrients on the ecophysiology of the habitat-forming seaweed Phyllospora comosa in a laboratory experiment using temperature (12 degrees C, 17 degrees C, 22 degrees C) and nutrient (0.5, 1.0, 3.0 MUM NO3 (-) ) scenarios representative of observed variation among geographic regions. Changes in growth, photosynthetic characteristics (via chlorophyll fluorescence), pigment content, tissue chemistry (delta(13) C, % C, % N, C:N) and nucleic acid characteristics (absolute RNA and DNA, RNA:DNA ratios) were determined in seaweeds derived from cool, high-latitude and warm, low-latitude portions of the species' range. Performance of P. comosa was unaffected by nitrate availability but was strongly temperature-dependent, with photosynthetic efficiency, growth, and survival significantly impaired at 22 degrees C. While some physiological processes (photosynthesis, nucleic acid, and accessory pigment synthesis) responded rapidly to temperature, others (C/N dynamics, carbon concentrating processes) were largely invariant and biogeographic variation in these characteristics may only occur through genetic adaptation. No link was detected between nutrient availability, RNA synthesis and growth, and the GRH was not supported in this species. While P. comosa at high latitudes may be less susceptible to oligotrophy than predicted by the GRH, warming water temperatures will have deleterious effects on this species across its range unless rapid adaptation is possible. PMID- 26986887 TI - Reproductive morphology and DNA sequences of the brown alga Platysiphon verticillatus support the new combination Platysiphon glacialis. AB - Platysiphon verticillatus, a brown alga endemic to the Arctic, was described based on vegetative specimens collected at Inglefield Bay, West Greenland. The species is distinctive in having a lanceolate blade-like thallus terminated by a terete portion, both covered with hair-like assimilatory filaments. Punctaria glacialis was described from Eastern Greenland, and the species differs from other Punctaria species in lacking hairs and plurilocular zoidangia. Unilocular zoidangia were reported, but instead of zoids being released they formed cell walls in situ developing the appearance of plurilocular zoidangia. However, the fate of the zoids, as well as the walled cells was not traced, and the life history of the alga has remained unclear. By comparing DNA sequences (cox1, cox3, and rDNA ITS2) of specimens morphologically referable to Platysiphon verticillatus and Punctaria glacialis collected at Baffin Island, as well as re examining morphology and studying crude cultures, we concluded that they are the same taxonomic entity. Furthermore, their cox3 sequence and vegetative morphology agreed with those of the type specimen of Punctaria glacialis. Consequently, we propose Platysiphon glacialis comb. nov. The life cycle could not be completed in culture, but we hypothesize that in situ germination of the unizoids produces reduced gametophytes housed in peripheral tissue of erect sporophytic thalli. PMID- 26986889 TI - A new molecular phylogeny of the Laurencia complex (Rhodophyta, Rhodomelaceae) and a review of key morphological characters result in a new genus, Coronaphycus, and a description of C. novus. AB - Within the Laurencia complex (Rhodophyta, Rhodomelaceae), six genera have been recognized based on both molecular analyses and morphology: Laurencia, Osmundea, Chondrophycus, Palisada, Yuzurua, and Laurenciella. Recently, new material from Australia has been collected and included in the current molecular phylogeny, resulting in a new clade. This study examined the generic delineations using a combination of morphological comparisons and phylogenetic analysis of chloroplast (rbcL) nucleotide sequence. The molecular phylogeny recovered eight (rather than six) clades; Yuzurua, Laurenciella, Palisada, and Chondrophycus showed as monophyletic clades each with strong support. However, the genera Osmundea and Laurencia were polyphyletic. Consequently, the new genus Coronaphycus is proposed, resulting in the new combination Coronaphycus elatus and a description of the new species C. novus. PMID- 26986888 TI - Molecular phylogeny of two unusual brown algae, Phaeostrophion irregulare and Platysiphon glacialis, proposal of the Stschapoviales ord. nov. and Platysiphonaceae fam. nov., and a re-examination of divergence times for brown algal orders. AB - The molecular phylogeny of brown algae was examined using concatenated DNA sequences of seven chloroplast and mitochondrial genes (atpB, psaA, psaB, psbA, psbC, rbcL, and cox1). The study was carried out mostly from unialgal cultures; we included Phaeostrophion irregulare and Platysiphon glacialis because their ordinal taxonomic positions were unclear. Overall, the molecular phylogeny agreed with previously published studies, however, Platysiphon clustered with Halosiphon and Stschapovia and was paraphyletic with the Tilopteridales. Platysiphon resembled Stschapovia in showing remarkable morphological changes between young and mature thalli. Platysiphon, Halosiphon and Stschapovia also shared parenchymatous, terete, erect thalli with assimilatory filaments in whorls or on the distal end. Based on these results, we proposed a new order Stschapoviales and a new family Platysiphonaceae. We proposed to include Phaeostrophion in the Sphacelariales, and we emended the order to include this foliose member. Finally, using basal taxa not included in earlier studies, the origin and divergence times for brown algae were re-investigated. Results showed that the Phaeophyceae branched from Schizocladiophyceae ~260 Ma during the Permian Period. The early diverging brown algae had isomorphic life histories, whereas the derived taxa with heteromorphic life histories evolved 155-110 Ma when they branched from the basal taxa. Based on these results, we propose that the development of heteromorphic life histories and their success in the temperate and cold-water regions was induced by the development of the remarkable seasonality caused by the breakup of Pangaea. Most brown algal orders had diverged by roughly 60 Ma, around the last mass extinction event during the Cretaceous Period, and therefore a drastic climate change might have triggered the divergence of brown algae. PMID- 26986890 TI - The diversity of algal phospholipase D homologs revealed by biocomputational analysis. AB - Phospholipase D (PLD) participates in the formation of phosphatidic acid, a precursor in glycerolipid biosynthesis and a second messenger. PLDs are part of a superfamily of proteins that hydrolyze phosphodiesters and share a catalytic motif, HxKxxxxD, and hence a mechanism of action. Although HKD-PLDs have been thoroughly characterized in plants, animals and bacteria, very little is known about these enzymes in algae. To fill this gap in knowledge, we performed a biocomputational analysis by means of HMMER iterative profiling, using most eukaryotic algae genomes available. Phylogenetic analysis revealed that algae exhibit very few eukaryotic-type PLDs but possess, instead, many bacteria-like PLDs. Among algae eukaryotic-type PLDs, we identified C2-PLDs and PXPH-like PLDs. In addition, the dinoflagellate Alexandrium tamarense features several proteins phylogenetically related to oomycete PLDs. Our phylogenetic analysis also showed that algae bacteria-like PLDs (proteins with putative PLD activity) fall into five clades, three of which are novel lineages in eukaryotes, composed almost entirely of algae. Specifically, Clade II is almost exclusive to diatoms, whereas Clade I and IV are mainly represented by proteins from prasinophytes. The other two clades are composed of mitochondrial PLDs (Clade V or Mito-PLDs), previously found in mammals, and a subfamily of potentially secreted proteins (Clade III or SP-PLDs), which includes a homolog formerly characterized in rice. In addition, our phylogenetic analysis shows that algae have non-PLD members within the bacteria-like HKD superfamily with putative cardiolipin synthase and phosphatidylserine/phosphatidylglycerophosphate synthase activities. Altogether, our results show that eukaryotic algae possess a moderate number of PLDs that belong to very diverse phylogenetic groups. PMID- 26986891 TI - Transformation of Ulva mutabilis (Chlorophyta) by vector plasmids integrating into the genome. AB - A method for the stable transformation of the green marine macroalga Ulva mutabilis was developed based on vector plasmids integrating into the genome. By combination of the expression signals (promoter, enhancer, and transcriptional termination sequences) of a chromosomal rbcS gene from U. mutabilis with the bleomycin resistance gene (ble) from Streptoalloteichus hindustanus, a dominant selectable marker gene was constructed for the preparation of a series of E. coli U. mutabilis shuttle vector plasmids. Special vectors were prepared for the introduction and expression of foreign genes in Ulva, for insertional mutagenesis and gene tagging by plasmid integration into the genome, and for protein tagging by the green fluorescent protein, as well as tools for posttranscriptional gene silencing and cosmid cloning to prepare genomic gene libraries for mutant gene complementation. The vectors were successfully tested in pilot experiments, where they were efficiently introduced into Ulva gametes, zoospores or protoplasts of somatic blade cells by treatment with Ca(2+) -ions and polyethylene glycol under isotonic conditions at low ionic strength. The parthenogenetically propagated phleomycin-resistant transformants of the mutant slender (sl) and the wildtype (wt) were demonstrated to be carrying the plasmids randomly integrated into the chromosomes often as tandem repeat clusters. PMID- 26986892 TI - Life history, excystment features, and growth characteristics of the Mediterranean harmful dinoflagellate Alexandrium pseudogonyaulax. AB - Studies considering the biology and ecology of the toxic bloom-forming species, Alexandrium pseudogonyaulax, are rare. Our results highlight five features not described before in A. pseudogonyaulax life cycle: (i) A. pseudogonyaulax gametes showed two modes of conjugation, anisogamy and isogamy, (ii) sexual conjugation occurs either in the dark or in the light phase by engulfment or a fusion process, (iii) the presence of planozygote and newly formed cysts in monoclonal culture suggests homothallism, (iv) newly formed cysts have very dark vesicular content and are mostly unparatabulated when observed under light microscope and (v) natural resting cysts are able to give either a planomeiocyte or two vegetative cells. Cyst viability was enhanced after 5 months of cold storage (4 degrees C), with excystment rate reaching 97% after 3 d of incubation. Excystment rate was highest (43%-79%) in Enriched Natural Sea Water diluted culture medium, whereas few germling cells were able to survive without the culture medium (0% 13%). Salinity-irradiance experiments revealed that the highest cell concentrations occur at high irradiances for all the tested salinities. Vegetative growth rates generally increased with increasing irradiance, and were less dependent on salinity variations. The relatively low growth rate, low cell densities in the laboratory, and the notable capacity of producing cysts along growth phases of A. pseudogonyaulax could explain the occurrence of high resting cysts densities in the sediment of Bizerte lagoon and the relatively low abundances of vegetative cells in the water column. PMID- 26986893 TI - Cyst-motile stage relationship, morphology, ultrastructure, and molecular phylogeny of the gymnodinioid dinoflagellate Barrufeta resplendens comb. nov., formerly known as Gyrodinium resplendens, isolated from the Gulf of Mexico. AB - In the present study, we redescribed Gyrodinium resplendens through incubation of process bearing cysts extracted from sediment collected in the northern Gulf of Mexico. The morphology and ultrastructure of the motile stage and cyst stage were examined using light microscopy, scanning electron microscopy, and transmission electron microscopy and this revealed that the species should be transferred to the genus Barrufeta. This genus differs from other gymnodinioid genera in possessing a Smurf-cap apical structure complex (ASC) and currently encompasses only one species, Barrufeta bravensis. B. resplendens shows a Smurf-cap ASC that consists of three rows of elongated vesicles with small knobs in the middle one. B. resplendens is very similar to B. bravensis in cell morphology, but can be separated using the ultrastructure such as the shape and location of nucleus and pyrenoids, which highlights the importance of ultrastructure at inter-specific level in the genus Barrufeta. The unique cysts of B. resplendens are brown and process bearing, and have a tremic archeopyle with a zigzag margin on the dorsal side of the epicyst, and not polar as in cysts of Polykrikos. The cysts do not survive the palynological treatment used here and probably have a wide distribution. Maximum-likelihood and Bayesian inference were carried out based on partial large subunit ribosomal DNA (LSU rDNA) sequences. Molecular phylogeny supports that the genus Barrufeta is monophyletic, and that the genus Gymnodinium is polyphyletic. Our results suggest that details of the ASC together with ultrastructure are potential features to subdivide the genus Gymnodinium. PMID- 26986894 TI - Taxonomic revision of oil-producing green algae, Chlorococcum oleofaciens (Volvocales, Chlorophyceae), and its relatives. AB - Historically, species in Volvocales were classified based primarily on morphology. Although the taxonomy of Chlamydomonas has been re-examined using a polyphasic approach including molecular phylogeny, that of Chlorococcum (Cc.), the largest coccoid genus in Volvocales, has yet to be reexamined. Six species thought to be synonymous with the oil-producing alga Cc. oleofaciens were previously not confirmed by molecular phylogeny. In this study, seven authentic strains of Cc. oleofaciens and its putative synonyms, along with 11 relatives, were examined based on the phylogeny of the 18S ribosomal RNA (rRNA) gene, comparisons of secondary structures of internal transcribed spacer 1 (ITS1) and ITS2 rDNA, and morphological observations by light microscopy. Seven 18S rRNA types were recognized among these strains and three were distantly related to Cc. oleofaciens. Comparisons of ITS rDNA structures suggested possible separation of the remaining four types into different species. Shapes of vegetative cells, thickness of the cell walls in old cultures, the size of cells in old cultures, and stigma morphology of zoospores also supported the 18S rRNA grouping. Based on these results, the 18 strains examined were reclassified into seven species. Among the putative synonyms, synonymy of Cc. oleofaciens, Cc. croceum, and Cc. granulosum was confirmed, and Cc. microstigmatum, Cc. rugosum, Cc. aquaticum, and Cc. nivale were distinguished from Cc. oleofaciens. Furthermore, another related strain is described as a new species, Macrochloris rubrioleum sp. nov. PMID- 26986895 TI - A new Eocene fossil of the genus Phycopeltis (Ulvophyceae, Chlorophyta). AB - A fossil of the aerophytic green algal genus Phycopeltis (Trentepohliaes, Ulvophyceae) dated to 35 Ma, is reported from the Pikopiko Fossil Forest, Southland, New Zealand. Previous reports of fossilized Phycopeltis have been subsequently synonymized with fungi by other authors; however, our specimen is not vulnerable to their criticisms. Inflated cells present in two approximately concentric rings are interpreted as gametangia, with irregular structures resembling the gametangial pores of modern material; sporophytic material is absent. The fossil resembles the modern disc-forming species P. novae-zelandiae, P. expansa, and P. arundinacea. The limited material available prevents the assignation of a specific epithet, but the habit and dimensions of the fossil clearly fall within those of modern representatives of the genus. Its single cell thickness throughout, absence of distinct melanization, and larger size demonstrate that it is not a fungal shield. The specimen constitutes arguably the most convincing fossil belonging to Trentepohliales, and the first unambiguously for the genus Phycopeltis. It is consistent in age with other known fossils of the order that, when combined with molecular evidence, suggests a terrestrial radiation far more recent than that of land plants. PMID- 26986896 TI - Correction to Obtaining Optical Purity for Product Diols in Enzyme-Catalyzed Epoxide Hydrolysis: Contributions from Changes in both Enantio- and Regioselectivity. PMID- 26986897 TI - Study of Molecular Conformation and Activity-Related Properties of Lipase Immobilized onto Core-Shell Structured Polyacrylic Acid-Coated Magnetic Silica Nanocomposite Particles. AB - A facile approach for the preparation of core-shell structured poly(acrylic acid) (PAA)-coated Fe3O4 cluster@SiO2 nanocomposite particles as the support materials for the lipase immobilization is reported. Low- or high-molecular-weight (1800 and 100,000, respectively) PAA molecules were covalently attached onto the surface of amine-functionalized magnetic silica nanoacomposite particles. The successful preparation of particles were verified by scanning transmission electron microscopy (STEM), X-ray diffraction (XRD), vibrating sample magnetometer (VSM), thermogravimetric analysis (TGA), zeta potential measurement, and Fourier-transform infrared (FTIR) techniques. Once lipase is covalently immobilized onto the particles with an average diameter of 210 +/- 50 nm, resulting from high binding sites concentrations on the low- and high-molecular weight PAA-coated particles, high lipase immobilization efficiencies (86.2% and 89.9%, respectively), and loading capacities (786 and 816 mg g(-1), respectively) are obtained. Results from circular dichroism (CD) analysis and catalytic activity tests reveal an increase in the beta-sheet content of lipase molecules upon immobilization, along with an enhancement in their activities and stabilities. The lipases immobilized onto the low- and high-molecular-weight PAA coated particles show maximum activities at 55 and 50 degrees C, respectively, which are ~28% and ~15% higher than that of the free lipase at its own optimum temperature (40 degrees C), respectively. The immobilized lipases exhibit excellent performance at broader temperature and pH ranges and high thermal and storage stabilities, as well as superior reusability. These prepared magnetic nanocomposite particles can be offered as suitable support materials for efficient immobilization of enzymes and improvement of the immobilized enzymes properties. PMID- 26986899 TI - Clinical Characteristics of Parotid Gland Sarcoidosis: A Population-Based Study. PMID- 26986898 TI - Characterizing the Epothilone Binding Site on beta-Tubulin by Photoaffinity Labeling: Identification of beta-Tubulin Peptides TARGSQQY and TSRGSQQY as Targets of an Epothilone Photoprobe for Polymerized Tubulin. AB - Photoaffinity labeling with an epothilone A photoprobe led to the identification of the beta-tubulin peptides TARGSQQY and TSRGSQQY as targets of the photoprobe for polymerized tubulin. These peptides represent residues 274-281 in different beta-tubulin isotypes. Placing the carbene producing 21-diazo/triazolo moiety of the photoprobe in the vicinity of the TARGSQQY peptide in a homology model of TBB3 predicted a binding pose and conformation of the photoprobe that are very similar to the ones reported for 1) the high resolution cocrystal structure of epothilone A with an alpha,beta-tubulin complex and for 2) a saturation transfer difference NMR and transferred NOESY NMR study of dimeric and polymerized tubulin. Our findings thus provide additional support for these models as physiologically the most relevant among several modes of binding that have been proposed for epothilone A in the taxane pocket of beta-tubulin. PMID- 26986901 TI - A window on the world. PMID- 26986902 TI - In the absence of clear evidence: substantiate all aspects of an issue. PMID- 26986900 TI - Transcription factor E2-2 inhibits the proliferation of endothelial progenitor cells by suppressing autophagy. AB - Endothelial progenitor cells (EPCs) play a key role in repairing the injured vascular endothelium by differentiating into mature endothelial cells (ECs) or secreting cytokines in a paracrine manner to promote proliferation of existing ECs. However, the mechanisms underlying the proliferation of EPCs were not fully understood. In order to investigate the mechanisms of EPC proliferation, we isolated EPCs from mononuclear cells of mouse spleens. By manipulating E2-2 expression in vitro, we observed that E2-2 negatively regulated the proliferation of EPCs. Moreover, we noted that E2-2 negatively regulated the autophagy of EPCs by studying the expression of LC3II and p62. We also demonstrated that an autophagy inhibitor chloroquine (CQ) decreased the proliferation of EPCs in a concentration-dependent manner. Interestingly, CQ reversed the increase in cell proliferation and autophagy in the E2-2 knockdown group. Furthermore, we detected the expression of autophagy-related protein ATG7 in EPCs which had been transfected with small interfering (siRNA)-E2-2 and siRNA-autophagy related 7 (ATG7) or were untransfected. Our study revealed that E2-2 regulated EPC autophagy via mediating ATG7 expression. We conclude that E2-2 inhibited EPC proliferation via suppressing their autophagy, and E2-2 regulated EPC autophagy by mediating the expression of ATG7. PMID- 26986903 TI - Smoking, vaping and public health: Time to be creative. AB - The development of policies on vaping in health care organizations (HCOs) needs to be based on a solid understanding of science and a recognition of individual rights. It should also be seen in the broader public health context of innovative alternative nicotine delivery systems playing a key role in ending the immense devastation of combustible cigarettes. Opposition to vaping based on inaccurate and incomplete information, or fear of unlikely and avoidable hypothetical unintended consequences, will invariably cause great harm to individuals, impede rather than assist the attainment of public health objectives, and unnecessarily prolong the epidemic of cigarette-caused diseases. PMID- 26986904 TI - Victimless vapour? Health care organizations should restrict the use of e cigarettes. AB - Electronic cigarettes (e-cigarettes) are battery-powered devices that heat a liquid containing either vegetable glycerin or propylene glycol in combination with nicotine and/or flavours; an aerosol is produced that is inhaled by the user. Health Canada currently prohibits the importation, marketing or selling of e-cigarettes containing nicotine, although they can be easily purchased. Because of the availability of e-cigarettes, patients and visitors to health care organizations (HCOs) are inquiring about their use within and on the grounds of those facilities. We contend that in provinces or municipalities where e cigarette use has not been restricted, HCOs should develop institutional policies to do so. We argue that the following reasons collectively justify measures to restrict the use of e-cigarettes within HCOs: unknown long-term safety, uncertain effectiveness in harm reduction, the conflict with the mission of HCOs to promote health, the potential negative health impacts on vulnerable patients with a compromised health status, and the risk of re-normalization of smoking. However, because of the rapidly developing evidence base in this area, HCOs should remain responsive to emerging evidence regarding the status of e-cigarettes as an effective harm reduction tool. PMID- 26986905 TI - Active Canada 20/20: A physical activity plan for Canada. AB - Physical inactivity is a pressing public health concern. In this commentary we argue that Canada's approach to increasing physical activity (PA) has been fragmented and has lacked coordination, funding and a strategic approach. We then describe a potential solution in Active Canada 20/20 (AC 20/20), which provides both a national plan and a commitment to action from non-government and public sectors with a view to engaging corporate Canada and the general public. It outlines a road map for initiating, coordinating and implementing proactive initiatives to address this prominent health risk factor. The identified actions are based on the best available evidence and have been endorsed by the majority of representatives in the relevant sectors. The next crucial steps are to engage all those involved in public health promotion, service provision and advocacy at the municipal, provincial and national levels in order to incorporate AC 20/20 principles into practice and planning and thus increase the PA level of every person in Canada. Further, governments, as well as the private, not-for-profit and philanthropic sectors, should demonstrate leadership and continue their efforts toward providing the substantial and sustained resources needed to recalibrate Canadians' habitual PA patterns; this will ultimately improve the overall health of our citizens. PMID- 26986906 TI - A common public health-oriented policy framework for cannabis, alcohol and tobacco in Canada? AB - Support for a public health approach to cannabis policy as an alternative to prohibition and criminalization is gaining momentum. Recent drug policy changes in the United States suggest growing political feasibility for legal regulation of cannabis in other North American jurisdictions. This commentary discusses the outcomes of an interdisciplinary policy meeting with Canadian experts and knowledge users in the area of substance use interventions. The meeting explored possibilities for applying cross-substance learning on policy interventions for alcohol, tobacco and cannabis, towards the goal of advancing a public health framework for reducing harms associated with substance use in Canada. The meeting also explored how the shift in approach to cannabis policy can provide an opportunity to explore potential changes in substance use policy more generally, especially in relation to tobacco and alcohol as legally regulated substances associated with a heavy burden of illness. Drawing from the contributions and debates arising from the policy meeting, this commentary identifies underlying principles and opportunities for learning from policy interventions across tobacco, alcohol and cannabis, as well as research gaps that need to be addressed before a public health framework can be effectively pursued across these substances. PMID- 26986908 TI - Prevalence and risk factors of asthma in First Nations children living on reserves in Canada. AB - OBJECTIVES: To explore the prevalence and determine the risk factors of asthma in First Nations children aged 0 to 11 years living on reserves in Canada. METHODS: In this cross-sectional study, we considered the data collected as part of the First Nations Regional Health Survey involving 6,657 children living in 238 First Nations communities in the 10 Canadian provinces, the Northwest Territories and the Yukon. RESULTS: The overall prevalence of asthma that has lasted or is expected to last at least six months (ever-asthma) among children living on reserves was 14.6%: a prevalence of 12.9% among 0 to 4 year olds and 15.6% among 5 to 11 year olds. The prevalence of ever-asthma was greater among boys (16.1%) than girls (13.2%). Children from homes with two or more children aged less than 11 years and those who were engaged in daily physical activities were less likely to have a report of ever-asthma. Children from high-income families and smoke free homes were more likely to have a report of ever-asthma. The association between allergy and ever-asthma was stronger in children with low birth weight. The association between chronic ear infections and ever-asthma was stronger in girls than boys. CONCLUSIONS: The overall prevalence of ever-asthma and factors associated with ever-asthma in First Nations children living on reserves were similar to those reported for off-reserve Aboriginal children and non-Aboriginal Canadian children. PMID- 26986909 TI - [Not Available]. AB - OBJECTIVES: Risky sexual behaviour associated with sexually transmitted infections (STI) and sexual harassment are important topics in university environments and public health. This article compares these behaviours between student cohorts in 2005 and 2012 from a Western Canadian university. The sexual habits of young adults with multiple partners are also examined. METHODS: Researchers conducted a comparative study of sexual behaviour among approximately 400 students per cohort. Estimates of prevalence and adjusted odds for age group and sex were used to analyze associations between the two cohorts and their sexual behaviours. RESULTS: Trends in sexual behaviour of young adults are maintained with respect to the proportion of those who are sexually active and their number of partners. A reduction in sexual harassment is observed, especially towards women. The condom remains the most frequently used method of contraception, but its use is erratic, particularly among respondents with multiple sexual partners. Drinking and the use of drugs predisposes to unplanned sexual relations and to non-use of means to prevent STIs and pregnancy, particularly among respondents with multiple sexual partners. CONCLUSIONS: The postsecondary student population should be informed of the risks associated with multiple sexual partners and alcohol and drug consumption leading to unplanned sexual acts. A sexual harassment policy contributes to reduction of incidents of harassment within a postsecondary institution. PMID- 26986907 TI - Mandatory labeling requirements and over-the-counter cough and cold medication use in early childhood. AB - OBJECTIVES: Due to rare but severe adverse events, Health Canada in October 2009 required manufacturers to relabel over-the-counter (OTC) cough and cold medication (CCM) to state that the products should not be used in children <6 years of age. The main objective of this study was to determine whether this labeling standard decreased OTC CCM use among young children with a recent cough, cold or flu. METHODS: An interrupted time series study was conducted using data from the TARGet Kids! practice-based research network. A total of 3,515 healthy children 1-5 years of age were recruited from 2008-2011; of these, 1,072 had a cough, cold or flu in the previous month. Parents completed a standardized survey instrument. For the primary analysis, use of OTC CCMs prior to and after October 1, 2009 was compared using time series analyses. For the secondary analysis, multivariable logistic regression was used to identify predictors of recent OTC CCM use. RESULTS: OTC CCM use was reported in 222 of 1,072 (20.7%) children with a cough, cold or flu within the previous month. OTC CCM use declined from 22.2% to 17.8% following the October 2009 Health Canada labeling standard (p = 0.014). Maternal age <35 years (OR 1.49; 95% CI: 1.05-2.13) and having older siblings (OR 1.65; 95% CI: 1.16-2.35) were independently associated with OTC CCM use. CONCLUSION: Labeling legislation against OTC CCM use for children <6 years resulted in a small decrease in OTC CCM use. Stronger measures may be needed to curtail OTC CCM use, particularly for younger parents and those with multiple children. PMID- 26986910 TI - Investigation of anxiety and depression symptom co-morbidity in a community sample with type 2 diabetes: Associations with indicators of self-care. AB - OBJECTIVES: Ascertain the association of elevated co-occurring anxiety and depression symptoms, elevated anxiety symptoms alone or elevated depression symptoms alone with indicators of self-care behaviours in people with type 2 diabetes. METHODS: Data from a community sample of 1,990 people diagnosed with type 2 diabetes for less than 10 years were assessed. All participants took part in a telephone interview. Questionnaires examined depression, anxiety, health, and indicators of self-care (physical activity, blood glucose monitoring, diet and smoking). Data were assessed with cross tabulations, ANOVA and logistic regression. RESULTS: Groups who met criteria for elevated co-occurring anxiety and depression symptoms, elevated anxiety symptoms and elevated depression symptoms were more likely to report poor eating habits. Meeting criteria for either elevated depression symptoms (with and without anxiety) was also associated with an increased likelihood of not meeting physical activity recommendations. Those people with elevated depression and anxiety scores were more likely to be a current smoker. CONCLUSIONS: Those people who meet criteria for elevated anxiety and/or depression symptoms are less likely to report adhering to self-care recommendations. These associations are particularly marked in those people with elevated depression symptoms with or without co-occurring anxiety symptoms. There is a lot of evidence emphasising the importance of monitoring depressive symptoms in people with diabetes. Our results add to this, indicating that adherence to self-care recommendations should be carefully monitored in people with depression and anxiety symptoms. PMID- 26986911 TI - An investigation of the healthy migrant hypothesis: Pre-emigration characteristics of those in the British 1946 birth cohort study. AB - OBJECTIVES: The finding that migrants to high-income countries have lower rates of morbidity and mortality than non-migrants, controlling for socioeconomic position, is often attributed to the "healthy migrant" hypothesis, which suggests that only the healthiest individuals choose to migrate. This prospective study investigates the healthy migrant hypothesis in a cohort of British emigrants using pre-migration health indicators. We also investigate how early-life health characteristics relate to age at emigration and whether or not the emigrant returned home. METHODS: Data are from the Medical Research Council National Survey of Health and Development, a nationally representative cohort study of people born in England, Scotland or Wales in March 1946. Childhood socio-economic position, health and cognitive ability were compared between 4,378 non-emigrants and 984 emigrants. Of the emigrants, 427 emigrated before age 20 and 557 after that age; 602 emigrants remained abroad and 382 returned home. RESULTS: Emigrants had better childhood health (especially greater height), higher childhood socio economic position and better childhood cognitive ability at age 8 than non emigrants. Return emigrants were very similar to emigrants who remained abroad. CONCLUSIONS: We found support for the healthy migrant hypothesis in a cohort of British emigrants. Our findings improve an understanding of how health is distributed within and across nations. PMID- 26986912 TI - Folate status of women in Toronto: Implications of folate fortification and supplementation. AB - OBJECTIVES: To assess the percentage of women of childbearing age with suboptimal levels of folate for protecting against neural tube defects (<906 nM), and assess folate status among the elderly. METHODS: A total of 1,035 anonymous blood samples from a centralized clinical laboratory, with a catchment area across the Greater Toronto Area, were assessed for red blood cell (RBC) folate concentrations using a chemiluminescent immunoassay. Folate analysis was requested by physicians as part of clinical care. Available data included age, sex, and RBC folate concentration. Descriptive statistics were used to characterize the percent of women who had suboptimal blood folate concentrations, and a multiple regression was used to analyze determinants of folate status. RESULTS: Our data from 2013 show that 7% of women of childbearing age (15-45 years) had RBC folate concentrations below 906 nM, a substantially lower percentage than in our 2006 study (40%). Results from the multiple regression showed that age is a significant positive predictor of higher RBC folate status (p < 0.001). CONCLUSION: Compared to our earlier data, we report a significant decrease in the suboptimal folate status among women of childbearing age. We also show that age is a predictor of higher RBC folate levels. Our data are limited due to a lack of information regarding patient or physician characteristics, and to the nature of our sample, yet our results are consistent with the continued increase in folate status observed among several population-level studies in the US and Canada post-fortification. Further research is needed to determine the reasons for and future implications of this continued increase in the elderly. PMID- 26986913 TI - Ten-year trends in overweight/obesity among Ontario middle and high school students and their use in establishing baseline measures for government reduction targets. AB - OBJECTIVES: Public health concern about increasing levels of child/youth overweight and obesity has resulted in initiatives to address this issue. In 2012, the Ontario Ministry of Health and Long-Term Care (MOHLTC) established a target to reduce childhood obesity by 20% within five years. In this paper, we examine trends and establish baseline levels of overweight/obesity to assess the impacts of population-level interventions. METHODS: We analyzed 10 years (2003 2013) of data accumulated from six cycles of the Ontario Student Drug Use and Health Survey using logistic regression to assess trends in the prevalence of overweight/obesity among middle and high school students. The 2013 data are used to begin monitoring progress toward achieving the MOHLTC target. RESULTS: From 2003 through 2013, the prevalence of overweight/obesity among middle school students in the province remained stable overall and among all subgroups except 7th-grade females, who showed a significant linear decline. Among high school students, the prevalence of overweight/obesity showed a significant linear increase and an increase among 11th graders, females, and 10th- and 11th-grade females specifically. The prevalence remained stable but elevated among 9th- and 12th-grade females as well as among males in all grades. In 2013 (baseline for the MOHLTC target), 25.1% of students in grades 7-12 were overweight or obese, implying a presumed 2018 target of 20.1%. CONCLUSION: Ten-year trends in overweight/obesity indicate stability among males and significant linear increases in some female subgroups. Also, baseline data (2013) will facilitate the monitoring of future interventions aimed at achieving the 2018 MOHLTC target. PMID- 26986914 TI - Food safety knowledge, attitudes and self-reported practices among Ontario high school students. AB - OBJECTIVES: To measure the food safety knowledge, attitudes and self-reported practices of high school students in Ontario. METHODS: We administered a school wide paper survey to the student body (n = 2,860) of four Ontario high schools. We developed the survey by selecting questions from existing, validated questionnaires, prioritizing questions that aligned with the Canadian Partnership for Consumer Food Safety Education's educational messages and the food safety objectives from the 2013 Ontario High School Curriculum. RESULTS: One in five students reported currently handling food in commercial or public-serving venues; of these, 45.1% had ever taken a course that taught them how to prepare food (e.g., food and nutrition classes, food handler certification). Food safety knowledge among respondents was low. For example, 17.3% knew that the best way to determine whether hamburgers were cooked enough to eat was to measure the temperature with a food thermometer. Despite low knowledge, most respondents (72.7%) reported being confident that they could cook safe, healthy meals for themselves and their families. Safe food handling practices were frequently self reported. Most students (86.5%) agreed that being able to cook safe, healthy meals was an important life skill, although their interest in learning about safe food handling and concern about foodborne disease were less pronounced. CONCLUSION: Our findings suggest that food safety knowledge is low, yet confidence in preparing safe, healthy meals is high, among high school students. Because work and volunteer opportunities put students in contact with both the public and food, this group is important to target for increased education about safe food handling. PMID- 26986915 TI - [Not Available]. AB - OBJECTIVE: To understand parents' representations based on their own lived experiences and their influence on the decision to vaccinate their children. METHODS: This was a qualitative, in-depth, phenomenological study using semi structured interviews with 14 volunteer parents who have children age-eligible for vaccination. The participants were recruited through family doctors in the Montpellier region (France). The methodology is modeled on grounded theory. The data, collected by audio recording, were analyzed using a semio-pragmatic method that brought forth conceptual categories giving meaning to the phenomenon being studied. RESULTS: Parents are unaware of the diseases for which there are vaccines and express a need for information. A perception of the inequality of the individual in face of the disease and the vaccine greatly influences the parents' vaccination decision. It induces in them a reasoned "sifting" of vaccines and leads them to strike a risk/benefit balance. They trust more in their doctor and their personal experience than in publicized information. CONCLUSION: Parents' lack of awareness of diseases, even those for which immunization exists, would suggest a need to better inform parents on this matter. Their perception of the inequality of the individual (their child) in face of the disease and the vaccine is the main determinant in their decision to vaccinate. Parents approach immunization in a thoughtful educated way, influenced by such factors as lifestyle, personal experiences and confidence in their doctor. These results make them very "critical" with regard to basic vaccination recommendations. PMID- 26986916 TI - Understanding young bisexual women's sexual, reproductive and mental health through syndemic theory. AB - OBJECTIVES: We sought to understand how young bisexual women in Toronto perceive their sexual and reproductive health needs, the challenges to achieving those needs, and the factors contributing both positively and negatively to their sexual and reproductive health. METHODS: We conducted a community-based research project that included an advisory committee of young bisexual women, academic partners, and a community health centre. Four 2-hour focus group sessions were conducted with a total of 35 participants. Data were analyzed through a constructivist grounded theory approach using Nvivo software. RESULTS: Participants' discussion of their sexual and reproductive health indicated that they perceived social marginalization, particularly biphobia and monosexism, as a significant challenge to their health. Participants also discussed their sexual, reproductive and mental health as interconnected. CONCLUSIONS: Young bisexual women in this study perceived their sexual, reproductive and mental health as interconnected and negatively influenced by social marginalization. This perception is in line with syndemic research that illustrates the interrelationship between psychosocial and sexual health. Researchers should further explore the utility of syndemic theory in understanding the complexity of young bisexual women's health. PMID- 26986917 TI - Low-income working immigrant families in Quebec: Exploring their challenges to well-being. AB - OBJECTIVES: To identify low-income working families' health challenges and understand their barriers and facilitators to navigating those challenges. METHODS: We conducted a focused ethnographic study in a food bank in Montreal, Quebec. Using purposeful sampling, we recruited participants who had at least one employed family member and one live-in child. Sensitizing concepts included social determinants of health (SDH) and family strengths. Participant observation, focus groups and in-depth interviews constituted the primary means of data collection. Thematic and contextual analyses were conducted iteratively. RESULTS: We recruited 25 participants, 22 clients (15 women and 7 men with up to 5 children per family) and 3 members of staff. All clients were immigrants, having been in Canada for a range of 2 months to 23 years, thus reflecting the ethnic demography of the site. Families described health as physical, mental and socio-cultural well-being. Challenges to well-being included insufficient finances, non-standard work, hurdles in professional equivalency, isolation, children's acculturation, inadequate access to health care and the Canadian winter. Personal and structural barriers and facilitators to navigating challenges centred on parents' sense of the challenges being finite, control over discrete dimensions of life and hope of children's future success. Families who incorporated these perceptions into their narratives seemed to describe the challenges as navigable. Importantly, the SDH model did not anticipate the degree to which challenges would be defined by immigration factors. CONCLUSION: In order to help low-income working immigrant families face diverse challenges to well being, community workers and policy-makers must consider the specific challenges of immigration and the importance of individual families' outlooks as they navigate them. PMID- 26986918 TI - The health of temporary foreign workers in Canada: A scoping review. AB - OBJECTIVES: Temporary foreign workers contribute to economic prosperity in Canada, but they experience forms of structural inequities and have minimal rights, which can contribute to their ill health. The objective of this scoping review is to examine the extent, range and nature of the Canadian literature on the health of temporary foreign workers and their families in Canada. METHODS: The review was guided by Arksey and O'Malley's five stages for conducting a scoping review. We performed a comprehensive search of seven databases, which revealed 994 studies. In total, 10 published research papers, which focused exclusively on the health of temporary foreign workers in Canada, were included in the study; these 10 papers represented the findings from 9 studies. SYNTHESIS: The majority of the studies involved seasonal agricultural workers in the province of Ontario (n = 8). Major health issues of temporary foreign workers included mental health, occupational health, poor housing and sanitation, and barriers to accessing health care, including fear of deportation and language barriers. These health issues are highly shaped by temporary foreign workers' precarious immigration status in Canada. CONCLUSION: Findings from this study demonstrate the need to reduce barriers to health care and to conduct more research on other groups of temporary foreign workers, outside the agricultural sector. PMID- 26986919 TI - Parents and Tots Together: Pilot randomized controlled trial of a family-based obesity prevention intervention in Canada. AB - OBJECTIVE: To test the feasibility, acceptability and preliminary impact of Parents and Tots Together (PTT), a family-based obesity prevention intervention, in Canada. PARTICIPANTS: Canadian parents of preschoolers (aged 2-5 years). SETTING: Ontario Early Years centres in southwestern Ontario. INTERVENTION: A pilot randomized controlled trial involving 48 parents who received either the PTT intervention (n = 27) or an attention-matched control home safety intervention (n = 21). To evaluate the feasibility of PTT, we assessed participant retention and outcome evaluation completion rates. To evaluate acceptability, we assessed program attendance and parents' responses to program satisfaction surveys. To evaluate preliminary impact, we assessed children's body mass index (BMI) at baseline, after intervention (end of 9-week intervention) and at 9-month follow-up. As well, at each time point, parents completed surveys assessing stress and self-efficacy related to parenting, children's sleep, activity, TV viewing and diet. OUTCOMES: Retention rates were high in the intervention (93%) and control (84%) study arms, and 87% of parents reported that they would highly recommend PTT to a friend. At 9-month follow-up, intervention parents reported lower parenting stress (beta^ = 15.83, 95% confidence interval [CI] -29.57, -2.07, p = 0.02) and greater self-efficacy in managing their child's behaviour (beta^ = 0.16, 95% CI 0.002, 0.33, p = 0.05) than control parents. PTT had minimal influence on children's weight-related behaviours and BMI. CONCLUSIONS: The results suggest that PTT can feasibly be implemented and tested in the Canadian context. Preliminary impact results suggest that the program may be effective in changing general parenting; however, program content should be modified to adequately address children's weight-related behaviours. PMID- 26986920 TI - Pregnancy Physical Activity Questionnaire. PMID- 26986921 TI - Reasons for non-timely completion of the routine infant immunization schedule by children in rural South West Uganda. PMID- 26986923 TI - The Value of PD-L1 Testing in Non-Small-Cell Lung Cancer. PMID- 26986922 TI - The contribution to mothers' health by village health team promotion practices: A case study of Kyabugimbi subcounty Bushenyi District. PMID- 26986924 TI - Physiologically based pharmacokinetic model of docetaxel and interspecies scaling: comparison of simple injection with folate receptor-targeting amphiphilic copolymer-modified liposomes. AB - 1. To compare the disposition of docetaxel (DTX) in male/female rats after intravenous administration of simple injection and folate-poly(PEG-cyanoacrylate co-cholesteryl cyanoacrylate)-modified liposomes utilising a physiologically based pharmacokinetic (PBPK) modelling method, and extrapolate this model to mice and humans by taking into account the interspecies differences in physiological- and chemical-specific parameters. 2. Four structural models for single organs were evaluated, and the whole-body PBPK model included artery, vein, lung, brain, heart, spleen, liver, gastrointestinal tract, kidney, muscle and remainder compartment. 3. Rats following modified liposomes administration were characterised by significant decrease in the partition coefficients for brain, spleen, liver and remainder compartment. The blood-to-plasma partition coefficient also decreased significantly, while a marked rise of partition coefficients for lung, kidney and muscle was revealed. Partition coefficient for heart was approximately 1.3-fold higher in females than males, while the decrease of intestinal clearance was revealed in females compared to males. The final model successfully characterised the time course of DTX in rats, mice and humans. 4. This PBPK model is beneficial to the prediction of the effects of DTX in different species. It also represented a platform to encompass both formulation- and sex-related effects on DTX disposition and elimination in the future. PMID- 26986926 TI - Phenethyl isothiocyanate induces apoptosis and inhibits cell proliferation and invasion in Hep-2 laryngeal cancer cells. AB - The dietary compound phenethyl isothiocyanate (PEITC), an important tumoricidal component found in cruciferous vegetables, exhibits strong anticancer and chemopreventive effects in a variety of tumors. However, its role in human laryngeal cancer is unclear. The aim of the present study was to investigate whether PEITC exhibits anticancer properties in human laryngeal carcinoma Hep-2 cells in vitro and to identify the potential molecular mechanisms. The results showed that treatment of Hep-2 cells with PEITC significantly inhibited cell proliferation in a dose- and time-dependent manner, promoted apoptosis with concurrent G2/M cell cycle arrest and inhibited cell invasion in a dose-dependent manner. These effects were accompanied by significant alterations in the expression levels of key proteins associated with pro-survival signaling pathways, including PI3K, Akt, ERK, NF-kappaB, Bcl, Bax, cyclin B, CDK4 and CDK6. Importantly, these effects were not reflected in 16HBE normal human bronchial epithelial cells, suggesting a safe range of treatment concentrations between 0 and 10 uM PEITC. In summary, PEITC exhibited significant anticancer effects against human laryngeal cancer cells in vitro with low toxicological impact on normal bronchial epithelial cells. This was achieved through dysregulation of key proteins involved in the occurrence and development of tumors, thereby offering a valuable contribution to future strategies for the treatment and screening of patients with laryngocarcinoma. PMID- 26986927 TI - Clinical significance of an easy-to-use dual task for assessing inattention. AB - Purpose To investigate clinical significance of a newly developed paper-and pencil type dual-task (Oiso-DT) for assessing inattention of brain-damaged patients. Methods A total of 134 healthy individuals and 44 patients with traumatic brain injury (TBI) were the subjects. Oiso-DT combined a cancelation sub-task and a written calculation sub-task on paper. The performance was scored based on the correct rate (CR) and success rate in the cancelation sub-task, and the number of correct answers and CR in the calculation sub-task for three minutes. Performances of Clinical Assessment for Attention (CAT) developed by The Japan Society for Higher Brain Dysfunction were also measured in TBI patients. Results Based on a simple and unique definition of cutoff values, abnormal performance was detected more often in the Oiso-DT than in any sub-task of CAT including Symbol Digit Modalities Test, The Memory Updating Test and Paced Auditory Serial Addition Task, etc. although the specificity was comparable. Conclusion This easy-to-use Oiso-DT might be valuable and sensitive for detecting inattention including mild deficit. Implications for Rehabilitation The Oiso-DT, a paper-and-pencil clinical test for assessing inattention demonstrates higher sensitivity for traumatic-brain-injury patients than standard neuropsychological tests. The task performance is evaluated by a simple and unique method without specific equipment or even a personal computer. The Oiso-DT might be valuable for detecting inattention including mild deficit. The Oiso-DT is easily applicable to patients with severe inattention who failed to complete complex tasks like paced auditory serial addition task. PMID- 26986928 TI - Our panel of experts highlight the most important research articles across the spectrum of topics relevant to the field of regenerative medicine. PMID- 26986925 TI - Novel indolyl-chalcones target stathmin to induce cancer cell death. AB - Efficacy of current therapies for advanced and metastatic cancers remains a challenge in clinical practice. We investigated the anti-cancer potency of 3 novel indoly-chalcones (CITs). Our results indicated the lead molecule CIT-026 (Formula = C20H16FNO) induced cell death in prostate and lung cancer cell lines at sub-micromolar concentration. CITs (CIT-026, CIT-214, CIT-223) lead to microtubule destabilization, cell death and low cell proliferation, which in part was dependent on stathmin (STMN1) expression. Knockdown of STMN1 with siRNA against STMN1 in part restored viability of cancer cells in response to CITs. Further, CIT-026 and CIT-223 blocked cancer cell invasion through matrigel-coated chambers. Mechanistically, CITs inhibited phosphorylation of STMN1 leading to STMN1 accumulation and mitotic catastrophe. In summary, we have synthetized novel anti-cancer CIT molecules and defined their mechanism of action in vitro. PMID- 26986929 TI - Toxicity of canavanine in tomato (Solanum lycopersicum L.) roots is due to alterations in RNS, ROS and auxin levels. AB - Canavanine (CAN) is non-proteinogenic aminoacid and a structural analog of arginine (Arg). Naturally, CAN occurs in legumes e.g. jack bean and is considered as a strong allelochemical. As a selective inhibitor of inducible nitric oxide synthase in mammalians, it could act as a modifier of nitric oxide (NO) concentration in plants. Modifications in the content of endogenous reactive nitrogen species (RNS) and reactive oxygen species (ROS) influence root structure and architecture, being also under hormonal control. The aim of the work was to investigate regulation of root growth in tomato (Solanum lycopersicum L. cv. Malinowy Ozarowski) seedling by application of CAN at concentration (10 and 50 MUM) leading to 50% or 100% restriction of root elongation. CAN at higher concentration led to slight DNA fragmentation, increased total RNA and protein level. Decline in total respiration rate after CAN supplementation was not associated with enhanced membrane permeability. Malformations in root morphology (shorter and thicker roots, limited number of lateral roots) were accompanied by modification in NO and ONOO(-) localization; determined mainly in peridermal cells and some border cells. Although, CAN resulted in low RNS production, addition of exogenous NO by usage of NO donors did not reverse its negative effect, nor recovery effect was detected after roots imbibition in Arg. To build up a comprehensive view on mode of action of CAN as root growth inhibitor, it was shown an elevated level of auxin. To summarize, we demonstrated several secondary mode of action of CAN, indicating its toxicity in plants linked to restriction in RNS formation accompanied by simultaneous overaccumulation of ROS. PMID- 26986930 TI - Salt-responsive mechanisms in chromosome segment substitution lines of rice (Oryza sativa L. cv. KDML105). AB - Two chromosome segment substitution lines of Khao Dawk Mali 105 (KDML105) rice that carry quantitative trait loci for drought tolerance located on chromosome 8 (DT-QTL8) designated CSSL8-94 and CSSL8-116 were investigated for co-expression network and physiological responses to salinity compared to their parents (KDML105; drought and salt sensitive recurrent parent, and DH103; drought tolerant QTL donor). These CSSL lines show different salt-response traits under salt stress (CSSL8-94 shows higher tolerance than CSSL8-116) and possess different segments of DT-QTL8. To identify specific biological process(es) associated with salt-stress response, co-expression network analysis was constructed from each DT-QTL segment. To evaluate differential physiological mechanisms responding to salt stress, all rice lines/cultivar were grown for 21 d in soils submerged in nutrient solutions, then subjected to 150 mM NaCl for 7 d. Physiological parameters related to co-expression network analysis (photosynthetic parameters) and salt responsive parameters (Na(+)/K(+) ratio, proline content, malondialdehyde and ascorbate peroxidase activity; EC1.11.1.1) were investigated along with the expression analysis of related genes. Physiological responses under salt stress particularly photosynthesis-related parameters of CSSL8-94 were similar to DH103, whereas those of CSSL8-116 were similar to KDML105. Moreover, expression levels of photosynthesis-related genes selected from the co-expression networks (Os08g41460, Os08g44680, Os06g01850, Os03g07300 and Os02g42570) were slightly decreased or stable in CSSL8-94 and DH103 but were dramatically down-regulated in CSSL8-116 and KDML105. These differential responses may contribute to the photosynthesis systems of CSSL8-94 being less damaged under salt stress in comparison to those of CSSL8-116. It can be concluded that the presence of the specific DT-QTL8 segment in CSSL8-94 not only confers drought tolerant traits but also enhances its salt tolerant ability. PMID- 26986931 TI - Genome-wide characterization and comparative analysis of the MLO gene family in cotton. AB - In plants, MLO (Mildew Locus O) gene encodes a plant-specific seven transmembrane (TM) domain protein involved in several cellular processes, including susceptibility to powdery mildew (PM). In this study, a genome-wide characterization of the MLO gene family in G. raimondii L., G. arboreum L. and G. hirsutum L. was performed. In total, 22, 17 and 38 homologous sequences were identified for each species, respectively. Gene organization, including chromosomal location, gene clustering and gene duplication, was investigated. Homologues related to PM susceptibility in upland cotton were inferred by phylogenetic relationships with functionally characterized MLO proteins. To conduct a comparative analysis between MLO candidate genes from G. raimondii L., G. arboreum L. and G. hirsutum L., orthologous relationships and conserved synteny blocks were constructed. The transcriptional variation of 38 GhMLO genes in response to exogenous application of salt, mannitol (Man), abscisic acid (ABA), ethylene (ETH), jasmonic acid (JA) and salicylic acid (SA) was monitored. Further studies should be conducted to elucidate the functions of MLO genes in PM susceptibility and phytohormone signalling pathways. PMID- 26986932 TI - Preparation, characterization and pharmacokinetic studies of linalool-loaded nanostructured lipid carriers. AB - Context Linalool (LL) is associated with numerous pharmacological activities. However, its poor solubility usually results in poor bioavailability, and further limited its applications. Objective To reduce volatilization and improve bioavailability of LL, linalool-loaded nanostructured lipid carriers (LL-NLCs) were prepared. Materials and methods LL-NLCs were prepared using high-pressure homogenization method and optimized via response surface methodology-central composite design, followed by characterization, including particle size (PS), zeta potential (ZP), transmission electron microscope (TEM), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and in vitro release study. Rats were administered 300 mg * kg (-) (1) LL with each preparation (LL-NLCs or LL) via oral gavage. Results LL-NLCs had a PS of 52.72 nm with polydispersity index of 0.172, and ZP of -16.0 mV. The encapsulation efficiency and drug loading gave 79.563 and 7.555%, respectively. The cumulative release of LL from free LL reached 51.414% at 180 min, while LL from LL-NLCs was 15.564%. All the pharmacokinetics parameters of LL-NLCs were better than those of LL, including Cmax (from 1915.45 to 2182.45 ng * mL (-) (1)), AUC0-t (from 76003.40 to 298948.46 ng * min * mL (-) (1)) and relative bioavailability (393.34%). The t1/2, MRT and tmax of LL-NLCs (110.50, 146.66 and 60 min) were also longer than that of LL (44.72, 45.66 and 40 min). Discussion and conclusion LL-NLCs were for the first time prepared and its oral administration in rats thoroughly investigated. LL-NLCs exhibited sustained release effect and increased absorption of LL. Therefore, these findings might provide a potential possibility for clinical application of LL. PMID- 26986933 TI - A Detailed Study on the Low-Energy Structures of Charged Colloidal Clusters. AB - The target of this investigation is the systematic characterization of the low energy structures of charged colloidal clusters that may be important to understand the self-assembling process of biomolecules. The aggregation of charged colloidal particles is governed by the attractive short-ranged Morse potential and the Yukawa repulsive tail to describe the long-range charge effect. A global optimization strategy, based on our own evolutionary algorithm, was adopted to discover the low-energy structures of colloidal clusters composed of up to 20 particles. A detailed analysis of the low-energy structures involving charged particles shows that the appearance of the Bernal spiral as the most stable motif occurs, first, at N = 6, but it is favored for larger clusters (N >= 13); for 6 <= N <= 12, there is a competition between the spiral (which is favored for higher charges) and more spherical-like structures. Finally, we study binary clusters composed by two sets of differently charged colloidal particles. Although a great diversity of low-energy structures is observed (especially for aggregates with one of the components in excess), the global minimum is disputed by three structural motifs depending on the composition of the cluster and, in some cases, on the range of the Morse potential. PMID- 26986936 TI - Spontaneous Oxygenation of Siloxy-N-silylketenimines to alpha-Ketoamides. AB - Siloxy-N-silylketenimines generated in situ from O-silyl cyanohydrins were converted to alpha-ketoamides by brief exposure to air or oxygen. Oxidation under extremely mild conditions can be explained by assuming the intermediacy of a 3 imino-1,2-dioxetane derivative generated via triplet-singlet intersystem crossing after the reaction of siloxy-N-silylketenimines with triplet oxygen. PMID- 26986935 TI - Conformation-specific anti-Mad2 monoclonal antibodies for the dissection of checkpoint signaling. AB - The spindle assembly checkpoint (SAC) ensures accurate chromosome segregation during mitosis by delaying the activation of the anaphase-promoting complex/cyclosome (APC/C) in response to unattached kinetochores. The Mad2 protein is essential for a functional checkpoint because it binds directly to Cdc20, the mitotic co-activator of the APC/C, thereby inhibiting progression into anaphase. Mad2 exists in at least 2 different conformations, open-Mad2 (O-Mad2) and closed-Mad2 (C-Mad2), with the latter representing the active form that is able to bind Cdc20. Our ability to dissect Mad2 biology in vivo is limited by the absence of monoclonal antibodies (mAbs) useful for recognizing the different conformations of Mad2. Here, we describe and extensively characterize mAbs specific for either O-Mad2 or C-Mad2, as well as a pan-Mad2 antibody, and use these to investigate the different Mad2 complexes present in mitotic cells. Our antibodies validate current Mad2 models but also suggest that O-Mad2 can associate with checkpoint complexes, most likely through dimerization with C Mad2. Furthermore, we investigate the makeup of checkpoint complexes bound to the APC/C, which indicate the presence of both Cdc20-BubR1-Bub3 and Mad2-Cdc20-BubR1 Bub3 complexes, with Cdc20 being ubiquitinated in both. Thus, our defined mAbs provide insight into checkpoint signaling and provide useful tools for future research on Mad2 function and regulation. PMID- 26986937 TI - [Adverse prognostic factors for preeclampsia in Madagascar]. AB - INTRODUCTION: Hypertensive disorders of pregnancy are serious diseases that cause high rates of maternal and fetal morbidity and mortality. Our goal was to determine the epidemiological, clinical, and laboratory findings associated with complications in these patients after the onset of hypertension. METHODS: This retrospective analytical study examined the files of women with hypertension who delivered at the Hospital of Gynecology Obstetrics in Befelatanana, Madagascar, in 2008-2010. RESULTS: During this four-year study period, 1320 women giving birth at our center had been hypertensive during pregnancy, for a prevalence of 5.11%; 409 (30.98%) had preeclampsia. The main maternal complications were eclampsia (14.46%), renal failure (3.40%), maternal death (3.03%), and placental abruption (2.95%). For the fetus, maternal preeclampsia was complicated by preterm birth (35.07%), perinatal death (21.42%), perinatal asphyxia (14.50%), and fetal growth restriction (9.71%). Patients younger than 20 years were at the highest risk of eclampsia (RR 2.18, 95% CI [(1.83 to 3.75]). Primiparity and history of eclampsia or fetal growth restriction were risk factors for eclampsia. Hyperproteinuria and elevated serum creatinine concentrations were associated with adverse fetal outcome. Isolated hyperuricemia was not associated with outcome. CONCLUSION: When preeclampsia has been diagnosed, some aspects of obstetric history and impaired kidney function are poor prognostic factors that can require early emergency delivery. PMID- 26986934 TI - Genetic biomarkers of drug response for small-molecule therapeutics targeting the RTK/Ras/PI3K, p53 or Rb pathway in glioblastoma. AB - Glioblastoma is the most deadly and frequently occurring primary malignant tumor of the central nervous system. Genomic studies have shown that mutated oncogenes and tumor suppressor genes in glioblastoma mainly occur in three pathways: the RTK/Ras/PI3K signaling, the p53 and the Rb pathways. In this review, we summarize the modulatory effects of genetic aberrations in these three pathways to drugs targeting these specific pathways. We also provide an overview of the preclinical efforts made to identify genetic biomarkers of response and resistance. Knowledge of biomarkers will finally promote patient stratification in clinical trials, a prerequisite for trial design in the era of precision medicine. PMID- 26986939 TI - Flashes, Floaters, and an Unfamiliar Fundus. PMID- 26986938 TI - Spatial Control of Laser-Induced Doping Profiles in Graphene on Hexagonal Boron Nitride. AB - We present a method to create and erase spatially resolved doping profiles in graphene-hexagonal boron nitride heterostructures. The technique is based on photoinduced doping by a focused laser beam and does neither require masks nor photoresists. This makes our technique interesting for rapid prototyping of unconventional electronic device schemes, where the spatial resolution of the rewritable, long-term stable doping profiles is limited by only the laser spot size (~600 nm) and the accuracy of sample positioning. Our optical doping method offers a way to implement and to test different, complex doping patterns in one and the very same graphene device, which is not achievable with conventional gating techniques. PMID- 26986940 TI - 2015 Reviewers. PMID- 26986941 TI - Silberman School of Social Work, Hunter College, City University of New York, Mourns the Loss of the Beloved Dr. Rose Dobrof. PMID- 26986942 TI - Establishment of an effective TLC bioautographic method for the detection of Mycobacterium tuberculosis H37Ra phosphoglucose isomerase inhibition by phosphoenolpyruvate. AB - A bioautographic assay based on thin layer chromatography was developed for phosphoenolpyruvate (PEP) detecting as a known but rarely studied inhibitor of phosphoglucose isomerase (PGI). The protocol with NADP(+)/NBT/PMS (beta nicotinamide adenine dinucleotide phosphate/nitrotetrazolium blue chloride/phenazine methosulfate) staining was capable of detecting Mycobacterium tuberculosis H37Ra PGI inhibition using PEP. According to this method, visibly brighter spots (zones) against purple background are observed in the area of inhibition of the above-mentioned enzyme activity. The detection limit for PEP as an inhibitor of Mycobacterium tuberculosis H37Ra PGI was 226 MUg per spot/zone. Noteworthy is that we are the first authors to have successfully used a bioautographic assay to detect Mycobacterium tuberculosis H37Ra PGI inhibition by PEP. PMID- 26986943 TI - Clinical-Radiological Parameters Improve the Prediction of the Thrombolysis Time Window by Both MRI Signal Intensities and DWI-FLAIR Mismatch. AB - BACKGROUND: With regard to acute stroke, patients with unknown time from stroke onset are not eligible for thrombolysis. Quantitative diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) MRI relative signal intensity (rSI) biomarkers have been introduced to predict eligibility for thrombolysis, but have shown heterogeneous results in the past. In the present work, we investigated whether the inclusion of easily obtainable clinical radiological parameters would improve the prediction of the thrombolysis time window by rSIs and compared their performance to the visual DWI-FLAIR mismatch. METHODS: In a retrospective study, patients from 2 centers with proven stroke with onset <12 h were included. The DWI lesion was segmented and overlaid on ADC and FLAIR images. rSI mean and SD, were calculated as follows: (mean ROI value/mean value of the unaffected hemisphere). Additionally, the visual DWI FLAIR mismatch was evaluated. Prediction of the thrombolysis time window was evaluated by the area-under-the-curve (AUC) derived from receiver operating characteristic (ROC) curve analysis. Factors such as the association of age, National Institutes of Health Stroke Scale, MRI field strength, lesion size, vessel occlusion and Wahlund-Score with rSI were investigated and the models were adjusted and stratified accordingly. RESULTS: In 82 patients, the unadjusted rSI measures DWI-mean and -SD showed the highest AUCs (AUC 0.86-0.87). Adjustment for clinical-radiological covariates significantly improved the performance of FLAIR mean (0.91) and DWI-SD (0.91). The best prediction results based on the AUC were found for the final stratified and adjusted models of DWI-SD (0.94) and FLAIR mean (0.96) and a multivariable DWI-FLAIR model (0.95). The adjusted visual DWI FLAIR mismatch did not perform in a significantly worse manner (0.89). ADC-rSIs showed fair performance in all models. CONCLUSIONS: Quantitative DWI and FLAIR MRI biomarkers as well as the visual DWI-FLAIR mismatch provide excellent prediction of eligibility for thrombolysis in acute stroke, when easily obtainable clinical-radiological parameters are included in the prediction models. PMID- 26986944 TI - Vertical Microcavity Organic Light-emitting Field-effect Transistors. AB - Organic light-emitting field-effect transistors (OLEFETs) are regarded as a novel kind of device architecture for fulfilling electrical-pumped organic lasers. However, the realization of OLEFETs with high external quantum efficiency (EQE) and high brightness simultaneously is still a tough task. Moreover, the design of the resonator structure in LED is far from satisfactory. Here, OLEFETs with EQE of 1.5% at the brightness of 2600 cdm(-2), and the corresponding ON/OFF ratio and current efficiency reaches above 10(4) and 3.1 cdA(-1), respectively, were achieved by introducing 1,4,5,8,9,12-hexaazatriphenylene-hexacarbonitrile (HAT CN) as a charge generation layer. Moreover, a vertical microcavity based on distributed Bragg reflector (DBR) and Ag source/drain electrodes is successfully introduced into the high performance OLEFETs, which results in electroluminescent spectrum linewidth narrowing from 96 nm to 6.9 nm. The results manifest the superiority of the vertical microcavity as an optical resonator in OLEFETs, which sheds some light on achieving the electrically pumped organic lasers. PMID- 26986945 TI - ALK gene copy number gain and immunohistochemical expression status using three antibodies in neuroblastoma. AB - Anaplastic lymphoma kinase (ALK) gene aberrations-such as mutations, amplifications, and copy number gains-represent a major genetic predisposition to neuroblastoma (NB). This study aimed to evaluate the correlation between ALK gene copy number status, ALK protein expression, and clinicopathological parameters. We retrospectively retrieved 30 cases of poorly differentiated NB and constructed tissue microarrays (TMAs). ALK copy number changes were assessed by fluorescence in situ hybridization (FISH) assays, and ALK immunohistochemistry (IHC) testing was performed using three different antibodies (ALK1, D5F3, and 5A4 clones). ALK amplification and copy number gain were observed in 10% (3/30) and 53.3% (16/30) of the cohort, respectively. There were positive correlations between ALK copy number and IHC positive rate in ALK1 and 5A4 antibodies (p= < 0.001 and 0.019, respectively). ALK1, D5F3, and 5A4 antibodies equally showed 100% sensitivity in detecting ALK amplification. However, the sensitivity for detecting copy number gain differed among the three antibodies, with 75% sensitivity in D5F3 and 0% sensitivity in ALK1. ALK-amplified NBs were correlated with synchronous MYCN amplification and chromosome 1p deletion. ALK IHC positivity was frequently observed in INSS stage IV and high-risk group patients. In conclusion, this study identified that an increase in the ALK copy number is a frequent genetic alteration in poorly differentiated NB. ALK-amplified NBs showed consistent ALK IHC positivity with all kinds of antibodies. In contrast, the detection performance of ALK copy number gain was antibody dependent, with the D5F3 antibody showing the best sensitivity. PMID- 26986946 TI - Polycyclic aromatic hydrocarbons in cereal products on the Turkish market. AB - The contamination level of four EU marker polycyclic aromatic hydrocarbons (PAHs) in some cereal-derived products was surveyed in this study. Thirty-eight samples, 20 bread and 18 breakfast cereals, were purchased from retail shops and local markets of East Black sea region in Turkey. The samples were analysed for four EU marker PAHs, using ultrasonic extraction, solid-phase extraction (SPE) clean up and stable-isotope dilution gas chromatography with mass-spectrometric (GC/MS) detection. The method was validated with the parameters linearity, accuracy, precision, limit of detection (LOD), limit of quantitation (LOQ) and uncertainty. Total content of the four PAHs in bread varied from 0.19 to 0.46 ug kg(-1) and in breakfast cereals from 0.10 to 0.87 ug kg(-1). PMID- 26986947 TI - Morphological Alterations in Gastrocnemius and Soleus Muscles in Male and Female Mice in a Fibromyalgia Model. AB - BACKGROUND: Fibromyalgia (FM) is a chronic musculoskeletal pain disorder, characterized by chronic widespread pain and bodily tenderness and is often accompanied by affective disturbances, however often with unknown etiology. According to recent reports, physical and psychological stress trigger FM. To develop new treatments for FM, experimental animal models for FM are needed to be development and characterized. Using a mouse model for FM including intermittent cold stress (ICS), we hypothesized that ICS leads to morphological alterations in skeletal muscles in mice. METHODS: Male and female ICS mice were kept under alternating temperature (4 degrees C/room temperature [22 degrees C]); mice constantly kept at room temperature served as control. After scarification, gastrocnemius and soleus muscles were removed and snap-frozen in liquid nitrogen cooled isopentane or fixed for electron microscopy. RESULTS: In gastrocnemius/soleus muscles of male ICS mice, we found a 21.6% and 33.2% decrease of fiber cross sectional area (FCSA), which in soleus muscle concerns the loss of type IIa and IIx FCSA. This phenomenon was not seen in muscles of female ICS mice. However, this loss in male ICS mice was associated with an increase in gastrocnemius of the density of MIF+ (8.6%)-, MuRF+ (14.7%)-, Fbxo32+ (17.8%)-cells, a 12.1% loss of capillary contacts/muscle fiber as well as a 30.7% increase of damaged mitochondria in comparison with male control mice. Moreover, significant positive correlations exist among densities (n/mm(2)) of MIF+, MuRF+, Fbxo32+-cells in gastrocnemius/ soleus muscles of male ICS mice; these cell densities inversely correlate with FCSA especially in gastrocnemius muscle of male ICS mice. CONCLUSION: The ICS-induced decrease of FCSA mainly concerns gastrocnemius muscle of male mice due to an increase of inflammatory and atrogenic cells. In soleus muscle of male ICS and soleus/gastrocnemius muscles of female ICS mice morphological alterations seem to occur not at all or delayed. The sex-specificity of findings, which is not easily reconciled with the epidemiology of FM (female predominance), implicate that gastrocnemius muscle of male ICS mice should preferentially be used for future investigations with FM. Moreover, we suggest to investigate morphological and/or molecular alterations at different time-points (up to two weeks) after ICS. PMID- 26986948 TI - An Interleukin 13 Polymorphism Is Associated with Symptom Severity in Adult Subjects with Ever Asthma. AB - Different genes are associated with categorical classifications of asthma severity. However, continuous outcomes should be used to catch the heterogeneity of asthma phenotypes and to increase the power in association studies. Accordingly, the aim of this study was to evaluate the association between single nucleotide polymorphisms (SNPs) in candidate gene regions and continuous measures of asthma severity, in adult patients from the general population. In the Gene Environment Interactions in Respiratory Diseases (GEIRD) study (www.geird.org), 326 subjects (aged 20-64) with ever asthma were identified from the general population in Verona (Italy) between 2007 and 2010. A panel of 236 SNPs tagging 51 candidate gene regions (including one or more genes) was analysed. A symptom and treatment score (STS) and pre-bronchodilator FEV1% predicted were used as continuous measures of asthma severity. The association of each SNP with STS and FEV1% predicted was tested by fitting quasi-gamma and linear regression models, respectively, with gender, body mass index and smoking habits as potential confounders. The Simes multiple-test procedure was used for controlling the false discovery rate (FDR). SNP rs848 in the IL13 gene region (IL5/RAD50/IL13/IL4) was associated with STS (TG/GG vs TT genotype: uncorrected p-value = 0.00006, FDR corrected p-value = 0.04), whereas rs20541 in the same gene region, in linkage disequilibrium with rs848 (r(2) = 0.94) in our sample, did not reach the statistical significance after adjusting for multiple testing (TC/CC vs TT: uncorrected p-value = 0.0003, FDR-corrected p-value = 0.09). Polymorphisms in other gene regions showed a non-significant moderate association with STS (IL12B, TNS1) or lung function (SERPINE2, GATA3, IL5, NPNT, FAM13A) only. After adjusting for multiple testing and potential confounders, SNP rs848 in the IL13 gene region is significantly associated with a continuous measure of symptom severity in adult subjects with ever asthma. PMID- 26986949 TI - Expression of alpha-fetoprotein in gastric cancer AGS cells contributes to invasion and metastasis by influencing anoikis sensitivity. AB - alpha-fetoprotein (AFP) is a valuable tumor marker for many types of cancers, including primary gastric cancer (GC). However, the effects of AFP expression on the metastasis and anoikis sensitivity of GC remain unclear. The present study aimed to explore the role and possible mechanism of AFP in the invasion and metastasis of GC AGS cells, particularly in the anoikis sensitivity of AGS cells. In the present study, the expression of AFP in cultured AGS cells was assayed firstly by RT-PCR, western blotting and sequencing. Then, a specific AFP siRNA was applied to interfere with AFP expression and poly(2-hydroxyethyl methacrylate) (poly-HEMA) was used to block cell anchorage. The invasion and metastatic ability, and anoikis sensitivity detections were conducted based on Transwell chamber assay, anoikis assay kit and western blotting. Our results confirmed the expression of AFP in AGS cells. Then, we found that interference of AFP with siRNA attenuated the invasion and metastasis of AGS cells and induced a significant upregulation of E-cadherin and downregulation of N-cadherin expression (P<0.05). Cell apoptosis and anoikis were induced when cell anchorage was blocked by poly-HEMA treatment, which was exacerbated significantly when cells were exposed to AFP siRNA. Moreover, interference of AFP when cell anchorage was blocked enhanced the expression of the pro-apoptotic proteins Bax, caspase-3 and -9, and decreased the expression of the anti-apoptotic protein B cell lymphoma-2 (Bcl-2). In conclusion, the present study demonstrated that interference of AFP reduced AGS cell invasion and metastasis by enhancing anoikis sensitivity. The present study provides new insight for the treatment of GC and suggests AFP as a potential therapeutic target by regulating anoikis sensitivity. PMID- 26986950 TI - Subacute inhalation exposure to ozone induces systemic inflammation but not insulin resistance in a diabetic mouse model. AB - Epidemiological studies suggest that diabetics may be more susceptible to the adverse health effects from exposure to high ambient concentrations of ozone, the primary oxidant gas in photochemical smog. While increased morbidity and mortality from ozone inhalation has been linked to disruption of normal cardiovascular and airway functions, potential effects on glucose and insulin homeostasis are not understood. We tested the hypothesis that ozone exposure would worsen metabolic homeostasis in KKAy mice, a genetic diabetic animal model. Male KKAy mice were exposed to 0.5 ppm ozone for 13 consecutive weekdays, and then assessed for airway, adipose and systemic inflammation, glucose homeostasis, and insulin signaling. Ozone exposure increased plasma TNFalpha, as well as expression of VCAM-1, iNOS and IL-6 in both pulmonary and adipose tissues. Pro inflammatory CD11b(+)Gr-1(lo)7/4(hi) macrophages were increased by 200% in adipose tissue, but unchanged in blood. Interestingly, glucose levels were not significantly different in the insulin tolerance test between air- and ozone exposed mice, whereas fasting insulin levels and HOMA-IR in ozone-exposed animals were significantly reduced. These changes were accompanied by increased insulin signaling in skeletal muscle and liver, but not adipose tissues. Ozone also caused decrease in body weight and plasma leptin. Our results show that in addition to marked local and systemic inflammation, ozone increases insulin sensitivity that may be related to weight loss/leptin sensitization-dependent mechanisms in KKAy mice, warranting further study on the role of hyperglycemia in mediating cardiometabolic effects of ozone inhalation. PMID- 26986952 TI - Morning NO2 exposure sensitizes hypertensive rats to the cardiovascular effects of same day O3 exposure in the afternoon. AB - CONTEXT: Within urban air sheds, specific ambient air pollutants typically peak at predictable times throughout the day. For example, in environments dominated by mobile sources, peak nitrogen dioxide (NO2) levels coincide with morning and afternoon rush hours, while peak levels of ozone (O3), occur in the afternoon. OBJECTIVE: Given that exposure to a single pollutant might sensitize the cardiopulmonary system to the effects of a subsequent exposure to a second pollutant, we hypothesized that a morning exposure to NO2 will exaggerate the cardiovascular effects of an afternoon O3 exposure in rats. MATERIALS AND METHODS: Rats were divided into four groups that were each exposed for 3 h in the morning (m) and 3 h in the afternoon (a) on the same day: (1) m-Air/a-Air, (2) m Air/a-O3 (0.3 ppm), (3) m-NO2 (0.5 ppm)/a-Air and (4) m-NO2/a-O3. Implanted telemetry devices recorded blood pressure and electrocardiographic data. Sensitivity to the arrhythmogenic agent aconitine was measured in a separate cohort. RESULTS: Only m-NO2/a-O3-exposed rats had significant changes in electrophysiological, mechanical and autonomic parameters. These included decreased heart rate and increased PR and QTc intervals and increased heart rate variability, suggesting increased parasympathetic tone. In addition, only m-NO2/a O3 exposure decreased systolic and diastolic blood pressures and increased pulse pressure and QA interval, suggesting decreased cardiac contractility. DISCUSSION AND CONCLUSION: The findings indicate that initial exposure to NO2 sensitized rats to the cardiovascular effects of O3 and may provide insight into the epidemiological data linking adverse cardiovascular outcomes with exposures to low concentrations of O3. PMID- 26986951 TI - Effects of immunological and hematological parameter in mice exposed to mixture of volatile organic compounds. AB - Exposure to some kinds of volatile organic compounds (VOCs) leads to immune system disorders, liver and kidney damage, hematological change. However, there is little information about the effect of VOCs mixture on immune system and hematological parameter. In this study, 50 Kunming male mice were exposed in five similar chambers, 0 (control) and four different doses of VOCs mixture (G1-4) for consecutively 10 days at 2 h/day. The concentrations of VOCs mixture were as follows: formaldehyde, benzene, toluene and xylene 1.0 + 1.1 + 2.0 + 2.0, 3.0 + 3.3 + 6.0 + 6.0, 5.0 + 5.5 + 10.0 + 10.0 and 10.0 + 11.0 + 20.0 + 20.0 mg/m(3), respectively, which corresponded to 10, 30, 50 and 100 times of indoor air quality standard in china. One day following VOCs exposure, spleen T lymphocyte subpopulation, serum biochemical markers and peripheral blood cells in mice were analyzed, respectively. VOCs exposure decreased significantly erythrocyte count (RBC), platelet (PLT) in peripheral blood in mice. While aspartate aminotransaminase (AST), alanine aminotransaminase (ALT), alkaline phosphatase (ALP) and creatinine (CREA) in serum increased significantly in G4 mice versus controls. Flow cytometry analysis showed that the number of splenic lymphocyte subpopulation cells decreased significantly in G2, 3 and 4 mice in comparison with normal Kunming mice. These results indicate inhalation of VOCs mixture affects CD4/8 subpopulations, liver, kidney function and some hematological parameters in mice. PMID- 26986953 TI - Modeling particle deposition in the Balb/c mouse respiratory tract. AB - The mouse lung has become increasingly important as a surrogate of the human lung for inhalation risk assessment. The main structural difference between the two lungs is that the airway branching of the human lung is relatively symmetric, while that of the mouse lung is distinctly asymmetric or monopodial. The objectives of this study were to develop a stochastic, asymmetric particle deposition model for the Balb/c mouse and to compare predicted deposition patterns with those in the human lung. The asymmetric bronchial airway geometry of the Balb/c mouse was based on a statistical analysis of several lung casts, while, in the absence of pertinent data, the asymmetric acinar airway geometry was represented by an allometrically scaled-down version of the rat acinar region, assuming structural similarity. Deposition of inhaled particles in nasal, bronchial and acinar airways for mouse-specific breathing conditions was computed with the Monte Carlo deposition model IDEAL-mouse. While total deposition for submicron particles decreases with increasing diameter in a fashion similar to that in the human lung, the effect of inhalability and nasal pre-filtration significantly reduces total deposition in the mouse lung for particles with diameters greater than about 3 MUm. The most notable difference between submicron particle deposition in the mouse and human airways is the shift of the deposition distribution from distal airway generations in the human lung to upper airway generations in the mouse lung. However, if plotted as a function of airway diameter, both deposition distributions are quite similar, indicating that airway diameter may be a more appropriate morphometric parameter for extrapolation purposes than airway generation. PMID- 26986955 TI - A critical review of 20 years of parotid gland surgery. AB - Conclusion PG surgery provides sufficient radicality with a minimum of functional loss. Patient's outcome is associated with the reliable estimation of the lesional entity/dignity. Diagnostic approaches are required to determine morphological aspects, avoid unnecessary surgery, and to reliable identify primary carcinomas/occult metastases. Objectives The pre-operative assessment of parotid gland (PG) lesions is of major clinical impact, whilst surgery remains the diagnostic/therapeutic mainstay. There are still controversies about the distribution of entities, clinical course, functional outcome, and survival. Methods In total, 1211 patients were retrospectively analyzed for disease-related data. Differences were analyzed using the Chi-square/Fisher exact/unpaired student's t-test; survival by Kaplan-Meier. Results There were 946 benign and 265 malignant tumours. In primary PG malignancy the disease-free/overall survival was 78/127 months. Metastases into the PG demonstrated a decreased survival (67 months). Extended surgery was associated with post-operative facial nerve alteration. Extracapsular dissection and superficial parotidectomy did not show differences in the facial palsy rate. PMID- 26986954 TI - Comparison of realistic and idealized breathing patterns in computational models of airflow and vapor dosimetry in the rodent upper respiratory tract. AB - CONTEXT: Computational fluid dynamics (CFD) simulations of airflows coupled with physiologically based pharmacokinetic (PBPK) modeling of respiratory tissue doses of airborne materials have traditionally used either steady-state inhalation or a sinusoidal approximation of the breathing cycle for airflow simulations despite their differences from normal breathing patterns. OBJECTIVE: Evaluate the impact of realistic breathing patterns, including sniffing, on predicted nasal tissue concentrations of a reactive vapor that targets the nose in rats as a case study. MATERIALS AND METHODS: Whole-body plethysmography measurements from a free breathing rat were used to produce profiles of normal breathing, sniffing and combinations of both as flow inputs to CFD/PBPK simulations of acetaldehyde exposure. RESULTS: For the normal measured ventilation profile, modest reductions in time- and tissue depth-dependent areas under the curve (AUC) acetaldehyde concentrations were predicted in the wet squamous, respiratory and transitional epithelium along the main airflow path, while corresponding increases were predicted in the olfactory epithelium, especially the most distal regions of the ethmoid turbinates, versus the idealized profile. The higher amplitude/frequency sniffing profile produced greater AUC increases over the idealized profile in the olfactory epithelium, especially in the posterior region. CONCLUSIONS: The differences in tissue AUCs at known lesion-forming regions for acetaldehyde between normal and idealized profiles were minimal, suggesting that sinusoidal profiles may be used for this chemical and exposure concentration. However, depending upon the chemical, exposure system and concentration and the time spent sniffing, the use of realistic breathing profiles, including sniffing, could become an important modulator for local tissue dose predictions. PMID- 26986956 TI - [n]Ferrocenophanes (n = 2, 3) with Nitrogen and Phosphorus in Bridging Positions. AB - The in situ prepared dilithio derivative of the known species 1-bromo-1' (trimethylsilylamino)ferrocene (1) reacted with tBuPCl2 to form the first example of a [2]ferrocenophane ([2]FCP) bridged by nitrogen and phosphorus (2). Sulfurization of 2 followed by column chromatography on silica gel gave the expected [2]FCP with a tBu(S)PN(SiMe3) bridging moiety (3a) and its desilylated counterpart with a tBu(S)PNH bridging moiety (3b). The molecular structure of 3b was determined by single-crystal X-ray analysis (alpha = 18.40(11) degrees ). Using a common synthetic methodology, two new 1-amino-1'-bromoferrocene derivatives were prepared, one species with a PhCH2 (6a) and another with a tBuCH2 group (6b) on nitrogen. Dilithiation of 6a followed by addition of tBuPCl2 gave a mixture of three constitutional isomers: the targeted [2]FCP (7a), the 1,1'-disubstituted ferrocene derivative (tBuPH)(PhCH?N)fc (8a), and the [3]FCP bridged by a (NH)(CHPh)PtBu moiety (9a). NMR spectroscopy revealed that 8a is the precursor for 9a. The salt-metathesis reaction of the dilithio derivative of 6b with tBuPCl2 exclusively gave the 1,1'-disubstituted ferrocene derivative (tBuPH)(tBuCH?N)fc (8b), which does not isomerize to the respective [3]FCP. DFT calculations at the M06/6-311+G(d,p) level were used to better rationalize these unexpected results. PMID- 26986957 TI - Direct Visualization of Excited-State Symmetry Breaking Using Ultrafast Time Resolved Infrared Spectroscopy. AB - Most symmetric quadrupolar molecules designed for two-photon absorption behave as dipolar molecules in the S1 electronic excited state. This is usually explained by a breakup of the symmetry in the excited state. However, the origin of this process and its dynamics are still not fully understood. Here, excited-state symmetry breaking in a quadrupolar molecule with a D-pi-A-pi-D motif, where D and A are electron donating and accepting units, is observed in real time using ultrafast transient infrared absorption spectroscopy. The nature of the relaxed S1 state was found to strongly depend on the solvent polarity: (1) in nonpolar solvents, it is symmetric and quadrupolar; (2) in weakly polar media, the quadrupolar state observed directly after excitation transforms to a symmetry broken S1 state with one arm bearing more excitation than the other; and (3) in highly polar solvents, the excited state evolves further to a purely dipolar S1 state with the excitation localized entirely on one arm. The time scales associated with the transitions between these states coincide with those of solvation dynamics, indicating that symmetry breaking is governed by solvent fluctuations. PMID- 26986960 TI - Fluctuation between grandiose and vulnerable narcissism. AB - Current literature on narcissistic personality disorder has emphasized a distinction between grandiose and vulnerable narcissism. Some researchers have further suggested that narcissistic persons fluctuate between grandiose and vulnerable narcissism. However, this perception has been confined largely to clinical experience with no systematic research testing the hypothesis. Clinicians and clinical psychology professors in the current study identified 143 persons who fit a description of either a grandiose or a vulnerable narcissist and indicated the extent to which these persons ever demonstrated traits of the complementary variant. The results supported the fluctuation hypothesis, particularly for episodes of vulnerable narcissism in persons identified as a grandiose narcissist. Correlations of the grandiose and vulnerable narcissism traits with a brief five-factor model measure corroborated past trait descriptions of the 2 respective variants of narcissism. The results of the current study are compared with existing cross-sectional and longitudinal research, and suggestions for future research are provided. (PsycINFO Database Record PMID- 26986958 TI - Long Term Association between Serum 25-Hydroxyvitamin D and Mortality in a Cohort of 4379 Men. AB - OBJECTIVE: A number of observational studies have shown an inverse association between circulating 25-hydroxyvitamin D and total mortality, but a reverse J shaped association has also been reported. In a large nested case-control study, serum-25-hydroxyvitamin D (s-25(OH)D) was positively associated with incident prostate cancer. Based on the same study population, the primary aim of the present study was to investigate the association between s-25(OH)D and total mortality. METHODS: Men participating in population based health screenings during 1981-1991 and enrolled in a nested case-control study were followed throughout 2007 with respect to all-cause and cause-specific mortality. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox proportional hazards regression. RESULTS: In men with prostate cancer (n = 2282), there was a significant inverse association between s-25(OH)D and total mortality after controlling for potential confounders (HR = 1.25 (95% CI 1.05-1.50), s 25(OH)D <50 nmol/l versus s-25(OH)D >= 50 nmol/l). The corresponding figure among controls (n = 2147) was HR = 1.15 (95% CI 0.88-1.50) and in the total study population HR = 1.19 (95% CI 1.03-1.38). For cause-specific deaths, we found no significant associations. CONCLUSIONS: In this study population, s-25(OH)D was inversely associated with total mortality during more than two decades of follow up, despite, as previous reported, high s-25(OH)D was associated with increased risk of prostate cancer. PMID- 26986959 TI - Disorganized attachment and personality functioning in adults: A latent class analysis. AB - Though researchers have attended to disorganized attachment in infants and children, they have infrequently focused on the character of disorganized attachment in adults. In this study, we aimed to identify clusters of participants based on attachment levels and styles, seeking to better delineate severity and stylistic differences in disorganized attachment than has been previously articulated. We used a new assessment approach focused on a hierarchy of attachment organization, including secure, insecure (dismissive and preoccupied), rigid-controlling (hostile control and compulsive caregiving), and disorganized (contradictory, impoverished, and unresolved) levels of attachment. Clinical evaluators used information from diagnostic and attachment-based interviews to rate participants on each of these aspects of attachment. Latent class analysis (LCA) revealed a 4-class solution, including a secure (n = 33), insecure (n = 110), and 2 disorganized classes. One disorganized class (disorganized-oscillating) was characterized by elevations on contradictory and preoccupied styles (n = 77) and another (disorganized-impoverished) showed elevations on impoverished and dismissive styles (n = 53). The disorganized oscillating class exhibited elevated personality disorder (PD) severity and general symptom severity, borderline personality disorder (BPD), histrionic, and antisocial dimensional scores, and the most severe identity disturbance compared with the other classes. The impoverished-dismissive class exhibited the highest avoidant and schizoid PD dimensional scores of the classes, and higher PD severity compared with the insecure and secure classes. These results highlight the possibility of identifying distinct classes of attachment organization, differentiated both by aspects of severity and interpersonal style. They also shed light on the manifestation of attachment disorganization in adults. (PsycINFO Database Record PMID- 26986961 TI - Examining the incremental and interactive effects of boldness with meanness and disinhibition within the triarchic model of psychopathy. AB - The triarchic model of psychopathy (Patrick, Fowles, & Krueger, 2009) comprises 3 phenotypic domains: Meanness, Disinhibition, and Boldness. Ongoing controversy surrounds the relevance of Boldness in the conceptualization and assessment of psychopathy. In the current study, undergraduate students (N = 439) completed the Triarchic Psychopathy Measure (Patrick, 2010) to examine the association between Boldness and a host of theoretically relevant external criteria. Boldness was generally unrelated to either prosocial or harmful criteria. Boldness rarely provided incremental value above or interacted with Meanness and Disinhibition with respect to external criteria. Curvilinear effects of Boldness rarely emerged. The findings suggest that Boldness might not be a central construct in the definition of psychopathic personality disorder. Implications for the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 2013) psychopathic specifier are discussed. (PsycINFO Database Record PMID- 26986962 TI - Utilizing interview and self-report assessment of the Five-Factor Model to examine convergence with the alternative model for personality disorders. AB - An alternative model for personality disorders is included in Section III (Emerging Models and Measures) of Diagnostic and Statistical Manual of Mental Disorders, (5th ed.; DSM-5). The DSM-5 dimensional trait model is an extension of the Five-Factor Model (FFM; American Psychiatric Association, 2013). The Personality Inventory for DSM-5 (PID-5) assesses the 5 domains and 25 traits in the alternative model. The current study expands on recent research to examine the relationship of the PID-5 with an interview measure of the FFM. The Structured Interview for the Five Factor Model of Personality (SIFFM) assesses the 5 bipolar domains and 30 facets of the FFM. Research has indicated that the SIFFM captures maladaptive aspects of personality (as well as adaptive). The SIFFM, NEO PI-R, and PID-5 were administered to participants to examine their respective convergent and discriminant validity. Results provide evidence for the convergence of the 2 models using self-report and interview measures of the FFM. Clinical implications and future directions are discussed, particularly a call for the development of a structured interview for the assessment of the DSM-5 dimensional trait model. (PsycINFO Database Record PMID- 26986963 TI - Transcriptomic and Proteomic Analysis of Arion vulgaris--Proteins for Probably Successful Survival Strategies? AB - The Spanish slug, Arion vulgaris, is considered one of the hundred most invasive species in Central Europe. The immense and very successful adaptation and spreading of A. vulgaris suggest that it developed highly effective mechanisms to deal with infections and natural predators. Current transcriptomic and proteomic studies on gastropods have been restricted mainly to marine and freshwater gastropods. No transcriptomic or proteomic study on A. vulgaris has been carried out so far, and in the current study, the first transcriptomic database from adult specimen of A. vulgaris is reported. To facilitate and enable proteomics in this non-model organism, a mRNA-derived protein database was constructed for protein identification. A gel-based proteomic approach was used to obtain the first generation of a comprehensive slug mantle proteome. A total of 2128 proteins were unambiguously identified; 48 proteins represent novel proteins with no significant homology in NCBI non-redundant database. Combined transcriptomic and proteomic analysis revealed an extensive repertoire of novel proteins with a role in innate immunity including many associated pattern recognition, effector proteins and cytokine-like proteins. The number and diversity in gene families encoding lectins point to a complex defense system, probably as a result of adaptation to a pathogen-rich environment. These results are providing a fundamental and important resource for subsequent studies on molluscs as well as for putative antimicrobial compounds for drug discovery and biomedical applications. PMID- 26986964 TI - Identifying Metabolic Subpopulations from Population Level Mass Spectrometry. AB - Metabolism underlies many important cellular decisions, such as the decisions to proliferate and differentiate, and defects in metabolic signaling can lead to disease and aging. In addition, metabolic heterogeneity can have biological consequences, such as differences in outcomes and drug susceptibilities in cancer and antibiotic treatments. Many approaches exist for characterizing the metabolic state of a population of cells, but technologies for measuring metabolism at the single cell level are in the preliminary stages and are limited. Here, we describe novel analysis methodologies that can be applied to established experimental methods to measure metabolic variability within a population. We use mass spectrometry to analyze amino acid composition in cells grown in a mixture of (12)C- and (13)C-labeled sugars; these measurements allow us to quantify the variability in sugar usage and thereby infer information about the behavior of cells within the population. The methodologies described here can be applied to a large range of metabolites and macromolecules and therefore have the potential for broad applications. PMID- 26986965 TI - Prognostic Significance of Molecular Analysis of Peritoneal Fluid for Patients with Gastric Cancer: A Meta-Analysis. AB - BACKGROUND: Accurately distinguishing serosal invasion in patients with gastric cancer (GC) prior to surgery can be difficult. Molecular analysis of peritoneal fluid (MAPF) for free cancer cells with higher sensitivity than other methods; however, its prognostic value for GC remains controversial, precluding its application in clinical practice. METHODS: PubMed, EMBASE and other databases were systematically searched. Thirty-one studies were eligible for the meta analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled for overall survival (OS), disease-free survival (DFS) and peritoneal recurrence-free survival (PRF). RESULTS: The current meta-analysis focused on patients with GC and negative cytological diagnoses. The results showed that positive MAPF status (MAPF+) led to poorer prognoses for OS (HR 2.59, 95% CI 1.99-3.37), DFS (HR 4.92, 95% CI 3.28-7.37) and PRF (HR 2.81, 95% CI 2.12-3.72) compared with negative MAPF status (MAPF-). Moreover, among the patients with GC who received curative treatment, the MAPF+ patients had poorer prognoses for OS (HR 3.27, 95% CI 2.49 4.29), DFS (HR 3.90, 95% CI 2.74-5.57) and PRF (HR 5.45, 95% CI 3.70-8.03). A meta-analysis of multivariate-adjusted HRs demonstrated that MAPF+ status was an independent prognostic factor for patients with GC who underwent curative treatment (OS: HR 2.19, 95% CI 1.47-3.28; PRF: HR 3.44, 95% CI 2.01-5.87). Using the identical target genes (CEA, CEA/CK20) as molecular markers, the patients with GC who were MAPF+ had significantly worse prognoses for OS (CEA: HR 3.03, 95% CI 2.29-4.01; CEA/CK20: HR 4.24, 95% CI 2.42-7.40), DFS (CEA: HR 3.99, 95% CI 2.24-7.12; CEA/CK20: HR 4.31, 95% CI 1.49-2.48) and PRF (CEA: HR 4.45, 95% CI 2.72-7.31; CEA/CK20: HR 6.46, 95% CI 3.62-11.55) than the patients who were MAPF . CONCLUSION/SIGNIFICANCE: The above results demonstrate that MAPF could be a prognostic indicator for patients with GC who have a negative cytological diagnosis and/or are receiving curative treatment. MAPF could provide clinicians with additional prognostic information that could aid in developing individualized treatment plans prior to surgery. The widely used target genes CEA, CEA/CK20 were confirmed to be valuable MAPF markers for predicting the prognosis of GC. PMID- 26986967 TI - Oridonin inhibits the proliferation of human colon cancer cells by upregulating BMP7 to activate p38 MAPK. AB - Oridonin (ORI), a diterpenoid purified from Rabdosia rubescens, has been reported as a promising chemotherapy drug for colon cancer treatment; yet, the precise mechanisms underlying this anticancer activity remain unclear. In the present study, we investigated the anticancer effect of ORI in HCT116 cells, and dissected the possible molecular mechanisms underlying this activity. With crystal violet staining, flow cytometry and western blot assay, we found that ORI effectively inhibited the proliferation and induced the apoptosis of HCT116 cells. Further analysis of the results indicated that BMP7 was greatly upregulated by ORI in the HCT116 cells, but its endogenous expression in FHC cells was apparently lower than that in the colon cancer cell lines. Exogenous expression of BMP7 inhibited the proliferation of the HCT116 cells, and substantially potentiated the anticancer effect of ORI. However, the specific antibody of BMP7 nearly abolished this anticancer activity of ORI in the HCT116 cells. Meanwhile, ORI exerted no significant effect on the level of phosphorylated Smad1/5/8 or total p38 MAPK, but greatly increased the level of phosphorylated p38 MAPK in the HCT116 cells. A p38 MAPK-specific inhibitor partly reversed the antiproliferative effect of BMP7 in the HCT116 cells, but prominently promoted the effect of the BMP7 antibody on proliferation. Exogenous expression of BMP7 increased the ORI-induced phosphorylation of p38 MAPK, while the BMP7 antibody almost abolished the ORI-elevated p38 MAPK phosphorylation. Our findings suggest that ORI may be an efficacious drug for colon cancer treatment. This anticancer activity of ORI may be mediated by upregulating BMP7 at least to increase the activation of p38 MAPK. PMID- 26986968 TI - A Cd(II)-based metal-organic framework as a luminance sensor to nitrobenzene and Tb(III) ion. AB - A Cd(II)-based metal-organic framework, [Cd2(DPDC)2(BTB)]infinity (Cd-MOF, DPDC = 2,2'-diphenyldicarboxylate and BTB = 1,4-bis(1,2,4-triazol-1-yl)butane) was successfully constructed via a hydrothermal reaction. Structural analysis shows that the synthesized Cd-MOF is a three-dimensional (3D) architecture crystallized in the hexagonal system with a chiral space group P61. Powder X-ray diffraction experiments and thermogravimetric analysis reveal that the constructed Cd-MOF has a high chemical and thermal stability. A study of additional mechanical properties indicates that it exhibits a moderate stiffness with the average values of Young's modulus (E) and H as 11.3(2) and 0.9(7) GPa, respectively. The luminescence properties of the Cd-MOF were further studied. The result shows that it could be an effective sensor to the organic nitrobenzene molecule via a strong quenching effect, and also to the inorganic Tb(III) ion by a strong green emission effect. Moreover, when loading bimetal ions (Eu(III) and Tb(III) into the Cd-MOF/methanol suspension, tunable visible luminescence can also be achieved by carefully adjusting the excitation wavelengths. PMID- 26986966 TI - Evolution of Pentameric Ligand-Gated Ion Channels: Pro-Loop Receptors. AB - Pentameric ligand-gated ion channels (pLGICs) are ubiquitous neurotransmitter receptors in Bilateria, with a small number of known prokaryotic homologues. Here we describe a new inventory and phylogenetic analysis of pLGIC genes across all kingdoms of life. Our main finding is a set of pLGIC genes in unicellular eukaryotes, some of which are metazoan-like Cys-loop receptors, and others devoid of Cys-loop cysteines, like their prokaryotic relatives. A number of such "Cys less" receptors also appears in invertebrate metazoans. Together, those findings draw a new distribution of pLGICs in eukaryotes. A broader distribution of prokaryotic channels also emerges, including a major new archaeal taxon, Thaumarchaeota. More generally, pLGICs now appear nearly ubiquitous in major taxonomic groups except multicellular plants and fungi. However, pLGICs are sparsely present in unicellular taxa, suggesting a high rate of gene loss and a non-essential character, contrasting with their essential role as synaptic receptors of the bilaterian nervous system. Multiple alignments of these highly divergent sequences reveal a small number of conserved residues clustered at the interface between the extracellular and transmembrane domains. Only the "Cys loop" proline is absolutely conserved, suggesting the more fitting name "Pro loop" for that motif, and "Pro-loop receptors" for the superfamily. The infered molecular phylogeny shows a Cys-loop and a Cys-less clade in eukaryotes, both containing metazoans and unicellular members. This suggests new hypotheses on the evolutionary history of the superfamily, such as a possible origin of the Cys loop cysteines in an ancient unicellular eukaryote. Deeper phylogenetic relationships remain uncertain, particularly around the split between bacteria, archaea, and eukaryotes. PMID- 26986970 TI - An Efficient Object Tracking Method on Quad-/Oc-Trees. AB - We introduce a fast error-free tracking method applicable to sequences of two and three dimensional images. The core idea is to use Quadtree (resp. Octree) data structures for representing the spatial discretization of an image in two (resp. three) spatial dimensions. This representation enables one to merge into large computational cells the regions that can be faithfully described with such a coarse representation, thus significantly reducing the total number of degrees of freedom that are processed, without compromising accuracy. This encoding is particularly effective in the case of algorithms based on moving fronts, since the adaptive refinement provides a natural means to focus the processing resources on information near the moving front. In this paper, we use an existing contour based tracker and reformulate it to the case of Quad-/Oc-tree data structures. Relevant mathematical assumptions and derivations are presented for this purpose. We then demonstrate that, on standard bio-medical image sequences, a speed up of 5X is easily achieved in 2D and about 10X in 3D. PMID- 26986969 TI - Antioxidants Abrogate Alpha-Tocopherylquinone-Mediated Down-Regulation of the Androgen Receptor in Androgen-Responsive Prostate Cancer Cells. AB - Tocopherylquinone (TQ), the oxidation product of alpha-tocopherol (AT), is a bioactive molecule with distinct properties from AT. In this study, AT and TQ are investigated for their comparative effects on growth and androgenic activity in prostate cancer cells. TQ potently inhibited the growth of androgen-responsive prostate cancer cell lines (e.g., LAPC4 and LNCaP cells), whereas the growth of androgen-independent prostate cancer cells (e.g., DU145 cells) was not affected by TQ. Due to the growth inhibitory effects induced by TQ on androgen-responsive cells, the anti-androgenic properties of TQ were examined. TQ inhibited the androgen-induced activation of an androgen-responsive reporter and inhibited the release of prostate specific antigen from LNCaP cells. TQ pretreatment was also found to inhibit AR activation as measured using the Multifunctional Androgen Receptor Screening assay. Furthermore, TQ decreased androgen-responsive gene expression, including TM4SF1, KLK2, and PSA over 5-fold, whereas AT did not affect the expression of androgen-responsive genes. Of importance, the antiandrogenic effects of TQ on prostate cancer cells were found to result from androgen receptor protein down-regulation produced by TQ that was not observed with AT treatment. Moreover, none of the androgenic endpoints assessed were affected by AT. The down-regulation of androgen receptor protein by TQ was abrogated by co-treatment with antioxidants. Overall, the biological actions of TQ were found to be distinct from AT, where TQ was found to be a potent inhibitor of cell growth and androgenic activity in androgen-responsive prostate cancer cells. PMID- 26986971 TI - The 'selfish brain' is regulated by aquaporins and autophagy under nutrient deprivation. AB - The brain maintains its mass and physiological functional capacity compared with other organs under harsh conditions such as starvation, a mechanism termed the 'selfish brain' theory. To further investigate this phenomenon, mice were examined following water and/or food deprivation. Although the body weights of the mice, the weight of the organs except the brain and blood glucose levels were significantly reduced in the absence of water and/or food, the brain weight maintained its original state. Furthermore, no significant differences in the water content of the brain or its energy balance were observed when the mice were subjected to water and/or food deprivation. To further investigate the mechanism underlying the brain maintenance of water and substance homeostasis, the expression levels of aquaporins (AQPs) and autophagy-specific protein long-chain protein 3 (LC3) were examined. During the process of water and food deprivation, no significant differences in the transcriptional levels of AQPs were observed. However, autophagy activity levels were initially stimulated, then suppressed in a time-dependent manner. LC3 and AQPs have important roles for the survival of the brain under conditions of food and water deprivation, which provided further understanding of the mechanism underlying the 'selfish brain' phenomenon. Although not involved in the energy regulation of the 'selfish brain', AQPs were observed to have important roles in water and food deprivation, specifically with regards to the control of water content. Additionally, the brain exhibits an 'unselfish strategy' using autophagy during water and/or food deprivation. The present study furthered current understanding of the 'selfish brain' theory, and identified additional regulating target genes of AQPs and autophagy, with the aim of providing a basis for the prevention of nutrient shortage in humans and animals. PMID- 26986972 TI - Effects of intravenous infusion of glycerol on blood parameters and urinary glycerol concentrations. AB - In sports, the oral intake and intravenous administration of glycerol as a potential masking agent have been prohibited. The effect of glycerol on blood parameters was investigated by comparing the intravenous administration of glycerol (20g/200mL) with that of an electrolyte (8g glucose/200mL) as a comparator (n=7, fixed-dose-rate i.v. infusion, 200mL in 1h). This study was also designed to evaluate whether the urinary concentrations reached the positivity threshold after the intravenous infusion of glycerol. Significant decreases of the haemoglobin (HGB, g/dL), haematocrit (HCT, %) and OFF-h Score (OFF-score) values were observed after the infusion of glycerol (P<0.05 at 1-6h). The differences in the HGB, HCT and OFF-score between pre- and post-administration were -0.49+/-0.23g/dL (2h), -1.54+/-0.73% (2h) and -3.89+/-3.66 (2h), respectively. Glycerol infusion significantly increased the plasma volume by 12.1% (1h), 6.3% (2h) and 5.7% (3h) compared with the initial values. The infusion of the comparator also increased the plasma volume by 9.6% (1h), 5.8% (2h) and 4.9% (3h) compared with the values before infusion. There were no significant differences in the change of the plasma volume between the intravenous infusions of glycerol and the glucose-based electrolyte (as the comparator) (P>=0.05). This finding might indicate that glycerol itself only exhibited limited effects on the expansion of plasma. After administration of glycerol, the urinary glycerol concentrations increased from 0.0013+/-0.0004mg/mL to 6.86+/-2.86mg/mL at 1h and 6.45+/-3.08mg/mL at 2h. The intravenous infusion of glycerol can most likely be detected using the current urine analysis; however, the dependence of the concentration of urinary glycerol on the urine volume should be considered. PMID- 26986973 TI - Post-mortem levels and tissue distribution of codeine, codeine-6-glucuronide, norcodeine, morphine and morphine glucuronides in a series of codeine-related deaths. AB - This article presents levels and tissue distribution of codeine, codeine-6 glucuronide (C6G), norcodeine, morphine and the morphine metabolites morphine-3 glucuronide (M3G) and morphine-6-glucuronide (M6G) in post-mortem blood (peripheral and heart blood), vitreous fluid, muscle, fat and brain tissue in a series of 23 codeine-related fatalities. CYP2D6 genotype is also determined and taken into account. Quantification of codeine, C6G, norcodeine, morphine, M3G and M6G was performed with a validated solid phase extraction LC-MS method. The series comprise 19 deaths (83%) attributed to mixed drug intoxication, 4 deaths (17%) attributed to other causes of death, and no cases of unambiguous monointoxication with codeine. The typical peripheral blood concentration pattern in individual cases was C6G?codeine?norcodeine>morphine, and M3G>M6G>morphine. In matrices other than blood, the concentration pattern was similar, although in a less systematic fashion. Measured concentrations were generally lower in matrices other than blood, especially in brain and fat, and in particular for the glucuronides (C6G, M3G and M6G) and, to some extent, morphine. In brain tissue, the presumed active moieties morphine and M6G were both below the LLOQ (0.0080mg/L and 0.058mg/L, respectively) in a majority of cases. In general, there was a large variability in both measured concentrations and calculated blood/tissue concentration ratios. There was also a large variability in calculated ratios of morphine to codeine, C6G to codeine and norcodeine to codeine in all matrices, and CYP2D6 genotype was not a reliable predictor of these ratios. The different blood/tissue concentration ratios showed no systematic relationship with the post-mortem interval. No coherent degradation or formation patterns for codeine, morphine, M3G and M6G were observed upon reanalysis in peripheral blood after storage. PMID- 26986974 TI - Development of a laboratory test for knicker tearing re-creation studies. AB - False sexual assault and rape claims result in wasted forensic and police resources and stigma for the alleged offender. In this work a laboratory method was developed to (i) recreate the ripping of knickers and (ii) measure the force required to rip the garments. The effect of laundering was considered as a means to mimic age of garment, and the effect of speed of ripping was used as a measure of forcible removal of garments. Whilst laundering resulted in visual damage to the thongs, it did not affect the mechanical properties. Faster test speeds resulted in higher measured forces and increased levels of damage. This may allow comment to be made regarding the level of force used during an attack. PMID- 26986975 TI - Co-Expression of Wild-Type P2X7R with Gln460Arg Variant Alters Receptor Function. AB - The P2X7 receptor is a member of the P2X family of ligand-gated ion channels. A single-nucleotide polymorphism leading to a glutamine (Gln) by arginine (Arg) substitution at codon 460 of the purinergic P2X7 receptor (P2X7R) has been associated with mood disorders. No change in function (loss or gain) has been described for this SNP so far. Here we show that although the P2X7R-Gln460Arg variant per se is not compromised in its function, co-expression of wild-type P2X7R with P2X7R-Gln460Arg impairs receptor function with respect to calcium influx, channel currents and intracellular signaling in vitro. Moreover, co immunoprecipitation and FRET studies show that the P2X7R-Gln460Arg variant physically interacts with P2X7R-WT. Specific silencing of either the normal or polymorphic variant rescues the heterozygous loss of function phenotype and restores normal function. The described loss of function due to co-expression, unique for mutations in the P2RX7 gene so far, explains the mechanism by which the P2X7R-Gln460Arg variant affects the normal function of the channel and may represent a mechanism of action for other mutations. PMID- 26986976 TI - Characterization of the Treg Response in the Hepatitis B Virus Hydrodynamic Injection Mouse Model. AB - Regulatory T cells (Tregs) play an important role in counter-regulating effector T cell responses in many infectious diseases. However, they can also contribute to the development of T cell dysfunction and pathogen persistence in chronic infections. Tregs have been reported to suppress virus-specific T cell responses in hepatitis B virus (HBV) infection of human patients as well as in HBV animal models. However, the phenotype and expansion of Tregs has so far only been investigated in other infections, but not in HBV. We therefore performed hydrodynamic injections of HBV plasmids into mice and analyzed the Treg response in the spleen and liver. Absolute Treg numbers significantly increased in the liver but not the spleen after HBV injection. The cells were natural Tregs that surprisingly did not show any activation or proliferation in response to the infection. However, they were able to suppress effector T cell responses, as selective depletion of Tregs significantly increased HBV-specific CD8+ T cell responses and accelerated viral antigen clearance. The data implies that natural Tregs infiltrate the liver in HBV infection without further activation or expansion but are still able to interfere with T cell mediated viral clearance. PMID- 26986977 TI - An Examination of the Association between FOXA1 Staining Level and Biochemical Recurrence following Salvage Radiation Therapy for Recurrent Prostate Cancer. AB - BACKGROUND: Standardly collected clinical and pathological patient information has demonstrated only moderate ability to predict risk of biochemical recurrence (BCR) of prostate cancer in men undergoing salvage radiation therapy (SRT) for a rising PSA after radical prostatectomy (RP). Although elevated FOXA1 staining has been associated with poor patient outcomes following RP, it has not been studied in the specific setting of SRT after RP. The aim of this study was to evaluate the association between FOXA1 staining level and BCR after SRT for recurrent prostate cancer. METHODS: A total of 141 men who underwent SRT at our institution were included. FOXA1 staining levels in primary tumor samples were detected using immunohistochemistry. FOXA1 staining percentage and intensity were measured and multiplied together to obtain a FOXA1 H-score (range 0-12) which was our primary staining measure. P-values <= 0.0056 were considered as statistically significant after applying a Bonferroni correction for multiple comparisons. RESULTS: There was not a significant association between FOXA1 H-score and risk of BCR when considering H-score as an ordinal variable or as a categorical variable (all P >= 0.090). Similarly, no significant associations with BCR were observed for FOXA1 staining percentage or staining intensity (all P >= 0.14). CONCLUSIONS: FOXA1 staining level does not appear to have a major impact on risk of BCR after SRT. PMID- 26986981 TI - A Tribute to Prof. Dr. Dr. h.c. Rudolf Speich. PMID- 26986980 TI - The synthesis, lipophilicity and cytotoxic effects of new ruthenium(II) arene complexes with chromone derivatives. AB - A series of arene ruthenium(II) complexes with the general formula [(eta(6) arene)Ru(L)X2] (where arene=p-cymene, benzene, hexamethylbenzene or mesitylene, L=aminoflavone or aminochromone derivatives and X=Cl, I) were synthesized and characterized by elemental analysis, MS, IR and (1)H NMR spectroscopy. The stability of the selected complexes was assessed by UV-Vis spectroscopy in 24 hour period. The lipophilicity of the synthesized complexes was determined by the shake-flask method, and their cytotoxicity evaluated in vitro on patient-derived melanoma populations. The most active complexes against melanoma cells contain 7 aminoflavone and 6-aminoflavone as a ligand. The relationship between the cytotoxicity of all the obtained compounds and their logP values was determined and briefly analyzed with two different patterns observed. PMID- 26986978 TI - Induction Therapy for Locally Advanced, Resectable Esophagogastric Cancer: A Phase I Trial of Vandetanib (ZD6474), Paclitaxel, Carboplatin, 5-Fluorouracil, and Radiotherapy Followed by Resection. AB - OBJECTIVES: Preoperative chemotherapy and radiation for localized esophageal cancer produces cure rates near 30% when combined with surgical resection. Vandetanib, a small molecule receptor tyrosine kinase inhibitor of VEGFR-2, VEGFR 3, RET, and EGFR, demonstrated synergy with radiation and chemotherapy in preclinical models. We conducted a phase I study to assess the safety and tolerability of vandetanib when combined with preoperative chemoradiation in patients with localized esophageal carcinoma who were surgical candidates. METHODS: Patients with stage II-III esophageal and gastroesophageal junction carcinoma without prior therapy were enrolled in a 3+3 phase I design. Patients received once-daily vandetanib (planned dosing levels of 100, 200, and 300 mg) with concomitant daily radiotherapy (1.8 Gy/d, 45 Gy total) and chemotherapy, consisting of infusional 5-FU (225 mg/m/d over 96 h, weekly), paclitaxel (50 mg/m, days 1, 8, 15, 22, 29) and carboplatin (AUC of 5, days 1, 29). RESULTS: A total 9 patients were enrolled with 8 having either distal esophageal or gastroesophageal junction carcinomas. All patients completed the planned preoperative chemoradiation and underwent esophagectomy. Nausea (44%) and anorexia (44%) were the most common acute toxicities of any grade. One grade 4 nonhematologic toxicity was observed (gastrobronchial fistula). One additional patient suffered a late complication, a fatal aortoenteric hemorrhage, not definitively related to the investigational regimen. Five (56%) patients achieved a pathologic complete response. Three (33%) additional patients had only microscopic residual disease. Five (56%) patients remain alive and disease free with a median follow-up of 3.7 years and median overall survival of 3.2 years. The maximum tolerated dose was vandetanib 100 mg/d. CONCLUSIONS: Vandetanib at 100 mg daily is tolerable in combination with preoperative chemotherapy (5-FU, paclitaxel, carboplatin) and radiation therapy with encouraging efficacy worthy of future study. PMID- 26986979 TI - Water-soluble and photo-stable silver(I) dicarboxylate complexes containing 1,10 phenanthroline ligands: Antimicrobial and anticancer chemotherapeutic potential, DNA interactions and antioxidant activity. AB - The complexes [Ag2(OOC-(CH2)n-COO)] (n=1-10) (1-10) were synthesised and reacted with 1,10-phenanthroline (phen) to yield derivatives formulating as [Ag2(phen)x(OOC-(CH2)y-COO)].zH2O (x=2 or 3; y=1-10; z=1-4) (11-20) which are highly water-soluble and photo-stable in aqueous solution. The phen derivatives 11-20 exhibit chemotherapeutic potential against Candida albicans, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa and against cisplatin sensitive breast (MCF-7) and resistant ovarian (SKOV-3) cancer cell lines. Cyclic voltammetric analysis and DNA binding and intercalation studies indicate that the mechanism of action of 11-20 is significantly different to that of their silver(I) dicarboxylate precursors and they do not induce DNA damage or ROS generation in mammalian cells. The representative complexes 9 and 19 (containing the undecanedioate ligand) were both found to significantly reduce superoxide and hydrogen peroxide induced oxidative stress in the yeast S. cerevisiae. PMID- 26986983 TI - Cortical actin and the plasma membrane: inextricably intertwined. AB - The plasma membrane serves as a barrier, separating the cell from its external environment. Simultaneously it acts as a site for information transduction, entry of nutrients, receptor signaling, and adapts to the shape of the cell. This requires local control of organization at multiple scales in this heterogeneous fluid lipid bilayer with a plethora of proteins and a closely juxtaposed dynamic cortical cytoskeleton. New membrane models highlight the influence of the underlying cortical actin on the diffusion of membrane components. Myosin motors as well as proteins that remodel actin filaments have additionally been implicated in defining the organization of many membrane constituents. Here we provide a perspective of the intimate relationship of the membrane lipid matrix and the underlying cytoskeleton. PMID- 26986982 TI - How could differences in 'control over destiny' lead to socio-economic inequalities in health? A synthesis of theories and pathways in the living environment. AB - We conducted the first synthesis of theories on causal associations and pathways connecting degree of control in the living environment to socio-economic inequalities in health-related outcomes. We identified the main theories about how differences in 'control over destiny' could lead to socio-economic inequalities in health, and conceptualised these at three distinct explanatory levels: micro/personal; meso/community; and macro/societal. These levels are interrelated but have rarely been considered together in the disparate literatures in which they are located. This synthesis of theories provides new conceptual frameworks to contribute to the design and conduct of theory-led evaluations of actions to tackle inequalities in health. PMID- 26986984 TI - Mechanics of mitochondrial motility in neurons. AB - A properly organized, healthy mitochondrial network is critical for preserving neuronal form and function. Large, elaborately branched neuronal morphologies, energetic demands that fluctuate in time and space, and long neuronal lifespans make the distribution of mitochondria in neurons a particularly complex problem. Moreover, mitochondrial networks are dynamic systems in which mitochondria grow, divide and fuse, move along cytoskeletal filaments, and are degraded in an active fashion. Although the molecular mechanisms that govern mitochondrial motility, in particular, are increasingly well-characterized, the manner in which these mechanisms are coordinated to give rise to the global mitochondrial distribution in neurons is less well understood. Here I review several molecular mechanisms for mitochondrial motility in the context of a general mechanical framework. In this framework, molecular pathways that control mitochondrial movement can be reduced to their effects on the balance of forces that act on mitochondria, driving and opposing movement. PMID- 26986985 TI - ADAM10 mediates the cell invasion and metastasis of human esophageal squamous cell carcinoma via regulation of E-cadherin activity. AB - A disintegrin and metalloprotease 10 (ADAM10) is involved in the tumorigenesis, invasion and metastasis of several types of solid tumors. However, the potential role of ADAM10 in human esophageal squamous cell carcinoma (ESCC) is not yet well understood. The present study showed that ADAM10 was overexpressed in human ESCC tissues in vivo, and positively associated with depth of tumor invasion, lymph node metastasis and TNM stage, contributing to tumor carcinogenesis, invasion and metastasis. Additionally, ADAM10 was overexpressed in 3 types of ESCC cell lines in vitro, as compared to that in normal esophageal epithelial cells (NEECs); and moreover, ESCC cells with high ADAM10 expression obtained enhanced invasion and migration ability. Subsequently, ADAM10 silencing by small interfering (si) RNA in ESCC cell line, EC-1, reduced cell invasion, migration and proliferation in vitro. Finally, ADAM10 negatively regulated E-cadherin in ESCC in vivo and in vitro. In conclusion, active ADAM10 promotes the carcinogenesis, invasion, metastasis and proliferation of ESCC and controls invasion and metastasis at least in part through the shedding of E-cadherin activity, which makes it a potential biomarker and a useful therapeutic target for ESCC. PMID- 26986987 TI - Building the Composite Face Lift: A Personal Odyssey. AB - This article is a 42-year history of the development of a comprehensive face-lift technique by the author. It describes how the composite rhytidectomy has been constructed, anatomical area by anatomical area, over the author's lifetime career as a plastic surgeon. Over the course of these years, beginning with Skoog's 1973 description of using the platysma muscle of the lower face, it describes how progressively the other significant structures of anatomy necessary to be used in achieving significant rejuvenation have been analyzed by the author and in turn surgically repositioned. The theory was based on creating a composite flap of the face, keeping the orbicularis oculi muscle, facial platysma muscle, and cheek fat in their normal anatomical and intimate relationship with each other by using the skin as the carriage. In addition, differences of vectors between the composite rhytidectomy and traditional techniques are demonstrated. The gradual and persistent pursuit of periorbital rejuvenation using the lower eyelid fat and the septal orbitale is described. Each of the anatomical structures involved and the description of their importance and surgical execution have been published over the surgical career of the author, including use of the same principles for reversing suboptimal face-lift results. PMID- 26986986 TI - Modeling Granulomas in Response to Infection in the Lung. AB - Alveolar macrophages play a large role in the innate immune response of the lung. However, when these highly immune-regulatory cells are unable to eradicate pathogens, the adaptive immune system, which includes activated macrophages and lymphocytes, particularly T cells, is called upon to control the pathogens. This collection of immune cells surrounds, isolates and quarantines the pathogen, forming a small tissue structure called a granuloma for intracellular pathogens like Mycobacterium tuberculosis (Mtb). In the present work we develop a mathematical model of the dynamics of a granuloma by a system of partial differential equations. The 'strength' of the adaptive immune response to infection in the lung is represented by a parameter alpha, the flux rate by which T cells and M1 macrophages that immigrated from the lymph nodes enter into the granuloma through its boundary. The parameter alpha is negatively correlated with the 'switching time', namely, the time it takes for the number of M1 type macrophages to surpass the number of infected, M2 type alveolar macrophages. Simulations of the model show that as alpha increases the radius of the granuloma and bacterial load in the granuloma both decrease. The model is used to determine the efficacy of potential host-directed therapies in terms of the parameter alpha, suggesting that, with fixed dosing level, an infected individual with a stronger immune response will receive greater benefits in terms of reducing the bacterial load. PMID- 26986988 TI - Generating an Engineered Adipose Tissue Flap Using an External Suspension Device. AB - BACKGROUND: The tissue-engineering chamber technique can generate large volumes of adipose tissue, which provides a potential solution for the complex reconstruction of large soft-tissue defects. However, major drawbacks of this technique are the foreign-body reaction and the volume limitation imposed by the chamber. METHODS: In this study, the authors developed a novel tissue-engineering method using a specially designed external suspension device that generates an optimized volume of adipose flap and avoids the implantation of foreign material. The rabbits were processed using two different tissue-engineering methods, the external suspension device technique and the traditional tissue-engineering chamber technique. RESULTS: The adipose flaps generated by the external suspension device had a normal adipose tissue structure that was as good as that generated by the traditional tissue-engineering chamber, but the flap volume was much larger. The final volume of the engineered adipose flap grew between weeks 0 and 36 from 5.1 ml to 30.7 ml in the traditional tissue-engineering chamber group and to 80.5 ml in the external suspension device group. During the generation process, there were no marked differences between the two methods in terms of structural and cellular changes of the flap, except that the flaps in the traditional tissue-engineering chamber group had a thicker capsule at the early stage. In addition, the enlarged flaps generated by the external suspension device could be reshaped into specific shapes by the implant chamber. CONCLUSIONS: This minimally invasive external suspension device technique can generate large-volume adipose flaps. Combined with a reshaping method, this technique should facilitate clinical application of adipose tissue engineering. PMID- 26986989 TI - Hospital Quality and Performance of a Complex Surgical Procedure after Traumatic Digit Amputation. AB - BACKGROUND: Traumatic digit amputations are prevalent injuries that have long term disabling consequences. Although replantation after traumatic digit amputation is a complex procedure, the aesthetic, functional, and long-term economic benefits of replantation render it preferable to revision amputation when clinically indicated. The authors adapted the Donabedian quality-of-care conceptual framework to examine the association between hospital outcome quality measured by observed-to-expected mortality ratio and the treatment received after traumatic digit amputation. The authors hypothesized that the probability of undergoing replantation is higher in hospitals with lower observed-to-expected mortality ratios. METHODS: Data from 106 qualified Level I and II trauma centers included in the 2007 to 2012 National Trauma Data Bank were used to estimate hospital-specific observed-to-expected mortality ratio. The authors then used a two-level logistic hierarchical model, adjusting for patient, clinical, and hospital characteristics, to examine whether observed-to-expected mortality ratio, as one of the commonly used hospital quality measures, is a predictor of the treatment received for 4169 patients with traumatic digit amputation. RESULTS: Compared with trauma centers with high observed-to-expected mortality ratios, the probability of undergoing replantation was substantially higher in trauma centers with low observed-to-expected mortality ratios (OR, 5.09; 95 percent CI, 2.51 to 10.30; p < 0.001). Seeking care at hospitals with more than 400 beds increased the probability of digit replantation (OR, 2.08; 95 percent CI, 1.08 to 4.01; p = 0.029). Having no insurance decreased the odds of undergoing replantation (OR, 0.70; 95 percent CI, 0.53 to 0.91; p = 0.009). CONCLUSIONS: Hospital observed-to-expected mortality ratio was the greatest predictor of undergoing replantation after digit amputation injury. The observed to-expected mortality ratio, as an outcome measure of hospital quality, is an important predictor of the treatment received. PMID- 26986990 TI - Analyzing Regional Differences over a 15-Year Trend of One-Stage versus Two-Stage Breast Reconstruction in 941,191 Postmastectomy Patients. AB - BACKGROUND: Implant-based reconstruction is the predominant form of breast reconstruction, with the two-stage tissue expander/implant approach being the most popular. Recently, the direct-to-implant, one-stage breast reconstruction procedure has gained momentum. In this study, national and regional trends across the United States for the two different types of implant-based reconstructions were evaluated. METHODS: The Nationwide Inpatient Sample database was used to extrapolate data on type of mastectomy, implant-based reconstructive technique (one-stage or two-stage), and sociodemographic and hospital variables. Differences were assessed using the chi-square test, impact of variables on reconstructive method was analyzed using logistic regression, and trends were analyzed using the Cochrane-Armitage test. RESULTS: Between 1998 and 2012, a total of 1,444,587 patients treated for breast cancer or at increased risk of breast cancer met the defined selection criteria. Of these, 194,377 patients underwent implant-based breast reconstruction (13.6 percent one-stage and 86.4 percent two-stage). In both, there was a significant increase in procedures performed over time (p < 0.001). The highest increase in both was seen in the Northeast region of the United States, and the lowest increase was seen in the South. When stratified into regions, analysis showed differences in socioeconomic and hospital characteristics within the different regions. CONCLUSIONS: There is an observed increase in the number of one-stage and two-stage breast reconstructions being performed. Sociodemographic and hospital factors of influence vary in the different regions of the United States. This study provides important information for clinicians and policy makers who seek to ensure equitable and appropriate access for patient to the different types of implant based procedures. PMID- 26986991 TI - A Novel Approach to Keloid Reconstruction with Bilaminar Dermal Substitute and Epidermal Skin Grafting. AB - BACKGROUND: Keloids represent a challenging problem. Surgical excision remains the definitive treatment for immediate lesion debulking, but recurrence rates are reported to be 45 to 100 percent. The authors present a staged reconstructive approach using a dermal regeneration substrate and epidermal grafting to minimize recurrence and donor-site morbidity. METHODS: Keloids were completely excised down to normal subcutaneous tissue or perichondrium. A bilaminar dermal regeneration matrix was approximated to the entire wound, with the silicone lamina oriented superficially. Reconstruction was delayed for at least 21 days to allow for neodermal ingrowth. The silicone lamina was then removed, and an epidermal skin graft was harvested from the thigh and secured to the neodermis with nonocclusive dressing. Reconstructed defects and donor sites were assessed for recurrence of keloids and scar appearance. RESULTS: Five patients underwent treatment; two had keloids involving the superior helix of the ear (average area, 2.6 cm), two had keloids involving the chest (average area, 28 cm), and one had a keloid in the pubic region (area, 10 cm). All had failed at least one previous treatment with direct excision and steroid injections. Mean follow-up was 48.8 weeks (range, 38 to 60 weeks). Average time to complete wound epithelialization was 5.5 weeks. There were no infections or cellulitis. All reconstructed defects were aesthetically acceptable and remained flat without significant widening. There were no long-term complaints of pruritus or pain and there was no evidence of donor-site scarring. CONCLUSIONS: Epidermal grafting provides significant advantages when used with a dermal regeneration matrix. This approach obviates reliance on skin creep and flap undermining to achieve primary closure. Exclusion of dermis and significant extracellular matrix components limits contracture, further facilitating tension-free wound healing. Scarring response within the donor site and graft is also minimized. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26986992 TI - Molecular Turnstiles Regulated by Metal Ions. AB - A family of novel molecular turnstiles 1-3 composed of two stators with pyridyl binding sites and a different-sized triptycene rotor was synthesized. The molecular turnstiles behave in an open state at room temperature in the absence of metal ions but display significantly different closed states in the presence of Ag(+) and Pd(2+). The Ag(+)-mediated turnstiles 1-3Ag exhibited closed states but unreadable bistability at ambient temperature because the Ag(+)-mediated macrocyclic framework is not able to restrict the rotations of the rotors; while temperature was decreased, the macrocyclic frameworks became stable enough to halt the rotations of the rotors, eventually leading to the readable closed states for 1-3Ag. In contrast, Pd(2+)-mediated macrocyclic frameworks are stable, giving rise to a detectable closed state of turnstiles 1-3Pd in a wide range of temperatures. These findings have also been supported by DFT calculations. PMID- 26986993 TI - The impact of detraining on cardiac autonomic function and specific endurance and muscle power performances of high-level endurance runners. AB - BACKGROUND: The purpose of this study was to analyze the effects of four weeks of training cessation (TC) on specific endurance performance, resting and postexercise heart rate variability (HRV) and neuromuscular capacities of high level endurance runners. METHODS: Eighteen endurance runners, 8 men and 10 women (25.5+/-7.5 years; 166.9+/-7.6 cm; 54.2+/-6.9 kg), took part in this study. The 3000 m time trial performance, resting HRV, 5'-5' test, squat and countermovement jumps (SJ and CMJ, respectively) and mean propulsive power in the jump squat exercise relative to body mass (MPP JS REL) were performed pre and immediately following the 4-week TC. The inference based on magnitudes were used to analyze the differences between pre and post values. RESULTS: The time in the 3000 m time trial was almost certainly higher after TC. A very likely decrease was noticed in the resting HRV Index after the TC period. The differences in all variables analyzed during the 5'-5' test were rated as unclear. No differences were observed in SJ and CMJ comparing the pre and post moments of TC, while the MPP JS REL was very likely improved after the TC period. CONCLUSIONS: The resting HRV accompanied the reductions in the specific endurance performance while the 5'-5' test variables did not. The lack of training stimulus led to improvement in the MPP JS REL, possibly due to the withdrawal of specific endurance training, which strongly concurs with neuromuscular performance. PMID- 26986994 TI - Negative Poisson's Ratio in Single-Layer Graphene Ribbons. AB - The Poisson's ratio characterizes the resultant strain in the lateral direction for a material under longitudinal deformation. Though negative Poisson's ratios (NPR) are theoretically possible within continuum elasticity, they are most frequently observed in engineered materials and structures, as they are not intrinsic to many materials. In this work, we report NPR in single-layer graphene ribbons, which results from the compressive edge stress induced warping of the edges. The effect is robust, as the NPR is observed for graphene ribbons with widths smaller than about 10 nm, and for tensile strains smaller than about 0.5% with NPR values reaching as large as -1.51. The NPR is explained analytically using an inclined plate model, which is able to predict the Poisson's ratio for graphene sheets of arbitrary size. The inclined plate model demonstrates that the NPR is governed by the interplay between the width (a bulk property), and the warping amplitude of the edge (an edge property), which eventually yields a phase diagram determining the sign of the Poisson's ratio as a function of the graphene geometry. PMID- 26986996 TI - Luigi Provasoli Award Recipients. PMID- 26986995 TI - Extended-interval gentamicin administration in neonates: a simplified approach. AB - OBJECTIVE: Gentamicin dosing is highly variable and remains complicated in the neonatal population. Traditional dosing in our unit resulted in an excessive number of elevated trough serum gentamicin levels. We hypothesized that one uniform gentamicin dose for neonates of all gestational ages will reduce the incidence of elevated trough levels from 50 to 10%. STUDY DESIGN: Our prospective, randomized, controlled trial enrolled eligible neonates into two groups, according to gestational age (?34 6/7 (group I) and >35 0/7 weeks (group II)). Patients in the study arm received a dose of gentamicin 5 mg kg(-1) intravenous (i.v.) every 36 h, whereas patients in the control arm received traditional dosage. Patients were monitored for resolution of infection, serum gentamicin levels and adverse effects. We confirmed our findings in a follow-up study. Fisher's exact and Mann-Whitney tests were used for statistical analysis. RESULTS: We enrolled 96 neonates, 50 in group I (n=25 per arm) and 46 in group II (n=23 per arm). Elevated trough levels were reduced by 66% in group I (P=0.61) and 100% in group II (P=0.0015). In the study arm of both groups, 48/49 neonates had Cmin serum gentamicin concentration (SGC) <2 mg l(-1) and the majority had a trough SGC <1 mg l(-1) (P<0.0001). The study dose resulted in maximum gentamicin levels in the goal range and a 50% reduction in dosage modifications. There were no treatment failures or adverse effects. Our follow-up study phase confirmed these results. CONCLUSION: A standardized gentamicin dosage of 5 mg kg(-1) i.v. every 36 h to neonates of all gestational ages was safe and resulted in SGCs in goal therapeutic ranges. The implications of this simplified gentamicin dosage are to reduce health-care costs by less frequent dosing of gentamicin and reducing medication errors in physician prescribing from complicated dosing schemes. PMID- 26986997 TI - Interspecific plastidial recombination in the diatom genus Pseudo-nitzschia. AB - Plastids are usually uni-parentally inherited and genetic recombination between these organelles is seldom observed. The genus Pseudo-nitzschia, a globally relevant marine diatom, features bi-parental plastid inheritance in the course of sexual reproduction. This observation inspired the recombination detection we pursued in this paper over a ~1,400-nucleotide-long region of the plastidial rbcL, a marker used in both molecular taxonomy and phylogenetic studies in diatoms. Among all the rbcL-sequences available in web-databases for Pseudo nitzschia, 42 haplotypes were identified and grouped in five clusters by Bayesian phylogeny. Signs of hybridization were evident in four of five clusters, at both intra- and interspecific levels, suggesting that, in diatoms, (i) plastidial recombination is not absent and (ii) hybridization can play a role in speciation of Pseudo-nitzschia spp. PMID- 26986999 TI - The surprising world of cyanobacteria: cylindrospermopsin has a soil face. PMID- 26986998 TI - Why we need more algal metagenomes(1). AB - A recent perspective article ably argued that fully sequencing more algal genomes would enable progress in diverse areas of fundamental and applied studies. More algal genomes would add resources needed to build well-supported phylogenies, improve our understanding of how horizontal gene transfer has influenced the evolution of algal genomes, provide useful ecological insights, and generate information essential to manipulating the genomes of industrially useful algae (J. Phycol. 51:1). We agree that more algal genomes would be quite beneficial, and also propose that more algal metagenomes would enable progress in both predictable and unforeseen directions. PMID- 26987000 TI - A combined morphological, ultrastructural, molecular, and biochemical study of the peculiar family Gomontiellaceae (Oscillatoriales) reveals a new cylindrospermopsin-producing clade of cyanobacteria. AB - Members of the morphologically unusual cyanobacterial family Gomontiellaceae were studied using a polyphasic approach. Cultured strains of Hormoscilla pringsheimii, Starria zimbabweensis, Crinalium magnum, and Crinalium epipsammum were thoroughly examined, and the type specimen of the family, Gomontiella subtubulosa, was investigated. The results of morphological observations using both light microscopy and transmission electron microscopy were consistent with previous reports and provided evidence for the unique morphological and ultrastructural traits of this family. Analysis of the 16S rRNA gene confirmed the monophyletic origin of non-marine repre-sentatives of genera traditionally classified into this family. The family was phylogenetically placed among other groups of filamentous cyanobacterial taxa. The presence of cellulose in the cell wall was analyzed and confirmed in all cultured Gomontiellaceae members using Fourier transform infrared spectroscopy and fluorescence microscopy. Evaluation of toxins produced by the studied strains revealed the hepatotoxin cylindrospermopsin (CYN) in available strains of the genus Hormoscilla. Production of this compound in both Hormoscilla strains was detected using high performance liquid chromatography in tandem with high resolution mass spectrometry and confirmed by positive PCR amplification of the cyrJ gene from the CYN biosynthetic cluster. To our knowledge, this is the first report of CYN production by soil cyanobacteria, establishing a previously unreported CYN producing lineage. This study indicates that cyanobacteria of the family Gomontiellaceae form a separate but coherent cluster defined by numerous intriguing morphological, ultrastructural, and biochemical features, and exhibiting a toxic potential worthy of further investigation. PMID- 26987001 TI - Seasonal succession of the travertine-forming desmid Oocardium stratum. AB - The calcifying Conjugatophyte Oocardium stratum occurs exclusively in spring associated limestones (SAL) with active meteogene limestone deposition. The macroscopic colonies of Oocardium stratum form hemispherical, pinhead-like structures with a diameter of 0.5-2.0 mm. As its autecology is still poorly understood, we focused on the seasonal development of Oocardium stratum and linked environmental factors to its abundance. The study was conducted in a rivulet in Lunz/See (Austria) for 16 months on a weekly (growing season) to monthly (winter season) basis. Oocardium colonies were found throughout the whole year, with maximum abundance during the mid-summer months July and August. Repeated macro-mapping of three SAL sites measuring 750 cm(2) each showed a maximum Oocardium cover of around 30% in August; two smaller peaks developed in early summer and late autumn with ~10% cover. Diatom mats dominated by Cymbella excisiformis occurred in spring, autumn and winter, with more than 75% cover. The seasonal change between Oocardium and diatoms in limestone-precipitating springs causes a typical sequence pattern of limestone layers. Redundancy analysis revealed water temperature and bicarbonate content as the main structuring factors; these control the occurrence and growth of Oocardium, reflecting season as a background variable. Optimum growth conditions for Oocardium were an alkalinity around 4.7 meq . L(-1) and a water temperature around 13 degrees C. Site openness, nitrate and dissolved carbon dioxide were inversely related to Oocardium biomass, the opposite for diatoms. Other environmental factors such as total ions or soluble reactive phosphorus had no significant influence on Oocardium stratum abundance. PMID- 26987003 TI - Insight into glucosidase II from the red marine microalga Porphyridium sp. (Rhodophyta). AB - N-glycosylation of proteins is one of the most important post-translational modifications that occur in various organisms, and is of utmost importance for protein function, stability, secretion, and loca-lization. Although the N-linked glycosylation pathway of proteins has been extensively characterized in mammals and plants, not much information is available regarding the N-glycosylation pathway in algae. We studied the alpha 1,3-glucosidase glucosidase II (GANAB) glycoenzyme in a red marine microalga Porphyridium sp. (Rhodophyta) using bioinformatic and biochemical approaches. The GANAB-gene was found to be highly conserved evolutionarily (compo-sed of all the common features of alpha and beta subunits) and to exhibit similar motifs consistent with that of homolog eukaryotes GANAB genes. Phylogenetic analysis revealed its wide distribution across an evolutionarily vast range of organisms; while the alpha subunit is highly conserved and its phylogenic tree is similar to the taxon evolutionary tree, the beta subunit is less conserved and its pattern somewhat differs from the taxon tree. In addition, the activity of the red microalgal GANAB enzyme was studied, including functional and biochemical characterization using a bioassay, indicating that the enzyme is similar to other eukaryotes ortholog GANAB enzymes. A correlation between polysaccharide production and GANAB activity, indicating its involvement in polysaccharide biosynthesis, is also demonstrated. This study represents a valuable contribution toward understanding the N-glycosylation and polysaccharide biosynthesis pathways in red microalgae. PMID- 26987002 TI - Examination of the structures of several glycerolipids from marine macroalgae by NMR and GC-MS. AB - Several classes of glycerolipids were isolated from the total lipids of the algae Saccharina cichorioides, Eualaria fistulosa, Fucus evanescens, Sargassum pallidum, Silvetia babingtonii (Ochrophyta, Phaeophyceae), Tichocarpus crinitus, and Neorhodomela larix (Rhodophyta, Florideophyceae). The structures of these lipids were examined by nuclear magnetic resonance (NMR) spectroscopy, including 1D ((1) H and (13) C) and 2D (COSY, HSQC and HMBC) experiments. All of the investigated algae included common galactolipids and sulfonoglycolipids as the major glycolipids. Minor glycolipids isolated from S. cichorioides, T. crinitus, and N. laris were identified as lyso-galactolipids with a polar group consisted of the galactose. Comparison of the (1) H NMR data of minor nonpolar lipids isolated from the extracts of the brown algae S. pallidum and F. evanescens with the (1) H NMR data of other lipids allowed them to be identified as diacylglycerols. The structures of betaine lipids isolated from brown algae were confirmed by NMR for the first time. The fatty acid compositions of the isolated lipids were determined by gas chromatography-mass spectrometry. PMID- 26987004 TI - Balechina and the new genus Cucumeridinium gen. nov. (Dinophyceae), unarmored dinoflagellates with thick cell coverings. AB - The genus Balechina (=subgenus Pachydinium) was established for heterotrophic gymnodinioid dinoflagellates with a thick cell covering. The type species, B. pachydermata (=Gymnodinium pachyderm-atum), showed numerous fine longitudinal striae, whereas B. coerulea (=G. coeruleum) showed ~24 prominent longitudinal surface ridges or furrows and a distinctive blue pigmentation. We have investigated the morphology and molecular phylogeny of these taxa and the species Gymnodinium cucumis, G. lira and G. amphora from the western Mediterranean, Brazil and Japan. Sudden contractions at the cingulum level were seen in B. pachydermata, which also showed a high morphological variability which included morphotypes that have been described as Amphidinium vasculum, G. amphora, G. dogielii and G. gracile sensu Kofoid and Swezy. Molecular phylogeny based on small subunit rRNA gene sequences revealed that Balechina coerulea, G. cucumis and G. lira formed a clade distantly related to the clade of the type species, B. pachydermata, and G. amphora. We propose the new genus Cucumeridinium for the species with longitudinal ridges and a circular apical groove (Cucumeridinium coeruleum comb. nov., C. lira comb. nov. and C. cucumis comb. nov.), and Gymnodinium canus and G. costatum are considered synonyms of C. coeruleum. The genus Balechina remains for the species with a double-layer cell covering, bossed surface with fine striae, and an elongated elliptical apical groove. At present, the genus is monotypic containing only B. pachydermata. PMID- 26987006 TI - Seasonal differences in the effects of oscillatory and uni-directional flow on the growth and nitrate-uptake rates of juvenile Laminaria digitata (Phaeophyceae). AB - The influence of oscillatory versus unidirectional flow on the growth and nitrate uptake rates of juvenile kelp, Laminaria digitata, was determined seasonally in experimental treatments that simulated as closely as possible natural environmental conditions. In winter, regardless of flow condition (oscillatory and unidirectional) or water velocity, no influence of water motion was observed on the growth rate of L. digitata. In summer, when ambient nitrate concentrations were low, increased water motion enhanced macroalgal growth, which is assumed to be related to an increase in the rate of supply of nutrients to the blade surface. Nitrate-uptake rates were significantly influenced by water motion and season. Lowest nitrate-uptake rates were observed for velocities <5 cm . s(-1) and nitrate-uptake rates increased by 20%-50% under oscillatory motion compared to unidirectional flow at the same average speed. These data further suggested that the diffusion boundary layer played a significant role in influencing nitrate-uptake rates. However, while increased nitrate-uptake in oscillatory flow was clear, this was not reflected in growth rates and further work is required to understand the disconnection of nitrate-uptake and growth by L. digitata in oscillatory flow. The data obtained support those from related field-based studies, which suggest that in summer, when insufficient nitrogen is available in the water to saturate metabolic demand, the growth rate of kelps will be influenced by water motion restricting mass transfer of nitrogen. PMID- 26987005 TI - Microsensor studies on Padina from a natural CO2 seep: implications of morphology on acclimation to low pH. AB - Low seawater pH can be harmful to many calcifying marine organisms, but the calcifying macroalgae Padina spp. flourish at natural submarine carbon dioxide seeps where seawater pH is low. We show that the microenvironment created by the rolled thallus margin of Padina australis facilitates supersaturation of CaCO3 and calcifi-cation via photosynthesis-induced elevated pH. Using microsensors to investigate oxygen and pH dynamics in the microenvironment of P. australis at a shallow CO2 seep, we found that, under saturating light, the pH inside the microenvironment (pHME ) was higher than the external seawater (pHSW ) at all pHSW levels investigated, and the difference (i.e., pHME - pHSW ) increased with decreasing pHSW (0.9 units at pHSW 7.0). Gross photosynthesis (Pg ) inside the microenvironment increased with decreasing pHSW , but algae from the control site reached a threshold at pH 6.5. Seep algae showed no pH threshold with respect to Pg within the pHSW range investigated. The external carbonic anhydrase (CA) inhibitor, acetazolamide, strongly inhibited Pg of P. australis at pHSW 8.2, but the effect was diminished under low pHSW (6.4-7.5), suggesting a greater dependence on membrane-bound CA for the dehydration of HCO3 (-) ions during dissolved inorganic carbon uptake at the higher pHSW . In comparison, a calcifying green alga, Halimeda cuneata f. digitata, was not inhibited by AZ, suggesting efficient bicarbonate transport. The ability of P. australis to elevate pHME at the site of calcification and its strong dependence on CA may explain why it can thrive at low pHSW . PMID- 26987007 TI - Different strategies of energy storage in cultured and freshly isolated Symbiodinium sp. AB - The endosymbiotic relationship between cnidarians and Symbiodinium is critical for the survival of coral reefs. In this study, we developed a protocol to rapidly and freshly separate Symbiodinium from corals and sea anemones. Furthermore, we compared these freshly-isolated Symbiodinium with cultured Symbiodinium to investigate host and Symbiodinium interaction. Clade B Symbiodinium had higher starch content and lower lipid content than those of clades C and D in both freshly isolated and cultured forms. Clade C had the highest lipid content, particularly when associated with corals. Moreover, the coral-associated Symbiodinium had higher protein content than did cultured and sea anemone-associated Symbiodinium. Regarding fatty acid composition, cultured Symbiodinium and clades B, C, and D shared similar patterns, whereas sea anemone associated Symbiodinium had a distinct pattern compared coral-associated Symbiodinium. Specifically, the levels of monounsaturated fatty acids were lower than those of the saturated fatty acids, and the level of polyunsaturated fatty acids (PUFAs) were the highest in all examined Symbiodinium. Furthermore, PUFAs levels were higher in coral-associated Symbiodinium than in cultured Symbiodinium. These results altogether indicated that different Symbiodinium clades used different energy storage strategies, which might be modified by hosts. PMID- 26987008 TI - New diagnostic characters for the order Sporolithales (Corallinophycidae, Rhodophyta). AB - The diagnosis of the order Sporolithales is currently restricted to tetrasporangial anatomy. Until recently, there were few reports about gametangial, and more specifically carposporangial material for the Sporolithales. This study provides the first detailed observations of the anatomy of the mature carposporophyte phase from three species of Sporolithales commonly found in rhodolith beds from Brazil: Sporolithon episporum, S. ptychoides, and Sporolithon sp. Using these observations, along with previously published descriptions and illustrations from other representative species in the order, a comparison was made with the other three orders (Corallinales, Hapalidiales, and Rhodogorgonales) of the Corallinophycidae. We amend the diagnosis of the order Sporolithales to include the anatomy of the mature carposporophyte as follows: carposporangial conceptacles that lack a central fusion cell, but instead with numerous, short, one to two-celled, filaments that bear oblong terminal carposporangia that are distributed across the conceptacle chamber floor and walls. PMID- 26987009 TI - Delimiting species in the Phacus longicauda complex (Euglenida) through morphological and molecular analyses. AB - Although Phacus longicauda is the type species of the genus Phacus and one of the most common species among autotrophic euglenids, its correct identification is nearly impossible. Over 30 morphologically similar taxa appear in the literature, but there are no good diagnostic features to distinguish them. Using environmental sampling and whole genome amplification, we delimited species within the Phacus longicauda complex. Morphological and molecular characters were analyzed for 36 strains isolated from environmental samples (mainly from Poland). DNA was obtained from a small number of cells (20-30) isolated with a micropipette from every sample (i.e., without setting up laboratory cultures), and phylogenetic analyses were based on variation in nSSU rDNA. Apart from Phacus longicauda, three other species (Phacus circumflexus, Phacus helikoides, and Phacus tortus) were distinguished. Phacus cordata comb. nov. Zakrys et M. Lukomska and Phacus rotunda comb. nov. Zakrys et M. Lukomska had their taxonomic ranks changed and two species new to science, Phacus cristatus sp. nov. Zakrys et M. Lukomska and Phacus crassus sp. nov. Zakrys et M. Lukomska, were described. For all verified species, diagnostic descriptions were amended and epitypes designated. PMID- 26987010 TI - Etheliaceae fam. nov. (Gigartinales, Rhodophyta), with a clarification of the generitype of Ethelia and the addition of six novel species from warm waters. AB - Based upon COI-5P, LSU rDNA, and rbcL sequence data and morphological characteristics, six new members of the noncalcified crustose genus of red algae Ethelia are described in a new family, Etheliaceae (Gigartinales), sister to the recently described Ptilocladiopsidaceae. The novel species are described from subtropical to tropical Atlantic and Indo-Pacific Ocean basins; E. mucronata sp. nov. and E. denizotii sp. nov. from southern and northern Western Australia respectively, E. wilcei sp. nov. from the Cocos (Keeling) Islands of Australia, E. suluensis sp. nov. from the Philippines, E. umbricola sp. nov. from Bermuda and E. kraftii sp. nov. from Lord Howe Island, Australia. The generitype, Ethelia biradiata, originally reported from the Seychelles, Indian Ocean, is added to the Western Australian flora. PMID- 26987012 TI - Corrigendum. PMID- 26987011 TI - Chodatodesmus australis sp. nov. (Scenedesmaceae, Chlorophyta) from Antarctica, with the emended description of the genus Chodatodesmus, and circumscription of Flechtneria rotunda gen. et sp. nov. AB - The family Scenedesmaceae is a taxonomically complicated group due to its simple morphology, high phenotypic plasticity, and the presence of cryptic taxa. Over the years several taxonomic revisions, based on molecular data, affected the family. Here, we describe a new scenedesmacean species from Antarctica, Chodatodesmus australis, based on phylogenetic analyses of data from nuclear (ITS2 spacer, 18S rDNA), and plastid (rbcL, tufA) markers. Morphological (LM and SEM) and ultrastructural (TEM) observations, carried out both on the holotype of C. australis and on the generitype of Chodatodesmus, allow us to emend the original generic description of this genus. Our molecular and phylogenetic data also reveal the existence of a new monotypic genus, Flechtneria, inside the family Scenedesmaceae and lead to the taxonomic reassignment of some microalgal strains available in International Culture Collections to new taxa. Of the considered genomic regions, the tufA gene was the easiest to amplify and sequence and it showed the highest phylogenetic signal, even if the number of sequences already available for this marker in the public databases was considerably lower than for the other chosen loci. The rbcL gene also provided good phylogenetic signal, but its amplification and sequencing were generally more problematic. The nuclear markers gave lower phylogenetic signals, but the 18S rDNA allowed distinction at the genus level and the ITS2 spacer had the advantage that secondary structures could be considered in the analyses. The use of more than one molecular locus is suggested to obtain reliable results in the characterization of scenedesmacean strains. PMID- 26987013 TI - A New Series of Orally Bioavailable Chemokine Receptor 9 (CCR9) Antagonists; Possible Agents for the Treatment of Inflammatory Bowel Disease. AB - Chemokine receptor 9 (CCR9), a cell surface chemokine receptor which belongs to the G protein-coupled receptor, 7-trans-membrane superfamily, is expressed on lymphocytes in the circulation and is the key chemokine receptor that enables these cells to target the intestine. It has been proposed that CCR9 antagonism represents a means to prevent the aberrant immune response of inflammatory bowel disease in a localized and disease specific manner and one which is accessible to small molecule approaches. One possible reason why clinical studies with vercirnon, a prototype CCR9 antagonist, were not successful may be due to a relatively poor pharmacokinetic (PK) profile for the molecule. We wish to describe work aimed at producing new, orally active CCR9 antagonists based on the 1,3-dioxoisoindoline skeleton. This study led to a number of compounds that were potent in the nanomolar range and which, on optimization, resulted in several possible preclinical development candidates with excellent PK properties. PMID- 26987014 TI - Ferrocene-Modified Phospholipid: An Innovative Precursor for Redox-Triggered Drug Delivery Vesicles Selective to Cancer Cells. AB - Controlled payload release is one of the key elements in the creation of a reliable drug delivery system. We report the discovery of a drug delivery vessel able to transport chemotherapeutic agents to target cancer cells and selectively trigger their release using the electrochemical activity of a ferrocene-modified phospholipid. Supported by in vitro assays, the competitive advantages of this discovery are (i) the simple one step scalability of the synthetic process, (ii) the stable encapsulation of toxic drugs (doxorubicin) during transport, and (iii) the selective redox triggering of the liposomes to harness their cytotoxic payload at the cancer site. Specifically, the redox-modified giant unilamellar vesicle and liposomes were characterized using advanced methods such as scanning electrochemical microscopy (SECM), transmission electron microscopy (TEM), dynamic light scattering (DLS), and fluorescent imaging. PMID- 26987015 TI - Quantitative Assessment of Cochlear Histopathologic Findings in Patients With Suppurative Labyrinthitis. AB - IMPORTANCE: Better understanding of the effects of suppurative labyrinthitis (SL) on cochlear elements will aid the development of new approaches to treat its sequelae and complications in the ear. OBJECTIVE: To quantitatively evaluate the effects of SL on cochlear elements in humans. DESIGN, SETTING, AND PARTICIPANTS: A comparative study was conducted at a tertiary academic medical center from October 20, 2014, to January 3, 2015, of the histopathologic characteristics of 28 archived human temporal bone samples from 19 deceased patients with SL and 20 temporal bone samples from 14 deceased, age-matched controls. EXPOSURES: Evaluation of archived human temporal bone samples. MAIN OUTCOMES AND MEASURES: The locations of SL in the inner ear and the degree of endolymphatic hydrops were noted; the area of the stria vascularis and the spiral ligament in all turns of the cochlea at the midmodiolar level and in the adjacent 2 sections were measured; and the number of remaining outer and inner hair cells of the cochlea were counted to calculate the loss of both types of cells. To evaluate the loss of fibrocytes in the spiral ligament, a rating scale in each cochlear turn was used. For each segment of the cochlea, the number of spiral ganglion cells was determined. Outcomes between the group with SL and the control group were compared. RESULTS: Of the 28 temporal bone samples from the 19 deceased patients (16 men and 3 women; mean [SD] age, 23.1 [24.6] years) with SL, all showed SL in the scala tympani of the basal turn. In the group with SL vs the control group, the mean (SD) loss of outer hair cells was significantly higher in the lower (28.6% [11.4%] vs 12.4% [6.2%]; P = .02) and upper (22.3% [9.7%] vs 8.8% [3.2%]; P = .01) basal cochlear turn, the mean (SD) loss of inner hair cells was significantly higher in the lower (15.4% [6.7%] vs 2.6% [1.1%]; P = .02) and upper (10.6% [4.6%] vs 2.2% [0.7%]; P = .03) basal cochlear turn, the mean (SD) total number of spiral ganglion cells (28,132 [2068] vs 30,358 [2036]; P = .001) and the mean (SD) number of spiral ganglion cells in segment I (3554 [847] vs 4223 [649]; P = .003) was significantly decreased, the mean (SD) degree of atrophy of the stria vascularis in the lower (8455 [924] vs 9368 [1049] MUm2; P = .003) and upper (7911 [837] vs 8474 [813] MUm2; P = .02) basal cochlear turn was significantly greater, and the degree of endolymphatic hydrops was significantly greater (10 bone samples [36%] vs 1 [5%]; P = .006). No significant differences were found between the 2 groups in the number of fibrocytes and in the presence of atrophy of the spiral ligament in any cochlear turn. CONCLUSIONS AND RELEVANCE: This study demonstrates that SL can lead to cochlear damage, especially in the basal turn of the cochlea. These pathological observations have formed the basis for clinical findings of hearing loss and tinnitus detected in those patients with SL. PMID- 26987016 TI - The role and mechanisms of action of SIRT6 in the suppression of postoperative epidural scar formation. AB - In order to investigate the role which sirtuin-6 (SIRT6) plays in lumbar spinal epidural fibrosis (EF) and scar formation in vitro and in vivo, SIRT6 and transforming growth factor beta (TGF-beta) protein levels in the lumbar disc of patients were detected using western blotting in patients who had undergone a laminectomy. The results demonstrated that SIRT6 expression was significantly reduced in the lumbar discs of patients in whom an epidural scar had formed, but the expression pattern of TGF-beta2 was much higher. Subsequently, a pcDNA-SIRT6 expression vector was constructed and transfected into the primary fibroblasts isolated from the epidural scars. Flow cytometric and MTT analyses indicated that overexpression of SIRT6 suppressed the proliferation of the fibroblasts, and TGF beta2 and interleukin-1alpha expression, as well as collagen type I (Col I) production. The results of bioinformatics and molecular biological analyses demonstarted that TGF-beta2 was a target of microRNA-21 (miR-21) and SIRT6 overexpression suppressed the levels of TGF-beta2 through promoting the expression of miR-21. Finally, by injecting the pcDNA-SIRT6 vector, it was possible to observe that SIRT6 suppressed EF and epidural scar formation in vivo. In conclusion, we noted that SIRT6 suppressed EF and epidural scar formation in vitro and in vivo. It was also noted that SIRT6 overexpression suppressed TGF beta2 levels by promoting the expression of miR-21. PMID- 26987020 TI - Transposed Corrugator Supercilii Muscle-Tendon Unit Flap for Contralateral Paralytic Medial Ectropion Repair. PMID- 26987017 TI - Birth order dependent growth cone segregation determines synaptic layer identity in the Drosophila visual system. AB - The precise recognition of appropriate synaptic partner neurons is a critical step during neural circuit assembly. However, little is known about the developmental context in which recognition specificity is important to establish synaptic contacts. We show that in the Drosophila visual system, sequential segregation of photoreceptor afferents, reflecting their birth order, lead to differential positioning of their growth cones in the early target region. By combining loss- and gain-of-function analyses we demonstrate that relative differences in the expression of the transcription factor Sequoia regulate R cell growth cone segregation. This initial growth cone positioning is consolidated via cell-adhesion molecule Capricious in R8 axons. Further, we show that the initial growth cone positioning determines synaptic layer selection through proximity based axon-target interactions. Taken together, we demonstrate that birth order dependent pre-patterning of afferent growth cones is an essential pre-requisite for the identification of synaptic partner neurons during visual map formation in Drosophila. PMID- 26987018 TI - Nucleosomes impede Cas9 access to DNA in vivo and in vitro. AB - The prokaryotic CRISPR (clustered regularly interspaced palindromic repeats) associated protein, Cas9, has been widely adopted as a tool for editing, imaging, and regulating eukaryotic genomes. However, our understanding of how to select single-guide RNAs (sgRNAs) that mediate efficient Cas9 activity is incomplete, as we lack insight into how chromatin impacts Cas9 targeting. To address this gap, we analyzed large-scale genetic screens performed in human cell lines using either nuclease-active or nuclease-dead Cas9 (dCas9). We observed that highly active sgRNAs for Cas9 and dCas9 were found almost exclusively in regions of low nucleosome occupancy. In vitro experiments demonstrated that nucleosomes in fact directly impede Cas9 binding and cleavage, while chromatin remodeling can restore Cas9 access. Our results reveal a critical role of eukaryotic chromatin in dictating the targeting specificity of this transplanted bacterial enzyme, and provide rules for selecting Cas9 target sites distinct from and complementary to those based on sequence properties. PMID- 26987021 TI - Cocoa and Whey Protein Differentially Affect Markers of Lipid and Glucose Metabolism and Satiety. AB - Food formulation with bioactive ingredients is a potential strategy to promote satiety and weight management. Whey proteins are high in leucine and are shown to decrease hunger ratings and increase satiety hormone levels; cocoa polyphenolics moderate glucose levels and slow digestion. This study examined the effects of cocoa and whey proteins on lipid and glucose metabolism and satiety in vitro and in a clinical trial. In vitro, 3T3-L1 preadipocytes were treated with 0.5-100 MUg/mL cocoa polyphenolic extract (CPE) and/or 1-15 mM leucine (Leu) and assayed for lipid accumulation and leptin production. In vivo, a 6-week clinical trial consisted of nine panelists (age: 22.6 +/- 1.7; BMI: 22.3 +/- 2.1) consuming chocolate-protein beverages once per week, including placebo, whey protein isolate (WPI), low polyphenolic cocoa (LP), high polyphenolic cocoa (HP), LP-WPI, and HP-WPI. Measurements included blood glucose and adiponectin levels, and hunger ratings at baseline and 0.5-4.0 h following beverage consumption. At levels of 50 and 100 MUg/mL, CPE significantly inhibited preadipocyte lipid accumulation by 35% and 50%, respectively, and by 22% and 36% when combined with 15 mM Leu. Leu treatment increased adipocyte leptin production by 26-37%. In the clinical trial, all beverages significantly moderated blood glucose levels 30 min postconsumption. WPI beverages elicited lowest peak glucose levels and HP levels were significantly lower than LP. The WPI and HP beverage treatments significantly increased adiponectin levels, but elicited no significant changes in hunger ratings. These trends suggest that combinations of WPI and cocoa polyphenols may improve markers of metabolic syndrome and satiety. PMID- 26987019 TI - Hepatocyte Growth Factor-mediated satellite cells niche perturbation promotes development of distinct sarcoma subtypes. AB - Embryonal Rhabdomyosarcoma (ERMS) and Undifferentiated Pleomorphic Sarcoma (UPS) are distinct sarcoma subtypes. Here we investigate the relevance of the satellite cell (SC) niche in sarcoma development by using Hepatocyte Growth Factor (HGF) to perturb the niche microenvironment. In a Pax7 wild type background, HGF stimulation mainly causes ERMS that originate from satellite cells following a process of multistep progression. Conversely, in a Pax7 null genotype ERMS incidence drops, while UPS becomes the most frequent subtype. Murine EfRMS display genetic heterogeneity similar to their human counterpart. Altogether, our data demonstrate that selective perturbation of the SC niche results in distinct sarcoma subtypes in a Pax7 lineage-dependent manner, and define a critical role for the Met axis in sarcoma initiation. Finally, our results provide a rationale for the use of combination therapy, tailored on specific amplifications and activated signaling pathways, to minimize resistance emerging from sarcomas heterogeneity. PMID- 26987022 TI - Alpinate Oxyphyllae Fructus Inhibits IGFII-Related Signaling Pathway to Attenuate Ang II-Induced Pathological Hypertrophy in H9c2 Cardiomyoblasts. AB - Angiotensin II (Ang II) is a very important cardiovascular disease inducer and may cause cardiac pathological hypertrophy and remodeling. We evaluated a Chinese traditional medicine, alpinate oxyphyllae fructus (AOF), for therapeutic efficacy for treating Ang II-induced cardiac hypertrophy. AOF has been used to treat patients with various symptoms accompanying hypertension and cerebrovascular disorders in Korea. We investigated its protective effect against Ang II-induced cytoskeletal change and hypertrophy in H9c2 cells. The results showed that treating cells with Ang II resulted in pathological hypertrophy, such as increased expression of transcription factors NFAT-3/p-NFAT-3, hypertrophic response genes (atrial natriuretic peptide [ANP] and b-type natriuretic peptide [BNP]), and Galphaq down-stream effectors (PLCbeta3 and calcineurin). Pretreatment with AOF (60-100 MUg/mL) led to significantly reduced hypertrophy. We also found that AOF pretreatment significantly suppressed the cardiac remodeling proteins, metalloproteinase (MMP9 and MMP2), and tissue plasminogen activator (tPA), induced by Ang II challenge. In conclusion, we provide evidence that AOF protects against Ang II-induced pathological hypertrophy by specifically inhibiting the insulin-like growth factor (IGF) II/IIR-related signaling pathway in H9c2 cells. AOF might be a candidate for cardiac hypertrophy and ventricular remodeling prevention in chronic cardiovascular diseases. PMID- 26987023 TI - Cichorium intybus Linn. Extract Prevents Type 2 Diabetes Through Inhibition of NLRP3 Inflammasome Activation. AB - This study provides the scientific basis for the inhibitory effect of the aerial parts of Cichorium intybus Linn. (C. intybus) on the activation of the NLRP3 inflammasome in vitro and on high-fat diet (HFD)-induced type-2 diabetes (T2D). Lipopolysaccharide (LPS)-primed bone marrow-derived macrophages were used to study the effects methanolic extract of C. intybus leaf (CI) on inflammasome activation. An insulin resistance model (mice fed a HFD) was used to study the in vivo effect of CI on T2D. CI attenuated interleukin-1beta (IL-1beta) secretion by inhibiting the activation of the NLRP3 inflammasome in mouse bone marrow macrophages. The CI treatment attenuated the intracellular movement of NLRP3 in Triton X-100 insoluble fraction, without affecting the expression of other NLRP3 inflammasome-related proteins. Attenuated IL-1beta secretion may improve glucose metabolism in the HFD-fed insulin resistance mouse model. CI also attenuated the infiltration of M1 macrophages and increased the M2 macrophage population in white adipose tissue. Collectively, our data showed that CI inhibits IL-1beta secretion through attenuation of NLRP3 inflammasome activation, leading to an antidiabetic effect by improving glucose metabolism and inhibiting metainflammation. PMID- 26987024 TI - Extension of Drosophila Lifespan by Rhodiola rosea Depends on Dietary Carbohydrate and Caloric Content in a Simplified Diet. AB - The root and rhizome extract of Rhodiola rosea has been extensively used in traditional medicine to improve physical and mental performance and to protect against stress. We, and others, have reported that R. rosea can extend lifespan in flies, worms, and yeast. We also previously found that the extract can act independently of dietary restriction (DR), a treatment that can extend lifespan in a range of model organisms. In flies, DR is implemented through a reduction in dietary yeast content. Here, we report that the ability of R. rosea extract to extend lifespan in flies is dependent on the carbohydrate and caloric content when supplemented with a simplified diet composed of yeast and sucrose. R. rosea extract elevated the sugar content in flies and down-regulated hexokinase expression, suggesting that it perturbs carbohydrate metabolism in flies. In our previous studies, bananas, barley malt, and corn syrup provided dietary carbohydrates, and R. rosea extract could extend lifespan with a range of caloric levels. We conclude that the lifespan-extending effect of R. rosea extract in flies is dependent on dietary carbohydrate and caloric contents coupled with an interaction with complex dietary components present in bananas, barley, or corn. PMID- 26987025 TI - Phytochemical Constituents and Antioxidant and Antimicrobial Activity of Selected Plants Used Traditionally as a Source of Food. AB - Many indigenous plants have also been used as a source of food and medicine in many African rural communities in the past. The study investigated the antimicrobial activity, phytochemical constituent, and antioxidant activity of selected traditional plants used traditionally as a source of food and medicine. The methanol and water extracts of different plant parts were analyzed for phytochemicals using standard phytochemical screening reagents while the broth microdilution assays were used to analyze antimicrobial activities. Alkaloids, phenols, flavonoids, saponins, tannins, and terpenes were found in one or more of the plant extracts, and all the plant extracts demonstrated scavenging activities. The back extracts of Sclerocarya birrea and the leaf extracts of Garcinia livingstonei exhibit the best antioxidant activities, while the water and methanol back extracts of S. birrea and G. livingstonei were the most active against all the tested foodborne bacteria. PMID- 26987026 TI - Evaluation of Safety and Antioxidant Activity of Yellow Tea (Camellia sinensis) Extract for Application in Food. AB - The article presents an evaluation of the safety of yellow tea (Camellia sinensis) extract consumption and its antioxidant activity in an animal model. Wistar rats were exposed through diet to 2, 6, and 10 g yellow tea extract/kg feed for 90 days. No signs of toxicity and no differences in mean body weight gain in the treated and control rats were recorded throughout the experiment. No statistically significant differences in hematology findings and clinical chemistry parameters were observed between controls and treated groups. Microscopic examination of tissue sections revealed no pathology attributable to yellow tea extract intake. Lipid peroxidation level in the liver was slightly increased in medium-dose males and high-dose females and decreased in two female groups receiving 2 and 6 g/kg of the extract tested. Content of carbonyl groups in protein, as well as the basal level of DNA damage, was not changed. In a majority of rats, the activity of antioxidant enzymes was increased except superoxide dismutase in high-dose groups, glutathione peroxidase in high-dose females, glutathione reductase in low- and mid-dose groups, and glutathione S transferase in mid-dose females and high-dose males. It could be concluded that rats tolerated well dietary treatment with yellow tea extract up to 0.8 g/kg b.w./day for 90 days. Results showed that yellow tea extract at the doses tested did not demonstrate adverse effects and improved the antioxidant status in the liver of rats. PMID- 26987027 TI - "Free" Raptor - a novel regulator of metabolism. PMID- 26987028 TI - Gallic acid induces apoptosis and enhances the anticancer effects of cisplatin in human small cell lung cancer H446 cell line via the ROS-dependent mitochondrial apoptotic pathway. AB - Small cell lung cancer (SCLC) is the most aggressive lung cancer subtype and accounts for more than 15% of all lung cancer cases. Cisplatin [cis diamminedichloroplatinum (CDDP)]-based combination chemotherapy is the cornerstone for all stages of SCLC. However, acquired multidrug resistance (MDR) and intolerable toxicities lead to a high mortality rate in SCLC patients. Gallic acid [3,4,5-trihydroxybenzoic acid (GA)] is a natural botanic phenolic compound which can induce cell apoptosis in several types of cancers. In the present study, we aimed to explore the anticancer effects of GA on human SCLC H446 cells and its promotive effects on the anticancer activities of cisplatin. The viability of the H446 cells was analyzed by MTT assay. Morphological changes in the H446 cells were observed under an inverted microscope. Apoptosis induction was determined by Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. The level of reactive oxygen species (ROS) was assessed by 2'7' dichlorofluorescein diacetate (DCFH-DA), mitochondrial membrane potential (MMP) by JC-1, and western blotting was used to examine the expression of mitochondrial apoptosis-related proteins. The results showed that both GA and cisplatin changed the morphology, inhibited the growth and induced apoptosis in the H446 cells by inducing generation of ROS, disruption of MMP, downregulation of XIAP expression, and upregulation of Bax, Apaf-1, DIABLO and p53 expression. More importantly, GA combined with cisplatin exhibited synergistic effects on inducing of these pro apoptotic mediators and modulating the activation of apoptosis-related molecules. However, inhibition of the generation of ROS by N-acetyl-l-cysteine (NAC), a specific ROS inhibitor, reversed the cell apoptosis induced by cisplatin combined with GA. In conclusion, the results from the present study revealed that GA exhibited an anticancer effect on human SCLC H446 cells and enhanced the antitumor activities of cisplatin via the ROS-dependent mitochondrial apoptotic pathway. PMID- 26987029 TI - A qualitative study analyzing access to physical rehabilitation for traffic accident victims with severe disability in Brazil. AB - Purpose To identify access barriers to physical rehabilitation for traffic accident (TA) victims with severe disability and build a theoretical model to provide guidance towards the improvement of these services. Methods Qualitative research carried out in the city of Natal (Northeast Brazil), with semi structured interviews with 120 subjects (19 key informer health professionals and 101 TA victims) identified in a database made available by the emergency hospital. The interviews were analyzed using Alceste software, version 4.9. Results The main barriers present in the interviews were: (1) related to services: bureaucratic administrative practises, low offer of rehabilitation services, insufficient information on rehabilitation, lack of guidelines that integrate hospital and ambulatory care and (2) related to patients: financial difficulties, functional limitations, geographic distance, little information on health, association with low education levels and disbelief in the system and in rehabilitation. Conclusion The numerous access barriers were presented in a theoretical model with causes related to organizational structure, processes of care, professionals and patients. This model must be tested by health policy makers and managers to improve the quality of physical rehabilitation and avoid unnecessary prolongation of the suffering and disability experienced by TA survivors. Implications for rehabilitation Traffic accidents (TAs) are a global health dilemma that demands integrality of preventive actions, pre-hospital and hospital care and physical rehabilitation (PR). This study lays the foundation for improving access to PR for TA survivors, an issue of quality of care that results in preventable disabilities. The words of the patients interviewed reveal the suffering of victims, which is often invisible to society and given low priority by health policies that relegate PR to a second plan ahead of prevention and urgent care. A theoretical model of the causes of the problem of access to PR was built. The identified barriers are potentially preventable through the intervention of health policy-makers, managers, regulators and rehabilitation professionals, and by encouraging the participation of patients. Addressing timely access barriers involves the expansion of the supply of services and rehabilitation professionals, regulation and standardization of referencing practises and encouraging the provision of information to patients about continuity of care and their health needs. PMID- 26987030 TI - Regulatory requirements in the good manufacturing practice production of an epithelial cell graft for ocular surface reconstruction. AB - In the past decade, stem cell therapy has been increasingly employed for the treatment of various diseases. Subsequently, there has been a great interest in the manufacture of stem cells under good manufacturing practice, which is required by law for their use in humans. The cells for sight Stem Cell Therapy Research Unit, based at UCL Institute of Ophthalmology, delivers somatic cell based and tissue-engineered therapies to patients suffering from blinding eye diseases at Moorfields Eye Hospital (London, UK). The following article is based on our experience in the conception, design, construction, validation and manufacturing within a good manufacturing practice manufacturing facility based in the UK. As such the regulations can be extrapolated to the 28 members stated within the EU. However, the principles may have a broad relevance outside the EU. PMID- 26987031 TI - A new fatty acid ester from an edible mushroom Rhizopogon luteolus. AB - Phytochemical investigation of the Rhizopogon luteolus Fr. led to the isolation of one new fatty acid ester, 3-hydroxy-2,4-dimethylheptacosyl acetate (1) together with two known compounds tetracosanoic acid (2) and ergosterol (3). 1D and 2D NMR, and MS techniques were used for structural elucidation. Phenolic and fatty acid compositions were identified using HPLC-DAD and GC-MSD, respectively. Fumaric acid was the major phenolic acid, whereas linoleic, stearic and oleic acids were the most abundant fatty acids. Antioxidant and anticholinesterase activities of the extracts and compounds (1-3) were tested spectrophotometrically. Among the extracts, hexane extract showed the highest activity in all tests, particularly in beta-carotene-linoleic acid assay (IC50: 16.65 +/- 1.12 MUg/mL). Furthermore, compound 3 exhibited higher antioxidant and anticholinesterase activities. The study indicates that R. luteolus can be used in food, cosmetic and pharmaceutical industries. PMID- 26987032 TI - Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression. AB - Metformin has been reported to inhibit the growth of various types of cancers, including prostate cancer. Yet the mode of anti-cancer action of metformin and the underlying mechanisms remain not fully elucidated. We hypothesized that the antitumorigenic effects of metformin are mediated through upregulation of pigment epithelium-derived factor (PEDF) expression in prostate cancer cells. In this report, metformin treatment significantly inhibited the proliferation and colony formation of prostate cancer cells, in a dose- and time-dependent manner. Meanwhile, Metformin markedly suppressed migration and invasion and induced apoptosis of both LNCaP and PC3 cancer cells. Metformin also reduced PC3 tumor growth in BALB/c nude mice in vivo. Furthermore, metformin treatment was associated with higher PEDF expression in both prostate cancer cells and tumor tissue. Taken together, metformin inhibits prostate cancer cell proliferation, migration, invasion and tumor growth, and these activities are mediated by upregulation of PEDF expression. These findings provide a novel insight into the molecular functions of metformin as an anticancer agent. PMID- 26987033 TI - Variables associated with co-existing epileptic and psychogenic nonepileptic seizures: a systematic review. AB - PURPOSE: Epileptic seizures (ES) have many mimickers, perhaps the most relevant being psychogenic nonepileptic seizures (PNES). The picture is even more challenging when PNES are associated with ES in a given patient. The aim of this research paper was to delineate the demographic, epileptological and psychiatric profile of that specific population. METHODS: A systematic review was carried out from 2000 to 2015 for articles in English, French, Italian, Spanish and Portuguese in PUBMED and EMBASE. Cohort or case-control studies reporting prospective or retrospective original data comparing patients with co-existing ES and PNES with those who had PNES only and ES only have been included. In retained studies, the presence of PNES was confirmed by video-electroencephalography (V EEG). Forty-eight abstracts were identified. RESULTS: Nine studies were retained. Most showed that female gender predominated in both groups with PNES. Patients with co-existing ES and PNES take higher number of antiepileptic drugs (AEDs) than PNES alone. Two studies showed association of concomitant ES and PNES with earlier age of seizure onset. Localizing EEG features and ES type were evaluated in only two studies and their association with either group was inconclusive. Somatoform, conversion or cluster B personality disorders were more frequent in subjects with PNES than with ES. DISCUSSION: Patients with concomitant ES and PNES are highly heterogeneous, challenging differentiation on clinical grounds. A diagnosis of conversion or somatoform, anxiety disorders, and the use of a higher number of AEDs than psychiatric medications may have an association with co existing ES and PNES. Further studies are warranted to differentiate patients who only have PNES from those with co-existing ES and PNES. PMID- 26987034 TI - Lamotrigine monotherapy for paroxysmal kinesigenic dyskinesia in children. AB - PURPOSE: To evaluate the efficacy and tolerability of lamotrigine monotherapy in children with paroxysmal kinesigenic dyskinesia. METHOD: A sample of eighteen children aged between 2 years old and 13 years old who fulfilled the diagnostic criteria from January 2008 to December 2014 was enrolled, they received video electroencephalography, brain image scans and proline-rich transmembrane protein 2 genetic tests. Children with known or suspected diseases which would cause secondary paroxysmal kinesigenic dyskinesia were excluded. The initial dosage of lamotrigine was 6.25 mg, and it was gradually increased every week until attacks were controlled. Patients entered the maintenance dose phase upon reaching the effective dosage, and by being attack free at two consecutive outpatient visits. They were followed up for a couple of years until December 2014. RESULTS: By the end of the 4th week, the attack-free rate reached 100% among all the patients. During the maintenance dose phase, 16 patients remained attack free, 2 patients received additional drug due to attack relapses when they entered puberty. Three patients had relapses because of non-compliance to the therapy, but they became attack free as soon as they re-started the medicine. The mean daily dosage was 26.4 mg (range 6.25-50). Definite adverse effect related to the drug was not reported in follow up. CONCLUSION: LTG monotherapy is effective and well tolerated for PKD in children. PMID- 26987035 TI - Skin rash following levetiracetam. PMID- 26987037 TI - Antifungal potential of Sideroxylon obtusifolium and Syzygium cumini and their mode of action against Candida albicans. AB - Context The emergence of resistant pathogens and toxicity of antifungals have encouraged an active search for novel candidates to manage Candida biofilms. Objective In this study, the little known species Sideroxylon obtusifolium T.D. Penn (Sapotacea) and Syzygium cumini (L.) Skeels (Myrtaceae), from the Caatinga biome in Brazil were chemically characterized and explored for their antifungal potential against C. albicans. Materials and methods We determined the effects of hydroalcoholic extracts/fractions upon fungal growth (minimum inhibitory and fungicidal concentrations, MIC/MFC), biofilm morphology (scanning electron microscopy) and viability (confocal laser scanning microscopy), proposed their mode of action (sorbitol and ergosterol assays), and finally investigated their effects against macrophage and keratinocyte cells in a cell-based assay. Data were analysed using one-way analysis of variance with Tukey-Kramer post-test (alpha = 0.05). Results The n-butanol (Nb) fraction from S. obtusifolium and S. cumini extract (Sc) showed flavonoids (39.11 +/- 6.62 mg/g) and saponins (820.35 +/- 225.38 mg/g), respectively, in their chemical composition and demonstrated antifungal activity, with MICs of 62.5 and 125 MUg/mL, respectively. Nb and Sc may complex with ergosterol as there was a 4-16-fold increase in MICs in the presence of exogenous ergosterol, leading to disrupted permeability of cell membrane. Deleterious effects were observed on morphology and viability of treated biofilms from concentrations as low as their MICs and higher. Sc was not toxic to macrophages and keratinocytes at these concentrations (p > 0.05), unlike Nb. Conclusions Nb and Sc demonstrated considerable antifungal activity and should be further investigated as potential alternative candidates to treat Candida biofilms. PMID- 26987036 TI - Assessment of the association between Apgar scores and seizures in infants less than 1 year old. AB - PURPOSE: The study aimed to assess the association between Apgar scores at 1 and 5 min after birth and seizures in infants less than 1 year old. METHODS: We conducted a retrospective, observational, hospital-based study by utilising medical records from the Chung-Ang University Hospital admissions from January 2006 to May 2015 in order to identify infants less than 1 year old who had a history of seizures. Using electronic medical records, infants who were diagnosed with infantile seizures at the Chung-Ang University Hospital from January 2006 to May 2015 were included in the seizure group (n=93), and a control group consisting of 296 age-matched cases without a history of seizures was selected from a group of infants born at Chung-Ang University Hospital during the same study period. RESULTS: We found that Apgar scores were significant risk factors for infantile seizures. Apgar scores differed depending on gestational age and birth weight. We found strong associations between Apgar scores and infantile seizures in the full-term and the normal-birth weight groups (bodyweight >=2.5 kg), regardless of delivery mode. The Apgar scores were inversely correlated with the EEG class, and only the 1-min Apgar scores were correlated with MRI findings. CONCLUSION: Low Apgar scores are significant perinatal risk factors for infantile seizures, especially in full-term and normal-birth weight infants, and have a strong negative linear relationship with EEG and brain MRI results in the seizure group. PMID- 26987040 TI - Synthesis of 2-Alkenylquinoline by Reductive Olefination of Quinoline N-Oxide under Metal-Free Conditions. AB - Synthesis of 2-alkenylquinoline by reductive olefination of quinoline N-oxide under metal-free conditions is disclosed. Practically, the reaction could be performed with quinoline as starting material via a one-pot, two-step process. A possible mechanism is proposed that involves a sequential 1,3-dipolar cycloaddition and acid-assisted ring opening followed by a dehydration process. PMID- 26987038 TI - Fatigue among patients with brain tumors. AB - Fatigue is a ubiquitous and an extremely distressing symptom among patients with brain tumors (BT), particularly those with high-grade gliomas. The pathophysiology of cancer-related fatigue (CRF) in the context of patients with BT is multifactorial and complex, involving biological, behavioral, medical and social factors. The etiology of CRF in the general oncology population is pointing to the role of inflammatory cytokines as a key factor in the genesis of CRF, but this research is currently limited in the setting of BT. CRF should be screened, assessed and managed according to clinical practice guidelines. Fatigue has recently emerged as a strong, independent prognostic factor for survival that provides incremental prognostic value to the traditional markers of prognosis in recurrent high-grade gliomas. Therefore, strategies to treat fatigue warrant investigation, not only to improve the QOL of a group of patients with often limited life expectancy, but also possibly to optimize survival. PMID- 26987039 TI - In vitro and in vivo evidence for the inhibition of brassinosteroid synthesis by propiconazole through interference with side chain hydroxylation. AB - We carried out the biochemical evaluation of the target site of propiconazole in BR biosynthesis. Applying BR biosynthesis intermediates to Arabidopsis seedlings grown in the presence of propiconazole under dark condition, we found that the target site of propiconazole in BR biosynthesis can be identified among the C22 and C23 side chain hydroxylation steps from campestanol to teasterone. Using differential spectra techniques to determine the binding affinity of propiconazole to CYP90D1, which is responsible for C23 hydroxylation of BR, we found that propiconazole induced typical type II binding spectra in response to purified recombinant CYP90D1 and the Kd value was found approximately 0.76 MUM. PMID- 26987041 TI - Hierarchical MnO2 Spheres Decorated by Carbon-Coated Cobalt Nanobeads: Low-Cost and High-Performance Electrode Materials for Supercapacitors. AB - MnO2 is a promising electrode material for supercapacitors, because it exhibits high theoretical specific capacitance (1380 F g(-1)) for electrical charge while also being inexpensive and environmentally benign. However, owing to its low electrical conductivity, the intrinsic pseudocapacity of MnO2 is not fully utilized. In this work, hierarchically structured spheres composed of MnO2 nanoplatelets and carbon coated cobalt nanobeads (MnO2-NPs@Co/C) are chosen as electrode materials for supercapacitor. With a Co/C mass loading of 19 wt %, the electrical conductivity of the hybrid is 122-fold larger than that of pristine MnO2, showing a specific capacitance of the constituent MnO2 as high as 1240 F g( 1), being close to the theoretical value. Such improved specific capacitance of MnO2-NPs@Co/C electrode is largely contributed from the enhanced double-layer charging and Faradaic pseudocapacity of MnO2. Moreover, the fabricated symmetrical supercapacitor also exhibits excellent cycling stability with 89.1% capacitance retention over 10000 cycles, as well as high energy densities in both aqueous and organic electrolyte (24 Wh kg(-1) and 33 W kg(-1), respectively). Compared with frequently used noble metals to enhance the electrochemical performance of MnO2, the utilization of low cost Co/C nanobeads is proven to be more efficient and thus showing great potential for commercial application. PMID- 26987043 TI - Which Test Is the Best for Hydroxychloroquine Toxicity Screening? PMID- 26987042 TI - Management of peptic pyloroduodenal stenosis in Sylvanus Olympio teaching hospital in Lome (Togo). AB - This study's aim was to describe the management of ulcerous pyloroduodenal stenosis in Sylvanus Olympio teaching hospital of Lome (Togo). It was a retrospective study of medical files of all patients managed for peptic pyloroduodenal stenosis at the visceral surgery department of Sylvanus Olympio teaching hospital in Lome (Togo) from january 1(st), 2002 to december 31(th), 2011. Twenty-five patients were selected. Mean age was 38 +/- 7.4 years. Sex ratio was 5. Twenty four patients underwent upper digestive tract endoscopy, completed by upper gastrointestinal series in 18 cases. One patient had only an upper gastrointestinal series. Pyloroduodenal stenosis was improved by antisecretory therapy in 3 cases. Twenty two patients underwent laparotomy. Truncal vagotomy was performed in 15 cases associated with pyloroplasty in 8 cases, and gastrojejunostomy in 7 cases. An antrectomy was performed in 5 cases. Selective vagotomy was associated with pyloroplasty in 1 case, and a gastrojejunostomy in 1 case. One patient died in postoperative period. Functional results were classified Visick I (17 cases) and II (4 cases). Peptic pyloroduodenal stenosis affects young adults. Its tight nature requires association of upper gastrointestinal series and esophagogastroduodenoscopy for diagnosis. Its surgical treatment is exclusively performed by laparotomy at present. Mortality is low and functionnal prognosis is good. PMID- 26987044 TI - Establishing the fluorescent amyloid ligand h-FTAA for studying human tissues with systemic and localized amyloid. AB - Rapid and accurate detection of amyloid deposits in routine surgical pathology settings are of great importance. The use of fluorescence microscopy in combination with appropriate amyloid specific dyes is very promising in this regard. Here we report that a luminescent conjugated oligothiophene, h-FTAA, rapidly and with high sensitivity and selectivity detects amyloid deposits in verified clinical samples from systemic amyloidosis patients with AA, AL and ATTR types; as well as in tissues laden with localized amyloidosis of AANF, AIAPP and ASem1 type. The probe h-FTAA emitted yellow red fluorescence on binding to amyloid deposits, whereas no apparent staining was observed in surrounding tissue. The only functional structure stained with h-FTAA showing the amyloidotypic fluorescence spectrum was Paneth cell granules in intestine. Screening of 114 amyloid containing tissues derived from 107 verified (Congo red birefringence and/or immunohistochemistry) amyloidosis patients revealed complete correlation between h-FTAA and Congo red fluorescence (107/107, 100% sensitivity). The majority of Congo red negative control cases (27 of 32, 85% specificity) were negative with h-FTAA. Small Congo red negative aggregates in kidney, liver, pancreas and duodenum were found by h-FTAA fluorescence in five control patients aged 72-83 years suffering from diverse diseases. The clinical significance of these false-positive lesions is currently not known. Because h FTAA fluorescence is one magnitude brighter than Congo red and as the staining is performed four magnitudes lower than the concentration of dye, we believe that these inclusions are beyond detection by Congo red. We conclude that h-FTAA is a fluorescent hypersensitive, rapid and powerful tool for identifying amyloid deposits in tissue sections. Use of h-FTAA can be exploited as a rapid complementary technique for accurate detection of amyloid in routine surgical pathology settings. Our results also implicate the potential of the technique for detection of prodromal amyloidosis as well as for discovery of new amyloid-like protein aggregates in humans. PMID- 26987045 TI - Dual Site-Controlled and Lysosome-Targeted Intramolecular Charge Transfer Photoinduced Electron Transfer-Fluorescence Resonance Energy Transfer Fluorescent Probe for Monitoring pH Changes in Living Cells. AB - Acidic pH is a critical physiological factor for controlling the activities and functions of lysosome. Herein, we report a novel dual site-controlled and lysosome-targeted intramolecular charge transfer-photoinduced electron transfer Fluorescence resonance energy transfer (ICT-PET-FRET) fluorescent probe (CN-pH), which was essentially the combination of a turn-on pH probe (CN-1) and a turn-off pH probe (CN-2) by a nonconjugated linker. Coumarin and naphthalimide fluorophores were selected as donor and acceptor to construct the FRET platform. Hydroxyl group and morpholine were simultaneously employed as the two pH sensing sites and controlled the fluorescence of coumarin and naphthalimide units by ICT and PET, respectively. The sensing mechanism of CN-pH to pH was essentially an integration of ICT, PET, and FRET processes. Meanwhile, the morpholine also can serve as a lysosome-targeted group. By combining the two data analysis approaches of the ratios of the two emission intensities (R) and the reverse ratio R' (R' = 1/R), the fluorescent ratio of CN-pH can show proportional relationship to pH values in a very broad range from pH 4.0 to 8.0 with high sensitivity. The probe has been successfully applied for the fluorescence imaging of the lysosomal pH values, as well as ratiometrically visualizing chloroquine-stimulated changes of intracellular pH in living cells. These features demonstrate that the probe can afford practical application in biological systems. PMID- 26987046 TI - Benzimidazolium-based novel silver N-heterocyclic carbene complexes: synthesis, characterisation and in vitro antimicrobial activity. AB - This study reports the synthesis, characterisation and antimicrobial activity of five novel silver N-heterocyclic carbene (Ag-NHC) complexes obtained by N propylphthalimide and N-methyldioxane substituted benzimidazolium salts with silver oxide. The reactions were performed at room temperature for 24 h in the absence of light. The obtained complexes were identified and characterised by (1)H and (13)C NMR, FT-IR and elemental analysis techniques. The minimum inhibitory concentration (MIC) of the complexes was determined for E. coli, P. aeruginosa, E. faecalis, S. aureus, C. tropicalis and C. albicans in vitro through agar and broth dilution. The results indicated that these complexes exhibit antimicrobial activity. In particular, complex 3 presented the significant broad spectrum antimicrobial activity. PMID- 26987048 TI - Multicolor Spectral Analyses of Mitotic and Meiotic Mouse Chromosomes Involved in Multiple Robertsonian Translocations. I. The CD/Cremona Hybrid Strain. AB - Multicolor spectral analysis (spectral karyotyping) was applied to mitotic and male diakinetic chromosomes of hybrid mice carrying a unique system of 18 autosomal Robertsonian translocation chromosomes with alternating arm homologies. Only the autosomes 19 and the XY sex chromosomes are excluded from these Robertsonian translocations. The translocations, previously identified by conventional banding analyses, could be verified by spectral karyotyping. Besides the Robertsonian translocations, no other interchromosomal rearrangements were detected. In diakineses of male meiosis, the 18 metacentric Robertsonian translocation chromosomes form a very large meiotic 'superring'. The predictable, specific order of the chromosomes along this 'superring' was completely confirmed by multicolor spectral analysis. In the majority of diakineses analyzed, the free autosomal bivalent 19 and the XY sex bivalent form a conspicuous complex which tightly associates with the 12;14 Robertsonian translocation chromosome in the 'superring'. PMID- 26987047 TI - Effects of Different Combinations of Er:YAG Laser-Adhesives on Enamel Demineralization and Bracket Bond Strength. AB - OBJECTIVE: The purpose of this study was to investigate the demineralization around brackets and shear bond strength (SBS) of brackets bonded to Er:YAG laser irradiated enamel at different power settings with various adhesive systems combinations. METHODS: A total of 108 premolar teeth were used in this study. Teeth were assigned into three groups according to the etching procedure, then each group divided into three subgroups based on the application of different adhesive systems. There were a total of nine groups as follows. Group 1: Acid + Transbond XT Primer; group 2: Er:YAG (100 mJ, 10 Hz) etching + Transbond XT Primer; group 3: Er:YAG (200 mJ, 10 Hz) etching + Transbond XT Primer; group 4: Transbond Plus self-etching primer (SEP); group 5: Er:YAG (100 mJ, 10 Hz) etching + Transbond Plus SEP; group 6: Er:YAG (200 mJ, 10 Hz) etching + Transbond Plus SEP; group 7: Clearfil Protect Bond; group 8: Er:YAG (100 mJ, 10 Hz) etching + Clearfil Protect Bond; group 9: Er:YAG (200 mJ, 10 Hz) etching + Clearfil Protect Bond. Brackets were bonded with Transbond XT Adhesive Paste in all groups. Teeth to be evaluated for demineralization and SBS were exposed to pH and thermal cyclings, respectively. Then, demineralization samples were scanned with micro-CT to determine lesion depth values. For SBS test, a universal testing machine was used and adhesive remnant was index scored after debonding. Data were analyzed statistically. RESULTS: No significant differences were found among the lesion depth values of the various groups, except for G7 and G8, in which the lowest values were recorded. The lowest SBS values were in G7, whereas the highest were in G9. The differences between the other groups were not significant. CONCLUSIONS: Er:YAG laser did not have a positive effect on prevention of enamel demineralization. When two step self-etch adhesive is preferred for bonding brackets, laser etching at 1 W (100 mJ, 10 Hz) is suggested to improve SBS of brackets. PMID- 26987049 TI - Using Sex to Cure the Genome. AB - The diversification of prokaryotes is accelerated by their ability to acquire DNA from other genomes. However, the underlying processes also facilitate genome infection by costly mobile genetic elements. The discovery that cells can uptake DNA by natural transformation was instrumental to the birth of molecular biology nearly a century ago. Surprisingly, a new study shows that this mechanism could efficiently cure the genome of mobile elements acquired through previous sexual exchanges. PMID- 26987050 TI - Sedum sarmentosum Bunge extract induces apoptosis and inhibits proliferation in pancreatic cancer cells via the hedgehog signaling pathway. AB - Sedum sarmentosum Bunge, a traditional Chinese herbal medicine, has a wide range of clinical applications including antibiosis, anti-inflammation and anti oxidation. In the present study, we identified that its extract (SSBE) exerts pancreatic anticancer activity in vitro and in vivo. In the cultured pancreatic cancer PANC-1 cell line, SSBE inhibited cell growth in a concentration-dependent manner, and it was accompanied by the downregulated expression of proliferating cell nuclear antigen (PCNA). In addition, SSBE treatment also increased cellular apoptosis in a mitochondrial-dependent manner. Moreover, SSBE induced p53 expression, reduced c-Myc expression, and inhibited epithelial-mesenchymal transition (EMT). The antiproliferative activity of SSBE in the pancreatic cancer cells was found to be closely related to cell cycle arrest at the G2/M phase by upregulating p21(Waf1/CIP1) expression. Further study showed that this inhibitory effect of SSBE was through downregulation of the activity of the proliferation related Hedgehog signaling pathway. Exogenous recombinant protein Shh was used to activate Hedgehog signaling, thereby resulting in the abolishment of the SSBE mediated inhibition of pancreatic cancer cell growth. In animal xenograft models of pancreatic cancer, activated Hedgehog signaling was also observed compared with the vehicle controls, but was reduced by SSBE administration. As a result, SSBE suppressed the growth of pancreatic tumors. Thus, these findings demonstrate that SSBE has therapeutic potential for pancreatic cancer, and this anticancer effect in pancreatic cancer cells is associated with inhibition of the Hedgehog signaling pathway. PMID- 26987051 TI - Utility of bilateral acoustic hearing in combination with electrical stimulation provided by the cochlear implant. AB - OBJECTIVE: The aim of the study was to quantify the benefit provided by having access to amplified acoustic hearing in the implanted ear for use in combination with contralateral acoustic hearing and the electrical stimulation provided by the cochlear implant. DESIGN: Measures of spatial and non-spatial hearing abilities were obtained to compare performance obtained with different configurations of acoustic hearing in combination with electrical stimulation. In the combined listening condition participants had access to bilateral acoustic hearing whereas the bimodal condition used acoustic hearing contralateral to the implanted ear only. Experience was provided with each of the listening conditions using a repeated-measures A-B-B-A experimental design. STUDY SAMPLE: Sixteen post linguistically hearing-impaired adults participated in the study. RESULTS: Group mean benefit was obtained with use of the combined mode on measures of speech recognition in coincident speech in noise, localization ability, subjective ratings of real-world benefit, and musical sound quality ratings. CONCLUSIONS: Access to bilateral acoustic hearing after cochlear implantation provides significant benefit on a range of functional measures. PMID- 26987053 TI - Effect of Two Interacting Rings in Metalloporphyrin Dimers upon Stepwise Oxidations. AB - The interaction between two porphyrin macrocycles, connected covalently through either a rigid ethylene or a flexible ethane bridge, in the metalloporphyrin dimers (M: 2H, Zn(2+)) have been investigated upon stepwise oxidations. Upon 1e oxidation, two porphyrin macrocycles come closer and cofacial to each other while 2e-oxidation forces them to be separated as far as possible. This has resulted in the conversion of the cis isomer to trans for the ethylene bridged porphyrin dimer with the stabilization of an unusual "U" form, which has unique spectral and geometrical features. Detailed ultraviolet-visible-near-infrared (UV-vis NIR), infrared (IR), electron paramagnetic resonance (EPR), and nuclear magnetic resonance (NMR) spectroscopic investigations, along with X-ray structure determination of the 2e-oxidized complexes, have demonstrated strong electronic communications between two porphyrin pi-cation radicals through the bridging ethylene group. Such extensive pi-conjugation also results in strong antiferromagnetic coupling between the radical spins of both of the macrocycles, which generates a diamagnetic compound. The experimental observations are also strongly supported by density functional theory (DFT) calculations. PMID- 26987052 TI - Holothurian Nervous System Diversity Revealed by Neuroanatomical Analysis. AB - The Echinodermata comprise an interesting branch in the phylogenetic tree of deuterostomes. Their radial symmetry which is reflected in their nervous system anatomy makes them a target of interest in the study of nervous system evolution. Until recently, the study of the echinoderm nervous system has been hindered by a shortage of neuronal markers. However, in recent years several markers of neuronal and fiber subpopulations have been described. These have been used to identify subpopulations of neurons and fibers, but an integrative study of the anatomical relationship of these subpopulations is wanting. We have now used eight commercial antibodies, together with three antibodies produced by our group to provide a comprehensive and integrated description and new details of the echinoderm neuroanatomy using the holothurian Holothuria glaberrima (Selenka, 1867) as our model system. Immunoreactivity of the markers used showed: (1) specific labeling patterns by markers in the radial nerve cords, which suggest the presence of specific nerve tracts in holothurians. (2) Nerves directly innervate most muscle fibers in the longitudinal muscles. (3) Similar to other deuterostomes (mainly vertebrates), their enteric nervous system is composed of a large and diverse repertoire of neurons and fiber phenotypes. Our results provide a first blueprint of the anatomical organization of cells and fibers that form the holothurian neural circuitry, and highlight the fact that the echinoderm nervous system shows unexpected diversity in cell and fiber types and their distribution in both central and peripheral nervous components. PMID- 26987054 TI - Correction: Are Husbands Involving in Their Spouses' Utilization of Maternal Care Services?: A Cross-Sectional Study in Yangon, Myanmar. PMID- 26987055 TI - Cost-Effectiveness of Treatments for Relapsing Remitting Multiple Sclerosis: A French Societal Perspective. AB - OBJECTIVES: The paper aimed to estimate the incremental cost-effectiveness ratio (ICER) at the public published price for delayed-release dimethyl fumarate versus relevant Multiple Sclerosis disease-modifying therapies available in France in June 2015. METHODS: The economic model was adapted to the French setting in accordance with the Haute Autorite de Sante guidelines using a model previously developed for NICE. A cohort of Relapsing Remitting Multiple Sclerosis patients was simulated over a 30-year time horizon. Twenty one health states were taken into account: Kurtzke Expanded Disability Status Scale (EDSS) 0-9 for Relapsing Remitting Multiple Sclerosis patients, EDSS 0-9 for Secondary Progressive Multiple Sclerosis patients, and death. Estimates of relative treatment efficacy were determined using a mixed-treatment comparison. Probabilities of events were derived from the dimethyl fumarate pivotal clinical trials and the London Ontario Dataset. Costs and utilities were extracted from the published literature from both the payer and societal perspectives. Univariate and probabilistic sensitivity analyses were performed to assess the robustness of the model results. RESULTS: From both perspectives, dimethyl fumarate and interferon beta 1a (IFN beta-1a) 44 mcg were the two optimal treatments, as the other treatments (IFN beta-1a 30 mcg, IFN beta-1b 250 mcg, teriflunomide, glatiramer acetate, fingolimod) were dominated on the efficiency frontier. From the societal perspective, dimethyl fumarate versus IFN beta-1a 44 mcg incurred an incremental cost of ?3,684 and an incremental quality-adjusted life year (QALY) of 0.281, corresponding to an ICER of ?13,110/QALY. CONCLUSIONS: Despite no reference threshold for France, dimethyl fumarate can be considered as a cost-effective option as it is on the efficiency frontier. PMID- 26987056 TI - Effects of a Follow-On Formula Containing Isomaltulose (PalatinoseTM) on Metabolic Response, Acceptance, Tolerance and Safety in Infants: A Randomized Controlled Trial. AB - Effects of the dietary glycaemic load on postprandial blood glucose and insulin response might be of importance for fat deposition and risk of obesity. We aimed to investigate the metabolic effects, acceptance and tolerance of a follow-on formula containing the low glycaemic and low insulinaemic carbohydrate isomaltulose replacing high glycaemic maltodextrin. Healthy term infants aged 4 to 8 completed months (n = 50) were randomized to receive the intervention follow on formula (IF, 2.1g isomaltulose (PalatinoseTM)/100mL) or an isocaloric conventional formula (CF) providing 2.1g maltodextrin/100mL for four weeks. Plasma insulinaemia 60 min after start of feeding (primary outcome) was not statistically different, while glycaemia adjusted for age and time for drinking/volume of meal 60 min after start of feeding was 122(105,140) mg/dL in IF (median, interquartile range) and 111(100,123) in CF (p = 0.01). Urinary c peptide:creatinine ratio did not differ (IF:81.5(44.7, 96.0) vs. CF:56.8(37.5, 129),p = 0.43). Urinary c-peptide:creatinine ratio was correlated total intake of energy (R = 0.31,p = 0.045), protein (R = 0.42,p = 0.006) and fat (R = 0.40,p = 0.01) but not with carbohydrate intake (R = 0.22,p = 0.16). Both formulae were well accepted without differences in time of crying, flatulence, stool characteristics and the occurrence of adverse events. The expected lower postprandial plasma insulin and blood glucose level due to replacement of high glycaemic maltodextrin by low glycaemic isomaltulose were not observed in the single time-point blood analysis. In infants aged 4 to 8 completed months fed a liquid formula, peak blood glucose might be reached earlier than 60 min after start of feeding. Non-invasive urinary c-peptide measurements may be a suitable marker of nutritional intake during the previous four days in infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT01627015. PMID- 26987057 TI - Soil C, N, P and Its Stratification Ratio Affected by Artificial Vegetation in Subsoil, Loess Plateau China. AB - Artificial vegetation restoration can induce variations in accumulation and distribution of soil carbon (C), nitrogen (N) and phosphorus (P). However, little is known about variations in soil C, N and P nutrient fraction stratification following artificial vegetation in Loess Plateau China. Based on the hypothesis that re-vegetated can improve soil quality and stratification ratios (SR) can be used as an indicator to evaluate soil quality. This study measured contents and storages of soil organic carbon (SOC), total nitrogen (TN), total phosphorus (TP) and their SRs in topsoil (0-20 cm) and subsoil (20-60 cm) in three 30-year re vegetated lands that had been converted from arable land (Robinia pseudoacacia L., Caragana Korshinskii Kom. and abandoned cropland with low interferences and few management measures) and one slope cropland (SC) as a control for three soil profiles(0-20 cm, 20-40 cm and 40-60 cm) from June 2009 to June 2013. The results showed that the contents and storages of SOC, TN and TP in re-vegetated land were significantly higher than those in the SC in both topsoil and subsoil. The storages of SOC, TN and TP in the topsoil (0-20 cm) of the re-vegetated lands increased by 16.2%-26.4%, 12.7%-28.4% and 16.5%-20.9%, respectively, and increased by smaller but significant amounts in subsoil from 2009 to 2013. The SRs for SOC, TN and TP in the re-vegetated lands were mostly >2 (either for 0 20:20-40 cm or 0-20:40-60 cm) and greater than that in the SC. The SRs showed an increasing trend with increasing restoration age. The results also showed that the land use type and soil depth were the most influential factors for the SRs and storages, and the SRs of SOC and TN had significantly positive correlations with their storages. The SRs were concluded to be a good indicator for evaluating the soil quality, which can be significantly enhanced through vegetation restoration. Moreover, vegetation restoration can significantly enhance SOC, TN and TP accumulation in both topsoil and subsoil. PMID- 26987058 TI - Correction: Zebra Stripes through the Eyes of Their Predators, Zebras, and Humans. PMID- 26987059 TI - In-Hospital Disease Burden of Sarcoidosis in Switzerland from 2002 to 2012. AB - Sarcoidosis is a multisystem disease with an unpredictable and sometimes fatal course while the underlying pathomechanism is still unclear. Reasons of the increasing hospitalization rate and mortality in the United States remain in dispute but incriminated are a number of distinct comorbidities and risk factors as well as the application of more aggressive therapeutic agents. Studies reflecting the recent development in central Europe are lacking. Our aim was to investigate the recent mortality and hospitalization rates as well as the underlying comorbidities of hospitalized sarcoidosis patients in Switzerland. In this longitudinal, nested case-control study, a nation-wide database provided by the Swiss Federal Office for Statistics enclosing every hospital entry covering the years 2002-2012 (n = 15,627,573) was analyzed. There were 8,385 cases with a diagnosis of sarcoidosis representing 0.054% (8,385 / 15,627,573) of all hospitalizations in Switzerland. These cases were compared with age- and sex matched controls without the diagnosis of sarcoidosis. Hospitalization and mortality rates in Switzerland remained stable over the observed time period. Comorbidity analysis revealed that sarcoidosis patients had significantly higher medication-related comorbidities compared to matched controls, probably due to systemic corticosteroids and immunosuppressive therapy. Sarcoidosis patients were also more frequently re-hospitalized (median annual hospitalization rate 0.28 [IQR 0.15-0.65] vs. 0.19 [IQR 0.13-0.36] per year; p < 0.001), had a longer hospital stay (6 [IQR 2-13] vs. 4 [IQR 1-8] days; p < 0.001), had more comorbidities (4 [IQR 2-7] vs. 2 [IQR 1-5]; p < 0.001), and had a significantly higher in-hospital mortality (2.6% [95% CI 2.3%-2.9%] vs. 1.8% [95% CI 1.5%-2.1%] (p < 0.001). A worse outcome was observed among sarcoidosis patients having co occurrence of associated respiratory diseases. Moreover, age was an important risk factor for re-hospitalization. PMID- 26987060 TI - Molecular Variability and Distribution of Sugarcane Mosaic Virus in Shanxi, China. AB - BACKGROUND: Sugarcane mosaic virus (SCMV) is responsible for large-scale economic losses in the global production of sugarcane, maize, sorghum, and some other graminaceous species. To understand the evolutionary mechanism of SCMV populations, this virus was studied in Shanxi, China. A total of 86 maize leaf samples (41 samples in 2012 and 45 samples in 2013) were collected from 4 regions of Shanxi. RESULTS: Double-antibody sandwich (DAS)-ELISA and RT-PCR showed 59 samples (30 samples in 2012 and 29 samples in 2013) to be positive for SCMV, from which 10 new isolates of SCMV were isolated and sequenced. The complete genomes of these isolates are 9610 nt long, including the 5' and 3' non-coding regions, and encode a 3063-amino acid polyprotein. Phylogenetic analyses revealed that 24 SCMV isolates could be divided on the basis of the whole genome into 2 divergent evolutionary groups, which were associated with the host species. Among the populations, 15 potential recombination events were identified. The selection pressure on the genes of these SCMV isolates was also calculated. The results confirmed that all the genes were under negative selection. CONCLUSIONS: Negative selection and recombination appear to be important evolutionary factors shaping the genetic structure of these SCMV isolates. SCMV is distributed widely in China and exists as numerous strains with distinct genetic diversity. Our findings will provide a foundation for evaluating the epidemiological characteristics of SCMV in China and will be useful in designing long-term, sustainable management strategies for SCMV. PMID- 26987062 TI - The novel dipeptide Tyr-Ala (TA) significantly enhances the lifespan and healthspan of Caenorhabditis elegans. AB - Food-derived bioactive peptides may have various physiological modulatory and regulatory functions and are now being studied extensively. Recently, the novel dipeptide Tyr-Ala was isolated from hydrolyzed maize protein. Tyr-Ala significantly prolonged the lifespan of wild-type Caenorhabditis elegans and extended the nematode healthspan and lifespan during heat/oxidative stress. Compared with its constituent amino acids, Tyr-Ala was more efficient in enhancing stress resistance. Further studies demonstrated that the significant longevity-extending effects of Tyr-Ala on Caenorhabditis elegans were attributed to its in vitro and in vivo free radical-scavenging effects, in addition to its ability to up-regulate stress resistance-related proteins, such as SOD (Superoxide Dismutase)-3 and HSP (Heat Shock Protein)-16.2. Real-time PCR results showed that the up-regulation of aging-associated genes, such as daf-16, sod-3, hsp-16.2 and skn-1, also contributed to the stress-resistance effect of Tyr-Ala. These results indicate that the novel dipeptide Tyr-Ala can protect against external stress and thus extend the lifespan and healthspan of Caenorhabditis elegans. Thereby, Tyr-Ala could be used as a potential medicine in anti-aging research. PMID- 26987063 TI - Goniothalamin induces apoptosis associated with autophagy activation through MAPK signaling in SK-BR-3 cells. AB - Goniothalamin, a plant bioactive styrly-lactone, possesses many biological activities. In the present study, the anticancer effect of goniothalamin on human breast cancer cell line SK-BR-3 was investigated. The results showed that goniothalamin induced nuclear condensation, DNA fragmentation, apoptotic bodies and mitochondrial dysfunction as determined by JC-1 staining. Goniothalamin also increased the Bax/Bcl-2 ratio and expression of cleaved caspase-7, cleaved caspase-9 and cleaved PARP, but decreased Bcl-2 expression. In addition, goniothalamin induced apoptosis via p-JNK1/2 and p-p38 upregulation and inhibited cell survival via p-ERK1/2 and p-Akt downregulation. Notably, goniothalamin induced autophagy through upregulation of Atg7, Atg12-Atg5 conjugation and LC3II. The increased p-p38 and p-JNK1/2 and decreased p-Akt may lead to autophagy induction. Therefore, goniothalamin promoted apoptosis associated with autophagy induction in SK-BR-3 cells through p-p38 and p-JNK1/2 upregulation and p-Akt downregulation. The present study indicated that goniothalamin may be further used as a potential therapeutic candidate or may offer an alternative treatment for breast cancer. PMID- 26987061 TI - Raphanus sativus cv. Sango Sprout Juice Decreases Diet-Induced Obesity in Sprague Dawley Rats and Ameliorates Related Disorders. AB - BACKGROUND: Obesity is recognized as a leading global health problem, correlated with an increased risk for several chronic diseases. One strategy for weight control management includes the use of vegetables rich in bioactive compounds to counteract weight gain, improve the antioxidant status and stimulate lipid catabolism. AIM OF THE STUDY: The aim of this study was to investigate the role of Raphanus sativus Sango sprout juice (SSJ), a Brassica extraordinarily rich in anthocyanins (AC) and isothiocyanates (ITCs), in a non-genetic model of obesity (high fat diet-HFD induced). METHODS: Control groups were fed with HFD or regular diet (RD). After a 10-week period, animals were assigned to experimental units and treated by gavage for 28 days as follows: HFD and RD control groups (rats fed HFD or RD and treated with vehicle only) and HFD-treated groups (rats fed HFD and treated with 15, 75 or 150 mg/kg b.w. of SSJ). Body weight and food consumption were recorded and serum lipid profile was measured (total cholesterol, triglycerides, and non-esterified fatty acids). Hepatic phase-I, phase-II as well as antioxidant enzymatic activities were assessed. RESULTS: SSJ lowered total cholesterol level, food intake and liver weight compared with HFD rodents. SSJ at medium dose proved effective in reducing body-weight (~19 g reduction). SSJ was effective in up-regulating the antioxidant enzymes catalase, NAD(P)H: quinone reductase, oxidised glutathione reductase and superoxide dismutase, which reached or exceeded RD levels, as well as the phase II metabolic enzyme UDP-glucuronosyl transferase (up to about 43%). HFD up-regulated almost every cytochrome P450 isoform tested, and a mild down-regulation to baseline was observed after SSJ intervention. CONCLUSION: This work reveals, for the first time, the antioxidant, hypolipidemic and antiobesity potential of SSJ, suggesting its use as an efficient new functional food/nutraceutical product. PMID- 26987065 TI - Effects of urinary cortisol levels and resting heart rate on the risk for fatal and nonfatal cardiovascular events. AB - BACKGROUND AND AIMS: Higher cortisol levels are associated with cardiovascular mortality in the elderly. It is unclear whether this association also exists in a general population of younger adults and for non-fatal cardiovascular events. Likewise, resting heart rate is associated with cardiovascular mortality, but fewer studies have also considered non-fatal events. The goal of this study was to investigate whether twenty-four-hour urinary cortisol (24-h UFC) levels and resting heart rate (RHR) predict major adverse fatal and non-fatal cardiovascular events (MACE) in the general population. METHODS: We used data from a subcohort of the PREVEND study, a prospective general population based cohort study with a follow-up of 6.4 years for 24-h UFC and 10.6 years for RHR. Participants were 3432 adults (mean age 49 years, range 28-75). 24-h UFC was collected and measured by liquid chromatography-tandem mass spectrometry. RHR was measured at baseline in a supine position for 10 min with the Dinamap XL Model 9300. Information about cardiovascular events and mortality was obtained from the Dutch national registry of hospital discharge diagnoses and the municipal register respectively. RESULTS: 24-h UFC did not significantly increase the hazard of MACE (hazard ratio = 0.999, 95% confidence interval = 0.993-1.006, p = 0.814). RHR increased the risk for MACE with 17% per 10 extra heart beats per minute (hazard ratio = 1.016, 95% confidence interval = 1.001-1.031, p = 0.036) after adjustment for conventional risk factors. CONCLUSIONS: In contrast to 24-h UFC, RHR is a risk marker for MACE in the general population. PMID- 26987064 TI - Corneal Wound Healing Requires IKB kinase beta Signaling in Keratocytes. AB - IkB kinase beta (IKKbeta) is a key signaling kinase for inflammatory responses, but it also plays diverse cell type-specific roles that are not yet fully understood. Here we investigated the role of IKKbeta in the cornea using Ikkbeta(DeltaCS) mice in which the Ikkbeta gene was specifically deleted in the corneal stromal keratocytes. The Ikkbeta(DeltaCS) corneas had normal morphology, transparency and thickness; however, they did not heal well from mild alkali burn injury. In contrast to the Ikkbeta(F/F) corneas that restored transparency in 2 weeks after injury, over 50% of the Ikkbeta(DeltaCS) corneas failed to fully recover. They instead developed recurrent haze with increased stromal thickness, severe inflammation and apoptosis. This pathogenesis correlated with sustained myofibroblast transformation with increased alpha smooth muscle actin (alpha-SMA) expression, higher levels of senescence beta-Gal activity and scar tissue formation at the late stage of wound healing. In addition, the Ikkbeta(DeltaCS) corneas displayed elevated expression of hemo-oxygenase-1 (HO-1), a marker of oxidative stress, and activation of stress signaling pathways with increased JNK, c-Jun and SMAD2/3 phosphorylation. These data suggest that IKKbeta in keratocytes is required to repress oxidative stress and attenuate fibrogenesis and senescence in corneal wound healing. PMID- 26987066 TI - Long noncoding RNAs and atherosclerosis. AB - Atherosclerosis is universally recognized as a chronic lipid-induced inflammation of the vessel wall in response to dyslipidemia and haemodynamic stress involving dysfunction and activation of resident vascular cells as well as infiltration of leukocytes. As members of nonprotein-coding RNAs, the long noncoding RNAs (lncRNAs) are implicated in various biological processes. Accumulating evidences suggest that lncRNAs regulate the function of vascular wall, activation of macrophages, lipid metabolism and immune response. Here, we review the effects of lncRNAs on the progress of atherosclerosis. PMID- 26987067 TI - Targeting PCSK9 for therapeutic gains: Have we addressed all the concerns? AB - Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) regulates the expression of low-density lipoprotein (LDL)-receptors, through reducing their recycling by binding to the receptor along with LDL and targeting it for lysosomal destruction. PCSK9 also enhances the degradation of very-low-density-lipoprotein receptor (VLDLR) and lipoprotein receptor-related protein 1 (LRP-1) in a LDL receptor independent manner. This role in lipid homeostasis presents PCSK9 as an attractive target for the therapeutic management of familial hypercholesterolemia as well as other refractory dyslipidaemias. However, PCSK9 mediates multifarious functions independent of its role in lipid homeostasis, which can be grouped under "pleiotropic functions" of the protein. This includes PCSK9's role in: trafficking of epithelial sodium channel; hepatic regeneration; pancreatic integrity and glucose homeostasis; antiviral activity; antimalarial activity; regulation of different cell signalling pathways; cortical neural differentiation; neuronal apoptosis and Alzheimer's disease. The question that needs to be investigated in depth is "How will the pleotropic functions of PCSK9, be affected by the therapeutic intervention of the protease's LDL-receptor lowering activity?" In this review, we appraise the different lipid lowering strategies targeting PCSK9 in light of the protein's different pleiotropic functions. Additionally, we delineate the key areas that require further examination, to ensure the long-term safety of the above lipid-lowering strategies. PMID- 26987068 TI - Effects of phytosterols on markers of inflammation: A systematic review and meta analysis. AB - BACKGROUND AND AIMS: Regular intake of phytosterols (PS) is proven to dose dependently lower LDL-cholesterol (LDL-C). Whether PS consumption can also impact low-grade inflammation is unclear. Considering the low feasibility of outcomes studies involving PS consumption, investigation of surrogate markers of atherosclerosis represents a valuable approach. This study assessed the anti inflammatory effect of PS consumption, according to inflammatory biomarkers, mainly C-reactive protein (CRP). METHODS AND RESULTS: A systematic search of Medline, Cab Abstracts, and Food Science & Technology Abstracts was conducted through January 2015. Our study selection included randomized controlled trials (RCT), involving intake of PS-enriched foods as active treatment, and measurement of plasma inflammatory biomarkers. Random-effects meta-analyses were performed using average baseline and end-of-intervention concentrations and control adjusted absolute changes in CRP and blood lipids. There were 20 eligible RCTs including a total of 1308 subjects. The absolute change of plasma CRP levels with PS consumption was -0.10 mg/L (95%CI -0.26; 0.05), a non-significant change, and heterogeneity had borderline significance (I(2) = 29.1; p-value = 0.073). The absolute reduction of LDL-C was -14.3 mg/dL (95%CI -17.3; -11.3). Meta-regression analyses showed that both the dose and duration of PS intake significantly influenced the absolute changes in plasma CRP (beta = -0.35, p = 0.0255 and beta = -0.03, p = 0.0209, respectively). CONCLUSIONS: In this meta-analysis, regular intake of PS-enriched foods did not significantly change CRP, whilst LDL-C concentrations were significantly reduced. Further studies with higher PS doses may provide more definite conclusions on a potential anti-inflammatory effect of PS intake. PMID- 26987069 TI - Comparison of Trifecta and Pentafecta Outcomes between T1a and T1b Renal Masses following Robot-Assisted Partial Nephrectomy (RAPN) with Minimum One Year Follow Up: Can RAPN for T1b Renal Masses Be Feasible? AB - PURPOSE/OBJECTIVES: To investigate the feasibility of RAPN on T1b renal mass by assessment of Trifecta and Pentafecta rate between T1a and T1b renal mass. MATERIALS/METHODS: We retrospectively reviewed the medical records of 277 cases of RPN performed from 2006 to 2015. Sixty patients with clinically T1b renal masses (> 4 cm and <= 7 cm) were identified, and from 180 patients with clinically T1a renal mass, 60 patients were matched with T1b renal mass by propensity score. Tumor complexity was investigated according to R.E.N.A.L nephrometry score. "Pentafecta" was defined as achievement of Trifecta (negative surgical margin, no postoperative complications and warm ischemia time of <= 25 minutes) with addition of over 90% estimated GFR preservation and no chronic kidney disease stage upgrading at 1 year postoperative period. Propensity score matching was performed by OneToManyMTCH. Logistic regression models were used to identify the variables which predict the Trifecta, and Pentafecta ac. RESULTS: Preoperative variables (age, sex, body mass index, ASA score) were similar between T1a and T1b after propensity score matching. The median R.E.N.A.L. nephrometry score was 8 vs 9 for T1a and T1b respectively (p<0.001). The median warm ischemia time was 20.1 min vs 26.2 min (p<0.001). Positive surgical margin rate was 5% vs 6.6% (p = 0.729) and overall complication rate of 13.3%. vs 15% (p = 0.793). The rate of achievement of Trifecta rate were 65.3% vs 43.3% (p = 0.017) and Pentafecta rate were 38.3% vs 26.7% (p = 0.172). For achievement of Pentafecta, R.E.N.A.L nephrometry score (HR 0.80; 95% CI (0.67-0.97); p = 0.031) was significant predictor of achieving Pentafecta. Subanalyis to assess the component of R.E.N.A.L nephrometry score, L component (location relative to the polar lines, HR 0.63; 95% CI (0.38-1.03); P = 0.064) was relatively important component for Pentafecta achievement. CONCLUSIONS: The rate of Pentafecta after RAPN was comparable between T1a and T1b renal masses. RAPN is a feasible modality with excellent long term outcome for patients with larger renal mass (cT1b). PMID- 26987070 TI - Opposing effects of dopamine D1- and D2-like agonists on intracranial self stimulation in male rats. AB - Dopamine acts through dopamine Type I receptors (comprising D1 and D5 subtypes) and dopamine Type II receptors (comprising D2, D3, and D4 subtypes). Intracranial self-stimulation (ICSS) is 1 experimental procedure that can be used to evaluate abuse-related effects of drugs targeting dopamine receptors. This study evaluated effects of dopamine receptor ligands on ICSS in rats using experimental procedures that have been used previously to examine abused indirect dopamine agonists such as cocaine and amphetamine. Male Sprague-Dawley rats responded under a fixed-ratio 1 schedule for electrical stimulation of the medial forebrain bundle, and frequency of stimulation varied from 56-158 Hz in 0.05 log increments during each experimental session. Drug potency and time course were determined for the D1 ligands A77636, SKF82958, SKF38393, fenoldopam, and SCH39166 and the D2/3 ligands sumanirole, apomorphine, quinpirole, PD128907, pramipexole, aripiprazole, eticlopride, and PG01037. The high-efficacy D1 agonists A77636 and SKF82958 produced dose-dependent, time-dependent, and abuse-related facilitation of ICSS. Lower efficacy D1 ligands and all D2/3 ligands failed to facilitate ICSS at any dose or pretreatment time. A mixture of SKF82958 and quinpirole produced a mixture of effects produced by each drug alone. Quinpirole also failed to facilitate ICSS after regimens of repeated treatment with either quinpirole or cocaine. These studies provide more evidence for divergent effects of dopamine D1 and D2-family agonists on ICSS procedure in rats and suggest that ICSS may be a useful complement to other approaches for preclinical abuse potential assessment, in part because of the reproducibility of results. (PsycINFO Database Record PMID- 26987071 TI - Involvement of Endoplasmic Reticulum Stress in TULP1 Induced Retinal Degeneration. AB - Inherited retinal disorders (IRDs) result in severe visual impairments in children and adults. A challenge in the field of retinal degenerations is identifying mechanisms of photoreceptor cell death related to specific genetic mutations. Mutations in the gene TULP1 have been associated with two forms of IRDs, early-onset retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). TULP1 is a cytoplasmic, membrane-associated protein shown to be involved in transportation of newly synthesized proteins destined for the outer segment compartment of photoreceptor cells; however, how mutant TULP1 causes cell death is not understood. In this study, we provide evidence that common missense mutations in TULP1 express as misfolded protein products that accumulate within the endoplasmic reticulum (ER) causing prolonged ER stress. In an effort to maintain protein homeostasis, photoreceptor cells then activate the unfolded protein response (UPR) complex. Our results indicate that the two major apoptotic arms of the UPR pathway, PERK and IRE1, are activated. Additionally, we show that retinas expressing mutant TULP1 significantly upregulate the expression of CHOP, a UPR signaling protein promoting apoptosis, and undergo photoreceptor cell death. Our study demonstrates that the ER-UPR, a known mechanism of apoptosis secondary to an overwhelming accumulation of misfolded protein, is involved in photoreceptor degeneration caused by missense mutations in TULP1. These observations suggest that modulating the UPR pathways might be a strategy for therapeutic intervention. PMID- 26987073 TI - Determining the Lowest Optimally Effective Methotrexate Dose for Individual RA Patients Using Their Dose Response Relation in a Tight Control Treatment Approach. AB - OBJECTIVE: To determine the optimal methotrexate dose in individual patients and to explore whether this optimal dose and the level of disease activity at that dose could be predicted. METHODS: Data from CAMERA II trial comparing MTX and MTX with 10 mg of prednisone both in a tight control treatment strategy in early RA was used. For each patient a curve for disease activity over time was fitted and the MTX dose after which further step-up did not result in relevant improvement in disease activity anymore was determined the 'lowest optimally effective MTX dose (LOED)'. The association of demographic and clinical characteristics at baseline with this LOED and with the level of disease activity reached at LOED was studied. RESULTS: In 204 (100 MTX and 104 MTX with prednisone) out of 236 patients LOED could be defined. 10 mg/wk was the most prevalent LOED in patients treated with MTX and prednisone and 10 mg/wk, 20 mg/wk and 30 mg/wk in the MTX strategy. Although the specific LOED could not reliably be predicted, higher baseline disease activity, height and lower weight were associated with higher LOEDs (i.e at least 15 mg/wk). A score was presented to decide on a starting dose of 10 mg/wk or (at least) 15 mg/wk. The level of disease activity at LOED could not be reliably predicted. CONCLUSION: A starting dose of 10 mg/wk might be a good choice for most patients and is frequently already the optimal dose. However, a subgroup of patient can be determined who would require higher MTX doses. PMID- 26987078 TI - Effect of recombinant human erythropoietin and doxorubicin in combination on the proliferation of MCF-7 and MDA-MB231 breast cancer cells. AB - Patients with cancer often exhibit signs of anemia as the result of the disease. Thus, cancer chemotherapies often include erythropoietin (EPO) in the regime to improve the survival rate of these patients. The aim of the present study was to determine the effect of EPO on doxorubicin-treated breast cancer cells. The cytotoxicity of doxorubicin alone or in combination with EPO against the MCF-7 and MDA-MB-231 human breast cancer cells were determined using an MTT cell viability assay, neutral red (NR) uptake assay and lactate dehydrogenase (LDH) assay. The estimated half maximal inhibitory concentration values for doxorubicin and the combination of doxorubicin with EPO were between 0.140 and 0.260 ug/ml for all cells treated for 72 h. Treatment with doxorubicin in combination with EPO led to no notable difference in cytotoxicity, compared with treatment with doxorubicin alone. The antiproliferative effect of doxorubicin at a concentration of 1 ug/ml on the MDA-MB-231 cells was demonstrated by the decrease in viable cells from 3.6x10(5) at 24 h to 2.1x10(5) at 72 h of treatment. In order to confirm apoptosis in the doxorubicin-treated cells, the activities of caspases 3/7 and -9 were determined using a TBE assay. The results indicated that the activities of caspases-3/7 and -9 were significantly elevated in the doxorubicin treated MDA-MB-231 cells by 571 and 645%, respectively, and in the MCF 7 cells by 471 and 345%, respectively, compared with the control cells. EPO did not modify the effect of doxorubicin on these cell lines. The results of the present study suggested that EPO was safe for use in combination with doxorubicin in the treatment of patients with breast cancer and concurrent anemia. PMID- 26987079 TI - An Ag(I) energetic metal-organic framework assembled with the energetic combination of furazan and tetrazole: synthesis, structure and energetic performance. AB - A novel Ag(I) energetic MOF [Ag16(BTFOF)9]n.[2(NH4)]n () assembled with Ag(iI ions and a furazan derivative, 4,4'-oxybis[3,3'-(1H-5-tetrazol)]furazan (H2BTFOF) was successfully synthesized and structurally characterized, featuring a three dimensional porous structure incorporating ammonium cations. The thermal stability and energetic properties were determined, revealing that the 3D energetic MOF had an outstanding insensitivity (IS > 40 J), an ultrahigh detonation pressure (P) of 65.29 GPa and a detonation velocity (D) of 11.81 km cm(-3). In addition, the self-accelerating decomposition temperature (TSADT) and the critical temperature of thermal explosion (Tb) are also discussed in detail. The finding exemplifies that the assembly strategy plays a decisive role in the density and energetic properties of MOF-based energetic materials. PMID- 26987080 TI - Intrapatient variation in antiepileptic drug plasma concentration after generic substitution vs stable brand-name drug regimens. AB - Generic substitution of antiepileptic drugs (AEDs) is still a matter of controversy and concern among clinicians and patients. We aimed to assess intrasubject variation in plasma concentrations of lamotrigine (LTG), levetiracetam (LEV) and topiramate (TPM) after generic substitution compared with a stable brand-name drug regimen in a population of patients with epilepsy. A retrospective analysis was performed on prospectively collected and stored data from our therapeutic drug monitoring (TDM) database for the years 2009-2014. The main outcome variable was the proportion of patients who, after switching from branded to generic formulations, showed a greater than +/-20% change in AED plasma concentrations compared to the proportion of control patients showing a change in AED plasma concentrations of the same extent while receiving stable branded formulations over repeated TDM tests. Fifty patients on LTG, 27 on LEV and 16 on TPM showing at least one TDM test while receiving generic products fulfilled the inclusion/exclusion criteria for the analysis and were compared with 200 control patients for LTG, 120 for LEV and 80 for TPM. The proportion of patients showing an intrasubject change greater than +/-20% in AED plasma concentrations was similar in the brand name vs generic group compared with the control one for LTG (22% vs 33%) and LEV (44% vs 38%), while it was higher in the control group for TPM (41% vs 6%, p<0.01). These are the first data in the literature about the within-patient variation in steady-state plasma concentrations of a series of stable treatments with brand-name AEDs in a real clinical setting. In conclusion, a significant interday variability in intrapatient LTG, LEV and TPM plasma concentrations can be observed even in patients stabilized with the same brand name product over time. This suggests that any change in plasma AED concentration and possible related clinical effects after generic substitution may be not necessarily related to the switch. Our results should be confirmed by large, prospective, blinded, randomized controlled studies in people with epilepsy. PMID- 26987081 TI - Functional fitness norms for community-dwelling older adults in Hong Kong. AB - OBJECTIVE: This study aimed to establish normative data for older adults in Hong Kong and explore age and sex differences in functional fitness. METHODS: A sample of 944 independent community-dwellers, aged 65-74 years, was evaluated using the Senior Fitness Test battery in addition to hand grip and single leg stance tests. Normative data were reported for the 10th, 25th, 50th, 75th, and 90th percentiles in 5-year age groups. RESULTS: Except for upper extremity muscle strength in women and body mass index (BMI) in both sexes, ageing-associated degradation was observed in all testing parameters especially in flexibility, balance, and agility. Significant sex differences were found in all testing parameters with the exception of BMI and static balance with eyes open. Moreover, men demonstrated higher capacities for muscle strength, agility, balance, and aerobic endurance, whereas women showed superior flexibility. CONCLUSION: The normative values enable the evaluation of individual performance regarding the fitness status of older adults in Hong Kong. PMID- 26987082 TI - CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. AB - This guideline provides recommendations for primary care clinicians who are prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care. The guideline addresses 1) when to initiate or continue opioids for chronic pain; 2) opioid selection, dosage, duration, follow-up, and discontinuation; and 3) assessing risk and addressing harms of opioid use. CDC developed the guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, and recommendations are made on the basis of a systematic review of the scientific evidence while considering benefits and harms, values and preferences, and resource allocation. CDC obtained input from experts, stakeholders, the public, peer reviewers, and a federally chartered advisory committee. It is important that patients receive appropriate pain treatment with careful consideration of the benefits and risks of treatment options. This guideline is intended to improve communication between clinicians and patients about the risks and benefits of opioid therapy for chronic pain, improve the safety and effectiveness of pain treatment, and reduce the risks associated with long-term opioid therapy, including opioid use disorder, overdose, and death. CDC has provided a checklist for prescribing opioids for chronic pain (http://stacks.cdc.gov/view/cdc/38025) as well as a website (http://www.cdc.gov/drugoverdose/prescribingresources.html) with additional tools to guide clinicians in implementing the recommendations. PMID- 26987083 TI - Hydrogen sulfide promotes cell proliferation of oral cancer through activation of the COX2/AKT/ERK1/2 axis. AB - Hydrogen sulfide, the third gaseous transmitter, is one of the main causes of halitosis in the oral cavity. It is generally considered as playing a deleterious role in many oral diseases including oral cancer. However, the regulatory mechanisms involved in the effects of hydrogen sulfide on oral cancer growth remain largely unknown. In the present study, we investigated the underlying mechanisms through CCK-8 assay, EdU incorporation, real-time PCR, western blot and pathway blockade assays. Our results showed that hydrogen sulfide promoted oral cancer cell proliferation through activation of the COX2, AKT and ERK1/2 pathways in a dose-dependent manner. Blocking any of the three above pathways inhibited hydrogen sulfide-induced oral cancer cell proliferation. Meanwhile, blockade of COX2 by niflumic acid downregulated NaHS-induced p-ERK and p-AKT expression. Inactivation of the AKT pathway by GSK690693 significantly decreased NaHS-induced p-ERK1/2 expression, and inhibition of the ERK1/2 pathway by U0126 markedly increased NaHS-induced p-AKT expression. Either the AKT or ERK1/2 inhibitor did not significantly alter the COX2 expression level. Our data revealed, for the first time, that hydrogen sulfide promotes oral cancer cell proliferation through activation of the COX2/AKT/ERK1/2 axis, suggesting new potential targets to eliminate the effect of hydrogen sulfide on the development of oral cancer. PMID- 26987072 TI - Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis. AB - (R)-Roscovitine, a pharmacological inhibitor of kinases, is currently in phase II clinical trial as a drug candidate for the treatment of cancers, Cushing's disease and rheumatoid arthritis. We here review the data that support the investigation of (R)-roscovitine as a potential therapeutic agent for the treatment of cystic fibrosis (CF). (R)-Roscovitine displays four independent properties that may favorably combine against CF: (1) it partially protects F508del-CFTR from proteolytic degradation and favors its trafficking to the plasma membrane; (2) by increasing membrane targeting of the TRPC6 ion channel, it rescues acidification in phagolysosomes of CF alveolar macrophages (which show abnormally high pH) and consequently restores their bactericidal activity; (3) its effects on neutrophils (induction of apoptosis), eosinophils (inhibition of degranulation/induction of apoptosis) and lymphocytes (modification of the Th17/Treg balance in favor of the differentiation of anti-inflammatory lymphocytes and reduced production of various interleukins, notably IL-17A) contribute to the resolution of inflammation and restoration of innate immunity, and (4) roscovitine displays analgesic properties in animal pain models. The fact that (R)-roscovitine has undergone extensive preclinical safety/pharmacology studies, and phase I and II clinical trials in cancer patients, encourages its repurposing as a CF drug candidate. PMID- 26987084 TI - The importance of effective sampling for exploring the population dynamics of haploid-diploid seaweeds. AB - The mating system partitions genetic diversity within and among populations and the links between life history traits and mating systems have been extensively studied in diploid organisms. As such most evolutionary theory is focused on species for which sexual reproduction occurs between diploid male and diploid female individuals. However, there are many multicellular organisms with biphasic life cycles in which the haploid stage is prolonged and undergoes substantial somatic development. In particular, biphasic life cycles are found across green, brown and red macroalgae. Yet, few studies have addressed the population structure and genetic diversity in both the haploid and diploid stages in these life cycles. We have developed some broad guidelines with which to develop population genetic studies of haploid-diploid macroalgae and to quantify the relationship between power and sampling strategy. We address three common goals for studying macroalgal population dynamics, including haploid-diploid ratios, genetic structure and paternity analyses. PMID- 26987086 TI - The Age of Discovery is still with us. PMID- 26987085 TI - Phosphorus physiological ecology and molecular mechanisms in marine phytoplankton. AB - Phosphorus (P) is an essential nutrient for marine phytoplankton and indeed all life forms. Current data show that P availability is growth-limiting in certain marine systems and can impact algal species composition. Available P occurs in marine waters as dissolved inorganic phosphate (primarily orthophosphate [Pi]) or as a myriad of dissolved organic phosphorus (DOP) compounds. Despite numerous studies on P physiology and ecology and increasing research on genomics in marine phytoplankton, there have been few attempts to synthesize information from these different disciplines. This paper is aimed to integrate the physiological and molecular information on the acquisition, utilization, and storage of P in marine phytoplankton and the strategies used by these organisms to acclimate and adapt to variations in P availability. Where applicable, we attempt to identify gaps in our current knowledge that warrant further research and examine possible metabolic pathways that might occur in phytoplankton from well-studied bacterial models. Physical and chemical limitations governing cellular P uptake are explored along with physiological and molecular mechanisms to adapt and acclimate to temporally and spatially varying P nutrient regimes. Topics covered include cellular Pi uptake and feedback regulation of uptake systems, enzymatic utilization of DOP, P acquisition by phagotrophy, P-limitation of phytoplankton growth in oceanic and coastal waters, and the role of P-limitation in regulating cell size and toxin levels in phytoplankton. Finally, we examine the role of P and other nutrients in the transition of phytoplankton communities from early succession species (diatoms) to late succession ones (e.g., dinoflagellates and haptophytes). PMID- 26987088 TI - Evidence of an evolutionary-developmental trade-off between drag avoidance and tolerance strategies in wave-swept intertidal kelps (Laminariales, Phaeophyceae). AB - Kelps are a clade of morphologically diverse, ecologically important habitat forming species. Many kelps live in wave-swept environments and are exposed to chronic flow-induced stress. In order to grow and survive in these harsh environments, kelps can streamline (reducing drag coefficient) to avoid drag or to increase attachment and breakage force to tolerate it. We aimed to quantify the drag tolerance and streamlining strategies of kelps from wave-swept intertidal habitats. We measured drag coefficient and tenacity of populations from eight kelp species over a wide range of sizes to determine whether kelps avoid dislodgement by reducing drag coefficient or by increasing tenacity as they grow, and whether these traits are traded off. We employed phylogenetic comparative methods to rule out potentially confounding effects of species' relatedness. There was a significant negative relationship between drag avoidance and tolerance strategies, even after incorporating phylogeny. Kelps that were more tenacious were less able to reduce drag, resulting in a continuum from "tolerators" to "streamliners," with some species demonstrating intermediate, mixed strategies. Drag and tenacity were correlated with geometric properties (i.e., second moment of area) of the stipe in large kelps. Results presented in this study suggest that kelps are either strong or streamlined, but not both. This continuum is consistent with avoidance and tolerance trade-offs that have been documented in many different biological systems and may have widespread implications for the evolution of large macroalgae, perhaps driving morphological diversity within this group. PMID- 26987087 TI - New Ulvaceae (Ulvophyceae, Chlorophyta) from mesophotic ecosystems across the Hawaiian Archipelago. AB - Ulvalean algae (Chlorophyta) are most commonly described from intertidal and shallow subtidal marine environments worldwide, but are less well known from mesophotic environments. Their morphological simplicity and phenotypic plasticity make accurate species determinations difficult, even at the generic level. Here, we describe the mesophotic Ulvales species composition from 13 locations across 2,300 km of the Hawaiian Archipelago. Twenty-eight representative Ulvales specimens from 64 to 125 m depths were collected using technical diving, submersibles, and remotely operated vehicles. Morphological and molecular characters suggest that mesophotic Ulvales in Hawaiian waters form unique communities comprising four species within the genera Ulva and Umbraulva, each with discrete geographic and/or depth-related distributional patterns. Three genetically distinct taxa are supported by both plastid (rbcL and tufA) and nuclear (ITS1) markers, and are presented here as new species: Umbraulva kaloakulau, Ulva ohiohilulu, and Ulva iliohaha. We also propose a new Umbraulva species (Umbraulva kuaweuweu), which is closely related to subtidal records from New Zealand and Australia, but not formally described. To our knowledge, these are the first marine species descriptions from Hawai'i resulting from the collaboration of traditional Hawaiian nomenclature specialists, cultural practitioners and scientists. The difficulty of finding reliable diagnostic morphological characters for these species reflects a common problem worldwide of achieving accurate identification of ulvalean taxa using solely morphological criteria. Mesophotic Ulvales appear to be distinct from shallow-water populations in Hawai'i, but their degree of similarity to mesophotic floras in other locations in the Pacific remains unknown. PMID- 26987089 TI - Differences in pigmentation between life cycle stages in Scrippsiella lachrymosa (dinophyceae). AB - Various life cycle stages of cyst-producing dinoflagellates often appear differently colored under the microscope; gametes appear paler while zygotes are darker in comparison to vegetative cells. To compare physiological and photochemical competency, the pigment composition of discrete life cycle stages was determined for the common resting cyst-producing dinoflagellate Scrippsiella lachrymosa. Vegetative cells had the highest cellular pigment content (25.2 +/- 0.5 pg . cell(-1) ), whereas gamete pigment content was 22% lower. The pigment content of zygotes was 82% lower than vegetative cells, even though they appeared darker under the microscope. Zygotes of S. lachrymosa contained significantly higher cellular concentrations of beta-carotene (0.65 +/- 0.15 pg . cell(-1) ) than all other life stages. Photoprotective pigments and the de-epoxidation ratio of xanthophylls-cycle pigments in S. lachrymosa were significantly elevated in zygotes and cysts compared to other stages. This suggests a role for accessory pigments in combating intracellular oxidative stress during sexual reproduction or encystment. Resting cysts contained some pigments even though chloroplasts were not visible, suggesting that the brightly colored accumulation body contained photosynthetic pigments. The differences in pigmentation between life stages have implications for interpretation of pigment data from field samples when sampled during dinoflagellate blooms. PMID- 26987090 TI - Effects of sodium sulfate on the freshwater microalga Chlamydomonas moewusii: implications for the optimization of algal culture media. AB - The study of the microalgal growth kinetics is an indispensable tool in all fields of phycology. Knowing the optimal nutrient concentration is an important issue that will help to develop efficient growth systems for these microorganisms. Although nitrogen and phosphorus are well studied for this purpose, sulfur seems to be less investigated. Sulfate is a primary sulfur source used by microalgae; moreover, the concentration of this compound is increasing in freshwater systems due to pollution. The aim of this study was to investigate the effects of different sodium sulfate concentrations in the culture medium on growth and growth kinetics of the freshwater microalga Chlamydomonas moewusii. Production of biomass, chl content, kinetic equations, and a mathematical model that describe the microalgal growth in relation with the concentration of sodium sulfate were obtained. The lowest concentration of sodium sulfate allowing optimal growth was 0.1 mM. Concentrations higher than 3 mM generated a toxic effect. This work demonstrates that this toxic effect was not directly due to the excess of sulfate ion but by the elevation of the ionic strength. An inhibition model was successfully used to simulate the relationship between specific growth rate and sodium sulfate in this microalga. PMID- 26987091 TI - Gymnoxanthella radiolariae gen. et sp. nov. (Dinophyceae), a dinoflagellate symbiont from solitary polycystine radiolarians. AB - The symbiotic dinoflagellate Gymnoxanthella radiolariae T. Yuasa et T. Horiguchi gen. et sp. nov. isolated from polycystine radiolarians is described herein based on light, scanning and transmission electron microscopy as well as molecular phylogenetic analyses of SSU and LSU rDNA sequences. Motile cells of G. radiolariae were obtained in culture, and appeared to be unarmored. The cells were 9.1-11.4 MUm long and 5.7-9.4 MUm wide, and oval to elongate oval in the ventral view. They possessed an counterclockwise horseshoe-shaped apical groove, a nuclear envelope with vesicular chambers, cingulum displacement with one cingulum width, and the nuclear fibrous connective; all of these are characteristics of Gymnodinium sensu stricto (Gymnodinium s.s.). Molecular phylogenetic analyses also indicated that G. radiolariae belongs to the clade of Gymnodinium s.s. However, in our molecular phylogenetic trees, G. radiolariae was distantly related to Gymnodinium fuscum, the type species of Gymnodinium. Based on the consistent morphological, genetic, and ecological divergence of our species with the other genera and species of Gymnodinium s.s., we considered it justified to erect a new, separate genus and species G. radiolariae gen. et sp. nov. As for the peridinioid symbiont of radiolarians, Brandtodinium has been erected as a new genus instead of Zooxanthella, but the name Zooxanthella is still valid. Brandtodinium is a junior synonym of Zooxanthella. Our results suggest that at least two dinoflagellate symbiont species, peridinioid Zooxanthella nutricula and gymnodinioid G. radiolariae, exist in radiolarians, and that they may have been mixed and reported as "Z. nutricula" since the 19th century. PMID- 26987092 TI - Capsular polysaccharides facilitate enhanced iron acquisition by the colonial cyanobacterium Microcystis sp. isolated from a freshwater lake. AB - Microcystis sp., especially in its colonial form, is a common dominant species during cyanobacterial blooms in many iron-deficient water bodies. It is still not entirely clear, however, how the colonial forms of Microcystis acclimate to iron deficient habitats, and the responses of unicellular and colonial forms to iron replete and iron-deficient conditions were examined here. Growth rates and levels of photosynthetic pigments declined to a greater extent in cultures of unicellular Microcystis than in cultures of the colonial form in response to decreasing iron concentrations, resulting in the impaired photosynthetic performance of unicellular Microcystis as compared to colonial forms as measured by variable fluorescence and photosynthetic oxygen evolution. These results indicate that the light-harvesting ability and photosynthetic capacity of colonial Microcystis was less affected by iron deficiency than the unicellular form. The carotenoid contents and nonphotochemical quenching of colonial Microcystis were less reduced than those of the unicellular form under decreasing iron concentrations, indicating that the colonial morphology enhanced photoprotection and acclimation to iron-deficient conditions. Furthermore, large amounts of iron were detected in the capsular polysaccharides (CPS) of the colonies, and more iron was found to be attached to the colonial Microcystis CPS under decreasing iron conditions as compared to unicellular cultures. These results demonstrated that colonial Microcystis can acclimate to iron deficiencies better than the unicellular form, and that CPS plays an important role in their acclimation advantage in iron-deficient waters. PMID- 26987093 TI - Kinetic flux profiling dissects nitrogen utilization pathways in the oleaginous green alga Chlorella protothecoides. AB - As a promising candidate for biodiesel production, the green alga Chlorella protothecoides can efficiently produce oleaginous biomass and the lipid biosynthesis is greatly influenced by the availability of nitrogen source and corresponding nitrogen assimilation pathways. Based on isotope-assisted kinetic flux profiling (KFP), the fluxes through the nitrogen utilization pathway were quantitatively analyzed. We found that autotrophic C. protothecoides cells absorbed ammonium mainly through glutamate dehydrogenase (GDH), and partially through glutamine synthetase (GS), which was the rate-limiting enzyme of nitrogen assimilation process with rare metabolic activity of glutamine oxoglutarate aminotransferase (GOGAT, also known as glutamate synthase); whereas under heterotrophic conditions, the cells adapted to GS-GOGAT cycle for nitrogen assimilation in which GS reaction rate was associated with GOGAT activity. The fact that C. protothecoides chooses the adenosine triphosphate-free and less ammonium-affinity GDH pathway, or alternatively the energy-consuming GS-GOGAT cycle with high ammonium affinity for nitrogen assimilation, highlights the metabolic adaptability of C. protothecoides exposed to altered nitrogen conditions. PMID- 26987094 TI - Bacterial influence on alkenones in live microalgae. AB - The microalga Emiliania huxleyi produces alkenone lipids that are important proxies for estimating past sea surface temperatures. Field calibrations of this proxy are robust but highly variable results are obtained in culture. Here, we present results suggesting that algal-bacterial interactions may be responsible for some of this variability. Co-cultures of E. huxleyi and the bacterium Phaeobacter inhibens resulted in a 2.5-fold decrease in algal alkenone-containing lipid bodies. In addition levels of unsaturated alkenones increase in co cultures. These changes result in an increase in the reconstructed growth temperature of up to 2 degrees C relative to axenic algal cultures. PMID- 26987095 TI - Recovery and identification of Pseudo-nitzschia (Bacillariophyceae) frustules from natural samples acquired using the environmental sample processor. AB - Many species within the diatom genus Pseudo-nitzschia are difficult to distinguish without applying molecular analytical or microscopy-based methods. DNA, antibody and lectin probes have previously been used to provide rapid and specific detection of species and strains in complex field assemblages. Recently, however, well-documented cryptic genetic diversity within the group has confounded results of DNA probe tests in particular. Moreover, the number of species descriptions within the genus continues to increase, as do insights into toxin production by both new and previously described species. Therefore, a combination of classical morphological techniques and modern molecular methodologies is needed to resolve ecophysiological traits of Pseudo-nitzschia species. Here, we present an approach to recover and identify frustules from sample collection filters used for toxin analysis onboard the Environmental Sample Processor (ESP), an in situ sample collection and analytical platform. This approach provides a new and powerful tool for correlating species presence with toxin detected remotely and in situ by the ESP, and has the potential to be applied broadly to other sampling configurations. This new technique will contribute to a better understanding of naturally occurring Pseudo-nitzschia community structure with respect to observed domoic acid outbreaks. PMID- 26987096 TI - Endemic or introduced? Phylogeography of Asparagopsis (Florideophyceae) in Australia reveals multiple introductions and a new mitochondrial lineage. AB - The red seaweed Asparagopsis taxiformis embodies five cryptic mitochondrial lineages (lineage 1-5) introduced worldwide as a consequence of human mediated transport and climate change. We compared globally collected mitochondrial cox2-3 intergenic spacer sequences with sequences produced from multiple Australian locations and South Korea to identify Asparagopsis lineages and to reveal cryptic introductions. We report A. taxiformis lineage 4 from Cocos (Keeling) Islands, Australia, and the highly invasive Indo-Pacific Mediterranean lineage 2 from South Korea and Lord Howe Island, Australia. Phylogeographic analysis showed a clear haplotype and geographic separation between western Australian and Great Barrier Reef (GBR) isolates belonging to the recently described lineage 5. The same lineage, however, was characterized by a substantial genetic and geographic break between the majority of Australian specimens and Asparagopsis collections from South Solitary Island, Southern GBR, Lord Howe Island, Kermadec Islands, Norfolk Island, New Caledonia and French Polynesia. The disjunct geographic distribution and sequence divergence between these two groups supports the recognition of a sixth cryptic A. taxiformis mitochondrial lineage. As climatic changes accelerate the relocation of biota and offer novel niches for colonization, periodic surveys for early detection of cryptic invasive seaweeds will be critical in determining whether eradication or effective containment of the aliens are feasible. PMID- 26987098 TI - Corrigendum. PMID- 26987097 TI - Photosynthetic pigments of oceanic Chlorophyta belonging to prasinophytes clade VII. AB - The ecological importance and diversity of pico/nanoplanktonic algae remains poorly studied in marine waters, in part because many are tiny and without distinctive morphological features. Amongst green algae, Mamiellophyceae such as Micromonas or Bathycoccus are dominant in coastal waters while prasinophytes clade VII, yet not formerly described, appear to be major players in open oceanic waters. The pigment composition of 14 strains representative of different subclades of clade VII was analyzed using a method that improves the separation of loroxanthin and neoxanthin. All the prasinophytes clade VII analyzed here showed a pigment composition similar to that previously reported for RCC287 corresponding to pigment group prasino-2A. However, we detected in addition astaxanthin for which it is the first report in prasinophytes. Among the strains analyzed, the pigment signature is qualitatively similar within subclades A and B. By contrast, RCC3402 from subclade C (Picocystis) lacks loroxanthin, astaxanthin, and antheraxanthin but contains alloxanthin, diatoxanthin, and monadoxanthin that are usually found in diatoms or cryptophytes. For subclades A and B, loroxanthin was lowest at highest light irradiance suggesting a light harvesting role of this pigment in clade VII as in Tetraselmis. PMID- 26987099 TI - Concurrent Surgery and Informed Consent. PMID- 26987100 TI - Cochrane Physical and Rehabilitation Medicine: Current State of Development and Next Steps. PMID- 26987101 TI - MRI-related thermal injury due to skin-to-skin contact. PMID- 26987102 TI - The Application of a Moldable Skin Barrier in the Self-Care of Elderly Ostomy Patients. AB - The quality of ostomy directly affects the stoma patient's quality of life. This study investigated the application of a moldable skin barrier in the self-care of elderly stoma patients after colostomy for colorectal cancer. A total of 104 elderly stoma patients (65-79 years) who underwent colostomy because of colorectal cancer were randomly divided into an experimental group (56 cases) receiving a moldable skin barrier and a control group (48 cases) receiving a conventional skin barrier. The information on peristomal irritant dermatitis occurrence, the satisfaction of self-care, and related care costs were collected 1 month after patients were discharged from the hospital. The overall incidence of irritant dermatitis was significantly lower (p = .01), the self-care satisfaction score was significantly higher (p = .02), and the cost for leakage proof cream (p < .001) was significantly lower in the experimental group than in the control group. In contrast, no significant differences in the cost of ostomy equipment and the barrier replacement interval were observed. In conclusion, a moldable skin barrier can reduce the incidence of irritant dermatitis in elderly stoma patients, improve their self-care satisfaction, and reduce the cost of leakage-proof cream use compared with the conventional stoma skin barrier. PMID- 26987103 TI - The Psychosocial Influences of Waiting Periods on Patients Undergoing Endoscopic Submucosal Dissection. AB - This study aimed to clarify psychosocial influences of waiting periods on patients undergoing endoscopic submucosal dissection for cancer at an advanced medical care facility in Japan. Subjects were consenting patients hospitalized from 2009 to 2010. Qualitative and quantitative data were gathered about patients' characteristics, disease and stage, and waiting period. Qualitative content analysis was used to analyze free statements and interview data. Subjects included 154 patients with an average wait period of 46.28 days for admission. Qualitative analysis revealed the following wait period perceptions. For calmness, results indicated (1) no anxiety, (2) relief based on doctors' positive judgment, (3) whatever happens/no choice, and (4) trust in doctor. For uneasiness, perceptions included (1) the sooner, the better/eagerly waiting, (2) anxiety and concern, and (3) emotional instability. Four waiting period coping types were identified: (1) making phone inquiries, (2) busy and forgot about the medical procedure, (3) relief from anxiety, and (4) unable to function well in daily life. Patients need to be educated about cancer progression and provided an estimated wait time. They also require more information about how to manage daily life such as monitoring factors from the nursing domain including physical condition, digestive symptoms, diet, and exercise. PMID- 26987105 TI - Efficacy of Coblation Endoscopic Lingual Lightening in Multilevel Surgery for Obstructive Sleep Apnea. AB - IMPORTANCE: Multilevel obstruction is involved in the pathogenesis of obstructive sleep apnea (OSA). Coblation endoscopic lingual lightening (CELL) is a variation of glossectomy to reduce tongue collapse and can be considered in the surgical management of adults with OSA. OBJECTIVE: To evaluate the clinical and polysomnographic outcomes of tongue base reduction using CELL in multilevel surgery for OSA. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case-control study was performed to review the medical records of adults with OSA (apnea hypopnea index [AHI], >20) and Friedman stage III (tongue position III and tonsil size I-II) who underwent combined CELL and relocation pharyngoplasty (group 1) or relocation pharyngoplasty alone (group 2) for OSA between January 1, 2012, and December 31, 2013, at a tertiary referral sleep center. The groups were matched by age, sex, body mass index, and AHI at baseline. The dates of the analysis were May 30 to June 29, 2014. INTERVENTION: Coblation endoscopic lingual lightening. MAIN OUTCOMES AND MEASURES METHODS: The primary outcome measure was change in AHI after surgery (after >=6 months). Other outcomes were differences in surgical response rates, perioperative apnea index, lowest oxygen saturation, and Epworth Sleepiness Scale score. RESULTS: The study cohort comprised 90 participants. Their mean (SD) age was 40.7 (9.2) years, and 96% (86 of 90) were male. Group 1 patients (n = 30) underwent combined CELL and relocation pharyngoplasty, and group 2 patients (n = 60) underwent relocation pharyngoplasty only. The mean (SD) AHI decreased from 48.4 (16.9) to 16.5 (11.2) (P < .001) in group 1 and from 44.2 (19.3) to 20.1 (15.6) (P < .001) in group 2 . Percentage change in AHI was significantly different between group 1 and group 2 (mean [SD], -65.5 [20.5] vs 53.2 [30.3]) (P = .047). The surgical response rate was greater in group 1 (73% [22 of 30]) than in group 2 (50% [30 of 60]) (P = .04). CONCLUSIONS AND RELEVANCE: Without increasing complications, combined CELL and relocation pharyngoplasty achieved greater AHI reduction and a higher surgical response rate among adults with OSA and Friedman stage III compared with relocation pharyngoplasty alone. PMID- 26987104 TI - Changes in small intestinal chromogranin A-immunoreactive cell densities in patients with irritable bowel syndrome after receiving dietary guidance. AB - Chromogranin A (CgA) is a common marker for enteroendocrine cells in the gut, and CgA-immunoreactive cell densities are abnormal in patients with irritable bowel syndrome (IBS). The majority of patients with IBS report that their symptoms develop after consuming certain foodstuffs. In the present study, we investigated the effects of dietary guidance on the total enteroendocrine cell densities in the small intestine, as detected by CgA. A total of 14 patients with IBS underwent a gastroscopy with duodenal biopsies and 11 of them also underwent a colonoscopy, with biopsy samples obtained from the ileum. Fourteen control subjects were also included. Each patient received 3 sessions of dietary guidance. Gastroscopies and colonoscopies were performed on both the controls and patients with IBS (at baseline and at 3-9 months after receiving guidance). Biopsy samples obtained from the duodenum and ileum were immunostained for CgA using the avidin-biotin complex (ABC) method and were quantified using computerized image analysis. The density of CgA-immunoreactive cells in the duodenum (mean +/- SEM values) in the control subjects was 235.9 +/- 31.9 cells/mm2; in the patients with IBS, the density was 36.9 +/- 9.8 and 103.7 +/- 16.9 cells/mm2 before and after they received dietary guidance, respectively (P=0.007). The density of CgA-immunoreactive cells in the ileum in the control subjects was 47.4 +/- 8.3 cells/mm2; in the patients with IBS, the density was 48.4 +/- 8.1 and 17.9 +/- 4.4 cells/mm2, before and after they received dietary guidance, respectively (P=0.0006). These data indicate that changes in CgA immunoreactive cell densities in patients with IBS after receiving dietary guidance may reflect a change in the densities of the small intestinal enteroendocrine cells, which may contribute to an improvement in the IBS symptoms. PMID- 26987107 TI - Association Between Lumbar Spine Sagittal Alignment and L4-L5 Disc Degeneration Among Asymptomatic Young Adults. AB - STUDY DESIGN: Cross-sectional observational study on the relationship between the degrees of disc degeneration and sagittal alignment in asymptomatic healthy individuals. OBJECTIVE: This study sought to determine whether the sagittal spine alignment subtype is related to the prevalence of lumbar disc degeneration. SUMMARY AND BACKGROUND DATA: Sagittal balance and spinopelvic parameters might be risk factors for disc degeneration. METHODS: A total of 70 asymptomatic participants (36 women and 34 men) without regular physical activity were categorized according to the four subtypes of sagittal alignment proposed by Roussouly. All participants underwent magnetic resonance imaging of the lumbar spine (1.5T) and panoramic radiography of the spine. The degree of disc degeneration was graded using T2-weighted images according to the Pfirrmann classification. Spinopelvic parameters and vertebral curvatures were measured on digital panoramic radiographs using Surgimap software. Interobserver analyses for the Pfirrmann classification and spinopelvic parameters were assessed using the weighted Kappa and intraclass correlation coefficient (ICC), respectively. RESULTS: The Kappa associated with disc degeneration classification was 0.79 (95% confidence intervals 0.72-0.87). The ICCs were excellent, with small confidence intervals for all spinopelvic parameters. The type II group (flat lordosis) showed a higher frequency of degenerated discs at L4-L5 (P = 0.03) than the type IV group (long and curved lumbar spine). No significant differences in disc degeneration were observed among the four subtypes at the other disc levels. We found a negative, moderate correlation between the spinopelvic parameters and the occurrence of disc degeneration in the type II group. CONCLUSION: The Roussouly subtype II sagittal alignment is significantly associated with disc degeneration at L4-L5 in asymptomatic young adults. Our results support the hypothesis that spinal sagittal alignment plays a role in early disc degeneration. LEVEL OF EVIDENCE: 3. PMID- 26987106 TI - Clinical Features and Prognostic Factors of Pediatric Spine Tumors: A Single Center Experience With 190 Cases. AB - STUDY DESIGN: A retrospective study was performed. OBJECTIVE: The aim of the study was to illustrate the characteristics of pediatric spine tumors (PSTs) and obtain better insight into therapeutic strategies of such kinds of tumors. SUMMARY OF BACKGROUND DATA: PSTs, a heterogeneous group of tumors occurred among pediatric group, are relatively uncommon and rarely reported in the literature. METHODS: A retrospective study was performed to analyze clinical features and prognostic factors of patients with PSTs who were treated in our center between 2000 and 2013. Local relapse-free survival (LRFS) and overall survival (OS) rate were estimated using the Kaplan-Meier method to identify potential prognostic factors. Factors with P values of 0.1 or lower were subjected to multivariate analysis by Cox regression analysis. P values of 0.05 or lower were considered statistically significant. RESULTS: A total of 190 patients with PSTs were included in the study. The mean follow-up period was 53.5 months. Of the 190 patients, 127 cases (66.8%) were diagnosed as benign lesions or tumor-like lesions, with 19 cases as aggressive lesions and 44 cases as malignant lesions. Recurrence was detected in 30 patients after initial surgery in our center, whereas death occurred in 24 cases. Implant failure and spinal deformity occurred in 3 and 5 patients, respectively. The statistical analysis suggested that multiple segments involvement (n >= 3), aggressive and malignant lesion were independent prognostic factors for LRFS, whereas malignant lesion was the only unfavorable factors for OS. In the subgroup analysis, multiple segments involvement (n >= 3) and Enneking stages III were independent factors for LRFS of patients with benign or aggressive lesions. CONCLUSION: Malignant lesion was significantly associated with decreased OS and LRFS of PSTs, whereas multiple segments involvement (n >= 3) and aggressive lesions were significantly associated with LRFS. LEVEL OF EVIDENCE: 4. PMID- 26987108 TI - Mini-open Anterior Lumbar Interbody Fusion for Recurrent Lumbar Disc Herniation Following Posterior Instrumentation. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: The aim of this study is to evaluate, clinically and radiographically, the efficacy of mini-open retroperitoneal anterior lumbar discectomy followed by anterior lumbar interbody fusion (ALIF) for recurrent lumbar disc herniation following primary posterior instrumentation. SUMMARY OF BACKGROUND DATA: Recurrent disc herniation following previous disc surgery occurs in 5 to 15% of cases. This is often treated by further surgical intervention where posterior approach is generally preferred. However, posterior surgery may be problematic if the initial surgery involved posterior instrumentation. An anterior approach may be indicated in these patients, and recent findings suggest that a "mini-open" procedure may have some benefits when compared with traditional open techniques and their associated morbidities. METHODS: A total of 35 recurrent lumbar disc herniation patients (10 male, 25 female) following primary posterior instrumentation with an average age of 52.8 years (range: 34-70 yrs) who underwent the mini-open ALIF procedures between August 2001 and February 2012 were evaluated retrospectively. The ALIF was performed at the levels L4-L5 (n = 14), L5-S1 (n = 15), or both L4-L5 and L5 S1 (n = 6). Visual Analog pain Scale (VAS) and Oswestry Disability Index (ODI) together with radiological results were assessed. RESULTS: The mean operating time, intraoperative estimated blood loss, and hospital stay were 115 minutes, 70 mL, and 6 days, respectively. No blood transfusion was needed. Transient complication was recorded in two patients. Postoperative follow-up was a minimum 24.3 months. VAS score and ODI percentage decreased significantly from 7.9 +/- 0.8 and 78.8% +/- 12.4% pre-operatively to 1.4 +/- 0.6 and 21.7 +/- 4.2% at final follow-up, respectively. There was no neurological worsening and radicular pain improved significantly compared with pre-operation in all the patients. Computed tomographic reconstruction 12 and 24 months after surgery showed bony fusion, normal position, and morphology of the fusion cage in all patients. CONCLUSION: Mini-open retroperitoneal ALIF is an effective treatment for patients with recurrent lumbar disc herniation following primary posterior instrumentation. LEVEL OF EVIDENCE: 4. PMID- 26987110 TI - Precisely Patterned Growth of Ultra-Long Single-Crystalline Organic Microwire Arrays for Near-Infrared Photodetectors. AB - Owing to extraordinary properties, small-molecule organic micro/nanocrystals are identified to be prospective system to construct new-generation organic electronic and optoelectronic devices. Alignment and patterning of organic micro/nanocrystals at desired locations are prerequisite for their device applications in practice. Though various methods have been developed to control their directional growth and alignment, high-throughput precise positioning and patterning of the organic micro/nanocrystals at desired locations remains a challenge. Here, we report a photoresist-assisted evaporation method for large area growth of precisely positioned ultralong methyl-squarylium (MeSq) microwire (MW) arrays. Positions as well as alignment densities of the MWs can be precisely controlled with the aid of the photoresist-template that fabricated by photolithography process. This strategy enables large-scale fabrication of organic MW arrays with nearly the same accuracy, uniformity, and reliability as photolithography. Near-infrared (NIR) photodetectors based on the MeSq MW arrays show excellent photoresponse behavior and are capable of detecting 808 nm light with high stability and reproducibility. The high on/off ratio of 1600 is significantly better than other organic nanostructure-based optical switchers. More importantly, this strategy can be readily extended to other organic molecules, revealing the great potential of photoresist-assisted evaporation method for future high-performance organic optoelectronic devices. PMID- 26987109 TI - Room-temperature electron spin relaxation of nitroxides immobilized in trehalose: Effect of substituents adjacent to NO-group. AB - Trehalose has been recently promoted as efficient immobilizer of biomolecules for room-temperature EPR studies, including distance measurements between attached nitroxide spin labels. Generally, the structure of nitroxide influences the electron spin relaxation times, being crucial parameters for room-temperature pulse EPR measurements. Therefore, in this work we investigated a series of nitroxides with different substituents adjacent to NO-moiety including spirocyclohexane, spirocyclopentane, tetraethyl and tetramethyl groups. Electron spin relaxation times (T1, Tm) of these radicals immobilized in trehalose were measured at room temperature at X- and Q-bands (9/34GHz). In addition, a comparison was made with the corresponding relaxation times in nitroxide-labeled DNA immobilized in trehalose. In all cases phase memory times Tm were close to 700ns and did not essentially depend on structure of substituents. Comparison of temperature dependences of Tm at T=80-300K shows that the benefit of spirocyclohexane substituents well-known at medium temperatures (~100-180K) becomes negligible at 300K. Therefore, unless there are specific interactions between spin labels and biomolecules, the room-temperature value of Tm in trehalose is weakly dependent on the structure of substituents adjacent to NO moiety of nitroxide. The issues of specific interactions and stability of nitroxide labels in biological media might be more important for room temperature pulsed dipolar EPR than differences in intrinsic spin relaxation of radicals. PMID- 26987111 TI - Skin necrosis caused by prallethrin-A worldwide used insecticide. AB - We report a case of necrosis caused by the use of prallethrin (mosquito repellent) on the skin in a 67-year-old diabetic female patient suffering from delusions of parasitosis. Cutaneous toxicity due to pyrethroids is less known or reported, despite well-documented pyrethroid poisoning involving the gastrointestinal, respiratory, cardiac, and nervous systems. Skin irritation has been described after acute accidental exposure but, as far as we know, no data have been published on the effects of pyrethroids when applied directly to the skin. PMID- 26987114 TI - Geographical Detector-Based Identification of the Impact of Major Determinants on Aeolian Desertification Risk. AB - Arid and semi-arid areas in North China are facing the challenge of a rising aeolian desertification risk (ADR) due to the intertwined effects of complex natural processes and intensified anthropogenic activities. An accurate quantitative assessment of the relationship between ADR and its determinants is beneficial for understanding the driving mechanisms of aeolian desertification and for controlling future desertification. Previous studies have failed to quantify the relative role of determinants driving ADR and have been limited in assessing their interactive impacts. In this study, a spatial variance analysis based geographical detector methodology is used to quantify the effects of geological, physical, and human factors on the occurrence of ADR in an area characterized by mountains and hills in northern China. It is found that soil type, precipitation, and wind velocity are the major determinants of ADR, which implies that geological and physical elements (e.g., soil attribute) and climatic factors (e.g., precipitation and wind velocity) rather than human activities have played a greater role in the incidence of ADR. Particularly, the results show that the interaction of various determinants causes significant non-linearly enhanced impacts on the ADR. The findings of our study will assist local inhabitants and policy makers in developing measures for wind prevention and sand control to mitigate the effects of desertification in the region. PMID- 26987112 TI - Phenolic acid protects of renal damage induced by ochratoxin A in a 28-days-oral treatment in rats. AB - The present study aimed to characterize the chlorogenic acid (ChlA) capacity to reverse the toxic effects induced by ochratoxin A (OTA) in a subacute toxicity test in rats. Male Wistar rats were fed orally by gavage for 28 days with OTA (0.4mg/kg bw/day), ChlA (5mg/kg bw/day) or the combination OTA (0.4mg/kg bw/day)+ChlA (5mg/kg bw/day). No deaths, no decrease in feed intake or body weight in any experimental group were recorded. The negative control group and the animals treated with ChlA alone showed no changes in any parameters evaluated. In OTA-treated group significant changes such as decrease in urine volume, proteinuria, occult blood, increase in serum creatinine values; decrease in absolute and relative kidney weight and characteristics histopathological lesions that indicated kidney damage were observed. However, limited effect on oxidative stress parameters were detected in kidneys of OTA-treated group. Animals treated with the combination OTA+ChlA were showed as negative control group in the evaluation of several parameters of toxicity. In conclusion, ChlA, at given concentration, improved biochemical parameters altered in urine and serum and pathological damages in kidneys induced by OTA exposure, showing a good protective activity, but not by an apparent antioxidant mechanism. PMID- 26987113 TI - Penehyclidine Hydrochloride Pretreatment Ameliorates Rhabdomyolysis-Induced AKI by Activating the Nrf2/HO-1 Pathway and Alleviating [corrected] Endoplasmic Reticulum Stress in Rats. The. AB - Acute kidney injury (AKI) is one of the most severe complications of rhabdomyolysis (RM). The underlying mechanisms and potential preventions need to be investigated. Penehyclidine hydrochloride (PHC) was reported to ameliorate renal ischemia-reperfusion injury, but the effect of PHC on RM-reduced AKI is unknown. In this study, we established a rat model of RM-induced AKI using an intramuscular glycerol injection in the hind limbs. Rats were pretreated with PHC before the glycerol injection, and the heme oxygenase-1 (HO-1) inhibitor ZnPP was introduced to evaluate the effect of HO-1 on RM-induced AKI. PHC pretreatment ameliorated the pathological renal injury and renal dysfunction, and decreased the renal apoptosis rate in RM-induced AKI. PHC significantly up-regulated HO-1 expression, increased HO-1 enzymatic activity and decreased the accumulation of myoglobin in renal tissues. This effect was partly inhibited by ZnPP. PHC pretreatment also effectively up-regulated nuclear factor erythroid 2-related factor 2 (Nrf2) and down-regulated glucose regulated protein 78 (GRP78) and caspase-12 at both the gene and protein levels. These results suggest that the protective effects of PHC pretreatment on RM-induced AKI occur at least in part through activating the Nrf2/HO-1 pathway and alleviating endoplasmic reticulum stress (ERS) in rat renal tissues. PMID- 26987115 TI - Emotional and Affective Temperaments in Smoking Candidates for Bariatric Surgery. AB - INTRODUCTION: The prevalence of smoking habits in severe obesity is higher than in the general population. There is some evidence that smokers have different temperaments compared to non-smokers. The aim of this study is to evaluate the associations between smoking status (smokers, ex-smokers and non-smokers) and temperament characteristics in bariatric surgery candidates. METHODS: We analyzed data on temperament of 420 bariatric surgery candidates, as assessed by the AFECTS scale, in an exploratory cross-sectional survey of bariatric surgery candidates who have been grouped into smokers, ex-smokers and non-smokers. RESULTS: We detected significant statistical differences in temperament related to the smoking status in this population after controlling the current use of psychiatric medication. Smokers had higher anxiety and lower control than non smokers. Ex-smokers with BMI >50 kg/m(2) presented higher coping and control characteristics than smokers. CONCLUSIONS: Smoking in bariatric surgery candidates was associated with lower control and higher anxious temperament, when controlled by current use of psychiatric medication. Smokers with BMI >50 kg/m(2) presented lower coping and control than ex-smokers. Assessment of temperament in bariatric surgery candidates may help in decisions about smoking cessation treatment and prevention of smoking relapse after surgery. PMID- 26987116 TI - The Extracellular and Cytoplasmic Domains of Syndecan Cooperate Postsynaptically to Promote Synapse Growth at the Drosophila Neuromuscular Junction. AB - The heparan sulfate proteoglycan (HSPG) Syndecan (Sdc) is a crucial regulator of synapse development and growth in both vertebrates and invertebrates. In Drosophila, Sdc binds via its extracellular heparan sulfate (HS) sidechains to the receptor protein tyrosine phosphatase LAR to promote the morphological growth of the neuromuscular junction (NMJ). To date, however, little else is known about the molecular mechanisms by which Sdc functions to promote synapse growth. Here we show that all detectable Sdc found at the NMJ is provided by the muscle, strongly suggesting a post-synaptic role for Sdc. We also show that both the cytoplasmic and extracellular domains of Sdc are required to promote synapse growth or to rescue Sdc loss of function. We report the results of a yeast two hybrid screen using the cytoplasmic domains of Sdc as bait, and identify several novel candidate binding partners for the cytoplasmic domains of Sdc. Together, these studies provide new insight into the mechanism of Sdc function at the NMJ, and provide enticing future directions for further exploring how Sdc promotes synapse growth. PMID- 26987117 TI - Drosophila Food-Associated Pheromones: Effect of Experience, Genotype and Antibiotics on Larval Behavior. AB - Animals ubiquitously use chemical signals to communicate many aspects of their social life. These chemical signals often consist of environmental cues mixed with species-specific signals-pheromones-emitted by conspecifics. During their life, insects can use pheromones to aggregate, disperse, choose a mate, or find the most suitable food source on which to lay eggs. Before pupariation, larvae of several Drosophila species migrate to food sources depending on their composition and the presence of pheromones. Some pheromones derive from microbiota gut activity and these food-associated cues can enhance larval attraction or repulsion. To explore the mechanisms underlying the preference (attraction/repulsion) to these cues and clarify their effect, we manipulated factors potentially involved in larval response. In particular, we found that the (i) early exposure to conspecifics, (ii) genotype, and (iii) antibiotic treatment changed D. melanogaster larval behavior. Generally, larvae-tested either individually or in groups-strongly avoided food processed by other larvae. Compared to previous reports on larval attractive pheromones, our data suggest that such attractive effects are largely masked by food-associated compounds eliciting larval aversion. The antagonistic effect of attractive vs. aversive compounds could modulate larval choice of a pupariation site and impact the dispersion of individuals in nature. PMID- 26987120 TI - PopulationProfiler: A Tool for Population Analysis and Visualization of Image Based Cell Screening Data. AB - Image-based screening typically produces quantitative measurements of cell appearance. Large-scale screens involving tens of thousands of images, each containing hundreds of cells described by hundreds of measurements, result in overwhelming amounts of data. Reducing per-cell measurements to the averages across the image(s) for each treatment leads to loss of potentially valuable information on population variability. We present PopulationProfiler-a new software tool that reduces per-cell measurements to population statistics. The software imports measurements from a simple text file, visualizes population distributions in a compact and comprehensive way, and can create gates for subpopulation classes based on control samples. We validate the tool by showing how PopulationProfiler can be used to analyze the effect of drugs that disturb the cell cycle, and compare the results to those obtained with flow cytometry. PMID- 26987119 TI - The Effect of Probiotic Treatment on Patients Infected with the H7N9 Influenza Virus. AB - BACKGROUND: A novel avian-origin influenza A (H7N9) virus emerged and spread among humans in Eastern China in 2013. Prophylactic treatment with antibiotics and probiotics for secondary infection is as important as antiviral treatment. This study aims to assess the ability of probiotic treatment to restore internal homeostasis under antibiotic pressure and to reduce/ameliorate the risk of secondary infections resulting from infection with the H7N9 virus. METHODS: This is a retrospective study in archival samples. Between April 1 and May 10, 2013, 113 stool, sputum, and blood specimens were collected and analyzed by denaturing gradient gel electrophoresis (DGGE) to determine the composition of the patient microbiomes. Microbial diversity was calculated using Gel-Pro analyzer and Past software. Cluster analysis of DGGE pattern profiles was employed to create a phylogenetic tree for each patient, and multidimensional scaling (MDS) and principal component analysis (PCA) were performed to visualize relationships between individual lanes. RESULTS: Five patients had secondary infections, including Klebsiella pneumonia, Acinetobacter baumanii and Candida albicans infection. The DGGE profiles of fecal samples obtained at different time points from the same individual were clearly different, particularly for patients with secondary infections. Shannon's diversity index and evenness index were lower in all infected groups compared to the control group. After B. subtilis and E. faecium or C. butyricum administration, the fecal bacterial profiles of patients who had not been treated with antibiotics displayed a trend of increasing diversity and evenness. C. butyricum failed to reduce/ameliorate secondary infection in H7N9-infected patients, but administration of B. subtilis and E. faecium appeared to reduce/ameliorate secondary infection in one patient. CONCLUSION: H7N9 infection might decrease intestinal microbial diversity and species richness in humans. C. butyricum failed to reduce/ameliorate secondary infection in H7N9-infected patients. B. subtilis and E. faecium may also play a role in reducing/ameliorating secondary infection in these patients. PMID- 26987118 TI - Criterion-Related Validity of the Distance- and Time-Based Walk/Run Field Tests for Estimating Cardiorespiratory Fitness: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: The main purpose of the present meta-analysis was to examine the criterion-related validity of the distance- and time-based walk/run tests for estimating cardiorespiratory fitness among apparently healthy children and adults. MATERIALS AND METHODS: Relevant studies were searched from seven electronic bibliographic databases up to August 2015 and through other sources. The Hunter-Schmidt's psychometric meta-analysis approach was conducted to estimate the population criterion-related validity of the following walk/run tests: 5,000 m, 3 miles, 2 miles, 3,000 m, 1.5 miles, 1 mile, 1,000 m, 1/2 mile, 600 m, 600 yd, 1/4 mile, 15 min, 12 min, 9 min, and 6 min. RESULTS: From the 123 included studies, a total of 200 correlation values were analyzed. The overall results showed that the criterion-related validity of the walk/run tests for estimating maximum oxygen uptake ranged from low to moderate (rp = 0.42-0.79), with the 1.5 mile (rp = 0.79, 0.73-0.85) and 12 min walk/run tests (rp = 0.78, 0.72-0.83) having the higher criterion-related validity for distance- and time based field tests, respectively. The present meta-analysis also showed that sex, age and maximum oxygen uptake level do not seem to affect the criterion-related validity of the walk/run tests. CONCLUSIONS: When the evaluation of an individual's maximum oxygen uptake attained during a laboratory test is not feasible, the 1.5 mile and 12 min walk/run tests represent useful alternatives for estimating cardiorespiratory fitness. As in the assessment with any physical fitness field test, evaluators must be aware that the performance score of the walk/run field tests is simply an estimation and not a direct measure of cardiorespiratory fitness. PMID- 26987121 TI - Harmonization of the Volume of Interest Delineation among All Eleven Radiotherapy Centers in the North of France. AB - BACKGROUND: Inter-observer delineation variation has been detailed for many years in almost every tumor location. Inadequate delineation can impair the chance of cure and/or increase toxicity. The aim of our original work was to prospectively improve the homogeneity of delineation among all of the senior radiation oncologists in the Nord-Pas de Calais region, irrespective of the conditions of practice. METHODS: All 11 centers were involved. The first studied cancer was prostate cancer. Three clinical cases were studied: a low-risk prostate cancer case (case 1), a high-risk prostate cancer case (pelvic nodes, case 2) and a case of post-operative biochemical elevated PSA (case 3). All of the involved physicians delineated characteristically the clinical target volume (CTV) and organs at risk. The volumes were compared using validated indexes: the volume ratio (VR), common and additional volumes (CV and AV), volume overlap (VO) and Dice similarity coefficient (DSC). A second delineation of the same three cases was performed after discussion of the slice results and the choice of shared guidelines to evaluate homogenization. A comparative analysis of the indexes before and after discussion was conducted using the Wilcoxon test for paired samples. A p-value less than 0.05 was considered to indicate statistical significance. RESULTS: The indexes were not improved in case 1, for which the inter-observer agreement was considered good after the first comparison (DSC = 0.83 +/- 0.06). In case 2, the second comparison showed homogenization of the CTV delineation with a significant improvement in CV (81.4 +/- 11.7 vs. 88.6 +/- 10.26, respectively, p = 0.048), VO (0.41 +/- 0.09 vs. 0.47 +/- 0.07, respectively; p = 0.009) and DSC (0.58 +/- 0.09 vs. 0.63 +/- 0.07, respectively; p = 0.0098). In case 3, VR and AV were significantly improved: VR: 1.71(+/- 0.6) vs. 1.34(+/- 0.46), respectively, p = 0.0034; AV: 46.58(+/- 14.50) vs. 38.08(+/- 15.10), respectively, p = 0.0024. DSC was not improved, but it was already superior to 0.6 in the first comparison. CONCLUSION: Our prospective work showed that a collaborative discussion about clinical cases and the choice of shared guidelines within an established framework improved the homogeneity of CTV delineation among the senior radiation oncologists in our region. PMID- 26987122 TI - Charge Variants of an Avastin Biosimilar Isolation, Characterization, In Vitro Properties and Pharmacokinetics in Rat. AB - The similarity between a proposed biosimilar product and the reference product can be affected by many factors. This study is designed to examine whether any subtle difference in the distribution of the charge variants of an Avastin biosimilar can affect its in vitro potency and in vivo PK. Here, the acidic, basic and main peak fractions of a biosimilar product were isolated using high performance cation-exchange chromatography and were subjected to various studies to compare their in vitro properties and in vivo PK profile. A serial of analytical methods, including size exclusion chromatography (SEC), imaged capillary isoelectric focusing (icIEF) capillary zone electrophoresis (CZE) and cation-exchange chromatography (CEX-HPLC) were also used to characterize the isolated charge variants. The kinetics constant was measured using a Biacore X100 system. The study indicates the biosimilar product has a high similarity with avastin in physicochemical properties. The potency in vitro and PK profile in rat of charge variants and biosimilar product are consistent with avastin. PMID- 26987123 TI - SiteOut: An Online Tool to Design Binding Site-Free DNA Sequences. AB - DNA-binding proteins control many fundamental biological processes such as transcription, recombination and replication. A major goal is to decipher the role that DNA sequence plays in orchestrating the binding and activity of such regulatory proteins. To address this goal, it is useful to rationally design DNA sequences with desired numbers, affinities and arrangements of protein binding sites. However, removing binding sites from DNA is computationally non-trivial since one risks creating new sites in the process of deleting or moving others. Here we present an online binding site removal tool, SiteOut, that enables users to design arbitrary DNA sequences that entirely lack binding sites for factors of interest. SiteOut can also be used to delete sites from a specific sequence, or to introduce site-free spacers between functional sequences without creating new sites at the junctions. In combination with commercial DNA synthesis services, SiteOut provides a powerful and flexible platform for synthetic projects that interrogate regulatory DNA. Here we describe the algorithm and illustrate the ways in which SiteOut can be used; it is publicly available at https://depace.med.harvard.edu/siteout/. PMID- 26987124 TI - Metabolic Tumour Burden Measured by 18F-FDG PET/CT Predicts Malignant Transformation in Patients with Neurofibromatosis Type-1. AB - BACKGROUND: To investigate the diagnostic and prognostic performances of 18F-FDG PET/CT measures of metabolic tumour burden in patients with neurofibromatosis type-1 (NF1), suspect of malignant transformation. METHODS: This retrospective study included 49 patients (15-60 years old, 30 women) with a diagnosis of NF1, followed in our Reference Centre for Rare Neuromuscular Diseases, who presented clinical signs of tumour progression (pain, neurological deficit, tumour growth). Quantitative metabolic parameters were measured on 149 tumoral targets, using semi-automatic software and the best cut off values to predict transformation was assessed by Receiver Operating Characteristics (ROC) analysis. Prognostic value of PET/CT metabolic parameters was assessed by Kaplan-Meier estimates of overall survival. RESULTS: Lesions were histologically documented in 40 patients: a sarcomatous transformation was found in 16, a dysplastic neurofibroma (NF) in 7, and a benign NF in 17; in the remaining 9 patients, a minimal follow-up of 12 mo (median 59 mo) confirmed the absence of transformation. The optimal cut off values for detection of malignant transformation were, in decreasing order of area under the ROC curves, a tumour-to-liver (T/L) ratio >2.5, SUVmax > 4.5, total lesion glycolysis (TLG) > 377, total metabolic tumour volume (TMTV) > 88 cm3, and heterogeneity index (HIsuv) > 1.69. The best prognostic marker was the TLG: the 4-y estimates of survival were 97% [95% CI, 90% - 100%] in patients with TLG <= 377 vs. 27% [95% CI, 5% - 49%] in patients with TLG > 377 (P < 0.0001; chi2 27.85; hazard ratio 13.27 [95% CI, 3.72-47.35]). T/L ratio, SUVmax and TMTV demonstrated slightly lower performance to predict survival, with chi2 ranging 14.41-19.12. The HIsuv index was not predictive of survival. CONCLUSION: Our study demonstrates that TLG and TMTV, as PET/CT measures of metabolic tumour burden, may be used clinically to identify sarcomatous transformation in patients with NF1 and predict overall survival, with a higher specificity for the TLG. Conventional measures such as the SUVmax, and T/L ratio also demonstrate high prognostic value. PMID- 26987125 TI - Influence of Serum Levels of Vitamins A, D, and E as well as Vitamin D Receptor Polymorphisms on Micronucleus Frequencies and Other Biomarkers of Genotoxicity in Workers Exposed to Formaldehyde. AB - BACKGROUND/AIM: Formaldehyde is classified as carcinogenic to humans, making it a major concern, particularly in occupational settings. Fat-soluble vitamins, such as vitamins A, D, and E, are documented as antigenotoxic and antimutagenic and also correlate with the cell antioxidant potential. This study investigates the influence of these vitamins on genotoxicity biomarkers of formaldehyde-exposed hospital workers. METHODS: The target population were hospital workers exposed to formaldehyde (n = 55). Controls were nonexposed individuals (n = 80). The most used genotoxicity biomarkers were the cytokinesis-block micronucleus assay for lymphocytes and the micronucleus test for exfoliated buccal cells. Vitamins A and E were determined by high-performance liquid chromatography with a diode array detector (HPLC-DAD) and vitamin D receptor (VDR) polymorphisms by real-time PCR. RESULTS: Significant correlations were found between genotoxicity biomarkers and between vitamins A and E in controls. Multiple regression showed that vitamin A was significantly associated with a higher mean of nucleoplasmic bridges (p < 0.001), and vitamin E was significantly associated with a decreased frequency of nuclear buds (p = 0.045) in the exposed group. No effect of vitamin D was observed. The VDRBsmI TT genotype carriers presented higher means of all the genotoxicity biomarkers; however, we found no significant associations. CONCLUSIONS: The study suggests that vitamin levels may modulate direct signs of genotoxicity. PMID- 26987126 TI - Cardiovascular Variability Analysis and Baroreflex Estimation in Patients with Type 2 Diabetes in Absence of Any Manifest Neuropathy. AB - INTRODUCTION: Indexes derived from spontaneous heart period (HP) and systolic arterial pressure (SAP) fluctuations can detect autonomic dysfunction in individuals with type 2 diabetes mellitus (DM) associated to cardiovascular autonomic neuropathy (CAN) or other neuropathies. It is unknown whether HP and SAP variability indexes are sensitive enough to detect the autonomic dysfunction in DM patients without CAN and other neuropathies. METHODS: We evaluated 68 males aged between 40 and 65 years. The group was composed by DM type 2 DM with no manifest neuropathy (n = 34) and healthy (H) subjects (n = 34). The protocol consisted of 15 minutes of recording of HP and SAP variabilities at rest in supine position (REST) and after active standing (STAND). The HP power in the high frequency band (HF, from 0.15 to 0.5 Hz), the SAP power in the low frequency band (LF, from 0.04 to 0.15 Hz) and BRS estimated via spectral approach and sequence method were computed. RESULTS: The HF power of HP was lower in DM patients than in H subjects, while the two groups exhibited comparable HF power of HP during STAND. The LF power of SAP was similar in DM and H groups at REST and increased during STAND in both groups. BRSs estimated in the HF band and via baroreflex sequence method were lower in DM than in H and they decreased further during STAND in both populations. CONCLUSION: Results suggest that vagal control of heart rate and cardiac baroreflex control was impaired in type 2 DM, while sympathetic control directed to vessels, sympathetic and baroreflex response to STAND were preserved. Cardiovascular variability indexes are sensitive enough to typify the early, peculiar signs of autonomic dysfunction in type-2 DM patients well before CAN becomes manifest. PMID- 26987127 TI - Medical Therapy for Macular Edema Secondary to Retinal Vein Occlusion. PMID- 26987128 TI - Telephone Enrollment in the VA Healthcare System. Interim final rule. AB - This rulemaking amends VA's medical regulations to allow veterans to complete applications for health care enrollment by telephone by providing application information to a VA employee, agreeing to VA's provisions regarding copayment liability and assignment of third-party insurance benefits, and attesting to the accuracy and authenticity of the information provided over the phone. This action will make it easier for veterans to apply to enroll and will speed VA processing of applications. PMID- 26987129 TI - Alternative route for controlling wild horse and burro population. PMID- 26987130 TI - In defense of low-cost vaccination clinics. PMID- 26987131 TI - [Editorial Note]. PMID- 26987132 TI - [CRITERIA FOR THE FORMATION OF PATIENTS' AGE GROUPS FOR MEDICAL RESEARCH]. AB - At present, a variety of methods for age group formation and classification of clinical and morphological manifestations of diseases and their complications are available for the analysis of strategies of the choice of therapy and evaluation of its efficiency. Analysis of the results of diagnostic studies and the choice of therapeutic modalities need to be based on an individual approach to patients of different age groups. Age-related morphological, functional and histochemical changes responsible for combined normal and pathological alterations in the tissues, organs and their systems are associated with mild, moderate and severe clinical symptoms or their absence; they can be regarded as reflecting peculiarities of the development of the organism and subsequent tanatogenesis. Because age-specific changes are known to be risk factors of cardiovascular pathology, it suggests the necessity of more detailed objectivization and substantiation of division of such patients into age groups taking account of specific morphological and functional changes in the heart anatomical structures. PMID- 26987133 TI - [DNA POLYMORPHISM AND RISK OF OCCLUSIVE VASCULAR LESIONS IN PATIENTS WITH CARDIOVASCULAR DISEASES]. AB - A method for diagnostics of occlusive vascular lesions in patients with cardiovascular diseases is proposed. Results of this study extend possibilities for diagnostics of occlusive vascular lesions in patients with cardiovascular diseases. PMID- 26987134 TI - [LEFT HIS BUNDLE BRANCH BLOCK ASSOCIATED WITH LEFT VENTRICULAR TORSION AND REDUCED EJECTION FRACTION]. AB - The influence of left His bundle branch block (LBBB) on left ventricular (LV) torsion in patients with cardiomyopathy remains to be elucidated. The aim of this study was to evaluate LV torsion associated with LBBB and hemodynamic consequences of possible changes. We studied 64 patients with ischemic and dilatation cardiomyopathy (LV ejection fraction less than 40%) divided into 2 groups, with narrow and middle (153 ms) duration QRS complexes. Despite similar LV contractility, patients with LBBB had much less pronounced LV rotation and torsion. Torsion in patients with LBBB and narrow QRS complex was estimated at 2.95 +/- 3.34 and 5.87 +/- 3.83 respectively (p < 0.01). Moreover; the group of patients with LBBB contained much more subjects with abnormal unidirectional rotation of the basal and apical parts than the group with narrow QRS complex, namely 11 (50%) and 9 (21.9%) respectively (p < 0.001). Patients with LBBB and abnormal LV rotation sowed much longer delay of posterior wall contractility (63.3 +/- 35.1 mc) compared with those having LBBB and multidirectional physiological LV rotation (8.0 +/- 17/9 mc) (p < 0.001) which suggests a higher degree of mechanical desynchronization. T is concluded that LBBB has negative effect on LV electrical activation and contractility resulting in abnormal torsion and mechanical desynchronization. PMID- 26987135 TI - [EVALUATION OF THE REGULATORY-ADAPTIVE STATUS FOR PROGNOSTICATION IN SYSTOLIC CHRONIC HEART FAILURE]. AB - We studied a new approach to prognostication in systolic chronic heart failure (CHF) based on the quantitative evaluation of the regulatory-adaptive status (RAS) in 100 patients with FC III CHF and compromised LV systolic function associated with hypertensive disease and/or ischemic heart disease. The patients managed by combined therapy (quinapril, torasemid, spironolactone) were randomized into 2 groups. Group 1 included 56 patients (57.5 +/- 21.7 yr) treated with metoprolol succinate (59.1 +/- 12.1 mg/d), group 2 contained 44 patients (57.5 +/- 21.4 yr) treated with ivabradine (12.1 +/- 4.6 mg/d). A test of cardio respiratory synchronism for quantitative RAS evaluation, echocardiography, treadmill exercise, determination of N-terminal precursor of brain natriuretic peptide in blood plasma, and 6 min walk test were performed before and 6 months after the onset of the study. A 12 month follow up study with controlled pharmacotherapy was carried out to analyse cardiovascular complications. The clinical efficiency of pharmacotherapy was found to be identical in both groups. The frequency of hospitalization for the treatment of CHF, ischemic stroke, and myocardial infarction as well as the number of deaths from cardiovascular disorders were not significantly different. Cardiovascular complications occurred more frequently in patients with initially low or inadequate RAS associated with an enhanced risk of sudden cardiac death. These data are comparable with results of conventional diagnostic tests and reflect independent significance of RAS evaluation for prognostication of the outcome of systolic CHE PMID- 26987136 TI - [THE RELATIONSHIP BETWEEN POLYMORPHISMS OF G-1082A AND C-592A LOCI OF THE IL10 GENE AND MULTIFOCAL ATHEROSCLEROSIS IN PATIENTS WITH ACUTE CORONARY SYNDROME WITHOUT SEGMENT ST ELEVATION]. AB - AIM: To study the relationship between polymorphous G-1082A (rs3024491) and C 592A (rs1800872) variants of the IL10 gene and multifocal atherosclerosis (MFA) in patients with acute coronary syndrome (ACS) without segment ST elevation. MATERIALS AND METHODS: Genotypes of polymorphous G-1082A (rs3024491) and C-592A (rs1800872) variants of the IL10 gene were determined in 178 patients. Interleukin-10 (IL-10) level was measured in 93 of them using solid-phase immunoenzymatic assay. All patients underwent visualization of coronary and peripheral arteries. RESULTS: C-592A (rs1800872) polymorphism ofthe IL10 gene tended to be associated with type 2 diabetes mellitus in the carriers of the CC (gg) genotype and with elevated concentration of high density lipoproteins and reduced intima-media thickness in the carriers of the AA (tt) genotype. The frequency of MFA in the carriers of different genotypes of rs1800872 polymorphism was practically identical while the CA(gt) genotype was associated with more severe manifestations of atherosclerosis and AA(tt) genotype with lower frequency of peripheral artery stenosis. Patients with AA(tt) genotype of rs1800872 polymorphism had higher IL-10 levels. No relationship between rs3024491 polymorphism of IL10 gene, blood IL-10 level, clinical risk factors, and MFA was documented. CONCLUSION: CC (gg) genotype of C-592A (rs1800872) polymorphism of the IL10 gene in patients with acute coronary syndrome (ACS) without segment ST elevation was associated with type 2 diabetes mellitus while the AA(tt) genotype of the same polymorphism with elevated concentration of high density lipoproteins, reduced intima-media thickness, low frequency of peripheral artery stenosis, and increased IL-10 production. CA (gt) genotype of rs1800872 polymorphism of the IL10 gene was associated with MFA. PMID- 26987137 TI - [DIFFUSE NEUROENDOCRINE SYSTEM OF THE STOMACH AND CHARACTERISTICS OF PROLIFERATION IN REALIZATION OF CORREA'S CASCADE IN DISEASES ASSOCIATED WITH HELICOBACTER PYLORI]. AB - AIM: To study the role of the vascular endothelial growth factor (VEGF), Ki-67, BCL-2, and endocrine cells (EC) of gastric mucosa producing somatostatin (SS), glucagon (GL), and pancreatic polypeptide (PP) in diseases associated with Helicobacter pylori. To use the data obtained to develop early diagnostic criteria for the progress of structural changes in gastric mucosa of the patients with stomach ulcer disease [SUD), chronic atrophic gastritis (CAG), gastric adenomatous polyps (GAP), and gastric cancer (GC) before and after surgical intervention and eradication of H. pylori. MATERIALS AND METHODS: We examined 104 patients with gastric pathology associated with Helicobacter pylori including 30 with SUD, 30 with CAG, 20 with GAP and CAG, 24 with stage II noncardia GC. The effectiveness of the treatment was evaluated 2 months after alleviation of inflammation in the stomachfollowing polypectomy in case of GAP or gastrectomy in case of GC. Material for immunohistochemical studies was taken from the fundus. Monoclonal antibodies against VEGF SS, GL, PP Ki-67, BCL-2 (1:100, Novocastra) were used. Histobacterioscopy was conducted using antral mucosal smears stained by the Romanowsky-Giemsa procedure. RESULTS: Exacerbation of SUD was accompanied by a decrease in the number of epithelial cells and EC producing VEGF glucagon (GL), and pancreatic polypeptide (PP) with the increase in the number of SS secreting EC along with intensification of proliferative processes determined from the number of Ki-67 and BCL-2 immunopositive epithelial cells. CAG and GC were associated with persistence of H. pylori, hyperplasia of EC producing VEGF glucagon (GL), pancreatic polypeptide (PP) and hypoplasia of SS-secreting EC along with high proliferative activity of epitheliocytes expressed via Ki-67 and BCL-2. CONCLUSION: Endothelial growth factor (VEGF), somatostatin (SS), glucagon (GL), and pancreatic polypeptide (PP) are of importance for the prognostication of development and clinical course of diseases associated with Helicobacter pylori since their pathological properties are realized either directly or indirectly through H. pylori, Ki-67 and BCL-2. Eradication of H. pylori does not result in the disappearance of intestinal metaplasia. PMID- 26987138 TI - [THE INFLUENCE OF CYTOMEGALOVIRUS ON THE RESULTS OF KIDNEY TRANSPLANTATION]. AB - To understand whether the presence of cytomegalovirus in blood influences the results of kidney transplantation from live relative donors, we analysed materials from 258 recipients divided into 2 groups. Group 1 included 113 patients with negative results of PCR for cytomegalovirus, group 2 contained 139 patients with positive PCR. We evaluated lethality, the loss of transplanted kidneys, frequency of rejection and infectious complications. Statistical treatment of the data obtained included Kaplan-Meier survival analysis, the Wilcoxon test showing the cumulative hazard risk, and comparative analysis by Fisher's and Student's tests. It was shown that cytomegalovirus present in blood increases lethality and the frequency of infectious complications in recipients of transplanted kidneys but does not influence their rejection. The cumulative survival rate was significantly higher and cumulative risk lower in group 1 than in group 2. PMID- 26987139 TI - [PECULIAR CLINICAL FEATURES OF OSTEOPOROSIS IN PATIENTS WITH METABOLIC SYNDROME]. AB - AIM: To study peculiar clinical features of osteoporosis in patients with metabolic syndrome (MS). METHODS: We examined 160 patients with osteoarthrosis divided into 2 groups each containing 80 patients with MS and without it (control). Osteoarthrosis was diagnosed using the R. Althmann (1995) criteria. The parameters measured were localization of articular lesions, frequency of inflammatory processes (synovitis), and pain intensity based on a VAS at rest and in motion, WOMAC index, characteristics of acute inflammation (ESR, C-reactive protein and TNF levels). RESULTS: Frequency of joint lesions of different localization, occurrence of synovitis, inflammation and pain intensity in patients with MS was higher than in controls. CONCLUSION: Results of the study confirm negative effect of MS on the clinical picture of osteoarthrosis. PMID- 26987140 TI - [COMPREHENSIVE PROPHYLAXIS OF EARLY THROMBOEMBOLISM AND HEMORRHAGE AFTER LARGE JOINT ENDOPROSTHETIC SURGERY]. AB - We examined 160 patients treated by endoprosthetic surgery of hip, knee, shoulder and elbow joints. 80 patients received i/v injections of 250 mg tranexam 30 min before and 4 hr after surgery. 220 mg ofpradax was given within 10-12 hr after surgery and thereafter on a daily basis. Fraxiparin (0.3-0.4 ml) was administered subcutaneously to 80 control patients 12 hr before surgery and once daily in the postoperative period. The intra- andpostoperative blood volume loss, dynamics of hematological parameters, and frequency of thromboembolic complications were determined. A Cell-Trans system was used to drain the surgical wound in the patients of the study group with subsequent reinfusion of blood. In controls, the wound was drained using conventional polyvinyl chloride drains with active aspiration of the contents without reinfusion. It was shown that combined application of tranexam, pradax, and the Cell-Trans system with postoperative blood reinfusion allows to reduce blood losses by 40% at all stages of the study. The total blood loss was 585.4 +/- 124.2 ml and 959.8 +/- 178.3 ml in study and control groups respectively. The proposed approach provides an effective and safe tool for the prevention of thromboembolic complications and hemorrhage in the early postoperative period after large joint endoprosthetic surgery. PMID- 26987141 TI - [RATIONAL COMBINATION OF MEDICATIONS FOR THE TREATMENT OF VASCULAR PATHOLOGY IN GERIATRICS]. AB - We undertook retrospective analysis of combination of medications recommended for the long-term treatment of co-morbid vascular pathology (arterial hypertension + coronary heart disease + vascular atherosclerosis) in elderly patients (women, mean age 73 +/- 4 yr) hospitalized in a multidisciplinary clinic of the Perm krai from January 2010 to December 2014. Data on the interaction (type A reactions) of concurrently prescribed drugs were compared with those of the National Register of Medicinal Remedies and WHO Classification of Adverse Drug Reactions. Polypragmasia was found to be a characteristic feature of all recommended combinations (4-5 medications were simultaneously prescribed to 56.7% of the patients and 6 or more drugs to 43.3% of them). Nine combinations of drugs were distinguished among those prescribed to elderly patients with vascular co morbidity. Probability and peculiarities of their interaction (type A reactions) were analyzed and optimal combinations in terms of safety for the treatment of vascular co-morbidity identified. PMID- 26987142 TI - [THROMBOLYTIC THERAPY OF ACUTE VASCULAR DISEASES IN IRKUTSK REGION]. AB - Cardiovascular diseases rank first as the cause of mortality, morbidity, and disability. This paper concerns evolution of thrombolytic therapy for acute coronary syndrome and ischemic stroke in the Irkutsk region characterized by low population density. PMID- 26987143 TI - [DIAGNOSTICS AND TREATMENT OF MALIGNANT TUMOURS WITHOUT DETECTED PRIMARY SITE]. AB - Tumours without detected primary site (CUP syndrome) make up a heterogenous group of malignant neoplasms in which symptoms of metastatic process appear earlier than symptoms ofprimary tumour that is impossible to identify by the existing methods. The number of patients with CUP syndrome remains practically unaltered (3-5% of all oncological patients, according to WHO statistics) despite marked extension of the range of modern instrumental and radiodiagnostic methods. Unique biological nature of these tumours awaits elucidation. The available data suggest that dissemination ofthe process may occur in the absence ofprimary tumour growth due to hereditary aggressiveness of cancer cells or alteration of their properties after penetration into a target organ. Comprehensive examination of patients with CUP syndromefor the search of the primary site must include a series of physical, instrumental, radiodiagnostic, laboratory and morphological studies on a simple-to-complex basis. The treatment of CUP syndrome must take into consideration the extent of the lesion and the necessity of morphological verification of metastases. Anti-tumour therapy should be started immediately after establishment of diagnosis while continuing the search for the primary site. Once the primary tumour is detected, the primary site and metastases must be treated simultaneously in order to improve the long-term results of therapy. PMID- 26987144 TI - [A RARE CLINICAL CASE OF CONGENITAL HYPOPROCONVERTINEMIA]. AB - The paper reports a rare clinical case of congenital hypoproconvertinemia in an elderly woman repeatedly admitted to the Cardiological Department for the management of coronary heart disease and arterial hypertension. The detection of low prothrombin index in a series of analysis requiredfurther hematological examination that revealed the history of postoperative and postnatal hemorrhage along with markedly reduced factor VII level. These results were interpreted as evidence of a rare congenital pathology, hypoproconvertinemia. PMID- 26987146 TI - [Prophylaxis of ischemic stroke]. PMID- 26987145 TI - [TYPE 1 MULTIPLE ENDOCRINE NEOPLASIA SYNDROME AND FAMILIAL ISOLATED HYPERPARATHYROIDISM]. AB - Type 1 multiple endocrine neoplasia syndrome (MEN-1) is a rare autosomal dominant disorder caused by mutation in the MEN-1 gene and manifest as a combination of tumours of parathyroid glands, endocrine pancreas, and adenohypophysis. Familial isolated hyperparathyroidism (FIHP) is another rare autosomal dominant disorder characterized by the development ofparathyroid tumours as the sole endocrinopathy within a single family. The notion of FIHP encompasses different hereditary forms of primary hyperparathyroidism, such as a variant of MEN-1 syndrome. This paper is a brief literature review of the problems related to primary hyperparathyroidism, MEN-1, and FIHP. Also, It describes a family presenting with genetically confirmed MEN-1 syndrome, manifest as primary hyperparathyroidism. PMID- 26987147 TI - [Aleksndr Leonidovich Myasnikov]. PMID- 26987148 TI - The Accuracy of the Osteological Sexing of Cremated Human Remains: A Test Based on Grave Goods from East Lithuanian Barrows. AB - The accuracy of the sex determination of cremated human remains is one of the vital parameters for archaeologists and skeletal anthropologists dealing with cremations. Few studies have so far aimed at testing it. In the present paper, the accuracy of the sexing techniques was assessed by paralleling biological sex (identified morphologically) to gender (presumed on the basis of the grave goods which accompanied the deceased). A collection of cremated bones from East Lithuanian barrows (c. fourth/fifth--eleventh/twelfth centuries AD) was employed. The fragmentary nature and poor state of the bones generally represents cremains from similar archaeological contexts. The database inevitably underwent several stages of filtration. Out of 364 cremations with a minimum of 445 individuals, only 157 were sexed single adult burials, of which only 81 had "gender-related" grave goods. The relationship of artefact type to gender was defined statistically, revising the results in line with the chronological and typological differences and the probable symbolism of the grave goods. Sex and gender coincided in 56 cases (69.14%), but a considerable distance between the results for both sexes was observed. Biological females displayed a fairly high match level, i.e. 35 out of the 41 (85.37%) individuals osteologically identified as females had been given "feminine" items. The burials of biological males, on the other hand, yielded a surprisingly low match rate, i.e. only 21 out of 40 (52.50%). This disparity suggests a possible misinterpretation of grave goods as gender markers, rather than (only?) erroneous sexing. It is thus argued that for females, the mean value for the accuracy of sexing is 85.5%. In most cases, such precision is entirely satisfactory for the analysis of a poorly-preserved osteological material. For males, however, the accuracy is likely to fall somewhere in the range between 52.5 and 85.5%, with the applied methodology so far failing to contribute to higher precision. PMID- 26987149 TI - Diet at the Roman Village of Virovitica Kiskorija South, Croatia. AB - The Virovitica Kiskorija South site was a Roman village. In this paper archaeological, archaeobotanical, and archaeo-zoological finds are presented and interpreted, then compared with similar sites and information available from ancient sources. The site was divided into complexes that made a whole. The finds within each complex are presented and compared to similar archaeological sites, as well as data from ancient written sources. The goal of the paper is to determine which kind of diet was present at this Roman village in Pannonia, and to analyze the differences and similarities between this village and analogous sites. PMID- 26987150 TI - Comparison between Inbreeding Analyses Methodologies. AB - Surnames are widely used in inbreeding analysis, but the validity of results has often been questioned due to the failure to comply with the prerequisites of the method. Here we analyze inbreeding in Hallstatt (Austria) between the 17th and the 19th centuries both using genealogies and surnames. The high and significant correlation of the results obtained by both methods demonstrates the validity of the use of surnames in this kind of studies. On the other hand, the inbreeding values obtained (0.24 x 10-3 in the genealogies analysis and 2.66 x 10-3 in the surnames analysis) are lower than those observed in Europe for this period and for this kind of population, demonstrating the falseness of the apparent isolation of Hallstatt's population. The temporal trend of inbreeding in both analyses does not follow the European general pattern, but shows a maximum in 1850 with a later decrease along the second half of the 19th century. This is probably due to the high migration rate that is implied by the construction of transport infrastructures around the 1870's. PMID- 26987151 TI - The Disruption of Subsistence Agricultural Systems in Rural Yucatan, Mexico may have Contributed to the Coexistence of Stunting in Children with Adult Overweight and Obesity. AB - This paper attempts to link last century's disruption of local agricultural systems to today's presence of childhood under nutrition and adult overweight and obesity in the Yucatan Peninsula. It first compares Height for Age (H/A), Weight for Age (W/A) and Body Mass Index (BMI) of children from three rural populations in Yucatan and Campeche, Mexico whose subsistence strategy had been altered to different degrees since 1970. It then compares BMI in adults, in the same regions, born before and after the alteration of their environment in the 1970's. Children in the least disrupted zone were taller and had lower BMI than children in the other two, but were not heavier than children from the richest disrupted zone. Children in the poorest disrupted zone were shorter and lighter than the rest. BMI in adult men was higher in the two most disrupted zones only in those cohorts that grew up after the traditional agricultural regime was altered. It is concluded that disruptions of staple-based subsistence agriculture promoted a stockier phenotype in children and a tendency to accumulate body fat. Persistence of these conditions in the twenty first century has favored the coexistence of stunting during childhood with adults who easily become overweight. PMID- 26987152 TI - The Difference in the Severity of Premenstrual Symptoms between Users and Non users of Oral Contraceptives. PMID- 26987153 TI - Secular Changes in Education, Urban-rural Living, Menarche and Abortion Rates in Perinatal Population. AB - Over a 25-year period we examined the anthropological characteristics of mothers and their partners, such as the place of living: urban vs. rural, the degree of education, parity, the time of menarche, and the frequency of intentional abortions. We examined 2 414 mothers and their partners in four periods of time extending from 1985 to 2009 in order to establish changes in the said anthropological characteristics over a period of 25 years. The degree of education of mothers and their partners is on the rise. In the period from 1985 to 1994, the percentage of mothers from the country was on the rise. Women with less education have on average more children, and those with better education the least children. Women from rural areas have on average more children than women from urban areas. The time of menarche dropped by 9 months over the period of 25 years. Girls from urban areas have their first menstrual cycle earlier. Women with higher professional qualifications had their first period earlier. The number of intentional abortions over the 25-year period dropped. PMID- 26987154 TI - Elderly Abuse and Alcohol Consumption. AB - Excessive alcohol consumption and the exposure of the elderly to family violence are in close connection. They represent both a general and social problem from a legal, medical and social aspect. The objectives of this study were to 1) test the frequency of alcohol consumption in older persons with respect to certain social and demographic characteristics; and 2) test the correlation between alcohol consumption and family violence towards the elderly. The sample used in this study was constructed as probabilistic with a random selection of participants in order to ensure representativeness for the City of Zagreb population over 65 years. The study included 1000 persons older than 65, among which 38% were male (N = 380) and 62% female (N = 620). The results showed a significantly more frequent consumption of alcohol among older men aged between 65 and 74, elderly people with life partners (unmarried), and financially independent older persons. A correlation between alcohol consumption frequency and exposure to violence was also established, as well as that older persons who consume alcohol are more likely to commit acts of violence. Further research is needed on the risk and protective factors for specific forms of family violence so as to detect the causes of violence within families as well as mechanisms that al- leviate coping with violence. PMID- 26987155 TI - Nursing Staffs' Views on Physical and Psychosocial Care Provision in Slovenian Nursing Homes. AB - The aim of this study was to explore nursing staffs' perceptions of the physical and psychological care needs of elderly residents, their views on the relative importance of these needs and their perceived ability to meet them. The literature reveals that the quality of elder care in nursing homes should comprise both physical and psychosocial care. Despite this, the nursing staffs' perceptions of the physical and psychosocial care provision have not often been researched. As a method cross-sectional research design was used, with structured questionnaires and unstructured interviews. Our sample consisted of members of the nursing staff from four nursing homes in Slovenia (survey: N = 148; interview: N = 16). The resulting data was processed by means of statistical analysis and conventional content analysis. The nursing staff reported more knowledge of, skills with and willingness to meet residents'physical needs than psychosocial needs. On the other hand, communication, conversation, self-care and a home-like environment were considered by nursing staff as marking quality elder care. Consequently, nursing home administrators should try to strengthen psychosocial care provision to improve the residents' quality of life. Conversation, as the most often recognised aspect of psychosocial care, should be promoted, since improvements in this area would not be costly, and each nursing staff member may decide individually how best to include more conversation in the daily routines of elder care provision. PMID- 26987156 TI - Adaptive Changes in Basal Metabolic Rate in Humans in Different Eco-Geographical Areas. AB - Our aim was to establish whether the human basal metabolic rate (BMR) shifts towards the reduction of vital functions as an adaptation response to extreme environmental conditions. Data was collected in arid and Extreme North zones. The arid zone samples included Bedouins living in the Sinai Peninsula in Egypt, Turkmen students, the Pedagogical University of Chardzhou, Turkmenistan born Russians and Russian soldiers. Soldiers were divided into 3 groups according to the length of their tour of duty in the area: 1st group: up to six months, 2nd group: up to 2 years and the 3rd group: 3-5 years. The Extreme North samples comprised Chukchi natives, 1st generation Russian immigrants born in the area and 3 groups of soldiers comparable to the soldiers from Turkmenistan. BMR values of the new recruits had the highest values of total and relative BMR (1769 +/- 16 and 28.3 +/- 0.6, correspondingly). The total and relative BMR tended to decrease within a longer adaptation period. The BMR values of officers who served >3 years in Turkmenistan were very similar to the Turkmenistan born Russians (1730 +/- 14 vs. 1726 +/- 18 and 26.5 +/- 0.6 vs. 27.3 +/- 0.7, correspondingly). Similarly, in Chukotka, the highest relative BMR was found in the new recruits, serving up to 6 months (28.1 +/- 0.7) and was significantly (p < 0.05) lower in the Russians serving in Chukotka over 1.5 years (27.1 +/- 0.3). The BMR was virtually similar in Russian officers serving > 3 years, compared to the middle-aged Chukchi or Chukotka-born Russians (25.8 +/- 0.5 vs. 25.6 +/- 0.5 and 25.5 +/- 0.6, correspondingly). The BMR parameters demonstrated a stronger association with body weight than with age. In extreme environmental conditions, migrant populations showed a decrease in BMR, thus reducing its vital functions. The BMR reduction effect with the adequate adaptive transformation is likely to be the key strategy for developing programs to facilitate human and animal adaptation to extreme factors. This process is aimed at preserving the optimum energy balance and homeostasis while minimizing stress on the body's vital functions. PMID- 26987157 TI - The Influence of the Age, the Years of Training, and the BMI on the Average Muscle Power in Male and Female Rowers. AB - The aim of the study was to evaluate the influence of the age, the body mass index (BMI), and the years of training on the average muscle power in male and female rowers. The analysis of the testing results of the members of the Rowing club Iktus from Osijek in Croatia was performed. Results were obtained during the regular yearly testing on the rowing ergometer for the rowing season of 2009. Members of the Rowing club Iktus were divided into two subgroups according to their sex. The obtained results were analysed in accordance with the age, the BMI, and the years of training independently for the each of the two subgroups. The results have showed that the average muscle power is independent of all the three parameters in the male rowers, while it is dependent on the age and the years of training in the female rowers. It seems that the BMI does not play any role at all in the average muscle power. As a conclusion, it could be stated that while one can suggest to female rowers to improve their performance with prolonged training, there is a need for a further research in order to formulate a suitable advice for male rowers. PMID- 26987158 TI - Anthropometric Characteristics of Chinese Professional Female Marathoners and Predicted Variables for Their Personal Bests. AB - To investigate anthropometric characteristics of Chinese professional female marathoners and suitable predicted variables correlated with their personal bests (PB), 96 Chinese female long-distance runners were divided into international (< 2 h 34 min), national (2 h 34 min~2 h 45 min) and average (2 h 45 min~3 h 19 min) levels according to their PB in marathon during the process of talent identification for London Olympic Games. Selected anthropometric variables, including height, body mass, percentages of body fat, girths, breadths, lengths and skin-folds were measured. Only iliac crest skin-fold of international athletes was significantly lower than it is in national group. Girth of forearm and lower limbs, length of lower limbs, and all skin-folds of national athletes were significantly lower than those from average level group. Percentages of body fat, girth of forearm and calf, length of lower limbs, and skin-folds at sites of subscapular, abdominal and iliac crest of athletes from average level group were significantly higher than those in international athletes. Positive correlation was found between forearm girth and PB, and between the subscapular, abdominal, iliac crest and triceps surae skin-folds and PB for total athletes. Negative correlation between biiliac breadth and PB in international athletes, and positive correlations between abdominal and triceps surae skin-folds and PB in national athletes were found. For average runners, high positive correlation was found between upper arm girth and PB, and between subscapular, abdominal, iliac crest and triceps surae skin-folds and PB. The findings suggested that compared to stride length, stride frequency and efficiency were more important factors influencing running performance, which were in accordance with running technique in Chinese female marathoners. PMID- 26987159 TI - Frequency Distribution and Association of some Morpho- and Physiological Traits in Patients with Lung Diseases in Kosova. AB - The aim of this study was to investigate the distribution of specific phenotypes in patients with lung diseases as well as their eventual association with the risk of developing lung diseases. For this purpose 2777 patients with lung diseases and 2778 healthy individuals from all over Kosova were examined for the appearance of the following selected phenotypes: ear lobe free (ELF)/ear lobe attached, normal chin (NC)/cleft chin, tongue roller (TR)/non roller, hand clasping right thumb over (HC)/hand clasping left thumb over, righthanded (RH)/lefthanded. In addition, the blood group from ABO system and the presence or absence of the Rhesus factor asphenotypical markers were observed. The results obtained show significant differences between control and lung disease patients for NC (p <= 0.05) and TR (p <= 0.005) as well as for blood groups AB (p <= 0.05) and O (p <= 0.005). These results point to eventually increased levels of genetic load as a result of the increased homozygosity in some gene loci causing an increased frequency of some recessive phenotypes in patients with lung diseases. Together with the specific associations observed, these preliminary findings could serve as a basis for further in depth investigations with respect to the types of lung diseases, occupational exposure and dietary habits, and thus is expected to contribute to an understanding of predispositions and susceptibility to lung diseases. PMID- 26987160 TI - Health Impact of Elevated Levels of Lead Encountered in the Manufacture of Crystal Glass. AB - Lead is known to cause harmful effects in the haematopoietic, nervous, digestive, renal, and other organ systems, inhibiting a number of enzymes in the biosynthesis of haem, as well as other enzymes with haematological significance. Our study involved 151 employees involved with the cutting of crystal, i.e. leaded glass, who had been found using eco-monitoring to have been exposed to above normal levels of lead. Our bio-monitoring process followed the values of lead, delta-ALAD and EPP.The highest level of lead detected was 276 ug/L, the lowest level of delta-ALAD was 99 nkat/L), and the highest level of EPP was 14.2 nmol/gHb). We had found that contrary to expectations, lead levels were not correlated to haemoglobin levels, or to gender or age, but were instead based only on the post of the employee and their time spent working at the glassworks. The levels of haematopoiesis were directly proportional to the levels of lead, however, the correlation was not statistically significant or had perhaps been masked by the exposure due to the employee's post and gender. We had also found a significant correlation of lead levels to the levels of renal function. The study had indicated some health impacts of lead on the exposed glass workers, but also at least partly diverged from the results of previous studies, prompting us to continue our research. PMID- 26987161 TI - The Value of Hormone Receptor Assessment in Ultrasound Guided Core Needle Biopsy of the Breast. AB - Breast cancer is the most common cancer in women in Western countries after skin tumors. Successful treatment depends on many factors, relies on clinical examination, diagnostic procedures, pathologic evaluation, and good therapy decision. The Pathologic diagnosis should be the determining factor in the decision on therapeutic approach. There are several methods of obtaining tissue samples. The percutaneous ultrasound guided breast Core needle biopsy (CNB) is one of them. The Aim of this Study is to evaluate our experience in the accuracy of hormone receptors assessment in ultrasound guided CNB. In our institution, in last 12 month 60 women (with 67 lesions) underwent Breast CNB. The CNB was performed with 16 Gauge semiautomatic biopsy needle with 15 Gauge coordinated introducer needle. 3-6 specimen (mean 4) were taken during the procedure. We analyzed five factors (histological type, histological grade, estrogen and progesterone receptor status, and HER2 from the biopsied sample. All results were presented at the Multidisciplinary Oncology Team. In addition to demographic data and morphological features of the lesion, we analyzed five pathological factors (histological type, histological grade, estrogen and progesterone receptor status, and HER2 from the biopsied sample. All results were presented at the Multidisciplinary Oncology Team. Ultrasound-guided CNB has proven to be a reliable technique for performing a biopsy for breast. It is a good and reliable, complication free method, for preoperative staging, operative planning as well for prognostic value. It is a cost-effective method, can be performed quickly and in outpatient population, does not deform the breast and multiple lesions can be biopsied. This technique shows a high sensitivity value and offers many advantages over other imaging methods to guide a biopsy. All advantages have made this technique the most widespread used technique to perform a biopsy for a suspicious breast lesion. PMID- 26987162 TI - Advanced Clinical and Radiological Features of Ankylosing Spondylitis: Relation to Gender, Onset of First Symptoms and Disease Duration. AB - To determine the frequency of advanced clinical and radiological features of AS with reference to gender, onset of symptoms and disease duration. Fifty-seven patients diagnosed with AS were included in this study. Functional evaluation of the musculoskeletal system detected advanced clinical features: rubber-ball phenomenon, flattening of the chest anterior wall, diastasis of rectus abdominis muscle, steel back phenomenon, umbilical extrusion, skiing posture. Conventional radiographs of sacroiliac joints, pelvis and axial skeleton were obtained in order to analyze signs of sacroiliitis, syndesmophytes, vertebral squaring and ligamentous ossification. Statistical significance is found in the distribution of particular advanced clinical and radiological features of AS between men and women: rubber-ball phenomenon (p = 0.002), flat chest (p = 0.002), diastasis of rectus abdominis muscle (p = 0.002), skiing position (p = 0.000), syndesmophytes (p = 0.009) and ligamentous ossification (p = 0.030) in thoracic and lumbar spine. Onset of first disease symptoms (> 20 years of age) is significantly associated with radiological changes in thoracic spine (ligamentous ossification, p = 0.015) and cervical spine (vertebral squaring, p = 0.032). Longer disease duration (> 10 years) is significantly associated with the appearance of particular clinical features: rubber-ball phenomenon, p < 0.01; rectus abdominis diastasis, p=0.042) and radiological changes of sacroiliac joints (grade IV sacroileitis, p = 0.012), thoracic and lumbar spine (syndesmophytes, p = 0.015; ligamentous ossification, p = 0.027). Our study shows that the occurrence of clinical and some radiological features of AS appears to be gender dependent. Furthermore, onset of first disease symptoms (> 20 years of age) and longer disease duration (> 10 years) are associated with the higher risk of developing particular clinical signs and radiological features in sacroiliac joints and axial skeleton. PMID- 26987163 TI - Mediatisation or PR-ization of Public--Media Communication--Analysis of Mediated Communication of Zoran Milanovic. AB - Politicians and their public relations advisors depend on the mass communication media to transmit messages dailyand communicate effectively. The development of the mass media, from traditional to new, has changed the working conditions of these professions where one inevitably affects the other. Consequently, the way of formatting information in the newshas changed, along with the way of monitoring the political developments and informs the public on political activities. Amajor role in this process, over and above the political actors, has advisers for public relations, who choose moments andevents to publicise (PR ization). With the increasing influence of public relations to media reports, politics also changes thepicture of the media and the impact on media coverage. Similarly, the impact on the manner in which the media reportprocess, what topics will be discussed topics and what tone the given information will have. We are living in a world characterized by mediation (Mazzoleni and Schulz, 1999) of the politics and the society as a whole, because politics and publicrelations necessarily need the media to communicate with their audiences. In this regard, we can talk about PR-izationmedia as the fundamental role of public relations practitioners affect attitudes, which skillfully make careful design ofmessages and events that are not included herein are the three professions each other should one without the other does notmake sense. This paper will focus on the influence of the media on politics and on influence of the public relations as profession in the content media perception. In view of the drawn by daily public appearances of Prime Minister, Zoran Milanovi6,and as says Lali63 few politics related phenomena have over the past twenty years engaged so many reviews by experts andscholars as the Prime Minister's rhetoric. The particular form of the political communication will be reviewed in this paper.Through the interviews and the content analysis of key moments and statements from the media, we shall try to determinehow the communication by Zoran Milanovi6 has changed with the new public relations advisor, and that the change hasaffected the public attitudes that Milanovi6 communication seen through the media-mediated reality. PMID- 26987164 TI - Bronze and Iron Age Finds from Romuald's Cave, Istria: 2014 Excavation Season. AB - Archaeological excavations in Romuald's Cave (Lim Channel, Istria, Croatia) have yielded evidence of human activity stretching back to the Middle Palaeolithic. This paper reports on recent Bronze Age/Early Iron Age discoveries uncovered during excavations as part of the Croatian National Science Foundation funded project: "Archaeological Investigations into the Late Pleistocene and Early Holocene of the Lim Channel, Istria". Fragmentary skeletal remains from at least two individuals were excavated, and a direct radiocarbon date from one of the remains is commensurate with a Bronze Age attribution. The recovered ceramics confirm this age attribution, although they range from the Middle Bronze Age to incipient Iron Age in character. Furthermore, the ceramics indicate that the human activities in Romuald's Cave were associated with the nearby settlements of Gradina and St. Martin. PMID- 26987165 TI - Nationwide Survey of Klebsiella Pneumoniae Strains Producing CTX-M Extended spectrum beta-lactamases in Croatia. AB - Extended-spectrum beta-lactamases (ESBL) producing bacteria have been increasingly reported in both hospital and community patients. Production of ESBLs is the major mechanism of resistance to oxymino-cephalosporins and aztreonam in Gram-negative bacteria. Recently a new family of ESBLs with predominant activity against cefotaxime (CTX-M beta-lactamases) has been reported. Over 80 CTX-M enzymes have been described so far, which can be grouped into five main subgroups according to amino acid sequence identity (CTX-M-1, CTX M-2, CTX-M-8, CTX-M-9 and CTX-M-25). In some countries, CTX-M beta-lactamases are the most prevalent types of ESBLs, for instance in Russia, Greece, Spain, Switzerland, Japan, Taiwan, China and Argentina. These enzymes have been identified in countries near Croatia such is Italy, Hungary and Austria. The aim of this study was to determine the prevalence and the types of CTX-M beta lactamases produced by Klebsiella pneumoniae clinical isolates collected from October 2006 to January 2007 from both community- and hospital-based isolates were included (Figure 1.). 128 ESBL isolates were subjected to further analysis: screening with double disc diffusion test and confirmed by ESBL E test. PMID- 26987166 TI - Successful Treatment of Acute Aortic Dissection Type Stanford A Presenting as Limb Ischemia, Successfully Treated with Operative and Endovascular Procedures. AB - We report a successful treatment of unusual case of a 48 year old male patient with acute aortic dissection type Stanford A that expanded into left common and external iliac artery diagnosed by MSCT angiography, presenting as a single leg paresis, without symptoms of a chest or back pain. Patient was operated with conventional ascending aortic replacement. Patient had no known prior medical condition. He has been treated for acute thrombosis of the left popliteal artery developing one day after ascending aortic replacement surgery, embolectomy was performed. Critical limb ischemia developed due to preocclusive stenosis of the left common and left external iliac artery and was treated by endovascular procedure of iliac artery stenting performed on the fifth postoperative day. After 17 days patient was discharged form hospital, showing no neurological or vascular deficit. For successful treatment of acute aortic dissection type Stanford A complicated with limb ischemia, rapid and accurate diagnosis is essential, together with close cooperation of cardio surgeons, vascular surgeons and invasive radiologists and individual approach to these demanding patients. PMID- 26987167 TI - Historical and Social Evolution of the Healers' Charisma. AB - This study aims to explore the relation between charisma and healing and how the concept of charisma evolved within medical profession over time. The development of medical profession from shamans to modern medical doctors, the gradual transition from ritual to physical healing, the relation between the physician and common people, and the transition from personal to professional charisma are presented in a medico-historical context. The article concludes that there is an indisputable link between the phenomenon of charisma and healing. Healers have often been considered among the most significant charismatic figures in their societies. With time physicians have lost their personal charisma and replaced it by a stable professional charisma. Today, the growing involvement of patients in healing and demystification of the medical profession is diminishing the charisma of the physicians, although medical profession still retains qualities found in classic charismatics and with it also some authority over patients. PMID- 26987168 TI - [THE MODERN CONDITION AND PROGNOSTIC ESTIMATES OF MEDICAL DEMOGRAPHIC PROCESSES IN THE RUSSIAN FEDERATION]. AB - The prognostic estimates offurther development of medical demographic processes in the Russian Federation are presented on the basis of analysis of long-term patterns of natural science order: The deduction is proposed concerning necessity of focusing attention on issues ofpremature mortality and its preventability. PMID- 26987169 TI - [THE DIVERGENCE OF MEDICAL DEMOGRAPHIC SITUATION IN RUSSIA]. AB - The factors impacting demographic situation in largest cities are discussed. The transformation of correlation relationships ofvariation offertility and total mortality ofpopulation with intensity of its aging, labor payment, supply with physicians and capacity of medical institutions is analyzed PMID- 26987170 TI - [THE DISPENSARIZATION AND HEALTH OF SOCIALLY ECONOMICALLY PRIORITY GROUPS OF POPULATION OF THE KUZBAS]. AB - The results of fragment of study concerning analysis of morbidity and dispensarization of socially economically active and priority groups ofpopulation, children included are presented. The volumes of dispensarization activities and directed cash resources are compared with. The estimates ofmorbidity of workers of metallurgic enterprises and dispensarized children are applied with subsequent health groups distribution. The territorialfoundation of mandatory medical insurance granted substantial cash resources to implement this task that required implementation ofestimate activities. The results are applied in planned curative preventive working, medical and preventive activities that constitute tasks of activities of the territorial foundation of mandatory medical insurance related to priority groups. PMID- 26987171 TI - [THE SOCIAL HYGIENIC AND MEDICAL DEMOGRAPHIC CHARACTERISTICS OF FAMILIES OF INDIGENOUS POPULATION OF YAKUTIA]. AB - Nowadays, in indigenous populations of the North and Siberia lower indicators ofpsychic health are registered. The evidence ofthis occurrence is high mortality due to external causes and significant prevalence of alcoholism. The high level of suicide among indigenous children and adolescents reflects extreme social troubles. The sampling included 478 families of indigenous population of Yakutia (families of Yakut, Evenk, Even and Yukagir) residing in the northern, central eastern andsouthern regions ofthe Republic. The specially developed social hygienic questionnaire was applied. The study established that 52-55.5% of indigenous families have three and more children and are positioned as large families. At the same time, 22.6-32.2% offamilies are incomplete and 11.5-38.5% of children are born in unregistered marriage. The income lower than living wage have 55.9-67.9% of indigenous families. The lacking of permanent income is one of the causes of such situation in case of 20-28.6% of parents. Only 30.7-53.6% of indigenous families can be considered as well-to-do ones. From 464% to 69.3% offamilies are considered as disadvantaged in consequence of unfavorable psychological climate (in 33.7-43.6% of families); occurrence of frequent quarrels and conflicts (in 3.8-9.0% offamilies), alcoholization of one or both parents (in 5.7-10.9% of families), presence of relatives with previous convictions (in 7.4-11.4%). PMID- 26987172 TI - [THE MULTI-VECTOR MODE OF EVALUATION OF INTER-SECTORAL INTERACTION CONCERNING ISSUES OF POPULATION HEALTH CARE]. AB - The algorithm of constructing mode of multi-vector evaluation of intersectoral interaction concerning issues of population health care is substantiated and implemented. The items ofevaluation included identification of informative vectors and criteria including their gradation, coefficients of significance and model versions. PMID- 26987173 TI - [THE CHARACTERISTIC OF SOMATOTYPE AND FUNCTIONAL STATE OF CIRCULATORY SYSTEM OF STUDENT YOUTH OF THE NORTHEAST OF RUSSIA]. AB - The article considers results of single-step study in random sampling of female students of the M.K. Ammosov north-east federal university (n=456). The study was carried out to investigate somatotype and functional state of circulatory system. The standard technique was applied to measure height, body mass, chest circumference, level of arterial pressure and rate of heart beats. The type of somatotype was established using Pignet index. The tone of vegetative system was determined using Kerdo index. The adaptation potential of circulatory system was determined using functional changes index. The results of study established that in 61% of examined female students the type of constitution corresponds to normosthenic one. The percentage of persons with asthenic and hypersthenic type of constitution amounted to 27% and 12% correspondingly. The signs of increasing oftone ofsympathetic nervous system are observed in 89% of girls. The functional condition of circulatory system is evaluated as "tension of adaptation mechanisms" that is apparently related to period of adaptation to new conditions. The prolonged preservation of such states results in exhaustion offunctional resources of organism and can promote development of diseases. In conditions of impacting of unfavorable ecological factors the deconditionning disorders can significantly contribute to health disturbances and decreasing of life quality. To preserve youth's health during period of education the comprehensive strategy is to be implemented such components as dynamic monitoring of health, organization of adequate diet, explanation of necessity of observance of sleep and rest pattern, development of conditions for active aerobic physical exertion and activities on correction of risk factors of development of diseases are to be included. PMID- 26987174 TI - [THE ORGANIZATION OF REHABILITATION CARE OF POPULATION USING INNOVATIVE MEDICAL ORGANIZATIONAL TECHNOLOGIES AND PRINCIPLES OF PUBLIC PRIVATE PARTNERSHIP]. AB - The article considers actual problems of actual stage of development of health care related to using innovative approaches to organization and management of rehabilitation care ofpopulation. The rehabilitation is most important direction of medical sector supporting complex of services in closed cycle of rendering medical care to population and significant social economic effects. The capacity and extreme unprofitability of rehabilitation services determine necessity of searching alternative forms of organization of this type of care and financing including mechanisms of public-private partnership. The experience is presented related to involvement of resources of non-public medical organizations for implementing public commitments on rendering qualitative rehabilitation services to population using innovative medical organizational technologies. PMID- 26987175 TI - [THE EVALUATION OF EFFECTIVENESS OF FUNCTIONING OF TUBERCULOSIS HOSPITALS AND CALCULATION OF NECESSARY NUMBER OF BEDS AT THE REGIONAL LEVEL]. AB - The adequate planning of capacity of hospital medical care accounting regional characteristics of prevalence of tuberculosis infection and functioning of anti tuberculosis institutions are one of activities increasing effectiveness of resources using. So far, in the Russian Federation no techniques was developed permitting to determine need of tuberculosis service of region in number of beds based on epidemiological indicators of tuberculosis. To bring nearer as much as possible to reliable level of such a need in the Irkutskaia oblast the technique was developed on the basis of listing of indications for hospitalization of tuberculosis patients. This technique permits to substantiate the need of the subject of the Russian Federation in necessary number of beds in consideration of regional characteristics of prevalence of tuberculosis. This approach supports development of organization, planning and increasing of effectiveness of anti tuberculosis activities in modern conditions. PMID- 26987177 TI - [THE STATE AND PERSPECTIVES OF DEVELOPMENT OF TRAUMATOLOGICAL ORTHOPEDIC OUT PATIENT CARE TO POPULATION OF THE PRIVOLJSKII FEDERAL OKRUG]. AB - The article presents the results of analysis ofmanpower support of specialized out-patient traumatological orthopedic care in the Privoljskii federal okrug. The manpower deficiency of traumatologist-orthopedist at the out-patient stage was established especially especially in rural area. This is cause of low indicators ofdispensary monitoring of patients with consequences of traumas and diseases of musculo-skeletal system and factual unavailability of rehabilitation care to patients of given profile. The experience oftraining and re-training of traumatologist-orthopedist is presented. The organization of hospital substituting forms of medical service of profile patients in the Saratovskaia oblast. The directions of development of organization of specialized out-patient care to population of the region. PMID- 26987176 TI - [THE ORGANIZATIONAL TECHNOLOGIES OF INCREASING OF EFFECTIVENESS OF DISPENSARY MONITORING OF HIV-INFECTED PERSONS]. AB - The organizational technologies of increasing effectiveness ofdispensarization monitoring of HIV-infected persons are to targeted to development in patients commitment to get medical care. The cohort monitoring of registered patients receiving anti-retrovirus therapy permitted to evaluate effectiveness of organizational model of multi-professional team developing commitment ofpatients to anti-retrovirus therapy in conditions of center ofprevention and struggle with AIDS and infectious diseases. The criteria ofeffectiveness offunctioning ofmulti professional team are developed and implemented The list of criteria include percentage of patients in cohort with optimal commitment (not lower than 95% of applied dosage of anti-retrovirus pharmaceuticals at 12th, 24th, 36th, 48th and 60th month), percentage ofpatients with achieved effect of anti-retrovirus therapy, percentage of patients proceeding anti-retrovirus therapy. The multi professional team implemented motivational techniques of behavior alteration and patient-oriented care. The main strategy of development of of commitment to anti retrovirus therapy under HIV-infection is determined as management of resources and risks capable decreasing commitment to dispensarization monitoring. The analysis of problems permitted to structure them in risks of commitment failure: medical (13.7%), medical biological under using psychoactive substances (43.1%), psychological (27.7%), social (15.5%). This listing determined the profile of specialists of multi-professional team. The ranking of risks lead out to the first ranking place medical risks, including diagnosed tuberculosis, combination of secondary and concomitant diseases inpatient, number of intaking pills more than 7 per day. The second ranking place took medical biological risks in users of psychoactive substances. Up to 60th month the anti-retrovirus therapy was proceeded by 61.5% of users of psychoactive substances with optimal commitment in 60%. The implementation of model of multi-professional team was accompanied by increasing of coverage of HIV-infected patients by dispensary monitoring and anti retrovirus therapy. The applied organizational technologies permit to develop commitment to dispensary monitoring and anti-retrovirus therapy in patients with any risks of breach of commitment. PMID- 26987178 TI - [THE ORGANIZATIONAL TECHNOLOGIES OF INCREASING QUALITY OF SPECIALIZED MEDICAL CARE UNDER ACUTE CORONARY SYNDROME AS EXEMPLIFIED BY THE KEMEROVSKAIA OBLAST]. AB - The article considers means of development ofsystem of specialized medical care under acute coronary syndrome. The new organizational approaches provide optimization of structure of specialized hospital, development of mechanisms of multi-stage and multi-level interaction of medical organizations of the subject of the Russian Federation as exemplifed by the Kemerovskaia oblast and integration of resources of institutions of health care, science and education. PMID- 26987179 TI - [THE ROLE OF DEVELOPMENT OF MATERIAL AND TECHNICAL RESOURCES OF MULTIFIELD HOSPITAL AND ITS IMPACT ON EFFECTIVENESS OF INSTITUTION FUNCTIONING]. AB - The role of development of material and technical resources of Moscow multifield hospital within the framework of program of modernization of capital health care and its impact on effectiveness offunctioning of institution. The comparison was implemented between capital investment level of physicians related to medical equipment and corresponding target indicators in Moscow. The correlation is established between indicators of capital investment level ofphysicians, average bed stay and clinical efficiency. PMID- 26987180 TI - [THE DEVELOPMENT OF MOBILE APPLICATION OF PHYSICIAN FOR IMPLEMENTING REMOTE MONITORING]. AB - The issues are considered concerning necessity of development and implementation of mobile application of physician within the framework of automated system of remote monitoring of indicators of human health as a mean of increasing of quality medical care of patients. The main characteristics of development of the given mobile application of physician are considered. PMID- 26987181 TI - [THE BOLOGNA PROCESS AND THE FEDERAL STATE EDUCATIONAL STANDARD OF HIGH EDUCATION]. AB - The article reveals characteristics of entering of high medical school of Russia in the Bologna process. The Russian Federation joined this process in 2003. The features of implementation of the new Federal state educational standard of high education of the third generation in area of training "Health care and medical sciences". PMID- 26987183 TI - [THE CANCELED FACULTY: ON THE ISSUE OF ESTABLISHMENT OF MEDICAL FACULTY OF THE PETROGRAD UNIVERSITY DURING THE FIRST WORLD WAR]. AB - The article considers history of attempts to organize medicalfaculty in the Petrograd university on the eve and during the First World War The actuality of issue is in both insufficient investigation of this page of history of national medicine and medical education and history of development of national medicine in the period of the First World War which centenary is observed this year On the basis of large spectrum of published and archive sources the article considers the prerequisites of organization of medical faculty in St. Petersburg-Petrograd The discussions around its organization, positioning and augmentation of its supporters and opponents are called to mind The attempt is cited concerning organization offaculty in context of existed relationship between professional and teaching staff corporation of the Petrograd university and authorities. The separate attention is paid to the issue of corporative aspiration of professorate which determined model of their behavior and in spite of all social politic alterations provide no permission to compromise with authorities. The similar behavior model continued and after the February Revolution and this became the cause of giving up the idea of organization of medical faculty after overthrow of czarism. PMID- 26987182 TI - [THE TRAUMAS IN PERSONS OF OLDER AGE]. AB - The aging of population is one of the most signifcant demographic occurrences of actual century. The Republic of Kazakhstan is the country with accelerated rate of population aging. The rate of traumas in population older than 60 years gradually increases concurrently with increasing ofpopulation size. The study was organized to investigate traumas in persons of older age hospitalized in hospitals of town ofSemeii of the Eastern-Kazakystan oblast. The study was carried out in the traumatological department of emergency care hospital oftown of Semeii and the neurosurgical department of the Medical center of the Semeii state medical university. The period of study amounted to January 1 2010 - December 31 2012. The criteria of inclusion were determined as age 60 years and older hospitalization as a result of trauma. The sampling consisted of 746 patients of geriatric profile. The average age consisted 70.4 years. During the established period increasing of number of hospitalized patients was detected. The percentage of male contingent diminishes with every year in comparison with female contingent. The traumas of area of coxofemoral joint and thigh comprised the most percentage among older patients in 2011-2012. The gender indicators among older patients reflect demography of total size of older population in Kazakhstan. The study established significant predominance ofwomen. Independently ofthe season, the traumas of area of coxofemoral joint and thigh prevail over all population of older people. PMID- 26987184 TI - [EMMANUIL ISAAKOVICH DEICHMAN (1889-1967) AS ONE OF LEADERS OF ANTI-ALCOHOLIC MOVEMENT OF THE I920S IN THE USSR: TO ONE HUNDRED TWENTY-FIFTH ANNIVERSARY]. AB - The article presents for the first time the biography of E.I. Deichman, one of leaders of anti-alcoholic movement. The input of E.I. Deichman into struggle with drunkenness and alcoholism in the 1920s is concertized. PMID- 26987185 TI - [ZINAIDA KAZIMIROVNA ZABEGALSKAIA--THE FOUNDER OF SURGERY SCHOOL IN ORENBURG]. AB - In 2014, the year of the seventieth anniversary of the Orenburg medical academy, will be ninetieth birthday of prominent surgeon, scientist, public figure, excellent pedagogue Zinaida Kazimirovna Zabegalskaia. PMID- 26987186 TI - [The Moscow scientitic society of historians of medicine in 2014]. PMID- 26987187 TI - [Effect of FABP2 gene G54A polymorphism on lipid and glucose metabolism in simple obesity children]. AB - OBJECTIVE: To explore the relationship between intestinal fatty acid binding protein (FABP2) gene G54A polymorphism and simple childhood obesity, the effect of mutant 54A FABP2 gene on serum lipids and glucose metabolism. METHODS: The total of 83 subjects with overweight/obesity and 100 subjects with healthy/normal weight were involved in this study. The G54A FABP2 gene allele and genotype frequencies between control group and overweight/obesity group were detected using polymerase chain reaction (PCR) -restriction fragment length polymorphism (RFLP) technology, and DNA sequences were confirmed by DNA sequencing. The automatic biochemical analyzer was used to detect fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels. Plasma insulin (Ins) was detected by radiation immune method, free fatty acids (FFA) was tested by ELISA method, insulin resistance index ( HOMA-IR ) was also calculated. The correlation between FABP2 G54A polymorphism and the development of children' obesity was analyzed. The relation between FABP2 G54A polymorphism and abnormal blood lipid and insulin resistance was assessed. RESULTS: The results of study on FABP2 gene polymorphism revealed as followed. In overweight/obese groups, the frequencies of GG, GA, AA genotypes was 33.7%, 49.4% and 16.9%, respectively. In control group, the frequencies of GG, GA, AA genotypes was 51. 0% , 40. 0% and 9. 0% , respectively. The differences between two groups was statistically significant (Chi2 = 6.27, P < 0.05). In overweight/obesity group, the frequencies of alleles were 58.4% for 54G and 41.6% for 54A. In control group, the frequencies of alleles were 71.0% for 54G and 29.0% for 54A. There was significant differences (Chi2 = 6.32, P < 0.05). The plasma biochemical variables results showed that compared with the normal control group, plasma TG (P < 0.01), Ins (P < 0.05), HOMA-IR (P < 0.05) were elevated in overweight/obesity group, the difference between two groups was statistically significant. At the same time, in overweight/obesity group, the carriers of AA homozygous genotypes had significantly higher plasma TG levels than those with GG wild genotypes (P < 0.05). A increased tendency of plasma Ins, FFA levels and HOMA-IR was found in the carriers with AA homozygous genotypes, but no differences compared with those with GG wild genotypes. Compared with those with GG wild genotypes, related plasma biochemical variables in the carriers with GA heterozygous genotypes had no differences (P > 0.05). CONCLUSION: The FABP2 gene G54A polymorphism is related to simple children obesity and lipid metabolism abnormality. The allele encoding in FABP2 gene may be a potential factor contributing to promoting lipid metabolism abnormality of and insulin resistance. PMID- 26987188 TI - [Proteomics study on ficolin 3 in the human plasma of type 2 diabetics]. AB - OBJECTIVE: To explore the expression trend of ficolin 3 (FCN3) in type 2 diabetes (T2DM) plasma. METHODS: Two-dimensional polyacrylamide gel electrophoresis (2DE) was used to separate the plasma proteins from T2DM patients and healthy control subjects. MALDI-TOF-TOF was used to identify the differential proteins. Western Blot and enzyme-linked immune response (ELISA) were used to verify the results from 2DE. RESULTS: The experiment on 2DE showed complement C1s subcomponent, complement C3, C9 and FCN3 were up-regulated in the plasma of T2DM patients. The Western Blot results showed that C9 and FCN3 increased in the plasma of T2DM patients with respect to T2DM-free subjects. The experiment results on ELISA showed that the plasma concentration of FCN3 were (50.88 +/- 3.85 ) and (36.20 +/ 2.75 ) MUg/mL (P = 0.0062) in T2DM and T2DM-free, respectively. The plasma concentration of C9 were (26.22 +/- 1.43) and (19.23 +/- 1.55) MUg/mL (P = 0.0022) in T2DM and T2DM-free. FCN3 and C9 were up-regulated in T2DM plasma. CONCLUSION: FCN3 over-expressed in the plasma of T2DM patients,which activated the complement system in greater degree. PMID- 26987189 TI - [Repeated cross-sectional studies on urinary iodine and iodine content of salt among school-aged children from 2012 to 2014 in Yuhuan County, Zhejiang Province]. AB - OBJECTIVE: To investigate the iodine status and its change among school-aged children in their morning urine and eating salt from 2012 to 2014 in Yuhuan County, Zhejiang Province, China. METHODS: Three repeated cross-sectional studies were carried out at a same primary school in 2012, 2013 and 2014, respectively. Three classes were randomly selected from each of 3 to 5 grade by the cluster stratified sampling every year. Totally, 1343 out of 1350 eligible children aged 8 to 10 years old were involved into this study. Their morning urine and salt eating at home were collected and tested. RESULTS: The overall median of urine iodine was 116.0 MUg/L, and no significant change was found over year. The overall proportions of subjects with urine iodine < 50 MUg/L, < 100 MUg/L, and >= 300 MUg/L were 4.8%, 38.6% and 3.5%, respectively, and there were little differences over year, gender and grade of children. An overall median of iodine from 1343 salt samples was 0.0 mg/kg and no year difference was statistically observed. The proportions of subjects consumed iodized salt significantly decreased from 25.1% in 2012 to 21.8% in 2013 and to 14.2% in 2014. There was a significant difference in urine iodine between subjects taken iodized salt or not and also a weak positive correlation between salt iodine and urine iodine. CONCLUSION: The nutritional status of iodine is overall stable, proper and safety in recent 3 years among school children in Yuhuan County. The coverage rate of iodized salt is very low. PMID- 26987190 TI - [Association of pubertal timing and the different dimensionality of adolescents' aggressive behavior]. AB - OBJECTIVE: To explore the relationship between pubertal timing and aggressive behaviors. METHODS: Stratified random sampling was used to choose 5760 students from one junior high school and one high school. The pubertal development scale (PDS) questionnaire and perceived pubertal timing were used to evaluate the pubertal timing, and the Buss-Perry questionnaire was used to explore the students' aggressive behaviors. RESULTS: The score of aggressive behavior was significantly different in junior high school students with different perceived pubertal timing, the score of early pubertal timing was highest and the score of delay pubertal timing was lowest, and the score of physical aggression and verbal aggression of schoolboy in early pubertal timing and normal pubertal timing in high school was higher than the delay pubertal timing (P < 0.05). The score of physical aggression, anger and hostility of schoolgirl in early pubertal timing was highest, there was significant difference between them. The relationship between the perceived pubertal timing and the aggressive behavior was the physical aggression, anger and hostility score was highest in schoolgirls both in junior high school and high school, and the score of verbal aggression was higher in normal pubertal timing and early pubertal timing in schoolboys (P < 0.05), there was significant difference between them. CONCLUSION: There are closely relationship between the early pubertal timing and aggressive behaviors by used the PDS questionnaire, and the perceived pubertal timing is in a relatively large impact on girls' aggressive behaviors. PMID- 26987191 TI - [Body composition investigation of 2321 Shenzhen government and enterprise staffs]. AB - OBJECTIVE: To understand the laws of human body composition change and the status of the overweight and obesity of government and enterprise staffs. METHODS: In July 2013 - January 2014, 2321 adults more than 20-year-old healthy check-up crowd with complete human body composition and height as well as weight data in a medical center in Shenzhen were collected by convenience sampling method. RESULTS: The overweight rates of male and female were 46.41% and 18.94% respectively (standardized overweight rates were 44.02% and 14.51%, respectively), and the difference between them was statisically significant (Chi2 = 201.01, P = 0. 000). The obesity rates of male and female were 12.13% and 3.57%, respectively (standardized overweight rates were 11.11% (see symbol) 2.63%, respectively), and the difference between them was statisically significant (X2 = 48.45, P = 0.000). The parameters of bone mineral quality, visceral fat area, body fat, body fat percentage, abdominal obesity, body moisture and free fat weight increased with body weight, and there were statistical significance among normal weight, overweight and obesity groups (P = 0.000). Bone mineral quality was highest at the age of 30 to 40 for men and women, and there was the statistical significance. There was statistical significance in visceral fat area between different ages in the same gender. Body fat percentage (34.24 + 5.39)% of all ages 50 to 59 years old and body moisture (28.53 + 3.77)% of age 40 - 49 group were highest in women. Male body fat percentage (27.08 + 5.01)% at the age of 60-age group was the highest. Male and female visceral fat area increasesd with age, but there was no statistical difference between men and women at the same age. The human body composition had not a statistically significant difference among normal weight and overweight groups, but a significant difference between normal weight and obesity groups (P = 0.000). CONCLUSION: Overweight and obesity rates in Shenzhen government and enterprise staffs increase with age. Body composition increase with the weight. PMID- 26987192 TI - [Cross-sectional association between diabetes and obesity among the elderly of different genders in Yantai City]. AB - OBJECTIVE: To explore the cross-sectional association between the incidence of diabetes and obesity among the elderly of different genders, which intends to provide the scientific basis for undertaking glycemia interventions in the early stage to be conducive to the old folks' health status in Yantai City. METHODS: A total of 986 old people (>= 60 years old) were recruited from 4 districts in Laishan District Yantai City, Penglai City, Qixia City, Haiyang City by stratified cluster of random sampling and surveyed using questionnaires, while the physical examinations and blood glucose tests were conducted. The logistic regression model was used to analyze the cross-sectional association between the incidence of diabetes and obesity among the elderly of different genders in Yantai City. RESULTS: The rates of obesity and abdominal obesity were 10.04% and 60.85% among the old people in Yantai, respectively. The morbidity rate of diabetes was 10.85%. The influencing factors such as age, cultural standard, monthly income, past job category, smoking, drinking were adjusted, the fat old people had 3.121 times as much chance of suffering from obesity as the normal weight ones (OR = 3.121, 95% CI 1.978 - 5.119). And there was a gender difference between diabetes and obesity. The cross-sectional association between the incidence of diabetes and masculine obesity was of statistical significance alone (OR = 3.924, 95% CI 1.561 - 7.174). The elderly with the abdominal obesity 2.398 times as likely to suffer from diabetes as the elderly with the non-abdominal obesity (OR = 2.398, 95% CI 2.123 - 4.412). There was a gender difference between diabetes and abdominal obesity. The cross-sectional association between the incidence of diabetes and masculine abdominal obesity was of statistical significance alone (OR = 2.917, 95% CI 1.249 - 4.019). CONCLUSION: There are gender difference in the relationship between obesity, abdominal obesity and diabetes in the elderly in Yantai. BMI and waist circumference can be used as the predictive indexes of masculine diabetes. PMID- 26987193 TI - [Dietary exposure and health risk assessment of heavy metal in grains of Shaanxi Province]. AB - OBJECTIVE: To investigate heavy metal contamination of grains, and to assess the health risk of the contamination on local inhabitants. METHODS: The contents of 6 heavy metals of grains were detected, according to the food contamination monitor plan of Shaanxi Province. The levels of heavy metal contamination on grains were evaluated by pollution indices. Health risks associated with the daily dietary intake of heavy metals were assessed using USEPA health risk assessment model. RESULTS: 562 grain samples were randomly collected from 94 representative sites in Shaanxi Province. The contaminations of Cd and Pb were more seriously than the other metals. The pollution indices of Cd, As, Cr, Hg, Ni and Pb in 4 kinds of grains were less than 0.7, they were safe to eat. The dietary expose doses of Cd, As, Cr, Hg, Ni and Pb were also at the level of safety. The individual health risk of heavy metal pollution was 3.08 x 10(-4)/year for Cr, which was exceed the standard (5.0 x 10(-5)/year) of Inernational Commission on Radiological Protection (ICRP). The individual health risks of the other five metals were lower than the standard of ICRP. CONCLUSION: The most of grains are considered safe to eat for consumers, excepting a few samples are polluted by lead and cadmium. The individual health risk of Cr is higher than the standand of ICRP. PMID- 26987194 TI - [Analysis of colliery migrant workers quality of life and its influential factors]. AB - OBJECTIVE: To study colliery migrant workers' quality of life and related influential factors. METHODS: By multi-stage random sampling, 1161 colliery migrant workers were collected and assessed with the SF-36 and the self-made questionnaires. Multiple covariance and optimal scaling regression statistical methods were used to analyze the data. RESULTS: Physiological and mental health filed of colliery migrant workers, the physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH) and vitality (VT) score of those colliery migrant workers whose working age was less than 5 years higher than those over 10 years. The PF, RP, BP, GH, mental health (MH), VT and SF based within the health group, resulted in a higher score, compared to those who suffer from chronic diseases. The RP, GH and social functioning (SF) based within the mild labor intensity, resulted in a higher score, compared to those who severe labor intensity. The PF and RE based within the non-initial coal mine work, resulted in a higher score, compared to those who initial coal mine work. The PF, BP and VT based within the pre-employment physical examination, resulted in a higher score, compared to those who non pre-employment physical examination. The MH based within the smoking, resulted in a higher score, compared to those who no smoking. These differences were statistical significance (P < 0.05). Multiple factors analysis showed that working age (F = 19.26, P < 0.01), chronic diseases (F = 13.89, P < 0.01) and initial coal mine work (F = 8.48, P < 0.01) were the influential factors of physical component summary (PCS). Labor intensity (F = 5.90, P < 0.01), smoking (F = 10.45, P < 0.01) and chronic diseases (F = 7.91, P < 0.01) were the influential factors of mental component summary (MCS). CONCLUSION: There are some difference in individual characteristics (e. g. working age). Working age, chronic diseases, initial coal mine work, labor intensity, smoking are the influential factors for quality of life. PMID- 26987195 TI - [Association between life style, diet intake and high risk-human papillomavirus persistent infection among rural women in Xinmi City, Henan Province]. AB - OBJECTIVE: To explore the association between life style, diet intake and high risk human papillomavirus (HR-HPV) persistent infection among Chinese rural women living in Xinmi City, Henan Province. METHODS: In 2010, a 3-year prospective study in which 2500 women were enrolled and screened by different HR-HPV DNA tests was conducted, part of women among them was followed and tested for HR-HPV DNA in 2012 and 2014. Furthermore, socio demographic factors, gynecological information and diet intake in the past 12 months were collected by self-designed questionnaire in 2014. A total of 721 women with complete test results were eligible for the final analysis. Study participants were divided into 3 groups (persistent infection group, transient infection group, and negative group) by HR HPV status, and the association between life style, diet intake and HR-HPV persistence was evaluated using ordinal logistic regression model. RESULTS: The average age of 721 women included in the analysis was 50 years old. 141 women had HR-HPV persistent infection, 180 women had HR-HPV transient infection, and 400 women were negative for HR-HPV in 3 years. Age (Chi2 = 58.449, P < 0.001, P(trend) < 0.001), smoking (Chi2 = 6.981, P = 0.021), contraception method (Chi2 = 8.448, P = 0.015) , menopause (Chi2 = 35.712, P < 0.001), number of live births (Chi2 = 16.340, P < 0.001, P(trend) < 0.001), and the intake frequency of cereals (Chi2 = 17.937, P = 0.001) or others (Chi2 = 12.107, P = 0.017) varied significantly between women grouped by different HR-HPV status. Compared to women who were older than 59 years, women in the younger groups had a much lower risk of HR-HPV persistence (adjusted OR1 = 0.39, 95% CI 0.26 - 0.59, OR2 = 0.40, 95% CI 0.23 - 0.69, and OR3 = 0.28, 95% CI 0.12 - 0.68). CONCLUSION: Age is the main risk factor of HR-HPV persistent infection. Lifestyle, diet intake do not associate with HR-HPV persistence after adjustment by age. PMID- 26987196 TI - [Determination of 8 hindered phenolic antioxidantsin olive oil by ultra performance liquid chromatography and its migration research]. AB - OBJECTIVE: To develop a method for determination of PG, TBHQ, NDGA, BHA, Ionox100, OG, DG and BHT in olive oil by ultra-performance liquid chromatography (UPLC), and to study the migration rule of hindered phenolic antioxidants in food simulation solvent. METHODS: The samples were extracted with acetonitrile, and C18 dispersion matrix solid-phase, the separation were performed by UPLC. The migration amount of PG, BHA, BHT from polyethylene film to different simulated solvent (olive oil, 20% ethanol, 10% ethanol, 3% acetic acid) were determined at 20, 60 and 100 degrees C. RESULTS: The retention time of 8 hindered phenolic antioxidants was less than 8.5 min. The limits of detection were in the range of 0.01 - 0.05 MUg/mL, and the linear correlations were > 0.999. The average recoveries were from 80.0% to 106.8%, and the relative standard deviations were between 0.69% and 7.94%. The original heating migration experiments of PG, BHA and BHT were performed by such method. As the extension of heating time, the migration amounts were increased, and the migration amounts of PG in water-based food simulation solvent was similar in olive oil. BHA and BHT easily migrated to simulate fat solvents. The migration amount was the maximum in olive oil, while the migration amounts of BHA and BHT were little as the ethanol decreased in other simulation solvents. The migration amount of BHA in 20% ethanol was more than in 10% ethanol and 3% acetic acid. CONCLUSION: With the increase of temperature, the migration amount increase, and the hindered phenolic antioxidants easily migrate to simulate fat solvents. PMID- 26987197 TI - [Determination of 3-nitropropionic acid in poisoning samples by ultra-performance liquid chromatography-tandem mass spectrometry]. AB - OBJECTIVE: An ultra-performance liquid chromatography-tandem mass spectrometric method was established for determination of 3-nitropropionic acid of sugarcane, sugarcane bagasse, vomit, serum and urine. METHODS: The 3-nitropropionic acid in poisoning samples was extracted by acetonitrile in super-sonic instrument. The supernatant was cleaned up with PSA column and eluted with 10% ammonia water methanol (10: 90, V/V), then the purified solution was concentrated by nitrogen, dissolved with water (containing 0.4% formic acid) and cleaned by 0.22 MUm millipore filter. The filtrate was detected by ultra-performance liquid chromatography-tandem mass spectrometry, identified by electrospray ionization (ESI) in negative mode using multiple reaction monitoring, and quantified with external standards of sample matrix matching. The sample extract was separated on an acquity BEH C18 column (2.1 mm x 150 mm x 1.7 MUm) by gradient elution in 10 minutes with acetronitrile-water as mobile phase. RESULTS: The calibration curves of 3-nitropropionic acid residues showed good linearity in the range of 1.0 - 50 MUg/kg with correlation coefficient of 0.9993 or 0.9998. The detection limits of the method were from 0.06 MUg/kg to 0.30 MUg/kg, and limits of quantitation ranged from 0.20 MUg/kg to 1.0 MUg/kg. The recoveries of three spiking levels (1.0, 10.0 and 100.0 MUg/kg) ranged from 86.9% to 102.0%, and the relative standard deviations of 1.80%- 4.19% were obtained. CONCLUSION: The method for determination of 3-nitropropionic acid in poisoning samples by UPLC-MS/MS is of operation convenience, less interference from impurities and good accuracy, which could provide evidence and treatment for mouldy sugarcane poisoning. PMID- 26987198 TI - [Determination of streptomycin and dihydrostreptomycin residues in tomato ketchup by UPLC-MS/MS]. AB - OBJECTIVE: To develop a method for simultaneous determination of streptomycin and dihydrostreptomycin residues in tomato ketchup by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). METHODS: The sample was dissolved with phosphorus solution (pH 2) and extracted by ultrasonic. The pigment was removed with n-hexane. Then, the sample was cleaned up by HLB SPE. The HILIC chromatographic column (100 mm x 2.1 mm, 1.7 MUm) was used to complete the separation under gradient elution. The mixed solution of 0.1% formic acid solution and acetonitrile was used as mobile phase. The detection of streptomycin and dihydrostreptomycin were carried out by MS/MS under multiple reaction monitoring (MRM) mode. The external standard method was used for quantitative analysis. RESULTS: The calibration curves for streptomycin and dihydrostreptomycin were indicated in the range of 0.005 - 0.100 mg/kg, and the detection limits were both 0.005 mg/kg. The recoveries of streptomycin and dihydrostreptomycin were ranged from 79.5% to 93.9% with relative standard deviations no more than 10%. CONCLUSION: The method is simple and accurate to meet the requirements for determination of streptomycin and dihydrostreptomycin residues in tomato ketchup. PMID- 26987199 TI - [Determination of free selenomethionine in cow milk by UPLC-MS/MS]. AB - OBJECTIVE: To establish an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the quantification of free selenomethionine (SeMet), and be applied to the quantification of free SeMet in cow milk. METHODS: The analyte was separated on a BEH C18 column (2.1 mm x 100 mm, 1.7 MUm) at 40 degrees C with a mobile phase of water: acetonitrile: formic acid (95: 5: 0.1, V/V) , a flow rate of 0.3 mL/min, and an analysis time of 2. 5 min. At positive electrospray ionization mode, multiple reaction monitoring of the precursor product ion transitions of m/z 198.0 --> 181.1 was used for the quantification. RESULTS: The linear calibration curve was obtained in a concentration range of 0.5 - 100 ng/mL with a lower limit of quantification of 0.5 ng/mL. The value of intra- and inter-day accuracy for SeMet fell in the range of 97.6%-100.6% and 97.7%-99.2%, and value of intra- and inter-day precision 0.53%-4.49% and 1.03% 4.54%. CONCLUSION: The method is specific, sensitive, rapid, and accurate, suitable for the quantification of free SeMet in cow milk. PMID- 26987200 TI - [Determination of 41 pesticides in vegetables and fruits by GPC-GC-MS/MS]. AB - OBJECTIVE: A method for the determination of 41 pesticides including 26 organophosphorus pesticides, 6 kinds of carbamate, 7 pryethoids insecticides, 1 kinds of organochlorine and fungicide in vegetables and fruits, was established based on optimized QuEChERS with on line gel permeation chromatography-gas chromatography-mass spectrometry (GPC-GC-MS/MS). METHODS: The method obtained the optimized conditions by comparing different methods of extraction and purification. The analytes were extracted from the samples using acetonitrile buffer of acetic acid and sodium acetate. Then the extracts were determined by GC MS/MS in multireaction monitoring (MRM) mode after being cleaned up with mixed solid-phase dispersion. And the external standard method was applied to quantify. RESULTS: All the 41 pesticides had good linearity in the ranges of 2-200 ng/mL with the correlation coefficients higher than 0.995. The average recoveries of the most of 41 pesticides in celery and apple were in the range of 71.0%-125.4% at the spiked levels of 5, 10 and 50 MUg/kg,with relative standard deviations (RSDs) of 0.34%-15.0%. The limits of quantification (LOQs) of the method at the spiked levels of 5 MUg/kg were 0.107-10.100 MUg/kg. CONCLUSION: The method is simple, rapid, sensitive and specific. PMID- 26987201 TI - [Determination of 13 elements in food by microwave plasma-atomic emission spectrometry]. AB - OBJECTIVE: A novel method for quantitative analysis of multi-elements (Ca, Fe, K, Na, Cu, Mn, Zn, Mg, Ni, Sr, Cr, Cd and Co) in food was established by using microwave plasma-atomic emission spectrometry (MP-AES). METHODS: Samples were digested with HNO3 and H2O2 followed by dilution with ultrapure water to 25 mL (g), and then analyzed directly by MP-AES. RESULTS: In the optimal conditions, the linear calibration curve was established for each element, and the linear regression correlation coefficient was more than 0.9999. The limit of detection (LOD) of these multi-elements varied from 0.04 MUg/kg to 3.90 MUg/kg. The spiked recovery was between 89.8% and 110.4% . The relative standard deviation of precision measurement was between 1.33% and 3.85%. The accurate and reliable results were obtained for validation of the MP-AES method with food reference material according to the standard reference materials (Nist 1549, Nist 1567, Nist 1568 and Nist 1570) and national standard (GBW08501 and GBW10051), and the measured values were in good agreement with the certified values. CONCLUSION: The established method is accurate, simple, fast, reproducible and environmentally friendly. PMID- 26987202 TI - [Inhibition effect of aquaculture water of Salvinia natans (L.) All. on Microcystis aeruginosa PCC7806]. AB - OBJECTIVE: To study the inhibiting effect of aquaculture water of Salvinia natans (L.) All. on Microcystis aeruginosa and the mechanism. METHODS: Microcystis aeruginosa of 7.5 x 10(5) cells/mL was treated by the culture water of Salvinia natans density of 5%, 10%, 20% and 40%, respectively. The inhibition ratios were calculated, conductivity of algal cells, content of nucleic acid and protein in algae solution, influence of superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were measured. RESULTS: The inhibition rate of 40% treatment group up to 100% on the fourth day. The inhibition rate of 5% treatment group up to 65% on the 7th day. The conductivity of algae cell gone up while the concentration of cultured water was increasing, as well as its content of nucleic acid, protein and MDA. However, the activity of SOD rose at first and then fall down while the concentration of cultured water of Salvinia natans was increasing. CONCLUSION: The aquaculture water of Salvinia natans has a powerful inhibitory effect on Microcystis aeruginosa by changing the structure of algal cells and intracellular enzyme activity, etc. PMID- 26987205 TI - [Intravitreal Injection Therapy: the Past, Present and Future]. PMID- 26987204 TI - [Study on congenital cardiac anomalies induced by arsenic exposure before and during maternal pregnancy in fetal rats]. AB - OBJECTIVE: To investigate the effects of arsenic exposure before and during maternal pregnancy on heart development of fetal rats. METHODS: According to body weight, thirty-two female SD rats (30 to 40 days of age) were randomly divided into control group, low dose group, middle dose group and high dose group with 8 rats per group. They were allowed free access to drinking water with 0, 37.5, 75 and 150 mg/L of sodium arsenite (NaAsO2) for 6 weeks, respectively. Then all the female rats and adult male SD rats were caged together for mating. Once female rats were determined to be pregnant, they would continue to drink deionized distilled water containing different concentrations of sodium arsenite for another 2 weeks. On embryonic day 16, rats were sacrificed to harvest fetuses. Female rats' weight changes, abortions, absorbed fetus number, growth and development of fetal rats were observed. Hematoxylin-eosin staining of serial cardiac slices was performed in embryos to observe cardiac morphology and structure. Fur arsenic contents of female rats were determined with the method of atomic fluorescence spectrometry. RESULTS: Subchronic arsenic exposure caused slow weight growth in female rats. There were two cases of abortion in middle dose group and high dose group, respectively. Compared with these of control group, fetal and placental weight decreased (P < 0.05), and the incidence of fetal absorption increased (P < 0.05) in all arsenic-treated groups. Cardiac malformations in fetal rats including ventricular septal defect, atrial septal defect and tetralogy of Fallot were observed in low, middle and high dose group. The incidence of cardiac malformations increased with the increase of arsenic concentrations in drinking water. Compared with that of control group, the incidence of cardiac malformations remarkably increased in both middle and high dose groups (P < 0.05). Fur arsenic contents increased with the increase of arsenic concentrations in drinking water (P < 0.01). CONCLUSION: Arsenic exposure before and during maternal pregnancy could cause abnormal cardiac development in fetal rats, and increased the risk of congenital heart disease. PMID- 26987203 TI - [Study on the resveratrol and arsenic trioxide combination induced apoptosis and its mechanism on lung adenocarcinoma cells]. AB - OBJECTIVE: To explore the synergistically effects and mechanisms of resveratrol (RES) enhanced the oxidative stress and apoptotic cell death induced by As2O3 (arsenic trioxide). METHODS: According to the result of MTT assay, human lung adenocarcinoma A549 cells were divided into four treatment groups as follow: control group, single RES or As2O3 treated group and the group treated with RES and As2O3. Then the differences of cell viability, colony formation, level of ROS, GSH content, mitochondrial membrane potential and apoptosis rate were compared with single or combined treatment. In addition, pre-treatment with L buthionine sulfoximine (L-BSO), the inhibitory of GSH synthesis, was used to identify the role of GSH in synergistically apoptosis induced by RES and As2O3. RESULTS: The detected results demonstrated that RES could effectively inhibited the growth of A549 cells when its concentration above 20 MUmol/L, and inhibition effects was concentration dependent manner. The rate of colony formation, GSH content, mitochondrial membrane potential and apoptosis rate in combination group were significantly lower than that of single RES or As2O3 treatment group (P < 0.05), whereas, RES markedly increased the level of ROS, the expression of cytochrome c and caspase 3 induced by As2O3. When pre-treatment with BSO before RES and As2O3 combination incubation, beside the apoptosis rate was increased from 30.0% to 77.7%, the GSH content was sharply depleted while ROS massively accumulated in intracellular. CONCLUSION: RES could significantly intensified the effects of As2O3 in inhibiting the proliferation, depleting GSH content, ROS accumulation, mitochondrial membrane potential decline and cytochrome c releasing, thus leading to cells apoptosis via Cas-3 activation in a mitochondria dependent pathway. PMID- 26987206 TI - [Guidelines for Intravitreal Injection for Macular Diseases]. AB - The guidelines for intravitreal injections for macular diseases are listed. Indication and drug information, injection techniques, pre -and peri-injection management, and complications due to injections are stated. Safe intravitreal injections are expected as a result of following these guidelines. PMID- 26987207 TI - [Anti-vascular Endothelial Growth Factor Therapy on Exudative Age-related Macular Degeneration in Routine Clinical Practice of a Single Site: the Effectiveness of Cases Followed for More than Two Years]. AB - PURPOSE: To investigate the long-term effectiveness of as-needed anti-vascular endothelial growth factor therapy on age-related macular degeneration (AMD). SUBJECTS AND METHODS: The number of treatments, treatment period, visual acuity and morphological changes were investigated retrospectively in 257 eyes of 248 patients (189 men and 59 women, mean age +/- SD; 71.1 +/- 9.2 years old) who were followed up for two years and more. Re-treatment was mainly decided based on patient's will. RESULTS: The mean number of treatments was 6.4 3.8 in the observational period of 3.7 years. Exudative changes were resolved at least once in the observational period in 240 eyes, and 160 eyes had no exudative changes at the final visit. Type 2 neovascularization by Gass resulted in fibrotic scar more frequently than type 1. The mean decimal visual acuity was 0.36 before the initiation of treatment and 0.26 at the final visit. The treatment period was less than 100 days in 54 eyes, and multivariate analysis revealed that polypoidal choroidal vasculopathy (PCV) was a factor of prolonged treatment period. No severe adverse effects were admitted locally and systemically. CONCLUSIONS: The deterioration of mean visual acuity was assumed to be due to the relatively small number of treatments. Twenty-one percent of all eyes preserved well without any recurrence of treatments for short periods, and PCV needed treatments for longer periods than typical AMD. PMID- 26987208 TI - [Characteristics of Fifty Cases of Pituitary Tumors in Eyes Diagnosed with Glaucoma]. AB - PURPOSE: To determine the characteristics of 50 cases of pituitary tumor. METHODS: The medical records of 50 cases of pituitary tumor found in glaucoma patients treated between June 2013 and June 2014 were reviewed. RESULTS: There were 37 women and 13 men whose average age was 55.7 years with a range of 24 to 79 years. The glaucoma was unilateral in 19 and bilateral in 31. The pituitary tumors were classified as Rathke's Cleft Cyst (RCC) in 38 cases (76%), RCC with Cushing disease in 5 (10%), adenoma in 4 (8%), adenoma + growth hormone (GH) producing tumors in 2 (4%), and RCC with adenoma in 1 (2%). Of the 50 patients, 23 were treated by surgery (46%), 2 (4%) by hormone supplement therapy, 2 (4%) rejected therapy, and 23 (46%) were followed without treatment. The visual field defects corresponded with typical pituitary visual field defects in 26 (52%) cases, with that typical of unilateral glaucoma in 6 (23%), and with that typical of bilateral glaucoma in 20 (77%) cases. The major symptom was headaches in 24 (48%), headache with dizziness in 10 (20%), dizziness in only 8 (16%), and no complaints in 8 (16%). CONCLUSIONS: Fifty patients diagnosed with glaucoma had concurrent pituitary tumors. Special attention must be paid to glaucoma patients who complain of headaches with and without dizziness. PMID- 26987209 TI - [Evaluation of Iris Morphology Viewed through Stromal Edematous Corneas by Infrared Camera]. AB - BACKGROUND: We reported that the application of infrared camera enables us to observe iris morphology in Peters' anomaly through edematous corneas. PURPOSE: To observe the iris morphology in bullous keratopathy or failure grafts with an infrared camera. SUBJECTS AND METHODS: Eleven bullous keratopathy or failure grafts subjects (6 men and 5 women, mean age +/- SD; 72.7 +/- 13.0 years old) were enrolled in this study. The iris morphology was observed by applying visible light mode and near infrared light mode of infrared camera (MeibomPen). The detectability of pupil shapes, iris patterns and presence of iridectomy was evaluated. RESULTS: Infrared mode observation enabled us to detect the pupil shapes in 11 out of 11 cases, iris patterns in 3 out of 11 cases, and presence of iridetomy in 9 out of 11 cases although visible light mode observation could not detect any iris morphological changes. CONCLUSION: Applying infrared optics was valuable for observation of the iris morphology through stromal edematous corneas. PMID- 26987210 TI - [A Clinical Case Report Including In Vivo Laser Confocal Microscopic Findings of Keratitis Complicated with Takayasu's Arteritis]. AB - BACKGROUND: We present a clinical case report including in vivo laser confocal microscopic findings of keratitis complicated with Takayasu's arteritis (aortitis syndrome). CASE: A 47-year-old woman was referred to the outpatient clinic of ophthalmology with blurred vision in her both eyes at the onset of Takayasu's arteritis. Since multifocal infiltrates in the stromal corneas with injection were observed with slit-lamp biomicroscope in the both eyes, the diagnosis was keratitis. A large amount of cells infiltrating the stromal cornea and activated keratocytes were also observed with in vivo laser confocal microscope in the both eyes. Systemic and local steroidal agents were initiated, which resolved the keratitis, and the active lesions turned into mild corneal scars. In vivo laser confocal microscopy showed no infiltrating cells in the stromal cornea of both eyes. No recurrence has been observed since. CONCLUSION : A rare case of keratitis complicated with Takayasu's arteritis is reported. An immune response to the stromal cornea as the etiology of the keratitis may be indicated by in vivo laser confocal microscopy. PMID- 26987211 TI - [INTERACTION OF PRO- AND EUKARYOTES AND THE PROBLEMS OF TISSUE BIOLOGY]. AB - The article considers the interaction of pro- and eukaryotes from the standpoint of tissue biology. Examples of long-term persistence of prokaryotes in eukaryotic cells are presented. Morpho-functional characteristics of the interactions of pro and eukaryotic cells are given, including their ultrastructural relationship. It is shown that the symbiosis between unrelated organisms is a reflection of their adaptation to the use of trophic resources of the environment. One of the implications of endocytobiosis of non-pathogenic bacteria in eukaryotic cells is to increase the biodiversity. The concept of multicellular eukaryotic organisms as complex cell and tissue systems of symbiotic interactions of pro- and eukaryotic cells, is discussed. PMID- 26987212 TI - [CHANGES OF THE CEREBRAL CORTEX AFTER DOSED TRAUMATIC BRAIN INJURY IN RATS OF DIFFERENT AGES]. AB - Using dosed lateral fluid percussion, moderate and severe traumatic brain injury (TBI) was modeled in one- and two-year-old rats. Brain sections were stained using the Nissl cresyl violet method and an immunohistochemical reaction was performed for the demonstration of glial fibrillary acidic protein (GFAP), a marker of astrocytes. The results obtained indicate the formation in the cerebral cortex, ipsilateral to the impact, the zones of direct and remote of injury. The zone of direct injury corresponded to the area of immediate contact of the liquid column with the dura mater, whereas the remote area of damage was located laterally and caudally to the former. Morphological signs of the injury depended on the force of impact and were manifested in both age groups by astrocytic gliosis and the thinning of layer I of the cortex resulting from neuronal death. The emergence of ischemia-modified neurons, probably, was due to a local disruption of the blood supply. Disorders in the brain in one-year-old rats had a local character and those in two-year-old rats were diffuse, while gliosis was inhomogeneous. The reproducibility and adequacy of the model allow its use for research of molecular-genetic mechanisms of TBI outcomes in humans, as well as for the identification of common mechanisms of TBI consequences and the pathogenesis of the major diseases, comorbid with TBI, primarily depression and epilepsy. PMID- 26987213 TI - [CHANGE IN BCL-2 PROTEIN EXPRESSION IN NEURONS OF THE HIPPOCAMPAL AREAS AFTER THE APPLICATION OF ISCHEMIC CEREBRAL POSTCONDITIONING]. AB - Bcl-2 protein expression was studied in hippocampal CA1, CA2, CA3 and CA4 pyramidal neurons in Mongolian gerbils (Meriones unguiculatus), of the in in the early (Day 2) and late (Day 7) reperfusion period after a 7-minute forebrain ischemia and following ischemic postconditioning (IPostC), as well as in sham operated animals (n=60). In the latter, the highest level, of Bcl-2-expression was found in CA4 neurons, while the lowest--in-CA1 neurons (P<0.01). Reversible ischemic brain damage led to the increasing deficit of morphologically unchanged hippocampal neurons with the increasing duration of reperfusion period. This was accompanied by a significant decrease in expression of Bcl-2 in the early reperfusion period, but in the late reperfu- sion period this decrease largely disappeared. IPostC, applied as three episodes of ischemia-reperfusion lasting 15/15 seconds, contributed to significant increase in the number of morphologically unchanged CA1 and CA3 neurons in the early reperfusion period, while the expression of Bel-2 was increased in morphologically unchanged neurons in all the hippocampal areas. In the late reperfusion period after IPostC, the number of unchanged neurons was increased in hippocampal areas CA1, CA3 and CA4 (P<0.05), while a significant increase in Bcl-2 expression (by 12.7%, P<0.01) was detected only in CA1 neurons. The results suggest that the cytoprotective effect of IPostC in hippocampal CA1 area is realized through a mechanism leading to increased expression of Bcl-2 protein, i.e., by blocking apoptosis. PMID- 26987214 TI - [DISTRIBUTION OF THE MARINESCO BODIES IN THE NEURONS OF HUMAN BRAIN SUBSTANTIA NIGRA]. AB - The aim of the study was to investigate the occurrence and intranuclear distribution of Marinesco bodies in substantia nigra neurons of the human brain. Marinesco bodies were identified in substantia nigra sections of 5 men aged 28 to 58 years old using Nissl staining and immunohistochemical detection of ubiquitin- the protein characteristic of this intranuclear inclusion. Marinesco bodies were found in 1-2% of the substantia nigra neurons, but not in adjacent brain areas. One neuron contained 1-4 Marinesco bodies sized up to 6.7x5.1 microm, which were located both near and at a distance from the nucleolus. Most Marinesco bodies exhibited ubiquitin expression. A trend was found for the increased incidence of Marinesco bodies in human substantia nigra neurons with age. PMID- 26987215 TI - [PLASTIC REORGANIZATION OF THE ULTRASTRUCTURE OF SYNAPSES IN THE CEREBELLUM DUE TO TOXIC EFFECTS OF GLUTAMATE AND NO-GENERATING COMPOUND]. AB - Ultrastructural changes in synapses between parallel fibers (PF) and the spines of Purkinje cell dendrites (PCD) in frog cerebellum were studied after exposure to high concentrations (1 mM) of glutamate (Glu) and NO-generating compound in experimental model. It was shown that exposure to Glu resulted in the envelopment of the terminal bouton by the spine, while under the influence of NO-generating compound, on the contrary, the spine was surrounded by the bouton. Morphological study has shown that in Glu solution there was the predominance of synapses in which the glial cells surrounded the spines, while in the presence of NO they covered the boutons. After the electrical stimulation of PF, the relative number of synapses, containing the boutons surrounded by glial cells, was 10 times higher as compared to those in which the glial cells surrounded the spines. The observed morphological changes reflect the functional state of synapses between PF and PCD in response to the damaging effects of excess Glu and NO, that is expressed in different forms of synaptic contacts and neuronglial structures. PMID- 26987216 TI - [EXPRESSION OF SEROTONIN TRANSPORTER IN THE VENTROLATERAL PART OF THE NUCLEUS OF THE SOLITARY TRACT IN RATS IN THE EARLY POSTNATAL PERIOD IN NORM AND FOLLOWING SEROTONERGIC SYSTEM DEFICIENCY IN THE PRENATAL PERIOD OF DEVELOPMENT]. AB - The expression of serotonin transporter (5-HTT) was examined using the immunocytochemical method in the ventrolateral part of the nucleus of the solitary tract in Wistar rats in the early postnatal period (Days 5 and 10) in norm (n=10) and after prenatal serotonin deficiency (n=12). Temporary expression of the 5-HTT was demonstrated during the early postnatal period in the ventrolateral division of the nucleus of the solitary tract, that was more pronounced in the most caudal part of the ventral submucleus. It was shown that in the rostral part of ventral and lateral subnuclei, the number of neurons synthesizing 5-HTT was low and remained unchanged with age. In the caudal region of the ventral subnucleus, a large number of neurons synthesizing 5-HTT was found on Day 5 of postnatal period, that was significantly reduced with age. In the caudal region of the lateral subnucleus, a small number of neurons expressing 5 HTT was detected, that also decreased with age. It was found that in the caudal region of both ventral and lateral subnuclei, the level of 5-HTT expression was significantly higher than in the rostral region. Prenatal deficiency of serotonin resulted in a reduction of the number of neurons synthesizing 5-NTT in all the subnuclei investigated. PMID- 26987217 TI - [CHANGES OF THE SUPERFICIAL PERONEAL NERVE IN RELATION TO THE FREQUENCY OF HIGH FRACTIONAL AUTODISTRACTION IN ORTHOPEDIC LENGTHENING OF THE TIBIA IN DOGS WITH A DAILY RATE OF 3 mm]. AB - The experiments on the elongation of the tibia in 18 dogs were performed for 10 days using the Ilizarov apparatus with an automatic drive providing the pace of 3 mm/day for 120 moves (group 1) and 180 moves (group 2). The impact of fractionation of distraction on the structure of the peroneal nerve was estimated. In group 1, perineurium micro-injuries and endoneural blood vessel destruction were detected. In group 2, perineurium preserved its integrity and fine-lamellar structure, endoneural blood vessels were also preserved, however, the decrease in the total area of nerve fiber bundles was more pronounced. Morphometric analysis of the preserved myelinated nerve fibers 60 days after the cessation of distraction indicated less marked axonal atrophy and better myelination in group 2. PMID- 26987218 TI - [MORPHOLOGICAL CHANGES AFTER THE USE OF MULTIPOTENT STROMAL CELLS OF BONE MARROW ORIGIN TO RESTORE THE LYMPH FLOW IN THE REGION OF THROMBOSED VEIN]. AB - In the male Wag rats aged 6 months with the body mass of 180-200 g the luminescent microscopy was used to examine the possibility of lymphatic vessel formation after injection into thrombosed vein of the thigh of autologous multipotent stromal cells of bone marrow origin (AMSCBMO) transfected with green fluorescent protein gene. Animals were sacrificed 4 days and 1, 2, 3, 4 and 5 weeks after the injection of AMSCBMO. The control group consisted of intact rats, animals with venous thrombosis receiving no injection of AMSCBMO and those injected with AMSCBMO but without the prior modelling of venous thrombosis. In each experimental and control groups at each time point 11-12 animals were used (total number equal to 226). After the main vein ligation with the subsequent injection of thrombin solution, in addition to the thrombosis of the blood vessels, morphological signs of thrombosis of the lymphatic bed and lymphostasis were present: the dilation of lymphatic vessel lumen, thinning of their layers, intense staining of their luminal heterogeneous content. AMSCBMO, injected into thrombosed vein, were found to directly participate in lymphangiogenesis in the connective tissue around vein, its tissue region and in the area of regional lymph nodes. This is indicated by bright specific luminescence of both individual cells in the wall of the lymphatic vessels, and all their tunics together with the valves, when exposed to UV light. PMID- 26987219 TI - [STRUCTURAL TRANSFORMATION OF CRANIAL CAVAL VEINS IN POSTNATAL ONTOGENESIS (A MORPHOMETRIC STUDY)]. AB - The peculiarities of structural transformations of different portions of the cranial caval veins were studied in 60 rats at Days 1-30 after birth. The alternating periods of rapid and slow increase in the length of the cranial caval veins were identified. Wall thickness in all the parts of the right cranial caval vein increased less significantly as compared with its length during the early period after birth (Days 1-11). At Days 16-30, the rate of growth of the length was reduced, while the vessel wall thickness increased. This regularity was not observed in the development of the left cranial caval vein. Instead, this vessel demonstrated alternating periods of accelerated and decelerated growth of the wall thickness. PMID- 26987220 TI - [CHARACTERIZATION OF THE CELLULAR COMPOSITION OF THE MUCOSAL LAMINA PROPRIA OF THE JEJUNUM IN MICE SUBJECTED TO THE CONDITIONS SIMULATING LONG-DURATION SPACEFLIGHT]. AB - The cellular composition of the lamina propria of the mucous membrane of the jejunum was examined in the villi (LPV) and between the crypts (LPC). Two groups of male C57/BL6 mice aged 4-5 months were studied. Experimental group of animals (n=8) for 30 days was living under the terrestrial conditions in "BIOS-SLA" blocks and received a paste-like food made with standard feed containing water and casein. The control group of animals (n=6) were kept in standard vivarium conditions and received standard dry pellets. Studies have shown no significant changes in the content of lymphocytes in LPV and LPC in a terrestrial experiment. LPV was characterized by a sharp reduction in the number of plasma cells. In both LPV and LPC the number of eosinophils was increased, while the content of low differentiated forms of cells (blasts and large lymphocytes) was decreased. It is suggested that the changes in the contents of different cell types in ground based experiment were due not only to the limited mobility of the animals but also to different composition of the feed. PMID- 26987221 TI - [THE PROCESSES OF CELL PROLIFERATION, APOPTOSIS AND ANGIOGENESIS IN PATHOLOGICALLY UNCHANGED LUNG AND IN NON-SMALL CELL LUNG CANCER]. AB - The objective of this study was to examine cell proliferation, apoptosis and angiogenesis in pathologically unchanged lung and in non-small cell lung cancer with the use of appropriate markers. The material studied included samples of pathologically unchanged lung (n=80) and those obtained at operations in 237 cases of non-small cell lung cancer. Immunohistochemical methods were used to demonstrate Ki-67, topoisomerase IIalpha (TopoIIalpha), p53, bcl-2, bax, CD34 and podoplanin. Argyrophilic proteins associated with nucleolar organizer regions (Ag NOR proteins), were detected by impregnation with silver nitrate. The quantitative data were obtained and the peculiarities of the expression of markers associated with proliferation, apoptosis and angiogenesis in pathologically unchanged lung were determined. In the alveoli, the labeling index of Ki-67 and Topolla was less than 1%, AgNOR area index was equal to 1.31 +/- 0.20; p53, bcl-2, bax expression was absent, density of blood vessels was equal to 86 (73-102), while lymphatic vessels were absent. In the bronchus, the labeling index of Ki-67 and TopoIIalpha were respectively 4 (1-8) and less than 1%, AgNOR area index--1.85 +/- 0.24, bax expression--100%, density of blood and lymph vessels--22 (17-31) and 4 (2-7) respectively; p53 and bcl-2 expression were absent. The results were compared with the expression of markers in non-small cell lung cancer. This comparison has fundamental and differential diagnostic value in the study of histopathological lung material. The expression of markers associated with proliferation, apoptosis and angiogenesis changes from pathologically unchanged lung to non-small cell lung cancer. PMID- 26987222 TI - [CHANGES IN THE FOLLICULAR APPARATUS AND BLOOD VESSELS OF THE OVARIES IN RATS INDUCED BY MELATONIN UNDER CONDITIONS OF HYPERTHERMIA]. AB - The study was conducted on 155 female Wistar rats (aged 3 months, body mass--180 200 g), in diestrus phase of the sexual cycle. The effect of the pineal hormone melatonin (MT) on morphological organization of the follicular apparatus and the vasculature of the ovaries was studied in rats after overheating achieving a rectal temperature of 43.5 degrees C. It was found that hyperthermic exposure lead to an increase of the relative areas of the arteries, veins and lymph vessels of the ovaries. Overheating caused disturbances of folliculogenesis. The injection of MT after exposure to hyperthermia resulted in a quick (already on Day 7 after exposure) recovery of the disturbances of the venous circulation and lymphatic drainage of the ovary, as evidenced by the normalization of the relative sizes of arteries, veins and lymphatic vessels of the ovary, reaching control values. This, in turn, contributed to the reduction of morphological disorders of folliculogenesis and created the conditions for accelerated recovery of the relative area of generative elements of the ovary (at the stages of primary, preovulatory and atretic follicles) as early as 7 days after hyperthermia. PMID- 26987224 TI - [MORPHOMETRIC PARAMETERS OF PALATO-ALVEOLAR COMPLEX IN ADULTS WITH DIFFERENT FORMS OF CEREBRAL AND FACIAL SKULL]. AB - Morphometric characteristics of a palato-alveolar complex were studied in the skulls of 150 adult individuals with various shapes of a facial and cerebral skull. No statistically significant differences in the parameters of a palato alveolar complex were established between the groups systematized by the value of their transverse-longitudinal index of the brain skull. However, the significant differences were found between the groups of skulls, selected by the value of upper facial index. Thus, the width of the palate at the level of canines, premolars and molars, the width of the alveolar arc at the same levels and the distances between greater palatine foramena were significantly higher in the group of euriprosops. Using Pearson linear correlation, a positive correlation of various degrees was shown between the parameters of a cerebral and facial skull and the sizes of a palato-alveolar complex. The dependence between the shape of the facial skull and the form of a palato-alveolar complex was also noted. Parameters characterizing the position of greater palatine foramen relative to other anatomical structures were found to have low variability. PMID- 26987223 TI - [EMBRYONIC SOURCES OF "RESERVE CELLS" DEVELOPMENT IN THE EPITHELIAL LINING OF THE CERVIX]. AB - Using general histological and immunohistochemical methods, the sources of "reserve cells" of the epithelial lining of the uterus and vagina were studied on the material obtained from human embryos and fetuses. From 13th to 20th week of fetal development, the epithelial lining of the cervix was formed with the participation of the urogenital sinus (UGS). The cells of the latter interacted with the coelomic epithelial cells of the paramesonephric ducts (PMD). After 25th week, UGS cells were dispersed along the length of the cervix, lying on the basement membrane beneath the columnar epithelial cells. It is suggested that epitheliocytes of UGS are the source of the "reserve cells". Taking into account the tissue nature of the "reserve cell" it is expedient to determine them as mesonephroblasts. Cells are present in the cervical epithelium as a concomitant determined cellular differon. PMID- 26987225 TI - [CYTOPLASMIC LOCALIZATION OF NEUN/Fox-3 NUCLEAR PROTEIN IN THE PANCREATIC CELLS]. AB - The study of the sections of Wistar rat pancreas (n=4) using the methods of immunocytochemistry and confocal laser microscopy has demonstrated previously unknown fact of the presence of NeuN protein in the secretory epithelial cells of the exocrine part of this organ. The protein was located in the apical part of the cytoplasm slightly below the zone of zymogen granules. Until now the nuclear protein NeuN was considered to be the panneuronal differentiation marker and was used in the studies of neurogenesis. PMID- 26987226 TI - [STUDYING THE ROLE OF BRAIN MELANOCORTIN RECEPTORS IN THE SUPPRESSING OF FOOD INTAKE UNDER ETHER STRESS IN MICE]. AB - Melanocortin (MC) system regulates food intake under the rest conditions. Stress inhibits food intake. It is not clear whether brain MC system is involved in stress-induced anorexia in mice. The aim of the work was to investigate the effect of pharmacological blockade and activation of brain MC receptors on food intake under stress. C57B1/6J male mice were subjected to ether stress (0.5 minute ether anesthesia) before the administration of saline solution or synthetic non-selective blocker (SHU9119) or agonist (Melanotan II) of MC receptors into the lateral brain ventricle. Food intake was pre-stimulated with 17 hours of fasting in all mice. Ether stress decreased food intake, increased the plasma corticosterone level and hypothalamic mRNA AgRP (natural MC receptor antagonist) level at 1 hour after the stress. Pharmacological blockade of the MC receptors weakened stress-induced anorexia and decreased mRNA AgRP level in the hypothalamus. Pharmacological stimulation of the MC receptors enhanced ether stress-induced anorexia and hypercortisolism. Thus, our data demonstrated that the central MC system was involved in the development of stress-induced anorexia in mice. PMID- 26987227 TI - [STRESS-INDUCED PATTERNS OF THE HYPOTHALAMIC CRH AND VASOPRESSIN EXPRESSION IN FEMALE RATS IN A MODEL OF POSTTRAUMATIC STRESS DISORDER]. AB - The neuroendocrine mechanisms underlying anxiety-like state development in cycling female rats with different plasma estradiol levels have been studied in a stress-restress paradigm, an animal model of posttraumatic stress disorder (PTSD). The effect of stress-restress on the hypothalamic expression of corticotropin-releasing hormone (CRH) and vasopressin was analyzed by quantitative immunocytochemistry. Stress-restress was found to increase CRH expression in the hypothalamic paraventricular nucleus (PVN) on the 10th post restress day, but the level of CRH expression in the PVN restored to the basal values on the 30th post-restress day in all experimental groups. It was shown an increase in vasopressin immunoreactivity in the PVN from the 10th to the 30th post-restress days in female rats exposed to stress during the estrus phase (low plasma estradiol level). In summary, female rats with low plasma estradiol level exhibited the most significant changes in the hypothalamic neuroendocrine system following stress-restress exposure. It might be hypothesized that hyperactivity of the hypothalamic circuit of the central vasopressinergic system is one of the possible mechanisms underlying PTSD-like state development in female rats in a stress-restress paradigm. PMID- 26987228 TI - [OPEN FIELD BEHAVIOR AS A PREDICTIVE CRITERIA REFLECTING RATS CORTICOSTERONELEVEL BEFORE AND AFTER STRESS]. AB - In the presented study we investigated the possibility to use the open field behavior data for prediction of corticosterone level in rat blood plasma before and after stress. It is shown that the most reliable open field behavior parameters, reflecting high probability of significant upregulation of corticosterone after 3 hours of immobilization, are the short latency of first movement and low locomotor activity during the test. Rats with high corticosterone at normal non-stress conditions are characterized by low locomotor activity and on the contrary long latency period for the entrance of open field center. PMID- 26987229 TI - [PARTICIPATION OF NO-ERGIC MECHANISMS IN REALIZATION OF RESPIRATORY EFFECTS OF PRO-INFLAMMATORY CYTOKINE INTERLEUKIN-1-BETA]. AB - The role of NO-ergic mechanisms in the realization of the respiratory effects of pro-inflammatory cytokine IL-1beta was investigated in acute experiments on anesthetized rats. To achieve this, we studied the effect of intravenous administration of IL-1beta during inhibition of NO-synthase by N-nitro-L-arginine methyl ester (L-NAME, a non-specific blocker of NO-synthase) on the parameters of breathing and the Hering-Breuer inspiratory-inhibitory reflex. It was shown that the effect of L-NAME eliminates the IL-1beta-dependent increase of the Hering Breuer reflex, whereas effects on breathing pattern does not change: the increase in IL-1beta system-level evokes an increase in respiratory rate, tidal volume and lung ventilation. It is assumed that one of the mechanisms of enhance in the strength inspiratory-inhibitory reflex by increasing circulatory IL-1beta level is the increased glutamate-ergic transmission on pump-neurons induced by increase in nitric oxide synthesis in cerebrovascular endothelial cells. In conclusion, NO ergic mechanisms participate in the modulation of the vagal respiratory reflexes during the development of the acute phase of systemic inflammation. PMID- 26987230 TI - [MECHANISMS OF THE PULMONARY CIRCULATORY CHANGES FOLLOWING EXPERIMENTAL PULMONARY THROMBOEMBOLISM]. AB - In acute experiments the pulmonary hemodynamics changes following pulmonary embolism were studied in rabbits with intact circulation and isolated lungs perfusion. In both cases the pulmonary vascular resistance increased to the same extent. The pulmonary artery pressure following pulmonary embolism in intact animals increased less, than in the case of isolated lungs perfusion, because the pulmonary artery flow decreased. The experiments with the restriction of the inferior vena cava flow have revealed that pulmonary artery pressure and flow decreased, where the pulmonary artery flow was reduced in the same level as following pulmonary embolism. At the same time the pulmonary vascular resistance was increased in two times less, than following pulmonary thrombosis. Thus we concluded, that following pulmonary embolism the pulmonary artery pressure is dependent on the pulmonary artery flow and pulmonary vascular resistance. The pulmonary artery flow changes are caused by the venous return and right ventricular contractility changes and not correlated with the pulmonary vascular resistance alterations. PMID- 26987231 TI - [MODIFICATION OF ALVEOLAR MACROPHAGE POOL UNDER INFLUENCE OF PEPTIDE THERAPY IN THE BLEOMYCIN PNEUMOFIBROSIS MODEL]. AB - Effect of peptide therapy on morphological and functional characteristics of alveolar macrophages and role of their phenotypic reprogramming in modulation of pulmonary fibrosing process were evaluated on the rat's model of pulmonary fibrosis, initiated by intratracheal administration of bleomycin. Status of alveolar macrophages was evaluated on the basis of electron microscopic studies and phagocytic activity. In lung tissue of control animals widespread diffuse interstitial fibrosis was determined. Alveolar macrophage cytoplasm was filled geterophagosomes with surfactant fragments, lipid droplets and cholesterol crystals; foam cells were a third of macrophage pool. After the course of peptide therapy the young cell with rare geterophagosomes and lipid droplets, without cholesterol crystals and increased phagocytic activity prevailed in macrophage population. There were rare sites of fibrosis in lungs; connective tissue contained much less collagen fibers than in the control; there was a growing proliferation of the bronchial epithelium. It may be assumed that under the influence of the peptide therapy a certain balance in the alveolar macrophage population was established with a predominance of M2 phenotype for the formation of the optimal ratio of cellular and humoral immune response, providing effective remedy of bronchial epithelium and prevention of lung tissue remodeling with the interstitial fibrosis formation. PMID- 26987233 TI - [EFFECT OF HYPOXIA ON THE CHARACTERISTICS OF HUMAN AUDITORY PERCEPTION]. AB - The effect of normobaric hypoxic hypoxia (single and interval training) on the characteristics of human hearing was investigated. The hearing thresholds (tonal audiograms), reaction time of subjects in psychophysical experiments (pause detection, perception of rhythm and target words), and short-term auditory memory were measured before and after hypoxia. The obtained data revealed improvement of the auditory sensitivity and characteristics of working memory, and increasing of response speed. It was demonstrated that interval hypoxic training had positive effect on the processes of auditory perception. PMID- 26987232 TI - NON-VERBAL BEHAVIOR OF 6- AND 12-MONTH OLD INFANTS HAVING THE NEUROLOGICAL PROBLEMS FROM THE BIRTH: A PILOT STUDY. AB - Ethological approach was applied to compare a non-verbal behavior of the 6- and 12-month old infants having neurological diagnosis by the birth (P 91.8 according to ICD-10 scale; risk infants) with the behavior of their healthy (norm infants) peers. The double-blind controlled uninterrupted observation of 1- and 2-minute videos was done to estimate duration and sequence of behavioral elements manifested by infants in familiar home environment during everyday activity. We suggested that if the specific behavioral differences exist it would be considered as predictive markers of infant's development problems. Ethological analysis indicated that the main behavioral differences were related with infant's eye and hand activities. The risk infants of the both age distracted from an object in their hands "looking aside" more often than their healthy peers. The 12-month old risk infants displayed less communicative and explorative abilities than their norm peers. It was proposed that the short-term observations of nonverbal behavior would be useful like an addition to a diagnostic scale to estimate briefly an infant's cognitive condition. PMID- 26987234 TI - [ACTIVE AND PASSIVE DISCRIMINATION OF MOVING SOUNDS: RHYTHMIC ACTIVITY OF HUMAN BRAIN]. AB - The spectral dynamics of the EEG rhythmicity during active and passive discrimination of stationary and moving sound stimuli presented according to the oddball paradigm were investigated. Standard stimuli represented stationary midline sounds. Deviant stimuli simulated smooth and stepwise sound source motion (to the left/right from head midline) produced by linear and stepwise changes of interaural time delay. Significant changes of the brain oscillations were found in the frequency range of 3-30 Hz. The dynamics of the moving deviant stimuli (smooth vs. stepwise) had greater impact on theta-rhythm power in active listening conditions: a stronger theta-power increase was evoked by the stepwise sound motion as compared to smooth motion. Significant increase in theta-power was also observed with rightward sound displacement as compared to leftward displacements. Active deviant discrimination reduced alpha-power (8-11 Hz) mostly during smooth deviant motion. The power increase of lower alpha-oscillations (12 15 Hz) was stronger with step- wise motion than with smooth motion of deviants. The interhemispheric asymmetry of beta-power decrease in active conditions (as compared to passive) was found in the whole beta-range. The sup- pression of beta power was stronger at the right hemisphere than at the midline or left hemisphere and showed no dependence on spatial properties of the deviant stimuli. This asymmetry may be related to selective attention to task-relevant sounds and with preparation to motor response. Generally, active auditory discrimination resulted in stronger deviant-related changes of the wide-ranged EEG spectral power than passive discrimination with attentional tuning to task-irrelevant stimuli. PMID- 26987235 TI - UNANSWERED QUESTIONS IN THE TRANSCRANIAL MAGNETIC STIMULATION TREATMENT OF PATIENTS WITH DEPRESSION. AB - According to the WHO fact sheet depression is a common mental disorder affecting 350 million people of all ages worldwide. Transcranial Magnetic Stimulation (TMS) is a technique which allows the investigator to stimulate and study cortical functions in healthy subjects and patients suffering from various mental and neurological disorders. In the early 1990s, studies revealed that it is possible to evoke long term mood changes in healthy volunteers by rapid rate repetitive, TMS (rTMS) over the frontal cortex. Subsequent studies involving depressed patients found frontal cortical rTMS administered daily to be clinically effective. In the past two decades, numerous trials examined the therapeutic potential of rTMS application in the treatment of mood disorders with constantly evolving treatment protocols. The aim of this paper is to review the literature of the past two decades, focusing on trials addressing the efficacy and safety of rTMS in depressed patients. Our primary goal is to evaluate the results in order to direct future studies which may help investigators in the development of treatment protocols suitable in hospital settings. The time is not far when TMS devices will be used routinely by practitioners primarily for therapeutic purpose rather than clinical research. To our knowledge, a widely accepted "gold standard" that would offer the highest efficacy, with the best tolerability has not been established yet. In order to approach this goal, the most important factors to be addressed by further studies are: localization, frequency, intensity, concurrent medication, maintenance treatments, number of pulses, trains, unilateral, or bilateral mode of application. PMID- 26987236 TI - [EVENT-RELATED POTENTIALS AND CLINICAL SYMPTOMS IN SCHIZOPHRENIA]. AB - The investigation of schizophrenia's aetiology and pathomechanism is of high importance in neurosciences. In the recent decades, analyzing event-related potentials have proven to be useful to reveal the neuropsychological dysfunctions in schizophrenia. Even the very early stages of auditory stimulus processing are impaired in this disorder; this might contribute to the experience of auditory hallucinations. The present review summarizes the recent literature on the relationship between auditory hallucinations and event-related potentials. Due to the dysfunction of early auditory sensory processing, patients with schizophrenia are not able to locate the source of stimuli and to allocate their attention appropriately. These deficits might lead to auditory hallucinations and problems with daily functioning. Studies involving high risk groups may provide tools for screening and early interventions; thus improving the prognosis of schizophrenia. PMID- 26987237 TI - LONG TERM FOLLOW-UP OF LESIONAL AND NON-LESIONAL PATIENTS WITH ELECTRICAL STATUS EPILEPTICUS IN SLOW WAVE SLEEP. AB - OBJECTIVES: A retrospective study has been done at the Bethesda Children's Hospital Epilepsy Center with those patients whose EEG records fulfilled in one or more records the criteria of electrical status epilepticus in slow wave sleep (ESES) pattern, occupying at least 75% of NREM sleep with bilateral discharges, and had detailed disease history and long term follow-up data, between 2000 and 2012. PATIENTS AND METHODS--Thirty-three patients (mean 11.1 +/- 4.2 years of age) were studied by 171 sleep EEG records. Sleep was recorded after sleep deprivation or during spontaneous sleep at least for one hour length of NREM. From the 492 EEGs, 171 sleep records were performed (average five/patient). Average follow-up time was 7.5 years. Eighty-two ESES records have been analyzed in 15 non-lesional and 18 lesional (11 with dysgenetic and seven with perinatal asphyxic or vascular origin) patients. Variability of seizure types, seizure frequency and frequency of status epilepticus was higher in the lesional group. Impairment of the cognitive functions was moderate and partial in the non lesional, while severely damaged in the lesional group. RESULTS: EEG records of 29 patients shawed unihemispherial spike fields with a perpendicular axis (in anterior, medial and posterior variants) to the Sylvian fissure, regardless their lesional or non-lesional origin. Only three (lone nonlesional and two lesional) patients had bilateral synchronous spike-wave discharges with bilateral symmetric frontocentral spike fields. The individual discharges of the sleep EEG pattern were very similar to the awake interictal records except their extension in time and field, their increased number, amplitude, and continuity of them and furthermore in the increased trans-hemispheral propagation and their synchronity. CONCLUSIONS: Assumed circuits involved in the pathomechanism of discharges during NREM sleep in ESES are discussed based on our findings. PMID- 26987238 TI - INTERNET AND STROKE AWARENESS IN THE YOUNG HUNGARIAN POPULATION. AB - BACKGROUND: Although stroke mortality rate in Hungary has tapered off over the last years, it is still twice the European average. This statistic is alarming and a coordinated response is needed to deal with this situation when considering new ways of communication. There are currently more than 300 websites in Hungarian related to stroke prevention, acute stroke treatment, recovery and rehabilitation. AIMS AND/OR HYPOTHESIS: We sought to identify base level of stroke knowledge of the Hungarian students and the efficiency with which the knowledge disseminated by internet is actually utilized. METHODS: We surveyed 321 high-school and university students to determine their ability to extract specific information regarding stroke from Hungarian websites. The base level of knowledge was established by asking 15 structured, close-ended questions. After completing the questionnaire, students were asked to search individually on stroke in the internet where all the correct answers were available. After a 25 min search session they answered the same questionnaire. We recorded and analyzed all their internet activity during the search period. RESULTS: The students displayed a fair knowledge on the basics of stroke but their results did not change significantly after the 25-min search (53 +/- 13% vs. 63 +/- 14%). Only correct information given on demographic facts improved significantly. Most of the students used very simple search strategies and engines and only the first 5 10 web-pages were visited. CONCLUSION: Analysis of the most often visited web pages revealed that although stroke-related Hungarian web-based resources contain almost all the important and required information the unsuitable structure, lack of simplicity and verbosity hinder their effective public utilization. PMID- 26987239 TI - [FINANCING OF MEDICINES FOR TREATMENT OF RARE DISEASES OF THE NERVOUS SYSTEM. ORPHAN DRUGS IN RARE NEUROLOGICAL DISEASES]. AB - OBJECTIVES: Nervous system involvement is expected up to 60-70% in case of rare diseases. This article aims to present the financial methods and expenditures of rare neurological diseases' orphan medicinal products being financed in the frame of Hungarian social insurance system in 2012. METHODS: The subsidized orphan medicines were selected on the Orphanet portal 2012 while orphans financed by compessionate use were provided by the Hungarian National Insurance Fund Administration (OEP) database. Three products exist without orphan designation, however those are intended for the treatment of rare neurological ailments. The medicines were categorized by financial methods and determined by costs. RESULTS: Numerically, out of 36 pieces of subsidized orphan or orphan criteria fulfilled medicines 17 were authorized for the treatments of rare neurological diseases in the year of 2012. Most of the drugs (14 pieces) were to be financed in the frame of compassionate use by the reimbursement system. The cost amount of social insurance for 387 rare neurological disease patients reached more than 4.5 billion HUF (1.4% of the total pharmaceutical budget in outpatient care). CONCLUSIONS: In Hungary half of the subsidized orphans are intended for the treatments of rare neurological ailments. 30% of the total amount of social insurance for rare diseases' medicinal treatments were used to subsidizing rare neurological disease patients in 2012. Most of the orphan medicines were to be financed in the frame of compassionate use by the reimbursement system for outpatient care. Consequently, a great deal of crucial problems occurred in relation with the unconventional subsidizing method. At the end of 2012 new financial methods have been elaborated and introduced in a pilot phase from 1 January 2013. In spite of the high cost commitment, nearly the entire diagnosed rare disease subpopulation has been provided with subsidized treatments in Hungary. In order to facilitate the access to orphan drugs, collaboration is needed between the financing agencies and the professional representatives for identifying the optimal form of financial subsidy. PMID- 26987240 TI - COMPARISON OF HOSPITALIZED ACUTE STROKE PATIENTS' CHARACTERISTICS USING TWO LARGE CENTRAL-EASTERN EUROPEAN DATABASES. AB - OBJECTIVES: Stroke is the third leading cause of death in the European region. In spite of a decreasing trend, stroke related mortality remains higher in Hungary and Romania when compared to the EU average. This might be due to higher incidence, increased severity or even less effective care. METHODS: In this study we used two large, hospital based databases from Targu Mures (Romania) and Debrecen (Hungary) to compare not only the demographic characteristics of stroke patients from these countries but also the risk factors, as well as stroke severity and short term outcome. RESULTS: The gender related distribution of patients was similar to those found in the European Survey, whereas the mean age of patients at stroke onset was similar in the two countries but lower by four years. Although the length of hospital stay was significantly different in the two countries it was still much shorter (about half) than in most reports from western European countries. The overall fatality rate in both databases, regardless of gender was comparable to averages from Europe and other countries. In both countries we found a high number of risk factors, frequently overlapping. The prevalence of risk factors (hypertension, smoking, hyperlipidaemia) was higher than those reported in other countries, which can explain the high ratio of recurring stroke. PMID- 26987241 TI - [THE PROPAGATION AND SEMIOLOGY OF FOCAL EPILEPTIC SEIZURES. CASES CONNECTED TO THE INSULA. THEORETICAL CONSIDERATIONS]. AB - STUDY OBJECTIVES: The developing of diagnostical examinations in epileptology provides new challenges in seizure semiology. On the analysis of seizures it is important to examine the mechanisms of their propagation. The brain connectivity (based on the neuroimaging), the shadowing of the movement of excessive neuronal activity (based on computerized EEG and MEG methods), the cognition of the physiological and pathological brain networks are the footstone of the epileptic seizure propagation. The investigators prove, by means of case demonstrations of the role of the network nodes and the role of the epileptic hubs in the seizure symptomatology. METHODS: The preoperative, intra and postoperative data are analised of three insular and one parietal epileptic patients in point of view of their seizure symptomes. Complex neuroimaging, noninvasive and invasive electrophysiology, intensive long-term video-EEG monitoring, computerized EEG analysis, fuctional mapping, intraoperative corticography were used. The etiology were confirmed with hystology. RESULTS: It is observed that on seizure semiology our patients plays the insula a double role. In some cases, it is the focus of insular seizures with their symptoms difficult to identify. However, in the majority of cases and as a consequence of its rich neural connections, the insula has a peculiar property in the evolution of the symptomatogenic features of seizures. This observations are developing new relationships between the mechanism of seizure propagation and its semiological consequences. CONCLUSIONS: On epileptological point of view there are brain structures which has peculiar role in the "designe" of propagation of the epileptic excitement. The numerous new methods in neuroimaging and neurophysiology allowed the connectomical examination of the epileptic networks. The role of the epileptic diathesis is approachable with the metholdology of the brain connectivity. Theoretically the node of the epileptic network consist of the potential pathes where the localised excessive excitement can propagete. The route where the actual seizure can go adhead is determined by the actual edpileptic propensity of the above mentioned potential pathes. PMID- 26987243 TI - Ottawa's,role in advancing PHC. PMID- 26987244 TI - Act means simplified death reporting. PMID- 26987242 TI - TO TREAT OR NOT TO TREAT, CHEYNE-STOKES RESPIRATION IN A YOUNG ADULT WITH VASCULAR ENCEPHALOPATHY. AB - Cheyne-Stokes respiration (CSR) is a form of sleep-disordered breathing characterised by recurrent central sleep apnoea alternating with a crescendo decrescendo pattern of tidal volume, relatively rare observation in sleep labs. It is mainly seen in severe heart failure and stroke. We report the case of a young man with CSR after sudden onset of seizure in the context of hypertensive exacerbation leading to the diagnosis of a leukoencephalopathy, and comment on differential diagnoses, prognostic and therapeutic outcomes. The very uniqueness of this case consists in the extremely young age for developing a vascular encephalopathy in the absence of genetic diseases and without previous diagnosis of hypertension. There is no adequate explanation for the origin of vascular encephalopathy; also there is lack of evidence regarding the benefits and modality of treatment for CSR in neurologic diseases. Thus, we were forced to find the best compromise in a nocturnal oxygen therapy and follow-up. PMID- 26987245 TI - Screening tests and predictive values. PMID- 26987246 TI - A New Government: A New Open and Collaborative Era? PMID- 26987247 TI - A political force for health. PMID- 26987248 TI - Public health strategy: Photovoice contest. PMID- 26987249 TI - Team player. PMID- 26987250 TI - Thinking on our feet. PMID- 26987251 TI - A campaign woven into the fabric of patient safety. PMID- 26987252 TI - Managing Online Reviews. PMID- 26987253 TI - Medication Management Key To Improving Quality. PMID- 26987255 TI - OT: The Misunderstood Therapy. PMID- 26987254 TI - 10 STEPS TO STAFF STABILITY. PART TWO: MAXIMIZE STABILITY BY SUPPORTING AND ENGAGING STAFF. PMID- 26987257 TI - Expanding the Strained Alkyne Toolbox: Generation and Utility of Oxygen Containing Strained Alkynes. AB - We report synthetic methodology that permits access to two oxacyclic strained intermediates, the 4,5-benzofuranyne and the 3,4-oxacyclohexyne. In situ trapping of these intermediates affords an array of heterocyclic scaffolds by the formation of one or more new C-C or C-heteroatom bonds. Experimentally determined regioselectivities were consistent with predictions made using the distortion/interaction model and were also found to be greater compared to selectivities seen in the case of trapping experiments of the corresponding N containing intermediates. These studies demonstrate the synthetic versatility of oxacyclic arynes and alkynes for the synthesis of functionalized heterocycles, while further expanding the scope of the distortion/interaction model. Moreover, these efforts underscore the value of harnessing strained heterocyclic intermediates as a unique approach to building polycyclic heteroatom-containing frameworks. PMID- 26987256 TI - Guidelines for Diagnosis and Management of Bronchial Asthma: Joint Recommendations of National College of Chest Physicians (India) and Indian Chest Society. AB - Bronchial asthma is an important public health problem in India with significant morbidity. Several international guidelines for diagnosis and management of asthma are available, however there is a need for country-specific guidelines due to vast differences in availability and affordability of health-care facilities across the globe. The Indian Chest Society (ICS) and the National College of Chest Physicians (NCCP) of India have collaborated to develop evidence-based guidelines with an aim to assist physicians at all levels of health-care in diagnosis and management of asthma in a scientific manner. Besides a systematic review of the literature, Indian studies were specifically analysed to arrive at simple and practical recommendations. The evidence is presented under these five headings: (1) definitions, epidemiology and impact, (2) diagnosis, (3) pharmacologic management of stable disease, (4) management of acute exacerbations, and (5) non-pharmacologic management and special situations. The modified grade system was used for classifying the quality of evidence as 1, 2, 3, or usual practice point (UPP). The strength of recommendation was graded as A or B depending upon the level of evidence. PMID- 26987260 TI - Corrigendum. Ambient ionization MS for bioanalysis: recent developments and challenges. PMID- 26987258 TI - Npas4: Linking Neuronal Activity to Memory. AB - Immediate-early genes (IEGs) are rapidly activated after sensory and behavioral experience and are believed to be crucial for converting experience into long term memory. Neuronal PAS domain protein 4 (Npas4), a recently discovered IEG, has several characteristics that make it likely to be a particularly important molecular link between neuronal activity and memory: it is among the most rapidly induced IEGs, is expressed only in neurons, and is selectively induced by neuronal activity. By orchestrating distinct activity-dependent gene programs in different neuronal populations, Npas4 affects synaptic connections in excitatory and inhibitory neurons, neural circuit plasticity, and memory formation. It may also be involved in circuit homeostasis through negative feedback and psychiatric disorders. We summarize these findings and discuss their implications. PMID- 26987259 TI - Secondary Progression in Multiple Sclerosis: Neuronal Exhaustion or Distinct Pathology? AB - Prevention of progression in neurological diseases, particularly in multiple sclerosis (MS) but also in neurodegenerative diseases, remains a significant challenge. MS patients switch from a relapsing-remitting to a progressive disease course, but it is not understood why and how this conversion occurs and why some patients never experience disease progression. Do aging and accumulation of neuronal damage induce progression, or do cognitive symptoms and accelerated grey matter (GM) atrophy point to distinct processes affecting networks? This review weighs accepted dogma against real data on the secondary progressive phase of the disease, highlighting current challenges in this important field and directions towards development of treatment strategies to slow or prevent progression of disability. PMID- 26987261 TI - Stress levels during emergency care: A comparison between reality and simulated scenarios. AB - PURPOSE: Medical simulation is fast becoming a standard of health care training throughout undergraduate, postgraduate and continuing medical education. Our aim was to evaluate if simulated scenarios have a high psychological fidelity and induce stress levels similarly to real emergency medical situations. MATERIALS AND METHODS: Medical residents had their stress levels measured during emergency care (real-life and simulation) in baseline (T1) and immediately post-emergencies (T2). Parameters measuring acute stress were: heart rate, systolic and diastolic blood pressure, salivary alpha-amylase, salivary interleukin-1beta, and State Trait Anxiety Inventory score. RESULTS: Twenty-eight internal medicine residents participated in 32 emergency situations (16 real-life and 16 simulated emergencies). In the real-life group, all parameters increased significantly (P < .05) between T1 and T2. In the simulation group, only heart rate and interleukin 1beta increased significantly after emergencies. The comparison between groups demonstrates that acute stress response (T2 - T1) and State-Trait Anxiety Inventory score (in T2) did not differ between groups. CONCLUSIONS: Acute stress response did not differ between both groups. Our results indicate that emergency medicine simulation may create a high psychological fidelity environment similarly to what is observed in a real emergency room. PMID- 26987262 TI - Comments on "Impact of bronchoalveolar lavage multiplex polymerase chain reaction on microbiological yield and therapeutic decisions in severe pneumonia in intensive care unit". PMID- 26987263 TI - White adipose tissue IFN-gamma expression and signalling along the progression of rodent cancer cachexia. AB - Cachexia is associated with increased morbidity and mortality in cancer. The White adipose tissue (WAT) synthesizes and releases several pro-inflammatory cytokines that play a role in cancer cachexia-related systemic inflammation. IFN gamma is a pleiotropic cytokine that regulates several immune and metabolic functions. To assess whether IFN-gamma signalling in different WAT pads is modified along cancer-cachexia progression, we evaluated IFN-gamma receptors expression (IFNGR1 and IFNGR2) and IFN-gamma protein expression in a rodent model of cachexia (7, 10, and 14days after tumour implantation). IFN-gamma protein expression was heterogeneously modulated in WAT, with increases in the mesenteric pad and decreased levels in the retroperitoneal depot along cachexia progression. Ifngr1 was up-regulated 7days after tumour cell injection in mesenteric and epididymal WAT, but the retroperitoneal depot showed reduced Ifngr1 gene expression. Ifngr2 gene expression was increased 7 and 14days after tumour inoculation in mesenteric WAT. The results provide evidence that changes in IFN gamma expression and signalling may be perceived at stages preceding refractory cachexia, and therefore, might be employed as a means to assess the early stage of the syndrome. PMID- 26987264 TI - Efficacy of zoledronic acid in Erdheim-Chester disease: A case report. AB - Erdheim-Chester disease is rare form of non-Langerhans cell histiocytosis characterized by organ infiltration of CD68+ CD1a- histiocytes. Between 500 and 600 cases have been reported. It is a multifaceted disease ranging from a solely asymptomatic bone to a fatal multisystem pattern. Bone involvement occurs in more than 90% of cases. Although not life-threatening, bone localizations can be responsible of difficult-to-treat pain and disability. Treatment depends on lesion severity. Bisphosphonates have been reported to be efficient and safe in bone involvement. We report a case of a biopsy proven bone Erdheim-Chester disease in a 65-year-old woman with history of breast cancer. Her pain was relieved after 3 perfusions of zoledronic acid and the efficiency remained at one year of follow-up. PMID- 26987265 TI - Atlantooccipital arthritis inaugurating axial spondyloarthritis. PMID- 26987266 TI - NT-proANP and NT-proBNP circulating levels as predictors of cardiovascular outcome following coronary stent implantation. AB - BACKGROUND: Natriuretic peptides are diagnostic/prognostic biomarkers in major cardiovascular diseases. We aimed at assessing the predictive role of N-terminal pro-A-type (NT-proANP) and pro-B-type (NT-proBNP) natriuretic peptides levels toward cardiovascular outcome in both stable and unstable coronary artery disease (CAD) patients after percutaneous coronary intervention (PCI) in a non-primary PCI setting. METHODS: A total of 395 patients undergoing PCI with stent implantation for either stable angina (SA) or non ST-elevation acute coronary syndrome (NSTE-ACS) were enrolled. Pre-procedural NT-proANP and NT-proBNP levels were measured. Occurrence of major adverse cardiac events (MACEs), composite of cardiac death, non-fatal myocardial infarction, and clinically driven target lesion revascularization (c-TLR), was the endpoint of the study. Follow up mean time was 48.53+/-14.69months. RESULTS: MACEs occurred in forty-four patients (11%) during follow up. Both NT-proANP levels [3170 (2210-4630) vs 2283 (1314 3913) fmol/mL, p=0.004] and NT-proBNP levels [729 (356-1353) vs 511 (267-1006) fmol/mL, p=0.04] were significantly higher in patients with MACEs compared to patients without MACEs. Similar results were found when considering hard MACEs (myocardial infarction and cardiac death). NT-proANP levels were significantly higher in patients with c-TLR compared with patients without c-TLR [3705 (2766 5184) vs 2343 (1340-3960) fmol/mL, p=0.021]. At multivariate analysis, NT-proANP levels were a significant predictor of MACEs (HR 1.09, 95% CI 1.03-1.18, p=0.04). Kaplan-Meyer curves revealed that patients with elevated NT-proANP levels (>2.100fmol/mL) had a lower MACE free survival (p=0.003). CONCLUSIONS: Both NT proANP and NT-proBNP levels were higher in CAD patients experiencing MACEs following PCI in a non-primary setting. Notably, only NT-proANP levels significantly affected prognosis after PCI. PMID- 26987267 TI - Daily rhythms of digestive enzyme activity and gene expression in gilthead seabream (Sparus aurata) during ontogeny. AB - In order to identify daily changes in digestive physiology in developing gilthead seabream larvae, the enzyme activity (trypsin, lipases and alpha-amylase) and gene expression (trypsinogen-try, chymotrypsinogen-ctrb, bile salt-activated lipase-cel1b, phospholipase A2-pla2 and alpha-amylase-amy2a) were measured during a 24h cycle in larvae reared under a 12h light/12h dark photoperiod. Larvae were sampled at 10, 18, 30 and 60days post-hatch. In each sampling day, larvae were sampled every 3h during a complete 24h cycle. The enzyme activity and gene expression exhibited a marked dependent behavior to the light/darkness cycle in all tested ages. The patterns of activity and expression of all tested enzymes were compared to the feeding pattern found in the same larvae, which showed a rhythmic feeding pattern with a strong light synchronization. In the four tested ages, the activities of trypsin, and to a lesser extent lipases and amylase, were related to feeding activity. Molecular expression of the pancreatic enzymes tended to increase during the night, probably as an anticipation of the forthcoming ingestion of food that will take place during the next light period. It follows that the enzymatic activities are being regulated at translational and/or post-translational level. The potential variability of enzyme secretion along the whole day is an important factor to take into account in future studies. A particularly striking consequence of the present results is the reliability of studies based in only one daily sample taken at the same hour of the day, as those focused to assess ontogeny of digestive enzymes. PMID- 26987268 TI - Monoammonium glycyrrhizinate protects rifampicin- and isoniazid-induced hepatotoxicity via regulating the expression of transporter Mrp2, Ntcp, and Oatp1a4 in liver. AB - CONTEXT: Drug-induced liver injury (DILI) is associated with altering expression of hepatobiliary membrane transporters. Monoammonium glycyrrhizin (MAG) is commonly used for hepatic protection and may have a correlation with the inhibition effect of multidrug resistance-associated protein 2 (Mrp2). OBJECTIVE: This study evaluates the dynamic protective effect of MAG on rifampicin (RIF)- and isoniazid (INH)-induced hepatotoxicity in rats. MATERIALS AND METHODS: Male Wistar rats were randomly divided into four groups of 15 rats. Liver injury was induced by co-treatment with RIF (60 mg/kg) and INH (60 mg/kg) by gavage administration; MAG was orally pretreated at the doses of 45 or 90 mg/kg 3 h before RIF and INH. Rats in each group were sacrificed at 7, 14, and 21 d time points after drug administration. RESULTS: Liver function, histopathological analysis, and oxidative stress factors were significantly altered in each group. The expression of Mrp2 was significantly increased 230, 760, and 990% at 7, 14, and 21 time points, respectively, in RIF- and INH-treated rats. Compared with the RIF and INH groups, Mrp2 was reduced and Ntcp was significantly elevated by 180, 140, and 160% in the MAG high-dose group at the three time points, respectively. The immunoreaction intensity of Oatp1a4 was increased 170, 190, and 370% in the MAG low-dose group and 160, 290, and 420% in the MAG high-dose group at the three time points, respectively, compared with the RIF and INH groups. DISCUSSION AND CONCLUSION: These results indicated that MAG has a protective effects against RIF and INH-induced hepatotoxicity. The underlying mechanism may have correlation with its effect on regulating the expression of hepatobiliary membrane transporters. PMID- 26987269 TI - Targeting Holliday junctions by origin DNA-binding protein of herpes simplex virus type 1. AB - In the present paper, the interactions of the origin binding protein (OBP) of herpes simplex virus type 1 (HSV1) with synthetic four-way Holliday junctions (HJs) were studied using electrophoresis mobility shift assay and the FRET method and compared with the interactions of the protein with duplex and single-stranded DNAs. It has been found that OBP exhibits a strong preference for binding to four way and three-way DNA junctions and possesses much lower affinities to duplex and single-stranded DNAs. The protein forms three types of complexes with HJs. It forms complexes I and II which are reminiscent of the tetramer and octamer complexes with four-way junction of HJ-specific protein RuvA of Escherichia coli. The binding approaches saturation level when two OBP dimers are bound per junction. In the presence of Mg2+ ions (>=2 mM) OBP also interacts with HJ in the stacked arm form (complex III). In the presence of 5 mM ATP and 10 mM Mg2+ ions OBP catalyzes processing of the HJ in which one of the annealed oligonucleotides has a 3'-terminal tail containing 20 unpaired thymine residues. The observed preference of OBP for binding to the four-way DNA junctions provides a basis for suggestion that OBP induces large DNA structural changes upon binding to Box I and Box II sites in OriS. These changes involve the bending and partial melting of the DNA at A+T-rich spacer and also include the formation of HJ containing Box I and Box II inverted repeats and flanking DNA sequences. PMID- 26987271 TI - Isolated lung model for assessing drug absorption from PLGA microparticles. PMID- 26987273 TI - Pseudo-Jahn-Teller Distortion in Two-Dimensional Phosphorus: Origin of Black and Blue Phases of Phosphorene and Band Gap Modulation by Molecular Charge Transfer. AB - Phosphorene (Pn) is stabilized as a layered material like graphite, yet it possess a natural direct band gap (Eg = 2.0 eV). Interestingly, unlike graphene, Pn exhibits a much richer phase diagram which includes distorted forms like the stapler-clip (black Pn, alpha form) and chairlike (blue Pn, beta form) structures. The existence of these phases is attributed to pseudo-Jahn-Teller (PJT) instability of planar hexagonal P6(6-) rings. In both cases, the condition for vibronic instability of the planar P6(6-) rings is satisfied. Doping with electron donors like tetrathiafulvalene and tetraamino-tetrathiafulvalene and electron acceptors like tetracyanoquinodimethane and tetracyanoethylene convert blue Pn into N-type and black Pn into efficient P-type semiconductors, respectively. Interestingly, pristine blue Pn, an indirect gap semiconductor, gets converted into a direct gap semiconductor on electron or hole doping. Because of comparatively smaller undulation in blue Pn (with respect to black Pn), the van der Waals interactions between the dopants and blue Pn is stronger. PJT distortions for two-dimensional phosphorus provides a unified understanding of structural features and chemical reactivity in its different phases. PMID- 26987272 TI - Composition of connective tissues and morphometry of vascular smooth muscle in arterial wall of DOCA-salt hypertensive rats - In relation with arterial remodeling. AB - Hypertension (HT) was induced in Wistar rats aged 16 and 48 weeks by a deoxycortico-sterone acetate (DOCA)-salt procedure. Common carotid arteries were resected 16 weeks after, and their histological specimens were selectively stained for observations of collagen, elastin, and vascular smooth muscle (VSM) cells. Then, the fractions of collagen and elastin and their radial distributions, and the size and number of VSM cells were determined with an image analyzer. These results were compared with the results from age-matched, non treated, normotensive (NT) animals and also with those from our previous biomechanical studies. In both age groups, there were no significant differences in the fractions of collagen and elastin, and the ratio of collagen to elastin content between HT and NT arteries. These results correspond well with our previous biomechanical results, which showed no significant difference in wall elasticity between HT and NT vessels. Moreover, in the innermost layer out of 4 layers bordered with thick elastic lamellae, the fraction of collagen was significantly greater in HT arteries than in NT ones, which is attributable to HT related stress concentration in the layer. VSM cells were significantly hypertrophied and their content was increased by HT, although their total number in the media remained unchanged. The increased size and content of cells correspond to the enhancement of vascular tone and contractility in HT arteries. PMID- 26987270 TI - Vegetarian dietary patterns and the risk of breast cancer in a low-risk population. AB - Among cancers in American women, breast cancer (BC) has the second highest incidence and mortality. The association of BC with diet has been inconsistent. Studies that evaluate associations with dietary patterns are less common and reflect an individual's whole diet. We associated dietary patterns with the risk of BC in American women of the Adventist Health Study-2 (AHS-2), a prospective cohort of 96 001 subjects recruited between 2002 and 2007. Answers to a previously validated FFQ were used to classify subjects to vegan, lacto-ovo vegetarian, pesco-vegetarian, semi-vegetarian and non-vegetarian dietary patterns. Incident BC were identified by matching AHS-2 subjects to data from forty-eight state cancer registries. Statistical analyses used proportional hazard regression analyses with covariates that were chosen a priori. From 50 404 female participants (26 193 vegetarians), we identified 892 incident BC cases, with 478 cases among vegetarians. As compared with non-vegetarians, all vegetarians combined did not have a significantly lower risk (hazard ratio (HR) 0.97; CI 0.84, 1.11; P=0.64). However, vegans showed consistently lower (but non significant) point estimates when compared with non-vegetarians (all cases: HR 0.78; CI 0.58, 1.05; P=0.09). In summary, participants in this cohort who follow a vegetarian dietary pattern did not experience a lower risk of BC as compared with non-vegetarians, although lower risk in vegans is possible. These findings add to the very limited literature associating vegetarian diets with BC risk and can assist nutritionists when evaluating the impact of these diets. The findings will also motivate further evaluation of vegan diets and their special characteristics. PMID- 26987274 TI - [The Use of the Objective Structured Clinical Examination for Paediatric residents in the City of Buenos Aires]. AB - INTRODUCTION: The Objective Structured Clinical Examination (OSCE) is considered the reference standard for competence evaluation, but its use in Latin America is limited. The City of Buenos Aires Government (CBAG) administers a Paediatric residency system that includes 400 residents distributed in 13 hospitals, sharing an admission system and education program. We aim to describe the experience of administering an OSCE for evaluating all the Paediatric residents of the CBAG. SUBJECTS AND METHOD: Descriptive study, including all paediatric residents of the CBAG, belonging to 13 hospitals (2 paediatric and 11 general), ending their first year of training. The OSCE included 10 stations. RESULTS: Eighty-five residents participated in the OSCE, and 88.2% (95% CI 79.7-93.5) passed the examination. There were no significant differences in the pass rate between residents from paediatric hospitals and from general hospitals (89.5 vs. 85.7%; OR=1.4; 95% CI 0.4-5.5; P=.8). CONCLUSIONS: In 2015, the OSCE was administered to all paediatric residents of the CBAG for the first time. This experience allowed identifying weaknesses in the education system, in order to develop strategies to overcome them. PMID- 26987275 TI - Cervical intertrigo: Think beyond fungi. PMID- 26987276 TI - Multifunctionality of plastid nucleoids as revealed by proteome analyses. AB - Protocols aimed at the isolation of nucleoids and transcriptionally active chromosomes (TACs) from plastids of higher plants have been established already decades ago, but only recent improvements in the mass spectrometry methods enabled detailed proteomic characterization of their components. Here we present a comprehensive analysis of the protein compositions obtained from two proteomic studies of TAC fractions isolated from Arabidopsis/mustard and spinach chloroplasts, respectively, as well as nucleoid fractions from Arabidopsis, maize and pea. Interestingly, different approaches as well as the use of diverse starting materials resulted in the detection of varying protein catalogues with a number of shared proteins. Possible reasons for the discrepancies between the protein repertoires and for missing out some of the nucleoid proteins that have been identified previously by other means than mass spectrometry as well as the repeated identification of "unexpected" proteins indicating potential links between DNA/RNA-associated nucleoid core functions and energy metabolism as well as biosynthetic activities of plastids will be discussed. In accordance with the nucleoid association of proteins involved in key functions of plastids including photosynthesis, the phenotypes of mutants lacking one or the other plastid nucleoid-associated protein (ptNAP) show the importance of nucleoid proteins for overall plant development and growth. This article is part of a Special Issue entitled: Plant Proteomics--a bridge between fundamental processes and crop production, edited by Dr. Hans-Peter Mock. PMID- 26987278 TI - [Conflicts between nursing ethics and health care legislation in Spain]. AB - OBJECTIVE: To identify the ethical conflicts that may arise between the nursing codes of ethics and the Royal Decree-law 16/2012 modifying Spanish health regulations. METHOD: We conducted a review and critical analysis of the discourse of five nursing codes of ethics from Barcelona, Catalonia, Spain, Europe and International, and of the discourse of the Spanish legislation in force in 2013. Language structures referring to five different concepts of the theoretical framework of care were identified in the texts: equity, human rights, right to healthcare, access to care, and continuity of care. RESULTS: Codes of ethics define the function of nursing according to equity, acknowledgement of human rights, right to healthcare, access to care and continuity of care, while legal discourse hinges on the concept of beneficiary or being insured. CONCLUSIONS: The divergence between the code of ethics and the legal discourse may produce ethical conflicts that negatively affect nursing practice. The application of RDL 16/2012 promotes a framework of action that prevents nursing professionals from providing care to uninsured collectives, which violates human rights and the principles of care ethics. PMID- 26987279 TI - [Problems in the process of adapting to change among the family caregivers of elderly people with dementia]. AB - OBJECTIVE: To identify and analyse problems in adapting to change among the family caregivers of relatives with dementia. METHOD: Qualitative study based on the methodology of Charmaz's Constructivist Grounded Theory. Seven focus groups were conducted in different primary health care centres in the province of Jaen (Spain). Eighty-two primary family caregivers of relatives with dementia participated by purposeful maximum variation sampling and theoretical sampling. Triangulation analysis was carried out to increase internal validity. RESULTS: We obtained three main categories: 'Changing Care', 'Problems in the process of adapting to change' and 'Facilitators of the process of adapting to change'. Family caregivers perform their role in a context characterized by personal change, both in the person receiving the care and in the social and cultural context. The challenge of adaptation lies in the balance between the problems that hamper adaptation of the caregiver to new situations of care and the factors that facilitate the caregiver role. CONCLUSIONS: The adaptation of family caregivers to caring for a person with dementia is hindered by the lack of formal support and under-diagnosis of dementia. The adaptation process could be improved by strengthening formal support in the early stages of care to reduce the stress of family caregivers who must teach themselves about their task and by interventions adapted to each phase in the development of the caregiver role. PMID- 26987280 TI - [Perceptions of primary care physicians in Madrid on the austerity measures in the health care system]. AB - OBJECTIVE: To address the current economic crisis, governments have promoted austerity measures that have affected the taxpayer-funded health system. We report the findings of a study exploring the perceptions of primary care physicians in Madrid (Spain) on measures implemented in the Spanish health system. METHODS: We carried out a qualitative study in two primary health care centres located in two neighbourhoods with unemployment and migrant population rates above the average of those in Madrid. Interviews were conducted with 12 primary health care physicians. Interview data were analysed by using thematic analysis and by adopting some elements of the grounded theory approach. RESULTS: Two categories were identified: evaluation of austerity measures and evaluation of decision-making in this process. Respondents believed there was a need to promote measures to improve the taxpayer-funded health system, but expressed their disagreement with the measures implemented. They considered that the measures were not evidence-based and responded to the need to decrease public health care expenditure in the short term. Respondents believed that they had not been properly informed about the measures and that there was adequate professional participation in the prioritization, selection and implementation of measures. They considered physician participation to be essential in the decision making process because physicians have a more patient-centred view and have first hand knowledge of areas requiring improvement in the system. CONCLUSIONS: It is essential that public authorities actively involve health care professionals in decision-making processes to ensure the implementation of evidence-based measures with strong professional support, thus maintaining the quality of care. PMID- 26987281 TI - [Sexually transmitted infections in male prison inmates: risk of development of new diseases]. AB - OBJECTIVE: To measure incidence and main risk factors related to sexually transmitted infections (STIs) in Daroca Prison (Zaragoza, Spain). METHOD: A retrospective cohort study (2005-2013) to measure the incidence of STI and a cross-sectional study to measure risk factors. RESULTS: Of the 203 inmates, 79 developed an STI, 37 had a previous STI, 55.2% lacked knowledge on STI prevention, and 28.9% showed behaviours unfavourable for STI prevention. The incidence rate was 6.5 STIs per 1,000 inmates-year. The most frequent STIs were hepatitis B (39.7%), Ureaplasma urealyticum (19.1%), herpes simplex (16.2%) and HIV (8.8%). The risk (hazard ratio, HR) of acquiring a new STI was significantly higher in inmates with a history of previous STI (HR=2.61; 95%CI: 1.01 to 6.69), and was at the limit of significance for non-preventive behaviour (HR=2.10; 95%CI: 0.98 to 4.53), but not in knowledge related to STIs (HR=1.33; 95%CI: 0.58 to 3.07). CONCLUSION: The most important risk factors in prison are behaviours related to STIs and previous history of STIs. Other factors are being a repeat offender, injecting drug use, or being in a methadone programme. Health personnel and peer education can facilitate prevention and control. PMID- 26987277 TI - Methylmercury and brain development: A review of recent literature. AB - Methylmercury (MeHg) is a potent environmental pollutant, which elicits significant toxicity in humans. The central nervous system (CNS) is the primary target of toxicity, and is particularly vulnerable during development. Maternal exposure to MeHg via consumption of fish and seafood can have irreversible effects on the neurobehavioral development of children, even in the absence of symptoms in the mother. It is well documented that developmental MeHg exposure may lead to neurological alterations, including cognitive and motor dysfunction. The neurotoxic effects of MeHg on the developing brain have been extensively studied. The mechanism of toxicity, however, is not fully understood. No single process can explain the multitude of effects observed in MeHg-induced neurotoxicity. This review summarizes the most current knowledge on the effects of MeHg during nervous system development considering both, in vitro and in vivo experimental models. Considerable attention was directed towards the role of glutamate and calcium dyshomeostasis, mitochondrial dysfunction, as well as the effects of MeHg on cytoskeletal components/regulators. PMID- 26987282 TI - CAD/CAM-designed 3D-printed electroanalytical cell for the evaluation of nanostructured gas-diffusion electrodes. AB - The ability to effectively screen and validate gas-diffusion electrodes is critical to the development of next-generation metal-air batteries and regenerative fuel cells. The limiting electrode in a classic two-terminal device such as a battery or fuel cell is difficult to discern without an internal reference electrode, but the flooded electrolyte characteristic of three electrode electroanalytical cells negates the prime function of an air electrode a void volume freely accessible to gases. The nanostructured catalysts that drive the energy-conversion reactions (e.g., oxygen reduction and evolution in the air electrode of metal-air batteries) are best evaluated in the electrode structure as-used in the practical device. We have designed, 3D-printed, and characterized an air-breathing, thermodynamically referenced electroanalytical cell that allows us to mimic the Janus arrangement of the gas-diffusion electrode in a metal-air cell: one face freely exposed to gases, the other wetted by electrolyte. PMID- 26987285 TI - DNA barcoding and wing morphometrics to distinguish three Aedes vectors in Thailand. AB - Aedes aegypti (Diptera: Culicidae) (L.), Ae. albopictus (Skuse), and Ae. scutellaris (Walker) are important mosquito vectors of dengue and chikungunya viruses. They are morphologically similar and sympatric in some parts of their distribution; therefore, there is a risk of incorrect morphological identification. Any confusion could have a negative impact on epidemiological studies or control strategies. Therefore, we explored two modern tools to supplement current morphological identification: DNA barcoding and geometric morphometric analyses. Field larvae were reared to adults and carefully classified based on morphological traits. The genetic analysis was based on the 658bp each of 30COI sequences. Some Culex spp., Mansonia bonneae, were included as outgroups, and inclusion of a few other Aedes spp. facilitated phylogenetic inference of the relationship between Ae. albopictus and Ae. scutellaris. The two species were separated by an average interspecific divergence of 0.123 (0.119 0.127). Morphometric examination included landmark- (392 specimens) and outline based (317 specimens) techniques. The shape of the wing showed different discriminating power based on sex and digitizing technique. This is the first time that Ae. scutellaris and Ae. albopictus have been compared using these two techniques. We confirm that these morphologically close species are valid, and that geometric morphometrics can considerably increase the reliability of morphological identification. PMID- 26987286 TI - End-of-life care in residential care homes: a retrospective study of the perspectives of family members using the VOICES questionnaire. AB - BACKGROUND: In Europe, residential care homes (RCHs) are replacing hospitals as the place where death occurs, and they play an important role in end-of-life (EOL) care. OBJECTIVE: The aim was to describe the quality of care during the last 3 months and last 3 days of life of those who died in RCHs as reported by family members. We also investigated whether there were differences in the EOL care of younger patients (<85 years) vs. the oldest old patients (>=85 years) as reported by family members. DESIGN: A retrospective survey design. METHODS: Deaths (n = 189) at 19 RCHs in one municipality in Sweden were included. Family members were sent the VOICES questionnaire 1 month after their elderly relative had died. Descriptive statistics were used. RESULTS: In the last 3 days before death, most family members reported there was enough help with nursing (93%) and personal care (78.5%). Among the family members, 86% were told that the resident was likely to die shortly. Most (94.1%) of residents were reported to have died at their preferred place. No significant difference was found between age groups. Family members also reported that about half of the elderly had pain (46.5%) and 86.4% received treatment; 55.9% had breathlessness and 39.7% received treatment. Breathlessness was significantly (p = 0.01) more common in the younger group, and they were treated more often (p = 0.006) than the oldest old. CONCLUSION: This study revealed an overall positive picture of personal and nursing care and communication. These findings indicate that the quality of EOL care at RCHs is high. Inadequate management was found for symptom relief the last days of life. This suggests that this subject merits further attention by care professionals. To achieve better quality of EOL care at RCHs, we emphasise the importance of systematically working to improve symptom relief. PMID- 26987287 TI - Sex-dependent expression of anti-Mullerian hormone (amh) and amh receptor 2 during sex organ differentiation and characterization of the Mullerian duct development in Xenopus tropicalis. AB - Amphibian gonadal differentiation involves the action of sex steroids. Recent research indicates that the anti-Mullerian hormone (AMH) is involved in testicular development in some lower vertebrate species. For amphibians there is a lack of data on ontogenetic expression of the AMH receptor AMHR2/amhr2 and of progesterone receptors (PGRS/pgrs). Here we expand the knowledge on amphibian sex differentiation by characterizing ontogenetic mRNA levels of amh, amhr2, intracellular and membrane pgrs (ipgr and mpgr beta) and cytochrome P450 19a1 (cyp19a1) (ovarian marker) in the urogenital complex of the model species Xenopus (Silurana) tropicalis. Furthermore, we characterized the ontogenetic development of the Mullerian ducts (precursors of the female reproductive tract) histologically. The developmental period investigated spanned from beginning of gonadal differentiation, Nieuwkoop and Faber (NF) stage 51, to 4weeks post metamorphosis. The Mullerian ducts were first observed at NF 64 in both sexes. Male-enhanced amh mRNA levels from NF 53/54 to 6days post-metamorphosis and female-enhanced cyp19a1 levels from NF 53 to 4weeks post-metamorphosis were noted. The sexually dimorphic mRNA level profile was more distinct for amh than for cyp19a1. The pgrs mRNA levels increased over the studied period and showed no sex differences. At later developmental stages, the amhr2 mRNA level was increased in putative females compared with males. Our findings suggest that AMH has a role in gonadal differentiation in X. tropicalis. We propose relative gonadal amh mRNA level as a testicular marker during early gonadal development in amphibians. PMID- 26987288 TI - Androgens modulate gene expression and specific DNA methylation pattern of steroid 5alpha-reductases in the frog Silurana tropicalis. AB - In vertebrates, androgens are essential in many biological functions, including reproduction, immune system, metabolism, cardiovascular function, and the central nervous system. The most potent androgen 5alpha-dihydrotestosterone (5alpha-DHT), which is actively involved in sexual differentiation and development, is converted from testosterone (T) by the steroid 5alpha-reductases type 1, 2, and 3 (Srd5alpha1, Srd5alpha2, and Srd5alpha3). Alternatively, steroid 5beta-reductase (Srd5beta) converts T to 5beta-dihydrotestosterone (5beta-DHT), a metabolite believed to be involved in steroid clearance. Recent studies suggested that Srd5 isoforms are targets for endocrine disruption. Thus, understanding the regulation of Srd5 is important to expand our knowledge on how exogenous compounds can interfere with these enzymes. In this study, we exposed frog brain, liver, and gonads ex vivo to T, 5alpha-DHT, and 5beta-DHT in order to investigate the regulation of srd5 in response to androgens as a simulation of endocrine disrupting chemicals with androgenic properties. Androgens did not modulate srd5alpha2, suggesting that this isoform is not regulated by T and 5alpha-DHT in frogs. However, the DNA methylation of srd5alpha2 increased following 5alpha-DHT treatment suggesting that androgens can modulate epigenetic mechanisms in amphibians. In contrast, the DNA methylation of srd5alpha1 and srd5alpha3 remained stable after androgen exposure, but the mRNA levels of srd5alpha1 and srd5alpha3 were modulated by T, 5alpha-DHT, and 5beta-DHT in a sex- and tissue specific manner. While T positively regulates srd5alpha1 and srd5alpha3 in testes, T negatively regulates srd5alpha3 in ovaries. Moreover, exposure to T also increased the mRNA level of srd5beta in the male brain suggesting a mechanism to protect the brain from androgen action by elimination of T into 5beta-DHT. Thus, exogenous compounds with androgenic properties potentially interact with srd5 transcription and DNA methylation pattern, which could adversely affect biological functions of vertebrates during development and reproduction. PMID- 26987289 TI - Adenovirus-directed expression of TIPE2 suppresses gastric cancer growth via induction of apoptosis and inhibition of AKT and ERK1/2 signaling. AB - Tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TNFAIP8L2/TIPE2) as a novel anti-inflammatory factor plays an important role in maintaining immune homeostasis. Recently, TIPE2 has been shown to inhibit hepatocarcinoma growth and metastasis through targeting Ras and Rac1. However, its effects in human cancers are poorly understood. In the present study, we analyzed TIPE2 mRNA expression in a panel of human gastric cancer cells (AGS, HGC-27 and SGC-7901) and then examined the cell-autonomous effects of adenovirus-mediated human TIPE2 gene transfer (AdVTIPE2) on AGS and HGC-27 human gastric cancer cells. We found that compared with the GES-1 normal human gastric mucous epithelial cells, human TIPE2 was lost in the AGS, HGC-27 and SGC-7901 gastric cancer cells. Adenovirus mediated human TIPE2 overexpression significantly inhibited AGS and HGC-27 gastric cancer cell growth and induced AGS and HGC-27 tumor cell apoptosis in vitro. Furthermore, AdVTIPE2 treatment obviously suppressed the growth of AGS gastric cancer subcutaneously xenografted tumors implanted in athymic BALB/c nude mice in vivo. Mechanistically, AdVTIPE2 exhibited marked effects on the upregulation of Bax, cleaved Caspase-9, cleaved Caspase-3, cleaved poly ADP ribose polymerase as well as the downregulation of B-cell lymphoma (Bcl)-XL, phosphorylated-protein kinase B (p-PKB/AKT), phosphorylated-extracellular signal regulated kinase 1/2 (p-ERK1/2) in AGS gastric cancer cells in vitro and in vivo. Collectively, AdVTIPE2 suppressed gastric cancer growth very possibly by the activation of intrinsic apoptotic pathway and the attenuation of AKT and ERK1/2 signaling. Thus, our data indicated that TIPE2 may be a novel potential therapeutic target for human gastric cancer. PMID- 26987290 TI - Let-7c blocks estrogen-activated Wnt signaling in induction of self-renewal of breast cancer stem cells. AB - Let-7 miRNAs are involved in carcinogenesis and tumor progression through their roles in maintaining differentiation and normal development. However, there is little research focusing on the effects of let-7 on Wnt-activated self-renewal of breast cancer stem cells. By analyzing the expression levels of let-7 family members in clinical tissues, we found that higher expression levels of let-7b and let-7c were correlated with better clinical prognosis of patients with estrogen receptor (ER)alpha-positive breast tumor. Further, we found that only let-7c was inversely correlated with ERalpha expression, and there is corelationship between let-7c and Wnt signaling in clinical tissues. Aldehyde dehydrogenase (ALDH)1 sorting and mammosphere formation assays showed that let-7c inhibited the self renewal of stem cells in ERalpha-positive breast cancer. Let-7c decreased ERalpha expression through directly binding to the 3'UTR (untranslated region), and let 7c inhibited the estrogen-induced activation of Wnt signaling. Depletion of ERalpha abolished let-7c functions in stem cell signatures, which further confirmed that let-7c inhibited estrogen-induced Wnt activity through decreasing ERalpha expression. Taken together, our findings identified a biochemical and functional link between let-7c with ERalpha/Wnt signaling in breast cancer stem cells. PMID- 26987291 TI - Immunogenic cell death by oncolytic herpes simplex virus type 1 in squamous cell carcinoma cells. AB - Molecules essential for the induction of immunogenic cell death (ICD) are called damage-associated molecular patterns (DAMPs). The effects of oncolytic herpes simplex virus type 1 (HSV-1) on the production of DAMPs were examined in squamous cell carcinoma (SCC) cells. The cytopathic effects of HSV-1 RH2 were observed in mouse SCCVII cells infected at a high multiplicity of infection (MOI), and the amounts of viable cells were decreased. After being infected with RH2, ATP and high mobility group box 1 (HMGB1) were released extracellulary, while calreticulin (CRT) translocated to the cell membrane. A flow-cytometric analysis revealed an increase in the number of annexin-V and propidium iodide (PI)-stained cells; and the amount of cleaved poly (ADP-ribose) polymerase (PARP) was increased. The killing effect of RH2 was reduced by pan-caspase inhibitor z-VAD fmk and the caspase-1 inhibitor z-YVAD-fmk, suggesting the involvement of apoptosis and pyroptosis. In C3H mice bearing synergic SCCVII tumors, the growth of tumors injected with the supernatant of RH2-infected cells was less than that of tumors injected with phosphate-buffered saline (PBS). These results indicate that oncolytic HSV-1 RH2 produces DAMPs from SCC cells to induce cell death. This may contribute to the enhancement of tumor immunity by oncolytic HSV-1. PMID- 26987293 TI - Retinol and alpha-tocopherol in human milk and their relationship with dietary intake during lactation. AB - Human milk is considered as an optimal nutrition source for neonates, and vitamins A and E improve oxidative stress in offspring through breast milk. We aim to determine alpha-tocopherol and retinol contents in breast milk obtained over the course of lactation stages from mothers in three regions in China, and to investigate their correlation with maternal dietary intake during lactation. Human milk samples and 24 hour food records were obtained from mothers in Hangzhou (n = 34), Lanzhou (n = 34) and Beijing (n = 34) on day 1 (colostrum), day 14 (transitional milk) and day 42 (mature milk) postpartum. Concentrations of alpha-tocopherol and retinol in breast milk samples were measured by high performance liquid chromatography. The breast milk concentrations of alpha tocopherol and retinol decreased over progress of lactation stages (P < 0.001). The retinol content of transitional milk from Hangzhou was higher than that in Lanzhou (P = 0.019) and Beijing (P < 0.001), and the alpha-tocopherol content in colostrum from Hangzhou showed a lower concentration than that from Lanzhou (P = 0.001). There was a significantly positive correlation between retinol and alpha tocopherol contents in colostrum (r = 0.37, P = 0.002), transitional (r = 0.41, P < 0.001) and mature milk (r = 0.53, P < 0.001). No significant correlation was found between any dietary constituents (grain, fruit, vegetable, dairy, egg and meat, oil and bean products) and either retinol or alpha-tocopherol. PMID- 26987292 TI - Precise and efficient siRNA design: a key point in competent gene silencing. AB - RNA interference-related strategies have become appealing methods in various fields of research. Exact sequence design of these small molecules is an essential step in the silencing procedure. Numerous researchers have tried to define some algorithms in order to increase the chance of short interfering RNA's (siRNA's) success. In recent decades, online designing software has aimed at promoting the quality of siRNA designing based on the most cited algorithms. According to our previous experiments, a combination of different criteria would be helpful. That is, siRNAs suggested by a combination of tools seem to be more efficient. Furthermore, different factors such as distance of target region to transcription start site, nucleotide composition, absence of off-target effects and secondary structures in the target site and siRNA and the presence of asymmetry and energy valley within the siRNA will increase the efficiency of siRNAs. Despite application of different online tools and fulfilling the criteria, there is no guarantee for designing an effective siRNA. However, meticulous designing of siRNAs according to the suggested algorithms and scoring systems and using different siRNAs for targeting the same gene would lead to improved silencing outcome. In this review, we focus on common algorithms and online software, and introduce a new scoring system used in our experiments. PMID- 26987295 TI - ECG feature extraction based on the bandwidth properties of variational mode decomposition. AB - It is a difficult process to detect abnormal heart beats, known as arrhythmia, in long-term ECG recording. Thus, computer-aided diagnosis systems have become a supportive tool for helping physicians improve the diagnostic accuracy of heartbeat detection. This paper explores the bandwidth properties of the modes obtained using variational mode decomposition (VMD) to classify arrhythmia electrocardiogram (ECG) beats. VMD is an enhanced version of the empirical mode decomposition (EMD) algorithm for analyzing non-linear and non-stationary signals. It decomposes the signal into a set of band-limited oscillations called modes. ECG signals from the MIT-BIH arrhythmia database are decomposed using VMD, and the amplitude modulation bandwidth B AM, the frequency modulation bandwidth B FM and the total bandwidth B of the modes are used as feature vectors to detect heartbeats such as normal (N), premature ventricular contraction (V), left bundle branch block (L), right bundle branch block (R), paced beat (P) and atrial premature beat (A). Bandwidth estimations based on the instantaneous frequency (IF) and amplitude (IA) spectra of the modes indicate that the proposed VMD-based features have sufficient class discrimination capability regarding ECG beats. Moreover, the extracted features using the bandwidths (B AM, B FM and B) of four modes are used to evaluate the diagnostic accuracy rates of several classifiers such as the k-nearest neighbor classifier (k-NN), the decision tree (DT), the artificial neural network (ANN), the bagged decision tree (BDT), the AdaBoost decision tree (ABDT) and random sub-spaced k-NN (RSNN) for N, R, L, V, P, and A beats. The performance of the proposed VMD-based feature extraction with a BDT classifier has accuracy rates of 99.06%, 99.00%, 99.40%, 99.51%, 98.72%, 98.71%, and 99.02% for overall, N-, R-, L-, V-, P-, and A-type ECG beats, respectively. PMID- 26987294 TI - Co-production of acetone and ethanol with molar ratio control enables production of improved gasoline or jet fuel blends. AB - The fermentation of simple sugars to ethanol has been the most successful biofuel process to displace fossil fuel consumption worldwide thus far. However, the physical properties of ethanol and automotive components limit its application in most cases to 10-15 vol% blends with conventional gasoline. Fermentative co production of ethanol and acetone coupled with a catalytic alkylation reaction could enable the production of gasoline blendstocks enriched in higher-chain oxygenates. Here we demonstrate a synthetic pathway for the production of acetone through the mevalonate precursor hydroxymethylglutaryl-CoA. Expression of this pathway in various strains of Escherichia coli resulted in the co-production of acetone and ethanol. Metabolic engineering and control of the environmental conditions for microbial growth resulted in controllable acetone and ethanol production with ethanol:acetone molar ratios ranging from 0.7:1 to 10.0:1. Specifically, use of gluconic acid as a substrate increased production of acetone and balanced the redox state of the system, predictively reducing the molar ethanol:acetone ratio. Increases in ethanol production and the molar ethanol:acetone ratio were achieved by co-expression of the aldehyde/alcohol dehydrogenase (AdhE) from E. coli MG1655 and by co-expression of pyruvate decarboxylase (Pdc) and alcohol dehydrogenase (AdhB) from Z. mobilis. Controlling the fermentation aeration rate and pH in a bioreactor raised the acetone titer to 5.1 g L(-1) , similar to that obtained with wild-type Clostridium acetobutylicum. Optimizing the metabolic pathway, the selection of host strain, and the physiological conditions employed for host growth together improved acetone titers over 35-fold (0.14-5.1 g/L). Finally, chemical catalysis was used to upgrade the co-produced ethanol and acetone at both low and high molar ratios to higher-chain oxygenates for gasoline and jet fuel applications. Biotechnol. Bioeng. 2016;113: 2079-2087. (c) 2016 Wiley Periodicals, Inc. PMID- 26987296 TI - Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival. AB - CLEC16A is in a locus genetically linked to autoimmune diseases including multiple sclerosis, but the function of this gene in the nervous system is unknown. Here we show that two mouse strains carrying independent Clec16a mutations developed neurodegenerative disease characterized by motor impairments and loss of Purkinje cells. Neurons from Clec16a-mutant mice exhibited increased expression of the autophagy substrate p62, accumulation of abnormal intra-axonal membranous structures bearing the autophagy protein LC3, and abnormal Golgi morphology. Multiple aspects of endocytosis, lysosome and Golgi function were normal in Clec16a-deficient murine embryonic fibroblasts and HeLa cells. However, these cells displayed abnormal bulk autophagy despite unimpaired autophagosome formation. Cultured Clec16a-deficient cells exhibited a striking accumulation of LC3 and LAMP-1 positive autolysosomes containing undigested cytoplasmic contents. Therefore Clec16a, an autophagy protein that is critical for autolysosome function and clearance, is required for Purkinje cell survival. PMID- 26987298 TI - Actin nucleation at the centrosome controls lymphocyte polarity. AB - Cell polarity is required for the functional specialization of many cell types including lymphocytes. A hallmark of cell polarity is the reorientation of the centrosome that allows repositioning of organelles and vesicles in an asymmetric fashion. The mechanisms underlying centrosome polarization are not fully understood. Here we found that in resting lymphocytes, centrosome-associated Arp2/3 locally nucleates F-actin, which is needed for centrosome tethering to the nucleus via the LINC complex. Upon lymphocyte activation, Arp2/3 is partially depleted from the centrosome as a result of its recruitment to the immune synapse. This leads to a reduction in F-actin nucleation at the centrosome and thereby allows its detachment from the nucleus and polarization to the synapse. Therefore, F-actin nucleation at the centrosome--regulated by the availability of the Arp2/3 complex--determines its capacity to polarize in response to external stimuli. PMID- 26987300 TI - Screening and quantification of anticancer compounds in traditional Chinese medicine by hollow fiber cell fishing and hollow fiber liquid/solid-phase microextraction. AB - Hollow fiber cell fishing, based on HepG-2, SKOV-3, and ACHN cancer cells, and hollow fiber liquid/solid microextraction with HPLC were developed and introduced for researching the anticancer activity of Rhizoma Curcumae Longae, Radix Curcumae, and Rhizoma Curcumae. The structures of curcumin, demethoxycurcumin, and bisdemethoxycurcumin screened were identified and their contents were determined. The compound target fishing factors and cell apoptosis rates under the effect of the three medicines were determined. The binding sites (cell membrane and cell organelle) and binding target (phospholipase C) on the cell were researched. Hollow fiber liquid/solid-phase microextraction mechanism was analyzed and expounded. Before the application, cell seeding time, growth state and survival rate, compound nonspecific binding, positive and negative controls, repeatability in hollow fiber cell fishing with high-performance liquid chromatography; extraction solvent, sample pH, salt concentration, agitation speed, extraction time, temperature and sample volume in hollow fiber liquid/solid-phase microextraction with high-performance liquid chromatography were investigated. The results demonstrated that the proposed strategy is a simple and quick method to identify bioactive compounds at the cellular level as well as determine their contents (particularly trace levels of the bioactive compounds), analyze multicompound and multitarget entirety effects, and elucidate the efficacious material base in traditional medicine. PMID- 26987297 TI - Microcin determinants are associated with B2 phylogroup of human fecal Escherichia coli isolates. AB - Escherichia coli strains are classified into four main phylogenetic groups (A, B1, B2, and D) and strains of these phylogroups differ in a number of characteristics. This study tested whether human fecal E. coli isolates belonging to different phylogroups differ in prevalence of bacteriocinogenic isolates and prevalence of individual bacteriocinogenic determinants. A set of 1283 fecal E. coli isolates from patients with different diseases was tested for the presence of DNA regions allowing classification into E. coli phylogroups and for the ability to produce bacteriocins (23 colicins and 7 microcins). Of the isolates tested, the most common was phylogroup B2 (38.3%) followed by phylogroups A (28.3%), D (26.3%) and B1 (7.2%). Altogether, 695 bacteriocin producers were identified representing 54.2% of all tested isolates. The highest prevalence of bacteriocin producers was found in group B2 (60.3%) and the lowest in group B1 (44.6%). Determinants encoding colicins E1, Ia, and microcin mV were most common in phylogroup A, determinants encoding microcins mM and mH47 were most common in phylogroup B2, and determinant encoding mB17 was most common in phylogroup D. The highest prevalence of bacteriocinogeny was found in phylogroup B2, suggesting that bacteriocinogeny and especially the synthesis of microcins was associated with virulent and resident E. coli strains. PMID- 26987299 TI - Labeling of virus components for advanced, quantitative imaging analyses. AB - In recent years, investigation of virus-cell interactions has moved from ensemble measurements to imaging analyses at the single-particle level. Advanced fluorescence microscopy techniques provide single-molecule sensitivity and subdiffraction spatial resolution, allowing observation of subviral details and individual replication events to obtain detailed quantitative information. To exploit the full potential of these techniques, virologists need to employ novel labeling strategies, taking into account specific constraints imposed by viruses, as well as unique requirements of microscopic methods. Here, we compare strengths and limitations of various labeling methods, exemplify virological questions that were successfully addressed, and discuss challenges and future potential of novel approaches in virus imaging. PMID- 26987301 TI - Further deliberating the relationship between do-not-resuscitate and the increased risk of death. AB - Few studies have examined the outcome of do-not-resuscitate (DNR) patients in surgical intensive care units (SICUs). This study deliberated the association between a DNR decision and the increased risk of death methodologically and ethically. This study was conducted in three SICUs. We collected patients' demographic characteristics, clinical characteristics, and the status of death/survival at SICU and hospital discharge. We used Kaplan-Meier survival curves to compare the time from SICU admission to the end of SICU stay for the DNR and non-DNR patients. Differences in the Kaplan-Meier curves were tested using log-rank tests. We also conducted a Cox proportional hazards model to account for the effect of a DNR decision on mortality. We found that having a DNR order was associated with an increased risk of death during the SICU stay (aRR = 2.39, p < 0.01) after adjusting for severity of illness upon SICU admission and other confounding variables. To make the conclusion that a DNR order is causally related to an increased risk of death, or that a DNR order increases the risk of death is absolutely questionable. By clarifying this key point, we expect that the discussion of DNR between healthcare professionals and patients/surrogate decision-makers will not be hampered or delayed. PMID- 26987303 TI - Public health implications of waterpipe tobacco use in the United States warrant initial steps towards assessing dependence. PMID- 26987302 TI - The fertilization-induced zinc spark is a novel biomarker of mouse embryo quality and early development. AB - Upon activation, mammalian eggs release billions of zinc ions in an exocytotic event termed the "zinc spark." The zinc spark is dependent on and occurs coordinately with intracellular calcium transients, which are tightly associated with embryonic development. Thus, we hypothesized that the zinc spark represents an early extracellular physicochemical marker of the developmental potential of the zygote. To test this hypothesis, we monitored zinc exocytosis in individual mouse eggs following parthenogenetic activation or in vitro fertilization (IVF) and tracked their development. Retrospective analysis of zinc spark profiles revealed that parthenotes and zygotes that developed into blastocysts released more zinc than those that failed to develop. Prospective selection of embryos based on their zinc spark profile significantly improved developmental outcomes and more than doubled the percentage of embryos that reached the blastocyst stage. Moreover, the zinc spark profile was also associated with embryo quality as the total cell number in the resulting morulae and blastocysts positively correlated with the zinc spark amplitude (R = 0.9209). Zinc sparks can thus serve as an early biomarker of zygote quality in mouse model. PMID- 26987305 TI - An innovative co-axial system to electrospin in situ crosslinked gelatin nanofibers. AB - Crosslinking of gelatin nanofibers maintaining a fibrous morphology after exposure to an aqueous solution is still a challenge. In this work, we developed an innovative method based on the use of an ad hoc designed co-axial needle to fabricate gelatin mats crosslinked with a very small amount of genipin and still able to retain their morphology when immersed in aqueous solution. Genipin containing gelatin nanofibers are obtained by allowing mixing of the two solutions just within the needle. Genipin content of the electrospun mats can be modulated by varying feeding rates of the inner and outer solutions and their relative concentration. A subsequent thermal treatment of the mats, performed at 55 degrees C or 37 degrees C for 1 or 3 days and followed by rapid rinsing in ethanol and then in PB, allows one to obtain highly crosslinked gelatin nanofibers that perfectly maintain their morphology after immersion in an aqueous solution, display improved mechanical properties and enhanced stability. This new approach allows us to achieve gelatin mat stabilization using a very small amount of genipin with respect to other methods and to avoid post-treatment of the mats with the crosslinking agent, with a consequent significant reduction of the final cost of the materials. Moreover, in vitro tests demonstrate that the crosslinked mats support normal human primary chondrocyte culture, promoting their differentiation. PMID- 26987304 TI - Characterization and biological evaluation of the introduction of PLGA into biosilicate(r). AB - The aims of this study were to characterize different BS/PLGA composites for their physicochemical and morphological characteristics and evaluate the in vitro and in vivo biological performance. The physicochemical and morphological modifications were analyzed by pH, mass loss, XRD, setting time, and SEM. For in vitro analysis, the osteoblast and fibroblast viability was evaluated. For in vivo evaluations, histopathology and immunohistochemistry were performed in a tibial defect in rats. After incubation, all composites presented lower values in pH and mass loss over time. Moreover, XRD and SEM analysis confirmed that the composites degraded over time. Additionally, pore formation was observed by SEM analysis after incubation mainly in BS/PLGA groups. BS/PLGA showed significantly increased in osteoblast viability 24 h. Moreover, BS/PLGA composites demonstrated an increase in fibroblast viability in all periods analyzed when compared to BS. In the in vivo study, after 2 and 6 weeks of implantation of biomaterials, histopathological findings revealed that the BS/PLGA composites degrades over time, mainly at periphery. Moreover, can be observed the presence of granulation tissue, bone formation, Runx-2, and RANKL immunoexpression in all groups. In conclusion, BS/PLGA composites present appropriate physicochemical characteristics, stimulate the cellular viability, and enhance the bone repair in vivo. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1063-1074, 2017. PMID- 26987306 TI - The effect of positioning cations on acidity and stability of the framework structure of Y zeolite. AB - The investigation on the modification of NaY zeolite on LaHY and AEHY (AE refers Ca and Sr and the molar ratio of Ca and Sr is 1:1) zeolites was proformed by XRD, N2-physisorption (BET), XRF, XPS, NH3-TPD, Py-IR, hydrothermal stability, and catalytic cracking test. These results indicate that HY zeolite with ultra low content Na can be obtained from NaY zeolite through four exchange four calcination method. The positioning capability of La(3+) in sodalite cage is much better than that of AE(2+) and about 12 La(3+) can be well coordinated in sodalite cages of one unit cell of Y zeolite. Appropriate acid amount and strength favor the formation of propylene and La(3+) is more suitable for the catalytic cracking of cyclohexane than that of AE(2+). Our results not only elaborate the variation of the strong and weak acid sites as well as the Bronsted and Lewis acid sites with the change of exchanged ion content but also explore the influence of hydrothermal aging of LaHY and AEHY zeolites and find the optimum ion exchange content for the most reserved acid sites. At last, the coordination state and stabilization of ion exchanged Y zeolites were discussed in detail. PMID- 26987307 TI - Detection of Circulating Tumor Cells Using a Novel Immunomagnetic Bead Method in Lung Cancer Patients. AB - BACKGROUND: Circulating tumor cells (CTCs) are detectable in peripheral blood of metastatic lung cancer patients. In this article, we evaluate a new CTC separation method based on a combination of anti-EpCAM and immunomagnetic beads with the aim to detect CTCs more conveniently and specifically. METHODS: Lung cancer cells were magnetically labeled by anti-EpCAM magnetic beads, and subsequently captured by magnetic separation using our novel device. Isolated lung cancer cells were identified by pathomorphological by hematoxylin-eosin staining protocol. The system was used to detect CTCs in 2 ml blood. Blood samples of healthy donors spiked with lung cancer cell line A549 cells were used to determine the sensitivity and specificity of the method. Prevalence of CTCs was examined in samples from 56 patients with lung cancer. RESULTS: Regression analysis of number of recovered versus spiked A549 cells yielded a coefficient of determination of R(2) = 0.996 (P < 0.001). The average recovery was 68% or more at each spiking level. The coefficient of variation increased as the number of spiked cells decreased, ranging from 6.4% (1,000-cell spike) to 18.4% (50-cell spike). Forty-nine of the fifty-six patients (87.5%) were found to have CTCs in peripheral blood. None of the 2 ml peripheral blood samples of the 20 healthy subjects analyzed were found to have CTCs. CONCLUSIONS: This novel turbulence device provides a new tool allowing for feasible and specific detection of CTCs in lung cancer patients. It is likely clinically useful in diagnosis and monitoring of lung cancer and may have a role in clinical decision making. PMID- 26987309 TI - The Human Variome Project. AB - The practical realization of genomics has meant a growing realization that variant interpretation is a major barrier to practical use of DNA sequence data. The late Professor Dick Cotton devoted his life to innovation in molecular genetics and was a prime mover in the international response to the need to understand the "variome." His leadership resulted in the launch first of the Human Genetic Variation Society and then, in 2006, an international agreement to launch the Human Variome Project (HVP), aimed at data integration enabled by standards and infrastructure of the databases of variants being identified in families with a range of inherited disorders. The project attracted a network of affiliates across 81 countries and earned formal recognition by UNESCO, which now hosts its biennial meetings. It has also signed a Memorandum of Understanding with the World Health Organization. Future progress will depend on longer term secure funding and integration with the efforts of the genomics community where the rapid advances in sequencing technology have enabled variant capture on a previously unimaginable scale. Efforts are underway to integrate the efforts of HVP with those of the Global Alliance for Genomics and Health to provide a lasting legacy of Dick Cotton's vision. PMID- 26987308 TI - Granger causality reveals a dominant role of memory circuit in chronic opioid dependence. AB - Resting-state magnetic resonance imaging has uncovered abnormal functional connectivity in heroin-dependent individuals (HDIs). However, it remains unclear how brain regions implicated in addictions are related in baseline state without conditioned cues in heroin dependent individuals during opioid maintenance treatment (HDIs-OMT). Previous connectivity analysis assessed the strength of correlated activity between brain regions but lacked the ability to infer directional neural interactions. In the current study, we employed Granger causality analysis to investigate directional causal influences among the brain circuits in HDIs-OMT and non-opioid users. The results revealed a weaker effective connectivity between the caudate nucleus implicated in mediating the reward circuit and other brain regions and also a weaker connectivity between the anterior cingulate cortex and medial prefrontal cortex implicated in mediating inhibitory control. Conversely, HDIs-OMT exhibited stronger effective connectivity between the hippocampus and amygdala implicated in mediating learning-memory, and the anterior cingulate cortex involved in mediating inhibitory control while the putamen mediated learned habits, suggesting that the hippocampus and amygdala may propel the memory circuit to override the control circuit and drive the learned habit in HDIs-OMT. Alterations in learning-memory and inhibitory control may contribute jointly and form a basis for relapse risk even after a period of heroin abstinence. Sustained neural effect of opioid dependence on methadone maintenance including hyperactivation in the memory circuit and impairment in the control circuit support the role of the memory circuitry in relapse and may help redefine targets for treatment. PMID- 26987310 TI - A galinstan-based inkjet printing system for highly stretchable electronics with self-healing capability. AB - We report a galinstan-based inkjet printing system to realize highly stretchable electronics with self-healing capability. The printing head made of polydimethylsiloxane (PDMS) consists of a main microfluidic channel and a coplanar channel. The main channel containing the oxidized galinstan is surrounded by the coplanar channel, which is filled with HCl. The HCl vapor effectively permeates the channel wall due to the high gas permeability of PDMS. The oxide skin of galinstan is consistently removed by chemical reaction with the HCl vapor. This allows one to maintain galinstan in a true liquid phase in the main channel. After the fabrication of the printing head with PDMS, the sizes of droplets ejected from the printing head with various flow rates have been characterized. The fabricated inkjet printing system is also utilized to generate complex galinstan patterns on various substrates. An LED-integrated circuit with self-healing capability shows excellent electrical and mechanical performance even after it is twisted more than 180 degrees or stretched up to ~60% more than 2000 times. The experimental results reveal that the proposed system has tremendous potential for stretchable electronic applications in the future. PMID- 26987311 TI - Exploring the implications of distinct mutational signatures and mutation rates in aging and cancer. AB - Signatures of mutagenesis provide a powerful tool for dissecting the role of somatic mutations in both normal and pathological processes. Significantly, cancer genomes are dominated by mutation signatures distinct from those that accumulate in normal tissues with age, with potentially important translational implications. PMID- 26987312 TI - Determination of Nitrogen, Phosphorus, and Potassium Release Rates of Slow- and Controlled-Release Fertilizers: Single-Laboratory Validation, First Action 2015.15. AB - A previously validated method for the determination of nitrogen release patterns of slow- and controlled-release fertilizers (SRFs and CRFs, respectively) was submitted to the Expert Review Panel (ERP) for Fertilizers for consideration of First Action Official Method(SM) status. The ERP evaluated the single-laboratory validation results and recommended the method for First Action Official Method status and provided recommendations for achieving Final Action. The 180 day soil incubation-column leaching technique was demonstrated to be a robust and reliable method for characterizing N release patterns from SRFs and CRFs. The method was reproducible, and the results were only slightly affected by variations in environmental factors such as microbial activity, soil moisture, temperature, and texture. The release of P and K were also studied, but at fewer replications than for N. Optimization experiments on the accelerated 74 h extraction method indicated that temperature was the only factor found to substantially influence nutrient-release rates from the materials studied, and an optimized extraction profile was established as follows: 2 h at 25 degrees C, 2 h at 50 degrees C, 20 h at 55 degrees C, and 50 h at 60 degrees C. PMID- 26987313 TI - Genotyping bacterial and fungal pathogens using sequence variation in the gene for the CCA-adding enzyme. AB - BACKGROUND: To allow an immediate treatment of an infection with suitable antibiotics and bactericides or fungicides, there is an urgent need for fast and precise identification of the causative human pathogens. Methods based on DNA sequence comparison like 16S rRNA analysis have become standard tools for pathogen verification. However, the distinction of closely related organisms remains a challenging task. To overcome such limitations, we identified a new genomic target sequence located in the single copy gene for tRNA nucleotidyltransferase fulfilling the requirements for a ubiquitous, yet highly specific DNA marker. In the present study, we demonstrate that this sequence marker has a higher discriminating potential than commonly used genotyping markers in pro- as well as eukaryotes, underscoring its applicability as an excellent diagnostic tool in infectology. RESULTS: Based on phylogenetic analyses, a region within the gene for tRNA nucleotidyltransferase (CCA-adding enzyme) was identified as highly heterogeneous. As prominent examples for pro- and eukaryotic pathogens, several Vibrio and Aspergillus species were used for genotyping and identification in a multiplex PCR approach followed by gel electrophoresis and fluorescence-based product detection. Compared to rRNA analysis, the selected gene region of the tRNA nucleotidyltransferase revealed a seven to 30-fold higher distinction potential between closely related Vibrio or Aspergillus species, respectively. The obtained data exhibit a superb genome specificity in the diagnostic analysis. Even in the presence of a 1,000-fold excess of human genomic DNA, no unspecific amplicons were produced. CONCLUSIONS: These results indicate that a relatively short segment of the coding region for tRNA nucleotidyltransferase has a higher discriminatory potential than most established diagnostic DNA markers. Besides identifying microbial pathogens in infections, further possible applications of this new marker are food hygiene controls or metagenome analyses. PMID- 26987316 TI - Erratum to: Blood or spores? A cautionary note on interpreting cellular debris on human skeletal remains. PMID- 26987314 TI - The matrix domain contributes to the nucleic acid chaperone activity of HIV-2 Gag. AB - BACKGROUND: The Gag polyprotein is a multifunctional regulator of retroviral replication and major structural component of immature virions. The nucleic acid chaperone (NAC) activity is considered necessary to retroviral Gag functions, but so far, NAC activity has only been confirmed for HIV-1 and RSV Gag polyproteins. The nucleocapsid (NC) domain of Gag is proposed to be crucial for interactions with nucleic acids and NAC activity. The major function of matrix (MA) domain is targeting and binding of Gag to the plasma membrane but MA can also interact with RNA and influence NAC activity of Gag. Here, we characterize RNA binding properties and NAC activity of HIV-2 MA and Gag, lacking p6 domain (GagDeltap6) and discuss potential contribution of NC and MA domains to HIV-2 GagDeltap6 functions and interactions with RNA. RESULTS: We found that HIV-2 GagDeltap6 is a robust nucleic acid chaperone. HIV-2 MA protein promotes nucleic acids aggregation and tRNA(Lys3) annealing in vitro. The NAC activity of HIV-2 NC is affected by salt which is in contrast to HIV-2 GagDeltap6 and MA. At a physiological NaCl concentration the tRNA(Lys3) annealing activity of HIV-2 GagDeltap6 or MA is higher than HIV-2 NC. The HIV-2 NC and GagDeltap6 show strong binding to the packaging signal (Psi) of HIV-2 RNA and preference for the purine rich sequences, while MA protein binds mainly to G residues without favouring Psi RNA. Moreover, HIV-2 GagDeltap6 and NC promote HIV-2 RNA dimerization while our data do not support MA domain participation in this process in vitro. CONCLUSIONS: We present that contrary to HIV-1 MA, HIV-2 MA displays NAC activity and we propose that MA domain may enhance the activity of HIV-2 GagDeltap6. The role of the MA domain in the NAC activity of Gag may differ significantly between HIV-1 and HIV-2. The HIV-2 NC and MA interactions with RNA are not equivalent. Even though both NC and MA can facilitate tRNA(Lys3) annealing, MA does not participate in RNA dimerization in vitro. Our data on HIV-2 indicate that the role of the MA domain in the NAC activity of Gag differs not only between, but also within, retroviral genera. PMID- 26987317 TI - Tongue protrusion in burned bodies. AB - Protrusion of the tongue is a common, though often neglected finding in fire fatalities. According to a study recently published by Bernitz et al., it is an indicator of vital burning. This statement has been doubted repeatedly. Retrospective analysis of 61 fire fatalities from our own autopsy material did not show any statistically significant increased incidence of tongue protrusion in deaths with vital exposure to heat. Similarly, there was no correlation with the degree of destruction by the fire in general or the extent of cervical burning. Further prospective studies seem to be necessary also with regard to the pathophysiological processes. PMID- 26987315 TI - Japan Unified Protocol Clinical Trial for Depressive and Anxiety Disorders (JUNP study): study protocol for a randomized controlled trial. AB - BACKGROUND: The unified protocol for the transdiagnostic treatment of emotional disorders is a promising treatment approach that could be applicable to a broad range of mental disorders, including depressive, anxiety, trauma-related, and obsessive-compulsive disorders. However, no randomized controlled trial has been conducted to verify the efficacy of the unified protocol on the heterogeneous clinical population with depressive and anxiety disorders. METHODS/DESIGN: The trial was designed as a single-center, assessor-blinded, randomized, 20-week, parallel-group superiority study in order to compare the efficacy of the combination of unified protocol and treatment-as-usual versus waiting-list with treatment-as-usual for patients with depressive and/or anxiety disorders. The primary outcome was depression at 21 weeks, assessed by the 17-item version of the GRID-Hamilton Rating Scale for Depression. Estimated minimum sample size was 27 participants in each group. We will also examine the treatment mechanisms, treatment processes, and neuropsychological correlates. DISCUSSION: The results of this study will clarify the efficacy of the unified protocol for depressive and anxiety disorders, and the treatment mechanism, process, and neurological correlates for the effectiveness of the unified protocol. If its efficacy can be confirmed, the unified protocol may be of high clinical value for Japan, a country in which cognitive behavioral treatment has not yet been widely adopted. TRIAL REGISTRATION: ClinicalTrials.gov NCT02003261 (registered on December 2, 2013). PMID- 26987318 TI - Fatal toxicity index of medicinal drugs based on a comprehensive toxicology database. AB - The fatal toxicity index (FTI) is the absolute number of fatal poisonings caused by a particular drug divided by its consumption figure. Consequently, it is a useful measure in evaluating toxicity of the drug and its relevance in fatal poisonings. In this study, we assessed the FTI of medicinal drugs in 3 years (2005, 2009, and 2013) in Finland. As the measure of drug consumption, we used the number of defined daily doses (DDD) per population in each year. There were 70 medicinal drugs in Finland for which the mean FTI expressed as the number of deaths per million DDD over the three study years was higher or equal to 0.1. The Anatomical Therapeutic Chemical (ATC) classification system was used for the classification of the active ingredients of medicinal drugs according to the organ or system which they act on. Of these 70 drugs, 55 drugs (78.6 %) acted on the nervous system (denoted by ATC code N), 11 (15.7 %) on the cardiovascular system (C), three (4.3 %) on the alimentary tract and metabolism (A), and one (1.4 %) on the musculoskeletal system (M). The nervous system drugs consisted of 20 psycholeptics, (ATC code N05), 20 psychoanaleptics (N06), eight analgesics (N02), six antiepileptics (N03), and one other nervous system drug (N07). The highest individual FTIs were associated with the opioids methadone, dextropropoxyphene, oxycodone, tramadol, and morphine; the antipsychotics levomepromazine and chlorprothixene; and the antidepressants doxepin, amitriptyline, trimipramine, and bupropion. Buprenorphine was not included in the study, because most of the fatal buprenorphine poisonings were due to smuggled tablets. A clearly increasing trend in FTI was observed with pregabalin and possibly with bupropion, both drugs emerging as abused substances. PMID- 26987319 TI - Genetic distribution of 15 autosomal STR markers in the Punjabi population of Pakistan. AB - Genetic diversity of 15 autosomal short tandem repeat (STR) loci was evaluated in 713 unrelated individual samples of a Punjabi population of Pakistan. These loci were scrutinized to establish allelic frequencies and statistical parameters of forensic and paternity interests. A total of 165 alleles were observed with the corresponding allele frequencies ranging from 0.001 to 0.446. D2S1338 was found as the most informative locus while TPOX (0.611) was the least discriminating locus. The combined power of discrimination (CPD), the combined probability of exclusion (CPE), and cumulative probability of matching (CPM) were found equaled to 0.999999999999999998606227424808, 0.999995777557989, and 1.37543 * 10-18, respectively. All the loci followed the Hardy-Weinberg equilibrium after the Bonferroni correction (p < 0.0033) except one locus D3S1358. The study revealed that these STR loci are highly polymorphic, suitable for forensic and parentage analyses. In comparison to different populations (Asians and non-Asians), significant differences were recorded for these loci. PMID- 26987320 TI - Application of Array Comparative Genomic Hybridization in Newborns with Multiple Congenital Anomalies. AB - Major congenital anomalies are detectable in 2-3 % of the newborn population. Some of their genetic causes are attributable to copy number variations identified by array comparative genomic hybridization (aCGH). The value of aCGH screening as a first-tier test in children with multiple congenital anomalies has been studied and consensus adopted. However, array resolution has not been agreed upon, specifically in the newborn or infant population. Moreover, most array studies have been focused on mixed populations of intellectual disability/developmental delay with or without multiple congenital anomalies, making it difficult to assess the value of microarrays in newborns. The aim of the study was to determine the optimal quality and clinical sensitivity of high resolution array comparative genomic hybridization in neonates with multiple congenital anomalies. We investigated a group of 54 newborns with multiple congenital anomalies defined as two or more birth defects from more than one organ system. Cytogenetic studies were performed using OGT CytoSure 8 * 60 K microarray. We found ten rearrangements in ten newborns. Of these, one recurrent syndromic microduplication was observed, whereas all other changes were unique. Six rearrangements were definitely pathogenic, including one submicroscopic and five that could be seen on routine karyotype analysis. Four other copy number variants were likely pathogenic. The candidate genes that may explain the phenotype were discussed. In conclusion, high-resolution array comparative hybridization can be applied successfully in newborns with multiple congenital anomalies as the method detects a significant number of pathogenic changes, resulting in early diagnoses. We hypothesize that small changes previously considered benign or even inherited rearrangements should be classified as potentially pathogenic at least until a subsequent clinical assessment would exclude a developmental delay or dysmorphism. PMID- 26987321 TI - Cytogenomic Evaluation of Children with Congenital Anomalies: Critical Implications for Diagnostic Testing and Genetic Counseling. AB - Identification of submicroscopic chromosomal aberrations, as a cause of structural malformations, is currently performed by MLPA (multiplex ligation dependent probe amplification) or array CGH (array comparative genomic hybridization) techniques. The aim of this study was the evaluation of diagnostic usefulness of MLPA and array CGH in patients with congenital malformations or abnormalities (at least one major or minor birth defect, including dysmorphism) with or without intellectual disability or developmental delay and the optimization of genetic counseling in the context of the results obtained. The MLPA and array CGH were performed in 91 patients diagnosed with developmental disorders and major or minor congenital anomalies. A total of 49 MLPA tests toward common microdeletion syndromes, 42 MLPA tests for subtelomeric regions of chromosomes, two tests for common aberrations in autism, and five array CGH tests were performed. Eight (9 %) patients were diagnosed with microdeletion MLPA, four (4 %) patients with subtelomeric MLPA, one (1 %) patient with autism MLPA. Further three (3 %) individuals had rearrangements diagnosed by array CGH. Altogether, chromosomal microaberrations were found in 16 patients (17 %). All the MLPA-detected rearrangements were found to be pathogenic, but none detected with array CGH could unequivocally be interpreted as pathogenic. In patients with congenital anomalies, the application of MLPA and array CGH techniques is efficient in detecting syndromic and unique microrearrangements. Consistent pre MLPA test phenotyping leads to better post-test genetic counseling. Incomplete penetrance and unknown inheritance of detected variants are major issues in clinical interpretation of array CGH data. PMID- 26987322 TI - Respiratory Function and Language Abilities of Profoundly Deaf Adolescents with and without Cochlear Implants. AB - The objective of the study was to investigate whether hearing loss has an effect on the ventilatory functional capability and whether possible deviations of ventilatory variables from the reference ranges could have to do with the language abilities of deaf adolescents. Spirometric evaluations were performed in 72 prelingually profoundly deaf adolescents with and without cochlear implants (CI) and compared with the results of a control group consisting of 48 participants with normal hearing (CG). The deaf adolescents showed a significantly lower vital capacity (VC), forced vital capacity (FVC), and expiratory flows (PEF and MEF) compared with their hearing peers. The adolescents with CI demonstrated predominantly the oral communication mode, which however did not affect the students' education achievements. Perseverance of oral communication was also associated with higher FVC and PEF, compared with deaf participants without CI. We conclude that sensory deprivation of prelingually deaf adolescents affects the respiratory system function. The use of oral communication seems to have beneficial effects on respiratory performance in profoundly deaf adolescents. PMID- 26987323 TI - High-Frequency Jet Ventilation against Small-Volume Conventional Mechanical Ventilation in the Rabbit Models of Neonatal Acute Lung Injury. AB - Patients with acute lung injury are ventilated by conventional mechanical ventilation (CMV) rather than high-frequency jet ventilation (HFJV). This study estimated the potential usefulness of HFJV in acute lung injury. The issue was addressed by comparing the effects on lung function of CMV and HFJV in two rabbit models of neonatal acute lung injury: repetitive saline lung lavage (LAV) and meconium aspiration syndrome (MAS) induced by intratracheal meconium instillation. The animals were then ventilated with either HFJV or CMV for 4 h. Ventilatory pressures, blood gases, and indexes of gas exchange were assessed. Lung edema formation was expressed as wet-dry lung weight ratio. Both LAV and MAS significantly decreased lung compliance, increased airway resistance, and caused severe hypoxemia, hypercarbia, and acidosis. Although CMV was superior to HFJV at 1 h of ventilation, there were no clinically relevant differences in lung function or edema formation between CMV and LAV in both models of respiratory insufficiency at 4 h of ventilation. We conclude that, HFJV may be used for ventilation in acute non-homogenous lung injury. PMID- 26987324 TI - Impact of Endobronchial Ultrasound Guided Transbronchial Needle Aspiration on Diagnostic Yield of Bronchoscopy in Patients with Mediastinal Lymph Node Enlargement. AB - Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) had an enormous impact on the current advancement in diagnostic bronchoscopy. The aims of the present study were: (1) to evaluate the added value of EBUS-TBNA to routine diagnostic bronchoscopy performed in patients with mediastinal lymph node enlargement and (2) to identify factors that affect the diagnostic yield of EBUS TBNA. We retrospectively analyzed 712 EBUS-TBNA procedures out of the 4081 bronchoscopies performed in the years 2009-2014. The number of EBUS-TBNA procedures increased from 61 (8.8 % of all bronchoscopies) in 2009 to 160 (21.4 %) in 2014. In 625 (87.8 %) patients adequate cytological material was obtained. Based on cytological examination of EBUS-TBNA aspirates, specific diagnosis was made in 367 (51.5 %) patients. The forceps biopsy of endobronchial lesions provided specific diagnosis in only 204 (28.6 %) patients. The percentage of patients with EBUS-TBNA based diagnosis increased steadily from 34.4 % in 2009 to 65.0 % in 2014 (p < 0.0001). The median lymph node diameter in patients with positive EBUS-TBNA findings was 20 (IQR 15-30) mm and was significantly larger than that in patients with negative EBUS-TBNA results (15 (IQR 10-20) mm, p = 0.0001). The highest diagnostic yield (78.5 %) was found in patients with lymph node dimension between 31 mm and 40 mm. We conclude that EBUS-TBNA is a valuable diagnostic method in an unselected group of patients with mediastinal lymph node enlargement. The percentage of positive EBUS-TBNA diagnoses is related to lymph node dimensions. The overall efficacy of EBUS-TBNA improves with increasing years of experience. PMID- 26987325 TI - Lung Cancer and Multiple Neoplasms: A Retrospective Analysis. AB - Over the past 30 years there has been an increase in the survival of cancer patients resulting from the advances in cancer management and improved detection of cancer in its early stages. The aim of the study was to analyze the frequency of multiple malignancies in a sample of hospitalized patients in Poland. We analyzed retrospectively the records of 1112 cancer patients hospitalized in the period of January 2013 - August 2014. The criterion for inclusion into the group of multiple malignancy patients was the presence of at least two different malignancies. We found 52 cases in which lung cancer accompanied different malignancies and 4 cases where the multiple malignancy was not associated with the respiratory system. Lung cancer was chronologically the first malignancy unravelled in 11 patients, the second in 39, and the third in 2. Other malignancies chronologically being the first to be unravelled in patients included the following: colorectal cancer in 8 patients, prostatic cancer in 6, renal cell carcinoma 4, and the subsequent: prostate cancer 4, bladder cancer 3, hematopoietic malignancies 3, and breast cancer 2. We conclude that patients with multiple malignancy account for 5.0 % of lung cancer patients. Lung cancer is more frequent as a second malignancy developing in patients with multiple malignancy. Synchronous cancers become apparent at older age than metachronous cancers. PMID- 26987326 TI - Cryptogenic Organizing Pneumonia: IL-1beta, IL-6, IL-8, and TGF- beta1 Serum Concentrations and Response to Clarithromycin Treatment. AB - Cryptogenic organizing pneumonia (COP) is a distinct clinicopathological entity with unknown etiology. Inflammatory cytokines play a role in the development of the disease. The present study was performed to assess the correlation between concentrations of IL-1beta, IL-6, IL-8, and TGF-beta1 in the serum with response to clarithromycin (CAM) treatment in patients with COP. A total of 39 patients with COP were enrolled in to this study. An oral dose of 500 mg CAM was administered to all of the patients twice daily for 3 months. A complete response was noticed in 31 (80 %) of patients, and 8 (20 %) patients failed to respond to treatment. The concentration of cytokines were assessed by ELISAs before and after treatment. CAM treatment was associated with decreases in serum IL-6 (3.8 pg/mL [IQR 0.9-11.8] vs. 1.1 pg/mL [IQR 0.2-3.1]; p = 0.004), IL-8 (13.6 pg/mL [IQR 9.8-17.5] vs. 8.1 pg/mL [IQR 6.2-13.2]; p = 0.004), and TGF-beta1 (37.1 ng/mL [IQR 31.7-46.2] vs. 25.7 ng/mL [IQR 22-41.7];p = 0.0001), which was particularly notable in the responders. We conclude that IL-6, IL-8, and TGF beta1 may play a role in the pathogenesis of COP, as their decreased concentrations were associated with a positive response to CAM treatment. PMID- 26987328 TI - The Role of Dysregulated MicroRNA Expression in Lung Cancer. AB - MicroRNAs (miRNAs) are a class of small single-stranded non-protein-coding RNAs that play important regulatory roles in many cellular processes including cell proliferation, differentiation, growth control, and apoptosis. They regulate gene expression on the posttranscriptional level by translational repression, mRNA cleavage, or mRNA degradation in various physiological and pathological processes. In addition, some miRNAs can function as oncogenes or tumor suppressors, so they can regulate several genes that play important roles in tumorigenesis. It was found that miRNAs are directly involved in many types of cancer, including lung cancer. Lung cancer is the leading cause of cancer mortality worldwide with a substantially low survival rate. In this work, we summarize recent findings related to miRNAs mechanisms of action and the role of their dysregulated expression in lung tumorigenesis. We describe the most important miRNAs involved in lung cancer development and targets of their activity. The understanding of the miRNA regulation in cancer may help better understand the molecular mechanisms of tumorigenesis and their importance in cancerous transformation. PMID- 26987327 TI - Associations of CYP1A2 Polymorphisms with the Risk Haplotypes in Lung Cancer in the Slovak Population. AB - Phase I enzymes, including cytochrome P450, family 1, subfamily A, and polypeptide 2 (CYP1A2), are involved in the activation of carcinogens to reactive intermediates that are capable of binding covalently to DNA to form DNA adducts, potentially initiating the carcinogenic process. The aim of present study was to investigate the association of CYP1A2 gene polymorphisms and haplotypes with lung cancer risk. A case-control study was carried out on 105 lung cancer patients and 189 controls. To investigate three CYP1A2 polymorphisms: rs2472299, rs2470890, rs11072508 we used a high resolution melting analysis. We found significant allele associations (rs2470890 and rs2422299) with lung cancer risk. We searched for meaningful associations for all variants in the dominant, recessive, and additive genetic models. Genotype associations in the recessive model were of marginal significance for the same single nucleotide polymorphisms. A haplotype analysis included five variants with the frequency higher than 1 %. The haplotype "acc", present with the highest frequency, was associated with increased lung cancer risk (38.7 % vs. 31.5 %; OR 1.38; 95 %CI 0.95-2.01). On the contrary, rare haplotype "gtc" was significantly associated with decreased lung cancer risk in the Slovak population. In conclusion, the present study identified the risk alleles and haploid genotype associations of the CYP1A2 gene in lung cancer. PMID- 26987329 TI - Viral Infections in Children in the 2014/2015 Epidemic Season in Poland. AB - In every epidemic season, viral infections affect the general population, including children, which is an underestimated issue. The present study demonstrates the results of examination of 802 clinical samples obtained from pediatric patients aged 0-14 years during the 2014/2015 epidemic season in Poland. The study was part of the virological surveillance systems - SENTINEL and NON-SENTINEL. A positive result for virological infection was obtained in 50.9 % of samples tested. The distribution of positive results by the age-groups was as follows: 38.2 % in 0-4 years old, 8.5 % in 5-9 years old, and 4.2 % in 10-14 years old children. Influenza viruses accounted for 48.0 % and influenza-like viruses for 52.0 % of all positive samples. Concerning the influenza virus, molecular biology-based techniques confirmed the infection caused by influenza type A in 63.3 % of samples, consisting of unsubtyped A virus detected in 65.3 % of cases of this sample group, subtype A/H1N1/pdm09 in 28.2 %, and subtype A/H3N2/ in 6.5 %. Genetic material of influenza B was detected in 36.7 % of samples. In a group of influenza-like viruses, the predominant virus was respiratory syncytial virus (RSV) in as many as 96.2 % of samples, followed by parainfluenza viruses: PIV3 - 1.4 % and PIV1 - 1.0 %. Attention should be paid to the coinfection of respiratory viruses. There were six possible coinfection combinations reported in Poland, with four of them related to children up to 14 years old. PMID- 26987330 TI - Impairment of Immune Function in Children with Familial Hemophagocytic Lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a severe systemic syndrome associated with hyperactivation of macrophages and impaired regulation of the immune system. Two forms of HLH are currently recognized: genetically determined or familial (FHLH), and secondarily developed in the course of primary diseases, like autoimmune disorders, rheumatoid disorders, cancers, or infections. In the Polish population, FHLH is rather rare. The aim of the present study was to assess the immune function in a group of children with clinical symptoms suggesting FHLH. Forty five children with suspected HLH of the median age of 4 years and 15 healthy children, taken as a control group, were enrolled into the study. All presented results were obtained with the use of flow cytometry. In the HLH group, there were only three cases identified with the UNC13D gene mutation responsible for the FHLH3 phenotype. Another four children, without known mutation, were classified as FHLH because of frequent recurrence of the disease. In all cases of FHLH, cell cytotoxicity was impaired compared with healthy children (p = 0.003). Perforin expression in FHLH was normal or higher than that observed in controls (p = 0.09). In case of patients with mutation in the Munc13 protein, degranulation was lower than that in healthy children (<5 %). The findings of this study demonstrate that children with known mutations responsible for the FHLH development are immunocompromised. However, it requires further elucidation whether the presence of currently unknown mutations could lead to a similar phenotype. PMID- 26987332 TI - Obstructive Sleep Apnea Is Related to Increased Arterial Stiffness in Ultrasound Speckle-Tracking Analysis. AB - Obstructive sleep apnea (OSA) is an independent risk factor for atherosclerosis. The aim of our study was to determine arterial stiffness in OSA patients by means of the ultrasound speckle-tracking-based method. Twenty six OSA patients and 17 control subjects were enrolled in the study. The speckle-tracking-based analysis of carotid artery included circumferential strains, circumferential strain rates, radial displacement, and radial strain rates. We found that the global average circumferential strains, circumferential strain rates, and radial displacement were significantly lower in OSA patients compared to controls (2.19 +/- 0.30 % vs. 4.17 +/- 0.33 %, 0.22 +/- 0.03 l/s vs. 0.31 +/- 0.02 l/s, 0.10 +/- 0.01 mm vs. 0.16 +/- 0.02 mm, respectively, p < 0.05 for all). There were no significant differences in radial strain rates between the groups (0.32 +/- 0.04 % vs. 0.33 +/- 0.01 %). We conclude that OSA is associated with an increased arterial stiffness. PMID- 26987331 TI - Frequency of Rare Alpha-1 Antitrypsin Variants in Polish Patients with Chronic Respiratory Disorders. AB - The SERPINA1 gene encoding the alpha-1 antitrypsin (A1AT) protein is highly polymorphic. It is known that, apart from the most prevalent PI*S and PI*Z A1AT deficiency variants, other so-called rare variants also predispose individuals to severe chronic respiratory disorders such as emphysema and chronic obstructive pulmonary disease. Our aim was to assess the frequencies of common and rare SERPINA1 mutations in a group of 1033 Polish patients referred for A1AT deficiency diagnostics due to chronic respiratory disorders in the period of January 2014-September 2015. All blood samples were analyzed according to the routine diagnostic protocol, including A1AT serum concentration assessment by nephelometry and immune isoelectric focusing, followed by PCR genotyping and direct sequencing when necessary. A total of 890 out of the 1033 samples (86 %) carried the normal PI*MM genotype, whereas, in 143 samples (14 %), at least one A1AT deficiency variant was detected. In 132 subjects, PI*S (2.1 %) and PI*Z (10.8 %) common deficiency alleles were identified, yielding frequencies of 0.011 and 0.062, respectively. Rare SERPINA1 variants were detected in nine patients: PI*F (c.739C>T) (n = 5) and PI*I (c.187C>T) (n = 4). Samples from the patients with an A1AT serum concentration below 120 mg/dl and presenting a PI*MM-like phenotypic pattern were retrospectively analyzed by direct sequencing for rare SERPINA1 mutations, revealing a PI*M2Obernburg (c.514G>T) mutation in one patient and a non-pathogenic mutation (c.922G>T) in another. We conclude that the deficiency PI*Z A1AT allele is considerably more common in patients with chronic respiratory disorders than in the general Polish population. The prevalence of the PI*F allele seems higher than in other European studies. PMID- 26987333 TI - Polymorphisms of Selected DNA Repair Genes and Lung Cancer in Chromium Exposure. AB - Chromium is a well-known mutagen and carcinogen involved in lung cancer development. DNA repair genes play an important role in the elimination of genetic changes caused by chromium exposure. In the present study, we investigated the polymorphisms of the following DNA repair genes: XRCC3, participating in the homologous recombination repair, and hMLH1 and hMSH2, functioning in the mismatch repair. We focused on the risk the polymorphisms present in the development of lung cancer regarding the exposure to chromium. We analyzed 106 individuals; 45 patients exposed to chromium with diagnosed lung cancer and 61 healthy controls. Genotypes were determined by a PCR-RFLP method. We unravelled a potential for increased risk of lung cancer development in the hMLH1 (rs1800734) AA genotype in the recessive model. In conclusion, gene polymorphisms in the DNA repair genes underscores the risk of lung cancer development in chromium exposed individuals. PMID- 26987334 TI - The Effect on Cognition of Mitochondrial Respiratory System Proteins in Peripheral Blood Mononuclear Cells in the Course of Lung Cancer. AB - Peripheral blood mononuclear cells (PBMC) represent an easily available population of cells for the studies on remote effects of lung cancer. NADH dehydrogenase (ubiquinone) Fe-S protein-1 (Ndufs1), a marker of mitochondrial complex I, and mitochondrially encoded cytochrome c oxidase 1 (MTCO1), a marker of complex IV, may participate in cognitive decline during the course of lung cancer. In this study, Ndufs1 and MTCO1 expression in PBMC was evaluated by means of ELISA in 80 lung cancer patients. Mini-Mental State Examination (MMSE) were conducted Trail Making Tests (TMT-A and TMT-B) at baseline and after the 6 months' follow-up. Autoantibodies were identified by means of indirect immunofluorescence and line blot. We found that enhanced levels of Ndufs1 in PBMC were related to impaired cognitive performance; TMT-A of 13.6 +/- 3.1 s and TMT-B of 162.5 +/- 46.4 s compared with 8.6 +/- 4.5 s (p = 0.003) and 124.8 +/- 51.8 s (p < 0.05), respectively, in the case of low Ndufs-1 levels. The Ndufs1 expression at baseline was associated with MMSE - taub (Kendall's tau-b) = -0.31; p = 0.024; TMT-A - taub = 0.30; p = 0.001), and TMT-B - taub = 0.199; p = 0.012) after the 6 months' follow-up. Higher MTCO1 expression was accompanied by worse TMT-A results than in case of inhibited MTCO1; 11.1 +/- 5.8 s vs. 8.5 +/- 4.1 s; respectively; p = 0.048. MTCO1 expression was correlated with TMT-A results (taub = 0.17; p = 0.034) at baseline. We conclude that stimulation of PBMC mitochondrial function in lung cancer patients is associated with cognitive impairment. Mitochondrial dysfunction in PBMC may reflect cytotoxicity responsible for neurological deficits. PMID- 26987335 TI - Humoral Immune Response against Neural Antigens and Its Effects on Cognition in Lung Cancer Patients. AB - Cognitive impairment develops as a clinical manifestation of immune-mediated indirect effects of malignancy in lung cancer patients. This study aimed to evaluate the effects of humoral immune response on cognition in lung cancer patients. Fifty-one lung cancer patients were subjected to neurological examination: Mini Mental State Examination (MMSE), Trail Making Test (TMT), and Hamilton scale. The Psychology Experiment Building Language software was used for the evaluation of digit span, simple reaction time (SRT), and choice reaction time (CRT) tests. Serum samples were tested for the presence of onconeuronal antibodies and antineural antibodies. The results demonstrate that autoantibodies were found in 31 % patients. MMSE scores were lower (26.7 +/- 2.7) in seropositive patients than in seronegative subjects (28.7 +/- 1.2; p = 0.013). Executive functions were also influenced by the presence of autoantibodies. The humoral immune response in lung cancer patients affected both SRT and CRT. We conclude that the humoral immune response in lung cancer patients is associated with cognitive impairment. Cognitive impairment is associated with both specific reactions against onconeuronal or antineural antigens and non-organ specific reactions against nucleosome antigens. PMID- 26987336 TI - Relationship Between 25(OH)D and IGF-I in Children and Adolescents with Growth Hormone Deficiency. AB - Recent studies have shown that vitamin D has an impact on the production and secretion of IGF-I in the liver. The aim of our study was to investigate the relationship between the concentrations of 25-hydroxy vitamin D [25(OH)D] and insulin-like growth factor I (IGF-I) in growth hormone deficient children and adolescents before recombinant human growth hormone (rhGH) treatment. The study was retrospective and included 84 children and adolescents aged 4-17. Prior to initiating rhGH therapy, concentrations of 25(OH)D and IGF-I were measured in all patients. IGF-I concentrations were normalized for bone age. The studied group was divided into two subgroups according to serum 25(OH)D levels. Significant positive correlations between 25(OH)D concentration and IGF-I SDS-normalized for bone age were observed in both studied subgroups. The results of our study suggest that vitamin D deficiency could influence IGF-I concentrations in children and adolescents with growth hormone deficiency, and vitamin D deficiency should be normalized before the measurement of IGF-I concentrations to obtain the reliable and unbiased IGF-I values. PMID- 26987337 TI - Intracellular and Extracellular Cytokines in A549 Cells and THP1 Cells Exposed to Cigarette Smoke. AB - Cigarette smoke (CS) activates inflammatory cells and increases cytokine levels producing local and systemic inflammation. To assess changes in intracellular and extracellular cytokine levels we used human epithelial (A549 cells) and monocyte (THP-1) cell lines grown for 24 h in cigarette smoke-conditioned media. Cytokines were assessed using immunostaining/flow cytometry and ELISA assay. In THP1cells, grown in CS-conditioned media, the intracellular interleukins IL-1beta, IL-6, and IL-10 increased by more than tenfold, while less significant increases were found in A549 cells. IL-1alpha and IL-1beta, but not IL-6 or IL-10, were increased in the culture media, while IL-2 was raised by about fivefold only in the culture medium of A549 cells. IL-4, IL-6, IL-8, IL-10, IL-12, and tumor necrosis factor alpha were undetectable, while only a slight increase was observed in extracellular IL-17A (by about 60 %) in the medium of A549 cells and by about 115 % in the medium of THP1 cells. The interferon gamma (IFNgamma) was increased by about eightfold, but only in the medium of THP1 cells grown with CS. We conclude that IL-1 and INFgamma are the key cytokines responsible for pro-inflammatory signaling in epithelial cells and monocytes, respectively, exposed to cigarette smoke. PMID- 26987338 TI - The Guinea Pig Sensitized by House Dust Mite: A Model of Experimental Cough Studies. AB - The guinea pig sensitized by ovalbumin is the most widely used model to study cough experimentally, as the neurophysiology of the vagus nerve in the guinea pig is closest to humans. Nonetheless, the choice of the antigen remains questionable, which influences the translation of results into clinical medicine. The present study seeks to develop an alternative model of cough study using house dust mite sensitization (HDM). Thirty guinea pigs were divided into the HDM group, ovalbumin (OVA) group, and control group based on their cough response to 0.4 M citric acid. In the HDM group animals were sensitized by 0.25 %HDM aerosol, which they inhaled for 5 min over 5 days, followed by inhalation of 0.5 %HDM in the same protocol. Sensitization was confirmed by a skin test. Symptoms of allergic rhinitis were induced by intranasal application of 15 MUl 0.5 %HDM and cough challenges with citric acid were performed. Airway resistance was measured in vivo by Pennock's method. We found that both HDM and OVA-sensitized groups showed a significantly enhanced nasal reactivity and cough response compared with controls. The airway resistance data did not show significant differences. We conclude that the HDM cough model replicates functional aspects of the OVA model, which may make it an alternative to the latter. However, the superiority of the HDM model for experimental cough studies remains to be further explored. PMID- 26987339 TI - Characterization of temporal expressions of FOXO and pFOXO proteins in the hippocampus by kainic acid in mice: involvement of NMDA and non-NMDA receptors. AB - In the present study, we characterized the expression and role of forkhead box O (FoxO3a) in kainic acid (KA)-induced hippocampal neuronal cell death. FoxO3a and pFoxO3a expression in the CA1, CA2, and dentate gyrus regions in the hippocampus increased 0.5 and 1 h after intracerebroventricular administration of KA. In addition, both FoxO3a and pFoxO3a expression in the hippocampal CA3 region increased significantly and equally for 1 h but decreased gradually for 24 h after KA administration. In particular, the KA-induced increases in FoxO3a and pFoxO3a expression in the hippocampal CA3 region were inhibited by pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist (MK-801, dizocilpine, 1 ug/5 ul) or a non-NMDA receptor antagonist (CNQX, 6-cyano-7-nitroquinoxaline-2,3 dione, 0.5 ug/5 ul). Furthermore, dizocilpine and CNQX produced a neuroprotective effect against KA-induced neuronal death in the CA3 region of the hippocampus. Our results suggest that FoxO3a and pFoxO3 expression is upregulated by KA. Both FoxO3a and pFoxO3a expression appear to be responsible for KA-induced neuronal death in the CA3 region of the hippocampus. PMID- 26987340 TI - Re: "Did you write a protocol before starting your project?". AB - We read the article "did you write a protocol before starting your project?" by Bando et al. In this letter, we express our opinion regarding the importance of writing protocols prior to starting projects. PMID- 26987341 TI - Ankylosing spondylitis diagnosis in US patients with back pain: identifying providers involved and factors associated with rheumatology referral delay. AB - This study aimed to identify providers involved in diagnosing ankylosing spondylitis (AS) following back pain diagnosis in the USA and to identify factors leading to the delay in rheumatology referrals. The Truven Health MarketScan(r) US Commercial Database was searched for patients aged 18-64 years with back pain diagnosis in a non-rheumatology setting followed by AS diagnosis in any setting during January 2000-December 2012. Patients with a rheumatologist visit on or before AS diagnosis were considered referred. Cox regression was used to determine factors associated with referral time after adjusting for age, sex, comorbidities, physician specialty, drug therapy, and imaging procedures. Of 3336 patients included, 1244 (37 %) were referred to and diagnosed by rheumatologists; the others were diagnosed in primary care (25.7 %), chiropractic/physical therapy (7 %), orthopedic surgery (3.8 %), pain clinic (3.6 %), acute care (3.4 %), and other (19.2 %) settings. Median time from back pain diagnosis to rheumatology referral was 307 days and from first rheumatologist visit to AS diagnosis was 28 days. Referred patients were more likely to be younger (hazard ratio [HR] = 0.986; p < 0.0001), male (HR = 1.15; p = 0.0163), diagnosed with uveitis (HR = 1.49; p = 0.0050), referred by primary care physicians (HR = 1.96; p < 0.0001), prescribed non-steroidal anti-inflammatory drugs (HR = 1.55; p < 0.0001), disease modifying antirheumatic drugs (HR = 1.33; p < 0.0001), and tumor necrosis factor inhibitors (HR = 1.40; p = 0.0036), and to have had spinal/pelvic X-ray prior to referral (HR = 1.28; p = 0.0003). During 2000-2012, most patients with AS were diagnosed outside of rheumatology practices. The delay before referral to rheumatology was 10 months; AS diagnosis generally followed within a month. Earlier referral of patients with AS signs and symptoms may lead to more timely diagnosis and appropriate treatment. PMID- 26987343 TI - The oxalate content of oolong tea and its relationship with soaking times. PMID- 26987344 TI - Calculating the cost of reusable materials in endourological stone surgeries. PMID- 26987345 TI - It's the workforce, stupid. PMID- 26987346 TI - The 2004 tsunami and mental health in Thailand: a longitudinal analysis of one and two-year post-disaster data. AB - Some 280,000 people died in the Indian Ocean tsunami on 26 December 2004. This cohort study examined its impact on mental health one and two years later. It did so by investigating the association between six consequent variables (personal injury, loss of home, loss of business, death of a family member, injury to a family member, or loss of a family member's business) and mental health, as measured by the 36-item Short Form Health Survey (SF-36), among residents in four provinces of Thailand. One year later, participants who suffered a personal injury, the loss of a business, or the loss of a family member reported poorer mental health than those who were unaffected. Two years later, participants who experienced the loss of a family member reported poorer mental health than those who were unaffected. This research shows that such a disaster may have long lasting ramifications for mental health, and that diverse losses may influence mental health differently. PMID- 26987348 TI - Improving Pain Care Through Telemedicine: Future or Folly? PMID- 26987342 TI - Substrate engagement of integrins alpha5beta1 and alphavbeta3 is necessary, but not sufficient, for high directional persistence in migration on fibronectin. AB - The interplay between specific integrin-mediated matrix adhesion and directional persistence in cell migration is not well understood. Here, we characterized fibroblast adhesion and migration on the extracellular matrix glycoproteins fibronectin and vitronectin, focusing on the role of alpha5beta1 and alphavbeta3 integrins. Fibroblasts manifested high directional persistence in migration on fibronectin-, but not vitronectin-coated substrates, in a ligand density dependent manner. Fibronectin stimulated alpha5beta1-dependent organization of the actin cytoskeleton into oriented, ventral stress fibers, and assembly of dynamic, polarized protrusions, characterized as regions free of stress fibers and rich in nascent adhesions at their edge. Such protrusions correlated with persistent, local leading edge advancement, but were not sufficient, nor necessary for directional migration over longer times. Selective blocking of alphavbeta3 or alpha5beta1 integrins using small molecule integrin antagonists reduced directional persistence on fibronectin, indicating integrin cooperativity in maintaining directionality. On the other hand, patterned substrates, designed to selectively engage either integrin, or their combination, were not sufficient to establish directional migration. Overall, our study demonstrates adhesive coating-dependent regulation of directional persistence in fibroblast migration and challenges the generality of the previously suggested role of beta1 and beta3 integrins in directional migration. PMID- 26987349 TI - Theoretical rationalisation for the mechanism of N-heterocyclic carbene-halide reductive elimination at Cu(III), Ag(III) and Au(III). AB - Reductive elimination of imidazolium salts from Cu(III) is extremely sensitive to the anionic ligand (X or Y) type on Cu (e.g.DeltaG(?) ranges from 4.7 kcal mol( 1) to 31.8 kcal mol(-1), from chloride to benzyl). Weakly sigma-donating ligands dramatically accelerate reductive elimination. Comparison with Ag/Au shows that the HOMO energy, strength of M-NHC and M-Y bonds and inherent stability of M(III) with respect to M(I) are critical to governing reaction feasibility. PMID- 26987347 TI - Analyzing Health-Related Quality of Life in the EVOLVE Trial: The Joint Impact of Treatment and Clinical Events. AB - BACKGROUND: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) clinical trial evaluated the effects of cinacalcet on clinical events in patients with secondary hyperparathyroidism (sHPT) who were on hemodialysis. Health-related quality of life (HRQoL) was assessed by a generic, preference-based health outcome measure (EQ-5D) at scheduled visits and after a study event. Here, we report the HRQoL analysis from EVOLVE. METHODS: We assessed changes in HRQoL from baseline to scheduled visits, and estimated the acute (3 mo) and chronic (beyond 3 mo) effects of sHPT-related events on HRQoL using generalized estimating equation analysis controlling for baseline HRQoL and randomized assignment. RESULTS: Data on HRQoL were available for 3547 of 3883 subjects, with 1650 events in the placebo and 1502 in the cinacalcet arm. At the study end, no difference in change from baseline HRQoL was observed in the direct comparison of EQ-5D by treatment arms. The regression analysis showed significant effects of events on HRQoL and a modest positive effect of cinacalcet. Estimated quality-adjusted life-year gains were of similar magnitude based on the observed data or the predictions from the model, with only a small gain in precision from the predicted analysis. CONCLUSIONS: By contrast with a conventional comparison, a regression analysis demonstrated large decrements in HRQoL after events and a modest improvement in HRQoL with cinacalcet. As randomized controlled trials are rarely powered to detect differences in HRQoL, a prespecified regression analysis may be acceptable to improve precision of the effects and understand their origin. PMID- 26987350 TI - Novel effect of Daflon and low-dose gamma-radiation in modulation of thioacetamide-induced hepatic encephalopathy in male albino rats. AB - This study was designed to evaluate the hepato and neuroprotective activity of Daflon and low-dose gamma radiation on thioacetamide (TAA)-induced liver damage and hepatic encephalopathy (HE) in rats. Effect of daily Daflon treatment (100 mg/kg body weight, Per OS (p.o.) for consecutive 3 days) and/or fractionated low dose gamma-radiation (LDR; 0.25 Gy, twice the total dose of 0.5 Gy at the 1st and 3rd day, respectively) was evaluated against TAA (300 mg/kg, intraperitoneal * 3) induced liver damage and HE in rats. Serum aspartate transaminase, alanine transaminase, gamma-glutamyltransferase, total bilirubin, ammonia, and manganese were estimated to evaluate liver function. In addition, malondialdehyde (MDA) as well as reduced glutathione (GSH), glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT) were determined to assess antioxidant capacity in liver tissue. Moreover, hepatic apoptotic markers (cysteine-dependent aspartate-directed proteases 3, 8 (caspase-3, 8) and cytochrome C) were estimated to indicate hepatic apoptosis. HE was evaluated through the determination of whole brain ammonia, manganese, MDA, GSH, GPX, SOD, CAT, and caspase-3. The cognitive and locomotor deficits were assessed via step through passive avoidance test, activity cage (actophotometer), gamma-aminobutyric acid, and N-methyl-d aspartate/adenosine triphosphate-neuronal nitric oxide synthase/nitric oxide cyclic guanosine monophosphate axis in rats' cerebella and hippocampi. The involvement of hypoxia inducible factor-1alpha, aquaporine-4, and matrix metalloproteinase 9 in association with the brain water content (%) in the whole brain as an index for brain edema was also evaluated. The obtained results showed a marked amelioration of the aforementioned biochemical parameters and behavioral tasks which is supported by histopathological and immunohistochemical examination. It could be concluded that Daflon and LDR afforded hepatoprotection and neuroprotection against TAA-induced acute liver damage and HE. PMID- 26987351 TI - The healthcare workers' clinical skill set requirements for a uniformed international response to the Ebola virus disease outbreak in West Africa: the Canadian perspective. AB - Since December 2013, the Zaire Ebola virus disease (EVD) epidemic has ravaged West Africa. In collaboration with the Public Health Agency of Canada, healthcare workers (HCWs) and support staff from the Royal Canadian Medical Services (RCMS) of the Canadian Armed Forces (CAF) were deployed to Kerry Town, Sierra Leone. A total of 79 RCMS personnel deployed over the course of the 6-month mission in collaboration with the British Armed Forces to support efforts in West Africa. The treatment centre was mandated to treat international and local HCWs exposed to the infection. The goal of the Ebola virus disease treatment unit (EVDTU) was to provide care to affected HCWs and a beacon to attract and engage foreign HCWs to work in one of the international non-governmental organisation Ebola treatment centres in Sierra Leone. We focus on the CAF experience at the Kerry Town Ebola treatment unit in Sierra Leone in particular on the various clinical skill sets demonstrated in physicians, nurses and medical technicians deployed to the EVDTU. We outline some of the staffing challenges that arose and suggest that the necessary clinical skills needed to effectively manage patients with EVD in an austere environment can be shared across a small and diverse team of healthcare providers. PMID- 26987354 TI - Effects of beta-glucans ingestion (Saccharomyces cerevisiae) on metabolism of rats receiving high-fat diet. AB - We investigated the effects of beta-glucans (Saccharomyces cerevisiae) ingestion on metabolic parameters of Wistar rats receiving high-fat diet. The experimental period was divided into two stages: in the first one, the animals were divided into two groups containing 12 animals each. The first group received commercial feed and the second received high-fat diet containing 20% of pork fat during 60 days. At the end of this period, body weight, blood glucose and Lee index were assessed. In the second stage, those 24 animals were redivided into four groups: (C) - control diet; (CB) - control diet and treated with Beta-glucan (BG); (O) - obese animals and (OB) - obese animals treated with BG. Animals from groups CB and OB received 30 mg/kg of BG dissolved in saline solution by gavage. Animals from groups C and O received only saline solution for 28 days. The design used was totally randomized in 2 * 2 factorial scheme. Data were submitted to analysis of variance (anova). Animals from OB group showed inferior levels (p < 0.05) of total cholesterol (13.33%), triacylglycerols (16.77%) and blood glucose (23.97%) when compared to the animals from group O. The use of BG has provided smaller increase in Lee index (p < 0.05), without promoting alteration in feed and water consumption, organs weight, HDL-C, LDL+VLDL-C, carcass composition, villus/crypt ratio, and pancreas, kidney and stomach histology. BG from S. cerevisiae promoted beneficial metabolic effects in rats receiving high-fat diet. PMID- 26987353 TI - Systemic Mesenchymal Stromal Cell Transplantation Prevents Functional Bone Loss in a Mouse Model of Age-Related Osteoporosis. AB - Age-related osteoporosis is driven by defects in the tissue-resident mesenchymal stromal cells (MSCs), a heterogeneous population of musculoskeletal progenitors that includes skeletal stem cells. MSC decline leads to reduced bone formation, causing loss of bone volume and the breakdown of bony microarchitecture crucial to trabecular strength. Furthermore, the low-turnover state precipitated by MSC loss leads to low-quality bone that is unable to perform remodeling-mediated maintenance--replacing old damaged bone with new healthy tissue. Using minimally expanded exogenous MSCs injected systemically into a mouse model of human age related osteoporosis, we show long-term engraftment and markedly increased bone formation. This led to improved bone quality and turnover and, importantly, sustained microarchitectural competence. These data establish proof of concept that MSC transplantation may be used to prevent or treat human age-related osteoporosis. SIGNIFICANCE: This study shows that a single dose of minimally expanded mesenchymal stromal cells (MSCs) injected systemically into a mouse model of human age-related osteoporosis display long-term engraftment and prevent the decline in bone formation, bone quality, and microarchitectural competence. This work adds to a growing body of evidence suggesting that the decline of MSCs associated with age-related osteoporosis is a major transformative event in the progression of the disease. Furthermore, it establishes proof of concept that MSC transplantation may be a viable therapeutic strategy to treat or prevent human age-related osteoporosis. PMID- 26987355 TI - Macroevolutionary patterns of ultraviolet floral pigmentation explained by geography and associated bioclimatic factors. AB - Selection driven by biotic interactions can generate variation in floral traits. Abiotic selection, however, also contributes to floral diversity, especially with respect to patterns of pigmentation. Combining comparative studies of floral pigmentation and geography can reveal the bioclimatic factors that may drive macroevolutionary patterns of floral color. We create a molecular phylogeny and measure ultraviolet (UV) floral pattern for 177 species in the Potentilleae tribe (Rosaceae). Species are similar in flower shape and visible color but vary in UV floral pattern. We use comparative approaches to determine whether UV pigmentation variation is associated with geography and/or bioclimatic features (UV-B, precipitation, temperature). Floral UV pattern was present in half of the species, while others were uniformly UV-absorbing. Phylogenetic signal was detected for presence/absence of pattern, but among patterned species, quantitative variation in UV-absorbing area was evolutionarily labile. Uniformly UV-absorbing species tended to experience higher UV-B irradiance. Patterned species occurring at higher altitudes had larger UV-absorbing petal areas, corresponding with low temperature and high UV exposure. This analysis expands our understanding of the covariation of UV-B irradiance and UV floral pigmentation from within species to that among species, and supports the view that abiotic selection is associated with floral diversification among species. PMID- 26987356 TI - Comparative analysis of bacterial profiles in unstimulated and stimulated saliva samples. AB - BACKGROUND AND OBJECTIVE: The microbial profiles of stimulated saliva samples have been shown to differentiate between patients with periodontitis, patients with dental caries, and orally healthy individuals. Saliva was stimulated to allow for easy and rapid collection; however, microbial composition may not reflect the more natural, unstimulated state. The purpose of this study was to validate whether stimulated saliva is an adequate surrogate for unstimulated saliva in determining salivary microbiomes. DESIGN: Unstimulated (n=20) and stimulated (n=20) saliva samples were collected from 20 orally and systemically healthy, non-smoking participants. Salivary bacterial profiles were analyzed by means of the Human Oral Microbe Identification using Next Generation Sequencing (HOMINGS), and statistical analysis was performed using Mann-Whitney test with Benjamini-Hochberg's correction for multiple comparison, cluster analysis, principal component analysis, and correspondence analysis. RESULTS: From a total of 40 saliva samples, 496 probe targets were identified with a mean number of targets per sample of 203 (range: 146-303), and a mean number of probe targets of 206 and 200 in unstimulated and stimulated saliva samples, respectively (p=0.62). Based on all statistical methods used for this study, the microbial profiles of unstimulated and stimulated saliva samples collected from the same person were not statistically significantly different. CONCLUSIONS: Analysis of bacterial salivary profiles in unstimulated and stimulated saliva samples collected from the same individual showed comparable results. Thus, the results verify that stimulated saliva is an adequate surrogate of unstimulated saliva for microbiome related studies. PMID- 26987357 TI - Influence of transport conditions and pre-slaughter water shower spray during summer on protein characteristics and water distribution of broiler breast meat. AB - This study investigated the effects of pre-slaughter transport during summer and subsequent water shower spray on broiler meat quality and protein characteristics. Arbor Acres broiler chickens (n = 126, 42 days old, mixed sex, 2.5-3 kg) were randomly categorized into three treatments: (i) control group without transport (C); (ii) 30 min transport (T); and (iii) 30 min transport followed by 10 min water shower spray and 20 min lairage (T/W). Each treatment consisted of six replicates with seven birds each. Ambient temperature was 32-35 degrees C during transportation. Results indicated that transport during high ambient temperature denatured myosin and sarcoplasmic proteins, led to decreased protein solubility and resulted in glycogen phosphorylase precipitated to the myofibrillar fraction. Furthermore, meat quality in the transport group showed a pale, soft and exudative (PSE)-like syndrome. Water shower spray during lairage after transport reduced the degree of protein denaturation and lessened the deterioration of meat quality. PMID- 26987352 TI - Tumor-Free Transplantation of Patient-Derived Induced Pluripotent Stem Cell Progeny for Customized Islet Regeneration. AB - Human induced pluripotent stem cells (iPSCs) and derived progeny provide invaluable regenerative platforms, yet their clinical translation has been compromised by their biosafety concern. Here, we assessed the safety of transplanting patient-derived iPSC-generated pancreatic endoderm/progenitor cells. Transplantation of progenitors from iPSCs reprogrammed by lentiviral vectors (LV-iPSCs) led to the formation of invasive teratocarcinoma-like tumors in more than 90% of immunodeficient mice. Moreover, removal of primary tumors from LV-iPSC progeny-transplanted hosts generated secondary and metastatic tumors. Combined transgene-free (TGF) reprogramming and elimination of residual pluripotent cells by enzymatic dissociation ensured tumor-free transplantation, ultimately enabling regeneration of type 1 diabetes-specific human islet structures in vivo. The incidence of tumor formation in TGF-iPSCs was titratable, depending on the oncogenic load, with reintegration of the cMYC expressing vector abolishing tumor-free transplantation. Thus, transgene-free cMYC-independent reprogramming and elimination of residual pluripotent cells are mandatory steps in achieving transplantation of iPSC progeny for customized and safe islet regeneration in vivo. SIGNIFICANCE: Pluripotent stem cell therapy for diabetes relies on the safety as well as the quality of derived insulin-producing cells. Data from this study highlight prominent tumorigenic risks of induced pluripotent stem cell (iPSC) products, especially when reprogrammed with integrating vectors. Two major underlying mechanisms in iPSC tumorigenicity are residual pluripotent cells and cMYC overload by vector integration. This study also demonstrated that combined transgene-free reprogramming and enzymatic dissociation allows teratoma free transplantation of iPSC progeny in the mouse model in testing the tumorigenicity of iPSC products. Further safety assessment and improvement in iPSC specification into a mature beta cell phenotype would lead to safe islet replacement therapy for diabetes. PMID- 26987359 TI - End-tidal carbon dioxide monitoring and load band device for mechanical cardio pulmonary resuscitation: Never trust the numbers, believe at the curves. PMID- 26987361 TI - Cardiopulmonary exercise testing in the MRI environment. AB - Maximal oxygen consumption ([Formula: see text]max) measured by cardiopulmonary exercise testing (CPX) is the gold standard for assessment of cardiorespiratory fitness. Likewise, cardiovascular magnetic resonance (CMR) is the gold standard for quantification of cardiac function. The combination of CPX and CMR may offer unique insights into cardiopulmonary pathophysiology; however, the MRI-compatible equipment needed to combine these tests has not been available to date. We sought to determine whether CPX testing in the MRI environment, using equipment modified for MRI yields results equivalent to those obtained in standard exercise physiology (EP) lab. Ten recreationally trained subjects completed [Formula: see text]max tests in different locations; an EP laboratory and an MRI laboratory, using site specific equipment. CMR cine images of the heart were acquired before and immediately after maximal exercise to measure cardiac function. Subjects in all tests met criteria indicating that peak exercise was achieved. Despite equipment modifications for the MRI environment, [Formula: see text]max was nearly identical between tests run in the different labs (95% lower confidence limit (LCL) = 0.8182). The mean difference in [Formula: see text]max was less than 3.40 ml (kg/min)(-1), within the variability expected for tests performed on different days, in different locations, using different metabolic carts. MRI performed at rest and following peak exercise stress indicated cardiac output increased from 5.1 +/- 1.0 l min(-1) to 16.4 +/- 5.6 l min(-1), LVEF increased from 65.2 +/- 3.3% to 78.4 +/- 4.8%, while RVEF increased from 52.8 +/- 5.3% to 63.4 +/- 5.3%. Regression analysis revealed a significant positive correlation between [Formula: see text]max and stroke volume (R = 0.788, P = 0.006), while the correlation with cardiac output did not reach statistical significance (R = 0.505, P = 0.137). [Formula: see text]max CPX testing can be effectively performed in the MRI environment, enabling direct combination of physiological data with advanced post-exercise imaging in the same test session. PMID- 26987360 TI - Near-infrared light-triggered thermochemotherapy of cancer using a polymer-gold nanorod conjugate. AB - A biocompatible polymer-gold nanorod (P-AuNR) conjugate was developed as a thermo chemotherapeutic nano-sized drug carrier for cancer therapy using near-infrared (NIR) light as an external trigger. The amphiphilic polymer, poly(ethylene glycol)-block-poly(caprolactone) (PEG-b-PCL) bearing a disulfide bond, was prepared using a facile synthetic route via copper(I)-free click chemistry and covalently linked to AuNR. The chemical structures and successful conjugation of PEG-b-PCL were analyzed using (1)H NMR and FT-IR. Doxorubicin (DOX), a hydrophobic anticancer drug, was effectively loaded into the hydrophobic PCL domain of P-AuNR through a simple dialysis method. P-AuNR showed longitudinal plasmon resonance absorption at the NIR region, thus generating heat under irradiation at 808 nm. Interestingly, exposure of P-AuNRs to NIR induced a structural change in the PCL block from a crystalline to an amorphous state, leading to the temporally controlled release of DOX. No significant release of DOX was observed from P-AuNRs under physiological conditions (pH 7.4), whereas the release rate of DOX was remarkably enhanced in response to NIR irradiation. In vitro cellular experiments to assess cytotoxicity and intracellular drug release behavior of DOX-P-AuNRs demonstrated that the release of DOX could be selectively regulated by NIR irradiation. Overall, DOX-P-AuNRs might have the potential to overcome the indiscriminate toxicity of free DOX. PMID- 26987362 TI - Molecular Packing Determines Charge Separation in a Liquid Crystalline Bisthiophene-Perylene Diimide Donor-Acceptor Material. AB - Combined electronic structure and quantum dynamical calculations are employed to investigate charge separation in a novel class of covalently bound bisthiophene perylene diimide type donor-acceptor (DA) co-oligomer aggregates. In an earlier spectroscopic study of this DA system in a smectic liquid crystalline (LC) film, efficient and ultrafast (subpicosecond) initial charge separation was found to be followed by rapid recombination. By comparison, the same DA system in solution exhibits ultrafast resonant energy transfer followed by slower (picosecond scale) charge separation. The present first-principles study explains these contrasting observations, highlighting the role of an efficient intermolecular charge transfer pathway that results from the molecular packing in the LC phase. Despite the efficiency of this primary charge-transfer step, long-range charge separation is impeded by a comparatively high Coulomb barrier in conjunction with small electron- and hole-transfer integrals. Quantum dynamical calculations are carried out for a fragment-based model Hamiltonian, parametrized by ab initio second order Algebraic Diagrammatic Construction (ADC(2)) and Time-Dependent Density Functional Theory (TDDFT) electronic structure calculations. Simulations of coherent vibronic quantum dynamics for up to 156 electronic states and 48 modes are performed using the Multi-Layer Multi-Configuration Time-Dependent Hartree (ML-MCTDH) method. Excellent agreement with experimentally determined charge separation time scales is obtained, and the spatially coherent nature of the dynamics is analyzed. PMID- 26987358 TI - Factors associated with malaria chemoprophylaxis compliance among French service members deployed in Central African Republic. AB - BACKGROUND: Malaria is a public health concern in the French armed forces, with 400-800 cases reported every year and three deaths in the past 2 years. However, lack of chemoprophylaxis (CP) compliance is often reported among service members. The aim of this study was to explore factors associated with CP compliance. METHODS: A retrospective study (1296 service members) was carried out among troops deployed in Central African Republic. Determinants of CP were collected by self-questionnaire. Socio-demographic variables, behavioural characteristics, belief variables, operational determinants such as troops in contact (TIC) and number of nights worked per week and peer-to-peer reinforcement were studied. Relationships between covariates and compliance were explored using logistic regressions (outcome: compliance as a dummy variable). RESULTS: Chemoprophylaxis compliance was associated with other individual preventive measures against mosquito bites (bed net use, OR (odds ratio) = 1.41 (95% CI [1.08-1.84]), and insecticide on clothing, OR = 1.90 ([1.43-2.51]) and malaria-related behaviours (taking chemoprophylaxis at the same time every day, OR = 2.37 ([1.17-4.78]) and taking chemoprophylaxis with food, OR = 1.45 ([1.11-1.89])). High perceived risk of contracting malaria, OR = 1.59 ([1.02-2.50]), positive perception of CP effectiveness, OR = 1.62 ([1.09-2.40]) and the practice of peer-to-peer reinforcement, OR = 1.38 ([1.05-1.82]) were also associated with better compliance. No association was found with TIC and number of nights worked. CONCLUSIONS: This study, which shows a positive relationship between peer-to-peer reinforcement and CP compliance, also suggests the existence of two main personality profiles among service members: those who seek risks and those who are health-conscious. Health education should be expanded beyond knowledge, know how and motivational factors by using a comprehensive approach based on identification of health determinants, development of psychosocial skills and peer-to-peer reinforcement. PMID- 26987364 TI - Impact of elastin incorporation into electrochemically aligned collagen fibers on mechanical properties and smooth muscle cell phenotype. AB - Application of tissue-engineered vascular grafts (TEVGs) for the replacement of small-diameter arteries is limited due to thrombosis and intimal hyperplasia. Previous studies have attempted to address the limitations of TEVGs by developing scaffolds that mimic the composition (collagen and elastin) of native arteries to better match the mechanical properties of the graft with the native tissue. However, most existing scaffolds do not recapitulate the aligned topography of the collagen fibers found in native vessels. In the current study, based on the principles of isoelectric focusing, two different types of elastin (soluble and insoluble) were incorporated into highly oriented electrochemically aligned collagen (ELAC) fibers and the effect of elastin incorporation on the mechanical properties of the ELAC fibers and smooth muscle cell (SMC) phenotype was investigated. The results indicate that elastin incorporation significantly decreased the modulus of ELAC fibers to converge upon that of native vessels. Further, a significant increase in yield strain and decrease in Young's modulus was observed on all fibers post SMC culture compared with before the culture. Real-time polymerase chain reaction results showed a significant increase in the expression of alpha-smooth muscle actin and calponin on ELAC fibers with insoluble elastin, suggesting that incorporation of insoluble elastin induces a contractile phenotype in SMCs after two weeks of culture on ELAC fibers. Immunofluorescence results showed that calponin expression increased with time on all fibers. In conclusion, insoluble elastin incorporated ELAC fibers have the potential to be used for the development of functional TEVGs for the repair and replacement of small-diameter arteries. PMID- 26987363 TI - A Chemical Controller of SNARE-Driven Membrane Fusion That Primes Vesicles for Ca(2+)-Triggered Millisecond Exocytosis. AB - Membrane fusion is mediated by the SNARE complex which is formed through a zippering process. Here, we developed a chemical controller for the progress of membrane fusion. A hemifusion state was arrested by a polyphenol myricetin which binds to the SNARE complex. The arrest of membrane fusion was rescued by an enzyme laccase that removes myricetin from the SNARE complex. The rescued hemifusion state was metastable and long-lived with a decay constant of 39 min. This membrane fusion controller was applied to delineate how Ca(2+) stimulates fusion-pore formation in a millisecond time scale. We found, using a single vesicle fusion assay, that such myricetin-primed vesicles with synaptotagmin 1 respond synchronously to physiological concentrations of Ca(2+). When 10 MUM Ca(2+) was added to the hemifused vesicles, the majority of vesicles rapidly advanced to fusion pores with a time constant of 16.2 ms. Thus, the results demonstrate that a minimal exocytotic membrane fusion machinery composed of SNAREs and synaptotagmin 1 is capable of driving membrane fusion in a millisecond time scale when a proper vesicle priming is established. The chemical controller of SNARE-driven membrane fusion should serve as a versatile tool for investigating the differential roles of various synaptic proteins in discrete fusion steps. PMID- 26987366 TI - Talking about cross-talk: the immune system and the microbiome. AB - A report on the first EMBO conference entitled "Next Gen Immunology-From Host Genome to the Microbiome: Immunity in the Genomic Era", held at the Weizmann Institute of Science, Israel, 14-16 February, 2016. PMID- 26987365 TI - Barraquer-Simons syndrome: a rare form of acquired lipodystrophy. AB - BACKGROUND: Human lipodystrophies are uncommon disorders, with important clinical consequences, which are often undiagnosed. The Barraquer-Simons syndrome is a form of partial symmetric lipodystrophy of unknown etiology, characterized by the loss of subcutaneous adipose tissue, limited to upper part of the body. Insulin resistance and metabolic complications are less common than with other lipodystrophy subtypes. Patients usually have decreased serum complement component 3 levels, associated with complement activation by the alternative pathway, which may indicate the presence of renal involvement. CASE PRESENTATION: The authors report a case of a 31-year-old woman with progressive loss of subcutaneous fat, limited to the face, neck and thorax. She presented no severe metabolic complications, neither signs of insulin resistance. Laboratory tests revealed mild dyslipidemia, and low serum levels of complement-component 3. Clinical and biochemical characteristics were consistent with the diagnosis of Barraquer-Simons syndrome. CONCLUSION: The present case illustrates the importance of recognizing the clinical features of this lipodystrophic syndrome, which may present potentially severe consequences and psychological distress. A brief overview is made, addressing the clinical signs of the disease, its course, and how to manage it. PMID- 26987367 TI - Prevalence of plasmid-bearing and plasmid-free Chlamydia trachomatis infection among women who visited obstetrics and gynecology clinics in Malaysia. AB - BACKGROUND: The 7.5 kb cryptic plasmid of Chlamydia trachomatis has been shown to be a virulence factor in animal models, but its significance in humans still remains unknown. The aim of this study was to investigate the prevalence and potential involvement of the C. trachomatis cryptic plasmid in causing various clinical manifestations; including infertility, reproductive tract disintegrity, menstrual disorder, and polycystic ovarian syndrome (PCOS) among genital C. trachomatis-infected patients. RESULTS: A total of 180 female patients of child bearing age (mean 30.9 years old, IQR:27-35) with gynecological complications and subfertility issues, who visited Obstetrics and Gynecology clinics in Kuala Lumpur, Malaysia were recruited for the study. Prevalence of genital chlamydial infection among these patients was alarmingly high at 51.1% (92/180). Of the 92 chlamydia-infected patients, 93.5% (86/92) were infected with plasmid-bearing (+) C. trachomatis while the remaining 6.5% (6/92) were caused by the plasmid-free ( ) variant. Our data showed that genital C. trachomatis infection was associated with infertility issues, inflammation in the reproductive tract (mucopurulent cervicitis or endometriosis), irregular menstrual cycles and polycystic ovarian syndrome (PCOS). However, no statistical significance was detected among patients with plasmid (+) versus plasmid (-) C. trachomatis infection. Interestingly, plasmid (+) C. trachomatis was detected in all patients with PCOS, and the plasmid copy numbers were significantly higher among PCOS patients, relative to non-PCOS patients. CONCLUSION: Our findings show a high incidence of C. trachomatis infection among women with infertility or gynecological problems in Malaysia. However, due to the low number of plasmid (-) C. trachomatis cases, a significant role of the plasmid in causing virulence in human requires further investigation of a larger cohort. PMID- 26987368 TI - Engaging with community-based public and private mid-level providers for promoting the use of modern contraceptive methods in rural Pakistan: results from two innovative birth spacing interventions. AB - BACKGROUND: Family planning (FP) interventions aimed at reducing population growth have negligible during the last two decades in Pakistan. Innovative FP interventions that help reduce the growing population burden are the need of the hour. Marie Stopes Society--Pakistan implemented an operational research project- 'Evidence for Innovating to Save Lives', to explore effective and viable intervention models that can promote healthy timing and spacing of pregnancy in rural and under-served communities of Sindh, Punjab and Khyber Pakhtunkhwa provinces of Pakistan. METHODS: We conducted a quasi-experimental (pre- and post intervention with control arm) study to assess the effectiveness of each of the two intervention models, (1) Suraj model (meaning 'Sun' in English), which uses social franchises (SF) along with a demand-side financing (DSF) approach using free vouchers, and (2) Community Midwife (CMW) model, in promoting the use of modern contraceptive methods compared to respective controls. Baseline and endline cross-sectional household surveys were conducted, 24 months apart, by recruiting 5566 and 6316 married women of reproductive age (MWRA) respectively. We used Stata version 8 to report the net effect of interventions on outcome indicators using difference-in-differences analysis. Multivariate Cox proportional hazard regression analysis was used to assess the net effect of the intervention on current contraceptive use, keeping time constant and adjusting for other variables in the model. RESULTS: The Suraj model was effective in significantly increasing awareness about FP methods among MWRA by 14% percentage points, current contraceptive use by 5% percentage points and long term modern method--intrauterine device (IUD) use by 6% percentage points. The CMW model significantly increased contraceptive awareness by 28% percentage points, ever use of contraceptives by 7% percentage points and, IUD use by 3% percentage points. Additionally the Suraj intervention led to a 35% greater prevalence (prevalence ratio: 1.35, 95% CI: 1.22-1.50) of contraceptive use among MWRA. CONCLUSION: Suraj intervention highlights the importance of embedding subsidized FP services within the communities of the beneficiaries. The outcomes of the CMW intervention also improved the use of long-term contraceptives. These findings indicate the necessity of designing and implementing FP initiatives involving local mid-level providers to expand contraceptive coverage in under-served areas. PMID- 26987369 TI - Cocaine self-administration differentially affects allosteric A2A-D2 receptor receptor interactions in the striatum. Relevance for cocaine use disorder. AB - In the current study behavioral and biochemical experiments were performed to study changes in the allosteric A2AR-D2R interactions in the ventral and dorsal striatum after cocaine self-administration versus corresponding yoked saline control. By using ex vivo [(3)H]-raclopride/quinpirole competition experiments, the effects of the A2AR agonist CGS 21680 (100 nM) on the KiH and KiL values of the D2-like receptor (D2-likeR) were determined. One major result was a significant reduction in the D2-likeR agonist high affinity state observed with CGS 21680 after cocaine self-administration in the ventral striatum compared with the yoked saline group. The results therefore support the hypothesis that A2AR agonists can at least in part counteract the motivational actions of cocaine. This action is mediated via the D2-likeR by targeting the A2AR protomer of A2AR D2-like R heteroreceptor complexes in the ventral striatum, which leads to the reduction of D2-likeR protomer recognition through the allosteric receptor receptor interaction. In contrast, in the dorsal striatum the CGS 21680-induced antagonistic modulation in the D2-likeR agonist high affinity state was abolished after cocaine self-administration versus the yoked saline group probably due to a local dysfunction/disruption of the A2AR-D2-like R heteroreceptor complexes. Such a change in the dorsal striatum in cocaine self-administration can contribute to the development of either locomotor sensitization, habit-forming learning and/or the compulsive drug seeking by enhanced D2-likeR protomer signaling. Potential differences in the composition and stoichiometry of the A2AR-D2R heteroreceptor complexes, including differential recruitment of sigma 1 receptor, in the ventral and dorsal striatum may explain the differential regional changes observed in the A2A-D2-likeR interactions after cocaine self-administration. PMID- 26987370 TI - Depression-like behaviors in tree shrews and comparison of the effects of treatment with fluoxetine and carbetocin. AB - Tree shrews, a species phylogenetically close to primates, are regarded as a suitable and naturalistic animal model for depression studies. However, psychological symptoms that are essential for depression diagnosis and treatment, such as helplessness and social withdrawal, have not been studied in this model. Therefore, in this study, we first investigated learned helplessness, social interaction and sucrose preference induced by two chronic stress paradigms: uncontrollable foot shocks (1-week foot shocks) and multiple unpredictable stimuli (1-week foot shocks and 3-week unpredictable stressors) in tree shrews. Our results showed that uncontrollable foot shocks could only induce learned helplessness in animals; whereas animals treated with multiple unpredictable stimuli exhibited more depression-like behaviors including social withdrawal, anhedonia and learned helplessness. These findings suggested that multiple unpredictable stimuli could effectively induce various depression-like behaviors in tree shrews. More importantly, we compared the antidepressant effects of fluoxetine and carbetocin, a long-acting oxytocin analog, on specific depression like behaviors. Our present data displayed that, compared with fluoxetine, carbetocin was also effective in reversing learned helplessness, elevating sucrose preference and improving social interaction behaviors in depression-like animals. Therefore, carbetocin might be a potential antidepressant with applications in humans. PMID- 26987371 TI - 6-Gingerol inhibits Vibrio cholerae-induced proinflammatory cytokines in intestinal epithelial cells via modulation of NF-kappaB. AB - Context The effect of 6-gingerol (6G), the bioactive component of Zingiber officinale Roscoe (Zingiberaceae), in the reduction of Vibrio cholerae (Vibrionaceae)-induced inflammation has not yet been reported. Materials and methods Cell viability assay was performed to determine the working concentration of 6G. Elisa and RT-PCR were performed with Int 407 cells treated with 50 MUM 6G and 100 multiplicity of infection (MOI) V. cholerae for 0, 2, 3, 3.5, 6 and 8 h to determine the concentration of IL-8, IL-6, IL-1alpha and IL-1beta in both protein and RNA levels. Furthermore, the effect of 50 MUM 6G on upstream MAP kinases and NF-kappaB signalling pathways was evaluated at 0, 10, 15, 30, 60 and 90 min. Results The effective dose (ED50) value of 6G was found to be 50 MUM as determined by cell viability assay. Pre-treatment with 50 MUM 6G reduced V. cholerae infection-triggered levels of IL-8, IL-6, IL-1alpha and IL-1beta by 3.2 fold in the protein level and two-fold in the RNA level at 3.5 h. The levels of MAP-kinases signalling molecules like p38 and ERK1/2 were also reduced by two- and three-fold, respectively, after 30 min of treatment. Additionally, there was an increase in phosphorylated IkappaBalpha and down-regulation of p65 resulting in down-regulation of NF-kappaB pathway. Conclusion Our results showed that 6G could modulate the anti-inflammatory responses triggered by V. cholerae-induced infection in intestinal epithelial cells by modulating NF-kappaB pathway. PMID- 26987373 TI - The prevalence and significance of thoracic findings in patients undergoing extended coverage computed tomography for assessment of abdominal aortic aneurysms. AB - OBJECTIVE: Many major vascular centres, including ours, incorporate coverage of the thoracic aorta in CT scans evaluating abdominal aortic aneurysms (AAAs) (extended coverage contrast-enhanced CT (EC-CECT) scan]. We sought to determine the prevalence of thoracic pathology in a large consecutive series of patients with AAA undergoing EC-CECT. METHODS: All patients who underwent EC-CECT for AAA between April 2013 and 2014 were identified from our radiology information system. Reports were retrospectively reviewed and for each study, sex, age and reported thoracic aortic and other non-vascular findings were extracted. Findings were initially categorized into "major" or "minor" depending on if they were mentioned in the report impression/conclusion. Any major thoracic pathology was termed "significant" if there was a new diagnosis/patient intervention/investigation and a change in patient management. RESULTS: Of the 150 scans included in the study, 97 (65%) had at least one thoracic finding. These findings included 24 scans (16%) with major findings and 73 scans (48%) with minor findings. In 13 scans (9%), the findings were significant and resulted in a delay (n = 11) or cancellation (n = 2) of AAA repair. CONCLUSION: Pre procedural EC-CECT helps to identify significant intrathoracic findings in patients with AAA, which can have a major impact on AAA repair. This study supports the routine use of pre-procedural EC-CECT in planning AAA repair. ADVANCES IN KNOWLEDGE: This study describes the prevalence of significant thoracic pathology, which can impact on AAA repair. This information could potentially change the pre-procedure imaging protocol for patients with AAA. PMID- 26987372 TI - Awareness, treatment and control of type 2 diabetes among Chinese elderly and its changing trend for past decade. AB - BACKGROUND: This study aims to evaluate the awareness, treatment, control rate of type 2 diabetes and its risk factors among Chinese community elderly, and also examine the changing trend for the past decade. METHODS: We conducted two population-based cross-sectional studies in a representative urban area of Beijing in 2001 and 2010 respectively, using with the same method. A total of 2,277 participants (943 male, 1,334 female) in 2001 and 2,102 participants (848 male, 1,254 female) in 2010 were recruited. All the participants diagnosed with diabetes were included in this study. RESULTS: The prevalence of diabetes was 21.4% and 24.8% in 2001 and 2010 respectively. Among participants with diabetes, 74.2% were aware of the condition, 51.0% were treated, 20.1% well controlled the condition in 2001, and the corresponding rates were 78.5%, 69.3%,15.9% in 2010 respectively. Higher education level and a positive family history were related to better management of diabetes, while obesity and alcohol drinking showed a reverse direction. CONCLUSIONS: The prevalence and awareness of diabetes stayed high for the past decade. The treatment increased 18.3% while the control rate decreased among community elderly for the past 10 years. It's urgent to carry out effective measures to raise awareness, treatment, and control rate of diabetes in order to avoid growing disease burden in China. PMID- 26987375 TI - Connectivity to the 'four corners of the world'. PMID- 26987374 TI - Quantification of epicardial adipose tissue in coronary calcium score and CT coronary angiography image data sets: comparison of attenuation values, thickness and volumes. AB - OBJECTIVE: The aim of the study was to compare epicardial adipose tissue (EAT) characteristics assessed with coronary calcium score (CS) and CT coronary angiography (CTCA) image data sets. METHODS: In 76 patients (mean age 59 +/- 13 years) who underwent CS and CTCA owing to suspected coronary artery disease (CAD), EAT was quantified in terms of density (Hounsfield units), thickness and volume. The EAT volume was extracted with a semi-automatic software. RESULTS: A moderate correlation was found between EAT density in CS and CTCA image data sets (-100 +/- 19 HU vs -70 +/- 24 HU; p < 0.05, r = 0.55). The distribution of EAT was not symmetrical with a maximal thickness at the right atrioventricular groove (14.2 +/- 5.3 mm in CS, 15.7 +/- 5 mm in CTCA; p > 0.05, r = 0.76). The EAT volume resulted as 122 +/- 50 cm(3) in CS and 86 +/- 40 cm(3) in CTCA (Delta = 30%, p < 0.05, r = 0.92). After adjustment for post-contrast EAT attenuation difference (Delta = 30 HU), the volume was 101 +/- 47 cm(3) (Delta = 17%, p < 0.05, r = 0.92). Based on EAT volume median values, no differences were found between groups with smaller and larger volumes in terms of Agatston score and CAD severity. CONCLUSION: CS and CTCA image data sets may be equally employed for EAT assessment; however, an underestimation of volume is found with the latter acquisition even after post-contrast attenuation adjustment. ADVANCES IN KNOWLEDGE: EAT may be measured by processing either the CS or CTCA image data sets. PMID- 26987376 TI - Rosuvastatin vs. protease inhibitor switching for hypercholesterolaemia: a randomized trial. AB - OBJECTIVES: The aim of the study was to compare the efficacy and safety of rosuvastatin initiation with those of switching of ritonavir-boosted protease inhibitors (PI/rs) in HIV-1-infected adults with hypercholesterolaemia and increased cardiovascular risk scores. METHODS: In this open-label, multicentre study, HIV-1-infected adults on PI/r-based therapy with viral load < 50 HIV-1 RNA copies/mL, fasting total cholesterol >= 5.5 mmol/L (both for >= 6 months) and elevated cardiovascular risk (Framingham score >= 8% or diabetes or family history), and not on lipid-lowering therapy, were randomized to open-label rosuvastatin 10 mg/day or to PI/r switching, both with standardized diet/exercise advice. The primary endpoint was change in total cholesterol at week 12 (intention to treat). RESULTS: There were 43 participants (23 on rosuvastatin). Baseline characteristics were: mean [+/- standard deviation (SD)] age 55 (8.5) years, 42 (98%) male, 41 (95%) white race, and mean (+/- SD) total cholesterol 6.2 (1.2) mmol/L. At enrolment, PI/rs were lopinavir/ritonavir (n = 22; 51%), atazanavir/ritonavir (n = 12; 28%) and darunavir/ritonavir (n = 9; 21%). The commonest PI/r substitutes were raltegravir (n = 9; 45%) and rilpivirine (n = 4; 20%). All participants were adherent through to week 12. Rosuvastatin yielded greater declines than PI/r switching in total (- 21.4% vs. - 8.7%, respectively; P = 0.003) and low-density lipoprotein (- 29.9% vs. - 1.0%, respectively; P < 0.001) cholesterol, but smaller declines in very low-density lipoprotein cholesterol and triglycerides (P < 0.01). Cholesterol lowering was greater in participants on atazanavir/ritonavir or once-daily darunavir/ritonavir (vs. lopinavir/ritonavir). More study drug-related adverse events (mostly grade 1 nausea/diarrhoea; 10 vs. one, respectively; P = 0.001) occurred with PI/r switching than with rosuvastatin. CONCLUSIONS: In adults receiving a PI/r, rosuvastatin 10 mg/day for 12 weeks yielded larger decreases in total and low density lipoprotein cholesterol than PI/r switching, and was better tolerated. PMID- 26987377 TI - Comprehensive European dietary exposure model (CEDEM) for food additives. AB - European methods for assessing dietary exposures to nutrients, additives and other substances in food are limited by the availability of detailed food consumption data for all member states. A proposed comprehensive European dietary exposure model (CEDEM) applies summary data published by the European Food Safety Authority (EFSA) in a deterministic model based on an algorithm from the EFSA intake method for food additives. The proposed approach can predict estimates of food additive exposure provided in previous EFSA scientific opinions that were based on the full European food consumption database. PMID- 26987378 TI - Towards a methodology to formulate sustainable diets for livestock: accounting for environmental impact in diet formulation. AB - The objective of this study was to develop a novel methodology that enables pig diets to be formulated explicitly for environmental impact objectives using a Life Cycle Assessment (LCA) approach. To achieve this, the following methodological issues had to be addressed: (1) account for environmental impacts caused by both ingredient choice and nutrient excretion, (2) formulate diets for multiple environmental impact objectives and (3) allow flexibility to identify the optimal nutritional composition for each environmental impact objective. An LCA model based on Canadian pig farms was integrated into a diet formulation tool to compare the use of different ingredients in Eastern and Western Canada. By allowing the feed energy content to vary, it was possible to identify the optimum energy density for different environmental impact objectives, while accounting for the expected effect of energy density on feed intake. A least-cost diet was compared with diets formulated to minimise the following objectives: non renewable resource use, acidification potential, eutrophication potential, global warming potential and a combined environmental impact score (using these four categories). The resulting environmental impacts were compared using parallel Monte Carlo simulations to account for shared uncertainty. When optimising diets to minimise a single environmental impact category, reductions in the said category were observed in all cases. However, this was at the expense of increasing the impact in other categories and higher dietary costs. The methodology can identify nutritional strategies to minimise environmental impacts, such as increasing the nutritional density of the diets, compared with the least-cost formulation. PMID- 26987379 TI - Role of enterohepatic recirculation in drug disposition: cooperation and complications. AB - Enterohepatic recirculation (EHC) concerns many physiological processes and notably affects pharmacokinetic parameters such as plasma half-life and AUC as well as estimates of bioavailability of drugs. Also, EHC plays a detrimental role as the compounds/drugs are allowed to recycle. An in-depth comprehension of this phenomenon and its consequences on the pharmacological effects of affected drugs is important and decisive in the design and development of new candidate drugs. EHC of a compound/drug occurs by biliary excretion and intestinal reabsorption, sometimes with hepatic conjugation and intestinal deconjugation. EHC leads to prolonged elimination half-life of the drugs, altered pharmacokinetics and pharmacodynamics. Study of the EHC of any drug is complicated due to unavailability of the apposite model, sophisticated procedures and ethical concerns. Different in vitro and in vivo methods for studies in experimental animals and humans have been devised, each having its own merits and demerits. Involvement of the different transporters in biliary excretion, intra- and inter species, pathological and biochemical variabilities obscure the study of the phenomenon. Modeling of drugs undergoing EHC has always been intricate and exigent models have been exploited to interpret the pharmacokinetic profiles of drugs witnessing multiple peaks due to EHC. Here, we critically appraise the mechanisms of bile formation, factors affecting biliary drug elimination, methods to estimate biliary excretion of drugs, EHC, multiple peak phenomenon and its modeling. PMID- 26987380 TI - Apigenin ameliorates hypertension-induced cardiac hypertrophy and down-regulates cardiac hypoxia inducible factor-lalpha in rats. AB - Apigenin is a natural flavonoid compound that can inhibit hypoxia-inducible factor (HIF)-1alpha expression in cultured tumor cells under hypoxic conditions. Hypertension-induced cardiac hypertrophy is always accompanied by abnormal myocardial glucolipid metabolism due to an increase of HIF-1alpha. However, whether or not apigenin may ameliorate the cardiac hypertrophy and abnormal myocardial glucolipid metabolism remains unknown. This study aimed to examine the effects of apigenin. Rats with cardiac hypertrophy induced by renovascular hypertension were treated with apigenin 50-100 mg kg(-1) (the doses can be achieved by pharmacological or dietary supplementation for an adult person) by gavage for 4 weeks. The results showed that after treatment with apigenin, the blood pressure, heart weight, heart weight index, cardiomyocyte cross-sectional area, serum angiotensin II, and serum and myocardial free fatty acids were reduced. It is important to note that apigenin decreased the expression level of myocardial HIF-1alpha protein. Moreover, apigenin simultaneously increased the expression levels of myocardial peroxisome proliferator-activated receptor (PPAR) alpha, carnitine palmitoyltransferase (CPT)-1, and pyruvate dehydrogenase kinase (PDK)-4 proteins and decreased the expression levels of myocardial PPARgamma, glycerol-3-phosphate acyltransferase genes (GPAT), and glucose transporter (GLUT) 4 proteins. These findings demonstrated that apigenin could improve hypertensive cardiac hypertrophy and abnormal myocardial glucolipid metabolism in rats, and its mechanisms might be associated with the down-regulation of myocardial HIF 1alpha expression and, subsequently increasing the expressions of myocardial PPARalpha and its target genes CPT-1 and PDK-4, and decreasing the expressions of myocardial PPARgamma and its target genes GPAT and GLUT-4. PMID- 26987381 TI - Characterization of exhaled breath particles collected by an electret filter technique. AB - Aerosol particles that are present in exhaled breath carry nonvolatile components and have gained interest as a specimen for potential biomarkers. Nonvolatile compounds detected in exhaled breath include both endogenous and exogenous compounds. The aim of this study was to study particles collected with a new, simple and convenient filter technique. Samples of breath were collected from healthy volunteers from approximately 30 l of exhaled air. Particles were counted with an optical particle counter and two phosphatidylcholines were measured by liquid chromatography-tandem mass spectrometry. In addition, phosphatidylcholines and methadone was analysed in breath from patients in treatment with methadone and oral fluid was collected with the Quantisal device. The results demonstrated that the majority of particles are <1 MUm in size and that the fraction of larger particle contributes most to the total mass. The phosphatidylcholine PC(16 : 0/16 : 0) dominated over PC(16 : 0/18 : 1) and represented a major constituent of the particles. The concentration of the PC(16 : 0/16 : 0) homolog was significantly correlated (p < 0.001) with total mass. From the low concentration of the two phosphatidylcholines and their relative abundance in oral fluid a major contribution from the oral cavity could be ruled out. The concentration of PC(16 : 0/16 : 0) in breath was positively correlated with age (p < 0.01). An attempt to use PC(16 : 0/16 : 0) as a sample size indicator for methadone was not successful, as the large intra-individual variability between samplings even increased after normalization. In conclusion, it was demonstrated that exhaled breath sampled with the filter device represents a specimen corresponding to surfactant. The possible use of PC(16 : 0/16 : 0) as a sample size indicator was supported and deserves further investigations. We propose that the direct and selective collection of the breath aerosol particles is a promising strategy for measurement of nonvolatiles in breath. PMID- 26987382 TI - Bi(iii) polybromides: a new chapter in coordination chemistry of bismuth. AB - A new family of bismuth coordination compounds - Bi(iii) polybromides - is introduced. Four representatives of this class - (N-EtPy)3[Bi2Br9](Br2)2 (1), (4 MePyH)3[Bi2Br9](Br2) (2), (H2bpe){[BiBr5]}(Br2) (3) and (BPB)2[BiBr5(Br3)](Br3)(Br2) (4) - were obtained in a simple way from HBr solutions of BiBr3 with added Br2, highlighting the diversity of the structural types in the new family of complexes. PMID- 26987383 TI - Graphene-Molybdenum Disulfide-Graphene Tunneling Junctions with Large-Area Synthesized Materials. AB - Tunneling devices based on vertical heterostructures of graphene and other 2D materials can overcome the low on-off ratios typically observed in planar graphene field-effect transistors. This study addresses the impact of processing conditions on two-dimensional materials in a fully integrated heterostructure device fabrication process. In this paper, graphene-molybdenum disulfide-graphene tunneling heterostructures were fabricated using only large-area synthesized materials, unlike previous studies that used small exfoliated flakes. The MoS2 tunneling barrier is either synthesized on a sacrificial substrate and transferred to the bottom-layer graphene or synthesized directly on CVD graphene. The presence of graphene was shown to have no impact on the quality of the grown MoS2. The thickness uniformity of MoS2 grown on graphene and SiO2 was found to be 1.8 +/- 0.22 nm. XPS and Raman spectroscopy are used to show how the MoS2 synthesis process introduces defects into the graphene structure by incorporating sulfur into the graphene. The incorporation of sulfur was shown to be greatly reduced in the absence of molybdenum suggesting molybdenum acts as a catalyst for sulfur incorporation. Tunneling simulations based on the Bardeen transfer Hamiltonian were performed and compared to the experimental tunneling results. The simulations show the use of MoS2 as a tunneling barrier suppresses contributions to the tunneling current from the conduction band. This is a result of the observed reduction of electron conduction within the graphene sheets. PMID- 26987385 TI - Fullerenic particles for the growth of carbon nanowall-like flowers on multilayer graphene. AB - Carbon nanowalls (CNWs) are composed of stacks of planar graphene layers with open edges that grow almost vertically on a substrate. Their morphology makes them a promising material for field emission, batteries, light absorbers and enhanced detectors for electrochemical and gas sensors. However, three main challenges prevent the fast development of CNWs: the synthesis is energetically demanding, poorly transferable to suitable substrates, and the growth mechanism is not understood. Here, we present a simple method to grow carbon nanowall-like flowers on multilayer graphene through fullerenic particles using thermal CVD and copper. The hydrophobicity of the fabricated hybrid material facilitates its transfer to any substrate. Our findings can boost the understanding of the physical properties and the practical applicability of CNWs. At the same time, our work is a concrete example of the role of multilayer graphene as a platform to one-step synthesis of new transferable graphenic materials. PMID- 26987384 TI - Monodisperse polyethylene glycol diacrylate hydrogel microsphere formation by oxygen-controlled photopolymerization in a microfluidic device. AB - PEG-based hydrogels have become widely used as drug delivery and tissue scaffolding materials. Common among PEG hydrogel-forming polymers are photopolymerizable acrylates such as polyethylene glycol diacrylate (PEGDA). Microfluidics and microfabrication technologies have recently enabled the miniaturization of PEGDA structures, thus enabling many possible applications for nano- and micro- structured hydrogels. The presence of oxygen, however, dramatically inhibits the photopolymerization of PEGDA, which in turn frustrates hydrogel formation in environments of persistently high oxygen concentration. Using PEGDA that has been emulsified in fluorocarbon oil via microfluidic flow focusing within polydimethylsiloxane (PDMS) devices, we show that polymerization is completely inhibited below critical droplet diameters. By developing an integrated model incorporating reaction kinetics and oxygen diffusion, we demonstrate that the critical droplet diameter is largely determined by the oxygen transport rate, which is dictated by the oxygen saturation concentration of the continuous oil phase. To overcome this fundamental limitation, we present a nitrogen micro-jacketed microfluidic device to reduce oxygen within the droplet, enabling the continuous on-chip photopolymerization of microscale PEGDA particles. PMID- 26987386 TI - Medical students' self-efficacy in problem-based learning and its relationship with self-regulated learning. AB - BACKGROUND: Problem-based learning (PBL) is most commonly used in medical education to enhance self-regulated learning (SRL) skills. Self-efficacy beliefs affect students' motivation through self-regulatory processes. The purpose of this study is to examine the relationship between medical students' self-reported SRL skills and their self-efficacy in PBL. METHODS: A cross-sectional study was conducted with second (286; 83.1%) and third (275; 80.2%) year students at the Ankara University School of Medicine. The SRL perception (SRLP) scale and self efficacy for problem-based learning (SPBL) scale were used in the study. RESULTS: The SRLP subscales were positively correlated with the SPBL subscales. There was a weak but meaningful correlation between the subscales of SRLP (with the exception of the lack of self-directedness scale) and the subscales of SPBL and the students' views on benefiting from PBL. The female students' mean score was higher for the 'planning and goal setting' subscale of SRLP (p=0.017), and the second-year students' mean score was higher than that of the third-year students for the 'lack of self-directedness' subscale of SRLP (p=0.001) with small effect sizes (Cohen's d is 0.17 and 0.27). There was no statistically significant difference between the year and subscales of SPBL. With regard to gender, the female students had higher scores than the male students on the 'responsibility' subscale of SPBL (p=0.003; Cohen's d=0.26). CONCLUSIONS: The study showed that medical students used SRL skills and believed in their ability to learn effectively in the PBL context and demonstrated the relationship between SRL skills and self-efficacy beliefs. Monitoring students' development in these skills and giving them feedback could be beneficial for the cognitive achievement of students with learning difficulties and insufficient study skills. Further studies need to be undertaken to investigate issues such as the curriculum, learning environment, individual differences, and how these can affect the SRL process. PMID- 26987387 TI - Assessment of the usage and effectiveness of intermittent preventive treatment and insecticide-treated nets on the indicators of malaria among pregnant women attending antenatal care in the Buea Health District, Cameroon. AB - BACKGROUND: Malaria in pregnancy is an immense public health problem with at least 50 million pregnant women living in malaria endemic areas. To prevent malaria and its complications in pregnancy the World Health Organization recommends the use of intermittent preventive treatment sulfadoxine-pyrimethamine (IPTp-SP), the use of insecticide-treated nets (ITNs), and effective case management. In most malaria endemic countries in Africa, 40% of pregnant women sleep under ITNs. In Cameroon, about 90% of pregnant women receive the first dose of SP, while 64% take the complete dose. Following the 2011 mass-campaign of free distribution of ITNs coupled with routine ANC distribution of ITN and adoption of IPTp in Cameroon, little has been done to assess the effectiveness of both interventions outside of Yaounde, the capital city. This study sought to assess the usage and effectiveness of IPTp-SP and ITNs on malaria in pregnancy. METHODS: The research was a cross-sectional hospital-based study that included 410 pregnant women attending antenatal clinics in the Buea Health District. Capillary blood samples were collected to check malaria parasite by microscopy and haemoglobin levels by microhaematocrit technique. RESULTS: A prevalence of 13.4 and 41.7% was detected for malaria and anaemia, respectively. The Overall coverage of ITN was 32.4% while that of ITPp was 63.2%. Malaria prevalence was least (7.2%) amongst women using both IPTp-SP and ITN while those with no intervention had the highest malaria prevalence of 18.6% (chi2 = 6.188; P = 0.103). Of the women with malaria, 12.73% were using ITN and had taken at least one dose of SP, 38.18% had taken at least one dose IPTp only, 10.91% were using only ITN and 38.18% were not using any preventive measure. There was a difference in anaemia status within the different intervention groups (chi2 = 8.673; P = 0.034). Pregnant women using both interventions were less associated to malaria (OR = 0.341, 95% CI = 0.138-0.841) compared to those using only one control method. CONCLUSION: Repeated doses of SP in combination with ITN use are effective in reducing malaria parasitaemia and improving haemoglobin level of pregnant women. PMID- 26987388 TI - Dramatic response to alectinib in a patient of ALK-rearranged lung cancer with poor performance status. AB - BACKGROUND: Lung cancers with anaplastic lymphoma kinase rearrangements are highly sensitive to anaplastic lymphoma kinase tyrosine kinase inhibition, underscoring the notion that such cancers are addicted to anaplastic lymphoma kinase activity. Several anaplastic lymphoma kinase inhibitors have been identified and are being evaluated in clinical trials. However patients with poor performance status (3 or 4) were not involved in these clinical trials, it has been unclear to use anaplastic lymphoma kinase-tyrosine kinase inhibitors for these patients. Here, we report an anaplastic lymphoma kinase-positive non small cell lung cancer patient with performance status 4, who was successfully treated with alectinib. CASE PRESENTATION: We report on a 52-year-old patient diagnosed as non small cell lung cancer harboring echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase fusion gene. His performance status was 4 because of severe respiratory failure. We treated this patient with alectinib as the first line therapy. Dramatic response was obtained and his performance status improved from 4 to 1 without severe adverse events. CONCLUSION: Alectinib is a therapeutic option for the anaplastic lymphoma kinase positive patients with poor performance status. PMID- 26987389 TI - The protective effect of qiancao naomaitong mixture on neuronal damage and cerebral ischemia/reperfusion injury. AB - Context Qiancao Naomaitong Mixture (QNM) is mainly used to treat ischemic stroke patients in the clinic. Objective This study evaluates the protective effect of QNM on neuronal damage in vitro, and clarifies the underlying mechanism against cerebral ischemia-reperfusion (I/R) injury in vivo. Materials and methods Activity assay of caspase 3 (C-3) and caspase 8 (C-8) were measured with microplate reader and cell apoptosis was investigated. Cerebral I/R injury was induced by MCAO model. QNM groups were given at 0.27, 0.54 and 1.08 mL/100 g body weight. The weight ratio of cerebral infarction tissue was obtained. The cytokine levels in serum and brain tissue were measured using ELISA. Results Compared with the OGD group (C-3: 29.69 +/- 5.63, C-8: 74.05 +/- 6.86), 100 mg/mL QNM (C-3: 19.80 +/- 2.62, C-8: 48.94 +/- 6.41) and 200 mg/mL QNM (C-3: 16.28 +/- 4.55, C-8: 41.08 +/- 4.05) treatments decreased C-3 and C-8 activities significantly, and inhibited apoptosis of SH-SY5Y cells. The weight ratios of cerebral tissues in low, medium and high dose groups were 17.33 +/- 5.1%, 17.78 +/- 5.4% and 14.25 +/ 4.2%, respectively, significantly lower than in control group. QNM also improved the cytokine levels in serum and brain tissue. In addition, histological examination indicated that dense neuropil and largely surviving neurons were seen in treated rats. Conclusion QNM exerted protective effect by inhibiting the cell apoptosis in vitro. The protective mechanisms of QNM were associated with its properties of anti-apoptosis and antioxidation as well as improved neuronal nutrition in I/R rats. PMID- 26987390 TI - Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a Surrogate Biomarker for Bevacizumab in Colorectal Cancer Liver Metastasis: A Single-Arm, Exploratory Trial. AB - PURPOSE: The purpose of this study is to investigate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and plasma cytokines and angiogenic factors (CAFs) as pharmacodynamic and prognostic biomarkers of bevacizumab monotherapy in colorectal cancer with liver metastasis (CRCLM). MATERIALS AND METHODS: From July 2011 to March 2012, 28 patients with histologically confirmed CRCLM received bevacizumab monotherapy followed by combined FOLFOX therapy. The mean age of the patients was 57 years (range, 30 to 77 years). DCE-MRI (Ktransand IAUC60) was performed at baseline, first follow-up (3 days after bevacizumab monotherapy), and second follow-up (3 days after combined therapy). CAF levels (vascular endothelial growth factor [VEGF], placental growth factor [PlGF], and interleukin 8) were assessed on the same days. Progression-free survival (PFS) time distributions were summarized using the Kaplan-Meier method and compared using log-rank tests. RESULTS: The median PFS period was 11.2 months. Ktrans, IAUC60, VEGF, and PlGF values on the first follow-up day were significantly different compared with baseline values. No differences were observed on the second follow up day. A > 40% decrease in Ktrans from baseline to first follow-up was associated with a longer PFS (hazard ratio, 0.349; 95% confidence interval, 0.133 to 0.912; p=0.032). Changes in CAFs did not show correlation with PFS time. CONCLUSION: DCE-MRI parameters and CAFs are pharmacodynamic biomarkers of bevacizumab for CRCLM. In our study, change in Ktrans at 3 days after bevacizumab monotherapy was a favorable prognostic factor; however, the value of CAFs as a prognostic biomarker was not found. PMID- 26987391 TI - TRIM29 Overexpression Promotes Proliferation and Survival of Bladder Cancer Cells through NF-kappaB Signaling. AB - PURPOSE: TRIM29 overexpression has been reported in several human malignancies and showed correlation with cancer cell malignancy. The aim of the current study is to examine its clinical significance and biological roles in human bladder cancer tissues and cell lines. MATERIALS AND METHODS: A total of 102 cases of bladder cancer tissues were examined for TRIM29 expression by immunohistochemistry. siRNA and plasmid transfection were performed in 5637 and BIU-87 cell lines. Cell Counting Kit-8, flow cytometry, western blot, and real time polymerase chain reaction were performed to examine its biological roles and mechanism in bladder cancer cells. RESULTS: We found that TRIM29 overexpression showed correlation with invading depth (p=0.0087). Knockdown of TRIM29 expression in bladder cancer cell line 5637 inhibited cell growth rate and cell cycle transition while its overexpression in BIU-87 cells accelerated cell proliferation and cell cycle progression. TRIM29 overexpression also inhibited cell apoptosis induced by cisplatin. In addition, we demonstrated that TRIM29 depletion decreased while its overexpression led to upregulated expression of cyclin D1, cyclin E, and Bcl-2. We also showed that TRIM29 knockdown inhibited protein kinase C (PKC) and nuclear factor kappaB (NF-kappaB) signaling while its overexpression stimulated the PKC and NF-kappaB pathways. BAY 11-7082 (NF-kappaB inhibitor) partly attenuated the effect of TRIM29 on expression of cyclin and Bcl 2. Treatment with PKC inhibitor staurosporine resulted in ameliorated TRIM29 induced activation of NF-kappaB. CONCLUSION: The current study demonstrated that TRIM29 upregulates cyclin and Bcl family proteins level to facilitate malignant cell growth and inhibit drug-induced apoptosis in bladder cancer, possibly through PKC-NF-kappaB signaling pathways. PMID- 26987393 TI - Radiation Therapy Alone in cT1-3N0 Non-small Cell Lung Cancer Patients Who Are Unfit for Surgical Resection or Stereotactic Radiation Therapy: Comparison of Risk-Adaptive Dose Schedules. AB - PURPOSE: High dose definitive radiation therapy (RT) alone is recommended to patients with cT1-3N0 non-small cell lung cancer, who are unfit for surgery or stereotactic RT. This study was conducted to evaluate the clinical outcomes and cost-effectiveness following RT alone using two different modest hypofractionation dose schemes. MATERIALS AND METHODS: Between 2001 and 2014, 124 patients underwent RT alone. From 2001 till 2010, 60 Gy in 20 fractions was delivered to 79 patients (group 1). Since 2011, 60 Gy in 20 fractions (group 2, 20 patients), and 60 Gy in 15 fractions (group 3, 25 patients) were selectively chosen depending on estimated risk of esophagitis. RESULTS: At follow-up of 16.7 months, 2-year rates of local control, progression-free survival, and overall survival were 62.6%, 39.1%, and 59.1%, respectively. Overall survival was significantly better in group 3 (p=0.002). In multivariate analyses, cT3 was the most powerful adverse factor affecting clinical outcomes. Incidence and severity of radiation pneumonitis were not different among groups, while no patients developed grade 2 esophagitis in group 3 (p=0.003). Under current Korean Health Insurance Policy, RT cost per person was 22.5% less in group 3 compared with others. CONCLUSION: The current study demonstrated that 60 Gy in 15 fractions instead of 60 Gy in 20 fractions resulted in comparable clinical outcomes with excellent safety, direct cost saving, and improved convenience to the patients with tumors located at >= 1.5 cm from the esophagus. PMID- 26987392 TI - Clinicopathologic Features and Long-Term Outcomes of Elderly Breast Cancer Patients: Experiences at a Single Institution in Korea. AB - PURPOSE: The purpose of this study was to assess the tumor characteristics and long-term clinical outcomes of adjuvant treatments after surgery with a curative aim for patients with breast cancer who are 65 years and older. MATERIALS AND METHODS: Patients with breast cancer who underwent curative surgery from 2000 to 2009 were analyzed (n=4,388). Tumor characteristics and survival outcome were compared by dividing the patients into two age groups (< 65 and >= 65 years old). The Kaplan-Meier method was used for comparison of survival rates by log-rank test, and a Cox regression model was used to examine the effect of variables. RESULTS: Among 4,388 patients with invasive breast cancer, 317 patients (7.2%) were 65 years or older and the median age of all patients was 47 years (range, 18 to 91 years). Tumor characteristics were similar between the two age groups, but the older patients were treated less often with adjuvant treatments. During a median follow-up period of 122 months, recurrence-free survival (RFS) was equivalent for patients 65 years and older compared to younger patients, but significantly worse in overall survival (OS) and breast cancer-specific survival (BCSS) (5-year OS, 94.3% vs. 90.5%; p < 0.001 and 5-year BCSS, 94.7% vs. 91.8%; p=0.031). In the multivariate model, age >= 65 years old was identified as an independent risk factor for OS and RFS. CONCLUSION: Elderly breast cancer appeared to have worse outcomes with very low prevalence in Korea, despite similar tumor characteristics. More active adjuvant therapies would have a role for aggressive subtypes for fit, elderly patients. PMID- 26987394 TI - The Impact of High-Risk HPV Genotypes Other Than HPV 16/18 on the Natural Course of Abnormal Cervical Cytology: A Korean HPV Cohort Study. AB - PURPOSE: The purpose of this study is to evaluate the impact of high-risk human papillomaviruses (HPVs) other than HPV 16/18 on the natural course of atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion (LSIL). MATERIALS AND METHODS: The study population was derived from the Korean HPV cohort (2010-2014). Women aged 20 to 60 who satisfied the criteria of having both HPV infection and abnormal cervical cytology of either ASC-US or LSIL were recruited from five institutions nationwide. Enrolled patients underwent cervical cytology and HPV DNA testing every 6 months. RESULTS: A total of 1,158 patients were enrolled. The 10 most common HPV types were HPV 16 (12.3%), 58 (10.0%), 56 (8.8%), 53 (8.4%), 52 (7.7%), 39 (6.2%), 18 (6.0%), 51 (5.7%), 68 (5.1%), and 66 (4.6%). Among these patients, 636 women were positive for high-risk HPVs other than HPV 16 or 18, and 429 women were followed for more than 6 months. Cytology evaluations showed progression in 15.3% of women, no change in 22.6%, and regression in 62.1% of women at 12 months. In cases of HPV 58 single infection, a more highly significant progression rate, compared to other high-risk types, was observed at 6 months (relative risk [RR], 3.3; 95% confidence interval [CI], 2.04 to 5.30; p < 0.001) and 12 months (RR, 5.03; 95% CI, 2.56 to 9.91; p < 0.001). CONCLUSION: HPV genotypes numbered in the 50s were frequent in Korean women with ASC-US and LSIL. HPV 58 was the second most common type, with a high progression rate of cervical cytology. PMID- 26987395 TI - Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2013. AB - PURPOSE: This study described the 2013 nationwide cancer statistics in Korea, including cancer incidence, survival, prevalence, and mortality. MATERIALS AND METHODS: Cancer incidence data from 1999-2013 were obtained from Korea National Cancer Incidence Database and followed until December 31, 2014. Mortality data from 1983-2013 were obtained from Statistics Korea. The prevalence was defined as the number of cancer patients alive on January 1, 2014 among all cancer patients diagnosed since 1999. Crude, and age-standardized and 5-year relative survival rates were also calculated. RESULTS: In 2013, a total of 225,343 and 75,334 Koreans were newly diagnosed and died from cancer, respectively. The age standardized rates for cancer incidence and mortality in 2013 were 290.5 and 87.9 per 100,000, respectively. The age-standardized cancer incidence rate increased 3.1% annually between 1999 and 2013. However, the overall cancer incidence rates have decreased slightly in recent years (2011 to 2013). The age-standardized rate for all-cancer mortality has decreased 2.7% annually since 2002. Overall, the 5 year relative survival rate for people diagnosed with cancer between 2009 and 2013 was 69.4%, which represents an improved survival rate as compared with 41.2% for people diagnosed between 1993 and 1995. CONCLUSION: Age-standardized cancer incidence rates have decreased between 2011 and 2013; mortality rates have also declined since 2002, while 5-year survival rates have improved remarkably from 1993-1995 to 2009-2013 in Korea. PMID- 26987397 TI - A Pilot Study Evaluating Steroid-Induced Diabetes after Antiemetic Dexamethasone Therapy in Chemotherapy-Treated Cancer Patients. AB - PURPOSE: Dexamethasone is a mainstay antiemetic regimen for the prevention of chemotherapy-induced nausea and vomiting. The aim of this pilot study was to assess the incidence of and factors associated with steroid-induced diabetes in cancer patients receiving chemotherapy with dexamethasone as an antiemetic. MATERIALS AND METHODS: Non-diabetic patients with newly diagnosed gastrointestinal cancer who received at least three cycles of highly or moderately emetogenic chemotherapy with dexamethasone as an antiemetic were enrolled. Fasting plasma glucose levels, 2-hour postprandial glucose levels, and hemoglobin A1C tests for the diagnosis of diabetes were performed before chemotherapy and at 3 and 6 months after the start of chemotherapy. The homeostasis model assessment of insulin resistance (HOMA-IR) was used as an index for measurement of insulin resistance, defined as a HOMA-IR >= 2.5. RESULTS: Between January 2012 and November 2013, 101 patients with no history of diabetes underwent laboratory tests for assessment of eligibility; 77 of these patients were included in the analysis. Forty-five patients (58.4%) were insulin resistant and 17 (22.1%) developed steroid-induced diabetes at 3 or 6 months after the first chemotherapy, which included dexamethasone as an antiemetic. Multivariate analysis showed significant association of the incidence of steroid-induced diabetes with the cumulative dose of dexamethasone (p=0.049). CONCLUSION: We suggest that development of steroid-induced diabetes after antiemetic dexamethasone therapy occurs in approximately 20% of non-diabetic cancer patients; this is particularly significant for patients receiving high doses of dexamethasone. PMID- 26987396 TI - Predictors of Distant Metastasis after Radical Surgery Followed by Postoperative Radiotherapy with or without Chemotherapy for Oropharyngeal Cancer. AB - PURPOSE: We investigated the prognostic factors for distant metastasis (DM) in patients with locally advanced oropharyngeal cancer (OPC) treated with surgery and adjuvant radiotherapy with or without concurrent chemotherapy. MATERIALS AND METHODS: Eighty-five patients treated between January 1995 and August 2014 were evaluated retrospectively. Data regarding the pathological tumour and nodal status, human papillomavirus (HPV) status, treatment characteristics, and pretreatment maximum standardized uptake value (SUVmax) of 18-fluoro-2 deoxyglucose positron emission tomography-computed tomography scan (18F-FDG PET CT) were evaluated, and their influence on DM and survival outcomes were analyzed. RESULTS: Median follow-up period was 48.0 months. Recurrence was observed in 20 patients, including locoregional recurrence and DM. DM was observed in 13 patients. A multivariate analysis confirmed that the presence of lymphovascular invasion (p=0.031), lower neck lymph node (LN) involvement (p=0.006), SUVmax >= 9.7 (p=0.014), and tumour size >= 3 cm (p=0.037) significantly affected DM. HPV status was not associated with DM. Perineural invasion (p=0.048), lower neck LNinvolvement (p=0.008), SUVmax >= 9.7 (p=0.019), and tumour size >= 3 cm (p=0.033) were also significant factors for the DM-free survival rate. CONCLUSION: Lower neck LN involvement, high SUVmax in pretreatment 18F-FDG PET-CT, and large tumour size were predictive factors for DM in patients of OPC. PMID- 26987398 TI - Overexpression of Endoplasmic Reticulum Oxidoreductin 1-alpha (ERO1L) Is Associated with Poor Prognosis of Gastric Cancer. AB - PURPOSE: Gastric cancer is the second leading cause of cancer-related death worldwide. Although surgery is the standard curative treatment for gastric cancer, relapse occurs in a large number of patients, except in the case of early diagnosed gastric cancer. Following previous studies that identified endoplasmic reticulum oxidoreductin 1-alpha (ERO1L) as a potential marker for gastric cancer, we investigated the functional role of ERO1L in gastric cancer. MATERIALS AND METHODS: For validation of microarray data, the mRNA expression level of ERO1L was measured by quantitative real-time reverse transcription polymerase chain reaction in 56 independent stage III gastric cancer patients. Immunohistochemical staining was performed to examine the protein expression level of ERO1L in 231 gastric cancer patients. Correlation between gene expression and cancer prognosis was evaluated. RESULTS: Patients with high ERO1L expression had poorer survival than those with low expression (p < 0.01). Functional assays demonstrated that ERO1L knockdown inhibited cell proliferation, migration, invasion, and chemoresistance. In addition, involvement of inactivation of Akt and JNK signaling in molecular mechanisms of ERO1L inhibition was demonstrated. CONCLUSION: High expression of ERO1L is associated with poor prognosis of patients with gastric cancer. These results indicate that ERO1L expression may be a clinically promising therapeutic target for prevention of gastric cancer. PMID- 26987400 TI - Message from the new CMI Editor-in-Chief. PMID- 26987399 TI - Sound Interferes with the Early Tactile Manual Abilities of Preterm Infants. AB - Premature birth is a sudden change of the sensory environment of a newborn, while their senses are still in development, especially in the stressful and noisy environment of the NICU. The study aimed to evaluate the effect of noise on the early tactile manual abilities of preterm infants (between 29 and 35 weeks PCA). Infants were randomly assigned to one of the two conditions: Silence and Noise. For each condition, two phases were introduced: a habituation phase (repeated presentation of the same object, prism or cylinder), followed by a test phase (presentation of the familiar or a novel object). In the Silence condition, they received the tactile habituation and test phases: In the Noise condition, they went through the same phases, while an alarm sounded. Sixty-three preterm infants were included. They displayed a strong and effective ability to memorize tactile manual information and to detect the difference between two shape features, but this ability seems to be impaired by the concomitant exposure to an alarm sound. This study is the first to highlight the effect of a negative stimulus on sensory functioning in premature infants. It reinforces the importance of developing environmental measures to lower the sound level in NICUs. PMID- 26987401 TI - Spin-orbit coupling of light in asymmetric microcavities. AB - When spinning particles, such as electrons and photons, undergo spin-orbit coupling, they can acquire an extra phase in addition to the well-known dynamical phase. This extra phase is called the geometric phase (also known as the Berry phase), which plays an important role in a startling variety of physical contexts such as in photonics, condensed matter, high-energy and space physics. The geometric phase was originally discussed for a cyclically evolving physical system with an Abelian evolution, and was later generalized to non-cyclic and non Abelian cases, which are the most interesting fundamental subjects in this area and indicate promising applications in various fields. Here, we enable optical spin-orbit coupling in asymmetric microcavities and experimentally observe a non cyclic optical geometric phase acquired in a non-Abelian evolution. Our work is relevant to fundamental studies and implies promising applications by manipulating photons in on-chip quantum devices. PMID- 26987403 TI - Photo-induced Doping in GaN Epilayers with Graphene Quantum Dots. AB - We demonstrate a new doping scheme where photo-induced carriers from graphene quantum dots (GQDs) can be injected into GaN and greatly enhance photoluminescence (PL) in GaN epilayers. An 8.3-fold enhancement of PL in GaN is observed after the doping. On the basis of time-resolved PL studies, the PL enhancement is attributed to the carrier transfer from GQDs to GaN. Such a carrier transfer process is caused by the work function difference between GQDs and GaN, which is verified by Kelvin probe measurements. We have also observed that photocurrent in GaN can be enhanced by 23-fold due to photo-induced doping with GQDs. The improved optical and transport properties from photo-induced doping are promising for applications in GaN-based optoelectronic devices. PMID- 26987405 TI - Non-antigenic regulators of targeting for imaging and therapy. PMID- 26987402 TI - Numb regulates vesicular docking for homotypic fusion of early endosomes via membrane recruitment of Mon1b. AB - Numb is an endocytic protein that plays crucial roles in diverse cellular processes such as asymmetric cell division, cell migration and differentiation. However, the molecular mechanism by which Numb regulates endocytic trafficking is poorly understood. Here, we demonstrate that Numb is a docking regulator for homotypic fusion of early endosomes (EEs). Numb depletion causes clustered but unfused EEs, which can be rescued by overexpressing cytosolic Numb 65 and Numb 71 but not plasma membrane-attached Numb 66 or Numb 72. Time-lapse analysis reveals that paired vesicles tend to tether but not fuse with each other in the absence of Numb. We further show that Numb binds to another docking regulator, Mon1b, and is required for the recruitment of cytosolic Mon1b to the EE membrane. Consistent with this, deletion of Mon1b causes similar defects in EE fusion. Our study thus identifies a novel mechanism by which Numb regulates endocytic sorting by mediating EE fusion. PMID- 26987404 TI - Spines slow down dendritic chloride diffusion and affect short-term ionic plasticity of GABAergic inhibition. AB - Cl(-) plays a crucial role in neuronal function and synaptic inhibition. However, the impact of neuronal morphology on the diffusion and redistribution of intracellular Cl(-) is not well understood. The role of spines in Cl(-) diffusion along dendritic trees has not been addressed so far. Because measuring fast and spatially restricted Cl(-) changes within dendrites is not yet technically possible, we used computational approaches to predict the effects of spines on Cl(-) dynamics in morphologically complex dendrites. In all morphologies tested, including dendrites imaged by super-resolution STED microscopy in live brain tissue, spines slowed down longitudinal Cl(-) diffusion along dendrites. This effect was robust and could be observed in both deterministic as well as stochastic simulations. Cl(-) extrusion altered Cl(-) diffusion to a much lesser extent than the presence of spines. The spine-dependent slowing of Cl(-) diffusion affected the amount and spatial spread of changes in the GABA reversal potential thereby altering homosynaptic as well as heterosynaptic short-term ionic plasticity at GABAergic synapses in dendrites. Altogether, our results suggest a fundamental role of dendritic spines in shaping Cl(-) diffusion, which could be of relevance in the context of pathological conditions where spine densities and neural excitability are perturbed. PMID- 26987406 TI - Nighttime dissolution in a temperate coastal ocean ecosystem increases under acidification. AB - Anthropogenic emissions of carbon dioxide (CO2) are causing ocean acidification, lowering seawater aragonite (CaCO3) saturation state (Omega arag), with potentially substantial impacts on marine ecosystems over the 21(st) Century. Calcifying organisms have exhibited reduced calcification under lower saturation state conditions in aquaria. However, the in situ sensitivity of calcifying ecosystems to future ocean acidification remains unknown. Here we assess the community level sensitivity of calcification to local CO2-induced acidification caused by natural respiration in an unperturbed, biodiverse, temperate intertidal ecosystem. We find that on hourly timescales nighttime community calcification is strongly influenced by Omega arag, with greater net calcium carbonate dissolution under more acidic conditions. Daytime calcification however, is not detectably affected by Omega arag. If the short-term sensitivity of community calcification to Omega arag is representative of the long-term sensitivity to ocean acidification, nighttime dissolution in these intertidal ecosystems could more than double by 2050, with significant ecological and economic consequences. PMID- 26987408 TI - Effect of continuous and interval aerobic exercise training on baroreflex sensitivity in heart failure. AB - INTRODUCTION: The ability of continuous aerobic exercise training (AET) to increase baroreflex control and cardiac function in heart failure (HF) has been well described, but the comparison between continuous and interval AET on these functions is inconclusive. OBJECTIVES: To compare the effects of continuous and interval AET on cardiac function and baroreflex sensitivity (BrS) in an experimental model of HF. METHODS: Rats were divided into the following groups: continuous training (HF-CT), intense interval training (HF-IIT), moderate interval training (HF-MIT), sedentary group (HF-SED), and sham sedentary (SHAM SED). Animals underwent surgery to induce HF by ligation of the interventricular coronary artery. Six weeks after surgery, AET was started (8weeks, 3sessions/week). Echocardiography studies to assess cardiac function were performed before and after AET. At the end of the training protocols, the BrS index was assessed by stepwise intravenous infusions of sodium nitroprusside and phenylephrine. RESULTS: All methods of exercise prevented the HF-induced increase in left ventricular diameter in diastole observed in the HF-SED rats (0.88+/-0.09 vs. 1.03+/-0.09cm; P<0.05), but only the HF-CT (28.5+/-6.3 vs. 39.2+/-12.7%; P<0.05) and HF-MIT (31.0+/-8.5 vs. 42.0+/-10.3%; P<0.05) groups exhibited an increase in ejection fraction. Nevertheless, the HF-CT group was the only group that showed a tachycardia reflex higher than that of the HF-SED group (0.87+/ 0.34 vs. 0.20+/-0.05bpm/mmHg; P<0.05) and similar to that of the SHAM-SED group (1.04+/-0.11bpm/mmHg). CONCLUSIONS: These results suggest that continuous and moderate interval training induced similar improvements in cardiac function but that only continuous training induced higher BrS in HF rats. PMID- 26987407 TI - Snake Venom Disintegrin Inhibits the Activation of Toll-Like Receptors and Alleviates Sepsis through Integrin alphaVbeta3 Blockade. AB - Bacterial infection-induced sepsis is the leading cause of septic inflammatory disease. Rhodostomin (Rn), a snake venom disintegrin, was previously reported to interact with the alphaVbeta3 integrin and the TLR4 on phagocyte in attenuating LPS-induced endotoxemia. In this report, we further evaluated the effects of Rn on TLR2-activated monocytes and its in vivo efficacy. Rn effectively suppressed the adhesion, migration, and cytokine release of Pam3CSK4-activated THP-1 cells. Rn specifically bound to integrin alphaVbeta3 of TLR2-activated THP-1. Integrin alphaV and Akt siRNA transfection both restrained Pam3CSK4-elicited cytokine release. Rn decreased the Pam3CSK4-induced phosporylation of MAPKs, degradation of IkappaB and activation of FAK, Akt, c-Src and Syk. The Pam3CSK4-induced translocation of MyD88, a central adaptor of TLR2, to the cell membrane was also inhibited by Rn treatment. In the polymicrobial inflammatory caecal ligation and puncture model, Rn significantly reduced pro-inflammatory cytokine and chemokine release, alleviated tissue injury and elevated survival rate in vivo. Taken together, in addition to inhibiting the activation of TLR4, Rn exhibits anti inflammatory activity through antagonizing the activation of phagocytes and interrupting the crosstalk between alphaVbeta3 and TLR2-dependent signaling pathways. PMID- 26987409 TI - Acute effect of oral sensation of sweetness on celiac artery blood flow and gastric myoelectrical activity in humans. AB - Little is known about the effect of sweet taste stimulus on gastrointestinal motility and splanchnic blood flow. We examined whether gastric myoelectrical activity and/or celiac artery blood flow (CABF), which perfuses the stomach, are increased following an oral sensation of sweetness. After overnight fasting, 11 subjects rested for 5min and sipped, but not swallowed, one of four solutions for 1min. The fluid was then spat out, and subjects remained at rest for a further 10min. Fluids were approximately 15ml of three glucose solutions (4, 16, or 48%) or distilled water. Subjects completed trials with all four solutions in a randomized order. During each trial, gastric myoelectrical activity and CABF were continuously measured using electrogastrography and pulsed Doppler ultrasonography, respectively. None of the four solutions affected gastric myoelectrical activity. CABF was significantly increased after oral stimuli by all three glucose solutions, but not by water. There were no significant differences in the increments in CABF among the three glucose solutions. These results suggest that a sweet taste stimulus above a certain level of intensity acutely increases CABF during cephalic phase, without augmentation of gastric myoelectrical activity. PMID- 26987410 TI - Accidental usage of an adrenaline auto-injector in Japanese children with a food allergy. PMID- 26987411 TI - Genome engineering using CRISPR/Cas: getting more versatile and more precise at the same time. AB - A report on the second meeting on 'Genome Engineering and Synthetic Biology: Tools and Technologies', held 28-29 January 2016 in Ghent, Belgium. PMID- 26987412 TI - Genome-wide identification and validation of simple sequence repeats (SSRs) from Asparagus officinalis. AB - Garden asparagus (Asparagus officinalis), an important vegetable cultivated worldwide, can also serve as a model dioecious plant species in the study of sex determination and sex chromosome evolution. However, limited DNA marker resources have been developed and used for this species. To expand these resources, we examined the DNA sequences for simple sequence repeats (SSRs) in 163,406 scaffolds representing approximately 400 Mbp of the A. officinalis genome. A total of 87,576 SSRs were identified in 59,565 scaffolds. The most abundant SSR repeats were trinucleotide and tetranucleotide, accounting for 29.2 and 29.1% of the total SSRs, respectively, followed by di-, penta-, hexa-, hepta-, and octanucleotides. The AG motif was most common among dinucleotides and was also the most frequent motif in the entire A. officinalis genome, representing 14.7% of all SSRs. A total of 41,917 SSR primers pairs were designed to amplify SSRs. Twenty-two genomic SSR markers were tested in 39 asparagus accessions belonging to ten cultivars and one accession of Asparagus setaceus for determination of genetic diversity. The intra-species polymorphism information content (PIC) values of the 22 genomic SSR markers were intermediate, with an average of 0.41. The genetic diversity between the ten A. officinalis cultivars was low, and the UPGMA dendrogram was largely unrelated to cultivars. It is here suggested that the sex of individuals is an important factor influencing the clustering results. The information reported here provides new information about the organization of the microsatellites in A. officinalis genome and lays a foundation for further genetic studies and breeding applications of A. officinalis and related species. PMID- 26987413 TI - Effect of pre- and post-column band broadening on the performance of high-speed chromatography columns under isocratic and gradient conditions. AB - We report on the results of an experimental and theoretical study of the effect of the extra-column band broadening (ECBB) on the performance of narrow-bore columns filled with the smallest particles that are currently commercially available. Emphasis is on the difference between the effect of ECBB under gradient and isocratic conditions, as well as on the ability to model and predict the ECBB effects using well-established band broadening expressions available from the theory of chromatography. The fine details and assumptions that need to be taken into account when using these expressions are discussed. The experiments showed that, the steeper the gradient, the more pronounced the extra-column band broadening losses become. Whereas the pre-column band broadening can in both isocratic and gradient elution be avoided by playing on the possibilities to focus the analytes on top of the column (e.g. by using the POISe injection method when running isocratic separations), the post-column extra-column band broadening is inescapable in both cases. Inducing extra-column band broadening by changing the inner diameter of the post-column tubing from 65 to 250 MUm, we found that all peaks in the chromatogram are strongly affected (around a factor of 1.9 increase in relative peak width) when running steep gradients, while usually only the first eluting peak was affected in the isocratic mode or when running shallow gradients (factor 1.6-1.8 increase in relative peak width for the first eluting analyte). PMID- 26987414 TI - Photodegradation of fluorene in aqueous solution: Identification and biological activity testing of degradation products. AB - Degradation of fluorene under UV-vis irradiation in water was investigated and structural elucidation of the main photoproducts was achieved using gas chromatography coupled with mass spectrometry. Twenty-six photoproducts were structurally identified, mainly on the basis of electron ionization mass spectra interpretation. The main generated transformation products are hydroxy derivatives. Some secondary photoproducts including fluorenone, hydroxy fluorenone, 2-biphenyl carboxylic acid, biphenylene, methanol fluorene congeners and hydroxy fluorene dimers were also observed. A photodegradation pathway was suggested on the basis of the chemical structures of photoproducts. Fluorene as well as its main photoproducts for which chemical standards were commercially available were tested for their ability to elicit cytotoxic, estrogenic and dioxin-like activity by using in vitro cell-based bioassays. None of the tested compounds was cytotoxic at concentrations up to 100 MUM. However, 2 hydroxyfluorene and 3-hydroxyfluorene exerted significant estrogenic and dioxin like activity on a concentration range of 3-30 MUM, while fluorene and 9 hydroxyfluorene were weakly or not active, respectively, in our assays. This supports the view that photodegradation processes can generate by-products of higher toxicological concern than the parent compound and strengthens the need to further identify transformation products in the aquatic environment. PMID- 26987415 TI - Advanced analysis of polymer emulsions: Particle size and particle size distribution by field-flow fractionation and dynamic light scattering. AB - Field flow fractionation (FFF) is an advanced fractionation technique for the analyses of very sensitive particles. In this study, different FFF techniques were used for the fractionation and analysis of polymer emulsions/latexes. As model systems, a pure acrylic emulsion and emulsions containing titanium dioxide were prepared and analyzed. An acrylic emulsion polymerization was conducted, continuously sampled from the reactor and subsequently analyzed to determine the particle size, radius of gyration in specific, of the latex particles throughout the polymerization reaction. Asymmetrical flow field-flow fractionation (AF4) and sedimentation field-flow fractionation (SdFFF), coupled to a multidetector system, multi-angle laser light scattering (MALLS), ultraviolet (UV) and refractive index (RI), respectively, were used to investigate the evolution of particle sizes and particle size distributions (PSDs) as the polymerization progressed. The obtained particle sizes were compared against batch-mode dynamic light scattering (DLS). Results indicated differences between AF4 and DLS results due to DLS taking hydration layers into account, whereas both AF4 and SdFFF were coupled to MALLS detection, hence not taking the hydration layer into account for size determination. SdFFF has additional separation capabilities with a much higher resolution compared to AF4. The calculated radii values were 5 nm larger for SdFFF measurements for each analyzed sample against the corresponding AF4 values. Additionally a low particle size shoulder was observed for SdFFF indicating bimodality in the reactor very early during the polymerization reaction. Furthermore, different emulsions were mixed with inorganic species used as additives in cosmetics and coatings such as TiO2. These complex mixtures of species were analyzed to investigate the retention and particle interaction behavior under different AF4 experimental conditions, such as the mobile phase. The AF4 system was coupled online to inductively coupled plasma mass spectrometry (ICP-MS) for elemental speciation and identification of the inorganic additive. SdFFF had a larger separation power to distinguish different particle size populations whereas AF4 had the capability of separating the organic particles and inorganic TiO2 particles, with high resolution. PMID- 26987416 TI - Prospects of in vivo singlet oxygen luminescence monitoring: Kinetics at different locations on living mice. AB - BACKGROUND: Singlet oxygen observation is considered a valuable tool to assess and optimize PDT treatment. In complex systems, such as tumors in vivo, only the direct, time-resolved singlet oxygen luminescence detection can give reliable information about generation and interaction of singlet oxygen. Up to now, evaluation of kinetics was not possible due to insufficient signal-to-noise ratio. Here we present high signal-to-noise ratio singlet oxygen luminescence kinetics obtained in mouse tumor model under PDT relevant conditions. METHODS: A highly optimized system based on a custom made laser diode excitation source and a high aperture multi-furcated fiber, utilizing a photomultiplier tube with a multi photon counting device was used. RESULTS: Luminescence kinetics with unsurpassed signal-to-noise ratio were gained from tumor bearing nude mice in vivo upon topic application, subcutaneous injection as well as intravenous injection of different photosensitizers (chlorin e6 and dendrimer formulations of chlorin e6). Singlet oxygen kinetics in appropriate model systems are discussed to facilitate the interpretation of complex kinetics obtained from in vivo tumor tissue. CONCLUSIONS: This is the first study addressing the complexity of singlet oxygen luminescence kinetics in tumor tissue. At present, further investigations are needed to fully explain the processes involved. Nevertheless, the high signal to-noise ratio proves the applicability of direct time-resolved singlet oxygen luminescence detection as a prospective tool for monitoring photodynamic therapy. PMID- 26987418 TI - No correlation between health care expenditure and mortality in the European Union. PMID- 26987417 TI - Personality in multiple sclerosis (MS): impact on health, psychological well being, coping, and overall quality of life. AB - Personality has long been considered a factor that can account for differences in health, well-being, and overall quality of life (QOL). A 'Distressed or Type D Personality' has been studied in medical populations as a predictor of several outcomes. The purpose of the present investigation was to determine the presence of Type D Personality in multiple sclerosis (MS) and its role on disease symptoms, disease management, health-related behaviors, coping, psychological well-being, and overall QOL and functioning. Two hundred and thirty (230) individuals with MS completed a survey assessing personality, disease symptoms, disease management, coping, self-efficacy, locus of control (LOC), psychological well-being, and QOL. Thirty-seven (16%) individuals were found to be 'Type D+.' Such individuals reported greater fatigue, pain, depression, and anxiety and worse disease management and adherence. They also reported engaging in maladaptive means of coping. Compared to 'Type D-' they reported lower self efficacy, LOC, QOL and greater perceived stress. Finally, 'Type D+' individuals were more likely to be considering leaving the workforce. Findings suggest that 'Type D' Personality is associated with various negative outcomes in MS. Consideration of the routine assessment of personality in MS seems warranted and may better inform interventions and ward off poor outcomes. PMID- 26987419 TI - Ocean literacy: a 'new' socio-ecological concept for a sustainable use of the seas. PMID- 26987420 TI - Amniotic fluid embolism: diagnosis and management. AB - OBJECTIVE: We sought to provide evidence-based guidelines regarding the diagnosis and management of amniotic fluid embolism. STUDY DESIGN: A systematic literature review was performed using MEDLINE, PubMed, EMBASE, and the Cochrane Library. The search was restricted to English-language articles published from 1966 through March 2015. Priority was given to articles reporting original research, in particular randomized controlled trials, although review articles and commentaries were consulted. Abstracts of research presented at symposia and scientific conferences were not considered adequate for inclusion. Evidence reports and published guidelines were also reviewed, and additional studies were located by reviewing bibliographies of identified articles. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used for defining the strength of recommendations and rating quality of the evidence. Consistent with US Preventive Task Force guidelines, references were evaluated for quality based on the highest level of evidence. RESULTS AND RECOMMENDATIONS: We recommend the following: (1) we recommend consideration of amniotic fluid embolism in the differential diagnosis of sudden cardiorespiratory collapse in the laboring or recently delivered woman (GRADE 1C); (2) we do not recommend the use of any specific diagnostic laboratory test to either confirm or refute the diagnosis of amniotic fluid embolism; at the present time, amniotic fluid embolism remains a clinical diagnosis (GRADE 1C); (3) we recommend the provision of immediate high-quality cardiopulmonary resuscitation with standard basic cardiac life support and advanced cardiac life support protocols in patients who develop cardiac arrest associated with amniotic fluid embolism (GRADE 1C); (4) we recommend that a multidisciplinary team including anesthesia, respiratory therapy, critical care, and maternal-fetal medicine should be involved in the ongoing care of women with AFE (Best Practice); (5) following cardiac arrest with amniotic fluid embolism, we recommend immediate delivery in the presence of a fetus >=23 weeks of gestation (GRADE 2C); (6) we recommend the provision of adequate oxygenation and ventilation and, when indicated by hemodynamic status, the use of vasopressors and inotropic agents in the initial management of amniotic fluid embolism. Excessive fluid administration should be avoided (GRADE 1C); and (7) because coagulopathy may follow cardiovascular collapse with amniotic fluid embolism, we recommend the early assessment of clotting status and early aggressive management of clinical bleeding with standard massive transfusion protocols (GRADE 1C). PMID- 26987421 TI - An artificial intelligence approach for modeling volume and fresh weight of callus - A case study of cumin (Cuminum cyminum L.). AB - Cumin (Cuminum cyminum Linn.) is valued for its aroma and its medicinal and therapeutic properties. A supervised feedforward artificial neural network (ANN) trained with back propagation algorithms, was applied to predict fresh weight and volume of Cuminum cyminum L. calli. Pearson correlation coefficient was used to evaluate input/output dependency of the eleven input parameters. Area, feret diameter, minor axis length, perimeter and weighted density parameters were chosen as input variables. Different training algorithms, transfer functions, number of hidden nodes and training iteration were studied to find out the optimum ANN structure. The network with conjugate gradient fletcher-reeves (CGF) algorithm, tangent sigmoid transfer function, 17 hidden nodes and 2000 training epochs was selected as the final ANN model. The final model was able to predict the fresh weight and volume of calli more precisely relative to multiple linear models. The results were confirmed by R(2)>=0.89, R(i)>=0.94 and T value >=0.86. The results for both volume and fresh weight values showed that almost 90% of data had an acceptable absolute error of +/-5%. PMID- 26987422 TI - Nutritional regulation of long-chain PUFA biosynthetic genes in rainbow trout (Oncorhynchus mykiss). AB - Most studies on dietary vegetable oil in rainbow trout (Oncorhynchus mykiss) have been conducted on a background of dietary EPA (20 : 5n-3) and DHA (22 : 6n-3) contained in the fishmeal used as a protein source in aquaculture feed. If dietary EPA and DHA repress their endogenous synthesis from alpha-linolenic acid (ALA, 18 : 3n-3), then the potential of ALA-containing vegetable oils to maintain tissue EPA and DHA has been underestimated. We examined the effect of individual dietary n-3 PUFA on the expression of the biosynthetic genes required for metabolism of ALA to DHA in rainbow trout. A total of 720 juvenile rainbow trout were allocated to twenty-four experimental tanks and assigned one of eight diets. The effect of dietary ALA, EPA or DHA, in isolation or in combination, on hepatic expression of fatty acyl desaturase (FADS)2a(Delta6), FADS2b(Delta5), elongation of very long-chain fatty acid (ELOVL)5 and ELOVL2 was examined after 3 weeks of dietary intervention. The effect of these diets on liver and muscle phospholipid PUFA composition was also examined. The expression levels of FADS2a(Delta6), ELOVL5 and ELOVL2 were highest when diets were high in ALA, with no added EPA or DHA. Under these conditions ALA was readily converted to tissue DHA. Dietary DHA had the largest and most consistent effect in down-regulating the gene expression of all four genes. The ELOVL5 expression was the least responsive of the four genes to dietary n-3 PUFA changes. These findings should be considered when optimising aquaculture feeds containing vegetable oils and/or fish oil or fishmeal to achieve maximum DHA synthesis. PMID- 26987423 TI - Treatment effect on biases in size estimation in spider phobia. AB - BACKGROUND: The current study investigates biases in size estimations made by spider-phobic and healthy participants before and after treatment. METHOD: Forty one spider-phobic and 20 healthy participants received virtual reality (VR) exposure treatment and were then asked to rate the size of a real spider immediately before and, on average, 15days after the treatment. During the VR exposure treatment skin conductance response was assessed. RESULTS: Prior to the treatment, both groups tended to overestimate the size of the spider, but this size estimation bias was significantly larger in the phobic group than in the control group. The VR exposure treatment reduced this bias, which was reflected in a significantly smaller size rating post treatment. However, the size estimation bias was unrelated to the skin conductance response. CONCLUSION: Our results confirm the hypothesis that size estimation by spider-phobic patients is biased. This bias is not stable over time and can be decreased with adequate treatment. PMID- 26987424 TI - CBM research needs more power: Commentary on the special issue on cognitive bias modification. PMID- 26987425 TI - Mortality trends and years of potential life lost from gastric cancer in Mexico, 2000-2012. AB - BACKGROUND: In 2013 in Mexico, gastric cancer (GC) was the third leading cause of death from cancer in individuals 20 years of age or older. GC remains a public health problem in Mexico due to its high mortality and low survival rates, and the significantly lower quality of life of patients with this condition. OBJECTIVES: The aims of this study were to determine mortality trends nationwide, by state and socioeconomic region, and to determine rates of age-adjusted years of potential life lost due to GC, by state and socioeconomic region, within the period of 2000-2012. METHODS: Mortality records associated with GC for 2000-2012 were obtained from the National Health Information System of the Mexican Department of Health. Codes from the Tenth Revision of the International Classification of Diseases corresponding to the basic cause of death from GC were identified. Mortality and age-adjusted years of potential life lost rates, by state and socioeconomic region, were also calculated. RESULTS: In Mexico, 69,107 individuals died from GC within the time frame of 2000-2012. The age-adjusted mortality rate per 100,000 inhabitants decreased from 7.5 to 5.6. The male:female ratio was 1.15:1.0. Chiapas had the highest death rate from GC (9.2, 95% CI 8.2 10.3 [2000] and 8.2, 95% CI 7.3-9 [2012]), as well as regions 1, 2, and 5. Chiapas and socioeconomic region 1 had the highest rate of years of potential life lost. CONCLUSIONS: Using the world population age distribution as the standard, the age-adjusted mortality rate in Mexico per 100,000 inhabitants that died from GC decreased from 7.5 to 5.6 between 2000 and 2012. Chiapas and socioeconomic regions 1, 2, and 5 had the highest mortality from GC (Chiapas: 9.2, 95% CI 8.2-10.3 [2000] and 8.2, 95% CI 7.3-9 [2012], region 1: 5.5, 95% CI 5.2-5.9 [2000] and 5.3, 95% CI 4.9-5.7 [2012]; region 2: 5.3, 95% CI 5-5.6 [2000] and 5.4, 95% CI 5.1-5.8 [2012]; region 5: 6.1, 95% CI 5.6-6.6 [2000] and 4.6, 95% CI 4.2-5 [2012]). Chiapas and socioeconomic region 1 had the highest rate of years of potential life lost (Chiapas: 97.4 [2000] and 79.6 [2012] and region 1: 73.5 [2000] 65 [2012]). PMID- 26987427 TI - Increased Risk of Autoimmune Hepatitis in Patients with Psoriasis: A Danish Nationwide Cohort Study. PMID- 26987426 TI - Modification in a single meal is sufficient to provoke benefits in inflammatory responses of individuals at low-to-moderate cardiometabolic risk. AB - BACKGROUND & AIMS: Postprandial state is characterized by metabolic changes which may elevate circulating inflammatory biomarkers, used to assess cardiometabolic risk. It is unclear if biological benefits of certain food components could be obtained by a short-term change in a single meal of Brazilian's habitual diet. We investigated the postprandial effects of 2 fat tolerance tests (FTT) with different isocaloric meals (a typical Brazilian and a modified meal) differing by type of fatty acids and fiber contents, prior to and after breakfast interventions. METHODS: This crossover clinical trial included 80 overweight individuals with at least one cardiometabolic risk factor, (35-69 years) who received two isocaloric breakfast interventions for 4 weeks, with a 2-week washout. The Brazilian breakfast was saturated fat-enriched while the modified one was rich in unsaturated fatty acids and fibers. Before and after intervention periods, individuals underwent two FTT with meals with similar composition to the interventions breakfasts but higher energy content. Variables were compared by repeated-measures ANOVA. Correlations were assessed by Pearson's coefficient. RESULTS: At the end of both interventions, participants did not change plasma glucose or triglycerides. The higher IL-6 and IL-8 responses to the FTT with the Brazilian meal compared to that with the modified meal was accentuated after the interventions (p-diet <0.01; p-time <0.01). Acutely, E-selectin, TNF-alpha, IFN gamma, IL-10 and IL-17 concentrations did not increase in response to the FTTs, but showed higher values only after the Brazilian intervention. In contrast, intervention with the modified breakfast induced reductions in fasting and postprandial cytokines (p-diet <0.01). Changes in MUFA and PUFA intakes were inversely correlated to changes in inflammatory markers, while changes in saturated fat intake were directly correlated to IFN-gamma and IL-6. CONCLUSION: Isocaloric meals with distinct nutrient composition elicit different postprandial inflammatory responses after a relatively short intervention in a single meal. Each saturated fat-enriched meal consumed, as well as each unsaturated fat and fiber-enriched meal may induce pro- or anti-inflammatory responses that could impact on the cardiometabolic risk profile. PMID- 26987428 TI - Epicutaneous Allergic Sensitization by Cooperation between Allergen Protease Activity and Mechanical Skin Barrier Damage in Mice. AB - Allergen sources such as mites, insects, fungi, and pollen contain proteases. Airway exposure to proteases induces allergic airway inflammation and IgE/IgG1 responses via IL-33-dependent mechanisms in mice. We examined the epicutaneous sensitization of mice to a model protease allergen, papain; the effects of tape stripping, which induces epidermal barrier dysfunction; and the atopic march upon a subsequent airway challenge. Papain painting on ear skin and tape stripping cooperatively promoted dermatitis, the skin gene expression of proinflammatory cytokines and growth factors, up-regulation of serum total IgE, and papain specific IgE/IgG1 induction. Epicutaneous sensitization induced T helper (Th) 2 cells and Th17 differentiation in draining lymph nodes. Ovalbumin and protease inhibitor-treated papain induced no or weak responses, whereas the co administration of ovalbumin and papain promoted ovalbumin-specific IgE/IgG1 induction. Wild-type and IL-33-deficient mice showed similar responses in the epicutaneous sensitization phase. The subsequent airway papain challenge induced airway eosinophilia and maintained high papain-specific IgE levels in an IL-33 dependent manner. These results suggest that allergen source-derived protease activity and mechanical barrier damage such as that caused by scratching cooperatively promote epicutaneous sensitization and skin inflammation and that IL-33 is dispensable for epicutaneous sensitization but is crucial in the atopic march upon a subsequent airway low-dose encounter with protease allergens. PMID- 26987430 TI - Anti-tumor and anti-virus activity of polysaccharides extracted from Sipunculus nudus(SNP) on Hepg2.2.15. AB - Many polysaccharides have biological activities and have been investigated for their antitumor effects. In this study, we investigated the anti-tumor activity and anti-virus activity of SNP-the water-soluble polysaccharides extracted from Sipunculus nudus on Hepg2.2.15. Flow cytometry analysis demonstrated that SNP induced dose-dependent cell apoptosis on Hepg2.2.15. Real-time PCR and Western Blot analysis showed that SNP down-regulated the synthesis of HBsAg, HBV-DNA and enhanced the expression of pro-apoptosis proteins TNF-alpha, caspase-3, and Bax, while decreasing the expression of the anti-apoptosis proteins survivin, Bcl-2, and VEGF. These results suggested that SNP suppressed cell viability of Hepg2.2.15 and that could be a novel anti-tumor and anti-HBV agent. PMID- 26987431 TI - Charge state of arginine as an additive on heat-induced protein aggregation. AB - Arginine (Arg) is one of the most versatile solvent additives, such as suppressing protein aggregation, increasing solubility of small aromatic compounds and peptides, and preventing protein binding on solid surfaces. In this study, we investigated the role of the charged state of alpha-amino group of Arg for the prevention of protein aggregation. As expected, Arg effectively suppressed thermal aggregation of hen egg-white lysozyme at neutral pH, whereas the suppression effect diminished at and above pH 9.0, which corresponds to the pK of Arg's alpha-amino group. The pH dependence of Arg as an aggregation suppressor was confirmed by additional experiments with neutral proteins, bovine hemoglobin and bovine gamma-globulin. Interestingly, N-acetylated arginine, which lacks the alpha-amino group, showed a weaker suppressive effect on protein aggregation than Arg, even at neutral pH. These results indicate that both positively charged alpha-amino group and guanidinium group play important roles in suppressing heat-induced protein aggregation by Arg. The elucidated limitation of Arg at alkaline pH provides new insight in the application as well as the mechanism of Arg as a solvent additive. PMID- 26987429 TI - Combining energy and Laplacian regularization to accurately retrieve the depth of brain activity of diffuse optical tomographic data. AB - Diffuse optical tomography (DOT) provides data about brain function using surface recordings. Despite recent advancements, an unbiased method for estimating the depth of absorption changes and for providing an accurate three-dimensional (3-D) reconstruction remains elusive. DOT involves solving an ill-posed inverse problem, requiring additional criteria for finding unique solutions. The most commonly used criterion is energy minimization (energy constraint). However, as measurements are taken from only one side of the medium (the scalp) and sensitivity is greater at shallow depths, the energy constraint leads to solutions that tend to be small and superficial. To correct for this bias, we combine the energy constraint with another criterion, minimization of spatial derivatives (Laplacian constraint, also used in low resolution electromagnetic tomography, LORETA). Used in isolation, the Laplacian constraint leads to solutions that tend to be large and deep. Using simulated, phantom, and actual brain activation data, we show that combining these two criteria results in accurate (error <2 mm) absorption depth estimates, while maintaining a two-point spatial resolution of <24 mm up to a depth of 30 mm. This indicates that accurate 3-D reconstruction of brain activity up to 30 mm from the scalp can be obtained with DOT. PMID- 26987432 TI - Dendrimer-based nanoparticles for potential personalized therapy in chronic lymphocytic leukemia: Targeting the BCR-signaling pathway. AB - Chronic lymphocytic leukemia (CLL) is one of the most prevalent forms of leukemia in western society. Although classic chemoimmune therapy is still the gold standard of care for leukemic patients, effective therapy of CLL is yet to be achieved. The present study examines the influence of poly(propylene)imine (PPI) dendrimers with primary amino surface groups modified with maltotriose residues in approximately 90% (PPI-G4-DS-Mal-III) or 30% (PPI-G4-OS-Mal-III) of cases on CLL cells (MEC-1 cell line with del(17p)), and confirms that the main trigger in this interaction is the induction of the apoptotic mechanism. The efficacy of each dendrimer was compared using fludarabine (FA). Gene expression profiling (GEP) by microarray identified a group of genes in the BCR signaling pathway characterized by different levels of expression directly associated with the tested agent and type of interaction. Network analysis revealed the potential patterns involved in potential personalized therapy of CLL. The expression of most BCR genes decreased under the influence of dendrimers, which might translate into decreased maturation and proliferation of CLL lymphocytes. Moreover, PPI-G4 OS/DS-Mal-III dendrimers affected gene expression and CLL cells in a different way to FA. Thanks to unique properties, dendrimers may be specifically targeted, thus improving the effectiveness of CLL therapy. PMID- 26987433 TI - Formation scheme and antioxidant activity of a novel Maillard pigment, pyrrolothiazolate, formed from cysteine and glucose. AB - We recently identified 6-hydroxy-3[R],7a[S]-dimethyl-7-oxo-2,3-dihydropyrrolo[2,1 b]thiazole-3-calboxylic acid, a novel pyrrolothiazole derivative carrying a carboxy group and named pyrrolothiazolate, as a Mallard pigment formed from l cysteine and d-glucose. Here we described the formation of its enantiomer, the plausible formation scheme of pyrrolothiazolate, and its antioxidant activity. When d-cysteine was used instead of l-cysteine in the reaction mixture, the enantiomer of pyrrolothiazolate was obtained. The carbon at position 1 of glucose was incorporated into two methyl groups of pyrrolothiazolate. The pigment was considered to be formed through 1-deoxyglucosone (1-DG). The dehydrated isomer of 1-DG would be condensed with the thiol and amino groups of cysteine. This condensate was dehydrated and cyclized to form pyrrolothiazolate. This compound was an antioxidant showing radical scavenging activity. PMID- 26987434 TI - Transfemoral Rescue for a Transapical Malpositioned TAVI Device. PMID- 26987435 TI - The effective combination therapy against human osteosarcoma: doxorubicin plus curcumin co-encapsulated lipid-coated polymeric nanoparticulate drug delivery system. AB - OBJECTIVE: To overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) in osteosarcoma (OS), biodegradable lipid-coated polymeric nanoparticles (LPNs) were explored for the loading of doxorubicin (DOX) and curcumin (CUR). METHODS: DOX plus CUR co-encapsulated LPNs (DOX + CUR LPNs) of mixed lipid monolayer shell and biodegradable polymer core were prepared. The cytotoxicity effect of DOX + CUR LPNs, single drug loaded LPNs, and free drug solutions were evaluated on human OS cell line KHOS cells and mice KHOS cells xenograft in vivo. RESULTS: DOX + CUR LPNs displayed a curative effect on OS cell lines than the free drug counterparts. Also, best anti-OS effects were observed on the animal model compared with other groups tested. CONCLUSION: This promising dual drugs co-encapsulated lipid-coated polymeric nanoparticulate drug delivery system enhanced the cell delivery and activity of drugs against human OS cancer cell lines and in cancer bearing mice. This research may offer new options for the treatment of OS. PMID- 26987436 TI - Quantum electrodynamics and plasmonic resonance of metallic nanostructures. AB - Plasmonic resonance of a metallic nanostructure results from coherent motion of its conduction electrons driven by incident light. At the resonance, the induced dipole in the nanostructure is proportional to the number of the conduction electrons, hence 10(7) times larger than that in an atom. The interaction energy between the induced dipole and fluctuating virtual field of the incident light can reach a few tenths of an eV. Therefore, the classical electromagnetism dominating the field may become inadequate. We propose that quantum electrodynamics (QED) may be used as a fundamental theory to describe the interaction between the virtual field and the oscillating electrons. Based on QED, we derive analytic expressions for the plasmon resonant frequency, which depends on three easily accessible material parameters. The analytic theory reproduces very well the experimental data, and can be used in rational design of materials for plasmonic applications. PMID- 26987438 TI - Reducing the global burden of Preterm Birth through knowledge transfer and exchange: a research agenda for engaging effectively with policymakers. AB - Preterm birth (PTB) is the world's leading cause of death in children under 5 years. In 2013, over one million out of six million child deaths were due to complications of PTB. The rate of decline in child death overall has far outpaced the rate of decline attributable to PTB. Three key reasons for this slow progress in reducing PTB mortality are: (a) the underlying etiology and biological mechanisms remain unknown, presenting a challenge to discovering ways to prevent and treat the condition; (ii) while there are several evidence-based interventions that can reduce the risk of PTB and associated infant mortality, the coverage rates of these interventions in low- and middle-income countries remain very low; and (c) the gap between knowledge and action on PTB--the "know do gap"--has been a major obstacle to progress in scaling up the use of existing evidence-based child health interventions, including those to prevent and treat PTB.In this review, we focus on the know-do gap in PTB as it applies to policymakers. The evidence-based approaches to narrowing this gap have become known as knowledge transfer and exchange (KTE). In our paper, we propose a research agenda for promoting KTE with policymakers, with an ambitious but realistic goal of reducing the global burden of PTB. We hope that our proposed research agenda stimulates further debate and discussion on research priorities to soon bend the curve of PTB mortality. PMID- 26987437 TI - Off-treatment durability of antiviral response to nucleoside analogues in patients with chronic hepatitis B. AB - BACKGROUND: Off-treatment durability of nucleoside analogue (NA) therapy in patients with chronic hepatitis B has not been well investigated. In this study we monitored antiviral effect of NA therapy and evaluated off-treatment durability after NA cessation in patients with chronic hepatitis B. PATIENTS AND METHODS: A total of 94 consecutive patients (39 HBeAg-negative and 55 HBeAg positive patients) who received NA therapy were followed up for approximately 9 years. We discontinued NA according to the following criteria; undetectable serum HBV-DNA by polymerase chain reaction (PCR) on three separate occasions at least 6 months apart in HBeAg-negative patients (APASL stopping recommendation), and seroconversion from HBeAg-positive to HBeAb-positive and undetectable serum HBV DNA by PCR for at least 12 months in HBeAg-positive patients. RESULTS: The cumulative rate of relapse after NA cessation was 48 % and 40 % in HBeAg-negative and -positive patients, respectively. Higher baseline serum alanine aminotransferase level was the only significant predictor for maintaining remission. No patients experienced decompensation after relapse. HBsAg loss occurred at an annual rate of 1.4 % and 0.4 % in HBeAg-negative and -positive patients, respectively. Hepatocellular carcinoma developed at an annual rate of 0.6 % in both HBeAg-negative and -positive patients. CONCLUSIONS: Almost half of the patients did not relapse after cessation of NA therapy in both HBeAg-negative and -positive patients. Therefore, NA therapy could be discontinued with close monitoring if the APASL stopping recommendation is satisfied even in HBeAg negative patients. PMID- 26987439 TI - An examination of internet and land-based gambling among adolescents in three Canadian provinces: results from the youth gambling survey (YGS). AB - BACKGROUND: With the rapid proliferation of new gambling technology and online gambling opportunities, there is a concern that online gambling could have a significant impact on public health, particularly for adolescents. The aim of this study is to examine online and land-based gambling behaviour among adolescents in 3 Canadian provinces (Ontario, Newfoundland and Labrador, Saskatchewan) prior to the implementation of legalized online gambling. METHODS: Data are from 10,035 students in grades 9 to 12 who responded to the 2012-2013 Youth Gambling Survey (YGS) supplement, a questionnaire administered as part of the Canadian Youth Smoking Survey (YSS, 2012) in 3 provinces: Newfoundland and Labrador (n = 2,588), Ontario (n = 3,892), and Saskatchewan (n = 3,555). RESULTS: Overall, 41.6% of adolescents (35.9% of females and 47.4% of males) had gambled in the past 3 months. 9.4% of adolescents had gambled online in the past 3 months alone (3.7% of females and 15.3% of males). The most popular form of online gambling was online sports betting. Adolescents also engaged in online simulated gambling including internet poker (9.1%) and simulated gambling on Facebook (9.0%). Few adolescents participated in online gambling exclusively and online gamblers were more likely than land-based gamblers to engage in multiple forms of gambling. A higher proportion of adolescent online gamblers scored "high" or "low to moderate" in problem gambling severity compared to land-based only gamblers. CONCLUSIONS: Despite restrictions on online gambling at the time of the study, adolescents were engaging in online gambling at a significantly higher rate than has been previously found. Adolescents were also using technology such as video games to gamble and free online gambling simulations. PMID- 26987440 TI - Peptide based hydrogels for cancer drug release: modulation of stiffness, drug release and proteolytic stability of hydrogels by incorporating d-amino acid residue(s). AB - Synthetic tripeptide based noncytotoxic hydrogelators have been discovered for releasing an anticancer drug at physiological pH and temparature. Interestingly, gel stiffness, drug release capacity and proteolytic stability of these hydrogels have been successfully modulated by incorporating d-amino acid residues, indicating their potential use for drug delivery in the future. PMID- 26987442 TI - Correlation between siblings in caries in Norway. A quantitative study. AB - BACKGROUND: The role of the family for caries between siblings has been a focus for researchers for almost 100 years. However, the contribution of the family to the variation in caries has not been determined. OBJECTIVES: To estimate the correlation between siblings in caries, and to investigate whether this varied according to number of siblings, mother's level of education, marital status and country of birth. METHODS: The population included families with two or more siblings, altogether 409 766 children and adolescents aged 6-18 years, and 181 551 mothers. Data on caries were from electronic dental journals, which were merged with data from Statistics Norway about the characteristics of the mothers. The analyses were performed using random-effects regression, in which separate regressions were run for the extent of the carious lesion. Caries was scored for permanent teeth only. Mothers were used to identify siblings within families. The correlation between siblings in caries was measured using the intraclass correlation coefficient. RESULTS: The proportion of the variance in the outcome measures that was due to between-family variability was in the range 13-29%. The intraclass correlation coefficients from the analyses of the subpopulations that described the characteristics of the mothers were fairly similar to the ICCs as estimated on the whole population. CONCLUSION: We identified a fairly strong family effect, which confirms that the family is an important arena in which the dental health of the children is formed. An improvement in dental health for one of the siblings was associated with a positive effect on the dental health of the other sibling, and vice versa. PMID- 26987441 TI - The HigB/HigA toxin/antitoxin system of Pseudomonas aeruginosa influences the virulence factors pyochelin, pyocyanin, and biofilm formation. AB - Toxin/antitoxin (TA) systems are prevalent in most bacterial and archaeal genomes, and one of the emerging physiological roles of TA systems is to help regulate pathogenicity. Although TA systems have been studied in several model organisms, few studies have investigated the role of TA systems in pseudomonads. Here, we demonstrate that the previously uncharacterized proteins HigB (unannotated) and HigA (PA4674) of Pseudomonas aeruginosa PA14 form a type II TA system in which antitoxin HigA masks the RNase activity of toxin HigB through direct binding. Furthermore, toxin HigB reduces production of the virulence factors pyochelin, pyocyanin, swarming, and biofilm formation; hence, this system affects the pathogencity of this strain in a manner that has not been demonstrated previously for TA systems. PMID- 26987443 TI - Furanodiene alters mitochondrial function in doxorubicin-resistant MCF-7 human breast cancer cells in an AMPK-dependent manner. AB - Furanodiene is a bioactive sesquiterpene isolated from the spice-producing Curcuma wenyujin plant (Y. H. Chen and C. Ling) (C. wenyujin), which is a commonly prescribed herb used in clinical cancer therapy by modern practitioners of traditional Chinese medicine. Previously, we have shown that furanodiene inhibits breast cancer cell growth both in vitro and in vivo, however, the mechanism for this effect is not yet known. In this study, therefore, we asked (1) whether cultured breast cancer cells made resistant to the chemotherapeutic agent doxorubicin (DOX) via serial selection protocols are susceptible to furanodiene's anticancer effect, and (2) whether AMP-activated protein kinase (AMPK), which is a regulator of cellular energy homeostasis in eukaryotic cells, participates in this effect. We show here (1) that doxorubicin-resistant MCF-7 (MCF-7/DOX(R)) cells treated with furanodiene exhibit altered mitochondrial function and reduced levels of ATP, resulting in apoptotic cell death, and (2) that AMPK is central to this effect. In these cells, furanodiene (as opposed to doxorubicin) noticeably affects the phosphorylation of AMPK and AMPK pathway intermediates, ACLY and GSK-3beta, suggesting that furanodiene reduces mitochondrial function and cellular ATP levels by way of AMPK activation. Finally, we find that the cell permeable agent and AMPK inhibitor compound C (CC), abolishes furanodiene-induced anticancer activity in these MCF-7/DOX(R) cells, with regard to cell growth inhibition and AMPK activation; in contrast, AICAR (5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside, acadesine), an AMPK activator, augments furanodiene-induced anticancer activity. Furthermore, specific knockdown of AMPK in MCF-7/DOX(R) cells protects these cells from furanodiene-induced cell death. Taken together, these findings suggest that AMPK and its pathway intermediates are promising therapeutic targets for treating chemoresistant breast cancer, and that furanodiene may be an important chemical agent incorporated in next-generation chemotherapy protocols. PMID- 26987444 TI - Unraveling the role of mechanical stimulation on smooth muscle cells: A comparative study between 2D and 3D models. AB - A thorough understanding of cell response to combined culture configuration and mechanical cues is of paramount importance in vascular tissue engineering applications. Herein, we investigated and compared the response of vascular smooth muscle cells (vSMCs) cultured in different culture environments (2D cell monolayers and 3D cellularized collagen-based gels) in combination with mechanical stimulation (7% uniaxial cyclic strain, 1 Hz) for 2 and 5 days. When cyclic strain was applied, two different responses, in terms of cell orientation and expression of contractile-phenotype proteins, were observed in 2D and 3D models. Specifically, in 2D configuration, cyclic strain caused ~50% of cell population to align nearly perpendicular (80-90 degrees) to the strain direction, while not influencing the contractile-phenotype protein expression, as compared to the 2D static controls. Conversely, the application of uniaxial strain to 3D constructs induced a ~60% cell alignment almost parallel (0-10 degrees) to the strain direction. Moreover, 3D mechanical stimulation applied for 5 days induced a twofold increase of SM alpha-actin level and a 14-fold increase of calponin expression as compared to 3D static controls. Altogether these findings provide a new insight into the potential to drive cell behavior by modulating the extracellular matrix and the biomechanical environment. Biotechnol. Bioeng. 2016;113: 2254-2263. (c) 2016 Wiley Periodicals, Inc. PMID- 26987445 TI - Microspheres Assembled from Chitosan-Graft-Poly(lactic acid) Micelle-Like Core Shell Nanospheres for Distinctly Controlled Release of Hydrophobic and Hydrophilic Biomolecules. AB - To simultaneously control inflammation and facilitate dentin regeneration, a copolymeric micelle-in-microsphere platform is developed in this study, aiming to simultaneously release a hydrophobic drug to suppress inflammation and a hydrophilic biomolecule to enhance odontogenic differentiation of dental pulp stem cells in a distinctly controlled fashion. A series of chitosan-graft poly(lactic acid) copolymers is synthesized with varying lactic acid and chitosan weight ratios, self-assembled into nanoscale micelle-like core-shell structures in an aqueous system, and subsequently crosslinked into microspheres through electrostatic interaction with sodium tripolyphosphate. A hydrophobic biomolecule either coumarin-6 or fluocinolone acetonide (FA) is encapsulated into the hydrophobic cores of the micelles, while a hydrophilic biomolecule either bovine serum albumin or bone morphogenetic protein 2 (BMP-2) is entrapped in the hydrophilic shells and the interspaces among the micelles. Both hydrophobic and hydrophilic biomolecules are delivered with distinct and tunable release patterns. Delivery of FA and BMP-2 simultaneously suppresses inflammation and enhances odontogenesis, resulting in significantly enhanced mineralized tissue regeneration. This result also demonstrates the potential for this novel delivery system to deliver multiple therapeutics and to achieve synergistic effects. PMID- 26987446 TI - Improving Medicare's Hospital Compare Mortality Model. AB - OBJECTIVE: To improve the predictions provided by Medicare's Hospital Compare (HC) to facilitate better informed decisions regarding hospital choice by the public. DATA SOURCES/SETTING: Medicare claims on all patients admitted for Acute Myocardial Infarction between 2009 through 2011. STUDY DESIGN: Cohort analysis using a Bayesian approach, comparing the present assumptions of HC (using a constant mean and constant variance for all hospital random effects), versus an expanded model that allows for the inclusion of hospital characteristics to permit the data to determine whether they vary with attributes of hospitals, such as volume, capabilities, and staffing. Hospital predictions are then created using directly standardized estimates to facilitate comparisons between hospitals. DATA COLLECTION/EXTRACTION METHODS: Medicare fee-for-service claims. PRINCIPAL FINDINGS: Our model that included hospital characteristics produces very different predictions from the current HC model, with higher predicted mortality rates at hospitals with lower volume and worse characteristics. Using Chicago as an example, the expanded model would advise patients against seeking treatment at the smallest hospitals with worse technology and staffing. CONCLUSION: To aid patients when selecting between hospitals, the Centers for Medicare and Medicaid Services (CMS) should improve the HC model by permitting its predictions to vary systematically with hospital attributes such as volume, capabilities, and staffing. PMID- 26987448 TI - Focus on Epigenetics. PMID- 26987447 TI - An evolutionary insight into the hatching strategies of pipefish and seahorse embryos. AB - Syngnathiform fishes carry their eggs in a brood structure found in males. The brood structure differs from species to species: seahorses carry eggs within enclosed brood pouch, messmate pipefish carry eggs in the semi-brood pouch, and alligator pipefish carry eggs in the egg compartment on abdomen. These egg protection strategies were established during syngnathiform evolution. In the present study, we compared the hatching mode of protected embryos of three species. Electron microscopic observations revealed that alligator pipefish and messmate pipefish egg envelopes were thicker than those of seahorses, suggesting that the seahorse produces a weaker envelope. Furthermore, molecular genetic analysis revealed that these two pipefishes possessed the egg envelope-digesting enzymes, high choriolytic enzyme (HCE), and low choriolytic enzyme (LCE), as do many euteleosts. In seahorses, however, only HCE gene expression was detected. When searching the entire seahorse genome by high-throughput DNA sequencing, we did not find a functional LCE gene and only a trace of the LCE gene exon was found, confirming that the seahorse LCE gene was pseudogenized during evolution. Finally, we estimated the size and number of hatching gland cells expressing hatching enzyme genes by whole-mount in situ hybridization. The seahorse cells were the smallest of the three species, while they had the greatest number. These results suggest that the isolation of eggs from the external environment by paternal bearing might bring the egg envelope thin, and then, the hatching enzyme genes became pseudogenized. J. Exp. Zool. (Mol. Dev. Evol.) 9999B:XX-XX, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26987451 TI - Probing sol-gel matrices microenvironments by PGSE HR-MAS NMR. AB - We applied Pulsed Gradient Spin Echo diffusion with high-resolution magic angle spinning NMR to study sol-gel matrices used to encapsulate enzymes for biocatalysis (TMOS/MTMS and TMOS/BTMS) to gain insight into the local chemical microenvironment. Transport properties of solvents with different polarities (1 pentanol, acetonitrile and n-hexane) were studied through their apparent self diffusion coefficients. The spin echo attenuation of the solvents shows two distinct diffusion domains, one with fast diffusion (Dfast ) associated with interparticle diffusion and another with slow diffusion (Dslow ) corresponding to the displacement inside the pores within the sol-gel particles. The analysis of the root mean square displacements at different diffusion times showed that the Dfast domain has a free diffusion regime in both matrices (the root mean square displacement is linearly dependent of the diffusion time), while the Dslow domain shows a different regime that depends on the matrix. We investigated the exchange regime between the two diffusion sites. In both matrices, n-hexane was in intermediate exchange between diffusion domains, while the polar solvents were in slow exchange in TMOS/BTMS and in intermediate exchange in TMOS/MTMS. Data were fitted for TMOS/BTMS with the Karger model, and the physical parameters were obtained. The results add to the evidence that the pores are a hydrophobic environment but that the presence of some free hydrophilic groups inside the pore, as observed in the TMOS/BTMS, has a key role in slowing down the exchange of polar solvents and that this is relevant to explain previously reported enzyme activity in these materials. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26987452 TI - Ag-catalysed cutting of multi-walled carbon nanotubes. AB - In this work, the cutting of carbon nanotubes is investigated using silver nanoparticles deposited on arc discharge multi-walled carbon nanotubes. The composite is subsequently heated in air to fabricate shortened multi-walled nanotubes. Complementary transmission electron microscopy and spectroscopy techniques shed light on the cutting mechanism. The nanotube cutting is catalysed by the fundamental mechanism based on the coordination of the silver atoms to the pi-bonds of carbon nanotubes. As a result of the metal coordination, the strength of the carbon-carbon bond is reduced, promoting the oxidation of carbon at lower temperature when heated in air, or lowering the activation energy required for the removal of carbon atoms by electron beam irradiation, assuring in both cases the cutting of the nanotubes. PMID- 26987453 TI - Analysis of Hemogram of Radiation Workers in Tangshan, China. AB - OBJECTIVES: This study aimed to investigate changes in peripheral blood cells of radiation workers and explore the impact of long-term ionizing radiation (IR) on human peripheral hemogram. METHODS: With a cohort method, we selected 1,392 radiation workers (case group) and 1,430 non-health-ray-exposure history persons (control group) to detect and analyze their peripheral hemogram. FAITH3000 automatic biochemical analyzer was used for blood testing. Examination of peripheral hemogram includes the examination of white blood cells (WBCs), platelet (PLTs), red blood cells (RBCs), hemoglobin (Hb), lymphocytes (LYMs), and mononuclear cells (MOs). The data analysis was conducted with software SPSS19.0. RESULTS: All the peripheral hemogram indicators (WBCs, RBCs, Hb, PLTs, LYMs, and MOs) in the case group, in accordance with the order of radiology diagnostic medical group, industrial inspection group, petroleum logging group, and radiotherapy medical group, showed a significant decreasing trend and were lower than those in the control group (all P < 0.05). Besides, with the increase of radiation seniority and accumulative radiation dose, all the peripheral hemogram indicators (WBCs, RBCs, Hb, PLTs, LYMs, and MOs) in the case group dramatically decreased and were lower than those in the control group (all P < 0.05). Seniority was in negative association with the expressions of WBCs, PLTs, RBCs, Hb, LYMs, and MOs and radiation dose with Hb, LYMs, and MOs (all P < 0.05). CONCLUSION: Long-term IR has some effects on the health of radiation workers, thus protective measures should be further strengthened. PMID- 26987454 TI - Should we measure ambivalence to change? PMID- 26987455 TI - Defining disaster resilience: comparisons from key stakeholders involved in emergency management in Victoria, Australia. AB - Three years after the introduction of the National Strategy for Disaster Resilience there remains no unanimously adopted definition of disaster resilience within Australia's emergency management sector. The aim of this study is to determine what the concept means to key stakeholders in the emergency management sector in the Australian State of Victoria, and how these conceptualisations overlap and diverge. Via an online survey, 113 people were asked how they define disaster resilience in their work in the emergency management sector. A data mining software tool, Leximancer, was employed to uncover the relationships between the definitions provided. The findings show that stakeholders see resilience as an 'ability' that encompasses emergency management activities and personal responsibility. However, the findings also highlight some possible points of conflict between stakeholders. In addition, the paper outlines and discusses a number of potential consequences for the implementation and the success of the resilience-based approach in Australia. PMID- 26987456 TI - Variation Interpretation Predictors: Principles, Types, Performance, and Choice. AB - Next-generation sequencing methods have revolutionized the speed of generating variation information. Sequence data have a plethora of applications and will increasingly be used for disease diagnosis. Interpretation of the identified variants is usually not possible with experimental methods. This has caused a bottleneck that many computational methods aim at addressing. Fast and efficient methods for explaining the significance and mechanisms of detected variants are required for efficient precision/personalized medicine. Computational prediction methods have been developed in three areas to address the issue. There are generic tolerance (pathogenicity) predictors for filtering harmful variants. Gene/protein/disease-specific tools are available for some applications. Mechanism and effect-specific computer programs aim at explaining the consequences of variations. Here, we discuss the different types of predictors and their applications. We review available variation databases and prediction methods useful for variation interpretation. We discuss how the performance of methods is assessed and summarize existing assessment studies. A brief introduction is provided to the principles of the methods developed for variation interpretation as well as guidelines for how to choose the optimal tools and where the field is heading in the future. PMID- 26987458 TI - Effects of dietary oil blend on fatty acid composition, oxidative stability and physicochemical properties of Longissimus thoracis et lumborum muscle in goats. AB - This study examined the effects of dietary blend of 80% canola oil and 20% palm oil (BCPO) on the physicochemical properties, antioxidant status, oxidative stability and fatty acid composition of Longissimus thoracis et lumborum (LTL) muscle from goats during chill storage. Over a 14-week feeding trial, 24 Boer bucks were randomly assigned to and supplemented with diets containing 0, 4 or 8% BCPO on a dry matter basis, slaughtered and the LTL was subjected to a 7 day chill storage. Neither diet nor post mortem ageing influenced (P > 0.05) antioxidant enzyme activities, chemical composition and cholesterol. Diet had no effect on the carbonyl content, free thiol content, water-holding capacity, tenderness, pH and glycogen. Oil-supplemented goats had higher (P < 0.05) C18:1 trans-11, C18:3n-3 and C20:5n-3, carotenoid, tocopherol and redness, and lower thiobarbituric acid reactive substances values than the control goats. Post mortem ageing decreased (P < 0.05) shear force and oxidative stability of chevon. No significant (P > 0.05) changes were found in the proportion of individual fatty acids throughout storage. Total polyunsaturated fatty acids (PUFA) decreased while total saturated fatty acids increased as storage progressed. Dietary BCPO enhanced n-3 PUFA without compromising the quality attributes of chevon. PMID- 26987457 TI - Rice PROTEIN l-ISOASPARTYL METHYLTRANSFERASE isoforms differentially accumulate during seed maturation to restrict deleterious isoAsp and reactive oxygen species accumulation and are implicated in seed vigor and longevity. AB - PROTEIN l-ISOASPARTYL O-METHYLTRANSFERASE (PIMT) is a protein-repairing enzyme involved in seed vigor and longevity. However, the regulation of PIMT isoforms during seed development and the mechanism of PIMT-mediated improvement of seed vigor and longevity are largely unknown. In this study in rice (Oryza sativa), we demonstrate the dynamics and correlation of isoaspartyl (isoAsp)-repairing demands and PIMT activity, and their implications, during seed development, germination and aging, through biochemical, molecular and genetic studies. Molecular and biochemical analyses revealed that rice possesses various biochemically active and inactive PIMT isoforms. Transcript and western blot analyses clearly showed the seed development stage and tissue-specific accumulation of active isoforms. Immunolocalization studies revealed distinct isoform expression in embryo and aleurone layers. Further analyses of transgenic lines for each OsPIMT isoform revealed a clear role in the restriction of deleterious isoAsp and age-induced reactive oxygen species (ROS) accumulation to improve seed vigor and longevity. Collectively, our data suggest that a PIMT mediated, protein repair mechanism is initiated during seed development in rice, with each isoform playing a distinct, yet coordinated, role. Our results also raise the intriguing possibility that PIMT repairs antioxidative enzymes and proteins which restrict ROS accumulation, lipid peroxidation, etc. in seed, particularly during aging, thus contributing to seed vigor and longevity. PMID- 26987459 TI - Support and preferences for intermediate health care services for back and neck pain: a survey among members of the Dutch patient association for spinal pain. AB - RATIONALE, AIMS AND OBJECTIVES: Recent health care reforms in the Netherlands have led to the introduction of intermediate health care. Intermediate health care combines features of primary care and secondary (hospital) care. It is characterized by a task shift from hospital care to primary care. The initial experiences of medical specialists and general practitioners with intermediate health care are positive. However, the patients' perspectives regarding this reform are unknown. This study aimed to evaluate the level of support from patients with back and/or neck pain for intermediate health care services and to provide insight into their preferences how this care should be organized. METHODS: A cross-sectional survey was conducted in which members of the patient association for spinal pain in the Netherlands completed electronic questionnaires to measure the level of support and preferred organization of intermediate health care services. RESULTS: Questionnaires were returned by 367 patients (response rate: 51%). Respondents supported the concept of intermediate health care (numeric rating scale: 7/10). Aspects considered important for intermediate health care included knowledge and expertise of staff, multidisciplinary cooperation, patient contact time, reimbursement via health insurance, quality control of care, evidence-based treatments and electronic medical records. Although intermediate care is a health care reform, patients continued to think according to traditional primary and secondary care constitutions. CONCLUSIONS: Patients with neck and/or back pain support the introduction of intermediate health care services and have explicit preferences regarding its organization, but may need to be better informed when intermediate care is introduced. PMID- 26987460 TI - Gamma-aminobutyric acid (GABA) permeates ovine ruminal and jejunal epithelia, mainly by passive diffusion. AB - Gamma-aminobutyric acid (GABA) represents the most abundant inhibitory neurotransmitter in the mammalian brain. GABA is also produced in plants and/or by the microbial conversion of amino acids. Thus, ruminants may be forced to take up significant amounts of GABA from their diet. However, it is not known whether exogenously acquired GABA might permeate the gastrointestinal barrier in such quantities as to induce systemic alterations. Thus, this study pursues the question of where within the ruminant's GI tract and by which pathways GABA may be taken up from the ingesta. The jejunal and ruminal epithelia of sheep were mounted in Ussing chambers under short-circuit conditions. The flux rates of radiolabelled GABA from the mucosal to the serosal side (Jms ) and vice versa (Jsm ) were measured. GABA was applied in various concentrations with adjustment of the mucosal pH to 6.1 or 7.4. Furthermore, beta-alanine or glycine was used as a competitive inhibitor for GABA transport. In both the jejunal and ruminal epithelium, the Jms of GABA was linearly correlated to the mucosal GABA concentration. However, Jms across the jejunal epithelium was approximately 10 fold higher than Jms across the ruminal epithelium. When 0.5 mmol/l GABA was applied on both sides of the epithelium, no net flux could be observed in the jejunal epithelia. Additionally, there was no effect of decreased mucosal pH or the application of glycine or beta-alanine under these conditions. The Jms and Jsm of GABA were linearly correlated to the transepithelial conductance. Our results suggest that GABA is taken up from the small intestine rather than from the rumen. Due to the lack of influence of pH and competitive inhibitors, this uptake seems to occur primarily via passive diffusion. PMID- 26987461 TI - Pneumococcal Conjugate Vaccine--Equally Effective for Everyone? PMID- 26987463 TI - Two Very Different Patient Populations. PMID- 26987464 TI - Unrealistic View. PMID- 26987462 TI - The Clinical Effectiveness of Pneumococcal Conjugate Vaccines: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND: Streptococcus pneumoniae is responsible for approximately 1.6 million yearly deaths worldwide. An up-to-date evidence base on the effects of pneumococcal conjugate vaccines (PCVs) on infectious diseases and mortality in any population or setting regardless of age or health status is currently lacking. METHODS: We systematically searched MEDLINE and EMBASE for pertinent randomized controlled trials (RCTs). Two reviewers independently screened 9498 titles/abstracts and 430 full-text papers for eligible trials. The outcomes of our meta-analysis were pooled using relative risks (RRs) with a random effects model or Peto's odds ratios (ORs) if event rates were :lt;1%. RESULTS: 21 RCTs comprising 361 612 individuals were included. PCVs reduced the risk for invasive pneumococcal disease (odds ratio [OR]: 0.43, 95% confidence interval [CI]: [0.36; 0.51]), all-cause acute otitis media (AOM) (RR: 0.93, 95% CI: [0.86; 1.00]), pneumococcal AOM (RR: 0.57, 95% CI: [0.39; 0.83]), allcause pneumonia (RR: 0.93, 95% CI: [0.89; 0.97]), and pneumococcal pneumonia (RR: 0.78, 95% CI: [0.62; 0.97]). We found no significant effect of PCVs on all-cause mortality (RR: 0.95, 95% CI: [0.88; 1.03]) or recurrent AOM (RR: 0.87, 95% CI: [0.72; 1.05]). CONCLUSION: PCVs are associated with large risk reductions for pneumococcal infectious diseases, smaller risk reductions for infectious diseases from any cause, and no significant effect on all-cause mortality. PMID- 26987465 TI - In Reply. PMID- 26987466 TI - Simple Solution. PMID- 26987467 TI - In Reply. PMID- 26987469 TI - Effects of guided breath exercise on complex behaviour of heart rate dynamics. AB - INTRODUCTION: Cardiac autonomic regulation is influenced by changes in respiratory rate, which has been demonstrated by linear analysis of heart rate variability (HRV). Conversely, the complex behaviour is not well defined for HRV during this physiological state. In this sense, Higuchi Fractal Dimension is applied directly to the time series. It analyses the fractal dimension of discrete time sequences and is simpler and faster than correlation dimension and many other classical measures derived from chaos theory. We investigated chaotic behaviour of heart rate dynamics during guided breath exercises. METHOD: We investigated 21 healthy male volunteers aged between 18 and 30 years. HRV was analysed 10 min before and 10 min during guided breath exercises. HRV was analysed in the time and frequency domain for linear analysis and through HFD for non-linear analysis. RESULTS: Linear analysis indicated that SDNN, pNN50, RMSSD, LF, HF and LF/HF increased during guided breath exercises. HFD analysis illustrated that between Kmax 20 to Kmax 120 intervals, was enhanced during guided breath exercises. CONCLUSION: Guided breath exercises acutely increased chaotic behaviour of HRV measured by HFD. PMID- 26987468 TI - Evidence-Based Hernia Treatment in Adults. AB - BACKGROUND: Inguinal hernia repair is the most common general surgical procedure in industrialized countries, with a frequency of about 200 operations per 100 000 persons per year. Suture- and mesh-based techniques can be used, and the procedure can be either open or minimally invasive. METHODS: This review is based on a selective search of the literature, with interpretation of the published findings according to the principles of evidence-based medicine. RESULTS: Inguinal hernia is diagnosed by physical examination. Surgery is not necessarily indicated for a primary, asymptomatic inguinal hernia in a male patient, but all inguinal hernias in women should be operated on. For hernias in women, and for all bilateral hernias, a laparoscopic or endoscopic procedure is preferable to an open procedure. Primary unilateral hernias in men can be treated either by open surgery or by laparoscopy/endoscopy. Patients treated by laparoscopy/endoscopy develop chronic pain less often than those treated by open surgery. A mesh-based repair is generally recommended; this seems reasonable in view of the pathogenesis of the condition, which involves an abnormality of the extracellular matrix. CONCLUSION: The choice of procedure has been addressed by international guidelines based on high-level evidence. Surgeons should deviate from their recommendations only in exceptional cases and for special reasons. Guideline conformity implies that hernia surgeons must master both open and endoscopic/laparoscopic techniques. PMID- 26987470 TI - Non-nociceptive pain in rheumatoid arthritis is frequent and affects disease activity estimation: cross-sectional data from the FRAME study. AB - BACKGROUND: The painDETECT questionnaire (PDQ) is a mechanism-based pain classification tool assigning patients to one of three categories depending on the quality of the experienced pain. Patients with non-nociceptive pain score high on the PDQ. The objective was to assess the proportions of the three PDQ classification groups in patients with rheumatoid arthritis (RA) and to explore differences in clinical characteristics. METHOD: RA patients initiating or escalating their RA therapy were included prospectively and underwent a thorough examination programme. Low (PDQ score < 13), medium (PDQ score 13-18), and high (PDQ score > 18) scores indicate nociceptive, unclear/possible neuropathic, or neuropathic pain mechanisms, respectively. RESULTS: The 102 included patients were classified into the following PDQ classification groups: low = 65%, medium = 23%, and high = 12%. Patients in the medium and high PDQ groups scored worse on indicators of anxiety, depression, disability, mental health-related quality of life, pain, and fatigue. They also had more tender points and an RA disease activity score based on 28 joints (DAS28) where a higher fraction of the composite score pertained to non-inflammatory factors compared to patients in the low PDQ classification group. There were no differences in objective inflammatory indices across groups. Multiple regression analysis demonstrated that the tender joint count (TJC) and the 36-item Short Form Health Survey (SF36) mental component summary (MCS) score were independently associated with the PDQ score. CONCLUSIONS: In patients initiating or intensifying medical treatment for their RA, non-nociceptive pain (PDQ score >= 13) is common. In these patients, the pain mechanisms result in increased disease activity scores on a non-inflammatory basis. PMID- 26987471 TI - Gender bias in individual radiosensitivity and the association with genetic polymorphic variations. AB - PURPOSE: To assess the extent of variation in radiosensitivity between individuals, gender-related dissimilarity and impact on the association with single nucleotide polymorphisms (SNPs). MATERIALS AND METHODS: Survival curves of 152 fibroblast cell strains derived from both gender were generated. Individual radiosensitivity was characterized by the surviving fraction at 2Gy (SF2). SNPs in 10 radiation responsive genes were genotyped by direct sequencing. RESULTS: The wide variation in SF2 (0.12-0.50; mean=0.33) was significantly associated with 3 SNPs: TP53 G72C (P=0.007), XRCC1 G399A (P=0.002) and ATM G1853A (P=0.01). Females and males differed significantly in radiosensitivity (P=0.004) that impacted genetic association where only XRCC1 remained significant in both gender (P<0.05). Meanwhile, discordant association was observed for TP53 that was significant in females (P=0.012) and ATM that was significant in males (P=0.0006). When gender-specific SF2-mean (0.31 and 0.35 for females and males; respectively) was considered, further discordance was observed where XRCC1 turned out not to be associated with radiosensitivity in males (P>0.05). CONCLUSIONS: Although the variation in individual radiosensitivity was associated with certain SNPs, gender bias for both endpoints was evident. Therefore, assessing the risk of radiation exposure in females and males should be considered separately in order to achieve the ultimate goal of personalized radiation medicine. PMID- 26987472 TI - Effect of contrast enhancement in delineating GTV and constructing IGTV of thoracic oesophageal cancer based on 4D-CT scans. AB - OBJECTIVE: To investigate the effect of contrast enhancement on delineating the gross tumour volumes (GTVs) of different respiratory phases and constructing the corresponding internal GTVs (IGTVs) of primary thoracic oesophageal cancer based on four-dimensional computed tomography (4D-CT) scans. METHODS: Forty-five patients with upper (14 cases), middle (16 cases), or lower (15 cases) thoracic oesophageal cancer sequentially underwent conventional plain and contrast enhanced 4D-CT scans during free breathing. First, the GTVs were delineated on plain 4D-CT, and the corresponding IGTVs were constructed by a physician. Then the GTVs were delineated on contrast-enhanced 4D-CT images, and the corresponding IGTVs were constructed by the same physician using the same standards. RESULTS: The coefficient of variation for the target volume delineated on contrast enhanced 4D-CT images was constantly smaller than that for plain 4D-CT images. The length of the GTVs along the z axis, as well as the volumes of the GTVs that were delineated and the IGTVs that were constructed, did not change between contrast-enhanced and plain 4D-CT images in patients with upper or lower thoracic oesophageal cancer (P>0.05), but showed significant differences in patients with middle thoracic oesophageal cancer (P<0.05). CONCLUSIONS: Contrast-enhanced 4D-CT scans can reduce the error of target volume delineation and be used to construct a more accurate internal target volume in patients with middle thoracic oesophageal cancer, however, whether GTV delineation or IGTV construction for patients with upper or lower thoracic oesophageal cancer, no significant benefit was found from contrast-enhanced 4D-CT scan. PMID- 26987473 TI - A tumour control probability model for radiotherapy of prostate cancer using magnetic resonance imaging-based apparent diffusion coefficient maps. AB - BACKGROUND AND PURPOSE: Standard tumour control probability (TCP) models assume uniform tumour cell density across the tumour. The aim of this study was to develop an individualised TCP model by including index-tumour regions extracted form multi-parametric magnetic resonance imaging (MRI) and apparent diffusion coefficient (ADC) maps-based cell density distributions. MATERIALS AND METHODS: ADC maps in a series of 20 prostate cancer patients were applied to estimate the initial number of cells within each voxel, using three different approaches for the relation between ADC values and cell density: a linear, a binary and a sigmoid relation. All TCP models were based on linear-quadratic cell survival curves assuming alpha/beta=1.93Gy (consistent with a recent meta-analysis) and alpha set to obtain a 70% of TCP when 77Gy was delivered to the entire prostate in 35 fractions (alpha=0.18Gy(-1)). RESULTS: Overall, TCP curves based on ADC maps showed larger differences between individuals than those assuming uniform cell densities. The range of the dose required to reach 50% TCP across the patient cohort was 20.1Gy, 18.7Gy and 13.2Gy using an MRI-based voxel density (linear, binary and sigmoid approach, respectively), compared to 4.1Gy using a constant density. CONCLUSIONS: Inclusion of tumour-index information together with ADC maps-based cell density increases inter-patient tumour response differentiation for use in prostate cancer RT, resulting in TCP curves with a larger range in D50% across the cohort compared with those based on uniform cell densities. PMID- 26987474 TI - Cannabis use among Navy personnel in Sri Lanka: a cross sectional study. AB - BACKGROUND: Prevalence of cannabis use among military populations vary. There is evidence that drug use is associated with combat exposure and PTSD. The objective of the study was to assess the prevalence of cannabis use among Sri Lanka Navy (SLN) personnel and to identify any relationship with cannabis use and combat exposure. METHODS: This cross sectional study was carried out among representative samples of SLN Special Forces (Special Boat Squadron) and regular forces deployed in combat areas. Both Special Forces and regular forces were selected using simple random sampling. Personnel who had served continuously in combat areas during the 1 year period prior to end of combat operations were included in the study. Cannabis use was defined as smoking cannabis at least once during the past 12 months. RESULTS: The sample consisted of 259 Special Forces and 412 regular navy personnel. Prevalence of cannabis use was 5.22% (95% CI 3.53 6.9). There was no significant difference in prevalence of cannabis use among Special Forces personnel compared to regular forces. Cannabis use was significantly higher in the age group 18-24 years [OR 4.42 (95% CI 2.18-8.97)], personnel who were never married [OR 2.02 (95% CI 0.99-4.12)], or had an educational level less than GCE O'Level [OR 4.02 (95% CI 1.17-13.78)]. There was significant association between cannabis use and hazardous alcohol use [adjusted OR 5.47 (95% CI 2.65-11.28)], PTSD [adjusted OR 4.20 (95% CI 1.08-16.38)], GHQ caseness [adjusted OR 2.83 (95% CI 1.18-6.79)] and multiple somatic complaints [adjusted OR 3.61 (95% CI 1.5-8.7)]. Cannabis use was not associated with smoking. Risk of cannabis use was less in those who had seen dead or wounded [adjusted OR 0.42 (95% CI 0.20-0.85)]. Experiencing hostility from civilians was the only combat exposure that significantly increased the risk of cannabis use [adjusted OR 4.06 (95% CI 1.06-15.56)]. CONCLUSIONS: Among Sri Lanka Navy personnel exposed to combat cannabis use was significantly associated with hazardous alcohol use but not smoking. PTSD and other adverse mental health outcomes were associated with an increased risk of cannabis use. Exposure to combat was not associated with increased risk of cannabis use. PMID- 26987475 TI - Contrast-enhanced optical coherence tomography with picomolar sensitivity for functional in vivo imaging. AB - Optical Coherence Tomography (OCT) enables real-time imaging of living tissues at cell-scale resolution over millimeters in three dimensions. Despite these advantages, functional biological studies with OCT have been limited by a lack of exogenous contrast agents that can be distinguished from tissue. Here we report an approach to functional OCT imaging that implements custom algorithms to spectrally identify unique contrast agents: large gold nanorods (LGNRs). LGNRs exhibit 110-fold greater spectral signal per particle than conventional GNRs, which enables detection of individual LGNRs in water and concentrations as low as 250 pM in the circulation of living mice. This translates to ~40 particles per imaging voxel in vivo. Unlike previous implementations of OCT spectral detection, the methods described herein adaptively compensate for depth and processing artifacts on a per sample basis. Collectively, these methods enable high-quality noninvasive contrast-enhanced imaging of OCT in living subjects, including detection of tumor microvasculature at twice the depth achievable with conventional OCT. Additionally, multiplexed detection of spectrally-distinct LGNRs was demonstrated to observe discrete patterns of lymphatic drainage and identify individual lymphangions and lymphatic valve functional states. These capabilities provide a powerful platform for molecular imaging and characterization of tissue noninvasively at cellular resolution, called MOZART. PMID- 26987476 TI - Communicable diseases as health risks at mass gatherings other than Hajj: what is the evidence? AB - Mass gatherings are characterized by the concentration of people temporally and spatially, and may lead to the emergence of infectious diseases due to enhanced transmission between attendees. This is well-demonstrated in the context of the Hajj and Umrah pilgrimages in Saudi Arabia. The goal of this review was to present the available evidence on outbreaks associated with a variety of pathogens, or also the lack thereof, as assessed by thorough surveillance at any mass gatherings with the exception of those in Saudi Arabia. A systematic search for relevant articles in the literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Sixty-eight studies were identified. Although outbreaks have not been reported frequently in or after mass gatherings outside the Hajj and Umrah pilgrimages, they have sometimes occurred at Muslim, Christian, and Hindu religious events, at sports events, and at large-scale open air festivals. In this review it was found that the most common outbreaks at these mass gatherings involved vaccine preventable diseases, mainly measles and influenza, but also mumps and hepatitis A. Meningococcal disease has rarely been recorded. Additionally it was found that the transmission of various communicable diseases that may not be prevented by vaccination has been recorded in association with mass gatherings. These were mainly gastrointestinal infections, caused by a variety of pathogens. It was also noted that some outbreaks occurring at mass gatherings have resulted in the international spread of communicable diseases. PMID- 26987477 TI - Is nodding syndrome an Onchocerca volvulus-induced neuroinflammatory disorder? Uganda's story of research in understanding the disease. AB - Nodding syndrome is a devastating neurological disorder, mostly affecting children in eastern Africa. An estimated 10000 children are affected. Uganda, one of the most affected countries, set out to systematically investigate the disease and develop interventions for it. On December 21, 2015, the Ministry of Health held a meeting with community leaders from the affected areas to disseminate the results of the investigations made to date. This article summarizes the presentation and shares the story of studies into this peculiar disease. It also shares the results of preliminary studies on its pathogenesis and puts into perspective an upcoming treatment intervention. Clinical and electrophysiological studies have demonstrated nodding syndrome to be a complex epilepsy disorder. A definitive aetiological agent has not been established, but in agreement with other affected countries, a consistent epidemiological association has been demonstrated with infection by Onchocerca volvulus. Preliminary studies of its pathogenesis suggest that nodding syndrome may be a neuroinflammatory disorder, possibly induced by antibodies to O. volvulus cross-reacting with neuron proteins. Histological examination of post-mortem brains has shown some yet to be characterized polarizable material in the majority of specimens. Studies to confirm these observations and a clinical trial are planned for 2016. PMID- 26987478 TI - Yersiniosis in France: overview and potential sources of infection. AB - OBJECTIVES: The aim of this study was to exploit the extensive database on strains of Yersinia collected over more than 50 years in France in order to gain an overview of yersiniosis and potential sources of contamination in this country. METHODS: The 19 670 strains of Yersinia of human, animal, environmental, and food origin isolated in France were grouped by species, biotype, and serotype. RESULTS: Most human strains (59%) were pathogenic, with a marked predominance of Yersinia enterocolitica bioserotype 4/O:3 (66.8%), followed by Y. enterocolitica 2/O:9 (23.8%) and Yersinia pseudotuberculosis (6.1%). Pigs and pork meat were the nearly exclusive sources of Y. enterocolitica 4/O:3. Other pathogenic strains were rarely isolated from food or environmental samples (0.2%). The major source of pathogenic Yersinia was the animal reservoir, with a remarkable association between Y. enterocolitica 4/O:3 and pigs, Y. pseudotuberculosis and wildlife, Y. enterocolitica 2/O:9 and grazing farm animals, Y. enterocolitica 5/O:2,3 and hares, and Y. enterocolitica 3/O:1,2,3 and chinchillas. CONCLUSIONS: The frequency of human infection caused by certain Yersinia subgroups might be related to the frequency of exposure to specific animal sources. In contrast, non-pathogenic Yersinia were commonly isolated from foodstuffs and the environment, most probably accounting for the abundance of non pathogenic Yersinia recovered from human stools. PMID- 26987479 TI - Clindamycin resistance among Staphylococcus aureus strains in Israel: implications for empirical treatment of skin and soft tissue infections. AB - OBJECTIVES: The objectives of this study were to characterize isolates of Staphylococcus aureus obtained from skin and soft tissue infections in the community in Israel and to document the sensitivity patterns for commonly used antimicrobial agents. METHODS: The susceptibilities of S. aureus isolates from skin and soft tissue infections in the community in Israel were reviewed to determine the appropriate empirical therapy for these infections. RESULTS: A total of 7221 isolates were collected during the period 2009-2012; 39% were from children (age 0-18 years). In children, S. aureus oxacillin resistance dropped from 8.4% to 3.8% (p=0.073). While inducible clindamycin resistance increased slightly from 20% to 25%, there was a prominent increase in constitutive clindamycin resistance from 0.1% to 26.8% (p=0.012). In adults, oxacillin resistance increased from 16% to 23% (p<0.001) and constitutive clindamycin resistance increased notably from 5% to 29% (p<0.001). These findings demonstrate a dramatic increase in clindamycin resistance among S. aureus isolates and suggest against the usage of clindamycin as empirical treatment for suspected S. aureus infections in Israel. CONCLUSIONS: Beta-lactam anti-staphylococcal agents may be given as empirical treatment for children, but should be considered according to risk factors for adults in Israel. PMID- 26987481 TI - Lithium-coated polymeric matrix as a minimum volume-change and dendrite-free lithium metal anode. AB - Lithium metal is the ideal anode for the next generation of high-energy-density batteries. Nevertheless, dendrite growth, side reactions and infinite relative volume change have prevented it from practical applications. Here, we demonstrate a promising metallic lithium anode design by infusing molten lithium into a polymeric matrix. The electrospun polyimide employed is stable against highly reactive molten lithium and, via a conformal layer of zinc oxide coating to render the surface lithiophilic, molten lithium can be drawn into the matrix, affording a nano-porous lithium electrode. Importantly, the polymeric backbone enables uniform lithium stripping/plating, which successfully confines lithium within the matrix, realizing minimum volume change and effective dendrite suppression. The porous electrode reduces the effective current density; thus, flat voltage profiles and stable cycling of more than 100 cycles is achieved even at a high current density of 5 mA cm(-2) in both carbonate and ether electrolyte. The advantages of the porous, polymeric matrix provide important insights into the design principles of lithium metal anodes. PMID- 26987480 TI - Low prevalence of Plasmodium and absence of malaria transmission in Conakry, Guinea: prospects for elimination. AB - BACKGROUND: Over the past 15 years, mortality and morbidity due to malaria have been reduced substantially in sub-Saharan Africa and local elimination has been achieved in some settings. This study addresses the bio-ecology of larval and adult stages of malaria vectors, Plasmodium infection in Anopheles gambiae s.l. in the city of Conakry, Guinea, and discusses the prospect for malaria elimination. METHODS: Water bodies were prospected to identify potential mosquito breeding sites for 6 days each in the dry season (January 2013) and in the rainy season (August 2013), using the dipping method. Adult mosquitoes were collected in 15 communities in the five districts of Conakry using exit traps and indoor spraying catches over a 1-year period (November 2012 to October 2013). Molecular approaches were employed for identification of Anopheles species, including An. coluzzii and An. gambiae s.s. Individual An. gambiae mosquitoes were tested for Plasmodium falciparum and P. vivax sporozoites using the VecTestTM malaria panel assay and an enzyme-linked immunosorbent assay. A systematic research of Ministry of Health statistical yearbooks was performed to determine malaria prevalence in children below the age of 5 years. RESULTS: Culex larval breeding sites were observed in large numbers throughout Conakry in both seasons. While Anopheles larval breeding sites were less frequent than Culex breeding sites, there was a high odds of finding An. gambiae mosquito larvae in agricultural sites during the rainy season. Over the 1-year study period, a total of 14,334 adult mosquitoes were collected; 14,135 Culex (98.6%) and 161 (1.1%) from the An. gambiae complex. One-hundred and twelve Anopheles mosquitoes, mainly collected from rice fields and gardens, were subjected to molecular analysis. Most of the mosquitoes were An. gambiae s.s. (n = 102; 91.1%) while the remaining 10 (8.9%) were An. melas. The molecular M form of An. gambiae s.s. was predominant (n = 89; 79.5%). The proportions of kdr genotype in the An. gambiae s.s. M and S form were 65.2 and 81.8% (n = 9), respectively. No sporozoite infection were detected in any of the mosquitoes tested. The prevalence of Plasmodium recorded in children aged below 5 years was relatively low and varied between 2.2 and 7.6% from 2009 to 2012. CONCLUSIONS: The low density of larval and adult stages of Anopheles mosquitoes, the absence of infected An. gambiae species and the low prevalence of Plasmodium in under 5-year-old children are important features that might facilitate malaria elimination in Conakry. The heterogeneity in species composition and resistance profiles call for vector control interventions that are tailored to the local bio ecological setting. PMID- 26987482 TI - Nighttime warming enhances drought resistance of plant communities in a temperate steppe. AB - Drought events could have profound influence on plant community structure and ecosystem function, and have subsequent impacts on community stability, but we know little about how different climate warming scenarios affect community resistance and resilience to drought. Combining a daytime and nighttime warming experiment in the temperate steppe of north China with a natural drought event during the study period, we tested how daytime and nighttime warming influences drought resistance and resilience. Our results showed that the semi-arid steppe in north China was resistant to both daytime and nighttime warming, but vulnerable to drought. Nighttime warming, but not daytime warming, enhanced community resistance to drought via stimulating carbon sequestration, whereas neither daytime nor nighttime warming affected community resilience to drought. Large decline in plant community cover, primarily caused by the reduction in the cover of dominant and rare species rather than subordinate species during drought, did not preclude rapid ecosystem recovery. These findings suggest that nighttime warming may facilitate ecosystem sustainability and highlight the need to assess the effects of climate extremes on ecosystem functions at finer temporal resolutions than based on diurnal mean temperature. PMID- 26987483 TI - Study on the biodegradation of perfluorooctanesulfonate (PFOS) and PFOS alternatives. AB - OBJECTIVES: In this study, we investigated the biodegradation features of 4 perfluorooctanesulfonate (PFOS) alternatives developed at Changwon National University compared to those of PFOS. METHODS: Biodegradation testing was performed with microorganisms cultured in the good laboratory practice laboratory of the Korea Environment Corporation for 28 days following the Organization for Economic Cooperation and Development guidelines for the testing of chemicals (Test No. 301 C). RESULTS: While C8F17SO3Na, PFOS sodium salt was not degraded after 28 days, the 4 alternatives were biodegraded at the rates of 20.9% for C15F9H21S2O8Na2, 8.4% for C17F9H 25S2O8Na2, 22.6% for C23F18H28S2O8Na2, and 23.6% for C25F17H32O13S3Na3. CONCLUSIONS: C25F17H32S3O13Na3, C23F18H28S2O8Na2, and C15F9H21S2O8Na2 were superior to PFOS in terms of biodegradation rates and surface tension, and thus they were considered highly applicable as PFOS alternatives. Environmental toxicity, human toxicity, and economic feasibility of these compounds should be investigated prior to their commercialization. PMID- 26987484 TI - Myeloid deletion of SIRT1 suppresses collagen-induced arthritis in mice by modulating dendritic cell maturation. AB - The type III histone deacetylase silent information regulator 1 (SIRT1) is an enzyme that is critical for the modulation of immune and inflammatory responses. However, the data on its role in rheumatoid arthritis (RA) are limited and controversial. To better understand how SIRT1 regulates adaptive immune responses in RA, we evaluated collagen-induced arthritis (CIA) in myeloid cell-specific SIRT1 knockout (mSIRT1 KO) and wild-type (WT) mice. Arthritis severity was gauged on the basis of clinical, radiographic and pathologic scores. Compared with their WT counterparts, the mSIRT1 KO mice exhibited less severe arthritis, which was less destructive to the joints. The expression levels of inflammatory cytokines, matrix metalloproteinases and ROR-gammaT were also reduced in the mSIRT1 KO mice compared with the WT mice and were paralleled by reductions in the numbers of Th1 and Th17 cells and CD80- or CD86-positive dendritic cells (DCs). In addition, impaired DC maturation and decreases in the Th1/Th17 immune response were observed in the mSIRT1 KO mice. T-cell proliferation was also investigated in co cultures with antigen-pulsed DCs. In the co-cultures, the DCs from the mSIRT1 KO mice showed decreases in T-cell proliferation and the Th1/Th17 immune response. In this study, myeloid cell-specific deletion of SIRT1 appeared to suppress CIA by modulating DC maturation. Thus, a careful investigation of DC-specific SIRT1 downregulation is needed to gauge the therapeutic utility of agents targeting SIRT1 in RA. PMID- 26987485 TI - Abnormal proplatelet formation and emperipolesis in cultured human megakaryocytes from gray platelet syndrome patients. AB - The Gray Platelet Syndrome (GPS) is a rare inherited bleeding disorder characterized by deficiency of platelet alpha-granules, macrothrombocytopenia and marrow fibrosis. The autosomal recessive form of GPS is linked to loss of function mutations in NBEAL2, which is predicted to regulate granule trafficking in megakaryocytes, the platelet progenitors. We report the first analysis of cultured megakaryocytes from GPS patients with NBEAL2 mutations. Megakaryocytes cultured from peripheral blood or bone marrow hematopoietic progenitor cells from four patients were used to investigate megakaryopoiesis, megakaryocyte morphology and platelet formation. In vitro differentiation of megakaryocytes was normal, whereas we observed deficiency of megakaryocyte alpha-granule proteins and emperipolesis. Importantly, we first demonstrated that platelet formation by GPS megakaryocytes was severely affected, a defect which might be the major cause of thrombocytopenia in patients. These results demonstrate that cultured megakaryocytes from GPS patients provide a valuable model to understand the pathogenesis of GPS in humans. PMID- 26987486 TI - High Nutritional-Related Risk on Admission Predicts Less Improvement of Functional Independence Measure in Geriatric Stroke Patients: A Retrospective Cohort Study. AB - BACKGROUND: The aim of the present study was to establish whether high nutritional-related risk on admission predicts less improvement of Functional Independence Measure (FIM) in geriatric stroke patients. METHODS: We performed a retrospective cohort study of patients admitted for stroke at 5 major hospitals in the Noto district of Japan from July 2009 to June 2013. Patients were divided into 2 groups according to Geriatric Nutritional Risk Index (GNRI) at admission. Patient characteristics were compared between the low GNRI (<92) and high GNRI (>=92) groups. We assessed nutritional status using GNRI and activities of daily living using the FIM. RESULTS: A total of 540 participants (mean age, 80 years; interquartile range, 75-85 years) were included in the present study. Patients were admitted because of cerebral infarction (394 patients), intracerebral hemorrhage (123 patients), and subarachnoid hemorrhage (23 patients). Univariate analysis of FIM gain demonstrated significant differences between groups. Multivariate analysis of FIM gain adjusting for confounding factors demonstrated age (beta = -.139; 95% confidence interval [CI] = -.629 to -.140), cerebral infarction (beta = -.264; 95% CI = -12.956 to -6.729), National Institutes of Health Stroke Scale (beta = -.180; 95% CI = -.688 to -.248), and GNRI score (beta = .089; 95% CI = .010-.347) as independent factors associated with FIM gain (P < .05 for all). CONCLUSIONS: GNRI at admission may independently predict FIM gain. Poor nutritional status is a predictor of lower FIM improvement in geriatric stroke patients. PMID- 26987487 TI - Peak Systolic Velocity Measured by Continuous-Wave Doppler Ultrasonography without Angle Correction in Patients with Internal Carotid Artery Stenosis. AB - BACKGROUND: Peak systolic velocity (PSV) is measured with pulse-wave (PW) Doppler with angle correction in patients with internal carotid artery stenosis (ICAS). However, the correlation between conventional angiography and PSV shows considerable scattering. We hypothesized that measuring PSV without angle correction would lead to better inter-rater reliability. This hypothesis was tested using a sector probe and continuous-wave (CW) Doppler without angle correction. METHODS: Consecutive patients with more than 50% ICAS were enrolled from a prospective database. PSV was measured with PW Doppler with angle correction (PW PSV) and CW Doppler without angle correction (CW PSV) by 2 examiners. The inter-rater reliabilities of PW PSV and CW PSV were analyzed by Spearman's rank correlation test. RESULTS: A total of 37 ICAS sites (median 67 [interquartile range 57-78] % stenosis) were enrolled. Measuring PSV using a sector probe insonating nearly parallel to the flow was feasible in all cases. Inter-rater reproducibility of CW PSV (Spearman's rho = .810) was similar to that of PW PSV (Spearman's rho = .796). When limited to patients with a PSV greater than 200 cm/s with both PW Doppler examinations (25 ICAS sites), inter-rater reliability was relatively higher for CW PSV (Spearman's rho = .674) than for PW PSV (Spearman's rho = .423). CONCLUSIONS: Measuring PSV with CW Doppler using a sector probe was feasible. Inter-rater reliability was similar between PW Doppler with angle correction and CW Doppler without angle correction in evaluating PSV in patients with ICAS. CW Doppler appears to have better inter-rater reproducibility than PW Doppler in assessing high PSV. PMID- 26987489 TI - Why Clinicians Prognosticate Stroke Patients Poorly: Results from the Clinician Judgment versus Risk Score to Predict Stroke Outcomes Randomized Study. AB - BACKGROUND: Prognostication after a stroke has important implications for care and for decisions made by patients and their families. It is not clear why clinicians, even experienced stroke neurologists, poorly estimate the risk of disability and death following stroke. METHODS: We analyzed the results from the Clinician Judgment versus Risk Score to predict Stroke Outcomes study in which each clinician estimated the risk of death and the risk of death or disability in 5 case-based ischemic stroke scenarios. We employed a mixed-effect linear model to disentangle the ability of clinicians to discriminate between poor and good prognosis cases (slope) from the calibration of quantitative estimates (intercept), and to assess for any effect of anchoring in the death or disability condition (through a comparison with the death condition). RESULTS: One hundred eleven clinicians made 1665 predictions. Clinicians were able to discriminate between cases with low and high risks of death (slope of .81, 95% confidence interval [CI] .70-.93), but the quantitative estimates were not well calibrated (intercept of 5.14, 95% CI 3.97-6.33). The discrimination was poorer (slope of .67, 95% CI .60-.75), but the calibration was better (intercept of -.34, 95% CI 5.43 to 4.98) in the death or disability estimates. CONCLUSION: Poor stroke prognostication can be explained by poor calibration and an anchoring effect, which are both amenable to specific training interventions. PMID- 26987488 TI - Design and Rationale of the RELAXED (Recurrent Embolism Lessened by rivaroxaban, an Anti-Xa agent, of Early Dosing for acute ischemic stroke and transient ischemic attack with atrial fibrillation) Study. AB - BACKGROUND: In the acute phase of cardioembolic stroke in patients with nonvalvular atrial fibrillation (NVAF), the recurrence rate is high. Nonvitamin K antagonist oral anticoagulants may be appropriate for prevention of early recurrence because they have a much lower risk of hemorrhagic stroke than warfarin. METHODS: RELAXED (Recurrent Embolism Lessened by rivaroxaban, an Anti Xa agent, of Early Dosing for acute ischemic stroke and transient ischemic attack with atrial fibrillation) study is an observational study designed to investigate the optimal timing to start administration of rivaroxaban for prevention of recurrence in NVAF patients in the acute phase of cardioembolic stroke (ClinicalTrials.gov: NCT02129920 and UMIN-clinical trials registry: UMIN000013932). It will evaluate the efficacy and safety of rivaroxaban with regard to infarct size, timing of initiation of rivaroxaban medication, and other patient characteristics. A total of 2000 consecutive patients with acute ischemic stroke in the territory of the middle cerebral artery and NVAF will be enrolled in 100 institutes throughout Japan, and they will receive rivaroxaban within 30 days of the index stroke for secondary prevention of stroke. The infarct size within 48 hours after stroke onset will be measured by diffusion-weighted magnetic resonance imaging. The primary efficacy endpoint is recurrent ischemic stroke, and the primary safety endpoint is major bleeding during the observational period of 3 months after stroke onset. The optimal timing to start treatment with rivaroxaban during the acute stage of ischemic stroke will be determined by analysis of the correlation between primary endpoints and the size of cerebral infarct. CONCLUSIONS: The RELAXED observational registry study will elucidate the optimal timing of the initiation of rivaroxaban in acute cardioembolic stroke associated with NVAF. PMID- 26987490 TI - Monounsaturated Fatty Acid Intake and Stroke Risk: A Meta-analysis of Prospective Cohort Studies. AB - BACKGROUND: We performed a meta-analysis aiming to clarify the relationship between monounsaturated fatty acid (MUFA) intake and stroke risk. METHODS: Relevant studies were identified by searching relevant databases through January 2016. We included cohort studies that reported relative risks (RRs) with 95% confidence intervals (CIs) for the association between MUFA intake and stroke risk. A random-effects model was used to derive composite RR estimates for stroke. RESULTS: Ten prospective cohort studies including 314,511 nonoverlapping individuals and 5827 strokes were included. Higher MUFA intake was not associated with risk of overall stroke (RR = .86 [95% CI, .74-1.00]) and risk of ischemic stroke (RR = .92 [95% CI, .79-1.08]), but was associated with a reduced risk of hemorrhagic stroke (RR = .68 [95% CI, .49-.96]). In subgroup analyses, higher MUFA intake was associated with a reduced risk of stroke for a follow-up duration of 14 years or more (RR = .77 [95% CI, .68-.87]), for males (RR = .79 [95% CI, .69-.91]), for 24-hour recall (RR = .74 [95% CI, .63-.86]), and for a quality score of more than 8 stars (RR = .78 [95% CI, .61-.98]). CONCLUSIONS: There is no significant evidence for concluding that dietary MUFA is associated with a reduced risk of overall stroke. However, higher MUFA intake seems to be associated with a reduced risk of hem orrhagic stroke but not ischemic stroke. Duration of MUFA intake and sex are considered as factors affecting the relationship between MUFA intake and stroke risk. Further studies are needed to evaluate the relationship between specific food sources of MUFA (i.e., plant versus animal) and stroke risk. PMID- 26987493 TI - Erratum: Spectral variation of fluorescence lifetime near single metal nanoparticles. PMID- 26987492 TI - Thrombosis of the Cerebral Veins and Sinuses in Hamadan, West of Iran. AB - BACKGROUND AND PURPOSE: Cerebral venous sinuses thrombosis (CVST) is an uncommon type of stroke with an incidence of 3-4 cases per million. There have been reports of higher incidence of this disease in Iran. Our objective is to describe the incidence, clinical presentation, predisposing factors, and outcomes of CVST at Sina Hospital in Hamadan, west of Iran. METHODS: This is a prospective, single center, longitudinal study of all patients referred to Sina Hospital in Hamadan, west of Iran, between May 2009 to May 2015 who were diagnosed with CVST. RESULTS: In this study, 151 patients were included. There were 118 women and 33 men. The mean age was 37.48 years. The mean incidence rate of CVST in the duration of our study was 13.49 per 1 million. Oral contraceptives, the most common risk factor, were used by 55.1% of women and half of these patients had fasting simultaneously. Fifty-eight patients had more than 1 risk factor. After 12 months' follow-up, 73.1% of the patients were functionally independent (mRS score 0-1). Ten percent were dependent. The overall mortality was 16.9%. CONCLUSIONS: The incidence of CVST in Hamadan is higher than the world's average, and overall outcome is worse. It seems that fasting and subsequent dehydration in women with recent use of oral contraceptives make them more susceptible to CVST. PMID- 26987491 TI - Characteristics of Cerebral Microbleeds in Patients with Fabry Disease. AB - BACKGROUND AND PURPOSE: Fabry disease (FD) is an X-linked lysosomal storage disorder frequently associated with the central nervous system manifestations. Although white matter hyperintensity (WMH) on MRI has been previously reported, little is known about cerebral microbleeds (CMBs) in patients with FD. Our aim is to investigate the clinical characteristics of CMBs in patients with FD. METHODS: All patients with FD were diagnosed by enzyme activity and/or gene analysis at Jikei University Hospital. We retrospectively enrolled consecutive patients with FD who underwent MRI study, including fluid-attenuated inversion recovery and susceptibility-weighted imaging, between July 2008 and September 2013. After categorizing the patients into CMB-positive and CMB-negative groups, we compared the clinical characteristics between the 2 groups. RESULTS: We enrolled 54 patients (males, 24; median age 39 years, interquartile range; 29-50 years). The CMB-positive group included 16 (30%) patients. The number of males was significantly higher in the CMB-positive group than in the CMB-negative group (75% versus 32%, P = .003). The prevalence rates of chronic kidney disease (CKD) (estimated glomerular filtration rate < 60 mL/min/1.73 m(2)) and WMH were higher in the CMB-positive group than in the CMB-negative group (CKD: 44% versus 13%, P = .013; WMH: 88% versus 58%, P = .035). No significant differences in the number of vascular risk factors were observed between the 2 groups. CONCLUSIONS: The distinct characteristics of FD patients with CMBs were male sex, presence of CKD, and WMH. These factors may play an important role in the mechanism of hemorrhagic stroke in FD. PMID- 26987494 TI - Clinical relevance of high sensitivity C-reactive protein in cardiology. AB - Coping with cardiovascular diseases (CVD), which are of the main causes of death worldwide, has influenced investigation of high sensitivity CRP (hsCRP) and its role in pathogenesis, prognosis and prevention of CVD. hsCRP can be synthesized in vascular endothelium, atherosclerotic plaques, and theory of inflammatory origin of atherosclerosis is being more widely debated, raising questions, whether higher hsCRP plasma concentration might be the cause or the consequence. Summing up controversial data from multiple studies, guidelines recommend hsCRP testing for both, primary (stratifying CVD risk groups, selecting patients for statin therapy) and secondary CVD prevention (prognosis of CVD and its treatment complications, evaluation of treatment efficacy in moderate CVD risk group). hsCRP testing also has role in heart failure, atrial fibrillation, arterial hypertension, valve pathology and prognosis of coronary stent thrombosis or restenosis. Medications (the well-known and the new specific - CRP binding) affecting its concentration are being investigated as well. PMID- 26987495 TI - Moving into the wide clinical spectrum of consciousness disorders: Pearls, perils and pitfalls. AB - The last few years have been characterized by a growing interest of the medical and scientific world for the field of consciousness and its related disorders. Medically speaking, consciousness can be defined as the state of awareness of self and environment and the alertness to external stimulation, besides responsiveness to inner need. Transient loss of consciousness can be due to alterations in cerebral blood flow leading to fainting or syncope, migraine, metabolic dysfunctions, unexpected intracranial pressure increases, epileptic seizures, and sleep disorders. Chronic disorders of consciousness are a tragic success of high-technology treatment, in an attempt to maintain or reestablish brain function, which is to be considered as the main goal of therapeutics. Management of vegetative or a minimally conscious state individuals involves charily getting the right diagnosis with an evidence-based prognosis, also taking into account the medical, ethical, and legal key factors of the ideal treatment. This paper is aimed at exploring the wide spectrum of consciousness disorders and their clinical differential diagnosis, with particular regards to those with a negative impact on patient and their caregiver quality of life, including epilepsy, sleep disorders, and vegetative/minimally conscious state. PMID- 26987496 TI - Hypertension and physical exercise: The role of oxidative stress. AB - Oxidative stress is associated with the pathogenesis of hypertension. Decreased bioavailability of nitric oxide (NO) is one of the mechanisms involved in the pathogenesis. It has been suggested that physical exercise could be a potential non-pharmacological strategy in treatment of hypertension because of its beneficial effects on oxidative stress and endothelial function. The aim of this review is to investigate the effect of oxidative stress in relation to hypertension and physical exercise, including the role of NO in the pathogenesis of hypertension. Endothelial dysfunction and decreased NO levels have been found to have the adverse effects in the correlation between oxidative stress and hypertension. Most of the previous studies found that aerobic exercise significantly decreased blood pressure and oxidative stress in hypertensive subjects, but the intense aerobic exercise can also injure endothelial cells. Isometric exercise decreases normally only systolic blood pressure. An alternative exercise, Tai chi significantly decreases blood pressure and oxidative stress in normotensive elderly, but the effect in hypertensive subjects has not yet been studied. Physical exercise and especially aerobic training can be suggested as an effective intervention in the prevention and treatment of hypertension and cardiovascular disease via reduction in oxidative stress. PMID- 26987497 TI - Effect of probiotics on glucose metabolism in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials. AB - OBJECTIVE: Our aim was to investigate the effects of probiotics on glucose metabolism in patients with type 2 diabetes mellitus using a meta-analysis of randomized, controlled trials. MATERIALS AND METHODS: Online databases Embase, Web of Science, and PubMed were searched until August 2014 to identify eligible articles. Finally, 7 trials were included. RESULTS: Probiotic consumption significantly changed fasting plasma glucose (FPG) by -15.92mg/dL (95% confidence interval [CI], -29.75 to -2.09) and glycosylated hemoglobin (HbA1c) by -0.54% (95% CI, -0.82 to -0.25) compared with control groups. Subgroup analysis was conducted to trials with non-yogurts control. Meta-analysis of trials with multiple species of probiotics found a significant reduction in FPG (weighted mean difference [WMD]: -35.41mg/dL, 95% CI: -51.98 to -18.89). The duration of intervention for >=8 weeks resulted in a significant reduction in FPG (WMD: 20.34mg/dL, 95% CI: -35.92 to -4.76). Subgroup analysis of trials with species of probiotics did not result in a significant meta-analysis effect. Furthermore, the duration of intervention <8 weeks did not result in a significant reduction in FPG. The results also showed that probiotic therapy significantly decreased homeostasis model assessment of insulin resistance (HOMA-IR) and insulin concentration (WMD: -1.08, 95% CI: -1.88 to -0.28; and WMD: -1.35mIU/L, 95% CI: 2.38 to -0.31, respectively). CONCLUSIONS: The present meta-analysis suggests that consuming probiotics may improve glucose metabolism by a modest degree, with a potentially greater effect when the duration of intervention is >=8 weeks, or multiple species of probiotics are consumed. PMID- 26987498 TI - The importance of MTHFR C677T/A1298C combined polymorphisms in pulmonary embolism in Turkish population. AB - BACKGROUND AND OBJECTIVE: Pulmonary embolism (PE) is an important cardiovascular emergency with high mortality. There are still problems related to the diagnosis of PE and genetic research may play a key role on diagnosis as well as determining risk stratification. In the present study, the aim was to evaluate MTHFR C677T and A1298C polymorphisms that play a role on folate metabolism in PE patients. MATERIALS AND METHODS: A total of 118 PE patients and 126 controls were enrolled in the current study. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) analyses for the MTHFR C677T and A1298C polymorphisms. RESULTS: There was no association between clinical and demographic characteristics of PE patients and both MTHFR C677T and A1298C polymorphisms. Allele frequencies showed a significant difference between patients and controls. T allele frequency was significantly higher in the patients' group than the control group. There was an association between PE and combined MTHFR C677T and A1298C polymorphisms. CONCLUSION: We found an association between MTHFR C677T/A1298C combined mutations and PE in the Turkish population. Future genetic studies investigating combined mutations could be very helpful to identify risk population in PE. PMID- 26987500 TI - Association between the outcome of traumatic brain injury patients and cerebrovascular autoregulation, cerebral perfusion pressure, age, and injury grades. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to explore the association of cerebrovascular autoregulation (CA) and optimal cerebral perfusion pressure (CPP) managing conditions with the outcome of traumatic brain injury (TBI) patients including additional information about the patients' age and grade of diffuse axonal injury (DAI). MATERIALS AND METHODS: The CA monitoring of 28 TBI patients was performed by using ICM+ software (Cambridge, UK). The CA status estimating pressure reactivity indexes (PRx) and CPP data were processed in order to obtain information on the patient-specific treatment conditions by calculating the optimal CPP. RESULTS: There was a negative correlation between the Glasgow outcome scale (GOS) score and PRx (r=-0.448 at hospital discharge and r=-0.402 after 6 months). The estimated threshold value PRx of >0.24 was associated with mortality. The correlation coefficients between the GOS score and the difference CPP-optimal CPP were 0.549 at hospital discharge and 0.484 after 6 months. The threshold value of CPP declination from DeltaCPPopt per -6mmHg was associated with mortality. Poorer outcome was predicted for elderly TBI patients (aged >47 years) and patients having a DAI grade of 3. CONCLUSIONS: The association of the GOS score with CPP, CA impairment conditions, age and diffuse axonal injury (DAI) grade showed that the outcomes of TBI patients were associated with patient specific CPP management and better outcomes were obtained for younger patients, for patients having lower DAI grade and for patients whose CPP was kept within the range from the optimal CPP to the optimal CPP+10mmHg. PMID- 26987499 TI - Effects of cluster vs. traditional plyometric training sets on maximal-intensity exercise performance. AB - OBJECTIVE: The aim of this study was to compare the effects of 6-week cluster versus traditional plyometric training sets on jumping ability, sprint and agility performance. MATERIALS AND METHODS: Thirteen college students were assigned to a cluster sets group (N=6) or traditional sets group (N=7). Both training groups completed the same training program. The traditional group completed five sets of 20 repetitions with 2min of rest between sets each session, while the cluster group completed five sets of 20 [2*10] repetitions with 30/90-s rest each session. Subjects were evaluated for countermovement jump (CMJ), standing long jump (SLJ), t test, 20-m and 40-m sprint test performance before and after the intervention. RESULTS: Both groups had similar improvements (P<0.05) in CMJ, SLJ, t test, 20-m, and 40-m sprint. However, the magnitude of improvement in CMJ, SLJ and t test was greater for the cluster group (effect size [ES]=1.24, 0.81 and 1.38, respectively) compared to the traditional group (ES=0.84, 0.60 and 0.55). Conversely, the magnitude of improvement in 20-m and 40 m sprint test was greater for the traditional group (ES=1.59 and 0.96, respectively) compared to the cluster group (ES=0.94 and 0.75, respectively). CONCLUSIONS: Although both plyometric training methods improved lower body maximal-intensity exercise performance, the traditional sets methods resulted in greater adaptations in sprint performance, while the cluster sets method resulted in greater jump and agility adaptations. PMID- 26987501 TI - Prevalence and severity of dental caries among 18-year-old Lithuanian adolescents. AB - OBJECTIVE: The aim of the study was to evaluate the prevalence and severity of dental caries among 18-year-old Lithuanian adolescents and to disclose possible differences in the prevalence and severity of dental caries related to gender, urbanization, and different county. MATERIAL AND METHODS: A total of 1063 18-year old adolescents attending school, 427 boys and 636 girls from 10 Lithuanian counties including urban and rural areas, were included in the cross-sectional study on dental caries. The method of multistage cluster sampling was used. The dental examination was performed according to the methodology of oral status evaluation recommendations by the World Health Organization (WHO). The prevalence of dental caries, DMFT score, Significant Caries Index, and dental care index were determined. RESULTS: The overall prevalence of dental caries among 18-year old Lithuanian adolescents was 78.3%. The study population had a mean DMFT score of 2.93 [SD, 2.81]. Considering the gender, a higher DMFT score was observed among girls than boys (3.03 [SD, 2.88] versus 2.73 [SD, 2.71]) and in rural than urban areas (3.02 [SD, 2.98] versus 2.89 [SD, 2.73]). The Significant Caries Index and the dental care index among 18-year-old adolescents were 6.14 and 62.3%, respectively. CONCLUSION: This study showed a relatively high prevalence of dental caries. The existing differences of caries experience between the urban and the rural areas as well as between the counties could be influenced by the socioeconomic differences in the country. PMID- 26987502 TI - Evaluation of daily outpatient multidisciplinary rehabilitative treatment of patients with musculoskeletal, neurological and traumatic disorders in a municipality outpatient setting. AB - BACKGROUND AND OBJECTIVE: Musculoskeletal, neurological, and traumatic injuries are a considerably increasing problem. There is a lack of studies evaluating the results of outpatient rehabilitative treatment of patients with the abovementioned diseases. The aim of this study was to determine the effectiveness of daily outpatient multidisciplinary rehabilitation. MATERIALS AND METHODS: This observational study enrolled 223 adult people undergoing outpatient rehabilitation performed in a municipality outpatient clinic during 14 days. The functional assessment of disability was performed by using the Barthel index (BI), functional performance was estimated by the modified Keitel functional test (MKFT), and pain perception was evaluated by the visual analogue scale (VAS). The mean scores of the tests were compared before and after outpatient multidisciplinary rehabilitation. RESULTS: Significantly reduced disability and pain perception as well as increased functional performance were documented after outpatient rehabilitation. The mean scores of BI, MKFT, and VAS before and after rehabilitation did not differ significantly among patients ranked to each cluster of diseases. Increased functional performance of patients had a moderate-to-weak association with decreased disability and pain perception. The positive changes in health status considering disability, functional performance, and pain perception were documented after 14-day rehabilitation. CONCLUSIONS: Multidisciplinary outpatient rehabilitation can be considered as effective treatment. However, it is necessary to implement specific, well-adapted consuming assessment instruments in order to evaluate the outcomes of daily multidisciplinary outpatient rehabilitative treatment. PMID- 26987504 TI - Introduction: Natural product-based drug discovery in Immunopharmacology. PMID- 26987503 TI - Label-free electrochemical immunosensor based on enhanced signal amplification between Au@Pd and CoFe2O4/graphene nanohybrid. AB - The improvement of sensitivity of electrochemical immunosensor can be achieved via two approaches: increasing loading capacities of antibody and enlarging responding electrochemical signals. Based on these, CoFe2O4/graphene nanohybrid (CoFe2O4/rGO) as support was firstly used for preparing electrochemical biosensor, and with the addition of Au@Pd nanorods (NRs) as mimic enzyme, a label free electrochemical immunosensor was prepared. Due to the high electrical conductivity, open porous structure and large loading capacities of CoFe2O4/rGO, the enhanced signal amplification between Au@Pd NRs and CoFe2O4/rGO was studied. Fabricated as a novel substrate, the prepared immunosensor had a good analytical performance and exhibited a wide linear range from 0.01 to 18.0 ng . mL(-1) with a low detection limit of 3.3 pg . mL(-1) for estradiol, which was succeeded in applying to detect estradiol in the natural water. PMID- 26987506 TI - Beyond the corrupting influence of pharmaceutical companies on antidepressant meta-analyses (Letter commenting on: J Clin Epidemiol. 70, 2016, 155-163). PMID- 26987505 TI - Indirubin, a component of Ban-Lan-Gen, activates CYP3A4 gene transcription through the human pregnane X receptor. AB - Ban-Lan-Gen is the common name for the dried roots of indigo plants, including Polygonum tinctorium, Isatis indigotica, Isatis tinctoria, and Strobilanthes cusia. Ban-Lan-Gen is frequently used as an anti-inflammatory and an anti-viral for the treatment of hepatitis, influenza, and various types of inflammation. One of the cytochrome P450 (CYP) enzymes, CYP3A4, is responsible for the metabolism of a wide variety of xenobiotics, including an estimated 60% of all clinically used drugs. In this study, we investigated the effect of Ban-Lan-Gen on the transcriptional activation of the CYP3A4 gene. Ban-Lan-Gen extract increased CYP3A4 gene reporter activity in a dose-dependent manner. Indirubin, one of the biologically active ingredients in the Ban-Lan-Gen, also dose-dependently increased CYP3A4 gene reporter activity. Expression of short hairpin RNA for the human pregnane X receptor (hPXR-shRNA) inhibited CYP3A4 gene reporter activity, and overexpression of human PXR increased indirubin- and rifampicin-induced CYP3A4 gene reporter activity. Furthermore, indirubin induced CYP3A4 mRNA expression in HepG2 cells. Taken together, these results indicate that indirubin, a component of Ban-Lan-Gen, activated CYP3A4 gene transcription through the activation of the human PXR. PMID- 26987507 TI - Modern modeling techniques had limited external validity in predicting mortality from traumatic brain injury. AB - BACKGROUND AND OBJECTIVE: Prediction of medical outcomes may potentially benefit from using modern statistical modeling techniques. We aimed to externally validate modeling strategies for prediction of 6-month mortality of patients suffering from traumatic brain injury (TBI) with predictor sets of increasing complexity. METHODS: We analyzed individual patient data from 15 different studies including 11,026 TBI patients. We consecutively considered a core set of predictors (age, motor score, and pupillary reactivity), an extended set with computed tomography scan characteristics, and a further extension with two laboratory measurements (glucose and hemoglobin). With each of these sets, we predicted 6-month mortality using default settings with five statistical modeling techniques: logistic regression (LR), classification and regression trees, random forests (RFs), support vector machines (SVM) and neural nets. For external validation, a model developed on one of the 15 data sets was applied to each of the 14 remaining sets. This process was repeated 15 times for a total of 630 validations. The area under the receiver operating characteristic curve (AUC) was used to assess the discriminative ability of the models. RESULTS: For the most complex predictor set, the LR models performed best (median validated AUC value, 0.757), followed by RF and support vector machine models (median validated AUC value, 0.735 and 0.732, respectively). With each predictor set, the classification and regression trees models showed poor performance (median validated AUC value, <0.7). The variability in performance across the studies was smallest for the RF- and LR-based models (inter quartile range for validated AUC values from 0.07 to 0.10). CONCLUSION: In the area of predicting mortality from TBI, nonlinear and nonadditive effects are not pronounced enough to make modern prediction methods beneficial. PMID- 26987508 TI - Capnometry in children with bronchiolitis: A pathophysiological point of view. PMID- 26987509 TI - Fatal Systemic Toxoplasma gondii Infection in a Red Squirrel (Sciurus vulgaris), a Swinhoe's Striped Squirrel (Tamiops swinhoei) and a New World Porcupine (Erethizontidae sp.). AB - Toxoplasmosis is a parasitic disease that affects man and animals worldwide. The primary hosts and major reservoir for Toxoplasma gondii are felids and the intermediate hosts are most warm-blooded animals including man. This report describes fatal toxoplasmosis in three different rodent species in Germany: a female red squirrel (Sciurus vulgaris) and a male Swinhoe's striped squirrel (Tamiops swinhoei), both kept as pets, and a female New World porcupine (Erethizontidae sp.) from a zoo. All three animals had multifocal necrotizing hepatitis. Additional findings included lymphohistiocytic and necrotizing myocarditis in the New World porcupine and the Swinhoe's striped squirrel, lymphohistiocytic encephalomyelitis in the New World porcupine and suppurative lymphadenitis in the red squirrel. Numerous tachyzoites were identified associated with the lesions. The diagnosis was confirmed by Toxoplasma. gondii immunohistochemistry and electron microscopy. This is the first report of toxoplasmosis in a New World porcupine and a Swinhoe's striped squirrel. PMID- 26987510 TI - Intracerebral Malignant Plasmacytoma in a Mule Deer (Odocoileus hemionus). AB - A wild, mature, gravid female mule deer (Odocoileus hemionus) was presented with marked neurological signs, including abnormal behaviour, circling and incoordination. The animal was humanely destroyed and submitted for diagnostic investigation. Grossly, a well-demarcated, 3 * 3 * 3 cm intracranial mass replaced the left olfactory bulb and frontal lobe. Histologically, there was a highly cellular, infiltrative and unencapsulated neoplastic mass of round cells with eccentrically located nuclei. Neoplastic cells were immunohistochemically labelled for lambda immunoglobulin light chain. Clusters of CD20- and CD79a positive cells were scattered throughout the tumour and CD3- and Iba1-positive cells diffusely infiltrated the neoplasm. Ultrastructurally, the cytoplasm of the neoplastic cells had prominent rough endoplasmic reticulum with a variable degree of dilation. Histopathological, immunohistochemical and electron microscopical results were diagnostic for a solitary extramedullary plasmacytoma. Intracranial neoplasms are rarely diagnosed in wildlife species, but they should be included in the differential diagnosis for potential causes of central nervous system disease. PMID- 26987511 TI - Morphometric Properties of the Thoracic Aorta of Warmblood and Friesian Horses with and without Aortic Rupture. AB - Rupture of the aorta is much more common in Friesians compared with other breeds of horse. Rupture always occurs adjacent to the scar of the ligamentum arteriosum. Previous histological examination of ruptured aortic walls suggested the presence of an underlying connective tissue disorder. Therefore, the aim of the present study was to compare the structural characteristics of the tunica media of the mid-thoracic aorta, distant to the lesion, in warmblood and Friesian horses with and without thoracic aortic rupture. In unaffected Friesian horses, the thickness of the tunica media, as well as the percentage area comprised of collagen type I, were significantly higher compared with the warmblood horses, supporting the hypothesis of a primary collagen disorder in the Friesian horse breed. However, in the tunica media of the affected Friesian horses there was no significant wall thickening. Moreover, the percentage area comprised of elastin was significantly lower, while the percentage area comprised of smooth muscle was higher, compared with unaffected Friesian and warmblood horses. These lesions are suggestive of an additional mild elastin deficiency with compensatory smooth muscle cell hypertrophy in affected Friesians. PMID- 26987512 TI - Relationships between perceived social support and retention among patients in methadone maintenance treatment in mainland China. AB - The study purpose was to explore relationships between perceived social support and retention in mainland Chinese patients receiving methadone maintenance treatment (MMT). Data collection included baseline information, perceived social support, and retention. A total of 1212 patients completed the cross-sectional survey; 809 (66.7%) perceived good social support and 458 (37.8%) had been re admitted. Despite controlling baseline information, past retention did not significantly influence perceived social support. At the two-year follow-up, 527 (43.5%) patients terminated MMT. Patients with poorer perceived social support were more likely to terminate treatment, with hazard ratios of 1.31 (95% confidence interval [CI]: 1.10-1.57 without controlling baseline information and past retention) and 1.25 (95% CI: 1.04-1.51 controlling baseline information and past retention). Thus, while MMT retention does not significantly influence perceived social support, good perceived social support is a strong predictor of retention. PMID- 26987513 TI - The surgical treatment of esophageal cancer in Sudan: A 100 consecutive cases. AB - OBJECTIVE: Esophageal cancer is the most common gastrointestinal (GI) cancer in The Sudan. This study aimed to evaluate the outcome of the surgical management. METHODS: A 100 consecutive patients who underwent esophagectomy in Shaab Hospital in Khartoum during the period June 2003-Aug 2007 were studied. RESULTS: The mean age was 55 +/- 14 years with an equal sex ratio. Fifty five per cent of patients presented with stage III&IV locally advanced and or metastatic disease. Sixty seven percent of the patients underwent a 2-stage resection, Lewis Tanner type while 27% underwent a 3-stage resection, McKeon operation and 6% had total gastrectomy with distal esophagectomy and roux-en-y reconstruction. The 30 days postoperative mortality was 10%. In 75 patients who could be traced, the overall 5 years survival was 21% (n = 16) and the 10 years survival was 8% (n = 6). CONCLUSION: There was great improvement in the early postoperative mortality from 27% in 1986 to 10% in this series. The surgical treatment offered a rapid symptoms relief which suited most patients coming from distant locations and couldn't afford to stay for long in the Capital as will be required if chemo radiotherapy was used as sole or as a neo-adjuvant treatment. PMID- 26987514 TI - Transtibial vs anatomical single bundle technique for anterior cruciate ligament reconstruction: A Retrospective Cohort Study. AB - INTRODUCTION: Most of the ACL reconstruction is done with isometric single-bundle technique. Traditionally, surgeons were trained to use the transtibial technique (TT) for drilling the femoral tunnel. Our study compared the early postoperative period functional and clinical outcomes of patients who had ACL reconstruction with TT and patients who had ACL reconstruction with anatomical single-bundle technique (AT). MATERIAL METHOD: Fifty-five patients who had ACL reconstruction and adequate follow-up between January 2010-December 2013 were included the study. Patients were grouped by their surgery technique. 28 patients included into anatomical single-bundle ACL reconstruction surgery group (group 1) and 27 patients were included into transtibial AC reconstruction group (group 2). Average age of patients in group 1 and group 2 was 28.3 +/- 6, and 27.9 +/- 6.4, respectively. Lachman and Pivot-shift tests were performed to patients. Laxity was measured by KT-1000 arthrometer test with 15, 20 and 30 pound power. All patients' muscle strength between both extremities were evaluated with Cybex II (Humac) at 60 degrees /sec, 240 degrees /sec frequencies with flexion and extension peak torque. The maximum force values of non-operated knee and the operated knee were compared to each other. Groups were evaluated by using International Knee Documentation Committee (IKDC) knee ligament healing Standard form, IKDC activity scale, modified Lysholm and Cincinnati evaluation forms. Return to work and exercise time of patients were compared. Functional and clinical outcomes of two groups were compared. NCSS 2007 and PASS 2008 Statistical Software programs were used for statistical analysis. RESULT: There was no statistically significant difference between Lachman and Pivot-shift results (p > 0.01). Positive value of Pivot-shift test and incidence of anterior translation in Lachman test were higher in the patients who had TT. Lysholm activity level of patients who had TT, 33.3% (n = 9) were excellent, 51.9% (n = 14) were good and 14.8% (n = 4) were moderate; patients who had AT, 57.1% (n = 16) were excellent, 39.3% (n = 11) were good and 3.6% (n = 1) was good level. There was no statistically significant difference between Lysholm Activity level of the patients (p < 0.01). Lysholm Activity level of patients who had AT significantly higher than TT. There was no statistically significant difference between Modified Cincinnati activity level of the patients (p < 0.05). Modified Cincinnati activity level of patients who had AT were significantly higher than those had TT. There was no statistically significant difference between two groups with post treatment IKDC activity level (p < 0.01). Intense activity after treatment rate of patient who had AT was significantly higher than those had TT. There was statistically significant difference between Cybex extension-flexion 60 measurement and extension 240 measurement of the patients (p < 0.01). KT-1000 arthrometer test results with AT was better than the TT in antero-posterior translation of the knee kinematics at 20 and 30 pound of forces. Return to exercise time of patients who had TT was significantly higher than those had AT (p < 0.01). There was no statistically significant difference between return to work time of patients (p > 0.05). CONCLUSION: Single-bundle anatomic ACL reconstruction was better than the TT in term of clinical, functional, and laboratory results. We believe that AT ACL reconstruction will increase in use and traditional method which is TT ACL reconstruction surgery will decrease in the long term. Theoretically, anatomic relocation of the ACL can provide better knee kinematics. PMID- 26987515 TI - MONGKIE: an integrated tool for network analysis and visualization for multi omics data. AB - BACKGROUND: Network-based integrative analysis is a powerful technique for extracting biological insights from multilayered omics data such as somatic mutations, copy number variations, and gene expression data. However, integrated analysis of multi-omics data is quite complicated and can hardly be done in an automated way. Thus, a powerful interactive visual mining tool supporting diverse analysis algorithms for identification of driver genes and regulatory modules is much needed. RESULTS: Here, we present a software platform that integrates network visualization with omics data analysis tools seamlessly. The visualization unit supports various options for displaying multi-omics data as well as unique network models for describing sophisticated biological networks such as complex biomolecular reactions. In addition, we implemented diverse in house algorithms for network analysis including network clustering and over representation analysis. Novel functions include facile definition and optimized visualization of subgroups, comparison of a series of data sets in an identical network by data-to-visual mapping and subsequent overlaying function, and management of custom interaction networks. Utility of MONGKIE for network-based visual data mining of multi-omics data was demonstrated by analysis of the TCGA glioblastoma data. MONGKIE was developed in Java based on the NetBeans plugin architecture, thus being OS-independent with intrinsic support of module extension by third-party developers. CONCLUSION: We believe that MONGKIE would be a valuable addition to network analysis software by supporting many unique features and visualization options, especially for analysing multi-omics data sets in cancer and other diseases. . PMID- 26987516 TI - dsRNA-protein interactions studied by molecular dynamics techniques. Unravelling dsRNA recognition by DCL1. AB - Double stranded RNA (dsRNA) participates in several biological processes, where RNA molecules acquire secondary structure inside the cell through base complementarity. The double stranded RNA binding domain (dsRBD) is one of the main protein folds that is able to recognize and bind to dsRNA regions. The N terminal dsRBD of DCL1 in Arabidopsis thaliana (DCL1-1), in contrast to other studied dsRBDs, lacks a stable structure, behaving as an intrinsically disordered protein. DCL1-1 does however recognize dsRNA by acquiring a canonical fold in the presence of its substrate. Here we present a detailed modeling and molecular dynamics study of dsRNA recognition by DCL1-1. We found that DCL1-1 forms stable complexes with different RNAs and we characterized the residues involved in binding. Although the domain shows a binding loop substantially shorter than other homologs, it can still interact with the dsRNA and results in bending of the dsRNA A-type helix. Furthermore, we found that R8, a non-conserved residue located in the first dsRNA binding region, recognizes preferentially mismatched base pairs. We discuss our findings in the context of the function of DCL1-1 within the microRNA processing complex. PMID- 26987517 TI - Re: Prognostic Significance of Sarcopenia in Patients with Metastatic Renal Cell Carcinoma: H. Fukushima, Y. Nakanishi, M. Kataoka, K. Tobisu and F. Koga J Urol 2016;195:26-32. PMID- 26987519 TI - A prospective cohort study on the association between coffee drinking and risk of non-gallstone-related acute pancreatitis. AB - Only one previous study has examined the association between coffee consumption and risk of acute pancreatitis, and it found a reduced risk for alcohol-related episodes among high consumers of coffee. Therefore, we examined (1) the association between coffee consumption and risk of non-gallstone-related acute pancreatitis and (2) whether this association was modified by alcohol intake. Data were obtained from two prospective cohorts, the Cohort of Swedish Men and the Swedish Mammography Cohort, including 76 731 men and women (born 1914-1952). Coffee consumption was assessed at baseline with a FFQ, and the cohorts were followed up between 1998 and 2012 via linkage to national health registries. Hazard ratios were estimated using Cox models, with adjustment for potential confounding factors. During 1 035 881 person-years of total follow-up, 383 cases (246 in men and 137 in women) of incident non-gallstone-related acute pancreatitis were identified. Overall, and irrespective of whether a categorical or a continuous exposure model was used, we observed no association between coffee consumption and risk of non-gallstone-related acute pancreatitis (e.g. the multivariable-adjusted hazard ratio for each 1 cup/d increase in coffee consumption was 0.97; 95 % CI 0.92, 1.03). There was no evidence of effect modification by alcohol intake (P interaction=0.77). In conclusion, coffee consumption was not associated with risk of non-gallstone-related acute pancreatitis in this large prospective cohort study. Because of the limited number of epidemiological studies and their conflicting results, further research is needed to elucidate this potential association. PMID- 26987518 TI - Targeted inactivation of the mouse epididymal beta-defensin 41 alters sperm flagellar beat pattern and zona pellucida binding. AB - During epididymal maturation, sperm acquire the ability to swim progressively by interacting with proteins secreted by the epididymal epithelium. Beta-defensin proteins, expressed in the epididymis, continue to regulate sperm motility during capacitation and hyperactivation in the female reproductive tract. We characterized the mouse beta-defensin 41 (DEFB41), by generating a mouse model with iCre recombinase inserted into the first exon of the gene. The homozygous Defb41(iCre/iCre) knock-in mice lacked Defb41 expression and displayed iCre recombinase activity in the principal cells of the proximal epididymis. Heterozygous Defb41(iCre/+) mice can be used to generate epididymis specific conditional knock-out mouse models. Homozygous Defb41(iCre/iCre) sperm displayed a defect in sperm motility with the flagella primarily bending in the pro-hook conformation while capacitated wild-type sperm more often displayed the anti-hook conformation. This led to a reduced straight line motility of Defb41(iCre/iCre) sperm and weaker binding to the oocyte. Thus, DEFB41 is required for proper sperm maturation. PMID- 26987521 TI - WITHDRAWN: Declarations of interest. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26987520 TI - Assessing 30-day quantity-frequency of U.S. adolescent cigarette smoking as a predictor of adult smoking 14 years later. AB - BACKGROUND: To improve measures of monthly tobacco cigarette smoking among non daily smokers, predictive of future non-daily monthly and daily smoking. METHODS: Data from United States National Longitudinal Study of Adolescent to Adult Health, tracking adolescents, ages 12-21, over 14 years were analyzed. At baseline, 6501 adolescents were assessed; 5114 individuals provided data at waves 1 and 4. Baseline past 30-day non-daily smokers were classified using quantity frequency measures: cigarettes smoked/day by number of days smoked in the past 30 days. RESULTS: Three categories of past 30-day non-daily smokers emerged using cigarettes/month (low:1-5, moderate: 6-60, high: 61+) and predicted past 30-day smoking at follow-up (low: 44.5%, moderate: 60.0%, high: 77.0%, versus 74.2% daily smokers; rtau=-0.2319, p<0.001). Two categories of non-smokers plus low, moderate and high categories of non-daily smokers made up a five-category non daily smoking index (NDSI). High NDSI (61+ cigs/mo.) and daily smokers were equally likely to be smoking 14 years later (High NDSI OR=0.97, 95% CI=0.53-1.80 [daily as reference]). Low (1-5 cigs/mo.) and moderate (6-60 cigs/mo.) NDSI were distinctly different from high NDSI, but similar to one another (OR=0.21, 95% CI=0.15-0.29 and OR=0.22, 95% CI=0.14-0.34, respectively) when estimating future monthly smoking. Among those smoking at both waves, wave 1 non-daily smokers, overall, were less likely than wave 1 daily smokers to be smoking daily 14 years later. CONCLUSIONS: Non-daily smokers smoking over three packs/month were as likely as daily smokers to be smoking 14-years later. Lower levels of non-daily smoking (at ages 12-21) predicted lower likelihood of future monthly smoking. In terms of surveillance and cessation interventions, high NDSI smokers might be treated similar to daily smokers. PMID- 26987522 TI - Single parameter of inverse proportion between mortality and age could determine all mortality indicators in the first year of life. AB - Mortality increase with age in adult population has been studied and modeled by many authors, but relatively little attention has been given to mortality decrease with age after birth. Data split in more detailed age categories can newly test mortality decrease with age. Age trajectories of mortality are studied in 20 age categories in the specific age interval 1-365 days. Four basic models mentioned in literature are tested here. The linear model and the linear model with the specific slope -1 in the log-log scale represent the most successful formalism. Mortality indicators describing the first year could be determined by a single parameter of the model with slope -1 in the log-log scale. All conclusions are based on published data which are presented as a supplement. PMID- 26987523 TI - Vascular phenotype identification and anti-angiogenic treatment recommendation: A pseudo-multiscale mathematical model of angiogenesis. AB - The development of anti-angiogenic drugs for cancer therapy has yielded some promising candidates, but novel approaches for interventions to angiogenesis have led to disappointing results. In addition, there is a shortage of biomarkers that are predictive of response to anti-angiogenic treatments. Consequently, the complex biochemical and physiological basis for tumour angiogenesis remains incompletely understood. We have adopted a mathematical approach to address these issues, formulating a spatially averaged multiscale model that couples the dynamics of VEGF, Ang1, Ang2 and PDGF, with those of mature and immature endothelial cells and pericyte cells. The model reproduces qualitative experimental results regarding pericyte coverage of vessels after treatment by anti-Ang2, anti-VEGF and combination anti-VEGF/anti-Ang2 antibodies. We used the steady state behaviours of the model to characterise angiogenic and non angiogenic vascular phenotypes, and used mechanistic perturbations representing hypothetical anti-angiogenic treatments to generate testable hypotheses regarding transitions to non-angiogenic phenotypes that depend on the pre-treatment vascular phenotype. Additionally, we predicted a synergistic effect between anti VEGF and anti-Ang2 treatments when applied to an immature pre-treatment vascular phenotype, but not when applied to a normalised angiogenic pre-treatment phenotype. Based on these findings, we conclude that changes in vascular phenotype are predicted to be useful as an experimental biomarker of response to treatment. Further, our analysis illustrates the potential value of non-spatial mathematical models for generating tractable predictions regarding the action of anti-angiogenic therapies. PMID- 26987526 TI - The complement system of elasmobranches revealed by liver transcriptome analysis of a hammerhead shark, Sphyrna zygaena. AB - Comprehensive studies of the complement genes in basal vertebrates have revealed that cyclostomes have apparently primitive complement systems whereas bony fish have well-developed complement systems comparable to those of mammals. Here we have performed liver transcriptome analysis of a hammerhead shark, Sphyrna zygaeana, to elucidate the early history of vertebrate complement evolution. Identified genes were; one C1qB, one C1r, one C1s, one MASP-1/-3, one MASP-2, two factor B/C2, one C3, three C4, one C5, one C6, one C7, one C8A, three C8B, one C8G, one C9, two factor I and one S protein. No MBL, ficolin, C1qA or C1qC were found. These results indicate that the lectin, classical, alternative and lytic pathways were established in the common ancestor of jawed vertebrates. In addition to the absence of MBL and ficolin, the MASP transcripts lacked the serine protease domain, suggesting that the lectin pathway was lost in the hammerhead shark lineage. PMID- 26987525 TI - TLR21's agonists in combination with Aeromonas antigens synergistically up regulate functional TLR21 and cytokine gene expression in yellowtail leucocytes. AB - The purpose of this study was to characterize the TLR21 gene from yellowtail (Seriola lalandi) and its functional activity using TLR agonist stimulation and Aeromonas antigens. The TLR21 nucleotide sequence from yellowtail was obtained using the whole-genome shotgun sequencing method and bioinformatics tools. Basal TLR21 gene expression was analyzed in several tissues. Subsequently, the gene expression of TLR21 and cytokines IL-1beta and TNF-alpha was evaluated in TLR agonist (CpG-ODN2006, LPS, and Poly I:C) exposing head kidney leucocytes, which were then subjected to Aeromonas antigen stimulation. The yellowtail full-length cDNA sequence of SlTLR21 was 3615 bp (980 aa) showing a high degree of similarity with the counterparts of other fish species and sharing the common structural architecture of the TLR family, including LRR domains, one C-terminal LRR region, and a TIR domain. Gene expression studies revealed the constitutive expression of TLR21 mRNA in all the analyzed tissues; the highest levels were observed in spleen and head kidney where they play an important role in the fish immune system. Transcripts of TLR21 and the downstream IL-1beta and TNF-alpha cytokine genes were most strongly up-regulated after exposure to the TLR agonists following Aeromonas antigen stimulation, suggesting they are involved in immune response. The results indicated that TLR agonists, in combination with Aeromonas antigens in head kidney leucocytes, synergistically enhance TLR21 and cytokines in yellowtail. PMID- 26987524 TI - The emerging roles of exosomes in tumor-stroma interaction. AB - PURPOSE: The tumor-stroma interaction is critical for the development and progression of cancer. Cancer-associated fibroblasts (CAFs), one of the major components of the tumor stroma, can promote tumor growth and metastasis. Exosomes are secreted microvesicles that mediate cell-to-cell communication. Exosomal contents, including proteins, nucleic acids, and lipids, can be shuttled from donor cells to target cells. Recent studies suggest that exosomes play important roles in the tumor-stroma interaction. Herein, we review the multifaceted roles of exosomes in the tumor-stroma interaction and the underlying molecular mechanisms. METHODS: Literature search for all relevant publications was performed on PubMed databases. The keywords of exosomes, tumor, stroma, CAFs, mesenchymal stem cells (MSCs) and other closely related terms were used for searching. RESULTS: Tumor cell-derived exosomes induce the differentiation of fibroblasts and MSCs into CAFs. In turn, exosomes secreted by CAFs promote tumor growth, metastasis, and drug resistance through distinct mechanisms. Moreover, exosomes from stromal cells can be used as therapeutic vehicles for the delivery of anticancer drugs. CONCLUSIONS: Tumor cells communicate with CAFs through exosomes, which establishes a bidirectional cross talk to promote tumor growth, metastasis, and drug resistance. Targeting exosomes in tumor-stroma interaction may have important implications for anticancer therapy. PMID- 26987527 TI - Photobiomodulation on human annulus fibrosus cells during the intervertebral disk degeneration: extracellular matrix-modifying enzymes. AB - Destruction of extracellular matrix (ECM) leads to degeneration of the intervertebral disk (IVD), which is a major contributor to many spine disorders. IVD degeneration is induced by pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta), which are secreted by immune cells, including macrophages and neutrophils. The cytokines modulate ECM modifying enzymes such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in human annulus fibrosus (AF) cells. The resulting imbalance in catabolic and anabolic enzymes can cause generalized back, neck, and low back pain (LBP). Photobiomodulation (PBM) is known to regulate inflammatory responses and wound healing. The aim of this study was to mimic the degenerative IVD microenvironment, and to investigate the effect of a variety of PBM conditions (wavelength: 635, 525, and 470 nm; energy density: 16, 32, and 64 J/cm(2)) on the production of ECM-modifying-enzymes by AF cells under degenerative conditions induced by macrophage-conditioned medium (MCM), which contains pro-inflammatory cytokines such as TNF-alpha and IL-beta secreted by macrophage during the development of intervertebral disk inflammation. We showed that the MCM-stimulated AF cells express imbalanced ratios of TIMPs (TIMP-1 and TIMP-2) and MMPs (MMP-1 and MMP-3). PBM selectively modulated the production of ECM-modifying enzymes in AF cells. These results suggest that PBM can be a therapeutic tool for degenerative IVD disorders. PMID- 26987528 TI - Comparing the transcriptomes of embryos from domesticated and wild Atlantic salmon (Salmo salar L.) stocks and examining factors that influence heritability of gene expression. AB - BACKGROUND: Due to selective breeding, domesticated and wild Atlantic salmon are genetically diverged, which raises concerns about farmed escapees having the potential to alter the genetic composition of wild populations and thereby disrupting local adaptation. Documenting transcriptional differences between wild and domesticated stocks under controlled conditions is one way to explore the consequences of domestication and selection. We compared the transcriptomes of wild and domesticated Atlantic salmon embryos, by using a custom 44k oligonucleotide microarray to identify perturbed gene pathways between the two stocks, and to document the inheritance patterns of differentially-expressed genes by examining gene expression in their reciprocal hybrids. RESULTS: Data from 24 array interrogations were analysed: four reciprocal cross types (W? * W?, D? * W?; W? * D?, D? * D?) * six biological replicates. A common set of 31,491 features on the microarrays passed quality control, of which about 62 % were assigned a KEGG Orthology number. A total of 6037 distinct genes were identified for gene-set enrichment/pathway analysis. The most highly enriched functional groups that were perturbed between the two stocks were cellular signalling and immune system, ribosome and RNA transport, and focal adhesion and gap junction pathways, relating to cell communication and cell adhesion molecules. Most transcripts that were differentially expressed between the stocks were governed by additive gene interaction (33 to 42 %). Maternal dominance and over-dominance were also prevalent modes of inheritance, with no convincing evidence for a stock effect. CONCLUSIONS: Our data indicate that even at this relatively early developmental stage, transcriptional differences exist between the two stocks and affect pathways that are relevant to wild versus domesticated environments. Many of the identified differentially perturbed pathways are involved in organogenesis, which is expected to be an active process at the eyed egg stage. The dominant effects are more largely due to the maternal line than to the origin of the stock. This finding is particularly relevant in the context of potential introgression between farmed and wild fish, since female escapees tend to have a higher spawning success rate compared to males. PMID- 26987531 TI - Incorporating Biomarkers in Studies of Chemoprevention. AB - Despite Food and Drug Administration approval of tamoxifen and raloxifene for breast cancer risk reduction and endorsement by multiple agencies, uptake of these drugs for primary prevention in the United States is only 4% for risk eligible women likely to benefit from their use. Side effects coupled with incomplete efficacy and lack of a survival advantage are the likely reasons. This disappointing uptake, after the considerable effort and expense of large Phase III cancer incidence trials required for approval, suggests that a new paradigm is required. Current prevention research is focused on (1) refining risk prediction, (2) exploring behavioral and natural product interventions, and (3) utilizing novel translational trial designs for efficacy. Risk biomarkers will play a central role in refining risk estimates from traditional models and selecting cohorts for prevention trials. Modifiable risk markers called surrogate endpoint or response biomarkers will continue to be used in Phase I and II prevention trials to determine optimal dose or exposure and likely effectiveness from an intervention. The majority of Phase II trials will continue to assess benign breast tissue for response and mechanism of action biomarkers. Co-trials are those in which human and animal cohorts receive the same effective dose and the same tissue biomarkers are assessed for modulation due to the intervention, but then additional animals are allowed to progress to cancer development. These collaborations linking biomarker modulation and cancer prevention may obviate the need for cancer incidence trials for non-prescription interventions. PMID- 26987532 TI - Breast Molecular Profiling and Radiotherapy Considerations. AB - The last decade has seen major changes in the management of breast cancer. Heterogeneity regarding histology, therapeutic response, dissemination patterns, and patient outcome is evident. Molecular profiling provides an accurate tool to predict treatment outcome compared with classical clinicopathologic features. The genomic profiling unveiled the heterogeneity of breast cancer and identified distinct biologic subtypes. These advanced techniques were integrated into the clinical management; predicting systemic therapy benefit and overall survival. Utilizing genotyping to guide locoregional management decisions needs further characterization. In this chapter we will review available data on molecular classification of breast cancer, their association with locoregional outcome, their radiobiological properties and radiotherapy considerations. PMID- 26987534 TI - Biomarkers for Predicting Response to Anti-HER2 Agents. AB - The HER2 receptor is amplified or overexpressed in approximately 20% of all breast cancers, but despite significant efforts of the clinical research community and a growing number of anti-HER2 agents, a significant number of patients with HER2-positive breast cancer either progress or suffer disease relapse within 5-10 years. The development of robust biomarkers that predict response to anti-HER2 agents is therefore an important clinical need to prevent overtreatment and to enable earlier assignment of patients to more optimal therapies. Here we review some of the recent advances in the field by focusing on pathways mediating resistance to anti-HER2 therapies, and the role of the immune system and cancer stem cells in therapy response. We also review preoperative treatment strategies and research paradigms that show promise in identifying novel biomarkers of response while also enabling the delineation of the mechanisms underlying clinical benefit from anti-HER2 therapies. PMID- 26987533 TI - Prognostic and Predictive Biomarkers of Endocrine Responsiveness for Estrogen Receptor Positive Breast Cancer. AB - The estrogen-dependent nature of breast cancer is the fundamental basis for endocrine therapy. The presence of estrogen receptor (ER), the therapeutic target of endocrine therapy, is a prerequisite for this therapeutic approach. However, estrogen-independent growth often exists de novo at diagnosis or develops during the course of endocrine therapy. Therefore ER alone is insufficient in predicting endocrine therapy efficacy. Several RNA-based multigene assays are now available in clinical practice to assess distant recurrence risk, with majority of these assays evaluated in patients treated with 5 years of adjuvant endocrine therapy. While MammaPrint and Oncotype Dx are most predictive of recurrence risk within the first 5 years of diagnosis, Prosigna, Breast Cancer Index (BCI), and EndoPredict Clin have also demonstrated utility in predicting late recurrence. In addition, PAM50, or Prosigna, provides further biological insights by classifying breast cancers into intrinsic molecular subtypes. Additional strategies are under investigation in prospective clinical trials to differentiate endocrine sensitive and resistant tumors and include on-treatment Ki-67 and Preoperative Endocrine Prognostic Index (PEPI) score in the setting of neoadjuvant endocrine therapy. These biomarkers have become important tools in clinical practice for the identification of low risk patients for whom chemotherapy could be avoided. However, there is much work ahead toward the development of a molecular classification that informs the biology and novel therapeutic targets in high risk disease as chemotherapy has only modest benefit in this population. The recognition of somatic mutations and their relationship to endocrine therapy responsiveness opens important opportunities toward this goal. PMID- 26987529 TI - Genomic Biomarkers for Breast Cancer Risk. AB - Clinical risk assessment for cancer predisposition includes a three-generation pedigree and physical examination to identify inherited syndromes. Additionally genetic and genomic biomarkers may identify individuals with a constitutional basis for their disease that may not be evident clinically. Genomic biomarker testing may detect molecular variations in single genes, panels of genes, or entire genomes. The strength of evidence for the association of a genomic biomarker with disease risk may be weak or strong. The factors contributing to clinical validity and utility of genomic biomarkers include functional laboratory analyses and genetic epidemiologic evidence. Genomic biomarkers may be further classified as low, moderate or highly penetrant based on the likelihood of disease. Genomic biomarkers for breast cancer are comprised of rare highly penetrant mutations of genes such as BRCA1 or BRCA2, moderately penetrant mutations of genes such as CHEK2, as well as more common genomic variants, including single nucleotide polymorphisms, associated with modest effect sizes. When applied in the context of appropriate counseling and interpretation, identification of genomic biomarkers of inherited risk for breast cancer may decrease morbidity and mortality, allow for definitive prevention through assisted reproduction, and serve as a guide to targeted therapy . PMID- 26987536 TI - Pharmacogenetic Predictors of Response. AB - Pharmacogenetics attempts to predict treatment response using a patient's "germline" genome as the biomarker of interest. This chapter on pharmacogenetic predictors of breast cancer response is divided into four sections. The first introduces readers to genetic variation and describes how variation in the germline genome can affect biology or pharmacology. The second section introduces the translational pathway for pharmacogenetic research and discusses the specific challenges to identifying pharmacogenetic predictors of breast cancer response. The third section is divided into three subsections, each of which discusses a distinct category of pharmacogenetic response predictors; pharmacokinetics, cancer cell sensitivity, and effector cell activation. Within each subsection a specific pharmacogenetic association is described in detail; CYP2D6-tamoxifen, BRCA-PARP inhibitors, and FCGRA-trastuzumab, respectively, followed by a general discussion of other less well-established examples or areas for further research. The chapter concludes with a summary of the current status of pharmacogenetic predictors of breast cancer response and a few predictions for the future of this field. PMID- 26987530 TI - Epigenetic Biomarkers of Breast Cancer Risk: Across the Breast Cancer Prevention Continuum. AB - Epigenetic biomarkers, such as DNA methylation, can increase cancer risk through altering gene expression. The Cancer Genome Atlas (TCGA) Network has demonstrated breast cancer-specific DNA methylation signatures. DNA methylation signatures measured at the time of diagnosis may prove important for treatment options and in predicting disease-free and overall survival (tertiary prevention). DNA methylation measurement in cell free DNA may also be useful in improving early detection by measuring tumor DNA released into the blood (secondary prevention). Most evidence evaluating the use of DNA methylation markers in tertiary and secondary prevention efforts for breast cancer comes from studies that are cross sectional or retrospective with limited corresponding epidemiologic data, raising concerns about temporality. Few prospective studies exist that are large enough to address whether DNA methylation markers add to the prediction of tertiary and secondary outcomes over and beyond standard clinical measures. Determining the role of epigenetic biomarkers in primary prevention can help in identifying modifiable pathways for targeting interventions and reducing disease incidence. The potential is great for DNA methylation markers to improve cancer outcomes across the prevention continuum. Large, prospective epidemiological studies will provide essential evidence of the overall utility of adding these markers to primary prevention efforts, screening, and clinical care. PMID- 26987535 TI - Intratumor Heterogeneity in Breast Cancer. AB - Intratumor heterogeneity is the main obstacle to effective cancer treatment and personalized medicine. Both genetic and epigenetic sources of intratumor heterogeneity are well recognized and several technologies have been developed for their characterization. With the technological advances in recent years, investigators are now elucidating intratumor heterogeneity at the single cell level and in situ. However, translating the accumulated knowledge about intratumor heterogeneity to clinical practice has been slow. We are certain that better understanding of the composition and evolution of tumors during disease progression and treatment will improve cancer diagnosis and the design of therapies. Here we review some of the most important considerations related to intratumor heterogeneity. We discuss both genetic and epigenetic sources of intratumor heterogeneity and review experimental approaches that are commonly used to quantify it. We also discuss the impact of intratumor heterogeneity on cancer diagnosis and treatment and share our perspectives on the future of this field. PMID- 26987537 TI - Metabolomics in Breast Cancer: Current Status and Perspectives. AB - Metabolomics refers to the study of the whole set of metabolites in a biological sample that constitute a reflection of cellular functions. Cancer cells display significantly altered cellular processes, and thus metabolites, compared to normal cells. This can be detected in a number of ways, and is already exploited to a limited extent in the diagnosis of cancer. The host response to the tumor is perhaps equally important, as it either rejects or permits tumor growth, and this may also potentially result in a measurable metabolite signature. Analysis then of entire pools of metabolites may yield critical information about both tumor presence and host response, and represent a possible novel collective biomarker for cancer behaviour that could allow prediction of relapse, response to therapy, or progression. Isolating meaningful differences in the sea of metabolites and within the context of significant metabolic heterogeneity both within and between patients remains a great challenge. This chapter will review current metabolomic research in breast cancer, with a focus on efforts to translate the technology into clinical practice. PMID- 26987538 TI - Circulating Tumor Cells. AB - Circulating Tumor Cells (CTC) are shed from primary or secondary tumors. Prior studies have demonstrated that enumeration of CTC is a robust independent prognostic factor of progression free and overall survival in patients with early and metastatic breast cancer. CTC, as well as other circulating tumor markers, have the appealing advantages over tissue biopsy of (1) ease of collection, (2) serial evaluation, and (3) interrogation of the entire tumor burden instead of just a limited part of the tumor. Advances have been recently made in phenotyping and genotyping of CTC, which should provide insights into the predictive role of CTC for sensitivity or resistance to therapies. In addition, CTC phenotypic marker changes during the course of treatment may serve as pharmacodynamic monitoring tools. Therefore, CTC may be considered "liquid biopsies," providing prognostic and predictive clinical information as well as additional understanding of tumor heterogeneity. PMID- 26987539 TI - Circulating Plasma Tumor DNA. AB - Circulating cell-free DNA (ccfDNA)--first identified in 1947--is "naked" DNA that is free-floating in the blood, and derived from both normal and diseased cells. In the 1970s, scientists observed that patients with cancer had elevated levels of ccfDNA as compared to their healthy, cancer-free counterparts. The maternal fetal medicine community first developed techniques to identify the small fraction of fetal-derived ccfDNA for diagnostic purposes. Similarly, due to the presence of tumor-specific (somatic) variations in all cancers, the fraction of circulating cell-free plasma tumor DNA (ptDNA) in the larger pool of ccfDNA derived from normal cells can serve as extremely specific blood-based biomarkers for a patient's cancer. In theory this "liquid biopsy" can provide a real-time assessment of molecular tumor genotype (qualitative) and existing tumor burden (quantitative). Historically, the major limitation for ptDNA as a biomarker has been related to a low detection rate; however, current and developing techniques have improved sensitivity dramatically. In this chapter, we discuss these methods, including digital polymerase chain reaction and various approaches to tagged next-generation sequencing. PMID- 26987540 TI - Exposure Assessment to Environmental Chemicals in Children from Ciudad Juarez, Chihuahua, Mexico. AB - It has been demonstrated that the human biomonitoring of susceptible populations is a valuable method for the identification of critical contaminants. Therefore, the purpose of this study was to assess the exposure profile for arsenic (As), lead (Pb), mercury (Hg), 1-hydroxypyrene (1-OHP), 1,1-bis(p-chlorophenyl)-2,2,2 trichloroethane (DDT), 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (DDE), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs) in children living in Ciudad Juarez, Chihuahua, Mexico (a major manufacturing center in Mexico). In 2012, we evaluated a total of 135 healthy children living in Ciudad Juarez since birth. The total PBDEs levels ranged from nondetectable (< LOD) to 215 ng/g lipid, with a mean total PBDEs level of 29.5 +/- 53.0 ng/g lipid (geometric mean +/- standard deviation). The mean total PCBs level in the study participants was 29.0 +/- 10.5 ng/g lipid (range 4.50-50.0 ng/g lipid). The mean concentration of total DDT (DDT + DDE) was 11.9 +/- 6.70 ng/g lipid (range 3.00 26.0 ng/g lipid). The mean 1-OHP levels was 1.2 +/- 1.1 umol/mol creatinine (range =3 falls) performed significantly worse in the CSRT test than non-frequent fallers (0-2 falls). With the odds of suffering frequent falls increasing 69% with each SD increase in CSRT (OR = 1.69, 95% CI: 1.27-2.26, p = <0.001). In regression analysis, CSRT was best explained by sway, time to complete the 9-Hole Peg test, knee extension strength of the weaker leg, proprioception and the time to complete the Trails B test (multiple R2 = 0.449, p < 0.001). Conclusions A simple low tech CSRT test has excellent discriminative and predictive validity in relation to falls in people with MS. This test may prove useful in documenting longitudinal changes in fall risk in relation to MS disease progression and effects of interventions. Implications for rehabilitation Good choice stepping reaction time (CSRT) is required for maintaining balance. A simple low-tech CSRT test has excellent discriminative and predictive validity in relation to falls in people with MS. This test may prove useful documenting longitudinal changes in fall risk in relation to MS disease progression and effects of interventions. PMID- 26987548 TI - High pressure and temperature equation of state and spectroscopic study of CeO2. AB - One of the most widely used x-ray standards and a highly applied component of catalysis systems, CeO2 has been studied for the purpose of better understanding its equation of state and electronic properties. Diamond anvil cells have been used to extend the equation of state for this material to 130 GPa and explore the electronic behavior with applied load. From the x-ray diffraction studies, it has been determined that the high pressure phase transition extends from approximately 35-75 GPa at ambient temperature. Elevation of temperature is found to decrease the initiation pressure for this transition, with multiple distinct temperature regions which indicate structural related anomalies. In addition, hydrostatic and non-hydrostatic effects are compared and exhibit a drastic difference in bulk moduli. The electronic results indicate a change in the scattering environment of the cerium atom, associated with the high pressure phase transition. Overall, these results present the first megabar pressure study and the first high pressure and temperature study of ceria. Additionally, this shows the first combined study of the K and L III edges of this material to 33 GPa. PMID- 26987547 TI - The influence of chronic kidney disease and age on revascularization rates and outcomes in acute myocardial infarction - a cohort study. AB - BACKGROUND: There is a paucity of data on the complex interaction between chronic kidney disease, age and its impact on management and outcomes in acute myocardial infarction. METHODS: A state based claims dataset that collects data on all hospitalizations (representing 32.3% of the Australian population) was used to identify all patients admitted with a principal diagnosis of acute myocardial infarction (ICD10 codes: I21.0-I21.4) over a four-year period. Patients were linked to the state death registry and followed until death or end of follow-up (31 December 2009). Chronic kidney disease was defined as the presence of any of 65 ICD10 diagnostic codes for chronic kidney disease. The primary outcomes were receipt of revascularization, length of hospital stay and mortality adjusted for age, comorbidities and prior revascularization at presentation. RESULTS: Of the 40,472 patients with acute myocardial infarction, chronic kidney disease was present in 4814 patients (11.9%). Median follow-up was 2.8 years (range 0-5.5 years). In the multivariable model, there was a marked interaction between chronic kidney disease and age ( p<0.001). Chronic kidney disease was a powerful marker of lower revascularization rates (median age group of 70-79 years: odds ratio 0.68; 95% confidence interval 0.59-0.78; p<0.001), especially in those over the age of 50 years. The impact of chronic kidney disease on length of stay (median age group of 70-79 years vs. referent age group 18-39 years: incidence rate ratio 1.41; 95% confidence interval 1.32-1.51; p<0.001) and long-term mortality (median age group of 70-79 years: hazard ratio 2.19; 95% confidence interval 2.01-2.39; p<0.001) was mitigated with increasing age. CONCLUSION: Chronic kidney disease is an important deterrent for the receipt of revascularization in older patients, but age is the primary determinant of length of stay and mortality. PMID- 26987549 TI - Sugar tax will double funding for sport in primary schools, says chancellor. PMID- 26987550 TI - Enzyme classification using complex dynamic hemithioacetal systems. AB - A complex dynamic hemithioacetal system was generated for the evaluation of lipase reactivities in organic media. In combination with pattern recognition methodology, twelve different lipases were successfully classified into four distinct groups following their reaction selectivities and reactivities. A probe lipase was further categorized using the training matrix with predicted reactivity. PMID- 26987551 TI - Twenty years of enamel matrix derivative: the past, the present and the future. AB - BACGROUND: On June 5th, 2015 at Europerio 8, a group of leading experts were gathered to discuss what has now been 20 years of documented evidence supporting the clinical use of enamel matrix derivative (EMD). Original experiments led by Lars Hammarstrom demonstrated that enamel matrix proteins could serve as key regenerative proteins capable of promoting periodontal regeneration including new cementum, with functionally oriented inserting new periodontal ligament fibres, and new alveolar bone formation. This pioneering work and vision by Lars Hammarstrom has paved the way to an enormous amount of publications related to its biological basis and clinical use. Twenty years later, it is clear that all these studies have greatly contributed to our understanding of how biologics can act as mediators for periodontal regeneration and have provided additional clinical means to support tissue regeneration of the periodontium. AIMS: This review article aims to: (1) provide the biological background necessary to understand the rational for the use of EMD for periodontal regeneration, (2) present animal and human histological evidence of periodontal regeneration following EMD application, (3) provide clinically relevant indications for the use of EMD and (4) discuss future avenues of research including key early findings leading to the development of Osteogain, a new carrier system for EMD specifically developed with better protein adsorption to bone grafting materials. PMID- 26987553 TI - A multimodal imaging workflow to visualize metal mixtures in the human placenta and explore colocalization with biological response markers. AB - Fetal exposure to essential and toxic metals can influence life-long health trajectories. The placenta regulates chemical transmission from maternal circulation to the fetus and itself exhibits a complex response to environmental stressors. The placenta can thus be a useful matrix to monitor metal exposures and stress responses in utero, but strategies to explore the biologic effects of metal mixtures in this organ are not well-developed. In this proof-of-concept study, we used laser ablation-inductively coupled plasma-mass spectrometry (LA ICP-MS) to measure the distributions of multiple metals in placental tissue from a low-birth-weight pregnancy, and we developed an approach to identify the components of metal mixtures that colocalized with biological response markers. Our novel workflow, which includes custom-developed software tools and algorithms for spatial outlier identification and background subtraction in multidimensional elemental image stacks, enables rapid image processing and seamless integration of data from elemental imaging and immunohistochemistry. Using quantitative spatial statistics, we identified distinct patterns of metal accumulation at sites of inflammation. Broadly, our multiplexed approach can be used to explore the mechanisms mediating complex metal exposures and biologic responses within placentae and other tissue types. Our LA-ICP-MS image processing workflow can be accessed through our interactive R Shiny application 'shinyImaging', which is available at or through our laboratory's website, . PMID- 26987554 TI - Least-Squares Regression and Spectral Residual Augmented Classical Least-Squares Chemometric Models for Stability-Indicating Analysis of Agomelatine and Its Degradation Products: A Comparative Study. AB - Two accurate, sensitive, and selective stability-indicating methods are developed and validated for simultaneous quantitative determination of agomelatine (AGM) and its forced degradation products (Deg I and Deg II), whether in pure forms or in pharmaceutical formulations. Partial least-squares regression (PLSR) and spectral residual augmented classical least-squares (SRACLS) are two chemometric models that are being subjected to a comparative study through handling UV spectral data in range (215-350 nm). For proper analysis, a three-factor, four level experimental design was established, resulting in a training set consisting of 16 mixtures containing different ratios of interfering species. An independent test set consisting of eight mixtures was used to validate the prediction ability of the suggested models. The results presented indicate the ability of mentioned multivariate calibration models to analyze AGM, Deg I, and Deg II with high selectivity and accuracy. The analysis results of the pharmaceutical formulations were statistically compared to the reference HPLC method, with no significant differences observed regarding accuracy and precision. The SRACLS model gives comparable results to the PLSR model; however, it keeps the qualitative spectral information of the classical least-squares algorithm for analyzed components. PMID- 26987552 TI - Anaerobic microbial community response to methanogenic inhibitors 2 bromoethanesulfonate and propynoic acid. AB - Methanogenic inhibitors are often used to study methanogenesis in complex microbial communities or inhibit methanogens in the gastrointestinal tract of livestock. However, the resulting structural and functional changes in archaeal and bacterial communities are poorly understood. We characterized microbial community structure and activity in mesocosms seeded with cow dung and municipal wastewater treatment plant anaerobic digester sludge after exposure to two methanogenic inhibitors, 2-bromoethanesulfonate (BES) and propynoic acid (PA). Methane production was reduced by 89% (0.5 mmol/L BES), 100% (10 mmol/LBES), 24% (0.1 mmol/LPA), and 95% (10 mmol/LPA). Using modified primers targeting the methyl-coenzyme M reductase (mcrA) gene, changes in mcrA gene expression were found to correspond with changes in methane production and the relative activity of methanogens. Methanogenic activity was determined by the relative abundance of methanogen 16S rRNA cDNA as a percentage of the total community 16S rRNA cDNA. Overall, methanogenic activity was lower when mesocosms were exposed to higher concentrations of both inhibitors, and aceticlastic methanogens were inhibited to a greater extent than hydrogenotrophic methanogens. Syntrophic bacterial activity, measured by 16S rRNA cDNA, was also reduced following exposure to both inhibitors, but the overall structure of the active bacterial community was not significantly affected. PMID- 26987555 TI - Pre-caruncular approach to the medial orbit and landmarks for anterior ethmoidal artery ligation: a cadaveric study. AB - OBJECTIVE: In epistaxis and skull base surgery, the anterior ethmoidal artery sometimes needs to be ligated. We describe a novel, quick and scar-free surgical technique to ligate this artery with salient landmarks allowing rapid identification. PATIENTS AND METHODS: Twenty medial orbital walls from 10 randomly selected fresh-frozen, non-formalinised cadaver heads were examined. Dissection was performed by a pre-caruncular external approach to expose the AEA in all cases. RESULTS: The Horner's muscle and nasion, two salient landmarks, have been identified for use during the pre-caruncular approach. DISCUSSION/CONCLUSION: The pre-caruncular approach is a novel combined open and endoscopic surgical approach to the anterior ethmoidal artery. It is a simple, quick and scar-free technique. The identification of the artery is easy when using the two anatomic landmarks we describe in our study, that is Horner's muscle and the nasion. PMID- 26987556 TI - Hepatitis B in Ghana: a systematic review & meta-analysis of prevalence studies (1995-2015). AB - BACKGROUND: Although, chronic hepatitis B (HBV) is considered to be of significant public health importance in Ghana, not many reviews detailing the burden (prevalence) of the disease have been conducted. This study was aimed at summarizing the available information and to make an accurate estimate of HBV infection prevalence in Ghana over the last two decades (1995-2015). METHODS: A systematic search was conducted in PubMed, ScienceDirect, Google Scholar and Africa Journals Online (AJOL) databases to retrieve primary studies published between 1st January 1995 and 4th October 2015, assessing the prevalence of HBV among populations in Ghana. This was supplemented by a manual search of retrieved references. RESULTS: Thirty (30) studies across all the ten (10) regions of Ghana and involving an overall population size of 105,435 were analyzed. The national prevalence of HBV as determined by HBsAg seropositivity was 12.3%. HBV prevalence among voluntary blood donors (VBDs), replacement blood donors (RBDs) and pregnant women were 10.8, 12.7 and 13.1% respectively. HBV infection prevalence was highest among studies published within the period 1995-2002 (17.3%), followed by those published within 2003-2009 (14.7%) and the lowest prevalence rate being recorded across studies published in the period 2010-2015 (10.2%). Regional prevalence were determined for Ashanti, Greater Accra, Eastern, Northern, central and Brong-Ahafo regions as 13.1, 10.6, 13.6, 13.1, 11.5 and 13.7% respectively. No aggregate data were derived for Volta, Western, Upper East and Upper West regions. Higher prevalence of HBV infection was attained for rural (13.3%) compared to urban settings (12.2%). Across the country, highest HBV infection prevalence rates were recorded in persons within the age group 16-39 years. CONCLUSION: Hepatitis B infection is clearly an important public health problem in Ghana. The burden of the disease as dictated by a high prevalence rate calls for urgent public health interventions and strategic policy directions to controlling the disease to avert any potential future explosion. PMID- 26987559 TI - Skin surgery, an evidence-based update: meeting report. AB - The Evidence Based Update on Skin Surgery was held in Nottingham in May 2015. The meeting featured presentations on new diagnostic techniques, trials in development, discussions of recently published trials, and a question and answer session with an expert panel. This report aims to summarize the presentations and discussions from the day. PMID- 26987558 TI - The height-, weight- and BMI-for-age of preschool children from Nizhny Novgorod city, Russia, relative to the international growth references. AB - BACKGROUND: Monitoring a child's growth status helps to diagnose diseases and implement curative and preventive measures. The aim of this study was to assess how well preschool children of Russian city (Nizhny Novgorod) match with, or diverge from, international growth charts (WHO2006,2007; USCDC2000). METHODS: Cross-sectional study included 3,130 children aged 3-7 years attending municipal preschools of Nizhny Novgorod, the city in the European part of Russia. The study was held from February 2012 to October 2013. The international WHO2006,2007 and USCDC2000 growth references were used to calculate the height, weight and BMI z scores. The distributions of z-scores were analysed with descriptive and inferential statistical methods. Z-score equal 0.25 was considered as a benchmark for clinically significant differences. RESULTS: Means height z-scores calculated with the use of WHO2006, 2007 and USCDC2000 references were above the 50th centile (0.13 - 0.47) for both boys and girls. The means height z-scores was less than 0.25 SD above the 50th centile only for WHO2006. Stunting prevalence (the height-for-age z-score less than -2) was slightly higher under WHO2006 (3-4%) than under USCDC 2000 (2-3%). Stunting prevalence among children aged 5-7 years was similar under WHO2007 and USCDC2000 references (1%). For boys and girls aged 3-4 years the thinness prevalence, using WHO2006 was 2%, using USCDC2000 was 6% (p < 0.05). At the age 5-7 years this proportion under WHO2007 was 3% in both sex groups, under USCDC2000 was 8% for boys and 6% for girls (p < 0.05). A proportion of preschoolers aged 3-4 years with overweight was slightly higher under WHO2006 reference (13-15%) than under USCDC2000 (12-14%). In the case of age 5-7 years the overweight prevalence under WHO2007 (13-12 %) was lower than under USCDC2000 (14%). Obesity prevalence under WHO2006,2007 (3-4%) was slightly higher than that under USCDC2000 reference (2-3%). Preschoolers' distribution by groups of normal weight, overweight, obesity didn't significantly differ among the references (chi square). CONCLUSIONS: The growth assessment of children aged 3-7 years attending municipal preschools of the Russian city Nizhny Novgorod under the international references (WHO2006,2007; USCDC 2000), demonstrated that the height fit to the WHO2006 standard for the children aged 3 and 4 was generally fine, since all the mean values were within 0.25 of the standard deviations of the mean. Beyond the age of 5 the fit to the WHO2007 was poor while the fit to the USCDC2000 was poor throughout. PMID- 26987557 TI - Normative NeuroFlexor data for detection of spasticity after stroke: a cross sectional study. AB - BACKGROUND AND OBJECTIVE: The NeuroFlexor is a novel instrument for quantification of neural, viscous and elastic components of passive movement resistance. The aim of this study was to provide normative data and cut-off values from healthy subjects and to use these to explore signs of spasticity at the wrist and fingers in patients recovering from stroke. METHODS: 107 healthy subjects (age range 28-68 years; 51 % females) and 39 stroke patients (age range 33-69 years; 33 % females), 2-4 weeks after stroke, were assessed with the NeuroFlexor. Cut-off values based on mean + 3SD of the reference data were calculated. In patients, the modified Ashworth scale (MAS) was also applied. RESULTS: In healthy subjects, neural component was 0.8 +/- 0.9 N (mean +/- SD), elastic component was 2.7 +/- 1.1 N, viscous component was 0.3 +/- 0.3 N and resting tension was 5.9 +/- 1 N. Age only correlated with elastic component (r = 0.3, p = 0.01). Elasticity and resting tension were higher in males compared to females (p = 0.001) and both correlated positively with height (p = 0.01). Values above healthy population cut-off were observed in 16 patients (41 %) for neural component, in 2 (5 %) for elastic component and in 23 (59 %) for viscous component. Neural component above cut-off did not correspond well to MAS ratings. Ten patients with MAS = 0 had neural component values above cut-off and five patients with MAS >= 1 had neural component within normal range. CONCLUSION: This study provides NeuroFlexor cut-off values that are useful for detection of spasticity in the early phase after stroke. PMID- 26987560 TI - Effect of individual thinking styles on item selection during study time allocation. AB - The influence of individual differences on learners' study time allocation has been emphasised in recent studies; however, little is known about the role of individual thinking styles (analytical versus intuitive). In the present study, we explored the influence of individual thinking styles on learners' application of agenda-based and habitual processes when selecting the first item during a study-time allocation task. A 3-item cognitive reflection test (CRT) was used to determine individuals' degree of cognitive reliance on intuitive versus analytical cognitive processing. Significant correlations between CRT scores and the choices of first item selection were observed in both Experiment 1a (study time was 5 seconds per triplet) and Experiment 1b (study time was 20 seconds per triplet). Furthermore, analytical decision makers constructed a value-based agenda (prioritised high-reward items), whereas intuitive decision makers relied more upon habitual responding (selected items from the leftmost of the array). The findings of Experiment 1a were replicated in Experiment 2 notwithstanding ruling out the possible effects from individual intelligence and working memory capacity. Overall, the individual thinking style plays an important role on learners' study time allocation and the predictive ability of CRT is reliable in learners' item selection strategy. PMID- 26987562 TI - Synthesis and structure elucidation of a series of chloroquinoline-2-chalcones by the Doebner-Miller reaction. PMID- 26987563 TI - The effect of Cu doping on the mechanical and optical properties of zinc oxide nanowires synthesized by hydrothermal route. AB - Zinc oxide (ZnO) is a wide-bandgap semiconductor material with applications in a variety of fields such as electronics, optoelectronic and solar cells. However, much of these applications demand a reproducible, reliable and controllable synthesis method that takes special care of their functional properties. In this work ZnO and Cu-doped ZnO nanowires are obtained by an optimized hydrothermal method, following the promising results which ZnO nanostructures have shown in the past few years. The morphology of as-prepared and copper-doped ZnO nanostructures is investigated by means of scanning electron microscopy and high resolution transmission electron microscopy. X-ray diffraction is used to study the impact of doping on the crystalline structure of the wires. Furthermore, the mechanical properties (nanoindentation) and the functional properties (absorption and photoluminescence measurements) of ZnO nanostructures are examined in order to assess their applicability in photovoltaics, piezoelectric and hybrids nanodevices. This work shows a strong correlation between growing conditions, morphology, doping and mechanical as well as optical properties of ZnO nanowires. PMID- 26987564 TI - Sensitivity of the Standard Chlamydia trachomatis Culture Method Is Improved After One Additional In Vitro Passage. AB - BACKGROUND: Chlamydia trachomatis causes the most common bacterial sexually transmitted infection (STI) worldwide. Although highly sensitive nucleic acid amplification tests (NAATs) are used to routinely diagnose chlamydial infection, C. trachomatis isolation by cell culture is still preferred for legal cases and epidemiological studies because of its high specificity; however, the sensitivity of traditional two-passage diagnostic cultures is significantly lower than that of NAATs. Therefore, we sought to analyze if additional in vitro passaging of clinical samples would improve detection sensitivity of C. trachomatis. METHODS: Clinical swabs (n = 428) were collected from Tianjin Medical University General Hospital, grown in McCoy cells for up to five passages, and analyzed for the presence of inclusions by iodine staining. Results were confirmed by routine PCR based methods. RESULTS: Viable C. trachomatis organisms were detected in 91 (21.26%) swabs with the traditional two-passage protocol, which increased to 145 (33.88%) and 149 (34.81%) following three and four passages, respectively. Thus, the standard protocol yielded a false-negative rate of nearly 39%. Subsequent PCR based diagnostics revealed a concordance rate of 80.98% between these two methods without any false negatives. CONCLUSION: The results of this study support the use of a three-passage Chlamydia culture procedure to increase the detection sensitivity of this method. PMID- 26987561 TI - Aminothiazoles inhibit RANKL- and LPS-mediated osteoclastogenesis and PGE2 production in RAW 264.7 cells. AB - Periodontitis is characterized by chronic inflammation and osteoclast-mediated bone loss regulated by the receptor activator of nuclear factor-kappaB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG). The aim of this study was to investigate the effect of aminothiazoles targeting prostaglandin E synthase-1 (mPGES-1) on RANKL- and lipopolysaccharide (LPS)-mediated osteoclastogenesis and prostaglandin E2 (PGE2 ) production in vitro using the osteoclast precursor RAW 264.7 cells. RAW 264.7 cells were treated with RANKL or LPS alone or in combination with the aminothiazoles 4-([4-(2-naphthyl)-1,3-thiazol-2 yl]amino)phenol (TH-848) or 4-(3-fluoro-4-methoxyphenyl)-N-(4-phenoxyphenyl)-1,3 thiazol-2-amine (TH-644). Aminothiazoles significantly decreased the number of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclast like cells in cultures of RANKL- and LPS-stimulated RAW 264.7 cells, as well as reduced the production of PGE2 in culture supernatants. LPS-treatment induced mPGES-1 mRNA expression at 16 hrs and the subsequent PGE2 production at 72 hrs. Conversely, RANKL did not affect PGE2 secretion but markedly reduced mPGES-1 at mRNA level. Furthermore, mRNA expression of TRAP and cathepsin K (CTSK) was reduced by aminothiazoles in RAW 264.7 cells activated by LPS, whereas RANK, OPG or tumour necrosis factor alpha mRNA expression was not significantly affected. In RANKL-activated RAW 264.7 cells, TH-848 and TH-644 down-regulated CTSK but not TRAP mRNA expression. Moreover, the inhibitory effect of aminothiazoles on PGE2 production was also confirmed in LPS-stimulated human peripheral blood mononuclear cell cultures. In conclusion, the aminothiazoles reduced both LPS- and RANKL-mediated osteoclastogenesis and PGE2 production in RAW 264.7 cells, suggesting these compounds as potential inhibitors for treatment of chronic inflammatory bone resorption, such as periodontitis. PMID- 26987565 TI - Structural Hierarchy and Polymorphic Transformation in Shear-Induced Shish-Kebab of Stereocomplex Poly(Lactic Acid). AB - The realization of hierarchical shish-kebab structures for stereocomplex poly(lactic acid) (PLA) is achieved by the application of a shear flow (100 s(-1) for 1 s) mimicking what can be expected during polymer processing. Compared to the normal shearing scenarios, this transient and strong shear flow enables the creation of dense shish precursors in time- and energy-saving manner. The distribution of crystal form associated with the hierarchical structure is revealed by 2D Fourier transform infrared spectroscopy imaging, creating a unique visualization for both spatial resolution and polymorphism identification. Interestingly, in the shear stereocomplex chains are preferentially extended and crystallized as stable central cores with weak temperature dependence, whereas the development of lateral kebabs is defined by the distinct relation to the crystallization temperature. Below the melting point of homocrystals, both homo and stereocomplex crystallization are engaged in lamellar packing. Above that, exclusive stereocomplex crystals are organized into ordered lamellae. Combining the direct observations at multiscale, the ordered alignment of stereocomplex chains is recognized as the molecular origin of fibrillar extended chain bundles that constitute the central row-nuclei. The proposed hypothesis affords elucidation of shish-kebab formation and unique polymorphism in sheared stereocomplex PLA, which generates opportunities for engendering hierarchically structured PLA with improved performance. PMID- 26987566 TI - Developing indicators to measure post-disaster community recovery in the United States. AB - Disaster recovery is a key capability of federal, state, and local government. To support this capability effectively practitioners need useful and validated metrics to document how well a community is recovering from a particular disaster. This study developed and categorised recovery indicators according to the Federal Emergency Management Agency (FEMA)'s Recovery Support Functions and Recovery Mission Area Core Capabilities through a literature review, an evaluation of the pre-disaster recovery plans for 87 coastal jurisdictions, and a case study of two communities (New Hanover County, North Carolina, and the City of Hoboken, New Jersey). Metrics identified in the literature were validated through the recovery plan review and the case study. The research team also identified sources for both baseline and current status data. Based on these findings, a user-friendly checklist for practitioners was established, which will be piloted with practice partners during a future disaster recovery initiative. PMID- 26987568 TI - A Collapsed Sportsman With a Shock Advised in Sinus Rhythm: The Importance of Automated External Defibrillator Rhythm Strip Retrieval Prior to Defibrillator Implantation. PMID- 26987567 TI - Relationship Between Arrhythmogenic Right Ventricular Cardiomyopathy and Brugada Syndrome: New Insights From Molecular Biology and Clinical Implications. PMID- 26987569 TI - The Experience of Postnatal Depression in Immigrant Mothers Living in Western Countries: A Meta-Synthesis. AB - BACKGROUND: Postnatal depression affects women from all cultures and countries. The postnatal period is thought to be a vulnerable time for all mothers. Immigrant women may be at particular risk as they attempt to adhere to childbirth rituals in western societies which might exacerbate stress, while navigating through the multiple stressors they face from migration in the transition to motherhood. METHODS: This study utilized a meta-synthesis approach to synthesize qualitative studies exploring postnatal depression in immigrant mothers living in western countries. Searching six databases identified 16 studies that met criteria. RESULTS: The synthesis revealed two overarching themes of migration and cultural influences on immigrant mothers that interact and give rise to psychosocial understandings of postnatal depression, remedies and healthcare barriers. Mothers used self-help coping strategies in line with this. CONCLUSIONS: Immigrant mothers living in western countries are subject to multifactorial stressors following childbirth, increasing their susceptibility to postnatal depression. These stressors relate to being an immigrant in a western society and cultural influences, which may be harder to comply with, when removed from their sociocultural context. Social support appears to play a mediating role for these immigrant mothers. There were several similarities between immigrant and non-immigrant mothers including their views of healthcare and medication, their health-seeking behaviours and their fears of having their baby removed. All these findings have implications for healthcare settings in terms of assessments and service delivery. Copyright (c) 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: In this meta-synthesis, we explored the experience of postnatal depression in immigrant women living in western countries, including the UK, the USA and Canada. Sixteen qualitative studies were reviewed, and their methodological quality was examined. The findings are based a total sample of 337 women. Two overarching themes were identified that are termed 'cultural influences' and 'migration factors', which influenced how these mothers coped with their postnatal depression. Social support played a mediating role for these immigrant mothers. PMID- 26987570 TI - Immunocytochemical localization of kisspeptin and kisspeptin receptor in the primate testis. AB - BACKGROUND: Hypothalamic kisspeptin-kisspeptin receptor signalling in primates ensures the successful progression into puberty during development and maintenance of reproductive capacity during adulthood. Human testis has been shown to express high-to-moderate levels of kisspeptin and kisspeptin receptor gene expression. In this study, we aimed at characterizing the localization of kisspeptin and kisspeptin receptor in adult primate testis tissue. METHODS: Immunocytochemistry was performed on paraffin-embedded testicular sections from adult rhesus monkeys and from common marmoset monkeys. RESULTS: Kisspeptin receptor was detected in Sertoli cells in the periphery of the seminiferous tubules in adult testes of both species. In contrast, kisspeptin was not localized in the seminiferous epithelium and was detected only in the interstitial compartment of the adult rhesus monkey testis. CONCLUSION: Kisspeptin receptor and kisspeptin are localized in the testis of Old World and New World primates. PMID- 26987572 TI - Validation of the Turkish version of medication regimen complexity index among elderly patients. AB - OBJECTIVE: The aim of this study was to validate the Turkish version of the 'Medication Regimen Complexity Index' (MRCI). METHODS: This validation study has been conducted in prescriptions of the first 100 elderly patients who had visited the pharmacy for their prescription refill to evaluate convergent and divergent validity of the Turkish version. The reliability of the Turkish version was assessed with inter-rater and test-retest analysis after its translation and cultural adaptation. RESULTS: The mean age of the 100 patients (53 women) was 74.9 years (SD = 7.58, 65-95). The scale showed high inter-rater reliability and test-retest reliability for the total and subscale scores (p < 0.05). A strong and positive correlation between the number of medications in a prescription and the total Medication Regimen Complexity Index scores (r = 0.930, p < 0.001) was determined. There were no statistically significant differences between age, gender and MRCI scores (p > 0.05). CONCLUSION: These results show that the Turkish version of MRCI is a reliable and valid tool in elderly patients. PMID- 26987571 TI - Enhanced efficacy against cervical carcinomas through polymeric micelles physically incorporating the proteasome inhibitor MG132. AB - Treatment of recurrent or advanced cervical cancer is still limited, and new therapeutic choices are needed for improving prognosis and quality of life of patients. Because human papilloma virus (HPV) infection is critical in cervical carcinogenesis, with the E6 and E7 oncogenes of HPV degrading tumor suppressor proteins through the ubiquitin proteasome system, the inhibition of the ubiquitin proteasome system appears to be an ideal target to suppress the growth of cervical tumors. Herein, we focused on the ubiquitin proteasome inhibitor MG132 (carbobenzoxy-Leu-Leu-leucinal) as an anticancer agent against cervical cancer cells, and physically incorporated it into micellar nanomedicines for achieving selective delivery to solid tumors and improving its in vivo efficacy. These MG132-loaded polymeric micelles (MG132/m) showed strong tumor inhibitory in vivo effect against HPV-positive tumors from HeLa and CaSki cells, and even in HPV negative tumors from C33A cells. Repeated injection of MG132/m showed no significant toxicity to mice under analysis by weight change or histopathology. Moreover, the tumors treated with MG132/m showed higher levels of tumor suppressing proteins, hScrib and p53, as well as apoptotic degree, than tumors treated with free MG132. This enhanced efficacy of MG132/m was attributed to their prolonged circulation in the bloodstream, which allowed their gradual extravasation and penetration within the tumor tissue, as determined by intravital microscopy. These results support the use of MG132 incorporated into polymeric micelles as a safe and effective therapeutic strategy against cervical tumors. PMID- 26987573 TI - The elderly pancreas transplant recipient. PMID- 26987574 TI - Exclusive enteral nutrition in active pediatric Crohn disease: Effects on intestinal microbiota and immune regulation. PMID- 26987575 TI - The Use of Personalized Video Training for Orthopaedic Surgeons. PMID- 26987576 TI - Waning immunity against mumps in vaccinated young adults, France 2013. AB - In 2013, 15 clusters of mumps were notified in France; 72% (82/114) of the cases had been vaccinated twice with measles-mumps-rubella vaccine. To determine whether the risk of mumps increased with time since the last vaccination, we conducted a case-control study among clusters in universities and military barracks. A confirmed case had an inflammation of a salivary gland plus laboratory confirmation in 2013. A probable case presented with inflammation of a salivary gland in 2013 either lasting for > 2 days or with epidemiological link to a confirmed case. Controls had no mumps symptoms and attended the same university course, student party or military barracks. We collected clinical and vaccination data via web questionnaire and medical records. We calculated adjusted odds ratios (aOR) using logistic regression. 59% (50/85) of cases and 62% (199/321) of controls had been vaccinated twice. The odds of mumps increased for twice-vaccinated individuals by 10% for every year that had passed since the second dose (aOR 1.10; 95% confidence interval (CI): 1.02-1.19; p = 0.02). Mumps immunity waned with increasing time since vaccination. Our findings contributed to the French High Council of Public Health's decision to recommend a third MMR dose during outbreaks for individuals whose second dose dates > 10 years. PMID- 26987578 TI - Flow of Information in Biological Systems. PMID- 26987579 TI - Xenopus as a model for developmental biology. PMID- 26987577 TI - Impact of limiting visual input on gait: Individuals with Parkinson disease, age matched controls, and healthy young participants. AB - Normal and limited vision gait was investigated in individuals with Parkinson disease (PD), healthy older and healthy young individuals. Participants walked a GAITRite mat with normal vision or vision of lower limbs occluded. Results indicate individuals with PD walked more slowly, with shorter and wider steps, and spent more time in double support with limited vision as compared to full vision. Healthy young and old individuals took shorter steps but were otherwise unchanged between conditions. PMID- 26987581 TI - Contemporary Obstetric Triage. AB - IMPORTANCE: The role of obstetric triage in the care of pregnant women has expanded significantly. Factors driving this change include the Emergency Medical Treatment and Active Labor Act, improved methods of testing for fetal well-being, increasing litigation risk, and changes in resident duty hour guidelines. The contemporary obstetric triage facility must have processes in place to provide a medical screening examination that complies with regulatory statues while considering both the facility's maternal level of care and available resources. OBJECTIVE: This review examines the history of the development of obstetric triage, current considerations in a contemporary obstetric triage paradigm, and future areas for consideration. An example of a contemporary obstetric triage program at an academic medical center is presented. RESULT: A successful contemporary obstetric triage paradigm is one that addresses the questions of "sick or not sick" and "labor or no labor," for every obstetric patient that presents for care. Failure to do so risks poor patient outcome, poor patient satisfaction, adverse litigation outcome, regulatory scrutiny, and exclusion from federal payment programs. CONCLUSIONS: Understanding the role of contemporary obstetric triage in the current health care environment is important for both providers and health care leadership. TARGET AUDIENCE: This study is for obstetricians and gynecologists as well as family physicians. LEARNING OBJECTIVES: After completing this activity, the learner should be better able to understand the scope of a medical screening examination within the context of contemporary obstetric triage; understand how a facility's level of maternal care influences clinical decision making in a contemporary obstetric triage setting; and understand the considerations necessary for the systematic evaluation of the 2 basic contemporary obstetric questions, "sick or not sick?" and "labor or no labor?" PMID- 26987582 TI - Vaccination During Pregnancy. AB - Active immunization during pregnancy for maternal and neonatal benefit is a remarkably promising strategy to reduce infectious morbidity in both women and infants. The aim of this review is to present current clinical guidelines for vaccination during pregnancy and review evidence-based strategies for the implementation of maternal immunization recommendations. Observational studies, clinical trials, cost-effectiveness analyses, systematic reviews, and meta analyses were evaluated to generate the evidence base for this review. In addition, recommendations from major national professional and public health organizations were examined. We present current clinical recommendations for vaccination during pregnancy and review medical and public health strategies to implement these guidelines. We also discuss a research agenda to advance the field of maternal immunization and achieve further improvements in maternal and child health. PMID- 26987580 TI - Identification of a novel interaction between corticotropin releasing hormone (Crh) and macroautophagy. AB - In inflammatory bowel disease (IBD), compromised restitution of the epithelial barrier contributes to disease severity. Owing to the complexity in the pathogenesis of IBD, a variety of factors have been implicated in its progress. In this study, we report a functional interaction between macroautophagy and Corticotropin Releasing Hormone (Crh) in the gut. For this purpose we used DSS colitis model on Crh -/- or wild-type (wt) with pharmacological inhibition of autophagy. We uncovered sustained basal autophagy in the gut of Crh -/- mice, which persisted over the course of DSS administration. Autophagy inhibition resulted in partial rescue of Crh -/- mice, while it increased the expression of Crh in the wt gut. Similarly, Crh deficiency was associated with sustained activation of base line autophagy. In vitro models of amino acid deprivation- and LPS-induced autophagy confirmed the in vivo findings. Our results indicate a novel role for Crh in the intestinal epithelium that involves regulation of autophagy, while suggesting the complementary action of the two pathways. These data suggest the intriguing possibility that targeting Crh stimulation in the intestine may provide a novel therapeutic approach to support the integrity of the epithelial barrier and to protect from chronic colitis. PMID- 26987583 TI - Vitamin C: Promises Not Kept. AB - Vitamin C has been suggested as beneficial in preventing and curing the common cold, decreasing the incidence of preterm delivery and preeclampsia, decreasing risk of cancer and cardiovascular disease, and improving the quality of life by inhibiting blindness and dementia. In this article, we review the hypothesized mechanisms of these purported health benefits and the evidence behind such claims. PMID- 26987584 TI - A case of Paget-Schroetter syndrome (PSS) in a young judo tutor: a case report. AB - BACKGROUND: We present a case of unsuspected Paget-Schroetter syndrome (also called effort thrombosis), one of the rare causes of upper extremity deep vein thrombosis. To the best of our knowledge, this was the first such case in our hospital. Our patient may have been discharged with an incomplete diagnosis and inappropriate management but for one of the few physicians who knew about effort thrombosis, made the diagnosis, and referred the patient promptly to the appropriate team. CASE PRESENTATION: A 37-year-old Caucasian man who was an active judo tutor presented to the acute medical unit in our hospital. He had initially presented to his primary care physician complaining of redness and swelling of his right arm and elbow of 1 week's duration. He had been prescribed some antibiotics by his general practitioner, but his symptoms worsened. At that point, he was referred to our hospital for further review of his arm swelling. CONCLUSIONS: When considering a diagnosis of deep vein thrombosis, the age, hobbies, and occupation, among other things, of individual patients should be put into context at all times to avoid missing rare causes such as Paget-Schroetter syndrome. This report is intended to raise awareness of this rare condition. Knowledge of this condition and its management is essential for all medical practitioners, especially medical doctors who are involved in unselected medical admissions in accident and emergency or medical admission units, where the majority of such patients are seen. PMID- 26987585 TI - Redox signaling in the cardiomyocyte: From physiology to failure. AB - The specific effect of oxygen and reactive oxygen species (ROS) in mediating post translational modification of protein targets has emerged as a key mechanism regulating signaling components, a process termed redox signaling. ROS act in the post-translational modification of multiple target proteins including receptors, kinases, phosphatases, ion channels and transcription factors. Both O2 and ROS are major source of electrons in redox reactions in aerobic organisms. Because the heart has the highest O2 consumption among body organs, it is not surprising that redox signaling is central to heart function and pathophysiology. In this article, we review some of the main cardiac redox signaling pathways and their roles in the cardiomyocyte and in heart failure, with particular focus on the specific molecular targets of ROS in the heart. PMID- 26987586 TI - Inside story of Group I Metabotropic Glutamate Receptors (mGluRs). AB - Metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors (GPCRs) that are activated by the neurotransmitter glutamate in the central nervous system. Among the eight subtypes, mGluR1 and mGluR5 belong to the group I family. These receptors play important roles in the brain and are believed to be involved in multiple forms of experience dependent synaptic plasticity including learning and memory. In addition, group I mGluRs also have been implicated in various neuropsychiatric disorders like Fragile X syndrome, autism etc. The normal signaling depends on the precise location of these receptors in specific region of the neuron and the process of receptor trafficking plays a crucial role in controlling this localization. Intracellular trafficking could also regulate the desensitization, resensitization, down-regulation and intracellular signaling of these receptors. In this review I focus on the current understanding of group I mGluR regulation in the central nervous system and also their role in neuropsychiatric disorders. PMID- 26987587 TI - Tuning-free controller to accurately regulate flow rates in a microfluidic network. AB - We describe a control algorithm that can improve accuracy and stability of flow regulation in a microfluidic network that uses a conventional pressure pump system. The algorithm enables simultaneous and independent control of fluid flows in multiple micro-channels of a microfluidic network, but does not require any model parameters or tuning process. We investigate robustness and optimality of the proposed control algorithm and those are verified by simulations and experiments. In addition, the control algorithm is compared with a conventional PID controller to show that the proposed control algorithm resolves critical problems induced by the PID control. The capability of the control algorithm can be used not only in high-precision flow regulation in the presence of disturbance, but in some useful functions for lab-on-a-chip devices such as regulation of volumetric flow rate, interface position control of two laminar flows, valveless flow switching, droplet generation and particle manipulation. We demonstrate those functions and also suggest further potential biological applications which can be accomplished by the proposed control framework. PMID- 26987588 TI - Silencing of S100A4, a metastasis-associated protein, inhibits retinal neovascularization via the downregulation of BDNF in oxygen-induced ischaemic retinopathy. AB - BackgroundTo investigate the underlying mechanism of S100A4 function and whether it has a role in retinal neovascularization (RNV) in a mouse model of oxygen induced retinopathy (OIR).MethodsRetinas from a mouse model of OIR were treated with and without an intravitreous injection of adenoviral-S100A4-RNAi or adenoviral green fluorescence protein (GFP) at postnatal day 12 (P12). At P17, the efficacy of adenoviral gene transfer was assessed using fluorescence microscopy and western blot analysis. RNV was evaluated by whole-mount immunofluorescence staining of the mouse retina and by counting the number of pre retinal neovascular cells. Protein and mRNA expression levels of S100A4, brain derived growth factor (BDNF), and vascular endothelial growth factor (VEGF) were measured using western blot analysis and real-time PCR.ResultsRetinal S100A4 levels were positively correlated with the progression of RNV. In the OIR-S100A4 RNAi group, both protein and mRNA expression levels of S100A4 in the retina significantly decreased at P17 compared with those in the OIR group. Ad-S100A4 RNAi transfer was clearly demonstrated by GFP fluorescence in many layers of the retina 5 days after the Ad-S100A4-RNAi transfer. Whole-mount immunofluorescence staining of the retina and quantification of the pre-retinal neovascular cells demonstrated that RNV was significantly inhibited. Meanwhile, the levels of the transcription and translation of BDNF, VEGF, and hypoxia-inducible factor-1alpha (HIF-1alpha) significantly decreased in the OIR-S100A4-RNAi group.ConclusionsAd S100A4-RNAi transfer ameliorates RNV. The related mechanism may involve silencing S100A4 to decrease the activation of BDNF, which downregulates VEGF expression via HIF-1alpha. This finding could provide a new therapeutic target for the treatment of ocular neovascularization diseases. PMID- 26987589 TI - 5-Fluorouracil vs avastin as adjunct to conjunctival autograft in the surgical treatment of pterygium. AB - BACKGROUND: The use of adjunct antimetabolite therapy along with conjunctiva autograft has been shown to be effective in preventing pterygium recurrence. There has however been fewer reports on the effect of anti-vascular endothelial growth factor on pterygium recurrence. OBJECTIVE: To compare 5-fluorouracil with conjunctival autograft with bevacizumab (avastin) used along with autograft in the surgical treatment of pterygium. METHODS: A randomized controlled prospective study of outcome of pterygium treatment using 5-fluorouracil with conjunctiva autograft as adjuvant treatment compared avastin with conjunctiva autograft. RESULTS: A total of 70 eyes of 70 patients were recruited into the study with a mean age of 51.49 (+/-14.36) years. Thirty-five patients each were randomized into the 5-fluorouracil treatment group and into the avastin treatment group respectively. The mean follow-up was 18.35 months (18.44 for the 5-FU and 18.26 for the avastin group). Post operative, pterygium recurrence was observed in 1/27 (3.7%) eyes treated with 5-fluorouracil and 1/26 (3.9%) eyes of the avastin group. Both recurrences were observed at 1 year of follow-up and they were both female patients aged 46 and 52 years, respectively. CONCLUSIONS: Both 5 fluorouracil and avastin are comparably effective as adjunct to conjunctival autograft. However, cost, availability, and convenience are other considerations with use of avastin. PMID- 26987590 TI - Glaucoma detection with damato multifixation campimetry online. AB - PurposeTo evaluate Damato Multifixation Campimetry Online (DMCO), a free-of charge internet-based visual field test. DMCO exists in three versions: DMCO BASIC, DMCO STANDARD, and DMCO ADVANCED. The main focus was (i) to investigate the sensitivity and the specificity of the existing DMCO versions in the detection of glaucomatous visual field loss and (ii) to define and evaluate algorithms for the interpretation of DMCO results.MethodsThe study design was an evaluation of a diagnostic test and included 97 individuals performing DMCO and white-on-white perimetry. Interpretation algorithms were devised to define abnormality, and these were evaluated using the Glaucoma Staging System as gold standard. Receiver operating characteristic (ROC) curves and area under the ROC (AUC) were calculated.ResultsAUCs from 15 algorithms ranged from 0.79 to 0.90. The most promising algorithm combined results from two successive DMCO STANDARD tests. The sensitivity was highly dependent on the severity of glaucoma. Hence, for eyes with mild, moderate, advanced, and severe glaucoma, the DMCO test demonstrated a sensitivity of 11.8, 71.4, 100, and 100%, respectively. The specificity was as high as 98.1%. Median duration per eye to complete the DMCO STANDARD test was 86 s for the control group and 125 s in participants with glaucoma.ConclusionsDMCO shows promise as a free-of-charge online tool to identify glaucomatous visual field defects in a preselected population. Ongoing studies are evaluating the use of DMCO in a nonselected population. PMID- 26987592 TI - The accuracy of the Edinburgh diplopia diagnostic algorithm. AB - PurposeTo assess the diagnostic accuracy of the Edinburgh diplopia diagnostic algorithm.MethodsThis was a prospective study. Details of consecutive patients referred to ophthalmology clinics at Falkirk Community Hospital and Princess Alexandra Eye Pavilion, Edinburgh, with double vision were collected by the clinician first seeing the patient and passed to the investigators. The investigators then assessed the patient using the algorithm. An assessment of the degree of concordance between the 'algorithm assisted' diagnosis and the 'gold standard' diagnosis, made by a consultant ophthalmologist was then carried out. The accuracy of the pre-algorithm diagnosis made by the referrer was also noted.ResultsAll patients referred with diplopia were eligible for inclusion. Fifty-one patients were assessed; six were excluded. The pre-algorithm accuracy of referrers was 24% (10/41). The algorithm assisted diagnosis was correct 82% (37/45) of the time. It correctly diagnosed: cranial nerve (CN) III palsy in 6/6, CN IV palsy in 7/8, CN VI palsy in 12/12, internuclear ophthalmoplegia in 4/4, restrictive myopathy in 4/4, media opacity in 1/1, and blurred vision in 3/3. The algorithm assisted diagnosis was wrong in 18% (8/45) of the patients.ConclusionsThe baseline diagnostic accuracy of non-ophthalmologists rose from 24 to 82% when patients were assessed using the algorithm. The improvement in the diagnostic accuracy resulting from the use of the algorithm would, hopefully, result in more accurate triage of patients with diplopia that are referred to the hospital eye service. We hope we have demonstrated its potential as a learning tool for inexperienced clinicians. PMID- 26987591 TI - Introduction to metabolomics and its applications in ophthalmology. AB - Metabolomics is the study of endogenous and exogenous metabolites in biological systems, which aims to provide comparative semi-quantitative information about all metabolites in the system. Metabolomics is an emerging and potentially powerful tool in ophthalmology research. It is therefore important for health professionals and researchers involved in the speciality to understand the basic principles of metabolomics experiments. This article provides an overview of the experimental workflow and examples of its use in ophthalmology research from the study of disease metabolism and pathogenesis to identification of biomarkers. PMID- 26987593 TI - Peripheral Intravenous Catheterisation in Obstetric Patients in the Hand or Forearm Vein: A Randomised Trial. AB - A peripheral intravenous catheter is often inserted as part of care during labour. The catheter is inserted into the back of the hand or lower forearm vein in usual practice. There is no trial data to guide the care provider on which is the better insertion site in any clinical setting. 307 women admitted to the labour ward who required insertion of intravenous catheter were randomised to back of hand or lower forearm vein catheter insertion. Catheter insertion is by junior to mid-grade providers. We evaluated insertion success at the first attempt, pain during insertion and catheter replacement due to malfunction as main outcomes. After catheter removal, we recorded patient satisfaction with site, future site preference and insertion site swelling, bruising, tenderness, vein thrombosis and pain. Insertion of a catheter into back of hand vein is more likely to be successful at the first attempt. Insertion pain score, catheter replacement rate, patient satisfaction, patient fidelity to site in a future insertion and insertion site complications rate are not different between trial arms. In conclusion, both insertion sites are suitable; the back of the hand vein maybe easier to cannulate and seems to be preferred by our frontline providers. PMID- 26987595 TI - Lung capillary blood volume and membrane diffusion in precapillary pulmonary hypertension. AB - BACKGROUND: Combined diffusion capacity of the lung for carbon monoxide (DLco) and nitric oxide (DLno) measurements allow for the estimation of pulmonary capillary blood volume (Vc) and alveolar membrane diffusion (Dm). The clinical usefulness of these measurements in pulmonary hypertension (PH) is unclear. METHODS: Combined DLco and DLno were measured in 290 consecutive patients with precapillary PH (pulmonary arterial hypertension (PAH), n = 153; pulmonary veno occlusive disease (PVOD), n = 33; and chronic thromboembolic pulmonary hypertension (CTEPH), n = 104). Clinical correlates of Vc and Dm were assessed in a sub-group of PAH patients without comorbidities. RESULTS: PVOD patients compared with PAH and CTEPH patients displayed the lowest values of Vc (29.4 +/- 16.8 ml vs 56.3 +/- 26.5 ml vs 56.9 +/- 26.2 ml, p < 0.01, respectively) and Dm (27.7 +/- 11.6 ml/mm Hg/min vs 43.4 +/- 14.8 ml/mm Hg/min vs 44.7 +/- 17.7 ml/mm Hg/min, p < 0.01, respectively). The DLno/DLco ratio was highest in the PVOD group (5.82 +/- 2.04 vs 4.95 +/- 1.31 vs 5.16 +/- 1.58, p < 0.05). In a sub-set of 69 PAH patients without comorbidities, Vc and Dm correlated significantly with functional capacity (6-minute walking distance, oxygen consumption) and New York Heart Association Functional Classification but not with invasive hemodynamics. Only Dm was significantly associated with survival. On receiver operating characteristic curve analysis, Vc, Dm, and DLno/DLco were not superior to DLco for discriminating PVOD from PAH or CTEPH. CONCLUSIONS: PVOD patients display higher values of the DLno/DLco ratio compared with PAH and CTEPH, suggesting proportionally greater reduction in Vc relative to Dm. However, partitioning of diffusion failed to be more clinically relevant than conventional DLco for detection of PVOD. PMID- 26987596 TI - Two rare neurologic complications after heart transplantation: Posterior reversible encephalopathy syndrome, followed by reversible cerebral vasoconstriction syndrome. PMID- 26987594 TI - Structure and mechanism of the essential two-component signal-transduction system WalKR in Staphylococcus aureus. AB - Most low GC Gram-positive bacteria possess an essential walKR two-component system (TCS) for signal transduction involved in regulating cell wall homoeostasis. Despite the well-established intracellular regulatory mechanism, the role of this TCS in extracellular signal recognition and factors that modulate the activity of this TCS remain largely unknown. Here we identify the extracellular receptor of the kinase 'WalK' (erWalK) as a key hub for bridging extracellular signal input and intracellular kinase activity modulation in Staphylococcus aureus. Characterization of the crystal structure of erWalK revealed a canonical Per-Arnt-Sim (PAS) domain for signal sensing. Single amino acid mutation of potential signal-transduction residues resulted in severely impaired function of WalKR. A small molecule derived from structure-based virtual screening against erWalK is capable of selectively activating the walKR TCS. The molecular level characterization of erWalK will not only facilitate exploration of natural signal(s) but also provide a template for rational design of erWalK inhibitors. PMID- 26987597 TI - Epicardial infarct repair with bioinductive extracellular matrix promotes vasculogenesis and myocardial recovery. AB - BACKGROUND: Infarcted myocardium can remodel after successful reperfusion, resulting in left ventricular dilation and heart failure. Epicardial infarct repair (EIR) using a bioinductive extracellular matrix (ECM) biomaterial is a novel surgical approach to promote endogenous myocardial repair and functional recovery after myocardial infarction. Using a pre-clinical porcine model of coronary ischemia-reperfusion, we assessed the effects of EIR on regional functional recovery, safety, and possible mechanisms of benefit. METHODS: An ECM biomaterial (CorMatrix ECM) was applied to the epicardium after 75 minutes of coronary ischemia in a porcine model. Following ischemia-reperfusion injury, animals were randomly assigned in 2:1 fashion to EIR (n = 8) or sham treatment (n = 4). Serial cardiac magnetic resonance imaging was performed on normal (n = 4) and study animals at baseline (1 week) and 6 weeks after treatment. Myocardial function and tissue characteristics were assessed. RESULTS: Functional myocardial recovery was significantly increased by EIR compared with sham treatment (change in regional myocardial contraction at 6 weeks, 28.6 +/- 14.0% vs 4.2 +/- 13.5% wall thickening, p < 0.05). Animals receiving EIR had reduced adhesions compared with animals receiving sham treatment (1.44 +/- 0.51 vs 3.08 +/- 0.89, p < 0.05). Myocardial fibrosis was not increased, and EIR did not cause myocardial constriction, as left ventricular compliance by passive pressure distention at matched volumes was similar between groups (13.9 +/- 4.0 mm Hg in EIR group vs 16.0 +/- 5.2 mm Hg in sham group, p = 0.61). Animals receiving EIR showed evidence of vasculogenesis in the region of functional recovery. CONCLUSIONS: In addition to the beneficial effects of successful reperfusion, EIR using a bioinductive ECM enhances myocardial repair and functional recovery. Clinical translation of EIR early after myocardial infarction as an adjunct to surgical revascularization may be warranted in the future. PMID- 26987598 TI - Longitudinal changes in hemostatic parameters and reduced pulsatility contribute to non-surgical bleeding in patients with centrifugal continuous-flow left ventricular assist devices. AB - BACKGROUND: Bleeding and thromboembolic events are identified complications in patients supported with newer centrifugal continuous-flow left ventricular assist devices (cfLVADs). Bleeding events have been associated with acquired von Willebrand syndrome (vWS) in these patients, though longitudinal changes and the effect of pulsatility remain unquantified. We evaluated longitudinal effects of third-generation cfLVADs on hemostatic biomarkers, non-surgical bleeding, and thromboembolic events. We investigated the association between pulsatility (as defined by aortic valve opening) on von Willebrand Factor (VWF) profile and bleeding. METHODS: We prospectively studied 28 patients implanted with the HeartWare (HeartWare International, Framingham, MA) cfLVAD for up to 360 days. We performed bleeding and coagulation assays 8 times from pre-implant to Day 360 (D360) post-implant, including platelet aggregometry, VWF collagen binding activity-to-antigen (CBA/Ag) ratio, thromboelastography, soluble P-selectin, platelet-specific marker soluble glycoprotein VI (sGPVI), and platelet microparticles. Aortic valve opening was assessed by echocardiography at each assessment. Bleeding and thromboembolic events were documented. RESULTS: Bleeding events occurred in 14 patients (50%). Maximal platelet inhibition occurred by D30. VWF profile impairment (VWF CBA/Ag < 0.8) was demonstrated in 89% of patients at D30, with subsequent recovery but further deterioration after D180. Bleeding was associated with elevated pre-implant sGPVI (p = 0.008). Pulsatility was associated with higher VWF CBA/Ag (p = 0.02) and a trend to less bleeding. CONCLUSIONS: Third-generation cfLVADs were associated with longitudinal changes in hemostatic markers, and bleeding was associated with elevated pre-implant plasma sGPVI. Further, pulsatility may contribute to recovery of the VWF profile and potentially lower bleeding risk. PMID- 26987599 TI - High early event rates in patients with questionable eligibility for advanced heart failure therapies: Results from the Medical Arm of Mechanically Assisted Circulatory Support (Medamacs) Registry. AB - BACKGROUND: The prognosis of ambulatory patients with advanced heart failure (HF) who are not yet inotrope dependent and implications for evaluation and timing for transplant or destination therapy with a left ventricular assist device (DT-LVAD) are unknown. We hypothesized that the characteristics defining eligibility for advanced HF therapies would be a primary determinant of outcomes in these patients. METHODS: Ambulatory patients with advanced HF (New York Heart Association class III-IV, Interagency Registry for Mechanically Assisted Circulatory Support profiles 4-7) were enrolled across 11 centers from May 2013 to February 2015. Patients were stratified into 3 groups: likely transplant eligible, DT-LVAD eligible, and ineligible for both transplant and DT-LVAD. Clinical characteristics were collected, and patients were prospectively followed for death, transplant, and left ventricular assist device implantation. RESULTS: The study enrolled 144 patients with a mean follow-up of 10 +/- 6 months. Patients in the ineligible cohort (n = 43) had worse congestion, renal function, and anemia compared with transplant (n = 51) and DT-LVAD (n = 50) eligible patients. Ineligible patients had higher mortality (23.3% vs 8.0% in DT-LVAD group and 5.9% in transplant group, p = 0.02). The differences in mortality were related to lower rates of transplantation (11.8% in transplant group vs 2.0% in DT-LVAD group and 0% in ineligible group, p = 0.02) and left ventricular assist device implantation (15.7% in transplant group vs 2.0% in DT-LVAD group and 0% in ineligible group, p < 0.01). CONCLUSIONS: Ambulatory patients with advanced HF who were deemed ineligible for transplant and DT-LVAD had markers of greater HF severity and a higher rate of mortality compared with patients eligible for transplant or DT-LVAD. The high early event rate in this group emphasizes the need for timely evaluation and decision making regarding lifesaving therapies. PMID- 26987601 TI - Identification of Plasmodium falciparum specific translation inhibitors from the MMV Malaria Box using a high throughput in vitro translation screen. AB - BACKGROUND: A major goal in the search for new anti-malarial compounds is to identify new mechanisms of action or new molecular targets. While cell-based, growth inhibition-based screening have enjoyed tremendous success, an alternative approach is to specifically assay a given pathway or essential cellular process. METHODS: Here, this work describes the development of a plate-based, in vitro luciferase assay to probe for inhibitors specific to protein synthesis in Plasmodium falciparum through the use of an in vitro translation system derived from the parasite. RESULTS: Using the Medicines for Malaria Venture's Malaria Box as a pilot, 400 bioactive compounds with minimal human cytotoxicity profiles were screened, identifying eight compounds that displayed greater potency against the P. falciparum translation machinery relative to a mammalian translation system. Dose-response curves were determined in both translation systems to further characterize the top hit compound (MMV008270). CONCLUSIONS: This assay will be useful not only in future anti-malarial screening efforts but also in the investigation of P. falciparum protein synthesis and essential processes in P. falciparum biology. PMID- 26987606 TI - Time trend of malaria in relation to climate variability in Papua New Guinea. AB - OBJECTIVES: This study was conducted to describe the regional malaria incidence in relation to the geographic and climatic conditions and describe the effect of altitude on the expansion of malaria over the last decade in Papua New Guinea. METHODS: Malaria incidence was estimated in five provinces from 1996 to 2008 using national health surveillance data. Time trend of malaria incidence was compared with rainfall and minimum/maximum temperature. In the Eastern Highland Province, time trend of malaria incidence over the study period was stratified by altitude. Spatio-temporal pattern of malaria was analyzed. RESULTS: Nationwide, malaria incidence was stationary. Regionally, the incidence increased markedly in the highland region (292.0/100000/yr, p =0.021), and remained stationary in the other regions. Seasonality of the malaria incidence was related with rainfall. Decreasing incidence of malaria was associated with decreasing rainfall in the southern coastal region, whereas it was not evident in the northern coastal region. In the Eastern Highland Province, malaria incidence increased in areas below 1700 m, with the rate of increase being steeper at higher altitudes. CONCLUSIONS: Increasing trend of malaria incidence was prominent in the highland region of Papua New Guinea, while long-term trend was dependent upon baseline level of rainfall in coastal regions. PMID- 26987602 TI - Expanded CURB-65: a new score system predicts severity of community-acquired pneumonia with superior efficiency. AB - Aim of this study was to develop a new simpler and more effective severity score for community-acquired pneumonia (CAP) patients. A total of 1640 consecutive hospitalized CAP patients in Second Affiliated Hospital of Zhejiang University were included. The effectiveness of different pneumonia severity scores to predict mortality was compared, and the performance of the new score was validated on an external cohort of 1164 patients with pneumonia admitted to a teaching hospital in Italy. Using age >= 65 years, LDH > 230 u/L, albumin < 3.5 g/dL, platelet count < 100 * 10(9)/L, confusion, urea > 7 mmol/L, respiratory rate >= 30/min, low blood pressure, we assembled a new severity score named as expanded-CURB-65. The 30-day mortality and length of stay were increased along with increased risk score. The AUCs in the prediction of 30-day mortality in the main cohort were 0.826 (95% CI, 0.807-0.844), 0.801 (95% CI, 0.781-0.820), 0.756 (95% CI, 0.735-0.777), 0.793 (95% CI, 0.773-0.813) and 0.759 (95% CI, 0.737 0.779) for the expanded-CURB-65, PSI, CURB-65, SMART-COP and A-DROP, respectively. The performance of this bedside score was confirmed in CAP patients of the validation cohort although calibration was not successful in patients with health care-associated pneumonia (HCAP). The expanded CURB-65 is objective, simpler and more accurate scoring system for evaluation of CAP severity, and the predictive efficiency was better than other score systems. PMID- 26987609 TI - Modifying release characteristics from 3D printed drug-eluting products. AB - This work describes an approach to modify the release of active compound from a 3D printed model drug product geometry intended for flexible dosing and precision medication. The production of novel polylactic acid and hydroxypropyl methylcellulose based feed materials containing nitrofurantoin for 3D printing purposes is demonstrated. Nitrofurantoin, Metolose(r) and polylactic acid were successfully co-extruded with up to 40% Metolose(r) content, and subsequently 3D printed into model disk geometries (o10mm, h=2mm). Thermal analysis with differential scanning calorimetry and solid phase identification with Raman spectroscopy showed that nitrofurantoin remained in its original solid form during both hot-melt extrusion and subsequent 3D printing. Rheological measurements of the different compositions showed that the flow properties were sensitive to the amount of undissolved particles present in the formulation. Release of nitrofurantoin from the disks was dependent on Metolose(r) loading, with higher accumulated release observed for higher Metolose(r) loads. This work shows the potential of custom-made, drug loaded feed materials for 3D printing of precision drug products with tailored drug release characteristics. PMID- 26987607 TI - Substance use and HIV infection awareness among HIV-infected female sex workers in Lilongwe, Malawi. AB - BACKGROUND: HIV diagnosis, the first step in HIV care and treatment engagement, may be inhibited by substance use among female sex workers (FSW). We assessed the relationship between alcohol and cannabis use and lack of HIV infection awareness among HIV-infected FSW in Lilongwe, Malawi. METHODS: From July to September, 2014, 200 FSW aged >=18 years were enrolled using venue-based sampling to examine substance use, HIV testing history, and serostatus ascertained by HIV rapid test. We used Poisson regression with robust variance estimates to estimate the associations of alcohol and cannabis use and lack of HIV infection awareness. RESULTS: Of the 138 HIV-infected FSW, 20% were unaware of their HIV infection, with 70% not testing within 6 months prior. According to the Alcohol Use Disorder Identification Tests (AUDIT), 55% of FSW unaware of their HIV infection reported hazardous, harmful, or dependent alcohol consumption. We observed a dose-response relationship between alcohol use and lack of HIV infection awareness, with alcohol dependency significantly associated with lack of HIV infection awareness (adjusted prevalence ratio: 3.0, 95% CI: 1.3, 6.8). Current cannabis use was uncommon (26%) among unaware HIV-infected FSW and weakly associated with lack of HIV infection awareness adjusted prevalence ratio: 1.1, 95% CI: 0.5, 2.5). CONCLUSION: Increased levels of alcohol use is associated with lack of HIV infection awareness among HIV-infected FSW in Malawi. Frequent, consistent HIV testing integrated with alcohol reduction strategies could improve the health and infection awareness of substance-using FSW. PMID- 26987608 TI - Multimodal molecular imaging system for pathway-specific reporter gene expression. AB - Preclinical imaging modalities represent an essential tool to develop a modern and translational biomedical research. To date, Optical Imaging (OI) and Magnetic Resonance Imaging (MRI) are used principally in separate studies for molecular imaging studies. We decided to combine OI and MRI together through the development of a lentiviral vector to monitor the Wnt pathway response to Lithium Chloride (LiCl) treatment. The construct was stably infected in glioblastoma cells and, after intracranial transplantation in mice, serial MRI and OI imaging sessions were performed to detect human ferritin heavy chain protein (hFTH) and firefly luciferase enzyme (FLuc) respectively. The system allowed also ex vivo analysis using a constitutive fluorescence protein expression. In mice, LiCl administration has shown significantly increment of luminescence signal and a lower signal of T2 values (P<0.05), recorded noninvasively with OI and a 7 Tesla MRI scanner. This study indicates that OI and MRI can be performed in a single in vivo experiment, providing an in vivo proof-of-concept for drug discovery projects in preclinical phase. PMID- 26987610 TI - Optimising the controlled release of dexamethasone from a new generation of PLGA based microspheres intended for intravitreal administration. AB - Successful therapy for chronic diseases affecting the posterior segment of the eye requires sustained drug concentrations at the site of action for extended periods of time. To achieve this, it is necessary to use high systemic doses or frequent intraocular injections, both associated with serious adverse effects. In order to avoid these complications and improve patient's quality of life, an experimental study has been conducted on the preparation of a new generation of biodegradable poly(D,L-lactide-co-glycolide) (50:50) (PLGA) polymer microspheres (MSs) loaded with Dxm, vitamin E and/or human serum albumin (HSA). Particles were prepared according to a S/O/W encapsulation method and the 20-40MUm fraction was selected. This narrow size distribution is suitable for minimally invasive intravitreal injection by small calibre needles. Characterisation of the MSs showed high Dxm loading and encapsulation efficiency (> 90%) without a strong interaction with the polymer matrix, as revealed by DSC analysis. MSs drug release studies indicated a small burst effect (lower than 5%) during the first five hours and subsequently, drug release was sustained for at least 30days, led by diffusion and erosion mechanisms. Dxm release rate was modulated when solid state HSA was incorporated into MSs formulation. SDS-PAGE analysis showed that the protein maintained its integrity during the encapsulation process, as well as for the release study. MSs presented good tolerance and lack of cytotoxicity in macrophages and HeLa cultured cells. After 12months of storage under standard refrigerated conditions (4+/-1 degrees C), MSs retained appropriate physical and chemical properties and analogous drug release kinetics. Therefore, we conclude that these microspheres are promising pharmaceutical systems for intraocular administration, allowing controlled release of the drug. PMID- 26987611 TI - RNase L and the NLRP3-inflammasome: An old merchant in a new trade. AB - The type I/III interferon (IFN)-inducible 2'-5'- oligoadenylate synthetase (OAS)/endoribonuclease L (RNase L) is a classical innate immune pathway that has been implicated in antiviral and antibacterial defense and also in hereditary prostate cancer. The OAS/RNase L pathway is activated when OAS senses double stranded RNA and catalyzes the synthesis of 2'-5' linked oligodenylates (2-5A) from ATP. 2-5A then binds and activates RNase L, resulting cleavage of single stranded RNAs. RNase L cleavage products are capable of activating RIG-like receptors such as RIG-I and MDA5 that leads to IFN-beta expression during viral infection. Our recent findings suggest that beside the RLR pathway, RNase L cleavage products can also activate the NLRP3-inflammasome pathway, which requires DHX33 (DExD/H-box helicase) and the mitochondrial adaptor protein MAVS. Here we discuss this newly identified role of OAS-RNase L pathway in regulation of inflammasome signaling as an alternative antimicrobial mechanism that has potential as a target for development of new broad-spectrum antimicrobial and anti-inflammatory therapies. PMID- 26987612 TI - Chemokine binding proteins: An immunomodulatory strategy going viral. AB - Chemokines are chemotactic cytokines whose main function is to direct cell migration. The chemokine network is highly complex and its deregulation is linked to several diseases including immunopathology, cancer and chronic pain. Chemokines also play essential roles in the antiviral immune response. Viruses have therefore developed several counter strategies to modulate chemokine activity. One of these is the expression of type I transmembrane or secreted proteins with the ability to bind chemokines and modulate their activity. These proteins, termed viral chemokine binding proteins (vCKBP), do not share sequence homology with host proteins and are immunomodulatory in vivo. In this review we describe the discovery and characterization of vCKBP, explain their role in the context of infection in vivo and discuss relevant novel findings. PMID- 26987614 TI - The emerging role of interferon regulatory factor 9 in the antiviral host response and beyond. AB - The host response to viral infections relies on tightly regulated and intricate signaling pathways involving type I interferons (IFN-Is). The IFN-Is mediate their antiviral effects predominantly through a signaling factor complex that comprises the transcription factors, interferon regulatory factor 9 (IRF9) and the signal transducers and activators of transcription (STAT) 1 and STAT2. While STAT1 and STAT2 have been studied extensively, the biological significance of IRF9 is only beginning to emerge. Recent studies have revealed a unique role for IRF9 as a conductor of the cellular responses to IFN-Is. Intriguingly, novel roles for IRF9 outside of the antiviral response are also being identified. Thus IRF9 may have a more extensive influence on cellular processes than previously recognized, ranging from antiviral immune responses to oncogenesis and gut homeostasis. In this review, we will focus on the distinct and emerging roles of IRF9 in the antiviral host response and beyond. PMID- 26987615 TI - Vision for the ECG Challenge Within Circulation. PMID- 26987613 TI - Microbial pathogenesis and type III interferons. AB - The innate immune system possesses a multitude of pathways to sense and respond to microbial pathogens. One such family are the interferons (IFNs), a family of cytokines that are involved in several cellular functions. Type I IFNs are appreciated to be important in several viral and bacterial diseases, while the recently identified type III IFNs (IFNL1, IFNL2, IFNL3, IFNL4) have been studied primarily in the context of viral infection. Viral and bacterial infections however are not mutually exclusive, and often the presence of a viral pathogen increases the pathogenesis of bacterial infection. The role of type III IFN in bacterial and viral-bacterial co-infections has just begun to be explored. In this mini review we discuss type III IFN signaling and its role in microbial pathogenesis with an emphasis on the work that has been conducted with bacterial pathogens. PMID- 26987616 TI - Quantitative T-wave alternans analysis for sudden cardiac death risk assessment and guiding therapy: answered and unanswered questions: For: Proceedings of ICE2015 Comandatuba, Brazil, Sudden Death Symposium. AB - This review addresses current questions regarding use of T-wave alternans to stratify risk for sudden cardiac death. Both of the currently available commercial methodologies, namely, the frequency-domain spectral method and the time-domain modified moving average (MMA) method, are supported by guideline statements, cleared by the US FDA, and covered by the US Center for Medicare and Medicaid services. Similar numbers of patients have been enrolled in predictive studies; odds ratios generated by the two methods are similar including in a head to-head study. However, in two prospective studies, prediction by TWA with the spectral method was negative, likely due to withdrawal of beta-blockade before the test with later resumption, while all studies with MMA have achieved prediction when the commercial software was used appropriately. Questions currently undergoing investigation include TWA's potential to guide ICD implantation, to track changes in risk during cardiac disease progression, and to evaluate the adequacy of medical therapy. PMID- 26987617 TI - Scientific STAFF and MALT meetings - past, present, and future. AB - The scientific STAFF and MALT meetings were created around the turn of the century for scientists engaged in enhancing the role of the 12-lead ECG for detection and quantification of involved myocardium in patients with acute coronary syndrome. These meetings were initially focused on computer processing of data from two single-center databases. The STAFF database was collected in the mid-nineties on patients with prolonged total coronary occlusion; high-resolution 12-lead ECGs were collected before, during, and after 5 minutes of occlusion. The MALT database was created in the early years of this century on consecutive patients with chest pain admitted to a large teaching hospital. Delayed enhancement magnetic resonance imaging and electrocardiograms were recorded in these acutely ill patients. The paper highlights the first 2 decades of the STAFF and MALT meetings and details the meeting format. PMID- 26987620 TI - Extracorporeal Shock Wave Therapy for Breast Cancer-Related Lymphedema: A Pilot Study. AB - OBJECTIVE: To investigate the clinical effect of extracorporeal shock wave therapy (ESWT) in patients with secondary lymphedema after breast cancer treatment. DESIGN: Prospective clinical pilot study. SETTING: Education and research hospital. PARTICIPANTS: Women with a diagnosis of lymphedema secondary to breast cancer (N=11). INTERVENTIONS: Patients were treated for 12 sessions of ESWT with 2500 impulses each. The treatment frequency was 4Hz in multiple shock mode. The energy flow density during treatment was equal to a working pressure of 2 bar. MAIN OUTCOME MEASURES: The primary outcome measure was volumetric measurements. The secondary outcome measures were the short version of the Disabilities of the Arm, Shoulder and Hand Questionnaire (QuickDASH) and the brief version of the World Health Organization Quality of Life (WHOQOL-BREF). Assessments were conducted by the same investigator at baseline, posttreatment, and at 1, 3, and 6 months after treatment for all patients. RESULTS: Significant reduction was found in the amount of lymphedema with ESWT treatment in all patients, and this reduction was maintained for 6 months. A statistically significant reduction was observed in volumetric measurements for the follow-up period (P=.001). The mean volume displacement of the affected upper extremity before treatment was 870.45+/-384.19mL at 6 months, and after the treatment it was 604.54+/-381.74mL. In addition, improvements were observed in the QuickDASH functional assessment tool and in the physical health domain of the WHOQOL-BREF questionnaire (P=.002 and P=.007, respectively). CONCLUSIONS: ESWT was shown to provide a reduction in the amount of lymphedema in patients with lymphedema secondary to breast cancer. Also, a marked improvement was observed in the functional status and quality of life of study patients. Treatment efficacy was maintained in the long term. As a noninvasive, novel, and effective method, ESWT is a promising treatment modality for the treatment of lymphedema, which is a chronic, progressive, and refractory condition. PMID- 26987619 TI - Surgical Staff Radiation Protection During Fluoroscopy-Guided Urologic Interventions. AB - INTRODUCTION: Over the past 20 years, the use of fluoroscopy to guide urologic surgical interventions has been constantly growing. Thus, in their daily practice, urologists and other operating room (OR) staff are exposed to X radiation increasingly frequently. This raises questions as to the risks they encounter and the actions needed to reduce them. OBJECTIVE: Evaluate X-ray dose exposure in the members of the surgical team and determine urologist radioprotection knowledge and practices. MATERIALS AND METHODS: A prospective bicenter study was conducted within AFUF (French urology resident association) and in association with The French Nuclear Safety Authority/The Institute for Radiological Protection and Nuclear Safety (ASN/IRSN). Radiation exposure was measured on 12 operators using dosimeters (seven per operator), in staff-occupied locations in the OR using ionization chambers, and on anthropomorphic phantoms. A survey was used to gather information on radiation knowledge and safety practices of the AFUF members. RESULTS: Annual whole-body radiation doses were low (0.1-0.8 millisieverts [mSv], mostly at around 0.3 mSv), and equivalent doses were low for the fingers (0.7-15 mSv, mostly at around 2.5 mSv), and low for the lens of the eye (0.3-2.3 mSv, mostly at around 0.7 mSv). In percutaneous nephrolithotomy, extremity doses were lower when the patient was placed in dorsal decubitus compared with ventral decubitus. Pulsed fluoroscopy reduced radiation dose exposure by a factor of 3 compared with continuous fluoroscopy with no image quality loss. Radiation safety practices were poor: only 15% of urologists wore dosimeters and only 5% had been trained in the handling of X-ray generators. CONCLUSION: In the present study, radiation exposure for urologists was low, but so was knowledge of radiation safety and optimization practices. This absence of training for radiation safety and reduction, teamed with novel techniques involving long fluoroscopy-guided interventions, could result in unnecessarily high exposure for patients and OR personnel. PMID- 26987618 TI - Self-Monitoring Artificial Red Cells with Sufficient Oxygen Supply for Enhanced Photodynamic Therapy. AB - Photodynamic therapy has been increasingly applied in clinical cancer treatments. However, native hypoxic tumoural microenvironment and lacking oxygen supply are the major barriers hindering photodynamic reactions. To solve this problem, we have developed biomimetic artificial red cells by loading complexes of oxygen carrier (hemoglobin) and photosensitizer (indocyanine green) for boosted photodynamic strategy. Such nanosystem provides a coupling structure with stable self-oxygen supply and acting as an ideal fluorescent/photoacoustic imaging probe, dynamically monitoring the nanoparticle biodistribution and the treatment of PDT. Upon exposure to near-infrared laser, the remote-triggered photosensitizer generates massive cytotoxic reactive oxygen species (ROS) with sufficient oxygen supply. Importantly, hemoglobin is simultaneously oxidized into the more active and resident ferryl-hemoglobin leading to persistent cytotoxicity. ROS and ferryl-hemoglobin synergistically trigger the oxidative damage of xenograft tumour resulting in complete suppression. The artificial red cells with self-monitoring and boosted photodynamic efficacy could serve as a versatile theranostic platform. PMID- 26987621 TI - Do Performance-Based Wheelchair Propulsion Tests Detect Changes Among Manual Wheelchair Users With Spinal Cord Injury During Inpatient Rehabilitation in Quebec? AB - OBJECTIVE: To quantify and compare the responsiveness and concurrent validity of 3 performance-based manual wheelchair propulsion tests among manual wheelchair users with subacute spinal cord injury (SCI) undergoing inpatient rehabilitation. DESIGN: Quasi-experimental repeated-measures design. SETTING: Publicly funded comprehensive inpatient SCI rehabilitation program. PARTICIPANTS: Consenting adult manual wheelchair users with a subacute SCI admitted and discharged from inpatient rehabilitation (N=14). INTERVENTION: Participants performed 20-m propulsion at both self-selected natural and maximal speeds, the slalom, and the 6-minute propulsion tests at rehabilitation admission and discharge. MAIN OUTCOME MEASURES: Time required to complete the performance-based wheelchair propulsion tests. Standardized response means (SRMs) were computed for each performance test and Pearson correlation coefficients (r) were calculated to explore the associations between performance tests. RESULTS: The slalom (SRM=1.24), 20-m propulsion at maximum speed (SRM=.99), and 6-minute propulsion tests (SRM=.84) were the most responsive. The slalom and 20-m propulsion at maximum speed were strongly correlated at both admission (r=.93) and discharge (r=.92). CONCLUSIONS: The slalom and 6-minute propulsion tests best document wheelchair propulsion performance change over the course of inpatient rehabilitation. Adding the 20-m propulsion test performed at maximal speed provides a complementary description of performance change. PMID- 26987622 TI - Acute Trauma Factor Associations With Suicidality Across the First 5 Years After Traumatic Brain Injury. AB - OBJECTIVE: To determine whether severity of head and extracranial injuries (ECI) is associated with suicidal ideation (SI) or suicide attempt (SA) after traumatic brain injury (TBI). DESIGN: Factors associated with SI and SA were assessed in this inception cohort study using data collected 1, 2, and 5 years post-TBI from the National Trauma Data Bank and Traumatic Brain Injury Model Systems (TBIMS) databases. SETTING: Level I trauma centers, inpatient rehabilitation centers, and the community. PARTICIPANTS: Participants with TBI from 15 TBIMS Centers with linked National Trauma Data Bank trauma data (N=3575). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: SI was measured via the Patient Health Questionnaire 9 (question 9). SA in the last year was assessed via interview. ECI was measured by the Injury Severity Scale (nonhead) and categorized as none, mild, moderate, or severe. RESULTS: There were 293 (8.2%) participants who had SI without SA and 109 (3.0%) who had SA at least once in the first 5 years postinjury. Random effects logit modeling showed a higher likelihood of SI when ECI was severe (odds ratio=2.73; 95% confidence interval, 1.55-4.82; P=.001). Drug use at time of injury was also associated with SI (odds ratio=1.69; 95% confidence interval, 1.11-2.86; P=.015). Severity of ECI was not associated with SA. CONCLUSIONS: Severe ECI carried a nearly 3-fold increase in the odds of SI after TBI, but it was not related to SA. Head injury severity and less severe ECI were not associated with SI or SA. These findings warrant additional work to identify factors associated with severe ECI that make individuals more susceptible to SI after TBI. PMID- 26987623 TI - B4GALT3 up-regulation by miR-27a contributes to the oncogenic activity in human cervical cancer cells. AB - beta-1,4-Galactosyltransferase III (B4GALT3) is an enzyme responsible for the generation of poly-N-acetyllactosamine and is involved in tumorigenesis. However, B4GALT3-dysregulation and its role in cervical cancer cells are unknown. Herein, we found that B4GALT3 was upregulated in cervical cancer tissues compared to adjacent non-tumor tissues. B4GALT3-overexpression promoted, whereas B4GALT3 knockdown suppressed the cellular migration, invasion and EMT of HeLa and C33A cervical cancer cells. To explore the mechanism of dysregulation, B4GALT3 was predicted to be a target of miR-27a. EGFP and pGL3-promoter reporter assay showed miR-27a binds to B4GALT3 3'UTR region but enhanced its expression. RT-qPCR showed miR-27a was also upregulated and presented positive correlation with B4GALT3 expression in cervical cancer tissues. miR-27a-overexpression promoted, but blocking-miR-27a repressed these malignancies in HeLa and C33A cells. Furthermore, shR-B4GALT3 counteracted the promotion of malignancies induced by miR-27a, suggesting miR-27a upregulates B4GALT3 to enhance tumorigenic activities. In addition, we found that B4GALT3 significantly enhances beta1 integrin stability, thus mediating promotion of B4GALT3 on malignancy in cervical cancer cells. Altogether, our findings evidenced that B4GALT3 upregulated by miR 27a contributes to the tumorigenic activities by beta1-integrin pathway and might provide potential biomarkers for cervical cancer. PMID- 26987624 TI - Precision oncology: A new era of cancer clinical trials. AB - Traditionally, site of disease and anatomic staging have been used to define patient populations to be studied in individual cancer clinical trials. In the past decade, however, oncology has become increasingly understood on a cellular and molecular level, with many cancer subtypes being described as a function of biomarkers or tumor genetic mutations. With these changes in the science of oncology have come changes to the way we design and perform clinical trials. Increasingly common are trials tailored to detect enhanced efficacy in a patient subpopulation, e.g. patients with a known biomarker value or whose tumors harbor a specific genetic mutation. Here, we provide an overview of traditional and newer biomarker-based trial designs, and highlight lessons learned through implementation of several ongoing and recently completed trials. PMID- 26987625 TI - Nanoparticles in radiation oncology: From bench-side to bedside. AB - Nanoparticles (NP) are "in vogue" in medical research. Pre-clinical studies accumulate evidence of NP enhancing radiation therapy. On one hand, NP, selected for their intrinsic physicochemical characteristics, are radio-sensitizers. Thus, when NP accumulate in cancer cells, they increase the radiation absorption coefficient specifically in tumour tissue, sparing healthy surrounding tissue from toxicity. On the other hand, NP, by being drug vectors, can carry radio sensitizer therapeutics to cancer cells. Finally, NP present theranostic effects. Indeed they are used in imaging as contrast agents. NP therefore can be multi tasking and have promising prospect in radiotherapy field. In spite of the numerous encouraging preclinical evidence, the very small number of clinical trials investigating NP possible involvement in the radiotherapy clinical practice suggests a physicians' unwillingness. Many prerequisites seem necessary including define biological mechanisms of NP radiosensitization pathways and of NP clearance. NP biocompatibility and toxicities should be better investigated to select, among the extensive range of possible systems, the harmless and most efficient one, and to finally come to a safe and successful clinical use. The present review focuses on the various interests of NP in the radiotherapy area and proposes a discussion about their role in the future clinical practice. PMID- 26987628 TI - Deep Brain Stimulation for Depression: Is It a Gray or White "Matter"? PMID- 26987626 TI - beta2-1 Fructan supplementation alters host immune responses in a manner consistent with increased exposure to microbial components: results from a double blinded, randomised, cross-over study in healthy adults. AB - beta2-1 Fructans are purported to improve health by stimulating growth of colonic bifidobacteria, increasing host resistance to pathogens and stimulating the immune system. However, in healthy adults, the benefits of supplementation remain undefined. Adults (thirteen men, seventeen women) participated in a double blinded, placebo-controlled, randomised, cross-over study consisting of two 28-d treatments separated by a 14-d washout period. Subjects' regular diets were supplemented with beta2-1 fructan or placebo (maltodextrin) at 3*5 g/d. Fasting blood and 1-d faecal collections were obtained at the beginning and at the end of each phase. Blood was analysed for clinical, biochemical and immunological variables. Determinations of well-being and general health, gastrointestinal (GI) symptoms, regularity, faecal SCFA content, residual faecal beta2-1 fructans and faecal bifidobacteria content were undertaken. beta2-1 Fructan supplementation had no effect on blood lipid or cholesterol concentrations or on circulating lymphocyte and macrophage numbers, but significantly increased serum lipopolysaccharide, faecal SCFA, faecal bifidobacteria and indigestion. With respect to immune function, beta2-1 fructan supplementation increased serum IL-4, circulating percentages of CD282+/TLR2+ myeloid dendritic cells and ex vivo responsiveness to a toll-like receptor 2 agonist. beta2-1 Fructans also decreased serum IL-10, but did not affect C-reactive protein or serum/faecal Ig concentrations. No differences in host well-being were associated with either treatment, although the self-reported incidence of GI symptoms and headaches increased during the beta2-1 fructan phase. Although beta2-1 fructan supplementation increased faecal bifidobacteria, this change was not directly related to any of the determined host parameters. PMID- 26987627 TI - Proposal for agar disk diffusion interpretive criteria for susceptibility testing of bovine mastitis pathogens using cefoperazone 30MUg disks. AB - Cefoperazone is a third generation cephalosporin which is commonly used for bovine mastitis therapy. Bacterial pathogens involved in bovine mastitis are frequently tested for their susceptibility to cefoperazone. So far, the cefoperazone susceptibility testing using 30MUg disks has been hampered by the lack of quality control (QC) ranges as well as the lack of interpretive criteria. In 2014, QC ranges for 30 MUg cefoperazone disks have been established for Staphylococcus aureus ATCC(r) 25923 and Escherichia coli ATCC(r) 25922. As a next step, interpretive criteria for the susceptibility testing of bovine mastitis pathogens should be developed. For this, 637 bovine mastitis pathogens (including 112 S. aureus, 121 coagulase-negative staphylococci (CoNS), 103 E. coli, 101 Streptococcus agalactiae, 100 Streptococcus dysgalactiae and 100 Streptococcus uberis) were investigated by agar disk diffusion according to the document Vet01 A4 of the Clinical and Laboratory Standards Institute (CLSI) using 30MUg cefoperazone disks and the results were compared to the corresponding MIC values as determined by broth microdilution also according to the aforementioned CLSI document. Based on the results obtained and taking into account the achievable milk concentration of cefoperazone after regular dosing, the following interpretive criteria were proposed as a guidance for mastitis diagnostic laboratories: for staphylococci and E. coli >=23mm (susceptible), 18-22mm (intermediate) and <=17mm (resistant) and for streptococci >=18mm (susceptible), and <=17mm (non-susceptible). These proposed interpretive criteria shall contribute to a harmonization of cefoperazone susceptibility testing of bovine mastitis pathogens. PMID- 26987629 TI - Reply to: Deep Brain Stimulation for Depression: Is It a Gray or White "Matter"? PMID- 26987631 TI - Flow Behavior and Distribution of Embolus-Model Particles at the Terminal Bifurcation of the Human Internal Carotid Artery. AB - BACKGROUND: To investigate the possible role of fluid mechanical factors in thromboembolism that occurs at a high rate in the human middle cerebral artery (MCA). METHODS: Isolated transparent cerebral arterial trees containing the terminal bifurcation of the internal carotid artery (ICA), where the ICA bifurcated into the MCA and the anterior cerebral artery, were prepared from human cadavers. The flow behavior and distribution of embolus-model polystyrene particles in dilute suspensions at the bifurcation were studied in detail by means of flow visualization and high-speed cinemicrographic techniques. RESULTS: Large particles in suspensions flowing through the ICA migrated radially away from the vessel wall toward the axis of the ICA. It became more remarkable by increasing the flow rate in the ICA (Q0), flow rate ratio of Q1 to Q0 (MCA/ICA), and particle diameter. As a result, redistribution of particles flowing in the ICA occurred at the bifurcation. The particles >1 mm in diameter (~1/4 of vessel diameter) selectively entered the MCA, even when the flow rate ratio of Q1 to Q0 was decreased to as low as 0.34. In contrast, the particles whose diameters were <0.3 mm (~1/10 of vessel diameter) and that did not show radial migration entered the MCA at the same rate as the flow rate ratio of Q1 to Q0. CONCLUSIONS: Due to the flow-dependent migration of particles away from the vessel wall toward the axis of the ICA, large particles selectively enter the MCA to which the core flow of the ICA is generally directed. This might explain why the incidence of thromboembolism is higher in the MCA than in the anterior cerebral artery in humans. PMID- 26987632 TI - Endoscopic Posterior Cervical Foraminotomy as a Treatment for Osseous Foraminal Stenosis. AB - BACKGROUND: Posterior cervical foraminotomy is a valuable treatment option for cervical radiculopathy. Here the authors present their technique and results in the treatment of a series of patients suffering from osseous foraminal stenosis. METHODS: Forty-three patients suffering from cervical osseous foraminal stenosis were operated on via a posterior approach with the EasyGO endoscopic system. Decompression was performed in 1 segment in 31 patients, in 2 segments in 11 patients, and in 3 segments in 1 patient. Bilateral decompression was performed in 4 cases. Twenty-four (55.8%) patients had been subjected to previous spine surgery. All procedures were video recorded and afterwards retrospectively analyzed. In addition, particular reference was given to previous cervical spine surgery, postoperative outcome, reoperation rate, and complications. RESULTS: The endoscopic system was easy to handle intraoperatively in all procedures. No emergency stopping was required. Forty-one patients reported improved and/or even no remaining pain postoperatively (95%). Thirty-five patients (81.4%) regained full motor strength. Clinical success rate with respect to Odom's criteria reached 39 patients (90.7%). One reoperation was needed due to postoperative hematoma (2.3%). One patient suffered from transient worsening of his preoperative paresis (2.3%). Neither dural tear nor nerve root injury was observed. Reoperation rate due to degenerative changes was 18.6% (8 of 43 patients). CONCLUSIONS: This retrospective analysis shows that posterior endoscopic decompression is a successful option in the treatment of osseous cervical foraminal stenosis. PMID- 26987633 TI - The Inferolateral Transorbital Endoscopic Approach: A Preclinical Anatomic Study. AB - BACKGROUND: In recent years, transorbital endoscopic approaches are increasing in popularity as they provide several corridors to reach lateral areas of the ventral skull base through the orbit. The aim of this study is to investigate the feasibility of the inferolateral transorbital endoscopic approach (ILTEA) by detailing the step-by-step dissection, anatomic landmarks, and target anatomic areas. METHODS: Seven cadaveric specimens (14 sides) were dissected in the Laboratory of Endoscopic Anatomy of the University of Brescia. Step-by-step dissection of ILTEA was performed to identify the main anatomic landmarks and corridors. Skin incision, dural incision, and boundaries of craniectomy were measured. Neuronavigation was used to check landmarks, track boundaries of surgical volumes, and measure orbital dislocation. RESULTS: The study on the 14 ILTEAs defined 1 anatomic area ("waterline door") that leads to 4 corridors: Meckel's cave corridor, carotid foramen corridor, petrous corridor, and transdural middle fossa corridor. Crucial anatomic landmarks were identified and analyzed. Orbital dislocation was <10 mm. CONCLUSIONS: ILTEA provides the surgeon with a direct route to the region of the "waterline door," lateral areas of the ventral skull base, and middle cranial fossa. In addition, it allows an optimal view of the intracranial and extracranial portions of the maxillary and mandibular nerves. Further anatomic and clinical studies are needed to validate ILTEA in surgical practice. PMID- 26987634 TI - Functional Outcomes of Salvage Surgery for Vestibular Schwannomas after Failed Gamma Knife Radiosurgery. AB - OBJECTIVE: We reviewed our experience with salvage surgery following failed gamma knife radiosurgery (GKS) for vestibular schwannomas. METHODS: The study comprised 18 patients with unilateral vestibular schwannomas. The median prescribed radiation dose was 12 Gy (range, 10-12.5 Gy). Nine patients had regrowth after GKS, and 9 had regrowth after surgical resection plus GKS. The median interval between GKS and surgical resection was 26 months (range: 4-66 months). The maximum tumor diameter of all patients ranged 25-43 mm (median 35.5 mm). The tumor was removed subtotally in 2 patients and partially in the other 16 patients. The median follow-up period after surgical resection was 60 months (range: 12-144 months). RESULTS: Among the 17 patients with preoperative preserved facial nerve function (House-Brackmann [HB] grade I-III), 14 of them (82%) had an HB score of grade I at the last follow-up. There were no differences in facial nerve preservation between those with failed GKS and those with failed GKS plus surgery (78% vs. 100%, P = 0.156). At the post-salvage surgery follow up, the residual tumor was unchanged or decreased in 15 patients (83%) and increased in 3 patients (17%). CONCLUSION: A surgical indication after GKS should be carefully considered because of the natural regression of transient tumor expansion with time, and surgical resection is limited to subtotal or partial removal for functional preservation. Careful follow-up is necessary in patients with tumor regrowth several years after GKS due to delayed radiation effects. PMID- 26987635 TI - Usefulness of Extradural Optic Nerve Decompression via Trans-Superior Orbital Fissure Approach for Treatment of Traumatic Optic Nerve Injury: Surgical Procedures and Techniques from Experience with 8 Consecutive Patients. AB - OBJECTIVE: To describe our experience of extradural optic nerve decompression via the trans-superior orbital fissure approach for traumatic optic neuropathy (TON) and retrospectively analyze its advantages and pitfalls. METHODS: Between September 2009 and August 2014, 8 consecutive patients with TON underwent extradural optic canal decompression via the trans-superior orbital fissure approach. We retrospectively reviewed medical charts, radiologic findings, surgical techniques, complications, and final surgical results. RESULTS: All 8 patients presented with visual disturbance caused by head injury; 2 patients had no light perception, 6 had light perception, and 2 had ophthalmoplegia. All patients underwent extradural optic canal decompression and high-dose steroid administration within 24 hours after injury. Postoperative visual acuity on discharge was improved in 6 patients and unchanged in 2. The 2 patients with ophthalmoplegia gradually recovered by 3 months after operation. The postoperative outcome was good recovery in 7 patients and moderate disability in 1 patient. There were no complications related to the surgical procedure. CONCLUSIONS: Emergent optic canal release has been recommended in patients with TON. The advantage of the extradural optic canal decompression via the trans superior orbital fissure approach is easy identification of the optic canal after partial removal of the anterior clinoid process, resulting in fewer surgical complications. In addition, this procedure can achieve intraorbital decompression if necessary. We recommend this modified approach with mini-peeling as a safe and reliable procedure in patients with TON. PMID- 26987636 TI - Neurosurgical Management of Nonmissile Penetrating Cranial Lesions. AB - OBJECTIVE: The objective of this study is to present a case series of nonmissile penetrating (NMP) injuries and to establish a workflow for an uncommon mechanism of traumatic head injury through the analysis of each case, classification of the type of lesion, management, and outcome score at follow-up. METHODS: From January 1991 to December 2008, 36,000 patients presenting with traumatic brain injury (TBI) were admitted in the Department of Neurosurgery, Hospital Antonio Targino, Campina Grande-PB, Brazil. From these patients, 11 presenting with lesions caused by NMP objects were selected. RESULTS: Among the 11 patients, 9 were men and 2 were women. Their ages ranged from 7 to 74 years old (mean age +/- SD, 29.1 +/- 22.99 years). All patients underwent neuroradiologic evaluation. The entry point was classified as natural (orbit) or artificial (skull transfixation), and we also divided the patients presenting with secondary parenchymal or vascular damage from those presenting with only lesions caused by the primary penetration into the cranium and meninges. All patients were neurosurgically treated with removal of the foreign body through craniotomy, except the patient whose object (pen) was removed without craniotomy with local anesthesia. Glasgow Coma Scale (GCS) score on admission was a statistically significant factor on prognosis, and any patient who presented with a GCS score of 15 evolved satisfactorily, and there were no deaths in this group of patients (P = 0.04). CONCLUSIONS: TBIs caused by NMP objects are unusual and caused by aggression, self-inflicted harm (in the case of psychiatric patients), and accident. The foreign body may enter into the skull through a natural hole (orbit, nose, mouth, or ear) or crosses the skull, causing a fracture and creating an artificial hole. Preoperative neuroradiologic assessment is paramount for the correct neurosurgical approach. The main prognostic factor for these patients is the GCS score at admission. PMID- 26987637 TI - A Cost-Effective Delivery System for FloSeal During Endoscopic and Microscopic Brain Surgery. AB - OBJECTIVE: To share our experience with a new delivery system for the flowable hemostatic matrix, FloSeal, in endoscopic and microscopic skull base surgery. METHODS: We prospectively analyzed the use of FloSeal with a hemostatic delivery system in transnasal endoscopic and microscopic skull base procedures performed at the authors' institution from January 1, 2015, to June 30, 2015. In all cases the number of aliquots was noted for the entire operation, and the total number of FloSeal ampules of 5 mL was also recorded. RESULTS: Our device allowed controlled application of small amounts (0.5-1 mL) of FloSeal to the site of bleeding. This controlled application resulted not only in increased visibility during its application, but it also reduced the amount of FloSeal required during the procedure. We were able to use 5-10 applications per 5-mL ampule of FloSeal within an individual procedure. No procedure required more than one 5-mL ampule of FloSeal. Therefore, the use of our device results in a reduction of costs. Prior to the use of our device, we were often only able to use 1 vial of 5 ml of material for 1 or 2 applications, especially in transnasal endoscopic procedures when working along a deep corridor. CONCLUSIONS: Our results indicate that our delivery device of FlowSeal can effectively control hemostasis by applying small amounts of FlowSeal to the site of bleeding. This results in increased visibility during hemostasis and a reduction of cost. PMID- 26987638 TI - Treatment Results of Gamma Knife Radiosurgery for Central Neurocytoma: Report of a Japanese Multi-Institutional Cooperative Study. AB - OBJECTIVE: Central neurocytoma (CN) is a rare benign neuronal tumor, and a limited number of reports have described the usefulness of radiosurgery for a relatively large group of patients. We evaluated the effectiveness and outcomes of Gamma Knife radiosurgery (GKS) for CN in a Japanese multi-institutional study. METHODS: We performed retrospective analysis of 36 patients with CN who were treated with GKS in 12 institutes in Japan. All patients underwent surgery before GKS. The median tumor volume at GKS was 4.9 mL (range, 0.07-23.4 mL), and the median radiation dose prescribed to the tumor margin was 15 Gy (range, 10-20 Gy). The median follow-up period was 54.5 months (range, 3-180 months). RESULTS: The local tumor progression-free survival rates at 5 and 10 years were 94% and 86%, respectively. Three patients developed distant dissemination 16-90 months later. Overall progression-free survival was unrelated to the prescribed dose (<15 Gy vs. >=15 Gy, P = 0.62), tumor size (<6 mL vs. >=6 mL, P = 0.46), gender (P = 0.36), age (<30 vs. >=30 years, P = 0.37), target of GKS (residual vs. recurrence, P = 0.90), and type of enhancement (homogeneous vs. inhomogeneous, P = 0.19). Two permanent complications occurred with 1 intratumoral hemorrhage and 1 radiation injury. CONCLUSIONS: GKS is effective for CN because of its high rate of long-term local tumor control. GKS may have a potential role as a primary treatment for asymptomatic, relatively small tumors in the absence of hydrocephalus without surgical resection. PMID- 26987640 TI - Tryptophan supplementation modulates social behavior: A review. AB - Tryptophan (TRP), the precursor of serotonin (5-HT), is one of the most investigated amino-acids. TRP supplementation can increase 5-HT levels in the brain and for this reason numerous studies have investigated whether administration of TRP can positively influence social behavior that relies on serotonergic function. Here we review the available studies on TRP, to clarify if and under what circumstances TRP supplementation might modulate social behavior. TRP supplementation seems to improve control over social behavior in patients and individuals suffering from disorders or behaviors associated with dysfunctions in serotonergic functioning. In contrast, in healthy humans TRP supplementation seems to promote social behavior. Although more research is needed to disentangle and understand the relations between individual differences, TRP effectivity, 5 HT functioning, social interactions, and context, we conclude TRP can be a promising tool for modulating social behavior. PMID- 26987639 TI - Outcomes associated with early removal versus retention of peripherally inserted central catheters after diagnosis of catheter-associated infections in neonates. AB - OBJECTIVE: To compare clinical outcomes and hospital resource utilization of infants who had peripherally inserted central catheters removed early versus retained following diagnosis of central line-associated bloodstream infection. STUDY DESIGN: In a single centre retrospective cohort study, we compared outcomes of infants who had peripherally inserted central catheters removed early versus retained after diagnosis of central line-associated bloodstream infection. Mortality, cardio-respiratory deterioration, use of blood products and antibiotics were compared between groups. RESULTS: Over a 10-year period, of the 119 eligible infants, 38 had peripherally inserted central catheters removed early and 81 had catheters retained after diagnosis of central line-associated bloodstream infection. Baseline demographics, illness severity at onset of sepsis and distribution of organisms were similar between the groups. Infants in "catheter-retained" group required longer antibiotic usage (17 +/- 9 versus 13 +/ 6 days; p = 0.025) and more frequent sequential positive blood cultures [31/81 (47%) versus 8/38 (22%), p = 0.014). Infants with Gram-negative bacteremia demonstrated higher mortality when catheters were retained [43% (9/21) versus 7% (1/14); p = 0.028]. CONCLUSIONS: Retaining peripherally inserted central catheters after diagnosis of central line-associated bloodstream infection was associated with longer duration of bacteremia and prolonged exposure to systemic antibiotics as well as increased mortality in Gram-negative bacteremia. PMID- 26987641 TI - Effect of cannabis on glutamate signalling in the brain: A systematic review of human and animal evidence. AB - Use of cannabis or delta-9-tetrahydrocannabinol (Delta9-THC), its main psychoactive ingredient, is associated with psychotic symptoms or disorder. However, the neurochemical mechanism that may underlie this psychotomimetic effect is poorly understood. Although dopaminergic dysfunction is generally recognized as the final common pathway in psychosis, evidence of the effects of Delta9-THC or cannabis use on dopaminergic measures in the brain is equivocal. In fact, it is thought that cannabis or Delta9-THC may not act on dopamine firing directly but indirectly by altering glutamate neurotransmission. Here we systematically review all studies examining acute and chronic effects of cannabis or Delta9-THC on glutamate signalling in both animals and man. Limited research carried out in humans tends to support the evidence that chronic cannabis use reduces levels of glutamate-derived metabolites in both cortical and subcortical brain areas. Research in animals tends to consistently suggest that Delta9-THC depresses glutamate synaptic transmission via CB1 receptor activation, affecting glutamate release, inhibiting receptors and transporters function, reducing enzyme activity, and disrupting glutamate synaptic plasticity after prolonged exposure. PMID- 26987642 TI - Fresh fruit, vegetables, and mushrooms as transmission vehicles for Echinococcus multilocularis in Europe: inferences and concerns from sample analysis data from Poland. AB - Fresh fruit, vegetables, mushrooms, and other fresh produce are recognised as important vehicles of infection for several foodborne parasites, particularly those with a faecal-oral transmission route and robust environmental transmission stages. Nevertheless, analysis of such foods for parasite transmission stages, even during outbreaks, tends to show only low contamination. Echinococcus multilocularis is considered one of the most important foodborne parasites, but there are few studies in which fresh produce or like foods collected in their natural habitat is analysed for contamination with E. multilocularis eggs. In this article, we question a recent study from Poland reporting over 23 % of fresh berries, vegetables, and mushroom being highly contaminated with E. multilocularis eggs. In particular, it appears unlikely that 20 % of raspberries, which are elevated from ground level, should be exposed to faecal contamination. Additionally, the similar egg contamination of vegetation in forest and plantation environments is surprising considering the preference of the parasite's most competent intermediate hosts for the latter environment. Furthermore, a lack of specific temporal information is concerning due to the varying infection pressure (and therefore environmental contamination) occurring in definitive hosts over the course of the year. Several important aspects of the study seem to us to have been neglected, and we are concerned that the published data might, if not questioned, lead to incorrect interpretation, and unnecessary losses in the agricultural sector. PMID- 26987643 TI - Prevalence and predictors associated with intestinal infections by protozoa and helminths in southern Brazil. AB - Approximately 2 billion people are infected with soil-transmitted helminths worldwide, mainly in tropical and subtropical areas. This research aimed to investigate the prevalence and predictors associated with parasitic infections in primary health care. A cross-sectional study was performed with a large random sample to identify the prevalence and predictors associated with parasitic infections in primary health care in Marialva, southern Brazil, from April 2011 to September 2013. Stool samples from 775 individuals were analyzed for the presence of protozoan cysts, helminth eggs, and larvae. The overall prevalence of intestinal parasites was 13.94 %, and the prevalence of protozoa and helminths was 15.1 and 2.9 %, respectively. The predictor variables that were associated with intestinal parasites were male gender odds ratio (OR) 1.60, 95 % confidence interval (CI 1.10-2.40) and the absence of a kitchen garden (OR 2.28, 95 % CI, 1.08-4.85). Positive associations were found between Giardia duodenalis and individuals aged <=18 with high risk (OR 19.0, 95 % CI 2.16-167.52), between Endolimax nana and the absence of a kitchen garden (p < 0.01), and between Trichuris trichiura and the presence of a kitchen garden (p = 0.014). Polyparasitism was present in 27.27 % of infected individuals. Our findings confirmed a relatively low prevalence in primary care, compared to international standards, despite the rare publications in the area. As variables, male gender and the absence of a kitchen garden stood out as important predictors. It is highly relevant that the health conditions of the population comply with consistent standards. PMID- 26987644 TI - The complete mitochondrial genome of Gasterophilus intestinalis, the first representative of the family Gasterophilidae. AB - Gasterophilus spp. (Diptera: Gasterophilidae) has a worldwide distribution; however, no complete mitochondrial (mt) genome data is available for Diptera which has greatly impeded population genetics, phylogenetics, and systematics studies in Gasterophilidae. Mt genome is known to provide genetic markers for investigations in these areas, but complete mt genomic datasets have been lacking for many Gasterophilidae species. Herein, we present the complete mt genome of the third-stage larvae (L3) of Gasterophilus intestinalis from the stomach wall of naturally infected horses in Heilongjiang province (HLJ) and Xinjiang Uygur Autonomous Region (XJ), China. The complete mt genome of G. intestinalis was 15,687 bp (HLJ) and 15,660 bp (XJ) in length and consists of 37 genes, including 13 genes for proteins, 22 genes for tRNA, and 2 genes for rRNA. The gene arrangement is the same as those of Oestroidae species. Phylogenetic analyses using concatenated amino acid sequences of 12 protein-coding genes by Bayesian inference (BI) and maximum likelihood (ML), suggested that the families Gasterophilidae and Oestroidae were more closely related than to Tachinidae. The mt genome of G. intestinalis represents the first mt genome of any member of the family Gasterophilidae. These data provide novel mtDNA markers for studying the molecular epidemiology and population genetics of the G. intestinalis and its congeners. PMID- 26987645 TI - Cysticercus fasciolaris infection induced oxidative stress and apoptosis in rat liver: a strategy for host-parasite cross talk. AB - Parasitic helminths have developed various strategies to induce or inhibit apoptosis in the cells of their host, thereby modulating the host's immune response and aiding dissemination to the host. Cysticercus fasciolaris, the larval form of Taenia taeniaeformis, parasitized different intermediate hosts like rats, rabbits, etc. and is cosmopolitan in distribution. In the present study, we have investigated host-parasite interactions and the resulting effect of C. fasciolaris in the liver of rat. Histology of the infected livers showed dilation and damages of hepatic cells near the parasite. Infected liver cells showed an increase in DNA fragmentation and chromatin condensation compared to the normal liver. Acridine orange and ethidium bromide dual staining revealed the presence of apoptotic cells in the infected liver. The decline in the mitochondrial membrane potential in the infected liver suggested that the observed apoptosis is mitochondria mediated. Occurrence of an elevated level of active executioner caspases 3/7 in the infected rat liver further confirms the occurrence of apoptosis. Different antioxidant enzymes were also evaluated and revealed a notable decline in the level of glutathione and glutathione-S transferase activity leading to the augmented generation of reactive oxygen species. Results of the present study revealed that C. fasciolaris infection leads to apoptosis in the liver of rats which may be a surviving strategy for the parasitic larvae. PMID- 26987647 TI - 'Appropriateness' in Italy: A 'Magic Word' in Pharmaceuticals? PMID- 26987648 TI - Thiazides are useful agents in CKD. PMID- 26987646 TI - Risk factors for recurrent biliary obstruction following placement of self expandable metallic stents in patients with malignant perihilar biliary stricture. AB - BACKGROUND AND STUDY AIM: Self-expandable metallic stents (SEMSs) are used for palliation in patients with malignant perihilar biliary strictures. However, recurrent biliary obstruction occasionally causes cholangitis and jaundice. This study aimed to identify risk factors for recurrent biliary obstruction in such patients. METHODS: Data from consecutive patients with malignant perihilar biliary strictures treated with endoscopic placement of SEMSs between 2007 and 2014 in Tohoku University Hospital were retrospectively reviewed. Risk factors for recurrent biliary obstruction were calculated using the Cox proportional hazards models (with hazard ratios [HRs] and 95 % confidence interval [95 %CIs]), and SEMS patency period was examined using the Kaplan - Meier method. SEMS patency was defined as the period between SEMS insertion and the development of recurrent biliary obstruction. RESULTS: 104 patients were included. Median survival time was 281 days; and 85 patients died during a median follow-up period of 320 days. Recurrent biliary obstruction occurred in 35 patients. Median SEMS patency period was 549 days. Multivariable analyses showed that: compared with bile duct carcinoma, gallbladder carcinoma was associated with shorter SEMS patency (HR 8.18, 95 %CI 2.41 - 26.83); patency of left-sided SEMS was inferior to that of bilateral (HR 0.5, 95 %CI 0.32 - 0.93) and right-sided SEMS (HR 0.1, 95 %CI 0.02 - 0.65). Cholangitis before SEMS placement increased the risk of recurrent biliary obstruction (HR 11.44; 95 %CI 4.48 - 32.35) and reduced the SEMS patency period (746 vs. 210 days). CONCLUSION: Gallbladder carcinoma, left sided stent placement, and cholangitis before SEMS placement are risk factors for recurrent biliary obstruction after SEMS placement. PMID- 26987649 TI - A comparative study of SMILES-based compound similarity functions for drug-target interaction prediction. AB - BACKGROUND: Molecular structures can be represented as strings of special characters using SMILES. Since each molecule is represented as a string, the similarity between compounds can be computed using SMILES-based string similarity functions. Most previous studies on drug-target interaction prediction use 2D based compound similarity kernels such as SIMCOMP. To the best of our knowledge, using SMILES-based similarity functions, which are computationally more efficient than the 2D-based kernels, has not been investigated for this task before. RESULTS: In this study, we adapt and evaluate various SMILES-based similarity methods for drug-target interaction prediction. In addition, inspired by the vector space model of Information Retrieval we propose cosine similarity based SMILES kernels that make use of the Term Frequency (TF) and Term Frequency Inverse Document Frequency (TF-IDF) weighting approaches. We also investigate generating composite kernels by combining our best SMILES-based similarity functions with the SIMCOMP kernel. With this study, we provided a comparison of 13 different ligand similarity functions, each of which utilizes the SMILES string of molecule representation. Additionally, TF and TF-IDF based cosine similarity kernels are proposed. CONCLUSION: The more efficient SMILES-based similarity functions performed similarly to the more complex 2D-based SIMCOMP kernel in terms of AUC-ROC scores. The TF-IDF based cosine similarity obtained a better AUC-PR score than the SIMCOMP kernel on the GPCR benchmark data set. The composite kernel of TF-IDF based cosine similarity and SIMCOMP achieved the best AUC-PR scores for all data sets. PMID- 26987650 TI - Psychometric properties of the HI-FI problem checklist in a sample of adults with neurological and neuropsychiatric disorders: factors contributing to life satisfaction after long-term disability. AB - Purpose To assess psychometric properties of the problem checklist (PCL) in a sample of individuals with neurological and neuropsychiatric disorders many years after trauma; to identify factors that impact life satisfaction and promote functional competence after long-term disability. Method Cross-sectional, interview- and assessment-based study. Participants were community-dwelling adults with disabilities resulting from neurological and neuropsychiatric disorders (N = 53), who participated in a pre-vocational readiness and social skills training program. The Problem Checklist from the New York University Head Injury Family Interview (PCL), a battery of self-rated and clinician-rated measures of social/emotional status, and neuropsychological tests were main outcome measures. Results PCL is a valid and reliable instrument with acceptable psychometric properties (reliability coefficients for two scales and the total score are above (0.795). Use of maladaptive coping strategies in our sample was reflected in inverse relationship between depression and denial of disability, and in the tendency to overrate self-reported symptoms by participants with acquired trauma. Considerably lower self-ratings of symptoms across all PCL scales were seen in those of our participants who live with parents. Conclusions The study offers initial support for the use of PCL as a measure of long-term functional outcome in individuals with neurological and neuropsychiatric diagnoses. The goal of rehabilitation in patients with long-term disabilities is increase in life satisfaction. Implications for Rehabilitation An important goal of rehabilitation and training programs for individuals with long-term disabilities due to dysfunction of the central nervous system is to improve their quality of life. The HI-FI Problem Checklist (PCL) is a brief and efficient instrument for assessing functional outcomes after long-term disability. This study demonstrated acceptable psychometric properties of the PCL in a sample of 53 individuals participating in a pre-vocational training program and provided initial support for its utility for patients with various diagnoses. PMID- 26987651 TI - Reply to Letter to the Editor. PMID- 26987652 TI - Reliability of the Ultrasound Cardiac Output Monitor for Pediatric Patients. PMID- 26987653 TI - Theory of electron spin resonance in bulk topological insulators Bi2Se3, Bi2Te3 and Sb2Te3. AB - We report a theoretical study of electron spin resonance in bulk topological insulators, such as Bi2Se3, Bi2Te3 and Sb2Te3. Using the effective four-band model, we find the electron energy spectrum in a static magnetic field and determine the response to electric and magnetic dipole perturbations, represented by oscillating electric and magnetic fields perpendicular to the static field. We determine the associated selection rules and calculate the absorption spectra. This enables us to separate the effective orbital and spin degrees of freedom and to determine the effective g factors for electrons and holes. PMID- 26987654 TI - Altered neural circuits accompany lower performance during narrative comprehension in children with reading difficulties: an fMRI study. AB - Narrative comprehension is a linguistic ability that is foundational for future reading ability. The aim of the current study was to examine the neural circuitry of children with reading difficulties (RD) compared to typical readers during a narrative-comprehension task. We hypothesized that due to deficient executive functions, which support narrative comprehension abilities, children with RD would display altered activation and functional connectivity, as well as lower performance on a narrative-comprehension task. Children with RD and typical readers were scanned during a narrative-comprehension task and administered reading behavioral tests. Children with RD scored significantly lower on the narrative-comprehension task than did typical readers. Composite activation maps showed more diffused activation during narrative comprehension in the RD group. Maps comparing the two reading groups showed more activation in the frontal lobes (regions responsible for executive functions), and functional connectivity showed higher global efficiency in children with RD than in typical readers. Global efficiency was negatively correlated with phonological awareness and reading and executive function scores in the entire study group. Children with RD may suffer from narrative-comprehension difficulties due to diffused activation of language areas, as was observed during a narrative-comprehension task. Greater effort in this task may be reflected by the engagement of brain regions related to executive functions and higher functional connectivity or attributed to difficulties in phonological processing and reading and executive functions. Therefore, the accommodation given to children with RD of reading aloud may need to be revised due to the observed difficulty in this domain. PMID- 26987655 TI - K(+)-Induced in situ self-assembly of near-infrared luminescent membrane material armored with bigger Yb(III) complex crystallites. AB - A semi-rigid ligand could capture effectively Yb(3+) ions to form a stable Yb(3+) complex and provide a potential cavity to accommodate alkali metal ions. Only K(+) ions could induce the Yb(3+) complex to form a 1D coordination polymer and promote the in situ formation of an NIR membrane coated with bigger Yb(3+) complex crystallites under mild conditions. PMID- 26987656 TI - The effects of ventricular drainage on the intracranial pressure signal and the pressure reactivity index. AB - In subarachnoid hemorrhage (SAH) patients intracranial pressure (ICP) is usually monitored via an extraventricular drain (EVD), which can produce false readings when the drain is open. It is established that both the ICP cardiac pulse frequency and long term trends over several hours are often seriously corrupted. The aim of this study was to establish whether or not the intermediate frequency bands [respiratory, Mayer wave and very low frequency (VLF)] were also corrupted. The VLF range is of special interest because it is important in cerebral autoregulation studies. Using a pattern recognition algorithm we retrospectively identified 718 cases of EVD opening in 80 SAH patients. An analysis of differences between closed and open-drain periods showed that ICP amplitude decreased significantly in all of the three lower frequency bands when the EVD was open. A similar analysis of systemic arterial pressure signal revealed similar changes in the same frequency bands that were positively correlated with the ICP changes. Therefore we concluded that the changes in the ICP signal represented real, physiological changes and not artifact. Pressure reactivity index (PRx) values were also computed during closed and open-drain periods. We found a small but statistically significant decrease during open-drain periods. Based on analysis of the change in the PRx distribution during open drainage we concluded that this decrease also represented physiological changes rather than artifact. In summary the ICP respiratory, Mayer wave, and VLF frequency bands are not corrupted when the EVD is open, and it safe to use these for autoregulation studies. PMID- 26987657 TI - Psychosocial Influences on Parental Decision-Making Regarding Vaccination Against Seasonal Influenza for Young Children in Hong Kong: a Longitudinal Study, 2012 2013. AB - PURPOSE: Vaccination uptake remained low, although annual subsidies are provided to encourage 6-72-month-old Hong Kong children to be vaccinated against seasonal influenza. This study was aimed to investigate the psychosocial influences on parental decision-making regarding young children's seasonal influenza vaccination. METHODS: One-thousand two-hundred twenty-six parents of eligible children were recruited using random digit dialing in August-October 2012 to assess baseline perceptions and re-contacted in March 2013 to record children's vaccination uptake. Structural equation modeling (SEM) was performed to examine factors associated with parental decision about children's vaccination based on the complete data of 1222 respondents. RESULTS: Of the 1226 respondents who completed the follow-up survey, 34.3 % reported that their child was vaccinated during the follow-up period. Child's past influenza vaccination history (beta = 0.48), belief in vaccination safety (beta = 0.35), and social norms (beta = 0.25) were strongly associated with parental intention to vaccinate their child which directly predicted child vaccination uptake (beta = 0.57). Belief in vaccination safety (beta = 0.42) and social norms (beta = 0.36) were strongly associated with vaccination intention of parents whose children never received influenza vaccine. CONCLUSION: Interventions that address concerns on vaccination safety and utilize social norms may be effective to initiate Chinese parents to vaccinate their children. PMID- 26987658 TI - Preventing childhood obesity in early care and education settings: lessons from two intervention studies. AB - BACKGROUND: Obesity prevention in young children is a public health priority. In the USA, nearly 10% of children less than 5 years of age are obese, and most attend some form of out-of-home child care. While a number of interventions have been conducted in early care and education settings, few have targeted the youngest children in care or the less formal types of child care like family child care homes. Additionally, only two previous studies provided recommendations to help inform future interventions. METHODS: This paper presents lessons learned from two distinct intervention studies in early care and education settings to help guide researchers and public health professionals interested in implementing and evaluating similar interventions. We highlight two studies: one targeting children ages 4 to 24 months in child care centres and the other intervening in children 18 months to 4 years in family child care homes. We include lessons from our pilot studies and the ongoing larger trials. RESULTS: To date, our experiences suggest that an intervention should have a firm basis in behaviour change theory; an advisory group should help evaluate intervention materials and plan for delivery; and realistic recruitment goals should recognize economic challenges of the business of child care. A flexible data collection approach and realistic sample size calculations are needed because of high rates of child (and sometimes facility) turnover. An intervention that is relatively easy to implement is more likely to appeal to a wide variety of early care and education providers. CONCLUSIONS: Interventions to prevent obesity in early care and education have the potential to reach large numbers of children. It is important to consider the unique features and similarities of centres and family child care homes and take advantage of lessons learned from current studies in order to develop effective, evidence-based interventions. PMID- 26987659 TI - Refactoring the lambda phage lytic/lysogenic decision with a synthetic regulator. AB - In this work, we explore the refactoring of the circuitry of lambda phage by engineering a new-to-nature regulator that responds to an ad hoc input signal that behaves orthogonal with respect to the host cell. We tailored a chimeric regulator, termed Qlambda, between the CI protein of the lambda phage and the BzdR repressor from Azoarcus sp. strain CIB that responds to benzoyl-CoA. When the Qlambda was expressed in the appropriate Escherichia coli cells, it was able to reprogram the lytic/lysogenic lambda phage decision according to the intracellular production of benzoyl-CoA. Our results are also an example of how generating new artificial regulators that respond to effectors of choice may be useful to control different cellular processes. PMID- 26987661 TI - Intraoperative 3D imaging in the treatment of elbow fractures--a retrospective analysis of indications, intraoperative revision rates, and implications in 36 cases. AB - BACKGROUND: Three-dimensional (3D) imaging with a mobile C-arm has proven to be a valuable intraoperative tool in trauma surgery. However, little data is available concerning its use in the treatment of elbow fractures. The aim of the current study was to determine the intraoperative findings and consequences of 3D imaging in the treatment of elbow fractures. METHODS: Between 2001 and 2015, prospectively collected data of 36 patients who underwent intraoperative 3D imaging during elbow surgery were recorded. The findings and consequences of the intraoperative 3D scans were analyzed in a retrospective chart review. For clinical evaluation the analysis included the patients' medical history, the injury pattern of the affected elbow and concomitant injuries. Intraoperative and postoperative complications and revision surgeries were evaluated as well. RESULTS: In 6 patients (16.7%) analysis of the intraoperative 3D scan led to an immediate revision due to the detection of intra-articular screw placement (n = 3, 8.3%) and remaining intra-articular step of >2 mm (n = 3, 8.3%). In all of these patients, correct implant positioning and anatomical reduction could be achieved after immediate intraoperative revision, which was verified by a repeated intraoperative 3D scan. None of the 36 patients needed surgical revision based on postoperative radiological examinations due to secondary dislocation, wrong implant placement or remaining steps in the articular surface. CONCLUSIONS: Intraoperative 3D imaging offers additional information about fracture reduction and implant positioning in the treatment of elbow fractures compared to conventional intraoperative 2D imaging. It may therefore reduce the need for revision surgery. The value of intraoperative 3D imaging for clinical outcomes still needs to be assessed. PMID- 26987662 TI - Blending of brain-machine interface and vision-guided autonomous robotics improves neuroprosthetic arm performance during grasping. AB - BACKGROUND: Recent studies have shown that brain-machine interfaces (BMIs) offer great potential for restoring upper limb function. However, grasping objects is a complicated task and the signals extracted from the brain may not always be capable of driving these movements reliably. Vision-guided robotic assistance is one possible way to improve BMI performance. We describe a method of shared control where the user controls a prosthetic arm using a BMI and receives assistance with positioning the hand when it approaches an object. METHODS: Two human subjects with tetraplegia used a robotic arm to complete object transport tasks with and without shared control. The shared control system was designed to provide a balance between BMI-derived intention and computer assistance. An autonomous robotic grasping system identified and tracked objects and defined stable grasp positions for these objects. The system identified when the user intended to interact with an object based on the BMI-controlled movements of the robotic arm. Using shared control, BMI controlled movements and autonomous grasping commands were blended to ensure secure grasps. RESULTS: Both subjects were more successful on object transfer tasks when using shared control compared to BMI control alone. Movements made using shared control were more accurate, more efficient, and less difficult. One participant attempted a task with multiple objects and successfully lifted one of two closely spaced objects in 92 % of trials, demonstrating the potential for users to accurately execute their intention while using shared control. CONCLUSIONS: Integration of BMI control with vision-guided robotic assistance led to improved performance on object transfer tasks. Providing assistance while maintaining generalizability will make BMI systems more attractive to potential users. TRIAL REGISTRATION: NCT01364480 and NCT01894802 . PMID- 26987664 TI - Community -and hospital laboratory-based surveillance for respiratory viruses. AB - Traditional surveillance for respiratory viruses relies on symptom detection and laboratory detection during medically attended encounters for acute respiratory infection/influenza-like illness (ARI/ILI). Ecological momentary reporting using text messages is a novel method for surveillance. This study compares respiratory viral activity detected through longitudinal community-based surveillance using text message responses for sample acquisition and testing to respiratory viral activity obtained from hospital laboratory data from the same community. We demonstrate a significant correlation between community- and hospital laboratory based surveillance for most respiratory viruses, although the relative proportions of viruses detected in the community and hospital differed significantly. PMID- 26987663 TI - Traumatic injuries among adult obese patients in southern Taiwan: a cross sectional study based on a trauma registry system. AB - BACKGROUND: The adverse impact of obesity has been extensively studied in the general population; however, the added risk of obesity on trauma-related mortality remains controversial. This study investigated and compared mortality as well injury patterns and length of stay (LOS) in obese and normal-weight patients hospitalized for trauma in the hospital and intensive care unit (ICU) of a Level I trauma center in southern Taiwan. METHODS: Detailed data of 880 obese adult patients with body mass index (BMI) >= 30 kg/m(2) and 5391 normal-weight adult patients (25 > BMI >= 18.5 kg/m(2)) who had sustained a trauma injury between January 1, 2009 and December 31, 2013 were retrieved from the Trauma Registry System. Pearson's chi-squared, Fisher's exact, and independent Student's t-tests were used to compare differences between groups. Propensity score matching with logistic regression was used to evaluate the effect of obesity on mortality. RESULTS: In this study, obese patients were more often men, motorcycle riders and pedestrians, and had a lower proportion of alcohol intoxication compared to normal-weight patients. Analysis of Abbreviated Injury Scale scores revealed that obese trauma patients presented with a higher rate of injury to the thorax, but a lower rate of facial injuries than normal-weight patients. No significant differences were found between obese and normal-weight patients regarding Injury Severity Score (ISS), Trauma-Injury Severity Score (TRISS), mortality, the proportion of patients admitted to the ICU, or LOS in ICU. After propensity score matching, logistic regression of 66 well-matched pairs did not show a significant influence of obesity on mortality (odds ratio: 1.51, 95% confidence interval: 0.54-4.23 p = 0.438). However, significantly longer hospital LOS (10.6 vs. 9.5 days, respectively, p = 0.044) was observed in obese patients than in normal-weight patients, particularly obese patients with pelvic, tibial, or fibular fractures. CONCLUSION: Compared to normal-weight patients, obese patients presented with different injury characteristics and bodily injury patterns but no difference in mortality. PMID- 26987665 TI - The role of hydrogen in oxygen-assisted chemical vapor deposition growth of millimeter-sized graphene single crystals. AB - Involving oxygen in the traditional chemical vapor deposition (CVD) process has proven a promising approach to achieve large-scale graphene single crystals (GSCs), but its many relevant fundamental aspects are still not fully understood. Here we report a systematic study on the role of hydrogen in the growth of millimeter-sized GSCs using enclosure-like Cu structures via the oxygen-assisted CVD process. Results show that GSCs have different first layer growth behaviors on the inside and outside surfaces of a Cu enclosure when the H2 environment is varied, and these behaviors will consequently and strongly influence the adlayer formation in these GSCs, leading to two entirely different growth modes. Low H2 partial pressure (PH2) tends to result in fast growth of dendritically shaped GSCs with multiple small adlayers, but high PH2 can modify the GSC shape into hexagons with single large adlayer nuclei. This difference of adlayers is attributed to the different C diffusion paths determined by the shapes of their host GSCs. On the basis of these observations, we developed an isothermal two step method to obtain GSCs with significantly improved growth rate and sample quality, in which low PH2 is first set to accelerate the growth rate followed by high PH2 to restrict the adlayer nuclei. Our results prove that the growth of GSCs can reach a reasonable optimization between their growth rates and sample quality by simply adjusting the CVD H2 environment, which we believe will lead to more improvements in graphene synthesis and fundamental insight into the related growth mechanisms. PMID- 26987666 TI - Drilling and modeling studies expose Antarctica's Miocene secrets. PMID- 26987667 TI - Tuning in by tuning out distractions. PMID- 26987668 TI - Proteomic analysis of Rhodotorula mucilaginosa: dealing with the issues of a non conventional yeast. AB - Red yeasts ascribed to the species Rhodotorula mucilaginosa are gaining increasing attention, due to their numerous biotechnological applications, spanning carotenoid production, liquid bioremediation, heavy metal biotransformation and antifungal and plant growth-promoting actions, but also for their role as opportunistic pathogens. Nevertheless, their characterization at the 'omic' level is still scarce. Here, we applied different proteomic workflows to R. mucilaginosa with the aim of assessing their potential in generating information on proteins and functions of biotechnological interest, with a particular focus on the carotenogenic pathway. After optimization of protein extraction, we tested several gel-based (including 2D-DIGE) and gel-free sample preparation techniques, followed by tandem mass spectrometry analysis. Contextually, we evaluated different bioinformatic strategies for protein identification and interpretation of the biological significance of the dataset. When 2D-DIGE analysis was applied, not all spots returned a unambiguous identification and no carotenogenic enzymes were identified, even upon the application of different database search strategies. Then, the application of shotgun proteomic workflows with varying levels of sensitivity provided a picture of the information depth that can be reached with different analytical resources, and resulted in a plethora of information on R. mucilaginosa metabolism. However, also in these cases no proteins related to the carotenogenic pathway were identified, thus indicating that further improvements in sequence databases and functional annotations are strictly needed for increasing the outcome of proteomic analysis of this and other non-conventional yeasts. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26987669 TI - Evaluation of the MicroSEQTM Salmonella spp. Detection Kit with the PrepSEQTM Rapid Spin Sample Preparation Kit for Detection of Salmonella spp. in Dry Pet Food. AB - A method modification validation study was conducted to validate the Applied Biosystems MicroSEQTM Salmonella spp. Detection Kit for the detection of Salmonella spp. in 375 g samples of dried pet food. The MicroSEQ assay protocol, using the Applied Biosystems PrepSEQTM Rapid Spin DNA Sample Preparation Kit, was compared to the reference method detailed in the U.S Food and Drug Administration (FDA) Bacteriological Analytical Manual (BAM; Chapter 5, Salmonella) for detection of Salmonella spp. For each method, 20 replicates were analyzed at a low contamination level of 0.2-2 CFU/test portion, five replicates were analyzed at a high level of contamination of 2-5 CFU/test portion, and five control replicates were also analyzed at 0 CFU/test portion (uninoculated). Statistical analysis was conducted using the Probability of Detection statistical test to determine the ability of the MicroSEQ Salmonella spp. Detection Kit to detect Salmonella from 375 g samples of dried pet food in comparison to the FDA-BAM reference method. The results demonstrated that the MicroSEQ Salmonella spp. Detection Kit was able to accurately detect Salmonella spp. present in dry pet food after an enrichment time of 20 h. PMID- 26987670 TI - Effects of regions of interest methods on apparent coefficient measurement of the parotid gland in early Sjogren's syndrome at 3T MRI. AB - BACKGROUND: The apparent diffusion coefficient (ADC) has been used to assess parotid gland abnormalities in Sjogren's syndrome (SS) patients; however, few data exist on the influence of region of interest (ROI) methods on ADC measurements. PURPOSE: To assess the influence of ROI methods on ADC measurement, and their diagnostic ability in detecting parotid gland abnormalities in early SS patients. MATERIAL AND METHODS: Thirteen early SS patients underwent parotid gland diffusion-weighted imaging scans at a 3.0 T MR unit. Two readers independently measured the parotid gland ADC value using three different ROIs (whole-gland [WG], single-slice [SS], and reader-based circular [RBC]). The ADC value based on three different ROIs (ADC-ROIWG, ADC-ROISS, ADC-ROIRBC) were compared between the SS group and a matched healthy control (HC) group (n = 19). Receiver operating characteristic (ROC) curves and intra-class correlation coefficients (ICC) were used to determine the diagnostic ability and reproducibility of the parameters. RESULTS: The ADC-ROIWG, ADC-ROISS, and ADC ROIRBC in the SS group were all significantly higher than those in HC group (all P < 0.05). The ADC-ROIWG showed better diagnostic ability than did ADC-ROIRBC (P = 0.0200), while no significant difference was found between ADC-ROIWG and ADC ROISS (P = 0.4636). The ROIWG method showed the best inter- and intra-reader agreement (ICC, 0.902 and 0.928, respectively), followed by ROISS and ROIRBC. CONCLUSION: The ROI methods can influence the parotid gland ADC measurements and their diagnostic ability. Considering our results, we suggest using in clinical practice single-slice ROIs to measure the ADC of the parotid gland. PMID- 26987671 TI - Classification of spondylolytic clefts in patients with spondylolysis or isthmic spondylolisthesis using positional MRI. AB - Background Posterior instability is a pathologic movement occurring in the spondylolytic cleft. Purpose To present a new classification system for the evaluation of spondylolytic cleft by positional magnetic resonance imaging (MRI) and determine the prevalence of the different types. Material and Methods A total of 176 segments of the lumbar spine with spondylolysis or isthmic spondylolisthesis were examined using positional MRI. Scans were obtained in neutral sitting, flexion, and extension positions. No visible movement in the cleft was defined as type A, fluid displaced into the cleft as type BI, displacement of the flava ligaments at the level of the cleft as type BII, and intraspinal cysts arising from the spondylolytic cleft as type BIII. The movements were characterized by a radiologist and a neurosurgeon experienced in positional MRI. Clinical findings were correlated with the different types of instability. Results A high agreement was found between the two observers. In total, 131 segments were characterized as type A, six as type BI, 24 as type BII, and 10 as type BIII. In five segments, the type differed between the right and the left side. Two patients had a mixed type BI/II, another two patients had a mixed type BII/III, and one patient had a mixed type BI/III. Patients with type BII and BIII instabilities suffered more often from radicular symptoms compared to patients without any instability. Conclusion The presented classification might help to better understand and study changes encountered in the spondylolytic cleft in patients with spondylolysis and isthmic spondylolisthesis using positional MRI. PMID- 26987672 TI - Hemobilia following laparoscopic cholecystectomy: computed tomography findings and clinical outcome of transcatheter arterial embolization. AB - BACKGROUND: Hemobilia following laparoscopic cholecystectomy (LC) can occur in the early or late postoperative course and poses a diagnostic and therapeutic challenge. PURPOSE: To assess computed tomography (CT) findings and clinical outcomes after transcatheter arterial embolization (TAE) in patients presenting with hemobilia following LC. MATERIAL AND METHODS: Fourteen patients treated for hemobilia following LC were included in the study. Three patients were diagnosed by endoscopy and 11 by abdominal contrast-enhanced CT. Coils or microcoils were superselectively deployed to occlude the bleeding vessel during TAE. Abdominal CT findings of hemobilia, and the success rate and complication of TAE were observed. RESULTS: Abdominal CT provided the following signs of hemobilia: hematoma within the abdominal cavity and gallbladder fossa, blood clots containing high attenuation within the bile duct, biliary dilatation, pseudoaneurysm of the right hepatic artery, contrast extravasation, enhancement of the bile duct wall, and hypoperfusion of the right lobe. The success rate of TAE was 100% and rebleeding did not occur in any patient. Post-embolization syndrome and hepatic ischemia occurred in nine patients, which was associated with age and the time interval between the LC and TAE. CONCLUSION: Abdominal CT provided direct signs that can aid in the diagnosis of hemobilia after LC. TAE allowed for successful treatment of hemobilia with minor complications. PMID- 26987673 TI - Multifunctional Hydrogels with Temperature, Ion, and Magnetocaloric Stimuli Responsive Performances. AB - In this work, multifunctional hydrogels with vivid color change and shrinking swelling response to temperature, ion strength, and alternating magnetic field are fabricated via magnetic assembly. The hydrogels show gradual shift colors from yellowish green to green, cyan, blue, purple, and even reddish violet in response to temperature or ion strength. In the response process, the whole color modulation process is fully reversible and transferable along with a relative short response time. Especially, the magnetism and porous structure of the hybrid hydrogel enable it to be a potential carrier for hydrophobic molecules. Taking advantage of the magnetocaloric responsiveness, the dyed oil loaded hydrogel exhibits a controllable release behavior in each reversible shrinking-swelling cycle under an alternating magnetic field. This multi-responsive hydrogel can hold promise for practical engineering applications, including sensors, displays, and controlled release. PMID- 26987675 TI - An experimental challenge model of visceral leishmaniasis by Leishmania donovani promastigotes in mice. AB - Although visceral leishmaniasis is a fatal disease in humans and dogs, the use of mouse models is important for obtaining a better understanding of the pathogenesis, immunity, and host-parasite interactions of this disease. Such models are also useful for the evaluation of vaccines and chemotherapies for treatment of visceral leishmaniasis. Here, we present our method of experimental inoculation of mice with Leishmania donovani promastigotes. Nutrient-enriched undefined media may be beneficial for laboratory maintenance of promastigotes for maintaining their virulence or infectivity in mice. With this method, we could preserve the infectivity of promastigote lines recovered from inoculated animals and use these lines for further in vivo experiments. Furthermore, the use of cryopreserved stabilates is highly recommended for the reproducibility of experiments. To assess a newly developed method for determination of parasite burden in infected animal tissues, initial comparison of parasite burden in the liver obtained in the classic Leishman-Donovan units (LDU) with values obtained from the new method is recommended. As an example, the association between parasite burden determined by LDU and real-time PCR assay targeting the leishmanial gp63 gene in the liver of mice is presented. PMID- 26987676 TI - Detailed methodology for high resolution scanning electron microscopy (SEM) of murine malaria parasitized-erythrocytes. AB - Scanning electron microscopy (SEM) is a powerful tool used to investigate object surfaces and has been widely applied in both material science and biology. With respect to the study of malaria, SEM revealed that erythrocytes infected with Plasmodium falciparum, a human parasite, display 'knob-like' structures on their surface comprising parasitized proteins. However, detailed methodology for SEM studies of malaria parasites is lacking in the literature making such studies challenging. Here, we provide a step-by-step guide to preparing Plasmodium infected erythrocytes from two mouse strains for SEM analysis with minimal structural deterioration. We tested three species of murine malaria parasites, P. berghei, P. yoelii, and P. chabaudi, as well as non-parasitized human erythrocytes and P. falciparum-infected erythrocytes for comparisons. Our data demonstrated that the surface structures of parasitized erythrocytes between the three species of murine parasites in the two different strains of mice were indistinguishable and no surface alterations were observed in P. falciparum erythrocytes. Our SEM observations contribute towards an understanding of the molecular mechanisms of parasite maturation in the erythrocyte cytoplasm and, along with future studies using our detailed methodology, may help to gain insight into the clinical phenomena of human malaria. PMID- 26987674 TI - Serum From Advanced Heart Failure Patients Promotes Angiogenic Sprouting and Affects the Notch Pathway in Human Endothelial Cells. AB - It is unknown whether components present in heart failure (HF) patients' serum provide an angiogenic stimulus. We sought to determine whether serum from HF patients affects angiogenesis and its major modulator, the Notch pathway, in human umbilical vein endothelial cells (HUVECs). In cells treated with serum from healthy subjects or from patients at different HF stage we determined: (1) Sprouting angiogenesis, by measuring cells network (closed tubes) in collagen gel. (2) Protein levels of Notch receptors 1, 2, 4, and ligands Jagged1, Delta like4. We found a higher number of closed tubes in HUVECs treated with advanced HF patients serum in comparison with cells treated with serum from mild HF patients or controls. Furthermore, as indicated by the reduction of the active form of Notch4 (N4IC) and of Jagged1, advanced HF patients serum inhibited Notch signalling in HUVECs in comparison with mild HF patients' serum and controls. The circulating levels of NT-proBNP (N-terminal of the pro-hormone brain natriuretic peptide), a marker for the detection and evalutation of HF, were positively correlated with the number of closed tubes (r = 0.485) and negatively with Notch4IC and Jagged1 levels in sera-treated cells (r = -0.526 and r = -0.604, respectively). In conclusion, we found that sera from advanced HF patients promote sprouting angiogenesis and dysregulate Notch signaling in HUVECs. Our study provides in vitro evidence of an angiogenic stimulus arising during HF progression and suggests a role for the Notch pathway in it. J. Cell. Physiol. 231: 2700-2710, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26987677 TI - Conserved interaction of Ctf18-RFC with DNA polymerase epsilon is critical for maintenance of genome stability in Saccharomyces cerevisiae. AB - Human Ctf18-RFC, a PCNA loader complex, interacts with DNA polymerase epsilon (Polepsilon) through a structure formed by the Ctf18, Dcc1 and Ctf8 subunits. The C-terminal stretch of Ctf18, which is highly conserved from yeast to human, is necessary to form the Polepsilon-capturing structure. We found that in the budding yeast Saccharomyces cerevisiae, Ctf18, Dcc1 and Ctf8 formed the same structure through the conserved C-terminus and interacted specifically with Polepsilon. Thus, the specific interaction of Ctf18-RFC with Polepsilon is a conserved feature between these proteins. A C-terminal deletion mutant of Ctf18 (ctf18(DeltaC) ) exhibited the same high sensitivity to hydroxyurea as the complete deletion strain (ctf18Delta) or ATPase-deficient mutant (ctf18(K189A) ), but was somewhat less sensitive to methyl methanesulfonate than either of them. These phenotypes were also observed in dcc1Delta and ctf8Delta, predicted to be deficient in the interaction with Polepsilon. Furthermore, both plasmid loss and gross chromosomal rearrangement (GCR) rates were increased in ctf18(DeltaC) cells to the same extent as in ctf18Delta cells. These results indicate that the Ctf18 RFC/Polepsilon interaction plays a crucial role in maintaining genome stability in budding yeast, probably through recruitment of this PCNA loader to the replication fork. PMID- 26987678 TI - Effects of the antipsychotic paliperidone on stress-induced changes in the endocannabinoid system in rat prefrontal cortex. AB - Objectives There is a need to explore novel mechanisms of action of existing/new antipsychotics. One potential candidate is the endocannabinoid system (ECS). The present study tried to elucidate the effects of the antipsychotic paliperidone on stress-induced ECS alterations. Methods Wister rats were submitted to acute/chronic restraint stress. Paliperidone (1 mg/kg) was given prior each stress session. Cannabinoid receptors and endocannabinoids (eCBs) synthesis and degradation enzymes were measured in prefrontal cortex (PFC) samples by RT-PCR and Western Blot. Results In the PFC of rats exposed to acute stress, paliperidone increased CB1 receptor (CB1R) expression. Furthermore, paliperidone increased the expression of the eCB synthesis enzymes N acylphosphatidylethanolamine- hydrolysing phospholipase D and DAGLalpha, and blocked the stress-induced increased expression of the degrading enzyme fatty acid amide hydrolase. In chronic conditions, paliperidone prevented the chronic stress-induced down-regulation of CB1R, normalised DAGLalpha expression and reverted stress-induced down-regulation of the 2-AG degrading enzyme monoacylglycerol lipase. ECS was analysed also in periphery. Acute stress decreased DAGLalpha expression, an effect prevented by paliperidone. Contrarily, chronic stress increased DAGLalpha and this effect was potentiated by paliperidone. Conclusions The results obtained described a preventive effect of paliperidone on stress-induced alterations in ECS. Considering the diverse alterations on ECS described in psychotic disease, targeting ECS emerges as a new therapeutic possibility. PMID- 26987679 TI - ECDC publishes updated evidence-based guidance for chlamydia prevention and control and makes latest chlamydia figures available online through interactive Surveillance Atlas. PMID- 26987680 TI - Robust fluence map optimization via alternating direction method of multipliers with empirical parameter optimization. AB - For the treatment planning during intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT), beam fluence maps can be first optimized via fluence map optimization (FMO) under the given dose prescriptions and constraints to conformally deliver the radiation dose to the targets while sparing the organs-at-risk, and then segmented into deliverable MLC apertures via leaf or arc sequencing algorithms. This work is to develop an efficient algorithm for FMO based on alternating direction method of multipliers (ADMM). Here we consider FMO with the least-square cost function and non-negative fluence constraints, and its solution algorithm is based on ADMM, which is efficient and simple-to-implement. In addition, an empirical method for optimizing the ADMM parameter is developed to improve the robustness of the ADMM algorithm. The ADMM based FMO solver was benchmarked with the quadratic programming method based on the interior-point (IP) method using the CORT dataset. The comparison results suggested the ADMM solver had a similar plan quality with slightly smaller total objective function value than IP. A simple-to-implement ADMM based FMO solver with empirical parameter optimization is proposed for IMRT or VMAT. PMID- 26987681 TI - Pharmacokinetics and Pharmacodynamics for Medical Students: A Proposed Course Outline. PMID- 26987682 TI - Pt-free carbon-based fuel cell catalyst prepared from spherical polyimide for enhanced oxygen diffusion. AB - The development of a non-precious metal (NPM) fuel cell catalyst is extremely important to achieve globalization of polymer electrolyte fuel cells due to the cost and scarcity of platinum. Here, we report on a NPM cathode catalyst prepared by the pyrolysis of spherical polyimide nanoparticles that contain small amounts of Fe additive. 60 nm diameter Fe-containing polyimide nanoparticles were successfully synthesized by the precipitation polymerization of pyromellitic acid dianhydride and 1,3,5-tris(4-aminophenyl)benzene with Fe(acac)3 (acac = acetylacetonate) as an additive. The particles were subsequently carbonized by multistep pyrolysis to obtain the NPM catalyst while retaining the small particle size. The catalyst has good performance and promising durability for fuel cell applications. The fuel cell performance under a 0.2 MPa air atmosphere at 80 degrees C of 1.0 A cm(-2) at 0.46 V is especially remarkable and better than that previously reported. PMID- 26987683 TI - Effects of Microporosity and Surface Chemistry on Separation Performances of N Containing Pitch-Based Activated Carbons for CO2/N2 Binary Mixture. AB - In this study, N-containing pitch-based activated carbons (NPCs) were prepared using petroleum pitch with a low softening point and melamine with a high nitrogen content. The major advantage of the preparation method is that it enables variations in chemical structures and textural properties by steam activation at high temperatures. The adequate micropore structures, appropriate chemical modifications, and high adsorption enthalpies of NPCs are favorable for CO2 adsorption onto carbon surfaces. Furthermore, the structure generates a considerable gas/N-containing carbon interfacial area, and provides selective access to CO2 molecules over N2 molecules by offering an increased number of active sites on the carbon surfaces. The highest CO2/N2 selectivity, i.e., 47.5, and CO2 adsorption capacity for a CO2/N2 (0.15:0.85) binary gas mixture, i.e., 5.30 tw%, were attained at 298 K. The NPCs also gave reversible and durable CO2 capturing performances. All the results suggest that NPCs are promising CO2 sorbents, which can meet the challenges of current CO2 capture and separation techniques. PMID- 26987684 TI - A CEP215-HSET complex links centrosomes with spindle poles and drives centrosome clustering in cancer. AB - Numerical centrosome aberrations underlie certain developmental abnormalities and may promote cancer. A cell maintains normal centrosome numbers by coupling centrosome duplication with segregation, which is achieved through sustained association of each centrosome with a mitotic spindle pole. Although the microcephaly- and primordial dwarfism-linked centrosomal protein CEP215 has been implicated in this process, the molecular mechanism responsible remains unclear. Here, using proteomic profiling, we identify the minus end-directed microtubule motor protein HSET as a direct binding partner of CEP215. Targeted deletion of the HSET-binding domain of CEP215 in vertebrate cells causes centrosome detachment and results in HSET depletion at centrosomes, a phenotype also observed in CEP215-deficient patient-derived cells. Moreover, in cancer cells with centrosome amplification, the CEP215-HSET complex promotes the clustering of extra centrosomes into pseudo-bipolar spindles, thereby ensuring viable cell division. Therefore, stabilization of the centrosome-spindle pole interface by the CEP215-HSET complex could promote survival of cancer cells containing supernumerary centrosomes. PMID- 26987685 TI - Telocytes in exercise-induced cardiac growth. AB - Exercise can induce physiological cardiac growth, which is featured by enlarged cardiomyocyte cell size and formation of new cardiomyocytes. Telocytes (TCs) are a recently identified distinct interstitial cell type, existing in many tissues and organs including heart. TCs have been shown to form a tandem with cardiac stem/progenitor cells in cardiac stem cell niches, participating in cardiac regeneration and repair. Although exercise-induced cardiac growth has been confirmed as an important way to promote cardiac regeneration and repair, the response of cardiac TCs to exercise is still unclear. In this study, 4 weeks of swimming training was used to induce robust healthy cardiac growth. Exercise can induce an increase in cardiomyocyte cell size and formation of new cardiomyocytes as determined by Wheat Germ Lectin and EdU staining respectively. TCs were identified by three immunofluorescence stainings including double labelling for CD34/vimentin, CD34/platelet-derived growth factor (PDGF) receptor-alpha and CD34/PDGF receptor-beta. We found that cardiac TCs were significantly increased in exercised heart, suggesting that TCs might help control the activity of cardiac stem/progenitor cells, cardiomyocytes or endothelial cells. Adding cardiac TCs might help promote cardiac regeneration and renewal. PMID- 26987687 TI - Sexually Transmitted Infection Testing Among Adolescents and Young Adults in the United States. AB - PURPOSE: Persons aged 15-25 years have high sexually transmitted infection (STI) rates and suboptimal screening. There has been limited research analyzing barriers to STI testing at a national level. We examined STI testing among 15-25 year olds and reasons for not testing. METHODS: We used data from a national survey of youth. Bivariate and multivariable analyses examined differences in testing behaviors by demographics, separately by sex. Among sexually experienced respondents who reported never being tested, health system-related reasons for not testing were examined in bivariate and multivariable analyses. RESULTS: Females (16.6%) were more likely to have ever been tested compared with males (6.1%, p < .01) in the last 12 months. Among sexually experienced respondents who were never tested, 41.8% did not seek testing because they felt they were not at risk for STIs. Males (60.1%) had significantly higher reports of foregoing testing for confidentiality reasons compared with females (39.9%, p < .01). Non Hispanic whites (44.9%) the highest reports of this compared with other ethnic/racial groups (p < .01). CONCLUSIONS: This national-level study found that most of the 15-25 year olds never received an STI test. In addition, confidentiality concerns may deter youth from seeking STI testing. Appropriate strategies to minimize these concerns may be useful. Potential strategies to ameliorate these issues may include engaging clinicians who frequently serve adolescents and young adults to address confidentiality issues with youth patients. PMID- 26987688 TI - Micro-Computed Tomography Study of Filling Material Removal from Oval-shaped Canals by Using Rotary, Reciprocating, and Adaptive Motion Systems. AB - INTRODUCTION: This study evaluated filling material removal from distal oval shaped canals of mandibular molars with rotary, reciprocating, and adaptive motion systems by using micro-computed tomography. METHODS: After cone-beam computed tomography scanning, 21 teeth were selected, prepared up to a size 40 file, root filled, and divided into 3 groups (n = 7) according to the filling material removal technique: group PTUR, ProTaper Universal Retreatment combined with ProTaper Universal F2, F3, F4, and F5 files; group RP, Reciproc R50 file; and group TFA: TF Adaptive 50.04 files. The specimens were scanned preoperatively and postoperatively to assess filling material removal by using micro-computed tomography imaging, and the percent volume of residual filling material was calculated. RESULTS: The statistical analysis showed the lowest percent volume of residual filling material at the coronal third in all groups (P < .05). There was no significant difference among the systems in the coronal third (P > .05). In the middle third, group TFA (31.2 +/- 10.1) showed lower volume of residual filling material than group RP (52.4 +/- 14.1) (P < .05). In the apical third, groups TFA (44.8 +/- 20.6) and PTUR (48.6 +/- 16.8) presented a lower percent volume of filling material than group RP (70.6 +/- 7.2) (P < .05), as confirmed by the qualitative analysis. CONCLUSIONS: The use of the adaptive motion increased the amount of root filling removed in the middle and apical thirds compared with the reciprocating motion. However, no technique was able to completely remove the filling material from the canals. PMID- 26987689 TI - The ethics of extracorporeal membrane oxygenation in brain-dead potential organ donors. AB - Organ-preserving extracorporeal membrane oxygenation (OP-ECMO) is defined as the use of extracorporeal support for the primary purpose of preserving organs for transplantation, rather than to save the patient's life. This paper discusses the ethics of using OP-ECMO in donation after brain determination of death (DBDD) to avoid the loss of organs for transplantation. We review case reports in the literature and analyze the ethical issues raised. We conclude that there is little additional ethical concern in continuing OP-ECMO in patients already on ECMO if they become brain dead. The implementation of OP-ECMO in hemodynamically unstable brain-dead patients is ethically permissible in certain clinical situations but requires specific consent from relatives if the patient's wish to donate is not clear. If no evidence of a patient's wish to donate is available, OP-ECMO is not recommended. In countries with presumed consent legislation, failure to opt out should be considered as a positive wish to donate. If a patient is not-yet brain-dead or is undergoing testing for brain death, OP-ECMO is not recommended. Further research on OP-ECMO is needed to better understand the attitudes of professionals, families, and lay people to ensure agreement on key ethical issues. PMID- 26987692 TI - Exercise and weight gain in pregnancy. PMID- 26987690 TI - Beta-palmitate - a natural component of human milk in supplemental milk formulas. AB - The composition and function of human milk is unique and gives a basis for the development of modern artificial milk formulas that can provide an appropriate substitute for non-breastfed infants. Although human milk is not fully substitutable, modern milk formulas are attempting to mimic human milk and partially substitute its complex biological positive effects on infants. Besides the immunomodulatory factors from human milk, research has been focused on the composition and structure of human milk fat with a high content of beta-palmitic acid (sn-2 palmitic acid, beta-palmitate). According to the available studies, increasing the content of beta-palmitate added to milk formulas promotes several beneficial physiological functions. beta-palmitate positively influences fatty acid metabolism, increases calcium absorption, improves bone matrix quality and the stool consistency, and has a positive effect on the development of the intestinal microbiome. PMID- 26987691 TI - The Special Challenges of Psychotherapy with Persons with Psychosis: Intersubjective Metacognitive Model of Agreement and Shared Meaning. AB - : Agreement between client and therapist is an essential part of the therapeutic alliance. While there are general challenges to the creation of agreement and shared meaning in all psychotherapies, there are specific challenges while working with persons with psychosis. These challenges include the different narratives of the client and the therapist with regard to their roles and the description of the condition or problem, as well as possible stigmatic views and theoretical bias. Here we present a metacognitive intersubjective model as a framework for the understanding and resolutions of these challenges. Copyright (c) 2016 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Goal consensus, agreement and shared meaning are essential for a collaborative process and positive outcome in psychotherapy. Challenges to psychotherapy with persons with psychosis include the different narratives of the client and the therapist with regard to their roles and the description of the condition or problem, as well as possible stigmatic views and theoretical bias. In the intersubjective exchange, the concepts of metacognition and empathy can act as a framework for navigating between the possible challenges and the desired shared meaning and agreement. PMID- 26987686 TI - Increased expression with differential subcellular location of cytidine deaminase APOBEC3G in human CD4(+) T-cell activation and dendritic cell maturation. AB - APOBEC3G (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G; A3G) is an innate defense protein showing activity against retroviruses and retrotransposons. Activated CD4(+) T cells are highly permissive for HIV-1 replication, whereas resting CD4(+) T cells are refractory. Dendritic cells (DCs), especially mature DCs, are also refractory. We investigated whether these differences could be related to a differential A3G expression and/or subcellular distribution. We found that A3G mRNA and protein expression is very low in resting CD4(+) T cells and immature DCs, but increases strongly following T-cell activation and DC maturation. The Apo-7 anti-A3G monoclonal antibody (mAb), which was specifically developed, confirmed these differences at the protein level and disclosed that A3G is mainly cytoplasmic in resting CD4(+) T cells and immature DCs. Nevertheless, A3G translocates to the nucleus in activated-proliferating CD4(+) T cells, yet remaining cytoplasmic in matured DCs, a finding confirmed by immunoblotting analysis of cytoplasmic and nuclear fractions. Apo-7 mAb was able to immunoprecipitate endogenous A3G allowing to detect complexes with numerous proteins in activated-proliferating but not in resting CD4(+) T cells. The results show for the first time the nuclear translocation of A3G in activated proliferating CD4(+) T cells. PMID- 26987693 TI - Drug-resin drug interactions in patients with delayed gastric emptying: What is optimal time window for drug administration? AB - Most drug-drug interactions involve overlap or competition in drug metabolic pathways. However, there are medications, typically resins, whose function is to bind injurious substances such as bile acids or potassium within the digestive tract. The objective of this article is to review the functions of the stomach and the kinetics of emptying of different food forms or formulations to make recommendations on timing of medication administration in order to avoid intragastric drug interactions. Based on the profiles and kinetics of emptying of liquid nutrients and homogenized solids, a window of 3 h between administration of a resin drug and another 'target' medication would be expected to allow a median of 80% of medications with particle size <1 mm to empty from the stomach and, hence, avoid potential interaction such as binding of the 'target' medication within the stomach. PMID- 26987694 TI - A comparison of three treatment methods for fractures of the mandibular angle. AB - The purpose of this study was to determine a practical and cost-effective treatment method for fixing mandibular angle fractures using miniplates. Patients were divided into three groups for comparison, based on the intraoperative plates and maxillomandibular fixation (MMF) used: group A, single miniplate fixation with MMF (n=37); group B, double miniplate fixation with MMF (n=59); group C, double miniplate fixation without MMF (n=38). Details of the characteristics of the fractures and the treatments and outcomes were collected retrospectively and analyzed statistically. This study was based on 134 cases of isolated mandibular angle fracture. Of the surgically treated patients, 78.4% (n=105) were completely free of complications. A detailed complication correlation matrix is given in the text. Besides screw loosening and malocclusion, no statistically significant difference was observed between the groups. The results of this study suggest that treatment with single miniplate fixation and MMF has a low incidence rate of complications, and this method of treatment is considered to be simple. PMID- 26987695 TI - Effectiveness of platelet-rich plasma as an adjunctive material to bone graft: a systematic review and meta-analysis of randomized controlled clinical trials. AB - The use of platelet-rich plasma (PRP) has become a strategic therapy in tissue regeneration medicine. PRP represents a good source of growth factors. Due to this property, it has been considered a reliable adjunctive material in bone augmentation procedures, such as the sinus lift technique. The aim of this review was to assess the scientific evidence on the effectiveness of PRP as an adjunctive material in the sinus floor elevation technique. The following databases were searched for relevant published studies: Medline, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL, Science Direct, ISI Web of Knowledge, and SCOPUS. Only randomized controlled clinical trials comparing a group receiving PRP as an adjunctive material to a control group without PRP, involving adult human subjects (age >18 years) with no systemic disease, were included. Of the studies identified, only one reported a significant difference in bone augmentation in favour of the adjunctive use of PRP, while four studies did not find any significant difference. None of the studies included reported a significant difference in the implant survival rate. Further randomized clinical trials are needed to clarify the effectiveness of adjunctive PRP. PMID- 26987696 TI - Virtues and humanitarian ethics. AB - This paper analyses the contribution of virtue ethics, the study of good character traits, to the humanitarian context. It argues that a virtue ethics perspective paints a realistic picture of the use of ethical standards in morally complex circumstances. Virtuous relief workers can employ standards in their thinking, but they are also committed to professional excellence that goes beyond any formal code. The concept of virtue ethics places a stress on moral development, which can be facilitated by role models that impart modest and feasible ideals. However, virtue ethics cannot provide simple guidelines on how to resolve difficult situations. It is possible that two virtuous persons can disagree on what should be done in a particular instance. In addition, a virtue ethics perspective emphasises the need for both individuals and organisations to discuss the actual purpose of relief work in order to pinpoint the virtues of a good relief professional. PMID- 26987698 TI - Analysis on the Radiation Property of the Bounded Modes of Periodic Leaky-Wave Structure with Finite-Length Using a Hybrid Method. AB - In this paper the radiation property of the one-dimensional periodic leaky-wave structure is analysed using a new hybrid method, which involves the mode expansion method for expanding the periodic aperture field in terms of spatial harmonics and the method of effective radiation sections for transforming the expanded fields into far fields. Using this method, the radiation of each spatial harmonic can be achieved, and the contributions of the harmonics (especially the bounded modes) to the total radiation of the periodic leaky-wave structure can be calculated. The main findings in this paper demonstrate that the bounded modes in a finite length structure have obvious contribution to the far-field radiation, which was considered to be non-radiative and always ignored in the conventional researches. PMID- 26987697 TI - Genome-wide Long Non-coding RNA Analysis Identified Circulating LncRNAs as Novel Non-invasive Diagnostic Biomarkers for Gynecological Disease. AB - Increasing evidence indicates that long non-coding RNAs (lncRNAs) play important roles in human diseases. This study aimed to investigate the tissue and serum lncRNAs that are differentially expressed between patients with endometriosis, a gynecological disease, to evaluate the potential of these lncRNAs as non-invasive markers for the disease. The differentially expressed lncRNAs as competing endogenous RNAs (ceRNAs) were also analyzed to predict their functions in disease development. Genome-wide profiling of lncRNA expression patterns revealed that many lncRNAs were abnormally expressed between sera and tissuesof the patient samples. A set of aberrant differentially expressed lncRNAs were further validated in a validation cohort of 110 serum and 24 tissue samples. Functional analysis predicted that differentially expressed lncRNAs may participate in disease development through crosstalk between the ceRNAs of miRNAs and may be involved in a range of cellular pathways including steroid or hormone responses. We also found a unique set of lncRNAs that were associated with disease severity and progression, and their diagnostic values were also investigated. Our study demonstrated that lncRNAs could potentially serve as non-invasive biomarkers for the diagnosis of endometriosis and as important regulators in the progression of this disease. PMID- 26987699 TI - Sex differences in Alzheimer's disease and other dementias. PMID- 26987700 TI - Fighting dementia in Europe: the time to act is now. PMID- 26987702 TI - Anti-Mitotic Spindle Apparatus Antoantibodies: Prevalence and Disease Association in Chinese Population. AB - BACKGROUND: Mitotic spindle apparatus (MSA) antibodies are rare findings with undefined clinical significance in clinical research. We aimed at investigating the prevalence and clinical significance of anti-MSA antibodies in Chinese population. METHODS: Between 2008 and 2013, a total of 180,180 patients were studied for the presence of anti-MSA antibodies. The clinical details and laboratory data of anti-MSA-positive patients were retrospectively collected and analyzed. RESULTS: Of the 180,180 patients tested, 68,640 patients presented with positive antinuclear antibodies (ANAs, 38.10%), but only 32 patients with positive anti-MSA antibodies (0.018%). Diagnoses were established in 22 of 32 patients: 16 connective tissue diseases (CTDs), mainly Sjogren syndrome (SS, 5/16), rheumatoid arthritis (RA, 4/16), and systemic lupus erythematosus (SLE, 3/16), and 6 nonautoimmune conditions. The most frequent clinical symptoms of the anti-MSA-positive patients were arthralgia and eyes and mouth drying. Additionally, 70% of anti-MSA antibodies were not associated with other ANAs, however, when associated, the most frequent ANA was anti-SSA. CONCLUSIONS: Anti MSA antibodies have a low prevalence and female gender predominance. Anti-MSA antibodies are primarily associated with CTDs, mainly SS, RA, and SLE. The presence of anti-MSA antibodies might be the unique serological markers of the CTDs, especially when anti-SSA, SSB, and dsDNA antibodies are negative, or the level of RF is low. PMID- 26987701 TI - Defeating Alzheimer's disease and other dementias: a priority for European science and society. PMID- 26987703 TI - Double targeting and aptamer-assisted controlled release delivery of epirubicin to cancer cells by aptamers-based dendrimer in vitro and in vivo. AB - Clinical use of epirubicin (Epi) in the treatment of cancer has been limited, due to its cardiotoxicity. Targeted delivery of chemotherapeutic agents could increase their efficacy and reduce their off-target effects. High drug loading and excellent stability of DNA dendrimers make these DNA nanostructures unique candidates for biological applications. In this study a modified and promoted dendrimer using three kinds of aptamers (MUC1, AS1411 and ATP aptamers) was designed for targeted delivery of Epi and its efficacy was evaluated in target cells including MCF-7 cells (breast cancer cell) and C26 cells (murine colon carcinoma cell). Aptamers (Apts)-Dendrimer-Epi complex formation was analyzed by fluorometric analysis and gel retardation assay. Release profiles of Epi from the designed complex were assessed at pHs 5.4 and 7.4. For MTT assay (cytotoxic study) MCF-7 and C26 cells (target cells) and CHO cells (Chinese hamster ovary cell, nontarget) were treated with Epi, Apts-Dendrimer-Epi complex and Apts Dendrimer conjugate. Internalization was evaluated using flow cytometry analysis. Finally, the developed complex was used for inhibition of tumor growth in vivo. 25MUM Epi was efficiently intercalated to 1MUM dendrimer. Epi was released from the Apts-Dendrimer-Epi complex in a pH-sensitive manner (more release at pH 5.5). The results of flow cytometry analysis indicated that the designed complex was efficiently internalized into target cells, but not into control cells. The internalization data were confirmed by the results of MTT assay. Apts-Dendrimer Epi complex had less cytotoxicity in CHO cells compared to Epi alone. The complex had more cytotoxicity in C26 and MCF-7 cells compared to Epi alone. Moreover, the Apts-Dendrimer-Epi complex could efficiently prohibit tumor growth in vivo. In conclusion, the designed targeted drug delivery system inherited characteristics of pH-dependent drug release, high drug loading and tumor targeting in vitro and in vivo. PMID- 26987704 TI - Editorial overview: Neurobiology of cognitive behavior: Complexity of neural computation and cognition. PMID- 26987705 TI - A 'time and motion' evaluation of automated dispensing machines in the emergency department. AB - BACKGROUND: There has been limited assessment of the impact that automated medication dispensing machines have on the medication administration process, particularly in Australian emergency departments. The aim of this study is to examine the change in medication retrieval times, number of medications retrieved and staff perceptions before and after the installation of automated dispensing machines in an Australian emergency and trauma centre. METHODS: A time and motion method recorded the time taken and number of medications retrieved from the medication room by emergency department staff, before and after the installation of two automated dispensing machines. Surveys were administered to staff members to elicit the perceived impact on clinical practice, utilising 5-point Likert scales. RESULTS: A total of 954 medication retrievals (1030 medications) were recorded in the pre-implementation period and 842 (991 medications) in the post implementation period. The mean time taken to retrieve any medication was significantly longer in the post-implementation period (+5.7s; p<0.01). For schedules 2, 3, 4 or unscheduled medications, the mean time increased by 26.9s (p<0.01), but decreased by 36.1s (p<0.01) for schedule 8 or 11 medications. The mean number of medications per retrieval increased slightly in the post implementation period (+0.10; p<0.01). Staff perceptions were that automated dispensing machines improve knowledge of medications on imprest (p=0.03) and reduced medication retrieval time (p<0.01). CONCLUSIONS: This study found that the medication retrieval process was slower with automated dispensing machines for Schedules 2, 3, 4 and unscheduled medications, but quicker for Schedule 8 and 11 medications in an Australian emergency and trauma centre. Although retrieving medications took slightly longer overall, staff believed automated dispensing machines save time. PMID- 26987706 TI - Liposarcoma masquerading as an inflammatory pseudotumor: a case report. AB - BACKGROUND: Distinguishing an atypical lipomatous tumor/well-differentiated liposarcoma from a benign lipomatous tumor on morphology alone can be difficult and there is an established role for MDM2 fluorescent in situ hybridization studies in making this differential diagnosis. There is no literature on the role for MDM2 fluorescent in situ hybridization studies in distinguishing between a well-differentiated liposarcoma with extreme fibrosis and a fibrosing inflammatory pseudotumor. CASE PRESENTATION: We report the case of a 76-year-old Australian woman initially diagnosed by an excision biopsy with a retroperitoneal fibrosing inflammatory pseudotumor. She was then diagnosed 5 years later with a pleomorphic undifferentiated sarcoma. Upon review of the original resection specimen, we were able to show that the tumor demonstrated MDM2 amplification. MDM2 amplification was also present in some adjacent bland adipose tissue, and also in the tumor recurrence as a pleomorphic undifferentiated sarcoma. CONCLUSION: Taken together, our findings provide strong evidence that the original tumor was a misdiagnosed well-differentiated liposarcoma with extreme fibrosis, and the pleomorphic undifferentiated sarcoma represented a recurrence of the same tumor with dedifferentiation. PMID- 26987708 TI - (Why) Does Evolution Favour Embryogenesis? AB - Complex multicellular organisms typically possess life cycles in which zygotes (formed by gamete fusion) and meiosis occur. Canonical animal embryogenesis describes development from zygote to birth. It involves polarisation of the egg/zygote, asymmetric cell divisions, establishment of axes, symmetry breaking, formation of organs, and parental nutrition (at least in early stages). Similar developmental patterns have independently evolved in other eukaryotic lineages, including land plants and brown algae. The question arises whether embryo-like structures and associated developmental processes recurrently emerge because they are local optima of the evolutionary landscape. To understand which evolutionary principles govern complex multicellularity, we need to analyse why and how similar processes evolve convergently - von Baer's and Haeckel's phylotypic stage revisited in other phyla. PMID- 26987707 TI - Lack of association between polymorphisms in interleukin (IL)-12, IL-12R, IL-23, IL-23R genes and Takayasu arteritis in a Chinese population. AB - OBJECTIVE: The goal of this study was to investigate the relationship between polymorphisms in interleukin (IL)-12, IL-12R, IL-23, and IL-23R genes and Takayasu arteritis (TA) in a Chinese population. METHODS: A case-control study was performed to investigate the associations of 19 single nucleotide polymorphisms (SNPs) mapping to IL12A, IL12B, IL12RB1, IL12RB2 and IL23R with susceptibility to TA in 145 Chinese TA patients and 300 healthy controls. Genotype identification was performed with the MassARRAY system from Sequenom. The statistical analysis was conducted by Chi square test and unconditional logistic regression with plink. RESULTS: No significant differences were found for the distribution of allele and genotype frequencies of these SNPs between TA patients and healthy controls. However, a trend for IL12A rs582054 and IL23R rs1004819 in association with the TA phenotype was detected. TA patients carrying the rs582054/rs568408 haplotype (P' = 0.019) appeared less likely to progress to a more severe form of disease. And the C allele (P' = 0.082) of IL23R rs1004819 appeared to be a protective factor to refractory disease. CONCLUSIONS: These findings suggest that the polymorphisms of IL12A, IL12B, IL12RB1, IL12RB2 and IL23R might make no contribution to the susceptibility of TA in the Chinese population. PMID- 26987709 TI - Pediatric surgery - a changing field: national trends in pediatric surgical practice. AB - BACKGROUND: Over the last decade, our institution has experienced a relative increase in the number of mundane cases, such as appendectomy and incision and drainage of abscess, versus index (complex) cases. We sought to determine if this trend is present at the national level. METHODS: A retrospective review of surgical case volume at 36 freestanding children's hospitals was performed between January 2004 and December 2013 using the Pediatric Health Information System (PHIS) database. Procedures were classified as "mundane" or "index", and 10 procedures of each type were selected for analysis. Results were reported as a percentage of total cases. Statistical analysis of linear trends was performed with the Mann-Kendall test. RESULTS: Overall, index procedures had a significant downward trend (p<0.01), whereas mundane procedures had a significant upward trend (p<0.01). Individually, 5 mundane procedures had significant upward trends, and 3 had downward trends. Five index procedures had significant downward trends, and none had an upward trend. CONCLUSION: The field of pediatric surgery is undergoing change with mundane procedures constituting an increasing proportion of the surgical caseload, while complex procedures are proportionately decreasing. These trends may be useful to inform decisions regarding future pediatric surgery workforce planning. PMID- 26987710 TI - Prepubertal testicular tumors: a single-center experience of 44years. AB - PURPOSE: To present the clinical and histological features of prepubertal testicular tumors (PTTs), the long-term experience of a single institution was reviewed. MATERIALS AND METHODS: A total of 62 prepubertal children who were treated for testicular tumors at Kanagawa Children's Medical Center from 1971 to 2014 were retrospectively reviewed. Histopathological findings, age at operation, clinical stage, and outcomes were analyzed. Clinical findings between the two eras, 1971-1990 and 1991-2014, were also compared. RESULT: The median age at operation was 17months. Pathology revealed 29 teratomas (47%), 26 yolk sac tumors (42%), 5 epidermoid cysts (8%), 1 Sertoli cell tumor (1.5%), and 1 benign cyst (1.5%). Teratoma was the most common tumor in this series, and children with immature teratomas were operated at a significantly younger age than those with mature teratomas. Yolk sac tumor was the second most common. The clinical stages of yolk sac tumors were stage I in 23 (89%) and stage II in 3 (11%). Clinical findings were not significantly different between the early and late eras. CONCLUSIONS: To the best of our knowledge, this is the largest single-center study of PTTs in Japan. The most common PTT in this study was teratoma, followed by yolk sac tumor. There was no significant difference in the histological distribution of PTTs between the two eras. Compared with the current data of single-center series in North America, the incidence of yolk sac tumor was markedly higher in the present study. This discrepancy is possibly explained by racial differences. PMID- 26987711 TI - An evaluation of the role of concomitant anomalies on the outcomes of fetuses with congenital diaphragmatic hernia. AB - PURPOSE: The purpose of this study was to evaluate the impact of various types of associated anomalies on CDH mortality and morbidity. METHODS: All CDH patients at a tertiary care center from January 2004 to January 2014 were reviewed retrospectively. Isolated CDH was defined as CDH without any associated anomalies. Cardiac anomalies were stratified into minor and major based on the Risk Adjustment for Congenital Heart Surgery-1 (RACHS-1) scoring system. Other anatomic anomalies requiring intervention in the perinatal period were classified as major anomalies. The outcomes of interest were 6-month mortality as well as pulmonary and gastrointestinal morbidity. RESULTS: Of 189 CDH patients, 93 (49%) had isolated CDH. Others had: cardiac anomalies alone (n=47, 25%), genetic anomalies (n=28, 15%), structural anomalies alone (n=18, 10%), and both cardiac and genetic anomalies (n=20, 11%). Fifty (26.5%) patients were dead before six months of age. Mortality rate at 6months was higher in patients with genetic and major cardiac anomalies. A major cardiac anomaly was independently associated with a 102-fold increased risk of mortality at 6months (95%CI: 3.1-3402). Pulmonary morbidity was increased in patients with genetic, major cardiac, and major structural anomalies, while gastrointestinal morbidity was higher in patients with major structural anomalies alone. CONCLUSION: Major cardiac and genetic anomalies were associated with increased 6-month mortality in CDH patients. However, the association with minor cardiac anomalies and/or structural anomalies did not affect mortality and morbidity of CDH patients. The presence of minor anomalies should not adversely impact their perinatal management or consideration for in-utero therapy. PMID- 26987712 TI - Biological insertion of computationally designed short transmembrane segments. AB - The great majority of helical membrane proteins are inserted co-translationally into the ER membrane through a continuous ribosome-translocon channel. The efficiency of membrane insertion depends on transmembrane (TM) helix amino acid composition, the helix length and the position of the amino acids within the helix. In this work, we conducted a computational analysis of the composition and location of amino acids in transmembrane helices found in membrane proteins of known structure to obtain an extensive set of designed polypeptide segments with naturally occurring amino acid distributions. Then, using an in vitro translation system in the presence of biological membranes, we experimentally validated our predictions by analyzing its membrane integration capacity. Coupled with known strategies to control membrane protein topology, these findings may pave the way to de novo membrane protein design. PMID- 26987713 TI - Humidifier disinfectants, unfinished stories. AB - Once released into the air, humidifier disinfectants became tiny nano-size particles, and resulted in chemical bronchoalveolitis. Families had lost their most beloved members, and even some of them became broken. Based on an estimate of two million potential victims who had experienced adverse effects from the use of humidifier disinfectants, we can say that what we have observed was only the tip of the iceberg. Problems of entire airways, as well as other systemic effects, should be examined, as we know these nano-size particles can irritate cell membranes and migrate into systemic circulation. The story of humidifier disinfectant is not finished yet. PMID- 26987714 TI - Palbociclib: an approval at last for HER2-negative breast cancer. PMID- 26987715 TI - Upregulated expression of Nogo-A and NgR in an experimental model of focal microgyria regulates the migration, proliferation and self-renewal of subventricular zone neural progenitors. AB - Nogo-A and its receptor (NgR) were first described as myelin-associated inhibitors of neuronal regeneration in response to injury. In recent years, knowledge about the important role of the Nogo-A protein in several neuronal pathologies has grown considerably. Here, we employed a neonatal cortex freeze lesion (NFL) model in neonatal rats and measured the expression of Nogo-A and NgR in the resulting cerebrocortical microdysgenesis 5-75 days after freezing injury. We observed marked upregulation of Nogo-A and NgR in protein levels. Furthermore, the migration of neural precursor cells (NPCs) derived from the subventricular zone (SVZ) toward the sits of injury was perturbed by treatment of NgR antagonist peptide NEP1-40. In vitro analysis showed that the knockdown of NgR by lentivirus delivered siRNA promoted in axonal regeneration and SVZ-derived neural stem cell/progenitor cell (SVZ-NPCs) adhesion and migration, findings which were similar to the effects of NEP1-40. Taken together, our results indicate an important role for NgR in regulating the physiological processes of SVZ-NPCs. The observation of upregulated Nogo-A/NgR in lesion sites in the NFL model suggest that the effects of the perturbed Nogo-A are a key feature during the development and/or the progression of cortical malformation. PMID- 26987717 TI - A crucial role of Cys218 in configuring an unprecedented auto-inhibition form of MAP2K7. AB - Mitogen-activated protein kinase kinase 7 (MAP2K7) is an indispensable kinase of the c-Jun N-terminal kinase signal cascade and is rigorously regulated via phosphorylation. To investigate the regulatory mechanism of the inactive non phosphorylated state of MAP2K7, the crystal structures of the wild-type and C218S mutant were solved. The wild-type apo-structure revealed an unprecedented auto inhibition form that occluded the ATP site. This closed form was configured by the n-sigma* interaction of Cys218, a non-conserved residue among the MAP2K family kinases, with Gly145 in the glycine-rich loop. The interaction was unaltered in the presence of an ATP analog, whereas the C218S mutation precluded the closed configuration. These structural insights are potentially valuable for drug discovery of highly selective MAP2K7 inhibitors. PMID- 26987716 TI - Expression of the Nrf2 and Keap1 proteins and their clinical significance in osteosarcoma. AB - OBJECTIVE: To investigate the expression and clinical significance of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) in osteosarcoma tissue. METHODS: The data of 102 osteosarcoma patients who underwent surgical treatment at our hospital from June 2000 to March 2009 were collected. The expression levels of the Nrf2 and Keap1 proteins in osteosarcoma tissue and normal peritumour tissues were detected by immunohistochemistry, and the relationship between the expression level and the clinical and pathological features as well as the prognosis was explored. RESULTS: The nuclear expression rate of Nrf2 was 77.5% in osteosarcoma tissue, which was significantly higher than the rate in normal peritumour bone tissue (9.8%) (P < 0.05). The expression rate of the Keap1 protein in osteosarcoma tissue was 13.7%, which was significantly lower than the rate in normal peritumour tissue (80.4%). In addition, Nrf2/Keap1 expression was unrelated to patient gender and age, tumour site, and histological type and was related to metastasis and patient response to chemotherapy (P < 0.05). The five-year survival rate was significantly lower in patients with positive Nrf2 expression than in those with negative Nrf2 expression (p = 0.023), and it was significantly higher in patients with positive Keap1 expression than in those with negative Keap1 expression (P = 0.018). CONCLUSION: The expression of Nrf2-Keap1 is abnormal in osteosarcoma tissue and shows significant clinical relevance for determining the prognosis of osteosarcoma. PMID- 26987719 TI - Hierarchical spike clustering analysis for investigation of interneuron heterogeneity. AB - Action potentials represent the output of a neuron. Especially interneurons display a variety of discharge patterns ranging from regular action potential firing to prominent spike clustering or stuttering. The mechanisms underlying this heterogeneity remain incompletely understood. We established hierarchical cluster analysis of spike trains as a measure of spike clustering. A clustering index was calculated from action potential trains recorded in the whole-cell patch clamp configuration from hippocampal (CA1, stratum radiatum) and entorhinal (medial entorhinal cortex, layer 2) interneurons in acute slices and simulated data. Prominent, region-dependent, but also variable spike clustering was detected using this measure. Further analysis revealed a strong positive correlation between spike clustering and membrane potentials oscillations but an inverse correlation with neuronal resonance. Furthermore, clustering was more pronounced when the balance between fast-activating K(+) currents, assessed by the spike repolarisation time, and hyperpolarization-activated currents, gauged by the size of the sag potential, was shifted in favour of fast K(+) currents. Simulations of spike clustering confirmed that variable ratios of fast K(+) and hyperpolarization-activated currents could underlie different degrees of spike clustering and could thus be crucial for temporally structuring interneuron spike output. PMID- 26987718 TI - Mitochondrial energy-dissipation pathway and cellular redox disruption compromises Arabidopsis resistance to turnip crinkle virus infection. AB - Members of the plant mitochondrial energy-dissipation pathway (MEDP) coordinate cellular energy metabolism, redox homeostasis and the balance of ROS production. However, the roles of MEDP members, particularly uncoupling protein (UCP), in resistance to turnip crinkle virus infection (TCV) are poorly understood. Here, we showed that disrupting some MEDP genes compromises plant resistance to TCV viral infection and this is partly associated with damaged photosynthetic characteristics, altered cellular redox and increased ROS production. Experiments using mutant plants with impaired cellular compartment redox poising further demonstrated that impaired chloroplast/mitochondria and cystosol redox increases the susceptibility of plants to viral infection. Our results illustrate a mechanism by which MEDP and cellular compartment redox act in concert to regulate plant resistance to viral infections. PMID- 26987720 TI - The dissociable neural dynamics of cognitive conflict and emotional conflict control: An ERP study. AB - This study investigated differences in the neural time-course of cognitive conflict and emotional conflict control, using event-related potentials (ERPs). Although imaging studies have provided some evidence that distinct, dissociable neural systems underlie emotional and nonemotional conflict resolution, no ERP study has directly compared these two types of conflict. Therefore, the present study used a modified face-word Stroop task to explore the electrophysiological correlates of cognitive and emotional conflict control. The behavioral data showed that the difference in response time of congruency (incongruent condition minus the congruent condition) was larger in the cognitive conflict task than in the emotional conflict task, which indicated that cognitive conflict was stronger than the emotional conflict in the present tasks. Analysis of the ERP data revealed a main effect of task type on N2, which may be associated with top-down attention. The N450 results showed an interaction between cognitive and emotional conflict, which might be related to conflict detection. In addition, we found the incongruent condition elicited a larger SP than the congruent condition, which might be related to conflict resolution. PMID- 26987721 TI - Duloxetine and 8-OH-DPAT, but not fluoxetine, reduce depression-like behaviour in an animal model of chronic neuropathic pain. AB - The current study assessed whether antidepressant and/or antinociceptive drugs, duloxetine, fluoxetine as well as (+/-)-8-hydroxy-2-[di-n-propylamino] tetralin (8-OH-DPAT), are able to reverse depression-like behaviour in animals with chronic neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve in rats was selected as neuropathic pain model. Mechanical hypersensitivity and depression-like behaviour were evaluated 4 weeks after surgery by "electronic algometer" and forced swimming test (FST), which measured the time of immobility, and active behaviours climbing and swimming. The selective noradrenergic and serotonergic uptake blocker duloxetine (20mg/kg) and the selective 5-HT1A agonist 8-OH-DPAT (0.5mg/kg) significantly reversed both mechanical hypersensitivity and depression-like behaviour in CCI animals. Duloxetine significantly reversed depression-like behaviour in CCI rats by increasing the time of climbing and swimming, while 8-OH-DPAT attenuated depression-like behaviour mainly by increasing the time of swimming. However, the selective serotonergic uptake blocker fluoxetine (20mg/kg) failed to attenuate mechanical hypersensitivity and depression-like behaviour, possibly due to confounding pro-nociceptive actions at 5-HT3 receptors. These data suggest to target noradrenergic and 5-HT1A receptors for treatment of chronic pain and its comorbidity depression. PMID- 26987722 TI - Effects of stimulation of muscarinic acetylcholine receptors in medial septum on some immune responses in rats. AB - OBJECTIVES: Though the immunomodulatory role of medial septum (MS) has been indicated, but the contribution of the muscarinic acetylcholine (mAch) receptors presented in the internal network of the neurons of MS in this regard is not known. The aim of the present study is to assess the contribution of mAch receptors of MS on some immunological parameters. METHODS: Different immunological parameters i.e. phagocytic activity of peripheral leukocytes, adhesibility and cytotoxicity of splenic mononuclear cells (MNC), delayed type of hypersensitivity (DTH) responses, Total Count (TC) and Differential Count (DC) of WBC with serum corticosterone (CORT) concentration have been measured after stimulation and blocking of mAch receptors of MS in rats. Ach or atropine has been micro infused into MS of separate groups of rats for stimulating or blocking of the mAch receptors respectively. RESULTS: In Ach or atropine microinfused rats, the TC of WBC remained unaltered in the present study. The percentage of neutrophil has increased and the percentage of lymphocyte has decreased in Ach microinfused rats, but these parameters remain unaltered in atropine microinfused rats. The observed immunological parameters have increased after microinfusion of 0.60MUM and 0.12MUM of Ach and serum CORT concentration has decreased in those animals. These immunological parameters have decreased and serum CORT has increased after microinfusion of atropine (2 and 4mM) in MS of rats. CONCLUSION: It appears that the Ach receptors in MS can modulate the observed immunological parameters, and serum CORT plays an important role for these immune changes. PMID- 26987723 TI - Acute tryptophan depletion and Lewy body dementias. AB - BACKGROUND: Studies using acute tryptophan depletion (ATD) to examine the effects of a rapid reduction in serotonin function have shown a reduction in global cognitive status during ATD in Alzheimer's disease (AD) and Parkinson's disease (PD). Based on the severe cholinergic loss evident in dementia with Lewy bodies (DLB) and Parkinson's disease and dementia (PDD), we predicted that a reduction of global cognitive status during ATD would be greater in these conditions than in AD. METHODS: Patients having DLB or PDD underwent ATD in a double-blind, placebo-controlled, randomized, counterbalanced, crossover design. RESULTS: While the study intended to test 20 patients, the protocol was poorly tolerated and terminated after six patients attempted, but only four patients - three with DLB and one with PDD - completed the protocol. The Modified Mini-Mental State Examination (3MSE) score was reduced in all three DLB patients and unchanged in the PDD and dementia patient during ATD compared with placebo. CONCLUSIONS: This reduction in global cognitive function and the poor tolerability may fit with the hypothesis that people with dementia with Lewy bodies have sensitivity to the effects of reduced serotonin function. PMID- 26987724 TI - How to use immunoglobulin levels in investigating immune deficiencies. AB - Children are often referred to immunologists for the evaluation of reduced serum immunoglobulins. Knowledge of the immunoglobulin levels in healthy children of different ages is necessary when estimating immunological deficiency states of various kinds. After the measurement of the serum levels of the three major isotypes, examination of the capacity of the child to form antibodies to several antigens is a reasonable next step in the evaluation. We can rely on vaccine responses to make the distinction between significant primary immunodeficiency diseases and transiently low immunoglobulin levels. On the other hand, normal values of IgM, IgG and IgA are not always enough to exclude a more serious condition. Regardless of immunoglobulin concentrations, if a child's history indicates that further evaluation is warranted, a complete humoral immunity study should be carried out, including IgG subclasses, specific antibody responses and identification of B lymphocyte populations. PMID- 26987726 TI - Classic Spotlight: the Physiological State of Competence and So Much More. PMID- 26987725 TI - Comparative studies on testicular and epididymal morphology, and serum hormone concentrations in foxes and the hybrids during the breeding season. AB - The silver fox and the blue fox belong to different genera, and the hybrid males are fully or partially sterile. In the present study, the objective was to evaluate the causes of hybrid male sterility, and therefore analyze the differences in testicular, and epididymal morphology and serum hormone concentrations among silver foxes, blue foxes, and the hybrids during the breeding season. Samples were collected from 20 male silver foxes, 20 male blue foxes, 15 male HSBs (silver fox female * blue fox male hybrids) and 14 male HBSs (blue fox male * silver fox female hybrids), respectively. Seminal evaluation showed large numbers of sperm present in the semen of blue foxes and silver foxes, but no sperm present in the hybrids. Mean testicular volume and the diameter of seminiferous tubules in silver foxes and blue foxes were greater than in the hybrids; and there were many Sertoli cells, spermatogenic cells, and sperm in silver foxes and blue foxes, while spermatogenic cells decreased with no sperm in the hybrids. Mean serum LH and prolactin concentrations in silver foxes and blue foxes were less and testosterone was greater than in the hybrids (P<0.05). The results indicate that germ cell meioses in the hybrids were arrested at the prophase stage of meiosis, and that lesser concentrations of testosterone and greater concentrations of LH and prolactin can inhibit the completion of spermatogenesis. PMID- 26987727 TI - Classic Spotlight: Bacteria versus Phage-the Battle Rages! PMID- 26987731 TI - Comparison of module detection algorithms in protein networks and investigation of the biological meaning of predicted modules. AB - BACKGROUND: It is generally acknowledged that a functional understanding of a biological system can only be obtained by an understanding of the collective of molecular interactions in form of biological networks. Protein networks are one particular network type of special importance, because proteins form the functional base units of every biological cell. On a mesoscopic level of protein networks, modules are of significant importance because these building blocks may be the next elementary functional level above individual proteins allowing to gain insight into fundamental organizational principles of biological cells. RESULTS: In this paper, we provide a comparative analysis of five popular and four novel module detection algorithms. We study these module prediction methods for simulated benchmark networks as well as 10 biological protein interaction networks (PINs). A particular focus of our analysis is placed on the biological meaning of the predicted modules by utilizing the Gene Ontology (GO) database as gold standard for the definition of biological processes. Furthermore, we investigate the robustness of the results by perturbing the PINs simulating in this way our incomplete knowledge of protein networks. CONCLUSIONS: Overall, our study reveals that there is a large heterogeneity among the different module prediction algorithms if one zooms-in the biological level of biological processes in the form of GO terms and all methods are severely affected by a slight perturbation of the networks. However, we also find pathways that are enriched in multiple modules, which could provide important information about the hierarchical organization of the system. PMID- 26987730 TI - RUDI, a short interspersed element of the V-SINE superfamily widespread in molluscan genomes. AB - Short interspersed elements (SINEs) are non-autonomous retrotransposons that are widespread in eukaryotic genomes. They exhibit a chimeric sequence structure consisting of a small RNA-related head, an anonymous body and an AT-rich tail. Although their turnover and de novo emergence is rapid, some SINE elements found in distantly related species retain similarity in certain core segments (or highly conserved domains, HCD). We have characterized a new SINE element named RUDI in the bivalve molluscs Ruditapes decussatus and R. philippinarum and found this element to be widely distributed in the genomes of a number of mollusc species. An unexpected structural feature of RUDI is the HCD domain type V, which was first found in non-amniote vertebrate SINEs and in the SINE from one cnidarian species. In addition to the V domain, the overall sequence conservation pattern of RUDI elements resembles that found in ancient AmnSINE (~310 Myr old) and Au SINE (~320 Myr old) families, suggesting that RUDI might be among the most ancient SINE families. Sequence conservation suggests a monophyletic origin of RUDI. Nucleotide variability and phylogenetic analyses suggest long-term vertical inheritance combined with at least one horizontal transfer event as the most parsimonious explanation for the observed taxonomic distribution. PMID- 26987732 TI - Spatio-temporal dynamics of a cell signal pathway with negative feedbacks: the MAPK/ERK pathway. AB - We studied the spatio-temporal dynamics of a cell signal cascade with negative feedback that quantitatively emulates the regulative process that occurs in the Mitogen Activated Protein Kinase/Extracellular Regulated Kinase (MAPK/ERK) pathway. The model consists of a set of six coupled reaction-diffusion equations that describes the dynamics of the six-module pathway. In the basic module the active form of the protein transmits the signal to the next pathway's module. As suggested by experiments, the model considers that the fifth module's kinase down regulates the first and third modules. The feedback parameter is defined as, MU(r)( j)= k(kin)5/k(kin)(j), (j = 1, 3). We analysed the pathway's dynamics for MU(r)( j) = 0.10, 1.0, and 10 in the kinetic regimes: i) saturation of both kinases and phosphatases, ii) saturation of the phosphatases and iii) saturation of the kinases. For a regulated pathway the Total Activated Protein Profiles (TAPPs) as a function of time develop a maximum during the transient stage in the three kinetic regimes. These maxima become higher and their positions shift to longer times downstream. This scenario also applies to the TAPP's regulatory kinase that sums up its inhibitory action to that of the phosphatases leading to a maximum. Nevertheless, when MU(r)(j)= 1.0 , the TAPPs develop two maxima, with the second maximum being almost imperceptible. These results are in qualitative agreement with experimental data obtained from NIH 3T3 mouse fibroblasts. In addition, analyses of the stationary states as a function of position indicate that in the kinetic regime i) which is of physiological interest, signal transduction occurs with a relatively large propagation length for the three values of the regulative parameter. However, for MU(r)(j)= 0.10 , the sixth module concentration profile is transmitted with approximately 45% of its full value. The results obtained for MU(r)(j) = 10 , indicate that the first five concentration profiles are small with a short propagation length; nonetheless, the last concentration profile, c6, attains more than 90% of its full value with a relatively large propagation length as an indication of signal transduction. Signal transduction also occurred favourably in the kinetic regimes ii) and iii), but the signal was longer-ranged in the regime ii). PMID- 26987733 TI - On the different sources of cooperativity in pH titrating sites of a membrane protein channel. AB - Cooperative interactions play a central role in the regulation of protein functions. Here we show that in multi-site systems like ion channels the application of the Hill formalism could require a combination of different experiments, even involving site-directed mutagenesis, to identify the different sources of cooperativity and to discriminate between genuine and apparent cooperativity. We discuss the implications for the channel function in the bacterial porins PorA (N. meningitidis) and OmpF (E. coli) and the viroporin SARS CoV E. PMID- 26987734 TI - Pediatric thoracic CT angiography at 70 kV: a phantom study to investigate the effects on image quality and radiation dose. AB - BACKGROUND: Studies have demonstrated that 70-kilovolt (kV) imaging enhances the contrast of iodine, potentially affording a reduction in radiation dose while maintaining the contrast-to-noise ratio (CNR). There is a maximum amount of image noise beyond which increased contrast does not improve structure visualization. Thus, noise should be constrained during protocol optimization. OBJECTIVE: This phantom study investigated the effect of 70-kV imaging for pediatric thoracic CT angiography on image quality and radiation dose in a pediatric population when a noise constraint was considered. MATERIALS AND METHODS: We measured contrast and noise using anthropomorphic thoracic phantoms ranging in size from newborn age equivalent to 10-year-old age equivalent. We inserted contrast rods into the phantoms to simulate injected contrast material used in a CT angiography study. The image-quality metric "iodine CNR with a noise constraint" was used to determine the relative dose factor for each phantom size, kV setting (70-140 kV) and noise constraint (1.00-1.20). A noise constraint of 1.20 indicates that noise should not increase by more than 20% of the noise level in images performed at the reference kV, selected to be 80 kV in this study. The relative dose factor can be applied to the original dose obtained at 80 kV in order to maintain iodine CNR with the noise constraint. A relative dose factor <1.0 indicates potential for dose reduction while a relative dose factor >1.0 indicates a dose penalty. RESULTS: Iodine contrast was highest for 70 kV and decreased with higher kV settings for all phantom sizes. The relative dose factor at 70 kV was <1.0 for all noise constraint >1.0, indicating potential for dose reduction, for the newborn, 1-year-old and 5-year-old age-equivalent phantom sizes. For the 10-year old age-equivalent phantom, relative dose factor at 70 kV=1.22, 1.11, 1.01, 0.92 and 0.83 for noise constraint=1.00, 1.05, 1.10, 1.15, 1.20, respectively, indicating a dose penalty for noise constraint <=1.10 and potential for dose reduction for noise constraint >1.10. CONCLUSION: Using 70 kV does allow for radiation dose reduction if the radiologist is willing to accept a higher level of image noise as a trade-off for increased vessel contrast. This increase in noise is small (<5%) for the nominal newborn, 1- and 5-year-old but is >10% for the 10-year-old. Therefore, we recommend limiting 70 kV thoracic CT angiography to newborn through 5-year-old patients. PMID- 26987735 TI - Decomposition and humification of dissolved organic matter in swine manure during housefly larvae composting. AB - Housefly larvae (Musca domestica) composting has been increasingly adopted as an efficient practice to achieve value-added swine manure bioconversion, but few researches have evaluated the features of compost maturity by examining the biochemical compositions of dissolved organic matter (DOM) in compost. Here, we adopted spectrum fingerprint technologies to explore the related transformation mechanisms of DOM in compost by conducting field investigations in a full-scale housefly larvae composting farm. The 1-week composting with larvae significantly decreased DOM concentrations from 192.9 to 77.1 g kg(-1) The hydrolysis of proteins and lipids were enhanced during composting, as well as a build-up of aromatic substances, while contents of fulvic- and humic-like substances were augmented on Day 5 and Day 6 (ranged from 0.04 to 0.65 and 0.11 to 0.59 for Fmax, respectively). Compared with traditional composting without the aid of larvae, the stronger biodegradation of DOM and the subsequent formation of humus in compost, led to a higher level of aromaticity and humification under housefly larvae bioconversion, generating a more stable bio-product for downstream utilisation. PMID- 26987736 TI - Copper and cobalt recovery from pyrite ashes of a sulphuric acid plant. AB - The pyrite ashes formed as waste material during the calcination of concentrated pyrite ore used for producing sulphuric acid not only has a high iron content but also contains economically valuable metals. These wastes, which are currently landfilled or dumped into the sea, cause serious land and environmental pollution problems owing to the release of acids and toxic substances. In this study, physical (sulphation roasting) and hydrometallurgical methods were evaluated for their efficacy to recover non-iron metals with a high content in the pyrite ashes and to prevent pollution thereby. The preliminary enrichment tests performed via sulphation roasting were conducted at different roasting temperatures and with different acid amounts. The leaching tests investigated the impact of the variables, including different solvents, acid concentrations and leach temperatures on the copper and cobalt leaching efficiency. The experimental studies indicated that the pre-enrichment via sulphation roasting method has an effect on the leaching efficiencies of copper and cobalt, and that approximate recoveries of 80% copper and 70% cobalt were achieved in the H2O2-added H2SO4 leaching tests. PMID- 26987737 TI - A pilot-scale steam autoclave system for treating municipal solid waste for recovery of renewable organic content: Operational results and energy usage. AB - A pilot-scale (1800 kg per batch capacity) autoclave used in this study reduces municipal solid waste to a debris contaminated pulp product that is efficiently separated into its renewable organic content and non-renewable organic content fractions using a rotary trommel screen. The renewable organic content can be recovered at nearly 90% efficiency and the trommel rejects are also much easier to sort for recovery. This study provides the evaluation of autoclave operation, including mass and energy balances for the purpose of integration into organic diversion systems. Several methods of cooking municipal solid waste were explored from indirect oil heating only, a combination of oil and direct steam during the same cooking cycle, and steam only. Gross energy requirements averaged 1290 kJ kg(-1) material in vessel, including the weight of free water and steam added during heating. On average, steam recovery can recoup 43% of the water added and 30% of the energy, supplying on average 40% of steam requirements for the next cook. Steam recycle from one vessel to the next can reduce gross energy requirements to an average of 790 kJ kg(-1). PMID- 26987738 TI - Learning crisis resource management: Practicing versus an observational role in simulation training - a randomized controlled trial. AB - AIM: Simulation training has been shown to be an effective way to teach crisis resource management (CRM) skills. Deliberate practice theory states that learners need to actively practice so that learning is effective. However, many residency programs have limited opportunities for learners to be "active" participants in simulation exercises. This study compares the effectiveness of learning CRM skills when being an active participant versus being an observer participant in simulation followed by a debriefing. METHODS: Participants were randomized to two groups: active or observer. Active participants managed a simulated crisis scenario (pre-test) while paired observer participants viewed the scenario via video transmission. Then, a trained instructor debriefed participants on CRM principles. On the same day, each participant individually managed another simulated crisis scenario (post-test) and completed a post-test questionnaire. Two independent, blinded raters evaluated all videos using the Ottawa Global Rating Scale (GRS). RESULTS: Thirty-nine residents were included in the analysis. Normally distributed data were analyzed using paired and unpaired t-tests. Inter rater reliability was 0.64. Active participants significantly improved from pre test to post-test (P=0.015). There was no significant difference between the post test performance of active participants compared to observer participants (P=0.12). CONCLUSION: We found that learning CRM principles was not superior when learners were active participants compared to being observers followed by debriefing. These findings challenge the deliberate practice theory claiming that learning requires active practice. Assigning residents as observers in simulation training and involving them in debriefing is still beneficial. PMID- 26987739 TI - Innate danger signals in acute injury: From bench to bedside. AB - The description of the systemic inflammatory response syndrome (SIRS) as a reaction to numerous insults marked a turning point in the understanding of acute critical states, which are intensive care basic cases. This concept highlighted the final inflammatory response features whichever the injury mechanism is: infectious, or non-infectious such as extensive burns, traumas, major surgery or acute pancreatitis. In these cases of severe non-infectious insult, many endogenous mediators are released. Like infectious agents components, they can activate the immune system (via common signaling pathways) and initiate an inflammatory response. They are danger signals or alarmins. These molecules generally play an intracellular physiological role and acquire new functions when released in extracellular space. Many progresses brought new information on these molecules and on their function in infectious and non-infectious inflammation. These danger signals can be used as biomarkers and provide new pathophysiological and therapeutic approaches, particularly for immune dysfunctions occurring after an acute injury. We present herein the danger model, the main danger signals and the clinical consequences. PMID- 26987740 TI - Empyema management: A cohort study evaluating antimicrobial therapy. AB - OBJECTIVES: Empyemas require aggressive antimicrobial and surgical management. However, the specifics of antimicrobial therapy have not been studied in clinical trials. The present study examines management and outcomes among a cohort of patients with empyema cared for in a tertiary-care referral hospital over a decade. METHODS: We retrospectively identified patients hospitalized with empyema from January 2000 through December 2010 at one institution. Patient demographics, laboratory findings, treatments, and patient outcomes were abstracted using a standard form. Data were summarized with standard descriptive statistics. RESULTS: A total of 91 patients were identified. The predominant organisms were viridans group streptococci, which were isolated in 64% of cases with cultures. The median length of hospitalization was 9 days. Length of antimicrobial therapy from time of source control was variable, with a median (interquartile range) duration of 27 (15-31) days. Of note, longer courses of parenteral, but not oral, therapy were associated with fewer cases of clinical failure. CONCLUSIONS: This descriptive analysis demonstrated a higher rate of viridans group streptococci than expected. Three weeks of therapy was generally adequate and prevented clinical failure, but further study is needed with a much larger cohort to better define the optimal drug regimen, route, and duration of antimicrobial therapy for empyema. PMID- 26987741 TI - Understanding the magnetic interaction between intrinsic defects and impurity ions in room-temperature ferromagnetic Mg1-xFexO thin films. AB - Understanding the nature and characteristics of the intrinsic defects and impurities in the dielectric barrier separating the ferromagnetic electrodes in a magnetic tunneling junction is of great importance for understanding the often observed 'barrier-breakdown' therein. In this connection, we present herein systematic experimental (SQUID and synchrotron-radiation-based x-ray absorption spectroscopy) and computational studies on the electronic and magnetic properties of Mg1-xFexO thin films. Our studies reveal: (i) defect aggregates comprised of basic and trimer units (Fe impurity coupled to 1 or 2 Mg vacancies) and (ii) existence of two competing magnetic orders, defect- and dopant-induced, with spin densities aligning anti-parallel if the trimer is present in the oxide matrix. These findings open up new avenues for designing tunneling barriers with high endurance and tunneling effect upon tuning the concentration/distribution of the two magnetic orders. PMID- 26987742 TI - Influence of alkoxy chain envelopes on the interfacial photoinduced processes in tetraarylporphyrin-sensitized solar cells. AB - The introduction of alkoxy chains in the molecular architecture of meso push-pull porphyrins is of paramount importance aiming at high performing dye-sensitized solar cells (DSSCs) based on these specific sensitizers. Recently, we have demonstrated that the same approach is fruitful even if it is applied to tetraarylporphyrins with an acceptor/anchoring substituent in the beta-pyrrolic position. In particular, among the ortho-ortho, the ortho-para and the ortho functionalization of the aryl rings with an octyloxy chain, we identified the latter as the most performing in the series, showing a good balance between the dye loading and the reduction of pi-pi aggregation. Herein, focusing our attention on the mono-ortho-functionalized molecular structure, we have investigated the effect of the alkoxy chain length and nature on the reduction of dye-to-dye aggregation as well as on the enhancement of light harvesting capabilities, finding an almost linear relationship between the device photon conversion efficiency (PCE) and the alkoxy chain length both in the presence and in the absence of a co-disaggregating agent. PMID- 26987743 TI - Current Findings and Mechanisms of Action of Disulfiram in the Treatment of Alcohol Dependence. AB - As an alcohol-aversive agent, disulfiram occupies an exceptional position in the pharmacological relapse prevention of alcohol dependence. In contrast to anti craving drugs, disulfiram does not modulate neurobiological mechanisms of addiction, but rather works by producing an aversive reaction when combined with alcohol. Therapeutic and adverse effects are therefore closely related: On the one hand, the aversiveness of the disulfiram ethanol reaction has the potential to support abstinence in a subgroup of alcohol-dependent patients, while on the other hand it becomes a health threat if the patient fails to maintain complete abstinence. The exceptional position of disulfiram is also related to the role that expectations play in the mediation of therapeutic effects. These are not determined by the pharmacological effects or the actual occurrence of a disulfiram-ethanol reaction, but are attributable to patient awareness that the drug was consumed and the corresponding anticipation of an aversive reaction if combined with alcohol. This is in line with the findings of a recent meta analysis that only showed significant effects for disulfiram in open-label trials. The authors of the meta-analysis conclude that due to expectations induced in both the treatment and placebo groups, blinded studies are incapable of distinguishing a difference between groups. The mediation of therapeutic effects through expectation has a number of consequences for clinical practice and future research on disulfiram. PMID- 26987744 TI - Self limiting atomic layer deposition of Al2O3 on perovskite surfaces: a reality? AB - The feasibility of self-saturated atomic layer deposition of Al2O3 on an organolead halide perovskite (MAPbI3-xClx) surface through a well known trimethylaluminium (TMA)-water (H2O) chemistry is studied. Though the sequential dosages of reactants form films on the perovskite surfaces, a self saturated growth is never observed. Self-saturation leads to the degradation of the material. Both experimental and density functional theory calculations are carried out for complete understanding of the growth mechanism of self-limiting Al2O3 on the perovskite surface. PMID- 26987746 TI - Japanese regulation of biosimilar products: past experience and current challenges. AB - Seven biosimilar products have been approved in Japan since the March 2009 publication of the 'Guideline for quality, safety and efficacy assurance of biosimilar products' by the Ministry of Health, Labor and Welfare (MHLW). Four years previously, the 'Guideline on similar biological medicinal products' was issued in the European Union (EU), and 13 products as of February 2016 have been approved as biosimilar. The US Food and Drug Administration (FDA) approved the first biosimilar product in the US in March 2015 and final Guidance was issued at the end of April 2015. Over the past decade, the challenges regarding the development of biosimilar products have been discussed extensively. In this article, the data packages of biosimilar products in Japan are compared with those overseas in order to clarify the concepts used by the Japanese regulatory authority, i.e., the Pharmaceuticals and Medical Devices Agency (PMDA). The challenges in the development of biosimilar products in Japan are also addressed. PMID- 26987747 TI - Stabilization of HIF-1alpha modulates VEGF and Caspase-3 in the hippocampus of rats following transient global ischemia induced by asphyxial cardiac arrest. AB - AIMS: Hypoxia inducible factor-1 (HIF-1) contributes to pathophysiological changes of homeostasis under conditions of oxygen deprivation as well as ischemia. In this study, we examined protein expression of subtype HIF-1alpha and its downstream product, namely vascular endothelial growth factor (VEGF) in the rat hippocampus after transient global ischemia induced by asphyxial cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR). We also examined the effects of stabilization of HIF-1alpha by systemic administration of dimethyloxalylglycine (DMOG) and ML228 on expression of VEGF receptor subtype 2 (VEGFR-2), Caspase-3 and NF-kB in the hippocampus. MAIN METHODS: Ninety-six adult Sprague-Dawley rats were used in this study. The animals surviving from CPR were sacrificed 0, 3, 6 and 24h following CPR and the protein levels of HIF-1alpha and VEGF in the hippocampus were determined. VEGFR-2, Caspase-3 and NF-kB were also examined in control rats, and rats that survived for 24h after CPR and were given with DMOG/ML228. Moreover, neurological functions were estimated in control rats and rats with DMOG/ML228. KEY FINDINGS: Our results show that HIF-1alpha and VEGF were significantly increased in the hippocampus 3-24h after CA. Significant increases in VEGFR-2, Caspase-3 and NF-kappaB were observed in the hippocampus 24h after CA (P<0.05 vs. control group). Nonetheless, DMOG and ML228 significantly augmented VEGFR-2, attenuated Caspase-3 and neuronal apoptosis, and improved neurological Severity Score and tissue edema (P<0.05 vs. saline group), without affecting expression of NF-kappaB. SIGNIFICANCE: Our data revealed specific signaling pathways in alleviating CA-evoked global cerebral ischemia by elucidating that HIF-1alpha plays an important role in regulating expression of VEGFR-2 and Caspase-3 as well as improving neurological functions and neuronal edema. The subsequent induction of HIF-1alpha and its target signal pathways is likely a part of the intrinsic neuroprotective effects aimed at attenuating damage as a result of global cerebral ischemia. Thus, targeting one or more of these signaling molecules has clinical implications for treatment and management of CA-evoked global cerebral ischemia often observed in clinics. PMID- 26987745 TI - The Zn(II) nanocomplex: Sonochemical synthesis, characterization, DNA- and BSA binding, cell imaging, and cytotoxicity against the human carcinoma cell lines. AB - The focus of this article is preparation of a new kind of nanomaterial, the Zn(II) nanocomplex, to decrease growth of human carcinoma cell lines. The Zn(II) nanocomplex coordinated by phendione, [Zn(phendione)3](PF6)2 (where phendione is 1,10-phenanthroline-5,6-dione), has been synthesized by sonochemical method and characterized by FT-IR, dynamic light scattering (DLS), and scanning electron microscopy (SEM). The interaction of the complex and nanocomplex with fish sperm DNA (FS-DNA) has been investigated under physiological conditions by a series of experimental methods (fluorescence titration, viscosity, cyclic voltammetry (CV), competitive DNA-binding studies with ethidium bromide, and SEM). Results have indicated that the complex binds to FS-DNA by two biding modes, viz., electrostatic and partial insertion phendione between the base stacks of double stranded DNA. The quenching constants (Ksv), binding constants (Kbin), and number of binding sites (n) at different temperatures, as well as thermodynamic parameters (DeltaH(o), DeltaS(o) and DeltaG(o)) have been calculated for the BSA complex system. Protein binding studies show that the complex and nanocomplex could bind with BSA. Results of synchronous fluorescence of BSA show that addition of the complex affect the microenvironment of both tyrosine and tryptophan residues during the binding process. The in vitro cytotoxicity of the complex and nanocomplex against the human carcinoma cell lines (MCF-7 and A-549) was evaluated by MTT assay. Results indicate that the complex and nanocomplex have greater cytotoxicity activity against MCF-7 with IC50 values of 0.2 and 0.9 mg/L, respectively. Results of the microscopic analyses of the cancer cells confirm results of cytotoxicity. PMID- 26987749 TI - Chinese and Iranian Scientific Publications: Fast Growth and Poor Ethics. PMID- 26987748 TI - Increased xanthine oxidase-related ROS production and TRPV1 synthesis preceding DOMS post-eccentric exercise in rats. AB - AIMS: It is well-known that unaccustomed exercise, especially eccentric exercise, is associated to delayed onset muscle soreness (DOMS). Whether DOMS is associated with reactive oxygen species (ROS) and the transient receptor potential vanilloid 1 (TRPV1) is still an open question. Thus, the aim of this study was to investigate the association between TRPV1 and xanthine oxidase-related ROS production in muscle and DOMS after a bout of eccentric exercise. MAIN METHODS: Male Wistar rats performed a downhill running exercise on a treadmill at a -16 degrees tilt and a constant speed for 90min (5min/bout separated by 2min of rest). Mechanical allodynia and grip force tests were performed before and 1, 3, 6, 9, 12, 24, 48 and 72h after the downhill running. Biochemical assays probing oxidative stress, purine degradation, xanthine oxidase activity, Ca(2+) ATPase activity and TRPV1 protein content were performed in gastrocnemius muscle at 12, 24, and 48h after the downhill running. KEY FINDINGS: Our statistical analysis showed an increase in mechanical allodynia and a loss of strength after the downhill running. Similarly, an increase in carbonyl, xanthine oxidase activity, uric acid levels and TRPV1 immunoreactivity were found 12h post-exercise. On the other hand, Ca(2+) ATPase activity decreased in all analyzed times. SIGNIFICANCE: Our results suggest that a possible relationship between xanthine oxidase-related ROS and TRPV1 may exist during the events preceding eccentric exercise-related DOMS. PMID- 26987750 TI - Profiling of potential driver mutations in sarcomas by targeted next generation sequencing. AB - Comprehensive genetic profiling by massively parallel sequencing, commonly known as next generation sequencing (NGS), is becoming the foundation of personalized oncology. For sarcomas very few targeted treatments are currently in routine use. In clinical practice the preoperative diagnostic workup of soft tissue tumours largely relies on core needle biopsies. Although mostly sufficient for histopathological diagnosis, only very limited amounts of formalin fixated paraffin embedded tissue are often available for predictive mutation analysis. Targeted NGS may thus open up new possibilities for comprehensive characterization of scarce biopsies. We therefore set out to search for driver mutations by NGS in a cohort of 55 clinically and morphologically well characterized sarcomas using low input of DNA from formalin fixated paraffin embedded tissues. The aim was to investigate if there are any recurrent or targetable aberrations in cancer driver genes in addition to known chromosome translocations in different types of sarcomas. We employed a panel covering 207 mutation hotspots in 50 cancer-associated genes to analyse DNA from nine gastrointestinal stromal tumours, 14 synovial sarcomas, seven myxoid liposarcomas, 22 Ewing sarcomas and three Ewing-like small round cell tumours at a large sequencing depth to detect also mutations that are subclonal or occur at low allele frequencies. We found nine mutations in eight different potential driver genes, some of which are potentially actionable by currently existing targeted therapies. Even though no recurrent mutations in driver genes were found in the different sarcoma groups, we show that targeted NGS-based sequencing is clearly feasible in a diagnostic setting with very limited amounts of paraffin embedded tissue and may provide novel insights into mesenchymal cell signalling and potentially druggable targets. Interestingly, we also identify five non synonymous sequence variants in 4 established cancer driver genes in DNA from normal tissue from sarcoma patients that may possibly predispose or contribute to neoplastic development. PMID- 26987751 TI - Effects of singing on voice, respiratory control and quality of life in persons with Parkinson's disease. AB - Purpose Interventions focused on singing may provide additional benefits to established voice and respiratory therapies, due to their greater emphasis on the respiratory muscle control system in those with Parkinson's disease (PD) progresses. The purpose of this study was to examine if singing can improve voice, respiratory pressure and quality of life (QOL) in persons with PD. Methods This pilot study measured the effects of a singing intervention in 27 participants with PD. Participants were assigned to a high (met twice weekly) or low (met once weekly) dosage group. Voice, respiratory and QOL measures were recorded before and after an 8-week singing intervention. Sessions were led by board-certified music therapists and included a series of vocal and articulation exercises and group singing. Results Both groups demonstrated significant improvements in maximum inspiratory and expiratory pressure, as well as phonation time. While other voice measures improved, they did not reach statistical significance. Voice QOL and whole health QOL also significantly improved. Conclusion These results suggest singing may be a beneficial and engaging treatment choice for improving and maintaining vocal function and respiratory pressure in persons with PD. Implications for Rehabilitation In a small sample, group singing proved beneficial for improving voice and respiratory impairment in persons with Parkinson's disease. Completing group singing one time per week for 8 weeks was as effective as completing group singing two times per week for 8 weeks in persons with Parkinson's disease. Group singing is an effective means of improving overall quality of life in persons with Parkinson's disease. PMID- 26987752 TI - HLA-A*24:334, a novel variant of HLA-A*24, discovered in a Taiwanese individual. AB - One nucleotide replacement at residue 587 of HLA-A*24:02:01:01 results in a novel allele, HLA-A*24:334. PMID- 26987754 TI - Solvent-molecule-mediated manipulation of crystalline grains for efficient planar binary lead and tin triiodide perovskite solar cells. AB - Binary lead and tin perovskites offer the benefits of narrower band gaps for broader adsorption of solar spectrum and better charge transport for higher photocurrent density. Here, we report the growth of large, smooth crystalline grains of bianry lead and tin triiodide perovskite films via a two-step solution process with thermal plus solvent vapor-assisted thermal annealing. The crystalline SnxPb1-xI2 films formed in the first step served as the templates for the formation of crystalline CH3NH3SnxPb1-xI3 films during the second step interdiffusion of methylammonium iodide (MAI). Followed by dimethylsulfoxide (DMSO) vapor-assisted thermal annealing, small, faceted perovskite grains grew into large, smooth grains via the possible mechanism involving bond breaking and reforming mediated by DMSO solvent molecules. The absorption onset was extended to 950 and 1010 nm for the CH3NH3SnxPb1-xI3 perovskites with x = 0.1 and 0.25, respectively. The highest PCE of 10.25% was achieved from the planar perovskite solar cell with the CH3NH3Sn0.1Pb0.9I3 layer prepared via the thermal plus DMSO vapor-assisted thermal annealing. This research provides a way to control and manipulate film morphology, grain size, and especially the distribution of metal cations in binary metal perovskite layers, which opens an avenue to grow perovskite materials with desired properties to enhance device performance. PMID- 26987753 TI - Development of an HSV-1 neutralization test with a glycoprotein D specific antibody for measurement of neutralizing antibody titer in human sera. AB - BACKGROUND: Investigating the neutralizing antibody (NAb) titer against HSV-1 is essential for monitoring the immune protection against HSV-1 in susceptible populations, which would facilitate the development of vaccines against herpes infection and improvement of HSV-1 based oncolytic virotherapy. RESULTS: In this study, we have developed a neutralization test based on the enzyme-linked immunospot assay (ELISPOT-NT) to determine the neutralizing antibody titer against HSV-1 in human serum samples. This optimized assay employed a monoclonal antibody specifically recognizing glycoprotein D to detect the HSV-1 infected cells. With this test, the neutralizing antibody titer against HSV-1 could be determined within one day by automated interpretation of the counts of cell spots. We observed good correlation in the results obtained from ELISPOT-NT and plaque reduction neutralization test (PRNT) by testing 22 human serum samples representing different titers. Moreover, 269 human serum samples collected from a wide range of age groups were tested, the average neutralizing antibody titer (log2NT50) was 8.3 +/- 2.8 and the prevalence of NAbs was 83.6 % in this cohort, it also revealed that the average neutralizing antibody titer in different groups increased with the age, and no significant difference in neutralizing antibody titers was observed between males and females. CONCLUSIONS: These results prove that this novel assay would serve as an accurate and simple assay for the assessment of the neutralizing antibody titers against HSV-1 in large cohorts. PMID- 26987755 TI - Clinical trial on tonal tinnitus with tailor-made notched music training. AB - BACKGROUND: Tinnitus is a result of hyper-activity/hyper-synchrony of auditory neurons coding the tinnitus frequency, which has developed due to synchronous mass activity owing to the lack of inhibition. We assume that removal of exactly these frequencies from a complex auditory stimulus will cause the brain to reorganize around tonotopic regions coding the tinnitus frequency through inhibition-induced plasticity. Based on this assumption, a novel treatment for tonal tinnitus--tailor-made notched music training (TMNMT)--has been introduced and was tested in this clinical trial. METHODS: A randomized controlled trial in parallel group design was performed in a double-blinded manner. We included 100 participants with chronic, tonal tinnitus who listened to tailor-made notched music for two hours a day for three consecutive months. Our primary outcome measures were the Tinnitus Handicap Questionnaire and Visual Analog Scales measuring perceived tinnitus loudness, awareness, distress and handicap. Participants rated their tinnitus before and after the training as well as one month after cessation of the training. RESULTS: While no effect was found for the primary outcome measures, tinnitus distress, as measured by the Tinnitus Questionnaire, a secondary outcome measure, developed differently in the two groups. The treatment group showed higher distress scores while the placebo group revealed lower distress scores after the training. However, this effect did not reach significance in post-hoc analysis and disappeared at follow-up measurements. At follow-up, tinnitus loudness in the treatment group was significantly reduced as compared to the control group. Post hoc analysis, accounting for low reliability scores in the Visual Analog Scales, showed a significant reduction of the overall Visual Analog Scale mean score in the treatment group even at the post measurement. CONCLUSION: This is the first study on TMNMT that was planned and conducted following the CONSORT statement standards for clinical trials. The current work is one more step towards a final evaluation of TMNMT. Already after three months the effect of training with tailor-made notched music is observable in the most direct rating of tinnitus perception - the tinnitus loudness, while more global measures of tinnitus distress do not show relevant changes. TRIAL REGISTRATION: Current Controlled Trials ISRCTN04840953; Trial registration date: 17.07.2013. PMID- 26987757 TI - Coronary artery disease: screen or treat? PMID- 26987756 TI - Knowledge, attitudes, and practices about influenza illness and vaccination: a cross-sectional survey in two South African communities. AB - BACKGROUND: Understanding knowledge and sentiment toward influenza and vaccination is important for effective health messages and prevention strategies. We aimed to characterize knowledge, attitudes, and practices surrounding influenza illness and vaccination in two South African communities and explore reasons for vaccine hesitancy. METHODS: Household primary caregivers in Soweto and Klerksdorp townships were interviewed about knowledge of influenza and intention to receive an influenza vaccine using a structured questionnaire. Factors associated with unwillingness to receive vaccine were explored using multivariable regression. RESULTS: We interviewed representatives of 973 households in Soweto and 1,442 in Klerksdorp. Most respondents in Soweto (692, 71%) and Klerksdorp (1247, 87%) thought weather or cold caused influenza. While most would get a free influenza vaccine, those unwilling to receive vaccine had concerns about efficacy (Soweto: 19%; Klerksdorp: 19%) and safety (Soweto: 17%; Klerksdorp: 10%). In Soweto, females (aRR 2.0, 95% CI 1.3-3.2) and those with higher household income (aRR 1.8, 95% CI 1.2-2.7) were less willing to receive vaccine. In Klerksdorp, more educated respondents (aRR 1.6, 95% CI 1.1-2.4) were less willing to receive vaccine; households reporting an HIV-positive member were more willing to receive vaccine (aRR 0.3, 95% CI 0.1-0.8). CONCLUSIONS: Although findings suggest most community participants were amenable to influenza vaccination, knowledge gaps were present. Emphasizing the importance of influenza as a health problem and addressing vaccine safety and efficacy concerns may improve uptake. Populations less amenable to vaccination, including those with higher education and income, may benefit from targeted messaging efforts. PMID- 26987758 TI - Effects of healthcare reform on health resource allocation and service utilization in 1110 Chinese county hospitals: data from 2006 to 2012. AB - The central government of China launched a large-scale, expensive health reform in April 2009 because of the serious health-related problems in the country. This reform aims to re-establish a universal healthcare system, which is expected to provide affordable basic healthcare. Independent two-sample t-test, one-way ANOVA and chi-squared test were conducted to analyze the effect of the health reform on health resource allocation and service utilization in Chinese county hospitals. First, we described the hospitals' financial performance in terms of funding sources, balances and fiscal compensations (for personnel expenditure). Second, we discussed the total number of health personnel as well as the structure (number of medical personnel per thousand population and ratio of doctors and nurses) and quality of the health personnel. Lastly, we investigated the county hospitals' health resource utilization, bed occupancy and average medical expense per visit. Then, we probed different reasons and provided multiple approaches to existing problems. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26987759 TI - Predictors of knowledge about tuberculosis: results from SANHANES I, a national, cross-sectional household survey in South Africa. AB - BACKGROUND: South Africa is one of the 22 high tuberculosis burden countries that contribute 80% of the global tuberculosis cases. Tuberculosis is infectious and due to its rapid and easy transmission route poses a threat to population health. Considering the importance of social and psychological factors in influencing health outcomes, appraising knowledge and awareness of tuberculosis, remain vital for effective tuberculosis control. The main aim of this study was to investigate the factors that predict knowledge about tuberculosis among 18-64 year old adults in South Africa. METHODS: A cross-sectional survey method was used. Multi-stage disproportionate, stratified cluster sampling was used to select households within enumeration areas stratified by province and locality type. Based on the Human Sciences Research Council 2007 master sample, 500 Enumerator Areas representative of the socio-demographic profile of South Africa were identified and a random sample of 20 households was randomly selected from each Enumerator Area, yielding an overall sample of 10,000 households. The tuberculosis module contained in the South African National Health And Nutrition Examination Survey I was the only module that examined the social determinants of an infectious disease. This module was questionnaire-based with no biomarkers obtained to screen for the presence of tuberculosis disease among the participants. Data was collected by administering a researcher developed individual level questionnaire. Simple and multiple linear regression was used to determine the independent variables associated with tuberculosis knowledge. RESULTS: Half the sample (52.6%) was female and the majority of the respondents were black African (76.5%). More than two thirds (68.0%) resided in urban areas, 56.9% did not complete high school and half were not in formal employment. Significant predictors of tuberculosis knowledge were race, sex, completion of high school, being in employment, having a diagnosis of the disease in ones' life-time and learning about tuberculosis from television, brochures, health workers, and teachers. CONCLUSIONS: To reduce the burden of tuberculosis in South Africa, media campaigns targeting both rural and urban communities should include conveying accurate information about the disease. Policy makers should also address structural barriers that vulnerable communities face. PMID- 26987760 TI - Thermoresponsive Poly(Ionic Liquid)s in Aqueous Salt Solutions: Salting-Out Effect on Their Phase Behavior and Water Absorption/Desorption Properties. AB - Here, a thermoresponsive phase behavior of polymerized ionic liquids (PILs) composed of poly([tri-n-alkyl(vinylbenzyl)phosphonium]chloride) (poly([Pnnn VB ]Cl) is reported, where n (the number of carbon atoms of an alkyl chain) = 4, 5, or 6 after mixing with aqueous sodium chloride solutions. Both monomeric [P555VB ]Cl and the resulting poly([P555VB ]Cl) linear homopolymer show a lower critical solution temperature (LCST)-type phase behavior in aq. NaCl solutions. The phase transition temperature of the PIL shifts to lower value by increasing concentration of NaCl. Also the swelling degree of cross-linked poly([P555VB ]Cl) gel decreases by increasing NaCl concentration, clearly suggesting the "salting out" effect of NaCl results in a significant dehydration of the poly([P555VB ]Cl) gel. The absorbed water in the PIL gel is desorbed by moderate heating via the LCST behavior, and the absolute absorption/desorption amount is improved by copolymerization of [P555VB ]Cl with more hydrophilic [P444VB ]Cl monomer. PMID- 26987762 TI - Critical Evaluation and Compilation of Physicochemical Determinants and Membrane Interactions of MMGP1 Antifungal Peptide. AB - A growing issue of pathogen resistance to antibiotics has fostered the development of innovative approaches for novel drug development. Here, we report the physicochemical and biological properties of an antifungal peptide, MMGP1, based on computational analysis. Computation of physicochemical properties has revealed that the natural biological activities of MMGP1 are coordinated by its intrinsic properties such as net positive charge (+5.04), amphipathicity, high hydrophobicity, low hydrophobic moment, and higher isoelectric point (11.915). Prediction of aggregation hot spots in MMGP1 had revealed the presence of potentially aggregation-prone segments that can nucleate in vivo aggregation (on the membrane), whereas no aggregating regions were predicted for in vitro aggregation (in solutions) of MMGP1. This ability of MMGP1 to form oligomeric aggregates on membrane further substantiates its direct-cell penetrating potency. Monte Carlo simulation of the interactions of MMGP1 in the aqueous phase and different membrane environments revealed that increasing the proportion of acidic lipids on membrane had led to increase in the peptide helicity. Furthermore, the peptide adopts energetically favorable transmembrane configuration, by inserting peptide loop and helix termini into the membrane containing >60% of anionic lipids. The charged lipid-based insertion of MMGP1 into membrane might be responsible for the selectivity of peptide toward fungal cells. Additionally, MMGP1 possessed DNA-binding property. Computational docking has identified DNA binding residues (TRP3, SER4, MET7, ARG8, PHE10, ALA11, GLY20, THR21, ARG22, MET23, TRP34, and LYS36) in MMGP1 crucial for its DNA-binding property. Furthermore, computational mutation analysis revealed that aromatic amino acids are crucial for in vivo aggregation, membrane insertion, and DNA-binding property of MMGP1. These data provide new insight into the molecular determinants of MMGP1 antifungal activity and also serves as the template for the design of novel peptide antibiotics. PMID- 26987763 TI - Platelet Indices in Patients With Acute Coronary Syndromes: A Bedside Marker of Prognosis? PMID- 26987765 TI - Birds of a feather - Analysis of travel health advice provided to international avitourists. PMID- 26987766 TI - Prostate-specific antigen testing rates and referral patterns from general practice data in England. AB - BACKGROUND: There is currently no national screening programme for prostate cancer in England, but eligible men can request a prostate-specific antigen (PSA) test from their general practitioner (GP). There are no routinely available data to monitor the extent of PSA testing and referral. AIM: The aim of this study was to investigate the rate of PSA testing in general practice and subsequent patterns of referral. DESIGN AND SETTING: Data obtained from the Clinical Practice Research Datalink (CPRD) for men aged 45-84 years who had a PSA test during 2010-2011, registered in practices in England with linked Hospital Episode Statistics (HES) data. METHOD: Patient data were linked to previous tests and consultations. Rates of PSA testing and proportions of men retested and referred to secondary care were calculated. RESULTS: Overall, 8.74 (95% CI 8.67-8.82) of men per 100 person-years were tested at least once in 2010, and 9.45 (95% CI 9.37 9.53) in 2011. Rates increased with age and decreased with increasing level of deprivation. Of the 53,069 men tested in 2010, 11,289 (21.3%) had a previous PSA test within the past 12 months. Of men with raised PSA according to age specific guidelines, 22.4% (2113/9425) were referred to secondary care within 14 days, with 36% of the remainder retested within 6 months. CONCLUSIONS: Rates of PSA testing have increased compared with earlier studies; the data suggest that many GPs are retesting men with raised PSA rather than referring immediately. More routine data on PSA testing, including reasons for testing, and subsequent management and outcomes, are required. PMID- 26987764 TI - Unusual microorganisms and antimicrobial resistances in a group of Syrian migrants: Sentinel surveillance data from an asylum seekers centre in Italy. AB - BACKGROUND: Three years of civil war in Syria have caused death and increase of communicable diseases. The suffering population has been forced to migrate creating a fertile condition for epidemic spread of infection within the refugee camps. METHODS: Forty-eight Syrian migrants, upon their arrival in Italy, were accommodated at the asylum seekers centre of Castelnuovo di Porto. They received a physical examination and were subjected to microbiological surveillance by blood, rectal, pharyngeal and nasal swabs collection and delivering to the Clinical Pathology and Microbiology Laboratory of the University Campus Bio Medico of Rome. RESULTS: All refugees resulted negative for HBV, HCV and HIV infections. In swabs a large number of unusual gram-negative bacteria species were isolated, such as Pseudomonas putida, Pseudomonas monteilii, Pseudomonas fulva, Pseudomonas moselii, Aeromonas veronii, Aeromonas caviae, Aeromonas hydrophila, Acinteobacter guilloviae, Acinteobacter lowffii; Acinetobacter johnsonii; Acinteobacter tjernbergae; Pantoea agglomerans; Pantoea calida. Among isolates, strains resistant to carbapenems, ESBL producers and methicillin resistant were found. CONCLUSIONS: The microbiological surveillance performed represents a useful action to understand refugees health status and to trace unusual microorganisms movement even carriers of antimicrobial resistance during migrants traveling. PMID- 26987767 TI - Frontal fibrosing alopecia: possible association with leave-on facial skin care products and sunscreens; a questionnaire study. AB - BACKGROUND: Since its first description in 1994, frontal fibrosing alopecia (FFA) has become increasingly common, suggesting that environmental factors are involved in the aetiology. OBJECTIVES: To identify possible causative environmental factors in FFA. METHODS: A questionnaire enquiring about exposure to a wide range of lifestyle, social and medical factors was completed by 105 women with FFA and 100 age- and sex-matched control subjects. A subcohort of women with FFA was patch tested to an extended British standard series of allergens. RESULTS: The use of sunscreens was significantly greater in the FFA group compared with controls. Subjects with FFA also showed a trend towards more frequent use of facial moisturizers and foundations but, compared with controls, the difference in frequencies just failed to reach statistical significance. The frequency of hair shampooing, oral contraceptive use, hair colouring and facial hair removal were significantly lower in the FFA group than in controls. Thyroid disease was more common in subjects with FFA than controls and there was a high frequency of positive patch tests in women with FFA, mainly to fragrances. CONCLUSIONS: Our findings suggest an association between FFA and the use of facial skin care products. The high frequency of sunscreen use in patients with FFA, and the fact that many facial skin care products now contain sunscreens, raises the possibility of a causative role for sunscreen chemicals. The high frequency of positive patch tests in women with FFA and the association with thyroid disease may indicate a predisposition to immune-mediated disease. PMID- 26987770 TI - Floral Nectar: Pollinator Attraction or Manipulation? AB - The literature suggests that floral nectar acts principally to attract pollinator visitation (and/or revisitation), thereby enhancing plant reproductive success. However, floral nectar also manipulates pollinator behaviour during and immediately following plant visits, affecting pollen transfer, and plant reproduction. I argue that floral nectar should really be viewed as a pollinator manipulant rather than attractant, thus potentially explaining why its concentration is not generally high and why it decreases with increasing pollinator body size. Otherwise, such patterns may remain mysterious and unexplained. PMID- 26987769 TI - Isolation of infectious Zika virus from saliva and prolonged viral RNA shedding in a traveller returning from the Dominican Republic to Italy, January 2016. AB - We report the isolation of infectious Zika virus (ZIKV) in cell culture from the saliva of a patient who developed a febrile illness after returning from the Dominican Republic to Italy, in January 2016. The patient had prolonged shedding of viral RNA in saliva and urine, at higher load than in blood, for up to 29 days after symptom onset. Sequencing of ZIKV genome showed relatedness with strains from Latin America. PMID- 26987771 TI - Restoration, Reintroduction, and Rewilding in a Changing World. AB - The increasing abandonment of marginal land creates new opportunities for restoration, reintroduction, and rewilding, but what do these terms mean in a rapidly and irreversibly changing world? The 're' prefix means 'back', but it is becoming clear that the traditional use of past ecosystems as targets and criteria for success must be replaced by an orientation towards an uncertain future. Current opinions in restoration and reintroduction biology range from a defense of traditional definitions, with some modifications, to acceptance of more radical responses, including assisted migration, taxon substitution, de extinction, and genetic modification. Rewilding attempts to minimize sustained intervention, but this hands-off approach is also threatened by rapid environmental change. PMID- 26987761 TI - Research Review: Environmental exposures, neurodevelopment, and child mental health - new paradigms for the study of brain and behavioral effects. AB - BACKGROUND: Environmental exposures play a critical role in the genesis of some child mental health problems. METHODS: We open with a discussion of children's vulnerability to neurotoxic substances, changes in the distribution of toxic exposures, and cooccurrence of social and physical exposures. We address trends in prevalence of mental health disorders, and approaches to the definition of disorders that are sensitive to the subtle effects of toxic exposures. We suggest broadening outcomes to include dimensional measures of autism spectrum disorders, attention-deficit hyperactivity disorder, and child learning capacity, as well as direct assessment of brain function. FINDINGS: We consider the impact of two important exposures on children's mental health: lead and pesticides. We argue that longitudinal research designs may capture the cascading effects of exposures across biological systems and the full-range of neuropsychological endpoints. Neuroimaging is a valuable tool for observing brain maturation under varying environmental conditions. A dimensional approach to measurement may be sensitive to subtle subclinical toxic effects, permitting the development of exposure related profiles and testing of complex functional relationships between brain and behavior. Questions about the neurotoxic effects of chemicals become more pressing when viewed through the lens of environmental justice. CONCLUSIONS: Reduction in the burden of child mental health disorders will require longitudinal study of neurotoxic exposures, incorporating dimensional approaches to outcome assessment, and measures of brain function. Research that seeks to identify links between toxic exposures and mental health outcomes has enormous public health and societal value. PMID- 26987772 TI - Determination of sulfadiazine, trimethoprim, and N(4) -acetyl-sulfadiazine in fish muscle plus skin by Liquid Chromatography-Mass Spectrometry. Withdrawal-time calculation after in-feed administration in gilthead sea bream (Sparus aurata L.) fed two different diets. AB - This study presents a depletion study for sulfadiazine and trimethoprim in muscle plus skin of gilthead sea bream (Sparus aurata L.). N(4) -acetyl-sulfadiazine, the main metabolite of sulfadiazine (SDZ), was also examined. The fish were held in seawater at a temperature of 24-26 degrees C. SDZ and trimethoprim (TMP) were administered orally with medicated feed for five consecutive days at daily doses of 25 mg SDZ and 5 mg TMP per kg of fish body weight per day. Two different diets, fish oil- and plant oil-based diets, were investigated. Ten fish were sampled at each of the days 1, 3, 5, 6, 8, 9, 10, and 12 after the start of veterinary medicine administration. However for the calculation of the withdrawal periods, sampling day 1 was set as 24 h after the last dose of the treatment. Fish samples were analyzed for SDZ, TMP, and acetyl-sulfadiazine (AcSDZ) residues by liquid chromatography-mass spectrometry. SDZ and TMP concentrations declined rapidly from muscle plus skin. Considering a maximum residue limit of 100 MUg/kg for the total of sulfonamides and 50 MUg/kg for TMP residues in fish muscle plus skin, the withdrawal periods of the premix trimethoprim-sulfadiazine 50% were calculated as 5 and 6 days, at 24-26 degrees C, in fish oil (FO) and plant oil (PO) groups, respectively. The investigation of this work is important to protect consumers by controlling the undesirable residues in fish. PMID- 26987773 TI - Robotic surgery rapidly and successfully implemented in a high volume laparoscopic center on living kidney donation. AB - BACKGROUND: It is important to minimize risks associated with live donor nephrectomy. In this study we evaluated the results of left-sided robot-assisted donor nephrectomies in comparison with standard techniques. METHODS: Data on perioperative results, kidney function, and recipient and graft survival were collected. All left-sided laparoscopic and hand-assisted procedures were selected as control groups. RESULTS: Fifty-nine robot-assisted procedures were performed by two surgeons. Operative time was significantly longer in the robot-assisted group compared with both control groups. However, it decreased significantly during procedures 40-59 compared with procedures 20-39 (P = 0.014) to median 172.5 (114.0-242.0) min. One conversion to the open approach occurred in the robot group due to a bleeding of the renal artery stump. No difference was found between all techniques at 3 months post-donation. CONCLUSION: Left-sided robot assisted donor nephrectomy is feasible with over time a significant decrease in operative time with good outcomes for donor and recipient. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26987774 TI - Initial PET performance evaluation of a preclinical insert for PET/MRI with digital SiPM technology. AB - Hyperion-II(D) is a positron emission tomography (PET) insert which allows simultaneous operation in a clinical magnetic resonance imaging (MRI) scanner. To read out the scintillation light of the employed lutetium yttrium orthosilicate crystal arrays with a pitch of 1 mm and 12 mm in height, digital silicon photomultipliers (DPC 3200-22, Philips Digital Photon Counting) (DPC) are used. The basic PET performance in terms of energy resolution, coincidence resolution time (CRT) and sensitivity as a function of the operating parameters, such as the operating temperature, the applied overvoltage, activity and configuration parameters of the DPCs, has been evaluated at system level. The measured energy resolution did not show a large dependency on the selected parameters and is in the range of 12.4%-12.9% for low activity, degrading to ~13.6% at an activity of ~100 MBq. The CRT strongly depends on the selected trigger scheme (trig) of the DPCs, and we measured approximately 260 ps, 440 ps, 550 ps and 1300 ps for trig 1 4, respectively. The trues sensitivity for a NEMA NU 4 mouse-sized scatter phantom with a 70 mm long tube of activity was dependent on the operating parameters and was determined to be 0.4%-1.4% at low activity. The random fraction stayed below 5% at activity up to 100 MBq and the scatter fraction was evaluated as ~6% for an energy window of 411 keV-561 keV and ~16% for 250 keV 625 keV. Furthermore, we performed imaging experiments using a mouse-sized hot rod phantom and a large rabbit-sized phantom. In 2D slices of the reconstructed mouse-sized hot-rod phantom (? = 28 mm), the rods were distinguishable from each other down to a rod size of 0.8 mm. There was no benefit from the better CRT of trig 1 over trig 3, where in the larger rabbit-sized phantom (? = 114 mm) we were able to show a clear improvement in image quality using the time-of-flight information. The findings will allow system architects-aiming at a similar detector design using DPCs-to make predictions about the design requirements and the performance that can be expected. PMID- 26987775 TI - Human Umbilical Vein Endothelial Cells foster conversion of CD4+CD25-Foxp3- T cells into CD4+Foxp3+ Regulatory T Cells via Transforming Growth Factor-beta. AB - Trans-placental cell trafficking is a naturally occurring process during pregnancy that results in the direct recognition of foreign maternal antigens by fetal tissue and vice versa. Immigration of potentially harmful allo-reactive maternal T cells into fetal circulation may provoke anti-fetal immune responses. However, the contact with fetal tissue may favor differentiation of maternal immune cells into cells with a regulatory phenotype. Human Umbilical Vein Endothelial Cells (HUVECs) possess immune-regulating properties and are one of the first fetal cells to get in contact with foreign maternal immune cells. Therefore, here we studied whether HUVECs induce the conversion of maternal T cells into regulatory T (Treg) cells. Moreover, we assessed whether this response is changing according to the sex of the HUVECs. Both female and male HUVECs induced the conversion of maternal T cells into Treg cells which is partially mediated via TGF-beta. Female HUVECs showed a stronger capacity to induce Treg cells compared to male HUVECs. Our findings propose that HUVECs contribute to fetal-maternal tolerance by the increase of the Treg cell population. Sex specific differences in Treg cell induction may partly account for the disparities on the incidence of infectious and autoimmune diseases between both sexes during early childhood. PMID- 26987779 TI - Electrosensitization assists cell ablation by nanosecond pulsed electric field in 3D cultures. AB - Previous studies reported a delayed increase of sensitivity to electroporation (termed "electrosensitization") in mammalian cells that had been subjected to electroporation. Electrosensitization facilitated membrane permeabilization and reduced survival in cell suspensions when the electric pulse treatments were split in fractions. The present study was aimed to visualize the effect of sensitization and establish its utility for cell ablation. We used KLN 205 squamous carcinoma cells embedded in an agarose gel and cell spheroids in Matrigel. A local ablation was created by a train of 200 to 600 of 300-ns pulses (50 Hz, 300-600 V) delivered by a two-needle probe with 1-mm inter-electrode distance. In order to facilitate ablation by engaging electrosensitization, the train was split in two identical fractions applied with a 2- to 480-s interval. At 400-600 V (2.9-4.3 kV/cm), the split-dose treatments increased the ablation volume and cell death up to 2-3-fold compared to single-train treatments. Under the conditions tested, the maximum enhancement of ablation was achieved when two fractions were separated by 100 s. The results suggest that engaging electrosensitization may assist in vivo cancer ablation by reducing the voltage or number of pulses required, or by enabling larger inter-electrode distances without losing the ablation efficiency. PMID- 26987776 TI - Differential TGFbeta pathway targeting by miR-122 in humans and mice affects liver cancer metastasis. AB - Downregulation of a predominantly hepatocyte-specific miR-122 is associated with human liver cancer metastasis, whereas miR-122-deficient mice display normal liver function. Here we show a functional conservation of miR-122 in the TGFbeta pathway: miR-122 target site is present in the mouse but not human TGFbetaR1, whereas a noncanonical target site is present in the TGFbeta1 5'UTR in humans and other primates. Experimental switch of the miR-122 target between the receptor TGFbetaR1 and the ligand TGFbeta1 changes the metastatic properties of mouse and human liver cancer cells. High expression of TGFbeta1 in human primary liver tumours is associated with poor survival. We identify over 50 other miRNAs orthogonally targeting ligand/receptor pairs in humans and mice, suggesting that these are evolutionarily common events. These results reveal an evolutionary mechanism for miRNA-mediated gene regulation underlying species-specific physiological or pathological phenotype and provide a potentially valuable strategy for treating liver-associated diseases. PMID- 26987780 TI - MicroRNA expression profile of human periodontal ligament cells under the influence of Porphyromonas gingivalis LPS. AB - Periodontitis is a chronic inflammatory disease which is caused by bacterial infection and leads to the destruction of periodontal tissues and resorption of alveolar bone. Thus, special attention should be paid to the mechanism under lipopolysaccharide (LPS)-induced periodontitis because LPS is the major cause of periodontitis. However, to date, miRNA expression in the LPS-induced periodontitis has not been well characterized. In this study, we investigated miRNA expression patterns in LPS-treated periodontal ligament cells (PDLCs). Through miRNA array and differential analysis, 22 up-regulated miRNAs and 28 down regulated miRNAs in LPS-treated PDLCs were identified. Seven randomly selected up regulated (miR-21-5p, 498, 548a-5p) and down-regulated (miR-495-3p, 539-5p, 34c 3p and 7a-2-3p) miRNAs were examined by qRT-PCR, and the results proved the accuracy of the miRNA array. Moreover, targets of these deregulated miRNAs were analysed using the miRWalk database. Database for Annotation, Visualization and Integration Discovery software were performed to analyse the Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes pathway of differential expression miRNAs, and the results shown that Toll-like receptor signalling pathway, cAMP signalling pathway, transforming growth factor-beta signalling pathway, mitogen activated protein kinase (MAPK) signalling pathway and other pathways were involved in the molecular mechanisms underlying LPS-induced periodontitis. In conclusion, this study provides clues for enhancing our understanding of the mechanisms and roles of miRNAs as key regulators of LPS-induced periodontitis. PMID- 26987781 TI - [Incidence of community-acquired infections of lower airways among infants]. AB - OBJECTIVE: To estimate the incidence of community-acquired infections of the lower respiratory tract and the risk factors associated with its occurrence in infants, in their first year of life. METHODS: A prospective cohort study of infants who were followed up during the first 12 months of life. Interviews were conducted with their mothers, and children were clinically monitored bimonthly to investigate the occurrence of the incidence density of community-acquired infections of the lower respiratory tract. Cox regression analysis was used to estimate the crude and adjusted relative risk of the variables associated with the outcome. RESULTS: The mean age of the mothers was 26 years, 62% of them had more than 11 years of schooling, and 23.5 were at risk of social exclusion regarding economic income. The incidence density of pneumonia and bronchiolitis were, respectively, 0.51 and 3.10 episodes per 100 children-months. Children who had low birth weight (<2500g) were 5.96 (95%CI 1.75-20.40) times more likely to have pneumonia than infants weighing 2500g or over. CONCLUSIONS: The incidence of acute lower respiratory tract infection in children was similar to that found in other studies. Only low birth weight was an independent risk factor for the occurrence of pneumonia. PMID- 26987783 TI - A highly sensitive electrochemiluminescence biosensor for the detection of organophosphate pesticides based on cyclodextrin functionalized graphitic carbon nitride and enzyme inhibition. AB - A signal on an electrochemiluminescence (ECL) biosensor using beta-cyclodextrin (CD) functionalized graphitic carbon nitride (g-C3N4) as the luminophore was constructed for sensitive organophosphate pesticides (OPs) detection based on the enzyme inhibition of OPs, showing that the consumption of coreactant triethylamine (Et3N) decreased with a lessening of the acetic acid (HAc) in situ generated by enzymatic reaction. PMID- 26987782 TI - Association between clinical variables related to asthma in schoolchildren born with very low birth weight with and without bronchopulmonary dysplasia. AB - OBJECTIVE: to assess the prevalence, spirometry findings and risk factors for asthma in schoolchildren who were very low birth weight infants with and without bronchopulmonary dysplasia. METHODS: Observational and cross-sectional study. The parents and/or tutors answered the International Study of Asthma and Allergies in Childhood questionnaire. The schoolchildren were submitted to the skin prick test and spirometry assessment. RESULTS: 54 schoolchildren who were very low birth weight infants were assessed and 43 met the criteria for spirometry. Age at the assessment (bronchopulmonary dysplasia=9.5+/-0.85; without bronchopulmonary dysplasia=10.1+/-0.86 years) and birth weight (bronchopulmonary dysplasia=916.7+/ 251.2; without bronchopulmonary dysplasia=1,171.3+/-190.5g) were lower in the group with bronchopulmonary dysplasia (p<0.05). The prevalence of asthma among very low birth weight infants was 17/54 (31.5%), being 6/18 (33.3%) in the group with bronchopulmonary dysplasia. There was an association between wool blanket use in the first year of life (p=0.026) with the presence of asthma at school age. The skin prick test was positive in 13/17 (76.5%) and 23/37 (62.2%) of patients with and without asthma, respectively. The schoolchildren with asthma had lower z-score values of forced expiratory flow between 25% and 75% of forced vital capacity (n=16; -1.04+/-1.19) when compared to the group of patients without asthma (n=27; -0.38+/-0.93) (p=0.049). There was no difference between the spirometry variables in the groups regarding the presence or absence of bronchopulmonary dysplasia. CONCLUSIONS: Very low birth weight infants with and without bronchopulmonary dysplasia showed a high prevalence of asthma (33.3% and 30.6%, respectively). Pulmonary flow in the small airways was lower in children with asthma. PMID- 26987784 TI - Preliminary Findings on the Association Between Symptoms of Depression and Adherence to Antiretroviral Therapy in Individuals Born Inside Versus Outside of Canada. AB - For optimal health, people living with HIV (PLWH) need to adhere to antiretroviral therapy (ART). We explored the relationship between symptoms of depression and ART adherence for PLWH born inside versus outside of Canada. PLWH taking ART (N = 57) completed self-assessments of depression and adherence to ART. Adherence rates did not differ significantly for PLWH who were born outside (66.7% were >=95% adherent) versus inside Canada (51.6% were >=95% adherent), but the relationship between symptoms of depression and ART adherence depended on the country of birth: for individuals born in Canada, depression was associated with lower ART adherence (beta = -.21, p = .005, 95% confidence interval -.35 to .07); for PLWH born outside of Canada there was no association between symptoms of depression and ART adherence. Symptoms of depression may not universally affect ART adherence; country of birth may be one critical variable impacting this relationship. PMID- 26987785 TI - Impact of graft implantation order on graft survival in simultaneous pancreas kidney transplantation. AB - The optimal order of revascularization for pancreas and kidney grafts in simultaneous pancreas-kidney transplantation has not been established. In this study, we investigate the influence of graft implantation order on graft survival in SPK. 12 700 transplantations from the Scientific Registry of Transplant Recipients were analyzed retrospectively. Graft implantation order was determined based on the reported ischemia times of pancreas and kidney grafts. Pancreas and kidney graft survivals were analyzed depending on graft implantation order at 3 months and 5 years using Kaplan-Meier plots. Significance was tested with log rank test and Cox regression model. In 8454 transplantations, the pancreas was implanted first (PBK), and in 4246 transplantations, the kidney was implanted first (KBP). The proportion of lost pancreas grafts at 3 months was significantly lower in PBK (9.4% vs. 10.8%, P = 0.011). Increasing time lag (>2 h) between kidney and pancreas graft implantation in KBP accentuated the detrimental impact on pancreas graft survival (12.5% graft loss at 3 months, P = 0.001). Technical failure rates were reduced in PBK (5.6 vs. 6.9%, P = 0.005). Graft implantation order had no impact on kidney graft survival. In summary, although observed differences are small, pancreas graft implantation first increases short-term pancreas graft survival and reduces rates of technical failure. PMID- 26987786 TI - Pregnancy Reveals Evolving Risk for Cardiometabolic Disease in Women. AB - Pregnancy serves as a cardiometabolic stressor that may unmask underlying metabolic and vascular abnormalities in an evolving continuum of pathophysiology. In 2011, the American Heart Association indicated that a diagnosis of pre eclampsia, gestational hypertension, or gestational diabetes classified a woman as at risk for cardiovascular disease. In this article, we discuss hypertensive disorders of pregnancy, gestational diabetes, and preterm birth as risk factors for future cardiovascular disease in women. PMID- 26987787 TI - Detail-preserving construction of neonatal brain atlases in space-frequency domain. AB - Brain atlases are commonly utilized in neuroimaging studies. However, most brain atlases are fuzzy and lack structural details, especially in the cortical regions. This is mainly caused by the image averaging process involved in atlas construction, which often smoothes out high-frequency contents that capture fine anatomical details. Brain atlas construction for neonatal images is even more challenging due to insufficient spatial resolution and low tissue contrast. In this paper, we propose a novel framework for detail-preserving construction of population-representative atlases. Our approach combines spatial and frequency information to better preserve image details. This is achieved by performing atlas construction in the space-frequency domain given by wavelet transform. In particular, sparse patch-based atlas construction is performed in all frequency subbands, and the results are combined to give a final atlas. For enhancing anatomical details, tissue probability maps are also used to guide atlas construction. Experimental results show that our approach can produce atlases with greater structural details than existing atlases. Hum Brain Mapp 37:2133 2150, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26987788 TI - Multiple non-parkinsonian rest tremors: dystonic rest tremor is the next candidate. PMID- 26987789 TI - Circadian variations in laboratory measurements of coagulation assays after administration of rivaroxaban or warfarin in patients with nonvalvular atrial fibrillation. AB - BACKGROUND: Although rivaroxaban has a relatively shorter half-life and peak and trough plasma concentrations throughout the day than warfarin, rivaroxaban has been found to be non-inferior to warfarin in preventing thromboembolic events in patients with nonvalvular atrial fibrillation (NVAF). We measured circadian variations in laboratory measurements of coagulation assays for chronic treatment with rivaroxaban or warfarin in patients with NVAF. METHODS: We included 28 consecutive patients with NVAF who were treated with rivaroxaban (n=13) or warfarin (n=15). Blood samples were collected at 6 AM, 11 AM, and 3 PM on the same day and on the next morning at 6 AM. Prothrombin time (PT), international normalized ratio of the PT (PT-INR), activated partial thromboplastin time (APTT), prothrombin fragment 1+2 (F1+2), and protein C level/activity were measured in each patient. RESULTS: PT and PT-INR were significantly and consistently lower, and the F1+2 and protein C level/activity were significantly and consistently higher throughout the day in rivaroxaban-treated patients than in warfarin-treated patients. Significant increases in PT and PT-INR were observed 3h after oral administration in the patients taking rivaroxaban in the morning, whereas, significant increases in the protein C level/activity were observed 3h after oral administration in the patients taking warfarin in the morning. CONCLUSIONS: The protein C level/activity was significantly and consistently higher in the rivaroxaban-treated patients than in the warfarin treated patients throughout the day, which was in contrast to the findings for other coagulation assays. These findings may partly explain the specific persistent anticoagulant effects of rivaroxaban even during the trough phase of the plasma concentration. PMID- 26987790 TI - Minimal energy requirement for external cardioversion and catheter ablation for long-standing persistent atrial fibrillation. AB - BACKGROUND: The minimal energy requirement (Emin) for electrical cardioversion (ECV) reflects the atrial substrate in patients with long-standing persistent atrial fibrillation (L-PeAF), but the relationship between EminECV and radiofrequency catheter ablation (RFCA) has not yet been studied. We hypothesize that EminECV before ablation (EminECVpre) predicts clinical outcome of RFCA, and that catheter ablation reduces EminECVpost. METHODS: We included 172 patients with L-PeAF who underwent RFCA (79.7% males, 57.5+/-10.0 years) due to AF recurrence after ECV with an anti-arrhythmic drug (AAD). ECV began with 70J (patch electrode on anterior-posterior position) and was serially increased to 100, 150, 200, and 250J until sinus rhythm was achieved, at an average 5.0+/-5.6 months before RFCA. After RFCA, ECV was repeated (ECVpost) in 42 patients with recurrent AF that was not controlled by AAD. RESULTS: (1) During 34.8+/-20.0 months of follow-up after RFCA, 103 patients (59.9%) showed clinical recurrence of AF after RFCA. EminECVpre was significantly higher in patients with recurrent AF (129.0+/-58.6J) than those who remained in sinus rhythm (94.2+/-39.4J, p<0.001). (2) EminECVpre >=150J (HR=3.31, 95% CI 2.18-5.03, p<0.001) and left atrial volume index (HR=1.02, 95% CI 1.00-1.04, p=0.021) were significantly associated with post-RFCA recurrence. (3) Shorter post-RFCA recurrence timing was also independently related to EminECVpre (beta=-0.147, 95% CI -0.20 to -0.09, p<0.001). (4) Among 103 patients with recurrent AF after RFCA, 42 AAD-resistant AF patients underwent ECVpost. EminECVpost (100.9+/-50.8J) was significantly lower than EminECVpre (130.0+/-66.1J, p=0.006). CONCLUSIONS: Higher EminECVpre was independently associated with clinical recurrence and earlier recurrence timing of AF after catheter ablation among patients with AAD-resistant L-PeAF. Catheter ablation for L-PeAF significantly reduces EminECV. PMID- 26987791 TI - Impact of preoperative dual antiplatelet therapy on bleeding complications in patients with acute coronary syndromes who undergo urgent coronary artery bypass grafting. AB - BACKGROUND: A 5- to 7-day washout period before coronary artery bypass grafting (CABG) is recommended for patients who have recently received a thienopyridine derivative; however, data supporting this guideline recommendation are lacking in Japanese patients. METHODS: Urgent isolated CABG was performed in 130 consecutive patients with acute coronary syndromes (ACS) (101 men; mean age, 69 years). Urgent CABG was defined as operation performed within 5 days after coronary angiography. All patients continued to receive aspirin 100mg/day. The subjects were retrospectively divided into 2 groups: 30 patients with preoperative thienopyridine (clopidogrel in 15 patients, ticlopidine in 15) exposure within 5 days [dual antiplatelet therapy (DAPT) group] and 100 patients without exposure [single antiplatelet therapy (SAPT) group]. RESULTS: Although the DAPT group had a higher proportion of patients who received perioperative platelet transfusions than the SAPT group (50% vs. 18%, p<0.001), intraoperative bleeding (median, 1100ml; interquartile range, 620-1440 vs. 920ml; 500-1100) and total drain output within 48h after surgery (577+/-262 vs. 543+/-277ml) were similar. CABG-related major bleeding, which was defined as type 4 or 5 bleeding according to the Bleeding Academic Research Consortium definitions, occurred in a significantly higher proportion of patients in the DAPT group than in the SAPT group (20% vs. 3%, p=0.005). This difference in major bleeding was driven mainly by the higher rate of transfusion of >=5U red blood cells within a 48-h period in the DAPT group (13% vs. 1%, p=0.01). There was no significant difference in the 30-day composite endpoint including death, myocardial (re)infarction, ischemic stroke, and refractory angina between the DAPT group and SAPT group (17% vs. 19%). CONCLUSIONS: Preoperative DAPT increases the risk of CABG-related major bleeding in Japanese patients with ACS undergoing urgent CABG. PMID- 26987792 TI - Relationship between local production of microRNA-328 and atrial substrate remodeling in atrial fibrillation. AB - BACKGROUND: The underlying mechanism of atrial substrate remodeling in atrial fibrillation (AF) remains unknown. In this study, we investigated whether local and systemic levels of microRNA (miR) might be associated with the presence of AF and with left atrial (LA) substrate properties. METHODS: Blood from the periphery, pulmonary vein (PV), and left atrial appendage (LAA) was sampled from 30 patients with AF undergoing PV isolation, and from 10 control subjects with Wolff-Parkinson-White syndrome and without AF. We measured peripheral, PV, and LAA plasma levels of miR-1, -26, -133a, -328, and -590 by reverse transcription polymerase chain reaction. LA global contact mapping during sinus rhythm was performed before PV isolation. RESULTS: Plasma levels of miR-328 were higher in patients with AF than in control subjects. Plasma miR-328 levels were significantly higher in the LAA than in the periphery and PV in patients with AF, but not in control subjects. Plasma miR-1 levels were also higher in the LAA than in the PV in AF patients. Interestingly, LAA plasma levels of miR-328 showed a positive correlation with the LA voltage zone index (area with voltage <0.5mV divided by total LA surface area) and a weak correlation with LA volume. CONCLUSION: Local production of miR-328 in the left atrium may be involved in the process of atrial remodeling in patients with AF. PMID- 26987793 TI - Involvement of a universal amino acid synthesis impediment in cytoplasmic male sterility in pepper. AB - To explore the mechanisms of pepper (Capsicum annuum L.) cytoplasmic male sterility (CMS), we studied the different maturation processes of sterile and fertile pepper anthers. A paraffin section analysis of the sterile anthers indicated an abnormality of the tapetal layer and an over-vacuolization of the cells. The quantitative proteomics results showed that the expression of histidinol dehydrogenase (HDH), dihydroxy-acid dehydratase (DAD), aspartate aminotransferase (ATAAT), cysteine synthase (CS), delta-1-pyrroline-5-carboxylate synthase (P5CS), and glutamate synthetase (GS) in the amino acid synthesis pathway decreased by more than 1.5-fold. Furthermore, the mRNA and protein expression levels of DAD, ATAAT, CS and P5CS showed a 2- to 16-fold increase in the maintainer line anthers. We also found that most of the amino acid content levels decreased to varying degrees during the anther tapetum period of the sterile line, whereas these levels increased in the maintainer line. The results of our study indicate that during pepper anther development, changes in amino acid synthesis are significant and accompany abnormal tapetum maturity, which is most likely an important cause of male sterility in pepper. PMID- 26987794 TI - Facebook and Twitter, communication and shelter, and the 2011 Tuscaloosa tornado. AB - This paper represents one of the first attempts to analyse the many ways in which Facebook and Twitter were used during a tornado disaster. Comparisons between five randomly selected campus samples and a city of Tuscaloosa, Alabama, sample revealed that campus samples used Facebook and Twitter significantly more both before and after the tornado, but Facebook usage was not significantly different after the event. Furthermore, differences in social media usage and other forms of communication before the tornado were found for age, education, and years lived in Tuscaloosa. Generally, age and education were inversely proportionate to social media usage. Influences on shelter-seeking actions varied between social media users and three random samples of non-social media users; however, it appears that social media respondents were likely to be using a smartphone simultaneously to access warning polygon information, to receive text message alerts, and to listen or respond to environmental cues. PMID- 26987795 TI - The Australian Racism, Acceptance, and Cultural-Ethnocentrism Scale (RACES): item response theory findings. AB - BACKGROUND: Racism and associated discrimination are pervasive and persistent challenges with multiple cumulative deleterious effects contributing to inequities in various health outcomes. Globally, research over the past decade has shown consistent associations between racism and negative health concerns. Such research confirms that race endures as one of the strongest predictors of poor health. Due to the lack of validated Australian measures of racist attitudes, RACES (Racism, Acceptance, and Cultural-Ethnocentrism Scale) was developed. METHODS: Here, we examine RACES' psychometric properties, including the latent structure, utilising Item Response Theory (IRT). Unidimensional and Multidimensional Rating Scale Model (RSM) Rasch analyses were utilised with 296 Victorian primary school students and 182 adolescents and 220 adults from the Australian community. RESULTS: RACES was demonstrated to be a robust 24-item three-dimensional scale of Accepting Attitudes (12 items), Racist Attitudes (8 items), and Ethnocentric Attitudes (4 items). RSM Rasch analyses provide strong support for the instrument as a robust measure of racist attitudes in the Australian context, and for the overall factorial and construct validity of RACES across primary school children, adolescents, and adults. CONCLUSIONS: RACES provides a reliable and valid measure that can be utilised across the lifespan to evaluate attitudes towards all racial, ethnic, cultural, and religious groups. A core function of RACES is to assess the effectiveness of interventions to reduce community levels of racism and in turn inequities in health outcomes within Australia. PMID- 26987796 TI - The nematode Caenorhabditis elegans as a tool to predict chemical activity on mammalian development and identify mechanisms influencing toxicological outcome. AB - To determine whether a C. elegans bioassay could predict mammalian developmental activity, we selected diverse compounds known and known not to elicit such activity and measured their effect on C. elegans egg viability. 89% of compounds that reduced C. elegans egg viability also had mammalian developmental activity. Conversely only 25% of compounds found not to reduce egg viability in C. elegans were also inactive in mammals. We conclude that the C. elegans egg viability assay is an accurate positive predictor, but an inaccurate negative predictor, of mammalian developmental activity. We then evaluated C. elegans as a tool to identify mechanisms affecting toxicological outcomes among related compounds. The difference in developmental activity of structurally related fungicides in C. elegans correlated with their rate of metabolism. Knockdown of the cytochrome P450s cyp-35A3 and cyp-35A4 increased the toxicity to C. elegans of the least developmentally active compounds to the level of the most developmentally active. This indicated that these P450s were involved in the greater rate of metabolism of the less toxic of these compounds. We conclude that C. elegans based approaches can predict mammalian developmental activity and can yield plausible hypotheses for factors affecting the biological potency of compounds in mammals. PMID- 26987797 TI - Assessing Differences in the Availability of Opioid Addiction Therapy Options: Rural Versus Urban and American Indian Reservation Versus Nonreservation. AB - BACKGROUND: Opioid misuse is a large public health problem in the United States. Residents of rural areas and American Indian (AI) reservation/trust lands represent traditionally underserved populations with regard to substance-use disorder therapy. PURPOSE: Assess differences in the number of opioid agonist therapy (OAT) facilities and physicians with Drug Addiction Treatment Act (DATA) waivers for rural versus urban, and AI reservation/trust land versus non-AI reservation/trust land areas in Washington State. METHODS: The unit of analysis was the ZIP code. The dependent variables were the number of OAT facilities and DATA-waivered physicians in a region per 10,000 residents aged 18-64 in a ZIP code. A region was defined as a ZIP code and its contiguous ZIP codes. The independent variables were binary measures of whether a ZIP code was classified as rural versus urban, or AI reservation/trust land versus non-AI reservation/trust land. Zero-inflated negative binomial regressions with robust standard errors were estimated. RESULTS: The number of OAT clinics in a region per 10,000 ZIP-code residents was significantly lower in rural versus urban areas (P = .002). This did not differ significantly between AI reservation/trust land and non-AI reservation/trust land areas (P = .79). DATA-waivered physicians in a region per 10,000 ZIP-code residents was not significantly different between rural and urban (P = .08), or AI reservation/trust land versus non-AI reservation/trust land areas (P = .21). CONCLUSIONS: It appears that the potential for Washington State residents of rural and AI reservation areas to receive OAT is similar to that of residents outside of those areas; however, difficulties in accessing therapy may remain, highlighting the importance of expanding health care insurance and providing support for DATA-waivered physicians. PMID- 26987798 TI - Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis. AB - Dysregulated repair of lung injury often results in lung fibrosis characterized by unremitting deposition of matrix components including glycosaminoglycan hyaluronan (HA). HA is mainly produced by hyaluronan synthases (HAS) in mesenchymal cells. We previously demonstrated that over-expression of HAS2 in mesenchymal cells in mice regulates the invasiveness of fibroblasts and promotes severe lung fibrosis. The mechanisms that control the resolution of lung fibrosis are unknown. We propose that a critical step in resolving fibrosis is the induction of senescence in fibrotic fibroblasts and hyaluronan synthase 2 may regulate this process. We found that fibrotic fibroblasts developed the characteristics of replicative senescence in culture and that HAS2 expression was dramatically down-regulated. Furthermore, down-regulation of HAS2 initiated and regulated fibroblast senescence through a p27-CDK2-SKP2 pathway. Deletion of HAS2 in mouse mesenchymal cells increased the cellular senescence of fibroblasts in bleomycin-induced mouse lung fibrosis in vivo. These data suggest that HAS2 may be a critical regulator of the fate of pulmonary fibrosis and we propose a model where over-expression of HAS2 promotes an invasive phenotype resulting in severe fibrosis and down-regulation of HAS2 promotes resolution. Targeting HAS2 to induce fibroblast senescence could be an attractive approach to resolve tissue fibrosis. PMID- 26987800 TI - Management implications of resection margin histology in patients undergoing resection for IPMN: A meta-analysis. AB - INTRODUCTION: IPMN is a relatively new clinical entity and surgeons are continuing to develop their understanding of this complex pathology. Little is known of the natural disease process post-resection of an IPMN, particularly the impact of gland histology and margin status on the chance of recurrence and survival in benign and invasive IPMN. METHODS: An online search was conducted to evaluate and include those studies which reported on gland histology, margin status and disease recurrence in resected benign and malignant IPMN. A Meta analysis was then performed using a random effects model. RESULTS: The chance of recurrence in non-invasive margin positive IPMN is similar to margin negative IPMN. The chance of recurrence is higher in invasive gland IPMN compared to non invasive gland. The vast majority of recurrences occurred in patients with positive margins demonstrating invasion. CONCLUSION: All patients with intra- or post-operative evidence of invasive carcinoma at the resection margin should undergo further resection to achieve a negative margin. Patients with evidence of IPMN at the transaction margin (even with changes of high grade dysplasia/CIS) may not achieve any benefit from further resection. Patients with recurrence in benign/non-invasive IPMN should undergo re-resection, whereas patients with recurrence in invasive IPMN should not. PMID- 26987801 TI - Retrospective Study of Obesity in Children with Down Syndrome. AB - OBJECTIVES: To assess whether children with Down syndrome in the US are at an increased risk for obesity, we determined the obesity prevalence and analyzed obesity development throughout childhood in a cohort of children with Down syndrome. In addition, we analyzed a comorbidity that is associated with Down syndrome and obesity, obstructive sleep apnea syndrome (OSAS). STUDY DESIGN: This study was a retrospective chart review that evaluated 303 children ages 2 through 18 years with a diagnosis of Down syndrome. All children were patients at Cincinnati Children's Hospital Medical Center with multiple height and weight measurements. To determine obesity burden, the rate of obesity was compared with a local control cohort using contingency tables. Change in obesity rate through time was determined with mixed models. Association of obesity with OSAS was determined with contingency tables. RESULTS: We evaluated 303 individuals, 47.8% of whom were obese (body mass index >=95th percentile for age and sex). This was significantly higher than the general pediatric population, which had a 12.1% obesity rate (P < .0001). Body mass index z-scores did not change markedly over time (P = .40). The majority of children with Down syndrome also had OSAS (74.0% of the 177 children who had polysomnography studies). However, OSAS risk was elevated in obese children (risk ratio = 2.4, P = .0015). CONCLUSIONS: Our results indicate that children with Down syndrome are at a substantial risk for obesity and OSAS. These findings support the need for more aggressive weight management in early childhood and throughout the lifespan. PMID- 26987799 TI - DNA damage signalling barrier, oxidative stress and treatment-relevant DNA repair factor alterations during progression of human prostate cancer. AB - The DNA damage checkpoints provide an anti-cancer barrier in diverse tumour types, however this concept has remained unexplored in prostate cancer (CaP). Furthermore, targeting DNA repair defects by PARP1 inhibitors (PARPi) as a cancer treatment strategy is emerging yet requires suitable predictive biomarkers. To address these issues, we performed immunohistochemical analysis of multiple markers of DNA damage signalling, oxidative stress, DNA repair and cell cycle control pathways during progression of human prostate disease from benign hyperplasia, through intraepithelial neoplasia to CaP, complemented by genetic analyses of TMPRSS2-ERG rearrangement and NQO1, an anti-oxidant factor and p53 protector. The DNA damage checkpoint barrier (gammaH2AX, pATM, p53) mechanism was activated during CaP tumorigenesis, albeit less and with delayed culmination compared to other cancers, possibly reflecting lower replication stress (slow proliferation despite cases of Rb loss and cyclin D1 overexpression) and progressive loss of ATM activator NKX3.1. Oxidative stress (8-oxoguanine lesions) and NQO1 increased during disease progression. NQO1 genotypes of 390 men did not indicate predisposition to CaP, yet loss of NQO1 in CaP suggested potential progression-opposing tumour suppressor role. TMPRSS2-ERG rearrangement and PTEN loss, events sensitizing to PARPi, occurred frequently along with heterogeneous loss of DNA repair factors 53BP1, JMJD1C and Rev7 (all studied here for the first time in CaP) whose defects may cause resistance to PARPi. Overall, our results reveal an unorthodox DNA damage checkpoint barrier scenario in CaP tumorigenesis, and provide novel insights into oxidative stress and DNA repair, with implications for biomarker guidance of future targeted therapy of CaP. PMID- 26987802 TI - A rapid method to authenticate vegetable oils through surface-enhanced Raman scattering. AB - Vegetable oils are essential in our daily diet. Among various vegetable oils, the major difference lies in the composition of fatty acids, including unsaturated fatty acids (USFA) and saturated fatty acids (SFA). USFA include oleic acid (OA), linoleic acid (LA), and alpha-linolenic acid (ALA), while SFA are mainly palmitic acid (PA). In this study, the most typical and abundant USFA present with PA in vegetable oils were quantified. More importantly, certain proportional relationships between the integrated intensities of peaks centered at 1656 cm(-1) (S1656) in the surface-enhanced Raman scattering spectra of different USFA were confirmed. Therefore, the LA or ALA content could be converted into an equivalent virtual OA content enabling the characterization of the USFA content in vegetable oils using the equivalent total OA content. In combination with the S1656 of pure OA and using peanut, sesame, and soybean oils as examples, the ranges of S1656 corresponding to the National Standards of China were established to allow the rapid authentication of vegetable oils. Gas chromatograph-mass spectrometer analyses verified the accuracy of the method, with relative errors of less than 5%. Moreover, this method can be extended to other detection fields, such as diseases. PMID- 26987805 TI - Can age-related biology impact on clinical management and outcome of primary breast cancer in older women? PMID- 26987804 TI - Involvement of orexin-1 and orexin-2 receptors within the dentate gyrus of the hippocampus in the acquisition, expression and extinction of lateral hypothalamic induced conditioned place preference in the rats. AB - Orexinergic projections originating from the lateral hypothalamus (LH) have an important role in the acquisition of the LH-stimulation conditioned place preference (CPP). Among the brain areas associated with reward processing, LH orexinergic neurons send projections to the dentate gyrus (DG) region of the hippocampus, and it has been shown that orexin receptors are expressed in the DG. In this study, we investigated the role of intra-DG orexin-1 (OX1) and orexin-2 (OX2) receptors on acquisition, expression and extinction of CPP induced by stimulation of the LH. Rats were unilaterally implanted by two separate cannulae into the LH and DG. The CPP paradigm was done; conditioning scores and locomotor activities were recorded by Ethovision software. The results showed that intra-DG administration of SB334867, a selective OX1r antagonist, and TCS OX2 29, a selective OX2r antagonist, (0.5, 5, 12.5 and 50nM/0.5ul DMSO) before carbachol microinjection (250nM; effective dose) during the 3-days conditioning phase, dose dependently inhibited the development of LH stimulation-induced CPP in the rats. However, this reduction in OX1r antagonist treated groups was more than that in OX2r antagonist treated animals. In addition, these antagonists decreased the expression of LH-induced CPP. Moreover, OX1r but not OX2r antagonist could shorten the extinction duration of place preference. We conclude that the orexinergic projections from the LH to DG are involved in the development, expression and extinction of CPP induced by LH stimulation. PMID- 26987806 TI - Artificial Photosynthesis: Hybrid Systems. AB - Oxidoreductases are promising catalysts for organic synthesis. To sustain their catalytic cycles they require efficient supply with redox equivalents. Today classical biomimetic approaches utilizing natural electron supply chains prevail but artificial regeneration approaches bear the promise of simpler and more robust reaction schemes. Utilizing visible light can accelerate such artificial electron transport chains and even enable thermodynamically unfeasible reactions such as the use of water as reductant.This contribution critically summarizes the current state of the art in photoredoxbiocatalysis (i.e. light-driven biocatalytic oxidation and reduction reactions). PMID- 26987807 TI - Are we being exposed to radiation in the hospital? PMID- 26987808 TI - Mining for genes related to choroidal neovascularization based on the shortest path algorithm and protein interaction information. AB - BACKGROUND: Choroidal neovascularization (CNV) is a serious eye disease that may cause visual loss, especially for older people. Many factors have been proven to induce this disease including age, gender, obesity, and so on. However, until now, we have had limited knowledge on CNV's pathogenic mechanism. Discovering the genes that underlie this disease and performing extensive studies on them can help us to understand how CNV occurs and design effective treatments. METHODS: In this study, we designed a computational method to identify novel CNV-related genes in a large protein network constructed using the protein-protein interaction information in STRING. The candidate genes were first extracted from the shortest paths connecting any two known CNV-related genes and then filtered by a permutation test and using knowledge of their linkages to known CNV-related genes. RESULTS: A list of putative CNV-related candidate genes was accessed by our method. These genes are deemed to have strong relationships with CNV. CONCLUSIONS: Extensive analyses of several of the putative genes such as ANK1, ITGA4, CD44 and others indicate that they are related to specific biological processes involved in CNV, implying they may be novel CNV-related genes. GENERAL SIGNIFICANCE: The newfound putative CNV-related genes may provide new insights into CNV and help design more effective treatments. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang. PMID- 26987803 TI - Restrained Th17 response and myeloid cell infiltration into the central nervous system by human decidua-derived mesenchymal stem cells during experimental autoimmune encephalomyelitis. AB - BACKGROUND: Multiple sclerosis is a widespread inflammatory demyelinating disease. Several immunomodulatory therapies are available, including interferon beta, glatiramer acetate, natalizumab, fingolimod, and mitoxantrone. Although useful to delay disease progression, they do not provide a definitive cure and are associated with some undesirable side-effects. Accordingly, the search for new therapeutic methods constitutes an active investigation field. The use of mesenchymal stem cells (MSCs) to modify the disease course is currently the subject of intense interest. Decidua-derived MSCs (DMSCs) are a cell population obtained from human placental extraembryonic membranes able to differentiate into the three germ layers. This study explores the therapeutic potential of DMSCs. METHODS: We used the experimental autoimmune encephalomyelitis (EAE) animal model to evaluate the effect of DMSCs on clinical signs of the disease and on the presence of inflammatory infiltrates in the central nervous system. We also compared the inflammatory profile of spleen T cells from DMSC-treated mice with that of EAE control animals, and the influence of DMSCs on the in vitro definition of the Th17 phenotype. Furthermore, we analyzed the effects on the presence of some critical cell types in central nervous system infiltrates. RESULTS: Preventive intraperitoneal injection of DMSCs resulted in a significant delay of external signs of EAE. In addition, treatment of animals already presenting with moderate symptoms resulted in mild EAE with reduced disease scores. Besides decreased inflammatory infiltration, diminished percentages of CD4(+)IL17(+), CD11b(+)Ly6G(+) and CD11b(+)Ly6C(+) cells were found in infiltrates of treated animals. Early immune response was mitigated, with spleen cells of DMSC-treated mice displaying low proliferative response to antigen, decreased production of interleukin (IL)-17, and increased production of the anti inflammatory cytokines IL-4 and IL-10. Moreover, lower RORgammaT and higher GATA 3 expression levels were detected in DMSC-treated mice. DMSCs also showed a detrimental influence on the in vitro definition of the Th17 phenotype. CONCLUSIONS: DMSCs modulated the clinical course of EAE, modified the frequency and cell composition of the central nervous system infiltrates during the disease, and mediated an impairment of Th17 phenotype establishment in favor of the Th2 subtype. These results suggest that DMSCs might provide a new cell-based therapy for the control of multiple sclerosis. PMID- 26987809 TI - Fragment-wise design of inhibitors to 3C proteinase from enterovirus 71. AB - BACKGROUND: Enterovirus 71 (EV71) is a causative agent of hand, foot and mouth disease (HFMD), which can spread its infection to central nervous and other systems with severe consequence. A key factor in the replication of EV71 is its 3C proteinase (3C(pro)), a significant drug target. Peptidomimetics were employed as inhibitors of this enzyme for developing antivirals. However, the peptide bonds in these peptidomimetics are a source of low bioavailability due to their susceptibility to protease digestion. To produce non-peptidomimetic inhibitors by replacing these peptide bonds, it would be important to gain better understanding on the contribution of each component to the interaction and potency. METHODS: A series of compounds of different lengths targeting 3C(pro) and having an alpha,beta-unsaturated ester as the warhead were synthesized and their interactions with the enzyme were evaluated by complex structure analyses and potency assays for a better understanding on the relationship between potency and evolution of interaction. RESULTS: The P2 moiety of the compound would need to be oriented to interact in the S2 site in the substrate binding cleft and the P3-P4 moieties were required to generate sufficient potency. A hydrophobic terminal group will benefit the cellular uptake and improve the activity in vivo. CONCLUSIONS AND GENERAL SIGNIFICANCE: The data presented here provide a basis for designing a new generation of non-peptidomimetics to target EV71 3C(pro). PMID- 26987810 TI - The promise of protein glycosylation for personalised medicine. AB - BACKGROUND: Complex diseases such as cancer are a consequence of numerous causes. State of the art personalised medicine approaches are mostly based on evaluating patients' individual genetic background. Despite the advances of genomics it fails to take individual dynamic influences into account that contribute to the individual and unique glycomic and glycoproteomic "configurations" of every living being. SCOPE OF REVIEW: Glycomic and glycoproteomic-based personalised medicine diagnostics are still in their infancies, however some initial success stories indicate that these fields are highly promising to mediate novel early diagnosis and disease stratification markers, subsequently resulting in improved patient well-being and reduced treatment costs. In this review we not only summarise current protein glycosylation based examples that substantially improve or possess great potential for personalised medicine, but also describe current limitations as well as future perspectives and challenges associated with establishing protein glycosylation aspects for this purpose. MAJOR CONCLUSIONS: Many protein biomarkers currently in clinical use are glycoproteins, however, their glycosylation status is seldom evaluated in a clinical context. To date just few examples have already been successfully translated into clinical practice, making protein glycosylation a highly promising diagnostic target with humongous potential for personalised medicine. GENERAL SIGNIFICANCE: There is an urgent need for markers that enable the establishment of an individualised and optimised patient treatment at the earliest disease stage possible. The glycosylation status of a patient and/or specific marker proteins can provide important clues that result in improved patient management. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc. PMID- 26987811 TI - Engineered Cx26 variants established functional heterotypic Cx26/Cx43 and Cx26/Cx40 gap junction channels. AB - Gap junction (GJ) channels mediate direct intercellular communication and are composed of two docked hemichannels (connexin oligomers). It is well documented that the docking and formation of GJs are possible only between compatible hemichannels (or connexins). The mechanisms of heterotypic docking compatibility are not fully clear. We aligned the protein sequences of docking-compatible and incompatible connexins with that of connexin26 (Cx26). We found that two docking hydrogen bond (HB)-forming residues on the second extracellular domain (E2) of Cx26 and their equivalent residues are well conserved within docking-compatible connexins, but different between docking-incompatible connexins. Replacing one or both of these residues of Cx26 into the corresponding residues in the docking incompatible connexins (K168V, N176H or K168V-N176H) increased the formation of morphological and functional heterotypic GJs with connexin43 (Cx43) or connexin40 (Cx40), indicating that these two residues are important for docking incompatibility between Cx26 and these connexins. Our homology structure models predict that both HBs and hydrophobic interactions at the E2 docking interface are important docking mechanisms in heterotypic Cx26 K168V-N176H/Cx43 GJs and probably other docking compatible connexins. Revealing the key residues and mechanisms of heterotypic docking compatibility will assist us in understanding why these putative docking residues are hotspots of disease-linked mutants. PMID- 26987812 TI - Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74. AB - The presenilin homologue signal peptide peptidase-like 2a (SPPL2a) is an intramembrane protease of lysosomes/late endosomes which cleaves type II transmembrane proteins. We recently identified CD74, the invariant chain of the MHCII complex, as the first in vivo validated substrate of this protease. In endosomal compartments, CD74 undergoes sequential proteolysis leading to the generation of a membrane-bound N-terminal fragment (NTF) that requires cleavage by SPPL2a for its turnover. In SPPL2a(-/-) mice, this fragment accumulates in B cells and significantly disturbs their maturation and functionality. To date, the substrate requirements of the protease SPPL2a have not been investigated. In the present study, we systematically analysed the molecular determinants of CD74 with regard to the intramembrane cleavage by SPPL2a. Using domain-exchange experiments, we demonstrate that the intracellular domain (ICD) of CD74 can be substituted without affecting cleavability by SPPL2a. Based on IP-MS analysis of the cleavage product, we report identification of the primary SPPL2a cleavage site between Y52 and F53 within the CD74 transmembrane segment. Furthermore, systematic alanine-scanning mutagenesis of the transmembrane and membrane proximal parts of the CD74 NTF has been performed. We show that none of the analysed determinants within the CD74 NTF including the residues flanking the primary cleavage site are absolutely essential for SPPL2a cleavage. Importantly, we found that alanine substitution of helix-destabilizing glycines within the transmembrane segment and distinct residues within the luminal membrane-proximal segment led to a reduced efficiency of SPPL2a-mediated processing. Therefore we propose that elements within the transmembrane segment and the luminal juxtamembrane domain facilitate intramembrane proteolysis of CD74 by SPPL2a. PMID- 26987814 TI - Molecular basis of lipo-chitooligosaccharide recognition by the lysin motif receptor-like kinase LYR3 in legumes. AB - LYR3 [LysM (lysin motif) receptor-like kinase 3] of Medicago truncatula is a high affinity binding protein for symbiotic LCO (lipo-chitooligosaccharide) signals, produced by rhizobia bacteria and arbuscular mycorrhizal fungi. The present study shows that LYR3 from several other legumes, but not from two Lupinus species which are incapable of forming the mycorrhizal symbiosis, bind LCOs with high affinity and discriminate them from COs (chitooligosaccharides). The biodiversity of these proteins and the lack of binding to the Lupinus proteins were used to identify features required for high-affinity LCO binding. Swapping experiments between each of the three LysMs of the extracellular domain of the M. truncatula and Lupinus angustifolius LYR3 proteins revealed the crucial role of the third LysM in LCO binding. Site-directed mutagenesis identified a tyrosine residue, highly conserved in all LYR3 LCO-binding proteins, which is essential for high affinity binding. Molecular modelling suggests that it may be part of a hydrophobic tunnel able to accommodate the LCO acyl chain. The lack of conservation of these features in the binding site of plant LysM proteins binding COs provides a mechanistic explanation of how LCO recognition might differ from CO perception by structurally related LysM receptors. PMID- 26987816 TI - Facial emotion recognition and its relationship to cognition and depressive symptoms in patients with Parkinson's disease. AB - BACKGROUND: Impairments in facial emotion recognition (FER) have been detected in patients with Parkinson disease (PD). Presently, we aim at assessing differences in emotion recognition performance in PD patient groups with and without mild forms of cognitive impairment (MCI) compared to healthy controls. METHODS: Performance on a concise emotion recognition test battery (VERT-K) of three groups of 97 PD patients was compared with an age-equivalent sample of 168 healthy controls. Patients were categorized into groups according to two well established classifications of MCI according to Petersen's (cognitively intact vs. amnestic MCI, aMCI, vs. non-amnestic MCI, non-aMCI) and Litvan's (cognitively intact vs. single-domain MCI, sMCI, vs. multi-domain MCI, mMCI) criteria. Patients and controls underwent individual assessments using a comprehensive neuropsychological test battery examining attention, executive functioning, language, and memory (Neuropsychological Test Battery Vienna, NTBV), the Beck Depression Inventory, and a measure of premorbid IQ (WST). RESULTS: Cognitively intact PD patients and patients with MCI in PD (PD-MCI) showed significantly worse emotion recognition performance when compared to healthy controls. Between groups effect sizes were substantial, showing non-trivial effects in all comparisons (Cohen's ds from 0.31 to 1.22). Moreover, emotion recognition performance was higher in women, positively associated with premorbid IQ and negatively associated with age. Depressive symptoms were not related to FER. CONCLUSIONS: The present investigation yields further evidence for impaired FER in PD. Interestingly, our data suggest FER deficits even in cognitively intact PD patients indicating FER dysfunction prior to the development of overt cognitive dysfunction. Age showed a negative association whereas IQ showed a positive association with FER. PMID- 26987813 TI - Regulator of G-protein signalling and GoLoco proteins suppress TRPC4 channel function via acting at Galphai/o. AB - Transient receptor potential canonical 4 (TRPC4) forms non-selective cation channels implicated in the regulation of diverse physiological functions. Previously, TRPC4 was shown to be activated by the Gi/o subgroup of heterotrimeric G-proteins involving Galphai/o, rather than Gbetagamma, subunits. Because the lifetime and availability of Galpha-GTP are regulated by regulators of G-protein signalling (RGS) and Galphai/o-Loco (GoLoco) domain-containing proteins via their GTPase-activating protein (GAP) and guanine-nucleotide dissociation inhibitor (GDI) functions respectively, we tested how RGS and GoLoco domain proteins affect TRPC4 currents activated via Gi/o-coupled receptors. Using whole-cell patch-clamp recordings, we show that both RGS and GoLoco proteins [RGS4, RGS6, RGS12, RGS14, LGN or activator of G-protein signalling 3 (AGS3)] suppress receptor-mediated TRPC4 activation without causing detectable basal current or altering surface expression of the channel protein. The inhibitory effects are dependent on the GAP and GoLoco domains and facilitated by enhancing membrane targeting of the GoLoco protein AGS3. In addition, RGS, but not GoLoco, proteins accelerate desensitization of receptor-activation evoked TRPC4 currents. The inhibitory effects of RGS and GoLoco domains are additive and are most prominent with RGS12 and RGS14, which contain both RGS and GoLoco domains. Our data support the notion that the Galpha, but not Gbetagamma, arm of the Gi/o signalling is involved in TRPC4 activation and unveil new roles for RGS and GoLoco domain proteins in fine-tuning TRPC4 activities. The versatile and diverse functions of RGS and GoLoco proteins in regulating G-protein signalling may underlie the complexity of receptor-operated TRPC4 activation in various cell types under different conditions. PMID- 26987817 TI - Prognostic factors for recurrence after endoscopic sinus surgery for chronic rhinosinusitis with nasal polyps. AB - OBJECTIVE: In this study, we aimed to clarify the prognostic factors affecting the ethmoid condition during a long-term follow-up after endoscopic sinus surgery in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: Thirty-six patients with CRSwNP underwent surgery from December 2008 to February 2012. All surgeries were performed by one surgeon, and all patients were followed up for at least 2 years postoperatively. We investigated the association of postoperative endoscopic findings with clinical parameters, mucosal eosinophil count and mRNA expression of CCL11, IL-5, and IFN-gamma in nasal polyps. RESULTS: Seventeen patients (47.2%) had severe mucosal edema, and the patency of each sinus was not confirmed during the >2-year follow-up. The mucosal eosinophil count and two eosinophil-associated factors, namely the CCL11 and IL-5 mRNA levels, were higher in the severe mucosal edema group than in the control group. The severe mucosal edema group was divided into two subgroups: the steroid responsive and -resistant groups. Five patients (13.9%) had frank polyp formation because the oral steroids were less effective. The mucosal eosinophil count was significantly different among the four groups, including the control group (p=0.001); however, the CCL11, IL-5, and IFN-gamma mRNA levels were not significantly different. Although the IL-5 mRNA level was not significantly different among the four groups, it tended to increase when the sinus condition worsened. In the severe mucosal edema group, a higher IL-5 mRNA level was associated with earlier severe mucosal edema in the ethmoid cavity. CONCLUSION: The IL-5 mRNA level is associated with the time of severe edema formation in the ethmoid cavity. This finding permits early intervention on the postoperative course and would prevent polyp recurrence. PMID- 26987815 TI - alphaB-crystallin is essential for the TGF-beta2-mediated epithelial to mesenchymal transition of lens epithelial cells. AB - Transforming growth factor (TGF)-beta2-mediated pathways play a major role in the epithelial to mesenchymal transition (EMT) of lens epithelial cells (LECs) during secondary cataract formation, which is also known as posterior capsule opacification (PCO). Although alphaB-crystallin is a major protein in LEC, its role in the EMT remains unknown. In a human LEC line (FHL124), TGF-beta2 treatment resulted in changes in the EMT-associated proteins at the mRNA and protein levels. This was associated with nuclear localization of alphaB crystallin, phosphorylated Smad2 (pSmad2) (S245/250/255), pSmad3 (S423/425), Smad4 and Snail and the binding of alphaB-crystallin to these transcription factors, all of which were reduced by the down-regulation of alphaB-crystallin. Expression of the functionally defective R120G mutant of alphaB-crystallin reduced TGF-beta2-induced EMT in LECs of alphaB-crystallin knockout (KO) mice. Treatment of bovine lens epithelial explants and mouse LEC with TGF-beta2 resulted in changes in the EMT-associated proteins at the mRNA and protein levels. This was accompanied by increase in phosphorylation of p44/42 mitogen activated protein kinases (MAPK) (T202/Y204), p38 MAPK (T180/Y182), protein kinase B (Akt) (S473) and Smad2 when compared with untreated cells. These changes were significantly reduced in alphaB-crystallin depleted or knocked out LEC. The removal of the fibre cell mass from the lens of wild-type (WT) mice resulted in the up-regulation of EMT-associated genes in the capsule-adherent epithelial cells, which was reduced in the alphaB-crystallin KO mice. Together, our data show that alphaB-crystallin plays a central role in the TGF-beta2-induced EMT of LEC. alphaB-Crystallin could be targeted to prevent PCO and pathological fibrosis in other tissues. PMID- 26987818 TI - A behavioural change package to prevent hand dermatitis in nurses working in the national health service (the SCIN trial): study protocol for a cluster randomised controlled trial. AB - BACKGROUND: Hand dermatitis can be a serious health problem in healthcare workers. While a range of skin care strategies and policy directives have been developed in recent years to minimise the risk, their effectiveness and cost effectiveness remain unclear. Evidence now suggests that psychological theory can facilitate behaviour change with respect to improved hand care practices. Therefore, we will test the hypothesis that a behavioural change intervention to improve hand care, based on the Theory of Planned Behaviour and implementation intentions, coupled with provision of hand moisturisers, can produce a clinically useful reduction in the occurrence of hand dermatitis, when compared to standard care, among nurses working in the UK National Health Service (NHS) who are particularly at risk. Secondary aims will be to assess impacts on participants' beliefs and behaviour regarding hand care. In addition, we will assess the cost effectiveness of the intervention in comparison with normal care. METHODS/DESIGN: We will conduct a cluster randomised controlled trial at 35 NHS hospital trusts/health boards/universities, focussing on student nurses with a previous history of atopic disease or hand eczema and on nurses in intensive care units. Nurses at 'intervention-light' sites will be managed according to what would currently be regarded as best practice, with provision of an advice leaflet about optimal hand care to prevent hand dermatitis and encouragement to contact their occupational health (OH) department early if hand dermatitis occurs. Nurses at 'intervention-plus' sites will additionally receive a behavioural change programme (BCP) with on-going active reinforcement of its messages, and enhanced provision of moisturising cream. The impact of the interventions will be compared using information collected by questionnaires and through standardised photographs of the hands and wrists, collected at baseline and after 12 months follow-up. In addition, we will assemble relevant economic data for an analysis of costs and benefits, and collect information from various sources to evaluate processes. Statistical analysis will be by multi-level regression modelling to allow for clustering by site, and will compare the prevalence of outcome measures at follow-up after adjustment for values at baseline. The principal outcome measure will be the prevalence of visible hand dermatitis as assessed by the study dermatologists. In addition, several secondary outcome measures will be assessed. DISCUSSION: This trial will assess the clinical and cost effectiveness of an intervention to prevent hand dermatitis in nurses in the United Kigdom. TRIAL REGISTRATION: ISRCTN53303171 : date of registration, 21 June 2013. PMID- 26987819 TI - Uterine Prx2 restrains decidual differentiation through inhibiting lipolysis in mice. AB - Uterine decidualization, characterized as extensive stromal cell proliferation, differentiation and polyploidization, is a crucial event for successful pregnancy and is tightly regulated by many different molecules and pathways. Prx2, an evolutionarily conserved homeobox transcription factor expressed in both embryos and adults, plays an important role during mesenchymal cell differentiation. However, it remains unclear what the exact function of Prx2 is in the uterine stromal cells, one type of mesenchymal cells. In the present study, employing in vivo and in vitro stromal cell decidualization models, combining adenovirus mediated overexpression of Prx2, we found that the expression of Prx2 is initiated in the uterine stromal cells once the blastocyst attached to the epithelium and is always detected around the differentiated decidual zone in the anti-mesometrium of the uterus during post-implantation uterine development. Also, overexpression of Prx2 disturbed stromal-decidual differentiation, which is reflected by the decreased expression of decidual/trophoblast prolactin-related protein (Dtprp), the marker for uterine decidualization in mice. Further, we demonstrate that Prx2 overexpression disturbs lipolysis, leading to lipid droplets accumulation in uterine stromal cells, partially mediated by downregulated expression of adipocyte triglyceride lipase. Collectively, these data indicate that uterine Prx2 restrains uterine decidual differentiation through regulating lipid metabolism. PMID- 26987821 TI - Fast calcium wave inhibits excessive apoptosis during epithelial wound healing. AB - Successful wound closure is mainly the result of two cellular processes: migration and proliferation. Apoptosis has also been suggested to play a role in the mechanisms of wound healing. The fast calcium wave (FCW), triggered immediately after a wound is produced, has been proposed to be involved in determining healing responses in epithelia. We have explored the effects of the reversible inhibition of FCW on the apoptotic and proliferative responses of healing bovine corneal endothelial (BCE) cells in culture. The most important findings of this study are that caspase-dependent apoptosis occurs during the healing process, that the amount of apoptosis has a linear dependence on the migrated distance, and that FCW inhibition greatly increases the apoptotic index. We have further been able to establish that FCW plays a role in the control of cell proliferation during BCE wound healing. These results indicate that one of the main roles of the wave is to inhibit an excessive apoptotic response of the healing migrating cells. This property might represent a basic mechanism to allow sufficient migration and proliferation of the healing cells to assure proper restitution of the injured tissue. PMID- 26987822 TI - SIB health psychology in Brazil: The challenges for working in public health settings. AB - Considering the diversity of theoretical approaches and settings for psychological practice, this editorial provides a background for the articles that have been included in this special issue concerning health psychology in the context of the Brazilian Unified Health System (Sistema Unico de Saude). We addressed issues concerning the national curricular outline for undergraduate training in psychology and historical data on the social movements that led to the creation of the Sistema Unico de Saude and the Psychiatric Reform which created an important area for psychological work absorbing a considerable number of psychologists. PMID- 26987820 TI - Changes of myoid and endothelial cells in the peritubular wall during contraction of the seminiferous tubule. AB - The wall of the seminiferous tubule in rodents consists of an inner layer of myoid cells covered by an outer layer of endothelial cells. Myoid cells are a type of smooth muscle cell containing alpha-actin filaments arranged in two independent layers that contract when stimulated by endothelin-1. The irregular surface relief of the tubular wall is often considered a hallmark of contraction induced by a variety of stimuli. We examine morphological changes of the rat seminiferous tubule wall during contraction by a combination of light, confocal, transmission and scanning electron microscopy. During ET-1-induced contraction, myoid cells changed from a flat to a conical shape, but their actin filaments remained in independent layers. As a consequence of myoid cell contraction, the basement membrane became wavy, orientation of collagen fibers in the extracellular matrix was altered and the endothelial cell layer became folded. To observe the basement of the myoid cell cone, the endothelial cell monolayer was removed by collagenase digestion prior to SEM study. In contracted tubules, it is possible to distinguish cell relief: myoid cells have large folds on the external surface oriented parallel to the tubular axis, whereas endothelial cells have numerous cytoplasmic projections facing the interstitium. The myoid cell cytoskeleton is unusual in that the actin filaments are arranged in two orthogonal layers, which adopt differing shapes during contraction with myoid cells becoming cone-shaped. This arrangement impacts on other components of the seminiferous tubule wall and affects the propulsion of the tubular contents to the rete testis. PMID- 26987823 TI - Psychologists in public health: Historical aspects and current challenges. AB - This article presents the historical context of the insertion of psychology, as a profession, in health policies in Brazil, in order to understand its current challenges. Analysis was based on a non-systematic literature review about professional training, practice, and research in psychology. Three challenges were identified: working in high social vulnerability contexts, practice in multidisciplinary teams and the need to expand the research agenda. We conclude that dealing with these challenges will depend on the area's capacity to reinvent itself and become more permeable to interdisciplinary dialogue. PMID- 26987824 TI - A good training based on insufficiency: Work in health care as an ethics. AB - The article discusses psychology training in health care at the Federal University of Sao Paulo. It places curriculum guidelines in a changing movement of training for health professions, proposing Work in Health Care as one of its common axes. In the Baixada Santista campus, the course is based on learning by experience, public health services and multidisciplinary team work. Three vectors derived from the experience in this project and its assessment are discussed: a common clinic, work in health care as an ethics and the idea of good training by insufficiency. PMID- 26987825 TI - Experiences in the health services network and in the street: Captures and detours in psychology training for public health services. AB - This article discusses the internships at the psychosocial health system of Natal, Northeast region of Brazil, as part of training in psychology. The objective of these internships is to offer students work experiences in public health both inside and outside health services. Based on Institutional Analysis and Schizoanalysis, these experiences were examined through two analysers: (1) the power of knowledge and (2) the need for by-passes. We conclude that health provokes tensions between instituted practices in health services and those instituted in psychology training. PMID- 26987826 TI - Group work in the public health context: A proposal for training in psychology. AB - The entry of psychologists into the public health sector in Brazil is usually connected to a traditional clinical model, and, thus, marked by a lack of training for group work. A reflection on the training of psychologists for group work is essential. Aiming at contributing to this theme, the objective of this article is to discuss the training for group work in the public health sector. In particular, we aim to introduce a proposal for training in psychology in a Brazilian public university, covering a theoretical-practical module, as well as basic and professionalizing internship programmes. PMID- 26987827 TI - Care in movement: Health psychology in the Sofia Feldman Maternity Hospital in Belo Horizonte, Brazil. AB - Psychologists in hospital settings are part of a complex network of professional relationships in constant negotiation. In addition, psychologists have skills that enable them to work with social phenomena and to act strategically within them. This is especially important in inter-disciplinary team work where professional boundaries can generate barriers to change. This article shows how psychologists of a maternity hospital in a working-class district of a large Brazilian city adapted to an integral approach to health care in a way that helped other professionals to rethink practices. PMID- 26987828 TI - The matrix approach to mental health care: Experiences in Florianopolis, Brazil. AB - This article reports on the experience of a matrix approach to mental health in primary health care. Professionals who work in the Family Health Support Nuclei, Nucleos de Apoio a Saude da Familia, pointed to challenges of this approach, especially regarding the difficulties of introducing pedagogic actions in the health field and problems related to work relationships. As the matrix approach and its practice are new aspects of the Brazilian Unified Health System, the academic knowledge must walk hand in hand with everyday professional practice to help improve the quality of the services offered in this context. PMID- 26987829 TI - Matrix Support in mental health: The experience in Vitoria, Espirito Santo. AB - This study discusses the implementation of Matrix Support in Vitoria, Espirito Santo, Brazil, through analysis of documents and semi-structured interviews. Results indicate that Matrix Support evolved over time to provide community services that reflect local reality, enabling the integration of mental health into primary care practices as well as boosting reduction in the number of psychiatric hospital admissions. Results suggest that the use of collaborative spaces to evaluate Matrix Support network and the services it provides helps to ensure that this strategy is not lost in hierarchies and specialisms. PMID- 26987830 TI - Effectiveness of a multidimensional web-based intervention program to change Brazilian health practitioners' attitudes toward the lesbian, gay, bisexual and transgender population. AB - The objective of this study was to assess the effectiveness of a multidimensional (educational, affective and behavioural) web-based intervention to change healthcare practitioners' attitudes toward lesbian, gay, bisexual and transgender population. It aimed to measure gender and sexual (GenSex) prejudice pre- and post-intervention in relation to sociodemographic characteristics. A total of 307 health practitioners from southern Brazil enrolled and completed the follow-up assessment. The intervention had significant effects, varying across traditionally high prejudiced groups. State- and street-level continuous prejudice reduction policies are suggested. PMID- 26987831 TI - Health care provision in Brazil: A dialogue between health professionals and lesbian, gay, bisexual and transgender service users. AB - The aim of this study was to encourage the development of resources to improve health care for lesbian, gay, bisexual and transgender service users. Dialogues between health professionals and lesbian, gay, bisexual and transgender service users (inspired by the Public Conversations Project) highlighted the need (a) to improve communication between users and health professionals; (b) to question what constitutes an expert on lesbian, gay, bisexual and transgender care; (c) to reconfigure rigid notions about sexual identity; (d) to deconstruct the association between sexually transmitted diseases and lesbian, gay, bisexual and transgender service users; and (e) to adopt a less judgemental attitude towards lesbian, gay, bisexual and transgender people during hospital admissions. PMID- 26987832 TI - Counselling in STD/HIV/AIDS in the context of rapid test: Perception of users and health professionals at a counselling and testing centre in Porto Alegre. AB - This article discusses the perceptions of professionals and users about counselling practices at a counselling and testing centre in Porto Alegre/RS based on interviews with 27 service users and 14 members of the staff. The following categories emerged from thematic analysis: professionals' perceptions on counselling, users' perceptions on counselling and changes in counselling due to the introduction of rapid test procedures. The results show that, although initially there were some imprecision and apparent contradictions in its use, rapid testing was considered an invitation to rethink practices, bringing service closer to users' needs. PMID- 26987833 TI - Work-related mental disorders and their inclusion in health policies in the Brazilian Unified Health System (Sistema Unico de Saude). AB - This study discusses the inclusion of mental disorders as work-related diseases in occupational health policies in Brazil. Mental disorders first appeared as a group of occupational diseases in 1999. Establishing mental disorders as occupational diseases was a result of the confluence of several factors: a broader notion of health, a positive shift in public perception regarding preconceived judgements relating to mental disorders and the improvement in the process that defines social security benefit entitlements due to the implementation of a new methodology in 2007. PMID- 26987834 TI - From manicomial logic to territorial logic: Impasses and challenges of psychosocial care. AB - The present study describes Psychosocial Care as a new paradigm currently operating within the Brazilian Psychiatric Reform, emphasising one of its key elements: the provision of mental care within a network and a territory. To this end, the social and cultural diversity of each territory is taken as fundamental aspects to enable appropriate care for mental suffering, overcoming exclusionist thinking patterns that recently have taken on worrying conservative manifestations, and eliminating misconceptions about what defines a mental health sufferer, as well as those who choose alternative ways of being. PMID- 26987835 TI - A critical view of the 'social reinsertion' concept and its implications for the practice of psychologists in the area of mental health in the Brazilian Unified Health System (Sistema Unico de Saude). AB - Improving psychological practice in mental health services in the Brazilian Unified Health System (Sistema Unico de Saude) requires a critical analysis of core concepts of the psychiatric reform, such as 'social reinsertion'. This analysis, oriented by the dialectics of exclusion/inclusion, showed that this concept is impregnated with the adaptation paradigm and asylum view which prevents its effective implantation. The results suggest it is necessary to include social aspects in the discussion of mental health, articulating it with networks of social work and recuperating the revolutionary aspects of the psychiatric reform, thus demarcating the political nature of professional practices. PMID- 26987836 TI - The construction of autonomy for professionals who work with drug users: An analysis of two intervention projects in the largest asylum centre in Brazil. AB - Based on results of two intervention projects with professionals working with drug users in Sorocaba, Sao Paulo, the article discusses the possibilities of health promotion in the field of mental health, understood as a form of resistance to the regulatory powers of official policies. The projects proved to be promising for the construction of autonomy of these workers. The guiding principles of humanized care in health care and respect for human rights of drug users proved to be important tools for these interventions as were university extramural activities. PMID- 26987837 TI - Temporary housing as a mental health intervention for the needs of children and adolescents users of alcohol and other drugs: Hybridity between care and protection. AB - This article discusses temporary housing for children and adolescents as a modality of health care. Using the framework of French Institutional Analysis, the research was based on interviews with practitioners, participant observation and analysis of individual records so as to understand the trajectory of the cases and the implications of the temporary and volunteer nature of this service. The hybridity of this home and its acceptance of other possible life norms generate tension with custodial and stigmatizing practices in the Brazilian health and social assistance services available to children and adolescents. PMID- 26987838 TI - The Forum for Defence of the Brazilian Unified Health System (Sistema Unico de Saude) and its role in building community participation in the fight against the privatization of health. AB - Based on a Foucauldian framework, this article discusses the involvement of the Forum for Defence of the Sistema Unico de Saude in the fight against health care privatization. Community participation is a locus of experience that produces subjects implicated in the production of public health care. The locus of experience in this instance derives from the rejection of private elements that historically have been part of Brazilian public policies. It is an experience that produces workers and service users as agents able to defend the public system and endowed with instituting power. PMID- 26987840 TI - On the comparison of regulatory sequences with multiple resolution Entropic Profiles. AB - BACKGROUND: Enhancers are stretches of DNA (100-1000 bp) that play a major role in development gene expression, evolution and disease. It has been recently shown that in high-level eukaryotes enhancers rarely work alone, instead they collaborate by forming clusters of cis-regulatory modules (CRMs). Although the binding of transcription factors is sequence-specific, the identification of functionally similar enhancers is very difficult and it cannot be carried out with traditional alignment-based techniques. RESULTS: The use of fast similarity measures, like alignment-free measures, to detect related regulatory sequences is crucial to understand functional correlation between two enhancers. In this paper we study the use of alignment-free measures for the classification of CRMs. However, alignment-free measures are generally tied to a fixed resolution k. Here we propose an alignment-free statistic, called [Formula: see text], that is based on multiple resolution patterns derived from the Entropic Profiles (EPs). The Entropic Profile is a function of the genomic location that captures the importance of that region with respect to the whole genome. As a byproduct we provide a formula to compute the exact variance of variable length word counts, a result that can be of general interest also in other applications. CONCLUSIONS: We evaluate several alignment-free statistics on simulated data and real mouse ChIP-seq sequences. The new statistic, [Formula: see text], is highly successful in discriminating functionally related enhancers and, in almost all experiments, it outperforms fixed-resolution methods. We implemented the new alignment-free measures, as well as traditional ones, in a software called EP-sim that is freely available: http://www.dei.unipd.it/~ciompin/main/EP-sim.html . PMID- 26987841 TI - [Intrathecal methotrexate in breast cancer meningeal carcinomatosis - Experience with a new administration schedule]. AB - Methotrexate represents the standard intrathecal treatment of breast cancer meningeal carcinomatosis. However, its optimal schedule remains undefined. The aim of the present study was to evaluate results obtained with the methotrexate schedule used in Saint-Louis hospital (Paris). Patients followed in Saint-Louis hospital for breast cancer and who received intrathecal methotrexate were included in this retrospective monocentric study. Intrathecal treatment received contained methotrexate 12 mg/day (days: 1-5) and then 15 mg/week until progression or toxicity. Between 2003 and 2015, 41 patients were included. Primitive tumours were RH+/HER2-, HER2+ and triple-negative in respectively 66%, 14%, 5% and 15% of patients, 22% of them had meningeal carcinomatosis as metastatic disease initial manifestation. Objective response rate was 54%, median overall survival was 4.0 mois [CI 95%: 3-7.3] and 1-year survival rate was 15.2% (11.4%, 50% et 0% in RH+/HER2-, HER2+ and triple-negative subgroups; HR=0.45 [0.21-0.97] between HER2+ and RH+/HER2-). In univariate analysis, prognostic factors were brain involvement (p=0.049), initial cerebrospinal fluid protein level (p=0.0002) and concomitant systemic treatment received (p=0.049). This intrathecal methotrexate schedule demonstrates a similar median overall survival as the one obtained with a dose-dense schedule and an improved quality of life. Nevertheless, as the objective response and 1-year survival rates are slightly inferior, a dose-dense schedule remains still preferred in HER2+ patients or in those harboring a mainly meningeal progression. PMID- 26987842 TI - [Iron status in 72 Congolese patients with sickle cell anemia]. AB - Multiple blood transfusions, intestinal parasites, and high iron needs during the growth period are all factors that influence iron status in African children. To determine their iron status and its association with these factors, we studied 72 homozygous sickle-cell patients in a steady state in Kinshasa. Iron status was determined by a combination of several indicators: ferritin, transferrin, blood count, total iron binding capacity, transferrin saturation, and C-reactive protein. These results were compared with those from a matched control group without sickle-cell disease. Compared to the control group, 5 patients (11%) were iron-deficient, while 18 (35%) had an iron overload, probably due to multiple blood transfusions. This study shows the importance of periodic assessments of iron status in homozygous sickle cell patients to prevent and manage any iron imbalance. PMID- 26987843 TI - Genkwadaphnin promotes leukocyte migration by increasing CD44 expression via PKD1/NF-kappaB signaling pathway. AB - Genkwadaphnin (GD), an extract from the flower buds of Daphne genkwa Siebold & Zucc. (Thymelaeaceae) has been reported a significant anti-leukemic activity. However, its functional mechanism has not been defined well. To study the biological mechanism of GD function, we have investigated whether GD affects CD44 expression, which has a role in the regulation of immune cell motilities, and identified the related signaling pathways. GD treatment induced the increase of CD44 expression in a time- and concentration-dependent manner, which was specific for immune cells. GD activated PKD1/NF-kappaB signaling to induce CD44 expression, and resulted in the increased migration of K562 cells. In invasion assay, cell migratory ability was induced by GD and the transfection with CD44 specific short hairpin RNA resulted in reduction of its cell migration. GD treated human peripheral blood mononuclear cell (PBMC) were also shown the increased CD44 expression and migration. These data suggest that the induction of CD44 expression by GD treatment promotes immune cell transmigration resulting in the enhanced innate immunity. PMID- 26987845 TI - First-principles study of the Fe | MgO(0 0 1) interface: magnetic anisotropy. AB - We present a systematic first-principles study of Fe | MgO bilayer systems emphasizing the influence of the iron layer thickness on the geometry, the electronic structure and the magnetic properties. Our calculations ensure the unconstrained structural relaxation at scalar relativistic level for various numbers of iron layers placed on the magnesium oxide substrate. Our results show that due to the formation of the interface the electronic structure of the interface iron atoms is significantly modified involving charge transfer within the iron subsystem. In addition, we find that the magnetic anisotropy energy increases from 1.9 mJ m(-2) for 3 Fe layers up to 3.0 mJ m(-2) for 11 Fe layers. PMID- 26987844 TI - Pro-lymphangiogenic properties of IFN-gamma-activated human dendritic cells. AB - Dendritic cells (DCs) play a crucial role in the initiation of adaptive immune responses. In addition, through the release of pro- and anti-angiogenic mediators, DCs are key regulators of blood vessel remodeling, a process that characterizes inflammation. Less information is available on the role of DCs in lymphangiogenesis. This study reports that human DCs produce VEGF-C, a cytokine with potent pro-lymphangiogenic activity when stimulated with IFN-gamma. DC derived VEGF-C was biologically active, being able to promote tube-like structure formation in cultures of human lymphatic endothelial cells (LECs). DCs co cultured with IL-15-activated NK cells produced high levels of VEGF-C, suggesting a role for NK-DC cross-talk in peripheral lymphoid and non-lymphoid tissues in inflammation-associated lymphangiogenesis. Induction of VEGF-C by IFN-gamma was detected also in other myeloid cells, such as blood-purified CD1c(+) DCs, CD14(+) monocytes and in monocyte-derived macrophages. In all these cell types, VEGF-C was found associated with the cell membrane by low affinity, heparan sulphate mediated, interactions. Therefore, human DCs should be considered as new players in inflammation-associated lymphangiogenesis. PMID- 26987847 TI - Introduction. PMID- 26987846 TI - Chondrocytes, Mesenchymal Stem Cells, and Their Combination in Articular Cartilage Regenerative Medicine. AB - Articular cartilage (AC) is a highly organized connective tissue lining, covering the ends of bones within articulating joints. Its highly ordered structure is essential for stable motion and provides a frictionless surface easing load transfer. AC is vulnerable to lesions and, because it is aneural and avascular, it has limited self-repair potential which often leads to osteoarthritis. To date, no fully successful treatment for osteoarthritis has been reported. Thus, the development of innovative therapeutic approaches is desperately needed. Autologous chondrocyte implantation, the only cell-based surgical intervention approved in the United States for treating cartilage defects, has limitations because of de-differentiation of articular chondrocytes (AChs) upon in vitro expansion. De-differentiation can be abated if initial populations of AChs are co cultured with mesenchymal stem cells (MSCs), which not only undergo chondrogenesis themselves but also support chondrocyte vitality. In this review we summarize studies utilizing AChs, non-AChs, and MSCs and compare associated outcomes. Moreover, a comprehensive set of recent human studies using chondrocytes to direct MSC differentiation, MSCs to support chondrocyte re differentiation and proliferation in co-culture environments, and exploratory animal intra- and inter-species studies are systematically reviewed and discussed in an innovative manner allowing side-by-side comparisons of protocols and outcomes. Finally, a comprehensive set of recommendations are made for future studies. PMID- 26987849 TI - Enhanced anion binding by heteroatom replacement in bambusurils. AB - This study was driven by the hypothesis that heteroatom replacement in bambusurils could significantly modify their anion binding properties. Indeed, calculations with various glycoluril and bambusuril analogs predict that such replacements significantly alter their molecular electrostatic potential and binding properties. Both polarization and electrostatic interactions contribute to anion binding, leading to a general trend of affinity among the neutral molecules: X = S > O > NH. In bambusurils the heteroatom replacement at the portal carbonyls affect the induced dipole more significantly than replacements at the equatorial carbonyls. The stronger polarization and stronger anion binding manifest the increased aptitude of the portal heteroatoms as electron sinks. Notably, this study predicts that protonated aza-bambusurils would not only bind multiple anions along their main axis, but could also function as synthetic anion channels. PMID- 26987848 TI - Reduction of peristalsis-related gastrointestinal streak artifacts with dual energy CT: a patient and phantom study. AB - OBJECTIVE: The purpose of the study was to assess the ability of rapid-kV switching (rs) dual-energy computed tomography (DECT) to reduce peristalsis related streak artifact. METHODS: rsDECT images of 100 consecutive patients (48 male, 52 female, mean age 57 years) were retrospectively evaluated in this institutional review board-approved study. Image reconstructions included virtual monochromatic 70 and 120 keV images, as well as iodine(-water) and water(-iodine) material decomposition images. We recorded the presence and severity of artifacts qualitatively (4-point scale) and quantitatively [iodine/water concentrations, Hounsfield units, gray scale values (GY)] and compared to corresponding unaffected reference tissue. Similar measures were obtained in DECT images of a peristalsis phantom. Wilcoxon signed-rank and paired t tests were used to compare results between different image reconstructions. RESULTS: Peristalsis-related streak artifacts were found in 49 (49%) of the DECT examinations. Artifacts were significantly more severe in 70, 120, and water(-iodine) images than in iodine( water) images (qualitative readout P < 0.001, each). Quantitative measurements were significantly different between the artifact and the reference tissue in 70, 120 keV, and water(-iodine) images (P < 0.001 for both HU and GY for each image reconstruction), but not significantly different in iodine(-water) images (iodine concentrations P = 0.088 and GY P = 0.111). Similar results were seen in the peristalsis DECT phantom study. CONCLUSIONS: Peristalsis-related streak artifacts seen in 70, 120 keV, and water(-iodine) images are substantially reduced in iodine(-water) images at rsDECT. PMID- 26987850 TI - Defect segregation and optical emission in ZnO nano- and microwires. AB - The spatial distribution of defect related deep band emission has been studied in zinc oxide (ZnO) nano- and microwires using depth resolved cathodoluminescence spectroscopy (DRCLS) in a hyperspectral imaging (HSI) mode within a UHV scanning electron microscope (SEM). Three sets of wires were examined that had been grown by pulsed laser deposition or vapor transport methods and ranged in diameter from 200 nm-2.7 MUm. This data was analyzed by developing a 3D DRCLS simulation and using it to estimate the segregation depth and decay profile of the near surface defects. We observed different dominant defects from each growth process as well as diameter-dependent defect segregation behavior. PMID- 26987851 TI - Plant cystine-knot peptides: pharmacological perspectives. AB - Cystine-knot miniproteins are a class of 30-50 amino acid long peptides widespread in eukaryotic organisms. Due to their very peculiar three-dimensional structure, they exhibit high resistance to heat and peptidase attack. The cystine knot peptides are well represented in several plant species including medicinal herbs and crops. The pharmacological interest in plant cystine-knot peptides derives from their broad biological activities, mainly cytotoxic, antimicrobial and peptidase inhibitory and in the possibility to engineer them to incorporate pharmacophoric information for oral delivery or disease biomonitoring. The mechanisms of action of plant cystine-knot peptides are still largely unknown, although the capacity to interfere with plasma membranes seems a feature common to several cystine-knot peptides. In some cases, such as potato carboxypetidase inhibitor (PCI) and tomato cystine-knot miniproteins (TCMPs), the cystine-knot peptides target human growth factor receptors either by acting as growth factor antagonist or by altering their signal transduction pathway. The possibility to identify specific molecular targets of plant cystine-knot peptides in human cells opens novel possibilities for the pharmacological use of these peptides besides their use as scaffold to develop stable disease molecular markers and therapeutic agents. PMID- 26987853 TI - Immune response to infection by Leishmania: A mathematical model. AB - Leishmaniasis is a disease caused by the Leishmania parasites. The injection of the parasites into the host occurs when a sand fly, which is the vector, bites the skin of the host. The parasites, which are obligate, take advantage of the immune system response and invade both the classically activated macrophages (M1) and the alternatively activated macrophages (M2). In this paper, we develop a mathematical model to explain the evolution of the disease. Simulations of the model show that, M2 macrophages steadily increase and M1 macrophages steadily decrease, while M1+M2 reach a steady state which is approximately the same as at healthy state of the host. Furthermore, the ratio of Leishmania parasites to macrophages depends homogeneously on their ratio at the time of the initial infection, in agreement with in vitro experimental data. The model is used to simulate treatment by existing or potential new drugs, and to compare the efficacy of different schedules of drug delivery. PMID- 26987852 TI - Neurogenesis in Stroke Recovery. AB - Stroke, resulting from limited blood flow to the brain, is one of the most important causes of morbidity and mortality worldwide. Stroke is classified as ischemic, due to lack of blood flow, or hemorrhagic, due to bleeding. Because 87 % of strokes are classified as ischemic, this type will be the predominant focus of this review. Except for thrombolytic therapy, there is no established treatment to reduce the neurological deficits caused by ischemic stroke. Therefore, it is necessary to develop new therapeutic strategies designed to improve neurological functions after ischemic stroke. Recently, therapies to enhance neurogenesis after ischemic stroke have been investigated. However, these approaches have not led to successful clinical outcomes. This review addresses the pathophysiology of stroke, neurogenesis after stroke, and how to stimulate these processes based on the current literature. Finally, ongoing clinical trials to improve neurological functions after stroke by enhancing neurogenesis are discussed in this review. PMID- 26987854 TI - You have no Choice but to go on: How Physicians and Midwives in Ghana Cope with High Rates of Perinatal Death. AB - Objectives Healthcare providers in low-resource settings confront high rates of perinatal mortality. How providers cope with such challenges can affect their well-being and patient care; we therefore sought to understand how physicians and midwives make sense of and cope with these deaths. Methods We conducted semi structured interviews with midwives, obstetrician-gynecologists, pediatricians and trainee physicians at a large teaching hospital in Kumasi, Ghana. Interviews focused on participants' coping strategies surrounding perinatal death. We identified themes from interview transcripts using qualitative content analysis. Results Thirty-six participants completed the study. Themes from the transcripts revealed a continuum of control/self-efficacy and engagement with the deaths. Providers demonstrated a commitment to push on with their work and provide the best care possible. In select cases, they described the transformative power of attitude and sought to be agents of change. Conclusions Physicians and midwives in a low-resource country in sub-Saharan Africa showed remarkable resiliency in coping with perinatal death. Still, future work should focus on training clinicians in coping and strengthening their self-efficacy and engagement. PMID- 26987855 TI - Fragmentation of Care in Ectopic Pregnancy. AB - OBJECTIVES: Ectopic pregnancy is an important cause of maternal morbidity and mortality. Women who experience fragmented care may undergo unnecessary delays to diagnosis and treatment. Based on ectopic pregnancy cases observed in clinical practice that raised our concern about fragmentation of care, we designed an exploratory study to describe the number, characteristics, and outcomes of fragmented care among patients with ectopic pregnancy at one urban academic hospital. METHODS: Chart review with descriptive statistics. Fragmented care was defined as a patient being evaluated at an outside facility for possible ectopic pregnancy and transferred, referred, or discharged before receiving care at the study institution. RESULTS: Of 191 women seen for possible or definite ectopic pregnancy during the study period, 42 (22 %) met the study definition of fragmented care. The study was under-powered to observe statistically significant differences across groups, but we found concerning, non-significant trends: patients with fragmented care were more likely to be Medicaid recipients (65.9 vs. 58.8 %) and to experience a complication (23.8 vs. 18.1 %) compared to those with non-fragmented care. Most patients (n = 37) received no identifiable treatment prior to transfer and arrived to the study hospital with no communication to the receiving hospital from the outside provider (n = 34). Nine patients (21 %) presented with ruptured ectopic pregnancies. The fragmentation we observed in our study may contribute to previously identified socio-economic disparities in ectopic pregnancy outcomes. CONCLUSION: If future research confirms these findings, health information exchanges and regional coordination of care may be important strategies for reducing maternal mortality. PMID- 26987857 TI - Exploratory Cross-Sectional Study of Factors Associated with the Healthfulness of Parental Responses to Child Food Purchasing Requests. AB - Objective The main objective of this study was to investigate the relationship between various factors (e.g., sociodemographic, child, and parental factors) and the healthfulness of parental responses to child in-store food purchasing requests. Additionally, a secondary objective is to describe "resist strategies" used by parents to respond to child food-purchasing requests and their efficacy in avoiding conflict. Methods Parent-child dyads (children aged 2-6 years) completed an audio-/visual-recoded food shopping trip at their usual grocery store and time. Recordings of trips were coded for behavioral and environmental factors. Parental healthful response rate (i.e., percent of responses that were healthful) was the primary outcome variable. A healthful response occurred when a parent yielded to a healthful child request, or resisted a non-healthful request. Parents also completed a questionnaire. Kruskal-Wallis tests were used to assess the relationship between the main outcome variable and sociodemographic, child, and parent factors. Results Parents (n = 39) responded healthfully to 62.9 % (+/ 26.7 %) of child food purchasing requests. Low- and middle-income parents, and black and white parents, had significantly higher healthful response rates compared to high-income parents (p = 0.03) and Hispanic/Indian-descent parents (p = 0.02), respectively. Using the "ignore" strategy proved an effective resist strategy in this study, leading to no parent-child conflicts. Conclusions Programming that seeks to improve the healthfulness of food purchasing in families with young children should address unhealthful response behaviors in Hispanic/Indian-descent parents and high-income parents; although, the needs of these groups are different. Further research is needed to confirm and expand on these findings. PMID- 26987856 TI - Visceral Adiposity in the First Half of Pregnancy in Association with Glucose, Lipid and Insulin Profiles in Later Pregnancy: A Cohort Study. AB - Background Obesity is the most common risk factor in pregnancy but few studies have assessed the association of between visceral adiposity (VAT) depth in early to mild pregnancy and insulin resistance (IR), dysglycemia and dyslipidemia in later pregnancy. Objective To assess the association between VAT depth in early to mid pregnancy and IR [homeostatic model assessment of IR (HOMA-IR)], dysglycemia and dyslipidemia in later pregnancy. Methods We completed a prospective cohort study of 344 pregnant women at a single large hospital in Recife, Brazil. VAT depth was measured by ultrasound at 15-20 weeks gestation. Serum glucose, insulin and lipids were evaluated at 32-37 weeks gestation. Results In contrast to pre-pregnancy body mass index (BMI), VAT depth at 15-20 weeks was generally inferior in explaining the variation in the biochemical measures at 32-37 weeks gestation. This was the case for fasting HOMA-IR (adjusted r(2): 0.21 vs. 0.11, respectively), fasting insulin (adjusted r(2): 0.27 vs. 0.09, respectively), and lipids. Only for fasting glucose was the opposite true, but marginally (adjusted r(2) 0.03 vs. 0.06, respectively). Conclusion VAT depth measured in the first half of pregnancy is not better than pre-pregnancy BMI in predicting IR and related biochemical measures in later pregnancy. PMID- 26987859 TI - The Effect of Local Smokefree Regulations on Birth Outcomes and Prenatal Smoking. AB - Objectives We assessed the impact of varying levels of smokefree regulations on birth outcomes and prenatal smoking. Methods We exploited variations in timing and regulation restrictiveness of West Virginia's county smokefree regulations to assess their impact on birthweight, gestational age, low birthweight, very low birthweight, preterm birth, and prenatal smoking. We conducted regression analysis using state Vital Statistics individual-level data for singletons born to West Virginia residents between 1995-2010 (N = 293,715). Results Only more comprehensive smokefree regulations were associated with statistically significant favorable effects on birth outcomes in the full sample: Comprehensive (workplace/restaurant/bar ban) demonstrated increased birthweight (29 grams, p < 0.05) and gestational age (1.64 days, p < 0.01), as well as reductions in very low birthweight (-0.4 %, p < 0.05) and preterm birth (-1.5 %, p < 0.01); Restrictive (workplace/restaurant ban) demonstrated a small decrease in very low birthweight (-0.2 %, p < 0.05). Among less restrictive regulations: Moderate (workplace ban) was associated with a 23 g (p < 0.01) decrease in birthweight; Limited (partial ban) had no effect. Comprehensive's improvements extended to most maternal groups, and were broadest among mothers 21+ years, non-smokers, and unmarried mothers. Prenatal smoking declined slightly (-1.7 %, p < 0.01) only among married women with Comprehensive. Conclusions Regulation restrictiveness is a determining factor in the impact of smokefree regulations on birth outcomes, with comprehensive smokefree regulations showing promise in improving birth outcomes. Favorable effects on birth outcomes appear to stem from reduced secondhand smoke exposure rather than reduced prenatal smoking prevalence. This study is limited by an inability to measure secondhand smoke exposure and the paucity of data on policy implementation and enforcement. PMID- 26987858 TI - Social Integration and Maternal Smoking: A Longitudinal Analysis of a National Birth Cohort. AB - Objectives Social support and engagement are related to smoking behavior in general populations, but it is unknown whether these measures of social integration as experienced by recent mothers are related to longitudinal maternal smoking patterns. The purpose of this study is, first, to describe longitudinal patterns of maternal smoking before, during, and after pregnancy through the early childhood parenting years, as well as variation in these patterns; and second, to examine these patterns in relation to social integration, emotional, behavioral, and sociodemographic factors. Methods Among 9050 mothers of the Early Childhood Longitudinal Study-Birth Cohort (a nationally representative probability sample of children born in 2001), we estimated trajectories of maternal smoking with a general growth mixture model and examined how baseline predictors are associated with these patterns over a 5-6 year period beginning 3 months prior to pregnancy. Results A 5-class solution identified trajectories of nonsmokers (70.5 %), temporary quitters (9.4 %), pregnancy-inspired quitters (3.3 %), delayed initiators (5.1 %), and persistent smokers (11.7 %). Modifiable risk factors included postpartum alcohol consumption and behavioral cues from co resident smokers, while breastfeeding beyond 6 months and social engagement through religious service attendance were protective characteristics. Conclusions for Practice Prevention of and treatment for maternal perinatal and postpartum smoking is best informed by mothers' emotional, behavioral and sociodemographic characteristics. Religious service attendance, but not measures of social support or social engagement, was a protective factor for maternal smoking trajectories. PMID- 26987860 TI - Reducing Iron Deficiency in 18-36-months-old US Children: Is the Solution Less Calcium? AB - Objectives National surveys consistently identify iron deficiency (ID) in US children between 1 and 3 years of age, when the brain is rapidly developing and vulnerable to the effects of ID. However, controversy remains as to how best to recognize and prevent ID in young children, in part because of the multiple potential etiologies. The objective of this project was to assess ID in children and identify potential individual dietary predictors of status. Methods We examined three biomarkers of ID [soluble transferrin receptor (sTfR) and serum ferritin (SF), and body iron (calculated from sTfR and SF)] against parent provided dietary calcium and iron intake for eight-three 18-36 month old children from middle class families. Results Using literature-based cutoffs, fourteen children (16.9 %) had at least one indicator of ID: low SF(<10 MUg/l, 7.2 %), negative body iron (<0 mg/kg, 7.2 %) or elevated sTfR (>8.4 MUg/ml, 13.2 %). All children consumed more than the Dietary Reference Intake (DRI) Estimated Average Requirement of 3 mg/d iron. The mean iron intake of children identified with ID approximated the Recommended Dietary Allowance of 7 mg/d. Most children (81 %) consumed above the DRI Adequate Intake of 500 mg/d of calcium. Calcium intakes were generally high and predicted lower body iron (p = 0.0005), lower SF (p = 0.0086) and higher sTfR (p = 0.0176). Conclusions for Practice We found rates of ID similar to US national averages. Dietary calcium intake predicted lower iron status more than deficits in iron intake. Teaching parents to balance calcium and iron intake in toddlers could be a strategy to prevent ID. PMID- 26987861 TI - Healthcare Utilization After a Children's Health Insurance Program Expansion in Oregon. AB - OBJECTIVE: The future of the Children's Health Insurance Program (CHIP) is uncertain after 2017. Survey-based research shows positive associations between CHIP expansions and children's healthcare utilization. To build on this prior work, we used electronic health record (EHR) data to assess temporal patterns of healthcare utilization after Oregon's 2009-2010 CHIP expansion. We hypothesized increased post-expansion utilization among children who gained public insurance. METHODS: Using EHR data from 154 Oregon community health centers, we conducted a retrospective cohort study of pediatric patients (2-18 years old) who gained public insurance coverage during the Oregon expansion (n = 3054), compared to those who were continuously publicly insured (n = 10,946) or continuously uninsured (n = 10,307) during the 2-year study period. We compared pre-post rates of primary care visits, well-child visits, and dental visits within- and between groups. We also conducted longitudinal analysis of monthly visit rates, comparing the three insurance groups. RESULTS: After Oregon's 2009-2010 CHIP expansions, newly insured patients' utilization rates were more than double their pre expansion rates [adjusted rate ratios (95 % confidence intervals); increases ranged from 2.10 (1.94-2.26) for primary care visits to 2.77 (2.56-2.99) for dental visits]. Utilization among the newly insured spiked shortly after coverage began, then leveled off, but remained higher than the uninsured group. CONCLUSIONS: This study used EHR data to confirm that CHIP expansions are associated with increased utilization of essential pediatric primary and preventive care. These findings are timely to pending policy decisions that could impact children's access to public health insurance in the United States. PMID- 26987863 TI - Perspectives of school-work transitions among youth with spina bifida, their parents and health care providers. AB - Purpose Youth with disabilities encounter many challenges in finding employment and transitioning to post-secondary education. In this article, we explore the nature of school-work transitions for youth with spina bifida, which few studies have previously addressed. Method We conducted in-depth interviews with 44 participants (nine youth and 12 young adults with spina bifida, 11 parents and 12 clinicians). We analyzed our data using a qualitative content analysis approach. Results We identified several enablers to school-work transitions, including professional support, social support and school accommodations. Lacking such support created several challenges for youth with spina bifida. We also identified several barriers to school-work transitions, including lack of education and information on finances, housing and transportation; discrimination and stigma; and challenges coping with spina bifida at school and work. Conclusions Although some supports are available, youth with spina bifida encounter many challenges in transitioning to post-secondary education and employment. With clinicians at the helm, efforts should be put in place within the health and social services system to better prepare youth, as they transition to adulthood, to become connected to appropriate information and resources to help them to succeed in their school and employment goals. Implications for Rehabilitation Youth with spina bifida encounter many challenges in transitioning to post-secondary education or work. Clinicians, educators and parents should continue to support youth with spina bifida in choosing their vocations, setting career goals and developing career plans. Starting from a young age, parents, clinicians and educators should help youth with spina bifida prepare for school work transitions by fostering their independence, life skills and self-management of spina bifida-related symptoms. Clinicians and educators should help connect youth with spina bifida to appropriate information and resources to support their school-work transitions, including information on finances, housing, transportation, school accommodations and employment supports. PMID- 26987862 TI - Grandmothers' Beliefs and Practices in Infant Safe Sleep. AB - Background Sudden infant death syndrome (SIDS) and suffocation are leading causes of infant mortality. Supine sleep position and use of appropriate sleep surfaces reduce SIDS risk but are not universally practiced. Mothers' decisions about sleep position and environment may be influenced by guidance provided by infants' grandmothers and other caregivers. Methods A survey was conducted of a convenience sample of grandmothers aged 30-70 years who provide care at least weekly for an infant grandchild <6 months old. The survey was distributed through community partners of a university-based research team. Respondents received home safety items as compensation. Analyses focused on the relationship of grandmother demographic characteristics and beliefs on their reported practices related to infant sleep. Results Among the 239 grandmothers, 45 % reported placing infants to sleep supine on an appropriate sleep surface at the grandmother's house, while 58 % reported doing so when the infant was sleeping in the mother's house. After adjusting for other factors, respondents were less likely to adhere to recommended guidelines when they believed supine position increased choking risk (OR 0.34, 95 % CI 0.18-0.62) or believed infants are more comfortable or sleep longer when on their stomachs (OR 0.51, 95 % CI 0.28-0.93). Discussion Grandmothers do not universally observe evidence-based safe sleep practices, particularly if the infant is not sleeping in the home of the parent. Interventions for senior caregivers focused on perceived choking risk, infant comfort in the supine position, and other recent changes in recommended safety practices are warranted. PMID- 26987864 TI - Gendered Innovations in Orthopaedic Science: Hollywood and Orthopaedics: Through the Glass Ceiling-Darkly. PMID- 26987865 TI - CORR Insights((r)): Does Preadmission Cutaneous Chlorhexidine Preparation Reduce Surgical Site Infections After Total Hip Arthroplasty? PMID- 26987868 TI - Following the nanostructural molecular orientation guidelines for sulfur versus thiophene units in small molecule photovoltaic cells. AB - In bulk heterojunction (BHJ) organic photovoltaics, particularly those using small molecules, electron donor and/or electron acceptor materials form a distributed network in the photoactive layer where critical photo-physical processes occur. Extensive research has recently focused on the importance of sulfur atoms in the small molecules. Little is known about the three-dimensional orientation of these sulfur atom-containing molecules. Herein, we report on our research concerning the heterojunction textures of the crystalline molecular orientation of small compounds having sulfur-containing units in the side chains, specifically, compounds known as DR3TSBDT that contain the alkylthio group and DR3TBDTT that does not. The improved performance of the DR3TBDTT-based devices, particularly in the photocurrent and the fill factor, was attributed to the large population of donor compound crystallites with a favorable face-on orientation along the perpendicular direction. This orientation resulted in efficient charge transport and a reduction in charge recombination. These findings underscore the great potential of small-molecule solar cells and suggest that even higher efficiencies can be achieved through materials development and molecular orientation control. PMID- 26987866 TI - Complications Are Not Increased With Acetabular Revision of Metal-on-metal Total Hip Arthroplasty. AB - BACKGROUND: Isolated revision of the acetabular component in the setting of total hip arthroplasty has an increased risk of dislocation. With local soft tissue destruction frequently associated with failed metal-on-metal (MoM) bearings, it is presumed that acetabular revision of these hips will have even greater risk of complications. However, no study directly compares the complications of MoM with metal-on-polyethylene (MoP) acetabular revisions. QUESTIONS/PURPOSES: In the context of a large database analysis, we asked the following questions: (1) Are there differences in early medical or wound complications after isolated acetabular revision of MoM and MoP bearing surfaces? (2) Are there differences in the frequency of dislocation, deep infection, and rerevision based on the bearing surface of the original implant? METHODS: A review of the 100% Medicare database from 2005 to 2012 was performed using International Classification of Diseases, 9th Revision and Current Procedural Terminology codes. We identified 451 patients with a MoM bearing and 628 patients with a MoP bearing who had an isolated acetabular revision and a minimum followup of 2 years. The incidence, odds ratios, and 95% confidence intervals for early medical or wound complications were calculated using a univariate analysis at 30 days with patient sex and age group-adjusted analysis for blood transfusion. The incidence, odds ratio, and 95% confidence intervals for dislocation, deep infection, and rerevision were calculated using a univariate analysis at 30 day, 90 days, 1 year, and 2 years using a subgroup analysis with the Cochran-Mantel-Haenszel test to adjust for patient gender and age groups. RESULTS: There were no differences between the MoM and MoP isolated acetabular revisions in the incidence of 30-day local complications. There was a greater risk of transfusion in the MoP group than the MoM group (134 of 451 [30%] versus 230 of 628 [37%]; odds ratio [OR], 0.731; 95% confidence interval [CI], 0.565-0.948; p = 0.018). There were no differences at 2 years between the MoM and MoP acetabular revisions in the incidence of dislocation, infection, or rerevision. When analyzed by patient sex and age group, there were more infections in the age 70 to 79 years MoP group compared with MoM (10 of 451 [5%] versus 29 of 628 [10%]; OR, 4.47; CI, 1.699-11.761; p = 0.001). CONCLUSIONS: There were high rates of dislocation, infection, and rerevision in both revision cohorts. The rate of dislocation was not greater after acetabular revision of MoM bearings at 2 years. Based on these findings, clinicians should counsel these patients preoperatively about the risks of these complications. Dual-mobility and constrained components have specific advantages and disadvantages in these settings and should be further studied. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26987867 TI - Comprehensive Mechanism Analysis of Mesoporous-Silica-Nanoparticle-Induced Cancer Immunotherapy. AB - A plain mesoporous silica nanoparticle without any immunomodulatory molecules significantly enhances anticancer immunity in vivo. Comprehensive mechanism of mesoporous-silica-nanoparticle-induced cancer immunotherapy is analyzed in this paper. The mesoporous silica nanoparticle promotes both Th1 and Th2 immune responses, as it accelerates lymphocytes proliferation, stimulates IFN-gamma, IL 2, IL-4, and IL-10 cytokine secretion by lymphocytes ex vivo, and increases IgG, IgG1, IgG2a, IgM, and IgA antibody titers in mice serum compared with those of alum and adjuvant-free groups. Moreover, the mesoporous silica nanoparticle enhances effector memory CD4(+) and CD8(+) T cell populations in three most important immune organs (bone marrow, lymph node, and spleen) of mice compared with those of alum and adjuvant-free groups three months after adjuvant injection. The present study paves the way for the application of mesoporous silica nanoparticle as immunoadjuvant for cancer immunotherapy. PMID- 26987869 TI - Determining the Number of Ischemic Strokes Potentially Eligible for Endovascular Thrombectomy: A Population-Based Study. AB - BACKGROUND AND PURPOSE: Endovascular thrombectomy (ET) is standard-of-care for ischemic stroke patients with large vessel occlusion, but estimates of potentially eligible patients from population-based studies have not been published. Such data are urgently needed to rationally plan hyperacute services. Retrospective analysis determined the incidence of ET-eligible ischemic strokes in a comprehensive population-based stroke study (Adelaide, Australia 2009-2010). METHODS: Stroke patients were stratified via a prespecified eligibility algorithm derived from recent ET trials comprising stroke subtype, pathogenesis, severity, premorbid modified Rankin Score, presentation delay, large vessel occlusion, and target mismatch penumbra. Recognizing centers may interpret recent ET trials either loosely or rigidly; 2 eligibility algorithms were applied: restrictive (key criteria modified Rankin Scale score 0-1, presentation delay <3.5 hours, and target mismatch penumbra) and permissive (modified Rankin Scale score 0-3 and presentation delay <5 hours). RESULTS: In a population of 148 027 people, 318 strokes occurred in the 1-year study period (crude attack rate 215 [192-240] per 100 000 person-years). The number of ischemic strokes eligible by restrictive criteria was 17/258 (7%; 95% confidence intervals 4%-10%) and by permissive criteria, an additional 16 were identified, total 33/258 (13%; 95% confidence intervals 9%-18%). Two of 17 patients (and 6/33 permissive patients) had thrombolysis contraindications. Using the restrictive algorithm, there were 11 (95% confidence intervals 4-18) potential ET cases per 100 000 person-years or 22 (95% confidence intervals 13-31) using the permissive algorithm. CONCLUSIONS: In this cohort, ~7% of ischemic strokes were potentially eligible for ET (13% with permissive criteria). In similar populations, the permissive criteria predict that <=22 strokes per 100 000 person-years may be eligible for ET. PMID- 26987870 TI - Distinct Short-Term Outcomes in Patients With Mild Versus Rapidly Improving Stroke Not Treated With Thrombolytics. AB - BACKGROUND AND PURPOSE: Mild stroke (MS) and rapidly improving stroke (RIS) symptoms are common stroke presentations. Our objective is to describe the short term outcomes in this population. METHODS: A retrospective analysis of patients with ischemic stroke in the Get With The Guidelines-Stroke registry who arrived <=4.5 hours from symptom onset not treated with thrombolytics because of MS and RIS. Outcomes included in-hospital death, home discharge, independent ambulation at discharge, and length of stay; these were analyzed for the categories of MS, RIS, and MS+RIS. Multivariable models evaluated the associations of individual and hospital covariates with outcomes. RESULTS: Among 42 394 patients with MS and RIS not treated with thrombolytics, 27% were not discharged directly home, 27.2% did not ambulate independently, and 61.1% had length of stay >=3 days, despite a low in-hospital mortality of 0.8%. Adjusted outcomes were better for MS+RIS compared with MS; RIS also had better independent ambulation and home discharge compared with MS. Among those with a documented National Institutes of Health Stroke Scale, 25% of those with National Institutes of Health Stroke Scale 0 to 5 and half of those with National Institutes of Health Stroke Scale >5 could not be discharged directly to home or ambulate independently. Older individuals, women, blacks, transport by ambulance, delayed arrival, greater severity and greater burden of vascular risk factors, except for dyslipidemia, had worse adjusted outcomes for home discharge and independent ambulation. CONCLUSIONS: A significant proportion of patients with MS and RIS not treated with thrombolytics have suboptimal discharge outcomes. We found significant differences between MS, RIS, and MS+RIS and identified factors associated with worse outcomes. PMID- 26987872 TI - Poly(1-Vinyl-1,2,4-triazolium) Poly(Ionic Liquid)s: Synthesis and the Unique Behavior in Loading Metal Ions. AB - Herein, the synthesis of a series of poly(4-alkyl-1-vinyl-1,2,4-triazolium) poly(ionic liquid)s is reported either via straightforward free radical polymerization of their corresponding ionic liquid monomers or via anion metathesis of the polymer precursors bearing halide as counter anion. The ionic liquid monomers are first prepared via N-alkylation reaction of commercially available 1-vinyl-1,2,4-triazole with alkyl iodides, followed by anion metathesis with targeted fluorinated anions. The thermal properties and solubilities of these poly(ionic liquid)s have been systematically investigated. Interestingly, it is found that the poly(4-ethyl-1-vinyl-1,2,4-triazolium) poly(ionic liquid) exhibited an improved loading capacity of transition metal ions in comparison with its imidazolium counterpart. PMID- 26987871 TI - Exercise as an intervention for first-episode psychosis: a feasibility study. AB - AIM: Exercise can improve psychiatric symptoms, neurocognitive functioning and physical health in schizophrenia. However, the effects in early psychosis have not been explored. This study aimed to assess the feasibility of an exercise intervention for early psychosis and to determine if it was associated with changes in physical and mental health. METHODS: Thirty-one patients with first episode psychosis (FEP) were recruited from early intervention services to a 10 week exercise intervention. The intervention group received individualized training programmes, aiming to achieve >=90 min of moderate-to-vigorous activity each week, using exercise programmes tailored to individual preferences and needs. A comparison FEP sample from the same services (n = 7) received treatment as usual. RESULTS: Rates of consent and retention in the exercise group were 94% and 81%, respectively. Participants achieved an average of 107 min of moderate-to vigorous exercise per week. Positive and Negative Syndrome Scale total scores reduced by 13.3 points after 10 weeks of exercise, which was significantly greater than the treatment as usual comparison group (P = 0.010). The greatest differences were observed in negative symptoms, which reduced by 33% in the intervention group (P = 0.013). Significant improvements were also observed in psychosocial functioning and verbal short-term memory. Increases in cardiovascular fitness and processing speed were positively associated with the amounts of exercise achieved by participants. CONCLUSION: Individualized exercise training could provide a feasible treatment option for improving symptomatic, neurocognitive and metabolic outcomes in FEP. PMID- 26987873 TI - Racial and ethnic disparities in universal cervical length screening with transvaginal ultrasound. AB - OBJECTIVE: Determine if race or ethnicity is associated with missed or late transvaginal cervical length screening in a universal screening program. METHODS: Retrospective cohort study of nulliparous women with singleton gestations and a fetal anatomical ultrasound from 16-24 weeks' gestation from January 2012 to November 2013. We classified women into mutually exclusive racial and ethnic groups: non-Hispanic black (black), Hispanic, Asian, non-Hispanic white (white), and other or unknown race. We used log-binomial regression to calculate the risk ratio (RR) and 95% confidence interval (CI) of missed or late (>=20 weeks' gestation) screening versus optimally timed screening between the different racial and ethnic groups. RESULTS: Among the 2967 women in our study population, 971 (32.7%) had either missed or late cervical length screening. Compared to white women, black (RR: 1.3; 95% CI: 1.1-1.5) and Hispanic (RR:1.2; 95% CI: 1.01 1.5) women were more likely to have missed or late screening. Among women screened, black (versus white) women were more likely to be screened late (RR: 2.2; 95% CI: 1.6-3.1). CONCLUSIONS: Black and Hispanic women may be more likely to have missed or late cervical length screenings. PMID- 26987874 TI - Compensatory patterns of collateral flow in stroke patients with unilateral and bilateral carotid stenosis. AB - BACKGROUND: Collateral pathways are important in maintaining adequate cerebral blood flow in patients with carotid stenosis. We aimed to evaluate the hemodynamic patterns in relation to carotid stenosis in acute stroke patients. METHODS: Consecutive 586 stroke patients in a hospital based cohort were included in the present study. Carotid duplex was performed to identify patients with absolute minimal diameter reductions of 50% or greater in their internal carotid arteries (ICAs). Color velocity imaging quantification ultrasound (CVIQ) was used to measure extracranial arterial blood flow volume (BFV) in bilateral common carotid arteries (CCAs) and bilateral vertebral arteries (VAs). The absolute values of BFV and the ratios were compared between patients with and without ICA stenosis. RESULTS: Among 586 acute ischemic stroke patients (mean age: 67.5 +/- 12.4y), ICA stenosis was detected in 112 patients (19.1%), including unilateral ICA stenosis in 81 patients (13.8%) and bilateral ICA stenosis in 31 patients (5.3%). Among patients with unilateral ICA stenosis, the BFV in contralateral CCA was significantly higher than that in ipsilateral CCA (325.5 +/- 99.8 mL/min vs. 242.2 +/- 112.2 mL/min, P < 0.001). Among patients with bilateral ICA stenosis, the sum of BFV in bilateral VAs accounted for 22% of the whole cerebral blood flow, which was significantly higher than that in those without ICA stenosis (14.8%, P < 0.001) or with unilateral ICA stenosis (16.9%, P = 0.007). CONCLUSIONS: In patients with unilateral carotid stenosis, contralateral carotid blood flow increases to compensate decreased blood flow, while posterior circulation may compensate for the decreased brain perfusion in those with bilateral carotid stenosis. PMID- 26987875 TI - Spondyloocular Syndrome: Novel Mutations in XYLT2 Gene and Expansion of the Phenotypic Spectrum. AB - Spondyloocular syndrome is an autosomal-recessive disorder with spinal compression fractures, osteoporosis, and cataract. Mutations in XYLT2, encoding isoform of xylosyltransferase, were recently identified as the cause of the syndrome. We report on 4 patients, 2 unrelated patients and 2 siblings, with spondyloocular syndrome and novel mutations in XYLT2. Exome sequencing revealed a homozygous nonsense mutation, NM_022167.3(XYLT2): c.2188C>T, resulting in a premature stop codon (p.Arg730*) in a female patient. The patient presents visual impairment, generalized osteoporosis, short stature with short trunk, spinal compression fractures, and increased intervertebral disc space and hearing loss. We extended our XYLT2 analysis to a cohort of 22 patients with generalized osteoporosis, mostly from consanguineous families. In this cohort, we found by Sanger sequencing 2 siblings and 1 single patient who were homozygous for missense mutations in the XYLT2 gene (p.Arg563Gly and p.Leu605Pro). The patients had osteoporosis, compression fractures, cataracts, and hearing loss. Bisphosphonate treatment in 1 patient resulted in almost complete normalization of vertebral structures by adolescence, whereas treatment response in the others was variable. This report together with a previous study shows that mutations in the XYLT2 gene result in a variable phenotype dominated by spinal osteoporosis, cataract, and hearing loss. (c) 2016 American Society for Bone and Mineral Research. PMID- 26987878 TI - Penetrating chest injury caused by self-inflicted crossbow arrow traversing the hemithorax. PMID- 26987876 TI - Study protocol for a multi-component kindergarten-based intervention to promote healthy diets in toddlers: a cluster randomized trial. AB - BACKGROUND: There is concern about the lack of diversity in children's diets, particularly low intakes of fruit and vegetables and high intakes of unhealthy processed food. This may be a factor in the rising prevalence of obesity. A reason for the lack of diversity in children's diets may be food neophobia. This study aimed to promote a healthy and varied diet among toddlers in kindergarten. The primary objectives were to reduce food neophobia in toddlers, and promote healthy feeding practices among kindergarten staff and parents. Secondary objectives were to increase food variety in toddlers' diets and reduce future overweight and obesity in these children. METHODS: This is an ongoing, cluster randomized trial. The intervention finished in 2014, but follow-up data collection is not yet complete. Eighteen randomly selected kindergartens located in two counties in Norway with enrolled children born in 2012 participated in the intervention. The kindergartens were matched into pairs based on background information, and randomly assigned to the intervention or control groups. A 9 week multi-component intervention was implemented, with four main elements: 1) kindergarten staff implemented a pedagogical tool (Sapere method) in daily sessions to promote willingness to try new food; 2) kindergarten staff prepared and served the toddlers a cooked lunch from a menu corresponding to the pedagogical sessions; 3) kindergarten staff were encouraged to follow 10 meal principles on modeling, responsive feeding, repeated exposure, and enjoyable meals; and 4) parents were encouraged to read information and apply relevant feeding practices at home. The control group continued their usual practices. Preference taste tests were conducted to evaluate behavioral food neophobia, and children's height and weight were measured. Parents and staff completed questionnaires before and after the intervention. Data have not yet been analyzed. DISCUSSION: This study provides new knowledge about whether or not a Sapere-sensory education and healthy meal intervention targeting children, kindergarten staff, and parents will: reduce levels of food neophobia in toddlers; improve parental and kindergarten feeding practices; improve children's dietary variety; and reduce childhood overweight and obesity. TRIAL REGISTRATION: ISRCTN74823448 DOI 10.1186/ISRCTN74823448. PMID- 26987879 TI - Pulmonary endarterectomy is effective and safe in patients with haemoglobinopathies and abnormal red blood cells: the Papworth experience. AB - OBJECTIVES: Patients with haemoglobinopathies and congenital haemolytic anaemia constitute a unique population more predisposed to developing chronic thromboembolic pulmonary hypertension (CTEPH). Although pulmonary endarterectomy (PEA) is accepted as the best treatment for CTEPH, PEA in these patients poses significant practical challenges. Apart from a few case reports, the results of PEA in this patient population have not been previously reported. The aim of this study was to review the outcome of PEA in this patient population. METHODS: We performed a retrospective analysis, from our dedicated CTEPH database, of all patients who underwent PEA surgery and had abnormal haemoglobin or congenital haemolytic anaemia. We reviewed diagnosis, exchange transfusions on cardiopulmonary bypass, preoperative and postoperative pulmonary haemodynamic and functional data and outcomes for this group. Paired data analysis was performed by Student's t-test; P < 0.05 was statistically significant. RESULTS: Between the start of our PEA programme in 1997 and April 2015, we performed PEA in 19 patients with haemoglobinopathy or congenital haemolytic anaemia. The mean age was 52 +/- 15 years. There were 9 patients with sickle cell trait, 2 with coexisting alpha+ thalassaemia trait, 2 patients with HbSC disease, 2 patients with beta-thalassaemia major, 3 patients with hereditary spherocytosis, 2 patients with stomatocytosis (one with the cryohydrocytosis subtype) and 1 patient with HbC trait. In the 9 HbAS patients, the mean HbS% was 31.9 +/- 6%, and in the HbSC patients, the mean HbS% was 46.5 +/- 1.3% preoperatively. To reduce this HbS to <=20%, for safe PEA with deep hypothermic circulatory arrest, we used exchange blood transfusion. Immediately postoperatively, there was a significant improvement in pulmonary vascular resistance (938 +/- 462 to 260 +/- 167 dyne s cm(-5); P < 0.0001). One patient died 81 days following surgery; 18 patients are alive at a median follow-up of 3.4 +/- 3 years. Six months postoperatively, the patients showed significant improvement in New York Heart Association status (P < 0.0001), and in 6-min walk distance from 251 +/- 111 to 399 +/- 69 m (P < 0.0001). CONCLUSIONS: Results of PEA in this complex patient group were satisfactory. Expert haematological advice is important and exchange blood transfusions may be necessary. The presence of abnormal haemoglobin does not contra-indicate PEA surgery. PMID- 26987877 TI - Diagnostic efficacy of cell block method for vitreoretinal lymphoma. AB - BACKGROUND: Vitreoretinal lymphoma (VRL) is a life- and sight-threatening disorder. The aim of this study was to analyze the usefulness of the cell block method for diagnosis of VRL. METHODS: Sixteen eyes in 12 patients with VRL, and 4 eyes in 4 patients with idiopathic uveitis presenting with vitreous opacity were enrolled in this study. Both undiluted vitreous and diluted fluids were isolated during micro-incision vitrectomy. Cell block specimens were prepared in 19 eyes from diluted fluid containing shredding vitreous. These specimens were then submitted for HE staining as well as immunocytological analyses with antibodies against the B-cell marker CD20, the T-cell marker CD3, and cell proliferation marker Ki67. Conventional smear cytology was applied in 14 eyes with VRL using undiluted vitreous samples. The diagnosis of VRL was made based on the results of cytology, concentrations of interleukin (IL)-10 and IL-6 in undiluted vitreous, and immunoglobulin heavy chain gene rearrangement analysis. RESULTS: Atypical lymphoid cells were identified in 14 out of 15 cell block specimens of VRL (positive rate: 93.3 %), but in 5 out of 14 eyes in conventional smear cytology (positive rate: 35.7 %). Atypical lymphoid cells showed immunoreactivity for CD20 and Ki67. Seven cell block specimens were smear cytology-negative and cell block positive. The cell block method showed no atypical lymphoid cells in any patient with idiopathic uveitis. CONCLUSIONS: Cell block specimens using diluted vitreous fluid demonstrated a high diagnostic sensitivity and a low pseudo-positive rate for the cytological diagnosis of VRL. The cell block method contributed to clear differentiation between VRL and idiopathic uveitis with vitreous opacity. PMID- 26987880 TI - Risk of the preoperative underestimation of tumour size of lung cancer in patients with idiopathic interstitial pneumonias. AB - OBJECTIVES: Sublobar resection of lung cancer (LC) is a valuable procedure in patients with idiopathic interstitial pneumonias (IIPs). Having adequate surgical margins is the key to successful sublobar resection, and evaluation of the precise extent of LC is mandatory. However, tumour extent in IIPs is difficult to evaluate. This study assessed the risk of underestimating tumour size by preoperative computed axial tomography (CAT) scan in LC patients with IIPs. METHODS: A retrospective study was performed on 1221 patients who underwent surgical resection of primary LC at our institute between 2009 and 2013. Review of CAT findings revealed that 136 (11.1%) patients were complicated with IIPs. The discrepancy between radiological and pathological tumour dimensions was measured and underestimation was defined as 10 mm or more in pathological tumour dimension. The rate and cause of preoperative underestimation were also compared between patients with and without IIPs. Univariate and multivariate analyses were performed using a logistic regression model to predict underestimation of the preoperative tumour size. RESULTS: Maximum tumour dimension was underestimated in 14 (10.3%) patients with IIPs and 35 (3.2%) patients without IIPs. A multivariable analysis revealed that IIP was the only predictive factor for tumour size underestimation identified in this study (hazard ratio = 3.52, P = 0.017). Underestimation of tumour size in patients with IIPs was mainly due to extension of tumour cells in the honeycomb lung. CONCLUSIONS: IIPs pose a high risk for underestimating tumour size of LCs in preoperative measurements. Thus, tumour extent should be assessed carefully in order to maintain adequate surgical margins. PMID- 26987881 TI - True patient participation is difficult and takes dialogue. PMID- 26987883 TI - Rh-Catalyzed One-Pot Sequential Asymmetric Hydrogenation of alpha-Dehydroamino Ketones for the Synthesis of Chiral Cyclic trans-beta-Amino Alcohols. AB - Catalyzed by a rhodium complex of P-stereogenic diphosphine ligand (R)-2-tert butylmethylphosphino-3-(di-tert-butylphosphino)quinoxaline ((R)-3H-QuinoxP*), five-membered cyclic alpha-dehydroamino ketones bearing endocyclic vinyl and endocyclic keto-carbonyl groups were sequentially hydrogenated to give chiral cyclic trans-beta-amino alcohols with two contiguous stereocenters in quantitative conversions, excellent enantioselectivities and good diastereoselectivities. PMID- 26987882 TI - Cyclopropenes in Metallacycle-Mediated Cross-Coupling with Alkynes: Convergent Synthesis of Highly Substituted Vinylcyclopropanes. AB - Stereodivergent metallacycle-mediated cross-coupling reactions are described for the synthesis of densely functionalized vinylcyclopropanes from the union of alkynes with cyclopropenes. Strategies explored include hydroxyl-directed and nondirected processes, with the latter of these delivering vinylcyclopropanes with exquisite levels of regio- and stereoselectivity. Challenges inherent to these coupling reactions include diastereoselectivity (with respect to the cyclopropene) and regioselectivity (with respect to both coupling partners). PMID- 26987884 TI - Synergistic Rhodium/Copper Catalysis: Synthesis of 1,3-Enynes and N-Aryl Enaminones. AB - Synergistic rhodium/copper catalysis enables new three-component coupling reactions of terminal alkynes and alpha-diazoketones and/or arylamines, allowing dediazotized carbene C-H insertion for the synthesis of functionalized 1,3-enynes and N-aryl enaminones with high stereoselectivity. The synthetic utility of these transformations results in subsequent C-C or/and C-N bond-forming reactions to effectively build up functional molecules with potential significance. PMID- 26987885 TI - Syntheses of D-Glucose Derivatives Emitting Blue Fluorescence through Pd Catalyzed C-N Coupling. AB - Green fluorescence-emitting D-glucose derivatives such as 2-NBDG have been effectively used to monitor D-glucose uptake through glucose transporters GLUTs at the single cell level. By contrast, GLUT-permeable D-glucose derivatives emitting blue fluorescence have been long awaited. A glucose tracer, 2-deoxy-2-(2 oxo-2H-chromen-7-yl)amino-D-glucose (CDG) (1), together with related compounds have been synthesized by Pd-catalyzed C-N coupling. Of these, CDG (1) is a promising blue fluorescence-emitting candidate molecule that may enter into mammalian cells through GLUTs. PMID- 26987888 TI - Drug-induced toxicity and patient reported outcomes in rheumatoid arthritis patients following intensive treated-to-target strategy: does ceasing therapy due to toxicity worsen outcomes in long term? AB - AIM: While the introduction of the treat-to-target (T2T) strategy has been an important advance in the management of rheumatoid arthritis (RA), the potential for increased toxicity due to use of concurrent drugs could adversely affect patient reported outcomes (PROs). The objective was to determine whether the cessation of therapy due to toxicity affects long-term improvement in PROs in patients treated according to T2T strategy. METHODS: A total of 149 patients from an inception cohort of early RA were included. The occurrence and severity of toxicity were monitored at each visit over 3 years. PROs studied were function (measured using health assessment questionnaire); pain, fatigue and patient global assessment (PtGA) all assessed using a 100 mm visual analogue scale; helplessness and health-related quality of life (HRQoL). For each PRO, effect of drug withdrawal was measured by comparing mean change in PROs among patients with no/temporary vs. permanent withdrawal. In addition, effects of frequency of drug withdrawals, weeks to withdrawal and number of drugs withdrawn were analysed using linear regression. RESULT: After 3 years, 56 (37.4%) patients ceased at least one drug permanently due to toxicity. Patients with no/temporary withdrawal (n = 93) achieved significantly greater improvement in function (mean change = 0.54 vs. -0.31, p = 0.033), pain (mean change = -39.82 vs. -5.02, p = 0.018), fatigue (mean change = -29.14 vs. -14.76, p = 0.015) and PtGA (mean change = 29.64 vs. -17.00, p = 0.018) compared with their counterparts. Higher frequency of withdrawals was associated with lesser improvements in function, pain, fatigue and PtGA, while the number of drugs withdrawn and the weeks to withdrawal had lesser effects. However, the cessation of the drugs due to their toxicity did not have a significant association with HRQoL and helplessness. CONCLUSION: Improvements in function, pain, fatigue and PtGA at 3 years were diminished for patients who ceased drugs due to toxicity while broader measures of HRQoL were not affected. PMID- 26987886 TI - Titanium ions form particles that activate and execute interleukin-1beta release from lipopolysaccharide-primed macrophages. AB - BACKGROUND AND OBJECTIVE: Peri-implantitis is a destructive inflammatory process characterized by destruction of the implant-supporting bone. Inflammasomes are large intracellular multiprotein complexes that play a central role in innate immunity by activating the release of proinflammatory cytokines. Although inflammasome activation has previously been linked to periodontal inflammation, there is still no information on a potential association with peri-implantitis. The aim of this study was to examine cytotoxic and proinflammatory effects, including inflammasome activation, of metals used in dental implants, in an in vitro model, as well as from clinical tissue samples. MATERIAL AND METHODS: Human macrophages were exposed to different metals [titanium (Ti), cobalt, chromium and molybdenum] in a cell-culture assay. Cytotoxicity was determined using the neutral red uptake assay. Cytokine secretion was quantified using an ELISA, and the expression of genes of various inflammasome components was analysed using quantitative PCR. In addition, the concentrations of interleukin-1beta (IL-1beta) and Ti in mucosal tissue samples taken in the vicinity of dental implants were determined using ELISA and inductively coupled plasma mass spectrometry, respectively. RESULTS: Ti ions in physiological solutions stimulated inflammasome activation in human macrophages and consequently IL-1beta release. This effect was further enhanced by macrophages that have been exposed to lipopolysaccharides. The proinflammatory activation caused by Ti ions disappeared after filtration (0.22 MUm), which indicates an effect of particles. Ti ions alone did not stimulate transcription of the inflammasome components. The Ti levels of tissue samples obtained in the vicinity of Ti implants were sufficiently high (>= 40 MUm) to stimulate secretion of IL-1beta from human macrophages in vitro. CONCLUSION: Ti ions form particles that act as secondary stimuli for a proinflammatory reaction. PMID- 26987890 TI - Response to 'Darier disease in Israel: combined evaluation of genetic and neuropsychiatric aspects'. PMID- 26987889 TI - Overview of ICRP Committee 5: protection of the environment. AB - Protection of the environment is integral to the system of radiological protection, as outlined in the 2007 Recommendations of the International Commission on Radiological Protection (ICRP, Publication 103). The Commission's activities in this area are mainly pursued by Committee 5 and its associated Task Groups. Publication 91 broadly outlines the approach to radiological protection of the environment, and its alignment with approaches to environmental protection from hazardous substances in general. Publications 108 and 114 provide the cornerstones of the environmental protection system and relevant databases. Publication 124 considers its application in planned, existing, and emergency exposure situations. The system centres on 12 Reference Animals and Plants (RAPs) with broad relevance for environmental protection based on their ubiquity and significance as well as other criteria, as described in Publication 108 The databases comprise general biology of the RAPs, transfer parameters, dose conversion coefficients, and effects data. Derived Consideration Reference Levels (DCRLs) were established for each RAP; a DCRL represents a band of dose rates that might result in some deleterious effects in individuals of that type of RAP. Newly established Task Group 99 will compile the RAP-specific reference information into monographs, with the view of updating information and improving the applicability of the system in different exposure situations. For certain scenarios, more precise and ecosystem-specific protection benchmarks may be justified, which would have to be informed by consideration of representative organisms (i.e. representative of a particular ecosystem and relevant to the specific scenario; Publication 124). Committee 5 will explore this further, making use of a limited number of case studies. PMID- 26987887 TI - A plant-derived quadrivalent virus like particle influenza vaccine induces cross reactive antibody and T cell response in healthy adults. AB - Recent issues regarding efficacy of influenza vaccines have re-emphasized the need of new approaches to face this major public health issue. In a phase 1-2 clinical trial, healthy adults received one intramuscular dose of a seasonal influenza plant-based quadrivalent virus-like particle (QVLP) vaccine or placebo. The hemagglutination inhibition (HI) titers met all the European licensure criteria for the type A influenza strains at the 3MUg/strain dose and for all four strains at the higher dosages 21days after immunization. High HI titers were maintained for most of the strains 6months after vaccination. QVLP vaccine induced a substantial and sustained increase of hemagglutinin-specific polyfunctional CD4 T cells, mainly transitional memory and TEMRA effector IFN gamma(+) CD4 T cells. A T cells cross-reactive response was also observed against A/Hong-Kong/1/1968 H3N2 and B/Massachusetts/2/2012. Plant-based QVLP offers an attractive alternative manufacturing method for producing effective and HA-strain matching seasonal influenza vaccines. PMID- 26987891 TI - 1,3,5-Triazapentadienes by Nucleophilic Addition to 1,3- and 1,4-Dinitriles Sterically Constrained Examples by Incorporation into Cyclic Peripheries: Synthesis, Aggregation, and Photophysical Properties. AB - 1,3,5-Triazapentadienes usually show U- or twisted S-shaped conformations along the N-C-N-C-N skeleton due to dominating n/pi* interactions. If, however, the 1,3,5-triazapentadiene unit is part of a ring, its W conformation might be restricted to the plane. Here, we describe the synthesis of 13 new 1,3,5 triazapentadienes 10-12, which are sterically restrained by incorporation into six- or seven-membered ring systems, by addition of a lithiated primary amine or hydrazine 5 to a dinitrile 7, 8, or 9 with the two cyano groups in 1,3 or 1,4 distance. These novel compounds show very strong tendency for aggregation due to hydrogen bonding, especially to form homodimers as seen from X-ray data in the solid state. Additional hydrogen bonding generates also linear chains in the crystal. Several of the new compounds show fluorescence in solution. Quantum chemical DFT calculations were used for evaluation of the dimerization energies and for interpretation of the photophysical properties. PMID- 26987892 TI - Targeted, triggered drug delivery to tumor and biofilm microenvironments. PMID- 26987893 TI - Profile of illness in Syrian refugees: A GeoSentinel analysis, 2013 to 2015. AB - Screening of 488 Syrian unaccompanied minor refugees (< 18 years-old) in Berlin showed low prevalence of intestinal parasites (Giardia, 7%), positive schistosomiasis serology (1.4%) and absence of hepatitis B. Among 44 ill adult Syrian refugees examined at GeoSentinel clinics worldwide, cutaneous leishmaniasis affected one in three patients; other noteworthy infections were active tuberculosis (11%) and chronic hepatitis B or C (9%). These data can contribute to evidence-based guidelines for infectious disease screening of Syrian refugees. PMID- 26987894 TI - Thermoluminescent properties of some phosphor glasses based on aluminum oxide. AB - The transparent thermoluminescent aluminum oxide-based glass of 15Al2 O3 -35P2 O5 -25CaO-25Na2 CO3 , abbreviated as APCN (all in mol%) doped with different concentrations of SiO2 from 0.0-500 ppm was prepared using a conventional melt quenching technique. The TL sensitivities of the prepared glasses were investigated at 3 Gy gamma-dose using a 60 Co source and measured at a heating rate 10 C/sec. The highest TL intensity of the material doped with SiO2 was found at a concentration of 500 ppm (APCNSi5 ). Deconvolution of the glow curve from APCNSi5 resulted in four peaks at about 161, 194, 237 and 293 C with a Figure Of Merit (FOM) of 1.28%. The APCNSi5 specimen had the best dosimetric properties when compared with the other samples. Reproducibility, repeatability, dose response curve and fading effect were checked for peak 3, which appeared at about 237 C. The results displayed that the APCNSi5 glass system was a low-Z material (Zeff ~ 10), and had good reproducibility and good repeatability. Peak 3 showed good linearity over a dose range up to 20 Gy (R2 = 0.999) and sublinearity behaviour was found. The signal from APCNSi5 faded by about 11% after 2 days post irradiation, therefore it showed almost no significant loss. Such properties make the newly prepared glasses suitable for and highly recommended for use in gamma dosimeters. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26987895 TI - In vivo characterization of lamina cribrosa pore morphology in primary open-angle glaucoma. AB - PURPOSE: To characterize the in vivo morphology of human lamina cribrosa pores in healthy and glaucoma eyes. PATIENTS AND METHODS: In this cross-sectional, observational study, a flood-illumination adaptive optics fundus (FIAO) camera was used to perform in vivo, high-resolution, noninvasive imaging of the optic disc and lamina cribrosa in 30 patients diagnosed with primary open-angle glaucoma (POAG), in 15 healthy controls and in 14 healthy subjects with at least one direct relative with POAG. Two masked graders measured each visible lamina cribrosa pore along the major and minor axes in order to categorize pores as oval (minor/major axis ratio<0.75) or round. We used these same measurements to calculate pore surface area as a best-fit oval. RESULTS: Lamina cribrosa pores were visible in 95.2% of the subjects. In 52% of controls, the pores were visualized under the neuroretinal rim. In POAG patients, 78% of visible pores had an oval shape versus 19.4% in controls (P<0.01). Average pore surface area was significantly different (1561 px(2) versus 724 px(2); P<0.01). In healthy subjects with at least one direct relative with POAG, 21% had pores with an appearance comparable to that of subjects in the glaucoma group. CONCLUSION: On average, lamina cribrosa pores are elongated in POAG eyes and also in healthy eyes of POAG relatives. In vivo characterization of lamina cribrosa pore morphology by FIAO imaging may enhance our understanding of glaucoma, and offer new means for its early detection. PMID- 26987896 TI - [Pediatric uveitis, report of 33 cases]. PMID- 26987897 TI - [Post-traumatic Morgagnian cataract]. PMID- 26987898 TI - Achieving fast timing performance with multiplexed SiPMs. AB - Using time of flight (ToF) measurements for positron emission tomography (PET) is an attractive avenue for increasing the signal to noise (SNR) ratio of PET images. However, achieving excellent time resolution required for high SNR gain using silicon photomultipliers (SiPM) requires many resource heavy high bandwidth readout channels. A method of multiplexing many SiPM signals into a single electronic channel would greatly simplify ToF PET systems. However, multiplexing SiPMs degrades time resolution because of added dark counts and signal shaping. In this work the relative contribution of dark counts and signal shaping to timing degradation is simulated and a baseline correction technique to mitigate the effect of multiplexing on the time resolution of analog SiPMs is simulated and experimentally verified. A charge sharing network for multiplexing is proposed and tested. Results show a full width at half maximum (FWHM) coincidence time resolution of [Formula: see text] ps for a single 3 mm * 3 mm * 20 mm LYSO scintillation crystals coupled to an array of sixteen 3 mm * 3 mm SiPMs that are multiplexed to a single timing channel (in addition to 4 position channels). A [Formula: see text] array of 3 mm * 3 mm * 20 mm LFS crystals showed an average FWHM coincidence time resolution of [Formula: see text] ps using the same timing scheme. All experiments were performed at room temperature with no thermal regulation. These results show that excellent time resolution for ToF can be achieved with a highly multiplexed analog SiPM readout. PMID- 26987899 TI - ARPES view on surface and bulk hybridization phenomena in the antiferromagnetic Kondo lattice CeRh2Si2. AB - The hybridization between localized 4f electrons and itinerant electrons in rare earth-based materials gives rise to their exotic properties like valence fluctuations, Kondo behaviour, heavy-fermions, or unconventional superconductivity. Here we present an angle-resolved photoemission spectroscopy (ARPES) study of the Kondo lattice antiferromagnet CeRh2Si2, where the surface and bulk Ce-4f spectral responses were clearly resolved. The pronounced 4f (0) peak seen for the Ce terminated surface gets strongly suppressed in the bulk Ce 4f spectra taken from a Si-terminated crystal due to much larger f-d hybridization. Most interestingly, the bulk Ce-4f spectra reveal a fine structure near the Fermi edge reflecting the crystal electric field splitting of the bulk magnetic 4f (1)5/2 state. This structure presents a clear dispersion upon crossing valence states, providing direct evidence of f-d hybridization. Our findings give precise insight into f-d hybridization penomena and highlight their importance in the antiferromagnetic phases of Kondo lattices. PMID- 26987900 TI - MP-4 Contributes to Snake Venom Neutralization by Mucuna pruriens Seeds through an Indirect Antibody-mediated Mechanism. AB - Mortality due to snakebite is a serious public health problem, and available therapeutics are known to induce debilitating side effects. Traditional medicine suggests that seeds of Mucuna pruriens can provide protection against the effects of snakebite. Our aim is to identify the protein(s) that may be important for snake venom neutralization and elucidate its mechanism of action. To this end, we have identified and purified a protein from M. pruriens, which we have named MP 4. The full-length polypeptide sequence of MP-4 was obtained through N-terminal sequencing of peptide fragments. Sequence analysis suggested that the protein may belong to the Kunitz-type protease inhibitor family and therefore may potentially neutralize the proteases present in snake venom. Using various structural and biochemical tools coupled with in vivo assays, we are able to show that MP-4 does not afford direct protection against snake venom because it is actually a poor inhibitor of serine proteases. Further experiments showed that antibodies generated against MP-4 cross-react with the whole venom and provide protection to mice against Echis carinatus snake venom. This study shows that the MP-4 contributes significantly to the snake venom neutralization activity of M. pruriens seeds through an indirect antibody-mediated mechanism. PMID- 26987901 TI - NEU3 Sialidase Protein Interactors in the Plasma Membrane and in the Endosomes. AB - NEU3 sialidase has been shown to be a key player in many physio- and pathological processes, including cell differentiation, cellular response to hypoxic stress, and carcinogenesis. The enzyme, peculiarly localized on the outer leaflet of the plasma membrane, has been shown to be able to remove sialic acid residues from the gangliosides present on adjacent cells, thus creating cell to cell interactions. Nonetheless, herein we report that the enzyme localization is dynamically regulated between the plasma membrane and the endosomes, where a substantial amount of NEU3 is stored with low enzymatic activity. However, under opportune stimuli, NEU3 is shifted from the endosomes to the plasma membrane, where it greatly increases the sialidase activity. Finally, we found that NEU3 possesses also the ability to interact with specific proteins, many of which are different in each cell compartment. They were identified by mass spectrometry, and some selected ones were also confirmed by cross-immunoprecipitation with the enzyme, supporting NEU3 involvement in the cell stress response, protein folding, and intracellular trafficking. PMID- 26987904 TI - Thermodynamic theory of the plasmoelectric effect. AB - Resonant metal nanostructures exhibit an optically induced electrostatic potential when illuminated with monochromatic light under off-resonant conditions. This plasmoelectric effect is thermodynamically driven by the increase in entropy that occurs when the plasmonic structure aligns its resonant absorption spectrum with incident illumination by varying charge density. As a result, the elevated steady-state temperature of the nanostructure induced by plasmonic absorption is further increased by a small amount. Here, we study in detail the thermodynamic theory underlying the plasmoelectric effect by analyzing a simplified model system consisting of a single silver nanoparticle. We find that surface potentials as large as 473 mV are induced under 100 W/m(2) monochromatic illumination, as a result of a 11 mK increases in the steady-state temperature of the nanoparticle. Furthermore, we discuss the applicability of this analysis for realistic experimental geometries, and show that this effect is generic for optical structures in which the resonance is linked to the charge density. PMID- 26987902 TI - Loss of Mitochondrial Function Impairs Lysosomes. AB - Alterations in mitochondrial function, as observed in neurodegenerative diseases, lead to disrupted energy metabolism and production of damaging reactive oxygen species. Here, we demonstrate that mitochondrial dysfunction also disrupts the structure and function of lysosomes, the main degradation and recycling organelle. Specifically, inhibition of mitochondrial function, following deletion of the mitochondrial protein AIF, OPA1, or PINK1, as well as chemical inhibition of the electron transport chain, impaired lysosomal activity and caused the appearance of large lysosomal vacuoles. Importantly, our results show that lysosomal impairment is dependent on reactive oxygen species. Given that alterations in both mitochondrial function and lysosomal activity are key features of neurodegenerative diseases, this work provides important insights into the etiology of neurodegenerative diseases. PMID- 26987903 TI - Estrogen Enhances Linkage in the Vascular Endothelial Calmodulin Network via a Feedforward Mechanism at the G Protein-coupled Estrogen Receptor 1. AB - Estrogen exerts many effects on the vascular endothelium. Calmodulin (CaM) is the transducer of Ca(2+) signals and is a limiting factor in cardiovascular tissues. It is unknown whether and how estrogen modifies endothelial functions via the network of CaM-dependent proteins. Here we show that 17beta-estradiol (E2) up regulates total CaM level in endothelial cells. Concurrent measurement of Ca(2+) and Ca(2+)-CaM indicated that E2 also increases free Ca(2+)-CaM. Pharmacological studies, gene silencing, and receptor expression-specific cell studies indicated that the G protein-coupled estrogen receptor 1 (GPER/GPR30) mediates these effects via transactivation of EGFR and subsequent MAPK activation. The outcomes were then examined on four distinct members of the intracellular CaM target network, including GPER/GPR30 itself and estrogen receptor alpha, the plasma membrane Ca(2+)-ATPase (PMCA), and endothelial nitric-oxide synthase (eNOS). E2 substantially increases CaM binding to estrogen receptor alpha and GPER/GPR30. Mutations that reduced CaM binding to GPER/GPR30 in separate binding domains do not affect GPER/GPR30-Gbetagamma preassociation but decrease GPER/GPR30-mediated ERK1/2 phosphorylation. E2 increases CaM-PMCA association, but the expected stimulation of Ca(2+) efflux is reversed by E2-stimulated tyrosine phosphorylation of PMCA. These effects sustain Ca(2+) signals and promote Ca(2+) dependent CaM interactions with other CaM targets. Consequently, E2 doubles CaM eNOS interaction and also promotes dual phosphorylation of eNOS at Ser-617 and Ser-1179. Calculations using in-cell and in vitro data revealed substantial individual and combined contribution of these effects to total eNOS activity. Taken together, E2 generates a feedforward loop via GPER/GPR30, which enhances Ca(2+)/CaM signals and functional linkage in the endothelial CaM target network. PMID- 26987905 TI - Pathologic activation of thrombopoietin receptor and JAK2-STAT5 pathway by frameshift mutants of mouse calreticulin. PMID- 26987906 TI - High CIP2A levels correlate with an antiapoptotic phenotype that can be overcome by targeting BCL-XL in chronic myeloid leukemia. AB - Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a predictive biomarker of disease progression in many malignancies, including imatinib-treated chronic myeloid leukemia (CML). Although high CIP2A levels correlate with disease progression in CML, the underlying molecular mechanisms remain elusive. In a screen of diagnostic chronic phase samples from patients with high and low CIP2A protein levels, high CIP2A levels correlate with an antiapoptotic phenotype, characterized by downregulation of proapoptotic BCL-2 family members, including BIM, PUMA and HRK, and upregulation of the antiapoptotic protein BCL-XL. These results suggest that the poor prognosis of patients with high CIP2A levels is due to an antiapoptotic phenotype. Disrupting this antiapoptotic phenotype by inhibition of BCL-XL via RNA interference or A-1331852, a novel, potent and BCL XL-selective inhibitor, resulted in extensive apoptosis either alone or in combination with imatinib, dasatinib or nilotinib, both in cell lines and in primary CD34(+) cells from patients with high levels of CIP2A. These results demonstrate that BCL-XL is the major antiapoptotic survival protein and may be a novel therapeutic target in CML. PMID- 26987909 TI - The frontotemporal dementia-motor neuron disease continuum. AB - Early reports of cognitive and behavioural deficits in motor neuron disease might have been overlooked initially, but the concept of a frontotemporal dementia motor neuron disease continuum has emerged during the past decade. Frontotemporal dementia-motor neuron disease is now recognised as an important dementia syndrome, which presents substantial challenges for diagnosis and management. Frontotemporal dementia, motor neuron disease, and frontotemporal dementia-motor neuron disease are characterised by overlapping patterns of TAR DNA binding protein (TDP-43) pathology, while the chromosome 9 open reading frame 72 (C9orf72) repeat expansion is common across the disease spectrum. Indeed, the C9orf72 repeat expansion provides important clues to disease pathogenesis and suggests potential therapeutic targets. Variable diagnostic criteria identify motor, cognitive, and behavioural deficits, but further refinement is needed to define the clinical syndromes encountered in frontotemporal dementia-motor neuron disease. PMID- 26987908 TI - Internalization of nanopolymeric tracers does not alter characteristics of placental cells. AB - In the cell therapy scenario, efficient tracing of transplanted cells is essential for investigating cell migration and interactions with host tissues. This is fundamental to provide mechanistic insights which altogether allow for the understanding of the translational potential of placental cell therapy in the clinical setting. Mesenchymal stem/stromal cells (MSC) from human placenta are increasingly being investigated for their potential in treating patients with a variety of diseases. In this study, we investigated the feasibility of using poly (methyl methacrylate) nanoparticles (PMMA-NPs) to trace placental MSC, namely those from the amniotic membrane (hAMSC) and early chorionic villi (hCV-MSC). We report that PMMP-NPs are efficiently internalized and retained in both populations, and do not alter cell morphofunctional parameters. We observed that PMMP-NP incorporation does not alter in vitro immune modulatory capability of placental MSC, a characteristic central to their reparative/therapeutic effects in vitro. We also show that in vitro, PMMP-NP uptake is not affected by hypoxia. Interestingly, after in vivo brain ischaemia and reperfusion injury achieved by transient middle cerebral artery occlusion (tMCAo) in mice, iv hAMSC treatment resulted in significant improvement in cognitive function compared to PBS-treated tMCAo mice. Our study provides evidence that tracing placental MSC with PMMP-NPs does not alter their in vitro and in vivo functions. These observations are grounds for the use of PMMP-NPs as tools to investigate the therapeutic mechanisms of hAMSC and hCV-MSC in preclinical models of inflammatory-driven diseases. PMID- 26987907 TI - Restoration of normal embryogenesis by mitochondrial supplementation in pig oocytes exhibiting mitochondrial DNA deficiency. AB - An increasing number of women fail to achieve pregnancy due to either failed fertilization or embryo arrest during preimplantation development. This often results from decreased oocyte quality. Indeed, reduced mitochondrial DNA copy number (mitochondrial DNA deficiency) may disrupt oocyte quality in some women. To overcome mitochondrial DNA deficiency, whilst maintaining genetic identity, we supplemented pig oocytes selected for mitochondrial DNA deficiency, reduced cytoplasmic maturation and lower developmental competence, with autologous populations of mitochondrial isolate at fertilization. Supplementation increased development to blastocyst, the final stage of preimplantation development, and promoted mitochondrial DNA replication prior to embryonic genome activation in mitochondrial DNA deficient oocytes but not in oocytes with normal levels of mitochondrial DNA. Blastocysts exhibited transcriptome profiles more closely resembling those of blastocysts from developmentally competent oocytes. Furthermore, mitochondrial supplementation reduced gene expression patterns associated with metabolic disorders that were identified in blastocysts from mitochondrial DNA deficient oocytes. These results demonstrate the importance of the oocyte's mitochondrial DNA investment in fertilization outcome and subsequent embryo development to mitochondrial DNA deficient oocytes. PMID- 26987910 TI - Fortune Favors the Prepared: Safety and Efficacy of Allogeneic Hypoxia Preconditioned Mesenchymal Stromal Cells in Primates. PMID- 26987911 TI - Cell Therapy Augments Myocardial Perfusion and Improves Quality of Life in Patients With Refractory Angina. PMID- 26987912 TI - Revisiting Preadolescent Cardiomyocyte Proliferation in Mice. PMID- 26987913 TI - Healing a Heart Through Genetic Intervention. PMID- 26987914 TI - Cardio-Oncology: An Update on Cardiotoxicity of Cancer-Related Treatment. AB - Through the success of basic and disease-specific research, cancer survivors are one of the largest growing subsets of individuals accessing the healthcare system. Interestingly, cardiovascular disease is the second leading cause of morbidity and mortality in cancer survivors after recurrent malignancy. This recognition has helped stimulate a collaboration between oncology and cardiology practitioners and researchers, and the portmanteau cardio-oncology (also known as onco-cardiology) can now be found in many medical centers. This collaboration promises new insights into how cancer therapies impact cardiovascular homeostasis and long-term effects on cancer survivors. In this review, we will discuss the most recent views on the cardiotoxicity related to various classes of chemotherapy agents and radiation. We will also discuss broadly the current strategies for treating and preventing cardiovascular effects of cancer therapy. PMID- 26987916 TI - Correction. PMID- 26987917 TI - Visible light-photocatalysed carbazole synthesis via a formal (4+2) cycloaddition of indole-derived bromides and alkynes. AB - We successfully developed an unprecedented route to carbazole synthesis through a visible light-photocatalysed formal (4+2) cycloaddition of indole-derived bromides and alkynes. This novel protocol features extremely mild conditions, a broad substrate scope and high reaction efficiency. PMID- 26987918 TI - Achilles or biceps tendon rupture in women and men with type 2 diabetes: A population-based case-control study. AB - AIMS: Previous studies suggest that diabetes causes alterations in tendon collagen structure, but evidence on how such findings translate into clinical practice is scarce. We aimed to analyze the association between type 2 diabetes and the risk of tendon rupture. MATERIALS AND METHODS: We conducted a matched case-control analysis using the UK-based Clinical Practice Research Datalink. Cases (n=7895) were aged 30-89years and had an incident diagnosis of Achilles- or biceps tendon rupture between 1995 and 2013. In multivariable logistic regression analyses we compared the odds of tendon rupture between patients with or without type 2 diabetes, in men and women separately, and taking into account diabetes severity (HbA1c), duration, and antidiabetic drug treatment. RESULTS: Within 165 (7.1%) female cases with type 2 diabetes, odds ratios (ORs) were increased with poorer diabetes control (OR 2.03, 95% CI 1.20-3.41, HbA1c >=9% [>=75mmol/mol]), longer disease duration (OR 1.60, 95% CI 0.93-2.74, >=10years), and current insulin use (OR 2.25, 95% CI 1.30-3.90, >=20 prescriptions). Among 372 (6.7%) male cases, there was no effect of type 2 diabetes on the risk of tendon rupture. CONCLUSIONS: Our results suggest that the risk of tendon ruptures may be increased in women with poorly controlled type 2 diabetes, but not in men. PMID- 26987919 TI - The relationship between depressive symptoms and diabetic complications in elderly patients with diabetes: Analysis using the Diabetes Study from the Center of Tokyo Women's Medical University (DIACET). AB - AIMS: To investigate the association between likelihood or severity of depression and symptoms associated with diabetic complications in elderly Japanese patients with diabetes. METHODS: This single-center cross-sectional study included 4283 patients with diabetes, 65 years and older (mean age was 73 +/- 6 years, 38.7% were women, 3.9% had type 1 diabetes). Participants completed a self-administered questionnaire including items on subjective symptoms associated with diabetic microangiopathy, frequency of clinical visits due to vascular diseases (heart diseases, stroke, or gangrene), hospitalization, and the Patient Health Questionnaire-9 (PHQ-9), a simple but reliable measure of depression. The associations between severity of depression and diabetic complications were examined using logistic regression analysis. RESULTS: According to the PHQ-9 scores, patients were classified into the following 3 categories: 0-4 points (n=2975); 5-9 points (n=842); and 10 or more points (n=466). Higher PHQ-9 scores were associated with increased odds ratios for retinopathy, symptoms related to peripheral polyneuropathy and autonomic neuropathy, and end-stage renal disease requiring dialysis after adjustment for age, gender, smoking status, and HbA1c (all p<0.05). CONCLUSIONS: Significant relationships were found between depression severity and chronic diabetic complications among elderly Japanese patients with diabetes. PMID- 26987920 TI - Reprogramming of mouse amniotic fluid cells using a PiggyBac transposon system. AB - Induced pluripotent stem (iPS) cells are generated from mouse and human somatic cells by forced expression of defined transcription factors using different methods. Amniotic fluid (AF) cells are easy to obtain from routinely scheduled procedures for prenatal diagnosis and iPS cells have been generated from human AF. Here, we generated iPS cells from mouse AF cells, using a non-viral-based approach constituted by the PiggyBac (PB) transposon system. All iPS cell lines obtained exhibited characteristics of pluripotent cells, including the ability to differentiate toward derivatives of all three germ layers in vitro and in vivo. PMID- 26987921 TI - Generation of an iPS cell line from bone marrow derived mesenchymal stromal cells from an elderly patient. AB - An induced pluripotent stem cell line was generated from primary human bone marrow derived mesenchymal stromal cells of a 74 year old donor using retroviruses harboring OCT4, SOX2, KLF4 and c-MYC in combination with the following inhibitors TGFbeta receptor-SB 431542, MEK-PD325901, and p53-Pifithrin alpha. Pluripotency was confirmed both in vitro and in vivo. PMID- 26987915 TI - Cardiac Fibrosis: The Fibroblast Awakens. AB - Myocardial fibrosis is a significant global health problem associated with nearly all forms of heart disease. Cardiac fibroblasts comprise an essential cell type in the heart that is responsible for the homeostasis of the extracellular matrix; however, upon injury, these cells transform to a myofibroblast phenotype and contribute to cardiac fibrosis. This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy and apoptosis, and ultimately leads to the progression to heart failure. Despite the critical importance of fibrosis in cardiovascular disease, our limited understanding of the cardiac fibroblast impedes the development of potential therapies that effectively target this cell type and its pathological contribution to disease progression. This review summarizes current knowledge regarding the origins and roles of fibroblasts, mediators and signaling pathways known to influence fibroblast function after myocardial injury, as well as novel therapeutic strategies under investigation to attenuate cardiac fibrosis. PMID- 26987922 TI - Generation of iPSC line epiHUVEC from human umbilical vein endothelial cells. AB - Human umbilical vein endothelial cells (HUVECs) were used to generate the iPSC line epiHUVEC employing a combination of three episomal-based plasmids expressing OCT4, SOX2, NANOG, LIN28, c-MYC and KLF4. Pluripotency was confirmed both in vivo and in vitro. The transcriptome profile of epiHUVEC and the human embryonic stem cell line - H1 have a Pearson correlation of 0.899. PMID- 26987923 TI - Generation of poikiloderma with neutropenia (PN) induced pluripotent stem cells (iPSCs). AB - Poikiloderma with neutropenia (PN, Clericuzio-type poikiloderma with neutropenia) is a rare autosomal recessive disorder caused by biallelic mutations in the USB1 gene (Alias C16orf57 and MPN1). To date, there have been only 37 reported cases worldwide of this disorder that presents with neutropenia, early onset poikiloderma, respiratory infections, palmo-plantar hyperkeratosis, and skeletal defects. Here we described the generation of human induced pluripotent stem cell lines (PN1 and PN2) from the peripheral blood of a 1-year-old patient using the dox-inducible STEMCCA vector. This patient presented with bacteremia, pneumonia, and neutropenia. Analysis of bone marrow demonstrated normal cellularity with trilineage hematopoiesis and neutropenia. PMID- 26987924 TI - Generation and characterization of the human iPSC line PBMC1-iPS4F1 from adult peripheral blood mononuclear cells. AB - Here we describe the generation and characterization of the human induced pluripotent stem cell (iPSC) line PBMC1-iPS4F1 from peripheral blood mononuclear cells from a healthy female with Spanish background. We used heat sensitive, non integrative Sendai viruses containing the reprogramming factors Oct3/4, Sox2, Klf4 and c-Myc, whose expression was silenced in the established iPSC line. Characterization of the PBMC1-iPS4F1 cell line included analysis of typical pluripotency-associated factors at mRNA and protein level, alkaline phosphatase enzymatic activity, and in vivo and in vitro differentiation studies. PMID- 26987925 TI - Generation of iPSC lines from a Nijmegen Breakage Syndrome patient. AB - Human dermal fibroblasts from a Nijmegen Breakage Syndrome (NBS) patient bearing the 657del5 mutation within the DNA repair gene NIBRIN were used to generate two iPSC-lines (vNBS8-iPS-c1, vNBS8-iPS-c2) by retroviral transduction of OCT4, SOX2, c-MYC and KLF4. Pluripotency was confirmed both in vivo and in vitro. PMID- 26987926 TI - Development of buffalo (Bubalus bubalis) embryonic stem cell lines from somatic cell nuclear transferred blastocysts. AB - We developed buffalo embryonic stem cell lines from somatic cell nuclear transfer derived blastocysts, produced by hand-guided cloning technique. The inner cell mass of the blastocyst was cut mechanically using a Microblade and cultured onto feeder cells in buffalo embryonic stem (ES) cell culture medium at 38 degrees C in a 5% CO2 incubator. The stem cell colonies were characterized for alkaline phosphatase activity, karyotype, pluripotency and self-renewal markers like OCT4, NANOG, SOX2, c-Myc, FOXD3, SSEA-1, SSEA-4, TRA-1-60, TRA-1-81 and CD90. The cell lines also possessed the capability to differentiate across all the three germ layers under spontaneous differentiation conditions. PMID- 26987927 TI - Human embryonic stem cells derived from abnormal blastocyst donated by Marfan syndrome patient. AB - Human embryonic stem cell (hESC) line was derived from abnormal blastocyst donated by Marfan syndrome patient after preimpantation genetic diagnosis (PGD) treatment. DNA sequencing analysis confirmed that the hESC line carried the heterozygous deletion mutation, c.3536delA, of FBN1 gene. Characteristic tests proved that the hESC line presented typicalmarkers of pluripotency and had the capability to formthe three germlayers both in vitro and in vivo. PMID- 26987928 TI - Generation of integration-free induced pluripotent stem cells from a patient with Familial Mediterranean Fever (FMF). AB - Fibroblasts from a Familial Mediterranean Fever (FMF) patient were reprogrammed with episomal vectors by using the Neon Transfection System for the generation of integration-free induced pluripotent stem cells (iPSCs). The resulting iPSC line was characterized to determine the expression of pluripotency markers, proper differentiation into three germ layers, the presence of normal chromosomal structures as well as the lack of genomic integration. A homozygous missense mutation in the MEFV gene (p.Met694Val), which lead to typical FMF phenotype, was shown to be present in the generated iPSC line. PMID- 26987929 TI - Generation of iPSC lines from primary human chorionic villi cells. AB - Primary human chorionic villi (CV) cells were used to generate the iPSC line by retroviral transduction of the four Yamanaka-factors OCT4, SOX2, KLF4 and c-MYC. Pluripotency was confirmed both in vivo and in vitro. The transcriptomes of the CV-derived iPSC lines and the human embryonic stem cell lines-H1 and H9 have a Pearson correlation of 0.929 and 0.943 respectively. PMID- 26987930 TI - Generation of iPSC lines from primary human amniotic fluid cells. AB - By means of retroviral transduction using the four Yamanaka-factors OCT4, SOX2, KLF4 and c-MYC primary human amniotic fluid cells (AFCs) were reprogrammed into several iPSC lines. Pluripotency was confirmed both in vitro and in vivo. A comparative transcriptome analysis of the AF-derived iPSC line 41 and the human embryonic stem cell lines (H1 and H9) revealed a Pearson correlation of 0.953 and 0.941 respectively. PMID- 26987931 TI - Paolo Bianco (1955-2015). PMID- 26987932 TI - Investigation of the electrophysiological correlates of negative BOLD response during intermittent photic stimulation: An EEG-fMRI study. AB - Although the occurrence of concomitant positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to visual stimuli is increasingly investigated in neuroscience, it still lacks a definite explanation. Multimodal imaging represents a powerful tool to study the determinants of negative BOLD responses: the integration of functional Magnetic Resonance Imaging (fMRI) and electroencephalographic (EEG) recordings is especially useful, since it can give information on the neurovascular coupling underlying this complex phenomenon. In the present study, the brain response to intermittent photic stimulation (IPS) was investigated in a group of healthy subjects using simultaneous EEG-fMRI, with the main objective to study the electrophysiological mechanisms associated with the intense NBRs elicited by IPS in extra-striate visual cortex. The EEG analysis showed that IPS induced a desynchronization of the basal rhythm, followed by the instauration of a novel rhythm driven by the visual stimulation. The most interesting results emerged from the EEG-informed fMRI analysis, which suggested a relationship between the neuronal rhythms at 10 and 12 Hz and the BOLD dynamics in extra-striate visual cortex. These findings support the hypothesis that NBRs to visual stimuli may be neuronal in origin rather than reflecting pure vascular phenomena. Hum Brain Mapp 37:2247-2262, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26987933 TI - Chronic Obstructive Pulmonary Disease Increases the Risk of Hip Fracture: A Nationwide Population-Based Cohort Study. AB - Hip fractures can lead to functional disability and high mortality rates among elderly patients. The aim of this study was to investigate whether chronic obstructive pulmonary disease (COPD) is a risk factor for hip fracture. A retrospective population-based 4-year cohort study was conducted using case control matched analysis of data from the Taiwan Longitudinal Health Insurance Database 2005 (LHID2005). Patients with a diagnosis of COPD between January 1, 2004 and December 31, 2007 were enrolled. A 2-stage approach and data from the National Health Interview Survey 2005 were applied to adjust for missing confounders in the LHID2005 cohort. Hazard ratios (HRs) and adjusted HRs were estimated hip fracture risk for the COPD. We enrolled 16,239 patients in the COPD cohort and 48,747 (1:3) patients in non-COPD cohort. The hip fracture incidences were 649 per 100,000 person-years in the study cohort and 369 per 100,000 person years in non-COPD cohort. The hip fracture HR during the follow-up period was 1.78 (P < 0.001) and the adjusted hip fracture HR was 1.57 (P < 0.001) after adjustment for covariates by using the 2-stage approach method. Patients with COPD were at hip fracture risk and fracture-prevention strategies are essential for better quality of care. PMID- 26987935 TI - A randomized study of very low-dose factor VIII prophylaxis in severe haemophilia - A success story from a resource limited country. AB - INTRODUCTION: Current factor prophylaxis strategy practised in developed countries is not feasible in resource constraint developing countries like India. AIM: The aim of this study was to investigate the efficacy and safety of very low dose factor prophylaxis in India. METHODS: Children of 1-10 years of age with severe haemophilia were randomized to Prophylaxis group and Episodic (On demand) group. Children in prophylaxis group received very low-dose factor VIII (FVIII) concentrate, i.e. 10 units kg(-1) body weights on 2 days a week. Episodic group received factor concentrate in standard recommended doses. The study period was 11.5 months. RESULTS: In total 21 children were enrolled in this study, 11 assigned to prophylaxis and 10 to episodic group. Children on prophylaxis had 11 joint bleeds in comparison to 57 joint bleeds in episodic group. Mean number of haemarthrosis per patient per month were 0.08 (0.08 +/- 0.13) in prophylaxis group compared to 0.48 (0.48 +/- 0.34) in episodic group (P < 0.05). Total FVIII consumption was 87.51 and 56.32 units kg(-1) month(-1) in prophylaxis and episodic group respectively (P = ns). Overall median hospital emergency visits were 1 day in prophylaxis group and 9 days in episodic group (P <= 0.05). Median days of absenteeism from school were 25 days in episodic group and 3 days in prophylaxis group (P < 0.05). No significant complications were noted in prophylaxis group and compliance was 98%. CONCLUSION: To conclude, low-dose FVIII prophylaxis is cost effective, efficacious and a safe method of preventing joint bleeds and consequent joint damages. PMID- 26987936 TI - The humanitarian common logistic operating picture: a solution to the inter agency coordination challenge. AB - Although significant progress has been made in developing the practice of humanitarian logistics, further improvements in efficiency and effectiveness have the potential to save lives and reduce suffering. This paper explores how the military/emergency services' concept of a common operating picture (COP) can be adapted to the humanitarian logistics context, and analyses a practical and proven approach to addressing the key challenge of inter-agency coordination and decision-making. Successful adaptation could provide the mechanism through which predicted and actual demands, together with the location and status of material in transit, are captured, evaluated, and presented in real time as the basis for enhanced decision-making between actors in the humanitarian supply network. Through the introduction of a humanitarian logistics COP and its linkages to national disaster management systems, local communities and countries affected by disasters and emergencies will be better placed to oversee and manage their response activities. PMID- 26987934 TI - Does the meld system provide equal access to liver transplantation for patients with different ABO blood groups? AB - This study investigates the relationship between blood group and waiting time until transplantation or death on the waiting list. All patients listed for liver transplantation in the Netherlands between 15 December 2006 and 31 December 2012, were included. Study variables were gender, age, year of listing, diagnosis, previous transplantations, blood group, urgency, and MELD score. Using a competing risks analysis, separate cumulative incidence curves were constructed for death on the waiting list and transplantation and used to evaluate outcomes.In 517 listings, the mean death rate per 100 patient-years was 10.4. A total of 375 (72.5% of all listings) were transplanted. Of all transplantations, 352 (93.9%) were ABO-identical and 23 (6.1%) ABO-compatible. The 5-year cumulative incidence of death was 11.2% (SE 1.4%), and of transplantation 72.5% (SE 2.0%). Patient blood group had no multivariate significant impact on the hazard of dying on the waiting list nor on transplantation. Age, MELD score, and urgency status were significantly related to the death on the waiting list and transplantation. More recent listing had higher probability of being transplanted. In the MELD era, patient blood group status does not have a significant impact on liver transplant waiting list mortality nor on waiting time for transplantation. PMID- 26987937 TI - Strain-induced magnetic domain wall control by voltage in hybrid piezoelectric BaTiO3 ferrimagnetic TbFe structures. AB - This paper reports on the voltage dependence of the magnetization reversal of a thin amorphous ferromagnetic TbFe film grown on a ferroelectric and piezoelectric BaTiO3 single crystal. Magneto-optical measurements, at macroscopic scale or in a microscope, demonstrate how the ferroelectric BaTiO3 polarisation history influences the properties of the perpendicularly magnetized TbFe film. Unpolarised and twinned regions are obtained when the sample is zero voltage cooled whereas flat and saturated regions are obtained when the sample is voltage cooled through the ferroelectric ordering temperature of the BaTiO3 crystal, as supported by atomic force microscopy experiments. The two steps involved in the TbFe magnetization reversal, namely nucleation and propagation of magnetic domain walls, depend on the polarisation history. Nucleation is associated to coupling through strains with the piezoelectric BaTiO3 crystal and propagation to pinning with the ferroelastic surface patterns visible in the BaTiO3 topography. PMID- 26987938 TI - Comparison of treatment effectiveness and medical costs for different long-acting injectable antipsychotics in patients with schizophrenia in Taiwan: A nationwide population-based cohort study. AB - OBJECTIVE: To assess the comparative effectiveness and medical costs of five long acting injectable (LAI) antipsychotics, flupentixol, fluphenazine, haloperidol, risperidone, and clopentixol/zuclopentixol, in patients with schizophrenia. METHOD: We conducted a retrospective cohort study of patients with schizophrenia using data from Taiwan's National Health Insurance Research Database. Patients aged 15years or older who began treatment with LAI antipsychotics between June 1, 2004 and December 31, 2008 were enrolled and followed for 1year. We evaluated the medical costs and treatment effectiveness, which was assessed using the rates of treatment discontinuation, psychiatric hospitalization, and emergency department visits. Risperidone was used as a reference group. RESULTS: Compared to risperidone, flupentixol was associated with higher hazard ratios of treatment discontinuation and psychiatric hospitalization, fluphenazine was associated with higher hazard ratios of treatment discontinuation, and haloperidol was associated with higher rates of psychiatric hospitalization and emergence department visits. However, fluphenazine, flupentixol, and haloperidol were associated with lower medical costs compared to risperidone. Clopentixol/zuclopentixol was inferior to risperidone in treatment effectiveness and medical cost. CONCLUSIONS: Our findings suggest that patients taking the LAI risperidone may be more effective in some but not all outcome measures; however, risperidone was also associated with higher medical costs in the Taiwanese healthcare setting. PMID- 26987940 TI - Role of thioredoxin-1 in ischemic preconditioning, postconditioning and aged ischemic hearts. AB - Thioredoxin is one of the most important cellular antioxidant systems known to date, and is responsible of maintaining the reduced state of the intracellular space. Trx-1 is a small cytosolic protein whose transcription is induced by stress. Therefore it is possible that this antioxidant plays a protective role against the oxidative stress caused by an increase of reactive oxygen species concentration, as occurs during the reperfusion after an ischemic episode. However, in addition to its antioxidant properties, it is able to activate other cytoplasmic and nuclear mediators that confer cardioprotection. It is remarkable that Trx-1 also participates in myocardial protection mechanisms such as ischemic preconditioning and postconditioning, activating proteins related to cellular survival. In this sense, it has been shown that Trx-1 inhibition abolished the preconditioning cardioprotective effect, evidenced through apoptosis and infarct size. Furthermore, ischemic postconditioning preserves Trx-1 content at reperfusion, after ischemia. However, comorbidities such as aging can modify this powerful cellular defense leading to decrease cardioprotection. Even ischemic preconditioning and postconditioning protocols performed in aged animal models failed to decrease infarct size. Therefore, the lack of success of antioxidants therapies to treat ischemic heart disease could be solved, at least in part, avoiding the damage of Trx system. PMID- 26987939 TI - Geographic Variations of Colorectal and Breast Cancer Late-Stage Diagnosis and the Effects of Neighborhood-Level Factors. AB - PURPOSE: The purpose of this study was to examine the geographic variations of late-stage diagnosis in colorectal cancer (CRC) and breast cancer as well as to investigate the effects of 3 neighborhood-level factors-socioeconomic deprivation, urban/rural residence, and spatial accessibility to health care-on the late-stage risks. METHODS: This study used population-based South Dakota cancer registry data from 2001 to 2012. A total of 4,878 CRC cases and 6,418 breast cancer cases were included in the analyses. Two-level logistic regression models were used to analyze the risk of late-stage CRC and breast cancer. FINDINGS: For CRC, there was a small geographic variation across census tracts in late-stage diagnosis, and residing in isolated small rural areas was significantly associated with late-stage risk. However, this association became nonsignificant after adjusting for census-tract level socioeconomic deprivation. Socioeconomic deprivation was an independent predictor of CRC late-stage risk, and it explained the elevated risk among American Indians. No relationship was found between spatial accessibility and CRC late-stage risk. For breast cancer, no geographic variation in the late-stage diagnosis was observed across census tracts, and none of the 3 neighborhood-level factors was significantly associated with late-stage risk. CONCLUSIONS: Results suggested that socioeconomic deprivation, rather than spatial accessibility, contributed to CRC late-stage risks in South Dakota as a rural state. CRC intervention programs could be developed to target isolated small rural areas, socioeconomically disadvantaged areas, as well as American Indians residing in these areas. PMID- 26987941 TI - The reduction of oxidative stress by nanocomposite Fullerol decreases mucositis severity and reverts leukopenia induced by Irinotecan. AB - Irinotecan is a useful chemotherapeutic agent for the treatment of several solid tumors. However, this therapy is associated with side effects, including leukopenia and mucositis. Reactive oxygen species (ROS) activate inflammatory pathways and contribute to Irinotecan-induced mucositis. Fullerol is a nanocomposite with anti-oxidant properties that may reduce tissue damage after inflammatory stimuli. In this paper, the effects of Fullerol and mechanisms of protection were investigated in a model of Irinotecan-induced mucositis. Mucositis was induced by an injection of Irinotecan per 4 days in C57BL/6. Fullerol or a vehicle was injected every 12h. On day 7, the intestines were removed to evaluate histological changes, leukocyte influx, and the production of cytokines and ROS. Irinotecan therapy resulted in weight loss, an increased clinical score and intestinal injury. Treatment with Fullerol attenuated weight loss, decreased clinical score and intestinal damage. Irinotecan also induced increased ROS production in enterocytes, oxidative stress, IL-1beta production, neutrophil and eosinophil influx in the ileum. Fullerol treatment decreased production of ROS in the enterocytes, oxidative stress, IL-1beta production, neutrophil and eosinophil influx in the ileum. Irinotecan therapy also induced leukopenia in an ROS-dependent manner because leukopenia reverted in WT mice treated with Fullerol or Apocynin or in Gp91phox(-/-) mice. Mice treated with Irinotecan presented less melanoma tumor growth compared to the control group. Fullerol does not interfere in the anti-tumor action of Irinotecan. Fullerol has a great pharmacology potential to decreases the severity of mucositis and of leukopenia during chemotherapy treatment. PMID- 26987943 TI - The prognostic value of a classification system for centrally located liver tumors in the setting of hepatocellular carcinoma after mesohepatectomy. AB - BACKGROUND: A classification system of centrally located liver tumors (CLLTs) was proposed by our group in 2013, which divided CLLTs into four subtypes by focusing on the involvement of resected segments and the anatomical location of lesions relative to the principal hepatic vascular structures. The current study aimed to analyze the clinical characteristics and compare the surgical outcomes of the different CLLTs classification system for patients with hepatocelluar carcinoma (HCC) underwent mesohepatectomy (MH). Moreover, we sought to validate the prognostic value of the new classification system. METHODS: Data from 353 consecutive patients with centrally located HCC who were treated with MH between 2005 and 2013 were prospectively collected and retrospectively reviewed. RESULTS: The 1-, 3-, and 5-y overall recurrence rates were 21.4%, 41.3%, and 55.6%, respectively. The 1-, 3-, and 5-y overall (OS) and corresponding recurrence-free survival rates (RFS) were 82.5%, 61.6%, 40.2%, and 68.8%, 42.5%, 30.7%, respectively. According the CLLTs classification system, 106 patients were classified as type I, 68 as type II, 94 as type III and 85 as type IV. There were no significant differences in RFS rate among the CLLTs groups, however, a significant decrease in OS rates was observed in the type IV classification, respectively. Multivariate analysis reveal that patients with microvascular invasion, portal vein thrombosis, the largest tumor size>=5 cm, tumor number>=3, liver cirrhosis, hepatic inflow occlusion >=60 min, intraoperative blood loss>=1500 ml, pTNM staging and CLLTs classification of Type IV to be independent adverse factors for long-term survivals. CONCLUSION: The classification system of CLLTs is meant to help clinicians in defining the extent of resection, providing a risk assessment and predicting prognosis. However, it is need to be validated in more HCC patients and medical centers. PMID- 26987944 TI - Absence of IDH mutation in colorectal cancers with microsatellite instability. AB - BACKGROUND: Colorectal cancers (CRCs) with deficient DNA mismatch repair system (dMMR) represents approximately 12% of all CRCs. Sporadic dMMR CRCs are due to hypermethylation MLH1 gene promoter and associated with the CpG island methylator phenotype (CIMP). Isocitrate dehydrogenase (IDH) mutant tumors are associated with DNA hypermethylation in various cancers. AIMS: Look if dMMR CRC are associated with IDH mutations. METHODS: All consecutive dMMR CRCs between 2005 and 2014 were included in this study. Tumoral DNA used for dMMR analysis was also used to determine IDH1 and IDH2 mutations using pyrosequencing method. RESULTS: A total of 152 dMMR CRCs patients were analyzed. No IDH mutation was observed in dMMR CRC, nor in IDH1 or IDH2. Especially, no mutation was found in sporadic dMMR CRC which is known to be associated with CIMP. CONCLUSIONS: In contrast with others types of hypermethylated tumors, dMMR CRCs are not associated with IDH mutations. PMID- 26987942 TI - Targeting mutant NRAS signaling pathways in melanoma. AB - Cutaneous melanoma is a devastating form of skin cancer and its incidence is increasing faster than any other preventable cancer in the United States. The mutant NRAS subset of melanoma is more aggressive and associated with poorer outcomes compared to non-NRAS mutant melanoma. The aggressive nature and complex molecular signaling conferred by this transformation has evaded clinically effective treatment options. This review examines the major downstream effectors of NRAS relevant in melanoma and the associated advances made in targeted therapies that focus on these effector pathways. We outline the history of MEK inhibition in mutant NRAS melanoma and recent advances with newer MEK inhibitors. Since MEK inhibitors will likely be optimized when combined with other targeted therapies, we focus on recently identified targets that can be used in combination with MEK inhibitors. PMID- 26987945 TI - Venous infarction mimicking a neoplasm in spontaneous intracranial hypotension: an unusual cause of Parinaud's syndrome. AB - We present a case of longstanding, undiagnosed spontaneous intracranial hypotension (SIH) with an acute presentation of Parinaud's syndrome, in whom serial imaging demonstrated development of a midbrain mass. The patient was ultimately diagnosed with tumefactive venous infarction secondary to SIH. However, this patient underwent a brainstem biopsy, which in retrospect may have been avoidable. This case demonstrates the imaging features of tumefactive venous infarction in SIH and highlights the risk of misinterpretation as a neoplasm with potentially catastrophic consequences. PMID- 26987946 TI - Association of current phthalate exposure with neurobehavioral development in a national sample. AB - BACKGROUND: Previous studies have indicated that phthalate exposure may influence the development of children, but the current data are limited, and controversy remains regarding the sex-specific and age-specific effects of phthalate exposure. METHODS: We investigated the sex- and age-specific associations of current phthalate exposure with neurobehavioral development scores in a nationally representative sample of 6-18-year-olds participating in the Korean Environmental Health Survey in Children and Adolescents (KorEHS-C). Neurobehavioral development was assessed using the Korean Child Behavior Checklist (CBCL, N=1723) and the Korean Attention Deficit Hyperactivity Disorder Rating Scale (ARS, N=867). We measured the concentrations of phthalate metabolites in urine samples using high-performance liquid chromatography tandem mass spectrometry. The associations between urine phthalate metabolite concentrations and neurobehavioral development were examined by survey regression analysis for complex sampling and penalized regression splines using a generalized additive model. RESULTS: Survey regression analysis revealed that a higher mono-n-butyl phthalate (MnBP) level was associated with social (beta=0.60; 95% confidence interval=0.15-1.05), thought (0.55; 0.08-1.03), and attention (0.68; 0.21-1.14) problems on the CBCL. A significant association was found between the MnBP level and the ARS hyperactivity subscale score (0.42; 0.05 0.58). Higher levels of MnBP (0.87; 0.20-1.54), mono-2-ethyl-5-oxohexyl phthalate (MEOHP, 0.61; 0.11-1.11) and mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP, 0.51; 0.04-0.97) were associated with an increase in thought problems among the girls. Among the younger children aged 6-11 years, significant positive associations between the MnBP (0.71; 0.09-1.33), MECPP (0.74, 0.14-1.34), MEOHP (0.65; 0.10 1.20), and MEHHP (0.71; 0.21-1.21) levels and social problems and between the MnBP (1.11; 0.37-1.84), MEOHP (0.64; 0.13-1.15), and MEHHP (0.66; 0.18-1.14) levels and attention problems were observed. The penalized regression splines for the age-specific relationships between the urinary MnBP, MEOHP, and MEHHP levels and social and attention problems exhibited positive supralinear relationships with downward curvature in the 6-11 year age group. In contrast, the score for social problems exhibited nearly linear relationships with these levels in the 12 18 year age group. CONCLUSIONS: In this national sample, increased phthalate exposure exhibited supralinear associations with social, thought and attention problems in children aged 6-11 years, who showed greater vulnerability to phthalate exposure. The results highlight the need for the environmental regulation of phthalate exposure in younger children, even at low dosages. PMID- 26987948 TI - Rapid-Onset Sildenafil Sublingual Drug Delivery Systems: In Vitro Evaluation and In Vivo Pharmacokinetic Studies in Rabbits. AB - The aim of the present study was to prepare sublingual delivery systems for sildenafil and evaluate its relative bioavailability after sublingual administration in rabbits to attain a rapid onset of action with good efficacy at lower doses. For sublingual application, sildenafil and its citrate were formulated in 2 different dosage forms: the first was a sublingual spray consisting of sildenafil in 2 microemulsion systems, oleic acid or propylene glycol (PG), and the second was sublingual tablets prepared with various granulated sublingual sprays adsorbed onto a silicate adsorbant (Florite((r)) R), binders (Cyclocel((r)) or EMDEX((r))), and disintegrants (Ac-Di-Sol((r)) or Kollidon((r)) CL). Results showed that sublingual absorption of sildenafil spray prepared with PG was fairly rapid. At a 0.5-mg dose, the mean onset of action was 1.3 +/- 0.6 min and lasted for about 1.5 h according to the pharmacokinetic studies. In vivo studies also showed that for sublingual tablets formulated with sildenafil in PG adsorbed onto Florite((r)) R at a 1:1 weight ratio then mixed with Cycloel((r)) and Ac-Di-Sol((r)), the onset action was fast at 1.9 +/- 0.4 min and lasted for about 1 h at 0.5 mg. These findings suggest the potential for the sublingual delivery of sildenafil instead of the conventional oral administration. PMID- 26987949 TI - Exploratory Investigation of the Limiting Steps of Oral Absorption of Fluconazole and Ketoconazole in Children Using an In Silico Pediatric Absorption Model. AB - Due to the higher total clearance of certain drugs in children than in adults, it is recommended that, in such cases, higher relative doses on a milligram/kilogram basis should be administered to children in order to achieve similar systemic exposure to adults. This is the case for fluconazole and ketoconazole. Even though the lower absorptive surface area and smaller volumes of intestinal fluids in children does not affect fluconazole absorption, cumulative fraction absorbed of ketoconazole seems to be dose dependent. A dose of 200 mg of ketoconazole, which belongs to the class 2a of the Developability Classification System (DCS) in adults, seems to be higher than the maximum absorbable dose in children, and ketoconazole absorption is expected to be solubility limited (i.e., DCS class 2b) in this population, indicating a DCS class migration. Therefore, extrapolating DCS and DCS drug classification from adults to pediatric groups does not seem to be straightforward and the development of specific pediatric classification systems should be a high priority. PMID- 26987947 TI - Novel Ricin Subunit Antigens With Enhanced Capacity to Elicit Toxin-Neutralizing Antibody Responses in Mice. AB - RiVax is a candidate ricin toxin subunit vaccine antigen that has proven to be safe in human phase I clinical trials. In this study, we introduced double and triple cavity-filling point mutations into the RiVax antigen with the expectation that stability-enhancing modifications would have a beneficial effect on overall immunogenicity of the recombinant proteins. We demonstrate that 2 RiVax triple mutant derivatives, RB (V81L/C171L/V204I) and RC (V81I/C171L/V204I), when adsorbed to aluminum salts adjuvant and tested in a mouse prime-boost-boost regimen were 5- to 10-fold more effective than RiVax at eliciting toxin neutralizing serum IgG antibody titers. Increased toxin neutralizing antibody values and seroconversion rates were evident at different antigen dosages and within 7 days after the first booster. Quantitative stability/flexibility relationships analysis revealed that the RB and RC mutations affect rigidification of regions spanning residues 98-103, which constitutes a known immunodominant neutralizing B-cell epitope. A more detailed understanding of the immunogenic nature of RB and RC may provide insight into the fundamental relationship between local protein stability and antibody reactivity. PMID- 26987951 TI - Molecular mechanisms of protein-cholesterol interactions in plasma membranes: Functional distinction between topological (tilted) and consensus (CARC/CRAC) domains. AB - The molecular mechanisms that control the multiple possible modes of protein association with membrane cholesterol are remarkably convergent. These mechanisms, which include hydrogen bonding, CH-pi stacking and dispersion forces, are used by a wide variety of extracellular proteins (e.g. microbial or amyloid) and membrane receptors. Virus fusion peptides penetrate the membrane of host cells with a tilted orientation that is compatible with a transient interaction with cholesterol; this tilted orientation is also characteristic of the process of insertion of amyloid proteins that subsequently form oligomeric pores in the plasma membrane of brain cells. Membrane receptors that are associated with cholesterol generally display linear consensus binding motifs (CARC and CRAC) characterized by a triad of basic (Lys/Arg), aromatic (Tyr/phe) and aliphatic (Leu/Val) amino acid residues. In some cases, the presence of both CARC and CRAC within the same membrane-spanning domain allows the simultaneous binding of two cholesterol molecules, one in each membrane leaflet. In this review the molecular basis and the functional significance of the different modes of protein cholesterol interactions in plasma membranes are discussed. PMID- 26987952 TI - Implication of protein tyrosine phosphatase SHP-1 in cancer-related signaling pathways. AB - The altered expression of SHP-1 (SH2 domain-containing protein tyrosine phosphatase) as a consequence of promoter hypermethylation or mutations has evidently been linked to cancer development. The notion of being a cancer drug target is conceivable as SHP-1 negatively regulates cell cycle and inflammatory pathways which are an inevitable part of oncogenic transformation. In the present review, we try to critically analyze the role of SHP-1 in cancer progression via regulating the above mentioned pathways with the major emphasis on cell cycle components and JAK/STAT pathway, commencing with the SHP-1 biology in immune cell signaling. Lastly, we have provided the future directions for researchers to encourage SHP-1 as a prognostic marker and curative target for this debilitating disease called as cancer. PMID- 26987950 TI - AHNAK deficiency promotes browning and lipolysis in mice via increased responsiveness to beta-adrenergic signalling. AB - In adipose tissue, agonists of the beta3-adrenergic receptor (ADRB3) regulate lipolysis, lipid oxidation, and thermogenesis. The deficiency in the thermogenesis induced by neuroblast differentiation-associated protein AHNAK in white adipose tissue (WAT) of mice fed a high-fat diet suggests that AHNAK may stimulate energy expenditure via development of beige fat. Here, we report that AHNAK deficiency promoted browning and thermogenic gene expression in WAT but not in brown adipose tissue of mice stimulated with the ADRB3 agonist CL-316243. Consistent with the increased thermogenesis, Ahnak(-/-) mice exhibited an increase in energy expenditure, accompanied by elevated mitochondrial biogenesis in WAT depots in response to CL-316243. Additionally, AHNAK-deficient WAT contained more eosinophils and higher levels of type 2 cytokines (IL-4/IL-13) to promote browning of WAT in response to CL-316243. This was associated with enhanced sympathetic tone in the WAT via upregulation of adrb3 and tyrosine hydroxylase (TH) in response to beta-adrenergic activation. CL-316243 activated PKA signalling and enhanced lipolysis, as evidenced by increased phosphorylation of hormone-sensitive lipase and release of free glycerol in Ahnak(-/-) mice compared to wild-type mice. Overall, these findings suggest an important role of AHNAK in the regulation of thermogenesis and lipolysis in WAT via beta-adrenergic signalling. PMID- 26987953 TI - Gastrodin suppresses BACE1 expression under oxidative stress condition via inhibition of the PKR/eIF2alpha pathway in Alzheimer's disease. AB - The expression of beta-site APP-cleaving enzyme 1 (BACE1) is increased in the brain of late-onset sporadic Alzheimer's disease (AD) and oxidative stress may be the potential cause of this event. The phenolic glucoside gastrodin (Gas), a main component of a Chinese herbal medicine Gastrodia elata Blume, has been demonstrated to display antioxidant activity and suppresses BACE1 expression. However, the mechanisms by which Gas suppresses BACE1 expression are not clear. Morris water maze test was performed to assess the effect of Gas treatment on memory impairments in Tg2576 mice. The level of oxidative stress in the brain of Tg2576 mice was determined by measuring the superoxide dismutase (SOD) activity, catalase (CAT) activity, and the levels of malondialdehyde (MDA) and ROS. In vivo and in vitro, we detected the expression levels of BACE1, pPKRThr446, PKR, pPERKThr981, PERK, peIF2alphaSer51, and eIF2alpha using western blot analysis. We found that Gas improved learning and memory abilities of Tg2576 transgenic mice and attenuated intracellular oxidative stress in hippocampi of Tg2576 mice. We discovered that the expression levels of BACE1, activated PKR (pPKRThr446) and activated eIF2alpha (peIF2alphaSer51) were elevated in the brains of Tg2576 mice and hydrogen peroxide (H2O2)-stimulated SH-SY5Y cells. Moreover, peptide PKR inhibitor (PRI) and Gas down-regulated BACE1 expression in Tg2576 mice and H2O2 stimulated SH-SY5Y cells by inhibiting activation of PKR and eIF2alpha. Gas alleviates memory deficits in mice and suppresses BACE1 expression by inhibiting the protein kinase/Eukaryotic initiation factor-2alpha (PKR/eIF2alpha) pathway. The research suggested that Gas may develop as an drug candidate in neurodegenerative diseases. PMID- 26987954 TI - Brain-derived neurotrophic factor signaling is altered in the forebrain of Engrailed-2 knockout mice. AB - Engrailed-2 (En2), a homeodomain transcription factor involved in regionalization and patterning of the midbrain and hindbrain regions has been associated to autism spectrum disorders (ASDs). En2 knockout (En2(-/-)) mice show ASD-like features accompanied by a significant loss of GABAergic subpopulations in the hippocampus and neocortex. Brain-derived neurotrophic factor (BDNF) is a crucial factor for the postnatal development of forebrain GABAergic neurons, and altered GABA signaling has been hypothesized to underlie the symptoms of ASD. Here we sought to determine whether interneuron loss in the En2(-/-) forebrain might be related to altered expression of BDNF and its signaling receptors. We first evaluated the expression of different BDNF mRNA isoforms in the neocortex and hippocampus of wild-type (WT) and En2(-/-) mice. Quantitative RT-PCR showed a marked down-regulation of several splicing variants of BDNF mRNA in the neocortex but not hippocampus of adult En2(-/-) mice, as compared to WT controls. Accordingly, levels of mature BDNF protein were lower in the neocortex but not hippocampus of En2(-/-) mice, as compared to WT. Increased levels of phosphorylated TrkB and decreased levels of p75 receptor were also detected in the neocortex of mutant mice. Accordingly, the expression of low density lipoprotein receptor (LDLR) and RhoA, two genes regulated via p75 was significantly altered in forebrain areas of mutant mice. These data indicate that BDNF signaling alterations might be involved in the anatomical changes observed in the En2(-/-) forebrain and suggest a pathogenic role of altered BDNF signaling in this mouse model of ASD. PMID- 26987955 TI - Nonlinear interactions in the thalamocortical loop in essential tremor: A model based frequency domain analysis. AB - There is increasing evidence to suggest that essential tremor has a central origin. Different structures appear to be part of the central tremorogenic network, including the motor cortex, the thalamus and the cerebellum. Some studies using electroencephalogram (EEG) and magnetoencephalography (MEG) show linear association in the tremor frequency between the motor cortex and the contralateral tremor electromyography (EMG). Additionally, high thalamomuscular coherence is found with the use of thalamic local field potential (LFP) recordings and tremulous EMG in patients undergoing surgery for deep brain stimulation (DBS). Despite a well-established reciprocal anatomical connection between the thalamus and cortex, the functional association between the two structures during "tremor-on" periods remains elusive. Thalamic (Vim) LFPs, ipsilateral scalp EEG from the sensorimotor cortex and contralateral tremor arm EMG recordings were obtained from two patients with essential tremor who had undergone successful surgery for DBS. Coherence analysis shows a strong linear association between thalamic LFPs and contralateral tremor EMG, but the relationship between the EEG and the thalamus is much less clear. These measurements were then analyzed by constructing a novel parametric nonlinear autoregressive with exogenous input (NARX) model. This new approach uncovered two distinct and not overlapping frequency "channels" of communication between Vim thalamus and the ipsilateral motor cortex, defining robustly "tremor-on" versus "tremor-off" states. The associated estimated nonlinear time lags also showed non overlapping values between the two states, with longer corticothalamic lags (exceeding 50ms) in the tremor active state, suggesting involvement of an indirect multisynaptic loop. The results reveal the importance of the nonlinear interactions between cortical and subcortical areas in the central motor network of essential tremor. This work is important because it demonstrates for the first time that in essential tremor the functional interrelationships between the cortex and thalamus should not be sought exclusively within individual frequencies but more importantly between cross-frequency nonlinear interactions. Should our results be successfully reproduced on a bigger cohort of patients with essential tremor, our approach could be used to create an on-demand closed-loop DBS device, able to automatically activate when the tremor is on. PMID- 26987956 TI - Revisiting the supratrigeminal nucleus in the rat. AB - The supratrigeminal nucleus (Vsup), originally proposed as a premotoneuron pool in the trigeminal reflex arc, is a key structure of jaw movement control. Surprisingly, however, the location of the rat Vsup has not precisely been defined. In light of our previous cat studies, we made two hypotheses regarding the rat Vsup: (1) the Vsup is cytoarchitectonically distinguishable from its surrounding structures; (2) the Vsup receives central axon terminals of the trigeminal mesencephalic nucleus (Vmes) neurons which are primary afferents innervating muscle spindles of jaw-closing muscles and periodontal ligaments around the teeth. To test the first hypothesis, we examined the cytoarchitecture of the rat Vsup. The Vsup was identified as an area medially adjacent to the dorsomedial part of trigeminal principal sensory nucleus (Vp), and extended from the level just rostral to the caudal two-thirds of the trigeminal motor nucleus (Vmo) to the level approximately 150 MUm caudal to the Vmo. Our rat Vsup was much smaller and its location was considerably different in comparison to the Vsup reported previously. To evaluate the second hypothesis, we tested the distribution patterns of Vmes primary afferent terminals in the cytoarchitectonically identified Vsup. After transganglionic tracer applications to the masseter, deep temporal, and medial pterygoid nerves, a large number of axon terminals were observed in all parts of Vsup (especially in its medial part). After applications to the inferior alveolar, infraorbital, and lingual nerves, a small number of axon terminals were labeled in the caudolateral Vsup. The Vsup could also be identified electrophysiologically. After electrical stimulation of the masseter nerve, evoked potentials with slow negative component were isolated only in the Vsup. The present findings suggest that the rat Vsup can be cytoarchitectonically and electrophysiologically identified, receives somatotopic termination of the trigeminal primary afferents, and principally receives strong termination of the spindle Vmes primary afferents. PMID- 26987957 TI - 17beta-Estradiol upregulates ecto-5'-nucleotidase (CD73) in hippocampal synaptosomes of female rats through action mediated by estrogen receptor-alpha and -beta. AB - 17beta-Estradiol (E2) crucially affects several processes in the hippocampus of both sexes. E2 acts upon estradiol receptors ERalpha and ERbeta, influencing target gene expression and/or modulates intracellular signaling cascades. Another potent modulator of hippocampal function is nucleoside adenosine, the final product of ectonucleotidase cascade, enzymes which hydrolyze extracellular ATP to adenosine. The last and rate-limiting step of the hydrolysis is catalyzed by membrane-bound ecto-5'-nucleotidase (eN). Previous findings obtained on adenosine metabolism in brain suggest that eN may be modulated by ovarian steroids. Therefore, the present study reports that the activity and protein abundance of membrane-bound eN fluctuates across the estrus cycle in the hippocampal synaptosomes of female rats. Further, we analyzed the role of E2 and its intracellular receptors on the expression of eN in ovariectomized females. We found that E2 upregulated eN activity and protein abundance in the hippocampal synaptosomes. Application of nonspecific ER antagonist, ICI 182,780 and selective ERalpha and ERbeta agonists, PPT and DPN, respectively, demonstrated the involvement of both receptor subtypes in observed actions. Selective ERalpha receptor agonist, PPT, induced upregulation of both the protein level and activity of eN, while application of selective ERbeta receptor agonist, DPN, increased only the activity of eN. In both cases, E2 entered into the intracellular compartment and activated ER(s), which was demonstrated by membrane impermeable E2-BSA conjugate. Together these results imply that E2-induced effects on connectivity and functional properties of the hippocampal synapses may be in part mediated through observed effect on eN. PMID- 26987958 TI - Antidepressant use and mortality in very old people. AB - BACKGROUND: Antidepressant treatment may increase the risk of death. The association between antidepressants and mortality has been evaluated in community dwelling older people, but not in representative samples of very old people, among whom dementia, multimorbidity, and disability are common. METHODS: Umea 85+/GERDA study participants (n = 992) aged 85, 90, and >=95 years were followed for up to five years. Cox proportional hazard regression models were used to analyze mortality risk associated with baseline antidepressant treatment, adjusted for potential confounders. RESULTS: Mean age was 89 years; 27% of participants had dementia, 20% had stroke histories, 29% had heart failure, and 16% used antidepressants. In age- and sex-adjusted analyses, antidepressant use was associated with a 76% increased mortality risk (hazard ratio [HR] = 1.76; 95% confidence interval [CI], 1.41-2.19). Adding adjustment for Geriatric Depression Scale score, HR was 1.62 (95% CI, 1.29-2.03). The association was not significant when adjusting for additional confounding factors (HR = 1.08; 95% CI, 0.85-1.38). Interaction analyses in the fully adjusted model revealed a significant interaction between sex and antidepressant use (HR: 1.76; 95% CI, 1.05-2.94). Among male and female antidepressant users, the HRs for death were 0.76 (95% CI, 0.47-1.24) and 1.28 (95% CI, 0.97-1.70), respectively. CONCLUSION: Among very old people, baseline antidepressant treatment does not seem to be independently associated with increased mortality risk. However, the risk may be different in men and women. This difference and the potential risk of initial treatment require further investigation in future cohort studies of very old people. PMID- 26987959 TI - Regulation of tracheal antimicrobial peptide gene expression in airway epithelial cells of cattle. AB - beta-defensins are an important element of the mucosal innate immune response against bacterial pathogens. Tracheal antimicrobial peptide (TAP) has microbicidal activity against the bacteria that cause bovine respiratory disease, and its expression in tracheal epithelial cells is upregulated by bacterial products including lipopolysaccharide (LPS, a TLR4 agonist), Pam3CSK4 (an agonist of Toll-like receptor 2/1), and interleukin (IL)-17A. The objectives of this study were to identify the signalling pathway by which LPS, Pam3CSK4 and IL-17A induce TAP gene expression, and to determine the effect of glucocorticoid as a model of stress on this epithelial innate immune response. In primary cultures of bovine tracheal epithelial cells (bTEC), LPS, Pam3CSK4 and IL-17A each stimulated TAP gene expression. This effect was abrogated by caffeic acid phenylester (CAPE), an inhibitor of NF-kappaB. Similarly, western analysis showed that LPS, Pam3CSK4 and IL-17A each induced translocation of NF-kappaB p65 from the cytoplasm to the nucleus, but pre-treatment with CAPE inhibited this response. Finally, pre-treatment of bTEC with the glucocorticoid dexamethasone abolished the stimulatory effect of LPS, Pam3CSK4 and IL-17A on upregulation of TAP gene expression. These findings indicate that NF-kappaB activation is necessary for induction of TAP gene expression by LPS (a TLR4 agonist), Pam3CSK4 (a TLR2/1 agonist), or IL-17A. Furthermore, this stimulatory response is inhibited by glucocorticoid, suggesting this as one mechanism by which stress increases the risk of bacterial pneumonia. These findings have implications for understanding the pathogenesis of stress-associated bacterial pneumonia, and for developing methods to stimulate innate immune responses in the respiratory tract of cattle. PMID- 26987960 TI - The impact of the web and social networks on vaccination. New challenges and opportunities offered to fight against vaccine hesitancy. AB - OBJECTIVE: Vaccine hesitancy is a growing and threatening trend, increasing the risk of disease outbreaks and potentially defeating health authorities' strategies. We aimed to describe the significant role of social networks and the Internet on vaccine hesitancy, and more generally on vaccine attitudes and behaviors. METHODS: Presentation and discussion of lessons learnt from: (i) the monitoring and analysis of web and social network contents on vaccination; (ii) the tracking of Google search terms used by web users; (iii) the analysis of Google search suggestions related to vaccination; (iv) results from the Vaccinoscopie((c)) study, online annual surveys of representative samples of 6500 to 10,000 French mothers, monitoring vaccine behaviors and attitude of French parents as well as vaccination coverage of their children, since 2008; and (v) various studies published in the scientific literature. RESULTS: Social networks and the web play a major role in disseminating information about vaccination. They have modified the vaccination decision-making process and, more generally, the doctor/patient relationship. The Internet may fuel controversial issues related to vaccination and durably impact public opinion, but it may also provide new tools to fight against vaccine hesitancy. CONCLUSION: Vaccine hesitancy should be fought on the Internet battlefield, and for this purpose, communication strategies should take into account new threats and opportunities offered by the web and social networks. PMID- 26987961 TI - [Histopathological diagnostic work-up of joint endoprosthesis-associated pathologies]. AB - Increasing classes of joint implants and the combination of materials results in increased and wear-associated pathologies. According to the revised consensus classification, the following types can be recognized at conventional histological examination: Type I, particle-induced type; Type II, infection type; Type III, combination type; Type IV, indifferent type; Type V arthrofibrotic type; Type VI, allergic/immunological/toxic adverse reactions and Type VII, bone pathologies. Wear particles are histopathologically characterized according to the Krenn particle algorithm which focuses on a descriptive identification of wear particles and the differentiation of other nonwear-related particles. Type VII is considered histologically when there is evidence of a perivascular/interstitial lymphocytic CD20- and CD3-positive infiltrate, presence of mast cells and eosinophils, and tissue necrosis/infarction associated with implant wear material. Since wear particle-induced toxicity cannot be differentiated with certainty from hypersensitivity/allergic reaction on histological examination, immunological-allergological and clinical data should be used as supplementary criteria for the differential diagnosis. Tissue sampling should be performed from periprosthetic soft tissue with location mapping and when feasible also from bone tissue. Additional information regarding the type of implant and clinical, radiological, immunological, and microbiology data should be available to the pathologist. Further immunohistochemical studies are recommended in the following settings: infection (CD15, CD20, CD68); prosthesis associated arthrofibrosis (beta-catenin); allergic/immunologic/toxic adverse reactions (CD20, CD3, CD4, CD8, CD117 and for T-cell characterization T-bet, GATA 3, and FOXP3). PMID- 26987962 TI - Spatial assessment of soil contamination by heavy metals from informal electronic waste recycling in Agbogbloshie, Ghana. AB - OBJECTIVES: This study examined the spatial distribution and the extent of soil contamination by heavy metals resulting from primitive, unconventional informal electronic waste recycling in the Agbogbloshie e-waste processing site (AEPS) in Ghana. METHODS: A total of 132 samples were collected at 100 m intervals, with a handheld global position system used in taking the location data of the soil sample points. Observing all procedural and quality assurance measures, the samples were analyzed for barium (Ba), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), mercury (Hg), nickel (Ni), lead (Pb), and zinc (Zn), using X-ray fluorescence. Using environmental risk indices of contamination factor and degree of contamination (Cdeg), we analyzed the individual contribution of each heavy metal contamination and the overall Cdeg. We further used geostatistical techniques of spatial autocorrelation and variability to examine spatial distribution and extent of heavy metal contamination. RESULTS: Results from soil analysis showed that heavy metal concentrations were significantly higher than the Canadian Environmental Protection Agency and Dutch environmental standards. In an increasing order, Pb>Cd>Hg>Cu>Zn>Cr>Co>Ba>Ni contributed significantly to the overall Cdeg. Contamination was highest in the main working areas of burning and dismantling sites, indicating the influence of recycling activities. Geostatistical analysis also revealed that heavy metal contamination spreads beyond the main working areas to residential, recreational, farming, and commercial areas. CONCLUSIONS: Our results show that the studied heavy metals are ubiquitous within AEPS and the significantly high concentration of these metals reflect the contamination factor and Cdeg, indicating soil contamination in AEPS with the nine heavy metals studied. PMID- 26987964 TI - Patterns of Treatment Switching in Multiple Sclerosis Therapies in US Patients Active on Social Media: Application of Social Media Content Analysis to Health Outcomes Research. AB - BACKGROUND: Social media analysis has rarely been applied to the study of specific questions in outcomes research. OBJECTIVE: The aim was to test the applicability of social media analysis to outcomes research using automated listening combined with filtering and analysis of data by specialists. After validation, the process was applied to the study of patterns of treatment switching in multiple sclerosis (MS). METHODS: A comprehensive listening and analysis process was developed that blended automated listening with filtering and analysis of data by life sciences-qualified analysts and physicians. The population was patients with MS from the United States. Data sources were Facebook, Twitter, blogs, and online forums. Sources were searched for mention of specific oral, injectable, and intravenous (IV) infusion treatments. The representativeness of the social media population was validated by comparison with community survey data and with data from three large US administrative claims databases: MarketScan, PharMetrics Plus, and Department of Defense. RESULTS: A total of 10,260 data points were sampled for manual review: 3025 from Twitter, 3771 from Facebook, 2773 from Internet forums, and 691 from blogs. The demographics of the social media population were similar to those reported from community surveys and claims databases. Mean age was 39 (SD 11) years and 14.56% (326/2239) of the population was older than 50 years. Women, patients aged 30 to 49 years, and those diagnosed for more than 10 years were represented by more data points than other patients were. Women also accounted for a large majority (82.6%, 819/991) of reported switches. Two-fifths of switching patients had lived with their disease for more than 10 years since diagnosis. Most reported switches (55.05%, 927/1684) were from injectable to oral drugs with switches from IV therapies to orals the second largest switch (15.38%, 259/1684). Switches to oral drugs accounted for more than 80% (927/1114) of the switches away from injectable therapies. Four reasons accounted for more than 90% of all switches: severe side effects, lack of efficacy, physicians' advice, and greater ease of use. Side effects were the main reason for switches to oral or to injectable therapies and search for greater efficacy was the most important factor in switches to IV therapies. Cost of medication was the reason for switching in less than 0.5% of patients. CONCLUSIONS: Social intelligence can be applied to outcomes research with power to analyze MS patients' personal experiences of treatments and to chart the most common reasons for switching between therapies. PMID- 26987965 TI - Massive colonic ischemia secondary to sigmoid volvulus. PMID- 26987966 TI - Abdominal Cocoon: A rare cause of intestinal obstruction. PMID- 26987963 TI - The biomechanical effect of acupuncture for poststroke cavovarus foot: study protocol for a randomized controlled pilot trial. AB - BACKGROUND: Poststroke cavovarus foot greatly affects patients' activities of daily life and raises the risks of falls and consequent fractures. Acupuncture appears to be safe and effective in promoting motor functions and enhancing the activities of daily life among patients with poststroke cavovarus foot. The current study aims to study the biomechanical effect of acupuncture for poststroke cavovarus foot with objective outcome measurements. METHODS/DESIGN: This is an assessor and analyst-blinded, randomized, controlled pilot study. A total of 60 eligible patients with poststroke cavovarus foot will be allocated by a 1:1 ratio into an acupuncture treatment group and a control group. Patients in the control group will receive conventional rehabilitation therapies, whereas a combination of acupuncture and conventional rehabilitation therapies will be applied in the acupuncture group. The primary outcome measures are three objective biomechanical parameters from the RSSCAN gait system: varus angle, dynamic plantar pressure distribution, and static plantar contact area. Scores of the Berg Balance Scale, the Fugl-Meyer Assessment, and the Stroke-Specific Quality of Life Scale, as well as other biomechanical parameters such as the step length and width, step time phase, and weight shifting phase will be selected as secondary outcome measurements. All assessments will be conducted at baseline, 4 weeks after the treatment course, and after a follow-up period of 3 months. DISCUSSION: Results of the current study will provide detailed interpretations of the biomechanical effect of acupuncture for stroke rehabilitation and foundations for future larger clinical studies. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-IPC-15006889 (8 August 2015). PMID- 26987967 TI - Gastric ulcer penetrating the liver. PMID- 26987969 TI - Single molecules as whispering galleries for electrons. AB - Whispering gallery modes, well-known for acoustic and optical waves, have been shown recently for electrons in molecules on surfaces. The existence of such waves opens new possibilities for nanoelectronic devices. Here we propose a simple analytical textbook model which allows the main characteristic features of such electronic waves to be understood. The model is illustrated by two- and three-dimensional experimental situations. PMID- 26987968 TI - Three-dimensional protein model similarity analysis based on salient shape index. AB - BACKGROUND: Proteins play a special role in bioinformatics. The surface shape of a protein, which is an important characteristic of the protein, defines a geometric and biochemical domain where the protein interacts with other proteins. The similarity analysis among protein models has become an important topic of protein analysis, by which it can reveal the structure and the function of proteins. RESULTS: In this paper, a new protein similarity analysis method based on three-dimensional protein models is proposed. It constructs a feature matrix descriptor for each protein model combined by calculating the shape index (SI) and the related salient geometric feature (SGF), and then analyzes the protein model similarity by using this feature matrix and the extended grey relation analysis. CONCLUSIONS: We compare our method to the Multi-resolution Reeb Graph (MRG) skeleton method, the L1-medial skeleton method and the local-diameter descriptor method. Experimental results show that our protein similarity analysis method is accurate and reliable while keeping the high computational efficiency. PMID- 26987970 TI - Multiplex real-time PCR for identification of canine parvovirus antigenic types. AB - Canine parvovirus (CPV) is an important disease causing gastroenteritis and/or haemorrhagic gastroenteritis in dogs. There are four antigenic types of CPV reported worldwide viz. CPV 2, CPV 2a, CPV 2b and CPV 2c. The diagnosis of CPV with the identification of the antigen type responsible remains problematic. In the present study, identification as well as antigenic typing of CPV was done using a de novo multiplex real time PCR to combat the problem of antigenic type identification. From the study it could be concluded that the here developed multiplex real time PCR assay could be used for rapid detection of CPV as well as typing of its three antigenic types. PMID- 26987972 TI - Time-dependent Dyson orbital theory. AB - Although time-dependent density functional theory (TDDFT) has become the tool of choice for real-time propagation of the electron density rho(N)(t) of N-electron systems, it also encounters problems in this application. The first problem is the neglect of memory effects stemming from the, in TDDFT virtually unavoidable, adiabatic approximation, the second problem is the reliable evaluation of the probabilities P(n)(t) of multiple photoinduced ionization, while the third problem (which TDDFT shares with other approaches) is the reliable description of continuum states of the electrons ejected in the process of ionization. In this paper time-dependent Dyson orbital theory (TDDOT) is proposed. Exact TDDOT equations of motion (EOMs) for time-dependent Dyson orbitals are derived, which are linear differential equations with just static, feasible potentials of the electron-electron interaction. No adiabatic approximation is used, which formally resolves the first TDDFT problem. TDDOT offers formally exact expressions for the complete evolution in time of the wavefunction of the outgoing electron. This leads to the correlated probability of single ionization P(1)(t) as well as the probabilities of no ionization (P(0)(t)) and multiple ionization of n electrons, P(n)(t), which formally solves the second problem of TDDFT. For two-electron systems a proper description of the required continuum states appears to be rather straightforward, and both P(1)(t) and P(2)(t) can be calculated. Because of the exact formulation, TDDOT is expected to reproduce a notorious memory effect, the "knee structure" of the non-sequential double ionization of the He atom. PMID- 26987973 TI - Crime Seasonality: Examining the Temporal Fluctuations of Property Crime in Cities With Varying Climates. AB - This study investigates whether crime patterns fluctuate periodically throughout the year using data containing different property crime types in two Canadian cities with differing climates. Using police report data, a series of ordinary least squares (OLS; Vancouver, British Columbia) and negative binomial (Ottawa, Ontario) regressions were employed to examine the corresponding temporal patterns of property crime in Vancouver (2003-2013) and Ottawa (2006-2008). Moreover, both aggregate and disaggregate models were run to examine whether different weather and temporal variables had a distinctive impact on particular offences. Overall, results suggest that cities that experience greater variations in weather throughout the year have more distinct increases of property offences in the summer months and that different climate variables affect certain crime types, thus advocating for disaggregate analysis in the future. PMID- 26987971 TI - Parameters of Instrumental Swallowing Evaluations: Describing a Diagnostic Dilemma. AB - The aim of this study was to compare selected parameters of two swallow evaluations: fiberoptic endoscopic evaluation of swallowing (FEES) and the modified barium swallow (MBS) study. This was a cross-sectional, descriptive study. Fifty-five clinicians were asked to watch video recordings of swallow evaluations of 2 patients that were done using fluoroscopy and endoscopy simultaneously. In a randomized order, clinicians viewed 4 edited videos from simultaneous evaluations: the FEES and MBS videos of patient 1 and 2 each taking one swallow of 5 mL applesauce. Clinicians filled out a questionnaire that asked (1) which anatomical sites they could visualize on each video, (2) where they saw pharyngeal residue after a swallow, (3) their overall clinical impression of the pharyngeal residue, and (4) their opinions of the evaluation styles. Clinicians reported a significant difference in the visualization of anatomical sites, 11 of the 15 sites were reported as better-visualized on the FEES than on the MBS video (p < 0.05). Clinicians also rated residue to be present in more locations on the FEES than on the MBS. Clinicians' overall impressions of the severity of residue on the same exact swallow were significantly different depending on the evaluation type (FEES vs. MBS for patient 1 chi(2) = 20.05, p < 0.0001; patient 2 chi(2) = 7.52, p = 0.006), with FEES videos rated more severely. FEES advantages were: more visualization of pharyngeal and laryngeal swallowing anatomy and residue. However, as a result, clinicians provided more severe impressions of residue amount on FEES. On one hand, this suggests that FEES is a more sensitive tool than MBS studies, but on the other hand, clinicians might provide more severe interpretations on FEES. PMID- 26987974 TI - Investigations of ion transport through nanoscale polymer membranes by fluorescence quenching of CdSe/CdS quantum dot/quantum rods. AB - Detailed steady-state and time-resolved fluorescence quenching measurements give deep insight into ion transport through nanometer thick diblock copolymer membranes, which were assembled as biocompatible shell material around CdSe/CdS quantum dot in quantum rods. We discuss the role of polymer chain length, intermolecular cross-linking and nanopore formation by analysing electron transfer processes from the photoexcited QDQRs to Cu(II) ions, which accumulate in the polymer membrane. Fluorescence investigations on single particle level additionally allow identifying ensemble inhomogeneities. PMID- 26987976 TI - Immunohistochemical detection of BRAF V600E mutation status in anaplastic thyroid carcinoma. PMID- 26987975 TI - Safety, Tolerability and Pharmacokinetics of FAAH Inhibitor V158866: A Double Blind, Randomised, Placebo-Controlled Phase I Study in Healthy Volunteers. AB - BACKGROUND AND OBJECTIVE: The inhibition of fatty acid amide hydrolase 1 (FAAH) has been proposed as a novel mechanism for treating pain syndromes by increasing the levels of endogenous cannabinoids (ECs). This study describes the safety, tolerability, pharmacokinetics and pharmacodynamics of V158866, a reversible FAAH inhibitor, after first administration to man. METHODS: 51 healthy male subjects were recruited into this double-blind, randomised, placebo-controlled, adaptive dose, phase I single (Part A) and repeated ascending dose (Part B) study. The primary outcome was the safety and tolerability of V158866. Secondary outcomes were (1) pharmacokinetics of V158866 and (2) pharmacodynamics of V158866, as assessed by changes in plasma EC concentrations. RESULTS: Single oral doses of 5 300 mg and repeated oral doses of 50-500 mg were evaluated. V158866 was well tolerated, with no apparent treatment-related effects on laboratory variables. V158866 was rapidly absorbed with a mean terminal elimination half-life of 9.6 18.3 h (Day 7; Part B). V158866 reached steady state within 2-3 days of administration, with an accumulation ratio, based on AUC0-24h, of approximately 2 on Day 7. V158866 showed a linear relationship between dose and AUC across the entire dose range. V158866 caused reversible, dose-related increases in plasma ECs. At hemi-equilibrium, there was a sigmoidal maximum effect relationship between plasma V158866 concentrations and changes in plasma ECs. CONCLUSIONS: V158866 is well tolerated, with linear pharmacokinetics suitable for once-daily administration, and reversible effects on plasma ECs. Maximum increases in plasma ECs occur with V158866 doses of 300-500 mg/day. PMID- 26987977 TI - Cruising Venues as a Context for HIV Risky Behavior Among Men Who Have Sex With Men. AB - We examined differences in sexual risk behaviors, HIV prevalence, and demographic characteristics between men who have sex with men (MSM) who visit different types of venues to meet sexual partners, and identified correlates of high-risk behaviors. A cross-sectional behavioral survey was conducted with a venue-based sample of 1011 MSM in Portugal. Overall, 36.3 % of MSM usually visit cruising venues to meet sexual partners (63.7 % only visit social gay venues). Cruising venues' visitors reported higher HIV prevalence (14.6 % [95 % CI 11-18 %] vs. 5.5 % [95 % CI 4-7 %]). Visiting cruising venues was more likely among those older, reporting high number of male sexual partners, group sex, and unprotected anal sex with a partner whose HIV status was unknown. Cruising venues play an important role in increasing risk of HIV transmission among MSM who frequent them. Venue-focused behavioral interventions that promote healthy sexual behaviors are needed. PMID- 26987978 TI - Transforaminal percutaneous endoscopic discectomy in the treatment of far-lateral lumbar disc herniations in children. AB - PURPOSE: The use of transforaminal percutaneous endoscopic discectomy for the treatment of far-lateral lumbar disc herniations has been applied mostly in adults. However, transforaminal percutaneous endoscopic discectomy in children has probably been rarely documented. The aim of this study was to assess the efficacy of transforaminal percutaneous endoscopic discectomy in the treatment of far-lateral lumbar disc herniations in children. METHODS: Overall, 12 cases of far-lateral lumbar disc herniations were treated with the procedure of transforaminal percutaneous endoscopic discectomy between January 2010 and December 2014. There were seven male and five female children included, with an average age of 12.6 years (11-16 years). Pre-operative and post-operative (6 weeks, 6 months and 12 months) clinical outcome data (back and leg visual analog scale [VAS] and Macnab criteria) were collected along with clinical assessments of motor strength (graded 0-5). RESULTS: All patients were discharged to home on the same day of surgery. The average leg VAS score improved from 8.6 +/- 1.6 to 2.1 +/- 0.4 (p < 0.005). Six patients had excellent outcomes, five had good outcomes, one had fair outcomes, and none had poor outcomes, according to the Macnab criteria. Eleven of 12 patients had excellent or good outcomes, for an overall success rate of 91.6 %. No patients required re-operation. There were no incidental durotomies, infections, vascular or visceral injuries. There was one complication, a case of leg numbness caused by ganglion injury. The numbness improved after two weeks. After three months, it was obvious that the total area of numbness in the legs had become smaller. At last follow-up, the patient had no pain, and only a few areas with numbness remained and did not affect the patient's activities of daily living. CONCLUSIONS: Transforaminal percutaneous endoscopic discectomy achieved satisfactory results for children with far-lateral lumbar disc herniations. PMID- 26987979 TI - Minimally invasive versus open transforaminal lumbar fusion: a systematic review of complications. AB - PURPOSE: The aim of this study is to compare mTLIF vs. oTLIF with regard to peri operative complications, operative time, estimated blood loss, fluoroscopic time, and the length of hospital stay. METHODS: The PubMed and EMBASE databases were searched for relevant articles reporting patients undergoing TLIF, and a comparison between mTILF and oTLIF was performed. The database included patient demographic information, complications, operative time, fluoroscopic time, and the length of hospital stay. RESULTS: Fourteen studies were included in this systematic review. The total number of subjects included was 901, of which 455 underwent mTLIF (50 %) and 446 underwent oTLIF (50 %). The operating time for the mTLIF was ranged from 116 to 390 minutes, compared with 102 to 365 minutes for oTLIF, the operating time tended to be longer in the mTLIF group than the oTLIF group. The estimated blood loss was lower in the mTLIF group, ranging from 51 to 578 ml in mTLIF and 225 to 961 ml in oTLIF, respectively. Length of hospital stay was short for the mTLIF with a 2.3 to 10.6 days hospitalization compared to 2.9 to 14.6 days for oTLIF. However the fluoroscopic time was consistently higher in the mTLIF group with a 49 to 106 seconds of fluoroscopy compared to 16.4 to 44 seconds for oTLIF. The complications divided into technical complications and infection complications. The main technical and infection complications included dural tears, screw malposition, and wound infection. Systemic complications included pneumonia, urinary tract infection, and DVT. The numbers of patients with complication was 54 out of 455 (11.87 %) in the mTLIF, and 64 out of 446 (14.35 %) in the oTLIF. CONCLUSION: The review shows mTLIF offers several potential advantages in reducing blood loss and the length of hospital stay, especially lowering the complication rates for patients compared with oTLIF. However, it required much more operative time and radiation exposure. Class I evidence and high-quality randomized controlled trials are needed for further study. PMID- 26987980 TI - Outcomes of lumbar facet syndrome treated with oral diclofenac or methylprednisolone facet injection: a randomized trial. AB - PURPOSE: This prospective randomized trial is to determine the effectiveness of treating lumbar facet syndrome with oral diclofenac, methylprednisolone facet joint injection or both. METHODS: We enrolled lumbar facet syndrome patients treated at Srinagarind Hospital. Enrolled patients were randomly assigned to receive 100 mg/day oral diclofenac, an 80 mg injection of methylprednisolone into each symptomatic facet joint, or both. Endpoints were the Oswestry disability index (ODI) and visual analogue scale (VAS) before treatment, and at four and 12 weeks after treatment. RESULTS: Of the 99 patients, the mean age was 46.4 years and 48 were men. The initial ODI (mean +/- SD) for the diclofenac, methylprednisolone and combined treatment was 45.1 +/- 9.3, 42.9 +/- 15.6, and 42.2 +/- 11.5, respectively. The respective four week ODI was 30.1 +/- 8.1, 20.2 +/- 8.0, and 15.1 +/- 5.5. The 12-week ODI was 42.4 +/- 9.0, 32.2 +/- 15.6, and 26.2 +/- 11.7. The initial VAS was 7.1 +/- 1.2, 7.6 +/- 1.1, and 7.3 +/- 1.0. The four week VAS was 5.3 +/- 1.4, 3.6 +/- 0.7, and 3.3 +/- 1.1. The 12-week VAS was 6.1 +/- 1.1, 5.8 +/- 1.4, and 5.1 +/- 0.9. The four week ODI and VAS for the combined treatment and the methylprednisolone treatment were significantly less than the diclofenac alone. The combined treatment also showed better scores than the methylprednisolone injection. Within each treatment, the best treatment effect was found at four weeks after which the ODI and VAS gradually increased but were still less than the initial scores. CONCLUSIONS: The combined treatment was more effective in reducing lumbar facet pain and improving the functional index than either treatment alone. This approach should be the preferred treatment. PMID- 26987981 TI - Hamstring tendon autograft versus fresh-frozen tibialis posterior allograft in primary arthroscopic anterior cruciate ligament reconstruction: a retrospective cohort study with three to six years follow-up. AB - INTRODUCTION: Selection of various grafts for anterior cruciate ligament (ACL) reconstructions have been employed in order to improve on stability and function of the knee. This study aimed to compare stability and function of the knee after ACL arthroscopic reconstruction by single-loop tibialis posterior (TP) allograft and four-strand hamstring tendon (HT) autograft. MATERIALS AND METHODS: The retrospective cohort study included 104 patients in the TP group matched with 118 patients in the HT group in terms of demographic characteristics, associated meniscus injury, subjective and objective knee characteristics. All patients were followed up for at least three years with regards to mentioned criteria and time of return to former activities. RESULTS: The mean (range) age of TP (88 males and 16 females) and HT (99 males and 19 females) groups was 34.4 (19-48) and 36.9 (20 51) years, respectively. Median (range) follow-up durations were 55 (37-71) and 56 (36-72) months, respectively. No significant differences were observed post operatively, regarding subjective and objective evaluations. Additionally, time duration for return to former activity was similar in both groups. Post-operative paresthesia and numbness of medial aspect of the calf were observed for two months in eight patients of the HT group which persisted to the final visit in one case. No similar symptom was seen in the TP group. CONCLUSION: In arthroscopic ACL reconstruction, fresh frozen doubled TP allograft compared to HT autograft was equally effective in restoring function and stability of knee, permitting return to former activities. LEVEL OF EVIDENCE: Retrospective comparative, Level III. PMID- 26987982 TI - Mono segmental fixation of selected types of thoracic and lumbar fractures; a prospective study. AB - AIM OF STUDY: A prospective study to evaluate the results of monosegmental fixation; fixation of the fractured level with the adjacent vertebra sharing the same disc, in selected types of lumbar and thoracic fractures. This technique aims at saving motion levels by fusion of the only affected motion segment without sacrificing other levels. METHODS: Forty patients enrolled in this study between August 2011 and October 2013. The inclusion criteria were recent thoracic or lumbar vertebral fractures (less than 2 weeks). The fracture involves only one of the end plates of the vertebrae (either the superior or the inferior). The other end plate and both pedicles should be intact. The exclusion criteria were cervical fractures, fractures that include both end plates or pedicles of the vertebra, fracture dislocation, and load sharing classification score more than seven. All patients underwent monosegmental fixation with pedicle screw fixation. Eight patients were supplemented with interbody grafts. Radiological evaluation was done to assess local kyphosis angle, degree of compression of the anterior column, the degree of comminution, retropulsed fragment, neural canal compromise, integrity of the affected end plate, exclusion of pedicle fracture, and most important to assure that only one end plate is affected. All patients were assessed neurologically according to Frankel grading system. Patient were assessed by Denis pain scale and Denis work scale. RESULTS: The age of the patients was of a mean of 34.5 years old. All patients were Frankle E at time of presentation and remained the same post-operative. The mean operative time from incision time to end of skin closure was 74.2 min. The mean blood loss was 230 ml. The pre-operative degree of local kyphosis; was of a mean 8.22 degrees . This was improved to 2.25 degrees at the immediate postoperative x-rays. At two years follow up, the loss of correction was of a mean 0.85 degrees which was insignificant. The pre-operative percentage of height lost improved from a mean of 56.05 % to post-operative mean of 90.125 %. At the end of follow up, no pseudoarthrosis cases or metal failure were noticed. DISCUSSION: Thoracic and lumbar fractures are common in young adults. Surgical treatment offers early rehabilitation and preserves spine alignment. Monosegmental fixation technique in selected types of dorsal and lumbar fractures offers spine stability and preserves motion segments. It fuses only one motion segment that is prone for later instability or deformity. Reconstrcution of the anterior column can be achieved through TLIF approach in combination of monosegmental fixation to achieve 360 degrees fusion. CONCLUSION: Monosegmental fixation is an effective technique. It can save motion segments in young patients with adequate spine stability and good functional outcomes. PMID- 26987983 TI - Prevalence and influence of cys407* Grm2 mutation in Hannover-derived Wistar rats: mGlu2 receptor loss links to alcohol intake, risk taking and emotional behaviour. AB - Modulation of metabotropic glutamate 2 (mGlu2) receptor function has huge potential for treating psychiatric and neurological diseases. Development of drugs acting on mGlu2 receptors depends on the development and use of translatable animal models of disease. We report here a stop codon mutation at cysteine 407 in Grm2 (cys407*) that is common in some Wistar rats. Therefore, researchers in this field need to be aware of strains with this mutation. Our genotypic survey found widespread prevalence of the mutation in commercial Wistar strains, particularly those known as Han Wistar. Such Han Wistar rats are ideal for research into the separate roles of mGlu2 and mGlu3 receptors in CNS function. Previous investigations, unknowingly using such mGlu2 receptor-lacking rats, provide insights into the role of mGlu2 receptors in behaviour. The Grm2 mutant rats, which dominate some selectively bred lines, display characteristics of altered emotionality, impulsivity and risk-related behaviours and increased voluntary alcohol intake compared with their mGlu2 receptor-competent counterparts. In addition, the data further emphasize the potential therapeutic role of mGlu2 receptors in psychiatric and neurological disease, and indicate novel methods of studying the role of mGlu2 and mGlu3 receptors. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'. PMID- 26987984 TI - Effectiveness of 13-valent pneumococcal conjugate vaccine for prevention of invasive pneumococcal disease in children in the USA: a matched case-control study. AB - BACKGROUND: In 2010, 13-valent pneumococcal conjugate vaccine (PCV13) was licensed and recommended in the USA for prevention of invasive pneumococcal disease in children. Licensure was based on immunogenicity data comparing PCV13 with the earlier seven-valent formulation. Because clinical endpoints were not assessed for the new antigens, we did a postlicensure matched case-control study to assess vaccine effectiveness. METHODS: Cases in children aged 2-59 months were identified through active surveillance in 13 sites. Controls were identified via birth registries and matched to cases by age and postal (zip) code. The primary objective was the vaccine effectiveness of at least one dose against the 13 serotypes included in PCV13. Secondary objectives included vaccine effectiveness against all-cause invasive pneumococcal disease, against antibiotic non susceptible invasive pneumococcal disease, and among children with and without underlying conditions. Vaccine effectiveness was calculated as (1 - matched odds ratio) * 100%. FINDINGS: We enrolled 722 children with invasive pneumococcal disease and 2991 controls; PCV13 serotype cases (217 [30%]) included most commonly serotypes 19A (128 [18%]), 7F (32 [4%]), and 3 (43 [6%]). Vaccine effectiveness against PCV13 serotypes was 86.0% (95% CI 75.5 to 92.3), driven by serotypes 19A and 7F, for which vaccine effectiveness was 85.6% (95% CI 70.6 to 93.5) and 96.5% (82.7 to 100), respectively. We also identified statistically significant effectiveness against serotype 3 (79.5%, 95% CI 30.3 to 94.8) and against antibiotic non-susceptible invasive pneumococcal disease (65.6%, 44.9 to 78.7). Vaccine effectiveness against all-cause invasive pneumococcal disease was 60.2% (95% CI 46.8 to 70.3). Vaccine effectiveness was similar among children with (81.4%, 95% CI 45.4 to 93.6) and without (85.8%, 74.9 to 91.9) underlying conditions. INTERPRETATION: PCV13 appears highly effective against invasive pneumococcal disease among children in the USA in the context of routine and catch-up schedules, although some new vaccine antigens could not be assessed. PCV13 immunisation provides a robust strategy for combating pneumococcal antimicrobial resistance. FUNDING: Centers for Disease Control and Prevention. PMID- 26987987 TI - Safety reports on the off-label use of baclofen for alcohol-dependence: recommendations to improve causality assessment. AB - INTRODUCTION: The off-label use of high-dose baclofen (HDB) for alcohol dependence has recently spread. However, HDB has been associated with numerous reports of adverse events (AEs). Pharmacovigilance reporting is supposed to differentiate AEs from adverse drug reactions (ADRs), for which the causality of the drug is determined using validated methods. AREAS COVERED: Since 2010, we found 20 publications on baclofen-related AEs in alcohol dependence, in Medline referenced journals or national pharmacovigilance reports. We focused on whether these reports used causality algorithms, and provided essential elements for determining baclofen causality and excluding the involvement of alcohol and other psychoactive substances or psychotropic drugs. In half of the cases, no causality algorithm was used. Detailed information on baclofen dosing was found in 17 out of 20 (85%) articles, whereas alcohol doses were given only in 10 (50%) publications. Other psychoactive substances and psychotropic drugs were broached in 14 (70%) publications. EXPERT OPINION: future publications reporting suspected HDB-induced ADRs should use validated causality algorithms and provide sufficient amount of contextual information for excluding other potential causes. For HDB, the psychiatric history, and the longitudinal description of alcohol consumptions and associated doses of psychoactive substances or psychotropic medications should be detailed for every reported case. PMID- 26987985 TI - Acinar phenotype is preserved in human exocrine pancreas cells cultured at low temperature: implications for lineage-tracing of beta-cell neogenesis. AB - The regenerative medicine field is expanding with great successes in laboratory and preclinical settings. Pancreatic acinar cells in diabetic mice were recently converted into beta-cells by treatment with ciliary neurotrophic factor (CNTF) and epidermal growth factor (EGF). This suggests that human acinar cells might become a cornerstone for diabetes cell therapy in the future, if they can also be converted into glucose-responsive insulin-producing cells. Presently, studying pancreatic acinar cell biology in vitro is limited by their high plasticity, as they rapidly lose their phenotype and spontaneously transdifferentiate to a duct like phenotype in culture. We questioned whether human pancreatic acinar cell phenotype could be preserved in vitro by physico-chemical manipulations and whether this could be valuable in the study of beta-cell neogenesis. We found that culture at low temperature (4 degrees C) resulted in the maintenance of morphological and molecular acinar cell characteristics. Specifically, chilled acinar cells did not form the spherical clusters observed in controls (culture at 37 degrees C), and they maintained high levels of acinar-specific transcripts and proteins. Five-day chilled acinar cells still transdifferentiated into duct-like cells upon transfer to 37 degrees C. Moreover, adenoviral-mediated gene transfer evidenced an active Amylase promoter in the 7-day chilled acinar cells, and transduction performed in chilled conditions improved acinar cell labelling. Together, our findings indicate the maintenance of human pancreatic acinar cell phenotype at low temperature and the possibility to efficiently label acinar cells, which opens new perspectives for the study of human acinar-to-beta-cell transdifferentiation. PMID- 26987986 TI - Tighter alphaC-helix-alphaL16-helix interactions seem to make p38alpha less prone to activation by autophosphorylation than Hog1. AB - Many eukaryotic protein kinases (EPKs) are autoactivated through autophosphorylation of their activation loop. Mitogen-activated protein (MAP) kinases do not autophosphorylate spontaneously; relying instead upon mitogen activated protein kinase (MAPK) kinases (MKKs) for their activation loop phosphorylation. Yet, in previous studies we identified mutations in the yeast MAPK high osmolarity glycerol (Hog1) that render it capable of spontaneous autophosphorylation and consequently intrinsically active (MKK-independent). Four of the mutations occurred in hydrophobic residues, residing in the alphaC-helix, which is conserved in all EPKs, and in the alphaL16-helix that is unique to MAPKs. These four residues interact together forming a structural element termed 'hydrophobic core'. A similar element exists in the Hog1's mammalian orthologues p38s. Here we show that the 'hydrophobic core' is a loose suppressor of Hog1's autophosphorylation. We inserted 18 point mutations into this core, 17 of which were able to render Hog1 MKK-independent. In p38s, however, only a very few mutations in the equivalent residues rendered these proteins intrinsically active. Structural analysis revealed that a salt bridge between the alphaC-helix and the alphaL16-helix that exists in p38alpha may not exist in Hog1. This bond further stabilizes the 'hydrophobic core' of p38, making p38 less prone to de repressing its concealed autophosphorylation. Mutating equivalent hydrophobic residues in Jnk1 and Erk2 has no effect on their autophosphorylation. We propose that specific structural elements developed in the course of evolution to suppress spontaneous autophosphorylation of Hog1/p38. The suppressors were kept wobbly, probably to allow activation by induced autophosphorylation, but became stricter in mammalian p38s than in the yeast Hog1. PMID- 26987989 TI - Carbon-Quantum-Dots-Loaded Mesoporous Silica Nanocarriers with pH-Switchable Zwitterionic Surface and Enzyme-Responsive Pore-Cap for Targeted Imaging and Drug Delivery to Tumor. AB - Mesoporous silica nanocarriers with pH-switchable antifouling zwitterionic surface, enzyme responsive drug release properties and blue fluorescence are reported. Prolonged circulation in the blood system with zero premature release as well as efficient cellular uptake and intracellular drug release in tumor tissue are achieved. PMID- 26987988 TI - A RANKL Wrinkle: Denosumab-Induced Hypocalcemia. AB - The human monoclonal antibody denosumab inhibits osteoclast-mediated bone resorption by binding to receptor activator of nuclear factor kappaB ligand (RANKL), which is upregulated by tumor cells. Denosumab is indicated to prevent skeletal-related events (SREs) from osteoporosis and metastatic bone disease. We report a case of denosumab-induced hypocalcemia to highlight potential toxicity and treatment considerations. A 66-year-old man with prostate cancer, small cell lung cancer, and bone metastases presented with fatigue, weakness, and muscle spasm. Sixteen days prior, he received cycle 6 of cisplatin and etoposide, leuprolide, and denosumab (120 mg subcutaneously). His examination demonstrated a slight resting tremor, normal strength, and negative Chvostek sign. Laboratory analysis revealed hemoglobin, 8.0 g/dL; total calcium, 5.2 mg/dL (pre-denosumab, 8.9 mg/dL); and magnesium, 0.7 mg/dL. He initially received two units packed red blood cells, intravenous calcium and magnesium, and vitamin D. During his hospitalization, he required multiple doses of intravenous and oral calcium, magnesium, and vitamin D. Despite ongoing oral supplementation, his post discharge serum calcium fluctuated significantly, requiring close monitoring and frequent dose adjustments. Denosumab's unique antiresorptive properties yield fewer SREs. The trade-off is increased hypocalcemia risk, which may be severe and require aggressive, prolonged supplementation and monitoring. PMID- 26987990 TI - Superhydrophobic meshes that can repel hot water and strong corrosive liquids used for efficient gravity-driven oil/water separation. AB - Oil-polluted water has become a worldwide problem due to increasing industrial oily wastewater as well as frequent oil-spill pollution. Compared with underwater superoleophobic (water-removing) filtration membranes, superhydrophobic/superoleophilic (oil-removing) materials have advantages as they can be used for the filtration of heavy oil or the absorption of floating oil from water/oil mixtures. However, most of the superhydrophobic materials used for oil/water separation lose their superhydrophobicity when exposed to hot (e.g. >50 degrees C) water and strong corrosive liquids. Herein, we demonstrate superhydrophobic overlapped candle soot (CS) and silica coated meshes that can repel hot water (about 92 degrees C) and strong corrosive liquids, and were used for the gravity driven separation of oil-water mixtures in hot water and strong acidic, alkaline, and salty environments. To the best of our knowledge, we are unaware of any previously reported studies on the use of superhydrophobic materials for the separation of oil from hot water and corrosive aqueous media. In addition, the as-prepared robust superhydrophobic CS and silica coated meshes can separate a series of oils and organic solvents like kerosene, toluene, petroleum ether, heptane and chloroform from water with a separation efficiency larger than 99.0%. Moreover, the as-prepared coated mesh still maintained a separation efficiency above 98.5% and stable recyclability after 55 cycles of separation. The robust superhydrophobic meshes developed in this work can therefore be practically used as a highly efficient filtration membrane for the separation of oil from harsh water conditions, benefiting the environment and human health. PMID- 26987991 TI - Analysis of HER2 status in gastroesophageal tumor specimens using a new automated HER2 IQFISH pharmDxTM (Dako Omnis) assay. AB - The human epidermal growth factor receptor 2 (HER2) is an important target for treatment of gastroesophageal cancer. Different slide-based assays are available for assessment of HER2 status. Overexpression of the HER2 protein is assessed by immunohistochemistry (IHC) whereas amplification of the HER2 gene is assessed by fluorescence in situ hybridization (FISH) or other in situ hybridization (ISH) methods. Here we report a summary of the validation data on HER2 IQFISH pharmDxTM (Dako Omnis), a newly developed assay for the automated staining platform Dako Omnis. This assay uses a non-toxic buffer that significantly reduces the hybridization time, which results in a total turnaround time of less than 4 hours from deparaffinization to counting of the gene and centromere signals. The data reported in the current summary cover method comparison, assessment of staining quality, observer-to-observer reproducibility as well as reproducibility within and between laboratories. Based on data from the different studies it was concluded that HER2 IQFISH pharmDx (Dako Omnis) is a reliable and robust assay, with high precision and at least comparable to the manual HER2 IQFISH pharmDxTM assay. The HER2 IQFISH pharmDx (Dako Omnis) assay is currently not commercially available outside the Europe Union. PMID- 26987993 TI - Synthesis of Copolymers by Living Carbanionic Alternating Copolymerization. AB - The synthesis and characterization of copolymers from styrene and 1,3-pentadiene (two isomers) are reported. Styrene/1,3-pentadiene (1:1) copolymerization with carbanion initiator yield living, well-defined, alternating (r1 = 0.037, r2 = 0.056), and highly stereoregular copolymers with 90%-100% trans-1,4 units, designed Mn s and low DM s (1.07-1.17). The first-order kinetic resolution and NMR spectra demonstrate that the copolymers obtained possess strictly alternating structure containing both 1,4- and 4,1-enchaiments. Also a series of copolymers with varying degrees of alternation are synthesized from para-alkyl substituted styrene derivatives and 1,3-pentadiene. The degree of alternation is strongly dependent on the polarity of solvent, reaction temperature, type of trans-cis isomer of 1,3-pentadiene and para-substituted group in styrene. The macro zwitterion forms (SPC) through the distribution of electronic charges from the donor (1,3-pentadiene) to the acceptor (styrenes) are proposed to interpret the carbanion alternating copolymerization mechanism. Owing to the versatility of the carbanion-initiating reaction, the present alternating strategy based on 1,3 pentadiene (especially cis isomer) can serve as a powerful tool for precise control of polymer chain microstructure, architecture, and functionalities in one pot polymerization. PMID- 26987992 TI - Current status and future of clinical islet xenotransplantation. AB - beta-Cell replacement therapy, including allogeneic pancreas and islet transplantation, can normalize HbA1c levels in unstable type 1 diabetic (T1D) patients, but a donor shortage is a serious issue. To overcome this problem, xenotransplantation is an attractive option. In fact, islet transplantation from porcine pancreata was performed in the 1990s, which opened the door for islet xenotransplantation, but the possibility of porcine endogenous retrovirus (PERV) infection was raised, which has restricted progress in this field. The International Xenotransplantation Association published a consensus statement on conditions for undertaking clinical trials of porcine islet products in T1D to restart islet xenotransplantation safely. Clinical porcine islet xenotransplantation was restarted under comprehensive regulations in New Zealand. In addition, newly emerged gene-editing technologies have activated the xenotransplantation field. Islet xenotransplantation is becoming a clinical reality, with the results of recent studies showing promise to advance this field. PMID- 26987994 TI - PICALM rs3851179 Variant and Alzheimer's Disease in Asian Population. PMID- 26987995 TI - Bone Material Properties in Osteogenesis Imperfecta. AB - Osteogenesis imperfecta entrains changes at every level in bone tissue, from the disorganization of the collagen molecules and mineral platelets within and between collagen fibrils to the macroarchitecture of the whole skeleton. Investigations using an array of sophisticated instruments at multiple scale levels have now determined many aspects of the effect of the disease on the material properties of bone tissue. The brittle nature of bone in osteogenesis imperfecta reflects both increased bone mineralization density-the quantity of mineral in relation to the quantity of matrix within a specific bone volume-and altered matrix-matrix and matrix mineral interactions. Contributions to fracture resistance at multiple scale lengths are discussed, comparing normal and brittle bone. Integrating the available information provides both a better understanding of the effect of current approaches to treatment-largely improved architecture and possibly some macroscale toughening-and indicates potential opportunities for alternative strategies that can influence fracture resistance at longer-length scales. PMID- 26987997 TI - A randomized, double-blinded, double-dummy efficacy and safety study of budesonide-formoterol Spiromax(r) compared to budesonide-formoterol Turbuhaler(r) in adults and adolescents with persistent asthma. AB - BACKGROUND: Budesonide and formoterol (BF) Spiromax(r) is a dry powder inhaler designed to deliver BF with maximum ease of use for patients with asthma or chronic obstructive pulmonary disease. METHODS: A phase 3b, 12-week, multicenter, double-blind, double-dummy, randomized, controlled trial in patients (>=12 years) with persistent asthma. PRIMARY OBJECTIVE: to demonstrate non-inferiority of twice-daily BF Spiromax 160/4.5 mcg to BF Turbuhaler(r) 200/6 mcg in change from baseline in weekly average of daily trough morning peak expiratory flow (PEF). Secondary endpoints included: Patient Satisfaction and Preference Questionnaire scores, change from baseline in evening PEF, trough forced expiratory volume in one second, percentage of symptom-free and rescue-free 24-hour periods, and safety. RESULTS: The analysis was based on the per-protocol population (BF Spiromax, n = 290; BF Turbuhaler, n = 284). The least squares mean change from baseline to week 12 in morning PEF was: BF Spiromax, 18.8 L/min and BF Turbuhaler, 21.8 L/min. Non-inferiority of BF Spiromax vs BF Turbuhaler was demonstrated (the lower limit of the 95% two-sided confidence interval was -9.02 L/min, which is greater than -15 L/min [the criteria specified for non inferiority]). The mean difference in the total performance domains scores for BF Spiromax vs BF Turbuhaler were 0.248 at baseline and 0.353 at week 12 (both, p <0.001), indicating statistical superiority for BF Spiromax. No statistical or numerical differences were recorded in the total convenience domain score between the two devices. Scores for 'device preference' and 'willingness to continue' supported BF Spiromax at baseline and at week 12 (p = 0.0005 vs BF Turbuhaler). No significant between-group differences were observed in the other secondary efficacy endpoints. Both treatments were well tolerated, with no significant differences in adverse events or asthma exacerbations. CONCLUSIONS: This study demonstrates the non-inferiority of BF Spiromax vs BF Turbuhaler in patients (>=12 years) with asthma. More patients preferred the Spiromax device over Turbuhaler for its performance, and were willing to continue therapy with BF Spiromax beyond the 12-week study period. TRIAL REGISTRATION: NCT01803555; February 28, 2013. PMID- 26987998 TI - Transplacental sildenafil rescues lung abnormalities in the rabbit model of diaphragmatic hernia. AB - INTRODUCTION: The management of congenital diaphragmatic hernia (DH) would benefit from an antenatal medical therapy, which addresses both lung hypoplasia and persistent pulmonary hypertension. We aimed at evaluating the pulmonary effects of sildenafil in the fetal rabbit model for DH. METHODS: We performed a dose-finding study to achieve therapeutic fetal plasmatic concentrations without toxicity following maternal sildenafil administration. Subsequently, DH fetuses were randomly exposed to transplacental placebo or sildenafil 10 mg/kg/day from gestational day 24 until examination at term (day 30). Efficacy measures were ipsilateral pulmonary vascular and airway morphometry, micro-CT-based branching analysis, Doppler flow in the main pulmonary artery and postnatal lung mechanics. RESULTS: Fetal sildenafil plasmatic concentration was above the minimal therapeutic level for at least 22 h/day without maternal and fetal side effects. The placebo-exposed DH fetuses had increased wall thickness in peripheral pulmonary vessels and significantly less fifth-order vessels compared with controls (CTR). Sildenafil-exposed DH fetuses, instead, had a medial and adventitial thickness in peripheral pulmonary vessels in the normal range and normal vascular branching. Fetal pulmonary artery Doppler showed a reduction of pulmonary vascular resistances both in DH and in CTR fetuses treated by sildenafil compared with the placebo-treated ones. Sildenafil also reversed the mean terminal bronchiolar density to normal and improved lung mechanics, yet without measurable impact on lung-to-bodyweight ratio. CONCLUSIONS: In the rabbit model for DH, antenatal sildenafil rescues vascular branching and architecture, reduces pulmonary vascular resistances and also improves airway morphometry and respiratory mechanics. PMID- 26987999 TI - Barriers around access to abortion experienced by rural women in New South Wales, Australia. AB - INTRODUCTION: Little is known about Australian rural women's overall experiences of accessing an abortion service and the barriers they encounter. Approximately one in three Australian women access an abortion at some time in their lives. Most abortions are undertaken during the first trimester of pregnancy in private clinics. Although both medical and surgical abortions are uncomplicated medical procedures, abortion remains a contentious area of women's health. Whilst it is clear that rural women experience disparities in relation to access to health care, there is a gap in the evidence on rural women's experiences of accessing an abortion. The aim of the present study was to identify factors that women in rural New South Wales (NSW) experience in accessing abortion services and suggestions about how rural women could be better supported when seeking access to an abortion service. METHODS: In-depth qualitative interviews were undertaken with rural women living in NSW who had had an abortion in the previous 15 years. Participants self-selected for a phone or face-to-face interview, in response to promotion of the study through women's services, community flyers and press releases. RESULTS: Rural women in this study experienced many barriers to accessing an abortion. Women travelled 1-9 hours one way to access an abortion in clinics. Several women borrowed money for the abortion fee. Five themes were identified: finding information about the provider; stigma, shame and secrecy; logistics involved in accessing the clinic related to travel, money and support; medical and surgical abortion; and ways rural women could be better supported in this process. Suggestions to improve rural women's access to abortion services included more affordable services that were 'closer to home' as a way to reduce travel and cost, and to normalise abortion as a women's health rights issue. CONCLUSIONS: Despite welcome legal and pharmaceutical reform in Australia, results from this small study indicate that there is a long way to go remove barriers on issues rural women experience in their process of accessing reproductive care, including the pervasiveness of abortion stigma. Services closer to home may help reduce inequities in access to health care experienced by rural women. Strategies such as broader use of tele-health and willingness of general practitioners to become authorised prescribers for medical abortions could help to reduce long distances to travel to services and the financial burden experienced by rural women. PMID- 26988000 TI - Integrated knowledge translation (IKT) in health care: a scoping review. AB - BACKGROUND: Integrated knowledge translation (IKT) refers to collaboration between researchers and decision-makers. While advocated as an approach for enhancing the relevance and use of research, IKT is challenging and inconsistently applied. This study sought to inform future IKT practice and research by synthesizing studies that empirically evaluated IKT and identifying knowledge gaps. METHODS: We performed a scoping review. We searched MEDLINE, EMBASE, and the Cochrane Library from 2005 to 2014 for English language studies that evaluated IKT interventions involving researchers and organizational or policy-level decision-makers. Data were extracted on study characteristics, IKT intervention (theory, content, mode, duration, frequency, personnel, participants, timing from initiation, initiator, source of funding, decision maker involvement), and enablers, barriers, and outcomes reported by studies. We performed content analysis and reported summary statistics. RESULTS: Thirteen studies were eligible after screening 14,754 titles and reviewing 106 full-text studies. Details about IKT activities were poorly reported, and none were formally based on theory. Studies varied in the number and type of interactions between researchers and decision-makers; meetings were the most common format. All studies reported barriers and facilitators. Studies reported a range of positive and sub-optimal outcomes. Outcomes did not appear to be associated with initiator of the partnership, dedicated funding, partnership maturity, nature of decision-maker involvement, presence or absence of enablers or barriers, or the number of different IKT activities. CONCLUSIONS: The IKT strategies that achieve beneficial outcomes remain unknown. We generated a summary of IKT approaches, enablers, barriers, conditions, and outcomes that can serve as the basis for a future review or for planning ongoing primary research. Future research can contribute to three identified knowledge gaps by examining (1) how different IKT strategies influence outcomes, (2) the relationship between the logic or theory underlying IKT interventions and beneficial outcomes, and (3) when and how decision-makers should be involved in the research process. Future IKT initiatives should more systematically plan and document their design and implementation, and evaluations should report the findings with sufficient detail to reveal how IKT was associated with outcomes. PMID- 26988002 TI - Complete response to short-term sorafenib treatment alone for hepatocellular carcinoma with bone, lymph node, and peritoneum metastases. AB - We report a 60-year-old male patient who developed extrahepatic metastases in bone, peritoneum, and lymph nodes (confirmed by computed tomography and positron emission tomography-computed tomography) after hepatectomy for hepatocellular carcinoma. He was treated with sorafenib (800 mg/day) but developed grade 3 hand foot syndrome. He continued to be treated with sorafenib but at a lower dose (400 mg/week). The response to sorafenib therapy was graded as complete response at 6 months by the Response Evaluation Criteria in Solid Tumors. Sorafenib was continued for 8 months and the patient remained in complete response for 11 months. Further reporting of similar cases should help design treatment strategies and evaluate predictors of the response to sorafenib therapy. PMID- 26988001 TI - Utilizing a structural meta-ontology for family-based quality assurance of the BioPortal ontologies. AB - An Abstraction Network is a compact summary of an ontology's structure and content. In previous research, we showed that Abstraction Networks support quality assurance (QA) of biomedical ontologies. The development of an Abstraction Network and its associated QA methodologies, however, is a labor intensive process that previously was applicable only to one ontology at a time. To improve the efficiency of the Abstraction-Network-based QA methodology, we introduced a QA framework that uses uniform Abstraction Network derivation techniques and QA methodologies that are applicable to whole families of structurally similar ontologies. For the family-based framework to be successful, it is necessary to develop a method for classifying ontologies into structurally similar families. We now describe a structural meta-ontology that classifies ontologies according to certain structural features that are commonly used in the modeling of ontologies (e.g., object properties) and that are important for Abstraction Network derivation. Each class of the structural meta-ontology represents a family of ontologies with identical structural features, indicating which types of Abstraction Networks and QA methodologies are potentially applicable to all of the ontologies in the family. We derive a collection of 81 families, corresponding to classes of the structural meta-ontology, that enable a flexible, streamlined family-based QA methodology, offering multiple choices for classifying an ontology. The structure of 373 ontologies from the NCBO BioPortal is analyzed and each ontology is classified into multiple families modeled by the structural meta-ontology. PMID- 26988004 TI - Bringing order to little green balls: new insights from the Chlorophycean order Sphaeropleales. PMID- 26988003 TI - Chemical mediation of mutualistic interactions between macroalgae and mesograzers structure unique coastal communities along the western Antarctic Peninsula. AB - Hard bottom communities along the western Antarctic Peninsula region are dominated by thick macroalgal forests, which support high densities of mesograzers, particularly amphipods, and also numerous gastropods. The macroalgae are chemically defended from consumption by the mesograzers and other herbivores and they provide the mesograzers a chemically defended refuge from predation by omnivorous fish. The macroalgae benefit in return because the mesograzers remove epiphytic algae from them. Since these two assemblages are major components of the community, this can be viewed as a community-wide mutualism. Most subcomponents of these interactions have also been documented in lower latitude communities and the similarities and differences between the communities in Antarctica and in other regions are discussed. PMID- 26988006 TI - Morphological complexity, plasticity, and species diagnosability in the application of old species names in DNA-based taxonomies. PMID- 26988005 TI - Putting incertae sedis taxa in their place: a proposal for ten new families and three new genera in Sphaeropleales (Chlorophyceae, Chlorophyta). AB - Best known for aquatic colonial algae such as Hydrodictyon, Pediastrum, or Scenedesmus, the order Sphaeropleales also contains numerous coccoid taxa from aquatic and terrestrial habitats. Recent findings indicate that coccoid lineages in this order are very diverse genetically and may be the prevalent form, although their diversity is often hidden morphologically. This study characterizes coccoid algae recently discovered from desert soil crusts that share morphological and ecological features with the genera Bracteacoccus, Pseudomuriella, and Chromochloris. Analyses of a multi-gene data set that includes members from all sphaeroplealean families are used to examine the monophyly of these morphologically similar taxa, which are shown instead to be phylogenetically distinct and very divergent. We propose new generic names for these lineages: Bracteamorpha, Rotundella, and Tumidella. In addition, we propose an updated family-level taxonomy within Sphaeropleales that includes ten new families of coccoid algae to accommodate the newly presented genera and many incertae sedis taxa in the order: Bracteamorphaceae, Chromochloridaceae, Dictyococcaceae, Dictyochloridaceae, Mychonastaceae, Pseudomuriellaceae, Rotundellaceae, Schizochlamydaceae, Schroederiaceae, and Tumidellaceae. PMID- 26988008 TI - Mixotrophy and loss of phototrophy among geographic isolates of freshwater Esoptrodinium/Bernardinium sp. (Dinophyceae). AB - The genus Esoptrodinium Javornicky consists of freshwater, athecate dinoflagellates with an incomplete cingulum. Strains isolated thus far feed on microalgae and most possess obvious pigmented chloroplasts, suggesting mixotrophy. However, some geographic isolates lack obvious pigmented chloroplasts. The purpose of this study was to comparatively examine this difference and the associated potential for mixotrophy among different isolates of Esoptrodinium. All isolates phagocytized prey cells through an unusual hatch like peduncle located on the ventral episome, and were capable of ingesting various protist taxa. All Esoptrodinium isolates required both food and light to grow. However, only the tested strain with visible pigmented chloroplasts benefited from light in terms of increased biomass (phototrophy). Isolates lacking obvious chloroplasts received no biomass benefit from light, but nevertheless required light for sustained growth (i.e., photoobligate, but not phototrophic). Isolates with visible chloroplasts exhibited chlorophyll autofluorescence and formed a monophyletic psbA gene clade that suggested Esoptrodinium possesses inherited, peridinoid-type plastids. One isolate with cryptic, barely visible plastids lacked detectable chlorophyll and exhibited an apparent loss-of-function mutation in psbA, indicating the presence of nonphotosynthetic plastids. The other isolate that lacked visible chloroplasts lacked both detectable chlorophyll and an amplifiable psbA sequence. The results demonstrate mixotrophy quantitatively for the first time in a freshwater dinoflagellate, as well as apparent within-clade loss of phototrophy along with a correlated mutation sufficient to explain that phenotype. Phototrophy is a variable trait in Esoptrodinium; further study is required to determine if this represents an inter- or intraspecific (allelic) characteristic in this taxon. PMID- 26988007 TI - Resolving phenotypic plasticity and species designation in the morphologically challenging Caulerpa racemosa-peltata complex (Chlorophyta, Caulerpaceae). AB - Although recent molecular studies have indicated the presence of a number of distinct species within the Caulerpa racemosa-peltata complex, due to the difficulties presented by high levels of phenotypic plasticity and the large number of synonyms, infra-specific taxa, and names of uncertain affinity, taxonomic proposals are yet to be made. In this study, we aimed to resolve the taxonomy of the complex and provide an example of how historical nomenclature can best be integrated into molecular based taxonomies. We accomplished this by first determining the number of genetic species within our globally sampled data set through a combination of phylogenetic and species-delimitation approaches of partial elongation factor TU and RUBISCO large subunit gene sequences. Guided by these results, comparative morphological examinations were then undertaken to gauge the extent of phenotypic plasticity within each species, as well as any morphological overlap between them. Our results revealed the presence of 11 distinct species within the complex, five of which showed high levels of phenotypic plasticity and partial overlap with other species. On the basis of observations of a large number of specimens, including type specimens/descriptions, and geographic inferences, we were able to confidently designate names for the lineages. Caulerpa peltata, C. imbricata and C. racemosa vars. laetevirens, occidentalis and turbinata were found to represent environmentally induced forms of a single species, for which the earlier described C. chemnitzia, previously regarded as a synonym of C. racemosa var. turbinata, is reinstated. C. cylindracea, C. lamourouxii, C. macrodisca, C. nummularia and C. oligophylla are also reinstated and two new species, C. macra stat. nov. and C. megadisca sp. nov., are proposed. PMID- 26988009 TI - Reactive oxygen species and the Antarctic macroalgal wound response. AB - Reactive oxygen species (ROS) are commonly produced by algal, vascular plant, and animal cells involved in the innate immune response as cellular signals promoting defense and healing and/or as a direct defense against invading pathogens. The production of reactive species in macroalgae upon injury, however, is largely uncharacterized. In this study, we surveyed 13 species of macroalgae from the Western Antarctic Peninsula and show that the release of strong oxidants is common after macroalgal wounding. Most species released strong oxidants within 1 min of wounding and/or showed cellular accumulation of strong oxidants over an hour post-wounding. Exogenous catalase was used to show that hydrogen peroxide was a component of immediate oxidant release in one of five species, but was not responsible for the entire oxidative wound response as is common in vascular plants. The other component(s) of the oxidant cocktail released upon wounding are unknown. We were unable to detect protein nitration in extracts of four oxidant producing species flash frozen 30 s after wounding, but a role for reactive nitrogen species such as peroxynitrite cannot be completely ruled out. Two species showed evidence for the production of a catalase-activated oxidant, a mechanism previously known only from the laboratory and from the synthetic drug isoniazid used to kill the human pathogen Mycobacterium tuberculosis. The rhodophyte Palmaria decipiens, which released strong oxidants after wounding, also produced strong oxidants upon grazing by a sympatric amphipod, suggesting that oxidants are involved in the response to grazing. PMID- 26988010 TI - Phylogenetic relationships, morphological variation, and toxin patterns in the Alexandrium ostenfeldii (Dinophyceae) complex: implications for species boundaries and identities. AB - Alexandrium ostenfeldii (Paulsen) Balech and Tangen and A. peruvianum (Balech and B.R. Mendiola) Balech and Tangen are morphologically closely related dinoflagellates known to produce potent neurotoxins. Together with Gonyaulax dimorpha Biecheler, they constitute the A. ostenfeldii species complex. Due to the subtle differences in the morphological characters used to differentiate these species, unambiguous species identification has proven problematic. To better understand the species boundaries within the A. ostenfeldii complex we compared rDNA data, morphometric characters and toxin profiles of multiple cultured isolates from different geographic regions. Phylogenetic analysis of rDNA sequences from cultures characterized as A. ostenfeldii or A. peruvianum formed a monophyletic clade consisting of six distinct groups. Each group examined contained strains morphologically identified as either A. ostenfeldii or A. peruvianum. Though key morphological characters were generally found to be highly variable and not consistently distributed, selected plate features and toxin profiles differed significantly among phylogenetic clusters. Additional sequence analyses revealed a lack of compensatory base changes in ITS2 rRNA structure, low to intermediate ITS/5.8S uncorrected genetic distances, and evidence of reticulation. Together these data (criteria currently used for species delineation in dinoflagellates) imply that the A. ostenfeldii complex should be regarded a single genetically structured species until more material and alternative criteria for species delimitation are available. Consequently, we propose that A. peruvianum is a heterotypic synonym of A. ostenfeldii and this taxon name should be discontinued. PMID- 26988011 TI - cPPB-aE is discovered from photosynthetic benthic dinoflagellates. AB - Although chlorophyll degradation pathways in higher plants have been well studied, little is known about the mechanisms of chlorophyll degradation in microalgae. In this article, we report the occurrence of a chlorophyll a derivative that has never been discovered in photosynthetic organisms. This chlorophyll derivative emits no fluorescence and has a peculiar absorbance peak at 425, 451, 625, and 685 nm. From these features, it was identified as 13(2) ,17(3) -cyclopheophorbide a enol (cPPB-aE), reported as a degradation product of chlorophyll a derived from prey algal cells in heterotrophic protists. We discovered cPPB-aE in six benthic photosynthetic dinoflagellates that are phylogenetically separated into four clades based on SSU rDNA molecular phylogeny. This is the first report of this chlorophyll derivative in photosynthetic organisms and we suggest that the derivative is used to quench excess light energy. PMID- 26988012 TI - Ecosystem functioning impacts of the invasive seaweed Sargassum muticum (Fucales, Phaeophyceae). AB - Ongoing changes in natural diversity due to anthropogenic activities can alter ecosystem functioning. Particular attention has been given to research on biodiversity loss and how those changes can affect the functioning of ecosystems, and, by extension, human welfare. Few studies, however, have addressed how increased diversity due to establishment of nonindigenous species (NIS) may affect ecosystem function in the recipient communities. Marine algae have a highly important role in sustaining nearshore marine ecosystems and are considered a significant component of marine bioinvasions. Here, we examined the patterns of respiration and light-use efficiency across macroalgal assemblages with different levels of species richness and evenness. Additionally, we compared our results between native and invaded macroalgal assemblages, using the invasive brown macroalga Sargassum muticum (Yendo) Fensholt as a model species. Results showed that the presence of the invader increased the rates of respiration and production, most likely as a result of the high biomass of the invader. This effect disappeared when S. muticum lost most of its biomass after senescence. Moreover, predictability-diversity relationships of macroalgal assemblages varied between native and invaded assemblages. Hence, the introduction of high-impact invasive species may trigger major changes in ecosystem functioning. The impact of S. muticum may be related to its greater biomass in the invaded assemblages, although species interactions and seasonality influenced the magnitude of the impact. PMID- 26988013 TI - Linking elements to biochemicals: effects of nutrient supply ratios and growth rates on fatty acid composition of phytoplankton species. AB - Three species of marine phytoplankton, Rhodomonas sp., Isochrysis galbana Parke, and Phaeodactylum tricornutum Bohlin, were cultivated in semicontinuous cultures to test biochemical responses (fatty acids; FAs) to five nitrogen (N):phosphorus (P) supply ratios and four growth rates (dilution rates). The characteristic FA profile was observed for each algal species (representing particular algal class), which remained relatively stable across the entire ranges of N:P supply ratios and growth rates. For all species, significant direct effects of N:P supply ratios on FAs were found at lower growth rates. The highest saturated and monounsaturated fatty acid (SFA and MUFA) contents were observed under N deficiency at the lowest growth rate in all three species, while responses of polyunsaturated fatty acids (PUFAs) revealed no consistent pattern. Total FAs (and SFAs and MUFAs) in all species showed significant negative correlations with N cell quota (QN ) under N deficiency, but PUFAs had species-specific correlations with QN . The results show that characteristic FA profiles of algal genus or species (representing particular algal classes) underlie fluctuations according to culture conditions. The significant correlation between FAs and QN under N deficiency suggests that elemental and biochemical limitation of phytoplankton should be considered mutually as determinants of food quality for zooplankton in marine ecosystems. PMID- 26988014 TI - Tolerance of soil algae and cyanobacteria to drought stress. AB - Tolerance to drought stress in soil crust microorganisms is essential for exploiting suitable organisms for restoring soil. In this study, the responses to drought stress of two drought-tolerant species, a green alga and a cyanobacterium, were compared with those of two non-tolerant green algae. In response to drought stress, induced by treatment with polyethylene glycol, the intracellular proline levels increased and were associated with increases in malondialdehye, pigment contents, and enzyme activities such as superoxide dismutase (SOD) and peroxidase (POD). Our results suggest that tolerance to drought stress could be indicated by the intracellular levels of proline, SOD, and carotenoids. This study provides insights into the drought physiology of the photosynthetic microorganisms and suggests that Leptolyngbya boryana and Chlorella vulgaris are suitable pioneer organisms for soil restoration. PMID- 26988015 TI - Genetic delineation between and within the widespread coccolithophore morpho species Emiliania huxleyi and Gephyrocapsa oceanica (Haptophyta). AB - Emiliania huxleyi and Gephyrocapsa oceanica are abundant coccolithophore morpho species that play key roles in ocean carbon cycling due to their importance as both primary producers and cal-cifiers. Global change processes such as ocean acidification impact these key calcifying species. The physiology of E. huxleyi, a developing model species, has been widely studied, but its genetic delineation from G. oceanica remains unclear due to a lack of resolution in classical genetic markers. Using nuclear (18S rDNA and 28S rDNA), mitochondrial (cox1, cox2, cox3, rpl16, and dam), and plastidial (16S rDNA, rbcL, tufA, and petA) DNA markers from 99 E. huxleyi and 44 G. oceanica strains, we conducted a multigene/multistrain survey to compare the suitability of different markers for resolving phylogenetic patterns within and between these two morpho-species. The nuclear genes tested did not provide sufficient resolution to discriminate between the two morpho species that diverged only 291Kya. Typical patterns of incomplete lineage sorting were generated in phylogenetic analyses using plastidial genes. In contrast, full morpho-species delineation was achieved with mitochondrial markers and common intra-morpho-species phylogenetic patterns were observed despite differing rates of DNA substitution. Mitochondrial genes are thus promising barcodes for distinguishing these coccolithophore morpho-species, in particular in the context of environmental monitoring. PMID- 26988016 TI - Ligulate Desmarestia (Desmarestiales, Phaeophyceae) revisited: D. japonica sp. nov. and D. dudresnayi differ from D. ligulata. AB - The phylogeny of ligulate and sulfuric-acid containing species of Desmarestia, occurring worldwide from polar to temperate regions, was revised using a multigenic and polyphasic approach. Sequence data, gametophyte characteristics, and sporophyte morphology support reducing a total of 16 taxa to four different species. (1) D. herbacea, containing broad-bladed and highly branched forms, has dioecious gametophytes. The three other species have monoecious gametophytes: (2) D. ligulata which is profusely branched and, except for one subspecies, narrow bladed, (3) Japanese ligulate Desmarestia, here described as D. japonica sp. nov., which is morphologically similar to D. ligulata but genetically distant from all other ligulate taxa. This species may have conserved the morphology of original ligulate Desmarestia. (4) D. dudresnayi, including unbranched or little branched broad-bladed taxa. A figure of the holotype of D. dudresnayi, which was lost for decades, was relocated. The taxonomy is complemented by a comparison of internal transcribed spacer and cytochrome c oxidase subunit I (cox1) as potential barcode loci, with cox1 offering good resolution, reflecting species delimitations within the genus Desmarestia. PMID- 26988018 TI - Morphological and molecular characterization within 26 strains of the genus Cylindrospermum (Nostocaceae, Cyanobacteria), with descriptions of three new species. AB - Twenty-six strains morphologically identified as Cylindrospermum as well as the closely related taxon Cronbergia siamensis were examined microscopically as well as phylogenetically using sequence data for the 16S rRNA gene and the 16S-23S internal transcribed spacer (ITS) region. Phylogenetic analysis of the 16S rRNA revealed three distinct clades. The clade we designate as Cylindrospermum sensu stricto contained all five of the foundational species, C. maius, C. stagnale, C. licheniforme, C. muscicola, and C. catenatum. In addition to these taxa, three species new to science in this clade were described: C. badium, C. moravicum, and C. pellucidum. Our evidence indicated that Cronbergia is a later synonym of Cylindrospermum. The phylogenetic position of Cylindrospermum within the Nostocaceae was not clearly resolved in our analyses. Cylindrospermum is unusual among cyanobacterial genera in that the morphological diversity appears to be more evident than sequence divergence. Taxa were clearly separable using morphology, but had very high percent similarity among ribosomal sequences. Given the high diversity we noted in this study, we conclude that there is likely much more diversity remaining to be described in this genus. PMID- 26988019 TI - The impact of CO2 emission scenarios and nutrient enrichment on a common coral reef macroalga is modified by temporal effects. AB - Future coral reefs are expected to be subject to higher pCO2 and temperature due to anthropogenic greenhouse gas emissions. Such global stressors are often paired with local stressors thereby potentially modifying the response of organisms. Benthic macroalgae are strong competitors to corals and are assumed to do well under future conditions. The present study aimed to assess the impact of past and future CO2 emission scenarios as well as nutrient enrichment on the growth, productivity, pigment, and tissue nutrient content of the common tropical brown alga Chnoospora implexa. Two experiments were conducted to assess the differential impacts of the manipulated conditions in winter and spring. Chnoospora implexa's growth rate averaged over winter and spring declined with increasing pCO2 and temperature. Furthermore, nutrient enrichment did not affect growth. Highest growth was observed under spring pre-industrial (PI) conditions, while slightly reduced growth was observed under winter A1FI ("business-as usual") scenarios. Productivity was not a good proxy for growth, as net O2 flux increased under A1FI conditions. Nutrient enrichment, whilst not affecting growth, led to luxury nutrient uptake that was greater in winter than in spring. The findings suggest that in contrast with previous work, C. implexa is not likely to show enhanced growth under future conditions in isolation or in conjunction with nutrient enrichment. Instead, the results suggest that greatest growth rates for this species appear to be a feature of the PI past, with A1FI winter conditions leading to potential decreases in the abundance of this species from present day levels. PMID- 26988017 TI - The monospecific genus Meredithia (Kallymeniaceae, Gigartinales) is species rich and geographically widespread with species from temperate Atlantic, Pacific, and Indian Oceans. AB - Using sequences of 5' region of the cytochrome oxidase subunit 1 gene, large subunit rDNA, and ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit gene as genetic markers to elucidate their phylogenetic positions, six unknown species from Western Australia, Tasmania, Lord Howe Is., and Norfolk Is. cluster with Meredithia in the Kallymeniaceae (Gigartinales), and are described as new members of this previously monospecific genus. Specimens from Bermuda referable to Kallymenia limminghei Mont. in the 20th century also clustered with this genetic grouping, not with the generitype of Kallymenia. The Bermudian specimens are further shown to be morphologically distinct from the type of K. limminghei (Guadeloupe, Caribbean Sea) and are described as a new species, Meredithia crenata. Using these Indo-Pacific and Bermudian collections, our analyses further show that Psaromenia is closely related to Meredithia, and that Cirrulicarpus nanus sensu stricto should be returned to Meredithia. PMID- 26988020 TI - Variation in amino acid content and its relationship to nitrogen content and growth rate in Ulva ohnoi (Chlorophyta). AB - To evaluate the quantitative and qualitative changes in amino acids related to internal nitrogen content and growth rate of Ulva ohnoi, the supply of nitrogen to outdoor cultures of the seaweed was manipulated by simultaneously varying water nitrogen concentrations and renewal rate. Both internal nitrogen content and growth rate varied substantially, and the quantitative and qualitative changes in amino acids were described in the context of three internal nitrogen states: nitrogen-limited, metabolic, and luxury. The nitrogen limited state was defined by increases in all amino acids with increasing nitrogen content and growth up until 1.2% internal nitrogen. The metabolic nitrogen state was defined by increases in all amino acids with increasing internal nitrogen content up to 2.6%, with no increases in growth rate. Luxury state was defined by internal nitrogen content above 2.6%, which occurred only when nitrogen availability was high but growth rates were reduced. In this luxury circumstance, excess nitrogen was accumulated as free amino acids, in two phases. The first phase was distinguished by a small increase in the majority of amino acids up to ~3.3% internal nitrogen, and the second by a large increase in glutamic acid, glutamine, and arginine up to 4.2% internal nitrogen. These results demonstrate that the relationship between internal nitrogen content and amino acid quality is dynamic but predictable, and could be used for the selective culture of seaweeds. PMID- 26988022 TI - Vanishing bile duct syndrome associated with diffuse large B-cell lymphoma. PMID- 26988021 TI - Guidelines for reporting of health interventions using mobile phones: mobile health (mHealth) evidence reporting and assessment (mERA) checklist. PMID- 26988024 TI - Minimally invasive procedures for neuropathic pain. AB - Neuropathic pain is "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system". The prevalence of neuropathic pain ranges from 7 to 11% of the population and minimally invasive procedures have been used to both diagnose and treat neuropathic pain. Diagnostic procedures consist of nerve blocks aimed to isolate the peripheral nerve implicated, whereas therapeutic interventions either modify or destroy nerve function. Procedures that modify how nerves function include epidural steroid injections, peripheral nerve blocks and sympathetic nerve blocks. Neuroablative procedures include radiofrequency ablation, cryoanalgesia and neurectomies. Currently, neuromodulation with peripheral nerve stimulators and spinal cord stimulators are the most evidence-based treatments of neuropathic pain. PMID- 26988025 TI - 3-Year Randomized Controlled Prospective Clinical Trial on Different CAD-CAM Implant Abutments. AB - BACKGROUND: Zirconia abutments were introduced to restore esthetic regions and showed sufficient stability to support implant restorations. Nonetheless, to date the observation periods are shorter than those of titanium abutments. PURPOSE: To assess the survival of implant crowns supported by computer aided design-computer aided manufacturing (CAD-CAM) abutments after 3 years. MATERIALS AND METHODS: Fifty-six patients were selected for this prospective clinical study. Each patient received at least 1 titanium implant for a total of 89 fixtures. A two stage surgical technique and no additional soft or hard tissue graft were used. The implants were randomly divided into 3 groups receiving different CAD-CAM abutments: titanium, titanium nitride, and zirconia. Zirconia or metal-ceramic crowns were used as final restorations. Cementation was the baseline and the restorations were checked after 6 months, 1, 2, and 3 years, assessing any mechanical complication. Statistical analyses were performed to evaluate the 3 year success rates. RESULTS: Five failures were reported in the zirconia group; all the failed restorations showed fractures of the abutment connection. Four failures occurred in posterior regions and one more occurred while screwing the abutment. Titanium and titanium nitride abutments had significantly higher 3-year success rates than zirconia abutments (p < .05). CONCLUSIONS: Atlantis titanium and titanium nitride abutments showed optimal clinical performances after 3 years. Conversely, Atlantis zirconia abutments should be avoided to restore posterior regions. PMID- 26988027 TI - Letter to the editor: diagnostic challenges to be considered regarding Zika virus in the context of the presence of the vector Aedes albopictus in Europe. PMID- 26988026 TI - Unfractionated bone marrow cells attenuate paraquat-induced glomerular injury and acute renal failure by modulating the inflammatory response. AB - The aim of this study was to evaluate the efficacy of unfractionated bone marrow cells (BMCs) in attenuating acute kidney injury (AKI) induced by paraquat (PQ) in a mouse model. PQ (55 mg/kg BW) was intraperitoneally injected into C57BL/6 female mice to induce AKI, including renal function failure, glomerular damage and renal tubule injury. Glomerular podocytes were the first target damaged by PQ, which led to glomerular injury. Upon immunofluorescence staining, podocytes depletion was validated and accompanied by increased urinary podocin levels, measured on days 1 and 6. A total of 5.4 * 10(6) BMCs obtained from the same strain of male mice were injected into AKI mice through the tail vein at 3, 24, and 48 hours after PQ administration. As a result, renal function increased, tubular and glomerular injury were ameliorated, podocytes loss improved, and recipient mortality decreased. In addition, BMCs co-treatment decreased the extent of neutrophil infiltration and modulated the inflammatory response by shifting from pro-inflammatory Th1 to an anti-inflammatory Th2 profile, where IL 1beta, TNF-alpha, IL-6 and IFN-gamma levels declined and IL-10 and IL-4 levels increased. The present study provides a platform to investigate PQ-induced AKI and repeated BMCs injection represents an efficient therapeutic strategy. PMID- 26988028 TI - Stray light in cone beam optical computed tomography: I. Measurement and reduction strategies with planar diffuse source. AB - Optical cone-beam computed tomographic (CBCT) scanning of 3D radiochromic dosimeters may provide a practical method for 3D dose verification in radiation therapy. However, in cone-beam geometry stray light contaminates the projection images, degrading the accuracy of reconstructed linear attenuation coefficients. Stray light was measured using a beam pass aperture array (BPA) and structured illumination methods. The stray-to-primary ray ratio (SPR) along the central axis was found to be 0.24 for a 5% gelatin hydrogel, representative of radiochromic hydrogels. The scanner was modified by moving the spectral filter from the detector to the source, changing the light's spatial fluence pattern and lowering the acceptance angle by extending distance between the source and object. These modifications reduced the SPR significantly from 0.24 to 0.06. The accuracy of the reconstructed linear attenuation coefficients for uniform carbon black liquids was compared to independent spectrometer measurements. Reducing the stray light increased the range of accurate transmission readings. In order to evaluate scanner performance for the more challenging application to small field dosimetry, a carbon black finger gel phantom was prepared. Reconstructions of the phantom from CBCT and fan-beam CT scans were compared. The modified source resulted in improved agreement. Subtraction of residual stray light, measured with BPA or structured illumination from each projection further improved agreement. Structured illumination was superior to BPA for measuring stray light for the smaller 1.2 and 0.5 cm diameter phantom fingers. At the costs of doubling the scanner size and tripling the number of scans, CBCT reconstructions of low scattering hydrogel dosimeters agreed with those of fan-beam CT scans. PMID- 26988023 TI - Haem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance. AB - Progesterone-receptor membrane component 1 (PGRMC1/Sigma-2 receptor) is a haem containing protein that interacts with epidermal growth factor receptor (EGFR) and cytochromes P450 to regulate cancer proliferation and chemoresistance; its structural basis remains unknown. Here crystallographic analyses of the PGRMC1 cytosolic domain at 1.95 A resolution reveal that it forms a stable dimer through stacking interactions of two protruding haem molecules. The haem iron is five coordinated by Tyr113, and the open surface of the haem mediates dimerization. Carbon monoxide (CO) interferes with PGRMC1 dimerization by binding to the sixth coordination site of the haem. Haem-mediated PGRMC1 dimerization is required for interactions with EGFR and cytochromes P450, cancer proliferation and chemoresistance against anti-cancer drugs; these events are attenuated by either CO or haem deprivation in cancer cells. This study demonstrates protein dimerization via haem-haem stacking, which has not been seen in eukaryotes, and provides insights into its functional significance in cancer. PMID- 26988029 TI - Recent advances in capillary electrophoretic migration techniques for pharmaceutical analysis (2013-2015). AB - This review updates and follows-up a previous review by highlighting recent advancements regarding capillary electromigration methodologies and applications in pharmaceutical analysis. General approaches such as quality by design as well as sample injection methods and detection sensitivity are discussed. The separation and analysis of drug-related substances, chiral CE, and chiral CE-MS in addition to the determination of physicochemical constants are addressed. The advantages of applying affinity capillary electrophoresis in studying receptor ligand interactions are highlighted. Finally, current aspects related to the analysis of biopharmaceuticals are reviewed. The present review covers the literature between January 2013 and December 2015. PMID- 26988031 TI - Correspondence: Reply to 'Reassessing the contribution of natural gas to US CO2 emission reductions since 2007'. PMID- 26988030 TI - Glycoprotein nonmetastatic melanoma protein B extracellular fragment shows neuroprotective effects and activates the PI3K/Akt and MEK/ERK pathways via the Na+/K+-ATPase. AB - Glycoprotein nonmetastatic melanoma protein B (GPNMB) plays important roles in various types of cancer and amyotrophic lateral sclerosis (ALS). The details of GPNMB function and its interacting protein have not been clarified. Therefore, to identify GPNMB binding partners on the cell membrane, we used membrane protein library/BLOTCHIP-MS technology, which enables us to analyze all cell membrane proteins as binding partners of the GPNMB extracellular fragment. As a result of a comprehensive search, we identified the alpha subunits of Na(+)/K(+)-ATPase (NKA) as a possible binding partner. We confirmed the interaction between the GPNMB extracellular fragment and NKA by immunoprecipitation and immunostaining in NSC-34 cells. Indeed, endogenous GPNMB extracellular fragment bound to and colocalized with NKA alpha subunits. Furthermore, exogenous GPNMB extracellular fragment, i.e., human recombinant GPNMB, also bound to and colocalized with NKA alpha subunits. Additionally, we found that the GPNMB extracellular fragment had neuroprotective effects and activated the phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathways via NKA. These findings indicated that NKA may act as a novel "receptor" for the GPNMB extracellular fragment, offering additional molecular targets for the treatment of GPNMB-related diseases, including various types of cancer and ALS. PMID- 26988032 TI - eIF4A inactivates TORC1 in response to amino acid starvation. AB - Amino acids regulate TOR complex 1 (TORC1) via two counteracting mechanisms, one activating and one inactivating. The presence of amino acids causes TORC1 recruitment to lysosomes where TORC1 is activated by binding Rheb. How the absence of amino acids inactivates TORC1 is less well understood. Amino acid starvation recruits the TSC1/TSC2 complex to the vicinity of TORC1 to inhibit Rheb; however, the upstream mechanisms regulating TSC2 are not known. We identify here the eIF4A-containing eIF4F translation initiation complex as an upstream regulator of TSC2 in response to amino acid withdrawal in Drosophila We find that TORC1 and translation preinitiation complexes bind each other. Cells lacking eIF4F components retain elevated TORC1 activity upon amino acid removal. This effect is specific for eIF4F and not a general consequence of blocked translation. This study identifies specific components of the translation machinery as important mediators of TORC1 inactivation upon amino acid removal. PMID- 26988035 TI - Improved High-Quality Draft Genome Sequence of the Eurypsychrophile Rhodotorula sp. JG1b, Isolated from Permafrost in the Hyperarid Upper-Elevation McMurdo Dry Valleys, Antarctica. AB - Here, we report the draft genome sequence of Rhodotorula sp. strain JG1b, a yeast that was isolated from ice-cemented permafrost in the upper-elevation McMurdo Dry Valleys, Antarctica. The sequenced genome size is 19.39 Mb, consisting of 156 scaffolds and containing a total of 5,625 predicted genes. This is the first known cold-adapted Rhodotorula sp. sequenced to date. PMID- 26988034 TI - Complete Genome Sequence of Alternanthera mosaic virus, Isolated from Achyranthes bidentata in Asia. AB - Alternanthera mosaic virus (AltMV) infecting Achyranthes bidentata was first detected in Asia, and the complete genome sequence (6,604 nucleotides) was determined. Sequence identity analysis and phylogenetic analysis confirmed that this isolate is the most phylogenetically distant AltMV isolate worldwide. PMID- 26988036 TI - Whole-Genome Sequencing of Macrolide-Resistant Mycoplasma pneumoniae Strain S355, Isolated in China. AB - Macrolide-resistant Mycoplasma pneumoniae plays an important role in refractory M. pneumoniae pneumonia. Here, we present the whole-genome sequencing of the macrolide-resistant M. pneumoniae strain S355. The annotated full-genome sequence might provide a new insight into drug resistance in M. pneumoniae and can help pediatricians recognize the disease earlier. PMID- 26988037 TI - Complete Genome Sequence of Cyanobacterium Leptolyngbya sp. NIES-3755. AB - Cyanobacterial genus Leptolyngbya comprises genetically diverse species, but the availability of their complete genome information is limited. Here, we isolated Leptolyngbya sp. strain NIES-3755 from soil at the Toyohashi University of Technology, Japan. We determined the complete genome sequence of the NIES-3755 strain, which is composed of one chromosome and three plasmids. PMID- 26988033 TI - USP19 modulates autophagy and antiviral immune responses by deubiquitinating Beclin-1. AB - Autophagy, mediated by a number of autophagy-related (ATG) proteins, plays an important role in the bulk degradation of cellular constituents. Beclin-1 (also known as Atg6 in yeast) is a core protein essential for autophagic initiation and other biological processes. The activity of Beclin-1 is tightly regulated by multiple post-translational modifications, including ubiquitination, yet the molecular mechanism underpinning its reversible deubiquitination remains poorly defined. Here, we identified ubiquitin-specific protease 19 (USP19) as a positive regulator of autophagy, but a negative regulator of type I interferon (IFN) signaling.USP19 stabilizes Beclin-1 by removing the K11-linked ubiquitin chains of Beclin-1 at lysine 437. Moreover, we foundthat USP19 negatively regulates type IIFNsignaling pathway, by blockingRIG-I-MAVSinteraction in a Beclin-1-dependent manner. Depletion of eitherUSP19 or Beclin-1 inhibits autophagic flux and promotes type IIFNsignaling as well as cellular antiviral immunity. Our findings reveal novel dual functions of theUSP19-Beclin-1 axis by balancing autophagy and the production of type IIFNs. PMID- 26988039 TI - Draft Whole-Genome Sequence of Urease-Producing Sporosarcina koreensis. AB - Urease-producing microbes are of significance due to their potential application in biocement production. Sporosarcina koreensis Q1 is a urease-producing bacterium belonging to the phylum Firmicutes. Here, we present the draft whole genome sequence of S. koreensis Q1, isolated from a barchan sand dune in Qatar. PMID- 26988040 TI - Whole-Genome Sequences of Staphylococcus haemolyticus Isolated from Infected Eyes and Healthy Conjunctiva in Bhubaneswar, India. AB - Staphylococcus haemolyticus, an opportunistic pathogen, is known to exhibit multidrug resistance and produce biofilm. We sequenced the genome of four multidrug resistant, biofilm forming isolates from infected eyes and asymptomatic healthy conjunctiva. PMID- 26988038 TI - Draft Genome Sequences of Two Pseudoalteromonas porphyrae Strains Isolated from Seagrass Sediment. AB - Here, we present the draft genome sequences of Pseudoalteromonas porphyrae UCD SED9 and UCD-SED14 (phylum Proteobacteria). These strains were isolated from sediment surrounding the roots of the seagrass, Zostera marina, collected near the UC, Davis Bodega Marine Laboratory (Bodega Bay, California). The assemblies contain 4,847,456 bp and 4,817,752 bp, respectively. PMID- 26988041 TI - Complete Genome Sequence of Enterococcus faecium Commensal Isolate E1002. AB - The emergence of vancomycin-resistant enterococci (VRE) has been associated with an increase in multidrug-resistant nosocomial infections. Here, we report the 2.614-Mb genome sequence of the Enterococcus faecium commensal isolate E1002, which will be instrumental in further understanding the determinants of the commensal and pathogenic lifestyle of E. faecium. PMID- 26988042 TI - Complete Genome Sequence of Vancomycin-Intermediate Staphylococcus aureus Strain MI (HIP5827). AB - We report the complete genome sequence of vancomycin-intermediate Staphylococcus aureus (VISA) strain MI (HIP5827). PMID- 26988043 TI - Draft Genome Sequences of 10 Bacillus subtilis Strains That Form Spores with High or Low Heat Resistance. AB - Here, we report the draft genome sequences of 10 isolates of Bacillus subtilis, a spore forming Gram-positive bacterium. The strains were selected from food products and produced spores with either high or low heat resistance. PMID- 26988044 TI - Draft Genome Sequence of Burkholderia ambifaria RZ2MS16, a Plant Growth-Promoting Rhizobacterium Isolated from Guarana, a Tropical Plant. AB - Burkholderia ambifaria strain RZ2MS16 was isolated from the rhizosphere of Amazon guarana in Brazil. This bacterium exhibits a remarkable capacity to promote the growth of corn and soybean. Here, we report the draft genome sequence of RZ2MS16 and some genes related to multiple traits involved in plant growth promotion. PMID- 26988045 TI - Complete Genome Sequence of Bradyrhizobium sp. Strain CCGE-LA001, Isolated from Field Nodules of the Enigmatic Wild Bean Phaseolus microcarpus. AB - We present the complete genome sequence of Bradyrhizobium sp. strain CCGE-LA001, a nitrogen-fixing bacterium isolated from nodules of Phaseolus microcarpus. Strain CCGE-LA001 represents the first sequenced bradyrhizobial strain obtained from a wild Phaseolus sp. Its genome revealed a large and novel symbiotic island. PMID- 26988046 TI - Complete Genome Sequence of emm4 Streptococcus pyogenes MEW427, a Throat Isolate from a Child Meeting Clinical Criteria for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS). AB - We report the complete genome assembly of the Streptococcus pyogenes type emm4 strain MEW427 (also referred to as strain UM001 in the Pediatric Acute-Onset Neuropsychiatric Syndrome [PANS] Research Consortium), a throat isolate from a child with acute-onset neuropsychiatric symptoms meeting clinical criteria for PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus). The genome length is 1,814,455 bp with 38.51% G+C%. PMID- 26988047 TI - Whole-Genome Sequence of Multidrug-Resistant Campylobacter coli Strain COL B1 266, Isolated from the Colombian Poultry Chain. AB - Campylobacter coli is considered one of the main causes of food-borne illness worldwide. We report here the whole-genome sequence of multidrug-resistant Campylobacter coli strain COL B1-266, isolated from the Colombian poultry chain. The genome sequences encode genes for a variety of antimicrobial resistance genes, including aminoglycosides, beta-lactams, lincosamides, fluoroquinolones, and tetracyclines. PMID- 26988048 TI - Whole-Genome Sequences of Two Campylobacter coli Isolates from the Antimicrobial Resistance Monitoring Program in Colombia. AB - Campylobacter coli, along with Campylobacter jejuni, is a major agent of gastroenteritis and acute enterocolitis in humans. We report the whole-genome sequences of two multidrug-resistance C. coli strains, isolated from the Colombian poultry chain. The isolates contain a variety of antimicrobial resistance genes for aminoglycosides, lincosamides, fluoroquinolones, and tetracycline. PMID- 26988049 TI - Complete Genome and Methylome Sequences of Salmonella enterica subsp. enterica Serovar Panama (ATCC 7378) and Salmonella enterica subsp. enterica Serovar Sloterdijk (ATCC 15791). AB - Salmonella enterica spp. are pathogenic bacteria commonly associated with food borne outbreaks in human and animals. Salmonella enterica spp. are characterized into more than 2,500 different serotypes, which makes epidemiological surveillance and outbreak control more difficult. In this report, we announce the first complete genome and methylome sequences from two Salmonella type strains associated with food-borne outbreaks, Salmonella enterica subsp. enterica serovar Panama (ATCC 7378) and Salmonella enterica subsp. enterica serovar Sloterdijk (ATCC 15791). PMID- 26988050 TI - Draft Genome Sequence of an ortho-Nitrophenyl-beta-d-Galactoside (ONPG)-Negative Strain of Vibrio cholerae, Isolated from Drakes Bay, California. AB - We present the draft whole-genome sequence of a Vibrio cholerae strain (Vc25-3) isolated from Drakes Bay, California. This environmental isolate has an atypical morphology and is ortho-nitrophenyl-beta-d-galactoside (ONPG)-negative. PMID- 26988051 TI - Complete Genome Sequence of emm28 Type Streptococcus pyogenes MEW123, a Streptomycin-Resistant Derivative of a Clinical Throat Isolate Suitable for Investigation of Pathogenesis. AB - We present here the complete genome sequence of Streptococcus pyogenes type emm28 strain MEW123, a streptomycin-resistant derivative of a pediatric throat isolate. The genome length is 1,878,699 bp, with 38.29% G+C% content. The genome sequence adds value to this virulent emm28 representative strain and will aid in the investigation of streptococcal pathogenesis. PMID- 26988052 TI - Draft Genome Sequence of Mycobacterium wolinskyi, a Rapid-Growing Species of Nontuberculous Mycobacteria. AB - Mycobacterium wolinskyi is a nonpigmented, rapidly growing nontuberculous mycobacterium species that is associated with bacteremia, peritonitis, infections associated with implants/prostheses, and skin and soft tissue infections often following surgical procedures in humans. Here, we report the first functionally annotated draft genome sequence of M. wolinskyi CDC_01. PMID- 26988053 TI - Complete Genome Sequence of Methylobacterium sp. Strain AMS5, an Isolate from a Soybean Stem. AB - Nonrhizobial Methylobacterium spp. inhabit the phyllosphere of a wide variety of plants. We report here the complete genome sequence of Methylobacterium sp. AMS5, which was isolated from a soybean stem. The information is useful for understanding the molecular mechanisms of the interaction between nonrhizobial Methylobacterium spp. and plants. PMID- 26988054 TI - Draft Genome Sequence of Aliiroseovarius crassostreae CV919-312, the Causative Agent of Roseovarius Oyster Disease (Formerly Juvenile Oyster Disease). AB - Aliiroseovarius crassostreae CV919-312 is a marine alphaproteobacterium and the causative agent of Roseovarius oyster disease. We announce here the draft genome sequence of A. crassostreae CV919-312 and identify potential virulence genes involved in pathogenicity. PMID- 26988055 TI - Complete Genome Sequence of a Variant Pseudorabies Virus Strain Isolated in Central China. AB - Pseudorabies virus (PRV) variants have been prevalent in China since 2011 and have caused huge economic losses to the Chinese pig industry. Here, we report the genome sequence of a PRV variant HN1201 that was isolated from diseased animals in central China in 2011. PMID- 26988056 TI - Draft Genome Sequence of Photorhabdus luminescens subsp. laumondii HP88, an Entomopathogenic Bacterium Isolated from Nematodes. AB - Photorhabdus luminescens subsp. laumondii HP88 is an entomopathogenic bacterium that forms a symbiotic association with Heterorhabditis nematodes. We report here a 5.27-Mbp draft genome sequence for P. luminescens subsp. laumondii HP88, with a G+C content of 42.4% and containing 4,243 candidate protein-coding genes. PMID- 26988057 TI - Complete Genome Sequence of Aggregatibacter actinomycetemcomitans Serotype g Strain NUM4039 (JCM 30399). AB - Aggregatibacter actinomycetemcomitans is considered to be a major etiological agent of aggressive periodontitis and includes serotype a to g strains. We herein report the first complete genome sequence of A. actinomycetemcomitans serotype g strain NUM4039. The genome is 2,382,853 bp in length with a G+C content of 44.34%. PMID- 26988058 TI - Draft Genome Sequence of "Halomonas chromatireducens" Strain AGD 8-3, a Haloalkaliphilic Chromate- and Selenite-Reducing Gammaproteobacterium. AB - Here, we report the complete genome sequence (3.97 Mb) of "Halomonas chromatireducens" AGD 8-3, a denitrifying bacterium capable of chromate and selenite reduction under extreme haloalkaline conditions. This strain was isolated from soda solonchak soils of the Kulunda steppe, Russian Federation. PMID- 26988059 TI - Erratum for Fontana et al., Genome Sequence of Acidovorax avenae Strain T10_61 Associated with Sugarcane Red Stripe in Argentina. PMID- 26988060 TI - Erratum for Alves et al., Complete Genome Sequence of Corynebacterium pseudotuberculosis Strain PA01, Isolated from Sheep in Para, Brazil. PMID- 26988061 TI - Draft Genome Sequence of an NDM-5-Producing Klebsiella pneumoniae Sequence Type 14 Strain of Serotype K2. AB - We report here the draft genome sequence of uropathogenic Klebsiella pneumoniae sequence type 14 strain of serotype K2 possessing blaNDM-5, isolated from a 65 year-old male in China without a history of travel abroad. PMID- 26988062 TI - Draft Genome Sequence of "Acidibacillus ferrooxidans" ITV01, a Novel Acidophilic Firmicute Isolated from a Chalcopyrite Mine Drainage Site in Brazil. AB - Here, we report the draft genome sequence of "Acidibacillus ferrooxidans" strain ITV01, a ferrous iron- and sulfide-mineral-oxidizing, obligate heterotrophic, and acidophilic bacterium affiliated with the phylum Firmicutes. Strain ITV01 was isolated from neutral drainage from a low-grade chalcopyrite from a mine in northern Brazil. PMID- 26988064 TI - Identifying neuropeptide Y (NPY) as the main stress-related substrate of dipeptidyl peptidase 4 (DPP4) in blood circulation. AB - BACKGROUND: Dipeptidyl peptidase 4 (DPP4; EC 3.4.14.5; CD26) is a membrane-bound or shedded serine protease that hydrolyzes dipeptides from the N-terminus of peptides with either proline or alanine at the penultimate position. Substrates of DPP4 include several stress-related neuropeptides implicated in anxiety, depression and schizophrenia. A decline of DPP4-like activity has been reported in sera from depressed patient, but not fully characterized regarding DPP4-like enzymes, therapeutic interventions and protein. METHODS: Sera from 16 melancholic and 16 non-melancholic-depressed patients were evaluated for DPP4-like activities and the concentration of soluble DPP4 protein before and after treatment by anti-depressive therapies. Post-translational modification of DPP4 isoforms and degradation of NPY, Peptide YY (PYY), Galanin-like peptide (GALP), Orexin B (OrxB), OrxA, pituitary adenylate cyclase-activating polypeptide (PACAP) and substance P (SP) were studied in serum and in ex vivo human blood. N-terminal truncation of biotinylated NPY by endothelial membrane-bound DPP4 versus soluble DPP4 was determined in rat brain perfusates and spiked sera. RESULTS: Lower DPP4 activities in depressed patients were reversed by anti-depressive treatment. In sera, DPP4 contributed to more than 90% of the overall DPP4-like activity and correlated with its protein concentration. NPY displayed equal degradation in serum and blood, and was equally truncated by serum and endothelial DPP4. In addition, GALP and rat OrxB were identified as novel substrates of DPP4. CONCLUSION: NPY is the best DPP4-substrate in blood, being truncated by soluble and membrane DPP4, respectively. The decline of soluble DPP4 in acute depression could be reversed upon anti-depressive treatment. Peptidases from three functional compartments regulate the bioactivity of NPY in blood. PMID- 26988065 TI - Synthesis, phase composition, Mossbauer and magnetic characterization of iron oxide nanoparticles. AB - The present work describes the synthesis of iron oxide nanoparticles by thermal decomposition of Fe-precursors in argon and vacuum environments with control over particle size distribution, phase composition and the resulting magnetic properties. The Rietveld refinement analysis of X-ray diffraction data revealed the crystallinity as well the single-phase of gamma-Fe2O3 nanoparticles prepared under vacuum, whereas the argon environment leads to the formation of multi-phase composition of gamma-Fe2O3/Fe3O4 (90%) and wustite (10%). Synchrotron X-ray absorption near edge structure (XANES) indicates that the predominant phase in both samples is gamma-Fe2O3, which is subsequently verified from the Mossbauer spectra. DC magnetic measurements indicate behavior typical of a superparamagnetic system validated by Mossbauer analysis. However, further investigation of ac susceptibility by typical Neel-Arrhenius and Vogel Fulcher magnetic models suggests an influence of interparticle interactions on the overall magnetic behavior of the system. PMID- 26988066 TI - Blood drop patterns: Formation and applications. AB - The drying of a drop of blood or plasma on a solid substrate leads to the formation of interesting and complex patterns. Inter- and intra-cellular and macromolecular interactions in the drying plasma or blood drop are responsible for the final morphologies of the dried patterns. Changes in these cellular and macromolecular components in blood caused by diseases have been suspected to cause changes in the dried drop patterns of plasma and whole blood, which could be used as simple diagnostic tools to identify the health of humans and livestock. However, complex physicochemical driving forces involved in the pattern formation are not fully understood. This review focuses on the scientific development in microscopic observations and pattern interpretation of dried plasma and whole blood samples, as well as the diagnostic applications of pattern analysis. Dried drop patterns of plasma consist of intricate visible cracks in the outer region and fine structures in the central region, which are mainly influenced by the presence and concentration of inorganic salts and proteins during drying. The shrinkage of macromolecular gel and its adhesion to the substrate surface have been thought to be responsible for the formation of the cracks. Dried drop patterns of whole blood have three characteristic zones; their formation as functions of drying time has been reported in the literature. Some research works have applied engineering treatment to the evaporation process of whole blood samples. The sensitivities of the resultant patterns to the relative humidity of the environment, the wettability of the substrates, and the size of the drop have been reported. These research works shed light on the mechanisms of spreading, evaporation, gelation, and crack formation of the blood drops on solid substrates, as well as on the potential applications of dried drop patterns of plasma and whole blood in diagnosis. PMID- 26988067 TI - Release of the Inferior Crus in Antihelix Plasty. AB - OBJECTIVE: Protruding ears with a hypoplastic antihelix often have poorly developed inferior cura. Publications on this topic until now have only dealt with absent inferior crus and have neglected its importance in everyday antihelix plasty. This article describes a new surgical technique to improve treatment of the antihelix. METHODS: Patients with protruding upper third ears received either standard otoplasty with crus superior remodeling (ST) or the newly developed surgical procedure including crus inferior release (STI). To evaluate the results, a survey containing 10 questions about different outcome parameters was conducted with the patients. Each question was given a score ranging from 0 to 10, where 10 meant the best outcome and 0 the worst. RESULTS: From January 2013 to March 2014, 216 patients underwent otoplasty, of which 99 completed the questionnaire. No differences could be found between ST and STI patients except for their duration of pain, which was significantly less in group STI. Overall, the scores from the questionnaire were 89.85 in ST and 92.35 in STI. Mean values for satisfaction were 9.33 in group ST and 9.56 in group STI. CONCLUSION: When correcting the antihelix, the inferior crus must always be checked because the protruding upper third cannot be compensated only by overcorrecting the superior crus. It should be a matter of routine to recognize the degree of malformation and determine the best possible treatment. This novel technique is an additional valuable option in otoplasty to improve the upper third in a more natural way and create highly satisfactory results. PMID- 26988063 TI - Ambient particulate matter exposure and cardiovascular diseases: a focus on progenitor and stem cells. AB - Air pollution is a major challenge to public health. Ambient fine particulate matter (PM) is the key component for air pollution, and associated with significant mortality. The majority of the mortality following PM exposure is related to cardiovascular diseases. However, the mechanisms for the adverse effects of PM exposure on cardiovascular system remain largely unknown and under active investigation. Endothelial dysfunction or injury is considered one of the major factors that contribute to the development of cardiovascular diseases such as atherosclerosis and coronary heart disease. Endothelial progenitor cells (EPCs) play a critical role in maintaining the structural and functional integrity of vasculature. Particulate matter exposure significantly suppressed the number and function of EPCs in animals and humans. However, the mechanisms for the detrimental effects of PM on EPCs remain to be fully defined. One of the important mechanisms might be related to increased level of reactive oxygen species (ROS) and inflammation. Bone marrow (BM) is a major source of EPCs. Thus, the number and function of EPCs could be intimately associated with the population and functional status of stem cells (SCs) in the BM. Bone marrow stem cells and other SCs have the potential for cardiovascular regeneration and repair. The present review is focused on summarizing the detrimental effects of PM exposure on EPCs and SCs, and potential mechanisms including ROS formation as well as clinical implications. PMID- 26988068 TI - A Five-Year Analysis of Airway Foreign Body Management: Toward a Better Understanding of Negative Bronchoscopies. AB - OBJECTIVE: To identify characteristics in patients who undergo positive and negative bronchoscopy for a suspected airway foreign body (AFB). METHODS: Review medical records between 2008 and 2012. RESULTS: There were 145 patients who went to the operating room with the pre-bronchoscopy diagnosis of suspected AFB during the study period. There was an overall negative bronchoscopy rate of an average of 37%, with an annual range between 21% and 50%. The findings of history or suspicion of choking, asymmetric breath sounds, and wheezing were statistically more common in patients with an AFB. Chest roentograms (CXR) had a sensitivity and specificity of 62% and 57%. Twenty patients had a chest computed tomography (CT) scan, and 100% were clinically significant. Four CT scans were diagnostic of an AFB, and 16 patients avoided bronchoscopy after negative CT. CONCLUSIONS: In current clinical practice, it is difficult to identify patients with an AFB without performing bronchoscopy. This results in a significant number of negative bronchoscopes. Certain elements in the history and physical exam were more common in patients who were found to have an AFB. Our preliminary data suggest that chest CT scans may be useful to decrease the number of negative bronchoscopies. PMID- 26988070 TI - Influence of pH, competing ions, and salinity on the sorption of strontium and cobalt onto biogenic hydroxyapatite. AB - Anthropogenic radionuclides contaminate a range of environments as a result of nuclear activities, for example, leakage from waste storage tanks/ponds (e.g. Hanford, USA or Sellafield sites, UK) or as a result of large scale nuclear accidents (e.g. Chernobyl, Ukraine or Fukushima, Japan). One of the most widely applied remediation techniques for contaminated waters is the use of sorbent materials (e.g. zeolites and apatites). However, a key problem at nuclear contaminated sites is the remediation of radionuclides from complex chemical environments. In this study, biogenic hydroxyapatite (BHAP) produced by Serratia sp. bacteria was investigated for its potential to remediate surrogate radionuclides (Sr(2+) and Co(2+)) from environmentally relevant waters by varying pH, salinity and the type and concentration of cations present. The sorption capacity of the BHAP for both Sr(2+) and Co(2+) was higher than for a synthetically produced hydroxyapatite (HAP) in the solutions tested. BHAP also compared favorably against a natural zeolite (as used in industrial decontamination) for Sr(2+) and Co(2+) uptake from saline waters. Results confirm that hydroxyapatite minerals of high surface area and amorphous calcium phosphate content, typical for biogenic sources, are suitable restoration or reactive barrier materials for the remediation of complex contaminated environments or wastewaters. PMID- 26988071 TI - Perception of Parental Bonds and Suicide Intent Among Egyptian Adolescents. AB - PROBLEM: Suicidal adolescents, compared to their nonsuicidal peers, tend to perceive their parents as less "caring" and more "controlling"-which characterizes the "affectionless control" parenting style. Research findings are inconsistent regarding the distinct influence of mother versus father parenting on youth suicide intent; moreover, the influence of parents' joint parenting styles on suicide intent has not been investigated. METHODS: Using a cross sectional design and large sample (N = 150 youth, 13-21 years old), currently hospitalized in a treatment center in Egypt for a recent suicide attempt, data were collected using the Suicide Intent Scale, Parental Bonding Instrument, and Center for Epidemiologic Studies Depression Scale. FINDINGS: Seventy percent of youth reported high suicide intent. Mother and father parenting styles, assessed independently, were not associated with adolescent suicide intent. The joint effect of both parents' parenting style, however, was positively associated with suicide intent (Wald chi(2) = 8.79, p = .03). Suicide intent was stronger among adolescents who experienced neglectful compared with optimal parenting style (B = 1.93, Wald chi(2) = 4.28, p = .04). CONCLUSIONS: The findings have direct implications for mental health nursing interventions, signaling the critical need to engage both parents in family-based interventions to address youth suicidal behavior. PMID- 26988069 TI - CD70 Exacerbates Blood Pressure Elevation and Renal Damage in Response to Repeated Hypertensive Stimuli. AB - RATIONALE: Accumulating evidence supports a role of adaptive immunity and particularly T cells in the pathogenesis of hypertension. Formation of memory T cells, which requires the costimulatory molecule CD70 on antigen-presenting cells, is a cardinal feature of adaptive immunity. OBJECTIVE: To test the hypothesis that CD70 and immunologic memory contribute to the blood pressure elevation and renal dysfunction mediated by repeated hypertensive challenges. METHODS AND RESULTS: We imposed repeated hypertensive challenges using either N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME)/high salt or repeated angiotensin II stimulation in mice. During these challenges effector memory T cells (T(EM)) accumulated in the kidney and bone marrow. In the L NAME/high-salt model, memory T cells of the kidney were predominant sources of interferon-gamma and interleukin-17A, known to contribute to hypertension. L NAME/high salt increased macrophage and dendritic cell surface expression of CD70 by 3- to 5-fold. Mice lacking CD70 did not accumulate T(EM) cells and did not develop hypertension to either high salt or the second angiotensin II challenge and were protected against renal damage. Bone marrow-residing T(EM) cells proliferated and redistributed to the kidney in response to repeated salt feeding. Adoptively transferred T(EM) cells from hypertensive mice homed to the bone marrow and spleen and expanded on salt feeding of the recipient mice. CONCLUSIONS: Our findings illustrate a previously undefined role of CD70 and long lived T(EM) cells in the development of blood pressure elevation and end-organ damage that occur on delayed exposure to mild hypertensive stimuli. Interventions to prevent repeated hypertensive surges could attenuate formation of hypertension specific T(EM) cells. PMID- 26988072 TI - Early renal function recovery and long-term graft survival in kidney transplantation. AB - Following kidney transplantation (KTx), renal function improves gradually until a baseline eGFR is achieved. Whether or not a recipient achieves the best-predicted eGFR after KTx may have important implications for immediate patient management, as well as for long-term graft survival. The aim of this cohort study was to calculate the renal function recovery (RFR) based on recipient and donor eGFR and to evaluate the association between RFR and long-term death-censored graft failure (DCGF). We studied 790 KTx recipients between January 1990 and August 2014. The last donor SCr prior to organ procurement was used to estimate donor GFR. Recipient eGFR was calculated using the average of the best three SCr values observed during the first 3 months post-KTx. RFR was defined as the ratio of recipient eGFR to half the donor eGFR. 53% of recipients had an RFR >=1. There were 127 death-censored graft failures (16%). Recipients with an RFR >=1 had less DCGF compared with those with an RFR <1 (HR 0.56; 95% CI 0.37-0.85; P = 0.006). Transplant era, acute rejection, ECD and DGF were also significant determinants of graft failure. Early recovery of predicted eGFR based on donor eGFR is associated with less DCGF after KTx. PMID- 26988073 TI - Minimal Requirements for the Emergence of Learned Signaling. AB - The emergence of signaling systems has been observed in numerous experimental and real-world contexts, but there is no consensus on which (if any) shared mechanisms underlie such phenomena. A number of explanatory mechanisms have been proposed within several disciplines, all of which have been instantiated as credible working models. However, they are usually framed as being mutually incompatible. Using an exemplar-based framework, we replicate these models in a minimal configuration which allows us to directly compare them. This reveals that the development of optimal signaling is driven by similar mechanisms in each model, which leads us to propose three requirements for the emergence of conventional signaling. These are the creation and transmission of referential information, a systemic bias against ambiguity, and finally some form of information loss. Considering this, we then discuss some implications for theoretical and experimental approaches to the emergence of learned communication. PMID- 26988074 TI - Effects of moderate-intensity physical exercise on pharmacokinetics of factor VIII and von Willebrand factor in young adults with severe haemophilia A: a pilot study. AB - INTRODUCTION: In persons with severe haemophilia A (pwshA), infused factor VIII (FVIII) half-life can vary according to such determinants as blood group, von Willebrand factor (VWF) level or age; however, FVIII pharmacokinetics (PK) has not been well studied in pwshA during exercise. AIM: To investigate FVIII PK in pwshA performing moderate-intensity aerobic exercise. METHODS: Twelve young-adult pwshA with the intron-22 inversion mutation, on relatively low-dose FVIII prophylaxis regimens, and relatively good musculoskeletal status were recruited. Abbreviated PK of FVIII activity and von Willebrand factor antigen (VWF:Ag) level were compared - during rest, and with 60-min exercise (2 * 15 min each of moderate-intensity stationary cycling and treadmill walking). During rest and exercise visits, a baseline blood specimen was drawn, routine prophylaxis FVIII infused; then six blood specimens were taken over the following 24 h. RESULTS: For all subjects, mean half-life of infused FVIII did not change significantly with exercise vs. at rest (577 +/- 190 vs. 614 +/- 163 min; P = 0.4131). VWF:Ag rose transiently by 40-50% for 6-8 h with exercise (P < 0.01), particularly in non-O blood group subjects. No musculoskeletal bleeds occurred during the study. CONCLUSION: Four * 15 min of moderate-intensity aerobic exercise increased VWF:Ag levels for 6-8 h, and showed no evidence of accelerated FVIII clearance or of musculoskeletal bleeding in these young-adult pwshA with relatively good musculoskeletal status, on relatively low-dose FVIII prophylaxis regimens. However, O blood group impact would merit larger studies, with longer durations of similar or more vigorous exercise intensities. PMID- 26988075 TI - Risk of fractures in vitiligo patients treated with phototherapy-A retrospective population-based cohort study. AB - BACKGROUND: Phototherapy might increase bone mineral density. However, it is unknown whether phototherapy can reduce the risk of fractures in patients with vitiligo. OBJECTIVES: To investigate the effect of phototherapy on fracture risks in vitiligo patients aged 40 or older. METHODS: This population-based cohort study used the 2000-2010 Taiwan National Health Insurance Research Database (NHIRD) to identify 3863 patients newly diagnosed with vitiligo between 2003 and 2009 at age >=40 years. Study subjects were classified into three cohorts: (1) frequent phototherapy; (2) infrequent phototherapy; and (3) no phototherapy. Patients were followed until the first hip or vertebral fracture or 31 December 2010. Data were analysed using Cox regression models and also stratified by age and gender. RESULTS: Frequent phototherapy decreased the fracture risks (adjusted hazard ratio (aHR)=0.32, p=0.009) in vitiligo patients. Stratification by age and gender confirmed the fracture prevention effect of frequent phototherapy in patients aged 40-64 years (aHR=0.14, p=0.016) and in female patients (aHR=0.31, p=0.024). CONCLUSIONS: This study provides the first evidence that frequent phototherapy can reduce the risk of fractures among middle-aged and among female vitiligo patients. PMID- 26988077 TI - Proton beam therapy. PMID- 26988076 TI - Identification of Potential Drug Targets in Cancer Signaling Pathways using Stochastic Logical Models. AB - The investigation of vulnerable components in a signaling pathway can contribute to development of drug therapy addressing aberrations in that pathway. Here, an original signaling pathway is derived from the published literature on breast cancer models. New stochastic logical models are then developed to analyze the vulnerability of the components in multiple signalling sub-pathways involved in this signaling cascade. The computational results are consistent with the experimental results, where the selected proteins were silenced using specific siRNAs and the viability of the cells were analyzed 72 hours after silencing. The genes elF4E and NFkB are found to have nearly no effect on the relative cell viability and the genes JAK2, Stat3, S6K, JUN, FOS, Myc, and Mcl1 are effective candidates to influence the relative cell growth. The vulnerabilities of some targets such as Myc and S6K are found to vary significantly depending on the weights of the sub-pathways; this will be indicative of the chosen target to require customization for therapy. When these targets are utilized, the response of breast cancers from different patients will be highly variable because of the known heterogeneities in signaling pathways among the patients. The targets whose vulnerabilities are invariably high might be more universally acceptable targets. PMID- 26988078 TI - Correction. PMID- 26988080 TI - Ischaemic stroke in the setting of glioblastoma: A case series and review of the literature. AB - Ischaemic strokes are an uncommon occurrence in the setting of glioblastoma, and clinically challenging due to co-existing deficits from the tumour, but important to consider as a possible cause of clinical deterioration. Modern therapies and their associated improvements in survival may lead to a greater overall incidence. The possible underlying causes of ischaemia are multiple, and several factors may contribute in a given patient. This review discusses the causative mechanisms of ischaemic strokes in the setting of glioblastoma, with some illustrative cases. PMID- 26988081 TI - Usefulness of quantitative peritumoural perfusion and proton spectroscopic magnetic resonance imaging evaluation in differentiating brain gliomas from solitary brain metastases. AB - OBJECTIVES: The purpose of our study was to evaluate whether peritumoural perfusion weighted and proton spectroscopic magnetic resonance imaging can be used in differentiating between primary gliomas and solitary metastases. METHODS: Ten low-grade gliomas, eight high-grade gliomas and 10 metastases were prospectively evaluated with magnetic resonance imaging, dynamic susceptibility contrast enhanced perfusion imaging and single-voxel proton magnetic resonance spectroscopy before surgical resection or stereotactic biopsy. Maximal relative cerebral blood volume values were calculated drawing three regions of interest of 2 cm(2) in the non-enhancing peritumoural areas. Maximal relative cerebral blood volume values were normalised to that of contralateral normal-appearing white matter. Maximal choline/creatine ratios were calculated from three voxels of 10 cm(3) placed in the peritumoural areas defined as non-enhancing peritumoural white matter surrounding the tumour. The tumour grade presumed with these values was compared to histopathological grading. Differences in the study parameters between groups were assessed using the Mann-Whitney test. A receiver operating characteristic analysis was performed to determine cut-off values. RESULTS: A clear relative cerebral blood volume cut-off value of 1.88 was detected for differentiating low-grade gliomas from high-grade gliomas. A clear relative cerebral blood volume cut-off value of 1.20 was detected for differentiation of metastases from gliomas. The differences in the choline/creatine ratios in the peritumoural regions of high-grade gliomas and of solitary metastasis were statistically significant (P < 0.001) but a clear cut-off value was not found. CONCLUSION: Our preliminary data support the hypothesis that peritumoural perfusion-weighted imaging can assist in preoperative differentiation between a glioma and a solitary metastasis. PMID- 26988082 TI - Imaging of connective tissue diseases of the head and neck. AB - We review the imaging appearance of connective tissue diseases of the head and neck. Bilateral sialadenitis and dacryoadenitis are seen in Sjogren's syndrome; ankylosis of the temporo-mandibular joint with sclerosis of the crico-arytenoid joint are reported in rheumatoid arthritis and lupus panniculitis with atypical infection are reported in patients with systemic lupus erythematosus. Relapsing polychondritis shows subglottic stenosis, prominent ear and saddle nose; progressive systemic sclerosis shows osteolysis of the mandible, fibrosis of the masseter muscle with calcinosis of the subcutaneous tissue and dermatomyositis/polymyositis shows condylar erosions and autoimmune thyroiditis. Vascular thrombosis is reported in antiphospholipid antibodies syndrome; cervical lymphadenopathy is seen in adult-onset Still's disease, and neuropathy with thyroiditis reported in mixed connective tissue disorder. Imaging is important to detect associated malignancy with connective tissue disorders. Correlation of the imaging findings with demographic data and clinical findings are important for the diagnosis of connective tissue disorders. PMID- 26988083 TI - Why a standard contrast-enhanced MRI might be useful in intracranial internal carotid artery stenosis. AB - In patients with ischemic stroke of unknown cause cerebral vasculitis is a rare but relevant differential diagnosis, especially when signs of intracranial artery stenosis are found and laboratory findings show systemic inflammation. In such cases, high-resolution T1w vessel wall magnetic resonance imaging (MRI; 'black blood' technique) at 3 T is preferentially performed, but may not be available in every hospital. We report a case of an 84-year-old man with right hemispheric transient ischemic attack and signs of distal occlusion in the right internal carotid artery (ICA) in duplex sonography. Standard MRI with contrast agent pointed the way to the correct diagnosis since it showed an intramural contrast uptake in the right ICA and both vertebral arteries. Temporal artery biopsy confirmed the suspected diagnosis of a giant cell arteritis and dedicated vessel wall MRI performed later supported the suspected intracranial large artery inflammation. Our case also shows that early diagnosis and immunosuppressive therapy may not always prevent disease progression, as our patient suffered several infarcts in the left middle cerebral artery (MCA) territory with consecutive high-grade hemiparesis of the right side within the following four months. PMID- 26988084 TI - Safety of coil occlusion of the parent artery for endovascular treatment of anterior communicating artery aneurysm. AB - Many studies lay emphasis on the clinical importance of perforating branches of the anterior communicating artery (ACoA) and report that vascular damage of the perforators from ACoA aneurysm during surgery cause subsequent postoperative amnesia. The purpose of our study was to analyze the safety of parent artery occlusion for ACoA aneurysm coiling based on the anatomical features of the ACoA complex in 13 patients with 13 ACoA aneurysms. All patients underwent coiling of the aneurysm sac and ACoA. Aneurysm characteristics including size, dome-to-neck ratio, anterior/posterior orientation of the aneurysm dome with respect to the axis of the pericallosal artery, location of the aneurysm neck with respect to the A1-A2 segment of the anterior cerebral artery (ACA) or the ACoA, and the presence of hypoplasia/aplasia of A1 segment were assessed. The aneurysm neck was located directly on the ACoA in five aneurysms (38%), whereas eight (62%) had the neck located at the A1-A2 junction. Of the five patients whose aneurysm neck was located in the ACoA, four patients had infarcts in the basal forebrain. Three of the patients complained of amnesia. None of the aneurysms with the neck located at the A1-A2 junction were associated with infarction. There has been little evidence thus far that parent vessel occlusion of ACoA aneurysms is a safe method for the treatment of aneurysms. Patients with the aneurysm neck located at the A1 A2 junction and without A1 aplasia, who were treated with aneurysm sac and ACoA embolism, were potentially safe. PMID- 26988087 TI - [Dr. Simon M. Danner - MedUni Wien RESEARCHER OF THE MONTH, Marz 2015]. PMID- 26988086 TI - Secondhand smoke exposure and mental health problems in Korean adults. AB - OBJECTIVES: To evaluate the association between secondhand smoke exposure (SHSE) and mental health problems among Korean adults. METHODS: We analyzed data from the 2011 Korean Community Health Survey. From the total of 229,226 participants aged 19 years or above, we excluded 48,679 current smokers, 36,612 former smokers, 3,036 participants with a history of stroke, 2,264 participants with a history of myocardial infarction, 14,115 participants who experienced at least one day in bed per month due to disability, and 855 participants for whom information regarding SHSE or mental health problems was not available. The final analysis was performed with 22,818 men and 100,847 women. Participants were classified into four groups according to the duration of SHSE: none, <1 hr/d, 1 <3 hr/d, and >=3 hr/d. The presence of depressive symptoms, diagnosed depression, and high stress were measured by questionnaire. RESULTS: After adjusting for demographic factors, lifestyle, and chronic disease, the odds ratio (OR) and 95% confidence interval (CI) of depressive symptoms with 1-<3 hr/d and >=3 hr/d SHSE were 1.44 (95% CI, 1.14 to 1.82) and 1.59 (95% CI, 1.46 to 1.74), respectively. However, SHSE >=3 hr/d had a higher OR of 1.37 (95% CI, 1.20 to 1.58) for diagnosed depression. SHSE was also associated with high stress (1-<3 hr/d: OR, 1.56; 95% CI, 1.38 to 1.76; >=3 hr/d: OR, 1.33 95% CI, 1.28 to 1.40). However, the association between SHSE and symptoms of depression and stress did not differ significantly by region. CONCLUSIONS: SHSE may be associated with mental health problems such as depression and stress in Korean adults. PMID- 26988085 TI - Comparative analysis of routes of immunization of a live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine in a heterologous virus challenge study. AB - Porcine reproductive and respiratory syndrome (PRRS) is caused by PRRS virus (PRRSV), which infects primarily the respiratory tract of pigs. Thus intranasal (IN) delivery of a potent vaccine-adjuvant formulation is promising. In this study, PRRS-MLV (VR2332) was coadministered +/- an adjuvant Mycobacterium vaccae whole cell lysate or CpG ODN through intramuscular (IM) or IN route as a mist, and challenged with a heterologous PRRSV 1-4-4 IN at 42 days post-vaccination (dpv). At 14 and 26 dpv, vaccine viral RNA copies were one log greater in the plasma of PRRS-MLV IM compared to IN vaccinated pigs, and the infectious replicating vaccine virus was detected only in the IM group. In PRRS-MLV +/- adjuvant IM vaccinated pigs, reduced viral RNA load and absence of the replicating challenged virus was observed at 7, 10 and 14 days post-challenge (dpc). At 14 dpc, in BAL fluid >= 5 log viral RNA copies were detected in all the pig groups, but the replicating challenged virus was undetectable only in IM groups. Immunologically, virus neutralizing antibody titers in the plasma of IM (but not IN) vaccine groups was >= 8 against the vaccine and challenged viruses. At 26 dpv, PRRS-MLV IM (without adjuvant) received pigs had significantly increased population of CD4 and CD8 T cells in PBMC. At 14 dpc, relatively increased population of IFN-gamma(+) total lymphocytes, NK, CD4, CD8 and gammadelta T cells were observed in the MLV-IM group. In conclusion, PRRS-MLV IM vaccination induced the virus specific T cell response in pigs, but still it is required to improve its cross-protective efficacy. PMID- 26988088 TI - Double sternal foramina in a dried sternum: a rare normal variant and its radiologic assessment. AB - Sternal foramina (SF) constitute developmental defects of the sternum and are usually radiologic or postmortem accidental findings. A rare case is presented, concerning the dried sternum of Greek origin and unknown age. The manubrium, sternal body and xiphoid process were fused and ossified, while two SF of undocumented size were present. The proximal SF was located at the sternal body extending between the fourth and fifth intercostal spaces, whereas the distal SF was located at the xiphoid process being surrounded by a thin "ring-like" osseous rim. Computed tomography was utilized for further investigation. Awareness of this variation is essential for the radiologist to avoid misdiagnosis and interpret with accuracy the current combination of normal anatomic variants. Moreover, SF existence is associated with clinical and forensic implications that are shortly discussed. PMID- 26988089 TI - Outcome of patients with local recurrent gynecologic malignancies after resection combined with intraoperative electron radiation therapy (IOERT). AB - BACKGROUND: Treatment of recurrent gynecologic cancer is a challenging issue. Aim of the study was to investigate clinical features and outcomes of patients with recurrent gynecologic malignancies who underwent resection including IOERT (intraoperative electron radiation therapy) with regard to clinical outcome and potential predictive factors or subgroups that benefit most from this radical treatment regime. METHODS: A total of 36 patients with recurrent gynecologic malignancies (cervical (n = 18), endometrial (n = 12) or vulvar cancer (n = 6)) were retrospectively identified through hospital databases in accordance with institutional ethical policies. Patient characteristics and outcomes were assessed. Survival data was analyzed using the Kaplan-Meier-method and log-rank test, categorical variables were analyzed with chi-square-method. RESULTS: For the entire cohort 1-/2-/5-year Overall Survival (OS) was 65.3 %/36.2 %/21.7 %. Patients with endometrial, cervical, and vulvar carcinoma had a 1-/2-/5-year OS of 83.3 %/62.5 %/50 %, 44.5 %/25.4 %/6.4 %, and 83.3 %/16.7 %/16.7 %, respectively. Patients with endometrial carcinoma showed a significantly better OS (p = 0.038). 1-/2-/5-year Local Progression-free Survival (LPFS) for the entire cohort was 44.1 %/28 %/21 % with 76.2 %/61 %/40.6 % for endometrial, 17.2 %/0 %/0 % for cervical, and 40 %/20 %/20 % for vulvar cancer, respectively. Patients with endometrial cancer showed a significantly (p = 0.017) and older patients a trend (p = 0.059) for a better LPFS. 1-/2-/5-year Distant Progression free Survival (DPFS) for the entire cohort was 53.1 %/46.5 %/38.7 % with 74.1 %/74.1 %/74.1 % for endometrial, 36.7 %/36.7 %/0 % for cervical, and 60 %/30 %/30 % for vulvar cancer, respectively. There was a significantly better DPFS for older patients (p = 0.015) and a trend for a better DPFS for patients with endometrial carcinoma (p = 0.075). CONCLUSION: The radical procedure of resection combined with IOERT seems to be a valid curative treatment option for patients with recurrent endometrial carcinoma with 5-year survival rates of 50 %. For patients with cervical or vulvar cancer this treatment should be considered a rather palliative one and must be weighted carefully against other treatment options like chemotherapy, targeted therapies or new highly conformal radiotherapy techniques. PMID- 26988094 TI - Genome analysis of the sugar beet pathogen Rhizoctonia solani AG2-2IIIB revealed high numbers in secreted proteins and cell wall degrading enzymes. AB - BACKGROUND: Sugar beet (Beta vulgaris) is a crop cultivated for its high content in sugar, but it is vulnerable to many soil-borne pathogens. One of them is the basidiomycete Rhizoctonia solani. This fungal species has a compatibility system regulating hyphal fusions (anastomosis). Consequently, R. solani species are categorized in anastomosis groups (AGs). AG2-2IIIB isolates are most aggressive on sugar beet. In the present study, we report on the draft genome of R. solani AG2-2IIIB using the Illumina technology. Genome analysis, interpretation and comparative genomics of five sequenced R. solani isolates were carried out. RESULTS: The draft genome of R. solani AG2-2IIIB has an estimated size of 56.02 Mb. In addition, two normalized EST libraries were sequenced. In total 20,790 of 21,980 AG2-2IIIB isotigs (transcript isoforms) were mapped on the genome with more than 95 % sequence identity. The genome of R. solani AG2-2IIIB was predicted to harbor 11,897 genes and 4908 were found to be isolate-specific. R. solani AG2 2IIIB was predicted to contain 1142 putatively secreted proteins and 473 of them were found to be unique for this isolate. The R. solani AG2-2IIIB genome encodes a high number of carbohydrate active enzymes. The highest numbers were observed for the polysaccharide lyases family 1 (PL-1), glycoside hydrolase family 43 (GH 43) and carbohydrate estarase family 12 (CE-12). Transcription analysis of selected genes representing different enzyme clades revealed a mixed pattern of up- and down-regulation six days after infection on sugar beets featuring variable levels of resistance compared to mycelia of the fungus grown in vitro. CONCLUSIONS: The established R. solani AG2-2IIIB genome and EST sequences provide important information on the gene content, gene structure and transcriptional activity for this sugar beet pathogen. The enriched genomic platform provides an important platform to enhance our understanding of R. solani biology. PMID- 26988095 TI - Efficacy of an educational intervention in primary health care in inhalation techniques: study protocol for a pragmatic cluster randomised controlled trial. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) accounts for 10-12 % of primary care consultations, 7 % of hospital admissions and 35 % of chronic incapacity related to productivity. The misuse of inhalers is a significant problem in COPD because it is associated with reduced therapeutic drug effects leading to lack of control of both symptoms and disease. Despite all advice, health care professionals' practice management of inhalation treatments is usually deficient. Interventions to improve inhaler technique by health care professionals are limited, especially among primary care professionals, who provide the most care to patients with COPD. The aim of this study is to evaluate the efficacy of an educational intervention to train general practitioners (GPs) in the right inhalation technique for the most commonly used inhalers. METHODS/DESIGN: We are conducting a pragmatic cluster randomised controlled trial. The sample population is composed of 267 patients diagnosed with COPD using inhalation therapy selected from among those in 20 general practices, divided into two groups (control and intervention) by block randomisation at 8 primary care centres. The sample has two levels. The first level is patients with COPD who agree to participate in the trial and receive the educational intervention from their GPs. The second level is GPs who are primary health care professionals and receive the educational intervention. The intervention is one session of the educational intervention with a monitor given to GPs for training in the right inhalation technique. The primary outcome is correct inhalation technique in patients. Secondary outcomes are functional status (spirometry) and quality of life. The follow-up period will be 1 year. GPs will have two visits (baseline and at the 1-year follow-up visit. Patients will have four visits (at baseline and 3, 6 and 12 months). Analysis will be done on an intention-to-treat basis. DISCUSSION: We carried out three previous clinical trials in patients with COPD, which showed the efficacy of an educational intervention based on monitor training to improve the inhalation technique in patients. This intervention is suitable and feasible in the context of clinical practice. Now we are seeking to know if we can improve it when the monitor is the GP (the real care provider in daily practise). TRIAL REGISTRATION: ISRCTN Registry identifier ISRCTN93725230 . Registered on 18 August 2014. PMID- 26988098 TI - Health Beliefs of Midwifery Students at Istanbul University about Breast Cancer and Breast Self-Examination Acknowledgements. AB - Knowing the attitudes and beliefs of midwifery students toward breast cancer and breast self-examination (BSE) practice may reduce breast cancer-related deaths by increasing breast cancer awareness. This study was conducted to examine the attitudes and beliefs of midwifery students toward breast cancer and the BSE practice. The study was conducted with 160 midwifery students at Istanbul University as a descriptive, cross-sectional study. Data were collected by a part of Champion's Health Belief Model Scale and a self-administered questionnaire. The descriptive characteristics were given as frequencies and percentages. The evaluation was done with Kruskal-Wallis test, a non-parametric test. It has been observed 70.0 % among midwifery students have knowledge of breast cancer. 90.0 % of midwifery students know about BSE, however only 14.4 % among them practice BSE regularly every month. The benefit, barrier and confidence sub-dimension scores were positively associated with BSE practice regularity (p <= 0.05). It has been determined that more than half of midwifery students have knowledge about breast cancer and BSE, and that only a fraction of those with knowledge about BSE practice BSE regularly every month. The perceived seriousness of breast cancer and knowledge about breast cancer affect the ability of individuals to perform BSE, initiating BSE and continuing to practice BSE for early diagnosis of breast cancer. The results from the study provide the midwifery students awareness of breast cancer and BSE both for themselves and for the women for whom they take responsibility. PMID- 26988099 TI - Drought-induced changes in photosynthetic apparatus and antioxidant components of wheat (Triticum durum Desf.) varieties. AB - Water deficit is a key factor influencing the yield and quality of crops. In the present study, the photosynthetic responses by means of chlorophyll fluorescence of chloroplasts, thylakoid membrane proteins, and antioxidant components were analyzed in wheat (Triticum durum Desf.) plants differing in their tolerance to drought. Two durum winter wheat varieties, Barakatli 95 (drought tolerant) and Garagylchyg 2 (drought sensitive) were grown under field well-watered and drought conditions. It was found that contents of the PS I core (CPI) with Mr of 123 kD and apoprotein P700 with Mr of 63 kD were relatively higher in Barakatli 95 variety under drought stress compared with the control plants. Synthesis of alpha and beta-subunits of CF1 ATP-synthase complex with Mr of 55 and 53.5 kD also slightly increased in the tolerant Barakatli 95 and decreased in the drought sensitive variety Garagylchyg 2. A decrease in the intensity of 30 kD band and a significant increase were found in the content of the 25-16 kD region in Garagylchyg 2 variety. The synthesis of 60 kD and content of low molecular mass polypeptides (21.5 and 12 kD) were increased in the tolerant genotype Barakatli 95. The intensity of peaks at 687, 695, and 742 nm considerably increases in the fluorescence spectra (77 K) of chloroplasts isolated from the sensitive variety Garagylchyg 2, and there is a stimulation of the ratio of fluorescence band intensity F687/F740. At the same time, higher level of glycine betaine was found in the drought tolerant variety compared with the control one throughout the different periods of growth. PMID- 26988096 TI - GLI pathogenesis-related 1 functions as a tumor-suppressor in lung cancer. AB - BACKGROUND: GLI pathogenesis-related 1 (GLIPR1) was originally identified in glioblastomas and its expression was also found to be down-regulated in prostate cancer. Functional studies revealed both growth suppression and proapoptotic activities for GLIPR1 in multiple cancer cell lines. GLIPR1's role in lung cancer has not been investigated. Protein arginine methyltransferase 5 (PRMT5) is a protein arginine methyltransferase and forms a stoichiometric complex with the WD repeat domain 77 (WDR77) protein. Both PRMT5 and WDR77 are essential for growth of lung epithelial and cancer cells. But additional gene products that interact genetically or biochemichally with PRMT5 and WDR77 in the control of lung cancer cell growth are not characterized. METHODS: DNA microarray and immunostaining were used to detect GLIPR1 expression during lung development and lung tumorigenesis. GLIPR1 expression was also analyzed in the TCGA lung cancer cohort. The consequence of GLIPR1 on growth of lung cancer cells in the tissue culture and lung tumor xenografts in the nude mice was observed. RESULTS: We found that GLIPR1 expression is negatively associated with PRMT5/WDR77. GLIPR1 is absent in growing epithelial cells at the early stages of mouse lung development and highly expressed in the adult lung. Expression of GLIPR1 was down-regulated during lung tumorigenesis and its expression suppressed growth of lung cancer cells in the tissue culture and lung tumor xenografts in mice. GLIPR1 regulates lung cancer growth through the V-Erb-B avian erythroblastic leukemia viral oncogene homolog 3 (ErbB3). CONCLUSIONS: This study reveals a novel pathway that PRMT5/WDR77 regulates GLIPR1 expression to control lung cancer cell growth and GLIPR1 as a potential therapeutic agent for lung cancer. PMID- 26988100 TI - Early pregnancy fasting plasma glucose and lipid concentrations in pregnancy and association to offspring size: a retrospective cohort study. AB - BACKGROUND: Hyperlipidemia and high fasting plasma glucose levels at the first prenatal visit (First Visit FPG) are both related to gestational diabetes mellitus, maternal obesity/overweight and fetal overgrowth. The purpose of the present study is to investigate the correlation between First Visit FPG and lipid concentrations, and their potential association with offspring size at delivery. MATERIALS AND METHODS: Pregnant women that received regular prenatal care and delivered in our center in 2013 were recruited for the study. Fasting plasma glucose levels were tested at the first prenatal visit (First Visit FPG) and prior to delivery (Before Delivery FPG). HbA1c and lipid profiles were examined at the time of OGTT test. Maternal and neonatal clinical data were collected for analysis. Data was analyzed by independent sample t test, Pearson correlation, and Chi-square test, followed by partial correlation and multiple linear regression analyses to confirm association. Statistical significance level was alpha =0.05. RESULTS: Analyses were based on 1546 mother-baby pairs. First Visit FPG was not correlated with any lipid parameters after adjusting for maternal pregravid BMI, maternal age and gestational age at First Visit FPG. HbA1c was positively correlated with triglyceride and Apolipoprotein B in the whole cohort and in the NGT group after adjusting for maternal age and maternal BMI at OGTT test. Multiple linear regression analyses showed neonatal birth weight, head circumference and shoulder circumference were all associated with First Visit FPG and triglyceride levels. CONCLUSION: Fasting plasma glucose at first prenatal visit is not associated with lipid concentrations in mid-pregnancy, but may influence fetal growth together with triglyceride concentration. PMID- 26988101 TI - Midwives' oral health recommendations for pregnant women, infants and young children: results of a nationwide survey in Germany. AB - BACKGROUND: Studies suggest that poor oral health during pregnancy can lead to perinatal complications, such as low birth weight and preterm delivery as well as poor oral health in children. Aim of this study was to assess the German midwives knowledge about oral health and preventive recommendations for pregnant women, infants and young children. METHODS: The nationwide online-survey was conducted with use of a self-developed, pretested and validated standardized questionnaire. The German association of midwives (Deutscher Hebammenverband e.V.) informed their members about the survey through email, newsletter, website and association journal (Hebammenforum) (n = 7.500). Data were analyzed using descriptive statistics. RESULTS: Response rate was 12.6 % (mean age 42.9 +/- 9.3 years). The majority of midwives advised pregnant women about periodontal diseases (78.6 %). Of the midwives, 8.4 % mentioned the possible associations between periodontal diseases and perinatal complications. In general, half of the midwives (53.5 %) recommended a dental visit during pregnancy. A total of 65.5 % of midwives advised parents about early childhood caries. The majority of midwives recommended that oral hygiene starts with eruption of the first tooth (60.4 %) and the first dental visit of the child should be at age 2 or 3 years (51.6 %). Midwives recommendations regarding the implementation of oral hygiene and the referral to a dentist during pregnancy and childhood were highly variable. CONCLUSIONS: To increase oral awareness and to improve the oral health knowledge among midwives and all other health-care professionals, uniform guidelines should be developed in Germany. TRIAL REGISTRATION: German Clinical Trial Register DRKS00008021. PMID- 26988103 TI - Involvement of NMDA receptors and L-arginine/nitric oxide/cyclic guanosine monophosphate pathway in the antidepressant-like effects of topiramate in mice forced swimming test. AB - Topiramate (TPM) is an agent primarily used in the treatment of epilepsy. Using mice model of forced swimming test (FST) the current study was basically aimed to investigate the influence of TPM on depression by inhibiting NMDA receptor and nitric oxide-cGMP production. When TPM was administered in a dose of 20 and 30 mg/kg by i.p. route it reduced the immobility time during FST. However this effect of TPM (30 mg/kg, i.p.) in the FST was abolished when the mice were pretreated either with NMDA (75 mg/kg, i.p.), or l-arginine (750 mg/kg, i.p. NO precursor), or sildenafil (5mg/kg, i.p. Phosphodiesterase 5 inhibitor). The immobility time in the FST was reduced after administration of L-NAME (10mg/kg, i.p, a non-specific NOS inhibitor), 7-nitoinidazol (30 mg/kg, i.p. a nNOS inhibitor) or MK-801 (0.05 mg/kg, i.p, a NMDA receptor antagonist) in combination with a subeffective dose of TPM (10mg/kg, i.p.) as compared with single use of either drug. Co-administrated of lower doses of MK-801 (0.01 mg/kg) or L-NAME (1mg/kg) failed to effect immobility time. However, simultaneous administration of these two agents in the same doses with subeffective dose of TPM (10mg/kg, i.p.), reduced the immobility time during FST. None of these drugs were found to have a profound effect on the locomotor activity per se during the open field test. Taken together, our data demonstrates that TPM exhibit antidepressant-like effect which is accomplished either due to inhibition of NMDA receptors or NO cGMP production. PMID- 26988102 TI - Generation and deposition of Abeta43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease. AB - As stated by the prevailing amyloid cascade hypothesis, Alzheimer's disease (AD) is caused by the aggregation and cerebral deposition of long amyloid-beta peptide (Abeta) species, which are released from a C-terminal amyloid precursor protein fragment by gamma-secretase. Mutations in its catalytic subunit presenilin-1 (PS1) increase the Abeta42 to Abeta40 ratio and are the major cause of familial AD (FAD). An opposing hypothesis states that loss of essential presenilin functions underlies the disease. A major argument for this hypothesis is the observation that the nearly inactive PS1 L435F mutant, paradoxically, causes FAD We now show that the very little Abeta generated by PS1 L435F consists primarily of Abeta43, a highly amyloidogenic species which was overlooked in previous studies of this mutant. We further demonstrate that the generation of Abeta43 is not due to a trans-dominant effect of this mutant on WT presenilin. Furthermore, we found Abeta43-containing plaques in brains of patients with this mutation. The aberrant generation of Abeta43 by this particular mutant provides a direct objection against the presenilin hypothesis. PMID- 26988104 TI - N-butyl cyanoacrylate- and alpha-cyanoacrylate induced hepatotoxicity and venous sclerosis in a rabbit model. AB - BACKGROUND AND STUDY AIMS: Tissue adhesives are commonly used. The aim of this study was to assess the efficacy and hepatotoxicity of intravenous injection of N butyl cyanoacrylate versus alpha-cyanoacrylate in a rabbit model. MATERIALS AND METHODS: A total of 20 rabbits were divided into three groups: group I included four rabbits injected with lipiodol in the dorsal vein of a pinna (control group); group II included eight rabbits injected with N-butyl cyanoacrylate/lipiodol; and group III included eight rabbits injected with alpha cyanoacrylate/lipiodol. All animals were left under normal living conditions for 1week, and then euthanised. Specimens of ear and liver were taken and fixed in 10% formalin saline for histological examination. Secondary fixation was performed using Bouin solution. Specimens of ear were decalcified in ethylenediaminetetraacetic acid (EDTA) at room temperature for 3months. Then, all specimens were processed, embedded in paraffin, sectioned, and stained with haematoxylin and eosin stains for microscopic examination. RESULTS: Microscopic examination of all specimens of the control group revealed normal structure of pinna and liver tissue. Both test groups demonstrated a wide variability of structural changes ranging from oedema and congestion to necrosis and marked cellular inflammatory infiltration. The two groups were compared using a self designed inflammatory score. This revealed that alpha-cyanoacrylate caused more venous sclerosis with extensive perivenous reaction and hepatotoxicity than both N-butyl cyanoacrylate and control (p<0.05 and p<0.05). N-butyl cyanoacrylate was also found to cause more venous sclerosis and hepatotoxicity than control (p<0.05). CONCLUSION: This study suggested that injection of Krazy Glue, either the clinically usable N-butyl cyanoacrylate or the commercially available alpha cyanoacrylate, caused comparable venous sclerosis. Unfortunately, both induced significant hepatotoxicity. Therefore, neither of them should be used unless all other safe options are absent. Larger studies have to be conducted and effects of these components on other organs should be investigated; however, caution must be exercised in their clinical use. PMID- 26988105 TI - Impact of point-of-care ultrasonography on ED time to disposition for patients with nontraumatic shock. AB - STUDY OBJECTIVE: Nontraumatic shock in the emergency department (ED) has multiple causes and carries in-hospital mortality approaching 20%, underscoring the need for prompt diagnosis and treatment. Diagnostic ultrasonography at the point of care is one method that may improve the ability of ED physicians to quickly diagnose and treat. This study assesses the effect of the use and timing of point of-care (POC) ultrasonography on time to disposition request. METHODS: This retrospective study across 4 Connecticut EDs compared propensity score matched shock patients who did and did not receive POC ultrasonography. Two propensity score matches were performed: the first using covariates of time to disposition from previous literature and the second using 25 novel covariates identified from electronic health records using machine learning to reduce variable selection biases. RESULTS: A total of 3834 unique patients presented with shock during an 18-month period, and 703 (18.3%) patients received POC ultrasonography. Mean time to disposition for all patients was 255.4minutes (interquartile range, 163.8). After propensity score matching, patients had a mean reduction of 26.7minutes (95% confidence interval [CI], 2.8-58.3) in time to disposition when POC ultrasonography was performed within 1hour of ED arrival and a lesser reduction of 16.7minutes (95% CI, -2.8 to 35.5) when POC ultrasonography was performed within 2hours. There was no evidence of reduction in time to disposition when ultrasonography was performed after 2hours (16.7minutes; 95% CI, -14.3 to 29.9). Propensity score models using machine learning-selected variables yielded similar results. CONCLUSION: Performance of POC ultrasonography likely improves time to disposition when performed early on ED patients with shock. PMID- 26988106 TI - Acute lethargy in a young woman due to latent disseminated cancer mimicking bacterial meningitis: a diagnostic pitfall. PMID- 26988107 TI - Stray light in cone beam optical computed tomography: II. Reduction using a convergent light source. AB - Optical cone beam computed tomography (CBCT) using a broad beam and CCD camera is a fast method for densitometry of 3D optical gel dosimeters. However, diffuse light sources introduce considerable stray light into the imaging system, leading to underestimation of attenuation coefficients and non-uniformities in CT images unless corrections are applied to each projection image. In this study, the light source of a commercial optical CT scanner is replaced with a convergent cone beam source consisting of almost exclusively image forming primary rays. The convergent source is achieved using a small isotropic source and a Fresnel lens. To characterize stray light effects, full-field cone beam CT imaging is compared to fan beam CT (FBCT) using a 1 cm high fan beam aperture centered on the optic axis of the system. Attenuating liquids are scanned within a large 96 mm diameter uniform phantom and in a small 13.5 mm diameter finger phantom. For the uniform phantom, cone and fan beam CT attenuation coefficients agree within a maximum deviation of (1 +/- 2)% between mean values over a wide range from 0.036 to 0.43 cm(-1). For the finger phantom, agreement is found with a maximum deviation of (4 +/- 2)% between mean values over a range of 0.1-0.47 cm(-1). With the convergent source, artifacts associated with refractive index mismatch and vessel optical features are more pronounced. Further optimization of the source size to achieve a balance between quantitative accuracy and artifact reduction should enable practical, accurate 3D dosimetry, avoiding time consuming 3D scatter measurements. PMID- 26988108 TI - Social and attention-to-detail subclusters of autistic traits differentially predict looking at eyes and face identity recognition ability. AB - This study distinguished between different subclusters of autistic traits in the general population and examined the relationships between these subclusters, looking at the eyes of faces, and the ability to recognize facial identity. Using the Autism Spectrum Quotient (AQ) measure in a university-recruited sample, we separate the social aspects of autistic traits (i.e., those related to communication and social interaction; AQ-Social) from the non-social aspects, particularly attention-to-detail (AQ-Attention). We provide the first evidence that these social and non-social aspects are associated differentially with looking at eyes: While AQ-Social showed the commonly assumed tendency towards reduced looking at eyes, AQ-Attention was associated with increased looking at eyes. We also report that higher attention-to-detail (AQ-Attention) was then indirectly related to improved face recognition, mediated by increased number of fixations to the eyes during face learning. Higher levels of socially relevant autistic traits (AQ-Social) trended in the opposite direction towards being related to poorer face recognition (significantly so in females on the Cambridge Face Memory Test). There was no evidence of any mediated relationship between AQ Social and face recognition via reduced looking at the eyes. These different effects of AQ-Attention and AQ-Social suggest face-processing studies in Autism Spectrum Disorder might similarly benefit from considering symptom subclusters. Additionally, concerning mechanisms of face recognition, our results support the view that more looking at eyes predicts better face memory. PMID- 26988109 TI - In Memoriam Patrick J. Mulrow, MD (1926-2015). PMID- 26988110 TI - Adult human metapneumonovirus (hMPV) pneumonia mimicking Legionnaire's disease. AB - In adults hospitalized with viral pneumonias the main differential diagnostic consideration is influenza pneumonia. The respiratory viruses causing viral influenza like illnesses (ILIs), e.g., RSV may closely resemble influenza. Rarely, extrapulmonary findings of some ILIs may resemble Legionnaire's disease (LD), e.g., adenovirus, human parainfluenza virus (HPIV-3). We present a most unusual case of human metapneumonovirus pneumonia (hMPV) with some characteristic extrapulmonary findings characteristic of LD, e.g., relative bradycardia, as well as mildly elevated serum transaminases and hyphosphatemia. We believe this is the first reported case of hMPV pneumonia in a hospitalized adult that had some features of LD. PMID- 26988111 TI - Graphene "microdrums" on a freestanding perforated thin membrane for high sensitivity MEMS pressure sensors. AB - We present a microelectromechanical system (MEMS) graphene-based pressure sensor realized by transferring a large area, few-layered graphene on a suspended silicon nitride thin membrane perforated by a periodic array of micro-through holes. Each through-hole is covered by a circular drum-like graphene layer, namely a graphene "microdrum". The uniqueness of the sensor design is the fact that introducing the through-hole arrays into the supporting nitride membrane allows generating an increased strain in the graphene membrane over the through hole array by local deformations of the holes under an applied differential pressure. Further reasons contributing to the increased strain in the devised sensitive membrane include larger deflection of the membrane than that of its imperforated counterpart membrane, and direct bulging of the graphene microdrum under an applied pressure. Electromechanical measurements show a gauge factor of 4.4 for the graphene membrane and a sensitivity of 2.8 * 10(-5) mbar(-1) for the pressure sensor with a good linearity over a wide pressure range. The present sensor outperforms most existing MEMS-based small footprint pressure sensors using graphene, silicon, and carbon nanotubes as sensitive materials, due to the high sensitivity. PMID- 26988113 TI - Interlayer breathing and shear modes in few-layer black phosphorus. AB - The interlayer breathing and shear modes in few-layer black phosphorus are investigated for their symmetry and lattice dynamical properties. The symmetry groups for the even-layer and odd-layer few-layer black phosphorus are utilized to determine the irreducible representation and the infrared and Raman activity for the interlayer modes. The valence force field model is applied to calculate the eigenvectors and frequencies for the interlayer breathing and shear modes, which are explained using the atomic chain model. The anisotropic puckered configuration for black phosphorus leads to a highly anisotropic frequency for the two interlayer shear modes. More specifically, the frequency for the shear mode in the direction perpendicular to the pucker is less than half of the shear mode in the direction parallel with the pucker. We also report a set of specular interlayer modes having the same frequency for all few-layer black phosphorus with layer numbers N being a multiple of 3, because these modes manifest themselves as collective vibrations of atoms in specific layers. The optical activity of the collective modes enables possible experimental identification for these modes. PMID- 26988114 TI - When prediction is fulfilled: Insight from emotion processing. AB - Research on prediction in language processing has focused predominantly on the function of predictive context and less on the potential contribution of the predicted word. The present study investigated how meaning that is not immediately prominent in the contents of predictions but is part of the predicted words influences sentence processing. We used emotional meaning to address this question. Participants read emotional and neutral words embedded in highly predictive and non-predictive sentential contexts, with the two sentential contexts rated similarly for their emotional ratings. Event Related Potential (ERP) effects of prediction and emotion both started at ~200ms. Confirmed predictions elicited larger P200s than violated predictions when the target words were non-emotional (neutral), but such an effect was absent when the target words were emotional. Likewise, emotional words elicited larger P200s than neutral words when the target words were non-predictive, but such effect were absent when the contexts were predictive. We conjecture that the prediction and emotion effects at ~200ms may share similar neural process(es). We suggest that such process(es) could be affective, where confirmed predictions and word emotion give rise to 'aha' or rewarding feelings, and/or cognitive, where both prediction and word emotion quickly engage attention. PMID- 26988115 TI - Does a single neurostimulation session really affect mood in healthy individuals? A systematic review. AB - Non-invasive neurostimulation or neuromodulation techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) were welcomed as promising tools for investigating cognitive and mood processes in healthy participants as well as in patients suffering from neuropsychiatric conditions. Due to their rather easy application, both modalities have been used to experimentally examine prefrontal cognitive and emotional control. However, it remains unclear whether a single session of such stimulation may affect the mood of participants in a healthy state. We provide a systematic review of studies reporting the effects of a single session of rTMS or tDCS (...-2014) on self-reported mood in healthy participants. Although early studies reported significant effects on self-reported mood in healthy participants, more recent work investigating mood effects after a single rTMS/tDCS session has failed to find any significant changes in self-reported mood. Therefore it appears that a single session of rTMS/tDCS has no impact on mood in the healthy state. PMID- 26988112 TI - Risk Factors for Hip Fracture in Older Men: The Osteoporotic Fractures in Men Study (MrOS). AB - Almost 30% of hip fractures occur in men; the mortality, morbidity, and loss of independence after hip fractures are greater in men than in women. To comprehensively evaluate risk factors for hip fracture in older men, we performed a prospective study of 5994 men, primarily white, age 65+ years recruited at six US clinical centers. During a mean of 8.6 years of 97% complete follow-up, 178 men experienced incident hip fractures. Information on risk factors including femoral neck bone mineral density (FNBMD) was obtained at the baseline visit. Cox proportional hazards models were used to calculate the hazard ratio (HR) with 95% confidence intervals; Fine and Gray models adjusted for competing mortality risk. Older age (>=75 years), low FNBMD, currently smoking, greater height and height loss since age 25 years, history of fracture, use of tricyclic antidepressants, history of myocardial infarction or angina, hyperthyroidism or Parkinson's disease, lower protein intake, and lower executive function were all associated with an increased hip fracture risk. Further adjustment for competing mortality attenuated HR for smoking, hyperthyroidism, and Parkinson's disease. The incidence rate of hip fracture per 1000 person-years (PY) was greatest in men with FNBMD T-scores <-2.5 (white women reference database) who also had 4+ risk factors, 33.4. Men age >=80 years with 3+ major comorbidities experienced hip fracture at rates of 14.52 versus 0.88 per 1000 PY in men age <70 years with zero comorbidities. Older men with low FNBMD, multiple risk factors, and multimorbidity have a high risk of hip fracture. Many of these assessments can easily be incorporated into routine clinical practice and may lead to improved risk stratification. (c) 2016 American Society for Bone and Mineral Research. PMID- 26988116 TI - Intra-hemispheric intrinsic connectivity asymmetry and its relationships with handedness and language Lateralization. AB - Asymmetry in intra-hemispheric intrinsic connectivity, and its association with handedness and hemispheric dominance for language, were investigated in a sample of 290 healthy volunteers enriched in left-handers (52.7%). From the resting state FMRI data of each participant, we derived an intra-hemispheric intrinsic connectivity asymmetry (HICA) matrix as the difference between the left and right intra-hemispheric matrices of intrinsic correlation computed for each pair of the AICHA atlas ROIs. We defined a similarity measure between the HICA matrices of two individuals as the correlation coefficient of their corresponding elements, and computed for each individual an index of intra-hemispheric intrinsic connectivity asymmetry as the average similarity measure of his HICA matrix to those of the other subjects of the sample (HICAs). Gaussian-mixture modeling of the age-corrected HICAs sample distribution revealed that two types of HICA patterns were present, one (Typical_HICA) including 92.4% of the participants while the other (Atypical_HICA) included only 7.6% of them, mostly left-handers. In addition, we investigated the relationship between asymmetry in intra hemispheric intrinsic connectivity and language hemispheric dominance, including a potential effect of handedness on this relationship, thanks to an FMRI acquisition during language production from which an hemispheric functional lateralization index for language (HFLI) and a type of hemispheric dominance for language, namely leftward, ambilateral, or rightward, were derived for each individual. There was a significant association between the types of language hemispheric dominance and of intra-hemispheric intrinsic connectivity asymmetry, occurrence of Atypical_HICAs individuals being very high in the group of individuals rightward-lateralized for language (80%), reduced in the ambilateral group (19%) and rare in individuals leftward-lateralized for language (less than 3%). Quantitatively, we found a significant positive linear relationship between the HICAs and HFLI indices, with an effect of handedness on the intercept but not on the slope of this relationship. These findings demonstrate that handedness and hemispheric dominance for language are significantly but independently associated with the asymmetry of intra-hemispheric intrinsic connectivity. These findings suggest that asymmetry in intra-hemispheric connectivity is a variable phenotype shaped in part by hemispheric lateralization for language, but possibly also depending on other lateralized functions. PMID- 26988117 TI - Slow cycling cells in the continuous dental lamina of Scyliorhinus canicula: new evidence for stem cells in sharks. AB - In the lesser spotted catshark (Scyliorhinus canicula), as in most non-mammalian vertebrates, the dentition renews throughout life. To contribute to our understanding of how continuous tooth replacement is achieved, we searched for evidence for the presence of stem cells in this species. Three-dimensional reconstructions of juvenile (2-3 weeks post-hatch) specimens showed that tooth families merge imperceptibly with so-called interdental zones within a continuous and permanent dental lamina. Interdental regions are composed of three layers, continuous with cervical loop, middle, and outer dental epithelium of the tooth families, respectively. A BrdU pulse-chase experiment revealed that cell proliferation is initiated in the lingual part of the dental lamina and the resulting population shifts one tooth position towards the oral epithelium in around four to five weeks. In the longest chase time (114 days) label-retaining and arguably non-differentiated cells were present at the lingual border of the dental lamina. These were found in the outer and middle dental epithelium, both within and between tooth families. This area of the dental lamina did not show expression or distribution of Sox2. Our data support the hypothesis that stem cells reside at the lingual border of the continuous dental lamina, more specifically in the middle dental epithelium at the level of the tooth families, and in its extension between the tooth families. To demonstrate their true stemness and their role in continuous tooth replacement, it remains to be shown that these cells have the potential to give rise to a complete new successor. PMID- 26988121 TI - The impact of thyroid abnormalities during pregnancy on subsequent neuropsychological development of the offspring: a meta-analysis. AB - OBJECTIVE: To investigate the relationship between specific thyroid abnormalities in women during pregnancy and the subsequent neuropsychological development of their offspring. METHODS: A systematic literature search of PubMed, Embase and Web of Science was conducted. Eligible studies were case-control or cohort study that explored this association with euthyroid thyroid abnormalities during pregnancy. The outcomes included intelligence scores and motor scores. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated and heterogeneity was assessed with Cochrane Q chi-square test and I(2) statistics. A fixed-effects or random-effects model was used to pool the estimates according to the heterogeneity among the included studies. RESULTS: Six studies, involving 4449 participants, were included. Children of women with thyroid abnormalities had mean intelligence score of 6.27 points and motor score of 5.99 points lower than that of children of euthyroid women. Subgroup analysis suggested that, children of women with hypothyroxinaemia, subclinical hypothyroidism and positive TPOAb had mean intelligence scores of 5.69 points, 8.76 points and 10.55 points, and mean motor scores of 4.19 points, 9.98 points and 9.03 points lower than those of the controls, respectively. CONCLUSIONS: The thyroid abnormalities in pregnant women may adversely affect neuropsychological development of their offspring. PMID- 26988120 TI - Epicardium is required for cardiac seeding by yolk sac macrophages, precursors of resident macrophages of the adult heart. AB - A subset of macrophages that reside in adult tissues originate from the fetal yolk sac, while others derive from circulating monocytes. These ontologically different macrophage subsets have distinct roles in tissue injury responses, with the embryonic population overall having beneficial activity in cardiac repair. Here we show that fetal yolk macrophages are recruited to a niche within and just below the epicardium, the mesothelial covering of the heart. The epicardium was required for establishment of yolk sac macrophages in this region of the fetal heart, and this function of epicardium depended on its expression of the transcription factor WT1. Thus, tissue-specific cues and transcriptional programs recruit or retain embryonic macrophages in their final abodes, where they help to shape organ homeostasis and injury responses. PMID- 26988118 TI - In vivo time-lapse imaging reveals extensive neural crest and endothelial cell interactions during neural crest migration and formation of the dorsal root and sympathetic ganglia. AB - During amniote embryogenesis the nervous and vascular systems interact in a process that significantly affects the respective morphogenesis of each network by forming a "neurovascular" link. The importance of neurovascular cross-talk in the central nervous system has recently come into focus with the growing awareness that these two systems interact extensively both during development, in the stem-cell niche, and in neurodegenerative conditions such as Alzheimer's Disease and Amyotrophic Lateral Sclerosis. With respect to the peripheral nervous system, however, there have been no live, real-time investigations of the potential relationship between these two developing systems. To address this deficit, we used multispectral 4D time-lapse imaging in a transgenic quail model in which endothelial cells (ECs) express a yellow fluorescent marker, while neural crest cells (NCCs) express an electroporated red fluorescent marker. We monitored EC and NCC migration in real-time during formation of the peripheral nervous system. Our time-lapse recordings indicate that NCCs and ECs are physically juxtaposed and dynamically interact at multiple locations along their trajectories. These interactions are stereotypical and occur at precise anatomical locations along the NCC migratory pathway. NCCs migrate alongside the posterior surface of developing intersomitic vessels, but fail to cross these continuous streams of motile ECs. NCCs change their morphology and migration trajectory when they encounter gaps in the developing vasculature. Within the nascent dorsal root ganglion, proximity to ECs causes filopodial retraction which curtails forward persistence of NCC motility. Overall, our time-lapse recordings support the conclusion that primary vascular networks substantially influence the distribution and migratory behavior of NCCs and the patterned formation of dorsal root and sympathetic ganglia. PMID- 26988119 TI - A cellular and molecular mosaic establishes growth and differentiation states for cranial sensory neurons. AB - We compared apparent origins, cellular diversity and regulation of initial axon growth for differentiating cranial sensory neurons. We assessed the molecular and cellular composition of the developing olfactory and otic placodes, and cranial sensory ganglia to evaluate contributions of ectodermal placode versus neural crest at each site. Special sensory neuron populations-the olfactory and otic placodes, as well as those in vestibulo-acoustic ganglion- are entirely populated with cells expressing cranial placode-associated, rather than neural crest associated markers. The remaining cranial sensory ganglia are a mosaic of cells that express placode-associated as well as neural crest-associated markers. We found two distinct populations of neural crest in the cranial ganglia: the first, as expected, is labeled by Wnt1:Cre mediated recombination. The second is not labeled by Wnt1:Cre recombination, and expresses both Sox10 and FoxD3. These populations-Wnt1:Cre recombined, and Sox10/Foxd3-expressing- are proliferatively distinct from one another. Together, the two neural crest-associated populations are substantially more proliferative than their placode-associated counterparts. Nevertheless, the apparently placode- and neural crest-associated populations are similarly sensitive to altered signaling that compromises cranial morphogenesis and differentiation. Acute disruption of either Fibroblast growth factor (Fgf) or Retinoic acid (RA) signaling alters axon growth and cell death, but does not preferentially target any of the three distinct populations. Apparently, mosaic derivation and diversity of precursors and early differentiating neurons, modulated uniformly by local signals, supports early cranial sensory neuron differentiation and growth. PMID- 26988122 TI - Immune responses induced by recombinant Bacillus subtilis expressing the spike protein of transmissible gastroenteritis virus in pigs. AB - Transmissible gastroenteritis (TGE) causes severe diarrhea in suckling piglets, results in enormous economic loss in swine-producing areas of the world. To develop an effective, safe, and convenient vaccine for the prevention of TGE, we have constructed a recombinant Bacillus subtilis strain (B. subtilis CotGSG) displaying the transmissible gastroenteritis virus (TGEV) spike (S) protein and discussed its immune function to intestinal submucosal dendritic cells (DCs). Our results showed that the recombinant B. subtilis had the ability to recruit more DCs to sample B. subtilis CotGSG, migrate to MLNs, and induce immune responses. Immunized piglets with B. subtilis CotGSG could significantly elevate the specific SIgA titers in feces, IgG titers and neutralizing antibodies in serum. Collectively, our results suggested that recombinant B. subtilis CotGSG expressing the TGEV S protein could effectively induce immune responses via DCs, and provided a perspective on potential novel strategy and approach that may be applicable to the development of the next generation of TGEV vaccines. PMID- 26988123 TI - Hand hygiene compliance: are we kidding ourselves? PMID- 26988124 TI - Preferred Barefoot Step Frequency is Influenced by Factors Beyond Minimizing Metabolic Rate. AB - Humans tend to increase their step frequency in barefoot walking, as compared to shod walking at the same speed. Based on prior studies and the energy minimization hypothesis we predicted that people make this adjustment to minimize metabolic cost. We performed an experiment quantifying barefoot walking metabolic rate at different step frequencies, specifically comparing preferred barefoot to preferred shod step frequency. We found that subjects increased their preferred frequency when walking barefoot at 1.4 m/s (~123 vs. ~117 steps/min shod, P = 2e 5). However, average barefoot walking metabolic rates at the preferred barefoot and shod step frequencies were not significantly different (P = 0.40). Instead, we observed subject-specific trends: five subjects consistently reduced (-8% average), and three subjects consistently increased (+10% average) their metabolic rate at preferred barefoot vs. preferred shod frequency. Thus, it does not appear that people ubiquitously select a barefoot step frequency that minimizes metabolic rate. We concluded that preferred barefoot step frequency is influenced by factors beyond minimizing metabolic rate, such as shoe properties and/or perceived comfort. Our results highlight the subject-specific nature of locomotor adaptations and how averaging data across subjects may obscure meaningful trends. Alternative experimental designs may be needed to better understand individual adaptations. PMID- 26988125 TI - Cdon, a cell surface protein, mediates oligodendrocyte differentiation and myelination. AB - During central nervous system development, oligodendrocyte progenitors (OLPs) establish multiple branched processes and axonal contacts to initiate myelination. A complete understanding of the molecular signals implicated in cell surface interaction to initiate myelination/remyelination is currently lacking. The objective of our study was to assess whether Cdon, a cell surface protein that was shown to participate in muscle and neuron cell development, is involved in oligodendrocyte (OLG) differentiation and myelination. Here, we demonstrate that endogenous Cdon protein is expressed in OLPs, increasing in the early differentiation stages and decreasing in mature OLGs. Immunocytochemistry of endogenous Cdon showed localization on both OLG cell membranes and cellular processes exhibiting puncta- or varicosity-like structures. Cdon knockdown with siRNA decreased protein levels by 62% as well as two myelin-specific proteins, MBP and MAG. Conversely, overexpression of full-length rat Cdon increased myelin proteins in OLGs. The complexity of OLGs branching and contact point numbers with axons were also increased in Cdon overexpressing cells growing alone or in coculture with dorsal root ganglion neurons (DRGNs). Furthermore, myelination of DRGNs was decreased when OLPs were transfected with Cdon siRNA. Altogether, our results suggest that Cdon participates in OLG differentiation and myelination, most likely in the initial stages of development. PMID- 26988128 TI - "Smart" RCTs: Development of a Smartphone App for Fully Automated Nutrition Labeling Intervention Trials. AB - BACKGROUND: There is substantial interest in the effects of nutrition labels on consumer food-purchasing behavior. However, conducting randomized controlled trials on the impact of nutrition labels in the real world presents a significant challenge. OBJECTIVE: The Food Label Trial (FLT) smartphone app was developed to enable conducting fully automated trials, delivering intervention remotely, and collecting individual-level data on food purchases for two nutrition-labeling randomized controlled trials (RCTs) in New Zealand and Australia. METHODS: Two versions of the smartphone app were developed: one for a 5-arm trial (Australian) and the other for a 3-arm trial (New Zealand). The RCT protocols guided requirements for app functionality, that is, obtaining informed consent, two stage eligibility check, questionnaire administration, randomization, intervention delivery, and outcome assessment. Intervention delivery (nutrition labels) and outcome data collection (individual shopping data) used the smartphone camera technology, where a barcode scanner was used to identify a packaged food and link it with its corresponding match in a food composition database. Scanned products were either recorded in an electronic list (data collection mode) or allocated a nutrition label on screen if matched successfully with an existing product in the database (intervention delivery mode). All recorded data were transmitted to the RCT database hosted on a server. RESULTS: In total approximately 4000 users have downloaded the FLT app to date; 606 (Australia) and 1470 (New Zealand) users met the eligibility criteria and were randomized. Individual shopping data collected by participants currently comprise more than 96,000 (Australia) and 229,000 (New Zealand) packaged food and beverage products. CONCLUSIONS: The FLT app is one of the first smartphone apps to enable conducting fully automated RCTs. Preliminary app usage statistics demonstrate large potential of such technology, both for intervention delivery and data collection. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12614000964617. New Zealand trial: Australian New Zealand Clinical Trials Registry ACTRN12614000644662. PMID- 26988126 TI - Structural and functional assessment of APOBEC3G macromolecular complexes. AB - There are eleven members in the human APOBEC family of proteins that are evolutionarily related through their zinc-dependent cytidine deaminase domains. The human APOBEC gene clusters arose on chromosome 6 and 22 through gene duplication and divergence to where current day APOBEC proteins are functionally diverse and broadly expressed in tissues. APOBEC serve enzymatic and non enzymatic functions in cells. In both cases, formation of higher-order structures driven by APOBEC protein-protein interactions and binding to RNA and/or single stranded DNA are integral to their function. In some circumstances, these interactions are regulatory and modulate APOBEC activities. We are just beginning to understand how macromolecular interactions drive processes such as APOBEC subcellular compartmentalization, formation of holoenzyme complexes, gene targeting, foreign DNA restriction, anti-retroviral activity, formation of ribonucleoprotein particles and APOBEC degradation. Protein-protein and protein nucleic acid cross-linking methods coupled with mass spectrometry, electrophoretic mobility shift assays, glycerol gradient sedimentation, fluorescence anisotropy and APOBEC deaminase assays are enabling mapping of interacting surfaces that are essential for these functions. The goal of this methods review is through example of our research on APOBEC3G, describe the application of cross-linking methods to characterize and quantify macromolecular interactions and their functional implications. Given the homology in structure and function, it is proposed that these methods will be generally applicable to the discovery process for other APOBEC and RNA and DNA editing and modifying proteins. PMID- 26988129 TI - Platelet-rich plasma as a novel treatment for lichen planopillaris. AB - Treatment of lichen planopillaris (LPP) remains a significant challenge due to the irreversible damage inflicted on hair follicles combined with the low efficacy of existing treatments. We hypothesized that growth factors released by the use of platelet-rich plasma (PRP) may arrest the development of LPP. To test our hypothesis, we treated an LPP patient that has failed previous treatments with a new PRP regimen. Following PRP treatment and six months follow-up, the patient experienced complete regression of itching and hair shedding. To the best of our knowledge, this is the first report of successful treatment of LPP with a PRP regimen. PMID- 26988131 TI - A pillared-layer framework with high uptake and selective sorption of light hydrocarbons. AB - A new pillared-layer metal-organic framework [Zn2(NH2-BTB)(2-nim)] () was successfully synthesized based on mixed ligands, where binuclear [Zn2(CO2)3](+) cluster-based cationic layers [Zn2(NH2-BTB)](+) (NH2-H3BTB = 1,3,5-(three-benzoic acid)aniline) are connected by 2-nitroimidazoles. Compound shows high uptake and good adsorption selectivities for C3/C1 and C2/C1. Particularly, the C2H2 uptake capacity of is up to 152 cm(3) g(-1) at 273 K and the selectivity for C3H8/CH4 is over 85 at room temperature. PMID- 26988130 TI - Investigational therapies for Ewing sarcoma: a search without a clear finding. AB - INTRODUCTION: Ewing sarcoma family tumors (ESFT) are a group of aggressive diseases, characterized histologically by small, round, blue cells and genetically by translocation involving EWS and ETS partner genes. The current treatment of localized Ewing sarcoma (ES) requires a multi-disciplinary approach, including multidrug chemotherapy, administrated before and after local treatment, surgery and radiation therapy. Unfortunately, the cure rate of metastatic or refractory/recurrent disease is still very poor. AREAS COVERED: In this review, the authors summarize the new types of therapy and strategies aimed to improve the prognosis or cure ES. Herein, the authors discuss several preclinical and phase I-II studies with new-targeted therapies. The most studied therapies are insulin-like growth factor receptor (IGF1R) inhibitors but have limited efficacy. Other strategies include Mammalian Target of Rapamycin (mTOR) Inhibition, poly ADP ribose polymerase (PARP) inhibition, vascular endothelial growth factor (VEGF) inhibition, tyrosine kinase inhibitors and telomerase inhibitors, all with limited effectiveness. EXPERT OPINION: Future treatment strategies should combine one or more targeted therapies with conventional chemotherapy. Some combined modality treatments are under clinical study. However, treatment breakthroughs are still needed to improve the relatively poor prognosis of recurrent/metastatic ESFT. PMID- 26988127 TI - Refinement of atomic models in high resolution EM reconstructions using Flex-EM and local assessment. AB - As the resolutions of Three Dimensional Electron Microscopic reconstructions of biological macromolecules are being improved, there is a need for better fitting and refinement methods at high resolutions and robust approaches for model assessment. Flex-EM/MODELLER has been used for flexible fitting of atomic models in intermediate-to-low resolution density maps of different biological systems. Here, we demonstrate the suitability of the method to successfully refine structures at higher resolutions (2.5-4.5A) using both simulated and experimental data, including a newly processed map of Apo-GroEL. A hierarchical refinement protocol was adopted where the rigid body definitions are relaxed and atom displacement steps are reduced progressively at successive stages of refinement. For the assessment of local fit, we used the SMOC (segment-based Manders' overlap coefficient) score, while the model quality was checked using the Qmean score. Comparison of SMOC profiles at different stages of refinement helped in detecting regions that are poorly fitted. We also show how initial model errors can have significant impact on the goodness-of-fit. Finally, we discuss the implementation of Flex-EM in the CCP-EM software suite. PMID- 26988133 TI - Spontaneous Regression of Hepatocellular Carcinoma-a Case Report. PMID- 26988134 TI - Acceptance and Body Dissatisfaction: Examining the Efficacy of a Brief Acceptance Based Intervention for Body Dissatisfaction in College Women. AB - BACKGROUND: Body dissatisfaction among college women is concerning given its high prevalence and associated negative consequences. While cognitive-behavioral approaches to reducing body dissatisfaction have considerable support, it may be beneficial to target the problematic relationship that some individuals have with their internal experiences. AIMS: To examine the relative efficacy of an acceptance-based compared to a cognitive restructuring approach to targeting body dissatisfaction. METHOD: College women were randomly assigned to an acceptance (n = 21), cognitive restructuring (n = 21) or a neutral comparison condition (n = 24). Participants completed a body dissatisfaction challenge postintervention and their dissatisfaction, distress about body-related thoughts and emotions, and the extent they felt defined by their outward appearance were measured. RESULTS: Both approaches provided a protective effect against decreases in body satisfaction and related feelings. CONCLUSION: Acceptance and CBT approaches to treating body dissatisfaction are worthy of future investigation. PMID- 26988132 TI - 2-phenylethynesulphonamide (PFT-MU) enhances the anticancer effect of the novel hsp90 inhibitor NVP-AUY922 in melanoma, by reducing GSH levels. AB - Heat shock proteins (HSPs), are molecular chaperones that assist the proper folding of nascent proteins. This study aims to evaluate the antitumour effects of the hsp90 inhibitor NVP-AUY922 in melanoma, both in vitro and in vivo. Our results show that NVP-AUY922 inhibits melanoma cell growth in vitro, with down regulation of multiple signalling pathways involved in melanoma progression such as NF-KB and MAPK/ERK. However, NVP-AUY922 was unable to limit tumour growth in vivo. Cotreatment of A375M xenografts with NVP-AUY922 and PFT-MU, a dual inhibitor of both hsp70 and autophagy, induced a synergistic increase of cell death in vitro, and delayed tumour formation in A375M xenografts. PFT-MU depleted cells from the reduced form of glutathione (GSH) and increased oxidative stress. The oxidative stress induced by PFT-MU further enhanced NVP-AUY922-induced cytotoxic effects. These data suggest a potential therapeutic role for NVP-AUY922 used in combination with PFT-MU, in melanoma. PMID- 26988135 TI - Fate of antibiotic resistance genes and its drivers during anaerobic co-digestion of food waste and sewage sludge based on microwave pretreatment. AB - In this study, anaerobic digestion of mono-SS, MW-SS:FW and SS:MW-FW was investigated to understand the fate of ARGs and its drivers. Anaerobic digestion was effective for the reduction of metal resistance genes (MRGs), and could reduce the abundance of blaOXA-1, sulI and tetG, while sulII in co-digestion and blaTEM and ereA only in MW-SS. ARGs reduction could be partly attributed to the reduction of co-selective pressure from heavy metals reflected by MRGs. However, the abundance of mefA/E, ermB, ermF, tetM and tetX increased significantly. Anaerobic co-digestion, especially for MW-SS, could reduce total ARGs abundance compared with mono-SS, and evolution of bacterial community was the main driver for the fate of ARGs. PMID- 26988136 TI - A new Burgess Shale-type deposit from the Ediacaran of western Mongolia. AB - Preservation of soft-bodied organisms is exceedingly rare in the fossil record. One way that such fossils are preserved is as carbonaceous compressions in fined grained marine sedimentary rocks. These deposits of exceptional preservation are known as Burgess Shale-type (BST) deposits. During the Cambrian Period, BST deposits are more common and provide a crucial view of early animal evolution. The earliest definitive fossil evidence for macroscopic animal-grade organisms is found in the preceding Ediacaran Period. BST deposits from the Ediacaran are rarer and lack conclusive evidence for animals. Here we report the discovery of a new Ediacaran BST deposit with exceptional preservation of non-mineralizing macro organisms in thinly bedded black shale from Zavkhan Province, western Mongolia. This fossil assemblage, here named the Zuun-Arts biota, currently consists of two new species of probable macroscopic multicellular benthic algae. One species, Chinggiskhaania bifurcata n. gen., n. sp., dominates the biota. The other species, Zuunartsphyton delicatum n. gen., n. sp., is known from three specimens. SEM-EDS analysis shows that the fossils are composed of aluminosilicate clay minerals and some carbon, a composition comparable to fossils from the Cambrian Burgess Shale biota. This discovery opens a new window through which to view late Precambrian life. PMID- 26988137 TI - Banff Borderline Changes Suspicious for Acute T Cell-Mediated Rejection: Where Do We Stand? AB - The definition of Banff Borderline became ambiguous when the Banff 2005 consensus modified the lower threshold from i1t1 (10-25% interstitial inflammation with mild tubulitis) to i0t1 (0-10% interstitial inflammation with mild tubulitis). We conducted a worldwide survey among members of the Renal Pathology Society about their approach to this diagnostic category. A web-based survey was sent out to all 503 current members (153 respondents). A database search yielded which threshold for Banff i was applied in the most influential manuscripts about Borderline. Among the 139 nephropathologists using the Borderline category, 67% use the Banff 1997 definition, requiring Banff i1. Thirty-seven percent admitted to sometimes exaggerating Banff i in the presence of tubulitis, to reach a diagnosis of Borderline. Forty-eight percent were dissatisfied with the definition of Borderline. The majority of the most influential manuscripts used the 1997 definition, contrary to the current one. There is considerable dissatisfaction with Borderline, and practice in Banff i thresholds is variable. Until additional studies inform a revision, we suggest leaving it to each pathologist's discretion whether to use i0 or i1 as the minimal threshold. In order to avoid future ambiguity, a web-based synopsis of all scattered current Banff definitions and rules should be created. PMID- 26988138 TI - Bubble Stripping as a Tool To Reduce High Dissolved CO2 in Coastal Marine Ecosystems. AB - High dissolved CO2 concentrations in coastal ecosystems are a common occurrence due to a combination of large ecosystem metabolism, shallow water, and long residence times. Many important coastal species may have adapted to this natural variability over time, but eutrophication and ocean acidification may be perturbing the water chemistry beyond the bounds of tolerance for these organisms. We are currently limited in our ability to deal with the geochemical changes unfolding in our coastal ocean. This study helps to address this deficit of solutions by introducing bubble stripping as a novel geochemical engineering approach to reducing high CO2 in coastal marine ecosystems. We use a process based model to find that air/sea gas exchange rates within a bubbled system are 1 2 orders of magnitude higher than within a nonbubbled system. By coupling bubbling-enhanced ventilation to a coastal ecosystem metabolism model, we demonstrate that strategically timed bubble plumes can mitigate exposure to high CO2 under present-day conditions and that exposure mitigation is enhanced in the more acidic conditions predicted by the end of the century. We argue that shallow water CO2 bubble stripping should be considered among the growing list of engineering approaches intended to increase coastal resilience in a changing ocean. PMID- 26988139 TI - Versatile protein tagging in cells with split fluorescent protein. AB - In addition to the popular method of fluorescent protein fusion, live cell protein imaging has now seen more and more application of epitope tags. The small size of these tags may reduce functional perturbation and enable signal amplification. To address their background issue, we adapt self-complementing split fluorescent proteins as epitope tags for live cell protein labelling. The two tags, GFP11 and sfCherry11 are derived from the eleventh beta-strand of super folder GFP and sfCherry, respectively. The small size of FP11-tags enables a cost effective and scalable way to insert them into endogenous genomic loci via CRISPR mediated homology-directed repair. Tandem arrangement FP11-tags allows proportional enhancement of fluorescence signal in tracking intraflagellar transport particles, or reduction of photobleaching for live microtubule imaging. Finally, we show the utility of tandem GFP11-tag in scaffolding protein oligomerization. These experiments illustrate the versatility of FP11-tag as a labelling tool as well as a multimerization-control tool for both imaging and non imaging applications. PMID- 26988141 TI - Kilohertz Pulsed-Laser-Polymerization: Simultaneous Determination of Backbiting, Secondary, and Tertiary Radical Propagation Rate Coefficients for tert-Butyl Acrylate. AB - For the first time, a 1000 Hz pulse laser has been applied to determine detailed kinetic rate coefficients from pulsed laser polymerization-size exclusion chromatography experiments. For the monomer tert-butyl acrylate, apparent propagation rate coefficients kp (app) have been determined in the temperature range of 0-80 degrees C. kp (app) in the range of few hundreds to close to 50 000 L.mol(-1) .s(-1) are determined for low and high pulse frequencies, respectively. The apparent propagation coefficients show a distinct pulse frequency dependency, which follows an S-shape curve. From these curves, rate coefficients for secondary radial propagation (kp (SPR) ), backbiting (kbb ), midchain radical propagation (kp (tert) ), and the (residual) effective propagation rate (kp (eff) ) can be deduced via a herein proposed simple Predici fitting procedure. For kp (SPR) , the activation energy is determined to be (17.9 +/- 0.6) kJ.mol(-1) in excellent agreement with literature data. For kbb , an activation energy of (25.9 +/- 2.2) kJ.mol(-1) is deduced. PMID- 26988140 TI - Sox2 in the differentiation of cochlear progenitor cells. AB - HMG domain transcription factor, Sox2, is a critical gene for the development of cochlear hair cells, the receptor cells for hearing, but this has been ascribed to expansion of the progenitors that become hair cells. Here, we show that Sox2 activated Atoh1, a transcription factor important for hair cell differentiation, through an interaction with the 3' enhancer of Atoh1. Binding to consensus sequences in the Atoh1 enhancer was dependent on the level of Sox2, and the extent of enhancer binding correlated to the extent of activation. Atoh1 activation by Sox2 was required for embryonic hair cell development: deletion of Sox2 in an inducible mutant, even after progenitor cells were fully established, halted development of hair cells, and silencing also inhibited postnatal differentiation of hair cells induced by inhibition of gamma-secretase. Sox2 is thus required in the cochlea to both expand the progenitor cells and initiate their differentiation to hair cells. PMID- 26988142 TI - [Epidemiology of oral diseases in a university hospital specialized consultation]. AB - INTRODUCTION: Oral diseases (OD) are common and affect, according to studies, 2.5 to 61.6% of general population. The main objective of our study was to determine the most common diagnoses of OD in a dedicated consultation in a University Hospital. MATERIAL AND METHOD: We conducted a descriptive observational study over 12 months from weekly OD consultations provided within the oral and maxillofacial surgery department at the Timone university hospital, Marseille, France. We divided our patient population into 4 subgroups: subgroup A, in which each patient was considered as a new one for each consultation; subgroup B, in which each patient was only considered once; subgroup C, including patients seen three times at least and subgroup D, including the children. At each consultation, were identified: age, sex, alcohol and tobacco consumption, corresponding physician specialty, time between onset of symptoms and consultation, reason for consultation and final diagnosis. RESULTS: Subgroups A, B, C and D respectively included 393, 208, 23 and 11 cases. Age and sex were similar in the subgroups A, B and C (mean age: 53.6, 54.3 and 51.4 years, respectively; female predominance: 62.9%, 66.8% and 65.2%, respectively). The most commonly encountered diagnoses were similar in the subgroups A and B: oral lichen planus (19.6% and 19.2%), aphthous stomatitis (11.5 and 7.2%), burning mouth syndrome (11.5 and 14.9%). In subgroup C, were found: oral lichen planus (34.8%), aphthous stomatitis (21.7%), cicatricial pemphigoid (13%) and pemphigus (13%). In the subgroup D, the most common diagnoses were aphthous stomatitis (45.5%) and traumatic injury (18.2%). The mean time before diagnosis was about 2 years. DISCUSSION: The most common diagnoses in a specialized OD consultation are: lichen planus, aphthous stomatitis and burning mouth syndrome. The time before diagnosis could be improved by means of more information for practitioners and patients. PMID- 26988145 TI - Palladium-catalyzed enantioselective allylic alkylation of trifluoromethyl group substituted racemic and acyclic unsymmetrical 1,3-disubstituted allylic esters with malonate anions. AB - We examined the palladium-catalyzed allylic alkylation of trifluoromethyl group substituted racemic and acyclic unsymmetrical 1,3-disubstituted allylic benzoate with a malonate anion, and succeeded in obtaining an enantiomerically enriched product in high yields with high ee values through the dynamic kinetic asymmetric transformation (DYKAT). The best result was attained by the [Pd(C3H5)(cod)]BF4/(S)-tol-BINAP in the presence of BSA or DMAP as a base. PMID- 26988144 TI - Decreased Cathepsin K Plasma Level may Reflect an Association of Osteopoenia/Osteoporosis with Coronary Atherosclerosis and Coronary Artery Calcification in Male Patients with Stable Angina. AB - BACKGROUND: The aim of this study was to evaluate the plasma levels of bone turnover markers (BTMs) in male patients with stable angina depending on the bone mineral density (BMD), coronary atherosclerosis (CA) and coronary artery calcification (CAC). METHODS: We recruited 112 males with verified stable angina. All the patients underwent coronary angiography, multislice spiral computed tomography, and dual-energy X-ray absorptiometry. Plasma levels of BTMs were measured by enzyme-linked immunosorbent assay. RESULTS: Osteopoenia and osteoporosis were reported in 90 (80.4%) and 34 (30.4%) patients, respectively. Multivessel coronary artery disease, severe CA and CAC, decreased cathepsin K plasma level, and increased osteocalcin plasma level were significantly more prevalent in patients with osteopoenia/osteoporosis compared to the subjects with normal BMD. Patients with severe CA and CAC had significantly reduced cathepsin K plasma levels. CONCLUSIONS: We revealed a significant association of osteopoenia/osteoporosis with severe CA and CAC in males with stable angina. Cathepsin K and osteocalcin plasma levels may be suggested as the significant markers of osteopoenia/osteoporosis. In addition, cathepsin K plasma level can be also a valuable marker of severe CA and CAC. PMID- 26988143 TI - Human adaptation and population differentiation in the light of ancient genomes. AB - The influence of positive selection sweeps in human evolution is increasingly debated, although our ability to detect them is hampered by inherent uncertainties in the timing of past events. Ancient genomes provide snapshots of allele frequencies in the past and can help address this question. We combine modern and ancient genomic data in a simple statistic (DAnc) to time allele frequency changes, and investigate the role of drift and adaptation in population differentiation. Only 30% of the most strongly differentiated alleles between Africans and Eurasians changed in frequency during the colonization of Eurasia, but in Europe these alleles are enriched in genic and putatively functional alleles to an extent only compatible with local adaptation. Adaptive alleles- especially those associated with pigmentation--are mostly of hunter-gatherer origin, although lactose persistence arose in a haplotype present in farmers. These results provide evidence for a role of local adaptation in human population differentiation. PMID- 26988147 TI - Diagnosing and treating HIV-associated sensory neuropathy: a global perspective. AB - HIV-associated sensory neuropathy (HIV-SN) is a common complication of HIV and remains highly prevalent even with modern HIV management strategies, causing debilitating pain in millions globally. We review HIV-SN diagnosis and management. We suggest most HIV-SN cases are easily recognized using clinical screening tools, with physician assessment and/or specialized testing prioritized for atypical cases. Management aims to prevent further nerve damage and optimize symptom control. Symptom relief is difficult and rarely complete, with a lack of proven pharmacological strategies. Work is needed to clarify optimal use of available medications. This includes understanding the marked placebo effect in HIV-SN analgesic trials and exploring 'responder phenotypes'. Limited data support nondrug strategies including hypnosis, meditation, psychology, physical activity and a positive therapeutic relationship. PMID- 26988148 TI - Effects of electrical stimulation at different locations in the central nucleus of amygdala on gastric motility and spike activity. AB - The aim of the study was to determine the effects of electrical stimulation of different locations in the central nucleus of amygdala (CNA) on gastric motility and spike activity in dorsal vagal complex. Gastric motility index (GMI) and firing rate (FR) of dorsal vagal complex neurons were measured in adult Wistar rats respectively. Neuronal spikes in dorsal vagal complex (DVC) were recorded extracellularly with single-barrel glass microelectrodes. Each type of responses elicited by electrical stimulation in medial (CEM) and lateral (CEL) subdivisions of CNA were recorded, respectively. GMI was significantly increased after stimulation of CEM (p<0.01), and significantly decreased in response to CEL stimulation (p<0.01). After stimulation of CEM, FR in medial nucleus of the solitary tract (mNST) decreased by 31.6 % (p<0.01) and that in dorsal motor nucleus of the vagus (DMNV) increased by 27.1 % (p<0.01). On the contrary, FR in mNST increased (p<0.01) and that in DMNV decreased in response to CEL stimulation (p<0.05). In conclusions, our findings indicated that different loci of CNA may mediate differential effects on gastric activity via changes in the firing of brainstem neurons controlling gut activity. PMID- 26988146 TI - Exploring regulatory networks of miR-96 in the developing inner ear. AB - Mutations in the microRNA Mir96 cause deafness in mice and humans. In the diminuendo mouse, which carries a single base pair change in the seed region of miR-96, the sensory hair cells crucial for hearing fail to develop fully and retain immature characteristics, suggesting that miR-96 is important for coordinating hair cell maturation. Our previous transcriptional analyses show that many genes are misregulated in the diminuendo inner ear and we report here further misregulated genes. We have chosen three complementary approaches to explore potential networks controlled by miR-96 using these transcriptional data. Firstly, we used regulatory interactions manually curated from the literature to construct a regulatory network incorporating our transcriptional data. Secondly, we built a protein-protein interaction network using the InnateDB database. Thirdly, gene set enrichment analysis was used to identify gene sets in which the misregulated genes are enriched. We have identified several candidates for mediating some of the expression changes caused by the diminuendo mutation, including Fos, Myc, Trp53 and Nr3c1, and confirmed our prediction that Fos is downregulated in diminuendo homozygotes. Understanding the pathways regulated by miR-96 could lead to potential therapeutic targets for treating hearing loss due to perturbation of any component of the network. PMID- 26988149 TI - Perindoprilat changes ANG (1-9) production in renal arteries isolated from young spontaneously hypertensive rats after ANG I incubation. AB - We used mass spectrometry to quantitate production of angiotensinogen metabolites in renal artery of 3- and 7-month-old Wistar-Kyoto (WKY) and Spontaneously Hypertensive Rats (SHR). Tissue fragments were incubated for 15 min in oxygenated buffer, with added angiotensin I. Concentrations of angiotensins I (ANG I), II (ANG II), III (ANG III), IV (ANG IV), angiotensin (1-9) [ANG (1-9)], angiotensin (1-7) [ANG (1-7)], and angiotensin (1-5) [ANG (1-5)], excreted into the buffer during experiment, were measured using liquid chromatography-mass spectrometry (LC/MS) and expressed per mg of dry tissue. Effects of pretreatment with 10 microM perindoprilat on the production of ANG I metabolites were quantitated. Background production of any of ANG I metabolites differed neither between WKY and SHR rats nor between 3- and 7-month-old rats. Perindoprilat pretreatment of renal arteries resulted, as expected, in decrease of ANG II production. However, renal arteries of 7-month-old SHR rats were resistant to ACE inhibitor and did not change ANG II production in response to perindoprilat. In renal arteries, taken from 3-month-old rats, pretreated with perindoprilat, incubation with ANG I, resulted in the level of ANG (1-9) significantly higher in SHR than WKY rats. Our conclusion is that in SHR rats, sensitivity of renal artery ACE to perindoprilat inhibition changes with age. PMID- 26988150 TI - Expression of aquaporin 1 and 5 and their regulation by ovarian hormones, arachidonic acid, forskolin and cAMP during implantation in pigs. AB - Aquaporin proteins (AQPs) are a family of channels expressed in numerous mammalian tissues, where they play a fundamental role in regulating water transport across cell membranes. Based on reports that AQPs are present in the reproductive system and participate in reproductive processes, our aim was to investigate the effect of progesterone (P(4)), estradiol (E(2)), oxytocin (OT), arachidonic acid (AA), forskolin (FSK) and cyclic adenosine monophosphate (cAMP) on AQP1 and AQP5 expression at mRNA and protein levels in porcine uterine explants from Days 14-16 of gestation in order to determine if they play a role in implantation period in pigs. Quantitative real time PCR and Western-blot analysis revealed that the uterine explants treated with FSK and cAMP produce delayed, but long-term effects on AQP1 abundance (24 h) while AQP5 had a rapid and sustained response to FSK and cAMP in protein content (3 and 24 h). AA increases gene and protein content of AQP1 after longer exposition whereas AQP5 increases after 3 h only at the protein level. Both AQPs potentially remains under control of steroid hormones. OT has been shown to increase AQP1, and decrease AQP5 mRNA, without visible changes in protein content. P(4), E(2), AA, FSK and cAMP caused the appearance of AQP5 expression in the basolateral plasma membrane of the epithelial cells. The staining represents most likely AQP5 functioning mechanism for both absorption and reabsorption across the glandular epithelium. PMID- 26988151 TI - Perfusion of isolated carotid sinus with hydrogen sulfide attenuated the renal sympathetic nerve activity in anesthetized male rats. AB - The purpose of the present study was to define the indirect central effect of hydrogen sulfide (H(2)S) on baroreflex control of sympathetic outflow. Perfusing the isolated carotid sinus with sodium hydrosulfide (NaHS), a H(2)S donor, the effect of H(2)S was measured by recording changes of renal sympathetic nerve activity (RSNA) in anesthetized male rats. Perfusion of isolated carotid sinus with NaHS (25, 50, 100 micromol/l) dose and time-dependently inhibited sympathetic outflow. Preconditioning of glibenclamide (20 micromol/l), a ATP sensitive K(+) channels (K(ATP)) blocker, the above effect of NaHS was removed. With 1, 4-dihydro-2, 6-dimethyl-5-nitro-4-(2-[trifluoromethyl] phenyl) pyridine-3 carboxylic acid methyl ester (Bay K8644, 500 nmol/l) pretreatment, which is an agonist of L-calcium channels, the effect of NaHS was eliminated. Perfusion of cystathionine gamma-lyase (CSE) inhibitor, DL-propargylglycine (PPG, 200 micromol/l), increased sympathetic outflow. The results show that exogenous H(2)S in the carotid sinus inhibits sympathetic outflow. The effect of H(2)S is attributed to opening K(ATP) channels and closing the L-calcium channels. PMID- 26988153 TI - Characteristic enhancement of blood pressure V-shaped waves in sinoaortic denervated rats in a conscious and quiet state. AB - A hemodynamic feature of chronic sinoaortic-denervated (SAD) rats is the increase in blood pressure variability (BPV) without significant changes in the average level of blood pressure (BP). The current study was designed to investigate the changes in BP V-shaped waves (V waves) in SAD rats. Sprague-Dawley (SD) rats were divided into 2 groups: SAD rats and sham-operated rats (n=13). Hemodynamics measurements were obtained in conscious, freely moving rats, four weeks after sinoaortic denervation or sham operation. V wave indices were evaluated in rats in both conscious and quiet states. Additionally, normal and high BPV was simulated by the production of V waves with different amplitudes. The results showed that the V wave amplitude was dramatically increased, with a significantly prolonged duration and reduced frequency in SAD rats. V wave BPV in SAD rats was significantly increased, though BP remained unchanged. The twenty-four hour BPV in all rats was positively correlated with amplitude, duration time and V wave BPV and negatively correlated with frequency. The systolic BP spectral powers in the low frequency range (0.38-0.45 Hz) were significantly reduced in the V waves of SAD rats. Moreover, there was a remarkable increase in mean BPV and a normal mean BP after simulating high BPV in SAD rats. These results suggest that enhancement of V waves might be a waveform character of BP in SAD rats in both the conscious and quiet states. These types of V waves appear to be related to a depression of sympathetic regulation of BP induced by sinoaortic denervation. PMID- 26988152 TI - Characterization of acetaminophen toxicity in human kidney HK-2 cells. AB - Acetaminophen (APAP) overdose causes liver injury, but in some cases it is associated also with renal impairment. While several studies exist in relation to acetaminophen nephrotoxicity, no reports have been published describing intracellular changes related to APAP nephrotoxicity in vitro. Because proximal tubular cells are considered to constitute a secondary site of drug-induced injury after hepatocytes, our study's aim was to estimate the toxicity in the human HK-2 cell line. We used a range of APAP concentrations (1-10 mM) to examine toxicity in the cells (1-48 h). We evaluated cell viability using the WST-1 and LDH tests. Cells impairment was also determined by monitoring ROS production, glutathione levels. We proved that HK-2 cells are able to metabolize acetaminophen. We observed moderate impairment of cells already after 1 h of treatment based on a finding of increased ROS production and decreased cell viability. After 24 h, the results showed significant cellular impairment at all tested concentrations except for 1 mM APAP, but no glutathione depletion was found. We conclude that HK-2 cells are susceptible to acetaminophen toxicity but, unlike hepatocytes, it might be not linked to glutathione depletion. PMID- 26988154 TI - The influence of the anastomosis angle on the hemodynamics in the distal anastomosis in the infrainguinal bypass: an in vitro study. AB - The geometric shape of the distal anastomosis in an infrainguinal bypass has an influence on its durability. In this article, we compared three different angles of the anastomosis with regard to the hemodynamics. Three experimental models of the distal infrainguinal anastomosis with angles of 25 degrees , 45 degrees , and 60 degrees respectively were constructed according to the similarity theory to assess flow in the anastomoses using particle image velocimetry and computational fluid dynamics. In the toe, heel, and floor of the anastomosis that correspond to the locations worst affected by intimal hyperplasia, adverse blood flow and wall shear stress were observed in the 45 degrees and 60 degrees models. In the 25 degrees model, laminar blood flow was apparent more peripherally from the anastomosis. In conclusions, decreasing the distal anastomosis angle in a femoropopliteal bypass results in more favorable hemodynamics including the flow pattern and wall shear stress in locations susceptible to intimal hyperplasia. PMID- 26988155 TI - The molecular mechanisms of calpains action on skeletal muscle atrophy. AB - Skeletal muscle atrophy is associated with a loss of muscle protein which may result from both increased proteolysis and decreased protein synthesis. Investigations on cell signaling pathways that regulate muscle atrophy have promoted our understanding of this complicated process. Emerging evidence implicates that calpains play key roles in dysregulation of proteolysis seen in muscle atrophy. Moreover, studies have also shown that abnormally activated calpain results muscle atrophy via its downstream effects on ubiquitin-proteasome pathway (UPP) and Akt phosphorylation. This review will discuss the role of calpains in regulation of skeletal muscle atrophy mainly focusing on its collaboration with either UPP or Akt in atrophy conditions in hope to stimulate the interest in development of novel therapeutic interventions for skeletal muscle atrophy. PMID- 26988156 TI - Effect of continuous passive motion initiated after the onset of arthritis on inflammation and secondary hyperalgesia in rats. AB - This study investigated the effect of continuous passive motion (CPM) initiated after the onset of arthritis in rats. Rats were injected with 3 % kaolin/carrageenan in the knee joint and randomized to the control, immobilization (IM), or CPM group. The knee joints of the IM and CPM groups were immobilized with a cast for 56 days. In the CPM group, CPM exercise was administered for 60 min/day (6 times/week). Joint transverse diameter and pressure pain threshold (PPT) were assessed as indicators of inflammation, and paw withdrawal response (PWR) was assessed as indicator of secondary hyperalgesia. Central sensitization was analyzed by measuring calcitonin gene related peptide (CGRP) expression levels in the spinal dorsal horn. In the CPM group, the PPT was significantly increased compared with the IM group from 14 to 35 days, and PWR was significantly decreased from 14 to 56 days. Additionally, CGRP expression in the super facial layer (I-II) of the spinal dorsal horn (L4-5) in the CPM group was significantly decreased compared with the IM group. Our study found the CPM initiated after the onset of arthritis promoted the recovery of inflammation and mitigated secondary hyperalgesia. PMID- 26988157 TI - No change in serum incretins levels but rise of leptin levels after smoking cessation: a pilot study. AB - The mechanisms behind the changes of body weight after smoking cessation are only partially understood. To this end, we explored the possible effects of smoking cessation on incretin hormones, leptin and selected anthropometric, biochemical and other hormonal parameters. Twenty-two non-obese male adult smokers attending an ambulatory smoking cessation program in Prague, Czech Republic, were examined at the baseline. Thirteen patients (mean age 37.92+/-2.66 years, mean body mass index 25.56+/-0.69 kg/m(2)) successfully quit smoking and were examined three months after smoking cessation; relapsed smokers were not followed up. The patients underwent 2-h liquid meal test with Fresubin and repeated blood sampling for measurements of blood glucose, gastric inhibitory polypeptide (GIP), glucagon like peptide 1 (GLP-1), amylin, insulin, leptin, peptide-YY (PYY) and pancreatic polypeptide (PP). Three months after smoking cessation, body weight increased (4.35+/-3.32 kg, p<0.001). Leptin levels increased significantly in all repeated samples, while levels of GIP, GLP-1, amylin, insulin, PYY and PP remained unchanged. In conclusions, smoking cessation increased leptin levels probably owing to weight gain while it did not influence incretin levels. PMID- 26988159 TI - Predicting blood flow responses to rhythmic handgrip exercise from one second isometric contractions. AB - The aim of this work was to predict blood flow responses to rhythmic handgrip exercise from one second isometric contractions. Seven healthy men were studied. Each subject performed a single 1 s handgrip contraction at 10 %, 20 % and 40 % of the maximum handgrip strength. We then repeatedly summed hyperaemic responses from single contractions to predict hyperaemic response to a prolonged bout of rhythmic exercise. There was similarity between steady state brachial blood flow velocity (BBV) extrapolated from single handgrip contractions and during 2 min of rhythmic exercise for 20 % (10.0+/-3.8 cm/s vs. 10.2+/-2.6 cm/s, r=0.93, p=0.003) and 40 % of maximum contractions (14.2+/-5.5 cm/s vs. 15.6+/-3.4 cm/s, r=0.88, p=0.009), but not for 10 % (7.5+/-4.1 cm/s vs. 5.7+/-3.3 cm/s, r=0.94, p=0.018). BBV progressively rose substantially higher during rhythmic contractions than peak BBV observed during single contractions at matched intensity. Respective peak BBV during single contractions and steady state BBV rhythmic contractions were 4.4+/-2.1 and 5.7+/-3.3 cm.s(-1) at 10 % forearm strength (p=0.14), 5.6+/ 2.4 and 10.2+/-2.8 cm.s(-1) at 20 % (p=0.002), and 7.0+/-2.5 and 15.6+/-3.6 cm.s( 1) at 40 % (p=0.003). In conclusion, there is similarity between the summated blood flow velocity calculated from a single 1 s muscle contraction and the steady state blood flow velocity response of rhythmic exercise. PMID- 26988158 TI - Comparison of the effects of tert-butyl hydroperoxide and peroxynitrite on the oxidative damage to isolated beef heart mitochondria. AB - Isolated beef heart mitochondria have been exposed to tert-butyl hydroperoxide (tBHP) and peroxynitrite (PeN) in order to model the effects of reactive oxygen and nitrogen species on mitochondria in vivo. The formation of malondialdehyde (MDA), protein carbonyls, lipofuscin-like pigments (LFP), and nitrotyrosine was studied during incubations with various concentrations of oxidants for up to 24 h. The oxidants differed in their ability to oxidize particular substrates. Fatty acids were more sensitive to the low concentrations of tBHP, whereas higher concentrations of PeN consumed MDA. Oxidation of proteins producing carbonyls had different kinetics and also a probable mechanism with tBHP or PeN. Diverse proteins were affected by tBHP or PeN. In both cases, prolonged incubation led to the appearance of proteins with molecular weights lower than 29 kDa bearing carbonyl groups that might have been caused by protein fragmentation. PeN induced nitration of protein tyrosines that was more intensive in the soluble proteins than in the insoluble ones. LFP, the end products of lipid peroxidation, were formed more readily by PeN. On the other hand, fluorometric and chromatographic techniques have confirmed destruction of LFP by higher PeN concentrations. This is a unique feature that has not been described so far for any oxidant. PMID- 26988160 TI - Postnatal expression of bone morphogenetic proteins and their receptors in the mouse testis. AB - TGF-beta superfamily members including bone morphogenetic proteins (BMPs) and their receptors (BMPR-1A, -1B and -2) have been shown to be important for reproductive function in both males and females, while information on the role of BMPs in males is limited. Functional studies on select BMPs and BMP receptors have demonstrated vital roles for these proteins in somatic and germ cell proliferation, steroidogenesis and overall fertility. In order to gain insight into the importance of these genes during postnatal reproductive development in males, our study was undertaken to specify the distribution of BMP and BMPR mRNA in male reproductive and steroidogenic tissues and quantify these genes in the testis using the mouse as our model. We screened testis at two, four, six and eight weeks of age for the expression of ten BMPs and three BMP receptors using RT-qPCR. All three BMP receptor mRNAs - Bmpr1a, Bmpr1b and Bmpr2, and ten BMP mRNAs - Bmp2, Bmp3, Bmp3b, Bmp4, Bmp5, Bmp6, Bmp7, Bmp8a, Bmp8b and Bmp15 were expressed in mouse testis at all stages screened. Testicular expression of genes varied within age groups and at specific developmental stages. Our study establishes an extensive BMP system in mouse reproductive and steroidogenic tissues. PMID- 26988161 TI - Analysis of expression profiles of genes involved in F(o)F(1)-ATP synthase biogenesis during perinatal development in rat liver and skeletal muscle. AB - During the process of intra-uterine mammalian fetal development, the oxygen supply in growing fetus is low. A rapid switch from glycolysis-based metabolism to oxidative phosphorylation (OXPHOS) must proceed during early postnatal adaptation to extra-uterine conditions. Mitochondrial biogenesis and mammalian mitochondrial F(o)F(1)-ATP synthase assembly (complex V, EC 3.6.3.14, ATPase) are complex processes regulated by multiple transcription regulators and assembly factors. Using RNA expression analysis of rat liver and skeletal tissue (Rattus norvegicus, Berkenhout, 1769), we describe the expression profiles of 20 genes involved in mitochondrial maturation and ATP synthase biogenesis in detail between the 16th and 22nd day of gestation and the first 4 days of life. We observed that the most important expression shift occurred in the liver between the 20th and 22nd day of gestation, indicating that the fetus prepares for birth about two days before parturition. The detailed mechanism regulating the perinatal adaptation process is not yet known. Deeper insights in perinatal physiological development will help to assess mitochondrial dysfunction in the broader context of cell metabolism in preterm newborns or neonates with poor adaptation to extra-uterine life. PMID- 26988162 TI - The role of the insular cortex in naloxone-induced conditioned place aversion in morphine-dependent mice. AB - A negative emotional state resulting from the withdrawal of drug addiction is thought to be an important factor that triggers and exacerbates relapse. Since the insular cortex is a key brain structure involved in the modulation of negative emotions, we investigated whether the integrity of the insular cortex was important for motivational aversion associated with morphine withdrawal as well as whether this kind of negative emotion induced neuroadaptation in the insular cortex. In this present study, a sensitive mouse conditioned place aversion (CPA) model measuring the motivational aversion of morphine withdrawal was first established. Our results showed that bilateral insular cortex lesions by kainic acid completely inhibited the expression of CPA. The expression of FosB/deltaFosB in the insular cortex was significantly increased 24 h after the CPA regime was performed, but the expression of c-Fos in the insular cortex did not changed. These findings indicate that the integrity of the insular cortex is essential to motivational aversion associated with morphine withdrawal, and that this kind of aversion induces neuroadaptation, observed as the increase of FosB/deltaFosB expression, in the insular cortex. PMID- 26988163 TI - CL316243 induces phosphatidylinositol 3,4,5-triphosphate production in rat adipocytes in an adenosine deaminase-, pertussis toxin-, or wortmannin-sensitive manner. AB - The effect of beta(3)-adrenoceptor (beta(3)-AR) agonists on adipocytes treated or not treated with signaling modulators has not been sufficiently elucidated. Using rat epididymal adipocytes (adipocytes) labeled with [(32)P]orthophosphate, we found that treatment with the selective beta(3)-AR agonist CL316243 (CL; 1 microM) induces phosphatidylinositol (PI) 3,4,5-triphosphate (PI[3,4,5]P(3)) production and that this response is inhibited by adenosine deaminase (ADA, an adenosine-degrading enzyme; 2 U/ml), pertussis toxin (PTX, an inactivator of inhibitory guanine-nucleotide-binding protein; 1 microg/ml), or wortmannin (WT, a PI-kinase inhibitor; 3 microM). The results showed that CL induced PI(3,4,5)P(3) production in intact adipocytes and that this production was affected by signaling modulators. Taken together, our findings indicate that CL produces PI(3,4,5)P(3) in an ADA-sensitive, PTX-sensitive, or WT-sensitive manner and will advance understanding of the effect of beta(3)-AR agonists on adipocytes. PMID- 26988164 TI - Two new asterriquinols from Aspergillus sp. CBS-P-2 with anti-inflammatory activity. AB - Two new bisindolylbenzenoid alkaloids asterriquinol E (1) and asterriquinol F (2), together with four known compounds (3-6) were isolated from the fermentation products of the fungus Aspergillus sp. CBS-P-2. Their structures were established on the basis of extensive spectroscopic analysis, including HR-ESI-MS, UV, IR, 1D, and 2D NMR (HSQC, HMBC, and NOESY) methods. The stereochemical structure of 2 was confirmed via the CD data of the in situ formed [Rh2(OCOCF3)4] complex method. All of the isolated compounds were tested for inhibitory activity against LPS (lipopolysaccharide)-induced nitric oxide production in microglia. PMID- 26988165 TI - Hardiness, psychosocial factors and shift work tolerance among nurses - a 2-year follow-up study. AB - AIM: To examine the predictive power of the subfactors of hardiness (commitment, control and challenge) on shift work tolerance (measured with sleepiness, fatigue, anxiety and depression) over 2 years in nurses working shifts. We also investigated the direct effects of psychosocial variables such as role conflict, social support and fair leadership on shift work tolerance, as well as their moderating role on the relationship between hardiness and shift work tolerance. BACKGROUND: Several scholars have discussed the role of individual differences and psychosocial variables in predicting shift work tolerance. The conclusions are not clear. DESIGN: Longitudinal questionnaire study. METHODS: A sample of Norwegian nurses employed in shift work including nights participated in this longitudinal questionnaire study: 1877 at baseline, 1228 at 1-year follow-up and 659 nurses at 2-year follow-up. Data were collected in three waves, first wave in 2008 and third in 2011 and were analysed with a series of hierarchical multiple regression analyses. RESULTS: We found that the subfactor commitment could predict fatigue over 1 year and anxiety and depression over 2 years. Challenge could predict anxiety over 1 year. Control was unrelated to shift work intolerance. Hardiness did not predict sleepiness. Social support, role conflict and fair leadership were important for some aspects of shift work tolerance; however, hardiness seemed to be more eminent for shift work tolerance than the psychosocial variables. Social support moderated the relationship between hardiness and shift work tolerance to some degree, but this interaction was weak. CONCLUSION: Hardiness can to some degree predict shift work tolerance over 2 years among nurses. PMID- 26988166 TI - [The importance of sleep deprivation as a mechanism for activating interictal epileptiform paroxysms]. AB - INTRODUCTION: Although sleep deprivation has been used for years in electroencephalography (EEG) as a method for activating interictal epileptiform discharges (IED) in patients with a strong suspicion of epilepsy, its sensitivity and specificity are still under discussion. PATIENTS AND METHODS: We conducted a descriptive retrospective study of paediatric patients who were referred to a neurophysiology clinic for epilepsy assessment. The results of the sleep-deprived EEG (SD-EEG) were compared with those of the wakefulness EEG (W-EEG) carried out in each patient in order to describe the performance of each method as a mechanism for activating IED. RESULTS: A total of 500 patients were analysed (830 SD-EEG and 1018 W-EEG). IED were detected in 44% of the W-EEG. SD-EEG increased the capacity of the test to detect IED by 35%. IED (not detected in the W-EEG) were detected in 25.1% of the SD-EEG in which spontaneous sleep was achieved. In the group of focal epilepsies, it was found that W-EEG detected IED in 60.1% versus the 79.12% displayed with SD-EEG. In generalised epilepsies this difference was more marked (27.2% and 77.2%, respectively). In patients in whom no IED were detected following an SD-EEG (23.7%) and the clinical suspicion of epilepsy was still high, nocturnal polysomnography was performed and interictal epileptiform activity was observed in 13.6%. CONCLUSIONS: SD-EEG increases the chances of recording IED by 35% with respect to W-EEG. Sleep deprivation is a method for activating epileptiform paroxysms, regardless of whether the EEG is performed while sleeping or not, although this effect is more pronounced in patients who do manage to sleep. PMID- 26988167 TI - [Frontal symptoms, self-perceived stress, and subjective memory complaints in substance abusers]. AB - INTRODUCTION: Substance addiction is a public health problem considering that every day increases the number of individuals with problem drug use, in this sense it is interesting the study of neuropsychological variables to understand the nature of addiction, understanding that brain circuits are involved in the establishment, maintenance and rehabilitation of the same. AIMS: To determine the influence of addiction on the frontal symptoms, self-perceived stress and subjective memory complaints, secondly, to analyze how these variables relate to people with addictions and finally, establish differences in them between addicts with and without subjective memory complaints. SUBJECTS AND METHODS: ISP, EEP-14 and MFE-30 instruments were applied to a sample of 115 substance abusers, and 115 people from non-clinical population, matched for age, sex and educational level. RESULTS: Significant differences are evident between addicted to substances and non-clinical subjects in the emotional scale ISP and MFE-30, also in the clinical sample highly significant correlations between all scales are observed; Finally, among people with addictions who reported memory complaints and those who do not, significant differences are evident on all scales except for the self-perceived stress. CONCLUSIONS: It is considered necessary to take into account the levels of self-perceived stress, frontal symptoms and subjective memory complaints in substance abusers, because the executive, attentional and mnemonic problems may affect several variables in the process of treatment and rehabilitation. PMID- 26988169 TI - [Refractory encephalitis because of seronegative celiac disease: a case report]. AB - INTRODUCTION: The celiac disease is an autoimmune bowel disease trigger by gliadine proteins, that can has systemic involvement with varied neurological manifestation since polineuropathy, ataxia, epilepsy, migraine to encephalitis. The aim of the current work is to report a case of possible refractory encephalitis due to celiac disease. CASE REPORT: A 45 years-old man with histopathologic diagnosis of celiac disease but negative celiac antibodies developed encephalic, brainstem and periphery nervous system manifestations: cognitive declaim and seizures, diplopia and ataxia, polyneuropathy and polyradiculopathy respectively; inflammatory cebrospinal fluid and cortico subcortical and multiple brainstem lesions with mild contrast enhancement; the neurologic deficits progress in spite of gluten a free diet and immuno suppressive treatment. During the illness process some pathologies with nervous system and intestinal involvement were discarded: sarcoidosis, systemic lupus; Sjogren syndrome, paraneoplastic syndromes, Whipple disease, AIDS and B12 vitamin deficit. CONCLUSION: The encephalitis is an infrequent clinical manifestation of the celiac disease despite the high prevalence of the celiac disease in the general population. It presents with numerous differential diagnosis, with requires high suspicious diagnosis. PMID- 26988171 TI - [XXX Reunion Annual de la Sociedad Andaluza de Neurofisiologia Clinica]. PMID- 26988168 TI - [Urgent stroke care in hospitals with a stroke unit. Quick Project]. AB - INTRODUCTION: A stroke is a time-dependent medical emergency. Swiftness in its recognition and in the care received by the patients plays a key role in the prognosis. AIMS: To analyse the medical intervention times, to evaluate possible areas where improvements can be made and to examine the allocation of resources in the centres. PATIENTS AND METHODS: The study was based on a prospective register of patients with suspected stroke and stroke code activation treated in eight experienced Spanish stroke units. Onset-to-door, door-to-computed tomography (CT), door-to-needle, CT-to-needle and onset-to-needle times were collected. Information about the means of transport used to get to the hospital, the type of stroke and reperfusion therapies was also collected. With regard to the structural resources of the centres, data were gathered about the nurse-to patient ratio, bed monitoring, availability of multimodal CT and magnetic resonance, and doing information or training courses. RESULTS: Altogether 197 patients were included, of whom 181 (151 infarctions and 30 brain haemorrhages) were valid. The medians (p25-p75) in minutes were: onset-to-door, 104 (70-188); door-to-CT, 27 (19-41); CT-to-needle, 30 (21-43); door-to-needle, 64 (49-83); and onset-to-needle, 156 (129-202). Reperfusion therapies were applied in 68 patients (45% of the cerebral infarctions), of which 81% were intravenous thrombolyses; 7%, endovascular treatments; and 12%, a combination of the two. The resources available in the centres were in accordance with those recommended by the clinical guidelines. There was a low percentage of patients who were studied by means of magnetic resonance. CONCLUSION: The percentage of patients treated with thrombolysis was very high and although the times of the in-hospital circuits were good, there is still room for further improvement. PMID- 26988170 TI - Epidemiology and neurological complications of infection by the Zika virus: a new emerging neurotropic virus. AB - INTRODUCTION: The current epidemic outbreak due to Zika virus began in 2015 and since then it has been reported in 31 countries and territories in America. The epidemiological and clinical aspects related to infection by Zika virus are reviewed. DEVELOPMENT: Since 2007, 55 countries in America, Asia, Africa and Oceania have detected local transmission of the virus. This epidemic has affected almost 1.5 million people in Brazil. 80% of the cases are asymptomatic. The symptoms of Zika virus disease include fever, maculopapular rash, arthralgia and non-purulent conjunctivitis. The symptoms are usually self-limiting and last one week. An increase in the incidence of cases of microcephaly, retinal lesions and Guillain-Barre syndrome associated with the Zika virus has been reported. Zika associated Guillain-Barre syndrome in Polynesia is a pure motor axonal variant. The RNA of the Zika virus has been identified in samples of brain tissue, placenta and amniotic liquid of children with microcephaly and in the still-born infants of women infected by Zika during pregnancy. The reverse transcription polymerase chain reaction test is recommended to detect viral RNA, and serological tests (IgM ELISA and neutralising antibodies) should be conducted to confirm infection by Zika. The differential diagnosis includes infection by the dengue and chikungunya viruses. CONCLUSIONS: Knowledge about the pathogenic mechanisms involved in infection due to Zika virus and its long-term consequences in adults and newborn infants is still limited. PMID- 26988172 TI - [Cerebellar syndrome induced by metronidazole: a rare side effect]. PMID- 26988173 TI - IV and V cranial nerves dysfunction as initial manifestations of superficial siderosis of the central nervous system. PMID- 26988174 TI - [Quantification of stress: incomplete information plus excessive triumphalism]. PMID- 26988175 TI - [Quantification of stress: incomplete information plus excessive triumphalism. Reply]. PMID- 26988176 TI - Curvature-dependent adsorption of water inside and outside armchair carbon nanotubes. AB - The curvature dependence of the physisorption properties of a water molecule inside and outside an armchair carbon nanotube (CNT) is investigated by an incremental density-fitting local coupled cluster treatment with single and double excitations and perturbative triples (DF-LCCSD(T)) study. Our results show that a water molecule outside and inside (n, n) CNTs (n = 4, 5, 6, 7, 8, 10) is stabilized by electron correlation. The adsorption energy of water inside CNTs decreases quickly with the decrease of curvature (increase of radius) and the configuration with the oxygen pointing toward the CNT wall is the most stable one. However, when the water molecule is adsorbed outside the CNT, the adsorption energy varies only slightly with the curvature and the configuration with hydrogens pointing toward the CNT wall is the most stable one. We also use the DF LCCSD(T) results to parameterize Lennard-Jones (LJ) force fields for the interaction of water both with the inner and outer sides of CNTs and with graphene representing the zero curvature limit. It is not possible to reproduce all DF-LCCSD(T) results for water inside and outside CNTs of different curvature by a single set of LJ parameters, but two sets have to be used instead. Each of the two resulting sets can reproduce three out of four minima of the effective potential curves reasonably well. These LJ models are then used to calculate the water adsorption energies of larger CNTs, approaching the graphene limit, thus bridging the gap between CNTs of increasing radius and flat graphene sheets. PMID- 26988177 TI - Clear cell renal cell tumors: Not all that is "clear" is cancer. AB - Continued improvement of our understanding of the clinical, histologic, and genetic features of renal cell tumors has progressively evolved renal tumor classification, revealing an expanding array of distinct tumor types with different implications for prognosis, patient counseling, and treatment. Although clear cell renal cell carcinoma is unequivocally the most common adult renal tumor, there is growing evidence that some "clear cell" renal neoplasms, such as exemplified by multilocular cystic clear cell renal neoplasm of low malignant potential (formerly multilocular cystic renal cell carcinoma), do not have the same potential for insidious progression and metastasis, warranting reclassification as low malignant potential tumors or benign neoplasms. Still other novel tumor types such as clear cell papillary renal cell carcinoma have been more recently recognized, which similarly have shown a conspicuous absence of aggressive behavior to date, suggesting that these too may be recategorized as noncancerous or may be premalignant neoplasms. This importance for prognosis is increasingly significant in the modern era, in which renal masses are increasingly found incidentally by imaging techniques at a small tumor size, raising consideration for less aggressive management options guided by renal mass biopsy diagnosis, including imaging surveillance, tumor ablation, or partial nephrectomy. PMID- 26988180 TI - Gender-Related Factors for Depressive Symptoms in Turkish Adolescents. AB - PROBLEM: Currently more adolescents suffer from mental health problems than compared to the past. PURPOSE: This study was designed to extend the knowledge of depressive symptoms in adolescence and to determine the gender-related factors associated with it. METHODS: The study sample consisted of (N = 487) adolescents. The Children's Depression Inventory (CDI), Multidimensional Scale of Perceived Social Support (MSPSS), Strengths and Difficulties Questionnaire (SDQ-S), and UCLA loneliness scale (UCLA-LS) were completed by the participants. FINDINGS: Among the study population, 26.6% (n = 130) scored >= 19 on the CDI, which was the cut-off point. UCLA-LS, hyperactivity and conduct problems, and peer problems subscale scores of SDQ-S were found significantly higher in males (p < .05). Emotional symptoms, pro-social behavior subscale scores of SDQ-S, and a family member, a friend subscale scores of MSPSS were found significantly higher in females (p < .05). For males, loneliness and hyperactivity and conduct problems, while for females, emotional symptoms and loneliness (p < .05) were predictive variables. Pro-social behavior and perceived family member support were protective variables for females scoring high enough to be diagnosed with depression (p < .05). CONCLUSION: We suggest further studies to confirm these results as well as establishing strategies for better detection of depressive symptoms when working on adolescents. PMID- 26988179 TI - Molecular Signaling Pathways Behind the Biological Effects of Salvia Species Diterpenes in Neuropharmacology and Cardiology. AB - The genus Salvia, from the Lamiaceae family, has diverse biological properties that are primarily attributable to their diterpene contents. There is no comprehensive review on the molecular signaling pathways of these active components. In this review, we investigated the molecular targets of bioactive Salvia diterpenes responsible for the treatment of nervous and cardiovascular diseases. The effects on different pathways, including apoptosis signaling, oxidative stress phenomena, the accumulation of amyloid beta plaques, and tau phosphorylation, have all been considered to be mechanisms of the anti-Alzheimer properties of Salvia diterpenes. Additionally, effects on the benzodiazepine and kappa opioid receptors and neuroprotective effects are noted as neuropharmacological properties of Salvia diterpenes, including tanshinone IIA, salvinorin A, cryptotanshinone, and miltirone. Tanshinone IIA, as the primary diterpene of Salvia miltiorrhiza, has beneficial activities in heart diseases because of its ability to scavenge free radicals and its effects on transcription factors, such as nuclear transcription factor-kappa B (NF-kappaB) and the mitogen activated protein kinases (MAPKs). Additionally, tanshinone IIA has also been proposed to have cardioprotective properties including antiarrhythmic activities and effects on myocardial infarction. With respect to the potential therapeutic effects of Salvia diterpenes, comprehensive clinical trials are warranted to evaluate these valuable molecules as lead compounds. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26988181 TI - Phototrophic pigment production with microalgae: biological constraints and opportunities. AB - There is increasing interest in naturally produced colorants, and microalgae represent a bio-technologically interesting source due to their wide range of colored pigments, including chlorophylls (green), carotenoids (red, orange and yellow), and phycobiliproteins (red and blue). However, the concentration of these pigments, under optimal growth conditions, is often too low to make microalgal-based pigment production economically feasible. In some Chlorophyta (green algae), specific process conditions such as oversaturating light intensities or a high salt concentration induce the overproduction of secondary carotenoids (beta-carotene in Dunaliella salina (Dunal) Teodoresco and astaxanthin in Haematococcus pluvialis (Flotow)). Overproduction of all other pigments (including lutein, fucoxanthin, and phycocyanin) requires modification in gene expression or enzyme activity, most likely combined with the creation of storage space outside of the photosystems. The success of such modification strategies depends on an adequate understanding of the metabolic pathways and the functional roles of all the pigments involved. In this review, the distribution of commercially interesting pigments across the most common microalgal groups, the roles of these pigments in vivo and their biosynthesis routes are reviewed, and constraints and opportunities for overproduction of both primary and secondary pigments are presented. PMID- 26988178 TI - The changing tobacco landscape: What dental professionals need to know. AB - BACKGROUND: Tobacco products in the United States and the patterns of tobacco use are changing. Although cigarette smoking prevalence has declined, dental professionals are likely to encounter substantial numbers of patients who have tried and are continuing to use new and alternative tobacco products, including cigars, water pipes (hookahs), and electronic cigarettes, as well as conventional and new smokeless tobacco products. METHODS: The authors reviewed conventional and new tobacco products in the United States, their adverse oral and systemic health effects, and their prevalence of use. RESULTS: Tobacco products other than cigarettes account for a substantial portion of tobacco use. For this reason, tobacco-use prevention and cessation counseling provided by dental health care professionals must address all tobacco products, including cigarettes, cigars, water pipes, and electronic cigarettes, as well as conventional and new smokeless tobacco products. Cigarette smoking and smokeless tobacco use are associated with immediate and long-term adverse health effects, including nicotine addiction, oral and systemic disease, and death. Novel products may attract new tobacco users, potentially leading to addiction that results in enduring tobacco product use and associated adverse health effects. CONCLUSIONS: This critical review of conventional, new, and emerging tobacco products presents information that dental professionals can use in providing tobacco-related counseling to patients who use or who are at risk for using tobacco products. PRACTICAL IMPLICATIONS: It is essential that dental professionals are knowledgeable about tobacco products and are able to answer patients' questions and provide them with evidence-based tobacco-related counseling. This information may prevent patients from initiating use or help reduce or cease use to avoid immediate and long-term adverse health effects, including nicotine addiction, oral and systemic disease, and death. PMID- 26988182 TI - Acclimation conditions modify physiological response of the diatom Thalassiosira pseudonana to elevated CO2 concentrations in a nitrate-limited chemostat. AB - Diatoms are responsible for a large proportion of global carbon fixation, with the possibility that they may fix more carbon under future levels of high CO2 . To determine how increased CO2 concentrations impact the physiology of the diatom Thalassiosira pseudonana Hasle et Heimdal, nitrate-limited chemostats were used to acclimate cells to a recent past (333 +/- 6 MUatm) and two projected future concentrations (476 +/- 18 MUatm, 816 +/- 35 MUatm) of CO2 . Samples were harvested under steady-state growth conditions after either an abrupt (15-16 generations) or a longer acclimation process (33-57 generations) to increased CO2 concentrations. The use of un-bubbled chemostat cultures allowed us to calculate the uptake ratio of dissolved inorganic carbon relative to dissolved inorganic nitrogen (DIC:DIN), which was strongly correlated with fCO2 in the shorter acclimations but not in the longer acclimations. Both CO2 treatment and acclimation time significantly affected the DIC:DIN uptake ratio. Chlorophyll a per cell decreased under elevated CO2 and the rates of photosynthesis and respiration decreased significantly under higher levels of CO2 . These results suggest that T. pseudonana shifts carbon and energy fluxes in response to high CO2 and that acclimation time has a strong effect on the physiological response. PMID- 26988183 TI - Differences in the chemical composition of organic-walled dinoflagellate resting cysts from phototrophic and heterotrophic dinoflagellates. AB - Dinoflagellates constitute a large proportion of the planktonic biomass from marine to freshwater environments. Some species produce a preservable organic walled resting cyst (dinocyst) during the sexual phase of their life cycle that is an important link between the organisms, the environment in which their parent motile theca grew, and the sedimentary record. Despite their abundance and widespread usage as proxy indicators for environmental conditions, there is a lack of knowledge regarding the dinocyst wall chemical composition. It is likely that numerous factors, including phylogeny and life strategy, determine the cyst wall chemistry. However, the extent to which this composition varies based on inherent (phylogenetic) or variable (ecological) factors has not been studied. To address this, we used micro-Fourier transform infrared spectroscopy to analyze nine cyst species produced by either phototrophic or heterotrophic dinoflagellates from the extant orders Gonyaulacales, Gymnodiniales, and Peridiniales. Based on the presence of characteristic functional groups, two significantly different cyst wall compositions are observed that correspond to the dinoflagellate's nutritional strategy. The dinocyst wall compositions analyzed appeared carbohydrate-based, but the cyst wall produced by phototrophic dinoflagellates suggested a cellulose-like glucan, while heterotrophic forms produced a nitrogen-rich glycan. This constitutes the first empirical evidence nutritional strategy is related to different dinocyst wall chemistries. Our results indicated phylogeny was less important for predicting composition than the nutritional strategy of the dinoflagellate, suggesting potential for cyst wall chemistry to infer past nutritional strategies of extinct taxa preserved in the sedimentary record. PMID- 26988184 TI - Regulation of polyamine metabolism in Pyropia cinnamomea (W.A. Nelson), an important mechanism for reducing UV-B-induced oxidative damage. AB - It is generally accepted that ultraviolet (UV) radiation can have adverse affects on phototrophic organisms, independent of ozone depletion. The red intertidal seaweed Pyropia cinnamomea W.A. Nelson (previously Porphyra cinnamomea Sutherland et al. 2011), similar to many other intertidal macrophytes, is exposed to high levels of UV radiation on a daily basis due to emersion in the upper littoral zone. It has been shown that seaweeds, like higher plants, respond to an increased activity of antioxidative enzymes when exposed to stress. However, earlier investigations have shown that P. cinnamomea also compensates for stress due to UV radiation by increasing polyamine (PA) levels, especially bound-soluble and bound-insoluble PAs. The PA precursor putrescine (PUT) can be synthesized via two enzymatic pathways: arginine decarboxylase (ADC) and ornithine decarboxylase (ODC). Both of these enzymes showed increased activity in P. cinnamomea under UV stress. In higher plants, ADC is the enzyme responsible for increased PA levels during stress exposure, while ODC is correlated with cell division and reproduction. However, there are contrary findings in the literature. Using two irreversible inhibitors, we identified the enzyme most likely responsible for increased PUT synthesis and therefore increased stress tolerance in P. cinnamomea. Our results show that changes in the PA synthesis pathway in P. cinnamomea under UV stress are based on an increased activity of ADC. When either inhibitor was added, lipid hydroperoxide levels increased even under photosynthetically active radiation, suggesting that PAs are involved in protection mechanisms under normal light conditions as well. We also show that under optimum or low-stress conditions, ODC activity is correlated with PUT synthesis. PMID- 26988185 TI - Lacustrine Nostoc (Nostocales) and associated microbiome generate a new type of modern clotted microbialite. AB - Microbialites are mineral formations formed by microbial communities that are often dominated by cyanobacteria. Carbonate microbialites, known from Proterozoic times through the present, are recognized for sequestering globally significant amounts of inorganic carbon. Recent ecological work has focused on microbial communities dominated by cyanobacteria that produce microbial mats and laminate microbialites (stromatolites). However, the taxonomic composition and functions of microbial communities that generate distinctive clotted microbialites (thrombolites) are less well understood. Here, microscopy and deep shotgun sequencing were used to characterize the microbiome (microbial taxa and their genomes) associated with a single cyanobacterial host linked by 16S sequences to Nostoc commune Vaucher ex Bornet & Flahault, which dominates abundant littoral clotted microbialites in shallow, subpolar, freshwater Laguna Larga in southern Chile. Microscopy and energy-dispersive X-ray spectroscopy suggested the hypothesis that adherent hollow carbonate spheres typical of the clotted microbialite begin development on the rigid curved outer surfaces of the Nostoc balls. A surface biofilm included >50 nonoxygenic bacterial genera (taxa other than Nostoc) that indicate diverse ecological functions. The Laguna Larga Nostoc microbiome included the sulfate reducers Desulfomicrobium and Sulfospirillum and genes encoding all known proteins specific to sulfate reduction, a process known to facilitate carbonate deposition by increasing pH. Sequences indicating presence of nostocalean and other types of nifH, nostocalean sulfide:ferredoxin oxidoreductase (indicating anoxygenic photosynthesis), and biosynthetic pathways for the secondary products scytonemin, mycosporine, and microviridin toxin were identified. These results allow comparisons with microbiota and microbiomes of other algae and illuminate biogeochemical roles of ancient microbialites. PMID- 26988186 TI - Photosynthetic characteristics of two Cylindrospermopsis raciborskii strains differing in their toxicity. AB - We studied the growth and photosynthetic characteristics of a toxic (CS506) and a nontoxic strain (CS509) of the bloom-forming cyanobacterium Cylindrospermopsis raciborskii grown under identical experimental conditions. When exposed to light saturating growth conditions (100 MUmol photons . m(-2) . s(-1) ), values for maximal photosynthetic capacity (Pmax ) and maximum quantum yield (Fv /Fm ) indicated that both strains had an equal ability to process captured photons and deliver them to PSII reaction centers. However, CS506 grew faster than CS509. This was consistent with its higher light requirement for saturation of photosynthesis (Ik ). Greater shade tolerance of CS509 was indicated by its higher ability to harvest light (alpha), lower photosynthetic light compensation point (Ic ), and higher chlorophyll a to biovolume ratio. Strain-specific differences were found in relation to non-photochemical quenching, effective absorption cross-sectional area of PSIIalpha-centers (sigmaPSIIalpha), and the antenna connectivity parameter of PSIIalpha (Jcon PSIIalpha). These findings highlighted differences in the transfer of excitation from phycobilisome/PSII to PSI, on the dependence on different pigments for light harvesting and on the functioning of the PSII reaction centers between the two strains. The results of this study showed that both performance and composition of the photosynthetic apparatus are different between these strains, though with only two strains examined we cannot attribute the performance of strain 506 to its ability to produce cylindrospermopsins. The emphasis on a strain-specific light adaptation/acclimation is crucial to our understanding of how different light conditions (both quantity and quality) can trigger the occurrence of different C. raciborskii strains and control their competition and/or dominance in natural ecosystems. PMID- 26988187 TI - Microalgal assemblages in a poikilohaline pond. AB - Microalgal strains for algal biofuels production in outdoor ponds will need to have high net growth rates under diverse environmental conditions. A small, variable salinity pond in the San Elijo Lagoon estuary in southern California was chosen to serve as a model pond due to its routinely high chlorophyll content. Profiles of microalgal assemblages from water samples collected from April 2011 to January 2012 were obtained by constructing 18S rDNA environmental clone libraries. Pond assemblages were found to be dominated by green algae Picochlorum sp. and Picocystis sp. throughout the year. Pigment analysis suggested that the two species contributed most of the chlorophyll a of the pond, which ranged from 21.9 to 664.3 MUg . L(-1) with the Picocystis contribution increasing at higher salinities. However, changes of temperature, salinity or irradiance may have enabled a bloom of the diatom Chaetoceros sp. in June 2011. Isolates of these microalgae were obtained and their growth rates characterized as a function of temperature and salinity. Chaetoceros sp. had the highest growth rate over the temperature test range while it showed the most sensitivity to high salinity. All three strains showed the presence of lipid bodies during nitrogen starvation, suggesting they have potential as future biofuels strains. PMID- 26988188 TI - Physiological performance of intertidal coralline algae during a simulated tidal cycle. AB - Intertidal macroalgae endure light, desiccation, and temperature variation associated with sub-merged and emerged conditions on a daily basis. Physiological stresses exist over the course of the entire tidal cycle, and physiological differences in response to these stresses likely contribute to spatial separation of species along the shore. For example, marine species that have a high stress tolerance can live higher on the shore and are able to recover when the tide returns, whereas species with a lower stress tolerance may be relegated to living lower on the shore or in tidepools, where low tide stresses are buffered. In this study, we monitored the physiological responses of the tidepool coralline Calliarthron tuberculosum (Postels and Ruprecht) E.Y. Dawson and the nontidepool coralline Corallina vancouveriensis Yendo during simulated tidal conditions to identify differences in physiology that might underlie differences in habitat. During high tide, Corallina was more photosynthetically active than Calliarthron as light levels increased. During low tide, Corallina continued to out-perform Calliarthron when submerged in warming tidepools, but photosynthesis abruptly halted for both species when emerged in air. Surprisingly, pigment composition did not differ, suggesting that light harvesting does not account for this difference. Additionally, Corallina was more effective at resisting desiccation by retaining water in its branches. When the tide returned, only Corallina recovered from combined temperature and desiccation stresses associated with emergence. This study broadens our understanding of intertidal algal physiology and provides a new perspective on the physiological and morphological underpinnings of habitat partitioning. PMID- 26988189 TI - Isomerization of octadecapentaenoic acid (18:5n-3) in algal lipid samples under derivatization for GC and GC-MS analysis. AB - During gas chromatography (GC) analysis of fatty acid (FA) composition of the dinoflagellate Gymnodinium kowalevskii, we found unex-pectedly low and irreproducible content of all-cis-3,6,9,12,15-octadecapentaenoic acid (18:5n-3), which is an important chemotaxonomic marker of several classes of microalgae. We compared chromatographic behavior of 18:5n-3 methyl ester and other GC derivatives obtained using different conventional methods of derivatization. The use of methods based on saponification or base-catalyzed transesterification resulted in a mixture of double-bond positional isomers of 18:5. On a SUPELCOWAX 10 column, the equivalent chain length (ECL) value for authentic 18:5n-3 methyl ester was 20.22, whereas the main component after base-catalyzed methylation had ECL 20.88. Attempts to prepare N-acyl pyrrolidides or 4,4-dimethyloxazoline (DMOX) derivatives of 18:5n-3 also gave inadequate results. These derivatives also showed a main peak corresponding to isomerized 18:5. Mass spectra for both DMOX and pyrrolidide derivatives of this compound showed the base peak at m/z 139, probably corresponding to 2,6,9,12,15-18:5 acid. Of all methods tested for methylation, only derivatization with 5% HCl or 1% sulphuric acid in methanol gave satisfactory results. Therefore, GC or GC-mass spectrometry analyses of algal lipids containing 18:5n-3 may be inaccurate when base-catalyzed methods of FA derivatization are applied. The best and simplest way to avoid incorrect GC results is to use standard acid-catalyzed methylation. PMID- 26988190 TI - Analysis of diversity of chromophytic phytoplankton in a mangrove ecosystem using rbcL gene sequencing. AB - Phytoplankton forms the basis of primary production in mangrove environments. The phylogeny and diversity based on the amplification and sequencing of rbcL, the large subunit encoding the key enzyme ribulose-1, 5-bisphosphate carboxylase/oxygenase was investigated for improved understanding of the community structure and temporal trends of chromophytic eukaryotic phytoplankton assemblages in Sundarbans, the world's largest continuous mangrove. Diatoms (Bacillariophyceae) were by far the most frequently detected group in clone libraries (485 out of 525 clones), consistent with their importance as a major bloom-forming group. Other major chromophytic algal groups including Cryptophyceae, Haptophyceae, Pelagophyceae, Eustigmatophyceae, and Raphidophyceae which are important component of the assemblages were detected for the first time from Sundarbans based on rbcL approach. Many of the sequences from Sundarbans rbcL clone libraries showed identity with key bloom forming diatom genera namely Thalassiosira, Skeletonema and Nitzschia. Similarly, several rbcL sequences which were diatom-like were also detected highlighting the need to explore diatom communities from the study area. Some of the rbcL sequences detected from Sundarbans were ubiquitous in distribution showing 100% identities with uncultured rbcL sequences targeted previously from the Gulf of Mexico and California upwelling system that are geographically separated from study area. Novel rbcL lineages were also detected highlighting the need to culture and sequence phytoplankton from the ecoregion. Principal component analysis revealed that nitrate is an important variable that is associated with observed variation in phytoplankton assemblages (operational taxonomic units). This study applied molecular tools to highlight the ecological significance of diatoms, in addition to other chromophytic algal groups in Sundarbans. PMID- 26988192 TI - Nitrogen retention and partitioning at the initiation of lipid accumulation in nitrogen-deficient algae. AB - Nitrogen (N) deficiency promotes lipid accumulation in many oleaginous algae, but we have a poor understanding of the associations between the initiation of lipid accumulation and algal N retention and partitioning. Here, we report on total cell N, five bulk pools of N in the cell (protein, free amino acids, DNA, RNA, chl), and lipids from N saturation to growth cessation in three species. While the maximum level of N uptake differed among species, the ratio of minimum retained N to N retained at the initiation of lipid accumulation was consistent among species at 0.5 +/- 0.04. This suggests that the cellular initiation of lipid accumulation was associated with a common magnitude of N deficiency among species. Concerning the partitioning of N, the concentration of RNA and the protein to RNA ratio were most similar among species at the initiation of lipid accumulation with averages of 3.2 +/- 0.26 g . L(-1) (8.2% variation) and 16 +/- 1.5 (9.2% variation), respectively. All other pools and physiologically relevant ratios were considerably more variable. The species commonalities in RNA and protein show a similar reduction in general cellular function due to N deficiency before cellular initiation of lipid accumulation. These results provide insight into the physiological drivers for lipid accumulation in N-deficient algae and data for modeling these associations. PMID- 26988191 TI - Curvature in models of the photosynthesis-irradiance response. AB - An equation for the rate of photosynthesis as a function of irradiance introduced by T. T. Bannister included an empirical parameter b to account for observed variations in curvature between the initial slope and the maximum rate of photosynthesis. Yet researchers have generally favored equations with fixed curvature, possibly because b was viewed as having no physiological meaning. We developed an analytic photosynthesis-irradiance equation relating variations in curvature to changes in the degree of connectivity between photosystems, and also considered a recently published alternative, based on changes in the size of the plastoquinone pool. When fitted to a set of 185 observed photosynthesis irradiance curves, it was found that the Bannister equation provided the best fit more frequently compared to either of the analytic equations. While Bannister's curvature parameter engendered negligible improvement in the statistical fit to the study data, we argued that the parameter is nevertheless quite useful because it allows for consistent estimates of initial slope and saturation irradiance for observations exhibiting a range of curvatures, which would otherwise have to be fitted to different fixed-curvature equations. Using theoretical models, we also found that intra- and intercellular self-shading can result in biased estimates of both curvature and the saturation irradiance parameter. We concluded that Bannister's is the best currently available equation accounting for variations in curvature precisely because it does not assign inappropriate physiological meaning to its curvature parameter, and we proposed that b should be thought of as the expression of the integration of all factors impacting curvature. PMID- 26988193 TI - Temperature response of photosynthetic light- and carbon-use characteristics in the red seaweed Gracilariopsis lemaneiformis (Gracilariales, Rhodophyta). AB - The red seaweed Gracilariopsis is an important crop extensively cultivated in China for high-quality raw agar. In the cultivation site at Nanao Island, Shantou, China, G. lemaneiformis experiences high variability in environmental conditions like seawater temperature. In this study, G. lemaneiformis was cultured at 12, 19, or 26 degrees C for 3 weeks, to examine its photosynthetic acclimation to changing temperature. Growth rates were highest in G. lemaneiformis thalli grown at 19 degrees C, and were reduced with either decreased or increased temperature. The irradiance-saturated rate of photosynthesis (Pmax ) decreased with decreasing temperature, but increased significantly with prolonged cultivation at lower temperatures, indicating the potential for photosynthesis acclimation to lower temperature. Moreover, Pmax increased with increasing temperature (~30 MUmol O2 . g(-1) FW . h(-1) at 12 degrees C to 70 MUmol O2 . g(-1) FW . h(-1) at 26 degrees C). The irradiance compensation point for photosynthesis (Ic ) decreased significantly with increasing temperature (28 MUmol photons . m(-2) . s(-1) at high temperature vs. 38 MUmol photons . m(-2) . s(-1) at low temperature). Both the photosynthetic light- and carbon-use efficiencies increased with increasing growth or temperatures (from 12 degrees C to 26 degrees C). The results suggested that the thermal acclimation of photosynthetic performance of G. lemaneiformis would have important ecophysiological implications in sea cultivation for improving photosynthesis at low temperature and maintaining high standing biomass during summer. Ongoing climate change (increasing atmospheric CO2 and global warming) may enhance biomass production in G. lemaneiformis mariculture through the improved photosynthetic performances in response to increasing temperature. PMID- 26988194 TI - Allelopathic effects of Alexandrium fundyense (Dinophyceae) on Thalassiosira cf. gravida (Bacillariophyceae): a matter of size. AB - Allelopathic interactions among phytoplankton are well documented. The potency of allelopathic species and responses of target species to allelochemicals are quite variable, however, limiting full understanding of the role these interactions may play in nature. One trait that may influence the sensitivity of an individual to allelochemicals is cell size. The few studies that have examined relationships between cell size and susceptibility to allelochemicals have compared different species and thus could not distinguish between the role of size and species specific physiological differences. Culturing an actively sexually reproducing diatom allowed us to focus on the influence of target cell size within a single species. We studied growth and nutrient acquisition by the chain-forming Thalassiosira cf. gravida Clever in the presence and absence of allelochemicals released by Alexandrium fundyense Balech as a function of T. cf. gravida cell size. Upon exposure to filtrate of A. fundyense, T. cf. gravida cultures "bleached" and both growth and nutrient utilization ceased for up to 4 d. The magnitude of the effect was dependent on filtrate concentration and T. cf. gravida cell surface area:volume ratio. The greatest inhibition was observed on the smallest cells, while T. cf. gravida cultures that had undergone cell enlargement via sexual reproduction were least sensitive to A. fundyense filtrate. These results demonstrate that competitor cell size, independent from taxonomy, may influence the outcome of allelopathic interactions. The findings presented here suggest a potential ecological impact of diatom cell size reduction and sexual reproduction that has not yet been described and that may be important in determining diatom survival and success. PMID- 26988195 TI - Brandtodinium gen. nov. and B. nutricula comb. Nov. (Dinophyceae), a dinoflagellate commonly found in symbiosis with polycystine radiolarians. AB - Symbiotic interactions between pelagic hosts and microalgae have received little attention, although they are widespread in the photic layer of the world ocean, where they play a fundamental role in the ecology of the planktonic ecosystem. Polycystine radiolarians (including the orders Spumellaria, Collodaria and Nassellaria) are planktonic heterotrophic protists that are widely distributed and often abundant in the ocean. Many polycystines host symbiotic microalgae within their cytoplasm, mostly thought to be the dinoflagellate Scrippsiella nutricula, a species originally described by Karl Brandt in the late nineteenth century as Zooxanthella nutricula. The free-living stage of this dinoflagellate has never been characterized in terms of morphology and thecal plate tabulation. We examined morphological characters and sequenced conservative ribosomal markers of clonal cultures of the free-living stage of symbiotic dinoflagellates isolated from radiolarian hosts from the three polycystine orders. In addition, we sequenced symbiont genes directly from several polycystine-symbiont holobiont specimens from different oceanic regions. Thecal plate arrangement of the free living stage does not match that of Scrippsiella or related genera, and LSU and SSU rDNA-based molecular phylogenies place these symbionts in a distinct clade within the Peridiniales. Both phylogenetic analyses and the comparison of morphological features of culture strains with those reported for other closely related species support the erection of a new genus that we name Brandtodinium gen. nov. and the recombination of S. nutricula as B. nutricula comb. nov. PMID- 26988196 TI - Meiospores produced in sori of nonsporophyllous laminae of Macrocystis pyrifera (Laminariales, Phaeophyceae) may enhance reproductive output. AB - Different lamina of Macrocystis pyrifera sporophytes (i.e., sporophylls, pneumatocyst-bearing blades, and apical scimitars) in a wave-sheltered site were found to be fertile. We quantified their sorus surface area, reproductive output (number of spores released) and the viability of released spores (germination rate). Sorus area was greatest on the sporophylls, with sporangia developing on >57% of the total area and smallest on the pneumatocyst-bearing blades with 21% of the total area bearing sporangia. The apical scimitar released the greatest number of meiospores (cells . mL(-1) . cm(-2) ) and the sporophylls the least. Meiospores produced from all types of fertile laminae were equally viable. This reproductive plasticity may enhance reproductive output, and contribute to short and long-distance spore dispersal and the cryptic gametophyte propagule bank for the next generation of sporophytes. PMID- 26988199 TI - Human rabies following a non-human primate bite in India. PMID- 26988198 TI - A Bootstrapping Model of Frequency and Context Effects in Word Learning. AB - Prior research has shown that people can learn many nouns (i.e., word-object mappings) from a short series of ambiguous situations containing multiple words and objects. For successful cross-situational learning, people must approximately track which words and referents co-occur most frequently. This study investigates the effects of allowing some word-referent pairs to appear more frequently than others, as is true in real-world learning environments. Surprisingly, high frequency pairs are not always learned better, but can also boost learning of other pairs. Using a recent associative model (Kachergis, Yu, & Shiffrin, 2012), we explain how mixing pairs of different frequencies can bootstrap late learning of the low-frequency pairs based on early learning of higher frequency pairs. We also manipulate contextual diversity, the number of pairs a given pair appears with across training, since it is naturalistically confounded with frequency. The associative model has competing familiarity and uncertainty biases, and their interaction is able to capture the individual and combined effects of frequency and contextual diversity on human learning. Two other recent word-learning models do not account for the behavioral findings. PMID- 26988197 TI - Children and young people with perinatal HIV in Europe: epidemiological situation in 2014 and implications for the future. AB - Accurate ascertainment of the number of children living with human immunodeficiency virus (HIV) is important to plan paediatric and adolescent health services. In Europe, the first generation of perinatally HIV-infected survivors are transferring to adult care and their health needs are unknown. We undertook an online survey of HIV cohort studies participating in the EuroCoord Network of Excellence to ascertain the number of perinatally HIV-infected (pHIV) patients included, to compare it with those published by the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) and to assess the ability of countries to follow up pHIV patients after transfer to adult care. At the end of 2013, 16 countries in EuroCoord reported 8,229 pHIV patients in follow-up in cohorts, compared with 5,160 cumulative diagnoses reported by the ECDC in the same area. Follow-up of pHIV patients after transfer to adult care varied. It is likely that the number of diagnoses of perinatal HIV reported to ECDC is an underestimate, although this varies by country. Further work is needed to refine estimates and encourage follow-up in adult HIV cohorts to investigate long-term outcomes and improve the care of the next generation of children with HIV. PMID- 26988200 TI - Twitter for travel medicine providers. AB - Travel medicine practitioners, perhaps more so than medical practitioners working in other areas of medicine, require a constant flow of information to stay up-to date, and provide best practice information and care to their patients. Many travel medicine providers are unaware of the popularity and potential of the Twitter platform. Twitter use among our travellers, as well as by physicians and health providers, is growing exponentially. There is a rapidly expanding body of published literature on this information tool. This review provides a brief overview of the ways Twitter is being used by health practitioners, the advantages that are peculiar to Twitter as a platform of social media, and how the interested practitioner can get started. Some key points about the dark side of Twitter are highlighted, as well as the potential benefits of using Twitter as a way to disseminate accurate medical information to the public. This article will help readers develop an increased understanding of Twitter as a tool for extracting useful facts and insights from the ever increasing volume of health information. PMID- 26988201 TI - Treatment of chronic hepatitis C with direct acting antiviral agents in patients with haemophilia, end-stage liver disease and coinfected with HIV. PMID- 26988203 TI - An exploratory study on speech and hearing outcomes in children with cleft lip and palate. AB - INTRODUCTION: Little is known about the treatment outcomes of children with cleft lip and/or palate (CLP) receiving surgical care for primary lip and palate closure in Malaysia. OBJECTIVES: This study examined the speech and hearing status of Malay-speaking children with CLP residing in Kuala Lumpur. METHODS: Parents whose children were between the age of 5 and 7 years were recruited via the Cleft Lip and Palate Association of Malaysia (CLAPAM) registry. Parents completed a survey and the children completed a speech and hearing assessment at the Audiology and Speech Sciences Clinic, Universiti Kebangsaan Malaysia. OUTCOMES: Speech measures include nasality rating, nasalance scores, articulation errors and speech intelligibility rating, while hearing measures include hearing thresholds and tympanometry results for each child. RESULTS: Out of 118 registered members who fulfilled the inclusion criteria, 21 agreed to participate in the study. The overall speech and hearing status of children in this sample were poor. Only four (19%) participants had normal speech intelligibility rating and normal hearing bilaterally. In terms of overall cleft management, only four (19%) participants were seen by a cleft team while seven (33%) had never had their hearing tested prior to this study. CONCLUSION: Participants in this sample had poor outcomes in speech and hearing and received uncoordinated and fragmented cleft care. This finding calls for further large scale research and collaborative efforts into improving and providing centralised, multidisciplinary care for children born with CLP. PMID- 26988204 TI - Comparison on the use of semi-automated and automated core biopsy needle in ultrasound guided breast biopsy. AB - OBJECTIVE: The aim of this study was to compare the use of semi-automated (Medax Velox 2; Poggio Rusco, Italy) and automated (Bard Magnum Biopsy Instrument; Covington, GA, USA) core biopsy needles, for ultrasound guided breast biopsy. MATERIALS AND METHODS: A 14G semi-automatic spring loaded core biopsy needle with a 22-mm-throw (Medax Velox 2; Poggio Rusco, Italy) and 14-gauge automated needle device with a 22-mm-throw biopsy gun (Bard-Magnum Biopsy Instrument, Covington, GA, USA) were used for breast biopsies under ultrasound guidance on alternate months during the study period between July 2009 and May 2011. One hundred and sixty lesions were biopsied and specimens were sent for histological evaluation. RESULTS: The automated needle obtained a higher number of histology reports at 84% (67/80) as compared with the semiautomated needle at 60% (48/80) (Fisher exact test, p value=0.023). Inadequate samples with the automated needle were much less at 9% (7/60) than with the semiautomated needle at 23% (18/60) (Fisher exact test, p value=0.028). The semi-automated needle showed slightly less fragmented samples. However, the number of fragmented samples with definitive diagnosis was slightly higher with the automated compared with the semiautomated needle, at 16% (13/80) and 13% (10/80) respectively. Compared with histology of 29 lesions that were excised, the semi-automated needle had higher sensitivity (100%) but lower specificity (75%) and accuracy (90%) compared with the automated needle (88% sensitivity, 100% specificity, 95% accuracy). CONCLUSION: Definitive diagnosis from the study samples slightly favours the use of automated core biopsy needle as compared to semi-automated core biopsy needle. PMID- 26988202 TI - Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. AB - To establish a new lineage in the human population, avian influenza A viruses (AIV) must overcome the intracellular restriction factor MxA. Partial escape from MxA restriction can be achieved when the viral nucleoprotein (NP) acquires the critical human-adaptive amino acid residues 100I/V, 283P, and 313Y. Here, we show that introduction of these three residues into the NP of an avian H5N1 virus renders it genetically unstable, resulting in viruses harboring additional single mutations, including G16D. These substitutions restored genetic stability yet again yielded viruses with varying degrees of attenuation in mammalian and avian cells. Additionally, most of the mutant viruses lost the capacity to escape MxA restriction, with the exception of the G16D virus. We show that MxA escape is linked to attenuation by demonstrating that the three substitutions promoting MxA escape disturbed intracellular trafficking of incoming viral ribonucleoprotein complexes (vRNPs), thereby resulting in impaired nuclear import, and that the additional acquired mutations only partially compensate for this import block. We conclude that for adaptation to the human host, AIV must not only overcome MxA restriction but also an associated block in nuclear vRNP import. This inherent difficulty may partially explain the frequent failure of AIV to become pandemic. PMID- 26988205 TI - A study on the use of abbreviations among doctors and nurses in the medical department of a tertiary hospital in Malaysia. AB - INTRODUCTION: Misinterpretation of abbreviations by healthcare professionals has been reported to compromise patient safety. This study was done to determine the prevalence of abbreviations usage among medical doctors and nurses and their ability to interpret commonly used abbreviations in medical practice. METHODS: Seventy-seven medical doctors and eighty nurses answered a self-administered questionnaire designed to capture demographic data and information regarding abbreviation use in medical practice. Comparisons were made between doctors and nurses with regards to frequency and reasons for using abbreviations; from where abbreviations were learned; frequency of encountering abbreviations in medical practice; prevalence of medical errors due to misinterpretation of abbreviations; and their ability to correctly interpret commonly used abbreviations. RESULTS: The use of abbreviations was highly prevalent among doctors and nurses. Time saving, avoidance of writing sentences in full and convenience, were the main reasons for using abbreviations. Doctors learned abbreviations from fellow doctors while nurses learned from fellow nurses and doctors. More doctors than nurses reported encountering abbreviations. Both groups reported no difficulties in interpreting abbreviations although nurses reported often resorting to guesswork. Both groups felt abbreviations were necessary and an acceptable part of work. Doctors outperformed nurses in correctly interpreting commonly used standard and non-standard abbreviations. CONCLUSION: The use of standard and non standard abbreviation in clinical practice by doctors and nurses was highly prevalent. Significant variability in interpretation of abbreviations exists between doctors and nurses. PMID- 26988206 TI - Natural history of asymptomatic gallstones: differential behaviour in male and female subjects. AB - OBJECTIVE: The natural history of asymptomatic (silent) gallstones has been inadequately studied. Existing information derives from studies based on oral cholecystography or relatively small sample sizes. We planned a retrospective cohort study in subjects with gallstones to determine conversion rates from asymptomatic to symptomatic. METHODS: We extracted data from computerised databases of one government hospital and two private clinics in Malaysia. Files were scrutinised to ensure that criteria for asymptomatic gallstones were fulfilled. Patients were called on telephone, further questioned to confirm that the gallstones at detection were truly asymptomatic, and asked about symptoms that were consistent with previously defined criteria for biliary colic. Appropriate ethical clearances were taken. RESULTS: 213 (112 males) patients fulfilled the criteria for asymptomatic gallstones and could be contacted. 23 (10.8%) developed pain after an average follow up interval of 4.02 years (range 0.1-11 years). Conversion rates from asymptomatic to symptomatic gallstones were high in the first two years of follow up, averaging 4.03+/-0.965 per year. Over time the conversion rates slowed, and by year 10 the annual conversion rate averaged only 1.38+/-0.29. Conversion rates were much higher for females compared to males (F:M hazard ratio 3.23, SE 1.54, p>z 0.014). The lifetime risks for conversion approached 6.15% for males, and 22.1% for females. CONCLUSION: In conclusion, asymptomatic gallstones are much more likely to convert to symptomatic in females than in males. Males in whom asymptomatic stones are discovered should be advised conservative treatment. Surgery may be preferable to conservative management if the subject is a young female. PMID- 26988207 TI - Renal doppler assessment in differentiating obstructive from non-obstructive hydronephrosis in children. AB - BACKGROUND: to determine the usefulness of Doppler ultrasound measurement of resistive index (RI) in differentiating obstructive from non-obstructive hydronephrosis in children. METHODS: From August 2011 to November 2012, renal Doppler assessments of the intra-renal renal arteries were performed on 16 children (19 kidneys) with congenital hydronephrosis. the independent t-test was used to assess for significant difference in RI values between those with obstructive hydronephrosis (6 kidneys) and those with non-obstructive hydronephrosis (13 kidneys) as determined by dynamic renal scintigraphy. the assessor was blinded to the clinical findings and scintigraphy results. RESULTS: RI was significantly different between obstructive and non-obstructive hydronephrosis. Obstructive hydronephrosis returned higher RI values, with mean RI of 0.78. Mean RI in non-obstructive hydronephrosis was 0.70, and the difference was significant (p <0.05). the sensitivity and specificity of Doppler ultrasound were 100% and 53% respectively. CONCLUSION: Doppler ultrasound measurement of resistive index is useful in differentiating obstructive from nonobstructive hydronephrosis and provides an alternative non-ionizing investigation. PMID- 26988208 TI - Leptospirosis: recent incidents and available diagnostics - a review. AB - OBJECTIVE: The aim of this article was to review published research articles on leptospirosis, in particular the recent incidence of leptospirosis in Malaysia and the currently available diagnostic methods for the detection of leptospirosis. METHODS: PubMed, Google Scholar and Google Search databases were searched using the key words Leptospira and leptospirosis. A total of seventy-six references were reviewed including sixty-seven research articles, three annual reports from Ministry of Health and six online newspaper articles. This review includes the following five sub-headings: introduction, leptospirosis transmission, leptospirosis incidents, laboratory diagnosis of leptospirosis and treatment and prevention of leptospirosis. RESULTS: An increase in incidents of leptospirosis cases has been seen in recent years in Malaysia. The recent floods have contributed to the rise in the number of reported cases. Current diagnostic approaches such as dark field microscopy, microscopic agglutination test (MAT), Polymerase chain reaction and serological tests are inadequate as the organism is a slow grower. CONCLUSION: There is an urgent need to develop newer techniques for rapid detection of leptospirosis. The combination of PCR and ELISA are suggested for rapid and accurate diagnosis of leptospirosis. Studies on the mechanism of pathogenesis of Leptospira are needed for the development of vaccines that are safe for human use. PMID- 26988209 TI - The use of SPECT-CT improves accuracy of post-radioiodine therapy imaging and changes the management strategy in a case of advanced follicular thyroid carcinoma. AB - This is a case of follicular thyroid carcinoma with extensive lung, bone and brain metastases. Multi-modality treatments including total thyroidectomy, modified radical neck dissection, cranial radiotherapy and Iodine-131 (RAI) therapy were instituted. Post RAI therapy planar whole body scan showed RAI avid metastases in the skull, cervical spine, bilateral lungs and abdomen. With the use of SPECTCT imaging, rare adrenal metastasis and additional rib metastasis were identified. Besides, management strategy was altered due to detection of non RAI avid brain and lung metastatic lesions. PMID- 26988210 TI - Recalcitrant cystoid macular oedema in an eye with ischaemic central retinal vein occlusion - what's next? AB - We report a case of a middle-aged gentleman with recalcitrant macular oedema (RMO) secondary to ischaemic central retinal vein occlusion (CRVO). He was given six injections of intravitreal ranibizumab (anti-VEGF) monthly. However, his visual acuity (VA) deteriorated and the macular oedema worsened. He then received an intravitreal dexamethasone implant eight months post-CRVO. His VA and macular oedema improved dramatically and significantly at first follow-up and remained stable at six months after implant. This case can be a reference for those who treating recalcitrant macular oedema. It shows the effect of an intravitreal dexamathasone implant might have in a patient with RMO due to CRVO. The patient enjoyed improvement of vision, with clinical evidence of reduction in central macular thickness (CMT) and with no serious adverse events after a single injection up to six months post implant. PMID- 26988211 TI - Penile Paraffinoma. AB - Penile augmentation with injection of paraffin is a common practice in South East Asia. Penile paraffinoma occurring due to injection of liquid paraffin to enhance the size of the penis is an uncommon condition. Normally, this procedure is carried out by nonmedical personnel, without the prior knowledge or consultation of any urologist. The occurrence of such a deforming procedure is not commonly known to the medical profession in Malaysia. PMID- 26988212 TI - Anti N-Methyl-D-Aspartate receptor encephalitis: An under-recognised cause of encephalitis. AB - Anti-N-Methyl-D-Aspartate receptor (NMDAR) encephalitis is an immune mediated condition with characteristic clinical presentation. We report the first case from Borneo, Sabah and the use of electroconvulsive therapy (ECT) in treating recalcitrant psychiatrist symptoms associated with this condition. PMID- 26988213 TI - Fulminant necrotising amoebic colitis: A diagnostic conundrum. AB - Fulminant necrotising amoebic colitis is a complication of untreated amoebiasis. This is seen in mainly low-income countries. It has a high mortality rate and is difficult to diagnose. We present an extremely rare case of fulminant necrotising amoebic colitis that caused diagnostic confusion in mimicking an acute abdomen, presumably caused by a perforated duodenal ulcer. PMID- 26988214 TI - Temporal bone squamous cell carcinoma - Penang experience. AB - Temporal bone squamous cell carcinoma (TBSCC) is rare and poses difficulties in diagnosing, staging and management. We describe a case series with six patients who were diagnosed TBSCC, from January 2009 to June 2014, with median age of 62 years old. All patients presented with blood-stain discharge and external auditory canal mass, showing that these findings should highly alert the diagnosis of TBSCC. Three patients staged T3 and another three with T4 disease. High-resolution CT (HRCT) temporal findings were noted to be different from intraoperative findings and therefore we conclude that MRI should be done to look for middle ear involvement or other soft tissue invasion for more accurate staging. Lateral temporal bone resection (LTBR) and parotidectomy was done for four patients with or without neck dissection. Patients with positive margin, perineural invasion or parotid and glenoid involvement carry poorer prognosis and postoperative radiotherapy may improve the survival rate. One patient had successful tumor resection via piecemeal removal approach in contrast with the recommended en bloc resection shows that with negative margin achieved, piecemeal removal approach can be a good option for patients with T2-3 disease. In general, T4 tumor has dismal outcome regardless of surgery or radiotherapy given. PMID- 26988215 TI - A case of successful extracorporeal membrane oxygenation for right ventricular failure following pericardiectomy. AB - Extracorporeal membrane oxygenation (ECMO) is a useful but less commonly used technique in right ventricular failure post cardiac surgery in our region. We report a case of successful use of ECMO for right ventricular failure post cardiac surgery. Our patient is a 27-year-old male presented with constrictive pericarditis post completion of treatment for disseminated Tuberculosis. He underwent pericardiectomy that was complicated with acute right ventricular failure. He was placed on extracorporeal membrane oxygenation after few hours post op that lasted for five days. The patient survived to hospital discharge and remained well on follow-up. From our experience, this aggressive management approach is beneficial in right ventricular failure and can be safely utilised in all cardiothoracic centres. PMID- 26988216 TI - Intrauterine management of fetal supraventricular tachycardia (SVT) with cardiac failure. AB - Fetal arrhythmias are not uncommon in pregnancy. The diagnosis can be established on routine ultrasound scan. Fetal supraventricular tachycardia (SVT) is the most common cause of fetal tachycardia. If left undiagnosed and untreated, these fetuses may develop cardiac failure, hydrops fetalis and eventually death. We report two fetuses diagnosed antenatally to have fetal SVT. Both fetuses were in cardiac failure and were successfully treated with maternal administration of antiarrhythmic medications. Digoxin, and in severe instances, a combination with flecanaide significantly improved fetal outcomes and prevented fetal mortality. The long term prognosis of such patients are good. PMID- 26988217 TI - Techniques to Repair Implant Malposition after Breast Augmentation: A Review. AB - BACKGROUND: Implant malposition is a complication of breast augmentation that adversely affects aesthetic outcomes. It is one of the most common reasons for revisionary aesthetic breast surgery yet there is a lack of peer reviewed literature dedicated to the management of this complication. OBJECTIVES: The purpose of this article was to summarize the malposition literature, review the types and causes of this complication, and evaluate the strengths and weakness of procedures aimed at addressing it. METHODS: A review of the literature was performed using the PubMed database. Articles describing surgical techniques for correction of implant malposition, as well as outcome data for patients undergoing revision with described techniques, were included. Articles describing revisionary surgery following breast reconstruction were excluded. A series of cases are presented to illustrate techniques discussed. RESULTS: Search criteria resulted in 763 articles. Title and abstract review followed by application of inclusion and exclusion criteria resulted in a total of 21 clinical studies from 1988 to 2014 that were included in this review. All studies included in this study were of level IV or V evidence. CONCLUSIONS: Despite the overall low level of evidence in the literature regarding secondary breast augmentation, a thorough understanding of the corrective techniques presented will allow surgeons to make the most informed judgments. Weighing the strengths and weakness of these surgical techniques in the context of each patient will allow surgeons to develop the most appropriate treatment strategy. LEVEL OF EVIDENCE 4: Therapeutic. PMID- 26988219 TI - Association analysis for disease resistance to Fusarium oxysporum in cape gooseberry (Physalis peruviana L). AB - BACKGROUND: Vascular wilt caused by Fusarium oxysporum is the most important disease in cape gooseberry (Physalis peruviana L.) in Colombia. The development of resistant cultivars is considered one of the most cost-effective means to reduce the impact of this disease. In order to do so, it is necessary to provide breeders with molecular markers and promising germplasm for introgression of different resistance loci as part of breeding schemes. Here we described an association mapping study in cape gooseberry with the goal to: (i) select promising materials for use in plant breeding and (ii) identify SNPs associated with the cape gooseberry resistance response to the F. oxysporum pathogen under greenhouse conditions, as potential markers for cape gooseberry breeding. RESULTS: We found a total of 21 accessions with different resistance responses within a diversity panel of 100 cape gooseberry accessions. A total of 60,663 SNPs were also identified within the same panel by means of GBS (Genotyping By Sequencing). Model-based population structure and neighbor-joining analyses showed three populations comprising the cape gooseberry panel. After correction for population structure and kinship, we identified SNPs markers associated with the resistance response against F. oxysporum. The identification of markers was based on common tags using the reference genomes of tomato and potato as well as the root/stem transcriptome of cape gooseberry. By comparing their location with the tomato genome, 16 SNPs were found in genes involved in defense/resistance response to pathogens, likewise when compared with the genome of potato, 12 markers were related. CONCLUSIONS: The work presented herein provides the first association mapping study in cape gooseberry showing both the identification of promising accessions with resistance response phenotypes and the identification of a set of SNP markers mapped to defense/resistance response genes of reference genomes. Thus, the work also provides new knowledge on candidate genes involved in the P. peruviana - F. oxysporum pathosystem as a foundation for further validation in marker-assisted selection. The results have important implications for conservation and breeding strategies in cape gooseberry. PMID- 26988222 TI - Pharmacokinetics of high-dose methotrexate in infants aged less than 12 months treated for aggressive brain tumors. AB - PURPOSE: In infants aged less than 12 months, there are few data on pharmacokinetics of high-dose methotrexate (MTX) for brain tumors at the dose of 8 g/m(2). Consolidated knowledges are present only with the dose of 5 g/m(2) in acute lymphoblastic leukemia. METHODS: We collected data on 8 infants at the time of their first treatment with high-dose MTX, 8 g/m(2), to evaluate the pharmacokinetic profile. All children had a dose adjustment with a weight-based prescription (1 m(2) = 30 kg). RESULTS: The median age was 4.5 months (range 0 9). The median weight was 5.63 kg (range 3.12-9.0). The median steady-state MTX concentration at the end of 6-hr infusion was 486 uM/L (range 227-790). The median systemic MTX clearance was 4.14 L/h/m(2) (range 1.98-9.35). The median MTX concentration after 24 h from the beginning of infusion was 3.29 uM/L (range 1.14 100.44). Three (37.5 %) patients had a delayed elimination of MTX (delayed early, delayed late, or total delayed: one for each). These altered elimination occurred principally in children weighing less than 4 kg (p: 0.0179). Moreover, a systemic MTX clearance at the end of infusion minor than 3 L/h/m(2) can predict a delayed elimination (p: 0.0179). Patients with altered elimination underwent rescue measures (leucovorin supplement and/or exchange transfusion). CONCLUSIONS: Our data suggest that a higher dose of MTX for the treatment of aggressive brain tumors in early infants had an acceptable pharmacokinetic profile. Greater attention must be used in the treatment of children weighing less than 4 kg. PMID- 26988220 TI - The effect of high dose oral manganese exposure on copper, iron and zinc levels in rats. AB - Manganese is an essential dietary nutrient and trace element with important roles in mammalian development, metabolism, and antioxidant defense. In healthy individuals, gastrointestinal absorption and hepatobiliary excretion are tightly regulated to maintain systemic manganese concentrations at physiologic levels. Interactions of manganese with other essential metals following high dose ingestion are incompletely understood. We previously reported that gavage manganese exposure in rats resulted in higher tissue manganese concentrations when compared with equivalent dietary or drinking water manganese exposures. In this study, we performed follow-up evaluations to determine whether oral manganese exposure perturbs iron, copper, or zinc tissue concentrations. Rats were exposed to a control diet with 10 ppm manganese or dietary, drinking water, or gavage exposure to approximately 11.1 mg manganese/kg body weight/day for 7 or 61 exposure days. While manganese exposure affected levels of all metals, particularly in the frontal cortex and liver, copper levels were most prominently affected. This result suggests an under-appreciated effect of manganese exposure on copper homeostasis which may contribute to our understanding of the pathophysiology of manganese toxicity. PMID- 26988221 TI - Inhibition of E-selectin expression on the surface of endothelial cells inhibits hepatocellular carcinoma growth by preventing tumor angiogenesis. AB - PURPOSE: Interactions between endothelial and tumor cells via E-selectin and sialyl Lewis x (sLex) have been suggested to play a significant role in the development of metastasis and tumor growth. In this work, we tested whether inhibition of E-selectin expression on the surface of endothelial cells might impair endothelial/tumor cells interactions and tumor growth of hepatocarcinoma cells in vitro and in vivo. METHODS: We used HepG2 cells that highly express sLex antigens and HuH7 cells that do not express sLex. Inhibition of E-selectin expression on the surface of endothelial cells was obtained by using cimetidine and amiloride treatment. RESULTS: Cimetidine and amiloride inhibited, respectively, by 20 and 64 % E-selectin expression by activated endothelial cells and significantly subsequent adhesion of HepG2 cells to activated endothelial cells. Subcutaneous injection of cimetidine or amiloride resulted in a significant inhibition of HepG2 cells tumor growth in nu/nu mice but not of HuH7 cells. Thus, cimetidine and amiloride administration led to an inhibition of 57 and 75 % of HepG2 tumor growth in vivo, respectively. This effect was associated with an inhibition of vasculogenesis as demonstrated by anti-CD31 immunostaining. CONCLUSION: Inhibition of E-selectin expression allows an anti-tumoral effect on sLex-expressing HCC tumors in vivo. This suggests that interactions between HCC cells and endothelial cells through sLex antigens and E-selectin might be a target for treatment of HCC. Further studies might evaluate the clinical impact of cimetidine and amiloride in the treatment of HCC patients alone or in combination with other anti-tumoral agents. PMID- 26988223 TI - A Rapid, Fluorescence-Based Field Screening Technique for Organic Species in Soil and Water Matrices. AB - Real-time detection of hydrocarbon contaminants in the environment presents analytical challenges because traditional laboratory-based techniques are cumbersome and not readily field portable. In the current work, a method for rapid and semi-quantitative detection of organic contaminants, primarily crude oil, in natural water and soil matrices has been developed. Detection limits in the parts per million and parts per billion were accomplished when using visual and digital detection methods, respectively. The extraction technique was modified from standard methodologies used for hydrocarbon analysis and provides a straight-forward separation technique that can remove interference from complex natural constituents. For water samples this method is semi-quantitative, with recoveries ranging from 70 % to 130 %, while measurements of soil samples are more qualitative due to lower extraction efficiencies related to the limitations of field-deployable procedures. PMID- 26988224 TI - Levels of PCBs in Oysters Coming from Galicia Coast: Comparison to Mussels from the Same Region. AB - PCBs were analyzed in two species of oyster (Crassostrea gigas and Ostrea edulis) cultured in intertidal beds and rafts coming from the Galician Rias during the period 2011-2014. PCBs were also analyzed in mussel (Mytilus galloprovincialis) collected in the same Rias during 2011. The main objective of this work is to investigate the distribution of PCBs in Galician oysters and to study their suitability as bioindicator in comparison to mussels. The levels of SigmaPCBs (ten congeners) ranged from 5.58 to 179.49 ng g(-1) d.w. The effect of biological parameters (shell length, lipid content and condition index) on bioaccumulation of PCBs was also evaluated. ANOVA showed a statistically significant difference between species for higher chlorinated biphenyls (CBs 153 and 138). The spatial patterns were investigated. Principal Component Analysis (PCA) showed differences between geographical areas (Rias Altas, Centrales and Baixas) in the distribution of PCBs. PMID- 26988225 TI - Assessment of Giant Duckweed (Spirodela polyrhiza L. Schleiden) Turions as Model Objects in Ecotoxicological Applications. AB - In this study germination of Spirodela polyrhiza (L.) Schleiden (giant duckweed) turions was assessed under cadmium exposure to test applicability of a novel turion-based ecotoxicology method. Floating success of germinating turions, protrusion of the first and subsequent fronds as test endpoints were investigated and compared to results of standard duckweed growth inhibition tests with fronds of the same species. Our results indicate that turions can be used to characterize effects of toxic substances. Initial phase of turion germination (floating up and appearance of the first frond) was less sensitive to Cd treatments than the subsequent frond production. The calculated effective concentrations for growth rates in turion and normal frond tests were similar. Single frond area produced by germinating turions proved to be the most sensitive test endpoint. Single frond area and colony disintegration as additionally measured parameters in normal frond cultures also changed due to Cd treatments but the sensitivity of these parameters was lower than that of growth rates. PMID- 26988226 TI - Imidacloprid Extraction from Citrus Leaves and Analysis by Liquid Chromatography Mass Spectrometry (HPLC-MS/MS). AB - A procedure was developed to extract Imidacloprid (IMD) from newly-flushed and fully-expanded citrus leaves. The extraction was conducted in a bullet blender, using a small sample mass (0.5 g of fresh tissue), stainless-steel beads (24 g), and methanol as extractant (10 mL). The extracts did not require further clean-up before analysis by HPLC-MS/MS. The method was validated with control samples from IMD-untreated Hamlin orange trees. The method limit of detection and limit of quantitation were 0.04 and 0.12 MUg g(-1), respectively. IMD recoveries from fortified leaf tissue were between 92 % and 102 %, with relative standard deviations of <8 %. The method was further evaluated by extracting leaves from Hamlin orange trees treated with IMD. The treated trees showed maximum concentrations of 10.8 and 21.8 ug g(-1), observed at 20 days after applying two soil-drenching rates (0.51 and 1.02 kg IMD ha(-1)), respectively. This extraction technique will generate useful data on IMD plant uptake, foliar concentration, and correlations with Asian citrus psyllid (ACP) mortality or control. The method could be used to generate baseline data to improve IMD soil-drenching applications as the main management practice to control the ACP. PMID- 26988227 TI - Medial approach to treat humeral mid-shaft fractures: a retrospective study. AB - BACKGROUND: Plate fixation is the gold standard for diaphyseal fracture management, and the anterolateral approach is widely used by reconstructive surgeons. However, the outcomes of humeral shaft fracture fixation using a medial approach are rarely reported. The aim of this study is to explore the management and outcomes of humeral mid-shaft fractures fixed through a medial incision. METHODS: Thirty-four patients who sustained a humeral mid-shaft fracture and underwent an open-reduction internal fixation (ORIF) in our department between January 2010 and January 2013 were included in this study. Sixteen patients had an ORIF performed through a medial approach, while the remaining 18 were fixed through an anterolateral approach. Postoperative clinical and radiographic results were reviewed. RESULTS: There were no significant differences in the blood loss and the range of motion of the shoulder and elbow between the anterolateral and medial fixation groups. One patient in the medial group and two patients in the anterolateral group had radial nerve dysfunction that improved after 8, 3 and 6 weeks, respectively. All patients healed radiographically except one from the anterolateral group who underwent grafting and re-fixation for a non union. No vascular injuries, infections, malunions, broken plates or loose screws were noted in either group. CONCLUSIONS: The medial approach to the humerus had equivalent outcomes to anterolateral fixation. It is an available choice for humeral mid-shaft fracture fixation in cases where there is no need to expose the radial nerve. The medial approach does not require a pre-bent plate and creates a large operative exposure. A well-hidden incision can also be designed, improving cosmetic outcomes. However, the medial approach is not suitable to proximal or distal humerus fractures. PMID- 26988229 TI - Can microteaching be used for teaching postgraduate psychiatry residents in a small group? AB - OBJECTIVE: The objective of this study was to examine the feasibility of using microteaching for teaching postgraduate psychiatry residents in a small-group setting. METHODS: Twelve postgraduate psychiatry residents attending the tutorial program were employed as study participants. Five of the consenting residents took part in the microteaching session in which subtopics were assigned. Feedback was obtained from the presenters and other participants regarding the microteaching session. RESULTS: All of the presenters reported the microteaching session to be helpful in gaining a deeper understanding of the topic. Among the other participants, most found the microteaching exercise to be useful. CONCLUSION: Although preliminary, our findings suggest that microteaching can be used for training postgraduate psychiatry residents. PMID- 26988228 TI - Preferences for the organization of long-term follow-up in adolescent and young adult cancer survivors. AB - PURPOSE: As survival rates of adolescent and young adult (AYA) cancer patients increase, a growing number of AYA cancer survivors need follow-up care. However, there is little research on their preferences for follow-up care. We aimed to (1) describe AYA cancer survivors' preferences for the organization and content of follow-up care, (2) describe their preferences for different models of follow-up, and (3) investigate clinical and sociodemographic characteristics associated with preferences for the different models. METHODS: AYA cancer survivors (diagnosed with cancer at age 16-25 years; >=5 years after diagnosis) were identified through the Cancer Registry Zurich and Zug. Survivors completed a questionnaire on follow-up attendance, preferences for organizational aspects of follow-up care (what is important during follow-up, what should be included during appointments, what specialists should be involved, location), models of follow-up (telephone/questionnaire, general practitioner (GP), pediatric oncologist, medical oncologist, multidisciplinary team), and sociodemographic characteristics. Information on tumor and treatment was available through the Cancer Registry Zurich and Zug. RESULTS: Of 389 contacted survivors, 160 (41.1 %) participated and 92 (57.5 %) reported still attending follow-up. Medical aspects of follow-up care were more important than general aspects (p < 0.001). Among different organizational models, follow-up by a medical oncologist was rated higher than all other models (p = 0.002). Non-attenders of follow-up rated GP-led follow-up significantly higher than attenders (p = 0.001). CONCLUSION: Swiss AYA cancer survivors valued medical content of follow-up and showed a preference for medical oncologist-led follow-up. Implementation of different models of follow-up care might improve accessibility and attendance among AYA cancer survivors. PMID- 26988230 TI - Correlates of a single-item Self-Rated Mental Health Question in people with schizophrenia. AB - OBJECTIVE: The objective of this study was to explore the correlates of a single item Self-Rated Mental Health Question in people with schizophrenia, in order to achieve a better understanding of what it is measuring. METHODS: A cross sectional survey was conducted exploring the responses of 71 adults with schizophrenia to a single-item Self-Rated Mental Health Question and the relationship with psychological distress, illness perception, and self-rated general health. Measures included the 10-item Kessler Psychological Distress Scale, the Brief Illness Perception Questionnaire, and the single-item Self-Rated Health Question. RESULTS: People with schizophrenia who reported poorer levels of mental health on a single-item Self-Rated Mental Health Question were more likely to have: higher levels of psychological distress; depressive and anxiety symptoms; and negative illness perceptions, especially a lack of perceived personal control over their illness. There was a moderate positive correlation between self-rated mental health and self-rated general health. CONCLUSION: The single-item Self-Rated Mental Health Question is a predictor of important clinical features in people with schizophrenia. As such, there are implications for health services, with a possible role as a brief, easily administered screening tool for the detection of clinical vulnerability. PMID- 26988233 TI - Call intercalation in dyadic interactions in natural choruses of Johnstone's whistling frog Eleutherodactylus johnstonei (Anura: Eleutherodactylidae). AB - Communal signaling increases the likelihood of acoustic interference and impairs mate choice; consequently, mechanisms of interference avoidance are expected. Adjustment of the timing of the calls between signalers, specifically call alternation, is probably the most efficient strategy. For this reason, in the present study we analyzed call timing in dyads of males of E. johnstonei in six natural assemblages. We addressed whether males entrain their calls with those of other males at the assemblage and if they show selective attention in relation to perceived amplitude of the other males' calls, inter-male distance, or intrinsic call features (call duration, period or dominant frequency). We expected males to selectively attend to closer or louder males and/or to those of higher or similar attractiveness for females than themselves, because those would be their strongest competitors. We found that most males intercalated their calls with those of at least one male. In assemblages of 3 individuals, males seemed to attend to a fixed number of males regardless of their characteristics. In assemblages of more than 3 individuals, the perceived amplitude of the call of the neighboring male was higher, and the call periods of the males were more similar in alternating dyads than in the non-alternating ones. At the proximate level, selective attention based on perceived amplitude may relate to behavioral hearing thresholds. Selective attention based on the similarity of call periods may relate to the properties of the call oscillators controlling calling rhythms. At the ultimate level, selective attention may be related to the likelihood of acoustic competition for females. PMID- 26988231 TI - Room temperature stable carbetocin for the prevention of postpartum haemorrhage during the third stage of labour in women delivering vaginally: study protocol for a randomized controlled trial. AB - BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in low-income countries and contributes to nearly a quarter of maternal deaths globally. The current available interventions for prevention of postpartum haemorrhage, oxytocin and carbetocin, are limited by their need for refrigeration to maintain potency, as the ability to maintain a cold chain across the drug distribution and storage network is inconsistent, thus restricting their use in countries with the highest burden of maternal mortality. We describe a randomized, double-blind non-inferiority trial comparing a newly developed room temperature stable formulation of carbetocin to the standard intervention (oxytocin) for the prevention of PPH after vaginal birth. METHODS/DESIGN: Approximately 30,000 women delivering vaginally will be recruited across 22 centres in 10 countries. The primary objectives are to evaluate the non inferiority of room temperature stable carbetocin (100 MUg intramuscular) versus oxytocin (10 IU intramuscular) in the prevention of PPH and severe PPH after vaginal birth. The primary endpoints are blood loss >=500 mL or the use of additional uterotonics (composite endpoint required by drug regulatory authorities) and blood loss >=1,000 mL (WHO requirement). Non-inferiority will be assessed using a two-sided 95 % confidence interval for the relative risk of the above endpoints for room temperature stable carbetocin versus oxytocin. The upper limit of the two-sided 95 % confidence interval for the relative risk for the composite endpoint of blood loss >=500 mL or the use of additional uterotonics, and for the endpoint of blood loss >=1,000 mL, will be compared to a non inferiority margin of 1.16 and 1.23, respectively. If the upper limit is below the corresponding margin, non-inferiority will have been demonstrated. The safety analysis will include all women receiving treatment. Safety and tolerability will be assessed by a review of adverse events, by conducting inferential testing with significance levels for between-group comparisons. DISCUSSION: If the results of the study show that room temperature stable carbetocin is a safe and effective alternative to oxytocin, this could have a substantial impact on the prevention of postpartum haemorrhage and maternal survival worldwide. TRIAL REGISTRATION: ACTRN12614000870651 (14 August 2014). PMID- 26988234 TI - [Hypovitaminosis D and associated factors in 4-year old children in northern Spain]. AB - INTRODUCTION: Vitamin D is an essential prohormone in calcium and phosphorus homeostasis. Recent studies show a high frequency of insufficiency/deficiency of vitamin D in the general population worldwide. Our objective was to estimate the prevalence of circulating vitamin D [25(OH)D3] deficiency and insufficiency in children and examine the associated factors. MATERIAL AND METHODS: A total of 283 children, participants in the cohort INMA-Asturias, were studied. The 25(OH)D3 concentrations were quantified by high performance liquid chromatography. The prevalence of deficiency [25(OH)D3<20 ng/ml] and insufficiency [20-29.9 ng/ml] of vitamin D was estimated. Distribution of 25(OH)D3 for month of extraction of specimen, ingestion, and other factors were analysed. RESULTS: The mean 25(OH)D3 was 20.1 ng/ml (range 2.7-49.8), with 8.8% >= 30 ng/ml, 38.5% from 20-20.9 ng/ml, and 52.7%<20 ng/ml. Seasonal variation was found, with lower values in winter. There was no relationship between plasma levels and intake of vitamin D (median 2.7MUg/day, range 0.81-12.62), time outdoors (mean 3hours, range: 0:21-6:55), or BMI or gender, but there was one found with the mother's levels during gestation. CONCLUSIONS: There is a high prevalence of vitamin D deficiency/insufficiency in children at 4 years. Solar exposure might not be enough in our region. Healthy children should be encouraged to follow adequate outdoor activities with associated sun exposure. Due the deficit of intake in childhood, recommendations are needed about a varied diet with vitamin D-containing foods in this age group, especially during the winter, and assessing the need of vitamin D supplementation in children at risk. PMID- 26988232 TI - Hedgehog signaling: modulation of cancer properies and tumor mircroenvironment. AB - Cancer poses a serious health problem in society and is increasingly surpassing cardiovascular disease as the leading cause of mortality in the United States. Current therapeutic strategies for cancer are extreme and harsh to patients and often have limited success; the danger of cancer is intensified as it metastasizes to secondary locations such as lung, bone, and liver, posing a dire threat to patient treatment and survival. Hedgehog signaling is an important pathway for normal development. Initially identified in Drosophila, the vertebrate and mammalian equivalent of the pathway has been studied extensively for its role in cancer development and progression. As this pathway regulates key target genes involved in development, its action also allows for the modulation of the microenvironment to prepare a tumor-suitable niche by manipulating tumor cell growth, differentiation, and immune regulation, thus creating an enabling environment for progression and metastasis. In this review, we will summarize recent scientific discoveries reporting the impact of the Hedgehog signaling pathway on the tumor initiation process and metastatic cascade, shedding light on the ability of the tumor to take over a mechanism crucially intended for development and normal function. PMID- 26988235 TI - [High levels of atrial natriuretic peptide and copeptin and mortality risk]. AB - OBJECTIVE: To determine whether high levels of mid-regional pro-atrial natriuretic peptide (MR-proANP), copeptin, and procalcitonin (PCT) plasma concentrations are associated with increased mortality risk. METHODS: Prospective observational study including 254 critically ill children. MR-proANP, copeptin and PCT were compared between children with high (Group A; n=33) and low (Group B; n=221) mortality risk, and between patients with failure of more than 1 organ (Group 1; n=71) and less than 2 (Group 2; n=183). RESULTS: Median (range) of MR proANP, copeptin, and PCT levels in group A vs B were, respectively: 209.4 (30.5 1415.8) vs. 75.0 (14.6-867.2) pmol/L (P<.001); 104.4 (7.4-460.9) vs. 26.6 (0.00 613.1) pmol/L (P<.001), and 7.8 (0.3-552.0) vs. 0.3 (0.02-107.0) ng/mL (P<.001). The area under the curve (AUC) for the differentiation of group A and B was 0.764 (95% CI: 0.674-0.854) for MR-proANP; 0.735 (0.642-0.827) for copeptin, and 0.842 (0.744-0.941) for PCT, with no statistical differences. The AUCs for the differentiation of group 1 and 2 were: 0.837 (0.784-0.891) for MR-proANP, 0.735 (0.666-0.804) for copeptin, and 0.804 (0.715-0.892) for PCT, with statistical differences between MR-proANP and copeptin, P=.01. CONCLUSIONS: High levels of MR proANP, copeptin and PCT were associated with increased mortality risk scores. MR proANP showed a higher association than copeptin with number of organs in failure. PMID- 26988236 TI - Purinergic signalling in a latent stem cell niche of the rat spinal cord. AB - The ependyma of the spinal cord harbours stem cells which are activated by traumatic spinal cord injury. Progenitor-like cells in the central canal (CC) are organized in spatial domains. The cells lining the lateral aspects combine characteristics of ependymocytes and radial glia (RG) whereas in the dorsal and ventral poles, CC-contacting cells have the morphological phenotype of RG and display complex electrophysiological phenotypes. The signals that may affect these progenitors are little understood. Because ATP is massively released after spinal cord injury, we hypothesized that purinergic signalling plays a part in this spinal stem cell niche. We combined immunohistochemistry, in vitro patch clamp whole-cell recordings and Ca(2+) imaging to explore the effects of purinergic agonists on ependymal progenitor-like cells in the neonatal (P1-P6) rat spinal cord. Prolonged focal application of a high concentration of ATP (1 mM) induced a slow inward current. Equimolar concentrations of BzATP generated larger currents that reversed close to 0 mV, had a linear current-voltage relationship and were blocked by Brilliant Blue G, suggesting the presence of functional P2X7 receptors. Immunohistochemistry showed that P2X7 receptors were expressed around the CC and the processes of RG. BzATP also generated Ca(2+) waves in RG that were triggered by Ca(2+) influx and propagated via Ca(2+) release from internal stores through activation of ryanodine receptors. We speculate that the intracellular Ca(2+) signalling triggered by P2X7 receptor activation may be an epigenetic mechanism to modulate the behaviour of progenitors in response to ATP released after injury. PMID- 26988237 TI - Herpes simplex virus-1 encephalitis induced by chemoradiotherapy and steroids in an esophageal cancer patient: a case report. AB - BACKGROUND: Systemic chemotherapy combined with steroids used as prophylactic antiemetics have been reported to induce immunosuppression. Further, herpes simplex virus-1 (HSV-1) infection has been reported to occur in patients with small cell carcinomas after chemoradiotherapy that includes brain irradiation. Here, we report a case of HSV-1 encephalitis that occurred in a patient undergoing chemoradiotherapy for advanced esophageal cancer. CASE PRESENTATION: A 77-year-old woman received chemoradiotherapy (5-fluorouracil, 700 mg/m(2); cisplatin, 70 mg/m(2); and radiotherapy, 60 Gy in total) for stage III esophageal cancer. The total radiation dose was administered concurrently with the first two courses of chemotherapy, together with dexamethasone as a prophylactic antiemetic. Two days before completion of the fourth course of chemotherapy, the patient developed acute neurological symptoms of disorientation, clouding of consciousness, and fever. T2-weighted magnetic resonance imaging showed a high intensity area in the bilateral temporal lobes and insular cortex. Furthermore, DNA PCR testing of cerebrospinal fluid showed clear positivity for HSV-1 DNA, and the patient was diagnosed with herpetic encephalitis. Intravenous administration of acyclovir for 3 weeks led to gradual improvement of consciousness, and the patient was able to respond to verbal cues. CONCLUSION: In advanced esophageal cancer patients, standard treatment involves chemoradiotherapy and surgery. However, primary infection with or reactivation of endogenous latent HSV-1 in the brain cortex during chemoradiotherapy combined with administration of a steroid may compromise the benefits of treatment. PMID- 26988238 TI - A case study of vocal features associated with galvanic skin response to stressors in a clinical interaction. AB - OBJECTIVE: We investigated vocal characteristics associated with physiologically determined stressful episodes by means of post-hoc acoustic analyses of speech recorded in a clinical setting. Our research addressed the understudied question of which vocal features may serve as cues naturally occurring stress and is the first to explore this issue in a pitch accent language. METHODS: The vocal profile of a single female patient interacting with a physician was analyzed with standard speech analysis software for acoustic indicators of stress-related arousal determined by galvanic skin response measurements. RESULTS: Vocal jitter, representing an aspect of voice quality perceived as hoarseness, appeared to increase during and immediately after skin conductance response intervals. Skin conductance levels during the response intervals were negatively correlated with acoustic features used to approximate the perception of voice unsteadiness (slope and standard deviation of fundamental frequency). CONCLUSION: An acoustic analysis of vocal properties of speech uttered during independently detected skin conductance response intervals revealed individual patterns for some acoustic features linked to stress in earlier studies. PRACTICE IMPLICATIONS: Non-invasive methods of arousal detection in physician-patient communication based on acoustic analyses of vocal profiles may, in combination with other analyses, help identify stressful events and thus improve the process of medical information gathering and decision-making. PMID- 26988239 TI - Survey of medical genetic services in Italy: year 2011. AB - BACKGROUND: The aim of this study was to collect information about 2011 genetic activities in Italy, with the purpose of providing guidance to the national health systems in order to improve genetic services. METHODS: A web-based survey was carried out to achieve the information. RESULTS: Data were collected from 268 macrostructures hosting 517 services and employing 3246 persons. About 295,000 cytogenetic, 35,000 immunogenetic and 263,000 molecular genetic analyses of 902 genes were recorded. Seventy-four percent of the services were accredited with institutional bodies and 57 % were also certified according to ISO 9001 standard. Twenty percent of cytogenetic laboratories had participated in an European External Quality Assessment (EQA) while 44 % participated in a national EQA. Only 28 % of the molecular laboratories had participated in a national Cystic Fibrosis EQA. The percentage of diagnoses confirmed by genetic tests varied among disorders, ranging from 52 % for coeliac disease to 4 % for fragile X syndrome. CONCLUSIONS: This study highlights the need for reorganizing the Italian genetic services network, improving EQA participation and developing national plans for implementing next generation technologies. Concerted effort has to be addressed in the education of the professionals prescribing tests to improve appropriateness and to inform patients, who now have exposure to direct-to consumer multifactorial genetic testing where clinical utility is unproven. PMID- 26988240 TI - Real-time monitoring of focused ultrasound blood-brain barrier opening via subharmonic acoustic emission detection: implementation of confocal dual frequency piezoelectric transducers. AB - Burst-tone focused ultrasound exposure in the presence of microbubbles has been demonstrated to be effective at inducing temporal and local opening of the blood brain barrier (BBB), which promises significant clinical potential to deliver therapeutic molecules into the central nervous system (CNS). Traditional contrast enhanced imaging confirmation after focused ultrasound (FUS) exposure serves as a post-operative indicator of the effectiveness of FUS-BBB opening, however, an indicator that can concurrently report the BBB status and BBB-opening effectiveness is required to provide effective feedback to implement this treatment clinically. In this study, we demonstrate the use of subharmonic acoustic emission detection with implementation on a confocal dual-frequency piezoelectric ceramic structure to perform real-time monitoring of FUS-BBB opening. A confocal dual-frequency (0.55 MHz/1.1 MHz) focused ultrasound transducer was designed. The 1.1 MHz spherically-curved ceramic was employed to deliver FUS exposure to induce BBB-opening, whereas the outer-ring 0.55 MHz ceramic was employed to detect the subharmonic acoustic emissions originating from the target position. In stage-1 experiments, we employed spectral analysis and performed an energy spectrum density (ESD) calculation. An optimized 0.55 MHz ESD level change was shown to effectively discriminate the occurrence of BBB opening. Wideband acoustic emissions received from 0.55 MHz ceramics were also analyzed to evaluate its correlations with erythrocyte extravasations. In stage-2 real-time monitoring experiments, we applied the predetermined ESD change as a detection threshold in PC-controlled algorithm to predict the FUS exposure intra operatively. In stage-1 experiment, we showed that subharmonic ESD presents distinguishable dynamics between intact BBB and opened BBB, and therefore a threshold ESD change level (5.5 dB) can be identified for BBB-opening prediction. Using this ESD change threshold detection as a surrogate to on/off control the FUS exposure in stage-2 experiments, we demonstrated both excellent sensitivity (92%) and specificity (92.3%) in discriminating BBB-opening occurrence can be obtained in animal treatments, while concurrently achieving a high positive predicted value (95.8%). Wideband ESD was also highly correlated with the occurrence and level of erythrocyte extravasations (r (2) = 0.81). The proposed system configuration and corresponding analysis based on subharmonic acoustic emissions has the potential to be implemented as a real-time feedback control structure for reliable indication of intact FUS-BBB opening for CNS brain drug delivery. PMID- 26988241 TI - Definition and clinical significance of tumour rupture in gastrointestinal stromal tumours of the small intestine. AB - BACKGROUND: Tumour rupture is a risk factor for recurrence of gastrointestinal stromal tumour (GIST). In this study, patterns of recurrence after potential tumour seeding were investigated, and a new definition of tumour rupture, based on major and minor defects of tumour integrity, is proposed. METHODS: Patients undergoing surgery for non-metastatic small intestinal GIST from 2000 to 2012 were included in the study. Tumour spillage, tumour fracture or piecemeal resection, bowel perforation at the tumour site, blood-tinged ascites, microscopic tumour infiltration into an adjacent organ, and surgical biopsy were defined as major defects of tumour integrity. Peritoneal tumour penetration, iatrogenic peritoneal laceration and microscopically involved margins were defined as minor defects. RESULTS: Seventy-two patients were identified. Median follow-up was 58 (range 7-122) months. Radical surgery was performed in 71 patients. A major defect was recorded in 20 patients, and a minor defect in 21. The 5-year recurrence rate was 64, 29 and 31 per cent in patients with major, minor and no defect respectively (P = 0.001). The hazard ratio (HR) for major defect versus no defect was 3.55 (95 per cent c.i. 1.51 to 8.35). Peritoneal recurrence rates for major, minor and no defect were 52, 25 and 19 per cent respectively (P = 0.002), and the HR for major defect versus no defect was 4.98 (1.69 to 14.68). On multivariable analysis, mitotic index, major defect of tumour integrity, tumour size and age were independently associated with risk of recurrence. CONCLUSION: Recurrence rates were increased after major, but not minor tumour ruptures. PMID- 26988242 TI - Reply to: The Triglyceride to High-Density Lipoprotein Cholesterol Ratio Is a Useful Marker to Predict Unfavorable Cardiovascular Outcomes, But Other Confounding Factors Should Be Considered. PMID- 26988243 TI - Biosimilars: A Multidisciplinary Perspective. AB - A biosimilar is an officially regulated and approved copy of an originator biologic therapy. Improved affordability and consequent wider patient access compared with biologics are a significant appeal of biosimilars. Regulatory guidelines for biosimilar development and approval are rigorous and undergoing constant refinement. The process of licensing approval for all biosimilars requires demonstration of comparability in quality, efficacy, and safety between the biosimilar and reference (originator) product, which is undertaken in a stepwise procedure of nonclinical and clinical evaluation. The approval of >20 biosimilars in Europe in several drug classes, including the first monoclonal antibody biosimilar, bears testimony to the increasing regulatory acceptance of these agents. In contrast, the clinical application of biosimilars remains underrecognized by physicians across therapy areas. Therefore, this article aims to provide a comprehensive review of the biosimilar development process and to provide multidisciplinary guidance on the potential therapeutic utility of biosimilars in clinical practice. Specifically, experts discuss clinical developments in the introduction of biosimilars across the disciplines of gastroenterology, nephrology, oncology, and rheumatology, and from a payer perspective, and also highlight a common need for ongoing pharmacovigilance, robust head-to-head clinical studies, and real-world data to establish the long term risk-benefit profile of biosimilars. In conclusion, significant potential exists for biosimilars to revolutionize biologic therapy by widening patient access across therapy areas. PMID- 26988244 TI - Cofactor-embedded nanoporous activated carbon matrices for the immobilization of intracellular enzymes and degradation of endocrine disruptor. AB - The mixed intracellular enzyme (MICE) from Citrobacter freundii, capable of degrading o-phenylene diamine (OPD), was extracted and characterized. Cofactors such as zinc and copper ions enhanced the MICE activity. The functionalized nanoporous-activated carbon (FNAC) matrix, zinc-impregnated FNAC matrix (Zn2+ FNAC), copper-impregnated FNAC matrix (Cu2+ -FNAC), and zinc- and copper impregnated FNAC matrix (Zn2+ -Cu2+ -FNAC) were prepared and characterized to immobilize MICE. The parameters such as time (0-240 Min), pH (1-10), temperature (20-50 oC), amount of MICE (1-5 mg), particle size of carbon (100-600 MUm), and mass of carbon (0.5-2.5 g) were optimized for immobilization of MICE on different FNAC matrices. The carrier matrices in the free and MICE immobilized form were characterized using SEM, FT-IR, XPS, XRD, thermogravimetric analysis (TGA), and DSC analyses. The kinetic and adsorption models for the immobilization of MICE on FNAC matrices were studied. The parameters such as time, pH, temperature, concentration of OPD, and agitation speed were optimized for the degradation of OPD using FNAC-MICE and MICE-immobilized metal-impregnated FNAC matrices. The maximum amount of pyruvic acid formed was found to be 133 MUg/mg of OPD using Zn2+ -Cu2+ -FNAC-MICE matrix. The kinetic models were studied for the formation of pyruvic acid on OPD degradation and confirmed using FT-IR spectroscopy. PMID- 26988245 TI - Acute encephalopathy with combination dabrafenib/trametinib therapy. AB - Biomarkers have improved the clinical application of numerous targeted agents used to treat solid tumors. In melanoma, the finding that approximately 60% of tumor cells harbor specific Val600 mutations of BRAF has increased the likelihood of response to certain agents aimed at inhibiting the mutant kinase. While dabrafenib is an effective anti-tumor agent with acceptable tolerability in patients with BRAF-mutated melanoma, we report the development (and outcome) of a previously unpublished acute toxic reaction observed in a patient receiving the drug. PMID- 26988246 TI - Improving adherence to the Epic Beacon ambulatory workflow. AB - Computerized physician order entry has been shown to significantly improve chemotherapy safety by reducing the number of prescribing errors. Epic's Beacon Oncology Information System of computerized physician order entry and electronic medication administration was implemented in Henry Ford Health System's ambulatory oncology infusion centers on 9 November 2013. Since that time, compliance to the infusion workflow had not been assessed. The objective of this study was to optimize the current workflow and improve the compliance to this workflow in the ambulatory oncology setting. This study was a retrospective, quasi-experimental study which analyzed the composite workflow compliance rate of patient encounters from 9 to 23 November 2014. Based on this analysis, an intervention was identified and implemented in February 2015 to improve workflow compliance. The primary endpoint was to compare the composite compliance rate to the Beacon workflow before and after a pharmacy-initiated intervention. The intervention, which was education of infusion center staff, was initiated by ambulatory-based, oncology pharmacists and implemented by a multi-disciplinary team of pharmacists and nurses. The composite compliance rate was then reassessed for patient encounters from 2 to 13 March 2015 in order to analyze the effects of the determined intervention on compliance. The initial analysis in November 2014 revealed a composite compliance rate of 38%, and data analysis after the intervention revealed a statistically significant increase in the composite compliance rate to 83% ( p < 0.001). This study supports a pharmacist-initiated educational intervention can improve compliance to an ambulatory, oncology infusion workflow. PMID- 26988247 TI - Precision Medicine for Diffuse Large B-cell Lymphoma. AB - This study demonstrates the clinical utility of a targeted gene sequencing panel "the Lymphopanel," which enables the detection of actionable mutations and subtype-enriched gene alterations in diffuse large B-cell lymphoma that will pave the way to precision therapy era for patients with this form of aggressive lymphoma. Clin Cancer Res; 22(12); 2829-31. (c)2016 AACRSee related article by Dubois et al., p. 2919. PMID- 26988248 TI - Cervical Cancer Stem Cells Selectively Overexpress HPV Oncoprotein E6 that Controls Stemness and Self-Renewal through Upregulation of HES1. AB - PURPOSE: Perturbation of keratinocyte differentiation by E6/E7 oncoproteins of high-risk human papillomaviruses that drive oncogenic transformation of cells in squamocolumnar junction of the uterine cervix may confer "stem-cell like" characteristics. However, the crosstalk between E6/E7 and stem cell signaling during cervical carcinogenesis is not well understood. We therefore examined the role of viral oncoproteins in stem cell signaling and maintenance of stemness in cervical cancer. EXPERIMENTAL DESIGN: Isolation and enrichment of cervical cancer stem-like cells (CaCxSLCs) was done from cervical primary tumors and cancer cell lines by novel sequential gating using a set of functional and phenotypic markers (ABCG2, CD49f, CD71, CD133) in defined conditioned media for assessing sphere formation and expression of self-renewal and stemness markers by FACS, confocal microscopy, and qRT-PCR. Differential expression level and DNA-binding activity of Notch1 and its downstream targets in CaCxSLCs as well as silencing of HPVE6/Hes1 by siRNA was evaluated by gel retardation assay, FACS, immunoblotting, and qRT-PCR followed by in silico and in vivo xenograft analysis. RESULTS: CaCxSLCs showed spheroid-forming ability, expressed self-renewal and stemness markers Oct4, Sox2, Nanog, Lrig1, and CD133, and selectively overexpressed E6 and HES1 transcripts in both cervical primary tumors and cancer cell lines. The enriched CaCxSLCs were highly tumorigenic and did recapitulate primary tumor histology in nude mice. siRNA silencing of HPVE6 or Hes1 abolished sphere formation, downregulated AP-1-STAT3 signaling, and induced redifferentiation. CONCLUSIONS: Our findings suggest the possible mechanism by which HPVE6 potentially regulate and maintain stem-like cancer cells through Hes1. Clin Cancer Res; 22(16); 4170-84. (c)2016 AACR. PMID- 26988250 TI - How Archiving by Freezing Affects the Genome-Scale Diversity of Escherichia coli Populations. AB - In the experimental evolution of microbes such as Escherichia coli, many replicate populations are evolved from a common ancestor. Freezing a population sample supplemented with the cryoprotectant glycerol permits later analysis or restarting of an evolution experiment. Typically, each evolving population, and thus each sample archived in this way, consists of many unique genotypes and phenotypes. The effect of archiving on such a heterogeneous population is unknown. Here, we identified optimal archiving conditions for E. coli. We also used genome sequencing of archived samples to study the effects that archiving has on genomic population diversity. We observed no allele substitutions and mostly small changes in allele frequency. Nevertheless, principal component analysis of genome-scale allelic diversity shows that archiving affects diversity across many loci. We showed that this change in diversity is due to selection rather than drift. In addition, ~1% of rare alleles that occurred at low frequencies were lost after treatment. Our observations imply that archived populations may be used to conduct fitness or other phenotypic assays of populations, in which the loss of a rare allele may have negligible effects. However, caution is appropriate when sequencing populations restarted from glycerol stocks, as well as when using glycerol stocks to restart or replay evolution. This is because the loss of rare alleles can alter the future evolutionary trajectory of a population if the lost alleles were strongly beneficial. PMID- 26988249 TI - Genome Hotspots for Nucleotide Substitutions and the Evolution of Influenza A (H1N1) Human Strains. AB - In recent years a number of studies have brought attention to the role of positive selection during the evolution of antigenic escape by influenza strains. Particularly, the identification of positively selected sites within antigenic domains of viral surface proteins has been used to suggest that the evolution of viral-host receptor binding specificity is driven by selection. Here we show that, following the 1918 outbreak, the antigenic sites of the hemagglutinin (HA) viral surface protein and the stalk region of neuraminidase became substitution hotspots. The hotspots show similar patterns of nucleotide substitution bias at synonymous and nonsynonymous sites. Such bias imposes directionality in amino acid replacements that can influence signals of selection at antigenic sites. Our results suggest that the high accumulation of substitutions within the antigenic sites of HA can explain not only cases of antigenic escape by antigenic drift but also lead to occasional episodes of viral extinction. PMID- 26988251 TI - Evaluating and Characterizing Ancient Whole-Genome Duplications in Plants with Gene Count Data. AB - Whole-genome duplications (WGDs) have helped shape the genomes of land plants, and recent evidence suggests that the genomes of all angiosperms have experienced at least two ancient WGDs. In plants, WGDs often are followed by rapid fractionation, in which many homeologous gene copies are lost. Thus, it can be extremely difficult to identify, let alone characterize, ancient WGDs. In this study, we use a new maximum likelihood estimator to test for evidence of ancient WGDs in land plants and estimate the fraction of new genes copies that are retained following a WGD using gene count data, the number of gene copies in gene families. We identified evidence of many putative ancient WGDs in land plants and found that the genome fractionation rates vary tremendously among ancient WGDs. Analyses of WGDs within Brassicales also indicate that background gene duplication and loss rates vary across land plants, and different gene families have different probabilities of being retained following a WGD. Although our analyses are largely robust to errors in duplication and loss rates and the choice of priors, simulations indicate that this method can have trouble detecting multiple WGDs that occur on the same branch, especially when the gene retention rates for ancient WGDs are very low. They also suggest that we should carefully evaluate evidence for some ancient plant WGD hypotheses. PMID- 26988253 TI - Mechanisms of vascular dysfunction in acute phase of Trypanosoma cruzi infection in mice. AB - Vascular disorders have a direct link to mortality in the acute phase of Trypanosoma cruzi infection. However, the underlying mechanisms of vascular dysfunction in this phase are largely unknown. We hypothesize that T. cruzi invades endothelial cells causing dysfunction in contractility and relaxation of the mouse aorta. Immunodetection of T. cruzi antigen TcRBP28 was observed in endothelial cells. There was a decreased endothelial nitric oxide synthase (eNOS) derived NO-dependent vascular relaxation, and increased vascular contractility accompanied by augmented superoxide anions production. Endothelial removal, inhibition of cyclooxygenase 2 (COX-2), blockade of thromboxane A2 (TXA2) TP receptors, and scavenger of superoxide normalized the contractile response. COX 2, thromboxane synthase, inducible nitric oxide synthase (iNOS), p65 NFkappaB subunit and p22(phox) of NAD(P)H oxidase (NOX) subunit expressions were increased in vessels of chagasic animals. Serum TNF-alpha was augmented. Basal NO production, and nitrotyrosine residue expression were increased. It is concluded that T. cruzi invades mice aorta endothelial cells and increases TXA2/TP receptor/NOX-derived superoxide formation. Alongside, T. cruzi promotes systemic TNF-alpha increase, which stimulates iNOS expression in vessels and nitrosative stress. In light of the heart failure that develops in the chronic phase of the disease, to understand the mechanism involved in the increased contractility of the aorta is crucial. PMID- 26988254 TI - The dilemma of raising awareness "responsibly": The need to discuss controversial research with the public raises a conundrum for scientists: when is the right time to start public debates? PMID- 26988252 TI - A Phylogenomic Assessment of Ancient Polyploidy and Genome Evolution across the Poales. AB - Comparisons of flowering plant genomes reveal multiple rounds of ancient polyploidy characterized by large intragenomic syntenic blocks. Three such whole genome duplication (WGD) events, designated as rho (rho), sigma (sigma), and tau (tau), have been identified in the genomes of cereal grasses. Precise dating of these WGD events is necessary to investigate how they have influenced diversification rates, evolutionary innovations, and genomic characteristics such as the GC profile of protein-coding sequences. The timing of these events has remained uncertain due to the paucity of monocot genome sequence data outside the grass family (Poaceae). Phylogenomic analysis of protein-coding genes from sequenced genomes and transcriptome assemblies from 35 species, including representatives of all families within the Poales, has resolved the timing of rho and sigma relative to speciation events and placed tau prior to divergence of Asparagales and the commelinids but after divergence with eudicots. Examination of gene family phylogenies indicates that rho occurred just prior to the diversification of Poaceae and sigma occurred before early diversification of Poales lineages but after the Poales-commelinid split. Additional lineage specific WGD events were identified on the basis of the transcriptome data. Gene families exhibiting high GC content are underrepresented among those with duplicate genes that persisted following these genome duplications. However, genome duplications had little overall influence on lineage-specific changes in the GC content of coding genes. Improved resolution of the timing of WGD events in monocot history provides evidence for the influence of polyploidization on functional evolution and species diversification. PMID- 26988255 TI - Spin transport in p-type germanium. AB - We report on the spin transport properties in p-doped germanium (Ge-p) using low temperature magnetoresistance measurements, electrical spin injection from a ferromagnetic metal and the spin pumping-inverse spin Hall effect method. Electrical spin injection is carried out using three-terminal measurements and the Hanle effect. In the 2-20 K temperature range, weak antilocalization and the Hanle effect provide the same spin lifetime in the germanium valence band (~1 ps) in agreement with predicted values and previous optical measurements. These results, combined with dynamical spin injection by spin pumping and the inverse spin Hall effect, demonstrate successful spin accumulation in Ge. We also estimate the spin Hall angle theta(SHE) in Ge-p (6-7 x 10(-4) at room temperature, pointing out the essential role of ionized impurities in spin dependent scattering. PMID- 26988256 TI - Immunogenicity and safety of two doses of catch-up immunization with Haemophilus influenzae type b conjugate vaccine in Indian children living with HIV. AB - BACKGROUND: Children living with HIV are at increased risk of disease from Haemophilus influenzae type b (Hib). Data are limited on the immunogenicity of a two-dose, catch-up schedule for Hib conjugate vaccine (HibCV) among HIV-infected children accessing antiretroviral therapy (ART) late. OBJECTIVES: The objectives of the study were to: (1) evaluate baseline immunity to Hib and the immunogenicity and safety of two doses of HibCV among HIV-infected Indian children; and (2) document the threshold antibody level required to prevent Hib colonization among HIV-infected children following immunization. METHODS: We conducted a prospective cohort study among HIV-infected children 2-15 years of age and HIV-uninfected children 2-5 years of age. HIV-infected children received two doses of HibCV and uninfected children received one. Serum anti-Hib PRP IgG antibodies were measured at baseline and two months after immunization in the HIV infected children. Nasopharyngeal (NP) swabs were collected at baseline and follow-up. RESULTS: 125 HIV-infected and 44 uninfected children participated. 40% of HIV-infected children were receiving ART and 26% had a viral load >100,000 copies/mL. The geometric mean concentration of serum anti-Hib PRP antibody increased from 0.25 MUg/mL at baseline to 2.65 MUg/mL after two doses of HibCV, representing a 10.6-fold increase (p<0.0001). 76% percent of HIV-infected children mounted an immune response. Moderate or severe immune suppression, trimethoprim/sulfamethoxazole prophylaxis, and lower baseline antibody levels were associated with lower post-vaccine serum anti-Hib PRP IgG antibodies. A serum anti-Hib PRP IgG antibody level >= 3.3 MUg/mL was protective against Hib NP colonization. There were no differences in adverse events between HIV-infected and uninfected children. CONCLUSION: Including a catch-up immunization schedule for older HIV infected children in countries introducing Hib vaccines is important. Older HIV-infected children with delayed access to ART and without suppressed viral loads mounted an adequate immune response following two doses of HibCV. PMID- 26988258 TI - Status of vaccine research and development of vaccines for GBS. AB - Streptococcus agalactiae (group B streptococcus (GBS)) is the leading cause of neonatal sepsis and meningitis in many countries. Intrapartum antibiotic strategies have reduced the incidence of early-onset neonatal GBS in a number of countries but have had no impact on late onset GBS infection (LOD). In low/middle income settings, the disease burden remains uncertain although in several countries of Southern Africa appears comparable to or higher than that of high income countries. As disease may be rapidly fulminating cases can be missed before appropriate samples are obtained and this may lead to underestimation of the true burden. Given the rapid onset and progression within hours of birth as well as the deficiencies in IAP strategies and absence of a solution for preventing LOD, it is clear that administration of a suitable vaccine in pregnancy could provide a better solution in all settings; it should also be cost effective. The current leading vaccine candidates are CPS-protein conjugate vaccines but protein-based vaccines are also in development and one has recently commenced clinical trials. PMID- 26988257 TI - The cost-effectiveness of pneumococcal vaccination in healthy adults over 50: An exploration of influential factors for Belgium. AB - BACKGROUND: A recent trial demonstrated the 13 valent conjugate pneumococcal vaccine (PCV13) to be effective against invasive and non-invasive pneumococcal disease in healthy adults. PCV13 might therefore be considered as an alternative to the 23 valent polysaccharide vaccine (PPV23). AIM: To explore the cost effectiveness of vaccinating healthy adults over 50, with either PCV13 or PPV23 alone, or with a combined strategy using both PCV13 and PPV23. METHODS: A static multi-cohort model was developed simulating the consequences of pneumococcal vaccination in adults over 50 from a health care payer's perspective, for different scenarios of duration of vaccine protection and serotype evolution. RESULTS: At currently expected prices, PCV13 vaccination of healthy adults over 50 is unlikely to be cost-effective either compared with no vaccination or in combination with PPV23 versus PPV23 only. CONCLUSION: Further research is needed on vaccine efficacy of the combination strategy and of risk groups, as well as the duration of vaccine protection. Serotype evolutions under the influence of the childhood PCV program should be closely monitored. PMID- 26988259 TI - Status of vaccine research and development for enterotoxigenic Escherichia coli. AB - Enterotoxigenic Escherichia coli (ETEC) is one of the most common bacterial causes of diarrhea-associated morbidity and mortality, particularly among infants and young children in developing countries. Still, the true impact on child and traveler health is likely underestimated. There are currently no licensed vaccines for ETEC, but studies indicate high public health impact, cost effectiveness, and feasibility of immune protection through vaccination. ETEC vaccine development remains a World Health Organization priority. Traditionally, ETEC vaccine development efforts have focused on inducing antitoxin and anticolonization antigen immunity, as studies indicate that antibodies against both antigen types can contribute to protection and thus have potential for vaccines. Leading cellular vaccine candidates are ETVAX (a mixture of four inactivated strains) and ACE527 (a mixture of three live attenuated strains), both of which have been found to be safe and immunogenic in Phase 1/2 trials. ETVAX is the furthest along in development with descending-age studies already underway in Bangladesh. Other ETEC vaccine candidates based on protein subunits, toxoids (both LT and ST), or novel, more broadly conserved ETEC antigens are also under development. Of these, a protein adhesin-based subunit approach is the most advanced. Impact and economic models suggest favorable vaccine cost effectiveness, which may help expand market interest in ETEC vaccines. Combination vaccine formulations may help improve the economic case for development and use, and better point-of-care diagnostics will help to raise awareness of the true health burden of ETEC and highlight the potential public health benefit of ETEC vaccine introduction. Better diagnostics and vaccine demand forecasting will also improve vaccine development financing and support accelerated uptake once a licensed vaccine becomes available. PMID- 26988260 TI - Monitoring the process of measles elimination by serosurveillance data: The Apulian 2012 study. AB - In 2003 Italy adopted the National Plan for Measles and Congenital Rubella Elimination, but some outbreaks of measles are still occurring, as the target coverage rate (>= 95%) for new-borns has currently not been achieved. In order to support the monitoring of the measles elimination programme, the authors carried out a survey about the seroprevalence of measles among Apulia young adults. The study was carried out from May 2011 to June 2012 among blood donors of the Department of Transfusion Medicine of Policlinico General Hospital in Bari. Subjects were enrolled by a convenience sampling. For each enrolled patient we collected a 5 mL serum sample. Collected sera were tested by chemiluminescence (CLIA) for anti-Measles IgG. We enrolled 1764 subjects; 1362 (77.2%) were male with a mean age of 38.4 +/- 11.7 years. Anti-Measles IgG titre was >16.5UA/mL in 95.1% (95% CI=94.1-96.1) of enrolled subjects with a Geometric Mean Titre (GMT) of 2.3 +/- 0.4, which did not differ dividing the enrolled subjects into age groups. As our data showed, the universal routine vaccination changed the epidemiological pattern among adults, in particular young adults (18-24 years), who showed lowest seropositivity rates; in these groups of population there is a risk of the onset of outbreaks due to the presence of susceptible population. This is a paradox linked to the vaccination strategy: when coverage rates keep sub-optimal, measles is more likely to affect young adults and a higher percentage of complications is expected. According to our data, health authorities have to plan a mop-up strategy to actively offer measles vaccination to susceptible young adults. PMID- 26988263 TI - Emphysematous pyelonephritis. PMID- 26988262 TI - CT Permeability Imaging Predicts Clinical Outcomes in Acute Ischemic Stroke Patients Treated with Intra-arterial Thrombolytic Therapy. AB - In this study, we determined whether a prediction of final infarct volume (FIV) and clinical outcomes in patients with an acute stroke is improved by using a contrast transfer coefficient (K trans) as a biomarker for blood-brain barrier (BBB) dysfunction. Here, consecutive patients admitted with signs and symptoms suggesting acute hemispheric stroke were included in this study. Ninety-eight participants with intra-arterial therapy were assessed (46 female). Definition of predicted FIV was performed using conventional perfusion CT (PCT-PIV) parameters alone and in combination with K trans (K trans-PIV). Multiple logistic regression analyses and linear regression modeling were conducted to determine independent predictors of the 90-day modified Rankin score (mRS) and FIV, respectively. We found that patients with favorable outcomes were younger and had lower National Institutes of Health Stroke Scale (NIHSS) score, smaller PCT-PIV, K trans-PIV, and smaller FIV (P < 0.001). K trans-PIV showed good correlation with FIV (P < 00.001, R 2 = 0.6997). In the regression analyses, K trans-PIV was the best predictor of clinical outcomes (P = 0.009, odds ratio (OR) = 1.960) and also the best predictor for FIV (F = 75.590, P < 0.0001). In conclusion, combining PCT and K trans maps derived from first-pass PCT can identify at-risk cerebral ischemic tissue more precisely than perfusion parameters alone. This provides improved accuracy in predicting FIV and clinical outcomes. PMID- 26988264 TI - Mitochondrial DNA 4977-base pair common deletion in blood leukocytes and melanoma risk. AB - The 4977-base pair common deletion DmtDNA4977 is the most frequently observed mitochondrial DNA mutation in human tissues. Because mitochondrial DNA mutations are mainly caused by reactive oxygen species (ROS), and given that oxidative stress plays an important role in melanoma carcinogenesis, the investigation of DmtDNA4977 may be particularly relevant to the development of melanoma. In this study, we compared DmtDNA4977 levels in blood leukocytes from 206 melanoma patients and 219 healthy controls. Overall, melanoma cases had significantly higher levels of DmtDNA4977 than healthy controls (median: 0.60 vs 0.20, P = 0.008). The difference was evident among individuals who were older than 47 yrs, women, and had pigmentation risk factors (e.g., blond or red hair, blue eye, fair skin, light, or none tanning ability after prolonged sun exposure, and freckling in the sun as a child). The difference was also evident among those who had at least one lifetime sunburn with blistering and had no reported use of a sunlamp. Interestingly, among controls, DmtDNA4977 levels differed by phenotypic index and reported use of a sunlamp. In the risk assessment, increased levels of DmtDNA4977 were associated with a 1.23-fold increased risk of melanoma (odds ratio (OR): 1.23, 95% confidence interval (90% CI): 1.01, 1.50). A significant dose-response relationship was observed in quartile analysis (P = 0.001). In summary, our study suggests that high levels of DmtDNA4977 in blood leukocytes are associated with increased risk of melanoma and that association is affected by both pigmentation and personal history of sun exposure. PMID- 26988265 TI - Delocalized Plastic Flow in Proton-Irradiated Monolithic Metallic Glasses. AB - Creating new materials with novel properties through structural modification is the Holy Grail of materials science. The range of targetable structures for amplification of mechanical properties in metallic glasses would include types of atomic short range orders at the smallest scale through compositions or morphologies of phases in composites. Even though the usefulness of the latter approach has been successfully demonstrated in the past decades, the feasibility of the former has been incompletely proved with only marginal property improvements reported within experimentally-accessible atomic-level structural changes. Here, we report the significant enhancement of deformability in Zr-based monolithic metallic glass only through the atomic disordering by proton irradiation without altering any other structural traits. Metallic glass nanopillars that originally failed catastrophically without any notable plasticity become capable of attaining more than 30% uniaxial plastic strain accommodated by homogeneous deformation when irradiated to ~1 displacement per atom (DPA). We discuss the atomistic origin of this improved plasticity in terms of density and spatial distributions of icosahedral short range order influenced by irradiation. PMID- 26988267 TI - Watch one, do one, teach one. PMID- 26988266 TI - TOGETHER Project to Increase Understanding of the HIV Epidemic Among Sub-Saharan African Migrants: Protocol of Community-Based Participatory Mixed-Method Studies. AB - BACKGROUND: Sub-Saharan African Migrants (SAM) are the second largest group affected by HIV/AIDS in Belgium and the rest of Western Europe. Increasing evidence shows that, more than previously thought, SAM are acquiring HIV in their host countries. This calls for a renewed focus on primary prevention. Yet, knowledge on the magnitude of the HIV epidemic among SAM (HIV prevalence estimates and proportions of undiagnosed HIV infections) and underlying drivers are scarce and limit the development of such interventions. OBJECTIVE: By applying a community-based participatory and mixed-methods approach, the TOGETHER project aims to deepen our understanding of HIV transmission dynamics, as well as inform future primary prevention interventions for this target group. METHODS: The TOGETHER project consists of a cross-sectional study to assess HIV prevalence and risk factors among SAM visiting community settings in Antwerp city, Belgium, and links an anonymous electronic self-reported questionnaire to oral fluid samples. Three formative studies informed this method: (1) a social mapping of community settings using an adaptation of the PLACE method; (2) a multiple case study aiming to identify factors that increase risk and vulnerability for HIV infection by triangulating data from life history interviews, lifelines, and patient files; and (3) an acceptability and feasibility study of oral fluid sampling in community settings using participant observations. RESULTS: Results have been obtained from 4 interlinked studies and will be described in future research. CONCLUSIONS: Combining empirically tested and innovative epidemiological and social science methods, this project provides the first HIV prevalence estimates for a representative sample of SAM residing in a West European city. By triangulating qualitative and quantitative insights, the project will generate an in-depth understanding of the factors that increase risk and vulnerability for HIV infection among SAM. Based on this knowledge, the project will identify priority subgroups within SAM communities and places for HIV prevention. Adopting a community-based participatory approach throughout the full research process should increase community ownership, investment, and mobilization for HIV prevention. PMID- 26988268 TI - Higher rate alternative non-drug reinforcement produces faster suppression of cocaine seeking but more resurgence when removed. AB - Relapse following removal of an alternative source of reinforcement introduced during extinction of a target behavior is called resurgence. This form of relapse may be related to relapse of drug taking following loss of alternative non-drug reinforcement in human populations. Laboratory investigations of factors mediating resurgence with food-maintained behavior suggest higher rates of alternative reinforcement produce faster suppression of target behavior but paradoxically generate more relapse when alternative reinforcement is discontinued. At present, it is unknown if a similar effect occurs when target behavior is maintained by drug reinforcement and the alternative is a non-drug reinforcer. In the present experiment three groups of rats were trained to lever press for infusions of cocaine during baseline. Next, during treatment, cocaine reinforcement was suspended and an alternative response was reinforced with either high-rate, low-rate, or no alternative food reinforcement. Finally, all reinforcement was suspended to test for relapse of cocaine seeking. Higher rate alternative reinforcement produced faster elimination of cocaine seeking than lower rates or extinction alone, but when treatment was suspended resurgence of cocaine seeking occurred following only high-rate alternative reinforcement. Thus, although higher rate alternative reinforcement appears to more effectively suppress drug seeking, should it become unavailable, it can have the unfortunate effect of increasing relapse. PMID- 26988269 TI - Loss of the trpc4 gene is associated with a reduction in cocaine self administration and reduced spontaneous ventral tegmental area dopamine neuronal activity, without deficits in learning for natural rewards. AB - Among the canonical transient receptor potential (TRPC) channels, the TRPC4 non selective cation channel is one of the most abundantly expressed subtypes within mammalian corticolimbic brain regions, but its functional and behavioral role is unknown. To identify a function for TRPC4 channels we compared the performance of rats with a genetic knockout of the trpc4 gene (trpc4 KO) to wild-type (WT) controls on the acquisition of simple and complex learning for natural rewards, and on cocaine self-administration (SA). Despite the abundant distribution of TRPC4 channels through the corticolimbic brain regions, we found trpc4 KO rats exhibited normal learning in Y-maze and complex reversal shift paradigms. However, a deficit was observed in cocaine SA in the trpc4 KO group, which infused significantly less cocaine than WT controls despite displaying normal sucrose SA. Given the important role of ventral tegmental area (VTA) dopamine neurons in cocaine SA, we hypothesized that TRPC4 channels may regulate basal dopamine neuron excitability. Double-immunolabeling showed a selective expression of TRPC4 channels in a subpopulation of putative dopamine neurons in the VTA. Ex vivo recordings of spontaneous VTA dopamine neuronal activity from acute brain slices revealed fewer cells with high-frequency firing rates in trpc4 KO rats compared to WT controls. Since deletion of the trpc4 gene does not impair learning involving natural rewards, but reduces cocaine SA, these data demonstrate a potentially novel role for TRPC4 channels in dopamine systems and may offer a new pharmacological target for more effective treatment of a variety of dopamine disorders. PMID- 26988270 TI - Diphosphane 2,2'-binaphtho[1,8-de][1,3,2]dithiaphosphinine and the easy formation of a stable phosphorus radical cation. AB - A convenient synthesis route to 2,2'-binaphtho[1,8-de][1,3,2]di-thiaphosphinine () was found. Its stable radical cation 3(+) was accessed easily through one electron oxidation with NOBF4. PMID- 26988271 TI - Placental tumor necrosis factor-alpha protein expression during normal human gestation. AB - OBJECTIVE: Placental tumor necrosis factor-alpha (TNF-alpha) is a cell signaling protein. During pregnancy, TNF-alpha induces synthesis of matrix metalloproteinases (MMPs) which allows cytotrophoblasts to reach the spiral arteries deeper within the uterine decidua. TNF-alpha also augments apoptosis of vascular smooth muscle cells surrounding these arteries. In this study, chorionic villi TNF-alpha protein expression throughout normal human gestation were investigated. METHODS: Placental chorionic villi tissues obtained from elective surgical terminations of pregnancy and from uncomplicated term births were assayed using EIA kits (Cayman Chemicals, Ann Arbor, MI, Item # 589201). RESULTS: The median, 25th percentile and 75th percentile values in the first (N = 99), second (N = 58) and third trimester (N = 42) were: 36.46, 27.25, 45.90 pg/100 mg tissue; 55.43, 40.09, 110.88 pg/100 mg tissue; and 16.63, 9.32, 31.92 pg/100 mg tissue, respectively. CONCLUSIONS: Variations in placental TNF-alpha protein expression noted at different trimesters may suggest gestational age specific roles for the cytokine. The increase in TNF-alpha protein expression observed in the second trimester may be involved in upregulating synthesis of MMP and in augmenting apoptosis of vascular smooth muscle cells of the spiral arteries. A failure in this second trimester increase in TNF-alpha protein could contribute to gestational compromise. PMID- 26988273 TI - YKL-40 protein in osteosarcoma tumor tissue. AB - YKL-40, a cellular glycoprotein isolated from the human osteosarcoma (OS) cell line MG63, is increased in the blood of patients with various types of cancer, and is found as an independent prognostic variable for survival. YKL-40 is also present with variable intensity in the tumor cells of some cancer types, but survival results have been conflicting. The aim of this study was to investigate the tissue expression of YKL-40 and its possible role as a predictive marker in patients with OS. Forty-eight patients were included in the study. Diagnostic biopsies were analyzed by immunohistochemistry; YKL-staining scores as well as CD14 and CD163 scores were determined, and survival data were determined statistically. A universal intense immunostaining for YKL-40 was found in all tumor cells, but tumor cell/stroma ratio varied, and this ratio (%) served as staining score. Using 24% as mean score to divide the material, patients with tumors of high YKL-40 score had a better survival than patients with low score (p = 0.05). YKL-positive macrophages had no influence on the result. Unexpectedly and contrary to some other findings in cancer tissues, this study has shown a correlation between high YKL-40 tumor cell/matrix ratio and longer overall survival in OS. PMID- 26988274 TI - Concomitant NSAID use during antipsychotic treatment and risk of 2-year relapse - a population-based study of 16,253 incident patients with schizophrenia. AB - OBJECTIVE: Clinical trials have indicated antipsychotic effects of non-steroidal anti-inflammatory drugs (NSAIDs) among incident patients with schizophrenia. We aimed to study, in a population-based setting, whether concomitant use of NSAIDs or paracetamol, changed 2-year relapse risk for schizophrenia. METHODS: We identified all incident patients with schizophrenia in Denmark diagnosed 1996 2012 initiating antipsychotic treatment within the year after diagnosis. We calculated concomitant treatment intervals for antipsychotic and NSAID or paracetamol use. Hazard rate ratios (HRR) were estimated using Cox regression adjusted for important covariates. MAIN OUTCOME MEASURES: 2-year relapse, i.e. (re)-hospitalizations with schizophrenia. RESULTS: Among 16,235 incident patients with schizophrenia using antipsychotics, 1480 (9.1%) used NSAIDs and 767 (4.7%) paracetamol. Concomitant use of NSAIDs was associated with an increased risk of schizophrenia relapse (HRR = 1.21; 95%-CI = 1.11-1.31), particularly associated with acetylsalicylic acid and diclofenac. Concomitant use of paracetamol was not associated with schizophrenia relapse (HRR = 0.97; 95%-CI = 0.87-1.08). Subgroup analyses showed that individuals with somatic comorbidity and NSAID use had an increased relapse-risk, except for individuals with a prior hospital diagnosis for musculoskeletal disease and NSAID use who had a decreased relapse-risk (HRR = 0.82; 95%-CI = 0.71-0.94). CONCLUSIONS: The increased relapse risk associated with concomitant NSAID use among incident patients with schizophrenia may indicate a potential impact of underlying somatic comorbidity. PMID- 26988272 TI - Efficacy and safety of sofosbuvir/ledipasvir for the treatment of patients with hepatitis C virus re-infection after liver transplantation. AB - BACKGROUND: Hepatitis C virus (HCV) infection is associated with a particularly poor outcome after liver transplantation. In December 2014, sofosbuvir/ledipasvir (SOF/LDV) fixed-dose combination (FDC) was approved for HCV genotype 1 and 4 in Europe. In orthotopic liver transplantation (OLT) recipients, the interferon-free treatment of HCV re-infection with novel direct-acting antivirals has been demonstrated to be safe and effective in clinical trials, but real-world data are missing. The aim of this study was to investigate the safety and efficacy of SOF/LDV FDC in OLT recipients in the real-life setting. METHODS: All consecutive OLT patients started on SOF/LDV FDC for 12 or 24 weeks at the University Medical Center Hamburg-Eppendorf and Medical School Hannover between October 2014 and August 2015 were retrospectively analyzed (n = 30). The primary efficacy endpoint was sustained virological response (SVR), i.e., absence of viremia 12 weeks after end of treatment (SVR 12). Liver function tests, creatinine, blood count, and HCV RNA (by polymerase chain reaction assay) were determined at each visit. RESULTS: SVR was achieved in 29/30 patients (96.67%) treated with SOF/LDV +/- ribavirin (RBV) for 12 (n = 4) or 24 weeks (n = 25). Twenty-five patients (86.2%) received RBV. However, in 15 of the 25 patients, RBV administration had to be discontinued because of severe anemia (57.7%). One RBV-treated patient died of a myocardial infarction during antiviral therapy; this event was most likely not directly related to SOF/LDV. Aside from RBV-associated anemia, no severe side effects of the antiviral regimen were observed. CONCLUSION: Antiviral treatment with SOF/LDV is highly effective, safe, and well tolerated in OLT recipients. The addition of RBV often results in severe anemia, requiring dose reduction or discontinuation. PMID- 26988275 TI - In situ synthesis of Bi2S3 sensitized WO3 nanoplate arrays with less interfacial defects and enhanced photoelectrochemical performance. AB - In this study, Bi2S3 sensitive layer has been grown on the surface of WO3 nanoplate arrays via an in situ approach. The characterization of samples were carried out using scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and ultraviolet-visible absorption spectroscopy (UV-vis). The results show that the Bi2S3 layer is uniformly formed on the surface of WO3 nanoplates and less interfacial defects were observed in the interface between the Bi2S3 and WO3. More importantly, the Bi2S3/WO3 films as photoanodes for photoelectrochemical (PEC) cells display the enhanced PEC performance compared with the Bi2S3/WO3 films prepared by a sequential ionic layer adsorption reaction (SILAR) method. In order to understand the reason for the enhanced PEC properties, the electron transport properties of the photoelectrodes were studied by using the transient photocurrent spectroscopy and intensity modulated photocurrent spectroscopy (IMPS). The Bi2S3/WO3 films prepared via an in situ approach have a greater transient time constant and higher electron transit rate. This is most likely due to less interfacial defects for the Bi2S3/WO3 films prepared via an in situ approach, resulting in a lower resistance and faster carrier transport in the interface between WO3 and Bi2S3. PMID- 26988276 TI - A cross-sectional survey on consequences of nurses' burnout: moderating role of organizational politics. AB - AIM: The aim of the study was to assess whether perceptions of organizational politics (defined as self-serving behaviours at the expense of others) influence the prospective associations between nurses' burnout and its consequences, namely, intention to quit and neglect of work. BACKGROUND: Researchers have previously investigated relationships between nurses' burnout, intention to quit, neglect of work and perceptions of organizational politics in different research models and from different perspectives. As far as we know, no studies have considered whether nurses' perceptions of organizational politics moderate the influence of burnout. DESIGN: A cross-sectional survey using self-report questionnaires. METHOD: Data were collected by questionnaire from a sample of 456 nurses from six private hospitals in Ankara, Turkey in March 2015. Four different previously designed scales were used to measure research variables (burnout, intention to quit, neglect of work and perceptions of organizational politics). Following confirmatory validity and reliability analyses of data collection instruments, descriptive statistics for each research variable were analysed. Structural regression models were created to assess relationships among variables. FINDINGS: Burnout resulted in intention to quit and neglect. Intention to quit partially mediated the association between burnout and neglect. Burnout gave rise to intention to quit slightly more strongly in nurses who had greater perceptions of organizational politics. CONCLUSION: This study uncovers and emphasizes the moderating role of perceptions of organizational politics in consequences of burnout. This may help hospital managers and nurses to improve costs, efficiency, satisfaction and productivity. PMID- 26988278 TI - Electron tunneling through molecule-electrode contacts of single alkane molecular junctions: experimental determination and a practical barrier model. AB - An advanced understanding of the molecule-electrode contact interfaces of single molecule junctions is a necessity for real world application of future single molecule devices. This study aims to elucidate the change in the contact tunnelling barrier induced by junction extension and how this change affects the resulting junction conductance. The contact barrier of Au octanedithiol/octanediamine-Au junctions was studied under triangle (TRI) mechanical modulations using the modified scanning tunneling microscopy (STM) break junction technique. The experimental results reveal that as the junction separation extends, the contact barrier of octanedithiol follows a unique trend, a linear increase followed by a plateau in barrier height, which is in contrast to that of octanediamine, a nearly rectangle barrier. We propose a modified contact barrier model for the unique barrier shape of octanedithiol, based on which the calculation agrees well with the experimental data. This study shows unprecedented experimental features of the molecule-electrode contact barrier of single-molecule junctions and provides new insights into the nature of contact effect in determining electron transport through single-molecule junctions. PMID- 26988279 TI - Erratum: Graphene oxide/metal nanocrystal multilaminates as the atomic limit for safe and selective hydrogen storage. PMID- 26988277 TI - Genetic Association of Curative and Adverse Reactions to Tyrosine Kinase Inhibitors in Chinese advanced Non-Small Cell Lung Cancer patients. AB - Epidermal growth factor receptor (EGFR) Tyrosine kinase inhibitor (TKI) is an effective targeted therapy for advanced non-small cell lung cancer (NSCLC) but also causes adverse drug reactions (ADRs) e.g., skin rash and diarrhea. SNPs in the EGFR signal pathway, drug metabolism/ transport pathways and miRNA might contribute to the interpersonal difference in ADRs but biomarkers for therapeutic responses and ADRs to TKIs in Chinese population are yet to be fully investigated. We recruited 226 Chinese advanced NSCLC patients who received TKIs erlotinib, gefitinib and icotinib hydrochloride and systematically studied the genetic factors associated with therapeutic responses and ADRs. Rs884225 (T > C) in EGFR 3' UTR was significantly associated with lower risk of ADRs to erlotinib (p value = 0.0010, adjusted p value = 0.042). A multivariant interaction four-SNP model (rs884225 in EGFR 3'UTR, rs7787082 in ABCB1 intron, rs38845 in MET intron and rs3803300 in AKT1 5'UTR) was associated with ADRs in general and the more specific drug induced skin injury. The SNPs associated with both therapeutic responses and ADRs indicates they might share a common genetic basis. Our study provided potential biomarkers and clues for further research of biomarkers for therapeutic responses and ADRs in Chinese NSCLC patients. PMID- 26988280 TI - New C-19-modified geldanamycin derivatives: synthesis, antitumor activities, and physical properties study. AB - Thiazinogeldanamycin (2) was identified from Streptomyces hygroscopicus 17997 at the late stage of the fermentation. The pH was firstly proposed as an important factor in the biosynthesis of it. It was verified that 2 was produced by direct chemical reactions between geldanamycin (1, GDM) and cysteine or aminoethanethiol hydrochloride at pH > 7 in vitro. The proposed synthesis pathway for compound 2 was also discussed. Eleven new C-19-modified GDM derivatives, including five stable hydroquinone form derivatives, were synthesized, most of which exhibited desirable properties such as lower cytotoxicity, increased water solubility, and potent antitumor activity. Especially, compounds 5 and 8 showed antitumor activities against HepG2 cell with IC50 values of 2.97-6.61 MUM, lower cytotoxicity and at least 15-fold higher water solubility compared with 1 in pH 7.0 phosphate buffer. PMID- 26988282 TI - Blunted cardiac stress reactors exhibit relatively high levels of behavioural impulsivity. AB - Blunted physiological reactions to acute psychological stress are associated with a range of adverse health and behavioural outcomes. This study examined whether extreme stress reactors differ in their behavioural impulsivity. Individuals showing blunted (N=23) and exaggerated (N=23) cardiovascular reactions to stress were selected by screening a healthy student population (N=276). Behavioural impulsivity was measured via inhibitory control and motor impulsivity tasks. Blunted reactors exhibited greater impulsivity than exaggerated reactors on both stop-signal, F(1,41)=4.99, p=0.03, etap(2)=0.108, and circle drawing, F(1,43)=4.00, p=0.05, eta p(2)=0.085, tasks. Individuals showing blunted cardiovascular stress reactions are characterized by greater impulsivity which may contribute to their increased susceptibility to outcomes such as obesity and addiction. PMID- 26988281 TI - Insulin receptor activation in the nucleus accumbens reflects nutritive value of a recently ingested meal. AB - With respect to feeding, insulin is typically thought of as a satiety hormone, acting in the hypothalamus to limit ingestive behavior. However, accumulating evidence suggests that insulin also has the ability to alter dopamine release in the striatum and influence food preferences. With increased access to high calorie foods, Western societies have a high prevalence of obesity, accompanied by insulin insensitivity. Little is known about how insulin is trafficked into the brain following food consumption and whether insulin insensitivity in the periphery is mirrored in the central nervous system. We investigated insulin receptor activation in the ventral striatum of rats receiving water or 16% glucose either orally or intragastrically. We also investigated whether glucose induced insulin receptor activation was altered in food-restricted (FR) or diet induced obesity (OB) rat models. Lastly, we examined whether insulin plays a significant role in flavor-nutrient preference learning. Glucose intake stimulated a rapid increase in insulin receptor activity in the ventral striatum of FR and ad libitum (AL) fed rats, but not OB rats. Similarly, both AL and FR, but not OB rats demonstrated significant flavor-nutrient preferences. However AL rats receiving brief inhibition of insulin activity during conditioning failed to acquire a significant flavor-nutrient preference. These findings suggest that impaired insulin receptor activation in the ventral striatum may result in inaccurate valuation of nutritive foods, which could lead to overconsumption of food or the selection of foods that don't accurately meet the body's current physiological needs. PMID- 26988284 TI - Clinical Implications of Basic Science Discoveries: Microchimerism Finds a Major Role in Reproductive Success; but Does It Also Contribute to Transplant Success? AB - Conventional wisdom argues against inbreeding, to maintain hybrid vigor and increase MHC diversity in response to pathogens. A recent report from the laboratory of Sing-Sing Way uses a mouse model to test a hypothesis put forward by Ray D. Owen more than 60 years ago: that a certain amount of inbreeding is a good thing. Owen proposed that antigens not inherited from the mother (noninherited maternal antigens), when replicated on the mate of the daughter, could protect the latter's developing child from fetal wastage due to immune attack during her pregnancy. Kinder et al use elegant mouse breeding models and MHC class II peptide tetramers to show that Owen's hypothesis, based only on humoral (anti-Rh IgG) data and a small sample size, was indeed correct. The mediators of this cross-generational protection turn out to be a special kind of Foxp3+ T regulatory cell, the development of which requires the persistence of maternal microchimerism into adulthood. The implications of this discovery for the role of microchimerism in tolerance to transplants are discussed. PMID- 26988283 TI - Hippotherapy acute impact on heart rate variability non-linear dynamics in neurological disorders. AB - Neurological disorders are associated with autonomic dysfunction. Hippotherapy (HT) is a therapy treatment strategy that utilizes a horse in an interdisciplinary approach for the physical and mental rehabilitation of people with physical, mental and/or psychological disabilities. However, no studies have been carried out which evaluated the effects of HT on the autonomic control in these patients. Therefore, the objective of the present study was to investigate the effects of a single HT session on cardiovascular autonomic control by time domain and non-linear analysis of heart rate variability (HRV). The HRV signal was recorded continuously in twelve children affected by neurological disorders during a HT session, consisting in a 10-minute sitting position rest (P1), a 15 minute preparatory phase sitting on the horse (P2), a 15-minute HT session (P3) and a final 10-minute sitting position recovery (P4). Time domain and non-linear HRV indices, including Sample Entropy (SampEn), Lempel-Ziv Complexity (LZC) and Detrended Fluctuation Analysis (DFA), were calculated for each treatment phase. We observed that SampEn increased during P3 (SampEn=0.56+/-0.10) with respect to P1 (SampEn=0.40+/-0.14, p<0.05), while DFA decreased during P3 (DFA=1.10+/-0.10) with respect to P1 (DFA=1.26+/-0.14, p<0.05). A significant SDRR increase (p<0.05) was observed during the recovery period P4 (SDRR=50+/-30ms) with respect to the HT session period P3 (SDRR=30+/-10ms). Our results suggest that HT might benefit children with disabilities attributable to neurological disorders by eliciting an acute autonomic response during the therapy and during the recovery period. PMID- 26988285 TI - Identification and characterization of Bacillus subtilis from grass carp (Ctenopharynodon idellus) for use as probiotic additives in aquatic feed. AB - Bacillus subtilis is widely used as probiotic species in aquaculture for water quality control, growth promoting, or immunity enhancing. The aim of this study is to find novel B. subtilis strains from fish as potential probiotics for aquaculture. Eleven B. subtilis isolates derived from the intestinal tract of grass carp were identified by gene sequencing and biochemical tests. These isolates were classified into 4 groups, and the representatives (GC-5, GC-6, GC 21 and GC-22) of each group were further investigated for antibiotic susceptibility, sporulation rate, biofilm formation, activity against pathogenic bacteria, resistance to stress conditions of intestinal tract (high percentage of bile and low pH) and high temperature, which are important for probiotics to be used as feed additives. Additionally, the adhesion properties of the 4 characterized strains were assessed using Caco-2 cell and gut mucus models. The results showed that the 4 strains differed in their capacities to adhere to intestinal epithelial cells and mucus. Furthermore, the strains GC-21 and GC-22 up-regulated the expression levels of IL-10 and TGF-beta but down-regulated IL 1beta, suggesting their potential anti-inflammatory abilities. Based on physiological properties of the 4 characterized B. subtilis strains, one or more strains may have potential to be used as probiotics in aquaculture. PMID- 26988286 TI - Genome-wide identification, characterization and expression analyses of two TNFRs in Yesso scallop (Patinopecten yessoensis) provide insight into the disparity of responses to bacterial infections and heat stress in bivalves. AB - Tumor necrosis factors receptors (TNFRs) comprise a superfamily of proteins characterized by a unique cysteine-rich domain (CRD) and play important roles in diverse physiological and pathological processes in the innate immune system, including inflammation, apoptosis, autoimmunity and organogenesis. Although significant effects of TNFRs on immunity have been reported in most vertebrates as well as some invertebrates, the complete TNFR superfamily has not been systematically characterized in scallops. In this study, two different types of TNFR-like genes, including PyTNFR1 and PyTNFR2 genes were identified from Yesso scallop (Patinopecten yessoensis, Jay, 1857) through whole-genome scanning. Phylogenetic and protein structural analyses were carried out to determine the identities and evolutionary relationships of the two genes. The expression profiling of PyTNFRs was performed at different development stages, in healthy adult tissues and in hemocytes after bacterial infection and heat stress. Expression analysis revealed that both PyTNFRs were significantly induced during the acute phase (3 h) after infection with Gram-positive (Micrococcus luteus) and Gram-negative (Vibrio anguillarum) bacteria, though much more dramatic chronic phase (24 h) changes were observed after V. anguillarum challenge. For heat stress, only PyTNFR2 displayed significant elevation at 12 h and 24 h, which suggests a functional difference in the two PyTNFRs. Collectively, this study provides novel insight into the PyTNFRs and the specific role and response of TNFR-involved pathways in host immune responses against different bacterial pathogens and heat stress in bivalves. PMID- 26988287 TI - Dietary choline regulates antibacterial activity, inflammatory response and barrier function in the gills of grass carp (Ctenopharyngodon idella). AB - An 8-week feeding trial was conducted to determine the effects of graded levels of choline (197-1795 mg/kg) on antibacterial properties, inflammatory status and barrier function in the gills of grass carp. The results showed that optimal dietary choline supplementation significantly improved lysozyme and acid phosphatase activities, complement component 3 (C3) content, and the liver expressed antimicrobial peptide 2 and Hepcidin mRNA levels in the gills of fish (P < 0.05). In addition, appropriate dietary choline significantly decreased the oxidative damage, which might be partly due to increase copper, zinc superoxide dismutase (Cu/Zn-SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST) and glutathione reductase (GR) activities and increased glutathione content in the gills of fish (P < 0.05). Moreover, appropriate dietary choline significantly up-regulated the mRNA levels of interleukin 10 and transforming growth factor beta1, Zonula occludens 1, Occludin, Claudin-b, c, 3 and 12, inhibitor of kappaBalpha, target of rapamycin, Cu/Zn-SOD, CAT, GR, GPx, GST and NF-E2-related factor 2 in the gills of fish (P < 0.05). Conversely, appropriate dietary choline significantly down-regulated the mRNA levels of pro inflammatory cytokines, tumor necrosis factor alpha, interleukin 8, interferon gamma, interleukin 1beta, and related signaling factors, nuclear factor kappa B p65, IkappaB kinase beta, IkappaB kinase gamma, myosin light chain kinase and Kelch-like-ECH-associated protein 1a (Keap1a) in the gills of fish (P < 0.05). However, choline did not have a significant effect on the mRNA levels of IkappaB kinase alpha, Claudin-15 and Keap1b in the gills of fish. Collectively, appropriate dietary choline levels improved gill antibacterial properties and relative gene expression levels of tight junction proteins, and decreased inflammatory status, as well as up-regulated the mRNA levels of related signaling molecules in the gills of fish. Based on gill C3 content and AHR activity, the dietary choline requirements for young grass carp (266.5-787.1 g) were estimated to be 1191.0 and 1555.0 mg/kg diet, respectively. PMID- 26988289 TI - Litopenaeus vannamei clathrin coat AP17 involved in white spot syndrome virus infection. AB - White spot syndrome virus (WSSV) is the main pathogen of shrimp culture, and has brought great losses of the shrimp aquaculture industry every year since it has been found. However, the specific mechanism of the virus into the cell is not very clear. Recent research suggests that clathrin-mediated endocytosis is involved in WSSV infection. By sequence analysis, clathrin coat AP17 is an sigma subunit of AP-2 complex which is involved in clathrin-mediated endocytosis. To obtain the full-length sequence of Clathrin coat AP17 of Litopenaeus vannamei (LvCCAP17), the rapid amplification of cDNA ends (RACE) was performed to get the sequence of 3'and 5' end and splicing by DNAMAN. The full-length sequence of LvCCAP17 is 842 bp and expected to encoding 142 amino acids, and the amino acid sequence was analyzed by online software. The mRNA expression of LvCCAP17 in different tissues was carried out with quantitative real-time PCR and the LvCCAP17 was detected in all tested tissues of Litopenaeus vannamei. The transcriptional expression level of LvCCAP17 in epithelium and hepatopancreas was significantly up-regulated after WSSV infection. Far-Western blotting and ELISA assay showed that LvCCAP17 interacted with rVP26 and rVP37. Silencing of LvCCAP17 gene by double-strand RNA (dsRNA) interference significantly delay of cumulative mortality rate in WSSV infected shrimp and reduced the expression level of immediate early gene 1(ie1) and vp28. These results indicated that clathrin meated endocytosis is responsible for WSSV infection. PMID- 26988288 TI - Grass carp (Ctenopharyngodon idella) ATF6 (activating transcription factor 6) modulates the transcriptional level of GRP78 and GRP94 in CIK cells. AB - ATF transcription factors are stress proteins containing alkaline area-leucine zipper and play an important role in endoplasmic reticulum stress. ATF6 is a protective protein which regulates the adaptation of cells to ER stress by modulating the transcription of UPR (Unfolded Protein Response) target genes, including GRP78 and GRP94. In the present study, a grass carp (Ctenopharyngodon idella) ATF6 full-length cDNA (named CiATF6, KT279356) has been cloned and identified. CiATF6 is 4176 bp in length, comprising 159 nucleotides of 5' untranslated sequence, a 1947 nucleotides open reading frame and 2170 nucleotides of 3'-untranslated sequences. The largest open reading frame of CiATF6 translates into 648 aa with a typical DNA binding domain (BRLZ domain) and shares significant homology to the known ATF6 counterparts. Phylogenetic reconstruction confirmed its closer evolutionary relationship with other fish counterparts, especially with Zebrafish ATF6. RT-PCR showed that CiATF6 was ubiquitously expressed and significantly up-regulated after stimulation with thermal stress in all tested grass carp tissues. In order to know more about the role of CiATF6 in ER stress, recombinant CiATF6N with His-tag was over-expressed in Rosetta Escherichia coli, and the expressed protein was purified by affinity chromatography with Ni-NTA His-Bind Resin. In vitro, gel mobility shift assays were employed to analyze the interaction of CiATF6 protein with the promoters of grass carp GRP78 and GRP94, respectively. The result has shown that CiATF6 could bind to these promoters with high affinity by means of its BRLZ mainly. To further study the transcriptional regulatory mechanism of CiATF6, Dual-luciferase reporter assays were applied. Recombinant plasmids of pGL3-GRP78P and pGL3 CiGRP94P were constructed and transiently co-transfected with pcDNA3.1-CiATF6 (pcDN3.1-CiATF6-nBRLZ, respectively) into C. idella kidney (CIK) cells. The result has shown that CiATF6 could activate CiGRP78 and CiGRP94 promoters. PMID- 26988290 TI - Culturing murine embryonic organs: Pros, cons, tips and tricks. AB - There are three established techniques described for ex vivo culture of the early embryonic organs: filter culture, agar block culture and hanging drop culture. Each of these protocols has advantages and disadvantages; here we assess the merits of each approach. Agar block culture has a long history and has been well described. This method results in good embryonic organ morphology. Filter culture has been used to culture a number of different embryonic organs and there are a variety of filter choices available. The key disadvantage of agar-block and filter based culture is that the large amount of media required can make the approach expensive, especially if biologicals such as growth factors are necessary; in addition, using these methods it can be difficult to track particular samples. Hanging drop culture is most commonly used to enable the aggregation of embryonic stem cells into embryoid bodies but it has also been employed for ex vivo organ culture. This method requires only 40MUL of media per drop and isolates every organ to a trackable unit. We describe each of these methods and the use of different medias and provide the user with a matrix to help determine the optimal culture method for their needs. Glass-based culture methods required for live imaging are not discussed here. PMID- 26988291 TI - Evaluating structured assessment of anaesthesiologists' non-technical skills. AB - BACKGROUND: Non-technical skills (NTS) are essential for safe and efficient anaesthesia. Assessment instruments with appropriate validity evidence can be used to ensure that anaesthesiologists possess the NTS necessary to deliver high standard patient care. The aims were to collect validity evidence using a contemporary validity framework for the assessment instrument Anaesthesiologists' Non-Technical Skills in Denmark (ANTSdk) regarding response process and internal structure (including reliability), and to investigate the effect of rater training on these properties. METHODS: An explorative study was undertaken at the Danish Institute for Medical Simulation, Copenhagen, Denmark. In a 1-day session, using ANTSdk, a convenience sample of 19 anaesthesiologists rated trainee anaesthesiologists' NTS in nine video-recorded simulation scenarios before and after a 3-h training session. RESULTS: Response process evidence: participants considered ANTSdk useful and feasible for NTS assessment. Internal structure evidence: inter-rater reliability (single measures) largely expressed substantial agreement (ICC >= 0.55 and ICC >= 0.60 for pre- and post-training ratings respectively). Strong internal consistency of ratings was found (Spearman's correlation coefficient >= 0.82). Accuracy of participants' ratings compared with reference ratings (+/- 1 scale point) was notable (76% and 78% for pre- and post training ratings, respectively). The results indicate that the elements 'Demonstrating self-awareness', 'Reassessing decisions', 'Assessing competencies', and 'Supporting others' need more attention in future rater training. CONCLUSION: The validity evidence collected on content, response process, and internal structure, suggests that ANTSdk is easy to use on video recorded simulation scenarios, indicating that ANTSdk is a feasible instrument for NTS assessment during anaesthesia training. PMID- 26988292 TI - Monocyte Toll-Like Receptor Expression in Patients With Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia. Inflammation has been suggested to play a vital role in the pathogenesis. Previous studies have investigated expression of inflammatory markers in AF. Several studies have focused on the effects of toll-like receptors (TLRs) on heart in terms of capability of modulating inflammation. In this study, we aimed to investigate whether peripheral monocyte TLR expression was associated with the AF presence, and recurrence of AF after cryoablation, as a reflection of inflammatory status. Patients with AF who were scheduled for cryoballoon-based ablation for AF and age and gender-matched subjects in sinus rhythm were included. Peripheral monocyte TLR-2 and TLR-4 expressions were evaluated by flow cytometric analysis in peripheral venous blood samples obtained during evaluation in outpatient clinics: 172 patients (56.5 +/- 6.6 years, 52.3% men) were included in the study. Peripheral monocyte TLR-2 and TLR-4 expression levels were significantly higher in patients with AF (p <0.05). Among patients with AF, 12 patients (14.0%) developed AF recurrence at a follow- up of 17 months. Multivariate Cox regression analysis showed that left atrial volume index (hazard ratio 2.040, 95% CI 1.197 to 3.477, p = 0.009) and monocyte TLR-4 expression (hazard ratio 1.226, 95% CI 1.042 to 1.443, p = 0.014) were independent predictors of AF recurrence after blanking period following second-generation cryoballoon-based pulmonary vein isolation for paroxysmal AF. In conclusion, our study highlights the role of TLR mediated inflammation in the pathogenesis of AF. This link may also constitute a therapeutic target in patients with AF. PMID- 26988294 TI - A Wasp Sting and a Broken Heart. PMID- 26988293 TI - Analysis of Epstein-Barr virus infection models in a series of pediatric carriers from a developing country. AB - Epstein-Barr virus (EBV) is a B lymphotropic human herpesvirus. Two models, germinal center (GC) and direct infection, describe how EBV infects B-cells. Since in Argentina primary infection is mostly subclinical at young ages, children represent an interesting population where to analyze EBV infection, especially considering that most studies are usually performed in adults. Tonsil biopsies from pediatric carriers were studied to describe infection characteristics. EBV+ lymphocytes at the interfollicular region were mainly observed. Latency III pattern in subepithelial (SubEp) lymphocytes was observed at young ages, probably indicating a recent infection. In older patients EBV was mostly detected in epithelial cells, suggesting that they could have been infected some time ago. This finding was sustained by tonsillar viral load, which was higher in cases with LMP1+SubEp cells vs. LMP1+nonSubEp cells (p = 0.0237, Mann-Whiney test). Latency III was prevalent and related to the GC, while latency II was associated with non-GC (p = 0.0159, chi2 test). EBERs+/IgD+ cells were statistically prevalent over EBERs+/CD27+ cells (p = 0.0021, chi2 test). These findings indicated that both EBV infection models are not mutually exclusive and provide some basis for further understanding of EBV infection dynamics. Moreover, we provide a more accurate explanation of EBV infection in pediatric asymptomatic carriers from a developing country. PMID- 26988295 TI - The influence of chronic nicotine treatment on proteins expressed in the mouse hippocampus and cortex. AB - Chronic treatment with nicotine, the primary psychoactive substance in tobacco smoke, affects central nervous system functions, such as synaptic plasticity. Here, to clarify the effects of chronic nicotine treatment on the higher brain functions, proteomic analysis of the hippocampus and cortex of mice treated for 6 months with nicotine was performed using two-dimensional gel electrophoresis (2 DE) followed by mass spectrometry. There was significant change in the expression of 16 proteins and one phosphoprotein in the hippocampus (increased tubulin beta 5, atp5b, MDH1, cytochrome b-c1 complex subunit 1, Hsc70, dynamin, profilin-2, 4 aminobutyrate aminotransferase, mitochondrial isoform 1 precursor, calpain small subunit 1, and vacuolar adenosine triphosphatase subunit B and decreased gamma actin, alpha-tubulin isotype M-alpha-2, putative beta-actin, tubulin beta-2A, NDUFA10, and G6PD) and 24 proteins and two phosphoproteins in the cortex (increased spectrin alpha chain, non-erythrocytic 1 isoform 1, tubulin beta-5, gamma-actin, creatine kinase B-type, LDH-B, secernin-1, UCH-L1, 14-3-3 gamma, type II peroxiredoxin 1, PEBP-1, and unnamed protein product and decreased tubulin alpha-1C, alpha-internexin, gamma-enolase, PDHE1-B, DPYL2, vacuolar adenosine triphosphatase subunit A, vacuolar adenosine triphosphatase subunit B, TCTP, NADH dehydrogenase Fe-S protein 1, protein disulfide-isomerase A3, hnRNP H2, gamma-actin, atp5b, and unnamed protein product). Additionally, Western blotting validated the changes in dynamin, Hsc70, MDH1, NDUFA10, alpha internexin, tubulin beta-5 chain, and secernin-1. Thus, these findings indicate that chronic nicotine treatment changes the expression of proteins and phosphoproteins in the hippocampus and cortex. We propose that effect of smoking on higher brain functions could be mediated by alterations in expression levels of these proteins. PMID- 26988296 TI - Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice. AB - Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14+/-5% vs. 36+/-2%), and was ameliorated in MI+Aliskiren (34+/-5%) mice. Insulin stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress. PMID- 26988297 TI - The influence of erythrocyte maturity on ion transport and membrane lipid composition in the rat. AB - Significant relationships between ion transport and membrane lipid composition (cholesterol, total phospholipids and sphingomyelins) were found in erythrocytes of salt hypertensive Dahl rats. In these animals mean cellular hemoglobin content correlated negatively with Na(+)-K(+) pump activity and Na(+) leak but positively with Na(+)-K(+) cotransport activity. Immature erythrocytes exhibit lower mean cellular hemoglobin content (MCHC) than mature ones. The aim of the present study was to find a relationship between erythrocyte maturity, membrane lipid composition and ion transport activity in Wistar rats aged three months which were subjected to repeated hemorrhage (blood loss 2 ml/day for 6 days) to enrich circulating erythrocytes with immature forms. Immature and mature erythrocyte fractions in control and hemorrhaged rats were separated by repeated centrifugation. Hemorrhaged rats had increased number of reticulocytes but reduced hematocrit and MCHC compared to control rats. Immature erythrocytes of hemorrhaged rats differed from mature ones of control animals by elevated Na(+) K(+) pump activity, reduced Na(+)-K(+) cotransport activity and increased Rb(+) leak. These ion transport changes in immature erythrocytes were accompanied by higher concentration of total phospholipids in their cell membranes. Membrane phospholipid content correlated positively with Na(+)-K(+) pump activity and cation leaks but negatively with Na(+)-K(+) cotransport activity. Moreover, they were also negatively related with MCHC which correlated negatively with Na(+) K(+) pump activity and Rb(+) leak but positively with Na(+)-K(+) cotransport activity. Thus certain abnormalities of erythrocyte ion transport and membrane lipid composition detected in hypertensive animals might be caused by higher incidence of immature cells. PMID- 26988298 TI - Bioactive lignan constituents from the twigs of Sambucus williamsii. AB - As part of our ongoing search for bioactive constituents of natural Korean medicinal plants, three new lignan derivatives, sambucasinol A-C (1-3), together with 7 known compounds (4-10) were isolated from the twigs of Sambucus williamsii. The structures of these new compounds were determined by a combination of 1D and 2D NMR spectroscopic data analysis, as well as circular dichroism (CD) spectroscopy studies. Here, we evaluated the anti-inflammatory effects of 1-10 in lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cells. Compounds 1-3 exhibited significant inhibitory effects on nitric oxide production in LPS-activated BV-2 cells, with IC50 values of 6.82, 7.04, and 14.70 MUM, respectively. Additionally, we evaluated the effects of compounds 1-10 on NGF induction in a C6 rat glioma cell line. Compounds 1-3 upregulated NGF secretion to 183.95 +/- 2.63%, 153.99 +/- 5.15%, and 155.96 +/- 5.15%, respectively, without any significant cell toxicity. Moreover, all isolates were evaluated for their cytotoxicity against A549, SK-OV-3, SK-MEL-2, and XF498 cell lines. Compounds 1-3 showed consistent cytotoxicity against the four human cell lines, with IC50 values in the range of 11.07-19.62 MUM. PMID- 26988299 TI - Ecdysones from Zoanthus spp. with inhibitory activity against dengue virus 2. AB - Bioassay-guided fractionation of an ethanolic extract of Zoanthus spp. collected in Taiwan has resulted in the isolation of one new ecdysone, zoanthone A (1), along with thirteen known compounds (2-14). The structures of these compounds were determined by spectroscopic methods, especially 2D NMR analyses. The in vitro antiviral activities of all isolated ecdysones (1-14) against dengue virus type 2 (DENV-2) were evaluated using DENV infectious system. New compound (1) exhibited potent antiviral activity (EC50=19.61 +/- 2.46 MUM) with a selectivity index (CC50/EC50) value of 36.7. The structure-activity relationships of isolated ecdysones against DENV-2 were concluded. Molecular docking information of 3 and NS5 polymerase was performed either. PMID- 26988301 TI - Identification of nonabsorbable inhibitors of the scavenger receptor-BI (SR-BI) for tissue-specific administration. AB - The identification of a low-permeability scavenger receptor BI (SR-BI) inhibitor starting from the ITX-5061 template is described. Structure-activity and structure-permeability relationships were assessed for analogs leading to the identification of compound 8 as a potent and nonabsorbable SR-BI inhibitor. PMID- 26988300 TI - Induction of apoptosis and differentiation by atractylenolide-1 isolated from Atractylodes macrocephala in human leukemia cells. AB - Atractylodes macrocephula Koidz (A. macrocephula, also known as Baizhu) is an important ingredient in several traditional Chinese herb complexes for the treatment of abdominal pain and gastroenterology diseases for thousands of years. We previously demonstrated the induction of ROS-mediated apoptosis by methanol extract of A. macrocephula in human leukemia cells. After purification and assessment of those active compounds from A. macrocephula ethanol extracts, in this study, we focused on the major active compound, atractylenolide I (ATL-I). Through MTT assay and morphology observation, we found cytotoxic effect of ATL-I in human K562 chronic myeloblastic leukemia (CML), U937 acute myeloblastic leukemia (AML) and Jurkat T lymphoma cells. In addition, ATL-I-induced apoptosis was demonstrated by sub G1 and fragmented chromosomal DNA detection using flow cytometry, enzyme-linked immunosorbent assay (ELISA) and agarose electrophoresis. Finally, we found ATL-I also induced caspase-3 and caspase-9 activation through the detection of procaspase-3, procaspase-9 and caspase-3 substrate poly(ADP ribose) polymerase (PARP) by immunoblotting. Interestingly, we found that ATL-I induced not only apoptosis but also differentiation, as upregulation of CD14 and CD68 surface markers and increase of phagocytosis ability were discovered in ATL I-treated K562 CML and U937 AML cells. Our study thus suggests the potential of developing new leukemia therapies by using ATL-I for leukemia treatment in the future. PMID- 26988303 TI - New pentasubstituted pyrrole hybrid atorvastatin-quinoline derivatives with antiplasmodial activity. AB - Cerebral malaria is caused by Plasmodium falciparum. Atorvastatin (AVA) is a pentasubstituted pyrrole, which has been tested as an adjuvant in the treatment of cerebral malaria. Herein, a new class of hybrids of AVA and aminoquinolines (primaquine and chloroquine derivatives) has been synthesized. The quinolinic moiety was connected to the pentasubstituted pyrrole from AVA by a linker group (CH2)n=2-4 units. The activity of the compounds increased with the size of the carbons chain. Compound with n=4 and 7-chloroquinolinyl has displayed better activity (IC50=0.40 MUM) than chloroquine. The primaquine derivative showed IC50=1.41 MUM, being less toxic and more active than primaquine. PMID- 26988302 TI - Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 3. Engineering plasma stability by discovery and optimization of isoindolinone analogs. AB - This Letter describes the further lead optimization of the VU0486321 series of mGlu1 positive allosteric modulators (PAMs), focused on addressing the recurrent issue of plasma instability of the phthalimide moiety. Here, we evaluated a number of phthalimide bioisosteres, and ultimately identified isoindolinones as the ideal replacement that effectively address plasma instability, while maintaining acceptable mGlu1 PAM potency, DMPK profile, CNS penetration and mGluR selectivity. PMID- 26988304 TI - Pharmacophore elucidation of phosphoiodyn A - Potent and selective peroxisome proliferator-activated receptor beta/delta agonists with neuroprotective activity. AB - We report the pharmacophore of the peroxisome proliferator-activated receptor delta (PPARdelta) agonist natural product phosphoiodyn A is the phosphonate core. Synthesis of simplified phosphonate esters 13 and 15 provide structurally novel, highly selective and potent PPARdelta agonists (EC50=78 and 112 nM, respectively). Further, both compounds demonstrate significant neuroprotective activity in an in vitro cellular model indicating that phosphonates may be an effective novel scaffold for the design of therapeutics for the treatment of neurodegenerative disorders. PMID- 26988305 TI - Inhibitors of HIV-1 maturation: Development of structure-activity relationship for C-28 amides based on C-3 benzoic acid-modified triterpenoids. AB - We have recently reported on the discovery of a C-3 benzoic acid (1) as a suitable replacement for the dimethyl succinate side chain of bevirimat (2), an HIV-1 maturation inhibitor that reached Phase II clinical trials before being discontinued. Recent SAR studies aimed at improving the antiviral properties of 2 have shown that the benzoic acid moiety conferred topographical constraint to the pharmacophore and was associated with a lower shift in potency in the presence of human serum albumin. In this manuscript, we describe efforts to improve the polymorphic coverage of the C-3 benzoic acid chemotype through modifications at the C-28 position of the triterpenoid core. The dimethylaminoethyl amides 17 and 23 delivered improved potency toward bevirimat-resistant viruses while increasing C24 in rat oral PK studies. PMID- 26988306 TI - Selective inhibitors of Bcl-2 and Bcl-xL: Balancing antitumor activity with on target toxicity. AB - The induction of apoptosis in tumor cells represents a promising approach to the treatment of cancer. Accordingly, compounds that interact with the Bcl-2 family of proteins, which are critical regulators of the apoptotic process, have been widely pursued as potential anticancer agents. While encouraging antitumor activity in clinical trials has been observed with some of these compounds, their therapeutic utility is often limited by accompanying toxicities associated with the interaction with this family of proteins. As a result, there has been recent interest in identifying agents that can selectively target a single Bcl-2 family member (such as Bcl-2 or Bcl-xL), with the expectation that improved therapeutic margins can be achieved. In this review, we outline the biological rationale behind this approach, and highlight key examples of selective compounds from the recent literature alongside the structural basis for the reported selectivity. PMID- 26988307 TI - Three diketopiperazines from marine-derived bacteria inhibit LPS-induced endothelial inflammatory responses. AB - Diketopiperazine is a natural products found from bacteria, fungi, marine sponges, gorgonian and red algae. They are cyclic dipeptides possessing relatively simple and rigid structures with chiral nature and various side chains. Endothelial dysfunction is a key pathological feature of many inflammatory diseases, including sepsis. In the present study, three (1-3) of diketopiperazines were isolated from two strains of marine-derived bacteria. The compounds were investigated for their effects against lipopolysaccharide (LPS) mediated endothelial inflammatory responses in vitro and in vivo. From 1 MUM, 1-3 inhibited LPS-induced hyperpermeability, adhesion, and migration of leukocytes across a human endothelial cell monolayer and in mice in a dose-dependent manner suggesting that 1-3 may serve as potential scaffolds for the development of therapeutic agents to treat vascular inflammatory disorders. PMID- 26988309 TI - Slimming and Appetite-Suppressing Effects of Caraway Aqueous Extract as a Natural Therapy in Physically Active Women. AB - Following the current 'Globesity' trend, there is an increasing demand for alternative natural therapies for weight management. Numerous phytoconstituents reduce body weight through suppressing appetite and reducing food intake. Caraway (Carum carvi L.) is one of the medicinal plants that is traditionally used for weight loss. In this study, the appetite-suppressing effects of caraway aqueous extract (CAE) on 70 aerobically trained, overweight, and obese women were examined in a triple-blind, placebo-controlled, clinical study. Subjects were randomly allocated into placebo and experimental groups and consumed either 30 mL/day of CAE or placebo without changing their diet or physical activity over a period of 90 days. Calorie and macronutrient intake and anthropometric indices were measured before and after the intervention. In addition, appetite changes were assessed through a visual analog scale and an ad libitum pizza test. After the intervention, the results showed a significant reduction in appetite levels and carbohydrate intake of the experimental group compared with the placebo group. All of the anthropometric indices were reduced significantly in CAE compared with placebo group (p < 0.01). These preliminary outcomes suggest that a dietary CAE might be effective in weight management of physically active, adult females, reducing their body size and hunger level. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26988308 TI - N-Alkylpyrido[1',2':1,5]pyrazolo-[4,3-d]pyrimidin-4-amines: A new series of negative allosteric modulators of mGlu1/5 with CNS exposure in rodents. AB - Selective negative allosteric modulators (NAMs) of each of the group I metabotropic glutamate receptors (mGlu1 and mGlu5) have been well characterized in the literature and offer potential as therapeutics in several disorders of the central nervous system (CNS). Still, compounds that are potent mGlu1/5 NAMs with selectivity versus the other six members of the mGlu family as well as the balance of properties required for use in vivo are lacking. A medicinal chemistry effort centered on the identification of a lead series with the potential of delivering such compounds is described in this Letter. Specifically, a new class of pyrido[1',2':1,5]pyrazolo[4,3-d]pyrimidin-4-amines was designed as a novel isosteric replacement for 4-aminoquinazolines, and compounds from within this chemotype exhibited dual NAM activity at both group I mGlus. One compound, VU0467558 (29), demonstrated near equipotent activity at both receptors, selectivity versus other mGlus, a favorable ancillary pharmacology profile, and CNS exposure in rodents. PMID- 26988310 TI - (18)F-FDG PET/CT in staging and follow-up of adamantinoma. PMID- 26988311 TI - The developmental expression of the CDK inhibitor p57(kip2) (Cdkn1c) in the early mouse placenta. AB - p57(kip2) (encoded by the Cdkn1c gene) is a member of the cip/kip family of cyclin-dependent kinase inhibitors that mediates cell cycle arrest in G1, allowing cells to differentiate. In the placenta, p57(kip2) is involved in endoreduplication, formation of trophoblast giant cells, trophoblast invasion, and expansion of placental cell layers. Here, we quantitatively and qualitatively define the cell- and region-specific expression of mouse placental p57(kip2) using laser-capture microdissection, in situ hybridization, and immunohistochemistry. Cdkn1c RNA was quantified by real-time quantitative PCR. Co expression of Pl1 was used to identify trophoblast giant cells while Tbpba was used to identify spongiotrophoblast cells. Timed sacrifices were also carried out at embryonic days E7.5, E8.5, E9.5, and E12.5 to profile the expression in embryos and their placentas. At E8.5, intense expression of Cdkn1c was seen in invasive TGCs and the ectoplacental cone. Cdkn1c expression was more diffuse and more abundant in the labyrinth that in the junctional zone at both E9.5 and E12.5. Immunohistochemistry revealed robust p57(kip2) staining in trophoblast giant cells and in the ectoplacental cone at E8.5. p57(kip2) protein was seen in giant cells and throughout the labyrinth, although its abundance was reduced in the junctional zone at E9.5, and became more diffuse by E12.5. The early and intense expression in trophoblast giant cells is consistent with a role for p57(kip2) in the invasive phenotype of these cells. Mol. Reprod. Dev. 83: 405 412, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26988312 TI - The opioid epidemic and the long-term opioid therapy for chronic noncancer pain revisited: a transatlantic perspective. AB - The rise of opioid prescriptions and associated deaths ('opioid epidemic') in North America has evoked worldwide discussions on the long-term efficacy and safety of long-term opioid therapy (LtOT) for chronic noncancer pain (CNCP). We discuss if the opioid epidemic is a real worldwide or a more North American phenomenon. We consider reasons of the opioid epidemic. We highlight differences in the appraisal of the evidence of recent systematic reviews on LtOT for CNCP of US and European authors. We discuss similarities and differences of recent North American and European guidelines on LtOT for chronic CNCP. We point out potential indications and contraindications of LtOT in CNCP syndromes. PMID- 26988314 TI - Communicating Science: Lessons from Film. AB - Films engage us visually, aurally, viscerally, and emotionally. Incorporating science themes into films has the potential to open up new audiences to scientific ideas, pique their interests, and inspire them to engage in a broader discussion of the science itself. Here, I discuss several narrative techniques and strategies employed in film to effectively engage the audience around science themes, which may be useful tools for scientists looking to become better communicators. PMID- 26988313 TI - Phase-selective entrainment of nonlinear oscillator ensembles. AB - The ability to organize and finely manipulate the hierarchy and timing of dynamic processes is important for understanding and influencing brain functions, sleep and metabolic cycles, and many other natural phenomena. However, establishing spatiotemporal structures in biological oscillator ensembles is a challenging task that requires controlling large collections of complex nonlinear dynamical units. In this report, we present a method to design entrainment signals that create stable phase patterns in ensembles of heterogeneous nonlinear oscillators without using state feedback information. We demonstrate the approach using experiments with electrochemical reactions on multielectrode arrays, in which we selectively assign ensemble subgroups into spatiotemporal patterns with multiple phase clusters. The experimentally confirmed mechanism elucidates the connection between the phases and natural frequencies of a collection of dynamical elements, the spatial and temporal information that is encoded within this ensemble, and how external signals can be used to retrieve this information. PMID- 26988315 TI - Algal assessment of threats to freshwater ecosystems: trends, challenges, and opportunities. PMID- 26988316 TI - Taxonomic identification of algae (morphological and molecular): species concepts, methodologies, and their implications for ecological bioassessment. AB - Algal taxonomy is a key discipline in phycology and is critical for algal genetics, physiology, ecology, applied phycology, and particularly bioassessment. Taxonomic identification is the most common analysis and hypothesis-testing endeavor in science. Errors of identification are often related to the inherent problem of small organisms with morphologies that are difficult to distinguish without research-grade microscopes and taxonomic expertise in phycology. Proposed molecular approaches for taxonomic identification from environmental samples promise rapid, potentially inexpensive, and more thorough culture-independent identification of all algal species present in a sample of interest. Molecular identification has been used in biodiversity and conservation, but it also has great potential for applications in bioassessment. Comparisons of morphological and molecular identification of benthic algal communities are improved by the identification of more taxa; however, automated identification technology does not allow for the simultaneous analysis of thousands of samples. Currently, morphological identification is used to verify molecular taxonomic identities, but with the increased number of taxa verified in algal gene libraries, molecular identification will become a universal tool in biological studies. Thus, in this report, successful application of molecular techniques related to algal bioassessment is discussed. PMID- 26988317 TI - Roles of benthic algae in the structure, function, and assessment of stream ecosystems affected by acid mine drainage. AB - Tens of thousands of stream kilometers worldwide are degraded by a legacy of acid loads, high metal concentrations, and altered habitat caused by acid mine drainage (AMD) from abandoned underground and surface mines. As the primary production base in streams, the condition of algal-dominated periphyton communities is particularly important to nutrient cycling, energy flow, and higher trophic levels. Here, we synthesize current knowledge regarding how AMD associated stressors affect (i) algal communities and their use as ecological indicators, (ii) their functional roles in stream ecosystems, and (iii) how these findings inform management decisions and evaluation of restoration effectiveness. A growing body of research has found ecosystem simplification caused by AMD stressors. Species diversity declines, productivity decreases, and less efficient nutrient uptake and retention occur as AMD severity increases. New monitoring approaches, indices of biological condition, and attributes of algal community structure and function effectively assess AMD severity and effectiveness of management practices. Measures of ecosystem processes, such as nutrient uptake rates, extracellular enzyme activities, and metabolism, are increasingly being used as assessment tools, but remain in their infancy relative to traditional community structure-based approaches. The continued development, testing, and implementation of functional measures and their use alongside community structure metrics will further advance assessments, inform management decisions, and foster progress toward restoration goals. Algal assessments will have important roles in making progress toward improving and sustaining the water quality, ecological condition, and ecosystem services of streams in regions affected by the legacy of unregulated coal mining. PMID- 26988318 TI - Ecological assessments with algae: a review and synthesis. AB - Algae have been used for a century in environmental assessments of water bodies and are now used in countries around the world. This review synthesizes recent advances in the field around a framework for environmental assessment and management that can guide design of assessments, applications of phycology in assessments, and refinements of those applications to better support management decisions. Algae are critical parts of aquatic ecosystems that power food webs and biogeochemical cycling. Algae are also major sources of problems that threaten many ecosystems goods and services when abundances of nuisance and toxic taxa are high. Thus, algae can be used to indicate ecosystem goods and services, which complements how algal indicators are also used to assess levels of contaminants and habitat alterations (stressors). Understanding environmental managers' use of algal ecology, taxonomy, and physiology can guide our research and improve its application. Environmental assessments involve characterizing ecological condition and diagnosing causes and threats to ecosystems goods and services. Recent advances in characterizing condition include site-specific models that account for natural variability among habitats to better estimate effects of humans. Relationships between algal assemblages and stressors caused by humans help diagnose stressors and establish targets for protection and restoration. Many algal responses to stressors have thresholds that are particularly important for developing stakeholder consensus for stressor management targets. Future research on the regional-scale resilience of algal assemblages, the ecosystem goods and services they provide, and methods for monitoring and forecasting change will improve water resource management. PMID- 26988319 TI - Toward an empirical framework for interpreting plastid evolution. AB - The idea that evolutionary models should minimize plastid endosymbioses has dominated thinking about the history of eukaryotic photosynthesis. Although a reasonable starting point, this framework has not gained support from observed patterns of algal and plant evolution, and can be an obstacle to fully understanding the modern distribution of plastids. Empirical data indicate that plastid losses are extremely uncommon, that major changes in plastid biochemistry/architecture are evidence of an endosymbiotic event, and that comparable selection pressures can lead to remarkable convergences in algae with different endosymbiotic origins. Such empirically based generalizations can provide a more realistic philosophical framework for interpreting complex and often contradictory results from phylogenomic investigations of algal evolution. PMID- 26988320 TI - Salt tolerance and polyphyly in the cyanobacterium Chroococcidiopsis (Pleurocapsales). AB - Chroococcidiopsis Geitler (Geitler 1933) is a genus of cyanobacteria containing desiccation and radiation resistant strains. Members of the genus live in habitats ranging from hot and cold deserts to fresh and saltwater environments. Morphology and cell division pattern have historically been used to define the genus. To better understand the evolution and ability of the Chroococcidiopsis genus to survive in diverse environments we investigated how salt tolerance varies among 15 strains previously isolated from different locations, and if salt tolerant strains are monophyletic to those isolated from freshwater and land environments. Four markers were sequenced from these 15 strains, the 16S rRNA, rbcL, desC1, and gltX genes. Phylogenetic trees were generated which identified a distinct clade of salt-tolerant strains. This study demonstrates that the genus is polyphyletic based on saltwater and freshwater phenotypes. To understand the resistance to salt in more details, the strains were grown on a range of sea salt concentrations which demonstrated that the freshwater strains were salt intolerant whilst the saltwater strains required salt for growth. This study shows an increased resolution of the phylogeny of Chroococcidiopsis and provides further evidence that the genus is polyphyletic and should be reclassified to improve clarity in the literature. PMID- 26988321 TI - Detection of flavonoids in microalgae from different evolutionary lineages. AB - Flavonoids are important secondary plant metabolites believed to be present mainly in land plants. As phenolics were detected previously in microalgae using photometric assays, we wanted to investigate the nature of these phenolics and verify whether flavonoids are present. Therefore, in this study, we used state-of the-art ultra-high performance liquid chromatography-two-dimensional mass spectrometry (UHPLC-MS/MS) technology to investigate whether microalgae also contain flavonoids. For this, representative microalgal biomass samples from divergent evolutionary lineages (Cyanobacteria, Rhodophyta, Chlorophyta, Haptophyta, Ochrophyta) were screened for a set of carefully selected precursors, intermediates, and end products of the flavonoid biosynthesis pathways. Our data unequivocally showed that microalgae contain a wide range of flavonoids and thus must possess the enzyme pool required for their biosynthesis. Further, some of the microalgae displayed an intricate flavonoid pattern that is compatible with the established basic flavonoid pathway as observed in higher plants. This implies that the flavonoid biosynthesis pathway arose much earlier in evolution compared to what is generally accepted. PMID- 26988322 TI - Allelopathy in the tropical alga Lobophora variegata (Phaeophyceae): mechanistic basis for a phase shift on mesophotic coral reefs? AB - Macroalgal phase shifts on Caribbean reefs have been reported with increasing frequency, and recent reports of these changes on mesophotic coral reefs have raised questions regarding the mechanistic processes behind algal population expansions to deeper depths. The brown alga Lobophora variegata is a dominant species on many shallow and deep coral reefs of the Caribbean and Pacific, and it increased in percent cover (>50%) up to 61 m on Bahamian reefs following the invasion of the lionfish Pterois volitans. We examined the physiological and ecological constraints contributing to the spread of Lobophora on Bahamian reefs across a mesophotic depth gradient from 30 to 61 m, pre- and post-lionfish invasion. Results indicate that there were no physiological limitations to the depth distribution of Lobophora within this range prior to the lionfish invasion. Herbivory by acanthurids and scarids in algal recruitment plots at mesophotic depths was higher prior to the lionfish invasion, and Lobophora chemical defenses were ineffective against an omnivorous fish species. In contrast, Lobophora exhibited significant allelopathic activity against the coral Montastraea cavernosa and the sponge Agelas clathrodes in laboratory assays. These data indicate that when lionfish predation on herbivorous fish released Lobophora from grazing pressure at depth, Lobophora expanded its benthic cover to a depth of 61 m, where it replaced the dominant coral and sponge species. Our results suggest that this chemically defended alga may out-compete these species in situ, and that mesophotic reefs may be further impacted in the near future as Lobophora continues to expand to its compensation point. PMID- 26988323 TI - Morphology of Gambierdiscus scabrosus sp. nov. (Gonyaulacales): a new epiphytic toxic dinoflagellate from coastal areas of Japan. AB - A new epiphytic dinoflagellate is described, G ambierdiscus scabrosus sp. nov., from tidal pools and rocky shores along the coastal areas of Japan. Cells are 63.2 +/- 5.7 MUm in depth, 58.2 +/- 5.7 MUm in width, and 37.3 +/- 3.5 MUm in length. The plate formula of G . scabrosus is Po, 4', 0a, 6'', 6c, ?s, 5''', 0p, and 2''''. Morphologically, G . scabrosus resembles G . belizeanus as follows: anterioposteriorly compressed cell shape, narrow 2'''' plate, and areolated surface. Despite this similarity, the cells of G . scabrosus can be distinguishable by the presence of the asymmetric shaped 3'' plate and the rectangular shaped 2' plate. PMID- 26988324 TI - Effects of light and circadian clock on growth and chlorophyll accumulation of Nannochloropsis gaditana. AB - Circadian clocks synchronize various physiological, metabolic and developmental processes of organisms with specific phases of recurring changes in their environment (e.g. day and night or seasons). Here, we investigated whether the circadian clock plays a role in regulation of growth and chlorophyll (Chl) accumulation in Nannochloropsis gaditana, an oleaginous marine microalga which is considered as a potential feedstock for biofuels and for which a draft genome sequence has been published. Optical density (OD) of N. gaditana culture was monitored at 680 and 735 nm under 12:12 h or 18:6 h light-dark (LD) cycles and after switching to continuous illumination in photobioreactors. In parallel, Chl fluorescence was measured to assess the quantum yield of photosystem II. Furthermore, to test if red- or blue-light photoreceptors are involved in clock entrainment in N. gaditana, some of the experiments were conducted by using only red or blue light. Growth and Chl accumulation were confined to light periods in the LD cycles, increasing more strongly in the first half than in the second half of the light periods. After switching to continuous light, rhythmic oscillations continued (especially for OD680 ) at least in the first 24 h, with a 50% decrease in the capacity to grow and accumulate Chl during the first subjective night. Pronounced free-running oscillations were induced by blue light, but not by red light. In contrast, the photosystem II quantum yield was determined by light conditions. The results indicate interactions between circadian and light regulation of growth and Chl accumulation in N. gaditana. PMID- 26988325 TI - Molecular and morphological evidence for Sheathia gen. nov. (Batrachospermales, Rhodophyta) and three new species. AB - The freshwater red algal genus Batrachospermum has been shown to be paraphyletic since the first molecular studies of the Batrachospermales. Previous research, along with this study, provides strong support for the clade Batrachospermum section Helminthoidea. This study has found that heterocortication, the presence of both cylindrical and bulbous cells on the main axis, is an underlying synapomorphy of this clade. Based on support from DNA sequences of the rbcL gene, the COI barcode region and the rDNA ITS 1 and 2, along with morphological studies, the new genus Sheathia is proposed. Seven heterocorticate species were recognized from the molecular clades. Sheathia boryana and S. exigua sp. nov. appear to be restricted to Europe, whereas S. confusa occurs in Europe and New Zealand. Sheathia involuta is widespread in the USA and reported for the first time from Europe. Sheathia americana sp. nov., has been collected in the USA and Canada, and S. heterocortica and S. grandis sp. nov. have been collected only in the USA. Sheathia confusa and S. grandis can be distinguished based on morphological characters, whereas DNA sequence data are required to conclusively distinguish the other species. Sheathia fluitans and S. carpoinvolucra also are placed within this genus based on the presence of heterocortication. These data also hint at greater diversity among non-heterocorticate Sheathia than is recognized by the single species name S. arcuata. PMID- 26988326 TI - Comparative transcriptome analysis of Discosporangium mesarthrocarpum (Phaeophyceae), Schizocladia ischiensis (Schizocladiophyceae), and Phaeothamnion confervicola (Phaeothamniophyceae), with special reference to cell wall-related genes. AB - Within the stramenopile lineage, only brown algae (Phaeophyceae) have evolved complex multicellularity, although some other members of the lineage (e.g., Schizocladia in Schizocladiophyceae; Phaeothamnion in Phaeothamniophyceae) also develop simple multicellular thalli. The development of an adherent extracellular matrix (ECM) is considered to be one of the key steps in the evolution of multicellularity, because ECM is involved in adhesion of cells to each other and in cell-cell communication essential for developmental, reproductive, and sophisticated defense systems. Because there are no unicellular organisms within brown algae, we considered that comparison of other stramenopile taxa closely related to brown algae and having multicellular thalli could yield clues to elucidate the evolution of multicellularity in brown algae. In this study, we investigated transcriptomes involved in cell wall polysaccharide metabolism of three stramenopile species, Discosporangium mesarthrocarpum, which is suggested to be one of the most basal taxa within Phaeophyceae, S. ischiensis, and P. confervicola. We employed 454-FLX high-throughput pyrosequencing to generate expressed sequence tag (EST) databases for these species, and performed comparative analyses between these databases and the genome sequence of the brown alga Ectocarpus siliculosus. Results indicate that cell wall polysaccharide metabolism pathways of D. mesarthrocarpum are similar to E. siliculosus, whereas those of S. ischiensis and P. confervicola are significantly different from E. siliculosus, suggesting that the components of the cell wall in S. ischiensis and P. confervicola are likely to be different from those of E. siliculosus. PMID- 26988327 TI - Symbiodinium (Dinophyceae) diversity in reef-invertebrates along an offshore to inshore reef gradient near Lizard Island, Great Barrier Reef. AB - Despite extensive work on the genetic diversity of reef invertebrate dinoflagellate symbioses on the Great Barrier Reef (GBR; Australia), large information gaps exist from northern and inshore regions. Therefore, a broad survey was done comparing the community of inshore, mid-shelf and outer reefs at the latitude of Lizard Island. Symbiodinium (Freudenthal) diversity was characterized using denaturing gradient gel electrophoresis fingerprinting and sequencing of the ITS2 region of the ribosomal DNA. Thirty-nine distinct Symbiodinium types were identified from four subgeneric clades (B, C, D, and G). Several Symbiodinium types originally characterized from the Indian Ocean were discovered as well as eight novel types (C1kk, C1LL, C3nn, C26b, C161a, C162, C165, C166). Multivariate analyses on the Symbiodinium species diversity data showed a strong link with host identity, consistent with previous findings. Of the four environmental variables tested, mean austral winter sea surface temperature (SST) influenced Symbiodinium distribution across shelves most significantly. A similar result was found when the analysis was performed on Symbiodinium diversity data of genera with an open symbiont transmission mode separately with chl a and PAR explaining additional variation. This study underscores the importance of SST and water quality related variables as factors driving Symbiodinium distribution on cross-shelf scales. Furthermore, this study expands our knowledge on Symbiodinium species diversity, ecological partitioning (including host-specificity) and geographic ranges across the GBR. The accelerating rate of environmental change experienced by coral reef ecosystems emphasizes the need to comprehend the full complexity of cnidarian symbioses, including the biotic and abiotic factors that shape their current distributions. PMID- 26988328 TI - Induced resistance to periwinkle grazing in the brown seaweed Fucus vesiculosus (Phaeophyceae): molecular insights and seaweed-mediated effects on herbivore interactions. AB - Herbivory is a key factor for controlling seaweed biomass and community structure. To cope with grazers, constitutive and inducible defenses have evolved in macroalgae. Inducible chemical defenses show grazer-specificity and, at the same time, have the potential to mediate interactions among different herbivores. Furthermore, temporal variations in defense patterns, which may adjust antiherbivory responses to grazing pressure, were reported in two brown seaweeds. However, underlying cellular processes are only rudimentarily characterized. To investigate the response of Fucus vesiculosus (L.) to periwinkle (Littorina obtusata) grazing, feeding assays were conducted at several times during a 33 d induction experiment. Underlying cellular processes were analyzed through gene expression profiling. Furthermore, direct processes driving the antiherbivory response to periwinkle grazing and indirect effects on another herbivore, the isopod Idotea baltica, were elucidated. F. vesiculosus showed multiple defense pulses in response to periwinkle grazing, suggesting a high level of temporal variability in antiherbivory traits. Defense induction was accompanied by extensive transcriptome changes. Approximately 400 genes were significantly up /down-regulated relative to controls, including genes relevant for translation and the cytoskeleton. Genes involved in photosynthesis were mostly down regulated, while genes related to the respiratory chain were up-regulated, indicating alterations in resource allocation. The comparison of genes regulated in response to isopod (previous study) and periwinkle grazing suggests specific induction of several genes by each herbivore. However, grazing by both herbivores induced similar metabolic processes in F. vesiculosus. These common defense related processes reflected in strong indirect effects as isopods were also repelled after previous grazing by L. obtusata. PMID- 26988329 TI - Effects of brefeldin A on the endomembrane system and germ tube formation of the tetraspore of Gelidium floridanum (Rhodophyta, Florideophyceae). AB - Gelidium floridanum W.R. Taylor tetraspores are units of dispersal and are responsible for substrate attachment. This study aimed to examine evidence of direct interaction between germ tube formation and Golgi activity during tetraspore germination of G. floridanum. After release, the tetraspores were incubated with brefeldin A (BFA) in concentrations of 4 and 8 MUM over a 6 h period. The controls and treatments were analyzed with light, fluorescence (FM4 64 dye) and transmission electron microscopy. In the control samples, the Golgi bodies were responsible for germ tube formation. In contrast, BFA-treated samples were observed to inhibit spore adhesion and germ tube formation. These tetraspores also showed an increase in volume (>=30 MUm width). BFA treatment also resulted in the disassembly of Golgi cisternae and the formation of vesiculated areas of the cytoplasm, blocking the secretion of protein and amorphous matrix polysaccharides. When stained with FM4-64, the control samples showed fluorescence in the apical region of the germ tube, but the treated samples showed an intense fluorescence throughout the cytoplasm. From these results, we can conclude that the germ tube is formed by the incorporation of vesicles derived from Golgi. Thus, vesicle secretion and Golgi organization are basic processes and essential in adhesion and tube formation. By blocking the secretion of protein and amorphous matrix polysaccharides, BFA treatment precluded tetraspore germination. PMID- 26988330 TI - Menadione-induced caspase-dependent programmed cell death in the green chlorophyte Chlamydomonas reinhardtii. AB - Menadione, a quinone that undergoes redox cycles leading to the formation of superoxide radicals, induces programmed cell death (PCD) in animals and plants. In this study, we investigated whether the unicellular green alga Chlamydomonas reinhardtii P.A.Dangeard is capable of executing PCD upon exposure to menadione stress. We report here, the morphological, molecular, and biochemical changes after menadione exposure of C. reinhardtii cells. The effect of menadione on cell death has been shown to be dose-dependent; 5-100 MUM menadione causes 20%-46% cell death, respectively. It appears that growth is inhibited with the concomitant degradation of the photosynthetic pigments and by a decrease in the photosynthetic capacity. Being an oxidative stress, we found an H2 O2 burst within 15 min of menadione exposure, followed by an increase in antioxidant enzyme (superoxide dismutase [SOD], catalase [CAT], and ascorbate peroxidase [APX]) activities. In parallel, RT-PCR was performed for transcript analyses of Mn-SOD, CAT, and APX. Our results clearly revealed that expression of these genes were up-regulated upon menadione exposure. Furthermore, classical hallmarks of PCD such as alteration of mitochondrial membrane potential, significant increase in caspase-3-like DEVDase activity, cleavage of poly (ADP) ribose polymerase (PARP)-1-like enzyme, and DNA fragmentation as detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and oligosomal DNA fragmentation were observed. Moreover, antibodies against a mammalian active caspase-3 shared epitopes with a caspase-3-like protein of ~17 kDa; its pattern of expression and activity correlated with the onset of cell death. To the best of our knowledge, this is the first report on menadione induced PCD through a mitochondrian-caspase protease pathway in an algal species. PMID- 26988331 TI - Effects of silicate resupply to silicate-deprived Thalassiosira weissflogii (Bacillariophyceae) in stationary or senescent phase: short-term patterns of growth and cell death. AB - The ability of nutrient-deprived phytoplankton to recover in the short term when nutrients are resupplied has been studied for nitrogen and phosphorus, but the case for silicate (Si) is poorly understood. Si-limited Thalassiosira weissflogii (Grunow) Fryxell et Hasle (grown in batch culture) was harvested in stationary phase (when cell numbers stopped increasing ~2 d after Si depletion) and senescence (when cell numbers declined ~4 d after Si depletion) and Si was resupplied at different concentrations (from 0 to 100 MUM). Cell numbers, proportion of dead cells, variable fluorescence emissions (Fv /Fm ), and activities of proteases were measured during Si depletion and for 24 h after Si resupply. As Si was depleted, the specific growth rate declined, dead cells increased from ~2% in log phase, to ~25% in stationary phase to over 35% in senescence, and activities of proteases associated with cell death increased several-fold. Concentration-dependent recovery of growth rate was seen after 24 h for cultures resupplied with Si in stationary phase but not in senescence. However, resupply of Si at 100 MUM to stationary phase cultures alone increased protease activity to nearly the levels seen in senescence. Differences in the responses to Si resupply suggest that the ability and time to recover from Si depletion depend not only on the growth phase but also on the concentration resupplied. PMID- 26988332 TI - Direct health care costs and length of hospital stay related to health care acquired infections in adult patients based on point prevalence measurements. AB - BACKGROUND: The incidence of health care-acquired infection (HAI) and the consequence for patients with HAI tend to vary from study to study. By including all patients, all medical specialties, and performing a follow-up analysis, this study contributes to previous findings in this research field. METHODS: Data from the Swedish National Point Prevalence Surveys of HAI 2010-2012 was merged with cost per patient data from the county Health Care Register (N = 6,823). Extended length of stay (LOS) and costs related to an HAI were adjusted for sex, age, intensive care unit use, and surgery. RESULTS: Patients with HAI (n = 732) had a larger proportion of readmissions compared with patients with no HAI (29.0% vs 16.5%). Of the total bed days, 9.3% was considered to be excess days attributed to the group of patients with an HAI. The excess LOS comprised 11.4% of the total costs (95% CI, 10.2-12.7). The 1-year overall mortality rate for patients with HAI in comparison to all other patients was 1.75 (95% CI, 1.45-2.11), all 5 of these differences were statistically significant (P < .001). CONCLUSIONS: Even if not all outcomes for patients with an HAI can be explained by the HAI itself, the increase in inpatient days, readmissions, associated costs, and higher mortality rates are quite notable. PMID- 26988334 TI - Rapid access to unsymmetrical tolanes and alkynones by sequentially palladium catalyzed one-pot processes. AB - Alkynones as well as unsymmetrically substituted tolanes (diarylalkynes) can be rapidly generated in a one-pot fashion via sequential palladium catalysis. Terminal alkynes, formed in situ by protecting-group free palladium-catalyzed coupling of aryl iodides with ethynyl magnesium bromide, are subsequently transformed by Sonogashira coupling with aryl halides or aroyl chlorides to furnish unsymmetrically substituted alkynes in good to excellent yields. PMID- 26988333 TI - Eight-year sustainability of a successful intervention to prevent urinary tract infection: A mixed-methods study. AB - BACKGROUND: Data on long-term effects of interventions in infection control are scarce. We aimed to evaluate the 8-year sustainability of a successful intervention to reduce urinary tract infections (UTIs) through restriction of urinary catheter (UC) use in an orthopedic surgical population. METHODS: Prospective UTI surveillance from November 2009-January 2010 was conducted to compare the results against the 2-year sustainability assessment performed in 2004. Semistructured staff interviews focused on UC indication, training, insertion techniques, and recall of the former intervention. RESULTS: A total of 336 consecutive patients were included (median age, 63 years; range, 16-95 years; 55% women). A UC was placed in 17.6% of patients (operating room [OR], 10.1%; postanesthesia care unit [PACU], 3.6%; surgical wards [SW], 3.9%) compared with 20.0% in 2004 (OR, 15.7%; PACU, 1.0%; SW, 3.7%). The incidence rate of UTI was 2.4 per 1,000 patient-days in 2010 versus 2.6 per 1,000 patient-days in 2004; adjusted incidence rate ratio 0.76; 95% confidence interval, 0.21-2.76; P = .67. The qualitative inquiry demonstrated poor recall of the intervention and knowledge of guidelines except in the OR, where we identified a champion leader. DISCUSSION: The intervention effect was sustained with regard to overall UTI rate and UC placement in the OR, but less in the PACU and SW. CONCLUSIONS: Continuous leadership of a single opinion leader in a pivotal position can contribute critically to sustainability. PMID- 26988335 TI - Persistent Postoperative Pain after Cardiac Surgery: Incidence, Characterization, Associated Factors and its impact in Quality of Life. AB - BACKGROUND: Cardiac surgery (CS) ranks among the most frequently performed interventions worldwide and persistent postoperative pain (PPP) has been recognized as a relevant clinical outcome in this context. We aimed to evaluate its incidence, characteristics, associated factors and patient's quality of life (QoL). METHODS: Observational prospective study conducted in patients undergoing CS in a tertiary university hospital. PPP was defined as persistent pain after surgery with higher than 3 months' duration, after excluding other causes of pain. We used a set of questionnaires for data collection: Pain Catastrophizing Scale, Duke Health Profile, Brief Pain Inventory Short Form, McGill Pain Questionnaire Short Form, Douleur Neuropathique en 4 Questions and standardized questions regarding pain periodicity. RESULTS: A total of 288 patients have completed the study and 43% presented PPP assessed at 3 months (PPP3M); out of which 84% were not under any treatment. PPP patients reported significantly lower QoL, and a neuropathic pain (NP) component was present in 50% of them. Younger age, female gender, higher body mass index, catastrophizing, coronary artery bypass graft, osteoarthritis, history of previous surgery (excluding sternotomy) and moderate to severe acute postoperative pain were independent predictors of PPP3M. CONCLUSION: This is the first study comprehensively describing PPP after CS and identifying NP in half of them. Our results support the important role that PPP plays after CS in considering its interference in patients' daily life and their lower QoL, which deserves the attention of health care professionals in order to improve prevention, assessment and treatment of these patients. WHAT DOES THIS STUDY ADD?: This study comprehensively describes persistent postoperative pain (PPP) after cardiac surgery (CS) and identifies neuropathic pain (NP) in half of them. Our results support the important role that PPP plays after CS in considering its interference in patients' daily life and their lower quality of life. PMID- 26988337 TI - Authors' reply: diagnostic challenges to be considered regarding Zika virus in the context of the presence of the vector Aedes albopictus in Europe. PMID- 26988336 TI - Placental biomarkers and angiogenic factors in oral fluids of patients with preeclampsia. AB - OBJECTIVES: The objectives of this study are to explore the feasibility of measuring endothelial and placental biomarkers in saliva and gingival crevicular fluid (GCF) and to determine if patients with preeclampsia (PE) have a different profile of these biomarkers in oral fluids. METHOD: A case-control study was conducted, including patients with PE (n = 10) and a control group with normal pregnancies randomly selected (n = 20) admitted at the Sotero del Rio Hospital in Santiago, Chile. A complete periodontal and obstetric history that involved the collection of oral fluids was performed at the same gestational age. Levels of Cd63(+) extracellular vesicles, placental alkaline phosphatase (PLAP), placental growth factor (PlGF), and sFlt-1 levels were determined by ELISA assays. Data analysis was performed with chi-square or Fisher's exact test, and Mann-Whitney U test for continuous variables. The association was assessed using a multiple logistic regression model. RESULTS: sFlt-1 concentrations in saliva and GCF were significantly higher in patients with PE (p = 0.045 and p = 0.033 respectively). Concentrations of PLAP were elevated in GCF of patients with PE (p = 0.049). The PLAP/CD63(+) ratio in GCF of patients with PE was significantly higher (p = 0.0008). No differences in PlGF levels were observed. CONCLUSION(S): GCF of patients with PE concentrates higher levels of biomarkers related with the PE development. (c) 2016 John Wiley & Sons, Ltd. PMID- 26988338 TI - Semantic Coherence Facilitates Distributional Learning. AB - Computational models have shown that purely statistical knowledge about words' linguistic contexts is sufficient to learn many properties of words, including syntactic and semantic category. For example, models can infer that "postman" and "mailman" are semantically similar because they have quantitatively similar patterns of association with other words (e.g., they both tend to occur with words like "deliver," "truck," "package"). In contrast to these computational results, artificial language learning experiments suggest that distributional statistics alone do not facilitate learning of linguistic categories. However, experiments in this paradigm expose participants to entirely novel words, whereas real language learners encounter input that contains some known words that are semantically organized. In three experiments, we show that (a) the presence of familiar semantic reference points facilitates distributional learning and (b) this effect crucially depends both on the presence of known words and the adherence of these known words to some semantic organization. PMID- 26988339 TI - Effect of obesity on the pharmacokinetics of antimicrobials in critically ill patients: A structured review. AB - The increased prevalence of obesity presents challenges for clinicians aiming to provide optimised antimicrobial dosing in the intensive care unit. Obesity is likely to exacerbate the alterations to antimicrobial pharmacokinetics when the chronic diseases associated with obesity exist with the acute pathophysiological changes associated with critical illness. The purpose of this paper is to review the potential pharmacokinetic (PK) changes of antimicrobials in obese critically ill patients and the implications for appropriate dosing. We found that hydrophilic antimicrobials (e.g. beta-lactams, vancomycin, daptomycin) were more likely to manifest altered pharmacokinetics in critically ill patients who are obese. In particular for beta-lactam antibiotics, obesity is associated with a larger volume of distribution (V(d)). In obese critically ill patients, piperacillin is also associated with a lower drug clearance (CL). For doripenem, these PK changes have been associated with reduced achievement of pharmacodynamic (PD) targets when standard drug doses are used. For vancomycin, increases in Vd are associated with increasing total body weight (TBW), meaning that the loading dose should be based on TBW even in obese patients. For daptomycin, an increased Vd is not considered to be clinically relevant. For antifungals, little data exist in obese critically ill patients; during fluconazole therapy, an obese patient had a lower V(d) and higher CL than non-obese comparators. Overall, most studies suggested that standard dosage regimens of most commonly used antimicrobials are sufficient to achieve PD targets. However, it is likely that larger doses would be required for pathogens with higher minimum inhibitory concentrations. PMID- 26988340 TI - A successful physiotherapy management case of a patient with acquired haemophilia A prior to factor VIII inhibitor eradication. PMID- 26988342 TI - A Case of Cardiac Light Chain Deposition Disease in a Patient with Solitary Plasmacytoma. AB - BACKGROUND: Light chain deposition disease is a systemic disease characterized by deposition of immunoglobin light chains in various organs. Cardiac involvement of light chain deposition disease, also known as cardiac nonamyloidotic immunoglobin deposition disease (CIDD), is a rare clinical entity, where clinical outcome is very variable and best treatment approaches are not well known. CASE REPORT: We present the case of a 31-year-old man with a solitary thoracic plasmacytoma and cardiac light chain deposition disease with evidence of congestive heart failure by echocardiography and cardiac markers. The patient underwent surgical resection of the plasmacytoma followed by systemic therapy with 50% VDT-PACE and then VRD with near-normalization of his heart function. A melphalan-based stem cell transplant is planned in this young patient to achieve the best possible long term remission. CONCLUSIONS: CIDD is a very rare disease, with previous reports showing diverse manifestations with variable outcome. A high level of clinical suspicion should be maintained in such cases and early intervention, as in our patient, can restore cardiac function. There is very little literature on the optimal management of these patients. A combination of surgery and chemotherapy were pursued in our patient with very good results. PMID- 26988341 TI - Chlamydia trachomatis growth and development requires the activity of host Long chain Acyl-CoA Synthetases (ACSLs). AB - The obligate-intracellular pathogen Chlamydia trachomatis (Ct) has undergone considerable genome reduction with consequent dependence on host biosynthetic pathways, metabolites and enzymes. Long-chain acyl-CoA synthetases (ACSLs) are key host-cell enzymes that convert fatty acids (FA) into acyl-CoA for use in metabolic pathways. Here, we show that the complete host ACSL family [ACSL1 and ACSL3-6] translocates into the Ct membrane-bound vacuole, termed inclusion, and remains associated with membranes of metabolically active forms of Ct throughout development. We discovered that three different pharmacologic inhibitors of ACSL activity independently impede Ct growth in a dose-dependent fashion. Using an FA competition assay, host ACSLs were found to activate Ct branched-chain FAs, suggesting that one function of the ACSLs is to activate Ct FAs and host FAs (recruited from the cytoplasm) within the inclusion. Because the ACSL inhibitors can deplete lipid droplets (LD), we used a cell line where LD synthesis was switched off to evaluate whether LD deficiency affects Ct growth. In these cells, we found no effect on growth or on translocation of ACSLs into the inclusion. Our findings support an essential role for ACSL activation of host-cell and bacterial FAs within the inclusion to promote Ct growth and development, independent of LDs. PMID- 26988344 TI - Situating the Embodied Mind in a Landscape of Standing Affordances for Living Without Chairs: Materializing a Philosophical Worldview. AB - Sitting too much is unhealthy, but a widespread habit in many societies. Realizing behavioral change in this area is hard. Our societies promote being seated via the way its places are structured: they are filled with chairs for example. How can we make healthier environments that invite people to move around more? This article shows how philosophical research in the area of embodied/enactive cognitive science let to a built vision for the office of the future, of 2025. Multidisciplinary studio RAAAF [Rietveld Architecture-Art Affordances] and visual artist Barbara Visser built this world without chairs, titled The End of Sitting. This large rock-like landscape integrates many affordances for standing. Affordances are the possibilities for action provided by the environment. This landscape of standing affordances allows people to work standing while being supported by the material structure of the environment. This unorthodox working landscape is both an enactive art installation and the materialization of a philosophical worldview that understands people as embodied minds situated in a landscape of affordances. It stimulates reflection on the way built environments can naturally invite more active and healthy behavior. PMID- 26988343 TI - The Functions of Serine 687 Phosphorylation of Human DNA Polymerase eta in UV Damage Tolerance. AB - DNA polymerase eta (poleta) is a Y-family translesion synthesis polymerase that plays a key role in the cellular tolerance toward UV irradiation-induced DNA damage. Here, we identified, for the first time, the phosphorylation of serine 687 (Ser(687)), which is located in the highly conserved nuclear localization signal (NLS) region of human poleta and is mediated by cyclin-dependent kinase 2 (CDK2). We also showed that this phosphorylation is stimulated in human cells upon UV light exposure and results in diminished interaction of poleta with proliferating cell nuclear antigen (PCNA). Furthermore, we demonstrated that the phosphorylation of Ser(687) in poleta confers cellular protection from UV irradiation and increases the efficiency in replication across a site specifically incorporated cyclobutane pyrimidine dimer in human cells. Based on these results, we proposed a mechanistic model where Ser(687) phosphorylation functions in the reverse polymerase switching step of translesion synthesis: The phosphorylation brings negative charges to the NLS of poleta, which facilitates its departure from PCNA, thereby resetting the replication fork for highly accurate and processive DNA replication. Thus, our study, together with previous findings, supported that the posttranslational modifications of NLS of poleta played a dual role in polymerase switching, where Lys(682) deubiquitination promotes the recruitment of poleta to PCNA immediately prior to lesion bypass and Ser(687) phosphorylation stimulates its departure from the replication fork immediately after lesion bypass. PMID- 26988345 TI - Validation of the Flourishing Scale in a sample of people with suboptimal levels of mental well-being. AB - BACKGROUND: There is growing interest in measuring the eudaimonic perspective of mental well-being (social and psychological well-being) alongside existing measures of the hedonic perspective of mental well-being (subjective well-being). The Flourishing Scale (FS) assesses core aspects of social-psychological functioning and is now widely used in research in practice. However, the reliability and validity of eudaimonic measures such as the FS has not yet been tested in people with low or moderate levels of well-being. This group is at risk for developing mental disorders and, therefore, an important target group for public mental health. METHODS: We extensively evaluated the psychometric properties of the 8-item FS in a sample of adults with low or moderate levels of well-being in The Netherlands (N = 275) using confirmatory factor analysis (CFA), item response theory analysis and a multitrait matrix. RESULTS: The unidimensional structure of the scale was confirmed with CFA and an adequate fit to the Rasch model. However, our sample showed positive skewness of the scale, but lacked measurement precision at the higher end of the social-psychological continuum. In general, the multitrait matrix demonstrated the convergent validity of the scale, with strong to weak correlations between the FS and (1) overall well-being, (2) social and psychological well-being (3) positive eudaimonic states, (4) hedonic states, (5) psychopathology and (6) personality traits. Nevertheless, relatively low correlations were found, specifically in comparison with the Mental Health Continuum-Short Form (MHC-SF). CONCLUSIONS: The FS seems a reliable and valid instrument for measuring social-psychological functioning in adults with suboptimal well-being, but its use in intervention studies and clinical practice might be debatable. Therefore, the FS seems most suitable to include in epidemiological studies alongside existing hedonic measures to more fully capture mental well-being. Future research should examine the temporal stability of the FS and the consequences of the positive skewness and limited external validity of the scale found in the current study. PMID- 26988346 TI - Expanding access to high-cost medicines through the E2 access program in Thailand: effects on utilisation, health outcomes and cost using an interrupted time-series analysis. AB - OBJECTIVE: In 2008, the Thai government introduced the 'high-cost medicines E2 access program' as a part of the National List of Essential Medicines to increase patient access to medicines, improve clinical outcomes and make medicines more affordable. Our objective was to examine whether the 'high-cost medicines E2 access program' achieved its goals. DESIGN: Interrupted time-series design study. SETTING: 3 tertiary hospitals in different regions of Thailand, January 2006 to December 2012. PARTICIPANTS: Patients with target acute and chronic disease diagnoses who newly met E2 program criteria for selected study medicines. INTERVENTION: High-cost medicines E2 access program. MAIN OUTCOMES MEASURES: Level and trend changes over time in the proportions of eligible patients who received the indicated E2 medicines and who improved clinically, as well as in costs of treatment. RESULTS: A total of 2024 patients were included in utilisation analyses and 1375 patients with selected acute diseases contributed to analyses of clinical outcome. After 1 year of the E2 program implementation, the percentage of eligible patients receiving the indicated E2 program medicines increased significantly (relative change 12.7% (95% CI 4.4% to 21.0%), especially among those insured by the government's universal coverage scheme (relative change 19.9% (95% CI 9.5% to 30.5%)). The increase in the proportion of clinically improved patients with acute conditions was not significant (relative change 6.2% (95% CI -1.9% to 15.1%)). Quarterly healthcare costs per patient dropped significantly (relative change -13.5% (95% CI -26.9% to -1.7%)). CONCLUSIONS: In the study hospitals, the E2 access program seems to have facilitated patient access to specialty medicines, may have contributed to improved health outcomes, and decreased treatment costs. Routine monitoring is needed to assess effects of expanding the programme, including effects on quality of care and financial sustainability. PMID- 26988347 TI - Antiplatelet regimens in the long-term secondary prevention of transient ischaemic attack and ischaemic stroke: an updated network meta-analysis. AB - OBJECTIVE: To examine the comparative efficacy and safety of different antiplatelet regimens in patients with prior non-cardioembolic ischaemic stroke or transient ischaemic attack. DESIGN: Systematic review and network meta analysis. DATA SOURCES: As on 31 March 2015, all randomised controlled trials that investigated the effects of antiplatelet agents in the long-term (>= 3 months) secondary prevention of non-cardioembolic transient ischaemic attack or ischaemic stroke were searched and identified. OUTCOME MEASURES: The primary outcome measure of efficacy was serious vascular events (non-fatal stroke, non fatal myocardial infarction and vascular death). The outcome measure of safety was any bleeding. RESULTS: A total of 36 randomised controlled trials (82,144 patients) were included. Network meta-analysis showed that cilostazol was significantly more effective than clopidogrel (OR 0.77, 95% credible interval 0.60-0.98) and low-dose (75-162 mg daily) aspirin (0.69, 0.55-0.86) in the prevention of serious vascular events. Aspirin (50 mg daily) plus dipyridamole (400 mg daily) and clopidogrel reduced the risk of serious vascular events compared with low-dose aspirin; however, the difference was not statistically significant. Furthermore, low-dose aspirin was as effective as higher daily doses. Cilostazol was associated with a significantly lower bleeding risk than most of the other regimens. Moreover, aspirin plus clopidogrel was associated with significantly more haemorrhagic events than other regimens. Direct comparisons showed similar results as the network meta-analysis. CONCLUSIONS: Cilostazol was significantly more effective than aspirin and clopidogrel alone in the long-term prevention of serious vascular events in patients with prior non cardioembolic ischaemic stroke or transient ischaemic attack. Cilostazol was associated with a significantly lower bleeding risk than low-dose aspirin (75-162 mg daily) and aspirin (50 mg daily) plus dipyridamole (400 mg daily). Low-dose aspirin was as effective as higher daily doses. However, further large, randomised, controlled, head-to-head trials are needed, especially in non-Asian ethnic groups. PMID- 26988348 TI - Trial protocol to compare the efficacy of a smartphone-based blood glucose management system with standard clinic care in the gestational diabetic population. AB - INTRODUCTION: The prevalence of gestational diabetes mellitus (GDM) is rising in the UK. Good glycaemic control improves maternal and neonatal outcomes. Frequent clinical review of patients with GDM by healthcare professionals is required owing to the rapidly changing physiology of pregnancy and its unpredictable course. Novel technologies that allow home blood glucose (BG) monitoring with results transmitted in real time to a healthcare professional have the potential to deliver good-quality healthcare to women more conveniently and at a lower cost to the patient and the healthcare provider compared to the conventional face-to face or telephone-based consultation. We have developed an integrated GDm-health management system and aim to test the impact of using this system on maternal glycaemic control, costs, patient satisfaction and maternal and neonatal outcomes compared to standard clinic care in a single large publicly funded (National Health Service (NHS)) maternity unit. METHODS AND ANALYSIS: Women with confirmed gestational diabetes in a current pregnancy are individually randomised to either the GDm-health system and half the normal clinic visits or normal clinic care. Primary outcome is mean BG in each group from recruitment to delivery calculated, with adjustments made for number of BG measurements, proportion of preprandial and postprandial readings and length of time in study, and compared between the groups. The secondary objective will be to compare the two groups for compliance to the allocated BG monitoring regime, maternal and neonatal outcomes, glycaemic control using glycated haemoglobin (HbA1c) and other BG metrics, and patient attitudes to care assessed using a questionnaire and resource use. ETHICS AND DISSEMINATION: Thresholds for treatment, dietary advice and clinical management are the same in both groups. The results of the study will be published in a peer reviewed journal and disseminated electronically and in print. TRIAL REGISTRATION NUMBER: NCT01916694; Pre-results. PMID- 26988350 TI - Arrival by ambulance in acute heart failure: insights into the mode of presentation from Acute Studies of Nesiritide in Decompensated Heart Failure (ASCEND-HF). AB - OBJECTIVES: Limited data exist assessing the relationship between ambulance versus self-presentation and outcomes in patients with acute heart failure (AHF). SETTING: Clinical trial sites in North America. PARTICIPANTS: 1068 patients enrolled in the Acute Studies of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. PRIMARY AND SECONDARY OUTCOME MEASURES: The association between ambulance use and dyspnoea improvement, 30-day mortality or HF rehospitalisation and 180-day mortality. RESULTS: Of the 1068 patients in the substudy, 832 (78%) self-presented (SP) and 236 (22%) patients presented via ambulance. Patients presenting via ambulance were older, more likely to be female, have a higher ejection fraction but similar natriuretic peptide levels as patients who SP. Patients presenting by ambulance (compared with SP) trended towards more dyspnoea improvement at 6 (p=0.09) and 24 h (p=0.10). The co-primary end point (30-day mortality or HF rehospitalisation) was similar between groups (ambulance 12.2% vs SP 11.4%, p=0.74). Patients who presented by ambulance had a higher 30-day and 180-day mortality rate than those who SP (30-day: 4.3% vs 2.2%, p=0.08; 180-day: 15.1% vs 10.3%, p=0.04). After adjustment for baseline characteristics, patients arriving by ambulance (compared with SP) had a 2-fold high risk of 30-day mortality (OR 2.12, 95% CI 0.94 to 4.79), but no relationship to the composite of 30-day mortality/HF rehospitalisation (OR 1.01, 95% CI 0.63 to 1.63). CONCLUSIONS: Among patients with AHF, 30-day and 180-day mortality is 1.5-2 times higher for those with presenting via ambulance compared with patients who self-present. Understanding patient-related and system-related factors of ambulance use for patients with AHF is important. TRIAL REGISTRATION NUMBER: NCT00475852. PMID- 26988351 TI - Smoke-free homes: what are the barriers, motivators and enablers? A qualitative systematic review and thematic synthesis. AB - OBJECTIVE: To thematically synthesise primary qualitative studies of the barriers, motivators and enablers of smoke-free homes (SFHs). DESIGN: Systematic review and thematic synthesis. DATA SOURCES: Searches of MEDLINE, EBM Reviews (Cochrane Database of Systematic Reviews), PsycINFO, Global Health, CINAHL, Web of Science, Informit and EMBASE, combining terms for families, households and vulnerable populations; SFH and secondhand smoke; and qualitative research, were supplemented by searches of PhD theses, key authors, specialist journals and reference lists. STUDY SELECTION: We included 22 articles, reporting on 18 studies, involving 646 participants. INCLUSION CRITERIA: peer-reviewed; English language; published from 1990 onwards (to week 3 of April 2014); used qualitative data collection methods; explored participants' perspectives of home smoking behaviours; and the barriers, motivators and enablers to initiating and/or maintaining a SFH. DATA EXTRACTION: 1 of 3 authors extracted data with checking by a second. DATA SYNTHESIS: A thematic synthesis was performed to develop 7 core analytic themes: (1) knowledge, awareness and risk perception; (2) agency and personal skills/attributes; (3) wider community norms and personal moral responsibilities; (4) social relationships and influence of others; (5) perceived benefits, preferences and priorities; (6) addiction and habit; (7) practicalities. CONCLUSIONS: This synthesis highlights the complexity faced by many households in having a SFH, the practical, social, cultural and personal issues that need to be addressed and balanced by households, and that while some of these are common across study settings, specific social and cultural factors play a critical role in shaping household smoking behaviours. The findings can inform policy and practice and the development of interventions aimed at increasing SFHs. TRIAL REGISTRATION NUMBER: CRD42014014115. PMID- 26988352 TI - Do patients hospitalised in high-minority hospitals experience more diversion and poorer outcomes? A retrospective multivariate analysis of Medicare patients in California. AB - OBJECTIVE: We investigated the association between crowding as measured by ambulance diversion and differences in access, treatment and outcomes between black and white patients. DESIGN: Retrospective analysis. SETTING: We linked daily ambulance diversion logs from 26 California counties between 2001 and 2011 to Medicare patient records with acute myocardial infarction and categorised patients according to hours in diversion status for their nearest emergency departments on their day of admission: 0, <6, 6 to <12 and >= 12 h. We compared the amount of diversion time between hospitals serving high volume of black patients and other hospitals. We then use multivariate models to analyse changes in outcomes when patients faced different levels of diversion, and compared that change between black and white patients. PARTICIPANTS: 29,939 Medicare patients from 26 California counties between 2001 and 2011. MAIN OUTCOME MEASURES: (1) Access to hospitals with cardiac technology; (2) treatment received; and (3) health outcomes (30-day, 90-day, and 1-year death and 30-day readmission). RESULTS: Hospitals serving high volume of black patients spent more hours in diversion status compared with other hospitals. Patients faced with the highest level of diversion had the lowest probability of being admitted to hospitals with cardiac technology compared with those facing no diversion, by 4.4% for cardiac care intensive unit, and 3.4% for catheterisation laboratory and coronary artery bypass graft facilities. Patients experiencing increased diversion also had a 4.3% decreased likelihood of receiving catheterisation and 9.6% higher 1-year mortality. CONCLUSIONS: Hospitals serving high volume of black patients are more likely to be on diversion, and diversion is associated with poorer access to cardiac technology, lower probability of receiving revascularisation and worse long-term mortality outcomes. PMID- 26988353 TI - Understanding tensions and identifying clinician agreement on improvements to early-stage chronic kidney disease monitoring in primary care: a qualitative study. AB - OBJECTIVES: Since 2006, general practitioners (GPs) in England, UK, have been incentivised to keep a register and monitor patients with chronic kidney disease (CKD) stages 3-5. Despite tensions and debate around the merit of this activity, there has been little qualitative research exploring clinician perspectives on monitoring early-stage CKD in primary care. This study aimed to examine and understand a range of different healthcare professional views and experiences of identification and monitoring in primary care of early-stage CKD, in particular stage 3. DESIGN: Qualitative design using semistructured interviews. SETTING: National Health Service (NHS) settings across primary and secondary care in South West England, UK. PARTICIPANTS: 25 clinicians: 16 GPs, 3 practice nurses, 4 renal consultants and 2 public health physicians. RESULTS: We identified two related overarching themes of dissonance and consonance in clinician perspectives on early-stage CKD monitoring in primary care. Clinician dissonance around clinical guidelines for CKD monitoring emanated from different interpretations of CKD and different philosophies of healthcare and moral decision-making. Clinician consonance centred on the need for greater understanding of renal decline and increasing proteinuria testing to reduce overdiagnosis and identify those patients who were at risk of progression and further morbidity and who would benefit from early intervention. Clinicians recommended adopting a holistic approach for patients with CKD representing a barometer of overall health. CONCLUSIONS: The introduction of new National Institute for Health and Care Excellence (NICE) CKD guidelines in 2014, which focus the meaning and purpose of CKD monitoring by increased proteinuria testing and assessment of risk, may help to resolve some of the ethical and moral tensions clinicians expressed regarding the overmedicalisation of patients with a CKD diagnosis. PMID- 26988354 TI - Analysis of the interactome of the Ser/Thr Protein Phosphatase type 1 in Plasmodium falciparum. AB - BACKGROUND: Protein Phosphatase 1 (PP1) is an enzyme essential to cell viability in the malaria parasite Plasmodium falciparum (Pf). The activity of PP1 is regulated by the binding of regulatory subunits, of which there are up to 200 in humans, but only 3 have been so far reported for the parasite. To better understand the P. falciparum PP1 (PfPP1) regulatory network, we here report the use of three strategies to characterize the PfPP1 interactome: co-affinity purified proteins identified by mass spectrometry, yeast two-hybrid (Y2H) screening and in silico analysis of the P. falciparum predicted proteome. RESULTS: Co-affinity purification followed by MS analysis identified 6 PfPP1 interacting proteins (Pips) of which 3 contained the RVxF consensus binding, 2 with a Fxx[RK]x[RK] motif, also shown to be a PP1 binding motif and one with both binding motifs. The Y2H screens identified 134 proteins of which 30 present the RVxF binding motif and 20 have the Fxx[RK]x[RK] binding motif. The in silico screen of the Pf predicted proteome using a consensus RVxF motif as template revealed the presence of 55 potential Pips. As further demonstration, 35 candidate proteins were validated as PfPP1 interacting proteins in an ELISA-based assay. CONCLUSIONS: To the best of our knowledge, this is the first study on PfPP1 interactome. The data reports several conserved PP1 interacting proteins as well as a high number of specific interactors to PfPP1. Their analysis indicates a high diversity of biological functions for PP1 in Plasmodium. Based on the present data and on an earlier study of the Pf interactome, a potential implication of Pips in protein folding/proteolysis, transcription and pathogenicity networks is proposed. The present work provides a starting point for further studies on the structural basis of these interactions and their functions in P. falciparum. PMID- 26988349 TI - Epidemic potential of Escherichia coli ST131 and Klebsiella pneumoniae ST258: a systematic review and meta-analysis. AB - OBJECTIVES: Observational studies have suggested that Escherichia coli sequence type (ST) 131 and Klebsiella pneumoniae ST258 have hyperendemic properties. This would be obvious from continuously high incidence and/or prevalence of carriage or infection with these bacteria in specific patient populations. Hyperendemicity could result from increased transmissibility, longer duration of infectiousness, and/or higher pathogenic potential as compared with other lineages of the same species. The aim of our research is to quantitatively estimate these critical parameters for E. coli ST131 and K. pneumoniae ST258, in order to investigate whether E. coli ST131 and K. pneumoniae ST258 are truly hyperendemic clones. PRIMARY OUTCOME MEASURES: A systematic literature search was performed to assess the evidence of transmissibility, duration of infectiousness, and pathogenicity for E. coli ST131 and K. pneumoniae ST258. Meta-regression was performed to quantify these characteristics. RESULTS: The systematic literature search yielded 639 articles, of which 19 data sources provided information on transmissibility (E. coli ST131 n=9; K. pneumoniae ST258 n=10)), 2 on duration of infectiousness (E. coli ST131 n=2), and 324 on pathogenicity (E. coli ST131 n=285; K. pneumoniae ST258 n=39). Available data on duration of carriage and on transmissibility were insufficient for quantitative assessment. In multivariable meta-regression E. coli isolates causing infection were associated with ST131, compared to isolates only causing colonisation, suggesting that E. coli ST131 can be considered more pathogenic than non-ST131 isolates. Date of isolation, location and resistance mechanism also influenced the prevalence of ST131. E. coli ST131 was 3.2 (95% CI 2.0 to 5.0) times more pathogenic than non-ST131. For K. pneumoniae ST258 there were not enough data for meta-regression assessing the influence of colonisation versus infection on ST258 prevalence. CONCLUSIONS: With the currently available data, it cannot be confirmed nor rejected, that E. coli ST131 or K. pneumoniae ST258 are hyperendemic clones. PMID- 26988355 TI - Quality of life, fatigue and mental health in patients with the m.3243A > G mutation and its correlates with genetic characteristics and disease manifestation. AB - BACKGROUND: Mitochondrial disorders belong to the most prevalent inherited metabolic diseases with the m.3243A > G mutation reflecting being one of the most common mutations in mitochondrial DNA. Previous studies showed little relationship between mitochondrial genetics and disease manifestation. Relationship between genotype and disease manifestation with patient reported quality of life and other patient reported outcomes is still unexplored. METHODS: Seventy-two out of the 122 invited adult patients with m.3243A > G mutation completed online standardized questionnaires on quality of life, functional impairment, fatigue and mental health as assessed by the RAND-SF36, the Sickness Impact Profile (SIP), the Checklist Individual Strength (CIS) and the Hospital Anxiety and Depression scale (HADS). Data were related to clinical manifestation reflected by the Newcastle Mitochondrial Disease Adult Scale (NMDAS) score and heteroplasmy levels of the mutation in urine epithelial cells. RESULTS: Patients reported impaired quality of life. Sixty percent showed severe levels of fatigue, and 37% showed clinical relevant mental health problems, which was significantly more than healthy norms. These patient reported health outcomes showed negligible relationship with levels of heteroplasmy (r = <.30) and weak (.30 < r < .50) to moderate (.50 < r < .70) relationship with clinical manifestation. CONCLUSIONS: Patient reported outcomes on quality of life, fatigue and mental health problems, are only partly reflected by clinical assessments. In order to support patients more effectively, integration of patient reported outcomes, alongside symptoms of their disease, in clinical practice is warranted. PMID- 26988357 TI - Should the hyperechogenic halo around malignant breast lesions be included in the measurement of tumor size? AB - The estimation of tumor size is important for treatment strategies of breast cancer. The hyperechogenic zone around breast cancer is a recognized criterion for malignancy, but its impact on preoperative tumor size estimations has been poorly investigated. Data of prospectively maintained database of 513 patients with primary breast tumors were analyzed retrospectively. A total of 196 patients with complete datasets including preoperative ultrasound (US) were eligible for analysis. The median age of the patients was 58.5 years (range 33-87). With all of the 196 patients, US has been performed. In 170 of 196 (86.7 %) cases, an echogenic halo was detected. We use two ways to measure tumor size with US: without (US-0) and with (US-1) echogenic halo. Mammography (MG) was used as standard. Tumor size measured by US and MG was compared with the actual histopathological (HP) tumor size. Mean differences between the sizing obtained by US-0, US-1, and MG and the HP sizing were -6.5, -1.5, and -1.8 mm, respectively. All three methods tend to underestimate the tumor size. The US-1 measurement was the closest to the HP size in comparison to the MG and US-0 measurements and the match was higher in tumors <2 cm. The estimated Pearson correlation coefficients (r) were 0.72, 0.68, and 0.61 for US-1, US-0, and MG, respectively. Moreover, the predictive value of US-1 regarding tumor size was not influenced by histological type and grade of the tumor, receptor status, and presence of intraductal component. Estimation of tumor size by US should include the hyperechogenic zone around the tumor. PMID- 26988356 TI - Submillisievert CT using model-based iterative reconstruction with lung-specific setting: An initial phantom study. AB - OBJECTIVE: To assess image quality of filtered back-projection (FBP) and model based iterative reconstruction (MBIR) with a conventional setting and a new lung specific setting on submillisievert CT. METHODS: A lung phantom with artificial nodules was scanned with 10 mA at 120 kVp and 80 kVp (0.14 mSv and 0.05 mSv, respectively); images were reconstructed using FBP and MBIR with conventional setting (MBIRStnd) and lung-specific settings (MBIRRP20/Tx and MBIRRP20). Three observers subjectively scored overall image quality and image findings on a 5 point scale (1 = worst, 5 = best) compared with reference standard images (50 mA FBP at 120, 100, 80 kVp). Image noise was measured objectively. RESULTS: MBIRRP20/Tx performed significantly better than MBIRStnd for overall image quality in 80-kVp images (p < 0.01), blurring of the border between lung and chest wall in 120p-kVp images (p < 0.05) and the ventral area of 80-kVp images (p < 0.001), and clarity of small vessels in the ventral area of 80-kVp images (p = 0.037). At 120 kVp, 10 mA-MBIRRP20 and 10 mA-MBIRRP20/Tx showed similar performance to 50 mA-FBP. MBIRStnd was better for noise reduction. Except for blurring in 120 kVp-MBIRStnd, MBIRs performed better than FBP. CONCLUSION: Although a conventional setting was advantageous in noise reduction, a lung specific setting can provide more appropriate image quality, even on submillisievert CT. KEY POINTS: * Lung-specific submillisievert 10 mA-MBIR CT setting has similar performance to 50 mA-FBP * The new lung-specific settings improve vessel clarity and blurring of borders * The new settings may provide more appropriate images than conventional settings. PMID- 26988359 TI - Our study 20 years on: UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. PMID- 26988358 TI - A comparison of toxicity profiles between the lower and standard dose capecitabine in breast cancer: a systematic review and meta-analysis. AB - Capecitabine 1000 mg/m(2) bid * 14 days every 21 days (14/21) has been reported to have similar efficacy but more favorable toxicity profile than the approved dosage of 1250 mg/m(2). However, a dose-toxicity relationship of capecitabine in breast cancer patients has not been fully elucidated. We performed a systematic review and meta-analysis to compare a safety profile between capecitabine starting dose of 1000 and 1250 mg/m(2) bid. Studies were identified using PubMed, ASCO, and San Antonio Breast Cancer Symposium abstract databases through December 2015. Eligible trials included phase II/III trials of capecitabine monotherapy at 1000 or 1250 mg/m(2) bid (14/21) for breast cancer patients that reported adequate safety data for all (grade 1-4) or high (grade 3-4) grade hand foot syndrome (HFS), diarrhea, fatigue, nausea, vomiting, stomatitis, neutropenia, thrombocytopenia, or anemia, as well as dose reductions, treatment discontinuation or treatment-related deaths. The summary incidence was calculated using random-effects models. A total of 4833 patients from 34 trials were included. 1218 and 3615 patients were treated with capecitabine 1000 and 1250 mg/m(2) bid, respectively. A significantly lower incidence of dose reduction (15.9 vs. 39.0 %; P = 0.007), high-grade HFS (12.0 vs. 19.0 %; P = 0.01), diarrhea (5.3 vs. 9.1 %; P = 0.01), and neutropenia (1.8 vs. 7.3 %; P < 0.01), and all-grade neutropenia (5.8 vs. 25.4 %; P = 0.01) was seen in capecitabine 1000 mg/m(2) compared to 1250 mg/m(2). Capecitabine monotherapy at 1000 mg/m(2) bid (14/21) has a clinically meaningful and significantly better toxicity profile compared to 1250 mg/m(2) bid (14/21). PMID- 26988360 TI - Focus on acute kidney injury and fluids. PMID- 26988361 TI - Pancreatic cysts in general population on ultrasonography: Prevalence and development of risk score. AB - BACKGROUND: Pancreatic cysts are related to the presence of ductal adenocarcinomas elsewhere in the pancreas, and are also associated with an increased risk of pancreatic adenocarcinoma in the future. Most of the previous studies that investigated the prevalence of pancreatic cysts focused on patients within a hospital or out-patient setting, which may not be representative of the general population. We investigated the prevalence and predictive factors for the presence of pancreatic cysts within a large number of subjects via general health examination. METHODS: Between December 2007 and December 2013, a total of 5198 subjects were enrolled that underwent ultrasonography (US) on general health examination. We established a scoring system for predicting the presence of one or more pancreatic cysts using a split-sample method. RESULTS: Among the enrolled subjects, the prevalence of a pancreatic cyst was 3.5 %. In multivariate analysis, the prevalence was significantly increased with older age, female sex, and the presence of gall bladder adenomyomatosis (GB-ADM). Based on multivariate analysis in the training sample (n = 2,599), we established the scoring system consisting of age, sex, and the presence of GB-ADM to predict the presence of pancreatic cysts. This scoring system was validated in the testing sample (n = 2,599) and produced an area under the curve of 0.711. CONCLUSIONS: The prevalence of pancreatic cyst detected by US was 3.5 % in the general population, and increased with age, female sex, and the presence of GB-ADM. A new scoring system developed in the present study may help to identify better candidates for further examination when the pancreas is not visible by US. PMID- 26988362 TI - Effects of additional fermented food wastes on nitrogen removal enhancement and sludge characteristics in a sequential batch reactor for wastewater treatment. AB - In order to enhance nitrogen removal from domestic wastewater with a carbon/nitrogen (C/N) ratio as low as 2.2:1, external carbon source was prepared by short-term fermentation of food wastes and its effect was evaluated by experiments using sequencing batch reactors (SBRs). The addition of fermented food wastes, with carbohydrate (42.8 %) and organic acids (24.6 %) as the main organic carbon components, could enhance the total nitrogen (TN) removal by about 25 % in contrast to the 20 % brought about by the addition of sodium acetate when the C/N ratio was equally adjusted to 6.6:1. The fermented food waste addition resulted in more efficient denitrification in the first anoxic stage of the SBR operation cycle than sodium acetate. In order to characterize the metabolic potential of microorganisms by utilizing different carbon sources, Biolog-ECO tests were conducted with activated sludge samples from the SBRs. As a result, in comparison with sodium acetate, the sludge sample by fermented food waste addition showed a greater average well color development (AWCD590), better utilization level of common carbon sources, and higher microbial diversity indexes. As a multi-organic mixture, fermented food wastes seem to be superior over mono-organic chemicals as an external carbon source. PMID- 26988363 TI - Effect of temperature on the release and remobilization of ecotoxic elements in AMD colloidal precipitates: the example of the Libiola copper mine, Liguria, (Italy). AB - Due to their characteristics, colloidal particles are able to control the dispersion of many organic and inorganic pollutants in soils and streams. Colloidal precipitates generated by acid mine drainage (AMD) process are usually amorphous or nanocrystalline materials, and their stability plays a crucial role in controlling the fate of metals released by sulphide oxydation. This paper describes a study of elements release (Fe, Al, Mn, Cd, Co, Cr, Cu, Ni, S, Zn) due to desorption or destabilization of three different colloidal precipitates, two ochreous and a greenish-blue precipitate, sampled at the Libiola mine site (northwest Italy). The samples were heated at high temperature in order to verify this treatment as inertization process. At room temperature, the most easily extracted element was S (with released percentages from 8.39 to 29.17 %), but considerable amounts of Cu, Zn and Mn (up to 16.6, 610.6 and 595.6 mg/kg, respectively) were also observed in the leachates for greenish-blue precipitates. The highest release of elements (S > Cu, Zn, Mn, Cd > Co, Ni > Al, Fe, Cr), with minor differences depending on the mineralogical composition of the samples, was observed for heat-treated samples obtained through moderate heating and mainly formed by anhydrous phases. Samples treated at high temperature had the lowest release, with only Cu showing a significant concentration in the leachate of greenish-blue precipitates. The results showed that dissolution/desorption is limited from ochreous natural colloidal precipitates occurring at the Libiola mine site but also that high amounts of some metals can be remobilized from greenish-blue precipitates. The destabilization of all percipitates through dehydratation-dehydroxylation can further remobilize important amounts of ecotoxic elements. Heat treatment at high temperature could be a definitive, although expensive, way to fix heavy metals in the solid fraction, preventing their dispersion in the surrounding environment. PMID- 26988364 TI - From immunotoxicity to carcinogenicity: the effects of carbamate pesticides on the immune system. AB - The immune system can be the target of many chemicals, with potentially severe adverse effects on the host's health. In the literature, carbamate (CM) pesticides have been implicated in the increasing prevalence of diseases associated with alterations of the immune response, such as hypersensitivity reactions, some autoimmune diseases and cancers. CMs may initiate, facilitate, or exacerbate pathological immune processes, resulting in immunotoxicity by induction of mutations in genes coding for immunoregulatory factors and modifying immune tolerance. In the present study, direct immunotoxicity, endocrine disruption and inhibition of esterases activities have been introduced as the main mechanisms of CMs-induced immune dysregulation. Moreover, the evidence on the relationship between CM pesticide exposure, dysregulation of the immune system and predisposition to different types of cancers, allergies, autoimmune and infectious diseases is criticized. In addition, in this review, we will discuss the relationship between immunotoxicity and cancer, and the advances made toward understanding the basis of cancer immune evasion. PMID- 26988365 TI - Concentration, sources, and flux of dissolved organic carbon of precipitation at Lhasa city, the Tibetan Plateau. AB - Dissolved organic carbon (DOC) plays an important role in the climate system, but few data are available on the Tibetan Plateau (TP). In this study, 89 precipitation samples were collected at Lhasa, the largest city of southern Tibet, from March to December 2013. The average concentration and wet deposition flux of DOC was 1.10 mg C L(-1) and 0.63 g C m(-2) year(-1), respectively. Seasonally, low DOC concentration and high flux appeared during the monsoon period, which were in line with heavy precipitation amount, reflecting dilution effect of precipitation for the DOC. Compared to other regions, the values of Lhasa were lower than those of large cities (e.g., Beijing and Seoul) mainly because of less air pollution of Lhasa. The principal component analysis (PCA) of DOC and ions (Ca(2+), Mg(2+), Na(+), K(+), NH4 (+), Cl(-), NO3 (-), and SO4 (2-)) showed that DOC of Lhasa was derived mainly from the natural sources, followed by anthropogenic burning activities. Furthermore, ?(14)C value of DOC indicated that fossil fuel combustion contributed around 28 % of the rainwater DOC of Lhasa, indicating that the atmosphere of Lhasa has been influenced by emission from fossil fuel combustion or high-temperature industrial processes. PMID- 26988366 TI - Methylparaben removal using heterogeneous photocatalysis: effect of operational parameters and mineralization/biodegradability studies. AB - Methylparaben (MePB) is an organic compound employed mainly in the manufacture of different personal care products. However, it has been recently listed as a potential endocrine disrupter chemical. Therefore, the main objective of this work was to evaluate the degradation of MePB in aqueous solutions using heterogeneous photocatalysis with TiO2 and hydrogen peroxide. In this way, effects of pH and the initial concentrations of catalyst, H2O2, and pollutant on treatment were analyzed. A face centered, central composite design was used for determination of the influence of each parameter in the process and the conditions under which the pollutant suffers the highest rates of degradation were selected. In general, results indicate that combination TiO2/H2O2/light irradiation leads to ~90 % of substrate removal after 30 min of reaction and that hydroxyl free radicals are the main specie responsible for organic matter elimination. Finally, in terms of mineralization and biodegradability, experimental results indicated that part of the organic matter was transformed into CO2 and water and the photo-treatment promoted an increase in samples biodegradability. PMID- 26988369 TI - The evolution of the health system outcomes in Central and Eastern Europe and their association with social, economic and political factors: an analysis of 25 years of transition. AB - BACKGROUND: After the fall of communism, the countries of Central and Eastern Europe started the process of political, economic, and social transformation. In health system the reform directions were often similar, despite differences in transition dynamics and the degree of government determination to implement reforms. Nonetheless, for most post-communist countries, there is a gap in evidence regarding the effectiveness of implemented reforms and their impact on health system performance. The presented study attempts to analyse and evaluate the results of health reforms in CEE countries with regard to their influence on health system outcomes. We also analysed the external and internal health system environments during the transition period to determine the factors affecting the effectiveness of health reforms. METHODS: We compared the indicators of population health status, lifestyle, occupational safety issues and health system resources in 21 post-communist countries between sub-periods across the entire transition period at the aggregate level. The dynamics of change in health system outcomes in individual countries, as well as between countries, was also compared. Finally, we analysed the correlations between health system outcomes gathered into one synthetic measure and factors considered as potential determinants affecting the effectiveness of health reforms. The analyses were performed based on one-dimensional, two-dimensional and multidimensional statistical methods. The data were retrieved from the international databases, such as WHO, World Bank, International Labour Organization, World Value Survey and the European Social Survey. RESULTS: Among the factors positively stimulating improvements in health system outcomes were the total expenditure on health and a lower financial burden on patients, but primarily they were determined by the broader economic context of the country. Another finding was that better initial position positively determined health system outcomes at later stages, but did not affect the degree of improvements. Countries that embarked on comprehensive reforms early on tended to achieve the greatest improvements in health system outcomes. CONCLUSIONS: Poorer countries may have only limited ability to improve health system outcomes by committing more financial resources to the health system. Progress can still be made in terms of health behaviours, since policies to address these have so far been insufficient or ineffective. PMID- 26988368 TI - Dorsal penile nerve block for rigid cystoscopy in men: study protocol for a randomized controlled trial. AB - BACKGROUND: Pain is common in men undergoing rigid cystoscopy. Even with the application of a lubricant containing 2 % lidocaine, about 76 % of men suffer from mild to severe pain when undergoing rigid cystoscopy. The most painful part of the procedure for men is when the cystoscope passes through the membranous urethra. Song et al. (Neurourol Urodyn 29:592-5, 2010) did autopsies on males and found that the dorsal nerve of the penis (DNP), the terminal branch of the pudendal nerve, innervates the membranous urethra in 53.3 % of specimens. In addition, the urethral mucosa has branches of innervated DNP. Dorsal penile nerve block (DPNB) is usually used for circumcision in children, and it has been shown to provide effective analgesia for penile surgeries. In this study, we hypothesized that DPNB could reduce the overall pain level in men during rigid cystoscopy. METHODS/DESIGN: The trial is a prospective, randomized, double-blind, placebo-controlled, single-center trial to evaluate the effectiveness and safety of DPNB in analgesia for men undergoing rigid cystoscopy. Participants will be enrolled and randomly allocated into one of three groups according to the different analgesia regimens: 1) tetracaine gel group (DPNB with saline), 2) DPNB group (DPNB with ropivacaine plus plain lubricant), 3) combination group (DPNB with ropivacaine plus tetracaine gel). The primary outcome of this study is the visual analog scale (VAS, 0-10) for pain at cystoscopic inspection of the external sphincter. VAS scores evaluated at other time points serve as secondary outcomes. Vital signs are secondary outcomes that address the discomfort and pain during the procedure. Furthermore, the incidence of adverse events as secondary outcomes will also be recorded for evaluation of the safety of DPNB in rigid cystoscopy. Clinical assessments will be evaluated prior to DPNB, at administration of the lubricant gel, at cystoscopic inspection of the penile and bulbar urethra, external sphincter, prostate, and bladder, as well as at withdrawal of the cystoscope. DISCUSSION: This research will determine the effectiveness and safety of DPNB in men undergoing rigid cystoscopy. The results of this trial may have important implications for exploring the role of DPNB in analgesia for cystoscopy in men. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02502487 (6 Jul 2015). PMID- 26988367 TI - Randomised controlled trial of a home-based physical activity intervention in breast cancer survivors. AB - BACKGROUND: To improve adherence to physical activity (PA), behavioural support in the form of behavioural change counselling may be necessary. However, limited evidence of the effectiveness of home-based PA combined with counselling in breast cancer patients exists. The aim of this current randomised controlled trial with a parallel group design was to evaluate the effectiveness of a home based PA intervention on PA levels, anthropometric measures, health-related quality of life (HRQoL), and blood biomarkers in breast cancer survivors. METHODS: Eighty post-adjuvant therapy invasive breast cancer patients (age = 53.6 +/- 9.4 years; height = 161.2 +/- 6.8 cm; mass = 68.7 +/- 10.5 kg) were randomly allocated to a 6-month home-based PA intervention or usual care. The intervention group received face-to-face and telephone PA counselling aimed at encouraging the achievement of current recommended PA guidelines. All patients were evaluated for our primary outcome, PA (International PA Questionnaire) and secondary outcomes, mass, BMI, body fat %, HRQoL (Functional assessment of Cancer Therapy-Breast), insulin resistance, triglycerides (TG) and total (TC), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) cholesterol were assessed at baseline and at 6-months. RESULTS: On the basis of linear mixed-model analyses adjusted for baseline values performed on 40 patients in each group, total, leisure and vigorous PA significantly increased from baseline to post-intervention in the intervention compared to usual care (between-group differences, 578.5 MET-min?wk( 1), p = .024, 382.2 MET-min?wk(-1), p = .010, and 264.1 MET-min?wk(-1), p = .007, respectively). Both body mass and BMI decreased significantly in the intervention compared to usual care (between-group differences, -1.6 kg, p = .040, and -.6 kg/m(2), p = .020, respectively). Of the HRQoL variables, FACT-Breast, Trial Outcome Index, functional wellbeing, and breast cancer subscale improved significantly in the PA group compared to the usual care group (between-group differences, 5.1, p = .024; 5.6, p = .001; 1.9 p = .025; and 2.8, p = .007, respectively). Finally, TC and LDL-C was significantly reduced in the PA group compared to the usual care group (between-group differences, -.38 mmol?L(-1), p = .001; and -.3 mmol?L(-1), p = .023, respectively). CONCLUSIONS: We found that home-based PA resulted in significant albeit small to moderate improvements in self-reported PA, mass, BMI, breast cancer specific HRQoL, and TC and LDL-C compared with usual care. CLINICALTRIALS. GOV IDENTIFIER: NCT02408107 (March 25, 2015). PMID- 26988371 TI - Fragmentation of Protonated N-(3-Aminophenyl)Benzamide and Its Derivatives in Gas Phase. AB - An ion of m/z 110.06036 (ion formula [C6H8NO](+); error: 0.32 mDa) was observed in the collision induced dissociation tandem mass spectrometry experiments of protonated N-(3-aminophenyl)benzamide, which is a rearrangement product ion purportedly through nitrogen-oxygen (N-O) exchange. The N-O exchange rearrangement was confirmed by the MS/MS spectrum of protonated N-(3-aminophenyl) O (18) -benzamide, where the rearranged ion, [C6H8NO (18) ](+) of m/z 112 was available because of the presence of O (18) . Theoretical calculations using Density Functional Theory (DFT) at B3LYP/6-31 g(d) level suggest that an ion neutral complex containing a water molecule and a nitrilium ion was formed via a transition state (TS-1), followed by the water molecule migrating to the anilide ring, eventually leading to the formation of the rearranged ion of m/z 110. The rearrangement can be generalized to other protonated amide compounds with electron-donating groups at the meta position, such as, -OH, -CH3, -OCH3, NH(CH3)2, -NH-Ph, and -NHCOCH3, all of which show the corresponding rearranged ions in MS/MS spectra. However, the protonated amide compounds containing electron-withdrawing groups, including -Cl, -Br, -CN, -NO2, and -CF3, at the meta position did not display this type of rearrangement during dissociation. Additionally, effects of various acyl groups on the rearrangement were investigated. It was found that the rearrangement can be enhanced by substitution on the ring of the benzoyl with electron-withdrawing groups. PMID- 26988370 TI - Anatomic distribution, clinical features, and survival data of 87 cases primary gastrointestinal lymphoma. AB - BACKGROUND: The purpose of this study is to analyze the anatomic distribution, clinical features, therapeutic methods, and prognosis factors of primary gastrointestinal lymphoma (PGIL). METHODS: Clinical data of 87 cases PGIL in the First Affiliated Hospital of Dalian Medical University from January 1999 to December 2010 were collected. Follow-ups were made according to the clinical feature, pathological pattern, clinical stage, and therapeutic method. Kapan Meier method was used for the survival analysis. Log-rank test was used to perform univariate survival analysis. COX multivariate analysis was carried out to analyze factors of P < 0.05 in univariate survival analysis. RESULTS: The incidence of PGIL significantly increased in patients more than 40 years old (87.4%). Clinical symptoms of PGIL were indistinguishable from other digestive system diseases, which included abdominal pain or discomfort (72.4%), lack of appetite (16.3%), gastrointestinal hemorrhage (14.9%), and diarrhea (12.8%). Some patients presented with systemic symptoms or complications, such as weight loss (35.6%) and digestive tract obstruction (13.8%). Primary gastric lymphoma (PGL) was the most common, followed by primary intestine lymphoma (PIL). The majority of PGIL were single lesion, which included 40 cases (87%) PGL and 35 cases (94.5%) PIL. The most frequent site of PGL was antrum of the stomach (43.5%), as to PIL, the small intestine (90.2%) was the most frequent site, especially within 100 cm far away from ileocecal valve. Most of PGIL were derived from B cell (93.1%). The most common pathological type was mucosa-associated lymphoid tissue (MALT) (67.4%) in the PGL group and diffuse large B cell lymphoma (DLBCL) (46.3%) in the PIL group. Surgical treatment had been performed in most of PGIL, which included 32 cases in the PGL group and 38 cases in the PIL group. The 1-year overall survival (OS) and the 3-year OS were 82 and 77%, respectively. Analysis of single factor affecting prognosis showed that lesion location, sources of cells, and clinical stage were associated with OS. PGL group had better OS than that of PIL group (1-year 89 vs 62%, 3-year 84 vs 50%, P = 0.03). B cell originated group had better OS than that of T cell-originated group (1-year 89 vs 36%, 3-year 85 vs 0 %, P = 0.008). Stage I + II group had better OS than that of stage III + IV group (1-year 89 vs 38%, 3-year 87 vs 0 %, P = 0.007). Multivariate analysis showed that clinical stage and sources of cells were the significant independent prognostic factors. CONCLUSIONS: It was more common to find location of PGIL in the stomach than that in the intestine. The most common pathological type was MALT in the PGL and DLBCL in the PIL. The treatment of PGL was focused on chemotherapy. It was noting that since PIL was not only difficult to make confirmed diagnosis but also likely to develop with complications, so it was usually needed surgical excision. Clinical stage and pathological pattern were related to prognosis of PGIL. PMID- 26988373 TI - Exploratory Analysis of Biological Networks through Visualization, Clustering, and Functional Annotation in Cytoscape. AB - Biological networks define how genes, proteins, and other cellular components interact with one another to carry out specific functions, providing a scaffold for understanding cellular organization. Although in-depth network analysis requires advanced mathematical and computational knowledge, a preliminary visual exploration of biological networks is accessible to anyone with basic computer skills. Visualization of biological networks is used primarily to examine network topology, identify functional modules, and predict gene functions based on gene connectivity within the network. Networks are excellent at providing a bird's-eye view of data sets and have the power of illustrating complex ideas in simple and intuitive terms. In addition, they enable exploratory analysis and generation of new hypotheses, which can then be tested using rigorous statistical and experimental tools. This protocol describes a simple procedure for visualizing a biological network using the genetic interaction similarity network for Saccharomyces cerevisiae as an example. The visualization procedure described here relies on the open-source network visualization software Cytoscape and includes detailed instructions on formatting and loading the data, clustering networks, and overlaying functional annotations. PMID- 26988372 TI - Evaluation of Ion Mobility-Mass Spectrometry for Comparative Analysis of Monoclonal Antibodies. AB - Analytical techniques capable of detecting changes in structure are necessary to monitor the quality of monoclonal antibody drug products. Ion mobility mass spectrometry offers an advanced mode of characterization of protein higher order structure. In this work, we evaluated the reproducibility of ion mobility mass spectrometry measurements and mobiligrams, as well as the suitability of this approach to differentiate between and/or characterize different monoclonal antibody drug products. Four mobiligram-derived metrics were identified to be reproducible across a multi-day window of analysis. These metrics were further applied to comparative studies of monoclonal antibody drug products representing different IgG subclasses, manufacturers, and lots. These comparisons resulted in some differences, based on the four metrics derived from ion mobility mass spectrometry mobiligrams. The use of collision-induced unfolding resulted in more observed differences. Use of summed charge state datasets and the analysis of metrics beyond drift time allowed for a more comprehensive comparative study between different monoclonal antibody drug products. Ion mobility mass spectrometry enabled detection of differences between monoclonal antibodies with the same target protein but different production techniques, as well as products with different targets. These differences were not always detectable by traditional collision cross section studies. Ion mobility mass spectrometry, and the added separation capability of collision-induced unfolding, was highly reproducible and remains a promising technique for advanced analytical characterization of protein therapeutics. Graphical Abstract ?. PMID- 26988375 TI - Why (not) disagree? Human values and the readiness to question experts' views. AB - Whether people blindly trust experts on all occasions or whether they evaluate experts' views and question them if necessary is a vital question. This study investigates associations of human values with the readiness to question experts' views and one's reasons for not disagreeing with experts among randomly sampled Finns. Readiness to question experts' views and one's reasons for not disagreeing were inferred from self-reported written accounts. Value priorities were measured with Schwartz et al.'s Portrait Values Questionnaire and Wach and Hammer's items concerning rational and non-rational truth. The results showed that after adjusting for the effects of age, sex and education, the values of power and rational truth were positively associated, whereas the values of security, conformity and tradition were negatively associated with readiness to question experts' views. Furthermore, the analysis indicated that the reasons for not disagreeing with experts were related to individual factors, situational factors, social risks and views about experts. PMID- 26988374 TI - Predicting the growth of nanoscale nuclei by histotripsy pulses. AB - Histotripsy is a focused ultrasound therapy that ablates tissue through the mechanical action of cavitation. Histotripsy-initiated cavitation activity is generated from shocked ultrasound pulses that scatter from incidental nuclei (shock scattering histotripsy), or purely tensile ultrasound pulses (microtripsy). The Yang/Church model was numerically integrated to predict the behavior of the cavitation nuclei exposed to measured shock scattering histotripsy pulses. The bubble motion exhibited expansion only behavior, suggesting that the ablative action of a histotripsy pulse is related to the maximum size of the bubble. The analytic model of Holland and Apfel was extended to predict the maximum size of cavitation nuclei for both shock scattering histotripsy and microtripsy excitations. The predictions of the analytic model and the numerical model agree within 2% for fully developed shock scattering histotripsy pulses (>72 MPa peak positive pressure). For shock scattering histotripsy pulses that are not fully developed (<72 MPa), the analytic model underestimated the maximum size by less than 5%. The analytic model was also used to predict bubble growth nucleated from microtripsy insonations, and was found to be consistent with experimental observations. Based on the extended analytic model, metrics were developed to predict the extent of the treatment zone from histotripsy pulses. PMID- 26988376 TI - An efficient dual-loaded multifunctional nanocarrier for combined photothermal and photodynamic therapy based on copper sulfide and chlorin e6. AB - The therapeutic effectiveness of photodynamic therapy (PDT) was hampered by the poor water solubility and instability in physiological conditions of the photosensitizers. Here, we designed folate conjugated thermosensitive liposomes (TSL) as the nanocarrier to improve the solubility, stability and biocompatibility of photosensitizer Chlorin e6 (Ce6). Based on the photothermal effect, we combined copper sulfide (CuS) as the photothermal agent to realize heat-triggered Ce6 release as well as synergistic effect of photothermal and photodynamic therapy. In vitro MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) assay showed that Ce6-CuS-TSL had low dark toxicity, while performed excellent phototoxicity under the combined 660 and 808 nm laser irradiation compared to any single laser irradiation alone. Moreover, in vivo combination therapy study revealed that Ce6-CuS-TSL inhibited tumor growth to a great extent without evident side effect under the laser irradiation. All detailed evidence demonstrated a considerable potential of Ce6-CuS-TSL for synergistic cancer treatment. PMID- 26988378 TI - Impact on Hip Fracture Mortality After the Establishment of an Orthogeriatric Care Program in a Colombian Hospital. AB - OBJECTIVE: The aim of this study is to evaluate mortality and survival rates of patients aged 65 years or older who sustained a hip fracture and were treated at a hospital in Bogota, Colombia, after the establishment of an Orthogeriatric Program. METHOD: In total, 298 patients were treated according to the program's protocol. The primary outcome was 1-year mortality. Mortality predictors were estimated using Cox proportional hazards model, and survival was measured with Kaplan-Meier analysis. RESULTS: The annual survival rate increased from 80% to 89% ( p = .039) 4 years after its implementation. There was a significant decrease in mortality risk (Hazard Ratio = 0.54, p = .049). Arrhythmia, valvular heart disease, history of myocardial infarction, and age greater than 85 years were predictors of mortality. DISCUSSION: This is the first study in Latin America to show decreased mortality rates 1 year after the implementation of an Orthogeriatric Program. Our rates were lower than developed countries, suggesting the existence of additional factors that influence long-term outcomes. PMID- 26988377 TI - Cold stress improves the production of artemisinin depending on the increase in endogenous jasmonate. AB - Previous publications reported that the artemisinin level was increased in Artemisia annua following a night-frost period. However, the molecular mechanism was not clear. In this study, we found that exogenous jasmonate (JA) effectively enhanced the freezing tolerance of A. annua. The JA biosynthetic genes (LOX1, LOX2, allene oxide cyclase [AOC], and jasmonate resistant 1 [JAR1]) were induced by cold stress, leading to an increase in endogenous JA in cold-treated A. annua. Increased endogenous JA enhanced the expression of three JA-responsive transcription factors, ethylene response factor 1, ethylene response factor 2, and octadecanoid-responsive AP2/ERF, all of which were reported to transcriptionally activate the expression of artemisinin biosynthetic genes, such as amorpha-4,11-diene synthase (ADS), CYP71AV1, DBR2, and aldehyde dehydrogenase 1 (ALDH1). Furthermore, the expression levels of the four artemisinin biosynthetic genes were also significantly increased under cold stress. Consequently, the levels of artemisinin and related secondary metabolites, such as dihydroartemisinic acid, artemisinin B, and artemisinic acid, were increased in A. annua under cold stress. Our study points to a molecular mechanism in which the production of artemisinin is regulated by cold stress in A. annua. PMID- 26988379 TI - Extended detection time to reduce shocks is safe in secondary prevention patients: The secondary prevention substudy of PainFree SST. AB - BACKGROUND: Prolonged ventricular fibrillation (VF) detection has been shown to reduce implantable cardioverter-defibrillator (ICD) therapies and improve prognosis in primary prevention ICD patients. Data in secondary prevention patients are limited. OBJECTIVE: The PainFree SST secondary prevention study is the largest trial of secondary prevention patients randomized between standard and prolonged detection to assess the safety of this strategy in these patients. METHODS: A total of 705 secondary prevention patients implanted with an ICD in the PainFree SST trial were enrolled in this substudy; 353 patients were randomized to VF detection of 18/24 intervals and 352 patients to 30/40. All other VF parameters were standardized by protocol. RESULTS: The 1-year arrhythmic syncope-free rates in the standard and prolonged groups were 97.7% vs 96.9%, respectively, (P = .0034 for noninferiority). Freedom from all-cause syncope was 96% in both arms (P = .0013 for noninferiority). There was no difference in the time to first appropriate or inappropriate VF therapy. However, the rates of treated VF episodes were lower in the prolonged arm (1.48 per patient per year vs 0.44 per patient per year, P = .0001). A trend toward lower mortality in the prolonged group was not statistically different (5.6% 1 year, 12% 2 years vs 3.8% 1 year, 7.7% 2 years, adjusted hazard ratio = 0.60, P = .061). CONCLUSION: This large prospective randomized study shows that prolonged detection can safely be programmed in secondary prevention ICD patients with new or existing devices. This programming strategy decreases the rate of treated events and is not associated with an increased risk of syncope or mortality. PMID- 26988380 TI - [Cosmetic nail products]. AB - Cosmetic embellishment of fingernails involves the use of substance that harden either after the evaporation of solvents (varnishes) or after polymerisation (artificial acrylic nails, gel tips, glue-on artificial nails). Pathological reactions to cosmetics usually occur at a remote site for varnishes, and, most commonly, in situ with polymerising substances. Unvarnished artificial nails do not affect pulse oximetry readings, and in theory, patients are not required to remove them. However, a real problem of contamination via artificial nails exists. Increased carriage of pathological Gram-negative organisms and of Staphylococcus aureus and yeasts has been noted among nursing staff wearing artificial nails, both before and after fingernail cleaning. Fingernail fragility manifests itself through a number of different physical signs such as soft, breaking nails, with longitudinal or transverse fissures, showing distal doubling or friability. In some subjects, excessive manicuring with metal instruments or manicure sticks results in rolled onycholysis, of evocative appearance, or transverse onycholysis. PMID- 26988381 TI - [Role of dermoscopy and reflectance confocal microscopy as an aid in the diagnosis of exogenous ochronosis]. PMID- 26988382 TI - [Bowel-associated dermatosis-arthritis syndrome during ulcerative colitis: A rare extra-intestinal sign of inflammatory bowel disease]. AB - INTRODUCTION: Bowel-associated dermatosis-arthritis syndrome (BADAS) is characterized by combined pustular skin eruption and arthralgia. It may be associated with inflammatory bowel disease or bowel bypass surgery. We report a case of BADAS in a patient with ulcerative colitis. CASE REPORT: A 39-year-old woman was being treated for a severe flare-up of ulcerative colitis present over the preceding 2 months and treated with prednisone, azathioprine and cyclosporine. She was also presenting a cutaneous eruption and arthralgia that had begun three days earlier. Dermatological examination revealed profuse vesicular and pustular lesions. Biopsy specimens showed mature neutrophilic infiltrate within the dermis. A diagnosis of BADAS was made and the same treatment was maintained. Systemic symptoms were resolved but the vesicular lesions were superseded by hypertrophic scars. DISCUSSION: Bowel-associated dermatosis-arthritis syndrome consists of a vesiculopustular eruption associated with arthralgia and/or arthritis and fever, as was the case in our patient. The histological picture is characterized by abundant neutrophilic infiltrate in the superficial dermis. The clinical and histological features and the course of BADAS allow this entity to be classified within the spectrum of neutrophilic dermatoses. Treatment chiefly involves systemic corticosteroids. PMID- 26988383 TI - [Livedo-like cutaneous sarcoidosis]. AB - BACKGROUND: The cutaneous signs of sarcoidosis are extremely polymorphous and may be classified under several different headings. PATIENTS AND METHODS: Herein, we report the case of a 51-year-old female patient presenting bilateral livedo of the knees accompanied by systemic signs with polyarthralgia, impaired general state of health, weight loss, and a sensation of dyspnoea. Skin biopsy revealed giant-cell granuloma around the dermal vessels, with no caseous necrosis. Histopathological examination of the patient's blood vessels revealed no abnormalities. Laboratory tests showed high levels of angiotensin converting enzyme (1.5*ULN), bilateral mediastinal adenomegaly and incipient pulmonary fibrosis. Systemic sarcoidosis was diagnosed on the basis of the overall clinical and laboratory picture. The patient subsequently presented hepatic involvement and hypercalcaemia associated with the sarcoidosis; systemic corticosteroid therapy (prednisone) was initiated, with slow dose-reduction. The outcome was favourable with a return to normal laboratory values, regression of the adenomegaly and subsidence of the livedo. DISCUSSION: The literature contains reports of a number of cases of livedo heralding sarcoidosis. The majority of such cases involved young or middle-aged female patients of Asian origin presenting systemic sarcoidosis, with a high frequency of ocular and neural involvement. Livedo could be accounted for by the specific disposition of granulomas around the arterioles, resulting in disturbance of local blood flow, which was probably associated with the mechanical compression of vessels and with the micro-thrombi noted at histology. CONCLUSION: Livedo may be considered a clinical sign of cutaneous sarcoidosis. Laboratory tests to screen for sarcoidosis may be proposed in the exploration of atypical livedo. PMID- 26988384 TI - [Surface membrane markers (clusters of differentiation) used in dermatopathology (2): Inflammatory infiltrates]. PMID- 26988385 TI - Valence fluctuation and magnetic ordering in EuNi2(P(1-x)Ge(x))2 single crystals. AB - Unusual phases and phase transitions are seen at the magnetic-nonmagnetic boundary in Ce-, Eu- and Yb-based compounds. EuNi2P2 is a very unusual valence fluctuating Eu system, because at low temperatures the Eu valence stays close to 2.5 instead of approaching an integer value. The Eu valence, and thus the magnetic property in this system, can be tuned by Ge substitution in the P site as EuNi2Ge2 is known to exhibit the antiferromagnetc (AFM) ordering of divalent Eu moments with T(N)=30K. We have grown EuNi2(P(1-x)Ge(x))2 (0.0<= x <=0.5)) single crystals and studied their magnetic, thermodynamic and transport properties. Increasing Ge doping to x > 0.4 results in a well-defined AFM ordered state with T(N)=12K for x = 0.5. Moreover, the reduced value of magnetic entropy for x = 0.5 at T(N) suggests the presence of valance fluctuation/the Kondo effect in this compound. Interestingly, the specific heat exhibits an enhanced Sommerfeld coefficient upon Ge doping. Subsequently, electronic structure calculations lead to a non-integral valence in EuNi2P2 but a stable divalent Eu state in EuNi2Ge2, which is in good agreement with the experimental results. PMID- 26988386 TI - Selection and outcome of the potential live liver donor. AB - BACKGROUND AND AIM: A thorough donor evaluation in the living donation process is mandatory to ensure a safe outcome in an otherwise healthy individual. The aim of the current study was to evaluate the reasons for not proceeding to donation and the outcome of live liver donors. METHODS: A prospective study of potential donors who underwent evaluation and proceeded to surgery from 1 April 2012 to 31 January 2015 was conducted. The process of donor selection, its outcome and peri operative complications were recorded. RESULTS: A total of 460 donors were evaluated in a stepwise manner for 367 potential recipients. Of the 321 (69.7 %) donors not proceeding to donation, the reasons were donor-related in 63.6 % and recipient-related in the rest. Common donor-related reasons were: donor reluctance (23.5 %), negative liver attenuation index (16.2 %), anatomic variations (10.3 %), inadequate remnant liver volume (9.8 %), unacceptable liver biopsy (8.8 %), and inadequate graft volume (5.4 %). A majority of donors (82.8 %) were turned down early in the (steps 1 and 2) evaluation process. Recipient death was the most common recipient-related reason [n = 51 (43.6 %)] for not proceeding to donation. There was no donor mortality. The overall complication rate was 19.8 % and major complication rate (grade 3 or higher) was 4.4 %. CONCLUSIONS: A stringent stepwise donor evaluation process leads to early recognition of unsuitable donors and a low complication rate. PMID- 26988387 TI - Seeking Synthesis: The Integrative Problem in Understanding Language and Its Evolution. AB - We discuss two problems for a general scientific understanding of language, sequences and synergies: how language is an intricately sequenced behavior and how language is manifested as a multidimensionally structured behavior. Though both are central in our understanding, we observe that the former tends to be studied more than the latter. We consider very general conditions that hold in human brain evolution and its computational implications, and identify multimodal and multiscale organization as two key characteristics of emerging cognitive function in our species. This suggests that human brains, and cognitive function specifically, became more adept at integrating diverse information sources and operating at multiple levels for linguistic performance. We argue that framing language evolution, learning, and use in terms of synergies suggests new research questions, and it may be a fruitful direction for new developments in theory and modeling of language as an integrated system. PMID- 26988388 TI - The Science of Salt: A Regularly Updated Systematic Review of the Implementation of Salt Reduction Interventions (June-October 2015). PMID- 26988389 TI - Antipsychotic use in dementia patients in a general practice setting: a Dutch population-based study. PMID- 26988390 TI - Origins and features of oil slicks in the Bohai Sea detected from satellite SAR images. AB - Oil slicks were detected using satellite Synthetic Aperture Radar (SAR) images in 2011. We investigated potential origins and regional and seasonal features of oil slick in the Bohai Sea. Distance between oil slicks and potential origins (ships, seaports, and oil exploitation platforms) and the angle at which oil slicks move relative to potential driving forces were evaluated. Most oil slicks were detected along main ship routes rather than around seaports and oil exploitation platforms. Few oil slicks were detected within 20km of seaports. Directions of oil slicks movement were much more strongly correlated with directions of ship routes than with directions of winds and currents. These findings support the premise that oil slicks in the Bohai Sea most likely originate from illegal disposal of oil-polluted wastes from ships. Seasonal variation of oil slicks followed an annual cycle, with a peak in August and a trough in December. PMID- 26988391 TI - Effects of emerging contaminants on neurotransmission and biotransformation in marine organisms - An in vitro approach. AB - The effects of gold (ionic form and nanoparticles - AuNPs) and pharmaceuticals (carbamazepine and fluoxetine) on enzymes involved in neurotransmission (acetylcholinesterase - AChE) and biotransformation (glutathione S-transferases - GST) were assessed by their incubation with Mytilus galloprovincialis' hemolymph and subcellular fraction of gills, respectively. AuNPs did not alter enzymatic activities unlike ionic gold that inhibited AChE and GST activities at 2.5 and 0.42mg.L(-1), respectively. Carbamazepine inhibited AChE activity at 500mg.L(-1) and fluoxetine at 1000mg.L(-1). GST was inhibited by carbamazepine at 250mg.L(-1) and by fluoxetine at 125mg.L(-1). Increased AChE activity was found in simultaneous exposures to fluoxetine and bovine serum albumin coated AuNPs (BSA AuNPs). Concerning GST, in the simultaneous exposures, AuNPs revealed protective effects against carbamazepine (citrate and polyvinylpyrrolidone coated) and fluoxetine (citrate and BSA coated) induced inhibition. However, BSA-AuNPs increased the inhibition caused by carbamazepine. AuNPs demonstrated ability to interfere with other chemicals toxicity justifying further studies. PMID- 26988392 TI - Chiral nematic self-assembly of minimally surface damaged chitin nanofibrils and its load bearing functions. AB - Chitin is one of the most abundant biomaterials in nature, with 10(10) tons produced annually as hierarchically organized nanofibril fillers to reinforce the exoskeletons of arthropods. This green and cheap biomaterial has attracted great attention due to its potential application to reinforce biomedical materials. Despite that, its practical use is limited since the extraction of chitin nanofibrils requires surface modification involving harsh chemical treatments, leading to difficulties in reproducing their natural prototypal hierarchical structure, i.e. chiral nematic phase. Here, we develop a chemical etching-free approach using calcium ions, called "natural way", to disintegrate the chitin nanofibrils while keeping the essential moiety for the self-assembly, ultimately resulting in the reproduction of chitin's natural chiral structure in a polymeric matrix. This chiral chitin nanostructure exceptionally toughens the composite. Our resultant chiral nematic phase of chitin materials can contribute to the understanding and use of the reinforcing strategy in nature. PMID- 26988393 TI - Fed-batch production and secretion of streptavidin by Hansenula polymorpha: Evaluation of genetic factors and bioprocess development. AB - Streptavidin - a protein secreted by the filamentous bacterium Streptomyces avidinii - is applied in a variety of methods, leading to numerous studies on its heterologous production. Development and characterization of a novel expression system for streptavidin genes by Hansenula polymorpha is described utilizing different target gene variants along with the two methanol-inducible promoters PMOX and PFMD. Extracellular product concentrations were higher for cultivation at 30 instead of 37 degrees C. The best performing strain carrying the full length streptavidin gene under control of PFMD was characterized in the bioreactor applying a synthetic medium and oxygen-controlled feeding of glucose. Derepression resulted in an extracellular concentration of 1.31+/-0.07MUM of tetrameric streptavidin after 48h (27.3nMh(-1)). Feeding of glycerol improved biomass formation, but lowered the product concentration. By combining derepression and methanol induction the final extracellular streptavidin concentration increased to 11.42+/-0.22MUM (approx. 751mgL(-1)), yielding a productivity of 52.5nMh(-1). Despite supplementing biotin the proportion of biotin-blocked binding sites in the supernatant dropped from 54.4+/-5.0 % after 18h to 17.2+/-6.5 % towards the end of glucose feeding to a final value of 1.1+/ 3.8 %, indicating a highly bioactive product. Thus, H. polymorpha proved to be a suitable host for the production of streptavidin. PMID- 26988394 TI - Complete genome sequence of Acinetobacter sp. TTH0-4, a cold-active crude oil degrading strain isolated from Qinghai-Tibet Plateau. AB - Acinetobacter sp. strain TTH0-4 was isolated from a permafrost region in Qinghai Tibet Plateau. With its capability to degrade crude oil at low temperature, 10 degrees C, the strain could be an excellent candidate for the bioremediation of crude oil pollution in cold areas or at cold seasons. We sequenced and annotated the whole genome to serve as a basis for further elucidation of the genetic background of this promising strain, and provide opportunities for investigating the metabolic and regulatory mechanisms and optimizing the biodegradative activity in cold environment. PMID- 26988395 TI - Complete genome of Martelella sp. AD-3, a moderately halophilic polycyclic aromatic hydrocarbons-degrading bacterium. AB - Martelella sp. strain AD-3, a moderate halophilic bacterium, was isolated from a petroleum-contaminated soil with high salinity in China. Here, we report the complete genome of strain AD-3, which contains one circular chromosome and two circular plasmids. An array of genes related to metabolism of polycyclic aromatic hydrocarbons and halophilic mechanism in this bacterium was identified by the whole genome analysis. PMID- 26988396 TI - Complete genome sequence of a bacterium Pseudomonas fragi P121, a strain with degradation of toxic compounds. AB - A newly isolated strain P121 was identified as Pseudomonas fragi. The complete genome sequence of P.fragi P121 was carried out using the PacBio RSII platform. The genome contains a circular chromosome with 5,101,809bp. The genome sequence suggests that the P121 exhibited the ability of degradation of toxic compounds. Genome sequencing information provides the genetic basis for the analysis of toxic compounds and the mechanism of extreme environmental adaptation of the strain. PMID- 26988397 TI - Complete genome sequence of 'Mycobacterium neoaurum' NRRL B-3805, an androstenedione (AD) producer for industrial biotransformation of sterols. AB - Microbial bioconversion of sterols into high value steroid precursors, such as 4 androstene-3,17-dione (AD), is an industrial challenge. Genes and enzymes involved in sterol degradation have been proposed, although the complete pathway is not yet known. The genome sequencing of the AD producer strain 'Mycobacterium neoaurum' NRRL B-3805 (formerly Mycobacterium sp. NRRL B-3805) will serve to elucidate the critical steps for industrial processes and will provide the basis for further genetic engineering. The genome comprises a circular chromosome (5 421 338bp), is devoid of plasmids and contains 4844 protein-coding genes. PMID- 26988398 TI - Synthesis, characterization, and mechanism analysis of S = 2 quasi-one dimensional ferromagnetic semiconductor Pb2Mn(VO4)2(OH). AB - A brackebuschite-type compound Pb2Mn(VO4)2(OH) was synthesized by a hydrothermal method. Single crystal X-ray diffraction reveals that Pb2Mn(VO4)2(OH) crystallizes in the space group P21/m, with the structure built of single [010] chains of edge-shared MnO6 octahedra bridged by VO4-PbO6 groups along a and c axes, as a result forming a very large inter-chain distance of about 7.67 A. The magnetic and optical measurements indicate that Pb2Mn(VO4)2(OH) is an S = 2 quasi one-dimensional ferromagnetic semiconductor, with a very small specific value of intra- and inter-chain exchange coupling Jintra/Jinter = 10(-3), and a band gap of 1.72 eV. The electronic structure calculations indicate that a 90 degrees Mn O-Mn dpsigma-dpsigma correlation superexchange dominates the intra-chain ferromagnetic coupling in Pb2Mn(VO4)2(OH). PMID- 26988399 TI - A new approach for fabrications of SiC based photodetectors. AB - We report on a new approach to quickly synthesize high-quality single crystalline wide band gap silicon carbide (SiC) films for development of high-performance deep ultraviolet (UV) photodetectors. The fabricated SiC based UV photodetectors exhibited high response while maintaining cost-effectiveness and size miniaturization. Focus of the experiments was on studies of electrical and electronic properties, as well as responsivity, response and recovery times, and repeatability of the deep UV photodetectors. Raman scattering spectroscopy and scanning electron microscope (SEM) were used to characterize the SiC materials. Analyses of the SEM data indicated that highly flat SiC thin films have been obtained. Based on the synthesized SiC, deep UV detectors are designed, fabricated, and tested with various UV wavelength lights at different radiation intensities. Temperature effect and bias effect on the photocurrent strength and signal-to-noise ratio, humidity effect on the response time and recovery time of the fabricated detectors have been carefully characterized and discussed. The detectors appear to have a very stable baseline and repeatability. The obtained responsivity is more than 40% higher compared to commercial detectors. The good performance of the photodetectors at operating temperature up to 300 degrees C remains nearly unchanged. PMID- 26988400 TI - Justifying the Gompertz curve of mortality via the generalized Polya process of shocks. AB - A new probabilistic model of aging that can be applied to organisms is suggested and analyzed. Organisms are subject to shocks that follow the generalized Polya process (GPP), which has been recently introduced and characterized in the literature. Distinct from the nonhomogeneous Poisson process that has been widely used in applications, the important feature of this process is the dependence of its future behavior on the number of previous events (shocks). The corresponding survival and the mortality rate functions are derived and analyzed. The general approach is used for justification of the Gompertz law of human mortality. PMID- 26988402 TI - More for less: Improving the biomass yield of a pear cell suspension culture by design of experiments. AB - Plant cell suspension cultures are widely used for the production of recombinant proteins and secondary metabolites. One of the most important steps during process development is the optimization of yields by testing different cultivation parameters, including the components of the growth medium. However, we have shown that the biomass yield of a cell suspension culture derived from the pear cultivar Pyrus communis cv. Champagner Bratbirne can be significantly improved solely by varying the temperature, inoculum density, illumination, and incubation time. In contrast to medium optimization, these simple physical factors are easily controlled and varied, thereby reducing the effort required. Using an experimental design approach, we improved the biomass yield from 146 g fresh weight (FW)/L to 407 g FW/L in only 5 weeks, simultaneously reducing the costs of goods sold per kg biomass from ? 125 to ? 45. Our simple approach therefore offers a rapid, efficient and economical process for the optimization of plant cell suspension cultures. PMID- 26988401 TI - Efficacy and safety of tenofovir, entecavir, and telbivudine for chronic hepatitis B in heart transplant recipients. AB - BACKGROUND: Treatment of chronic hepatitis B (CHB) with polymerase inhibitors is key to prevent disease flares and progression toward advanced liver disease. Efficacy and tolerability of newer agents has been reported anecdotally in transplant recipients. METHODS: In this prospective, observational study, we assessed outcomes of therapy with tenofovir (TDF), entecavir (ETV), and telbivudine (LdT) in 13 heart transplant recipients (HTR) with CHB. RESULTS: Most patients were hepatitis B e antigen negative, had low baseline hepatitis B virus (HBV) DNA, and normal aminotransferases. Liver biopsy showed a median fibrosis score of 1.5 (range 0-4). Glomerular filtration rate (GFR) was <50 mL/min in 7 patients (54%). Two patients were started on de novo ETV before transplant. Eleven previously treated patients were switched to TDF (n = 9) or LdT (n = 2). Median treatment duration was 33 months (range 1-71). HBV DNA remained suppressed in 6 patients and became undetectable in 5. Aminotransferases went down to the normal range in all patients, with a single flare in 1 patient. One patient lost hepatitis B surface antigen. No cases occurred of hepatic decompensation, hepatocellular carcinoma, or liver-related death. The GFR remained largely stable, and no cases of TDF-related hyper-phosphaturia were observed. CONCLUSIONS: This study indicates that newer antivirals are effective and safe in HTR with CHB. PMID- 26988403 TI - Pectin nanocoating of titanium implant surfaces - an experimental study in rabbits. AB - INTRODUCTION: A major determinant of successful osseointegration of endosseous implants is the surface of the implant, which influences the cellular response of the surrounding tissues. A new strategy to improve osseointegration and bone healing is biochemical stimulation by surface nanocoatings that may increase adhesion of bone proteins, and bone cells at the implant surface. Nanocoating with pectins, plant cell wall-derived polysaccharides, is frequently done using rhamnogalacturonan-I (RG-I). AIM: The aim of the study was to evaluate the effect of nanocoating titanium implants with plant cell wall-derived rhamnogalacturonan I, on bone healing and osseointegration. MATERIAL AND METHODS: Machined titanium implants were coated with three modifications of rhamnogalacturonan-I (RG-I). Chemical and physical surface properties were examined before insertion of nanocoated implants (n = 96) into the left and right tibia of rabbits. Machined titanium implants without RG-I nanocoating were used as controls (n = 32). Total number of 128 implants was placed in tibias of 16 rabbits. Fluorochrome bone labels, calcein green and alizarin red S were given intravenously after 9 and 12 days, respectively. The bone response to the nanocoated implants was analyzed qualitatively and quantitatively after 2, 4, 6, and 8 weeks of healing using light microscopy and histomorphometric methods. RESULTS: The RG-I coating influenced the surface chemical composition; wettability and roughness, making the surface more hydrophilic without any major effect on surface micro roughness compared to control implant surfaces. The different modifications of pectin RG-I did not significantly enhance bone healing and osseointegration analyzed after 2, 4, 6, and 8 weeks of healing compared to control implants. Although the qualitative analyses of the fluorochromes indicated a higher activity of bone formation in the mineralization front at the early stage, after 9 and 12 days at the RG-I nanocoated implants compared to the control implants although no significant quantitative difference was demonstrated. CONCLUSION: The present study showed that nanocoating of titanium implants with pectin RG-Is did not significantly enhance bone healing and osseointegration when placed in rabbit tibia bone. PMID- 26988404 TI - Psychometric Properties of a Structured Diagnostic Interview for DSM-5 Anxiety, Mood, and Obsessive-Compulsive and Related Disorders. AB - Three hundred sixty-two adult patients were administered the Diagnostic Interview for Anxiety, Mood, and OCD and Related Neuropsychiatric Disorders (DIAMOND). Of these, 121 provided interrater reliability data, and 115 provided test-retest reliability data. Participants also completed a battery of self-report measures that assess symptoms of anxiety, mood, and obsessive-compulsive and related disorders. Interrater reliability of DIAMOND anxiety, mood, and obsessive compulsive and related diagnoses ranged from very good to excellent. Test-retest reliability of DIAMOND diagnoses ranged from good to excellent. Convergent validity was established by significant between-group comparisons on applicable self-report measures for nearly all diagnoses. The results of the present study indicate that the DIAMOND is a promising semistructured diagnostic interview for DSM-5 disorders. PMID- 26988405 TI - On Measuring the Sixth Basic Personality Dimension: A Comparison Between HEXACO Honesty-Humility and Big Six Honesty-Propriety. AB - Recent developments in personality research led to the proposition of two alternative six-factor trait models, the HEXACO model and the Big Six model. However, given the lack of direct comparisons, it is unclear whether the HEXACO and Big Six factors are distinct or essentially equivalent, that is, whether corresponding inventories measure similar or distinct personality traits. Using Structural Equation Modeling (Study 1), we found substantial differences between the traits as measured via the HEXACO-60 and the 30-item Questionnaire Big Six (30QB6), particularly for Honesty-Humility and Honesty-Propriety (both model's critical difference to the Big Five approach). This distinction was further supported by Study 2, showing differential capabilities of the HEXACO-60 and the 30QB6 to account for several criteria representing the theoretical core of Honesty-Humility and/or Honesty-Propriety. Specifically, unlike the indicator of Honesty-Humility, the indicator of Honesty-Propriety showed low predictive power for some conceptually relevant criteria, suggesting a limited validity of the 30QB6. PMID- 26988406 TI - Psychopathy in a Multiethnic World: Investigating Multiple Measures of Psychopathy in Hispanic, African American, and Caucasian Offenders. AB - Despite the forensic relevance of psychopathy and the overrepresentation of Hispanics in the United States' criminal justice system, these two issues remain underexplored, particularly with self-report measures of psychopathy. We investigated the criterion validity of three psychopathy measures among African Americans, Caucasians, and Hispanics in a sample of 1,742 offenders. More similarity than dissimilarity emerged across groups. The factor structures of psychopathy measures among Hispanic offenders were consistent with previous findings. Few significant differences emerged between Hispanic and Caucasian offenders, with most differences emerging between African Americans and the other ethnic groups. In such instances, the correlates of psychopathy were typically weaker for African Americans. The Psychopathy Checklist-Revised yielded fewer psychopathy * ethnicity interactions than the Psychopathic Personality Inventory and Levenson Primary and Secondary Psychopathy Scales. Overall, these psychopathy measures showed reasonable validity across these cultural groups. PMID- 26988408 TI - Assessing interrater agreement on binary measurements via intraclass odds ratio. AB - Interrater agreement on binary measurements is usually assessed via Scott's pi or Cohen's kappa, which are known to be difficult to interpret. One reason for this difficulty is that these coefficients can be defined as a correlation between two exchangeable measurements made on the same subject, that is as an "intraclass correlation", a concept originally defined for continuous measurements. To measure an association between two binary variables, it is however more common to calculate an odds ratio rather than a correlation. For assessing interrater agreement on binary measurements, we suggest thus to calculate the odds ratio between two exchangeable measurements made on the same subject, yielding the concept of "intraclass odds ratio". Since it is interpretable as a ratio of probabilities of (strict) concordance and discordance (between two raters rating two subjects), an intraclass odds ratio might be easier to understand for researchers and clinicians than an intraclass correlation. It might thus be a valuable descriptive measure (summary index) to evaluate the agreement among a set of raters, without having to refer to arbitrary benchmark values. To facilitate its use, an explicit formula to calculate a confidence interval for the intraclass odds ratio is also provided. PMID- 26988409 TI - Verification of the isotopic composition of precipitation simulated by a regional isotope circulation model over Japan. AB - The isotopic composition (delta(18)O and delta(2)H) of precipitation simulated by a regional isotope circulation model with a horizontal resolution of 10, 30 and 50 km was compared with observations at 56 sites over Japan in 2013. All simulations produced reasonable spatio-temporal variations in delta(18)O in precipitation over Japan, except in January. In January, simulated delta(18)O values in precipitation were higher than observed values on the Pacific side of Japan, especially during an explosively developing extratropical cyclone event. This caused a parameterisation of precipitation formulation about the large fraction of precipitated water to liquid detrained water in the lower troposphere. As a result, most water vapour that transported from the Sea of Japan precipitated on the Sea of Japan side. The isotopic composition of precipitation was a useful verification tool for the parameterisation of precipitation formulation as well as large-scale moisture transport processes in the regional isotope circulation model. PMID- 26988407 TI - Chronic lymphocytic leukemia therapy: new targeted therapies on the way. AB - INTRODUCTION: The critical role of the tissue microenvironment and B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) pathogenesis, and the clinical success of targeted agents that disrupt BCR signaling are currently changing the CLL landscape. Three new drugs were recently approved for CLL therapy, and other agents are in late development. AREAS COVERED: In this review, we summarize data on promising new targeted drugs for CLL. The heterogeneous mechanisms of actions of these molecules are described, such as the inhibition of BCR signaling, direct targeting of CD20 molecules on the CLL cell surface, and BCL-2 inhibition. We present preclinical and clinical data from phase I to III studies in order to describe efficacy and side effect profile of these new drugs. Data are derived from peer-reviewed articles indexed in PubMed and from abstracts presented at major international meetings. EXPERT OPINION: Ibrutinib and idelalisib are challenging the role of chemo-immunotherapy in CLL therapy in the frontline and relapsed disease settings. High-risk CLL patients particularly benefit from these new agents. Venetoclax and obinutuzumab are other effective agents added to our therapeutic armamentarium. Studies to better define the optimal use of these drugs, alone, or rather in combination or sequenced are underway. PMID- 26988410 TI - Use of the PD-1 Pathway Inhibitor Nivolumab in a Renal Transplant Patient With Malignancy. PMID- 26988412 TI - Genetic divergence in the common bush-tanager Chlorospingus ophthalmicus (Aves: Emberizidae) throughout Mexican cloud forests: The role of geography, ecology and Pleistocene climatic fluctuations. AB - By integrating mitochondrial DNA (mtDNA), microsatellites and ecological niche modelling (ENM), we investigated the phylogeography of Mexican populations of the common bush-tanager Chlorospingus ophthalmicus to examine the relative role of geographical and ecological features, as well as Pleistocene climatic oscillations in driving the diversification. We sequenced mtDNA of individuals collected throughout the species range in Mexico and genotyped them at seven microsatellite loci. Phylogeographic, population genetics and coalescent methods were used to assess patterns of genetic structure, gene flow and demographic history. ENM was used to infer contractions and expansions at different time periods as well as differences in climatic conditions among lineages. The retrieved mitochondrial and microsatellite groups correspond with the fragmented cloud forest distribution in mountain ranges and morphotectonic provinces. Differing climatic conditions between mountain ranges were detected, and palaeodistribution modelling as well as demographic history analyses, indicated recent population expansions throughout the Sierra Madre Oriental (SMO). The marked genetic structure of C. ophthalmicus was promoted by the presence of ecological and geographical barriers that restricted the movement of individuals among mountain ranges. The SMO was mainly affected by Pleistocene climatic oscillations, with the moist forests model best fitting the displayed genetic patterns of populations in this mountain range. PMID- 26988413 TI - Phylogenetic systematics and a revised generic classification of anthidiine bees (Hymenoptera: Megachilidae). AB - The bee tribe Anthidiini (Hymenoptera: Megachilidae) is a large, cosmopolitan group of solitary bees that exhibit intriguing nesting behavior. We present the first molecular-based phylogenetic analysis of relationships within Anthidiini using model-based methods and a large, multi-locus dataset (five nuclear genes, 5081 base pairs), as well as a combined analysis using our molecular dataset in conjunction with a previously published morphological matrix. We discuss the evolution of nesting behavior in Anthidiini and the relationship between nesting material and female mandibular morphology. Following an examination of the morphological characters historically used to recognize anthidiine genera, we recommend the use of a molecular-based phylogenetic backbone to define taxonomic groups prior to the assignment of diagnostic morphological characters for these groups. Finally, our results reveal the paraphyly of numerous genera and have significant consequences for anthidiine classification. In order to promote a classification system based on stable, monophyletic clades, we hereby make the following changes to Michener's (2007) classification: The subgenera Afranthidium (Zosteranthidium) Michener and Griswold, 1994, Afranthidium (Branthidium) Pasteels, 1969 and Afranthidium (Immanthidium) Pasteels, 1969 are moved into the genus Pseudoanthidium, thus forming the new combinations Pseudoanthidium (Zosteranthidium), Pseudoanthidium (Branthidium), and Pseudoanthidium (Immanthidium). The genus Neanthidium Pasteels, 1969 is also moved into the genus Pseudoanthidium, thus forming the new combination Pseudoanthidium (Neanthidium). Based on morphological characters shared with our new definition of the genus Pseudoanthidium, the subgenus Afranthidium (Mesanthidiellum) Pasteels, 1969 and the genus Gnathanthidium Pasteels, 1969 are also moved into the genus Pseudoanthidium, thus forming the new combinations Pseudoanthidium (Mesanthidiellum) and Pseudoanthidium (Gnathanthidium). PMID- 26988414 TI - Virus classification in 60-dimensional protein space. AB - Due to vast sequence divergence among different viral groups, sequence alignment is not directly applicable to genome-wide comparative analysis of viruses. More and more attention has been paid to alignment-free methods for whole genome comparison and phylogenetic tree reconstruction. Among alignment-free methods, the recently proposed "Natural Vector (NV) representation" has successfully been used to study the phylogeny of multi-segmented viruses based on a 12-dimensional genome space derived from the nucleotide sequence structure. But the preference of proteomes over genomes for the determination of viral phylogeny was not deeply investigated. As the translated products of genes, proteins directly form the shape of viral structure and are vital for all metabolic pathways. In this study, using the NV representation of a protein sequence along with the Hausdorff distance suitable to compare point sets, we construct a 60-dimensional protein space to analyze the evolutionary relationships of 4021 viruses by whole proteomes in the current NCBI Reference Sequence Database (RefSeq). We also take advantage of the previously developed natural graphical representation to recover viral phylogeny. Our results demonstrate that the proposed method is efficient and accurate for classifying viruses. The accuracy rates of our predictions such as for Baltimore II viruses are as high as 95.9% for family labels, 95.7% for subfamily labels and 96.5% for genus labels. Finally, we discover that proteomes lead to better viral classification when reliable protein sequences are abundant. In other cases, the accuracy rates using proteomes are still comparable to that of genomes. PMID- 26988411 TI - Pursuit of a perfect insulin. AB - Insulin remains indispensable in the treatment of diabetes, but its use is hampered by its narrow therapeutic index. Although advances in peptide chemistry and recombinant DNA-based macromolecule synthesis have enabled the synthesis of structurally optimized insulin analogues, the growing epidemics of obesity and diabetes have emphasized the need for diabetes therapies that are more efficacious, safe and convenient. Accordingly, a broad set of drug candidates, targeting hyperglycaemia plus other disease abnormalities, is now progressing through the clinic. The development of an insulin therapy that is responsive to glucose concentration remains an ultimate goal, with initial prototypes now reaching the proof-of-concept stage. Simultaneously, the first alternatives to injectable delivery have progressed to registration. PMID- 26988415 TI - Phylogenetic relationships of Darwin's "Mr. Arthrobalanus": The burrowing barnacles (Cirripedia: Acrothoracica). AB - The barnacles of the superorder Acrothoracica are small, burrowing, epibiotic, and dioecious (large female with dwarf male) crustaceans largely found in the carbonate sediments and skeletons of marine invertebrates. The acrothoracicans represent the Cirripedia with the most plesiomorphic characters and have prominently featured in phylogenetic speculations concerning these crustaceans. Traditionally, Acrothoracica was divided into two main orders, Pygophora and Apygophora. The Apygophora had uniramus cirri and no anus. The Pygophora had biramus terminal cirri and an anus and was further divided into two families, Lithoglyptidae and Cryptophialidae. Kolbasov (2009) revised the superorder Acrothoracica on the basis of morphological examinations of females, dwarf males, and cyprids and rearranged the acrothoracican species into two new orders, Lithoglyptida and Cryptophialida. The present study is the first attempt to reconstruct the phylogenetic relationships of acrothoracican barnacles by sequencing two mitochondrial (cytochrome C oxidase I and 16S ribosomal DNA) and two nuclear (18S ribosomal DNA and histone H3) markers of 8 of the 11 genera comprising 23 acrothoracican species. All monophylies of the eight acrothoracican genera sampled in this study were strongly supported. The deep interfamilial relationship constructed is consistent with the recent morphological phylogenetic relationship proposed by Kolbasov, Newman, and Hoeg (Kolbasov, 2009) that Cryptophialidae (order Cryptophialida) is the sister group to all other acrothoracicans (order Lithoglyptida). According to an ancestral character state reconstruction analysis, the posterior lobes of females; armament of opercular bars, attachment stalk, lateral projections of the body, and aperture slits in dwarf males; and habitat use appear to have phylogenetic importance. PMID- 26988416 TI - Scandinavian clinical practice guideline on fluid and drug therapy in adults with acute respiratory distress syndrome. AB - BACKGROUND: The objective of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI) task force on fluid and drug therapy in adults with acute respiratory distress syndrome (ARDS) was to provide clinically relevant, evidence-based treatment recommendations according to standards for trustworthy guidelines. METHODS: The guideline was developed according to standards for trustworthy guidelines, including a systematic review of the literature and use of the GRADE methodology for assessment of the quality of evidence and for moving from evidence to recommendations. RESULTS: A total of seven ARDS interventions were assessed. We suggest fluid restriction in patients with ARDS (weak recommendation, moderate quality evidence). Also, we suggest early use of neuromuscular blocking agents (NMBAs) in patients with severe ARDS (weak recommendation, moderate quality evidence). We recommend against the routine use of other drugs, including corticosteroids, beta2 agonists, statins, and inhaled nitric oxide (iNO) or prostanoids in adults with ARDS (strong recommendations: low- to high-quality evidence). These recommendations do not preclude the use of any drug or combination of drugs targeting underlying or co existing disorders. CONCLUSION: This guideline emphasizes the paucity of evidence of benefit - and potential for harm - of common interventions in adults with ARDS and highlights the need for prudence when considering use of non-licensed interventions in this patient population. PMID- 26988417 TI - Is Pre-Operative Axillary Staging with Ultrasound and Ultrasound-Guided Fine Needle Aspiration Reliable in Invasive Lobular Carcinoma of the Breast? AB - Axillary ultrasound (US) with US-guided fine-needle aspiration (US-FNA) for suspicious lymph nodes is important for pre-operative staging and planning of surgical management. Invasive lobular carcinoma (ILC) metastases were previously thought to be difficult to detect, but with a limited amount of evidence. This study investigated the ability of US and US-FNA to detect ILC metastases by assessing 142 patients with ILC. The sensitivity of US in detection of metastasis was 52.3%, and US was able to exclude 96% of N2 and N3 axillary metastases. The false-negative rate of US-FNA in detection of metastasis for suspicious lymph nodes on US was 34.8%, and lymph nodes with longer maximal dimensions were associated with false-negative US-FNA results. Multiplicity of breast lesions and maximal cortical thickness >=3.1 mm of lymph nodes were independently associated with metastasis. Although pre-operative US in ILC can reliably exclude advanced axillary nodal disease, US-FNA results should be carefully interpreted. PMID- 26988420 TI - Response to "Antihypertensive Drug-Related Side Effects: Is it the Unique Indicator for Nonadherence?". PMID- 26988418 TI - The proper connection between shelterin components is required for telomeric heterochromatin assembly. AB - Telomeric regions contain prominent sites of heterochromatin, which is associated with unique histone modification profiles such as the methylation of histone H3 at Lys9 (H3K9me). In fission yeast, the conserved telomeric shelterin complex recruits the histone H3K9 methyltransferase complex CLRC to establish subtelomeric heterochromatin. Although many shelterin mutations affect subtelomeric heterochromatin assembly, the mechanism remains elusive due to the diverse functions of shelterin. Through affinity purification, we found that shelterin directly associates with CLRC through the Ccq1 subunit. Surprisingly, mutations that disrupt interactions between shelterin subunits compromise subtelomeric heterochromatin without affecting CLRC interaction with shelterin component Pot1, located at chromosome ends. We further discovered that telomeric repeats are refractory to heterochromatin spreading and that artificial restoration of shelterin connections or increased heterochromatin spreading rescued heterochromatin defects in these shelterin mutants. Thus, subtelomeric heterochromatin assembly requires both the recruitment of CLRC by shelterin to chromosome ends and the proper connection of shelterin components, which allows CLRC to skip telomeric repeats to internal regions. PMID- 26988421 TI - Antihypertensive Drug-Related Side Effects: Is It the Unique Indicator for Nonadherence? PMID- 26988419 TI - Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is a lethal form of cancer with few therapeutic options. We found that levels of the lysine methyltransferase SMYD2 (SET and MYND domain 2) are elevated in PDAC and that genetic and pharmacological inhibition of SMYD2 restricts PDAC growth. We further identified the stress response kinase MAPKAPK3 (MK3) as a new physiologic substrate of SMYD2 in PDAC cells. Inhibition of MAPKAPK3 impedes PDAC growth, identifying a potential new kinase target in PDAC. Finally, we show that inhibition of SMYD2 cooperates with standard chemotherapy to treat PDAC cells and tumors. These findings uncover a pivotal role for SMYD2 in promoting pancreatic cancer. PMID- 26988422 TI - A microfluidic Transwell to study chemotaxis. AB - Chemotaxis is typically studied in vitro using commercially available products such as the Transwell(r) in which cells migrate through a porous membrane in response to one or more clearly defined chemotactic stimuli. Despite its widespread use, the Transwell assay suffers from being largely an endpoint assay, with built-in errors due to inconsistent pore size and human sampling. In this study, we report a microfluidic chemotactic chip that provides real-time monitoring, consistent paths for cell migration, and easy on-chip staining for quantifying migration. To compare its performance with that of a traditional Transwell chamber, we investigate the chemotactic response of MDA-MB-231 1833 metastatic breast cancer cells to epidermal growth factor (EGF). The results show that while both platforms were able to detect a chemotactic response, we observed a dose-dependent response of breast cancer cells towards EGF with low non specific migration using the microfluidic platform, whereas we observed a dose independent response of breast cancer cells towards EGF with high levels of non specific migration using the commercially available Transwell.The microfluidic platform also allowed EGF-dependent chemotactic responses to be observed 24h, a substantially longer window than seen with the Transwell. Thus the performance of our microfluidic platform revealed phenomena that were not detected in the Transwell under the conditions tested. PMID- 26988424 TI - From Rhetoric to Reality: Commentary on Flynn & Brown (2016). PMID- 26988425 TI - Origin of the mysterious Yin-Shang bronzes in China indicated by lead isotopes. AB - Fine Yin-Shang bronzes containing lead with puzzlingly highly radiogenic isotopic compositions appeared suddenly in the alluvial plain of the Yellow River around 1400 BC. The Tongkuangyu copper deposit in central China is known to have lead isotopic compositions even more radiogenic and scattered than those of the Yin Shang bronzes. Most of the Yin-Shang bronzes are tin-copper alloys with high lead contents. The low lead and tin concentrations, together with the less radiogenic lead isotopes of bronzes in an ancient smelting site nearby, however, exclude Tongkuangyu as the sole supplier of the Yin-Shang bronzes. Interestingly, tin ingots/prills and bronzes found in Africa also have highly radiogenic lead isotopes, but it remains mysterious as to how such African bronzes may have been transported to China. Nevertheless, these African bronzes are the only bronzes outside China so far reported that have lead isotopes similar to those of the Yin Shang bronzes. All these radiogenic lead isotopes plot along ~2.0-2.5 Ga isochron lines, implying that deposits around Archean cratons are the most likely candidates for the sources. African cratons along the Nile and even micro-cratons in the Sahara desert may have similar lead signatures. These places were probably accessible by ancient civilizations, and thus are the most favorable suppliers of the bronzes. PMID- 26988423 TI - Hepatitis C Virus Testing and Treatment Among Persons Receiving Buprenorphine in an Office-Based Program for Opioid Use Disorders. AB - AIMS: In the United States, hepatitis C virus (HCV) infection is primarily spread through injection drug use. There is an urgent need to improve access to care for HCV among persons with opioid use disorders who inject drugs. The purpose of our study was to determine the prevalence of HCV, patient characteristics, and receipt of appropriate care in a sample of patients treated with buprenorphine for their opioid use disorders in a primary care setting. METHODS: This study used retrospective clinical data from the electronic medical record. The study population included patients receiving buprenorphine in the Office Based Opioid Treatment (OBOT) clinic within the adult primary medicine clinic at Boston Medical Center between October 2003 and August 2013 who received a conclusive HCV antibody (Ab) test within a year of clinic entry. We compared characteristics by HCV serostatus using Pearson's chi-square and provided numbers/percentages receiving appropriate care. RESULTS: The sample comprised 700 patients. Slightly less than half of all patients (n=334, 47.7%) were HCV Ab positive, and were significantly more likely to be older, Hispanic or African American, have diagnoses of post-traumatic stress disorder (PTSD) or bipolar disorder, have prior heroin or cocaine use, and be HIV-infected. Among the 334 HCV Ab positive patients, 226 (67.7%) had detectable HCV ribonucleic acid (RNA) indicating chronic HCV infection; only 5 patients (2.21%) with chronic HCV infection ever initiated treatment. CONCLUSIONS: Nearly half of patients (47.7%) receiving office-based treatment with buprenorphine for their opioid use disorder had a positive hepatitis C virus antibody screening test although initiation of HCV treatment was nearly non-existent (2.21%). PMID- 26988429 TI - Traditional Chinese medicine in the UK in the past forty years: an interview with Professor Bo-ying Ma. PMID- 26988428 TI - The phenotypical core of Alzheimer's disease-related and nonrelated variants of the corticobasal syndrome: A systematic clinical, neuropsychological, imaging, and biomarker study. AB - INTRODUCTION: The corticobasal syndrome (CBS) constitutes a neurodegenerative disease spectrum with substantial phenotypical or biological heterogeneity, requiring large or multimodal studies to identify its clinico-biological signature while disentangling Alzheimer's disease (AD)-related from non-AD related CBS. METHODS: We analyzed a large (N = 45) monocenter expert-clinic CBS cohort, recruited in motor and/or cognitive units to avoid recruitment biases, assessed with standardized motor and/or cognitive-language tests, brain perfusion imaging, and cerebrospinal fluid biomarkers. RESULTS: CBS mainly manifests as a motor and/or language disorder incorporating a "mixed progressive aphasia" phenotype, consistent with left-lateralized damage to frontal-parietal-temporal cortices. Biomarker expression indicates in 18% underlying AD causing predominant parietal-temporal damage and Gerstmann syndrome (sensitivity 75%; specificity 75%), whereas non-AD-CBS presented with predominant prefrontal and lexical semantic impairment. DISCUSSION: CBS is primarily a "motor-plus-aphasia" disease unfolding into AD-related and non-AD-related variants with distinctive cognitive anatomic patterns. CBS, and notably its "Gerstmann variant", should be included in the new AD "lexicon" and categorized in the evolving diagnostic spectrum of "atypical AD"d. PMID- 26988426 TI - Development and Evaluation of a Modified Fourth-Generation Human Immunodeficiency Virus Enzyme Immunoassay for Cross-Sectional Incidence Estimation in Clade B Populations. AB - BACKGROUND: Accurate methods for cross-sectional incidence estimation are needed for HIV surveillance and prevention research. We developed an avidity assay based on the fourth-generation Genetic Systems HIV Combo Ag/Ab EIA (Bio-Rad Combo assay) and evaluated its performance. MATERIALS AND METHODS: The Bio-Rad Combo assay was modified incubating samples with and without 0.025 M diethylamine (DEA). The avidity index (AI) was calculated as the ratio of the DEA-treated to untreated result for a specific sample. We analyzed 2,140 samples from 808 individuals from the United States with known duration of HIV infection. The mean duration of recent infection (MDRI) and the false-recent rate (FRR, fraction of samples from individuals known to be infected >2 years misclassified as recent) were calculated for AI cutoffs of 20%-90% for the avidity assay alone and in combination with a viral load assay (VL, limit of detection 400 copies/ml). Factors associated with misclassification of samples collected >=2 years after infections were also evaluated. RESULTS: The MDRI for the Bio-Rad Combo Avidity assay ranged from 50 days using an AI cutoff of 20% to 276 days using an AI cutoff of 90%; the FRR ranged from 0% to 9%. When samples with a VL <400 copies/ml were classified as nonrecent, the FRRs were reduced approximately twofold and the MDRI estimates were reduced by ~20%. An AI cutoff of 50% provided an MDRI of 135 days with an FRR of 2.1%. All samples from elite suppressors had an AI >80%. In adjusted analysis, viral suppression and low CD4 cell count were significantly associated with misclassification among individuals infected >2 years. CONCLUSIONS: This modified Bio-Rad Combo Avidity assay may be a useful tool for cross-sectional HIV incidence estimation. Further research is needed to evaluate use of this assay in combination with other assays to accurately estimate population-level HIV incidence. PMID- 26988430 TI - Health-promoting and disease-preventive potential of Trianthema portulacastrum Linn. (Gadabani) -An Indian medicinal and dietary plant. AB - It is estimated that 80% of the world population depends on traditional medicine for primary healthcare need. Trianthema portulacastrum Linn. (family: Aizoaceae) is a small perennial weed found in the Americas, Africa, India, and other regions of the world. This plant is used extensively in Indian traditional medicines and is also consumed as a vegetable throughout Asia for its perceived health benefits. Phytochemical analysis of T. portulacastrum reveals the presence of alkaloids, flavonoids, terpenoids, saponins, and phenolic compounds. Emerging studies demonstrate that crude extracts as well as bioactive phytoconstituents of T. portulacastrum exhibit potent antioxidant, anti-infective, analgesic, and anti inflammatory activities. A growing number of in vitro and in vivo studies demonstrate various biological and pharmacological activities, including prevention and amelioration of hepatotoxicity, nephrotoxicity, hyperglycemia, hyperlipidemia, infectious diseases and cancer. This review aims to present and analyze available literature to understand the full potential of T. portulacastrum in health promotion and disease prevention. Current limitations and future directions of research on this medicinal and dietary plant are also critically discussed. PMID- 26988431 TI - Traditional Chinese medicine wrist pulse-taking is associated with pulse waveform analysis and hemodynamics in hypertension. AB - BACKGROUND: Pulse wave analysis (PWA) quantifies the phenomenon of pulse waveform propagation in patients with cardiovascular diseases, whereas pulse image analysis (PIA) is a subjective examination in traditional Chinese medicine. OBJECTIVE: This study evaluated the association of PIA with PWA and hemodynamics in patients with hypertension. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This observational, cross-sectional study enrolled 45 patients (26 men, (55.2 +/- 10.3) years, systolic blood pressure (155 +/- 28) mmHg, diastolic blood pressure (93 +/- 17) mmHg) for assessment of clinical and laboratorial data. MAIN OUTCOME MEASURES: Primary outcomes comprised: pattern differentiation based on an automated method; PIA at the radial artery using the 'simultaneous pressing' method for identification of factors such as strength (strong/weak), depth (superficial/deep), and speed (fast/moderate/slow); and PWA at the same artery using a noninvasive system. RESULTS: Significant multivariate main effects were observed for depth (lambda=0.648, F5,29 =3.149, P=0.022, eta(2) =0.352), strength (lambda=0.608, F5,29 =3.736, P=0.010, eta(2) =0.392), and speed (lambda=0.535, F5,29 =5.302, P=0.002, eta(2) =0.465). General effects comprised high values of PWA and blood pressure for superficial, strong, and fast pulse images. A strong pulse was found for pulse pressure >= 62.5 mmHg and systolic blood pressure >= 149.5 mmHg, whereas a superficial pulse was found for heart rate >= 58.25 beats/min; a fast pulse was found for heart rate >= 69.6 beats/min and pulse wave velocity >= 9.185 m/s. CONCLUSION: Associations were explained by LaPlace's law, arterial remodeling in hypertension, alongside the traditional criterion for classifying speed in pulse images. PIA is associated with PWA and hemodynamics in patients with hypertension. Systolic and pulse pressures, heart rate, and pulse wave velocity are quantitative variables that have information to describe the qualitative pulse images such as strength, depth and speed. PMID- 26988427 TI - Ethical challenges in preclinical Alzheimer's disease observational studies and trials: Results of the Barcelona summit. AB - Alzheimer's disease (AD) is among the most significant health care burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals' biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants, and disclose or not biomarker status with attention to study type (observational studies vs clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants. PMID- 26988432 TI - Effects of Zingiber cassumunar (Plai cream) in the treatment of delayed onset muscle soreness. AB - OBJECTIVE: To evaluate the effects of Zingiber cassumunar (Plai cream) in either 7% or 14% concentration on delayed onset muscle soreness (DOMS). METHODS: Seventy five untrained healthy volunteers (28 males and 47 females), performed 4 sets of 25 eccentric repetitions of the dominant quadriceps muscle on an isokinetic dynamometry machine. Participants were then randomized into 3 groups: 14% Plai cream, 7% Plai cream and placebo cream. Two grams of the cream (strips of 5-cm long) were gently rubbed into the quadriceps muscles for 5 min immediately following the exercise and every 8 h thereafter for 7 d in all groups. Muscle soreness, muscle strength, jump height, thigh circumference and creatine kinase were measured before and after eccentric exercise. RESULTS: Compared to the placebo cream the 14% Plai cream substantially reduced muscle soreness over the 7 d by -82% (95% CI = -155% to -6%, P = 0.03), but had similar muscle soreness effects to 7% Plai cream (-34%, -96% to 27%, P = 0.2). Compared to the placebo cream the 7% Plai cream resulted in a small non-significant reduction in muscle soreness levels over the following 7 d (-40%, -116% to 36%, P = 0.3). Compared to placebo cream there was little effect of Plai cream (7% or 14%) on muscle strength, jump height, thigh circumference or creatine kinase concentration. CONCLUSION: Using 14% Plai cream over a 7-day period substantially reduced muscle soreness symptoms compared to 7% Plai cream or a placebo cream. The authors suggest that the administration of 14% Plai cream is a useful alternative in the management of DOMS. TRIAL REGISTRATION: Thai Clinical Trial Registry TCTR20140215001. PMID- 26988433 TI - Knowledge, attitude and use of complementary and integrative health strategies: a preliminary survey of Iranian nurses. AB - BACKGROUND: BACKGROUND: Disagreement exists regarding the need for knowledge about complementary and integrative health (CIH) strategies, as well as for the need to consider such strategies in clinical nursing practice. OBJECTIVE: This study was conducted to assess the knowledge, attitude and use of CIH strategies among nurses in Iran. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A cross sectional study of nurses working in two hospitals of Zabol University of Medical Sciences, in southeast Iran, was conducted from October 2014 to April 2015. The questionnaire, developed specifically for this research, was used to assess the knowledge, attitude and use of CIH by nurses. Descriptive and inferential statistics were used to interpret the survey responses. RESULTS: Most nurses (n=95, 60.5%) have average knowledge about CIH strategies with most holding a positive attitude about use (n=81, 51.6%). The majority (n=90, 57.3%) of nurses, however, never applied CIH methods. Where CIH was used, massage was most often clinically applied (n=129, 82.2%) and a large percentage believed it useful for treating illness (n=136, 87.9%). Other CIH methods commonly used included prayer and herbal medicine. CONCLUSION: Nurses have positive attitudes about CIH though knowledge was typically weak. Educational programs should carefully consider how knowledge about CIH methods could be strengthened within curricula. PMID- 26988434 TI - A study to investigate needle insertion at Shenshu (BL23) to puncture psoas major muscle. AB - OBJECTIVE: It is unknown whether the psoas major muscle, thought to be a key muscle for treatment of lower back pain, can be punctured at Shenshu (BL23). METHODS: Twelve dissected specimens were used for studying the needling pathway of BL23 by perpendicularly inserting the depth-measuring blade of a vernier caliper at BL23. Dimensions of psoas muscle were measured. Correlation studies were conducted. In addition, our samples were grouped by gender and underlying medical conditions for analysis. RESULTS: Half (50%) of the needle insertions successfully punctured psoas muscle. The mean depth of needle insertion to puncture psoas muscle (Dmin) in the group with short-term underlying medical conditions was 38.0 mm (interquartile range 29.0-51.8 mm), approximately 6 mm deeper than 32.0 (29.3-42.5) mm in the group with long-term health problems (P = 0.041). The cross-sectional area (CSA) of psoas muscle in the former group was on average approximately 1.5 times that of the latter group (P = 0.04). When the data were analysed by gender, the thickness of psoas muscle in the male group was 19.0 (6.5-24.0) mm compared to 19.5 (5.8-34.8) mm in the female group (P = 0.02). The age in the female group (P = 0.04) and the body length of the total group (P =0.04) negatively correlated to Dmin. CONCLUSION: Needle insertion at BL23 might be able to puncture psoas muscle. Differences in the CSA of psoas muscle and Dmin were observed in groups with short-term and long-term underlying medical conditions. PMID- 26988435 TI - Chungtaejeon, a Korean fermented tea, prevents the risk of atherosclerosis in rats fed a high-fat atherogenic diet. AB - OBJECTIVE: Hypercholesterolemia is one of the well-established risk factors for cardiovascular mortality and morbidity in coronary heart disease. The aim of this study was to investigate the anti-atherogenic effect of Chungtaejeon (CTJ, a Korean fermented tea) aqueous extract on proliferation and migration of human aortic smooth muscle cells (HASMCs) in vivo and in vitro. METHODS: The authors used high-fat atherogenic diet (HFAD) to induce hyperlipidemia in Wistar rats in in vivo animal experiments and used HASMCs for in vitro cell experiments. For the in vitro cell experiment, the proliferation of HASMCs was evaluated using the MTT assay. Similarly, the expression of matrix metalloproteinases (MMPs) in HASMCs was measured using gelatin zymography. Antimigratory activity of CTJ was revealed using the wound-healing model and Boyden 's chamber assay. In the in vivo experiment, CTJ was administered in three different doses for 20 d from the initiation of the HFAD. After 20 d, the serum lipid profile and total lipid contents in liver were measured. RESULTS: Treatment with CTJ for 24 h dose dependently inhibited the proliferation and migration of HASMCs and expression of MMP-2 in HASMCs. The oral administration of CTJ at concentrations of 200 and 400 mg/kg decreased the levels of low-density lipoprotein cholesterol, total serum cholesterol and hepatic cholesterol of HFAD-fed rats. CONCLUSION: CTJ possessed strong antiproliferative, antimigratory, as well as lipid-lowering activities. Thus, CTJ can be considered as a therapeutic option in the treatment of high-fat diet-induced atherosclerosis. PMID- 26988436 TI - Psorinum 6 * triggers apoptosis signals in human lung cancer cells. AB - OBJECTIVE: To provide in vitro evidence of Psorinum treatment against cancer cells in a controlled study. METHODS: Effects of homeopathic Psorinum 6* on cell viability were initially determined in several cancer cell lines, including A549, HepG2 and MCF-7, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and an ethanol 6* control. The cell line that exhibited highest inhibition was selected and used in the following experiments. A range of Psorinum 6* doses was used to explore treatment effects on cell cycle arrest, cell death (apoptosis), generation of reactive oxygen species (ROS) and change in mitochondrial membrane potential (MMP) using flow cytometry and fluorescence microscopy, respectively. Expression of several signal proteins related to apoptosis and cell survival were quantified with Western blotting and confocal microscopy. Further, circular dichroism (CD) spectroscopy was used to determine possible drug-DNA interactions, as well as the induction of conformational changes. RESULTS: Treatment of cancer cell lines with Psorinum showed greater anticancer effects in A549 cells than in others. In A549 cells Psorinum treatment inhibited cell proliferation at 24 h after treatment, and arrested cell cycle at sub-G1 stage. It also induced ROS generation, MMP depolarization, morphological changes and DNA damage, as well as externalization of phosphatidyl serine. Further, increases in p53 expression, Bax expression, cytochrome c release, along with reduction of Bcl-2 level and caspase-3 activation were observed after Psorinum 6* treatment, which eventually drove A549 cells towards the mitochondria mediated caspase-3-dependent pathway. CD spectroscopy revealed direct interaction of Psorinum with DNA, using calf thymus-DNA as target. CONCLUSION: Psorinum 6* triggered apoptosis in A549 cells via both up- and down-regulations of relevant signal proteins, including p53, caspase-3, Bax and Bcl-2. PMID- 26988437 TI - Management of low transsphincteric anal fistula with serial setons and interval muscle-cutting fistulotomy. AB - This study evaluates low transsphincteric anal fistula managed by serial setons and interval fistulotomy, with attention to healing without recurrence and preservation of continence. Following Institutional Review Board approval, consecutive anal fistula operations performed by a single surgeon from January 1, 2009 to December 31, 2013 were retrospectively reviewed using electronic medical records and telephone interviews for patients lost to follow up. Of the 71 patients, 26 (37%) had low transsphincteric fistula (23 males and 3 females; mean age: 46 years), treated at our institution by seton placement followed by interval surgical muscle cutting and subsequent seton replacement or final fistulotomy. Of the 26 patients, 22 (85%) were initially referred due to previous failed treatment, with a 30.6 month mean duration of fistula prior to referral and a mean of 2.2 (range: 0 -6) prior anorectal surgeries. At a mean follow-up of 11.9 months, none of the 21 patients experienced recurrence or fecal incontinence. Serial seton with interval muscle-cutting sphincterotomy followed by complete fistulotomy is an effective treatment for the management of patients who are either initially seen for low transsphincteric fistula, or referred after failed anorectal surgery for that condition. PMID- 26988439 TI - Therapeutic Targets of Triglyceride Metabolism as Informed by Human Genetics. AB - Human genetics has contributed to the development of multiple drugs to treat hyperlipidemia and coronary artery disease (CAD), most recently including antibodies targeting PCSK9 to reduce LDL cholesterol. Despite these successes, a large burden of CAD remains. Genetic and epidemiological studies have suggested that circulating triglyceride (TG)-rich lipoproteins (TRLs) are a causal risk factor for CAD, presenting an opportunity for novel therapeutic strategies. We discuss recent unbiased human genetics testing, including genome-wide association studies (GWAS) and whole-genome or -exome sequencing, that have identified the lipoprotein lipase (LPL) and hepatic lipogenesis pathways as important mechanisms in the regulation of circulating TRLs. Further strengthening the causal relationship between TRLs and CAD, findings such as these may provide novel targets for much-needed potential therapeutic interventions. PMID- 26988438 TI - Human Knockout Carriers: Dead, Diseased, Healthy, or Improved? AB - Whole-genome and whole-exome sequence data from large numbers of individuals reveal that we all carry many variants predicted to inactivate genes (knockouts). This discovery raises questions about the phenotypic consequences of these knockouts and potentially allows us to study human gene function through the investigation of homozygous loss-of-function carriers. Here, we discuss strategies, recent results, and future prospects for large-scale human knockout studies. We examine their relevance to studying gene function, population genetics, and importantly, the implications for accurate clinical interpretations. PMID- 26988440 TI - Fibrinolysis Treatment for Cerebral Intraventricular Hemorrhage: A Temporal and Spatial Voxel-Based Analysis. AB - OBJECTIVE: A voxel-based statistical approach on computer tomographic data in patients with intracerebral hemorrhage (ICH) and acute intraventricular hemorrhage (IVH) was used to evaluate spatial and temporal patterns of intraventricular blood in patients treated with intraventricular fibrinolysis (IVF) or without. METHODS: IVH shapes were systematically assessed three dimensionally in patients with supratentorial ICH at three intervals of time (day of admission, day 4 +/- 1, day 7+). The boundaries of the intraventricular blood clot were delineated on computed tomography (CT) scans using dedicated software. The CT scan and the IVH shape were transferred into stereotaxic space. In a second step, voxel-based statistics on group level were used to correlate the distribution of intraventricular blood with the interval and the treatment group. RESULTS: Altogether 45 patients, 29 with IVF therapy and 16 without, were eligible to be included into this study. We found significant (false discovery rate [FDR] correction, q < .05) reduction of the intraventricular blood between day of admission and day 7 + for the third and fourth ventricle and parts of both lateral ventricles. In addition, we were able to show a significant difference between the IVF therapy and the conventionally treated group at day 4 +/- 1 for the third ventricle. CONCLUSIONS: The data indicate that voxel-based analysis on group level can be used to compare the time course and the distribution of intraventricular hemorrhage. This technique could be an interesting tool for future research on ICH with IVH. PMID- 26988441 TI - p73 and FoxJ1: Programming Multiciliated Epithelia. AB - The mysteriously diverse phenotypes in mice lacking the p53 homolog p73 are recently unified by new analysis showing p73 is required for formation of multiciliated epithelia. p73 directly activates FoxJ1, the central transcriptional driver for multiciliation, and induces a host of genes critical for ciliogenesis. PMID- 26988442 TI - Over-generalization in youth with anxiety disorders. AB - Over-generalization of dangerous stimuli is a possible etiological account of anxiety. Recently, we demonstrated it could result from alterations in early perceptual mechanisms, i.e., a fundamental change in the way the stimulus is perceived. Yet it is still unclear if these mechanisms already exist in youth, or develop only later. The purpose of this study was therefore to explore the mechanism of generalization in youth suffering from anxiety disorders. Children and adolescents with anxiety disorders and age-matched control participants underwent a conditioning task where a loss or gain outcome was associated with two well-separated tones. A generalization probe then followed in which different surrounding tones were presented and classified. Generalization curves and changes in discrimination abilities were compared between groups and according to the background variables. We found that patients had lower perceptual discrimination thresholds after conditioning, and tended to have wider generalization curve. Relative enhanced generalization was observed in adolescents with anxiety, in males, and as the level of anxiety rose. Our results suggest that over-generalization in anxiety can start already during adolescence, and may suggest that an early perceptual source can give rise to later more cognitive over-generalization during adult anxiety. PMID- 26988445 TI - Aquatic ecotones-new insights from Arctic Canada. PMID- 26988443 TI - Biological Properties and Therapeutic Applications of Propolis. AB - Propolis is a resinous material collected by bees from bud and exudates of the plants, mixed with bee enzymes, pollen and wax. In this review, the biological properties of propolis and some therapeutic applications are discussed. The same biological activities have been investigated until today, using samples from different geographic regions. Thus, the study of the biological properties of a given sample should always be associated with its chemical composition and botanical source, representing a particular sample of a given geographic area, exploring its biological potential and the role of its constituents. Efforts have been carried out to explain propolis' mechanisms of action in vivo and in vitro, but the majority of propolis' targets and actions are still unclear. The number of formulations containing propolis and patents have increased, although propolis extracts have been used deliberately with different recommendations, not always mentioning the chemical composition, vegetal source and the methods of extraction. Clinical studies will help to obtain criterious recommendations in view of the expected outcomes. Further investigation should explore the effects of common compounds found in the samples from all over the world in an attempt to standardize the research on propolis and to obtain new drugs. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26988446 TI - Determining diatom ecotones and their relationship to terrestrial ecoregion designations in the central Canadian Arctic Islands. AB - Ecotones are key areas for the detection of global change because many are predicted to move with shifts in climate. Prince of Wales Island, in the Canadian Arctic Archipelago, spans the transition between mid- to high-Arctic ecoregions. We analyzed limnological variables and recent diatom assemblages from its lakes and ponds to determine if assemblages reflected this ecotone. Limnological gradients were short, and water chemistry explained 20.0% of diatom variance in a redundancy analysis (RDA), driven primarily by dissolved organic carbon, Ca and SO4 . Most taxa were small, benthic forms; key taxa such as planktonic Cyclotella species were restricted to the warmer, southern portion of the study area, while benthic Staurosirella were associated with larger, ice-dominated lakes. Nonetheless, there were no significant changes in diatom assemblages across the mid- to high-Arctic ecoregion boundary. We combined our data set with one from nearby Cornwallis Island to expand the study area and lengthen its environmental gradients. Within this expanded data set, 40.6% of the diatom variance was explained by a combination of water chemistry and geographic variables, and significant relationships were revealed between diatom distributions and key limnological variables, including pH, specific conductivity, and chl-a. Using principal coordinates analysis, we estimated community turnover with latitude and applied piecewise linear regression to determine diatom ecotone positions. A pronounced transition was present between Prince of Wales Island and the colder, more northerly Cornwallis Island. These data will be important in detecting any future northward ecotone movement in response to predicted Arctic climate warming in this highly sensitive region. PMID- 26988444 TI - A conserved motif in JNK/p38-specific MAPK phosphatases as a determinant for JNK1 recognition and inactivation. AB - Mitogen-activated protein kinases (MAPKs), important in a large array of signalling pathways, are tightly controlled by a cascade of protein kinases and by MAPK phosphatases (MKPs). MAPK signalling efficiency and specificity is modulated by protein-protein interactions between individual MAPKs and the docking motifs in cognate binding partners. Two types of docking interactions have been identified: D-motif-mediated interaction and FXF-docking interaction. Here we report the crystal structure of JNK1 bound to the catalytic domain of MKP7 at 2.4-A resolution, providing high-resolution structural insight into the FXF-docking interaction. The (285)FNFL(288) segment in MKP7 directly binds to a hydrophobic site on JNK1 that is near the MAPK insertion and helix alphaG. Biochemical studies further reveal that this highly conserved structural motif is present in all members of the MKP family, and the interaction mode is universal and critical for the MKP-MAPK recognition and biological function. PMID- 26988447 TI - Immunofluorescence localization of the tubulin cytoskeleton during cell division and cell growth in members of the Coleochaetales (Streptophyta). AB - Study of charophycean green algae, including the Coleochaetales, may shed light on the evolutionary history of characters they share with their land plant relatives. We examined the tubulin cytoskeleton during mitosis, cytokinesis, and growth in members of the Coleochaetales with diverse morphologies to determine if phragmoplasts occurred throughout this order and to identify microtubular patterns associated with cell growth. Species representing three subgroups of Coleochaete and its sister genus Chaetosphaeridium were studied. Cytokinesis involving a phragmoplast was found in the four taxa examined. Differential interference contrast microscopy of living cells confirmed that polar cytokinesis like that described in the model flowering plant Arabidopsis occurred in all species when the forming cell plate traversed a vacuole. Calcofluor labeling of cell walls demonstrated directed growth from particular cell regions of all taxa. Electron microscopy confirmed directed growth in the unusual growth pattern of Chaetosphaeridium. All four species exhibited unordered microtubule patterns associated with diffuse growth in early cell expansion. In subsequent elongating cells, Coleochaete irregularis Pringsheim and Chaetosphaeridium globosum (Nordstedt) Klebahn exhibited tubulin cytoskeleton arrays corresponding to growth patterns associated with tip growth in plants, fungi, and other charophycean algae. Hoop-shaped microtubules frequently associated with diffuse growth of elongating cells in plants were not observed in any of these species. Presence of phragmoplasts in the diverse species studied supports the hypothesis that cytokinesis involving a phragmoplast originated in a common ancestor of the Coleochaetales, and possibly in a common ancestor of Charales, Coleochaetales, Zygnematales, and plants. PMID- 26988448 TI - Variation in elemental stoichiometry of the marine diatom Thalassiosira weissflogii (Bacillariophyceae) in response to combined nutrient stress and changes in carbonate chemistry. AB - The combined consequences of the multi-stressors of pH and nutrient availability upon the growth of a marine diatom were investigated. Thalassiosira weissflogii was grown in N- or P-limited batch culture in sealed systems, with pH commencing at 8.2 ("extant" conditions) or 7.6 ("ocean acidification" [OA] conditions), and then pH was allowed to either drift with growth, or was held fixed. Results indicated that within the pH range tested, the stability of environmental pH rather than its value (i.e., OA vs. extant) fundamentally influenced biomass accumul-ation and C:N:P stoichiometry. Despite large changes in total alkalinity in the fixed pH systems, final biomass production was consistently greater in these systems than that in drifting pH systems. In drift systems, pH increased to exceed pH 9.5, a level of alkalinity that was inhibitory to growth. No statis tically significant differences between pH treatments were measured for N:C, P:C or N:P ratios during nutrient-replete growth, although the diatom expre-ssed greater plasticity in P:C and N:P ratios than in N:C during this growth phase. During nutrient-deplete conditions, the capacity for uncoupled carbon fixa-tion at fixed pH was considerably greater than that measured in drift pH systems, leading to strong contrasts in C:N:P stoichiometry between these treatments. Whether environmental pH was stable or drifted directly influenced the extent of physiological stress. In contrast, few distinctions could be drawn between "extant" versus "OA" conditions for cell physiology. PMID- 26988449 TI - Different speciation for bromine in brown and red algae, revealed by in vivo X ray absorption spectroscopic studies. AB - Members of various algal lineages are known to be strong producers of atmospherically relevant halogen emissions, that is a consequence of their capability to store and metabolize halogens. This study uses a noninvasive, synchrotron-based technique, X-ray absorption spectroscopy, for addressing in vivo bromine speciation in the brown algae Ectocarpus siliculosus, Ascophyllum nodosum, and Fucus serratus, the red algae Gracilaria dura, G. gracilis, Chondrus crispus, Osmundea pinnatifida, Asparagopsis armata, Polysiphonia elongata, and Corallina officinalis, the diatom Thalassiosira rotula, the dinoflagellate Lingulodinium polyedrum and a natural phytoplankton sample. The results highlight a diversity of fundamentally different bromine storage modes: while most of the stramenopile representatives and the dinoflagellate store mostly bromide, there is evidence for Br incorporated in nonaromatic hydrocarbons in Thalassiosira. Red algae operate various organic bromine stores - including a possible precursor (by the haloform reaction) for bromoform in Asparagopsis and aromatically bound Br in Polysiphonia and Corallina. Large fractions of the bromine in the red algae G. dura and C. crispus and the brown alga F. serratus are present as Br(-) defects in solid KCl, similar to what was reported earlier for Laminaria parts. These results are discussed according to different defensive strategies that are used within algal taxa to cope with biotic or abiotic stresses. PMID- 26988450 TI - Three-dimensional (3-D) fluorescence spectroscopy analysis of the fluorescent dissolved organic matter released by the marine toxic dinoflagellate Alexandrium catenella exposed to metal stress by zinc or lead. AB - We investigated the effects of zinc or lead on growth and on exudation of fluorescent dissolved organic matter (FDOM) by the marine toxic dinoflagellate Alexandrium catenella (Whedon & Kofoid) Balech. The species was exposed to increasing free zinc (1.34 * 10(-7) M-3.98 * 10(-6) M) or lead (5.13 * 10(-9) M 1.82 * 10(-7) M) concentra-tions. Low metal levels ([Zn(2+) ] = 1.34 * 10(-7) M; [Pb(2+) ] = 5.13 * 10(-9) M) had no effect on cell growth. Toxic effects were observed from higher metal contamination ([Zn(2+) ] = 3.98 * 10(-6) M; [Pb(2+) ] = 6.54 * 10(-8) M), as a conversion of vegetative cells into cysts. Analysis of the released FDOM by three-dimensional (3-D) fluorescence spectroscopy was achieved, using the parallel factor analysis (PARAFAC). The PARAFAC modeling revealed four components associated with two contributions: one related to the biological activity; the other linked to the organic matter decomposition in the culture medium. The C1 component combined a tryptophan peak and characteristics of humic substances, whereas the C2 component was considered as a tryptophan protein fluorophore. The two others C3 and C4 components were associated with marine organic matter production. Relea-sed fluorescent substances were induced by low ([Zn(2+) ]= 1.34 * 10(-7) M; [Pb(2+) ] = 5.13 * 10(-9) M) and moderate ([Zn(2+) ] = 6.21 * 10(-7) M; [Pb(2+) ] = 2.64* 10(-9) M) metal concentrations, suggesting the activation of cellular mechanisms in response to metal stress, to exudate FDOM that could complex metal cations and reduce their toxicity toward A. catenella cells. PMID- 26988451 TI - Nonheterocytous cyanobacteria from Brazilian saline-alkaline lakes. AB - Saline-alkaline lakes are extreme environments that limit the establishment and development of life. The Nhecolandia, a subregion of the Pantanal wetland in Brazil, is characterized by the existence of ~500 saline-alkaline lakes, which support an underexplored and rich diversity of microorganisms. In this study, unicellular and homocytous cyanobacteria from five saline-alkaline lakes were accessed by culture-dependent approaches. Morphological evaluation and analyses of near complete sequences (~1400 nt) of the 16S rRNA genes were applied for phylogenetic and taxonomic placement. This polyphasic approach allowed for the determination of the taxonomic position of the isolated strains into the following genera: Cyanobacterium, Geminocystis, Phormidium, Leptolyngbya, Limnothrix, and Nodosilinea. In addition, fourteen Pseudanabaenales and Oscillatoriales representatives of putative novel taxa were found. These sequences fell into five new clades that could correspond to new generic units of the Pseudanabaenaceae and Phormidiaceae families. PMID- 26988452 TI - Purification and culture characteristics of 36 benthic marine diatoms isolated from the Solthorn tidal flat (Southern North Sea). AB - Marine benthic diatoms growing in biofilms on sediment surfaces generally occur associated with heterotrophic bacteria, whereas modern molecular techniques and analyses of species-specific physiology create a demand for axenic cultures. Numerous benthic diatoms were isolated from surface sediments during a monitoring of the Solthorn tidal flat (southern North Sea, Germany) from May 2008 to May 2009. Of these, around 50% could be purified from the accompanying heterotrophic bacteria using different antibiotics combined with physical separation methods (vortexing, ultrasound). Overall, seven different antibiotics were tested at different concentrations, and a best working protocol was developed. The axenic strains were stable on average for only around 15 months, indicating a symbiotic interaction between the benthic diatoms and the associated bacteria. While most short-term effects during the purification process were restricted to differences in growth rates among xenic and axenic diatom strains, long-term cultivation led to distinct changes in cell volumes and growth characteristics of the axenic strains. PMID- 26988453 TI - Biodiversity of soil cyanobacteria in the hyper-arid Atacama Desert, Chile. AB - The cyanobacterial diversity of soils of the Atacama Desert (Chile) was investigated using 16S rRNA gene cloning/sequencing directly from soil samples and 16S rRNA gene sequencing from unialgal cultures. Within the hyper-arid Atacama Desert, one of the driest parts of the world, 10 sites with differing altitude and distance to the shore were sampled along a total air-line distance (from south to north) of ~1,100 km. Filamentous cyanobacteria belonging to Nostocophycideae and Synechococcophycideae were present. Oscillatoriophycideae exhibited the highest species richness among the subclasses of cyanobacteria, and included mostly filamentous species along with some coccoids (e.g., Chroococcidiopsis). Thirty species-level phylotypes could be recognized using a cut-off of 99% 16S rRNA sequence similarity within the 22 genera defined at 97% 16S rRNA sequence similarity. Eight of the 30 taxa could be detected by both clonal and culture sequences. Five taxa were observed only in cultures, whereas the cloning approach revealed 17 additional taxa, which might be in the collection but unsequenced, hard-to-cultivate, or entirely unculturable species using standard cultivation media. The Atacama Desert soils have a high diversity of phylotypes, among which are likely both new genera and new species awaiting characterization and description. PMID- 26988454 TI - Trichocytes in Lithophyllum kotschyanum and Lithophyllum spp. (Corallinales, Rhodophyta) from the NW Indian Ocean. AB - The current diagnosis of the genus Lithophyllum includes absent or rare trichocyte occurrence. After examining holotype material, single trichocytes have been revealed to occur abundantly in Lithophyllum kotschyanum Unger, and in freshly collected specimens of Lithophyllum spp. from the Red Sea, Gulf of Aden and Socotra Island (Yemen). Trichocyte occurrence is not considered a diagnostic character at specific or supraspecific levels in the Lithophylloideae, and the ecological significance of trichocyte formation is discussed. The generitype species, L. incrustans Philippi, does not show trichocytes nor do many other Lithophyllum species from diverse geographic localities, but the presence of abundant trichocytes in other congeneric taxa requires emendation of the genus diagnosis. Therefore, the diagnosis of Lithophyllum is here emended by eliminating the adjective "rare" in the sentence concerning trichocyte occurrence, as follows: "Trichocytes present or absent, if present occurring singly." PMID- 26988455 TI - Characterization of Prorocentrum elegans and Prorocentrum levis (Dinophyceae) from the southeastern Bay of Biscay by morphology and molecular phylogeny. AB - Benthic Prorocentrum species can produce toxins that adversely affect animals and human health. They are known to co-occur with other bloom-forming, potentially toxic, benthic dinoflagellates of the genera Ostreopsis, Coolia, and Gambierdiscus. In this study, we report on the presence of P. elegans M.Faust and P. levis M.A.Faust, Kibler, Vandersea, P.A. Tester & Litaker from the southeastern Bay of Biscay. Sampling was carried out in the Summer-Autumn 2010 2012 along the Atlantic coast of the Iberian Peninsula, but these two species were only found in the northeastern part of the Peninsula. Strains were isolated from macroalgae collected from rocky-shore areas bordering accessible beaches. Morphological traits of isolated strains were analyzed by LM and SEM, whereas molecular analyses were performed using the LSU and internal transcribed spacer (ITS)1-5.8S-ITS2 regions of the rDNA. A bioassay with Artemia fransciscana and liquid chromatography-high-resolution mass spectrometry analyses were used to check the toxicity of the species, whose results were negative. The strains mostly corresponded to their species original morphological characterization, which is supported by the phylogenetic analyses in the case of P. levis, whereas for P. elegans, this is the first known molecular characterization. This is also the second known report of P. elegans. PMID- 26988456 TI - Evaluation of biologically mediated changes in oil sands naphthenic acid composition by Chlamydomonas reinhardtii using negative-ion electrospray orbitrap mass spectrometry. AB - Industrial activity associated with oil-sands extraction in Canada's Athabasca region produces a variety of contaminants of concern, including naphthenic acid fraction components (NAFCs). NAFCs are a complex mixture of organic compounds that are poorly understood both in terms of their chemical composition and effects on the environment. NAFC toxicity in the unicellular green algae Chlamydomonas reinhardtii P.A.Dangeard was correlated with the presence of the algal cell wall. It was suggested that the toxicity of NAFCs in C. reinhardtii was due to surfactant effects. Surfactant-cell wall interactions are specific and governed by the compound class and structure, and by the nature of the biological material. Here, we investigate the effects of wildtype (WT) C. reinhardtii and two cell-wall mutants on specific classes of NAFCs when growing cultures were treated with a 100 mg . L(-1) solution of NAFCs. Changes in the NAFC composition in the media were examined using high resolution mass spectrometry over a period of 4 d. Algal mediated changes in the NAFCs were limited to specific classes of NAFCs. In particular, the removal of large, classical naphthenic acids, with a double bond equivalent of 8, was observed in WT C. reinhardtii cultures. The observed algal mediated changes in NAFC composition would have been masked by low resolution mass spectrometry and highlight the importance of this tool in examining bioremediation of complex mixtures of NAFCs. PMID- 26988457 TI - Phylogenetic study of Geitlerinema and Microcystis (Cyanobacteria) using PC-IGS and 16S-23S ITS as markers: investigation of horizontal gene transfer. AB - Selection of genes that have not been horizontally transferred for prokaryote phylogenetic inferences is regarded as a challenging task. The markers internal transcribed spacer of ribosomal genes (16S-23S ITS) and phycocyanin intergenic spacer (PC-IGS), based on the operons of ribosomal and phycocyanin genes respectively, are among the most used markers in cyanobacteria. The region of the ribosomal genes has been considered stable, whereas the phycocyanin operon may have undergone horizontal transfer. To investigate the occurrence of horizontal transfer of PC-IGS, phylogenetic trees of Geitlerinema and Microcystis strains were generated using PC-IGS and 16S-23S ITS and compared. Phylogenetic trees based on the two markers were mostly congruent for Geitlerinema and Microcystis, indicating a common evolutionary history among ribosomal and phycocyanin genes with no evidence for horizontal transfer of PC-IGS. Thus, PC-IGS is a suitable marker, along with 16S-23S ITS for phylogenetic studies of cyanobacteria. PMID- 26988458 TI - Growth and cell cycle of Ulva compressa (Ulvophyceae) under LED illumination. AB - The cell-cycle progression of Ulva compressa is diurnally gated at the G1 phase in accordance with light-dark cycles. The present study was designed to examine the spectral sensitivity of the G1 gating system. When blue, red, and green light emitting diodes (LEDs) were used for illumination either alone or in combination, the cells divided under all illumination conditions, suggesting that all colors of light were able to open the G1 gate. Although blue light was most effective to open the G1 gate, red light alone or green light alone was also able to open the G1 gate even at irradiance levels lower than the light compensation point of each color. Occurrence of a period of no cell division in the course of a day suggested that the G1 gating system normally functioned as under ordinary illumination by cool-white fluorescent lamps. The rise of the proportion of blue light to green light resulted in increased growth rate. On the other hand, the growth rates did not vary regardless of the proportion of blue light to red light. These results indicate that the difference in growth rate due to light color resulted from the difference in photosynthetic efficiency of the colors of light. However, the growth rates significantly decreased under conditions without blue light. This result suggests that blue light mediates cell elongation and because the spectral sensitivity of the cell elongation regulating system was different from that of the G1 gating system, distinct photoreceptors are likely to mediate the two systems. PMID- 26988459 TI - Abiotic stress modifies the synthesis of alpha-tocopherol and beta-carotene in phytoplankton species. AB - We performed laboratory experiments to investi-gate whether the synthesis of the antioxidants alpha-tocopherol (vitamin E) and beta-carotene in phytoplankton depends on changes in abiotic factors. Cultures of Nodularia spumigena, Phaeodactylum tricornutum, Skeletonema costatum, Dunaliella tertiolecta, Prorocentrum cordatum, and Rhodomonas salina were incubated at different tempe ratures, photon flux densities and salinities for 48 h. We found that abiotic stress, within natural ecological ranges, affects the synthesis of the two antioxidants in different ways in different species. In most cases antioxidant production was stimulated by increased abiotic stress. In P. tricornutum KAC 37 and D. tertiolecta SCCAP K-0591, both good producers of this compound, alpha tocopherol accumulation was negatively affected by environmentally induced higher photosystem II efficiency (Fv /Fm ). On the other hand, beta-carotene accumulation was positively affected by higher Fv /Fm in N. spumigena KAC 7, P. tricornutum KAC 37, D. tertiolecta SCCAP K-0591 and R. salina SCCAP K-0294. These different patterns in the synthesis of the two compounds may be explained by their different locations and functions in the cell. While alpha-tocopherol is heavily involved in the protection of prevention of lipid peroxidation in membranes, beta-carotene performs immediate photo-oxidative protection in the antennae complex of photosystem II. Overall, our results suggest a high variability in the antioxidant pool of natural aquatic ecosystems, which can be subject to short-term temperature, photon flux density and salinity fluctuations. The antioxidant levels in natural phytoplankton communities depend on species composition, the physiological condition of the species, and their respective strategies to deal with reactive oxygen species. Since alpha-tocopherol and beta carotene, as well as many other nonenzymatic antioxidants, are exclusively produced by photo-synthetic organisms, and are required by higher trophic levels through dietary intake, regime shifts in the phytoplankton as a result of large scale environmental changes, such as climate change, may have serious consequences for aquatic food webs. PMID- 26988460 TI - Misleading morphologies and the importance of sequencing type specimens for resolving coralline taxonomy (Corallinales, Rhodophyta): Pachyarthron cretaceum is Corallina officinalis. AB - Coralline red algae play a key role in the ecology of near shore marine ecosystems and are increasingly being used to study the effects of climate change in the marine environment. Corallines are very difficult to identify to species, and even to genus, using morpho-anatomy, likely complicating studies of their ecology, physiology, and biodiversity. We sequenced a 296 base pair fragment of chloroplast DNA from a 187-year-old isolectotype specimen of Pachyarthron cretaceum, a morphologically distinct geniculate species, to demonstrate that coralline morphology is often misleading and that species names can only be applied unequivocally by comparing DNA sequences from type material with sequences from field-collected specimens. Our results indicate that Pachyarthron cretaceum is synonymous with Corallina officinalis. PMID- 26988461 TI - Corrigendum. PMID- 26988462 TI - Rich Janus colloid phase behavior under steady shear. AB - We study the assembly of single-patch colloidal Janus particles under steady shear flow via Brownian dynamics simulations. In the absence of flow, by varying the Janus patch size and the range and strength of the anisotropic interaction potential, Janus colloids form different aggregates such as micelles, wormlike clusters, vesicles and lamellae. Under shear flow we observe rearrangement, deformation, and break-up of aggregates. At small and intermediate Peclet (Pe) numbers-the ratio between shear and Brownian forces-the competition between rearrangement, deformation, and break-up favors the growth of micelles and vesicles increasing mean cluster size, which is consistent with a previous numerical study of Janus particles under shear. This initial shear-induced growth causes micelles and vesicles to reach a maximum cluster size at Pe ~ 1 and Pe ~ 10, respectively. After this growth micelles dissociate continuously to reach a dilute colloidal "gas phase" at Pe ~ 10 while vesicles dissociate into micelles with high aspect ratio at Pe ~ 10 and finally break-up into a gas phase at Pe ~ 30. Wormlike clusters initially break-up into micelles with high aspect ratio at Pe ~ 0.1, and proceed to finally reach a gas phase at Pe ~ 10. Lamellae initially break into smaller lamellae that align with the flow in the velocity-velocity gradient plane and finally break-up into a gas phase at Pe ~ 100. The different cluster sizes and morphologies observed as functions of interaction range, Janus patch size, interaction strength, and shear rate, open new actuation routes for reconfigurable materials and applications. PMID- 26988463 TI - Transoral Surgery or Radiotherapy for Oropharyngeal Carcinoma - Is It Either Or...? AB - The management of oropharyngeal carcinoma represents an increasing clinical challenge, because of its rising incidence, particularly in younger patients as a result of human papillomavirus (HPV) infection, and because significant technological advances have occurred in radiotherapy and surgery over the last 10 years that have increased treatment options for patients, with little robust evidence yet of their relative merits. As a result, there is a lack of clinical consensus on the optimum treatment modality, reflected in wide variation in practice between different cancer networks across the UK. Here, we consider the evidence base for minimally invasive transoral surgery and for intensity modulated radiotherapy-based primary treatment for oropharyngeal cancer, in terms of both oncological and functional outcomes. Management strategies for HPV positive and HPV-negative disease, and for different stages of the disease, are considered. There is currently an unparalleled opportunity to shape the future management of oropharyngeal cancer, which is dependent on recruiting patients to ongoing clinical trials, in order to build an evidence base to support a clinical consensus on the optimal treatment strategies. It appears likely that future evidence-based decision-making will use both primary radiotherapy and primary surgical treatment modalities to maximise patient benefit. PMID- 26988464 TI - Non-Arbitrariness in Mapping Word Form to Meaning: Cross-Linguistic Formal Markers of Word Concreteness. AB - Arbitrary symbolism is a linguistic doctrine that predicts an orthogonal relationship between word forms and their corresponding meanings. Recent corpora analyses have demonstrated violations of arbitrary symbolism with respect to concreteness, a variable characterizing the sensorimotor salience of a word. In addition to qualitative semantic differences, abstract and concrete words are also marked by distinct morphophonological structures such as length and morphological complexity. Native English speakers show sensitivity to these markers in tasks such as auditory word recognition and naming. One unanswered question is whether this violation of arbitrariness reflects an idiosyncratic property of the English lexicon or whether word concreteness is a marked phenomenon across other natural languages. We isolated concrete and abstract English nouns (N = 400), and translated each into Russian, Arabic, Dutch, Mandarin, Hindi, Korean, Hebrew, and American Sign Language. We conducted offline acoustic analyses of abstract and concrete word length discrepancies across languages. In a separate experiment, native English speakers (N = 56) with no prior knowledge of these foreign languages judged concreteness of these nouns (e.g., Can you see, hear, feel, or touch this? Yes/No). Each naive participant heard pre-recorded words presented in randomized blocks of three foreign languages following a brief listening exposure to a narrative sample from each respective language. Concrete and abstract words differed by length across five of eight languages, and prediction accuracy exceeded chance for four of eight languages. These results suggest that word concreteness is a marked phenomenon across several of the world's most widely spoken languages. We interpret these findings as supportive of an adaptive cognitive heuristic that allows listeners to exploit non-arbitrary mappings of word form to word meaning. PMID- 26988465 TI - Correlation between FIX genotype and pharmacokinetics of Nonacog alpha according to a multicentre Italian study. AB - INTRODUCTION: Pharmacokinetic (PK) studies on recombinant FIX concentrate, Nonacog alpha, were conducted with different sampling time designs which gave rise to not complete and homogenous outcomes. In addition, patient's FIX genotype/PK relationship has never been investigated. AIM: Investigate how different sampling times may affect PK parameters and try to find a FIX genotype/PK relationship. PATIENTS AND METHODS: A cohort pharmacokinetic, Nonacog Alpha single-dose, open-label, non-comparative study was conducted in eight Comprehensive Care Haemophilia Centres in Italy. Seventeen previously treated moderate or severe haemophilia B patients were enrolled. Factors IX:C one-stage clotting assay, FIX genotype and PK analysis were centralized. RESULTS: The evaluation of PK outcomes showed a quite long half-life, smaller clearance and volume of distribution of Nonacog Alpha in comparison with the results from previously reported studies, where blood sampling was stopped too early. The relationship between PK outcomes and FIX genotype showed that small deletions displayed the higher clearance and shorter half-life, the nonsense mutations (the lower and the longer respectively), and missense mutations were in between. CONCLUSIONS: It is evident that area under the curve (AUC) and other PK parameters depend from the sampling time design. In order to have a complete evaluation of clotting factors in vivo decay, blood samples must be collected until the baseline factor concentration has been achieved again. Due to the relationship between FIX genotype and clearance, tailored prophylaxis of HB patients could be partially predicted by genotyping. PMID- 26988467 TI - Short lasting transient effects of a capsaicin 8% patch on nociceptor activation in humans. AB - BACKGROUND: At high concentration, the TRPV-1 agonist capsaicin de-sensitizes nociceptors and reduces the intra-epidermal nerve density. METHODS: We investigated the effects of a 5 * 10 cm capsaicin 8% patch on C- and A-delta nociceptor activation in ten healthy subjects before and at days 1-3-7-21 after patch application. Thermal thresholds, infrared thulium-YAG laser-evoked potentials (LEP) and heat pain (numeric rating scale, NRS, 0-10), electrically induced pain (10 pulses, 1.5-fold pain threshold intensity, five randomized series of 5-10-20-50-100 Hz), and axon-reflex flare (laser Doppler imaging) were recorded. RESULTS: Thermal hypoesthesia developed upon capsaicin 8% treatment. Warmth detection thresholds increased at day 1-3, heat pain thresholds were increased by about 2.6 degrees C after day 3, and laser-evoked heat pain remained significantly reduced for 7 days. Axon-reflex flare responses (days 1 3), but not supra-threshold electrically induced pain were significantly reduced by the capsaicin patch. CONCLUSIONS: Axonal nociceptor function assessed by electrical excitability tests supplements threshold tests of nociceptive endings. The differential analgesic effects of 8% capsaicin patches may be attributed to the kinetics of capsaicin and the different depth of nociceptive nerve fibres, yet, the time course does not match the long-lasting analgesia observed in neuropathic pain patients treated with the same patch. WHAT DOES THIS STUDY ADD?: Axonal nociceptor function assessed by supra-threshold electrical excitability tests did not coincide with capsaicin-induced transduction changes supplementing threshold measures of terminal nociceptor endings. Threshold measurements do not reflect the sustained effect of pain relief seen in neuropathic pain patients. Capsaicin-sensitive nociceptors responsible for spontaneous pain are either not specifically tested with currently available sensory stimulation protocols or have higher capsaicin sensitivity or slower recovery under neuropathic conditions. PMID- 26988466 TI - 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure influence the expression of glutamate transporter GLT-1 in C6 glioma cells via the Ca(2+) /protein kinase C pathway. AB - The widespread environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is considered one of the most toxic dioxin-like compounds. Although epidemiological studies have shown that TCDD exposure is linked to some neurological and neurophysiological disorders, the underlying mechanism of TCDD mediated neurotoxicity has remained unclear. Astrocytes are the most abundant cells in the nervous systems, and are recognized as the important mediators of normal brain functions as well as neurological, neurodevelopmental and neurodegenerative brain diseases. In this study, we investigated the role of TCDD in regulating the expression of glutamate transporter GLT-1 in astrocytes. TCDD, at concentrations of 0.1-100 nm, had no significantly harmful effect on the viability of C6 glioma cells. However, the expression of GLT-1 in C6 glioma cells was downregulated in a dose- and time-dependent manner. TCDD also caused activation of protein kinase C (PKC), as TCDD induced translocation of the PKC from the cytoplasm or perinuclear to the membrane. The translocation of PKC was inhibited by one Ca(2+) blocker, nifedipine, suggesting that the effects are triggered by the initial elevated intracellular concentration of free Ca(2+) . Finally, we showed that inhibition of the PKC activity reverses the TCDD triggered reduction of GLT-1. In summary, our results suggested that TCDD exposure could downregulate the expression of GLT-1 in C6 via Ca(2+) /PKC pathway. The downregulation of GLT-1 might participate in TCDD-mediated neurotoxicity. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26988468 TI - Effect of apotransferrin, lactoferrin and ovotransferrin on the hydroxyl radical mediated degradation of beta-glucan. AB - Beta-glucan is a polysaccharide widely accepted and used as a functional ingredient due to its positive effects on human health. However, beta-glucan is readily degraded in aqueous systems in presence of a hydroxyl radical generating system such as ascorbic/iron(II). In the present study, we tested whether iron binding proteins; apotransferrin, lactoferrin and ovotransferrin; could prevent the hydroxyl radical mediated degradation of beta-glucan. The radical formation was investigated by ESR spectroscopy and the polysaccharide degradation was monitored by the viscosity loss of the solutions. Apo-transferrin increased the formation of hydroxyl radicals and this related with a faster degradation of beta glucan. Lactoferrin did not have any effect on the ascorbate induced degradation of beta-glucan, whereas ovotransferrin completely inhibited the hydroxyl radical generation by a system containing ascorbic acid and iron(II). However, the presence of ovotransferrin in beta-glucan decreased the viscosity of the solution, which was accompanied by the apparition of a precipitate, indicating a potential interaction between the protein and beta-glucan. FT-IR analyses indicate the presence of beta-glucan and ovotransferrin in both precipitate and supernatant, as well as the occurrence of interactions between the two compounds. This study reveals that ovotransferrin is a promising candidate for inhibiting the formation of ascorbate/iron(II) induced hydroxyl radicals in beta-glucan solutions. PMID- 26988469 TI - Fast, cross cultivar determination of total carotenoids in intact carrot tissue by Raman spectroscopy and Partial Least Squares calibration. AB - In order to speed up the breeding of orange carrots for high carotenoid content it is imperative to develop a fast and non-destructive technique. 332 roots from 86 carrot varieties grown in 2014 at the experimental farm in Hoje Taastrup (DK) form the basis of this study. All roots were measured by Raman spectroscopy. The carotenoid content of the very same roots was estimated through a wet chemistry method coupled with UV-VIS at 447nm and 540nm. For the Raman spectroscopy, measurements were made on a cross section disk approximately 10cm from the root top at three different positions in the phloem. Since the top of the carrot is intact, it may still be used for growing. The final calibration model shows an uncertainty (RMSECV) of 20.5ppm, and a R(2)=0.86. It has thus proven to be well suited for prediction of carotenoids in orange carrots, and especially for ranking them according to the content. PMID- 26988470 TI - High variability in flavonoid contents and composition between different North European currant (Ribes spp.) varieties. AB - This study provides information on the variation of anthocyanin and flavonol contents and composition in 32 black and 12 redcurrant varieties, as well as flavonol contents and composition in two green-fruited blackcurrant (green currant) and one white currant varieties conserved in a national ex situ germplasm field collection in Finland, North Europe. Flavonols were analysed as aglycones and anthocyanins as authentic compounds using HPLC methods. In blackcurrants, total anthocyanin content varied 1260-2878mg/100g dry weight and total flavonol content 43.6-89.9mg/100g dry weight. In redcurrants, the content of anthocyanins and flavonols varied 138-462mg/100g dry weight and from not detectable to 17.7mg/100g dry weight, respectively. The green currants contained flavonols 26.1 and 15.4mg/100g dry weight, while in the white variety no flavonols were detected. A positive correlation was found between the total content of anthocyanins and flavonols in both black and redcurrants. Berry size was negatively related to the flavonoid content in redcurrants but not in blackcurrants. The results revealed that some old varieties may be of particular interest when high contents or special composition of flavonoids are desired. PMID- 26988471 TI - Stability of added and in situ-produced vitamin B12 in breadmaking. AB - Vitamin B12 exists naturally in foods of animal origin and is synthesised only by certain bacteria. New food sources are needed to ensure vitamin B12 intake in risk groups. This study aimed to investigate the stability of added cyanocobalamin (CNCbl, chemically modified form) and hydroxocobalamin (OHCbl, natural form) and in situ-synthesised vitamin B12 in breadmaking. Samples were analysed both with a microbiological (MBA) and a liquid chromatographic (UHPLC) method to test applicability of these two methods. Proofing did not affect CNCbl and OHCbl levels. By contrast, 21% and 31% of OHCbl was lost in oven-baking steps in straight- and sponge-dough processes, respectively, whereas CNCbl remained almost stable. In sourdough baking, 23% of CNCbl and 44% of OHCbl were lost. In situ-produced vitamin B12 was almost as stable as added CNCbl and more stable than OHCbl. The UHPLC method showed its superiority to the MBA in determining the active vitamin B12. PMID- 26988472 TI - Bioactive compounds contents, antioxidant and antimicrobial activities during ripening of Prunus persica L. varieties from the North West of Tunisia. AB - Bioactive molecules from fruits of four varieties of Prunus persica at different stages of ripening (green, small orange, red) were studied. For example, contents on polyphenols (20.36mg GAE/g FW) and flavonoids (0.764mg RE/g FW) were high and varied according variety. The antioxidant activity, using four different tests (DPPH radical scavenging activity, reducing power, beta carotene bleaching system and TBARS assay) showed that the variety Chatos exhibited the highest antioxidant activity comparing with others varieties. The antibacterial activity of Prunus persica varieties studied seems to be more sensitive against Staphylococcus aureus and Listeria monocytogenes. The capacity of peach DMSO extracts to inhibit Candida albicans growth was more pronounced, especially, in the presence of Chatos DMSO extract. Enzymes inhibition gives results which correlate with polyphenols, flavonoids and condensed tannins contents, and so, confirm the fascinating bioactivity of this fruit. PMID- 26988473 TI - Chemical profile of mango (Mangifera indica L.) using electrospray ionisation mass spectrometry (ESI-MS). AB - Mangifera indica L., mango fruit, is consumed as a dietary supplement with purported health benefits; it is widely used in the food industry. Herein, the chemical profile of the Uba mango at four distinct maturation stages was evaluated during the process of growth and maturity using negative-ion mode electrospray ionisation Fourier transform ion cyclotron resonance mass spectrometry (ESI(-)FT-ICR MS) and physicochemical characterisation analysis (total titratable acidity (TA), total soluble solids (TSS), TSS/TA ratio, and total polyphenolic content). Primary (organic acids and sugars) and secondary metabolites (polyphenolic compounds) were mostly identified in the third maturation stage, thus indicating the best stage for harvesting and consuming the fruit. In addition, the potential cancer chemoprevention of the secondary metabolites (phenolic extracts obtained from mango samples) was evaluated using the induction of quinone reductase activity, concluding that fruit polyphenols have the potential for cancer chemoprevention. PMID- 26988474 TI - Structure and IgE-binding properties of alpha-casein treated by high hydrostatic pressure, UV-C, and far-IR radiations. AB - alpha-Casein was treated by high hydrostatic pressure (HHP), UV-C, or far-IR (FIR). These treatments increased roughness, alpha-helicity, and beta-turn, but decreased beta-sheet and IgE-binding reactivity. One 5-min cycle at 600-MPa pressure caused maximum alpha-helicity, beta-turn, and surface hydrophobicity (Ho), but minimum stimulated intestinal fluid from alpha-casein. UV-C (15min) produced the maximum kurtosis, free sulfhydryl content (FSC), and stimulated intestinal fluid, minimum Ho, R, and simulated gastric fluid. FIR (15min) caused the minimum alpha-helicity and FSC, but maximum R and beta-sheet. The NMR peaks of the main allergenic characteristics affected were 15-17, 23-26, 40, 53, 59 and 85-88, respectively. Generally, all treatments decreased the allergenicity of alpha-casein by modifying its morphology, ultrastructure, characteristic domains, and peptides. Based on the stimulated digestion tests, UV-C (15min) was more efficient for lowering alpha-casein allergenicity, thus decreasing the allergenicity of milk. PMID- 26988475 TI - Solid-phase extraction of flavonoids in honey samples using carbamate-embedded triacontyl-modified silica sorbent. AB - In this study, carbamate-embedded triacontyl-modified silica (Sil-CBM-C30) is successfully prepared and used as an efficient sorbent for solid-phase extraction. The extraction performance of the resultant sorbent is evaluated with five flavonoids including myricetin, quercetin, luteolin, kaempferol and isorhamnetin. Main parameters, which affect extraction efficiencies, are carefully investigated and optimized. Comparative experiments between Sil-CBM-C30 and commercial C18 sorbents indicate that the extraction efficiencies of the former one surpass the latter one. The modification of carbamate-embedded triacontyl group on surface of silica causes analytes extracted by hydrophobic, hydrogen bonding and pi-pi interactions. Under optimal conditions, good linearities and satisfied LODs and LOQs are achieved. The SPE-HPLC-DAD method is successfully developed and applied for the honey sample analysis. PMID- 26988476 TI - Pressurized liquid extraction of Aglaonema sp. iminosugars: Chemical composition, bioactivity, cell viability and thermal stability. AB - Pressurized liquid extraction of Aglaonema sp. iminosugars has been optimized. A single cycle under optimal conditions (80mg, 100 degrees C, 2min) was enough to extract ?96% of most iminosugars. Further incubation with Saccharomyces cerevisiae for 5h removed coextracted interfering low molecular weight carbohydrates from extracts of different Aglaonema cultivars. A complete characterization of these extracts was carried out by gas chromatography-mass spectrometry: three iminosugars were tentatively identified for the first time; alpha-homonojirimycin and 2,5-dideoxy-2,5-imino-d-mannitol were the major iminosugars determined. alpha-Glucosidase inhibition activity, cell viability and thermal stability of Aglaonema extracts were also evaluated. Extracts with IC50 for alpha-glucosidase activity in the 0.010-0.079mgmL(-1) range showed no decrease of Caco-2 cell viability at concentrations lower than 125MUgmL(-1) and were stable at 50 degrees C for 30days. These results highlight the potential of Aglaonema extracts as a source of bioactives to be used as functional ingredients. PMID- 26988477 TI - Optimization of Ultrasound-Assisted Extraction of phenolic compounds and anthocyanins from blueberry (Vaccinium ashei) wine pomace. AB - Ultrasound-Assisted Extraction (UAE) of total anthocyanins (TA) and phenolics (TP) from Blueberry Wine Pomace (BWP) was optimized using Response Surface Methodology (RSM). A Box-Behnken design was used to predict that the optimized conditions were an extraction temperature of 61.03 degrees C, a liquid-solid ratio of 21.70mL/g and a sonication time of 23.67min. Using the modeled optimized conditions, the predicted and experimental yields of TA and TP were within a 2% difference. The yields of TA and TP obtained through the optimized UAE method were higher than those using a Conventional Solvent Extraction (CSE) method. Seven anthocyanins, namely delphinidin-3-O-glucoside, delphindin-3-O-arabinoside, petunidin-3-O-glucoside, cyanidin-3-O-arabinoside, cyanidin-3-O-glucoside, malvidin-3-O-glucoside and malvidin-3-O-arabinoside, were found in the BWP extract from both the UAE and CSE methods. PMID- 26988479 TI - Oligosaccharide formation during commercial pear juice processing. AB - The effect of enzyme treatment and processing on the oligosaccharide profile of commercial pear juice samples was examined by high performance anion exchange chromatography with pulsed amperometric detection and capillary gas chromatography with flame ionization detection. Industrial samples representing the major stages of processing produced with various commercial enzyme preparations were studied. Through the use of commercially available standards and laboratory scale enzymatic hydrolysis of pectin, starch and xyloglucan; galacturonic acid oligomers, glucose oligomers (e.g., maltose and cellotriose) and isoprimeverose were identified as being formed during pear juice production. It was found that the majority of polysaccharide hydrolysis and oligosaccharide formation occurred during enzymatic treatment at the pear mashing stage and that the remaining processing steps had minimal impact on the carbohydrate-based chromatographic profile of pear juice. Also, all commercial enzyme preparations and conditions (time and temperature) studied produced similar carbohydrate-based chromatographic profiles. PMID- 26988478 TI - Development of alginate microspheres containing thyme essential oil using ionic gelation. AB - Essential oils are a good antimicrobial and antioxidant agent alternative in human or animal feed. However, their direct use has several disadvantages such as volatilization or oxidation. The development of essential oil microspheres may help to avoid these problems. The objective of the present research was to microencapsulate thyme essential oil by generating emulsions with different dispersion degrees. The emulsions were encapsulated in calcium-alginate microspheres by ionic gelation. The microspheres were evaluated regarding size, shape, encapsulation efficiency, loading capacity and antimicrobial properties. The results indicate that encapsulation efficiency and loading capacity are dependent on concentration and degree of dispersion. The best encapsulation conditions were obtained at 2% v/v of thyme essential oil with a high dispersion degree (18,000rpm/5min), which was achieved with an efficiency of 85%. Finally, the microspheres obtained showed significant antimicrobial effect, especially in gram-positive bacteria. PMID- 26988480 TI - Contents and compositions of policosanols in green tea (Camellia sinensis) leaves. AB - Policosanol (PC) is a mixture of health promoting bioactive long-chain aliphatic alcohols. Here, we report that green tea (Camellia sinensis) leaves are the exceptionally rich plant-sources of PC. Young and tender leaves and old and turf leaves of C. sinensis were hand-picked in spring and autumn. The total contents of PC in the leaves were in the range of 726.2-1363.6mg/kg as determined by a GC MS/MS. The compositions of PC in the leaves were different with harvest season and types. The total contents of PC in commercial green tea leaves were found to be in the range of 856.7-1435.1mg/kg. Interestingly, the infused green tea leaves contained the higher PC than the non-infused green tea product, reaching to 1629.4mg/kg. This represents the first report on the contents and compositions of PC in green tea leaves, showing unambiguous evidence of their potential as rich sources of PC. PMID- 26988481 TI - (1)H NMR spectroscopy and chemometrics evaluation of non-thermal processing of orange juice. AB - This study evaluated the effect of atmospheric cold plasma and ozone treatments on the key compounds (sugars, amino acids and short chain organic acids) in orange juice by NMR and chemometric analysis. The juice was directly and indirectly exposed to atmospheric cold plasma field at 70kV for different treatment time (15, 30, 45 and 60sec). For ozone processing different loads were evaluated. The Principal Component Analysis shown that the groups of compounds are affected differently depending on the processing. The ozone was the processing that more affected the aromatic compounds and atmospheric cold plasma processing affected more the aliphatic compounds. However, these variations did not result in significant changes in orange juice composition as a whole. Thus, NMR data and chemometrics were suitable to follow quality changes in orange juice processing by atmospheric cold plasma and ozone. PMID- 26988482 TI - Laboratory to pilot scale: Microwave extraction for polyphenols lettuce. AB - Microwave hydrodiffusion and gravity (MHG) technique has been applied to pilot scale solvent-free microwave extraction (SFME) of polyphenols from Lettuce sativa. Following the dictates of green extraction and with the aim to save time and energy, the lab-scale knowledge on SFME was exploited for the development of a pilot-scale process. The investigation entailed the optimization of all main parameters (temperature, time, extracted water volume, etc.) and we showed that the polyphenols composition profile under SFME was similar to the classic methods though a bit lower in total content. The energy consumption in the optimized procedure (30min) was 1W/g of fresh matrix. PMID- 26988483 TI - Enzymatic milk clotting activity in artichoke (Cynara scolymus) leaves and alpine thistle (Carduus defloratus) flowers. Immobilization of alpine thistle aspartic protease. AB - Two different milk clotting enzymes, belonging to the aspartic protease family, were extracted from both artichoke leaves and alpine thistle flowers, and the latter was covalently immobilized by using a polyacrylic support containing polar epoxy groups. Our findings showed that the alpine thistle aspartic protease was successfully immobilized at pH 7.0 on Immobeads IB-150P beads and that, under these experimental conditions, an immobilization yield of about 68% and a recovery of about 54% were obtained. Since the enzyme showed an optimal pH of 5.0, a value very similar to the one generally used for milk clotting during cheese making, and exhibited a satisfactory stability over time, the use of such immobilized vegetable rennet for the production of novel dairy products is suggested. PMID- 26988484 TI - The use of delta(2)H and delta(18)O isotopic analyses combined with chemometrics as a traceability tool for the geographical origin of bell peppers. AB - Two approaches were investigated to discriminate between bell peppers of different geographic origins. Firstly, delta(18)O fruit water and corresponding source water were analyzed and correlated to the regional GNIP (Global Network of Isotopes in Precipitation) values. The water and GNIP data showed good correlation with the pepper data, with constant isotope fractionation of about 4. Secondly, compound-specific stable hydrogen isotope data was used for classification. Using n-alkane fingerprinting data, both linear discriminant analysis (LDA) and a likelihood-based classification, using the kernel-density smoothed data, were developed to discriminate between peppers from different origins. Both methods were evaluated using the delta(2)H values and n-alkanes relative composition as variables. Misclassification rates were calculated using a Monte-Carlo 5-fold cross-validation procedure. Comparable overall classification performance was achieved, however, the two methods showed sensitivity to different samples. The combined values of delta(2)H IRMS, and complimentary information regarding the relative abundance of four main alkanes in bell pepper fruit water, has proven effective for geographic origin discrimination. Evaluation of the rarity of observing particular ranges for these characteristics could be used to make quantitative assertions regarding geographic origin of bell peppers and, therefore, have a role in verifying compliance with labeling of geographical origin. PMID- 26988485 TI - Absolute quantification of Pru av 2 in sweet cherry fruit by liquid chromatography/tandem mass spectrometry with the use of a stable isotope-labelled peptide. AB - Pru av 2, a pathogenesis-related (PR) protein present in the sweet cherry (Prunus avium L.) fruit, is the principal allergen of cherry and one of the chief causes of pollen food syndrome (oral allergy syndrome). In this study, a quantitative assay for this protein was developed with the use of the protein absolute quantification (AQUA) method, which consists of liquid chromatography/tandem mass spectrometry (LC/MS/MS) employing TGC[CAM]STDASGK[(13)C6,(15)N2], a stable isotope-labelled internal standard (SIIS) peptide. This assay gave a linear relationship (r(2)>0.99) in a concentration range (2.3-600fmol/MUL), and the overall coefficient of variation (CV) for multiple tests was 14.6%. Thus, the contents of this allergenic protein in sweet cherry products could be determined using this assay. This assay should be valuable for allergological investigations of Pru av 2 in sweet cherry and detection of protein contamination in foods. PMID- 26988486 TI - Magnetic nanoparticles based dispersive micro-solid-phase extraction as a novel technique for the determination of estrogens in pork samples. AB - A simple and rapid magnetic nanoparticles (MNPs) based dispersive micro-solid phase extraction (D-MU-SPE) method coupled with HPLC-DAD has been proposed for simultaneous determination of three estrogens (17beta-estradiol (E2), estrone (E1) and diethylstilbestrol (DES)) in pork samples. In this paper, the synthesis of cetyltrimethyl ammonium bromide (CTAB)-coated Fe3O4@caprylic acid NPs as an efficient sorbent for its high surface area, excellent adsorption capacity, good dispersion ability and high super-paramagnetic property was successfully applied to adsorb estrogens. Vortex was used to enhance mass transfer rate as it provided mild and effective mixing of sample solution and increased the contact between analytes and MNPs. The parameters affecting the extraction efficiency were investigated in detail. The dosages of sorbent and eluate are 100MUL and 500MUL, respectively. The extraction equilibrium was achieved within 2min and the MNPs can be reused. The proposed technique provided high recoveries (93.3-106.7%), good linearity (0.9993-0.9999), low LODs (0.021-0.033ngmL(-1)) and repeatability (RSD%=1.87-2.92). PMID- 26988487 TI - The antioxidant potential of the New Zealand surf clams. AB - The antioxidant action of three New Zealand surf clams was evaluated for the first time. Aqueous (cd) and ethanolic extracts from Diamond shell - Crassula aequilatera, Storm shell - Mactra murchisoni, and Tua tua - Paphies donacina were studied for their antioxidant potentials using two in vitro assays. The ethanolic extracts were further fractioned into four parts; petroleum ether (pe), ethyl acetate (ea), n-butanol (nb), and the final aqueous fraction (w). Comparing among all fractions tested, the ea fraction of P. donacina showed the strongest free radical scavenging power, with a radical scavenging activity of 76.14% at 20MUg/mL. The ea fraction of C. aequilatera had the highest copper reducing activity with an absorbance of 1.596 at 20MUg/mL. Results from this study suggest that some bioactive compounds with significant antioxidant effects may exist in the New Zealand surf clams, and could potentially reduce oxidative stress to deliver health benefits or to produce functional foods. PMID- 26988488 TI - Antioxidant capacities and anthocyanin characteristics of the black-red wild berries obtained in Northeast China. AB - Various edible berries widely accessible in nature in Northeast China are poorly exploited. The compositions and contents of anthocyanins in black (Padus maackii, Padus avium, Lonicera caerulea, and Ribes nigrum) and red (Ribes rubrum, Sambucus williamsii, Rubus idaeus, and Ribes procumbens) wild berries in Northeast China were firstly characterized by HPLC-DAD/ESI-MS(2). Twenty-three anthocyanins were detected and identified. Cyanidin glycosides were dominant in both berries. Six anthocyanins were reported for the first time in P. avium, R. rubrum, and Sambucus. Total anthocyanin content (TAC) ranged from 10mg/100gfreshweight (FW) (R. procumbens) to 1058mg/100gFW (P. maackii) among berries. The TACs and antioxidant activities assessed by DPPH and FRAP assays were much higher in black than in red berries. Black-red berries, especially P. maackii and P. avium, can be used in developing functional foods and in improving breeding programs. PMID- 26988489 TI - Development of a low resolution (1)H NMR spectroscopic technique for the study of matrix mobility in fresh and freeze-thawed hen egg yolk. AB - Three experiments were conducted in developing a low resolution proton nuclear magnetic resonance ((1)H NMR) spectroscopic technique to study matrix mobility in fresh and freeze-thawed gelled yolk. The Carr-Purcell-Meiboom-Gill (CPMG) sequence was used to measure spin-spin relaxation times of proton pools representing major yolk constituents. A component identification test distinguished 3-4 pools. The least mobile pool was assigned to proteins, protein lipid and protein-water interactions, and the most mobile to unbound water. The remaining pools were assigned to lipids, lipid-protein and lipid-water interactions. A stability test indicated that yolk had varied matrix mobility within the same sample across five days of refrigeration storage. A reproducibility test demonstrated high repeatability of fresh yolk measurements, but significant differences (p<0.05) were found within gelled yolk samples. This research determined that (1)H NMR spectroscopy, a non-destructive technique, can identify yolk components and detect changes in the matrix. PMID- 26988490 TI - Application of ionic liquids for elution of bioactive flavonoid glycosides from lime fruit by miniaturized matrix solid-phase dispersion. AB - In this work, two flavonoid glycosides (neohesperidin and naringin) in lime fruit were effectively extracted by miniaturized matrix solid phase dispersion (MSPD), followed by ultra-performance liquid chromatography-ultraviolet detection. The best results were obtained using Florisil (150mg) as the sorbent and 1-butyl-3 methylimidazolium tetrafluoroborate (0.4mL, 250mM) as the elution solvent. This work represents the first attempt of using ionic liquids as a green eluent for extraction of the investigated compounds in miniaturized MSPD. Compared with the conventional methods, the proposed method is advantageous due to improved enrichment factor and reduced reagent consumption. A good linearity was observed with r(2) values (>0.998). Meanwhile, the method gave acceptable recoveries (90.16-96.47%) for the determination of flavonoids in plant samples. The limits of detection of the two analytes ranged between 4.08 and 5.04MUg/g. The results showed that the optimized method has a great potential for sample preparation in routine analysis of complex plant samples. PMID- 26988491 TI - Polyphenolic profiles and antioxidant and antiradical activity of Italian berries from Vaccinium myrtillus L. and Vaccinium uliginosum L. subsp. gaultherioides (Bigelow) S.B. Young. AB - Total soluble polyphenols (TSP), total monomeric anthocyanins (TMA), radical scavenging activity (RSA), ferric reducing antioxidant power (FRAP), and a number of anthocyanins, phenolic acids, coumarins, flavanols, dihydrochalcones and flavonols were investigated in Tuscan bilberry (i.e. Vaccinium myrtillus) and "false bilberry" (i.e. Vaccinium uliginosum subsp. gaultherioides Bigelow). V. myrtillus berries showed much higher TSP, TMA, RSA and FRAP values than V. uliginosum subsp. gaultherioides fruits. Moreover, very different profiles of individual phenolics were observed in the two species, being V. myrtillus mainly characterised by delphinidin and cyanidin glycosides, together with chlorogenic acid, and V. uliginosum subsp. gaultherioides dominated by malvidin derivatives and flavonols. Strong differences between the two species regarded also metabolites investigated herein for the first time, such as scopoletin, which was approximately two magnitude orders higher in V. uliginosum subsp. gaultherioides than in V. myrtillus berries. Very different abundances were also highlighted for cryptochlorogenic acid and quercetin-3-rhamnoside that were about ten-fold higher in bilberry than in "false bilberry". When the anthocyanin composition pattern of Tuscan "false bilberry" was compared to those elsewhere reported for V. uliginosum fruits harvested in different world areas, some important differences were observed. PMID- 26988492 TI - Chestnut and lemon balm based ingredients as natural preserving agents of the nutritional profile in matured "Serra da Estrela" cheese. AB - Chestnut flowers, lemon balm plants and their decoctions were incorporated into "Serra da Estrela" cheese, to assess their potential to preserve its nutritional properties and provide new foodstuffs. The analyses were carried out after the normal ripening period of 1month and after 6months of storage. The most abundant nutrients were proteins and fats. The most abundant minerals were Ca and Na, while C16:0 and C18:1 were the main fatty acids. Saturated fatty acids were the most abundant, followed by the monounsaturated. Moisture seemed to be lower in the samples with the plants incorporated. The dried plants, when incorporated, seemed to be more efficient as preservers then the decoctions, although these better preserved the proteins. These plants can be regarded as promising natural preservers in foodstuffs cheese, given the preservation of key parameters and the slight impact on the nutritional value. PMID- 26988493 TI - Co-surfactant free microemulsions: Preparation, characterization and stability evaluation for food application. AB - The aim of the study is to prepare co-surfactant free microalgal oil microemulsions and investigate their properties as well as processing stability for food application. The physicochemical characteristics of the microemulsions were investigated by dynamic light scattering (DLS), turbidity, conductivity, rheological measurements and transmission electron microscopy (TEM). Within the microemulsion region, when the surfactant to oil ratio was 9:1, the hydrodynamic diameter (Dh) was 18nm; when the surfactant to oil ratio was 7.5:1, the hydrodynamic diameter (Dh) was 50nm. Rheological studies proved that the microemulsion system was a pseudoplastic fluid, which followed a shear thinning flow behavior. The loss rate of docosahexaenoic acid (DHA) was less than 5%wt after ultra high temperature (UHT) and high temperature short time (HTST) thermal treatments. A high content of CaCl2 (10.0%wt) could not destroy the microemulsion system, and it could be stored at 4 degrees C for two years. PMID- 26988494 TI - Saffron authentication based on liquid chromatography high resolution tandem mass spectrometry and multivariate data analysis. AB - Saffron is one of the oldest and most expensive spices, which is often target of fraudulent activities. In this research, a new strategy of saffron authentication based on metabolic fingerprinting was developed. In the first phase, a solid liquid extraction procedure was optimized, the main aim was to isolate as maximal representation of small molecules contained in saffron as possible. In the second step, a detection method based on liquid chromatography coupled with high resolution mass spectrometry was developed. Initially, principal component analysis (PCA) revealed clear differences between saffron cultivated and packaged in Spain, protected designation of origin (PDO), and saffron packaged in Spain of unknown origin, labeled Spanish saffron. Afterwards, orthogonal partial least square discriminant analysis (OPLS-DA) was favorably used to discriminate between Spanish saffron. The tentative identification of markers showed glycerophospholipids and their oxidized lipids were significant markers according to their origin. PMID- 26988496 TI - Certain (-)-epigallocatechin-3-gallate (EGCG) auto-oxidation products (EAOPs) retain the cytotoxic activities of EGCG. AB - (-)-Epigallocatechin-3-gallate (EGCG) from green tea has anti-cancer effect. The cytotoxic actions of EGCG are associated with its auto-oxidation, leading to the production of hydrogen peroxide and formation of numerous EGCG auto-oxidation products (EAOPs), the structures and bioactivities of them remain largely unclear. In the present study, we compared several fundamental properties of EGCG and EAOPs, which were prepared using 5mg/mL EGCG dissolved in 200mM phosphate buffered saline (pH 8.0 at 37 degrees C) and normal oxygen partial pressure for different periods of time. Despite the complete disappearance of EGCG after the 4 h auto-oxidation, 4-h EAOPs gained an enhanced capacity to deplete cysteine thiol groups, and retained the cytotoxic effects of EGCG as well as the capacity to produce hydrogen peroxide and inhibit thioredoxin reductase, a putative target for cancer prevention and treatment. The results indicate that certain EAOPs possess equivalent cytotoxic activities to EGCG, while exhibiting simultaneously enhanced capacity for cysteine depletion. These results imply that EGCG and EAOPs formed extracellularly function in concert to exhibit cytotoxic effects, which previously have been ascribed to EGCG alone. PMID- 26988495 TI - Injection-port derivatization coupled to GC-MS/MS for the analysis of glycosylated and non-glycosylated polyphenols in fruit samples. AB - Polyphenols, including glycosylated polyphenols, were analyzed via a procedure based on injection-port derivatization coupled to gas chromatography-tandem mass spectrometry (GC-MS/MS). The polyphenols in lyophilized fruit samples were extracted with an acidified MeOH mixture assisted by ultrasound. Samples were dried under vacuum, and carbonyl groups were protected with methoxylamine. Free hydroxyl groups were subsequently silylated in-port. Mass fragmentations of 17 polyphenol and glycosylated polyphenol standards were examined using Multiple Reaction Monitoring (MRM) as the acquisition mode. Furthermore, in-port derivatization was optimized in terms of optimal injection port temperature, derivatization time and sample: N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) volume ratio. A C18 solid-phase-extraction clean-up method was used to reduce matrix effects and injection liner degradation. Using this clean-up method, recoveries for samples spiked at 1 and 10MUg/g ranged from 52% to 98%, depending on the chemical compound. Finally, the method was applied to real fruit samples containing the target compounds. The complete chromatographic runtime was 15min, which is faster than reported for recent HPLC methods able to analyze similar compounds. PMID- 26988497 TI - LC-DAD-ESI-MS/MS characterization of phenolic constituents in Turkish black tea: Effect of infusion time and temperature. AB - The influence of different infusion times and temperatures on phenolic, antioxidant, and color properties of black teas (Camellia sinensis L.) was investigated in the present study. The teas were prepared using infusion times of 3, 6, and 10min at 80 and 100 degrees C. Liquid chromatography coupled to diode array detection and electrospray ionization tandem mass spectrometry (LC-DAD-ESI MS/MS), whereby the two purine alkaloids were detected using positive ESI, and the other 33 phenolic compounds were detected using negative ESI. A total of 35 phenolic compounds were identified and quantified in the tea infusions, with the most abundant being gallic acid, (-)-epicatechin-gallate, 4-p-coumaroylquinic acid, quercetin-3-O-galactosyl-rhamnosyl-glucoside, kaempferol-3-O-glucosyl rhamnosyl-glucoside, theaflavin, and theobromine. The antioxidant capacity of the tea infusions was determined using two different methods: DPPH (2,2-diphenyl-1 picryl hydrazyl) and ABTS (2,2'-azino-bis-3-ethyl-benzothiazoline-6-sulfonic acid) assays. DPPH and the ABTS values varied largely among the tea preparations. The increment in infusion times and temperature led to increase in the tea's antioxidant capacities. PMID- 26988498 TI - Effect of protein structure on water and fat distribution during meat gelling. AB - Emulsion-type sausages were produced, at 80 degrees C for either 0, 10, 20 or 30min, using homogeneous Taihu pork batters. Low-field nuclear magnetic resonance (LF-NMR), with or without deuterium oxide (D2O) substitution, evaluated the proton mobility states related to both water and fat molecules, or fat molecules only, respectively, in the sausage samples, during heat-induced gelation. The decreasing trend in the area proportion of main peak T21, reflected a tighter gel structure in emulsion-type sausages. Raman spectra (400-3600cm(-1)) revealed decreased alpha-helix, but increased beta-sheet, beta-turns and random coil contents, during the gelling process. Moreover, principal component analysis (PCA) showed significant correlations between secondary protein structures with distribution of water and fat in the gel matrix. Furthermore, this study established the relationship of water and fat protons mobility with changes in secondary protein structures, and described the critical time of gel formation in emulsion-type pork sausages. PMID- 26988499 TI - Selenium modification of beta-lactoglobulin (beta-Lg) and its biological activity. AB - beta-Lg is a major whey protein in cow's milk. This study was aimed to find a new kind of organic selenium compound synthesized with beta-Lg and selenium dioxide as raw materials under the conditions of vacuum and low temperature. Fourier transformed infrared spectroscopy revealed that seleno-beta-lactoglobulin (Se beta-Lg) displayed a strong band at 878cm(-1), belonging to SeO. Circular dichroism spectra results indicated that the conformation of Se-beta-Lg was transformed and alpha-helical, and unordered structures were increased by 9% and 11.2%, respectively, while beta-sheet and beta-turn were reduced by 14.2% and 6%, respectively. Electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry results showed that there were two protein bands (1-Sebeta-Lg and 2-Sebeta-Lg) in Se-beta-Lg, only one beta-Lg connected with selenate in 1-Sebeta-Lg, but two beta-Lgs, connected to each other, and with selenate, in 2-Sebeta-Lg. Morphological observation and hematoxylin and eosin staining indicated that Se-beta-lg could induce K562 cell apoptosis. These results indicated that Se-beta-Lg could be synthesized by selenium conjugating beta-Lg and it had antitumor activity. PMID- 26988501 TI - Rapid direct analysis to discriminate geographic origin of extra virgin olive oils by flash gas chromatography electronic nose and chemometrics. AB - At present, the geographical origin of extra virgin olive oils can be ensured by documented traceability, although chemical analysis may add information that is useful for possible confirmation. This preliminary study investigated the effectiveness of flash gas chromatography electronic nose and multivariate data analysis to perform rapid screening of commercial extra virgin olive oils characterized by a different geographical origin declared in the label. A comparison with solid phase micro extraction coupled to gas chromatography mass spectrometry was also performed. The new method is suitable to verify the geographic origin of extra virgin olive oils based on principal components analysis and discriminant analysis applied to the volatile profile of the headspace as a fingerprint. The selected variables were suitable in discriminating between "100% Italian" and "non-100% Italian" oils. Partial least squares discriminant analysis also allowed prediction of the degree of membership of unknown samples to the classes examined. PMID- 26988500 TI - Multiresidue analysis of sulfonamides, quinolones, and tetracyclines in animal tissues by ultra-high performance liquid chromatography-tandem mass spectrometry. AB - A multiresidue method for the efficient identification and quantification of 38 compounds from 3 different classes of antibiotics (tetracyclines, sulfonamides, and quinolones) in animal tissues has been developed. The method optimization involved the selection of extraction solutions, comparison of different solid phase extraction cartridges and different mobile phases. As a result, the samples were extracted with Mcllvaine and phosphate buffers, followed by clean-up step based on solid-phase extraction with Oasis HLB cartridge. All compounds were determined by ultra-high performance liquid chromatography-tandem mass spectrometry, in one single injection with a chromatographic run time of only 9min. The method efficiency was evaluated in 5 tissues including muscle, liver, and kidney, and the mean recoveries ranged from 54% to 102%, with inter-day relative standard deviation lower than 14%. The limits of quantification were between 0.5 and 10MUg/kg, which were satisfactory to support future surveillance monitoring. The developed method was applied to the analysis of swine liver and chicken samples from local markets, and sulfamethazine was the most commonly detected compound in the animal samples, with the highest residue level of 998MUg/kg. PMID- 26988502 TI - Identification of flavonoids from Flammulina velutipes and its neuroprotective effect on pheochromocytoma-12 cells. AB - The flavonoids from Flammulina velutipes (FVF) were isolated and the chemical composition of FVF was identified by high-performance liquid chromatography/mass spectrometry (HPLC/MS). The antioxidant activity and the neuroprotective effect against H2O2-induced pheochromocytoma-12 cells (PC12) cytotoxicity of FVF was investigated. Six flavonoids from FVF were identified as arbutin, epicatechin, phillyrin, apigenin, kaempferol and formononetin. Obtained results suggested that FVF possesses strong antioxidant properties in 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical scavenging activities as well as reducing power. Pretreatment of PC12 cells with FVF significantly increased the survival rate of cells, glutathione level and superoxide dismutase activity. Conversely, the pretreatment reduced the release of lactate dehydrogenase and the accumulation of both intracellular reactive oxygen species and malondialdehyde. These findings collectively suggested that the protective effects of FVF against H2O2-induced neurotoxicity in PC12 cells as well as the potential for neuroprotection of FVF could be due to its antioxidant action. PMID- 26988503 TI - Optimization of arsenic extraction in rice samples by Plackett-Burman design and response surface methodology. AB - Statistical experimental designs were employed to optimize the extraction condition of arsenic species (As(III), As(V), monomethylarsonic acid (MMA) and dimethylarsonic acid (DMA)) in paddy rice by a simple solvent extraction using water as an extraction reagent. The effect of variables were estimated by a two level Plackett-Burman factorial design. A five-level central composite design was subsequently employed to optimize the significant factors. The desirability parameters of the significant factors were confirmed to 60min of shaking time and 85 degrees C of extraction temperature by compromising the experimental period and extraction efficiency. The analytical performances, such as linearity, method detection limits, relative standard deviation and recovery were examined, and these data exhibited broad linear range, high sensitivity and good precision. The proposed method was applied for real rice samples. The species of As(III), As(V) and DMA were detected in all the rice samples mostly in the order As(III)>As(V)>DMA. PMID- 26988504 TI - Combination of solid-phase extraction with dispersive liquid-liquid microextraction followed by GC-MS for determination of pesticide residues from water, milk, honey and fruit juice. AB - In this work, an effective preconcentration method for the extraction and determination of traces of multi-residue pesticides was developed using solid phase extraction (SPE) coupled with dispersive liquid-liquid microextraction and gas chromatography-mass spectrometry (GC-MS). Variables affecting the performance of both extraction steps such as type and volume of elution and extraction solvents, breakthrough volume, salt addition, extraction time were thoroughly investigated. The proposed method resulted in good linearities (R(2)>0.9915) over the ranges of 1-10,000ngkg(-1), limits of detection (LODs) in the range of 0.5 1.0ngkg(-1) at S/N=3, and precision of RSD% of ?11.8. Under optimal conditions, the preconcentration factors were obtained in the range of 2362-10,593 for 100mL sample solutions. Comparison of the proposed method with other ones demonstrated that SPE-DLLME method provides higher extraction efficiency and larger preconcentration factor for determination of pesticides residues. Further, it is simple, inexpensive, highly sensitive, and can be successfully applied to separation, preconcentration and determination of the pesticides (and other noxious materials) in different real food samples. PMID- 26988505 TI - Identification of the bioactive and consensus peptide motif from Momordica charantia insulin receptor-binding protein. AB - Many food bioactive peptides with diverse functions have been discovered by studying plant proteins. We have previously identified a 68-residue insulin receptor (IR)-binding protein (mcIRBP) from Momordica charantia that exhibits hypoglycemic effects in mice via interaction with IR. By in vitro digestion, we found that mcIRBP-19, spanning residues 50-68 of mcIRBP, enhanced the binding of insulin to IR, stimulated the phosphorylation of PDK1 and Akt, induced the expression of glucose transporter 4, and stimulated both the uptake of glucose in cells and the clearance of glucose in diabetic mice. Furthermore, mcIRBP-19 homologs were present in various plants and shared similar beta-hairpin structures and IR kinase-activating abilities to mcIRBP-19. In conclusion, our findings suggested that mcIRBP-19 is a blood glucose-lowering bioactive peptide that exhibits IR-binding potentials. Moreover, we newly identified novel IR binding bioactive peptides in various plants which belonged to different taxonomic families. PMID- 26988506 TI - Detection of regulated disinfection by-products in cheeses. AB - Cheese can contain regulated disinfection by-products (DBPs), mainly through contact with brine solutions prepared in disinfected water or sanitisers used to clean all contact surfaces, such as processing equipment and tanks. This study has focused on the possible presence of up to 10 trihalomethanes (THMs) and 13 haloacetic acids (HAAs) in a wide range of European cheeses. The study shows that 2 THMs, (in particular trichloromethane) and 3 HAAs (in particular dichloroacetic acid) can be found at MUg/kg levels in the 56 cheeses analysed. Of the two types of DBPs, HAAs were generally present at higher concentrations, due to their hydrophilic and non-volatile nature. Despite their different nature (THMs are lipophilic), both of them have an affinity for fatty cheeses, increasing their concentrations as the percentage of water decreased because the DBPs were concentrated in the aqueous phase of the cheeses. PMID- 26988507 TI - Optimizing elicitation and seed priming to enrich broccoli and radish sprouts in glucosinolates. AB - Elicitation is a cheaper and socially acceptable tool for improving plant food functionality. Our objective was to optimize the treatment doses of the elicitors: methyl jasmonate (MeJA), jasmonic acid (JA) and DL-methionine (MET), in order to find a successful and feasible treatment to produce broccoli and radish sprouts with enhanced levels of health-promoting glucosinolates. Also a priming of seeds as a novel strategy to trigger the glucosinolates content was carried out with water (control), MeJA (250MUM), JA (250MUM) and MET (10mM) before the elicitor exogenous treatment. The results showed that almost all treatments could enhance effectively the total glucosinolates content in the sprouts, achieving the most significant increases from 34% to 100% of increase in broccoli and from 45% to 118% of increase in radish sprouts after MeJA priming and treatments. Consequently, our work demonstrates the feasibility of using elicitors, such as plant stress hormones, by priming and exogenously, as a way of increase the phytochemical profile of these sprouts to enhance their consumption in the diet. PMID- 26988508 TI - Effects of extrusion conditions on the extrusion responses and the quality of brown rice pasta. AB - This research investigated the effects of extrusion temperature and screw speed on the extrusion system parameters and the qualities of brown rice pasta. The die pressure and motor torque value reached a maximum at 90 degrees C but decreased when the screw speed increased from 80 to 120rpm. The extrusion temperature and screw speed also significantly affected the cooking quality and textural properties of brown rice pasta. The pasta produced at an extrusion temperature of 120 degrees C and screw speed of 120rpm had the best quality with a cooking loss, hardness and adhesiveness of 6.7%, 2387.2g and -7.0g?s, respectively, similar to those of pasta made from gluten-free flour. The results indicated that brown rice can be used to produce gluten-free pasta with improved nutrition. PMID- 26988509 TI - Microencapsulation of Nigella sativa oleoresin by spray drying for food and nutraceutical applications. AB - Oleoresin of Nigella sativa L. (Black cumin) was obtained from the seeds using hexane extraction at room temperature. The oleoresin was emulsified in an aqueous solution containing gum Arabic/maltodextrin (1:1 w/w) and then encapsulated in powder form by spray drying. The characteristics of the obtained powder including moisture content, bulk density, wettability, morphology, encapsulation efficiency were evaluated. The effect of the spray drying on the chemical composition of the volatile oil fraction of N. sativa oleoresin was also evaluated using gas chromatographic-mass spectroscopic analysis. Results indicated that the encapsulation efficiency of the whole oleoresin in the powder can range from 84.2+/-1.5% to 96.2+/-0.2% depending on the conditions of extracting the surface oil from the powder. On the other hand the encapsulation efficiency of the volatile oil fraction was 86.2% +/-4.7. The formulated N. sativa L. oleoresin powder can be used in the fortification of processed food and nutraceuticals. PMID- 26988510 TI - Simultaneous determination of phenolic compounds in sesame oil using LC-MS/MS combined with magnetic carboxylated multi-walled carbon nanotubes. AB - A novel magnetic carboxylated multi-walled carbon nanotubes (c-MWCNT-MNPs) was proposed for magnetic solid-phase extraction coupled with liquid chromatography tandem mass spectrometry to determine phenolic compounds in sesame oil. In this study, c-MWCNT-MNPs were acquired by simply dispersing Fe3O4 magnetic nanoparticles into carboxylated multi-walled carbon nanotubes. The major parameters affecting extraction efficiency were optimized, including the type and volume of desorption solvents, extraction and desorption time, washing solution, and sorbent amount. The limit of quantifications and limit of detections were from 0.03MUg/kg to 43.00MUg/kg and from 0.01MUg/kg to 13.60MUg/kg, respectively. The recoveries of phenolic compounds in vegetable oils were in the range of 83.8 125.9% with inter-day and intra-day precisions of less than 13.2%. It was confirmed that this method was simple, rapid and reliable with an excellent potential for routine analysis of phenolic compounds in oil samples. PMID- 26988511 TI - The dynamics of the biological membrane surrounding the buffalo milk fat globule investigated as a function of temperature. AB - The biological membrane surrounding fat globules in milk (the MFGM) is poorly understood, despite its importance in digestion and in determining the properties of fat globules. In this study, in situ structural investigations of buffalo MFGM were performed as a function of temperature (4-60 degrees C), using confocal microscopy. We demonstrate that temperature and rate of temperature change affected the lipid domains formed in the MFGM with the lateral segregation (i) of high Tm lipids and cholesterol in a Lo phase for both TTm and (ii) of high Tm lipids in a gel phase for T97%) and identified by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR), then a rapid and simple HPLC coupled with evaporative light scattering detection (ELSD) method has been developed for the simultaneous determination of sucralose and related compounds. Under optimized conditions, the method showed good linearity in the range of 2-600MUgmL(-1) with determination coefficients R(2)?0.9990. Moreover, low limits of detection in the range of 0.5-2.0MUgmL(-1) and good repeatability (RSD<3%, n=6) were obtained. Recoveries were from 96.8% to 101.2%. Finally, the method has been successfully applied to sucralose quality control and purification process monitoring. PMID- 26988514 TI - Isolation, purification and characterization of antioxidative peptide of pearl millet (Pennisetum glaucum) protein hydrolysate. AB - Pearl millet (Pennisetum glaucum) is a rich source of protein, used for present study to hydrolyze protein, peptide separation and its functional activity. Antioxidative bioactive peptide was successfully identified from pearl millet using trypsin enzyme. Different antioxidative potential of isolated peptide were assessed based on activity of DPPH radical, ABTS radical, hydroxyl radical, Fe(2+) chelating ability and reducing power. Bioactive peptide separated by gel filtration chromatography, showed the higher antioxidant activity as tested by different free radicals. The activity of pearl millet protein hydrolysate fraction was found for DPPH assay (67.66%), ABTS assay (78.81%), Fe(2+) chelating ability (51.20%), hydroxyl assay (60.95%) and reducing power (0.375nm) was further purified using reversed-phase UFLC and subjected to matrix assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (MALDI TOF/TOF-MS) for sequential identification of the peptide. The sequence SDRDLLGPNNQYLPK was identified as antioxidant peptide. PMID- 26988515 TI - Nitric oxide mediates isoflavone accumulation and the antioxidant system enhancement in soybean sprouts. AB - In this study, we investigated the relationships between endogenous NO signal transduction pathways, the antioxidant system and isoflavone accumulation induced by UV-B radiation in soybean sprouts. Results showed that UV-B-triggered NO generation induced isoflavone accumulation by up-regulating the activity and gene expression of key enzymes (phenylalanine ammonia lyase, PAL; chalcone isomerase, CHI; chalcone synthase, CHS; isoflavone synthase, IFS) that participate in isoflavone biosynthesis and enhanced the antioxidant system by regulating levels of antioxidants (glutathione reductase, GR; glutathione S-transferase, GST; ascorbate peroxidase, APX; glutathione GSH; ascorbic acid, ASC), antioxidant enzyme activities (superoxide dismutase, SOD; peroxidase, POD; catalase, CAT) and their gene expression. These effects were inhibited by the addition of a specific NO-scavenger, carboxy-PTIO (cPTIO). The inhibition was reversed through application of the exogenous NO donor, SNP. Overall, NO is an essential signaling molecule, mediating UV-B-induced isoflavone accumulation and the antioxidant system enhancement in soybean sprouts. PMID- 26988516 TI - Variations in oxygen and ellagitannins, and organoleptic properties of red wine aged in French oak barrels classified by a near infrared system. AB - During wine aging in barrels, antioxidant molecules from wood, such as ellagitannins, are solubilized and react with wine molecules and oxygen. However, their concentrations are highly variable. Oxygen is an important factor, as it plays a role in wine parameters and organoleptic perceptions. Five barrel modalities were used; three polyphenol indices (IP), classified using the NIRS procedure, and three grain qualities. Barrels were equipped with windows to measure the oxygen using luminescence technology. The ellagitannin concentrations in the wine and its organoleptic properties were monitored. Oxygen concentrations decreased quickly during the first 8days of aging and this phenomenon was significantly more marked in barrels with a higher IP and medium grain. The ellagitannin concentrations were believed to be correlated with wood classification and oxygen consumption. Furthermore, the organoleptic properties were significantly impacted, as the wine with the lowest ellagitannin level was described as less astringent, bitter, woody, and smoky/toasty. PMID- 26988517 TI - Cationic beta-lactoglobulin nanoparticles as a bioavailability enhancer: Effect of surface properties and size on the transport and delivery in vitro. AB - BLG (beta-lactoglobulin) and CBLG (cationic BLG developed by our lab) were evaluated as potential nutraceutical/drug carriers. The cationic corona conferred CBLG with superior integrity and drug retention under gastrointestinal conditions, at most 40-fold higher mucoadhesion, up to 30-fold greater transepithelial permeation and, at most 285% higher cellular uptake, compared to BLG. Furthermore, the more hydrophilic CBLG species exhibited better mucoadhesion, while the more hydrophobic one exhibited higher cellular uptake. Intriguingly, protein molecules were more cytotoxic and exhibited up to 175% higher tight junction-opening capacity than did protein nanoparticles, whereas the nanoparticles displayed up to 770% higher mucoadhesion, greater transepithelial permeation and elevated cellular uptake. Finally, all these surface properties and performances were significantly altered as CBLG bound to serum proteins. Possible mechanisms underlying these findings are discussed in detail. This research sheds some light on the development of protein-based nanoencapsulants and their performance upon oral administration. PMID- 26988518 TI - Determination of benzoxazinoids in wheat and rye beers by HPLC-DAD and UPLC-QTOF MS. AB - Phenolic compounds in beer have received considerable interest. Besides the more typical phenolic acids and flavonoids, beer contains also lesser-known compounds, such as hordatines, their agmatine precursors and other phenolamines. Current work shows that beers brewed from wheat or rye malts, in addition to barley malts, contain benzoxazinoids, a group of nitrogen containing secondary metabolites typical to wheat and rye. In this work, HPLC-DAD was used for the quantification of major benzoxazinoids in 32 wheat and four rye beers. Of the wheat beers 22 samples and all of the rye beers contained benzoxazinoids, or their breakdown products. Concentrations of DIBOA (2,4-dihydroxy-1,4-benzoxazin-3 one) (as aglycon) varied from 1.7 to 21.9mg/l in wheat beers and from 5.6 to 31.6mg/l in rye beers. Breakdown products BOA (benzoxazolin-2-one), found in 15 beers, and MBOA (6-methoxy-benzoxazolin-2-one), found in two beers, were measured at concentrations ranging from 2.4 to 10.7mg/l and 8.4 to 10.5mg/l, respectively. Identification of benzoxazinoids by UPLC-QTOF MS was done on selected beers. Benzoxazinoid profiles varied greatly between different wheat beers, and compared to rye beers the chemical diversity of benzoxazinoids was higher. As far as the authors know, this is the first time that other benzoxazinoids, rather than just the decomposition products BOA or MBOA, have been reported in beer. The results also show that benzoxazinoids can be present in beer glycosylated with three or four hexose units. PMID- 26988519 TI - Antioxidant activity of cod (Gadus morhua) protein hydrolysates: Fractionation and characterisation of peptide fractions. AB - This study aimed to characterise peptide fractions (>5kDa, 3-5kDa and <3kDa) with antioxidative activity obtained from a cod protein hydrolysate. The free amino acids in all fractions were dominated by Ala, Gly, Glu and Ser. The total amino acid composition had high proportions of Lys, Ala and Glu. The 3-5kDa and <3kDa fractions were further fractionated by size exclusion chromatography. All sub fractions showed high Fe(2+) chelating activity. The DPPH radical-scavenging activity of the 3-5kDa fraction was exerted mainly by one sub-fraction dominated by peptides with masses below 600Da. The DPPH radical-scavenging activity of the <3kDa fraction was exerted by sub-fractions with low molecular weight. The highest reducing power was found in a sub-fraction containing peptides rich in Arg, Tyr and Phe. Both free amino acids and low molecular weight peptides thus seemed to contribute to the antioxidative activity of the peptide fractions, and Tyr seemed to play a major role in the antioxidant activity. PMID- 26988520 TI - Development of an antioxidant biomaterial by promoting the deglycosylation of rutin to isoquercetin and quercetin. AB - Quercetin-3-O-rutinoside (rutin), quercetin-3-O-glucoside (isoquercetin) and quercetin have shown antioxidant, cytoprotective, vasoprotective, antiproliferative and antiinflammatory properties. The aim of this work was to determine the conversion of rutin to isoquercetin and quercetin during the production of poly(l-lactic acid) films with potential to deliver these flavonoids toward tissues, pharmaceuticals or food matrices. Three poly(l-lactic acid) formulations with 17.7, 39.6 and 39.1mg/g of rutin were prepared by the extrusion process. Processing temperatures (130-165 degrees C) promoted the deglycosylation of rutin to produce isoquercetin and subsequently quercetin, identified by high performance liquid chromatography coupled to mass spectrometry. The effect of the process on the antioxidant activity of the films was determined by measuring the capacity to scavenge 2,2 diphenyl-1 picrylhydrazyl radicals. The material with the highest proportion of quercetin showed the highest antioxidant activity which could be used to produce delivering devices of the flavonoids to tissues, pharmaceuticals or food matrices. PMID- 26988522 TI - Synthesis and emulsifying properties of carbohydrate fatty acid esters produced from Agave tequilana fructans by enzymatic acylation. AB - Carbohydrate fatty acid esters are non-ionic surfactants with a broad spectrum of applications. These molecules are generally synthesized using short carbohydrates or linear fructans; however in this research carbohydrate fatty acid esters were produced for the first time with branched fructans from Agave tequilana. Using immobilized lipases we successfully acylated A. tequilana fructans with vinyl laurate, obtaining products with different degrees of polymerization (DP). Lipozyme 435 was the most efficient lipase to catalyze the transesterification reaction. HPLC and ESI-MS analysis proved the presence of a mixture of acylated products as a result of the chemical complexity of fructans in the A. tequilana. The ESI-MS spectra showed a molecular mass shift between 183 and 366g/mol for fructooligosaccharides with a DP lower than 6, which indicated the presence of Agave fructans that had been mono- and diacylated with lauric acid. The carbohydrate fatty acid esters (CFAE) obtained showed good emulsifying properties in W/O emulsions. PMID- 26988521 TI - Preparation of antioxidative corn protein hydrolysates, purification and evaluation of three novel corn antioxidant peptides. AB - Corn gluten meal is a major co-product of corn wet milling. Corn gluten meal was hydrolyzed with Alcalase, Flavourzyme, Alcalase+Flavourzyme and Flavourzyme+Alcalase. At the substrate concentration of 10%, corn protein hydrolysate catalyzed by Alcalase had a degree of hydrolysis of 17.83%, which was higher than that by Flavourzyme (3.65%). The hydrolysate catalyzed by Alcalase+Flavourzyme exhibited better antioxidant activities and was further purified. Three novel antioxidant peptides were purified by a series of chromatographic techniques. Sequences of the three peptides were identified as Cys-Ser-Gln-Ala-Pro-Leu-Ala, Tyr-Pro-Lys-Leu-Ala-Pro-Asn-Glu and Tyr-Pro-Gln-Leu Leu-Pro-Asn-Glu, respectively. Among the three peptides, Cys-Ser-Gln-Ala-Pro-Leu Ala exhibited good reducing power and excellent scavenging capacities for DPPH radical and superoxide anion radical, with IC50 values of 0.116 and 0.39mg/ml, respectively. The results from our study indicate antioxidant potency of corn protein hydrolysates and peptides separated from corn gluten meal and can provide basic understanding for the application of corn protein hydrolysates as natural antioxidants. PMID- 26988523 TI - Development of dual-emission ratiometric probe-based on fluorescent silica nanoparticle and CdTe quantum dots for determination of glucose in beverages and human body fluids. AB - A novel dual emission ratiometric fluorescence probe for determination of glucose has been developed. The reference dye fluorescence isothiocyanate (FITC) has been encapsulated in the silica nanoparticles and then the red emission CdTe QDs were grafted on the surface of the silica particles to obtain the fluorescence probe. With glucose and dopamine as substrates, the glucose level was proportional to the fluorescence ratio change of above probe caused by dopamine oxidation, which was produced via bienzyme catalysis (glucose oxidase and horseradish peroxidase). The established approach was sensitive and selective, and has been applied to determine the glucose in beverage, urine and serum samples. The average recoveries of the glucose at various spiking levels ranged from 95.5% to 108.9% with relative standard deviations from 1.5% to 4.3%. The results provided a clue to develop sensors for rapid determination of the target analytes from complex matrices. PMID- 26988524 TI - Biotransformation of polyphenols in a dynamic multistage gastrointestinal model. AB - A multi-reactor gastrointestinal model was used to digest a mixture of pure polyphenol compounds, including non-flavonoid phenolic acids (chlorogenic acid, caffeic acid, ferulic acid) and a flavonoid (rutin) to identify phenolic metabolites and short chain fatty acids (SCFAs) and compare relative antioxidant capacities following a 24h digestion. Biotransformation of these polyphenols occurred in the colonic compartments generating phenylpropionic, benzoic, phenylacetic and cinnamic acids. Total SCFAs increased in all colonic vessels with a rise in the proportion of propionic to acetic acid. Antioxidant capacity increased significantly in all compartments, but first in the stomach, small intestine and ascending colon. After 24h, the colonic vessels without parent polyphenols, but containing new metabolites, had antioxidant capacities similar to the stomach and small intestine, containing parent compounds. Biotransformation of pure polyphenols resulted in different phenolic metabolite and SCFAs profiles in each colonic segment, with important health implications for these colonic compartments. PMID- 26988525 TI - Terpene evolution during the development of Vitis vinifera L. cv. Shiraz grapes. AB - The flavour of wine is derived, in part, from the flavour compounds present in the grape, which change as the grapes accumulate sugar and ripen. Grape berry terpene concentrations may vary at different stages of berry development. This study aimed to investigate terpene evolution in grape berries from four weeks post-flowering to maturity. Grape bunches were sampled at fortnightly intervals over two vintages (2012-13 and 2013-14). In total, five monoterpenoids, 24 sesquiterpenes, and four norisoprenoids were detected in grape samples. The highest concentrations of total monoterpenoids, total sesquiterpenes, and total norisoprenoids in grapes were all observed at pre-veraison. Terpenes derived from the same biosynthetic pathway had a similar production pattern during berry development. Terpenes in grapes at harvest might not necessarily be synthesised at post-veraison, since the compounds or their precursors may already exist in grapes at pre-veraison, with the veraison to harvest period functioning to convert these precursors into final products. PMID- 26988526 TI - An evaluation of the bioaccessibility of arsenic in corn and rice samples based on cloud point extraction and hydride generation coupled to atomic fluorescence spectrometry. AB - A simple, inexpensive and rapid method was proposed for the determination of bioaccessible arsenic in corn and rice samples using an in vitro bioaccessibility assay. The method was based on the preconcentration of arsenic by cloud point extraction (CPE) using o,o-diethyldithiophosphate (DDTP) complex, which was generated from an in vitro extract using polyethylene glycol tert-octylphenyl ether (Triton X-114) as a surfactant prior to its detection by atomic fluorescence spectrometry with a hydride generation system (HG-AFS). The CPE method was optimized by a multivariate approach (two-level full factorial and Doehlert designs). A photo-oxidation step of the organic species prior to HG-AFS detection was included for the accurate quantification of the total As. The limit of detection was 1.34MUgkg(-1) and 1.90MUgkg(-1) for rice and corn samples, respectively. The accuracy of the method was confirmed by analyzing certified reference material ERM BC-211 (rice powder). The corn and rice samples that were analyzed showed a high bioaccessible arsenic content (72-88% and 54-96%, respectively), indicating a potential human health risk. PMID- 26988528 TI - Report of the International Symposium on Phytochemicals in Medicine and Food (ISPMF 2015). AB - The International Symposium on Phytochemicals in Medicine and Food (ISPMF2015) was held June 26-29, 2015, in Shanghai, China. This is the first time that a PSE meeting has been held in Asia and a PSE-PSA joint symposium provided an opportunity for communication between scientists from European and Asian countries. More than 270 scientists from 48 countries attended this meeting. ISPMF2015 assembled an exciting and diverse programme with 16 sessions, consisting of 12 plenary lectures, 20 invited talks, 55 short oral presentations, and in excess of 130 posters, dedicated to creating a podium for exchanging the latest research results on phytochemicals for food and human health. PMID- 26988527 TI - Phytochemistry and pharmacological activities of the genus Prunella. AB - Prunella is a genus of perennial herbaceous plants in the Labiatae family. There are approximately 15 species worldwide, distributed widely in the temperate regions and tropical mountains of Europe and Asia. In the genus Prunella, P. vulgaris is the most studied, following a several thousand-year history as a traditional antipyretic and antidotal Chinese herb. Furthermore, since ancient times, P. vulgaris has been widely used as a cool tea ingredient and consumed as a vegetable. The genus Prunella contains triterpenoids and their saponins, phenolic acids, sterols and associated glycosides, flavonoids, organic acids, volatile oil and saccharides. Modern pharmacological studies have revealed that Prunella possess antiviral, antibacterial, anti-inflammatory, immunoregulatory, anti-oxidative, anti-tumor, antihypertensive and hypoglycemic functions. The active components related to these functions are mainly triterpenoids, phenolic acids, flavonoids and polysaccharides. This review mainly summarizes recent advances in traditional usage, chemical components and pharmacological functions. PMID- 26988529 TI - Effect of toasting on non-volatile and volatile vine-shoots low molecular weight phenolic compounds. AB - Low molecular weight phenolic compounds (LMWPC), including non-volatile and volatile, of Airen and Moscatel vine-shoot cultivars waste submitted to different toasting conditions (light, 180 degrees /15min; medium, 180 degrees /30min; high 180 degrees /45min) were studied in order to exploit them with oenological purposes. The LMWPC differences were mainly due to the toasting times rather than vine-shoot variety. In non-volatile LMWPC fraction, flavanols and almost all phenolic acids decreased by toasting. The presence of trans-resveratrol has a special relevance at light toasting: 14 times more concentrated in Airen and 6 times in Moscatel vine-shoots, than their respective non-toasted samples. The volatile LMWPC showed a significant increment with toasting, being vanillin the one with the highest difference respect to non-toasted samples at high conditions: more than 15 times in Airen and 11 in Moscatel. Although toasting reduced some LMWPC, particular characteristics of these vine-shoots must be taken into account when considering its future use. PMID- 26988530 TI - Tannin profile of different Monastrell wines and its relation to projected market prices. AB - This study focuses on the differences or similarities in tannin composition and concentration in Monastrell wines from different wineries from the same geographic area and, within each winery, from wines elaborated based on different projected market prices, to determine whether there is any relationship between the wine tannin composition and the projected price. The tannin composition of the different wines, all of them analyzed at the same point during winemaking, indicated that those elaborated as premium wines presented higher phenol and tannin contents. The mean degree of polymerization of these wines was also positively related with the projected price, which agreed with the results obtained by size exclusion chromatography, that showed that wines with high projected prices had a higher proportion of polymeric tannins, suggesting that techniques favoring the extraction of skin tannins were mostly used in those wines projected as premium wines, probably looking for greater mouthfeel complexity. PMID- 26988531 TI - A green analytical method for rapid determination of pectin degree of esterification using micro sequential injection lab-on-valve system. AB - A novel method for automated determination pectin degree of esterification (DE) using micro sequential injection lab-on-valve (MUSI-LOV) system is developed. A face-centered central composite response surface methodology (RSM) was used to optimise system parameters. A calibration graph for determination of non esterified galacturonic acid (GalA) content in pectin solutions with linear range of 0.08-0.34% (w/v) and the limit of detection (LOD) of 0.057% (w/v) under optimal condition was achieved. The difference between concentrations (w/v, %) of total GalA and non-esterified GalA was applied to estimate DE (%) of pectin samples. Results indicated a good agreement (tstat0.05). CONCLUSIONS: As compared to BPSFB and BPSFC, UPSFB has the same reliability and effectiveness in treating single segment LDD with unilateral radicular symptoms in a single lower extremity, with the additional advantage being less expensive. PMID- 26988534 TI - Actualities in Ovarian Cancer in the Perspective of 2015 (ASCO and ECCO). AB - Ovarian cancer represents the 4-th reason of cancer related death in women, the majority of patients being diagnosed in advanced stages of the disease, (III-IV). The loco-regional advanced ovarian cancer should be considered a chronic disease, with multiple evolutionary relapses and where the adjuvant treatment is mandatory.The treatment of the disease is multidisciplinary and the oncologist is the centerpiece. PMID- 26988535 TI - Benefits and Disadvantages of Neoadjuvant Radiochemotherapy (RCT) in the Multimodal Therapy of Squamous Esophageal Cancer (ESC). AB - INTRODUCTION: The purpose of this paper is to present the advantages and disadvantages of neoadjuvant RCT in multimodal therapyof ESC. MATERIAL AND METHOD: Between 1998-2014 221 patients were treated with ESC, 85 of whom received neoadjuvant RCT. For these we have made imaging and pathologic assessment of response using RECIST and MANDARD criteria and statistical data were interpreted in terms of the factors that influence the response. Also, they were evaluated statistical correlations between RCT and resectability, postoperative morbidity, mortality and long-term survival. RESULTS: 45 patients were imagistic responders and 34 underwent surgery, 40 non-responders of which 14 underwent surgery. Of the 48 surgical patients with preoperative RCT, histopathological evaluation showed that 32 were pathological responders and 16 non responders. There were performed statistical analyzes of correlations between RCT and resectability, stage, location of ESC, morbidity, mortality and survival. CONCLUSION: RCT increase resectability, improves survival and maximum duration of survival, more in responders than in nonresponders and does not affect postoperative complications and postoperative mortality, nor among the responders or nonresponders. Imaging evaluation result of the response to RCT overestimate responders. PMID- 26988536 TI - Selective Intraoperative Cholangiography in Laparoscopic Cholecystectomy. AB - INTRODUCTION: Laparoscopic cholecystectomy (LC) is probably one of the most frequent surgical procedure performed worldwide. Intraoperative cholangiography (IOC) is required more often than in open procedures due to the need to clarify the anatomy or to diagnose common bile duct (CBD) stones. AIM: The present study analyzes the value of IOC performed on selective basis following preoperative and intraoperative criteria. Our experience covers 15 years of surgical activity in Elias Surgery Department and, as a result of a continuous scientific concern on the matter, we developed a set of criteria that are analyzed and discussed. MATERIAL AND METHOD: We studied the patients subjected to LC in our department between January 2013 and December 2014. A group of 945 patients was analyzed; IOC was performed in 147 cases. All IOC were selective procedures. The criteria were divided in two groups: Preoperative criteria (clinical, lab tests and imaging findings); Intraoperative criteria (dilated biliary ducts and obscure biliary anatomy). RESULTS: IOC was performed in 147 cases. We had a positive result, a finding that changed surgical management of the patient after IOC in over 50% of cases. The biliary tree anatomy was cleared in 100% of cases. IOC required a median period of time of 11 minutes. There were no complications caused by IOC. CONCLUSIONS: Intraoperative cholangiography, performed either routinely or selectively, represents an important tool in diagnosing unsuspected CBD stones during laparoscopic cholecystectomy. Criteria for selective IOC may significantly reduce the number of useless cholangiograms and are to be considered in daily practice. The main predictive factors used for selective intraoperative cholangiography in our study were: history of jaundice, elevated values of ALP, GGTP, SGO, SGP, and CBD diameter. PMID- 26988537 TI - Intestinal Infarction Through Arterial Vascular Obstruction - Case Series from 1st and 3rd Surgery Clinics Cluj-Napoca. AB - This article presents a case series of intestinal infarction through obstruction of superior mesenteric artery - two cases of acute mesenteric artery embolism, two cases of acute mesenteric artery thrombosis and a case of volvulus. PMID- 26988538 TI - The Early C-reactive Protein Trend Does Not Have a Role in Monitoring Acute Diverticulitis Progression. AB - OBJECTIVE: To investigate the variation of the values of the serum inflammation markers during the hospital stay of patients with acute diverticulitis and to evaluate the role of their initial trend in the early determination of the disease resistance to conservative measures. PATIENTS AND METHODS: The electronic records of patients presenting with acute diverticulitis at the Oulu University Hospital, Finland during a 2-year period starting from December 2006 were retrospectively reviewed. Acute diverticulitis that was successfully treated conservatively was graded as mild. Severe disease was considered when a percutaneous or surgical intervention was necessitated during the same hospitalization or within the first month. Comparisons of the means of continuous variables were performed using the paired samples T test. RESULTS: One hundred and thirty-nine patients with mild acute diverticulitis had available data concerning the initial trends of the inflammation markers. The C-reactive protein (CRP) mean value showed a paradoxical significant increase in uncomplicated cases whereas the WBC count declined within the first 24 hours of hospitalization. Thereafter the CRP levels showed a significant daily decrease below the initial levels for the remainder of the in-hospital duration. The inflammation markers' initial trends in patients with severe disease did not change significantly. CONCLUSION: A rise in the CRP value during the first 24 hours of hospitalization should not be necessarily considered as a deterioration of the clinical status. This trend has no role in the early evaluation of the clinical progression of acute diverticulitis as it may mislead the clinician towards potential invasive overtreatment. PMID- 26988539 TI - Laparoscopic Approach has Benefits in Gynecological Emergencies - Even for Massive Hemoperitoneum. AB - OBJECTIVE: The purpose of this study is to compare the laparoscopic with the open approach in hemoperitoneum of gynecological origin. MATERIALS AND METHODS: Retrospective study of patients admitted to a tertiary emergency hospital between January 2013 - January 2015. RESULTS: There were 56 patients, 27 in the laparoscopic group (LG) and 28 in the open group (OG). The gynecological emergency was a ruptured ovarian cyst in 20 (74%) versus 17 (59%) cases, and an ectopic pregnancy with tubal rupture in 7 (26%) versus 12 (41%) patients in both the laparoscopic and open approaches, respectively. The main outcome - mean intraoperative hemoglobin decrease - was 1.5 +- 1.2 g/dl in the laparoscopic and 1.9 ?+-1.4 in the open approach (p=0.344). There were no differences regarding red blood transfusion rate, needs for analgesics, postoperative complications and in-hospital stay. CONCLUSION: The laparoscopic approach in acute abdomen of gynecologic origin is non-inferior to open surgery. PMID- 26988540 TI - Ovarian Damage after Laparoscopic Cystectomy for Endometrioma. AB - INTRODUCTION: Despite extensive research endometriosis is an area with important controversies. The European Society of Human Reproduction and Embriology issued in 2014 the last Guideline for endometriosis management including the statement that among 83 recommendations in 32 cases the best available evidence was only based on good clinical practice, further research being necessary to solve the lack of evidence in this pathology. The prevalence of endometriosis is unknown in Romania but in the medical literature estimates range from 2 to 10% of women of reproductive age, to 50% of infertile women, worldwide. Ovarian endometrioma prevalence goes up to 44%. A Cochrane review published in 2008 by Hart et al. concluded that excisional surgery of ovarian endometriosis results in a more favorable outcome compared to drainage and ablation with regard to recurrence, pain symptoms and subsequent spontaneous pregnancy in subfertilewomen- so the gold standard was set. But several authors revealed that ovarian tissue was inadvertently excised together with the cyst wall and endometrioma cystectomy is associated with a significant decrease in residual ovarian volume that may result in diminished ovarian reserve and function. The aim of our retrospective study was to evaluate whether or not ovarian parenchyma is inadvertently removed during laparoscopic surgery for endometrioma in a Romanian academic center. MATERIAL AND METHOD: We performed a retrospective study including women having undergone endometrioma excision, between January 2009 to June 2014 in the Department of Gynecology and Obstetrics of Targu-Mures University Hospital. Histological specimens of excised endometriomas were reviewed by different pathologists, who carried out serial microscopic sections according to pathology protocol for diagnosis of ovarian mass but not specific for the ovarian parenchyma removed with the cyst. RESULTS: Among 202 endometriomas, drainage and ablation was done in 60 cases and excisional surgery in the remaining 152 cases. Ovarian parenchyma was found in 40% of cases of endometrioma cystectomy. DISCUSSION: We observed that endometrioma cystectomy leads to ovarian tissue removal in an important number of cases. Furthermore, at the time of surgery the amount of ovarian parenchyma loss may increases proportionally with increases in cyst diameter and patient age. Considering that most of the woman in our series were infertile and because of data from series using plasma energy, a shift in the endometrioma treatment paradigm is likely to occur. PMID- 26988541 TI - To Study the Aetiological Factors and Outcomes of Urgent Re-Laparotomy in Himalayan Hospital. AB - BACKGROUND: Treatment of a number of complications that occur after abdominal surgeries may require that Urgent Relaparotomy (UR), the life-saving and obligatory operations, are performed. The objectives of this study were to evaluate the reasons for performing URs, their outcomes and factors that affect mortality. METHODS: Observational, Prospective Study. The study included all the patients who underwent urgent re-laparotomy following laparotomy (emergency, elective) in Himalayan Hospital from 01.01.2013 to 01.06.2014 and excluded those who underwent laparotomy outside. RESULTS: UR was performed for 40 out of 1050 patients (4.2%), of which males were 25 and females 15. The average time interval between the index laparotomy and urgent re-exploration was 6.4 days. The most common reason for mortality was multi organ failure with septic shock. The most common criteria for re-exploration were anastomotic leak (n=13), followed by pyoperitoneum (n=11) and persistent peritonitis (n=6). Comparing the index surgery, lower gastro-intestinal procedures were most usually involved (n=21, 47.7%), followed by hepato-pancreato-biliary surgeries (n=8, 18.2%). There were 6 cases of upper gastro-intestinal surgeries that reexplored (13.6%). CONCLUSION: UR that is performed following complicated abdominal surgeries has high mortality rates. In particular, they have higher mortality rates following GIS surgeries or when infectious complications occur. PMID- 26988542 TI - Parotid Gland Lipoma: An Unusual Entity. AB - The occurrence of lipomas in the parotid gland is extremely rare, and impossible to differentiate clinically. A case of this bizarre entity is reported herein, which was treated successfully with superficial parotidectomy. A 57-year-old man with a well-circumscribed, rubbery mass, probably arising from the right parotid gland was investigated in our hospital initially with ultrasound scan, and finally with MRI-scan. Both imaging modalities implied a benign lipomatous tumor and the patient underwent an uneventful superficial parotidectomy. Although adipose tissue is a natural component of parotid glands, lipomas arising in the gland are very unusual. The entity'?s incidence is about 1% (0.6-4.4%) of parotid gland mass lesions and history of previous trauma in the area is the most common pathophysiological mechanism described. Tomographic imaging modalities are very accurate in preoperative diagnosis and cosmetic appearance is the usual indication for surgical intervention. Any particular symptoms jeopardize clinically the diagnosis of parotid lipoma. As always, surgical excision should respect the facial nerve and branches. PMID- 26988543 TI - Right Retroperitoneal and Subhepatic Abscess; Late Complications Due to Spilled Stones During Laparoscopic Cholecystectomy - Case Report. AB - BACKGROUND: Gallbladder perforation with gallstone spillage during laparoscopic cholecystectomy is usually an event with no consequences. CASE REPORT: We report the case of a 66 year-old female admitted in our hospital with severe large abscess in the right lumbar region. Her medical history reveals a laparoscopic cholecystectomy for acute gallstone cholecystitis. Emergent abscess incision and drainage are performed, noticing a mass of stone outline. The abdominal CT scan shows fluid, air-bubbled collection with biloculate walls located in the right retroperitoneal subhepatic region. Laparoscopic procedure is performed, the subhepatic abscess is located and drained, the abscess cavity containing 19 gallstones. OUTCOME: The post-operative evolution was favourable. The patient was discharged on the 6th post-operative day. CONCLUSIONS: The stones left in the peritoneal cavity during laparoscopic cholecystectomy may be sometimes the cause of severe late complications. PMID- 26988544 TI - Ileocecal Obstruction Due to B-cell Non-Hodgkin Lymphoma. AB - We report a rare case of non-Hodgkin lymphoma presented as an ileocecal mass. The patient was a 77-year-old man with history of symptoms of partial bowel obstruction, intermittent right iliac fossa pain, loss of weight, vomiting and fatigue. Clinical signs included moderate abdominal tenderness with a palpable mass in the right iliac fossa at the physical examination. Colonoscopy revealed an intussusception of the right colon causing a complete stenosis. The patient developed complete bowel obstruction during hospitalization that required emergent surgical intervention. Intraoperatively an ileocecal mass was found measuring 10-12 cm in diameter, causing complete stenosis at its level and bowel dilatation proximally. Multiple nodules were found in the liver and the parietal peritoneum as well. An ileotransverso-anastomosis was performed and biopsies of the nodules were taken. Pathological evaluation revealed a diffuse large B cell non-Hodgkin'?s lymphoma of the ileocecum and the parietal peritoneum. PMID- 26988545 TI - Highlighted Steps of the Management Algorithm in Acute Lower Gastrointestinal Bleeding - Case Reports and Literature Review. AB - Acute lower gastrointestinal bleeding is a major problem worldwide, being a rare and life threatening condition, with a mortality rate situated between 2 and 4%. Acute lower gastrointestinal bleeding is solvent for 1 - 2% of the entire hospital emergencies, 15% presenting as massive bleeding and up to 5% requiring surgery. Lower gastrointestinal bleeding can be classified depending on their location in the small or large intestine. The small bowel is the rarest site of lower gastrointestinal bleeding, at the same time being the commonest cause of obscure bleeding. 5% of total lower GI bleeding appears in the small bowel. When endoscopic therapy associated with medical treatment are insufficient, endovascular intervention can be lifesaving. Unfortunately in some rare cases of acute lower gastrointestinal bleeding with hemo-dynamic instability and the angiography performed being unable to locate the source of bleeding, the last therapeutic resource remains surgery. In the following we exemplify two cases of acute lower gastrointestinal bleeding which were resolved in different ways, followed by a thorough description of the different types of available treatment and finally, in the conclusions, we systematize the most important stages of the management algorithm in acute lower gastrointestinal bleeding. PMID- 26988546 TI - Total Pelvic Supralevator Exenteration with Ileo-Colic Orthotopic Neobladder for Locoregional Recurrence after Cervical Cancer - A Case Report. AB - Pelvic exenteration is one of the most aggressive surgical interventions in gynaecologic surgical oncology, but, in the same time, is the only potentially curative treatment of locoregional recurrence after cervical cancer. Due to improvements in surgical technique and postoperative management, the overall survival increased signifficantly in the last decades. Trying to improve the quality of life, multiple models of reconstruction of urinary and digestive tract have been developed. In this report we present the case of a 51 years old female who underwent a total supralevator exenteration with ileo colic neobladder reconstruction with good oncologic and functional outcomes. PMID- 26988548 TI - In what circumstances will a neonatologist decide a patient is not a resuscitation candidate? AB - OBJECTIVE: The purpose of this study was to determine the opinions of practising neonatologists regarding the ethical permissibility of unilateral Do Not Attempt Resuscitation (DNAR) decisions in the neonatal intensive care unit. STUDY DESIGN: An anonymous survey regarding the permissibility of unilateral DNAR orders for three clinical vignettes was sent to members of the American Academy of Pediatrics Section of Perinatal Medicine. RESULTS: There were 490 out of a possible 3000 respondents (16%). A majority (76%) responded that a unilateral DNAR decision would be permissible in cases for which survival was felt to be impossible. A minority (25%) responded 'yes' when asked if a unilateral DNAR order would be permissible based solely on neurological prognosis. CONCLUSIONS: A majority of neonatologists believed unilateral DNAR decisions are ethically permissible if survival is felt to be impossible, but not permissible based solely on poor neurological prognosis. This has significant implications for clinical care. PMID- 26988547 TI - Pitfalls in Cutaneous Melanoma Lymphatic Drainage. AB - Sentinel node (SN) biopsy has become standard in staging of cutaneous melanoma. As skin lymphatic drainage is complex, preoperative empirical assessment of SN localization is virtually impossible. Therefore in order to identify all regional lymphatic basins corresponding to a specific primary tumor is mandatory to carry out preoperative lymphoscintigraphy. In this paper we present a clinical case that highlights the importance of identifying, biopsy and histological analysis of all SN in order to achieve a correct staging of the patient, followed by appropriate treatment according to the real clinical stage of the disease. PMID- 26988549 TI - Special series on trending themes in Neurobiology in Biological Research. PMID- 26988550 TI - A method for near full-length amplification and sequencing for six hepatitis C virus genotypes. AB - BACKGROUND: Hepatitis C virus (HCV) is a rapidly evolving RNA virus that has been classified into seven genotypes. All HCV genotypes cause chronic hepatitis, which ultimately leads to liver diseases such as cirrhosis. The genotypes are unevenly distributed across the globe, with genotypes 1 and 3 being the most prevalent. Until recently, molecular epidemiological studies of HCV evolution within the host and at the population level have been limited to the analyses of partial viral genome segments, as it has been technically challenging to amplify and sequence the full-length of the 9.6 kb HCV genome. Although recent improvements have been made in full genome sequencing methodologies, these protocols are still either limited to a specific genotype or cost-inefficient. RESULTS: In this study we describe a genotype-specific protocol for the amplification and sequencing of the near-full length genome of all six major HCV genotypes. We applied this protocol to 122 HCV positive clinical samples, and had a successful genome amplification rate of 90%, when the viral load was greater than 15,000 IU/ml. The assay was shown to have a detection limit of 1-3 cDNA copies per reaction. The method was tested with both Illumina and PacBio single molecule, real-time (SMRT) sequencing technologies. Illumina sequencing resulted in deep coverage and allowed detection of rare variants as well as HCV co-infection with multiple genotypes. The application of the method with PacBio RS resulted in sequence reads greater than 9 kb that covered the near full-length HCV amplicon in a single read and enabled analysis of the near full-length quasispecies. CONCLUSIONS: The protocol described herein can be utilised for rapid amplification and sequencing of the near-full length HCV genome in a cost efficient manner suitable for a wide range of applications. PMID- 26988551 TI - Fertility-sparing surgery for young patients with borderline ovarian tumors (BOTs): single institution experience. AB - BACKGROUND: Fertility-sparing surgery for patients with borderline ovarian tumors (BOTs) is still controversial. This study aimed to evaluate the oncological safety and fertility benefits in conservative surgery,as well as efficiency of surgical procedures and approaches. RESULTS: In total 122 patients with BOTs, four types of fertility-sparing surgery were performed: unilateral adnexectomy (UA, n = 47), unilateral cystectomy (UC, n = 59), unilateral adnexectomy + contralateral cystectomy (UA + CC, n = 7) and bilateral cystectomy (BC, n = 9). Fifty-two (42.6 %) patients had undergone laparoscopy, while 70 (57.4 %) had undergone laparotomy. After a median follow-up of 58.0 months, eight patients (6.6 %) relapsed in average of 25.9 months. Only one patient progressed to invasive cancer. None died within our observational period. Univariate analysis showed that patients with elevated CA125, bilateral tumors, extra-ovary tumor or mucinous type tended to replase in shorter time (p < 0.05). Among all cases, 45 patients attempted to conceive and 34 (75.6 %) patients had successful pregnancy. The recurrence rates were successively increased (2.1 %, 6.8 %, 14.3 %, and 22.2 %), the recurrence interval were shortened (48.0, 25.3, 26.0 and 21.2 months) and the subsequent fertility rates were 76.9 %, 77.3 %, 66.7 % and 71.4 % in UA, UC, UA + CC, and BC groups, respectively. As for surgical approaches, three patients (5.8 %) relapsed in 26.3 months in the laparoscopy group and five (7.1 %) in 25.5 months in the laparotomy group. The subsequent fertility rate was higher in laparoscopy group (88.9 %) than in laparotomy group (66.7 %). In our study, 38 patients underwent staging surgery. Two patients (5.3 %) recurrent in average of 21.0 months, and the subsequent pregnancy rate of staging surgery group was 61.5 %. Twelve patients received adjuvant chemotherapy but they didn't get any benefit from it, both in term of recurrence (8.3 %, 26.0 months) and subsequent pregnancy rate (75.5 %). CONCLUSION: Fertility-sparing surgery is safe and beneficial for most young BOTs. UA through laparoscopy should be recommended as the first choice. To the patients with bilateral tumors, elevated CA125, extra-ovary tumor or mucinous type, conservative surgery should be carefully chosen and subsequent pregnancy should be attempted in short term. In addition, the benefit of comprehensive surgical staging is to be further investigated and adjuvant chemotherapy is not recommended. PMID- 26988552 TI - Non-metastatic castrate-resistant prostate cancer: a call for improved guidance on clinical management. AB - BACKGROUND: Guidelines on the clinical management of non-metastatic castrate resistant prostate cancer (nmCRPC) generally focus on the need to continue androgen deprivation therapy and enrol patients into clinical trials of investigational agents. This guidance reflects the lack of clinical trial data with established agents in the nmCRPC patient population and the need for trials of new agents. AIM: To review the evidence base and consider ways of improving the management of nmCRPC. CONCLUSION: Upon the development of castrate resistance, it is essential to rule out the presence of metastases or micrometastases by optimising the use of bone scans and possibly newer procedures and techniques. When nmCRPC is established, management decisions should be individualised according to risk, but risk stratification in this diverse population is poorly defined. Currently, prostate-specific antigen (PSA) levels and PSA doubling time remain the best method of assessing the risk of progression and response to treatment in nmCRPC. However, optimising imaging protocols can also help assess the changing metastatic burden in patients with CRPC. Clinical trials of novel agents in nmCRPC are limited and have problems with enrolment, and therefore, improved risk stratification and imaging may be crucial to the improved management. The statements presented in this paper, reflecting the views of the authors, provide a discussion of the most recent evidence in nmCRPC and provide some advice on how to ensure these patients receive the best management available. However, there is an urgent need for more data on the management of nmCRPC. PMID- 26988554 TI - Anterior versus posterior debridement fusion for single-level dorsal tuberculosis: the role of graft-type and level of fixation on determining the outcome. AB - PURPOSE: This study compared the clinical, radiological and functional outcome of anterior versus posterior approaches for single-level dorsal tuberculosis with analysis of effect of graft type and fixation level on the outcome. METHODS: Anterior group (AG): 43 cases (mean age: 49.5 years) fixed with Z-plate by anterior transthoracic-transpleural approach. Posterior group (PG): 49 cases (47.0 years) fixed with transpedicular-screws with unilateral facetectomy +/- pediculectomy. Assessment was done using Frankel classification, blood-loss, operative-time, Kyphus-angle, correction loss, union and Oswestry disability index (ODI). RESULTS: Both groups had similar operative-time, blood-loss, time to union, follow-up, and hospital-stay. Kyphus-angle improved from 36.6 +/- 8.4 degrees to 7.5 +/- 2.3 degrees (AG) and from 38.5 +/- 5.9 degrees to 11.1 +/- 3.6 degrees (PG) and this was significant. Postoperative Kyphus-angles were significantly better than preoperative ones in both groups. The correction percentage was 79.2 % (AG) and 69.9 % (PG) and this was significant. ODI was 3.4 +/- 4.1 (AG) and 3.0 +/- 4.2 % (PG) and this was insignificant. Correction loss was .8 +/- 1.2 degrees (AG) and 1.9 +/- 2.2 degrees (PG) and this was significant. Union was faster with iliac graft but with lower correction degree and higher correction loss than rib-strut graft. All patients achieved union. All but three patients achieved full neurological recovery. Superficial infection occurred in three cases (PG:2; AG:1) lung parenchymal injury in two case (AG), and DVT in one case (AG). CONCLUSIONS: Both approaches give very good union and kyphosis correction rate that were maintained overtime. Anterior approach gives statistically better kyphosis correction and less correction-loss, but this is clinically insignificant. Besides, it is more risky and difficult. Strut-graft is essential in reconstruction and correction of kyphosis and vertebral height. LEVEL OF EVIDENCE: III therapeutic. PMID- 26988553 TI - Meta-analysis and suggested guidelines for prevention of venous thromboembolism (VTE) in foot and ankle surgery. AB - PURPOSE: To perform a meta-analysis investigating venous thromboembolism (VTE) following isolated foot and ankle surgery and propose guidelines for VTE prevention in this group of patients. METHODS: Following a PRISMA compliant search, 372 papers were identified and meta-analysis performed on 22 papers using the Critical Appraisal Skills Programme and Centre for Evidence-Based Medicine level of evidence. RESULTS: 43,381 patients were clinically assessed for VTE and the incidence with and without chemoprophylaxis was 0.6% (95% CI 0.4-0.8%) and 1% (95% CI 0.2-1.7%), respectively. 1666 Patients were assessed radiologically and the incidence of VTE with and without chemoprophylaxis was 12.5% (95% CI 6.8 18.2%) and 10.5% (95% CI 5.0-15.9%), respectively. There was no significant difference in the rates of VTE with or without chemoprophylaxis whether assessed clinically or by radiological criteria. The risk of VTE in those patients with Achilles tendon rupture was greater with a clinical incidence of 7% (95% CI 5.5 8.5%) and radiological incidence of 35.3% (95% CI 26.4-44.3%). CONCLUSION: Isolated foot and ankle surgery has a lower incidence of clinically apparent VTE when compared to general lower limb procedures, and this rate is not significantly reduced using low molecular weight heparin. The incidence of VTE following Achilles tendon rupture is high whether treated surgically or conservatively. With the exception of those with Achilles tendon rupture, routine use of chemical VTE prophylaxis is not justified in those undergoing isolated foot and ankle surgery, but patient-specific risk factors for VTE should be used to assess patients individually. LEVEL OF EVIDENCE: II. PMID- 26988555 TI - Surgical site infections following operative management of cervical spondylotic myelopathy: prevalence, predictors of occurence, and influence on peri-operative outcomes. AB - PURPOSE: Studies have examined infection rates following spine surgery and their relationship to post-operative complications and increased length of stay. Few studies, however, have investigated predictors of infection, specifically in the setting of operative intervention for cervical spondylotic myelopathy (CSM). This study aims to identify the incidence and factors predictive of infection amongst this cohort. METHODS: This study performed a retrospective review of the prospectively collected American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. Patients included those treated surgically for CSM (ICD-9 code 721.1) from 2010 to 2012. Patient demographics and surgical data were collected with outcome variables including the occurrence of one of the following surgical site infections (SSIs) within 30 days of index operation: superficial SSI, deep incisional SSI, and organ/space SSI. RESULTS: 3057 patients were included in this analysis. Overall infection rate was 1.15 % (35/3057), of which 54.3 % (19/35) were superficial SSIs, 28.6 % (10/35) were deep incisional SSI, and 20 % (7/35) were peri-spinal SSI. Logistic regression revealed factors associated with SSI included: higher BMI [OR 1.162 (CI 1.269-1.064), p = 0.001] and operative time >=208 min [OR 4.769 (CI 20.220-1.125), p = 0.034]. CONCLUSIONS: The overall SSI rate for the examined CSM cohort was 1.15 %. This study identified increased BMI and operative time >=208 min as predictors of infection in surgical CSM patients. This information should be carefully considered in delivering patient education and future efforts to optimize risk in CSM patients indicated for surgical intervention. PMID- 26988556 TI - Publication rates: is more better? PMID- 26988557 TI - Local Actors' Frames of the Role of Living Conditions in Shaping Hypertension Risk and Disparities in a Colombian Municipality. AB - Conditions in the social and physical environment influence population health and risk for CVD, including hypertension. These environmental conditions are influenced by the decisions of public officials, community leaders, and service providers. Examining the frames that local decision makers bring to understanding hypertension can provide important insights into the decisions that they make about strategies for addressing this problem in their jurisdiction. The goal of this study was to examine the frames that local decision makers in Quibdo, Colombia, bring to understanding hypertension risk, and in particular, whether and how they use frames that encompass associations between living conditions and hypertension risk. Data for this qualitative study were collected using a stratified sampling strategy. Semi-structured interviews were conducted in 2012 with 13 local decision makers and analyzed using a framework approach. Participants linked the structural conditions experienced in Quibdo, including displacement, limited economic opportunities, and the infrastructure of the city, to hypertension risk through multiple pathways, including behavioral risk factors for hypertension and physiologic responses to stress. They described the social patterning of these factors across socioeconomic, racial/ethnic, and gender hierarchies. Although several conditions associated with hypertension risk are widely distributed in the city's population, social processes of marginalization and stratification create additional disadvantages for those on the lower rungs of the social hierarchy. PMID- 26988559 TI - Lutzomyia migonei is a permissive vector competent for Leishmania infantum. AB - BACKGROUND: Leishmania infantum is the most widespread etiological agent of visceral leishmaniasis (VL) in the world, with significant mortality rates in human cases. In Latin America, this parasite is primarily transmitted by Lutzomyia longipalpis, but the role of Lutzomyia migonei as a potential vector for this protozoan has been discussed. Laboratory and field investigations have contributed to this hypothesis; however, proof of the vector competence of L. migonei has not yet been provided. In this study, we evaluate for the first time the susceptibility of L. migonei to L. infantum. METHODS: Females of laboratory reared L. migonei were fed through a chick-skin membrane on rabbit blood containing L. infantum promastigotes, dissected at 1, 5 and 8 days post-infection (PI) and checked microscopically for the presence, intensity and localisation of Leishmania infections. In addition, morphometric analysis of L. infantum promastigotes was performed. RESULTS: High infection rates of both L. infantum strains tested were observed in L. migonei, with colonisation of the stomodeal valve already on day 5 PI. At the late-stage infection, most L. migonei females had their cardia and stomodeal valve colonised by high numbers of parasites, and no significant differences were found compared to the development in L. longipalpis. Metacyclic forms were found in all parasite-vector combinations since day 5 PI. CONCLUSIONS: We propose that Lutzomyia migonei belongs to sand fly species permissive to various Leishmania spp. Here we demonstrate that L. migonei is highly susceptible to the development of L. infantum. This, together with its known anthropophily, abundance in VL foci and natural infection by L. infantum, constitute important evidence that L. migonei is another vector of this parasite in Latin America. PMID- 26988560 TI - Exploiting redox activity in metal-organic frameworks: concepts, trends and perspectives. AB - Of the many thousands of new metal-organic frameworks (MOFs) that are now discovered each year, many possess potential redox activity arising from the constituent metal ions and/or organic ligands, or the guest molecules located within their porous structures. Those redox states that can be accessed via postsynthetic redox modulation often possess distinct physical properties; if harnessed, these provide a basis for applications including microporous conductors, electrocatalysts, energy storage devices and electrochemical sensors, amongst others. This feature article highlights the latest developments in experimental, theoretical and computational concepts relevant to redox-active MOFs, including new solid state electrochemical and spectroelectrochemical techniques that have great utility in this field. A particular emphasis is on current and emerging trends at the fundamental level which underscore the importance of this promising class of electroactive materials for a wide range of technologically- and industrially-relevant applications. PMID- 26988558 TI - Snail-induced epithelial-to-mesenchymal transition of MCF-7 breast cancer cells: systems analysis of molecular changes and their effect on radiation and drug sensitivity. AB - BACKGROUND: Epithelial-to-mesenchymal transition (EMT) has been associated with the acquisition of metastatic potential and the resistance of cancer cells to therapeutic treatments. MCF-7 breast cancer cells engineered to constitutively express the zinc-finger transcriptional repressor gene Snail (MCF-7-Snail cells) have been previously shown to display morphological and molecular changes characteristic of EMT. We report here the results of a comprehensive systems level molecular analysis of changes in global patterns of gene expression and levels of glutathione and reactive oxygen species (ROS) in MCF-7-Snail cells and the consequence of these changes on the sensitivity of cells to radiation treatment and therapeutic drugs. METHODS: Snail-induced changes in global patterns of gene expression were identified by microarray profiling using the Affymetrix platform (U133 Plus 2.0). The resulting data were processed and analyzed by a variety of system level analytical methods. Levels of ROS and glutathione (GSH) were determined by fluorescent and luminescence assays, and nuclear levels of NF-kappaB protein were determined by an ELISA based method. The sensitivity of cells to ionizing radiation and anticancer drugs was determined using a resazurin-based cell cytotoxicity assay. RESULTS: Constitutive ectopic expression of Snail in epithelial-like, luminal A-type MCF-7 cells induced significant changes in the expression of >7600 genes including gene and miRNA regulators of EMT. Mesenchymal-like MCF-7-Snail cells acquired molecular profiles characteristic of triple-negative, claudin-low breast cancer cells, and displayed increased sensitivity to radiation treatment, and increased, decreased or no change in sensitivity to a variety of anticancer drugs. Elevated ROS levels in MCF-7-Snail cells were unexpectedly not positively correlated with NF-kappaB activity. CONCLUSIONS: Ectopic expression of Snail in MCF-7 cells resulted in morphological and molecular changes previously associated with EMT. The results underscore the complexity and cell-type dependent nature of the EMT process and indicate that EMT is not necessarily predictive of decreased resistance to radiation and drug-based therapies. PMID- 26988563 TI - Comment on 'Predicting the efficacy of radiotherapy in individual glioblastoma patients in vivo: a mathematical modeling approach'. PMID- 26988561 TI - "The others look at you as if you are a grave": a qualitative study of subjective experiences of patients with epilepsy regarding their treatment and care in Cape Town, South Africa. AB - BACKGROUND: Existing evidence shows that the majority of people with epilepsy in lower and middle income countries are not receiving appropriate treatment and care. Although this problem has been reported as one of the factors affecting the quality of lives of people with epilepsy, very few studies have investigated patients' perspectives and their experiences about the problem. This qualitative study explored perspectives and subjective experiences of people with epilepsy about their illness in an urban township in South Africa. METHODS: Individual face-to-face interviews included twelve people who had epilepsy. A semi structured interview guide which was based on Kleinman (1980) Explanatory Models Framework was used to elicit participants' perspectives and subjective experiences about their illness and its treatment. Thematic analysis method was used to analyse the data. RESULTS: The main theme reflecting participants' verbatim accounts was about their perceived difficulties affecting their access to treatment and care during their routine clinical follow up visits. These concerned rushed consultations which focussed on seizure frequency and adherence to medication with no attention to personal concerns. They perceived that part of the problem could be that some health care practitioners were not adequately trained and lacked empathy, interest, respect and listening skills. We argue that in a health system where patients feel that they are not respected and their concerns are not listened to or are ignored, they may lack trust in the system and this may violate their right to access treatment and care. CONCLUSIONS: The findings provide a glimpse of the extent to which the power and nature of the routine task-centred system can lead to violation of patients' health rights - especially with epilepsy which is poorly understood and stigmatized. Appropriate interventions are needed to address health system factors affecting the treatment and care of this marginalized and vulnerable group of patients. PMID- 26988562 TI - How to meet the demand for good quality renal dialysis as part of universal health coverage in resource-limited settings? AB - BACKGROUND: It is very challenging for resource-limited settings to introduce universal health coverage (UHC), particularly regarding the inclusion of high cost renal dialysis as part of the UHC benefit package. This paper addresses three issues: (1) whether a setting commits to include renal dialysis in its UHC benefit package and if so, why and how; (2) how to ensure quality of renal dialysis services; and (3) how to improve the quality of life of patients using psychosocial and community interventions. DISCUSSION: This article reviews experiences of renal dialysis programs in seven settings based on presentations and discussions during the International Forum on Peritoneal Dialysis as a Priority Health Policy in Asia. A literature review was conducted to verify and validate the data as well as to fill information gaps presented in the forum. Five out of the seven settings implemented renal dialysis as part of their benefits package, while the other two have pilots or programs in their nascent stage. Renal replacement therapy has become part of the universal access package because these governments recognize the rising number of chronic kidney disease (CKD) cases, the catastrophically high costs of treatment, and that this is the only life-saving treatment available to patients. The recommendations are as follows: Governments should have a holistic approach to CKD interventions, including primary prevention as well as psychosocial interventions. Governments should consider subsidizing CKD treatment costs depending on their resources. Multi-stakeholder cooperation should be facilitated to enact these policies and conduct research and development for all aspects of interventions. International collaboration should be initiated to share experiences, good practices, and joint activities (e.g. capacity building and multinational procurement of medical supplies). CONCLUSION: This study provides practical recommendations to country governments as well as the international community on how to meet the demand for good quality renal dialysis as part of UHC in resource-limited settings. PMID- 26988564 TI - Extracts of Bauhinia championii (Benth.) Benth. inhibit NF-B-signaling in a rat model of collagen-induced arthritis and primary synovial cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bauhinia championii (Benth.) Benth. is used in Chinese traditional medicine to treat arthritis, especially has been used a long time ago on rheumatoid arthritis (RA) in She ethnic minority group. AIM OF THE RESEARCH: To investigate the anti-RA effect of Bauhinia championii (Benth.) Benth ethyl acetate extract (BCBEE) and the molecular bases of it. MATERIALS AND METHODS: BCBEE was studied on a rat model of RA induced by IIcollagen in vivo, as well as on primary synovial cells in vitro. RESULTS: After BCBEE treatment, in vivo, it was showed that paw and joint edema was inhibited, pathological joint changes was ameliorated and the levels of interleukin (IL)-1beta and tumor necrosis factor-(TNF-alpha) was decreased significantly. The protein and mRNA expressions of nuclear factor-B (NF-kappaB)(p65), IkappaB, p-IkappaB and IkappaB kinase beta (IkappaKbeta) were also down-regulated. Moreover, the in vitro study revealed that BCBEE treatment inhibited primary synovial cells proliferation, and promoted down-regulation of NF-kappaB(p65), IkappaB, p-IkappaB and IkappaKbeta. CONCLUSIONS: Taken together, the present study demonstrates that BCBEE produces a protection in a rat model of RA induced by IIcollagen via inhibiting paw and joint edema, ameliorating pathological joint changes and regulating the levels of cytokines and its action mechanism maybe is via down regulating NF-kappaB(p65), IkappaB, p-IkappaB and IkappaKbeta expression. PMID- 26988566 TI - Failure to replicate? PMID- 26988565 TI - Protection of tauroursodeoxycholic acid on high glucose-induced human retinal microvascular endothelial cells dysfunction and streptozotocin-induced diabetic retinopathy rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tauroursodeoxycholic acid (TUDCA), one of the main ingredients from bear gall which hold "Clearing heat and detoxification, Removing liver fire for improving eyesight" functions, is formed by the conjugation of ursodeoxycholic acid (UDCA) with taurine. However, the limited information of TUDCA on protecting diabetic retinopathy (DR) has been known. The present study was conducted to evaluate the protection of TUDCA on high glucose induced human retinal microvascular endothelial cells (HRMECs) dysfunction and streptozotocin (STZ)-induced diabetic retinopathy (DR) rats and the possible mechanism underlying was also explored. MATERIALS AND METHODS: The proliferation of high glucose-induced HRMECs was determined by MTT assay. DR rats' model was established by an administration of high-glucose-fat diet and an intraperitoneal injection of STZ (30mg/kg). The cell supernatant and rats' serum were collected for the assays of NO content by ELISA kits. Retinas were stained with hematoxylin and eosin (HE) to observe pathological changes. Immunohistochemical assay was applied to examine the protein expression of ICAM-1, NOS, NF-kappaB p65 and VEGF in rat retinas. Furthermore, western blot analysis was carried out to examine the protein expression of ICAM-1, NOS, NF-kappaB p65 and VEGF in high glucose-induced HRMECs. RESULTS: After treating with TUDCA, high glucose-induced HRMECs proliferation could be significantly inhibited. TUDCA (5.0MUM, 25.0MUM and 125.0MUM) could decrease NO content in high glucose-induced HRMECs. Furthermore, TUDCA (500mg/kg/d and 250mg/kg/d) also decrease NO content in serum of DR rats. Additionally, both immunocytochemistry analysis and western blot analysis showed that the over-expression of ICAM-1, NOS, NF-kappaB p65 and VEGF were significantly decreased by TUDCA. CONCLUSION: The data indicated that TUDCA could ameliorate DR by decreasing NO content and down-regulating the protein expression of ICAM-1, NOS, NF-kappaB p65 and VEGF. Thus, our experimental results suggested that TUDCA might be a potential drug for the prevention and treatment of DR. PMID- 26988567 TI - Cloning and functional analysis of farnesyl pyrophosphate synthase (FPPS) gene from Mylabris cichorii. AB - Cantharidin, a defensive terpene compound synthesized by the meloid beetle (Coleoptera, Meloidae), is an important anticancer agent. However, there has been little study done on how this compound synthesized by the beetle. In this paper, a farnesyl pyrophosphate synthase (FPPS) gene, designated McFPPS, was isolated from Mylabris cichorii by reverse transcription PCR based on conserved domains in other organisms. Multiple alignment analysis showed that the deduced amino acids shared >70% homology with FPPSs from other species and contained typically seven conservative regions. Gene expression profile analysis revealed that McFPPS was expressed throughout the tested growth stages of M. cichorii adults, whereas the transcripts accumulated to the highest level at 20 days in male adults while the highest expression level appeared at 15 days in females. Tissue expression pattern analysis showed that McFPPS was expressed constitutively in all tested tissues and a relatively higher expression level in the alimentary canal of males, but no significant tissue difference in the females. For the first time, a RNA interference strategy was employed to induce a greater suppression of McFPPS mRNA, and thus a sharp decrease in the expression levels of downstream genes and the concentration of product. All these results indicated that McFPPS may be directly involved or play an essential role in the biosynthesis of cantharidin. PMID- 26988568 TI - Activation of extracellular signal-related kinase in abdominal aortic aneurysm. AB - BACKGROUND: Extracellular matrix degeneration, caused by matrix metalloproteinase 2, facilitates smooth muscle cell migration leading to medial layer decline and, ultimately, abdominal aortic aneurysm. It remains unclear what exactly causes aneurysms to rupture, which leads to death in most patients. The extracellular signal-related kinase may be linked to the latter process. We aimed to clarify the role of extracellular signal-related kinase in aortic aneurysm development and rupture in patients. DESIGN: Aortic fragments were harvested during open repair of nonruptured (n = 20) and ruptured (n = 8) aneurysms. As control, nondilated aortas (n = 6) were obtained during autopsy. We determined levels of phosphorylated and total extracellular signal-related kinase by Western blot, matrix metalloproteinase-2 by immunohistochemistry and medial layer thickness by conventional microscopy. RESULTS: Nonruptured aneurysms had 1.8 times higher activation of extracellular signal-related kinase (ratio: phosphorylated/total) than controls (P = 0.011). However, the ruptured aneurysms had only 0.9 times the activation of controls (ns). Both nonruptured and ruptured aneurysms showed significantly higher matrix metalloproteinase-2 than controls (3.8 and 4.0-times, respectively; P < 0.005). Of the medial layer thickness in controls, the median was 1.5 mm, in nonruptured 1.0 mm and in ruptured aneurysms 0.7 mm. Activation of extracellular signal-related kinase correlated positively to medial layer thickness (Rs = 0.48; P = 0.014), but not to matrix metalloproteinase-2 (Rs = 0.36; P = 0.10). CONCLUSIONS: In this study, nonruptured aneurysms are associated with increased extracellular signal-related kinase activation while ruptured aneurysms are not. Extracellular signal-related kinase was not related to total matrix metalloproteinase-2 expression. We therefore speculate that increased extracellular signal-related kinase, in response to medial layer decline, could be protective against aneurysm rupture. PMID- 26988569 TI - Reliability Assurance of Detection of EML4-ALK Rearrangement in Non-Small Cell Lung Cancer: The Results of Proficiency Testing in China. AB - INTRODUCTION: Currently, several approaches are being used to detect echinoderm microtubule associated protein like 4 gene (EML4)-anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement, but the performance of laboratories in China is unknown. To evaluate the proficiency of different laboratories in detecting EML4-ALK rearrangement, we organized a proficiency test (PT). METHODS: We prepared formalin-fixed, paraffin-embedded samples derived from the xenograft tumor tissue of three non-small cell lung cancer cell lines with different EML4 ALK rearrangements and used PTs to evaluate the detection performance of laboratories in China. RESULTS: We received results from 94 laboratories that used different methods. Of the participants, 75.53% correctly identified all samples in the PT panel. Among the errors made by participants, false-negative errors were likely to occur. According to the methodology applied, 82.86%, 76.67%, 77.78%, and 66.67% of laboratories using reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, next-generation sequencing, and immunohistochemical analysis, respectively, could analyze all the samples correctly. Moreover, we have found that the laboratories' genotyping capacity is high, especially for variant 3. CONCLUSION: Our PT survey revealed that the performance and methodological problems of laboratories must be addressed to further increase the reproducibility and accuracy of detection of EML4-ALK rearrangement to ensure reliable results for selection of appropriate patients. PMID- 26988570 TI - Dramatic Response to Combination Erlotinib and Crizotinib in a Patient with Advanced, EGFR-Mutant Lung Cancer Harboring De Novo MET Amplification. PMID- 26988571 TI - A gallium(III) Schiff base-curcumin complex that binds to amyloid-beta plaques. AB - Gallium-68 is a positron-emitting isotope that can be used in positron-emission tomography imaging agents. Alzheimer's disease is associated with the formation of plaques in the brain primarily comprised of aggregates of a 42 amino acid protein called amyloid-beta. With the goal of synthesising charge neutral, low molecular weight, lipophilic gallium complexes with the potential to cross the blood-brain barrier and bind to Abeta plaques we have used an ancillary tetradentate N2O2 Schiff base ligand and the beta-diketone curcumin as a bidentate ligand to give a six-coordinate Ga3+ complex. The tetradentate Schiff base ligand adopts the cis-beta configuration with deprotonated curcumin acting as a bidentate ligand. The complex binds to amyloid-beta plaques in human brain tissue and it is possible that extension of this chemistry to positron-emitting gallium-68 could provide useful imaging agents for Alzheimer's disease. PMID- 26988572 TI - Influence of metallocene substitution on the antibacterial activity of multivalent peptide conjugates. AB - Peptide dendrimers and derivatisation of peptides with metallocenes showed promising results in the search for new antibacterial agents. The two concepts are combined in this work leading to multivalent, metallocene-containing peptide derivates. These new peptides were synthesised utilising microwave assisted, copper(I) catalyzed alkyne-azide cycloaddition (CuAAC, "click" chemistry). Twelve new peptide conjugates, containing either a ferrocenoyl group or a ruthenocenoyl group on so-called ultrashort (i.e. < 5 amino acids) peptides, and ranging from monovalent to trivalent conjugates, were synthesised and their antibacterial activity was investigated by minimal inhibitory concentration (MIC) assays on five different bacterial strains. The antibacterial activity was compared to the same peptide conjugates without metallocenes. The resulting MIC values showed a significant enhancement of the antibacterial activity of these peptide conjugates against Gram-positive bacteria by the metallocenoyl groups. Additionally, the compounds with two metallocenoyl groups presented the best antibacterial activities overall. PMID- 26988574 TI - Low-dimensional carbon and MXene-based electrochemical capacitor electrodes. AB - Due to their unique structure and outstanding intrinsic physical properties such as extraordinarily high electrical conductivity, large surface area, and various chemical functionalities, low-dimension-based materials exhibit great potential for application in electrochemical capacitors (ECs). The electrical properties of electrochemical capacitors are determined by the electrode materials. Because energy charge storage is a surface process, the surface properties of the electrode materials greatly influence the electrochemical performance of the cell. Recently, graphene, a single layer of sp(2)-bonded carbon atoms arrayed into two-dimensional carbon nanomaterial, has attracted wide interest as an electrode material for electrochemical capacitor applications due to its unique properties, including a high electrical conductivity and large surface area. Several low-dimensional materials with large surface areas and high conductivity such as onion-like carbons (OLCs), carbide-derived carbons (CDCs), carbon nanotubes (CNTs), graphene, metal hydroxide, transition metal dichalcogenides (TMDs), and most recently MXene, have been developed for electrochemical capacitors. Therefore, it is useful to understand the current issues of low dimensional materials and their device applications. PMID- 26988573 TI - Does Unilateral Temporomandibular Total Joint Reconstruction Result in Contralateral Joint Pain and Dysfunction? AB - PURPOSE: The purpose of this study was to evaluate patients requiring unilateral total temporomandibular joint (TMJ) reconstruction and the risk for development of postsurgical contralateral TMJ pain and dysfunction over time requiring subsequent contralateral total joint reconstruction. Long-term subjective and objective outcomes of unilateral TMJ reconstruction also were evaluated. MATERIALS AND METHODS: Seventy patients underwent unilateral total joint reconstruction using a patient-fitted total joint prosthesis from a single private practice from 1990 through 2012. The inclusion criteria were 1) unilateral TMJ reconstruction with TMJ Concepts or Techmedica patient-fitted total joint prosthesis; 2) operation performed by 1 surgeon (L.M.W.); 3) minimum 12-month follow-up; and 4) adequate records. There were no specific exclusion criteria. The primary outcome variable was to evaluate the effects of unilateral TMJ reconstruction with a total joint prosthesis on the contralateral TMJ relative to development of pain and dysfunction requiring subsequent contralateral reconstruction with a total joint prosthesis. Secondary outcome variables for all patients included TMJ pain, facial pain, headaches, diet, disability, quality of life, maximum incisal opening (MIO), and lateral excursion movements after unilateral TMJ reconstruction with the patient-fitted total joint prosthesis. Student t test and Wilcoxon test were used for statistical analyses, with a P value less than .01 for statistical significance. RESULTS: Sixty-one of 70 patients (87%) met the inclusion criteria (47 women [77%] and 14 men [23%]; average age, 38 yr; age range, 11 to 69 yr; average follow-up, 44 months; range, 12 to 215 months). Eight of 61 patients (13%) subsequently required contralateral TMJ reconstruction with a total joint prosthesis related to contralateral pain, dysfunction, and arthritis, but all 8 (8 of 27 [29.6%]) had previous contralateral TMJ disc repositioning surgery. For the secondary outcomes, TMJ pain decreased 63%, jaw function improved 61%, facial pain decreased 59%, headaches decreased 57%, diet improved 52%, disability decreased 58.5%, and MIO increased from 31.4 to 38.8 mm (mean change, 7.4 mm). All subjective factors and MIO showed statistically significant improvements at longest follow-up (P < .01). CONCLUSIONS: Patients requiring unilateral TMJ reconstruction with a patient fitted total joint prosthesis have a strong probability of improving their clinical condition and do not require bilateral reconstruction if the contralateral TMJ is healthy. Patients with previous or concomitant contralateral TMJ surgery (articular disc repositioning) have an approximately 30% chance of requiring a total joint prosthesis in the future. PMID- 26988575 TI - The Co-evolution of Speech and the Lexicon: The Interaction of Functional Pressures, Redundancy, and Category Variation. AB - The sound system of a language must be able to support a perceptual contrast between different words in order to signal communicatively relevant meaning distinctions. In this paper, we use a simple agent-based exemplar model in which the evolution of sound-category systems is understood as a co-evolutionary process, where the range of variation within sound categories is constrained by functional pressure to keep different words perceptually distinct. We show that this model can reproduce several observed effects on the range of sound variation. We argue that phonological systems can be seen as finding a relative optimum of variation: Efficient communication is sustained while at the same time, hidden category variation provides pathways for future evolution. PMID- 26988576 TI - Has the participation of older employees in the workforce increased? Study of the total Swedish population regarding exit from working life. AB - AIMS: This study investigated: (i) the workforce participation in Sweden among older employees before and after changes in eligibility for sickness absence and unemployment compensation by a social insurance reform; and (ii) absence and early exit mechanisms from the workforce for different professions by looking at sickness benefits, disability pension and unemployment, early statutory pension, employment pension and unregistered economic supply. METHODS: A register-based follow-up study of the total Swedish workforce population of 55-64-year-olds, measured in 2004 and 2011. RESULTS: The total proportion of individuals aged 55 64 in the workforce increased between 2004 and 2011, but the increase was mostly in professions with lower educational requirements, a lower salary and dominated by women. Both in 2004 and in 2011, men in professions with higher educational requirements more often exit working life with an early statutory pension and employment pension. In contrast, professions with lower educational requirements more often absence working life with sickness benefits, disability pension and unemployment compensation than other professions in both 2004 and 2011. CONCLUSIONS THE CHANGE IN REGULATIONS SEEMS TO HAVE CONTRIBUTED TO AN OVERALL SHRINKING PROPORTION OF INDIVIDUALS WITHIN THE SICKNESS BENEFIT AND DISABILITY PENSION SCHEMES AT THE SAME TIME THE PROPORTION OF INDIVIDUALS TAKING AN EARLY PENSION HAS INCREASED THE RESULTS INDICATED A TENDENCY OF PASSING ON THE COSTS OF LABOUR-MARKET EXIT WITHIN DIFFERENT ECONOMIC COMPENSATION ARRANGEMENTS, AS WELL AS TO THE INDIVIDUALS THEMSELVES; FOR EXAMPLE, LESS SICKNESS BENEFIT, DISABILITY PENSION, BUT MORE STATUTORY PENSION AND EMPLOYMENT PENSION EARLIER. PMID- 26988577 TI - Of Tweets and Men. PMID- 26988578 TI - Assessment of Left Ventricular Mass and Hypertrophy by Cardiovascular Magnetic Resonance Imaging in Pediatric Hypertension. AB - Cardiovascular magnetic resonance (CMR) imaging in adults is considered the gold standard for assessment of left ventricular mass (LVM) and left ventricular hypertrophy (LVH). The authors aimed to evaluate agreement of LVM measurements and LVH determination between echocardiography (ECHO) and CMR imaging in children with hypertension (HTN) confirmed by 24-hour ambulatory blood pressure monitoring (ABPM). The children (n=22) underwent contemporaneous ECHO, CMR imaging, and ABPM. Patients had a mean body mass index of 30.9+/-7.5 (kg/m2 ), and 81.8% had severe HTN. LVM measured by ECHO was 189.6+/-62.1 g and by CMR imaging was 164.6+/-44.7 g (P<.0001). Bland-Altman analysis revealed significant variability between ECHO and CMR imaging in the measurement of LVM. Interobserver error was higher with ECHO than with CMR imaging. ECHO had high sensitivity and low specificity in LVH determination. In conclusion, ECHO overestimates LVM and is less accurate in measuring LVM as compared with CMR imaging in children with HTN. Further prospective study using CMR imaging to assess LVM in children is warranted. PMID- 26988579 TI - Growth and Endocrinal Abnormalities in Pediatric Langerhans Cell Histiocytosis. AB - OBJECTIVE: To ascertain the growth and endocrinal disturbances associated with Pediatric Langerhans Cell Histiocytosis (LCH). METHODS: Retrospective analysis of hospital records of subjects with LCH, aged 1 mo to 18 y was performed. The diagnosis of LCH was made as per Histiocyte Society criteria. Subjects were classified as group A: multifocal bone disease; B: soft tissue involvement without organ dysfunction; and C: organ dysfunction and treated as per DAL-HX-83 protocol of the Histiocyte Society LCH treatment guidelines. Paired t-test was used to compare the baseline and follow-up data. RESULTS: Total 62 records (group A- 18, B-32 and C-12) were identified with median follow-up of 5.3 +/- 3.3 y. Growth failure [measured as weight/ height Standard deviation score (SDS) <=-2] was the commonest disorder seen in 27 (44 %) subjects. Central Diabetes Insipidus (DI) was seen in 12 (19 %) subjects. Subjects with group C of LCH had poorer weight and height at baseline and follow-up than subjects with group A or B. Height SDS were lower in subjects with concomitant DI than those without DI at baseline (-2.35 +/- 1.9 and -1.69 +/- 1.4; P 0.18). Subjects with DI did not show significant catch-up in their height (P 0.12) unlike those without DI who showed a catch-up in height (P 0.03) on follow-up. CONCLUSIONS: Growth monitoring and screening for DI should be essential part of follow-up in all subjects with LCH. PMID- 26988581 TI - The New Substance Abuse and Mental Health Services Administration Oral Fluid Cutoffs for Cocaine and Heroin-Related Analytes Applied to an Addiction Medicine Setting: Important, Unanticipated Findings with LC-MS/MS. AB - BACKGROUND: We implemented oral fluid (OF) as an alternative specimen type to urine for detection of cocaine (COC) and opiate abuse in outpatient addiction medicine clinics. METHODS: We implemented a 2-MUg/L limit of quantification OF LC MS/MS assay and compiled and reviewed all findings from a 22-month collection period for COC, benzoylecgonine (BZE), codeine (COD), 6-acetylmorphine (MAM), and morphine (MOR). We also compared the results of our clinical samples at different OF cutoffs and analytes specified in the new 2015 SAMHSA OF guidelines. RESULTS: Of 3608 OF samples, COC and BZE were positive in 593 and 508, respectively. COC or BZE was positive in 662 samples. Importantly and unexpectedly, 154 samples were COC positive and BZE negative, with 125 having COC 2.0-7.9 MUg/L. A simulation with the new guideline cutoffs confirmed 65% (430 of 662) of all COC- or BZE-positive data set samples. Similarly, the new guidelines confirmed 44% (263 of 603) of data set samples positive for MOR or COD. Simulation found that the new, lower MAM guideline cutoffs detected 89% of the 382 MAM-positive samples in the data set, 104 of which the new guidelines had identified as negative for MOR and COD. CONCLUSIONS: COC (not BZE) is the dominant low-concentration OF analyte in an addiction medicine setting. This information will aid OF test interpretation. It also illustrates the importance of the 2015 guideline's new immunoassay cross-reactivity requirements and the likely improvement in detection of heroin use stemming from the new, lower MAM cutoffs. PMID- 26988582 TI - Incorporating Clinical Considerations into Statistical Analyses of Markers: A Quiet Revolution in How We Think About Data. PMID- 26988580 TI - CDC Kerala--The Untold Story. AB - This article is our life time experience in conceptualizing and systematically developing Child Development Centre (CDC) Kerala in the last 25 years, from a research project to a national training centre in child and adolescent development and premarital counseling. CDC Kerala's major contribution was in creating a 'conceptual framework' of a valid link between childhood disability, low birth weight, adolescent girls' nutrition and fetal onset adult lifestyle diseases. It all started with a randomized controlled trial (RCT) proving beyond doubt that early stimulation is effective in improving the neurodevelopmental status of high risk babies at one and two years and the same cohort was followed up in detail at 5, 13, 16, 19 and 24 completed years. The process of establishing CDC Kerala is being presented under (i) clinical child development, (ii) adolescent care counseling, (iii) young adults and premarital counseling and (iv) institution building. PMID- 26988583 TI - DETECT the Extremes That Usually Remain Undetected in Conventional Observational Studies. PMID- 26988584 TI - B-Type Natriuretic Peptide Testing in the Era of Neprilysin Inhibition: Are the Winds of Change Blowing? PMID- 26988585 TI - Time to Pay Attention to Reagent and Calibrator Lots for Proficiency Testing. PMID- 26988586 TI - Postmarket Surveillance of Point-of-Care Glucose Meters through Analysis of Electronic Medical Records. AB - BACKGROUND: The electronic medical record (EMR) holds a promising source of data for active postmarket surveillance of diagnostic accuracy, particularly for point of-care (POC) devices. Through a comparison with prospective bedside and laboratory accuracy studies, we demonstrate the validity of active surveillance via an EMR data mining method [Data Mining EMRs to Evaluate Coincident Testing (DETECT)], comparing POC glucose results to near-in-time central laboratory glucose results. METHODS: The Roche ACCU-CHEK Inform II((r)) POC glucose meter was evaluated in a laboratory validation study (n = 73), a prospective bedside intensive care unit (ICU) study (n = 124), and with DETECT (n = 852-27 503). For DETECT, the EMR was queried for POC and central laboratory glucose results with filtering based on of bedside collection timestamps, central laboratory time delays, patient location, time period, absence of repeat testing, and presence of peripheral lines. RESULTS: DETECT and the bedside ICU study produced similar estimates of average bias (4.5 vs 5.0 mg/dL) and relative random error (6.3% vs 5.6%), with overlapping CIs. For glucose <100 mg/dL, the laboratory validation study estimated a lower relative random error of 3.6%. POC average bias correlated with central laboratory turnaround times, consistent with 4.8 mg . dL( 1) . h(-1) glycolysis. After glycolysis adjustment, average bias was estimated by the bedside ICU study at -0.4 mg/dL (CI, -1.6 to 0.9) and DETECT at -0.7 (CI, 1.3 to 0.2), and percentage POC results occurring outside Clinical Laboratory Standards Institute quality goals were 2.4% and 4.8%, respectively. CONCLUSIONS: This study validates DETECT for estimating POC glucose meter accuracy compared with a prospective bedside ICU study and establishes it as a reliable postmarket surveillance methodology. PMID- 26988588 TI - Counterpoint: Low-Density Lipoprotein Cholesterol Targets Are Not Needed in Lipid Treatment Guidelines. AB - On the basis of accumulating evidence, low-density lipoprotein cholesterol (LDL C) treat-to-goal approaches no longer seem to be the best way to optimize lipid modifying therapy to prevent atherosclerotic cardiovascular disease (ASCVD). The potential for a net ASCVD risk reduction benefit is a more individualized approach to clinical decision making and may better inform patient preferences. However, risk estimation tools will need to be developed to facilitate more personalized CVD risk estimation in statin-treated patients. In the meantime, LDL C thresholds rather than targets may aid in determining which patients might benefit from additional LDL-C-lowering therapy beyond statins. PMID- 26988587 TI - Signaling of Serum Amyloid A Through Receptor for Advanced Glycation End Products as a Possible Mechanism for Uremia-Related Atherosclerosis. AB - OBJECTIVE: Cardiovascular disease is the leading cause of death in patients with end-stage renal disease. Serum amyloid A (SAA) is an acute phase protein and a binding partner for the multiligand receptor for advanced glycation end products (RAGE). We investigated the role of the interaction between SAA and RAGE in uremia-related atherogenesis. APPROACH AND RESULTS: We used a mouse model of uremic vasculopathy, induced by 5 of 6 nephrectomy in the Apoe(-/-) background. Sham-operated mice were used as controls. Primary cultures of Ager(+/+) and Ager( /-) vascular smooth muscle cells (VSMCs) were stimulated with recombinant SAA, S100B, or vehicle alone. Relevance to human disease was assessed with human VSMCs. The surface area of atherosclerotic lesions at the aortic roots was larger in uremic Apoe(-/-) than in sham-operated Apoe(-/-) mice (P<0.001). Furthermore, atherosclerotic lesions displayed intense immunostaining for RAGE and SAA, with a pattern similar to that of alpha-SMA. Ager transcript levels in the aorta were 6* higher in uremic animals than in controls (P<0.0001). Serum SAA concentrations were higher in uremic mice, not only after 4 weeks of uremia but also at 8 and 12 weeks of uremia, than in sham-operated animals. We investigated the functional role of RAGE in uremia-induced atherosclerosis further, in animals lacking RAGE. We found that the induction of uremia in Apoe(-/-) Ager(-/-) mice did not accelerate atherosclerosis. In vitro, the stimulation of Ager(+/+) but not of Ager(-/-) VSMCs with SAA or S100B significantly induced the production of reactive oxygen species, the phosphorylation of AKT and mitogen-activated protein kinase-extracellular signal-regulated kinases and cell migration. Reactive oxygen species inhibition with N-acetyl cysteine significantly inhibited both the phosphorylation of AKT and the migration of VSMCs. Similar results were obtained for human VSMCs, except that the phosphorylation of mitogen-activated protein kinase-extracellular signal-regulated kinases, rather than of AKT, was subject to specific redox-regulation by SAA and S100B. Furthermore, human aortic atherosclerotic sections were positively stained for RAGE and SAA. CONCLUSIONS: Uremia upregulates SAA and RAGE expression in the aortic wall and in atherosclerotic lesions in mice. Ager(-/-) animals are protected against the uremia-induced acceleration of atherosclerosis. SAA modulates the functions of murine and human VSMCs in vitro in a RAGE-dependent manner. This study, therefore, identifies SAA as a potential new uremic toxin involved in uremia related atherosclerosis through interaction with RAGE. PMID- 26988590 TI - Pharmacologically Improved Contractility Protects Against Aortic Dissection in Mice With Disrupted Transforming Growth Factor-beta Signaling Despite Compromised Extracellular Matrix Properties. AB - OBJECTIVE: Transforming growth factor-beta is a pleiotropic cytokine having diverse roles in vascular morphogenesis, homeostasis, and pathogenesis. Altered activity of and signaling through transforming growth factor-beta has been implicated in thoracic aortic aneurysms and dissections, conditions characterized by a reduced structural integrity of the wall that associates with altered biomechanics and mechanobiology. We quantify and contrast the passive and active biaxial biomechanical properties of the ascending and proximal descending thoracic aorta in a mouse model of altered transforming growth factor-beta signaling, with and without treatment with rapamycin. APPROACH AND RESULTS: Postnatal disruption of the gene (Tgfbr2) that codes the type II transforming growth factor-beta receptor compromises vessel-level contractility and elasticity. Daily treatment with rapamycin, a mechanistic target of rapamycin inhibitor that protects against aortic dissection in these mice, largely preserves or restores the contractile function while the passive properties remain compromised. Importantly, this increased smooth muscle contractility protects an otherwise vulnerable aortic wall from pressure-induced intramural delaminations in vitro. CONCLUSIONS: Notwithstanding the protection afforded by rapamycin in vivo and in vitro, the residual mechanical dysfunctionality suggests a need for caution if rapamycin is to be considered as a potential therapeutic. There is a need for in vivo evaluations in cases of increased hemodynamic loading, including hypertension or extreme exercise, which could unduly stress a structurally vulnerable aortic wall. Given these promising early results, however, such studies are clearly warranted. PMID- 26988589 TI - Angiotensin II Destabilizes Coronary Plaques in Watanabe Heritable Hyperlipidemic Rabbits. AB - OBJECTIVE: Increased plasma concentrations of angiotensin II (Ang II) have been implicated in many cardiovascular diseases, such as atherosclerosis, aortic aneurysms, and myocardial infarction, in humans. However, it is not known whether high levels of plasma Ang II affect coronary plaque stability and subsequent myocardial infarction. This study was designed to examine whether elevated plasma Ang II can directly induce coronary events, such as acute coronary syndrome. APPROACH AND RESULTS: To examine the above hypothesis, we infused Ang II (100 ng/min per kg [low group] and 200 ng/min per kg [high group]) or saline vehicle via osmotic minipumps into Watanabe heritable hyperlipidemic rabbits, a model of human familial hypercholesterolemia and atherosclerosis. Infusion of Ang II resulted in mortality rates of 50% and 92% in the low- and high-Ang II groups, respectively, whereas there were no deaths in the vehicle group. Pathological analysis revealed that Ang II-infused Watanabe heritable hyperlipidemic rabbits that died showed myocardial infarction. Furthermore, Ang II-infused Watanabe heritable hyperlipidemic rabbits exhibited coronary plaque erosion and rupture that were associated with thrombosis. CONCLUSIONS: These findings suggest that increased blood levels of Ang II can destabilize coronary plaques and trigger the thrombosis, which possibly induces myocardial infarction. The model described in this study provides a novel means for the study of human acute coronary syndrome. PMID- 26988593 TI - Observationally and Genetically High YKL-40 and Risk of Venous Thromboembolism in the General Population: Cohort and Mendelian Randomization Studies. AB - OBJECTIVE: High baseline YKL-40 is associated with later development of ischemic stroke, but not with myocardial infarction. Whether high YKL-40 levels are associated with increased risk of venous thromboembolism is presently unknown. We tested the hypothesis that observationally and genetically high YKL-40 is associated with increased risk of venous thromboembolism in the general population. APPROACH AND RESULTS: Cohort and Mendelian randomization studies in 96 110 individuals from the Danish general population, with measured plasma levels of YKL-40 (N=21 647) and CHI3L1 rs4950928 genotype (N=94 579). From 1977 to 2013, 1489 individuals developed pulmonary embolism, 2647 developed deep vein thrombosis, and 3750 developed venous thromboembolism (pulmonary embolism and deep vein thrombosis). For the 91% to 100% versus 0% to 33% YKL-40 percentile category, the multifactorially adjusted hazard ratio was 2.38 (95% confidence interval, 1.25-4.55) for pulmonary embolism, 1.98 (1.09-3.59) for deep vein thrombosis, and 2.13 (1.35-3.35) for venous thromboembolism. Compared with rs4950928 GG homozygosity, presence of C-allele was associated with a doubling (CG) or tripling (CC) in YKL-40 levels, but not with risk of venous thromboembolism. A doubling in YKL-40 was associated with a multifactorially adjusted observational hazard ratio for pulmonary embolism of 1.17 (1.00-1.38) and a genetic odds ratio of 0.97 (0.76-1.23). Corresponding risk estimates were 1.28 (1.12-1.47) observationally and 1.11 (0.91-1.35) genetically for deep vein thrombosis and 1.23 (1.10-1.38) observationally and 1.08 (0.92-1.27) genetically for venous thromboembolism. CONCLUSIONS: High YKL-40 levels were associated with a 2-fold increased risk of venous thromboembolism, but the association was not causal. PMID- 26988591 TI - Mesenchymal Stem Cells Attenuate NADPH Oxidase-Dependent High Mobility Group Box 1 Production and Inhibit Abdominal Aortic Aneurysms. AB - OBJECTIVE: Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, smooth muscle activation, and matrix degradation. This study tests the hypothesis that macrophage-produced high mobility group box 1 (HMGB1) production is dependent on nicotinamide adenine dinucleotide phosphate oxidase (Nox2), which leads to increase in interleukin (IL)-17 production resulting in AAA formation and that treatment with human mesenchymal stem cells (MSCs) can attenuate this process thereby inhibiting AAA formation. APPROACH AND RESULTS: Human aortic tissue demonstrated a significant increase in HMGB1 expression in AAA patients when compared with controls. An elastase-perfusion model of AAA demonstrated a significant increase in HMGB1 production in C57BL/6 (wild-type [WT]) mice, which was attenuated by MSC treatment. Furthermore, anti-HMGB1 antibody treatment of WT mice attenuated AAA formation, IL-17 production, and immune cell infiltration when compared with elastase-perfused WT mice on day 14. Elastase-perfused Nox2(-/y) mice demonstrated a significant attenuation of HMGB1 and IL-17 production, cellular infiltration, matrix metalloproteinase activity, and AAA formation when compared with WT mice on day 14. In vitro studies showed that elastase-treated macrophages from WT mice, but not from Nox2(-/y) mice, produced HMGB1, which was attenuated by MSC treatment. The production of macrophage-dependent HMGB1 involved Nox2 activation and superoxide anion production, which was mitigated by MSC treatment. CONCLUSIONS: These results demonstrate that macrophage-produced HMGB1 leads to aortic inflammation and acts as a trigger for CD4(+) T-cell-produced IL-17 during AAA formation. HMGB1 release is dependent on Nox2 activation, which can be inhibited by MSCs leading to attenuation of proinflammatory cytokines, especially IL-17, and protection against AAA formation. PMID- 26988592 TI - CalDAG-GEFI Deficiency Reduces Atherosclerotic Lesion Development in Mice. AB - OBJECTIVE: Platelets are important for the development and progression of atherosclerotic lesions. However, relatively little is known about the contribution of platelet signaling to this pathological process. Our recent work identified 2 independent, yet synergistic, signaling pathways that lead to the activation of the small GTPase Rap1; one mediated by the guanine nucleotide exchange factor, CalDAG-GEFI (CDGI), the other by P2Y12, a platelet receptor for adenosine diphosphate and the target of antiplatelet drugs. In this study, we evaluated lesion formation in atherosclerosis-prone low-density lipoprotein receptor deficient (Ldlr(-/-)) mice lacking CDGI or P2Y12 in hematopoietic cells. APPROACH AND RESULTS: Lethally irradiated Ldlr(-/-) mice were reconstituted with bone marrow from wild-type (WT), Caldaggef1(-/-) (cdgI(-/-)), p2y12(-/-), or cdgI(-/-)p2y12(-/-) (double knockout [DKO]) mice and fed a high-fat diet for 12 weeks. Ldlr(-/-) chimeras deficient for CDGI or P2Y12 developed significantly smaller atherosclerotic lesions in the aortic sinus and in aortas when compared with the Ldlr(-/-)/WT controls. We also observed a significant reduction in platelet-leukocyte aggregates in blood from hypercholesterolemic Ldlr(-/-)/cdgI( /-) and Ldlr(-/-)/p2y12(-/-) chimeras. Consistently, fewer macrophages and neutrophils were detected in the aortic sinus of Ldlr(-/-)/cdgI(-/-) and Ldlr(-/ )/ p2y12(-/-) chimeras. Compared with controls, the plaque collagen content was significantly higher in Ldlr(-/-) chimeras lacking CDGI. Interestingly, no statistically significant additive effects were seen in Ldlr(-/-)/DKO chimeras when compared with chimeras lacking only CDGI. CONCLUSIONS: Our findings suggest that CDGI is critical for atherosclerotic plaque development in hypercholesterolemic Ldlr(-/-) mice because of its contribution to platelet leukocyte aggregate formation and leukocyte recruitment to the lesion area. PMID- 26988595 TI - Quantifying the consequences of nutritional strategies aimed at decreasing phosphorus excretion from pig populations: a modeling approach. AB - There is a global imperative to reduce phosphorous (P) excretion from pig systems. In this study, a previously validated deterministic model was modified to be stochastic, in order to investigate the consequences of different management strategies on P excretion by a group of growing pigs. The model predicts P digestion, retention and excretion from feed composition and growth parameters that describe a specified pig phenotype. Stochasticity was achieved by introducing random variation in the latter. The strategies investigated were: (1) changing feed composition frequently in order to match more closely pig digestible P (digP) requirements to feed composition (phase feeding) and (2) grouping pigs into light and heavy groups and feeding each group according to the requirements of their group average BW (sorting). Phase feeding reduced P excretion as the number of feeding phases increased. The effect was most pronounced as feeding phases increased from 1 to 2, with a 7.5% decrease achieved; the increase in phases from 2 to 3 was associated with a further 2.0% reduction. Similarly, the effect was more pronounced when the feed targeted the population requirements for digP at the average BW of the first third, rather than the average requirements at the mid-point BW of each feeding sequence plan. Increasing the number of feeding phases increased the percentage of pigs that met their digP requirements during the early stages of growth and reduced the percentage of pigs that were supplied <85% of their digP requirements at any stage of their growth; the latter may have welfare implications. Sorting of pigs reduced P excretion to a lesser extent; the reduction was greater as the percentage of pigs in the light group increased from 10% to 30% (from 1.5% to 3.0% reduction, respectively). This resulted from an increase in the P excreted by the light group, accompanied by a decrease in the P excreted by the remaining pigs. Sorting increased the percentage of light pigs that met their dig P requirements, but only slightly decreased the percentage of heavy pigs that met these requirements at any point of their growth. Exactly the converse was the case as far as the percentage of pigs that were supplied <85% of their digP requirements were concerned. The developed model is flexible and can be used to investigate the effectiveness of other management strategies in reducing P excretion from groups of pigs, including precision livestock feeding. PMID- 26988597 TI - New fluoroborate Cd8B5O15F with two different isolated borate anions prepared by an open high-temperature solution method. AB - The novel cadmium fluoroborate crystal Cd8B5O15F has been successfully obtained from the reaction of the high-temperature solution method in open air for the first time. An X-ray crystallographic study of the product reveals that Cd8B5O15F crystallizes in the space group Fd3[combining macron]m. The parameters of the cubic unit cell are a = 13.972(3) A, and Z = 8. The title compound exhibits a complicated three-dimensional (3D) network. And the crystal structure is composed of two isolated borate anions: BO3 and B(O/F)4. For the B(O/F)4 group, it consists of the occupancy of F and O with the ratio of 3 : 1. Spectroscopic properties using the IR spectrum, X-ray photoelectron spectroscopy, and Raman spectrum were measured to illustrate this feature. The thermal behavior and UV Vis-NIR diffuse-reflectance spectrum of Cd8B5O15F are also reported in this work. PMID- 26988594 TI - Differential Roles of the NADPH-Oxidase 1 and 2 in Platelet Activation and Thrombosis. AB - OBJECTIVE: Reactive oxygen species (ROS) are known to regulate platelet activation; however, the mechanisms of ROS production during platelet activation remain unclear. Platelets express different isoforms of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidases (NOXs). Here, we investigated the role of NOX1 and NOX2 in ROS generation and platelet activation using NOX1 and NOX2 knockout mice. APPROACH AND RESULTS: NOX1(-/Y) platelets showed selective defects in G-protein-coupled receptor-mediated platelet activation induced by thrombin and thromboxane A2 analog U46619, but were not affected in platelet activation induced by collagen-related peptide, a glycoprotein VI agonist. In contrast, NOX2(-/-) platelets showed potent inhibition of collagen-related peptide-induced platelet activation, and also showed partial inhibition of thrombin-induced platelet activation. Consistently, production of ROS was inhibited in NOX1(-/Y) platelets stimulated with thrombin, but not collagen related peptide, whereas NOX2(-/-) platelets showed reduced ROS generation induced by collagen-related peptide or thrombin. Reduced ROS generation in NOX1/2 deficient platelets is associated with impaired activation of Syk and phospholipase Cgamma2, but minimally affected mitogen-activated protein kinase pathways. Interestingly, laser-induced arterial thrombosis was impaired but the bleeding time was not affected in NOX2(-/-) mice. Wild-type thrombocytopenic mice injected with NOX2(-/-) platelets also showed defective arterial thrombosis, suggesting an important role for platelet NOX2 in thrombosis in vivo but not hemostasis. CONCLUSIONS: NOX1 and NOX2 play differential roles in different platelet activation pathways and in thrombosis. ROS generated by these enzymes promotes platelet activation via the Syk/phospholipase Cgamma2/calcium signaling pathway. PMID- 26988599 TI - Deconstruction of destruction stories: narrative, inequality, and disasters. AB - A commonly-held belief is that natural disasters do not discriminate. This paper, though, poses the following theoretical question: what does the elision of race, class, and gender in the news media say about disasters in the neoliberal era? It draws on the author's analysis of two prominent newspapers-The New York Times and USA Today-and their coverage of the recovery process after devastating tornadoes in two towns in the United States (Tuscaloosa, Alabama, and Joplin, Missouri) in 2011. The study asserts that the narrative of the news media is one with which people are familiar and that it fits into larger 'formula stories'. It utilises theoretical treatments of narrative to demonstrate how differences are erased and how they lead to complicity in hegemonic representations. Critical theory is used to elucidate why this occurs, and the paper sources Goldberg (2002) in suggesting that the news media employs 'fantasies of homogenisation' when representing post disaster communities. PMID- 26988596 TI - Multiscale method for modeling binding phenomena involving large objects: application to kinesin motor domains motion along microtubules. AB - Many biological phenomena involve the binding of proteins to a large object. Because the electrostatic forces that guide binding act over large distances, truncating the size of the system to facilitate computational modeling frequently yields inaccurate results. Our multiscale approach implements a computational focusing method that permits computation of large systems without truncating the electrostatic potential and achieves the high resolution required for modeling macromolecular interactions, all while keeping the computational time reasonable. We tested our approach on the motility of various kinesin motor domains. We found that electrostatics help guide kinesins as they walk: N-kinesins towards the plus end, and C-kinesins towards the minus-end of microtubules. Our methodology enables computation in similar, large systems including protein binding to DNA, viruses, and membranes. PMID- 26988598 TI - PI3K in the ventromedial hypothalamic nucleus mediates estrogenic actions on energy expenditure in female mice. AB - Estrogens act in the ventromedial hypothalamic nucleus (VMH) to regulate body weight homeostasis. However, the molecular mechanisms underlying these estrogenic effects are unknown. We show that activation of estrogen receptor-alpha (ERalpha) stimulates neural firing of VMH neurons expressing ERalpha, and these effects are blocked with intracellular application of a pharmacological inhibitor of the phosphatidyl inositol 3-kinase (PI3K). Further, we demonstrated that mice with genetic inhibition of PI3K activity in VMH neurons showed a sexual dimorphic obese phenotype, with only female mutants being affected. In addition, inhibition of VMH PI3K activity blocked effects of 17beta-estradiol to stimulate energy expenditure, but did not affect estrogen-induced anorexia. Collectively, our results indicate that PI3K activity in VMH neurons plays a physiologically relevant role in mediating estrogenic actions on energy expenditure in females. PMID- 26988600 TI - Single chain antibody fragments with pH dependent binding to FcRn enabled prolonged circulation of therapeutic peptide in vivo. AB - The neonatal Fc receptor for IgG (FcRn) is considered critical for the regulation of endogenous IgG and serum albumin (SA) and their circulation half-life in vivo. Both IgG and SA can bind to FcRn tightly at acidic pH but not so much at neutral pH. Here we reported a few novel single chain antibody fragments (scFv) obtained based on screening of a phage library. FnAb-8 and FnAb-12 can bind to human FcRn with higher affinities than IgG at acidic pH but similar or lower affinities than IgG at pH7.4. Fusion proteins consisted of the therapeutic peptide, GLP-1 (Glucagon-like peptide-1) connected to the N-terminus of FnAb-8 and FnAb-12, named as G8 and G12, were shown to retain the pH-dependent binding capabilities to FcRn while also bound to the GLP-1 receptor. In vivo efficacy studies in diet induced diabetes mice confirmed the GLP-1 receptor (GLP-1R) agonist activities and sustained blood sugar lowering effect. In vivo pharmacokinetics (PK) studies were performed in nonhuman primates and FnAb-8 was found to have circulation half life several folds longer than what have been reported for scFvs. G8 may be developed into long acting GLP-1R agonists with great potentials in clinical applications. PMID- 26988601 TI - Nano-biomaterials for cardiovascular applications: Clinical perspective. AB - Cardiovascular diseases, including ischemic heart disease and stroke, are responsible for nearly 25% of all deaths worldwide. Globally, their prevalence continues to increase, in spite of enormous progress in cardiovascular diagnostics and therapy. For therapeutic and regenerative purposes, biomaterials promise solutions with multiple advantages over synthetic materials. Furthermore, their easy availability as nanoformulations recommends their application as drug carriers or protective nanoshells improving the biocompatibility of imaging agents. In this work, we review the most promising and clinically meaningful scientific reports with regard to (nano)biomaterials with particular focus on potential improvements of existing, and development of novel constructs for cardiovascular applications. PMID- 26988602 TI - EGFR targeted nanobody-photosensitizer conjugates for photodynamic therapy in a pre-clinical model of head and neck cancer. AB - Photodynamic therapy (PDT) induces cell death through local light activation of a photosensitizer (PS) and has been used to treat head and neck cancers. Yet, common PS lack tumor specificity, which leads to collateral damage to normal tissues. Targeted delivery of PS via antibodies has pre-clinically improved tumor selectivity. However, antibodies have long half-lives and relatively poor tissue penetration, which could limit therapeutic efficacy and lead to long photosensitivity. Here, in this feasibility study, we evaluate at the pre clinical level a recently introduced format of targeted PDT, which employs nanobodies as targeting agents and a water-soluble PS (IRDye700DX) that is traceable through optical imaging. In vitro, the PS solely binds to cells and induces phototoxicity on cells overexpressing the epidermal growth factor receptor (EGFR), when conjugated to the EGFR targeted nanobodies. To investigate whether this new format of targeted PDT is capable of inducing selective tumor cell death in vivo, PDT was applied on an orthotopic mouse tumor model with illumination at 1h post-injection of the nanobody-PS conjugates, as selected from quantitative fluorescence spectroscopy measurements. In parallel, and as a reference, PDT was applied with an antibody-PS conjugate, with illumination performed 24h post-injection. Importantly, EGFR targeted nanobody-PS conjugates led to extensive tumor necrosis (approx. 90%) and almost no toxicity in healthy tissues, as observed through histology 24h after PDT. Overall, results show that these EGFR targeted nanobody-PS conjugates are selective and able to induce tumor cell death in vivo. Additional studies are now needed to assess the full potential of this approach to improving PDT. PMID- 26988604 TI - Radiological safety assessment inside ancient Egyptian tombs in Saqqara. AB - Many archaeological sites in Egypt are unique worldwide, such as ancient tombs and pyramids, because they document fundamental developments in human civilization that took place several thousands of years ago. For this reason, these sites are visited by numerous visitors every year. The present work is devoted to provide a pre-operational radiological baseline needed to quantify occupational radiation exposure at the famous Saqqara region in Cairo, Egypt. A hyperpure Ge detector has been used in the gamma-ray spectrometric analysis while the (222)Rn concentration was measured using a portable radon monitor RTM 1688-2, SARAD. The mean specific activities of (226)Ra, (232)Th and (40)K in the samples collected from the interior walls of the Saqqara tombs were determined and found to show average values of 16, 8.5 and 45 Bq kg(-1), respectively. The concentration of radon was measured inside the tombs Serapeum, South tomb and the Zoser Pyramid (fifth level) and an associated average working level of 0.83 WL was obtained. In order to avoid the health hazards associated with the exposure to radon during the long period of work inside these tombs, proposed solutions are introduced. PMID- 26988603 TI - Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization. AB - Glioblastoma multiforme (GBM) is the most common malignant brain tumor with a median survival time about one year. Invasion of GBM cells into normal brain is the major cause of poor prognosis and requires dynamic reorganization of the actin cytoskeleton, which includes lamellipodial protrusions, focal adhesions, and stress fibers at the leading edge of GBM. Therefore, we hypothesized that inhibitors of actin polymerization can suppress GBM migration and invasion. First, we adopted a drug repositioning system for screening with a pyrene-actin based actin polymerization assay and identified fluvoxamine, a clinically used antidepressant. Fluvoxamine, selective serotonin reuptake inhibitor, was a potent inhibitor of actin polymerization and confirmed as drug penetration through the blood-brain barrier (BBB) and accumulation of whole brain including brain tumor with no drug toxicity. Fluvoxamine inhibited serum-induced ruffle formation, cell migration, and invasion of human GBM and glioma stem cells in vitro by suppressing both FAK and Akt/mammalian target of rapamycin signaling. Daily treatment of athymic mice bearing human glioma-initiating cells with fluvoxamine blocked tumor cell invasion and prolonged the survival with almost same dose of anti-depressant effect. In conclusion, fluvoxamine is a promising anti-invasive treatment against GBM with reliable approach. PMID- 26988605 TI - Induction Therapy in Lung Transplantation? A Frustrating Message of Persisting Uncertainty. PMID- 26988607 TI - Deoxynivalenol exposure induces autophagy/apoptosis and epigenetic modification changes during porcine oocyte maturation. AB - Deoxynivalenol (DON) is a widespread trichothecene mycotoxin which contaminates agricultural staples and elicits a complex spectrum of toxic effects on humans and animals. It has been shown that DON impairs oocyte maturation, reproductive function and causes abnormal fetal development in mammals; however, the mechanisms remain unclear. In the present study, we investigate the possible reasons of the toxic effects of DON on porcine oocytes. Our results showed that DON significantly inhibited porcine oocyte maturation and disrupted meiotic spindle by reducing p-MAPK protein level, which caused retardation of cell cycle progression. In addition, up-regulated LC3 protein expression and aberrant Lamp2, LC3 and mTOR mRNA levels were observed with DON exposure, together with Annexin V FITC staining assay analysis, these results indicated that DON treatment induced autophagy/apoptosis in porcine oocytes. We also showed that DON exposure increased DNA methylation level in porcine oocytes through altering DNMT3A mRNA levels. Histone methylation levels were also changed showing with increased H3K27me3 and H3K4me2 protein levels, and mRNA levels of their relative methyltransferase genes, indicating that epigenetic modifications were affected. Taken together, our results suggested that DON exposure reduced porcine oocytes maturation capability through affecting cytoskeletal dynamics, cell cycle, autophagy/apoptosis and epigenetic modifications. PMID- 26988606 TI - Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A. AB - Chronic oral treatment of tetrabromobisphenol A (TBBPA) to female Wistar Han rats resulted in increased incidence of cell proliferation at 250mg/kg and tumor formation in the uterus at higher doses. The present study was designed to test the hypothesis that disruption of estrogen homeostasis was a major mode-of-action for the observed effects. Biological changes were assessed in serum, liver, and the proximal (nearest the cervix) and distal (nearest the ovaries) sections of the uterine horn of Wistar Han rats 24h following administration of the last of five daily oral doses of 250mg/kg. Expression of genes associated with receptors, biosynthesis, and metabolism of estrogen was altered in the liver and uterus. TBBPA treatment also resulted in changes in expression of genes associated with cell division and growth. Changes were also observed in the concentration of thyroxine in serum and in expression of genes in the liver and uterus associated with thyroid hormone receptors. Differential expression of some genes was tissue dependent or specific to tissue location in the uterus. The biological responses observed in the present study support the hypothesis that perturbation of estrogen homeostasis is a major mode-of-action for TBBPA-mediated cell proliferation and tumorigenesis previously observed in the uterus of TBBPA treated Wistar Han rats. PMID- 26988608 TI - Osteogenic potential of rhBMP9 combined with a bovine-derived natural bone mineral scaffold compared to rhBMP2. AB - OBJECTIVES: Combination therapies of growth factors and scaffolds for bone tissue engineering are becoming routine for clinical use. BMP9 has previously been characterized as one of the most osteogenic inducers among the BMP superfamily; however, up until recently, BMP9 has only been available through adenovirus transfection experiments (gene therapy). While recombinant human (rh)BMP2 is regarded as the gold standard for bone regeneration with recombinant growth factors, recently the successful development of rhBMP9 brings intriguing new possibilities for future clinical use. The purpose of this pioneering study was to investigate the effects of rhBMP9 in comparison with rhBMP2 on an in vitro cell behavior of bone-forming osteoblasts when combined with a bone grafting material. MATERIAL AND METHODS: Undifferentiated mouse ST2 stromal bone marrow cells were seeded onto bovine-derived natural bone mineral (NBM) particles treated with (i) control, (ii) rhBMP2 (10 ng/ml), (iii) rhBMP2 (100 ng/ml), (iv) rhBMP9 (10 ng/ml) and (v) rhBMP9 (100 ng/ml). The effects of rhBMPs were compared for cell adhesion at 8 h, cell proliferation at 1, 3 and 5 days and osteoblast differentiation as assessed by real-time PCR at 3 and 14 days for genes encoding Runx2, collagen1alpha2 (COL1a2), alkaline phosphatase (ALP) and osteocalcin (OCN). Furthermore, ALP staining and alizarin red staining were used to investigate localization of osteoblast differentiation marker and mineralization on NBM. RESULTS: Although neither rhBMP2 nor rhBMP9 influenced cell attachment to NBM particles, both were able to stimulate cell proliferation at 3 days. Furthermore, all concentrations of rhBMPs were able to significantly induce mRNA levels of Runx2, COL1a2 and OCN at 3 days. Interestingly, only rhBMP9 was able to significantly upregulate mRNA levels of ALP up to eightfold, and ALP staining up to 25-fold, when compared to rhBMP2. In addition, only rhBMP9 (100 ng/ml) significantly increased alizarin red staining when compared to control and rhBMP2 (10 ng/ml) samples. CONCLUSION: These results demonstrate that both rhBMP2 and rhBMP9 have osteopromotive properties on osteoblast differentiation. It was found that rhBMP9 additionally stimulated the osteopromotive potential of osteoblasts when compared to rhBMP2 by demonstrating higher levels of ALP expression and alizarin red staining. Further animal studies comparing both recombinant proteins are necessary to further characterize the osteoinductive potential of BMP9. PMID- 26988610 TI - Re: Jan P. Radtke, Constantin Schwab, Maya B. Wolf, et al. Multiparametric Magnetic Resonance Imaging (MRI) and MRI-Transrectal Ultrasound Fusion Biopsy for Index Tumor Detection: Correlation with Radical Prostatectomy Specimen. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2015.12.052. PMID- 26988611 TI - Is Combination Better than Escalation for Overactive Bladder Therapy? PMID- 26988612 TI - Half-sandwich rhodium and iridium metallamacrocycles constructed via C-H activation. AB - Half-sandwich rhodium and iridium complexes with carboxylic acid ligands were combined with pyrazine, 4,4'-bipyridine (bpy) or trans-1,2-bis(4-pyridyl) ethylene (bpe) to give a series of tetranuclear macrocycles. The metallamacrocycles [(Cp*Rh)4()2(pyrazine)2][OTf]2 (), [(Cp*Rh)4()2(bpy)2][OTf]2 (), [(Cp*Rh)4()2(bpe)2][OTf]4 () and [(Cp*Ir)4()2 (pyrazine)2] () ( = 3-(2 pyridyl)acrylic acid, = 1,4-di(4-carboxyphenyl)benzene) were characterized by elemental analysis, NMR, IR and single-crystal X-ray analyses. Due to the different structures of the carboxylate ligands, the complexes , and were synthesized through double-site C-H activation, and complexes were obtained by one-site C-H activation. PMID- 26988609 TI - Gene Expression Profile of the Clinically Aggressive Micropapillary Variant of Bladder Cancer. AB - BACKGROUND: Progression of conventional urothelial carcinoma of the bladder to a tumor with unique microscopic features referred to as micropapillary carcinoma is coupled with aggressive clinical behavior signified by a high propensity for metastasis to regional lymph nodes and distant organs resulting in shorter survival. OBJECTIVE: To analyze the expression profile of micropapillary cancer and define its molecular features relevant to clinical behavior. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified 43 patients with micropapillary bladder cancers and a reference set of 89 patients with conventional urothelial carcinomas and performed whole-genome expression messenger RNA profiling. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The tumors were segregated into distinct groups according to hierarchical clustering analyses. They were also classified according to luminal, p53-like, and basal categories using a previously described algorithm. We applied Ingenuity Pathway Analysis software (Qiagen, Redwood City, CA, USA) and gene set enrichment analysis for pathway analyses. Cox proportional hazards models and Kaplan-Meier methods were used to assess the relationship between survival and molecular subtypes. The expression profile of micropapillary cancer was validated for selected markers by immunohistochemistry on parallel tissue microarrays. RESULTS AND LIMITATIONS: We show that the striking features of micropapillary cancer are downregulation of miR-296 and activation of chromatin-remodeling complex RUVBL1. In contrast to conventional urothelial carcinomas that based on their expression can be equally divided into luminal and basal subtypes, micropapillary cancer is almost exclusively luminal, displaying enrichment of active peroxisome proliferator-activated receptor gamma and suppression of p63 target genes. As with conventional luminal urothelial carcinomas, a subset of micropapillary cancers exhibit activation of wild-type p53 downstream genes and represent the most aggressive molecular subtype of the disease with the shortest survival. The involvement of miR-296 and RUVBL1 in the development of micropapillary bladder cancer was identified by the analyses of correlative associations of genome expression profiles and requires mechanistic validation. CONCLUSIONS: Micropapillary cancer evolves through the luminal pathway and is characterized by the activation of miR-296 and RUVBL1 target genes. PATIENT SUMMARY: Our observations have important implications for prognosis and for possible future development of more effective therapies for micropapillary bladder cancer. PMID- 26988613 TI - Neural correlates of expression-independent memories in the crab Neohelice. AB - The neural correlates of memory have been usually examined considering that memory retrieval and memory expression are interchangeable concepts. However, our studies in the crab Neohelice (Chasmagnathus) granulata and in other memory models have shown that memory expression is not necessary for memory to be re activated and become labile. In order to examine putative neural correlates of memory in the crab Neohelice, we contrast changes induced by training in both animal's behavior and neuronal responses in the medulla terminalis using in vivo Ca(2+) imaging. Disruption of long-term memory by the amnesic agents MK-801 or scopolamine (5MUg/g) blocks the learning-induced changes in the Ca(2+) responses in the medulla terminalis. Conversely, treatments that lead to an unexpressed but persistent memory (weak training protocol or scopolamine 0.1MUg/g) do not block these learning-induced neural changes. The present results reveal a set of changes in the neural activity induced by training that correlates with memory persistence but not with the probability of this memory to be expressed in the long-term. In addition, the study constitutes the first in vivo evidence in favor of a role of the medulla terminalis in learning and memory in crustaceans, and provides a physiological evidence indicating that memory persistence and the probability of memory to be expressed might involve separate components of memory traces. PMID- 26988614 TI - Adipose tissue: 'Hot' and cold therapy reduces obesity. PMID- 26988615 TI - Diabetes: New mechanism for insulin resistance. PMID- 26988616 TI - Endocrine disruptors: Manmade and natural oestrogens: opposite effects on assisted reproduction. PMID- 26988617 TI - In vitro controlled release of clove essential oil in self-assembly of amphiphilic polyethylene glycol-block-polycaprolactone. AB - In this study, a micellar delivery system with an amphiphilic diblock copolymer of poly (ethylene glycol) and poly (E-caprolactone) was synthesised and used to incorporate hydrophobic clove essential oil (CEO). To determine an optimal delivery system, the effects of the copolymer's hydrophobic block length and the CEO-loading content on the encapsulation of CEO were investigated. Percentages of entrapment efficiency (%EE), CEO loading (%CEO), and in vitro release profiles were determined. The size, size distribution, zeta potential, and morphology of the obtained micelles were determined by DLS, FE-SEM, and TEM. The %EE, %CEO, and in vitro release profiles of CEO incorporated in micelles were analysed by HPLC. The study revealed a sustained release profile of CEO from CEO-loaded micelles. The results indicate the successful formulation of CEO-loaded PEG-b-PCL micelle nanoparticles. It is suggested that this micelle system has considerably potential applications in the sustained release of CEO in intravascular drug delivery. PMID- 26988618 TI - HIV positivity and anal cancer outcomes: A single-center experience. AB - BACKGROUND: Anal cancer remains common among human immunodeficiency virus (HIV) patients. Chemoradiation has had mixed results. We evaluated outcome differences by HIV status. METHODS: We retrospectively analyzed 14 HIV+ and 72 HIV- anal cancer patients (2000 to 2013). Outcomes included chemoradiation tolerance, recurrence, and survival. RESULTS: HIV+ patients were more often male (100% vs 38%, P < .001) but diagnosed at similar stages (P = .49). They were less likely to receive traditional chemotherapy (36% vs 86%, P < .001). Recurrence (P = .55) and survival time (P = .48) were similar across groups. HIV+ patients had similar colostomy-free survival (P = .053). Receipt of 5-fluorouracil/mitomycin C (MMC) chemotherapy predicted recurrence-free and overall survival (Hazard ratios .278, .32). HIV status did not worsen recurrence (P = .71) or survival (P = .57). CONCLUSIONS: HIV+ patients received more non-MMC-based chemoradiation but had equivalent colostomy-free, recurrence, and overall survival. Use of 5 fluorouracil/MMC chemotherapy increased after 2008. PMID- 26988619 TI - A night float week in a surgical clerkship improves student team cohesion. AB - BACKGROUND: We hypothesize that night float rotations in the third-year surgical clerkship improve student learning and perceptions of team cohesion. METHODS: A 1 week night float (NF) system was implemented during the 2013 to 2014 academic year for students. Each student completed 1 week of NF with the Trauma/Emergency General Surgery service. The Perceived Cohesion Scale survey was prospectively administered and National Board of Medical Examiners academic performance retrospectively reviewed. RESULTS: We surveyed 70 medical students, 37 traditional call and 33 NF students, with 91% response rate. Perception of team cohesion increased significantly, without perceived loss of educational benefit. Examination scores increased significantly comparing pre- and postintervention groups, with this trend continuing in the following academic year. CONCLUSIONS: A week-long student NF experience significantly improved perception of team cohesion and standardized examination results. A dedicated period of NF during the surgical clerkship may improve its overall educational value. PMID- 26988620 TI - No associations between five polymorphisms in COMT gene and migraine. AB - OBJECTIVES: The pathophysiology of migraine headaches is not clearly understood yet. The dopaminergic system has been hypothesized to be involved in migraine pathogenesis. The aim of this study was to investigate catechol-O methyltransferase (COMT) polymorphisms and chronic headaches. We analyzed five single nucleotide polymorphisms (SNPs) in COMT. MATERIALS & METHODS: The study population consisted of 71 patients with migraine with aura, 152 patients with migraine without aura, 86 patients with tension-type headache, and 191 healthy controls. The selected polymorphic markers included one causing His62His (rs4633) and two non-synonymous SNPs, Ala72Ser and Val158Met (rs6267, rs4680 respectively). Two other non-polymorphic SNPs (rs6270, rs740602) were examined. RESULTS: We found no significant differences in any genotypes, allele frequencies, or haplotypes among the patient groups and controls. CONCLUSIONS: Our results indicate that the five polymorphisms in COMT have no association with migraineurs in Western Japan. The possibility that segments elsewhere in the gene may contain a mutation responsible for modifying the expression of COMT or the activity of the enzyme is important. We cannot conclusively exclude the entire COMT gene from being involved in migraine pathogenesis. PMID- 26988621 TI - Growth Characteristics of Contemporary School-age Nigerian Children. AB - OBJECTIVE: There are no locally derived growth charts in Nigeria, and so, health workers rely on international reference charts. We therefore compared the growth characteristics of 4350 school-age Nigerian children (SNC) (2243 girls, 2107 boys) (4-16 years) from three ethnic groups (Hausa, Igbo and Yoruba) to both the UK (UK 1990) and US (2000 CDC) reference data. RESULTS: Height of SNC was similar to international references at the start of school age and then started to decline. The decline appeared to peak at 15 years for boys and 13 years for girls. At all ages, sex, ethnicity and affluence, SNC were lighter than international references. There were significant differences in the prevalence of stunting, underweight and obesity among the three ethnic groups (p < 0.05). CONCLUSION: There is a risk of over-diagnosing short stature and underweight if health workers continue to use growth charts derived from other geographical areas. PMID- 26988622 TI - Enhanced photovoltaic properties in dye sensitized solar cells by surface treatment of SnO2 photoanodes. AB - We report the fabrication and testing of dye sensitized solar cells (DSSC) based on tin oxide (SnO2) particles of average size ~20 nm. Fluorine-doped tin oxide (FTO) conducting glass substrates were treated with TiOx or TiCl4 precursor solutions to create a blocking layer before tape casting the SnO2 mesoporous anode. In addition, SnO2 photoelectrodes were treated with the same precursor solutions to deposit a TiO2 passivating layer covering the SnO2 particles. We found that the modification enhances the short circuit current, open-circuit voltage and fill factor, leading to nearly 2-fold increase in power conversion efficiency, from 1.48% without any treatment, to 2.85% achieved with TiCl4 treatment. The superior photovoltaic performance of the DSSCs assembled with modified photoanode is attributed to enhanced electron lifetime and suppression of electron recombination to the electrolyte, as confirmed by electrochemical impedance spectroscopy (EIS) carried out under dark condition. These results indicate that modification of the FTO and SnO2 anode by titania can play a major role in maximizing the photo conversion efficiency. PMID- 26988623 TI - Oncoplastic breast conserving surgery: Volume replacement vs. volume displacement. AB - Oncoplastic breast conserving surgery (BCS) has emerged as a third option between conventional BCS and mastectomy. Oncoplastic BCS includes two fundamentally different approaches: volume replacement and volume displacement. The former involves partial mastectomy and immediate reconstruction of the breast with the transposition of autologous tissue from elsewhere, while the latter involves partial mastectomy and using the remaining breast tissue to fill the defect resulting from extirpation of the tumor. There are several benefits associated with oncoplastic BCS. First, it allows partial mastectomy without cosmetic penalties, and can achieve better cosmetic outcomes than total mastectomy with immediate breast reconstruction. Second, it avoids the need for total mastectomy in an increasing number of patients without compromising local control. Third, partial breast reconstruction is less extensive and has fewer complications than conventional procedures. Partial mastectomy and partial breast reconstruction can be carried out either simultaneously as a one-stage procedure, or using a two stage approach. Although patients prefer a one-stage procedure, it requires intraoperative confirmation of complete tumor excision using frozen-section analysis. Moreover, oncoplastic BCS requires combined skills, knowledge, and understanding of both oncological and plastic surgeries, which may be optimally achieved by an oncoplastic surgeon. PMID- 26988624 TI - Cost effectiveness analysis of fesoterodine compared to mirabegron in first-line therapy setting for overactive bladder with urge urinary incontinence, from the Spanish National Health System perspective. AB - OBJECTIVES: To evaluate the cost-effectiveness of first-line treatment of Overactive Bladder (OAB) with fesoterodine relative to mirabegron, from the Spanish National Health System (NHS) perspective. METHODS: A decision tree model was developed to represent a typical clinical process of 52-week of treatment for an OAB patient with urge urinary incontinence (UUI) initiating first-line therapy with fesoterodine 4mg, including optional titration to 8mg, vs.mirabegron 50mg. Efficacy data were obtained from a Bayesian indirect treatment meta-analysis. Patients with UUI of less than one episode/day were defined as treatment responder and persistence was assessed at weeks 4, 12 and 24. At week 12, non responders discontinued treatment permanently. Quality-adjusted life years (QALYs) were calculated based on time spent in responder and non-responder states. OAB-related drug and medical care costs including physician visits, laboratory tests, incontinence pads, and comorbidities (fracture, skin infection, urinary tract infections and depression) were modeled and expressed in ?2015. RESULTS: At week 52, the percentage of responders was 20.8% for patients starting on fesoterodine 4mg who optionally titrated to 8mg and 19.4% for patients treated with mirabegron. QALYs were slightly higher with fesoterodine than mirabegron (0.7703vs. 0.7668, difference=0.0035). Fesoterodine treatment also had slightly higher total costs than mirabegron (3,296?vs. 3,217, difference=79?), resulting in a cost of 22,523/QALY? gained for fesoterodine versus mirabegron. Probabilistic sensitivity analysis confirmed the slight advantage of fesoterodine with a 61.1% probability of being cost-effective at the 30,000? willingness-to pay for 1QALY threshold. CONCLUSIONS: Given the relatively small 1-year cost difference between the two treatments, fesoterodine can be considered a cost effective option relative to mirabegron for the first-line management of OAB with UUI in Spain. PMID- 26988625 TI - A test of the stranger-interviewer norm in the Dominican Republic. AB - We offer the first empirical test of the 'stranger-interviewer norm', according to which interviewers in social, demographic, and health surveys should be strangers-not personally familiar with respondents. We use data from an experimental survey in the Dominican Republic that featured three types of interviewer: from out of town (outsiders); local but unknown to the respondent (local-strangers); and local with a previous relationship to the respondent (insiders). We were able to validate answers to up to 18 questions per respondent, mainly by checking official documents in their possession. Contrary to expectations derived from the stranger-interviewer norm, respondents were more reluctant to show the documents needed for validation when the interviewer was an outsider. Furthermore, and again at odds with the stranger-interviewer norm, we found no difference in accuracy by type of interviewer. Our results have important implications for the selection of survey interviewers in less developed and non-Western settings. PMID- 26988626 TI - A lost family-planning regime in eighteenth-century Ceylon. AB - Based on Dutch colonial registers (thombos), this paper reconstructs fertility for two districts in Ceylon, 1756-68. It overcomes challenges in data quality by establishing the outer bounds of plausible estimates in a series of scenarios. Among these, total fertility rates (TFRs) averaged 5.5 in one district, but only 2.7 in the other. These figures exclude the victims of infanticide, a custom noted in European travelogues between about 1660 and 1820. Sex ratios among children differed depending on the number of older siblings, and overall, 27 per cent of girls are missing in one district and 57 per cent in the other. There was little significant variation either in the TFR or the sex ratio by socio-economic status, suggesting that poverty was not a key factor in motivating infanticides. Instead, we argue that at least parts of Ceylon had a forward-looking culture of family planning in the eighteenth century, which was lost in subsequent decades. PMID- 26988629 TI - Messages for Clinicians: Moderators and Mediators of Treatment Outcome in Randomized Clinical Trials. AB - Many problems in randomized clinical trial design, execution, analysis, presentation and interpretation stem in part from an inadequate understanding of the roles of moderators and mediators of treatment outcome. As a result, 1) the results of clinical research are slow to have an impact on clinical decision making and thus to benefit patients; 2) it is difficult for clinicians or patients to apply randomized clinical trial results comparing two treatments (treatment versus control); 3) when such trials are conducted at various sites, the results often do not replicate; 4) when the results influence clinical decision making, the results clinicians obtain do not match what researchers report; and 5) the treatment effects comparing treatment and control conditions, particularly for psychiatric treatments, often seem trivial. In this review article, the author reviews and integrates the methodological literature concerning dealing with covariates in trials to emphasize their impact on clinical decision making. The goal of trials should ultimately be to establish who should get the treatment condition rather than the control condition (moderators) and to determine how to obtain the best outcomes with whatever is the preferred treatment (mediators). The author makes recommendations to clinicians as to which trials might best be ignored and which carefully considered, and urges clinical researchers to focus on studies best designed to reduce the burden of mental illness on patients. PMID- 26988627 TI - Organization of lipids in fiber-cell plasma membranes of the eye lens. AB - The plasma membrane together with the cytoskeleton forms the only supramolecular structure of the matured fiber cell which accounts for mostly all fiber cell lipids. The purpose of this review is to inform researchers about the importance of the lipid bilayer portion of the lens fiber cell plasma membranes in the maintaining lens homeostasis, and thus protecting against cataract development. PMID- 26988630 TI - Arteriovenous fistula in dialysis patients: Factors implicated in early and late AVF maturation failure. AB - Increasing numbers of patients are being diagnosed with end-stage renal disease (ESRD), and the demand for on haemodialysis (HD) is rising. Arteriovenous fistulae (AVFs) remain the best conduit for adequate HD, with fewer complications associated with long-term use compared to bypass grafts and central venous catheters. However, it is known that many newly formed fistulae do not mature to provide useful HD access. The paper provides a narrative overview of factors influencing the process of AVF maturation failure. PMID- 26988628 TI - The Bidirectional Associations Between Psychotic Experiences and DSM-IV Mental Disorders. AB - OBJECTIVE: While it is now recognized that psychotic experiences are associated with an increased risk of later mental disorders, we lack a detailed understanding of the reciprocal time-lagged relationships between first onsets of psychotic experiences and mental disorders. Using data from World Health Organization World Mental Health (WMH) Surveys, the authors assessed the bidirectional temporal associations between psychotic experiences and mental disorders. METHOD: The WMH Surveys assessed lifetime prevalence and age at onset of psychotic experiences and 21 common DSM-IV mental disorders among 31,261 adult respondents from 18 countries. Discrete-time survival models were used to examine bivariate and multivariate associations between psychotic experiences and mental disorders. RESULTS: Temporally primary psychotic experiences were significantly associated with subsequent first onset of eight of the 21 mental disorders (major depressive disorder, bipolar disorder, generalized anxiety disorder, social phobia, posttraumatic stress disorder, adult separation anxiety disorder, bulimia nervosa, and alcohol abuse), with odds ratios ranging from 1.3 (95% CI=1.2-1.5) for major depressive disorder to 2.0 (95% CI=1.5-2.6) for bipolar disorder. In contrast, 18 of 21 primary mental disorders were significantly associated with subsequent first onset of psychotic experiences, with odds ratios ranging from 1.5 (95% CI=1.0-2.1) for childhood separation anxiety disorder to 2.8 (95% CI=1.0 7.8) for anorexia nervosa. CONCLUSIONS: While temporally primary psychotic experiences are associated with an elevated risk of several subsequent mental disorders, these data show that most mental disorders are associated with an elevated risk of subsequent psychotic experiences. Further investigation of the underlying factors accounting for these time-order relationships may shed light on the etiology of psychotic experiences. PMID- 26988632 TI - Assessments of outcome in haemophilia - a patient perspective. PMID- 26988633 TI - Toxoplasma gondii and Giardia duodenalis infections in domestic dogs in New York City public parks. AB - Toxoplasma gondii and Giardia duodenalis have been widely reported to produce major diseases in humans and domestic animals. Little is known about the occurrence of these protozoan parasites in domestic dogs in the United States. The goal of this study was to determine the prevalence and genotypes of T. gondii and G. duodenalis among dogs in New York City. Fecal samples from domestic dogs were analyzed by polymerase chain reaction (PCR). Overall, 3% of the samples tested positive for T. gondii, while 15% were positive for G. duodenalis. PCR RFLP of T. gondii-positive samples revealed genotypes I and III, while sequence analysis of the G. duodenalis-positive samples indicated that 94.1% of the dogs were infected with the zoonotic assemblage A. Further studies are needed to determine the prevalence of zoonotic protozoan parasites in domestic dogs. PMID- 26988635 TI - Phylogeny and taxonomy of charophytes, good news from a battlefield of concepts. PMID- 26988634 TI - Upcoding in a National Health Service: the evidence from Portugal. AB - For many years, evidence from the USA has pointed out to the existence of upcoding in management practices. Upcoding is defined as classifying patients in diagnosis-related groups codes associated with larger payments. The incentive for upcoding is not restricted to private providers of care. Conceptually, any patient classification system that is used for payment purposes may be vulnerable to this sort of strategic behaviour by providers. We document here that upcoding occurs in a National Health Service where public hospitals have their payment (budget) tied to the classification of treatment episodes. Using diagnosis related groups data from Portugal, we found that the practice of upcoding has been used in the hospitals in a way leading to larger budgets (age of patients plays a key role). The effect is quantitatively small. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26988631 TI - Glia, sympathetic activity and cardiovascular disease. AB - NEW FINDINGS: What is the topic of this review? In this review, we discuss recent findings that provide a novel insight into the mechanisms that link glial cell function with the pathogenesis of cardiovascular disease, including systemic arterial hypertension and chronic heart failure. What advances does it highlight? We discuss how glial cells may influence central presympathetic circuits, leading to maladaptive and detrimental increases in sympathetic activity and contributing to the development and progression of cardiovascular disease. Increased activity of the sympathetic nervous system is associated with the development of cardiovascular disease and may contribute to its progression. Vasomotor and cardiac sympathetic activities are generated by the neuronal circuits located in the hypothalamus and the brainstem. These neuronal networks receive multiple inputs from the periphery and other parts of the CNS and, at a local level, may be influenced by their non-neuronal neighbours, in particular glial cells. In this review, we discuss recent experimental evidence suggesting that astrocytes and microglial cells are able to modulate the activity of sympathoexcitatory neural networks in disparate physiological and pathophysiological conditions. We focus on the chemosensory properties of astrocytes residing in the rostral ventrolateral medulla oblongata and discuss signalling mechanisms leading to glial activation during brain hypoxia and inflammation. Alterations in these mechanisms may lead to heightened activity of sympathoexcitatory CNS circuits and contribute to maladaptive and detrimental increases in sympathetic tone associated with systemic arterial hypertension and chronic heart failure. PMID- 26988636 TI - Phylogeny of North American Tolypella (Charophyceae, Charophyta) based on plastid DNA sequences with a description of Tolypella ramosissima sp. nov. AB - Characeae (Charophyceae, Charophyta) contains two tribes with six genera: tribe Chareae with four genera and tribe Nitelleae, which includes Tolypella and Nitella. This paper uses molecular and morphological data to elucidate the phylogeny of Tolypella species in North America. In the most comprehensive taxonomic treatment of Characeae, 16 Tolypella species worldwide were subsumed into two species, T. intricata and T. nidifica, in two sections, Rothia and Tolypella respectively. It was further suggested that Tolypella might be a derived group within Nitella. In this investigation into species diversity and relationships in North American Tolypella, sequence data from the plastid genes atpB, psbC, and rbcL were assembled for a broad range of charophycean and land plant taxa. Molecular data were used in conjunction with morphology to test monophyly of the genus and species within it. Phylogenetic analyses of the sequence data showed that Characeae is monophyletic but that Nitelleae is paraphyletic with Tolypella sister to a monophyletic Nitella + Chareae. The results also supported the monophyly of Tolypella and the sections Rothia and Tolypella. Morphologically defined species were supported as clades with little or no DNA sequence differences. In addition, molecular data revealed several lineages and a new species (T. ramosissima sp. nov.), which suggests greater species diversity in Tolypella than previously recognized. PMID- 26988637 TI - The dynamics of sexual phase in the marine diatom Pseudo-nitzschia multistriata (Bacillariophyceae). AB - Sexual reproduction represents a fundamental phase in the life cycle of diatoms, linked to both the production of genotypic diversity and the formation of large sized initial cells. Only cells below a certain size threshold can be sexualized, but various environmental factors can modulate the success of sexual reproduction. We investigated the role of cell density and physiological conditions of parental strains in affecting the success and timing of sexual reproduction in the marine heterothallic diatom Pseudo-nitzschia multistriata. We also studied the dynamics of the sexual phase in still conditions allowing cell sedimentation and in gently mixed conditions that keep cells in suspension. Our results showed that successful sexual reproduction can only be achieved when crossing parental strains in the exponential growth phase. Evidence was provided for the fact that sexual reproduction is a density-dependent event and requires a threshold cell concentration to start, although this might vary considerably amongst strains. Moreover, the onset of the sexual phase was coupled to a marked reduction in growth of the vegetative parental cells. The crosses carried out in physically mixed conditions produced a significantly reduced number of sexual stages as compared to crosses in still conditions, showing that mixing impairs sexualization. The results of our experiments suggest that the signaling that triggers the sexual phase is favored when cells can accumulate, reducing the distance between them and facilitating contacts and/or the perception of chemical cues. Information on the progression of the sexual phase in laboratory conditions help understanding the conditions at which sex occurs in the natural environment. PMID- 26988638 TI - Effect of linear alkylbenzene sulfonate on Cu(2+) removal by Spirulina platensis strain (FACHB-834). AB - The removal efficiency of Cu(2+) by Spirulina platensis (strain FACHB-834), in viable and heat-inactivated forms, was investigated in the presence and absence of linear alkylbenzene sulfonate (LAS). When the initial Cu(2+) concentration was in the range of 0.5-1.5 mg . L(-1) , a slight increase in growth rate of FACHB 834 was observed. In contrast, when Cu(2+) or LAS concentrations were at or higher than 2.0 or 6.0 mg . L(-1) , respectively, the growth of FACHB-834 was inhibited and displayed yellowing and fragmentation of filaments. The presence of LAS improved Cu(2+) removal by ~20%, and accelerated attainment of Cu(2+) retention equilibrium. For the 2- mg . L(-1) Cu(2+) treatments, retention equilibrium occurred within 2 d and showed maximum Cu(2+) removal of 1.83 mg . L( 1) . In the presence of LAS, the ratio of extracellular bound Cu(2+) to intracellular Cu(2+) taken up by the cells was lower (1.05-2.26) than corresponding ratios (2.46-7.85) in the absence of LAS. The percentages of extracellular bound Cu(2+) to total Cu(2+) removal (both bound and taken up by cells) in the presence of LAS ranged from 51.2% to 69.3%, which was lower than their corresponding percentages (71.1%-88.7%) in the absence of LAS. LAS promoted biologically active transport of the extracellular bound form of Cu(2+) into the cell. In contrast, the addition of LAS did not increase the maximum removal efficiency of Cu(2+) (61.4% +/- 5.6%) by heat-inactivated cells compared to that of living cells (59.6% +/- 6.0%). These results provide a theoretical foundation for designing bioremediation strategies using FACHB-834 for use in surface waters contaminated by both heavy metals and LAS. PMID- 26988639 TI - Adhesion molecules from the diatom Phaeodactylum tricornutum (Bacillariophyceae): genomic identification by amino-acid profiling and in vivo analysis. AB - Cell adhesion molecules (CAMs) are important in prokaryotes and eukaryotes for cell-cell and cell-substratum interactions. The characteristics of adhesive proteins in the model diatom Phaeodactylum tricornutum were investigated by bioinformatic analysis and in vivo characterization. Bioinformatic analysis of the protein coding potential of the P. tricornutum genome used an amino-acid profile that we developed as a new system to identify uncharacterized or novel CAMs. Putative diatom CAMs were identified and seven were characterized in vivo, by generation of transgenic diatom lines overexpressing genes encoding C-terminal yellow fluorescent protein (YFP) fusion proteins. Three of these selected genes encode proteins with weak similarity to characterized proteins, a c-type lectin and two fasciclins, whereas the others are novel. The resultant cell lines were investigated for alterations in their adhesive ability. Whole cell-substratum adhesion strength was measured in a fully turbulent flow chamber, while atomic force microscopy was used to quantify the relative frequency of adhesion, as well as the length and strength of single molecules in the secreted mucilage. Finally, quartz crystal microbalance analysis characterized the visco-elastic properties and interaction of the mucilage-substratum interface. These combined studies revealed a range of phenotypes affecting adhesion, and led to the identification of candidate proteins involved in diatom adhesion. In summary, our study has for the first time combined bioinformatics and molecular physiological studies to provide new insights into diatom adhesive molecules. PMID- 26988640 TI - Antigenic variation in mucilage secreted by members of the genus Symbiodinium (Dinophyceae). AB - Symbiodinium reside intracellularly in a complex symbiosome (host and symbiont derived) within cnidarian hosts in a specific host-symbiont association. Symbiodinium is a diverse genus with variation greater than other dinoflagellate orders. In this paper, our investigation into specificity examines antigenic variation in the algal mucilage secretions at the host-symbiont interface. Cultured Symbiodinium from a variety of clades were labeled with one of two antibodies to symbiont mucilage (PC3, developed using a clade B alga cultured from Aiptasia pallida; BF10, developed using a clade F alga cultured from Briareum sp.). The labeling was visualized with a fluorescent marker and examined with epifluorescence and confocal microscopy. PC3 antigen was found in cultured Symbiodinium from clades A and B, but not clades C, D, E and F. The correlation between labeling and clade may account for some of the specificity between host and symbiont in the field. Within clades A and B there was variation in the amount of label present. BF10 antigen was more specific and only found in cultures of the same cp23S-rDNA strain the antibody was created against. These results indicate that the mucilage secretions do vary both qualitatively and quantitatively amongst Symbiodinium strains. Since the mucilage forms the host symbiont interface, variation in its molecular composition is likely to be the source of any signals involved in recognition and specificity. PMID- 26988641 TI - Hanicella moenia, gen. et sp. nov., a ribbon-forming diatom (Bacillariophyta) with complex girdle bands, compared to Microtabella interrupta and Rhabdonema cf. adriaticum: implications for Striatellales, Rhabdonematales, and Grammatophoraceae, fam. nov. AB - Tropical benthic diatoms are poorly known but constitute a rich resource for studies of diatom morphology and phylogeny. A remarkable tabellarioid ribbon forming diatom with a very distinctive pattern of plastid distribution and unique valve and girdle band characters is described from Guam (Mariana Islands) as a new genus and species, Hanicella moenia. We were able to study the ultrastructure and ontogeny of the girdle bands, to compare several other genera in the Striatellales and the Rhabdonematales with numerous septate copulae and hyaline, nonseptate pleurae, and to evaluate their phylogenetic relationships. The last formed two copulae of Microtabella interrupta have distended septa, the last interlocking with the other via a transverse ridge between two unique "ligules." The fourth pleura of Hanicella is a delicate, fimbriate band. Views of developing copulae of H. moenia indicated that the septum was formed by ingrowth from the sides rather than from the apex; this blurs the distinction between septate and scalariform valvocopulae. Phylogenetic results (i) confirmed that the Striatellales and Striatellaceae, consisting of Striatella and Pseudostriatella, are unrelated to clades containing Hyalosira, Microtabella, Hanicella, and Rhabdonema; and (ii) showed that the fRhabdonemataceae is close to, but separate from, the strongly supported Hanicella/Microtabella/Grammatophora clade, for which we propose Grammatophoraceae fam. nov. Formal genus and species descriptions of H. moenia are given and we also propose to restore Hyalosira interrupta to Microtabella with an emended genus description. PMID- 26988643 TI - Speciation in the marine crop Pyropia yezoensis (Bangiales, Rhodophyta). AB - In the marine red alga Pyropia yezoensis, commonly known in Japan as nori, sympatric occurrence of two cryptic species Pyropia sp. 2 and Pyropia sp. 3 on the same rock in a natural habitat has been confirmed by molecular analysis and detailed morphological observations. To confirm whether Pyropia sp. 2 and Pyropia sp. 3 were reproductively isolated in the sympatric population, 170 blades that had previously been studied using a maternally inherited plastid marker were examined with a nuclear gene marker. The results suggested that Pyropia sp. 2 and Pyropia sp. 3 with identical morphological features were reproductively isolated in the sympatric population and that they were different species based on the biological species concept. Although gametophytic blades of Pyropia were usually assumed to be haploid, 18 of 170 blades possessed both of the two genotypes derived from Pyropia sp. 2 and from Pyropia sp. 3. These results inferred that allodiploid blades were generated from the interspecific hybridization between these two cryptic species. The present findings provide insights for future studies on the speciation mechanism in seaweeds, particularly for genera that contain numerous species. PMID- 26988642 TI - Genetic diversity and haplotype distribution of Pachymeniopsis gargiuli sp. nov. and P. lanceolata (Halymeniales, Rhodophyta) in Korea, with notes on their non native distributions. AB - The red alga Pachymeniopsis lanceolata, formerly known as Grateloupia lanceolata, is a component of the native algal flora of northeast Asia and has been introduced to European and North American waters. It has been confused with a cryptic species collected from Korea and Italy. Our analyses of rbcL, cox3 and ITS from P. lanceolata and this cryptic species has revealed two distinct entities, forming a clade, which were clearly separated from its congeners and positioned with other Asian species. Here, we describe the cryptic species as P. gargiuli sp. nov., a species that differs from others by molecular sequence and subtle anatomical characters. We hypothesize that P. gargiuli may have been recently dispersed by anthropogenic vectors, possibly at or near the same time as was P. lanceolata. Our cox3 data set revealed that one haplotype of P. gargiuli, shared between Korea and Italy, and two haplotypes of P. lanceolata, commonly occurring in Korea and USA, are invasive haplotypes. This is the first report of the utility of the mitochondrial coding cox3 sequences in red algae. PMID- 26988644 TI - Production rate estimation of mycosporine-like amino acids in two Arctic melt ponds by stable isotope probing with NAH(13) CO3. AB - The net carbon uptake rate and net production rate of mycosporine-like amino acids (MAAs) were measured in phytoplankton from 2 different melt ponds (MPs; closed and open type pond) in the western Arctic Ocean using a (13) C stable isotope tracer technique. The Research Vessel Araon visited ice-covered western central basins situated at 82 degrees N and 173 degrees E in the summer of 2012, when Arctic sea ice declined to a record minimum. The average net carbon uptake rate of the phytoplankton in polycarbonate (PC) bottles in the closed MP was 3.24 mg C . m(-3) . h(-1) (SD = +/-1.12 mg C . m(-3) . h(-1) ), while that in the open MP was 1.3 mg C . m(-3) . h(-1) (SD = +/-0.05 mg C . m(-3) . h(-1) ). The net production rate of total MAAs in incubated PC bottles was highest (1.44 (SD = +/ 0.24) ng C . L(-1) . h(-1) ) in the open MP and lowest (0.05 (SD = +/-0.003) ng C . L(-1) . h(-1) ) in the closed MP. The net production rate of shinorine and palythine in incubated PC bottles at the open MP presented significantly high values 0.76 (SD = +/-0.12) ng C . L(-1) . h(-1) and 0.53 (SD = +/-0.06) ng C . L( 1) . h(-1) . Our results showed that high net production rate of MAAs in the open MP was enhanced by a combination of osmotic and UVR stress and that in situ net production rates of individual MAA can be determined using (13) C tracer in MPs in Arctic sea ice. PMID- 26988646 TI - The effects of different light-dark cycles on the metabolism of the diazotrophic, unicellular cyanobacteria Cyanothece sp. ATCC 51142, and Cyanothecesp. PCC 7822. AB - The diazotrophic unicellular cyanobacterium Cyanothece sp. ATCC 51142 demonstrates circadian patterns in nitrogenase activity, H2 production and glycogen storage when grown under nitrogen-fixing, 12:12 light:dark (L:D) conditions. In this study, we grew Cyanothece sp. ATCC 51142, and another strain in this genus, Cyanothece sp. PCC 7822, under long-day (16:8 L:D) and short-day (8:16 L:D) nitrogen-fixing conditions to determine if they continued to display circadian rhythms. Both strains demonstrated similar circadian patterns for all three metabolic parameters when grown under long-day conditions. However, the strains responded differently to short-day growth conditions. Cyanothece sp. ATCC 51142 retained reasonable circadian patterns under 8:16 L:D conditions, whereas Cyanothece sp. PCC 7822 had quite damped patterns without a clear circadian pattern. In particular, glycogen storage changed very little throughout the day and we ascribe this to the difference in the type of glycogen granules in Cyanothece sp. PCC 7822 which has small beta-granules, compared to the large, starch-like granules in Cyanothece sp. ATCC 51142. The results suggested that both mechanistic and regulatory processes play a role in establishing the basis for these metabolic oscillations. PMID- 26988645 TI - Diversity of bladed Bangiales (Rhodophyta) in western Mediterranean: recognition of the genus Themis and descriptions of T. ballesterosii sp. nov., T. iberica sp. nov., and Pyropia parva sp. nov. AB - The diversity of the bladed species of the red algal order Bangiales from the Iberian Mediterranean shores has been reassessed after a detailed study of this region. Prior to this study, 11 bladed species of Bangiales had been reported from Mediterranean waters: Porphyra atropurpurea, P. cordata, P. coriacea, P. dioica, P. linearis, P. purpurea, P. umbilicalis, Pyropia leucosticta, Pyropia koreana (as P. olivii), Py. elongata (as P. rosengurttii) and Py. suborbiculata. A combined analysis of the nuclear nSSU and the plastid rbcL genes together with detailed morphological studies has confirmed the presence of species within the genera Porphyra and Pyropia and also revealed a third, undescribed genus, Themis gen. nov. Porphyra linearis, Pyropia elongata and the introduced Pyropia koreana had been previously listed for the Mediterranean and were recorded in this study. An additional four species, including the introduced Pyropia suborbiculata and three new species: Pyropia parva sp. nov., Themis ballesterosii sp. nov., and Themis iberica sp. nov. were also observed. Hence, most of the Porphyra species traditionally reported along these shores were not reported in this survey. This new floristic Bangiales composition confirms the importance of the Mediterranean basin as a hotspot for biodiversity, possible endemics of ancient origin and high proportion of introductions. Our data also continue to confirm the extent of Bangiales diversity at regional and worldwide levels. PMID- 26988647 TI - Hyperspectral imaging techniques for the characterization of Haematococcus pluvialis (Chlorophyceae). AB - A hyperspectral imaging camera was combined with a bright-field microscope to investigate the intracellular distribution of pigments in cells of the green microalga Haematococcus pluvialis, a synonym for H. lacustris (Chlorophyceae). We applied multivariate curve resolution to the hyperspectral image data to estimate the pigment contents in culture and revealed that the predicted values were consistent with actual measurements obtained from extracted pigments. Because it was possible to estimate pigment contents in every pixel, the intracellular distribution of the pigments was investigated during various life-cycle stages. Astaxanthin was localized specifically at the eyespot of zoospores in early culture stages. Then, it became widely distributed in cells, but subsequently localized differently than the chl. Integrated with our recently developed image processing program "HaematoCalMorph," the hyperspectral imaging system was useful for monitoring intracellular distributions of pigments during culture as well as for studying cellular responses under various conditions. PMID- 26988648 TI - Molecular Phylogeny and Cryptic Diversity of the Genus Phacus (Phacaceae, Euglenophyceae) and the Descriptions of Seven New Species. AB - The photosynthetic euglenoid genus Phacus is commonly found in freshwater; it is characterized by a rigid to semi-rigid cell, usually flat with numerous small discoid chloroplasts without pyrenoids. To understand the phylogenetic relationships among Phacus species, we used combined cytoplasmic SSU and LSU rDNA and plastid-encoded SSU and LSU rDNA sequence data from 82 strains, including seven Lepocinclis, three Discoplastis, one Eutreptia, and two Eutreptiella strains, as well as morphological data. The combined molecular dataset was analyzed using Bayesian and maximum likelihood methods. The resulting tree revealed that the genus Phacus was not monophyletic and fully resolved the phylogenetic relationships among eight lineages that were congruent with unique morphological characters in each clade. Molecular phylogeny and detailed morphological data led to the descriptions of seven new species: P. brevisulca, P. claviformis, P. hordei-formis, P. longisulca, P. minimus, P. paraorbicularis, and P. viridioryza. The new species were well supported as independent species and formed close relationships with small Phacus species and P. orbicularis in the tree. In addition, the new species had unique molecular signatures and showed high genetic diversity. Although the strains of P. orbicularis sensu Hubner were morphologically very similar, the phylogenetic analyses and genetic diversity suggested that P. orbicularis sensu Hubner should be divided into two subclades. PMID- 26988649 TI - High-throughput sequencing reveals neustonic and planktonic microbial eukaryote diversity in coastal waters. AB - Neustonic organisms inhabit the sea surface microlayer (SML) and have important roles in marine ecosystem functioning. Here, we use high-throughput 18S rRNA gene sequencing to characterize protist and fungal diversity in the SML at a coastal time-series station and compare with underlying plankton assemblages. Protist diversity was higher in February (pre-bloom) compared to April (spring bloom), and was lower in the neuston than in the plankton. Major protist groups, including Stramenopiles and Alveolata, dominated both neuston and plankton assemblages. Chrysophytes and diatoms were enriched in the neuston in April, with diatoms showing distinct changes in community composition between the sampling periods. Pezizomycetes dominated planktonic fungi assemblages, whereas fungal diversity in the neuston was more varied. This is the first study to utilize a molecular-based approach to characterize neustonic protist and fungal assemblages, and provides the most comprehensive diversity assessment to date of this ecosystem. Variability in the SML microeukaryote assemblage structure has potential implications for biogeochemical and food web processes at the air-sea interface. PMID- 26988650 TI - Yogurt consumption and abdominal obesity reversion in the PREDIMED study. AB - BACKGROUND AND AIMS: Evidence on the association yogurt consumption and obesity is not conclusive. The aim of this study was to prospectively evaluate the association between yogurt consumption, reversion of abdominal obesity status and waist circumference change in elderly. METHODS AND RESULTS: 4545 individuals at high cardiovascular risk were prospectively followed. Total, whole-fat and low fat yogurt consumption were assessed using food frequency questionnaires. Generalized estimating equations were used to analyze the association between yogurt consumption and waist circumference change (measured at baseline and yearly during the follow-up). Logistic regression models were used to evaluate the odds ratios (ORs) and 95% CIs of the reversion rate of abdominal obesity for each quintile of yogurt consumption compared with the lowest quintile. After multivariable adjustment, the average yearly waist circumference change in the quintiles of whole-fat yogurt consumption was: Q1: 0.00, Q2: 0.00 (-0.23 to 0.23), Q3: -0.15 (-0.42 to 0.13), Q4: 0.10 (-0.21 to 0.42), and Q5: -0.23 (-0.46 to -0.00) cm; p for trend = 0.05. The ORs for the reversion of abdominal obesity for whole-fat yogurt consumption were Q1: 1.00, Q2: 1.40 (1.04-1.90), Q3: 1.33 (0.94-1.89), Q4: 1.21 (0.83-1.77), and Q5: 1.43 (1.06-1.93); p for trend = 0.26. CONCLUSION: Total yogurt consumption was not significantly associated with reversion of abdominal obesity status and a lower waist circumference. However, consumption of whole-fat yogurt was associated with changes in waist circumference and higher probability for reversion of abdominal obesity. Therefore, it seems that whole-fat yogurt has more beneficial effects in management of abdominal obesity in elderly population at high cardiovascular risk. PMID- 26988651 TI - Transgenic Disruption of Glucocorticoid Signaling in Osteoblasts Attenuates Joint Inflammation in Collagen Antibody-Induced Arthritis. AB - The role of endogenous glucocorticoids (GCs) in rheumatoid arthritis remains unclear. Herein, we examined the role of osteoblastic GC signaling in collagen antibody-induced arthritis. Intracellular GC signaling was abrogated exclusively in mature osteoblasts via transgenic (tg) expression of 11beta-hydroxysteroid dehydrogenase type 2. Arthritis was induced in 8-week-old male tg mice and their wild-type (WT) littermates. Paw swelling was scored daily from induction to end point (day 14). Inflammation, cartilage degradation, and local bone erosion were assessed at the wrist, knee, and ankle joints. Systemic skeletal changes were determined by microcomputed tomography and histomorphometrical analysis of the tibiae. Both tg and WT mice developed acute arthritis in response to the administration of collagen antibodies. However, compared with WT mice, both clinical and histological indexes of joint inflammation were significantly mitigated in animals with disrupted osteoblastic GC signaling. In WT mice, arthritis was associated with increased bone resorption, decreased bone formation, and significant bone loss. In contrast, bone turnover and bone mass remained unchanged in tg arthritic mice. Disruption of GC signaling in osteoblasts significantly reduces joint inflammation and prevents structural bone and cartilage damage in collagen antibody-induced arthritis. These data corroborate the concept that osteoblasts modulate the inflammatory response in immune-mediated arthritis via a GC-dependent pathway. PMID- 26988653 TI - Normative Judgments and Individual Essence. AB - A growing body of research has examined how people judge the persistence of identity over time-that is, how they decide that a particular individual is the same entity from one time to the next. While a great deal of progress has been made in understanding the types of features that people typically consider when making such judgments, to date, existing work has not explored how these judgments may be shaped by normative considerations. The present studies demonstrate that normative beliefs do appear to play an important role in people's beliefs about persistence. Specifically, people are more likely to judge that the identity of a given entity (e.g., a hypothetical nation) remains the same when its features improve (e.g., the nation becomes more egalitarian) than when its features deteriorate (e.g., the nation becomes more discriminatory). Study 1 provides a basic demonstration of this effect. Study 2 shows that this effect is moderated by individual differences in normative beliefs. Study 3 examines the underlying mechanism, which is the belief that, in general, various entities are essentially good. Study 4 directly manipulates beliefs about essence to show that the positivity bias regarding essences is causally responsible for the effect. PMID- 26988652 TI - Transforming Growth Factor-beta Is an Upstream Regulator of Mammalian Target of Rapamycin Complex 2-Dependent Bladder Cancer Cell Migration and Invasion. AB - Our prior work identified the mammalian target of rapamycin complex 2 (mTORC2) as a key regulator of bladder cancer cell migration and invasion, although upstream growth factor mediators of this pathway in bladder cancer have not been well delineated. We tested whether transforming growth factor (TGF)-beta, which can function as a promotility factor in bladder cancer cells, could regulate mTORC2 dependent bladder cancer cell motility and invasion. In human bladder cancers, the highest levels of phosphorylated SMAD2, a TGF-beta signaling intermediate, were present in high-grade invasive bladder cancers and associated with more frequent recurrence and decreased disease-specific survival. Increased expression of TGF-beta isoforms, receptors, and signaling components was detected in invasive high-grade bladder cancer cells that expressed Vimentin and lacked E cadherin. Application of TGF-beta induced phosphorylation of the Ser473 residue of AKT, a selective target of mTORC2, in a SMAD2- and SMAD4-independent manner and increased bladder cancer cell migration in a modified scratch wound assay and invasion through Matrigel. Inhibition of TGF-beta receptor I using SB431542 ablated TGF-beta-induced migration and invasion. A similar effect was seen when Rictor, a key mTORC2 component, was selectively silenced. Our results suggest that TGF-beta can induce bladder cancer cell invasion via mTORC2 signaling, which may be applicable in most bladder cancers. PMID- 26988655 TI - Different mechanisms of action of 2, 2', 4, 4'-tetrabromodiphenyl ether (BDE-47) and its metabolites (5-OH-BDE-47 and 6-OH-BDE-47) on cell proliferation in OVCAR 3 ovarian cancer cells and MCF-7 breast cancer cells. AB - Data concerning the possible action of polybrominated diphenyl ethers (PBDEs) in hormone-dependent cancer are scarce. Some data showed that PBDEs may directly affect breast cancer cells formation and only one research showed increased proliferation of the OVCAR-3 cells, but the results are ambiguous and the mechanisms are not clear. There is growing evidence that not only parent compounds but also its metabolites may be involved in cancer development. The present study was, therefore, designed to determine the effect of BDE-47 and its metabolites (2.5 to 50 ng ml-1 ) on proliferation (BrdU), cell-cycle genes (real time PCR) and protein expression (Western blot), protein expression of oestrogen receptors (alpha beta), extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase Calpha (PKCalpha) in OVCAR-3 ovarian and MCF-7 breast cancer cells. In OVCAR-3 cells, the parent compound stimulated cell proliferation by activating CDK1, CDK7, E2F1 and E2F2. Independent of time of exposure, BDE-47 had no effect on ERalpha and ERbeta protein expression and ERK1/2 and PKCalpha phosphorylation. Metabolites had no effect on cell proliferation but increased both ERs protein expression and ERK1/2 and PKCalpha phosphorylation. In MCF-7 cells, the parent compound displayed no effect on cell proliferation but decreased ERalpha and increased ERbeta protein expression with concomitant induction of PKCalpha phosphorylation. Both metabolites increased MCF-7 cell proliferation, ERK1/2 and PKCalpha phosphorylation and decreased ERalpha and ERbeta protein expression.We suggest that studies concerning PBDEs with fewer bromine atoms should be continued to understand environmental links to different hormone-dependent cancers. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26988654 TI - Cross-modal representations of first-hand and vicarious pain, disgust and fairness in insular and cingulate cortex. AB - The anterior insula (AI) and mid-anterior cingulate cortex (mACC) have repeatedly been implicated in first-hand and vicarious experiences of pain, disgust and unfairness. However, it is debated whether these regions process different aversive events through a common modality-independent code, reflecting the shared unpleasantness of the experiences or through independent modality-specific representations. Using functional magnetic resonance imaging, we subjected 19 participants (and 19 confederates) to equally unpleasant painful and disgusting stimulations, as well as unfair monetary treatments. Multivoxel pattern analysis identified modality-independent activation maps in the left AI and mACC, pointing to common coding of affective unpleasantness, but also response patterns specific for the events' sensory properties and the person to whom it was addressed, particularly in the right AI. Our results provide evidence of both functional specialization and integration within AI and mACC, and support a comprehensive role of this network in processing aversive experiences for self and others. PMID- 26988656 TI - Overexpression of tissue microRNA10b may help predict glioma prognosis. AB - We investigated the relationship between microRNA-10b (miR-10b) expression and prognosis in human glioma patients. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was used to characterize the expression patterns of miR-10b in 128 glioma and 20 normal brain tissues. Clinical information - age, sex, Karnofsky Performance Status (KPS) and World Health Organization (WHO) grade - were also collected. The associations between miR-10b expression and the clinicopathological factors and outcome of glioma patients were statistically analyzed. Expression levels of miR-10b in glioma tissue were significantly higher than in normal brain tissue (P<0.001). High-grade glioma (WHO grade III and IV) had much higher miR-10b expression levels than low-grade tumors (WHO grade I and II). Additionally, the increased miR-10b expression in the glioma tissues was significantly associated with a low KPS (P=0.03). Kaplan-Meier survival curves and Cox regression analyses showed that overexpression of miR-10b (P=0.01) and high grade (P=0.02) were independent factors predicting poor outcome for glioma patients. Furthermore, subgroup analyses showed that the miR-10b expression level was significantly associated with poor overall survival in glioma patients with high grades (P<0.001). Up-regulation of miR-10b may have value in predicting clinical outcome in glioma patients, particularly for those with high pathological grades. PMID- 26988657 TI - [Haemostatic disorders in children]. AB - Haemorrhagic and thrombotic events occur in both children and adults. The underlying causes are congenital or acquired disorders. In contrast to haemorrhagic disorders, inherited thrombotic disorders nearly exclusively in association with additional external risk factors lead to thrombotic events predominantly during the newborn period and adolescence. It is necessary to be aware of age-specific properties of coagulation in order to correctly interpret clinical and laboratory findings and to provide optimal care for children with haemorrhagic and thrombotic complications. PMID- 26988658 TI - Raman Spectroscopy an Option for the Early Detection of Citrus Huanglongbing. AB - This research describes the application of portable field Raman spectroscopy combined with a statistical analysis of the resulting spectra, employing principal component analysis (PCA) and linear discriminant analysis (LDA), in which we determine that this method provides a high degree of reliability in the early detection of Huanglongbing (HLB) on Sweet Orange, disease caused by the bacteria Candidatus Liberibacter asiaticus. Symptomatic and asymptomatic plant samples of Sweet Orange (Citrus sinensis), Persian Lime (C. latifolia), and Mexican Lime (C. aurantifolia) trees were collected from several municipalities, three at Colima State and three at Jalisco State (HLB presence). In addition, Sweet Orange samples were taken from two other Mexican municipalities, one at San Luis Potosi and the other at Veracruz (HLB absent). All samples were analyzed by real-time PCR to determine its phytosanitary condition, and its spectral signatures were obtained with an ID-Raman mini. Spectral anomalies in orange trees HLB-positive, were identified in bands related to carbohydrates (905 cm( 1), 1043 cm(-1), 1127 cm(-1), 1208 cm(-1), 1370 cm(-1), 1272 cm(-1), 1340 cm(-1), and 1260-1280 cm(-1)), amino acids, proteins (815 cm(-1), 830 cm(-1), 852 cm(-1), 918 cm(-1), 926 cm(-1), 970 cm(-1), 1002 cm(-1), 1053 cm(-1), and 1446 cm(-1)), and lipids (1734 cm(-1), 1736 cm(-1), 1738 cm(-1), 1745 cm(-1), and 1746 cm(-1)). Moreover, PCA-LDA showed a sensitivity of 86.9 % (percentage of positives, which are correctly identified), a specificity of 91.4 % (percentage of negatives, which are correctly identified), and a precision of 89.2 % (the proportion of all tests that are correct) in discriminating between orange plants HLB-positive and healthy plants. The Raman spectroscopy technique permitted rapid diagnoses, was low-cost, simple, and practical to administer, and produced immediate results. These are essential features for phytosanitary epidemiological surveillance activities that may conduct a targeted selection of highly suspicious trees to undergo molecular DNA analysis. PMID- 26988659 TI - Cotton Micronaire Measurements Using Small Portable Near-Infrared (NIR) Analyzers. AB - A key quality and processing parameter for cotton fiber is micronaire, which is a function of the fiber's maturity and fineness. Near-infrared (NIR) spectroscopy has previously shown the ability to measure micronaire, primarily in the laboratory and using large, research-grade laboratory NIR instrumentation. International interest has been expressed by the industry in the measurement of fiber micronaire using small, portable NIR spectroscopy instruments for both laboratory and outside the laboratory (e.g., field or greenhouse) locations. New, very small NIR micro-spectrometers have been commercialized that offer the potential advantages of smaller size and lower weight, lower cost, and increased portability over current portable units. A program was implemented to determine the feasibility of a small NIR micro-spectrometer to measure fiber micronaire both in the laboratory and outside the laboratory, with initial emphasis on laboratory measurements prior to moving to field evaluations. In the laboratory, distinct spectral differences with increasing micronaire were observed. Optimal sampling and instrumental procedures and protocols for two units (different spectral wavelength capabilities) were established. Comparative evaluations established very good method micronaire agreement between the micro-spectrometer and a standard portable spectrometer, with high Regression (R) value, low residuals, and few outliers (less than 20%). The NIR micro-spectrometer measurements were fast (<1 min per sample), required no sample preparation, and were easy to perform. All end-state criteria were exceeded. The rapid and accurate laboratory measurement of fiber micronaire with a NIR micro-spectrometer was demonstrated. PMID- 26988660 TI - Assessment of Transition Element Speciation in Glasses Using a Portable Transmission Ultraviolet-Visible-Near-Infrared (UV-Vis-NIR) Spectrometer. AB - A new low-cost experimental setup based on two compact dispersive optical spectrometers has been developed to measure optical absorption transmission spectra over the 350-2500 nm energy range. We demonstrate how near-infrared (NIR) data are essential to identify the coloring species in addition to ultraviolet visible data. After calibration with reference glasses, the use of an original sample stage that maintains the window panel in the vertical position enables the comparison of ancient and modern glasses embedded in a panel from the Sainte Chapelle of Paris, without any sampling. The spectral resolution enables to observe fine resonances arising in the absorption bands of Cr(3+), and the complementary information obtained in the NIR enables to determine the contribution of Fe(2+), a key indicator of glassmaking conditions. PMID- 26988661 TI - Life Expectancy With and Without Pain in the U.S. Elderly Population. AB - BACKGROUND: This study contributes to dialogue on quality versus quantity of life by examining years older persons can expect to live in various states of pain. METHODS: Data from seven waves of the Health and Retirement Study; N = 26,896; age 55+. Estimations using the Interpolative Markov Chain approach apply probability transitions to multistate life table functions. Two estimates are interpreted: (i) population-based, which provide population averages aggregated across baseline states and (ii) status-based, which provide independent estimates by baseline state. Age- and sex-specific years with no pain, milder nonlimiting, and severe or limiting pain are reported as is percent of life in states of pain. RESULTS: Females have higher life expectancy than males but similar expectations of pain-free life. Total life expectancy varies only slightly by baseline pain states but pain-free life expectancy varies greatly. For example, an 85-year-old female pain-free at baseline expects 7.04 more years, 5.28 being pain-free. An 85 year-old female with severe pain at baseline expects 6.42 years with only 2.66 pain-free. Percent of life with pain decreases by age for those pain-free at baseline and increases for those with pain at baseline. CONCLUSION: Pain is moderately associated with quantity of or total life but substantially and importantly associated with quality of or pain-free life. PMID- 26988663 TI - Prevention and treatment of atypical haemolytic uremic syndrome after kidney transplantation. AB - Atypical haemolytic uraemic syndrome is a rare disorder characterized by an over activated, dysregulated alternative complement pathway due to genetic mutation and environmental triggers. Atypical haemolytic uraemic syndrome is a serious, life-threatening disease characterized by thrombotic microangiopathy, which causes haemolytic anaemia, thrombocytopaenia, and acute renal failure. Since recurrences of atypical haemolytic uraemic syndrome frequently lead to end-stage kidney disease even in renal allografts, kidney transplantation for patients with end-stage kidney disease secondary to atypical haemolytic uraemic syndrome has long been contraindicated. However, over the past several years, advancements in the management of atypical haemolytic uraemic syndrome have allowed successful kidney transplantation in these patients. The key factor of this success is eculizumab, a humanized anti-C5 monoclonal antibody, which inhibits terminal membrane-attack complex formation and thrombotic microangiopathy progression. In the setting of kidney transplantation, there are different possible triggers of post-transplant atypical haemolytic uraemic syndrome recurrence, such as brain death related injury, ischaemia-reperfusion injury, infections, the use of immunosuppressive drugs, and rejection. Principal strategies are to prevent endothelial damage that could potentially activate alternative complement pathway activation and subsequently lead to atypical haemolytic uraemic syndrome recurrence in kidney allograft. Published data shows that prophylactic eculizumab therapy is highly effective for the prevention of post-transplant atypical haemolytic uraemic syndrome recurrence, and prompt treatment with eculizumab as soon as recurrence is diagnosed is important to maintain renal allograft function. Further study to determine the optimal dosing and duration of prophylactic therapy and treatment of post-transplant atypical haemolytic uraemic syndrome recurrence is needed. PMID- 26988662 TI - Effect of Statin Use on Mobility Disability and its Prevention in At-risk Older Adults: The LIFE Study. AB - BACKGROUND: HMG-CoA reductase inhibitors (statins) are among the most commonly prescribed classes of medications. Although their cardiovascular benefits and myalgia risks are well documented, their effects on older adults initiating an exercise training program are less understood. METHODS: 1,635 sedentary men and women aged 70-89 years with Short Physical Performance Battery (SPPB) score of 9 or below and were able to walk 400 m were randomized to a structured, moderate intensity physical activity (PA) program consisting of both center-based (twice/wk) and home-based (3-4 times/wk) aerobic, resistance, and flexibility training or to a health education (HE) program combined with upper extremity stretching. RESULTS: Overall, the PA intervention was associated with lower risk of major mobility disability (hazard ratio [HR] = 0.82; 95% confidence interval [CI] = 0.69-0.98). The effect was similar (p value for interaction = .62) in both statin users (PA n = 415, HE n = 412; HR = 0.86, 95% CI = 0.67-1.1) and nonusers (PA n = 402, HE n = 404; HR = 0.78, 95% CI = 0.61-1.01). Attendance was similar for statin users (65%) and nonusers (63%). SPPB at 12 months was slightly greater for PA (8.35+/-0.10) than for HE (7.94+/-0.10) in statin users but not in nonusers (PA 8.25+/-0.10, HE 8.16+/-0.10), though the interaction effect was not statistically significant. Self-reported PA levels were not different between statin users and nonusers. CONCLUSIONS: Although statins have been associated with adverse effects on muscle, data from the LIFE Study show that statin users and nonusers both benefit from PA interventions. Older adults who require statin medications to manage chronic medical conditions and are sedentary will be able to benefit from interventions to increase PA. PMID- 26988665 TI - MYC-Overexpressing TNBCs Depend on Fatty Acid Oxidation. AB - Inhibiting fatty acid oxidation reduces tumor growth in models of TNBC overexpressing MYC. PMID- 26988666 TI - CD4+ T Cell Loss Drives NAFLD Progression to Hepatocellular Carcinoma. AB - Dysregulated lipid metabolism in NAFLD promotes hepatocarcinogenesis via loss of CD4(+) T cells. PMID- 26988667 TI - Prostate Cancer Risk Loci Are Associated with Gene Regulatory Mechanisms. AB - Gene regulatory mechanisms underlying all known prostate cancer risk loci were characterized. PMID- 26988668 TI - Milk Duct Engraftment Allows Preclinical Modeling of ER+ Breast Cancer. AB - Tumor cell engraftment into milk ducts generates a physiologically relevant model of ER(+) breast cancer. PMID- 26988669 TI - A High-Fat Diet Promotes Intestinal Stemness and Tumorigenesis. AB - A high-fat diet boosts Lgr5(+) intestinal stem cell number and function, enhancing tumor formation. PMID- 26988671 TI - [Clinical practice of acute pulmonary embolism: experience from Thrombosis and Vascular Medicine Center of Fuwai Hospital]. PMID- 26988672 TI - [Controversy on blood pressure target: is SPRINT the terminator?]. PMID- 26988670 TI - Functional Genome Screening to Elucidate the Colistin Resistance Mechanism. AB - Antibiogram profile of 1590 clinical bacterial isolates based on thirteen different antimicrobial compounds showed that 1.6% of the bacterial isolates are multidrug resistant. Distribution pattern based on 16S rRNA sequence analysis showed that Pseudomonas aeruginosa constituted the largest group (83.6%) followed by Burkholderia pseudomallei sp. A191 (5.17%), Staphylococcus sp. A261 (3.45%). Among the various antibiotics used, colistin appeared to be the most effective against the Gram negative bacteria. Burkholderia pseudomallei sp. A191 and Pseudomonas aeruginosa sp. A111 showed resistance to 1500 MUg/ml and 750 MUg/ml of colistin respectively which constitutes 7.7% of the bacterial population. A functional genomics strategy was employed to discover the molecular support for colistin resistance in Burkholderia pseudomallei sp. A191. A pUC plasmid-based genomic expression library was constructed with an estimated library size of 2.1 * 10(7)bp. Five colistin resistant clones were obtained after functional screening of the library. Analysis of DNA sequence of five colistin resistant clones showed homology to two component regularity systems (TCRS) encoding for a histidine kinase (mrgS) and its regulatory component (mrgR). Cross complementation assay showed that mutations in mrgS were sufficient enough to confer colistin resistant phenotype in a sensitive strain. PMID- 26988673 TI - [Pay attention to early screening for preeclampsia]. PMID- 26988674 TI - [Chinese expert consensus on the diagnosis and management of acute pulmonary embolism (2015)]. PMID- 26988675 TI - [Chinese expert consensus on obesity-related hypertension management]. PMID- 26988677 TI - [A clinical study on the relationship of autonomic nervous function and arteriosclerosis in patients with essential hypertension]. AB - OBJECTIVE: To investigate the relationship between autonomic nervous function and arteriosclerosis in patients with essential hypertension. METHODS: From January 2011 to December 2013, a total of 269 patients with essential hypertension hospitalized in Chang'an Branch of First People's Hospital of Liangshan were divided into normal PWV group (PWV<9 m/s, n=178) and high PWV group (PWV>=9 m/s, n=91) via the results of carotid-femoral pulse wave velocity (PWV). Synchronic 24 hours ambulatory blood pressure monitoring and dynamic electrocardiogram were performed for all participants to simultaneously monitor the heart rate variability (HRV) and blood pressure variability (BPV) in these patients. Pearson single factor analysis and multivariate logistic regression analysis were performed to define the relationship between PWV and HRV, BPV respectively. RESULTS: The level of nHR/dHR (index of heart rate variability), 24 hour'sSSD, dSSD, nSSD (indexes of blood pressure variability) increased significantly (all P<0.05), while the level of SDANN (index of heart rate variability) decreased significantly (P<0.05) in high PWV group compared with normal PWV group. Multiple linear regression analysis showed that PWV was positively correlated with 24 hour'sSSD, 24 hour'sPP, LF, LF/HF and night/day heart rate ratio (all P<0.05). CONCLUSIONS: HRV (LF, LF/HF, nHR/dHR) and BPV (24 hours'SSD, dSSD, nSSD) are positively correlated to arteriosclerosis in patients with essential hypertension. Our results show that sympathetic activation and vascular injury are closely related in patients with essential hypertension. PMID- 26988676 TI - [Clinical characteristics and outcomes of patients with acute aortic dissection: impact of hypertension]. AB - OBJECTIVE: To observe the clinical characteristics and outcomes of patients with acute aortic dissection (AAD) and explore the impact of hypertension. METHODS: The present study enrolled 1 087 consecutive patients with AAD who were confirmed by computed tomographic scanning in Fuwai Hospital from January 2008 to December 2010. The major endpoints were in-hospital death and long-term mortality during follow up. RESULTS: A total of 595 (54.7%) patients were Stanford type A and 492 (45.3%) patients were Stanford type B. The median length of follow-up was 24.2 months (interquartile range 10.9, 40.8 months). The prevalence of hypertension was 67.4%(733 cases), and was significantly higher in type B patients than in type A patients (71.3%(351/492) vs. 64.2%(382/595), P=0.01). Regardless of Stanford classification, patients complicating with hypertension were older, had higher comorbidities (coronary heart diseases or diabetes), and less likely to receive surgical treatment compared with those without hypertension (all P<0.05). In Stanford type A AAD group, patients with hypertension had higher levels of admission blood pressure, serum creatinine and inflammatory markers (including WBC count, D-dimer and CRP) than those without hypertension (all P<0.05). In hospital death (9.9% (38/382)vs. 5.6%(12/213), P=0.07) and long-term mortality (9.0% (31/344) vs. 8.9% (18/201), P=0.98) were similar in hypertensive and normotensive AAD type A patients. In type B AAD group, the in-hospital death rate was significantly higher in patients with hypertension than those without hypertension (5.4%(19/351) vs. 0.7%(1/141), P=0.02), while the long-term mortality was similar (6.9%(23/332) vs. 7.9%(11/140), P=0.71) between patients with and without hypertension. Multiple logistic regression analysis showed that hypertension did not predict the increased risk of in-hospital death of type A or type B AAD patients. The main protective factor of in-hospital mortality was operation in patients with type A AAD. The independent predictors of in-hospital death were age and surgical treatment in patients with type B AAD. CONCLUSIONS: Hypertension is a common co-morbidity in patients with AAD. AAD patients with hypertension are usually elder, have higher comorbidities of cardiovascular diseases, and less likely to receive surgical treatment compared with those without hypertension, but hypertension is not associated with increased risk of in-hospital and long-term mortality in both AAD type A and type B patients. PMID- 26988678 TI - [Impact of combined systolic blood pressure and body mass index on the risk of new-onset atrial fibrillation]. AB - OBJECTIVE: To observe the impact of combined systolic blood pressure and body mass index (BMI) on the risk of new-onset atrial fibrillation. METHODS: The participants who participated the health examination between July 2006 and October 2007 at Kailuan medical group and had no history of atrial fibrillation were selected as the observation cohort.The second, the third and the fourth health examination were conducted between July 2008 and October 2009, July 2010 and October 2011, July 2012 and October 2013, respectively.The participants were stratified by 3 systolic blood pressure levels (<=120, 120-140, >=140 mmHg (1 mmHg=0.133 kPa))*3 BMI levels (<=24, 24-28, >=28 kg/m(2)) at baseline.The combined effect of systolic blood pressure and BMI on the risk of new-onset atrial fibrillation was analyzed by multiple Cox regression analysis. RESULTS: A total of 99 206 participants were recruited and 88 715 participants were included in the final analysis after excluding participants who had new-onset valvular atrial fibrillation or lost to follow-up.A total of 265 participants developed atrial fibrillation during the 5.6 years follow-up.The incidence of atrial fibrillation increased with the BMI and systolic blood pressure, the incidence of new onset of atrial fibrillation was significantly higher in the group with systolic blood pressure>=140 mmHg and BMI>=28 kg/m(2) than the group with systolic blood pressure<=120 mmHg and BMI<=24 kg/m(2)(1.15/1 000 person-year vs. 0.25/1 000 person-year). Multiple Cox regression analysis showed that participants in the group with systolic blood pressure>=140 mmHg and BMI>=28 kg/m(2) carried 2.08 (95%CI 1.18-3.67) times higher risk for atrial fibrillation than the group with systolic blood pressure<=120 mmHg and BMI<=24 kg/m(2) after adjustment for age, gender and other confounders at baseline. CONCLUSION: Participants with systolic blood pressure>=140 mmHg and BMI>=28 kg/m(2) are at high risk for new onset of atrial fibrillation. PMID- 26988679 TI - [Efficacy of interventional therapy on paravalvular leakage after mitral valve replacement]. AB - OBJECTIVE: To evaluate the efficacy of transcatheter intervention of paravalvular leakage (PVL) after mitral valve replacement. METHODS: Present respective study included 15 patients (8 males and mean age (53.5+/-11.7) years) with mitral PVL who underwent interventional therapy in our hospital from April 2014 to May 2015. There were 9 cases with NYHA heart function III, 6 cases with NYHA heart function IV. Left ventricular ejection fraction was (46.8+/-8.2)%, and mitral regurgitation volume was 12.0 (10.0, 15.0)ml before the intervention. Transcatheter intervention was carried out in the catheterization laboratory or the hybrid operation room with initial local anesthesia. By puncturing femoral artery and implantation of different congenital heart disease devices, the mitral PVL were occluded interventionally. To some complicated cases, the occluder was implanted by puncturing apex and atrial septum. Follow-up evaluation included peri-operational mortality, complications and postoperative residual shunt. RESULTS: The median time between transcatheter intervention and previous operation was 5.0 (0.6, 7.0) years. One patient did not tolerate the operation and occlude was not implanted in this patient. The success rate of transcatheter intervention was 93.3% (14/15). The average operation time was (126.7+/-56.4)min, and X ray exposure time was (21.0+/-10.0)min, and median hospitalization time was 7.0 (6.0, 10.0)d. The main post-operative complications included 1 case of hemoptysis, 1 case of acute renal failure, 1 case of hematuria and 4 cases of blood transfusion. The median follow-up time was 7.0 (4.0, 12.0) months. During the follow-up, there was no death and no serious complications. One month after the procedure, left ventricular ejection fraction significantly increased to(52.1+/-4.3)%, and median mitral regurgitation significantly reduced to 0.5 (0, 2.0)ml (all P<0.05). CONCLUSION: The interventional therapy for PVL after mitral valve replacement is safe and effective, and further studies are warranted to observe the long-term effect of this procedure. PMID- 26988680 TI - [Effects of selenium supplement on atherogenesis of ApoE-knockout mice fed high fat diet]. AB - OBJECTIVE: To investigate the effects of selenium supplement on atherogenesis and endothelial function in ApoE-knockout mice fed high fat diet. METHODS: ApoE knockout mice fed with selenium-deficient and high fat diet were randomly allocated into 3 groups based on random number table including control group (not supplied with sodium selenite, n=10), low dosage selenium supplement group (supplied water with 0.1 mg/L sodium selenite, n=10) and high dosage selenium supplement group (supplied water with 0.2 mg/L sodium selenite, n=10). After 15 weeks, the following values were measured: the concentrations of selenium in heart and liver, the levels of serum lipid, the parameters of antioxidant function including activities of superoxide dismutase(SOD) and glutathion peroxidase (GSH-Px) and malondialdehyde (MDA) level in serum, the parameters of endothelial function including serum nitric oxide (NO), endothelin 1(ET-1), and vascular endothelial growth factor (VEGF) levels, and ET-1 and VEGF levels in aorta roots. The atherosclerotic lesions in aorta roots were analyzed with oil red O staining. RESULTS: (1) The selenium concentrations in heart and liver were significantly higher in high dosage and low dosage selenium supplement groups compared to control group (both P<0.05). (2) The levels of triglyceride, total cholesterol, low density lipoprotein cholesterol, very low density lipoprotein cholesterol and high-density lipoprotein cholesterol were similar among groups (all P>0.05). (3) The activity levels of serum SOD were significantly higher in low dosage ((113.8+/-12.5)U/ml) and high dosage selenium supplement group ((152.3+/-11.3)U/ml) compared to control group ((90.7+/-10.7)U/ml, all P<0.05). The activity levels of serum GSH-Px were significantly higher in low dosage ((53.9+/-7.2)U/ml) and high dosage ((69.6+/-8.7)U/ml) selenium supplement groups than that of control group ((36.4+/-5.6)U/ml, all P<0.05). The serum MDA levels in low dosage ((4.73+/-1.05)nmol/ml) and high dosage ((4.13+/-1.21)nmol/ml) selenium supplement groups were significantly lower than that of control group ((5.97+/-1.08)nmol/ml, all P<0.05). (4) The serum NO concentrations in low dosage ((61.5+/-12.8)MUmol/L) and high dosage ((79.0+/-14.6)MUmol/L)selenium supplement groups were significantly higher than that of control group((42.7+/-9.1)MUmol/L, all P<0.05). The concentrations of serum ET-1 in low dosage ((52.8+/-6.3)ng/L)and high dosage ((46.3+/-4.7)ng/L)selenium supplement groups were significantly lower than that of control group((72.2+/-6.3)ng/L, P<0.05). The concentrations of serum VEGF in low dosage ((97.4+/-16.5)ng/L)and high dosage ((83.5+/-22.0)ng/L)selenium supplement groups were significantly lower than that of control group((125.8+/ 18.6)ng/L, P<0.05). The expression levels of ET-1 and VEGF in aorta roots among low dosage and high dosage selenium supplement groups were significantly lower compared to control group (all P<0.05). (5) The plaque area of aorta roots in low dosage ((0.95+/-0.19)*10(5) MUm(2))and high dosage selenium supplement ((0.75+/ 0.15)*10(5) MUm(2)) groups were significantly smaller than that of control group((1.13+/-0.23)*10(5) MUm(2)), and the plaque area in high dosage selenium supplement group was significantly smaller than in low dosage selenium supplement group (P<0.05). CONCLUSION: Supplement of selenium can attenuate atherogenesis in ApoE-knockout mice fed high fat diet, which is possibly mediated via reducing lipid peroxidation and improving endothelial functions. PMID- 26988681 TI - [Phosphatase and tensin homolog deleted on chromosome ten/phosphatidyl Inositol 3 kinase/vascular endothelial growth factor signaling pathway changes in the rabbit Kawasaki disease model]. AB - OBJECTIVE: To observe the changes of phosphatase and tensin homolog deleted on chromosome ten(PTEN)/ phosphatidyl Inositol 3-kinase(PI3K)/ vascular endothelial growth factor(VEGF)signaling pathway in a rabbit Kawasaki disease model. METHODS: Model of Kawasaki disease was established in weanling Japanese big-eared rabbits with 10% bovine serum venous injection (2.5 ml/kg, 2 times, and 2 week's interval) through the ear. Twenty four rabbits were divided into 4 groups: control group (without injection of 10% bovine serum albumin, six rabbits); 1 day group (sacrificed a the second day after the establishment of Kawasaki disease models, six rabbits); 7 day group (sacrificed at the seventh day after establishment of Kawasaki disease model, six rabbits); 30 day group (sacrificed at the thirtieth day after establishment of Kawasaki disease model, six rabbits). Pathological analysis was performed on coronary artery tissue samples. The express of PTEN and PI3K were detected by immunohistochemistry. The levels of VEGF and CK were also examined with ELISA and white blood cells were counted. RESULTS: (1) Coronary artery of model groups was thinner, distorted and had enlarged lumen. (2) PTEN expression in 1 d group, 7 d group and 30 d group were 58.5 +/- 12.9, 73.2+/-9.9 and 109.6 +/- 24.4, respectively, significantly higher than in the control group (25.5 +/- 6.9, P<0.01 or 0.05). (3) The express of PI3K was significantly upregulated in 1 d group(57.2+/-11.1)and 7 d group(39.9+/-4.8) compared to control group(19.1+/-3.5, P<0.01 or 0.05). The expression level of PI3K in 30 d group was 18.8 +/- 7.5, which was similar as control group (P>0.05) and significantly lower than 1 d and 7 d group (both P<0.05). (4) Similarly, the level of VEGF in 1 d group, 7 d group ((89.1 +/- 15.5) ng/L, (76.9+/-9.9) ng/L) were significantly higher while it was significantly lower in 30 d group ((19.8 +/- 4.4)ng/L) compared with the control group ((33.9 +/- 6.7) ng/L, P<0.01 or 0.05). The level of VEGF in 7 d group was significantly lower than in 1 d group (P<0.05) and the level of VEGF was significantly lower in 30 d group than in 7 d group (P<0.01). (5)Creatine kinase levels were significantly higher in 30 d group than in control group (P<0.05) and there were no significantly different between control group, 1 d group and 7 d group(all P>0.05). (6)White blood cell count were significantly higher in 1 d group, 7 d group and 30 d group than in control group (all P<0.01). CONCLUSION: The level of PTEN/PI3K/VEGF signaling pathway change after establishment of rabbit Kawasaki disease model and the signaling pathway might be involved in this model. PMID- 26988682 TI - [Upregulated Notch1 expression promotes bone morphogenetic protein-2/4 expression of calcified human heart valve interstitial cells]. AB - OBJECTIVE: To observe the protein expression of Notch1 in the cultured calcified human heart valve interstitial cells (hVICs) in vitro and related mechanisms. METHODS: hVICs were divided into two groups: control hVICs were cultured in conventional media for 14 days and calcified hVICs were cultured with calcification inducers: beta-glycerophosphate (500 MUl), ascorbic acid (200 MUl), dexamethasone(100 MUl) for 7 days. The calcified hVICs were further divided into calcified hVICs group and inhibited calcified hVICs by adding specific Notch1 inhibitor DAPT (50 MUmol/L(4 MUl/hole))groups and cultured for another 7 days. Inflammatory response of all groups were induced by lipopolysaccharide (LPS) for 8 to 12 hours. Western blot was used to detect the protein expression of Notch1, phosphorylation nuclear transcription factor kappaB (p-NF-kappaB), bone morphogenetic protein-2/4(BMP-2/4). ELISA was applied to detect the content of BMP-2 secretion of the groups. Von Kossa staining was used to observe of cellular calcification. RESULTS: (1)Von Kossa staining is positive in the induced calcification group, the expression of Notch1, p-NF-kappaB, BMP-2 and BMP-4 is significantly higher in the induced calcification group than in the control group (all P<0.05). The expression of BMP-2 is significantly higher in the induced calcification group than in control group ((88.23+/-3.28) pg/ml vs. (25.41+/ 3.68) pg/ml, P=0.02). (2) After treatment with DAPT, the calcification and the expression of Notch1, p-NF-kappaB, BMP-2 and BMP-4 were significantly decreased compared to calcification group (all P<0.05). The expression of BMP-2 is (26.74+/ 4.62) pg/ml in the calcification inhibition group and (80.41+/-2.96) pg/ml in calcified control group (P=0.02). CONCLUSIONS: Upregulated Notch 1 expression promotes BMP-2/4 secretion in LPS stimulated hVICs, and contributes to osteogenic changes in hVICs. Inhibiting Notch1 can decrease the BMP-2/4 secretion and calcification in hVICs, which may serve as a novel therapeutic option for treating calcific valve disease. PMID- 26988683 TI - [Relationship of blood aryl hydrocarbon receptor mRNA and cytochrome P450 1A1 mRNA expression with corrected QT interval among residents exposed to arsenic via drinking water]. AB - OBJECTIVE: To investigate the relationship between blood aryl hydrocarbon receptor(AhR)mRNA and cytochrome P450(CYP)1A1 mRNA expression and corrected QT interval among residents exposed to arsenic via drinking water. METHODS: Arsenic exposure area in Bayannao'er city of Nei Monggol Autonomous Region was selected as the survey point, and the residents living more than 10 years in this area were investigated from December 2012 to January 2015.A total of 233 residents were divided into four groups according to drinking water arsenic concentration (ranged from 0.8 to 824.7 MUg/L): control group (drinking water arsenic concentration <10.0 MUg/L, n=55), low exposure group (drinking water arsenic concentration 10.0-99.9 MUg/L, n=47), middle exposure group (drinking water arsenic concentration 100.0-199.9 MUg/L, n=45), high exposure group (drinking water arsenic concentration >=200.0 MUg/L, n=86). Epidemiological investigation was performed.Real-time PCR technology was used to detect the expression levels of blood AhR mRNA and CYP1A1 mRNA, and the relationship between expression levels of blood AhR mRNA and CYP1A1 mRNA and corrected QT interval was analyzed. RESULTS: (1) Blood AhR mRNA and CYP1A1 mRNA expression levels were similar among control group, low exposure group and middle exposure group (all P>0.05) while blood AhR mRNA (3.18*10(-3)(2.42*10(-3), 4.45*10(-3)) vs.2.30*10(-3)(1.53*10(-3), 3.20*10(-3)), P<0.05) and CYP1A1 mRNA (1.58*10(-3)(0.80*10(-3), 2.73*10( 3))vs.1.00*10(-3)(0.59*10(-3), 2.09*10(-3)), P<0.05) expression levels were significantly higher in high dose group than in control group.(2) AhR mRNA expression level was similar between residents with longer corrected QT interval and residents with normal corrected QT interval (2.89*10(-3)(1.90*10(-3), 3.71*10(-3)) vs.2.58*10(-3)(1.85*10(-3), 3.57*10(-3)), P>0.05). CYP1A1 mRNA expression level was significantly higher in residents with longer corrected QT interval than in residents with normal corrected QT interval (1.50*10( 3)(0.78*10(-3), 2.63*10(-3)) vs.1.16*10(-3)(0.64*10(-3), 2.36*10(-3)), P<0.05). (3) AhR mRNA expression level was similar between residents with sinus tachycardia or bradycardia or normal heart rate(2.89*10(-3)(1.71*10(-3), 4.45*10( 3)) vs.2.64*10(-3)(1.86*10(-3), 3.52*10(-3)), P>0.05). CYP1A1 mRNA expression level was significantly higher in residents with sinus tachycardia or bradycardia than in residents with normal heart rate (1.47*10(-3)(0.87*10(-3), 2.77*10(-3)) vs.1.24*10(-3)(0.64*10(-3), 2.31*10(-3)), P<0.05). CONCLUSIONS: Long-term exposure to arsenic is associated with upregulated blood AhRmRNA and CYP1A1 mRNA expression.Blood CYP1A1 mRNA expression, but not AhRmRNA expression, is associated with prolonged corrected QT interval. PMID- 26988685 TI - [Case report of a patient with Heyde syndrome treated by transcatheter aortic valve implantation]. PMID- 26988684 TI - [Association between neutrophil-lymphocyte ratio and isolated coronary artery ectasia: a meta-analysis]. AB - OBJECTIVE: To evaluate the association between neutrophil-lymphocyte ratio (NLR) and isolated coronary artery ectasia by meta-analysis. METHODS: Case-control studies focusing the association between NLR and isolated coronary artery ectasia published before July 2015 were identified from PubMed, CBM, CNKI, WanFang, and VIP databases and references of related studies were also searched manually. After document screening, data extraction and quality evaluation, meta-analysis was performed using RevMan 5.3 software. RESULTS: Five case-control studies including 817 patients were identified. The result of meta-analysis showed the NLR level in the isolated coronary artery ectasia group was significantly higher than that of the control group (MD=0.89, 95%CI 0.07-1.00, P<0.01), and the loss of safety coefficient was 335 showing that the result of meta-analysis was reliable. CONCLUSIONS: Results from the present meta-analysis show that elevated NLR level may be associated with the presence of isolated coronary artery ectasia. However, further studies are warranted to establish the causal association between NLR level and presence of isolated coronary artery ectasia. PMID- 26988686 TI - [Research advances on the relationship between O-linked N-acetylglucosamine and cardiovascular diseases]. PMID- 26988687 TI - [Role and mechanisms of cardiomyocyte autophagy in cardiovascular diseases]. PMID- 26988688 TI - [Research update on the role of macrophages in atherosclerosis regression]. PMID- 26988689 TI - Comparison of the measurement properties of the Functional Independence and Difficulty Scale with the Barthel Index in community-dwelling elderly people in Japan. AB - BACKGROUND: The new Functional Independence and Difficulty Scale (FIDS) is a tool for assessing the performance of basic activities of daily living (BADL). Because many BADL measures already exist, it is important to know whether FIDS can offer added benefit over the existing measures. AIMS: This study compared measurement properties between the FIDS and a representative BADL assessment tool, the Barthel Index (BI). METHODS: Recruitment of the participants was done on the basis of convenience sampling. Participants were community-dwelling elderly Japanese subjects (n = 314; age >=65 years) divided into a healthy elderly group [n = 225; subjects not using long-term care insurance (LTCI) services] and frail elderly group (n = 89; subjects using LTCI services). For each group, ceiling effect (percent participation with the maximum score) was calculated, and it was compared between the two scales. Associations between the FIDS, BI and Medical Outcomes Study Short Form 8 Health Survey (SF-8) were evaluated by Spearman correlation coefficient and partial correlations. Partial correlations coefficients to SF-8 were compared between the two scales. RESULTS: FIDS showed a relatively small ceiling effect compared to the BI. Compared to the BI, FIDS showed a significant positive partial correlation with the broader aspect of the SF-8 subscales, but the strength of correlation between FIDS and SF-8 was weak to negligible. CONCLUSIONS: The FIDS might be less affected by ceiling effect than the BI. Additional studies using a sufficient number of probability samples are needed to clarify whether FIDS has any benefit over BI in terms of correlations with the SF-8. PMID- 26988690 TI - Cobalt oxide nanoparticles aggravate DNA damage and cell death in eggplant via mitochondrial swelling and NO signaling pathway. AB - BACKGROUND: Despite manifold benefits of nanoparticles (NPs), less information on the risks of NPs to human health and environment has been studied. Cobalt oxide nanoparticles (Co3O4-NPs) have been reported to cause toxicity in several organisms. In this study, we have investigated the role of Co3O4-NPs in inducing phytotoxicity, cellular DNA damage and apoptosis in eggplant (Solanum melongena L. cv. Violetta lunga 2). To the best of our knowledge, this is the first report on Co3O4-NPs showing phytotoxicity in eggplant. RESULTS: The data revealed that eggplant seeds treated with Co3O4-NPs for 2 h at a concentration of 1.0 mg/ml retarded root length by 81.5 % upon 7 days incubation in a moist chamber. Ultrastructural analysis by transmission electron microscopy (TEM) demonstrated the uptake and translocation of Co3O4-NPs into the cytoplasm. Intracellular presence of Co3O4-NPs triggered subcellular changes such as degeneration of mitochondrial cristae, abundance of peroxisomes and excessive vacuolization. Flow cytometric analysis of Co3O4-NPs (1.0 mg/ml) treated root protoplasts revealed 157, 282 and 178 % increase in reactive oxygen species (ROS), membrane potential (DeltaPsim) and nitric oxide (NO), respectively. Besides, the esterase activity in treated protoplasts was also found compromised. About 2.4-fold greater level of DNA damage, as compared to untreated control was observed in Comet assay, and 73.2 % of Co3O4-NPs treated cells appeared apoptotic in flow cytometry based cell cycle analysis. CONCLUSION: This study demonstrate the phytotoxic potential of Co3O4-NPs in terms of reduction in seed germination, root growth, greater level of DNA and mitochondrial damage, oxidative stress and cell death in eggplant. The data generated from this study will provide a strong background to draw attention on Co3O4-NPs environmental hazards to vegetable crops. PMID- 26988691 TI - Bifidobacterium thermophilum RBL67 impacts on growth and virulence gene expression of Salmonella enterica subsp. enterica serovar Typhimurium. AB - BACKGROUND: Bifidobacterium thermophilum RBL67 (RBL67), a human fecal isolate and health promoting candidate shows antagonistic and protective effects against Salmonella and Listeria spec. in vitro. However, the underlying mechanisms fostering these effects remain unknown. In this study, the interactions of RBL67 and Salmonella enterica subsp. enterica serovar Typhimurium N-15 (N-15) were explored by global transcriptional analysis. RESULTS: Growth experiments were performed in a complex nutritive medium with controlled pH of 6.0 and suitable for balanced growth of both RBL67 and N-15. RBL67 growth was slightly enhanced in presence of N-15. Conversely, N-15 showed reduced growth in the presence of RBL67. Transcriptional analyses revealed higher expression of stress genes and amino acid related function in RBL67 in co-culture with N-15 when compared to mono-culture. Repression of the PhoP regulator was observed in N-15 in presence of RBL67. Further, RBL67 activated virulence genes located on the Salmonella pathogenicity islands 1 and 2. Flagellar genes, however, were repressed by RBL67. Sequential expression of flagellar, SPI 1 and fimbrial genes is essential for Salmonella infection. Our data revealed that RBL67 triggers expression of SPI 1 and fimbrial determinants prematurely, potentially leading to redundant energy expenditure. In the competitive environment of the gut such energy expenditure could lead to enhanced clearing of Salmonella. CONCLUSION: Our study provides first insights into probiotic-pathogen interactions on global transcriptional level and suggests that deregulation of virulence gene expression might be an additional protective mechanism of probiotica against infections of the host. PMID- 26988694 TI - 'Is she alive? Is she dead?' Representations of chronic disorders of consciousness in Douglas Coupland's Girlfriend in a Coma. AB - Depictions of coma have come to dominate literary and filmic texts over the last half century, a phenomenon coinciding with advancements in medical technology that have led to remarkable increases in the survival rates of patients with chronic disorders of consciousness. Authors of coma fiction are preoccupied with the imagined subjective experience of coma, often creating complex, dream-like worlds from which the protagonist must escape if survival is to be achieved. However, such representations appear to conflict with medical case studies and patient narratives that reveal that most often survivors of coma have no recollection of the coma itself. Providing a close reading of Douglas Coupland's Girlfriend in a Coma (1998) against the context of medical literature and diagnoses, this article examines how the coma patient is represented, often depicting the realities of a prolonged vegetative state, in contrast with other popular representations of coma. It explores how the author develops a work of 'fantastic' fiction (a genre defined by the structuralist critic Tzvetan Todorov), using the condition of coma as a metaphor for a postmodern existential crisis, while simultaneously employing mimetic techniques that raise important medical, ethical and philosophical questions surrounding the ontological status of the comatose patient. It is argued that coma fiction, even in its misrepresentation of the condition, can help us to engage with and interrogate how we think about chronic disorders of consciousness, thereby providing a valuable insight into our attitudes towards illness and mortality. PMID- 26988695 TI - Lattice Strain Defects in a Ceria Nanolayer. AB - An ultrathin two-dimensional CeO2 (ceria) phase on a Cu(110) surface has been fabricated and fully characterized by high-resolution scanning tunneling microscopy, photoelectron spectroscopy, and density functional theory. The atomic lattice structure of the ceria/Cu(110) system is revealed as a hexagonal CeO2(111)-type monolayer separated from the Cu(110) surface by a partly disordered Cu-O intercalated buffer layer. The epitaxial coupling of the two dimensional ceria overlayer to the Cu(110)-O surface leads to a nanoscopic stripe pattern, which creates defect regions of quasi-periodic lattice distortions. The symmetry and lattice mismatch at the interface is clarified to be responsible for the topographic stripe geometry and the related anisotropic strain defect regions at the ceria surface. This ceria monolayer is in a fully oxidized and thermodynamically stable state. PMID- 26988693 TI - Effect of multi-strain probiotics (multi-strain microbial cell preparation) on glycemic control and other diabetes-related outcomes in people with type 2 diabetes: a randomized controlled trial. AB - AIM: Evidence of a possible connection between gut microbiota and several physiological processes linked to type 2 diabetes is increasing. However, the effect of multi-strain probiotics in people with type 2 diabetes remains unclear. This study investigated the effect of multi-strain microbial cell preparation also refers to multi-strain probiotics-on glycemic control and other diabetes related outcomes in people with type 2 diabetes. DESIGN: A randomized, double blind, parallel-group, controlled clinical trial. SETTING: Diabetes clinic of a teaching hospital in Kuala Lumpur, Malaysia. PARTICIPANTS: A total of 136 participants with type 2 diabetes, aged 30-70 years, were recruited and randomly assigned to receive either probiotics (n = 68) or placebo (n = 68) for 12 weeks. OUTCOMES: Primary outcomes were glycemic control-related parameters, and secondary outcomes were anthropomorphic variables, lipid profile, blood pressure and high-sensitivity C-reactive protein. The Lactobacillus and Bifidobacterium quantities were measured before and after intervention as an indicator of successful passage of the supplement through gastrointestinal tract. STATISTICAL ANALYSIS: Intention-to-treat (ITT) analysis was performed on all participants, while per-protocol (PP) analysis was performed on those participants who had successfully completed the trial with good compliance rate. RESULTS: With respect to primary outcomes, glycated hemoglobin decreased by 0.14 % in the probiotics and increased by 0.02 % in the placebo group in PP analysis (p < 0.05, small effect size of 0.050), while these changes were not significant in ITT analysis. Fasting insulin increased by 1.8 uU/mL in placebo group and decreased by 2.9 uU/mL in probiotics group in PP analysis. These changes were significant between groups at both analyses (p < 0.05, medium effect size of 0.062 in PP analysis and small effect size of 0.033 in ITT analysis). Secondary outcomes did not change significantly. Probiotics successfully passed through the gastrointestinal tract. CONCLUSION: Probiotics modestly improved HbA1c and fasting insulin in people with type 2 diabetes. PMID- 26988696 TI - Animal Models of Vascular Cognitive Impairment and Dementia (VCID). AB - Vascular cognitive impairment and dementia (VCID) is the most common etiology of dementia in the elderly. Both, vascular and Alzheimer's disease, pathologies work synergistically to create neurodegeneration and cognitive impairments. The main causes of VCID include hemorrhage/microbleed (i.e., hyperhomocysteinemia), cerebral small vessel disease, multi-infarct dementia, severe hypoperfusion (i.e., bilateral common carotid artery stenosis), strategic infarct, angiopathy (i.e., cerebral angiopathy), and hereditary vasculopathy (i.e., cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). In this review, we will discuss the experimental animal models that have been developed to study these pathologies. We will discuss the limitations and strengths of these models and the important research findings that have advanced the field through the use of the models. PMID- 26988698 TI - De Novo assembly and annotation of the freshwater crayfish Astacus astacus transcriptome. AB - We generated RNA-seq data to assemble the transcriptome of the noble crayfish (Astacus astacus) from four combined tissues (abdominal muscle, hepatopancreas, ovaries, green glands). A total of 194 million read pairs with a length of 100 bp were generated. The transcriptome was assembled de novo using Trinity software, producing 158,649 non-redundant transcripts. Lowly expressed transcripts were filtered out leaving 45,415 transcripts of which 14,559 were found to contain open reading frames with predicted gene function. The Transrate software revealed that 91% of the total reads were realigned to the assembly. Furthermore, BUSCO analysis indicated that our assembly is 64% complete. A total of 13,770 transcripts were assigned at least one GO term. This first de novo transcriptome assembly is an important foundation for future genomic research on the noble crayfish and adds to the general knowledge and further characterization of transcriptomes of non-model organisms. PMID- 26988699 TI - Displaced humeral shaft fractures in children and adolescents: results and adverse effects in patients treated by elastic stable intramedullary nailing. AB - PURPOSE: The objectives of this study were to retrospectively investigate the clinical and radiological outcome of humeral shaft fractures treated by ESIN in children <16 years old and to evaluate the functional outcome of these injuries using the short version of the Disabilities of the Arm, Shoulder and Hand Outcome questionnaire (Quick DASH((r))). METHODS: We retrospectively evaluated children with fractures of the humeral shaft, surgically treated by ESIN. All the patients were regularly followed clinically and radiographically for at least 1 year after their index surgery. After hardware removal, the patients were asked to answer the short version of the Disabilities of the Arm, Shoulder and Hand Outcome questionnaire (Quick DASH). RESULTS: Thirty-eight patients met the inclusion criteria. Mean age at the time of trauma was 11.1 years. Mean follow-up was 30 months. All fractures healed, but three patients had a residual valgus of >10 degrees , two a residual varum of >10 degrees , four a residual recurvatum deformity of >10 degrees , and one a residual procurvatum deformity of >10 degrees . Four complications were observed. Functional outcome was nevertheless good in all the patients, with a mean Quick DASH((r)) score of 3. CONCLUSION: The study shows good clinical and functional outcomes in children and adolescents with closed isolated fractures of the humeral shaft surgically treated by ESIN, even with ensuing mild residual frontal and sagittal plane deformity. However, conservative treatment has also been advocated in the scientific literature for this type of injuries, and surgical treatment should not be considered as the only option for the management of humeral shaft fractures in older children and adolescents. PMID- 26988700 TI - Structure of a novel 13 nm dodecahedral nanocage assembled from a redesigned bacterial microcompartment shell protein. AB - We report the crystal structure of a novel 60-subunit dodecahedral cage that results from self-assembly of a re-engineered version of a natural protein (PduA) from the Pdu microcompartment shell. Biophysical data illustrate the dependence of assembly on solution conditions, opening up new applications in microcompartment studies and nanotechnology. PMID- 26988701 TI - Reply to comment on: 'Predicting the efficacy of radiotherapy in individual glioblastoma patients in vivo: a mathematical modeling approach'. PMID- 26988702 TI - Simulation of Yeast Cooperation in 2D. AB - Evolution of cooperation has been an active research area in evolutionary biology in decades. An important type of cooperation is developed from group selection, when individuals form spatial groups to prevent them from foreign invasions. In this paper, we study the evolution of cooperation in a mixed population of cooperating and cheating yeast strains in 2D with the interactions among the yeast cells restricted to their small neighborhoods. We conduct a computer simulation based on a game theoretic model and show that cooperation is increased when the interactions are spatially restricted, whether the game is of a prisoner's dilemma, snow drifting, or mutual benefit type. We study the evolution of homogeneous groups of cooperators or cheaters and describe the conditions for them to sustain or expand in an opponent population. We show that under certain spatial restrictions, cooperator groups are able to sustain and expand as group sizes become large, while cheater groups fail to expand and keep them from collapse. PMID- 26988703 TI - Front-line intraperitoneal versus intravenous chemotherapy in stage III-IV epithelial ovarian, tubal, and peritoneal cancer with minimal residual disease: a competing risk analysis. AB - BACKGROUND: In the analysis of survival data for cancer patients, the problem of competing risks is often ignored. Competing risks have been recognized as a special case of time-to-event analysis. The conventional techniques for time-to event analysis applied in the presence of competing risks often give biased or uninterpretable results. METHODS: Using a prospectively collected administrative health care database in a single institution, we identified patients diagnosed with stage III or IV primary epithelial ovarian, tubal, and peritoneal cancers with minimal residual disease after primary cytoreductive surgery between 1995 and 2012. Here, we sought to evaluate whether intraperitoneal chemotherapy outperforms intravenous chemotherapy in the presence of competing risks. Unadjusted and multivariable subdistribution hazards models were applied to this database with two types of competing risks (cancer-specific mortality and other cause mortality) coded to measure the relative effects of intraperitoneal chemotherapy. RESULTS: A total of 1263 patients were recruited as the initial cohort. After propensity score matching, 381 patients in each arm entered into final competing risk analysis. Cumulative incidence estimates for cancer-specific mortality were statistically significantly lower (p = 0.017, Gray test) in patients receiving intraperitoneal chemotherapy (5-year estimates, 34.5%; 95% confidence interval [CI], 29.5-39.6%, and 10-year estimates, 60.7%; 95% CI, 52.2 68.0%) versus intravenous chemotherapy (5-year estimates, 41.3%; 95% CI, 36.2 46.3%, and 10-year estimates, 67.5%, 95% CI, 61.6-72.7%). In subdistribution hazards analysis, for cancer-specific mortality, intraperitoneal chemotherapy outperforms intravenous chemotherapy (Subdistribution hazard ratio, 0.82; 95% CI, 0.70-0.96) after correcting other covariates. CONCLUSIONS: In conclusion, results from this comparative effectiveness study provide supportive evidence for previous published randomized trials that intraperitoneal chemotherapy outperforms intravenous chemotherapy even eliminating the confounding of competing risks. We suggest that implementation of competing risk analysis should be highly considered for the investigation of cancer patients who have medium to long-term follow-up period. PMID- 26988705 TI - Complex-valued time-series correlation increases sensitivity in FMRI analysis. AB - PURPOSE: To develop a linear matrix representation of correlation between complex valued (CV) time-series in the temporal Fourier frequency domain, and demonstrate its increased sensitivity over correlation between magnitude-only (MO) time series in functional MRI (fMRI) analysis. MATERIALS AND METHODS: The standard in fMRI is to discard the phase before the statistical analysis of the data, despite evidence of task related change in the phase time-series. With a real-valued isomorphism representation of Fourier reconstruction, correlation is computed in the temporal frequency domain with CV time-series data, rather than with the standard of MO data. A MATLAB simulation compares the Fisher-z transform of MO and CV correlations for varying degrees of task related magnitude and phase amplitude change in the time-series. The increased sensitivity of the complex valued Fourier representation of correlation is also demonstrated with experimental human data. Since the correlation description in the temporal frequency domain is represented as a summation of second order temporal frequencies, the correlation is easily divided into experimentally relevant frequency bands for each voxel's temporal frequency spectrum. The MO and CV correlations for the experimental human data are analyzed for four voxels of interest (VOIs) to show the framework with high and low contrast-to-noise ratios in the motor cortex and the supplementary motor cortex. RESULTS: The simulation demonstrates the increased strength of CV correlations over MO correlations for low magnitude contrast-to-noise time-series. In the experimental human data, the MO correlation maps are noisier than the CV maps, and it is more difficult to distinguish the motor cortex in the MO correlation maps after spatial processing. CONCLUSIONS: Including both magnitude and phase in the spatial correlation computations more accurately defines the correlated left and right motor cortices. Sensitivity in correlation analysis is important to preserve the signal of interest in fMRI data sets with high noise variance, and avoid excessive processing induced correlation. PMID- 26988704 TI - Improvement of water saturation shift referencing by sequence and analysis optimization to enhance chemical exchange saturation transfer imaging. AB - PURPOSE: To optimize B0-field inhomogeneity correction for chemical exchange saturation transfer (CEST) imaging by investigating different water saturation shift referencing (WASSR) Z-spectrum shapes and different frequency correction techniques. METHODS: WASSR Z-spectra were simulated for different B1-fields and pulse durations (PD). Two parameter settings were used for further simulations and experiments (WASSR1: B1=0.1 MUT, PD=50ms; WASSR2: B1=0.3 MUT, PD=40ms). Four frequency correction techniques were investigated: 1) MinW: Minimum of the spline interpolated WASSR-spectrum; 2) MSCF: maximum symmetry center frequency algorithm; 3) PMSCF: further development of MSCF algorithm; 4) BFit: fit with Bloch equations. Performance of frequency correction was assessed with Monte Carlo simulations and in-vivo MR examinations in the brain and intervertebral disks. RESULTS: Different shapes of WASSR-Z-spectra were obtained by changing B1 and PD including spectra with one (1-Peak) or two (2-Peak) minima. WASSR1 resulted in 1-Peak WASSR-spectrum, whereas WASSR2 resulted in 2-Peak WASSR spectrum. Both Monte-Carlo simulations and in-vivo MR examinations revealed highest accuracy of field-inhomogeneity correction with WASSR1 combined with PMSCF or BFit. CONCLUSION: Using a WASSR sequence, which results in a Z-spectrum with a single absorption peak, in combination with advanced postprocessing algorithms enables improved B0-field inhomogeneity correction for CEST imaging. PMID- 26988697 TI - Microvascular Dysfunction and Cognitive Impairment. AB - The impact of vascular risk factors on cognitive function has garnered much interest in recent years. The appropriate distribution of oxygen, glucose, and other nutrients by the cerebral vasculature is critical for proper cognitive performance. The cerebral microvasculature is a key site of vascular resistance and a preferential target for small vessel disease. While deleterious effects of vascular risk factors on microvascular function are known, the contribution of this dysfunction to cognitive deficits is less clear. In this review, we summarize current evidence for microvascular dysfunction in brain. We highlight effects of select vascular risk factors (hypertension, diabetes, and hyperhomocysteinemia) on the pial and parenchymal circulation. Lastly, we discuss potential links between microvascular disease and cognitive function, highlighting current gaps in our understanding. PMID- 26988707 TI - Perceived needs for support among care home staff providing end of life care for people with dementia: a qualitative study. AB - OBJECTIVE: The aim of the current exploratory study was to investigate the impact on care home staff when working with people with dementia at the end of life and to explore how they cope with this aspect of their work. With UK policy encouraging death in the place of residence, rather than hospital, more people with dementia are dying in care homes. METHOD: A qualitative approach was employed; 20 care home staff working in five English care homes were interviewed. Thematic Analysis was used to analyse the data. RESULTS: Care home staff found the external demands on them and difficulties associated with interacting with people with dementia sometimes challenging, stressful and anxiety-provoking, particularly as residents approached end of life. Emotional aspects of caring for dying residents were sometimes heightened by close attachments with residents and their families. Staff were able to recognise these unmet needs and identified a need for further training and emotional support to manage these stressors. CONCLUSIONS: This study revealed rich and complex understandings of the practice dimensions of caring for people with dementia at the end of life and the impact these have on staff. There is a need to develop effective psychosocial interventions that focus on emotional support for care home staff. There will be challenges in providing this in employment settings that are generally low paid, low status, have high turnover and are reliant on temporary or migrant staff, where training is not rewarded, mandatory or culturally valued. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26988706 TI - A roadmap of constitutive NF-kappaB activity in Hodgkin lymphoma: Dominant roles of p50 and p52 revealed by genome-wide analyses. AB - BACKGROUND: NF-kappaB is widely involved in lymphoid malignancies; however, the functional roles and specific transcriptomes of NF-kappaB dimers with distinct subunit compositions have been unclear. METHODS: Using combined ChIP-sequencing and microarray analyses, we determined the cistromes and target gene signatures of canonical and non-canonical NF-kappaB species in Hodgkin lymphoma (HL) cells. RESULTS: We found that the various NF-kappaB subunits are recruited to regions with redundant kappaB motifs in a large number of genes. Yet canonical and non canonical NF-kappaB dimers up- and downregulate gene sets that are both distinct and overlapping, and are associated with diverse biological functions. p50 and p52 are formed through NIK-dependent p105 and p100 precursor processing in HL cells and are the predominant DNA binding subunits. Logistic regression analyses of combinations of the p50, p52, RelA, and RelB subunits in binding regions that have been assigned to genes they regulate reveal a cross-contribution of p52 and p50 to canonical and non-canonical transcriptomes. These analyses also indicate that the subunit occupancy pattern of NF-kappaB binding regions and their distance from the genes they regulate are determinants of gene activation versus repression. The pathway-specific signatures of activated and repressed genes distinguish HL from other NF-kappaB-associated lymphoid malignancies and inversely correlate with gene expression patterns in normal germinal center B cells, which are presumed to be the precursors of HL cells. CONCLUSIONS: We provide insights that are relevant for lymphomas with constitutive NF-kappaB activation and generally for the decoding of the mechanisms of differential gene regulation through canonical and non-canonical NF-kappaB signaling. PMID- 26988709 TI - Older coronary thrombus is an independent predictor of 1-year mortality in acute myocardial infarction. AB - BACKGROUND: We have previously shown that older thrombus is associated with a twofold higher long-term mortality in ST-segment elevation myocardial infarction (STEMI) patients after primary percutaneous coronary intervention (pPCI). We evaluated whether the addition of the presence of older thrombus to a multimarker model would result in increased predictive power for 1-year mortality in STEMI patients. METHODS: The study population (n = 1442) consists of STEMI patients treated with thrombus aspiration during pPCI. Patients were included if aspirated thrombus material could histopathologically be classified according to thrombus age (n = 870) and laboratory measurements of biomarkers (cardiac troponin T, glucose, N-terminal pro-brain natriuretic peptide, estimated glomerular filtration rate and C-reactive protein) were available. The additional prognostic value of the presence of older thrombus beyond multiple biomarkers and established clinical risk factors was evaluated using multivariate Cox regression models. RESULTS: Serum biomarker concentrations were similar between patients with fresh and older thrombus. Sixty patients (7%) died within 1 year. The presence of older thrombus remained strongly associated with mortality at 1 year after multivariable adjustment for multiple biomarkers and established clinical risk factors. Addition of older thrombus to either a model including clinical risk factors and biomarkers or a model including solely biomarkers resulted in significant increases in the discriminative value, evidenced by net reclassification improvement and integrated discriminative improvement. CONCLUSIONS: The presence of older thrombus provides independent complementary information to a multimarker model including established clinical risk factors and multiple biomarkers for predicting 1-year mortality in STEMI patients treated with pPCI and thrombus aspiration. PMID- 26988708 TI - The transcription factor scleraxis is a critical regulator of cardiac fibroblast phenotype. AB - BACKGROUND: Resident fibroblasts synthesize the cardiac extracellular matrix, and can undergo phenotype conversion to myofibroblasts to augment matrix production, impairing function and contributing to organ failure. A significant gap in our understanding of the transcriptional regulation of these processes exists. Given the key role of this phenotype conversion in fibrotic disease, the identification of such novel transcriptional regulators may yield new targets for therapies for fibrosis. RESULTS: Using explanted primary cardiac fibroblasts in gain- and loss of-function studies, we found that scleraxis critically controls cardiac fibroblast/myofibroblast phenotype by direct transcriptional regulation of myriad genes that effectively define these cells, including extracellular matrix components and alpha-smooth muscle actin. Scleraxis furthermore potentiated the TGFbeta/Smad3 signaling pathway, a key regulator of myofibroblast conversion, by facilitating transcription complex formation. While scleraxis promoted fibroblast to myofibroblast conversion, loss of scleraxis attenuated myofibroblast function and gene expression. These results were confirmed in scleraxis knockout mice, which were cardiac matrix-deficient and lost ~50% of their complement of cardiac fibroblasts, with evidence of impaired epithelial-to-mesenchymal transition (EMT). Scleraxis directly transactivated several EMT marker genes, and was sufficient to induce mesenchymal/fibroblast phenotype conversion of A549 epithelial cells. Conversely, loss of scleraxis attenuated TGFbeta-induced EMT marker expression. CONCLUSIONS: Our results demonstrate that scleraxis is a novel and potent regulator of cellular progression along the continuum culminating in the cardiac myofibroblast phenotype. Scleraxis was both sufficient to drive conversion, and required for full conversion to occur. Scleraxis fulfills this role by direct transcriptional regulation of key target genes, and by facilitating TGFbeta/Smad signaling. Given the key role of fibroblast to myofibroblast conversion in fibrotic diseases in the heart and other tissue types, scleraxis may be an important target for therapeutic development. PMID- 26988710 TI - Modified ground-truthing: an accurate and cost-effective food environment validation method for town and rural areas. AB - BACKGROUND: A major concern in food environment research is the lack of accuracy in commercial business listings of food stores, which are convenient and commonly used. Accuracy concerns may be particularly pronounced in rural areas. Ground truthing or on-site verification has been deemed the necessary standard to validate business listings, but researchers perceive this process to be costly and time-consuming. This study calculated the accuracy and cost of ground truthing three town/rural areas in Minnesota, USA (an area of 564 miles, or 908 km), and simulated a modified validation process to increase efficiency without comprising accuracy. For traditional ground-truthing, all streets in the study area were driven, while the route and geographic coordinates of food stores were recorded. RESULTS: The process required 1510 miles (2430 km) of driving and 114 staff hours. The ground-truthed list of stores was compared with commercial business listings, which had an average positive predictive value (PPV) of 0.57 and sensitivity of 0.62 across the three sites. Using observations from the field, a modified process was proposed in which only the streets located within central commercial clusters (the 1/8 mile or 200 m buffer around any cluster of 2 stores) would be validated. Modified ground-truthing would have yielded an estimated PPV of 1.00 and sensitivity of 0.95, and would have resulted in a reduction in approximately 88 % of the mileage costs. CONCLUSIONS: We conclude that ground-truthing is necessary in town/rural settings. The modified ground truthing process, with excellent accuracy at a fraction of the costs, suggests a new standard and warrants further evaluation. PMID- 26988712 TI - Joining, Leaving, and Staying in the American Indian/Alaska Native Race Category Between 2000 and 2010. AB - Conceptualizing and operationalizing American Indian populations is challenging. Each census for decades has seen the American Indian population increase substantially more than expected, with indirect and qualitative evidence that this is due to changes in individuals' race responses. We apply uniquely suited (but not nationally representative) linked data from the 2000 and 2010 decennial censuses (N = 3.1 million) and the 2006-2010 American Community Survey (N = 188,131) to address three research questions. First, to what extent do American Indian people have different race responses across data sources? We find considerable race response change, especially among multiple-race and/or Hispanic American Indians. Second, how are people who change responses different from or similar to those who do not? We find three sets of American Indians: those who (1) had the same race and Hispanic responses in 2000 and 2010, (2) moved between single-race and multiple-race American Indian responses, and (3) added or dropped the American Indian response, thus joining or leaving the enumerated American Indian population. People in groups (1) and (2) were relatively likely to report a tribe, live in an American Indian area, report American Indian ancestry, and live in the West. Third, how are people who join a group different from or similar to those who leave it? Multivariate models show general similarity between joiners and leavers in group (1) and in group (2). Population turnover is hidden in cross-sectional comparisons; people joining each subpopulation of American Indians are similar in number and characteristics to those who leave it. PMID- 26988711 TI - Comparative assessment on the prevalence of mutations in the Plasmodium falciparum drug-resistant genes in two different ecotypes of Odisha state, India. AB - Considering malaria as a local and focal disease, epidemiological understanding of different ecotypes of malaria can help in devising novel control measures. One of the major hurdles in malaria control lies on the evolution and dispersal of the drug-resistant malaria parasite, Plasmodium falciparum. We herewith present data on genetic variation at the Single Nucleotide Polymorphism (SNP) level in four different genes of P. falciparum (Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps) that confer resistance to different antimalarials in two different eco-epidemiological settings, i.e. Hilly-Forest (HF) and Riverine-Plain (RP), in a high malaria endemic district of Odisha state, India. Greater frequency of antimalarial resistance conferring SNPs and haplotypes was observed in all four genes in P. falciparum, and Pfdhps was the most variable gene among the four. No significant genetic differentiation could be observed in isolates from HF and RP ecotypes. Twelve novel, hitherto unreported nucleotide mutations could be observed in the Pfmdr1 and Pfdhps genes. While the Pfdhps gene presented highest haplotype diversity, the Pfcrt gene displayed the highest nucleotide diversity. When the data on all the four genes were complied, the isolates from HF ecotype were found to harbour higher average nucleotide diversity than those coming from RP ecotype. High and positive Tajima's D values were obtained for the Pfcrt and Pfdhfr genes in isolates from both the HF and RP ecotypes, with statistically significant deviation from neutrality in the RP ecotype. Different patterns of Linkage Disequilibrium (LD) among SNPs located in different drug-resistant genes were found in the isolates collected from HF and RP ecotypes. Whereas in the HF ecotype, SNPs in the Pfmdr1 and Pfdhfr were significantly associated, in the RP ecotype, SNPs located in Pfcrt were associated with Pfmdr1, Pfdhfr and Pfdhps. These findings provide a baseline understanding on how different micro eco epidemiological settings influence evolution and spread of different drug resistance alleles. Our findings further suggest that drug resistance to chloroquine and sulfadoxine-pyrimethamine is approaching fixation level, which requires urgent attention of malaria control programme in India. PMID- 26988713 TI - Using an organic radical precursor as an electron injection material for efficient and stable organic light-emitting diodes. AB - Materials with strong reducibility have been used as electron injection layers (EILs) to lower the work function of cathodes and reduce the driving voltage of organic light-emitting diodes (OLEDs). However, the most prominent electron injection materials presented so far are high-temperature-evaporable inorganic salts based on alkaline metals, which suffer from a high tendency of metal diffusion throughout the organic layer and thus reduce the device efficiency and stability. Here, we introduce a new kind of EIL based on a stable precursor of a strongly reducing organic radical. By using an organic precursor, we are able to take the advantage of the low-evaporation-temperature and avoid the problem of metal diffusion, thus improving the device efficiency and stability. Ultraviolet photoelectron spectroscopy (UPS) study indicates that inserting a thin layer of organic radical between the electron transport layer and cathode could greatly reduce the electron injection barrier due to the strong interaction of radical with cathode and the electron transporting material. As a result, OLEDs with an organic radical as the EIL showed a 25.2% higher efficiency and 2.2 times longer lifetime than the control device with conventional LiF as the EIL. PMID- 26988715 TI - A scary chest X-ray. PMID- 26988714 TI - Natural antigenic differences in the functionally equivalent extracellular DNABII proteins of bacterial biofilms provide a means for targeted biofilm therapeutics. AB - Bacteria that persist in the oral cavity exist within complex biofilm communities. A hallmark of biofilms is the presence of an extracellular polymeric substance (EPS), which consists of polysaccharides, extracellular DNA (eDNA), and proteins, including the DNABII family of proteins. The removal of DNABII proteins from a biofilm results in the loss of structural integrity of the eDNA and the collapse of the biofilm structure. We examined the role of DNABII proteins in the biofilm structure of the periodontal pathogen Porphyromonas gingivalis and the oral commensal Streptococcus gordonii. Co-aggregation with oral streptococci is thought to facilitate the establishment of P. gingivalis within the biofilm community. We demonstrate that DNABII proteins are present in the EPS of both S. gordonii and P. gingivalis biofilms, and that these biofilms can be disrupted through the addition of antisera derived against their respective DNABII proteins. We provide evidence that both eDNA and DNABII proteins are limiting in S. gordonii but not in P. gingivalis biofilms. In addition, these proteins are capable of complementing one another functionally. We also found that whereas antisera derived against most DNABII proteins are capable of binding a wide variety of DNABII proteins, the P. gingivalis DNABII proteins are antigenically distinct. The presence of DNABII proteins in the EPS of these biofilms and the antigenic uniqueness of the P. gingivalis proteins provide an opportunity to develop therapies that are targeted to remove P. gingivalis and biofilms that contain P. gingivalis from the oral cavity. PMID- 26988716 TI - How the routine reporting of laboratory measurement uncertainty might affect clinical decision making in acute and emergency medicine. PMID- 26988717 TI - Diagnostic and prognostic value of factor VIII binding antibodies in acquired hemophilia A: data from the GTH-AH 01/2010 study. AB - Essentials Factor VIII (FVIII) binding IgG detected by ELISA could be an alternative to the Bethesda assay. We studied the performance of anti-FVIII IgG ELISA in patients with acquired hemophilia and controls. Anti-FVIII IgG > 99th percentile of controls was highly sensitive and specific. Patients with high anti FVIII IgG have a lower chance of achieving remission. SUMMARY: Background Acquired hemophilia A is a severe bleeding disorder that requires fast and accurate diagnosis as it occurs often unexpectedly in previously healthy men and women of every age. The Nijmegen-modified Bethesda assay is the diagnostic reference standard for detecting neutralizing autoantibodies against factor VIII (FVIII), but is not widely available, not ideal for quantifying the complex type 2 inhibitors seen in acquired hemophilia, and suffers from high inter-laboratory variability. Objectives To assess the diagnostic and prognostic value of FVIII binding antibodies as detected by ELISA compared with the Nijmegen Bethesda assay. Methods Samples from the time of first diagnosis and clinical data were available from 102 patients with acquired hemophilia enrolled in the prospective GTH-AH 01/2010 study. Controls (n = 102) were matched for gender and age. Diagnostic cut-offs were determined by receiver-operator curve analysis. The prognostic value was assessed in 92 of the 102 patients by Cox regression analysis of time to partial remission. Results Anti-FVIII IgG above the 99th percentile (> 15 arbitrary units per mL) revealed high sensitivity and specificity (both 0.99; 95% confidence interval, 0.95-1.0) for diagnosing acquired hemophilia. The likelihood of achieving partial remission was related to anti-FVIII IgG concentration (< 300 arbitrary units, 1.0; 300-1050, 0.65; > 1050, 0.39). The Bethesda titer was only associated with the likelihood of partial remission when analyzed in the central laboratory, but not when data from local GTH study sites were used. Conclusion Although the Nijmegen-modified Bethesda assay is the reference standard for demonstrating neutralizing antibodies, the detection of FVIII-binding antibodies by ELISA is similarly sensitive and specific for diagnosing acquired hemophilia. In addition, anti-FVIII IgG may provide prognostic information. PMID- 26988719 TI - Hypertonic saline in severe traumatic brain injury: a systematic review and meta analysis of randomized controlled trials. AB - OBJECTIVES: Hypertonic saline solutions are increasingly used to treat increased intracranial pressure following severe traumatic brain injury. However, whether hypertonic saline provides superior management of intracranial pressure and improves outcome is unclear. We thus conducted a systematic review to evaluate the effect of hypertonic saline in patients with severe traumatic brain injury. METHODS: Two researchers independently selected randomized controlled trials studying hypertonic saline in severe traumatic brain injury and collected data using a standardized abstraction form. No language restriction was applied. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and BIOSIS databases. We searched grey literature via OpenGrey and National Technical Information Service databases. We searched the references of included studies and relevant reviews for additional studies. RESULTS: Eleven studies (1,820 patients) were included. Hypertonic saline did not decrease mortality (risk ratio 0.96, 95% confidence interval [CI] 0.83 to 1.11, I2=0%) or improve intracranial pressure control (weighted mean difference -1.25 mm Hg, 95% CI -4.18 to 1.68, I2=78%) as compared to any other solutions. Only one study reported monitoring for adverse events with hypertonic saline, finding no significant differences between comparison groups. CONCLUSIONS: We observed no mortality benefit or effect on the control of intracranial pressure with the use of hypertonic saline when compared to other solutions. Based on the current level of evidence pertaining to mortality or control of intracranial pressure, hypertonic saline could thus not be recommended as a first-line agent for managing patients with severe traumatic brain injury. PMID- 26988718 TI - Mapping nano-scale mechanical heterogeneity of primary plant cell walls. AB - Nanoindentation experiments are performed using an atomic force microscope (AFM) to quantify the spatial distribution of mechanical properties of plant cell walls at nanometre length scales. At any specific location on the cell wall, a complex (non-linear) force-indentation response occurs that can be deconvoluted using a unique multiregime analysis (MRA). This allows an unambiguous evaluation of the local transverse elastic modulus of the wall. Nanomechanical measurements on suspension-cultured cells (SCCs), derived from Italian ryegrass (Lolium multiflorum) starchy endosperm, show three characteristic modes of deformation and a spatial distribution of elastic moduli across the surface. 'Soft' and 'hard' domains are found across length scales between 0.1 um and 3 um, which is well above a typical pore size of the polysaccharide mesh. The generality and wider applicability of this mechanical heterogeneity is verified through in planta characterization on leaf epidermal cells of Arabidopsis thaliana and L. multiflorum The outcomes of this research provide a basis for uncovering and quantifying the relationships between local wall composition, architecture, cell growth, and/or morphogenesis. PMID- 26988720 TI - Paramedics assessing Elders at Risk for Independence Loss (PERIL): Derivation, Reliability and Comparative Effectiveness of a Clinical Prediction Rule. AB - OBJECTIVES: We conducted a program of research to derive and test the reliability of a clinical prediction rule to identify high-risk older adults using paramedics' observations. METHODS: We developed the Paramedics assessing Elders at Risk of Independence Loss (PERIL) checklist of 43 yes or no questions, including the Identifying Seniors at Risk (ISAR) tool items. We trained 1,185 paramedics from three Ontario services to use this checklist, and assessed inter observer reliability in a convenience sample. The primary outcome, return to the ED, hospitalization, or death within one month was assessed using provincial databases. We derived a prediction rule using multivariable logistic regression. RESULTS: We enrolled 1,065 subjects, of which 764 (71.7%) had complete data. Inter-observer reliability was good or excellent for 40/43 questions. We derived a four-item rule: 1) "Problems in the home contributing to adverse outcomes?" (OR 1.43); 2) "Called 911 in the last 30 days?" (OR 1.72); 3) male (OR 1.38) and 4) lacks social support (OR 1.4). The PERIL rule performed better than a proxy measure of clinical judgment (AUC 0.62 vs. 0.56, p=0.02) and adherence was better for PERIL than for ISAR. CONCLUSIONS: The four-item PERIL rule has good inter observer reliability and adherence, and had advantages compared to a proxy measure of clinical judgment. The ISAR is an acceptable alternative, but adherence may be lower. If future research validates the PERIL rule, it could be used by emergency physicians and paramedic services to target preventative interventions for seniors identified as high-risk. PMID- 26988721 TI - Health Care in Canada--Where? When? For Whom? PMID- 26988722 TI - ABO blood group system and the coronary artery disease: an updated systematic review and meta-analysis. AB - ABO blood group system, a well-known genetic risk factor, has clinically been demonstrated to be linked with thrombotic vascular diseases. However, the relationship between ABO blood group and coronary artery disease (CAD) is still controversial. We here performed an updated meta-analysis of the related studies and tried to elucidate the potential role of ABO blood group as a risk factor for CAD. All detectable case-control and cohort studies comparing the risk of CAD in different ABO blood groups were collected for this analysis through searching PubMed, Embase, and the Cochrane Library. Ultimately, 17 studies covering 225,810 participants were included. The combined results showed that the risk of CAD was significantly higher in blood group A (OR = 1.14, 95% CI = 1.03 to 1.26, p = 0.01) and lower in blood group O (OR = 0.85, 95% CI = 0.78 to 0.94, p = 0.0008). Even when studies merely about myocardial infarction (MI) were removed, the risk of CAD was still significantly higher in blood group A (OR = 1.05, 95% CI = 1.00 to 1.10, p = 0.03) and lower in blood group O (OR = 0.89, 95% CI = 0.85 to 0.93, p < 0.00001). This updated systematic review and meta-analysis indicated that both blood group A and non-O were the risk factors of CAD. PMID- 26988723 TI - (1)H, (13)C and (15)N resonance assignments of the Cdc42-binding domain of TOCA1. AB - TOCA1 is a downstream effector protein of the small GTPase, Cdc42. It is a multi domain protein that includes a membrane binding F-BAR domain, a homology region 1 (HR1) domain, which binds selectively to active Cdc42 and an SH3 domain. TOCA1 is involved in the regulation of actin dynamics in processes such as endocytosis, filopodia formation, neurite elongation, cell motility and invasion. Structural insight into the interaction between TOCA1 and Cdc42 will contribute to our understanding of the role of TOCA1 in actin dynamics. The (1)H, (15)N and (13)C NMR backbone and sidechain resonance assignment of the HR1 domain (12 kDa) presented here provides the foundation for structural studies of the domain and its interactions. PMID- 26988724 TI - Immobilization of Bacillus subtilis lipase on a Cu-BTC based hierarchically porous metal-organic framework material: a biocatalyst for esterification. AB - Bacillus subtilis lipase (BSL2) has been successfully immobilized into a Cu-BTC based hierarchically porous metal-organic framework material for the first time. The Cu-BTC hierarchically porous MOF material with large mesopore apertures is prepared conveniently by using a template-free strategy under mild conditions. The immobilized BSL2 presents high enzymatic activity and perfect reusability during the esterification reaction. After 10 cycles, the immobilized BSL2 still exhibits 90.7% of its initial enzymatic activity and 99.6% of its initial conversion. PMID- 26988725 TI - Heartbeat, embryo communication and hatching synchrony in snake eggs. AB - Communication is central to life at all levels of complexity, from cells to organs, through to organisms and communities. Turtle eggs were recently shown to communicate with each other in order to synchronise their development and generate beneficial hatching synchrony. Yet the mechanism underlying embryo to embryo communication remains unknown. Here we show that within a clutch, developing snake embryos use heart beats emanating from neighbouring eggs as a clue for their metabolic level, in order to synchronise development and ultimately hatching. Eggs of the water snake Natrix maura increased heart rates and hatched earlier than control eggs in response to being incubated in physical contact with more advanced eggs. The former produced shorter and slower swimming young than their control siblings. Our results suggest potential fitness consequences of embryo to embryo communication and describe a novel driver for the evolution of egg-clustering behaviour in animals. PMID- 26988726 TI - The cultural politics of mining and natural disaster in Indonesia: by fire and sword. AB - Natural disasters are inevitably the outcome of cultural agonisms. The cultural politics of natural disasters are shaped by competing claims and conceptions of 'nature'. Recent disasters in Indonesia are directly linked to these contending conceptions and the ways in which different social groups imagine risk and reward. The Sidoarjo volcanic mudflow of 2006 represents a volatile and violent exemplar of contending cultural and economic claims. Like other disasters in Indonesia and elsewhere in the developing world, this 'natural' disaster is characterised by differing conceptions of 'nature' as cultural tradition, divine force, and natural resource. A new extractive project in East Java is exhibiting similar economic and cultural agonisms, particularly around the notion of development, environment, self-determination, and tradition. This paper examines the 'disputes over meaning' associated with natural disasters in contemporary societies, and the ways in which they are related to human culture, social organisation, and hierarchical systems of violence. PMID- 26988727 TI - Benzoylsalicylic acid isolated from seed coats of Givotia rottleriformis induces systemic acquired resistance in tobacco and Arabidopsis. AB - Systemic acquired resistance (SAR), a whole plant defense response to a broad spectrum of pathogens, is characterized by a coordinated expression of a large number of defense genes. Plants synthesize a variety of secondary metabolites to protect themselves from the invading microbial pathogens. Several studies have shown that salicylic acid (SA) is a key endogenous component of local and systemic disease resistance in plants. Although SA is a critical signal for SAR, accumulation of endogenous SA levels alone is insufficient to establish SAR. Here, we have identified a new acyl derivative of SA, the benzoylsalicylic acid (BzSA) also known as 2-(benzoyloxy) benzoic acid from the seed coats of Givotia rottleriformis and investigated its role in inducing SAR in tobacco and Arabidopsis. Interestingly, exogenous BzSA treatment induced the expression of NPR1 (Non-expressor of pathogenesis-related gene-1) and pathogenesis related (PR) genes. BzSA enhanced the expression of hypersensitivity related (HSR), mitogen activated protein kinase (MAPK) and WRKY genes in tobacco. Moreover, Arabidopsis NahG plants that were treated with BzSA showed enhanced resistance to tobacco mosaic virus (TMV) as evidenced by reduced leaf necrosis and TMV-coat protein levels in systemic leaves. We, therefore, conclude that BzSA, hitherto unknown natural plant product, is a new SAR inducer in plants. PMID- 26988728 TI - Acetophenone derivatives from a freshwater fungal isolate of recently described Lindgomyces madisonensis (G416). AB - The exploration of freshwater ascomycetes, which have undergone only limited investigation, may provide opportunities both to characterize new genera/species of fungi and to uncover new chemical diversity. In this study, seven acetophenone derivatives, madisone, 4'-methoxymadisone, dehydromadisone, 2"-methoxymadisone, dihydroallovisnaginone, dimadisone, and 4'-methoxydimadisone were characterized from an organic extract of a recently described Lindgomyces madisonensis (G416) culture, which was isolated from submerged wood collected in a stream in North Carolina. Madisone, dehydromadisone, 2"-methoxymadisone, dimadisone and 4' demethoxydimadisone have not been reported previously, while 4'-methoxymadisone and dihydroallovisnaginone were previously unknown as natural products. Their structures were assigned on the basis of NMR and HRESIMS data, with the structure of madisone supported by X-ray crystallography. The antimicrobial activities of madisone, 4'-methoxymadisone and dihydroallovisnaginone were evaluated against a panel of bacteria and fungi. A heat map analysis of the surface of a G416 culture showed that most of the isolated compounds concentrated in the guttate compared with the vegetative mycelium of the fungus. PMID- 26988729 TI - Polyoxypregnane steroids with an open-chain sugar moiety from Marsdenia tenacissima and their chemoresistance reversal activity. AB - A polyoxypregnane aglycone, 12beta-O-acetyl-11alpha-O-isobutyryltenacigenin B, and four polyoxypregnane glycosides with a pachybionic acid ester moiety, 12beta O-acetyl-3-O-(6-deoxy-3-O-methyl-beta-D-allopyranosyl-(1->4)-beta-D-oleandronyl) 11alpha-O-isobutyryltenacigenin B, 12beta-O-acetyl-3-O-(6-deoxy-3-O-methyl-beta-D allopyranosyl-(1->4)-beta-D-oleandronyl)-11alpha-O-tigloyltenacigenin B, 12beta-O acetyl-3-O-(6-deoxy-3-O-methyl-beta-D-allopyranosyl-(1->4)-beta-D-oleandronyl) 11alpha-O-2-methylbutyryltenacigenin B, and 12beta-O-acetyl-3-O-(beta-D glucopyranosyl-(1->4)-6-deoxy-3-O-methyl-beta-D-allopyranosyl-(1->4)-D oleandronyl)-11alpha-O-tigloyltenacigenin B, were isolated from the canes of Marsdenia tenacissima, together with a disaccharide derivative. Their structures were elucidated by extensive spectroscopic analysis, and the absolute configurations were further determined by X-ray crystallographic analysis. With the exception of the disaccharide derivative, all five compounds are unusual naturally occurring polyoxypregnane glycosides bearing an open-chain sugar moiety. Two of these exhibit a wide spectrum of chemoresistance reversal activity, and potential mechanisms were studied accordingly. PMID- 26988730 TI - Functional characterisation of a tropine-forming reductase gene from Brugmansia arborea, a woody plant species producing tropane alkaloids. AB - Brugmansia arborea is a woody plant species that produces tropane alkaloids (TAs). The gene encoding tropine-forming reductase or tropinone reductase I (BaTRI) in this plant species was functionally characterised. The full-length cDNA of BaTRI encoded a 272-amino-acid polypeptide that was highly similar to tropinone reductase I from TAs-producing herbal plant species. The purified 29kDa recombinant BaTRI exhibited maximum reduction activity at pH 6.8-8.0 when tropinone was used as substrate; it also exhibited maximum oxidation activity at pH 9.6 when tropine was used as substrate. The Km, Vmax and Kcat values of BaTRI for tropinone were 2.65mM, 88.3nkatmg(-1) and 2.93S(-1), respectively, at pH 6.4; the Km, Vmax and Kcat values of TRI from Datura stramonium (DsTRI) for tropinone were respectively 4.18mM, 81.20nkatmg(-1) and 2.40S(-1) at pH 6.4. At pH 6.4, 6.8 and 7.0, BaTRI had a significantly higher activity than DsTRI. Analogues of tropinone, 4-methylcyclohexanone and 3-quinuclidinone hydrochloride, were also used to investigate the enzymatic kinetics of BaTRI. The Km, Vmax and Kcat values of BaTRI for tropine were 0.56mM, 171.62nkat.mg(-1) and 5.69S(-1), respectively, at pH 9.6; the Km, Vmax and Kcat values of DsTRI for tropine were 0.34mM, 111.90nkatmg(-1) and 3.30S(-1), respectively, at pH 9.6. The tissue profiles of BaTRI differed from those in TAs-producing herbal plant species. BaTRI was expressed in all examined organs but was most abundant in secondary roots. Finally, tropane alkaloids, including hyoscyamine, anisodamine and scopolamine, were detected in various organs of B. arborea by HPLC. Interestingly, scopolamine constituted most of the tropane alkaloids content in B. arborea, which suggests that B. arborea is a scopolamine-rich plant species. The scopolamine content was much higher in the leaves and stems than in other organs. The gene expression and TAs accumulation suggest that the biosynthesis of hyoscyamine, especially scopolamine, occurred not only in the roots but also in the aerial parts of B. arborea. PMID- 26988731 TI - Exosomes in liver pathology. AB - Exosomes are small (~100nm) membrane-bound extracellular vesicles released by various types of cells into biological fluids. They contain proteins, mRNAs and miRNAs as cargo. Different cell types can take up exosomes by endocytosis and the cargo contained within them can be transferred horizontally to these recipient cells. Exosomal proteins and miRNAs can be functional and regulate physiological cell events modifying the microenvironment in target cells, a key event of liver pathology. Exosome-mediated cell-cell communication can alter tumor growth, cell migration, antiviral infection and hepatocyte regeneration, indicating that exosomes have great potential for development as diagnostic or therapeutic tools. Analyses of circulating total or exosomal miRNAs have identified a large number of candidate miRNAs that are regulated in liver diseases, and the diagnostic testing using single or multiple miRNAs shows good sensitivity and specificity. Some candidate miRNAs have been identified to play an important role in various liver disorders. This review summarizes recent findings on the role of extracellular vesicles in liver diseases and their diagnostic and therapeutic potential, mainly focusing on exosomes but also includes microvesicles in liver pathology. PMID- 26988732 TI - Neutrophil gelatinase-associated lipocalin is a biomarker of acute-on-chronic liver failure and prognosis in cirrhosis. AB - BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a syndrome that occurs in cirrhosis characterized by organ failure(s) and high mortality rate. There are no biomarkers of ACLF. The LCN2 gene and its product, neutrophil gelatinase-associated lipocalin (NGAL), are upregulated in experimental models of liver injury and cultured hepatocytes as a result of injury by toxins or proinflammatory cytokines, particularly Interleukin-6. The aim of this study was to investigate whether NGAL could be a biomarker of ACLF and whether LCN2 gene may be upregulated in the liver in ACLF. METHODS: We analyzed urine and plasma NGAL levels in 716 patients hospitalized for complications of cirrhosis, 148 with ACLF. LCN2 expression was assessed in liver biopsies from 29 additional patients with decompensated cirrhosis with and without ACLF. RESULTS: Urine NGAL was markedly increased in ACLF vs. no ACLF patients (108(35-400) vs. 29(12-73)MUg/g creatinine; p<0.001) and was an independent predictive factor of ACLF; the independent association persisted after adjustment for kidney function or exclusion of variables present in ACLF definition. Urine NGAL was also an independent predictive factor of 28day transplant-free mortality together with MELD score and leukocyte count (AUROC 0.88(0.83-0.92)). Urine NGAL improved significantly the accuracy of MELD in predicting prognosis. The LCN2 gene was markedly upregulated in the liver of patients with ACLF. Gene expression correlated directly with serum bilirubin and INR (r=0.79; p<0.001 and r=0.67; p<0.001), MELD (r=0.68; p<0.001) and Interleukin-6 (r=0.65; p<0.001). CONCLUSIONS: NGAL is a biomarker of ACLF and prognosis and correlates with liver failure and systemic inflammation. There is remarkable overexpression of LCN2 gene in the liver in ACLF syndrome. LAY SUMMARY: Urine NGAL is a biomarker of acute-on-chronic liver failure (ACLF). NGAL is a protein that may be expressed in several tissues in response to injury. The protein is filtered by the kidneys due to its small size and can be measured in the urine. Ariza, Graupera and colleagues found in a series of 716 patients with cirrhosis that urine NGAL was markedly increased in patients with ACLF and correlated with prognosis. Moreover, gene coding NGAL was markedly overexpressed in the liver tissue in ACLF. PMID- 26988733 TI - NMR Observation of Mobile Protons in Proton-Implanted ZnO Nanorods. AB - The diffusion properties of H(+) in ZnO nanorods are investigated before and after 20 MeV proton beam irradiation by using (1)H nuclear magnetic resonance (NMR) spectroscopy. Herein, we unambiguously observe that the implanted protons occupy thermally unstable site of ZnO, giving rise to a narrow NMR line at 4.1 ppm. The activation barrier of the implanted protons was found to be 0.46 eV by means of the rotating-frame spin-lattice relaxation measurements, apparently being interstitial hydrogens. High-energy beam irradiation also leads to correlated jump diffusion of the surface hydroxyl group of multiple lines at ~1 ppm, implying the presence of structural disorder at the ZnO surface. PMID- 26988734 TI - Ferulone A and ferulone B: two new coumarin esters from Ferula orientalis L. roots. AB - Ferula orientalis (Apiaceae) is a well-known perennial herb growing wild in Iran used in traditional medicine. To perform phytochemical studies, dried ground roots of F. orientalis were sequentially Soxhlet-extracted using n-hexane, dichloromethane and methanol. A combination of vacuum liquid chromatography and preparative thin-layer chromatographic analyses were performed to isolate coumarin esters. The structures of the isolated compounds were elucidated by spectroscopic means, and in vitro free-radical-scavenging property was determined by the DPPH assay. Two new coumarin esters, 7-O-(4,8,12,16-tetrahydroxy-4,8,12,16 tetramethyl-heptadecanoyl)-coumarinand 7-O-(4-hydroxy-4,8,12-trimethyl-trideca 7,11-dienoyl)-coumarin, named ferulone A and ferulone B, respectively, were isolated from the n-hexane extract of the roots of F. orientalis. Both compounds showed a low level of free-radical-scavenging property with the RC50 values of 0.252 and 0.556 mg/mL for compounds 1 and 2, respectively, as opposed to that of the positive control (quercetin) 0.004 mg/mL. This is the first report on the purification of coumarin esters from the genus Ferula. PMID- 26988735 TI - Fatty Acid Patterns of Seeds of Some Salvia Species from Iran--A Chemotaxonomic Approach. AB - In this study, the seed oil content and fatty acid (FA) profile of 21 populations from 16 wild Salvia species of Iran were analyzed by GC. Patterns of chemical variations of the oils among species were identified via numerical analyses and also the taxonomic status of the infrageneric grouping was outlined in the genus. Salvia species were scored based on the contents of main FAs using principal coordinate analysis (PCO). The results showed that the total oil content in the seeds varied significantly, and ranged from 6.68 to 38.53% dry weight. alpha Linolenic (18:3omega3, 1.69 - 53.56%), linoleic (18:2omega6, 13.04 - 60.64%), oleic (18:1omega9, 6.15 - 27.06%), palmitic (16:0, 3.77 - 9.27%), and stearic (18:0, 1.78 - 3.05%) acid were identified as five major FAs in the oils. The amount of omega-3 and omega-6 FAs ranged between 1.90 - 53.80% and 13.46 - 60.83% of total FAs in the seed oils, respectively. The results confirmed that FA profiles were distinctive among the species and that they can be used as chemotaxonomic markers. The discrimination of Salvia species according to their botanical classification at intersectional level was supported. In general, seed oils of Salvia species were rich sources of polyunsaturated FAs, except in linoleic and alpha-linolenic acid, and may be valuable for food and pharmaceutical industries. PMID- 26988736 TI - Analysis of the intersexual variation in Thalassophryne maculosa fish venoms. AB - Gender related variation in the molecular composition of venoms and secretions have been described for some animal species, and there are some evidences that the difference in the toxin (s) profile among males and females may be related to different physiopathological effects caused by the envenomation by either gender. In order to investigate whether this same phenomenon occurs to the toadfish Thalassophryne maculosa, we have compared some biological and biochemical properties of female and male venoms. Twenty females and males were collected in deep waters of the La Restinga lagoon (Venezuela) and, after protein concentration assessed, the induction of toxic activities in mice and the biochemical properties were analyzed. Protein content is higher in males than in females, which may be associated to a higher size and weight of the male body. In vivo studies showed that mice injected with male venoms presented higher nociception when compared to those injected with female venoms, and both venoms induced migration of macrophages into the paw of mice. On the other hand, mice injected with female venoms had more paw edema and extravasation of Evans blue in peritoneal cavity than mice injected with male venoms. We observed that the female venoms had more capacity for necrosis induction when compared with male venoms. The female samples present a higher proteolytic activity then the male venom when gelatin, casein and FRETs were used as substrates. Evaluation of the venoms of females and males by SDS-PAGE and chromatographic profile showed that, at least three components (present in two peaks) are only present in males. Although the severity of the lesion, characterized by necrosis development, is related with the poisoning by female specimens, the presence of exclusive toxins in the male venoms could be associated with the largest capacity of nociception induction by this sample. PMID- 26988737 TI - Disease activity return after natalizumab cessation in multiple sclerosis. AB - Natalizumab (NAT) was the first monoclonal antibody to be approved for the treatment of relapsing-remitting multiple sclerosis. Its considerable and sustained efficacy has been demonstrated in two phase III studies. However, there are several reasons why its use is limited in clinical practice. The main argument for stopping use of the drug is the risk of the rare but serious progressive multifocal leukencephalopathy. Other reasons are neutralizing antibodies and pregnancy. There is compelling evidence from some clinical trials and many case series that disease activity returns upon suspension or cessation of NAT. Several therapeutic strategies that have been tested to prevent or reduce the recurrence of disease activity will be reviewed in this article. Considering these data, it is evident that the decision to stop NAT treatment has different implications and consequences. A subsequent therapy after cessation of NAT is needed to reduce the risk of disease recurrence. PMID- 26988738 TI - Orbital foreign body masquerading as orbital air. PMID- 26988739 TI - Bone volume changes after immediate implant placement with or without flap elevation. AB - OBJECTIVES: The aims of this prospective study were to evaluate bone dimensions after immediate implant placement with simultaneous grafting of the buccal gap, to determine if initial buccal bone width had an influence on bone remodelling and to compare bone volume changes using a flap or a flapless approach after 6 months of healing. MATERIAL AND METHODS: This prospective study included patients who required an extraction and a subsequent immediate implant placement at a non molar site. In those cases where tooth extraction was not feasible with a flapless approach (test group) a mucoperiosteal flap was carefully elevated (control group). After extraction, a cone beam computed tomography (CBCT) was taken. Then, an implant was placed and the buccal gap was grafted using anorganic bovine bone. After 6 months of healing, a second CBCT was performed. A blinded investigator superimposed both images and performed a series of measurements to determine bone volume changes between the two time points. RESULTS: Thirty-five patients were included in this study, 20 of which belonged to the test group. All together, the differences between baseline and 6 months in buccal plate height, lingual plate height and in ridge width at 2, 4 and 6 mm were 0.48 +/- 1.35; 0.58 +/- 1.51; 0.64 +/- 0.81; 0.59 +/- 1.36 and 0.52 +/- 1.16, respectively. Only a moderate correlation was observed between initial buccal plate width and buccal plate height at 6 months (P = 0.0001). No statistically significant differences were observed between flap and flapless approach. CONCLUSIONS: A mean reduction of around 0.5 mm in height and width after placing immediate implants and filling the residual gap with anorganic bovine bone may be expected. No significant association between initial buccal bone width and ridge width at 6 months was seen. No statistically significant differences were found between the two treatment protocols although more ridge reduction was observed for the flap group. PMID- 26988740 TI - Synthesis and structural properties of thermoelectric Ca3-xAgxCo4O9+delta powders. AB - A series of Ca3-xAgxCo4O9+delta (0 <= x <= 0.2) powders is prepared by the Pechini sol-gel method. The effect of dispersants on the size and morphology of the Ca2.9Ag0.1Co4O9+delta powders is investigated. The desired powders are obtained after calcinations of the dried powders at 800 degrees C for 12 h. The structural and morphological properties are studied with the help of XRD patterns, FE-SEM images, FT-IR spectra, Raman spectra, and XPS spectra. It is found that a mixed valence (+3 and +4) of Co exists in a CdI2-type CoO2 layer, while a mixed valence (+2, +3, and +4) exists in the CoO of a rock salt-type Ca2CoO3 layer. The mixed-valence state in the CoO2 layer can improve the high temperature thermoelectric properties of Ca3Co4O9 systems. PMID- 26988741 TI - Peritransplant Serum Albumin Decline Predicts Subsequent Severe Acute Graft versus-Host Disease after Mucotoxic Myeloablative Conditioning. AB - Conditioning-related gut toxicity can result in a protein-losing enteropathy manifesting as a decline in serum albumin in the peritransplant period. Inspired by the pathogenesis of acute graft-versus-host disease (aGVHD), we hypothesized that the magnitude of decline in serum albumin from the day of conditioning initiation until its nadir in the first 2 weeks after hematopoietic cell transplantation HCT (DeltaAlb) predicts the risk for subsequent severe aGVHD. We reviewed the medical records of all 88 patients with acute myeloid leukemia or myelodysplastic syndrome who underwent highly mucotoxic myeloablative (busulfan/cyclophosphamide or cyclophosphamide/total body irradiation) allogeneic HCT from a matched related donor (MRD) or matched unrelated donor (MUD) at our institution between January 1, 2012 and January 1, 2015. Severe aGVHD was associated with MUD (47% versus 14% with MRD; P = .001) and DeltaAlb, which was significantly greater among patients who developed versus did not develop severe aGVHD (1.2 +/- .5 versus .8 +/- .4 g/dL, respectively; P < .001). In multivariate analysis DeltaAlb remained a significant predictor of severe aGVHD (odds ratio, 5.68; 95% CI, 1.65 to 19.64; P = .006; area under the ROC curve, .74; 95% CI, .63 to .86; P < .001). The best cutoff for DeltaAlb to predict severe aGVHD was .9, with a sensitivity, specificity, and overall classification accuracy of 77%, 66%, and 69%, respectively. The model was validated using the bootstrap technique, with no significant change in its performance. These results were not generalizable to a cohort of 30 patients who received less mucotoxic myeloablative or reduced-intensity conditioning. In conclusion, with mucotoxic myeloablative HCT, each .1-g/dL increase in DeltaAlb was associated with an approximately 23% increase in the odds of developing severe aGVHD. As an early biomarker of gut damage, DeltaAlb can be incorporated in composite risk models for aGVHD prediction, with hopes for ultimately allowing for individualized GVHD prophylaxis and potential intervention according to the predicted risk. PMID- 26988742 TI - Time to Insurance Approval in Private and Public Payers Does Not Influence Survival in Patients Who Undergo Hematopoietic Cell Transplantation. AB - In the United States, insurance status has been implicated as a barrier to obtaining timely treatment. In this retrospective cohort study of 521 patients who underwent first hematopoietic cell transplantation (HCT), we investigated the association between timeliness of HCT and overall survival. Timeliness was operationally defined in the following 3 ways: (1) payer approval, from request for approval to actual payer approval; (2) transplantation speed, from payer approval to time of actual HCT; and (3) total time, from request for approval to HCT. Patients with private insurance had longer time to payer approval (P < .0001) than those with public payers but shorter time from approval to actual HCT (P < .0001) and total time to HCT (P < .0001). Multivariate Cox regression showed no significant differences in risk of death between slow and fast times in the 3 indices of timeliness in the models that used all patients (n = 509), autologous HCT in lymphoma (n = 278), and autologous HCT in multiple myeloma (n = 121). Additional studies to evaluate the effect of insurance timeliness on all patients for whom HCT is recommended, not just those who undergo HCT, should be conducted. PMID- 26988743 TI - Mechanistic basis of MAGUK-organized complexes in synaptic development and signalling. AB - Membrane-associated guanylate kinases (MAGUKs) are a family of scaffold proteins that are highly enriched in synapses and are responsible for organizing the numerous protein complexes required for synaptic development and plasticity. Mutations in genes encoding MAGUKs and their interacting proteins can cause a broad spectrum of human psychiatric disorders. Here, we review MAGUK-mediated synaptic protein complex formation and regulation by focusing on findings from recent biochemical and structural investigations. These mechanistic-based studies show that the formation of MAGUK-organized complexes is often directly regulated by protein phosphorylation, suggesting a close connection between neuronal activity and the assembly of dynamic protein complexes in synapses. PMID- 26988745 TI - Aneurysm Shrinkage Is Compatible With Massive Endoleak in the Presence of an Aortocaval Fistula: Potential Therapeutic Implications for Endoleaks and Spinal Cord Ischemia. AB - PURPOSE: To present a patient with ruptured abdominal aortic aneurysm (AAA) and aortocaval fistula who was successfully treated with endovascular aneurysm repair in spite of developing a massive endoleak. CASE REPORT: A 70-year-old man with ruptured AAA and aortocaval fistula was treated with endovascular aneurysm repair (EVAR). During 8 years of follow-up, he had massive perfusion of the aneurysm sac by retrograde flow from the inferior mesenteric artery into the caval vein through the aortocaval fistula. The aneurysm diameter decreased continuously in spite of the type II endoleak. This observation illustrates the mechanisms of sac expansion and may have therapeutic implications for complicated type II endoleaks and prevention of spinal cord ischemia in thoracic stent-grafting. CONCLUSION: EVAR can be applied in this rare setting because the ensuing high-flow endoleak is associated with sac shrinkage owing to depressurization by the caval shunt. PMID- 26988744 TI - A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. AB - There has been an explosion in the number of papers discussing the hypothesis of 'pathogenic spread' in neurodegenerative disease - the idea that abnormal forms of disease-associated proteins, such as tau or alpha-synuclein, physically move from neuron to neuron to induce disease progression. However, whether inter neuronal spread of protein aggregates actually occurs in humans and, if so, whether it causes symptom onset remain uncertain. Even if pathogenic spread is proven in humans, it is unclear how much this would alter the specific therapeutic approaches that are in development. A critical appraisal of this increasingly popular hypothesis thus seems both important and timely. PMID- 26988746 TI - Systematic Review and Patient-Level Meta-analysis of the Streamliner Multilayer Flow Modulator in the Management of Complex Thoracoabdominal Aortic Pathology. AB - PURPOSE: To examine the safety and short-term efficacy of the Streamliner Multilayer Flow Modulator (SMFM) in the management of patients with complex thoracoabdominal aortic pathology who are unfit for alternative interventions. METHODS: Biomedical databases were systematically searched for articles published between 2008 and 2015 on the SMFM. A patient-level meta-analysis was used to evaluate aneurysm-related survival. Secondary outcomes were all-cause survival, stroke, spinal cord ischemia, renal impairment, and branch vessel patency. Other considerations were the impact of compliance with the instructions for use (IFU) on clinical outcome. Mean values and Kaplan-Meier estimates are presented with the 95% confidence interval (CI). RESULTS: Fifteen articles (3 multicenter cohort studies, 3 observational cohort studies, and 9 case reports) were included, presenting 171 patients (mean age 68.8+/-12.3 years; 139 men). The mean aneurysm diameter was 6.7+/-1.6 cm (95% CI 6.4 to 6.9 cm). Technical success reported in 15 studies was 77.2%. Aneurysm-related survival at 1 year was 78.7% (95% CI 71.7% to 84.4%). One-year all-cause survival was 53.7% (95% CI 46.0% to 61.3%). There were no reported cases of spinal cord ischemia, renal insult, or stroke. CONCLUSION: The SMFM can be safely utilized in some patients with complex thoracoabdominal pathologies provided operators adhere to the IFU. The SMFM is a novel technology with no long-term published data on its sustained effectiveness and a lack of comparative studies. Randomized clinical trials, registries, and continued assessment are essential before this flow-modulating technology can be widely disseminated. PMID- 26988747 TI - Efficacy of rasagiline in early Parkinson's disease: a meta-analysis of data from the TEMPO and ADAGIO studies. AB - AIM OF THE STUDY: To evaluate the efficacy of rasagiline versus placebo in a pooled population of patients with early Parkinson's disease (PD). MATERIALS AND METHODS: TEMPO and ADAGIO were Phase III studies that evaluated the symptomatic efficacy of rasagiline versus placebo in patients with early PD. This meta analysis included Unified Parkinson's Disease Rating Scale (UPDRS) observations from weeks 12, 24 and 36 in ADAGIO and from weeks 14 and 26 in TEMPO; TEMPO visits were recoded to weeks 12 and 24, respectively. The present analysis includes all patients who received rasagiline 1 mg/day, 2 mg/day or placebo, and had >=1 post-baseline observations and a subgroup of patients whose baseline UPDRS Total scores were >=27 (Upper Quartile population). Change from baseline in UPDRS scores were evaluated using mixed models repeated measures analyses. RESULTS: Of the 1578 patients randomized to the two studies, 1546 patients met criteria for inclusion in the meta-analysis. Effects on UPDRS Total, motor and activities of daily living scores were significantly better for both doses of rasagiline compared with placebo at all time periods. The Upper Quartile population included 402 patients with a UPDRS Total score >=27 at baseline. These patients generally demonstrated a larger magnitude of treatment effect than was seen in the full population. CONCLUSIONS: This meta-analysis confirms the efficacy of rasagiline monotherapy over 36 weeks. Although TEMPO and ADAGIO are considered studies of "very early" PD, both contained a sizeable pool of patients with more severe disease. In addition, the meta-analysis showed a larger magnitude of effect in patients with more severe baseline disease. PMID- 26988748 TI - Comparative Survival among Older Adults with Advanced Kidney Disease Managed Conservatively Versus with Dialysis. AB - BACKGROUND AND OBJECTIVES: Outcomes of older patients with ESRD undergoing RRT or conservative management (CM) are uncertain. Adequate survival data, specifically of older patients, are needed for proper counseling. We compared survival of older renal patients choosing either CM or RRT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A retrospective survival analysis was performed of a single-center cohort in a nonacademic teaching hospital in The Netherlands from 2004 to 2014. Patients with ESRD ages >=70 years old at the time that they opted for CM or RRT were included. Patients with acute on chronic renal failure needing immediate start of dialysis were excluded. RESULTS: In total, 107 patients chose CM, and 204 chose RRT. Patients choosing CM were older (mean+/-SD: 83+/-4.5 versus 76+/ 4.4 years; P<0.001). The Davies comorbidity scores did not differ significantly between both groups. Median survival of those choosing RRT was higher than those choosing CM from time of modality choice (median; 75th to 25th percentiles: 3.1, 1.5-6.9 versus 1.5, 0.7-3.0 years; log-rank test: P<0.001) and all other starting points (P<0.001 in all patients). However, the survival advantage of patients choosing RRT was no longer observed in patients ages >=80 years old (median; 75th to 25th percentiles: 2.1, 1.5-3.4 versus 1.4, 0.7-3.0 years; log-rank test: P=0.08). The survival advantage was also substantially reduced in patients ages >=70 years old with Davies comorbidity scores of >=3, particularly with cardiovascular comorbidity, although the RRT group maintained its survival advantage at the 5% significance level (median; 75th to 25th percentiles: 1.8, 0.7-4.1 versus 1.0, 0.6-1.4 years; log-rank test: P=0.02). CONCLUSIONS: In this single-center observational study, there was no statistically significant survival advantage among patients ages >=80 years old choosing RRT over CM. Comorbidity was associated with a lower survival advantage. This provides important information for decision making in older patients with ESRD. CM could be a reasonable alternative to RRT in selected patients. PMID- 26988749 TI - Does the Evidence Support Conservative Management as an Alternative to Dialysis for Older Patients with Advanced Kidney Disease? PMID- 26988750 TI - [Prevalence and characteristics of acute coronary syndromes in a sub-Saharan Africa population]. AB - AIM: To assess prevalence, characteristics and management of acute coronary syndromes in sub-Saharan Africa population. PATIENTS AND METHODS: Prospective survey from January, 2010 to December, 2013, carried out among patients aged 18 years old, admitted to intensive care unit of Abidjan Heart Institute for acute coronary syndrome (ACS). RESULTS: Four hundred and twenty-five (425) patients were enrolled in this study. Prevalence of ACS was 13.5%. Mean age was 55.4+/-11 years. Clinical presentation was predominantly ST-segment elevation myocardial infarction (STEMI) in 71.5% of subjects, non-ST-segment elevation acute coronary syndrome (NSTE-ACS) accounted for 28.5%. Two hundred and eighty patients (65.9%) were transferred by unsafe transportation. Among the 89 patients admitted within 12hours of the onset of symptoms, primary percutaneous coronary intervention was performed in 20 patients (22.5%), or 6.6% of STEMI as a whole. Twenty-five patients (8.2%) received fibrinolytic therapy with alteplase. In-hospital death rate was 10%. CONCLUSION: The prevalence of acute coronary syndromes is increasing in sub-Saharan Africa. Excessive delays of admission and limited technical facilities are the major difficulties of their management in our regions. PMID- 26988751 TI - Toll-like receptor 2 gene polymorphisms in Korean women with human papillomavirus related cervical neoplasia. AB - INTRODUCTION: The aim of this study was to investigate the association between Toll-like receptor 2 (TLR2) gene polymorphisms and human papillomavirus (HPV) related cervical neoplasia in Korean women. MATERIAL AND METHODS: Peripheral blood samples collected from 127 patients with HPV-related cervical neoplasia and 175 healthy women were genotyped for the TLR2 -16934, +1350, intron1, and 3' untranslated region (UTR) polymorphisms using the polymerase chain reaction and restriction fragment length polymorphism method. RESULTS: The TLR2 -16934 A/A, intron1 A/A, and +1350 T/C genotypes were more frequent in patients than in controls [odds ratio (OR) = 2.1, 95% CI = 1.302-3.475, p = 0.002; OR = 1.9, 95% CI = 1.168-3.169, p = 0.010; and OR = 1.9, 95% CI = 1.211-3.123, p = 0.006, respectively]. The frequencies of the TLR2 + 1350 C and 3'UTR G alleles were also higher in patients (OR = 2.0, 95% CI = 1.236-3.121, p = 0.004 and OR = 1.7, 95% CI = 1.005-3.076, p = 0.046, respectively). The genotype frequencies of TLR2 16934 A/A and intron1 A/A increased with increasing oncogenic risk of the HPV genotype, as follows. low-risk type < high-risk type < HPV-16 and/or HPV-18 type (p = 0.008). CONCLUSIONS: Our study provides the first evidence that TLR2 gene polymorphisms are associated with high-risk type HPV-related cervical neoplasia and may play an important role in susceptibility to HPV infection. Further large scale and functional studies are needed to confirm the role of TLR2 gene polymorphisms in HPV-related cervical neoplasia. PMID- 26988753 TI - The mTOR inhibitor Everolimus synergizes with the PI3K inhibitor GDC0941 to enhance anti-tumor efficacy in uveal melanoma. AB - Uveal melanoma (UM) is the most frequent malignant ocular tumor in adults. While the primary tumor is efficiently treated by surgery and/or radiotherapy, about one third of UM patients develop metastases, for which no effective treatment is currently available. The PKC, MAPK and PI3K/AKT/mTOR signaling cascades have been shown to be associated with tumor growth. However, none of the compounds against those pathways results in tumor regression when used as single agents. To identify more effective therapeutic strategies for UM patients, we performed a combination screen using seven targeted agents inhibiting PKC, MEK, AKT, PI3K and mTOR in a panel of ten UM cell lines, representative of the UM disease. We identified a strong synergy between the mTOR inhibitor Everolimus and the PI3K inhibitor GDC0941. This combination resulted in an increase in apoptosis in several UM cell lines compared to monotherapies and enhanced the anti-tumor effect of each single agent in two patient-derived xenografts. Furthermore, we showed that the synergism between the two drugs was associated with the relief by GDC0491 of a reactivation of AKT induced by Everolimus. Altogether, our results highlight a novel and effective combination strategy, which could be beneficial for UM patients. PMID- 26988752 TI - HER2-siRNA delivered by EGFR-specific single chain antibody inhibits NSCLC cell proliferation and tumor growth. AB - Overexpression of human epidermal growth factor receptor type2 (HER2) is closely associated with aggressive progression and poor prognosis in non-small cell lung cancer (NSCLC). Here, we generated an EGFR-scFv-arginine nonamer peptide fusion protein (scFv-9R) as a cargo to deliver HER2 specific siRNA into HER2-positive NSCLC cells both in vitro and in vivo. HER2-siRNAs delivered by scFv-9R effeciently silenced HER2 expression in EGFR-positive NSCLC cells, and consequently resulted in G1 arrest and cell growth inhibition. Importantly, intravenous injection of scFv-9R/HER2-siRNA complex markedly suppressed growth of EGFR-positive NSCLC xenograft in nude mice, resulting from downregulated HER2 expression, reduced cell proliferation and enhanced cell apoptosis. Collectively, our study provides a novel therapeutic strategy for the treatment of EGFR positive, HER2-overexpressed NSCLC. PMID- 26988755 TI - SNP-SNP interactions of three new pri-miRNAs with the target gene PGC and multidimensional analysis of H. pylori in the gastric cancer/atrophic gastritis risk in a Chinese population. AB - Gastric cancer (GC) is a multistep complex disease involving multiple genes, and gene-gene interactions have a greater effect than a single gene in determining cancer susceptibility. This study aimed to explore the interaction of the let-7e rs8111742, miR-365b rs121224, and miR-4795 rs1002765 single nucleotide polymorphisms (SNPs) with SNPs of the predicted target gene PGC and Helicobacter pylori status in GC and atrophic gastritis (AG) risk. Three miRNA SNPs and seven PGC SNPs were detected in 2448 cases using the Sequenom MassArray platform. Two pairwise combinations of miRNA and PGC SNPs were associated with increased AG risk (let-7e rs8111742 - PGC rs6458238 and miR-4795 rs1002765 - PGC rs9471643). Singly, miR-365b rs121224 and PGC rs6912200 had no effect individually but in combination they demonstrated an epistatic interaction associated with AG risk. Similarly, let-7e rs8111742 and miR-4795 rs1002765 SNPs interacted with H. pylori infection to increase GC risk (rs8111742: Pinteraction = 0.024; rs1002765: Pinteraction = 0.031, respectively). A three-dimensional interaction analysis found miR-4795 rs1002765, PGC rs9471643, and H. pylori infection positively interacted to increase AG risk (Pinteraction = 0.027). Also, let-7e rs8111742, PGC rs6458238, and H. pylori infection positively interacted to increase GC risk (Pinteraction = 0.036). Furthermore, both of these three-dimensional interactions had a dosage-effect correspondence (Ptrend < 0.001) and were verified by MDR. In conclusion, the miRNAs SNPs (let-7e rs8111742 and miR-4795 rs1002765) might have more superior efficiency when combined with PGC SNPs and/or H. pylori for GC or AG risk than a single SNP on its own. PMID- 26988754 TI - Gedunin inhibits pancreatic cancer by altering sonic hedgehog signaling pathway. AB - INTRODUCTION: The lack of efficient treatment options for pancreatic cancer highlights the critical need for the development of novel and effective chemotherapeutic agents. The medicinal properties found in plants have been used to treat many different illnesses including cancers. This study focuses on the anticancer effects of gedunin, a natural compound isolated from Azadirachta indica. METHODS: Anti-proliferative effect of gedunin on pancreatic cancer cells was assessed using MTS assay. We used matrigel invasion assay, scratch assay, and soft agar colony formation assay to measure the anti-metastatic potential of gedunin. Immunoblotting was performed to analyze the effect of gedunin on the expression of key proteins involved in pancreatic cancer growth and metastasis. Gedunin induced apoptosis was measured using flow cytometric analysis. To further validate, xenograft studies with HPAC cells were performed. RESULTS: Gedunin treatment is highly effective in inducing death of pancreatic cancer cells via intrinsic and extrinsic mediated apoptosis. Our data further indicates that gedunin inhibited metastasis of pancreatic cancer cells by decreasing their EMT, invasive, migratory and colony formation capabilities. Gedunin treatment also inhibited sonic hedgehog signaling pathways. Further, experiments with recombinant sonic hedgehog protein and Gli inhibitor (Gant-61) demonstrated that gedunin induces its anti-metastatic effect through inhibition of sonic hedgehog signaling. The anti-cancer effect of gedunin was further validated using xenograft mouse model. CONCLUSION: Overall, our data suggests that gedunin could serve as a potent anticancer agent against pancreatic cancers. PMID- 26988757 TI - Habitat constraints and self-thinning shape Mediterranean red coral deep population structure: implications for conservation practice. AB - The Mediterranean red coral, Corallium rubrum, is one of the most precious corals worldwide. Below 50 m depth, C. rubrum populations are generally characterised by large and sparse colonies, whereas shallow populations (above 50 m depth) show high densities of small colonies. We show here instead that populations dwelling between 80 and 170 m depth exhibited a continuous range of population density (from 2 to 75 colonies per 0.25 m(2)), with less than 1% of variance explained by water depth. An inverse relationship between maximum population density and mean colony height was found, suggesting that self-thinning processes may shape population structure. Moreover, demographically young populations composed of small and dense colonies dominated along rocky vertical walls, whereas mature populations characterised by large and sparsely distributed colonies were found only in horizontal beds not covered by sediment. We hypothesise that, in the long term, shallow protected populations should resemble to present deep populations, with sparsely distributed large colonies. Since the density of red coral colonies can decay as a result of self-thinning mechanisms, we advise that future protection strategies should be based also on a measure of red coral spatial coverage instead of population density. PMID- 26988756 TI - The DEK oncogene activates VEGF expression and promotes tumor angiogenesis and growth in HIF-1alpha-dependent and -independent manners. AB - The DEK oncogene is overexpressed in various cancers and overexpression of DEK correlates with poor clinical outcome. Vascular endothelial growth factor (VEGF) is the most important regulator of tumor angiogenesis, a process essential for tumor growth and metastasis. However, whether DEK enhances tumor angiogenesis remains unclear. Here, we show that DEK is a key regulator of VEGF expression and tumor angiogenesis. Using chromatin immunoprecipitation assay, we found that DEK promoted VEGF transcription in breast cancer cells (MCF7, ZR75-1 and MDA-MB-231) by directly binding to putative DEK-responsive element (DRE) of the VEGF promoter and indirectly binding to hypoxia response element (HRE) upstream of the DRE through its interaction with the transcription factor hypoxia-inducible factor 1alpha (HIF-1alpha), a master regulator of tumor angiogenesis and growth. DEK is responsible for recruitment of HIF-1alpha and the histone acetyltransferase p300 to the VEGF promoter. DEK-enhanced VEGF increases vascular endothelial cell proliferation, migration and tube formation as well as angiogenesis in the chick chorioallantoic membrane. DEK promotes tumor angiogenesis and growth in nude mice in HIF-1alpha-dependent and -independent manners. Immunohistochemical staining showed that DEK expression positively correlates with the expression of VEGF and microvessel number in 58 breast cancer patients. Our data establish DEK as a sequence-specific binding transcription factor, a novel coactivator for HIF 1alpha in regulation of VEGF transcription and a novel promoter of angiogenesis. PMID- 26988758 TI - A role for PDGF-C/PDGFRalpha signaling in the formation of the meningeal basement membranes surrounding the cerebral cortex. AB - Platelet-derived growth factor-C (PDGF-C) is one of three known ligands for the tyrosine kinase receptor PDGFRalpha. Analysis ofPdgfcnull mice has demonstrated roles for PDGF-C in palate closure and the formation of cerebral ventricles, but redundancy with other PDGFRalpha ligands might obscure additional functions. In search of further developmental roles for PDGF-C, we generated mice that were double mutants forPdgfc(-/-)andPdgfra(GFP/+) These mice display a range of severe phenotypes including spina bifida, lung emphysema, abnormal meninges and neuronal over-migration in the cerebral cortex. We focused our analysis on the central nervous system (CNS), where PDGF-C was identified as a critical factor for the formation of meninges and assembly of the glia limitans basement membrane. We also present expression data onPdgfa,PdgfcandPdgfrain the cerebral cortex and microarray data on cerebral meninges. PMID- 26988759 TI - Estimating energetics in cetaceans from respiratory frequency: why we need to understand physiology. AB - The accurate estimation of field metabolic rates (FMR) in wild animals is a key component of bioenergetic models, and is important for understanding the routine limitations for survival as well as individual responses to disturbances or environmental changes. Several methods have been used to estimate FMR, including accelerometer-derived activity budgets, isotope dilution techniques, and proxies from heart rate. Counting the number of breaths is another method used to assess FMR in cetaceans, which is attractive in its simplicity and the ability to measure respiration frequency from visual cues or data loggers. This method hinges on the assumption that over time a constant tidal volume (VT) and O2exchange fraction (DeltaO2) can be used to predict FMR. To test whether this method of estimating FMR is valid, we measured breath-by-breath tidal volumes and expired O2levels of bottlenose dolphins, and computed the O2consumption rate (VO2 ) before and after a pre-determined duration of exercise. The measuredVO2 was compared with three methods to estimate FMR. Each method to estimateVO2 included variable VT and/or DeltaO2 Two assumption-based methods overestimatedVO2 by 216 501%. Once the temporal changes in cardio-respiratory physiology, such as variation in VT and DeltaO2, were taken into account, pre-exercise restingVO2 was predicted to within 2%, and post-exerciseVO2 was overestimated by 12%. Our data show that a better understanding of cardiorespiratory physiology significantly improves the ability to estimate metabolic rate from respiratory frequency, and further emphasizes the importance of eco-physiology for conservation management efforts. PMID- 26988761 TI - Laying the Foundation: Factors Associated With Medical Home Recognition Among Health Centers. AB - INTRODUCTION: The characteristics associated with medical home recognition among federally qualified health centers were explored. The results will help guide the transformation of health centers and other providers to the medical home model of practice. METHODS: This study included the universe of 1,198 federally qualified health centers in calendar year 2012; the data were collected in 2013 and analyzed in 2014-2015. Using the 2012 Uniform Data System, descriptive statistics were calculated and differences in means of health center characteristics by third-party medical home recognition status were tested. Multivariable logistic regression models examined correlates of recognition. RESULTS: In 2012, 17.3% of health centers had third-party medical home recognition. Health centers in the Northeast had more than three times the odds of being recognized as medical homes, compared with health centers located in the South (OR=3.3, p<0.001). Health centers with medical home recognition were larger and had higher odds of having electronic health records in all sites (OR=3.08, p<0.001). Recognized health centers had a higher percentage of total staffing composed of behavioral health specialists, compared with health centers that had not attained medical home recognition in 2012 (OR=1.06, p<0.001). CONCLUSIONS: These findings highlight the importance of monitoring which types of health centers are falling behind, encouraging the adoption of health information technology, and enabling the recruitment of onsite behavioral health staffing. PMID- 26988760 TI - Impact of bronchopulmonary dysplasia on brain and retina. AB - Many premature newborns develop bronchopulmonary dysplasia (BPD), a chronic lung disease resulting from prolonged mechanical ventilation and hyperoxia. BPD survivors typically suffer long-term injuries not only to the lungs, but also to the brain and retina. However, currently it is not clear whether the brain and retinal injuries in these newborns are related only to their prematurity, or also to BPD. We investigated whether the hyperoxia known to cause histologic changes in the lungs similar to BPD in an animal model also causes brain and retinal injuries. Sprague Dawley rat pups were exposed to hyperoxia (95% O2, 'BPD' group) or room air (21% O2, 'control' group) from postnatal day 4-14 (P4-14); the rat pups were housed in room air between P14 and P28. At P28, they were sacrificed, and their lungs, brain, and eyes were extracted. Hematoxylin and eosin staining was performed on lung and brain sections; retinas were stained with Toluidine Blue. Hyperoxia exposure resulted in an increased mean linear intercept in the lungs (P<0.0001). This increase was associated with a decrease in some brain structures [especially the whole-brain surface (P=0.02)], as well as a decrease in the thickness of the retinal layers [especially the total retina (P=0.0008)], compared to the room air control group. In addition, a significant negative relationship was observed between the lung structures and the brain (r= 0.49,P=0.02) and retina (r=-0.70,P=0.0008) structures. In conclusion, hyperoxia exposure impaired lung, brain, and retina structures. More severe lung injuries correlated with more severe brain and retinal injuries. This result suggests that the same animal model of chronic neonatal hyperoxia can be used to simultaneously study lung, brain and retinal injuries related to hyperoxia. PMID- 26988762 TI - Burkitt lymphoma with extensive ileocolonic extranodal involvement. Presentation as a rapidly growing abdominal mass. PMID- 26988763 TI - Increased Expression of EGR-1 in Diabetic Human Adipose Tissue-Derived Mesenchymal Stem Cells Reduces Their Wound Healing Capacity. AB - The prevalence of type 2 diabetes mellitus (T2DM), which leads to diabetic complications, has been increasing worldwide. The possible applications of T2DM derived stem cells in cell therapy are limited because their characteristics are still not fully understood. In this study, we characterized adipose tissue derived mesenchymal stem cells (AT-MSCs) from diabetic patients (dAT-MSCs) and found that insulin receptor substrate-1 (IRS-1) was highly phosphorylated at serine 636/639 in dAT-MSCs. Moreover, we found that early growth response factor 1 (EGR-1) and its target genes of PTEN and GGPS1 were highly expressed in dAT MSCs in comparison to healthy donor-derived AT-MSCs (nAT-MSCs). We observed impaired wound healing after the injection of dAT-MSCs in the ischemic flap mouse model. The expressions of EGR-1 and its target genes were diminished by small hairpin RNA-targeted EGR-1 (shEGR-1) and treatment with a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) inhibitor (PD98059). Importantly, dAT-MSCs with shEGR-1 were able to restore the wound healing ability in the mouse model. Interestingly, under hypoxic conditions, hypoxia-inducible factor-1alpha (HIF-1alpha) can bind to the EGR-1 promoter in dAT-MSCs, but not in nAT-MSCs. Together, these results demonstrate that the expression of EGR-1 was upregulated in dAT-MSCs through two pathways: the main regulatory pathway is the MAPK/ERK pathway, the other is mediated by HIF-1alpha through direct transcriptional activation at the promoter region of the EGR1 gene. Our study suggests that dAT-MSCs may contribute to microvascular damage and delay wound healing through the overexpression of EGR-1. Interrupting the expression of EGR-1 in dAT-MSCs may be a useful treatment for chronic wounds in diabetic patients. PMID- 26988765 TI - Association of work productivity with clinical and patient-reported factors in patients infected with hepatitis C virus. AB - Patients with HCV infection have reduced work productivity (WP), in terms of both presenteeism (impairment in work productivity while working) and absenteeism (productivity loss due to absence from work). The aim of this study was to identify clinical and patient-reported factors that are predictive of WP in HCV infected patients. HCV-infected patients enrolled in clinical trials completed 3 PRO questionnaires (CLDQ-HCV, SF-36 and FACIT-F) and one work productivity (WPAI:SHP) questionnaire. In employed subjects, work productivity and its absenteeism and presenteeism components were calculated using WPAI:SHP instrument. Of 4121 HCV-infected patients with work productivity data, 2480 (60.2%) reported to be employed, and of those, 2190 had completed all PRO questionnaires before treatment initiation. Of the study cohort, 519/2190 (23.7%) had severe work impairment. In multiple linear regression analysis, work productivity was predicted by lower scores in activity/energy domain of CLDQ-HCV, physical well-being domain of FACIT-F, worry domain of CLDQ-HCV and role physical domain of SF-36 (all P < 0.0005). Furthermore, presenteeism was independently predicted by the activity/energy of CLDQ-HCV, physical well-being of FACIT-F, worry domain of CLDQ-HCV, role physical scale of SF-36 and fatigue scale of FACIT F (P < 0.002). Finally, absenteeism was independently predicted by physical well being scale of FACIT-F and role physical scale of SF-36 (all P < 0.002). Clinically, work productivity impairment was predicted by the presence of cirrhosis, anxiety, depression and clinically overt fatigue (P < 0.01). Thus, the most important drivers of WP in HCV are impairment of physical aspects of PROs and clinical history of depression, anxiety, fatigue and cirrhosis. PMID- 26988766 TI - Whole-body fat oxidation increases more by prior exercise than overnight fasting in elite endurance athletes. AB - The purpose of this study was to compare whole-body fat oxidation kinetics after prior exercise with overnight fasting in elite endurance athletes. Thirteen highly trained athletes (9 men and 4 women; maximal oxygen uptake: 66 +/- 1 mL.min(-1).kg(-1)) performed 3 identical submaximal incremental tests on a cycle ergometer using a cross-over design. A control test (CON) was performed 3 h after a standardized breakfast, a fasting test (FAST) 12 h after a standardized evening meal, and a postexercise test (EXER) after standardized breakfast, endurance exercise, and 2 h fasting recovery. The test consisted of 3 min each at 30%, 40%, 50%, 60%, 70%, and 80% of maximal oxygen uptake and fat oxidation rates were measured through indirect calorimetry. During CON, maximal fat oxidation rate was 0.51 +/- 0.04 g.min(-1) compared with 0.69 +/- 0.04 g.min(-1) in FAST (P < 0.01), and 0.89 +/- 0.05 g.min(-1) in EXER (P < 0.01). Across all intensities, EXER was significantly higher than FAST and FAST was higher than CON (P < 0.01). Blood insulin levels were lower and free fatty acid and cortisol levels were higher at the start of EXER compared with CON and FAST (P < 0.05). Plasma nuclear magnetic resonance-metabolomics showed similar changes in both EXER and FAST, including increased levels of fatty acids and succinate. In conclusion, prior exercise significantly increases whole-body fat oxidation during submaximal exercise compared with overnight fasting. Already high rates of maximal fat oxidation in elite endurance athletes were increased by approximately 75% after prior exercise and fasting recovery. PMID- 26988767 TI - Is beetroot juice more effective than sodium nitrate? The effects of equimolar nitrate dosages of nitrate-rich beetroot juice and sodium nitrate on oxygen consumption during exercise. AB - Dietary nitrate has been reported to lower oxygen consumption in moderate- and severe-intensity exercise. To date, it is unproven that sodium nitrate (NaNO3(-); NIT) and nitrate-rich beetroot juice (BR) have the same effects on oxygen consumption, blood pressure, and plasma nitrate and nitrite concentrations or not. The aim of this study was to compare the effects of different dosages of NIT and BR on oxygen consumption in male athletes. Twelve healthy, well-trained men (median [minimum; maximum]; peak oxygen consumption: 59.4 mL.min(-1).kg(-1) [40.5; 67.0]) performed 7 trials on different days, ingesting different nitrate dosages and placebo (PLC). Dosages were 3, 6, and 12 mmol nitrate as concentrated BR or NIT dissolved in plain water. Plasma nitrate and nitrite concentrations were measured before, 3 h after ingestion, and postexercise. Participants cycled for 5 min at moderate intensity and further 8 min at severe intensity. End exercise oxygen consumption at moderate intensity was not significantly different between the 7 trials (p = 0.08). At severe-intensity exercise, end-exercise oxygen consumption was ~4% lower in the 6-mmol BR trial compared with the 6-mmol NIT (p = 0.003) trial as well as compared with PLC (p = 0.010). Plasma nitrite and nitrate concentrations were significantly increased after the ingestion of BR and NIT with the highest concentrations in the 12-mmol trials. Plasma nitrite concentration between NIT and BR did not significantly differ in the 6-mmol (p = 0.27) and in the 12-mmol (p = 0.75) trials. In conclusion, BR might reduce oxygen consumption to a greater extent compared with NIT. PMID- 26988764 TI - The multifaceted role of astrocytes in regulating myelination. AB - Astrocytes are the major glial cell of the central nervous system (CNS), providing both metabolic and physical support to other neural cells. After injury, astrocytes become reactive and express a continuum of phenotypes which may be supportive or inhibitory to CNS repair. This review will focus on the ability of astrocytes to influence myelination in the context of specific secreted factors, cytokines and other neural cell targets within the CNS. In particular, we focus on how astrocytes provide energy and cholesterol to neurons, influence synaptogenesis, affect oligodendrocyte biology and instigate cross-talk between the many cellular components of the CNS. PMID- 26988768 TI - Evaluating the effects of caffeine and sodium bicarbonate, ingested individually or in combination, and a taste-matched placebo on high-intensity cycling capacity in healthy males. AB - This study evaluated the effects of ingesting sodium bicarbonate (NaHCO3) or caffeine individually or in combination on high-intensity cycling capacity. In a counterbalanced, crossover design, 13 healthy, noncycling trained males (age: 21 +/- 3 years, height: 178 +/- 6 cm, body mass: 76 +/- 12 kg, peak power output (Wpeak): 230 +/- 34 W, peak oxygen uptake: 46 +/- 8 mL.kg(-1).min(-1)) performed a graded incremental exercise test, 2 familiarisation trials, and 4 experimental trials. Trials consisted of cycling to volitional exhaustion at 100% Wpeak (TLIM) 60 min after ingesting a solution containing either (i) 0.3 g.kg(-1) body mass sodium bicarbonate (BIC), (ii) 5 mg.kg(-1) body mass caffeine plus 0.1 g.kg(-1) body mass sodium chloride (CAF), (iii) 0.3 g.kg(-1) body mass sodium bicarbonate plus 5 mg.kg(-1) body mass caffeine (BIC-CAF), or (iv) 0.1 g.kg(-1) body mass sodium chloride (PLA). Experimental solutions were administered double-blind. Pre exercise, at the end of exercise, and 5-min postexercise blood pH, base excess, and bicarbonate ion concentration ([HCO3(-)]) were significantly elevated for BIC and BIC-CAF compared with CAF and PLA. TLIM (median; interquartile range) was significantly greater for CAF (399; 350-415 s; P = 0.039; r = 0.6) and BIC-CAF (367; 333-402 s; P = 0.028; r = 0.6) compared with BIC (313: 284-448 s) although not compared with PLA (358; 290-433 s; P = 0.249, r = 0.3 and P = 0.099 and r = 0.5, respectively). There were no differences between PLA and BIC (P = 0.196; r = 0.4) or between CAF and BIC-CAF (P = 0.753; r = 0.1). Relatively large inter- and intra-individual variation was observed when comparing treatments and therefore an individual approach to supplementation appears warranted. PMID- 26988769 TI - Relationships between maximal strength, muscle size, and myosin heavy chain isoform composition and postactivation potentiation. AB - The purpose of this study was to examine the relationships between maximal voluntary postactivation potentiation (PAP) and maximal knee extensor torque, quadriceps cross-sectional area (CSA) and volume, and type II myosin heavy chain (MHC) isoform percentage in human skeletal muscle. Thirteen resistance-trained men completed a test protocol consisting of 2 isokinetic knee extensions at 180 degrees .s(-)(1) performed before and 1, 4, 7, and 10 min after the completion of 4 maximal knee extensions at 60 degrees .s(-)(1) (i.e., a conditioning activity (CA)). Magnetic resonance imaging and muscle microbiopsy procedures were completed on separate days to assess quadriceps CSA and volume and MHC isoform content. Maximal voluntary PAP response was assessed as the ratio of the highest knee extensor torques measured before and after the CA. There were large to very large correlations between maximal voluntary PAP response and maximal knee extensor torque (r = 0.62) and quadriceps CSA (r = 0.68) and volume (r = 0.63). Nonetheless, these correlations were not statistically significant after adjusting for the influence of type II MHC percentage using partial correlation analysis. By contrast, the strongest correlation was observed for type II MHC percentage (r = 0.77), and this correlation remained significant after adjusting for the other variables. Maximal voluntary PAP response is strongly correlated with maximal knee extensor torque and quadriceps CSA and volume, but is mostly clearly associated with the type II myosin isoform percentage in human skeletal muscle. PMID- 26988770 TI - Skeletal muscle TLR4 and TACE are associated with body fat percentage in older adults. AB - Elevated skeletal muscle expression of toll-like receptor 4 (TLR4) has been linked to increased inflammation in clinical populations. TNFalpha converting enzyme (TACE), which cleaves membrane-bound TNFalpha (mTNFalpha) to its soluble (sTNFalpha) and more bioactive form, has been linked to chronic disease. In contrast, higher physical activity level is associated with decreased chronic disease risk and inflammation. The purpose of the present study was to examine the relationship between physical activity and skeletal muscle TLR4, TACE, and TNFalpha in older adults. In 26 older adults (age = 68 +/- 4 years, body mass index = 26 +/- 3 kg.m(-2)), self-reported physical activity (kcal.week(-1)), estimated maximal oxygen consumption, and body composition (air plethysmography) were measured. TLR4, TACE, mTNFalpha, and sTNFalpha were measured in skeletal muscle biopsies (vastus lateralis) using western blot analyses. Pearson product moment correlations were run between variables. Significance was set at p < 0.05. Skeletal muscle TACE was directly associated with sTNFalpha (r = 0.53, p < 0.01). Linear regression modeling showed that mTNFalpha and TACE expression were predictive of sTNFalpha expression. No correlations were observed between physical activity and TLR4, TACE, or sTNFalpha. Percent body fat was directly associated with skeletal muscle TLR4 (r = 0.52, p < 0.01) and TACE (r = 0.50, p < 0.01), whereas fasting blood glucose was directly associated with TACE and sTNFalpha. In conclusion, we found that percent body fat was directly associated with TLR4 and TACE expression in skeletal muscle of older adults. These findings suggest that elevated skeletal muscle expression of TLR4 and TACE may contribute to the augmented inflammation and chronic disease risk observed with increased adiposity. PMID- 26988771 TI - Inflammatory TNBC Breast Cancer: Demography and Clinical Outcome in a Large Cohort of Patients With TNBC. AB - INTRODUCTION: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer with poor 5-year survival. Knowledge and information about IBC with the triple negative (TNBC) phenotype are limited. Here, we report the characteristics and outcome of inflammatory TNBC (I-TNBC) cancer cohorts from a large TNBC dataset. PATIENTS AND METHODS: After obtaining institutional review board approval, we collected information on 476 women with a diagnosis of TNBC from 1996 to 2011. Data on patient characteristics, tumor, and treatment were collected. Overall survival (OS) was computed from the date of diagnosis to the date of death or last follow-up. For disease-free survival (DFS), patients were scored if they failed. Statistical analysis was performed using SAS v9.3. RESULTS: A total of 34 (7%) patients were diagnosed with inflammatory TNBC. The median age was 52 years, and 56% were white. The median follow-up was 13 months (interquartile range, 2-126 months). Twenty-one percent (n = 7) presented with stage IV disease, while 91% had axillary nodal involvement. All but 2 (94%; n = 32) patients had neoadjuvant chemotherapy, with 6% (n = 2) achieving complete response. Twenty-one (62%) patients underwent mastectomy; 71% (n = 24) received radiation. The 2- and 5-year OS and DFS were 34%, 26% (vs. 65%, 46%) and 27%, 23% (vs. 53%, 40%), respectively, for I-TNBC and non-inflammatory stage III-IV TNBC. Compared with the non-inflammatory group, the 2- and 5-year OS (P < .0005) and DFS (P < .0073) were significantly inferior for I-TNBC. CONCLUSION: IBC with the triple negative phenotype is an aggressive disease with a significantly inferior outcome compared with non-inflammatory locally advanced TNBC. Newer strategies are required to improve survival outcome. PMID- 26988772 TI - Minocycline-induced orbital rim discoloration. AB - A 20-year-old woman underwent lacrimal gland biopsy for unilateral swelling and was unexpectedly found to have olive-green discoloration of her orbital rim. Postoperative questioning revealed that as a teenager she had been treated for acne with minocycline, a semisynthetic tetracycline antibiotic and a first-line treatment for moderate and severe acne. While hyperpigmentation is a known side effect of minocycline, reports of pigmentation changes of the periorbital bones are relatively rare and could pose a diagnostic dilemma during surgery. PMID- 26988773 TI - Central retinal vein occlusion in an otherwise healthy child treated successfully with a single injection of bevacizumab. PMID- 26988774 TI - Choroidal thickness of children's eyes with anisometropic and strabismic amblyopia. PMID- 26988775 TI - Diffuse bilateral retinal hemorrhages in an infant with a coagulopathy and prolonged cardiopulmonary resuscitation. AB - We report a case of diffuse bilateral retinal and optic nerve sheath hemorrhages in an 8-week-old boy who was found unresponsive. The child underwent prolonged cardiopulmonary resuscitation and was noted on admission to have a coagulopathy. An autopsy determined the cause of death to be a myocardial infarct in the distribution of an anomalous coronary artery. This case demonstrates the difficulty that may occur in establishing whether child abuse caused death in the setting of another potential cause of mortality. PMID- 26988776 TI - Adult-onset chronic divergence insufficiency esotropia: clinical features and response to surgery. AB - PURPOSE: To analyze the clinical and demographic features and surgical outcomes of a series of patients with adult-onset chronic divergence insufficiency esotropia to investigate novel associations of this condition with race, sex, and surgical dose-response. METHODS: The medical records from a single practice were retrospectively reviewed to identify patients with adult-onset chronic divergence insufficiency esotropia who underwent strabismus surgery over a 12-year period. Demographic, clinical, surgical, and outcome data were analyzed to determine statistically significant findings with respect to race, sex, and surgical results. RESULTS: A total of 27 patients (all white; 23 females) were identified. The average age was 72 years. All patients underwent medial rectus recession bilaterally or unilaterally. The dose-response to surgery (1.6(Delta)/mm) was significantly less than that predicted by standard surgical nomograms; however the individual dose-responses varied directly with preoperative angle. CONCLUSIONS: Adult-onset chronic divergence insufficiency esotropia occurs predominantly in white women in our experience. Medial rectus recession is an effective surgical treatment when augmented recession amounts are employed. The findings that surgical dose-response was relatively low but increased with preoperative angle suggest a mixed mechanism of chronic lateral rectus weakness combined with reduced medial rectus elasticity. PMID- 26988778 TI - Long distance kelp rafting impacts seaweed biogeography in the Northeast Pacific: the kelp conveyor hypothesis. AB - Routine DNA barcoding of the Haida Gwaii seaweed flora revealed "endemic species" attributed initially to this region's past as a glacial refugium. However, subsequent barcode records from central California rapidly eroded this list leaving species characterized by disjunct distributions (DD) between California and Haida Gwaii. This observation prompted a more detailed look at species for California and British Columbia and revealed that 33 of 180 DNA-barcoded genetic groups in common between these regions (~18%) predominantly displayed DD between California and northern British Columbia. A previous discovery that a red abalone shell found in Haida Gwaii (far north of its range) had a float-bearing kelp (Nereocystis luetkeana) holdfast attached to it prompted a closer consideration of the COI-5P barcode data in support of a "kelp conveyor hypothesis." The hypothesis posits that there has been a net migration of Californian species to northern British Columbia the vector being species growing on substrata carried along with kelp rafts on the winter Davidson Current. PMID- 26988779 TI - On the trail of ancestors of diatoms. PMID- 26988780 TI - Transcriptomic Insights into the Life History of Bolidophytes, the Sister Lineage to Diatoms. AB - Diatoms are perhaps the most diverse lineage of eukaryotic algae, with their siliceous cell wall and diplontic life history often considered to have played important roles in their extraordinary diversification. The characteristic diminution of the diatom cell wall over the course of vegetative growth provides a reliable, intrinsic trigger for sexual reproduction, establishing a direct link between the evolution of their cell-wall and life-history features. It is unclear, however, whether the diplontic life cycle of diatoms represents an ancestral or derived trait. This uncertainty is based in part on our lack of understanding of the life cycle of the sister lineage to diatoms, which includes a mix of two free-living and separately classified forms: naked biflagellate unicells in the genus Bolidomonas and silicified forms in the order Parmales. These two forms might represent different life-history stages, although directly establishing such links can be difficult. We sequenced transcriptomes for Bolidomonas and two diatoms and found that ~0.1% of the coding regions in the two diploid diatoms are heterozygous, whereas Bolidomonas is virtually devoid of heterozygous alleles, consistent with expectations for a haploid genome. These results suggest that Bolidomonas is haploid and predict that parmaleans represent the diploid phase of a haplodiplontic life cycle. These data fill an important gap in our understanding of the origin of the diplontic life history of diatoms, which may represent an evolutionarily derived, adaptive feature. PMID- 26988781 TI - Latent virus-like infections are present in a diverse range of Symbiodinium spp. (Dinophyta). AB - Coral reefs are increasingly threatened by disease outbreaks, which affect the coral animal and/or its algal symbionts (Symbiodinium spp.) and can cause mass mortalities. Currently around half of the recognized coral diseases have unknown causative agents. While many of the diseases are thought to be bacterial in origin, there is growing evidence that viruses may play a role. In particular, it appears that viruses may infect the algal symbionts, causing breakdown of the coral-algal mutualism. In this study, we screened a wide range of Symbiodinium cultures in vitro for the presence of latent viral infections. Using flow cytometry and electron microscopy, we found that many types of Symbiodinium apparently harbor such infections, and that the type of putative virus varied within and among host types. Furthermore, the putative viral infections could be induced via abiotic stress and cause host cell lysis and population decline. If similar processes occur in Symbiodinium cells in hospite, they may provide an explanation for some of the diseases affecting corals and other organisms forming symbioses with these algae. PMID- 26988782 TI - Bicarbonate uptake via an anion exchange protein is the main mechanism of inorganic carbon acquisition by the giant kelp Macrocystis pyrifera (Laminariales, Phaeophyceae) under variable pH. AB - Macrocystis pyrifera is a widely distributed, highly productive, seaweed. It is known to use bicarbonate (HCO3 (-) ) from seawater in photosynthesis and the main mechanism of utilization is attributed to the external catalyzed dehydration of HCO3 (-) by the surface-bound enzyme carbonic anhydrase (CAext ). Here, we examined other putative HCO3 (-) uptake mechanisms in M. pyrifera under pHT 9.00 (HCO3 (-) : CO2 = 940:1) and pHT 7.65 (HCO3 (-) : CO2 = 51:1). Rates of photosynthesis, and internal CA (CAint ) and CAext activity were measured following the application of AZ which inhibits CAext , and DIDS which inhibits a different HCO3 (-) uptake system, via an anion exchange (AE) protein. We found that the main mechanism of HCO3 (-) uptake by M. pyrifera is via an AE protein, regardless of the HCO3 (-) : CO2 ratio, with CAext making little contribution. Inhibiting the AE protein led to a 55%-65% decrease in photosynthetic rates. Inhibiting both the AE protein and CAext at pHT 9.00 led to 80%-100% inhibition of photosynthesis, whereas at pHT 7.65, passive CO2 diffusion supported 33% of photosynthesis. CAint was active at pHT 7.65 and 9.00, and activity was always higher than CAext , because of its role in dehydrating HCO3 (-) to supply CO2 to RuBisCO. Interestingly, the main mechanism of HCO3 (-) uptake in M. pyrifera was different than that in other Laminariales studied (CAext -catalyzed reaction) and we suggest that species-specific knowledge of carbon uptake mechanisms is required in order to elucidate how seaweeds might respond to future changes in HCO3 (-) :CO2 due to ocean acidification. PMID- 26988783 TI - Eukaryotic pathogens (Chytridiomycota and Oomycota) infecting marine microphytobenthic diatoms - a methodological comparison. AB - Using sediment samples from the Solthorn tidal flat (southern North Sea, Germany), collected in bi-weekly intervals from June to July 2012, a range of qualitative and quantitative screening methods for oomycete and chytrid pathogens infecting benthic diatoms were evaluated. Pre-treatment of sediment samples using short ultrasound pulses and gradient centrifugation, in combination with CalcoFluor White, showed the best results in the visualization of both pathogen groups. The highest number of infected benthic diatoms was observed in mid July (5.8% of the total benthic diatom community). Most infections were caused by chytrids and, in a few cases, oomycetes (Lagenisma Drebes (host: Coscinodiscus radiatus Ehrenberg) and Ectrogella Zopf (hosts: Dimeregramma minor in Pritchard and Gyrosigma peisonis). Among the chytrids, sporangium morphology indicated the presence of five different morphotypes, infecting mainly epipelic taxa of the orders Naviculales (e.g., Navicula digitoradiata) and Achnanthales (e.g., Achnanthes brevipes Agardh). The presence of multiple pathogens in several epipelic diatom taxa suggests a significant role for fungal parasitism in affecting microphytobenthic diatom succession. PMID- 26988784 TI - A re-assessment of the infra-generic classification of the genus Caulerpa (Caulerpaceae, Chlorophyta) inferred from a time-calibrated molecular phylogeny. AB - The siphonous green algal family Caulerpaceae includes the monotypic genus Caulerpella and the species-rich genus Caulerpa. A molecular phylogeny was inferred from chloroplast tufA and rbcL DNA sequences analyzed together with a five marker dataset of non-caulerpacean siphonous green algae. Six Caulerpaceae lineages were revealed, but relationships between them remained largely unresolved. A Caulerpella clade representing multiple cryptic species was nested within the genus Caulerpa. Therefore, that genus is subsumed and Caulerpa ambigua Okamura is reinstated. Caulerpa subgenus status is proposed for the six lineages substantiated by morphological characters, viz., three monotypic subgenera Cliftonii, Hedleyi, and Caulerpella, subgenus Araucarioideae exhibiting stolons covered with scale-like appendages, subgenus Charoideae characterized by a verticillate branching mode, and subgenus Caulerpa for a clade regarded as the Caulerpa core clade. The latter subgenus is subdivided in two sections, i.e., Sedoideae for species with pyrenoids and a species-rich section Caulerpa. A single section with the same name is proposed for each of the other five subgenera. In addition, species status is proposed for Caulerpa filicoides var. andamanensis (W.R. Taylor). All Caulerpa species without sequence data were examined (or data were taken from species descriptions) and classified in the new classification scheme. A temporal framework of Caulerpa diversification is provided by calibrating the phylogeny in geological time. The chronogram suggests that Caulerpa diversified into subgenera and sections after the Triassic-Jurassic mass extinction and that infra-section species radiation happened after the Cretaceous-Tertiary mass extinction. PMID- 26988785 TI - Antioxidant plasticity and thermal sensitivity in four types of Symbiodinium sp. AB - Warmer than average summer sea surface temperature is one of the main drivers for coral bleaching, which describes the loss of endosymbiotic dinoflagellates (genus: Symbiodinium) in reef-building corals. Past research has established that oxidative stress in the symbiont plays an important part in the bleaching cascade. Corals hosting different genotypes of Symbiodinium may have varying thermal bleaching thresholds, but changes in the symbiont's antioxidant system that may accompany these differences have received less attention. This study shows that constitutive activity and up-regulation of different parts of the antioxidant network under thermal stress differs between four Symbiodinium types in culture and that thermal susceptibility can be linked to glutathione redox homeostasis. In Symbiodinium B1, C1 and E, declining maximum quantum yield of PSII (Fv /Fm ) and death at 33 degrees C were generally associated with elevated superoxide dismutase (SOD) activity and a more oxidized glutathione pool. Symbiodinium F1 exhibited no decline in Fv /Fm or growth, but showed proportionally larger increases in ascorbate peroxidase (APX) activity and glutathione content (GSx), while maintaining GSx in a reduced state. Depressed growth in Symbiodinium B1 at a sublethal temperature of 29 degrees C was associated with transiently increased APX activity and glutathione pool size, and an overall increase in glutathione reductase (GR) activity. The collapse of GR activity at 33 degrees C, together with increased SOD, APX and glutathione S transferase activity, contributed to a strong oxidation of the glutathione pool with subsequent death. Integrating responses of multiple components of the antioxidant network highlights the importance of antioxidant plasticity in explaining type-specific temperature responses in Symbiodinium. PMID- 26988786 TI - Isolation of turbinaric acid as a chemomarker of Turbinaria conoides (J. Agardh) Kutzing from South Pacific Islands. AB - Several species of the genus Turbinaria coexist along the coasts of islands in the Indian and Pacific Oceans. Among these brown algae, Turbinaria ornata and T. conoides are sister species that are difficult to differentiate using exclusively morphological characters. Based on in vivo nuclear magnetic resonance and chromatographic techniques, i.e., liquid and gas chromatography-mass spectrometry analysis, combined with phylogenetic data, we successfully identified turbinaric acid in T. conoides samples from several Indian and Pacific Ocean islands. This nonvariable discriminant molecule was only identified in T. conoides specimens, but not in the two allied species T. ornata and T. decurrens. Results are discussed with regard to turbinaric acid as an interesting chemomarker isolated from T. conoides and the rapid discrimination of Turbinaria specimens using chemical assays. PMID- 26988787 TI - Five Cyanophora (Cyanophorales, Glaucophyta) species delineated based on morphological and molecular data. AB - Cyanophora is an important glaucophyte genus of unicellular biflagellates that may have retained ancestral features of photosynthetic eukaryotes. The nuclear genome of Cyanophora was recently sequenced, but taxonomic studies of more than two strains are lacking for this genus. Furthermore, no study has used molecular methods to taxonomically delineate Cyanophora species. Here, we delimited the species of Cyanophora using light and electron microscopy, combined with molecular data from several globally distributed strains, including one newly established. Using a light microscope, we identified two distinct morphological groups: one with ovoid to ellipsoidal vegetative cells and another with dorsoventrally flattened or broad, bean-shaped vegetative cells containing duplicated plastids. Our light and scanning electron microscopy clearly distinguished three species with ovoid to ellipsoidal cells (C. paradoxa Korshikov, C. cuspidata Tos.Takah. & Nozaki sp. nov., and C. kugrensii Tos.Takah. & Nozaki sp. nov.) and two species with broad, bean-shaped cells (C. biloba Kugrens, B.L.Clay, C.J.Mey. & R.E.Lee and C. sudae Tos.Takah. & Nozaki sp. nov.) based on differences in cell shape and surface ornamentations of the vegetative cells under the field-emission scanning electron microscope. Molecular phylogenetic analyses of P700 chl a apoprotein A2 (psaB) genes and internal transcribed spacer (ITS) regions of nuclear ribosomal DNA (rDNA), as well as a comparison of secondary structures of nuclear rDNA ITS-2 and genetic distances of psaB genes, supported the delineation of five morphological species of Cyanophora. PMID- 26988788 TI - The pigment composition of Phaeocystis antarctica (Haptophyceae) under various conditions of light, temperature, salinity, and iron. AB - The pigment composition of Phaeocystis antarctica was monitored under various conditions of light, temperature, salinity, and iron. 19'-Hexanoyloxyfucoxanthin (Hex-fuco) always constituted the major light-harvesting pigment, with remarkably stable ratios of Hex-fuco-to-chl a under the various environmental conditions. Increased pigment-to-chl a ratios at low irradiance confirmed the light harvesting function of Fucoxanthin (Fuco), 19'-Hexanoyloxy-4-ketofucoxanthin (Hex kfuco), 19'-butanoyloxyfucoxanthin (But-fuco), and chl c2 and c3. Increased pigment-to-chl a ratios at high irradiance, low iron concentrations, and to a lesser extent at high salinity confirmed the photoprotective function of diadinoxanthin, diatoxanthin, and beta,beta-carotene. Pigment ratios were not always according to expectations. The consistent increase in But-fuco/chl at high temperature, high salinity, and low iron suggests a role in photoprotection rather than in light harvesting. Low Hex-kfuco/chl ratios at high salinity were consistent with a role as light harvester, but the high ratios at high temperature were not, leaving the function of Hex-kfuco enigmatic. Dedicated experiments were performed to test whether or not the light-harvesting pigment Fuco could be converted into its structural relative Hex-fuco, and vice versa, in response to exposure to light shifts. Rapid conversions could not be confirmed, but long-term conversions cannot be excluded. New pigment ratios are proposed for chemotaxonomic applications. The ratios will improve pigment-based diagnosis of algal species in waters dominated by P. antarctica. PMID- 26988789 TI - Selective feeding and foreign plastid retention in an Antarctic dinoflagellate. AB - The peridinin-containing plastid found in most photosynthetic dinoflagellates is thought to have been replaced in a few lineages by plastids of chlorophyte, diatom, or haptophyte origin. Other distinct lineages of phagotrophic dinoflagellates retain functional plastids obtained from algal prey for different durations and with varying source species specificity. 18S rRNA gene sequence analyses have placed a novel gymnodinoid dinoflagellate isolated from the Ross Sea (RSD) in the Kareniaceae, a family of dinoflagellates with permanent plastids of haptophyte origin. In contrast to other species in this family, the RSD contains kleptoplastids sequestered from its prey, Phaeocystis antarctica. Culture experiments were employed to determine whether the RSD fed selectively on P. antarctica when offered in combination with another polar haptophyte or cryptophyte species, and whether the RSD, isolated from its prey and starved, would take up plastids from P. antarctica or from other polar haptophyte or cryptophyte species. Evidence was obtained for selective feeding on P. antarctica, plastid uptake from P. antarctica, and increased RSD growth in the presence of P. antarctica. The presence of a peduncle-like structure in the RSD suggests that kleptoplasts are obtained by myzocytosis. RSD cells incubated without P. antarctica were capable of survival for at least 29.5 months. This remarkable longevity of the RSD's kleptoplasts and its species specificity for prey and plastid source is consistent with its prolonged co-evolution with P. antarctica. It may also reflect the presence of a plastid protein import mechanism and genes transferred to the dinokaryon from a lost permanent haptophyte plastid. PMID- 26988790 TI - Reassessment of the cyanobacterial family Microchaetaceae and establishment of new families Tolypothrichaceae and Godleyaceae. AB - The family Microchaetaceae is a large group of heterocytous cyanobacteria, whose members bear typical morphological features of uniseriate heteropolar filaments never terminated by thin hairs and with simple false branching. However, phylogenetic analyses of the gene for 16S rRNA showed that members of this traditionally morphologically delimited family form several distant groups and therefore the current concept is hereafter indefensible. In this study, we provide reassessment of the status of the family Microchaetaceae based on morphology, ecology, biogeography, and phylogeny of 16S rRNA gene. Thorough examination of strains of the nominate genus Microchaete revealed their affiliation to two groups, Nostocaceae and Rivulariaceae, and their distant position to other traditional members of Microchaetaceae such as Tolypothrix, Hassallia, and Coleodesmium. To reflect the phylogenetic relationships and to accommodate members of the traditional family Microchaetaceae that are clearly not related to any of the Microchaete representatives, we propose establishment of two new families, Tolypothrichaceae and Godleyaceae. Based on both molecular and morphological evidence, we also provide a description of three new species of the genus Fortiea. PMID- 26988792 TI - Ailadinium reticulatum gen. et sp. nov. (Dinophyceae), a New Thecate, Marine, Sand-Dwelling Dinoflagellate from the Northern Red Sea. AB - A new photosynthetic, sand-dwelling marine dinoflagellate, Ailadinium reticulatum gen. et sp. nov., is described from the Jordanian coast in the Gulf of Aqaba, northern Red Sea, based on detailed morphological and molecular data. A. reticulatum is a large (53-61 MUm long and 38-48 MUm wide), dorsoventrally compressed species, with the epitheca smaller than the hypotheca. The theca of this new species is thick and peculiarly ornamented with round to polygonal depressions forming a foveate-reticulate thecal surface structure. The Kofoidian thecal tabulation is APC (Po, cp), 4', 2a, 6'', 6c, 4s, 6''', 1p, 1'''' or alternatively it can be interpreted as APC, 4', 2a, 6'', 6c, 4s, 6''', 2''''. The plate pattern of A. reticulatum is noticeably different from described dinoflagellate genera. Phylogenetic analyses based on the SSU and LSU rDNA genes did not show any supported affinities with currently known thecate dinoflagellates. PMID- 26988791 TI - Toward an inordinate fondness for stars, beetles and Lobophora? Species diversity of the genus Lobophora (Dictyotales, Phaeophyceae) in New Caledonia. AB - Until the recent use of molecular markers, species diversity of Lobophora, an ecologically important brown algal genus with a worldwide distribution in temperate and tropical seas, has been critically underestimated. Using a DNA based taxonomic approach, we re-examined diversity of the genus from New Caledonia in the Southwest Pacific Ocean. First, species were delineated using general mixed Yule coalescent-based and barcoding gap approaches applied to a mitochondrial cox3 data set. Results were subsequently confirmed using chloroplast psbA and rbcL data sets. Species delimitation analyses agreed well across markers and delimitation algorithms, with the barcoding gap approach being slightly more conservative. Analyses of the cox3 data set resulted in 31-39 molecular operational taxonomic units (MOTUs), four of which are previously described species (L. asiatica, L. crassa, L. nigrescens s.l., L. pachyventera). Of the remaining MOTUs for which we obtained a representative number of sequences and results are corroborated across analyses and genes, we described 10 species de novo: L. abaculusa, L. abscondita, L. densa, L. dimorpha, L. gibbera, L. hederacea, L. monticola, L. petila, L. rosacea, and L. undulata. Our study presents an excellent case of how a traditional morphology-based taxonomy fails to provide accurate estimates of algal diversity. Furthermore, the level of Lobophora diversity unveiled from a single locality in the Pacific Ocean raises important questions with respect to the global diversity of the genus, the distributions and range sizes of the individual species, as well as the mechanisms facilitating coexistence. PMID- 26988793 TI - Cellular organelles facilitate dimerization of a newly identified Arf from Chlamydomonas reinhardtii. AB - GTPases of the Ras superfamily regulate a wide variety of cellular processes including vesicular transport and various secretory pathways of the cell. ADP - ribosylation factor (ARF) belongs to one of the five major families of the Ras superfamily and serves as an important component of vesicle formation and transport machinery of the cells. The binding of GTP to these Arfs and its subsequent hydrolysis, induces conformational changes in these proteins leading to their enzymatic activities. The dimeric form of Arf is associated with membrane pinch-off during vesicle formation. In this report, we have identified an arf gene from the unicellular green alga Chlamydomonas reinhardtii, CrArf, and showed that the oligomeric state of the protein in C. renhardtii is modulated by the cellular membrane environment of the organism. Protein cross-linking experiments showed that the purified recombinant CrArf has the ability to form a dimer. Both the 20-kDa monomeric and 40-kDa dimeric forms of CrArf were recognized from Chlamydomonas total cell lysate (CrTLC) and purified recombinant CrArf by the CrArf specific antibody. The membranous environment of the cell appeared to facilitate dimerization of the CrArf, as dimeric form was found exclusively associated with the membrane bound organelles. The subcellular localization studies in Chlamydomonas suggested that CrArf mainly localized in the cytosol and was mislocalized in vesicle transport machinery inhibitor treated cells. This research sheds light on the importance of the cellular membrane environment for regulating the oligomeric state of CrArf protein in this organism and associated functional role. PMID- 26988794 TI - Pigment composition and photoacclimation as keys to the ecological success of Gonyostomum semen (Raphidophyceae, Stramenopiles). AB - Aquatic habitats are usually structured by light attenuation with depth resulting in different microalgal communities, each one adapted to a certain light regime by their specific pigment composition. Several taxa contain pigments restricted to one phylogenetic group, making them useful as marker pigments in phytoplankton community studies. The nuisance and invasive freshwater microalga Gonyostomum semen (Raphidophyceae) is mainly found in brown water lakes with sharp vertical gradients in light intensity and color. However, its pigment composition and potential photoadaptations have not been comprehensively studied. We analyzed the photopigment composition of 12 genetically different strains of G. semen by high performance liquid chromatography after acclimation to different light conditions. We confirmed the pigments chl a, chl c1c2, diadinoxanthin, trans neoxanthin, cis-neoxanthin, alpha and beta carotene, which have already been reported for G. semen. In addition, we identified, for the first time, the pigments violaxan-thin, zeaxanthin, and alloxanthin in this species. Alloxanthin has never been observed in raphidophytes before, suggesting differences in evolutionary plastid acquisition between freshwater lineages and the well described marine species. The amount of total chl a per cell generally decreased with increasing light intensity. In contrast, the increasing ratios of the prominent pigments diadinoxanthin and alloxanthin per chl a with light intensity suggest photoprotective functions. In addition, we found significant variation in cell-specific pigment concentration among strains, grouped by lake of origin, which might correspond to genetic differences between strains and populations. PMID- 26988797 TI - Modification of Tet1 and histone methylation dynamics in dairy goat male germline stem cells. AB - OBJECTIVES: Tet (ten-eleven translocation) protein 1 is a key enzyme for DNA demethylation, which modulates DNA methylation and gene transcription. DNA methylation and histone methylation are critical elements in self-renewal of male germline stem cells (mGSCs) and spermatogenesis. mGSCs are the only type of adult stem cells able to achieve intergenerational transfer of genetic information, which is accomplished through differentiated sperm cells. However, numerous epigenetic obstacles including incomplete DNA methylation and histone methylation dynamics make establishment of stable livestock mGSC cell lines difficult. The present study was conducted to detect effects of DNA methylation and histone methylation dynamics in dairy goat mGSCs self-renewal and proliferation, through overexpression of Tet1. MATERIALS AND METHODS: An immortalized dairy goat mGSC cell line bearing mouse Tet1 (mTet1) gene was screened and characteristics of the cells were assayed by quantitative real-time PCR (qRT-PCR), immunofluorescence assay, western blotting, fluorescence activated cell sorting (FACS) and use of the cell counting kit (CCK8) assay. RESULTS: The screened immortalized dairy goat mGSC cell line bearing mTet1, called mGSC-mTet1 cells was treated with optimal doxycycline (Dox) concentration to maintain Tet1 gene expression. mGSC-mTet1 cells proliferated at a significantly greater rate than wild-type mGSCs, and mGSCs-specific markers such as proliferating cell nuclear antigen (PCNA), cyclinD1 (CCND1), GDNF family receptor alpha 1 (Gfra1) and endogenic Tet1, Tet2 were upregulated. The cells exhibited not only reduction in level of histone methylation but also changes in nuclear location of that methylation marker. While H3K9me3 was uniformly distributed throughout the nucleus of mGSC-mTet1 cells, it was present in only particular locations in mGSCs. H3K27me3 was distributed surrounding the edges of nuclei of mGSC-mTet1 cells, while it was uniformly distributed throughout nuclei of mGSCs. Our results conclusively demonstrate that modification of mGSCs with mTet1 affected mGSC maintenance and seemed to promote establishment of stable goat mGSC cell lines. CONCLUSIONS: Taken together, our data suggest that Tet1 had novel and dynamic roles for regulating maintenance of pluripotency and proliferation of mGSCs by forming complexes with PCNA and histone methylation dynamics. This may provide new solutions for mGSCs stability and livestock mGSC cell line establishment. PMID- 26988799 TI - Analytical and semi-preparative enantioresolution of (RS)-ketorolac from pharmaceutical formulation and in human plasma by HPLC. AB - An efficient, simple, validated, analytical and semi-preparative HPLC method has been developed for direct enantioresolution of (RS)-Ketorolac (Ket) using monochloro-methylated derivatives of cellulose and amylose, i.e. cellulose (tris 3-chloro-4-methylphenylcarbamate) and amylose (tris-5-chloro-2 methylphenylcarbamate) as chiral stationary phases (CSPs) with photo diode array detection at 320 nm. Enantioresolution was carried out in samples of human plasma spiked with (RS)-Ket under normal and reversed-phase elution modes with suitable mobile phase compositions. The effect of nature of alcohols (MeOH, EtOH, PrOH and n-BuOH) and other solvents (MeCN and MeOH) as organic modifiers in the mobile phase was investigated on the separation performance of two CSPs in terms of retention and separation of enantiomers. The best resolution was observed on cellulose-based CSP using EtOH, while using 2-PrOH (15%) and amylose-based CSP obtained the highest retention. Under reversed-phase elution mode the best enantioseparation was observed using 30% MeCN with ammonium formate buffer. The elution order of enantiomers was ascertained by determining specific rotations. The limit of detection and quantitation values were 5 and 15.5 ng/mL for each enantiomer of (RS)-Ket, respectively. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26988798 TI - Clinical efficacy of water extract of stem bark of Terminalia arjuna (Roxb. ex DC.) Wight & Arn. in patients of chronic heart failure: a double-blind, randomized controlled trial. AB - BACKGROUND: The stem bark of Terminalia arjuna (Roxb. ex DC.) Wight and Arn. (Arjuna) is used in Indian system of medicine (Ayurveda) for treatment of various cardiac diseases, including heart failure. However, well designed clinical trials exploring its efficacy and safety in chronic heart failure (CHF) are lacking. PURPOSE: To ascertain the add-on efficacy and safety of a standardized water extract of stem bark of Arjuna (Arjuna extract) in CHF patients on standard pharmacotherapy. STUDY DESIGN: Double-blind, parallel, randomized, placebo controlled add-on clinical trial. METHODS: After approval of institutional ethics committee, 100 patients of CHF of New York Heart Association (NYHA) functional class II on standard pharmacotherapy having an echocardiographic left ventricular ejection fraction (LVEF) <= 40% were consecutively recruited with informed consent and randomized 1:1 to Arjuna extract 750 mg or matching placebo twice daily. The primary outcome measure was change in LVEF at 12 weeks. Secondary outcome measures included changes in (i) NYHA functional class, (ii) distance covered in 6 min walk test (6MWT), (iii) quality of life (QoL), as determined by the Kansas City Cardiomyopathy Questionnaire (KCCQ), (iv) plasma brain natriuretic peptide, (v) plasma cytokines (interleukin-6, high sensitivity C reactive protein and tumour necrosis factor-alpha) and (vi) oxidative stress markers [serum thiobarbituric acid reactive substances (TBARS), red blood cell (RBC) superoxide dismutase (SOD), RBC catalase and RBC glutathione (GSH)] at 6 and 12 weeks. Safety assessment was done by adverse event monitoring and laboratory investigations. Results were expressed as mean +/- SD or median (interquartile range) and analysed with intention-to- treat principle using appropriate two-sided statistical tests. A p-value < 0.05 was considered significant. RESULTS: Arjuna extract was well-tolerated, but did not change LVEF (24.3 +/- 7.1 versus 25.5 +/- 7.7%; p = 0.4) or secondary outcome measures except preservation of RBC catalase activity [1275(104, 10350) versus 1243.5(104, 10350) U/g haemoglobin; p = 0.01] compared to placebo. Significantly greater percentage increases occurred in distance covered in 6 MWT, RBC-SOD, RBC catalase, RBC GSH and in symptom severity and stability domains of KCCQ in patients on Arjuna extract versus those on placebo, on a post-hoc analysis, between subgroups of patients who improved in these outcomes. CONCLUSION: Arjuna extract did not improve LVEF in CHF patients over 12 weeks, although there was improvement in functional capacity, antioxidant reserves and symptom-related QoL domains in some patients. PMID- 26988796 TI - Transcranial magnetic stimulation (TMS) inhibits cortical dendrites. AB - One of the leading approaches to non-invasively treat a variety of brain disorders is transcranial magnetic stimulation (TMS). However, despite its clinical prevalence, very little is known about the action of TMS at the cellular level let alone what effect it might have at the subcellular level (e.g. dendrites). Here, we examine the effect of single-pulse TMS on dendritic activity in layer 5 pyramidal neurons of the somatosensory cortex using an optical fiber imaging approach. We find that TMS causes GABAB-mediated inhibition of sensory evoked dendritic Ca(2+) activity. We conclude that TMS directly activates fibers within the upper cortical layers that leads to the activation of dendrite targeting inhibitory neurons which in turn suppress dendritic Ca(2+) activity. This result implies a specificity of TMS at the dendritic level that could in principle be exploited for investigating these structures non-invasively. PMID- 26988800 TI - Short-term effectiveness of a web-based tailored intervention for cancer survivors on quality of life, anxiety, depression, and fatigue: randomized controlled trial. AB - BACKGROUND: The aim of this study was to evaluate the short-term effectiveness of the web-based computer-tailored intervention Kanker Nazorg Wijzer (Cancer Aftercare Guide). The intervention aims to support cancer survivors with managing psychosocial and lifestyle-related issues. In this study, the impact on quality of life, anxiety, depression, and fatigue were evaluated. METHODS: Cancer survivors were recruited through 21 Dutch hospitals (November 2013-June 2014). Outcome measures included quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30), anxiety and depression (Hospital Anxiety and Depression Scale), and fatigue (Checklist Individual Strength). In a randomized controlled trial with an intervention group (n = 231) and a waiting list control group (n = 231), the short-term effectiveness was evaluated through multilevel linear regression analyses, controlling for selective dropout, baseline differences, and several demographic and disease related characteristics. RESULTS: In total, 188 participants of the intervention group and 221 of the control group completed the 6-month measurement (dropout = 11.5%). The intervention was effective in reducing depression (B = -0.63, p = 0.007, f2 = 0.019, d = 0.21) and fatigue (B = -4.36, p = 0.020, f2 = 0.013, d = 0.21). In addition, effects were found for emotional (B = 3.47, p = 0.022, f2 = 0.013, d = 0.15) and social functioning (B = 3.95, p = 0.011, f2 = 0.017, d = 0.15), although this evidence was less strong. There were indications that the effects of fatigue and social functioning were influenced by module use. CONCLUSIONS: While effect sizes were small, they can be considered as clinically relevant. With the Cancer Aftercare Guide being an effective, low-intensive, and easy accessible intervention, it could serve as a first step in stepped care for needs assessment and initial support for psychosocial problems that are present after cancer treatment. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26988801 TI - Design, physico-chemical properties and biological evaluation of some new N [(phenoxy)alkyl]- and N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols as anticonvulsant agents. AB - A series of thirty N-(phenoxy)alkyl or N-{2-[2 (phenoxy)ethoxy]ethyl}aminoalkanols has been designed, synthesized and evaluated for anticonvulsant activity in MES, 6Hz test, and pilocarpine-induced status epilepticus. Among the title compounds, the most promising seems R-(-)-2N-{2-[2 (2,6-dimethylphenoxy)ethoxy]ethyl}aminopropan-1-ol hydrochloride (22a) with proved absolute configuration with X-ray analysis and enantiomeric purity. The compound is effective in MES test with ED50=12.92 mg/kg b.w. and its rotarod TD50=33.26 mg/kg b.w. The activity dose is also effective in a neurogenic pain model-the formalin test. Within high throughput profile assay, among eighty one targets, the strongest affinity of the compound is observed towards sigma receptors and 5-HT transporter and the compound does not bind to hERG. It also does not exhibit mutagenic properties in the Vibrio harveyi test. Moreover, murine liver microsomal assay and pharmacokinetics profile (mice, iv, p.o., ip) indicate that the liver is the primary site of biotransformation of the compound, suggesting that both 22a and its metabolite(s) are active, compensating probably low bioavailability of the parent molecule. PMID- 26988802 TI - Design, synthesis, topoisomerase I & II inhibitory activity, antiproliferative activity, and structure-activity relationship study of pyrazoline derivatives: An ATP-competitive human topoisomerase IIalpha catalytic inhibitor. AB - A series of pyrazoline derivatives (5) were synthesized in 92-96% yields from chalcones (3) and hydrazides (4). Subsequently, topo-I and IIalpha-mediated relaxation and antiproliferative activity assays were evaluated for 5. Among the tested compounds, 5h had a very strong topo-I activity of 97% (Camptothecin, 74%) at concentration of 100 MUM. Nevertheless, all the compounds 5a-5i showed significant topo II inhibitory activity in the range of 90-94% (Etoposide, 96%) at the same concentration. Cytotoxic potential of these compounds was tested in a panel of three human tumor cell lines, HCT15, BT474 and T47D. All the compounds showed strong activity against HCT15 cell line with IC50 at the range of 1.9-10.4 MUM (Adriamycin, 23.0; Etoposide, 6.9; and Camptothecin, 7.1 MUM). Moreover, compounds 5c, 5f and 5i were observed to have strong antiproliferative activity against BT474 cell lines. Since, compound 5d showed antiproliferative activity at a very low IC50 thus 5d was then selected to study on their mode of action with diverse methods of ATP competition assay, ATPase assay and DNA-topo IIalpha cleavable complex assay and the results revealed that it functioned as a ATP competitive human topoisomerase IIalpha catalytic inhibitor. Further evaluation of endogenous topo-mediated DNA relaxation in cells has been conducted to find that, 5d inhibited endogenous topo-mediated pBR322 plasmid relaxation is more efficient (78.0 +/- 4.7% at 50 MUM) than Etoposide (36.0 +/- 1.7% at 50 MUM). PMID- 26988803 TI - Design and evaluation of novel glutaminase inhibitors. AB - A novel set of GAC (kidney glutaminase isoform C) inhibitors able to inhibit the enzymatic activity of GAC and the growth of the triple negative MDA-MB-231 breast cancer cells with low nanomolar potency is described. Compounds in this series have a reduced number of rotatable bonds, improved ClogPs, microsomal stability and ligand efficiency when compared to the leading GAC inhibitors BPTES and CB 839. Property improvements were achieved by the replacement of the flexible n diethylthio or the n-butyl moiety present in the leading inhibitors by heteroatom substituted heterocycloalkanes. PMID- 26988805 TI - The influence of salinity on the fate and behavior of silver standardized nanomaterial and toxicity effects in the estuarine bivalve Scrobicularia plana. AB - Because of their antibacterial properties, silver (Ag) engineered nanomaterials are included in many products. The present study used a standardized Ag nanomaterial (NM-300K, 20 nm) supplied with a stabilizing agent. The aim was to investigate the behavior of Ag nanomaterial in an estuarine-like medium at 2 salinities (15 psu and 30 psu). Uptake as well as sublethal effects of Ag nanomaterial (10 MUg Ag/L), its stabilizing agent, and AgNO3 (10 MUg Ag/L) were assessed in the clam Scrobicularia plana, after 7 d of exposure. The release of soluble Ag from Ag nanomaterial in the experimental media was quantified by using diffusive gradient in thin films and ultrafiltration. A multibiomarker approach was employed to reveal responses of clams at subindividual and individual levels. The bioaccumulation of Ag was significantly greater at 15 psu versus 30 psu, which could be explained by differences in Ag speciation. In conclusion, the present study showed different impacts of Ag nanomaterial that were not always explained by the release of Ag ions in clams at both salinities; such impacts were particularly characterized by induction of oxidative stress, cell damage, and impairment of energetic levels. Burrowing of clams was affected by the stabilizing agent depending on the salinity tested, with stronger effects at 15 psu. Finally, the present study highlighted salinity-dependent changes in the physiology of estuarine bivalves. Environ Toxicol Chem 2016;35:2550-2561. (c) 2016 SETAC. PMID- 26988804 TI - Investigation of 4-amino-5-alkynylpyrimidine-2(1H)-ones as anti-mycobacterial agents. AB - In vitro anti-mycobacterial activities of novel 4-amino-5-alkynylpyrimidine-2(1H) ones were investigated. 4-Amino-5-heptynylpyrimidine-2(1H)-one (3) and 4-amino-5 (2-phenylethynyl)pyrimidine-2(1H)-one (7) displayed potent in vitro activity against Mycobacterium bovis and Mycobacterium tuberculosis. Compounds 3 and 7 were also assessed for their in vivo activity in BALB/c mice infected with M. tuberculosis (H37Ra). Both compounds showed promising in vivo efficacy at a dose of 25 mg/kg for 2 weeks. Importantly, compounds 3 and 7 interacted synergistically with the front-line anti-tuberculosis drug isoniazid in vitro and in vivo. These results suggest that this class of compounds has strong anti mycobacterial potential. PMID- 26988807 TI - Genotype-phenotype correlation in a cohort of Portuguese patients comprising the entire spectrum of VWD types: impact of NGS. AB - The diagnosis of von Willebrand disease (VWD), the most common inherited bleeding disorder, is characterised by a variable bleeding tendency and heterogeneous laboratory phenotype. The sequencing of the entire VWF coding region has not yet become a routine practice in diagnostic laboratories owing to its high costs. Nevertheless, next-generation sequencing (NGS) has emerged as an alternative to overcome this limitation. We aimed to determine the correlation of genotype and phenotype in 92 Portuguese individuals from 60 unrelated families with VWD; therefore, we directly sequenced VWF. We compared the classical Sanger sequencing approach and NGS to assess the value-added effect on the analysis of the mutation distribution in different types of VWD. Sixty-two different VWF mutations were identified, 27 of which had not been previously described. NGS detected 26 additional mutations, contributing to a broad overview of the mutant alleles present in each VWD type. Twenty-nine probands (48.3 %) had two or more mutations; in addition, mutations with pleiotropic effects were detected, and NGS allowed an appropriate classification for seven of them. Furthermore, the differential diagnosis between VWD 2B and platelet type VWD (n = 1), Bernard Soulier syndrome and VWD 2B (n = 1), and mild haemophilia A and VWD 2N (n = 2) was possible. NGS provided an efficient laboratory workflow for analysing VWF. These findings in our cohort of Portuguese patients support the proposal that improving VWD diagnosis strategies will enhance clinical and laboratory approaches, allowing to establish the most appropriate treatment for each patient. PMID- 26988806 TI - Rapid erasure of hippocampal memory following inhibition of dentate gyrus granule cells. AB - The hippocampus is critical for the acquisition and retrieval of episodic and contextual memories. Lesions of the dentate gyrus, a principal input of the hippocampus, block memory acquisition, but it remains unclear whether this region also plays a role in memory retrieval. Here we combine cell-type specific neural inhibition with electrophysiological measurements of learning-associated plasticity in behaving mice to demonstrate that dentate gyrus granule cells are not required for memory retrieval, but instead have an unexpected role in memory maintenance. Furthermore, we demonstrate the translational potential of our findings by showing that pharmacological activation of an endogenous inhibitory receptor expressed selectively in dentate gyrus granule cells can induce a rapid loss of hippocampal memory. These findings open a new avenue for the targeted erasure of episodic and contextual memories. PMID- 26988808 TI - Changing state of gynecologic oncologist specialty in Japan. AB - Gynecologic oncologists must have extensive knowledge regarding the methods of treating a diverse range of gynecologic cancers as well as the ability to perform cutting-edge multidisciplinary treatments that frequently involve surgery. Given that coordination with other medical departments is vital for treatment, a high level of interpersonal and technical skills needs to be demonstrated to form the axis for medical treatment. One objective of the specialist certification system is the grooming of leaders as gynecologic oncologists while instructing trainees. The most distinguishing feature of Japanese gynecologic oncologists is that they need experience in more than 150 invasive cancer treatments, including more than 100 operations within the last 3-5 years. As for performance of surgery, at least 30 operations, including 15 radical hysterectomies, are required. Since surgical methods, including laparoscopic surgery, are undergoing a radical change, and increasing numbers of patients are undergoing radiotherapy for invasive cervical cancer, a review of the necessary requirements is critical. It is important to foster new leaders who are research-oriented. Now is the time for marked reform with the new specialist certification system being introduced by the Japanese Medical Specialty Board. Japan has the advantage of offering medical services at a much lower cost because of its national health insurance system. However, specialists are currently not receiving clear benefits befitting their efforts, and the question of how to maintain their motivation is an issue for the future. For these purposes, I believe securing incentives is a critical issue for specialists. PMID- 26988809 TI - Brain Injury in Neonates with Complex Congenital Heart Disease: What Is the Predictive Value of MRI in the Fetal Period? AB - BACKGROUND AND PURPOSE: Brain injury in neonates with congenital heart disease is an important predictor of adverse neurodevelopmental outcome. Impaired brain development in congenital heart disease may have a prenatal origin, but the sensitivity and specificity of fetal brain MR imaging for predicting neonatal brain lesions are currently unknown. We sought to determine the value of conventional fetal MR imaging for predicting abnormal findings on neonatal preoperative MR imaging in neonates with complex congenital heart disease. MATERIALS AND METHODS: MR imaging studies were performed in 103 fetuses with confirmed congenital heart disease (mean gestational age, 31.57 +/- 3.86 weeks) and were repeated postnatally before cardiac surgery (mean age, 6.8 +/- 12.2 days). Each MR imaging study was read by a pediatric neuroradiologist. RESULTS: Brain abnormalities were detected in 17/103 (16%) fetuses by fetal MR imaging and in 33/103 (32%) neonates by neonatal MR imaging. Only 9/33 studies with abnormal neonatal findings were preceded by abnormal findings on fetal MR imaging. The sensitivity and specificity of conventional fetal brain MR imaging for predicting neonatal brain abnormalities were 27% and 89%, respectively. CONCLUSIONS: Brain abnormalities detected by in utero MR imaging in fetuses with congenital heart disease are associated with higher risk of postnatal preoperative brain injury. However, a substantial proportion of anomalies on postnatal MR imaging were not present on fetal MR imaging; this result is likely due to the limitations of conventional fetal MR imaging and the emergence of new lesions that occurred after the fetal studies. Postnatal brain MR imaging studies are needed to confirm the presence of injury before open heart surgery. PMID- 26988810 TI - A Diffusion Tensor Imaging Study on White Matter Abnormalities in Patients with Type 2 Diabetes Using Tract-Based Spatial Statistics. AB - BACKGROUND AND PURPOSE: Patients with type 2 diabetes mellitus have considerably higher risk of developing cognitive impairment and dementia. WM changes in these patients have been reported. Our aim was to demonstrate that gradual and continuous WM change and the associated cognitive decline in patients with type 2 diabetes mellitus can be captured by DTI parameters, which can be used to complement neuropsychological test scores in identifying patients with type 2 diabetes mellitus with and without mild cognitive impairment. MATERIALS AND METHODS: Forty-two patients with type 2 diabetes mellitus, divided into a group with mild cognitive impairment (n = 20) and a group with normal cognition (n = 22), were enrolled with age-, sex-, and education-matched healthy controls (n = 26). 3T DTI followed by Tract-Based Spatial Statistics analysis was used to investigate the differences in fractional anisotropy, mean diffusivity, axial diffusivity (lambda1), and radial diffusivity (lambda23) among the groups. A receiver operating characteristic analysis assessed the performance of DTI parameters for separating the 2 groups with type 2 diabetes mellitus. RESULTS: The whole-brain Tract-Based Spatial Statistics analysis revealed that 7.3% and 24.9% of the WM exhibited decreased fractional anisotropy and increased mean diffusivity (P < .05), respectively, between the diabetes mellitus with mild cognitive impairment and the diabetes mellitus with normal cognition groups, while considerably larger WM regions showed fractional anisotropy (36.6%) and mean diffusivity (58.8%) changes between the diabetes mellitus with mild cognitive impairment and the healthy control groups. These changes were caused primarily by an elevated radial diffusivity observed in the patients with diabetes mellitus with mild cognitive impairment. Radial diffusivity also exhibited subtle but statistically significant changes between the diabetes mellitus with normal cognition and the healthy control groups. Analyses on individual fiber tracts showed pronounced fractional anisotropy reduction and mean diffusivity elevation in regions related to cognitive functions. The receiver operating characteristic analysis on the right cingulum (hippocampus) showed that fractional anisotropy produced a larger area under the curve (0.832) than mean diffusivity (0.753) for separating mild cognitive impairment from normal cognition among patients with type 2 diabetes mellitus. When fractional anisotropy was combined with mean diffusivity, the area under the curve was further improved to 0.857. CONCLUSIONS: DTI parameters can show a substantial difference between patients with type 2 diabetes mellitus with and without mild cognitive impairment, suggesting their potential use as an imaging marker for detecting cognitive decline in patients with type 2 diabetes mellitus. More important, DTI parameters may capture gradual and continuous WM changes that can be associated with early stages of cognitive decline in patients with type 2 diabetes mellitus before they can be diagnosed clinically by using conventional neuropsychological tests. PMID- 26988811 TI - Multimodal CT Imaging: Time to Treatment and Outcomes in the IMS III Trial. AB - BACKGROUND AND PURPOSE: The importance of time in acute stroke is well established. Using the Interventional Management of Stroke III trial data, we explored the effect of multimodal imaging (CT perfusion and/or CT angiography) versus noncontrast CT alone on time to treatment and outcomes. MATERIALS AND METHODS: We examined 3 groups: 1) subjects with baseline CTP and CTA (CTP+CTA), 2) subjects with baseline CTA without CTP (CTA), and 3) subjects with noncontrast head CT alone. The demographics, treatment time intervals, and clinical outcomes in these groups were studied. RESULTS: Of 656 subjects enrolled in the Interventional Management of Stroke III trial, 90 (13.7%) received CTP and CTA, 216 (32.9%) received CTA (without CTP), and 342 (52.1%) received NCCT alone. Median times for the CTP+CTA, CTA, and NCCT groups were as follows: stroke onset to IV tPA (120.5 versus 117.5 versus 120 minutes; P = .5762), IV tPA to groin puncture (77.5 versus 81 versus 91 minutes; P = .0043), groin puncture to endovascular therapy start (30 versus 38 versus 44 minutes; P = .0001), and endovascular therapy start to end (63 versus 46 versus 74 minutes; P < .0001). Compared with NCCT, the CTA group had better outcomes in the endovascular arm (OR, 2.12; 95% CI, 1.36-3.31; adjusted for age, NIHSS score, and time from onset to IV tPA). The CTP+CTA group did not have better outcomes compared with the NCCT group. CONCLUSIONS: Use of CTA with or without CTP did not delay IV tPA or endovascular therapy compared with NCCT in the Interventional Management of Stroke III trial. PMID- 26988813 TI - T1-Weighted Dynamic Contrast-Enhanced MRI Is a Noninvasive Marker of Epidermal Growth Factor Receptor vIII Status in Cancer Stem Cell-Derived Experimental Glioblastomas. PMID- 26988812 TI - Improving Perfusion Measurement in DSC-MR Imaging with Multiecho Information for Arterial Input Function Determination. AB - BACKGROUND AND PURPOSE: Clinical measurements of cerebral perfusion have been increasingly performed with multiecho dynamic susceptibility contrast-MR imaging techniques due to their ability to remove confounding T1 effects of contrast agent extravasation from perfusion quantification. However, to this point, the extra information provided by multiecho techniques has not been used to improve the process of estimating the arterial input function, which is critical to accurate perfusion quantification. The purpose of this study is to investigate methods by which multiecho DSC-MRI data can be used to automatically avoid voxels whose signal decreases to the level of noise when calculating the arterial input function. MATERIALS AND METHODS: Here we compare postprocessing strategies for clinical multiecho DSC-MR imaging data to test whether arterial input function measures could be improved by automatically identifying and removing voxels exhibiting signal attenuation (truncation) artifacts. RESULTS: In a clinical pediatric population, we found that the Pearson correlation coefficient between DeltaR2* time-series calculated from each TE individually was a valuable criterion for automated estimation of the arterial input function, resulting in higher peak arterial input function values while maintaining smooth and reliable arterial input function shapes. CONCLUSIONS: This work is the first to demonstrate that multiecho information may be useful in clinically important automatic arterial input function estimation because it can be used to improve automatic selection of voxels from which the arterial input function should be measured. PMID- 26988815 TI - Spectrum of Clinical and Associated MR Imaging Findings in Children with Olfactory Anomalies. AB - BACKGROUND AND PURPOSE: The olfactory apparatus, consisting of the bulb and tract, is readily identifiable on MR imaging. Anomalous development of the olfactory apparatus may be the harbinger of anomalies of the secondary olfactory cortex and associated structures. We report a large single-site series of associated MR imaging findings in patients with olfactory anomalies. MATERIALS AND METHODS: A retrospective search of radiologic reports (2010 through 2014) was performed by using the keyword "olfactory"; MR imaging studies were reviewed for olfactory anomalies and intracranial and skull base malformations. Medical records were reviewed for clinical symptoms, neuroendocrine dysfunction, syndromic associations, and genetics. RESULTS: We identified 41 patients with olfactory anomalies (range, 0.03-18 years of age; M/F ratio, 19:22); olfactory anomalies were bilateral in 31 of 41 patients (76%) and absent olfactory bulbs and olfactory tracts were found in 56 of 82 (68%). Developmental delay was found in 24 (59%), and seizures, in 14 (34%). Pituitary dysfunction was present in 14 (34%), 8 had panhypopituitarism, and 2 had isolated hypogonadotropic hypogonadism. CNS anomalies, seen in 95% of patients, included hippocampal dysplasia in 26, cortical malformations in 15, malformed corpus callosum in 10, and optic pathway hypoplasia in 12. Infratentorial anomalies were seen in 15 (37%) patients and included an abnormal brain stem in 9 and an abnormal cerebellum in 3. Four patients had an abnormal membranous labyrinth. Genetic testing was performed in 23 (56%) and findings were abnormal in 11 (48%). CONCLUSIONS: Olfactory anomalies should prompt careful screening of the brain, skull base, and the pituitary gland for additional anomalies. Genetic testing should be considered. PMID- 26988814 TI - Whole-Brain DTI Assessment of White Matter Damage in Children with Bilateral Cerebral Palsy: Evidence of Involvement beyond the Primary Target of the Anoxic Insult. AB - BACKGROUND AND PURPOSE: Cerebral palsy is frequently associated with both motor and nonmotor symptoms. DTI can characterize the damage at the level of motor tracts but provides less consistent results in nonmotor areas. We used a standardized pipeline of analysis to describe and quantify the pattern of DTI white matter abnormalities of the whole brain in a group of children with chronic bilateral cerebral palsy and periventricular leukomalacia. We also explored potential correlations between DTI and clinical scale metrics. MATERIALS AND METHODS: Twenty-five patients (mean age, 11.8 years) and 25 healthy children (mean age, 11.8 years) were studied at 3T with a 2-mm isotropic DTI sequence. Differences between patients and controls were assessed both voxelwise and in ROIs obtained from an existing DTI atlas. Clinical metrics included the Gross Motor Function Classification System, the Manual Ability Classification System, and intelligence quotient. RESULTS: The voxel-level and ROI-level analyses demonstrated highly significant (P < .001) modifications of DTI measurements in patients at several levels: cerebellar peduncles, corticospinal tracts and posterior thalamic radiations, posterior corpus callosum, external capsule, anterior thalamic radiation, superior longitudinal fasciculi and corona radiata, optic nerves, and chiasm. The reduction of fractional anisotropy values in significant tracts was between 8% and 30%. Statistically significant correlations were found between motor impairment and fractional anisotropy in corticospinal tracts and commissural and associative tracts of the supratentorial brain. CONCLUSIONS: We demonstrated the involvement of several motor and nonmotor areas in the chronic damage associated with periventricular leukomalacia and showed new correlations between motor skills and DTI metrics. PMID- 26988816 TI - Reduction of Oxygen-Induced CSF Hyperintensity on FLAIR MR Images in Sedated Children: Usefulness of Magnetization-Prepared FLAIR Imaging. AB - BACKGROUND AND PURPOSE: Oxygen-induced CSF hyperintensity on FLAIR MR imaging is often observed in sedated children. This phenomenon can mimic leptomeningeal pathology and lead to a misdiagnosis. The purpose of this study was to investigate whether magnetization-prepared FLAIR MR imaging can reduce oxygen induced CSF hyperintensity and improve image quality compared with conventional (non-magnetization-prepared) FLAIR MR imaging. MATERIALS AND METHODS: Bloch simulation for magnetization-prepared and non-magnetization-prepared FLAIR sequences was performed for tissue contrast. We retrospectively reviewed 85 children with epilepsy who underwent MR imaging under general anesthesia with supplemental oxygen (41 with non-magnetization-prepared FLAIR and 44 with magnetization-prepared FLAIR). CSF hyperintensity was scored from 0 to 3 points according to the degree of CSF signal intensity and was compared between the 2 sequences. The contrast-to-noise ratios among GM, WM, and CSF were evaluated to assess general image quality from both sequences. To assess the diagnostic accuracy for hemorrhage, we reviewed an additional 25 patients with hemorrhage. RESULTS: Bloch simulation demonstrated that CSF hyperintensity can be reduced on magnetization-prepared FLAIR compared with non-magnetization-prepared FLAIR. CSF hyperintensity scores were significantly lower in magnetization-prepared FLAIR than in non-magnetization-prepared FLAIR (P < .01). The contrast-to-noise ratios for GM-WM, GM-CSF, and WM-CSF were significantly higher in magnetization-prepared FLAIR than in non-magnetization-prepared FLAIR (P < .05). Hemorrhage was clearly demarcated from CSF hyperintensity in the magnetization-prepared group (100%, 12/12) and non-magnetization-prepared group (38%, 5/13). CONCLUSIONS: Magnetization-prepared 3D-FLAIR MR imaging can significantly reduce oxygen induced CSF artifacts and increase the tissue contrast-to-noise ratio beyond the levels achieved with conventional non-magnetization-prepared 3D-FLAIR MR imaging. PMID- 26988817 TI - A New Ultrasound Marker for Bedside Monitoring of Preterm Brain Growth. AB - BACKGROUND AND PURPOSE: Preterm neonates are at risk for neurodevelopmental impairment, but reliable, bedside-available markers to monitor preterm brain growth during hospital stay are still lacking. The aim of this study was to assess the feasibility of corpus callosum-fastigium length as a new cranial sonography marker for monitoring of preterm brain growth. MATERIALS AND METHODS: In this longitudinal prospective cohort study, cranial ultrasound was planned on the day of birth, days 1, 2, 3, and 7 of life; and then weekly until discharge in preterm infants born before 29 weeks of gestational age. Reproducibility and associations between clinical variables and corpus callosum-fastigium growth trajectories were studied. RESULTS: A series of 1-8 cranial ultrasounds was performed in 140 infants (median gestational age at birth, 27(+2) weeks (interquartile range, 26(+1) to 28(+1); 57.9% male infants). Corpus callosum fastigium measurements showed good-to-excellent agreement for inter- and intraobserver reproducibility (intraclass correlation coefficient >0.89). Growth charts for preterm infants between 24 and 32 weeks of gestation were developed. Male sex and birth weight SD score were positively associated with corpus callosum-fastigium growth rate. CONCLUSIONS: Corpus callosum-fastigium length measurement is a new reproducible marker applicable for bedside monitoring of preterm brain growth during neonatal intensive care stay. PMID- 26988819 TI - [Significance of precision medicine in pancreatic cancer prevention and treatment]. AB - The morbidity and mortality of pancreatic cancer has been increasing year by year, however, the treatment progress and prevention effect were minimal. With the development of basic research, especially the advances of gene sequencing technology, it was possible to clarify the etiology and pathogenesis of pancreatic cancer, and achieve the first stage prevention. The discovery of pancreatic cancer exosomes of high sensitivity and specificity made early diagnosis of pancreatic cancer (the second stage prevention) no longer a worldwide problem. The build of pancreatic cancer genotyping with clinical applicability made the precision treatment of pancreatic cancer (the third stage prevention) possible. Thus, the precision medicine which is based on advances of gene sequencing, popularity of the Internet and the big data technology has brought a ray of hope for the prevention and treatment of pancreatic cancer. PMID- 26988818 TI - Proteome analysis of the macroscopically affected colonic mucosa of Crohn's disease and intestinal tuberculosis. AB - Differentiation between intestinal tuberculosis (ITB) and Crohn's disease (CD) is challenging in geographical regions where both these diseases are prevalent. There is a need of biomarkers for differentiation between these two disorders. Colonic biopsies from inflamed mucosa of treatment-naive patients with ITB, CD and controls were used for analysis. Protein extracted from biopsies was digested with trypsin and resulting peptides were labeled with iTRAQ reagents. The peptides were subsequently analyzed using LC-MS/MS for identification and quantification. Gene ontology annotation for proteins was analyzed in PANTHER. Validation experiments were done for six differentially expressed proteins using immunohistochemistry. 533 proteins were identified and 241 proteins were quantified from 5 sets of iTRAQ experiments. While 63 were differentially expressed in colonic mucosa of patients with CD and ITB in at least one set of iTRAQ experiment, 11 proteins were differentially expressed in more than one set of experiments. Six proteins used for validation using immunohistochemistry in a larger cohort of patients; none of them however was differentially expressed in patients with ITB and CD. There are differentially expressed proteins in tissue proteome of CD and ITB. Further experiments are required using a larger cohort of homogeneous tissue samples. PMID- 26988820 TI - [Changes of macrophages in colitis-associated colonic carcinogenesis]. AB - OBJECTIVE: To investigate the changes of quantity and phenotype of macrophages during the progress of colitis-associated carcinogenesis, and to identify the chemokines mediating macrophage recruitment. METHODS: Colitis-associated cancer was induced by azoxymethane (AOM) combined with dextran sulfate sodium (DSS) in C57BL/6 mice. The three sequential developmental stages of colitis associated cancer in the mice were named AD1, AD2 and AD3, respectively. Colon tissues were collected and digested into single-cell suspension. The percentage and phenotype of macrophages in the colon tissues were determined by fluorescence activated cell sorter (FACS). Protein array and real-time polymerase chain reaction (PCR) were used to predict potential chemotatic factors of macrophages. RESULTS: Colitis-associated cancer was effectively induced in C57BL/6 mice using AOM combined with DSS. The percentage of macrophages was gradually elevated in the AD1, AD2 and AD3 groups [(9.93+/-1.28)%, (15.42+/-1.15)%, (21.25+/-0.62)%], respectively, significantly higher than that of the control group [(2.39+/ 0.54)%, P<0.01]. The macrophages infiltrating the colonic mucosa exhibited mainly a pro-inflammatory phenotype as CD206(-)CD86(+) MHCII(-). The positive rates of CD206 in the AD1, AD2 and AD3 groups were (15.03+/-1.54)%, (8.11+/-3.70)%, and (9.06+/-1.16)%, respectively, significantly lower than that of the control group [(19.43+/-7.31)%, P<0.01]. The positive rates of CD86 in the AD2 and AD3 groups were (46.73+/-6.58)% and (76.90+/-14.32)%, respectively, significantly higher than that of the control group [(19.37+/-9.69)%, P<0.01)]. The positive rates of MHCII in the AD1, AD2 and AD3 groups were (31.10+/-2.69)%, (33.93+/-14.08)%, and (29.93+/-1.41)%, respectively, significantly lower than that of the control group [(50.30+/-6.58)%, P<0.01]. Protein array analysis and real-time PCR data revealed that G-CSF was the potential chemokine to recruit macrophages in the AOM-DSS mouse model. CONCLUSION: Macrophages infiltrate increasingly during the carcinogenesis and development of colitis-associated cancer, which mostly express CD206(-)CD86(+) MHCII(-) and might be potentially recruited by G-CSF. PMID- 26988821 TI - [RNPC1 induces sensitivity of HER-2-positive breast cancer BT474 cells to trastuzumab through upregulation of HER2]. AB - OBJECTIVE: To explore the sensitivity of HER-2-positive BT474 breast cancer cells to trastuzumab after knockdown or overexpression of RNA binding protein 38 (RNPC1). METHODS: The expressions of RNPC1 and HER-2 mRNA were detected by qRT PCR, and the expressions of RNPC1, HER-2 and PI3K/AKT proteins were detected by Western blot after transfected with RNPC1 lentiviral vector, respectively. The experimental groups were treated with different concentration of trastuzumab, and cell apoptosis rate was analyzed by 7-AAD/APC double staining flow cytometry, and cell growth inhibition rate was tested by cell counting kit 8 (CCK-8). The expression of apoptosis-related proteins was detected by Western blot assay. RESULTS: The results of qRT-PCR showed that overexpression of RNPC1 increased the expressions of RNPC1 and HER-2 mRNA, and the expressions of RNPC1 and HER-2 were decreased after RNPC1 knockdown. The knockdown of RNPC1 decreased the expressions of RNPC1 and HER-2. Moreover, overexpression of RNPC1 decreased and knockdown of RNPC1 increased the levels of p-PI3K and p-AKT while the total protein expressions of both were marginally changed.The results of analysis using a cell counting CCK-8 kit showed that the RNPC1 overexpressed group had a higher growth inhibition rate [(20.33+/-1.25)%, (35.38+/-2.05)%, (50.43+/-2.12)%, (65.35+/ 2.08)% and(76.00+/-2.16)%, respectively] than that of the control group [(13.67+/ 1.24)%, (27.86+/-2.05)%, (39.72+/-1.69)%, (53.33+/-1.70)% and(62.68+/-2.07)% ] when treated with different concentrations of trastuzumab (5, 10, 15, 20 and 25 MUg/ml). The cell apoptosis rates in the RNPC1-overexpressed group [(19.46+/ 1.06)%, (30.87+/-0.98)%, (50.45+/-1.13)%, respectively] were also increased compared with that in the control group [(14.38+/-0.64)%, (21.65+/-1.24)%, (38.03+/-0.85)%] when treated with different concentrations of trastuzumab (0, 10, 20 and 30 MUg/ml)(P<0.05 for all). Reverse results were observed in the RNPC1 knockdown experiments [experimental groups: (9.67+/-1.18)%, (21.67+/-1.23)%, (30.33+/-1.25)%, (40.33+/-1.69)%, and (53.00+/-1.63)%] compared with those of control groups: [(14.00+/-0.82)%, (27.67+/-1.25)%, (39.67+/-1.79)%, (53.67+/ 1.50)%, and (63.33+/-1.52)%]; and experimental groups: [(11.64+/-0.68)%, (16.60+/ 1.01)%, and (25.14+/-3.12)%] compared with those of the control groups: [(14.71+/ 0.61)%, (22.65+/-0.96)%, and (39.03+/-0.85)%]. The overexpression of RNPC1 increased the expression levels of Bim and Bad and decreased the level of Bcl-xl, and reverse result was observed after knockdown of RNPC1. CONCLUSION: RNPC1 may promote the sensitivity of breast cancer cells to trastuzumab through the increased expression of HER-2 in the BT474 breast cancer cells. PMID- 26988822 TI - [Expression and significance of FoxM1 in esophageal squamous cell carcinoma cells in vitro and in vivo]. AB - OBJECTIVE: To investigate the expression and significance of FoxM1 in esophageal squamous cell carcinoma (ESCC) cell lines and tissues. METHODS: Western blot assay was used to detect the expression of FoxM1 in human esophageal epithelial cells and esophageal squamous cell cancer cell lines TE1, TE10, TE11 and Eca109 cells. To determine whether down-regulation of FoxM1 expression could inhibit the aggressive phenotype of ESCC cells, we knocked down the expression of FoxM1 by using FoxM1-shRNA in TE1 cells. Then we detected the cell proliferation, migration and invasion of TE1 cells by MTT assay, scratch assay and transwell assay. Furthermore, the effect of FoxM1 knockdown on tumorigenicity in nude mice was evaluated. Finally, immunohistochemical staining was used to detect the expression of FoxM1 in 99 cases of ESCC tissues and adjacent normal esophageal tissues. chi(2) test was used to analyze the correlations between the expression of FoxM1 and clinicopathologic characteristics and prognosis of ESCC patients. RESULTS: Western blot data showed that FoxM1 expression was lower in normal esophageal epithelial cells and highly expressed in four esophageal cancer cell lines, especially in TE1 cells. Knockdown of FoxM1 inhibited the growth, invasion and migration of TE1 cells and reduced their tumorigenicity in nude mice.The positive expression rate of FoxM1 in ESCC was 61.6% (61/99), significantly higher than that in the paired adjacent normal tissues (24.2%, 24/99) (P<0.05). The positive expression rate of FoxM1 in ESCC tissues was 61.6% (61/99), significantly higher than that in the paired adjacent normal tissues (24.2%, 24/99) (P<0.05). FoxM1 expression was significantly and positively correlated with lymph node metastasis, clinical stage and invasive depth (P<0.05). The median survival time was 42.3 months in 38 cases of patients with negative FoxM1 expression, and 33.0 months in 61 cases of positive FoxM1 expression, and the difference was statistically significant (P=0.036). CONCLUSIONS: FoxM1 is highly expressed in ESCC, and significantly correlated with the initiation, development and prognosis of esophageal cancer. FOXM1 might be an indicator to predict the prognosis and serve as a potential target for therapy in esophageal cancer. PMID- 26988823 TI - [Relationship of clinicopathological features and chemotherapeutic outcomes in women with BRCA1 and BRCA2 mutation-negative familial breast cancer]. AB - OBJECTIVE: To explore the relationship of clinicopathological features and response to neoadjuvant chemotherapy in women with BRCA1 and BRCA2 mutation negative familial breast cancer. METHODS: A total of 6 200 women with breast cancer were treated at our hospital from October 2003 to December 2012. All subjects underwent genetic testing for BRCA1 and BRCA2 genes. Patients with BRCA1 and BRCA2 mutations were excluded. This cohort of 5 842 patients with BRCA1 and BRCA2 mutation-negative breast cancer was classified as two groups: familial breast cancer patients (n=480) and sporadic breast cancer patients (n=5 362). The clinicalpathological data and response to neoadjuvant chemotherapy of the 480 patients with BRCA1 and BRCA2 mutation-negative familial breast cancer and the 5 362 patients with BRCA1 and BRCA2 mutation-negative sporadic breast cancer were compared retrospectively. Then the influencing factors of response to neoadjuvant chemotherapy were analyzed. RESULTS: Among the BRCA1 and BRCA2 mutation-negative breast cancer patients, 4.4% of the patients were diagnosed before 30 years of age in the familial breast cancer group, significantly higher than that of 2.6% in the sporadic breast cancer group(P=0.020). 5.0% of the patients in the familial breast cancer group had bilateral breast cancer, significantly higher than that of 2.7% in the sporadic breast cancer group (P=0.004). Compared with BRCA1 and BRCA2 mutation-negative sporadic breast cancer patients, the relative risk of early-onset breast cancer (<= 30 years) and bilateral breast cancer were 1.73 and 1.91, respectively, significantly higher than that in the BRCA1 and BRCA2 mutation-negative familial breast cancer cases (P=0.020 and P=0.004). 2 964 patients in this cohort of 5 842 case sreceived neoadjuvant chemotherapy.The pathologic complete response (pCR) rate was significantly higher in the BRCA1 and BRCA2 mutation-negative familial breast cancer group than in the BRCA1 and BRCA2 mutation-negative sporadic breast cancer group (21.7% vs. 14.0%, P=0.001). Independent factors associated with pCR in BRCA1 and BRCA2 mutation-negative breast cancer patients were tumor size less than 2 cm (P=0.012), histologic grade III (P<0.001), triple-negative breast cancers (P<0.001), and BRCA1 and BRCA2 mutation-negative familial breast cancer(P=0.001). CONCLUSIONS: Compared with BRCA1 and BRCA2 mutation-negative sporadic breast cancer, BRCA1 and BRCA2 mutation-negative familial breast cancer is more likely diagnosed before the age of 30 years and has a higher risk to develop bilateral breast cancer. BRCA1 and BRCA2 mutation-negative familial breast cancers are more likely to respond to neoadjuvant chemotherapy than BRCA1 and BRCA2 mutation-negative sporadic breast cancer. PMID- 26988824 TI - [Association between efficacy and molecular subtypes in breast cancer patients receiving neoadjuvant chemotherapy]. AB - OBJECTIVE: To investigate the association between pathological complete response (pCR), clinicopathological characteristics and clinical outcomes in breast cancer patients receiving neoadjuvant chemotherapy. METHODS: Medical records of 221 patients who underwent neoadjuvant chemotherapy for breast cancer between January 2006 and December 2008 were retrospectively reviewed. Their clinicopathological features, response to neoadjuvant chemotherapy, survivals and prognostic factors were then analyzed. RESULTS: The total pCR rate was 11.3% (25/221). The rate of pCR was 0%(0/12), 5.7%(6/106), 7.4%(2/27) and 16.9%(11/65) in the luminal A, luminal B, HER-2, and Basal-like subtypes, respectively. Statistically significant association was found between the pCR rate and the molecular substypes of breast cancer(P<0.05). The median 5-year disease free survival and the 5-year overall survival were 72 months and 79 months. The 5-year disease free survival rate and 5-year overall survival rate were 61.1% and 71.9% in all the 221 patients. The 5-year disease free survival rates of pCR and non-pCR patients were 84.0% and 58.2%, and the 5-year overall survival rates of pCR and non-pCR patients were 96.0% and 68.9%, respectively(P<0.05 for all). The multivariate survival analysis showed that clinical and pathological node stage and pCR are independent prognostic factors for the 5-year disease-free survival and 5-year total survival in patients with neoadjuvant chemotherapy (P<0.05 for both). CONCLUSIONS: pCR is more frequently observed in HER-2 and basal-like breast cancer subtypes compared with the luminal breast cancer subtype. The status of clinical and pathological node status and pCR are independent prognostic factors in patients treated with neoadjuvant chemotherapy. PMID- 26988825 TI - [Cone beam CT-derived adaptive radiotherapy for setup error assessment and correction in whole breast intensity modulated radiotherapy]. AB - OBJECTIVE: To quantify the setup error (SE) in breast cancer patients treated with intensity modulated radiotherapy (IMRT) based on cone beam CT (CBCT), and to explore the feasibility of using several CBCT scans to presume and correct SE in the treatment for breast cancer patients. METHODS: Eighteen breast cancer patients after breast conserving surgery who underwent whole breast IMRT were included in this study. Three dimensional interfraction motion before and after on-line CBCT-based corrections were quantified. The on-line CBCT-based corrections were performed using automated greyscale match. The system SE (Sigma) and random error (sigma) were calculated for each patient based on the consecutive multiple online scanning based on CBCT (>=5). The trends in magnitudes of Sigma and sigmawere assessed during the treatment. RESULTS: The magnitude variation of Sigma was less than 1 mm before and after on-line CBCT based corrections. As the CBCT scanning times increase (before 10 times), the Sigma in anteroposterior (AP) direction was increased significantly, and sigmain three dimensional directions was also increased after 7 times of CBCT scanning. After on-line CBCT-based corrections, the Sigma showed a steady trend by variation near zero for the first 20 times irradiation; but after 20 times, the Sigma in AP and superoinferior (SI) directions was increased slightly (less than 0.5 mm), and sigmadecreased in three-dimensional directions. There were no significant differences for Sigma, sigmaand setup margin (SM) before and after on line CBCT-based corrections in all three directions (P>0.05). CONCLUSIONS: For breast cancer patients who underwent IMRT after breast conserving surgery, the setup error is relatively stable during the whole irradiation. The first 5 CBCT scans are suitable to presume and correct SE, and also can be used as the right time for adaptive radiotherapy planning revision. PMID- 26988827 TI - [Clinical characteristics and prognosis of concurrent positive t(14; 18) and myc gene rearrangement in diffuse large B cell lymphoma]. AB - OBJECTIVE: To study the incidence of positive t(14; 18) and myc gene rearrangement, and the clinical features and prognosis of concurrent positive t(14; 18) and myc gene rearrangement "double-hit lymphoma" (DHL) in diffuse large B cell lymphoma. METHODS: The positive t(14; 18) and myc gene rearrangement in 106 cases of DLBCL were analyzed using interphase fluorescent in situ hybridization (FISH) technique. The expression of myc and bcl-2 proteins was determined by immunohistochemistry. The relationship of positive t(14; 18) and myc gene rearrangement with clinical features, pathogenesis and prognosis for the patients was analyzed. SPSS 16.0 software was used for statistical analysis. RESULTS: Among the 106 cases, there were 27 (25.5%) cases with positive t(14; 18) and 13 (12.3%) cases with myc gene rearrangement, and 7 cases (6.6%) of DLBCL with concurrent t(14; 18)-positive and myc gene rearrangement. A relationship was observed between positive t(14; 18) and myc gene rearrangement (P=0.019). The follow-up data showed that the 7 DHL patients were in age of 52-84 years, the International Prognostic Index (IPI) scores were 3 in two cases, 4 in four cases and 5 in one case, and the ECOG scores were 3 in all the 7 cases. Four patients had bone marrow involvement and were combined with leukemia. The survival time ranged from 0.5 to 6 months, with a median survival of 4 months. The univariate analysis showed that B symptom, Ann Arbor stage, ECOG score, LDH level, IPI score, immunophenotype, bcl-2 protein expression, myc protein expression, and myc gene rearrangement were all associated with poor prognosis (P<0.05 for all). The multivariate analysis using a COX proportional hazard model confirmed that ECOG score, bcl-2 protein expression, myc protein expression, myc gene rearrangement, and immunophenotype were independent prognostic factors affecting survival (P<0.05 for all), among them, the myc gene rearrangement was the strongest prognostic factor (OR=4.337, P<0.001). CONCLUSIONS: "Double-hit" DLBCL is rare and can be mainly identified only by molecular detection. Perhaps positive t(14; 18) and myc gene rearrangement play concurrent role in its "double-hit" pathogenesis. DHL are highly invasive, and most of DHL patients have poor prognosis. Further studies of larger case number are required to determine the pathologic features and the therapeutic strategy of this subgroup. PMID- 26988826 TI - [Prognostic significance of serum gamma-glutamyl transferase before transcatheter arterial chemoembolization in patients with hepatitis C virus-related hepatocellular carcinoma]. AB - OBJECTIVE: To evaluate the prognostic significance of serum GGT in patients with hepatitis C virus-related hepatocellular carcinoma (HCV-HCC) treated with transcatheeter arterial chemoembolization (TACE). METHODS: The clinicopathological data of 110 patients with hepatitis C virus-related stage B hepatocellular carcinoma, who received TACE treatment from January 2008 to May 2011, were retrospectively analyzed. The patients were divided into two groups: the normal GCT group (GGT<50 U/L, 41 cases) and high GCT group (GGT>=50 U/L, 69 cases). The Kaplan-Meier method was used to analyze the survival rates, log-rank test was used for univariate analysis, and Cox regression model was used for multivariate analysis. The factors affecting survival and prognosis of the patients were analyzed. RESULTS: The pretreatment GGT level was (160.0+/-120.2) U/L in the high GGT group and (40.1+/-8.5) U/L in the normal GGT group (P<0.001). After TACE treatment, the 1-, 2- and 3-year survival rates were 90.2%, 45.9% and 24.6% in the high GGT group, and 90.2%, 75.6% and 58.5%, respectively, in the normal GGT group (P=0.002). The univariate analysis showed that the pretreatment GGT level, ECOG score, alpha-fetoprotein, tumor size, tumor number, and Child grade are factors affecting the prognosis of HCV-related hepatocellular carcinoma patients (P<0.05 for all). The Cox multivariate survival analysis revealed that the tumor size, tumor number, Child grade, and serum GGT level are independent prognostic factors for patients with stage B HCV-related hepatocellular carcinoma. CONCLUSION: The level of serum GGT before TACE is an independent prognostic factor for patients with stage B HCV-related hepatocellular carcinoma. PMID- 26988828 TI - [Comparison of clinical outcomes of patients with non-small cell lung cancer harboring different types of epidermal growth factor receptor sensitive mutations after first-line EGFR-TKI treatment]. AB - OBJECTIVE: To analyze whether there are differences in the efficacy and clinical outcomes to first-line tyrosine kinase inhibitors (TKI) therapy in Chinese patients with metastatic non-small-cell lung cancer (NSCLC) harboring different subtypes of epidermal growth factor receptor (EGFR) mutations. METHODS: A retrospective analysis was made on the clinical data of stage IIIB or IV NSCLC patients who were diagnosed by histology and received EGFR mutation test, in order to confirm if there is any difference between the therapeutic effects of TKIs as first-line therapy and the prognosis. RESULTS: A total of 165 patients harboring EGFR exon 19 deletion (19del, n=71), exon 21 L858R mutation (L858R, n=80) or uncommon sensitive mutation (n=14) were treated with EGFR-TKIs for first line treatment. The comparison among different groups of common types of sensitive mutations revealed that the objective response rate (ORR) of group 19del and group L858R were 57.8% and 45.0%, respectively (P=0.113). The disease control rate (DCR) was 93.0% and 93.8%, respectively (P=0.158). However, the ORR and DCR of uncommon sensitive mutation were 35.7% and 78.6%, which were significantly lower than that of the group 19del (P=0.035) and group L858R (P=0.020). The median progression-free survival (PFS) of group 19del, group L858R and uncommon sensitive mutation were 14.0 months, 7.8 months and 5.1 months, respectively (P=0.001). The median PFS of the group 19del was significantly longer than that of the group L858R (P=0.009). The median overall survival (OS) of these three groups had significant difference (22.8, 15.2 and 10.0 months) (P=0.048). But those of group 19del and group L858R were similar (P=0.152). The multivariate analysis indicated that ECOG-PS (P=0.030), cigarette smoking (P=0.013) and EGFR mutation types (P=0.034) are independent prognostic factors of OS. CONCLUSIONS: For Chinese NSCLC patients with different types of sensitive mutation, there are differences between their efficacy and prognosis of EGFR-TKIs as first-line treatment. The PFS of group 19del is obviously longer than that of other types of sensitive mutations, but have no significant differences in OS. The PFS and OS of patients with common types of sensitive mutation are better than those with uncommon sensitive mutation. PMID- 26988829 TI - [Analysis of the therapeutic effects of different treatment modalities on the outcomes of 87 patients with lung oligometastasis from nasopharyngeal carcinoma after radiotherapy]. AB - OBJECTIVE: The aim of the present study was to evaluate the efficacy of three different modalities in treatment of lung oligometastases from nasopharyngeal carcinoma (NPC) after radiotherapy and to identify a more appropriate treatment modality. METHODS: The clinical data of 87 cases of lung oligometastases from NPC were analyzed retrospectively. Among them, 33 patients underwent local small field irradiation+ /- chemotherapy, 28 underwent whole-lung irradiation+ chemotherapy, and 26 underwent simple chemotherapy. The survival rates were calculated using Kaplan-Meier analysis. The differences among the modalities were evaluated using the log-rank test. Cox univariate and multivariate analyses were performed to determine the influencing factors. RESULTS: The 3-year lung metastasis survival (LMS) rates of patients with lung metastasis undergoing the three treatment modalities (local small-field irradiation+ /-chemotherapy, whole lung irradiation+ chemotherapy and chemotherapy alone) were 89.3%, 72.7%, and 72.4%, respectively, showing a significant difference between the groups (P=0.003). Further subgroup analysis showed that the 5-year LMS rate was significantly higher in the local small-field irradiation+ /-chemotherapy group than that in the whole-lung irradiation+ chemotherapy group and chemotherapy alone group (P=0.001). The 2-year progression-free survival (PFS) rates of the three groups were 57.1%, 25.8% and 3.8%, respectively, showing significant intergroup differences (P=0.002 and P<0.001). Multivariate analysis indicated that compared with the whole lung irradiation group and the chemotherapy alone group, the local irradiation+ /- chemotherapy is an independent favorable prognostic factor for LMS and PFS (P<0.05). CONCLUSION: Local radiotherapy combined with systemic chemotherapy is the best therapeutic modality for lung oligometastases derived from NPC after radiotherapy, improving the LMS and prolonging the PFS. PMID- 26988830 TI - [Clinical efficacy of (125)I seed implantation in the treatment of delayed hepatic metastasis from colon carcinoma]. AB - OBJECTIVE: To explore the clinical efficacy of ultrasound-guided (125)I seed implantation in the treatment of delayed hepatic metastasis from colon carcinoma. METHODS: From January 2012 to December 2014, 48 patients with delayed hepatic metastasis from colon carcinoma (study group) underwent (125)I seed implantation. The clinical data and therapeutic effect in the study group were retrospectively analyzed and the therapeutic efficacy was compared with that of 59 patients with delayed hepatic metastasis from colon carcinoma (control group) who underwent ultrasound-guided radiofrequency ablation (RFA). The clinical data of these patients were analyzed retrospectively. RESULTS: In the 48 patients of study group, there were 13 cases of complete response (CR), 23 cases of partial response (PR), 8 cases of stable disease (SD) and 4 cases of progressive disease (PD). In the 59 patients of control group, there were 16 cases of CR, 28 cases of PR, 9 cases of SD and 6 cases of PD. The objective response rate (ORR) was 75.0% in the study group and 74.6% in the control group.The results of Ridit analysis showed that the therapeutic effect in the two groups was similar (P>0.05). The 0.5-, 1- and 2-year overall survival rates in the study group and control group were 97.9%, 83.3%, 66.7% and 96.6%, 84.8%, 69.5%, respectively, showing no significant statistical difference between the two groups (P>0.05). CONCLUSION: (125)I seed implantation has positive effects in the treatment of delayed hepatic metastasis from colon carcinoma, and is of much value for clinic application. PMID- 26988831 TI - [Application of (125)I seeds combined with biliary stent implantation in the treatment of malignant obstructive jaundice]. AB - OBJECTIVE: To study the feasibility and therapeutic effect of the application of (125)I seeds combined with biliary stent implantation on the treatment of malignant obstructive jaundice. METHODS: Fifty patients with malignant obstructive jaundice treated from September 2010 to February 2013 in Yantai Yuhuangding Hospital were included in this study. Among them, 24 patients received biliary stent implantation combined with (125)I seeds intraluminal brachytherapy as experimental group, and 26 were treated by biliary stent implantation as control group.The total bilirubin, direct bilirubin and tumor markers (CA-199, CA-242, CEA) before and after surgery, the biliary stent patency status was assessed, and the survival time was evaluated. RESULTS: The 24 patients in experimental group were implanted with 30 (125)I seeds successfully in a total of 450 seeds. Jaundice was improved greatly in both groups. The CA-199 and CA-242 after treatment in the experimental group were significantly decreased than that before treatment (P=0.003 and P=0.004). CEA was also decreased, but showed no statistical significance (P>0.05). There were no significant improvement comparing the CA-199, CA-242 and CEA before and 2 months after surgery in the control group (P>0.05). The rate of biliary stent patency was 83.3% (20/24) in the experimental group and 57.7% (15/26) in the control group (P=0.048). The mean biliary stent patency time in the experimental group was 9.84 months (range 1-15.5 months). The mean biliary stent patency time in the control group was 5.57 months (range 0.8-9 months). There was a significant difference between the two groups (P=0.018). The median survival time was 10.2 months in the experimental group and 5.4 months in the control group (P<0.05). CONCLUSION: (125)I seeds combined with biliary stent implantation can inhibit the proliferation of vascular endothelial cells and the growth of tumor effectively, and can prolong the biliary stent patency time and the survival time obviously for patients with malignant obstructive jaundice, therefore, is a safe and effective treatment in this malignancy. PMID- 26988832 TI - [Clinical features and surgical treatment of chest aggressive fibromatosis]. AB - OBJECTIVE: To investigate the clinical features and surgical treatment of chest aggressive fibromatosis. METHODS: Twenty-five patients with aggressive fibromatosis treated from September 1998 to May 2014 in the Department of Thoracic Surgery of Cancer Hospital of Chinese Academy of Medical Sciences were included in this study. RESULTS: The 25 patients, including 12 males and 13 famales, had an average age of 38 (range 15-76 years). The initial manifestations included chest pain (9 patients, 36.0%) and shortness of breath (1 patient). In 13 patients (52.0%) the tumor was found in a physical examination. Two patients (8.0%) were detected during an operation for lung disease. The tumor was located in the left chest wall in 15 patients, and located on the right side in 10 patients. Among them, the most common locations were the left front chest wall and the right front chest wall. The operation method affects the prognosis. Radiological imaging and needle biopsy did not make a correct diagnosis, and the diagnosis of aggressive fibromatosis was confirmed by pathology using immunohistechmistry after surgery. 13 patients underwent tumor resection, 9 cases had expanded resection, 3 patients had palliative resection. Six cases received radiotherapy after surgery. The median follow-up time was 101.5 months. Currently, all of the 25 patients are still alive, but 5 cases had local recurrence after surgery, among them, 4 patients received tumor resection, and one patient underwent expanded resection. CONCLUSIONS: Aggressive fibromatosis is a low-grade malignant tumor. The diagnosis of aggressive fibromatosis needs to be confirmed by pathology using immunohistechmical staining after surgery. Although this tumor is liable to relapse, its prognosis is favorable. Radical surgery is the most important treatment for patients to get a higher quality of life and long-term survival without recurrence. PMID- 26988833 TI - [Analysis of life-threatening complications during perioperative period in patients undergoing radical cystectomy with orthotopic neobladder]. AB - OBJECTIVE: To investigate the factors influencing life-threatening complications during perioperative period in patients undergoing traditional cystectomy with orthotopic neobladder. METHODS: To retrospectively analyze the clinical data of 206 cases who underwent radical cystectomy with orthotopic neobladder. Logistic regression analysis was used to analyze the significance of the factors such as age, amount of bleeding, pathological stage, effective supplement of albumin, cardiovascular disease, diabetes mellitus, operation duration, intestinal preparation, etc., on the occurrence of severe complications. RESULTS: Among the 206 patients who underwent radical cystectomy with orthotopic neobladder, 22 cases (10.7%) had life-threatening complications (intestinal fistula, hemorrhagic shock, severe infection) during the perioperative period, and 9 cases died (mortality rate 4.4%). Logistic regression analysis showed that the elderly age, long operation duration, lack of effective supplement of albumin, diabetes mellitus are independent factors influencing the occurrence of life-threatening complications during the perioperative period of radical cystectomy with orthotopic ileal neobladder (P<0.05 for all), and are risk factors positively correlated with the severe complications. CONCLUSION: The elderly age, long operation duration, lack of effective supplement of albumin, and diabetes mellitus are risk factors of the occurrence of life-threatening complications during the perioperative period in patients undergoing radical cystectomy with orthotopic ileal neobladder, therefore, attention should be paid to this issue. PMID- 26988834 TI - [Transformation to small-cell lung cancer from advanced lung adenocarcinoma after gefitinib treatment -report of a case]. PMID- 26988835 TI - Practical Considerations for the Use of Direct Oral Anticoagulants in Patients With Atrial Fibrillation. AB - Atrial fibrillation (AF) is a significant risk factor for stroke and peripheral thromboembolic events (TEs). Preventing blood clots in the heart to reduce stroke and TE risk is a key goal of AF therapy. Traditional stroke risk assessment tools for patients with nonvalvular AF include the CHADS2 and CHA(2)DS(2)-VASc scores, while long-term outcome data with the newer direct oral anticoagulants (DOACs) are emerging. The goals of this review were to assess traditional therapies and existing treatment guidelines and to discuss key pharmacologic properties of the DOACS, noting how these may benefit at-risk patients with AF. This narrative review was developed on the basis of the authors' clinical knowledge, extensive reading of the literature, and broad pharmacy experience in the management of patients with AF. Limitations of oral vitamin K antagonists (VKAs) include slow onset of action, the need for regular monitoring of their anticoagulation effect, significant food and drug interactions, and unpredictable dose-response properties. Key clinical trial data led to the approvals of apixaban, dabigatran etexilate, edoxaban, and rivaroxaban in the United States to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF. With predictable pharmacologic properties and limited drug and/or dietary interactions, the DOACs offer several benefits over traditional oral anticoagulation therapy with VKA. However, they have limitations, including the absence of immediate reversal agents and limited options for monitoring their anticoagulation effects in clinical practice. As experience with the use of DOACs grows, optimized treatment regimens and improved patient care are expected. PMID- 26988836 TI - Conditional cash transfers and the double burden of malnutrition among children in Colombia: a quasi-experimental study. AB - Conditional cash-transfer (CCT) programmes have been shown to improve the nutritional and health status of children from poor families. However, CCT programmes may have unintended and not fully known consequences by increasing the risk of overweight and obesity. We examined the impact of Familias en Accion (FA), a large CCT programme in Colombia, on the double burden of malnutrition among pre-school and school-aged children. Height and weight were measured before programme enrolment and during follow-ups in 1290 children from thirty-one treatment municipalities, being compared with 1584 children from sixty-two matched control municipalities. We used a difference-in-differences approach to evaluate the effect of FA on children's stunting, BMI z-scores, thinness, overweight and obesity, controlling for individual and municipality-level confounders. At baseline, the prevalences of stunting and overweight were 30.3 and 15.4 %, respectively, in treatment municipalities and 27.9 and 17.4 % in control municipalities. FA was associated with reduced odds of thinness (OR 0.26; 95 % CI 0.09, 0.75) and higher BMI-for-age z-scores (BMI z-scores) (beta 0.14; 95 % CI 0.00, 0.27; P<0.05), although the latter was of small clinical significance. The prevalence of stunting, overweight and obesity decreased over time, but the effect of FA on these outcomes was not significant. The CCT programme in Colombia reduced the odds of thinness, but had no effect on stunting, a more prevalent outcome. The FA programme had no effect on overweight or obesity, although BMI z scores were higher for children under treatment, raising the possibility of an increase of small clinical significance on BMI among pre-school and school-aged children. PMID- 26988838 TI - Benefit of statin therapy in current smokers: Need for stronger evidence? PMID- 26988837 TI - The VALVAFRIC study: A registry of rheumatic heart disease in Western and Central Africa. AB - BACKGROUND: There are few African data available on rheumatic heart disease (RHD). AIM: To provide data on the clinical characteristics and treatment of patients with RHD hospitalized in sub-Saharan Africa. METHODS: The VALVAFRIC study is a multicentre hospital-based retrospective registry of patients with RHD hospitalized in African cardiology departments from 2004 to 2008. RESULTS: Among 3441 patients with at least one mild RHD lesion seen on echocardiography in 5 years in 12 cardiology departments from seven countries, 1385 had severe lesions (502 men; 803 women; mean age 29.3+/-15.6 years). The ratio of severe to any RHD valvular lesion was higher in countries with the lowest gross domestic product (GDP). Mitral valve regurgitation was seen in 52.8% of cases, aortic regurgitation in 32.1%, mitral stenosis in 13.4% and aortic stenosis in 1.8%. Combined valvular lesions were observed in 13% of cases. Heart failure was present in 40% of patients. Major left ventricular dilatation was observed in 13.6% of patients, ectasic left atrial dilatation in 13.8%, dilatation of the right cardiac chambers in 19.8% and pulmonary hypertension in 28.7%. Patients with no formal schooling (41.5%) were older and had a higher New York Heart Association (NYHA) class and a lower ejection fraction (EF). Among patients aged<20 years (mean age 14.5+/-3.8 years), those who were schooled had a lower NYHA class (2.86+/-0.92 vs 3.42+/-0.93; P<0.01) and a higher EF (60.3+/-11.7 vs. 54.8+/-12.8; P<0.05) than those who were not. RHD-related delays or school failures were affected by NYHA class, EF and the number of children in the household. Although 1200 of 1334 patients required valve repair or replacement, only 27 had surgery. In-hospital outcomes included death (16%), heart failure (62%), arrhythmias (22%), endocarditis (4%) and thromboembolic events (4%). Subsequently, 176 patients were readmitted (13.6%). CONCLUSIONS: Patients with RHD hospitalized in sub-Saharan Africa are young, socially disadvantaged, with a high mortality rate and extremely low access to surgery. Poverty, as quantified by GDP and educational level, affects RHD-related severity, NYHA class and left ventricular dysfunction. PMID- 26988839 TI - The new Occlutech((r)) patent ductus arteriosus occluder: Single centre experience. AB - BACKGROUND: Transcatheter therapy is the first-line treatment for closure of patent ductus arteriosus (PDA). A range of different devices have been used. AIM: To report our experience using the new Occlutech((r)) PDA occluder for closure of PDA. METHODS: All consecutive patients receiving an Occlutech((r)) PDA occluder for closure of PDA from March 2014 to May 2015 were included in the study. Occluders were implanted using a conventional technique. After cardiac catheterization, transthoracic echocardiography was performed sequentially. Residual shunting and procedural and mid-term complications, including embolization, device-induced left pulmonary artery stenosis and aortic coarctation, were systematically assessed and reported. RESULTS: Fifty-six patients (35 females) with a median age of 1 year (range: 29 days to 24 years) were included in the study. PDAs were closed successfully using device number 5/3.5 in 17 patients, 6/4 in 28 patients, 7/5 in four patients, 8/6 in six patients and 10/8 in one patient. Post-implantation angiography showed no residual shunt in 10 patients (17.8%), moderate intraprosthetic shunt in 43 patients (76.8%) and severe shunt in three patients (5.4%). One device embolized in the right pulmonary artery 1hour after successful closure; the device was retrieved surgically after unsuccessful snaring. After a mean follow-up of 10 months (range: 3-17.8 months), no residual shunt or device-related complications were noted. CONCLUSION: The new Occlutech((r)) PDA occluder allows safe and efficient PDA closure, similar to existing devices. PMID- 26988841 TI - Development and Use of Scripted Filmed Scenarios to Teach the One-Minute Preceptor Model. PMID- 26988840 TI - Reflections on an Innovation: The First Trainee-Led Academic Psychiatry Journal. PMID- 26988842 TI - Spatial and seasonal influences on culturable endophytic mycobiota associated with different tissues of Eugenia jambolana Lam. and their antibacterial activity against MDR strains. AB - BACKGROUND: Present study focuses on diversity and distribution analysis of endophytic fungi associated with different tissues of Eugenia jambolana. The influence of season and geographical location on diversity and distribution of endophytic fungi has been analyzed. Antibacterial activity of isolated fungal species has also been investigated against MDR bacterial strains. RESULT: A total of 1896 endophytic fungal isolates were obtained from healthy, surface sterilized tissues of leaf, stem and petiole tissues during summer, monsoon and winter season. Out of 24 fungal species isolated, 20 species belong to class Ascomycetes, 2 to Basidiomycetes and 2 to Zygomycetes. Maximum species diversity was in rainy season whereas colonization frequency was in winter. All the diversity indices showed maximum species diversity at site 5 (Yamunanager), rainy among the seasons and leaf among the tissues studied. Aspergillus genus was most frequently isolated. Aspergillus niger and Alternaria alternata were most dominant species. Three way ANOVA results showed that effect of season was highly significant on species diversity in relation to sites and tissues. 60% endophytic fungal extracts showed significant antibacterial activity against one or more than one MDR bacterial strain. CONCLUSION: Different fungal species were recovered from different sites but the inter-site comparisons were not significant according to Jaccard similarity coefficient. Diversity of such fungal endophytes indicates that Eugenia jambolana plant acts as an ecosystem facilitating survival of many microbes with impressive antibacterial potential. PMID- 26988844 TI - Dipyrrolonaphthyridinediones--structurally unique cross-conjugated dyes. AB - Red-emissive dyes based on a previously unknown skeleton--dipyrrolo[1,2-b:1',2' g][2,6]naphthyridine-5,11-dione--can be easily synthesized from simple and inexpensive reagents by one- or two-step routes. A careful selection of the substituents gives access to a variety of dipyrrolonaphthyridinedione derivatives with intense fluorescence in the range of 520-740 nm. PMID- 26988843 TI - Tau pathology-dependent remodelling of cerebral arteries precedes Alzheimer's disease-related microvascular cerebral amyloid angiopathy. AB - Alzheimer's disease (AD) is characterised by pathologic cerebrovascular remodelling. Whether this occurs already before disease onset, as may be indicated by early Braak tau-related cerebral hypoperfusion and blood-brain barrier (BBB) impairment found in previous studies, remains unknown. Therefore, we systematically quantified Braak tau stage- and cerebral amyloid angiopathy (CAA)-dependent alterations in the alpha-smooth muscle actin (alpha-SMA), collagen, and elastin content of leptomeningeal arterioles, small arteries, and medium-sized arteries surrounding the gyrus frontalis medialis (GFM) and hippocampus (HIPP), including the sulci, of 17 clinically and pathologically diagnosed AD subjects (Braak stage IV-VI) and 28 non-demented control subjects (Braak stage I-IV). GFM and HIPP paraffin sections were stained for general collagen and elastin with the Verhoeff-van Gieson stain; alpha-SMA and CAA/amyloid beta (Abeta) were detected using immunohistochemistry. Significant arterial elastin degradation was observed from Braak stage III onward and correlated with Braak tau pathology (rho = 0.909, 95% CI 0.370 to 0.990, p < 0.05). This was accompanied by an increase in neutrophil elastase expression by alpha-SMA-positive cells in the vessel wall. Small and medium-sized arteries exhibited significant CAA-independent alpha-SMA loss starting between Braak stage I and II-III, along with accumulation of phosphorylated paired helical filament (PHF) tau in the perivascular space of intraparenchymal vessels. alpha-SMA remained at the decreased level throughout the later Braak stages. In contrast, arterioles exhibited significant alpha-SMA loss only at Braak stage V and VI/in AD subjects, which was CAA-dependent/correlated with CAA burden (rho = -0.422, 95% CI -0.557 to -0.265, p < 0.0001). Collagen content was only significantly changed in small arteries. Our data indicate that vessel wall remodelling of leptomeningeal arteries is an early-onset, Braak tau pathology-dependent process unrelated to CAA and AD, which potentially may contribute to downstream CAA dependent microvascular pathology in AD. PMID- 26988845 TI - The effect of nutritional supplementation on the multifocal electroretinogram in healthy eyes. AB - BACKGROUND: Previous studies have demonstrated an increase in macular pigment optical density (MPOD) with lutein (L)-based supplementation in healthy eyes. However, not all studies have assessed whether this increase in MPOD is associated with changes to other measures of retinal function such as the multifocal ERG (mfERG). Some studies also fail to report dietary levels of L and zeaxanthin (Z). Because of the associations between increased levels of L and Z, and reduced risk of AMD, this study was designed to assess the effects of L-based supplementation on mfERG amplitudes and latencies in healthy eyes. METHODS: Multifocal ERG amplitudes, visual acuity, contrast sensitivity, MPOD and dietary levels of L and Z were assessed in this longitudinal, randomized clinical trial. Fifty-two healthy eyes from 52 participants were randomly allocated to receive a L-based supplement (treated group), or no supplement (non-treated group). RESULTS: There were 25 subjects aged 18-77 (mean age +/- SD; 48 +/- 17) in the treated group and 27 subjects aged 21-69 (mean age +/- SD; 43 +/- 16) in the non treated group. All participants attended for three visits: visit one at baseline, visit two at 20 weeks and visit three at 40 weeks. A statistically significant increase in MPOD (F = 17.0, p <= 0.001) and shortening of mfERG ring 2 P1 latency (F = 3.69, p = 0.04) was seen in the treated group. CONCLUSIONS: Although the results were not clinically significant, the reported trend for improvement in MPOD and mfERG outcomes warrants further investigation. PMID- 26988847 TI - Validation of the Amharic Version of the M. D. Anderson Symptom Inventory and Assessment of Symptoms in Ethiopian Cancer Patients. AB - CONTEXT: Cancer patients often face a variety of symptoms that impact their quality of life. The management of these symptoms is highly dependent on the accurate appraisal of their severity through the use of a standardized symptom assessment tool. The M. D. Anderson Symptom Inventory (MDASI), developed in English, is one of such tools that contain 13 core cancer related symptoms that can easily be rated on a scale of 0-10. OBJECTIVES: The present study tried to develop and validate the Amharic language version of the MDASI (MDASI-Am). METHODS: The MDASI-Am was developed by the standard forward/backward translation of the original English version of the MDASI. The MDASI-Am was completed by or administered to 145 randomly selected Ethiopian cancer patients. Factor analysis, Cronbach alpha coefficient, and mean comparison, respectively, were used to establish construct validity, internal consistency, and known-group validity (Eastern Cooperative Oncology Group Performance Status). RESULTS: Factor analysis identified three symptom constructs interpreted as general, gastrointestinal, and neuropsychiatric symptoms, with Cronbach alpha coefficients of 0.70, 0.80, and 0.82, respectively. The MDASI-Am significantly detected differences in symptom severity and interference levels in patient groups categorized according to Eastern Cooperative Oncology Group Performance Status (P < 0.01), establishing known-group validity. The most prevalent severe symptoms identified in the current sample were pain, sadness, numbness, distress, and fatigue. CONCLUSION: The MDASI-Am is a valid and reliable tool for measuring symptom severity and symptom interference with daily living in Ethiopian cancer patients. PMID- 26988848 TI - Palliative Care Education in Emergency Medicine Residency Training: A Survey of Program Directors, Associate Program Directors, and Assistant Program Directors. AB - CONTEXT: Emergency medicine (EM) residents perceive palliative care (PC) skills as important and want training, yet there is a general lack of formal PC training in EM residency programs. A clearer definition of the PC educational needs of EM trainees is a research priority. OBJECTIVES: To assess PC competency education in EM residency programs. METHODS: This was a mixed-mode survey of residency program directors, associate program directors, and assistant program directors at accredited EM residency programs, evaluating four educational domains: 1) importance of specific competencies for senior EM residents, 2) senior resident skills in PC competencies, 3) effectiveness of educational methods, and 4) barriers to training. RESULTS: Response rate was 50% from more than 100 residency programs. Most respondents (64%) identified PC competencies as important for residents to learn, and 59% reported that they teach7 PC skills in their residency program. In Domains 1 and 2, crucial conversations, management of pain, and management of the imminently dying had the highest scores for importance and residents' skill. In Domain 3, bedside teaching, mentoring from hospice and palliative medicine faculty, and case-based simulation were the most effective educational methods. In Domain 4, lack of PC expertise among faculty and lack of interest by faculty and residents were the greatest barriers. There were differences between competency importance and senior resident skill level for management of the dying child, withdrawal/withholding of nonbeneficial interventions, and ethical/legal issues. CONCLUSION: There are specific barriers and opportunities for PC competency training and gaps in resident skill level. Specifically, there are discrepancies in competency importance and residency skill in the management of the dying child, nonbeneficial interventions, and ethical and legal issues that could be a focus for educational interventions in PC competency training in EM residencies. PMID- 26988846 TI - Is it time for immunopsychiatry in psychotic disorders? AB - INTRODUCTION: Immune dysregulation is suggested to play an important aetiological role in schizophrenia (SZ) and bipolar disorder (BD) potentially driving neurodevelopmental pathways. Immune dysfunction may precede the onset of psychiatric disorders and parallel the development of multiaxial comorbidity, including suicidal behaviour and metabolic and autoimmune disorders. Depicting the source of the chronic low-grade inflammatory component in SZ and BD is thus a research priority. Strong environmental insults early in life, such as infections, acting on a background of genetic vulnerability, may induce potent and enduring inflammatory responses setting a state of liability to second-hit environmental encounters, namely childhood trauma, drug abuse or additional infectious exposures. The immunogenetic background of susceptibility, suggested to be not only lying within the HLA locus but also implicating inherited deficits of the innate immune system, may amplify the harmful biological effects of infections/psychosocial stress leading to the manifestation of a broad range of psychiatric symptoms. OBJECTIVES: The present review aims to discuss the following: (i) biological arguments in favour of a chronic low-grade inflammation in SZ and BD and its potential origin in the interaction between the immunogenetic background and environmental infectious insults, and (ii) the consequences of this inflammatory dysfunction by focusing on N-methyl-D-aspartate (NMDA) receptor antibodies and activation of the family of human endogenous retroviruses (HERVs). CONCLUSIONS: Specific therapeutic approaches targeting immune pathways may lead the way to novel personalized medical interventions, improvement of quality of life and average life expectancy of psychiatric patients, if not even prevent mood episodes and psychotic symptoms. PMID- 26988849 TI - A Multifaceted Approach to Improve the Availability and Accessibility of Opioids for the Treatment of Cancer Pain in Serbia: Results From the International Pain Policy Fellowship (2006-2012) and Recommendations for Action. AB - Cancer is the second leading cause of death in Serbia, and at least 14,000-16,000 patients experience moderate-to-severe cancer pain every year. Cancer pain relief has been impeded by inadequate availability of opioid analgesics and barriers to their accessibility. In 2006, a Serbian oncologist was selected as an International Pain Policy Fellow. The fellow identified barriers to opioid availability in Serbia and implemented an action plan to address the unavailability of oral morphine, attitudinal and knowledge barriers about opioids, and barriers in the national opioid control policy, in collaboration with the government, local partners, and international experts, including those from the World Health Organization. Collaborative efforts resulted in availability of immediate-release oral morphine, registration of controlled release hydromorphone, and reimbursement of oral methadone for cancer pain; numerous educational activities aimed at changing inadequate knowledge and negative attitudes toward opioids; recognition of opioids as essential medicines for palliative care in a new National Palliative Care Strategy; and recognition of the medical use of opioids as psychoactive-controlled substances for the relief of pain included in a new national law on psychoactive-controlled substances, and the development of recommendations for updating regulations on prescribing and dispensing opioids. An increase in opioid consumption at the institutional and national levels also was observed. This article outlines a multifaceted approach to improving access to strong opioids for cancer pain management and palliative care in a middle-income country and offers a potential road map to success. PMID- 26988850 TI - Eosinophilic myocarditis during treatment with olanzapine - report of two possible cases. AB - BACKGROUND: Drug-induced eosinophilic myocarditis is a life-threatening and frequently overlooked condition. The prevalence of myocarditis in clozapine treated patients may be as high as 3 %. An association between olanzapine and myocarditis has not previously been described, but given the chemical similarity between olanzapine and clozapine, we hypothesized the existence of such an association. We searched the spontaneous adverse drug reports database of the Danish Health and Medicines Authority for olanzapine and myocarditis in the period from October 21, 1996 to - June 03, 2015. We identified two fatal cases of eosinophilic myocarditis associated with the use of olanzapine. CASE PRESENTATION: Case 1 was a 39-year-old Caucasian man with known substance abuse and schizophrenia. He was found dead in his home. Olanzapine was prescribed at day -54, and dose at time of death was 40 mg/day. Post-mortem toxicological examination demonstrated presence of olanzapine, morphine, venlafaxine and oxazepam. Syringes indicating substance abuse were found in his home. Case 2 was a 36-year-old Caucasian man diagnosed with schizophrenia was found dead unexpectedly. There was no history of substance abuse. Current treatment was olanzapine 20 mg/day +5 mg as PRN (prescribed for almost 4 years), aripiprazole 30 mg/day (prescribed for 6 months) and mirtazapine 30 mg/day (prescribed for 6 months). Both cases of eosinophilic myocarditis were confirmed by autopsy findings and both patients received olanzapine in doses exceeding the recommendations. CONCLUSION: Olanzapine may have contributed to and/or worsened the two reported fatal cases of myocarditis. Additional studies are required to establish a causal link between olanzapine and eosinophilic myocarditis. PMID- 26988851 TI - Prospective associations between sedentary behaviour and incident depressive symptoms in older people: a 15-month longitudinal cohort study. AB - OBJECTIVE: This study aimed to investigate whether sitting time, as a form of sedentary behaviour, is related to incident depressive symptoms in older people. METHODS: This study included 3503 participants (mean age 71.7 years, 50.1% female) from the 'Obu Study of Health Promotion for the Elderly' cohort study. At baseline and then 15 months later, the participants reported their status of depressive symptoms using the 15-item Geriatric Depression Scale. During the baseline assessment, the participants were also asked about their sedentary behaviour on weekdays over the past 7 days and, from there, categorized into three groups (<240, 240-480, >=480 min/day). Demographic data and the other health behaviours were also assessed at the baseline. RESULTS: Cross-sectional analysis revealed that 437 participants (12.0%) had depressive symptoms. In a prospective analysis, the logistic regression model revealed that the odds ratio for depressive symptom incidence was higher in participants who, at baseline, spent 480 min or more per day sitting (1.636; 95% confidence interval [CI] 1.015 to 2.636, p = 0.043), and in those who spent 240-480 min (1.605; 95% CI 1.085 to 2.375, p = 0.018) in comparison with those who spent less than 240 min. CONCLUSIONS: Sedentary behaviour significantly affects the risk of incident depressive symptoms. Further research is needed to develop an intervention strategy to manage depressive symptoms, as the second most common cause of burden of disease among older adults. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26988852 TI - Negative-assortative mating for color in wolves. AB - There is strong negative-assortative mating for gray and black pelage color in the iconic wolves in Yellowstone National Park. This is the first documented case of significant negative-assortative mating in mammals and one of only a very few cases in vertebrates. Of 261 matings documented from 1995 to 2015, 63.6% were between gray and black wolves and the correlation between mates for color was 0.266. There was a similar excess of matings of both gray males * black females and black males * gray females. Using the observed frequency of negative assortative mating in a model with both random and negative-assortative mating, the estimated proportion of negative-assortative mating was 0.430. The estimated frequency of black wolves in the population from 1996 to 2014 was 0.452 and these frequencies appear stable over this 19-year period. Using the estimated level of negative-assortative mating, the predicted equilibrium frequency of the dominant allele was 0.278, very close to the mean value of 0.253 observed. In addition, the patterns of genotype frequencies, that is, the observed proportion of black homozygotes and the observed excess of black heterozygotes, are consistent with negative-assortative mating. Importantly these results demonstrate that negative assortative mating could be entirely responsible for the maintenance of this well known color polymorphism. PMID- 26988853 TI - Efficacy and hemodynamic response of pleural carbon dioxide insufflation during thoracoscopic surgery in a swine vessel injury model. AB - PURPOSES: Thoracoscopic anatomical lung resection is a minimally invasive technique, but intraoperative massive bleeding is a critical complication. We investigated the hemostatic efficacy and safety of intrapleural carbon dioxide (CO2) insufflation in thoracoscopic surgery in a swine vessel injury model. METHODS: Swines were assigned to one of four groups subjected to thoracoscopic surgery under target intrathoracic pressures of 0, 5, 10, or 15 mmHg CO2 insufflation, respectively. A pin-hole injury of the right cranial lobe pulmonary vein was inflicted thoracoscopically and we compared the blood loss and hemodynamic changes in each group. RESULTS: There were no signs or echographic findings of air embolus. Both the blood loss per minute and total blood loss during the experiment were significantly lower in the 10 and 15 mmHg groups than in the 0 mmHg group (p > 0.05, respectively). The hemodynamic signs, including heart rate, mean arterial pressure, and peripheral oxygen saturation, were not significantly different in the 0 and 10 mmHg groups at most times, although they were significantly correlated with the insufflation pressure during the experiments (p < 0.05). CONCLUSIONS: CO2 insufflation in thoracoscopic major lung resection appears to be safe, even in the short term, and can help to control vessel injury. PMID- 26988854 TI - New simple image overlay system using a tablet PC for pinpoint identification of the appropriate site for anastomosis in peripheral arterial reconstruction. AB - PURPOSE: To evaluate the accuracy and utility of a new image overlay system using a tablet PC for patients undergoing peripheral arterial reconstruction. METHODS: Eleven limbs treated with distal bypass surgery were studied. Three-dimensional images obtained by processing a preoperative contrast-enhanced computed tomography scan were superimposed onto the back-camera images of a tablet PC. We used this system to pinpoint a planned distal anastomotic site preoperatively and to make a precise incision directly above it during surgery. We used a branch artery near the distal anastomotic site as a reference point and the accuracy of the system was validated by comparing its results with the intraoperative findings. The precision of the system was also compared with that of a preoperative ultrasonographic examination. RESULTS: Both the image overlay system and ultrasonography (US) accurately identified the target branch artery in all except one limb. In that limb, which had a very small reference branch artery, preoperative US wrongly identified another branch, whereas the image overlay system located the target branch with an error of 10 mm. CONCLUSIONS: Our image overlay system was easy to use and allowed us to precisely identify a target artery preoperatively. Therefore, this system could be helpful for pinpointing the most accurate incision site during surgery. PMID- 26988855 TI - Is "functional end-to-end anastomosis" really functional? A review of the literature on stapled anastomosis using linear staplers. AB - PURPOSES: Anastomosis is one of the basic skills of a gastrointestinal surgeon. Stapling devices are widely used because stapled anastomosis (SA) can shorten operation times. Antiperistaltic stapled side-to-side anastomosis (SSSA) using linear staplers is a popular SA technique that is often referred to as "functional end-to-end anastomosis (FEEA)." The term "FEEA" has spread without any definite validation of its "function." The aim of this review is to show the heterogeneity of SA and conventional hand-sewn end-to-end anastomosis (HEEA) and to advocate the renaming of "FEEA." METHODS: We conducted a narrative review of the literature on SSSA. We reviewed the literature on ileocolic and small intestinal anastomosis in colonic cancer, Crohn's disease and ileostomy closure due to the simplicity of the technique. RESULTS: The superiority of SSSA in comparison to HEEA has been demonstrated in previous clinical studies concerning gastrointestinal anastomosis. Additionally, experimental studies have shown the differences between the two anastomotic techniques on peristalsis and the intestinal bacteria at the anastomotic site. CONCLUSIONS: SSSA and HEEA affect the postoperative clinical outcome, electrophysiological peristalsis, and bacteriology in different manners; no current studies have shown the functional equality of SSSA and HEEA. However, the use of the terms "functional end-to-end anastomosis" and/or "FEEA" could cause confusion for surgeons and researchers and should therefore be avoided. PMID- 26988858 TI - Functional neuroimaging of normal aging: Declining brain, adapting brain. AB - Early functional neuroimaging research on normal aging brain has been dominated by the interest in cognitive decline. In this framework the age-related compensatory recruitment of prefrontal cortex, in terms of executive system or reduced lateralization, has been established. Further details on these compensatory mechanisms and the findings reflecting cognitive decline, however, remain the matter of intensive investigations. Studies in another framework where age-related neural alteration is considered adaptation to the environmental change are recently burgeoning and appear largely categorized into three domains. The age-related increase in activation of the sensorimotor network may reflect the alteration of the peripheral sensorimotor systems. The increased susceptibility of the network for the mental-state inference to the socioemotional significance may be explained by the age-related motivational shift due to the altered social perception. The age-related change in activation of the self-referential network may be relevant to the focused positive self concept of elderly driven by a similar motivational shift. Across the domains, the concept of the self and internal model may provide the theoretical bases of this adaptation framework. These two frameworks complement each other to provide a comprehensive view of the normal aging brain. PMID- 26988857 TI - Medium chain length polyhydroxyalkanoates consisting primarily of unsaturated 3 hydroxy-5-cis-dodecanoate synthesized by newly isolated bacteria using crude glycerol. AB - BACKGROUND: Our study aimed to search for novel bacteria capable of producing polyhydroxyalkanoates (PHAs) using crude glycerol residue obtained from biodiesel production in which used cooking oils were the substrates. RESULTS: Newly isolated bacteria from soils in Thailand were screened for the efficient production of PHAs from crude glycerol. The bacterial strains were cultivated on glucose, refined glycerol, crude glycerol, or various cooking oils (canola oil, palm oil, soybean oil, sunflower oil, corn oil, grape seed oil, olive oil, rice bran oil, camellia seed oil) for growth and PHA production. The effects of the total organic carbon (TOC) concentration and the mole ratio of carbon to nitrogen were investigated in batch cultivation. (1)H NMR, two dimensional-(1)H correlation spectroscopy (2D-(1)H-COSY) and (13)C NMR analyses confirmed four bacterial strains were capable of producing medium-chain-length PHAs (mcl-PHAs), consisting of 3-hydroxyoctanoate (3HO) and 3-hydroxy-5-cis-dodecanoate (3H5DD), from crude glycerol. On the basis of phenotypic features and genotypic investigations, the bacterial strains were assigned as: ASC1, Acinetobacter genus (94.9% similarity); ASC2, Pseudomonas genus (99.2% similarity); ASC3, Enterobacter genus (99.2% similarity); ASC4, Bacillus genus (98.4% similarity). The highest amount of mcl-PHAs, 17.5 +/- 0.8 g/L (content 61.8 +/- 3.3% wt), with 3HO (14.7 +/- 2.2 mol %), 3H5DD (85.3 +/- 2.2 mol%), and a total biomass of 32.3 +/- 0.3 g/L, was obtained from Pseudomonas sp. ASC2 in batch cultivation after 36 h. The mcl-PHAs recovered had a number-average molecular weight (M N) of 3.6 * 10(4) Da. Homopolymeric 3H5DD was obtained when the cultivation time was prolonged to 96 h. CONCLUSIONS: Novel PHA-producing strains were isolated and identified. These bacterial strains are able to produce mcl-PHAs from crude glycerol. The mcl-PHAs produced contained a high percentage of 3H5DD, which suggests their future application as softeners mixed with other biomaterials. The unsaturated side chain of 3H5DD monomers containing double bounds offers additional potential for improving the properties of the mcl-PHAs or extending their applications to the food industry. PMID- 26988859 TI - The miR-143/miR-145 cluster and the tumor microenvironment: unexpected roles. AB - miR-143 and miR-145 have been widely described as tumor suppressors. Recent findings suggest these microRNAs (miRNAs) have a critical role that affects the stroma rather than epithelial cells. Understanding the part played by the miR 143/miR-145 cluster in the tumor microenvironment is essential for the development of future miRNA-related therapies. PMID- 26988861 TI - Pharmacokinetic modeling of [(18)F]fluorodeoxyglucose (FDG) for premature infants, and newborns through 5-year-olds. AB - BACKGROUND: Absorbed dose estimates for pediatric patients require pharmacokinetics that are, to the extent possible, age-specific. Such age specific pharmacokinetic data are lacking for many of the diagnostic agents typically used in pediatric imaging. We have developed a pharmacokinetic model of [(18)F]fluorodeoxyglucose (FDG) applicable to premature infants and to 0- (newborns) to 5-year-old patients, which may be used to generate model-derived time-integrated activity coefficients and absorbed dose calculations for these patients. METHODS: The FDG compartmental model developed by Hays and Segall for adults was fitted to published data from infants and also to a retrospective data set collected at the Boston Children's Hospital (BCH). The BCH data set was also used to examine the relationship between uptake of FDG in different organs and patient weight or age. RESULTS: Substantial changes in the structure of the FDG model were required to fit the pediatric data. Fitted rate constants and fractional blood volumes were reduced relative to the adult values. CONCLUSIONS: The pharmacokinetic models developed differ substantially from adult pharmacokinetic (PK) models which can have considerable impact on the dosimetric models for pediatric patients. This approach may be used as a model for estimating dosimetry in children from other radiopharmaceuticals. PMID- 26988860 TI - Hericium erinaceus mycelium and its isolated erinacine A protection from MPTP induced neurotoxicity through the ER stress, triggering an apoptosis cascade. AB - BACKGROUND: Hericium erinaceus is an edible mushroom; its various pharmacological effects which have been investigated. This study aimed to demonstrate whether efficacy of oral administration of H. erinaceus mycelium (HEM) and its isolated diterpenoid derivative, erinacine A, can act as an anti-neuroinflammatory agent to bring about neuroprotection using an MPTP (1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine) mouse model of Parkinson's disease, which results in motor disturbances, in addition to elucidating the mechanisms involved. METHODS: Mice were treated with and without HEM or erinacine A, after MPTP injection for brain injuries by the degeneration of dopaminergic nigrostriatal neurons. The efficacy of oral administration of HEM improved MPTP-induced loss of tyrosine hydroxylase positive neurons and brain impairment in the substantia nigra pars compacta as measured by brain histological examination. RESULTS: Treatment with HEM reduced MPTP-induced dopaminergic cell loss, apoptotic cell death induced by oxidative stress, as well as the level of glutathione, nitrotyrosine and 4-hydroxy-2 nonenal (4-HNE). Furthermore, HEM reversed MPTP-associated motor deficits, as revealed by the analysis of rotarod assessment. Our results demonstrated that erinacine A decreases the impairment of MPP-induced neuronal cell cytotoxicity and apoptosis, which were accompanied by ER stress-sustained activation of the IRE1alpha/TRAF2, JNK1/2 and p38 MAPK pathways, the expression of C/EBP homologous protein (CHOP), IKB-beta and NF-kappaB, as well as Fas and Bax. CONCLUSION: These physiological and brain histological changes provide HEM neuron-protective insights into the progression of Parkinson's disease, and this protective effect seems to exist both in vivo and in vitro. PMID- 26988862 TI - Maternal investment, life-history strategy of the offspring and adult chronic disease risk in South Asian women in the UK. AB - BACKGROUND AND OBJECTIVES: Patterns of development predict cardiovascular disease (CVD) risk, and ethnic differences therein, but it remains unclear why apparently 'adaptive plasticity' in early life should generate health costs in later life. We hypothesized that offspring receiving low maternal investment during fetal life, the primary period of organogenesis, should predict a shorter reproductive career and develop a fast life-history strategy, prioritizing reproduction over growth and homeostatic maintenance. METHODOLOGY: We studied 58 young adult South Asian women living in the UK, a group with high susceptibility to CVD. We obtained gestational age, birth weight (BW) and menarcheal age by recall and measured anthropometry, body composition, resting metabolic rate (RMR) and blood pressure (BP). RESULTS: BW and gestational age were inversely associated with menarcheal age, indicating that lower maternal investment is associated with faster maturation. Menarcheal age was positively associated with height but inversely with adiposity, indicating that rapid maturation prioritizes lipid stores over somatic growth. BW was inversely associated with BP, whereas adiposity was positively associated, indicating that lower maternal investment reduces BP homeostasis. BW was positively associated with RMR, whereas menarche was inversely associated, indicating that maternal investment influences adult metabolism. CONCLUSIONS AND IMPLICATIONS: Supporting our hypothesis, low maternal investment promoted faster life histories, demonstrated by earlier menarche, reduced growth and elevated adiposity. These traits were associated with poorer BP regulation. This is the first study demonstrating strategic adjustment of the balance between reproduction and metabolic health in response to the level of maternal investment during fetal life. PMID- 26988864 TI - Subgingivally delivered 1.2% atorvastatin in the treatment of chronic periodontitis among smokers: a randomized, controlled clinical trial. AB - AIM: Statins are known to have a beneficial effect in the treatment of chronic periodontitis (CP). The current study was designed to investigate the effectiveness of a 1.2% atorvastatin (ATV) local drug delivery system as an adjunct to scaling and root planing (SRP) in the treatment of intrabony defects (IBD) in CP among smokers. METHODS: Seventy-one smokers with CP were categorized into two treatment groups: SRP + 1.2% ATV gel and SRP + placebo gel. Clinical parameters, modified sulcus bleeding index, probing depth, and clinical attachment level were recorded at baseline before SRP and at 3, 6, and 9 months. At baseline, 6 months, and 9 months, the percentage of radiographic defect depth reduction was determined using computer-aided software. RESULTS: The mean probing depth reduction and mean clinical attachment level gain were found to be greater in the ATV group than the placebo group at 3, 6, and 9 months. A significantly greater mean percentage of radiographic defect depth reduction was found in the ATV group compared to the placebo group after 9 months. CONCLUSION: The ATV local drug delivery as an adjunct to SRP can be used in the treatment of IBD in CP among smokers. PMID- 26988865 TI - Editorial. PMID- 26988863 TI - Spent mushroom substrate of Pleurotus pulmonarius: a source of easily hydrolyzable lignocellulose. AB - Pleurotus pulmonarius was cultivated on a corncob-based substrate for producing of mushrooms and for assessing the transformation of the lignocellulosics during the development of fungal biomass. Associated events, such as the release of relevant enzymes and the H2O2 generation, were also monitored. The peaks of laccase and catalase activities occurred at the 5th day and that of Mn peroxidase at the 30th day, simultaneously with a high activity of superoxide dismutase. Increase in the endocellulase and xylanase activities was observed after 10 days, with maximal activities achieved during the 20-30-day period. Maximal values of H2O2 were found after 10 days of cultivation. Electron microscopy and Fourier transform infrared (FTIR) spectroscopy showed strong alterations in the lignocellulosic fibers. The uncultivated and the cultivated substrates at different times were hydrolyzed with commercial cellulase and beta-glucosidase. The highest values of reducing sugars (110.5 +/- 5.6 MUmol/mL), being 65 % glucose, were obtained using the 20-day cultivated substrate. After the fruiting stage (first flush), enzymatic hydrolysis of the spent mushroom substrate (SMS) yielded 53.0 +/- 2.8 and 77.5 +/- 4.0 MUmol/mL of glucose and total reducing sugars, respectively. Although the release of reducing sugars of the P. pulmonarius SMS was lower than that obtained after 20 days of cultivation, it was still 50 % higher than that obtained using the uncultured substrate. This observation, combined with the fact that SMS constitutes a residue generated as a by-product of the depletion of an agro-industrial residue, allows to conclude that this material offers an interesting economic perspective for the obtainment of cellulosic ethanol. PMID- 26988867 TI - How Does Employment-Based Insurance Coverage Relate to Health After Early Retirement? PMID- 26988866 TI - Boundary Extension Is Sensitive to Hand Position in Young and Older Adults. AB - Objectives: Based on preliminary reports, we expected an age-related increase in boundary extension (BE), a phenomenon in which people falsely remember seeing more of a scene than was presented. Given recent data suggesting hand-centered attentional frames in young adults contrasted with body-centered attentional frames in older adults, we predicted hand-position effects on BE in young adults only. Method: Participants (59 young, 60 older adults) viewed photographs of complex scenes (e.g., a market) and answered yes/no questions about each. Half answered with key presses while their hands were framing the computer monitor; half while their hands were on a lapdesk. At test, participants indicated whether photographs were the same as, or at a closer or wider angle than at study. Results: Both age groups demonstrated BE. When study-test angles were the same, participants rated test pictures as closer than at study. When study-test angles differed, older adults showed less BE than young adults. For both same- and different-angle conditions, there was a main effect of hand position (less BE when hands framed the monitor than when on participants' laps). Discussion: The data confirm older adults show BE but show no age-related increase. Surprisingly, both young and older adults showed hand-centered attention. PMID- 26988868 TI - Gist and Generalization in Young and Older Adults' Causal Learning. AB - Objectives: To investigate age differences in gist-based causal learning. Method: Young and older adults learned to predict whether eating foods from each of 6 categories was or was not followed by sickness. Experience with the categories was varied by presenting 5 exemplars of a category in only one of 2 training phases (small categories) or by presenting 5 exemplars of a category in the first phase and an additional 5 exemplars in the second phase (large categories). Trained and novel exemplars from all categories appeared in subsequent causal judgment and recognition tests. Results: There were no age differences in causal judgments for old exemplars or in generalization of causal associations to novel exemplars. For both groups, causal generalization was more successful and recognition was less successful for exemplars from large categories. There was no age difference in recognition for large categories, but older adults performed more poorly than young adults for small categories. Discussion: Older adults resemble young adults in their ability to induce unseen category features from presented exemplars, acquire causal associations for these gist representations, and generalize this knowledge to new exemplars. However, they continue to rely on these gist-based representations for memory discrimination, whereas young adults use both category and individuating features of cues. PMID- 26988869 TI - You're Just Like Your Dad: Intergenerational Patterns of Differential Treatment of Siblings. AB - Objectives: Past work highlights that parents' differential treatment has implications for offspring's mental and relational health across the life course. Although the current body of literature has examined offspring- and parent-level correlates of differential treatment, research has yet to consider whether and how patterns of differential treatment are transmitted across generations. Method: As part of a two-wave longitudinal study of 157 families, both grandparents (M age = 76.50 years, SD = 6.20) and parents (M age = 51.10 years, SD = 4.41) reported on differential treatment of their own offspring at both phases. Results: A series of residualized change models revealed support for both continuity and compensation hypotheses. Middle-aged parents tended to model the patterns of differential treatment exhibited by their fathers, but middle-aged men who experienced more differential treatment from their own parents in recent years tended to subsequently exhibit lower levels of differential treatment to their offspring. Discussion: These findings suggest that patterns of differential treatment both continue and diverge across generations, and those patterns vary by gender. On a broader level, these results also suggest that siblings not only impact one another's development, but in adulthood, they may indirectly influence their nieces' and nephews' development by virtue of their influence on their siblings' parenting. PMID- 26988870 TI - Predicting protein thermal stability changes upon point mutations using statistical potentials: Introducing HoTMuSiC. AB - The accurate prediction of the impact of an amino acid substitution on the thermal stability of a protein is a central issue in protein science, and is of key relevance for the rational optimization of various bioprocesses that use enzymes in unusual conditions. Here we present one of the first computational tools to predict the change in melting temperature DeltaTm upon point mutations, given the protein structure and, when available, the melting temperature Tm of the wild-type protein. The key ingredients of our model structure are standard and temperature-dependent statistical potentials, which are combined with the help of an artificial neural network. The model structure was chosen on the basis of a detailed thermodynamic analysis of the system. The parameters of the model were identified on a set of more than 1,600 mutations with experimentally measured DeltaTm. The performance of our method was tested using a strict 5-fold cross-validation procedure, and was found to be significantly superior to that of competing methods. We obtained a root mean square deviation between predicted and experimental DeltaTm values of 4.2 degrees C that reduces to 2.9 degrees C when ten percent outliers are removed. A webserver-based tool is freely available for non-commercial use at soft.dezyme.com. PMID- 26988872 TI - Endovascular reperfusion therapies for acute ischemic stroke: dissecting the evidence. AB - BACKGROUND: Ischemic stroke is a major cause of death and disability and intravenous thrombolysis has been the only approved acute reperfusion therapy (RT) for many years. METHODS: Seven randomized-controlled clinical trials (RCTs) evaluating the safety and efficacy of endovascular therapy in patients with acute ischemic stroke (AIS) due to emergent large vessel occlusion (ELVO) have been recently published. RESULTS: These studies have changed the treatment paradigm by establishing mechanical thrombectomy (MT) as the most effective acute stroke therapy for improving functional outcome in anterior circulation ELVO with a NNT of 6. CONCLUSIONS: The present review will critically evaluate the results of these RCTs and of the existing meta-analyses investigating the safety and efficacy of endovascular therapy for AIS. Points of debate such as acute stroke imaging, posterior circulation stroke and general anesthesia will be addressed. We will also discuss health policies aiming to increase the availability of endovascular treatment for stroke patients. PMID- 26988871 TI - Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery. AB - The periprocedural management of patients receiving chronic therapy with oral anticoagulants (OACs), including vitamin K antagonists (VKAs) such as warfarin and direct OACs (DOACs), is a common clinical problem. The optimal perioperative management of patients receiving chronic OAC therapy is anchored on four key principles: (i) risk stratification of patient-related and procedure-related risks of thrombosis and bleeding; (ii) the clinical consequences of a thrombotic or bleeding event; (iii) discontinuation and reinitiation of OAC therapy on the basis of the pharmacokinetic properties of each agent; and (iv) whether aggressive management such as the use of periprocedural heparin bridging has advantages for the prevention of postoperative thromboembolism at the cost of a possible increase in bleeding risk. Recent data from randomized trials in patients receiving VKAs undergoing pacemaker/defibrillator implantation or using heparin bridging therapy for elective procedures or surgeries can now inform best practice. There are also emerging data on periprocedural outcomes in the DOAC trials for patients with non-valvular atrial fibrillation. This review summarizes the evidence for the periprocedural management of patients receiving chronic OAC therapy, focusing on recent randomized trials and large outcome studies, to address three key clinical scenarios: (i) can OAC therapy be safely continued for minor procedures or surgeries; (ii) if therapy with VKAs (especially warfarin) needs to be temporarily interrupted for an elective procedure/surgery, is heparin bridging necessary; and (iii) what is the optimal periprocedural management of the DOACs? In answering these questions, we aim to provide updated clinical guidance for the periprocedural management of patients receiving VKA or DOAC therapy, including the use of heparin bridging. PMID- 26988873 TI - Structure activity relationship modelling of milk protein-derived peptides with dipeptidyl peptidase IV (DPP-IV) inhibitory activity. AB - Quantitative structure activity type models were developed in an attempt to predict the key features of peptide sequences having dipeptidyl peptidase IV (DPP IV) inhibitory activity. The models were then employed to help predict the potential of peptides, which are currently reported in the literature to be present in the intestinal tract of humans following milk/dairy product ingestion, to act as inhibitors of DPP-IV. Two models (z- and v-scale) for short (2-5 amino acid residues) bovine milk peptides, behaving as competitive inhibitors of DPP IV, were developed. The z- and the v-scale models (p<0.05, R(2) of 0.829 and 0.815, respectively) were then applied to 56 milk protein-derived peptides previously reported in the literature to be found in the intestinal tract of humans which possessed a structural feature of DPP-IV inhibitory peptides (P at the N2 position). Ten of these peptides were synthetized and tested for their in vitro DPP-IV inhibitory properties. There was no agreement between the predicted and experimentally determined DPP-IV half maximal inhibitory concentrations (IC50) for the competitive peptide inhibitors. However, the ranking for DPP-IV inhibitory potency of the competitive peptide inhibitors was conserved. Furthermore, potent in vitro DPP-IV inhibitory activity was observed with two peptides, LPVPQ (IC50=43.8+/-8.8MUM) and IPM (IC50=69.5+/-8.7MUM). Peptides present within the gastrointestinal tract of human may have promise for the development of natural DPP-IV inhibitors for the management of serum glucose. PMID- 26988874 TI - Assessment of RNA carrier function in peptide amphiphiles derived from the HIV fusion peptide. AB - A small library of amphiphilic peptides has been evaluated for duplex RNA carrier function into A549 cells. We studied peptides in which a C-terminal 7-residue cationic domain is attached to a neutral/hydrophobic 23-residue domain that is based on the viral fusion peptide of HIV. We also examined peptides in which the cationic charge was evenly distributed throughout the peptide. Strikingly, subtle sequence variations in the hydrophobic domain that do not alter net hydrophobicity result in wide variation in RNA uptake. Additionally, cyclic cystine variants are much less active as RNA carriers than their open-chain cysteine analogs. With regard to electrostatic effects, we find that lysine is less effective than arginine in facilitating uptake, and that even distribution of cationic residues throughout the peptide sequence results in especially effective RNA carrier function. Overall, minor changes in peptide hydrophobicity, flexibility and charge distribution can significantly alter carrier function. We hypothesize this is due to altered properties of the peptide-RNA assembly rather than peptide secondary structure. PMID- 26988875 TI - Risk agents related to work and amyotrophic lateral sclerosis: An occupational medicine focus. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons. In recent years, in addition to several studies about genetic mechanisms leading to motor neurons damage, various epigenetic theories have been developed, involving the study of the patients' work and lifestyle. The work aims at focusing the role of occupational exposure related to ALS by literature data analysis. Articles, selected on the basis of keywords, year of publication and topics, are related to occupational exposure, suggesting an impact on ALS onset. The literature review shows that there are still a lot of biases in the studies design, which actually do not allow to draw unequivocal conclusions. PMID- 26988876 TI - Update on work-exacerbated asthma. AB - Work-exacerbated asthma (WEA) is the term used to describe the worsening of asthma related to work but not the causation of asthma by work. It is common and has been reported to occur for 21.5% of working asthmatics on average. The frequency and severity may range from a single mild exacerbation that may lead to no time lost at work up to daily or severe exacerbations that may require a permanent change in work. Reports from general population surveys and primary care settings include more patients with short-term or mild exacerbations while those from tertiary care settings reflect the more severe end of the spectrum of severity or frequency, with socioeconomic outcomes that are similar to those of occupational asthma. In the minority of patients with the WEA, whose asthma starts while working, the differential diagnosis includes sensitizer-induced or possible irritant-induced occupational asthma. Optimizing work exposures and asthma management may improve outcome and prevent exacerbations. Worker education and screening of working asthmatics by primary health care workers may also prevent morbidity. PMID- 26988877 TI - Microbiological characterization of stable resuspended dust. AB - OBJECTIVES: Air quality in the stables is characterized by elevated level of dust and aeroallergens which are supposed to directly cause or exacerbate several respiratory disorders. The most often recognized problem is recurrent airway obstruction (RAO), previously known as chronic obstructive pulmonary disease (COPD). There is some indication that aeroallergens (among them endotoxins) may also cause inflammation in human airways and may exceed safe levels in stables. Monitoring studies have covered mainly the determination of the concentration of respirable particles and of culturable fungi and their toxins. However, these particles do not only directly affect the respiratory system, but might act as a carrier conveying toxic contaminants and biological agents such as bacteria. In a typical, 20-horse Hungarian stable, microbial community of respirable fraction of resuspended dust has been characterized to reveal if these particles convey hazardous pathogenic bacteria, posing risk to either horses or staff. MATERIAL AND METHODS: Resuspended dust was sampled using a mobile instrument. The instrument contains a PARTISOL-FRM model 2000 sampler that was operated at a flow rate of 16.7 l/min and a cyclone separator which collected the particulate matter with an aerodynamic size between 1 MUm and 10 MUm (PM1-10) fraction. Microbial taxa were identified by culture-independent next generation sequencing (NGS) of variable 16S ribosomal ribonucleic acid (rRNA) gene regions. RESULTS: In total, 1491 different taxa were identified, of them 384 were identified to species level, 961 to genus level. The sample was dominated by common ubiquitous soil and organic material-dwelling taxa. CONCLUSIONS: Pathogens occurred at low abundance, and were represented by mostly facultative human pathogens, with the prevalence of Staphylococcus species. PMID- 26988878 TI - Air pollution and emergency department visits for conjunctivitis: A case crossover study. AB - OBJECTIVES: The purpose of this study was to examine the associations between emergency department (ED) visits for conjunctivitis and ambient air pollution levels in urban regions across the province of Ontario, Canada. MATERIAL AND METHODS: Information from the National Ambulatory Care Reporting System was used to create time-series records, for the period of April 2004 to December 2011, on emergency department visits of patients suffering from conjunctivitis. A total of 77 439 emergency department visits for conjunctivitis were analyzed. A time stratified case-crossover design was applied, completed with meta-analysis in order to pool inter-city results. Odds ratio (OR) for an emergency department visit was calculated in different population strata per one-unit increase (one interquartile range - IQR increase in a pollutant's daily level) while controlling for the impacts of temperature and relative humidity. RESULTS: Statistically significant positive results were observed in the female population sample, for nitrogen dioxide (NO2) exposure lagged 5-8 days, with the highest result for the 7-day lag (OR = 1.035, 95% CI: 1.018-1.052) and for fine particulate matter with a median aerodynamic diameter of less than 2.5 MUm (PM2.5), for lags 6 and 7 days, with the highest result for lag 7 (OR = 1.017, 95% CI: 1.003-1.031). In the male population sample, statistically significant positive results were observed for NO2; at lag 5 days (OR = 1.024, 95% CI: 1.004 1.045) and for ozone (O3), at lags 0-3 and 7 days, with the highest result for lag 0 (OR = 1.038, 95% CI: 1.012-1.056). Also for males, statistically significant results were observed in the case of PM2.5 exposure lagged by 5 days (OR = 1.003, 95% CI: 1.000-1.038) and sulfur dioxide (SO2) exposure lagged by 1 and 2 days (OR = 1.016, 95% CI: 1.000-1.031 and OR = 1.018, 95% CI: 1.002-1.033). CONCLUSIONS: The findings of this study suggest that there are associations between levels of air pollution and ED visits for conjunctivitis, with different temporal trends and strength of association by age, sex, and season. PMID- 26988880 TI - Poor weight control, alcoholic beverage consumption and sudden sleep onset at the wheel among Italian truck drivers: A preliminary pilot study. AB - OBJECTIVES: The aim of this study was to investigate the prevalence of obesity, alcoholic beverage consumption, unhealthy alcohol use and sudden sleep onset at the wheel among Italian truck drivers. In addition to prevalence rates, this study also aimed at investigating potential predictors for sudden-onset sleepiness and obesity. MATERIAL AND METHODS: A sample of truck drivers was extracted from the database of the High Risk Professional Driver Study. Data concerning demographics, anthropometry, medical information and working conditions were collected using anonymous questionnaires. Logistic regression analyses were performed to assess the association of the reported body mass index (BMI), alcohol consumption and sudden sleep onset with working conditions and general lifestyle factors. RESULTS: Three hundred and thirty-five questionnaires were collected. According to their BMI, 45% of the participants were overweight and 21.4% of them were obese. Twenty-four point two percent declared they drank alcoholic beverages during working hours or work breaks and 21.3% of the drivers had an Alcohol Use Disorders Identification Test Consumption (AUDIT C) score >= 5 (the threshold value for unhealthy alcohol use). Forty-one point six percent of the interviewees experienced one episode of sudden sleep onset at the wheel per month (5.5% per week and 0.9% daily). Predictive factors for obesity were: length of service (odds ratio (OR) = 1.09, confidence interval (95% CI): 1.04-1.15, p < 0.001) and the AUDIT C total score (OR = 1.34, 95% CI: 1.08-1.66, p = 0.008). Predictive factors for sudden-onset sleepiness at the wheel were: age > 55 years old (OR = 5.22, 95% CI: 1.29-21.1, p = 0.020), driving more than 50 000 km per year (OR = 2.89, 95% CI: 1.37-6.11, p = 0.006) and the Chalder Fatigue Questionnaire (CFQ) score > 11 (adjusted OR = 2.97, 95% CI: 1.22-7.21, p = 0.016). CONCLUSIONS: This study strongly emphasizes the need for intervention in order to reduce and prevent important risk factors for the sake of road safety and truck drivers' health. PMID- 26988879 TI - Validity of mesothelin in occupational medicine practice. AB - OBJECTIVES: Malignant mesothelioma (MM) is the most serious asbestos-related disease. Its increasing incidence is alarming, suggesting the need for as early diagnosis as possible. This 4.5-year prospective longitudinal study aimed at assessing the benefit of measuring serum mesothelin as a marker for diagnosing malignant mesothelioma in individuals with previous occupational exposure to asbestos, as a part of their clinical follow-up care. MATERIAL AND METHODS: The study comprised 309 participants (235 males, 74 females) with a mean age of 58.9 years (standard deviation (SD) = 9.8) and a mean duration of exposure to asbestos dust of 13.4 years (SD = 9.3). From 2009 to June 2013, all subjects were followed at a department of occupational medicine in Olomouc. Apart from the standard parts of medical examination (history, physical examination, simple chest radiographs and spirometry), the patients' serum mesothelin levels were determined by the Mesomark immunoenzymatic diagnostic assay. Statistical analysis of the validity of serum mesothelin level measurement was carried out with respect to the diagnosis of MM. RESULTS: Among the participants, 16 (5.2%) individuals (14 males and 2 females) were diagnosed with malignant mesothelioma. Based on the detected mesothelin levels, their validity for prediction of malignant mesothelioma was calculated as follows: sensitivity - 0.75, specificity - 0.962, positive predictive value - 0.706, negative predictive value - 0.969, positive and negative likelihood ratios - 19.95 and 0.26, respectively, and diagnostic odds ratio - 76.8, at a 95% confidence interval. CONCLUSIONS: The high specificity was identified indicating the low false positivity as well. In the case of detecting elevated soluble mesothelin-related peptides (SMRP) levels in formerly asbestos-exposed individuals, the possibility of the presence of MM should be included into the clinical consideration. The high negative predictive value denotes a lower probability of the presence of MM in patients with normal SMRP levels but due to the limiting lower sensitivity this possibility cannot be entirely excluded. PMID- 26988881 TI - Overall human mortality and morbidity due to exposure to air pollution. AB - OBJECTIVES: Concentrations of particulate matter that contains particles with diameter <= 10 mm (PM10) and diameter <= 2.5 mm (PM2.5) as well as nitrogen dioxide (NO2) have considerable impact on human mortality, especially in the cases when cardiovascular or respiratory causes are attributed. Additionally, they affect morbidity. An estimation of human mortality and morbidity due to the increased concentrations of PM10, PM2.5 and NO2 between the years 2005-2013 was performed for the city of Krakow, Poland. For this purpose the Air Quality Health Impact Assessment Tool (AirQ) software was successfully applied. MATERIAL AND METHODS: The Air Quality Health Impact Assessment Tool was used for the calculation of the total, cardiovascular and respiratory mortality as well as hospital admissions related to cardiovascular and respiratory diseases. Data on concentrations of PM10, PM2.5 and NO2, which was obtained from the website of the Voivodeship Inspectorate for Environmental Protection (WIOS) in Krakow, was used in this study. RESULTS: Total mortality due to exposure to PM10 in 2005 was found to be 41 deaths per 100 000 and dropped to 30 deaths per 100 000 in 2013. Cardiovascular mortality was 2 times lower than the total mortality. However, hospital admissions due to respiratory diseases were more than an order of magnitude higher than the respiratory mortality. CONCLUSIONS: The calculated total mortality due to PM2.5 was higher than that due to PM10. Air pollution was determined to have a significant effect on human health. The values obtained by the use of the AirQ software for the city of Krakow imply that exposure to polluted air can result in serious health problems. PMID- 26988882 TI - Airborne peptidoglycans as a supporting indicator of bacterial contamination in a metal processing plant. AB - OBJECTIVES: The aim of this study was to assess exposure to airborne endotoxins and peptidoglycans (PGs) as well as possibility of using PGs as a surrogate measure of bacterial exposure in workplaces in a metal processing plant. MATERIAL AND METHODS: Personal dosimetry (N = 11) was used to obtain data on concentrations of viable bacteria, total number of bioaerosol particles, endotoxins and peptidoglycans. To investigate the size distributions of aerosol particles responsible for transport of endotoxins and PGs, air samples (N = 5) were additionally collected using the 8-stage cascade impactor. Endotoxins and PGs were assayed with the Limulus amebocyte lysate (LAL) test and a kinetic version of the silkworm larvae plasma (SLP) test, respectively. RESULTS: Median concentrations of airborne PGs (14.6 ng/m3), endotoxins (0.2 ng/m3), viable bacteria (1.16*103 CFU/m3) and the total number of bioaerosol particles (1.81*106 cells/m3) were determined. Qualitative analysis revealed presence of 19 bacterial species belonging to 14 genera. The calculations showed strong, significant correlations (p < 0.05) between endotoxins, viable bacteria (r = 0.75) and the total number of bioaerosol particle concentrations (r = 0.76) as well as between PGs and the total number of bioaerosol particle concentrations (r = 0.72). Size distribution analysis showed that the highest concentrations of bacterial aerosols occurred in the range of 2.1-3.3 MUm. In the case of endotoxins, an increase of concentrations in 2 ranges of aerodynamic diameters: 1.1-3.3 MUm and 5.8-9 MUm was shown. For PGs there was a visible gradual increase of their concentrations in the range 2.1-9 MUm. CONCLUSIONS: Peptidoglycans can be treated as a supporting indicator of bacterial contamination in metal processing plants, particularly when an assessment of an immunotoxic potential of microbiological hazards needs to be performed. However, to be extrapolated to other occupational and non-occupational environments, the obtained results require a further verification. PMID- 26988883 TI - Relationship between job demands and psychological outcomes among nurses: Does skill discretion matter? AB - OBJECTIVES: The aim of the present study was to assess both the direct and indirect effects (i.e., interacting with various job demands) of skill discretion on various psychological outcomes (i.e., emotional exhaustion, intention to leave, affective well-being, and job satisfaction). MATERIAL AND METHODS: Data were collected by a self-reported questionnaire in 3 hospitals in Italy. The sample consisted of 522 nurses. Moderated hierarchical regression analyses were employed. RESULTS: The findings highlighted the direct effect of skill discretion on reducing emotional exhaustion, intention to leave, sustaining affective well being and job satisfaction. As regards interaction effect, the analyses indicated that skill discretion moderates the negative effect of disproportionate patient expectations on all the considered psychological outcomes. On the other hand, skill discretion was found to moderate the effect of cognitive demands on turnover intention as well as the effect of quantitative demands on emotional exhaustion and job satisfaction only in conditions of low job demands. CONCLUSIONS: The study revealed some interesting findings, suggesting that skill discretion is not a resource in the pure sense, but that it also has some characteristics of a job demand. The study has relevant practical implications. Particularly, from a job design point of view, the present study suggests that job demands and skill discretion should be balanced carefully in order to sustain job well-being and worker retention. PMID- 26988884 TI - Geospatial clustering of gastroschisis in Poland: Data from the Polish Registry of Congenital Malformations (PRCM). AB - OBJECTIVES: The aims of this study were: to evaluate the prevalence of abdominal wall defects in the Polish population, to analyze temporal trends in the prevalence, to identify areas (clusters) of high risk of abdominal wall defects, and to characterize, with respect to epidemiology, children with abdominal wall defects and their mothers in the area defined as a cluster. MATERIAL AND METHODS: We used isolated congenital malformations (gastroschisis Q79.3 and omphalocele Q79.2 according to the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10, the extended version)) data reported to the Polish Registry of Congenital Malformations (PRCM) over the years 1998- 2008 based on the population of 2 362 502 live births. We analyzed 11 administrative regions of Poland with complete epidemiologic data. RESULTS: Of 11 regions, 2 had a significantly higher standardized prevalence of isolated gastroschisis: Dolnoslaskie (1.7/10 000 live births, p = 0.0052) and Slaskie (1.9/10 000 live births, p < 0.0001). Furthermore, within the region of Dolnoslaskie, we defined a clear prevalence of the isolated gastroschisis cluster (p = 0.023). We comprehensively examined demographic and socio-economic risk factors for abdominal wall defects in this area, and we found that these factors failed to account for the cluster. CONCLUSIONS: We identified a distinct prevalence cluster for isolated gastroschisis, although a precise reason for the disease clustering in this region remains unknown. Cluster identification enables more focused research aimed at identification of specific factors with teratogenic effects. PMID- 26988885 TI - Visual evoked potentials in patients after methanol poisoning. AB - OBJECTIVES: We report the results of the visual evoked potentials (VEP) examination in patients after severe poisoning by methanol. MATERIAL AND METHODS: The group of 47 patients (38 males and 9 females) was assembled out of persons who survived an outbreak of poisoning by the methanol adulterated alcohol beverages, which happened in the Czech Republic in 2012-2013. The visual evoked potentials examination was performed using monocular checkerboard pattern reversal stimulation. Two criteria of abnormality were chosen: missing evoked response, and wave P1 latency > 117 ms. Non-parametric statistical methods (median, range, and the median test) were used to analyze factors influencing the VEP abnormality. RESULTS: The visual evoked potential was abnormal in 20 patients (43%), 5 of them had normal visual acuity on the Snellen chart. The VEP abnormality did not correlate significantly with initial serum concentrations of methanol, formic acid or lactate; however, it showed statistically significant inverse relation to the initial serum pH: the subgroup with the abnormal VEP had significantly lower median pH in comparison with the subgroup with the normal VEP (7.16 vs. 7.34, p = 0.04). The abnormality was not related to chronic alcohol abuse. CONCLUSIONS: The visual evoked potentials examination appeared sensitive enough to detected even subclinical impairment of the optic system. Metabolic acidosis is likely to be the key factor related to the development of visual damage induced by methanol. The examination performed with a delay of 1-9 months after the poisoning documented the situation relatively early after the event. It is considered as a baseline for the planned long-term follow-up of the patients, which will make it possible to assess the dynamics of the observed changes, their reversibility, and the occurrence of potential late sequelae. PMID- 26988886 TI - Developmental toxicity of N-methylaniline following prenatal oral administration in rats. AB - OBJECTIVES: The objective of the study was to assess prenatal toxicity of N methylaniline (NMA) administered by gavage to pregnant female rats. MATERIAL AND METHODS: Pregnant female rats were administered N-methylaniline in corn oil by gavage at daily doses of 0.8 mg/kg of body weight (b.w.), 4 mg/kg b.w., 20 mg/kg b.w. and 100 mg/kg b.w. from implantation (the 5th day post mating) to the day prior to the scheduled caesarean section (the 20th day of pregnancy). General behavior, body weight, food and water consumption, hematological, biochemical analyses and pathomorphological changes of the dams were recorded. RESULTS: All the females survived until the end of the study. The test substance was toxic to pregnant females, even at the lowest of the used doses, i.e., 0.8 mg/kg b.w./day. Lower weight gain during pregnancy and significantly higher NMA-dose-dependent absolute weight of the organs were noted in the exposed females. The females from the groups exposed at doses of 20 mg/kg b.w./day and 100 mg/kg b.w./day developed anemia and showed higher concentrations of free thyroxine (FT3) and free triiodothyronine (FT4) thyroid hormones. Total protein concentration exhibited an increase in all the exposed groups of females. In the prenatal toxicity study, administration of N-methylaniline throughout the embryonic and fetal periods produced embryotoxic effects at doses ranging 4-100 mg/kg b.w./day. CONCLUSIONS: Considering the data obtained in this study, it is reasonable to assume that N methylaniline administered orally to pregnant rats is toxic for mothers even at a low dose of 0.8 mg/kg b.w./day. However, this dose was not associated with any significant effects to their offspring. This prenatal exposure level may be considered as no-observed-adverse-effect level (NOAEL) for the progeny and a dose of 4 mg/kg b.w./day as the lowest-observed-adverse-effect level (LOAEL) for the progeny. PMID- 26988887 TI - Methods of sampling airborne fungi in working environments of waste treatment facilities. AB - OBJECTIVES: The objective of the present study was to evaluate and compare the efficiency of a filter based sampling method and a high volume sampling method for sampling airborne culturable fungi present in waste sorting facilities. MATERIAL AND METHODS: Membrane filters method was compared with surface air system method. The selected sampling methods were modified and tested in 2 plastic waste sorting facilities. RESULTS: The total number of colony-forming units (CFU)/m3 of airborne fungi was dependent on the type of sampling device, on the time of sampling, which was carried out every hour from the beginning of the work shift, and on the type of cultivation medium (p < 0.001). Detected concentrations of airborne fungi ranged 2*102-1.7*106 CFU/m3 when using the membrane filters (MF) method, and 3*102-6.4*104 CFU/m3 when using the surface air system (SAS) method. CONCLUSIONS: Both methods showed comparable sensitivity to the fluctuations of the concentrations of airborne fungi during the work shifts. The SAS method is adequate for a fast indicative determination of concentration of airborne fungi. The MF method is suitable for thorough assessment of working environment contamination by airborne fungi. Therefore we recommend the MF method for the implementation of a uniform standard methodology of airborne fungi sampling in working environments of waste treatment facilities. PMID- 26988888 TI - Pathogenic and phylogenetic features of 2 multiresistant Pseudomonas aeruginosa strains originated from remediated sites. AB - OBJECTIVES: To evaluate the possible occupational hazard of environmental strains of opportunistic Pseudomonas aeruginosa on hydrocarbon contaminated sites during remediation, 2 multidrug-resistant isolates originating from environmental (soil and groundwater) samples were examined. MATERIAL AND METHODS: Antibiotic resistance profiles of the examined 2 strains were determined by Etest(r) against 20 different agents. Virulence investigations included the hemolytic activity test, the detection of virulence-related gene sequences such as exoA, exoU, exoS, exoY, exoT and the determination of intraperitoneal LD50 (the lethal dose, 50%) values in a mouse model. The hydrocarbon-degrading ability was evaluated in a gravimetric experiment, in vitro. The phylogenetic relationship of the isolates was investigated with a multilocus sequence typing scheme. RESULTS: Multidrug resistant environmental strains of P. aeruginosa are strongly related to isolates that have proven effects on the infection of patients who suffer from cystic fibrosis, have a notable hemolytic activity, carry important virulence markers (exoS or exoU, respectively) and retain their hydrocarbon degradation ability (87.4% and 62.8% hydrocarbon degradation rate, respectively). CONCLUSIONS: Pseudomonas aeruginosa presumably raise considerable concerns for human health in the environment, already well known among nosocomial isolates, and the application of environmental strains of this species for environmental purposes is questionable. PMID- 26988889 TI - Bilateral hypermobility of ulnar nerves at the elbow joint with unilateral left ulnar neuropathy in a computer user: A case study. AB - Occupational ulnar neuropathy at the elbow joint develops in the course of long term direct pressure on the nerve and a persistently flexed elbow posture, but first of all, it is strongly associated with "holding a tool in a certain position" repetitively. Therefore, computer work only in exceptional cases can be considered as a risk factor for the neuropathy. Ulnar hypermobility at the elbow might be one of the risk factors in the development of occupational ulnar neuropathy; however, this issue still remains disputable. As this condition is mostly of congenital origin, an additional factor, such as a direct acute or chronic professional or non-professional trauma, is needed for clinical manifestations. We describe a patient - a computer user with a right ulnar nerve complete dislocation and left ulnar nerve hypermobility, unaware of her anomaly until symptoms of left ulnar neuropathy occurred in the course of job exposure. The patient was exposed to repetitive long lasting pressure of the left elbow and forearm on the hard support on the cupboard and desk because of a non ergonomically designed workplace. The additional coexistent congenital abnormal displacement of the ulnar nerve from the postcondylar groove during flexion at the elbow increased the possibility of its mechanical injury. We recognized left ulnar neuropathy at the ulnar groove as an occupational disease. An early and accurate diagnosis of any form of hypermobility of ulnar nerve, informing patients about it, prevention of an ulnar nerve injury as well as compliance with ergonomic rules are essential to avoid development of occupational and non occupational neuropathy. PMID- 26988890 TI - Pleural mesothelioma: Case-report of uncommon occupational asbestos exposure in a small furniture industry. AB - The relationship between asbestos exposure and malignant mesothelioma is no longer disputed, although it is not always easy to trace past occupational exposure. This report describes a case of uncommon asbestos exposure of a small furniture industry worker, who subsequently died of pleural malignant mesothelioma, to stress the crucial importance of a full reconstruction of the occupational history, both for legal and compensation purposes. Sarcomatoid pleural mesothelioma was diagnosed in a 70-year-old man, who was previously employed as a carpenter in a small furniture industry. He worked for about 6 years in the small factory, was exposed to asbestos during the assembly of the furniture inspired by classical architecture, in which asbestos cement tubes were used to reproduce classical columns. During this production process no specific work safety measures were applied, nor masks or local aspirators. No extra professional exposure to asbestos was identified. This mesothelioma case was investigated by the Public Prosecutor's assignment that commissioned expert evidence on the legal accountability for the disease. Despite its uncommon expositive circumstance, the length of latency (about 30 years), the duration of exposure, the clinical and histochemical features are all consistent with literature evidence, accounting for the occupational origin of this malignancy. PMID- 26988891 TI - Blood biomarkers in the early stage of cerebral ischemia. AB - In ischemic stroke patients, blood-based biomarkers may be applied for the diagnosis of ischemic origin and subtype, prediction of outcomes and targeted treatment in selected patients. Knowledge of the pathophysiology of cerebral ischemia has led to the evaluation of proteins, neurotransmitters, nucleic acids and lipids as potential biomarkers. The present report focuses on the role of blood-based biomarkers in the early stage of ischemic stroke-within 72h of its onset-as gleaned from studies published in English in such patients. Despite growing interest in their potential role in clinical practice, the application of biomarkers for the management of cerebral ischemia is not currently recommended by guidelines. However, there are some promising clinical biomarkers, as well as the N-methyl-d-aspartate (NMDA) peptide and NMDA-receptor (R) autoantibodies that appear to identify the ischemic nature of stroke, and the glial fibrillary acidic protein (GFAP) that might be able to discriminate between acute ischemic and hemorrhagic strokes. Moreover, genomics and proteomics allow the characterization of differences in gene expression, and protein and metabolite production, in ischemic stroke patients compared with controls and, thus, may help to identify novel markers with sufficient sensitivity and specificity. Additional studies to validate promising biomarkers and to identify novel biomarkers are needed. PMID- 26988892 TI - Pathobiological Characterization of a Novel Reassortant Highly Pathogenic H5N1 Virus Isolated in British Columbia, Canada, 2015. AB - In the current study, we describe the pathobiologic characteristics of a novel reassortant virus - A/chicken/BC/FAV-002/2015 (H5N1) belonging to clade 2.3.4.4 that was isolated from backyard chickens in British Columbia, Canada. Sequence analyses demonstrate PB1, PA, NA and NS gene segments were of North American lineage while PB2, HA, NP and M were derived from a Eurasian lineage H5N8 virus. This novel virus had a 19 amino acid deletion in the neuraminidase stalk. We evaluated the pathogenic potential of this isolate in various animal models. The virus was highly pathogenic to mice with a LD50 of 10 plaque forming units (PFU), but had limited tissue tropism. It caused only subclinical infection in pigs which did result in seroconversion. This virus was highly pathogenic to chickens, turkeys, juvenile Muscovy ducks (Cairnia moschata foma domestica) and adult Chinese geese (Anser cynoides domesticus) causing a systemic infection in all species. The virus was also efficiently transmitted and resulted in mortality in naive contact ducks, geese and chickens. Our findings indicate that this novel H5N1 virus has a wide host range and enhanced surveillance of migratory waterfowl may be necessary in order to determine its potential to establish itself in the wild bird reservoir. PMID- 26988894 TI - Chemotaxonomic Approach to the Central Balkan Sedum Species Based on Distribution of Triterpenoids in Their Epicuticular Waxes. AB - Triterpenoid distribution in epicuticular waxes of 20 central Balkan Sedum L. species and four out-groups of genera: Hylotelephium H. Ohba, Crassula L., Echeveria DC., and Kalanchoe Adans. were investigated for chemotaxonomic purposes. Identification and quantification of wax triterpenoids were performed by GC/MS and GC-FID analyses. Distribution of identified triterpenoids (oleanane, lupane, and taraxerane series), as a pattern in statistical analysis, indicated very good agreement with phylogeny and systematics, except members of series Rupestria Berger, in which case the distribution of triterpenoids did not support known classification in a satisfactory manner. According to the obtained clustering, Kalanchoe is shown as similar to Sedum samples, while the other out groups were clearly separated. PMID- 26988893 TI - Ovariectomy May Induce Detrusor Overactivity in Rats: The Therapeutic Role of Rho Kinase Inhibition. AB - OBJECTIVE: To verify the impact of ovariectomy (OVX) on the micturition cycle in conscious rats; to examine the influence of rho kinase (ROCK) inhibition on the bladder detrusor in OVX rats; to assess the effect of the joint administration of the ROCK inhibitor (GSK 269962) and solifenacin succinate (SOL) to these animals. MATERIALS AND METHODS: The impact of OVX or a single dose of GSK 269962 and/or SOL on the cystometric parameters was assessed 28 days after the procedure. RESULTS: OVX caused an increase in detrusor overactivity index, amplitude, and frequency of nonvoiding contractions, along with a decrease in voided volume, volume threshold, intercontraction interval, bladder compliance, and volume threshold to elicit nonvoiding contractions. GSK 269962 administered in a dose of 10 mg/kg (but not 5 mg/kg) or SOL in a dose of 0.03 mg/kg (but not 0.015 mg/kg) triggered an increase in voided volume, volume threshold, intercontraction interval, bladder compliance, and volume threshold to elicit nonvoiding contractions, along with a decrease in detrusor overactivity index, amplitude, and frequency of nonvoiding contractions. A combined administration of GSK 269962 (5 mg/kg) and SOL (0.15 mg/kg), in doses ineffective in monotherapy, triggered a reversal in the OVX-induced cystometric changes. CONCLUSION: It appears that ROCK inhibitors can become an alternative worth considering in overactive bladder syndrome treatment, especially in the light of the findings pointing to the decreased efficiency of antimuscarinic drugs in the overactive bladder syndrome treatment of postmenopausal women. PMID- 26988896 TI - Attitudes towards relocation following Hurricane Sandy: should we stay or should we go? AB - This study explores the dilemma of whether to rebuild or relocate from the areas devastated by Hurricane Sandy in 2012. Since disasters represent the discernible manifestation of other complex coastal hazards, they offer a window of opportunity to engage residents in the dialogue on relocation as sometimes the most effective risk reduction strategy. The following research evaluates attitudes towards relocation and willingness to consider buyout among 46 surveyed households located in highly-affected communities five months after Sandy. It also gauges perceptions of coastal risks and recovery concerns as drivers of relocation, the level of support for different adaptation strategies, and preferences related to the relocation process itself on how and where to relocate and with what type of assistance. Responses indicate that, even though residents prefer structural solutions to address coastal hazards, they are not fully opposed to the possibility of relocation mostly for personal health and safety reasons. PMID- 26988895 TI - A search for synbiotics: effects of enzymatically modified arabinoxylan and Butyrivibrio fibrisolvens on short-chain fatty acids in the cecum content and plasma of rats. AB - Identification of dietary strategies to increase large intestinal production and absorption of short-chain fatty acids (SCFAs), especially butyrate, is of great interest due to the possible health promoting effects. We explored the effect of an enzymatically modified arabinoxylan-rich diet (EAXD) versus a Western-style control diet (WSD) low in dietary fiber with or without orally administrated Butyrivibrio fibrisolvens, a butyrate producer, on the SCFA pool in the cecal content and feces and the SCFA concentration in the blood of rats. The pool of acetate, butyrate and total SCFA was more than double in the cecal content from EAXD-fed rats compared with WSD-fed rats, and this was also reflected as an increase in portal plasma SCFA concentrations. Acetate, propionate and total SCFA concentrations were higher in mixed venous plasma following the EAXD. The number of B. fibrisolvens did not increase significantly in cecal content following administration of the bacteria. Furthermore, there was no interaction between the EAXD and B. fibrisolvens on the measured parameters. PMID- 26988897 TI - What are the combined effects of negative emotions and illness cognitions on self care in people with type 2 diabetes? A longitudinal structural equation model. AB - OBJECTIVE: To explore whether negative emotions mediate the effect of diabetes cognitions on diabetes self-care and conversely whether diabetes cognitions mediate the effect of negative emotions on diabetes self-care. DESIGN: Longitudinal observational study in adults with type 2 diabetes. MAIN OUTCOME MEASURES: Self-reported depression and anxiety (Diabetes Wellbeing Questionnaire), cognitions (Illness Perceptions Questionnaire-Revised; Beliefs about Medicines Questionnaire), and diabetes self-care (Summary of Diabetes Self Care Activities Scale) were completed at baseline and six months. Analyses used structural equation modelling. RESULTS: Baseline medication concerns were associated with elevated symptoms of depression and anxiety at follow-up, but emotions did not mediate medication concern's effect on diabetes self-care. Baseline depression and anxiety symptoms were associated with specific diabetes cognitions over time, but these cognition domains did not mediate emotion's effect on diabetes self-care. Personal control remained independent of emotions and was associated with diabetes self-care over time. CONCLUSIONS: Negative emotions did not act directly or alongside cognitions to influence diabetes self care. The reciprocal relationship between diabetes cognitions and emotions suggests cognitive restructuring, in addition to other mood management intervention techniques would likely improve the emotional wellbeing of adults with type 2 diabetes. Likewise, personal control beliefs are likely important intervention targets for improving self-care. PMID- 26988898 TI - Distinct iris gene expression profiles of primary angle closure glaucoma and primary open angle glaucoma and their interaction with ocular biometric parameters. AB - BACKGROUND: This study aimed to evaluate differences in iris gene expression profiles between primary angle closure glaucoma (PACG) and primary open angle glaucoma (POAG) and their interaction with biometric characteristics. DESIGN: Prospective study. PARTICIPANTS: Thirty-five subjects with PACG and thirty-three subjects with POAG who required trabeculectomy were enrolled at the Singapore National Eye Centre, Singapore. METHODS: Iris specimens, obtained by iridectomy, were analysed by real-time polymerase chain reaction for expression of type I collagen, vascular endothelial growth factor (VEGF)-A, -B and -C, as well as VEGF receptors (VEGFRs) 1 and 2. Anterior segment optical coherence tomography (ASOCT) imaging for biometric parameters, including anterior chamber depth (ACD), anterior chamber volume (ACV) and lens vault (LV), was also performed pre operatively. MAIN OUTCOME MEASURES: Relative mRNA levels between PACG and POAG irises, biometric measurements, discriminant analyses using genes and biometric parameters. RESULTS: COL1A1, VEGFB, VEGFC and VEGFR2 mRNA expression was higher in PACG compared to POAG irises. LV, ACD and ACV were significantly different between the two subgroups. Discriminant analyses based on gene expression, biometric parameters or a combination of both gene expression and biometrics (LV and ACV), correctly classified 94.1%, 85.3% and 94.1% of the original PACG and POAG cases, respectively. The discriminant function combining genes and biometrics demonstrated the highest accuracy in cross-validated classification of the two glaucoma subtypes. CONCLUSIONS: Distinct iris gene expression supports the pathophysiological differences that exist between PACG and POAG. Biometric parameters can combine with iris gene expression to more accurately define PACG from POAG. PMID- 26988900 TI - Electrochemical treatment of water containing Microcystis aeruginosa in a fixed bed reactor with three-dimensional conductive diamond anodes. AB - An electrochemical treatment was investigated to remove Microcystis aeruginosa from water. A fixed bed reactor in flow was tested, which was equipped with electrodes constituted by stacks of grids electrically connected in parallel, with the electric field parallel to the fluid flow. Conductive diamond were used as anodes, platinised Ti as cathode. Electrolyses were performed in continuous and in batch recirculated mode with flow rates corresponding to Re from 10 to 160, current densities in the range 10-60Am(-2) and Cl(-) concentrations up to 600gm(-3). The absorbance of chlorophyll-a pigment and the concentration of products and by-products of electrolysis were measured. In continuous experiments without algae in the inlet stream, total oxidants concentrations as equivalent Cl2, of about 0.7gCl2m(-3) were measured; the maximum values were obtained at Re=10 and i=25Am(-2), with values strongly dependent on the concentration of Cl( ). The highest algae inactivation was obtained under the operative conditions of maximum generation of oxidants; in the presence of microalgae the oxidants concentrations were generally below the detection limit. Results indicated that most of the bulk oxidants electrogenerated is constituted by active chlorine. The prevailing mechanism of M. aeruginosa inactivation is the disinfection by bulk oxidants. The experimental data were quantitatively interpreted through a simple plug flow model, in which the axial dispersion accounts for the non-ideal flow behaviour of the system; the model was successfully used to simulate the performances of the reactor in the single-stack configuration used for the experiments and in multi-stack configurations. PMID- 26988901 TI - Detection of ochratoxin A in beer samples with a label-free monolithically integrated optoelectronic biosensor. AB - An optical biosensor for label-free detection of ochratoxin A (OTA) in beer samples is presented. The biosensor consists of an array of ten Mach-Zehnder interferometers (MZIs) monolithically integrated along with their respective broad-band silicon light sources on the same Si chip (37mm2). The chip was transformed to biosensor by functionalizing the MZIs sensing arms with an OTA ovalbumin conjugate. OTA determination was performed by pumping over the chip mixtures of calibrators or samples with anti-OTA antibody following a competitive immunoassay format. An external miniaturized spectrometer was employed to continuously record the transmission spectra of each interferometer. Spectral shifts obtained due to immunoreaction were transformed to phase shifts through Discrete Fourier Transform. The assay had a detection limit of 2.0ng/ml and a dynamic range 4.0-100ng/ml in beer samples, recoveries ranging from 90.6 to 116%, and intra- and inter-assay coefficients of variation of 9% and 14%, respectively. The results obtained with the sensor using OTA-spiked beer samples spiked were in good agreement with those obtained by an ELISA developed using the same antibody. The good analytical performance of the biosensor and the small size of the proposed chip provide for the development of a portable instrument for point-of need determinations. PMID- 26988899 TI - Initial in vitro studies on tissues and cells from GTKO/CD46/NeuGcKO pigs. AB - BACKGROUND: The impact that the absence of expression of NeuGc in pigs might have on pig organ or cell transplantation in humans has been studied in vitro, but only using red blood cells (pRBCs) and peripheral blood mononuclear cells (pPBMCs) as the target cells for immune assays. We have extended this work in various in vitro models and now report our initial results. METHODS: The models we have used involve GTKO/hCD46 and GTKO/hCD46/NeuGcKO pig aortas and corneas, and pRBCs, pPBMCs, aortic endothelial cells (pAECs), corneal endothelial cells (pCECs), and isolated pancreatic islets. We have investigated the effect of the absence of NeuGc expression on (i) human IgM and IgG binding, (ii) the T-cell proliferative response, (iii) human platelet aggregation, and (iv) in an in vitro assay of the instant blood-mediated inflammatory reaction (IBMIR) following exposure of pig islets to human blood/serum. RESULTS: The lack of expression of NeuGc on some pig tissues (aortas, corneas) and cells (RBCs, PBMCs, AECs) significantly reduces the extent of human antibody binding. In contrast, the absence of NeuGc expression on some pig tissues (CECs, isolated islet cells) does not reduce human antibody binding, possibly due to their relatively low NeuGc expression level. The strength of the human T-cell proliferative response may also be marginally reduced, but is already weak to GTKO/hCD46 pAECs and islet cells. We also demonstrate that the absence of NeuGc expression on GTKO/hCD46 pAECs does not reduce human platelet aggregation, and nor does it significantly modify the IBMIR to pig islets. CONCLUSION: The absence of NeuGc on some solid organs from GTKO/hCD46/NeuGcKO pigs should reduce the human antibody response after clinical transplantation when compared to GTKO/hCD46 pig organs. However, the clinical benefit of using certain tissue (e.g., cornea, islets) from GTKO/hCD46/NeuGcKO pigs is questionable. PMID- 26988902 TI - Combination of nanofiltration and ozonation for the remediation of real municipal wastewater effluents: Acute and chronic toxicity assessment. AB - The purpose of this work was to study the ozonation of nanofiltration (NF) retentates of real municipal wastewater treatment plant (MWTP) effluents for removal of microcontaminants (MCs) and toxicity. MCs present in these effluents were monitored using LC-MS/MS. Acute and chronic toxicity was addressed with Daphnia magna, Vibrio fischeri and Selenastrum capricornutum. Up to 40 MCs were found, most of them in concentrations over 100ng/L. 90% degradation of the sum of MCs was the critical point of comparison. When the NF membrane system was applied to MWTP effluents, treatment of NF rejection needed 2.75-4.5g O3/m3,4.5g O3/m3, which is less than 50% of the ozone needed for direct treatment of MWTP effluent. Treatment time (lower than 11min) was not influenced by MCs concentration, at least in the range tested (25-190MUg/L). It has been demonstrated that consumption of ozone increased with organic load and inorganic content of different real effluents. MCs were eliminated by ozonation but acute toxicity (against V. fischeri and D. magna) increased. Chronic toxicity results were different and contrary in D. magna and S. capricornutum, due to the generation of new transformation products more toxic to D. magna than the parent contaminants. S. capricornutum inhibition percentage decreased in all cases after ozonation treatment. According to these results, before ozonation is implemented in MWTPs for the removal of MCs, the transformation products must first be examined and the treatment time or ozone doses should be extended to complete degradation if necessary. PMID- 26988904 TI - Chasing stress signals - Exposure to extracellular stimuli differentially affects the redox state of cell compartments in the wild type and signaling mutants of Botrytis cinerea. AB - Reactive oxygen species (ROS) are important molecules influencing intracellular developmental processes as well as plant pathogen interactions. They are produced at the infection site and affect the intracellular redox homeostasis. However, knowledge of ROS signaling pathways, their connection to other signaling cascades, and tools for the visualization of intra- and extracellular ROS levels and their impact on the redox state are scarce. By using the genetically encoded biosensor roGFP2 we studied for the first time the differences between the redox states of the cytosol, the intermembrane space of mitochondria and the ER in the filamentous fungus Botrytis cinerea. We showed that the ratio of oxidized to reduced glutathione inside of the cellular compartments differ and that the addition of hydrogen peroxide (H2O2), calcium chloride (CaCl2) and the fluorescent dye calcofluor white (CFW) have a direct impact on the cellular redox states. Dependent on the type of stress agents applied, the redox states were affected in the different cellular compartments in a temporally shifted manner. By integrating the biosensor in deletion mutants of bcnoxA, bcnoxB, bctrx1 and bcltf1 we further elucidated the putative roles of the different proteins in distinct stress-response pathways. We showed that the redox states of DeltabcnoxA and DeltabcnoxB display a wild-type pattern upon exposure to H2O2, but appear to be strongly affected by CaCl2 and CFW. Moreover, we demonstrated the involvement of the light-responsive transcription factor BcLtf1 in the maintenance of the redox state in the intermembrane space of the mitochondria. Finally, we report that CaCl2 as well as cell wall stress-inducing agents stimulate ROS production and that DeltabcnoxB produces significantly less ROS than the wild type and DeltabcnoxA. PMID- 26988903 TI - Patent foramen ovale (PFO), stroke and pregnancy. AB - Patent foramen ovale (PFO)-related stroke is increasingly recognized as an important etiology of ischemic embolic stroke-accounting for up to 50% of strokes previously considered 'cryptogenic' or with an unknown mechanism. As a 'back door to the brain,' PFO can allow venous clots to enter arterial circulation via interatrial right-to-left shunting, potentially resulting in ischemic stroke. We observe that clinically, PFO-related stroke affects women of childbearing age, and that pregnancy-owing to major changes in hemocoagulative, hormonal, and cardiovascular parameters-can enhance stroke risks. However, no systematic study has been performed and little is known regarding complications, pregnancy outcomes and treatment for PFO-related stroke during pregnancy. To identify and characterize the complications and clinical outcomes related to PFOs during pregnancy, we performed a literature review and analysis from all reported cases of pregnancy with PFO-related complications in the medical literature from 1970 to 2015. We find that during pregnancy and post-partum, PFO is associated with complications affecting multiple organs, including the brain, heart and lung. The three principal complications reported are stroke, pulmonary emboli and myocardial infarction. In contrast to other pregnancy-related stroke etiologies, which peak during later pregnancy and postpartum, PFO-related stroke peaks during early pregnancy (first and second trimester-60%), and most patients had good neurological outcome (77%). In patients with PFO with recurrent stroke during pregnancy, additional key factors include high-risk PFO morphology (atrial septal aneurysm), larger right-to-left shunt, multiple gestation and concurrent hypercoagulability. Compared to strokes of other etiologies during pregnancy, most PFO stroke patients experienced uneventful delivery (93%) of healthy babies with a good clinical outcome. We conclude with recommended clinical treatment strategies for pregnant patients with PFO suggested by the data from these cases, and the clinical experience of our Cardio-Neurology Clinic. PMID- 26988905 TI - CNS infections: Zika virus infection could trigger Guillain-Barre syndrome. PMID- 26988907 TI - Motor neuron disease: Loss of MHCI exposes motor neurons to astrocyte-mediated toxicity. PMID- 26988906 TI - Epilepsy: Trends in new-onset epilepsy - the importance of comorbidities. PMID- 26988908 TI - How I do it: Anterior pull-through tympanoplasty for anterior eardrum perforations. AB - Conclusions This technique is offered as a convenient and reliable method for cases with anterior TM perforation and inadequate anterior remnant. Objectives Chronic otitis media surgery is one of the most common procedures in otology. Anterior tympanic membrane (TM) perforation with inadequate anterior remnant is associated with higher rates of graft failure. It was the goal of this series to evaluate the anatomical and functional outcomes of a modified underlay myringoplasty technique-the anterior pull-through method. Materials and methods In a retrospective clinical study, 13 patients with anterior TM perforations with inadequate anterior remnants underwent tympanoplasty with anterior pull-through technique. The anterior tip of the temporalis fascia was pulled through and secured in a short incision lateral to the anterior part of the annulus. Data on graft take rate, pre-operative, and post-operative hearing status were analyzed. Results A graft success rate of 84.6% (11 out of 13) was achieved, without lateralization, blunting, atelectasia, or epithelial pearls. The air-bone gap was 21.5 +/- 6.8 dB before intervention and 11.75 +/- 5.7 dB after surgery (p = 0.003). PMID- 26988909 TI - Use of genetically encoded, light-gated ion translocators to control tumorigenesis. AB - It has long been known that the resting potential of tumor cells is depolarized relative to their normal counterparts. More recent work has provided evidence that resting potential is not just a readout of cell state: it regulates cell behavior as well. Thus, the ability to control resting potential in vivo would provide a powerful new tool for the study and treatment of tumors, a tool capable of revealing living-state physiological information impossible to obtain using molecular tools applied to isolated cell components. Here we describe the first use of optogenetics to manipulate ion-flux mediated regulation of membrane potential specifically to prevent and cause regression of oncogene-induced tumors. Injection of mutant-KRAS mRNA induces tumor-like structures with many documented similarities to tumors, in Xenopus tadpoles. We show that expression and activation of either ChR2D156A, a blue-light activated cation channel, or Arch, a green-light activated proton pump, both of which hyperpolarize cells, significantly lowers the incidence of KRAS tumor formation. Excitingly, we also demonstrate that activation of co-expressed light-activated ion translocators after tumor formation significantly increases the frequency with which the tumors regress in a process called normalization. These data demonstrate an optogenetic approach to dissect the biophysics of cancer. Moreover, they provide proof-of principle for a novel class of interventions, directed at regulating cell state by targeting physiological regulators that can over-ride the presence of mutations. PMID- 26988910 TI - MAPK15 upregulation promotes cell proliferation and prevents DNA damage in male germ cell tumors. AB - Germ cell tumors (GCT) are the most common malignancies in males between 15 and 35 years of age. Despite the high cure rate, achieved through chemotherapy and/or surgery, the molecular basis of GCT etiology is still largely obscure. Here, we show a positive correlation between MAPK15 (ERK8; ERK7) expression and specific GCT subtypes, with the highest levels found in the aggressive embryonal carcinomas (EC). Indeed, in corresponding cellular models for EC, MAPK15 enhanced tumorigenicity in vivo and promoted cell proliferation in vitro, supporting a role for this kinase in human GCT. At molecular level, we demonstrated that endogenous MAPK15 is necessary to sustain cell cycle progression of EC cells, by limiting p53 activation and preventing the triggering of p53-dependent mechanisms resulting in cell cycle arrest.To understand MAPK15-dependent mechanisms impinging on p53 activation, we demonstrate that this kinase efficiently protects cells from DNA damage. Moreover, we show that the ability of MAPK15 to control the autophagic process is necessary for basal management of DNA damage and for tumor formation controlled by the kinase.In conclusion, our findings suggest that MAPK15 overexpression may contribute to the malignant transformation of germ cells by controlling a "stress support" autophagic pathway, able to prevent DNA damage and the consequent activation of the p53 tumor suppressor. Moreover, in light of these results, MAPK15-specific inhibitors might represent new tools to enhance the therapeutic index of cytotoxic therapy in GCT treatment, and to increase the sensitivity to DNA-damaging drugs in other chemotherapy-resistant human tumors. PMID- 26988911 TI - ATP7B expression confers multidrug resistance through drug sequestration. AB - We previously reported that ATP7B is involved in cisplatin resistance and ATP7A confers multidrug resistance (MDR) in cancer cells.In this study, we show that ATP7B expressing cells also are resistant to doxorubicin, SN-38, etoposide, and paclitaxel as well as cisplatin.In ATP7B expressing cells, doxorubicin relocated from the nuclei to the late-endosome at 4 hours after doxorubicin exposure. EGFP ATP7B mainly colocalized with doxorubicin.ATP7B has six metal binding sites (MBSs) in the N-terminal cytoplasmic region. To investigate the role of the MBSs of ATP7B in doxorubicin resistance, we used three mutant ATP7B (Cu0, Cu6 and M6C/S) expressing cells. Cu0 has no MBSs, Cu6 has only the sixth MBS and M6C/S carries CXXC to SXXS mutation in the sixth MBS. Cu6 expressing cells were less resistance to the anticancer agents than wild type ATP7B expressing cells, and had doxorubicin sequestration in the late-endosome. Cu0- and M6C/S-expressing cells were sensitive to doxorubicin. In these cells, doxorubicin did not relocalize to the late-endosome. EGFP-M6C/S mainly localized to the trans-Golgi network (TGN) even in the presence of copper. Thus the cysteine residues in the sixth MBS of ATP7B are essential for MDR phenotype.Finally, we found that ammonium chloride and tamoxifen suppressed late endosomal sequestration of doxorubicin, thereby attenuating drug resistance. These results suggest that the sequestration depends on the acidity of the vesicles partly.We here demonstrate that ATP7B confers MDR by facilitating nuclear drug efflux and late endosomal drug sequestration. PMID- 26988912 TI - Loss of miR-449a in ERG-associated prostate cancer promotes the invasive phenotype by inducing SIRT1. AB - Epigenetic regulation by SIRT1, a multifaceted NAD+-dependent protein deacetylase, is one of the most common factors modulating cellular processes in a broad range of diseases, including prostate cancer (CaP). SIRT1 is over-expressed in CaP cells, however the associated mechanism is not well understood. To identify whether specific microRNAs might mediate this linkage, we have screened a miRNA library for differential expression in ERG-associated CaP tissues. Of 20 differentially and significantly expressed miRNAs that distinguish ERG-positive tumors from ERG-negative tumors, we find miR-449a is highly suppressed in ERG positive tumors. We establish that SIRT1 is a direct target of miR-449a and is also induced by ERG in ERG-associated CaP. Our data suggest that attenuation of miR-449a promotes the invasive phenotype of the ERG-positive CaP in part by inducing the expression of SIRT1 in prostate cancer cells. Furthermore, we also find that suppression of SIRT1 results in a significant reduction in ERG expression in ERG-positive CaP cells, indicating a feed-back regulatory loop associated with ERG, miR-449a and SIRT1. We also report that ERG suppresses p53 acetylation perhaps through miR-449a-SIRT1 axis in CaP cells. Our findings provide new insight into the function of miRNAs in regulating ERG-associated CaP. Thus, miR-449a activation or SIRT1 suppression may represent new therapeutic opportunity for ERG-associated CaP. PMID- 26988913 TI - Activation of mesenchymal stem cells by macrophages promotes tumor progression through immune suppressive effects. AB - Cancer development and progression is linked to tumor-associated macrophages (TAMs). Distinct TAMs subsets perform either protective or pathogenic effects in cancer. A protective role in carcinogenesis has been described for M1 macrophages, which activate antitumor mechanisms. By comparison, TAMs isolated from solid and metastatic tumors have a suppressive M2-like phenotype, which could support multiple aspects of tumor progression. Currently, it has not been clearly understood how macrophages in tumor-associated stroma could be hijacked to support tumor growth. Mesenchymal stem cells (MSCs) actively interact with components of the innate immune system and display both anti-inflammatory and pro inflammatory effects. Here, we tested whether MSCs could favor the tumor to escape from immunologic surveillance in the presence of M1 macrophages. We found that MSCs educated by M1 condition medium (cMSCs) possessed a greatly enhanced ability in promoting tumor growth in vivo. Examination of cytokines/chemokines showed that the cMSCs acquired a regulatory profile, which expressed high levels of iNOS and MCP1. Consistent with an elevated MCP1 expression in cMSCs, the tumor promoting effect of the cMSCs depended on MCP1 mediated macrophage recruitment to tumor sites. Furthermore, IL-6 secreted by the cMSCs could polarize infiltrated TAMs into M2-like macrophages. Therefore, when macrophages changed into M1 pro inflammation type in tumor microenvironment, the MSCs would act as poor sensors and switchers to accelerate tumor growth. PMID- 26988914 TI - Automethylation of SUV39H2, an oncogenic histone lysine methyltransferase, regulates its binding affinity to substrate proteins. AB - We previously reported that the histone lysine methyltransferase SUV39H2, which is overexpressed in various types of human cancer, plays a critical role in the DNA repair after double strand breakage, and possesses oncogenic activity. Although its biological significance in tumorigenesis has been elucidated, the regulatory mechanism of SUV39H2 activity through post-translational modification is not well known. In this study, we demonstrate in vitro and in vivo automethylation of SUV39H2 at lysine 392. Automethylation of SUV39H2 led to impairment of its binding affinity to substrate proteins such as histone H3 and LSD1. Furthermore, we observed that hyper-automethylated SUV39H2 reduced methylation activities to substrates through affecting the binding affinity to substrate proteins. Our finding unveils a novel autoregulatory mechanism of SUV39H2 through lysine automethylation. PMID- 26988915 TI - To treat or not to treat: metabolomics reveals biomarkers for treatment indication in chronic lymphocytic leukaemia patients. AB - In chronic lymphocytic leukaemia (CLL), the clinical course of patients is heterogeneous. Some present an aggressive disease onset and require immediate therapy, while others remain without treatment for years. Current disease staging systems developed by Rai and Binet may be useful in forecasting patient survival time, but do not discriminate between stable and progressive forms of the disease in the early stages. Recently ample attention has been directed towards identifying new disease prognostic markers capable of predicting clinical aggressiveness at diagnosis. In the present study serum samples from stable (n = 51) and progressive (n = 42) CLL patients and controls (n = 45) were used with aim to discover metabolic indicators of disease status. First an LC-MS based metabolic fingerprinting method was used to analyse selected samples in order to find a potential markers discriminating aggressive from indolent patients. Ten of these discovered markers were validated on the whole set of samples with an independent analytical technique. Linoleamide (p = 0.002) in addition to various acylcarnitines (p = 0.001-0.000001) showed to be significant markers of CLL in its aggressive form. Acetylcarnitine (p = 0.05) and hexannoylcarnitine (p = 0.005) were also distinguishable markers of indolent subjects. Forming a panel of selected acylcarnitines and fatty acid amides, it was possible to reach a potentially highly specific and sensitive diagnostic approach (AUC = 0.766). PMID- 26988917 TI - eIF3f reduces tumor growth by directly interrupting clusterin with anti-apoptotic property in cancer cells. AB - Clusterin is a secretory heterodimeric glycoprotein and the overexpression of secretory clusterin (sCLU) promotes cancer cell proliferation and reduces chemosensitivity. Therefore, sCLU might be an effective target for anticancer therapy. In the current study, we identified eIF3f as a novel CLU-interacting protein and demonstrated its novel function as a CLU inhibitor. The overexpression of eIF3f retarded cancer cell growth significantly and induced apoptosis. In addition, eIF3f interacted with the alpha-chain (1-227) of sCLU. This interaction blocked modification of psCLU, thereby decreasing the expression and secretion of alpha/beta CLU. Consequently, the overexpression of eIF3f suppressed Akt and ERK signaling and subsequently depleted CLU expression. In addition, eIF3F stabilized p53, which increased the expression of p21 and Bax. Interestingly, the expression of Bax was increased without the activation of p53. eIF3f injected into a xenograft model of human cervical cancer in nude mice markedly inhibited tumor growth. The identification of this novel function of eIF3f as a sCLU inhibitor might open novel avenues for developing improved strategies for CLU-targeted anti-cancer therapies. PMID- 26988919 TI - Demonstration of single crystal growth via solid-solid transformation of a glass. AB - Many advanced technologies have relied on the availability of single crystals of appropriate material such as silicon for microelectronics or superalloys for turbine blades. Similarly, many promising materials could unleash their full potential if they were available in a single crystal form. However, the current methods are unsuitable for growing single crystals of these oftentimes incongruently melting, unstable or metastable materials. Here we demonstrate a strategy to overcome this hurdle by avoiding the gaseous or liquid phase, and directly converting glass into a single crystal. Specifically, Sb2S3 single crystals are grown in Sb-S-I glasses as an example of this approach. In this first unambiguous demonstration of an all-solid-state glass -> crystal transformation, extraneous nucleation is avoided relative to crystal growth via spatially localized laser heating and inclusion of a suitable glass former in the composition. The ability to fabricate patterned single-crystal architecture on a glass surface is demonstrated, providing a new class of micro-structured substrate for low cost epitaxial growth, active planar devices, etc. PMID- 26988920 TI - Recovery of upper extremity function following endoscopically assisted contralateral C7 transfer for obstetrical brachial plexus injury. AB - Transfer of the contralateral C7 nerve for reconstruction of the brachial plexus in infants with obstetrical brachial plexus injury has rarely been reported. We developed a new endoscopy-assisted technique via the prevertebral (retroesophageal) route for the transfer of the contralateral C7 nerve in reconstruction of the brachial plexus. The reconstruction was performed in 20 infants (14 boys and six girls). Motor recovery was assessed using the Gilbert and Raimondi scales. The Narakas Sensory Grading System was used to evaluate hand sensation. The mean follow-up period was 45 months (SD 18.2). Of the 20 children, nine had contralateral C7 transfer to lower nerve roots, two had transfer to upper nerve roots and nine had transfer to both upper and lower roots. The postoperative shoulder and elbow functions were good or satisfactory according to the Gilbert classification in all children whose preoperative scores were poor. All patients with lower roots reconstruction (9) had satisfactory hand function. A total of 15 children had a Narakas score of S3. Our technique enables safe contralateral C7 transfer to the avulsed roots in severe obstetrical brachial plexus injury infants with a satisfactory functional recovery. LEVEL OF EVIDENCE: Level IV. PMID- 26988918 TI - MicroRNA-related polymorphisms in apoptosis pathway genes are predictive of clinical outcome in patients with limited disease small cell lung cancer. AB - We examined the impact of single nucleotide polymorphisms (SNPs) at miRNA binding sites in the 3'-UTRs of genes in the apoptosis pathway on the prognosis of patients with limited disease-small cell lung cancer (LD-SCLC). Twelve tagSNPs in seven genes were genotyped using blood samples from 146 LD-SCLC patients treated with chemoradiotherapy. Cox proportional hazard regression models and recursive partitioning analysis were performed to identify SNPs significantly associated with overall survival. Three SNPs, CASP8: rs1045494 (C > T), PIK3R1: rs3756668 (A > G) and CASP7: rs4353229 (T > C), were associated with longer overall survival in LD-SCLC patients after chemoradiotherapy. The adjusted hazard ratios (95% confidence intervals) were 0.480 (0.258-0.894), 0.405 (0.173-0.947) and 0.446 (0.247-0.802), respectively, and remained significant after multiple comparison correction. Moreover, subset analysis showed these SNPs were still predictive of overall survival in stage III patients. Recursive partitioning analysis enabled patients to be classified into three risk subgroups based on unfavorable genotype combinations of the rs1045494 and rs4353229 SNPs. These findings suggest miRNA related polymorphisms in the apoptosis pathway may be useful biomarkers for selection of LD-SCLC patients likely to benefit from chemoradiotherapy. PMID- 26988921 TI - [Termination of pregnancy: A survey about its evolution in French perinatal centres]. AB - CONTEXT: Termination of pregnancy (TOP) is regulated by French law for decades. Indications of TOP may vary depending on progress performed in perinatal medicine and in diagnosis of fetal anomalies, and also according to the way malformations are perceived in society. OBJECTIVES: To determine whether the frequency and indications of TOP had varied in the Lorraine Centre for Perinatal Diagnosis from 2000 to 2012. SUBJECTS AND METHODS: Retrospective study performed on a randomized sample of medical files presented in the Lorraine Centre for Perinatal Diagnosis in years 2000, 2006 and 2012. We analyzed the number of files presented by parents-to-be, the indication motivating TOP, general characteristics of both pregnancies and mothers. We also performed a prospective enquiry among the French Centres for Perinatal Diagnosis in order to determine national rates. RESULTS: General characteristics of mothers and pregnancies were similar from 2002 to 2012. No modification in indications of TOP was measured. In Lorraine, most TOPs were performed for chromosomal abnormality. On the national level, centres for perinatal diagnosis received more requests for TOPs in the study period. There were also more TOPs for non-lethal fetal anomalies, and parents refusing TOPs though the centres had agreed with its indication. CONCLUSION: The national trends were not measured in Lorraine region. PMID- 26988922 TI - Guideline for dialysate quality of Spanish Society of Nephrology (second edition, 2015). AB - A Best Practice Guideline about Dialysis fluid purity was developed under the leadership of the Spanish Society of Nephrology in 2004. The second edition revised Guideline considered new evidences and International Standard. The Guideline has established recommendations for standards for preparing dialysate: water, concentrates and hemodialysis proportioning systems. This Guideline is based on the ISO13959, European Pharmacopoeia, the Real Farmacopea Espanola, the AAMI Standards and Recommended Practices, European Best Practice Guidelines for Haemodialysis, literature reviews, according to their level of evidence, and the opinion of the expert Spanish group. Two levels of quality of water were defined: purified water and high purified water (ultra pure) and for dialysate: ultra pure dialysate. Regular use of ultra pure dialysate is recommended for all type of hemodialysis to prevent and delay the occurrence of complications: inflammation, malnutrition, anaemia and amiloidosis. Water, concentrates and dialysate quality requirements are defined as maximum allowable contaminant levels: chemicals (4.1.2), conductivity, microbial and endotoxins (4.1.1): Monitoring frequency, maintenance and corrective actions were specified. Methods of sampling and analysis were described in appendix (anexos). For microbiological monitoring, R2A medium is recommended, incubated during 7-14 days at a temperature of 17-23 degrees C. The dialysate quality assurance process involves all dialysis staff members and requires strict protocols. The physician in charge of hemodialysis has the ultimate responsibility for dialysate quality. All suggestions and questions about this Guideline are wellcome to www.senefro.org. PMID- 26988923 TI - Zoonotic trypanosomes in South East Asia: Attempts to control Trypanosoma lewisi using veterinary drugs. AB - A growing number of atypical human infections due to the livestock parasite Trypanosoma evansi, or to the rat parasite Trypanosoma lewisi, are reported in humans in Asia. In some cases, clinical evolutions request treatments, however, so far, there were very few attempts to control T. lewisi using trypanocidal drugs. In a study published elsewhere, the efficacy of human trypanocides is evaluated in laboratory rats, and it concludes that none of them is able to cure rats experimentally infected with T. lewisi. Control of T. lewisi in rat would be a step for identification of drugs against this parasite. In the present study, 4 veterinary drugs: diminazene aceturate, isometamidium chloride, melarsomine hydrochloride and quinapyramine sulfate and chloride, were evaluated at low and high doses, in intra-muscular injections to normal rats experimentally infected with a stock of T. lewisi from Thailand. None of these treatments being efficient, a trial was also made using melarsomine hydrochloride in T. evansi infected rats and in mixed T. lewisi and T. evansi infected rats, in order to demonstrate the efficacy of the drugs under the present protocol. T. evansi was cleared from the rat's blood the day after the treatment, while, T. lewisi remained unaffected until the end of the experiment. These observations clearly demonstrated the efficacy of melarsomine hydrochloride against T. evansi and its inefficacy against T. lewisi. In conclusion none of the veterinary drugs was efficient against this stock of T. lewisi. Other protocols using higher doses or other drugs and T. lewisi stocks should be investigated in further studies. The control of T. lewisi infection in Wistar rats, using veterinary trypanocidal drugs, remains so far unsuccessful. PMID- 26988916 TI - Emerging preclinical pharmacological targets for Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurological condition caused by the degeneration of dopaminergic neurons in the basal ganglia. It is the most prevalent form of Parkinsonism, categorized by cardinal features such as bradykinesia, rigidity, tremors, and postural instability. Due to the multicentric pathology of PD involving inflammation, oxidative stress, excitotoxicity, apoptosis, and protein aggregation, it has become difficult to pin-point a single therapeutic target and evaluate its potential application. Currently available drugs for treating PD provide only symptomatic relief and do not decrease or avert disease progression resulting in poor patient satisfaction and compliance. Significant amount of understanding concerning the pathophysiology of PD has offered a range of potential targets for PD. Several emerging targets including AAV-hAADC gene therapy, phosphodiesterase-4, potassium channels, myeloperoxidase, acetylcholinesterase, MAO-B, dopamine, A2A, mGlu5, and 5-HT-1A/1B receptors are in different stages of clinical development. Additionally, alternative interventions such as deep brain stimulation, thalamotomy, transcranial magnetic stimulation, and gamma knife surgery, are also being developed for patients with advanced PD. As much as these therapeutic targets hold potential to delay the onset and reverse the disease, more targets and alternative interventions need to be examined in different stages of PD. In this review, we discuss various emerging preclinical pharmacological targets that may serve as a new promising neuroprotective strategy that could actually help alleviate PD and its symptoms. PMID- 26988926 TI - Phase I/II dose-finding design for molecularly targeted agent: Plateau determination using adaptive randomization. AB - Conventionally, phase I dose-finding trials aim to determine the maximum tolerated dose of a new drug under the assumption that both toxicity and efficacy monotonically increase with the dose. This paradigm, however, is not suitable for some molecularly targeted agents, such as monoclonal antibodies, for which efficacy often increases initially with the dose and then plateaus. For molecularly targeted agents, the goal is to find the optimal dose, defined as the lowest safe dose that achieves the highest efficacy. We develop a Bayesian phase I/II dose-finding design to find the optimal dose. We employ a logistic model with a plateau parameter to capture the increasing-then-plateau feature of the dose-efficacy relationship. We take the weighted likelihood approach to accommodate for the case where efficacy is possibly late-onset. Based on observed data, we continuously update the posterior estimates of toxicity and efficacy probabilities and adaptively assign patients to the optimal dose. The simulation studies show that the proposed design has good operating characteristics. This method is going to be applied in more than two phase I clinical trials as no other method is available for this specific setting. We also provide an R package dfmta that can be downloaded from CRAN website. PMID- 26988925 TI - Impact of intervention targeting risk factors on chronic disease burden. AB - The aging of the population is accompanied by a sharp rise of chronic disease prevalences, such as dementia. These diseases generally cannot be prevented or cured and persist over time, with a progressive deterioration of health, requiring specific care. To reduce the burden of these diseases, it is appropriate to propose interventions targeting disease risk factors, but the association between most of these risk factors and mortality makes it difficult to anticipate the potential impact of such interventions. A method was previously proposed to estimate changes in disease prevalence following an intervention targeting subjects at a given age where the incidence of the disease is supposed to be null. Here, we propose a general framework to make projections for life expectancies with and without the disease, the age at onset, and the lifelong probability of the disease, and to evaluate the consequences of preventive interventions targeting risk factors on these various measures of disease burden. The methodology takes into account the mortality trend over calendar time and age in both healthy and diseased subjects, and the change in mortality due to the intervention. The method is applied to make projections for dementia in 2030 according to several scenarios of public health interventions. PMID- 26988924 TI - Statin intake is associated with MMP-1 level in gingival crevicular fluid of patients with periodontitis. AB - BACKGROUND: This study was conducted to assess whether statin intake is associated with clinical parameters of periodontitis and matrix metalloproteinase (MMP) levels in gingival crevicular fluid (GCF) of non-diabetic and diabetic patients. METHODS: We first determined the effect of simvastatin on MMP expression in mononuclear cells. We then recruited 117 non-diabetic and diabetic patients, who all had periodontitis and took or did not take statin, and measured periodontal probing depth (PPD) and clinical attachment level (CAL), and collected gingival crevicular fluid (GCF) to quantify MMPs. RESULTS: The in vitro studies showed that simvastatin potently inhibited the expression of MMP-1, MMP 8, and MMP-9 upregulated by lipopolysaccharide (LPS) and high glucose in mononuclear cells. The patient study showed that, after adjusting for age and smoking status, PPD in diabetic patients on statin was significantly less than that in diabetic patients not on statin. MMP-1 level in GCF of non-diabetic and diabetic patients on statin was lower than that of non-diabetic and diabetic patients not on statin, respectively. No difference was found for MMP-8 and -9 levels in GCF. CONCLUSION: Statin intake is associated with reduced PPD in diabetic patients and MMP-1 level in GCF in either non-diabetic or diabetic patients. PMID- 26988927 TI - Sample size determinations for stepped-wedge clinical trials from a three-level data hierarchy perspective. AB - Stepped-wedge (SW) designs have been steadily implemented in a variety of trials. A SW design typically assumes a three-level hierarchical data structure where participants are nested within times or periods which are in turn nested within clusters. Therefore, statistical models for analysis of SW trial data need to consider two correlations, the first and second level correlations. Existing power functions and sample size determination formulas had been derived based on statistical models for two-level data structures. Consequently, the second-level correlation has not been incorporated in conventional power analyses. In this paper, we derived a closed-form explicit power function based on a statistical model for three-level continuous outcome data. The power function is based on a pooled overall estimate of stratified cluster-specific estimates of an intervention effect. The sampling distribution of the pooled estimate is derived by applying a fixed-effect meta-analytic approach. Simulation studies verified that the derived power function is unbiased and can be applicable to varying number of participants per period per cluster. In addition, when data structures are assumed to have two levels, we compare three types of power functions by conducting additional simulation studies under a two-level statistical model. In this case, the power function based on a sampling distribution of a marginal, as opposed to pooled, estimate of the intervention effect performed the best. Extensions of power functions to binary outcomes are also suggested. PMID- 26988928 TI - Identification of predicted individual treatment effects in randomized clinical trials. AB - In most medical research, treatment effectiveness is assessed using the average treatment effect or some version of subgroup analysis. The practice of individualized or precision medicine, however, requires new approaches that predict how an individual will respond to treatment, rather than relying on aggregate measures of effect. In this study, we present a conceptual framework for estimating individual treatment effects, referred to as predicted individual treatment effects. We first apply the predicted individual treatment effect approach to a randomized controlled trial designed to improve behavioral and physical symptoms. Despite trivial average effects of the intervention, we show substantial heterogeneity in predicted individual treatment response using the predicted individual treatment effect approach. The predicted individual treatment effects can be used to predict individuals for whom the intervention may be most effective (or harmful). Next, we conduct a Monte Carlo simulation study to evaluate the accuracy of predicted individual treatment effects. We compare the performance of two methods used to obtain predictions: multiple imputation and non-parametric random decision trees. Results showed that, on average, both predictive methods produced accurate estimates at the individual level; however, the random decision trees tended to underestimate the predicted individual treatment effect for people at the extreme and showed more variability in predictions across repetitions compared to the imputation approach. Limitations and future directions are discussed. PMID- 26988930 TI - Correcting for dependent censoring in routine outcome monitoring data by applying the inverse probability censoring weighted estimator. AB - Censored data make survival analysis more complicated because exact event times are not observed. Statistical methodology developed to account for censored observations assumes that patients' withdrawal from a study is independent of the event of interest. However, in practice, some covariates might be associated to both lifetime and censoring mechanism, inducing dependent censoring. In this case, standard survival techniques, like Kaplan-Meier estimator, give biased results. The inverse probability censoring weighted estimator was developed to correct for bias due to dependent censoring. In this article, we explore the use of inverse probability censoring weighting methodology and describe why it is effective in removing the bias. Since implementing this method is highly time consuming and requires programming and mathematical skills, we propose a user friendly algorithm in R. Applications to a toy example and to a medical data set illustrate how the algorithm works. A simulation study was carried out to investigate the performance of the inverse probability censoring weighted estimators in situations where dependent censoring is present in the data. In the simulation process, different sample sizes, strengths of the censoring model, and percentages of censored individuals were chosen. Results show that in each scenario inverse probability censoring weighting reduces the bias induced in the traditional Kaplan-Meier approach where dependent censoring is ignored. PMID- 26988929 TI - Bayesian bivariate meta-analysis of correlated effects: Impact of the prior distributions on the between-study correlation, borrowing of strength, and joint inferences. AB - Multivariate random-effects meta-analysis allows the joint synthesis of correlated results from multiple studies, for example, for multiple outcomes or multiple treatment groups. In a Bayesian univariate meta-analysis of one endpoint, the importance of specifying a sensible prior distribution for the between-study variance is well understood. However, in multivariate meta analysis, there is little guidance about the choice of prior distributions for the variances or, crucially, the between-study correlation, rhoB; for the latter, researchers often use a Uniform(-1,1) distribution assuming it is vague. In this paper, an extensive simulation study and a real illustrative example is used to examine the impact of various (realistically) vague prior distributions for rhoB and the between-study variances within a Bayesian bivariate random-effects meta analysis of two correlated treatment effects. A range of diverse scenarios are considered, including complete and missing data, to examine the impact of the prior distributions on posterior results (for treatment effect and between-study correlation), amount of borrowing of strength, and joint predictive distributions of treatment effectiveness in new studies. Two key recommendations are identified to improve the robustness of multivariate meta-analysis results. First, the routine use of a Uniform(-1,1) prior distribution for rhoB should be avoided, if possible, as it is not necessarily vague. Instead, researchers should identify a sensible prior distribution, for example, by restricting values to be positive or negative as indicated by prior knowledge. Second, it remains critical to use sensible (e.g. empirically based) prior distributions for the between-study variances, as an inappropriate choice can adversely impact the posterior distribution for rhoB, which may then adversely affect inferences such as joint predictive probabilities. These recommendations are especially important with a small number of studies and missing data. PMID- 26988931 TI - A robust semi-parametric warping estimator of the survivor function with an application to two-group comparisons. AB - In this note, we develop a new and novel semi-parametric estimator of the survival curve that is comparable to the product-limit estimator under very relaxed assumptions. The estimator is based on a beta parametrization that warps the empirical distribution of the observed censored and uncensored data. The parameters are obtained using a pseudo-maximum likelihood approach adjusting the survival curve accounting for the censored observations. In the univariate setting, the new estimator tends to better extend the range of the survival estimation given a high degree of censoring. However, the key feature of this paper is that we develop a new two-group semi-parametric exact permutation test for comparing survival curves that is generally superior to the classic log-rank and Wilcoxon tests and provides the best global power across a variety of alternatives. The new test is readily extended to the k group setting. PMID- 26988932 TI - Confidence interval of difference of proportions in logistic regression in presence of covariates. AB - Comparison of treatment differences in incidence rates is an important objective of many clinical trials. However, often the proportion is affected by covariates, and the adjustment of the predicted proportion is made using logistic regression. It is desirable to estimate the treatment differences in proportions adjusting for the covariates, similarly to the comparison of adjusted means in analysis of variance. Because of the correlation between the point estimates in the different treatment groups, the standard methods for constructing confidence intervals are inadequate. The problem is more difficult in the binary case, as the comparison is not uniquely defined, and the sampling distribution more difficult to analyze. Four procedures for analyzing the data are presented, which expand upon existing methods and generalize the link function. It is shown that, among the four methods studied, the resampling method based on the exact distribution function yields a coverage rate closest to the nominal. PMID- 26988933 TI - Bayesian joint modeling for assessing the progression of chronic kidney disease in children. AB - Joint models are rich and flexible models for analyzing longitudinal data with nonignorable missing data mechanisms. This article proposes a Bayesian random effects joint model to assess the evolution of a longitudinal process in terms of a linear mixed-effects model that accounts for heterogeneity between the subjects, serial correlation, and measurement error. Dropout is modeled in terms of a survival model with competing risks and left truncation. The model is applied to data coming from ReVaPIR, a project involving children with chronic kidney disease whose evolution is mainly assessed through longitudinal measurements of glomerular filtration rate. PMID- 26988934 TI - Evaluating hospital infection control measures for antimicrobial-resistant pathogens using stochastic transmission models: Application to vancomycin resistant enterococci in intensive care units. AB - Nosocomial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) are the cause of significant morbidity and mortality among hospital patients. It is important to be able to assess the efficacy of control measures using data on patient outcomes. In this paper, we describe methods for analysing such data using patient-level stochastic models which seek to describe the underlying unobserved process of transmission. The methods are applied to detailed longitudinal patient-level data on vancomycin resistant Enterococci from a study in a US hospital with eight intensive care units (ICUs). The data comprise admission and discharge dates, dates and results of screening tests, and dates during which precautionary measures were in place for each patient during the study period. Results include estimates of the efficacy of the control measures, the proportion of unobserved patients colonized with vancomycin-resistant Enterococci, and the proportion of patients colonized on admission. PMID- 26988935 TI - Phase correlation applied to the 3D registration of CT and CBCT image volumes. AB - PURPOSE: In this study, a 3D phase correlation algorithm was investigated to test feasibility for use in determining the anatomical changes that occur throughout a patient's radiotherapy treatment. The algorithm determines the transformations between two image volumes through analysis in the Fourier domain and has not previously been used in radiotherapy for 3D registration of CT and CBCT volumes. METHODS: Various known transformations were applied to a patient's prostate CT image volume to create 12 different test cases. The mean absolute error and standard deviation were determined by evaluating the difference between the known contours and those calculated from the registration process on a point-by-point basis. Similar evaluations were performed on images with increasing levels of noise added. The improvement in structure overlap offered by the algorithm in registering clinical CBCT to CT images was evaluated using the Dice Similarity Coefficient (DSC). RESULTS: A mean error of 2.35 (sigma = 1.54) mm was calculated for the 12 deformations applied. When increasing levels of noise were introduced to the images, the mean errors were observed to rise up to a maximum increase of 1.77 mm. For CBCT to CT registration, maximum improvements in the DSC of 0.09 and 0.46 were observed for the bladder and rectum, respectively. CONCLUSIONS: The Fourier-based 3D phase correlation registration algorithm investigated displayed promising results in CT to CT and CT to CBCT registration, offers potential in terms of efficiency and robustness to noise, and is suitable for use in radiotherapy for monitoring patient anatomy throughout treatment. PMID- 26988936 TI - The influence of physical wedges on penumbra and in-field dose uniformity in ocular proton beams. AB - A physical wedge may be partially introduced into a proton beam when treating ocular tumours in order to improve dose conformity to the distal border of the tumour and spare the optic nerve. Two unwanted effects of this are observed: a predictable broadening of the beam penumbra on the wedged side of the field and, less predictably, an increase in dose within the field along a relatively narrow volume beneath the edge (toe) of the wedge, as a result of small-angle proton scatter. Monte Carlo simulations using MCNPX and direct measurements with radiochromic (GAFCHROMIC((r)) EBT2) film were performed to quantify these effects for aluminium wedges in a 60 MeV proton beam as a function of wedge angle and position of the wedge relative to the patient. For extreme wedge angles (60 degrees in eye tissue) and large wedge-to-patient distances (70 mm in this context), the 90-10% beam penumbra increased from 1.9 mm to 9.1 mm. In-field dose increases from small-angle proton scatter were found to contribute up to 21% additional dose, persisting along almost the full depth of the spread-out-Bragg peak. Profile broadening and in-field dose enhancement are both minimised by placing the wedge as close as possible to the patient. Use of lower atomic number wedge materials such as PMMA reduce the magnitude of both effects as a result of a reduced mean scattering angle per unit energy loss; however, their larger physical size and greater variation in density are undesirable. PMID- 26988938 TI - Prognostic significance of standardised uptake value (SUVmax ) measured on 18F fluorodeoxyglucose positron emission tomography/computed tomography in patients with small cell lung cancer. AB - Certain prognostic factors for small cell lung cancer (SCLC) have been validated, but the prognostic role of 18F-FDG PET/CT still remains unclear. The aim of this study was to evaluate the prognostic significance of 18F-FDG PET/CT in patients with SCLC. We reviewed 142 patients with pathologically proven SCLC who underwent pre-treatment 18F-FDG PET/CT. Standardised uptake value (SUVmax ) and other potential prognostic variables were chosen for analysis. The mean age of the study population was 58.2 +/- 10.1 years (range, 25-84), and 124 (87.3%) patients were men. The median SUVmax value was 11.6 (4.0-29.3). Among the variables included in the univariate analysis, performance status (P = 0.001), disease stage (P < 0.001), administration of thoracic radiotherapy (TRT; P < 0.001), albumin level (P = 0.030) and LDH level (P < 0.001) showed prognostic significance. Further, multivariate analysis showed that performance status (P = 0.007), albumin level (P = 0.002), LDH level (P < 0.001) and administration of TRT (P = 0.001) were independent prognostic factors for survival. In conclusion, performance status, TRT, LDH level and albumin level were identified as important prognostic factors, while 18F-FDG PET/CT uptake of the primary lesions did not have any prognostic significance for survival in patients with SCLC. PMID- 26988940 TI - Grief symptoms and difficult patient loss for oncologists in response to patient death. AB - OBJECTIVE: The study aimed to explore oncologist's grief symptoms over patient death and to identify why and which losses are particularly challenging when patients die. METHODS: The grounded theory method was used to collect and analyze the data. Twenty-two oncologists were interviewed between March 2013 and June 2014 from three adult oncology centers in the north, center, and south of Israel. Oncologists were at different stages of their careers and varied in their sub specialties, gender, and personal and professional backgrounds. RESULTS: Grief begun when the patient died, in anticipation of the patient's death, many days after the death, or when the patient received a poor prognosis. The phenomenological experience of grief for oncologists included behavioral, cognitive, physical, and emotional symptoms in response to patient death. Behavioral symptoms included crying and difficulties sleeping. Cognitive symptoms included self-doubt and rumination about the patient and the care the patient had received before death. Physical symptoms included chest pain, fatigue, and general physical discomfort. Emotional symptoms included sadness, anxiety, helplessness, guilt, relief, irritability, and loss. Difficult patient loss was caused by patient-related factors, family-related factors, and disease-related factors. CONCLUSIONS: Patient deaths result in behavioral, cognitive, physical, and emotional symptoms of grief in oncologists. These symptoms become particularly intense in the context of patient, family, and disease-related factors. Educational and supportive interventions for managing grief related to patient death are needed in order to support oncologists in their emotionally and mentally taxing work. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26988939 TI - Molecular characterization of a novel androgen receptor transgene responsive to MicroRNA mediated post-transcriptional control exerted via 3'-untranslated region. AB - BACKGROUND: Androgen Receptor (AR) gene is associated with Prostate cancer (PCa) and hence targeting androgen-and AR-signaling axis remains the most promising primary therapeutic option to treat the disease. The AR mRNA has a 6.8 kb long 3' untranslated region (UTR) which harbors several experimentally validated and numerous predicted miRNA binding sites. AR 3'-UTR is likely to positively or negatively regulate AR expression by interacting with miRNAs and possibly other trans-acting auxiliary factors including 3'-UTR RNA binding proteins. In this context, systematic understanding of the regulatory role of AR 3'-UTR in intrinsic post-transcriptional control of AR gene expression is of significance to understand AR related diseases including PCa. METHODS: In this study, we have constructed a heterologous reporter system in which Firefly luciferase and AR expression is experimentally influenced by the presence of AR 3'-UTR and its interactions with ectopically expressing miRNA. RESULTS: The expression of AR 3' UTR containing reporters, including the Firefly luciferase and the AR open reading frame (ORF) were repressed by the overexpression of miR-488* mimics. In addition, the AR expressed from 3'-UTR containing expression vectors was fully functional in its transactivation function as determined by a prostate specific antigen (PSA) reporter assay. Further, by using confocal microscopy we also demonstrate that AR can translocate to the nucleus upon DHT activation confirming the functional ability of AR. CONCLUSIONS: AR transgenes with AR 3'-UTR fragments closely resemble the endogenous AR expression than any other previously characterized AR expression constructs. The 3'-UTR containing AR expression system is amiable to post-transcriptional manipulations including miRNA mediated repression of AR expression. This AR reporter system has the potential to be used in determining specificity of AR targeting miRNAs and their role in AR functional regulatory networks. Prostate 76:834-844, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26988937 TI - Shaping of cutaneous function by encounters with commensals. AB - The skin is the largest organ in the human body and provides the first line of defence against environmental attack and pathogen invasion. It harbor multiple commensal microbial communities at different body sites, which play important roles in sensing the environment, protecting against colonization and infection of pathogens, and guiding the host immune system in response to foreign invasions. The skin microbiome is largely variable between individuals and body sites, with several core commensal members commonly shared among individuals at the healthy state. These microbial commensals are essential to skin health and can potentially lead to disease when their abundances and activities change due to alterations in the environment or in the host. While recent advances in sequencing technologies have enabled a large number of studies to characterize the taxonomic composition of the skin microbiome at various body sites and under different physiological conditions, we have limited understanding of the microbiome composition and dynamics at the strain level, which is highly important to many microbe-related diseases. Functional studies of the skin microbial communities and the interactions among community members and with the host are currently scant, warranting future investigations. In this review, we summarize the recent findings on the skin microbiome, highlighting the roles of the major commensals, including bacteria, fungi and bacteriophages, in modulating skin functions in health and disease. Functional studies of the skin microbiota at the metatranscriptomic and proteomic levels are also included to illustrate the interactions between the microbiota and the host skin. PMID- 26988941 TI - CHARACTERIZATION OF TRYPSIN-LIKE AND CHYMOTRYPSIN-LIKE SERINE PROTEASES FROM MIDGUT OF Mythimna separata Walker. AB - Two cDNA sequences encoding a trypsin-like and a chymotrypsin-like serine protease (MsT and MsCT, GenBank accession Nos. KP730443 and KP730444, respectively) were cloned from midgut of oriental armyworm, Mythimna separata Walker. Multiple alignments revealed that the deduced amino acid sequences of MsT and MsCT contained a serine protease catalytic motif GDSGGPL and catalytic triads (His, Asp, and Ser). Analyses of tissue and developmental expression of MsT and MsCT showed that they were mainly expressed in midguts and could be detected in first to sixth instar larvae, prepupal and pupal stages. Expressions of both MsT and MsCT were downregulated after 24 h of starvation and upregulated by subsequent insect refeeding. MsT expression in response to 20-hydroxyecdysone (20E) was dose dependent and upregulated after 24 h. However, MsCT expression in response to 20E was downregulated compared with controls. MsCT, but not MsT, transcripts were upregulated after 24 h of Cry1Ac protoxin exposure. These results suggested that MsT was most likely involved in food protein digestion and molting in M. separata whereas MsCT was most likely involved in food protein digestion and Bacillus thuringiensis (Bt) protoxin activation. RNA interference indicated that MsT and MsCT expression levels decreased 76.7 and 86.2% after treated with MsT and MsCT dsRNA, respectively. This study showed that M. separata expressed midgut proteases in line with known lepidopteran counterparts and contributed valuable sequence resource information regarding insect proteases. PMID- 26988943 TI - Age dependency for coagulation parameters in paediatric populations. Results of a multicentre study aimed at defining the age-specific reference ranges. AB - Understanding of developmental haemostasis is critical to ensure optimal prevention, diagnosis, and treatment of haemorrhagic and thrombotic diseases in children. As coagulation test results are known to be dependent on the reagents/analysers used, it is recommended for each laboratory to define the age dependent reference ranges by using its own technical condition. That study was carried out in seven centers to establish age-specific reference ranges using the same reagents and analyser. Plasma samples were obtained from 1437 paediatric patients from the following age groups: 15 days-4 weeks (n=36), 1-5 months (n=320), 6-12 months (n=176), 1-5 years (n=507), 6-10 years (n=132) and 11-17 years (n=262). Indication of coagulation testing was pre-operative screening for non-acute diseases in most cases. PT values were similar in the different age groups to those in adults, whereas longer aPTTs were demonstrated in the younger children. Plasma levels of all clotting factors, except for FV, were significantly decreased (p<0.0001) in the youngest children, adult values being usually reached before the end of the first year. The same applied to antithrombin, protein C/S, and plasminogen. In contrast, FVIII and VWF levels were elevated in the youngest children and returned to adult values within six months. The same applied to D-dimer levels, which were found elevated, particularly until six months of life, until puberty. These data suggest that most coagulation test results are highly dependent on age, mainly during the first year of life, and that age-specific reference ranges must be used to ensure proper evaluation of coagulation in children. PMID- 26988942 TI - Regulation at a distance of biomolecular interactions using a DNA origami nanoactuator. AB - The creation of nanometre-sized structures that exhibit controllable motions and functions is a critical step towards building nanomachines. Recent developments in the field of DNA nanotechnology have begun to address these goals, demonstrating complex static or dynamic nanostructures made of DNA. Here we have designed and constructed a rhombus-shaped DNA origami 'nanoactuator' that uses mechanical linkages to copy distance changes induced on one half ('the driver') to be propagated to the other half ('the mirror'). By combining this nanoactuator with split enhanced green fluorescent protein (eGFP), we have constructed a DNA protein hybrid nanostructure that demonstrates tunable fluorescent behaviours via long-range allosteric regulation. In addition, the nanoactuator can be used as a sensor that responds to specific stimuli, including changes in buffer composition and the presence of restriction enzymes or specific nucleic acids. PMID- 26988944 TI - Expression of DNA repair genes in porcine oocytes before and after fertilization by ICSI using freeze-dried sperm. AB - Boar sperm freeze-dried with trehalose showed a protective effect against sperm DNA fragmentation. However, normal fertilization and embryonic development were not improved. Damaged sperm may activate maternal DNA repair genes when injected into oocytes. Therefore, we investigated the expression profile of some DNA repair genes in porcine oocytes after intra-cytoplasmic sperm injection. First, the expression levels of MGMT, UDG, XPC, MSH2, XRCC6 and RAD51 genes that are concerned with different types of DNA repair were examined in in vitro mature (IVM) oocytes injected with ejaculated sperm, or freeze-dried sperm with or without trehalose. Quantitative reverse transcription polymerase chain reaction revealed that expression of six DNA repair genes in the oocytes at 4 h after injection did not differ among the four groups. Next, we investigated the gene expression levels of these genes at different stages of maturation. The relative expression levels of UDG and XPC were significantly up-regulated in mature oocytes compared with earlier stages. Furthermore, there was an increased tendency in relative expression of MSH2 and RAD51. These results suggested two possible mechanisms that messenger RNA of DNA repair genes are either accumulated during IVM to be ready for fertilization or increased expression levels of DNA repair genes in oocytes caused by suboptimal IVM conditions. PMID- 26988945 TI - Femoral and Carotid Subclinical Atherosclerosis Association With Risk Factors and Coronary Calcium: The AWHS Study. AB - BACKGROUND: Early subclinical atherosclerosis has been mainly researched in carotid arteries. The potential value of femoral arteries for improving the predictive capacity of traditional risk factors is an understudied area. OBJECTIVES: This study sought to evaluate the association of subclinical carotid and femoral plaques with risk factors and coronary artery calcium score (CACS) in middle-aged men. METHODS: Participants (n = 1,423) of the AWHS (Aragon Workers' Health Study), a study designed to assess cardiovascular risk and subclinical atherosclerosis in a cohort of middle-aged men (40 to 59 years of age), underwent carotid and femoral ultrasound plus noncontrast coronary computed tomography. Subclinical atherosclerosis was defined as the presence of any plaque in carotid or femoral arteries and/or CACS >=1. Logistic regression models were used to estimate the prevalence of atherosclerosis adjusted for risk factors and age, to evaluate the association of atherosclerosis with risk factors, and to calculate areas under the receiver-operating characteristic curves for the presence of positive CACS. RESULTS: Subclinical atherosclerosis was found in 72% of participants. Plaques were most common in femoral arteries (54%), followed by coronary calcification (38%) and carotid plaques (34%). Association of atherosclerosis with risk factors was stronger in femoral arteries than carotid or coronary arteries. The area under the receiver-operating characteristic curve for prediction of positive CACS increased from 0.665 when considering only risk factors (dyslipidemia, current smoking, hypertension, diabetes, and age) to 0.719 when adding femoral and carotid plaques (p < 0.001). In this model, the femoral odds ratio (2.58) exceeded the carotid odds ratio (1.80) for prediction of positive CACS. CONCLUSIONS: Subclinical atherosclerosis was highly prevalent in this middle-aged male cohort. Association with risk factors and positive CACS was stronger in femoral than carotid arteries. Screening for femoral plaques may be an appealing strategy for improving cardiovascular risk scales and predicting coronary disease. PMID- 26988946 TI - Screening for Atherosclerotic Cardiovascular Risk Using Ultrasound. PMID- 26988948 TI - Improving the Monitoring and Care of Patients With Familial Hypercholesterolemia. PMID- 26988947 TI - Attainment of LDL-Cholesterol Treatment Goals in Patients With Familial Hypercholesterolemia: 5-Year SAFEHEART Registry Follow-Up. AB - BACKGROUND: Familial hypercholesterolemia (FH) is the most common genetic disorder associated with premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data on attainment of treatment targets; large registries that reflect real-life clinical practice can uniquely provide this information. OBJECTIVES: We sought to evaluate the achievement of low-density lipoprotein cholesterol (LDL-C) treatment goals in FH patients enrolled in a large national registry. METHODS: The SAFEHEART study (Spanish Familial Hypercholesterolemia Cohort Study) is a large, ongoing registry of molecularly defined patients with heterozygous FH treated in Spain. The attainment of guideline-recommended plasma LDL-C goals at entry and follow-up was investigated in relation to use of lipid-lowering therapy (LLT). RESULTS: The study recruited 4,132 individuals (3,745 of whom were >=18 years of age); 2,752 of those enrolled were molecularly diagnosed FH cases. Mean follow-up was 5.1 +/- 3.1 years; 71.8% of FH cases were on maximal LLT, and an LDL-C treatment target <100 mg/dl was reached by only 11.2% of patients. At follow-up, there was a significant increase in the use of ezetimibe, drug combinations with statins, and maximal LLT. The presence of type 2 diabetes mellitus, a defective allele mutation, ezetimibe use, and the absence of previous ASCVD were predictors of the attainment of LDL-C goals. CONCLUSIONS: Despite the use of intensified LLT, many FH patients continue to experience high plasma LDL-C levels and, consequently, do not achieve recommended treatment targets. Type of LDL-receptor mutation, use of ezetimibe, coexistent diabetes, and ASCVD status can bear significantly on the likelihood of attaining LDL-C treatment goals. PMID- 26988950 TI - Save the Unlucky Unrevascularized Acute Coronary Syndrome Patient. PMID- 26988949 TI - Spontaneous MI After Non-ST-Segment Elevation Acute Coronary Syndrome Managed Without Revascularization: The TRILOGY ACS Trial. AB - BACKGROUND: Patients with acute coronary syndrome (ACS), especially those receiving medical management without revascularization, are at high risk for spontaneous myocardial infarction (MI), but its frequency and predictors are unknown. OBJECTIVES: This study sought to characterize spontaneous MI events in a randomized population during 30 months of follow-up and develop a prediction model for spontaneous MI to assign risk of spontaneous MI events in ACS populations. METHODS: We analyzed data from the randomized TRILOGY ACS (TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medically manage Acute Coronary Syndromes) trial of aspirin plus prasugrel or clopidogrel following ACS. The trial included 9,326 patients with non-ST-segment elevation myocardial infarction (NSTEMI)/unstable angina (UA) who were managed medically without planned revascularization. Our study population included 9,294 patients. A multivariable Cox proportional hazards model was developed to determine predictors of time to first spontaneous MI event through 30 months. After model validation, we developed a calculator for model implementation. RESULTS: Among 9,294 patients, 695 spontaneous MI events occurred over a median of 17 months, representing 94% of adjudicated MI events (n = 737). The Kaplan-Meier event rate of spontaneous MI through 30 months was 10.7%. The strongest predictors of spontaneous MI were older age, NSTEMI versus UA as index event, diabetes mellitus, no pre-randomization angiography, and higher baseline creatinine values. The model exhibited good predictive capabilities (c-index = 0.732) and had good calibration, especially for patients with low-to-moderate risk of spontaneous MI. CONCLUSIONS: Spontaneous MI following a medically managed UA/NSTEMI event is common. Baseline characteristics can be used to predict subsequent risk of spontaneous MI in this population. These findings provide insight into the long-term natural history of medically managed UA/NSTEMI patients and could be used to optimize risk stratification and treatment of these patients. (A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects [TRILOGY ACS]; NCT00699998). PMID- 26988952 TI - BRUISE CONTROL INFECTION Study: Blood and Bugs. PMID- 26988954 TI - Using Registries to Understand Clinical Practice: A Lesson for Rare Disease. PMID- 26988955 TI - Procedural Success and Adverse Events in Pulmonary Artery Stenting: Insights From the NCDR. AB - BACKGROUND: Risk factors associated with outcomes for pulmonary artery (PA) stenting remain poorly defined. OBJECTIVES: The goal of this study was to determine the effect of patient and procedural characteristics on rates of adverse events and procedural success. METHODS: Registry data were collected, and 2 definitions of procedural success were pre-specified for patients with biventricular circulation: 1) 20% reduction in right ventricular pressure or 50% increase in PA diameter; and 2) 25% reduction in right ventricular pressure or 50% decrease in PA gradient or post-procedure ratio of in-stent minimum to pre stent distal diameter >80%. A separate definition of procedural success based on normalization of PA diameter was pre-specified for patients with single ventricle palliation. RESULTS: Between January 2011 and January 2014, a total of 1,183 PA stenting procedures were performed at 59 institutions across 1,001 admissions; 262 (22%) procedures were performed in patients with a single ventricle. The rate of procedural success was 76% for definition 1, 86% for definition 2, and 75% for single ventricle patients. In the multivariate analysis, ostial stenosis was significantly associated with procedural success for biventricular patients according to both definitions. The overall complication rate was 14%, with 9% of patients experiencing death or a major adverse event (MAE). According to multivariate analysis, weight <4 kg, having a single ventricle, and emergency status were significantly associated with death or MAEs. CONCLUSIONS: In our analysis, success was >75% across all definitions, and adverse events were relatively common. Biventricular patients with an ostial stenosis had a higher probability of a successful outcome. Patients who had a single ventricle, weight <4 kg, or who underwent an emergency procedure had a higher risk of death or MAE. These findings may help inform patient selection for PA stenting. PMID- 26988956 TI - Congenital Interventions Enter the Era of Big Data: Risks and Rewards. PMID- 26988953 TI - Acute Vasodilator Response in Pediatric Pulmonary Arterial Hypertension: Current Clinical Practice From the TOPP Registry. AB - BACKGROUND: In pulmonary arterial hypertension (PAH), acute vasodilator response testing (AVT) is considered important to identify adult patients with favorable prognosis using calcium-channel blocker (CCB) therapy. However, in pediatric PAH, criteria used to identify acute responders and CCB use are insufficiently studied. OBJECTIVES: This study sought to describe current clinical practice of AVT and subsequent treatment decisions in pediatric PAH. METHODS: From January 2008 to May 2013, 529 consecutive children with confirmed pulmonary hypertension were enrolled in an international registry. We analyzed those children with evaluable AVT. RESULTS: Of 382 children with evaluable AVT, 212 had idiopathic/familial PAH (IPAH/FPAH) and 105 had PAH associated with congenital heart disease (PAH-CHD). In 70% of the patients, AVT was performed using inhaled nitric oxide; other agents were used in the remaining patients. In IPAH/FPAH patients, 78 (37%) patients were acute responders according to their physician, 62 (30%) according to REVEAL (Registry-to-Evaluate-Early-And-Long-term PAH disease management)-pediatric criteria, and 32 (15%) according to Sitbon criteria. For PAH-CHD patients, the numbers of AVT responders were 38 (36%), 14 (13%), and 7 (7%) respectively. Correlation between AVT responder status as judged by the treating physician and by published response criteria was poor. Moreover, of the IPAH/FPAH patients judged by the treating physician as acute responders, only 23% were treated with CCB without additional PAH-targeted therapy. The Sitbon criteria selected patients with better prognosis who had excellent outcome when treated with CCB. CONCLUSIONS: The current practice of identifying responders to AVT and subsequent treatment with CCB therapy demonstrated large discrepancies with current international guidelines. Also, in pediatric IPAH, the Sitbon criteria are the criteria of choice to identify patients with excellent survival when treated with CCB therapy. PMID- 26988951 TI - Clinically Significant Pocket Hematoma Increases Long-Term Risk of Device Infection: BRUISE CONTROL INFECTION Study. AB - BACKGROUND: The BRUISE CONTROL trial (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial) demonstrated that a strategy of continued warfarin during cardiac implantable electronic device surgery was safe and reduced the incidence of clinically significant pocket hematoma (CSH). CSH was defined as a post-procedure hematoma requiring further surgery and/or resulting in prolongation of hospitalization of at least 24 h, and/or requiring interruption of anticoagulation. Previous studies have inconsistently associated hematoma with the subsequent development of device infection; reasons include the retrospective nature of many studies, lack of endpoint adjudication, and differing subjective definitions of hematoma. OBJECTIVES: The BRUISE CONTROL INFECTION (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial Extended Follow-Up for Infection) prospectively examined the association between CSH and subsequent device infection. METHODS: The study included 659 patients with a primary outcome of device-related infection requiring hospitalization, defined as 1 or more of the following: pocket infection; endocarditis; and bloodstream infection. Outcomes were verified by a blinded adjudication committee. Multivariable analysis was performed to identify predictors of infection. RESULTS: The overall 1-year device-related infection rate was 2.4% (16 of 659). Infection occurred in 11% of patients (7 of 66) with previous CSH and in 1.5% (9 of 593) without CSH. CSH was the only independent predictor and was associated with a >7-fold increased risk of infection (hazard ratio: 7.7; 95% confidence interval: 2.9 to 20.5; p < 0.0001). Empiric antibiotics upon development of hematoma did not reduce long-term infection risk. CONCLUSIONS: CSH is associated with a significantly increased risk of infection requiring hospitalization within 1 year following cardiac implantable electronic device surgery. Strategies aimed at reducing hematomas may decrease the long-term risk of infection. (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial [BRUISE CONTROL]; NCT00800137). PMID- 26988957 TI - Peripheral Artery Disease: Evolving Role of Exercise, Medical Therapy, and Endovascular Options. AB - The prevalence of peripheral artery disease (PAD) continues to increase worldwide. It is important to identify patients with PAD because of the increased risk of myocardial infarction, stroke, and cardiovascular death and impaired quality of life because of a profound limitation in exercise performance and the potential to develop critical limb ischemia. Despite effective therapies to lower the cardiovascular risk and prevent progression to critical limb ischemia, patients with PAD continue to be under-recognized and undertreated. The management of PAD patients should include an exercise program, guideline-based medical therapy to lower the cardiovascular risk, and, when revascularization is indicated, an "endovascular first" approach. The indications and strategic choices for endovascular revascularization will vary depending on the clinical severity of the PAD and the anatomic distribution of the disease. In this review, we discuss an evidence-based approach to the management of patients with PAD. PMID- 26988958 TI - Implantable Cardiac Defibrillator Lead Failure and Management. AB - The implantable-cardioverter defibrillator (ICD) lead is the most vulnerable component of the ICD system. Despite advanced engineering design, sophisticated manufacturing techniques, and extensive bench, pre-clinical, and clinical testing, lead failure (LF) remains the Achilles' heel of the ICD system. ICD LF has a broad range of adverse outcomes, ranging from intermittent inappropriate pacing to proarrhythmia leading to patient mortality. ICD LF is often considered in the context of design or construction defects, but is more appropriately considered in the context of the finite service life of a mechanical component placed in chemically stressful environment and subjected to continuous mechanical stresses. This clinical review summarizes LF mechanisms, assessment, and differential diagnosis of LF, including lead diagnostics, recent prominent lead recalls, and management of LF and functioning, but recalled leads. Despite recent advances in lead technology, physicians will likely continue to need to understand how to manage patients with transvenous ICD leads. PMID- 26988960 TI - Hypertension Landmark Trials 2015: A European Perspective of the Practicing Clinician. PMID- 26988959 TI - State of the States: ACC Chapters Making a Difference in Communities Across the United States. PMID- 26988961 TI - The Necessity of High-Fidelity Simulation in Cardiology Training Programs. PMID- 26988963 TI - TAVI in Lower Risk Patients: Revolution or Nonsense? Keep Calm and Select Patients. PMID- 26988962 TI - Persistent but not Paroxysmal Atrial Fibrillation Is Independently Associated With Lower Cognitive Function: ARIC Study. PMID- 26988964 TI - Reply: TAVI in Lower Risk Patients: Revolution or Nonsense? Keep Calm and Select Patients. PMID- 26988965 TI - Nitrites/Nitrates in Heart Failure With Preserved Ejection Fraction. PMID- 26988966 TI - Reply: Nitrites/Nitrates in Heart Failure With Preserved Ejection Fraction. PMID- 26988968 TI - Genome-Based Microbial Taxonomy Coming of Age. AB - Reconstructing the complete evolutionary history of extant life on our planet will be one of the most fundamental accomplishments of scientific endeavor, akin to the completion of the periodic table, which revolutionized chemistry. The road to this goal is via comparative genomics because genomes are our most comprehensive and objective evolutionary documents. The genomes of plant and animal species have been systematically targeted over the past decade to provide coverage of the tree of life. However, multicellular organisms only emerged in the last 550 million years of more than three billion years of biological evolution and thus comprise a small fraction of total biological diversity. The bulk of biodiversity, both past and present, is microbial. We have only scratched the surface in our understanding of the microbial world, as most microorganisms cannot be readily grown in the laboratory and remain unknown to science. Ground breaking, culture-independent molecular techniques developed over the past 30 years have opened the door to this so-called microbial dark matter with an accelerating momentum driven by exponential increases in sequencing capacity. We are on the verge of obtaining representative genomes across all life for the first time. However, historical use of morphology, biochemical properties, behavioral traits, and single-marker genes to infer organismal relationships mean that the existing highly incomplete tree is riddled with taxonomic errors. Concerted efforts are now needed to synthesize and integrate the burgeoning genomic data resources into a coherent universal tree of life and genome-based taxonomy. PMID- 26988971 TI - Length of stay in acute hospitals: be careful what you wish for. PMID- 26988970 TI - Spatiotemporal transcriptome provides insights into early fruit development of tomato (Solanum lycopersicum). AB - Early fruit development is crucial for crop production in tomato. After fertilization, the ovary undergoes cell division and cell expansion before maturation. Although the roles of regulatory signals such as hormone and carbohydrate during early fruit development have been studied, the spatial distribution and the sequential initiation of these regulatory signals still need to be explored. Using the tomato cultivar 'Moneymaker', we analyzed the transcriptome of the ovule and the ovary wall/pericarp dissected from four different stages of the early developing fruits by stereoscope. These datasets give us the whole picture about the spatial and temporal signal distribution in early development of ovule and pericarp. Our results indicate that the hormone signal was initiated in both ovule and pericarp after fertilization. After that, different signals were activated in ovule and pericarp due to their distinct developmental processes. Our study provides spatiotemporal regulatory landscape of gene expression with sequential information which was not studied by previous work and further strengthens the comprehension of the regulatory and metabolic events controlling early fruit development. PMID- 26988972 TI - The relationship between posttraumatic stress symptoms and narrative structure among adolescent terrorist-attack survivors. AB - BACKGROUND: The structure of trauma narratives is considered to be related to posttraumatic stress symptomatology and thus the capacity to make a coherent narrative after stressful events is crucial for mental health. OBJECTIVE: The aim of this study is to understand more of the relationship between narrative structure and posttraumatic stress symptoms (PTSS). More specifically, we investigated whether internal and external focus, organization, fragmentation, and length differed between two groups of adolescent survivors of a mass shooting, one group with low levels of PTSS and one group with high levels of PTSS. METHOD: The sample comprised 30 adolescents who survived the shooting at Utoya Island in Norway in 2011. They were interviewed 4-5 months after the shooting and provided a free narrative of the event. PTSS were assessed using the UCLA Posttraumatic Stress Disorder Reaction Index (PTSD-RI). RESULTS: We found that survivors with high levels of PTSS described more external events and fewer internal events in their narratives compared with survivors with low levels of symptoms. The analysis also showed that especially narratives containing more descriptions of dialogue and fewer organized thoughts were related to higher levels of PTSS. The groups did not differ in levels of narrative fragmentation or in length of the narratives. CONCLUSION: Specific attributes of narrative structure proved to be related to the level of PTSS. On the basis of our results, we can recommend that practitioners focus especially on two elements of the trauma narratives, namely, the amount of external events, particularly dialogues, within the narrative and the number of organized thoughts. Participants with high levels of PTSS provided trauma narratives with low amount of organized (explanatory) thoughts accompanied by detailed descriptions of dialogues and actions, which is indicative for "here and now" quality of recall and a lack of trauma processing. PMID- 26988967 TI - Diversity of Neural Precursors in the Adult Mammalian Brain. AB - Aided by advances in technology, recent studies of neural precursor identity and regulation have revealed various cell types as contributors to ongoing cell genesis in the adult mammalian brain. Here, we use stem-cell biology as a framework to highlight the diversity of adult neural precursor populations and emphasize their hierarchy, organization, and plasticity under physiological and pathological conditions. PMID- 26988969 TI - Actin and Actin-Binding Proteins. AB - Organisms from all domains of life depend on filaments of the protein actin to provide structure and to support internal movements. Many eukaryotic cells use forces produced by actin polymerization for their motility, and myosin motor proteins use ATP hydrolysis to produce force on actin filaments. Actin polymerizes spontaneously, followed by hydrolysis of a bound adenosine triphosphate (ATP). Dissociation of the gamma-phosphate prepares the polymer for disassembly. This review provides an overview of the properties of actin and shows how dozens of proteins control both the assembly and disassembly of actin filaments. These players catalyze nucleotide exchange on actin monomers, initiate polymerization, promote phosphate dissociation, cap the ends of polymers, cross link filaments to each other and other cellular components, and sever filaments. PMID- 26988974 TI - Chronic kidney disease and prognosis in elderly patients with cardiovascular disease: Comparison between CKD-EPI and Berlin Initiative Study-1 formulas. AB - BACKGROUND: Chronic kidney disease (CKD) is frequent in patients with cardiovascular (CV) disease and impacts prognosis in these subjects. While current guidelines recommend the CKD-EPI equation for the estimated glomerular filtration rate (eGFR) and recognizing CKD, a new creatinine-based equation - the Berlin Initiative Study-1 (BIS-1) - was generated for elders with a high prevalence of CV disease. We assessed whether BIS-1 provided more accurate risk stratification than the CKD-EPI equation in unselected aged patients with CV disease. METHODS: Patients aged >=70 years who were seen consecutively at the Cardiovascular Centre of Trieste (Italy) between November 2009 and October 2013 were recruited into this study. The correlation and agreement between the BIS-1 and CKD-EPI formulas were evaluated and intra-class correlation coefficients (ICCs) were computed in order to estimate the correlation between the two formulas. Patients were followed for all-cause death, composite outcomes of all cause death/all-cause hospitalization and all-cause death/CV hospitalization. RESULTS: A total of 7845 subjects met the inclusion criteria for this study. GFR as estimated with the BIS-1 and the CKD-EPI equation was highly correlated (ICC: 0.81; 95% confidence interval [CI]: 0.79-0.82; p < 0.0001). When allocating patients in Kidney Disease Improving Global Outcomes classes of eGFR, compared to CKD-EPI, the BIS-1 formula reclassified 2720 (34.7%) patients: 53 (1.9%) were placed in a better class and 2667 (98.1%) were placed in a worse class. Multivariable Cox models showed that BIS-1 compared to CKD-EPI had a significantly better accuracy for predicting death (NRI: 0.12; 95% CI: 0.03-0.19; p = 0.001), death/CV hospitalization (net reclassification improvement [NRI]: 0.34; 95% CI: 0.27-0.38; p < 0.001) and death/all-cause hospitalization (NRI: 0.14; 95% CI: 0.06-0.21; p = 0.001). CONCLUSIONS: The BIS-1 formula is better than the CKD-EPI formula for risk stratification of CKD in elderly people with CV disease. PMID- 26988976 TI - An evaluation of the additional benefit of population screening for dementia beyond a passive case-finding approach. AB - OBJECTIVE: General practitioners (GPs) fail to identify more than 50% of dementia cases using the existing passive case-finding approach. Using data from the "Ageing in General Practice" study, we sought to establish the additional benefit of screening all patients over the age of 75 for dementia beyond those patients already identified by passive case-finding. METHOD: Patients were classified as "case-finding" (n = 425) or "screening" (n = 1006) based on their answers to four subjective memory related questions or their GP's clinical judgement of their dementia status. Cognitive status of each patient was formally assessed by a research nurse using the Cambridge Cognition Examination (CAMCOG-R). Patients then attended their usual GP for administration of the GP assessment of Cognition (GPCOG) dementia screening instrument, and follow-up care and/or referral as necessary in light of the outcome. RESULTS: The prevalence of dementia was significantly higher in the case-finding group (13.6%) compared to the screening group (4.6%; p < 0.01). The GPCOG had a positive predictive value (PPV) of 61% in the case-finding group and 39% in the screening group; negative predictive value was >95% in both groups. GPs and their patients both found the GPCOG to be an acceptable cognitive assessment tool. The dementia cases missed via case-finding were younger (p = 0.024) and less cognitively impaired (p = 0.020) than those detected. CONCLUSION: There is a very limited benefit of screening for dementia, as most people with dementia could be detected using a case-finding approach, and considerable potential for social and economic harm because of the low PPV associated with screening. PMID- 26988975 TI - Molecular mode of action of NKP-1339 - a clinically investigated ruthenium-based drug - involves ER- and ROS-related effects in colon carcinoma cell lines. AB - Sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (NKP-1339) is a clinically investigated ruthenium-based metal complex, which shows promising results in solid tumors, such as non-small cell lung cancer, colorectal carcinoma, and most distinctively in gastrointestinal neuroendocrine tumors. In previous studies, fast binding to albumin as well as transferrin could be shown. The enhanced permeability and retention (EPR) effect, which is diversely being exploited for tumor targeting, could therefore be applicable for NKP-1339. Here we studied the serum dependence of its biological activity in various methods, influencing its cellular accumulation, cytotoxicity as well as the generation of reactive oxygen species (ROS). ROS lead to Nrf2 activation, which is known to activate antioxidant response gene transcription. GRP78 down-regulation on the protein level suggests ER associated protein degradation (ERAD) as a mode of action, as RNA levels are only mildly affected. Another important part for the mode of action is endoplasmic reticulum (ER) stress, as different factors are highly upregulated on the protein level. For example PERK, a transmembrane receptor which is released by GRP78 when the ER is disturbed, is upregulated and phosphorylated. EIF2alpha is phosphorylated, which leads to an inhibition of CAP dependent translation and other stress responses. The transcription factor CHOP (DDIT3), which promotes ER stress dependent apoptosis, is time and concentration dependently upregulated. Finally cytotoxicity tests could prove that inhibition of ER stress and ER stress-mediated apoptosis leads to decreased cytotoxic effects of NKP-1339, which highlights the involvement of this mechanism in the mode of action. PMID- 26988977 TI - Introduction to the Special Issue on Multisensory Processing. PMID- 26988978 TI - Poor guideline adherence in the initiation of antidepressant treatment in children and adolescents in the Netherlands: choice of antidepressant and dose. AB - The Dutch guideline for the treatment of depression in young people recommends initiating antidepressant treatment with fluoxetine, as the evidence for its efficacy is strongest and the risk of suicidality may be lower than with other antidepressants. Furthermore, low starting doses are recommended. We aimed to determine whether antidepressant prescriptions are in accord with guidelines. A cohort of young people aged between 6 and 17 at the time of antidepressant initiation was selected from IABD, a Dutch pharmacy prescription database. The percentage of prescriptions for each antidepressant was determined. Starting and maintenance doses were determined and compared with recommendations for citalopram, fluoxetine, fluvoxamine, and sertraline. During the study period, 2942 patients initiated antidepressant treatment. The proportion of these young people who were prescribed fluoxetine increased from 10.1 % in 1994-2003 to 19.7 % in 2010-2014. However, the most commonly prescribed antidepressants were paroxetine in 1994-2003 and citalopram in 2004-2014. The median starting and maintenance doses were <=0.5 DDD/day for tricyclic antidepressants and 0.5-1 DDD/day for SSRIs and other antidepressants. Starting doses were guideline concordant 58 % of the time for children, 31 % for preteens, and 16 % for teens. Sixty percent of teens were prescribed an adult starting dose. In conclusion, guideline adherence was poor. Physicians preferred citalopram over fluoxetine, in contrast to the recommendations. Furthermore, although children were prescribed a low starting dose relatively frequently, teens were often prescribed an adult starting dose. These results suggest that dedicated effort may be necessary to improve guideline adherence. PMID- 26988979 TI - Improving Shared Decision Making with LGBT Racial and Ethnic Minority Patients. PMID- 26988973 TI - A best practice position statement on pregnancy in chronic kidney disease: the Italian Study Group on Kidney and Pregnancy. AB - Pregnancy is increasingly undertaken in patients with chronic kidney disease (CKD) and, conversely, CKD is increasingly diagnosed in pregnancy: up to 3 % of pregnancies are estimated to be complicated by CKD. The heterogeneity of CKD (accounting for stage, hypertension and proteinuria) and the rarity of several kidney diseases make risk assessment difficult and therapeutic strategies are often based upon scattered experiences and small series. In this setting, the aim of this position statement of the Kidney and Pregnancy Study Group of the Italian Society of Nephrology is to review the literature, and discuss the experience in the clinical management of CKD in pregnancy. CKD is associated with an increased risk for adverse pregnancy-related outcomes since its early stage, also in the absence of hypertension and proteinuria, thus supporting the need for a multidisciplinary follow-up in all CKD patients. CKD stage, hypertension and proteinuria are interrelated, but they are also independent risk factors for adverse pregnancy-related outcomes. Among the different kidney diseases, patients with glomerulonephritis and immunologic diseases are at higher risk of developing or increasing proteinuria and hypertension, a picture often difficult to differentiate from preeclampsia. The risk is higher in active immunologic diseases, and in those cases that are detected or flare up during pregnancy. Referral to tertiary care centres for multidisciplinary follow-up and tailored approaches are warranted. The risk of maternal death is, almost exclusively, reported in systemic lupus erythematosus and vasculitis, which share with diabetic nephropathy an increased risk for perinatal death of the babies. Conversely, patients with kidney malformation, autosomal-dominant polycystic kidney disease, stone disease, and previous upper urinary tract infections are at higher risk for urinary tract infections, in turn associated with prematurity. No risk for malformations other than those related to familiar urinary tract malformations is reported in CKD patients, with the possible exception of diabetic nephropathy. Risks of worsening of the renal function are differently reported, but are higher in advanced CKD. Strict follow-up is needed, also to identify the best balance between maternal and foetal risks. The need for further multicentre studies is underlined. PMID- 26988981 TI - Use of Decision Aids with Minority Patients: a Systematic Review. AB - BACKGROUND: One potential approach to reducing health disparities among minorities is through the promotion of shared decision making (SDM). The most commonly studied SDM intervention is the decision aid (DA). While DAs have been extensively studied, we know relatively little about their use in minority populations. We conducted a systematic review to characterize the application and effectiveness of DAs in racial, ethnic, sexual, and gender minorities. METHODS: We searched PubMed for randomized controlled trials (RCTs) evaluating DAs between 2004 and 2013. We included trials that enrolled adults (> 18 years of age) with > 50 % representation by minority patients. Four reviewers independently assessed 597 initially identified articles, and those with inconclusive results were discussed to consensus. We abstracted decision quality, patient-doctor communication, and clinical treatment decision outcomes. Results were considered significantly modified by the DA if the study reported p < 0.05. RESULTS: We reviewed 18 RCTs of DA interventions in minority populations. The majority of interventions (78 %) addressed cancer screening. The most common mode of delivery for the DAs was personal counseling (46 %), followed by multi-media (29 %), and print materials (25 %). Most of the trials studied racial (78 %) or ethnic (17 %) minorities with only one trial focused on sexual minorities and none on gender minorities. Ten studies tailored their interventions for their minority populations. Comparing intervention vs. control, decision quality outcomes improved in six out of eight studies and patient-doctor communication improved in six out of seven studies. Of the 15 studies that reported on clinical decisions, eight demonstrated significant changes in decisions with DAs. DISCUSSION: DAs have been effective in improving patient-doctor communication and decision quality outcomes in minority populations and could help address health disparities. However, the existing literature is almost non-existent for sexual and gender minorities and has not included the full breadth of clinical decisions that affect minority populations. PMID- 26988980 TI - A Model of Organizational Context and Shared Decision Making: Application to LGBT Racial and Ethnic Minority Patients. AB - Shared decision making (SDM) occurs when patients and clinicians work together to reach care decisions that are both medically sound and responsive to patients' preferences and values. SDM is an important tenet of patient-centered care that can improve patient outcomes. Patients with multiple minority identities, such as sexual orientation and race/ethnicity, are at particular risk for poor SDM. Among these dual-minority patients, added challenges to clear and open communication include cultural barriers, distrust, and a health care provider's lack of awareness of the patient's minority sexual orientation or gender identity. However, organizational factors like a culture of inclusion and private space throughout the visit can improve SDM with lesbian, gay, bisexual, and transgender ("LGBT") racial/ethnic minority patients who have faced stigma and discrimination. Most models of shared decision making focus on the patient provider interaction, but the health care organization's context is also critical. Context-an organization's structure and operations-can strongly influence the ability and willingness of patients and clinicians to engage in shared decision making. SDM is most likely to be optimal if organizations transform their contexts and patients and providers improve their communication. Thus, we propose a conceptual model that suggests ways in which organizations can shape their contextual structure and operations to support SDM. The model contains six drivers: workflows, health information technology, organizational structure and culture, resources and clinic environment, training and education, and incentives and disincentives. These drivers work through four mechanisms to impact care: continuity and coordination, the ease of SDM, knowledge and skills, and attitudes and beliefs. These mechanisms can activate clinicians and patients to engage in high-quality SDM. We provide examples of how specific contextual changes could make SDM more effective for LGBT racial/ethnic minority populations, focusing especially on transformations that would establish a safe environment, build trust, and decrease stigma. PMID- 26988983 TI - Violaxanthin inhibits nonphotochemical quenching in light-harvesting antenna of Chromera velia. AB - Non-photochemical quenching (NPQ) is a photoprotective mechanism in light harvesting antennae. NPQ is triggered by chloroplast thylakoid lumen acidification and is accompanied by violaxanthin de-epoxidation to zeaxanthin, which further stimulates NPQ. In the present study, we show that violaxanthin can act in the opposite direction to zeaxanthin because an increase in the concentration of violaxanthin reduced NPQ in the light-harvesting antennae of Chromera velia. The correlation overlapped with a similar relationship between violaxanthin and NPQ as observed in isolated higher plant light-harvesting complex II. The data suggest that violaxanthin in C. velia can act as an inhibitor of NPQ, indicating that violaxanthin has to be removed from the vicinity of the protein to reach maximal NPQ. PMID- 26988982 TI - IL-17 mediates inflammatory reactions via p38/c-Fos and JNK/c-Jun activation in an AP-1-dependent manner in human nucleus pulposus cells. AB - BACKGROUND: Low back pain and sciatica caused by intervertebral disc (IVD) disease are associated with inflammatory responses. The cytokine interleukin 17 (IL-17) is elevated in herniated and degenerated IVD tissues and acts as a regulator of disc inflammation. The objective of this study was to investigate the involvement of IL-17A in IVD inflammatory response and to explore the mechanisms underlying this response. METHODS: Cells were isolated from nucleus pulposus (NP) tissues collected from patients undergoing surgeries for IVD degeneration. The concentrations of COX2 and PGE2, as well as of select proteins involved in the mitogen-activated protein kinase (MAPK)/activating protein-1 (AP 1) pathway, were quantified in NP cells after exposure to IL-17 with or without pretreatment with MAPK or AP-1 inhibitors. RESULTS: Our results showed that IL 17A increased COX2 expression and PGE2 production via the activation of MAPKs, including p38 kinase and Jun N-terminal kinase (JNK). Moreover, IL-17A-induced COX2 and PGE2 production was shown to rely on p38/c-Fos and JNK/c-Jun activation in an AP-1-dependent manner. CONCLUSION: In summary, our results indicate that IL 17A enhances COX2 expression and PGE2 production via the p38/c-Fos and JNK/c-Jun signalling pathways in NP cells to mediate IVD inflammation. PMID- 26988984 TI - Reserpine Inhibit the JB6 P+ Cell Transformation Through Epigenetic Reactivation of Nrf2-Mediated Anti-oxidative Stress Pathway. AB - Nuclear factor erythroid-2 related factor 2 (Nrf2) is a crucial transcription factor that regulates the expression of defensive antioxidants and detoxification enzymes in cells. In a previous study, we showed that expression of the Nrf2 gene is regulated by an epigenetic modification. Rauvolfia verticillata, a traditional Chinese herbal medicine widely used in China, possesses anticancer and antioxidant effects. In this study, we investigated how Nrf2 is epigenetically regulated by reserpine, the main active component in R. verticillata, in mouse skin epidermal JB6 P+ cells. Reserpine induced ARE (antioxidant response element) luciferase activity in HepG2-C8 cells. Accordingly, in JB6 P+ cells, it upregulated the mRNA and protein levels of Nrf2 and its downstream target genes heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1), while it only increased the protein level of UDP-glucuronosyltransferase 1A1 (UGT1A1). Furthermore, reserpine decreased the TPA (12-O-tetradecanoylphorbol-13-acetate) induced colony formation of JB6 cells in a dose-dependent manner. DNA sequencing and methylated DNA immunoprecipitation further demonstrated the demethylation effect of reserpine on the first 15 CpGs of the Nrf2 promoter in JB6 P+ cells. Reserpine also reduced the mRNA and protein expression of DNMT1 (DNA methyltransferase 1), DNMT3a (DNA methyltransferases 3a), and DNMT3b (DNA methyltransferases 3b). Moreover, reserpine induced Nrf2 expression via an epigenetic pathway in skin epidermal JB6 P+ cells, enhancing the protective antioxidant activity and decreasing TPA-induced cell transformation. These results suggest that reserpine exhibits a cancer preventive effect by reactivating Nrf2 and inducing the expression of target genes involved in cellular protection, potentially providing new insight into the chemoprevention of skin cancer using reserpine. PMID- 26988985 TI - Combining Epigenetic and Immunotherapy to Combat Cancer. AB - The most exciting recent advance for achieving durable management of advanced human cancers is immunotherapy, especially the concept of immune checkpoint blockade. However, with the exception of melanoma, most patients do not respond to immunotherapy alone. A growing body of work has shown that epigenetic drugs, specifically DNA methyltransferase inhibitors, can upregulate immune signaling in epithelial cancer cells through demethylation of endogenous retroviruses and cancer testis antigens. These demethylating agents may induce T-cell attraction and enhance immune checkpoint inhibitor efficacy in mouse models. Current clinical trials are testing this combination therapy as a potent new cancer management strategy. Cancer Res; 76(7); 1683-9. (c)2016 AACR. PMID- 26988986 TI - Proteasomal Inhibition by Ixazomib Induces CHK1 and MYC-Dependent Cell Death in T cell and Hodgkin Lymphoma. AB - Proteasome-regulated NF-kappaB has been shown to be important for cell survival in T-cell lymphoma and Hodgkin lymphoma models. Several new small-molecule proteasome inhibitors are under various stages of active preclinical and clinical development. We completed a comprehensive preclinical examination of the efficacy and associated biologic effects of a second-generation proteasome inhibitor, ixazomib, in T-cell lymphoma and Hodgkin lymphoma cells and in vivo SCID mouse models. We demonstrated that ixazomib induced potent cell death in all cell lines at clinically achievable concentrations. In addition, it significantly inhibited tumor growth and improved survival in T-cell lymphoma and Hodgkin lymphoma human lymphoma xenograft models. Through global transcriptome analyses, proteasomal inhibition showed conserved overlap in downregulation of cell cycle, chromatin modification, and DNA repair processes in ixazomib-sensitive lymphoma cells. The predicted activity for tumor suppressors and oncogenes, the impact on "hallmarks of cancer," and the analysis of key significant genes from global transcriptome analysis for ixazomib strongly favored tumor inhibition via downregulation of MYC and CHK1, its target genes. Furthermore, in ixazomib-treated lymphoma cells, we identified that CHK1 was involved in the regulation of MYC expression through chromatin modification involving histone H3 acetylation via chromatin immunoprecipitation. Finally, using pharmacologic and RNA silencing of CHK1 or the associated MYC-related mechanism, we demonstrated synergistic cell death in combination with antiproteasome therapy. Altogether, ixazomib significantly downregulates MYC and induces potent cell death in T-cell lymphoma and Hodgkin lymphoma, and we identified that combinatorial therapy with anti-CHK1 treatment represents a rational and novel therapeutic approach. Cancer Res; 76(11); 3319 31. (c)2016 AACR. PMID- 26988987 TI - Induction of Therapeutic Senescence in Vemurafenib-Resistant Melanoma by Extended Inhibition of CDK4/6. AB - Dysregulation of the p16-cyclin D1-CDK4/6-Rb pathway occurs frequently in melanoma; however, the therapeutic efficacy of CDK4/6 inhibition remains to be critically evaluated. We demonstrate that CDK4/6 inhibition inhibits melanoma progression through induction of senescence. Palbociclib, a specific CDK4/6 inhibitor, rapidly induces cell cycle arrest within 24 hours and continued exposure for 8 days or longer induces senescence. The induction of senescence correlates with inhibition of mTOR and more specifically mTORC1 signaling. Vemurafenib, a specific BRAF(V600E) inhibitor, has significant clinical efficacy in BRAF(V600E)-positive melanomas, but its impact is hampered by a rapid acquisition of resistance. Strikingly, we found that vemurafenib-resistant tumors remain sensitive to palbociclib, suggesting that initial treatment with vemurafenib followed by palbociclib with or without mTOR inhibitors might provide an avenue to overcome recurrence of vemurafenib-resistant metastatic disease. Taken together, these results support palbociclib as a promising therapeutic for treatment of melanoma. Cancer Res; 76(10); 2990-3002. (c)2016 AACR. PMID- 26988988 TI - Elucidation of the Roles of Tumor Integrin beta1 in the Extravasation Stage of the Metastasis Cascade. AB - Tumor integrin beta1 (ITGB1) contributes to primary tumor growth and metastasis, but its specific roles in extravasation have not yet been clearly elucidated. In this study, we engineered a three-dimensional microfluidic model of the human microvasculature to recapitulate the environment wherein extravasation takes place and assess the consequences of beta1 depletion in cancer cells. Combined with confocal imaging, these tools allowed us to decipher the detailed morphology of transmigrating tumor cells and associated endothelial cells in vitro at high spatio-temporal resolution not easily achieved in conventional transmigration assays. Dynamic imaging revealed that beta1-depleted cells lacked the ability to sustain protrusions into the subendothelial matrix in contrast with control cells. Specifically, adhesion via alpha3beta1 and alpha6beta1 to subendothelial laminin was a critical prerequisite for successful transmigration. beta1 was required to invade past the endothelial basement membrane, whereas its attenuation in a syngeneic tumor model resulted in reduced metastatic colonization of the lung, an effect not observed upon depletion of other integrin alpha and beta subunits. Collectively, our findings in this novel model of the extravasation microenvironment revealed a critical requirement for beta1 in several steps of extravasation, providing new insights into the mechanisms underlying metastasis. Cancer Res; 76(9); 2513-24. (c)2016 AACR. PMID- 26988989 TI - DeltaNp63alpha Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGFbeta-Induced Metastasis. AB - Primary cancer cell dissemination is a key event during the metastatic cascade, but context-specific determinants of this process remain largely undefined. Multiple reports have suggested that the p53 (TP53) family member p63 (TP63) plays an antimetastatic role through its minor epithelial isoform containing the N-terminal transactivation domain (TAp63). However, the role and contribution of the major p63 isoform lacking this domain, DeltaNp63alpha, remain largely undefined. Here, we report a distinct and TAp63-independent mechanism by which DeltaNp63alpha-expressing cells within a TGFbeta-rich microenvironment become positively selected for metastatic dissemination. Orthotopic transplantation of DeltaNp63alpha-expressing human osteosarcoma cells into athymic mice resulted in larger and more frequent lung metastases than transplantation of control cells. Mechanistic investigations revealed that DeltaNp63alpha repressed miR-527 and miR 665, leading to the upregulation of two TGFbeta effectors, SMAD4 and TbetaRII (TGFBR2). Furthermore, we provide evidence that this mechanism reflects a fundamental role for DeltaNp63alpha in the normal wound-healing response. We show that DeltaNp63alpha-mediated repression of miR-527/665 controls a TGFbeta dependent signaling node that switches off antimigratory miR-198 by suppressing the expression of the regulatory factor, KSRP (KHSRP). Collectively, these findings reveal that a novel miRNA network involved in the regulation of physiologic wound-healing responses is hijacked and suppressed by tumor cells to promote metastatic dissemination. Cancer Res; 76(11); 3236-51. (c)2016 AACR. PMID- 26988990 TI - Intracrine VEGF Signaling Mediates the Activity of Prosurvival Pathways in Human Colorectal Cancer Cells. AB - The effects of vascular endothelial growth factor-A (VEGF-A/VEGF) and its receptors on endothelial cells function have been studied extensively, but their effects on tumor cells are less well defined. Studies of human colorectal cancer cells where the VEGF gene has been deleted suggest an intracellular role of VEGF as a cell survival factor. In this study, we investigated the role of intracrine VEGF signaling in colorectal cancer cell survival. In human colorectal cancer cells, RNAi-mediated depletion of VEGF decreased cell survival and enhanced sensitivity to chemotherapy. Unbiased reverse phase protein array studies and subsequent validation experiments indicated that impaired cell survival was a consequence of disrupted AKT and ERK1/2 (MAPK3/1) signaling, as evidenced by reduced phosphorylation. Inhibition of paracrine or autocrine VEGF signaling had no effect on phospho-AKT or phospho-ERK1/2 levels, indicating that VEGF mediates cell survival via an intracellular mechanism. Notably, RNAi-mediated depletion of VEGF receptor VEGFR1/FLT1 replicated the effects of VEGF depletion on phospho-AKT and phospho-ERK1/2 levels. Together, these studies show how VEGF functions as an intracrine survival factor in colorectal cancer cells, demonstrating its distinct role in colorectal cancer cell survival. Cancer Res; 76(10); 3014-24. (c)2016 AACR. PMID- 26988991 TI - Injection Site Lichenoid Dermatitis Following Pneumococcal Vaccination: Report and Review of Cutaneous Conditions Occurring at Vaccination Sites. AB - BACKGROUND: Cutaneous dermatoses and malignancies have occurred at the sites of vaccines. PURPOSE: To describe a man who developed a lichenoid dermatitis at the pneumococcal vaccine injection site and to review cutaneous dermatoses and malignancies occurring at vaccination sites. METHODS: PubMed was used to search the following terms, separately and in combination: adverse, condition, cutaneous, dermatosis, dermatitis, injection, PCV13, pneumococcal, pneumonia, prevnar, reaction, skin, site, vaccination, and vaccine. All papers were reviewed, and relevant manuscripts, along with their reference citations, were evaluated. RESULTS: Several vaccines-including bacillus Calmette-Guerin, hepatitis B, influenza, leishmaniasis, meningitis, pneumococcal, smallpox, tetanus (alone and in combination with diphtheria, pertussis, polio, Haemophilus influenza type B or plague and yellow fever), and varicella-zoster-have been associated with post-vaccination site reactions. A 70-year-old male developed a lichenoid dermatitis that occurred at the pneumococcal vaccine injection site within 2 weeks after PCV13 vaccination; the erythematous nodule resolved spontaneously within 9 weeks following immunization. CONCLUSIONS: Dermatoses at the injection sites of vaccines can be granulomatous, immunity-related conditions, infections, lichenoid, neutrophilic, or pseudolymphomatous. Basal cell carcinoma and squamous cell carcinoma are the most common vaccination site associated malignancies; however, melanoma and sarcomas (dermatofibrosarcoma protuberans, fibrosarcoma, and malignant fibrous histiocytoma) are also smallpox vaccine-related site neoplasms. A cutaneous immunocompromised district that is created by vaccine-induced local immunologic changes is hypothesized to be the pathogenesis of vaccination site reactions. PMID- 26988992 TI - Which index should be used to measure primary surgical outcome for unilateral cleft lip and palate patients? AB - OBJECTIVE: To determine the optimal dentoalveolar measure to assess unilateral cleft lip and palate (UCLP) patient plaster models. DESIGN: The models of 34 patients with UCLP taken at 5, 10, and 15-20 years of age were scored by two examiners on two separate occasions using five indices: the 5 Year Olds' (5YO), GOSLON, Modified Huddart/Bodenham (MHB), EUROCRAN, and Overjet. Reliability, validity, and ease of use were recorded for each index/examiner. SETTING: All models were scored in either Bristol Dental Hospital or Derriford Hospital, Plymouth, United Kingdom by senior orthodontic clinicians. RESULTS: Highest overall reliability was seen with MHB (Kappa = 0.56-0.97). Predictive validity was similar for MHB, GOSLON, and 5YO with a 50-65 per cent prediction of final outcome from 5 and 10 years. EUROCRAN palatal index showed no clear predictive validity (Spearman's correlation = 0.20-0.21). Agreement to the gold standard 5YO score at the 5-year age group was high for MHB (Kappa = 0.83) and moderate for GOSLON (Kappa = 0.59). Agreement to the gold standard GOSLON score at 10 years was highest for 5YO (Kappa = 0.69), followed by Overjet (Kappa = 0.59) and MHB (Kappa = 0.46). Time to score 34 models per index (minutes): GOSLON (13.4) < Overjet (13.6) < 5YO (19.4) < EUROCRAN (24.8) < MHB (27.4). CONCLUSION: As an outcome measure of UCLP models, only MHB and 5YO indices can be recommended for use at 5 years of age and GOSLON at 10 years of age. PMID- 26988993 TI - Reduced 25-OH vitamin D in patients with autoimmune cytopenias, clinical correlations and literature review. AB - Vitamin D deficiency is widespread in Western Countries and has been found related to autoimmune and hematologic disease incidence and clinical course. We evaluated vitamin D levels, vitamin D receptor (VDR) and T helper (Th)1, Th2 and Th17 immunomodulatory cytokines in patients with immune thrombocytopenic purpura (ITP, N=44), primary autoimmune hemolytic anemia (AIHA, n=35), Evans' syndrome (n=5) and chronic idiopathic neutropenia (CIN, n=19) and also tested vitamin D effect on the in vitro production of anti-erythrocyte autoantibodies. 25-OH vitamin D levels were significantly lower and vitamin D receptor higher in patients than in controls. Among ITP cases, those with very low vitamin D levels displayed reduced platelet counts, irrespective of the bleeding history. In AIHA patients, LDH values negatively correlated with vitamin D levels in mixed forms, and reticulocyte counts were positively related with vitamin D. Considering treatment, AIHA patients who had been treated with 2 therapy lines or more showed lower mean 25-OH-vitamin D levels than those untreated or treated with one line of therapy only. IL-6, IL-10, IL-17 and IFN-gamma levels were higher in patients versus controls, whereas TNF-alpha was significantly reduced. Finally, vitamin D at concentrations of 10, 20, and 40ng/mL reduced the in vitro production of anti erythrocyte autoantibodies both in pokeweed-stimulated and unstimulated cultures. In conclusion, vitamin D is reduced in autoimmune cytopenias and correlate with disease severity, supporting its possible protective role against the development of autoimmunity. Literature review showed vitamin D deficiency reports both in onco- and in non onco-hematologic diseases with a relationship with disease severity/activity in myeloid and lymphoid neoplasms, as well as in sickle cell disease. Supplementation has produced weak results in autoimmune and hematologic diseases, and further studies are needed. PMID- 26988994 TI - Increased risk of major bleeding after a minor bleed during treatment with vitamin K antagonists is determined by fixed common risk factors. AB - Essentials Minor bleeding is associated with subsequent major bleeding in patients treated with vitamin K antagonists. This study confirms that patients with minor bleeds have a 2.5-fold increased risk of major bleeds. A case crossover analysis revealed that the increased risk is due to fixed underlying risk factors. Future research may unveil these unknown fixed risk factors and improve major bleeding risk scores. SUMMARY: Background Patients who have a minor bleed during treatment with vitamin K antagonists (VKAs) have a 3-fold increased risk of subsequent major bleeding. The nature of the underlying risk factors is largely unknown. Objectives To indicate why patients with minor bleeds are at increased risk of subsequent major bleeds (e.g. are risk factors of a transient or a fixed nature). Methods Patients who started VKA treatment between 2003 and 2013 were included. Exposure was from the minor bleed until 3 months later. We used two analyses: a Cox model which we adjusted for several known risk factors, and a case-crossover (CCO) design, which corrects for all fixed risk factors (such as chronic diseases and genes) as patients are compared with themselves. The combination of both analyses gives insight into whether the association of minor with major bleeds is a result of fixed or transient risk factors. Results Out of 26 130 patients who were included and followed for '61 672 patient years', 7194 experienced a minor bleed and 913 a major bleed. The Cox model indicated that patients with minor bleeds had a 2.5-fold increased risk of experiencing subsequent major bleeding after adjustment for known risk factors, whereas the CCO gave risk estimates around unity (odds ratio, 0.9; 95% confidence interval, 0.5-1.5). Conclusions The combination of both analyses indicates that minor bleeds are markers for fixed and currently unknown risk factors for major bleeding events. PMID- 26988996 TI - Characteristics of Patients with Alcohol Dependence Seeking Baclofen Treatment in France: A Two-Centre Comparative Cohort Study. AB - AIM: To characterize the profile of patients seeking baclofen treatment for alcohol dependence in France. METHOD: We compared retrospectively baclofen seekers and baclofen non-seekers within a cohort of consecutive outpatients with alcohol dependence who attended a first appointment for alcohol treatment at two French addiction centres between September 2012 and March 2014. We documented socio-demographic characteristics; comorbid psychiatric, addiction, alcohol dependence features; patients' initial drinking goal, and referral status; and treatment retention at 6 and 12 months. RESULTS: Of the 289 patients identified, 107 were baclofen seekers and 182 were baclofen non-seekers. The only parameters significantly associated with baclofen seekers in multivariate analyses were a greater baseline alcohol consumption (beta = 15.4, 95% CI: 0.18-30.65, P = 0.05), a controlled-drinking initial goal (OR = 14.9, 95% CI: 7.7-29, P < 0.0001) and self-referral (OR = 6.6, 95% CI: 3.7-12, P < 0.0001), baclofen seekers being eight times more likely to be self-referred and treatment-naive (OR = 8.8, 95% CI: 4.1-18.9, P < 0.0001). Baclofen seekers were more likely to be retained in treatment at 6 months (OR = 3.5, 95% CI: 1.8-6.7, P < 0.0001) and 12 months (OR = 1.9, 95% CI: 1.1-3.2, P = 0.019). CONCLUSION: In France, the perspective of controlled drinking offered by baclofen treatment may have attracted more self referred patients, including those without previous alcohol treatment, to attend treatment, than the usual treatment options. These findings raise the question as to whether future public health strategies on alcohol should more prominently promote some aspects of alcohol treatment, such as patient's preference and treatment options, in order to reduce the treatment gap in alcohol dependence. PMID- 26988995 TI - Combined detection of serum Dickkopf-1 and its autoantibodies to diagnose esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) can be treated effectively if diagnosed at an early stage. We evaluated whether measurement of Dickkopf-1 (DKK-1) in combination of DKK-1 autoantibodies in serum may benefit early diagnosis of ESCC. Serum DKK-1 and DKK-1 autoantibodies were measured by enzyme-linked immunosorbent assay in a training cohort (185 ESCC samples vs. 97 normal controls) and validated in a validation cohort (104 ESCC samples vs. 53 normal controls). Receiver operating characteristic (ROC) was applied to calculate diagnostic accuracy. Testing of DKK-1 and DKK-1 autoantibodies together could differentiate ESCC from normal controls (area under the ROC curve [AUC] 0.769, 95% confidence interval (CI), 0.715-0.823, 50.3% sensitivity, and 90.7% specificity in the training cohort; AUC 0.752, 95% CI, 0.675-0.829, 50.0% sensitivity, and 84.9% specificity in the validation cohort). Importantly, the diagnostic performance of the combination of DKK-1 and DKK-1 autoantibodies persisted in early ESCC patients (AUC 0.780, 95% CI, 0.699-0.862, 50.0% sensitivity, and 90.7% specificity in the training cohort; AUC 0.745, 95% CI, 0.626-0.865, 53.8% sensitivity, and 84.9% specificity in the validation cohort). Furthermore, the levels of serum DKK-1 or DKK-1 autoantibody after surgical resection were lower, respectively, compared with the corresponding preoperative samples (P < 0.05). Our results suggest that measurement of DKK-1 combined with DKK-1 autoantibodies is a potentially valuable tool for the early detection of ESCC. PMID- 26988997 TI - Animal models of myocardial infarction: Mainstay in clinical translation. AB - Preclinical models with high prognostic power are a prerequisite for translational research. The closer the similarity of a model to myocardial infarction (MI), the higher is the prognostic value for clinical trials. An ideal MI model should present cardinal signs and pathology that resemble the human disease. The increasing understanding of MI stratification and etiology, however, complicates the choice of animal model for preclinical studies. An ultimate animal model, relevant to address all MI related pathophysiology is yet to be developed. However, many of the existing MI models comprising small and large animals are useful in answering specific questions. An appropriate MI model should be selected after considering both the context of the research question and the model properties. This review addresses the strengths, and limitations of current MI models for translational research. PMID- 26988998 TI - Pegfilgrastim Enhances the Antitumor Effect of Therapeutic Monoclonal Antibodies. AB - Therapeutic mAbs exert antitumor activity through various mechanisms, including apoptotic signalization, complement-dependent cytotoxicity, and antibody dependent cellular cytotoxicity (ADCC) or phagocytosis (ADCP). G-CSF and GM-CSF have been reported to increase the activity of antibodies in preclinical models and in clinical trials. To determine the potential role of pegfilgrastim as an enhancer of anticancer antibodies, we performed a comparative study of filgrastim and pegfilgrastim. We found that pegfilgrastim was significantly more potent than filgrastim in murine xenograft models treated with mAbs. This was observed with rituximab in CD20(+) models and with trastuzumab in HER2(+) models. Stimulation with pegfilgrastim was associated with significant enhancement of leukocyte content in spleen as well as mobilization of activated monocytes/granulocytes from the spleen to the tumor bed. These results suggest that pegfilgrastim could constitute a potent adjuvant for immunotherapy with mAbs possessing ADCC/ADCP properties. Mol Cancer Ther; 15(6); 1238-47. (c)2016 AACR. PMID- 26988999 TI - Sex hormones and adult hippocampal neurogenesis: Regulation, implications, and potential mechanisms. AB - Neurogenesis within the adult hippocampus is modulated by endogenous and exogenous factors. Here, we review the role of sex hormones in the regulation of adult hippocampal neurogenesis in males and females. The review is framed around the potential functional implications of sex hormone regulation of adult hippocampal neurogenesis, with a focus on cognitive function and mood regulation, which may be related to sex differences in incidence and severity of dementia and depression. We present findings from preclinical studies of endogenous fluctuations in sex hormones relating to reproductive function and ageing, and from studies of exogenous hormone manipulations. In addition, we discuss the modulating roles of sex, age, and reproductive history on the relationship between sex hormones and neurogenesis. Because sex hormones have diverse targets in the central nervous system, we overview potential mechanisms through which sex hormones may influence hippocampal neurogenesis. Lastly, we advocate for a more systematic consideration of sex and sex hormones in studying the functional implications of adult hippocampal neurogenesis. PMID- 26989000 TI - The effects of hormones and physical exercise on hippocampal structural plasticity. AB - The hippocampus plays an integral role in certain aspects of cognition. Hippocampal structural plasticity and in particular adult hippocampal neurogenesis can be influenced by several intrinsic and extrinsic factors. Here we review how hormones (i.e., intrinsic modulators) and physical exercise (i.e., an extrinsic modulator) can differentially modulate hippocampal plasticity in general and adult hippocampal neurogenesis in particular. Specifically, we provide an overview of the effects of sex hormones, stress hormones, and metabolic hormones on hippocampal structural plasticity and adult hippocampal neurogenesis. In addition, we also discuss how physical exercise modulates these forms of hippocampal plasticity, giving particular emphasis on how this modulation can be affected by variables such as exercise regime, duration, and intensity. Understanding the neurobiological mechanisms underlying the modulation of hippocampal structural plasticity by intrinsic and extrinsic factors will impact the design of new therapeutic approaches aimed at restoring hippocampal plasticity following brain injury or neurodegeneration. PMID- 26989001 TI - Multi-laboratory evaluation of SkinEthic HCE test method for testing serious eye damage/eye irritation using solid chemicals and overall performance of the test method with regard to solid and liquid chemicals testing. AB - A prospective multicentre study of the reconstructed human corneal epithelial tissue-based in vitro test method (SkinEthicTM HCE) was conducted to evaluate its usefulness to identify chemicals as either not classified for serious eye damage/eye irritation (No Cat.) or as classified (Cat. 1/Cat. 2) within UN GHS. The aim of this study was to demonstrate the transferability and reproducibility of the SkinEthicTM HCE EITS protocol for solids and define its predictive capacity. Briefly, 60 chemicals were three times tested (double blinded) in 3 laboratories and 35 additional chemicals were tested three times in one laboratory. Good within laboratory reproducibility was achieved of at least 95% (57/60) and 96.8% (92/95) for the extended data set. Furthermore, the overall concordance between the laboratories was 96.7% (58/60). The accuracy of the SkinEthicTM HCE EITS for the extended dataset, based on bootstrap resampling, was 81.0% (95% CI: 78.9% to 83.2%) with a sensitivity of 90.5% (95% CI: 88.1% to 92.9%) and specificity of 73.6% (95% CI: 71.7% to 75.5%). Overall, 200 chemicals were tested (105 liquids (EITL protocol) and 95 solids (EITS protocol)) resulting in a sensitivity of 95.2%, specificity of 72.1% and accuracy of 83.7%, thereby meeting all acceptance criteria for predictive capacity. PMID- 26989002 TI - Organisational challenges in the United Kingdom's post-disaster 'crisis support' work. AB - Local authorities in the United Kingdom are required to 'lead' multi-agency humanitarian responses to major disasters. Concerns mounted in the late twentieth century that responses to people bereaved in the immediate aftermath of such events at best failed to meet their needs and at worst compounded their distress. Subsequent reviews and reforms reframed some victim needs as 'rights' and established legal, administrative, and practice frameworks to improve matters. Local authority 'crisis support', provided in partnership with other actors, lies at the heart of the UK's contemporary emergency response to the bereaved. Drawing on primary research on the development and the deployment of crisis support in a local authority, and while acknowledging both incident- and context-related difficulties, this paper considers the significance of challenges with their origins in organisational factors. Recent developments within and between responders may exacerbate them. This paper argues, therefore, that further research into such developments is necessary. PMID- 26989003 TI - Meibomian gland dysfunction and tear cytokines after cataract surgery according to preoperative meibomian gland status. AB - BACKGROUND: To investigate the possible mechanisms by which cataract surgery aggravates meibomian gland dysfunction (MGD), we evaluated the changes in tear cytokines and ocular surface parameters after cataract surgery according to the preoperative MGD grade. DESIGN: Prospective, observational case series. PARTICIPANTS: A total of 50 eyes from 50 patients who underwent cataract surgery were included. METHODS: Patients were classified into two groups: Group I had no or minimal MGD, and group II had grades 2-4 MGD. Ocular surface parameters were measured, including tear film break-up time, Schirmer I test, ocular surface staining and Ocular Surface Disease Index, and tear cytokine levels were measured. MAIN OUTCOME MEASURES: The main outcomes were changes in ocular surface parameters and inflammatory tear cytokine concentrations. RESULTS: In group II, preoperative MGD grade, ocular surface staining, tear film break-up time and Ocular Surface Disease Index were worse, and mean interleukin (IL)-2, IL-6 and TNF-alpha levels were higher than those of group I. MGD and ocular surface parameters were worsened to a greater degree after surgery in group II than in group I (P < 0.050). In group II, IL-6 and TNF-alpha levels significantly increased at postoperative 1 month, and there were significant correlations between changes in ocular surface parameters and tear cytokines (IL-2, IL-6 and TNF-alpha; P < 0.050). CONCLUSIONS: The extent to which the MGD grade was aggravated following cataract surgery differed based on preoperative MGD grade. Preoperative MGD and ocular surface status should be carefully evaluated. PMID- 26989004 TI - Polydopamine-coated magnetic molecularly imprinted polymer for the selective solid-phase extraction of cinnamic acid, ferulic acid and caffeic acid from radix scrophulariae sample. AB - We describe novel cinnamic acid polydopamine-coated magnetic imprinted polymers for the simultaneous selective extraction of cinnamic acid, ferulic acid and caffeic acid from radix scrophulariae sample. The novel magnetic imprinted polymers were synthesized by surface imprinting polymerization using magnetic multi-walled carbon nanotubes as the support material, cinnamic acid as the template and dopamine as the functional monomer. The magnetic imprinted polymers were characterized by transmission electron microscopy, scanning electron microscopy, Fourier transform infrared spectroscopy and vibrating sample magnetometry. The results revealed that the magnetic imprinted polymers had outstanding magnetic properties, high adsorption capacity, selectivity and fast kinetic binding toward cinnamic acid, ferulic acid and caffeic acid. Coupled with high-performance liquid chromatography, the extraction conditions of the magnetic imprinted polymers as a magnetic solid-phase extraction sorbent were investigated in detail. The proposed imprinted magnetic solid phase extraction procedure has been used for the purification and enrichment of cinnamic acid, ferulic acid and caffeic acid successfully from radix scrophulariae extraction sample with recoveries of 92.4-115.0% for cinnamic acid, 89.4-103.0% for ferulic acid and 86.6-96.0% for caffeic acid. PMID- 26989005 TI - Trends in autopsy-verified dementia prevalence over 29 years of the Hisayama study. AB - We investigated the trends in dementia over the past 29 years in the town of Hisayama, Japan using 1266 autopsy specimens. The Hisayama study is a prospective cohort study of lifestyle-related diseases that was started in 1961. Clinical examination of dementia was started in 1985 with five detailed cross-sectional assessments conducted in 1985, 1992, 1998, 2005 and 2012. To examine the trends in dementia, we divided the 1266 autopsy samples into five groups according to the year of death: I (1986-1991, 257 cases), II (1992-1997, 268 cases), III (1998 2004, 318 cases), IV (2005-2011, 296 cases) and V (2012-2014, 127 cases). The prevalence of all-cause dementia significantly increased over time (28.4% in group I, 22.4% in group II, 32.1% in group III, 30.1% in group IV, 51.2% in group V; P for trend <0.001). A similar trend was observed for Alzheimer's disease (AD) (15.2%, 11.9%, 17.3%, 20.6% and 33.1%, respectively; P for trend <0.001). A significant increasing trend was observed in both men and women. A rapid increase in senile dementia of the NFT type (SD-NFT) in recent years was notable. Vascular dementia was the most common type of dementia in men prior to 2004; however, its prevalence decreased over time. Our study revealed that tauopathies, including AD and SD-NFT, significantly increased in the aged Japanese population over the course of this study. The neuritic plaque pathology of AD was associated with metabolic disorders such as insulin resistance and abnormal lipid metabolism, whereas the risk factors for tau pathology remain unclear. Although aging is considered one of the important risk factors accelerating tau pathology, there could be other risk factors associated with lifestyle diseases. PMID- 26989006 TI - [What do we know about perinatal sexuality? A scoping review on sexoperinatality Part 2]. AB - The intimate and sexual dimension of future and new parenting couples' relationship is the most affected and the most vulnerable during the transition to parenthood. The purpose of this scoping review is to present the portrait of perinatal sexuality through 123 empirical articles published in the last 15 years. This second article in a series of two is about sexuality during labor and birth, during the postpartum, and in relation to breastfeeding. A total of 29 sexual variables were analyzed. Sexuality during the intrapartal and postnatal periods is very diversified. Some recurring items, however, can be identified: a period of non-sexuality in the first postnatal months, followed by a gradual return of sexuality from 3 to 6 months postpartum and continuing until 12 months or more. Sexuality during the intrapartum is considered taboo and couples' experiences can be at opposite ends: some couples' experiences are sensual and erotic during childbirth, while others experience birth trauma with a negative sexual impact postnatally. Sexuality during breastfeeding is also taboo with a negative impact on women's sexuality. In all of these circumstances, women's and men's sexuality are affected and a multitude of simultaneous physiological and psychological factors affect their experiences. Fluctuations in the intimate and sexual dimensions of the conjugal relationship are considered as a natural phenomenon but temporary. Sexoperinatal interventions should be part of holistic perinatal health care in order to help couples maintain a positive intimate and sexual relationship. PMID- 26989007 TI - [Assessment patient's sexuality after prolapse repair using the ElevateTM kit]. AB - OBJECTIVES: The main aim of this study is to present the impact on the sexuality of patients after prolapse repair by a vaginal approach using the ElevateTM kit. Secondary objectives include the evaluation of the quality of life and presentation of anatomical results and complications. MATERIALS AND METHODS: This is a retrospective unicentric study of 177 patients with symptomatic urogenital prolapse, repair from 2009 to 2013, using anterior and/or posterior ElevateTM kit. Assessment sexuality was performed using a validated questionnaire, the PISQ 12. Anatomical outcomes and quality of life were assessed using the classification POP-Q and questionnaires PFDI20 and PFIQ-7 respectively. RESULTS: Response to the questionnaire was 53.1 % with a mean follow-up of 29 months (8 60). Forty-six patients were sexually (49 %) active after the procedure. The average score of postoperative questionnaire PISQ-12 was 34.5/48. De novo dyspareunia rate is 10.8 %. The anatomic success rate was 90 %, the exposure rate was 2.8 % and the retraction rate was 2.2 %. No patient with de novo dyspareunia had postoperative complication. CONCLUSION: The ElevateTM kit is associated with satisfactory functional and anatomical results. De novo dyspareunia rate is "acceptable" compared to the literature data. PMID- 26989008 TI - [Axillary management in breast cancer: The French practice versus recommendations in the post-2011 era]. AB - OBJECTIVES: Today, according to St-Gallen and ASCO clinical guidelines, axillary lymph node dissection (ALND) should be avoided in patients who meet the ACOSOG Z011 criteria. In French guidelines, ALND is still recommended in case of macrometastasis in sentinel lymph node (SLN) and in case of micrometastasis without systemic treatment. We performed a survey of the French practices in the management of the axilla. MATERIAL AND METHODS: A questionnaire was sent to 454 breast surgeons between June 2014 and January 2015. Questionnaire included items about: indications of SLN biopsy, frequency of ALND in case of metastatic SLN and modality of radiotherapy in case of metastatic SLN without ALND. RESULTS: A total of 169 surgeons (37%) answer the questionnaire. Twenty-one percent of surgeons avoid ALND in case of macrometastasis. Thirty-two percent do not perform extemporaneous examination of SLN. Only 8.4% of practionners performed a SLN biopsy after neoadjuvant chemotherapy. Fourteen percent performed a SLN biopsy in case of multicentric tumors, while it is not recommended. In case of positive SLN without ALND completion, radiotherapy does not change in 34% while irradiation fields are expanded in 44%. CONCLUSIONS: Significant unconformities are observed towards national recommendations. The divergence between French and international guidelines leads to heterogeneous surgical practices. PMID- 26989011 TI - Analysis of health promotion and prevention financing mechanisms in Thailand. AB - In the transition to the post-2015 agenda, many countries are striving towards universal health coverage (UHC). Achieving this, governments need to shift from curative care to promotion and prevention services. This research analyses Thailand's financing system for health promotion and prevention, and assesses policy options for health financing reforms. The study employed a mixed-methods approach and integrates multiple sources of evidence, including scientific and grey literature, expenditure data, and semi-structured interviews with key stakeholders in Thailand. The analysis was underpinned by the use of a well-known health financing framework. In Thailand, three agencies plus local governments share major funding roles for health promotion and prevention services: the Ministry of Public Health (MOPH), the National Health Security Office, the Thai Health Promotion Foundation and Tambon Health Insurance Funds. The total expenditure on prevention and public health in 2010 was 10.8% of the total health expenditure, greater than many middle-income countries that average 7.0-9.2%. MOPH was the largest contributor at 32.9%, the Universal Coverage scheme was the second at 23.1%, followed by the local governments and ThaiHealth at 22.8 and 7.3%, respectively. Thailand's health financing system for promotion and prevention is strategic and innovative due to the three complementary mechanisms in operation. There are several methodological limitations to determine the adequate level of spending. The health financing reforms in Thailand could usefully inform policymakers on ways to increase spending on promotion and prevention. Further comparative policy research is needed to generate evidence to support efforts towards UHC. PMID- 26989010 TI - Endothelial AMPK activation induces mitochondrial biogenesis and stress adaptation via eNOS-dependent mTORC1 signaling. AB - Metabolic stress sensors like AMP-activated protein kinase (AMPK) are known to confer stress adaptation and promote longevity in lower organisms. This study demonstrates that activating the metabolic stress sensor AMP-activated protein kinase (AMPK) in endothelial cells helps maintain normal cellular function by promoting mitochondrial biogenesis and stress adaptation. To better define the mechanisms whereby AMPK promotes endothelial stress resistance, we used 5 aminoimidazole-4-carboxamide riboside (AICAR) to chronically activate AMPK and observed stimulation of mitochondrial biogenesis in wild type mouse endothelium, but not in endothelium from endothelial nitric oxide synthase knockout (eNOS null) mice. Interestingly, AICAR-enhanced mitochondrial biogenesis was blocked by pretreatment with the mammalian target of rapamycin complex 1 (mTORC1) inhibitor, rapamycin. Further, AICAR stimulated mTORC1 as determined by phosphorylation of its known downstream effectors in wild type, but not eNOS-null, endothelial cells. Together these data indicate that eNOS is needed to couple AMPK activation to mTORC1 and thus promote mitochondrial biogenesis and stress adaptation in the endothelium. These data suggest a novel mechanism for mTORC1 activation that is significant for investigations in vascular dysfunction. PMID- 26989012 TI - Empowerment and the ecological determinants of health: three critical capacities for practitioners. AB - Human agency or the expression of intentionality towards some form of betterment has long occupied human imagination and creativity. The ways in which we express such aspirations are fundamentally informed by our beliefs about the nature of reality, meanings of human well-being and progress, and the ways in which our social locations shape our interests. Within Western health-promoting discourse and practice, such processes have largely been expressed through the construct of empowerment. To date, like health, much empowerment practice has been implicitly rooted in Cartesianism, has tended towards anthropocentrism and in cases where it has engaged with environmental issues, has mirrored environmentalism's focus on externalities and objectivity. These tendencies coupled with the increasing complexity of global, ecological, human well-being issues call empowerment practitioners to integrate new kinds of capacities more suited to addressing the ecological determinants of health. Drawing in part on the author's empowerment research over more than a decade, this article distinguishes between a range of epistemological perspectives underlying contemporary empowerment practices while fore-grounding the concepts of place-based agency and social-ecological resilience. These constructs in turn form the basis for three capacities considered critical for practitioners addressing human-ecological well-being. PMID- 26989013 TI - The role of neurocranial shape in defining the boundaries of an expanded Homo erectus hypodigm. AB - The main goals of this study were to evaluate the distinctiveness of Homo erectus neurocranial shape relative to other closely related species, and assess the likelihood that particular fossils were correctly attributed to H. erectus given how shape variation related to geography, time and brain size. This was accomplished through analyses of several sets of landmarks designed to maximize the fossil sample, including 24 putative H. erectus fossils. The question of taxonomic differentiation was initially assessed for the type specimen (Trinil II) and morphologically similar Sangiran fossils and subsequently for increasingly inclusive definitions of H. erectus. Results indicated that H. erectus fossils from China, Indonesia, Georgia and East Africa shared a neurocranial shape that was distinct from that of other Plio-Pleistocene Homo taxa, a pattern only partially accounted for by brain size. Early Indonesian H. erectus formed a morphological "bridge" between earlier and later populations assigned to H. erectus from Africa and Asia, respectively. These results were combined with discrete characters to create a more complete species definition for H. erectus. There were two notable exceptions to the general pattern of H. erectus uniqueness. The 0.8-1.0 Ma (millions of years ago) Daka calvaria from Ethiopia consistently grouped with mid-Pleistocene Homo, including Bodo and Kabwe, rather than African or Asian H. erectus. In addition, Daka also exhibited several traits derived for mid-Pleistocene Homo, and its scaling pattern mirrored mid-Pleistocene Homo rather than H. erectus. Daka may have belonged to an "advanced" H. erectus population close to the root of Homo heidelbergensis sensu lato (s.l.), or to an early population of H. heidelbergensis s.l.. The 1.5 Ma KNM ER 42700 specimen from Kenya exhibited a unique calvarial shape distinct from H. erectus despite the exclusion of problematic landmarks from the frontal bone. These unique aspects of shape were not present in two other subadult fossils, KNM WT 15000 and D2700. PMID- 26989014 TI - Brain, calvarium, cladistics: A new approach to an old question, who are modern humans and Neandertals? AB - The evolutionary history of the genus Homo is the focus of major research efforts in palaeoanthropology. However, the use of palaeoneurology to infer phylogenies of our genus is rare. Here we use cladistics to test the importance of the brain in differentiating and defining Neandertals and modern humans. The analysis is based on morphological data from the calvarium and endocast of Pleistocene fossils and results in a single most parsimonious cladogram. We demonstrate that the joint use of endocranial and calvarial features with cladistics provides a unique means to understand the evolution of the genus Homo. The main results of this study indicate that: (i) the endocranial features are more phylogenetically informative than the characters from the calvarium; (ii) the specific differentiation of Neandertals and modern humans is mostly supported by well known calvarial autapomorphies; (iii) the endocranial anatomy of modern humans and Neandertals show strong similarities, which appeared in the fossil record with the last common ancestor of both species; and (iv) apart from encephalisation, human endocranial anatomy changed tremendously during the end of the Middle Pleistocene. This may be linked to major cultural and technological novelties that had happened by the end of the Middle Pleistocene (e.g., expansion of the Middle Stone Age (MSA) in Africa and Mousterian in Europe). The combined study of endocranial and exocranial anatomy offers opportunities to further understand human evolution and the implication for the phylogeny of our genus. PMID- 26989015 TI - The impact of subsistence changes on humeral bilateral asymmetry in Terminal Pleistocene and Holocene Europe. AB - Analyses of upper limb bone bilateral asymmetry can shed light on manipulative behavior, sexual division of labor, and the effects of economic transitions on skeletal morphology. We compared the maximum (absolute) and directional asymmetry in humeral length, articular breadth, and cross-sectional diaphyseal geometry (CSG) in a large (n > 1200) European sample distributed among 11 archaeological periods from the Early Upper Paleolithic through the 20(th) century. Asymmetry in length and articular breadth is right-biased, but relatively small and fairly constant between temporal periods. Females show more asymmetry in length than males. This suggests a low impact of behavioral changes on asymmetry in length and breadth, but strong genetic control with probable sex linkage of asymmetry in length. Asymmetry in CSG properties is much more marked than in length and articular breadth, with sex-specific variation. In males, a major decline in asymmetry occurs between the Upper Paleolithic and Mesolithic. There is no further decline in asymmetry between the Mesolithic and Neolithic in males and only limited variation during the Holocene. In females, a major decline occurs between the Mesolithic and Neolithic, with resulting average directional asymmetry close to zero. Asymmetry among females continues to be very low in the subsequent Copper and Bronze Ages, but increases again in the Iron Age. Changes in female asymmetry result in an increase of sexual dimorphism during the early agricultural periods, followed by a decrease in the Iron Age. Sexual dimorphism again slightly declines after the Late Medieval. Our results indicate that changes in manipulative behavior were sex-specific with a probable higher impact of changes in hunting behavior on male asymmetry (e.g., shift from unimanual throwing to use of the bow-and-arrow) and food grain processing in females, specifically, use of two-handed saddle querns in the early agricultural periods and one-handed rotary querns in later agricultural periods. PMID- 26989016 TI - Reassessment of Olduvai Bed I cercopithecoids: A new biochronological and biogeographical link to the South African fossil record. AB - Fossil monkeys have long been used as important faunal elements in studies of African Plio-Pleistocene biochronology, particularly in the case of the South African karst cave sites. Cercopithecoid fossils have been known from Tanzania's Olduvai Gorge for nearly a century, with multiple taxa documented including Theropithecus oswaldi and Cercopithecoides kimeui, along with papionins and colobines less clearly attributable to species. A small number of large papionin fossils, including a partial male cranium and partial female skull, have been previously identified as an early form of Papio, but noted as distinct from extant baboons as well as other fossil Papio species. In 2013 we reviewed the Olduvai cercopithecoid material at the National Museum of Tanzania, with a particular focus on the specimens from Beds I-IV. Quantitative and qualitative comparisons of the Olduvai papionins largely confirmed previous observations, with one notable exception. The large papionin taxon from Bed I previously recognized as Papio sp. is more properly recognized as Gorgopithecus major, a taxon previously known only from South Africa. Features shared between the Olduvai specimens and G. major include relatively short and concavo-convex tubular nasals, antero-posteriorly curved upper incisor roots, downwardly curved brow ridges in the midline, and robust zygomatic arches. The recognition of G. major at Olduvai Bed I, a well-known horizon with precise radiometric dates, provides an important biochronological and biogeographical link with South African localities Kromdraai A, Swartkrans Member 1 and possibly Swartkrans Members 2-3 and Cooper's A and D. PMID- 26989017 TI - Primary bone microanatomy records developmental aspects of life history in catarrhine primates. AB - A central challenge in human origins research is to understand how evolution has shaped modern human life history. As fossilized remains of our ancestors provide the only direct evidence for life history evolution, efforts to reconstruct life history in paleontological contexts have focused on hard tissues, particularly on dental development. However, among investigators of other vertebrate groups, there is a long tradition of examining primary bone microstructure to decipher growth rates and maturational timing, based on an empirical relationship between the microanatomy of primary bone and the rate at which it is deposited. We examined ontogenetic variation in primary bone microstructure at the midshaft femur of Chlorocebus aethiops, Hylobates lar, and Pan troglodytes to test whether tissue type proportions vary in accordance with predictions based on body mass growth patterns described previously. In all taxa, younger age classes were characterized by significantly higher percent areas of fibro-lamellar and/or parallel-fibered tissues, while older age classes showed significantly higher proportions of lamellar bone. In prior experimental studies, fibro-lamellar and parallel-fibered tissue types have been associated with faster depositional rates than lamellar bone. Principal components analysis revealed differences among taxa in the timing of this transition, and in the particular tissue types observed among individuals of similar dental emergence status. Among M1 and M2 age classes, higher proportions of parallel-fibered and fibro-lamellar tissues were observed in those taxa characterized by reportedly faster body mass growth rates. Further, persistence of fibro-lamellar tissue throughout DECID, M1 and M2 age classes in chimpanzees contrasts with the pattern reported previously for modern humans. Despite the necessary limitations of our cross-sectional study design and the secondary remodeling of bone in primates, large areas of primary bone remain intact and represent a valuable and independent source of information about the evolution of growth and development in the fossil record. PMID- 26989018 TI - Comparative perspective on antemortem tooth loss in Neandertals. AB - Neandertal specimens with severe antemortem (before death) tooth loss (AMTL) are sometimes interpreted as evidence for human-like behaviors in Neandertals, such as conspecific care or cooking, although it is uncertain whether AMTL frequencies in Neandertals are similar to those in modern humans and exceed those in non human primates. This study characterizes AMTL (all tooth types) in Neandertals relative to recent human hunter-gatherers and several non-human primate taxa using binomial-normal regression models fit in a Bayesian framework to a sample of 25 Neandertals, 310 recent human hunter-gatherers, 61 chimpanzees, 38 orangutans, and 75 baboons. The probability that a tooth is lost antemortem is modeled to depend on tooth class, taxon, and estimated age at death. Neandertals have odds of AMTL above orangutans and baboons, similar to or somewhat lower than chimpanzees, and below recent humans, if we assume a human-like rate of senescence; or intermediate between chimpanzees and recent humans, if we assume a faster rate of senescence. These findings suggest that Neandertals can only be considered to have frequencies of AMTL above non-human primates if they had more rapid life histories than modern humans. Either Neandertals are not human-like in their life history or their frequency of AMTL. These interpretations are complicated, however, by the substantial inter-population variation in AMTL among recent humans, with some populations having odds of AMTL as low as in non-human primates. These results, together with theoretical considerations, suggest that only high frequencies of AMTL are diagnostic of behavior. Consequently, the behavioral implications of low frequencies of AMTL, such as those found in Neandertals, are ambiguous. Low frequencies in Neandertals could be because they had a low risk of AMTL rather than because they had high mortality from AMTL relative to an average modern human of similar age. PMID- 26989019 TI - Life history, cognition and the evolution of complex foraging niches. AB - Animal species that live in complex foraging niches have, in general, improved access to energy-rich and seasonally stable food sources. Because human food procurement is uniquely complex, we ask here which conditions may have allowed species to evolve into such complex foraging niches, and also how niche complexity is related to relative brain size. To do so, we divided niche complexity into a knowledge-learning and a motor-learning dimension. Using a sample of 78 primate and 65 carnivoran species, we found that two life-history features are consistently correlated with complex niches: slow, conservative development or provisioning of offspring over extended periods of time. Both act to buffer low energy yields during periods of learning, and may thus act as limiting factors for the evolution of complex niches. Our results further showed that the knowledge and motor dimensions of niche complexity were correlated with pace of development in primates only, and with the length of provisioning in only carnivorans. Accordingly, in primates, but not carnivorans, living in a complex foraging niche requires enhanced cognitive abilities, i.e., a large brain. The patterns in these two groups of mammals show that selection favors evolution into complex niches (in either the knowledge or motor dimension) in species that either develop more slowly or provision their young for an extended period of time. These findings help to explain how humans constructed by far the most complex niche: our ancestors managed to combine slow development (as in other primates) with systematic provisioning of immatures and even adults (as in carnivorans). This study also provides strong support for the importance of ecological factors in brain size evolution. PMID- 26989020 TI - Return rates from intertidal foraging from Blombos Cave to Pinnacle Point: Understanding early human economies. AB - The south coast of South Africa provides the earliest evidence for Middle Stone Age (MSA) coastal resource exploitation by early Homo sapiens. In coastal archaeology worldwide, there has been a debate over the general productivity of intertidal foraging, leading to studies that directly measure productivity in some regions, but there have been no such studies in South Africa. Here we present energetic return rate estimates for intertidal foraging along the southern coast of South Africa from Blombos Cave to Pinnacle Point. Foraging experiments were conducted with Khoi-San descendants of the region, and hourly caloric return rates for experienced foragers were measured on 41 days near low tide and through three seasons over two study years. On-site return rates varied as a function of sex, tidal level, marine habitat type and weather conditions. The overall energetic return rate from the entire sample (1492 kcal h(-1)) equals or exceeds intertidal returns reported from other hunter-gatherer studies, as well as measured return rates for activities as diverse as hunting mammals and plant collecting. Returns are projected to be exceptionally high (~ 3400 kcal h( 1) for men, ~ 1900 kcal h(-1) for women) under the best combination of conditions. However, because of the monthly tidal cycle, high return foraging is only possible for about 10 days per month and for only 2-3 h on those days. These experiments suggest that while intertidal resources are attractive, women and children could not have subsisted independently, nor met all their protein-lipid needs from marine resources alone, and would have required substantial additional energy and nutrients from plant gathering and/or from males contributing game. PMID- 26989021 TI - Knowledge and beliefs about nutrition and physical activity during pregnancy in women from South Auckland region, New Zealand. AB - BACKGROUND: Approximately 60% of women in South Auckland, a culturally diverse region in New Zealand, become pregnant with a high body mass index. However, little is known about these women's knowledge of nutrition and physical activity during pregnancy. AIMS: To assess knowledge of nutrition and physical activity during pregnancy, factors influencing eating habits and the willingness to participate in a nutritional intervention. MATERIALS AND METHODS: A total of 422 women completed the survey in late pregnancy between September and December 2013. Multivariable logistic regression investigated factors associated with infrequent healthy eating, adjusting for ethnicity and gestation at questionnaire completion. RESULTS: Ethnicity of participants was Maori (24.2%), Pacific (40.5%), Asian (12.8%) and European/Others (21.8%). Most (95.0%) reported receiving information about healthy eating while pregnant and 61% reported eating healthy frequently or very frequently. Forty-four point three per cent reported eating more in pregnancy; the commonest reasons were cravings and 'eating for two'. The adjusted odd ratios (aORs) indicated that the self-reported factors associated with infrequent healthy eating in this sample were Maori (aOR 17.66; 95% CI 8.49-36.77) and Pacific ethnicity (aOR 14.54; 95% CI 7.32-28.88); parity >=3 (aOR 2.09; 95%CI 1.26-3.48); obesity (aOR 2.84; 95% CI 1.35-5.97); unplanned pregnancy (aOR 1.95; 95%CI 1.18-3.22); and eating takeaways >=3 times/week (aOR 4.46; 95%CI 1.88-10.56). Of women sampled, 83.4% would likely/very likely participate in a nutritional intervention. CONCLUSION: Self-reported factors associated with infrequent healthy eating in pregnancy were identified in this sample. Our findings will assist development of a nutritional intervention for pregnant women in South Auckland. PMID- 26989022 TI - Epigenetic alterations leading to TMPRSS4 promoter hypomethylation and protein overexpression predict poor prognosis in squamous lung cancer patients. AB - Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, which highlights the need of innovative therapeutic options. Although targeted therapies can be successfully used in a subset of patients with lung adenocarcinomas (ADC), they are not appropriate for patients with squamous cell carcinomas (SCC). In addition, there is an unmet need for the identification of prognostic biomarkers that can select patients at risk of relapse in early stages. Here, we have used several cohorts of NSCLC patients to analyze the prognostic value of both protein expression and DNA promoter methylation status of the prometastatic serine protease TMPRSS4. Moreover, expression and promoter methylation was evaluated in a panel of 46 lung cancer cell lines. We have demonstrated that a high TMPRSS4 expression is an independent prognostic factor in SCC. Similarly, aberrant hypomethylation in tumors, which correlates with high TMPRSS4 expression, is an independent prognostic predictor in SCC. The inverse correlation between expression and methylation status was also observed in cell lines. In vitro studies showed that treatment of cells lacking TMPRSS4 expression with a demethylating agent significantly increased TMPRSS4 levels. In conclusion, TMPRSS4 is a novel independent prognostic biomarker regulated by epigenetic changes in SCC and a potential therapeutic target in this tumor type, where targeted therapy is still underdeveloped. PMID- 26989024 TI - Protein kinase C beta II suppresses colorectal cancer by regulating IGF-1 mediated cell survival. AB - Despite extensive efforts, cancer therapies directed at the Protein Kinase C (PKC) family of serine/threonine kinases have failed in clinical trials. These therapies have been directed at inhibiting PKC and have, in some cases, worsened disease outcome. Here we examine colon cancer patients and show not only that PKC Beta II is a tumour suppressor, but patients with low levels of this isozyme have significantly decreased disease free survival. Specifically, analysis of gene expression levels of all PKC genes in matched normal and cancer tissue samples from colon cancer patients revealed a striking down-regulation of the gene coding PKC Beta in the cancer tissue (n = 21). Tissue microarray analysis revealed a dramatic down-regulation of PKC Beta II protein levels in both the epithelial and stromal diseased tissue (n = 166). Of clinical significance, low levels of the protein in the normal tissue of patients is associated with a low (10%) 10 year survival compared with a much higher (60%) survival in patients with relatively high levels of the protein. Consistent with PKC Beta II levels protecting against colon cancer, overexpression of PKC Beta II in colon cancer cell lines reveals that PKC Beta II reverses transformation in cell based assays. Further to this, activation of PKC Beta II results in a dramatic downregulation of IGF-I-induced AKT, indicating a role for PKCs in regulating IGF-1 mediated cell survival. Thus, PKC Beta II is a tumour suppressor in colon cancer and low levels serve as a predictor for poor survival outcome. PMID- 26989025 TI - Long noncoding RNA H19 indicates a poor prognosis of colorectal cancer and promotes tumor growth by recruiting and binding to eIF4A3. AB - The overall biological role and clinical significance of long non-coding RNA H19 in colorectal cancer (CRC) remain largely unknown. Here, we firstly report that the lncRNA H19 recruits eIF4A3 and promotes the CRC cell proliferation. We observed higher expression of H19 was significantly correlated with tumor differentiation and advanced TNM stage in a cohort of 83 CRC patients. Multivariate analyses revealed that expression of H19 served as an independent predictor for overall survival and disease-free survival. Further experiments revealed that overexpression of H19 promoted the proliferation of CRC cells, while depletion of H19 inhibited cell viability and induced growth arrest. Moreover, expression profile data showed that H19 upregulated a series of cell cycle genes. Using bioinformatics prediction and RNA immunoprecipitation assays, we identified eIF4A3 as an RNA-binding protein that binds to H19. We confirmed that combining eIF4A3 with H19 obstructed the recruitment of eIF4A3 to the cell cycle gene mRNA. Our results suggest that H19, as a growth regulator, could serve as a candidate prognostic biomarker and target for new therapies in human CRC. PMID- 26989026 TI - SMAD7 loci contribute to risk of hepatocellular carcinoma and clinicopathologic development among Chinese Han population. AB - Genome-wide association studies (GWAS) have identified three loci at 18q21 (rs4939827, rs7240004, and rs7229639), which maps to SMAD7 loci, were associated with risk of diseases of the digestive system. However, their associations with hepatocellular carcinoma (HCC) risk remain unknown. A case-control study was conducted to assess genetic associations with HCC risk and clinicopathologic development among Chinese Han population. Three SNPs were genotyped among 1,000 HCC cases and 1,000 controls using Sequenom Mass-ARRAY technology. We observed statistically significant associations for the three SMAD7 loci and HCC risk. Each copy of minor allele was associated with a 1.24-1.36 fold increased risk of HCC. We also found that significant differences were observed between rs4939827 and clinical TNM stage and vascular invasion, as well as rs7240004 and vascular invasion. We also established a genetic risk score (GRS) by summing the risk alleles. The GRS was significantly associated with increased risk of HCC and vascular invasion. Our data revealed the SMAD7 loci is associated with HCC susceptibility and its clinicopathologic development. PMID- 26989028 TI - Metabolic Syndrome and Deep Vein Thrombosis After Total Knee and Hip Arthroplasty. AB - BACKGROUND: Metabolic syndrome (MS), defined as obesity, hypertension, hyperglycemia, and dyslipidemia, is prevalent among patients undergoing total joint arthroplasty (TJA). MS has proven to promote a proinflammatory and prothrombotic state in patients. Venous thromboembolism is one of the major complications of TJA. The purpose of this retrospective study is to identify whether MS and its components increase the risk of deep vein thrombosis (DVT) after TJA. METHODS: We retrospectively reviewed 1553 patients undergoing primary unilateral TJA from 2007 to 2014. MS was diagnosed based on the World Health Organization criteria. All subjects received venography after operation to screen for DVT. Symptomatic DVT events after TJA were also recorded. Univariate analysis and multivariate logistic regression analysis were used to identify the association of MS and its components with postoperative DVT. RESULTS: The prevalence of MS in patients undergoing TJA was 5.1% (n = 79). A total of 335 patients (21.6%) were diagnosed with DVT by venography. Seventy-eight patients (5.0%) developed symptomatic DVT. In the total knee arthroplasty group, MS and obesity were related to postoperative DVT. MS alone was found to be associated with symptomatic DVT. In the total hip arthroplasty group, MS increased the risk of symptomatic DVT. However, obesity, rather than MS, was associated with total DVT after total hip arthroplasty. CONCLUSIONS: MS was a significant risk factor for DVT after TJA. Strategies to minimize the adverse effect of MS should be considered for these patients. PMID- 26989029 TI - Bilateral Symmetrical Comparison of Femoral and Tibial Anatomic Features. AB - BACKGROUND: Variability in morphologic features of the human lower extremity within and across populations has been reported, but limb asymmetry within individuals is often overlooked. For example, in 19 studies of version of the lower extremity in the literature, 6 document asymmetry in the population, but none of these reports document asymmetry in an individual. The aim of this study was to identify the (a)symmetry and quantify variability in the tibiae and femora of matched pairs of limbs. More specifically, using a computed tomography scan database tool, we (1) identified (a)symmetry between paired left and right legs for angulation, version, and alignment features and (2) calculated the percentage of paired limbs with >1 degrees of (a)symmetry for each evaluated parameter. METHODS: Computerized axial tomographic scans (<1.0 mm slices) from bilateral lower limbs of 361 skeletally mature subjects without bone pathology were prospectively acquired. Bones were segmented and morphologic features were measured. RESULTS: Angular features are symmetric left to right, but rotational features are not, with 7 degrees of mean asymmetry in femoral anteversion (range: 0 degrees -23 degrees ) and 3 degrees of asymmetry in tibial version (range: 0 degrees -8 degrees ). CONCLUSIONS: This study disproves the hypothesis that human limbs are absolutely symmetric, confirming instead that there is asymmetry in version between left and right paired limbs. Surgeons strive for symmetry in lower extremity reconstruction, and they often compare side to side in outcome studies, believing that normal limbs are absolutely symmetric when this is not necessarily true. These assumptions concerning lower extremity symmetry need to be reassessed. PMID- 26989027 TI - Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients. AB - Approximately 45% of metastatic colorectal cancer (mCRC) patients with wild-type KRAS exon 2 are resistant to cetuximab treatment. We set out to identify additional genetic markers that might predict the response to cetuximab treatment. Fifty-three wild-type KRAS exon 2 mCRC patients were treated with cetuximab/irinotecan-based chemotherapy as a first- or third-line therapy. The mutational statuses of 10 EGFR pathway genes were analyzed in primary tumors using next-generation sequencing. BRAF, PIK3CA, KRAS (exons 3 and 4), NRAS, PTEN, and AKT1 mutations were detected in 6, 6, 5, 4, 1, and 1 patient, respectively. Four of the BRAF mutations were non-V600 variants. Four tumors harbored multiple co-existing (complex) mutations. All patients with BRAF mutations or complex mutation patterns were cetuximab non-responders. All patients but one harboring KRAS, NRAS, or BRAF mutations were non-responders. Mutations in any one of these three genes were associated with a poor response rate (7.1%) and reduced survival (PFS = 8.0 months) compared to wild-type patients (74.4% and 11.6 months). Our data suggest that KRAS, NRAS, and BRAF mutations predict response to cetuximab treatment in mCRC patients. PMID- 26989030 TI - Subcutaneous Fat Thickness Is Associated With Early Reoperation and Infection After Total Knee Arthroplasty in Morbidly Obese Patients. AB - BACKGROUND: Morbid obesity has been associated with increased complications after primary total knee arthroplasty (TKA), but previous studies have failed to take factors such as body composition and fat distribution into consideration. The aims of this study were to (1) assess the interobservable and intraobservable reliabilities of measuring anterior knee subcutaneous fat thickness on lateral knee radiographs and (2) determine if these measurements associate with early complications in patients with morbid obesity. METHODS: Using a retrospective case-control analysis, we reviewed 1689 primary TKAs performed in morbidly obese patients at our institution from 1995 to 2012. All patients (n = 58) who required reoperation for wound complication or infection within 90 days were compared to a matched cohort of morbidly obese patients who did not require early reoperation. Distances from patella skin (prepatellar thickness) and tibial tubercle skin (pretubercular thickness) were measured on routine lateral knee radiographs and associated with outcomes. RESULTS: Intraobserver and interobserver reliabilities were excellent for both measurements. Knees in the reoperation group had significantly greater prepatellar (P = .0001) and pretubercular (P = .0006) soft tissue thickness. Prepatellar thickness >=15 mm and pretubercular thickness >=25 mm increased the risk of early reoperation by 2.0* (P = .0003) and 1.6* (P = .023), respectively, and were more predictive measurements than body mass index. CONCLUSION: Anterior knee subcutaneous fat thickness can be reproducibly measured on lateral knee radiographs and is associated with a significantly increased risk of early reoperation for wound complications and infection after primary TKA in morbidly obese patients. PMID- 26989031 TI - Application of Far Cortical Locking Technology in Periprosthetic Femoral Fracture Fixation: A Biomechanical Study. AB - BACKGROUND: Lack of fracture movement could be a potential cause of periprosthetic femoral fracture (PFF) fixation failures. This study aimed to test whether the use of distal far cortical locking screws reduces the overall stiffness of PFF fixations and allows an increase in fracture movement compared to standard locking screws while retaining the overall strength of the PFF fixations. METHODS: Twelve laboratory models of Vancouver type B1 PFFs were developed. In all specimens, the proximal screw fixations were similar, whereas in 6 specimens, distal locking screws were used, and in the other six specimens, far cortical locking screws. The overall stiffness, fracture movement, and pattern of strain distribution on the plate were measured in stable and unstable fractures under anatomic 1-legged stance. Specimens with unstable fracture were loaded to failure. RESULTS: No statistical difference was found between the stiffness and fracture movement of the two groups in stable fractures. In the unstable fractures, the overall stiffness and fracture movement of the locking group was significantly higher and lower than the far cortical group, respectively. Maximum principal strain on the plate was consistently lower in the far cortical group, and there was no significant difference between the failure loads of the 2 groups. CONCLUSION: The results indicate that far cortical locking screws can reduce the overall effective stiffness of the locking plates and increase the fracture movement while maintaining the overall strength of the PFF fixation construct. However, in unstable fractures, alternative fixation methods, for example, long stem revision might be a better option. PMID- 26989033 TI - Use of volumetric laser endomicroscopy in staging multifocal superficial squamous carcinoma of the esophagus. PMID- 26989032 TI - Use of digital cholangioscopy in a dilated bile duct for detection of small symptomatic bile duct stones. PMID- 26989034 TI - EUS-guided, through-the-needle forceps: clenching down the diagnosis. PMID- 26989035 TI - Endoscopic full-thickness resection of gastric metastasis from malignant melanoma by use of a novel over-the-scope device. PMID- 26989036 TI - A novel training model composed of nonbiological materials for endoscopic submucosal dissection. PMID- 26989037 TI - Unintentional gastroduodenostomy complicating successful pancreatic necrosectomy with use of a double lumen-apposing stent. PMID- 26989038 TI - Endoscopic-guided transgastric stapled stricturoplasty. PMID- 26989039 TI - Over-the-scope clip-assisted endoscopic resection of a gastric submucosal nodule. PMID- 26989040 TI - New digital cholangioscopy-guided removal of a transpapillary plastic stent through the hepaticogastrostomy route. PMID- 26989041 TI - Successful closure of a large perforation during colorectal endoscopic submucosal dissection by application of polyglycolic acid sheets and fibrin glue. PMID- 26989043 TI - What's new in the management of complex tibial plateau fractures? AB - The management of complex tibial plateau fractures is ever evolving. The severity of the injury to the surrounding soft tissues influences the timing and the method of fixation. Minimal invasive techniques continue to dominate our philosophy of reduction and reconstruction whereas augmentation of depressed intra-articular fragments remains an accepted strategy to maintain reduction and prevent secondary collapse. Locking plates, conventional plates and fine wire fixators all have been used successfully with satisfactory outcomes. In this article we report on the latest advances made in the management of these complex injuries. PMID- 26989042 TI - Incubation of extinction responding and cue-induced reinstatement, but not context- or drug priming-induced reinstatement, after withdrawal from methamphetamine. AB - In rats trained to self-administer methamphetamine, extinction responding in the presence of drug-associated contextual and discrete cues progressively increases after withdrawal (incubation of methamphetamine craving). The conditioning factors underlying this incubation are unknown. Here, we studied incubation of methamphetamine craving under different experimental conditions to identify factors contributing to this incubation. We also determined whether the rats' response to methamphetamine priming incubates after withdrawal. We trained rats to self-administer methamphetamine in a distinct context (context A) for 14 days (6 hours/day). Lever presses were paired with a discrete light cue. We then tested groups of rats in context A or a different non-drug context (context B) after 1 day, 1 week or 1 month for extinction responding with or without the discrete cue. Subsequently, we tested the rats for reinstatement of drug seeking induced by exposure to contextual, discrete cue, or drug priming (0, 0.25 and 0.5 mg/kg). Operant responding in the extinction sessions in contexts A or B was higher after 1 week and 1 month of withdrawal than after 1 day; this effect was context-independent. Independent of the withdrawal period, operant responding in the extinction sessions was higher when responding led to contingent delivery of the discrete cue. After extinction, discrete cue-induced reinstatement, but not context- or drug priming-induced reinstatement, progressively increased after withdrawal. Together, incubation of methamphetamine craving, as assessed in extinction tests, is primarily mediated by time-dependent increases in non reinforced operant responding, and this effect is potentiated by exposure to discrete, but not contextual, cues. PMID- 26989044 TI - Concurrent sorafenib therapy extends the interval to subsequent TACE for patients with unresectable hepatocellular carcinoma. AB - BACKGROUND AND OBJECTIVES: To compare the impact of concurrent TACE + sorafenib versus TACE alone on overall survival (OS) and time to progression (TTP) in patients with unresectable hepatocellular carcinoma (uHCC). A secondary goal was to determine if sorafenib use increases the interval between courses of TACE. METHODS: This study enrolled 150 patients with uHCC from June 2011 to June 2014, including 50 treated with TACE + sorafenib and 100 treated with TACE alone. Factors associated with OS and TTP were identified by univariate and multivariate Cox-regression model analyses. Average TACE interval was defined as TTP/TACE frequency. RESULTS: The median OS (21.7 vs. 11.5 months) and TTP (10.2 vs. 6.7 months) were longer in the TACE + sorafenib group compared to the TACE group. Patients receiving combination therapy had higher survival rate (P < 0.032) and longer average interval to TACE (P < 0.001), but lower progression rate (P < 0.001). TACE + sorafenib therapy was associated with improved OS (P <= 0.009) and TTP (P <= 0.021). The majority of AEs identified in patients receiving the combination therapy were classified as Grades 1 and 2, and skin-related reactions and fatigue were the most common. CONCLUSION: Concurrent sorafenib with TACE provides survival benefits over TACE monotherapy, which may be related to a prolonged interval between subsequent TACE courses. J. Surg. Oncol. 2016;113:672 677. (c) 2016 Wiley Periodicals, Inc. PMID- 26989045 TI - A review of question prompt lists used in the oncology setting with comparison to the Patient Concerns Inventory. AB - A question prompt list (QPL) is a simple and inexpensive communication tool used to facilitate patient participation in medical consultations. The QPL is composed of a structured list of questions and has been shown to be an effective way of helping ensure patients' individual information needs are appropriately met. This intervention has been investigated in a variety of settings but not specifically head and neck cancer (HNC). The aim of this paper was to perform a narrative review of literature reporting the use of a QPL for oncology patients and to draw comparison to the Patient Concerns Inventory (PCI-HN). The databases Scopus, PubMed and MEDLINE were searched using the key terms 'question prompt list', 'question prompt sheet', 'cancer' and 'oncology'. Of 98 articles hand searched, 30 of which were found to meet all inclusion criteria, and described in a tabulated summary. The studies concluded that the QPL was an effective intervention, enabling active patient participation in medical consultations. The PCI-HN is specific for HNC and differs from many QPLs, which are more general cancer tools. The QPL approach should prove to be a useful intervention for HNC sufferers, however further research into the clinical utility is required. PMID- 26989047 TI - Lightening the burden of care in assisted reproductive technology. PMID- 26989046 TI - A Newly Designed Enterocutaneous Esophageal Fistula Model in the Pig. AB - Background Fistulas after esophagectomy are a significant cause of morbidity and mortality. Several endoscopic treatments have been attempted, with varying success. An experimental model that could validate new approaches such as cellular therapies is highly desirable. The aim of this study was to create a chronic esophageal enterocutaneous fistula model in order to study future experimental treatment options. Methods Eight pigs (six 35-kg young German and two 50-kg adult Yucatan pigs) were used. Through a left and right cervicotomy, under endoscopic view, 1 (group A, n = 6) or 2 (group B, n = 7) plastic catheters were introduced into the esophagus 30 cm from the dental arches bilaterally and left in place for 1 month. Radiologic and endoscopic fistula tract evaluations were performed at postoperative day (POD; 30) and at sacrifice (POD 45). Results Three fistulas were excluded from the study because of early (POD 5) dislodgment of the catheter, with complete fistula closure. At catheter removal (POD 30), the external orifice was larger in group B (5.2 +/- 1.1 mm vs 2.6 +/- 0.4 mm) with more severe inflammation (72% vs 33%). At POD 45, the external orifice was closed in all fistulas in group A and in 1/7 in group B. At necropsy, the fistula tract was still present in all animals. Yucatan pigs showed more complex tracts, with a high level of necrosis and substantial fibrotic infiltration. Conclusions In this article, we show a reproducible, safe, and effective technique to create an esophagocutaneous fistula model in a large experimental animal. PMID- 26989048 TI - A systematic review of inequalities in psychosocial outcomes for women with breast cancer according to residential location and Indigenous status in Australia. AB - BACKGROUND: The aim of this systematic review was to examine variations in psychosocial outcomes by residential location and Indigenous status in women diagnosed with breast cancer (BC) in Australia. METHODS: Systematic searches were undertaken using multiple databases covering articles between 1 January 1990 and 1 March 2015 focusing on adult women with BC in an Australian setting and measuring quality of life (QOL), psychological distress or psychosocial support. RESULTS: Thirteen quantitative and three qualitative articles were included. Two quantitative and one qualitative article were rated high quality, seven moderate and the remaining were low quality. No studies examining inequalities by Indigenous status were identified. Non-metropolitan women were more likely to record lower QOL relating to breast cancer-specific concerns and reported a lack of information and resources specific to their needs. Continuity of support, ongoing care and access to specialist and allied health professionals were major concerns for non-metropolitan women. Non-metropolitan women identified unmet needs in relation to travel, fear of cancer recurrence and lack of psychosocial support. CONCLUSIONS: Overall, there was a lack of evidence relating to variations in psychosocial outcomes for women with BC according to residential status or Indigenous status. While the review identified some specific concerns for non-metropolitan women with BC, it was limited by the lack of good quality studies using standardised measures. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26989049 TI - The clinical phenotype of hereditary versus sporadic prostate cancer: HPC definition revisited. AB - BACKGROUND: The definition of hereditary prostate cancer (HPC) is based on family history and age at onset. Intuitively, HPC is a serious subtype of prostate cancer but there are only limited data on the clinical phenotype of HPC. Here, we aimed to compare the prognosis of HPC to the sporadic form of prostate cancer (SPC). METHODS: HPC patients were identified through a national registry of HPC families in the Netherlands, selecting patients diagnosed from the year 2000 onward (n = 324). SPC patients were identified from the Netherlands Cancer Registry (NCR) between 2003 and 2006 for a population-based study into the genetic susceptibility of PC (n = 1,664). Detailed clinical data were collected by NCR-registrars, using a standardized registration form. Follow-up extended up to the end of 2013. Differences between the groups were evaluated by cross tabulations and tested for statistical significance while accounting for familial dependency of observations by GEE. Differences in progression-free and overall survival were evaluated using chi(2) testing with GEE in a proportional-hazards model. RESULTS: HPC patients were on average 3 years younger at diagnosis, had lower PSA values, lower Gleason scores, and more often locally confined disease. Of the HPC patients, 35% had high-risk disease (NICE-criteria) versus 51% of the SPC patients. HPC patients were less often treated with active surveillance. Kaplan-Meier 5-year progression-free survival after radical prostatectomy was comparable for HPC (78%) and SPC (74%; P = 0.30). The 5-year overall survival was 85% (95%CI 81-89%) for HPC versus 80% (95%CI 78-82%) for SPC (P = 0.03). CONCLUSIONS: HPC has a favorable clinical phenotype but patients more often underwent radical treatment. The major limitation of HPC is the absence of a genetics-based definition of HPC, which may lead to over-diagnosis of PC in men with a family history of prostate cancer. The HPC definition should, therefore, be re-evaluated, aiming at a reduction of over-diagnosis and overtreatment among men with multiple relatives diagnosed with PC. Prostate 76:897-904, 2016. (c) 2016 The Authors. The Prostate published by Wiley Periodicals, Inc. PMID- 26989050 TI - eQuIPS: eQTL Analysis Using Informed Partitioning of SNPs - A Fully Bayesian Approach. AB - We develop a Bayesian multi-SNP Markov chain Monte Carlo approach that allows published functional significance scores to objectively inform single nucleotide polymorphism (SNP) prior effect sizes in expression quantitative trait locus (eQTL) studies. We developed the Normal Gamma prior to allow the inclusion of functional information. We partition SNPs into predefined functional groups and select prior distributions that fit the group-specific observed functional significance scores. We test our method on two simulated datasets and previously analysed human eQTL data containing validated causal SNPs. In our simulations the modified Normal Gamma always performs at least as well, and generally outperforms, the other methods considered. When analysing the human eQTL data, we placed all SNPs into their actual functional group. The ranks of the four validated causal SNPs analysed using the modified Normal Gamma increase dramatically compared to those of the other methods considered. Using our new method, three of the four validated SNPs are ranked in the top 1% of SNPs and the other is in the top 2%. For the standard Normal Gamma, the best of the other methods, the four validated SNPs had ranks in the top 1%, 4%, 20% and 59%. Crucially these substantive improvements in the ranks make it highly likely that most, if not all, of these validated SNPs would have been flagged for follow-up using our new method, whereas at least two of them would certainly not have been using the current approaches. PMID- 26989052 TI - Effects of temperature and temperature-humidity index on the reproductive performance of sows during summer months under a temperate climate. AB - Heat stress is known to influence sow reproduction, but it is unknown to which extent under temperate climates. Therefore, the impact of temperature and temperature-humidity index (THI) on the reproductive performance of sows during summer months from 2009 to 2011 were studied. Reproductive parameters of 22 264 inseminations and 21 610 resulting farrowings of 22 German commercial farms were analyzed. Climatic records were available from the nearest weather station. Effects of temperature and THI at different periods of the reproductive cycle were estimated from May to September where temperatures were expected to influence climatic conditions indoors. High temperatures and THI values 5 days pre- and 14 days post-breeding reduced litter size by 0.01 to 0.03 piglets (P < 0.05). Prior to farrowing, the number of liveborn piglets was reduced (P < 0.05) and of stillborns increased with rising climatic variables (P < 0.001). On the day of farrowing, reduced numbers of weaned piglets were observed when temperature and THI values were elevated (P < 0.05), but pre-weaning mortality was not influenced (P > 0.05). In conclusion, even under temperate conditions adverse effects of climatic variables on the reproductive performance of sows are present. Thereby, the number of liveborn piglets can be considered as the most sensitive parameter to heat stress. Considering the impact of climate change and predicted heat waves, strategies to mitigate the impact of heat stress are necessary. PMID- 26989051 TI - Male breast cancer is not congruent with the female disease. AB - It has become customary to extrapolate from the results of treatment trials for female breastcancer and apply them to males with the disease. In the absence of results from national and international randomised trials for male breast cancer (MBC) this appears superficially to be an appropriate response. Closer examination of available data reveals that aspects of the aetiology and treatment of MBC do not fit the simplistic model that men usually have endocrine sensitive tumours which behave like those in postmenopausal women. Most females and males with breast cancer have none of the recognised risk factors, indicating the gaps in our knowledge of the epidemiology of this disease. Several studies have compared epidemiological risk factors for MBC and female breast cancer (FBC) but many have been blighted by small numbers. In comparison with FBC there is a larger proportion of BRCA2 tumours, (occurring in 10% of MBC), and underrepresentation of BRCA1 tumours (found in only 1%), suggesting significant differences in the genetic aetiology of MBC and FBC. Genome-wide association studies in FBC reported single nucleotide polymorphisms (SNPs) in 12 novel independent loci were consistently associated with disease but for MBC 2 SNPs had a significantly increased risk. Molecular profiles of matched cancers in males and females showed a gender-associated modulation of major processes including energy metabolism, regulation of translation, matrix remodelling and immune recruitment. Immunohistochemistry for kinase inhibitor proteins (KIPs) p27Kip1 and p21Waf1 indicate a significant difference in the immunostaining of tumours from male patients compared with females. MBC is almost always estrogen receptor positive (ER+ve) and so systemic treatment is usually endocrine. With evidence in FBC that aromatase inhibitors are more effective than tamoxifen in the postmenopausal it was seemingly logical that the same would be true for MBC. Results however suggest less efficacy with AIs and an increase in risk of mortality compared to tamoxifen. The overall survival in male breast cancer was significantly better after adjuvant treatment with tamoxifen compared to an aromatase inhibitor. These important biological differences point the way to the development of new therapies for MBC based on differences rather than similarities with FBC. PMID- 26989053 TI - Stepwise approach to curative surgery using percutaneous transhepatic cholangiodrainage and portal vein embolization for severe bile duct injury during laparoscopic cholecystectomy: a case report. AB - Laparoscopic cholecystectomy (LC) has been recently adapted to acute cholecystitis. Major bile duct injury during LC, especially Strasberg-Bismuth classification type E, can be a critical problem sometimes requiring hepatectomy. Safety and definitive treatment without further morbidities, such as posthepatectomy liver failure, is required. Here, we report a case of severe bile duct injury treated with a stepwise approach using (99m)Tc-galactosyl human serum albumin ((99m)Tc-GSA) single-photon emission computed tomography (SPECT)/CT fusion imaging to accurately estimate liver function.A 52-year-old woman diagnosed with acute cholecystitis underwent LC at another hospital and was transferred to our university hospital for persistent bile leakage on postoperative day 20. She had no jaundice or infection, although an intraperitoneal drainage tube discharged approximately 500 ml of bile per day. Recorded operation procedure showed removal of the gallbladder with a part of the common bile duct due to its misidentification, and each of the hepatic ducts and right hepatic artery was injured. Abdominal enhanced CT revealed obstructive jaundice of the left liver and arterial shunt through the hilar plate to the right liver. Magnetic resonance cholangiopancreatography revealed type E4 or more advanced bile duct injury according to the Bismuth-Strasberg classification. We planned a stepwise approach using percutaneous transhepatic cholangiodrainage (PTCD) and portal vein embolization (PVE) for secure right hemihepatectomy and biliary-jejunum reconstruction and employed (99m)Tc-GSA SPECT/CT fusion imaging to estimate future remnant liver function. The left liver function rate had changed from 26.2 % on admission to 26.3 % after PTCD and 54.5 % after PVE, while the left liver volume rate was 33.8, 33.3, and 49.6 %, respectively. The increase of liver function was higher than that of volume (28.3 vs. 15.8 %). On postoperative day 63, the curative operation, right hemihepatectomy and biliary jejunum reconstruction, was performed, and posthepatectomy liver failure could be avoided.Careful consideration of treatment strategy for each case is necessary for severe bile duct injury with arterial injury requiring hepatectomy. The stepwise approach using PTCD and PVE could enable hemihepatectomy, and (99m)Tc GSA SPECT/CT fusion imaging was useful to estimate heterogeneous liver function. PMID- 26989054 TI - JAB1 accelerates odontogenic differentiation of dental pulp stem cells. AB - Jun activation domain-binding protein 1 (JAB1) is a multifunctional protein that participates in the control of cell proliferation and the stability of multiple proteins. JAB1 regulates several key proteins, and thereby produces varied effects on cell cycle progression, genome stability and cell survival. Some studies have shown that the loss of JAB1 in osteochondral progenitor cells severely impairs embryonic limb development in mice. However, the biological significance of JAB1 activity in the odontogenic differentiation of dental pulp stem cells (DPSCs) remains unclear. This study aimed to determine the role of JAB1, a key player in tooth development, in reparative dentin formation, especially odontogenic differentiation. We found that increased expression of JAB1 promoted odontogenic differentiation of DPSCs via Wnt/beta-catenin signaling. The role of JAB1 in the odontogenic differentiation of DPSCs was further confirmed by knocking down JAB1. Our findings provide novel insights on odontogenic differentiation of DPSCs. PMID- 26989056 TI - Net Fluorescein Flux Across Corneal Endothelium Strongly Suggests Fluid Transport is due to Electro-osmosis. AB - We have presented prior evidence suggesting that fluid transport results from electro-osmosis at the intercellular junctions of the corneal endothelium. Such phenomenon ought to drag other extracellular solutes. We have investigated this using fluorescein-Na2 as an extracellular marker. We measured unidirectional fluxes across layers of cultured human corneal endothelial (HCE) cells. SV-40 transformed HCE layers were grown to confluence on permeable membrane inserts. The medium was DMEM with high glucose and no phenol red. Fluorescein-labeled medium was placed either on the basolateral or the apical side of the inserts; the other side carried unlabeled medium. The inserts were held in a CO2 incubator for 1 h (at 37 degrees C), after which the entire volume of the unlabeled side was collected. After that, label was placed on the opposite side, and the corresponding paired sample was collected after another hour. Fluorescein counts were determined with a (Photon Technology) DeltaScan fluorometer (excitation 380 nm; emission 550 nm; 2 nm bwth). Samples were read for 60 s. The cells utilized are known to transport fluid from the basolateral to the apical side, just as they do in vivo in several species. We used 4 inserts for influx and efflux (total: 20 1-h periods). We found a net flux of fluorescein from the basolateral to the apical side. The flux ratio was 1.104 +/- 0.056. That difference was statistically significant (p = 0.00006, t test, paired samples). The endothelium has a definite restriction at the junctions. Hence, an asymmetry in unidirectional fluxes cannot arise from osmosis, and can only point instead to paracellular solvent drag. We suggest, once more, that such drag is due to electro-osmotic coupling at the paracellular junctions. PMID- 26989057 TI - Efficient production and secretion of pyruvate from Halomonas sp. KM-1 under aerobic conditions. AB - The alkaliphilic, halophilic bacterium Halomonas sp. KM-1 can utilize both hexose and pentose sugars for the intracellular storage of bioplastic poly-(R)-3 hydroxybutyric acid (PHB) under aerobic conditions. In this study, we investigated the effects of the sodium nitrate concentration on PHB accumulation in the KM-1 strain. Unexpectedly, we observed the secretion of pyruvate, a central intermediate in carbon- and energy-metabolism processes in all organisms; therefore, pyruvate is widely used as a starting material in the industrial biosynthesis of pharmaceuticals and is employed for the production of crop protection agents, polymers, cosmetics, and food additives. We then further analyzed pyruvate productivity following changes in culture temperature and the buffer concentration. In 48-h batch-cultivation experiments, we found that wild type Halomonas sp. KM-1 secreted 63.3 g/L pyruvate at a rate of 1.32 g/(L.h), comparable to the results of former studies using mutant and recombinant microorganisms. Thus, these data provided important insights into the production of pyruvate using this novel strain. PMID- 26989055 TI - Airway Epithelial Cell Release of GABA is Regulated by Protein Kinase A. AB - INTRODUCTION: gamma-amino butyric acid (GABA) is not only the major inhibitory neurotransmitter in the central nervous system (CNS), but it also plays an important role in the lung, mediating airway smooth muscle relaxation and mucus production. As kinases such as protein kinase A (PKA) are known to regulate the release and reuptake of GABA in the CNS by GABA transporters, we hypothesized that beta-agonists would affect GABA release from airway epithelial cells through activation of PKA. METHODS: C57/BL6 mice received a pretreatment of a beta agonist or vehicle (PBS), followed by methacholine or PBS. Bronchoalveolar lavage (BAL) was collected and the amount of GABA was quantified using HPLC mass spectrometry. For in vitro studies, cultured BEAS-2B human airway epithelial cells were loaded with (3)H-GABA. (3)H-GABA released was measured during activation and inhibition of PKA and tyrosine kinase signaling pathways. RESULTS: beta-agonist pretreatment prior to methacholine challenge attenuated in vivo GABA release in mouse BAL and (3)H-GABA release from depolarized BEAS-2B cells. GABA release was also decreased in BEAS-2B cells by increases in cAMP but not by Epac or tyrosine kinase activation. CONCLUSION: beta-agonists decrease GABA release from airway epithelium through the activation of cAMP and PKA. This has important therapeutic implications as beta-agonists and GABA are important mediators of both mucus production and airway smooth muscle tone. PMID- 26989058 TI - Serum Leptin and Adiponectin Concentration in Type 2 Diabetes Patients in the Short and Long Term Following Biliopancreatic Diversion. AB - BACKGROUND: A deranged adipokine system is implicated in obesity and in type 2 diabetes mellitus (T2DM), and the lack of remission of T2DM after bariatric surgery could be also accounted for by the postoperative persistence of this condition. METHODS: Thirty T2DM patients undergoing biliopancreatic diversion (BPD) with a wide range of baseline body mass index (BMI) were evaluated prior to and at 1 and 5 years following BPD. Besides the usual clinical evaluations, acute insulin response (AIR) to intravenous glucose load as a parameter of insulin secretion and the serum leptin and adiponectin concentration were measured throughout the follow-up period in all patients. RESULTS: A long-term T2DM remission was observed in 21 patients (70 %). Serum leptin level reduced at the first year and remained substantially unchanged at a long term in both the remitter and non-remitter patients, while following the operation, a progressive significant increase of serum adiponectin level was observed only in remitter patients (from 9.2 to 12.3 MUg/mL at 1 year and to 15.18 MUg/mL at 5 years in the remitters and from 8.8 to 8.75 MUg/mL at 1 year and to 11.8 MUg/mL at 5 years in the non-remitters). Serum leptin mean values were positively associated with the BMI ones both prior to and following BPD (p < 0.005), while serum adiponectin values were positively related (p < 0.04) to the postoperative AIR data. CONCLUSIONS: The improvement of the pattern of cytokine production, as evidenced by postoperative rise in serum adiponectin concentration, might play a role in T2DM remission after bariatric surgery. PMID- 26989059 TI - Prevalence of Liver Fibrosis and its Association with Non-invasive Fibrosis and Metabolic Markers in Morbidly Obese Patients with Vitamin D Deficiency. AB - BACKGROUND: Morbidly obese patients are at risk for non-alcoholic fatty liver disease (NAFLD) and vitamin D deficiency (VDD). Non-alcoholic steatohepatitis (NASH) is the progressive variant of NAFLD and can advance to fibrosis, cirrhosis, and liver cancer. We aimed to examine prevalence of liver fibrosis and its non-invasive predictors in bariatric patients with VDD (<75 nmol/l). METHODS: Baseline liver biopsy of a randomized controlled trial was performed in 46 patients with omega loop gastric bypass. Clinical, laboratory, and histological data were examined and tested with univariate and multivariable analysis. RESULTS: In total, 80 % were females, aged 42 (SD 13) years with BMI 44 (4) kg/m(2). Twenty-six percent had diabetes mellitus (DM) and 44 % metabolic syndrome (MeS). Seventy-two percent had NASH, 11 % simple steatosis, and 17 % normal liver. In total, 30 % demonstrated significant fibrosis (F >= 2) with 9 % of advanced (F3) and 4 % cirrhosis (F4). Increased stages of fibrosis were primarily associated with higher levels of HOMA2-insulin resistance (IR), procollagen type I propeptide (P1NP), lower osteocalcin, albumin-corrected calcium, parathyroid hormone, vitamin D, male sex, and higher age. Other independent risk factors for advanced fibrosis were MeS (OR = 9.3 [0.99-87.5], p = 0.052) and DM (OR = 12.8 [1.2-137.4], p = 0.035). The fibrosis FIB-4 index <10.62 and NAFLD fibrosis score <-26.93 had a negative predictive value of 100 and 96 %, respectively. CONCLUSIONS: Liver fibrosis is frequent in morbidly obese patients with concurrent DM and/or MeS. Increased serum levels of IR, P1NP, lower osteocalcin, and VDD are clinically relevant predictors of fibrosis. Consequently, we suggest that patients with preoperative presence of these markers are at increased risk for liver fibrosis and should be monitored closely. PMID- 26989060 TI - Difficult Tracheal Intubation in Obese Gastric Bypass patients. AB - BACKGROUND: Endotracheal intubation is commonly perceived to be more difficult in obese patients than in lean patients. Primarily, we investigated the association between difficult tracheal intubation (DTI) and obesity, and secondarily, the association between DTI and validated scoring systems used to assess the airways, the association between DTI and quantities of anesthetics used to induce general anesthesia, and the association between DTI and difficulties with venous and arterial cannulation. METHODS: This is a monocentric prospective observational clinical study of a consecutive series of 539 obese patients undergoing gastric bypass. Tracheal intubation was done preoperatively together with scoring of Intubation Score (IS), Mallampati (MLP), and Cormack-Lehane classification (CLC) and registration of the quantities of anesthetics and total attempts on cannulation. RESULTS: The overall proportion of patients with DTI was 3.5 % and the patients with DTI were more frequently males, had higher CLC, higher American Society of Anesthesiologists physical status classification (ASA), and noticeably, a lower BMI compared to the patients with easy tracheal intubation. After adjustment with multivariable analyses body mass index (BMI) <40, CLC >2, ASA scores >2, and male gender were risk factors of DTI. Males generally had higher CLC, MLP, and ASA scores compared to females, but no difference in BMI. There was no difference in quantities of anesthetics used between the two groups with or without DTI. Intra-venous and intra-arterial cannulation was succeeded in first attempt in 85 and 86 % of the patients, respectively, and there were no association between BMI and difficult vascular access. CONCLUSIONS: We found no association between increasing BMI and DTI. PMID- 26989061 TI - The Effects of One-Anastomosis Gastric Bypass on Glucose Metabolism in Goto Kakizaki Rats. AB - BACKGROUND: The improvement in glucose metabolism after bariatric surgery is well established. The aim of this study was to investigate the hormones and glycemic control in diabetes after a one-anastomosis gastric bypass (OAGB) variant in an animal model of non-obese type 2 diabetes mellitus. METHODS: Thirty-six Goto Kakizaki rats were randomly assigned to undergo one of the following procedures: OAGB (18 rats) or sham intervention (18 rats). Each group was subdivided into three additional groups according to the time of surgery (early-12 weeks; intermediate-16 weeks; and late-20 weeks). Weight, fasting glycemia, glucose tolerance test (OGTT), and hormone levels (glucagon, insulin, glucagon-like peptide-1 [GLP-1], and glucose-dependent insulinotropic peptide [GIP]) were measured. RESULTS: All rats maintained their weight. The OGTT showed a significant improvement in glycemic levels in rats with OAGB in all time groups (p < 0.002, for all groups at 60 min). Insulin levels decreased significantly in all animals with OAGB, but glucagon levels increased (glucagon paradoxical response). GLP-1 and GIP increased in rats with OAGB at all times, but was only statistically significant in the early surgery group of GLP-1 (p < 0.005). CONCLUSION: OAGB in a non-obese diabetic rat model improves glycemic control, with a significant decrease in glucose and insulin levels. This reduction without weight loss suggests a surgically induced enhancement of pancreatic function. It appears that this improvement occurs, although the GLP-1 levels were significantly increased only in the early stages. The paradoxical response of glucagon should be further evaluated. PMID- 26989062 TI - Estimating HIV incidence among key affected populations in China from serial cross-sectional surveys in 2010-2014. AB - INTRODUCTION: HIV incidence is an important measure for monitoring the development of the epidemic, but it is difficult to ascertain. We combined serial HIV prevalence and mortality data to estimate HIV incidence among key affected populations (KAPs) in China. METHODS: Serial cross-sectional surveys were conducted among KAPs from 2010 to 2014. Trends in HIV prevalence were assessed by the Cochran-Armitage test, adjusted by risk group. HIV incidence was estimated from a mathematical model that describes the relationship between changes in HIV incidence with HIV prevalence and mortality. RESULTS: The crude HIV prevalence for the survey samples remained stable at 1.1 to 1.2% from 2010 to 2014. Among drug users (DUs), HIV prevalence declined from 4.48 to 3.29% (p<0.0001), and among men who have sex with men (MSM), HIV prevalence increased from 5.73 to 7.75% (p<0.0001). Changes in HIV prevalence among female sex workers (FSWs) and male patients of sexually transmitted disease clinics were more modest but remained statistically significant (all p<0.0001). The MSM population had the highest incidence estimates at 0.74% in 2011, 0.59% in 2012, 0.57% in 2013 and 0.53% in 2014. Estimates of the annual incidence for DUs and FSWs were very low and may not be reliable. CONCLUSIONS: Serial cross-sectional prevalence data from representative samples may be another approach to construct approximate estimates of national HIV incidence among key populations. We observed that the MSM population had the highest incidence for HIV among high-risk groups in China, and we suggest that interventions targeting MSM are urgently needed to curb the growing HIV epidemic. PMID- 26989063 TI - Spatial Variation of Pressure in the Lyophilization Product Chamber Part 2: Experimental Measurements and Implications for Scale-up and Batch Uniformity. AB - Product temperature during the primary drying step of freeze-drying is controlled by a set point chamber pressure and shelf temperature. However, recent computational modeling suggests a possible variation in local chamber pressure. The current work presents an experimental verification of the local chamber pressure gradients in a lab-scale freeze-dryer. Pressure differences between the center and the edges of a lab-scale freeze-dryer shelf were measured as a function of sublimation flux and clearance between the sublimation front and the shelf above. A modest 3-mTorr difference in pressure was observed as the sublimation flux was doubled from 0.5 to 1.0 kg.h-1.m-2 at a clearance of 2.6 cm. Further, at a constant sublimation flux of 1.0 kg.h-1.m-2, an 8-fold increase in the pressure drop was observed across the shelf as the clearance was decreased from 4 to 1.6 cm. Scale-up of the pressure variation from lab- to a manufacturing scale freeze-dryer predicted an increased uniformity in drying rates across the batch for two frequently used pharmaceutical excipients (mannitol and sucrose at 5% w/w). However, at an atypical condition of shelf temperature of +10 degrees C and chamber pressure of 50 mTorr, the product temperature in the center vials was calculated to be a degree higher than the edge vial for a low resistance product, thus reversing the typical edge and center vial behavior. Thus, the effect of local pressure variation is more significant at the manufacturing-scale than at a lab-scale and accounting for the contribution of variations in the local chamber pressures can improve success in scale-up. PMID- 26989067 TI - Quality Control of Insulins and Biosimilar Insulins: What Do We Know? PMID- 26989066 TI - Is there a role for DAZL in human female fertility? AB - The RNA binding protein deleted in azoospermia-like (Dazl) is a key determinant of germ cell maturation and entry into meiosis in rodents and other animal species. Although the complex phenotype of Dazl deficiency in both sexes, with defects at multiple stages of germ cell development and during meiosis, demonstrates its obligate significance in fertility in animal models, its involvement in human fertility is less clear. As an RNA binding protein, identification of the in vivo mRNA targets of DAZL is necessary to understand its influence. Thus far, only a small number of Dazl targets have been identified, which typically have pivotal roles in germ cell development and meiotic progression. However, it is likely that there are a number of additional germ cell and meiosis-relevant transcripts whose translation is affected in the absence of Dazl. Efforts to identify these RNA targets have mainly been focused on spermatogenesis, and restricted to mouse. In women, prophase I occurs in fetal life and it is during this period that the ovarian follicle pool is established, thus factors that have a role in determining the quality and quantity of the ovarian reserve may have significant impact on reproductive outcomes later in adult life. Here, we suggest that DAZL may be one such factor, and there is a need for greater understanding of the role of DAZL in human oogenesis and its contribution to lifelong female fertility. PMID- 26989064 TI - Epilepsy and Autism. AB - Epilepsy and autistic spectrum disorder frequently coexist in the same individual. Electroencephalogram (EEG) epileptiform activity is also present at a substantially higher rate in children with autism than normally developing children. As with epilepsy, there are a multitude of genetic and environmental factors that can result in autistic spectrum disorder. There is growing consensus from both animal and clinical studies that autism is a disorder of aberrant connectivity. As measured with functional magnetic resonance imaging (MRI) and EEG, the brain in autistic spectrum disorder may be under- or overconnected or have a mixture of over- and underconnectivity. In the case of comorbid epilepsy and autism, an imbalance of the excitatory/inhibitory (E/I) ratio in selected regions of the brain may drive overconnectivity. Understanding the mechanism by which altered connectivity in individuals with comorbid epilepsy and autistic spectrum disorder results in the behaviors specific to the autistic spectrum disorder remains a challenge. PMID- 26989068 TI - Performance of a Blood Glucose Monitoring System in a Point-of-Care Setting. AB - This study assesses and demonstrates that CONTOUR(r) XT-BGMS (CXT-BGMS) complies with the requirements of the German (RiliBAK) and Swiss (QUALAB) quality control guidelines for point-of-care testing (POCT) and fulfills the ISO15197:2013 accuracy limits criteria under the routine conditions of a hospital point-of care setting. This single-center study was conducted in Switzerland using 105 venous blood samples from hospitalized patients. Each sample was tested in comparison to the hexokinase reference method. Compliance with POCT guidelines was assessed by daily BGMS measurements using control solutions. Accuracy of CXT-BGMS according to ISO limits was 98.41%. All control measurements were within the limits defined by RiliBAK (within +/- 11% of target values and root mean square error [RMSE] within RMSE limits), and QUALAB (within +/- 10% of target values). PMID- 26989069 TI - Weak Educational Components in mHealth Devices for Diabetes Support Available on the Italian Market. PMID- 26989070 TI - Totally endoscopic robotic resection of left atrial myxoma with persistent left superior vena cava. AB - A 68-year old man with a cardiac tumour was admitted for robotic tumour resection using the da Vinci S Surgical System. While undergoing preoperative examination, he was found to have a persistent left superior vena cava. After general anaesthesia and single-lung ventilation, cardiopulmonary bypass was established, with venous drainage through bilateral internal jugular and right femoral veins and arterial return through the right femoral artery. Robotic tumour resection was performed by four ports in the right chest. There were no difficulties during the operation, and successful tumour resection was achieved with satisfactory margins. He was discharged without complications. Persistent left superior vena cava is very rare, but if diagnosed preoperatively and an appropriate operative plan is made, robotic cardiac surgery can be performed safely. With robotic surgery, cardiac tumour resection can be feasibly performed, with cosmetic benefits. PMID- 26989065 TI - Tetracycline Antibiotics and Resistance. AB - Tetracyclines possess many properties considered ideal for antibiotic drugs, including activity against Gram-positive and -negative pathogens, proven clinical safety, acceptable tolerability, and the availability of intravenous (IV) and oral formulations for most members of the class. As with all antibiotic classes, the antimicrobial activities of tetracyclines are subject to both class-specific and intrinsic antibiotic-resistance mechanisms. Since the discovery of the first tetracyclines more than 60 years ago, ongoing optimization of the core scaffold has produced tetracyclines in clinical use and development that are capable of thwarting many of these resistance mechanisms. New chemistry approaches have enabled the creation of synthetic derivatives with improved in vitro potency and in vivo efficacy, ensuring that the full potential of the class can be explored for use against current and emerging multidrug-resistant (MDR) pathogens, including carbapenem-resistant Enterobacteriaceae, MDR Acinetobacter species, and Pseudomonas aeruginosa. PMID- 26989071 TI - Lateral Acetabular Coverage Predicts the Size of the Hip Labrum. AB - BACKGROUND: Bony morphological abnormalities of the hip joint are often accompanied by adaptive soft tissue changes. These adaptive changes, if better understood and characterized, may serve to inform clinical decision making. PURPOSE: To investigate the correlation between the size of the hip labrum and lateral acetabular coverage in patients at our hip preservation clinic. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A cohort of 236 patients seen at a dedicated hip preservation service between June 2013 and June 2015 were retrospectively analyzed. Patients were grouped according to the degree of acetabular coverage, as measured by the lateral center-edge angle (LCEA): normal acetabular coverage (25 degrees -39.9 degrees ), acetabular overcoverage (>=40 degrees ), borderline dysplasia (20 degrees -24.9 degrees ), and frank dysplasia (<20 degrees ). Preoperative magnetic resonance imaging was utilized to measure the length of the labrum at 3 locations: laterally, anteriorly, and anteroinferiorly. RESULTS: Frankly dysplastic and borderline dysplastic hips exhibited larger values of labral length at all locations when compared with hips with normal acetabular coverage (P < .001) or acetabular overcoverage (P < .001). Interestingly, mean labral length values in frank dysplasia were statistically similar to corresponding measurements in borderline dysplasia. In hips with frank dysplasia, borderline dysplasia, or normal acetabular coverage, labral length was consistently greatest at the lateral labrum and correspondingly lowest at the anteroinferior labrum (P < .001). In hips with acetabular overcoverage, labral length did not vary significantly between the lateral, anterior, and anteroinferior locations. Multivariate analyses confirmed LCEA to be the strongest predictor of labral length, irrespective of measurement location. CONCLUSION: Patients with borderline dysplasia and frank dysplasia exhibited increased values of labral length in the weightbearing zone, potentially indicating a compensatory reaction to the lack of bony coverage. Labral length may serve as an instability marker and inform clinical decision making for patients with borderline dysplasia. PMID- 26989072 TI - Inside-Out Versus All-Inside Repair of Isolated Meniscal Tears: An Updated Systematic Review. AB - BACKGROUND: Meniscal tears are common in the young, active population. In this group of patients, repair is advised when possible. While inside-out repair remains the standard technique, recent advances in all-inside repair devices have led to a growth in their popularity. Previous reviews on the topic have focused on outdated implants of limited clinical relevance. PURPOSE: To determine the difference in failure rates, functional outcomes, and complications between inside-out and modern all-inside repairs. STUDY DESIGN: Systematic review. METHODS: A systematic review was registered with PROSPERO and performed following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines using the MEDLINE, EMBASE, and Cochrane databases. Inclusion criteria were (1) clinical study reporting on all-inside or inside-out repair, (2) evidence levels 1 to 4, and (3) use of modern all-inside implants for all-inside repairs. Exclusion criteria were (1) use of meniscal arrows or screws and (2) concomitant surgical procedures. Study characteristics, subjects, surgical technique, clinical outcomes, and complications were collected and analyzed. RESULTS: A total of 481 studies were screened and assessed for eligibility, which identified 27 studies for review. Studies defined clinical failure as persistent mechanical symptoms, effusion, or joint line tenderness, while anatomic failure was incomplete or no healing on MRI or second-look arthroscopy. There were no significant differences in clinical or anatomic failure rates between inside-out and all-inside repairs (clinical failure: 11% vs 10%, respectively, P = .58; anatomic failure: 13% vs 16%, respectively, P = .63). Mean +/- SD Lysholm and Tegner scores for inside-out repair were 88.0 +/- 3.5 and 5.3 +/- 1.2, while the respective scores for all-inside repair were 90.4 +/- 3.7 and 6.3 +/- 1.3. Complications occurred at a rate of 5.1% for inside-out repairs and 4.6% for all inside repairs. CONCLUSION: The quality of the evidence comparing inside-out and all-inside meniscal repair remains low, with a majority of the literature being evidence level 4 studies. In this review comparing modern all-inside devices with inside-out repair, no differences were seen in failure rates, functional outcome scores, or complication rates. PMID- 26989073 TI - Effects of different strategies of mineral supplementation (marine algae alone or combined with rumen boluses) in organic dairy systems. AB - This study was designed to evaluate the effect of marine algae supplementation alone or in combination with a regular mineral supplement (rumen boluses) to improve the mineral status in organic dairy cattle and their effect on the milk mineral composition, milk production, composition (% of fat and protein) and quality (SCC). Thirty-two Holstein Friesian lactating cows were randomly selected and assigned to the algae (A), boluses (B), algae+boluses (AB) and control group (C). For the algae groups (A, AB), a supplement composed of Sea Lettuce (80%), Japanese Wireweed (17.5%) and Furbelows (2.5%) was formulated to be given to the cows at the rate of 100 g/animal per day (A1) for the length of 4 weeks. In the second half of the experiment (weeks 5-8), the algae mixture was reformulated and the proportion of Furbelows was increased from 2.5% to 5.0% with a subsequent decrease of Lettuce to 77.5% (A2). In the boluses group (B), each cow received 2 boluses after calving. Blood (serum) and milk samples were collected at 2 and 4 week intervals, respectively, and analysed for trace element concentrations by ICP-MS. Information related to the milk composition and SCC during a 305-day lactation for each animal were obtained from the Dairy Records Management System. The supplementation with algae, boluses or the combination of both treatments showed a statistically significant effect on the iodine (algae), selenium (boluses) and cobalt (algae+boluses) status of the animals. In milk, treatments had a statistical significant increase on iodine, and a tendency to increase selenium concentrations. The assayed algae mixture combined with another source of selenium could be an effective tool to improve the mineral status in serum and milk. PMID- 26989074 TI - MicroRNA-137 inhibits tumor growth and sensitizes chemosensitivity to paclitaxel and cisplatin in lung cancer. AB - Chemotherapy resistance frequently drives tumour progression. However, the underlying molecular mechanisms are poorly characterized. In this study, we explored miR-137's role in the chemosensitivity of lung cancer. We found that the expression level of miR-137 is down-regulated in the human lung cancer tissues and the resistant cells strains: A549/paclitaxel(A549/PTX) and A549/cisplatin (A549/CDDP) when compared with lung cancer A549 cells. Moreover, we found that overe-expression of miR-137 inhibited cell proliferation, migration, cell survival and arrest the cell cycle in G1 phase in A549/PTX and A549/CDDP. Furthermore, Repression of miR-137 significantly promoted cell growth, migration, cell survival and cell cycle G1/S transition in A549 cells. We further demonstrated that the tumor suppressive role of miR-137 was mediated by negatively regulating Nuclear casein kinase and cyclin-dependent kinase substrate1(NUCKS1) protein expression. Importantly, miR-137 inhibits A549/PTX, A549/CDDP growth and angiogenesis in vivo. Our study is the first to identify the tumor suppressive role of over-expressed miR-137 in chemosensitivity. Identification of a novel miRNA-mediated pathway that regulates chemosensitivity in lung cancer will facilitate the development of novel therapeutic strategies in the future. PMID- 26989075 TI - EphA8 is a prognostic marker for epithelial ovarian cancer. AB - EphA8 is one of the Eph receptors in the Eph/ephrin receptor tyrosine kinase (RTK) subfamily. During tumorigenesis, EphA8 is involved in angiogenesis, cell adhesion and migration. In this study, we determined the mRNA and protein expression levels of EphA8 in cancerous and normal ovarian tissue samples by quantitative reverse transcription PCR (qRT-PCR) (N = 60) and tissue microarray immunohistochemistry analysis (TMA-IHC) (N = 223) respectively. EphA8 protein levels in cancer tissues were correlated with epithelial ovarian cancer (EOC) patients' clinical characteristics and overall survival. Both EphA8 mRNA and protein levels were significantly higher in EOC tissues than in normal or benign ovarian tissues (all P < 0.05). High EphA8 protein level was associated older age at diagnosis, higher FIGO stage, positive lymph nodes, presence of metastasis, positive ascitic fluid, and higher serum CA-125 level. High EphA8 protein level is an independent prognostic marker in EOC. We conclude that EphA8 acts as an oncogene in EOC development and progression. Detection of EphA8 expression could be a useful prognosis marker and targeting EphA8 represents a novel strategy for EOC treatment. PMID- 26989076 TI - beta-casein nanovehicles for oral delivery of chemotherapeutic Drug combinations overcoming P-glycoprotein-mediated multidrug resistance in human gastric cancer cells. AB - Multidrug resistance (MDR) is a primary obstacle to curative cancer therapy. We have previously demonstrated that beta-casein (beta-CN) micelles (beta-CM) can serve as nanovehicles for oral delivery and target-activated release of hydrophobic drugs in the stomach. Herein we introduce a novel nanosystem based on beta-CM, to orally deliver a synergistic combination of a chemotherapeutic drug (Paclitaxel) and a P-glycoprotein-specific transport inhibitor (Tariquidar) individually encapsulated within beta-CM, for overcoming MDR in gastric cancer. Light microscopy, dynamic light scattering and zeta potential analyses revealed solubilization of these drugs by beta-CN, suppressing drug crystallization. Spectrophotometry demonstrated high loading capacity and good encapsulation efficiency, whereas spectrofluorometry revealed high affinity of these drugs to beta-CN. In vitro cytotoxicity assays exhibited remarkable synergistic efficacy against human MDR gastric carcinoma cells with P-glycoprotein overexpression. Oral delivery of beta-CN - based nanovehicles carrying synergistic drug combinations to the stomach constitutes a novel efficacious therapeutic system that may overcome MDR in gastric cancer. PMID- 26989077 TI - MiR-448 promotes glycolytic metabolism of gastric cancer by downregulating KDM2B. AB - MicroRNAs are critical in various human cancers, including gastric cancer (GC). However, the mechanism underlying the GC development remains elusive. In this study, we demonstrate that miR-448 is increased in GC samples and cell lines. Overexpression of miR-448 facilitated the proliferation of GC cells by stimulating glycolysis. Mechanistically, we identified KDM2B, a reader for methylated CpGs, as the target of miR-448 that represses glycolysis and promotes oxidative phosphorylation. Overexpression of miR-448 reduced both the mRNA and protein levels of KDM2B, whereas KDM2B re-expression abrogated the miR-448 mediated glycolytic activities. Furthermore, we discovered Myc as a key target of KDM2B that controls metabolic switch in GC. Importantly, a cohort of 81 GC tissues revealed that miR-448 level closely associated with a battery of glycolytic genes, in which KDM2B showed the strongest anti-correlation coefficient. In addition, enhanced miR-448 level was significantly associated with poor clinical outcomes of GC patients. Hence, we identified a previously unappreciated mechanism by which miR-448 orchestrate epigenetic, transcriptional and metabolic networks to promote GC progression, suggesting the possibility of therapeutic intervention against cancer metabolic pathways. PMID- 26989079 TI - Geminin overexpression-dependent recruitment and crosstalk with mesenchymal stem cells enhance aggressiveness in triple negative breast cancers. AB - Resident mesenchymal stem cells (MSCs) promote cancer progression. However, pathways and mechanisms involved in recruiting MSCs into breast tumors remain largely undefined. Here we show that geminin-dependent acetylation releases HMGB1 from the chromatin to the cytoplasm and extracellular space. Extracellular acetylated HMGB1 (Ac-HMGB1) promotes geminin overexpressing (GemOE) cells survival by binding to RAGE and activating NF-kappaB signaling. Extracellular Ac HMGB1 also triggers expression and activation of RAGE in the non-expressing MSCs. RAGE activation induces expression of CXCR4 in MSCs and directional migration towards SDF1 (aka CXCL12)-expressing GemOE cells in vitro and in vivo. These effects augmented by the necrotic and hypoxic environment in GemOE tumors, especially within their cores. Reciprocal interactions between newly recruited MSCs and GemOE tumor cells elevate tumor-initiating (TIC), basal and epithelial to-mesenchymal transition (EMT) traits and enhance aggressiveness in vitro and in vivo in GemOE tumor cells. Indeed, faster, larger and more aggressive tumors develop when GemOE cells are co-injected with MSCs in orthotopic breast tumor model. Concurrently, inhibiting c-Abl (and thus geminin function), RAGE or CXCR4 prevented MSCs recruitment to GemOE cells in vitro and in vivo, and decreased the TIC, basal and EMT phenotypes in these tumor cells. Accordingly, we propose that GemOE tumor cells present within tumor cores represent metastatic precursors, and suppressing the GemOE->HMGB1/RAGE->SDF1/CXCR4 signaling circuit could be a valid target for therapies to inhibit GemOE tumors and their metastases. PMID- 26989081 TI - Carboxypeptidase D is the only enzyme responsible for antibody C-terminal lysine cleavage in Chinese hamster ovary (CHO) cells. AB - Heterogeneity of C-terminal lysine levels often observed in therapeutic monoclonal antibodies is believed to result from the proteolysis by endogenous carboxypeptidase(s) during cell culture production. Identifying the responsible carboxypeptidase(s) for C-terminal lysine cleavage in CHO cells would provide valuable insights for antibody production cell culture processes development and optimization. In this study, five carboxypeptidases, CpD, CpM, CpN, CpB, and CpE, were studied for message RNA (mRNA) expression by qRT-PCR analysis in two most commonly used blank hosts (DUXB-11 derived DHFR-deficient DP12 host and DHFR positive CHOK1 host), used for therapeutic antibody production, as well an antibody-expressing cell line derived from each host. Our results showed that CpD had the highest mRNA expression. When CpD mRNA levels were reduced by RNAi (RNA interference) technology, C-terminal lysine levels increased, whereas there was no obvious change in C-terminal lysine levels when a different carboxypeptidase mRNA level was knocked down suggesting that carboxypeptidase D is the main contributor for C-terminal lysine processing. Most importantly, when CpD expression was knocked out by CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology, C-terminal lysine cleavage was completely abolished in CpD knockout cells based on mass spectrometry analysis, demonstrating that CpD is the only endogenous carboxypeptidase that cleaves antibody heavy chain C-terminal lysine in CHO cells. Hence, our work showed for the first time that the cleavage of antibody heavy chain C-terminal lysine is solely mediated by the carboxypeptidase D in CHO cells and our finding provides one solution to eliminating C-terminal lysine heterogeneity for therapeutic antibody production by knocking out CpD gene expression. Biotechnol. Bioeng. 2016;113: 2100-2106. (c) 2016 Wiley Periodicals, Inc. PMID- 26989080 TI - Identification of differential PI3K pathway target dependencies in T-cell acute lymphoblastic leukemia through a large cancer cell panel screen. AB - Selective phosphoinositide 3-kinase (PI3K)/AKT/mTOR inhibitors are currently under evaluation in clinical studies. To identify tumor types that are sensitive to PI3K pathway inhibitors we screened compounds targeting PI3Kalpha/delta (AZD8835), PI3Kbeta/delta (AZD8186), AKT (AZD5363) and mTORC1/2 (AZD2014) against a cancer cell line panel (971 cell lines). There was an enrichment of hematological malignancies that were sensitive to AKT and mTOR inhibition, with the greatest degree of sensitivity observed in T-cell acute lymphoblastic leukemia (T-ALL). We found that all NOTCH mutant T-ALL cell lines were sensitive to AKT and mTORC1/2 inhibitors, with only partial sensitivity to agents that target the PI3K alpha, beta or delta isoforms. Induction of apoptosis only occurred following AKTi treatment in cell lines with PTEN protein loss and high levels of active AKT. In summary, we have demonstrated that T-ALL cell lines show differential sensitivity to inhibition at different nodes in the PI3K/AKT/mTOR pathway and inhibiting AKT or mTOR may have a therapeutic benefit in this disease setting. PMID- 26989078 TI - Quantification of mutant alleles in circulating tumor DNA can predict survival in lung cancer. AB - PURPOSE: We aimed to investigate the feasibility of droplet digital PCR (ddPCR) for the quantitative and dynamic detection of EGFR mutations and next generation sequencing (NGS) for screening EGFR-tyrosine kinase inhibitors (EGFR-TKIs) resistance-relevant mutations in circulating tumor DNA (ctDNA) from advanced lung adenocarcinoma (ADC) patients. RESULTS: Detection limit of EGFR mutation in ctDNA by ddPCR was 0.04%. Taking the EGFR mutation in tumor tissue as the golden standard, the concordance of EGFR mutations detected in ctDNA was 74% (54/73). Patients with EGFR mutation in ctDNA (n = 54) superior progression-free survival (PFS, median, 12.6 vs. 6.7 months, P < 0.001) and overall survival (OS, median, 35.6 vs. 23.8 months, P = 0.028) compared to those with EGFR wild type in ctDNA (n = 19). Patients with high EGFR-mutated abundance in ctDNA (> 5.15%) showed better PFS compared to those with low EGFR mutated abundance (<= 5.15%) (PFS, median, 15.4 vs. 11.1 months, P = 0.021). NGS results showed that 66.6% (8/12) total mutational copy number were elevated and 76.5% (26/34) mutual mutation frequency increased after disease progression. METHODS: Seventy-three advanced ADC patients with tumor tissues carrying EGFR mutations and their matched pre- and post-EGFR-TKIs plasma samples were enrolled in this study. Absolute quantities of plasma EGFR mutant and wild-type alleles were measured by ddPCR. Multi-genes testing was performed using NGS in 12 patients. CONCLUSIONS: Dynamic and quantitative analysis of EGFR mutation in ctDNA could guide personalized therapy for advanced ADC. NGS shows good performance in multiple genes testing especially novel and uncommon genes. PMID- 26989083 TI - Oxidized LDL signals through Rho-GTPase to induce endothelial cell stiffening and promote capillary formation. AB - Endothelial biomechanics is emerging as a key factor in endothelial function. Here, we address the mechanisms of endothelial stiffening induced by oxidized LDL (oxLDL) and investigate the role of oxLDL in lumen formation. We show that oxLDL induced endothelial stiffening is mediated by CD36-dependent activation of RhoA and its downstream target, Rho kinase (ROCK), via inhibition of myosin light chain phosphatase (MLCP) and myosin light-chain (MLC)2 phosphorylation. The LC MS/MS analysis identifies 7-ketocholesterol (7KC) as the major oxysterol in oxLDL. Similarly to oxLDL, 7KC induces RhoA activation, MLCP inhibition, and MLC2 phosphorylation resulting in endothelial stiffening. OxLDL also facilitates formation of endothelial branching networks in 3D collagen gels in vitro and induces increased formation of functional blood vessels in a Matrigel plug assay in vivo. Both effects are RhoA and ROCK dependent. An increase in lumen formation was also observed in response to pre-exposing the cells to 7KC, an oxysterol that induces endothelial stiffening, but not to 5alpha,6alpha epoxide that does not affect endothelial stiffness. Importantly, loading cells with cholesterol prevented oxLDL-induced RhoA activation and the downstream signaling cascade, and reversed oxLDL-induced lumen formation. In summary, we show that oxLDL-induced endothelial stiffening is mediated by the CD36/RhoA/ROCK/MLCP/MLC2 pathway and is associated with increased endothelial angiogenic activity. PMID- 26989082 TI - Both STAT3 activation and cholesterol efflux contribute to the anti-inflammatory effect of apoA-I/ABCA1 interaction in macrophages. AB - ABCA1 exports excess cholesterol from cells to apoA-I and is essential for HDL synthesis. Genetic studies have shown that ABCA1 protects against cardiovascular disease. We have previously shown that the interaction of apoA-I with ABCA1 activates signaling molecule Janus kinase 2 (JAK2), which optimizes the cholesterol efflux activity of ABCA1. ABCA1-mediated activation of JAK2 also activates signal transducer and activator of transcription 3 (STAT3), which significantly attenuates proinflammatory cytokine expression in macrophages. To determine the mechanisms of the anti-inflammatory effects of apoA-I/ABCA1 interaction, we identified two special ABCA1 mutants, one with normal STAT3 activating capacity but lacking cholesterol efflux ability and the other with normal cholesterol efflux ability but lacking STAT3-activating capacity. We showed that activation of STAT3 by the interaction of apoA-I/ABCA1 without cholesterol efflux could significantly decrease proinflammatory cytokine expression in macrophages. Mechanistic studies showed that the anti-inflammatory effect of the apoA-I/ABCA1/STAT3 pathway is suppressor of cytokine signaling 3 dependent. Moreover, we showed that apoA-I/ABCA1-mediated cholesterol efflux without STAT3 activation can also reduce proinflammatory cytokine expression in macrophages. These findings suggest that the interaction of apoA-I/ABCA1 activates cholesterol efflux and STAT3 branch pathways to synergistically suppress inflammation in macrophages. PMID- 26989084 TI - Repurposing Treprostinil for Enhancing Hematopoietic Progenitor Cell Transplantation. AB - Activation of Gs-coupled receptors enhances engraftment of hematopoietic stem and progenitor cells (HSPCs). We tested the hypothesis that treprostinil, a prostacyclin analog approved for the treatment of pulmonary hypertension, can be repurposed to improve hematopoietic stem cell transplantation. Murine and human HSPCs were isolated from bone marrow and umbilical cord blood, respectively. Prostanoid receptor agonists and the combination thereof with forskolin were tested for their capacity to stimulate [(3)H]cAMP accumulation in HSPCs. Three independent approaches were employed to verify the ability of agonist-activated HSPCs to reconstitute the bone marrow in lethally irradiated recipient mice. The underlying mechanism was explored in cellular migration assays and by blocking C X-C motif chemokine receptor 4 (CXCR4). Among several prostanoid agonists tested in combination with forskolin, treprostinil was most efficacious in raising intracellular cAMP levels in murine and human HPSCs. Injection of murine and human HSPCs, which had been pretreated with treprostinil and forskolin, enhanced survival of lethally irradiated recipient mice. Survival was further improved if recipient mice were subcutaneously administered treprostinil (0.15 mg kg(-1) 8 h( 1)) for 10 days. This regimen also reduced the number of HSPCs required to rescue lethally irradiated mice. Enhanced survival of recipient mice was causally related to treprostinil-enhanced CXCR4-dependent migration of HSPCs. Treprostinil stimulates the engraftment of human and murine hematopoietic stem cells without impairing their capacity for self-renewal. The investigated dose range corresponds to the dose approved for human use. Hence, these findings may be readily translated into a clinical application. PMID- 26989086 TI - Bioinspired monolithic polymer microsphere arrays as generically anti-adhesive surfaces. AB - Bioinspired surface topographies showing generic anti-adhesive behaviour by minimization of the real contact area not only with rigid, but also with soft and compliant counterpart surfaces recently attracted increasing attention. In the present study, we show that such generic anti-adhesive surfaces, which moreover demonstrate anti-fouling behaviour, can be produced on a large scale by a simple double replication of monolayers of microspheres with diameters of a few 10 MUm. Thus, we obtained mechanically stable monolithic arrays of microspheres tightly connected to a support of the same material. Adhesion of these microsphere arrays to sticky and compliant counterpart surfaces was one order of magnitude weaker than that of flat control samples of the same material. The generation of nanorod arrays with nanorod diameters of a few 100 nm as the second hierarchical structure level on monolithic microsphere arrays did not significantly affect the adhesion force. The experimental data on anti-adhesive behaviour were modelled using a modified Johnson-Kendall-Roberts theoretical approach that also provided general design criteria for topographic adhesion minimization to sticky counterpart surfaces. PMID- 26989085 TI - Dynamics of the spleen and its significance in a murine H22 orthotopic hepatoma model. AB - The dynamics of the spleen during tumor progression remains incompletely understood. In this study, we established a murine H22 orthotopic hepatoma model and dynamically detected alterations in the percentages of immunocytes in the spleen. We observed a prominent myeloid-derived suppressor cell (MDSC) accumulation during the early response which persisted through all the stages of tumor growth. In addition, the percentage of regulatory T cells (Tregs) increased by week 2. Although the percentage of CD3(+)CD49b(+) natural killer T (NKT) cells increased by day 3, and that of CD3(+)CD4(+) T cells slightly increased by week 1, they decreased to either normal or lower levels compared with those of normal mice. The percentages of total CD3(+), CD3(+)CD4(+), and CD3(+)CD8(+) T cells decreased by week 2, and that of NK cells decreased by week 3. The activation of non-Treg CD4(+) T cells was scarce. Moreover, splenic MDSCs of tumor-bearing mice suppressed the activation of splenocytes. Therefore, a negative immune response gradually prevailed over a positive immune response during tumor growth. In addition, splenectomy was performed at the time of tumor inoculation, and we found that splenectomy could prolong the survival time, reduce the tumor weights, decrease the ascites volumes, and ameliorate the immune status of the tumor bearing mice. Splenectomy also decreased the percentage of MDSCs and increased the percentages of CD8(+) T cells, NK, and NKT cells in tumor tissues. Additionally, splenectomy decreased the percentage of MDSCs and increased that of CD8(+) T cells in peripheral blood. Overall, our findings suggest that immune negative cells are dominant in the spleen during tumor progression. Splenectomy could be helpful to improve the immune responses of tumor-bearing hosts. PMID- 26989087 TI - Ankle Power and Endurance Outcomes Following Isolated Gastrocnemius Recession for Achilles Tendinopathy. AB - BACKGROUND: Studies have demonstrated improved ankle dorsiflexion and pain reduction following a gastrocnemius recession (GR) procedure. However, changes in muscle performance during functional activities are not known. The purpose of this study was to determine the effect of an isolated GR on ankle power and endurance in patients with Achilles tendinopathy. METHODS: Fourteen patients with chronic unilateral Achilles tendinopathy and 10 healthy controls participated in this study. Patient group data were collected 18 months following GR. Pain was compared to preoperative values using a 10-cm visual analog scale (VAS). Patient reported outcomes for activities of daily living (ADL) and sports were assessed using the Foot and Ankle Ability Measure (FAAM). Kinematic and kinetic data were collected during gait, stair ascent (standard and high step), and repetitive single-limb heel raises. Between-group and side-to-side differences in ankle plantarflexor muscle power and endurance were evaluated with appropriate t tests. RESULTS: Compared with preoperative data, VAS pain scores were reduced (pre 6.8, post 1.6, P < .05). Significant differences were observed between GR and Control groups for FAAM scores for both ADL (GR 90.0, Control 98.3, P = .01) and Sports subscales (GR 70.6, Control 94.6, P = .01). When compared to controls, ankle power was reduced in the involved limb of the GR group for all activities (all P < .05). Between-group and side-to-side deficits (GR group only) were also found for ankle endurance. CONCLUSION: The gastrocnemius recession procedure provided significant pain reduction that was maintained at the 18-month follow-up for patients with chronic Achilles tendinopathy who failed nonoperative interventions. There were good patient-reported outcomes for activities of daily living. However, compared to controls, ankle plantarflexion power and endurance deficits in the GR group were noted. The functional implications of the muscle performance deficits are unclear, but may be reflective of patients' self reported difficulty during more challenging activities. LEVEL OF EVIDENCE: Level III, comparative study. PMID- 26989090 TI - Decellularized tissues and organs: an historical perspective and prospects for the future. PMID- 26989088 TI - Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. AB - OBJECTIVE: We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype-phenotype correlations. METHODS: We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed. RESULTS: We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1 related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3' and 5' exons. Seizures in patients with mutations in exons 4-5 were more pharmacoresponsive than in patients with mutations in exons 8-15. CONCLUSIONS: SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers. PMID- 26989089 TI - AKAP2 identified as a novel gene mutated in a Chinese family with adolescent idiopathic scoliosis. AB - BACKGROUND: Adolescent idiopathic scoliosis exhibits high heritability and is one of the most common spinal deformities found in adolescent populations. However, little is known about the disease-causing genes in families with adolescent idiopathic scoliosis exhibiting Mendelian inheritance. OBJECTIVE: The aim of this study was to identify the causative gene in a family with adolescent idiopathic scoliosis. METHODS: Whole-exome sequencing was performed on this family to identify the candidate gene. Sanger sequencing was conducted to validate the candidate mutations and familial segregation. Real-time QPCR was used to measure the expression level of the possible causative gene. RESULTS: We identified the mutation c.2645A>C (p.E882A) within the AKAP2 gene, which cosegregated with the adolescent idiopathic scoliosis phenotypes. AKAP2 is located in a previously reported linkage locus (IS4) on chromosome 9q31.2-q34.2 and has been implicated in skeletal development. The mutation was absent in dbSNP144, ESP6500 and 503 ethnicity-matched controls. Real-time QPCR revealed that the mRNA expression level in the patients was increased significantly compared with the family controls (p<0.0001). CONCLUSIONS: AKAP2 was therefore implicated as a novel gene mutated in a Chinese family with adolescent idiopathic scoliosis. Further studies should be conducted to validate the results from the perspective of both the genetics and pathogenesis of this disease. PMID- 26989091 TI - Lung inflammation stalls Th17-cell migration en route to the central nervous system during the development of experimental autoimmune encephalomyelitis. AB - Recruiting pathogenic T cells to the central nervous system (CNS) is a critical step during the development of experimental autoimmune encephalomyelitis (EAE). Here, we report that the absence of autophagy and microtubule-associated protein 1A/1B-light chain 3-associated phagocytosis significantly delayed the onset of EAE in Atg7 conditional knockout (Atg7 CKO) mice in myeloid cells. T-helper cell cell priming appeared to be normal in the Atg7 CKO mice, but the mice showed significant accumulation of Th17 cells in the lung. The data suggested that the stalling of Th17 cells in the lung en route to the CNS caused the delay. The lung of Atg7 CKO mice, in which we previously demonstrated spontaneous mild inflammation, showed high expression of CCL20, a chemokine that attracts Th17 cells. We have also shown that LPS intranasal instillation delayed EAE onset, suggesting that pulmonary inflammation has an impact on EAE development. Based on our data, therapeutic immunomodulation targeted to the lung, rather than systemically, might be a possible future option to treat multiple sclerosis. PMID- 26989093 TI - Influence of baseline severity on antidepressant efficacy for anxiety disorders: meta-analysis and meta-regression. AB - BACKGROUND: Antidepressants are established first-line treatments for anxiety disorders, but it is not clear whether they are equally effective across the severity range. AIMS: To examine the influence of baseline severity of anxiety on antidepressant efficacy for generalised anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD) and panic disorder. METHOD: Fifty-six trials of second-generation antidepressants for the short-term treatment of an anxiety disorder were included. Baseline and change scores were extracted for placebo and treatment groups in each trial. Mixed effects meta-regression was used to investigate the effects of treatment group, baseline severity and their interaction. RESULTS: Increased baseline severity did not predict greater improvement in drug groups compared with placebo groups. Standardised regression coefficients of the interaction term between baseline severity and treatment group were 0.04 (95% CI 0.13 to 0.20, P = 0.65) for GAD, -0.06 (95% CI -0.20 to 0.09, P = 0.43) for SAD, 0.04 (95% CI -0.07 to 0.16, P = 0.46) for OCD, 0.16 (95% CI -0.22 to 0.53, P = 0.37) for PTSD and 0.002 (95% CI -0.10 to 0.10, P = 0.96) for panic disorder. For OCD, baseline severity did predict improvement in both placebo and drug groups equally (beta = 0.11, 95% CI 0.05 to 0.17, P = 0.001). CONCLUSIONS: No relationship between baseline severity and drug-placebo difference was found for anxiety disorders. These results suggest that if the efficacy of antidepressants is considered clinically relevant, they may be prescribed to patients with anxiety regardless of symptom severity. PMID- 26989092 TI - Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T cell-inflamed tumor microenvironment. AB - Checkpoint blockade therapy has been proven to be highly active across many cancer types but emerging evidence indicates that the therapeutic benefit is limited to a subset of patients in each cancer entity. The presence of CD8(+) T cells within the tumor microenvironment or the invasive margin of the tumor, as well as the up-regulation of PD-L1, have emerged to be the most predictive biomarkers for clinical benefit in response to checkpoint inhibition. Although the up-regulation of immune inhibitory mechanisms is one mechanism of immune escape, commonly used by T-cell-inflamed tumors, exclusion of an anti-tumor specific T-cell infiltrate displays another even more potent mechanism of immune escape. This review will contrast the mechanisms of immunogenic, T-cell-inflamed, and the novel concept of non-immunogenic, non-T-cell-inflamed, adaptive immune escape. PMID- 26989094 TI - Costs of the police service and mental healthcare pathways experienced by individuals with enduring mental health needs. AB - BACKGROUND: Substantial policy, communication and operational gaps exist between mental health services and the police for individuals with enduring mental health needs. AIMS: To map and cost pathways through mental health and police services, and to model the cost impact of implementing key policy recommendations. METHOD: Within a case-linkage study, we estimated 1-year individual-level healthcare and policing costs. Using decision modelling, we then estimated the potential impact on costs of three recommended service enhancements: street triage, Mental Health Act assessments for all Section 136 detainees and outreach custody link workers. RESULTS: Under current care, average 1-year mental health and police costs were L10 812 and L4552 per individual respectively (n = 55). The cost per police incident was L522. Models suggested that each service enhancement would alter per incident costs by between -8% and +6%. CONCLUSIONS: Recommended enhancements to care pathways only marginally increase individual-level costs. PMID- 26989095 TI - Behavioural and psychological symptoms in dementia and the challenges for family carers: systematic review. AB - BACKGROUND: Tailored psychosocial interventions can help families to manage behavioural and psychological symptoms in dementia (BPSD), but carer responses to their relative's behaviours contribute to the success of support programmes. AIMS: To understand why some family carers have difficulty in dealing with BPSD, in order to improve the quality of personalised care that is offered. METHOD: A systematic review and meta-ethnographic synthesis was conducted of high-quality quantitative and qualitative studies between 1980 and 2012. RESULTS: We identified 25 high-quality studies and two main reasons for behaviours being reported as challenging by family carers: changes in communication and relationships, resulting in 'feeling bereft'; and perceptions of transgressions against social norms associated with 'misunderstandings about behaviour' in the relative with dementia. The underlying belief that their relative had lost, or would inevitably lose, their identity to dementia was a fundamental reason why family carers experienced behaviour as challenging. CONCLUSIONS: Family carers' perceptions of BPSD as challenging are associated with a sense of a declining relationship, transgressions against social norms and underlying beliefs that people with dementia inevitably lose their 'personhood'. Interventions for the management of challenging behaviour in family settings should acknowledge unmet psychological need in family carers. PMID- 26989098 TI - Following the Francis report: investigating patient experience of mental health in-patient care. AB - BACKGROUND: The Francis report highlights perceptions of care that are affected by different factors including ward structures. AIMS: To assess patient and staff perceptions of psychiatric in-patient wards over time. METHOD: Patient and staff perceptions of in-patient psychiatric wards were assessed over 18 months. We also investigated whether the type of ward or service structure affected these perceptions. We included triage and routine care. The goal was to include at least 50% of eligible patients and staff. RESULTS: The most dramatic change was a significant deterioration in all experiences over the courseof the study. Systems of care or specific wards did not affect patient experience but staff were more dissatisfied in the triage system. CONCLUSIONS: This is the first report of deterioration in perceptions of the therapeutic in-patient environment that has been captured in a rigorous way. It may reflect contemporaneous experiences across the National Health Service of budget reductions and increased throughput. The ward systems we investigated did not improve patient experience and triage may have been detrimental to staff. PMID- 26989096 TI - New insights into the endophenotypic status of cognition in bipolar disorder: genetic modelling study of twins and siblings. AB - BACKGROUND: Twin studies have lacked statistical power to apply advanced genetic modelling techniques to the search for cognitive endophenotypes for bipolar disorder. AIMS: To quantify the shared genetic variability between bipolar disorder and cognitive measures. METHOD: Structural equation modelling was performed on cognitive data collected from 331 twins/siblings of varying genetic relatedness, disease status and concordance for bipolar disorder. RESULTS: Using a parsimonious AE model, verbal episodic and spatial working memory showed statistically significant genetic correlations with bipolar disorder (rg = |0.23| |0.27|), which lost statistical significance after covarying for affective symptoms. Using an ACE model, IQ and visual-spatial learning showed statistically significant genetic correlations with bipolar disorder (rg = |0.51|-|1.00|), which remained significant after covarying for affective symptoms. CONCLUSIONS: Verbal episodic and spatial working memory capture a modest fraction of the bipolar diathesis. IQ and visual-spatial learning may tap into genetic substrates of non-affective symptomatology in bipolar disorder. PMID- 26989099 TI - Evaluation of the validity and utility of a transdiagnostic psychosis dimension encompassing schizophrenia and bipolar disorder. AB - BACKGROUND: In recent years, the Kraepelinian dichotomy has been challenged in light of evidence on shared genetic and environmental factors for schizophrenia and bipolar disorder, but empirical efforts to identify a transdiagnostic phenotype of psychosis remain remarkably limited. AIMS: To investigate whether schizophrenia spectrum and bipolar disorder lie on a transdiagnostic spectrum with overlapping non-affective and affective psychotic symptoms. METHOD: Multidimensional item-response modelling was conducted on symptom ratings of the OPerational CRITeria (OPCRIT) system in 1168 patients with schizophrenia spectrum and bipolar disorder. RESULTS: A bifactor model with one general, transdiagnostic psychosis dimension underlying affective and non-affective psychotic symptoms and five specific dimensions of positive, negative, disorganised, manic and depressive symptoms provided the best model fit and diagnostic utility for categorical classification. CONCLUSIONS: Our findings provide support for including dimensional approaches into classification systems and a directly measurable clinical phenotype for cross-disorder investigations into shared genetic and environmental factors of psychosis. PMID- 26989097 TI - Genome-wide association study of response to cognitive-behavioural therapy in children with anxiety disorders. AB - BACKGROUND: Anxiety disorders are common, and cognitive-behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent. AIMS: To perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980). METHOD: Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up. RESULTS: No variants passed a genome-wide significance threshold (P = 5 * 10(-8)) in either analysis. Four variants met criteria for suggestive significance (P<5 * 10(-6)) in association with response post-treatment, and three variants in the 6-month follow-up analysis. CONCLUSIONS: This is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts. PMID- 26989101 TI - Asthmatics with high levels of serum surfactant protein D have more severe disease. PMID- 26989100 TI - Clinical applications of decellularized extracellular matrices for tissue engineering and regenerative medicine. AB - Decellularization is the process of removing the cellular components from tissues or organs. It is a promising technology for obtaining a biomaterial with a highly preserved extracellular matrix (ECM), which may also act as a biological scaffold for tissue engineering and regenerative therapies. Decellularized products are gaining clinical importance and market space due to their ease of standardized production, constant availability for grafting and mechanical or biochemical superiority against competing clinical options, yielding clinical results ahead of the ones with autografts in some applications. Current drawbacks and limitations of traditional treatments and clinical applications can be overcome by using decellularized or acellular matrices. Several companies are leading the market with versatile acellular products designed for diverse use in the reconstruction of tissues and organs. This review describes ECM-based decellularized and acellular products that are currently in use for different branches of clinic. PMID- 26989102 TI - Airflow obstruction is associated with increased smooth muscle extracellular matrix. PMID- 26989103 TI - A comparison of COPD patients with and without ACOS in the ECLIPSE study. PMID- 26989104 TI - Incorporating therapeutic drug monitoring into the World Health Organization hierarchy of tuberculosis diagnostics. PMID- 26989106 TI - Tidal flow variability measured by impedance pneumography relates to childhood asthma risk. AB - Lung function variability is a fundamental feature of asthma but has been difficult to quantify in children due to methodological limitations. We assessed the feasibility and clinical implications of overnight flow variability measurement at home using impedance pneumography in young children.44 children aged 3-7 years with recurrent or persistent lower airway symptoms were recruited. Patients were divided into high- or lower-risk groups (HR and LR groups) based on their risk of asthma (modified Asthma Predictive Index), and a third group was formed of children who had a history of wheeze and who were treated with inhaled corticosteroids (ICS group). Tidal volume and the derived flow were recorded through skin electrodes using impedance pneumography at home during sleep. Quantities describing overnight change in expiratory flow-volume minimum curve shape correlation (CSRmin) and respiratory chaoticity (minimum noise limit (NLmin)) were derived.Recordings were successful in 34 children. CSRmin differed between the HR and LR groups (p=0.002) and between the HR and ICS groups (p=0.003), indicating a stronger change in flow profile shape in the HR group. NLmin differed between the HR and LR groups (p=0.014), indicating momentarily lowered chaoticity in the HR group.Impedance pneumography was found feasible for quantifying nocturnal lung function variability and the measured variability was associated with risk of asthma in young children. PMID- 26989105 TI - Initial dual oral combination therapy in pulmonary arterial hypertension. AB - Treatment for pulmonary arterial hypertension (PAH) has been underpinned by single-agent therapy to which concomitant drugs are added sequentially when pre defined treatment goals are not met.This retrospective analysis of real-world clinical data in 97 patients with newly diagnosed PAH (86% in New York Heart Association functional class III-IV) explored initial dual oral combination treatment with bosentan plus sildenafil (n=61), bosentan plus tadalafil (n=17), ambrisentan plus tadalafil (n=11) or ambrisentan plus sildenafil (n=8).All regimens were associated with significant improvements in functional class, exercise capacity, dyspnoea and haemodynamic indices after 4 months of therapy. Over a median follow-up period of 30 months, 75 (82%) patients were still alive, 53 (71%) of whom received only dual oral combination therapy. Overall survival rates were 97%, 94% and 83% at 1, 2 and 3 years, respectively, and 96%, 94% and 84%, respectively, for the patients with idiopathic PAH, heritable PAH and anorexigen-induced PAH. Expected survival rates calculated from the French equation for the latter were 86%, 75% and 66% at 1, 2 and 3 years, respectively.Initial combination of oral PAH-targeted medications may offer clinical benefits, especially in PAH patients with severe haemodynamic impairment. PMID- 26989107 TI - Use of the modified Borg scale and numerical rating scale to measure chronic breathlessness: a pooled data analysis. PMID- 26989108 TI - Quantitative analysis of cation mixing and local valence states in LiNixMn2-xO4 using concurrent HARECXS and HARECES measurements. AB - Cation mixing in positive electrode materials for rechargeable lithium ion batteries, LiNixMn2-xO4 (x = 0, 0.2, 0.5) and Li0.21Ni0.7Mn1.64O4-delta (denoted as x = 0.7), is analyzed by high-angular-resolution electron-channeling X ray/electron spectroscopy (HARECXS/HARECES) techniques, using energy-dispersive X ray spectroscopy and electron energy-loss spectroscopy. Mixing between the tetrahedral lithium sites and the octahedral transition metal sites is quantified, and the site-dependent valence states of the transition metals are examined. In the non-doped (x = 0) sample, Mn was found to occupy only octahedral sites as either Mn(3+) or Mn(4+) For x = 0.2-0.7, some of the nickel ions (6-13% depending on x) occupy tetrahedral anti-sites. All the nickel ions are in the divalent state, regardless of the occupation site. For x = 0.2 and 0.7, manganese ions occupy both octahedral and tetrahedral sites; those in the octahedral sites are tetravalent, while the tetrahedral sites contain a mixture of divalent and trivalent ions. For x = 0.5, manganese occupies only the octahedral sites, with all ions determined to be in the tetravalent state (within experimental accuracy). All the samples substantially satisfied the local charge neutrality conditions. This study demonstrates the feasibility of using HARECXS/HARECES for quantitative analysis of the atomic configuration and valence states in lithium manganese oxide spinel materials. PMID- 26989109 TI - Disease activity accounts for long-term efficacy of IL-1 blockers in pyogenic sterile arthritis pyoderma gangrenosum and severe acne syndrome. AB - OBJECTIVE: To provide a rationale for anti-IL-1 treatment in pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) by defining whether IL-1beta secretion is enhanced; requires NLRP3; and correlates with proline-serine threonine phosphatase-interacting protein 1 mutations, disease activity and/or the clinical picture in PAPA. METHODS: Monocytes were isolated from 13 patients and 35 healthy donors and studied at baseline and following activation. Secretion pattern of IL-1beta, IL-1alpha, IL-1Ra, IL-6, IL-18 and TNF-alpha was assessed in supernatants by ELISA. The NLRP3 requirement for IL-1beta secretion was investigated by silencing technique in PAPA and healthy donor monocytes. Long term follow-up (mean 26 months, range 4-38) was performed in five patients enrolled in an anti-IL-1 regimen. RESULTS: IL-1beta secretion in PAPA is increased, requires NLRP3 and correlates with disease activity. Patients with a history of osteoarticular flares release more IL-1beta, IL-6 and TNF-alpha compared with those with predominant cutaneous recurrences. Monocytes from patients in anti-IL-1 treatment dramatically reduced IL-1beta secretion after ex vivo activation, and long-term follow-up demonstrated decreased frequency of flares and normalization of acute phase reactants in all the patients. A straightforward correlation between genotype and IL-1beta signalling was not observed suggesting that factors other than mutation itself may play a role in regulating IL-1beta secretion and response to treatment in PAPA. CONCLUSION: PAPA patients with active lesions display increased NLRP3-mediated IL-1beta secretion, and long-term efficacy of IL-1 blockade was demonstrated. Even if other mechanisms related to the complex proline-serine-threonine phosphatase interacting protein 1 protein networking might play additional roles, this study further supports the potential of IL-1 blockade as an effective therapeutic strategy in PAPA syndrome. PMID- 26989110 TI - Clinical and genetic features of diuretic-associated gout: a case-control study. AB - OBJECTIVE: Hyperuricaemia and gout are well-recognized complications of diuretic use. The aim of this study was to examine the clinical and genetic features of diuretic-associated gout. METHODS: Participants (n = 1365) fulfilling the 1977 ARA gout classification criteria, recruited from primary and secondary care, attended a study visit that included a detailed clinical assessment. Use of diuretic therapy was recorded during the study visit, and was confirmed by electronic dispensing data [n = 426 (31.2%) on diuretics]. Gout-associated single nucleotide polymorphisms were genotyped. Clinical and genetic features of diuretic-associated gout were analysed using a case-control study design (diuretics vs no diuretics). RESULTS: In the diuretic group there were more women, higher rates of comorbid conditions, higher BMI and lower estimated glomerular filtration rate compared with those not taking diuretics. Gout disease duration, frequency of gout flares and presence of tophi were similar in the two groups. Patients on diuretics had higher age of gout presentation and higher recorded serum urate. The ABCG2 rs2231142 risk allele was present less frequently in the diuretic group (36.1%) compared with those not on diuretics (47.6%, P = 1.2 * 10(-4)). The differences in ABCG2 were observed in both men and women with gout. CONCLUSION: Diuretic-associated gout represents a medically complex condition. Although age of gout onset is later and serum urate concentrations are higher in those on diuretics, other clinical features of gout are similar. The observed differences in the ABCG2 risk allele frequency suggest that some genetic factors play a less dominant role in diuretic-associated gout compared with primary gout. PMID- 26989112 TI - A cautionary approach to adult female groin swelling: hydrocoele of the canal of Nuck with a review of the literature. AB - Hydrocoele of the canal of Nuck in an adult female is a rare entity and analogous to hydrocoele in males. Its usual presentation is in children, and its occurrence in adults is very uncommon, more so of the hour-glass variety. We report a case of a 38-year-old woman presenting with a right inguinal swelling of 3-month duration. On physical examination, the swelling was non-tender, cystic and irreducible. There was no cough impulse. Ultrasonography and contrast-enhanced CT revealed a cystic swelling with clear contents in the right inguinal region. Surgery was performed with excision of the cyst. The histopathology report suggested flat mesothelium cells, confirming the diagnosis. PMID- 26989113 TI - Electrocardiographic clue for a mid-LAD lesion. AB - ECG is still the first diagnostic tool for coronary artery disease. It is possible to predict the localisation of affected vessel(s) through ST and T changes on ECG. Sometimes, reciprocal changes may be the only marker of acute myocardial ischaemia, as single T-wave inversion in lead aVL may represent a coronary artery lesion in the left anterior descending (LAD). A 49-year-old woman presented to the emergency department, with left-sided chest pain. Her initial ECG showed no ischaemic changes. On the third hour ECG there was T-wave inversion in leads aVL and V2, and troponin turned positive. Coronary angiography showed 90% mid-LAD occlusion. The importance of this case is that patients with ischaemic chest pain should be followed with serial ECG. Also, emergency physicians should be alert to identify new changes on ECG, as isolated T-wave inversion in lead aVL can be the only finding to take the patient into the catheterisation laboratory. PMID- 26989111 TI - Serum levels of vascular dysfunction markers reflect disease severity and stage in systemic sclerosis patients. AB - OBJECTIVE: To improve knowledge of vasculopathy in SSc through the assessment of serum levels of circulating angiogenetic and endothelial dysfunction markers in patients at different stages of the disease. METHODS: Sera from 224 subjects were obtained and concentrations of angiopoietin-2, chemokine (C-X-C motif) ligand (CXCL)-16 (CXCL16), E-selectin, soluble intercellular adhesion molecule-1, IL-8 (CXCL8), soluble vascular adhesion molecule-1 and VEGF were determined by a Luminex assay. Subjects included 43 healthy controls, 47 early SSc patients according to LeRoy and Medsger without other signs and symptoms of evolutive disease, 48 definitive SSc (defSSc) patients according to the 2013 ACR/EULAR criteria without skin or lung fibrosis, 51 lcSSc subjects and 35 dcSSc subjects. RESULTS: The four groups of patients showed well-distinct clinical and laboratory characteristics, with a linear decreasing trend in forced vital capacity and diffusing capacity for carbon monoxide % predicted values from early SSc to defSSc to lcSSc and to dcSSc, and a linear increasing trend in ESR, and in the prevalence of abnormal CRP, serum gamma globulins and lung fibrosis (all P < 0.0001). Highly significant linear trends pointing to an increase in angiopoietin 2 (P < 0.0001), CXCL16 (P < 0.0001), E-selectin (P = 0.001) and soluble intercellular adhesion molecule-1 (P = 0.002) in relation to the different disease subsets were observed. CONCLUSION: Markers characterizing vascular activation are found to be increased in SSc patients from the earliest stages of disease when clinical and laboratory findings of advanced disease cannot yet be detected. These abnormalities progress with the appraisal of the first sclerodermatous manifestation in defSSc and further increase with the onset of fibrotic manifestations. PMID- 26989114 TI - Atypical patterns of cardiac involvement in Fabry disease. AB - A 58-year-old woman was referred to our cardiology service with chest pain, exertional dyspnoea and palpitations on a background of known Fabry disease diagnosed with genetic testing in 1994. ECG showed sinus rhythm, shortened PR interval, widespread t wave inversion, q waves in the lateral leads and left ventricular hypertrophy (LVH). Coronary angiogram showed only mild atheroma. Transthoracic echocardiogram showed anterolateral LVH and reduced left ventricular cavity size in keeping with Fabry cardiomyopathy. Cardiac MRI demonstrated asymmetric hypertrophy with evidence of diffuse myocardial fibrosis in the maximally hypertrophied segments from base to apex with late gadolinium enhancement in the anterior and anteroseptal walls. This was quite an atypical appearance for Fabry cardiomyopathy. This case highlights the heterogeneity of patterns of cardiac involvement that may be associated with this rare X-linked lysosomal disorder. PMID- 26989115 TI - Isolated subglossopalatal membrane: a rare entity to encounter. PMID- 26989116 TI - Renal tubular acidosis type 4 in pregnancy. AB - We describe the clinical course of renal tubular acidosis (RTA) type 4 in pregnancy, which has not been previously published. Renal tubular acidosis type 4 is a condition associated with increased urinary ammonia secondary to hypoaldosteronism or pseudohypoaldosteronism. Pregnancy may worsen the hyperkalaemia and acidosis of renal tubular acidosis type 4, possibly through an antialdosterone effect. We advise regular monitoring of potassium and pH throughout pregnancy to ensure safe levels are maintained. PMID- 26989117 TI - Rare case of sarcoidosis presenting with pancytopenia, acute renal failure and hypercalcaemia. PMID- 26989118 TI - Is size really a contraindication for laparoscopic resection of giant adrenal myelolipomas? AB - A 55-year-old non-diabetic, normotensive man presented with dull aching pain in the left upper abdomen of 2-year duration. He had no significant medical, surgical or family history. Relevant blood tests and chest skiagram were normal. 24 h urinary vanillylmandelic acid levels and serum electrolyte levels were normal. Ultrasonogram and CT findings were suggestive of a 15 * 11 cm giant left adrenal myelolipoma. A left adrenalectomy was performed using a laparoscopic transperitoneal approach employing three ports. Pneumoperitoneum was achieved by this closed method. After successful excision, the internal contents were suctioned and the capsule was retrieved through a 2.5 cm incision. The operating time was 210 min and total blood loss 50-60 mL; no blood transfusions were needed. The patient was discharged on the third postoperative day. Histopathology confirmed an adrenal myelolipoma. The cited case is of the largest adrenal myelolipoma resected entirely using a laparoscopic approach. PMID- 26989119 TI - Enoxaparin and rivaroxaban have different effects on human mesenchymal stromal cells in the early stages of bone healing. AB - OBJECTIVES: Venous thromboembolism (VTE) is a major potential complication following orthopaedic surgery. Subcutaneously administered enoxaparin has been used as the benchmark to reduce the incidence of VTE. However, concerns have been raised regarding the long-term administration of enoxaparin and its possible negative effects on bone healing and bone density with an increase of the risk of osteoporotic fractures. New oral anticoagulants such as rivaroxaban have recently been introduced, however, there is a lack of information regarding how these drugs affect bone metabolism and post-operative bone healing. METHODS: We measured the migration and proliferation capacity of mesenchymal stem cells (MSCs) under enoxaparin or rivaroxaban treatment for three consecutive weeks, and evaluated effects on MSC mRNA expression of markers for stress and osteogenic differentiation. RESULTS: We demonstrate that enoxaparin, but not rivaroxaban, increases the migration potential of MSCs and increases their cell count in line with elevated mRNA expression of C-X-C chemokine receptor type 4 (CXCR4), tumor necrosis factor alpha (TNFalpha), and alpha-B-crystallin (CryaB). However, a decrease in early osteogenic markers (insulin-like growth factors 1 and 2 (IGF1, IGF2), bone morphogenetic protein2 (BMP2)) indicated inhibitory effects on MSC differentiation into osteoblasts caused by enoxaparin, but not by rivaroxaban. CONCLUSIONS: Our findings may explain the adverse effects of enoxaparin treatment on bone healing. Rivaroxaban has no significant impact on MSC metabolism or capacity for osteogenic differentiation in vitro.Cite this article: Dr H. Pilge. Enoxaparin and rivaroxaban have different effects on human mesenchymal stromal cells in the early stages of bone healing. Bone Joint Res 2016;5:95-100. DOI: 10.1302/2046-3758.53.2000595. PMID- 26989121 TI - Painless acute myocardial infarction on Mount Kilimanjaro. AB - An individual experiencing dyspnoea or syncope at high altitude is commonly diagnosed to have high-altitude pulmonary edema or cerebral edema. Acute myocardial infarction (AMI) is generally not considered in the differential diagnosis. There have been very rare cases of AMI reported only from Mount Everest. We report a case of painless ST segment elevation myocardial infarction (STEMI) that occurred while climbing Mount Kilimanjaro. A 51-year-old man suffered dyspnoea and loss of consciousness near the mountain peak, at about 5600 m. At a nearby hospital, he was treated as a case of high-altitude pulmonary edema. ECG was not obtained. Two days after the incident, he presented to our institution with continued symptoms of dyspnoea, light-headedness and weakness, but no pain. He was found to have inferior wall and right ventricular STEMI complicated by complete heart block. He was successfully managed with coronary angioplasty, with good recovery. PMID- 26989120 TI - Combined Assessment of Phospholipase A2 Receptor Autoantibodies and Glomerular Deposits in Membranous Nephropathy. AB - Serum phospholipase A2 receptor antibodies (SAbs) and glomerular phospholipase A2 receptor antigen (GAg) deposits have been observed in idiopathic membranous nephropathy (IMN). However, the clinical application of these two biomarkers, particularly GAg deposition, needs to be further evaluated. We measured SAb concentration by ELISA and GAg deposition by immunofluorescence in 572 patients with biopsy-proven IMN. Overall, 68.5% of patients (392 of 572) had detectable SAb (SAb+), and 98.7% of patients who were SAb+ (387 of 392) and 70.6% of patients who were SAb- (127 of 180) had GAg deposition (GAg+). Compared with patients who were SAb-/GAg+, patients who were SAb+/GAg+ exhibited higher levels of proteinuria (P<0.001) and a lower chance of proteinuria remission (P<0.001). In 52 patients who underwent repeat biopsies, patients who did not achieve remission had a higher SAb+ rate on the first biopsy than patients who went into remission (P=0.001). Furthermore, SAb+ levels persisted in patients who did not achieve remission but significantly decreased in patients who achieved remission by the second biopsy. Patients who did not achieve remission also had a higher GAg+ rate on the first biopsy than patients who achieved remission (P<0.01). Sustained GAg+ deposits correlated with disease relapse. In conclusion, combining the measurements of SAb levels and detection of GAg deposition may provide additional information regarding diagnoses, treatment response, and disease relapse in patients with IMN. PMID- 26989122 TI - In search of safe and sufficient water: a portrait of household wells in rural Guatemala. PMID- 26989124 TI - Changes between pre-crisis and crisis period in socioeconomic inequalities in health and stimulant use in Netherlands. AB - BACKGROUND: International research suggests an impact of economic crises on population health, with different effects among different socioeconomic groups. Since the end of 2008 the Netherlands experienced a period of economic crisis. Our study explores how inequalities in perceived general and mental health, and alcohol and tobacco use changed after the recession started. METHODS: We used data from the Dutch Health Interview Surveys: 2006-2008 (pre-crisis period) and 2009-2013 (crisis period). Respondents aged 25-64 were divided into socioeconomic groups based on labour status, income level and income change. Inequalities in health and stimulant use among these socioeconomic groups were described by period and changes between the pre-crisis and crisis period were investigated using logistic regression models. RESULTS: Most inequalities did not change, with some exceptions. For perceived general health, inequalities between employed persons and persons not in the labour force were larger in the crisis period (unfavourable trends for those not in the labour force). For smoking, inequalities between unemployed and employed persons were larger in the crisis period (decreasing smoking rates only for those employed), as did inequalities between persons with low and high income levels (decreasing smoking rates for those with higher income levels). Excessive drinking decreased among employed persons and persons with a decrease in income, while it remained stable among persons not in the labour force and among persons with an increase in income. CONCLUSION: The widening of some socioeconomic inequalities in health and stimulant use might suggest an enhanced vulnerability of lower socioeconomic groups to the post-2008 crisis. PMID- 26989123 TI - Associations between cancer and Parkinson's disease in U.S. elderly adults. AB - BACKGROUND: Several studies suggest that cancer is reduced before and after a Parkinson's disease (PD) diagnosis. However, determining relationships among diseases of ageing is challenging due to possible biases in ascertaining disease. This study evaluates the PD and cancer relationship, addressing potential biases. METHODS: Using Surveillance, Epidemiology, and End Results-Medicare linked data (1992-2005) of adults >= 65 years, we assessed PD risk after cancer comparing PD in 743 779 cancer patients with PD in a non-cancer group (n = 419 432) in prospective cohort analyses. We also conducted a case-control study of 836 947 cancer cases and 142 869 controls to assess cancer following PD. We applied Cox proportional hazards models to estimate hazards ratios (HRs) for PD after cancer and unconditional logistic regression to estimate odds ratios (ORs) for PD preceding cancer, controlling for physician visits and other factors. To explore biases in ascertaining cancer, we examined relationships between cancer and automobile accident injuries, which we expected to be null. RESULTS: No association was observed between cancer and subsequent PD [HR = 0.97; 95% confidence interval (CI) = 0.92-1.01] nor between cancer and subsequent automobile injuries (HR = 1.03; 95% CI = 0.98-1.07). One site, lung cancer, was associated with subsequent reduced PD, which may reflect confounding by smoking. In the case-control analysis, PD was associated with reduced subsequent cancer, overall (OR = 0.77; 95% CI = 0.71-0.82) and for several cancer sites. However, the automobile injury/ subsequent cancer association was similar (OR = 0.83; 95% CI = 0.78-0.88), suggesting a cancer detection bias after serious health outcomes. CONCLUSIONS: In totality, our data do not support a biological relationship between PD and cancer. PMID- 26989125 TI - Self-perceived health in older Europeans: Does the choice of survey matter? AB - BACKGROUND: Cross-national comparisons of health in European countries provide crucial information to monitor health and disease within and between countries and to inform policy and research priorities. However, variations in estimates might occur when information from cross-national European surveys with different characteristics are used. We compared the prevalence of very good or good self perceived health across 10 European countries according to three European surveys and investigated which survey characteristics contributed to differences in prevalence estimates. METHODS: We used aggregate data from 2004 to 2005 of respondents aged 55-64 years from the European Union Statistics on Income and Living Conditions (EU-SILC), the Survey of Health, Ageing and Retirement in Europe (SHARE) and the European Social Survey (ESS). Across the surveys, self perceived health was assessed by the same question with response options ranging from very good to very bad. RESULTS: Despite a good correlation between the surveys (intraclass correlation coefficient: 0.77), significant differences were found in prevalence estimates of very good or good self-perceived health. The survey response, sample size and survey mode contributed statistically significantly to the differences between the surveys. Multilevel linear regression analyses, adjusted for survey characteristics, showed a higher prevalence for SHARE (+6.96, 95% CIs: 3.14 to 10.8) and a lower prevalence ( 3.12; 95% CIs: -7.11 to 0.86) for ESS, with EU-SILC as the reference survey. CONCLUSION: Three important health surveys in Europe showed substantial differences for presence of very good or good self-perceived health. These differences limit the usefulness for direct comparisons across studies in health policies for Europe. PMID- 26989126 TI - Temporal distance decay of similarity of ectomycorrhizal fungal community composition in a subtropical evergreen forest in Japan. AB - Community compositions of ectomycorrhizal (ECM) fungi are known to show spatial distance decay of similarity, which arises from both deterministic niche-based processes and stochastic spatial-based processes (e.g. dispersal limitation). Recent studies have highlighted the importance of incorporating the spatial-based processes in the study of community ecology of ECM fungi. However, few studies have investigated the temporal distance decay of similarity of ECM fungal communities. More specifically, the role of stochastic temporal-based processes, which could drive the temporal distance decay of similarity independently of niche-based processes, in the temporal variation of the communities remains unclear. Here we investigated ECM fungi associated with roots of Castanopsis sieboldii at 3-month intervals over a 2-year period. We found that dissimilarity of the ECM fungal community composition was significantly correlated with temporal distance but not with environmental distance among sampling dates. Both climatic and temporal variables significantly explained the temporal variation of the community composition. These results suggest that temporal variations of ECM fungi can be affected not only by niche-based processes but also by temporal based processes. Our findings imply that priority effects may play important roles in the temporal turnover of ECM fungal community at the site. PMID- 26989129 TI - Creating clinical trial designs that incorporate clinical outcome assessments. AB - Clinical outcome assessments (COAs) are increasingly being used in determining the efficacy of new treatment regimens. This was typified in the recent use of a symptom-based instrument combined with an organ-based measure of response for the approval of ruxolitinib in myelofibrosis. There are challenges in incorporating these COAs into clinical trials, including designating the level of priority, incorporating these measures into a combined or composite endpoint, and dealing with issues related to compliance and interpretation of results accounting for missing data. This article describes the results of a recent panel discussion that attempted to address these issues and provide guidance to the incorporation of COAs into clinical trials, including novel statistical designs, so that the testing of new treatments in patients with cancers of the central nervous system can incorporate these important clinical endpoints. PMID- 26989128 TI - Clinical outcome assessment in malignant glioma trials: measuring signs, symptoms, and functional limitations. AB - The shared goal of all parties developing therapeutics against malignant gliomas is to positively impact the lives of people affected by these cancers. Clinical outcome assessment (COA) tools, including measures of patient-reported outcome, performance outcome, clinician-reported outcome, and observer-reported outcome, allow patient-focused assessments to complement traditional efficacy measures such as overall survival and radiographic endpoints. This review examines the properties of various COA measures used in malignant glioma clinical trials to date and cross references their content to the priority signs, symptoms, and functional limitations defined through a community survey conducted by the National Brain Tumor Society. The overarching goal of this initiative is to identify COA measures that are feasible and have appropriate psychometric properties for use in this patient population as well as highlight where further development is needed. PMID- 26989127 TI - Determining priority signs and symptoms for use as clinical outcomes assessments in trials including patients with malignant gliomas: Panel 1 Report. AB - Patients with primary brain tumors such as malignant gliomas are highly symptomatic, often from the time of diagnosis. Signs and symptoms (signs/symptoms) can cause functional limitations that often worsen over the disease trajectory and may impact patient quality of life. It is recognized that standard measurements of tumor response do not adequately measure this impact or the impact that a therapy may have to mitigate these signs/symptoms and potentially have clinical benefit. Identifying a core set of signs/symptoms and functional limitations is important for understanding their clinical impact and is the first step to including clinical outcomes assessment in primary brain tumor clinical trials. PMID- 26989130 TI - Report of the Jumpstarting Brain Tumor Drug Development Coalition and FDA clinical trials clinical outcome assessment endpoints workshop (October 15, 2014, Bethesda MD). AB - On October 15, 2014, a workshop was held on the use of clinical outcome assessments in clinical trials for high-grade glioma of the brain. This workshop was sponsored by the Jumpstarting Brain Tumor Drug Development Coalition, consisting of the National Brain Tumor Society, the Society for Neuro-Oncology, the Musella Foundation for Brain Tumor Research and Information, and Accelerate Brain Cancer Cure. It was planned and carried out with participation from the US Food and Drug Administration. The workshop also included stakeholders from all aspects of the brain tumor community, including clinicians, researchers, industry, clinical research organizations, patients and patient advocates, and the National Cancer Institute. This report summarizes the presentations and discussions of that workshop and the proposals that emerged to move the field forward and toward greater inclusion of these endpoints in future clinical trials for high-grade gliomas. PMID- 26989132 TI - Ca2+ is a key factor in alpha-synuclein-induced neurotoxicity. AB - Aggregation of alpha-synuclein leads to the formation of oligomeric intermediates that can interact with membranes to form pores. However, it is unknown how this leads to cell toxicity in Parkinson's disease. We investigated the species specific effects of alpha-synuclein on Ca(2+) signalling in primary neurons and astrocytes using live neuronal imaging and electrophysiology on artificial membranes. We demonstrate that alpha-synuclein induces an increase in basal intracellular Ca(2+) in its unfolded monomeric state as well as in its oligomeric state. Electrophysiology of artificial membranes demonstrated that alpha synuclein monomers induce irregular ionic currents, whereas alpha-synuclein oligomers induce rare discrete channel formation events. Despite the ability of monomeric alpha-synuclein to affect Ca(2+) signalling, it is only the oligomeric form of alpha-synuclein that induces cell death. Oligomer-induced cell death was abolished by the exclusion of extracellular Ca(2+), which prevented the alpha synuclein-induced Ca(2+) dysregulation. The findings of this study confirm that alpha-synuclein interacts with membranes to affect Ca(2+) signalling in a structure-specific manner and the oligomeric beta-sheet-rich alpha-synuclein species ultimately leads to Ca(2+) dysregulation and Ca(2+)-dependent cell death. PMID- 26989131 TI - Epiboly generates the epidermal basal monolayer and spreads the nascent mammalian skin to enclose the embryonic body. AB - Epiboly is a morphogenetic process that is employed in the surface ectoderm of anamniotes during gastrulation to cover the entire embryo. We propose here that mammals also utilise this process to expand the epidermis and enclose the body cavity and spinal cord with a protective surface covering. Our data supports a model whereby epidermal spreading is driven by the primary establishment of the epidermal basal progenitor monolayer through radial cell intercalation of a multi layered epithelium towards the basal lamina. By using a suspension organotypic culture strategy, we find that this process is fibronectin-dependent and autonomous to the skin. The radial cell rearrangements that drive epidermal spreading also require ROCK activity but are driven by cell protrusions and not myosin II contractility. Epidermal progenitor monolayer formation and epidermal spreading are delayed in Crash mice, which possess a dominant mutation in Celsr1, an orthologue of the core planar cell polarity (PCP) Drosophila protein Flamingo (also known as Stan). We observe a failure of ventral enclosure in Crash mutants suggesting that defective epidermal spreading might underlie some ventral wall birth defects. PMID- 26989133 TI - Cardiac resynchronisation therapy in the presence of left-to-right intracardiac shunting: more good than harm? AB - An elderly Chinese man with moderately impaired left ventricular function, left bundle branch block and ST-elevation myocardial infarction complicated by ventricular septal rupture had class IV heart failure symptoms refractory to medical and surgical interventions. As a treatment of last resort, a cardiac resynchronisation therapy (CRT) pacemaker was implanted apprehensively, as preoperative concerns were raised whether CRT could exacerbate left-to-right shunting, hence negating the potential benefits of CRT. Introduction of CRT significantly improved the patient's haemodynamic status and symptoms, allowing for successful discharge home. To the best of our knowledge, this is the first report of a patient with severely symptomatic acute heart failure, widened QRS and active left-to-right intracardiac shunting, treated successfully with CRT. PMID- 26989135 TI - Comments on: An Update on the Management of Pulmonary Arterial Hypertension and the Pharmacist's Role. PMID- 26989134 TI - Ebstein's anomaly of tricuspid valve with rheumatic mitral stenosis: a rare association. PMID- 26989136 TI - Presidential Address: Find Your Inner Bernie.... PMID- 26989137 TI - Mission Statement. PMID- 26989139 TI - Statutory prevention of work injuries in Italy: an effectiveness evaluation with interrupted time series analysis in a sample of 5000 manufacturing plants from the Veneto region. AB - OBJECTIVES: According to Italian law, prevention of injuries in the workplace falls under the National Health System Service of Prevention, Health and Safety at Work (SPISAL). In a sample of about 5000 industrial firms in the Veneto region (North-Eastern Italy), the study examines the impact of SPISAL safety programmes on injuries. METHODS: The study is based on the before-and-after comparison of injury rates in 795 industrial settings that were subject to SPISAL interventions and 4186 reference firms, which were all manufacturing industries with >10 employees; construction companies were excluded. The time window (2001-2007) was chosen in order to have 8 quarters of observation before and 8 after the intervention. The National Institute for Workers' Compensation provided data on injuries and plants, while SPISAL gave information on interventions carried out. The preintervention and postintervention rates of injuries were compared by means of interrupted time series analyses, estimating the rate ratio (RR) with a 95% CI. RESULTS: Inspection after injury reduced by 24% (RR=0.76; 95% CI 0.65 to 0.90; p=0.001) all injuries, and by 36% (RR=0.64; 95% CI 0.50 to 0.83; p=0.001) severe injuries (fatalities, lost workdays >30, degree of permanent disability >0). These changes occurred immediately and persisted for 2 years. The effects of programmed inspections were never significant. CONCLUSIONS: It can be presumed that, after a severe injury, the employees raised their standard of what they considered good work safety and, at the same time, the employers were pushed to improve the work environment as a result of the sudden attention from the workplace hygiene and safety authority and court authority. Inspection after injury was an effective strategy; however, confirmatory evidence is needed. PMID- 26989140 TI - Author response: 'Does cadmium exposure contribute to depressive symptoms in the elderly population?'. PMID- 26989143 TI - The Impact of Ethics Review on a Research-Led University Curriculum: Results of a Qualitative Study in Australia. AB - In the human sciences, a student research-centered pedagogy is constrained by institutional ethics review, yet there is little research on the impact of ethics review on research-led teaching. This article documents a range of ways that Australian universities are responding to ethics review of undergraduate human research. Forty teachers and administrators were interviewed at 14 universities using purposive sampling to document the range of ways teachers are avoiding ethics review or incorporating it into their curriculum. Some reported halting undergraduate research or evading ethics review, regarding it as meaningless bureaucracy divorced from actual ethical thinking. Those who incorporated ethics review into student research did so by collaborating with administrators. Institutions can facilitate research-led teaching by designing dedicated forms and decentralized review procedures for student research. PMID- 26989142 TI - Discovery and Characterization of AMPA Receptor Modulators Selective for TARP gamma8. AB - Members of the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) subtype of ionotropic glutamate receptors mediate the majority of fast synaptic transmission within the mammalian brain and spinal cord, representing attractive targets for therapeutic intervention. Here, we describe novel AMPA receptor modulators that require the presence of the accessory protein CACNG8, also known as transmembrane AMPA receptor regulatory protein gamma8 (TARP-gamma8). Using calcium flux, radioligand binding, and electrophysiological assays of wild-type and mutant forms of TARP-gamma8, we demonstrate that these compounds possess a novel mechanism of action consistent with a partial disruption of the interaction between the TARP and the pore-forming subunit of the channel. One of the molecules, 5-[2-chloro-6-(trifluoromethoxy)phenyl]-1,3-dihydrobenzimidazol-2-one (JNJ-55511118), had excellent pharmacokinetic properties and achieved high receptor occupancy following oral administration. This molecule showed strong, dose-dependent inhibition of neurotransmission within the hippocampus, and a strong anticonvulsant effect. At high levels of receptor occupancy in rodent in vivo models, JNJ-55511118 showed a strong reduction in certain bands on electroencephalogram, transient hyperlocomotion, no motor impairment on rotarod, and a mild impairment in learning and memory. JNJ-55511118 is a novel tool for reversible AMPA receptor inhibition, particularly within the hippocampus, with potential therapeutic utility as an anticonvulsant or neuroprotectant. The existence of a molecule with this mechanism of action demonstrates the possibility of pharmacological targeting of accessory proteins, increasing the potential number of druggable targets. PMID- 26989141 TI - Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac Induced Intestinal Ulcers. AB - Proton pump inhibitors such as omeprazole (OME) reduce the severity of gastrointestinal (GI) ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs) but can also increase the chance of dysbiosis. The aim of this study was to test the hypothesis that preventive use of a soluble epoxide hydrolase inhibitor (sEHI) such as TPPU can decrease NSAID-induced ulcers by increasing anti-inflammatory epoxyeicosatrienoic acids (EETs). Dose- [10, 30, and 100 mg/kg, by mouth (PO)] and time-dependent (6 and 18 hours) ulcerative effects of diclofenac sodium (DCF, an NSAID) were studied in the small intestine of Swiss Webster mice. Dose-dependent effects of TPPU (0.001-0.1 mg/kg per day for 7 days, in drinking water) were evaluated in DCF-induced intestinal toxicity and compared with OME (20 mg/kg, PO). In addition, the effect of treatment was studied on levels of Hb in blood, EETs in plasma, inflammatory markers such as myeloperoxidase (MPO) in intestinal tissue homogenates, and tissue necrosis factor-alpha (TNF-alpha) in serum. DCF dose dependently induced ulcers that were associated with both a significant (P < 0.05) loss of Hb and an increase in the level of MPO and TNF-alpha, with severity of ulceration highest at 18 hours. Pretreatment with TPPU dose dependently prevented ulcer formation by DCF, increased the levels of epoxy fatty acids, including EETs, and TPPU's efficacy was comparable to OME. TPPU significantly (P < 0.05) reversed the effect of DCF on the level of Hb, MPO, and TNF-alpha Thus sEHI might be useful in the management of NSAID-induced ulcers. PMID- 26989144 TI - Non-cirrhotic portal fibrosis at a tertiary care centre in South India. AB - BACKGROUND: Non-cirrhotic portal fibrosis (NCPF) is one of the important causes of upper gastrointestinal haemorrhage in patients in tropical countries. The aim of this study was to describe the clinical and laboratory profile of 68 patients with NCPF. MATERIAL AND METHODS: NCPF is defined as liver disease with: (1) evidence of portal hypertension; (2) a liver biopsy showing no cirrhosis or a Tc labelled sulphur colloid scan showing a pattern suggestive of NCPF; and (3) a patent splenoportal axis. The clinical, laboratory and demographic features of 68 patients with such criteria were studied and analysed. RESULTS: NCPF was common in women (73.5%) in the fourth decade of life. The median duration of illness was 24 months (range, 1 month-28 years). Patients presented to hospital with the sensation of a mass in the abdomen (50%) or with haematemesis (26.5%). They had splenomegaly (95.6%) and thrombocytopenia (88.2%). The majority of patients had normal liver function tests. Abdominal ultrasonography showed increased periportal and peri gallbladder echoes (72%), spontaneous collaterals (41.2%) and ascites (19.1%). Liver biopsy revealed portal venous sclerosis (76.3%) and periportal fibrosis (55.3%). Tc-labelled sulphur colloid scan was suggestive of NCPF in the remaining 30 cases. CONCLUSION: NCPF is common in South India. Transient ascites occurs due to decompensation of liver function after variceal bleeding and in long standing cases of NCPF. Our study used Tc-sulphur scan for diagnosing NCPF in patients where liver biopsy was contraindicated in view of severe thrombocytopenia; however, the diagnostic utility of Tc-sulphur nuclear scan to diagnose NCPF in patients with severe hypersplenism needs to be further evaluated in future studies. PMID- 26989146 TI - Chado use case: storing genomic, genetic and breeding data of Rosaceae and Gossypium crops in Chado. AB - The Genome Database for Rosaceae (GDR) and CottonGen are comprehensive online data repositories that provide access to integrated genomic, genetic and breeding data through search, visualization and analysis tools for Rosaceae crops and Gossypium (cotton). These online databases use Chado, an open-source, generic and ontology-driven database schema for biological data, as the primary data storage platform. Chado is highly normalized and uses ontologies to indicate the 'types' of data. Therefore, Chado is flexible such that it has been used to house genomic, genetic and breeding data for GDR and CottonGen. These data include whole genome sequence and annotation, transcripts, molecular markers, genetic maps, Quantitative Trait Loci, Mendelian Trait Loci, traits, germplasm, pedigrees, large scale phenotypic and genotypic data, ontologies and publications. We provide information about how to store these types of data in Chado using GDR and CottonGen as examples sites that were converted from an older legacy infrastructure. Database URL: GDR (www.rosaceae.org), CottonGen (www.cottongen.org). PMID- 26989145 TI - An integrative data analysis platform for gene set analysis and knowledge discovery in a data warehouse framework. AB - Data analysis is one of the most critical and challenging steps in drug discovery and disease biology. A user-friendly resource to visualize and analyse high throughput data provides a powerful medium for both experimental and computational biologists to understand vastly different biological data types and obtain a concise, simplified and meaningful output for better knowledge discovery. We have previously developed TargetMine, an integrated data warehouse optimized for target prioritization. Here we describe how upgraded and newly modelled data types in TargetMine can now survey the wider biological and chemical data space, relevant to drug discovery and development. To enhance the scope of TargetMine from target prioritization to broad-based knowledge discovery, we have also developed a new auxiliary toolkit to assist with data analysis and visualization in TargetMine. This toolkit features interactive data analysis tools to query and analyse the biological data compiled within the TargetMine data warehouse. The enhanced system enables users to discover new hypotheses interactively by performing complicated searches with no programming and obtaining the results in an easy to comprehend output format. Database URL: http://targetmine.mizuguchilab.org. PMID- 26989147 TI - HistoneDB 2.0: a histone database with variants--an integrated resource to explore histones and their variants. AB - Compaction of DNA into chromatin is a characteristic feature of eukaryotic organisms. The core (H2A, H2B, H3, H4) and linker (H1) histone proteins are responsible for this compaction through the formation of nucleosomes and higher order chromatin aggregates. Moreover, histones are intricately involved in chromatin functioning and provide a means for genome dynamic regulation through specific histone variants and histone post-translational modifications. 'HistoneDB 2.0--with variants' is a comprehensive database of histone protein sequences, classified by histone types and variants. All entries in the database are supplemented by rich sequence and structural annotations with many interactive tools to explore and compare sequences of different variants from various organisms. The core of the database is a manually curated set of histone sequences grouped into 30 different variant subsets with variant-specific annotations. The curated set is supplemented by an automatically extracted set of histone sequences from the non-redundant protein database using algorithms trained on the curated set. The interactive web site supports various searching strategies in both datasets: browsing of phylogenetic trees; on-demand generation of multiple sequence alignments with feature annotations; classification of histone-like sequences and browsing of the taxonomic diversity for every histone variant. HistoneDB 2.0 is a resource for the interactive comparative analysis of histone protein sequences and their implications for chromatin function. Database URL: http://www.ncbi.nlm.nih.gov/projects/HistoneDB2.0. PMID- 26989148 TI - Wikidata as a semantic framework for the Gene Wiki initiative. AB - Open biological data are distributed over many resources making them challenging to integrate, to update and to disseminate quickly. Wikidata is a growing, open community database which can serve this purpose and also provides tight integration with Wikipedia. In order to improve the state of biological data, facilitate data management and dissemination, we imported all human and mouse genes, and all human and mouse proteins into Wikidata. In total, 59,721 human genes and 73,355 mouse genes have been imported from NCBI and 27,306 human proteins and 16,728 mouse proteins have been imported from the Swissprot subset of UniProt. As Wikidata is open and can be edited by anybody, our corpus of imported data serves as the starting point for integration of further data by scientists, the Wikidata community and citizen scientists alike. The first use case for these data is to populate Wikipedia Gene Wiki infoboxes directly from Wikidata with the data integrated above. This enables immediate updates of the Gene Wiki infoboxes as soon as the data in Wikidata are modified. Although Gene Wiki pages are currently only on the English language version of Wikipedia, the multilingual nature of Wikidata allows for usage of the data we imported in all 280 different language Wikipedias. Apart from the Gene Wiki infobox use case, a SPARQL endpoint and exporting functionality to several standard formats (e.g. JSON, XML) enable use of the data by scientists. In summary, we created a fully open and extensible data resource for human and mouse molecular biology and biochemistry data. This resource enriches all the Wikipedias with structured information and serves as a new linking hub for the biological semantic web. Database URL: https://www.wikidata.org/. PMID- 26989149 TI - R-Syst::diatom: an open-access and curated barcode database for diatoms and freshwater monitoring. AB - Diatoms are micro-algal indicators of freshwater pollution. Current standardized methodologies are based on microscopic determinations, which is time consuming and prone to identification uncertainties. The use of DNA-barcoding has been proposed as a way to avoid these flaws. Combining barcoding with next-generation sequencing enables collection of a large quantity of barcodes from natural samples. These barcodes are identified as certain diatom taxa by comparing the sequences to a reference barcoding library using algorithms. Proof of concept was recently demonstrated for synthetic and natural communities and underlined the importance of the quality of this reference library. We present an open-access and curated reference barcoding database for diatoms, called R-Syst::diatom, developed in the framework of R-Syst, the network of systematic supported by INRA (French National Institute for Agricultural Research), see http://www.rsyst.inra.fr/en. R-Syst::diatom links DNA-barcodes to their taxonomical identifications, and is dedicated to identify barcodes from natural samples. The data come from two sources, a culture collection of freshwater algae maintained in INRA in which new strains are regularly deposited and barcoded and from the NCBI (National Center for Biotechnology Information) nucleotide database. Two kinds of barcodes were chosen to support the database: 18S (18S ribosomal RNA) and rbcL (Ribulose-1,5-bisphosphate carboxylase/oxygenase), because of their efficiency. Data are curated using innovative (Declic) and classical bioinformatic tools (Blast, classical phylogenies) and up-to-date taxonomy (Catalogues and peer reviewed papers). Every 6 months R-Syst::diatom is updated. The database is available through the R-Syst microalgae website (http://www.rsyst.inra.fr/) and a platform dedicated to next-generation sequencing data analysis, virtual_BiodiversityL@b (https://galaxy pgtp.pierroton.inra.fr/). We present here the content of the library regarding the number of barcodes and diatom taxa. In addition to these information, morphological features (e.g. biovolumes, chloroplasts...), life-forms (mobility, colony-type) or ecological features (taxa preferenda to pollution) are indicated in R-Syst::diatom. Database URL: http://www.rsyst.inra.fr/. PMID- 26989150 TI - Sustainable funding for biocuration: The Arabidopsis Information Resource (TAIR) as a case study of a subscription-based funding model. AB - Databases and data repositories provide essential functions for the research community by integrating, curating, archiving and otherwise packaging data to facilitate discovery and reuse. Despite their importance, funding for maintenance of these resources is increasingly hard to obtain. Fueled by a desire to find long term, sustainable solutions to database funding, staff from the Arabidopsis Information Resource (TAIR), founded the nonprofit organization, Phoenix Bioinformatics, using TAIR as a test case for user-based funding. Subscription based funding has been proposed as an alternative to grant funding but its application has been very limited within the nonprofit sector. Our testing of this model indicates that it is a viable option, at least for some databases, and that it is possible to strike a balance that maximizes access while still incentivizing subscriptions. One year after transitioning to subscription support, TAIR is self-sustaining and Phoenix is poised to expand and support additional resources that wish to incorporate user-based funding strategies. Database URL: www.arabidopsis.org. PMID- 26989151 TI - KinetochoreDB: a comprehensive online resource for the kinetochore and its related proteins. AB - KinetochoreDB is an online resource for the kinetochore and its related proteins. It provides comprehensive annotations on 1554 related protein entries in terms of their amino acid sequence, protein domain context, protein 3D structure, predicted intrinsically disordered region, protein-protein interaction, post translational modification site, functional domain and key metabolic/signaling pathways, integrating several public databases, computational annotations and experimental results. KinetochoreDB provides interactive and customizable search and data display functions that allow users to interrogate the database in an efficient and user-friendly manner. It uses PSI-BLAST searches to retrieve the homologs of all entries and generate multiple sequence alignments that contain important evolutionary information. This knowledgebase also provides annotations of single point mutations for entries with respect to their pathogenicity, which may be useful for generation of new hypotheses on their functions, as well as follow-up studies of human diseases. Database URL: http://lightning.med.monash.edu/kinetochoreDB2/. PMID- 26989152 TI - From one to many: expanding the Saccharomyces cerevisiae reference genome panel. AB - In recent years, thousands of Saccharomyces cerevisiae genomes have been sequenced to varying degrees of completion. The Saccharomyces Genome Database (SGD) has long been the keeper of the original eukaryotic reference genome sequence, which was derived primarily from S. cerevisiae strain S288C. Because new technologies are pushing S. cerevisiae annotation past the limits of any system based exclusively on a single reference sequence, SGD is actively working to expand the original S. cerevisiae systematic reference sequence from a single genome to a multi-genome reference panel. We first commissioned the sequencing of additional genomes and their automated analysis using the AGAPE pipeline. Here we describe our curation strategy to produce manually reviewed high-quality genome annotations in order to elevate 11 of these additional genomes to Reference status. Database URL: http://www.yeastgenome.org/. PMID- 26989153 TI - High-performance integrated virtual environment (HIVE): a robust infrastructure for next-generation sequence data analysis. AB - The High-performance Integrated Virtual Environment (HIVE) is a distributed storage and compute environment designed primarily to handle next-generation sequencing (NGS) data. This multicomponent cloud infrastructure provides secure web access for authorized users to deposit, retrieve, annotate and compute on NGS data, and to analyse the outcomes using web interface visual environments appropriately built in collaboration with research and regulatory scientists and other end users. Unlike many massively parallel computing environments, HIVE uses a cloud control server which virtualizes services, not processes. It is both very robust and flexible due to the abstraction layer introduced between computational requests and operating system processes. The novel paradigm of moving computations to the data, instead of moving data to computational nodes, has proven to be significantly less taxing for both hardware and network infrastructure.The honeycomb data model developed for HIVE integrates metadata into an object-oriented model. Its distinction from other object-oriented databases is in the additional implementation of a unified application program interface to search, view and manipulate data of all types. This model simplifies the introduction of new data types, thereby minimizing the need for database restructuring and streamlining the development of new integrated information systems. The honeycomb model employs a highly secure hierarchical access control and permission system, allowing determination of data access privileges in a finely granular manner without flooding the security subsystem with a multiplicity of rules. HIVE infrastructure will allow engineers and scientists to perform NGS analysis in a manner that is both efficient and secure. HIVE is actively supported in public and private domains, and project collaborations are welcomed. Database URL: https://hive.biochemistry.gwu.edu. PMID- 26989154 TI - CSCdb: a cancer stem cells portal for markers, related genes and functional information. AB - Cancer stem cells (CSCs), which have the ability to self-renew and differentiate into various tumor cell types, are a special class of tumor cells. Characterizing the genes involved in CSCs regulation is fundamental to understand the mechanisms underlying the biological process and develop treatment methods for tumor therapy. Recently, much effort has been expended in the study of CSCs and a large amount of data has been generated. However, to the best of our knowledge, database dedicated to CSCs is not available until now. We have thus developed a CSCs database (CSCdb), which includes marker genes, CSCs-related genes/microRNAs and functional annotations. The information in the CSCdb was manual collected from about 13 000 articles. The CSCdb provides detailed information of 1769 genes that have been reported to participate in the functional regulation of CSCs and 74 marker genes that can be used for identification or isolation of CSCs. The CSCdb also provides 9475 annotations about 13 CSCs-related functions, such as oncogenesis, radio resistance, tumorigenesis, differentiation, etc. Annotations of the identified genes, which include protein function description, post transcription modification information, related literature, Gene Ontology (GO), protein-protein interaction (PPI) information and regulatory relationships, are integrated into the CSCdb to help users get information more easily. CSCdb provides a comprehensive resource for CSCs research work, which would assist in finding new CSCs-related genes and would be a useful tool for biologists. Database URL: http://bioinformatics.ustc.edu.cn/cscdb. PMID- 26989155 TI - dbWGFP: a database and web server of human whole-genome single nucleotide variants and their functional predictions. AB - The recent advancement of the next generation sequencing technology has enabled the fast and low-cost detection of all genetic variants spreading across the entire human genome, making the application of whole-genome sequencing a tendency in the study of disease-causing genetic variants. Nevertheless, there still lacks a repository that collects predictions of functionally damaging effects of human genetic variants, though it has been well recognized that such predictions play a central role in the analysis of whole-genome sequencing data. To fill this gap, we developed a database named dbWGFP (a database and web server of human whole genome single nucleotide variants and their functional predictions) that contains functional predictions and annotations of nearly 8.58 billion possible human whole-genome single nucleotide variants. Specifically, this database integrates 48 functional predictions calculated by 17 popular computational methods and 44 valuable annotations obtained from various data sources. Standalone software, user-friendly query services and free downloads of this database are available at http://bioinfo.au.tsinghua.edu.cn/dbwgfp. dbWGFP provides a valuable resource for the analysis of whole-genome sequencing, exome sequencing and SNP array data, thereby complementing existing data sources and computational resources in deciphering genetic bases of human inherited diseases. PMID- 26989156 TI - ATF3 provides protection from Staphylococcus aureus and Listeria monocytogenes infections. AB - Activating transcription factor 3 (ATF3) is a stress-induced transcriptional regulator in eukaryote. The role of ATF3 in cancer has been well defined, but how ATF3 functions in bacterial infection is not well understood. Pneumococcal infection has been shown to induce ATF3 expression, which subsequently enhances cytokine production and provides protection from lethal Streptococcus pneumoniae infection, but the role of ATF3 in other Gram-positive (G(+)) infections remains unclear. Here, we report that infection with other G(+) bacteria (Staphylococcus aureus and Listeria monocytogenes) and with G(-) bacteria (uropathogenic Escherichia coli) also significantly induced ATF3 expression. Moreover, the production of cytokines (tumor necrosis factor alpha [TNF]-alpha, interleukin [IL]-1beta, IL-6 and interferon [IFN]-gamma) was enhanced by ATF3 in S. aureus and L. monocytogenes infection, but decreased in uropathogenic E. coli (UPEC) infection. In addition, in S. aureus and L. monocytogenes infections, ATF3 WT mice cleared bacteria more efficiently and had higher survival rates than ATF3 knockout mice. However, in UPEC infection, no significant difference was found in survival rate. Taken together, these data suggest that ATF3 provides protection from S. aureus and L. monocytogenes infections; however, the role of ATF3 in UPEC infection is more complicated and should be further elucidated. PMID- 26989157 TI - Overexpression of two stress-responsive, small, non-coding RNAs, 6S and tmRNA, imparts butanol tolerance in Clostridium acetobutylicum. AB - While extensively studied in several model organisms, the role of small, non coding RNAs in the stress response remains largely unexplored in Clostridium organisms. About 100 years after the first industrial Acetone-Butanol-Ethanol fermentation process, based on the Weizmann Clostridium acetobutylicum strain, strain tolerance to butanol remains a crucial factor limiting the economics of the process. Several studies have examined the response of this organism to metabolite stress, and several genes have been engaged to impart enhanced tolerance, but no sRNAs have yet been directly engaged in this task. We show that the two stress-responsive sRNAs, 6S and tmRNA, upon overexpression impart tolerance to butanol as assessed by viability assays under process-relevant conditions. 6S overexpression enhances cell densities as well as butanol titres. We discuss the likely mechanisms that these two sRNAs might engage in this tolerance phenotype. Our data support the continued exploration of sRNAs as a basis for engineering enhanced tolerance and enhanced solvent production, especially because sRNA-based strategies impose a minimal metabolic burden on the cells. PMID- 26989159 TI - School Nurses Avoid Addressing Child Sexual Abuse. AB - Child sexual abuse (CSA) is a global public health problem with major consequences for the individual child and society. An earlier Swedish study showed that the school nurses did not initially talk about nor mention CSA as one form of child abuse. For the child to receive adequate support, the disclosure is a precondition and is dependent on an available person prepared to listen. The aim of the study was to explore the ability of the school nurses to detect and support sexually abused children. It is a secondary analysis of focus group interviews with school nurses. Thematic analysis was performed. Results showed that the school nurses avoided addressing CSA due to arousal of strong emotions, ambivalence, and a complicated disclosure process. In order to detect CSA and support abused children, attentiveness of sexual abuse as a possible cause of physical and mental ill-health is crucial. PMID- 26989158 TI - Oxidative impairment and histopathological alterations in kidney and brain of mice following subacute lambda-cyhalothrin exposure. AB - Lambda cyhalothrin (LCT), a broad-spectrum type II (alpha-cyano) synthetic pyrethroid pesticide, is widely employed in various agricultural and animal husbandry practices for the control of pests. Acute and chronic exposure to LCT can elicit several adverse effects including oxidative stress. With the objective to investigate nephrotoxicity and neurotoxicity of LCT in mice, we evaluated oxidative stress parameters and histological changes in the kidney and brain of LCT exposed mice. Swiss albino mice were divided randomly into four groups ( n = 6 per group) as: (A) corn oil/vehicle control; (B) 0.5 mg/kg body weight (b.w.) LCT; (C) 1 mg/kg b.w. LCT; (D) 2 mg/kg b.w. LCT. Mice were treated orally for 28 days. LCT exposure significantly increased serum urea nitrogen, creatinine and urea levels. LCT exposure also increased lipid peroxidation, superoxide anion generation, nitrite level and decreased the level of reduced glutathione. The activities of superoxide dismutase, catalase and glutathione- S-transferase were depleted significantly in both kidney and brain. Histological examination revealed marked histopathological changes in the kidney and brain of mice that were more pronounced at high dose of LCT. Thus, results of the present study indicate that 28 days oral exposure of LCT causes oxidative damage to the kidney and brain of mice which in turn could be responsible for nephrotoxicity and neurotoxicity. Nevertheless, further detailed studies are required to prove these effects especially after long-term exposure. PMID- 26989160 TI - Mapping the contribution of Allied Health Professions to the wider public health workforce: a rapid review of evidence-based interventions. AB - Objectives: The objective was to identify a selection of the best examples of the public health contributions by Allied Health Professionals (AHPs) in order to encourage a wider awareness and participation from that workforce to public health practice. Study design: A mapping exercise was used to identify evidence based interventions that could lead to health improvements across a population. Methods: A rapid review was undertaken to identify evidence, followed by a survey of Allied Health Profession (AHP) practitioners and an expert panel consensus method to select the examples of AHP public health interventions. Results: Nine evidence-based interventions are identified and selected as examples of current AHP good practice. These examples represent a contribution to public health and include screening interventions, secondary prevention and risk management. Conclusions: This study contributes to a strategy for AHPs in public health by appraising the effectiveness and impact of some exemplar AHP practices that contribute to health improvement. There is a need for AHPs to measure the impact of their interventions and to demonstrate evidence of outcomes at population level. PMID- 26989161 TI - Description of a novel telemedicine-enabled comprehensive system of care: drip and ship plus drip and keep within a system of stroke care delivery. AB - United States (US) and worldwide telestroke programs frequently focus only on emergency room hyper-acute stroke management. This article describes a comprehensive, telemedicine-enabled, stroke care delivery system that combines "drip and ship" and "drip and keep" models with a comprehensive stroke center primary hub at Ochsner Medical Center in New Orleans, advanced stroke-capable regional hubs, and geographically-aligned, "stroke-ready" spokes. The primary hub provides vascular neurology expertise via telemedicine and monitors care for patients remaining at regional hubs and spokes using a multidisciplinary team approach. By 2014, primary hub telestroke consults grew to ~1000/year with 16 min average door to consult initiation and 20 min to completion, and 29% of ischemic stroke patients received recombinant tissue-type plasminogen activator (rtPA), increasing 275%. Most patients remained in hospitals close to home, but neurointensive care and interventional procedures were common reasons for primary hub transfer. Given the time sensitivity and expert consultation needed for complex acute stroke care delivery paradigms, telestroke programs are effective for fulfilling unmet care needs. Combining drip and ship and drip and keep management allows more patients to stay "local," limiting primary hub transfer unless more advanced services are required. Post admission telestroke management at spokes increases personnel efficiency and can positively impact stroke outcomes. PMID- 26989162 TI - Early Grade Writing Assessment: An Instrument Model. AB - The United Nations Educational, Scientific, and Cultural Organization promoted the creation of a model instrument for individual assessment of students' foundational writing skills in the Spanish language that was based on a literature review and existing writing tools and assessments. The purpose of the Early Grade Writing Assessment (EGWA) is to document learners' basic writing skills, mapped in composing units of increasing complexity to communicate meaning. Validation and standardization of EGWA was conducted in the Canary Islands (Spain) in 12 schools using a cross-sectional design with a sample of 1,653 Spanish-speaking students in Grades 1 through 3. The author describes EGWA's internal structure, along with the prevalence of learning disabilities (LD) in transcription and developmental differences in writing between Spanish speaking children with LD and typical peers. Findings suggest that EGWA's psychometric characteristics are satisfactory, and its internal structure can be attributed to four factors responsible for a high percentage of the variance. The odds ratio indicated that 2 Spanish-speaking children with LD in transcription are identified out of every 100. A comparison between students with and without LD in transcription revealed statistically significant differences concerning sentence and text production across grades. Results are interpreted within current theoretical accounts of writing models. PMID- 26989163 TI - Integrative Single-Cell Transcriptomics Reveals Molecular Networks Defining Neuronal Maturation During Postnatal Neurogenesis. AB - In mammalian hippocampus, new neurons are continuously produced from neural stem cells throughout life. This postnatal neurogenesis may contribute to information processing critical for cognition, adaptation, learning, and memory, and is implicated in numerous neurological disorders. During neurogenesis, the immature neuron stage defined by doublecortin (DCX) expression is the most sensitive to regulation by extrinsic factors. However, little is known about the dynamic biology within this critical interval that drives maturation and confers susceptibility to regulatory signals. This study aims to test the hypothesis that DCX-expressing immature neurons progress through developmental stages via activity of specific transcriptional networks. Using single-cell RNA-seq combined with a novel integrative bioinformatics approach, we discovered that individual immature neurons can be classified into distinct developmental subgroups based on characteristic gene expression profiles and subgroup-specific markers. Comparisons between immature and more mature subgroups revealed novel pathways involved in neuronal maturation. Genes enriched in less mature cells shared significant overlap with genes implicated in neurodegenerative diseases, while genes positively associated with neuronal maturation were enriched for autism related gene sets. Our study thus discovers molecular signatures of individual immature neurons and unveils potential novel targets for therapeutic approaches to treat neurodevelopmental and neurological diseases. PMID- 26989164 TI - Postsocialism, the psy-ences and mental health. AB - Over the past decades, the formerly socialist countries of East Central Europe and Eurasia have experienced a range of transformations which bear directly upon the domains of mental health, psychiatry, and psychology. In particular, the disciplines and professions concerned with the human mind, brain, and behavior ("the psy-ences") were strongly affected by sociopolitical changes spanning the state-socialist and postsocialist periods. These disciplines' relationship to the state, their modes of knowledge production, and the epistemic order and subjectivities they contributed to have all undergone dramatic ruptures. In this essay, we trace the literature on these issues across three thematic domains: (a) history and memory; (b) the reform of psychiatry in an era of global mental health; and (c) therapy and self-fashioning. We argue for a closer articulation between the social science and historical literature on socialism and its "posts" and the literature among anthropologists, sociologists, and historians on the sciences of the mind and brain, and we suggest that each of these literatures helps to critically open up and enrich the other. PMID- 26989165 TI - Does my daughter have lupus? PMID- 26989166 TI - Gender differences in systemic lupus erythematosus concerning anxiety, depression and quality of life. AB - Several studies have demonstrated a high prevalence of depression and anxiety in patients with systemic lupus erythematosus (SLE); however, few data address gender differences regarding these manifestations. This study aimed to investigate gender differences in the prevalence of depressive and anxiety symptoms, and their effect on the quality of life (QOL) of male and female SLE patients. This study included 54 male SLE patients, 54 female SLE patients, 54 male controls and 54 female controls. Depressive symptoms were assessed using the Beck Depression Inventory (BDI), the Center for Epidemiologic Studies Depression Scale (CES-D) and the Hospital Anxiety and Depression Scale (HADS); the anxiety symptoms were examined using HADS. We used the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) to assess QOL. Depressive symptoms were found in 22.2% of BDI respondents, 24.1% of CES-D respondents and 13% of HADS-D respondents who were male SLE patients; while in the female SLE patient group, they were found in 38.9% of BDI respondents (p = 0.063), 51.9% of CES-D respondents (p = 0.653) and 31.5% of HADS-D respondents (p = 0.003). Anxiety symptoms were found in 16.7% of the male SLE patients and 38.9% of the female SLE patients (p = 0.024). Lower scores on the SF-36 (for QOL) were found in both male and female SLE patients with depression and anxiety symptoms. In conclusion, we observed significant gender differences regarding the prevalence of depressive and anxiety symptoms in patients with SLE, with significantly higher values in the female group. The presence of these symptoms appears to have a negative effect on the QOL of patients of both genders. PMID- 26989167 TI - Analysis of killer cell immunoglobulin-like receptors and their human leukocyte antigen-ligands gene polymorphisms in Iranian patients with systemic lupus erythematosus. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease. Natural killer (NK) cells play a critical role in the pathogenesis of autoimmune disorders that mainly express killer cell immunoglobulin-like receptors (KIRs). The present study was undertaken to determine the association of the KIR alleles, genotypes, and KIR-human leukocyte antigen (HLA) ligand gene combinations with the susceptibility to SLE. METHODS: The genotyping of 17 KIR and 5 HLA loci was performed using the polymerase chain reaction-sequence specific primer (PCR-SSP) method. The study population consisted of 230 SLE patients and 273 ethnical-, age-, and sex-matched healthy controls. The association of the polymorphisms with the prevalence of 11 clinical criteria in patients was analyzed. RESULTS: The carrier frequency of HLA-A-Bw4 was modestly decreased in the SLE patients. The prevalence of hematological and renal disorders was significantly increased in patients with combination of KIR3DL1(+); HLA-B-Bw4(Thr80+) and KIR2DS1(+); HLA-C2(+) genes, respectively. Female patients with combination of KIR2DL2(+); HLA-C1(-) genes were more likely to develop serositis. In addition the prevalence of renal disorders, oral ulcer and serositis was significantly increased in male patients with KIR3DP1(+), KIR2DS1(+), and KIR2DS3(+) genotypes respectively. CONCLUSION: Our results showed that the presence of activating KIR receptors alone or in combination with their HLA ligands and the absence of inhibitory KIRs in combination with their HLA ligands may activate NK cells and are significantly correlated with the prevalence of renal disease, hematologic disorders, serositis, and oral ulcer in SLE patients. PMID- 26989168 TI - Intermittent accelerated idioventricular rhythm: a novel arrhythmia in lupus erythematosus. PMID- 26989169 TI - Aortic dissection. PMID- 26989170 TI - Species-specific contribution of volumetric growth and tissue convergence to posterior body elongation in vertebrates. AB - Posterior body elongation is a widespread mechanism propelling the generation of the metazoan body plan. The posterior growth model predicts that a posterior growth zone generates sufficient tissue volume to elongate the posterior body. However, there are energy supply-related differences between vertebrates in the degree to which growth occurs concomitantly with embryogenesis. By applying a multi-scalar morphometric analysis in zebrafish embryos, we show that posterior body elongation is generated by an influx of cells from lateral regions, by convergence-extension of cells as they exit the tailbud, and finally by a late volumetric growth in the spinal cord and notochord. Importantly, the unsegmented region does not generate additional tissue volume. Fibroblast growth factor inhibition blocks tissue convergence rather than volumetric growth, showing that a conserved molecular mechanism can control convergent morphogenesis through different cell behaviours. Finally, via a comparative morphometric analysis in lamprey, dogfish, zebrafish and mouse, we propose that elongation via posterior volumetric growth is linked to increased energy supply and is associated with an overall increase in volumetric growth and elongation. PMID- 26989171 TI - Development of the aboral domain in Nematostella requires beta-catenin and the opposing activities of Six3/6 and Frizzled5/8. AB - The development of the oral pole in cnidarians and the posterior pole in bilaterians is regulated by canonical Wnt signaling, whereas a set of transcription factors, including Six3/6 and FoxQ2, controls aboral development in cnidarians and anterior identity in bilaterians. However, it is poorly understood how these two patterning systems are initially set up in order to generate correct patterning along the primary body axis. Investigating the early steps of aboral pole formation in the sea anemone Nematostella vectensis, we found that, at blastula stage, oral genes are expressed before aboral genes and that Nvbeta catenin regulates both oral and aboral development. In the oral hemisphere, Nvbeta-catenin specifies all subdomains except the oral-most, NvSnailA-expressing domain, which is expanded upon Nvbeta-catenin knockdown. In addition, Nvbeta catenin establishes the aboral patterning system by promoting the expression of NvSix3/6 at the aboral pole and suppressing the Wnt receptor NvFrizzled5/8 at the oral pole. NvFrizzled5/8 expression thereby gets restricted to the aboral domain. At gastrula stage, NvSix3/6 and NvFrizzled5/8 are both expressed in the aboral domain, but they have opposing activities, with NvSix3/6 maintaining and NvFrizzled5/8 restricting the size of the aboral domain. At planula stage, NvFrizzled5/8 is required for patterning within the aboral domain and for regulating the size of the apical organ by modulation of a previously characterized FGF feedback loop. Our findings suggest conserved roles for Six3/6 and Frizzled5/8 in aboral/anterior development and reveal key functions for Nvbeta-catenin in the patterning of the entire oral-aboral axis of Nematostella. PMID- 26989172 TI - Trop2 marks transient gastric fetal epithelium and adult regenerating cells after epithelial damage. AB - Mouse fetal intestinal progenitors lining the epithelium prior to villogenesis grow as spheroids when cultured ex vivo and express the transmembrane glycoprotein Trop2 as a marker. Here, we report the characterization of Trop2 expressing cells from fetal pre-glandular stomach, growing as immortal undifferentiated spheroids, and their relationship with gastric development and regeneration. Trop2(+) cells generating gastric spheroids differed from adult glandular Lgr5(+) stem cells, but appeared highly related to fetal intestinal spheroids. Although they shared a common spheroid signature, intestinal and gastric fetal spheroid-generating cells expressed organ-specific transcription factors and were committed to intestinal and glandular gastric differentiation, respectively. Trop2 expression was transient during glandular stomach development, being lost at the onset of gland formation, whereas it persisted in the squamous forestomach. Undetectable under homeostasis, Trop2 was strongly re expressed in glands after acute Lgr5(+) stem cell ablation or following indomethacin-induced injury. These highly proliferative reactive adult Trop2(+) cells exhibited a transcriptome displaying similarity with that of gastric embryonic Trop2(+) cells, suggesting that epithelium regeneration in adult stomach glands involves the partial re-expression of a fetal genetic program. PMID- 26989173 TI - DRACULA2 is a dynamic nucleoporin with a role in regulating the shade avoidance syndrome in Arabidopsis. AB - When plants grow in close proximity basic resources such as light can become limiting. Under such conditions plants respond to anticipate and/or adapt to the light shortage, a process known as the shade avoidance syndrome (SAS). Following genetic screening using a shade-responsive luciferase reporter line (PHYB:LUC), we identified DRACULA2 (DRA2), which encodes an Arabidopsis homolog of mammalian nucleoporin 98, a component of the nuclear pore complex (NPC). DRA2, together with other nucleoporins, participates positively in the control of the hypocotyl elongation response to plant proximity, a role that can be considered dependent on the nucleocytoplasmic transport of macromolecules (i.e. is transport dependent). In addition, our results reveal a specific role for DRA2 in controlling shade-induced gene expression. We suggest that this novel regulatory role of DRA2 is transport independent and that it might rely on its dynamic localization within and outside of the NPC. These results provide mechanistic insights in to how SAS responses are rapidly established by light conditions. They also indicate that nucleoporins have an active role in plant signaling. PMID- 26989175 TI - Sebaceous lipids are essential for water repulsion, protection against UVB induced apoptosis and ocular integrity in mice. AB - Sebocytes, which are characterized by lipid accumulation that leads to cell disruption, can be found in hair follicle-associated sebaceous glands (SGs) or in free SGs such as the Meibomian glands in the eyelids. Because genetic tools that allow targeting of sebocytes while maintaining intact epidermal lipids are lacking, the relevance of sebaceous lipids in health and disease remains poorly understood. Using Scd3, which is expressed exclusively in mature sebocytes, we established a mouse line with sebocyte-specific expression of Cre recombinase. Both RT-PCR analysis and crossing into Rosa26-lacZ reporter mice and Kras(G12D) mice confirmed Cre activity specifically in SGs, with no activity in other skin compartments. Importantly, loss of SCD3 function did not cause detectable phenotypical alterations, endorsing the usefulness of Scd3-Cre mice for further functional studies. Scd3-Cre-induced, diphtheria chain A toxin-mediated depletion of sebaceous lipids resulted in impaired water repulsion and thermoregulation, increased rates of UVB-induced epidermal apoptosis and caused a severe pathology of the ocular surface resembling Meibomian gland dysfunction. This novel mouse line will be useful for further investigating the roles of sebaceous lipids in skin and eye integrity. PMID- 26989174 TI - NRPB3, the third largest subunit of RNA polymerase II, is essential for stomatal patterning and differentiation in Arabidopsis. AB - Stomata are highly specialized epidermal structures that control transpiration and gas exchange between plants and the environment. Signal networks underlying stomatal development have been previously uncovered but much less is known about how signals involved in stomatal development are transmitted to RNA polymerase II (Pol II or RPB), which plays a central role in the transcription of mRNA coding genes. Here, we identify a partial loss-of-function mutation of the third largest subunit of nuclear DNA-dependent Pol II (NRPB3) that exhibits an increased number of stomatal lineage cells and paired stomata. Phenotypic and genetic analyses indicated that NRPB3 is not only required for correct stomatal patterning, but is also essential for stomatal differentiation. Protein-protein interaction assays showed that NRPB3 directly interacts with two basic helix-loop-helix (bHLH) transcription factors, FAMA and INDUCER OF CBF EXPRESSION1 (ICE1), indicating that NRPB3 serves as an acceptor for signals from transcription factors involved in stomatal development. Our findings highlight the surprisingly conserved activating mechanisms mediated by the third largest subunit of Pol II in eukaryotes. PMID- 26989176 TI - Multicolor mapping of the cardiomyocyte proliferation dynamics that construct the atrium. AB - The orchestrated division of cardiomyocytes assembles heart chambers of distinct morphology. To understand the structural divergence of the cardiac chambers, we determined the contributions of individual embryonic cardiomyocytes to the atrium in zebrafish by multicolor fate-mapping and we compare our analysis to the established proliferation dynamics of ventricular cardiomyocytes. We find that most atrial cardiomyocytes become rod-shaped in the second week of life, generating a single-muscle-cell-thick myocardial wall with a striking webbed morphology. Inner pectinate myofibers form mainly by direct branching, unlike delamination events that create ventricular trabeculae. Thus, muscle clones assembling the atrial chamber can extend from wall to lumen. As zebrafish mature, atrial wall cardiomyocytes proliferate laterally to generate cohesive patches of diverse shapes and sizes, frequently with dominant clones that comprise 20-30% of the wall area. A subpopulation of cardiomyocytes that transiently express atrial myosin heavy chain (amhc) contributes substantially to specific regions of the ventricle, suggesting an unappreciated level of plasticity during chamber formation. Our findings reveal proliferation dynamics and fate decisions of cardiomyocytes that produce the distinct architecture of the atrium. PMID- 26989178 TI - Differential regulation of meristem size, morphology and organization by the ERECTA, CLAVATA and class III HD-ZIP pathways. AB - The shoot apical meristem (SAM) of angiosperm plants is a small, highly organized structure that gives rise to all above-ground organs. The SAM is divided into three functional domains: the central zone (CZ) at the SAM tip harbors the self renewing pluripotent stem cells and the organizing center, providing daughter cells that are continuously displaced into the interior rib zone (RZ) or the surrounding peripheral zone (PZ), from which organ primordia are initiated. Despite the constant flow of cells from the CZ into the RZ or PZ, and cell recruitment for primordium formation, a stable balance is maintained between the distinct cell populations in the SAM. Here we combined an in-depth phenotypic analysis with a comparative RNA-Seq approach to characterize meristems from selected combinations of clavata3 (clv3), jabba-1D (jba-1D) and erecta (er) mutants of Arabidopsis thaliana We demonstrate that CLV3 restricts meristem expansion along the apical-basal axis, whereas class III HD-ZIP and ER pathways restrict meristem expansion laterally, but in distinct and possibly perpendicular orientations. Our k-means analysis reveals that clv3, jba-1D/+ and er lead to meristem enlargement by affecting different aspects of meristem function; for example, clv3 displays an increase in the stem cell population, whereas jba-1D/+ er exhibits an increase in mitotic activity and in the meristematic cell population. Our analyses demonstrate that a combined genetic and mRNA-Seq comparative approach provides a precise and sensitive method to identify cell type-specific transcriptomes in a small structure, such as the SAM. PMID- 26989179 TI - Illness Identity in Adolescents and Emerging Adults With Type 1 Diabetes: Introducing the Illness Identity Questionnaire. AB - OBJECTIVE: The current study examined the utility of a new self-report questionnaire, the Illness Identity Questionnaire (IIQ), which assesses the concept of illness identity, or the degree to which type 1 diabetes is integrated into one's identity. Four illness identity dimensions (engulfment, rejection, acceptance, and enrichment) were validated in adolescents and emerging adults with type 1 diabetes. Associations with psychological and diabetes-specific functioning were assessed. RESEARCH DESIGN AND METHODS: A sample of 575 adolescents and emerging adults (14-25 years of age) with type 1 diabetes completed questionnaires on illness identity, psychological functioning, diabetes related problems, and treatment adherence. Physicians were contacted to collect HbA1c values from patients' medical records. Confirmatory factor analysis (CFA) was conducted to validate the IIQ. Path analysis with structural equation modeling was used to examine associations between illness identity and psychological and diabetes-specific functioning. RESULTS: CFA indicated that the IIQ has a clear factor structure, meaningfully differentiating four illness identity dimensions. Rejection was related to worse treatment adherence and higher HbA1c values. Engulfment was related to less adaptive psychological functioning and more diabetes-related problems. Acceptance was related to more adaptive psychological functioning, fewer diabetes-related problems, and better treatment adherence. Enrichment was related to more adaptive psychological functioning. CONCLUSIONS: The present findings underscore the importance of the concept of illness identity. A valid and reliable measure, the IIQ, is introduced to measure four illness identity dimensions in individuals with type 1 diabetes. These four illness identity dimensions were uniquely related to psychological and diabetes-specific functioning. PMID- 26989180 TI - Retinal Nerve Fiber Layer Loss in Patients With Type 2 Diabetes and Diabetic Neuropathy. PMID- 26989181 TI - Continuous Glucose Monitoring in the Self-management of Type 2 Diabetes: A Paradigm Shift. PMID- 26989182 TI - Diabetic Ketoacidosis With Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, in Patients With Type 1 Diabetes. AB - OBJECTIVE: To assess the incidence of serious adverse events (AEs) of diabetic ketoacidosis (DKA) with canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as an add-on to insulin in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: In this 18-week, randomized, double-blind, phase 2 study, patients (N = 351; HbA1c 7.0-9.0% [53-75 mmol/mol]) on multiple daily insulin injections or continuous subcutaneous insulin infusion received canagliflozin 100 or 300 mg or placebo once daily. The incidence of ketone-related AEs, defined as any event from a prespecified list of preferred terms (i.e., acidosis, blood ketone body increased, blood ketone body present, DKA, diabetic ketoacidotic hyperglycemic coma, ketoacidosis, ketonemia, ketonuria, ketosis, metabolic acidosis, urine ketone body present), including serious AEs of DKA, was assessed based on AE reports. RESULTS: At week 18, the incidence of any ketone-related AE with canagliflozin 100 and 300 mg was 5.1% (n = 6 of 117) and 9.4% (n = 11 of 117), respectively; no patients in the placebo group experienced a ketone-related AE. The incidence of serious AEs of DKA was 4.3% (n = 5 of 117) with canagliflozin 100 mg and 6.0% (n = 7 of 117) with canagliflozin 300 mg; all serious events occurred in the presence of circumstances that are known to potentially precipitate DKA (e.g., infection, insulin pump failure). Among the 12 patients with a serious AE of DKA, blood glucose levels ranged from 9.4 to >44.4 mmol/L (170 to >800 mg/dL). Baseline characteristics were generally similar in patients with and without a ketone-related AE. CONCLUSIONS: Canagliflozin was associated with an increased incidence of serious AEs of DKA in patients with type 1 diabetes inadequately controlled with insulin. Mitigation strategies are needed for use in future clinical trials to reduce the risk of DKA with canagliflozin treatment in patients with type 1 diabetes. PMID- 26989177 TI - Integrin signalling regulates YAP and TAZ to control skin homeostasis. AB - The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib. PMID- 26989183 TI - Erythrokinetics: quantitative measurements of red cell production and destruction in normal subjects and patients with anemia. AB - To study erythropoiesis and anemia, one must have a firm foundation of indices that accurately measure red blood cell production and destruction. This paper, authored by hematology legends Arno G. Motulsky and Clement A. Finch, provides that foundation. Using methods that would not be approved in today's environment, the authors studied a cohort of normal healthy patients and an equal number of patients with different forms of anemia. The results confirm a reciprocal model of red cell production and destruction, show that anemia can be the result of either underproduction (a regenerative anemia or ineffective erythropoiesis) or increased destruction, and define parameters for distinguishing these 2 possibilities that are still widely used today. PMID- 26989184 TI - Pediatric MDS: GATA screen the germline. AB - In this issue of Blood, Wlodarski and colleagues demonstrate that as many as 72% of adolescents diagnosed with myelodysplastic syndrome (MDS) and monosomy 7 harbor germline mutations in GATA2. Although pediatric MDS is a very rare diagnosis, occurring in 0.8 to 4 cases per million, Wlodarski et al screened >600 cases of primary or secondary MDS in children and adolescents who were enrolled in the European Working Group on MDS consortium over a period of 15 years. The overall frequency of germline GATA2 mutations in children with primary MDS was 7%, and 15% in those presenting with advanced disease. Notably, mutations in GATA2 were absent in patients with therapy-related MDS or acquired aplastic anemia. PMID- 26989185 TI - Less menorrhagia for women with VTE. AB - In this issue of Blood, Martinelli et al provide reassuring data that women taking oral anticoagulant therapy for venous thromboembolism (VTE) may use estrogen or progestin hormonal therapy to control the menstrual bleeding without increased risk for recurrent thromboembolism. PMID- 26989186 TI - S1PR2 deficiency in DLBCL: a FOXy connection. AB - Inactivating mutations in the sphingosine-1-phosphate (S1P) receptor 2 (S1PR2) promoter have been associated with the germinal center (GC) B-cell diffuse large B-cell lymphoma (GCB-DLBCL) subtype. In this issue of Blood, Flori et al have now identified S1PR2 as a tumor suppressor that is transcriptionally silenced by forkhead box protein 1 (FOXP1) in the aggressive, activated B-cell (ABC-DLBCL) subtype. PMID- 26989187 TI - Release the hounds: virotherapy with immunotherapy. AB - In this issue of Blood, Shen et al demonstrate that the vesicular stomatitis virus (VSV)-murine interferon beta (IFNbeta)-sodium iodide symporter (NIS) (VSV mIFNbeta-NIS) oncolytic virus has significant antileukemia activity, which is enhanced when combined with an anti-programmed death-ligand 1 (PD-L1) antibody. PMID- 26989188 TI - Arf6 arbitrates fibrinogen endocytosis. AB - In this issue of Blood, in a departure from studies of classic platelet function, Huang et al turn their attention to endocytosis and show that adenosine 5' diphosphate-ribosylation factor 6 (Arf6) plays a key role in fibrinogen engulfment. Although platelets are known to bind, absorb, and load their granules with plasma proteins, this report is one of the first to explore mechanisms that control endocytosis in this anucleate cell. Huang et al demonstrate that Arf6 dependent endocytosis is restricted to fibrinogen, implying that Arf6 also modulates trafficking of alphaIIbbeta3 integrins in platelets. Consistent with this notion, deletion of Arf6 in platelets enhances spreading on fibrinogen and accelerates clot retraction (see figure). However, activation of surface alphaIIbbeta3 is unaffected, and Arf6 deficiency does not alter thrombosis in vivo. These incongruous results point toward the complexity of anucleate platelets and the need for more detailed studies to understand intracellular trafficking, recycling, and endocytosis in platelets and their precurs PMID- 26989189 TI - Down the repressors! Up the fetal hemoglobin! AB - One of the major goals of hemoglobinopathy research has been to devise improved pharmacologic strategies for the induction of fetal hemoglobin (HbF) in people with sickle cell disease and beta-thalassemia. In this issue of Blood, Dulmovits and colleagues report that pomalidomide, a drug approved by the US Food and Drug Administration (FDA) for treatment of multiple myeloma, induces HbF production by decreasing levels of several key transcriptional repressors of fetal globin gene expression. In addition, they show that pomalidomide induces HbF in differentiating erythroid cells from people with sickle cell disease and in myeloma patients. PMID- 26989190 TI - An oxidase road to platelet adhesion. AB - Platelet adhesion to collagen via collagen receptors is an important part of thrombosis. In this issue of Blood, Matsuura et al identify collagen receptors as previously unrecognized targets of the extracellular enzyme lysyl oxidase (LOX), the level of which is increased in myeloproliferative neoplasms (MPNs) and other conditions associated with pathological thromboses. PMID- 26989194 TI - What Factors Might Drive Voluntary Childlessness (VC) in Women with IBD? Does IBD specific Pregnancy-related Knowledge Matter? AB - INTRODUCTION: Inflammatory Bowel Disease (IBD) affects many women of childbearing age, and rates of voluntary childlessness (VC) exceed those of the general population by far. The factors surrounding VC remain incompletely understood. METHODS: Female members of the patient organisation Crohn's and Colitis UK aged 18-45 years were invited to complete an online questionnaire collecting data on demographics, disease characteristics, Crohn's and Colitis pregnancy-specific disease-related knowledge (CCPKnow), and childlessness status. RESULTS: A total of 1324 women (mean age 33 years) completed the survey: 776 (59%) were diagnosed with Crohn's disease (CD), 496 (38%) with ulcerative colitis (UC) and 4% with inflammatory bowel disease-unclassified (IBD-U); 40% had children (14% pre diagnosis (I); 26% post-diagnosis (II)), 36% planned to have children at some stage (III), 7% reported fertility problems (IV), and 17% were classified as voluntarily childless (VC). VC was associated with poorer CCPKnow scores [5.98 vs. 7.47 in (III); p < 0.001], older age [35 years old vs. 28 years old in (II); p < 0.001], unemployment (9.7% VC; p < 0.001), being single (34.5% VC; p < 0.001) not seeking medical advice (p < 0.001), and diagnosis of CD (19.3% vs. 13.9% UC; p = 0.015). Women with VC had more hospital admissions [mean 2.85 vs. 2.17 (III); p = 0.03] and surgical interventions [mean 1.27 vs. 0.65 (III); p < 0.001] CONCLUSION: The aetiology of VC in women with IBD is multifactorial. Women's choice regarding children appears related to disease burden. VC is also associated with poor knowledge (CCPKnow), and women may stay childless unnecessarily. Patient education programmes could help to reduce the rate of VC in women with IBD, through correcting misconceptions and alleviating patient concerns. PMID- 26989192 TI - A mutation in the tuft mouse disrupts TET1 activity and alters the expression of genes that are crucial for neural tube closure. AB - Genetic variations affecting neural tube closure along the head result in malformations of the face and brain. Neural tube defects (NTDs) are among the most common birth defects in humans. We previously reported a mouse mutant called tuft that arose spontaneously in our wild-type 3H1 colony. Adult tuft mice present midline craniofacial malformations with or without an anterior cephalocele. In addition, affected embryos presented neural tube closure defects resulting in insufficient closure of the anterior neuropore or exencephaly. Here, through whole-genome sequencing, we identified a nonsense mutation in the Tet1 gene, which encodes a methylcytosine dioxygenase (TET1), co-segregating with the tuft phenotype. This mutation resulted in premature termination that disrupts the catalytic domain that is involved in the demethylation of cytosine. We detected a significant loss of TET enzyme activity in the heads of tuft embryos that were homozygous for the mutation and had NTDs. RNA-Seq transcriptome analysis indicated that multiple gene pathways associated with neural tube closure were dysregulated in tuft embryo heads. Among them, the expressions of Cecr2, Epha7 and Grhl2 were significantly reduced in some embryos presenting neural tube closure defects, whereas one or more components of the non-canonical WNT signaling pathway mediating planar cell polarity and convergent extension were affected in others. We further show that the recombinant mutant TET1 protein was capable of entering the nucleus and affected the expression of endogenous Grhl2 in IMCD-3 (inner medullary collecting duct) cells. These results indicate that TET1 is an epigenetic determinant for regulating genes that are crucial to closure of the anterior neural tube and its mutation has implications to craniofacial development, as presented by the tuft mouse. PMID- 26989193 TI - Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors. AB - Clinical management of abdominal aortic aneurysm (AAA) is currently limited to elective surgical repair because an effective pharmacotherapy is still awaited. Inhibition of histone deacetylase (HDAC) activity could be a promising therapeutic option in cardiovascular diseases. We aimed to characterise HDAC expression in human AAA and to evaluate the therapeutic potential of class I and IIa HDAC inhibitors in the AAA model of angiotensin II (Ang II)-infused apolipoprotein-E-deficient (ApoE(-/-)) mice. Real-time PCR, western blot and immunohistochemistry evidenced an increased expression of HDACs 1, 2 (both class I), 4 and 7 (both class IIa) in abdominal aorta samples from patients undergoing AAA open repair (n=22) compared with those from donors (n=14). Aortic aneurysms from Ang-II-infused ApoE(-/-) mice exhibited a similar HDAC expression profile. In these animals, treatment with a class I HDAC inhibitor (MS-275) or a class IIa inhibitor (MC-1568) improved survival, reduced the incidence and severity of AAA and limited aneurysmal expansion evaluated by Doppler ultrasonography. These beneficial effects were more potent in MC-1568-treated mice. The disorganisation of elastin and collagen fibres and lymphocyte and macrophage infiltration were effectively reduced by both inhibitors. Additionally, HDAC inhibition attenuated the exacerbated expression of pro-inflammatory markers and the increase in metalloproteinase-2 and -9 activity induced by Ang II in this model. Therefore, our data evidence that HDAC expression is deregulated in human AAA and that class selective HDAC inhibitors limit aneurysm expansion in an AAA mouse model. New generation HDAC inhibitors represent a promising therapeutic approach to overcome human aneurysm progression. PMID- 26989196 TI - Quantum criticality with two length scales. AB - The theory of deconfined quantum critical (DQC) points describes phase transitions at absolute temperature T = 0 outside the standard paradigm, predicting continuous transformations between certain ordered states where conventional theory would require discontinuities. Numerous computer simulations have offered no proof of such transitions, instead finding deviations from expected scaling relations that neither were predicted by the DQC theory nor conform to standard scenarios. Here we show that this enigma can be resolved by introducing a critical scaling form with two divergent length scales. Simulations of a quantum magnet with antiferromagnetic and dimerized ground states confirm the form, proving a continuous transition with deconfined excitations and also explaining anomalous scaling at T > 0. Our findings revise prevailing paradigms for quantum criticality, with potential implications for many strongly correlated materials. PMID- 26989195 TI - Sex differences in autism: a resting-state fMRI investigation of functional brain connectivity in males and females. AB - Autism spectrum disorders (ASD) are far more prevalent in males than in females. Little is known however about the differential neural expression of ASD in males and females. We used a resting-state fMRI-dataset comprising 42 males/42 females with ASD and 75 male/75 female typical-controls to examine whether autism-related alterations in intrinsic functional connectivity are similar or different in males and females, and particularly whether alterations reflect 'neural masculinization', as predicted by the Extreme Male Brain theory. Males and females showed a differential neural expression of ASD, characterized by highly consistent patterns of hypo-connectivity in males with ASD (compared to typical males), and hyper-connectivity in females with ASD (compared to typical females). Interestingly, patterns of hyper-connectivity in females with ASD reflected a shift towards the (high) connectivity levels seen in typical males (neural masculinization), whereas patterns of hypo-connectivity observed in males with ASD reflected a shift towards the (low) typical feminine connectivity patterns (neural feminization). Our data support the notion that ASD is a disorder of sexual differentiation rather than a disorder characterized by masculinization in both genders. Future work is needed to identify underlying factors such as sex hormonal alterations that drive these sex-specific neural expressions of ASD. PMID- 26989197 TI - SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions. AB - Tumor-derived extracellular vesicles (tEVs) are important signals in tumor-host cell communication, yet it remains unclear how endogenously produced tEVs affect the host in different areas of the body. We combined imaging and genetic analysis to track melanoma-derived vesicles at organismal, cellular, and molecular scales to show that endogenous tEVs efficiently disseminate via lymphatics and preferentially bind subcapsular sinus (SCS) CD169(+) macrophages in tumor draining lymph nodes (tdLNs) in mice and humans. The CD169(+) macrophage layer physically blocks tEV dissemination but is undermined during tumor progression and by therapeutic agents. A disrupted SCS macrophage barrier enables tEVs to enter the lymph node cortex, interact with B cells, and foster tumor-promoting humoral immunity. Thus, CD169(+) macrophages may act as tumor suppressors by containing tEV spread and ensuing cancer-enhancing immunity. PMID- 26989198 TI - Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals. AB - Although Neandertal sequences that persist in the genomes of modern humans have been identified in Eurasians, comparable studies in people whose ancestors hybridized with both Neandertals and Denisovans are lacking. We developed an approach to identify DNA inherited from multiple archaic hominin ancestors and applied it to whole-genome sequences from 1523 geographically diverse individuals, including 35 previously unknown Island Melanesian genomes. In aggregate, we recovered 1.34 gigabases and 303 megabases of the Neandertal and Denisovan genome, respectively. We use these maps of archaic sequences to show that Neandertal admixture occurred multiple times in different non-African populations, characterize genomic regions that are significantly depleted of archaic sequences, and identify signatures of adaptive introgression. PMID- 26989199 TI - Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone. AB - Steroids regulate cell proliferation, tissue development, and cell signaling via two pathways: a nuclear receptor mechanism and genome-independent signaling. Sperm activation, egg maturation, and steroid-induced anesthesia are executed via the latter pathway, the key components of which remain unknown. Here, we present characterization of the human sperm progesterone receptor that is conveyed by the orphan enzyme alpha/beta hydrolase domain-containing protein 2 (ABHD2). We show that ABHD2 is highly expressed in spermatozoa, binds progesterone, and acts as a progesterone-dependent lipid hydrolase by depleting the endocannabinoid 2 arachidonoylglycerol (2AG) from plasma membrane. The 2AG inhibits the sperm calcium channel (CatSper), and its removal leads to calcium influx via CatSper and ensures sperm activation. This study reveals that progesterone-activated endocannabinoid depletion by ABHD2 is a general mechanism by which progesterone exerts its genome-independent action and primes sperm for fertilization. PMID- 26989203 TI - Introduction to a review series: the paradox of indolent B-cell lymphoma. PMID- 26989200 TI - Peptidoglycan from the gut microbiota governs the lifespan of circulating phagocytes at homeostasis. AB - Maintenance of myeloid cell homeostasis requires continuous turnover of phagocytes from the bloodstream, yet whether environmental signals influence phagocyte longevity in the absence of inflammation remains unknown. Here, we show that the gut microbiota regulates the steady-state cellular lifespan of neutrophils and inflammatory monocytes, the 2 most abundant circulating myeloid cells and key contributors to inflammatory responses. Treatment of mice with broad-spectrum antibiotics, or with the gut-restricted aminoglycoside neomycin alone, accelerated phagocyte turnover and increased the rates of their spontaneous apoptosis. Metagenomic analyses revealed that neomycin altered the abundance of intestinal bacteria bearing gamma-d-glutamyl-meso-diaminopimelic acid, a ligand for the intracellular peptidoglycan sensor Nod1. Accordingly, signaling through Nod1 was both necessary and sufficient to mediate the stimulatory influence of the flora on myeloid cell longevity. Stimulation of Nod1 signaling increased the frequency of lymphocytes in the murine intestine producing the proinflammatory cytokine interleukin 17A (IL-17A), and liberation of IL-17A was required for transmission of Nod1-dependent signals to circulating phagocytes. Together, these results define a mechanism through which intestinal microbes govern a central component of myeloid homeostasis and suggest perturbations of commensal communities can influence steady-state regulation of cell fate. PMID- 26989202 TI - Optimizing therapy for nodal marginal zone lymphoma. AB - Nodal marginal zone lymphoma (NMZL) is a rare form of indolent small B-cell lymphoma which has only been clearly identified in the last 2 decades and which to date remains incurable. Progress in therapeutic management has been slow, largely due to the very small number of patients treated and the heterogeneity of treatments administered; thus, standard-of-care treatment is currently nonspecific for this lymphoma entity. In this review, treatments routinely used to manage adult NMZL patients are presented, principally based on immunochemotherapy (when treatment is needed). Biological research behind the key axes of agents currently under development is described; development of novel agents is heavily based on data from gene profiling and genome-wide sequencing research, uncovering a number of critical deregulated pathways specific to NMZL tumors. These include B-cell receptor, JAK/STAT, NF-kappaB, NOTCH, and Toll-like receptor signaling pathways, as well as intracellular processes such as the cell cycle, chromatin remodeling, and transcriptional regulation in terms of epigenetic modifiers, histones, or transcriptional co-repressors, along with immune escape via T-cell-mediated tumor surveillance. These pathways are examined in detail and a projection of how the field may evolve in the near future for an efficient personalized treatment approach for NMZL patients is presented. PMID- 26989201 TI - GNA13 loss in germinal center B cells leads to impaired apoptosis and promotes lymphoma in vivo. AB - GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre(+) GNA13-deficient mice demonstrate disordered GC architecture and dark zone/light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro. We also found that GNA13-deficient mice have increased numbers of GC B cells that display impaired caspase-mediated cell death and increased frequency of somatic hypermutation in the immunoglobulin VH locus. Lastly, GNA13 deficiency, combined with conditional MYC transgene expression in mouse GC B cells, promotes lymphomagenesis. Thus, GNA13 loss is associated with GC B-cell persistence, in which impaired apoptosis and ongoing somatic hypermutation may lead to an increased risk of lymphoma development. PMID- 26989204 TI - Follicular lymphoma: evolving therapeutic strategies. AB - Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. After decades of stagnation, the natural history of FL appears to have been favorably impacted by the introduction of rituximab. Randomized clinical trials have demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival. Maintenance rituximab strategies can improve progression-free survival. Even chemotherapy platforms have changed in the past 5 years, as bendamustine combined with rituximab has rapidly become a standard frontline strategy in North America and parts of Europe. Recent discoveries have identified patients at high risk for poor outcomes to first-line therapy (m7-Follicular Lymphoma International Prognostic Index [m7-FLIPI]) and for poor outcomes after frontline therapy (National LymphoCare Study). However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, and strategies to reduce the risk of transformation. The development of targeted agents, exploiting our current understanding of FL biology, is a high research priority. A multitude of novel therapies are under investigation in both the frontline and relapsed/refractory settings. It will be critical to identify the most appropriate populations for new agents and to develop validated surrogate end points, so that novel agents can be tested (and adopted, if appropriate) efficiently. PMID- 26989205 TI - The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance. AB - Extranodal marginal zone (MZ) B-cell lymphomas of the mucosa-associated lymphoid tissue (MALT) arise from lymphoid populations that are induced by chronic inflammation in extranodal sites. The best evidence of an etiopathogenetic link is provided by the association between Helicobacter pylori-positive gastritis and gastric MALT lymphoma. Indeed, successful eradication of this microorganism with antibiotics can be followed by gastric MALT lymphoma regression in most cases. Other microbial agents have been implicated in the pathogenesis of MZ lymphoma arising at different sites. Apart from gastric MALT lymphoma, antibiotic therapies have been adequately tested only in ocular adnexal MALT lymphomas where upfront doxycycline may be a reasonable and effective initial treatment of patients with Chlamydophila psittaci-positive lymphoma before considering more aggressive strategies. In all other instances, antibiotic treatment of nongastric lymphomas remains investigational. Indeed, there is no clear consensus for the treatment of patients with gastric MALT lymphoma requiring further treatment beyond H pylori eradication or with extensive disease. Both radiotherapy and systemic treatments with chemotherapy and anti-CD20 antibodies are efficacious and thus the experience of individual centers and each patient's preferences in terms of adverse effects are important parameters in the decision process. PMID- 26989206 TI - The role of autologous and allogeneic stem cell transplantation in the management of indolent B-cell lymphoma. AB - Despite improvements over the past decade in the overall survival of patients with indolent non-Hodgkin lymphomas, these lymphomas remain largely incurable with standard therapies. Immunochemotherapy with rituximab-based regimens has become a well-established standard of care in the primary and relapsed disease settings. The role of hematopoietic stem cell transplantation in indolent lymphoma has been defined by the adoption of this therapy largely in the relapse setting because randomized trials in the first-line setting have not shown survival advantages. Allogeneic stem cell transplantation has the possibility for cure because of the potential for immunologic graft-versus-lymphoma effect, but there are significant concerns regarding nonrelapse mortality. Autologous stem cell transplantation offers a safe treatment platform, but relapse remains a significant issue. The role of transplantation in the current treatment landscape of immunochemotherapy has not been conclusively proven, and randomized trials are lacking. This review summarizes the current relevant data regarding transplantation in indolent non-Hodgkin lymphoma and highlights the issues relevant to clinicians in the field. PMID- 26989208 TI - Sit-stand desks offer little evidence of health benefits, review finds. PMID- 26989207 TI - Splenic marginal zone lymphoma: from genetics to management. AB - Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy involving the spleen, bone marrow, and frequently the blood. SMZL lymphomagenesis involves antigen and/or superantigen stimulation and molecular deregulation of genes (NOTCH2 and KLF2) involved in the physiological differentiation of spleen marginal zone B cells. Diagnosis requires either spleen histology or, alternatively, the documentation of a typical cell morphology and immunophenotype on blood cells coupled with the detection of intrasinusoidal infiltration by CD20(+) cells in the bone marrow. Among B-cell tumors, deletion of 7q and NOTCH2 mutations are almost specific lesions of SMZL, thus representing promising diagnostic biomarkers of this lymphoma. Although the majority of SMZLs show an indolent course with a median survival of approximately 10 years, nearly 30% of patients experience a poor outcome. No randomized trials are reported for SMZL, and few prospective trials are available. A watch-and-wait approach is advisable for asymptomatic patients. Treatment options for symptomatic patients ranges from splenectomy to rituximab alone or combined with chemotherapy. In some geographic areas, a subset of patients with SMZL associates with hepatitis C virus infection, prompting virus eradication as an effective lymphoma treatment. It would be worthwhile to explore deregulated cellular programs of SMZL as therapeutic targets in the future; improved clinical and biological prognostication will be essential for identifying patients who may benefit from novel approaches. PMID- 26989209 TI - Cervical pessary does not prevent preterm births, study shows. PMID- 26989210 TI - This mismanagement of the NHS amounts to neglect. PMID- 26989211 TI - South Africa's sex workers will receive HIV prevention and treatment. PMID- 26989212 TI - Feasible experiments on the possibility of transmitting acquired habits by means of inheritance. PMID- 26989213 TI - Commentary: Before Weismann and germplasm there was Galton and eugenics: the biological and political meaning of the inheritance of acquired characteristics in the late 19th century. PMID- 26989215 TI - Commentary: Lamarckian inheritance and epigenetics: is there a connection? PMID- 26989216 TI - IJE Photo Essay Competition. PMID- 26989214 TI - Commentary: Inheritance of acquired characteristics: eliminating alternatives in the search for mechanisms. Commentary on Galton F: Feasible experiments on the possibility of transmitting acquired habits by means of inheritance. PMID- 26989217 TI - 2015 photo essay competition: a few judging reflections. PMID- 26989218 TI - Spontaneous hypothermia in human sepsis is a transient, self-limiting, and nonterminal response. AB - Hypothermia in sepsis is generally perceived as something dysregulated and progressive although there has been no assessment on the natural course of this phenomenon in humans. This was the first study on the dynamics of hypothermia in septic patients not subjected to active rewarming, and the results were surprising. A sample of 50 subjects presenting with spontaneous hypothermia during sepsis was drawn from the 2005-2012 database of an academic hospital. Hypothermia was defined as body temperature below 36.0 degrees C for longer than 2 h, with at least one reading of 35.5 degrees C or less. The patients presented with 138 episodes of hypothermia, 21 at the time of the sepsis diagnosis and 117 with a later onset. However, hypothermia was uncommon in the final 12 h of life of the patients that succumbed. The majority (97.1%) of the hypothermic episodes were transient and self-limited; the median recovery time was 6 h; body temperature rarely fell below 34.0 degrees C. Bidirectional oscillations in body temperature were evident in the course of hypothermia. Nearly half of the hypothermic episodes had onset in the absence of shock or respiratory distress, and the incidence of hypothermia was not increased during either of these conditions. Usage of antipyretic drugs, sedatives, neuroleptics, or other medications did not predict the onset of hypothermia. In conclusion, hypothermia appears to be a predominantly transient, self-limiting, and nonterminal phenomenon that is inherent to human sepsis. These characteristics resemble those of the regulated hypothermia shown to replace fever in animal models of severe systemic inflammation. PMID- 26989219 TI - Intestinal and sublingual microcirculation are more severely compromised in hemodilution than in hemorrhage. AB - The alterations in O2 extraction in hemodilution have been linked to fast red blood cell (RBC) velocity, which might affect the complete release of O2 from Hb. Fast RBC velocity might also explain the normal mucosal-arterial Pco2 (DeltaPco2). Yet sublingual and intestinal microcirculation have not been completely characterized in extreme hemodilution. Our hypothesis was that the unchanged DeltaPco2 in hemodilution depends on the preservation of villi microcirculation. For this purpose, pentobarbital-anesthetized and mechanically ventilated sheep were submitted to stepwise hemodilution (n = 8), hemorrhage (n = 8), or no intervention (sham, n = 8). In both hypoxic groups, equivalent reductions in O2 consumption (Vo2) were targeted. Microcirculation was assessed by videomicroscopy, intestinal DeltaPco2 by air tonometry, and Vo2 by expired gases analysis. Although cardiac output and superior mesenteric flow increased in hemodilution, from the very first step (Hb = 5.0 g/dl), villi functional vascular density and RBC velocity decreased (21.7 +/- 0.9 vs. 15.9 +/- 1.0 mm/mm(2) and 1,033 +/- 75 vs. 850 +/- 79 MUm/s, P < 0.01). In the last stage (Hb = 1.2 g/dl), these variables were lower in hemodiution than in hemorrhage (11.1 +/- 0.5 vs. 15.4 +/- 0.9 mm/mm(2) and 544 +/- 26 vs. 686 +/- 70 MUm/s, P < 0.01), and were associated with lower intestinal fractional O2 extraction (0.61 +/- 0.04 vs. 0.79 +/- 0.02, P < 0.01) but preserved DeltaPco2 (5 +/- 2 vs. 25 +/- 4 mmHg, P < 0.01). Therefore, alterations in O2 extraction in hemodilution seemed related to microvascular shunting, not to fast RBC velocity. The severe microvascular abnormalities suggest that normal DeltaPco2 was not dependent on CO2 washout by the villi microcirculation. Increased perfusion in deeper intestinal layers might be an alternative explanation. PMID- 26989222 TI - 3-Methylmethcathinone--Interpretation of Blood Concentrations Based on Analysis of 95 Cases. AB - 3-Methylmethcathinone (3-MMC) has been one of the most popular new psychoactive substances (NPS) in Poland in recent years. 3-MMC was found in blood in 95 cases sent to the Institute of Forensic Research (IFR) during the two and a half year period, from 2013 to half of 2015. 3-MMC was determined in 13 and 48 cases in 2013 and 2014 year-round casework, respectively, while only in the first half of 2015 year it was present in 34 cases. In most cases, 3-MMC was detected together with other novel psychoactive substances and conventional drugs. Blood analyses for 3-MMC were carried out using liquid chromatography-tandem mass spectrometry (LC-MS-MS). The concentrations of 3-MMC in all 95 cases were in the range from traces (<1 ng/mL) up to 1.6 ug/mL (mean concentration 51.3 ng/mL, median 18.5 ng/mL). Concentration ranges in particular types of cases were respectively: DUID cases: 1-171 ng/mL; traffic accidents: <1-29 ng/mL; drug possession: 2-408 ng/mL; intoxication: <1-1600 ng/mL and other: <1-61 ng/mL. The parameters of the developed method such as the LOD (0.02 ng/mL) and LOQ (1 ng/mL) demonstrate that the method is well suited for the analysis of blood samples for 3-MMC and covers the range of typical blood concentrations. PMID- 26989220 TI - Physiology in Medicine: neuromuscular consequences of diabetic neuropathy. AB - Diabetic polyneuropathy (DPN) refers to peripheral nerve dysfunction as a complication of diabetes mellitus. This condition is relatively common and is likely a result of vascular and/or metabolic disturbances related to diabetes. In the early or less severe stages of DPN it typically results in sensory impairments but can eventually lead to major dysfunction of the neuromuscular system. Some of these impairments may include muscle atrophy and weakness, slowing of muscle contraction, and loss of power and endurance. Combined with sensory deficits these changes in the motor system can contribute to decreased functional capacity, impaired mobility, altered gait, and increased fall risk. There is no pharmacological disease-modifying therapy available for DPN and the mainstay of treatment is linked to treating the diabetes itself and revolves around strict glycemic control. Exercise therapy (including aerobic, strength, or balance training-based exercise) appears to be a promising preventative and treatment strategy for patients with DPN and those at risk. The goal of this Physiology in Medicine article is to highlight important and overlooked dysfunction of the neuromuscular system as a result of DPN with an emphasis on the physiologic basis for that dysfunction. Additionally, we sought to provide information that clinicians can use when following patients with diabetes or DPN including support for the inclusion of exercise-based therapy as an effective, accessible, and inexpensive form of treatment. PMID- 26989221 TI - Dilution space ratio of 2H and 18O of doubly labeled water method in humans. AB - Variation of the dilution space ratio (Nd/No) between deuterium ((2)H) and oxygen 18 ((18)O) impacts the calculation of total energy expenditure (TEE) by doubly labeled water (DLW). Our aim was to examine the physiological and methodological sources of variation of Nd/No in humans. We analyzed data from 2,297 humans (0.25 89 yr old). This included the variables Nd/No, total body water, TEE, body mass index (BMI), and percent body fat (%fat). To differentiate between physiologic and methodologic sources of variation, the urine samples from 54 subjects were divided and blinded and analyzed separately, and repeated DLW dosing was performed in an additional 55 participants after 6 mo. Sex, BMI, and %fat did not significantly affect Nd/No, for which the interindividual SD was 0.017. The measurement error from the duplicate urine sample sets was 0.010, and intraindividual SD of Nd/No in repeats experiments was 0.013. An additional SD of 0.008 was contributed by calibration of the DLW dose water. The variation of measured Nd/No in humans was distributed within a small range and measurement error accounted for 68% of this variation. There was no evidence that Nd/No differed with respect to sex, BMI, and age between 1 and 80 yr, and thus use of a constant value is suggested to minimize the effect of stable isotope analysis error on calculation of TEE in the DLW studies in humans. Based on a review of 103 publications, the average dilution space ratio is 1.036 for individuals between 1 and 80 yr of age. PMID- 26989224 TI - Throwing deep. PMID- 26989223 TI - Simultaneous Measurement of Serum Chemical Castration Agents and Testosterone Levels Using Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry. AB - Chemical castration involves administration of drugs to prevent pathological sexual behavior, reduce abnormal sexual drive and treat hormone-dependent cancers. Various drugs have been used for chemical castration; however, substantial interindividual variability and side effects are often observed. In this study, we proposed a useful monitoring method for the application of chemical castration agents using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS). Testosterone, cyproterone acetate, medroxyprogesterone, goserelin acetate, leuprolide acetate and triptorelin acetate were analyzed by UPLC-MS-MS. The target drugs were extracted from serum samples by double protein precipitation using methanol. Testosterone-1,2-d2 and buserelin acetate were used as internal standards. Parameters of analytical performance were evaluated, including imprecision, linearity, ion suppression and detection capabilities. Testosterone measurements were compared with the results of immunoassays. Serum specimens from 51 subjects who underwent chemical castration were analyzed. All drugs and testosterone were well extracted and separated using our method. The method was essentially free from potential interferences and ion suppression. Within-run and between-run imprecision values were <15%. The lower limits of quantification were 0.125 and 0.5-1.0 ng/mL for testosterone and other drugs, respectively. Good correlations with pre-existing immunoassays for testosterone measurement were observed. Sera from subjects who underwent androgen deprivation therapy showed variable levels of drugs. We successfully developed a UPLC-MS-MS-based monitoring method for chemical castration. The performance of our method was generally acceptable. This method may provide a novel monitoring strategy for chemical castration to enhance expected effects while reducing unwanted side effects. PMID- 26989226 TI - PARTICLE PHYSICS. Giant atom-smasher gears up to chase whiff of new physics. PMID- 26989227 TI - CLIMATE SCIENCE. Efforts to link climate change to severe weather gain ground. PMID- 26989229 TI - RESEARCH FACILITIES. Europe on course for a neutron drought. PMID- 26989228 TI - HUMAN EVOLUTION. Five matings for moderns, Neandertals. PMID- 26989230 TI - DIAGNOSTICS. Tests of blood-borne DNA pinpoint tissue damage. PMID- 26989231 TI - Voyage into darkness. PMID- 26989232 TI - SCIENCE DIPLOMACY. Reboot Gitmo for U.S.-Cuba research diplomacy. PMID- 26989233 TI - PHYSICS. Squeezing into superconductivity. PMID- 26989234 TI - IONIC MATERIALS. Large, soft, and polarizable hydride ions sneak around in an oxyhydride. PMID- 26989235 TI - ANTIMICROBIAL RESISTANCE. New mechanisms, new worries. PMID- 26989236 TI - IMMUNOLOGY. The enigmatic tuft cell in immunity. PMID- 26989237 TI - BIOCHEMISTRY. A radically unexpected mechanism. PMID- 26989238 TI - CHEMISTRY. Quantum dynamics in the smallest water droplet. PMID- 26989239 TI - NEUROSCIENCE. A satiating signal. PMID- 26989240 TI - A wave of inspiration. PMID- 26989241 TI - Risks of Wolbachia mosquito control. PMID- 26989242 TI - Curbing Iran's academic misconduct. PMID- 26989243 TI - Comment on "Unique in the shopping mall: On the reidentifiability of credit card metadata". AB - De Montjoye et al. (Reports, 30 January 2015, p. 536) claimed that most individuals can be reidentified from a deidentified transaction database and that anonymization mechanisms are not effective against reidentification. We demonstrate that anonymization can be performed by techniques well established in the literature. PMID- 26989244 TI - Response to Comment on "Unique in the shopping mall: On the reidentifiability of credit card metadata". AB - Sanchez et al.'s textbook k-anonymization example does not prove, or even suggest, that location and other big-data data sets can be anonymized and of general use. The synthetic data set that they "successfully anonymize" bears no resemblance to modern high-dimensional data sets on which their methods fail. Moving forward, deidentification should not be considered a useful basis for policy. PMID- 26989247 TI - The maternal microbiota drives early postnatal innate immune development. AB - Postnatal colonization of the body with microbes is assumed to be the main stimulus to postnatal immune development. By transiently colonizing pregnant female mice, we show that the maternal microbiota shapes the immune system of the offspring. Gestational colonization increases intestinal group 3 innate lymphoid cells and F4/80(+)CD11c(+) mononuclear cells in the pups. Maternal colonization reprograms intestinal transcriptional profiles of the offspring, including increased expression of genes encoding epithelial antibacterial peptides and metabolism of microbial molecules. Some of these effects are dependent on maternal antibodies that potentially retain microbial molecules and transmit them to the offspring during pregnancy and in milk. Pups born to mothers transiently colonized in pregnancy are better able to avoid inflammatory responses to microbial molecules and penetration of intestinal microbes. PMID- 26989246 TI - The nutrient sensor OGT in PVN neurons regulates feeding. AB - Maintaining energy homeostasis is crucial for the survival and health of organisms. The brain regulates feeding by responding to dietary factors and metabolic signals from peripheral organs. It is unclear how the brain interprets these signals. O-GlcNAc transferase (OGT) catalyzes the posttranslational modification of proteins by O-GlcNAc and is regulated by nutrient access. Here, we show that acute deletion of OGT from alphaCaMKII-positive neurons in adult mice caused obesity from overeating. The hyperphagia derived from the paraventricular nucleus (PVN) of the hypothalamus, where loss of OGT was associated with impaired satiety. These results identify O-GlcNAcylation in alphaCaMKII neurons of the PVN as an important molecular mechanism that regulates feeding behavior. PMID- 26989249 TI - Formation of pseudomorphic nanocages from Cu2O nanocrystals through anion exchange reactions. AB - The crystal structure of ionic nanocrystals (NCs) is usually controlled through reaction temperature, according to their phase diagram. We show that when ionic NCs with different shapes, but identical crystal structures, were subjected to anion exchange reactions under ambient conditions, pseudomorphic products with different crystal systems were obtained. The shape-dependent anionic framework (surface anion sublattice and stacking pattern) of Cu2O NCs determined the crystal system of anion-exchanged products of CuxS nanocages. This method enabled us to convert a body-centered cubic lattice into either a face-centered cubic or a hexagonally close-packed lattice to form crystallographically unusual, multiply twinned structures. Subsequent cation exchange reactions produced CdS nanocages while preserving the multiply-twinned structures. A high-temperature stable phase such as wurtzite ZnS was also obtained with this method at ambient conditions. PMID- 26989248 TI - Observation of superconductivity in hydrogen sulfide from nuclear resonant scattering. AB - High-temperature superconductivity remains a focus of experimental and theoretical research. Hydrogen sulfide (H2S) has been reported to be superconducting at high pressures and with a high transition temperature. We report on the direct observation of the expulsion of the magnetic field in H2S compressed to 153 gigapascals. A thin (119)Sn film placed inside the H2S sample was used as a sensor of the magnetic field. The magnetic field on the (119)Sn sensor was monitored by nuclear resonance scattering of synchrotron radiation. Our results demonstrate that an external static magnetic field of about 0.7 tesla is expelled from the volume of (119)Sn foil as a result of the shielding by the H2S sample at temperatures between 4.7 K and approximately 140 K, revealing a superconducting state of H2S. PMID- 26989245 TI - The geology of Pluto and Charon through the eyes of New Horizons. AB - NASA's New Horizons spacecraft has revealed the complex geology of Pluto and Charon. Pluto's encounter hemisphere shows ongoing surface geological activity centered on a vast basin containing a thick layer of volatile ices that appears to be involved in convection and advection, with a crater retention age no greater than ~10 million years. Surrounding terrains show active glacial flow, apparent transport and rotation of large buoyant water-ice crustal blocks, and pitting, the latter likely caused by sublimation erosion and/or collapse. More enigmatic features include tall mounds with central depressions that are conceivably cryovolcanic and ridges with complex bladed textures. Pluto also has ancient cratered terrains up to ~4 billion years old that are extensionally faulted and extensively mantled and perhaps eroded by glacial or other processes. Charon does not appear to be currently active, but experienced major extensional tectonism and resurfacing (probably cryovolcanic) nearly 4 billion years ago. Impact crater populations on Pluto and Charon are not consistent with the steepest impactor size-frequency distributions proposed for the Kuiper belt. PMID- 26989250 TI - Concerted hydrogen-bond breaking by quantum tunneling in the water hexamer prism. AB - The nature of the intermolecular forces between water molecules is the same in small hydrogen-bonded clusters as in the bulk. The rotational spectra of the clusters therefore give insight into the intermolecular forces present in liquid water and ice. The water hexamer is the smallest water cluster to support low energy structures with branched three-dimensional hydrogen-bond networks, rather than cyclic two-dimensional topologies. Here we report measurements of splitting patterns in rotational transitions of the water hexamer prism, and we used quantum simulations to show that they result from geared and antigeared rotations of a pair of water molecules. Unlike previously reported tunneling motions in water clusters, the geared motion involves the concerted breaking of two hydrogen bonds. Similar types of motion may be feasible in interfacial and confined water. PMID- 26989251 TI - Pure H- conduction in oxyhydrides. AB - A variety of proton (H(+))-conducting oxides are known, including those used in electrochemical devices such as fuel cells. In contrast, pure H(-) conduction, not mixed with electron conduction, has not been demonstrated for oxide-based materials. Considering that hydride ions have an ionic size appropriate for fast transport and also a strong reducing ability suitable for high-energy storage and conversion devices, we prepared a series of K2NiF4-type oxyhydrides, La(2-x y)Sr(x + y)LiH(1-x + y)O(3-y), in the hope of observing such H(-) conductors. The performance of an all-solid-state TiH2/o-La2LiHO3 (x = y = 0, o: orthorhombic)/Ti cell provided conclusive evidence of pure H(-) conduction. PMID- 26989252 TI - Fine-tuning of a radical-based reaction by radical S-adenosyl-L-methionine tryptophan lyase. AB - The radical S-adenosyl-L-methionine tryptophan lyase NosL converts L-tryptophan into 3-methylindolic acid, which is a precursor in the synthesis of the thiopeptide antibiotic nosiheptide. Using electron paramagnetic resonance spectroscopy and multiple L-tryptophan isotopologues, we trapped and characterized radical intermediates that indicate a carboxyl fragment migration mechanism for NosL. This is in contrast to a proposed fragmentation-recombination mechanism that implied Calpha-Cbeta bond cleavage of L-tryptophan. Although NosL resembles related tyrosine lyases, subtle substrate motions in its active site are responsible for a fine-tuned radical chemistry, which selects the Calpha-C bond for disruption. This mechanism highlights evolutionary adaptation to structural constraints in proteins as a route to alternative enzyme function. PMID- 26989255 TI - How I made my own opportunities. PMID- 26989253 TI - C9orf72 is required for proper macrophage and microglial function in mice. AB - Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Decreased expression of C9orf72 is seen in expansion carriers, suggesting that loss of function may play a role in disease. We found that two independent mouse lines lacking the C9orf72 ortholog (3110043O21Rik) in all tissues developed normally and aged without motor neuron disease. Instead, C9orf72 null mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. C9orf72 expression was highest in myeloid cells, and the loss of C9orf72 led to lysosomal accumulation and altered immune responses in macrophages and microglia, with age related neuroinflammation similar to C9orf72 ALS but not sporadic ALS human patient tissue. Thus, C9orf72 is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in C9orf72 expansion carriers. PMID- 26989254 TI - Prostaglandin E2 constrains systemic inflammation through an innate lymphoid cell IL-22 axis. AB - Systemic inflammation, which results from the massive release of proinflammatory molecules into the circulatory system, is a major risk factor for severe illness, but the precise mechanisms underlying its control are not fully understood. We observed that prostaglandin E2 (PGE2), through its receptor EP4, is down regulated in human systemic inflammatory disease. Mice with reduced PGE2 synthesis develop systemic inflammation, associated with translocation of gut bacteria, which can be prevented by treatment with EP4 agonists. Mechanistically, we demonstrate that PGE2-EP4 signaling acts directly on type 3 innate lymphoid cells (ILCs), promoting their homeostasis and driving them to produce interleukin 22 (IL-22). Disruption of the ILC-IL-22 axis impairs PGE2-mediated inhibition of systemic inflammation. Hence, the ILC-IL-22 axis is essential in protecting against gut barrier dysfunction, enabling PGE2-EP4 signaling to impede systemic inflammation. PMID- 26989257 TI - Designer protein delivery: From natural to engineered affinity-controlled release systems. AB - Exploiting binding affinities between molecules is an established practice in many fields, including biochemical separations, diagnostics, and drug development; however, using these affinities to control biomolecule release is a more recent strategy. Affinity-controlled release takes advantage of the reversible nature of noncovalent interactions between a therapeutic protein and a binding partner to slow the diffusive release of the protein from a vehicle. This process, in contrast to degradation-controlled sustained-release formulations such as poly(lactic-co-glycolic acid) microspheres, is controlled through the strength of the binding interaction, the binding kinetics, and the concentration of binding partners. In the context of affinity-controlled release--and specifically the discovery or design of binding partners--we review advances in in vitro selection and directed evolution of proteins, peptides, and oligonucleotides (aptamers), aided by computational design. PMID- 26989256 TI - The small satellites of Pluto as observed by New Horizons. AB - The New Horizons mission has provided resolved measurements of Pluto's moons Styx, Nix, Kerberos, and Hydra. All four are small, with equivalent spherical diameters of ~40 kilometers for Nix and Hydra and ~10 kilometers for Styx and Kerberos. They are also highly elongated, with maximum to minimum axis ratios of ~2. All four moons have high albedos (~50 to 90%) suggestive of a water-ice surface composition. Crater densities on Nix and Hydra imply surface ages of at least 4 billion years. The small moons rotate much faster than synchronous, with rotational poles clustered nearly orthogonal to the common pole directions of Pluto and Charon. These results reinforce the hypothesis that the small moons formed in the aftermath of a collision that produced the Pluto-Charon binary. PMID- 26989261 TI - Designing dose finding studies with an active control for exponential families. AB - In a recent paper Dette et al. (2014) introduced optimal design problems for dose finding studies with an active control. These authors concentrated on regression models with normal distributed errors (with known variance) and the problem of determining optimal designs for estimating the smallest dose, which achieves the same treatment effect as the active control. This paper discusses the problem of designing active-controlled dose finding studies from a broader perspective. In particular, we consider a general class of optimality criteria and models arising from an exponential family, which are frequently used analyzing count data. We investigate under which circumstances optimal designs for dose finding studies including a placebo can be used to obtain optimal designs for studies with an active control. Optimal designs are constructed for several situations and the differences arising from different distributional assumptions are investigated in detail. In particular, our results are applicable for constructing optimal experimental designs to analyze active-controlled dose finding studies with discrete data, and we illustrate the efficiency of the new optimal designs with two recent examples from our consulting projects. PMID- 26989260 TI - Surface compositions across Pluto and Charon. AB - The New Horizons spacecraft mapped colors and infrared spectra across the encounter hemispheres of Pluto and Charon. The volatile methane, carbon monoxide, and nitrogen ices that dominate Pluto's surface have complicated spatial distributions resulting from sublimation, condensation, and glacial flow acting over seasonal and geological time scales. Pluto's water ice "bedrock" was also mapped, with isolated outcrops occurring in a variety of settings. Pluto's surface exhibits complex regional color diversity associated with its distinct provinces. Charon's color pattern is simpler, dominated by neutral low latitudes and a reddish northern polar region. Charon's near-infrared spectra reveal highly localized areas with strong ammonia absorption tied to small craters with relatively fresh-appearing impact ejecta. PMID- 26989262 TI - Whole Cell Modeling: From Single Cells to Colonies. AB - A great deal of research over the last several years has focused on how the inherent randomness in movements and reactivity of biomolecules can give rise to unexpected large-scale differences in the behavior of otherwise identical cells. Our own research has approached this problem from two vantage points - a microscopic kinetic view of the individual molecules (nucleic acids, proteins, etc.) diffusing and interacting in a crowded cellular environment; and a broader systems-level view of how enzyme variability can give rise to well-defined metabolic phenotypes. The former led to the development of the Lattice Microbes software - a GPU-accelerated stochastic simulator for reaction-diffusion processes in models of whole cells; the latter to the development of a method we call population flux balance analysis (FBA). The first part of this article reviews the Lattice Microbes methodology, and two recent technical advances that extend the capabilities of Lattice Microbes to enable simulations of larger organisms and colonies. The second part of this article focuses on our recent population FBA study of Escherichia coli, which predicted variability in the usage of different metabolic pathways resulting from heterogeneity in protein expression. Finally, we discuss exciting early work using a new hybrid methodology that integrates FBA with spatially resolved kinetic simulations to study how cells compete and cooperate within dense colonies and consortia. PMID- 26989258 TI - The atmosphere of Pluto as observed by New Horizons. AB - Observations made during the New Horizons flyby provide a detailed snapshot of the current state of Pluto's atmosphere. Whereas the lower atmosphere (at altitudes of less than 200 kilometers) is consistent with ground-based stellar occultations, the upper atmosphere is much colder and more compact than indicated by pre-encounter models. Molecular nitrogen (N2) dominates the atmosphere (at altitudes of less than 1800 kilometers or so), whereas methane (CH4), acetylene (C2H2), ethylene (C2H4), and ethane (C2H6) are abundant minor species and likely feed the production of an extensive haze that encompasses Pluto. The cold upper atmosphere shuts off the anticipated enhanced-Jeans, hydrodynamic-like escape of Pluto's atmosphere to space. It is unclear whether the current state of Pluto's atmosphere is representative of its average state--over seasonal or geologic time scales. PMID- 26989263 TI - Calls reveal population structure of blue whales across the southeast Indian Ocean and the southwest Pacific Ocean. AB - For effective species management, understanding population structure and distribution is critical. However, quantifying population structure is not always straightforward. Within the Southern Hemisphere, the blue whale (Balaenoptera musculus) complex is extremely diverse but difficult to study. Using automated detector methods, we identified "acoustic populations" of whales producing region specific call types. We examined blue whale call types in passive acoustic data at sites spanning over 7,370 km across the southeast Indian Ocean and southwest Pacific Ocean (SWPO) from 2009 to 2012. In the absence of genetic resolution, these acoustic populations offer unique information about the blue whale population complex. We found that the Australian continent acts as a geographic boundary, separating Australia and New Zealand blue whale acoustic populations at the junction of the Indian and Pacific Ocean basins. We located blue whales in previously undocumented locations, including the far SWPO, in the Tasman Sea off the east coast of Australia, and along the Lau Basin near Tonga. Our understanding of population dynamics across this broad scale has significant implications to recovery and conservation management for this endangered species, at a regional and global scale. PMID- 26989265 TI - Big Cypress fox squirrel (Sciurus niger avicennia) ecology and habitat use in a cypress dome swamp-pine forest mosaic. AB - Forested wetlands are in decline, as are many species that are obligate residents. Big Cypress fox squirrels (BCFS; Sciurus niger avicennia) are a threatened endemic to wet pine and cypress forests in southwestern Florida. The region is characterized by development resulting in habitat loss, habitat fragmentation, and hydrological change that influence the quality of these wet forests. Through radiotelemetry and field observations, we examined the ecology and habitat use of BCFS in a natural cypress dome-pine forest mosaic. BCFS selected cypress domes for food and nests throughout the year. Cypress dome habitats were the only habitat type to be used more than available; however, the availability of nearby pine forest was also important. Home ranges were large relative to other tree squirrels, with male home ranges exceeding female ranges. Males overlapped more females than males, while sharing similar food preferences and use patterns with females, suggesting that the sexual dimorphism in home range size is related to mate searching. Roads and oil extraction pads were used less frequently than expected and were incorporated into home ranges less than randomly generated features. The importance of cypress domes within the wet forests and grasslands of Big Cypress National Preserve demonstrates the value of maintaining this delicate mosaic. PMID- 26989264 TI - Fine-scale spatial patterns of genetic relatedness among resident adult prairie voles. AB - Characterizing the spatial arrangement of related individuals within populations can convey information about opportunities for the evolution of kin-selected social behaviors, the potential for inbreeding, and the geographic distribution of genetic variation. Prairie voles (Microtus ochrogaster) are socially monogamous rodents that sometimes breed cooperatively. Individuals of both sexes are highly philopatric, and among natal dispersers, the average dispersal distance is about 30 m. Such limited natal dispersal can result in the spatial clustering of kin and we used microsatellite data to estimate genetic relatedness among resident adult prairie voles in 2 natural populations to test the hypothesis that limited natal dispersal of male and female prairie voles results in the spatial clustering of kin. Spatial autocorrelation analyses of nest residency and microsatellite data indicated that proximate same-sex adult residents of both sexes were significantly more related than more spatially distant resident same-sex adults in Kansas. In Indiana, adult female voles residing less than 20 m apart were also significantly more related than more spatially distant resident adult females but spatial clustering of kin was not detected among resident adult males. The spatial clustering of kin indicates that opportunities for kin-selected behaviors exist in both populations, especially among females. Differences in the patterns of spatial genetic structure among resident males between the Kansas and Indiana populations may be due to population differences in factors such as demography and mating system, as well as in the extent of natal philopatry. PMID- 26989259 TI - Pluto's interaction with its space environment: Solar wind, energetic particles, and dust. AB - The New Horizons spacecraft carried three instruments that measured the space environment near Pluto as it flew by on 14 July 2015. The Solar Wind Around Pluto (SWAP) instrument revealed an interaction region confined sunward of Pluto to within about 6 Pluto radii. The region's surprisingly small size is consistent with a reduced atmospheric escape rate, as well as a particularly high solar wind flux. Observations from the Pluto Energetic Particle Spectrometer Science Investigation (PEPSSI) instrument suggest that ions are accelerated and/or deflected around Pluto. In the wake of the interaction region, PEPSSI observed suprathermal particle fluxes equal to about 1/10 of the flux in the interplanetary medium and increasing with distance downstream. The Venetia Burney Student Dust Counter, which measures grains with radii larger than 1.4 micrometers, detected one candidate impact in +/-5 days around New Horizons' closest approach, indicating an upper limit of <4.6 kilometers(-3) for the dust density in the Pluto system. PMID- 26989267 TI - Technology Diffusion and Productivity Growth in Health Care. AB - We draw on macroeconomic models of diffusion and productivity to explain empirical patterns of survival gains in heart attacks. Using Medicare data for 2.8 million patients during 1986-2004, we find that hospitals rapidly adopting cost-effective innovations such as beta blockers, aspirin, and reperfusion, had substantially better outcomes for their patients. Holding technology adoption constant, the marginal returns to spending were relatively modest. Hospitals increasing the pace of technology diffusion ("tigers") experienced triple the survival gains compared to those with diminished rates ("tortoises"). In sum, small differences in the propensity to adopt effective technology lead to wide productivity differences across hospitals. PMID- 26989266 TI - Natural history collections-based research: progress, promise, and best practices. AB - Specimens and associated data in natural history collections (NHCs) foster substantial scientific progress. In this paper, we explore recent contributions of NHCs to the study of systematics and biogeography, genomics, morphology, stable isotope ecology, and parasites and pathogens of mammals. To begin to assess the magnitude and scope of these contributions, we analyzed publications in the Journal of Mammalogy over the last decade, as well as recent research supported by a single university mammal collection (Museum of Southwestern Biology, Division of Mammals). Using these datasets, we also identify weak links that may be hindering the development of crucial NHC infrastructure. Maintaining the vitality and growth of this foundation of mammalogy depends on broader engagement and support from across the scientific community and is both an ethical and scientific imperative given the rapidly changing environmental conditions on our planet. PMID- 26989268 TI - Computational and experimental structure-reactivity relationships: evidence for a side reaction in Alpine-Borane reductions of d-benzaldehydes. AB - Extraordinary stereoselectivity, approaching 100%, has been reported in the reductions of d-benzaldehydes by B-isopinocampheyl-9-borabicyclo[3.3.1]nonane (Alpine-Borane). This is likely because of the extreme size disparity of groups on either side of the carbonyl. Here, we present a structure-reactivity study whereby the reductions of variably substituted d-benzaldehydes are explored using highly sensitive measures for enantiomeric excess and relative reactivity. These results are compared to the relative rates predicted from density functional calculations. The results indicate that 2,6-disubstitution adversely affects the stereoselectivity by means of a non-selective reduction via the dehydroboration product of Alpine-Borane, 9-borabicyclo[3.3.1]nonane. PMID- 26989269 TI - Facile purification and click labeling with 2-[18F]fluoroethyl azide using solid phase extraction cartridges. AB - A facile method was developed to purify 2-[18F]fluoroethyl azide ([18F]FEA) using a C18 cartridge and an Oasis(r) HLB cartridge in series, in which [18F]FEA was exclusively trapped on the HLB cartridge. [18F]FEA can be eluted for reactions in solution; alternatively click labeling can be carried out on the HLB cartridge itself by loading an alkyne substrate and copper (I) catalyst dissolved in DMF onto the cartridge. This solid phase extraction methodology for purification and click labeling with [18F]FEA, either in solution or on the cartridge, is safe, simple, reproducible in high yield, and compatible with automated synthesis of 18F-labeled PET tracers. PMID- 26989270 TI - Synthesis of extended oxazoles II: Reaction manifold of 2-(halomethyl)-4,5 diaryloxazoles. AB - 2-(Halomethyl)-4,5-diphenyloxazoles are effective, reactive scaffolds which can be utilized for synthetic elaboration at the 2-position. Through substitution reactions, the chloromethyl analogue is used to prepare a number of 2-alkylamino , 2-alkylthio- and 2-alkoxy-(methyl) oxazoles. The 2-bromomethyl analogue offers a more reactive alternative to the chloromethyl compounds and is useful in the C alkylation of a stabilized (malonate) carbanion as exemplified by a concise synthesis of Oxaprozin. PMID- 26989271 TI - Dressing and Addressing the Mental Patient: The Uses of Clothing in the Admission, Care and Employment of Residents in English Provincial Mental Hospitals, c. 1860-1960. AB - Scholars of insanity and its historical antecedents have paid very little attention to personal and institutional clothing. Such dress, distributed to patients in mental institutions, has always been inscribed with the conflicting narratives of the period in which it was made and worn. The language of civil and medical authority is more evident than personal choice in the shape and address of the attire. This article examines clothing worn by patients in three Devon mental hospitals during the century before 1960. We consider the ways in which institutional clothing formed part of a hospital regimen of overt control, as well as suiting considerations of economy and employment that figured in these institutions. PMID- 26989273 TI - Industrial Characteristics and Employment of Older Manufacturing Workers in the Early-Twentieth-Century United States. AB - This study explores how industry-specific technological, organizational, and managerial features affected the employment of old male manufacturing workers in the early twentieth-century United States. Industrial characteristics favorably related to the employment of old industrial workers include high labor productivity, less capital- and material-intensive production, short workdays, low intensity of work, high job flexibility, and formalized employment relationship. Results show that aged industrial workers were heavily concentrated in "unfavorable" industries, suggesting that the contemporary argument of "industrial scrap heap" was applicable for most of the manufacturing workers in the early twentieth century United States. PMID- 26989272 TI - Automated Research Impact Assessment: A New Bibliometrics Approach. AB - As federal programs are held more accountable for their research investments, The National Institute of Environmental Health Sciences (NIEHS) has developed a new method to quantify the impact of our funded research on the scientific and broader communities. In this article we review traditional bibliometric analyses, address challenges associated with them, and describe a new bibliometric analysis method, the Automated Research Impact Assessment (ARIA). ARIA taps into a resource that has only rarely been used for bibliometric analyses: references cited in "important" research artifacts, such as policies, regulations, clinical guidelines, and expert panel reports. The approach includes new statistics that science managers can use to benchmark contributions to research by funding source. This new method provides the ability to conduct automated impact analyses of federal research that can be incorporated in program evaluations. We apply this method to several case studies to examine the impact of NIEHS funded research. PMID- 26989274 TI - Comment. PMID- 26989275 TI - Actomyosin contraction, aggregation and traveling waves in a treadmilling actin array. AB - We use perturbation theory to derive a continuum model for the dynamic actomyosin bundle/ring in the regime of very strong crosslinking. Actin treadmilling is essential for contraction. Linear stability analysis and numerical solutions of the model equations reveal that when the actin treadmilling is very slow, actin and myosin aggregate into equidistantly spaced peaks. When treadmilling is significant, actin filament of one polarity are distributed evenly, while filaments of the opposite polarity develop a shock wave moving with the treadmilling velocity. Myosin aggregates into a sharp peak surfing the crest of the actin wave. Any actomyosin aggregation diminishes contractile stress. The easiest way to maintain higher contraction is to upregulate the actomyosin turnover which destabilizes nontrivial patterns and stabilizes the homogeneous actomyosin distributions. We discuss the model's implications for the experiment. PMID- 26989276 TI - Insect pollination reduces yield loss following heat stress in faba bean (Vicia faba L.). AB - Global food security, particularly crop fertilization and yield production, is threatened by heat waves that are projected to increase in frequency and magnitude with climate change. Effects of heat stress on the fertilization of insect-pollinated plants are not well understood, but experiments conducted primarily in self-pollinated crops, such as wheat, show that transfer of fertile pollen may recover yield following stress. We hypothesized that in the partially pollinator-dependent crop, faba bean (Vicia faba L.), insect pollination would elicit similar yield recovery following heat stress. We exposed potted faba bean plants to heat stress for 5 days during floral development and anthesis. Temperature treatments were representative of heat waves projected in the UK for the period 2021-2050 and onwards. Following temperature treatments, plants were distributed in flight cages and either pollinated by domesticated Bombus terrestris colonies or received no insect pollination. Yield loss due to heat stress at 30 degrees C was greater in plants excluded from pollinators (15%) compared to those with bumblebee pollination (2.5%). Thus, the pollinator dependency of faba bean yield was 16% at control temperatures (18-26 degrees C) and extreme stress (34 degrees C), but was 53% following intermediate heat stress at 30 degrees C. These findings provide the first evidence that the pollinator dependency of crops can be modified by heat stress, and suggest that insect pollination may become more important in crop production as the probability of heat waves increases. PMID- 26989277 TI - Sublingual versus Vaginal Misoprostol for the Induction of Labor at Term: A Randomized, Triple-Blind, Placebo-Controlled Clinical Trial. AB - BACKGROUND: We sought to compare the effectiveness and safety of sublingual versus vaginal misoprostol for the termination of pregnancy with a live full-term fetus. METHODS: This randomized, triple-blind, placebo-controlled clinical trial was performed on 200 primiparous women with normal, singleton, full-term pregnancies candidated for the induction of labor. Sublingual and vaginal tablets containing misoprostol (25 mcg) or placebo in similar shapes were administered every 4 hours until the Bishop score reached above 8. Maternal and neonatal complications and outcomes were compared. RESULTS: There were 100 parturient women in each group. The mean maternal age, gestational age, and Bishop score at the commencement of misoprostol had no statistical differences between the sublingual and vaginal groups. The mean time interval between misoprostol commencement and delivery was 497.10+/-291.49 and 511.67+/-08.46 minutes for the sublingual and vaginal groups, correspondingly. Twenty-two women had Cesarean deliveries in the sublingual group versus 14 in the vaginal group. Meconium stained amniotic fluid was seen in 12 women in the sublingual group and 4 in the vaginal group (P=0.03). Late fetal heart rate deceleration was observed in 8 women in the sublingual group and 4 in the vaginal group (P=0.22). The mean neonatal birth weight, blood gas value at birth, Apgar score, and length of admission time in the neonatal intensive care unit were not different between the 2 groups. CONCLUSION: Sublingual and vaginal misoprostol had similar effectiveness; however, meconium-stained liquor was observed considerably more frequently with sublingual misoprostol than with vaginal misoprostol. TRIAL REGISTRATION NUMBER: IRCT201402096541N3. PMID- 26989278 TI - Level of Agreement between Children with Asthma and their Parents on Quality of Life. AB - BACKGROUND: Child-parent agreement is a controversial aspect of measuring health related quality of life (HRQoL) in children and adolescents. The aim of this study was to assess the agreement between the child self-reports and parent proxy reports of the PedsQL 3.0 Asthma Module in Iranian children with asthma to evaluate HRQoL. Moreover, the psychometric properties of the child and parent reports of the PedsQL 3.0 Asthma Module were assessed in the present study. METHODS: Participants were 112 children with asthma and their parents, who completed the Farsi version of the PedsQL 3.0 Asthma Module. The multitrait multimethod correlation matrix and factor analysis were used to test whether the child self-reports and the parent proxy reports measured the same construct. Additionally, convergent and discriminant validity and internal consistency were assessed using the Pearson correlation. RESULTS: The correlation between the child and parent HRQoL perceptions ranged between 0.13 and 0.36 across the same domains. Our factor analysis revealed that the child self-reports and the parent proxy reports measured 2 different constructs of HRQoL. Furthermore, our findings showed that both the child self-reports and the parent proxy reports of the PedsQL 3.0 Asthma Module had excellent internal consistency and acceptable convergent and discriminant validity. CONCLUSION: Although the child self-reports and the parent proxy reports of the Farsi version of PedsQL 3.0 Asthma Module showed good psychometric properties, they were not interchangeable. Our children with asthma and their parents evaluated child HRQoL from their own viewpoints. PMID- 26989279 TI - Comparison of the Wave Amplitude of Visually Evoked Potential in Amblyopic Eyes between Patients with Esotropia and Anisometropia and a Normal Group. AB - BACKGROUND: We compared the wave amplitude of visually evoked potential (VEP) between patients with esotropic and anisometropic amblyopic eyes and a normal group. METHODS: The wave amplitude of VEP was documented in 2 groups of persons with amblyopia (15 with esotropia and 28 with anisometropia) and 1 group of individuals with normal visual acuity (n, 15). The amplitude of P100 was recorded monocularly with different spatial frequencies. RESULTS: Our statistical analysis revealed that the wave amplitude in the 2 groups with amblyopia was significantly decreased compared to that in the normal group (P<0.001). There was a significant difference regarding the amplitude in high spatial frequencies in both high- and low-contrast conditions between the groups with esotropia and anisometropia and the normal group (P<0.001). There were also significant differences in large check-size stimuli and low-contrast condition between the amblyopic groups with esotropia and anisometropia and the normal group (P=0.013 and P=0.044, respectively). In large check-size stimuli and high-contrast condition, a significant difference was indicated only in the comparison between the esotropic amblyopic eyes and the normal eyes (P=0.036). CONCLUSION: The wave amplitude parameter of VEP was influenced by both types of amblyopia, but it seems that this parameter was more sensitive to esotropic amblyopia than anisometropic amblyopia. This outcome may reflect a non-parallel pattern of cortical responses in the comparison of the 2 types of amblyopia with each other and with the control group, which may be beneficial for the diagnosis and treatment of amblyopia. PMID- 26989280 TI - Effects of Sesame Butter (Ardeh) versus Sesame Oil on Metabolic and Oxidative Stress Markers in Streptozotocin-Induced Diabetic Rats. AB - BACKGROUND: Diabetes is one of the most common metabolic disorders and is related to oxidative-stress-induced diseases. Given the role of dietary antioxidants in the control and prevention of diabetes, this study aimed to examine the effects of sesame butter versus sesame oil on the serum levels of glucose, lipid profile, and oxidative stress biomarkers in diabetic rats. METHODS: Forty male albino rats of Wistar strain were randomly divided into 4 groups (i.e., nondiabetic control rats, diabetic rats, diabetic rats treated with sesame butter, and diabetic rats treated with sesame oil). Experimental diabetes was induced with an intraperitoneal injection of streptozotocin (55 mg/kg). Sesame butter (1.25 g/kg) and sesame oil (0.5 g/kg) were given by oral gavage to the diabetic rats for 6 weeks. Finally, serum glucose, lipid profile, total antioxidant capacity (TAC), and malondialdehyde (MDA) levels were measured and analyzed statistically. RESULTS: Our data showed that the diabetic groups treated with sesame butter and sesame oil had significantly lower levels of glucose and higher levels of high density lipoprotein than did the diabetic control group at the end of the study (P<0.05). Sesame butter supplementation also increased TAC and decreased MDA concentrations significantly in the diabetic rats (P<0.05). CONCLUSION: The antihyperglycemic, antioxidative, and partly lipid-lowering effects of sesame butter make it an excellent candidate for future human studies on diabetes, although further research is needed to determine the exact dose and duration of supplementation. PMID- 26989281 TI - Relation between Working Memory Capacity and Auditory Stream Segregation in Children with Auditory Processing Disorder. AB - BACKGROUND: This study assessed the relationship between working memory capacity and auditory stream segregation by using the concurrent minimum audible angle in children with a diagnosed auditory processing disorder (APD). METHODS: The participants in this cross-sectional, comparative study were 20 typically developing children and 15 children with a diagnosed APD (age, 9-11 years) according to the subtests of multiple-processing auditory assessment. Auditory stream segregation was investigated using the concurrent minimum audible angle. Working memory capacity was evaluated using the non-word repetition and forward and backward digit span tasks. Nonparametric statistics were utilized to compare the between-group differences. The Pearson correlation was employed to measure the degree of association between working memory capacity and the localization tests between the 2 groups. RESULTS: The group with APD had significantly lower scores than did the typically developing subjects in auditory stream segregation and working memory capacity. There were significant negative correlations between working memory capacity and the concurrent minimum audible angle in the most frontal reference location (0 degrees azimuth) and lower negative correlations in the most lateral reference location (60 degrees azimuth) in the children with APD. CONCLUSION: The study revealed a relationship between working memory capacity and auditory stream segregation in children with APD. The research suggests that lower working memory capacity in children with APD may be the possible cause of the inability to segregate and group incoming information. PMID- 26989282 TI - Biphasic Response to Luteolin in MG-63 Osteoblast-Like Cells under High Glucose Induced Oxidative Stress. AB - BACKGROUND: Clinical evidence indicates the diabetes-induced impairment of osteogenesis caused by a decrease in osteoblast activity. Flavonoids can increase the differentiation and mineralization of osteoblasts in a high-glucose state. However, some flavonoids such as luteolin may have the potential to induce cytotoxicity in osteoblast-like cells. This study was performed to investigate whether a cytoprotective concentration range of luteolin could be separated from a cytotoxic concentration range in human MG-63 osteoblast-like cells in high glucose condition. METHODS: Cells were cultured in a normal- or high-glucose medium. Cell viability was determined with the MTT assay. The formation of intracellular reactive oxygen species (ROS) was measured using probe 2',7' dichlorofluorescein diacetate, and osteogenic differentiation was evaluated with an alkaline phosphatase bioassay. RESULTS: ROS generation, reduction in alkaline phosphatase activity, and cell death induced by high glucose were inhibited by lower concentrations of luteolin (EC50, 1.29+/-0.23 uM). Oxidative stress mediated by high glucose was also overcome by N-acetyl-L-cysteine. At high concentrations, luteolin caused osteoblast cell death in normal- and high-glucose states (IC50, 34+/-2.33 and 27+/-2.42 uM, respectively), as represented by increased ROS and decreased alkaline phosphatase activity. CONCLUSION: Our results indicated that the cytoprotective action of luteolin in glucotoxic condition was manifested in much lower concentrations, by a factor of approximately 26 and 20, than was its cytotoxic activity, which occurred under normal or glucotoxic condition, respectively. PMID- 26989283 TI - Efficacy of Biofeedback Therapy before and after Sphincteroplasty for Fecal Incontinence because of Obstetric Injury: A Randomized Controlled Trial. AB - Fecal incontinence is a challenging condition in that it exerts various psychosocial impacts on daily life. Different treatment modalities have been suggested for fecal incontinence. The present study aimed to evaluate the efficacy of biofeedback therapy in combination with surgery in the management of fecal incontinence. The present randomized controlled trial was performed on 27 women with a complaint of fecal incontinence because of delivery trauma. The patients underwent sphincteroplasty and levatorplasty via the same method by 2 colorectal surgeons. In Group I, biofeedback therapy was performed 3 months before and 6 months after the surgery; in Group II, biofeedback therapy was applied only 6 months after the surgery; and in Group III, only surgical management was performed. The results revealed a significant difference between the preoperative and postoperative Wexner scores of incontinence in all the 3 groups. Additionally, the difference between the preoperative and postoperative scores was significant only in Group I and Group III, but not in Group II. The reduction in the Wexner score was significantly less in Group III. However, no significant difference was observed between the 3 groups concerning the mean difference of preoperative and postoperative manometry. The present study revealed no significant role for biofeedback therapy alone in the improvement of manometric evaluation. However, the Wexner score, which is an indicator of patient satisfaction, increased with biofeedback therapy following sphincteroplasty. In general, surgical treatment is now reserved for selected patients with fecal incontinence and has recently been developed with biofeedback therapy. TRIAL REGISTRATION NUMBER: IRCT201206039936N1. PMID- 26989284 TI - Growth Kinetics, Characterization, and Plasticity of Human Menstrual Blood Stem Cells. AB - One of the readily available sources of mesenchymal stem cells (MSCs) is menstrual blood-derived stem cells (Men-SCs), which exhibit characteristics similar to other types of MSCs. This study was performed to determine the growth kinetics, plasticity, and characterization of Men-SCs in women. During spring 2014 in the southern Iranian city of Shiraz, menstrual blood (5 mL) was obtained from 10 women on their third day of menstruation in 2 age groups of 30 to 40 and 40 to 50 years old. Ficoll was used to separate the mononuclear cell fraction. After the Men-SCs were cultured, they were subcultured up to passage 4. Growth behavior and population doubling time were evaluated by seeding 5*10(4) cells into 12- and 24-well culture plates, and the colonies were enumerated. The expression of CD44, CD90, and CD34 was evaluated. The osteogenic potential was assessed by alizarin red staining. The Men-SCs were shown to be plastic adherent and spindle-shaped. Regarding the growth curves in the 12- and 24-well culture plates, it was demonstrated that in the women aged between 30 and 40 years, population doubling time was 55.5 and 62 hours, respectively, while these values in the women aged between 40 and 50 years were 70.4 and 72.4 hours, correspondingly. Positive expression of CD44 and CD90 and negative expression of CD34 were noted. In the osteogenic differentiation medium, the cells differentiated toward osteoblasts. As human Men-SCs are easily collectable without any invasive procedure and are a safe and rapid source of MSCs, they can be a good candidate for stem cell banking and cell transplantation in women. PMID- 26989285 TI - Effectiveness of Spiritual Group Therapy on Quality of Life and Spiritual Well Being among Patients with Breast Cancer. AB - Cancer is deemed the century's major health problem, and its increasing growth during the last decades has made experts concerned more than ever. Of all types of cancer, breast cancer is regarded as the second most common disease among women. The aim of this study was to determine the effectiveness of spiritual group therapy on quality of life and spiritual well-being among patients suffering from breast cancer. The present research was carried out between March and June 2011. The sample consisted of 24 participants randomly assigned to 2 groups: an experimental group (n, 12) and a control group (n, 12). All the subjects completed questionnaires on quality of life and spiritual well-being in pretest and posttest. The experimental group received 12 sessions of spiritual group therapy. The results demonstrated improvement in quality of life and spiritual well-being in the experimental group. In conclusion, spiritual group therapy can be used to improve quality of life and spiritual well-being (religious health and existential health) among patients with breast cancer. PMID- 26989287 TI - Intracardiac Thrombosis in Sickle Cell Disease. AB - In patients with sickle cell disease, thrombotic microangiopathy is a rare complication. Also in sickle cell disease, intracardiac thrombus formation without structural heart diseases or atrial arrhythmias is a rare phenomenon. We herein describe a 22-year-old woman, who was a known case of sickle cell betathalassemia, had a history of recent missed abortion, and was admitted with a vaso-occlusive crisis. The patient had manifestations of microangiopathic hemolytic anemia, including laboratory evidence of hemolytic anemia, thrombocytopenia, respiratory distress, fever, jaundice, and abnormal liver function and coagulation tests, accompanied by clot formation on the Eustachian valve of the inferior vena cava in the right atrium and also a long and worm-like thrombus in the right ventricle. Therapeutic plasma exchange improved her clinical condition, and her intracardiac thrombus was completely resolved after 1 week. Echocardiography, as a simple and inexpensive imaging modality, had a significant role in the diagnosis and follow-up of this patient. PMID- 26989286 TI - Aggressive Calcifying Epithelial Odontogenic Tumor of the Maxillary Sinus with Extraosseous Oral Mucosal Involvement: A Case Report. AB - Calcifying epithelial odontogenic tumors are benign odontogenic neoplasms whose occurrence in the maxillary sinus is rare. Maxillary tumors tend to be locally aggressive and may rapidly involve the surrounding vital structures. We report a case of a large calcifying epithelial odontogenic tumor of the maxilla, involving the maxillary sinus in a 48-year-old woman. The tumor was largely intraosseous. In the canine and first premolar regions, the loss of bone could be palpated but the oral mucosa appeared normal. Histologically, the tumor tissue could be seen in the connective tissue below the oral epithelium. The most significant finding was the presence of an intraosseous tumor with an extraosseous involvement in a single tumor, indicating aggressive behavior and warranting aggressive treatment. In this article, we discuss the rare presentation of the tumor and its radiological appearance and histological features. We also highlight the importance of a detailed histopathological examination of the excised specimen. PMID- 26989288 TI - Exsanguinating Hemorrhage during Open Biopsy in a Primary Breast Angiosarcoma: A Case Report. AB - Angiosarcomas are endothelial cell neoplasms in the lining of the blood vessel wall and account for about 0.04% of all breast malignancies with a high rate of error in primary diagnosis. The breast angiosarcoma is a rare and uncommon pathology and has been described mostly as case reports. Indeed, only a limited number of cases have been published. Accordingly, the natural history of this tumor and its clinical course remain unclear, and as a consequence, no uniform treatment strategy exists. We present the clinical course and challenges in the diagnosis of a primary angiosarcoma of the breast in a young woman, presenting with a mass in her left breast. Fine-needle aspiration and core needle biopsy failed to confer a correct diagnosis. She suffered severe bleeding at the time of open biopsy and underwent total mastectomy, followed by adjuvant chemotherapy. Young women with solid breast tumors, especially those that are highly vascular, should be considered malignant until proven otherwise. Accurate diagnosis may be difficult. Open biopsy can be diagnostic, although exsanguinating bleeding may occur. Thus, performing open biopsy in locations other than equipped operating rooms may be hazardous and should be avoided. PMID- 26989289 TI - Uterocutaneous Fistula Following Cesarean Section: Successful Management of a Case. AB - A uterocutaneous fistula is a rare clinical presentation that occurs following Cesarean section and other pelvic operations. There are only a few reports discussing the treatments. We describe a patient with successful surgical management and review the literature. A 25-year-old woman referred to our department 13 months after her first Cesarean section. She had a history of an abdominal mass and collection 2 months after surgery and some fistula opening with discharge from her previous incision. She had a previous surgical operation and antibiotic therapy without complete response. We performed fistulography to evaluate the tracts. In the operation - she had fistula tracts, one of which was between the uterus and skin. We debrided the necrotic tissue in the uterus, excised the fistula tracts, and drained the uterine cavity. At 8 months' postoperative follow-up, she had no recurrence. A uterocutaneous fistula is a rare condition with many causes and needs proper investigation and timely medical and surgical management. PMID- 26989290 TI - Minor Contribution of inhA-15 Mutations to the Rapid Detection of Isoniazid Resistance in Mycobacterium Tuberculosis Isolates. PMID- 26989291 TI - Nodular Melanoma. PMID- 26989292 TI - A comment on sample size calculations for binomial confidence intervals. AB - In this article we examine sample size calculations for a binomial proportion based on the confidence interval width of the Agresti-Coull, Wald and Wilson Score intervals. We pointed out that the commonly used methods based on known and fixed standard errors cannot guarantee the desired confidence interval width given a hypothesized proportion. Therefore, a new adjusted sample size calculation method was introduced, which is based on the conditional expectation of the width of the confidence interval given the hypothesized proportion. With the reduced sample size, the coverage probability can still maintain at the nominal level and is very competitive to the converge probability for the original sample size. PMID- 26989293 TI - Predictive Value of Plasma MicroRNA-216a/b in the Diagnosis of Esophageal Squamous Cell Carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is a common human malignancy with poor survival, which was usually diagnosed at an advanced stage. MicroRNAs (miRNAs), a class of single stranded noncoding RNAs with only 17-25 ribonucleotides, were demonstrated to play an important role in lots of cancers. In the recent years, increasing evidence revealed that circulating miRNAs exhibited great potential in the diagnosis of various types of cancers. The present study was designed to evaluate the diagnostic value of plasma miRNA-216a/b for ESCC. Our results showed that the expression level of plasma miRNA-216a/b was significantly lower in ESCC patients compared with that of healthy controls. The receiver operating characteristic (ROC) curve analysis yielded an area under the ROC curve (AUC) value of 0.877 [95% CI (confidence interval): 0.818-0.922] for miRNA-216a and 0.756 (95% CI: 0.685-0.819) for miRNA-216b. Clinical data indicated that plasma miRNA-216a/b were inversely correlated with lymph node metastasis and TNM stage. Additionally, the plasma miRNA-216b expression level was significantly upregulated in postoperative samples compared to preoperative samples. Our study, for the first time, demonstrated that plasma miRNA-216a/b might serve as potential biomarkers for the diagnosis of ESCC and dysregulation of miRNA-216a/b might be involved in the progression of ESCC. PMID- 26989294 TI - Soluble TNF-Like Weak Inducer of Apoptosis as a New Marker in Preeclampsia: A Pilot Clinical Study. AB - INTRODUCTION: All findings of preeclampsia appear as the clinical consequences of diffuse endothelial dysfunction. Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) was recently introduced as a TNF related cytokine in various inflammatory and noninflammatory disorders. sTWEAK was found to be related to endothelial dysfunction in patients with chronic kidney disease. In our study we aimed to compare sTWEAK levels in women with preeclampsia to corresponding levels in a healthy pregnant control group. MATERIALS AND METHODS: The study was undertaken with 33 patients with preeclampsia and 33 normal pregnant women. The concentration of sTWEAK in serum was calculated with an enzyme linked immunosorbent assay (ELISA) kit. RESULTS: Serum creatinine, uric acid, LDH levels, and uPCR were significantly higher in the patient group compared to the control group. sTWEAK levels were significantly lower in preeclamptic patients (332 +/- 144 pg/mL) than in control subjects (412 +/- 166 pg/mL) (p = 0.04). DISCUSSION: Our study demonstrates that sTWEAK is decreased in patients with preeclampsia compared to healthy pregnant women. There is a need for further studies to identify the role of sTWEAK in the pathogenesis of preeclampsia and to determine whether it can be regarded as a predictor of the development of preeclampsia. PMID- 26989296 TI - Effect of deoxycorticosterone acetate-salt-induced hypertension on diabetic peripheral neuropathy in alloxan-induced diabetic WBN/Kob rats. AB - The relationship between hypertension and diabetic peripheral neuropathy (DPN) has recently been reported in clinical research, but it remains unclear whether hypertension is a risk factor for DPN. To investigate the effects of hypertension on DPN, we analyzed morphological features of peripheral nerves in diabetic rats with hypertension. Male WBN/Kob rats were divided into 2 groups: alloxan-induced diabetic rats with deoxycorticosterone acetate-salt (DOCA-salt) treatment (ADN group) and nondiabetic rats with DOCA-salt treatment (DN group). Sciatic, tibial (motor) and sural (sensory) nerves were subjected to qualitative and quantitative histomorphological analysis. Systolic blood pressure in the two groups exhibited a higher value (>140 mmHg), but there was no significant difference between the two groups. Endoneurial blood vessels in both groups presented endothelial hypertrophy and narrowing of the vascular lumen. Electron microscopically, duplication of basal lamina surrounding the endothelium and pericyte of the endoneurial vessels was observed, and this lesion appeared to be more frequent and severe in the ADN group than the DN group. Many nerve fibers of the ADN and DN groups showed an almost normal appearance, whereas morphometrical analysis of the tibial nerve showed a significant shift to smaller fiber and myelin sizes in the ADN group compared with DN group. In sural nerve, the fiber and axon-size significantly shifted to a smaller size in ADN group compared with the DN group. These results suggest that combined diabetes and hypertension could induce mild peripheral nerve lesions with vascular changes. PMID- 26989297 TI - Heme oxygenase-1 alleviates alcoholic liver steatosis: histopathological study. AB - Excessive alcohol consumption is one of the most important causes of hepatic steatosis, which involves oxidative stress. In particular, increased oxidative stress has been strongly linked to stimulation of the expression of heme oxygenase-1 (HO-1). This study aimed to investigate whether HO-1 could alleviates alcoholic steatosis in rats. Male Wistar rats were randomly divided into 4 groups: 1) the control group, 2) the EtOH group, 3) the EtOH + ZnPP-IX group and 4) the EtOH + Hemin group. Liver histopathology was investigated in weeks 1 and 4 after the start of the treatment period. Alcohol treatment significantly increased the hepatic malondialdehyde (MDA) levels, an oxidative stress marker. In addition, it increased the triglyceride, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in both weeks. Gross examination demonstrated a yellowish and slightly enlarged liver in the alcohol-treated rats. Hematoxylin and eosin (H&E) and Oil Red O staining indicated hepatic steatosis, which was characterized by diffuse, extensive fatty accumulation and discrete lipid droplets of variable size in hepatocytes of the alcohol-treated rats. Administration of the HO-1 inducer hemin resulted in upregulation of hepatic HO-1 gene expression, reduced the MDA, triglyceride, ALT and AST levels and alleviated alcoholic hepatic steatosis, whereas administration of the HO-1 inhibitor zinc protoporphyrin IX (ZnPP-IX) resulted in downregulation of hepatic HO-1 gene expression and could not alleviate alcoholic hepatic steatosis either week. In conclusion, HO-1 could alleviate alcoholic hepatic steatosis in male Wistar rats and may be useful in development of a new therapeutic approach. PMID- 26989295 TI - Biopolymers and supramolecular polymers as biomaterials for biomedical applications. AB - Protein- and peptide-based structural biopolymers are abundant building blocks of biological systems. Either in their natural forms, such as collagen, silk or fibronectin, or as related synthetic materials they can be used in various technologies. An emerging area is that of biomimetic materials inspired by protein-based biopolymers, which are made up of small molecules rather than macromolecules and can therefore be described as supramolecular polymers. These materials are very useful in biomedical applications because of their ability to imitate the extracellular matrix both in architecture and their capacity to signal cells. This article describes important features of the natural extracellular matrix and highlight how these features are being incorporated into biomaterials composed of biopolymers and supramolecular polymers. We particularly focus on the structures, properties, and functions of collagen, fibronectin, silk, and the supramolecular polymers inspired by them as biomaterials for regenerative medicine. PMID- 26989298 TI - Histopathological nerve and skeletal muscle changes in rats subjected to persistent insulin-induced hypoglycemia. AB - New insulin analogues with a longer duration of action and a flatter pharmacodynamic profile are developed to improve convenience and safety for diabetic patients. During the nonclinical development of such analogues, safety studies must be conducted in nondiabetic rats, which consequently are rendered chronically hypoglycemic. A rat comparator model using human insulin would be valuable, as it would enable differentiation between effects related to either persistent insulin-induced hypoglycemia (IIH) or a new analogue per se. Such a model could alleviate the need for an in-study-comparator and thereby reduce the number of animals used during development. Thus, the aims of the present study were i) to develop a preclinical animal model of persistent hypoglycemia in rats using human insulin infusion for four weeks and ii) to investigate histopathological changes in sciatic nerves and quadriceps femoris muscle tissue, as little is known about the response to persistent hypoglycemia in these tissues. Histopathologic changes in insulin-infused animals included axonal degeneration and myofibre degeneration. To our knowledge, this is the first study to show that persistent IIH provokes peripheral nerve and skeletal myofiber degeneration within the same animals. This suggests that the model can serve as a nonclinical comparator model during development of long-acting insulin analogues. PMID- 26989299 TI - Malaria in cynomolgus monkeys used in toxicity studies in Japan. AB - Plasmodium spp. protozoa cause malaria and are known to infect humans and a variety of animal species including macaque monkeys. Here we report both our experience with malaria recrudescence in cynomolgus monkeys (Macaca fascicularis) in a toxicity study and the results of a survey on Plasmodium infection in cynomolgus monkeys imported to Japan for laboratory use. A cynomolgus monkey from the toxicity study presented with severe anemia and Plasmodium protozoa in erythrocytes on a thin blood smear and was subsequently diagnosed with symptomatic malaria. In this animal, congestion and accumulation of hemozoin (malaria pigment) in macrophages were noted in the enlarged and darkly discolored spleen. As a follow-up for the experience, spleen sections from 800 cynomolgus monkeys in toxicity studies conducted between 2003 and 2013 were retrospectively examined for hemozoin deposition as a marker of Plasmodium infection. The origin of the animals included Cambodia, China, Indonesia, and Vietnam. Hemozoin deposition was confirmed in 44% of all examined monkeys. Monkeys from Indonesia showed the highest incidence of hemozoin deposition (approx. 80%). A high prevalence of Plasmodium infection in laboratory monkeys was also confirmed with polymerase chain reaction (PCR) by using Plasmodium genus-specific primers. Although Japan is not a country with endemic malaria, it is important to be aware of the prevalence and potential impact of background infection with Plasmodium spp. and recrudescence of symptomatic malaria in imported laboratory monkeys on pharmaceutical toxicity studies. PMID- 26989301 TI - Autopsy results of a case of ingestion of sodium hydroxide solution. AB - Sodium hydroxide is a strongly corrosive alkali. We describe herein a case of suicide by ingestion of sodium hydroxide. A man in his 80s was found dead with a mug and a bottle of caustic soda. Macroscopically, liquefaction and/or disappearance of esophagus, trachea and lung tissue and a grayish discoloration of the mucosa of the stomach were seen along with blackish brown coloration of the skin, mouth, and oral cavity. The contents of the gastrointestinal tract showed a pH level of 7-8 on pH indicator strips. Histopathologically, liquefactive necrosis of remnant lung tissue and the stomach were seen. As biological reactions such as vasodilatation and inflammation were not detected in these organs, only a short number of hours must have passed between ingestion and death. This human case provides valuable information concerning the direct irritation induced by systemic exposure to corrosive substances. PMID- 26989300 TI - Spontaneous extraskeletal osteosarcoma with various histological growth patterns in the abdominal wall of an ICR mouse. AB - Extraskeletal osteosarcoma is extremely rare in mice. This case report demonstrates a spontaneous murine extraskeletal osteosarcoma that exhibited various histological growth patterns in an ICR mouse. At necropsy, the tumor mass was located in the abdominal wall and was 45 * 30 * 25 mm in size. Histopathologically, the tumor showed the following four growth patterns: a solid pattern of polygonal cells embedded in an osteoid eosinophilic matrix with calcification, an irregular sheet pattern of short spindle cells accompanying some eosinophilic multinucleated cells, a fascicular pattern of spindle cells and a cystic pattern lined by short spindle cells. Immunohistochemically, most of the tumor cells were positive for vimentin, proliferating cell nuclear antigen and osterix. The multinucleated cells mentioned above were desmin positive and were regarded as regenerative striated muscles but not tumor cells. Since no clear continuity with normal bone tissues was observed, the tumor was diagnosed as an "extraskeletal osteosarcoma." PMID- 26989302 TI - Cutaneous mastocytosis with a mutation in the juxtamembrane domain of c-kit in a young laboratory beagle dog. AB - Cutaneous mastocytosis, which resembles a subset of urticaria pigmentosa in humans, is rare in dogs. We herein report unrepresentative neoplastic proliferation of mast cells in ventral skin removed routinely from a nine-month old female laboratory beagle dog at necropsy. A histological examination revealed diffuse extensive cellular infiltration from the superficial to deep dermis in most parts of the skin around the fourth and fifth mammary papilla without nodule formation. Tumor cells were fairly monomorphic, well-differentiated mast cells with round nuclei of small distinct nucleoli and moderate to abundant, slightly eosinophilic and granular cytoplasm. A perivascular arrangement of mast cells was noted at the margin of the lesions. Infiltration of eosinophils and degeneration of collagen were not observed in the dermis. Cutaneous mastocytosis was diagnosed based on these features. A sequence analysis of lesions revealed the deletion of Gln555 to Ile570 within the juxtamembrane domain of c-kit (exon 11). PMID- 26989303 TI - A spontaneously occurring malignant ovarian Sertoli cell tumor in a young Sprague Dawley rat. AB - Primary ovarian tumors are generally uncommon in rats used in toxicologic studies. A malignant Sertoli cell tumor was present in the ovary of a 19-week-old female Sprague Dawley rat. Macroscopically, the mass was white and firm, 10 * 13 * 17 mm in size, and located in the right ovary. Histopathologically, the mass was composed of nests of pleomorphic cells, which formed seminiferous-like tubules separated by a thin fibrovascular stroma. The tubules were lined by tumor cells, which had basally located nuclei and abundant eosinophilic and vacuolated cytoplasm. In some areas, the tumor cells were arranged in a retiform growth pattern, mimicking a rete testis/ovarii. Disseminated metastases to the surfaces of the mesentery, spleen and liver were also present. Immunohistochemically, many tumor cells were strongly positive for vimentin, estrogen receptor alpha and Ki 67. Some tumor cells were positive for pancytokeratin and inhibin alpha. These findings closely resemble those of an ovarian-derived human malignant Sertoli cell tumor. From our review of the literature, we believe this is the first report of a spontaneous malignant Sertoli cell tumor in the ovary of a young laboratory rat. This case might provide useful historical control information for rat toxicity studies. PMID- 26989304 TI - Green tea extract attenuates MNU-induced photoreceptor cell apoptosis via suppression of heme oxygenase-1. AB - The effects of green tea extract (GTE) on N-methyl-N-nitrosourea (MNU)-induced photoreceptor cell apoptosis were examined, and the possible mechanisms of action of GTE were assessed. Alterations in the retinal morphological architecture were determined by hematoxylin-eosin staining, vimentin immunoreactivity, and photoreceptor cell apoptosis (TUNEL labeling). Expression of oxidant marker, heme oxygenase (HO)-1, mRNA levels in outer nuclear cells was assessed by laser capture microdissection (LCM). Sprague-Dawley rats were given 40 mg/kg MNU at 7 weeks of age in the absence and presence of 250 mg/kg GTE treatment (once daily from 3 days prior to MNU for a maximum 10 days). Although photoreceptor cell degeneration began 24 hr after MNU, the morphological effects of GTE at the time point were not definitive. However, GTE lowered TUNEL labeling and HO-1 mRNA expression. At 7 days after MNU, photoreceptor damage was attenuated by GTE treatment. Therefore, the ability of GTE to reduce MNU-induced photoreceptor cell apoptosis may be due to its antioxidant properties. PMID- 26989305 TI - Susceptibility to N-methyl-N-nitrosourea-induced retinal degeneration in different rat strains. AB - To evaluate the potential role of genetic background in the susceptibility to retinal degeneration induced by N-methyl-N-nitrosourea (MNU), female rats of the Sprague-Dawley (SD), Long-Evans (LE) and Copenhagen (CH) strains were administered 50 mg/kg MNU or saline at 7 weeks of age. Retina morphology and morphometric analysis of all rats was performed 7 days after MNU administration. Atrophy of both the peripheral and central outer retina occurred in all rat strains exposed to MNU. Decreased photoreceptor cell ratio and increased retinal damage ratio were observed. The severities of the retinal atrophy were similar among all three rat strains. In conclusion, MNU-induced photoreceptor degeneration developed consistently in all three strains regardless of the absence (SD rats) or presence (LE and CH rats) of melanin in the retina, suggesting that genetic and melanin factors did not affect photoreceptor cell death after MNU. PMID- 26989307 TI - Eye injuries: improving our practice. PMID- 26989308 TI - The Ocular Trauma Score. PMID- 26989306 TI - Errata (Printer's correction). AB - [This corrects the article on p. 11 in vol. 27.][This corrects the article on p. 43 in vol. 27.][This corrects the article on p. 51 in vol. 27.][This corrects the article on p. 123 in vol. 27.][This corrects the article on p. 163 in vol. 27.][This corrects the article on p. 175 in vol. 27.][This corrects the article on p. 183 in vol. 27.][This corrects the article on p. 197 in vol. 27.][This corrects the article on p. 205 in vol. 27.][This corrects the article on p. 217 in vol. 27.][This corrects the article on p. 223 in vol. 27.][This corrects the article on p. 231 in vol. 27.][This corrects the article on p. 1 in vol. 28.][This corrects the article on p. 11 in vol. 28.][This corrects the article on p. 21 in vol. 28.][This corrects the article on p. 27 in vol. 28.][This corrects the article on p. 33 in vol. 28.][This corrects the article on p. 37 in vol. 28.][This corrects the article on p. 43 in vol. 28.][This corrects the article on p. 51 in vol. 28.][This corrects the article on p. 57 in vol. 28.][This corrects the article on p. 65 in vol. 28.][This corrects the article on p. 73 in vol. 28.][This corrects the article on p. 79 in vol. 28.][This corrects the article on p. 89 in vol. 28.][This corrects the article on p. 99 in vol. 28.][This corrects the article on p. 109 in vol. 28.][This corrects the article on p. 121 in vol. 28.][This corrects the article on p. 125 in vol. 28.][This corrects the article on p. 133 in vol. 28.][This corrects the article on p. 141 in vol. 28.][This corrects the article on p. 151 in vol. 28.][This corrects the article on p. 165 in vol. 28.][This corrects the article on p. 171 in vol. 28.][This corrects the article on p. 177 in vol. 28.][This corrects the article on p. 181 in vol. 28.][This corrects the article on p. 189 in vol. 28.][This corrects the article on p. 197 in vol. 28.][This corrects the article on p. 207 in vol. 28.][This corrects the article on p. 217 in vol. 28.][This corrects the article on p. 225 in vol. 28.][This corrects the article on p. 229 in vol. 28.][This corrects the article on p. 233 in vol. 28.][This corrects the article on p. 237 in vol. 28.][This corrects the article on p. 243 in vol. 28.]. PMID- 26989309 TI - Implementing and applying the Ocular Trauma Score: the challenges. PMID- 26989310 TI - Assessing an eye injury patient. PMID- 26989311 TI - Managing eye injuries. PMID- 26989312 TI - Talking with eye injury patients. PMID- 26989314 TI - Challenges of agriculture-related eye injuries in Nigeria. PMID- 26989313 TI - Preventing eye injuries. PMID- 26989315 TI - Preventing eye injuries in quarries. PMID- 26989316 TI - Protective eyewear for agricultural workers. PMID- 26989318 TI - Dr Erika Sutter 1917-2015. PMID- 26989317 TI - Improving access to refractive and eye health services. PMID- 26989319 TI - Peek. PMID- 26989320 TI - A 'health system' perspective on scaling up hospital cataract services. PMID- 26989321 TI - Caring for A- and B-scans. PMID- 26989322 TI - Manuals, guidelines and toolkits to support the elimination of blinding trachoma. PMID- 26989323 TI - Test your knowledge and understanding. PMID- 26989324 TI - Ocular Trauma Score: case study and quiz. PMID- 26989325 TI - Picture quiz. PMID- 26989327 TI - Prevalence of eyelid lesions in cutaneous leishmaniasis in Pakistan. PMID- 26989328 TI - Vision testing to prevent road traffic accidents in Kenya. PMID- 26989329 TI - Genetic Investigation of Complement Pathway Genes in Type 2 Diabetic Retinopathy: An Inflammatory Perspective. AB - Diabetic retinopathy (DR) has complex multifactorial pathogenesis. This study aimed to investigate the association of complement pathway genes with susceptibility to DR. Eight haplotype-tagging SNPs of SERPING1 and C5 were genotyped in 570 subjects with type 2 diabetes: 295 DR patients (138 nonproliferative DR [NPDR] and 157 proliferative DR [PDR]) and 275 diabetic controls. Among the six C5 SNPs, a marginal association was first detected between rs17611 and total DR patients (P = 0.009, OR = 0.53 for recessive model). In stratification analysis, a significant decrease in the frequencies of G allele and GG homozygosity for rs17611 was observed in PDR patients compared with diabetic controls (Pcorr = 0.032, OR = 0.65 and Pcorr = 0.016, OR = 0.37, resp.); it was linked with a disease progression. A haplotype AA defined by the major alleles of rs17611 and rs1548782 was significantly predisposed to PDR with increased risk of 1.54 (Pcorr = 0.023). Regarding other variants in C5 and SERPING1, none of the tagging SNPs had a significant association with DR and its subgroups (all P > 0.05). Our study revealed an association between DR and C5 polymorphisms with clinical significance, whereas SERPING1 is not a major genetic component of DR. Our data suggest a link of complement pathway with DR pathogenesis. PMID- 26989330 TI - Recruitment of Immune Cells into Inflamed Tissues: Consequences for Endothelial Barrier Integrity and Tissue Functionality. PMID- 26989331 TI - T Cell Response in Patients with Implanted Biological and Mechanical Prosthetic Heart Valves. AB - The study was aimed at assessing T cell subsets of peripheral blood from recipients of long-term functioning (more than 60 months) biological and mechanical heart valve prostheses. The absolute and relative number of CD4 and CD8 T cell subsets was analyzed: naive (N, CD45RA(+)CD62L(+)), central memory (CM, CD45RA(-)CD62L(+)), effector memory (EM, CD45RA(-)CD62L(-)), and terminally differentiated CD45RA-positive effector memory (TEMRA, CD45RA(+)CD62L(-)) in 25 persons with biological and 7 with mechanical prosthesis compared with 48 apparently healthy volunteers. The relative and absolute number of central memory and naive CD3(+)CD8(+) in patients with biological prosthesis was decreased (p < 0.001). Meanwhile the number of CD45RA(+)CD62L(-)CD3(+)CD8(+) and CD3(+)CD4(+) was increased (p < 0.001). Patients with mechanical prosthesis had increased absolute and relative number of CD45RA(+)CD62L(-)CD3(+)CD8(+) cells (p = 0.006). Also the relative number of CD3(+)CD4(+) cells was reduced (p = 0.04). We assume that altered composition of T cell subsets points at development of xenograft rejection reaction against both mechanical and biological heart valve prostheses. PMID- 26989332 TI - Radiotherapy Suppresses Bone Cancer Pain through Inhibiting Activation of cAMP Signaling in Rat Dorsal Root Ganglion and Spinal Cord. AB - Radiotherapy is one of the major clinical approaches for treatment of bone cancer pain. Activation of cAMP-PKA signaling pathway plays important roles in bone cancer pain. Here, we examined the effects of radiotherapy on bone cancer pain and accompanying abnormal activation of cAMP-PKA signaling. Female Sprague-Dawley rats were used and received tumor cell implantation (TCI) in rat tibia (TCI cancer pain model). Some of the rats that previously received TCI treatment were treated with X-ray radiation (radiotherapy). Thermal hyperalgesia and mechanical allodynia were measured and used for evaluating level of pain caused by TCI treatment. PKA mRNA expression in dorsal root ganglion (DRG) was detected by RT PCR. Concentrations of cAMP, IL-1beta, and TNF-alpha as well as PKA activity in DRG and the spinal cord were measured by ELISA. The results showed that radiotherapy significantly suppressed TCI-induced thermal hyperalgesia and mechanical allodynia. The level of PKA mRNA in DRG, cAMP concentration and PKA activity in DRG and in the spinal cord, and concentrations of IL-1beta and TNF alpha in the spinal cord were significantly reduced by radiotherapy. In addition, radiotherapy also reduced TCI-induced bone loss. These findings suggest that radiotherapy may suppress bone cancer pain through inhibition of activation of cAMP-PKA signaling pathway in DRG and the spinal cord. PMID- 26989333 TI - Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes. AB - Rheumatoid arthritis (RA) is characterized by synovial inflammation and hyperplasia. Fibroblast-like synoviocytes (FLSs) are apoptosis-resistant and contribute to the pathogenesis of RA by producing cytokines and proteolytic enzymes, which degrade the extracellular matrix. We evaluated the proapoptotic and anti-inflammatory activity of the small molecule Smac127 on RA-FLSs cultured in synovial fluid (SF), in order to reproduce the physiopathological environmental characteristic of RA joints. In this context, Smac127 induces apoptosis by inhibiting apoptosis proteins (IAPs). This inhibition activates caspase 3 and restores the apoptotic pathway. In addition, Smac127 induces a significant inhibition of the secretion of IL-15 and IL-6, stimulation of pannus formation, and damage of bone and cartilage in RA. Also the secretion of the anti inflammatory cytokine IL-10 is dramatically increased in the presence of Smac127. The cartilage destruction in RA patients is partly mediated by metalloproteinases; here we show that the MMP-1 production by fibroblasts cultured in SF is significantly antagonized by Smac127. Conversely, this molecule has no significant effects on RANKL and OPG production. Our observations demonstrate that Smac127 has beneficial regulatory effects on inflammatory state of RA-FLSs and suggest a potential use of Smac127 for the control of inflammation and disease progression in RA. PMID- 26989334 TI - Melatonin Attenuates Contrast-Induced Nephropathy in Diabetic Rats: The Role of Interleukin-33 and Oxidative Stress. AB - BACKGROUND: Inflammation and oxidative stress (OxS) contribute to the pathogenesis of diabetic kidney disease (DKD) and contrast-induced nephropathy (CIN). Patients with DKD were found to be more prone to CIN. Interleukin-33 (IL 33) is a proinflammatory cytokine, but its role in DKD and CIN is unknown. METHODS: Thirty male Sprague-Dawley rats were enrolled. The first group was comprised of healthy rats (HRs), whereas the other four groups were made up of diabetic rats (DRs), diabetic rats with contrast-induced nephropathy (CIN + DRs), melatonin-treated diabetic rats (MTDRs), and melatonin-treated CIN + DRs (MTCIN + DRs). All groups except the HRs received 50 mg/kg/day streptozotocin (STZ). CIN + DRs were constituted by administrating 1.5 mg/kg of intravenous radiocontrast dye on the 35th day. MTDRs and MTCIN + DRs were given 20 mg/kg/day of intraperitoneal injection of melatonin (MT) from the 28th day for the constitutive seven days. RESULTS: We observed increased IL-33 in the kidney tissue following induction of CIN in DRs. To determine whether MT is effective in preventing CIN, we administered MT in CIN + DRs and demonstrated that kidney tissue levels of OxS markers, inflammatory cytokines, and IL-33 were significantly diminished in MTCIN + DRs compared with other groups without MT treatment (p < 0.05). CONCLUSION: Inhibition of IL-33 with MT provides therapeutic potential in DKD with CIN. PMID- 26989336 TI - Statistical Inference Models for Image Datasets with Systematic Variations. AB - Statistical analysis of longitudinal or cross sectional brain imaging data to identify effects of neurodegenerative diseases is a fundamental task in various studies in neuroscience. However, when there are systematic variations in the images due to parameter changes such as changes in the scanner protocol, hardware changes, or when combining data from multi-site studies, the statistical analysis becomes problematic. Motivated by this scenario, the goal of this paper is to develop a unified statistical solution to the problem of systematic variations in statistical image analysis. Based in part on recent literature in harmonic analysis on diffusion maps, we propose an algorithm which compares operators that are resilient to the systematic variations. These operators are derived from the empirical measurements of the image data and provide an efficient surrogate to capturing the actual changes across images. We also establish a connection between our method to the design of wavelets in non-Euclidean space. To evaluate the proposed ideas, we present various experimental results on detecting changes in simulations as well as show how the method offers improved statistical power in the analysis of real longitudinal PIB-PET imaging data acquired from participants at risk for Alzheimer's disease (AD). PMID- 26989335 TI - Proinflammatory and Anti-Inflammatory Cytokines Mediated by NF-kappaB Factor as Prognostic Markers in Mammary Tumors. AB - Inflammation results in the production of cytokines, such as interleukin- (IL-) 4 and IL-10 with immunosuppressive properties or IL-6 and TNF-alpha with procarcinogenic activity. Furthermore, NF-kappaB is the major link between inflammation and tumorigenesis. This study verified the interaction between active inflammatory cytokines in the tumor microenvironment and serum of female dogs with mammary tumors and their correlation with the clinicopathological characteristics and overall survival. Measurement of gene expression was performed by qPCR and protein levels by ELISA/Luminex. High gene and protein expression levels of NF-kappaB, IL-6, and TNF-alpha were found in association with characteristics that reflect worse prognosis and a negative correlation between TNF-alpha protein expression and survival time was observed (p < 0.05). In contrast, high gene and protein expression levels of IL-4 and IL-10 were associated with characteristics of better prognosis and an increased level of IL 4 and a longer survival time of animals were obtained (p < 0.05). In addition, there was a positive correlation between TNF-alpha and IL-6 expression in association with NF-kappaB. The results show a significant correlation of these cytokines with tumor development, associated with NF-kappaB expression and cytokines promodulation, showing that these biological factors could be used as predictive and prognostic markers in breast cancer. PMID- 26989337 TI - Clinical Characteristics Associated with Antibiotic Treatment Failure for Tuboovarian Abscesses. AB - OBJECTIVE: Although parenteral antibiotic treatment is a standard approach for tuboovarian abscesses, a significant proportion of patients fail therapy and require interventional radiology (IR) guided drainage. The objective of this study is to assess if specific clinical factors are associated with antibiotic treatment failure. STUDY DESIGN: Retrospective medical record review of patients hospitalized for tuboovarian abscesses from 2001 through 2012 was performed. Clinical characteristics were compared for patients who underwent successful parenteral antibiotic treatment, failed antibiotic treatment necessitating subsequent IR drainage, initial drainage with concurrent antibiotics, and surgery. RESULTS: One hundred thirteen patients admitted for inpatient treatment were identified. Sixty-one (54%) patients were treated with antibiotics alone. Within this group, 24.6% failed antibiotic treatment and required drainage. Mean white blood cell count (K/MUL) (18.7 +/- 5.94 versus 13.9 +/- 5.12) (p = 0.003), mean maximum diameter of tuboovarian abscess (cm) (6.8 +/- 2.9 versus 5.2 +/- 2.0) (p = 0.03), and length of stay (days) (9.47 +/- 7.43 versus 4.59 +/- 2.4) (p = 0.002) were significantly greater for patients who failed antibiotic treatment. CONCLUSIONS: Admission white blood cell count greater than 16 K/MUL and abscess size greater than 5.18 cm are associated with antibiotic treatment failure. These factors may provide guidance for initial selection of IR guided drainage. PMID- 26989339 TI - Treatment Process Predictors of Program Completion or Dropout among Minority Adolescents Enrolled in a Brief Motivational Substance Abuse Intervention. AB - This study documented significant differences in alliance in a predominantly Latino sample of adolescents who either completed or dropped out of a Guided Self Change treatment program. Therapeutic alliance, working alliance and patient involvement were assessed via ratings of audio-recorded segments of participants' counseling sessions. Descriptive discriminant function analysis identified working alliance goals, patient participation and therapist warmth and friendliness variables as significantly predictive of completion status. These results were confirmed via follow-up logistic regression analyses. The use of brief clinical tools to monitor and manage alliance among adolescents receiving treatment who are at risk for drop-out is discussed. PMID- 26989338 TI - Risk of Adverse Infant Outcomes Associated with Maternal Tuberculosis in a Low Burden Setting: A Population-Based Retrospective Cohort Study. AB - BACKGROUND: Maternal tuberculosis (TB) may be associated with increased risk of adverse infant outcomes. STUDY DESIGN: We examined the risk of low birth weight (LBW), small for gestational age (SGA), and preterm birth (<37 weeks) associated with maternal TB in a retrospective population-based Washington State cohort using linked infant birth certificate and maternal delivery hospitalization discharge records. We identified 134 women with births between 1987 and 2012 with TB-associated ICD-9 diagnosis codes at hospital delivery discharge and 536 randomly selected women without TB, frequency matched 4 : 1 on delivery year. Multinomial logistic regression analyses were performed to compare the risk of LBW, SGA, and preterm birth between infants born to mothers with and without TB. RESULTS: Infants born to women with TB were 3.74 (aRR 95% CI 1.40-10.00) times as likely to be LBW and 1.96 (aRR 95% CI 0.91-4.22) as likely to be SGA compared to infants born to mothers without TB. Risk of prematurity was similar (aRR 1.01 95% CI 0.39-2.58). CONCLUSION: Maternal TB is associated with poor infant outcomes even in a low burden setting. A better understanding of the adverse infant outcomes associated with maternal TB, reflecting recent trends in US TB epidemiology, may inform potential targeted interventions in other low prevalence settings. PMID- 26989341 TI - Age and Gender Differences in Teen Relationship Violence. AB - Research shows that abuse in adolescence can start early and current literature regarding gender differences in Teen Relationship Violence (TRV) is inconsistent. Age and Gender differences in TRV were examined. Measures assessing TRV and its correlates were completed by 231 teens from 7th, 9th, and 11th grade classes. A 2 (gender) by 3 (grade) multivariate analysis of variance revealed significant effects for grade and gender indicating that 7th graders have lower perpetration and victimization of TRV, less anger control, and fewer positive conflict resolution behaviors than 9th and 11th graders. Furthermore, girls perpetrate more physical and emotional abuse while boys perpetrate more sexual abuse. Results have implications for timing and content of prevention programs addressing dating violence in adolescence. PMID- 26989340 TI - An Inside Look at Homeless Youths' Social Networks: Perceptions of Substance Use Norms. AB - Substance use among homeless young people is a pervasive problem, and there have been many efforts to understand more about the dynamics of this health compromising behavior. The current study examined perceived substance use norms within homeless youths' social networks utilizing in-depth interviews. The sample included 19 homeless individuals aged 16 to 21. Four elements of substance use within networks emerged: substance use choices, drug use safety issues, encouragement and/or discouragement, and appropriate situations in which substance use is condoned. These findings provide unique insight into the norms associated with drug and alcohol use within homeless youths' social networks. PMID- 26989342 TI - Effects of Abusive Parenting, Caretaker Arrests, and Deviant Behavior on Dating Violence among Homeless Young Adults. AB - Though dating violence is widespread among young adult homeless populations, its risk factors are poorly understood by scholars. To address this gap, the current study uses a social learning theory to examine the effects of abusive parenting and caretaker arrests on dating violence among 172 homeless young adults. Results from path analyses revealed that child physical abuse and caretaker arrests were positively associated with engaging in a greater number of school fights, which, in turn, was strongly and positively correlated with participating in more deviant subsistence strategies (e.g., stealing) since being on the street. Young people who participated in a greater number of delinquent acts were more likely to report higher levels of dating violence. Study results highlight the extent of social learning within the lives of homeless young adults, which is evident prior to their leaving home and while they are on the street. PMID- 26989344 TI - Long-Term Behavior of Simulated Partial Lead Service Line Replacements. AB - In this 48-month pilot study, long-term impacts of copper:lead galvanic connections on lead release to water were assessed without confounding differences in pipe exposure prehistory or disturbances arising from cutting lead pipe. Lead release was tracked from three lead service line configurations, including (1) 100% lead, (2) traditional partial replacement with 50% copper upstream of 50% lead, and (3) 50% lead upstream of 50% copper as a function of flow rate, connection types, and sampling methodologies. Elevated lead from galvanic corrosion worsened with time, with 140% more lead release from configurations representing traditional partial replacement configurations at 14 months compared to earlier data in the first 8 months. Even when sampled consistently at moderate flow rate (8 LPM) and collecting all water passing through service lines, conditions representing traditional partial service line configurations were significantly worse (~40%) when compared to 100% lead pipe. If sampled at a high flow rate (32 LPM) and collecting 2 L samples from service lines, 100% of samples collected from traditional partial replacement configurations exceeded thresholds posing an acute health risk versus a 0% risk for samples from 100% lead pipe. Temporary removal of lead accumulations near Pb:Cu junctions and lead deposits from other downstream plastic pipes reduced risk of partial replacements relative to that observed for 100% lead. When typical brass compression couplings were used to connect prepassivated lead pipes, lead release spiked up to 10 times higher, confirming prior concerns raised at bench and field scale regarding adverse impacts of crevices and service line disturbances on lead release. To quantify semirandom particulate lead release from service lines in future research, whole-house filters have many advantages compared to other approaches. PMID- 26989343 TI - Childhood Maltreatment and PTSD: Spiritual Well-Being and Intimate Partner Violence as Mediators. AB - Childhood maltreatment places individuals, including African American women who are undereducated and economically disadvantaged, at risk for developing posttraumatic stress disorder (PTSD) symptoms. Participants were 192 African American women with a history in the prior year of both a suicide attempt and intimate partner violence (IPV) exposure. They were recruited from a public hospital that provides medical and mental health treatment to mostly low-income patients. A simple mediator model was used to examine if (1) existential well being (sense of purpose) and/or religious well-being (relationship with God) mediated the link between childhood maltreatment and adult PTSD symptoms. Sequential multiple mediator models determined if physical and nonphysical IPV enhanced our understanding of the mediational association among the aforementioned variables. Findings suggest that existential well-being mediated the association between childhood maltreatment and adult PTSD symptoms in a simple mediator model, and existential well-being and recent nonphysical IPV served as sequential multiple mediators of this link. However, religious well being and physical IPV were not significant mediators. Findings underscore the importance of enhancing existential well-being in the treatment of suicidal African American women with a history of childhood maltreatment and IPV. PMID- 26989345 TI - Additive Effect on Soybean Peroxidase-Catalyzed Removal of Anilines from Water. AB - Soybean peroxidase has been shown to be effective in removal of aromatic compounds from wastewater, while the use of additives effectively reduces enzyme concentration requirement, hence overall treatment cost. Enzymatic treatment, an oxidative polymerization, was successful in removal of over 95% of both aniline and o-anisidine. The originality of this study lies in the findings that the additives, sodium dodecyl sulfate (SDS), sodium dodecylbenzenesulfonate (SDBS), Triton X-100, and sodium dodecanoate (SDOD), reduced enzyme concentration requirement, while polyethylene glycol (PEG, average molar mass of 3350 g/mol) had no effect on the required enzyme concentration. In addition, the presence of SDS also enhanced treatment by improving precipitation and color removal. These results are enabling advancement of soybean peroxidase-catalyzed treatment of anilines found in wastewaters as a new sustainable method. PMID- 26989347 TI - Language co-activation and lexical selection in bimodal bilinguals: Evidence from picture-word interference. AB - We used picture-word interference (PWI) to discover a) whether cross-language activation at the lexical level can yield phonological priming effects when languages do not share phonological representations, and b) whether semantic interference effects occur without articulatory competition. Bimodal bilinguals fluent in American Sign Language (ASL) and English named pictures in ASL while listening to distractor words that were 1) translation equivalents, 2) phonologically related to the target sign through translation, 3) semantically related, or 4) unrelated. Monolingual speakers named pictures in English. Production of ASL signs was facilitated by words that were phonologically related through translation and by translation equivalents, indicating that cross language activation spreads from lexical to phonological levels for production. Semantic interference effects were not observed for bimodal bilinguals, providing some support for a post-lexical locus of semantic interference, but which we suggest may instead reflect time course differences in spoken and signed production in the PWI task. PMID- 26989346 TI - Tamoxifen Action in ER-Negative Breast Cancer. AB - Breast cancer is a highly heterogeneous disease. Tamoxifen is a selective estrogen receptor (ER) modulator and is mainly indicated for the treatment of breast cancer in postmenopausal women and postsurgery neoadjuvant therapy in ER positive breast cancers. Interestingly, 5-10% of the ER-negative breast cancers have also shown sensitivity to tamoxifen treatment. The involvement of molecular markers and/or signaling pathways independent of ER signaling has been implicated in tamoxifen sensitivity in the ER-negative subgroup. Studies reveal that variation in the expression of estrogen-related receptor alpha, ER subtype beta, tumor microenvironment, and epigenetics affects tamoxifen sensitivity. This review discusses the background of the research on the action of tamoxifen that may inspire future studies to explore effective therapeutic strategies for the treatment of ER-negative and triple-negative breast cancers, the latter being an aggressive disease with worse clinical outcome. PMID- 26989348 TI - Interventions to improve patient access to and utilisation of genetic and genomic counselling services. AB - : This is the protocol for a review and there is no abstract. The objectives are as follows. PRIMARY OBJECTIVE: The primary objective is to assess the effectiveness of interventions to improve patient identification, access to and utilisation of genetic and genomic counselling services when compared to: No intervention;Usual or current practice; andOther active intervention. SECONDARY OBJECTIVE: The secondary objective is to explore the resource use and costs associated with interventions aimed at improving patient identification, access to and utilisation of genetic and genomic counselling services from studies meeting the eligibility criteria. We will report on factors that may explain variation in the effectiveness of interventions aimed at improving patient identification, access to and utilisation of genetic and genomic counselling services from studies meeting the eligibility criteria. Another secondary objective is to explore how interventions which target improved patient identification, access to and utilisation of genetic and genomic counselling services affect the subsequent appropriate use of health services for the prevention or early detection of disease. It is also possible that the genetic counselling interaction itself will contribute to the possible use of preventative services. PMID- 26989349 TI - Interleukin-1beta-induced reduction of tissue water diffusion in the juvenile rat brain on ADC MRI is not associated with (31)P MRS-detectable energy failure. AB - BACKGROUND: It has long been known that an intrastriatal microinjection of the archetypal pro-inflammatory cytokine, interleukin-1beta (IL-1beta), in juvenile rats induces a chronic reduction in the apparent diffusion coefficient (ADC) of tissue water on magnetic resonance imaging (MRI). Reduced ADC during acute cerebral ischaemia is an established indicator of metabolic failure whereas the cause of the IL-1beta-induced reduction remains to be deciphered. Previously, it has been shown that IL-1beta does not perturb the phosphorus ((31)P) magnetic resonance spectroscopy (MRS)-detectable energy status of an ex vivo preparation of rat brain parenchyma that is devoid of a functional vasculature component. However, brain energy status following an IL-1beta challenge in vivo remains to be examined. METHODS: This study is the first longitudinal in vivo examination of the correlation of ADC MRI with localised (31)P MRS signals obtained specifically from within the injected and non-injected striatum following IL-1beta (1 ng/ul or 100 ng/ul) challenge, in real-time. RESULTS: Despite observing a chronic reduction in ADC at either dose of IL-1beta challenge, energy compromise was not detected at any time point. CONCLUSIONS: The IL-1beta-induced effects pertaining to a functional vasculature such as leukocyte recruitment, blood-brain barrier (BBB) breakdown and blood flow changes are unlikely to impact on overall tissue energy status. Compared to classic ischaemia, there is dissociation between ADC and energy status within an IL-1beta-induced lesion in vivo. PMID- 26989350 TI - Examining the Interplay of Processes Across Multiple Time-Scales: Illustration With the Intraindividual Study of Affect, Health, and Interpersonal Behavior (iSAHIB). AB - Human development is characterized by the complex interplay of processes that manifest at multiple levels of analysis and time-scales. We introduce the Intraindividual Study of Affect, Health and Interpersonal Behavior (iSAHIB) as a model for how multiple time-scale study designs facilitate more precise articulation of developmental theory. Combining age heterogeneity, longitudinal panel, daily diary, and experience sampling protocols, the study made use of smartphone and web-based technologies to obtain intensive longitudinal data from 150 persons age 18-89 years as they completed three 21-day measurement bursts (t = 426 bursts, t = 8,557 days) wherein they provided reports on their social interactions (t = 64,112) as they went about their daily lives. We illustrate how multiple time-scales of data can be used to articulate bioecological models of development and the interplay among more 'distal' processes that manifest at 'slower' time-scales (e.g., age-related differences and burst-to-burst changes in mental health) and more 'proximal' processes that manifest at 'faster' time scales (e.g., changes in context that progress in accordance with the weekly calendar and family influence processes). PMID- 26989351 TI - A Review of Isolation Gowns in Healthcare: Fabric and Gown Properties. AB - The threat of emerging infectious diseases including Ebola hemorrhagic fever, pandemic influenza, avian influenza, Hepatitis B, Hepatitis C, and SARS has highlighted the need for effective personal protective equipment (PPE) to protect healthcare workers (HCWs), patients, and visitors. PPE is a critical component in the hierarchy of controls used to protect HCWs from infectious hazards. HCW PPE may include gowns, respirators, face masks, gloves, eye protection, face shields, and head and shoe coverings. Important research has been conducted in certain areas, such as respirators and protective masks, but studies in other areas, particularly gowns, are scarce. Gowns are identified as the second-most-used piece of PPE, following gloves, in the healthcare setting. According to the Centers for Disease Control and Prevention's Guideline for Isolation Precautions, isolation gowns should be worn to protect HCWs' arms and exposed body areas during procedures and patient-care activities when anticipating contact with clothing, blood, bodily fluids, secretions and excretions. Isolation gowns currently available on the marketplace offer varying resistance to blood and other bodily fluids depending on the type of the material, its impermeability, and wear and tear. While some studies show no benefit of the routine use of isolation gowns, others demonstrate that its use is associated with a reduced infection rate. This paper reviews isolation gowns in healthcare settings, including the fabrics used, gown design and interfaces, as well as critical parameters that affect microorganism and liquid transmission through fabrics. PMID- 26989353 TI - Breast Cancer Is Our Global Responsibility. PMID- 26989352 TI - The moderating role of implicit alcohol-related cognitions in hazardous alcohol use. AB - The present study applied the Go/No-Go Association Test (GNAT; Nosek & Banaji, 2001) to measure alcohol-related implicit cognitions. Additionally, it assessed the role of implicit cognitions as a potential moderator in the relationship between explicit predictors of alcohol use and hazardous drinking behavior. University undergraduate students (N = 214) completed self-report questionnaires assessing reasons for drinking and reported alcohol use. Participants also completed two GNATs assessing implicit-alcohol-related cognitions associated with attitude (good-bad) and perceived safety (safe-dangerous). As expected, participants held implicit appraisals of alcohol as ''bad'' and ''dangerous'' in the context of nonalcoholic drinks, and as ''good'' and ''safe'' in the context of licit and illicit drugs. Implicit alcohol-related cognitions moderated the relationship between drinking to cope with negative affect and hazardous drinking and drinking due to cues or craving and hazardous drinking. These findings highlight the multidimensional nature of implicit cognitions and the role of negative implicit alcohol-related associations in moderating relationships between explicit processes and subsequent alcohol use behaviors. PMID- 26989355 TI - Current Status and Future Projections of Breast Cancer in Asia. AB - Asia is the world's largest continent comprising about 3/5 of the human population. Breast cancer is the most common type of cancer and the second leading cause of cancer-related deaths among women in Asia, accounting for 39% of all breast cancers diagnosed worldwide. The incidence of breast cancer in Asia varies widely across the continent and is still lower than in Western countries, but the proportional contribution of Asia to the global breast cancer rates is increasing rapidly in parallel to the socioeconomic development. However, the mortality-to-incidence ratios are much higher for Asia than for Western countries. Most Asian countries are low- and middle-income countries (LMICs) where breast cancer presents at a younger age and a later stage, and where patients are more likely to die from the disease than those in Western countries. Moreover, diagnostic workup, treatment and palliative services are inadequate in most Asian LMICs. In this review, we present an overview of the breast cancer risk factors and epidemiology, control measures, and cancer care among Asian countries. PMID- 26989354 TI - A Review on Breast Cancer Care in Africa. AB - BACKGROUND: The global incidence of breast cancer (BC) is rising, especially in low- and middle-income countries. The purpose of this review is to summarize existing publications on BC care in Africa. PATIENTS AND METHODS: A systematic search in MEDLINE and smaller databases was carried out to identify African studies on BC treatment, and an additional PubMed search was performed for relevant topics on BC care. RESULTS: A total of 219 publications, mainly from North and West Africa, were found by systematic search. We also selected articles on BC epidemiology, risk factors, clinical presentation, and cancer control in Africa. CONCLUSIONS: Publications on BC treatment are mostly from hospital case series. Evidence on treatment from prospective randomized trials that address the specific characteristics of African patients is lacking. The epidemiologic data shows rising incidences in Africa. The prevalence of risk factors is changing by age group, geographic region, and over time. The clinical picture of BC differs from that of Western countries due to the high proportion of young patients (on account of the African population with a high proportion of young people) and late presentation. Global collaborative efforts are needed to address the rising need for improved BC care in Africa. PMID- 26989356 TI - Microcalcification-Associated Breast Cancer: Presentation, Successful First Excision, Long-Term Recurrence and Survival Rate. AB - INTRODUCTION: In this study we evaluated mammographic, histological and immunohistochemical findings for microcalcification-associated breast cancer with regards to breast-conserving therapy, recurrence and survival rate. PATIENTS AND METHODS: We retrospectively analyzed 99 consecutive, non-palpable and microcalcification-associated breast cancers (94 women) that were treated surgically between January 2002 and December 2003 at a national academic breast cancer center. Calcifications were classified according to the Breast Imaging Reporting and Data System (BI-RADS). Descriptors, surgical outcome and histological findings were assessed. Recurrences and survival rates were evaluated based on medical records, standardized patient questionnaires and/or contacting the physician. RESULTS: 42 of the 99 lesions (42.4%) were invasive carcinomas, 57 (57.6%) were pure ductal carcinoma in situ (DCIS). 6 out of 99 (6.1%) lesions were triple negative, and 29 (29.3%) were HER2/neu positive. Successful first excision rate was 76/99 lesions (76.8%). Breast conservation was achieved in 73.7% (73/99). 10 women showed local recurrences without negatively impacting survival. The recurrences included round/punctate, amorphous, fine pleomorphic, and fine linear or fine-linear branching descriptors. The breast cancer-specific long-term survival rate was 91/94 (96.8%) for a mean follow-up of 81.4 months. The 3 patients who died due to breast carcinoma showed fine pleomorphic calcifications, and had nodal-positive invasive carcinoma at diagnosis. CONCLUSION: Microcalcification-associated breast cancers are frequently treated with breast-conserving therapy. Continuous clinical and mammographic follow-up is recommended for all descriptors. PMID- 26989358 TI - Association of Milk and Meat Consumption with the Development of Breast Cancer in a Western Mexican Population. AB - BACKGROUND: Breast cancer is a public health problem and it is the most common gynecologic neoplasia worldwide. The risk factors for its development are of both hereditary and environmental origin. Certain foods have been clearly associated with modifying the breast cancer risk. The aim of the present analysis was to evaluate the effects of cow's milk and meat consumption on the development of breast cancer in a population from Western Mexico (Colima). MATERIAL AND METHODS: We studied 97 patients presenting with a histopathologic diagnosis of breast cancer and 104 control individuals who did not present with the disease (Breast Imaging Report and Data System (BI-RADS) 1-2). 80% of the population belonged to a low socioeconomic stratum. The main clinical characteristics were analyzed along with the lifetime consumption of meat and milk. RESULTS: High milk consumption increased the breast cancer risk by 7.2 times (p = 0.008) whereas the consumption of meat was not significantly associated with the disease. CONCLUSIONS: High consumption of cow's milk was a risk factor for the development of breast cancer. Further studies are needed to evaluate the effects of dietary patterns on the development of breast cancer in diverse populations with ethnic, cultural, and economic differences. PMID- 26989357 TI - Clinicopathological Factors Related to the Prognosis of Metastatic Breast Cancer Patients after Development of Brain Metastasis. AB - BACKGROUND: The prognosis of breast cancer patients with brain metastasis (BM) is extremely poor, and the survival after development of BM is very short. We aimed to investigate clinicopathological factors related to significant effects on the prognosis after BM development. PATIENTS AND METHODS: This is a retrospective study of 75 early breast cancer patients who received the standard of care and subsequently developed BM. RESULTS: Breast cancer subtype was one of the significant predictors for prognosis after BM diagnosis. Luminal HER2 patients had the most favorable prognosis after BM diagnosis (p = 0.011). Favorable performance status (PS) at BM diagnosis (p < 0.001) and a single metastatic brain tumor (p = 0.032) were significantly associated with good prognosis after BM diagnosis. Metastatic time courses of the patients was found not to be significantly associated with survival after BM diagnosis. Univariate and multivariate analysis indicated that luminal HER2 cancer, favorable PS at BM diagnosis, and a single metastatic brain tumor were the independent prognostic factors for survival after BM development, making a decisive influence on local or systemic control. CONCLUSION: Appropriate treatments for tumor subtypes and to improve the general condition of patients would result in improved outcomes for the patients with BM. PMID- 26989359 TI - MMP-7 A-181G Polymorphism in Breast Cancer Patients from Western Iran. AB - BACKGROUND: Matrix metalloproteinases (MMPs) are upregulated in tumors. The MMP-7 A-181G polymorphism is associated with increased expression of the MMP-7 gene. Aim of the present study was to investigate the association between the MMP-7 A 181G polymorphism and susceptibility to breast cancer. PATIENTS AND METHODS: The MMP-7 A-181G variants were studied in a cohort of 251 subjects consisting of 100 breast cancer patients and 151 healthy controls; all were from Western Iran. The MMP-7 A-181G genotypes were identified using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: The frequencies of the MMP-7 AA, AG, and GG genotypes in healthy individuals were 34.4, 50.4, and 15.2%, respectively. In breast cancer patients, the frequencies of AA (34%), AG (52%), and GG (14%) genotypes (p = 0.95) were similar to those in the controls. There was a trend toward an increased frequency of the combined genotype of MMP-7 AG+GG in patients with lymph node metastasis (70.4%) compared to those without metastasis (66.7%). Also, in patients with invasive lobular carcinoma, the frequency of the MMP-7 AG+GG genotype tended to be higher (71.4%) compared to that in patients with invasive ductal carcinoma (66.2%) (p = 0.78). CONCLUSION: Our findings indicate that the MMP-7 A-181G polymorphism may not be correlated with susceptibility to breast cancer in our population. PMID- 26989360 TI - Metaplastic Breast Carcinoma with Unusual Presentation: Review of Three Cases. AB - BACKGROUND: Metaplastic breast carcinoma is an uncommon type of breast cancer that usually appears as a large, fast growing breast lump. CASE REPORT: We report 3 cases of metaplastic breast carcinoma presented at our clinic in 2014. The mean age at diagnosis was 67.3 years. 1 patient presented with a fast growing, large mass detected by herself. However, in the other 2 patients, the nodule was approximately 1.5 cm in size, not fast growing, and was detected on mammography. All 3 patients were treated surgically (2 lumpectomies and 1 mastectomy), with the final pathology of metaplastic carcinoma with chondroid mesenchymal differentiation in 2 cases and metaplastic carcinoma with myoepithelial differentiation in the 3rd case. The patients are still under adjuvant therapy. CONCLUSIONS: Metaplastic breast carcinoma may present unusually as a non-palpable lump. This entity must be considered in any breast lump. PMID- 26989361 TI - Role of Hyperthermia in Breast Cancer Locoregional Recurrence: A Review. AB - In patients with locoregional recurrences of breast cancer not suitable for resection, subsequent local control is difficult to maintain in previously irradiated areas when reirradiation alone or reirradiation with chemotherapy is used. Due to the limited number of treatment options there is a high risk of subsequent failure and uncontrollable local disease. In this group of patients, local hyperthermia combined with radiotherapy increases the clinical response and local control, adding limited acute and late toxicity, as has been shown in randomized trials. Hyperthermia is an artificial elevation of tissue temperature (range 40-44 degrees C for 30-60 min). If hyperthermia is applied shortly before or after radiation, the effect of radiation is enhanced by influencing intratumoral hypoxia and by inhibiting sublethal damage repair in the tumor. Moreover, hyperthermia combined with radiation reduces the total dose of radiation needed compared to radiation alone, of which a higher dose is needed to obtain the same effect. Few data are available on the combination of radiotherapy and hyperthermia with chemotherapy, although the results of trimodality treatment consisting of reirradiation and hyperthermia together with liposomal doxorubicin are promising. Therefore, this literature review was performed to provide more comprehensive data on the mechanism and use of hyperthermia in locoregional recurrence of breast cancer. PMID- 26989362 TI - Triple Negative Breast Cancer versus Non-Triple Negative Breast Cancer Treated with Breast Conservation Surgery Followed by Radiotherapy: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The aim of this study was to compare the efficacy of breast conservation surgery (BCS) followed by radiotherapy (RT) in triple negative breast cancer (TNBC) versus non-TNBC. METHODS: We searched the MEDLINE and EMBASE databases from inception through March 31, 2014, using search terms related to TNBC, BCS, and RT. Studies comparing the efficacy of BCS followed by RT in TNBC versus non-TNBC were reviewed. RESULTS: 5 studies including 2,922 non-TNBC and 510 TNBC cases were selected. The overall quality of included studies was deemed moderate to high. Compared with non-TNBC, the pooled relative risk of 5-year local relapse-free survival was 1.315 (95% confidence interval (CI) 0.967-1.789; p = 0.008) for TNBC, and that of 5-year overall survival, regional relapse-free survival, and distant metastasis-free survival was 1.929 (95% CI 1.392-2.674; p = 0.000), 3.052 (95% CI 1.629-5.715; p = 0.000), and 2.407 (95% CI 1.910-3.034; p = 0.000), respectively. CONCLUSION: The local control rate of TNBC treated with BCS plus RT is similar to that of non-TNBC. PMID- 26989363 TI - Effect of Pneumoperitoneum on Renal Function and Physiology in Patients Undergoing Robotic Renal Surgery. AB - Laparoscopic and minimally-invasive robotic access has transformed the delivery of urological surgery. While associated with numerous desirable outcomes including shorter post-operative stay and faster return to preoperative function, these techniques have also been associated with increased morbidity such as reduced renal blood flow and post-operative renal dysfunction. The mechanisms leading to these renal effects complex and multifactorial, and have not been fully elucidated. However they are likely to include direct effects from raised intra-abdominal pressure, and indirect effects secondary to carbon dioxide absorption, neuroendocrine factors and tissue damage from oxidative stress. This review summarises these factors, and highlights the need for further work in this area, to direct novel therapies and guide alterations in technique with the aim of reducing renal dysfunction post-laparoscopic and robotic surgery. PMID- 26989364 TI - Post-Operative Pain Management in Patients Undergoing Robotic Urological Surgery. AB - Robotic urological surgery is being increasingly performed worldwide. The main focus currently is on the operative technique but post operative patient care is an essential part of the process to make this technique safe and successful. We present a review on multiple analgesic techniques available to prevent and treat pain specifically caused after by urological robotic surgery; this article will explain the mechanism of pain pathways involved in laparoscopic procedures and review current evidence pertaining to systemic and regional analgesia methods. PMID- 26989365 TI - A Comparative in Vitro Study of Power Output Deterioration over Time Between Ho:YAG Laser Fibers from Different Manufacturers as a Function of Deflection and Power Input. AB - OBJECTIVES: To investigate the performance of laser fibers from 6 major manufacturers in vitro and to identify the effect of time and angulations (180 degrees and 0 degrees ) on fiber power output. MATERIALS AND METHODS: Overall, 36 single-use fibers were used. Each was tested with an energy input of 0.8, 1.4 and 2.0 Joules. A power detector measured power output after 1, 5, 10 and 15 minutes for three 15-minute cycles of continuous use. For the first 2 cycles, the fiber was bent to 180 degrees with the use of a pre fabricated mould. Analysis of the data was performed by ANOVA and Tukey's test when the results were significant amongst groups. Statistical significance was deemed p < 0.05. RESULTS: No fiber fracture occurred. There was no significant difference in output at 15 minutes of continuous use at 0 degrees and 180 degrees . The reduction in energy output at the 15th minute of continuous use at 180 degrees was not significant for any fiber type or initial input. Only output differences between the fibers proved to be significant (p = 0.001). CONCLUSION: Fiber fracture and decline in performance is not due to deflection and continuous use. Frictional forces that occur between the fiber tip and the stone fragments may be responsible. PMID- 26989366 TI - Impact of Robotic Fellowship Experience on Perioperative Outcomes of Robotic Assisted Laparoscopic Partial Nephrectomy. AB - BACKGROUND: We analyzed differences in patient selection and perioperative outcomes between robotic-fellowship trained and non-fellowship trained surgeons in their initial experience with robotic-assisted laparoscopic partial nephrectomy. METHODS: Data through surgeon case 10 was analyzed. Forty patients were identified from two fellowship trained surgeons (n = 20) and two non fellowship trained surgeons (n = 20). RESULTS: Fellowship trained surgeons performed surgery on masses of higher nephrometry score (8.0 vs. 6.0, p = 0.007) and more posterior location (60 vs. 25%, p = 0.03). Retroperitoneal approach was more common (50 vs. 0%, p = 0.0003). Fellowship trained surgeons trended toward shorter warm ischemia time (25.5 vs. 31.0 min, p = 0.08). There was no significant difference in perioperative complications (35 vs. 35%, p = 0.45) or final positive margin rates (0 vs. 15%, p = 0.23). CONCLUSION: Fellowship experience may allow for treating more challenging and posterior tumors in initial practice and significantly more comfort performing retroperitoneal robotic-assisted laparoscopic partial nephrectomy. PMID- 26989368 TI - Urinary Retention: Catheter Drainage Bag or Catheter Valve? AB - The management of patients with intractable urinary incontinence presents as a challenging priority in the ageing population. To preserve the antibacterial mechanisms of the bladder, a urine collection that enables the bladder to fill and empty regularly and completely, should be used. This mimics the action of the healthy bladder. We compared the success rates of two widely used urinary collection systems (catheter with drainage bag or a catheter valve) at our institution for those patients undergoing a trial of void. PMID- 26989367 TI - Can the Free/Total PSA Ratio Predict the Gleason Score Before Prostate Biopsy? AB - OBJECTIVES: To determine whether there is a correlation between high Gleason score and free/total (f/t) prostate specific antigen (PSA) in patients newly diagnosed with prostate carcinoma. MATERIALS AND METHODS: The study included 272 prostate biopsy patients whose total PSA value ranged from 4-10 ng/ml. The patients were divided into 2 groups according to the f/t PSA ratio: Group 1 <= 15% and Group 2 > 15%. Furthermore, the groups were also compared to each other in terms of mild (<= 6), moderate (= 7), and high (>= 8) Gleason score. RESULTS: Group 1 consisted of 135 (49.6%) patients and Group 2 consisted of 137 (50.4%) patients. While 27 (20%) patients had a high Gleason score in Group 1, only 10 (7.3%) patients had a high Gleason score in Group 2 (p = 0.008). Using Spearman's correlation test, we found that the f/t PSA ratios were observed to decrease significantly in all patients with increased Gleason scores (p = 0.002, r = 0.185). CONCLUSION: According to our study, there is a relationship between higher Gleason score and decreased f/t PSA ratio. Therefore, f/t PSA can be an indicator for predicting the Gleason score. PMID- 26989369 TI - Clinical Effect of Switching from a Luteinizing Hormone-Releasing Hormone Agonist to an Antagonist in Patients with Castration-Resistant Prostate Cancer and Serum Testosterone Level >= 20 ng/dl. AB - INTRODUCTION: The efficacy of conversion from a luteinizing hormone-releasing hormone agonist to an antagonist was evaluated prospectively in patients with castration-resistant prostate cancer. MATERIALS AND METHODS: From October 2012 to December 2014, 8 cases with a serum testosterone level >= 20 ng/dl during following androgen deprivation therapy were enrolled and received degarelix monthly. The primary end-pointgoal was to determine the effective prostate specific antigen response rate. The secondary end-pointgoal was to assess the proportion of cases with a decrease in serum testosterone level to < 20 ng/ml. RESULTS: One patient achieved a complete response, with a prostate-specific antigen level of 0.02 ng/ml at the nadirend of the study. The effective response rate was 25.0% (2/8), and the proportion of cases with prostate-specific antigen decline was 62.5% (5/8). In 5/8 cases (5/8, 62.5%), serum testosterone levels declined to < 20 ng/dl. CONCLUSION: Switching to a luteinizing hormone-releasing hormone antagonist in patients with testosterone levels >= 20 ng/dl may be an option in sequential androgen deprivation therapy for some patients. PMID- 26989370 TI - Managing Small Ureteral Stones: A Retrospective Study on Follow-Up, Clinical Outcomes and Cost-Effectiveness of Conservative Management vs. Early Surgery. AB - INTRODUCTION: The management of ureteral calculi has evolved over the past decades with the advent of new surgical and medical treatments. The current guidelines support conservative management as a possible approach for ureteral stones sized = 10 mm. OBJECTIVES: We purport to follow the natural history of ureteral stones managed conservatively in this retrospective study, and attempt to ascribe an estimated health-care and cost-effectiveness, from presentation to time of being stone-free. MATERIALS AND METHODS: 192 male and female patients with a single ureteral stone sized = 10 mm were included in this study. The clinical and cost-related outcome was analyzed for different stone sizes (0-4, 4 6 and 6-10 mm). The effectiveness of selected follow-up (FU) scans was also analyzed. RESULTS: Stone size was found to be related to the degree of hydronephrosis and to the likelihood of need for a surgical management. Conservative management was found to be clinically effective, as 88% of the patients did not require surgery for their stone. 96.1% of the patients with a stone 0-4mm managed to expel their ureteral stone. Bigger ureteral stones were found to be more costly. The cost-effectiveness of the single FU scans was found to be related to their efficiency, while the global cost-effectiveness of conservative management vs. early surgery was higher for smaller stones (26.8 vs. 17.32% for stones 0-4 vs. 6-10 mm). CONCLUSION: Conservative management is clinically effective with a significant cost-benefit, particularly for the subgroup of stones sized 0-4 mm, where a need for FU scans is in dispute. PMID- 26989371 TI - Ureteric Suture Urolithiasis Following Open Emergency Ureteric Repair. AB - Suture urolithiasis is an unusual but recognised phenomenon following surgery on the urinary tract. We report a case in a 30-year-old man who sustained a gunshot injury to the left ureter in Burundi and underwent open ureteric repair in a regional hospital. He migrated to the UK and presented one year later with left loin pain. An intravenous urogram revealed two foci of calcification to the left of L3, within a peri-ureteric position. The patient underwent left-sided ureteroscopy where two calculi each formed around a nylon suture were discovered within a ureteric pseudo-diverticulum, and basketed. This is the first reported case of suture urolithiasis occurring following ureteric surgery. PMID- 26989372 TI - Management of Primitive Neuroectodermal Tumor of the Kidney with Inferior Vena Cava Thrombus. AB - Primitive neuroectodermal tumors (PNET) are an aggressive group of small round cell tumors usually arising in the nervous system and affecting children. They have a tendency for local invasion, distant spread and formation of tumor thrombi. The kidney is a rare primary location for these tumors. Outcomes are frequently poor due to late diagnosis (Wilms tumor is a more common tumor in this population) and early spread. Immunohistochemistry is invaluable in making the diagnosis of PNET. We report a case of a primary renal PNET with extensive tumor thrombus into the inferior vena cava, and lung metastasis in a pediatric patient, and its successful management. Our 14-year-old patient with renal PNET was managed with radical nephrectomy, thrombectomy and chemotherapy and remains disease free to date. The diagnosis of renal PNETs should be considered in young adult patients who present with aggressive renal masses at initial presentations. Despite its aggressive nature, good outcomes can be achieved by a multimodality therapeutic strategy. PMID- 26989373 TI - Pulmonary Embolism Following Outpatient Vasectomy. AB - Venous thromboembolic events have several known major risk factors such as prolonged immobilization or major surgery. Pulmonary embolism has rarely been reported after an outpatient vasectomy was completed. We present the rare case of a healthy 32-year-old Caucasian male with no known risk factors who presented with pleuritic chest pain 26 days after his outpatient vasectomy was performed. Subsequently, he was found to have a pulmonary embolism as per radiological imaging. We explore the association between outpatient vasectomies and venous thromboembolic events. A review of the literature is also included. PMID- 26989374 TI - Aggressive Angiomyolipomas: the Clandestine Epithelioid Variant. AB - Epithelioid angiomyolipoma is a rare mesenchymal derived neoplasm of the kidney. Thought to be a variant of classical angiomyolipoma, a benign tumour, its malignant potential has been highlighted by case reports of loco-regional and distant metastasis. Given the potentially adverse clinical course associated with epithelioid angiomyolipoma compared to classical angiomyolipoma, the distinction and comprehensive histological characterisation of this rare entity is essential. PMID- 26989375 TI - Diverticulitis. PMID- 26989376 TI - Morphologic Basis for Developing Diverticular Disease, Diverticulitis, and Diverticular Bleeding. AB - Diverticula of the colon are pseudodiverticula defined by multiple outpouchings of the mucosal and submucosal layers penetrating through weak spots of the muscle coat along intramural blood vessels. A complete prolapse consists of a diverticular opening, a narrowed neck, and a thinned diverticular dome underneath the serosal covering. The susceptibility of diverticula to inflammation is explained by local ischemia, translocation of pathogens due to retained stool, stercoral trauma by fecaliths, and microperforations. Local inflammation may lead to phlegmonous diverticulitis, paracolic/mesocolic abscess, bowel perforation, peritonitis, fistula formation, and stenotic strictures. Diverticular bleeding is due to an asymmetric rupture of distended vasa recta at the diverticular dome and not primarily linked to inflammation. Structural and functional changes of the bowel wall in diverticular disease comprise: i) Altered amount, composition, and metabolism of connective tissue; ii) Enteric myopathy with muscular thickening, deranged architecture, and altered myofilament composition; iii) Enteric neuropathy with hypoganglionosis, neurotransmitter imbalance, deficiency of neurotrophic factors and nerve fiber remodeling; and iv) Disturbed intestinal motility both in vivo (increased intraluminal pressure, motility index, high amplitude propagated contractions) and in vitro (altered spontaneous and pharmacologically triggered contractility). Besides established etiologic factors, recent studies suggest that novel pathophysiologic concepts should be considered in the pathogenesis of diverticular disease. PMID- 26989378 TI - Diagnosis, Differential Diagnoses, and Classification of Diverticular Disease. AB - BACKGROUND: While detailed history, physical examination, and laboratory tests are of great importance when examining a patient with diverticular disease, they are not sufficient to diagnose (or stratify) diverticulitis without cross sectional imaging (ultrasonography (US), computed tomography (CT)). METHODS: Qualified US has diagnostic value equipotent to qualified CT, follows relevant legislation for radiation exposure protection, and is frequently effectual for diagnosis. Furthermore, its unsurpassed resolution allows detailed investigation down to the histological level. Subsequently, US is considered the first choice of imaging in diverticular disease. Vice versa, CT has definite indications in unclear/discrepant situations or insufficient US performance. RESULTS: Endoscopy is not required for the diagnosis of diverticulitis and shall not be performed in the acute attack. Colonoscopy, however, is warranted after healing of acute diverticulitis, prior to elective surgery, and in atypical cases suggesting other diagnoses. Perforation/abscess must be excluded before colonoscopy. CONCLUSION: Reliable diagnosis is fundamental for surgical, interventional, and conservative treatment of the different presentations of diverticular disease. Not only complications of acute diverticulitis but also a number of differential diagnoses must be considered. For an adequate surgical strategy, correct stratification of complications is mandatory. Subsequently, in the light of currently validated diagnostic techniques, the consensus conference of the German Societies of Gastroenterology (DGVS) and of Visceral Surgery (DGAV) has passed a new classification of diverticulitis displaying the different facets of diverticular disease. This classification addresses different types (not stages) of the condition, and includes symptomatic diverticular disease (SUDD), largely resembling irritable bowel syndrome, as well as diverticular bleeding. PMID- 26989379 TI - Prevention and Conservative Therapy of Diverticular Disease. AB - BACKGROUND: Diverticular disease is a common problem. Prevention and treatment of complications depend on the stage of the disease. Lifestyle modifications are suitable preventive measures, aiming to reduce obesity and to balance the diet with a high amount of fiber and a low amount of meat. However, evidence to guide the pharmacological treatment of diverticular disease and diverticulitis is limited. METHODS: Literature review. RESULTS: Antibiotics are not proven to be effective in patients with uncomplicated diverticulitis and without further risk factors; neither do they improve treatment nor prevent complications. Mesalazine might have an effect on pain relief in diverticular disease even though it has no significant effect on the outcome of diverticulitis. In complicated diverticulitis, inpatient treatment including antibiotics is mandatory. CONCLUSION: Evidence for the treatment of diverticular disease is limited. Further research is needed. PMID- 26989380 TI - Emergency Surgery for Acute Complicated Diverticulitis. AB - BACKGROUND: The optimal treatment of acute complicated diverticulitis is a matter of debate and has undergone significant changes. Currently, the main focus of surgical treatment concepts is on controlling the emergency situation triggered by acute complicated sigmoid diverticulitis through interventional and minimally invasive measures. METHODS: This article presents the current data and recommendations on differentiated treatment of acute complicated sigmoid diverticulitis, which are also summarized in a decision tree. RESULTS: In general, resection of the diverticular sigmoid is needed to treat acute complicated sigmoid diverticulitis, because without resection the recurrence rate is too high at 40%. Since the morbidity and mortality rates associated with emergency resection are extremely high, resulting in the creation of a stoma, efforts are made to control the acute situation through interventional and laparoscopic measures. Therefore, pericolic and pelvic abscesses (Hinchey stages I, II) are eliminated through percutaneous or laparoscopic drainage. Likewise, laparoscopic lavage and drainage are performed for purulent and feculent peritonitis (Hinchey stages III, IV). After elimination of the acute septic situation, interval elective sigmoid resection is conducted. If emergency resection cannot be avoided, it is performed, while taking account of the patient's overall condition, with primary anastomosis and a protective stoma or as discontinuity resection using Hartmann's procedure. CONCLUSION: Thanks to the progress made in interventional and laparoscopic treatment, differentiated concepts are now used to treat acute complicated sigmoid diverticulitis. PMID- 26989377 TI - Risk Factors for Diverticulosis, Diverticulitis, Diverticular Perforation, and Bleeding: A Plea for More Subtle History Taking. AB - BACKGROUND: Diverticulosis is a very common condition. Around 20% of diverticula carriers are believed to suffer from diverticular disease during their lifetime. This makes diverticular disease one of the clinically and economically most significant conditions in gastroenterology. The etiopathogenesis of diverticulosis and diverticular disease is not well understood. Epidemiological studies allowed to define risk factors for the development of diverticulosis and the different disease entities associated with it, in particular diverticulitis, perforation, and diverticular bleeding. METHODS: A comprehensive literature search was performed, and the current knowledge about risk factors for diverticulosis and associated conditions reviewed. RESULTS: Non-controllable risk factors like age, sex, and genetics, and controllable risk factors like foods, drinks, and physical activity were identified, as well as comorbidities and drugs which increase or decrease the risk of developing diverticula or of suffering from complications. In naming risk factors, it is of utmost importance to differentiate between diverticulosis and the different disease entities. CONCLUSION: Risk factors for diverticulosis and diverticular disease may give a clue towards the possible etiopathogenesis of the conditions. More importantly, knowledge of comorbidities and particularly drugs conferring a risk for development of complicated disease is crucial for patient management. PMID- 26989381 TI - Elective Surgery for Sigmoid Diverticulitis - Indications, Techniques, and Results. AB - Diverticulitis is one of the leading indications for elective colonic resections although there is an ongoing controversial discussion about classification, stage dependent therapeutic options, and therapy settings. As there is a rising trend towards conservative therapy for diverticular disease even in patients with a complicated form of diverticulitis, we provide a compact overview of current surgical therapy principles and the remaining questions to be answered. PMID- 26989382 TI - Management of Complications Following Emergency and Elective Surgery for Diverticulitis. AB - BACKGROUND: The clinical spectrum of sigmoid diverticulitis (SD) varies from asymptomatic diverticulosis to symptomatic disease with potentially fatal complications. Sigmoid colectomy with restoration of continuity has been the prevailing modality for treating acute and recurrent SD, and is often performed as a laparoscopy-assisted procedure. For elective sigmoid colectomy, the postoperative morbidity rate is 15-20% whereas morbidity rates reach up to 30% in patients who undergo emergency surgery for perforated SD. Some of the more common and serious surgical complications after sigmoid colectomy are anastomotic leaks and peritonitis, wound infections, small bowel obstruction, postoperative bleeding, and injuries to the urinary tract structures. Regarding the management of complications, it makes no difference whether the complication is a result of an emergency or an elective procedure. METHODS: The present work gives an overview of the management of complications in the surgical treatment of SD based on the current literature. RESULTS: To achieve successful management, early diagnosis is mandatory in cases of deviation from the normal postoperative course. If diagnostic procedures fail to deliver a correlate for the clinical situation of the patient, re-laparotomy or re-laparoscopy still remain among the most important diagnostic and/or therapeutic principles in visceral surgery when a patient's clinical status deteriorates. CONCLUSION: The ability to recognize and successfully manage complications is a crucial part of the surgical treatment of diverticular disease and should be mastered by any surgeon qualified in this field. PMID- 26989384 TI - Diagnosis and Treatment of Oesophageal Carcinoma: Changes in Every Respect. PMID- 26989383 TI - The Effect of Montelukast on Liver Damage in an Experimental Obstructive Jaundice Model. AB - BACKGROUND: Montelukast is a cysteinyl-leukotriene type 1 (CysLT1) selective receptor antagonist. In recent years, investigations have shown that montelukast possesses secondary anti-inflammatory activities and also antioxidant effects. For this reason, we aimed to determine the possible effects of montelukast on liver damage in experimental obstructive jaundice. METHODS: 30 Wistar-Albino male rats were randomized and divided into three groups of 10 animals each: group I, sham-operated; group II, ligation and division of the common bile duct (BDL) followed by daily intraperitoneal injection of 1 ml of saline; group III, BDL followed by daily intraperitoneal injection of 10 mg/kg montelukast dissolved in saline. The animals were killed on postoperative day 7 by high-dose diethyl ether inhalation. Blood and liver samples were taken for examination. RESULTS: In this study, liver malondialdehyde (MDA) (p = 0.001), myeloperoxidase (p = 0.003), and total sulfhydryl (SH) (p = 0.009) were found to be significantly different between the BDL + montelukast and the BDL groups. Plasma total SH (p = 0.002) and MDA (p = 0.027) values were also statistically different between these groups. Statistical analyses of histological activity index scores showed that the histopathological damage in the BDL + montelukast group was significantly less than the damage in the control group (p < 0.05 for all pathological parameters). CONCLUSION: According to the results of this study, montelukast showed a significant hepatoprotective effect in this experimental obstructive jaundice model, which might be due to its antioxidant and anti-inflammatory activities. PMID- 26989385 TI - Diagnostics and Early Diagnosis of Esophageal Cancer. AB - In the esophagus two different kinds of primary neoplasias may arise: squamocellular carcinomas (SCC) and esophageal adenocarcinomas (EAC). Although both types of carcinoma are rare diseases, especially the incidence of EAC rose in the last years. The management of esophageal cancer is challenging. There are no specific symptoms of early esophageal cancers. Due to this fact, most of the esophageal cancers are found incidentally, and only 12.5% of esophageal tumors are endoscopically resectable. Gastroscopy is the gold standard for the diagnosis of esophageal cancer. The sensitivity of detecting early-stage carcinoma may be improved by adjunct techniques such as chromoendoscopy, virtual chromoendoscopy, magnification endoscopy, and other advanced endoscopic imaging techniques. The diagnosis of esophageal cancer can be verified with targeted biopsies. Accurate staging information is crucial for establishing appropriate treatment choices for esophageal cancer, while the depth of the tumor determines the feasibility of therapy. In terms of staging, endosonography, abdominal ultrasound, and computed tomography scan of the thorax and abdomen should thus be performed before initiation of therapy. PMID- 26989386 TI - Endoscopic Therapy of Early Carcinoma of the Oesophagus. AB - BACKGROUND: Oesophageal cancer is a comparatively rare disease in the Western world. Prognosis is highly dependent on the choice of treatment. Early stages can be treated by endoscopic resection, whereas surgery needs to be performed in the case of advanced carcinomas. Technical progress has enabled high-definition endoscopes and technical add-ons which help the endoscopist in finding fine irregularities in the oesophageal mucosa, though interpretation still remains challenging. METHODS: In this review, we discuss both novel and old diagnostic procedures and their value, as well as the current recommendations for the diagnosis and treatment of early oesophageal carcinomas. The database of PubMed and Medline was searched and analysed to provide all relevant literature for this review. RESULTS AND CONCLUSION: Endoscopic resection is the therapy of choice in early oesophageal cancer. In case of adenocarcinoma it is mandatory to perform subsequent ablation of all residual Barrett's mucosa to avoid metachronous lesions. PMID- 26989387 TI - Surgical Therapy of Early Carcinoma of the Esophagus. AB - BACKGROUND: The modern therapy of early esophageal carcinomas (pT1) requires an excellent cooperation between experienced gastroenterologists, pathologists, and esophageal surgeons. While endoscopic resection (ER) is accepted as the standard curative treatment for mucosal esophageal carcinomas, submucosal tumors are regarded as a strict indication for surgery. There is an ongoing discussion about the operative approach and the extent of lymph node dissection in these cases. METHODS: A literature review was performed to evaluate the operative treatment of early esophageal cancer. In view of oncological risk factors, treatment strategies, and operative procedures, current studies are summarized and compared to the results of our own center. RESULTS AND CONCLUSION: In early esophageal cancer, lymph node involvement is the only independent risk factor for survival and recurrence rates. There is evidence that infiltrated lymph nodes (N+) are significantly correlated with tumor infiltration depth, lymphovascular (L1) and microvascular invasion (V1), and poor tumor differentiation (G3). Several studies suggest that early squamous cell carcinomas (eSCCs) and early adenocarcinomas (eACs) have a different tumor biology and therefore need a different treatment strategy. While eSCCs in stage m1 and m2 can be cured by ER, tumors infiltrating the submucosal layer (sm1-3) show a high rate of lymph node metastasis (LNM); thus, surgical resection (SR) is clearly indicated. In tumors with invasion into the deep mucosa (m3) the risk of LNM is up to 11%; however, reliable data are rare and the type of therapy should be discussed with the patients individually. In eACs, ER is the standard curative treatment for all mucosal tumors (m1-m4) and sm1 tumors with low-risk constellation (G1, L0, VO, R0). All high-risk sm1 tumors and those with deeper submucosal infiltration (sm2, sm3) show a high rate of LNM and require SR. The standard operative procedure for early esophageal carcinomas is an Ivor-Lewis esophagectomy with radical, at least two-field lymphadenectomy. PMID- 26989388 TI - Minimally Invasive Techniques and Hybrid Operations for Esophageal Cancer. AB - BACKGROUND: Minimally invasive esophagectomy (MIE) is slowly gaining acceptance due to advantages in short-term outcome. While evidence is slowly increasing, the discussion about MIE is still controversial. METHODS: A literature review was performed to compare MIE with open esophagectomy (OE). Current studies are summarized in view of short- and long-term outcome as well as oncological accuracy. RESULTS: The majority of studies show that MIE is associated with a significant reduction of pulmonary complications, blood loss, and shorter length of stay on the intensive care unit. Pulmonary complications are reduced by 14 65%. MIE shows an improved quality of life 6 weeks after surgery. There is some evidence that the endoscopic reintervention rate may be higher after MIE than after OE. Mortality rates do not differ. Regarding oncological results, the rate of R0 resections is comparable between MIE and OE, as is the number of retrieved lymph nodes. Long-term survival seems to be comparable. A few single center trials suggest oncological advantages of MIE over OE concerning the number of lymph nodes, R0 resection rate, and 1-year survival. CONCLUSION: Current evidence supports that MIE has advantages over OE in the short-term outcome. Oncological results are comparable to those achieved by OE. As a result, MIE has already been included in current guidelines for the treatment of esophageal cancer. PMID- 26989389 TI - Evidence-Based Operative Details in Esophageal Cancer Treatment: Surgical Approach, Lymphadenectomy, Anastomosis. AB - BACKGROUND: This review depicts surgical treatment strategies in the management of esophageal cancer under the focus of evidence-based medicine. The main emphasis lies on technical details, i.e. surgical approach, lymphadenectomy, and current techniques of anastomosis. METHODS: The current literature on operative details in esophageal cancer treatment was reviewed. Surgical approaches and different techniques of anastomotic reconstruction utilizing a gastric tube were compared. The grade of evidence regarding the necessity and extent of lymphadenectomy was discussed. RESULTS: There is no level-1 evidence-based difference regarding the surgical approach for esophagectomy. The preferred anastomosis site is intrathoracic compared to the neck. Extended lymphadenectomy is still imperative in esophagectomy although neoadjuvant protocols might also result in a downstaging effect of lymph nodes. Neoadjuvant regimens have no negative influence on complication rate and anastomotic integrity. CONCLUSION: A tailored interdisciplinary approach to the patients' physiology and esophageal cancer stage is the most important factor that influences operative outcome and oncological results after esophagectomy. PMID- 26989390 TI - Perioperative and Palliative Chemotherapy for Esophageal Cancer. AB - Perioperative and palliative chemotherapy for esophageal carcinoma has undergone substantial changes in recent years. The implementation of trastuzumab in the treatment of HER2-positive advanced adenocarcinoma is a milestone as it marked the introduction of the first molecularly targeted treatment of gastric cancer. Current studies are investigating whether anti-HER2-directed treatment also proves effective in the perioperative setting. Data from the CROSS study on neoadjuvant radio-/chemotherapy with paclitaxel and carboplatin have helped to establish a new standard of care for the treatment of localized esophageal cancer. Finally, preliminary experience in potentially curative treatment approaches for oligometastatic tumor stages may offer new treatment options for patients with stage IV gastric cancer. However, some of these innovative approaches urgently require validation in larger, prospective, and controlled multicenter studies. Highly active forms of radiotherapy, radio-/chemotherapy, or chemoimmunotherapy can achieve complete tumor remissions in some patients. Despite these advances, life expectancy unfortunately continues to be very limited in the majority of patients with locally advanced or metastatic esophageal carcinoma. PMID- 26989391 TI - Definitive, Preoperative, and Palliative Radiation Therapy of Esophageal Cancer. AB - BACKGROUND: Long-term survival in patients with esophageal cancer remains dismal despite the recent improvements in surgery, the advances in radiotherapy (RT) technology, and the refinement of systemic treatments, including the advent of targeted therapies. Although surgery constitutes the treatment of choice for early-stage disease (stage I), a multimodal approach, including preoperative or definitive chemoradiotherapy (CRT) and perioperative chemotherapy, is commonly pursued in patients with locally advanced disease. METHODS: A review of the literature was performed to assess the role of RT, alone or in combination with chemotherapy, in the management of esophageal cancer. RESULTS: Evidence from large, randomized phase III trials and meta-analyses supports the application of perioperative chemotherapy alone or preoperative concurrent CRT in patients with lower esophageal and esophagogastric junction adenocarcinomas. Preoperative CRT but not preoperative chemotherapy alone is now routinely used in patients with locally advanced squamous cell carcinoma (SCC). Additionally, definitive CRT without surgery has also emerged as a valuable approach in the management of resectable esophageal SCC to avoid surgery-related morbidity and mortality, whereas salvage surgery is reserved for those with persistent disease. Furthermore, brachytherapy offers a valuable option in the palliative treatment of patients with locally advanced, unresponsive disease. Fluorodeoxyglucose positron emission tomography (FDG-PET) can facilitate a more accurate treatment response assessment and patient selection. Finally, the development of modern RT techniques, such as intensity-modulated and image-guided RT as well as FDG-PET based RT planning, could further increase the therapeutic ratio of CRT. CONCLUSION: Altogether, CRT constitutes an important tool in the treatment armamentarium for esophageal cancer. Further optimization of CRT using modern technology and imaging, targeted therapies, and newer chemotherapeutic agents is a major challenge and should be the goal of future research and clinical trials. PMID- 26989392 TI - Palliative Endoscopic Therapy of Esophageal Cancer. AB - BACKGROUND: This is a review of endoscopic therapy in the setting of palliative management of patients suffering from esophageal cancer (EC). Unfortunately, many cases of EC present in a stage of disease in which curative therapy is not possible. The maintenance of quality of life includes the ability to swallow and of oral feeding, pain control, and the prevention of bleeding. METHODS: A review of the current literature was performed. RESULTS: Many endoscopic methods are available for the management of dysphagia, of which dilation, endoluminal tumor destruction, stenting, and brachytherapy are the most common. CONCLUSION: Surgical palliation should be avoided as much as possible since the alternatives show at least the same efficacy and have fewer complications. PMID- 26989393 TI - Laparoscopic Pylorus- and Spleen-Preserving Duodenopancreatectomy for a Multifocal Neuroendocrine Tumor. AB - BACKGROUND: In contrast to laparoscopic left pancreatic resection, laparoscopic total duodenopancreatectomy is a procedure that has not been standardized until now. It is not only the complexity that limits such a procedure but also its rare indication. The following article demonstrates the technical aspects of laparoscopic pylorus- and spleen-preserving duodenopancreatectomy. CASE REPORT: The indication for intervention in the underlying case was a patient diagnosed with a multiple endocrine neoplasia (MEN) I syndrome and a multifocal neuroendocrine tumor (NET) infiltrating the duodenum and the pancreas. The patient was post median laparotomy which was necessary after jejunal perforation due to a peptic ulcer. The resection was carried out entirely laparoscopically, and the reconstruction, which included a biliodigestive anastomosis and a gastroenterostomy, was carried out by means of a median upper abdomen laparotomy of 7 cm in length through which the resected specimen was also removed. The total operative time was 391 min. The blood loss accounted for 250 ml. The postoperative course was uneventful, and the patient was discharged on the eighth postoperative day. CONCLUSION: Laparoscopic pancreatectomy is a treatment option in carefully selected indications. The complexity of the operation demands a high level of expertise in the surgical team. PMID- 26989395 TI - Crosstalk of Various Biomarkers That Might Provide Prompt Identification of Acute or Chronic Cardiorenal Syndromes. AB - INTRODUCTION: Pathophysiological interaction between the heart and kidneys represents the basis for clinical entities called cardiorenal syndromes. The purpose of the study was to assess the relations between acute and chronic cardiorenal syndromes and biomarkers [advanced oxidation protein products, brain natriuretic peptide, malondialdehyde, xanthine oxidoreductase (XOD), xanthine oxidase, xanthine dehydrogenase, interleukin 8, cystatin C, plasminogen activator inhibitor-1, high-sensitive troponin T, C-reactive protein and glomerular filtration rate, measured by the Modification of Diet in Renal Disease (MDRD) formula], to hypothesize biomarkers that might provide a prompt identification of acute or chronic cardiorenal syndromes, and to distinguish acute versus chronic types of these syndromes. METHODS: A total of 114 participants were enrolled in this study, i.e. 79 patients divided into subgroups of acute and chronic cardiorenal syndromes and 35 volunteers. RESULTS: Nonadjusted odds ratio (OR) showed that there was a significant risk for acute cardiorenal syndrome with increased XOD activity (p = 0.037), elevated cystatin C concentration (p = 0.038) and MDRD (p = 0.028). Multivariable adjusted OR, on the other hand, revealed that only glomerular filtration rate measured by the MDRD formula had a significance for acute cardiorenal syndrome (p = 0.046). Nonadjusted OR showed a significant risk for chronic cardiorenal syndrome only in elderly (p = 0.002). Multivariable adjusted OR exhibited that age was the only risk factor for chronic cardiorenal syndrome (p = 0.012). CONCLUSION: Cystatin C, glomerular filtration rate measured by the MDRD equation and XOD were independent risk factors for acute cardiorenal syndrome, while age remained an independent risk factor for chronic cardiorenal syndrome. When comparing ORs of evaluated parameters, the highest significance for acute cardiorenal syndrome was plasma concentration of cystatin C. PMID- 26989394 TI - Current and Potential Therapeutic Strategies for Hemodynamic Cardiorenal Syndrome. AB - BACKGROUND: Cardiorenal syndrome (CRS) encompasses conditions in which cardiac and renal disorders co-exist and are pathophysiologically related. The newest classification of CRS into seven etiologically and clinically distinct types for direct patient management purposes includes hemodynamic, uremic, vascular, neurohumoral, anemia- and/or iron metabolism-related, mineral metabolism-related and protein-energy wasting-related CRS. This classification also emphasizes the pathophysiologic pathways. The leading CRS category remains hemodynamic CRS, which is the most commonly encountered type in patient care settings and in which acute or chronic heart failure leads to renal impairment. SUMMARY: This review focuses on selected therapeutic strategies for the clinical management of hemodynamic CRS. This is often characterized by an exceptionally high ratio of serum urea to creatinine concentrations. Loop diuretics, positive inotropic agents including dopamine and dobutamine, vasopressin antagonists including vasopressin receptor antagonists such as tolvaptan, nesiritide and angiotensin neprilysin inhibitors are among the pharmacologic agents used. Additional therapies include ultrafiltration (UF) via hemofiltration or dialysis. The beneficial versus unfavorable effects of these therapies on cardiac decongestion versus renal blood flow may act in opposite directions. Some of the most interesting options for the outpatient setting that deserve revisiting include portable continuous dobutamine infusion, peritoneal dialysis and outpatient UF via hemodialysis or hemofiltration. KEY MESSAGES: The new clinically oriented CRS classification system is helpful in identifying therapeutic targets and offers a systematic approach to an optimal management algorithm with better understanding of etiologies. Most interventions including UF have not shown a favorable impact on outcomes. Outpatient portable dobutamine infusion is underutilized and not well studied. Revisiting traditional and novel strategies for outpatient management of CRS warrants clinical trials. PMID- 26989396 TI - Metabolic Syndrome and Smoking Are Associated with Future Development of Advanced Chronic Kidney Disease in Older Adults. AB - INTRODUCTION: Metabolic syndrome (MetS) and smoking have been identified as risk factors for chronic kidney disease (CKD) in cross-sectional studies in various age groups, but longitudinal data on progression of CKD in older adults are limited. Our objectives were to examine whether MetS and its components and smoking predict the onset of CKD stage 3b (CKD-3b) in older adults. METHODS: A subset of participants of the Einstein Aging Study who were free of diabetes, dementia, and CKD-3b at enrollment were included in this analysis. CKD-3b was defined as an estimated glomerular filtration rate <45 ml/min/1.73 m(2). Cox proportional hazards models were used in these analyses. RESULTS: In total, 413 >=70-year-old individuals were eligible for this study. 65.4% were female and 26.6% were black. 22.3% of the participants had MetS at baseline, 4.4% were active smokers, and 6.1% developed CKD-3b over a mean of 4 years of follow-up. MetS and smoking independently predicted incident CKD in our fully adjusted model (hazard ratio 3.65, 95% CI 1.20-10.60, p = 0.022; hazard ratio 29.69, 95% CI 4.47 197.23, p = 0.000). CONCLUSION: MetS and smoking are associated with an increased incidence of CKD-3b. These risk factors are modifiable, easily identified and prevented through better health care practice and early diagnosis. PMID- 26989398 TI - A Possible New Multiple Endocrine Neoplasia Mutation in a Patient with a Prototypic Multiple Endocrine Neoplasia Presentation. AB - BACKGROUND: Multiple endocrine neoplasia (MEN) type 1 syndrome is an uncommon inherited disorder characterized by the occurrence of tumors involving two or more endocrine glands. These tumors include pheochromocytoma, adrenal cortical and neuroendocrine tumors including (bronchopulmonary, thymic, gastric), lipomas, angiofibromas, collagenomas, and meningiomas. MEN-4 is very rare and has been characterized by the occurrence of parathyroid and anterior pituitary tumors in association with tumors of the adrenals, kidneys, and reproductive organs. SUMMARY: We report the case of a 40-year-old male without significant family history of endocrine disease who was found to have primary hyperparathyroidism, a pituitary tumor causing acromegaly, thyroid cancer, renal cell carcinoma, and pancreatic cysts. We posit that this represents a new version of MEN-4. While renal tumors (angiomyolipoma) have been reported as part of the MEN-4 phenotype, to our knowledge, this is the first case reported of the association of MEN-1 and/or MEN-4 phenotype with this unique constellation of tumors, including renal cell carcinoma. Interestingly, this patient tested negative (DNA sequencing/deletion) for MEN-1 (menin), MEN-4 (CDKN1B) and VHL genes. KEY MESSAGE: Thus, while this case has clinical characteristics consistent with either MEN-1 or MEN-4, it may represent a unique genetic variant. PMID- 26989397 TI - Acute Kidney Injury in Cardiorenal Syndrome Type 1 Patients: A Systematic Review and Meta-Analysis. AB - BACKGROUND: We evaluated the epidemiology and outcome of acute kidney injury (AKI) in patients with cardiorenal syndrome type 1 (CRS-1) and its subgroups: acute heart failure (AHF), acute coronary syndrome (ACS) and after cardiac surgery (CS). SUMMARY: We performed a systematic review and meta-analysis. CRS-1 was defined by AKI (based on RIFLE, AKIN and KDIGO), worsening renal failure (WRF) and renal replacement therapy (RRT). We investigated the three most common clinical causes of CRS-1: AHF, ACS and CS. Out of 332 potential papers, 64 were eligible - with AKI used in 41 studies, WRF in 25 and RRT in 20. The occurrence rate of CRS-1, defined by AKI, WRF and RRT, was 25.4, 22.4 and 2.6%, respectively. AHF patients had a higher occurrence rate of CRS-1 compared to ACS and CS patients (AKI: 47.4 vs. 14.9 vs. 22.1%), but RRT was evenly distributed among the types of acute cardiac disease. AKI was associated with an increased mortality rate (risk ratio = 5.14, 95% CI 3.81-6.94; 24 studies and 35,227 patients), a longer length of stay in the intensive care unit [LOSICU] (median duration = 1.37 days, 95% CI 0.41-2.33; 9 studies and 10,758 patients) and a longer LOS in hospital [LOShosp] (median duration = 3.94 days, 95% CI 1.74-6.15; 8 studies and 35,227 patients). Increasing AKI severity was associated with worse outcomes. The impact of CRS-1 defined by AKI on mortality was greatest in CS patients. RRT had an even greater impact compared to AKI (mortality risk ratio = 9.2, median duration of LOSICU = 10.6 days and that of LOShosp = 20.2 days). KEY MESSAGES: Of all included patients, almost one quarter developed AKI and approximately 3% needed RRT. AHF patients experienced the highest occurrence rate of AKI, but the impact on mortality was greatest in CS patients. PMID- 26989399 TI - Prognostic Implications of Acute Renal Impairment among ST Elevation Myocardial Infarction Patients with Preserved Left Ventricular Function. AB - BACKGROUND: Only limited data is present regarding the incidence and prognostic implications of acute kidney injury (AKI) in ST elevation myocardial infarction (STEMI) patients with preserved left ventricular (LV) function in the primary percutaneous coronary intervention (PCI) era. METHODS: We conducted a retrospective study of 842 consecutive STEMI patients with preserved LV function (ejection fraction >=50%, assessed by echocardiography) who underwent primary PCI between January 2008 and January 2015. AKI was defined as an increase of >=0.3 mg/dl in serum creatinine within 48 h following admission. Patients were assessed for all-cause mortality up to 5 years. RESULTS: Fifty-two patients (6.2%) developed AKI. Patients with AKI were older, had impaired baseline renal function, and presented more often with heart failure throughout their hospitalization. Patients with AKI had a higher 5-year all-cause mortality (13.4 vs. 2.4%, p < 0.001). Compared to patients with no AKI, the adjusted hazard ratio for all-cause mortality was 2.64 (95% CI 1.25-5.56, p = 0.01). CONCLUSIONS: Among STEMI patients with preserved LV function undergoing primary PCI, AKI is associated with a higher long-term mortality. PMID- 26989400 TI - Risk Factors for New-Onset Cardiac Valve Calcification in Patients on Maintenance Peritoneal Dialysis. AB - OBJECTIVE: Patients with end-stage renal disease are susceptible to cardiac valve calcification (CVC) due to mineral metabolism disorders and other factors. The purpose of this study was to investigate the risk factors for new-onset CVC in patients on maintenance peritoneal dialysis (PD). METHODS: This study included patients who underwent PD catheter insertion from January 2006 to June 2013 in our Peritoneal Dialysis Center. Clinical data were collected on CVC status during echocardiography evaluations (twice) at an interval of >6 months. The data collected included intact parathyroid hormone, C-reactive protein (CRP), serum phosphorus (P), serum calcium (Ca), albumin (Alb), prealbumin and the use of five types of antihypertensive drugs, statins, active vitamin D3 and Ca tablets. RESULTS: In total, 194 patients - 105 (54.1%) men, average age 60.5 +/- 13.0 years - were included. CVC was present in 50 (25.8%) patients during PD catheter placement. After an average PD duration of 20.9 +/- 10.4 months, CVC was detected in 97 patients (50.0%). New-onset CVC was found in 62 patients (32.0%). Multivariate logistic regression analysis revealed that only serum P levels (p = 0.01, OR = 2.569), Alb levels (p = 0.04, OR = 0.935), dialysis duration (p = 0.03, OR = 1.039) and CRP levels (p = 0.02, OR = 1.031) were associated with CVC. CONCLUSION: Serum P, Alb and CRP levels as well as dialysis duration are independent risk factors for CVC. PMID- 26989401 TI - Association between Plaque Score of the Carotid Artery and the Severity of Sleep Apnea Syndrome in Patients with Chronic Kidney Disease. AB - BACKGROUND: Recently, sleep apnea syndrome (SAS) has been associated with hypertension, cardiovascular disease and death. Patients with chronic kidney disease (CKD) have higher rates of SAS, atherosclerotic complications and death than do patients without CKD. Although the relationship between SAS and atherosclerosis is well known, few papers have described this relationship in humans, especially in CKD patients. PATIENTS AND METHODS: This was a cross sectional study of 110 clinically stable, non-dialysis patients with CKD who attended a CKD educational program from April 2014 to September 2015. The diagnosis of SAS and its severity were assessed using a type 3 portable monitor. Other atherosclerosis-related data were obtained from the patients' medical records in order to determine the factors associated with the severity of SAS. RESULTS: 95 men and 15 women with a mean age of 71.4 +/- 9.9 years were included in the study. The patients' mean body mass index was 24.0 +/- 3.9, their mean blood pressure 134.3 +/- 21.2/73.6 +/- 13.4 mm Hg and their mean estimated glomerular filtration rate 19.8 +/- 9.5 ml/min/1.7 m(2). Adjusted plaque score was a significant predictor of severe SAS (odds ratio = 1.13, p = 0.0182). Mixed plaque was significantly associated with severe SAS (correlation ratio = 0.48, p < 0.0001). CONCLUSIONS: Many patients with CKD also have SAS. Our findings demonstrate the relationship between plaque score and the severity of SAS. PMID- 26989403 TI - Contribution of ultrasonography to the diagnosis of internal bleeding in snakebite envenomation. AB - BACKGROUND: In Africa, snakebite envenomations are frequently complicated by life threatening hemorrhagic syndromes. The authors of the present study conducted a prospective analysis at the University Hospital of Parakou (north of Benin) for seven months (January 1 to July 31, 2014) to assess the contribution of ultrasonography to the diagnosis of internal bleedings and management of envenomation. METHODS: An ultrasound examination was performed in all patients with clinical envenomation regardless of its severity. The study involved 32 patients admitted to the ICU of the University Hospital of Parakou. RESULTS: The average age was 27 +/- 13.9 years. The main signs of severity were: prolongation of clotting time (88 %), severe anemia (41 %), clinical hemorrhage (47 %), and shock (19 %). The ultrasound imaging showed internal hemorrhage in 18 patients (56 %). There were hematomas (22 %), hemoperitoneum (13 %) or a combination of both (22 %). The occurrence of internal bleeding and hemoperitoneum were mainly related to the delay of hospital presentation (p = 0.007) and the existence of external bleeding (p = 0.04). Thirty patients (94 %) received antivenom. Case fatality rate was 3.1 %. CONCLUSION: Ultrasonography may help in diagnosing internal bleeding, even in patients that did not show external hemorrhages, and evaluating its importance. As a consequence, the management of snakebite victims may be significantly improved. PMID- 26989402 TI - Emerging roles of autophagy in metabolism and metabolic disorders. AB - The global prevalence of metabolic disorders is an immediate threat to human health. Genetic features, environmental aspects and lifestyle changes are the major risk factors determining metabolic dysfunction in the body. Autophagy is a housekeeping stress-induced lysosomal degradation pathway, which recycles macromolecules and metabolites for new protein synthesis and energy production and regulates cellular homeostasis by clearance of damaged protein or organelles. Recently, a dramatically increasing number of literatures has shown that defects of the autophagic machinery is associated with dysfunction of multiple metabolic tissues including pancreatic beta cells, liver, adipose tissue and muscle, and is implicated in metabolic disorders such as obesity and insulin resistance. Here in this review, we summarize the representative works on these topics and discuss the versatile roles of autophagy in the regulation of cellular metabolism and its possible implication in metabolic diseases. PMID- 26989404 TI - An Integrated Method Based on PSO and EDA for the Max-Cut Problem. AB - The max-cut problem is NP-hard combinatorial optimization problem with many real world applications. In this paper, we propose an integrated method based on particle swarm optimization and estimation of distribution algorithm (PSO-EDA) for solving the max-cut problem. The integrated algorithm overcomes the shortcomings of particle swarm optimization and estimation of distribution algorithm. To enhance the performance of the PSO-EDA, a fast local search procedure is applied. In addition, a path relinking procedure is developed to intensify the search. To evaluate the performance of PSO-EDA, extensive experiments were carried out on two sets of benchmark instances with 800 to 20,000 vertices from the literature. Computational results and comparisons show that PSO-EDA significantly outperforms the existing PSO-based and EDA-based algorithms for the max-cut problem. Compared with other best performing algorithms, PSO-EDA is able to find very competitive results in terms of solution quality. PMID- 26989405 TI - Active Player Modeling in the Iterated Prisoner's Dilemma. AB - The iterated prisoner's dilemma (IPD) is well known within the domain of game theory. Although it is relatively simple, it can also elucidate important problems related to cooperation and trust. Generally, players can predict their opponents' actions when they are able to build a precise model of their behavior based on their game playing experience. However, it is difficult to make such predictions based on a limited number of games. The creation of a precise model requires the use of not only an appropriate learning algorithm and framework but also a good dataset. Active learning approaches have recently been introduced to machine learning communities. The approach can usually produce informative datasets with relatively little effort. Therefore, we have proposed an active modeling technique to predict the behavior of IPD players. The proposed method can model the opponent player's behavior while taking advantage of interactive game environments. This experiment used twelve representative types of players as opponents, and an observer used an active modeling algorithm to model these opponents. This observer actively collected data and modeled the opponent's behavior online. Most of our data showed that the observer was able to build, through direct actions, a more accurate model of an opponent's behavior than when the data were collected through random actions. PMID- 26989406 TI - Pilot Clinical Trial of Indocyanine Green Fluorescence-Augmented Colonoscopy in High Risk Patients. AB - White light colonoscopy is the current gold standard for early detection and treatment of colorectal cancer, but emerging data suggest that this approach is inherently limited. Even the most experienced colonoscopists, under optimal conditions, miss at least 15-25% of adenomas. There is an unmet clinical need for an adjunctive modality to white light colonoscopy with improved lesion detection and characterization. Optical molecular imaging with exogenously administered organic fluorochromes is a burgeoning imaging modality poised to advance the capabilities of colonoscopy. In this proof-of-principle clinical trial, we investigated the ability of a custom-designed fluorescent colonoscope and indocyanine green, a clinically approved fluorescent blood pool imaging agent, to visualize polyps in high risk patients with polyposis syndromes or known distal colonic masses. We demonstrate (1) the successful performance of real-time, wide field fluorescence endoscopy using off-the-shelf equipment, (2) the ability of this system to identify polyps as small as 1 mm, and (3) the potential for fluorescence imaging signal intensity to differentiate between neoplastic and benign polyps. PMID- 26989407 TI - Impact of an Innovative Classroom-Based Lecture Series on Residents' Evaluations of an Anesthesiology Rotation. AB - Introduction. Millennial resident learners may benefit from innovative instructional methods. The goal of this study is to assess the impact of a new daily, 15 minutes on one anesthesia keyword, lecture series given by faculty member each weekday on resident postrotation evaluation scores. Methods. A quasi experimental study design was implemented with the residents' rotation evaluations for the 24-month period ending by 7/30/2013 before the new lecture series was implemented which was compared to the 14-month period after the lecture series began on 8/1/2013. The primary endpoint was "overall teaching quality of this rotation." We also collected survey data from residents at clinical rotations at two other different institutions during the same two evaluation periods that did not have the education intervention. Results. One hundred and thirty-one residents were eligible to participate in the study. Completed surveys ranged from 77 to 87% for the eight-question evaluation instrument. On a 5-point Likert-type scale the mean score on "overall teaching quality of this rotation" increased significantly from 3.9 (SD 0.8) to 4.2 (SD 0.7) after addition of the lecture series, whereas the scores decreased slightly at the comparison sites. Conclusion. Rotation evaluation scores for overall teaching quality improved with implementation of a new structured slide daily lectures series. PMID- 26989408 TI - Impact of HIV Infection and Zidovudine Therapy on RBC Parameters and Urine Methylmalonic Acid Levels. AB - Background. Anaemia is a common complication of human immunodeficiency virus (HIV) infection. The aim of this study was to investigate the impact of HIV infection and zidovudine on red blood cells (RBC) parameters and urine methylmalonic acid (UMMA) levels in patients with HIV infection. Material and Methods. A cross-sectional study involving 114 subjects, 94 of which are HIV infected nonanaemic and 20 HIV negative subjects (Cg) as control. Full blood count parameters and urine methylmalonic acid (UMMA) level of each subject were determined. Associations were determined by Chi-square test and logistic regression statistics where appropriate. Results. Subjects on zidovudine-based ART had mean MCV (93 fL) higher than that of control group (82.9 fL) and ART naive (85.9 fL) subjects and the highest mean RDW. Mean UMMA level, which reflects vitamin B12 level status, was high in all HIV-infected groups but was significantly higher in ART-naive subjects than in ART-experienced subjects. Conclusion. Although non-zidovudine therapy may be associated with macrocytosis (MCV > 95 fL), zidovudine therapy and ART naivety may not. Suboptimal level of vitamin B12 as measured by high UMMA though highest in ART-naive subjects was common in all HIV-infected subjects. PMID- 26989410 TI - Large-Scale Recurrent Neural Network Based Modelling of Gene Regulatory Network Using Cuckoo Search-Flower Pollination Algorithm. AB - The accurate prediction of genetic networks using computational tools is one of the greatest challenges in the postgenomic era. Recurrent Neural Network is one of the most popular but simple approaches to model the network dynamics from time series microarray data. To date, it has been successfully applied to computationally derive small-scale artificial and real-world genetic networks with high accuracy. However, they underperformed for large-scale genetic networks. Here, a new methodology has been proposed where a hybrid Cuckoo Search Flower Pollination Algorithm has been implemented with Recurrent Neural Network. Cuckoo Search is used to search the best combination of regulators. Moreover, Flower Pollination Algorithm is applied to optimize the model parameters of the Recurrent Neural Network formalism. Initially, the proposed method is tested on a benchmark large-scale artificial network for both noiseless and noisy data. The results obtained show that the proposed methodology is capable of increasing the inference of correct regulations and decreasing false regulations to a high degree. Secondly, the proposed methodology has been validated against the real world dataset of the DNA SOS repair network of Escherichia coli. However, the proposed method sacrifices computational time complexity in both cases due to the hybrid optimization process. PMID- 26989409 TI - The Optimal Management of Acute Febrile Encephalopathy in the Aged Patient: A Systematic Review. AB - The elderly comprise less than 13 percent of world population. Nonetheless, they represent nearly half of all hospitalized adults. Acute change in mental status from baseline is commonly seen among the elderly even when the main process does not involve the central nervous system. The term "geriatric syndrome" is used to capture those clinical conditions in older people that do not fit into discrete disease categories, including delirium, falls, frailty, dizziness, syncope, and urinary incontinence. Despite the growing number of elderly population, especially those who require hospitalization and the high burden of common infections accompanied by encephalopathy among them, there are several unresolved questions regarding the optimal management they deserve. The questions posed in this systematic review concern the need to rule out CNS infection in all elderly patients presented with fever and altered mental status in the routine management of febrile encephalopathy. In doing so, we sought to identify all potentially relevant articles using searches of web-based databases with no language restriction. Finally, we reviewed 93 research articles that were relevant to each part of our study. No prospective study was found to address how should AFE in the aged be optimally managed. PMID- 26989411 TI - Modified Rice Straw as Adsorbent Material to Remove Aflatoxin B1 from Aqueous Media and as a Fiber Source in Fino Bread. AB - The aims of the current work are in large part the benefit of rice straw to be used as adsorbent material and natural source of fiber in Fino bread. The rice straw was subjected to high temperature for modification process and the chemical composition was carried out and the native rice straw contained about 41.15% cellulose, 20.46% hemicellulose, and 3.91% lignin while modified rice straw has 42.10, 8.65, and 5.81%, respectively. The alkali number was tested and showed an increase in the alkali consumption due to the modification process. The different concentrations of modified rice straw, aflatoxin B1, and pH were tested for removal of aflatoxin B1 from aqueous media and the maximum best removal was at 5% modified rice straw, 5 ng/mL aflatoxin B1, and pH 7. The modified rice straw was added to Fino bread at a level of 5, 10, and 15% and the chemical, rheological, baking quality, staling, and sensory properties were studied. Modified rice straw induced an increase of the shelf life and the produced Fino bread has a better consistency. PMID- 26989412 TI - Obesity and Insulin Resistance Are the Main Determinants of Postprandial Lipoprotein Dysmetabolism in Polycystic Ovary Syndrome. AB - Postprandial dyslipidaemia may be a plausible mechanism by which polycystic ovary syndrome (PCOS) increases cardiovascular risk. We sought to investigate whether the postprandial glucose and insulin and lipid and lipoprotein responses, including that of apolipoprotein B-48 (apoB-48) containing chylomicrons, to a mixed meal are different in obese PCOS women when compared to obese control subjects and whether differences, if any, are related to obesity, insulin resistance (IR), hyperandrogenaemia, or PCOS status. 26 women with PCOS (age 30.4 +/- 1.2 years (mean +/- SEM), body mass index (BMI) 36.8 +/- 1.5 kg/m(2)) and 26 non-PCOS subjects (age 34.1 +/- 0.9 years, BMI 31.5 +/- 1.0 kg/m(2)) were studied before and up to 8 hours following a standard mixed meal. AUC-triglyceride (AUC TG) was higher and AUC-high-density lipoprotein (AUC-HDL) lower in PCOS women. These differences were not apparent when BMI was accounted for. Insulin sensitivity (S I), AUC-apoB-48, and AUC-apolipoprotein B (AUC-apoB) were found to be independent predictors of AUC-TG, accounting for 55% of the variance. Only AUC insulin remained significantly elevated following adjustment for BMI. Obesity related IR explains postprandial hypertriglyceridaemia and hyperinsulinaemic responses. Management of obesity in premenopausal women with PCOS is likely to reduce their cardiovascular risk burden. PMID- 26989413 TI - Adapted Lethality: What We Can Learn from Guinea Pig-Adapted Ebola Virus Infection Model. AB - Establishment of small animal models of Ebola virus (EBOV) infection is important both for the study of genetic determinants involved in the complex pathology of EBOV disease and for the preliminary screening of antivirals, production of therapeutic heterologic immunoglobulins, and experimental vaccine development. Since the wild-type EBOV is avirulent in rodents, the adaptation series of passages in these animals are required for the virulence/lethality to emerge in these models. Here, we provide an overview of our several adaptation series in guinea pigs, which resulted in the establishment of guinea pig-adapted EBOV (GPA EBOV) variants different in their characteristics, while uniformly lethal for the infected animals, and compare the virologic, genetic, pathomorphologic, and immunologic findings with those obtained in the adaptation experiments of the other research groups. PMID- 26989415 TI - Development and Validation of HPLC Method for the Simultaneous Determination of Five Food Additives and Caffeine in Soft Drinks. AB - Box-Behnken design was applied to optimize high performance liquid chromatography (HPLC) conditions for the simultaneous determination of potassium sorbate, sodium benzoate, carmoisine, allura red, ponceau 4R, and caffeine in commercial soft drinks. The experimental variables chosen were pH (6.0-7.0), flow rate (1.0-1.4 mL/min), and mobile phase ratio (85-95% acetate buffer). Resolution values of all peak pairs were used as a response. Stationary phase was Inertsil OctaDecylSilane (ODS-) 3V reverse phase column (250 * 4.6 mm, 5 MUm) dimensions. The detection was performed at 230 nm. Optimal values were found 6.0 pH, 1.0 mL/min flow rate, and 95% mobile phase ratio for the method which was validated by calculating the linearity (r (2) > 0.9962), accuracy (recoveries >= 95.75%), precision (intraday variation <= 1.923%, interday variation <= 1.950%), limits of detection (LODs), and limits of quantification (LOQs) parameters. LODs and LOQs for analytes were in the range of 0.10-0.19 MUg/mL and 0.33-0.63 MUg/mL, respectively. The proposed method was applied successfully for the simultaneous determination of the mixtures of five food additives and caffeine in soft drinks. PMID- 26989414 TI - Influence of Type 2 Diabetes on Prevalence of Key Periodontal Pathogens, Salivary Matrix Metalloproteinases, and Bone Remodeling Markers in Sudanese Adults with and without Chronic Periodontitis. AB - This study compared the influence of type 2 diabetes on the occurrence of six periodontal pathogens in plaque samples of patients with and without chronic periodontitis. Levels of salivary MMP-8, MMP-9, RANKL, and OPG were also investigated. The study enrolled 31 patients with type 2 diabetes and chronic periodontitis (DM + CP), 29 with chronic periodontitis (CP), and 20 with type 2 diabetes (DM). Questionnaire-guided interviews were conducted and plaque index, bleeding on probing, and pocket depth were recorded. Polymerase chain reaction (PCR) was utilized to determine the prevalence of the bacteria. The levels of salivary molecules were determined by enzyme immunosorbent assay (ELISA). The CP group had the highest prevalence of P. gingivalis (81.5%), followed by the DM + CP (59.3%) and DM (55.0%) groups (P > 0.05). Similar trends were observed for P. intermedia and T. denticola. The prevalence of T. forsythia was 100% in both periodontitis groups compared to 90% in the DM group. There were no significant differences between the groups regarding the concentrations of MMP-8, MMP-9, or OPG. RANKL concentrations were below the detection limit. Our data show that type 2 diabetes has no significant influence on the prevalence of the investigated periodontal pathogens, or the levels of salivary MMP-8, MMP-9, and OPG. PMID- 26989416 TI - The Difference of Structural State and Deformation Behavior between Teenage and Mature Human Dentin. AB - Objective. The cause of considerable elasticity and plasticity of human dentin is discussed in the relationship with its microstructure. Methods. Structural state of teenage and mature human dentin is examined by using XRD and TEM techniques, and their deformation behavior under compression is studied as well. Result. XRD study has shown that crystallographic type of calcium hydroxyapatite in human dentin (calcium hydrogen phosphate hydroxide Ca9HPO4(PO4)5OH; Space Group P63/m (176); a = 9,441 A; c = 6,881 A; c/a = 0,729; Crystallite (Scherrer) 200 A) is the same for these age groups. In both cases, dentin matrix is X-ray amorphous. According to TEM examination, there are amorphous and ultrafine grain phases in teenage and mature dentin. Mature dentin is stronger on about 20% than teenage dentin, while teenage dentin is more elastic on about 20% but is less plastic on about 15% than mature dentin. Conclusion. The amorphous phase is dominant in teenage dentin, whereas the ultrafine grain phase becomes dominant in mature dentin. Mechanical properties of human dentin under compression depend on its structural state, too. PMID- 26989417 TI - Seroprevalence of Hepatitis C, Hepatitis B, Cytomegalovirus, and Human Immunodeficiency Viruses in Multitransfused Thalassemic Children in Upper Egypt. AB - Background. Frequent blood transfusions in thalassemia major children expose them to the risk of transfusion-transmitted infections (TTIs). The aim of this study was to estimate the prevalence of hepatitis C virus (HCV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), and cytomegalovirus (CMV) in thalassemic children attending the Pediatrics Departments of both Sohag and Minia Universities of Upper Egypt, during the period from May 2014 to May 2015. Methods. Serum samples were screened for hepatitis B surface antigen (HBsAg), anti-HCV, anti-CMV, and anti-HIV type 1 and type 2 using the Vitek Immunodiagnostic Assay System. Results. The frequencies of anti-HCV, HBsAg, anti CMV, and anti-HIV type 1 and type 2 were found to be 37.11%, 4.12%, 4.12%, 0.00%, and 0.00%, respectively. Seropositivity for anti-HCV, HBsAg, and anti-CMV increased with increasing age of the patients, duration of the disease, serum ferritin level (ng/mL), and liver enzymes (U/L), while it was not significantly associated with gender, frequency of blood transfusion, or the status of splenectomy operation (P > 0.05). Conclusion. The frequency of TTIs, especially HCV, is considerably high among Egyptian children with thalassemia major. It is therefore important to implement measures to improve blood transfusion screening, such as polymerase chain reaction, in order to reduce TTIs from blood donor units. PMID- 26989418 TI - Distinct Habitats Select Particular Bacterial Communities in Mangrove Sediments. AB - We investigated the relationship among environmental variables, composition, and structure of bacterial communities in different habitats in a mangrove located nearby to an oil exploitation area, aiming to retrieve the natural pattern of bacterial communities in this ecosystem. The T-RFLP analysis showed a high diversity of bacterial populations and an increase in the bacterial richness from habitats closer to the sea and without vegetation (S1) to habitats covered by Avicennia schaueriana (S2) and Rhizophora mangle (S3). Environmental variables in S1 and S2 were more similar than in S3; however, when comparing the bacterial compositions, S2 and S3 shared more OTUs between them, suggesting that the presence of vegetation is an important factor in shaping these bacterial communities. In silico analyses of the fragments revealed a high diversity of the class Gammaproteobacteria in the 3 sites, although in general they presented quite different bacterial composition, which is probably shaped by the specificities of each habitat. This study shows that microhabitats inside of a mangrove ecosystem harbor diverse and distinct microbiota, reinforcing the need to conserve these ecosystems as a whole. PMID- 26989420 TI - Loperamide Induced Torsades de Pointes: A Case Report and Review of the Literature. AB - Abuse of over the counter drugs often gets overlooked by health care providers. Loperamide is one such over the counter drug that is often abused by drug addicts. We present here a case of a young male attaining euphoria from taking massive doses of loperamide. He developed Torsades de Pointes and subsequent cardiac arrest. We found similarities in the progression of myocardial electrical conduction abnormalities among loperamide and other previously known arrhythmogenic drugs. We intend to raise concern over the ease of availability of such drugs over the counter and increase the index of suspicion for over the counter drug abuse from our experience. PMID- 26989419 TI - Hiding in Fresh Fruits and Vegetables: Opportunistic Pathogens May Cross Geographical Barriers. AB - Different microbial groups of the microbiome of fresh produce can have diverse effects on human health. This study was aimed at identifying some microbial communities of fresh produce by analyzing 105 samples of imported fresh fruits and vegetables originated from different countries in the world including local samples (Oman) for aerobic plate count and the counts of Enterobacteriaceae, Enterococcus, and Staphylococcus aureus. The isolated bacteria were identified by molecular (PCR) and biochemical methods (VITEK 2). Enterobacteriaceae occurred in 60% of fruits and 91% of vegetables. Enterococcus was isolated from 20% of fruits and 42% of vegetables. E. coli and S. aureus were isolated from 22% and 7% of vegetables, respectively. Ninety-seven bacteria comprising 21 species were similarly identified by VITEK 2 and PCR to species level. E. coli, Klebsiella pneumoniae, Enterococcus casseliflavus, and Enterobacter cloacae were the most abundant species; many are known as opportunistic pathogens which may raise concern to improve the microbial quality of fresh produce. Phylogenetic trees showed no relationship between clustering of the isolates based on the 16S rRNA gene and the original countries of fresh produce. Intercountry passage of opportunistic pathogens in fresh produce cannot be ruled out, which requires better management. PMID- 26989422 TI - N-Stearoyl-L-Tyrosine Inhibits the Senescence of Neural Stem/Progenitor Cells Induced by Abeta 1-42 via the CB2 Receptor. AB - Alzheimer's disease, one of the neurodegenerative diseases, shows the progressive senescence of neural progenitor/stem cells. N-Stearoyl-L-tyrosine (NsTyr) showed neuroprotective effect against chronic brain ischemia in previous reports. In the present study, we find the antisenescent effects of NsTyr-2K in NSPCs induced by Abeta 1-42 in vitro. Cell viability of NSPCs was evaluated by CCK8 assay; SA-beta gal staining was used to evaluate senescence of NSPCs. CB receptors were detected by immunohistochemistry in NSPCs. AM251 or AM630 was used to offset the anti senescence effects afforded by NsTyr-2K. The positive rate of SA-beta-gal staining was significantly increased in NSPCs after incubation with Abeta 1-42 for 9 days. CB receptors were found on the surface of NSPCs. The expression level of CB1 receptors was significantly decreased in NSPCs after incubation with Abeta 1-42. This phenomenon was reversed dose-dependently by NsTyr-2K. NsTyr-2K attenuated Abeta 1-42 induced NSPCs senescence dose-dependently, and its antisenescence effect was completely abolished by AM630. Abeta 1-42 dose dependently increased the prosenescence molecules p16 and Rb. Their expression was inhibited by NsTyr-2K dose-dependently and blocked by AM630 in NSPCs. These results suggest that NsTyr-2K can alleviate the senescence of NSPCs induced by Abeta 1-42 via CB2 receptor. PMID- 26989423 TI - Biomedical Application of Dental Tissue-Derived Induced Pluripotent Stem Cells. AB - The academic researches and clinical applications in recent years found interest in induced pluripotent stem cells (iPSCs-) based regenerative medicine due to their pluripotency able to differentiate into any cell types in the body without using embryo. However, it is limited in generating iPSCs from adult somatic cells and use of these cells due to the low stem cell potency and donor site morbidity. In biomedical applications, particularly, dental tissue-derived iPSCs have been getting attention as a type of alternative sources for regenerating damaged tissues due to high potential of stem cell characteristics, easy accessibility and attainment, and their ectomesenchymal origin, which allow them to have potential for nerve, vessel, and dental tissue regeneration. This paper will cover the overview of dental tissue-derived iPSCs and their application with their advantages and drawbacks. PMID- 26989421 TI - Noncoding RNAs in Tumor Epithelial-to-Mesenchymal Transition. AB - Epithelial-derived tumor cells acquire the capacity for epithelial-to-mesenchymal transition (EMT), which enables them to invade adjacent tissues and/or metastasize to distant organs. Cancer metastasis is the main cause of cancer related death. Molecular mechanisms involved in the switch from an epithelial phenotype to mesenchymal status are complicated and are controlled by a variety of signaling pathways. Recently, a set of noncoding RNAs (ncRNAs), including miRNAs and long noncoding RNAs (lncRNAs), were found to modulate gene expressions at either transcriptional or posttranscriptional levels. These ncRNAs are involved in EMT through their interplay with EMT-related transcription factors (EMT-TFs) and EMT-associated signaling. Reciprocal regulatory interactions between lncRNAs and miRNAs further increase the complexity of the regulation of gene expression and protein translation. In this review, we discuss recent findings regarding EMT-regulating ncRNAs and their associated signaling pathways involved in cancer progression. PMID- 26989425 TI - Modes of Antiviral Action of Chemical Portions and Constituents from Woad Root Extract against Influenza Virus A FM1. AB - Woad root has been used for the prevention of influenza for hundreds of years in many Asian countries. In this study, the antiviral modes of clemastanin B (CB), epigoitrin, phenylpropanoid portion (PEP), and the mixture of phenylpropanoids, alkaloids, and organic acid portions (PEP + ALK + OA) from wood root extract against influenza virus A FM1 were investigated. The results revealed that CB, epigoitrin, PEP, and PEP + ALK + OA exert their anti-influenza activity via inhibiting the virus multiplication, prophylaxis, and blocking the virus attachment. The primary mode of action of PEP and PEP + ALK + OA is the inhibition of virus replication. The inhibitory effect on virus attachment and multiplication is the main modes for epigoitrin. All the compounds or chemical portions from woad root extract tested in this study do not have direct virucidal activity. Our results provided the comprehensive analysis of the antiviral mechanism of wood root extract. PMID- 26989424 TI - Global Mapping of Traditional Chinese Medicine into Bioactivity Space and Pathways Annotation Improves Mechanistic Understanding and Discovers Relationships between Therapeutic Action (Sub)classes. AB - Traditional Chinese medicine (TCM) still needs more scientific rationale to be proven for it to be accepted further in the West. We are now in the position to propose computational hypotheses for the mode-of-actions (MOAs) of 45 TCM therapeutic action (sub)classes from in silico target prediction algorithms, whose target was later annotated with Kyoto Encyclopedia of Genes and Genomes pathway, and to discover the relationship between them by generating a hierarchical clustering. The results of 10,749 TCM compounds showed 183 enriched targets and 99 enriched pathways from Estimation Score <= 0 and >= 5% of compounds/targets in a (sub)class. The MOA of a (sub)class was established from supporting literature. Overall, the most frequent top three enriched targets/pathways were immune-related targets such as tyrosine-protein phosphatase nonreceptor type 2 (PTPN2) and digestive system such as mineral absorption. We found two major protein families, G-protein coupled receptor (GPCR), and protein kinase family contributed to the diversity of the bioactivity space, while digestive system was consistently annotated pathway motif, which agreed with the important treatment principle of TCM, "the foundation of acquired constitution" that includes spleen and stomach. In short, the TCM (sub)classes, in many cases share similar targets/pathways despite having different indications. PMID- 26989426 TI - Effects of Safflower Yellow on the Treatment of Severe Sepsis and Septic Shock: A Randomized Controlled Clinical Trial. AB - Objective. To evaluate the clinical effect of safflower yellow on the treatment of severe sepsis and septic shock. Methods. 85 patients with severe sepsis and septic shock were randomly selected to receive either therapy according to the international guidelines for management of severe sepsis and septic shock (Surviving Sepsis Campaign 2012) (control group, n = 45) or conventional therapy plus safflower yellow (study group, n = 40). The 28-day mortality and 28-day Kaplan-Meier survival curves were compared as primary outcomes. Results. The 28 day mortality from all causes and in-hospital mortality were significantly lower in the study group (50%, 17.5%) as compared to the control group (78.58%, 54.76%) (P = 0.007, all causes, P < 0.001, in-hospital), and the 28-day Kaplan-Meier survival curve was higher in the study group than in the control group (P = 0.008, all causes, P < 0.001, in-hospital, Log Rank). 72 hours after treatment, secondary outcomes including heart rate, leukocyte counts, lactate levels, and platelet counts of patients in the study group were ameliorated significantly as compared with the control group. Conclusion. This study offers a potential new strategy employing safflower yellow to more effectively treat patients with severe sepsis and septic shock. This trial is registered with identifier ChiCTR TRC-14005196. PMID- 26989427 TI - Hedyotis diffusa plus Scutellaria barbata Induce Bladder Cancer Cell Apoptosis by Inhibiting Akt Signaling Pathway through Downregulating miR-155 Expression. AB - Traditional Chinese medicine is increasingly used to treat cancer. Our clinical experiences identify Hedyotis diffusa plus Scutellaria barbata as the most common herb-pair (couplet medicinal) used for the core treatment of bladder cancer. This study aims to investigate the antitumor effect of the herb-pair in bladder cancer cells. The results show that Hedyotis diffusa plus Scutellaria barbata inhibited bladder cancer cell growth and clone formation in a dose-dependent and time dependent manner. It also induced cell apoptosis through decreasing Akt activation and reducing the expression of antiapoptotic proteins Bcl-2 and Mcl-1. Further experiments showed that miR-155 was reduced by the herb-pair and miRNA 155 inhibitor induced cell apoptosis and suppressed Akt activation. Overexpression of miR-155 reversed herb-pair induced cell apoptosis through activating Akt pathway in both bladder cancer cell lines. The findings reveal that Hedyotis diffusa plus Scutellaria barbata reduce Akt activation through reducing miR-155 expression, resulting in cell apoptosis. It demonstrated the potential mechanism of Hedyotis diffusa plus Scutellaria barbata for the core treatment of bladder cancer. PMID- 26989428 TI - Therapeutic Effects of Chinese Medicine Herb Pair, Huzhang and Guizhi, on Monosodium Urate Crystal-Induced Gouty Arthritis in Rats Revealed by Anti Inflammatory Assessments and NMR-Based Metabonomics. AB - The present study was undertaken to evaluate the therapeutic effects of Huzhang Guizhi herb pair (HG), firstly included in Hu-Zhang Power documented in Taiping Shenghui Fang, on monosodium urate (MSU) crystals-induced gouty arthritis in rats. We found that pretreatment with HG in rats with gouty arthritis could significantly attenuate the ankle joint swelling, and this beneficial antigout effect might be mediated, at least in part, by inhibiting tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) production in synovial fluid as well as nuclear transcription factor-kappaB p65 (NF-kappaB p65) protein expression in synovial tissue. Moreover, metabonomic analysis demonstrated that 5 and 6 potential biomarkers associated with gouty arthritis in plasma and urine, respectively, which were mainly involved in energy metabolism, amino acid metabolism, and gut microbe metabolism, were identified. HG could reverse the pathological process of MSU-induced gouty arthritis through regulating the disturbed metabolic pathways. These results provided important mechanistic insights into the protective effects of HG against MSU-induced gouty arthritis in rats. PMID- 26989429 TI - Survey of Medicinal Plants Used to Treat Malaria by Sidama People of Boricha District, Sidama Zone, South Region of Ethiopia. AB - In Ethiopia, malaria control has been complicated due to resistance of the parasite to the current drugs. Thus, new drugs are required against drug resistant Plasmodium strains. Historically, many of the present antimalarial drugs were discovered from plants. This study was, therefore, conducted to document antimalarial plants utilized by Sidama people of Boricha District, Sidama Zone, South Region of Ethiopia. An ethnobotanical survey was carried out from September 2011 to February 2012. Data were collected through semistructured interview and field and market observations. Relative frequency of citation (RFC) was calculated and preference ranking exercises were conducted to estimate the importance of the reported medicinal plants in Boricha District. A total of 42 antimalarial plants belonging to 27 families were recorded in the study area. Leaf was the dominant plant part (59.0%) used in the preparation of remedies and oral (97.4%) was the major route of administration. Ajuga integrifolia scored the highest RFC value (0.80). The results of this study revealed the existence of rich knowledge on the use of medicinal plants in the study area to treat malaria. Thus, an attempt should be made to conserve and evaluate the claimed antimalarial medicinal plants with priority given to those that scored the highest RFC values. PMID- 26989430 TI - Use of the non-radioactive SUnSET method to detect decreased protein synthesis in proteasome inhibited Arabidopsis roots. AB - BACKGROUND: In eukaryotic cells, the proteasome maintains homeostasis by selectively degrading regulatory and misfolded proteins, and in doing so contributes to the amino acid pool. Inhibition of the proteasome in yeast and human cells decreases de novo protein synthesis. However, it is not know if proteasome inhibition in plants similarly suppresses protein synthesis. To address this gap in plant biology, protein synthesis in Arabidopsis roots was estimated using SUface SEnsing of Translation (SUnSET) techniques. This non radioactive method has been validated in animal cells, but has not yet been applied to plants. The goal of this study was to investigate the suitability of SUnSET methodology to measure protein synthesis in plants, and to determine if proteasome inhibition decreases levels of newly synthesized proteins. RESULTS: The SUnSET technique revealed that Arabidopsis plants treated with cycloheximide an inhibitor of protein synthesis-severely decreased levels of newly synthesized proteins in root and shoot tissue, as detected on a Western Blot. Therefore, the non-radioactive method is suitable to detect changes in protein synthesis, and was subsequently used to monitor protein synthesis in proteasome-inhibited roots. The proteasome inhibitor MG132 decreased levels of newly synthesized proteins by 70-80 % after 4 and 16 h. Removal of MG132 from liquid media resulted in roots with increased levels of newly synthesized proteins compared to untreated plants, suggesting that recovery from proteasome inhibition results in elevated levels of protein synthesis. Additionally, SUnSET was used to detect a decrease in protein synthesis in the roots of plants subjected to salt stress or sulfur starvation. CONCLUSIONS: Proteasome inhibition has been shown to decrease protein synthesis in yeast and human cells, and this study now shows that MG132's inhibitory effects also applies to plants. These data represent the first time that SUnSET has been used to measure protein synthesis in plants. The study demonstrates that SUnSET is a suitable and robust technique to measure protein synthesis in plants. The use of this non-radioactive method to gauge protein synthesis offers a fast, safe, and cost-effective alternative compared to traditional techniques that rely upon radioactive material. The method is likely to have broad applicability to different disciplines in plant biology. PMID- 26989431 TI - Human skin organ culture for assessment of chemically induced skin damage. AB - The move away from animal models for skin safety testing is inevitable. It is a question of when, not if. As skin safety studies move away from traditional animal-based approaches, a number of replacement technologies are becoming available. Human skin in organ culture is one such technology. Organ-cultured skin has several features that distinguish it from other technologies. First and foremost, organ-cultured skin is real skin. Almost by definition, therefore, it approximates the intact skin better than other alternative models. Organ culture is an easy-to-use and relatively inexpensive approach to preclinical safety assessment. Although organ culture is not likely to replace high-throughput enzyme assays or monolayer culture/skin equivalent cultures for initial compound assessment, organ culture should find use when the list of compounds to be evaluated is small and when simpler models have narrowed the dose range. Organ cultured skin also provides a platform for mechanistic studies. PMID- 26989433 TI - Use of swabs for dry collection of self-samples to detect human papillomavirus among Malagasy women. AB - BACKGROUND: Most women in developing countries have never attended cervical screening programmes and often little information exists on type-specific human papillomavirus (HPV) prevalence among these populations. Self-sampling for HPV testing (self-HPV) using a dry swab may be useful for establishing a screening program and evaluating HPV prevalence. Our aim was to evaluate self-HPV using a dry swab stored at room temperature. METHODS: This community-based study in Madagascar consisted of 449 women aged 30-65. Eligible women were provided a dry swab to perform self-HPV. HPV analysis was accomplished by two different real time PCR tests using the same extracted DNA from the samples. RESULTS: Overall, 52 (11.6 %) specimens were invalid for HPV detection. The delay between sampling and laboratory processing of DNA extraction considerably increased invalid results. Overall HPV prevalence of 14 hrHPV types detected by the two PCR tests was found to be 38.2 % (n = 152). Distribution of 19 hrHPV and 9 low-risk HPV (lrHPV) types revealed most frequently 53 and 68 among hrHPV and HPV 54, HPV 70 and HPV 42 among lrHPV. Agreement between the two PCR methods for any of the 14 high-risk HPV (hrHPV) strains detected was 89.9 % (kappa = 0.77, 95 % CI: 0.71 0.84). In 385 (85.7 %) samples the DNA load of beta-globin demonstrated a signal with medium or high level copies. Conversely, in 28 (60.9 %) invalid samples the signal was undetectable. The HPV-DNA load signal was predominantly of intermediate level (58.5 %, n = 218). CONCLUSIONS: Self-HPV using a dry swab stored at room temperature could be a useful method for HPV screening and for conducting population-based surveys on HPV prevalence in resource-poor settings. PMID- 26989432 TI - Peritoneal Fluid Transport rather than Peritoneal Solute Transport Associates with Dialysis Vintage and Age of Peritoneal Dialysis Patients. AB - During peritoneal dialysis (PD), the peritoneal membrane undergoes ageing processes that affect its function. Here we analyzed associations of patient age and dialysis vintage with parameters of peritoneal transport of fluid and solutes, directly measured and estimated based on the pore model, for individual patients. Thirty-three patients (15 females; age 60 (21-87) years; median time on PD 19 (3-100) months) underwent sequential peritoneal equilibration test. Dialysis vintage and patient age did not correlate. Estimation of parameters of the two-pore model of peritoneal transport was performed. The estimated fluid transport parameters, including hydraulic permeability (LpS), fraction of ultrasmall pores (alpha u), osmotic conductance for glucose (OCG), and peritoneal absorption, were generally independent of solute transport parameters (diffusive mass transport parameters). Fluid transport parameters correlated whereas transport parameters for small solutes and proteins did not correlate with dialysis vintage and patient age. Although LpS and OCG were lower for older patients and those with long dialysis vintage, alphau was higher. Thus, fluid transport parameters--rather than solute transport parameters--are linked to dialysis vintage and patient age and should therefore be included when monitoring processes linked to ageing of the peritoneal membrane. PMID- 26989435 TI - A common garden design reveals population-specific variability in potential impacts of hybridization between populations of farmed and wild Atlantic salmon, Salmo salar L. AB - Released individuals can have negative impacts on native populations through various mechanisms, including competition, disease transfer and introduction of maladapted gene complexes. Previous studies indicate that the level of farmed Atlantic salmon introgression in native populations is population specific. However, few studies have explored the potential role of population diversity or river characteristics, such as temperature, on the consequences of hybridization. We compared freshwater growth of multiple families derived from two farmed, five wild and two F1 hybrid salmon populations at three contrasting temperatures (7 degrees C, 12 degrees C and 16 degrees C) in a common garden experiment. As expected, farmed salmon outgrew wild salmon at all temperatures, with hybrids displaying intermediate growth. However, differences in growth were population specific and some wild populations performed better than others relative to the hybrid and farmed populations at certain temperatures. Therefore, the competitive balance between farmed and wild salmon may depend both on the thermal profile of the river and on the genetic characteristics of the respective farmed and wild strains. While limited to F1 hybridization, this study shows the merits in adopting a more complex spatially resolved approach to risk management of local populations. PMID- 26989434 TI - Predation and selection for antibiotic resistance in natural environments. AB - Genes encoding resistance to antibiotics appear, like the antibiotics themselves, to be ancient, originating long before the rise of the era of anthropogenic antibiotics. However, detailed understanding of the specific biological advantages of antibiotic resistance in natural environments is still lacking, thus limiting our efforts to prevent environmental influx of resistance genes. Here, we propose that antibiotic-resistant cells not only evade predation from antibiotic producers but also take advantage of nutrients released from cells that are killed by the antibiotic-producing bacteria. Thus, predation is potentially an important mechanism for driving antibiotic resistance during slow or stationary phase of growth when nutrients are deprived. This adds to explain the ancient nature and widespread occurrence of antibiotic resistance in natural environments unaffected by anthropogenic antibiotics. In particular, we suggest that nutrient-poor environments including indoor environments, for example, clean rooms and intensive care units may serve as a reservoir and source for antibiotic producing as well as antibiotic-resistant bacteria. PMID- 26989436 TI - Rapid evolution of increased vulnerability to an insecticide at the expansion front in a poleward-moving damselfly. AB - Many species are too slow to track their poleward-moving climate niche under global warming. Pesticide exposure may contribute to this by reducing population growth and impairing flight ability. Moreover, edge populations at the moving range front may be more vulnerable to pesticides because of the rapid evolution of traits to enhance their rate of spread that shunt energy away from detoxification and repair. We exposed replicated edge and core populations of the poleward-moving damselfly Coenagrion scitulum to the pesticide esfenvalerate at low and high densities. Exposure to esfenvalerate had strong negative effects on survival, growth rate, and development time in the larval stage and negatively affected flight-related adult traits (mass at emergence, flight muscle mass, and fat content) across metamorphosis. Pesticide effects did not differ between edge and core populations, except that at the high concentration the pesticide-induced mortality was 17% stronger in edge populations. Pesticide exposure may therefore slow down the range expansion by lowering population growth rates, especially because edge populations suffered a higher mortality, and by negatively affecting dispersal ability by impairing flight-related traits. These results emphasize the need for direct conservation efforts toward leading-edge populations for facilitating future range shifts under global warming. PMID- 26989437 TI - Limiting opportunities for cheating stabilizes virulence in insect parasitic nematodes. AB - Cooperative secretion of virulence factors by pathogens can lead to social conflict when cheating mutants exploit collective secretion, but do not contribute to it. If cheats outcompete cooperators within hosts, this can cause loss of virulence. Insect parasitic nematodes are important biocontrol tools that secrete a range of significant virulence factors. Critically, effective nematodes are hard to maintain without live passage, which can lead to virulence attenuation. Using experimental evolution, we tested whether social cheating might explain unstable virulence in the nematode Heterorhabditis floridensis by manipulating relatedness via multiplicity of infection (MOI), and the scale of competition. Passage at high MOI, which should reduce relatedness, led to loss of fitness: virulence and reproductive rate declined together and all eight independent lines suffered premature extinction. As theory predicts, relatedness treatments had more impact under stronger global competition. In contrast, low MOI passage led to more stable virulence and increased reproduction. Moreover, low MOI lineages showed a trade-off between virulence and reproduction, particularly for lines under stronger between-host competition. Overall, this study indicates that evolution of virulence theory is valuable for the culture of biocontrol agents: effective nematodes can be improved and maintained if passage methods mitigate possible social conflicts. PMID- 26989438 TI - Developmental plasticity increases at the northern range margin in a warm dependent amphibian. AB - Accurate predictions regarding how climate change affects species and populations are crucial for the development of effective conservation measures. However, models forecasting the impact of climate change on natural environments do not often consider the geographic variation of an organism's life history. We examined variation in developmental plasticity to changing temperature in the pool frog (Pelophylax lessonae) across its distribution by studying populations from central areas (Poland), edge populations (Latvia) and northern marginal populations (Sweden). Relative to central and edge populations, northern populations experience lower and less variable temperature and fewer episodes of warm weather during larval development. Plasticity in larval life-history traits was highest at the northern range margin: larvae from marginal populations shortened larval period and increased growth rate more than larvae from central and edge populations when reared at high temperature. Maintaining high growth and development under the scarce spells of warm weather is likely adaptive for high latitude populations. The detection of high levels of developmental plasticity in isolated, marginal populations suggests that they may be better able to respond to the temperature regimes expected under climate change than often predicted, reflecting the need to incorporate geographic variation in life-history traits into models forecasting responses to environmental change. PMID- 26989439 TI - Parallel declines in species and genetic diversity driven by anthropogenic disturbance: a multispecies approach in a French Atlantic dune system. AB - Numerous studies assess the correlation between genetic and species diversities, but the processes underlying the observed patterns have only received limited attention. For instance, varying levels of habitat disturbance across a region may locally reduce both diversities due to extinctions, and increased genetic drift during population bottlenecks and founder events. We investigated the regional distribution of genetic and species diversities of a coastal sand dune plant community along 240 kilometers of coastline with the aim to test for a correlation between the two diversity levels. We further quantify and tease apart the respective contributions of natural and anthropogenic disturbance factors to the observed patterns. We detected significant positive correlation between both variables. We further revealed a negative impact of urbanization: Sites with a high amount of recreational infrastructure within 10 km coastline had significantly lowered genetic and species diversities. On the other hand, a measure of natural habitat disturbance had no effect. This study shows that parallel variation of genetic and species diversities across a region can be traced back to human landscape alteration, provides arguments for a more resolute dune protection, and may help to design priority conservation areas. PMID- 26989440 TI - Temporal sampling helps unravel the genetic structure of naturally occurring populations of a phytoparasitic nematode. 1. Insights from the estimation of effective population sizes. AB - The sustainability of modern agriculture relies on strategies that can control the ability of pathogens to overcome chemicals or genetic resistances through natural selection. This evolutionary potential, which depends partly on effective population size (N e ), is greatly influenced by human activities. In this context, wild pathogen populations can provide valuable information for assessing the long-term risk associated with crop pests. In this study, we estimated the effective population size of the beet cyst nematode, Heterodera schachtii, by sampling 34 populations infecting the sea beet Beta vulgaris spp. maritima twice within a one-year period. Only 20 populations produced enough generations to analyze the variation in allele frequencies, with the remaining populations showing a high mortality rate of the host plant after only 1 year. The 20 analyzed populations showed surprisingly low effective population sizes, with most having N e close to 85 individuals. We attribute these low values to the variation in population size through time, systematic inbreeding, and unbalanced sex-ratios. Our results suggest that H. schachtii has low evolutionary potential in natural environments. Pest control strategies in which populations on crops mimic wild populations may help prevent parasite adaptation to host resistance. PMID- 26989441 TI - Environmental influences on mosquito foraging and integrated vector management can delay the evolution of behavioral resistance. AB - Along with the scaled-up distribution of long-lasting insecticidal nets for malaria control has become concern about insecticide resistance. A related concern regards the evolution of host-seeking periodicity from the nocturnal to the crepuscular periods of the day. Why we observe such shifts in some areas but not others and which methods could prove useful in managing such behavioral resistance remain open questions. We developed a foraging model to explore whether environmental conditions affect the evolution of behavioral resistance. We looked at the role of the abundance of blood hosts and nectar sources and investigated the potential of attractive toxic sugar baits for integrated control. Higher encounter rates with hosts and nectar sources allowed behaviorally resistant populations to persist at higher levels of bed net coverage. Whereas higher encounter rates with nectar increased the threshold where resistance emerged, higher encounter rates of hosts lowered this threshold. Adding sugar baits lowered the coverage level of bed nets required to eliminate the vector population. In certain environments, using lower bed net coverage levels together with toxic sugar baits may delay or prevent the evolution of behavioral resistance. Designing sustainable control strategies will depend on an understanding of vector behavior expressed in local environmental conditions. PMID- 26989442 TI - Erratum to: Enhanced short chain fatty acids production from waste activated sludge conditioning with typical agricultural residues: carbon source composition regulates community functions. AB - [This corrects the article DOI: 10.1186/s13068-015-0369-x.]. PMID- 26989443 TI - Penicillium echinulatum secretome analysis reveals the fungi potential for degradation of lignocellulosic biomass. AB - BACKGROUND: The enzymatic degradation of lignocellulosic materials by fungal enzyme systems has been extensively studied due to its effectiveness in the liberation of fermentable sugars for bioethanol production. Recently, variants of the fungus Penicillium echinulatum have been described as a great producer of cellulases and considered a promising strain for the bioethanol industry. RESULTS: Penicillium echinulatum, wild-type 2HH and its mutant strain S1M29, were grown on four different carbon sources: cellulose, sugar cane bagasse pretreated by steam explosion (SCB), glucose, and glycerol for 120 h. Samples collected at 24, 96, and 120 h were used for enzymatic measurement, and the 96-h one was also used for secretome analysis by 1D-PAGE LC-MS/MS. A total of 165 proteins were identified, and more than one-third of these proteins belong to CAZy families. Glycosyl hydrolases (GH) are the most abundant group, being represented in larger quantities by GH3, 5, 17, 43, and 72. Cellobiohydrolases, endoglucanases, beta glycosidases, xylanases, beta-xylosidases, and mannanases were found, and in minor quantities, pectinases, ligninases, and amylases were also found. Swollenin and esterases were also identified. CONCLUSIONS: Our study revealed differences in the two strains of P. echinulatum in several aspects in which the mutation improved the production of enzymes related to lignocellulosic biomass deconstruction. Considering the spectral counting analysis, the mutant strain S1M29 was more efficient in the production of enzymes involved in cellulose and hemicellulose degradation, despite having a nearly identical CAZy enzymatic repertoire. Moreover, S1M29 secretes more quantities of protein on SCB than on cellulose, relevant information when considering the production of cellulases using raw materials at low cost. Glucose, and especially glycerol, were used mainly for the production of amylases and ligninases. PMID- 26989444 TI - Efficient malic acid production from glycerol with Ustilago trichophora TZ1. AB - BACKGROUND: The large surplus of crude glycerol, as main low-value waste stream in biodiesel production, has led to the investigation of new possibilities for the production of value-added chemicals from this feedstock. New and efficient (bio-) catalysts are needed that are able to convert glycerol to versatile chemical building blocks. This would contribute to further develop away from a mainly petroleum based, to a sustainable, bio-based industry. One promising group of discussed building block chemicals are dicarbonic acids. RESULTS: Here, we report the efficient synthesis of malate from glycerol using Ustilago trichophora RK089, which was identified in a screening of 74 Ustilaginaceae. For economically feasible production that can compete with existing processes, a high productivity is required. By adaptive laboratory evolution, the growth and production rate were increased by 2.5- and 6.6-fold, respectively. Further medium optimization increased the final titer, yield, and overall production rate to 196 g L(-1), 0.82 gmal ggly (-1), and 0.39 g L(-1) h(-1), respectively. CONCLUSIONS: This titer is the highest reported for microbial malate production, making U. trichophora TZ1 a promising microbial production host for malate from crude glycerol, especially since it is not genetically engineered. Since this production process starts from an industrial waste stream as substrate and yields an interesting platform chemical, which can be used to replace petro-chemicals, it greatly contributes to a sustainable bio-economy. PMID- 26989445 TI - The role of adipose tissue and adipokines in the manifestation of type 2 diabetes in the long-term period following myocardial infarction. AB - BACKGROUND: This study aimed to evaluate the markers of insulin resistance and adipokine status in patients with visceral obesity during hospitalization following myocardial infarction (MI) and assess the disturbances of carbohydrate metabolism present 1 year after MI onset. METHODS: 94 male patients with MI were recruited. The exclusion criteria were as follows: age less than 50 or greater than 80 years, the presence of type 2 diabetes mellitus (T2DM), and a prior history of pronounced renal failure.Obesity types were defined according to body mass index (BMI), waist circumference (WC) and visceral adipose tissue (VAT) area. Glucose, insulin, adiponectin, leptin, and insulin resistance (IR) index were measured on days 1 and 12 after the onset of MI. New-onset type 2 diabetes was assessed 1 year after MI onset. RESULTS: According to computed tomography assessments of all study patients, 69 % of patients with MI suffered from visceral obesity. The VAT area was more closely associated with the risk of developing type 2 diabetes compared with the obesity parameters, BMI and WC. Patients with a VAT area greater than 130 cm(2) had a 3.6-fold higher risk of developing type 2 diabetes. The presence of IR and hyperleptinemia increased the risk of developing diabetes in the post-MI period 3.5 and 3.7 times, respectively, in patients with visceral obesity compared with patients without visceral obesity. CONCLUSION: Visceral obesity is associated with IR, a 5.7-fold increase in leptin levels and a high risk of developing type 2 diabetes 1 year after MI onset. PMID- 26989446 TI - Baseline characteristics and risk factors for ulcer, amputation and severe neuropathy in diabetic foot at risk: the BRAZUPA study. AB - BACKGROUND: Studies on diabetic foot and its complications involving a significant and representative sample of patients in South American countries are scarce. The main objective of this study was to acquire clinical and epidemiological data on a large cohort of diabetic patients from 19 centers from Brazil and focus on factors that could be associated with the risk of ulcer and amputation. METHODS: This study presents cross sectional, baseline results of the BRAZUPA Study. A total of 1455 patients were included. Parameters recorded included age, gender, ethnicity, diabetes and comorbidity-related records, previous ulcer or amputation, clinical symptomatic score, foot classification and microvascular complications. RESULTS: Patients with ulcer had longer disease duration (17.2 +/- 9.9 vs. 13.2 +/- 9.4 years; p < 0.001), and poorer glycemic control (HbA1c 9.23 +/- 2.03 vs. 8.35 +/- 1.99; p < 0.001). Independent risk factors for ulcer were male gender (OR 1.71; 95 % CI 1.2-3.7), smoking (OR 1.78; 95 % CI 1.09-2.89), neuroischemic foot (OR 20.34; 95 % CI 9.31-44.38), region of origin (higher risk for those from developed regions, OR 2.39; 95 % CI 1.47 3.87), presence of retinopathy (OR 1.68; 95 % CI 1.08-2.62) and absence of vibratory sensation (OR 7.95; 95 % CI 4.65-13.59). Risk factors for amputation were male gender (OR 2.12; 95 % CI 1.2-3.73), type 2 diabetes (OR 3.33; 95 % CI 1.01-11.1), foot at risk classification (higher risk for ischemic foot, OR 19.63; 95 % CI 3.43-112.5), hypertension (lower risk, OR 0.3; 95 % CI 0.14-0.63), region of origin (South/Southeast, OR 2.2; 95 % CI 1.1-4.42), previous history of ulcer (OR 9.66; 95 % CI 4.67-19.98) and altered vibratory sensation (OR 3.46; 95 % CI 1.64-7.33). There was no association between either outcome and ethnicity. CONCLUSIONS: Ulcer and amputation rates were high. Age at presentation was low and patients with ulcer presented a higher prevalence of neuropathy compared to ischemic foot at risk. Ischemic disease was more associated with amputations. Ethnical differences were not of great importance in a miscegenated population. PMID- 26989447 TI - Projecting Event-Based Analysis Dates in Clinical Trials: An Illustration Based on the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) Collaboration. Projecting analysis dates for the IDEA collaboration. AB - PURPOSE: Clinical trials are expensive and lengthy, where success of a given trial depends on observing a prospectively defined number of patient events required to answer the clinical question. The point at which this analysis time occurs depends on both patient accrual and primary event rates, which typically vary throughout the trial's duration. We demonstrate real-time analysis date projections using data from a collection of six clinical trials that are part of the IDEA collaboration, an international preplanned pooling of data from six trials testing the duration of adjuvant chemotherapy in stage III colon cancer, and we additionally consider the hypothetical impact of one trial's early termination of follow-up. PATIENTS AND METHODS: In the absence of outcome data from IDEA, monthly accrual rates for each of the six IDEA trials were used to project subsequent trial-specific accrual, while historical data from similar Adjuvant Colon Cancer Endpoints (ACCENT) Group trials were used to construct a parametric model for IDEA's primary endpoint, disease-free survival, under the same treatment regimen. With this information and using the planned total accrual from each IDEA trial protocol, individual patient accrual and event dates were simulated and the overall IDEA interim and final analysis times projected. Projections were then compared with actual (previously undisclosed) trial specific event totals at a recent census time for validation. The change in projected final analysis date assuming early termination of follow-up for one IDEA trial was also calculated. RESULTS: Trial-specific predicted event totals were close to the actual number of events per trial for the recent census date at which the number of events per trial was known, with the overall IDEA projected number of events only off by eight patients. Potential early termination of follow-up by one IDEA trial was estimated to postpone the overall IDEA final analysis date by 9 months. CONCLUSIONS: Real-time projection of the final analysis time during a trial, or the overall analysis time during a trial collaborative such as IDEA, has practical implications for trial feasibility when these projections are translated into additional time and resources required. PMID- 26989449 TI - Heterogeneity of Human Research Ethics Committees and Research Governance Offices across Australia: An observational study. AB - BACKGROUND: Conducting ethically grounded research is a fundamental facet of all investigations. Nevertheless, the administrative burdens of current ethics review are substantial, and calls have been made for a reduction in research waste. AIMS: To describe the heterogeneity in administration and documentation required by Human Research Ethics Committees (HRECs) and Research Governance Offices (RGOs) across Australia. METHODS: In establishing a nationwide study to investigate the molecular aetiology of Giant Cell Arteritis (GCA), for which archived pathological specimens from around Australia are being recruited, we identified variation across separate HREC and RGO requirements. Submission paperwork and correspondence from each collaborating site and its representative office for research were reviewed. This data was interrogated to evaluate differences in current guidelines. RESULTS: Twenty-five pathology departments across seven Australian States collaborated in this study. All states, except Victoria, employed a single ethics review model. There was discrepancy amongst HRECs as to which application process applied to our study: seven requested completion of a "National Ethics Application Form" and three a "Low Negligible Risk" form. Noticeable differences in guidelines included whether electronic submission was sufficient. There was variability in the total number of documents submitted (range five to 22) and panel review turnaround time (range nine to 136 days). CONCLUSION: We demonstrate the challenges and illustrate the heavy workload involved in receiving widespread ethics and governance approval across Australia. We highlight the need to simplify, homogenise, and nationalise human ethics for non-clinical trial studies. Reducing unnecessary administration will enable investigators to achieve research aims more efficiently. PMID- 26989448 TI - Techniques to administer oral, inhalational, and IV sedation in dentistry. AB - BACKGROUND: Sedation in dentistry is a controversial topic given the variety of opinions regarding its safe practice. AIMS: This article evaluates the various techniques used to administer sedation in dentistry and specific methods practiced to form a recommendation for clinicians. METHODS: An extensive literature search was performed using PubMed, Medline, Google Scholar, Google, and local library resources. RESULTS: Most of the literature revealed a consensus that light sedation on low-risk American Society of Anesthesiologists (ASA) groups, that is ASA I, and possibly II, is the safest method for sedation in a dental outpatient setting. CONCLUSION: Formal training is essential to achieve the safe practice of sedation in dentistry or medicine. The appropriate setting for sedation should be determined as there is an increased risk outside the hospital setting. Patients should be adequately assessed and medication titrated appropriately, based on individual requirements. PMID- 26989450 TI - Patient experience a vital consideration in crafting solutions for healthcare challenges. PMID- 26989451 TI - Diffusion Tensor Imaging of Healthy and Infarcted Porcine Hearts: Study on the Impact of Formalin Fixation. AB - BACKGROUND: Due to complexities of in-vivo cardiac diffusion tensor imaging (DTI), ex-vivo formalin-fixed specimens are used to investigate cardiac remodeling in diseases, and reported results have shown conflicting trends. This study investigates the impact of formalin-fixation on diffusion properties and optimizes tracking parameters based on controls to understand remodeling in myocardial-infarction (MI). METHODS: DTI was performed on 4 healthy (controls) and 4 MI induced formalin-fixed (PoMI) ex-vivo porcine hearts. Controls were scanned pre-fixation (PrCtrl) and re-scanned (PoCtrl) after formalin-fixation. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were estimated in all hearts. Tracking parameters (FA, tract termination angle (TTA), fiber-length) were optimized in controls and then used to investigate structural remodeling in PoMI hearts. RESULTS: Fixation increased ADC and decreased FA. PoMI showed increased ADC but decreased FA in infarcted zone compared to remote zone. TTA showed sharp increase in slope from 5 degrees -10 degrees , which flattened after 25 degrees in all groups. Mean fiber-length for different tracking length range showed that PoCtrl had shorter fibers compared to PrCtrl. Fibers around infarction were shorter in length and disarrayed compared to PoCtrl group. CONCLUSION: Formalin-fixation affects diffusion properties and hence DTI parametric trends observed in pathology may be influenced by the fixation process which can cause contradictory findings. PMID- 26989453 TI - Alternatively Spliced Methionine Synthase in SH-SY5Y Neuroblastoma Cells: Cobalamin and GSH Dependence and Inhibitory Effects of Neurotoxic Metals and Thimerosal. AB - The folate and cobalamin (Cbl-) dependent enzyme methionine synthase (MS) is highly sensitive to oxidation and its activity affects all methylation reactions. Recent studies have revealed alternative splicing of MS mRNA in human brain and patient-derived fibroblasts. Here we show that MS mRNA in SH-SY5Y human neuroblastoma cells is alternatively spliced, resulting in three primary protein species, thus providing a useful model to examine cofactor dependence of these variant enzymes. MS activity was dependent upon methylcobalamin (MeCbl) or the combination of hydroxocobalamin (OHCbl) and S-adenosylmethionine (SAM). OHCbl based activity was eliminated by depletion of the antioxidant glutathione (GSH) but could be rescued by provision of either glutathionylcobalamin (GSCbl) or MeCbl. Pretreatment of cells with lead, arsenic, aluminum, mercury, or the ethylmercury-containing preservative thimerosal lowered GSH levels and inhibited MS activity in association with decreased uptake of cysteine, which is rate limiting for GSH synthesis. Thimerosal treatment decreased cellular levels of GSCbl and MeCbl. These findings indicate that the alternatively spliced form of MS expressed in SH-SY5Y human neuronal cells is sensitive to inhibition by thimerosal and neurotoxic metals, and lower GSH levels contribute to their inhibitory action. PMID- 26989454 TI - MnTBAP Therapy Attenuates Renal Fibrosis in Mice with 5/6 Nephrectomy. AB - Renal fibrosis is a common pathological feature of all kinds of chronic kidney diseases (CKDs) with uncertain mechanisms. Accumulating evidence demonstrated an important role of oxidative stress in the pathogenesis of CKD. Here we hypothesized that MnTBAP (manganese (III) tetrakis (4-benzoic acid)porphyrin chloride), a cell-permeable mimic of superoxide dismutase (SOD), may protect against the fibrotic response in CKD by antagonizing oxidative stress. To verify this hypothesis, we performed experiments in tubular epithelial cells and mice with 5/6 nephrectomy (Nx). In mouse tubular epithelial cells, TGF-beta1 induced a significant transition to fibrotic phenotype in line with a remarkable mitochondrial dysfunction, which was markedly improved by MnTBAP (1.14 MUM) pretreatment. In remnant kidneys of 5/6 Nx mice, tubulointerstitial fibrosis occurred in parallel with mitochondrial abnormality in renal tubular cells. Administration of MnTBAP significantly attenuated the deposition of extracellular matrix as evidenced by the blocked expressions of fibronectin, collagen I, and collagen III. Masson staining also displayed an ameliorated accumulation of collagenous matrix in MnTBAP-treated mice. Moreover, MnTBAP also significantly improved the severity of proteinuria without altering CKD-related hypertension. Collectively, MnTBAP therapy served as a promising strategy in preventing renal fibrosis in CKDs possibly via antagonizing mitochondrial-derived oxidative stress and subsequent protection of mitochondrial function. PMID- 26989452 TI - Exercise Training Attenuates Upregulation of p47(phox) and p67(phox) in Hearts of Diabetic Rats. AB - Exercise training (ExT) is currently being used as a nonpharmacological strategy to improve cardiac function in diabetic patients. However, the molecular mechanism(s) underlying its beneficial effects remains poorly understood. Oxidative stress is known to play a key role in the pathogenesis of diabetic cardiomyopathy and one of the enzyme systems that produce reactive oxygen species is NADH/NADPH oxidase. The goal of this study was to investigate the effect of streptozotocin- (STZ-) induced diabetes on expression of p47(phox) and p67(phox), key regulatory subunits of NADPH oxidase, in cardiac tissues and determine whether ExT can attenuate these changes. Four weeks after STZ treatment, expression of p47(phox) and p67(phox) increased 2.3-fold and 1.6-fold, respectively, in left ventricles of diabetic rats and these increases were attenuated with three weeks of ExT, initiated 1 week after onset of diabetes. In atrial tissues, there was increased expression of p47(phox) (74%), which was decreased by ExT in diabetic rats. Furthermore, increased collagen III levels in diabetic hearts (52%) were significantly reduced by ExT. Taken together, ExT attenuates the increased expression of p47(phox) and p67(phox) in the hearts of diabetic rats which could be an underlying mechanism for improving intracardiac matrix and thus cardiac function and prevent cardiac remodeling in diabetic cardiomyopathy. PMID- 26989455 TI - Age-Dependent Demethylation of Sod2 Promoter in the Mouse Femoral Artery. AB - We studied the age-dependent regulation of the expression of the antioxidant enzyme manganese superoxide dismutase (MnSOD encoded by Sod2) through promoter methylation. C57Bl/6 mice were either (i) sedentary (SED), (ii) treated with the antioxidant catechin (CAT), or (iii) voluntarily exercised (EX) from weaning (1 month old; mo) to 9 mo. Then, all mice aged sedentarily and were untreated until 12 mo. Sod2 promoter methylation was similar in all groups in 9 mo but decreased (p < 0.05) in 12 mo SED mice only, which was associated with an increased (p < 0.05) transcriptional activity in vitro. At all ages, femoral artery endothelial function was maintained; this was due to an increased (p < 0.05) contribution of eNOS-derived NO in 12 mo SED mice only. CAT and EX prevented these changes in age related endothelial function. Thus, a ROS-dependent epigenetic positive regulation of Sod2 gene expression likely represents a defense mechanism prolonging eNOS function in aging mouse femoral arteries. PMID- 26989457 TI - A wear simulation study of nanostructured CVD diamond-on-diamond articulation involving concave/convex mating surfaces. AB - Using microwave-plasma Chemical Vapor Deposition (CVD), a 3-micron thick nanostructured-diamond (NSD) layer was deposited onto polished, convex and concave components that were machined from Ti-6Al-4V alloy. These components had the same radius of curvature, 25.4mm. Wear testing of the surfaces was performed by rotating articulation of the diamond-deposited surfaces (diamond-on-diamond) with a load of 225N for a total of 5 million cycles in bovine serum resulting in polishing of the diamond surface and formation of very shallow, linear wear grooves of less than 50nm depth. The two diamond surfaces remained adhered to the components and polished each other to an average surface roughness that was reduced by as much as a factor of 80 for the most polished region located at the center of the condyle. Imaging of the surfaces showed that the initial wearing-in phase of diamond was only beginning at the end of the 5 million cycles. Atomic force microscopy, scanning electron microscopy, Raman spectroscopy, and surface profilometry were used to characterize the surfaces and verify that the diamond remained intact and uniform over the surface, thereby protecting the underlying metal. These wear simulation results show that diamond deposition on Ti alloy has potential application for joint replacement devices with improved longevity over existing devices made of cobalt chrome and ultra-high molecular weight polyethylene (UHMWPE). PMID- 26989456 TI - In Healthy Young Men, a Short Exhaustive Exercise Alters the Oxidative Stress Only Slightly, Independent of the Actual Fitness. AB - The aim of the present study was to evaluate the apparent disagreement regarding the effect of a typical cycling progressive exercise, commonly used to assess VO2max, on the kinetics of ex vivo copper induced peroxidation of serum lipids. Thirty-two (32) healthy young men, aged 24-30 years, who do not smoke and do not take any food supplements, participated in the study. Blood was withdrawn from each participant at three time points (before the exercise and 5 minutes and one hour after exercise). Copper induced peroxidation of sera made of the blood samples was monitored by spectrophotometry. For comparison, we also assayed TBARS concentration and the activity of oxidation-related enzymes. The physical exercise resulted in a slight and reversible increase of TBARS and slight changes in the activities of the studied antioxidant enzymes and the lag preceding peroxidation did not change substantially. Most altered parameters returned to baseline level one hour after exercise. Notably, the exercise-induced changes in OS did not correlate with the physical fitness of the subjects, as evaluated in this study (VO2max = 30-60 mL/min/kg). We conclude that in healthy young fit men a short exhaustive exercise alters only slightly the OS, independent of the actual physical fitness. PMID- 26989458 TI - Complete mesocolic excision: Lessons from anatomy translating to better oncologic outcome. AB - Since the introduction of complete mesocolic excision (CME) for colon cancer, the oncologic outcome of patients has been greatly improved, which has led to a longer survival and a lower recurrence, just like the total mesorectum excision for rectal cancer. Despite the fact that the exact anatomy of the organ is one of the most vital things for surgeons to conduct surgery, no team has really studied the exact structure of the mesocolon and related attachments for CME, until the mesocolonic anatomy was first formally characterized in 2012. Therefore, this article mainly focuses on the anatomy development of the mesocolon and the achievement in this field. Meanwhile, we introduce the latest progress in laparoscopic surgery for colon cancer achieved by our team. PMID- 26989460 TI - Perioperative treatment options in resectable pancreatic cancer - how to improve long-term survival. AB - Surgery remains the only chance of cure for pancreatic cancer, but only 15%-25% of patients present with resectable disease at the time of primary diagnosis. Important goals in clinical research must therefore be to allow early detection with suitable diagnostic procedures, to further broaden operation techniques and to determine the most effective perioperative treatment of either chemotherapy and/or radiation therapy. More extensive operations involving extended pancreatectomy, portal vein resection and pancreatic resection in resectable pancreatic cancer with limited liver metastasis, performed in specialized centers seem to be the surgical procedures with a possible impact on survival. After many years of stagnation in pharmacological clinical research on advanced pancreatic ductal adenocarcinomas (PDAC) - since the approval of gemcitabine in 1997 - more effective cytotoxic substances (nab-paclitaxel) and combinations (FOLFIRINOX) are now available for perioperative treatment. Additionally, therapies with a broader mechanism of action are emerging (stroma depletion, immunotherapy, anti inflammation), raising hopes for more effective adjuvant and neoadjuvant treatment concepts, especially in the context of "borderline resectability". Only multidisciplinary approaches including radiology, surgery, medical and radiation oncology as the backbones of the treatment of potentially resectable PDAC may be able to further improve the rate of cure in the future. PMID- 26989459 TI - Endoscopic palliation of malignant biliary strictures. AB - Malignant biliary strictures often present late after the window for curative resection has elapsed. In such patients, the goal of therapy is typically focused on palliation. While historically, palliative measures were performed surgically, the advent of endoscopic intervention offers minimally invasive options to provide relief of symptoms, improve quality of life, and in some cases, increase survival of these patients. Some of these therapies, such as endoscopic biliary decompression, have become mainstays of treatment for decades, whereas newer modalities, including radiofrequency ablation, and photodynamic therapy offer additional options for patients with incurable biliary malignancies. PMID- 26989461 TI - Primary prevention and treatment of venous thromboembolic events in patients with gastrointestinal cancers - Review. AB - Venous thromboembolism event (VTE) is a common and morbid complication in cancer patients. Patients with gastrointestinal cancers often suffer from symptomatic or incidental splanchnic vein thrombosis, impaired liver function and/or thrombocytopenia. These characteristics require a thorough risk/benefit evaluation for individual patients. Considering the risk factors for the development of VTE and bleeding events in addition to recent study results may be helpful for correct initiation of primary pharmacological prevention and treatment of cancer-associated thrombosis (CAT), preferably with low molecular weight heparins (LMWH). Whereas thromboprophylaxis is most often recommended in hospitalized surgical and non-surgical patients with malignancy, there is less agreement as to its duration. With regard to ambulatory cancer patients, the lack of robust data results in low grade recommendations against routine use of anticoagulant drugs. Anticoagulation with LMWH for the first months is the evidence-based treatment for acute CAT, but duration of secondary prevention and the drug of choice are unclear. Based on published guidelines and literature, this review will focus on prevention and treatment strategies of VTE in patients with gastrointestinal cancers. PMID- 26989462 TI - Gastric cancer development after the successful eradication of Helicobacter pylori. AB - Gastric cancer (GC) develops as a result of inflammation-associated carcinogenesis due to Helicobacter pylori (H. pylori) infection and subsequent defects in genetic/epigenetic events. Although the indication for eradication therapy has become widespread, clinical studies have revealed its limited effects in decreasing the incidence of GC. Moreover, research on biopsy specimens obtained by conventional endoscopy has demonstrated the feasibility of the restoration of some genetic/epigenetic alterations in the gastric mucosa. Practically, the number of sporadic cases of primary/metachronous GC that emerge after successful eradication has increased, while on-going guidelines recommend eradication therapy for patients with chronic gastritis and those with background mucosa after endoscopic resection for GC. Accordingly, regular surveillance of numerous individuals who have received eradication therapy is recommended despite the lack of biomarkers. Recently, the focus has been on functional reversibility after successful eradication as another cue to elucidate the mechanisms of restoration as well as those of carcinogenesis in the gastric mucosa after H. pylori eradication. We demonstrated that Congo-red chromoendoscopy enabled the identification of the multi-focal distribution of functionally irreversible mucosa compared with that of restored mucosa after successful eradication in individuals at extremely high risk for GC. Further research that uses functional imaging may provide new insights into the mechanisms of regeneration and carcinogenesis in the gastric mucosa post-eradication and may allow for the development of useful biomarkers. PMID- 26989463 TI - Emerging role of cystic fibrosis transmembrane conductance regulator - an epithelial chloride channel in gastrointestinal cancers. AB - Cystic fibrosis transmembrane conductance regulator (CFTR), a glycoprotein with 1480 amino acids, has been well established as a chloride channel mainly expressed in the epithelial cells of various tissues and organs such as lungs, sweat glands, gastrointestinal system, and reproductive organs. Although defective CFTR leads to cystic fibrosis, a common genetic disorder in the Caucasian population, there is accumulating evidence that suggests a novel role of CFTR in various cancers, especially in gastroenterological cancers, such as pancreatic cancer and colon cancer. In this review, we summarize the emerging findings that link CFTR with various cancers, with focus on the association between CFTR defects and gastrointestinal cancers as well as the underlying mechanisms. Further study of CFTR in cancer biology may help pave a new way for the diagnosis and treatment of gastrointestinal cancers. PMID- 26989466 TI - Expression of p-STAT3 and vascular endothelial growth factor in MNNG-induced precancerous lesions and gastric tumors in rats. AB - AIM: To investigate the dynamic expression of p-signal transducer and activator of transcription 3 (STAT3) and vascular endothelial growth factor (VEGF) in the formation of gastric tumors induced by drinking water containing N-methyl-N' nitro-N-nitrosoguanidine (MNNG) in Wistar rats. METHODS: One hundred and twenty Wistar rats were randomly divided into two groups (60 in each group): Control group and Model group. The rats in each group were then randomly divided into three groups (20 in each group): C/M15, C/M25 and C/M40 (15, 25 and 40 represent the number of feeding weeks from termination). Rats in the control group received normal drinking water and rats in the model group received drinking water containing 100 MUg/mL MNNG. Stomach tissues were collected at the end of the 15(th), 25(th) and 40(th) week, respectively, for microscopic measurement using hematoxylin and eosin staining. The expression of p-STAT3 and VEGF in different pathological types of gastric tissue, including normal, inflammation, atrophy, hyperplasia and gastric stromal tumor, was observed by immunohistochemistry and Western blot, and the corelation between p-STAT3 and VEGF was analyzed. RESULTS: (1) The expression of p-STAT3 in tissue with gastritis, atrophy, dysplasia and gastric stromal tumor were significantly increased in the model group compared with the control group (2.5 +/- 1.0, 2.75 +/- 0.36, 6.2 +/- 0.45, 5.67 +/- 0.55 vs 0.75 +/- 0.36, P = 0.026, 0.035, 0.001, 0.002, respectively); the expression of p-STAT3 in tissue with dysplasia was higher than that in samples with gastritis or atrophy (6.2 +/- 0.45 vs 2.5 +/- 1.0, P = 0.006; 6.2 +/- 0.45 vs 2.75 +/- 0.36, P = 0.005, respectively); however, the expression of p-STAT3 in gastritis and atrophy was not significantly different (P > 0.05); (2) the expression of VEGF in tissue with gastritis, atrophy, dysplasia and gastric stromal tumor was significantly increased in the model group compared with normal gastric mucosa; and the expression of VEGF in tissue with dysplasia was higher than that in tissue with inflammation and atrophy (10.8 +/- 1.96 vs 7.62 +/- 0.25, P = 0.029; 10.8 +/- 1.96 vs 6.26 +/- 0.76, P = 0.033, respectively); similarly, the expression of VEGF in tissue with gastritis and atrophy was not significantly different (P > 0.05); and (3) the expression of VEGF was positively correlated with p-STAT3. CONCLUSION: p-STAT3 plays an important role in gastric cancer formation by regulating the expression of VEGF to promote the progression of gastric tumor from gastritis. PMID- 26989464 TI - Role of genetic detection in peritoneal washes with gastric carcinoma: The past, present and future. AB - The most frequent cause of treatment failure following surgery for gastric cancer is peritoneal dissemination, mainly caused by the seeding of free cancer cells from the primary gastric cancer, which is the most common type of spread. Unfortunately, there is no standard modality of intraperitoneal free cancer cells detection to predict peritoneal metastasis until now. We reviewed English literature in PubMed was done using the MeSH terms for gastric cancer, peritoneal wash, and reverse transcriptase polymerase chain reaction. All the articles were reviewed and core information was tabulated for reference. After a comprehensive review of all articles, the data was evaluated by clinical implication and predictive value of each marker for peritoneal recurrence. There are still many limitations to overcome before the genetic diagnosis for free cancer cells detection can be considered as routine assay. To make it a reliable diagnostic tool for detecting free cancer cells, the process and method of genetic detection with peritoneal washes should be standardized, and the development of simple diagnostic devices and easily available kits are necessary. Herein, we reviewed the past, present and future perspectives of the peritoneal lavage for the detection of intraperitoneal free cancer cells in patients with gastric cancer. PMID- 26989467 TI - Clinical and epidemiologic variations of esophageal cancer in Tanzania. AB - AIM: To estimate the incidence of esophageal cancer (EC) in Kilimanjaro in comparison to other regions in Tanzania. METHODS: We also examined the clinical, epidemiologic, and geographic distribution of the 1332 EC patients diagnosed and/or treated at Ocean Road Cancer Institute (ORCI) during the period 2006-2013. Medical records were used to abstract patient information on age, sex, residence, smoking status, alcohol consumption, tumor site, histopathologic type of tumor, date and place of diagnosis, and type and date of treatment at ORCI. Regional variation of EC patients was investigated at the level of the 26 administrative regions of Tanzania. Total, age- and sex-specific incidence rates were calculated. RESULTS: Male patients 55 years and older had higher incidence of EC than female and younger patients. Of histopathologically-confirmed cases, squamous-cell carcinoma represented 90.9% of histopathologic types of tumors. The administrative regions in the central and eastern parts of Tanzania had higher incidence rates than western regions, specifically administrative regions of Kilimanjaro, Dar es Salaam, and Tanga had the highest rates. CONCLUSION: Further research should focus on investigating possible etiologic factors for EC in regions with high incidence in Tanzania. PMID- 26989465 TI - Is metastatic pancreatic cancer an untargetable malignancy? AB - Metastatic pancreatic cancer (MPC) is one of the most aggressive malignancies, known to be chemo-resistant and have been recently considered resistant to some targeted therapies (TT). Erlotinib combined to gemcitabine is the only targeted therapy that showed an overall survival benefit in MPC. New targets and therapeutic approaches, based on new-TT, are actually being evaluated in MPC going from immunotherapy, epigenetics, tumor suppressor gene and oncogenes to stromal matrix regulators. We aim in this paper to present the major causes rendering MPC an untargetable malignancy and to focus on the new therapeutic modalities based on TT in MPC. PMID- 26989468 TI - Myeloid sarcoma presenting as a colon polyp and harbinger of chronic myelogenous leukemia. AB - Myeloid sarcoma, also known as granulocytic sarcoma or chloroma is an unusual accumulation of malignant myeloid precursor cells in an extramedullary site, which disrupts the normal architecture of the involved tissue. It is known to occur more commonly in patients with acute myelogenous leukemia and less commonly in those with myelodysplastic syndrome and myeloproliferative neoplasm, such as chronic myelogenous leukemia. The most common sites of involvement include bone, skin and lymph nodes. However, rare cases have been reported in the gastrointestinal tract, genitourinary tract, or breast. Most commonly, a neoplastic extramedullary proliferation of myeloid precursors in a patient would have systemic involvement of a myeloid neoplasm, including in the bone marrow and peripheral blood. Infrequently, extramedullary disease may be the only site of involvement. It may also occur as a localized antecedent to more generalized disease or as a site of recurrence. Herein, we present the first case in the English literature of a patient presenting with an isolated site of myeloid sarcoma arising in the form of a colonic polyp which, after subsequent bone marrow biopsy, was found to be a harbinger of chronic myelogenous leukemia. PMID- 26989469 TI - Rare case of entero-enteric intussusception caused by small bowel metastasis from a cardiac liposarcoma. AB - Primary cardiac liposarcoma is exceedingly rare and its metastatic potential varies based on the actual tumor subclass. Intestinal intussusception is also an uncommon cause of abdominal pain and bowel obstruction in adults and it usually generates at a malignant lead point in this age group. We report a case of a primary cardiac dedifferentiated liposarcoma in a pregnant woman causing small bowel seeding leading to bowel intussusception. PMID- 24715981 TI - Software Carpentry: lessons learned. AB - Since its start in 1998, Software Carpentry has evolved from a week-long training course at the US national laboratories into a worldwide volunteer effort to improve researchers' computing skills. This paper explains what we have learned along the way, the challenges we now face, and our plans for the future. PMID- 26989472 TI - Recent advances in the elucidation of enzymatic function in natural product biosynthesis. AB - With the successful production of artemisinic acid in yeast, the promising potential of synthetic biology for natural product biosynthesis is now being realized. The recent total biosynthesis of opioids in microbes is considered to be another landmark in this field. The importance and significance of enzymes in natural product biosynthetic pathways have been re-emphasized by these advancements. Therefore, the characterization and elucidation of enzymatic function in natural product biosynthesis are undoubtedly fundamental for the development of new drugs and the heterologous biosynthesis of active natural products. Here, discoveries regarding enzymatic function in natural product biosynthesis over the past year are briefly reviewed. PMID- 26989470 TI - Targeting glucose metabolism in cancer: new class of agents for loco-regional and systemic therapy of liver cancer and beyond? AB - Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and the third leading cause of cancer-related deaths worldwide. In patients with unresectable disease, loco-regional catheter-based intra-arterial therapies (IAT) can achieve selective tumor control while minimizing systemic toxicity. As molecular features of tumor growth and microenvironment are better understood, new targets arise for selective anticancer therapy. Particularly, antiglycolytic drugs that exploit the hyperglycolytic cancer cell metabolism - also known as the 'Warburg effect' - have emerged as promising therapeutic options. Thus, future developments will combine the selective character of loco-regional drug delivery platforms with highly specific molecular targeted antiglycolytic agents. This review will exemplify literature on antiglycolytic approaches and particularly focus on intra arterial delivery methods. PMID- 26962435 TI - The importance of selecting the appropriate reference genes for quantitative real time PCR as illustrated using colon cancer cells and tissue. AB - Quantitative real-time reverse-transcription polymerase chain reaction (RT-qPCR) remains the most sensitive technique for nucleic acid quantification. Its popularity is reflected in the remarkable number of publications reporting RT qPCR data. Careful normalisation within RT-qPCR studies is imperative to ensure accurate quantification of mRNA levels. This is commonly achieved through the use of reference genes as an internal control to normalise the mRNA levels between different samples. The selection of appropriate reference genes can be a challenge as transcript levels vary with physiology, pathology and development, making the information within the transcriptome flexible and variable. In this study, we examined the variation in expression of a panel of nine candidate reference genes in HCT116 and HT29 2-dimensional and 3-dimensional cultures, as well as in normal and cancerous colon tissue. Using normfinder we identified the top three most stable genes for all conditions. Further to this we compared the change in expression of a selection of PKC coding genes when the data was normalised to one reference gene and three reference genes. Here we demonstrated that there is a variation in the fold changes obtained dependent on the number of reference genes used. As well as this, we highlight important considerations namely; assay efficiency tests, inhibition tests and RNA assessment which should also be implemented into all RT-qPCR studies. All this data combined demonstrates the need for careful experimental design in RT-qPCR studies to help eliminate false interpretation and reporting of results. PMID- 26989473 TI - Dynamic reorganization of the actin cytoskeleton. AB - Cellular processes, including morphogenesis, polarization, and motility, rely on a variety of actin-based structures. Although the biochemical composition and filament organization of these structures are different, they often emerge from a common origin. This is possible because the actin structures are highly dynamic. Indeed, they assemble, grow, and disassemble in a time scale of a second to a minute. Therefore, the reorganization of a given actin structure can promote the formation of another. Here, we discuss such transitions and illustrate them with computer simulations. PMID- 26989475 TI - Can ecosystem-scale translocations mitigate the impact of climate change on terrestrial biodiversity? Promises, pitfalls, and possibilities: Ecosystem-scale translocations. AB - Because ecological interactions are the first components of the ecosystem to be impacted by climate change, future forms of threatened-species and ecosystem management should aim at conserving complete, functioning communities rather than single charismatic species. A possible way forward is the deployment of ecosystem scale translocation (EST), where above- and below-ground elements of a functioning terrestrial ecosystem (including vegetation and topsoil) are carefully collected and moved together. Small-scale attempts at such practice have been made for the purpose of ecological restoration. By moving larger subsets of functioning ecosystems from climatically unstable regions to more stable ones, EST could provide a practical means to conserve mature and complex ecosystems threatened by climate change. However, there are a number of challenges associated with EST in the context of climate change mitigation, in particular the choice of donor and receptor sites. With the aim of fostering discussion and debate about the EST concept, we 1) outline the possible promises and pitfalls of EST in mitigating the impact of climate change on terrestrial biodiversity and 2) use a GIS-based approach to illustrate how potential source and receptor sites, where EST could be trialed and evaluated globally, could be identified. PMID- 26989477 TI - The development of a novel HAuCl4@MOF catalyst and its catalytic application in the formation of dihydrochalcones. AB - A novel HAuCl4@UiO-66-NH2 material has been obtained and utilized as a heterogeneous Au(III) catalyst. This Au(III) catalyst was able to promote the formation of a variety of dihydrochalcones starting from 2H-chromenes in moderate to good yields. A tandem hydride shift/hydration reaction sequence has been proposed based on deuterium labeling studies, which revealed a 1,5-hydride shift reaction pathway. A flavone intermediate has been synthesized to further support the proposed mechanism. Furthermore, the HAuCl4@UiO-66-NH2 catalyst can be recycled several times without compromising the catalytic activity. PMID- 26989478 TI - Application of aziridinium ring opening for preparation of optically active diamine and triamine analogues: Highly efficient synthesis and evaluation of DTPA based MRI contrast enhancement agents. AB - Ring opening of aziridinium ions with nitrogen nucleophiles was applied to the highly efficient synthesis of optically active vicinal diamines and diethylene triamine pentaacetic acid (DTPA) analogues as potential magnetic resonance imaging (MRI) contrast enhancement agents. The synthetic method features a column free isolation of the regiospecific and stereospecific nucleophilic substitution products of enantiomerically enriched aziridinium ions in excellent yield. PMID- 26989476 TI - Can follicular helper T cells be targeted to improve vaccine efficacy? AB - The success of most vaccines relies on the generation of antibodies to provide protection against subsequent infection; this in turn depends on a robust germinal centre (GC) response that culminates in the production of long-lived antibody-secreting plasma cells. The size and quality of the GC response are directed by a specialised subset of CD4 (+) T cells: T follicular helper (Tfh) cells. Tfh cells provide growth and differentiation signals to GC B cells and mediate positive selection of high-affinity B cell clones in the GC, thereby determining which B cells exit the GC as plasma cells and memory B cells. Because of their central role in the production of long-lasting humoral immunity, Tfh cells represent an interesting target for rational vaccine design. PMID- 26989479 TI - Tunable tissue scaffolds fabricated by in situ crosslink in phase separation system. AB - Three-dimensional (3-D) scaffolds with intrinsic porous structures are desirable in various tissue regeneration applications. In this study, a unique method that combines thermally induced phase separation with a photocrosslinking process was developed for the fabrication of 3-D crosslinked polymer scaffolds with densely interconnected porous structures. Biodegradable poly(propylene fumarate)-co poly(L-lactic acid) with crosslinkable fumarate bonds were used as the structural polymer material and a dioxane/water binary system was applied for the phase separation. By altering the polymer composition (9, 5 and 3 wt%), different types of scaffolds with distinct morphology, mechanical strength, degradation rate, cell growth and morphology, and extracellular matrix production were fabricated. These crosslinked 3-D porous scaffolds with tunable strength and biological responses show promise for potential applications in regenerative therapies, including bone and neural tissue engineering. PMID- 26989480 TI - Maximizing Fibroblast Adhesion on Protein-Coated Surfaces Using Microfluidic Cell Printing. AB - translation of in vitro cell based assays to in vivo cellular response is imprecise at best. The advent of three-dimensional cell cultures in addition to bioreactor type microfluidics has improved the situation. However, these technical advances cannot be easily combined due to practical limitations. Development of a vertical microfluidic cell printer overcomes this obstacle, providing the ability to more closely recapitulate complex cellular environments and responses. As a proof of concept, we investigated the adhesion of fibroblasts under flow on protein-coated surfaces using a novel vertical microfluidic print head to isolate and manipulate both mechanical and biological factors as a model of fibroblast behavior during the foreign body response following implant insertion. A low flow rate with larger microfluidic channels onto a serum-coated surface has been determined to allow the highest density of viable fibroblasts to attach to the surface. While these insights into fibroblast surface attachment may lead to better material designs, the methods developed herein will certainly be useful as a biomaterials testing platform. PMID- 26989481 TI - Contrasting effects of nanoparticle-protein attraction on amyloid aggregation. AB - Nanoparticles (NPs) have been experimentally found to either promote or inhibit amyloid aggregation of proteins, but the molecular mechanisms for such complex behaviors remain unknown. Using coarse-grained molecular dynamics simulations, we investigated the effects of varying the strength of nonspecific NP-protein attraction on amyloid aggregation of a model protein, the amyloid-beta peptide implicated in Alzheimer's disease. Specifically, with increasing NP-peptide attraction, amyloid aggregation on the NP surface was initially promoted due to increased local protein concentration on the surface and destabilization of the folded state. However, further increase of NP-peptide attraction decreased the stability of amyloid fibrils and reduced their lateral diffusion on the NP surface necessary for peptide conformational changes and self-association, thus prohibiting amyloid aggregation. Moreover, we found that the relative concentration between protein and NPs also played an important role in amyloid aggregation. With a high NP/protein ratio, NPs that intrinsically promote protein aggregation may display an inhibitive effect by depleting the proteins in solution while having a low concentration of the proteins on each NP's surface. Our coarse-grained molecular dynamics simulation study offers a molecular mechanism for delineating the contrasting and seemingly conflicting effects of NP protein attraction on amyloid aggregation and highlights the potential of tailoring anti-aggregation nanomedicine against amyloid diseases. PMID- 26989482 TI - Structure Activity Related, Mechanistic, and Modeling Studies of Gallotannins containing a Glucitol-Core and alpha-Glucosidase. AB - Gallotannins containing a glucitol core, which are only produced by members of the maple (Acer) genus, are more potent alpha-glucosidase inhibitors than the clinical drug, acarbose. While this activity is influenced by the number of substituents on the glucitol core (e.g. more galloyl groups leads to increased activity), the mechanisms of inhibitory action are not known. Herein, we investigated ligand-enzyme interactions and binding mechanisms of a series of 'glucitol-core containing gallotannins (GCGs)' against the alpha-glucosidase enzyme. The GCGs included ginnalins A, B and C (containing two, one, and one galloyl/s, respectively), maplexin F (containing 3 galloyls) and maplexin J (containing 4 galloyls). All of the GCGs were noncompetitive inhibitors of alpha glucosidase and their interactions with the enzyme were further explored using biophysical and spectroscopic measurements. Thermodynamic parameters (by isothermal titration calorimetry) revealed a 1:1 binding ratio between GCGs and alpha-glucosidase. The binding regions between the GCGs and alpha-glucosidase, probed by a fluorescent tag, 1,1'-bis(4-anilino-5-napththalenesulfonic acid, revealed that the GCGs decreased the hydrophobic surface of the enzyme. In addition, circular dichroism analyses showed that the GCGs bind to alpha glucosidase and lead to loss of the secondary alpha-helix structure of the protein. Also, molecular modeling was used to predict the binding site between the GCGs and the alpha-glucosidase enzyme. This is the first study to evaluate the mechanisms of inhibitory activities of gallotannins containing a glucitol core on alpha-glucosidase. PMID- 26989483 TI - Novel biodegradable poly(propylene fumarate)-co-poly(l-lactic acid) porous scaffolds fabricated by phase separation for tissue engineering applications. AB - Scaffolds with intrinsically interconnected porous structures are highly desirable in tissue engineering and regenerative medicine. In this study, three dimensional polymer scaffolds with highly interconnected porous structures were fabricated by thermally induced phase separation of novel synthesized biodegradable poly(propylene fumarate)-co-poly(l-lactic acid) in a dioxane/water binary system. Defined porous scaffolds were achieved by optimizing conditions to attain interconnected porous structures. The effect of phase separation parameters on scaffold morphology were investigated, including polymer concentration (1, 3, 5, 7, and 9%), quench time (1, 4, and 8 min), dioxane/water ratio (83/17, 85/15, and 87/13 wt/wt), and freeze temperature (-20, -80, and -196 degrees C). Interesting pore morphologies were created by adjusting these processing parameters, e.g., flower-shaped (5%; 85/15; 1 min; -80 degrees C), spherulite-like (5%; 85/15; 8 min; -80 degrees C), and bead-like (5%; 87/13; 1 min; -80 degrees C) morphology. Modulation of phase separation conditions also resulted in remarkable differences in scaffold porosities (81% to 91%) and thermal properties. Furthermore, scaffolds with varied mechanic strengths, degradation rates, and protein adsorption capabilities could be fabricated using the phase separation method. In summary, this work provides an effective route to generate multi-dimensional porous scaffolds that can be applied to a variety of hydrophobic polymers and copolymers. The generated scaffolds could potentially be useful for various tissue engineering applications including bone tissue engineering. PMID- 26989484 TI - Colorimetric and Optical Discrimination of Halides by a Simple Chemosensor. AB - A thiophene-based tripodal copper(II) complex has been synthesized as a new colorimetric and optical chemosensor for naked-eye discrimination of halides in acetonitrile and an acetonitrile-water mixture. The binding interactions of the new receptor with several anions were analyzed by UV-Vis titrations, electrospray ionization mass spectrometric (ESI-MS) experiments and density functional theory (DFT) calculations. The results from UV-Vis titrations indicate that the coordinative unsaturated copper(II) complex strongly binds a halide at its vacant copper(II) centre via a metal-ligand bond forming a 1:1 complex, exhibiting binding affinities in the order of fluoride > chloride > bromide > iodide. The interactions of the receptor with halides were further confirmed by ESI-MS, showing a distinct signal corresponding to a 1:1 complex for each halide, suggesting that the noncovalent interactions also exist in the gas phase. In addition, time-dependent DFT (TD-DFT) calculations were also carried out to understand the excited-state properties of the chemosensor complexes. A detailed analysis of the TD-DFT calculations shows a consistent red-shift in the first optically-allowed transition, consistent with the observed colorimetric experiments. PMID- 26989485 TI - Establishment of a Long-Term Chick Forebrain Neuronal Culture on a Microelectrode Array Platform. AB - The biosensor system formed by culturing primary animal neurons on a microelectrode array (MEA) platform is drawing an increasing research interest for its power as a rapid, sensitive, functional neurotoxicity assessment, as well as for many other electrophysiological related research purposes. In this paper, we established a long-term chick forebrain neuron culture (C-FBN-C) on MEAs with a more than 5 month long lifespan and up to 5 month long stability in morphology and physiological function; characterized the C-FBN-C morphologically, functionally, and developmentally; partially compared its functional features with rodent counterpart; and discussed its pros and cons as a novel biosensor system in comparison to rodent counterpart and human induced pluripotent stem cells (hiPSCs). Our results show that C-FBN-C on MEA platform 1) can be used as a biosensor of its own type in a wide spectrum of basic biomedical research; 2) is of value in comparative physiology in cross-species studies; and 3) may have potential to be used as an alternative, cost-effective approach to rodent counterpart within shared common functional domains (such as specific types of ligand-gated ion channel receptors and subtypes expressed in the cortical tissues of both species) in large-scale environmental neurotoxicant screening that would otherwise require millions of animals. PMID- 26989486 TI - Poly (vinylidene fluoride) / Poly (acrylonitrile)-based Superior Hydrophobic Piezoelectric Solid Derived by Aligned Carbon Nanotube in Electrospinning: Fabrication, the Phase Conversion and Surface Energy. AB - Multifunctional materials have attracted many interests from both fundamental and practical aspects, such as field-effect transistor, electric protection, transducers and biosensor. Here we demonstrated the first superior hydrophobic piezoelectric surface based on the polymer blend of polyvinylidene fluoride (PVDF)-polyacrilonitrile (PAN) assisted with functionalized multiwalled nanotubes (MWNTs), by a modified electrospinning method. Typically the beta-phase polyvinylidene fluoride (PVDF) was considered as the excellent piezoelectric and pyroelectric materials. However, polar beta-phase of PVDF exhibited a natural high hydrophilicity. As a well-known fact, the wettability of the surface is dominated by two major factors: surface composition and surface roughness. The significant conversions derived by the incorporation of MWNTs, from nonpolar alpha-phase to highly polar beta-phase of PVDF, were confirmed by FTIR. Meanwhile, the effects of MWNTs on the improvement of the roughness and the hydrophobicity of polymer blend were evaluated by atomic force microscopy (AFM) and contact angle (CA). Molar free energy of wetting of the polymer nanocomposite decreases with increasing the wt.% of MWNTs. All molar free energy of wetting of PVDF-PAN/MWNTs were negative, which means the non-wettability of film. The combination of surface roughness and low-surface-energy modification in nanostructured composites leads to high hydrophobicity. Particularly, fabrication of superior hydrophobic surfaces not only has fundamental interest but also various possible functional applications in micro- and nano-materials and devices. PMID- 26989487 TI - Influence of silk-silica fusion protein design on silica condensation in vitro and cellular calcification. AB - Biomaterial design via genetic engineering can be utilized for the rational functionalization of proteins to promote biomaterial integration and tissue regeneration. Spider silk has been extensively studied for its biocompatibility, biodegradability and extraordinary material properties. As a protein-based biomaterial, recombinant DNA derived derivatives of spider silks have been modified with biomineralization domains which lead to silica deposition and potentially accelerated bone regeneration. However, the influence of the location of the R5 (SSKKSGSYSGSKGSKRRIL) silicifying domain fused with the spider silk protein sequence on the biosilicification process remains to be determined. Here we designed two silk-R5 fusion proteins that differed in the location of the R5 peptide, C- vs. N-terminus, where the spider silk domain consisted of a 15mer repeat of a 33 amino acid consensus sequence of the major ampullate dragline Spidroin 1 from Nephila clavipes (SGRGGLGGQG AGAAAAAGGA GQGGYGGLGSQGT). The chemical, physical and silica deposition properties of these recombinant proteins were assessed and compared to a silk 15mer control without the R5 present. The location of the R5 peptide did not have a significant effect on wettability and surface energies, while the C-terminal location of the R5 promoted more controlled silica precipitation, suggesting differences in protein folding and possibly different access to charged amino acids that drive the silicification process. Further, cell compatibility in vitro, as well as the ability to promote human bone marrow derived mesenchymal stem cell (hMSC) differentiation were demonstrated for both variants of the fusion proteins. PMID- 26989488 TI - COPD heterogeneity: implications for management. PMID- 26989489 TI - A single oral dose of a polyglucosamine influences the bioavailability of [9 (14)C]-Oleic acid in adult female Gottingen minipigs. AB - BACKGROUND: Worldwide obesity has nearly doubled since 1980 and is a leading risk for global deaths, profoundly affecting morbidity, mortality, health-care costs, and professional and personal quality of life. Treatment of obesity and its consequences include lifestyle intervention, pharmacotherapy, and bariatric surgery. Polyglucosamines have been proposed as an alternative strategy for treating obesity, by reducing the amount of absorbed fat through interaction with dietary fat through various mechanisms. The objective of this study is to investigate the influence of polyglucosamine on the bioavailability of the model compound [9-(14)C]-oleic acid in female Gottingen minipigs. METHOD: The study consisted of two treatment groups, each consisting of six adult female Gottingen minipigs with a catheterized vena jugularis to enable frequent blood sampling. One group served as the untreated group (control) and the other group was pre treated with 2 tablets of 500 mg formoline L112. After 30 min, all animals were dosed orally with [9-(14)C]-oleic acid. Excreta and blood samples were collected for analysis of radioactivity from 48 h pre-dose up to 144 h post-dosing. At sacrifice, the liver and contents of the gastrointestinal tract were collected for radioanalysis. RESULTS: Upon treatment with polyglucosamine (formoline L112), the Tmax of [(14)C]-oleic acid in plasma was shifted from 4 to 16 h, and the Cmax decreased significantly from 14.1 MUg/g to 3.3 MUg/g. In addition, upon treatment with polyglucosamine the internal exposure to [(14)C]-oleic acid as reflected by the area under the curve during the 0-12 h post-dose time interval (AUC0-12h), is significantly decreased to 32.9 % of the plasma value of [(14)C]-oleic acid in untreated animals. Even up to 24 h post-dose, the AUC0-24h is significantly decreased to 50.7 % of the plasma value in untreated animals and this significant effect is prolonged up to 60 h post-dose. CONCLUSIONS: This study shows that treatment with polyglucosamine (formoline L112) reduces (as judged by Cmax & AUC) and delays (as judged by Tmax) fat absorption from the gastrointestinal tract into the systemic circulation and limits peak exposure to free fatty acids which may contribute to a more beneficial condition in overweight humans. PMID- 26989490 TI - Poly(epsilon-caprolactone) Microfiber Meshes for Repeated Oil Retrieval. AB - Electrospun non-woven poly(epsilon-caprolactone) (PCL) microfiber meshes are described as biodegradable, mechanically robust, and reusable polymeric oil sorbents capable of selectively retrieving oil from simulated oil spills in both fresh and seawater scenarios. Hydrophobic PCL meshes have >99.5% (oil over water) oil selectivity and oil absorption capacities of ~10 grams of oil per gram of sorbent material, which is shown to be a volumetrically driven process. Both the oil selectivity and absorption capacity remained constant over several oil absorption and vacuum assisted retrieval cycles when removing crude oil or mechanical pump oil from deionized water or simulated seawater mixtures. Finally, when challenged with surfactant stabilized water-in-oil emulsions, the PCL meshes continued to show selective oil absorption. These studies add to the knowledge base of synthetic oil sorbents highlighting a need for biodegradable synthetic oil sorbents which balance porosity and mechanical integrity enabling reuse, allowing for the efficient recovery of oil after an accidental oil spill. PMID- 26989491 TI - Yellow nail syndrome in rheumatoid arthritis: an aetiology beyond thiol drugs. AB - Yellow nail syndrome (YNS) is a rare entity characterized by a triad of nail changes, lymphoedema and lung involvement. We report a 57-year-old man with rheumatoid arthritis (RA) and YNS. We have reviewed the previous case reports of RA and YNS and discuss the pulmonary manifestations. PMID- 26989492 TI - Recurrent paraparesis and death of a patient with 'whippet' abuse. AB - Nitrous oxide is increasingly used as a recreational drug that is easily and legally available worldwide. Occasional nitrous oxide use has been considered relatively safe without the development of addiction or major adverse effects. However, heavy long-term nitrous oxide abuse can be associated with severe neurological complications, and even deaths have been described. The characteristic presentation is myeloneuropathy with dorsal column degeneration and demyelinating sensory polyneuropathy related to vitamin B12 deficiency. Described is a 23-year-old male who developed recurrent paraparesis related to nitrous oxide abuse. A second, more severe, episode of paraparesis was associated with predominantly lower motor neuron damage. A partial recovery was achieved by discontinuation of nitrous oxide use and initiation of vitamin B12 supplementation. However, the patient relapsed and ultimately died while being intoxicated with several abusive substances. The case adds to the cumulative literature about the clinical phenomenology and dangers of nitrous oxide abuse. PMID- 26989493 TI - Complete pancreatic duct disruption in an isolated pancreatic injury: successful endoscopic management. AB - Isolated pancreatic injury is uncommon and the management is challenging. Presentation is mostly delayed in such cases. We report a case of 26-year-old male, who was referred to our centre due to blunt abdominal trauma of 48 h duration with pain abdomen and vomiting. He was haemodynamically stable and was subjected to endoscopy after few hours of admission, but failed to cannulate the main pancreatic duct. Successful stenting was performed after 3 days of admission in the second attempt. He made an uneventful recovery and remains well 2 months after the injury. Management of isolated pancreatic injuries with complete duct disruption is challenging. Endoscopic management is an attractive minimally invasive option which avoids the need for surgery. Further studies are required regarding the selection of patients, safety and long-term outcome. PMID- 26989494 TI - Successful capecitabine rechallenge following 5-fluorouracil-induced Takotsubo syndrome. AB - Cardiac toxicity is a widely reported complication of fluoropyrimidine chemotherapies (5-fluorouracil and capecitabine); however, Takotsubo syndrome (TS) is less widely reported. There is little data available describing the viability of fluoropyrimidine rechallenge after fluoropyrimidine-induced TS. We report the case of Ms X, a 41-year-old woman with metastatic oesophageal cancer, who developed acute onset left ventricular dysfunction, with a measured left ventricular ejection fraction of 15% on cycle 1 day 3 of FOLFOX chemotherapy, after disconnection of the fluorouracil infusion pump. Her symptoms resolved over 2 days, and an echocardiogram returned to normal within 2 weeks. 5-Fluorouracil was discontinued, and replaced with capecitabine, without recurrence of symptoms. The remainder of her treatment was uneventful. This is the second case to describe successful capecitabine retreatment following 5-fluorouracil-induced TS. PMID- 26989495 TI - Household Context and Individual Departure: The Case of Escape in Three 'Unfree' East Asian Populations, 1700-1900. AB - In the past, many people were 'unfree' in the sense that their movement was restricted, and out-migration without permission was regarded and recorded as 'escape.' Even though such escape was common in the past, historical studies mostly neglect this form of migration. This paper examines escape in historical East Asia, focusing on the influence of household context and individual characteristics on the chances of escape, taking advantage of large-scale individual panel datasets from three adjacent unfree populations from northeast China, southeast Korea and northeast Japan in the 18th and 19th century. We not only find similar temporal, spatial, and age patterns of escape, but also similar patterns of associations between chances of escape and household context. In particular, the presence of dependent children and elderly in the household makes individuals less likely to escape. Other patterns of association also highlight the importance of gender and social class. Despite significant differences in political, social, and community context across these three East Asian populations, our empirical comparisons suggest important commonalities in terms of motivation driven by shared understandings of obligation to others. PMID- 26989497 TI - Comparison of Surgical Outcomes between Canaloplasty and Schlemm's Canal Scaffold at 24 Months' Follow-Up. AB - The results of canaloplasty (CP) and Hydrus Microstent (HM) implantation were retrospectively compared at 24 months' follow-up in a cohort of subjects referred to our Institution for uncontrolled IOP in primary or secondary (e.g., pseudoexfoliative and pigmentary) open-angle glaucoma. The outcome was labelled as "complete" success, "qualified" success, or "failure" if, two years after surgery, the eyes operated on needed "no" hypotensive medications, "some" hypotensive medications, or further glaucoma surgery to attain the target IOP, respectively. Both CP and HM implant allowed significant IOP reductions, with comparable rate of clinical success and safety profile. A slightly (albeit not significant) better trend for a "complete" clinical success was observed in the CP group. PMID- 26989496 TI - Therapeutic and Safety Evaluation of Combined Aqueous Extracts of Azadirachta indica and Khaya senegalensis in Chickens Experimentally Infected with Eimeria Oocysts. AB - Coccidiosis is a disease of economic importance in poultry causing morbidity and mortality. Reports show that Azadirachta indica and Khaya senegalensis have been used individually in the treatment of avian coccidiosis. We thus investigated the efficacy and safety of the combined aqueous extracts of these plants for the treatment of experimentally induced coccidiosis in broiler chickens using oocyst count, oxidative stress biomarkers, serum biochemistry, histology, and haematological parameters. The phytochemical screening revealed the presence of tannins, saponins, cardiac glycosides, and steroids in both extracts. In addition, alkaloids and flavonoids were present in Azadirachta indica. There was significant (p < 0.05) dose dependent decrease in oocyst count across the treatment groups with 400 mg/kg of the combined extract being the most efficacious dose. Immunomodulatory and erythropoietic activity was observed. There were decreased intestinal lesions and enhanced antioxidant activity across the treatment groups compared to the negative control. Administration of the combined extract did not cause damage to the liver as ALT, AST, and ALP levels were significantly reduced in the uninfected chickens treated with the extracts compared to control suggesting safety at the doses used. The combined aqueous extracts of K. senegalensis stem bark and Azadirachta indica leaves were ameliorative in chickens infected with coccidiosis. PMID- 26989498 TI - Retro-Mode Scanning Laser Ophthalmoscopy Planning for Navigated Macular Laser Photocoagulation in Macular Edema. AB - Purpose. To compare treatment areas and navigated macular laser photocoagulation (MLP) plans suggested by retro-mode scanning laser ophthalmoscopy (RM-SLO) image versus optical coherence tomography (OCT) central retinal thickness map and treatment planning among retina specialists. Methods. Thirty-nine eyes with diabetic or branch retinal vein occlusion-related ME undergoing navigated MLP with navigated photocoagulator had OCT and RM-SLO taken. OCT map and RM-SLO image were imported to the photocoagulator and aligned onto the retina. Two retina specialists placed laser spot marks separately based on OCT and RM-SLO images in a random fashion. The spots placed by each physician were compared between OCT and RM-SLO and among physicians. The areas of retinal edema on OCT and RM-SLO of the same eye were also compared. Results. The average number of laser spots using RM-SLO and OCT template was 189.6 +/- 77.4 and 136.6 +/- 46.8, respectively, P = 0.003. The average area of edema on RM-SLO image was larger than that on OCT map (14.5 +/- 3.9 mm(2) versus 10.3 +/- 2.8 mm(2), P = 0.005) because of a larger scanning area. There was narrow variability in treatment planning among retina specialists for both RM-SLO (P = 0.13) and OCT (P = 0.19). Conclusion. The RM-SLO image superimposed onto the fundus of the same eye can be used to guide MLP with narrow variability in treatment planning among retina specialists. The treatment areas suggested by RM-SLO-guided MLP plans for ME were shown to be larger than those suggested by OCT-guided plans. PMID- 26989501 TI - Challenging Glaucomas: Update on Diagnosis and Management. PMID- 26989499 TI - Comparison of Subconjunctival Mitomycin C and 5-Fluorouracil Injection for Needle Revision of Early Failed Trabeculectomy Blebs. AB - Background. To compare the efficacy of needle revision with 5-fluorouracil (5-FU) and mitomycin C (MMC) on dysfunctional filtration blebs shortly after trabeculectomy. Methods. It is a prospective randomized study comparing needle revision augmented with MMC or 5-FU for failed trabeculectomy blebs. Results. To date 71 patients (75 eyes) have been enrolled, 40 eyes in the MMC group and 35 in the 5-FU group. 68 patients (72 eyes) have completed 12-month follow-up, 38 eyes in the MMC group and 34 in the 5-FU group. The mean IOP before and that after needle revision in the MMC group were 26.5 +/- 4.3 mmHg and 11.3 +/- 3.4 mmHg, respectively (P < 0.05), and in the 5-FU group were 27.1 +/- 3.8 mmHg and 10.9 +/ 3.4 mmHg, respectively (P < 0.05). At 12-month follow-up, complete success rates were 57.5% for MMC group and 34.3% for 5-FU group (P = 0.042; log-rank test) and 75% and 60% (P = 0.145; log-rank test), respectively, for the qualified success. Complication rates between the two groups were not statistically different (P > 0.05). Conclusions. Needle revision and subconjunctival MMC injection were more effective than needling and subconjunctival 5-FU injection for early dysfunctional filtration blebs after trabeculectomies. PMID- 26989500 TI - Evaluation of Subfoveal Choroidal Thickness in Internal Carotid Artery Stenosis. AB - Purpose. To evaluate the relationship between internal carotid artery (ICA) stenosis and subfoveal choroidal thickness (SFCT) in the elderly population. Methods. A total of 42 eyes of 21 patients with more than 70% ICA stenosis (Group 1) on one side and less than 70% stenosis (Group 2) on the other side were recruited for this study. ICA stenosis was diagnosed using both the B-mode and Doppler ultrasound. The two groups were compared in terms of the percentage of stenosis, SFCT measurements, intraocular pressure, ocular perfusion pressure, refractive error, and peak systolic velocity. Eyes were examined with the RTVue 100 OCT device by the EDI-OCT technique. Results. The mean age of the patients was 71.9 +/- 10.8 years. The mean percentage of ICA stenosis was 74 +/- 4.9% in Group 1 and 47.5 +/- 7.7% in Group 2. The mean SFCT was 231.9 +/- 44.6 MUm in Group 1 and 216.2 +/- 46.8 MUm in Group 2, which was significantly lower (P = 0.028). A statistically significant positive correlation was found between the percentage of internal carotid artery stenosis and SFCT (r = 0896, P = 0.001). Conclusions. Compensatory SFCT increase can be seen in ipsilateral internal carotid artery stenosis greater than 70%. PMID- 26989502 TI - Wound Integrity of 2.0 mm Transconjunctival Single-Plane Sclerocorneal Incision: A Comparison between a Motorized Injector with/without Pause Time and a Manual Injector. AB - Purpose. To compare the final incision size and wound structure after the intraocular lens implantation from 2.0 mm transconjunctival single-plane sclerocorneal incision (TSSI) between the use of a motorized injector at first speed and the use of a manual injector. Methods. Patients were divided into three groups as follows: Group A, a manual injector, Group B, a motorized injector with 0.5 s pause time, and Group C, a motorized injector without pause time. The change in incision size and anterior segment optical coherence tomography findings of the wound structure were analyzed. Results. 110 eyes were enrolled (Group A: 40, Group B: 30, and Group C: 40). The averaged change in incision size (mm) was 0.08, 0.01, and 0.03 in Groups A, B, and C, respectively (p < 0.001). The incision enlargement in Group A was statistically larger compared with other groups (p < 0.01). Descemet's membrane detachments were seen in 26, 9, and 27 eyes one day after the surgery in Groups A, B, and C, respectively (p = 0.001). The rate of Descemet's membrane detachment in Group B was significantly lower than other groups (p < 0.01). Conclusions. The use of a motorized injector by fastest setting with 0.5 s pause time is the best for less wound damage in 2.0 mm TSSI. PMID- 26989503 TI - Effectiveness and Optical Quality of Topical 3.0% Diquafosol versus 0.05% Cyclosporine A in Dry Eye Patients following Cataract Surgery. AB - Purpose. To evaluate the effectiveness and optical quality of 3.0% topical diquafosol versus 0.05% cyclosporine A in dry eye patients following cataract surgery. Methods. In total, 40 eyes of 40 patients newly diagnosed with dry eye syndrome 1 week after cataract surgery were randomized to receive either 3.0% diquafosol ophthalmic solution six times daily or 0.05% cyclosporine A twice daily for 3 months. Outcome measures were tear film break-up time (TBUT), results on Schirmer 1 test, ocular surface staining score, the ocular surface disease index (OSDI) score, and higher-order aberrations (HOAs). Measurements were taken at baseline and at 1, 2, and 3 months. Results. In the diquafosol group, TBUT showed higher outcomes than the cyclosporine A group at 1 and 3 months. Both groups showed increased scores on Schirmer 1 test. The ocular surface staining score decreased in all periods in both groups. Vertical coma and total HOAs decreased more in the cyclosporine A group than in the diquafosol group at 3 months. Conclusion. Both 3.0% diquafosol and 0.05% cyclosporine A were effective in treating dry eye after cataract surgery. Diquafosol was more effective in increasing the tear secretion, but cyclosporine A was more effective in improving optical aberrations. PMID- 26989504 TI - Growing-Related Changes in Arterial Properties of Healthy Children, Adolescents, and Young Adults Nonexposed to Cardiovascular Risk Factors: Analysis of Gender Related Differences. AB - The aims of our work were to determine normal aging rates for structural and functional arterial parameters in healthy children, adolescents, and young adults and to identify gender-related differences in these aging rates. Methods. 161 subjects (mean: 15 years (range: 4-28 years), 69 females) were studied. Subjects included had no congenital or chronic diseases, nor had they been previously exposed to traditional cardiovascular risk factors. Arterial parameters assessed were (1) central blood pressure (BP) and aortic pulse wave analysis, (2) arterial local (pressure-strain elastic modulus) and regional (pulse wave velocity, PWV) stiffness, and (3) arterial diameters and carotid intima-media thickness (CIMT). Simple linear regression models (age as the independent variable) were obtained for all the parameters and the resulting rates of change were compared between genders. Results. No gender-related differences were found in mean values of arterial structural and functional parameters in prepubertal ages (4-8 years), but they started to appear at ~15 years. Boys showed a greater rate of change for central systolic BP, central pulse pressure, CIMT, and carotid-femoral PWV. Conclusion. Gender-related differences in arterial characteristics of adults can be explained on the basis of different growing-related patterns between boys and girls, with no existing differences in prepubertal ages. PMID- 26989505 TI - A Comparative Study of New Aspergillus Strains for Proteolytic Enzymes Production by Solid State Fermentation. AB - A comparative study of the proteolytic enzymes production using twelve Aspergillus strains previously unused for this purpose was performed by solid state fermentation. A semiquantitative and quantitative evaluation of proteolytic activity were carried out using crude enzymatic extracts obtained from the fermentation cultures, finding seven strains with high and intermediate level of protease activity. Biochemical, thermodynamics, and kinetics features such as optimum pH and temperature values, thermal stability, activation energy (E a), quotient energy (Q 10), K m , and V max were studied in four enzymatic extracts from the selected strains that showed the highest productivity. Additionally, these strains were evaluated by zymogram analysis obtaining protease profiles with a wide range of molecular weight for each sample. From these four strains with the highest productivity, the proteolytic extract of A. sojae ATCC 20235 was shown to be an appropriate biocatalyst for hydrolysis of casein and gelatin substrates, increasing its antioxidant activities in 35% and 125%, respectively. PMID- 26989507 TI - Mother-to-Child Transmission of HIV Infection and Its Determinants among Exposed Infants on Care and Follow-Up in Dire Dawa City, Eastern Ethiopia. AB - Since the scale-up for prevention of mother-to-child transmission (PMTCT) services, rates of HIV infection among exposed infants have significantly declined. However, current achievements fell short of achieving the target sets. We investigated mother-to-child transmission (MTCT) of HIV infection and its determinants among HIV-exposed infants on care at Dilchora Referral Hospital in Dire Dawa City Administration. A retrospective institutional cohort study was conducted by reviewing follow-up records of HIV-exposed infants who were enrolled into care. Infants' HIV serostatus was the outcome measure of the study. Bivariate and multivariate logistic regressions were employed to identify significant determinants. Of the 382 HIV-exposed infants enrolled into care, 60 (15.7%) became HIV positive. Rural residence (AOR: 3.29; 95% CI: 1.40, 7.22), home delivery (AOR: 3.35; 95% CI: 1.58, 8.38), infant not receiving ARV prophylaxis at birth (AOR: 5.83; 95% CI: 2.84, 11.94), mixed feeding practices (AOR: 42.21; 95% CI: 8.31, 214.38), and mother-child pairs neither receiving ARV (AOR: 4.42; 95% CI: 2.01, 9.82) were significant independent determinants of MTCT of HIV infection. Our findings suggest additional efforts to intensify scale-up of PMTCT services in rural setting and improve institutional delivery and postnatal care for HIV positive mothers and proper follow-up for HIV-exposed infants. PMID- 26989506 TI - Mechanism of Xinfeng Capsule on Adjuvant-Induced Arthritis via Analysis of Urinary Metabolomic Profiles. AB - We aimed to explore the potential effects of Xinfeng capsule (XFC) on urine metabolic profiling in adjuvant-induced arthritis (AA) rats by using gas chromatography time-of-flight mass spectrometry (GC-TOF/MS). GC-TOF/MS technology was combined with multivariate statistical approaches, such as principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal projections to latent structures discriminant analysis (OPLS-DA). These methods were used to distinguish the healthy group, untreated group, and XFC treated group and elucidate potential biomarkers. Nine potential biomarkers such as hippuric acid, adenine, and L-dopa were identified as potential biomarkers, indicating that purine metabolism, fat metabolism, amino acid metabolism, and energy metabolism were disturbed in AA rats. This study demonstrated that XFC is efficacious for RA and explained its potential metabolomics mechanism. PMID- 26989508 TI - Perceived versus Observed Patient Safety Measures in a Critical Care Unit from a Teaching Hospital in Southern Colombia. AB - Introduction. Patient safety is an important topic. The purpose of this study is to evaluate the perceived versus observed patient safety measures (PSM) in critically ill patients in a teaching hospital in Latin America. Materials and Methods. The level of perceived patient safety was evaluated with the patient safety hospital survey. Three months later, a qualitative study was conducted, including video recording of procedures, graded according to adherence to PSM. Levels of adherence were scored during patient mobilization (PM), placement of central catheters (PCC), other invasive procedures (OIP), infection control (IC), and endotracheal intubation (ETI). Results. The perceived adherence of PSM in the prestudy survey was considered fair by 89.1% of the ICU staff. After the survey, 829 ICU procedures were video-recorded. Mean observed adherence for fair patient safety measures was 20.8%. Perceived adherence was higher than the real patient safety protocol measures observed in the videos. Conclusion. Perception of PSM was higher than observed in the management of critically ill patients in a teaching hospital in southern Colombia. PMID- 26989510 TI - School Absenteeism due to Toothache among Secondary School Students Aged 16-18 Years in the Ha'il Region of Saudi Arabia. AB - Objective. This study assessed the impact of toothache on school attendance among secondary school students in the Ha'il Region, Saudi Arabia. Methods. A cross sectional, paper based survey was conducted among 16-18-year-old students of public sector secondary schools in the Ha'il Region, Saudi Arabia. Results. Of the 510 students selected from the participating schools, 480 were analyzed (94.1%). Of the sample, 50.4% were boys. Among the participants in the study, 86 students reported school absence due to toothache in the six months prior to the survey. Consequently, the prevalence of absenteeism due to toothache in this study was of 18%. Conclusion. The prevalence of school absenteeism due to toothache among students in the Ha'il Region was low. Yet, still, missed school days due to toothache may have implications for students also in the Ha'il Region, Saudi Arabia, as school absenteeism leads to missed opportunities for learning and academic advancement. PMID- 26989509 TI - A Review of the Literature on Extrarenal Retroperitoneal Angiomyolipoma. AB - BACKGROUND: Extrarenal retroperitoneal angiomyolipomas are rare. AIM: To review the literature. RESULTS: Angiomyolipomas, previously classified as hamartomas, are now classified as benign tumours. Thirty cases of primary retroperitoneal angiomyolipomas have been reported. Diagnosis of the disease upon is based radiological and pathological findings of triphasic features of (a) fat and (b) blood vessels and myoid tissue. Immunohistochemistry tends to be positive for HMB45, MART1, HHF35, calponin, NKI-C3, and CD117. The lesion is common in women. Treatment options have included the following: (a) radical surgical excision of the lesion with renal sparing surgery or radical nephrectomy in cases where malignant tumours could not be excluded and (b) selective embolization of the lesion alone or prior to surgical excision. One case of retroperitoneal angiomyolipoma was reported in a patient 15 years after undergoing radical nephrectomy for angiomyolipoma of kidney and two cases of distant metastases of angiomyolipoma have been reported following radical resection of the tumour. CONCLUSIONS: With the report of two cases of metastases ensuing surgical resection of the primary lesions there is need for academic pathologists to debate and review angiomyolipomas to decide whether to reclassify angiomyolipomas as slow-growing malignant tumours or whether the reported cases of metastases were de novo tumours or metastatic lesions. PMID- 26989511 TI - Biological Impact of Pd (II) Complexes: Synthesis, Spectral Characterization, In Vitro Anticancer, CT-DNA Binding, and Antioxidant Activities. AB - A new series of Pd (II) complexes of methyl substituted benzylamine ligands (BLs) has been synthesized and characterized via spectroscopic techniques such as UV/Vis. FTIR, LCMS, (1)H, and (13)C NMR. The UV/Vis study in DMSO, DMSO + water, and DMSO + PBS buffer (pH = 7.2) confirmed their molecular sustainability in liquids. Their in vitro anticancer activity against breast cancer cell lines such as MCF-7 and MDA-MB-231 makes them interesting for in vivo analysis. Their stronger DNA binding activity (DBA) compared with free ligand suggested them as a good DNA binder. DBA was further confirmed by physicochemical studies such as surface tension and viscosity of complex + DNA which inferred the disruption of DNA and intercalation of complexes, respectively. Their % binding activity, % disruption of DNA base pairs (DNABP), and % intercalating strength are reported in this paper for the first time for better understanding of DNA binding mechanism. Along with this, their scavenging activity (SA) determined through DPPH free radical and the results indicate good antioxidant behaviour of complexes. PMID- 26989512 TI - Serum Fatty Acids, Traditional Risk Factors, and Comorbidity as Related to Myocardial Injury in an Elderly Population with Acute Myocardial Infarction. AB - Background. Epidemiological and randomized clinical trials indicate that marine polyunsaturated n-3 fatty acids (n-3 PUFAs) may have cardioprotective effects. Aim. Evaluate the associations between serum fatty acid profile, traditional risk factors, the presence of cardiovascular diseases (CVD), and peak Troponin T (TnT) levels in elderly patients with an acute myocardial infarction (AMI). Materials and Methods. Patients (n = 299) consecutively included in the ongoing Omega-3 fatty acids in elderly patients with myocardial infarction (OMEMI) trial were investigated. Peak TnT was registered during the hospital stay. Serum fatty acid analysis was performed 2-8 weeks later. Results. No significant correlations between peak TnT levels and any of the n-3 PUFAs were observed. However, patients with a history of atrial fibrillation had significantly lower docosahexaenoic acid levels than patients without. Significantly lower peak TnT levels were observed in patients with a history of hyperlipidemia, angina, MI, atrial fibrillation, intermittent claudication, and previous revascularization (all p < 0.02). Conclusions. In an elderly population with AMI, no association between individual serum fatty acids and estimated myocardial infarct size could be demonstrated. However, a history of hyperlipidemia and the presence of CVD were associated with lower peak TnT levels, possibly because of treatment with cardioprotective medications. PMID- 26989513 TI - Inhibitory Effect of the Punica granatum Fruit Extract on Angiotensin-II Type I Receptor and Thromboxane B2 in Endothelial Cells Induced by Plasma from Preeclamptic Patients. AB - This study aims to evaluate whether the Punica granatum fruit extract modulates the Angiotensin-II Type I receptor (AT1-R) and thromboxane B2 level in endothelial cells induced by plasma from preeclamptic patients. Endothelial cells were obtained from human umbilical vascular endothelial cells. At confluence, endothelial cells were divided into five groups, which included endothelial cells exposed to 2% plasma from normal pregnancy (NP), endothelial cells exposed to 2% plasma from preeclamptic patients (PP), and endothelial cells exposed to PP in the presence of ethanolic extract of Punica granatum (PP + PG) at the following three doses: 14; 28; and 56 ppm. The expression of AT1-R was observed by immunohistochemistry technique, and thromboxane B2 level was done by immunoassay technique. Plasma from PP significantly increased AT1-R expression and thromboxane B2 levels compared to cells treated by normal pregnancy plasma. The increasing of AT1-R expression significantly (P < 0.05) attenuated by high dose treatments of Punica granatum extract. Moreover, the increasing of thromboxane B2 levels significantly (P < 0.05) attenuated by lowest dose treatments of Punica granatum extract. We further concluded that Punica granatum fruit protects and inhibits the sensitivity of endothelial cells to plasma from preeclamptic patients due to inhibition of AT1-R expression (56 ppm) and reduced thromboxane B2 levels (14 ppm). PMID- 26989516 TI - Perineuronal Nets and CNS Plasticity and Repair. PMID- 26989515 TI - Housing Complexity Alters GFAP-Immunoreactive Astrocyte Morphology in the Rat Dentate Gyrus. AB - Rats used in research are typically housed singly in cages with limited sensory stimulation. There is substantial evidence that housing rats in these conditions lead to numerous neuroanatomical and behavioral abnormalities. Alternatively, rats can be housed in an enriched environment in which rats are housed in groups and given room for exercise and exploration. Enriched environments result in considerable neuroplasticity in the rodent brain. In the dentate gyrus of the hippocampus, enriched environments evoke especially profound neural changes, including increases in the number of neurons and the number of dendritic spines. However, whether changes in astrocytes, a type of glia increasingly implicated in mediating neuroplasticity, are concurrent with these neural changes remains to be investigated. In order to assess morphological changes among astrocytes of the rat dentate gyrus, piSeeDB was used to optically clear 250 MUm sections of tissue labeled using GFAP immunohistochemistry. Confocal imaging and image analysis were then used to measure astrocyte morphology. Astrocytes from animals housed in EE demonstrated a reduced distance between filament branch points. Furthermore, the most complex astrocytes were significantly more complex among animals housed in EE compared to standard environments. PMID- 26989518 TI - Management of Anesthesia under Extracorporeal Cardiopulmonary Support in an Infant with Severe Subglottic Stenosis. AB - A 4-month-old female infant who weighed 3.57 kg with severe subglottic stenosis underwent tracheostomy under extracorporeal cardiopulmonary support. First, we set up extracorporeal cardiopulmonary support to the infant and then successfully intubated an endotracheal tube with a 2.5 mm inner diameter before tracheostomy by otolaryngologists. Extracorporeal cardiopulmonary support is an alternative for maintenance of oxygenation in difficult airway management in infants. PMID- 26989514 TI - Control of Dendritic Spine Morphological and Functional Plasticity by Small GTPases. AB - Structural plasticity of excitatory synapses is a vital component of neuronal development, synaptic plasticity, and behaviour. Abnormal development or regulation of excitatory synapses has also been strongly implicated in many neurodevelopmental, psychiatric, and neurodegenerative disorders. In the mammalian forebrain, the majority of excitatory synapses are located on dendritic spines, specialized dendritic protrusions that are enriched in actin. Research over recent years has begun to unravel the complexities involved in the regulation of dendritic spine structure. The small GTPase family of proteins have emerged as key regulators of structural plasticity, linking extracellular signals with the modulation of dendritic spines, which potentially underlies their ability to influence cognition. Here we review a number of studies that examine how small GTPases are activated and regulated in neurons and furthermore how they can impact actin dynamics, and thus dendritic spine morphology. Elucidating this signalling process is critical for furthering our understanding of the basic mechanisms by which information is encoded in neural circuits but may also provide insight into novel targets for the development of effective therapies to treat cognitive dysfunction seen in a range of neurological disorders. PMID- 26989519 TI - Staphylococcus aureus Endocarditis with Multivalvular Involvement Secondary to an Atrial Septal Defect. AB - Infective endocarditis is usually diagnosed using modified Duke's criteria. Our patient had a subacute presentation and a low suspicion for endocarditis during admission, unfortunately leading to her death. Despite advances in diagnostic and therapeutic measures including antibiotic therapy and surgical techniques, morbidity and mortality with staphylococcal infective endocarditis remain high. Hence, we stress the significance of having a low threshold for TEE in patients with multisystem involvement due to Staphylococcus aureus that have evidence of persistent infection despite antibiotic treatment, even if the suspicion for endocarditis is low based on Duke's criteria. TEE substantially improves the sensitivity of diagnosis but may not be readily available in many medical centers. Presence of an ASD has been noted to have increased the risk of left sided endocarditis even with conditions that predispose to right sided endocarditis, particularly in patients with hemodialysis and diabetes as morbid risk factors. PMID- 26989517 TI - Modulatory Action by the Serotonergic System: Behavior and Neurophysiology in Drosophila melanogaster. AB - Serotonin modulates various physiological processes and behaviors. This study investigates the role of 5-HT in locomotion and feeding behaviors as well as in modulation of sensory-motor circuits. The 5-HT biosynthesis was dysregulated by feeding Drosophila larvae 5-HT, a 5-HT precursor, or an inhibitor of tryptophan hydroxylase during early stages of development. The effects of feeding fluoxetine, a selective serotonin reuptake inhibitor, during early second instars were also examined. 5-HT receptor subtypes were manipulated using RNA interference mediated knockdown and 5-HT receptor insertional mutations. Moreover, synaptic transmission at 5-HT neurons was blocked or enhanced in both larvae and adult flies. The results demonstrate that disruption of components within the 5-HT system significantly impairs locomotion and feeding behaviors in larvae. Acute activation of 5-HT neurons disrupts normal locomotion activity in adult flies. To determine which 5-HT receptor subtype modulates the evoked sensory-motor activity, pharmacological agents were used. In addition, the activity of 5-HT neurons was enhanced by expressing and activating TrpA1 channels or channelrhodopsin-2 while recording the evoked excitatory postsynaptic potentials (EPSPs) in muscle fibers. 5-HT2 receptor activation mediates a modulatory role in a sensory-motor circuit, and the activation of 5-HT neurons can suppress the neural circuit activity, while fluoxetine can significantly decrease the sensory-motor activity. PMID- 26989520 TI - Spontaneous Coronary Dissection: "Live Flash" Optical Coherence Tomography Guided Angioplasty. AB - Optical Coherence tomography (OCT) is a light-based imaging modality which shows tremendous potential in the setting of coronary imaging. Spontaneous coronary artery dissection (SCAD) is an infrequent cause of acute coronary syndrome (ACS). The diagnosis of SCAD is made mainly with invasive coronary angiography, although adjunctive imaging modalities such as computed tomography angiography, IVUS, and OCT may increase the diagnostic yield. The authors describe a clinical case of a young woman admitted with the diagnosis of ACS. The ACS was caused by SCAD detected in the coronary angiography and the angioplasty was guided by OCT. OCT use in the setting of SCAD has been already described and the true innovation in this case was this unique use of OCT. The guidance of angioplasty with live and short images was very useful as it allowed clearly identifying the position of the guidewires at any given moment without the use of prohibitive amounts of contrast. PMID- 26989521 TI - A Rare but Reversible Cause of Hematemesis: "Downhill" Esophageal Varices. AB - "Downhill" varices are a rare cause of acute upper gastrointestinal bleeding and are generally due to obstruction of the superior vena cava (SVC). Often these cases of "downhill" varices are missed diagnoses as portal hypertension but fail to improve with medical treatment to reduce portal pressure. We report a similar case where recurrent variceal bleeding was initially diagnosed as portal hypertension but later found to have SVC thrombosis presenting with recurrent hematemesis. A 39-year-old female with history of end-stage renal disease presented with recurrent hematemesis. Esophagogastroduodenoscopy (EGD) revealed multiple varices. Banding and sclerotherapy were performed. Extensive evaluation did not show overt portal hypertension or cirrhosis. Due to ongoing bleeding requiring resuscitation, she underwent internal jugular (IJ) and SVC venogram in preparation for transjugular intrahepatic portosystemic shunt (TIPS), which demonstrated complete IJ and SVC occlusion. She underwent balloon angioplasty with stent placement across SVC occlusion with complete resolution of her varices and resolved hematemesis. "Downhill" varices are extremely rare, though previously well described. Frequently, patients are misdiagnosed with underlying liver disease. High index of suspicion and investigation of alternative causes of varices is prudent in those without underlying liver diseases. Prompt diagnosis and appropriate intervention can significantly improve morbidity and mortality. PMID- 26989522 TI - Wernicke's Encephalopathy Complicating Hyperemesis during Pregnancy. AB - Wernicke's encephalopathy is caused by severe thiamine deficiency; it is mostly observed in alcoholic patients. We report the case of a 28-year-old woman, at 17 weeks of gestational age, with severe hyperemesis gravidarum. She presented with disturbance of consciousness, nystagmus, ophthalmoplegia, and ataxia. The resonance magnetic imagery showed bilaterally symmetrical hyperintensities of thalamus and periaqueductal area. The case was managed with very large doses of thiamine. The diagnosis of Wernicke's encephalopathy was confirmed later by a low thiamine serum level. The patient was discharged home on day 46 with mild ataxia and persistent nystagmus. Wernicke's encephalopathy is a rare complication of hyperemesis gravidarum. It should be diagnosed as early as possible to prevent long-term neurological sequela or death. Thiamine supplementation in pregnant women with prolonged vomiting should be initiated, especially before parenteral dextrose infusion. Early thiamine replacement will reduce maternal morbidity and fetal loss rate. PMID- 26989523 TI - An Erupted Dilated Odontoma: A Rare Presentation. AB - A dilated odontoma is an extremely rare developmental anomaly represented as a dilatation of the crown and root as a consequence of a deep, enamel-lined invagination and is considered a severe variant of dens invaginatus. An oval shape of the tooth lacking morphological characteristics of a crown or root implies that the invagination happened in the initial stages of morphodifferentiation. Spontaneous eruption of an odontoma is a rare occurrence and the occurrence of a dilated odontoma in a supernumerary tooth is even rarer with only a few case reports documented in the English literature. We present an extremely rare case of erupted dilated odontoma occurring in the supernumerary tooth in anterior maxillary region in an 18-year-old male, which, to the best of our knowledge, is the first ever case reported in English literature. PMID- 26989524 TI - Treatment of a Refractory Skin Ulcer Using Punch Graft and Autologous Platelet Rich Plasma. AB - Background. Chronic ulceration of the lower legs is a relatively common condition amongst adults: one that causes pain and social distress and results in considerable healthcare and personal costs. The technique of punch grafting offers an alternative approach to the treatment of ulcers of the lower limbs. Objective. Combining platelet-rich plasma and skin graft enhances the efficacy of treating chronic diabetic wounds by enhancing healing rate and decreasing recurrence rate. Platelet-rich plasma could, by stimulating dermal regeneration, increase the take rate after skin grafting or speed up reepithelialization. Methods and Materials. The ulcer was prepared by removing fibrin with a curette and the edges of the ulcer were freshened. The platelet-rich plasma has been infiltrated on the bottom and edges of the ulcer. The punch grafts were placed in 5 mm holes arranged. The ulcer was medicated with hydrogel and a pressure dressing was removed after 8 days. Results. After a few days the patient did not report more pain. Granulation tissue appeared quickly between implants. Most of the grafts were viable in 2-3 weeks. The grafts gradually came together to close the ulcer and were completed in four months. PMID- 26989526 TI - Atraumatic Subdural Hematoma in a Third-Trimester Gravid Patient. AB - Acute atraumatic subdural hematoma is a rare occurrence and there exist few case studies which describe suspected cases and causes for this condition. We present a case of a 36-year-old female at 32-week gestation who initially presented to the emergency department for evaluation of lower extremity cellulitis but had acute neurologic change while being in the ED. Computed tomography revealed a right subdural hematoma with midline shift and mass effect. The primary cause for the patient's subdural hematoma is unknown; however, this patient had several risk factors for developing an atraumatic subdural hematoma. PMID- 26989525 TI - Spontaneous Arachnoid Cyst Rupture with Subdural Hygroma in a Child. AB - Arachnoid cyst of the brain is common in children but its association with spontaneous subdural hygroma is rare. A case of a nine-year-old boy, without any preceding history of trauma, is presented here who came to the emergency department of a tertiary care hospital with complaints of headache, nausea, and vomiting for the last two weeks but more for the last two days. Examination showed a young, fully conscious oriented boy with positive Cushing's reflex and papilledema of left eye. MRI (magnetic resonance imaging) of the brain showed left temporal extra-axial cystic lesion of 5.40 * 4.10 cm in size, representing arachnoid cyst, with bilateral frontoparietal subdural hygromas. Cyst was partially drained through left temporal craniectomy and subdural hygromas were drained through bilateral frontal burr holes. Postoperatively the child recovered uneventfully and was discharged on the seventh postoperative day. Histopathology proves it to be arachnoid cyst of the brain with subdural CSF (cerebrospinal fluid) collection or hygroma. PMID- 26989527 TI - Mifepristone Improves Octreotide Efficacy in Resistant Ectopic Cushing's Syndrome. AB - A 30-year-old Caucasian man presented with severe Cushing's syndrome (CS) resulting from ectopic adrenocorticotropin syndrome (EAS) from a metastatic pancreatic neuroendocrine tumor. The patient remained hypercortisolemic despite treatment with steroidogenesis inhibitors, chemotherapy, and octreotide long acting release (LAR) and was enrolled in a 24-week, phase 3 clinical trial of mifepristone for inoperable hypercortisolemia. After mifepristone was added to ongoing octreotide LAR treatment, EAS symptoms essentially resolved. Cortisol decreased dramatically, despite mifepristone's competitive glucocorticoid receptor antagonist effects. The clinical and biochemical effects reversed upon mifepristone discontinuation despite the continued use of octreotide LAR therapy. Substantial improvement in octreotide LAR efficacy with mifepristone use was noted in this patient with ectopic CS, consistent with upregulation of somatostatin receptors previously downregulated by hypercortisolemia. PMID- 26989528 TI - Small Intestinal and Mesenteric Multiple Gastrointestinal Stromal Tumors Causing Occult Bleeding. AB - Gastrointestinal stromal tumors are the meseancymal neoplasms which may involve any part of gastrointestinal tract. C-Kit and platelet derived factor receptor alpha polypeptide are believed to be responsible for the genetic basis. This case presentation aimed to discuss the diagnostic and therapeutic modality of multiple small intestinal, omental, and mesenteric GISTs with different sizes which caused occult bleeding in a 43-year-old male patient. PMID- 26989529 TI - A 54-Year-Old Woman with Donor Cell Origin of Multiple Myeloma after Allogeneic Hematopoietic Stem Cell Transplantation for the Treatment of CML. AB - Chronic myeloid leukemia is a myeloproliferative disorder that may be treated with hematopoietic stem cell transplantation (HSCT). While posttransplantation relapse of disease resulting from a failure to eradicate the patient's original leukemia could occur, patients may also rarely develop a secondary malignancy or myelodysplastic syndrome (MDS) of donor origin termed donor cell leukemia (DCL). Cases of donor-derived acute myeloid leukemia (AML) or MDS after HSCT or solid tumor transplantation have been published. However, very few cases of donor derived multiple myeloma (MM) exist. We describe a patient who developed a donor derived MM following allogeneic HSCT from a sibling donor. PMID- 26989530 TI - Successful Use of Plasma Exchange in the Treatment of Corticosteroid-Refractory Eosinophilic Granulomatosis with Polyangiitis Associated with Gastrointestinal Manifestations. AB - We describe the case of a 33-year-old woman having corticosteroid-refractory eosinophilic granulomatosis with polyangiitis (EGPA) who presented with abdominal pain and responded dramatically to plasma exchange. Eosinophilia, asthma history, neuropathy, pulmonary infiltrates, and paranasal sinus abnormalities confirmed the diagnosis of EGPA. Treatment was initiated with 1 g/day of methylprednisolone pulse therapy for 3 days followed by 60 mg/day of intravenous prednisolone without relieving abdominal pain. Then, plasma exchange was performed thrice. Abdominal pain disappeared after the first plasma exchange. Indication of plasma exchange for EGPA remains controversial; however, it may represent a valid option in cases with gastrointestinal involvement. PMID- 26989531 TI - IgA Nephropathy in a Patient Presenting with Pseudotumor Cerebri. AB - IgA nephropathy is the most common glomerulonephritis worldwide and typically has minimal signs for chronicity in histopathology at the time of initial presentation. Pseudotumor cerebri (PTC) is characterized by increased intracranial pressure in the absence of any intracranial lesions, inflammation, or obstruction. PTC has been reported in renal transplant and dialysis patients, but we are unaware of any reports of pseudotumor cerebri in patients with IgA nephropathy. We report a case of a young female who presented with signs and symptoms of pseudotumor cerebri and was subsequently diagnosed with IgA nephropathy and end-stage renal disease. To our knowledge this is the first report of IgA nephropathy presenting as end-stage renal disease in a patient who presented with pseudotumor cerebri. PMID- 26989532 TI - Cerebral Venous Thrombosis with Migraine-Like Headache and the Trigeminovascular System. AB - Cerebral venous thrombosis- (CVT-) associated headache is considered a secondary headache, commonly presenting as intracranial hypertension headache in association with seizures and/or neurological signs. However, it can occasionally mimic migraine. We report a patient presenting with a migraine-like, CVT-related headache refractory to several medications but intravenous dihydroergotamine (DHE). The response to DHE, which is considered to be an antimigraine medication, in addition to the neurovascular nature of migraine, points out to a probable similarity between CVT-headache and migraine. Based on experimental studies, we discuss this similarity and hypothesize a trigeminovascular role in the genesis of CVT-associated headache. PMID- 26989533 TI - Babinski-Nageotte Syndrome Diagnosed in Postpartum Period. AB - Babinski-Nageotte Syndrome (BNS) is one of the brainstem syndromes characterized by muscle weakness in the opposite half of the body with classic Wallenberg findings. According to our literature survey, only a few cases have been reported and none of them was in the postpartum period. We report a case of a typical BNS in a postpartum woman with an ischemic lesion in the medulla oblongata shown on magnetic resonance imaging. PMID- 26989534 TI - A Case of Ataxia with Isolated Vitamin E Deficiency Initially Diagnosed as Friedreich's Ataxia. AB - Ataxia with isolated vitamin E deficiency (AVED) is a rare autosomal recessive condition that is caused by a mutation in the alpha tocopherol transfer protein gene. It is almost indistinguishable clinically from Friedreich's ataxia but with appropriate treatment its devastating neurological features can be prevented. Patients can present with a progressive cerebellar ataxia, pyramidal spasticity, and evidence of a neuropathy with absent deep tendon reflexes. It is important to screen for this condition on initial evaluation of a young patient presenting with progressive ataxia and it should be considered in patients with a long standing ataxia without any diagnosis in view of the potential therapeutics and genetic counselling. In this case report we present a patient who was initially diagnosed with Friedreich's ataxia but was later found to have AVED. PMID- 26989535 TI - The Kleine-Levin Syndrome: A Rare Disease with Often Delayed Diagnosis-A Report of Two Cases in the Department of Neurology of the University Hospital of Cocody (Cote d'Ivoire). AB - The Kleine-Levin syndrome is a rare pathology characterized by recurrent episodes of hypersomnia associated with behavioral and cognitive disorders with, among others, hyperphagia and hypersexuality. The disease mainly affects young males. A few studies mention cases that occurred in Africa, especially in Cote d'Ivoire. In this paper, we report the very first two cases observed in the Neurology Department of the University Hospital of Cocody. The diagnosis was clinical, based on the recurrence of hypersomnia, cognitive and behavioral disorders during the periods of hypersomnia, and the return of patients to normal state between episodes. This diagnosis was delayed due to failure to understand the pathology, thereby leading patients to wandering. In fact, the two patients were consulted, respectively, 3 years and 6 years after the hypersomnia began. The objective was to report the very first cases observed in the Neurology Department of the University Hospital of Cocody, Cote d'Ivoire. PMID- 26989536 TI - Long Term Survival and Continued Complete Response of Vemurafenib in a Metastatic Melanoma Patient with BRAF V600K Mutation. AB - Introduction. BRAF kinase inhibitors such as Vemurafenib have shown improvement in overall survival, progression-free survival, and response rates in patients with metastatic melanoma with BRAF V600K mutation. However, there were no cases of complete remission reported in patients with V600K mutation before. Case Presentation. A 53-year-old man with metastatic melanoma and dialysis dependent end stage renal failure was treated safely with Vemurafenib for a BRAF V600K mutation positive melanoma and the case was reported elsewhere. After a long follow-up of the same patient treated with Vemurafenib, a complete radiological response was observed and the renal functions remained stable throughout the treatment. Main toxicities reported were grade 1 photosensitivity and skin cancers. Vemurafenib was discontinued but patient remains disease free 12 months after stopping treatment and the clinical review is ongoing. Conclusion. This is the first reported case of complete radiological response to a BRAF inhibitor in metastatic melanoma with BRAF V600K mutation and remains disease free even after discontinuation of treatment. This also shows clinical safety of Vemurafenib in end stage renal failure and highlights the need for closer look at the subgroup of patients with BRAF V600K mutation and its tumour biology. PMID- 26989537 TI - Choroid Melanoma Metastasis to Spine: A Rare Case Report. AB - Metastatic choroid melanoma is a highly malignant disease with a limited life expectancy. The liver is the most common site for metastasis of uveal melanoma followed by lung, bone, skin, and subcutaneous tissue. Metastasis from choroidal melanoma usually occurs within the first five years of treatment for primary tumours. Metastatic choroid melanoma to the spine/vertebrae is extremely rare. We report the first case of spinal metastasis from choroid melanoma in a 61-year-old man who had been treated for primary ocular melanoma three years earlier with radioactive plaque brachytherapy. Synchronously, at the time of metastasis, he was also diagnosed as having a new primary lung adenocarcinoma as well. The only other case reported on vertebral metastasis from malignant melanoma of choroid in literature in which primary choroid melanoma was enucleated. PMID- 26989538 TI - Is Optical Coherence Tomography a Useful Tool to Objectively Detect Actual Posterior Vitreous Adhesion Status? AB - Purpose. To objectively detect true posterior vitreous cortex (PVC) adhesion status using a commercially available swept-source OCT device (DRI OCT-1, Atlantis((c))). Material and Methods. Case report, review of the literature, and methodical discussion of concepts to improve OCT-guided PVC imaging. Results. Standard OCT imaging misdiagnosed PVC adhesion status as totally detached in this case report when using a horizontal 6 mm scan only. Contrariwise imaging the same eye with a 12 mm horizontal scan, partial posterior vitreous detachment (PVD) and the presence of a bursa premacularis were clearly discernible. Besides a broader scan, specific scan patterns, highest resolution, and contrast sensitivity, an anterior-to-posterior adjusted scan through the entire vitreous as well as the detection of characteristic undulating aftermovements might enhance the capability of OCT imaging to detect true PVC adhesion status. Conclusions. Further developments are needed to address these issues and to establish OCT recordings as the standard and objective method of choice in PVC adhesion status imaging. PMID- 26989539 TI - Conjunctival Involvement of T-Cell Lymphoma in a Patient with Mycosis Fungoides. AB - Background. Ocular involvement in mycosis fungoides (MF) cases occurs in one third of patients with the eyelid being the most frequent site affected; however, conjunctival involvement is rarely reported. Herein, we report a rare case of conjunctival involvement of MF. Case Presentation. A 66-year-old man who was previously diagnosed with MF in 2010 and was treated presented in 2014 complaining of foreign body sensation and redness in both eyes. Slit lamp examination of both eyes showed erythematous conjunctival growth that extended circumferentially. Physical examination revealed erythematous skin lesions on different body parts. Conjunctival biopsy was performed and revealed a dense, highly polymorphic lymphocytic population. The immunophenotype demonstrated a neoplastic T-cell origin consistent with MF. A diagnosis of conjunctival involvement by MF was made. The conjunctiva was treated with radiotherapy resulting in tumor regression. There were no recurrences at the 6-month follow up. Conclusion. T-cell lymphoma should be considered in patients with a history of MF presenting with conjunctival and skin lesions. PMID- 26989540 TI - Herpetic Stromal Keratitis following Selective Laser Trabeculoplasty. AB - This is a case report describing two cases of disciform corneal edema following uncomplicated selective laser trabeculoplasty (SLT) thought to be secondary to herpes simplex virus (HSV) given the presence of a dendrite, decreased corneal sensation, corneal thinning, and response to therapy with oral and topical antivirals. Corneal edema after SLT treatment has been reported before, but the etiology has been unclear. Our cases highlight HSV as a likely etiology, which may help with prevention and better management of such cases in the future. PMID- 26989541 TI - Inflammatory Neuropathy of the Lumbosacral Plexus following Periacetabular Osteotomy. AB - Introduction. During periacetabular osteotomy (PAO), the sciatic, femoral, and obturator nerves are at risk. Most frequently nerve lesions can be attributed to a mechanical cause; however, in the absence of a clear mechanical cause surgeons are faced with a diagnostic problem and in many cases no diagnosis will be established. We report a case of inflammatory neuropathy of the lumbosacral plexus following a PAO. Case Presentation. A 31-year-old female developed weakness of ankle and knee flexion and extension 6 months after a PAO. Electrophysiological studies revealed damage to the obturator, femoral, and sciatic nerve consistent with an inflammatory lumbosacral plexopathy. MRI of the lumbosacral plexus was normal. The patient was treated with multimodal pain therapy and prolonged physiotherapy; nevertheless, symptoms worsened over time. At 2-year follow-up, there were no signs of recovery. Discussion. Inflammatory neuropathy of the lumbosacral plexus is a potential cause of pain and weakness after ipsilateral orthopaedic procedures. It should be distinguished from more frequently encountered mechanical causes of postsurgical neuropathy based on clinical suspicion, electrophysiological studies, MRI, and nerve biopsy. It is important that the orthopaedic community is aware of this complication since there is some evidence that early recognition and initiation of immunosuppressive therapy can lead to improved clinical outcome. PMID- 26989543 TI - Iliopsoas Abscess Possibly due to Klebsiella pneumoniae Infection after Chemoradiotherapy for Hypopharyngeal Cancer. AB - Iliopsoas abscess was once an uncommon condition but now occurs somewhat more frequently due to the increasing number of immunocompromised patients, such as those with diabetes. We encountered a case of iliopsoas abscess following chemoradiotherapy for hypopharyngeal cancer. A 60-year-old man was admitted for a sore throat and left neck swelling. Hypopharyngeal cancer was diagnosed, but the patient refused surgery. After two rounds of chemotherapy, febrile neutropenia developed and chest computed tomography (CT) revealed an iliopsoas abscess. The platelet count was low but recovered after administration of antibiotics and could not be explained by puncture of the abscess. CT-guided drainage eventually improved his symptoms. Even for disorders of the head and neck region, iliopsoas abscess should be suspected in immunocompromised patients who develop a fever. CT and magnetic resonance imaging should be performed at an early stage as it is important to determine whether surgical drainage is indicated. PMID- 26989542 TI - Spinal Epidural Hematoma after Thoracolumbar Posterior Fusion Surgery without Decompression for Thoracic Vertebral Fracture. AB - We present a rare case of spinal epidural hematoma (SEH) after thoracolumbar posterior fusion without decompression surgery for a thoracic vertebral fracture. A 42-year-old man was hospitalized for a thoracic vertebral fracture caused by being sandwiched against his back on broken concrete block. Computed tomography revealed a T12 dislocation fracture of AO type B2, multiple bilateral rib fractures, and a right hemopneumothorax. Four days after the injury, in order to promote early orthostasis and to improve respiratory status, we performed thoracolumbar posterior fusion surgery without decompression; the patient had back pain but no neurological deficits. Three hours after surgery, he complained of acute pain and severe weakness of his bilateral lower extremities; with allodynia below the level of his umbilicus, postoperative SEH was diagnosed. We performed immediate revision surgery. After removal of the hematoma, his symptoms improved gradually, and he was discharged ambulatory one month after revision surgery. Through experience of this case, we should strongly consider the possibility of preexisting SEH before surgery, even in patients with no neurological deficits. We should also consider perioperative coagulopathy in patients with multiple trauma, as in this case. PMID- 26989544 TI - The Clinical Understaging of Recurrent Glottic Carcinoma after Radiation Failure. AB - Background. Recurrent glottic squamous cell carcinomas following radiation therapy for early staged tumors are oftentime early staged tumors. Management of these early stage recurrences presents a dilemma for the head and neck surgeon. Difficulties in appropriate tumor mapping, preoperative analysis, and poor understanding of the virulent pathologic nature of the recurrence may impede surgical decision-making. Methods. This is a single surgeon case report, presenting a patient with rapid recurrence following salvage transoral resection for an early stage recurrence, necessitating a total laryngectomy. Results. A review of the literature was performed, identifying studies that expound on the pathologic behavior of radiation recurrent disease. Conclusions. Radiation recurrent glottic squamous cell carcinoma has a distinct pathologic behavior and aggressive nature. Disease virulence, coupled with difficulty in appropriate staging and preoperative tumor mapping, should guide the surgeon when deciding the surgical management in the salvage setting. PMID- 26989545 TI - Partial Obstruction of the Endotracheal Tube by the Plastic Coating Sheared from a Stylet. AB - A preterm with gestational age of 24 weeks was intubated at day of life 16. The intubation was done in a routine manner with the use of a stylet. It took a significant effort from the clinician to pull the stylet out after intubation. After intubation the respiratory status of the neonate deteriorated requiring significantly greater support. When ventilating and oxygenating the infant was getting progressively difficult, the decision was made to change the endotracheal tube (ETT). The cause for deterioration of respiratory status was then determined to be a sheared piece of plastic from the sheath of the stylet which was lodged in the lumen of the ETT. After removal of the plastic particle, the condition of the infant improved significantly. PMID- 26989546 TI - Acute Respiratory Failure due to Neuromyelitis Optica Treated Successfully with Plasmapheresis. AB - Neuromyelitis Optica (NMO) is a demyelinating autoimmune disease involving the central nervous system. Acute respiratory failure from cervical myelitis due to NMO is known to occur but is uncommon in monophasic disease and is treated with high dose steroids. We report a case of a patient with NMO who developed acute respiratory failure related to cervical spinal cord involvement, refractory to pulse dose steroid therapy, which resolved with plasmapheresis. PMID- 26989547 TI - Key Features in the Management of Pulmonary Carcinosarcoma. AB - Pulmonary carcinosarcoma represents a category of extremely rare tumours accounting for 0.1% of all lung malignancies. It is defined as a poorly differentiated non-small-cell carcinoma that contains a component of sarcoma or sarcoma-like elements. These biphasic tumours typically have a poor prognosis due to late diagnosis and early metastases. Preoperative tissue diagnosis is usually difficult due to the heterogeneity of the tumour, with biopsies often just reflecting one element of the tumour. By means of a case illustration and review of the literature, we discuss the optimal management of patients with pulmonary carcinosarcoma. PMID- 26989548 TI - Community-Acquired Moraxella catarrhalis Bacteremic Pneumonia: Two Case Reports and Review of the Literature. AB - Moraxella (formerly Branhamella) catarrhalis was discovered at the end of the nineteenth century, and for many decades it was considered to be a harmless commensal of the upper respiratory tract. It is a Gram-negative, aerobic diplococcus considered to be the third most common pathogen isolated in childhood sinusitis and otitis media and in adult chronic lower respiratory disease, as well as an etiological agent of pneumonia in immunosuppressed patients or those with chronic obstructive pulmonary disease. Moraxella catarrhalis pneumonia is rarely associated with bacteremia. Here, we present two cases of community acquired Moraxella catarrhalis bacteremic pneumonia. PMID- 26989549 TI - Spontaneous Rupture of Pyometra Causing Peritonitis in Elderly Female Diagnosed on Dynamic Transvaginal Ultrasound. AB - Pyometra is collection of pus within the uterine cavity and is usually associated with underlying gynaecological malignancy or other benign causes. Spontaneous rupture of pyometra is a rare complication. We report a case of a 65-year-old female who presented with acute abdomen and was diagnosed with a ruptured uterus secondary to pyometra and consequent peritonitis on dynamic transvaginal sonography (TVS) which was later confirmed on contrast enhanced computed tomography (CECT). An emergency laparotomy was performed and about 800 cc of pus was drained from the peritoneal cavity. A rent was found in the anterior uterine wall and hence hysterectomy was performed. Histopathology revealed mixed inflammatory cell infiltrate with no evidence of malignancy. There are only 31 cases of ruptured pyometra reported till date, most of which were definitively diagnosed only on laparotomy. In only two of these cases the preoperative diagnosis was made on CECT. We report this case, as the correct and definitive diagnosis was made preoperatively on dynamic TVS. To our knowledge, this is the first case report revealing spontaneous ruptured pyometra being diagnosed preoperatively on dynamic TVS. This report is aimed at giving emphasis on the use of simple dynamic TVS for accurate diagnosis of rare spontaneous ruptured pyometra causing peritonitis. PMID- 26989550 TI - Imaging Findings of Duodenal Duplication Cyst Complicated with Duodenal Intussusception and Biliary Dilatation. AB - Duodenal duplication cyst is an extremely rare congenital anomaly usually diagnosed in childhood. However, it may remain asymptomatic for a long period. In adults it usually manifests with symptoms related to complications as pancreatitis, jaundice, or intussusception. We present the radiology findings of a patient with a duodenal intussusception secondary to a duplication cyst. The usefulness of the magnetic resonance (MR) in this case is highlighted. PMID- 26989551 TI - Intestinal Obstruction and Ileocolic Fistula due to Intraluminal Migration of a Gossypiboma. AB - Gossypiboma refers, as a term, to a retained surgical sponge. It is considered as a rare surgical complication which can occur despite precautions. We report a case of a 36-year-old woman who was admitted to our surgical department with symptoms of abdominal pain associated with episodes of nausea and vomiting that lasted for 2 months. Six months ago she had undergone a cesarean section in a private clinic. Computed tomography revealed a high-density mass occupying a portion of the intestinal lumen, which was reported as a "calcified parasite." The patient was subjected to laparotomy. The intraoperative findings included signs of obstructive ileus and ileosigmoid fistula and a large sponge was found at the resected portion of the small intestine. Although gossypiboma is a rare entity, it should be included in the differential diagnosis. PMID- 26989552 TI - Pneumomediastinum after Tooth Extraction. AB - Pneumomediastinum is defined as the presence of air in mediastinum. Pneumomediastinum can sometimes occur after surgery. Pneumomediastinum seen after dental procedures is rare. We presented the case of subcutaneous emphysema developed in the neck and upper chest after tooth extraction and discussed the possible mechanisms of pneumomediastinum. PMID- 26989553 TI - A Rare Case of Functioning Adrenocortical Oncocytoma Presenting as Cushing Syndrome. AB - Functioning adrenocortical oncocytoma is very rare neoplasm. It is usually nonfunctional and benign and incidentally detected. Generally, these tumors originate in the kidneys, thyroid, parathyroid, and salivary or pituitary glands; they have also been reported in other sites including choroid plexus, respiratory tract, and larynx. Histologically, they are characterized by cells with eosinophilic granular cytoplasm and numerous packed mitochondria. We reported a case of a 44-year-old female who presented with Cushing syndrome for hypersecretion of cortisol due to adrenocortical oncocytoma. Magnetic resonance of abdomen revealed a right adrenal mass. Laparoscopic adrenalectomy was performed and the tumor was pathologically confirmed as benign adrenocortical oncocytoma. After surgical treatment, Cushing's syndrome resolved. PMID- 26989554 TI - Fornix Rupture in Duplex Kidney due to Internal Iliac Artery Aneurysm. AB - A 70-year-old man presented with severe pain on the right side of the abdomen for 7 days. An abdominal CT angiographic scan showed an impending rupture of a large right internal iliac artery aneurysm which compressed to a right ureter causing hydroureteronephrosis. Fornix rupture of a right duplex kidney was also detected. Selective embolization of right gluteal arteries and then ligation of the right internal iliac artery and right ureterotomy with double J stenting were performed. At the 4-month follow-up appointment, an abdominal ultrasound demonstrated a decrease in the size of the aneurysm and no hydroureteronephrosis after the removal of double J stent. PMID- 26989556 TI - Comparison of the Postprocedural Quality of Life between Coronary Artery Bypass Graft Surgery and Percutaneous Coronary Intervention: A Systematic Review. AB - The treatment of choice between coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) has remained unclear. Considering quality of life (QOL) increases life expectancy, we believe QOL should be important in determining the optimum treatment. Thus the objective of this review was to illustrate the comparative effects of CABG and PCI on postprocedural QOL. Methods. We searched PubMed (Medline) and Embase from inception of the databases to May 2014 using "PCI versus CABG quality of life", "Percutaneous Coronary intervention versus Coronary artery bypass graft surgery Quality of life", "PCI versus CABG health status", "Angioplasty versus CABG", "Percutaneous coronary intervention versus coronary artery bypass surgery health status", and different combinations of the above terms. 447 articles were found. After applying strict exclusion criteria, we included 13 studies in this review. Results. From the 9 studies that compared QOL scores at 6 months after procedure, 5 studies reported CABG to be superior. From the 10 studies that compared QOL among patients at 1 year after procedure, 9 reported CABG to be superior. Conclusion. It can be established that CABG is superior to PCI in improving patient's QOL with respect to all scales used to determine quality of life. PMID- 26989555 TI - Postinfarct Left Ventricular Remodelling: A Prevailing Cause of Heart Failure. AB - Heart failure is a chronic disease with high morbidity and mortality, which represents a growing challenge in medicine. A major risk factor for heart failure with reduced ejection fraction is a history of myocardial infarction. The expansion of a large infarct scar and subsequent regional ventricular dilatation can cause postinfarct remodelling, leading to significant enlargement of the left ventricular chamber. It has a negative prognostic value, because it precedes the clinical manifestations of heart failure. The characteristics of the infarcted myocardium predicting postinfarct remodelling can be studied with cardiac magnetic resonance and experimental imaging modalities such as diffusion tensor imaging can identify the changes in the architecture of myocardial fibers. This review discusses all the aspects related to postinfarct left ventricular remodelling: definition, pathogenesis, diagnosis, consequences, and available therapies, together with experimental interventions that show promising results against postinfarct remodelling and heart failure. PMID- 26989559 TI - Hb A1c Separation by High Performance Liquid Chromatography in Hemoglobinopathies. AB - Hb A1c measurement is subject to interference by hemoglobin traits and this is dependent on the method used for determination. In this paper we studied the difference between Hb A1c measured by HPLC in hemoglobin traits and normal chromatograms. We also studied the correlation of Hb A1c with age. Hemoglobin analysis was carried out by high performance liquid chromatography. Spearman's rank correlation was used to study correlation between A1c levels and age. Mann Whitney U test was used to study the difference in Hb A1c between patients with normal hemoglobin and hemoglobin traits. A total of 431 patients were studied. There was positive correlation with age in patients with normal chromatograms only. No correlation was seen in Hb E trait or beta thalassemia trait. No significant difference in Hb A1c of patients with normal chromatograms and patients with hemoglobin traits was seen. There is no interference by abnormal hemoglobin in the detection of A1c by high performance liquid chromatography. This method cannot be used for detection of A1c in compound heterozygous and homozygous disorders. PMID- 26989558 TI - National Trends of Antiparkinsonism Treatment in Taiwan: 2004-2011. AB - Background. Several guidelines for Parkinson's disease (PD) management were recently updated. We examined temporal trends for antiparkinsonism drugs in Taiwan. Methods. Antiparkinsonism prescriptions, including levodopa, ergot/nonergot dopamine agonists (DAs), amantadine, selegiline, entacapone, and anticholinergics, were identified in the Taiwan National Health Insurance Database from 2004 to 2011. Time trend analyses were estimated assuming Poisson distribution. Results. A total of 19,302 PD patients in 2004 and 41,606 PD patients in 2011 were analyzed. Antiparkinsonism prescriptions increased significantly from 187,137 in 2004 to 414,587 in 2011. Levodopa monotherapy or combination therapy was the mainstay. Levodopa monotherapy comprised 37.4% of prescriptions in 2004 and 44.2% in 2011, with an annual increase rate of 18.14%. There was a substantially increasing trend of DA prescriptions, which were higher in younger-aged patients (<60 years) than in older-aged group (p = 0.0006). Among combination therapy, DA combined with levodopa or other antiparkinsonism medications became the main combinations for younger-aged patients after 2009. After 2005, the proportion of ergot DA usage markedly decreased and PD patients using nonergot DA increased. Conclusions. Levodopa was the major treatment from 2004 to 2011. There was a steeply increased trend of DA use, especially in younger-aged patients. Nonergot agents comprised the major DA group after 2005. PMID- 26989557 TI - Prenatal Exposures to Multiple Thyroid Hormone Disruptors: Effects on Glucose and Lipid Metabolism. AB - Background. Thyroid hormones (THs) are essential for normal human fetal development and play a major role in the regulation of glucose and lipid metabolism. Delivery of TH to target tissues is dependent on processes including TH synthesis, transport, and metabolism. Thyroid hormone endocrine disruptors (TH EDCs) are chemical substances that interfere with these processes, potentially leading to adverse pregnancy outcomes. Objectives. This review focuses on the effects of prenatal exposures to combinations of TH-EDCs on fetal and neonatal glucose and lipid metabolism and also discusses the various mechanisms by which TH-EDCs interfere with other hormonal pathways. Methods. We conducted a comprehensive narrative review on the effects of TH-EDCs with particular emphasis on exposure during pregnancy. Discussion. TH imbalance has been linked to many metabolic processes and the effects of TH imbalance are particularly pronounced in early fetal development due to fetal dependence on maternal TH for proper growth and development. The pervasive presence of EDCs in the environment results in ubiquitous exposure to either single or mixtures of EDCs with deleterious effects on metabolism. Conclusions. Further evaluation of combined effects of TH EDCs on fetal metabolic endpoints could improve advice provided to expectant mothers. PMID- 26989560 TI - Prevalence of Hypertension in a Tribal Land Locked Population at High Altitude. AB - Introduction. Extensive pubmed search reveals paucity of data on prevalence of hypertension in tribal population at high altitude. The data is all the more scarce from our part of India. Studies among tribal populations at high altitudes provide an interesting epidemiological window to study human evolution and adaptation to hypobaric hypoxia. Material and Methods. 401 participants above the age of 20 years were evaluated for blood pressure using a stratified simple random technique among villages located at high altitude. Results. Out of a total of 401 individuals studied 43 (males: 35; females: 8) were identified as hypertensive yielding a crude prevalence of 10.7%. The prevalence was higher in males (35/270; 12.9%) as compared to females (8/131; 6%). Prevalence was the highest in the age group of 30-39 among males (16/35; 45.7%) while it was the highest in the age group of 40-49 among females (7/8; 87%). Conclusions. Prevalence of 10.5% is noteworthy when interpreted in light of prevalence of hypertension in general population especially if hypobaric hypoxia is considered to have a protective effect on blood pressure in high altitude native populations. PMID- 26989562 TI - In Vitro and In Vivo Correlation of Colon-Targeted Compression-Coated Tablets. AB - This study was performed to assess and correlate in vitro drug release with in vivo absorption of prednisolone (PDL) from a colon-targeted tablet prepared by compression coating of core tablet. In vivo drug absorption study was conducted using a high performance liquid chromatographic (HPLC) method, which was developed and validated for the estimation of PDL in rabbit plasma. The calibration curve showed linearity in the concentration range of 0.05 to 50 MUg/mL with the correlation coefficient (r) of 0.999. The method was specific and sensitive with the limit of detection (LOD) and lower limit of quantification (LLOQ) of 31.89 +/- 1.10 ng/mL and 96.63 +/- 3.32 ng/mL, respectively. The extraction recovery (ER) of PDL from three different levels of quality control (QC) samples ranged from 98.18% to 103.54%. In vitro drug release study revealed that less than 10% drug was released in 6.34 h and almost complete (98.64%) drug release was achieved in the following 6 h. In vivo drug absorption study demonstrated lower values of C max, AUCtotal, and protracted T max from compression-coated tablet. The results confirmed the maximum release of drug in the colon while minimizing release in the upper gastrointestinal tract (GIT). An excellent in vitro and in vivo correlation (IVIVC) was also achieved after considering the lag time. PMID- 26989561 TI - Genetics of Nonsyndromic Congenital Hearing Loss. AB - Congenital hearing impairment affects nearly 1 in every 1000 live births and is the most frequent birth defect in developed societies. Hereditary types of hearing loss account for more than 50% of all congenital sensorineural hearing loss cases and are caused by genetic mutations. HL can be either nonsyndromic, which is restricted to the inner ear, or syndromic, a part of multiple anomalies affecting the body. Nonsyndromic HL can be categorised by mode of inheritance, such as autosomal dominant (called DFNA), autosomal recessive (DFNB), mitochondrial, and X-linked (DFN). To date, 125 deafness loci have been reported in the literature: 58 DFNA loci, 63 DFNB loci, and 4 X-linked loci. Mutations in genes that control the adhesion of hair cells, intracellular transport, neurotransmitter release, ionic hemeostasis, and cytoskeleton of hair cells can lead to malfunctions of the cochlea and inner ear. In recent years, with the increase in studies about genes involved in congenital hearing loss, genetic counselling and treatment options have emerged and increased in availability. This paper presents an overview of the currently known genes associated with nonsyndromic congenital hearing loss and mutations in the inner ear. PMID- 26989563 TI - Weekly Energy Drink Use Is Positively Associated with Delay Discounting and Risk Behavior in a Nationwide Sample of Young Adults. AB - Background: Energy drink use is associated with increased risk behavior among adolescents and college students. This study examined this relationship in a nationwide sample of young adults and also examined relations between energy drink use and delay discounting. Methods: Participants were 874 U.S. adults 18-28 years of age with past 30-day consumption of caffeine and alcohol. Participants completed an online survey of energy drink use, drug use, sexual activity, alcohol misuse (alcohol use disorders identification test [AUDIT]), sensation seeking (four-item Brief Sensation Seeking Scale [BSSS-4]), and delay discounting of monetary rewards and condom use. Results: Over one-third of participants (n = 303) reported consuming energy drinks at least once per week. Weekly energy drink users were more likely than less-than-weekly energy drink users to report a recent history of risk behaviors, including cigarette smoking (56% vs. 28%, p < 0.0001), illicit stimulant use (22% vs. 6%, p < 0.0001), and unprotected sex (63% vs. 45%, p < 0.0001). Covariate-adjusted analyses found that weekly energy drink users did not have significantly higher BSSS-4 scores (3.5 vs. 3.1, p = 0.098), but they had higher mean AUDIT scores (8.0 vs. 4.8, p < 0.0001), and they more steeply discounted delayed monetary rewards. Although weekly energy drink users did not show steeper discounting of delayed condom use, they showed a lower likelihood of using a condom when one was immediately available. Conclusions: This study extends findings that energy drink use is associated with risk behavior, and it is the first study to show that energy drink use is associated with monetary delay discounting. PMID- 26989564 TI - The Influence of a Crosshair Visual Aid on Observer Detection of Simulated Fetal Heart Rate Signals. AB - Objective To determine whether a visual aid overlaid on fetal heart rate (FHR) tracings increases detection of critical signals relative to images with no visual aid. Study Design In an experimental study, 21 undergraduate students viewed 240 images of simulated FHR tracings twice, once with the visual aids and once without aids. Performance was examined for images containing three different types of FHR signals (early deceleration, late deceleration, and acceleration) and four different FHR signal-to-noise ratios corresponding to FHR variability types (absent, minimal, moderate, and marked) identified by the National Institute of Child Health and Human Development (2008). Performance was analyzed using repeated-measures analyses of variance. Results The presence of the visual aid significantly improved correct detections of signals overall and decreased false alarms for the marked variability condition. Conclusion The results of the study provide evidence that the presence of a visual aid was useful in helping novices identify FHR signals in simulated maternal-fetal heart rate images. Further, the visual aid was most useful for conditions in which the signal is most difficult to detect (when FHR variability is highest). PMID- 26989565 TI - Severe Hyponatremia Associated with Use of Black Cohosh during Prolonged Labor and Unsuccessful Home Birth. AB - Introduction There has been an increase in the use of herbal supplements during pregnancy, which are frequently of unproven efficacy and safety. We present a case of severe hyponatremia and altered mental status associated with the use of black cohosh during prolonged labor. Case A 39-year-old primigravida at 38(5/7) weeks of gestational age presented to the emergency department after she became disoriented and lethargic while laboring at home with a midwife. She had consumed several doses of black cohosh to induce and augment labor. On presentation, she was nonverbal and unable to follow commands. Her serum sodium was 114 mmol/L (range, 132-145 mmol/L), serum osmolality was 253 mOsm/kg (range, 275-300 mOsm/kg), urine osmolality was 190 mOsm/kg (range, 300-900 mOsm/kg), and urine sodium was <10 mmol/L. The patient soon became uncooperative and combative and a cesarean section was performed. Postoperatively, she was transferred to the intensive care unit for monitoring and correction of her sodium. Her mental status returned to baseline and she was subsequently discharged home without further complication. Discussion Clinically significant hyponatremia associated with pregnancy is rare. Further investigation is needed to evaluate the safety and efficacy of black cohosh and other commonly used herbal supplements during pregnancy and labor. PMID- 26989566 TI - Pregnancy-Associated Atypical Hemolytic-Uremic Syndrome. AB - Introduction Early diagnosis of atypical uremic-hemolytic syndrome may be challenging during the puerperium period. Correct diagnosis and timely management are crucial to improve outcomes. Background Pregnancy-associated atypical hemolytic-uremic syndrome (p-aHUS) is a rare condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Triggered by pregnancy, genetically predisposed women develop the syndrome, leading to a disastrous hemolytic disease characterized by diffuse endothelial damage and platelet consumption. This disease is a life-threatening condition that requires prompt diagnosis and therapy. Case A 19-year-old G1P1 Caucasian female with suspicion of HELLP syndrome was treated at our facility for severe thrombocytopenia and acute kidney injury. A diagnosis of atypical uremic hemolytic syndrome was later confirmed. The patient's condition improved with normalization of platelets and improvement in kidney function after 14 days of plasmapheresis. She was subsequently treated with eculizumab, a monoclonal antibody against C5. The patient tolerated well the therapy and is currently in remission. Conclusion Diagnosis of p-aHUS is challenging, as it can mimic various diseases found during pregnancy and the postpartum. Plasma exchange should be promptly initiated within 24 hours of diagnosis. Eculizumab has risen to become an important tool to improve long-term comorbidities and mortality in this group population. PMID- 26989567 TI - Hemolytic Disease of the Fetus and Newborn due to Intravenous Drug Use. AB - Objectives The objective is to present a pregnancy complication associated with intravenous drug use, namely, that of red blood cell alloimmunization and hemolytic disease of the fetus and newborn. Methods An observational case series is presented including women with red blood cell alloimmunization most likely secondary to intravenous drug abuse Results Five pregnancies were identified that were complicated by red blood cell alloimmunization and significant hemolytic disease of the fetus and newborn, necessitating intrauterine transfusion, an indicated preterm birth, or neonatal therapy. Conclusions As opioid abuse continues to increase in the United States, clinicians should be aware of the potential for alloimmunization to red blood cell antibodies as yet another negative outcome from intravenous drug abuse. PMID- 26989568 TI - Seronegative Maternal Ocular Myasthenia Gravis and Delayed Transient Neonatal Myasthenia Gravis. AB - Background Myasthenia gravis (MG) is an autoimmune disorder with fluctuating muscle weakness, divided into generalized and localized (ocular) forms. Maternal antibodies to acetylcholine receptors cross the placenta and may cause transient neonatal myasthenia gravis (TNMG). We present a case of seronegative maternal ocular MG and delayed TNMG. Case A 29-year-old G3P1011 underwent cesarean birth of a male infant who developed oxygen desaturation requiring supplemental oxygen on day of life (DOL) 3. Based on the clinical course and after exclusion of other diagnoses, the infant was diagnosed with TNMG. Infant's condition improved spontaneously and he was weaned off supplemental oxygen and discharged home on DOL 12. Conclusion Infants born to mothers with seronegative localized (ocular) MG are also susceptible to TNMG which may be late in onset. PMID- 26989569 TI - Effect of Cervical Length Recovery after Laser Surgery for Twin-Twin Transfusion Syndrome. AB - Objective To evaluate the impact of polyhydramnios on preoperative cervical length and whether cervical length recovery after amnioreduction during selective fetoscopic laser photocoagulation (SFLP) is associated with a greater gestational age at delivery in pregnancies complicated by twin-twin transfusion syndrome (TTTS). Methods Retrospective study of 50 pregnancies complicated by TTTS treated with SFLP between March 2010 and July 2014 at a single center. Preoperative maximum vertical pocket (MVP) was measured along with pre- and postoperative cervical length. A cervical length difference was calculated, with a difference of +/- 3 mm considered no change. Results Only 12 (34%) patients showed an increased cervical length after amnioreduction during laser surgery. There was no statistical difference between either negative or positive change in cervical length groups and mean gestational age at delivery (p = 0.82). There also was no correlation between preoperative MVP and preoperative cervical length (p = 0.36) or gestational age at delivery (p = 0.77). However, there was a statistically shorter mean preoperative cervical length in patients who delivered <32 weeks of gestation (3.62 +/- 0.66 vs. 4.20 +/- 0.85 cm; p = 0.03). Conclusion Severity of polyhydramnios does not correlate with preoperative cervical length, and variability of the cervix postoperatively does not appear to affect gestational age at delivery. PMID- 26989570 TI - Prenatal Diagnosis of Ectrodactyly in the First Trimester by Three-Dimensional Ultrasonography. AB - Introduction Ectrodactyly, also known as split hand/foot malformation, is a rare developmental abnormality of the limbs that consists of absent central digits, a deep median cleft, and fusion of the remaining lateral digits, ultimately producing clawlike extremities. This case represents one of the earliest reported diagnoses of this anomaly to utilize three-dimensional (3D) ultrasonography. Case A nulliparous woman presented at 13 weeks of gestation for first-trimester aneuploidy screening. On two-dimensional (2D) imaging, she was noted to have a fetus with a shortened right upper limb and a malformed right hand with no clearly visualized digits. The anomaly was then further evaluated with both transabdominal and transvaginal 2D and 3D ultrasonography with postprocessing visualization, revealing absent central digits. Neither the patient nor her husband reported any personal or family history of skeletal or other structural malformations. Discussion Fetal limb abnormalities are being encountered at increasingly earlier gestational ages due to improvements in image quality and expanded use of ultrasound in the first trimester. Early identification of fetal limb malformations without a definitive diagnosis or a clear pattern of inheritance can present a challenging clinical scenario. Patients may opt for earlier termination of pregnancy rather than wait for additional information to guide decision-making. PMID- 26989571 TI - Clinical Spectrum of Stiff Person Syndrome: A Review of Recent Reports. AB - BACKGROUND: "Classic" stiff person syndrome (SPS) features stiffness, anti glutamic acid decarboxylase (anti-GAD) antibodies, and other findings. Anti-GAD antibodies are also detected in some neurological syndromes (such as ataxia) in which stiffness is inconsistently present. Patients with otherwise "classic" SPS may either lack anti-GAD antibodies or be seropositive for others. Hence, SPS cases appear to fall within a clinical spectrum that includes conditions such as progressive encephalomyelitis with rigidity and myoclonus (PERM), which exhibits brainstem and autonomic features. We have compiled herein SPS-spectrum cases reported since 2010, and have segregated them on the basis of likely disease mechanism (autoimmune, paraneoplastic, or cryptogenic) for analysis. METHODS: The phrases "stiff person syndrome", "PERM", "anti-GAD antibody syndrome", and "glycine receptor antibody neurological disorders" were searched for in PubMed in January 2015. The results were narrowed to 72 citations after excluding non English and duplicate reports. Clinical descriptions, laboratory data, management, and outcomes were categorized, tabulated, and analyzed. RESULTS: Sixty-nine autoimmune, 19 paraneoplastic, and 13 cryptogenic SPS-spectrum cases were identified. SPS was the predominant diagnosis among the groups. Roughly two thirds of autoimmune and paraneoplastic cases were female. Anti-GAD antibodies were most frequently identified, followed by anti-amphiphysin among paraneoplastic cases and by anti-glycine receptor antibodies among autoimmune cases. Benzodiazepines were the most commonly used medications. Prognosis seemed best for cryptogenic cases; malignancy worsened that of paraneoplastic cases. DISCUSSION: Grouping SPS-spectrum cases by pathophysiology provided insights into work-up, treatment, and prognosis. Ample phenotypic and serologic variations are present within the categories. Ruling out malignancy and autoimmunity is appropriate for suspected SPS-spectrum cases. PMID- 26989573 TI - Non-Motor Symptoms of Essential Tremor Are Independent of Tremor Severity and Have an Impact on Quality of Life. AB - BACKGROUND: Several publications have focused on accompanying non-motor symptoms (NMS) in essential tremor (ET) patients; however, it remains unclear if NMS are an intrinsic part of the disease or secondary phenomena. We present the results of several neuropsychiatric tests and their impact on quality of life (QoL) in community-dwelling patients with ET. METHODS: Participants were recruited via a newspaper article about ET published in the local media and on the internet. All participants completed several standard neuropsychiatric tests, including those that assess QoL. To compare differences between cases and controls, Student's t tests with Bonferroni-Holm post hoc tests were performed. Spearman's correlation coefficients were also calculated. RESULTS: We enrolled 110 patients with definite or probable ET. Highly significant changes were observed for apathy, anxiety, and cognition and negatively impacted QoL. Most aberrations were independent of tremor severity and duration. DISCUSSION: The significant neuropsychiatric deficits and reduced QoL demonstrate a degree of illness that appears to be a non-motor phenotype rather than a secondary effect of ET. In the future, NMS should carefully be explored in ET patients as they may have an impact on QoL and treatment. PMID- 26989572 TI - Essential Tremor: What We Can Learn from Current Pharmacotherapy. AB - BACKGROUND: The pathophysiology of essential tremor, especially at the cellular level, is poorly understood. Although no drug has been specifically designed to treat essential tremor, several medications improve tremor, and others worsen it. Studying the mechanism of actions of these medications can help our understanding of tremor pathophysiology and contribute to future rational drug design. METHODS: We reviewed literature, concentrating on mechanisms of action, of various medications that mitigate tremor. RESULTS: Many medications have multiple mechanisms of actions, making simple correlations difficult. Medications that increase the duration of opening of gamma-aminobutyric acid (GABA)-A receptors are most consistently associated with tremor improvement. Interestingly, drugs that increase GABA availability have not been associated with improved tremor. Other mechanisms possibly associated with tremor improvement include antagonism of alpha-2 delta subunits associated with calcium channels, inhibition of carbonic anhydrase, and inhibition of the synaptic vesicle protein 2A. Drugs that block voltage-gaited sodium channels do not affect tremor. The ideal beta adrenergic blocker requires B2 affinity (non-cardiac selective), has no sympathomimetic properties, does not require membrane stabilization properties, and may benefit from good central nervous system penetration. DISCUSSION: To date, serendipitous observations have provided most of our understanding of tremor cellular physiology. Based on similarities to currently effective drugs or rational approximations and inferences, several currently available agents should be considered for tremor trials. PMID- 26989574 TI - Improvement of Isolated Myoclonus Phenotype in Myoclonus Dystonia after Pallidal Deep Brain Stimulation. AB - BACKGROUND: Myoclonus-dystonia is a condition that manifests predominantly as myoclonic jerks with focal dystonia. It is genetically heterogeneous with most mutations in the epsilon sarcoglycan gene (SGCE). In medically refractory cases, deep brain stimulation (DBS) has been shown to provide marked sustainable clinical improvement, especially in SGCE-positive patients. We present two patients with myoclonus-dystonia (one SGCE positive and the other SGCE negative) who have the isolated myoclonus phenotype and had DBS leads implanted in the bilateral globus pallidus internus (GPi). METHODS: We review their longitudinal Unified Myoclonus Rating Scale scores along with their DBS programming parameters and compare them with published cases in the literature. RESULTS: Both patients demonstrated complete amelioration of all aspects of myoclonus within 6-12 months after surgery. The patient with the SGCE-negative mutation responded just as well as the patient who was SGCE positive. High-frequency stimulation (130 Hz) with amplitudes greater than 2.5 V provided therapeutic benefit. DISCUSSION: This case series demonstrates that high frequency GPi-DBS is effective in treating isolated myoclonus in myoclonus-dystonia, regardless of the presence of SGCE mutation. PMID- 26989576 TI - Autologous Bone Marrow Aspirate Therapy in Wound Healing. AB - Objective: To study the role of autologous bone marrow aspirate therapy (ABMAT) in wound healing. Approach: This is a retrospective analysis of 9 patients (11 chronic nonhealing wounds) in whom ABMAT was used. Patients (wounds) were grouped into two groups. Group 1 included 4 patients (5 wounds) refusing/unfit for reconstruction and managed only with ABMAT. Group 2 included 5 patients (6 wounds) who agreed/fit for reconstruction after wound bed preparation with ABMAT. End point of the study was complete wound healing. Results: ABMAT helped in complete healing of chronic nonhealing wounds by secondary intention in group 1 patients and enhanced process of wound bed preparation for reconstruction in group 2 patients. Innovation: This study highlights the importance of ABMAT in the management of chronic nonhealing wounds. Conclusion: ABMAT helps in wound bed preparation to allow the wound to heal completely or cover by skin graft/flap. PMID- 26989575 TI - Cardioprotective Role of Caveolae in Ischemia-Reperfusion Injury. AB - Caveolae are flask-like invaginations of the plasma membrane enriched in cholesterol, sphingolipids, the marker protein caveolin and the coat protein cavin. In cardiomyocytes, multiple signaling molecules are concentrated and organized within the caveolae to mediate signaling transduction. Recent studies suggest that caveolae and caveolae-associated signaling molecules play an important role in protecting the myocardium against ischemia-reperfusion injury. For example, cardiac-specific overexpression of caveolin-3 has been shown to lead to protection that mimics ischemic preconditioning, while the knockout of caveolin-3 abolished ischemic preconditioning. In this review, we discuss the molecular mechanisms and signaling pathways that are involved in caveolae mediated cardioprotection, and examine the potential for caveolae as a therapeutic target for pharmaceutical intervention to treat cardiovascular disease. PMID- 26989579 TI - Quality Randomized Clinical Trials of Topical Diabetic Foot Ulcer Healing Agents. AB - Significance: Diabetic foot ulcers (DFU) significantly add to global economic, social, and clinical burdens. Healing a DFU fast and well limits complications that can lead to lower extremity amputation, morbidity, and mortality. Recent Advances: Many promising topical DFU healing agents have been studied in randomized clinical trials (RCT), but only one, becaplermin, has been cleared for this use by the United States Food and Drug Administration (FDA). Critical Issues: This critical review of DFU topical healing RCTs summarizes issues identified in their design and conduct, highlighting ways to improve study quality so researchers can increase the likelihood of RCT success in propelling effective topical DFU healing agents toward clinical use. Key issues include (1) inadequate sample size, (2) risk of bias, (3) irrelevant or unreported inclusion criteria, (4) substandard outcome measures, (5) unmatched group characteristics that predict nonhealing at baseline, (6) unequal or uncontrolled concurrent interventions or standard of care, (7) heterogeneous subject or DFU samples (8) unblinded allocation, treatment, or outcome measures, or (9) inadequate follow-up for clinical relevance. These can add bias or unexplained variability to RCT outcomes, limiting clinical or statistical significance and accuracy of results. Future Directions: This critical review summarizes ways to overcome these deficiencies to optimize DFU clinical trial design and conduct. It provides a blueprint for future excellence in RCTs testing safety and efficacy of topical DFU healing agents and smoothing the path to their clinical use. PMID- 26989580 TI - A Comparison of Methods for Computing the Residual Resistivity Ratio of High Purity Niobium. AB - We compare methods for estimating the residual resistivity ratio (RRR) of high purity niobium and investigate the effects of using different functional models. RRR is typically defined as the ratio of the electrical resistances measured at 273 K (the ice point) and 4.2 K (the boiling point of helium at standard atmospheric pressure). However, pure niobium is superconducting below about 9.3 K, so the low-temperature resistance is defined as the normal-state (i.e., non superconducting state) resistance extrapolated to 4.2 K and zero magnetic field. Thus, the estimated value of RRR depends significantly on the model used for extrapolation. We examine three models for extrapolation based on temperature versus resistance, two models for extrapolation based on magnetic field versus resistance, and a new model based on the Kohler relationship that can be applied to combined temperature and field data. We also investigate the possibility of re defining RRR so that the quantity is not dependent on extrapolation. PMID- 26989577 TI - The Burn Wound Microenvironment. AB - Significance: While the survival rate of the severely burned patient has improved significantly, relatively little progress has been made in treatment or prevention of burn-induced long-term sequelae, such as contraction and fibrosis. Recent Advances: Our knowledge of the molecular pathways involved in burn wounds has increased dramatically, and technological advances now allow large-scale genomic studies, providing a global view of wound healing processes. Critical Issues: Translating findings from a large number of in vitro and preclinical animal studies into clinical practice represents a gap in our understanding, and the failures of a number of clinical trials suggest that targeting single pathways or cytokines may not be the best approach. Significant opportunities for improvement exist. Future Directions: Study of the underlying molecular influences of burn wound healing progression will undoubtedly continue as an active research focus. Increasing our knowledge of these processes will identify additional therapeutic targets, supporting informed clinical studies that translate into clinical relevance and practice. PMID- 26989581 TI - Workshop on Bridging Satellite Climate Data Gaps. AB - Detecting the small signals of climate change for the most essential climate variables requires that satellite sensors make highly accurate and consistent measurements. Data gaps in the time series (such as gaps resulting from launch delay or failure) and inconsistencies in radiometric scales between satellites undermine the credibility of fundamental climate data records, and can lead to erroneous analysis in climate change detection. To address these issues, leading experts in Earth observations from National Aeronautics and Space Administration (NASA), National Oceanic and Atmospheric Adminstration (NOAA), United States Geological Survey (USGS), and academia assembled at the National Institute of Standards and Technology on December 10, 2009 for a workshop to prioritize strategies for bridging and mitigating data gaps in the climate record. This paper summarizes the priorities for ensuring data continuity of variables relevant to climate change in the areas of atmosphere, land, and ocean measurements and the recommendations made at the workshop for overcoming planned and unplanned gaps in the climate record. PMID- 26989582 TI - Measures, Uncertainties, and Significance Test in Operational ROC Analysis. AB - In receiver operating characteristic (ROC) analysis, the sampling variability can result in uncertainties of performance measures. Thus, while evaluating and comparing the performances of algorithms, the measurement uncertainties must be taken into account. The key issue is how to calculate the uncertainties of performance measures in ROC analysis. Our ultimate goal is to perform the significance test in evaluation and comparison using the standard errors computed. From the operational perspective, based on fingerprint-image matching algorithms on large datasets, the measures and their uncertainties are investigated in the three scenarios: 1) the true accept rate (TAR) of genuine scores at a specified false accept rate (FAR) of impostor scores, 2) the TAR and FAR at a given threshold, and 3) the equal error rate. The uncertainties of measures are calculated using the nonparametric two-sample bootstrap based on our extensive studies of bootstrap variability on large datasets. The significance test is carried out to determine whether the difference between the performance of one algorithm and a hypothesized value, or the difference between the performances of two algorithms where the correlation is taken into account is statistically significant. Examples are provided. PMID- 26989578 TI - Extracellular Matrix and Dermal Fibroblast Function in the Healing Wound. AB - Significance: Fibroblasts play a critical role in normal wound healing. Various extracellular matrix (ECM) components, including collagens, fibrin, fibronectin, proteoglycans, glycosaminoglycans, and matricellular proteins, can be considered potent protagonists of fibroblast survival, migration, and metabolism. Recent Advances: Advances in tissue culture, tissue engineering, and ex vivo models have made the examination and precise measurements of ECM components in wound healing possible. Likewise, the development of specific transgenic animal models has created the opportunity to characterize the role of various ECM molecules in healing wounds. In addition, the recent characterization of new ECM molecules, including matricellular proteins, dermatopontin, and FACIT collagens (Fibril Associated Collagens with Interrupted Triple helices), further demonstrates our cursory knowledge of the ECM in coordinated wound healing. Critical Issues: The manipulation and augmentation of ECM components in the healing wound is emerging in patient care, as demonstrated by the use of acellular dermal matrices, tissue scaffolds, and wound dressings or topical products bearing ECM proteins such as collagen, hyaluronan (HA), or elastin. Once thought of as neutral structural proteins, these molecules are now known to directly influence many aspects of cellular wound healing. Future Directions: The role that ECM molecules, such as CCN2, osteopontin, and secreted protein, acidic and rich in cysteine, play in signaling homing of fibroblast progenitor cells to sites of injury invites future research as we continue investigating the heterotopic origin of certain populations of fibroblasts in a healing wound. Likewise, research into differently sized fragments of the same polymeric ECM molecule is warranted as we learn that fragments of molecules such as HA and tenascin-C can have opposing effects on dermal fibroblasts.